,PubMedID,Title,Abstract,Label
0,PubMedID,Title,Abstract,0
1,4733,Huntington's chorea. Changes in neurotransmitter receptors in the brain,"Neurotransmitter-receptor binding sites for apparent muscarinic cholinergic, beta-adrenergic, gamma-aminobutyric acid and serotonin receptors were measured in the caudate nucleus and frontal cerebral cortex from post-mortem brains of 16 patients with Huntington's chorea and 16 controls. In addition, the samples were assayed for the gamma-aminobutyric-acid-synthesizing enzyme, glutamic acid decarboxylase, and for the acetylcholine-synthesizing enzyme, choline acetyltransferase. In the caudate nucleus of choreic brain, both enzyme activities were markedly lower, with significant decreases in muscarinic cholinergic and serotonin receptor binding, whereas enzyme activities and receptor binding were unchanged in the cerebral cortex. By contrast, gamma-aminobutyric acid and beta-adrenergic receptor binding were not significantly different in choreic and control caudate nucleus or cortex, suggesting that, despite the loss of gamma-aminobutyric-acid-synthesizing ability in the corpus striatum, gamma-aminobuytric acid mimetic drugs might alleviate the movement disorders in Huntington's chorea.",0
2,19702,Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia,"To define the time course of the metabolic acidosis that follows a single grand-mal seizure, we obtained serial blood samples from eight consecutive patients. Immediately after a seizure, the mean (+/- S.E.M.) venous lactate concentration was 12.7 +/- 1.0 meq per liter, the mean carbon dioxide content 17.1 +/- 1.1 mmol per liter, and the mean arterial pH 7.14 +/- 0.06. Sixty minutes later their values were 6.6 +/- 0.7 meq per liter (P less than 0.005), 23.6 +/- 1.1 mmol per liter (P less than 0.005) and 7.38 +/- 0.04 (P less than 0.005) respectively. The spontaneous resolution of the acidosis was due, in large part, to the metabolism of lactate and to the concomitant removal of hydrogen ion. There was no change in the serum potassium concentration, despite the development of a severe systemic acidemia and the subsequent return to normal of the pH. We suggest that the patient with seizures may serve as a unique model of lactic acidosis.",0
3,25385,A manpower policy for primary health care,"A National Academy of Sciences study of policy options for the supply of primary health-care manpower has produced a comprehensive set of recommendations. The study finds an adequate overall supply of physicians, but a shortage of primary health-care practitioners. It recommends maintaining current enrollment levels in medical schools and training programs for nurse practitioners and physician assistants and increasing the proportion of primary-care residents. To enhance the availability of primary care, the report advocates reimbursement for all physicians within a state at the same payment level for the same primary-care service, a reduction in payment differentials between primary-care services and nonprimary-care services, and reimbursement for educational and preventive services and for new health-practitioner services. The report supports a team approach in primary-care training and recommends that all medical students obtain clinical experience in a primary-care setting and some instruction in epidemiology and behavioral and social sciences.",0
4,61558,Multiple sclerosis cerebrospinal fluid produces myelin lesions in tadpole optic nerves,"To investigate the myelinotoxicity of cerebropsinal fluid in multiple sclerosis, we used an in vivo model of the myelinated central-nervous-system tract of tadpoles for quantitative double-blind tests of 46 cerebrospinal-fluid samples. Groups of xenopus tadpoles were injected with cerebrospinal fluid near the optic nerve. Forty-eight hours later, whole mounts of optic nerves were prepared, and a differential interference microscope was used to count myelin lesions. Cerebrospinal-fluid samples from 60 per cent of the patients with an acute attack of definite multiple sclerosis had myelinotoxic activity. This activity correlated best with the severity and duration of the disease, rather than with gamma-globulin or total protein concentrations. Activity was negative in 85 per cent of cerebrospinal-fluid samples from a control group with other neurologic diseases. This assay is a useful method for investigating myelinotoxic factors of cerebrospinal fluid in patients with multiple sclerosis, but was not helpful diagnostically.",0
5,61560,Need for alpha-fetoprotein assays,"An alpha fetoprotein assay is useful in diagnosing open neural-tube defects. The U.S. Food and Drug Administration is urged to establish guidelines for reagent licensing so that this test can be available throughout the country. Correct data for fetuses of 15-16 weeks' gestation are now complete. With this data and available alpha fetoprotein, the test could be run at individual medical centers and hospitals.",0
6,84336,Effect of control of blood glucose on urinary excretion of albumin and beta2 microglobulin in insulin-dependent diabetes,"To study the effects of improved control of blood glucose on markers of renal glomerular and tubular function, we initially determined, by radioimmunoassay technics, urinary excretion rates of albumin and beta2 microglobulin in 17 nondiabetic subjects and in 43 insulin-dependent, clinically nonproteinuric diabetic patients. Duration of diabetes ranged from six months to 39 years, and the patients were studied while receiving conventional therapy. Mean urinary albumin excretion was significantly elevated in the diabetics, but beta2-microglobulin excretion rates were not different from those of the controls, suggesting that the increased albumin excretion was due to increased transglomerular loss of albumin. Seven patients with long-term diabetes (duration of six to 33 years), selected because of elevated albumin excretion, were studied before and during a continuous, subcutaneous insulin infusion for a period of one to three days. Urinary albumin excretion was significantly reduced during the insulin infusion, but mean beta2-microglobulin excretion did not change. Strict control of blood glucose, even in the short term, may reverse a functional renal abnormality in long-duration, insulin-dependent diabetes.",0
7,114830,Selective primary health care: an interim strategy for disease control in developing countries,"Priorities among the infectious diseases affecting the three billion people in the less developed world have been based on prevalence, morbidity, mortality and feasibility of control. With these priorities in mind a program of selective primary health care is compared with other approaches and suggested as the most cost-effective form of medical intervention in the least developed countries. A flexible program delivered by either fixed or mobile units might include measles and diphtheria-pertussis-tetanus vaccination, treatment for febrile malaria and oral rehydration for diarrhea in children, and tetanus toxoid and encouragement of breast feeding in mothers. Other interventions might be added on the basis of regional needs and new developments. For major diseases for which control measures are inadequate, research is an inexpensive approach on the basis of cost per infected person per year.",0
8,114833,Evaluation of medical practices. The case for technology assessment,"We believe that the systematic evaluation of medical practices, especially those that are risky or costly deserves more attention. Available methods are limited, and definitive assessments of innovative or controversial practices are infrequent. Nevertheless, some evaluations have successfully enhanced the use of effective practices and diminished the reliance on ineffective ones. Greater efforts at evaluation can improve the quality of patient care, avoid waste and promote the more rational use of health resources. The cost of assessing new practices should be viewed as an intrinsic part of the cost of medical care. Physicians and medical societies bear primary responsibility for recognizing the need for this evaluation, for enlisting other experts, participating in technology assessment and working to translate the results of evaluation into practice. The commitment of government agencies, insurance companies and teaching institutions is also essential to an effective program of evaluation.",0
9,123038,A disorder of muscle lipid metabolism and myoglobinuria. Absence of carnitine palmityl transferase,"Two brothers, 29 and 33 years of age, had recurrent myoglobinuria, renal failure and azotemia, but were otherwise normal, without apparent muscle weakness or exercise intolerance. Ischemic exercise resulted in normal lactate production. Muscle glycogen content and activities of phosphorylase and phosphofructokinase were normal. Plasma triglycerides were elevated (500 mg per deciliter) on a regular diet and rose during fasting. During a 72-hour fast, serum creatine phosphokinase rose more than 10 times, and myoglobin was detected in urine. Plasma ketone production was minimal during fasting, but prompt ketonemia ( a normal response) occurred after ingestion of medium-chain triglycerides. Carnitine palmityl transferase activity was virtually absent in crude muscle extracts and mitochondrial fractions. Lack of this enzyme impairs long-chain fatty acid utilization, reflected in increased content of plasma free fatty acids and plasma triglycerides. Depletion of ATP because of this metabolic block in muscle may account for the attacks of myoglobinuria.",0
10,146160,Circulating immune complexes in the idiopathic interstitial pneumonias,"We determined circulating immune complex levels and their correlation with pulmonary histopathology, immunofluorescence and steroid responsiveness in 24 patients with idiopathic interstitial pneumonias. Levels were elevated in all but three of 16 patients with cellular disease, but in none of eight with diffuse fibrosis (P less than 0.001). Granular deposition of IgG, usually with elevated levels, but in only 11 per cent of those with normal levels (P less than 0.001). The radiographic and physiologic response to corticosteroid therapy was better in patients with initially elevated levels than in those with normal levels (P less than 0.03). Circulating immune complexex are present in patients with cellular idiopathic interstitial pneumonias, have a pathogentic role in this disease and may identify a patient population that is potentially steroid responsive.",0
11,162806,Parthenogenic origin of benign ovarian teratomas,"To determine the origin of benign cystic teratomas of the ovary, chromosome-banding studies were done on normal tissues and teratomas from five patients. The normal tissues were heterozygous (+/-) for 17 chromosome polymorphisms at or near the centromere, whereas the teratomas were uniformly homozygous (+/+ or -/-). These findings and those employing electrophoretic variants indicate that ovarian teratomas are parthenogenic tumors that arise from a single germ cell after the first meiotic division.",0
12,170516,"Treatment of hypoparathyroidism and pseudohypoparathyroidism with metabolites of vitamin D: evidence for impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D","In hypoparathyroidism and pseudohypoparathyroidism, pharmacologic doses of vitamin D correct hypocalcemia, but the mechanism is unknown. In two children with hypoparathyroidism and one with pseudohypoparathyroidism we tested the hypothesis that in these conditions there is a defect in synthesis of 1 alpha,25-dihydroxyvitamin D3, the principal active metabolite of vitamin D. In both conditions, minute doses of the metabolite (0.04 to 0.08 mug per kilogram of body weight per day) quickly corrected hypocalcemia and increased intestinal calcium absorption. On the other hand, the effective dose of 25-hydroxyvitamin D3 to maintain normocalcemia was 3 to 4 mug per kilogram per day in the two conditions. Thus, the dosage ratio of 25-hydroxyvitamin D3 to 1 alpha,25-dihydroxyvitamin D3 approximated 100:1. By contrast this ratio was approximately 3:1 in two infants with vitamin D deficiency, a condition in which optimal metabolism of vitamin D would be expected. These findings suggest an impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D in both hypoparathyroidism and pseudohypoparathyroidism.",0
13,176581,The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man,"In six patients with acanthosis nigricans variable degrees of glucose intolerance, hyperinsulinemia and marked resistance to exogenous insulin were found. Studies of insulin receptors on circulating monocytes suggest that the insulin resistance in these patients was due to a marked decrease in insulin binding to its membrane receptors. When these patients were fasted, there was a fall in plasma insulin but no increase in insulin binding, suggesting that the receptor defect was not secondary to the hyperinsulinemia. The clinical features shared by these cases and several similar ones previously reported may be divided into two unique clinical syndromes: Type A, a syndrome in younger females with signs of virilization or accelerated growth, in whom the receptor defect may be primary, and Type B, a syndrome in older females with signs of an immunologic disease, in whom circulating antibodies to the insulin receptor are found.",0
14,177866,Adenine arabinoside therapy of herpes zoster in the immunosuppressed. NIAID collaborative antiviral study,"We evaluated adenine arabinoside treatment of herpes zoster in immunodeficient patients in a randomized, controlled crossover study. The two study groups had similar characteristics. In spite of rapid natural healing, those receiving adenine arabinoside over the first five days had accelerated clearance of virus from vesicles (P = 0.01), and cessation of new vesicle formation (P = 0.004), and a shorter time to total pustulation (P = 0.001). Factors modifying the response to therapy included age, underlying disease, and the duration of zoster prior to therapy. Clinical toxicity was minimal. Laboratory assessment of bone-marrow, liver and renal function showed insignificant alterations as a result of therapy. These studies show that adenine arabinoside is a drug with promise for therapy of systemic herpes zoster in immunocompromised patients. It is most efficacious when administered during the first six days of disease (P = 0.001) to those who have reticuloendothelial neoplasia (P = 0.001) and are less than 38 years of age (P = 0.001).",0
15,178999,Formaldehyde-induced hemolysis during chronic hemodialysis,"We investigated an outbreak of hemolytic anemia among patients on hemodialysis shortly after the installation of a new water-filtration system. Using in vitro technics, we demonstrated that a water-soluble inhibitor of red-cell metabolism could easily be extracted from the intact filters. Subsequent experiments showed this toxic substance to be formaldehyde, a potent reducing agent whose mechanism of action involves conversion of NAD to NADH. This alteration of the redox state of the erythrocyte leads to inhibition of glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase and rapid decline in cellular energy (ATP) stores. Because formaldehyde is widely used as a preservative for dialysis equipment, the toxicity of this agent for red blood cells is of clinical importance.",0
16,184384,Big renin and biosynthetic defect of aldosterone in diabetes mellitus,"""To determine the cause of selective aldosterone deficiency in two patients with diabetes mellitus, studies of renin and of aldosterone-precursor metabolites were performed under conditions of sodium depletion and ACTH stimulation. Plasma renin concentration was elevated in both patients, and stimulated plasma renin activity was low in one and normal in the other. Fractionation of plasma extracts demonstrated the presence of """"big renin,"""" a relatively inactive precursor of renin. Metabolites of aldosterone precursors were increased, suggesting deficient 18-hydroxylase in one patient and dehydrogenase in the other. The results suggest that hypoaldosteronism in diabetic patients may result from combined defects in both renin and aldosterone biosynthesis.""",0
17,189188,Familial hyperglucagonemia--an autosomal dominant disorder,"Basal immunoreactive glucagon was elevated in four of nine asymptomatic relatives of a patient with glucagonoma. Immunoreactive glucagon remained elevated throughout 22 to 25 hours of continuous observation. Glucagon responses to intravenous glucose and arginine or mixed meals (or both) were abnormal, whereas glucose and insulin responses were normal. Gel filtration of plasma revealed that over 85 per cent of the four relatives' immunoreactive glucagon had a molecular weight of greater than 9000 daltons whereas that of 70 per cent of the patients with glucagonoma had a molecular weight of 3500 daltons, with the remainder eluting in the area of 9000 daltons. Pancreatic angiograms and hepatic scintiscans were normal in all four relatives. The data suggest an autosomal dominant transmission of hyperglucagonemia in this family. Immunoreactive glucagon with a molecular weight of 3500 or 9000 daltons appears to be required for the development of the clinical glucagonoma syndrome.",0
18,193008,Cellular immunity and herpesvirus infections in cardiac-transplant patients,"We observed severe infection with herpes simplex virus in cardiac-transplant patients despite their high serum antibody levels to this virus. Therefore, we sought to correlate clinical susceptibility to two herpesvirus (simplex and zoster) infections with specific cellular immunity, assessed by the transformation and interferon responses of peripheral blood mononuclear cells to heat-inactivated antigens. Transformation and interferon response to herps simplex virus was maximally depressed immediately after transplantation, the time when severe and prolonged infection with herps simplex virus occurred. Six months to six years after transplantation, both clinical susceptibility and cellular immunity to herpes simplex virus were normal. Herpes zoster infections were more frequent than normal at all times after cardiac transplantation; depressed or absent cellular responses to the varicella zoster virus paralleled that susceptibility. In these patients the risk of severe herpesvirus infections correlated with depressed cellular immune responses to the specific viral agent involved.",0
19,194153,Adherence of human peripheral blood lymphycytes to measles-infected cells. Enhancement by prostaglandin E1,We studied the effect of prostaglandins in vitro on an immune reaction mediated by T cells; adherence of lymphocytes to measles-virus-infected human epithelial cells. Normal human lymphocytes adhered to a mean +/- S.D. 20.1 +/- 5.2 per cent of these HEp-2 cells. The percentage positive cells increased to 50.3 +/- 5.7 when lymphocytes were incubated with 10(-6) M prostaglandin E1 (P less than 0.01 vs. untreated lymphocytes); 10(-8) M and 10(-10) M were as effective. Prostaglandin F2alpha had no effect on lymphocyte adherence. Prostaglandin E1 increased lymphocyte cyclic AMP five to 10 times whereas prostagladin F2alpha did not affect cellular levels of this nucleotide. Dibutyryl cyclic AMP (10(-8) M) increased lymphocyte adherence: positive human epithelial cells increased from 16.0 +/- 2.4 to 38.7 +/- 1.1 per cent (P less than 0.01). Prostagladin E1 also increased adherence of lymphocytes from patients with systemic lupus erythematosus from 21.8 +/- 5.8 to 52.5 +/- 9.2 per cent (P less than 0.01). These results indicate that prostagladin E1 and cyclic AMP may serve to stimulate T-cell function and cell-mediated immunity.,0
20,195206,Chronic progressive poliomyelitis secondary to vaccination of an immunodeficient child,"We investigated an immunodeficient child in whom chronic progressive poliomyelitis developed after she had received live oral poliovirus vaccine. Poliovirus, Type II, was isolated from throat and stool during life and from several sites within the brain at autopsy. The brain isolate was classified as vaccine-like on the basis of temperature sensitivity and antigenic markers. However, in the monkey neurovirulence test, the brain isolate produced moderately severe lesions throughout the spinal cord and brainstem and appeared nonvaccine-like. Thus, the brain isolate demonstrated a dissociation between the antigenic and neurovirulence markers. Our observations suggest that, under unusual circumstances, such as immunodeficiency, attenuated poliovirus can produce a chronic progressive neurologic disease. This case also emphasizes the need to diagnose immunodeficiency as early as possible, so that live-virus vaccines will not be administered.",0
21,196197,A cluster of Epstein-Barr-virus-associated American Burkitt's lymphoma,"We investigated four patients in whom histologically confirmed Burkitt's lymphomas developed during a one-year period. They were young adults living within 50 km of each other in a rural area of Pennsylvania. Two patients were related by marriage, but there was no contact with or between the other two. Although the majority of American Burkitt's lymphomas are not associated with the Epstein-Barr virus, all four patients showed spectra and titers of antibodies to antigens related to that virus that were characteristic of virus-associated Burkitt's lymphoma in Africa. Viral DNA and numerous cells with virus-determined nuclear antigen were found in tumor specimens available from three patients. These cases are unusual, since time-space clustering of Burkitt's lymphoma associated with Epstein-Barr virus has been observed thus far only in Africa.",0
22,196198,Annual discourse--don't eat the quails,"Physicians were the first individuals recorded by name in history. Their attempts to define disease influenced fundamentally the cultures and religions of the world. Surgical skills, although highly developed in ancient times, appear to have been less well documented historically than medical disorders. Because of the greater threat to survival that diseases posed, they became incorporated into religious customs. Contagious diseases also influenced greatly the laws, traditions and historical events of the Bible. Leprosy provided a physical example that presumably represented an image of sin, but it probably was no more prevalent as a disease during Biblical times than at present. Many of the Biblical stories assumed to be allegorical may have been founded on medical fact. For example, it appears likely that the quails that poisoned the wandering Jews were contaminated with cyanide.",0
23,197408,Gonadotropin-releasing hormone,"Gonadotropin-releasing hormone (GnRH) is briefly discussed. Luteinizing hormone (LH) secretory response to GnRH in vitro was obtained even in calcium-free medium. It is concluded that calcium is not an absolute requirement for the GnRH-stimulated LH release. In the absence of calcium, however, there was no response of LH to nonspecific stimuli such as enhanced potassium concentration. It is proposed that GnRH receptor protein exists in allosteric forms with different binding activities and that molecular rearrangement of the protein may modifiy the properties of the plasma membrane enough to change its permeability to ionic environment and secretory products. Therefore, the receptor protein may have a regulatory role independent of the cyclic adenosine monophosphate system.",0
24,212678,Epidemiology of human rotavirus Types 1 and 2 as studied by enzyme-linked immunosorbent assay,"To determine the relative importance of two known serotypes of human rotavirus, we developed an enzyme-linked immunosorbent assay to differentiate serotype-specific rotavirus antigen and antibody. Using this technic, we studied the epidemiology of the two serotypes in acute gastroenteritis. Seventy-seven per cent of 414 rotavirus isolates were Type 2, and the remainder were Type 1. The serotype distribution was similar in specimens from children in Washington, D.C., and other parts of the world. Sero-epidemiologic studies revealed that most children living in the Washington, D.C., area acquired antibody to both types by the age of two years. An analysis of children who were reinfected indicated that sequential infections usually involved different serotypes and that illness caused by one serotype did not provide resistance to illness caused by the other serotype. These results suggest that, to be completely effective, a vaccine must provide resistance to both serotypes.",0
25,213722,Endometrial cancer and estrogen use. Report of a large case-control study,"Our case-control study of the relation between estrogen use and endometrial cancer involved 451 cases and 888 controls. The overall risk of endometrial carcinoma was sixfold for estrogen users as compared with nonusers; long-term users (greater than five years) had a 15-fold risk. Excess risk was present for both diethylstilberstrol and conjugated estrogens. The risk associated with cyclic use was as great as that for continuous use. Increased risk was associated with estrogen use for all histologic grades of the tumor. The risk of advanced-stage carcinoma was fourfold for estrogen users, but rhe confidence interval was wide, and this question requires further study. Finally, this investigation contradicts the speculation that the association between this cancer and estrogen use can be explained by swifter diagnosis for estrogen users, misclassification of estrogen-related hyperplasia or treatment of early symptoms of the tumor with estrogen.",0
26,215912,"Treatment of Cushing's disease by O,p'DDD. Survey of 62 cases","In a study of nonsurgical therapy of Cushing's disease, 62 patients received O,p'-dichlorodiphenyldichloroethane (O,p'DDD), 16 of whom also received cobalt irradiation of the pituitary. After an initial treatment period averaging eight months, a remission of the disease was obtained in 38 of the 46 patients given O,p'DDD alone and in all patients who received drug combined with radiation. Although 60 per cent of these patients subsequently relapsed, additional courses of drug or radiation therapy were usually effective, and 63 per cent of the entire group of patients have so far been kept under control without adrenalectomy. (Forty patients have been followed for at least two years after the initial course of treatment.). O,p'DDD produced little gastrointestinal discomfort; an increased serum cholesterol was the main side effect. This drug allows long-term medical management of Cushings disease in most cases. Whether the combination of O'p'DDD with pituitary radiation is the best therapy has not been established.",0
27,226883,Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis,"In 11 hypertriglyceridemic patients on hemodialysis, clofibrate (1 to 1.50 g per week) reduced plasma triglyceride (-40 +/- 20%, P less than 0.001), very-low-density-lipoprotein triglyceride (-44 +/- 20%, P less than 0.001) and very-low-density lipoprotein cholesterol (-39 +/- 25%, P less than 0.01), and it increased high-density-lipoprotein cholesterol (82 +/- 106%, P less than 0.005). Low pretreatment lipoprotein-lipase activity in adipose-tissue specimens and postheparin plasma increased to normal with clofibrate, whereas low hepatic triglyceride lipase activity did not change. The reduced very-low-density-lipoprotein triglyceride correlated with the increased lipoprotein-lipase activity in adipose tissue (rs = 0.792, P less than 0.02, n = 8) and postheparin plasma (rs = 0.851, P less than 0.02, n = 8), whereas increased high-density-lipoprotein cholesterol correlated with changes in this activity in adipose tissue (rs = 0.696, P less than 0.06) and post-heparin plasma (rs = 0.679, P less than 0.10). There was no correlation between changes in hepatic triglyceride lipase activity and plasma lipids during treatment. Reduced lipoprotein-lipase activity may cause hypertriglyceridemia and decreased high-density-lipoprotein cholesterol in patients on hemodialysis; clofibrate may correct these abnormalities by increasing lipoprotein-lipase activity to normal.",0
28,226884,Activation of suppressor T cells during Epstein-Barr-virus-induced infectious mononucleosis,"Infectious mononucleosis is caused by the Epstein-Barr virus (EBV), an unusual human pathogen because it preferentially infects B lymphocytes and consequently activates them to produce immunoglobulins. When cultures of lymphocytes from patients with infectious mononucleosis were stimulated with polyclonal activators, unseparated cells failed to produce immunoglobulins, whereas purified B cells responded normally. Cocultures demonstrated profound suppressor T-cell activity in blood from patients with infectious mononucleosis. Early in this disease, circulating immunoglobulin-secreting cells were elevated, but during the second week their number was strikingly depressed. These data indicate that during infectious mononucleosis, EBV causes polyclonal activation of B cells, reflected by hypergammaglobulinemia and increased circulating immunoglobulin-secreting cells. Next, suppressor T cells become activated and inhibit further B-cell activation. Thus, activation of suppressor T cells in infectious mononucleosis provides a unique additional mechanism of host defense because these T cells inhibit the activation and proliferation of an important target of the causative virus.",0
29,226885,Hormone receptors,"This article reviews the literature on hormone receptors and presents information on the following broad topics: 1) steroid hormone receptors (vs. cytoplasmic); 2) thyroid hormone receptors; 3) catecholamine and peptide hormone receptors; 4) internalization of polypeptide and catecholamine hormone-receptor complexes; 5) affinity (as the basis for discrimination of hormonal signals); 6) binding curves and Scatchard plots; 7) nonspecific and nonreceptor binding; 8) curvilinear Scatchard plots, indicating multiple sites and negative cooperativity; 9) definition of class of hormone action and hormonal occupancy of several classes of receptors; 10) receptor-response relation (close coupling and spare receptors); 11) regulation of receptors (a mechanism important for control of cellular sensitivity to hormones); 12) hormone antagonists and partial agonists and antagonists; 13) receptors and the clinical evaluation of hormone and drug levels; and 14) receptor-related diseases. Throughout the literature, identification of hormone-binding sites as receptors has relied mainly on correlations between hormone binding and biologic effects, on genetic and other studies where loss of (or changes in) receptors are associated with altered hormone responsiveness, and on the finding that receptor binding by anti-receptor antibodies or antagonists attentuates or abolishes the hormone responses.",0
30,226998,"Toad urinary bladder epithelial cells in culture: maintenance of epithelial structure, sodium transport, and response to hormones","Epithelial cells from the toad urinary bladder have been grown in continuous culture. Many of the cells resemble the granular cell type of the urinary bladder. They form an epithelium with typical tight junctions and gap junctions. The transport properties of two cell lines have been examined. When cells of the line designated TB-M or of line TB-6c are grown on collagen-coated nucleopore filters, epithelia are formed that have transepithelial potential differences of 40 and 20 mV, resistances of 5000 and 10,000 omega-cm2, and short-circuit currents (ISC) of 8.5 and 2.5 muA/cm2, respectively. Net mucosa to serosa sodium transport accounts for all of ISC in line TB-M and for 70% of ISC in line TB-6c. Vasopressin, which stimulates adenylate cylase and ISC in the intact bladder, has no effect on the cells in culture. Cyclic AMP stimulates ISC and lowers resistance in both lines. Aldosterone stimulates ISC in both lines. This is accompanied by a fall in resistance in line TB-M and no change in resistance in line TB-6c. Amiloride inhibits ISC in TB-M cells under basal conditions and after stimulation by aldosterone. In line TB-6c amiloride has no effect under basal conditions but lowers ISC of aldosterone-treated cells to the basal level. Thus, the cells have retained the ability to form oriented, high-resistance epithelial membranes that manifest hormone-sensitive transepithelial sodium transport. ",0
31,227138,Vitamin D-induced coronary atherosclerosis in normolipemic swine: comparison with human disease,"Coronary atherosclerosis developed in normolipemic swine fed a basal ration supplemented with 125,000 IU, 62,500 IU and 31,250 IU of vitamin D3/kg of diet for 3 months and subsequently only the basal ration for the following 3 months. Lesions consisted of intimal atheromata and calcified internal elastica and caused luminal narrowing. The incidence of atherosclerotic lesions was proportional to the vitamin D3 doses. The present experimentally induced lesions had many morphological features resembling those in coronary arteries from human subjects. ",0
32,227203,Corticosterone secreting adrenal carcinoma and empty sella turcica: a case report,"Pituitary adenoma was suspected in a woman of 74 with hypercorticism,hypokalaemic alkalosis and radiographically enlarged sella turcica. However, non-suppressibility of steroid excretion by high-dose dexamethasone and low plasma concentration of ACTH suggested adrenal tumour. Detailed analysis of urinary steroid excretions demonstrated unusually large amounts of corticosterone metabolites, 14.6 mg/24 h compared to a mean normal value of 0.5 mg. The basal levels of the remaining pituitary hormones were unremarkable. The patient died incidentally before a planned adrenalectomy. The autopsy disclosed an adrenal carcinoma and an empty sella turcica. The enlarged pituitary fossa was lined by a narrow rim of histological normal pituitary tissue. ",0
33,227314,Bone resorption in chronic otitis media,"Bone resorption is an important aspect of chronic otitis media contributing to many complications of this disease. It is postulated that the mechanism of this localized destructive process is chemical in origin. Collagenase, lysosomal enzymes, prostaglandins, and other cell mediators are thought to induce bone resorption, but the site of action and cellular origin of these substances remains unclear. In this report, we demonstrate the location and attempt to delineate the cellular origin of two enzymes, collagenase and the lysosomal enzyme acid phosphatase in guinea pig temporal bones and human ossicles from ears containing chronic otitis media. Tissue localization of these enzymes identifies sites of active bone resorption and demonstrates the cells initiating this process. Using immunohistochemical and immunocytochemical techniques, collagenase was seen surrounding mononuclear inflammatory cells of granulation tissue at bone resorbing margins and at the periphery of osteocyte lacunae adjacent to resorbing areas. Electron microscopic data suggests that collagenase is an extracellular enzyme foun at the periphery of osteocytes. In addition, abundant acid phosphatase activity was seen in the same cells that exhibited collagenase staining, lending credence to the destructive function of these cells. The chronic inflammatory reaction found in chronic otitis media appears to activate bone destruction through the dynamic activity of mononuclear inflammatory cells and stimulates bone cells to increase their destructive biochemical functions. ",0
34,227623,Spectrophotometric assay of angiotensin I-converting enzyme (author's transl)],"The method of chemical assay of angiotensin I-converting enzyme described is a modification of the previously published spectrophotometric assay based on quantitation of hippuric acid released from hippuryl-L-histidyl-L-leucine. The new procedure involves extraction of hippuric acid with ethylacetate, evaporation to dryness of the extract, solubilization of the residue with 1 mol/l NaCl and purification with petroleum ether before measurements of the absorbance at 228 nm of the aqueous phase. Under these conditions, hippuric acid insoluble in petroleum ether remains in the aqueous phase, whereas other A228-absorbing materials, readily soluble in the ether and able to interfere with the assay, are eliminated. ",0
35,227931,Low-density lipoprotein receptor activity in cultured human skin fibroblasts. Mechanism of insulin-induced stimulation,"""Low-density lipoproteins (LDL) receptor activity, as reflected by LDL degradation, was stimulated by the addition of insulin to cultures of human skin fibroblasts. These changes occurred independently of the glucose concentration of the incubation medium and occurred whether or not LDL receptor activity was suppressed. A comparison of the saturation kinetics of LDL receptor activity in the presence and absence of insulin indicated that insulin produced a 35% increase in Vmax with no difference in """"apparent Km"""". These results suggest that insulin enhances LDL receptor activity by increasing the number of LDL receptors rather than by influencing binding affinity. In confirmation, LDL degradation by receptor negative cells was not enhanced by insulin. Sterol synthesis from [14C]acetate was also stimulated by insulin, but egress of cholesterol and cellular cholesterol content were unaffected by the hormone. The effect of insulin on LDL receptors was not dependent on its known ability to enhance cellular DNA synthesis and proliferation, because insulin stimulated LDL receptor activity in cells kept quiescent by maintenance in plasma-derived serum that was devoid of platelet derived growth factor. Nevertheless, the effect of insulin in enhancing LDL receptor number, coupled with stimulation of endogenous cholesterol synthesis, provides a mechanism whereby the cell could theoretically increase its supply of cholesterol during times of additional need. """,0
36,228409,Acute nephritis and allergic vasculitis due to phenindione (author's transl)],The authors report a case of acute nephritis which appears during a treatment with phenindione. The nephropathy described after this medication are now well known. Their manifestations are either a proteinuria associated or not with a nephrotic syndrome or an interstitial nephritis whose pronostic is reserved. In this observation the mechanism is different : the lesion is glomerular and complicates an allergic vasculitis which was secondary to the phenindione's therapy. The pronostic was good. ,0
37,234174,Optimum end-expiratory airway pressure in patients with acute pulmonary failure,"To determine whether in the management of pulmonary failure, the maximum compliance produced by positive end-expiratory pressure coincides with optimum lung function, 15 normovolemic patients requiring mechanical ventilation for acute pulmonary failure were studied. The end-expiratory pressure resulting in maximum oxygen transport (cardiac output times arterial oxygen content) and the lowest dead-space fraction both resulted in the greatest total static compliance. This end-expiratory pressure varied between 0 and 15 cm of water and correlated inversely with functional residual capacity at zero end-expiratory pressure (r equal -0.72, p less than or equal to 0.005). Mixed venous oxygen tension increased between zero end-expiratory pressure and the end-expiratory pressure resulting in maximum oxygen transport, but then decreased at higher end-expiratory pressures. When measurements of cardiac output or of true mixed venous blood are not available, compliance may be used to indicate the end-expiratory pressure likely to result in optimum cardiopulmonary function.",0
38,235094,Medical education in China in the postcultural Revolution era,"The Cultural Revolution has had an important impact on Chinese medical education. The Chinese system is engaged in a vigorous program to solve health-manpower needs in the rural areas by emphasizing de-professionalization, mass orientation and accountability to the community. Among the notable changes within the medical schools are the following: an admission process favoring the recruitment of peasants, factory workers, and the military; a three-year program with heavy emphasis on practicing in rural communities; widespread integration of the traditional Chinese and Western systems of medical practice; and manual labor and political seminars, which compose more than 25 per cent of the required curriculum. These innovations have been greatly facilitated by a strong national commitment and supportive political system. The fact that less than 10 per cent of doctors in China today are graduates of college-level medical education indicates the importance of other entry possibilities.",0
39,236514,A career in ambulatory medicine,"To meet the need and resolve long standing conflicts in the delivery of primary care in an age of specialization, I propose an experiment with a different type of primary medical education based on the separation of careers into community-oriented primary and continuing care of ambulatory patients and hospital-based intensive care of acutely ill bed patients. High-school graduates selected for interest, aptitude, and personality would follow a six-year pathway through college and medical school. A singular feature of the proposal would be the replacement of bedside training with an undergraduate traineeship of two to 2 1/2 years in the hospital ambulatory specialty clinics, emergency clinic, and a primary-care model practice unit, followed by a one-year externship in this primary-care center. The graduate would be oriented toward group and team practice and would work in a system integrating primary, secondary, and tertiary care.",0
40,239338,Financial impact of physician assistants on medical practice,"A study of revenues generated and expenses incurred by 12 physician assistants (MEDEX) who had held salaried positions for at least one year was conducted to determine their financial impact on primary-care practices. Daily charge logs were used to make annual estimates of MEDEX-generated revenues. One method of estimating annual revenues produced a mean of $28,190 per year, and a second method yielded a figure of $30,210 per year. Financial statements were used in two different ways to estimate annual expenses related to the employment of the MEDEX. One procedure indicated average costs of employment were $15,900, and the other $20,100. Ten of the 12 practices in the study experienced substantial gains of estimated revenue over expenses ascribed to the activities of the MEDEX.",0
41,241018,Cerebrospinal-fluid acid base and electrolyte changes resulting from cerebral anoxia in man,"To study metabolic changes in the central nervous system after profound anoxia, we measured changes in cisternal and lumbar cerebrospinal fluid. Acid-base values and electrolyte concentrations were determined in cisternal and lumbar fluid from 12 severely anoxic patients (cardiac arrest), and from 15 within 24 hours after cardiac resuscitation. In the severely anoxia patients the normal cisternal-lumbar pH gradient was reversed, cisternal fluid was more acid (pH 6.815 vs. 6.953), and cisternal potassium concentration was twice that of lumbar (6.7 vs 3.5 mEq per liter). These findings indicate that during anoxia potassium and hydrogen ion flow from brain cells into the brain extracellular fluid, and that acute changes are reflected more accurately by cisternal than by lumbar fluid. In resuscitated patients cisternal fluid was normal, and normal cisternal-lumbar differences were found; thus, the normal milieu of brain cells is rapidly reestablished after resuscitation.",0
42,271271,Cellular distribution of hemoglobin F in a clonal hemopoietic stem-cell disorder,"""Because all erythroid cells in chronic myelogenous leukemia are believed to arise from a common pluripotent stem cell, we studied the cellular distribution of fetal hemoglobin in patients with the disease to test whether cells with and without hemoglobin F have a common or separate pluripotent stem-cell origin. In a patient with chronic myelogenous leukemia and sickle/beta thalassemia, 17 per cent of the red cells during remission and 18 to 22 per cent during the blastic phase contained fetal hemoglobin. In 24 non-hemoglobinopathic leukemic patients 0.3 to 28 per cent of red cells contained hemoglobin F. Since the erythrocytes in chronic myelogenous leukemia are almost exclusively derived from the malignant clone, these data suggest that cells containing fetal hemoglobin originate from the same pluripotent stem-cell progenitor as those without hemoglobin F. The findings argue against a separate line of """"partially switched"""" pluripotent stem cells as being responsible for maintenance of hemoglobin F production in the adult.""",0
43,301608,Impaired humoral immunity in treated Hodgkin's disease,"To define the contribution of aggressive lymphoma treatment to the risk of post-splenectomy septicemia, we investigated the humoral immunity of 44 patients with Hodgkin's disease. Specific antibody against Haemophilus influenzae Type b was significantly reduced (mean, 147 ng per milliliter, P less than 0.01) in patients receiving combined treatment (radiotherapy and chemotherapy), whereas single treatment reduced titers marginally (chemotherapy) or not at all (radiotherapy). Untreated patients had normal values (396 ng per milliliter), and splenectomy was without effect. In some patients who received combined treatment, titers were reduced to levels seen in infants. IgM levels were likewise normal in untreated patients. Chemotherapy, however, significantly reduced IgM levels (P less than 0.025), an effect potentiated by prior splenectomy. IgG, IgA, alternate-pathway activity, C3, C4 and CH50 were all normal or elevated. Aggressive treatment with chemotherapy and radiation impairs humoral defense against encapsulated micro-organisms, and thus magnifies the risk of post-splenectomy septicemia in patients with Hodgkin's disease.",0
44,306064,Acquired von Willebrand's disease. Evidence for a quantitative and qualitative factor VIII disorder,"To define further the factor VIII abnormality in acquired von Willebrand's disease, we performed immunoelectrophoresis of factor VIII antigen, as well as quantitative measurements of the antigen, factor VIII procoagulant activity and von Willebrand factor activity on plasma from an affected 57-year-old man who also had a poorly differentiated lymphocytic lymphoma. No evidence for an inhibitor against factor VIII procoagulant activity or von Willebrand factor activity was detected, but immunoelectrophoresis showed none of the less anodic forms of factor VIII antigen. There were concomitant decreases in total antigen (0.19 U per milliliter) and von Willebrand factor levels (0.12 U per milliliter). Factor VIII-procoagulant activity was borderline low (0.45 U per milliliter). Correction of both the abnormal immunoelectrophoresis pattern and the quantitative abnormalities followed radiotherapy of the lymphoma. The factor VIII abnormalities might have resulted from binding or destruction of theless anodic forms of factor VIII antigen by the malignant lymphocytes.",0
45,307183,"Role of helper, suppressor and B-cell defects in the pathogenesis of the hypogammaglobulinemias","We investigated suppressor and helper T cells in 19 patients with variable immunodeficiency to assess the possibility that defective interactions among these cells and B lymphocytes are the chief cause of the inadequate plasma-cell development and hypogammaglobulinemia characterizing these syndromes. We accomplished functional separation of the two T-cell subsets, using irradiation, which selectively inactivates T-cell suppressors. The patient B lymphocytes were usually capable of some differentiation into plasma cells when co-cultured with T cells manipulated to optimize helper effects. Eighteen of 19 patients showed quantitatively poor plasma-cell production even under these conditions. However, only one had defective enough helper function, and only one sufficiently excessive suppressor activity for these factors to be considered the major pathogenetic process in each case. Since neither an absolute defect in B cells nor consistent abnormalities in modulator T cells were demonstrable in most patients, other explanations must be sought for the mechanisms underlying this form of primary immune deficiency.",0
46,308183,Cellular immunity in Guamanians with amyotrophic lateral sclerosis and Parkinsonism-dementia,"To test the hypothesis that host resistance factors may be abnormal in Guamanians in whom amyotrophic lateral sclerosis and Parkinsonism-dementia develop, cellular immunity was evaluated in both diseases and compared to that of Guamanians with other nervous-system diseases, normal adult Guamanians and non-Guamanians with amyotrophic lateral sclerosis and Parkinsonism. Diminished responses to skin-test antigens, lymphopenia, diminished per cent and total T cells and, less frequently, decreased mitogen responses were seen in Guamanian patients with amytorophic lateral sclerosis and Parkinsonism-dementia but not in the other patient or normal groups. Guamanian patients with amyotrophic lateral sclerosis and diminished cellular immunity had an increased frequency of HLA-Bw35 (P less than 0.005) and shorter mean duration of disease (P less than 0.05) than those with normal cellular immunity. In Parkinsonism dementia diminished cellular immunity was less strongly associated with HLA-BW35 (P less than 0.05) and was not associated with differences in duration of disease. Normal Guamanians and those with other nervous-system diseases showed no association of diminished cellular immunity with HLA-Bw35. The association appeared disease-related, with onset concomitant with the neurologic expression of Guamanian amyotrophic lateral sclerosis and Parkinsonism-dementia.",0
47,308614,Systemic membrane defect in the proximal muscular dystrophies,"We studied lymphocyte capping in 61 patients with Duchenne, Becker, limb-girdle, facioscapulohumeral and congenital muscular dystrophies. All showed a markedly diminished percentage of capped cells when compared with 86 normal controls, providing support for previous evidence that an alteration in membrane fluidity may be a common pathogenic feature in several genetically distinct forms of proximal muscular dystrophy. Heterozygous carriers of Duchenne muscular dystrophy showed diminished capping that was indistinguishable from that of afflicted males and was often present even when serum enzyme levels were normal. Studies in 25 families with 16 suspected sporadic cases indicated that no more than four out of 30 afflicted males may represent new mutations. These findings imply that most cases of Duchenne dystrophy might be prevented by a population screening program for carrier females combined with prenatal detection of afflicted males.",0
48,308618,"Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease","The serum concentration of 1,25-dihydroxylvitamin D (1,25-[OH]2D) in normal children and in children with inherited diseases of bone was compared by use of a competitive binding assay. Observed values were: in 12 normal children and adolescents, 37.1 +/- 1.9 pg per milliliter (mean +/- S.D.); in 14 patients with X-linked hypophosphatemic rickets treated with vitamin D2 and phosphate supplements, 15.6 +/- 7.8 (P less than 0.01 versus control); in six patients with autosomal recessive vitamin D dependency treated with vitamin D2, 9.5 +/- 2.9 (P less than 0.01 versus control); and in four untreated patients with autosomal dominant hypophosphatemic (non-rachitic) bone disease, 30.2 +/- 6.3 (not significantly different from the controls). The difference in bone disease between X-linked hypophosphatemia (severe) and hypophosphatemic bone disease (mild) at comparable low serum levels of phosphate implies that 1,25-(OH)2D and phosphate may have independent roles in the pathogenesis of defective bone mineralization.",0
49,310515,In vivo and in vitro effects of thymosin and adenosine deaminase on adenosine-deaminase-deficient lymphocytes,"""Two siblings with adenosine deaminase deficiency were studied before and during """"enzyme replacement"""" therapy (partial exchange transfusions with normal red cells containing the missing enzyme). The younger sib showed improvement of immunologic function during red-cell therapy alone, whereas in the older sib this improvement occurred only when the transfusions were supplemented by thymosin injections. Their clinical courses correlated with in vitro findings: lymphocytes from the younger sib differentiated to T-cell-rosette-forming cells upon addition of adenosine deaminase alone; lymphocytes from the older sibling required supplemental thymosin to form these cells. Thymic factors appear to influence the response to transfusion therapy in some patients deficient in adenosine deaminase, and supplementation of red-cell transfusion with thymic factors may be required.""",0
50,314058,Identification of two serum components regulating the expression of T-lymphocyte function in childhood myasthenia gravis,"""We studied serums and cells from nine children with myasthenia gravis to determine whether there were alterations in the distribution or function of different T-lymphocyte subpopulations. The low numbers of E-rosette-forming T lymphocytes and their failure to respond to antigen by producing normal suppressor T cells were correlated with the presence of an IgG antibody directed toward the theophylline-sensitive T-cell subset; this activity could be blocked by d-tubocurarine. Incubation of normal T lymphocytes with serum from patients rendered the cells """"myasthenia-like"""" when assayed for E-rosettes and for antigen-induced suppressor-cell function. A second, non-IgG factor found in patients' serums had activity like that of thymic hormone and induced T-cell maturation in normal bone marrow. This factor was not inhibited by d-tubocurarine; its activity was strongest in the two patients most severely affected, and it disappeared after thymectomy in both these patients. We conclude that in childhood myasthenia gravis there may be two independent serum factors; one an IgG antibody directed at a subset of T lymphocytes, blocked by d-tubocurarine and apparently unaffected by thymectomy, and the other a thymus factor that induces T-lymphocyte maturation.""",0
51,314587,Familial abnormalities of suppressor-cell function in systemic lupus erythematosus,"We tested the hypothesis that abnormalities of central immune function are genetically controlled in patients with systemic lupus erythematosus. We used an in vitro suppressor-cell assay to evaluate central immunoregulation in 15 patients, 50 of their clinically healthy family members and 41 normal persons. Impaired suppressor-cell function was found in 11 patients; there was no correlation between disease activity and test results. Abnormal suppressor-cell activity was also found in 13 first-degree relatives, 12 of whom were women. We found no correlation between results of the suppressor-cell assay and the presence or absence of lymphocytotoxic antibodies in the relatives. Impaired suppressor-cell function cannot by itself explain the pathogenesis of systemic lupus erythematosus. Our results support the hypothesis that certain abnormalities of suppressor cells are genetic markers. We propose that the development of systemic lupus erythematosus requires the participation of at least two functionally distinct classes of genes.",0
52,315518,Abnormal lymphocyte capping in a patient with severe combined immunodeficiency disease,"Despite the presence of normal numbers and distribution of T and B lymphocutes and normal levels of serum immunoglobulins, a five-month-old infant failed to show any evidence of T-cell or B-cell immunity. In trying to identify a specific membrane abnormality as a potential cause of the immunologic dysfunction, we examined the lateral mobility of the cell-surface receptor for concanavalin A. In contrast to normal cells, in which the receptor is distributed uniformly over the cell surface, the patient's lymphocytes showed an unusually high accumulation of concanavalin A receptors in surface caps. This capping abnormality appeared in both T and B lymphocytes and was exaggerated by colchicine, an inhibitor of microtubule assembly. These findings support the theory that plasma-membrane-cytoskeleton interactions have a role in the expression of specific immunity; the findings also identify new areas that should be considered in trying to understand the primary immunodeficiency diseases.",0
53,325407,The evaluation of clinical predictions. A method and initial application,"Clinical predictions are never certain but are inherently probablisitc. The accuracy coefficient, a measure of probabilistic accuracy based on probability assigned to outcomes that occur, was used to assess the skill of clinical rheumatologists in predicting patient outcomes. Physicians' scores correlated well with degree of clinical experience. An approach to evaluation based on the measure provides a sensitive assessment of marginal benefit of technologies such as laboratory tests, diagnostic procedures or computer consultations. Most currently used methods of computer prediction were not as accurate as the best physicians tested. By allowing measurement of ability to individualize predictions to each patient's unique characteristics, the accuracy-coefficient approach has potential use in physician assessment.",0
54,340947,Predicting treatment costs and life expectancy for end-stage renal disease,"To estimate the cumulative 10-year direct medical costs and life expectancy associated with different methods of treatment for end-stage renal disease, we assessed predictively three treatment transition options. It is predicted that if 1000 patients shift from facility to home dialysis for each of 10 years, life expectancy of the cohort will not be reduced, but there will be a reduction of $241 million in total costs. The same number shifting from facility dialysis to cadaveric transplantation are predicted to have a $279 to $330 million reduction in total costs but a reduction of 7 to 17 per cent in life expectancy. Shifting from home dialysis to transplantation is predicted to reduce total costs by +103 to $142 million, and life expectancy by 10 to 20 per cent. As new program policies for treatment of end-stage renal disease are developed, their effect on both costs and life expectancy needs to be considered.",0
55,360062,Insulin binding and insulin sensitivity in isolated growth hormone deficiency,"125I-insulin binding to monocytes was examined in five children and one adult with isolated growth hormone deficiency before and after three to 12 weeks of growth hormone treatment, and in eight controls. Before treatment, mean plasma glucose was 15 mg per deciliter below controls, and plasma insulin was reduced by 40 per cent. Insulin binding to monocytes was 70 per cent greater than controls (P less than 0.005). Insulin-mediated glucose uptake (determined in the adult patient) was 25 per cent greater than mean control levels. After treatment, plasma glucose rose to control levels, plasma insulin increased to 75 per cent above controls (P less than 0.01), and insulin binding fell to 50 per cent below controls (P less than 0.01). Insulin-mediated glucose uptake fell to 30 per cent below the mean control rate. Insulin binding increases in growth hormone deficiency and falls after treatment. These changes may contribute to alterations in insulin sensitivity accompanying altered growth hormone availability.",0
56,362207,Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitary-adrenal function in children with chronic asthma,"Two corticosteroid regimens, alternate-day prednisone and inhaled beclomethasone dipropionate, have been more acceptable than daily oral corticosteroids for treatment of chronic asthma. To compare the effect of these regimens on hypothalamic-pituitary-adrenal function, 20 children with asthma were evaluated while receiving 20 to 40 mg of prednisone on alternate mornings or 400 to 800 microgram per day of inhaled beclomethasone dipropionate in divided daily doses; seven children requiring only non-corticosteroid medication served as controls. Early-morning serum cortisol concentration, urinary free-cortisol excretion and the 11-desoxycortisol response to metyrapone were decreased to a similar degree among children receiving both corticosteroid regimens in comparison with the control patients and were lowest when alternate-day prednisone and inhaled beclomethasone dipropionate were given together. Thus, inhaled beclomethasone dipropionate appears similar to alternate-day prednisone in its effect on hypothalamic-pituitary-adrenal function when used alone; the effect is additive when the two are used together.",0
57,384245,Financing graduate medical education,"The direct costs of residency training in the United States are over $1 billion per year. These educational programs have been organized predominantly around hospital services and supported by hospital revenues. Pressure has been increasing to reduce the rate of increase in hospital expenditures or costs or both. This article describes alternative methods for financing graduate medical education. Debate over the current sources of financing reveals several troublesome issues: the presence of residents allegedly decreases the productivity of professionals and leads to overusage of ancillary services, proposed methods to pay for faculty salaries and services have created confusion and concern, and the financing of ambulatory-care training has been insufficient and poorly coordinated. The medical-education community must resolve these professional and educational problems so that financing issues can be debated and properly defended.",0
58,388217,Hodgkin's disease,"During the past two decades, new approaches to the diagnosis and treatment of Hodgkin's disease have contributed to improved rates of survival and probable cure. Currently, patients with Hodgkin's disease are treated according to the stage and symptoms of their disease. The degree of certainty necessary for determining stage depends on the potential effectiveness of the therapeutic options available in a given case. Certain cases have been identified where treatment with a single modality has been disappointing, and the use of both radiotherapy and chemotherapy may be considered for these. Such decisions can be made only by evaluating the effectiveness of salvage after relapse following single-modality treatment and assessing the added hazards of initial treatment with both modalities.",0
59,402576,Foundations of cost-effectiveness analysis for health and medical practices,"Limits on health-care resources mandate that resource-allocation decisions be guided by considerations of cost in relation to expected benefits. In cost-effectiveness analysis, the ratio of net health-care costs to net health benefits provides an index by which priorities may be set. Quality-of-life concerns, including both adverse and beneficial effects of therapy, may be incorporated in the calculation of health benefits as adjustments to life expectancy. The timing of future benefits and costs may be accounted for by the appropriate use of discounting. Current decisions must inevitably be based on imperfect information, but sensitivity analysis can increase the level of confidence in some decisions while suggesting areas where further research may be valuable in guiding others. Analyses should be adaptable to the needs of various health-care decision makers, including planners, administrators and providers.",0
60,415235,Some effects of health insurance in Canada--from private enterprise toward public accountability,"Ten years after the introduction of national medical insurance in Canada, it is possible to view the effect of a comprehensive health-insurance program on the relations among physicians, society and government. With costs of health care paid from the public rather than the private purse, provincial efforts to control the cost of hospital and physician services are increasing, and various methods for cost containment are now visible. Since the budget for these expenses is publicly debated it competes for support against other publicly funded programs. The federal/provincial insurance system is evolving as an instrument of reform in the organization of health services and has led to the introduction of legislation that is changing the health-delivery system. A gradual shift in power between various health agencies, physicians, professional organizations and government is occurring.",0
61,415241,Consumer-Choice Health plan (second of two parts). A national-health-insurance proposal based on regulated competition in the private sector,"Medical costs are straining public finances. Direct economic regulation will raise costs, retard beneficial innovation and be increasingly burdensome to physicians. As an alternative, I suggest that the government change financial incentives by creating a system of competing health plans in which physicians and consumers can benefit from using resources wisely. Main proposals consist of changed tax laws, Medicare and Medicaid to subsidize individual premium payments by an amount based on financial and predicted medical need, as well as subsidies usable only for premiums in qualified health insurance or delivery plans operating under rules that include periodic open enrollment, community rating by actuarial category, premium rating by market area and a limit on each person's out-of pocket costs. Also, efficient systems should be allowed to pass on the full savings to consumers. Finally, incremental changes should be made in the present system to alter it fundamentally, but gradually and voluntarily. Freedom of choice for consumers and physicians should be preserved.",0
62,418337,"Doctors, damages and deterrence. An economic view of medical malpractice","""Damages awarded in a malpractice suit must be viewed not only as compensating the victim but also as deterring health-care providers from negligent behavior. Economic analysis of the malpractice system indicates that awards can send a signal to providers that informs them how much to invest in avoiding mishaps. The malpractice system is beset by difficulties, but not the ones commonly incriminated. The signal to the physician, as determined by the number of claims and size of awards (""""expected damages""""), appears to be insufficient for ideal deterrence. Moreover, the deterrence signal is attenuated because malpractice premiums are set for groups of physicians, not for individuals according to their record of previous malpractice incidents. Replacing the present tort system with a no-fault insurance scheme would not necessarily be cheaper, and might well abolish the deterrent signal or distort clinical decision making.""",0
63,418339,"""How do health-maintenance organizations achieve their """"savings""""?""","""Health-maintenance organizations have been suggested as a way to stop spiraling medical costs. Although many of the arguments have been largely rhetorical, theoretical considerations suggest that the shift from fee for service to a fixed budget for the providers (physicians and hospitals) will result in substantial savings. Total costs (premium and out-of-pocket) for enrollees are 10 to 40 per cent lower than those for comparable people with health insurance. Enrollees in health-maintenance organizations have about as many ambulatory visits as comparison groups. Most of the cost differences are attributable to hospitalization rates about 30 per cent lower than those of conventionally insured populations. These lower hospitalization rates, in turn, are due almost entirely to lower admission rates; the average lenth of stay shows little difference. There is no evidence that health-maintenance organizations reduce admissions in discretionary or """"unnecessary"""" categories; instead, the data suggest lower admission rates across the board.""",0
64,431646,Intramuscular pressures with limb compression. Clarification of the pathogenesis of the drug-induced muscle-compartment syndrome,"To study muscle necrosis due to prolonged limb compression, we measured intramuscular pressure by inserting wick catheters into 10 volar forearms and 10 anterior tibial compartments of adult volunteers. We then placed the subjects in positions in which victims of drug overdose are commonly found. Intramuscular pressures in the area of direct compression on hard surfaces ranged from 26 to 240 mm Hg, and averaged 101 mm Hg. Most remarkable was a mean pressure of 180 mm Hg on compression of the forearm by the rib cage. These pressures are sufficient to cause muscle and capillary ischemia and necrosis by local obstruction of the circulation. This local injury by limb compression may produce edema sufficient to start compartment tamponade and consequent muscle-compartment and crush syndromes.",0
65,431682,A new design for randomized clinical trials,"This paper proposes a new method for planning randomized clinical trials. This method is especially suited to comparison of a best standard or control treatment with an experimental treatment. Patients are allocated into two groups by a random or chance mechanism. Patients in the first group receive standard treatment; those in the second group are asked if they will accept the experimental therapy; if they decline, they receive the best standard treatment. In the analyses of results, all those in the second group, regardless of treatment, are compared with those in the first group. Any loss of statistical efficiency can be overcome by increased numbers. This experimental plan is indeed a randomized clinical trial and has the advantage that, before providing consent, a patient will know whether an experimental treatment is to be used.",0
66,440341,Estrogens and endometrial cancer,"""The only active research performed by Jick and colleagues concerning the alleged causal relation between estrogens and endometrial cancer consisted of telephone interviews with 60 of 67 patients with endometrial cancer and a """"control"""" group of 74 other women with intact uteri. In their case-control study, the authors describe no effort to deal with problems in surveillance or detection bis or to avoid bias in ascertainment of exposure to estrogens. The suggestion that 18,000 women were investigated is based on a statistical tour through secular trends in computerized accounts of estrogen prescriptions and separately reported diagnoses of endometrial cancer. Except for data in the small group selected for the case-control study, none of this information was checked or verified. On the basis of the statistical trends, the authors conclude that estrogens increase the risk of endometrial cancer to """"even higher"""" than 20 times than that in nonusers but that the changes are stopped or reversed shortly after discontinuation of the estrogens. This capacity for de-carcinogenesis is explained by the conjecture that estrogen is a """"promotor"""" rather than an """"inducer"""" of endometrial cancer. An alternative hypothesis is that many uterine cancers are asymptomatic, never detected during life and 1st found (if at all) at necropsy.""",0
67,440390,United States citizens in foreign medical schools and the future supply of physicians,"Between 1973 and 1977, the number of United States citizens in foreign medical schools increased from 12,000 to 15,000, with Mexico and Italy responsible for training 55 per cent of these students. If all these students can successfully meet the requirements for entry into graduate training in the United States, their numbers, combined with the increasing size of entering classes in American medical schools, may exceed the number of positions presently available for first-year graduate training. Serious problems in the quality of education received in several new foreign medical schools must be addressed if these students are to enter the American medical system.",0
68,449887,Can China's health care be transplanted without China's economic policies?,"China's economic policies of the past 25 years have shaped its present health-care system. China's leadership has decided to have neither a national health-insurance system nor a national health service. Instead, it decided that its health system would mirror the workings of its industrial and agricultural system. Decisions to minimize imports, ban private economic activity, assign university graduates on a compulsory basis, control wages, maintain a large domestic standing army and prevent professions or universities from acquiring independent status led directly to the present system of medical care. Consequently, transplantation of China's striking achievements in health-care delivery to the United States or other countries is unlikely to occur in the absence of transfer of the underlying economic policies.",0
69,449948,Increasing minority recruitment to the health professions by enlarging the applicant pool,"Over an eight-year period, 707 students from minority groups or with economically disadvantaged backgrounds were selected from junior and senior-high-school classes throughout the state of Arizona and admitted to a Med Start program emphasizing careers in the health professions. The program featured recruitment into clubs, training in leadership, counseling by other minority students, work experience and specialized courses in English, mathematics and basic biologic sciences. Attrition was remarkably low. At the time of follow-up study, 369 of these students had sought further education beyond high school, and 220 of this group had enrolled in or completed health-education programs. Although obviously not a controlled experiment, this experience suggests that the pool of minority and economically disadvantaged applicants for careers in the health professions can be enlarged.",0
70,450016,"Human chorionic gonadotropin in the plasma of normal, nonpregnant subjects","To determine whether ectopic secretion of a protein hormone can occur normally, we studied plasma from normal, nonpregnant subjects for the presence of a placental hormone, human chorionic gonadotropin. We extracted and purified this hormone from other plasma proteins. We identified the hormone in the final residue on the basis of its dose-response curves in a specific radioimmunoassay and calculated the plasma concentration after correction for losses. Because this assay is sensitive to concentrations as low as 2 pg per milliliter, human chorionic gonadotropin could be detected in the plasma of 12 of 16 blood donors; the median concentration was 19 pg per milliliter (range, less than 2 to 361). This immunologic human chorionic gonadotropin was further characterized from a pool of normal plasma by gel filtration on Sephadex G-100 and was found to be identical to the standard form of the hormone. The concentration in this pool from 13 normal men was 18 pg per milliliter. The source of this ectopic hormone production is unknown, but may be normal, rapidly proliferating nonmalignant cells.",0
71,454371,Effect of drugs on deoxyribonucleic acid synthesis in isolated mammalian cell nuclei. Comparison with partially purified deoxyribonucleic acid polymerases,"In order to ascertain the identity of the DNA-dependent DNA polymerase responsible for the observed DNA synthesis in nuclei isolated from baby-hamster kidney (BHK-21/C13) cells a comparative study was carried out on the effects of some drugs, reported to influence DNA synthesis, on DNA synthesis catalysed by these nuclei and by partially purified DNA polymerase-alpha and -beta. In all cases DNA synthesis by isolated nuclei and polymerase-alpha was inhibited to similar extents by N-ethylmaleimide, p-hydroxymercuribenzoate, novobiocin, heparin and phosphonoacetic acid; polymerase-beta was much less affected by these compounds. Ethidium bromide inhibited all DNA synthesis to similar extents, although at low concentrations (about 2 microgram/ml) synthesis in isolated nuclei was stimulated. The results are discussed in relation to the proposal that DNA polymerase-alpha catalyses the covalent extension of Okazaki fragments that these nuclei carry out in vitro. ",0
72,454664,Studies on factor VIII-related protein. II. Estimation of molecular size differences between factor VIII oligomers,"Human factor VIII-related protein was isolated from cryoprecipitate by agarose (Sepharose CL-2B) gel filtration. Electrophoresis on SDS-2% polyacrylamide-0.5% agarose gels revealed size heterogeneity of factor VIII-related protein which was similar to that shown by SDS-1% agarose gel electrophoresis and electron microscopy. The apparent molecular weights were compared with those of crosslinked IgM oligomers and corresponded to values of up to 20 . 10(6) for factor VIII eluting close to the void volume of our gel filtration column. Measurement of mobility intervals on electrophoretic gels suggested a constant size difference between adjacent bands. Smaller aggregates were found in later eluates from Sepharose columns as well as following partial reduction of factor VIII with cysteine. In order to compare the size difference between small and large aggregates of factor VIII-related protein we calibrated the SDS-2% polyacrylamide-0.5% agarose gels with factor VIII which had been crosslinked with dimethyl suberimidate and subsequently disulfied-reduced with 2-metcaptoethanol. By combination of calibration ranges, constant intervals were measured for large and smaller factor VIII aggregates. The interval between any neighboring protein bands, which were immunologically identified as factor VIII-related protein, was equal to the dimer of the basic factor VIII subunit chain. We conclude that factor VIII aggregates correspond to multimers of a dimeric molecule, i.e. pairs of the basic subunit chain. ",0
73,454885,Intoxication at the wheel],"A large body of experimental and statistical evidence demonstrates that even mild alcohol intoxication with blood alcohol concentrations above 0,5% is associated with a significantly increase in the susceptibility for an accident. The lowering of the critical concentration limit is indicated from a medical, social-political and economical point of view. ",0
74,455229,In situ carcinoma of the vocal cords,"Eighty-one patients with preinvasive carcinoma of the vocal cord, seen over a thirteen year period, were reviewed histologically and analyzed for response to treatment. Sixty-seven cases were clinically T1 and fourteen cases T2 (by virtue of extension of disease beyond the vocal cord). All patients had mobile cords. Histological criteria for in situ carcinoma and the spectrum of microscopic patterns are presented. Sixty-nine patients were treated by external beam radiotherapy--the remainder by a variety of surgical procedures. Five and ten year actuarial, recurrence-free rates 83% and 75%, respectively for the group treated by irradiation. No difference in local control was observed when analyzed for: 1) dose response, 2) initial extent of disease, 3) treatment plan, or 4) histologic diagnosis. Analysis of failures reveals that 15/17 patients with local failure were salvaged, eleven of these patients requiring laryngectomy. Time to appearance of recurrence ranged from seven to one hundred and seven months. ",0
75,456054,Vectorcardiographic detection of early hemodynamic abnormalities in chronic obstructive pulmonary disease,"The ability of the vectorcardiogram to detect mild circulatory abnormalities in patients with chronic obstructive pulmonary disease (COPD) is unclear. Therefore, vectorcardiographic changes were correlated with hemodynamic measurements made at rest and during supine exercise in 32 patients with COPD and no clinical or electrocardiographic evidence of right ventricular hypertrophy. Twelve patients had normal hemodynamic data (group 1), nine had abnormal hemodynamic data only during exercise (group 2), and 11 had abnormal hemodynamic data at rest and during exercise (group 3). The extent of rightward terminal QRS forces noted on the vectorcardiogram was significantly less in group 1 (5.5 +/- 8.7 percent) than in either group 2 (19.0 +/- 10.7 percent) or group 3 (17.8 +/- 14.8 percent). Sixty-five percent (13) of the 20 patients with hemodynamic abnormalities had rightward terminal QRS forces of 15 percent or more, whereas only 8 percent (one) of the 12 patients with normal hemodynamic data had such forces of 15 percent or more. The mean of the rightward terminal QRS forces in 27 age-matched normal subjects was 5.0 +/- 5.4 percent, and only one subject had forces of 15 percent or more. We conclude that hemodynamic abnormalities are frequent in patients with COPD and no clinical evidence of right ventricular hypertrophy and that the vectorcardiogram provides an indirect method of detecting these abnormalities. ",0
76,456281,Metastasising squamous-cell carcinoma of the skin in a ten-year-old girl],"""Because of recurrent paronychia of the right thumb """"granulation"""" tissue was removed from the nail-bed of a ten-year-old girl. Histological examination revealed a cornified squamous-cell carcinoma. About five months later a lymph-node metastasis was found in the right axilla. After radical dissection of the axillary region further lymph-node metastases were found, as well as a lymphangitic carcinosis with tumour infiltration in the veins. Despite telecobalt radiation there were recurrent retastases which could no longer be removed by operation. Two years after the diagnosis the girl died. Necrospy revealed diffuse tumour infiltration of the soft tissue of the axilla, upper arm, shoulder, neck and thoracic wall on the right, including the breast tissue, with thoracic para-aortic-abdominal and left-sided axillary lymph-node metastases, and lung and pleural metastases bilaterally. """,0
77,456333,An epilepsy workshop for professionals,"This experimental study evaluated the impact of an epilepsy workshop format designed for community professionals who may be involved in the treatment plan and follow-up of patients. The goals of the workshop were to increase the professional's knowledge and comfort in the presence of epilepsy and to effect better delivery of services to patients. To achieve this, a didactic approach to learning was modified to include patient contact and participant involvement in the learning process. A pre- and posttest experimental design was utilized. Those who attended the workshop improved significantly more than the two control groups in their knowledge of and comfort with epilepsy. Following the workshop, there was a marked increase in the referral of school children for possible neurological problems by teachers who had attended. There was a subsequent improvement in the delivery of health care services to such children in this county. ",0
78,456367,The phosphoenolpyruvate-dependent phosphotransferase system of Staphylococcus aureus. Complete tyrosine assignments in the 1H nuclear-magnetic-resonance spectrum of the phosphocarrier protein HPr,"Upon nitration of the phosphocarrier protein HPr three nitrated derivatives of the protein were isolated: mononitrated HPr, dinitrated HPr and trinitrated HPr. Tryptic digestion of the derivatives leads to nitrotyrosine-containing peptides which were isolated and characterized by amino acid analysis. This resulted in the determination of the positions of the nitrated tyrosyl residues in the amino acid sequence. In mononitrated HPr only Tyr-56 was modified, in dinitrated HPr both Tyr-56 and Tyr-37 had reacted with the nitrating agent; modification of all three tyrosyl residues in trinitrated HPr required more drastic reaction conditions. The nuclear magnetic resonance spectra of the three derivatives allowed the assignments of the tyrosine resonances as follows: Tyr-A and Tyr-B with pK values of 10.5 and 11.5 were designated Tyr-56 and Tyr-37 whereas Tyr-C, whose protons are not titratable before denaturation of the protein, was assigned to Tyr-6 in the amino acid sequence. The nitration studies, together with the titration behaviour of the three tyrosines, indicate the topology of the tyrosyl residues to be as follows: Tyr-56 is located at the surface, Tyr-37 is slightly buried, Tyr-6 is deeply buried. The nitrotyrosyl derivatives retain their biological activity. ",0
79,456893,Regional differences of neuron loss of rat brain in old age,"DNA content was measured in four areas of the brain (cerebral hemisphere, cerebellum, diencephalon, and lower brain stem) of young adult (5-month-old) and aged 24- to 30-month-old Long-Evans rats. There was no change in DNA content in all four areas in old age. The number of brain cells was counted in three areas of the brain (cerebral hemisphere, cerebellum and brain stem) with an ultrasonic separation method. In old age, there was significant loss in the total number of brain cells in the cerebellum but no cell loss in the cerebral hemisphere and the brain stem. The neuron number was significantly decreased and the glia/neuron ratio was increased in the cerebellum and cerebral hemisphere, but neither of them changed in the brain stem in old age. The cerebellum showed significantly more neuron loss than the cerebral hemisphere in old age. DNA content in individual brain cells in the cerebral hemisphere, cerebellum and brain stem does not change in old age; thus, calculation of brain cell number from DNA content in the brain of old rats is justified. ",0
80,457360,Mass cells in ocular tissues of normal rats and rats infected with Nippostrongylus brasiliensis,"In orbital exenteration specimens from 14 rats, 93% of the mast cells were found in the lids, the limbus, and the conjunctiva, 5% in the orbital tissues, and less than 1% in the globe. The density of mast cells was highest in lid (2843/mm3), limbus (2822/mm3), and orbit (2184/mm3) and lowest in bulbar conjunctiva (794/mm3), ciliary body (512/mm3), and sclera (176/mm3). There was no significant difference in the distribution or density of mast cells in orbital exenteration specimens from normal rats compared with rats infected with the worm Nippostrongylus brasiliensis. We concluded that certain ocular structures are rich in mast cells, which suggests that these structures might be susceptible to injury mediated by mast cell products. ",0
81,457574,Colorectal polyps of the dog: a clinicopathologic study of 17 cases,"Seventeen cases of colorectal polyps in the dog were seen at the Ontario Veterinary College over a 12-year period. The mean age of occurrence was 6.9 years, and males and females were almost equally affected. The Collie was the most frequently affected breed (4/17). The clinical signs were typically dyschezia, periodic intermittent diarrhea and melena, and rectal prolapse of the polyp. The histopatholic classifcation were hyperplastic polyp (1), papillary adenoma (1), tubular adenoma (4), papillotubular adenoma (10), and unclassified (1). Severe epithelial atypia, likely carcinoma in situ, was apparent in 5 of the papillotubular adenomas. Retrospective analysis of survival data after polypectomy suggested a good prognosis, but the results were inconclusive and it is possible that some of the polyps represented premalignant lesions. Large polyps (greater than 1 cm in diameter) frequently had marked epithelial atypia and were considered more likely to recur or to become malignant. ",0
82,457668,Developmental regulation of creatine kinase isoenzymes in myogenic cell cultures from chicken. Levels of mRNA for creatine kinase subunits M and B,"During the first 2 days of culture of myogenic chicken cells only minute amounts of mRNA for a subunit of creatine kinase, M-CK, could be found in cultures from the 3rd and 4th day; however, a dramatic increase of mRNA for the muscle-specific M-CK was observed. The mRNA for B-CK, another subunit of creatine kinase, was readily detectable in young cultures increased up to the 3rd day in culture but decreased significantly 1 day later. The comparison of the ratios of mRNA concentrations for M-CK and B-CK in polysomal and total cellular RNA did not reveal significant differences in polysomal and total cellular RNA from 24-, 48-, and 68-h cultures, indicating that specific accumulation of a nonpolysomal form containing translatable mRNA for M-CK prior to its appearance in the polysomes does not seem to represent a major mechanism of regulation. In RNA from cells grown in 5-bromo-2'-deoxyuridine (BrdUrd) for 3 days and subcultured into the same medium for another 3 days only mRNA for B-CK was found. If cells, however, were subcultured into standard medium both mRNAs, the one for B-CK and the one for M-CK could be detected. BrdUrd inhibition seems to affect only the mRNA for M-CK and not the one for B-CK. Removal of BrdUrd from the cultures probably allows new transcription or processing of mRNA for M-CK, or both. ",0
83,457678,Benzoyl-coenzyme A:glycine N-acyltransferase and phenylacetyl-coenzyme A:glycine N-acyltransferase from bovine liver mitochondria. Purification and characterization,"Two closely related acyl-CoA:amino acid N-acyl-transferases were purified to near-homogeneity from preparations of bovine liver mitochondria. Each enzyme consisted of a single polypeptide chain with a molecular weight near 33,000. One transferase was specific for benzoyl-CoA, salicyl-CoA, and certain short straight and branched chain fatty acyl-CoA esters as substrates while the other enzyme specifically used either phenylacetyl-CoA or indoleacetyl-CoA. Acyl-CoA substrates for one transferase inhibited the other. Glycine was the preferred acyl acceptor for both enzymes but either L-asparagine or L-glutamine also served. Peptide products for each transferase were identified by mass spectrometry. Enzymatic cleavage of acyl-CoA was stoichiometric with release of thiol and formation of peptide product. Apparent Km values were low for the preferred acyl-CoA substrates relative to the amino acid acceptors (10(-5) M range compared to greater than 10(-3) M). Both enzymes were inhibited by high nonphysiological concentrations of certain divalent cations (Mg2+, Ni2+, and Zn2+). In contrast to benzoyltransferase, phenylacetyltransferase was sensitive to inhibition by either 10(-4) M 5,5'-dithiobis(2-nitrobenzoate) or 10(-5) M p-chloromercuribenzoate; 10(-4) M phenylacetyl-CoA partially protected phenylacetyltransferase against 5,5'-dithiobis(2-nitrobenzoate) inactivation but 10(-1) M glycine did not. For activity, phenylacetyltransferase required addition of certain monovalent cations (K+, Rb+, Na+, Li+, Cs+, or (NH4)+) to the assay system but benzoyltransferase did not. Preliminary kinetic studies of both transferases were consistent with a sequential reaction mechanism in which the acyl-CoA substrate adds to the enzyme first, glycine adds before CoA leaves, and the peptide product dissociates last. ",0
84,457764,Tight junctions in the choroid plexus epithelium. A freeze-fracture study including complementary replicas,"""The tight junctions of the choroid plexus epithelium of rats were studied by freeze-fracture. In glutaraldehyde-fixed material, the junctions exhibited rows of aligned particles and short bars on P-faces, the E-faces showing grooves bearing relatively many particles. A particulate nature of the junctional strands could be established by using unfixed material. The mean values of junctional strands from the lateral, third, and fourth ventricles of Lewis rats were 7.5 +/- 2.6, 7.4 +/- 2.2, and 7.5 +/- 2.4; and of Sprague-Dawley rats 7.7 +/- 3.4, 7.4 +/- 2.3, and 7.3 +/- 1.6. Examination of complementary replicas (of fixed tissue) showed that discomtinuities are present in the junctional strands: 42.2 +/- 4.6% of the length of measured P-face ridges were discontinuities, and the total amount of complementary particles in E-face grooves constituted 17.8 +/- 4.4% of the total length of the grooves, thus approximately 25% of the junctional strands can be considered to be discontinuous. The average width of the discontinuities, when corrected for complementary particles in E-face grooves, was 7.7 +/- 4.5 nm. In control experiments with a """"tighter"""" tight junction (small intestine), complementary replicas revealed that the junctional fibrils are rather continuous and that the very few particles in E-face grooves mostly filled out discontinuities in the P-face ridges. Approximately 5% of the strands were found to be discontinuous. These data support the notion that the presence of pores in the junctional strands of the choroid plexus epithelium may explain the high transepithelial conductance in a """"leaky"""" epithelium having a high number of junctional strands. However, loss of junctional material during fracturing is also considered as an alternative explanation of the present results. """,0
85,458490,Toxicity of rac-1(3)-palmitoyl glycerol in weanling mice,"Reinvestigation of the previously reported toxicity of saturated fat on weanling mice has shown rac-1(3)-palmitoyl glycerol to be a more potent toxic agent than free palmitic acid when fed as the sole source of dietary fat. As shown before, protection against this toxicity can be afforded by the addition of 2 to 4% safflower oil. We have now shown that if the rac-1(3)-palmitoyl glycerol is acetylated the toxicity is much less. The protective effect of diacetyl rac-1(3)-palmitoyl glycerol cannot be totally ascribed either to the presence of acetate itself or to the blocking of the free hydroxyls of palmitoyl glycerol by acylation. In vivo absorption studies coupled with in vitro experiments with pancreatic lipase suggest that the major protective effects result from increased lipolysis of the acylated palmitoyl glycerol, causing conversion to the less toxic free palmitic acid. ",0
86,459517,Increased incidence of breast carcinoma in patients with irradiation for post-partum mastitis: a screening situation,"In Rochester, New York, 606 women were treated with ionizing radiation for post-partum mastitis, mostly between 1940 and 1955. Two-thirds of all breasts were treated, the average dose per breast being 377 rads (at 2.5 cm breast depth). Mammographic examinations were performed on 265 of these women still residing in this vicinity. Two nonpalpable carcinomas (with no axillary node metastases) were found in the twelve breast lesions that have been biopsied. Some of the biopsies revealed premalignant changes. It is recommended that women in this high-risk category have close medical supervision, as well as periodic mammographic evaluation, and that the importance of periodic breast self-examinations should be emphasized. ",0
87,459532,Effects of phenylephrine on transmural distribution of myocardial blood flow in regions supplied by normal and collateral arteries during cardiopulmonary bypass,"Cardiopulmonary bypass is frequently accompanied by decreased peripheral vascular resistance with resultant hypotension that is unresponsive to increased flow rates. Alpha adrenergic agonists are routinely used to increase peripheral vascular resistance and augment blood pressure. In this study, the effects of the alpha adrenergic stimulant phenylephrine on blood flow distribution during cardiopulmonary bypass in myocardium supplied by normal and collateral arteries were studied in eight mongrel dogs. Microsphere determinations of blood flow were made following augmentation of perfusion pressure with phenylephrine and were compared with intraoperative normotensive and hypotensive control levels. With systemic flow rates held constant, phenylephrine was infused in doses adequate to raise perfusion pressure to normotensive levels following hypotension. In the normal region (NR), blood flow was returned to normotensive control levels with flow favoring the subendocardium. In the region supplied by collateral vessels (CR), however, phenylephrine infusion failed to return flow to the normotensive control level in the subendocardial layer, and the flow imbalance present during hypotension was not corrected. An analogue model of the calculable resistances in the CR is presented, which indicates that phenylephrine increased resistance in the collateral vessels. Associated with this inflow restriction is decreased resistance or vasodilatation of the intramyocardial vessels supplied by collateral coronary arteries. ",0
88,460304,Lack of evidence for cancer due to use of metronidazole,"Experimental studies have shown that metronidazole is carcinogenic in rodents and mutagenic in bacteria. In 771 women given metronidazole for the treatment of vaginal trichomoniasis, more cancers developed than had been expected after exclusion of carcinoma of one uterine cervix (observed, 24 cases; expected on the basis of the Connecticut Tumor Registry, 21.7; expected on the basis of the Third National Cancer Survey, 18.4). However, the excess was not statistically significant (P greater than 0.05). The observed and expected numbers of breast-cancer cases were the same, but four lung-cancer cases were observed, whereas 0.6 would have been expected. This finding is confounded by the fact that all four lung cancers developed in women who were smokers. Overall, we observed no appreciable increase in cases of cancer.",0
89,460323,Use of antimicrobial drugs in general hospitals: patterns of prophylaxis,"The patterns of prophylactic use of antimicrobial drugs were reviewed in 5288 charts drawn by a random method from 20 randomly selected short-stay general hospitals in Pennsylvania. About 10 per cent of hospitalized patients received antimicrobial drugs for prophylaxis in operations or nonsurgical procedures, and prophylaxis accounted for about 30 per cent of all antimicrobial drugs administered in hospitals. The drugs used most often for prophylaxis were cephalosporins, followed by benzyl penicillins, ampicillin and tetracyclines, in that order. Despite indications that prophylaxis, when useful at all, is effective only when given concurrently with and for 24 to 48 hours after operation, it was usually continued throughout hospitalization. Almost 80 per cent of prophylactic antimicrobial drugs were administered at least 48 hours after an operation or procedure -- suggesting that limiting prophylaxis to the first 24 to 48 hours, as currently recommended, would substantially reduce expenditures for antimicrobial drugs in hospitals.",0
90,460363,Effect of intrathoracic pressure on left ventricular performance,"Left ventricular dysfunction is common in respiratory-distress syndrome, asthma and obstructive lung disease. To understand the contribution of intrathoracic pressure to this problem, we studied the effects of Valsalva and M�ller maneuvers on left ventricular function in eight patients. Implantation of intramyocardial markers permitted beat-by-beat measurement of the velocity of fiber shortening (VCF) and left ventricular volume. During the M�ller maneuver, VCF and ejection fraction decreased despite an increase in left ventricular volume and a decline in arterial pressure. In addition, when arterial pressure was corrected for changes in intrapleural pressure during either maneuver it correlated better with left ventricular end-systolic volumes than did uncorrected arterial pressures. These findings suggest that negative intrathoracic pressure affects left ventricular function by increasing left ventricular transmural pressures and thus afterload. We conclude that large intrathoracic-pressure changes, such as those that occur in acute pulmonary disease, can influence cardiac performance.",0
91,460364,Mechanisms of edema formation in myxedema--increased protein extravasation and relatively slow lymphatic drainage,"We assessed extravascular accumulation of albumin and fluid in primary myxedema by measuring metabolic turnover and transcapillary escape of 131I-labeled human albumin in seven patients. In the hypothyroid state, we found a low plasma volume (P less than 0.05), a reduced rate of albumin synthesis and catabolism (P less than 0.01), an increased transcapillary escape rate of albumin (P less than 0.01), a remarkable increase in the extravascular mass of albumin (1500 micronmol; P less than 0.01) and a longer mean transit time through the extravascular spaces in primary myxedema than in other states of generalized edema (P less than 0.05). All variables returned to normal during l-thyroxine treatment. The extravascular accumulation of albumin, and presumably of all other plasma proteins, is important in the generalized edema typically found in myxedema. Inadequate lymphatic drainage may also explain the formation of exudates in the serous cavities that are well known in myxedema.",0
92,471000,The use of in vitro technics to study drug-induced pancytopenia,"The confirmation of drug-induced marrow aplasia is difficult since rechallenging the patient can lead to serious morbidity. We used marrow-culture technics to challenge in vitro the bone marrow of a patient with marrow aplasia after ingestion of quinidine. There was no clinical or laboratory evidence of quinidine-mediated destruction of erythrocytes, leukocytes or platelets. By contrast, use of quinidine in combination with the patient's serum substantially inhibited in vitro growth of allogeneic marrow granulocytic and erythroid series. Furthermore, use of quinidine in combination with acute-phase serum (but not acute-phase serum alone or quinidine in combination with recovery-phase serum) inhibited growth of the patient's marrow. This observation suggests that both a transient serum factor and quinidine were responsible for the marrow aplasia. These technics could be applied with minimal risk to similar patients and would permit in vitro rechallenge with the suspected drug.",0
93,481462,Circulating and urinary catecholamines in pheochromocytoma. Diagnostic and pathophysiologic implications,"Three biochemical tests for the diagnosis of pheochromocytoma were evaluated in 24 patients with proved tumors and 40 patients whose clinical picture was suspect but who had no evidence of the disease. Measurement of resting, supine plasma catecholamines (by radioenzymatic assay) was more useful than either 24-hour urinary vanillylmandelic acid (VMA) or metanephrines or both. In only one of 23 patients with pheochromocytoma were plasma catecholamines within the range of those in patients without pheochromocytoma, as compared with urinary VMA in 11 of 22, urinary metanephrines in five of 22 and both metabolites in three of 22. These studies reaffirm the value of plasma catecholamines in the diagnosis of pheochromocytoma and indicate that urinary catecholamine metabolites are less useful. The poor correlation between the height of arterial pressure and circulating levels of catecholamines suggests that the regulation of arterial pressure in pheochromocytoma is complex.",0
94,481513,Competition in the delivery of medical care,"One approach to reform of the medical-care-delivery system emphasizes the development of constructive competition among providers of health care. In this article we describe competition among providers in Minneapolis-St. Paul, one of the few areas that can provide information concerning the practicality of this type of reform. We have found that competition has helped to reduce hospitalization, contain costs and improve access to medical services. At the same time it has focused attention on consumer satisfaction with medical services, increased the range of consumer choice and given consumers better information about providers. Certain public and private measures could facilitate the development of similar competition in other communities.",0
95,492252,Ventricular fibrillation in the Wolff-Parkinson-White syndrome,"To examine the risk of ventricular fibrillation in patients with the Wolff-Parkinson-White syndrome, we compared patients who had this syndrome and a history of ventricular fibrillation related to preexcitation with patients who had the syndrome without this history. Ventricular fibrillation occurred during atrial fibrillation, with rapid conduction over the accessory pathway, and these patients had a higher prevalence of both reciprocating tachycardia and atrial fibrillation (14 of 25 vs. 18 of 73, P = 0.004) and multiple accessory pathways (five of 25 vs. four of 73, P = 0.012). The shortest preexcitation R-R interval during atrial fibrillation was less in the group with ventricular fibrillation (mean shortest R-R, 180 vs. 240 milliseconds, P less than 0.0001) as was the average R-R interval (mean average R-R, 269 vs 340 milliseconds, P less than 0.0001). Patients with Wolff-Parkinson-White syndrome who are most susceptible to ventricular fibrillation have a history of atrial fibrillation and reciprocating tachycardia, demonstrate rapid conduction over an accessory pathway during atrial fibrillation and have multiple accessory pathways.",0
96,503127,Natural history of male psychologic health: effects of mental health on physical health,"Four decades ago 204 men were selected as adolescents for an interdisciplinary study of health; since then they have been followed biennially. Of the 185 men who remained in the study and in good health until 1964 (age, 42 +/- 1 years), 100 men remained in excellent physical health over the next 11 years, 54 acquired minor problems, and 31 acquired serious chronic illness or died. Of 59 men with the best mental health, assessed from the age of 21 to 46 years, only two became chronically ill or died by the age of 53. Of the 48 men with the worst mental health from the age of 21 to 46, 18 became chronically ill or died. The relation between previous mental health and subsequent physical health remained statistically significant when the effects on health of alcohol, tobacco use, obesity, and longevity of ancestors were excluded by multiple regression analysis. The data suggest that good mental health retards midlife deterioration in physical health.",0
97,569254,Immune thrombocytopenia. Use of a Coombs antiglobulin test to detect IgG and C3 on platelets,"We applied a radiolabeled Coombs antiglobulin test to the diagnosis and management of immune thrombocytopenia in adults and children. This assay substantiated that the majority of patients with idiopathic thrombocytopenic purpura have increased levels of IgG on their platelets. Platelet-associated C3 was elevated in a subset of these patients, some of whom had normal levels oet-associated IgG, thus suggesting a role for C3 in the pathogenesis of the thrombocytopenia. The assay enabled us to anticipate a change in clinical status, establish the presence of immunologic remission after splenectomy and propose several mechanisms by which corticosteroids act. Platelets from a patient with the post-transfusion-purpura syndrome also carried increased IgG, indicating a role for IgG antibody or IgG-containing immune complexes in the destruction of host platelets in this disease. The radiolabeled Coombs test provides a general means to help diagnose, manage and study immune platelet disorders.",0
98,570639,"H-Y antigen mosaicism in the gonad of a 46,XX true hermaphrodite","To clarify the mechanism for the coexistence of ovarian and testicular tissue in the 46,XX true hermaphrodite, we studied a 20-year-old phenotypic male with gynecomastia and elevated serum concentrations of estradiol in whom an ovotestis was discovered upon scrotal exploration. Y chromosomal material could not be detected by fluorescent Y-body analysis or Giemsa-banding technics in cells cultured from peripheral blood, breast or forearm skin or the ovarian or testicular portions of the ovotestis. However, serologic testing, using the sperm cytotoxicity assay, revealed that cells cultured from the testicular portion of the ovotestis were H-Y antigen positive whereas cells cultured from the ovarian portion were H-Y antigen negative. These observations indicate that the ovotestis arises from an H-Y+/H-Y- mosaic primordium.",0
99,581782,Comparison of the immediate effects of five beta-adrenoreceptor-blocking drugs with different ancillary properties in angina pectoris,"We compared the immediate effects of five beta-adrenoreceptor-blocking agents in 16 patients with stable angina pectoris. Acute dose-response studies showed that all five drugs improved exercise tolerance and reduced ST-segment depression, heart rate and blood pressure by a similar degree in comparison with a placebo (P less than 0.01). Near maximum improvement in exercise tolerance occurred when the acute cumulative oral dose had reached 160 mg for propranolol and oxprenolol, 200 mg for metoprolol and tolamolol and 400 mg for practolol. When these drugs were administered as a single doses, increase in walking time before the development of angina and reduction in ST-segment depression, heart rate and systolic blood pressure all occurred within one hour and persisted for eight hours--effects markedly different from the response to a placebo (P less than 0.01). These data show that non-cardioselective agents (propranolol and oxprenolol), cardioselective agents (practolol, metoprolol and tolamolol), as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective in the treatment of angina pectoris.",0
100,582008,The effect of digoxin on endothelaemia in rats and its modification by a combination of troxerutin and coumarin,The effect of digoxin on endothelium was tested with the method based on counting of circulating endothelial cells in rats. Digoxin in low doses had a protective and in high doses a damaging effect on endothelium. The latter effect was effectively suppressed by a concomitant administration of a combination of troxerutin and coumarin (Venalot). ,0
101,582143,Hydroxylation of testosterone and induction of steroid hydroxylases by phenobarbital in genetically obese mice (author's transl)],"In spite of the profound alterations in lipid metabolism in the liver of genetically obese mice (strain C57 BL/6J) the activity of the hepatic hydroxylases with testosterone as substrate does not differ from that of their litter mates of normal weight. However, when the increased liver weight of the obese animals is taken into account their total capacity for steroid hydroxylation exceeds that of their litter mates by a factor of more than 2. Moreover, the inducibility of the membrane-bound enzyme system is not affected: application of phenobarbital (20 or 40 mg/kg body weight twice daily for 4 days) leads to a 2--3fold increase of the activity. ",0
102,582605,"Multiple, prolonged actions of neuroendocrine bag cells on neurons in Aplysia. II. Effects on beating pacemaker and silent neurons","1. A survey of identified cells of the abdominal ganglion of Aplysia was undertaken to determine the extent of bag cell influence in the ganglion. Bursts of bag cell spike activity lasting 5--40 min were elicited by brief, 0.6- to 2 s local stimulation while recording simultaneously from bag cells and other ganglion cells with intracellular electrodes. 2. Slow inhibition occurs in giant cell R2, neurosecretory cells R3-R14, and ink-gland motoneurons, L14A, B, C. The cells remain hyperpolarized for from 15 to 60 min. 3. Transient excitation occurs in mechanoreceptor cells L1 and R1. The cells are strongly depolarized by a slow excitatory potential that lasts for about 10 min and produces spike activity for 3--7 min. 4. Prolonged excitation occurs in some cells of the LB and LC identified cell clusters. The cells are depolarized and spike activity is increased for 3 h or more. 5. A biphasic response occasionally occurs in the command interneuron L10. Inhibition of this cell lasts 10--15 min and is followed by excitation for several hours. Excitation is accompanied by facilitation of synaptic potentials for 40--60 min in cells innervated by L10; the facilitation apparently results from the increase in L10 firing rate. 6. The results indicate that the bag cells have multiple types of actions and affect large numbers of ganglion neurons. All effects have the slowly graded onsets and prolonged durations to be expected of hormonally mediated interactions. 7. Previous studies have indicated that in intact animals the bag cell burst discharge initates a stereotyped egg-laying behavioral pattern that persists for several hours (3, 27). The present data support the hypothesis that certain elements of egg-laying behavior and homeostasis are regulated by a direct action of the bag cells on the central nervous system. ",0
103,582770,Studies on percutaneous absorption of flumetasone pivalate and salicylic acid from a corticoid combination for topical use (author's transl)],"The combination of 0.02% flumetasone pivalate and 1% salicylic acid in a water-alcohol solution (Locasalen) is a novel therapeutic for topical treatment of the hairy scalp and also for the cosmetically acceptable treatment of other skin areas, that is, exposed skin. An investigation was carried out in 6 patients with psoriasis capitis and 6 control subjects in order to determine whether the use of Locasalen Tincture on the hairy scalp leads to percutaneous absorption of the corticosteroid and the salicylic acid. In the patients with psoriasis a few slight transient changes in biochemical-endocrinological parameters were observed, but not in the control subjects. However, these changes remained within the normal, non-pathological range so that they are of no clinical consequence. Percutaneous absorption of salicylic acid was not observed in either patient group. ",0
104,582850,"Neonatal non-ketotic hyperglycinemia: a clinical, biochemical and neuropathological study including electronmicroscopic findings","In a family of four children, three died within 8 days after birth. The fourth child survived after a critical first week with the same symptoms as the siblings. He was at the age of four found to have non-ketotic hyperglycinemia. The histories and neuropathology of the other children were then reexamined. It seems highly probable that all siblings suffered from non-ketotic hyperglycinemia. This report points to the clinical, biochemical and neuropathological diagnostic problems in this disease and also adds new information on the ultrastructural changes, not hitherto visualized. ",0
105,582971,Regional blood flow determination in rats by the microsphere method during i.v. infusion of vasodilating agents,"The present experiments were performed to gain information on changes in various organ flow rates during i.v. infusion of vasodilating substances. The microsphere method with the reference sample technique was used in rats to measure simultaneously different organ flow rates. The detection of the spheres (non-radioactive) was performed by macerating the tissues and counting samples under the microscope. As only one microsphere-infection per animal was performed, an untreated experimental group served as a control. The cardiac output was measured in a separate series. The effects of isoproterenol, pentoxifylline, bencyclane, acetylcholine, and dihydroergotoxine (mixture of 3 compounds, Hydergin) consisted of flow increases in several organs while the flow in others remained nearly unchanged. Only during the action of sodium nitroprusside the flow values were found decreased or remained unchanged. This substance led to decreased cardiac output, whereas that in the other groups was unchanged or raised. The experiments point to quantitatively different reactions on cardiac output distribution during application of the vasodilating substances tested. ",0
106,583285,A critical assessment of the Wilhelmy method in studying lung surfactants,"1. The surface properties of over 250 films of diplamitoyl lecithin (DPL) and Tween 20 on distilled water have been investigated using two different surface balances simultaneously, the Wilhelmy balance, popular in physiological studies, and the Du Nuoy ring method whose readings are independent of contact angle. 2. Using concentrations of DPL ranging from 0.08 to 1.90 microgram cm-2 on a Langmuir trough where the pool area was cycled from 100 to 27.5% of maximum, the Wilhelmy balance registered virtually the same force per wetted perimeter as the ring method for both pure water and Tween 20, but appreciably lower values for DPL over the whole cycle. 3. The above differences can be explained on the basis of a significant (45-70 degrees) contact angle, a surface property also demonstrated photographically and by direct measurement. 4. Contact angle was shown to vary with pool area, a relationship exhibiting hysteresis. 5. This study indicates that the Wilhelmy balance has been an unfortunate choice of instrument for studying DPL films whose surface tensions are appreciably higher than previously estimated. ",0
107,583367,Respiratory insufficiency in surgery],"""Acute respiratory insufficiency (ARI) (reduced PaO2 and/or increased PaCO2) in surgical patients is mostly caused by atelectasis or bronchopneumonia. These complications may develop if functional residual capacity (FRC) is reduced. Even in surgical patients with normal lungs the supine position, some pulmonary disorders after any general anaesthesia, pain, and atonic intestine cause reduced FRC in the postoperative phase. Successful prophylaxis is based on these mechanisms, which are described. The adult respiratory distress syndrome (ARDS, termed """"shock lung"""" a few years ago) is the most dangerous pulmonary complication leading to ARI. The evaluation of clinical data sugggests that noxious factors only active for a short time (so called """"triggers"""") may start the development of ARDS when some physiological conditions (so called """"constellations""""), such as low flow syndrome, reduced FRC and overhydration, pave the way for this. In the early state prognosis is good if the patient is ventilated (CPPV) and kept on the dry side, and if cardiac output is elevated compared to the normal value at rest. Once fully established, ARDS has such a poor prognosis that the need for earliest possible commencement of therapy must be stressed emphatically. The following values may be taken as clear and simple symptoms for early diagnosis: vital capacity below 15 ml/kg (reflects decreased FRC), PaO2 breathing spontaneously room air below 60 mm Hg or 8 kPa (reflects increased intrapulmonary right to left shunt or regional hypoventilation), and respiratory rate above 25/min (reflects loss of compliance). """,0
108,583541,Comparative pharmacokinetics and relative bioavailability for different preparations of nitrofurantoin,"In a single-dose study three different dosage forms of nitrofurantoin tablets are compared in order to attain a longer duration of efficacy by means of sustained-release dosage forms. In particular, bioavailability and the rate constants are estimated and show for one dosage form significant advantages. The measured serum and urine concentration levels are evaluated with a two-compartment model of first order which assumed the sustained release of the drug in an exponential manner. ",0
109,583955,A study of illness referral in a Spanish-speaking community,"In an anthropologic study of illness referral among Latin-American immigrants three phases were ascertained: First, there was extended use of self-treatment. Second, referrals were made to the social network, particularly to people from the same country of origin. Finally, referrals to the professional network were made to professionals with the same cultural heritage. Latin-American immigrant families living in a cooperative were studied over a 14-month period, utilizing the method of participant observation, a family health calendar, and interviews. This report focuses on the results of the family health calendar. Most illnesses reported by families did not go beyond self-treatment. Cultural influences including language, social network, priorities of daily living were related to the alternatives selected by families when illness incidents occurred. ",0
110,588320,Erythrocyte changes (echino- and stomatocytic) in muscular dystrophy: research on possible applications in diagnosis and eugenics],"The Authors, after a brief review of the factors which influence the echino and stomatocytic erythrocyte's deformations and of the biochemical basis of these alterations, report the comparative study of the echino-stomatocytogenesis in both normal subjects and myodystrophic patients. In order to investigate whether this phenomenon is more developed in pathological condition, the results confirm that between normal subjects and myodystrophic patients or healthy carriers there is a quantitative significant difference which can be utilized for diagnostic and eugenic purposes. To obtain reliable results, the evaluation should be made at regular intervals of time from the blood drawing and after the exclusion of the presence of other disease or echino-stomatocytogenetic factors (drugs, etc.). ",0
111,588322,Food consumption in a community of the Parma district (Langhirano). Clinico-metabolic considerations],"""Referring to the results of a """"pilot"""" nutritional investigation carried out in a representative mixed sample of a small community of Parma district (Langhirano), the AA. underline the clinical and metabolic implications resulting from the not quite correct nutritional behaviour observed. In fact, in agreement with the national average data reported for italian population from ISTAT, caloric excess, particularly of dietary fat and proteins, was confirmed in this community too. Nevertheless, want of vitamins (D, B1, B2), and minerals (Ca) was paradoxically found. Considering in detail the results some immediate clinical and metabolic consequences come out: namely, want of Ca is prevailing in women and just in the critical age classes (20-40 and 50-59 years, that is in fertile and climacteric ages). When the recommended intake levels are higher. Ferthermore in male-populations, in the class aged 30-50 (that is more vulnerable as to atherosclerosis), was found the highest caloric intake besides in fat and particularly in cholesterol, as to the recommended safety levels. The A.A. conclude pointing out the importance and the necessity of a nutritional notions wide spreading, involving the various responsible public health and social politic organisation of the Country. """,0
112,592681,Arteriovenous haemofiltration: a new and simple method for treatment of over-hydrated patients resistant to diuretics],"Fluid withdrawal in over-hydrated patients resistant to diuretics was obtained by means of a capillary haemofilter, using the arterio-venous pressure gradient for blood perfusion at a rate of 100 ml/min. The ultrafiltration rate was 200-600 ml/h and could be maintained as long as 48 h without changing the haemofilter. This method, which needs no technical investment, is easy and simple to handle for the physician, bears only a very low risk for the patient, and ensures a negative fluid balance even at a mean blood pressure of only 60 mm Hg. ",0
113,593278,Early diagnosis of severe brain damage of premature and newborn infants under intensive care. A polygraphic study (author's transl)],"24 premature and newborn infants under intensive care (intubation and artificial respiration) were subjected to a polygraphic examination in order to diagnose severe brain damage already in the acute stage of a disease. The results collected in the polygraphic recording were correlated to the further development and progress of the infant. Nine infants die within one week--all of these underwent a post-Mortem examination. Diagnosis of brain damage was confirmed by post-mortem examination or by a clinical neurological follow-up examination. All infants with severe brain damage showed pathological polygraphic recordings. In contrast to this, clinical neurological examination at the time of the polygraphic recording did not reveal such pathological results in all of these infants. Important was the EEG, supplemented by determining the bioelectric brain maturation, the differentiation of sleep states and the correlation of these derived parameter to the behavior pattern of the infant. The heart rate frequency and variability could not be used to make an useful diagnostic statement. ",0
114,594301,Localised nodular myositis: a clinical and pathological variant of polymyositis,"""Three cases of a painful, inflammatory, nodular myopathy in young and middle-aged adult males are described. In two of the cases the nodular process gradually evolved into a diffuse proximal myopathy accompanied by dysphagia, and manifesting the so-called """"facioscapulohumeral syndrome"""". The electromyogram (EMG) in all three cases was """"myopathic"""" in type and in two cases abnormalities consistent with an inflammatory muscle disorder were seen. Muscle biopsy revealed a consistent pattern of intense, predominantly interstitial, pleomorphic infiltration of muscle with scattered foci of muscle fibre destruction and regeneration, which resembled muscle infarcts. It is suggested that this syndrome, whilst readily recognizable from both the clinical and pathological standpoints, is not a nosological entity in its own right but rather an unusual presentation of polymyositis. """,0
115,594379,Termination of early gestation with a vaginal polysiloxane device impregnated with (15S)-15 methyl prostaglandin F2alpha methylester,"An investigation of the abortifacient activity of (15S)-15 methyl prostaglandin F2alpha methyl ester released from a vaginal polysiloxane device was performed in eleven pregnant women of 49 days gestation or less. Bleeding and contractions were induced in all women, but only seven aborted their pregnancies. Five subjects received a vaginal device impregnated with 3 mg of drug and two aborted fetal tissue. Six women were given a vaginal device containing 5 mg of drug and five aborted fetal tissue. Ten of the patients had significant side effects, nausea, emesis, diarrhea and chills. Six women expelled the device prior to the termination of therapy. This prostaglandin analogue, when administered from a vaginal polysiloxane device in early gestation was an effective abortifacient but was accompanied by systemic side effects and a high incidence of expulsion of the device prior to its scheduled removal. ",0
116,594638,Adenine metabolism in man. 1. After intravenous and peroral administration,"The basal plasma concentration of adenine and its renal excretion was studied in two men. For its analysis partly new chromatographic techniques were developed. The plasma concentration varied around 70 nmol/l; the renal excretion rate was, as reported earlier by other investigators, around 10 nmol/min. Loadings, intravenously during about 3 h and orally, both with about 30 nmol adenine per kg body mass revealed that most of the adenine was metabolized to nucleotide form. In the experiments with intravenous administration of adenine only about 2% of the given dose appeared in the urine as adenine and somewhat less as the easily precipitable metabolite 2,8-dihydroxyadenine. In the peroral loads, with higher plasma adenine concentrations, the ratios of the renally excreted two compounds were one to a few per cent higher. ",0
117,595133,Kajal eye staining for early detection of vitamin A deficiency in the field,"""Staining of the eyes with carbon black (""""kajal"""") was tried out in 500 children, age 1--15 years, partly urban and partly rural, in Jaisalmer District. Of the eyes of 280 rural boys 21.4% took the stain, of 50 girls 16.0%. In the urban groups the figures were 5.7% of 88 and 9.7% of 82, respectively. These figures conincided nearly wholly with the cases diagnosed X1A (conjunctival xerosis) or X1B (conjunctival xerosis with Bitot's spots) clinically. All Bitot's spots were stained black; in addition also 2.6% of cases diagnosed X1A. Eight cases presenting only nightblindness also stained. Since kajal application is harmless, cheap, and acceptable to Indian custom it is proposed as a diagnostic procedure suitable for the general duty doctor and paramedical staff in the field. """,0
118,595501,Effect of Ca2+ ions on the pyruvate kinase isoenzymes from rabbit kidney cortex],"""Ca2 ions showed the various effect on isoenzymes of pyruvate kinase from rabbit kidney cortex. Ca2 activated the """"L"""" type of pyruvate kinase at low concentrations of PEP and inhibited -- at high concentrations of the latter. """"M2"""" type of pyruvate kinase was inhibited by Ca2 under all the conditions studied. In presence of Ca2+ the activating effect of PDP on """"L"""" and """"M2"""" types of pyruvate kinase was absent; the inhibitory action of ATP on the """"M"""" type of pyruvate kinase was increased at all the concentrations above 1.3 mM. The effect of Ca2+ on the pyruvate kinase isoenzymes depended on content of Mg2+ in the medium. """,0
119,595881,Effect of precursors and cofactors of nucleic acid and protein synthesis on the response of cortical neurons induced by polarization],"Injection of K-orotate and folic acid in different proportions and of vitamine B12 produces changes in the S35-methionine inclusion in the proteins of the sensorimotor cortex, basal ganglia, hypothalamus and hippocampus depending on the proportions of the injected agents. In animals with activation of the synthesis in the brain, surface anode polarization increased the mean frequency of spike activity of the neurones in the sensorimotor cortex and reduced the relative number of units, which responded to polarization by inhibition, as compared with the control animals and those in which no activation of protein synthesis was observed. The characteristics of cortical unit responses to surface anode polarization in experimental rats are apparently due to changes in the chemoreactive properties of their membranes, which set in under the influence of changes in the nucleic acid and protein synthesis in these neurones. ",0
120,595938,Experiences with a biological adhesive system (fibrin) in the dressing of kidney parenchymal wounds (animal experiment and 1st clinical experiences)],We report on investigations describing the use of a biological adhesive system for tissue adhesion and local haemostasis. This system consists of highly concentrated native fibrinogen and thrombin. Clotting factor XIII is admitted for reinforcement of the fibrin network. In experimental partial kidney resection this system was used with excellent results. This experience led to successful application of this method in 15 patients who underwent partial nephrectomy for various diseases. ,0
121,596302,Human cathepsin D,"Cathepsin D was purified from human liver by a procedure involving autolysis, acetone fractionation, and chromatography on ion-exchange media and organomercurial-sepharose. Multiple forms of the enzyme were then separated by preparative isoelectric focusing. The molecular weight of the protein was found to be 43,000. Its amino acid composition was determined and it was shown to be a glycoprotein. When treated with sodium dodecyl sulphate or chaotropic agents (without reduction) all forms of the enzyme tested gave components of about 28,000 and 14,000 molecular weight. Specific antisera were raised against the enzyme, and the characteristics of immunoinhibition were investigated. Immuno-inhibition of rabbit cathepsin D within living macrophages was shown to interfere with degradation of some proteins endocytosed by the cells. The antisera against human and rabbit cathepsin D were used in immunofluorescent localization of the enzyme in sites of tissue damage in which cathepsin D might be implicated. The characteristics of inhibition of human cathepsin D by pepstatin were established. At pH values below 5, KD values of 5 x 10(-10)M were determined and pepstatin was shown to be an excellent titrant for cathepsin D. In the range pH 5-6.4 DK increased steeply and it was concluded that the binding site for substrate and inhibitor was abolished by a conformational change in the enzyme molecule in which three protons are lost. ",0
122,596467,Alterations of postural and Valsalva responses in coronary heart disease,"Patients in congestive heart failure are known to have altered autonomic responses to circulatory stress. In this study, two different age groups of male coronary heart disease (CHD) patients, not in failure, as well as normal male subjects, underwent standard 20-min 70 degrees head-up tilt and Valsalva tests. Responses were monitored by noninvasive methods and cardiac output was estamated with a transthoracic impedance method. During tilt, the CHD patients and control subjects had similar heart rate and diastolic pressure responses. However, the CHD patients had a greater decline in pulse pressure during tilt, mainly due to a decrease in systolic pressure. CHD patients had lesser declines in stroke volume and cardiac index and lesser increases in total vascular resistance than did control subjects. In the Valsalva, the heart rate phase increments (and decrements) from control and rate increments (and decrements) between successive phases were less in the coronary patients. The results indicate that coronary patients, not in failure, have diminished circulatory responses to the tilt and Valsalva maneuver and suggest that these tests may be useful functional indices of cardiovascular capability in coronary disease. ",0
123,596785,"Lingual thyroid: review, case reports, and therapeutic guidelines","The literature on lingual thyroid is reviewed. The incidence is relatively rare and sex incidence is four or five to one in favor of females. The embryology and development of the thyroid gland is discussed and some evidence presented to suggest that the lateral thyroid primordia are not involved in the formation of functional thyroid tissue. The pathologic findings of lingual thyroid tissue are similar to that of cervical thyroid tissue, including goiter formation. Diagnostic measures include mirror examination, I-125 scan, and tomography. Thyroid function studies are helpful in evaluating the level of thyroid function. Treatment includes surgical removal, transplantation, I-131, and thyroid replacement. Since the first three methods usually require supplemental thyroid treatment afterward, it is believed that initial thyroid replacement is the treatment of choice since it is simple, safe, effective, and noninvasive. Four new cases are reported. ",0
124,597239,Synthesis of procollagen by matrix-free cells from embryonic-chick arteries,"Cells were isolated from the major arteries of 17-day chick embryos by digestion of the tissue with collagenase and trypsin. The cells, when examined immediately after isolation, exhibited a high degree of viability and they were shown to synthesize and secrete procollagen at a high and constant rate for several hours when incubated in suspension in modified Krebs medium. Continuous labelling of the cells with [(14)C]proline demonstrated a lag of about 30min between the time at which the synthesis of non-diffusible peptide-bound hydroxy[(14)C]proline became linear and the time at which its secretion into the medium became linear. This lag time compares with that of 18min observed for freshly isolated matrix-free cells from embryonic-chick tendon, which synthesize and secrete the same type of collagen. Gel-filtration chromatography and polyacrylamide-gel electrophoresis indicated that the collagenous polypeptides secreted into the medium were in the precursor form, known as procollagen, and that the constituent pro-alpha-chains were linked by interchain disulphide bonds and were also in a triple-helical conformation. Characterization of the secreted procollagen by gel-filtration chromatography, polyacrylamide-gel electrophoresis, DEAE-agarose chromatography, and polyacrylamide-gel electrophoresis of peptides obtained by CNBr cleavage, indicated that the predominant form was type-I procollagen. This work extends the range of freshly isolated matrix-free cell systems, which have been characterized for use in studies on the biosynthesis and secretion of procollagen, and it indicates differences in the rates of secretion of procollagen in different cell types secreting the same type of procollagen. ",0
125,597861,Differential control of the synthesis of two hemoglobin beta chains in normal mice,"""A fetal-to-adult switch in the proportion of the mouse minor hemoglobin is described. Although mice have no fetal hemoglobin per se, the timing of this switch in the mouse suggests that the mechanism of its control may directly parallel that of the human switch from fetal to adult hemoglobin expression. The mouse minor hemoglobin is expressed only in strains with the """"diffuse"""" allele for the beta chain complex locus. Fetal liver cells of these mice synthesize a much greater proportion of the betaminor globin chain that do adult hematopoietic cells. Consequently, circulating fetal erythrocytes carry a high level of the minor hemoglobin containing it. By the time of birth, a lowered proportion of betaminor is synthesized in the liver. This low proportion continues to be expressed during early erythroid maturation in the adult. The fetal-to-adult switch is the first indication that in normal mice, the two beta chain loci can be expressed noncoordinately. The similarity between the patterns of the decline of the minor hemoglobin in mice and of the disappearance of fetal hemoglobin in humans suggests that the minor hemoglobin in the """"diffuse"""" mouse may function to some degree as a fetal hemoglobin in the period between the disappearance of the embryonic hemoglobins and the time of birth. """,0
126,598463,"Experimental investigations on increased resistance to infections with Candida albicans and Staphylococcus aureus Smith by 4-imino-1,4-diazobicyclo-(3.1.0)-hexane-2-on BM 06.002 (prop. INN imexon) in mice","BM 06.002 increases the resistance of mice to experimentally induced chronic infection with Candida albicans. Furthermore, BM 06.002 leads to increased resistance in the case of experimentally induced infection with Staphylococcus aureus Smith, when a subtherapeutic dose of sulfadiazine is applied. In mice immunosuppressively pretreated with hydrocortisone, BM 06.002 effectuates immunorestauration. ",0
127,598771,Reduction of nitro-BT by various chloroform-methanol fractions obtained from the grey matter of the rat brain,"Histochemical studies have shown, that nerve fibers can not be visualised in the grey matter of the brain by the reduction of Nitro-BT, if prior to incubation an extraction with chloroform-methanol of the brain slices was performed. According with this finding the grey matter of the rat brain was homogenized and extracted with chloroform-methanol. After centrifugation the obtained supernatant was three times evaporated. Each time before evaporation the supernatant was dissolved in chloroform-methanol solution v/v 2:1. The substance obtained was of teer-like consistency and brown colour. The substance was weight and used for further experiments. Similar extraction was done with phosphate buffer. It was found, that the phosphate buffer does not extract the searched for substance. The comparison of the extinction curves of various fractions has shown that the highest concentration of the substance which reduces Nitro-BT can be found in that fraction which was three times washed with chloroform-methanol. The same concentration was observed in the water fraction which was the result of purification with hexanmethanol. From our investigations it may be concluded that the substance which reduces Nitro-BT in tissue is bound with lipids and purified form lipids passes into water. ",0
128,599603,Amino acid incorporation into total protein and levels of S-100 protein in discrete rat brain areas after prolonged protein or amino acid restriction,"Young adult rats were fed an isocaloric diet for 28 days. The diet consisted of either 22% casein, or protein-restricted food consisting of a 5% mixture of soy and whey protein, or a synthetic amino acid mixed diet devoid of the essential amino acids tryptophan, valine, lysine, and threonine. The level of the nervous tissue-specific S-100 protein was quantified immunoelectrophoretically in 9 different brain areas. A marked decrease of S-100 was observed in hippocampus and posterior part of the cerebellar vermis per g wet weight in protein-restricted rats. An additional lowering was noticed in sensory motor cortex per mg soluble protein. This effect was potentiated with the amino acid-deficient diet. The in vitro incorporation of 3H-leucine into cerebellar proteins was slightly decreased in the low-protein-fed rats, and more markedly decreased in those receiving an amino acid-restricted diet. ",0
129,599740,The mechanism of Ca2+ action on the healing-over process in mammalian cardiac muscles: a kinetic analysis,"The effect of Ca2+ concentration and temperature on the recovery of membrane potential after investigating lesions using sucrose-gap technique in the guinea-pig papillary muscles were studied. At certain temperatures, this recovery showed increased accerelation with increasing Ca2+ concentration. The relation between rate constant of the recovery and Ca2+ concentration was quite similar to that of the reaction between an enzyme and substrate. This relationship could be expressed by the equation Y = xn(Km + xn), where Y is the normalized rate constant and x the Ca2+ concentration. The coefficient, n, was evaluated by performing Hill's plot. The value of n largely changed between 1 and ca. 2 at 32 degrees C--37 degrees C. The input resistance fell at the instant of formation of a lesion and started to rise with recovery of membrane potential. The resistance change after lesion formation was also observed in the potassium-Tyrode's solution in which Na+ was substituted with K+. The concentration-rate relationship of Ca2+ in the healing-over seems to indicate that Ca2+ binds to some molecules in the junctional membrane and produce a structural change of intercalated disc which brings about the healing-over. The large change of n suggests that Ca2+ has a cooperative action in the healing-over process, or alternatively that the state of membrane lipids has some effect on the process. ",0
130,600464,Study of changes in certain immunoglobulin fractions in acute and chronic hepatopathies treated with alpha-mercaptopropionylglycine],"15 patients have been treated with alpha-MPG (Thiola) by the intramuscular route and by venous infusion at doses varying from 500 mg to 1000 mg i.v. and from 100 mg to 200 mg i.m. for a treatment period of from 20 to 40 days. In a number of cases parenteral therapy was followed by oral therapy depending on the degree of liver insufficiency and the therapeutic response of the drug. In all cases, the drug proved to possess antitoxic and liver protector effectiveness and was without side effects gastroenterically and generally, even when administered at high doses for long periods. The results obtained are summarised in tables and data regarding patients at admission and discharge noted. ",0
131,601520,Nitroblue tetrazolium test in bacterial and viral infections,"The reduction of nitroblue tetrazolium (NBT) dye by neutrophils from 379 patients with infectious diseases and 268 controls has been examined. The mean NBT score was 29.8% (72.3% positive tests) in the 231 patients with non-tuberculous bacterial infections, 9.7% (28.1% positive tests) in the 135 patients with viral infections 5.3% (1.5% positive tests) in the controls. Positive tests were demonstrated in 1 of 7 patients with tuberculosis and in 4 of 6 with mycoplasma pneumonia. Patients with urinary tract infections or septicemia had the highest percentage of positive tests, particularly when the infections were caused by gram-negative bacteria. In acute bacterial infection, the 176 patients who had not received any antibacterial therapy prior to testing had a significantly higher mean NBT score and proportion (77.8%) of positive tests than the remaining 55 pretreated patients (54.5%). Recent antibiotic treatment seriously invalidates the NBT test results. In acute viral infection, 29 of the 38 positive tests were obtained from patients with acute hepatitis (mean score 20.0%) or infectious mononucleosis (mean score 9.3%). When evaluating the test results, special attention should be paid to patients with hepatitis. Endotoxin stimulated NBT tests disclosed normal enhancement of NBT reduction by neutrophils from the patients and the controls. Cautiously interpreted, the NBT reduction by neutrophils from the patients and the controls. Cautiously interpreted, the NBT test results may be useful as an adjunct in the differential diagnosis of major bacterial and viral infections. ",0
132,602105,Methandrostenolone residues in the tissues and biological fluids of agricultural animals stimulated by the preparation],"Residual amounts of hormonal-active substances were isolated from the tissues of farm animals stimulated with metandrostenolone-3H. The process of isolation included extraction with a mixture of polar solvents, hydrolysis, adsorption and partition column chromatography, thin-layer and paper chromatography, with radio-isotope, fluorometric, spectrophotometric and densitometric methods employed for identification. Results subsequent to determination of residual amounts of the compound are reported. ",0
133,602873,Effect of histidine on morphine-induced changes in brain histamine,"Chronic morphine administration to rats resulted in a significant decrease in the hypothalamic and cerebro-cortical histamine concentrations. These low histamine values were restored to control levels when L-histidine was administered daily along with morphine treatment. Chronic treatment with L-histidine prevented the midbrain and cerebro-cortical histamine depletion in morphine-withdrawn rats, whereas in the hypothalamus the histamine level remained significantly decreased. The present data suggests that histamine may play a role in morphine dependence and withdrawal. ",0
134,603217,Intensive physical therapy after fractures of the femoral shaft,"22 patients with fractures of the femoral shaft were divided into 2 groups. One group (12 patients) were given the standard postoperative physiotherapy and the remainder (10 patients) received intensive physiotherapy. Clinical examination of the knee joint was performed 2, 4 and 9 weeks postoperatively. The patients' mean age was 31 years; 15 of them were men. The fractures in 18 patients were treated with intramedullary nailing, 2 with a long-shanked Jewett nail and 2 with AO-nailing. Mobilisation and quadriceps atrophy of the injured limb of the patients given intensive physiotherapy appeared to improve faster than in the patients of the routine physiotherapy group. Nine weeks after  the operation the range of knee movement had normalised in the cases given intensive physiotherapy. The flexion strength of the knee in the operated limb was close to the values for the normal limb after nine weeks, but the extension strength was still 40-66% below the values for the healthy limb. The greatest increase in muscle power occurred during the first four postoperative weeks. Intensive physiotherapy seems to hasten the recovery of quadriceps strength of the patients with fractures of the femoral shaft, and to shorten the duration of sick leave of the patients operated on by closed intramedullary nailing. ",0
135,603456,Isolation of toxic metabolites of Phomopsis leptostromiformis responsible for lupinosis,Two metabolites of P. leptostromiformis (phomopsins A and B) have been isolated as a crystalline mixture from a culture of the fungus on lupin seed. The mixture has been shown to be capable of inducing lupinosis in sheep and in young rats. Key steps in the isolation were the transfer of the phomopsins from crude aqueous solution to tetrahydrofuran and chromatography on macroreticular polystyrene resin. The bioassays used in monitoring fractions were based on inhibition of cell cultures and the mitosis-arresting effect of the metabolites on liver cells in vivo. ,0
136,603740,Type and frequency of cardiac defects in embryofetal alcohol syndrome. Report of 16 cases,"Within a period of 3 years, 56 infants and children with embryofetal alcohol syndrome have been detected and examined for heart defects. All children were from mothers who had been addicted to alcohol even during pregnancy and they showed a typical pattern of malformations, as described by Lemoine et al. (1968) and Jones et al. (1973). In 16 cases cardiovascular malformations were confirmed by heart catheterisation or pathological examination. The overall incidence of heart defects in this syndrome was 29 per cent. The incidence rises to nearly 50 per cent in the more severe types of this syndrome. Atrial septal defects were found to be the most common heart defect (10 out of 16 cases); ventricular septal defects and other variable malformations occurred less frequently. The high incidence of heart defects indicates that alcoholism during pregnancy has to be considered as a serious and preventable cause of congenital heart disease. ",0
137,603797,Maternal-fetal relationships in corticosteroid metabolism,"Corticosterone in fetal mouse tissues after injection of mothers with 14C-corticosterone was determined by acetylation with 3H-acetic anhydride and cocrystallization to constant specific activity. The corticosterone content of whole fetal tissue varied between gestational days 13 and 17 from 641 to 300 ng/g. Specific activity of fetal hormone remained essentially constant; after a 15-min pulse this was as much as one-quarter that of maternal hormone. Placenta, head and liver showed distinctly different patterns which changed during this time, with a decrease in conversion of corticosterone to 11-dehydrocorticosterone. A sharp increase occurred in the activity of fetal liver 11beta-hydroxysteroid:NADP oxidoreductase activity. This mitochondrial enzyme, pH optimum 6, KM = 33 micrometer, reduced the metabolite, raising the relative amount of corticosterone in the fetus from 16 to 91%. 1 day after removal of maternal adrenals both maternal and fetal corticosterone were normal, indicating ability of fetal adrenals to function. Maternal corticosterone, however, crossed the placenta readily and it is considered likely that, normally, the maternal hormone predominates. Regardless of origin, corticosterone is maintained by enzymatic conversion in a distinct manner in different tissues. ",0
138,605195,A preventative approach to emotional illness in psychiatric residents,"""Emotional illness in psychiatric residents and its relationship to psychiatric postgraduate training is examined. First, the pertinent literature is reviewed. Psychological and social factors which predispose, precipitate, and perpetuate these emotional disturbances are discussed. The significance of emotional illness in psychiatric residents to the teaching and learning of psychiatry and to the psychiatric profession is clarified. Second, the currently unresolved dilemma of the psychiatric resident """"Teach or Treat?"""" is presented. It is the author's contention that by redefining """"treatment"""" in terms of the goals and philosophy of public health this dilemma can be resolved to the satisfaction of resident, faculty, and the psychiatric profession. """,0
139,605293,Increased survival from acute Salmonella gallinarum infection in chicks given diets with high levels of some forms of iron,Amounts exceeding 100 ppm of extra dietary iron as the ferric salts of ethylenediaminetetra-acetic acid (FeE) or nitrilotri-acetic acid (FeN) produced highly significant increases in survival among chicks infected with 10(6.4) living Salmonella gallinarum strain 9. Additional dietary iron (400 ppm) as the sulphate or chloride salts (or as ferric fructose) lacked activity comparable with FeE or FeN except when 0.2 per cent of NaE was also present in the diet. FeE iron (600 ppm) also diminished the severity of several of the pathological reactions which occur in chicks during the acute stage of experimental fowl typhoid. The enhanced survival and decreased severity of the pathological changes in infected chicks were associated with large reductions in the numbers of viable salmonellae in the spleen at the height of the acute infection. ,0
140,605380,Segregation studies in CHO hybrid cells: I. Spontaneous and mutagen-induced segregation events of two recessive drug-resistant loci,"The process of segreation or phenotypic expression of two recessive drug-resistant loci from heterozygous Chinese hamster ovary hybrid lines is examined. The spontaneous segregation rates of phytohaemagglutinin resistance (Phar) and a temperature-dependent 8-azaguanine-resistant locus (Azarts) from heterozygous quasitetraploid lines using Luria-Delbruck fluctuation analysis were 5 X 10(-5) and 10(-5) events/cell/generation, respectively. In quasihexaploid lines, the latter rates increased 40- and 200-fold, respectively, and were dependent on the number of presumptive drug-sensitive allelel. The mutagens EMS, MNNG, ICR-170, ICR-191, and gamma rays significantly increased the frequency of segregation events. The mutagen-induced frequency of dominant mutations to ouabain (Ouar) and alpha-amanitin (Amar) rsistance in the same hybrid line was much lower in comparison to segregation events and was mutagen specific. The chromosome number per metaphase cell was more variable than DNA content in quasitetraploid lines. These properties of marker segregation are consistent with mechanisms of either restricted chromosome loss, rearrangement, or mutation. ",0
141,605387,Mutants of Chinese hamster ovary cells with altered glucose-6-phosphate dehydrogenase activity,"Two mutant clones of a Chinese hamster ovary cell line deficient in glucose-6-phosphate dehydrogenase (G6PD) activity have been characterized. In each case, there is evidence that a structural gene mutation has taken place. The first mutant produces 11% specific enzyme activity compared to wild-type parental cells, but this residual activity is much more heat sensitive than that of the wild type. The second mutant contains no residual activity, but a revertant was isolated that exhibits a partial restoration of G6PD activity with, again, an increased heat sensitivity. The selection of G6PD+ cells from G6PD- populations can be effected by exploiting the increased sensitivity of the latter to diamide, a compound that depletes the cell of reduced glutathione. ",0
142,606038,The embryology of cysts and fistulae of the neck (author's transl)],"""The term """"branchial"""" should not lead to errors of interpretation and of classification. The essential points of normal embryology and comparative anatomy are reviewed: the special nature of the first entobranchial or spiracular pouch, the important role played in correlation by the second pouch, the general course of the two parts, external and internal, of the branchial apparatus and, finally, with regard to the latter, the problems posed by the development of lymphoid tissue in this region. The thyroglossal duct, although distinct from the branchial apparatus, remains in close relationship with it, in particular in the region of the hyoid where median cysts do not have an exclusively, thyroid origin. Amongst the lateral fistulae and cysts, the different types of which are described in relation to the tissue of their origin, the distinction must be drawn between two main types: those derived from the second pair of branchial pouches and those derived from the third entobranchial pouch only. It should be possible to recognise them on the basis of the characteristics described before operation, the latter being different in the two cases. """,0
143,606199,Cytologic evaluation of the hormonal state in female with breast tumours (author's transl)],"Physiologic changes, growth, differentiation, and involution of the female breast are closely connected to the endocrine activity of the ovary. We examined the relationship of progesteron and oestrogen in 69 women with tumours of the breast. Histology revealed benign tumours in 18 and malignant tumours in 51 patients. Both groups showed distinct alterations in hormonal cytology of the vaginal smear. Statistical evaluation of the findings gives hints of a hormonal imbalance. There is a relative increase of oestrogenic activity and a lack or a decrease of gestagenic activity in women before menopausis. In postmenopausal and old women, neoplasms of the breast are accompanied by signs of proliferative activity as shown by the laboratory data. ",0
144,607804,"Management and outcome of pregnancy in diabetes mellitus, classes B to R","During the period 1971 to 1975, 260 women with diabetes mellitus, Classes B through R, were delivered of their infants at Los Angeles County Women's Hospital. The plan of patient management included frequent clinic visits and hospitalization to assure good control. A program of intensive antepartum fetal surveillance was begun at 34 weeks' gestation, with the use of daily 24 hour urinary estriol determinations and a weekly contraction stress test (CST). A lecithin/sphingomyelin ratio was evaluated for all patients before elective delivery. The perinatal mortality rate in these diabetic pregnant women was 46 per 1,000 as compared to 24 per 1,000 in the general population. Only three stillbirths occurred in the diabetic group, none within one week of a negative CST. Congenital malformations were responsible for almost half of the neonatal deaths. There were no deaths due to iatrogenic prematurity or trauma. Mean gestational age at delivery was 37.9 weeks and vaginal delivery was the mode for approximately half of the women. Two thirds of the infants did experience some morbidity. ",0
145,607982,"A light microscopical study of healing incised dermal wounds in rats, with special reference to eosinophil leucocytes and to the collagenous fibres of the periwound areas","Incised wounding of rat skin had a significant effect on the number of eosinophils both within the scar and in the adjacent areas. The numbers increased, after the inflammatory phase, to a peak between the 7th and 12th-14th days after wounding and remained elevated for the rest of the 30-day experimental period. In the areas contiguous to wounds, the dense bundles of collagenous fibres characteristic of normal dermis became progressively more dispersed from the 3rd to the 14th day, and then gradually re-aggregated into bundles. The fact that eosinophils, which are known to be collagenolytic, increase in numbers and change in morphology at the same time as newly formed scar collagen is remodelled and fibres around wounds are aggregated indicates a role for these cells in connective tissue metabolism. It is suggested that the dispersion of the collagenous fibres in the areas around wounds which occurs before the rise in eosinophil numbers could be related to the known increase in sulphated glycosaminoglycans around incised wounds. ",0
146,608505,Cell mediated immunity to Corynebacterium parvum and its role in tumor control,"The injection of C. parvum provokes a transient cell-mediated immune response to its own bacterial antigens. During this period a subcutaneous challenge dose results in the appearance of a characteristic delayed type hypersensitivity (DTH) skin reaction. If a suspension of syngeneic tumor cells is included in this challenge, they are destroyed in immune but not control animals. Similarly, solid tumors of limited size can be made to regress under these conditions. Adoptive transfer studies revealed that, in keeping with other DTH reactions, this effect was mediated by a population of rapidly dividing, theta-bearing lymphocytes. The ramifications of this response with respect to antitumor therapy are discussed. ",0
147,608513,A comparison of the antitumour activities of glucans and C. parvum,"After i.v. injection of glucans (yeast cell walls, lentinan and pseudonigeran) into CBA mice, the peritoneal macrophages became cytostatic to R1 leukemia cells in vitro, and the mice showed resistance to lung nodule formation by i.v. injected T3 fibrosarcoma cells. The glucans were less active than C. parvum. None of the glucans reproducibly acted as an adjuvant when mixed with irradiated tumour cells; nor did they inhibit the growth of a subcutaneous tumour when injected i.v. or directly into the tumour. ",0
148,608539,In vitro and in vivo effects of Corynebacterium parvum on lymphocyte transformation,"Using a range of doses the effect of C. parvum on the in vitro response of lymphocytes to PHA was studied. C. parvum was not found to be mitogenic itself when added to unfractioned lymphocyte cultures from normal donors and patients with breast cancer, nor did it effect the response to PHA in these cultures except at the highest dose (20 microgram/100,000 cells) when it was inhibitory. 21 patients with breast cancer treated with C. parvum were assessed by their in vitro response to PHA prior to, during and on completion of treatment. We were unable to show consistent changes in PHA response following treatment with C. parvum; 9 patients having shown a fall, 4 having shown an increase and 8 remaining unchanged in their PHA response. ",0
149,619236,Are paranoid schizophrenics biologically different from other schizophrenics?,"Two studies were undertaken to verify the presence of lowered platelet monoamine oxidase activity in chronic schizophrenia. In the first study, a retrospective chart analysis, the mean platelet activity of patients with chronic schizophrenia (7.73+/-0.64 nmol of benzylaldehyde product per 10(8) platelets per hour [S.E.M.]) differed significantly from that of normal controls (12.13+/-0.2, P less than 0.001). Chronic paranoid schizophrenics (4.81+/-0.46) differed significantly from chronic nonparanoid schizophrenics (8.6+/-0.75, P less than 0.03). A separate prospective study confirmed significantly lower values for monoamine oxidase activity in chronic schizophrenic patients diagnosed as paranoid (5.97+/-1.17) or as having secondary paranoid features (6.28+/-0.71) as compared to chronic nonparanoid schizophrenics (9.81+/-0.87, P less than 0.001). Chronic paranoid schizophrenia may be a separate disorder from the other chronic forms of schizophrenia, and this difference may be related, at least in part, to biochemical characteristics.",0
150,619239,Familial azotemia. Impaired urea excretion despite normal renal function,"We performed detailed studies of renal function in two of five related patients with normal serum creatinine levels to determine the mechanism of their chronic azotemia. Inulin and para-amino-hippurate clearances, maximum tubular transport of para-aminohippurate, and renal acidification were within normal limits. In addition, renal concentrating and diluting abilities of these patients were similar to those of four normal controls. Urea clearances of both patients during maximum water diuresis (27.6 and 40.8 ml per minute per 1.73 m2) and antidiuresis (5.3 and 4.0), however, were much lower than mean (+/- S.E.M.) values in the normal controls (70.4 +/- 3.7 and 30.0 +/- 3.42 ml per minute per 1.73 m2, respectively). Thus decreased urea excretion despite otherwise normal renal function was responsible for the chronic azotemia of these patients. The genetic defect in renal urea clearance appeared to be inherited as an autosomal dominant trait.",0
151,634331,Taking care of the hateful patient,"""Hateful patients are not those with whom the physician has an occasional personality clash. As defined here they are those whom most physicians dread. The insatiable dependence of """"hateful patients"""" leads to behaviors that group them into four stereotypes: dependent clingers, entitled demanders, manipulative help-rejecters and self-destructive deniers. The physician' negative reactions constitute important clinical data that should facilitate better understanding and more appropriate psychological management for each. Clingers evoke aversion; their care requires limits on expectations for an intense doctor-patient relationship. Demanders evoke a wish to counterattack; such patients need to have their feelings of total entitlement rechanneled into a partnership that acknowledges their entitlement--not to unrealistic demands but to good medical care. Help-rejecters evoke depression; """"sharing"""" their pessimism diminishes their notion that losing the symptom implies losing the doctor. Self-destructive deniers evoke feeling of malice; their management requires the physician to lower Faustian expectations of delivering perfect care.""",0
152,651962,A follow-up study of vascular disease in growth-hormone-deficient dwarfs with diabetes,"Thirty-one growth-hormone-deficient dwarfs were re-examined after a period of 10 to 12 years. These subjects had initially shown glucose intolerance, insulinopenia and hyperlipidemia comparable to those of diabetic patients matched for age and sex, but vascular complications were not present in dwarfs. After 10 years glucose tolerance became progessively more abnormal in dwarfs than could be accounted for by expected deterioration with age, and hyperglycemia after mixed meals remained greater than in control subjects. Serum lipid and serum lipoprotein concentrations were abnormal in over one third of the dwarfs. Despite the metabolic similarity to the diabetic patients, clinical complications of diabetes were absent in dwarfs: retinopathy did not occur, and the prevalence of hypertension and arteriosclerosis was considerably lower in dwarfs than in the diabetic subjects in both study periods. The follow-up data support the hypothesis that growth hormone has at least a supportive role in the pathogenesis of vascular disease in the diabetic state.",0
153,661855,Frozen autologous platelet transfusion for patients with leukemia,"Platelets were removed from 25 patients with leukemia during remission and were frozen for subsequent transfusion. With 5 per cent dimethyl sulfoxide as a cryoprotective agent, we froze 3 to 5 units of pooled platelet concentrate by simply placing the platelets in the vapor phase of a liquid nitrogen freezer. Ninety-one transfusions of platelets stored for 13 to 400 days were administered. The mean freeze-thaw loss was 13 percent, and the corrected one-hour increment in platelet count was 13,700 per microliter, corresponding to a recovery of 53 per cent of the predicted value. In many patients most or all of the transfusion requirements were met with frozen platelets. Our results indicate that frozen platelets can circulate and function hemostatically. Autologous frozen platelets are of particular value in the management of alloimmunized patients and have become an integral part of our transfusion support program.",0
154,661862,Relation of education to sudden death after myocardial infarction,"We studied the influence of social and personal characteristics on prognosis among 1739 male survivors of myocardial infarction who had been monitored for one hour at a standard examination and subsequently followed for mortality. Over a three-year period men with little education (eight years of schooling or less) who had complex ventricular premature beats in the monitoring hour had over three times the risk of sudden coronary death found among better educated men with the same arrhythmia (cumulative mortality of 33 per cent and 9 per cent, respectively). No such differential appeared in the absence of complex ventricular premature beats. Neither risk factors for incidence of coronary heart disease nor clinical characteristics affecting prognosis accounted for the differences observed. There was no relation between education level and risk of recurrent infarction.",0
155,661870,"""Frequency of sexual dysfunction in """"normal"""" couples""","""In analyzing the responses of 100 predominantly white, well educated and happily married couples to a self-report questionnaire, this study examined the frequency of sexual problems experienced and the relations of those problems to sexual satisfaction. Although over 80 per cent of the couples reported that their marital and sexual relations were happy and satisfying, 40 per cent of the men reported erectile or ejaculatory dysfunction, and 63 per cent of the women reported arousal or orgasmic dysfunction. In addition, 50 per cent of the men and 77 per cent of the women reported difficulty that was not dysfunctional in nature (e.g., lack of interest or inability to relax). The number of """"difficulties"""" reported was more strongly and consistently related to overall sexual dissatisfaction than the number of """"dysfunctions.""""""",0
156,661890,Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion,"We applied a recently developed and more direct technic to diagnose thalassemia syndromes associated with deletion of particular globin structural genes and to assess a fetus at risk for one of those conditions, deltabeta-thalassemia. The method allows assessment of the globin genes present in total cellular DNA and is applicable to amniotic-fluid cell DNA. Cellular DNA fragments produced by cleavage using two specific restriction endonucleases are separated on the basis of size by agarose-gel electrophoresis, and the distribution of specific sequences among the DNA fragments determined by molecular hybridization. We observed the total deletion of alpha-globin genes in homozygous alpha-thalassemia (hydrops fetalis with hemoglobin Bart's) and the deletion of particular beta and beta-like sequences in cases homozygous for hereditary persistence of fetal hemoglobin and deltabeta-thalassemia. Analysis of amniotic-fluid cell DNA from a fetus at risk for deltabeta-thalassemia demonstrated the feasibility of these improved methods for antenatal diagnosis. The molecular studies confirmed the diagnosis predicted by analysis of fetal blood and established at birth.",0
157,661906,"""Career choice and performance on state licensing examinations of """"Fifth Pathway"""" students""","Between 1975 and 1977, 340 American citizens trained in foreign medical schools (mostly Mexican) completed a year of supervised clinical training (Fifth Pathway) in New York State before beginning residency training. Analysis of 335 such students revealed a greater tendency to remain in the State for residency training as compared to graduates of New York State medical schools (P less than 0.01). A primary-care specialty was chosen by these students significantly less often than be American graduates (P less than 0.001). Their pass rate on state licensing examinations, although higher than that of other foreign-trained medical graduates, was significantly lower than that of American-trained students (P less than 0.001). Fifth Pathway programs can provide a source of United States-citizen house officers for hospitals currently staffed mainly by alien physicians. Such programs offer foreign-trained United States physicians an opportunity to improve their clinical skills before starting residencies, but evidently do not fully overcome their educational deficits.",0
158,683235,Lung cancer after employment in shipyards during World War II,"A case-control study, undertaken to identify reasons for the exceptionally high rate of lung cancer among male residents of coastal Georgia, revealed a significantly increased risk associated with employment in area shipyards during World War II. The summary relative-risk estimate, adjusted for smoking, other occupations, age, race and county of residence was 1.6 (95 per cent confidence limits = 1.1 to 2.3). A synergistic relation was found between shipyard employment and cigarette smoking. These findings suggest that asbestos and possible other shipyard exposures during wartime employment account for part of the excess mortality from lung cancer in certain coastal areas of the United States.",0
159,692598,Problems of spectrum and bias in evaluating the efficacy of diagnostic tests,"""To determine why many diagnostic tests have proved to be valueless after optimistic introduction into medical practice, we reviewed a series of investigations and identified two major problems that can cause erroneous statistical results for the """"sensitivity"""" and """"specificity"""" indexes of diagnostic efficacy. Unless an appropriately broad spectrum is chosen for the diseased and nondiseased patients who comprise the study population, the diagnostic test may receive falsely high values for its """"rule-in"""" and """"rule-out"""" performances. Unless the interpretation of the test and the establishment of the true diagnosis are done independently, bias may falsely elevate the test's efficacy. Avoidance of these problems might have prevented the early optimism and subsequent disillusionment with the diagnostic value of two selected examples: the carcinoembryonic antigen and nitro-blue tetrazolium tests.""",0
160,703769,The medical care of mentally retarded persons in public residential facilities,"Large public residential facilities have traditionally been society's primary service resource for persons with serious mental retardation. Despite current emphasis on restricting admissions and community placement of retarded persons, approximately 175,000 people continue to reside in 230 institutions throughout the United States. This population is vulnerable to a variety of chronic medical disorders that diminish successful adaptation to a more normal life-style, especially when health services are marginal. Institutional medical staffs have been largely isolated from their physician peers, and their patients have not had access to medical care equivalent to that available in the community. We describe the recent affiliation of a teaching hospital with a Massachusetts institution. We suggest that such affiliations would assure better medical care for mentally retarded persons while increasing physicians' knowledge of attendant medical and societal problems.",0
161,703786,Red-cell uroporphyrinogen decarboxylase activity in porphyria cutanea tarda and in other forms of porphyria,"To test the diagnostic specificity of reduced red-cell uroporphyrinogen decarboxylase activity for porphyria cutanea tarda, we measured enzymic activity in 29 normal subjects and 65 patients with various forms of porphyria. Only patients with porphyria cutanea tarda had subnormal enzymic activity. Patients with acute intermittent porphyria, erythropoietic protoporphyria, variegate porphyria and hereditary coproporphyria had normal or slightly elevated activities. The enzymic activity in normal persons and patients with porphyria cutanea tarda did not differ according to sex. Reduction of iron stores did not alter the enzymic activity in porphyria cutanea tarda. We conclude that reduced red-cell uroporphyrinogen decarboxylase activity is a specific and intrinsic defect in porphyria cutanea tarda; measurement of this enzyme is a reliable diagnostic test for this disease.",0
162,714138,Nutrient deficiencies in breast-fed infants,"An editorial in a previous issue of the New England Journal of Medicine August 17, 1978, recommends iron supplementation as a countermeasure to the iron deficiency of breast-fed infants. However, the dosage suggested may saturate the binding capacity of lactoferrin, an iron-binding protein found in human milk. Since lactoferrin, in combination with specific antibody, is essential for the beneficial bacteriostatic effects of milk against Escherichia coli, an added regimen of iron may impair this effect and prove detrimental to the infant. The question, then, of iron deficiency becomes essential. Evidence shows that the hemoglobin values of infants fed by normal mothers for approximately 7 months and infants fed by iron-deficient mothers are normal. The need for additional iron seems unlikely, especially if the infant diet is supplemented with food containing iron.",0
163,758170,Oral contraceptives and birth defects,"""This letter questions the sample size validity in a study previously published in the New England Journal of Medicine by Rothman and Louik (7 September 1978), deeming it too small to draw valid conclusions from because the """"power"""" of the statistical tests used was not great enough to show major teratogenic hazards; hence, the earlier authors' statistical discounting (based on P values) of the teratogenic effects of oral contraceptives was unwarranted and misleading. A nontechnical argument, based on the knowledge that occurrence of malformations that are sensitive indicators of teratogenicity is a rare event, is presented. Down's syndrome is the example: """"In this typical Poisson situation, the power depends on the number of rare events that occur rather than on total sample size. Thus, there are only 7 reports of Down's syndrome, 3 in the 1448 births in the short-interval series and 4 in the remaining 6275 births. Because the effective sample size is so small, even though the observed incidence is about 3 times higher in the short-interval series, the statistical tests are not 'significant'.""""""""""",0
164,758579,Duodenal-ulcer disease associated with elevated serum pepsinogen I: an inherited autosomal dominant disorder,"To delineate genetic factors involved in the pathogenesis of duodenal ulcer, serum pepsinogen I levels were determined by radioimmunoassay in two large kindreds with multiple members affected with duodenal ulcer. An elevated serum immunoreactive pepsinogen I concentration (greater than 100 ng per milliliter) segregated as an autosomal dominant trait in these families. Furthermore, 10 of 11 patients with clinical ulcer disease in these families had hyperpepsinogenemia. An elevated serum pepsinogen I concentration appears to be a subclinical marker of the ulcer diathesis in families with this autosomal dominant form of peptic-ulcer disease.",0
165,758580,A rationale for continued federal support of medical education,"Changing circumstances and shifting public attitudes are forcing policy makers and educators to reconsider the rationale for a continuing federal role in support of medical education. Federal institutional support programs are criticized as being inappropriate to current and future needs, socially inequitable and subject to abuse by a coercive governmental apparatus. A rationale for federal support can be advanced, but such support must be designed to avoid unwarranted subsidies and to encourage maximum reliance upon private-sector resources, and should be confined to functions for which the federal government in uniquely suited. The appropriate federal role is conceived as being the ultimate guarantor of financial access to the medical-education system by otherwise qualified students, perfecting the market for human-capital investment.",0
166,759870,Gerontology and geriatrics in medical education,"The elderly are receiving more attention because of their increasing numbers and because of the substantial public funding for their health and welfare. This article summarizes the findings of an Institute of Medicine committee, whose recently completed report concludes that gerontology (study of aging) and geriatrics (care of the aged) are not covered adequately in medical education. Suggested remedies include increased attention to these subjects in existing medical-school courses, establishment of a complementary required course integrating information from diverse disciplines and emphasis in house-staff training programs on continuous care of the aged in settings other than acute-care facilities. Although an academic discipline of geriatrics is necessary to enhance teaching, research, and specialized patient care, development of a practice specialty would be unwise. More funds for training and research in gerontology and geriatrics are essential to increase the science base and to encourage the development of knowledgeable faculty.",0
167,759877,Diethylstilbestrol and the risk of cancer,"There is striking evidence that there is an increased risk of early cancer mortality in women treated with diethylstilbestrol during pregnancy. Exposure to the drug is associated with more than a twofold increase in risk of all cancer, which increases to 2.89 for breast cancer, and to 2.73 for endocrine related tumors. Most published studies on the subject lack the statistical power to reject the hypothesis that there are no significant differences between treated and untreated women, especially in the presence of a 50% increase in risk. There is a difference in the magnitude of the relative risk between premenopausal and postmenopausal breast cancer, the mortality cases being primarily in premenopausal women. Additional studies on diethylstilbestrol are needed.",0
168,763254,Potential effect of self-care algorithms on the number of physician visits,"To assess the potential effect of self-care algorithms on the number of physician visits, actual visits from the Seattle Virus Watch were compared retrospectively with those recommended by clinical algorithms for common illnesses from the book, Take Care of Yourself, by Vickery and Fries. From a total of 3929 illnesses, records indicating the presence of the index symptom for eight algorithms were identified, determining whether the criteria for seeing a physician were met and whether a physician visit was recorded. The number of visits observed was compared to the number of visits recommended by the algorithms. Strict adherence would have increased the number of visits over that observed for five, remained the same for two, and decreased for one of the algorithms. These results indicate that adherence to some commonly promulgated self-care algorithms may increase rather than decrease the number of physician visits.",0
169,763271,Current practice of artificial insemination by donor in the United States,"Of 711 physicians likely to perform artificial insemination by donor surveyed to determine their current practices, 471 responded, of whom 379 reported that they performed this procedure. They accounted for approximately 3576 births by this means in 1977. In addition to treating infertility, 26 per cent of these physicians used the procedure to prevent transmission of a genetic disease, and 10 per cent used if for single women. Donors of semen were primarily from universities, were only superficially screened for genetic diseases, and were then matched phenotypically to the recipient's husband. Most recipients were inseminated twice per cycle. Only 17 per cent of physicians used the same donor for a given recipient, and 32 per cent used multiple donors within a single cycle. Only 37 per cent kept records on children, and only 30 per cent on donors. The identity of donors usually was carefully guarded to ensure privacy and to avoid legal complications.",0
170,772426,Foreign medical graduates and Maryland Medicaid,"To determine whether foreign medical graduates provide a disproportionate share of medical care to the poor, Medicaid vendors in Maryland were compared with all licensed physicians in the State. Foreign medical graduates constitute 22 per cent of all physicians in Maryland but 36 per cent of the Medicaid vendors. In addition, of all the vendors for fiscal 1974, 94 per cent who were licensed in 1972 or 1973 were foreign medical graduates. This disproportional representation in the Medicaid program is concentrated in the specialties of general surgery, internal medicine and general practice. Thirty-two per cent of all foreign medical graduates in Maryland are board-certified physicians, but only 22 per cent of those who are Medicaid vendors are board certified. For United States medical graduates, 48 per cent of all physicians are board certified, but this figure increases to 52 per cent for the Medicaid vendors. Finally, representation of foreign medical graduates among Medicaid vendors tends to be highest in areas with the highest physician-to-population ratios and with the highest percentages of total Medicaid payments.",0
171,787788,Vitamin C and acute illness in Navajo school children,"To evaluate earlier observations, including our own, showing usefulness of vitamin C for managing the common cold, we performed a double-blind trial of vitamin C versus placebo in 868 children. There was no difference in number becoming ill (133 versus 129), number of episodes (166 versus 159) or mean illness duration (5.5 versus 5.8 days) between the groups. Children receiving vitamin C had fewer throat cultures yielding beta-hemolytic streptococcus (six versus 13, P less than 0.10), but no difference in overall complicated illness rate (24 versus 25). Plasma ascorbic acid levels were higher in the vitamin group 24 to 26 hours after supplementation (1.28 versus 1.04 mg per 100 ml, P less than 0.01). Children with high plasma ascorbic acid concentrations had longer mean illness (6.8 versus 4.0 days, P less than 0.05) than those with low levels. Vitamin C does not seem to be an effective prophylactic or therapeutic agent for upper respiratory illness.",0
172,790183,Maternal-fetal relation. Absence of an immunologic blocking factor from the serum of women with chronic abortions,"""We investigated an immunologic mechanism that might explain the apparent """"tolerant"""" state of the mother during pregnancy. Cellular-immune reactivity in vitro to paternal alloantigens was demonstrated in multigravid women by production of lymphocyte migration inhibitory factor. Serum from normal multigravid women contained a factor that blocked production of migration inhibitory factor by maternal lymphocytes to paternal antigens in a specific manner. The blocking factor was an IgG antibody whose activity was removed by absorption with paternal lymphocytes but not with pooled human platelets. We tested the biologic importance of this blocking factor in women who have difficulty maintaining a normal term pregnancy. Our observations indicate that women who experience idiopathic spontaneous abortions produce lymphocyte migration inhibitory factor to paternal alloantigens, but their serums lack the blocking factor. The presence of the serum blocking factor during pregnancy may contribute to the success of the fetus as an allograft.""",0
173,806804,Primer on certain elements of medical decision making,"The value of a diagnostic test lies in its ability to detect patients with disease (its sensitivity) and to exclude patients without disease (its specificity). For tests with binary outcomes, these measures are fixed. For tests with a continuous scale of values, various cutoff points can be selected to adjust the sensitivity and specificity of the test to conform with the physician's goals. Principles of statistical decision theory and information theory suggest technics for objectively determining these cutoff points, depending upon whether the physician is concerned with health costs, with financial costs, or with the information content of the test.",0
174,818562,Protein-sparing therapy in postoperative patients. Effects of added hypocaloric glucose or lipid,"In patients receiving hypocaloric total parenteral nutrition, protein sparing with infusions of amino acids alone is alleged to occur because low insulin levels allow mobilization of endogenous fat. Four groups of patients studied for their first four postoperative days received all their nutrition parenterally as: 150 g per day of glucose, protein (as amino acids, 1 g per kilogram per day) alone, protein plus 50 g per day of soybean-oil emulsion or protein plus 150 g per day of glucose. All groups of patients receiving protein had lesser negative nitrogen balance than patients receiving glucose alone. The addition of glucose to protein did not increase negative nitrogen balance. The protein-sparing effect of amino acids appears to be a function of the infused amino acids alone and is not related to the degree of endogenous fat mobilization.",0
175,825775,Abnormal purine metabolism and purine overproduction in a patient deficient in purine nucleoside phosphorylase,"To delineate the normal function of purine nucleoside phosphorylase and to understand the pathogenesis of the immune dysfunction associated with deficiency of this enzyme, we studied purine metabolism in a patient deficient in purine nucleoside phosphorylase, her erythrocytes and cultured fibroblasts. She exhibited severe hypouricemia and hypouricosuria but excreted excessive amounts of purines in her urine, the major components of which were inosine and guanosine. Her urine also contained deoxyinosine, deoxyguanosine and uric acid 9-N riboside. The patient's erythrocytes but not her cultured fibroblasts contained increased concentrations of phosphoribosylpyrophosphate and inosine. The metabolic abnormalities resembled those in the erythrocytes of patients with the Lesch-Nyhan syndrome. Purine nucleoside phosphorylase is a necessary component of the major, if not the sole, pathway for the conversion of purine nucleosides and nucleotides to uric acid. The increased intracellular concentrations of inosine may, by inhibiting adenosine deaminase, be related to the immunologic dysfunction.",0
176,830263,Suppression of erythroid-colony formation by lymphocytes from patients with aplastic anemia,"To explore the possible role of cell-mediated suppression of erythropoiesis in acquired aplastic anemia, we studied the effect of peripheral blood lymphocytes from seven patients with aplastic anemia on erythroid-colony formation by normal human bone marrow in an in vitro plasma clot-culture system. Varying numbers of peripheral blood lymphocytes (0.5 to 6 X 10(5) cells) were cocultured with 6 X 10(5) normal bone-marrow cells in the presence of 2 IU of erythropoietin for seven days. Peripheral blood lymphocytes from five of the seven patients with aplastic anemia caused a 79 to 94 per cent reduction of erythroid-colony formation. Thus, at a peripheral blood lymphocyte concentration of 2 X 10(5) cells, the numbers of erythroid colonies formed (control vs. experimental) were 374 +/- 16 (S.E.M.) vs. 22 +/- 6, 48 +/- 4, 50 +/- 16, 80 +/- 4 and 27 +/- 3. These results suggest that some patients with aplastic anemia possess a population of lymphocytes capable of suppressing in vitro erythropoiesis.",0
177,834210,Mild high-renin essential hypertension. Neurogenic human hypertension?,"""To determine whether the elevated plasma renin activity in some cases of mild essential hypertension expresses sympathetic-nervous-system over-activity, we compared indexes of sympathetic activity in 16 patients with mild high-renin essential hypertension, 15 hypertensive patients with normal plasma renin activity and 20 normal subjects. Patients with elevated activity exhibited a raised plasma norepinephrine concentration (P less than 0.05), a greater fall in cardiac output with cardiac beta-adrenergic blockade by intravenous propranolol (P less than 0.01), reduction in total peripheral vascular resistance with alpha-adrenergic blockade produced by intravenous phentolamine (P less than 0.01), and reduction to normal of blood pressure by """"total"""" autonomic blockade (atropine, propranolol and phentolamine). On psychometric testing, patients with high-renin hypertension, but not those with normal plasma renin activity, exhibited suppressed hostility (P less than 0.01), a behavioral pattern linked to increased sympathetic activity. The hypertension in these patients with high renin activity is neurogenic and possibly psychosomatic in origin.""",0
178,834224,Failure of complete bile diversion and oral bile acid therapy in the treatment of homozygous familial hypercholesterolemia,"Two patients with nomozygous familial hypercholesterolemia, refractory to medical therapy, underwent complete bile diversion by common-duct ligation and cholecystostomy, in an attempt to arrest the progression of their xanthomatosis and atherosclerosis by depletion of body cholesterol. Clofibrate was given after operation to one patient, and cholic acid to both, in an effort to enhance further the negative sterol balance. Bile diversion produced an increase of six to eight times in gastrointestinal sterol output, which was not increased further by either clofibrate or cholic acid therapy. Despite a calculated sterol loss of 560 g over 14 months in one patient and 400 g over 10 months in the other, neither plasma cholesterol nor xanthoma size decreased. Continuity of the biliary tree was therefore restored. The data suggest that patients with homozygous familial hypercholesterolemia respond to even massive gastrointestinal sterol depletion with equal increases in sterol synthesis.",0
179,840241,Reduction in mortality from coronary heart disease in men residing at high altitude,"In New Mexico, where inhabited areas vary from 914 to over 2135 m above sea level, we compared age-adjusted mortality rates for arteriosclerotic heart disease for white men and women for the years 1957-1970 in five sets of counties, grouped by altitude in 305-m (1000-foot) increments. The results show a serial decline in mortality from the lowest to the highest altitude for males but not for females. Mortality rates for males residing in the county groups higher than 1220 m in order of ascending altitude were 98, 90, 86 and 72 per cent of that for the county group below 1220-m altitude (P less than 0.0001). The results do not appear to be explained by artifacts in ascertainment, variations in ethnicity or urbanization. A possible explanation of the trend is that adjustment to residence at high altitude is incomplete and daily activities therefore represent greater exercise than when undertaken at lower altitudes.",0
180,857158,Mid-trimester abortion by dilatation and evacuation: a safe and practical alternative,"Abortions by dilatation and evacuation after the 12th menstrual week of pregnancy are said to be both hazardous and impractical. To evaluate this hypothesis, we compared the safety and feasibility of 6213 abortions by this means and 8662 induced by intra-amniotic instillation of saline during the 13th to the 20th week of pregnancy. Abortions by dilatation and evacuation had a lower rate for major complica-tions (0.69 vs. 1.78 per cent; P is less than 0.001) and lower rates for treatment of complications, including antibiotic administration (2.22 vs. 5.65 per cent; P is less than 0.001), blood transfusion (0.19 vs. 0.91 per cent; P is less than 0.001), and curettage or manual evacuation of the uterus (0.98 vs. 34.10 per cent; P is less than 0.001). Such abortions also had a lower rate for failure of the method to produced abortion (0.11 vs. 2.52 per cent; P is less than 0.001). Although large, randomized trials are required to determine the appropriate role of mid-trimester abortion by this means, this method appears safe and practical through the 20th week of pregnancy.",0
181,870824,Shattuck lecture--The general medical journal: for readers or repositories?,"""General medical journals seek newsworthiness but face obstacles because of their usually slow publication schedules and because of contents that readers find either obscure or contradictory to long held beliefs. In addition, since medical news has become """"big news,"""" general medical journals find themselves in competition with both the lay press and the medical giveaways. One effect of the escalating public interest in medical news is that general medical journals that are reliable and have maintained their newsworthiness are increasingly cited. These journals thus eventually transmit research findings to the public as well as to the health-care professions. To help prevent exaggeration and misinterpretation by the lay press and by the public, general medical journals must evaluate submissions in a broader than traditional context. Nevertheless, newsworthiness is an appropiate goal for such journals.""",0
182,876328,Elective surgical rates--do high rates mean lower standards? Tonsillectomy and adenoidectomy in Manitoba,"We used claims data from the Canadian province of Manitoba to test alternative explanations for regional differences in tonsillectomy and adenoidectomy rates. Respiratory morbidity, standards of selection for operation, and surgical resources were compared with elective surgical rates across geographic areas. Statistically significant correlations were not found. Individual practice patterns were then examined. In some regions, a few physicians accounted for the great majority of tonsil/adenoid operations. In other regions, the work was much more widely distributed. Despite great variation among individual physicians in the frequency of performing tonsil/adenoid operations and the standards of selection for operation, use of these procedures and standards applied were only weakly related to such variables as physician age, place of training and specialty.",0
183,882109,"Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii","We examined the relation of coffee and alcohol consumption to the risk of coronary heart disease during a six-year period in a cohort of 7705 Japanese men living in Hawaii. The analysis was based on 294 new cases of coronary heart disease. There was a positive association between coffee intake and risk, but it became statistically insignificant when cigarette smoking was taken into account. There was a strong negative association between moderate alcohol consumption (up to 60 ml per day), mainly from beer, and the risk of nonfatal myocardial infarction and death from coronary heart disease. This association remained significant in multivariate analysis, taking into account smoking and other risk factors. The correlation of alcohol consumption with the level of alpha cholesterol (positive) and beta cholesterol (negative) may partly account for the observed negative association between alcohol and coronary heart disease.",0
184,887105,Violent death in a metropolitan county. Changing patterns in homicide (1958-74),"Analysis of homicide patterns in Cuyahoga County, Ohio (metropolitan Cleveland), for 1958-1974 discloses the following major trends: a dramatic rise in overall homicide rates in the city (320 per cent) and suburbs (200 per cent); an increase in justifiable homicide; a doubling of the percentage of homicides incident to other felonies; a markedly increased incidence of homicide among younger persons; a conspicuous rise in firearm killings (now 81 per cent of all homicides); and a continued preponderance of intraracial homicide, with the highest rates among nonwhite males in the city. The trends in Cuyahoga County are consistent with those in other United States metropolitan counties. Homicide is responsible for a major part of the decreased life expectancy among young, urban, non-white men. The factor most consistently associated with these trends is the increased use of handguns.",0
185,887121,Sounding board. The pill: a perspective for assessing risks and benefits,"""Over the past 17 years, a """"contraceptive revolution"""" has occurred, based on highly effective methods which can be applied at a time unrelated to sexual intercourse. In the 1950s, birth control was thought to be a settled issue for the middle and upper class. Although motivated to limit family size, low-income women found the diaphragm and condom inappropriate for their life style. Between 1960-1965, Planned Parenthood's caseloads of low-income women tripled. By 1975, nearly 4 million women of low and marginal income were clinic patients, with 72% choosing oral contraceptives. Those who advocate replacing the pill because of medical risk with coitally related methods are ignoring the needs of many low-income women in the U.S. Tietze et al. have shown that except for older women who smoke, the risk of mortality from using any method of fertility control is lower than the risk from automobile accidents or from childbirth. A more comprehensive framework is needed for weighing the total benefits expected by contraceptors against the total risks of any particular method. We also need an enlarged research program for safer contraceptives; a higher priority in the National Institutes of Health budget.""",0
186,895765,Graduate education in primary care: an economic analysis,"To determine the financial requirements of an established primary-care educational program for house officers, we studied two prepaid and two fee-for-service Harvard Primary Care Program affiliated practices. Program-wide, each resident saw an average of 112 patients per month, with patient service costs of $2,580. With teaching and administrative expenses included, total monthly costs averaged $3,120 and $3,270 per trainee for prepaid and fee-for-service practices respectively. In fee-for-service practices, resident billings for patient services averaged $2,790, yielding revenues of $2,510 per month, which offset 77 per cent of total program costs. At current reimbursement rates, covering full program costs in the fee-for-service practices would require an increase of more than 40 per cent in resident-provided patient-care volume. By reducing time available for broad ambulatory experiences, such an increase would necessitate substantial program restructuring and limit opportunities for innovation in the Harvard Primary Care Program.",0
187,895789,"""Multicellular origin of parathyroid """"adenomas""""""","""Most cases of primary hyperparathyroidism are associated with enlargement of a single gland (i.e., an """"adenoma"""") or with chief-cell hyperplasia, but there is controversy about the relative frequency of each of these entities. It has even been postulated that adenomas do not arise spontaneously, bu- result from prolonged hyperplasia in response to unknown stimuli. We studied four parathyroid adenomas from three women with heterozygosity (GdB/GdA) for the X-chromosome-linked enzyme, glucose-6-phosphate dehydrogenase, to determine the number of cells from which the growths arise. Unicellular origin would be compatible with a rare oncogenic event, whereas multicellular origin might be seen with hyperplasia. Both B and A isoenzymes were found in each """"adenoma"""" in proportions similar to those observed in normal tissues, indicating that the lesions have multicellular origin. Thus, parathyroid hyperplasia and adenomas, which at best are difficult to distinguish from one another pathologically, may also be similar biologically.""",0
188,904660,In vitro cell-mediated immunity of cerebrospinal-fluid lymphocytes to myelin basic protein in primary demyelinating diseases,"In an attempt to characterize the immunologic reactivity of cerebrospinal-fluid lymphocytes in demyelinating diseases, we compared the myelin-basic-protein-induced in vitro responses of these cells to peripheral blood lymphocytes from the same subjects with a variety of neurologic diseases. Peripheral blood lymphocytes from patients with acute disseminated encephalomyelitis and progressive multiple sclerosis had increased reactivity as compared to those of normal volunteers (P less than 0.01 and P less than 0.05, respectively). Cerebrospinal-fluid lymphocytes from patients with acute disseminated encephalomyelitis and acute and progressive (but not stable) multiple sclerosis were more reactive than cells from subjects with other neurologic diseases (P less than 0.005, P less than 0.02 and P less than 0.05, respectively). Cerebrospinal-fluid lymphocytes manifested a greater reactivity than peripheral blood lymphocytes in acute and progressive multiple sclerosis but not in acute disseminated encephalomyelitis. These findings demonstrate that lymphocytic cells reactive to myelin basic protein are present in the spinal fluid during active demyelinating disease; and that these cells may be more reactive than peripheral blood lymphocytes.",0
189,917042,Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis,"Plasmapheresis combined with prednisone and azathioprine therapy produced striking clinical improvement in five patients with myasthenia gravis who still had moderate to severe disability despite thymectomy, high-dose prednisone therapy and optimal doses of cholinesterase inhibitors. Serial determinations of titers of serum antibody toward the acetylcholine receptor demonstrated a fall to 21 +/- 5 per cent (mean +/- S.D.) of the original levels concurrently with the patients' increasing strength. Clinically improved patients maintained lowered titers, whereas clinical relapses were associated with a rebound in titer. Our results suggest that plasmapheresis will find a place in the management of patients with myasthenia gravis, and they implicate antibodies to acetylcholine receptor as a pathogenic factor in this disease.",0
190,917043,Black under-representation in United States medical Schools,"To understand why blacks are under-represented in medical schools and how this situation might be changed, we analyzed statistics on medical-school applicants, medical-school students and college undergraduates. The pool of qualified black applicants to medical schools has not been large enough to achieve appropriate black representation. If black under-representation is to be corrected, the pool of qualified black applicants must be increased. Affirmative-action programs for blacks who are already in college are unlikely to be sufficient by themselves to increase the pool of black applicants substantially. Such programs should therefore be developed for high-school students.",0
191,942758,Measuring the quality of medical care. A clinical method,"""We outline the implementation of a new method of measuring the quality of medical care that counts cases of unnecessary disease and disability and unnecessary untimely deaths. First of all, conditions are listed in which the occurrence of a single case of disease or disability or a single untimely death would justify asking, """"Why did it happen?"""" Secondly, we have selected conditions in which critical increases in rates of disease, disability, or untimely death could serve as indexes of the quality of care. Finally, broad categories of illness are noted in which redefinition and intensive study might reveal characteristics that could serve as indexes of health. We describe how these inth of the general population and the effects of economic, political, and other environmental factors upon it, and to evaluate the quality of medical care provided both within and without the hospital to maintain health and to prevent and treat disease.""",0
192,943041,Vitamin A transport in human vitamin A toxicity,"The plasma retinol transport system was studied in three patients with chronic hypervitaminosis A. The toxic state in each was associated with increased plasma concentrations of total vitamin A, and particularly of retinyl esters. The concentrations of plasma retinol-binding protein and prealbumin were, in contrast, non to retinol-binding protein. These limited clinical data support conclusions from detailed studies with hypervitaminotic rats, which suggest that vitamin A toxicity occurs when excessive amounts of vitamin A are presented to cell membranes in association with plasma lipoproteins, rather than specifically bound to retinol-binding protein. Retinol-binding protein may not only regulate the supply of retinol to tissues but also protect tissues from the surface-active properties of the vitamin.",0
193,943694,e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants,"Testing of serum samples of 23 pregnant women who were asymptomatic carriers of hepatitis B surface antigen for e antigen and antibody to e with an immunodiffusion technic identified 10 mothers with e antigen and seven with e antibody. Their babies were tested for hepatitis B surface antigen in serum at intervals for more than 12 months. In all 10 babies born to e-antigen-positive mothers hepatitis B surface antigen developed and persisted through the observation period, and all 10 elder siblings of these newborn babies were found to be asymptomatic carriers. In remarkable contrast, all seven babies born to mothers positive for antibody to e escaped antigenemia, and none of their three elder siblings carried surface antigen. On the basis of these results, e antigen may be used as an indicator of transmission, and antibody to e as that of absence of transmission of hepatitis B virus from carrier mothers to children.",0
194,967222,Doctors who perform operations. A study on in-hospital surgery in four diverse geographic areas (second of two parts),"To facilitate manpower planning in the surgical field, a study was c onducted into the work loads of surgeons in various specialities in 4 different geographical areas. Surgeons in group practice and surgeons who were Board-certified specialists carried a statistically significant larger work load of surgery. The certified surgeons performed more and more complex operations. The mean operative work load increased steeply with age, reaching a maximum at 40-44 years, and fell linearly after that age. Approximately 18 years following medical school graduation were needed for a surgeon to achieve his maximum work load. The geographic factor had no appreciable effect on work loads. Tables which broke down frequencies for each major type of operation for each type of surgical specialist indicated that even commonplace operations were not frequent events on the average for any individual surgeon. It is concluded from the study that work loads are relatively low due to excessive supply of surgeons. This is of concern because there is some doubt about maintenance of surgical skills by those doctors who perform infrequent operations. The widest variation in practice was evident between ophthalmologists and thoracic surgeons, indicating that manpower planning in this field would have to be done on a specialty-by-specialty basis. 3 plans for redistributing the operative work load and reducing the number of specialist surgeons are considered.",0
195,980018,The intrauterine device and deaths from spontaneous abortion,"To evaluate the intrauterine device as a risk factor for mortality associated with spontaneous abortion, we analyzed all deaths from spontaneous abortions reported in the period 1972-1974. Women dying from spontaneous abortions with a device in place were more likely to be young, white and married than those not wearing a device. Risk of death from spontaneous abortion was over 50 times greater for women who continued their pregnancy with a device in place than for those who did not. The Dalkon shield carried an increased risk of death, as compared to other devices, even after rates were adjusted for duration of use. However, pregnant women with either a loop or a coil in place also had a higher risk of dying from spontaneous abortion than those without any device. The results support the clinical recommendation that any device should be removed when pregnancy is first diagnosed.",0
196,980094,Detection of intrapulmonary hemorrhage with carbon monoxide uptake. Application in goodpasture's syndrome,"We devised a noninvasive measure of pulmonary hemorrhage of value in the management of Goodpasture's syndrome. We reasoned that alveolar uptake of inhaled carbon monoxide during breath holding would increase in the presence of extravascular blood, but clearance of its radioisotope (C15O) from a lung field would be delayed. Thus, the ratio of uptake to clearance would indicate lung hemorrhage. In 15 controls and six patients with renal failure without hemorrhage, this ratio ranged from 0.73 to 1.5. In eight patients with Goodpasture's syndrome the ratio ranged from 1.5 to 16.5, returning to normal between episodes of bleeding. Measurements of carbon monoxide uptake alone in 10 patients with Goodpasture's syndrome were at times well above that predicted for their hemoglobin level, whereas in renal failure with acute pulmonary edema increased carbon monoxide uptake was rarely found. Thus, monitoring of the single-breath carbon monoxide uptake alone can detect episodes of lung hemorrhage.",0
197,983076,The effect of dihydroegotamine and propanolol on acute orthostasis (author's transl)],"10 Patients with positive orthostatic dysregulation were investigated with regard to venous capacity, heart frequency and arterial blood pressure both lying down and sitting up. The venous capacity was reduced by 14% after dehydroergotamine (DHE) in the lying position, which is an expression of increased venous tone. There is no change in venous capacity following the administration of beta blockers in the lying position. Under orthostatic conditions beta blockers bring about an approximate normalization of the venous capacity reaction, whereas the abnormal response following placebo administration is only slightly altered by DHE. ",0
198,984033,Arteriovenous shunts in the human spleen,"""The mission of this study was to determine whether or not arteriovenous connections, indicative of a """"closed"""" type of circulation, existed in the human spleen. Spleens from four patients requiring therapeutic splenectomy were the basis for this report. Scanning electron microscopy of plastic corrosion casts, prepared from these four spleens, revealed direct vascular conduits between splenic pulp arteries or arterial capillaries and the venous sinuses in the red pulp. Also demonstrated were a few arteriovenous shunts between pulp arteries or arterial capillaries and pulp or trabecular veins. Inclusion of sized microspheres in low-viscosity perfusion plastic illustrated that some diameters of the connecting shunts were 7-10 mum, with other shunts even smaller. Not only do arteriovenous connections exist in human spleens, but their frequency, as revealed by methods accentuating three-dimensional aspects of the splenic microcirculation, justify future reconsiderations of the functional significance of this closed type of circulation. Examination of samples of the same intact spleens, prepared by freeze-fracture and conventional critical-point drying, also revealed an """"open"""" type circulation structure, namely, pore-patterned sinus walls that could facilitate blood cell movement from pulp cords into venous sinuses. Scanning electron microscopy thus has provided direct evidence that human spleens have both """"open"""" and """"closed"""" circulatory pathways in their microvasculature. """,0
199,984129,Gonadoblastoma: clinicopathologic correlation in six patients,"Six patients with a total of nine gonadoblastomas are presented; three--and possibly a fourth--had dysgerminomatous overgrowth which was massive in two patients. Calcification detected by abdominal films was present in three sufficient for preoperative diagnosis. All patients were found to have a Y stem line on peripheral leukocyte chromosome cultures except one patient, who had a 46 XX/45 XO karyotype. She was found to have Y chromatin bodies in the germ cells of her tumor which was in a normal ovary found at exploration for an ectopic pregnancy. Three were found in virilized phenotypic females investigated for amenorrhea, and two for therapy of pelvic masses due to dysgerminomatous overgrowth. Y chromatin studies are reported on gonadal tissue. ",0
200,984354,"Plasma pentobarbitone levels. Influence of the preparation, route and method of administration",In fit women plasma pentobarbitone was measured by gas-liquid chromatography after 100 mg given by mouth or intramuscular injection in the buttock using aqueous and organic solutions. Differences in plasma levels with the two solutions were not striking. Considerable inter-administrator difference occurred with significantly higher plasma levels when the drug was injected by a doctor using a 4 cm 21 s.w.g. needle as compared with nurses who used no specified injection technique. The oral route gave significantly higher plasma levels than nurse-given injections. ,0
201,984376,Investigation on the morphokinetic reactions of the rat liver to ether anaesthesia of different length (author's transl)],"The nuclear volumes were measured in the central, intermediate and peripheral zone of the classic liver lobule of adult male albino rats exposed to ether anaesthesia lasting 15, 40 and 80 min. Related to control animals there was a significantly lower nuclear size after a 40 min duration of narcosis and a significant higher volume after 80 min in the central part of the lobule. With a slight but not significant decrease of nuclear volume in the intermediate zone after 15 min and a significant increase after 80 min respectively, the peripheral lobular region constantly showed significantly smaller nuclei. But here, too, a disappearance of decrease was recorded after 80 min. The interpretation of the data is based upon a typical distribution of cell organelles, enzymatic pathways, and metabolites in the different zones of the hepatic lobule. The intensity of reaction and appearance of diminution in nuclear volume, indicating a functional depression and probably accentuated by a circular dependent low O2-tension of tissue, is interpreted in connection with different local concentrations of ether. An improvement of the blood flow by augmental local metabolites and an increased arterial influx presumably support the recovery and favour a concentration-dependent induction of microsomal enzymes in the central part of the lobule especially. ",0
202,984926,Further experience with peritoneo-venous shunt for ascites,A specially devised pressure-sensitive valve forms the basis for a new peritoneo-venous shunt operation which delivers ascitic fluid continuously into the venous system. It is effective in ascites attributed to different causes. The procedure is simple and brings a long lasting relief with recovery in strength and nutrition and improved kidney function. Hepatorenal syndrome in ascites is reversed. ,0
203,984954,Observations on varions electrovectocardiographic aspects of the W-P-W syndrome],"""The  purpose of this study was to clarify certain electrovectorcardiographic aspects suggestive of heart disease associated with W-P-W syndrome. Seventy-six vectorcardiograms with W-P-W features were analyzed. The curves were obtained by Grishman's cube system and in 8 cases by Frank's method, as well. In addition, the conventional electrocardiograms corresponding to 55 vectorcardiograms, were studied. Not all the electrocardiographic and vectorcardiographic tracings were recorded simultaneously. The W-P-W syndrome was classified as type A when the electrical records suggested a pre-excitation phenomenon in the left postero-superior septal mass, probably with a partial """"wave jumping"""" toward the right anterior septal mass. The W-P-W syndrome was judged to be of type B when the electrical tracings showed a pre-excitation in the right anterior septal mass, probably with a partial """"wave jumping"""" toward the left posterior septal mass. The results of this study permit the following conclusions: 1. It seems justified to assert that the calssification of the W-P-W syndrome must be realized deductively on the basis of the sequence of the ventricular activation and of the heart position. 2. An interval of 30 msec. or more between the end of initial slurring and the vertex or middle point of the R loop permits inferring the coexistence of left ventricle hypertrophy. 3. The presence of an inactivable zone due to myocardial infarction should be suspected on the basis of segmentary irregularities or distortions of the electrical curves, while extensive deformations are more suggestive of myocardiopathy. 4. The duration of terminal slurrings does not depend on that of the initial ones. However, when the initial slurrings are very prolonged, the terminal ones are relatively short. 5. In the presence of W-P-W syndrome, the primary ventricular repolarization changes cannot be considered as pathognomonic of any associated cardiopathy because they are often provoked by drugs. """,0
204,985073,Is 80 years too old for aneurysmectomy?,"The records of 111 patients, 80 years of age or older, with a primary diagnosis of abdominal aortic aneurysm(AAA) showed that 86 patients underwent aneurysm resection and grafting. Ruptured AAAs (n=30) were associated with an operative mortality of 74%. By contrast, AAA resection in the expanding aneurysm group (n=19) and in the elective surgery group (n=44) was associated with a 10% and 2% mortality, respectively. Thus, resection of a nonruptured AAA in 63 octogenarians was carried out with an overall mortality of 4.7%. While nearly half of the patients had cardiac disease detected preoperatively, the elective group demonstrated a low incidence of previous myocardial infarction (7%) and congestive heart failure (8%). Concomitantly, the incidence of myocardial infarction (6%) and congestive heart failure was relatively low after AAA resection. Significant postoperative oliguric azotemia was observed in only 5% of the nonruptured patients. Long-term survival was comparable to that of the general population over the age of 80 years. The quality of life enjoyed by these patients was not adversely affected by AAA resection. By contrast, 50% of patients treated conservatively died of ruptured AAA. Physiologic rather than chronologic age should determine selection for AAA resection in the octogenarian. ",0
205,985148,The spectrum of myopathies in the city of São Paulo,"A review of all myopathic patients treated at the Neurologic Clinic of the Medical School of the University of São Paulo during the past 15 years  is reported. A total of 466 cases were examined and distributed as follows: 56% of progressive muscular dystrophy; 31% of myasthenia gravis; 6% of polymyositis; 4% of myotonic dystrophy; and the remainder of several different diseases (central core disease, Kearn-syndrome, myotonia congenita, adynamia episodica hereditaria, diabetic myopathy and Eaton-Lambert syndrome). Enzymatic dosages, electromyography, muscle biopsy, electrocardiography and genetic counselling are also reported. ",0
206,985201,Osmolality changes in perilymph after systemic administration of glycerin,"Blood osmolality was altered in guinea pigs by intravenous administration of glycerin (glycerol). After glycerin administration, serum osmolality increased rapidly, reaching a plateau within 15 minutes. Perilymph osmolality lagged significantly behind the increase of serum osmolality and equalled serum osmolality only after one hour. While perilymph osmolality responded to changes of serum osmolality, there was some time lag noted in the response of perilymph, suggesting the existence of a blood-labyrinth barrier. It was observed that this barrier is permeably to glycerin and water, suggesting the possibility of transient reduction of hydrostatic pressure in the labyrinth by the injection of an osmotic agent into the systemic circulation. ",0
207,985698,Crystalline 3-phospho-d-glycerate kinase from horse muscle,"Phosphoglycerate kinase has been isolated in crystalline form from horse muscle. A convenient isolation procedure is described that yields homogeneous enzyme of specific activity 700 units/mg (30 degrees C). The enzyme is monomeric, and has a molecular weight 47 000. Of the eight cysteine residues in the protein, two react rapidly with Nbs21 with the concomitant loss of the catalytic activity. Since the isolation of phosphoglycerate kinase from yeast (Bücher, 1955) there have been several reports of purification methods yielding enzyme approaching molecular homogeneity, from rabbit muscle (Beisenherz et al., 1953; Czok and Bücher, 1960; Rao and Oesper, 1961; Avramov and Repin, 1965; and Scopes, 1969) and from chicken muscle (Gosselin-Rey, 1965). Crystalline material has been isolated from human erythrocytes (Hashimoto and Yoshikawa, 1962), and from yeast and rabbit muscle (Krietsch and Bücher, 1970). Cystallographic work on phosphoglycerate kinase from horse muscle by Blake et al. (1972) and Blake and Evans (1974) has prompted mechanistic interest in the enzyme, and we report here a simplified isolation procedure and some properties of the crystalline material from this source. ",0
208,985737,Partial purification of the ovalbumin gene,"Cellulose-bound DNA complementary to ovalbumin mRNA was used in a continous hybridization system to isolate single-stranded DNA molecules containing the ovalbumin gene. Fragmented DNA segments containing the ovalbumin gene were enriched 300-350 fold in one cycle of purification. Two cycles of purification resulted in a DNA fraction which was enriched 2300 fold in the ovalbumin sequence. The method is suitable for purification of the ovalbumin sequence from both sheared DNA fragments, as well as larger molecular weight DNA containing more than twice the number of nucleotides necessary to code for ovalbumin mRNA. The chromatographic procedures were specific and reproducible. In addition, the recovery of ovalbumin DNA was essentially quantitative (80-100%), even when large amounts of starting DNA (70-75 mg) were used. This purification scheme should also be useful for the enrichment of other unique sequence gened form eucaryotic DNA. ",0
209,986006,Orphan data and the unclosed loop: a dilemma in PSRO and medical audit,"The experience of the Utah Professional Review Organization in conducting medical audit as a PSRO prototype, and later a PSRO, suggests that usage of diagnosis-oriented process audits, using criteria similar to those supplied by the American Medical Association, will result in accumulation of vast amounts of unusable data. Even studies based on outcome data may fail to change physician behavior substantially because of communication difficulties between the PSRO or hospital conducting the evaluation and the physicians subject to the audit. UPRO's experience suggests that medical audit can be made more effective if it employs a special study format that looks at a particular element of care, selected for its importance to patient welfare and potential for improvement. The study should be based on criteria solidly validated by clinical research, and should involve a direct and personal interaction between the review body and the physician being reviewed.",0
210,986008,Circular dichroism studies on the interaction of sulfonylureas with insulin,"The interaction of 5 sulfonylurea derivatives with insuline was investigated by means of circular dichroism measurements. It was found that all sulfonylureas investigated decrease the ellipticity band of insulin at 208 nm, whereas the band at 222 nm remains unaffected. It is suggested that these observations are due to a change of the insulin conformation, provoked by the interaction of the drugs with insulin. It is assumed that such an effect on the insulin conformation can influence the binding properties of insulin, e.g. in respect to the insulin aggregation, to the binding to insulin antibodies and to a bound, inactive form of insulin in the plasma. Some other drugs have similar, but mostly smaller effects on the CD spectrum of insulin. Therefore, the importance of these observations for the hypoglycaemic action of the sulfonylureas is not yet clear. ",0
211,986115,"Immunocytologic losses of isoantigens A, B, and H (O) in the endometrium and brain","Formalin-fixed tissues from 100 endometria and 50 brains were grouped and studied by the technic of mixed-cell agglutination reaction (MCAR) for studying isoantigens A, B, and H (O). MCAR's were negative in all 45 of the endometria from subjects with endometrial carcinomas, where as MCAR's were positive in the epithelium of endometrial glands of the remaining 55 subjects (cyclic phases of endometrium and benign lesions). MCAR's were negative in all benign and malignant brain tumors and normal brain tissues used in this study. In view of the present findings and in the light of previous observations, the isonatigen loss in adenocarcinomas is greater than such losses in other types of malignancies so far studied. The cause of the negative MCAR's in normal brain tissue and brain tumours is not known, but they may be attributable to lack of isoantigens in normal brain tissue. ",0
212,986369,Selective quantitative determination of single endogenously liberated nonesterified fatty acids in the blood of surgical patients],"Under defined external conditions of metabolism, a selective and quantitative determination of the single nonesterified fatty acids (NEFA) in serum allows the characterization of the interrelationship between the adipose tissue as a deposit of substrates for longterm energy production and the energy consumpting cells on the one side, as also the estimation of the extent of the stress itself. Compared with the amount of the whole lipidfraction, the very low concentrated NEFA may indicate the status of the endogenous delivery of energy-substrates only when analyzed with a high efficient selective, quantitative and direct method. The main question of the presented investigations on 14 surgical patients was the influence of an acute event of aggression on quality and quantity of fatty acid mobilization. After detailed characterization of experimental methodological conditions, the concentration-profiles and amounts of the mobilized NEFA and their modifications by the stress-reaction are reported. ",0
213,986661,Electroencephalographic correlates of audiogenic seizures during ethanol withdrawal in mice,"C57BL/6Bg mice had silver bead electrodes chronically implanted on the surface of the cortex and had their cortical EEG recorded during audiogenic seizures following ethanol withdrawal. For 7 days, the experimental groups were fed a liquid diet containing 6% v/v ethanol ad lib as the only source of food and water. The control group was fed a similar diet containing an isocaloric amount of sucrose. The cortical EEG's of experimental and control groups before, during, and after treatment were virtually identical. Only the experimental group was susceptible to audiogenic seizures. During audiogenic seizures, the cortical EEG showed no sign of spike waves or paroxysmal activity. This is in contrast to picrotoxin convulsions with these same mice as well as to spontaneous convulsions in animals following ethanol withdrawal. Similar EEG observations have been reported on audiogenic seizures from genetic and acoustically primed susceptibilities. Consequently, we suggest that all audiogenic seizure responses, including those during ethanol withdrawal, are a type of subcortical epilepsy. ",0
214,987567,Studies on the induction of permeability in Ascaris lumbricoides eggs,"The initial process in the hatching mechanism of Ascaris eggs is the sudden onset of permeability in the previously impermeable ascaroside membrane. During this change the ascaroside membrane remains intact and no chemical changes can be detected. Using the molecular probe 1-anilino-8-naphthalene sulphonic acid no conformational changes were detected in the ascaroside membrane during the induction of permeability. It is suggested that either the permeability change is due to a very localized chemical or conformational change, not detectable by conventional analytical techniques, or the change is due to mechanical damage of the ascaroside membrane, brought about by the activity of the infective larva. ",0
215,987845,Spontaneous occurrence of tumors in laboratory-reared arvicoline rodents,"Data from more than 2500 laboratory-reared rodents of four arvicoline genera raised since 1966 indicated that the incidence of neoplasia increased spontaneously in a nearly linear manner from 1968 to 1974. The incidence was highest in Clethrionomys rutilus, with an age-adjusted rate of 32 tumors/100 animals in 1974. The various species of Dicrostonyx exhibited dissimilar rates (22 tumors/100 animals, average for 1972 to 1973) with lower rates observed in the genera Microtus and Lemmus. Tumors of epithelial origin predominated with four common types accounting for 69% of the 260 tumors observed. A trend toward development of multiple primary tumors corresponded with the increase in incidence. An agent, identified as an adenovirus, was isolated from Harderian and preputial gland adenocarcinomas, and a second virus, tentatively identified as a hamster type H partcle, was observed in mammary and salivary gland tumors of Dicrostonyx stevensoni and C. rutilus, respectively. These and other data presented suggest an infectious etiology. ",0
216,987978,Mutants of Emmonsia crescens--their pathogenicity and size of adiaspores in vivo,"The pathogenicity of seven morphological mutants of Emmonsia crescens was tested by means of intraperitoneal inoculation in mice. All mutants caused adiaspiromycosis. Adiaspores were isolated from granulomas after 2 months and their diameters were determined. Adiaspores from granulomas caused by five mutants (M-5, M-6, M-8, M-9 and M-16) were significantly smaller than adiaspores from granulomas caused by the wild strain, from which the mutants were derived. Two mutants (M-6 and M-9) produced adiaspores of the smallest diameter (130.5 and 119.9 mum) with the lowest variance of values, differing thus most from the original wild strain with adiaspores of 230.4 mum in diameter. A positive correlation was found between the size of the adiaspore in vivo and growth rate of the mycelial stage of Emmonsia crescens in vitro. The mutation characterized by the decreased growth rate of the mycelial stage is phenotypically manifested in the adiasporic stage of the life cycle of Emmonsia crescens, i.e. by the smaller average size of adiaspores in granulomas. ",0
217,988425,Vater or Vacterl syndrome (author's transl)],"Analysis of malformations in 65 newborns with limb anomalies, 39 with esophageal atresia with tracheoesophageal fistula, and 41 with anal atresia confirmed the nonrandom tendency for the defects of the VATER or VACTERL syndrome to associate together. 11 new patients with 4 or more of these anomalies were compared with 41 previously reported cases. There was good agreement with reference to the frequency of the major malformations noted in the VACTERL association. While anal atresia was not so common in our patients, cardiac anomalies and radial limb dysplasia occurred somewhat more frequently. In accordance with previous findings we also emphasize a single umbilical artery as one of the malformations in the spectrum of the VACTERL association (V = vertebral defects and vascular anomalies). Because of the high incidence of rib anomalies in our patients and in earlier cases with complete medical records it is suggested that the scope of the VACTERL association should be enlarged by this malformation. Thus the R in VACTERL would stand not only for renal defects but als for rib anomalies. Furthermore, the spectrum of anomalies could be extended by auricular defects (A = anal atresia and auricular defects). When one of these VACTERL components is found attention should be drawn to the possibility of the presence of the other associated anomalies. The developmentally correlated malformations seen in the VACTERL syndrome are generally sporadically observed. At the present time the etiology is unknown but heterogeneity is suggested. Although a causal relationship between maternal intake of progesteron/estrogen during the vulnerable period of embryogenesis and the VACTERL syndrome has been suggested, none of the mothers of our patients were exposed to these hormones during early pregnancy. Cytogenetic investigation in one patient and his mother showed a so-called marker chromosome 9 (C9qh+ variant) which is difficult to interpret at the present time. ",0
218,988995,Changing pattern of residual tumor in Burkitt lymphoma: findings at autopsy,"Autopsies were performed on 47 patients who died of Burkitt lymphoma in Uganda between 1967 and 1971. The patients were separated into four groups based on the duration of survival from the time of diagnosis. Twenty patients survived less than three weeks; all had massive tumors. Six patients died between 10 and 16 weeks after diagnosis, usually from side effects of drug therapy. Of 16 patients who died between 24 and 52 weeks after diagnosis, 13 showed involvement of the central nervous system. Five patients died one year or more after diagnosis; two had a late relapse following a disease-free interval of one and four years, respectively; the other three had survived with clinically apparent tumor that was not responsive to therapy. In recent years, there has been a steady reduction in the proportion of patients showing residual systemic involvement at autopsy. This reduction is balanced by an increase in the proportion of patients with lesions of the central nervous system. ",0
219,989016,Digitoxin plasma half-life in the dog after administration of toxic doses,"Digitoxin plasma levels were determined in the dog by radioimmunoassy after i.v. infusion of this cardenolide in toxic amounts (388 +/- 13 mug/kg). Plasma values found immediately after the administration of this dose were 588.5 +/- 91 ng/ml and attained very low levels (10 ng/ml) 96 h later. The dominant half-life of digitoxin in the dog was found to be 49.6 +/- 6.5 h, but this value was attained only in the final part of our study. The results found are compared with previous data and controversial aspects are discussed. ",0
220,989389,The role of dopamine in withdrawal jumping in morphine dependent rats,"The role of dopamine (DA) in precipitated withdrawal jumping was studied in morphine dependent rats. Pretreatment with various dopaminergic agonists induced a dose-dependent increase in naloxone induced jumping. Pimocide totally blocked the facilitatory effect of piribedil while naloxone induced jumping was not dose-dependently decreased. Biochemical measurements revealed that during precipitated withdrawal the level of DA was elevated and the accumulation of 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) after probenecid as well as the level of 3-methoxytyramine in the striatum was reduced. Unilateral inactivation of the caudate by local injection of KCl induced contralateral circling during withdrawal. Additional systemic haloperidol pretreatment did not change the direction of circling while additional apomorphine pretreatment changed the direction to ipsilateral and increased the circling rate highly. These latter as well as the biochemical findings strongly suggest an inhibition of striatal DA-mechanisms during withdrawal. The apparent contradiction of these findings to the above finding showing a facilitatroy role of DA-agonists on jumping is discussed. ",0
221,989466,Early responses to chemotherapy detected by pulse cytophotometry,"DNA/cell distributions were recorded by  automated cytofluorometry (=pulse cytophotometry) in bone-marrow aspirates of leukaemia and lymphosarcoma patients subjected to chemotherapy. In most cases, early perturbations in DNA/cell histographs were observed, characteristically reflecting the known mode of action of the drugs. These changes in general preceded the clinical observation of drug response. In a series of 23 measurements in 19 patients, a positive correlation between early cytophotometric changes and clinical effects of chemotherapy was observed in 17 patients. Five patients were negative for both cytophotometric and clinical reactions and one patient was probably false-positive. The validity of the assay for early detection of drug resistance in acute leukaemia and related diseases is discussed. ",0
222,989947,The resistance to antibiotics and chemotherapeutics in bacteria (author's transl)],"Many people today, in agricolture, zootechny and animal feeding, operate with antibiotics and chemotherapeutics. Not all perhaps, know the inconveniences that the large and uncontrolled use of these substances may cause first of all the emergency of bacteria strains resistant to these drugs. We have devoted our attention particularly to the modalities of establishment of the phenomenon: to its incidence and variability in nature, to its transferability and, at least, to its biochemical aspects. ",0
223,990033,Auto-immunity in certain thyroid diseases,"In the years 1971-74, 88 patients were admitted to the Department of Otorhinolaryngology of the Finsen Institute because of thyroid disease. In 37 of these patients, who had also been tested for antibodies against the thyroid, the diagnosis was confirmed histologically. The existence of circulating antibodies against thyroid tissue was found to reflect the degree of lymphocyte infiltration in the thyroid gland, and is thus of significance in the evaluation of the patients' prognosis and potential risk at surgery. ",0
224,990171,Physical training and connective tissues in young mice. Biochemistry of skin,"The effect of physical training on some connective tissue components of the skin was studied in male mice of NMRI-strain. The mice to be trained and their controls were about 2-weeks-old at the beginning of the training, which took place on a 5 degree inclined treadmill 5 days a week for 3-22 weeks progressively. The final exercise bouts were 50 and 80 min for moderate programmes and 180 min for the intensive programme at a speed of 30 cm/s. At the end of each experiment skin samples from trained and control animals were taken for the analyses. We found increased concentrations of nitrogen, hexosamines and hydroxyproline in the skin of the trained mice compared to the controls. The unchanged DNA concentration suggests that the activation of synthesis occurred in a constant number of cells. ",0
225,990178,Platelet density and size: the interpretation of heterogeneity,"Platelets have been separated according to buoyant density using a colloidal silica-polyvinylpyrrolidone system and subjected to electronic sizing. All density populations were found to be heterogeneous in size, the most dense platelets ranging from less than 3 fl to greater than 21 fl in both man and rat. Light platelet fractions contained no platelets greater than 13 fl in either species. Cohort labeling with [75Se]selenomethionine showed no indication of significant change in platelet buoyant density with ageing; greater specific activity found in young, dense platelets appears to be related to increased protein synthetic activity shown in vitro and likely to occur also in their precursor megakaryocytes. It is postulated that dense, intermediate and light platelets are released synchronously by the three different ploidy classes of megakaryocyte, that varying density indicates differing structural characteristics and presumably differences in function. The present findings do not deny the possibility that platelets decrease in size with ageing but if such occurs, it is not associated with a significant change in platelet buoyant density. ",0
226,991121,Metastatic uterine leiomyomata. A case report,"Pulmonary metastases from uterine leiomyomata are extremely rare and unpredictable, despite the high frequency of uterine leiomyoma. Review of the literature reveals seven previous examples of pulmonary metastasis from uterine leiomyomata; other cases may exist, but they were not considered because there was little evidence to distinguish them from leiomyosarcoma. The case we report is unusual in: 1) its prolonged course of 21 years, 2) its lack of pulmonary symptoms, despite extensive multiple nodules; and 3) the cystic change of the multiple lesions, which mimicked cystic lung disease. ",0
227,991204,Granulolysis in neurosecretory neurons of the rat supraoptico-posthypophyseal system,"Ultrastructural and cytochemical observations on neurosecretory neurons of the rat supraoptico-posthypophyseal systems were made under experimental conditions which resulted in striking changes in the amount of neurosecretory granules and lysosomes. Attention was focused on granulolysis. At the onset of rehydration following a 4 days water deprivation, very active autophage took place in neurosecretory axons of the neural lobe involving the marked increase in smooth endoplasmic reticulum, microvesicles and neurosecretory granules, although the latter were still very few due to previous depletion. When axonal transport was inhibited by colchicine at the onset of rehydration, granules accumulated in the perikarya while granule reloading of the neural lobe was delayed. However autophagy, although always active in axons, remained scarce in perikarya. Moreover, in the latter there was only slight evidence of crinophagy. Hypophysectomy also induced granule accumulation in the perikarya, although accompanied by little granulolysis. Images indicative of crinophagy as shown by acid phosphatase localization were few and exclusively restricted to perikarya, while autophagy occurred essentially in axons. Autophagy appeared to be the predominant process for granulolysis and might be considered here as an aspect of the general turnover of cell constituents, related to the sudden regression of hyperactivity-induced hyperthrophy, rather than as an expression of a specific regulation of an excess of secretory material. ",0
228,991861,4-Alkyldihydroflavin: coenzyme synthesis and modification of flavodoxin,"A stable (i.e. non-oxidisable), reduced flavocoenzyme, 4a-(n-propyl)-4a,5-dihydro-riboflavin 5'-monophosphate, has been synthesized. The method of choice was selective photo-allylation in position 4a. Stabilization of this substituent was achieved by hydrogenation after N(5) protection, while hydrogenation of the unprotected compound would have led to removal of the allyl substituent. The mode of this substituent mobility has been checked with deuterated photosubstrate. Upon hydrogenation, the allyl substituent becomes firmly and irreversibly fixed to the flavin surface. The diastereomers thus formed have been separated and characterized by their ultraviolet, circular dichroic and nuclear magnetic resonance spectra. After subsequent side chain phosphorylation it has been shown that only one of the diastereomeric dihydro-flavocoenzymes is firmly bound by Peptostreptococcus elsdenii apoflavodoxin. This leads to the hypothesis that (a) the non-planar 4a,5-dihydro-flavin isomer and, therefore, C(4a) as active flavin center, may have biological relevance, while (b) the flavin site in flavodoxin is accessible to some extent for a stacking interaction with a redox-partner group. ",0
229,991903,Immune response region-associated antigens of the mouse: biochemical properties of detergent and papain solubilized molecules,"Immune response region-associated (Ia) antigens and classical H-2 antigens are glycoproteins which differ in their molecular weight and tissue distribution. Ia and H-2 molecules also show differences in overall charge, apparent isoelectric point and susceptibility to proteolytic degradation, acid treatment and exposure to 56 degrees C. In the present paper, Ia.11d antigens were shown to have a molecular weight of about 35000 after solubilization with nonionic detergents. Purified Iad antigens, solubilized by controlled papain digestion, display a molecular weight of about 26000 after final purification by indirect immune coprecipitation.  This figure corresponds to the molecular weight of a highly purified H-2 polypeptide fragment obtained after papain solubilization. The remarkable size similarity of proteolytic fragments from Ia and H-2 antigens could suggest that these genetically and functionally related molecules possess some structural features in common. ",0
230,992914,The imputation of motives for marijuana behavior,"The motives imputed to marijuana use and nonuse by both users and nonusers were investigated by means of open-ended questions. Verbal responses were categorized to symbolize typal vocabularies of motive, and these categories were tabulated against behavioral, social, experiential, and attitudinal variables. The results indicated that frequency of marijuana use and favorableness in drug attitude are the key factors that influence the degree to which different vocabular explanations are offered. Current users most often say that personal experience and personal reward are the motives behind use of the drug, and that legal sanctions and psychomedical effects largely account for its nonuse. Nonusers with unfavorable attitudes tend to verbalize emotional relief and psychological dependence as the motivations for use, and emotional independence for nonuse. Some of the vocabularies of both of these groups are emphasized by former users and nonusers with favorable attitudes. Interpretations of the data in terms of sociological theories of motives are presented. ",0
231,993792,Serum dopamine-beta-hydroxylase activity in rat during post-natal development,"Rat serum dopamine-beta-hydroxylase (DBH) activity is quite high in the immediate post-natal period reaching peak activity (75 units) at 16 days of age. Activity then decreases rapidly over the following weeks to approach adult levels (10 units) by seven weeks of age. Also, specific activity of DBH in heart increased rapidly during the first 2 1/2 weeks of life attaining adult levels by 18 days of age. In contrast, heart weight and total DBH activity in whole heart increased in a coordinate fashion at a relatively constant rate throughout the first seven weeks of life. Serum levels of non-copper sensitive endogenous inhibitor (s) of DBH increased throughout the first seven weeks of life while no change in copper sensitive inhibition was observed. Also, the rapid phase of decrease in serum DBH activity corresponded to the period of the most rapid increase in body weight. ",0
232,993950,Oral cholestyramine and paregoric therapy for intractable diarrhea following surgical correction of catastrophic disease of the GI tract in neonates,"Ten surgical neonates with postoperative intractable diarrhea and secondary weight loss were treated with combination cholestyramine and paregoric therapy. Within 3-5 days all infants except two showed significant clinical improvement with a decreasing number of stools, an increase in the consistency of the stool, and gradual weight gain. The exact mechanism of action of cholestyramine is not clear. It may act by binding with bile salts and/or endotoxins in the bowel lumen or decreasing the motility of the bowel. Used in combination with paregoric, a known bowel motility depressant, the doses of each medication can be kept quite low thus avoiding undesirable side effects. Medium chain triglyceride formula is helpful in some of these infants to improve fat absorption further. Medication in all of these infants has been discontinued without any adverse effects. ",0
233,994143,The incidence of epistaxis in racehorses in South Africa,"In South Africa 2,41% of horses bleed in a race. If all raced until they were 7 years old probably another 2,12% would bleed. Many others bleed after the race or during exercise or at rest. The incidence of epistaxis is significantly greater in geldings than in females and uncastrated males (P less than 0,001). There is an age distribution of bleeding which is highest at 4 years and lowest at 2 years of age (P less than 0,001). ",0
234,994516,Efforts in cancer diagnosis: national task forces--large bowel cancer,"Current information from the National Large Bowel Cancer Project and other sources is given concerning new leads and avenues of research that may be used in early diagnosis or possibly in monitoring therapy. The search for biological markers has developed in two general directions: (1) to identify by genetic studies patients with a high probability of developing cancer who will provide insight into biochemical changes as premalignant lesions develop into frankly developed cancer, and (2) to fine differences between tissue and body fluid constituents in normal subjects and patients with cancer. Screening for colon cancer is discussed with a selective diagnostic approach and with emphasis on this approach in early diagnosis of asymptomatic high risk patients. ",0
235,994744,Structure-function activity of azasterols and nitrogen-containing steroids,"Thirty-nine nitrogen-containing steroids were tested against two gram-negative, five gram-positive, and two yeast organisms. Many of these steroids have been previously reported to inhibit various metabolic processes involving sterol metabolism. While low minimal inhibitory concentration (MIC) values were recorded for sterol producing yeast, growth of bacteria which contain no sterols was also inhibited. Structure-function studies provided no relationship between biological activity and hypocholesteremic effects of these azasteroids. A hypothesis put forward is that amino and azasteroids are effectors of membrane which, in the case of mitochondria, lead to changes in adenosine triphosphate levels and/or dehydrogenase activity. Their effects on sterol metabolism, therefore, may be of secondary consideration. ",0
236,995031,Experiences with cephradine (Sefril) in septical-surgery (author's transl)],"100 patients with septic-surgical diseases were treated with the cephalosporine-derivate Cephradine (Sefril). 79 patients were treated by surgical intervention in advance of the antibiotic therapy, 21 by Sefril in combination with conservative therapy only. The continuance of medication amounted to two weeks in 94%. A complete healing of the pyogenic infection was obtained in 86 patients. Complications occured in 6%. ",0
237,996038,The effect of memory blocking antibiotics and their analogs on acetylcholinesterase,"The ability of antibiotics to inhibit acetylcholinesterase was measured in homogenates of goldfish brain. Puromycin aminonucleoside was the most potent inhibitor followed by puromycin, cycloheximide and acetoxycycloheximide. Puromycin effectively impaired retention of active-avoidance learning in goldfish when injected either immediately before or after training, while puromycin aminonucleoside did not regardless of injection time. These results suggest that the known amnestic effects of puromycin, cycloheximide and acetoxycycloheximide are not a consequence of interference with acetylcholinesterase. ",0
238,997329,Duration of use of intrauterine contraception],"Data from cytological examination of smears from the surface of IUD's were studied in 310 women;  94 of them had used IUDs up to 1 year, 150 from 1 to 3 years and 66 for 3 years or more.  The study revealed a membrane isolated from the endometrium, consisting of bloodcells (red corpuscles and dead leucocytes), mature squamous and glandular epithelium, amorphous protein mass, fibrin filaments, fibroblasts and multinuclear giant cells.  None of these smears revealed any atypical cells.  An examination of 116 washings from the surface of removed IUD's was done.  Biopsies were performed on the endometrium of 154 women;  the morphological picture was identical.  In several cases a local, nonspecific inflammation of the endometrium was detected.  There was no clinical disorder.  Intrauterine devices should not be used without interruption for more than 6 or 7 years, and the interruptions should last at least 2 or 3 months.  Regular, careful examinations should be performed on women using intrauterine devices. ",0
239,998045,Primary oxidation mechanisms in degradation of aliphatic hydrocarbons by bacterial enzyme systems (author's transl)],"The bacterial dissimilation of aliphatic hydrocarbons is catalysed by a monooxygenase mechanism with incorporation of molecular oxygen. Numerous publications have shown the cytochrome P 450-dependent hydroxylation of hydrocarbons, but there is considerably less information of hemo-protein-independent hydroxylations by alkanhydroxylases. In a marine Pseudomonad we found a system sensitive to cyanide: The oxygenase could be divided into three protein fractions. A cytochrome P 450 type spectrum was not detected. The NADH-dependent hydroxylation of n-decane can be activated by Mg2+ and Fe2+ ions. A noncompetitive product inhibition occurs which deserves special attention. An alcohol-dehydrogenase is closely associated with the oxygenase system by a kind of multienzyme-complex. Studies on kinetics and substrate specificity of this enzyme show an inhibition by excess substrate increasing with the chain length of the alcohols. The whole complex (alkanhydroxylase, alcoholdehydrogenase and aldehyddehydrogenase) is induceable by bacterial growth on alkanes, primary alcohols and fatty acids as sole carbon source. ",0
240,998270,C1 subcomponent conplexes in normal and pathological sera studied by crossed immunoelectrophoresis,"Selected pathological sera gave three molecular species of C1s protein on crossed immunoelectrophoresis in the presence of calcium. C1s precipitates were obtained at the origin and in the beta1 and alpha2 regions. 12 normal sera gave C1s protein peaks at the origin and in alpha2 position. One of the normal sera also contained a small amount of the beta1 C1s protein. The C1s protein at the origin represented macromolecular C1. The alpha2 peak was a complex composed of C1 IA, C1s and C1r proteins. This complex was preformed in serum and did not show C4 cleaving activity. The molecular species in the beta1 region was shown to be a calcium-dependent complex of C1r and C1s, probably in proenzyme form. the C1r-C1s complex formed macromolecular C1 on addition of purified C1q to serum. During electrophoresis activation of C1 subcomponents was initiated by a mechanism involving CIr with generation of CIs activity in eluted fractions corresponding to the position of macromolecular C1 as well as in the beta region. The significance of beta1 C1s complexes or of alpha2 C1s complexes in normal and pathological sera was discussed. ",0
241,998569,"Fibrinogen heterogeneity in cancer, in occlusive vascular disease, and after surgical procedures","""Electrophoresis in 3.5% polyacrylamide gel was used to determine the patterns of fibrinogen heterogeneity in healthy subjects, in postoperative patients and in patients with cancer or occlusive vascular disease. Two major and one minor fibrinogen fractions, differing in molecular weight, were identified, and their concentrations in blood determined. The high-molecular-weight (HWM) fraction was found in greatest concentration after operation, during the period of hyperfibrinogenemia, whereas no simultaneous increase of lower-molecular-weight (LMW and LMW') fractions occurred, suggesting that these were derivatives of HMW (""""native"""") fibrinogen. No correlation between the concentrations of the LMW and LMW' fractions and fibrinolytic activity was found, suggesting that direct degradation of HMW fibrinogen by plasmin was unlikely. The high fibrinogen level in cancer patients was related to increased concentrations of HMW and LMW fractions, whereas in the vascular-disease patients it was due exclusively to increased concentrations of LMW and LMW' fibrinogen. Serial observations indicated little fluctuation in the concentration of these fractions, indicating a persistently accelerated rate of conversion of HMW to LMW and LMW' fibrinogen in occlusive vascular disease. Possible pathogenic implications are discussed. """,0
242,998788,Effects of hypoxia on cardiac growth in neonatal rat,"To determine whether low oxygen environments enhance cardiac cell division in the neonatal period, newborn rat pups were reared for 21 days in 12-15% oxygen. Left ventricle and right ventricle weights were 30 and 180% greater than controls matched for body weight (P less than 0.001) as were left ventricle/body weight ratios (3.68+/-0.26 vs. 2.99+/-0.05 mg LV/g body wt,P less than 0.001). Left ventricular total DNA and DNA concentration was 95 and 48% greater than controls (P less than 0.001). Autoradiography confirmed that this increase in ventricular DNA resulted from an increased rate of division of cardiac muscle cells, fibroblast, and vascular endothelial cells. When [3H]thymidine was injected on day ), autoradiographs prepared on day 21 reflected an increased dilution of label in hypoxic rats consistent with enhanced proliferation. The labeling index and grains per nucleus of ventricular muscle cells was 25% (P less than 0.01) and 20% (P less than 0.02) less than controls, Thus, hypoxic stress applied early in the neonatal period augments the rate of division and ultimate number of cardiac muscle cells. Whether this enhancement results from a primary effect of oxygen or from secondary hemodynamic factors remains unknown. ",0
243,999065,"Acquired coagulation factor X activity deficiency connected with Hymenoxys odorata DC (Compositae), bitterweed poisoning in sheep","An acquired coagulation factor X activity deficiency was demonstrated in sheep fed Hymenoxys odorata, bitterweed plant. All coagulation tests were normal before the sheep were given the plant material. All tests involving the function of factor X, including a specific factor assay, became abnormal after the sheep were given bitterweed. Other specific factors remained within normal limits. The presence of an inhibitory activity could not be shown. ",0
244,999537,Use of radiologic methods in the study of pancreatic arteries],The intraorganic connections between separate arteries of the pancreas were studied in 26 dogs by methods of radioindication and radioisotope scanning. The results of measurings and the scannograms have shown the distribution of iodine-131 injected into the cranial pancreoduodenal artery to occur strictly within the limits of the head and the body of the pancreas. The radioactivity of tissues in the other parts of the pancreas was absent. The distribution of the isotope injected into the caudal pancreatic artery and into the pancreatic branches of the splenic artery was observed only in the uncinate process and in the caudal part of the gland. The data obtained show that in dogs the arteries of different parts of the pancreas are disconnected inside the organ. ,0
245,999736,Frequency of neoplasia in systemic lupus erythematosus and rheumatoid arthritis,"A patient population admitted to the hospital for either SLE or RA was surveyed for the subsequent development of neoplasms. The frequency of neoplasm in SLE patients appeared to be exaggerated, whereas the frequency of subsequent neoplasm in rheumatoid patients was unexpectedly low. A paucity of nephritis in the SLE group was noted. Further reports are encouraged so that the magnitude of the risk of malignancy developing with immunosuppressive therapy can be more precisely ascertained. ",0
246,1000141,"Height and personality characteristics of 47, XYY males in a sample of tall non-institutionalized males","A sample of 471 enlisted men 183 cm or taller serving in the US Navy, Coast Guard, and Marine Corps was screened for Y-chromosome aneuploidy by use of quinacrine fluorescence of peripheral blood smears. Two 47,XYY males were detected, resulting in a prevalence of 00425 or approximately 1 in 236. The prevalence of 47,XYY males (00331) in a number of samples of tall, non-institutionalized males is significantly higher than the incidence in newborn males (00061), indicating that 47,XYY males are disproportionately represented in tall male populations. The 47,XYY males had significantly higher scores than 46,XY males on the Schizophrenia, Schizophrenia+1K, and Prejudice scales of the Minnesota Multiphasic Personality Inventory and significantly lower scores on the Dominance scale. Since the probability that a randomly selected pair of subjects in the sample had four or more scale scores significantly different from the remainder of the group was greater than 05, it is possible that the differences between the 47,XYY and 46,XY males occurred by chance. On the other hand, one or more of these scales may measure personality dimensions on which non-institutionalized 47,XYY males may, in fact, differ from 46,XY males. ",0
247,1001025,Action of rotenone and related respiratory inhibitors on mammalian cell division. 2 Ultrastructural studies,"Light and electron microscopic examination of cultured mammalian cells treated with the respiratory inhibitor rotenone revealed that chromosome, spindle, and centriole configurations were virtually identical to that of mitotic cells arrested with Colcemid, a microtubule assembly inhibitor. The chromosomes of cells arrested in mitosis with either drug were grouped in a spherical mass near the cell centre and centrioles failed to opposite mitotic poles. Spindle microtubules were observed in limited numbers near some chromosome kinetochores and the centrioles. The outer portions of the cell cytoplasm were devoid of microtubules. Scanning and transmission electron microscopy revealed that cells did not progress beyond early stages of mitosis in the presence of rotenone or Colcemid. The ultrastructure of cells harvested from cultures grown in amytal was similar to that of untreated cells. These observations suggest that rotenone arrests mitosis in mammalian cells by inhibition of spindle microtubule assembly. ",0
248,1001242,Treatment of the neuroleptic syndrome by biperiden hydrochloride under its delayed-action form. A 9-month study on 55 hospitalized patients],"Biperiden hydrochloride has been used in the treatment of Parkinson's disease and related disorders within two drugs: --Akinophyl, --and Akineton which is chemically similar but has a slower effect. The first French publications upon its use as a neuroleptic corrector date from 1972. Our study deals with 55 chronic psychotic patients treated with neuroleptics and varied correctors of resulting Parkinson disorders. Akineton has been substituted for the preceding antiparkinson drugs. We may come to the following conclusions = Akineton is effective upon neuroleptic syndrom, gives few or no untoward reactions, has no toxicologic effects, shows no incompatibility with any other drug. It is very satisfactory to have at our disposal a drug effective in small doses and having a slow effect within average of 24 hours. ",0
249,1001257,Strain-dependent gonadal effects upon adrenal cholesterol ester concentration and composition in C57BL/10J and DBA/2J mice,"The effects of gonadectomy and sex hormone administration on the concentrations of the individual cholesterol esters in the adrenals of C57BL/10J and DBA/2J mice are described. The methyl esters of the fatty acids derived from the cholesterol ester fraction have been analyzed by gas-liquid chromatography. In both strains the females have a higher total adrenal cholesterol ester concentration than the males. However, different gonadal effects operate in the two strains. In the C57 strain the presence of the ovary or the administration of estradiol benzoate to the ovariectomized female increases the concentrations of all adrenal cholesterol esters. This effect does not occur in the DBA strain. In the DBA strain the presence of the testes or the administration of testosterone propionate to the castrate male lowers the concentration of all adrenal cholesterol esters. This effect does not occur in the C57 strain. The response to testosterone propionate in the castrate male of the DBA strain is significantly greater than that of ovariectomized female. This finding suggests that sexual differentiation influences the magnitude of the response. In both strains cholesteryl adrenate (C22:4) shows these gonadal effects to a greater degree than the other adrenal cholesterol esters. Thus, there are at least two types of gonadal control of adrenal cholesterol esters. One of these affects all the esters in general while the other affects adrenic acid metabolism specifically. ",0
250,1001267,Antiandrogenic and antirenotropic effect of spironolactone,Spironolactone given to male mice in dose 1.5 mg for 21 days produced significant changes not only in the highly androgen dependent seminal vesicles but also in the kidneys. Spironolactone blocked the action of endogenous testosterone in intact mice and led to further significant decrease in seminal vesicles and kidney weight in castrated mice. Such an effect could be due to a blocking of androgenic action of adrenal steroids. ,0
251,1001317,"Plasma volume, albumin and globulin concentrations and their intravascular masses. A comparative study in endurance athletes and sedentary subjects","Plasma volume, hematocrit, intravascular protein concentration, colloid osmotic pressure and the intravascular mass of proteins were measured in 49 sedentary subjects and 40 endurance athletes (long-, middle distance runners, cyclists). The plasma volume in sedentary subjects was 42.7(35.8-51.7) ml/kg body weight (BW) as compared to 54.6(46.7-65.9) ml/kg BW in athletes. The protein concentrations were 71.0 (66.5-77.1) g/l in sedentary subjects and 69.0 (64.8-75.2) g/l in athletes. The respective numbers for the hematocrit were 44.6 (40.1-49.25)% and 42.8 (38.2-49.6)%, for the colloid osmotic pressure 38.0 (36.0-40.5) cm H2O (n=35) and 30.0 (25.0-34.4) cm H2O (n=31), for the intravascular mass of proteins 3.09 (2.45-4.01) g/kg BW and 3.75 (3.31-4.67) g/kg BW. All differences were statistically significant at least on the 5% level. The physiological consequences for athletes of having a lower hematocrit and lower protein concentration but a higher intravascular mass of proteins (+22%) for their waterbalance as well as for their dietary protein intake are discussed. Endurance exercise stimulates mainly the synthesis of albumin and globulins produced by the liver resulting in an expansion of the PV. The protein synthesis of the RES does not seem to respond to exercise stimulus. ",0
252,1001846,Regulation of brittle diabetics by a pre-planned insulin infusion programme,"Eleven brittle diabetics, mean duration 11.5 years, all treated with highly purified porcine NPH insulin twice daily, were placed on highly purified porcine regular insulin 4 times daily for 2 days. Thereafter pre-planned intravenous insulin infusion was started. Insulin in an amount corresponding to the daily insulin requirement was infused by a mobile electric infusion pump at precalculated rates between 30 and 7 ml/hour during 2 days. The patients were ambulatory. Capillary blood glucose was taken every 30 min after meals and every two hours during the night. After an equilibration period of 7 hours, blood glucose fluctuations were in the physiological range in nearly all patients during the infusion period. [Only 1.3% of the blood samples showed glucose levels lower than 2.5 mmol/l and 2.9% levels exceeding 10.0 mmol/l during the infusion days]. Mean blood glucose (MBG) was 6.0 +/- 0.9 mmol/l (mean +/- s.d.), the standard deviation of MBG was 1.8 +/- 0.5 mmol/l, the mean amplitude of blood glucose excursions (MAGE) 4.7 +/- 1.4 mmol/l, and glucosuria 3.1 +/- 3.9 g/day. All these data of glucose  homeostasis were significantly lower during the infusion days. The incidence of hypoglycaemic attacks was low (0.32/patient/day) and not significantly higher than during NPH treatment. It is concluded that near normal blood glucose fluctuations can be achieved in brittle diabetics by preplanned insulin infusion without blood glucose monitoring. ",0
253,1001862,Effect of N-methyl-N'-nitro-N-nitrosoguanidine on immune response in rats in stomach carcinogenesis,"Subcutaneous injections of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at the dose of 50 mg/kg body weight for 10 days showed depressed production of hemolysin against sheep red blood cells (SRNC) in Wistar rats. On the other hand, oral administration at the dose of approximately 35 mg/kg body weight for 30 weeks scarcely suppressed antibody preduction to heterologous RBC and cell-mediated immune response to Walker-256 carcinosarcoma in Wistar rats during the experimental period of 55 weeks. The daily administration by way of oral route proved to be efficient for the induction of stomach cancer. The difference in immunosuppressive effect of MNNG by these two routes will be discussed in relation to the susceptibility of in vivo degradation of the carcinogen. ",0
254,1002006,Dose-dependent influence of acetylsalicyclic acid on platelet functions and plasmatic coagulation factors,"Lysine salt of acetylsalicylic acid (ASA) was given to ten patients by intravenous infusion. Blood samples taken at intervals during the infusion permitted the examination of the influence of the dose of ASA on platelet functions. Aggregation was significantly reduced when 50 mg ASA had entered circulation, while a diminution of PF3 and PF4 availability could only be demonstrated when the dose had reached 500 and 200 mg, respectively. In order to exclude a longer latency time for the diminution of PF3 and pf4 availability, a second series of ten patients received intravenous injections of 100 and 300 mg ASA, respectively. From these patients, blood was taken 1 h after the injection. The decrease of PF3 and PF4 availability in these cases was comparable to the results of the first group. In a third series of patients, a daily intravenous dose of 2,000 mg ASA was given. In these cases, a moderate decrease of factors II, VII, IX and X was observed. Since the appearance of a PIVKA effect could also be demonstrated, vitamin K antagonism was assumed when a high dose of AS ",0
255,1002301,Lung weight parallels disease severity in experimental coccidioidomycosis,"Evidence provided by histopathological study of lesions is a valuable adjunct for evaluating chemotherapeutic efficacy in experimental animal models, In addition, this should be correlated with a measure of disease severity in the same animal. The latter could be obtained by homogenization of infected organs and quantitative enumeration of viable cells of the etiological agent, but this would preclude histopathological studies in the same animal. Progression of disease in pulmonary infection is associated with replacement of air space by fluid, cells, and cellular debris. Therefore, an increase in lung weight should reflect severity of disease. Results with the murine model of coccidioidomycosis demonstrate that increasing lung weight parallels the increasing census of fungus cells in the lungs of both treated and nontreated infected mice. This was supported with evidence obtained from microscopic studies of lesions indicating that specific chemotherapy limited spread of the infection and inhibited multiplication of the fungus in the lung. Therefore, lung weight can be used as a measure of disease severity in the murine model of coccidioidomycosis. ",0
256,1002569,Morphology and histochemistry of the adrenal medulla. I. Various types of primary catecholamine-storing cells in the mouse adrenal medulla,"Semithin sections (Araldite) of mouse adreno-medullary tissue were examined in the light microscope after perfusion fixation with glutaraldehyde, glutaraldehyde/formaldehyde or after freeze-drying followed by a treatment with hot formaldehyde gas. The following methods were employed: (i) aldehyde-induced fluorescence of catecholamines, (ii) Schmorl's ferric ferricyanide reaction, (iii) argentaffin reaction, and (iiii) staining with alkaline lead citrate followed by Timm's silver sulphide reaction. The correspondence of results obtained by the various methods was proven in consecutive sections or by successively applying different methods to identical sections. Four types of primary catecholamine-storing cells were identified. NA1 cells contain cytoplasmic granules up to 0.3 mum in diameter which stain black with ammoniacal silver and display a bright white to yellow fluorescence. NA2 cells show smaller cytoplasmic granules which stain brown with the argentaffin method and give white catecholamine fluorescence. NA3 cells appear yellow-earth after applying the argentaffin reaction and show greenish fluorescence. NA4 cells are hardly identified in the light microscope. These cells are significantly smaller than the above mentioned cells and characterized by  a high nucleo-cytoplasmic ratio. They become straw coloured with ammoniacal silver and show greenish fluorescence. The argentaffin reaction was also used to identify these cells in semithin sections of glutaraldehyde/osmium tetroxide fixed material. The fine structure of the various noradrenalin-storing cells was studied in consecutive thin sections. NA1 cells were found to contain two populations of granules, the larger ones measuring between 300 and 350 nm, the smaller ones about 175 nm. The granules in NA2 cells correspond to this latter population (175 nm). NA3 cells contain an uniform granule population with a main diameter of 120 nm. The smallest granules are seen in NA4 cells being in the dimension of 80 nm. Granules in NA1 and NA2 cells show uniformly high density, whereas those in NA3 and NA4 cells display cores of varying density. Granules with moderately dense cores in NA3 and NA4 cells may represent partially emptied sites of noradrenalin storage or dopamin containing particles. ",0
257,1002639,Effect of altitude exposure on thermoregulatory response of man to cold,"The thermoregulatory responses to 10 degrees C (for 3 h) were investigated in 1) 12 natives from sea level (lowlanders) at 150 m, and on arrival at 3,350 and 4,340 m; 2) 6 of these during a 6-wk sojourn at 4,360 m, and on return to sea level; and 3) 5 natives from each of the two altitudes (highlanders) in their respective habitat, and after descent to 150 m. The cold-induced increase in the rate of O2 consumption (Vo2) of the lowlanders was significantly smaller at both altitudes than at sea level. It did not recover substantially during the 6 wk at altitude, but was restored to its initial rate on return to sea level. By contrast, visible shivering activity was augmented on arrival at altitude. It persisted throughout the 6 wk there, but was greatly depressed on return to sea level, despite the increased Vo2. Mean skin temperatures (Tsk) stabilized in the cold at significantly higher values at altitude. Rectal temperature (Tre) decreased similarly at all altitudes. Vo2 of the highlanders in the cold was significantly greater at sea level than at their resident altitudes, although shivering activity was less intense; Tsk stabilized at significantly lower levels at 150 m than at either altitude. These results indicate that altitude exposure reduces the calorigenic response of man to cold, and that this effect is not moderated by acclimatization to altitude, yet is reversible immediately on descent to sea level. The component of cold thermogenesis which appeared to be reduced by altitude exposure was nonshivering thermogenesis rather than visible shivering. ",0
258,1002809,Determination of beta-cetotetrine in plasma and urine using high-performance liquid chromatography with electrochemical detection,"A sensitive and specific method for the determination of beta-cetotetrine in biological fluids has been developed using reversed-phase high-performance liquid chromatography and thin-layer electrochemical detection. The limit of detection for beta-cetotetrine was less than 0.25 pmoles, or approx. 100 pg injected on-column. beta-Cetotetrin could be analyzed in plasma at concentrations of 25ng/ml. Linear responses were observed up to 2.5 mug/ml, and the relative standard deviation of the procedure was +/-5%. The method was also employed for the determination of similar levels of beta-cetotetrine in urine. ",0
259,1003064,Control of glycolytic enzymes by androgens in the rat epididymis,"""The influcnce of steroids on the specific activities of glycolytic enzymes was studied in the caput and cauda epididymidis of the rat. In castrated animals, increases in enzyme activities were induced by the administration of androgenic steroids whilst oestradiol and progesterone were without effect. On the other hand, the """"antiandrogenic"""" steroid, cyproterone acetate (16 mg/kg per day for 2 weeks) did not cause a decrease in enzyme activities when administered to animals with ligated efferent ducts. Not all glycolytic enzymes responded to androgens, but more enzymes responded in the caput than in the cauda epididymidis. Administration of testosterone propionate to castrated animals demonstrated that maximum enzyme activity was produced at a dose of 0-1 mg/kg per day whilst higher doses were required to achieve maximum weight of the epididymis, seminal vesicles and prostate. Following castration of animals with ligated efferent ducts, no changes in enzyme activities were observed for approximately 2 days, but then activities declined over the next 2 weeks. When testosterone propionate was administered to castrated animals, a similar lag of approximately 2 days occurred before enzyme activities began to increase. """,0
260,1003584,Expansion of interstitial fluid is required for full restitution of blood volume after hemorrhage,"Dogs with splenectomy and intact adrenals and adrenalectomized-splenectomized dogs infused with cortisol at a physiologically increased rate restored plasma volume and protein and demonstrated early extracellular hyperosmolality. In contrast, adrenalectomized-splenectomized dogs infused with cortisol at a basal rate did not restore volume or protein after a transient initial phase and did not demonstrate extracellular hyperosmolality. From the foregoing evidence, it is postulated that the second state of restitution of blood volume following hemorrhage proceeds as follows: 1) Hemorrhage and the subsequent increase in plasma cortisol concentration lead to an increase in extracellular osmolality. An osmotic shift of intracellular fluid to the interstitium ensues. 2) The small increase in interstitial fluid volume results in a relatively large increase in interstitial hydrostatic pressure (because of the low compliance of the interstitium), thus accelerating lymphatic movement of interstitial protein to the vascular system. This movement results in a reequilibration of extracellular fluid toward the plasma. 3) The osmotically active agents mobilized by cortisol and hemorrhage do not appear to be glucose, sodium, or potassium. 4) There may be an adrenal factor other than cortisol that is necessary for full restitution of blood volume with 24 hours after hemorrhage. ",0
261,1005039,"Studies of the renin-angiotension-aldosterone system, cortisol, DOC, and ADH in normal and hypertensive pregnancy","Compared with a group of normal pregnant women, matched for age, parity, posture, and length of gestation, women with hypertension and proteinuria in the last trimester had significantly lower plasma concentrations of renin, renin substrate and angiotensin II. Plasma aldosterone and DOC concentrations were also lower in the hypertensive group. The plasma levels of cortisol, corticosterone, and ADH showed no significant difference. Plasma renin concentration was raised throughout normal pregnancy, and part of this increase appeared to be due to the presence of an inactive form of renin. Plasma concentrations of renin substrate, angiotensin II, and aldosterone were also raised in normal pregnant women, but concurrent measurement of these substances showed no significant relationship between them, renin, and plasma electrolytes in mid- or late gestation. A study of five women in the weeks immediately after conception showed increases in plasma angiotensin II and aldosterone concentrations, which were significantly related at this very early stage of pregnancy. Total 24-hour urinary sodium increased gradually from about two weeks after gestation to the end of the study five weeks later. This increase was due mainly to a rise in overnight sodium excretion, with a fall in the day/night ratio. No relationship was found between plasma angiotension II or aldosterone concentrations and day, night, or total 24 hour sodium excretion. ",0
262,1006521,Importance of calf vein thrombophlebitis,"Fifty-four patients with phlebogram-proven deep vein thrombophlebitis limited to the tibial and popliteal veins were studied for evidence of pulmonary embolism, both symptomatic and silent. All but two patients were symptomatic of either phlebitis or embolism. Pulmonary embolism, as judged by lung scan defects with V-Q imbalance, changing serial scans, or positive pulmonary angiograms were found in 50%. Popliteal thrombi had an embolism incidence of 66%, whereas tibial thrombi had a 33% incidence. Emboli from the popliteal veins were more extensive than were tibial emboli. Forty-five percent of all emboli were silent. Bilateral phlebitis was accompanied by a 75% incidence of pulmonary embolism. Emboli from tibial veins were minor in five of nine instances, but three instances involved 20% or more of total lung volume and one involved over 40% of total lung volume. These results support the belief that popliteal thrombophlebitis merits anticoagulant therapy. They also suggest caution in the management of tibial vein phlebitis. Objective tests are recommended to monitor for pulmonary embolism and for propagation of the thrombus before deciding to withhold anticoagulants in tibial thrombophlebitis. ",0
263,1007761,Cardiac actions of arachidonic acid,"The cardiac actions of arachidonic acid (AA, C 20:4), the precursor of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha) were studied in isolated atria and papillary muscles of guniea-pigs as well as canine Purkinje fibers. In contrast to the cardio-depressant actions of some short and long-chain fatty acids (octanoate, oleate) AA (10(-6)-10(-4) M) increased sinoatrial rate and contractility in guinea-pig atrial preparations. This cardio-stimulant action of AA was accompanied by an increase in the amplitude and maximum rate of rise of the intracellularly recorded atrial action potential. Some increase in the resting membrane potential and a slight prolongation of the action potential duration could also be observed. AA did not induce any pace-maker activity in isolated papillary muscle of guinea pigs or in isolated Purkinje fibers. Similarly to AA, PGE2 and PGF2 alpha (2.1-10(-8)12.1-10(-5) M) were also found to increase atrial rate and contractile force. The stimulating actions of AA were reduced by application of high concentrations of indomethacin (5-10(-5) M). ",0
264,1008727,The porosity of bone cement (author's transl)],"""This paper describes a method of measuring the porosity, shape, distribution and formation of cavities in acrylic cement. We distinguish between big spherical cavities greater than 60 mu and small cavities less than 60 mu which form a variable """"basic porosity"""" with a large number, but a minor volume of bubbles. The bubbles are formed in two different ways. The first is through introduction of air bubbles in the mixing phase by stirring the cement before the working time. These bubbles expand little by temperature rise. The second method of formation is through neoformation of bubbles by evaporation of the monomer at about 100 degrees C. This neoformation of porosity expands the cement. The rise of volume through the neoformation and expansion of bubbles is able to compensate the shrinking of cement due to the polymerization. This effect, however, cannot be currently controlled. Cement strength is influenced by the degree of porosity. """,0
265,1008860,Regeneration of renal proximal tubules after mercuric chloride injury is accompanied by increased binding of aminoacyl-transfer ribonucleic acid,"Homogenates of rat kidney cortex obtained 1,3 or 14 days after a single injection of HgCl2 were used to prepare the post-microsomal pH5 supernatant fraction. The activity of this fraction for peptide synthesis from [14C]phenylalanyl-tRNA was significantly increased at 1 and 3 days, at which time the proximal tubules are regenerating [Cuppage & Tate (1967) Am. J. Pathol. 51, 405-429]. This increased activity could not be attributed to a decreased inhibitory activity, but was due to an increased aminoacyl-tRNA binding, i.e. elongation-factor-1 activity, in the supernatant fraction. ",0
266,1009116,A note on the dual role of glucose in the protection of glucokinase against inactivation,"Protection against thermal denaturation, urea denaturation and tryptic inactivation of rat liver glucokinase (ATP:D-glucose 6-phosphotransferase, EC 2979192) is provided by glucose and to a lesser degree sorbitol. 2. Protection by glucose exhibits two distinct stages, one occurring at the physiological substrate levels, while the other occurring well above that necessary for enzyme saturation. Sorbitol protection increases uniformly with increasing sorbitol concentration. 3. Several other enzymes also are protected against heat inactivation by high concentrations of glucose or sorbitol. ",0
267,1009910,Lipid mobilization in obesity without carbohydrate intolerance. 2. Caffeine-stimulated lipolysis],The lipolysis induced by i.v. injection of caffeine (3 mg/kg body weight) has been investigated in 11 normal subjects and 18 obese patients with normal 50 g oral glucose tolerance test and normal thyroid-function. The pattern of blood-glucose and immunoreactive insulin (IRI) secretion were not influenced by caffeine in both groups. Both in the controls and obese group a significant response of FFA and glycerole were noted. In the obese group the caffeine-induced lipolysis was slightly higher as compared with controls. There are no differences in FFA-response between obese group and controls. The observations suggest that an impaired lipolysis is not a pathogenetic factor for development of obesity. ,0
268,1010087,Functional specialization of stretch receptors in the triceps surae muscle of cats],"The behavior of 300 receptors in response to stepwise changes in muscle length was studied in passive m. triceps surae of cats anesthetized with nembutal. Distinct differences in receptor behavior were demonstrated, and receptors were divided into three functional groups according to their sensitivity to slow stretch (0.6 mm/sec in the limit range of 10 mm). The 1st group (elementary dynamic receptors) showed obvious sensitivity (over 70/sec) to dynamic components of stimulus and did not respond to static stretch in the physiological range. It was impossible to study the silent period during muscle contraction and stretch. The units of the 2nd group (elementary static receptors) reached maximal discharge frequency of 20--25/sec in the same range of muscle stationary stretch. The dynamic response of these receptors slightly exceeds the static response. The 3rd group, comprising 80% of units, served as universal detector of both dynamic and static phases of a stimulus. Some units showed significant dynamic response (over 70/sec) and moderate static response (about 30--40/sec), others exhibited moderate dynamic and static responses. The behavior of the receptors of universal type is similar to that of the well--known primary and secondary endings of the muscle spindles. Asto the endings of two elementary types they should be further indentified. ",0
269,1010464,Analysis by computer-controlled cell sorter of Friend virus-transformed cells in different stages of differentiation,"In most systems involving cellular differentiation and cellular transformation the biological process is non-synchronous and the sample heterogeneous. In order to answer some of the basic questions about the control mechanisms of cellular changes and the order in which they proceed one must have access to homogeneous classes of cells. Friend virus transformed erythroid cells which are stably maintained in tissue culture can be chemically induced to differentiate and are thus very advantageous for in vitro studies (1-3). With such a system the questions which we pose are a) the reversibility of the differentiation process; b) the order of steps in the production of specialized messenger RNA; c) the time of shut-off of undifferentiated messenger production; d) the relationship of viral RNA production to the differentiation process; e) the onset and extent of specific protein synthesis; f) the correlation of DNA metabolism with the timing or course of events. By using a computer-controlled cell separator we can select live cells on the basis of their macromolecular content, membrane properties (using a new parameter, fluorescence emission anisotropy), and size (4, 5, 34). Thus with proper probes as described here, we are able to select cells at different stages in their differentiation and can begin to attack the questions posed above. ",0
270,1010471,Influence of some cytostatics on leucocyte function,"Phagocytic activity, nitroblue tetrazolium reduction and candidacidal capacity have been studied in a group of normal persons and in three patients with acute leukaemia. The studies were performed in vitro in whole blood to which either a solvent only, or daunorubicin or vincristine had been added. The nuclei of all kinds of leucocytes showed characteristic changes in daunorubicin samples, resembling a beginning necrobiosis. In spite of this, these cells had an unchanged or even an increased phagocyting capacity. Vincristine reduced the phagocyting activity in most cases. The NBT test showed no significant change. Killing function of leucocytes, represented by their candidacidal capacity, was not affected by the cytostatics. ",0
271,1010660,Problems in the assessment of blood pressure: the Framingham Study,The reliability of casual blood pressures for reflecting blood pressure status and predicting cardiovascular sequelae of hypertension was examined in the Framingham cohort of 5209 men and women followed for 18 years. Blood pressures were more variable in persons with higher levels. After controlling for pressure level the degree of variability in an individual at one point in time did not correlate with the degree of varability at another time. Although a single casual measurement does not afford a precise characterization for an individual it was found to be highly predictive of future cardiovascular disease. A series of blood pressure measurements (averaged) improved the predictability somewhat but this seemed to be fully explicable by the  greater stability of an average of several measurements as against a single measurement. ,0
272,1011486,Metabolic disorders in chronic circulatory insufficiency],"Some enzymes of glycolysis and tissue respiratory were studied in 377 patients with chronic circulatory insufficiency developing due to atherosclerotic cardiosclerosis and rheumatic heart diseases. The severity of hyperenzymia was found to grow along with the increasing stages of circulatory insufficiency. A direct correlation was established between the total activity of LDH and MDH, as well as between LDH5 and MDH1. The presence of enzymatic shifts in patients with haemodynamic disorders permitted to include, with good substantiation and differentiation, such drugs into the complex therapy that favourably effect the disturbed metabolic processes. ",0
273,1033461,The quandary of quality assessment,"Inevitably, quality assurance reflects the context of which it is a part (e.g., underuse or overuse of services is partly a function of their availability and financing). Thus, it can promote change or rationalize lack of it, save money or cost money. Given the current state of the art, it is imperative to develop quality assurance on an evolutionary path while options are kept open and focus is clearly on outcomes. Also, quality assessment must be conceptualized as a behavioral tool, not a policing mechanism; its scope must be broadened to include the total episode of illness, taking into account life-style and environmental factors, with criteria developed and applied as close to the point of patient care as possible, within broad guidelines; it is essential to build on in-place capacities -- e.g., carrier data -- rather than to create new overlapping systems. Finally, the management setting within which quality assurance functions, in both the public and private sectors, must be improved.",0
274,1054106,Terminal deoxynucleotidyl transferase activity in human leukemic cells and in normal human thymocytes,"Peripheral leukocytes from patients with and without leukemia were assayed for presence of terminal deoxynucleotidyl transferase. Activity of this enzyme was detected in circulating leukemic cells from 11 to 13 patients with acute lymphoblastic leukemia, and in one of four with chronic myelogenous leukemia in blast crisis, but not in leukocytes from patients with other kinds of leukemia or in normal leukocytes. Its presence in a patient with chronic myelogenous leukemia in blast crisis lends biochemical support to the suggestion that some patients with chronic myelogenous leukemia undergo a lymphoblastic rather than a myeloblastic crisis. The thymocyte and leukemic-cell enzyme have the same substrate and primer preference. Normal thymocytes and leukemic cells contain two forms of terminal deoxynucleotidyl transferase that can be separated by phosphocellulose chromatography. The enzyme may provide a means for classifying leukemic cells on a biochemical basis independently of classic morphologic and clinical criteria.",0
275,1078593,Suppression of lymphocyte transformation after aspirin ingestion,"To learn whether in vitro blastogenesis of lymphocytes is affected by in vivo salicylate ingestion, blood samples were obtained from 19 normal volunteers before and after therapeutic doses of aspirin. Lymphocyte transformation studies performed on these blood samples showed marked and statistically significant suppression of blastogenesis. Maximum suppression was observed in blood samples obtained 12 hours after the last aspirin ingestion. As compared to controls, samples obtained at this time showed mean blastogenic responses to phytohemagglutinin and pokeweed mitogens of 49 and 56 per cent respectively. No correlation could be demonstrated between the plasma salicylic acid level and the degree of suppression of blastogenesis. Aspirin ingestion altered neither the proportions of circulating T and B cells nor the viability of lymphocytes in culture.",0
276,1079322,Serum immunoglobulins in the nephrotic syndrome. A possible cause of minimal-change nephrotic syndrome,"To assess immunologic factors in the pathogenesis of idiopathic minimal-change nephrotic syndrome (INS), serum immunoglobulin concentrations were measured in 37 children with this syndrome and compared with those found in 36 with nephrotic syndrome secondary to chronic glomerulonephritis (CGN). Serum IgG and IgA levels were significantly reduced in nephrotic patients with either INS or CGN, IgG averaging 18.5 and 25.9 per cent of normal (P less than 0.001) and IgA 59.8 and 44.1 per cent of normal (P less than 0.01) respectively. Values increased after treatment of INS with prednisone, but mean values remained low. Serum IgM concentrations in INS averaged more than twice normal before, during, and after successful treatment with steroids. Patients with CGN did not have equivalent elevations of serum IgM. Thus, the primary defect in INS may be immunologic and could consist of deficiency in the T-cell function that mediates conversion of IgM synthesis to IgG synthesis.",0
277,1080251,Impaired interaction (adhesion-aggregation) of platelets with the subendothelium in storage-pool disease and after aspirin ingestion. A comparison with von Willebrand's disease,"Possible defects in the interaction of platelets with the subendothelial surface were evaluated in six patients with storeage-pool disease, nine patients with von Willebrand's disease and seven normal subjects who ingested aspirin. Citrated blood was perfused through a chamber containing everted segments of rabbit aorta previously denuded of endothelium by means of a ballon catheter. With normal blood, 83.3 +/- 1.9 per cent (S.E.M.) of the surface was covered by adherent platelets. Platelet adhesion was normal after aspirin ingestion (89.7 +/- 4.6 per cent) and decreased in some patients with storage-pool disease. The most striking defect in both circumstances was the virtual absence of platelet thrombi. In contrast, decreased adhesion (57.3 +/- 3.4 per cent), but normal thrombus formation, was characteristic of von Willebrand's disease. These types of defects in platelet adhesion and aggregation may account for the hemostatic defects in a variety of bleeding disorders. The findings further suggest the possible usefulness of aspirin as an antithrombotic agent.",0
278,1089193,Psychiatry: the battered child of medicine,"""Psychiatry has had a troubled history. After the French Revolution """"moral treatment"""" brought to America a period of effective and humane hospital treatment, but this progress was corrupted by the Industrial Revolution, and psychiatry was rejected by society as well as by medicine. Although the Freudian enlightenment and the introduction of social psychiatry have led to greater acceptance, today's criticisms are strident. Psychiatry is criticized for imprecise diagnosis, conceptual vagaries, jargon, therapeutic impotence and class bias. The American system of mental-health care is seen by many as a disaster. The federal comprehensive Community Mental Health Act has been aborted at an early stage. Skills involved in the practice of psychotherapy are not unique to the profession. Social ills, over which psychiatry has little control, play a large part in causing mental disability and retardation. Nevertheless, though embattled, psychiatry has contributed to medical practice and to the humane consciousness of society.""",0
279,1089890,Atrioventricular block (first of two parts),The development of His-bundle (H) electrocardiography and the concept of hemiblocks have prompted a re-examination of conventional thinking about the indications for treatment of atrioventricular (AV) block. The technic of treatment is not the issue; ventricular pacemaking is the only really effective and reliable method. The problem for this review is what these recent developments have contributed to deciding when and if a pacemaker should be installed.,0
280,1097916,The future of chiropractic: a psychosocial view,"""As the total health-care delivery system in the United States has come under increasing public scrutiny, the role of chiropractic has become of interest. An overview of chiropractic, with an analysis of its social functions and a projection of its future indicates that chiropractic is more congruent with the values of its lower-middle-class clientele than is orthodox medicine. Chiropractors function adquately to legitimize their patients' entrance into the """"sick role"""" and to provide an alternative channel to therapy. The marginal role of the chiropractor in the health-care system, as compared to that of the physician, is stable and functional for the chiropractors thenselves, as well as for their patients. Chiropractic likewise serves the physician, both as a boundary-defining mechanism and as a means of disengagement from troublesome patients. For these reasons, we believe that the role of chiropractic within the health-care system will remain stable in the future.""",0
281,1097926,Demonstration of an intrathymic defect in a case of severe combined immunodeficiency disease,"An in vitro system has been developed to elucidate the nature of the cellular defect in primary immunodeficiency diseases. Incubation, on human thymic epithelial monolayer cultures, of peripheral blood lymphocytes and bone-marrow cells from a child with documented severe combined immunodeficiency disease resulted in the appearance of a population of cells that formed rosettes with sheep erythrocytes. The same cell preparation permitted the synthesis of antigen-specific, complement-dependent antibodies after in vitro education, as demonstrated in a plaque assay system. In addition, thymic tissue from the same child gave morphologic and functional evidence of maturation when cultured in vitro. The experimental results suggest that in this case, lymphoid precursor cells were present in the bone marrow but failed to differentiate to functional maturity due to a defect in maturation of thymic tissue.",0
282,1110726,Women in health care,"The occupational, class, and sex structure of the United States Health Labor Force is similar to the competitive sector of the economy (i.e., it is predominantly female, poorly paid and poorly unionized). Upper-middle-class men compose the great majority of medical professionals, whereas lower-middle and working-class women form the greatest proportion of all middle-level, clerical and service workers. This division of labor is due to the role of women both in the family and as a reserve of labor for the economy. There is a virtual absence of the majority of producers--lower-middle-class and working-class women-- in the decision-making bodies of the health institutions. The political strategy for change is to introduce institutional democracy in the health sector, with control on the institutions by those who work in them--and those who are served by them.",0
283,1117911,Function of the male sex organs in heroin and methadone users,"The function of the secondary sex organs was found to be markedly impaired in 29 participants in a methadone maintenance program. The ejaculate volume and seminal vesicular and prostatic secretions were reduced by over 50 per cent in methadone clients, as compared to 16 heroin addicts and 43 narcotic-free controls. Serum testosterone levels were also approximately 43 per cent lower in methadone clients than in controls or heroin users. Although the sperm count of methadone clients was more than twice the control levels, reflecting a lack of sperm dilution by secondary-sex-organ secretions, the sperm motility of these subjects was markedly lower than normal. On all measures of secondary-sex-organ and testicular function, heroin addicts appeared to fall between the methadone and control subjects, but, with the exception of sperm motility, the deviation from control values did not reach statisitcal significance.",0
284,1117913,Politics in the development of a migrant health center. A pilgrim's progress from idealism to pragmatism,"New methods of health-care delivery have been recommended to correct the inequities in the distribution of health services to rural and urban poor. A migrant health center developed in 1970 to accomplish this aim illustrated the many attendant problems. The award of the grant to an outside consumer group rather than to the country health department resulted in political pressures during the center's development. Other factors isolated the center. These included categorical funding specifically directed to a community's ethnic minority and the lack of a regional network of health care. Confusion was created when legitimate spokesmen of the target group, other segments of the local community or interested private and governmental agencies were not defined. Although a program for curative and preventive medicine was established for a minority, the center was less successful in becoming self-supporting and in affecting the social and economic determinants of health.",0
285,1124105,Total eosinophil counts in the management of bronchial asthma,"Total eosinophil counts were investigated in asthmatic patients to determine their usefulness in the diagnosis and management of steroid-dependent asthma. Counts averaged 122 plus or minus 74 (S.D.) per mm-3 (65 untreated normal subjects) and 43 plus or minus 22 per mm-3 (six prednisone-treated normal subjects). Fifty-two patients with active bronchial asthma showed significant eosinophilia (greater than 350/mm-3 off and greater than 85/mm-3 on steroids), suggesting that eosinophilia is an important diagnostic feature of bronchial asthma. In 14 patients (60 observations), the counts showed significant inverse correlation with specific airway conductance--r equals 0.74, p less than 0.001--and with a variety of other measurements of bronchial dynamics and lung volumes, suggesting that the total eosinophil count reflects asthmatic activity and is useful for regulating steroid dosage and for early detection of exacerbations.",0
286,1128590,Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain,"Glycine concentrations were measured in plasma and cerebrospinal fluid of five patients in different types of hyperglycinemia to determine why severe neurologic deterioration is confined to the so-called nonketotic form of hyperglycinemia. Glycine content and glycine-cleavage enzyme activity were also determined in brain obtained in autopsy from three of these patients. Spinal-fluid glycine concentrations were 15 to 30 times above normal in patients with nonketotic hyperglycinemia, but were normal in those with hyperglycinemias of undetermined type who had comparable elevations of plasma glycine. Glycine content was two to four times above normal in several brain regions, and brain glycine cleavage enzyme activity was absent in two patients dying of nonketotic hyperglycinemia. By contrast, glycine content was normal and glycine cleavage activity present in the brain of an infant who died of hyperglycinemia of unknown cause. These results suggest that elevated glycine levels may be harmless in blood, but lethal in brain.",0
287,1128591,Time lapse between hypothesis and publication in the medical sciences,"We studied a number of factors involved in the publication of 103 papers by Mayo Clinic authors. Basic-science and clinical-research articles averaged about four years from initiating the research idea until publishing; case reports averaged about two years, and literature reviews three years. Of this time, 75 per cent was spent contemplating the basic idea, performing the research, and writing the paper. The rest was required for processing, from institutional editing through publication. Most clinical workers wrote at home, and most basic researchers at the office. In a suprising 23 per cent of papers, about three fourths of the manuscript was written by someone other than the first author. Of references cited, between 10 per cent and 20 per cent were to the authors' own work or to that of co-workers. Half the papers were revised or rejected at least once, prolonging the journal handling time only in papers rejected or requiring more than one revision.",0
288,1134518,"A comparison of effectiveness of screening for phenylketonuria in the United States, United Kingdom and Ireland","A study of the effectiveness of screening for phenylketonuria in the United Kingdom, Ireland, and the United States indicated that the diagnosis is more likely to be missed in the latter two countries because of the earlier age at which infants are screened. Furthermore, in the United States, diagnosis and treatment are delayed as compared with Ireland and the United Kingdom. Because test most commonly used to detect phenylketonuria is identical in all three countries, the differences in effectiveness are attributable to the way in which it is applied. In the United Kingdom, personnel and facilities have clearly defined roles and responsibilities. There is co-ordination between in-hospital and extra-hospital health care, and follow-up care of young infants in the community is assured. Greater effectiveness of screening in the United States will require a more rational organization of health services.",0
289,1134519,Trends in survival rates of patients with cancer,"Reports on survival of patients with cancer issued by the National Cancer Institute indicate marked improvement for almost all forms of cancer from the 1940's to 1950's. Subsequently, prognosis for patients with forms of cancer accounting for approximately 42 per cent of all cancers continued to improve, although at a slower rate. For cancers of the lung, colon, rectum, stomach and pancreas, little improvement in patient survival during the 1960's was observed, and for women with invasive cervical cancer, survival rates decreased slightly. One-year survival results for patients with diagnoses made during 1970-71 suggest that improvement in five-year survival observed during the 1960's for many forms of cancer will be sustained. Continued reporting of survival of patients treated in the 1970's would ultimately demonstrate the degree of effectiveness of recently introduced therapeutic procedures.",0
290,1134530,Family medicine in perspective,"Family medicine is part of the process by which medicine adjusts itself to the changing needs of society. Family physicians have in common the fact that they obtain fulfillment from personal relations more than from the technical aspects of medicine. Their commitment is to a group of people more than to a body of knowledge. Their experience gives them a distinctive perspective of illness that includes its personal and social context. Medical knowledge includes information, skill and insight. Medical education has tended to emphasize the former: to concentrate on foreground rather than background. In the training of family physicians the education setting and the role of instructors are of crucial importance.",0
291,1134533,Editorial: Oral contraceptives and myocardial infarction,"Studies done in the United Kingdom suggest a correlation between ora l contraceptive (OC) use and increased risk of myocardial infarction (MI ). A study of 153 women under 50 years of age who died of MIs as compar ed with a control group of the same age and marital status showed a significant association between OC use and MI which became stronger with increasing age: e.g., risks for the 30-39 and 40-44 year-old groups were 2.8 and 4.7 respectively. Another study involving 63 MI survivors between 25 and 44 years of age compared with a similar control group showed a strongly positive association: 29% of the patients and 8% of the controls used OCs and risks for the 30-39 and 40-44 year old groups were 2.7 and 5.7 respectively. The risk in OC users was 4.5 times greater than in nonusers. Other risk factors such as diabetes, cigarett e smoking and obesity also have a positive association with MI. Only one of 17 OC users at the time of MI had no other identified risk factor . When ranked according to the number of risk factors present (includin g OCs) risks relative to women in whom none were present were 4.2 for 1 factor, 10.5 for 2 factors and 78.4 for 3 or more factors. These estimates suggest that in women under 45 years of age, OCs act synergist ically with other risk factors rather than additively, to produce MI. Stroke, also identified, did not appear as a result of a synergistic relationship between OC and other risk factors comparable to that found in relation to MI. Further study is needed but estimated incidence rates of fatal and nonfatal MI attributable to OC use are each about 3.5 per 100,000 30-39 year old users per year and each about 45 per 100,000 40-44 year old users per year. Women with more than 1 risk factor for MI should consider alternative methods of contraception. Those women who do use OCs regularly, especially older women, should be followed closely and advised against OC continuation.",0
292,1138163,Retrospective evidence favoring use of anticoagulants for myocardial infarctions,"During a state-wide retrospective study of myocardial infarction discharges from Maryland hospitals from July, 1966, through June, 1967, the relation of in-hospital case fatality rates to use of anticoagulants was examined in 1,156 patients. In patients who did not receive anticoagulants, the rate was 2.5 times that of those who did (p less than 0.0001). A large difference in case fatality rates between the anticoagulant and no-anticoagulant groups persisted when the data were analyzed by demographic and medical-care variables. When patients were classified according to clinical characteristics relating to prognosis, including arrhythmia, congestive heart failure and shock, the difference between the groups were also demonstrated. Although such a retrospective study cannot demonstrate conclusively the value of anticoagulant therapy, the data are sufficiently suggestive of a beneficial effect to warrant reopening the anticoagulant question.",0
293,1143300,Measures of clinical efficacy. Cost-effectiveness calculations in the diagnosis and treatment of hypertensive renovascular disease,"The sensitivity and specificity of the hypertensive intravenous pyelogram and the iodohippuran renogram have been determined for the diagnosis of renovascular disease, and cost-effectiveness calculations have been made for the diagnosis and surgical treatment of patients with renovascular hypertension. When the intravenous pyelogram alone is used to screen representative hypertensive population, 78 per cent of patients with renovascular disease are located, but at the same time an equal number of patients without renovascular diasease have abnormal pyelograms. The renogram, on the other hand, is associated with varying true-positive and false-positive ratios. These data can be plotted in the form of a receiver-operating-characteristic curve. The cost of finding a patient with renovascular disease is about $2,000, and that of a surgical cure is about $20,000. The number of deaths for 100 surgical cures is approximately 15. The dollar cost of screening and treating the total American renovascular hypertensive population is of the order of 10 to 13 billion dollars.",0
294,1143302,What do we gain from the sixth stool guaiac?,"The six sequential stool guaiac protocol has been advocated for screening of colonic cancer. Analysis of the expenditures involved in such a program shows that the cost of detecting cancer rises exponentially so that the marginal cost of the sixth test may be 20,000 times the average cost. The marginal cost is decreased with lower test sensitivity and increased with lower prevalence of colonic cancer. This result shows that even an inexpensive test can become quite costly in terms of cases detected. The marginal cost per case detected depends on the prevalence of the condition in the population screened and the sensitivity of the test applied.",0
295,1143304,Protecting the medical commons: who is responsible?,"The resources for medical care are clearly finite, but demands on those resources are growing rapidly. Of particular concern are the demands on those resources for medical practices of three kinds: those that pose conflicts between the interests of the individual and those of society; those of no value or of undetermined value; and those for potentially preventable conditions. Such practices must be evaluated in terms of social and medical priorities, and this requirement will become more urgent with the establishment of national health insurance. Who will make decisions is less clear, but it is not likely to be physicians alone. It is imperative that physicians and other health providers work closely with professionals from many fields, and with consumers, to ensure the availability and dissemination of information that will permit decisions that are in the best interests of society.",0
296,1143305,Rights and health care--beyond equity and efficiency,"Economic analysis in general has difficulty accommodating the concept of rights. The economic analysis of health care in particular proposes triage as the model of a rational delivery system, with no place for traditional ethical limits and obligations. Familiar arguments based on resource constraints do not prove that rights cannot reasonably be recognized. Nor are rights in general and rights in medical care in particular adequately respected by attending to considerations of just distribution or equity. Rights in medical care are different from rights to medical care, and must be respected in any decent, advanced society. That such rights may be overridden in emergencies does not mean that respect for rights is not a constraint upon the pursuit of equity and efficiency.",0
297,1152862,The effect of somatostatin on coagulation and platelet function in man,"Preliminary evidence has suggested that somatostatin might interfere with platelet function in the baboon. Because this agent is currently being administered experimentally to human beings, we studied its effect on coagulation and platelet function in man. In five subjects, a four-hour infusion of somatostatin (500 micrograms per hour) had no definite effect on platelet count, leukocyte count, hematocrit, platelet adhesiveness and aggregation, bleeding time, partial thromboplastin time, prothrombin time, and fibrinogen levels. A similar infusion for 18 hours in three subjects was likewise without effect. These studies indicate that somatostatin does not affect coagulation and platelet function in man and that its prolonged administration lacks ostensible toxicity.",0
298,1152892,Spontaneous abortion and aging of human ova and spermatozoa,"To test the hypothesis that aging of human gametes within the genital tract increases the chance of abortion, we measured the probabilities of abortion after insemination on a given day of the menstrual cycle in relation to the day of the shift in the basal body temperature in 965 patients. Cases came from family-planning and sterility clinics where basal body temperature and coital records are kept routinely. The probability of abortion diminished significantly (P less than 0.001) as the shift in temperature was approached and the increased to its highest point (24 per cent) three days later. Animal experiments have shown that aging of both spermatozoa and ova before fertilization is accompanied by higher probabilities of abortion. Present evidence indicates that this higher prevalence is also true for human beings.",0
299,1152895,Editorial: Perinatology begins before conception,"The liberalization of an abortion law in Oregon has resulted in the decline of fetal deaths and the prevention of maternal mortality. Since then the total population including that in the childbearing years has been steadily on the increase while the known conception rate has been decreasing by about 5% per year. While much progress has been made in identifying high-risk pregnancies and dealing more effectively with them, little progress has been made toward influencing events in the first half of pregnancy. Guerrero and Rojas have examined the outcome of pregnancy using basal temperature records to estimate ovulation time. Their findings have led to the belief that aging of sperm (before fertilization) or aging of eggs (before insemination) increases the probability of spontaneous abortion. In addition, overripeness may also lead to chromosomal abnormalities and to babies with Down's syndrome. However, proof is clearly lacking at this moment; careful testing is presently necessary. If proven true, prevention of such defects would be possible by educating people to juxtapose fertilization as close to ovulation time as possible.",0
300,1152923,"Internal medicine and family practice. Controversies, conflict and compromise","""Internal medicine and family practice have come into conflict because both specialties consider primary care to be part of their """"turf"""". Moreover, in academic medical centers there is competition for scarce resources, including patients and support for residents. Analysis of the number of physicians in practice as well as in training shows clearly that both internists and family physicians, as well as pediatricians and obstetricians, must participate in rendering primary care if the needs for this type of physician are to be met. Internal medicine also has to achieve a better balance between generalists and subspecialists, and family practice must define its limitations, monitor its rapid growth and assure the quality of its training programs. Most of these problems are internal to each speciality rather than between two specialties, and, where there is conflict, compromise is clearly possible.""",0
301,1167621,PSRO: an educational force for improving quality of care,"The major purpose of the PSRO program is to improve the quality of medical care. Peer review is expected not only to detect problems but to analyze causes, and to develop, implement, and evaluate corrective programs. Such peer-review efforts are in themselves educational. In addition, educational programs focusing on identified deficiencies must be organihe educational efforts of local health facilities and organizations of all types is urged. Although PSRO's will not specifically underwrite continuing health-care education, they should provide a community-wide means for integrating patient-care review with continuing medical education.",0
302,1172188,Autoimmune neutropenia,"Serologic tests for antineutrophil antibodies were used to determine if autoantibodies cause neutropenia. The serums of five patients with idiopathic neutropeniaopsonized normal neutrophils, causing them to be ingested by rabbit macrophages or else to activate glucose oxidation rates of other normal neutrophils by at least twice the rate of controls. Some of the serums inhibited the ability of normal neutrophils to ingest by 62 to 56 per cent. At splenectomy in two of the patients splenic macrophages contained ingested neutrophils, suggesting that the opsonic activity of the serum demonstrated in vitro had pathogenetic importance. In two adults, and possibly in an infant, corticosteroids raised the neutrophil count, although antibody activity remained in the serum of the adults. The findings indicate that autoantibodies are the basis of some cases of idiopathic neutropenia, and that they act by promoting the clearance of neutrophils by mononuclear phagocytes.",0
303,1177976,Pascal's wager and the hanging of crepe,"""Hanging of crepe refers to one type of strategy employed by physicians in communicating prognoses to families of critically ill patients. This approach offers the bleakest, most pessimistic prediction of the patient's outcome, presumably in an effort to lessen the family's suffering if the patient dies of his illness. Certain similarities exist between this technic and that used by Pascal, the 17th-century philosopher, in formulating his wager on the belief in God, in that both attempt to develop """"no-lose"""" strategies, in which chances for """"winning"""" are maximized. A detailed analysis of these strategies indicates that neither is truly """"no-lose,"""" and that both contain inherent disadvantages. Prognostication, an alternative approach to physician-family communication, appears to be strategically and morally superior to the hanging-of-crepe strategy.""",0
304,1178003,Beta-adrenergic mechanisms in action tremor,"To study the mechanisms by which propranolol suppresses essential tremor, accelerometric recordings were made from four normal subjects and eight patients with that tremor, and small amounts of isoproterenol and propranolol were infused intravenously or into one brachial artery. Intra-arterial isoproterenol increased tremor amplitude selectively in that arm in normal subjects and in patients with essential tremor (range, 1.85 to 3.50 with mean 2.74 times the base-line level). Intra-arterial or intravenous propranolol quickly blocked the enhanced action tremor in both groups. It did not simultaneously affect the underlying essential tremor, whereas long-term oral propranolol therapy did diminish the amplitude of the essential tremor in each patient. Peripheral beta-adrenergic tremorogenic receptors function normally even in patients with essential tremor; their function is not necessary for the production of essential tremor, and the efficacy of chronic propranolol therapy in the suppression of essential tremor is not mediated via its peripheral beta-adrenergic blocking action.",0
305,1186777,By the London post. Private rights and the public good - sterilization of minors - comment or report?,"The erosion of personal liberty and privacy is discussed in terms of the computer and data bank and the sterilization of minors. In Sussex C ounty, England a computerized school health service records the health a nd physique of school children. In 1970, 55 family physicians sent off personal details of their patients to be computerized without patient pe rmission. Mr. Hugh Macpherson has conceded the medical and administrative advantages of a computer system but thinks it is the perfect tool for the police state. The mother of an 11-year-old epileptic, mentally retarded, and sexually precocious girl asked to have the girl sterilized. A pediatrician had advocated the operation, and a gynecologist had agreed to perform it. A psychologist at the girl's school challenged the decision, and the girl was made a ward of court. Judge Heilbron ruled that the operation should not be carried out because it involved the deprivation of a fundamental human right. The Central Ethical Committee of the British Medical Association is reviewing the situation, and the Dept. of Health will publish a discussion document.",0
306,1186823,Testing the physician's knowledge of antibiotic use: Self-assessment and learning via videotape,"Because recent reports suggest that physicians in the United States do not use antimicrobial agents properly, we analyzed scores for the first 4513 physicians viewing the National Antibiotic Therapy Test, a nationally televised self-assessment test on the diagnosis and treatment of infectious diseases. The 75-minute videotape test, produced by the Network for Continuing Medical Education, contained three section: a 10-question pre-test, a 25-question teaching test, and a 15-question post-test. Scores were tabulated according to the specialty, years in practice, and volume of patients seen. The mean correct score was 68 per cent for all 50 questions, 55 per cent for the 10 pre-test questions, and 71 per cent for the 15 post-test questions. Physicians in practice for one to five years, residents and internists scored better than other subgroups. Answers to questions indicated deficiencies of knowledge and the need for further postgraduate education in the use of antibiotics.",0
307,1196339,"Licensure, competence, and manpower distribution. A follow-up study of foreign medical graduates","Medical statistics report United States medical graduates licensed at higher rates than foreign medical graduates. This difference is often interpreted to show greater medical competence of United States graduates. This study questions this interpretation by analyzing 1971 licensure rates for both groups who had been interns and residents in 1963. We found that factors unrelated to competence--namely, visa-citizenship status and state of examination--are associated with holding a license. Moreover, quality of medical education is not an accurate predictor of licensure. It follows that the use of licensure rates as measures of medical competence distorts understanding of the quality of medical care in the United States. More probably, the difficulties in obtaining medical licensure experienced by foreign graduates result from the use of such graduates to relieve specific medical-manpower shortages.",0
308,1237089,Expression of H-Y antigen in human males with two Y chromosomes,"""To determine whether the gene that controls the expression of H-Y (""""male"""") antigen on human cells is Y-linked, we have compared the H-Y antigen level in normal males with that in three males with two Y chromosomes. Leukocytes from one XXYY and two XYY males express more H-Y antigen than leukocytes from normal XY males. We conclude that a structural gene or positive regulatory gene for H-Y antigen is on the human Y chromosome. Testing for the H-Y antigen may be of benefit in patients who have signs of masculinization but who lack an identifiable Y chromosome. Positive results for the H-Y antigen would be tentative evidence that the corresponding region of the Y chromosome was present, perhaps as part of a translocation, despite the absence of a typical Y chromosome.""",0
309,1237793,Idiopathic hypertrophic subaortic stenosis: detection by thallium 201 myocardial perfusion imaging,"To determine whether thallium 201 myocardial imaging could be used to detect hypertrophic cardiomyopathy, 10 patients with idiopathic hypertrophic subaortic stenosis were studied. Asymmetric septal hypertrophy, an anatomic marker for this disease, was evident on thallium scans in the patients with idiopathic hypertrophic subaortic stenosis, with a ratio of septum to left ventricular free wall of 1.7 cm compared to 1.0 cm in eight normal volunteers, and 1.0 cm in eight patients with concentric left ventricular hypertrophy. Patients with hypertrophic cardiomyopathy also demonstrated apical ventricular wall thickening, and a thicker posterior ventricular free wall in the obstructive in contrast to the nonobstructive form of this disease. Thallium scans of three patients with pulmonary hypertension and secondary asymmetric septal hypertrophy were distinguished from idiopathic hypertrophic subaortic stenosis by marked right ventricular wall thickening. Thus, thallium 201 myocardial perfusion imaging provides a noninvasive method for detection and evaluation of idiopathic hypertrophic subaortic stenosis.",0
310,1244507,Subacute effects of heavy marihuana smoking on pulmonary function in healthy men,"To evaluate the subacute effects of heavy marihuana smoking on the lung, pulmonary function was tested in 28 healthy young male experienced cannabis users, before and after 47 to 59 days of daily ad-libitum marihuana smoking (mean of 5.2 marihuana cigarettes per day per subject, 2.2 per cent delta9-tetrahydrocannabinol). Base-line pulmonary-function studies were nearly all within normal limits, but after 47 to 59 days of heavy smoking, statistically significant decreases in forced expired volume in one second (3 +/- 1 per cent, S.E.), maximal mid-expiratory flow rate (11 +/- 2 per cent), plethysmographic specific airway conductance (16 +/- 2 per cent) and diffusing capacity (8 +/- 2 per cent) were noted as compared with the base-line studies. The decreases in maximal mid-expiratory flow rate and specific airway conductance were correlated with the quantity of marihuana smoked. These findings suggest that customary social use of marihuana may not result in detectable functional respiratory impairment in healthy young men, whereas very heavy marihuana smoking for six to eight weeks causes mild but statistically significant airway obstruction.",0
311,1244508,"Cancer incidence in Mormons and non-Mormons in Utah, 1966-1970","Between 1950 and 1969 cancer mortality in white Utah residents was 22 per cent less than that in the entire United States population. The religion of 72 per cent of the State residents (Mormon) proscribes use of tobacco and alcohol. We therefore analyzed the 10,641 cases of cancer identified in Utah from 1966 to 1970 and compared the incidence found in Utah Mormons, in Utah non-Mormons, and in a national survey. Comparison of Utah Mormons with non-Mormons showed that Mormons had a lower incidence of all cancers associated with cigarette smoking (P less than 0.00001). Mormon females had a low incidence of cancer of the breast (P = 0.008), uterine cervix (P less than 0.00001), and ovary (P = 0.04); Mormon males had a lower incidence of stomach cancers (P = 0.003). These findings addevidence to the association between cigarette smoking and certain cancers, but leave unexplained the significant differences between Mormons and non-Mormons for incidence of cancer of the breast, cervix, prostate and nervous system.",0
312,1244532,The dialysis encephalopathy syndrome. Possible aluminum intoxication,"The aluminum content of muscle, bone and brain was measured in control subjects and in uremic patients on dialysis who had been maintained on phosphate-binding aluminum gels. The mean muscle aluminum was 14.8 ppm, and the trabecular-bone aluminum 98.5 ppm in the patients on dialysis, as compared with 1.2 and 2.4 in control subjects (P less than 0.05). Brain gray-matter aluminum values in a group of uremic patients on dialysis who died of a neurologic syndrome of unknown cause were 25 ppm as compared with 6.5 ppm in a group of uremic patients on dialysis who died of other causes and 2.2 ppm in control subjects. The fact that brain gray-matter aluminum was higher in all patients with the dialysis-associated encephalopathy syndrome than any of the control subjects or other uremic patients on dialysis suggests that this syndrome may be due to aluminum in intoxication.",0
313,1244550,Saturation-inhibition index as a measure of the risk of calcium oxalate stone formation in the urinary tract,"Studies were carried out on multiple urine samples from eight patients with recurrent idiopathic calcium oxalate stone formation and eight normal persons to define an index of the risk of forming calcium oxalate stones. Under the same conditions of dietary and fluid intake the urine samples of the patients with stone formation were more supersaturated with calcium oxalate (P less than 0.001) and had lower concentrations of protective inhibitors of crystallization (P less than 0.001) than those of the controls. However, the best separation between the groups was defined by a discriminant line relating inhibitory activity and urine saturation. A measure of the risk of forming large crystals, the saturation-inhibition index, was defined as the distance of each urine from the discriminant line. The patients with stone formation had a significantly higher mean saturation-inhibition index than the controls (P less than 0.001). Both the percentage of large calcium oxalate crystals excreted (P less than 0.001) and the stone episode rate (P less than 0.005) were significantly correlated with the saturation-inhibition index.",0
314,1246289,Radiologic detection of breast cancer. Review and recommendations,"In response to recent public demand for mammographic examination after the discovery of breast cancer in two women of national prominence, the Ad Hoc Committee on Mammography of the Massachusetts Radiological Society reviewed the present indications, benefits, and risks of radiologic technics used in the detection of neoplastic breast disease. Either low-dose film mammography or xeromammography can provide diagnostic information with minimal radiation hazard, and thermography is a sensitive though nonspecific technic for interim follow-up observations and for screening of large groups of well patients. Mammographic examination should be performed before contemplated breast operations and in women at high risk for the development of breast cancer, especially those who have had previous neoplastic breast disease. Routine mammographic studies on well women may be initiated after the age of 35 years, the frequency of periodic re-examination being determined by clinical and mammographic findings.",0
315,1250280,Detection of anti-acetylcholine receptor factors in serum and thymus from patients with myasthenia gravis,"Since the blood and thymus of patients with myasthenia gravis may contain inhibitors of neuromuscular transmission that affect acetylcholine receptors of striated muscle, we used denervated rat muscle to test for inhibitors in 43 serums and 18 thymus glands from such patients. Seven per cent of serums inhibited the binding of 125l alpha-bungarotoxin to triton-solubilized receptors; 65 per cent interfered with binding of toxin-labeled receptors to concanavalin-A coupled to Sepharose gel, and 85 per cent formed IgG-receptor complexes detectable by immunoprecipitation. Serum inhibitory activity varied widely among patients with similar clinical manifestations and was not correlated with duration of myasthenia gravis or thymectomy. Among thymus extracts, 44 per cent were inhibitory in the concanavalin-A binding assay, whereas 72 per cent contained anti-receptor IgG. Thus, serums from patients with myasthenia gravis contain more than one anti-receptor factor.",0
316,1250282,Perinatal care of low-risk mothers and infants. Early discharge with home care,"A family-centered perinatal-care program featuring collaboration by nurse practitioners, obstetricians, pediatricians, and paramedical personnel was developed to enhance family participation and achieve a shorter but safe hospital stay. Discharge from the hospital was permitted as early as 12 hours after delivery. A perinatal nurse practitioner made daily home visits. The program's safety, feasibility, and acceptability to patients was studied by comparison of 44 patients so treated (study group) with 44 receiving traditional care (controls). Twenty-one study families, but no controls, went home within 24 hours. The study and control groups had no significant differences or trends in numbers of types of morbidity during hospitalization or the six-week post-partum period. The expense of the program is approximately equaled by hospital costs saved through early discharge. The results indicate that early discharge with home-care follow-up observation as described is safe, economically feasible, and well accepted by patients.",0
317,1256470,Sucrase-isomaltase deficiency. Absence of an inactive enzyme variant,"Deficiency of sucrase-isomaltase, an intestinal enzyme complex that is essential for digestion of nutritionally important carbohydrates, appears to be inherited as an autosomal recessive in 0.2 per cent of North Americans. The molecular basis of the deficiency has not been elucidated. To characterize the enzyme defect quantitatively, papain-solubilized intestinal biopsies were analyzed for total enzyme protein by radioimmunoassay and for enzyme activity by hydrolytic assay. Normal intestine had a close correlation between immunologically reactive enzyme and enzymic activity. In contrast, seven patients with sucrase-isomaltase deficiency were found to have complete absence of the enzyme protein by radioimmunoassay even though up to 10 times more intestinal protein was present than with normal tissue. This absence of an inactive enzyme variant can be explained by a major (no-sense) mutation of the structural gene or by a complete repression of the regulatory mechanism that controls structural gene function.",0
318,1256482,Salicylate-induced injury of pyruvate-kinase-deficient erythrocytes,"Salicylate is known to uncouple mitochondrial oxidative phosphorylation. Since the viability of pyruvate-kinase-deficient reticulocytes depends on ATP generated by mitochondrial metabolism, this study examined the effects of salicylate on erythrocytes deficient in pyruvate kinase. When deficient erythrocytes from patients with severe hemolysis were incubated with salicylate (2 to 30 mg per deciliter), there was a marked decrease (25 to 75 percent) in ATP. In addition, this drug-induced ATP depletion produced cell potassium and water loss, and the normal oxidant responsiveness of the hexose-monophosphate shunt was blunted. Since these cellular abnormalities are associated with accelerated hemolysis in vivo, the data suggest that aspirin therapy may aggravate hemolysis in patients with pyruvate kinase deficiency whose erythrocyte manifest sensitivity to salicylate in vitro.",0
319,1256511,Protein patterns of brush-border fragments in congenital lactose malabsorption and in specific hypolactasia of the adult,"Brush-border membrane proteins of the small-bowel mucosa were separated on polyacrylamide gels from intestinal biopsy specimens obtained from four children with congenital lactose malabsorption and from two adults with specific hypolactasia. In three patients with the congenital type of lactase deficiency the protein band corresponding to brush-border lactase was reduced in intensity, but was never completely absent. No difference in gel patterns was detected when this pattern in congenital deficiency was compared to that obtained from the two patients with adult-type selective hypolactasia. In one patient with congenital lactose malabsorption the protein band corresponding to lactase activity was not detectable. The findings suggest that the mechanisms leading to low lactase activity in the congenital and adult forms of lactose intolerance are similar.",0
320,1256523,Lung function and risk of myocardial infarction and sudden cardiac death,"In a serach for risk factors for myocardial infarction and sudden cardiac death, the mean total vital capacity as measured at multiphasic health checkups was lower in persons who later had a first myocardial infarction than in risk-factor-matched controls (3.17 vs. 3.29 liters, 395 pairs, P less than 0.05) and non-risk-factor-matched controls (3.16 vs. 3.41 liters, 401 pairs, P less than 0.001). Findings were little affected by age and height adjustment and were similar for sudden cardiac death. The first-second vital capacity was also inversely related to later development of these conditions, but the ratio of that measurement to total vital capacity was not. Heavy smoking, productive cough, exertional dyspnea and cardiac enlargement were associated with diminished total capacity. However, exclusion of subjects with these findings did not reduce the predictive value of total vital capacity. Diminished vital capacity deserves continued attention as a possible coronary risk factor. Its relation to subsequent coronary events is not well explained.",0
321,1256524,Effect of ketosis on respiratory sensitivity to carbon dioxide in obesity,"We investigated whether the respiratory defect in the obesity-hypoventilation syndrome might respond to dietary manipulation. The effects of hypocaloric ketogenic regimens on the ventilatory response to carbon dioxide were studied in a manner excluding changes in weight or thoracic mechanics as factors. Six obese subjects with hyporesponse (less than 1.1 1/min/mm Hg) and 12 with normal response were fasted or given a diet containing 400 kcal per day of protein. During ketosis carbon dioxide response more than doubled in those with hyporesponse (0.8 +/- 0.1 to 1.8 +/- 1/min/mm Hg, P less than 0.05) but was unchanged in those with normal response. This improvement could not be accounted for by changes in weight, pulmonary function, pH or degree of ketosis between the two groups. However, a significant positive (r = 0.70; P less than 0.001) correlation between ketone-body concentrations and carbon dioxide response was observed in subjects with hyporesponse. These results indicate that depressed sensitivity to carbon dioxide in obese patients can be increased by dietary manipulation.",0
322,1264136,"Research, the lifeline of medicine","Advances in medicine spring from discoveries in physics, chemistry and biology. Among key contributions to the diagnosis, treatment and prevention of cardiovascular and pulmonary diseases, a recent Comroe-Dripps analysis shows two thirds to have been basic rather than applied research. Without a firm foundation in basic knowledge innovations perceived as advances prove hollow and collapse. Strong social, economic and political pressures now threaten acquisition of basic knowledge. Scientists feel driven to undertake excessively complex problems and gamble against the historical record that science generally progresses by tackling discrete and well defined questions. Regardless of circumstances, professional standards require the physician and scientist to be creative and enlarge the fund of knowledge.",0
323,1272285,Community medicine: success or failure?,"The development of university-based community-medicine programs represents one of the most fundamental reforms in medical education in recent times. These programs have attempted to train and motivate students to undertake research and innovations in health service and health-care systems, and to provide service to those in need. Since community medicine is based upon the collective needs of population groups, its relevance, value and effectiveness as a teaching, research and service device in the United States must be seriously questioned unless the prevailing system of individualized care is fundamentally changed to one of collective and regionalized organization. Moreover, working with small population groups, university programs do not provide a large enough epidemiologic base to serve as models for this reform. In developing countries community medicine has proved to be ineffective when isolated from broader socioeconomic development, and should, as now constituted, be abandoned as an independent undertaking.",0
324,1280244,Multiple autoepitope presentation for specific detection of antibodies in primary biliary cirrhosis,"Antimitochondrial autoantibodies are present in sera from close to 95% of patients with primary biliary cirrhosis. The so-called primary biliary cirrhosis-specific antigen, named M2, was found to be associated with an enzyme complex of the inner mitochondrial membrane and, more precisely, with the E2 component, dihydrolipoamide acetyltransferase, of the pyruvate dehydrogenase complex. We recently established that an immunodominant epitope recognized in direct enzyme-linked immunosorbent assay by primary biliary cirrhosis M2+ sera, but not by non-primary biliary cirrhosis M2+ sera, could be mimicked by a synthetic peptide encompassing residues 167-184 of the E2 component and associated with lipoic acid. This fragment is present in the natural inner lipoyl-binding site of the human enzyme, and the presence of lipoic acid located on lysine 173 was found to be essential to allow IgG antibody binding. In this study we have improved the enzyme-linked immunosorbent assay test based on the synthetic peptide-lipoic acid conjugate by using a multiple antigen peptide system containing eight copies of the peptide as antigen. This approach avoids the use of a peptide conjugated to a carrier protein and was found to be particularly efficient because 23 of 27 primary biliary cirrhosis M2+ sera (85%) could be identified. A multiple antigen peptide without lipoic acid was not recognized by primary biliary cirrhosis antibodies. The peptide used in the multiple antigen peptide construction was a short 13-mer peptide encompassing a highly conserved sequence present in both the outer (residues 40-52) and the inner (residues 167-179) lipoyl-binding sites of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)",0
325,1280245,Increase of cytokeratin D during liver regeneration: association with the nuclear matrix,"An increase of a 45 kD protein (p45) in the nuclear matrix has been observed when rat liver cells were proliferatively activated in vivo by a partial hepatectomy. The maximal levels of the association of p45 with the nuclear matrix have been detected 24 hr after hepatectomy just at the time when DNA replication is also maximal. By amino acid sequence analysis, immunoblotting and immunocytochemical methods, it has been demonstrated that p45 is identical to rat cytokeratin D. Immunogold staining of nuclear matrix-intermediate filament preparations from cultured hepatocytes indicated that p45 is associated with cytoskeletal filaments that are strongly interconnected to the lamina, whereas no intranuclear localization of the protein has been detected. With an overlay assay a specific binding of labeled p45 to two nonidentified high-molecular weight proteins and also to lamin B has been observed. Northern blot analysis revealed a biphasic pattern of expression of the messenger RNA for cytokeratin D during liver regeneration. A sharp increase in the messenger RNA levels occurred in the prereplicative phase of liver regeneration a few hours before the accumulation of the protein in the nuclear matrix fraction, and a second peak occurred 48 hr after partial hepatectomy.",0
326,1317941,Correlation of expression of H/Le(y)/Le(b) antigens with survival in patients with carcinoma of the lung,"BACKGROUND: The level of expression of H/Le(y)/Le(b) antigens is high in various histologic types of lung cancer, a feature that may be related to deletion of A and B blood-group antigens. We evaluated the possibility that expression of this antigen, which can be defined by the monoclonal antibody MIA-15-5, might be of prognostic value, as suggested by our previous observation that MIA-15-5 inhibits tumor-cell motility and metastasis. METHODS: We used MIA-15-5 to stain tissue sections from 149 patients with primary lung cancer whose clinico-pathological histories were well documented. The survival curves for patients whose tumors stained positively were compared with the curves for those whose tumors stained negatively. Multivariate analyses were performed with a Cox proportional-hazards regression model. RESULTS: Among the 149 patients studied, five-year survival in the 91 patients with MIA-positive tumors was significantly lower than survival in the 58 with MIA-negative tumors (20.9 percent vs. 58.6 percent, P less than 0.001). Among the 67 patients with squamous-cell carcinoma, the rates also differed significantly (10.5 percent vs. 62.1 percent, P less than 0.001). The difference in survival between patients with MIA-positive tumors and those with MIA-negative tumors was significant among patients with blood groups A and AB (P less than 0.001), but not among those with blood group B or O (P = 0.071 and 0.068, respectively). Multivariate analysis with the Cox regression model indicated that positivity best correlated with five-year mortality, followed by lymph-node status (N stage) and tumor size status (T stage), whereas sex, age, and blood group did not correlate with mortality. CONCLUSIONS: Positivity for MIA (i.e., immunohistologic staining by MIA-15-5, which defines H/Le(y)/Le(b) antigens) is inversely correlated with survival among patients with primary lung cancer and may be of prognostic value.",0
327,1319951,Endotoxins inhibit endocytotic catabolism of low-density lipoproteins in Hep G2 cells,"The effects of endotoxins on the uptake and degradation of low-density lipoproteins in Hep G2, a well-differentiated human hepatoma cell line, were studied. The results showed that incubation of Hep G2 cells with 125I-labeled low-density lipoprotein in the presence of endotoxins caused decreased uptake and degradation of 125I-labeled low-density lipoprotein. The inhibitory effects of endotoxins on the uptake and degradation of 125I-labeled low-density lipoprotein were dose and time dependent. With a monoclonal low-density lipoprotein receptor antibody, it was found that endotoxins interfered with both low-density lipoprotein receptor-mediated and non-low-density lipoprotein receptor-mediated uptake. If, however, the cells were pretreated with endotoxins for 1 or 24 hr and then incubated with new medium without endotoxins, no inhibitory effect on the subsequent uptake and degradation of 125I-labeled low-density lipoprotein occurred. Endotoxins had no toxic effects on Hep G2 cells as judged by [3H]thymidine incorporation and by determination of cell growth. Also, endotoxins did not under our experimental conditions induce oxidative modification of low-density lipoprotein. Furthermore, reisolated low-density lipoprotein that had previously been incubated with endotoxin was catabolized to a lower extent by Hep G2 cells than was control low-density lipoprotein. We speculate that the inhibitory effect of endotoxins on cellular low-density lipoprotein catabolism is due to the formation of endotoxin-low-density lipoprotein complexes, which interfere with the binding of low-density lipoprotein to the cell surface.",0
328,1324218,Influence of dietary zinc on hepatic collagen and prolyl hydroxylase activity in alcoholic rats,"The effects of dietary zinc on hepatic collagen and prolyl hydroxylase activity in normal and alcoholic rats has been investigated in four groups of pair-fed male Wistar rats given either liquid ethanol or a control diet for 12 wk. Each group of pair-fed animals received a diet with a different zinc concentration (standard diet, 7.6 mg/L; low-zinc diet, 3.4 mg/L; zinc-supplemented diet, 76 mg/L; and zinc-extrasupplemented, 300 mg/L. There were no significant differences in hepatic collagen concentration and prolyl hydroxylase activity between alcoholic and normal rats receiving a standard diet (collagen, 77 +/- 5 and 73 +/- 6 micrograms/mg protein; and prolyl hydroxylase; 37 +/- 26 and 36 +/- 22 cpm/mg protein). Alcoholic rats fed a low-zinc diet showed increased prolyl hydroxylase activity (75 +/- 10 cpm/mg protein, p less than 0.05), although no changes in hepatic collagen (77 +/- 10 micrograms/mg protein) were observed in comparison with rats fed a standard alcoholic diet. By contrast, hepatic collagen was significantly lower in alcoholic rats fed a zinc-supplemented diet (66 +/- 4 and 63 +/- 3 micrograms/mg protein, p less than 0.05 and p less than 0.01, respectively), and hepatic prolyl hydroxylase activity was particularly lower in rats receiving zinc 300 mg/L (18 +/- 20 cpm/mg protein). Similar effects were observed in normal rats. We conclude that dietary zinc influences hepatic prolyl hydroxylase activity and collagen deposition in alcoholic rats, and in consequence, the control of dietary zinc is necessary to assess the effects of alcohol on collagen metabolism in rats.",0
329,1330868,Chronic ethanol consumption disturbs G-protein expression and inhibits cyclic AMP-dependent signaling in regenerating rat liver,"Evidence suggests that ethanol desensitizes hepatocytes to the trophic effects of hormones. Cyclic AMP-dependent signals are important regulators of intermediary metabolism, cellular proliferation and differentiation, and modulate liver growth during hepatic regeneration. The events leading to cyclic AMP accumulation after partial hepatectomy were characterized in rats consistently fed ethanol-containing diets and compared with results in rats fed isocaloric amounts of nonethanol diet to determine whether altered cyclic AMP-dependent signal transduction contributes to ethanol-associated aberrations in hepatic growth regulation. Ethanol treatment significantly inhibited hepatic accumulation of cyclic AMP after partial hepatectomy. This was most likely the result of decreased synthesis of cyclic AMP because activation of adenylyl cyclase by agents acting through receptors (e.g., glucagon or isoproterenol), GTP-binding proteins (GTP-gamma-S) and directly on adenylyl cyclase (e.g., forskolin) was significantly inhibited in ethanol-fed rats. Both homologous and heterologous desensitization contributed to this effect. beta 1-Adrenergic receptors were relatively down-regulated 6 hr after partial hepatectomy in ethanol-fed rats, whereas glucagon receptor kinetics were similar in the two groups. Liver membrane expression of GTP-binding proteins differed markedly after partial hepatectomy in ethanol-fed and pair-fed rats. Ethanol significantly inhibited post-partial hepatectomy induction of the stimulatory G protein, Gs alpha but led to overexpression of the inhibitory, G(i)2 alpha, subunit. Steady-state messenger RNA levels of these G proteins were similar in ethanol-fed and pair-fed rats, suggesting that ethanol inhibits G protein expression posttranscriptionally.(ABSTRACT TRUNCATED AT 250 WORDS)",0
330,1330869,Interaction of bile salts with calcium hydroxyapatite: inhibitors of apatite formation exhibit high-affinity premicellar binding,"""Of the major human bile salts, only the glycine-conjugated dihydroxy species prevent the transformation of amorphous calcium phosphate to calcium hydroxyapatite, a component of gallstones; we have proposed that this inhibition occurs by competition between the bile salt and HPO4(2-) anions for binding site on the apatite crystal embryo. Now we show that the binding affinity of bile salts to fully mature hydroxyapatite has the following order: glycine-conjugated dihydroxy salts > taurine-conjugated dihydroxy salts > glycocholate approximately taurocholate. Glycine-conjugated dihydroxy bile salts bound with high affinity as """"premicellar"""" aggregates, but the remaining species appeared to bind as a wider range of aggregate sizes. Glycochenodeoxycholate binding was decreased as the pH increased from 6.6 to 9.8 and the apatite surface charge reversed from net positive to net negative. Binding was competitively inhibited by HPO4(2-), but not by H2PO4-. Ca2+ promoted the binding of glycochenodeoxycholate, taurochenodeoxycholate and glycocholate, and for the latter two bile salts the increase was associated with enhanced """"premicellar"""" binding. The binding of taurocholate was not influenced by Ca2+. When either glycocholate or taurocholate was mixed with glycochenodeoxycholate, mixed aggregates were formed that had a lower affinity for apatite than had pure glycochenodeoxycholate aggregates. Because only glycine-conjugated dihydroxy bile salts inhibit apatite formation, these results suggest that inhibition depends on high-affinity """"premicellar"""" bile salt-apatite binding.""",0
331,1331788,Vitamin D3 and calcium to prevent hip fractures in elderly women,"BACKGROUND: Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. METHODS: We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women. RESULTS: Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. The results of analyses according to active treatment and according to intention to treat were similar. In the vitamin D3-calcium group, the mean serum parathyroid hormone concentration had decreased by 44 percent from the base-line value at 18 months (P < 0.001) and the serum 25(OH)D concentration had increased by 162 percent over the base-line value (P < 0.001). The bone density of the proximal femur increased 2.7 percent in the vitamin D3-calcium group and decreased 4.6 percent in the placebo group (P < 0.001). CONCLUSIONS: Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women.",0
332,1331790,Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis,"BACKGROUND AND METHODS: Sporadic amyotrophic lateral sclerosis is a chronic, progressive degenerative disease of the motor neurons of the spinal cord and motor cortex. The cause is unknown. Recent electrophysiologic studies in animals indicate that immunoglobulins from patients with this disease alter presynaptic voltage-dependent calcium currents and calcium-dependent release of neurotransmitters. To determine whether similar interactions might be identified biochemically, we used an enzyme-linked immunosorbent assay (ELISA) to detect the reaction of serum IgG with purified complexes of L-type voltage-gated calcium channels from rabbit skeletal muscle. The results from patients with amyotrophic lateral sclerosis were compared with those obtained from patients with other types of motor neuron disease, patients with autoimmune and non-autoimmune neurologic diseases, and normal subjects. RESULTS: Serum samples from 36 of 48 patients with sporadic amyotrophic lateral sclerosis (75 percent) contained IgG that reacted with L-type calcium-channel protein, and serum reactivity on ELISA correlated with the rate of disease progression (Spearman rank-correlation coefficient, 0.62). Reactive serum was present in only 1 of 25 normal subjects and 1 of 35 control patients with no motor neuron disease. Antibodies to L-type voltage-gated calcium channels were identified in 6 of 9 patients with Lambert-Eaton syndrome, and in 3 of 15 patients with Guillain-Barr� syndrome. CONCLUSIONS: Antibodies to L-type voltage-gated calcium channels are present in the serum of patients with amyotrophic lateral sclerosis, and antibody titers correlate with the rate of disease progression. Together with previous data, these results suggest a role for autoimmune mechanisms in the pathogenesis of sporadic amyotrophic lateral sclerosis.",0
333,1357554,A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma,"BACKGROUND: An effective, long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs. We compared a new long-acting, inhaled beta 2-adrenoceptor agonist, salmeterol, with a short-acting beta 2-agonist, albuterol, in the treatment of mild-to-moderate asthma. METHODS: We randomly assigned 234 patients (150 male and 84 female patients 12 to 73 years old) to one of three treatment groups: one group received 42 micrograms of salmeterol twice daily, one received 180 micrograms of albuterol four times daily, and one received placebo. Treatment was assigned in a double-blind fashion, and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period. RESULTS: Measurements of the forced expiratory volume in one second, performed hourly for 12 consecutive hours, showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart (6.3 vs. 4.9 liter.hr, P < 0.05). The difference was significant on day 1 and at week 4 of the study, but not at week 8 or 12. Salmeterol was also more effective than albuterol or placebo (with albuterol taken as needed) in increasing the morning peak expiratory flow rate: salmeterol induced a mean increase of 24 liters per minute over the pretreatment values, as compared with a decrease of 6 liters per minute with albuterol (P < 0.001) and an increase of 1 liter per minute with placebo (P = 0.002). The mean overall symptom score was improved most by salmeterol treatment (P < 0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively; there were no differences in results between albuterol treatment and placebo administration. We found no evidence of tolerance to the bronchodilating effects of salmeterol, and adverse reactions to all the treatments were infrequent and mild. CONCLUSIONS: For the management of mild-to-moderate asthma, salmeterol given twice daily is superior to albuterol given either four times daily or as needed.",0
334,1358779,"Estimated central blood volume in cirrhosis: relationship to sympathetic nervous activity, beta-adrenergic blockade and atrial natriuretic factor","The estimated central blood volume (i.e., blood volume in the heart cavities, lungs and central arterial tree) was determined by multiplying cardiac output by circulatory mean transit time in 19 patients with cirrhosis and compared with sympathetic nervous activity and circulating level of atrial natriuretic factor. Arterial norepinephrine level, an index of overall sympathetic nervous activity (3.08 nmol/L in patients vs. 1.36 nmol/L in controls; p < 0.01) was negatively correlated (r = -0.54, p < 0.01) with estimated central blood volume (mean = 23 ml/kg in patients vs. 27 ml/kg in controls; p < 0.05). Similarly, renal venous norepinephrine level (an index of renal sympathetic tone; 4.26 nmol/L in patients vs. 1.78 nmol/L in controls; p < 0.01) was inversely correlated with estimated central blood volume (r = -0.53, n = 18, p < 0.02). No significant correlation could be established between arterial atrial natriuretic factor level (8.9 pmol/L in patients vs. 9.6 pmol/L in controls; not significant) and estimated central blood volume. Hemodynamic values were subsequently modified with oral propranolol (80 mg). During beta-adrenergic blockade, the mean estimated central blood volume was not altered significantly, except in six patients who exhibited decreases in mean arterial blood pressure (85 to 69 mm Hg; n = 6) and decreases in mean estimated central blood volume (23.2 to 20.6 ml/kg; n = 6, p < 0.05). Slight increases were observed in mean right atrial pressure (2.2 to 3.7 mm Hg; n = 14, p < 0.05); this change was positively correlated with the change in estimated central blood volume (r = 0.44, n = 14, p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)",0
335,1370122,Improved light-microscopical detection of microsporidia spores in stool and duodenal aspirates. The Enteric Opportunistic Infections Working Group,"BACKGROUND: The diagnosis of infection with Enterocytozoon bieneusi, a microsporidian organism that causes chronic diarrhea in patients infected with the human immunodeficiency virus (HIV), has depended on invasive procedures. We have developed a new method to detect microsporidia spores in feces and duodenal aspirates. METHODS: Stool was obtained from four HIV-infected patients with biopsy-confirmed intestinal microsporidiosis. Slides prepared from unconcentrated, formalin-fixed stool specimens were stained with a new chromotrope-based technique and examined by light microscopy. Methods of stool concentration were also compared. The technique was then evaluated by examining 215 specimens from 134 HIV-infected persons with or without diarrhea. In addition, duodenal aspirates from 10 patients with unexplained chronic diarrhea were examined by light microscopy after staining according to the new and the traditional techniques. RESULTS: E. bieneusi spores were found in all unconcentrated stool specimens from the four patients with microsporidiosis. The use of various methods of stool concentration did not improve the detection of microsporidia spores. In the prospective study, microsporidiosis was detected in samples from 6 of 27 patients with chronic diarrhea, but in none of those from 42 patients with acute diarrhea or 65 patients without diarrhea. The presence of microsporidia spores in stool specimens and duodenal aspirates allowed the successful prediction of the presence of microsporidia in small-bowel biopsy specimens from all four patients who subsequently underwent endoscopy. CONCLUSIONS: E. bieneusi is an important cause of chronic diarrhea in HIV-infected persons. This new diagnostic technique serves as a practical, noninvasive means to detect microsporidia spores in stool specimens and is also applicable to the examination of duodenal aspirates.",0
336,1371982,"Differences in the abundance of variably spliced transcripts for the second asialoglycoprotein receptor polypeptide, H2, in normal and transformed human liver","The human hepatic asialoglycoprotein receptor comprises two homologous polypeptides designated H1 and H2. Two distinct complementary DNA clones encoding these receptor subunits have been previously isolated from the human hepatoblastoma cell line HepG2. We discovered that multiple variants of H2 transcripts exist both in HepG2 cells and in the normal human liver that, at least in part, appear to be the result of alternative splicing events. We have found that (a) the complementary DNA clone for H2 previously isolated from HepG2 cells, characterized by a 57-nucleotide insertion within the 5' end of the complementary DNA that is absent from H1, represented only one third of H2-related sequences in an unamplified normal human liver complementary DNA library and less than 10% of H2 clones in HepG2 cells; (b) the predominant message for H2 expressed in the liver and HepG2 cells, designated L-H2, appeared to represent the fully processed product of the gene encoding both L-H2 and H2; and (c) a variant H2 transcript existed in HepG2 cells, designated H2', that contained a novel, 5' 88-bp nucleotide insertion. Poly(A+) RNA analysis of the normal liver and HepG2 cells by complementary RNA hybridization and ribonuclease protection corroborated the observations made during the screening of complementary DNA libraries regarding the abundance of the various messages. A striking incongruity was found between the levels of messenger RNA containing the H2-specific 57-nucleotide sequence and the levels of polypeptide expressed in the liver and HepG2 cells as recognized by antiserum specifically raised against this sequence.",0
337,1375578,Inhibition of superoxide and nitric oxide release and protection from reoxygenation injury by Ebselen in rat Kupffer cells,"Luminol chemiluminescence in phorbolester-activated cultured rat liver Kupffer cells was strongly inhibited by the selenoorganic compound ebselen (IC50 = 2 mumol/L). Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one) also diminished reduction of ferricytochrome c (IC50 = 10 mumol/L), indicating a suppression of superoxide anion formation. Likewise, in lipopolysaccharide-pretreated Kupffer cells, ebselen proved to be a potent inhibitor of the conversion of oxyhemoglobin to methemoglobin (IC50 = 3 mumol/L) as a measure of nitric oxide formation. The sulfur-containing analog (2-phenyl-1,2-benzisothiazol-3[2H]one) and the ebselen derivative, methylselenobenzanilide, were inactive. These results indicate that ebselen is a potent inhibitor of NADPH oxidase in Kupffer cells, as has been reported for other macrophages and granulocytes. In addition, they suggest a novel characteristic of ebselen, namely very effective inhibition of nitric oxide synthase of macrophages. In line with its inhibitory effects on the release of reactive oxygen species by macrophages, complemented by its antioxidant properties, ebselen was potent in the prevention of reoxygenation injury of Kupffer cells (IC50 approximately 5 mumol/L).",0
338,1375580,Effects of partial hepatectomy on hepatic insulinlike growth factor binding protein-1 expression,"Insulinlike growth factor binding proteins modulate the action of the insulinlike growth factors in various bioassays and may regulate the bioavailability of the insulinlike growth factors in vivo. Because the insulinlike growth factors may influence hepatic regeneration, we have examined the effect of partial hepatectomy on serum insulinlike growth factor binding proteins and on the abundance of insulinlike growth factor binding protein-1 messenger RNA in the liver. All rats were fasted before and after partial hepatectomy or sham operation to avoid the confounding effects of difference in food intake. Using a conventional protocol, 70% of the liver was removed, and groups of four or five rats were killed at different intervals after partial hepatectomy. Sham-operated rats served as controls. Pooled sera from each group of rats were analyzed by ligand blotting with 125I-insulinlike growth factor-I. Liver RNA from individual rats was analyzed by slot-blot and Northern-blot hybridization. A small decrease in the 39- to 42-kD insulinlike growth factor binding protein was apparent in sera from both the sham-operated and partial hepatectomized rats. In contrast, a dramatic increase (fivefold) in the 29-kD serum insulinlike growth factor binding protein (insulinlike growth factor binding protein-1) was apparent only in the partial hepatectomized rats. Hepatic insulinlike growth factor binding protein-1 messenger RNA abundance was significantly increased (1.99 +/- 0.18-fold; p less than 0.05) at 1 hr, reached a peak of 2.32 +/- 0.22-fold (p less than 0.01) at 3 hr after partial hepatectomy and returned to basal levels over the subsequent 6 to 12 hr.(ABSTRACT TRUNCATED AT 250 WORDS)",0
339,1386652,Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators,"BACKGROUND: Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. METHODS: Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. RESULTS: Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction. CONCLUSIONS: In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.",0
340,1398485,The perfused liver is capable of producing all transferrin glycan variants found in the sera of intact rats,"The single oligosaccharide attachment in rat transferrin exhibits marked structural microheterogeneity. In this study we examined whether all microheterogeneous forms of rat transferrin found in plasma are derived from a single organ, such as the liver. To this end we analyzed the glycans of rat transferrin synthesized by the isolated perfused rat liver by a method established earlier for rat transferrin isolated from rat plasma. Our observations provide evidence that the liver can and does produce all variant rat transferrin glycans present in plasma. However, this discovery does not preclude the possibility that extrahepatic sources with an active rat transferrin gene may contribute to the circulation rat transferrin molecules, which bear glycan variants identical to those made by the liver. The glycan spectra of rat transferrin in plasma and in liver perfusate compared closely with each other in a quantitative sense. Nevertheless, rat transferrin in the perfusate was sialylated to a lesser extent and fucosylated to a greater extent than rat transferrin in plasma. These differences could not be eliminated by supplementation of the medium with insulin, dexamethasone, pyruvate and adenine or adenosine either alone or in combinations, nor could it be eliminated by use of a fluorocarbon O2 carrier. In contrast, epidermal growth factor normalized both parameters. The pH of the perfusing medium also influenced sialylation and fucosylation in such a way that higher pH brought these parameters closer to their values in plasma rat transferrin. Lower pH, on the other hand, reduced sialylation and left the fucosylation index unchanged.",0
341,1398499,Deficient interleukin-2 responsiveness of T lymphocytes from patients with primary biliary cirrhosis,"There is increasing evidence that primary biliary cirrhosis is associated with an alteration of the immune system. Although the cause remains unknown, it has been suggested that the immune system of patients with primary biliary cirrhosis is involved in the pathogenesis of their disease. We have investigated the T-cell function in patients with primary biliary cirrhosis and have found defective phytohemagglutinin-induced T-cell mitogenesis. Likewise, their blastogenic response to CD3 monoclonal antibody was also depressed, although the DNA synthesis induced by stimulation with phorbol esters (12-O-tetradecanoil-phorbol-13-acetate) plus ionophore (ionomycin) was normal. These alterations could not be ascribed either to a decreased synthesis of interleukin-2 or to a defective expression of interleukin-2 receptor after cellular activation. Moreover, this defective proliferative response of T lymphocytes was observed even in the presence of saturating concentrations of exogenous interleukin-2. These results represent evidence of the deficiency in the interleukin-2-dependent pathway found in T lymphocytes from patients with primary biliary cirrhosis.",0
342,1398507,"Role of cytochrome P-450 2E1 in ethanol-, carbon tetrachloride- and iron-dependent microsomal lipid peroxidation","This study investigated the role of cytochrome P-450 2E1 in enhanced microsomal lipid peroxidation in experimental alcoholic liver disease. We also examined the contribution of this isoform to the increased microsomal injury in alcoholic liver disease caused by carbon tetrachloride-induced or iron-induced oxidant stress. Adult male Wistar rats were intragastrically infused with a high-fat diet and ethanol or glucose for 16 wk; this resulted in hepatic lipid peroxidation and fibrogenesis in the ethanol-fed animals. Microsomes were isolated by differential centrifugation in the presence of 100 mumol/L deferoxamine, washed twice in buffer without deferoxamine and incubated in the absence or presence of ethanol (50 mmol/L), carbon tetrachloride (150 mumol/L), ferric citrate (50 mumol/L) or ferric citrate plus ethanol at 37 degrees C for 30 min in an NADPH-generating system. The basal rate of lipid peroxidation in microsomes isolated from ethanol-fed rats was increased by 52% compared with that in microsomes from controls. Carbon tetrachloride-induced and ferric citrate-induced lipid peroxidation were also accentuated in microsomes from ethanol-fed rats, by 76% and 108%, respectively. Ethanol added in vitro significantly reduced basal (-58%) and ferric citrate-induced (-48%) lipid peroxidation in microsomes from ethanol-fed rats, whereas it had an insignificant effect on that in control microsomes. In fact, this protective effect of ethanol on microsomes from ethanol-fed rats resulted in attenuation of the difference in the level of microsomal lipid peroxidation between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)",0
343,1406792,The use of viral culture and p24 antigen testing to diagnose human immunodeficiency virus infection in neonates. The HIV Infection in Newborns French Collaborative Study Group,"BACKGROUND: Early diagnosis of human immunodeficiency virus (HIV) infection in infants born to infected mothers is important for the infants' medical care, but the presence of maternal antibodies makes serologic tests uninformative. METHODS: In a cohort study of 181 infants born to HIV-infected mothers, we assessed the diagnostic value of HIV viral culture and testing for the presence of p24 antigen. The infants were tested at birth, again during the first 3 months, then followed and tested at the age of at least 18 months. RESULTS: Of the 181 infants, 3 died of HIV infection and 37 were seropositive after the age of 18 months. Viral cultures at birth were positive in 19 of the 40 infected infants and in none of the uninfected infants, yielding a sensitivity of 48 percent (95 percent confidence interval, 32 to 63 percent) and a specificity of 100 percent (95 percent confidence interval, 97 to 100 percent). By the age of three months, 30 of the 40 infants (75 percent) had positive cultures; again, there were no false positive results among the infants who were tested a second time, of the 141 who remained uninfected. The sensitivity of testing for p24 antigen at birth was only 18 percent, with a specificity of 100 percent. The presence of p24 antigen at birth was associated with the development of early and severe HIV-related disease (P less than 0.04). CONCLUSIONS: Viral culture at birth can correctly identify about half of newborns with HIV infection. The fact that this usually sensitive technique fails to identify about half the ultimately infected neonates suggests that vertical transmission of HIV may occur late in pregnancy or during delivery.",0
344,1406795,The relation between experience and outcome in heart transplantation,"BACKGROUND: Current policies related to organ transplantation in the United States are designed to ensure that centers and physicians with experience in transplantation perform these procedures. It is essential to confirm the validity of such policies, since they may limit access to transplantation services. METHODS: To determine the relation between experience with heart transplantation and mortality after the procedure, we merged data from the registry of the International Society for Heart and Lung Transplantation with data from a survey that provided additional information about patients and transplantation centers. Our study included 1123 patients who received a heart transplant at one of 56 hospitals in the United States from 1984 through 1986. We used univariate and bivariate techniques, as well as logistic regression, to analyze our data. RESULTS: We observed an institutional learning curve for heart transplantation. Patients who received one of a center's first five transplants had higher mortality rates than patients who received a subsequent transplant (20 percent vs. 12 percent; P = 0.002; relative risk = 2.2; 95 percent confidence interval, 1.6 to 3.4). In addition, we found a correlation between the training of key personnel on the transplantation team and mortality at new transplantation centers. For example, new centers staffed by cardiologists with previous training in heart transplantation had lower mortality rates among heart-transplant recipients than centers without experienced cardiologists (7 percent vs. 16 percent; P = 0.001; relative risk = 2.7; 95 percent confidence interval, 1.3 to 5.9). By contrast, the previous training of the surgeons who performed transplantations was not related to the mortality rate associated with the procedure. CONCLUSIONS: Experience with heart transplantation is associated with a better outcome for patients after that procedure. Opportunities exist to refine transplantation policies on the basis of the experience of a center and its transplantation team and to develop similar policies for other forms of organ transplantation.",0
345,1406834,Predictors of long-term outcome after percutaneous balloon mitral valvuloplasty,"BACKGROUND: Percutaneous balloon mitral valvuloplasty is known to produce short-term hemodynamic and symptomatic improvement in many patients with mitral stenosis. Comprehensive assessment of the clinical usefulness of balloon valvuloplasty requires evaluation of patients' long-term outcomes. METHODS: We performed balloon mitral valvuloplasty in 146 patients between October 1, 1985, and October 1, 1991. Base-line demographic, clinical, echocardiographic, and hemodynamic variables were evaluated in order to identify predictors of long-term event-free survival. RESULTS: Balloon mitral valvuloplasty was completed successfully in 136 (93 percent) of the patients in whom the procedure was attempted; it resulted in an increase in the mean (+/- SD) mitral-valve area from 1.0 +/- 0.4 to 2.1 +/- 0.9 cm2 and a decrease in the mean transmitral pressure gradient from 14 +/- 5 to 6 +/- 3 mm Hg (P < 0.001 for both comparisons). The estimated overall five-year survival rate was 76 +/- 5 percent, and the estimated five-year event-free survival rate (the percentage of patients without mitral-valve replacement, repeat valvuloplasty, or death from cardiac causes) was 51 +/- 6 percent. According to multivariate Cox proportional-hazards analysis, the independent predictors of longer event-free survival were a lower mitral-valve echocardiographic score (a measure of mitral-valve deformity; range, 0 for a normal valve to 16 for a seriously deformed valve; P < 0.001), lower left ventricular end-diastolic pressure (P = 0.001), and a lower New York Heart Association (NYHA) functional class (P = 0.04). Patients with no risk factors for early restenosis or only one risk factor (echocardiographic score > 8, left ventricular end-diastolic pressure > 10 mm Hg, or NYHA functional class IV) had a predicted five-year event-free survival rate of 60 to 84 percent, whereas patients with two or three risk factors had a predicted five-year event-free survival rate of only 13 to 41 percent. CONCLUSIONS: Balloon mitral valvuloplasty as a treatment for selected patients with mitral stenosis has good long-term results. The long-term outcome after this procedure can be predicted on the basis of patients' base-line characteristics.",0
346,1406881,Consequences of physicians' ownership of health care facilities--joint ventures in radiation therapy,"""BACKGROUND: Physicians are increasingly the owners of health care facilities to which they refer patients for services but at which they do not practice. We studied such ownership arrangements, known as """"joint ventures,"""" in the field of radiation therapy, examining their effects on access, use of services, costs, and quality. METHODS: Because 44 percent of free-standing facilities providing radiation therapy in Florida in 1989 were joint ventures, as compared with 7 percent elsewhere (95 percent confidence interval, 3 to 10 percent), we compared data for Florida with comparable data for the remainder of the United States. We also compared radiation-therapy facilities in Florida that were established as joint ventures with those that were not. Since most data were derived from entire populations rather than from samples, any differences found were of necessity statistically significant. RESULTS: No joint-venture facilities providing radiation therapy were located in inner-city neighborhoods or rural areas, but 11 percent of other free-standing facilities and hospital-based facilities were located in such areas. Among free-standing facilities, joint ventures received 39 percent of their revenues from patients with well-paying insurance coverage, as compared with 31 percent for facilities that were not joint ventures (P < 0.01). The frequency and costs of radiation-therapy treatments at free-standing centers were 40 to 60 percent higher in Florida than in the rest of the United States; there was no below-average use of radiation therapy at hospitals or higher cancer rates that explained the higher rates of use or higher costs in Florida. Radiation physicists at joint-venture facilities (the principal personnel involved in quality control other than physicians) spent 18 percent less time with each patient over the course of treatment than did their counterparts at free-standing facilities that were not joint ventures (P < 0.05). Mortality among patients with cancer in Florida was not lower than the U.S. average, even though joint ventures are much more common in that state. CONCLUSIONS: Joint ventures in radiation therapy appear to have adverse effects on patients' access to care. They also appear to increase the use of services and costs substantially. Some indicators show that joint ventures cause either no improvement in quality or a decline. Our results add to the evidence indicating that physicians' self-referral generally has negative consequences. We recommend legislation to ban ownership of joint ventures by referring physicians. Such legislation needs to be carefully designed in order to achieve its objectives and forestall new, financially abusive arrangements.""",0
347,1427655,Human cholecystitis is associated with increased gallbladder prostaglandin I2 and prostaglandin E2 synthesis,"Microsomal prostanoid synthesis was compared in normal gallbladders removed during organ donation and inflamed gallbladders removed at cholecystectomy. Normal human gallbladder microsomes demonstrated low rates of conversion of [14C]arachidonic acid to total labeled prostanoids, which increased during 1 to 30 min of incubation. Normal human gallbladder microsomes converted labeled substrate to all primary prostaglandins without demonstration of a major product. Inflamed human gallbladder microsomes increased the rate of conversion of [14C]arachidonic acid to total labeled prostanoids two or three times over the levels demonstrated by normal gallbladder microsomes at all times of incubation (p < 0.01). The main prostanoids synthesized by the inflamed human gallbladder microsomes were prostaglandin E2 and 6-keto-prostaglandin F1 alpha, which were increased four times over the levels demonstrated by normal gallbladder microsomes (p < 0.01). These data showed that inflammation of the human gallbladder was associated with increased synthesis of gallbladder 6-keto-prostaglandin F1 alpha and prostaglandin E2.",0
348,1427665,Effect on the canine Eck fistula liver of intraportal TGF-beta alone or with hepatic growth factors,"Transforming growth factor-beta canceled the hepatocyte proliferation caused by transforming growth factor-alpha when the two substances were mixed and administered through a disconnected central portal vein branch after creation of an Eck fistula. In contrast, transforming growth factor-beta had no antidotal action on the stimulatory effects of insulin or full test doses of insulinlike factor-2, hepatocyte growth factor, epidermal growth factor or triiodothymanine. A minor antidotal effect on hepatic stimulatory substance activity could be detected, but only with hepatic stimulatory substance was given in doses smaller than those known to cause maximum stimulatory response. These results suggest a highly specific pharmacological and physiological interaction between transforming growth factor-alpha and transforming growth factor-beta in the modulation of liver growth control.",0
349,1435898,Host-specific interleukin-2-secreting donor T-cell precursors as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings,"BACKGROUND: Acute graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation from an HLA-identical sibling. There is no practical test before transplantation that gives sufficient information to predict the degree of allogeneic reactivity between HLA-identical siblings. METHODS: We determined the frequency with which host-specific interleukin-2-secreting donor T-cell precursors occurred in 16 consecutive pairs of HLA-identical siblings before they underwent marrow grafting. The results were correlated with the development of acute GVHD after transplantation. RESULTS: High frequencies of host-specific T-cell precursors (> or = 1 per 100,000) were detectable before transplantation in eight donors whose siblings later had severe (grade II or III) acute GVHD. Among the donors to eight patients with mild (grade 0 or 1) acute GVHD, low frequencies (< 1 per 100,000) were found. CONCLUSIONS: Analysis of the frequency of such cells before transplantation may be a useful predictor of severe acute GVHD in allogeneic bone marrow transplantation between HLA-identical siblings. It is possible that the patients at risk for serious acute GVHD after marrow grafting may benefit from some alternative form of immunosuppressive therapy.",0
350,1445500,Results of a randomized trial of partner notification in cases of HIV infection in North Carolina,"""BACKGROUND: We sought to compare two methods of notifying sex partners of subjects infected with the human immunodeficiency virus (HIV) or persons who had shared needles with them (needle-sharing partners): """"patient referral,"""" in which the responsibility for notifying partners was left to the patient, and """"provider referral,"""" in which providers attempted to notify partners. METHODS: Names of sex partners and needle-sharing partners and information on how to locate them were obtained from consenting HIV-infected subjects identified in the HIV-testing programs at three public health departments in North Carolina. The subjects were randomly assigned to a patient-referral group (in which patients had the initial responsibility for notifying their partners) or a provider-referral group (in which the study counselor notified the partners). The success of attempts to notify partners was monitored by means of interviews with counselors conducted both in the field and at the health department. RESULTS: Of 534 HIV-positive persons identified at the health departments, 247 (46 percent) did not return for counseling after the test, 8 were counseled outside the study, and 117 (22 percent) were ineligible. Of the 162 invited to participate, 88 (54 percent) declined and 74 (46 percent) agreed. The subjects were mostly male (69 percent), black (87 percent), homosexual or bisexual (76 percent of the men), and had a median age of 30 years. Thirty-nine were assigned to the provider-referral group and 35 to the patient-referral group. In the provider-referral group 78 of 157 partners (50 percent) were successfully notified, whereas in the patient-referral group only 10 of 153 (7 percent) were notified. Of the partners notified by the counselors, 94 percent were not aware that they had been exposed to HIV. Overall, 23 percent of the partners notified and tested were HIV-positive. CONCLUSIONS: In this trial, leaving the notification of partners up to the subjects (patient referral) was quite ineffective, despite the North Carolina law requiring that partners be notified. Partner notification by public health counselors (provider referral) was significantly more effective. Although the effectiveness of notification procedures is constrained by the accuracy of the information provided by HIV-infected patients, counselors who notify the partners of an infected patient can refer them to educational, medical, and support services targeted to persons at high risk for HIV infection and may encourage the adoption of less risky behavior.""",0
351,1446898,Hemodynamic effects of calibrated stenosis of the superior mesenteric artery in conscious rats with portal vein stenosis,"Because superior mesenteric arterial blood flow is increased in portal hypertension and plays a role in elevated portal pressure, mechanical reduction of artery diameter should induce decreases in portal pressure and superior mesenteric arterial blood flow. In this study, calibrated superior mesenteric artery stenosis (induced with a 22-gauge needle) was performed in rats simultaneously with portal vein stenosis or 2 wk after creation of portal vein stenosis. Hemodynamic studies were performed 3 wk after induction of portal vein stenosis in conscious, unrestrained rats. At that time, neither weight loss nor digestive tract alterations were observed in rats with arterial stenosis. In neither group of rats with arterial stenosis was portal tributary blood flow significantly different from that of normal rats; nor was it significantly lower than in rats with portal vein stenosis without arterial stenosis. In both groups of rats with arterial stenosis, portal pressure was significantly lower (12.1 +/- 1.6 mm Hg and 12.5 +/- 1.8 mm Hg, respectively) than in rats subjected to portal vein stenosis (15.4 +/- 1.5 mm Hg) but significantly higher than in controls (7.2 +/- 1.0 mm Hg). In rats with arterial stenosis, cardiac index was also significantly lower than that in rats with portal vein stenosis but higher than that in controls. In conclusion, this study shows that both early and late superior mesenteric artery stenosis significantly reduce the degree of portal hypertension and the hyperkinetic state of rats with extrahepatic portal hypertension. Thus we can speculate that superior mesenteric artery stenosis might provide a new therapeutic approach for portal hypertension.",0
352,1454086,Sympathetic overactivity in patients with chronic renal failure,"BACKGROUND: Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure. METHODS: We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. RESULTS. The mean (+/- SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58 +/- 3 vs. 23 +/- 3 bursts per minute, P < 0.01). In contrast, the rate of sympathetic-nerve discharge was similar in the patients receiving hemodialysis who had undergone bilateral nephrectomy (21 +/- 6 bursts per minute) and the normal subjects. The rate of sympathetic-nerve discharge in the patients receiving hemodialysis who had not undergone nephrectomy was also significantly higher (P < 0.01) than that in the patients with bilateral nephrectomy, and it was accompanied in the former group by higher values for vascular resistance in the calf (45 +/- 4 vs. 22 +/- 4 units, P < 0.05) and mean arterial pressure (106 +/- 4 vs. 76 +/- 14 mm Hg, P < 0.05). The rate of sympathetic-nerve discharge was not correlated with either plasma norepinephrine concentrations or plasma renin activity. CONCLUSIONS: Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.",0
353,1501651,Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome,"BACKGROUND: Deposition of fibrin in glomeruli and renal failure are characteristic features of the hemolytic uremic syndrome. An inhibitor of glomerular fibrinolysis has been detected in plasma from children with this disorder. In this study, we define the inhibitor and show that its plasma level is correlated with the outcome of the disease. METHODS AND RESULTS: Plasminogen-activator inhibitor type 1 (PAI-1) in plasma was measured with an assay employing a specific monoclonal antibody in 40 consecutive children hospitalized with the hemolytic uremic syndrome: 12 who recovered adequate renal function (serum creatinine, less than or equal to 2.0 mg per deciliter [177 mumol per liter]) without dialysis, 23 who recovered adequate renal function after peritoneal dialysis, and 5 who did not recover adequate renal function after undergoing dialysis. At presentation, plasma PAI-1 levels were higher in the patients with the hemolytic uremic syndrome than in nine children with other forms of acute renal failure. That the inhibitor was PAI-1 was indicated by the fact that it was a potent inhibitor of tissue plasminogen activator, was acid-resistant, and was not inhibited by denaturation (all unique traits of PAI-1) and that it was neutralized by an antibody specific for PAI-1. Multivariate discriminant-function analysis revealed that the duration of elevated PAI-1 activity was strongly correlated with the outcome of the disease (P less than 0.001). Peritoneal dialysis reduced plasma PAI-1 levels dramatically. CONCLUSIONS: Our studies suggest that PAI-1 is the circulating inhibitor of fibrinolysis in the hemolytic uremic syndrome. Normalization of plasma PAI-1 levels (e.g., by peritoneal dialysis) is correlated with improvement in renal function. However, the possibility that increased plasma levels of PAI-1 are either causes or effects of the hemolytic uremic syndrome is not unequivocally established by these studies.",0
354,1501654,"Predisposing factors for severe, uncontrolled hypertension in an inner-city minority population","BACKGROUND: Hypertensive emergency and urgent hypertension are the most severe forms of uncontrolled hypertension and are now seen predominantly in poor, minority populations. We studied the characteristics of the medical care received by patients with these conditions in order to identify risk factors for severe, uncontrolled hypertension. METHODS: Using a case-control study design, we interviewed 93 patients with severe, uncontrolled hypertension who presented in the hospital emergency room and 114 control patients with hypertension; both groups were seen at two New York City hospitals from 1989 through 1991. All the patients were black or Hispanic. Multiple logistic-regression models were used to adjust for age, sex, race or ethnic background, education, smoking status, alcohol-related problems, and use of illicit drugs during the previous year. RESULTS: After additional adjustment for lack of health insurance, severe, uncontrolled hypertension was found to be more common among patients who had no primary care physician (adjusted odds ratio, 3.5; 95 percent confidence interval, 1.6 to 7.7) and among those who did not comply with treatment for their hypertension (adjusted odds ratio, 1.9; 95 percent confidence interval, 1.4 to 2.5). Lack of health insurance was marginally associated with severe, uncontrolled hypertension (adjusted odds ratio, 1.9; 95 percent confidence interval, 0.8 to 4.6) after adjustment for lack of a primary care physician and noncompliance with antihypertensive treatment. Patients without a primary care physician and without health insurance were more likely to have their blood pressure checked and receive prescriptions for blood-pressure medications in emergency rooms than in physicians' offices or clinics. CONCLUSIONS: Characteristics of both the health care system and patients' behavior are associated with severe, uncontrolled hypertension. Improving access to primary care physicians, through health insurance or other means, may be an effective strategy for improving control of hypertension in disadvantaged minority populations.",0
355,1505911,Localization of cytochrome P-450 gene expression in normal and diseased human liver by in situ hybridization of wax-embedded archival material,"The localization of the expression of several cytochrome P-450 genes in normal and diseased human liver was investigated by in situ hybridization of formalin-fixed, paraffin wax-embedded archival tissue samples with 35S-labeled antisense RNA probes. The results demonstrated that genes coding for members of the cytochrome P-450 3A subfamily (CYP3A) were preferentially expressed in hepatocytes in acinar zone 3 (the centrilobular region), whereas genes coding for CYP1A2, CYP2A, 2B and 2C were expressed uniformly throughout the liver acinus. In cirrhotic livers, CYP2A and 2B genes (and to a lesser extent, CYP3A genes) were highly expressed in isolated hepatocytes located at the junction of parenchyma with fibrous septa. The cause and significance of the position-dependent expression of specific cytochrome P-450 genes in normal and diseased human liver are discussed.",0
356,1508241,Genetic influence on smoking--a study of male twins,"BACKGROUND: The results of twin and family studies suggest that heredity has a small influence on smoking behavior. METHODS: We conducted a genetic analysis of several aspects of smoking behavior among subjects in the National Academy of Sciences-National Research Council Twin Registry. The registry includes male twins who were born in the United States between 1917 and 1927 and who were members of the armed services during World War II. Information on smoking history was available for 4775 pairs of twins, who were first surveyed in 1967 through 1969, when they were 40 to 50 years old, and then re-surveyed in 1983 through 1985, when they were 56 to 66. Eighty percent of the subjects in this cohort had smoked at some time in their lives, 60 percent were smokers in 1967 through 1969, and 39 percent were smoking in 1983 through 1985. Similarities between twins in smoking habits at base line and at the second follow-up 16 years later were examined. The comparison of concordance for smoking between monozygotic and dizygotic twins was used to assess the relative contribution of familial and genetic factors. RESULTS: In 1967-1969 survey the ratio of observed to expected concordance for smoking was higher among the monozygotic twins than among the dizygotic twins for those who had never smoked (overall rate ratio, 1.38; 95 percent confidence interval, 1.25 to 1.54), for former smokers (overall rate ratio, 1.59; 95 percent confidence interval, 1.35 to 1.85), for current cigarette smokers (overall rate ratio, 1.18; 95 percent confidence interval, 1.11 to 1.26), and for current cigar or pipe smokers (overall rate ratio, 1.60; 95 percent confidence interval, 1.22 to 2.06). The data also suggest genetic influences on quitting smoking. Monozygotic twins were more likely than dizygotic twins to be concordant for quitting smoking (overall rate ratio, 1.24; 95 percent confidence interval, 1.06 to 1.45). CONCLUSIONS: In this cohort of adult male twins, there were moderate genetic influences on lifetime smoking practices.",0
357,1508242,"Survival of nationally shared, HLA-matched kidney transplants from cadaveric donors. The UNOS Scientific Renal Transplant Registry","BACKGROUND: The importance of HLA histocompatibility typing to the outcome of transplantation of cadaveric kidneys has been controversial. Four years ago, a prospective trial began in all U.S. transplantation centers to determine whether the results of transplantation would improve with the nationwide shipment of kidneys from cadaveric donors to waiting patients undergoing dialysis when there was a match at the HLA-A, B, and DR loci. METHODS: A total of 1386 cadaveric kidneys were shipped from 108 organ centers to 198 transplantation centers and distributed among HLA-matched recipients, 1004 of whom were receiving a first transplant and 382 of whom were receiving a subsequent transplant. Graft survival in these recipients was compared with that in 22,188 recipients of first transplants and 3950 recipients of subsequent transplants whose HLA antigens differed from those of the donor. RESULTS: The rate of graft survival at one year in recipients of HLA-matched first transplants was 88 percent, as compared with 79 percent in the recipients of mismatched grafts (P less than 0.001). The estimated half-life of the kidney after the first year was 17.3 years for matched grafts, as compared with 7.8 years for mismatched grafts (P = 0.003). Among paired kidneys from 470 donors, one-year graft survival was 87 percent in the recipients of matched first grafts, as compared with 80 percent in the recipients of the contralateral kidneys, who did not have HLA matches with the donors. In donors and recipients matched for the more highly defined split Class I and Class II HLA antigens, the rate of graft survival after one year was as high as 90 percent. CONCLUSIONS: The collaborative renal-transplantation program for HLA matching of donors and recipients yielded an increased rate of one-year graft survival and an estimated half-life for matched grafts twice that for mismatched grafts. An increased role for HLA matching in kidney allocation is therefore indicated.",0
358,1523627,Which women should be tested for Chlamydia trachomatis in general practice?],"Specimens to test for Chlamydia trachomatis and Neisseria gonorrhoeae were collected as a routine from female patients undergoing gynecological examinations in general practice. In 3.9% of 517 non-pregnant women the culture for C trachomatis was positive. None were infected with N gonorrhoeae. C trachomatis was detected in ten of 138 (7.2%) women with genital symptoms, compared with ten of 379 (2.6%) without symptoms. The annual incidence rate for C trachomatis in asymptomatic patients was 0.3% for women older than 25 years, and 5.4% for women younger than 25 years. Routine testing for C trachomatis is recommended during gynecological examination in general practice of asymptomatic women younger than 25 years. Tests should be taken at minimum two-year intervals. Routine tests for N gonorrhoeae are not recommended. ",0
359,1524331,"Renal function and blood pressure in patients receiving long-term, low-dose cyclosporine therapy for idiopathic autoimmune uveitis","To determine the renal side effects of long-term, low-dose cyclosporine therapy (initial dose, 5 mg/kg body weight per day) in patients with autoimmune idiopathic uvetis. Cohort study with at least 2 years of follow-up. A teaching hospital in Paris, France (Hôpital Pitié-Salpétrière). Sixteen patients with idiopathic autoimmune uveitis who were normotensive and had normal renal function before treatment. Cyclosporine was administered orally for at least 2 years at an initial dosage of 5 mg/kg body weight per day. After 2 years of treatment, the serum creatinine level increased by 35 +/- 5 mumol/L (0.40 +/- 0.06 mg/dL) (95% CI, 25 to 46 mumol/L, [73 +/- 4 to 108 +/- 4 mumol/L]). Creatinine clearance decreased significantly from 120 +/- 5 mL/min to 75 +/- 4 mL/min. Glomerular filtration rate decreased from 116 +/- 8 mL/min to 75 +/- 3 mL/min, and effective renal plasma flow decreased from 455 +/- 24 mL/min to 338 +/- 30 mL/min (P less than 0.05). Cyclosporine induced a significant increase in serum uric acid, total cholesterol, and serum potassium levels. Blood pressure was normal in all patients before treatment; 81% (95% CI, 64% to 98%) of these patients developed hypertension after 24 months of treatment. Blood pressure was controlled with a single drug in all but two patients. In patients with healthy native kidneys, long-term cyclosporine therapy, even at a low dose (5 mg/kg per day), is nephrotoxic and is associated with a high incidence of hypertension. ",0
360,1524655,Interindividual variabilities in haloperidol interconversion and the reduced haloperidol/haloperidol ratio,"Metabolism of haloperidol in humans includes N-dealkylation to inactive metabolites and reduction to reduced haloperidol; reduced haloperidol is also oxidized back to haloperidol. A single 0.5 mg/kg (0.00133 mmol/kg) oral dose of haloperidol and reduced haloperidol was administered to seven Chinese schizophrenics in a randomized crossover manner separated by a 2-week interval. The clearance values for the different metabolic pathways of haloperidol and reduced haloperidol were determined. There were differences up to 10-fold in both oxidation and reduction capacities. There were also interindividual variabilities in the elimination of reduced haloperidol (0.37 +/- 0.20 L/hr/kg) and the N-dealkylation pathway (0.74 +/- 0.36 L/hr/kg). Four weeks after the single-dose study, the same patients also received haloperidol (10 mg) twice daily for 4 weeks. The reduced haloperidol to haloperidol concentration ratio (0.40 +/- 0.16) after the 4-week therapy is related to individual variabilities in the interconversion process and the N-dealkylation pathway of haloperidol. ",0
361,1525122,Siblings with normal LDL receptor activity and severe hypercholesterolemia,"""We report about a brother and sister having clinical symptoms similar to those of homozygous familial hypercholesterolemia (FH) but surprisingly who have normal low density lipoprotein (LDL) receptor activities (M. Harada-Shiba et al, J Jpn Atheroscler Soc 1991; 19:227-242). The LDL receptor activities in the cultured fibroblasts of the patients were compared with those of FH heterozygotes and homozygotes for the LDL receptor mutation. The LDL receptor activities in the cultured fibroblasts of the patients were in the normal range, but their plasma cholesterol concentrations were similar to patients with homozygous FH. After the plasma LDL was removed by plasmapheresis in both patients, plasma cholesterol levels started to increase. The """"rebound"""" of plasma cholesterol was compared with those for heterozygous and homozygous FH. The plasma cholesterol levels of the patients, which were greater than 410 mg/dl 2 weeks after plasmapheresis, were much higher than those of FH heterozygotes (232-311 mg/dl) but similar to those of FH homozygotes (345-464 mg/dl). The urinary mevalonate excretion rate, which reflects the rate of whole-body cholesterol synthesis, was higher for the brother (patient 1, 32.6 nmol/kg.day-1) than for the normal subjects (17.7 +/- 4.1 nmol/kg.day-1) but was similar to those of FH homozygotes (31.2 +/- 4.3 nmol/kg.day-1) and heterozygotes (29.8 +/- 10.9 nmol/kg.day-1). To estimate the catabolic and production rates of cholesterol in the brother, the time course for the increment in the total cholesterol level after plasmapheresis was analyzed by the two-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS) """,0
362,1525249,Change of alcohol dehydrogenase activity in sera after alcoholism treatment,Increased metabolic alcohol tolerance was found in chronic non-cirrhotic alcoholics after alcoholism treatment with disulfiram. This increased metabolic alcohol tolerance is connected with an increased activity of alcohol dehydrogenase due to the healing of hepatic tissue damage. This increase in alcohol dehydrogenase activity can help in monitoring the effectiveness of treatments for alcoholic liver disease. ,0
363,1525880,Retinal vein occlusion. III. Initial experience with therapy of retinal vein occlusion with an argon laser],"The authors report the results of laser treatment in 11 patients with chronic oedema of the macula and 6 patients with neovascularizations of the retina and disk of the optic nerve in occlusion of a branch of the retinal vein. In the treatment of chronic oedema of the macula they used their own modification of quadrant barrage suggested by L'Esperance and grid photocoagulation. After a mean follow up period of 3.2 years they achieved a resulting vision of 6/12 or better in 9 of 11 patients, i.e. in 82%, the poorest results were 6/18 in two patients of 11, i.e. in 18%. In the treatment of neovascularizations they used the method of sector photocoagulation. In all six patients, i.e. in 100% they observed regression of neovascularizations. During 2.5-3 years after photocoagulation they did not observe a relapse of neovascularization or haemorrhage into the vitreous body. The results of photocoagulation treatment in chronic oedema of the macula and treatment of neovascularization are of a long-term character. ",0
364,1525947,Preparation of 5-alkyl-3-carboxymethylrhodanines and their aldose reductase inhibitory activity,"5-Alkyl-3-carboxymethylrhodanines (2) were prepared from 5-alkylmethylidene-3-carboxymethylrhodanines (1). The exo double bond of 1 was successfully reduced with NaBH4. The 1,4-addition reaction path was confirmed on the basis of proton nuclear magnetic resonance spectrum of the product (4b) obtained from the reduction of 3 using NaBD4. Optical resolution of the tert-butyl compound (2i) was achieved upon epimerization-crystallization method using L-3-amino-epsilon-caprolactam. The alkyl compounds (2) and the optical active compounds ((+)-2i, (-)-2i) were evaluated for aldose reductase inhibitory potency. ",0
365,1526138,Rhodanese and ALA-S in mammary tumor and liver from normal and tumor-bearing mice,"1. Basal levels and allyl-isopropylacetamide (AIA) or veronal induced levels of delta-amino-levulinate synthetase (ALA-S), cytoplasmic and mitochondrial rhodanese were determined in tumor (T) and liver of both normal mice (NM) and T-bearing mice (TBM). 2. Rhodanese tumoral mitochondrial levels were higher than the hepatic normal mitochondrial fraction, while the cytoplasmic activity was nearly equal in all sources. 3. In neither case was the activity of tumoral ALA-S and rhodanese altered by any of the porphyrinogenic drugs. 4. Mitochondrial and cytoplasmic rhodanese activity was also measured in tumor and liver of TBM at different intervals after transplantation. We concluded that the behaviour of rhodanese is a property inherent to the tissue and not one attained with time. ",0
366,1526289,Chemoimmunotherapy of cancer: cyclophosphamide-resistant tumour cells are equally sensitive as the original tumour cell population to local IL-2 immunotherapy,"Chemotherapy and IL-2-mediated biotherapy represent two modalities of cancer treatment; combination of the two modalities could theoretically help to increase the efficacy of the treatment and decrease the doses as well as toxicity of both components if it could be shown that the chemotherapy-resistant tumour cells selected by treatment with cytostatics are not less sensitive to IL-2-mediated biotherapy than the original chemotherapy-sensitive tumour cell population. In this report we have tried to investigate whether the population of tumour cells selected by chemotherapy and resistant to a chemotherapeutic agent is more, equally, or less sensitive to IL-2 treatment than the parental tumour cell population. For these purposes, we have used a pair of homologous tumour cell lines differing in sensitivity to cyclophosphamide. It could be shown that both tumour cell lines, the CY-sensitive (MC 14) and CY-resistant (MC 14/8R) line were equally sensitive to local IL-2 immunotherapy. Similarly, comparison of the cyclophosphamide-sensitive and cyclophosphamide-resistant tumour target cells to LAK cell-mediated cytolysis in vitro revealed that both tumour cell populations were equally sensitive to the LAK cell effect. ",0
367,1526392,Reproducibility of orocecal transit time and hydrogen production measured by breath tests],"The hydrogen breath test after a lactulose oral load in the fasting period is currently used to measure mouth to cecum transit time (MCTT). However, the reproducibility of this test is poor, and normal values are very scattered. The aim of the study was to determine the reproducibility of hydrogen breath test for MCTT measurement and hydrogen production after administration of 2 disaccharides: lactulose and lactitol ingested in the fasting state and postprandial period. Twelve healthy volunteers (6 men and 6 women; mean age = 34.6 +/- 9.6 years) were studied eight times in a random order, each disaccharide being studied twice in the fasting state and twice in the postprandial period. In the later, lactulose or lactitol was ingested 30 min after a liquid meal completely absorbed (400 kcal; glucide: 55 p. 100, lipid: 30 p. 100, protein: 15 p. 100; 400 ml of Inkopeptide). The MCTT was significantly increased with both disaccharides in the postprandial period as compared with the fasting state (P less than 0.0001). There was nos significant correlation between the 2 measurements of the MCTT in the fasting state, in contrast, the 2 measurements of the MCTT were closely related in the fed state (r = 0.62, P less than 0.05, et r = 0.79, P less than 0.003 for lactulose and lactitol respectively). During both periods no significant difference was found in the MCTT between lactulose and lactitol. As well, hydrogen production did not differ between the 2 disaccharides, but was significantly increased in the postprandial period, and in non methane producers.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
368,1526862,Radiotherapy for locoregional relapses of rectal carcinoma after initial radical surgery: definite but limited influence on relapse-free survival and survival,"A group of 95 patients, treated with irradiation for relapse after radical surgery as only initial treatment modality for a rectal carcinoma was studied. The term locoregional relapse relates to evidence of tumor recurrent in the pelvis or the perineal area. Seventy-six patients presented with locoregional relapse only, and 19 patients presented with locoregional relapse and concomitant distant metastases. All patients were irradiated at the site of locoregional relapse. Total dose of irradiation was resp. 44 Gy median (range 6-66 Gy) and 40 Gy median (range 6-50 Gy). In the group of patients with locoregional relapse only, recurrence-free survival and survival after radiotherapy were, respectively, 23% and 61% at 1 year, and 6% and 13% at 3 years. In the group of patients with concomitant distant metastases, survival after radiotherapy was even worse, 33% at one year, and nihil at 3 years. Recurrences after radiotherapy occurred early during follow-up with 75% of the recurrences being recorded during the first year of follow-up. Recurrent or persistent disease inside the irradiation volume was the most important clinical problem in both groups, being documented in, respectively, 43/76 and 7/19 (7/13 if six patients were excluded with a survival of less than 3 months from onset of therapy). In the group of patients with locoregional relapse only, using recurrence-free survival as the endpoint, dose of irradiation (p = 0.01) was a significant multivariate prognostic factor and using survival as the endpoint, dose of irradiation (p = 0.005) and grade of tumor differentiation (p = 0.002) were significant. Potentials of current radiotherapy regimes are limited. Therefore, maximal initial treatment is warranted. In the event of a relapse after initial radical surgery, one should opt for either more aggressive standard therapy, or either new combined modalities approaches should be studied. ",0
369,1526885,The prophylactic effect of thyroxin on kanamycin ototoxicity in guinea pigs,"Guinea pigs receiving intramuscular kanamycin sulfate 400 mg/kg daily and thyroxin 10 mg/kg orally every other day for 9 days were studied to determine whether thyroxin prevents toxic damage to the cochlea from kanamycin. The auditory brainstem response thresholds of wave IV evoked by tone pip stimuli at 4 and 8 kHz were found to be 19.1 dB and 27.2 dB poorer, respectively, for the kanamycin-only animals. Less than 10% of outer hair cells were damaged in 80% of basal turns but without any involvement in the rest turns in animals given thyroxin. Over 50% of outer hair cells were damaged in 65.4% of basal turns and over 50% of the second and third turns were also involved in the kanamycin-only group. Our study suggests that thyroxin reduces the accumulation of kanamycin in the perilymph and prevents the ototoxicity of kanamycin. ",0
370,1526976,Immunological characterization of the complex forms of chloroplast translational initiation factor 2 from Euglena gracilis,"Euglena gracilis chloroplast translational initiation factor 2 (IF-2chl) occurs in several complex forms ranging in molecular mass from 200 to 800 kDa. Subunits of 97 to greater than 200 kDa have been observed in these preparations. Two monoclonal antibodies were prepared against the 97-kDa subunits of IF-2chl. Both of these antibodies recognize all of the higher molecular mass forms of this factor, suggesting that these subunits are closely related. Gel filtration chromatography indicates that the higher molecular mass subunits of IF-2chl are present in the higher molecular mass complexes, whereas the smaller subunits are present in the 200-400 kDa forms of IF-2chl. Probing extracts of light-induced and dark-grown cells with the antibodies indicates that the light induction of this chloroplast factor results from the synthesis of new polypeptide rather than from the activation of an inactive precursor form of the protein. Both the higher and lower molecular mass subunits of IF-2chl are present in 30 S initiation complexes as indicated by Western analysis. The binding of IF-2chl to chloroplast 30 S ribosomal subunits requires the presence of GTP, but does not require fMet-tRNA, messenger RNA, or other initiation factors. Neither polyclonal nor monoclonal antibodies against E. gracilis IF-2chl cross-react with Escherichia coli IF-2 or with animal mitochondrial IF-2. ",0
371,1527193,Pneumatic tourniquet paralysis. A differential diagnosis after loco-regional anesthesia of the upper limb],"A case is reported of a severe neurological deficit after hand surgical using pneumatic tourniquet. The 51 year old ASA I patient underwent an axillary block for hand surgery using 50 ml of mepivacaïne 1%. The tourniquet was remained at 300 mmHg for only 45 min. The following day, the patient's arm remained lumb. Electrophysiologic tests showed a severe conduction block of sensory and motor fibers, well localized to the presume lower margin of the tourniquet. As there was no improvement, epineurotomy was carried out on day 60, to liberate the median nerve which was severely compressed in the canal brachial. The patient then started to improve slowly. But many safety factors can decrease the rate complications: the accuracy and integrity of the pressure-monitoring must be verified, a tourniquet pressure above 300-500 mmHg would rarely be required in normotensive patient with compliant vessel, a pressure of 200 mmHg will almost all cases provide a bloodless field, tourniquet must be applied on diaphysis and not on bony relief. ",0
372,1527850,"Nuclear localization signals, but not putative leucine zipper motifs, are essential for nuclear transport of hepatitis delta antigen","Hepatitis delta antigen (HDAg) is the only known protein of hepatitis delta virus and was previously shown to localize in the nucleoplasm of infected liver cells. In this study, nuclear localization signals of HDAg were defined by expressing various domains of the antigen in both hepatic and nonhepatic cells as beta-galactosidase fusion proteins. A cytochemical staining assay demonstrated that a domain from amino acid residues 35 to 88 of HDAg was able to facilitate transport to the nucleus of the originally cytoplasm-localized protein beta-galactosidase. Two nuclear localization signals, NLS1 and NLS2, which are similar to those of simian virus 40 T antigen and polyomavirus T antigen, respectively, were identified. Either NLS1 or NLS2 alone was sufficient for the nuclear transport of HDAg. However, a fusion protein (N65Z) containing beta-galactosidase and the N-terminal 65 amino acids of HDAg, containing NLS1, was localized exclusively in the cytoplasm and perinuclear region. A possible hydrophobic subdomain between amino acid residues 50 and 65 may block the function of NLS1. Nevertheless, N65Z could enter the nuclei of transfected cells when it was coexpressed with full-length HDAg. Entry into the nucleus may be mediated by the coiled-coil structure rather than the putative leucine zipper motif located between amino acid residues 35 and 65. The existence of two independent nuclear localization signals may ensure the proper functioning of HDAg in the multiplication of delta virus in the nucleus. In addition, two putative casein kinase II sites (SRSE-5 and SREE-126) that may be important in controlling the rate of nuclear transport were found in HDAg. ",0
373,1528093,The analgesic effect of subarachnoid administration of tetracaine combined with low dose morphine or nalbuphine for spinal anesthesia],"The analgesic effect of subarachnoid administration of tetracaine combined with low dose morphine or nalbuphine for spinal anesthesia was evaluated in 60 ASA physical status class I or II patients. Dextrose solution (10%) was added to 0.4 mg morphine or 0.4 mg nalbuphine to make a total volume of 2 ml, which was injected intrathecally with tetracaine in a double-blind, randomized fashion. Vital signs, sensory level, motor block, pain score, and side effects were recorded every 2 min for the first 15 min and then at 15, 30, 45, and 60 min and at 30-min intervals until the patient complained of pain. Side effects and opioid requirements were recorded for the first 24 h. Complete analgesia (time from injection to first report of pain) lasted 180 +/- 51.6 min in the control group and increased to 238 +/- 71 min in group with addition of 0.4 mg nalbuphine, 250 +/- 74 min in group with addition of 0.4 mg morphine (p less than 0.05). The effective analgesia (time from injection to first opioid requirement) also increased in groups of nalbuphine and morphine than the control group. No differences in complete or effective analgesia was found between groups in the presence of nalbuphine or morphine. Results indicate that the addition of 0.4 mg nalbuphine or morphine to hyperbaric tetracaine for spinal anesthesia improves the quality of intraoperative analgesia and can last into the postoperative period. Side effects were less in nalbuphine group than with morphine group. ",0
374,1528188,Sexual experience and use of contraception among young adults in Latin America,"Although a formal public health surveillance system has not yet been established in Latin America to document the attitudes of young people toward sex education, sexual activity, and contraception and their behaviors in these areas, representative data are available from 12 household-based Young Adult Reproductive Health Surveys conducted in seven countries since 1985. The surveys indicate that the rate of sexual experience before marriage or consensual union for males is much higher than that for females, and first sexual experience occurs at a younger age for males than for females. However, from 34% to 90% of females 20-24 years of age report having had premarital sexual relations. No more than 41% of females and 31% of males report that they or their partner used contraception at first sexual experience. Less than one-third of both young men and young women could identify the most fertile period during the menstrual cycle. The results of such surveys have provided program officials and policymakers with data to plan, implement, and evaluate interventions targeted for young adults. ",0
375,1528209,The publication of sponsored symposiums in medical journals,"BACKGROUND: An increasing proportion of spending by the pharmaceutical industry has gone to funding symposiums that are published by peer-reviewed medical journals. This study tests the hypothesis that such sponsorship, particularly by a single pharmaceutical company, is associated with a promotional orientation of the symposium and a distortion of the peer-review process. METHODS: We counted the symposiums published in 58 journals of clinical medicine and surveyed the journal editors regarding their policies for symposium issues. We analyzed the symposium issues that appeared in the 11 journals that published the most symposiums in order to determine the sponsor or sponsors, the topics, whether the titles were misleading, whether brand names were used, and whether the featured drugs were classified by the Food and Drug Administration as innovative or approved. RESULTS: The number of symposiums published per year increased steadily from 1966 through 1989. Forty-two percent of those analyzed (262 of 625) had a single pharmaceutical company as the sponsor. These symposiums were more likely than those with other sponsors to have misleading titles (P less than 0.001) and to use brand names (P less than 0.001), and less likely to be peer-reviewed in the same manner as other articles in the parent journal (P less than 0.001). Of the 161 symposiums that focused on a single drug, 51 percent concerned unapproved therapies; 14 percent concerned drugs classified as bringing important therapeutic gains. CONCLUSIONS: Symposiums sponsored by drug companies often have promotional attributes and are not peer-reviewed. Financial relations among symposium participants, sponsors, and journals should be completely disclosed, symposiums should be clearly identified, and journal editors should maintain editorial control over contributions from symposiums.",0
376,1528305,"Combined chemotherapy (cisplatin, cyclophosphamide, lomustine and vincristine) and multifractionation radiotherapy in inoperable nonmetastatic squamous cell lung cancer","A modified protocol was used in the treatment of inoperable nonmetastatic squamous cell lung cancer which consisted of three courses of induction chemotherapy with cisplatin, cyclophosphamide, lomustine and vincristine. Radiotherapy was delivered in multifractionated regime, daily two fractions of 1.5 Gy, 4 hours apart up to the total dose of 51 Gy. During 1985-1989, 77 patients were entered into the study. Twenty-six patients did not complete treatment, but were evaluated for the response rate and in survival analysis. There were 29 patients with Stage I and II, and 48 patients with Stage III lung cancer. After combined treatment CR was 15%, PR 39% and RR 54%. One- to four-year overall survival of 48 evaluable patients with Stage III were: 58%, 30%, 17% and 7%, respectively. The overall survival of the whole treatment group was significantly better than the survival of historical control group of 65 patients treated by radiotherapy only. ",0
377,1528430,Changes seen on magnetic resonance imaging in the intervertebral disc space after chemonucleolysis: a hypothesis concerning regeneration of the disc after chemonucleolysis,"Measurements of the intervertebral disc space were made by magnetic resonance imaging and plain film examinations over a period of 2 years in 26 patients who had undergone chemonucleolysis. The height of the posterior portion of the disc decreased after 3 months and never recovered; the height of the anterior portion also decreased but recovered slightly over the same period. The angle of lordosis and the range of motion in the treated segment were decreased, but recovered. Marked decrease in signal from the disc was observed after 2 weeks which did not recover till 2 years after chemonucleolysis. We suspect that the disc degenerated markedly after chemonucleolysis and changed into a type of scar tissue, maturation of which could stabilize the affected segment. ",0
378,1528632,Effects of xylitol and fluoride on the response to glucose pulses of Streptococcus mutans T8 growing in continuous culture,"Streptococcus mutans T8 was grown glucose-limited at pH 7.0 in a chemostat and pulsed, under pH free-fall conditions, with glucose, xylitol or a mixture of the two. Experiments were conducted in the absence or continual presence of low levels (1 mmol.l-1) of fluoride. Culture filtrates of samples taken at frequent intervals were assayed for carbohydrate and fermentation end-products. Fluoride had little effect on the organism's response to glucose until the culture pH fell to ca. 5.0, at which point the rate of lactate production was reduced some 3-fold. Xylitol affected the response to glucose but its effect was most marked in the presence of fluoride. Under these conditions, the rate of lactate production was reduced at least 3-fold, the pH did not fall to 5.0 and only about 50% of the added glucose was consumed. This suggests that xylitol can augment the metabolic effects on S. mutans of low levels of fluoride. ",0
379,1528644,Outpatient management of chronic suppurative otitis media without cholesteatoma in children,"Prolonged antipseudomonal parenteral antibiotic therapy combined with daily aural toilet has been effective in resolving long standing ear discharge in children with chronic suppurative otitis media. However, such treatment suffered from the disadvantages of prolonged hospitalization. We conducted a prospective study to investigate the feasibility and efficacy of exclusive outpatient treatment of children with chronic suppurative otitis media without cholesteatoma who had failed ototopical/oral antimicrobial therapy. The treatment consisted of daily aural toilet (suction and debridement) and twice daily parenteral ceftazidime (50 mg/kg/dose). Thirty-seven children were included. The duration of discharge from the ear before treatment was 6 to 121 months (median, 30 months). Aerobic cultures yielded Pseudomonas aeruginosa in 97%, often with other organisms. The management and follow-up were performed jointly by otolaryngology and infectious diseases physicians using the hospital ambulatory services. The route of ceftazidime administration (intravenous or intramuscular) was chosen according to the parents' and patients' convenience. Discharge stopped within 3 to 20 days (median, 8 days) in all children but one. Seventy-six percent of the 29 children available for follow-up 12 months after treatment were still free of discharge. Our results demonstrate that a regiment combining daily aural toilet and twice daily parenteral ceftazidime is highly efficacious in resolving ear discharge in children with chronic suppurative otitis media without cholesteatoma and that such a regimen does not require hospitalization. ",0
380,1528785,Evaluation of the effect of nitrous oxide and hydroxyzine in controlling the behavior of the pediatric dental patient,"This study evaluated and compared the effect of three different sedation combinations on the young dental patient: hydroxyzine alone, hydroxyzine with nitrous oxide, and nitrous oxide alone. Nineteen uncooperative children with mean age of 37 months needing at least three restorative visits were selected for this study. Crying, alertness, and general behavior were evaluated during the dental procedure. The combination of hydroxyzine and nitrous oxide was more effective than the others for the majority of the sessions in terms of controlling crying and alertness. The results in the present study indicate that the sedative effect of hydroxyzine on children's behavior is enhanced by the addition of nitrous oxide. ",0
381,1529015,Behavioral and trigeminal neuronal effects of rat brainstem-nanoinjected opiates,"Single injections of Met-enkephalin (ME; 27 rats) and artificial cerebrospinal fluid (ACF; 9 rats) in nucleus reticularis paragigantocellularis (PGC) and periaqueductal gray (PAG), and simultaneous conjoint PAG + PGC injections were made, and effects on facial responsiveness and caudal-trigeminal nuclear neuronal activity studied. It was found that all ME injections depressed the evoked excitatory neuronal and behavioral responses to noxious stimulation. Conjoint injections had apparently additive effects in comparison to single injection effects. Neither conjoint nor single injections had systematic effects on spontaneous neuronal activity. The ACF had no effects on any neuronal or behavioral activity. ",0
382,1529544,The complete nucleotide sequence of a feline calicivirus,"We have determined the complete sequence of a feline calicivirus. The virus genome is 7690 bases long and contains two large open reading frames. Proteins specified by these have similarity to those encoded in the corresponding regions of a candidate calicivirus rabbit hemorrhagic disease virus, but are distinctly different from those specified by another such virus, hepatitis E virus. A third, small open reading frame at the 3' end of the genome is present in both feline and rabbit viruses but is absent from hepatitis E. These findings suggest that the calicivirus family, which consists of a single genus, may require subdivision. ",0
383,1529913,The use of a transportable Fourier transform infrared (FTIR) spectrometer for the direct measurement of solvents in breath and ambient air--I: Methanol,"A transportable Fourier transform infrared (FTIR) spectrometer has been tested for analysis of methanol vapor in alveolar and ambient air. The instrument has been found to be accurate and precise for both uses. The regions used for methanol and CO2 quantification are in the vicinity of 950-1100 cm-1 and 2000-2100 cm-1, respectively. The results of a standard addition experiment show a correlation coefficient of 0.97-0.99 for methanol in alveolar or ambient air at the 30-200 ppm concentration level. For CO2 analysis in 23 alveolar air samples at the 6.1-7.6% concentration level, the mean difference in results between a nondispersive infrared (NDIR) spectrometer and the FTIR was -0.092% with a standard deviation of 0.273% (p greater than 0.1). Methanol concentrations in alveolar air paralleled simultaneous measurements of methanol concentration in blood. Overall, these preliminary results suggest that FTIR spectroscopy is a practical and efficient approach for simultaneous biological and area monitoring of human exposure to organic solvents. ",0
384,1530007,From Fanny to Fernand: the development of consumerism in pain control during the birth process,"""Obstetric anesthesia has been the object of public interest and patient advocacy from its introduction in the 1840s to the present. Early arguments concerned the significance of pain in childbearing and became a popular issue involving physicians, clergymen, and journalists. The first obstetric anesthesia, either, given in the United States was administered in Cambridge, Massachusetts, in 1847. For the next several decades general anesthesia was the only feasible means of relieving labor pain. At the turn of the century a combination of scopolamine and morphine was introduced in the United States by a popular women's magazine; the National Twilight Sleep Association was launched. After the decline of this movement, the """"natural"""" childbirth method came into national prominence. In spite of their differing pharmacologic characteristics, there are sociologic parallels between the patient advocacy of Twilight Sleep and that of psychoprophylaxis. This study focuses on the public perception of these movements, which were begun by physicians and subsequently endorsed by militant lay groups. """,0
385,1530071,"Resident physician substance use, by specialty","This study compares substance use by medical specialty among resident physicians. The authors estimated the prevalence of substance use of 11 medical specialties from a national sample of 1,754 U.S. resident physicians. Emergency medicine and psychiatry residents showed higher rates of substance use than residents in other specialties. Emergency medicine residents reported more current use of cocaine and marijuana, and psychiatry residents reported more current use of benzodiazepines and marijuana. Contrary to recent concerns, anesthesiology residents did not have high rates of substance use. Family/general practice, internal medicine, and obstetrics/gynecology were not among the higher or lower use groups for most substances. Surgeons had lower rates of substance use except for alcohol. Pediatric and pathology residents were least likely to be substance users. The authors' previous research indicates that residents overall have lower rates of substance use than their age peers in society. Yet resident substance use patterns do differ by specialty. Residents in some specialties are more likely to use specific classes of drugs, to use a greater number of drug classes, and to be daily users of alcohol or cigarettes. ",0
386,1530313,Study of DDS to the lymph node-metastases of the gastric cancer by the endoscopic injection of Lip-ADM],"We studied the drug delivery and anti-tumor effect of the endoscopic injection of liposomal adriamycin (Lip-ADM) in the submucosa of stomach by rabbit model. Concerning the drug delivery to regional lymphnode, the lymphnode ADM concentration of Lip-ADM injection group was higher than that of free ADM group (p less than 0.05). We also studied the lymphnodes pathohistologically. The lymphnodes of the rabbits injected with Lip-ADM indicated massive necrosis, whereas those of the rabbits injected with free ADM indicated residual tumor. Among clinical cases, patients injected Lip-ADM had paraaortic lymphnodes in which the adriamycin remained 10 days. The endoscopic injection of Lip-ADM into the submucosa of the stomach appeared to be an effective drug delivery system. ",0
387,1530341,Clinical studies on locoregional immunochemotherapy of peritonitis carcinomatosa],"Although 58 patients with peritonitis carcinomatosa underwent multidisciplinary therapy over the last 5 years in our department, about half of them died within 3 months after treatment. In addition, the prognosis was poor for gastric and colon cancer patients, who had macroscopic peritoneal dissemination. Therefore intraoperative intraperitoneal administration of either BRM or anticancer drugs was performed for the microscopic peritoneal dissemination of the cancer, and the immunological response in the peritoneal cavity was examined. In terms of subpopulation of peritoneal exudate cells, neutrophil leucocytes were predominant and thereafter lymphocytes increased. As for the cytokines in the exudate from peritoneal cavity, the concentration of interleukin-6 peaked within 24 hours after administration, followed by a gradual decrease, while the concentration of interferon-gamma was detectable at more than 24 hours after operation, followed by a gradual increase. Tumor necrosis factor-alpha was also detectable in the exudate. Its concentration decreased when both OK-432 and MMC were administered, but it increased when CDDP was administered. The above results indicated that preventive intraoperative intraperitoneal administration of BRM and anticancer drugs should bring about individual immunokinetic modulation in tumor bearing host and both cytokines and immunocytes could play an important role in locoregional tumor immunity. ",0
388,1530378,"Growth of the graft and astrocytic reaction following transplantation of fetal brain to adult rat's brain. Part I: Tissue transplantation into cerebral cortex, lateral ventricle, subarachnoid space and cerebral cortical cavity]","Brain transplantation has been examined as one of the therapeutic methods in the animal models of Alzheimer's disease. Among a lot of problems inherent to therapeutic brain transplantation, we have investigated implanting techniques and methods. Small pieces of fetal basal forebrain tissue containing cholinergic neurons were transplanted into adult rats' cerebral cortex, lateral ventricle, subarachnoid space, and the cerebral cortical cavity which had been made 10 days before transplantation (delayed cavity technique). Two to 3 months after transplantation, growth of the grafts, neurites elongation and astrocytic reaction were observed by Nissl staining, histochemical staining for acetylcholinesterase and immunocytochemical staining for glial fibrillary acidic protein (GFAP). Intracortical grafts were small and surrounded by thick glial scar formation, but there was found a partial lack of glial scar and host-graft neuronal integration was also observed. Both intraventricular and subarachnoid grafts grew relatively well. GFAP-immunoreactive cells had a tendency to gather near the margin of the graft and perivascularly. These facts seemed to suggest that reactive astrocytes were also taking part in support of the homeostasis of environments in the graft tissue. By delayed cavity technique, better growth of the grafts was observed, but dense glial and connective tissue scar tissues developed and prevented the outgrowth of neuronal processes. Nevertheless, hyperinnervation from graft to host cortex was partially noticed. It should be stressed that although the hyperinnervation may be effective for recovery of the host from the central nervous system damages, it may possibly damage the host's neuronal circuits. ",0
389,1530752,Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery,"BACKGROUND: Extreme hormonal and metabolic responses to stress are associated with increased morbidity and mortality in sick adults. We hypothesized that administering deep opioid anesthesia to critically ill neonates undergoing cardiac surgery would blunt their responses to stress and might improve clinical outcomes. METHODS: In a randomized trial, 30 neonates were assigned to receive deep intraoperative anesthesia with high doses of sufentanil and postoperative infusions of opiates for 24 hours; 15 neonates were assigned to receive lighter anesthesia with halothane and morphine followed postoperatively by intermittent morphine and diazepam. Hormonal and metabolic responses to surgery were evaluated by assay of arterial blood samples obtained before, during, and after the operations. RESULTS: The neonates who received deep anesthesia (with sufentanil) had significantly reduced responses of beta-endorphin, norepinephrine, epinephrine, glucagon, aldosterone, cortisol, and other steroid hormones; their insulin responses and ratios of insulin to glucagon were greater during the operation. The neonates who received lighter anesthesia (with halothane plus morphine) had more severe hyperglycemia and lactic acidemia during surgery and higher lactate and acetoacetate concentrations postoperatively (P less than 0.025). The group that received deep anesthesia had a decreased incidence of sepsis (P = 0.03), metabolic acidosis (P less than 0.01), and disseminated intravascular coagulation (P = 0.03) and fewer postoperative deaths (none of 30 given sufentanil vs. 4 of 15 given halothane plus morphine, (P less than 0.01). CONCLUSIONS: In neonates undergoing cardiac surgery, the physiologic responses to stress are attenuated by deep anesthesia and postoperative analgesia with high doses of opioids. Deep anesthesia continued postoperatively may reduce the vulnerability of these neonates to complications and may reduce mortality.",0
390,1530826,Extrathoracic carotid reconstruction: the subclavian-carotid artery bypass,"Although the predominant location of symptomatic carotid artery occlusive disease is the carotid bifurcation, proximal common carotid artery lesions cause similar symptoms. Common carotid artery lesions occur as isolated disease or in tandem with carotid bulb disease. Restoration of carotid artery inflow from subclavian based extraanatomic bypasses should provide adequate reconstruction of these lesions. To evaluate subclavian-carotid artery bypass, a retrospective review of all patients undergoing this procedure from Jan. 1, 1977, to Feb. 20, 1989, was performed. Twenty patients (14 men, 6 women) with a mean age of 60 years were treated. Fifteen patients (75%) were admitted with transient ischemic attacks. Five (25%) had nonfocal symptoms (e.g., dizziness, syncope). Arteriographic evaluation demonstrated severe proximal occlusive disease of the common carotid artery in all cases. Reconstruction bypasses were performed to the carotid bulb (45%), internal carotid artery (30%), and external carotid artery (25%). Four patients underwent endarterectomy of the internal carotid artery in conjunction with subclavian-carotid artery bypass. Bypass conduits included saphenous vein (75%) and prosthetic grafts (25%). Asymptomatic phrenic nerve neuropraxia was identified by postoperative chest radiography in four cases, with no resultant respiratory disease. No perioperative strokes occurred. One postoperative death (5%) resulted from a myocardial infarction. Long-term results were available for 18 patients (90%), with a mean follow-up of 50 months (range, 1 to 122 months). Four patients have died of causes unrelated to carotid vascular disease. Serial duplex scans have documented graft patency in all 18 patients. A single patient returned with focal neurologic symptoms as a result of a posterior circulation infarct.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
391,1530827,Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma,"BACKGROUND: In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. METHODS: We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or depletion of T cells. RESULTS: As compared with the control subjects, the subjects with asthma had more BAL cells per 1000 cell that were positive for mRNA for interleukin-2 (P less than 0.05), 3 (P less than 0.01), 4 (P less than 0.001), and 5 (P less than 0.001) and GM-CSF (P less than 0.001). There was no significant difference between the two groups in the number of cells expressing mRNA for interferon gamma. In the subjects with asthma, mRNA for interleukin-4 and 5 was expressed predominantly by T lymphocytes. CONCLUSIONS: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.",0
392,1530977,D1 receptor stimulation inhibits dopamine cell activity after reserpine treatment but not after chronic SCH 23390: an effect blocked by N-methyl-D-aspartate antagonists,"Single unit recordings were conducted to examine the effects of systemic D1 agonist SKF 38393 on the firing rate of substantia nigra pars compacta dopamine (DA) neurons in rats pretreated subchronically with reserpine or chronically with a D1 antagonist. The effect of N-methyl-D-aspartate receptor antagonists on these processes was also investigated. An i.v. injection of SKF 38393 (10 mg/kg) significantly inhibited DA cell activity by approximately 70% in rats pretreated with reserpine (1 mg/kg, s.c.) for 6 days and studied under conditions of local anesthesia. SKF 38393 exerted no effect in reserpinized rats anesthetized with chloral hydrate. The SKF 38393-induced inhibition was reversed by the D1 antagonist SCH 23390, but not by the preferential D2 antagonist haloperidol. This effect of SKF 38393 was observed in 60% of the rats as early as 3 to 8 hr after the first reserpine injection, and the inhibition remained significant 5 to 15 days (averaging 64 and 58%) after termination of the 6-day reserpine treatment. The N-methyl-D-aspartate antagonists ketamine, at anesthetic doses (100 mg/kg, i.p.), and MK 801, at a nonanesthetic dose (0.15 mg/kg, i.v.), completely blocked the inhibitory effect of SKF 38393. In contrast, DA cells recorded in rats pretreated with SCH 23390 for 7 to 21 days, followed by a 4-day washout period, failed to respond to SKF 38393. Because nigrostriatal DA neurons do not appear to express D1 receptors, these results suggest that D1 receptors can exert an indirect inhibitory effect on the activity of nigral DA neurons, presumably through striatonigral neuronal pathways.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
393,1531199,Histopathology of five tubes after treatment with methotrexate for a tubal pregnancy,"To investigate whether treatment with a local high dose of methotrexate (MTX) for a tubal pregnancy hampers tubal repair. From a total of 67 cases treated with MTX for their tubal pregnancy, two tubes ruptured shortly after the MTX injection and were removed. One patient insisted on a removal of the affected tube in spite of the fact that serum human chorionic gonadotropin was negative. Two patients had her tube removed +/- 1 year after the MTX treatment during a salpingo-oophorectomy because of endometriosis and cystic enlarged ovary. In the ruptured tubes there were no findings supporting the idea that tubal rupture occurred because of the injection of MTX into the tube. There were also no signs of a hampered tubal-tissue response to the insult of invading chorionic tissue. Macroscopic and microscopic evaluation of the unruptured tubes showed no residual tubal destruction. In the tubal wall, all layers were normal and continuous, all unruptured tubes were gracile without distention. Methotrexate applied in a high local dose does not seem to hamper tubal response against the insult of invading chorionic tissue or to interfere with the ultimate tubal repair. ",0
394,1531218,First analysis of tumor regression for the European randomized trial of etanidazole combined with radiotherapy in head and neck carcinomas,"From July 1987 to July 1990, 374 patients were randomized in a multicenter trial coordinated by the Gustave-Roussy Institute. Patients were treated either by radiotherapy alone (RT) or by combined etanidazole with radiotherapy (ETA). The same radiotherapy protocol was used in both arms. Major deviations from the protocol occurred in 16% of the patients. Etanidazole was given at a dose of 2 g/m2, 3 times per week, for a total of 30-34 g/m2. Seventeen percent of the patients received less than 14 injections (4% refused, 12% presented a toxicity, 1% died before beginning). The rate of neuropathy was 28% in the ETA arm and 3% in the RT arm. Acute radiotherapy reactions occurred in similar proportions in both arms. The 3-month rates of complete regression are presently 75.3% in the RT alone group and 77.6% in the ETA group; this difference is not significant. No definitive results are presently available and we must wait for the two-year survival results. In addition, if a meta-analysis could be performed with the parallel RTOG study, the results would be more valid. ",0
395,1531278,The E3-10.4K protein of adenovirus is an integral membrane protein that is partially cleaved between Ala22 and Ala23 and has a Ccyt orientation,"The Ad2 E3-10.4K protein is required together with the E3-14.5K protein to down-regulate the epidermal growth factor receptor in adenovirus-infected cells. Both proteins are also required to prevent tumor necrosis factor cytolysis under certain conditions. 10.4K is a 91 amino acid membrane-associated protein that migrates as two bands, upper and lower, on SDS-PAGE. We show here that the upper band is the primary translation product which initiates at AUG2173 in the E3 transcription unit of Ad2. The upper band is processed slowly (greater than 4 hr to complete) into the lower band by proteolytic cleavage between residues Ala22 and Ala23 by a microsome-associated protease. The upper and lower bands become equal in abundance, after which they are very stable. The N-terminus of the in vivo-derived upper band is not blocked to sequencing and it retains its initiating Met. 10.4K has a hydrophobic domain (H1) near its N-terminus that is probably a signal sequence for membrane insertion; cleavage of this signal is atypical because it was not cotranslational in vivo and it was not complete. 10.4K has a second hydrophobic domain (H2) located within residues 35-60. H2 appears to be a transmembrane (stop transfer) domain because both the upper and the lower 10.4K bands remained associated with membranes after extraction at pH 11.5, because both bands were extracted into the detergent phase with Triton X-114, and because both bands were only partially reduced in size when 10.4K-containing microsomes were digested with proteinase K. These proteinase K-digested bands were immunoprecipitated with an antipeptide antiserum against residues 19-34 but not with an antiserum against residues 68-80 or 77-91, indicating that both 10.4K bands are orientated in the membrane with the C-terminus in the cytoplasm. We conclude that the lower band of 10.4K is a type I bitopic membrane protein and suggest that the upper band is a polytopic membrane protein with both the H1 and the H2 hydrophobic domains spanning the membrane. ",0
396,1531395,Successful induction of long-term specific tolerance to fully allogeneic renal allografts in miniature swine,"Major histocompatibility complex class II matching is of overwhelming importance for achieving tolerance to kidney transplants (KTX) in miniature swine. When class II antigens are matched, long-term specific tolerance across complete MHC class I antigen barriers can uniformly be induced by a 12-day perioperative course of cyclosporine. This same regimen is ineffective in fully MHC-mismatched combinations. We hypothesized that initial induction of tolerance to kidney donor class II antigens by bone marrow transplantation might allow tolerance to be induced to a subsequent fully allogeneic KTX in combination with CsA therapy. We report here the results of such fully allogeneic KTX performed in 4 recipients of prior single-haplotype class II-mismatched BMT. All animals received KTX from donors class II matched to the BMT donor and received a 12-day course of intravenous CsA (10 mg/kg/day). All four animals have maintained normal serum creatinine values (less than 2.0 mg/dl) for greater than 200 days posttransplant. Specific hyporesponsiveness to both BMT and KTX donor-type MHC antigens was found in mixed lymphocyte culture and cell-mediated lympholysis assays. Compared with third-party grafts, significantly prolonged survival of BMT donor-specific (P = 0.031) and KTX donor-specific (P = 0.031) skin grafts was observed. These results demonstrate that induction of tolerance to class II antigens by BMT allows a short course of CsA to induce specific tolerance to fully allogeneic renal allografts. ",0
397,1531410,Complement receptors in atherosclerotic lesions,"Accumulation of cholesterol in the tunica intima of arteries is a feature of atherosclerotic development. Recently, the demonstration of oxidized LDL in atherosclerotic lesions considerably strengthened the possibility of its role in the atherogenesis in vivo. However, the mechanism of lipid accumulation in monocyte-derived macrophages has not yet been clarified. It has been reported that the complement system may be related to atherosclerosis. In this report, complement receptors in the atherosclerotic lesions obtained from autopsy sample were investigated. Initially C3b receptors were detected using sheep erythrocytes bearing human C3b (EAC1423b cells). EAC1423b cells adherent to only aortic sections showing intimal thickening, but not to intact artery. Second, immunostaining of consecutive aortic sections was performed. Apo B and C5b-9 complex were stained using the indirect immunoperoxidase method, and macrophage, C3b receptor (CR1) and C3bi receptor (CR3) were stained using monoclonal antibody in the alkaliphosphatase anti-alkaliphosphatase method. In the intact artery of 3 month old patient, antigen- specific staining were not observed. In intimal thickening and atheroma of older patients, consecutive sections suggested that complement receptor-expressing cells were macrophages. Staining for apo B antigen existed at extracellular site in the intima, and C5b-9 complex was observed in intima and partially in the media. The above data showed that macrophage complement receptors were expressed in the atherosclerotic lesions when the complement system was activated. We conclude that these data suggest that the complement system and complement receptors may be related to the uptake of LDL by macrophages. ",0
398,1531626,Sites of interaction between epidermal growth factor and transforming growth factor-beta 1 in the control of steroidogenesis in cultured porcine Leydig cells,"The present study examines how the hormonal action of gonadotropin is modulated by transforming growth factor-beta 1 (TGF beta 1) and epidermal growth factor (EGF) in primary cultures of purified porcine Leydig cells. Although TGF beta 1 (1 ng/ml; 48 h) and EGF (10 ng/ml; 72 h) individually enhanced hCG-stimulated testosterone formation, the effects of EGF were more pronounced than those of TGF beta 1. When studied in combination, the effects of maximal concentrations of TGF beta 1 and EGF were additive on gonadotropin hormonal action. In the present study we demonstrate that their additive effects resulted from a complex interaction occurring at the levels of cholesterol substrate availability in the mitochondria and of 3 beta-hydroxysteroid dehydrogenase/isomerase activity (3 beta HSDI). First, TGF beta 1 (1 ng/ml; 48 h) and EGF (10 ng/ml; 72 h) were, respectively, shown to reduce and enhance dehydroepiandrosterone (DHEA) formation (evaluated in the presence of 10(-5) M WIN 24540, an inhibitor of 3 beta HSDI) in Leydig cells when acutely (3 h) stimulated with hCG (0.01-1 ng/ml), but not when incubated with 22R-hydroxycholesterol (3 micrograms/ml). Such findings indicate that TGF beta 1 and EGF did not affect cholesterol side-chain cleavage cytochrome P450 activity, but, respectively, decreased and increased cholesterol substrate availability for this enzyme in the mitochondria. Furthermore, when Leydig cells were treated with the combined factors, the formation of delta 5-steroid intermediates (such as DHEA) in untreated (control) and EGF-plus TGF beta 1-treated cells was not significantly different whether the cells were acutely stimulated with the gonadotropin or incubated with 22R-hydroxycholesterol. Such findings indicate that the effects of EGF and TGF beta 1 on cholesterol substrate availability in the mitochondria are antagonistic. Second, EGF, TGF beta 1, and EGF plus TGF beta 1 significantly (P less than 0.001) increased delta 5-steroid intermediate (i.e. pregnenolone and DHEA), but not delta 4-steroid intermediate (i.e. progesterone and androstenedione), conversion into testosterone, indicating that the growth factors increased, individually or in combination in an additive manner, 3 beta HSDI activity (respectively, 90.7 +/- 0.6%, 80.6 +/- 2.6%, and 164 +/- 4.5% increase in the presence of EGF, TGF beta 1, and EGF plus TGF beta 1). Together, the reciprocal suppression of the effects of TGF beta 1 and EGF on the mitochondrial cholesterol substrate availability coupled to their stimulatory additive actions on 3 beta HSDI activity provide an explanation of the additive actions of the two growth factors on gonadotropin-induced testicular androgen formation. ",0
399,1531721,Functional significance of post-myocardial infarction left ventricular hypertrophy: a beneficial response,"Hypertrophy of noninfarcted myocardium occurs as a chronic response to myocardial infarction, but no previous study has related the changes in wall thickness to serial changes in left ventricular function. Thus the functional significance of postinfarction hypertrophy is unknown. The purpose of this study was to determine the relationship between the development of postinfarction hypertrophy and the resting left ventricular ejection fraction measured by two-dimensional echocardiography. After occlusion of the proximal left anterior descending coronary artery in 11 dogs, the ejection fraction fell acutely (0.63 +/- 0.08 to 0.33 +/- 0.10, p less than 0.001) and rose at 3.5 months to 0.62 +/- 0.12. End-diastolic thickness of the noninfarcted left ventricle increased (11 +/- 1.0 mm to 13 +/- 1.4 mm, p less than 0.01) as did left ventricular mass (101 +/- 18 gm to 134 +/- 21 gm, p less than 0.0001). Restoration of the ejection fraction toward the baseline value correlated with the increases in left ventricular mass (r = 0.79, p = 0.007) and wall thickness (r = 0.71, p = 0.025). Hypertrophy of the noninfarcted myocardium correlated with the magnitude and approximately paralleled the time course of the improvement in the ejection fraction and therefore may have had a beneficial effect on resting left ventricular function as a chronic adaptation to myocardial infarction. ",0
400,1531799,The chicken IL-1 receptor: differential evolution of the cytoplasmic and extracellular domains,"The evolutionary conservation of a sequence or part of it can help to identify the essential functional and structural domains within a protein. We have cloned and characterised a cDNA coding for the type-I interleukin-1 receptor (IL-1R) of chick (ch) embryo fibroblasts. The comparison of the amino acid (aa) sequences of the avian with that of murine (m) and human (h) IL-1Rs shows a 60% homology. The intracellular domain is the most conserved region of the chIL-1R, showing 76-79% homology to the murine and human sequences, respectively. The striking conservation of the cytoplasmic region of the receptor is confirmed by its homology with the Toll receptor protein of Drosophila melanogaster. The alignment between the chicken and D. melanogaster proteins shows the presence of four aa blocks with more than 80% homology. The possible functional significance of this homology is discussed. The extracellular binding region of the receptor has a clearly recognisable immunoglobulin-like structure although the sequence divergence is higher than in the cytoplasmic domain. ",0
401,1531864,"Desipramine, administered chronically, influences 5-hydroxytryptamine1A-receptors, as measured by behavioral tests and receptor binding in rats","The 5-hydroxytryptamine1A (5-HT1A) receptor subtype seems to be of importance in the pathogenesis of depression and in the mode of action of antidepressants. In this study, behavioural experiments were performed in rats after oral administration of desipramine for 18-20 days, followed by an acute injection of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), either systemically or intrathecally. Chronic administration of desipramine prolonged the behavioural 5-HT syndrome in the animals injected systemically with 8-OH-DPAT. Treatment with desipramine was also found to potentiate and prolong the antinociceptive effect of an acute injection, systemically or intrathecally, of 8-OH-DPAT in the increasing temperature hot plate test. After systemic administration of 8-OH-DPAT, the colonic temperature was lowered similarly in the desipramine-treated group and in controls, whereas an intrathecal injection of 8-OH-DPAT resulted in a fall in the colonic temperature in the desipramine-treated group only. In vitro receptor binding studies, using [3H]8-OH-DPAT as the ligand, showed a statistically significant reduction of Kd and Bmax in the frontal cortex and of Kd in the spinal cord, after treatment with desipramine. No changes of Kd and Bmax were found in the hippocampus after this treatment. Thus, desipramine, administered chronically, resulted in a functional up-regulation of the 5-HT1A-receptors, both spinally and supraspinally, whereas in the in vitro receptor binding, a slight down-regulation or no change was found. It seems therefore that the results of in vitro receptor binding studies do not necessarily reflect the functional state of the neuronal system.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
402,1532243,Oncogenic activation of murine mos protein kinase by DNA rearrangement of its N-terminal coding region,"An activated c-mos oncogene was detected by DNA transfection assay of hamster SHOK cells with DNAs from X-ray-induced mouse osteosarcoma. It was molecularly cloned by the cosmid rescue method and found to form transformed foci of SHOK cells. Genomic DNA sequencing revealed that in this oncogene the N-terminal coding region of the mouse proto-mos gene was deleted and replaced by a hamster-derived sequence in the primary transformant, suggesting that activation was due to the rearrangement during transfection. The gene product was about 37 kDa and was immunoprecipitated with anti-mos antibody from a lysate of a SHOK cell transfectant. This truncated mos (t-mos) gene transformed SHOK cells more effectively than v-mos. A chimeric gene construct of this hamster-derived upstream sequence and normal mouse c-mos also transformed SHOK cells at a lower level, whereas neither t-mos nor the chimeric c-mos gene transformed NIH3T3 cells appreciably. The high transforming efficiency of t-mos in SHOK cells was due not only to truncation of the coding region but also to its integration under a putative promoter sequence derived from the hamster genome. This is the first report of detection of an activated c-mos gene by DNA transfection assay. ",0
403,1532336,Topical treatment of onychomycosis with amorolfine 5% nail lacquer: comparative efficacy and tolerability of once and twice weekly use,"456 patients with onychomycosis were treated once or twice weekly for up to 6 months with amorolfine 5% nail lacquer in an open, randomized study. The patients were examined at monthly intervals during treatment and followed-up 1 and 3 months after completion of treatment. Slightly better cure rates were achieved with twice weekly use than with once weekly use (overall cure rates 54.2 vs. 46.0%, p = 0.4). An overall cure or improvement was achieved in 74 and 68% of patients receiving twice- and once-weekly treatment, respectively. The mycological cure rate was 76.1% for twice-weekly treatment and 70.6% for once-weekly treatment. The nail lacquer was extremely well tolerated; 4 out of 456 patients reported mild local irritation. Plasma levels of amorolfine were determined in 19 patients and found to be below the detection limit of 0.5 ng/ml in all cases. ",0
404,1532337,IgE binding inhibits arachidonic acid-induced chemiluminescence of human platelets,"Arachidonic acid (AA)-induced chemiluminescence (CHL) was studied in vitro by means of a luminometer in platelets from nine healthy volunteers and six allergic patients. The amplitude of the CHL signal increased with AA concentration from 250 microM to 7 mM. At a low AA concentration (250 microM), the CHL signal consisted of two peaks. The first one occurred at 6 +/- 3 sec and the second one at 90 +/- 15 sec (n = 9). The mean amplitude of these peaks was 1.95 +/- 0.61 mV/sec and 0.82 +/- 0.22 mV/sec for normal subjects, and 2.35 +/- 0.62 mV/sec and 0.78 +/- 0.26 mV/sec for allergic patients, respectively. Aspirin (a cyclooxygenase inhibitor) and baicalein (a lipoxygenase inhibitor) reduced in a concentration-dependent manner, the first and second peak, respectively. The binding of immunoglobulin E (IgE) alone to platelets from both normal and allergic subjects inhibited both the first and second peak of AA-induced CHL. This inhibitory effect was specifically due to the action of IgE as it was (i) concentration-dependent and (ii) not observed when immunoglobulin G (IgG) was substituted for IgE. It is concluded that in normal subjects, as well as in allergic patients, the binding of IgE alone to its specific receptor on human platelets could alter arachidonate metabolism that probably involves cyclooxygenase and lipoxygenase pathways. ",0
405,1532867,"The determination and prevention of cytotoxic effects induced in human lymphocytes by the alkylating agent 2,2'-dichlorodiethyl sulfide (sulfur mustard, HD)","2,2'-Dichlorodiethyl sulfide (sulfur mustard, HD, 1,1'-thio-bis[2-chloroethane]) is a potent vesicant which can cause severe lesions to skin, lung, and eyes. There is no convenient in vitro or in vivo method(s) to objectively measure the damage induced by HD; therefore, a simple in vitro method was developed using human peripheral lymphocytes to study HD-induced cytotoxicity. The cytotoxicity of HD was measured using dye exclusion as an indicator of human lymphocyte viability. Exposure to HD resulted in both a time- and a concentration-dependent cytotoxic effect on human lymphocytes. Using this in vitro assay, the effectiveness of various therapeutics (niacin, niacinamide, and 3-aminobenzamide) in preventing HD-induced cytotoxicity was studied. Niacinamide and 3-aminobenzamide prevented the cytotoxic effects of HD for up to 2 days. ",0
406,1533161,Mechanisms of heterogeneity of Na(+)-Pi cotransport in superficial and juxtamedullary renal cortex,"To explore the mechanisms of axial heterogeneity of proximal tubular Pi transport, brush border membrane vesicles (BBMV) were prepared from superficial (BBMV-SC) and juxtamedullary (BBMV-JM) cortex of rat kidneys. Na+ gradient-dependent Pi transport was measured after the imposition of an inside-negative electrical potential created by either a K+ gradient ([K+]i greater than [K+]o) or a proton gradient ([H+]i greater than [H+]o) in the presence of ionophores. The initial Na(+)-dependent Pi uptake was higher in BBMV-SC than in BBMV-JM, both in the presence and absence of ionophores. Na(+)-dependent D-glucose uptake remained unchanged. We did not find a significant electrogenic transport component in either BBMV population when the non-specific effect of ionophores on Pi transport was taken into account. The stoichiometry of Na(+)-Pi cotransport was 2:1 in BBMV-SC and BBMV-JM. Phosphonoformic acid (PFA) competitively inhibited Pi transport. The inhibitory constant (Ki) for PFA was lower in BBMV-SC (237 +/- 1.7 microM) than in BBMV-JM (409 +/- 53 microM) (P less than 0.05). Arrhenius plots showed a higher rate of Pi uptake in BBMV-SC compared to BBMV-JM at all temperatures. However, the transition temperatures did not differ. We conclude that axial heterogeneity of Pi transport is not due to differences in electrogenicity or stoichiometry of transport. ",0
407,1533412,Evaluation of disability knowledge and skills among leprosy workers,The leprosy workers' knowledge and skills regarding disability prevention and control were quantified by a specially designed Objective Structured Clinical Examination (OSCE). The scorings were similar and showed no significant difference between supervisors and peripheral workers. It is suggested that the training component of disability control should be improved with emphasis on problem-oriented learning. ,0
408,1533623,Glycosylation of nuclear and cytoplasmic proteins. Purification and characterization of a uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylglucosaminyltransferase,"Using a combination of conventional and affinity chromatographic techniques, we have purified a uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylglucosaminyltransferase (O-GlcNAc transferase) over 30,000-fold from rat liver cytosol. The transferase is soluble and very large, migrating with an apparent molecular weight of 340,000 on molecular sieve chromatography. Analysis of the purified enzyme on sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveals two protein species migrating at 110 (alpha subunit) and 78 (beta subunit) kDa in approximately a two-to-one ratio. Thus, the enzyme likely exists as a heterotrimer complex with two subunits of 110 kDa and one of 78 kDa (alpha 2 beta). The alpha subunit appears to contain the enzyme's active site since it is selectively radiolabeled by a specific photoaffinity probe (4-[beta-32P]thiouridine diphosphate). Photoinactivation and photolabeling of the enzyme are dependent on time and long wavelength ultraviolet light. Photolabeling of the alpha subunit is specifically blocked by UDP. The enzyme has an extremely high affinity for UDP-GlcNAc (Km = 545 nM). This unusually high affinity for the sugar nucleotide donor probably provides the enzyme an advantage over the nucleotide transporters in the endoplasmic reticulum and Golgi apparatus which compete for available cytoplasmic UDP-GlcNAc. The multimeric state and large size of the O-GlcNAc transferase imply that its activity may be highly regulated within the cell. ",0
409,1533644,The inhibition of ATP-dependent shape change of human erythrocyte ghosts correlates with an inhibition of Mg(2+)-ATPase activity by fluoride and aluminofluoride complexes,"The vanadate-sensitive Mg(2+)-dependent ATPase activity of the human erythrocyte ghost is believed to be involved in the shape change events that convert echinocytic ghosts to smoothed forms (biconcave discs and stomatocytes). At physiological salt concentration, pH 7.4, 2 mM ATP, 5 mM Mg2+ and 1 mM EGTA, the Mg(2+)-ATPase activity of ghosts was inhibited strongly by millimolar concentrations of sodium fluoride: I50 = 1.31 +/- 0.23 mM (mean +/- S.D.; n = 12). The addition of aluminium chloride to 15 microM reduced the concentration of NaF required for 50% inhibition to 0.76 +/- 0.21 mM (n = 10). Aluminium alone had only a small inhibitory effect on the ATPase activity (13 +/- 9%; n = 10). Desferrioxamine, a strong chelator of tervalent aluminium ion, failed to reverse the inhibition by fluoride and reversed the inhibition in the presence of aluminium and fluoride back to those values obtained with fluoride alone. Of several metal salts tested only beryllium sulfate was able to replace aluminium as an effective inhibitor in the presence of fluoride. Inhibition of the Mg(2+)-ATPase activity by fluoride and the aluminofluoride complexes correlated with an inhibition of the rate of MgATP-dependent change in red cell ghost shape from echinocytes to smoothed forms. All gross morphological changes of the smoothing process were affected, including the production of discocytes, stomatocytes and endocyctic vesicles. ",0
410,1534070,Reactive astrocytes in myelin-deficient rat optic nerve reveal an altered distribution of orthogonal arrays of particles (OAP),"Reactive astrocytes are a common feature of various pathological conditions within the CNS. Morphological changes of reactive astrocytes include an altered nucleus-cytoplasm relationship, nuclear indentations, an increased amount of intermediate filaments, and an immunologically immature phenotype. Additionally, the number of orthogonal arrays of particles (OAP) was found to be increased within parenchymal membranes of reactive astrocytes. This observation prompted us to investigate the distribution of astroglial OAP in the amyelinated CNS of the myelin-deficient (md) rat in which reactive astrocytes prevail. In the present freeze-fracture study, astroglial OAP were determined within endfoot and nonendfoot (parenchymal) membranes in the developing optic nerve of md rats and normal littermates at the age of 12, 23, 40, and 64 days postnatally (dpn). The endfoot OAP density in md astrocytes remained constant during the entire period of investigation. In myelinated littermates, OAP densities continuously increased up to adult values. In contrast, the parenchymal OAP density in md astrocytes increased during the entire period of investigation. In normal littermates, OAP densities remained constant during the first 40 dpn and thereafter increased rapidly. These observations suggest that the absence of myelinogenesis in the md mutant may be a stimulus for parenchymal membranes of reactive astrocytes to insert OAP or to assemble OAP subunits into complete arrays. ",0
411,1534308,Intracellular calcium as a second messenger for human hepatocyte growth factor in hepatocytes,"Human hepatocyte growth factor is a newly discovered substance that stimulates DNA synthesis in vitro. In this study, we examined intracellular Ca2+ movement as one of the second messengers for human hepatocyte growth factor in primary-cultured hepatocytes. The addition of hHGF induced Ca2+ oscillation, but the frequency of oscillations varied from cell to cell. We also saw marked intercellular heterogeneity in the initial latent period for the Ca2+ response; the mean latent period was rather longer than those seen with phenylephrine and vasopressin. This difference in the initial latent period may be due to the difference in the pathways of Ca2+ elevation. Duration of culture determined the number of human hepatocyte growth factor-responsive cells; their number peaked at 2 to 5 hours of confluent culture, whereas the peak was earlier in a low-density culture. These changes in responsiveness during culture can be explained by the cell cycle-dependent sensitivity to human hepatocyte growth factor of hepatocytes. The Ca2+ response to human hepatocyte growth factor was dose dependent; 10(-10) mol/L hHGF gave the highest Ca2+ response, similar to the dose-response curve of DNA synthesis. We even observed the Ca2+ response in the Ca(2+)-free buffer, so the increase in Ca2+ was considered due to release from intracellular Ca2+ stores. These results suggest that human hepatocyte growth factor causes the intracellular Ca2+ elevation in the early stage of the cell cycle and that it plays important roles in the signal transduction systems for human hepatocyte growth factor and the proliferation of hepatocytes.",0
412,1534342,Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris,"The factors that initiate the inflammatory response in acne are not known. The presence of pro-inflammatory cytokines in acne comedones was therefore investigated. One hundred eight open comedones were collected from 18 untreated acne patients (10 male, 8 female). Each comedone was homogenized and centrifuged, and the supernatant was analyzed for bioactive and immunochemically detectable IL-1 alpha, IL-1 beta, and TNF alpha. Viable counts of propionibacteria, staphylococci, and Malassezia spp. were determined in the comedone pellet. Bioactive IL-1 alpha-like material was demonstrated in 76% of open comedones (range of 23-4765 pg IL-1 alpha-like bioactivity/mg of comedone material). In 58% of comedones, levels exceeded 100 pg/mg. There was no correlation between IL-1 alpha-like bioactivity and IL-1 alpha determined immunochemically. Bioactive IL-1 beta was not detected in any comedones. Twenty-four percent contained low levels of immunochemical IL-1 beta (range 12-103 pg IL-1 beta/mg comedone material). Bioactive TNF alpha was detected in three comedones with a further five comedones containing immunochemical TNF alpha (range of 61-820 pg TNF alpha/mg comedone material). The majority of open comedones (97%) contained microorganisms. There was, however, no significant correlation (Spearman's rank) between levels of any cytokine, in particular IL-1 alpha-like bioactivity, and numbers of microorganisms. Thus, bioactive IL-1 alpha-like material in the majority of open comedones may be concerned in the initiation of inflammation in acne following spongiosis or rupture of the pilosebaceous follicle wall. ",0
413,1534389,"Morphologic, immunologic and cytogenetic studies in children with acute lymphoblastic leukemia at diagnosis and relapse: a Pediatric Oncology Group study","The morphologic, immunologic and cytogenetic features of leukemic cells obtained at the time of first bone marrow relapse were compared with those obtained at initial diagnosis in 287 children with acute lymphoblastic leukemia (ALL) who were entered consecutively in a laboratory classification study of the Pediatric Oncology Group (POG). L1 to L2 shifts in French-American-British morphologic subtype were more common than the reverse (81/178 versus 15/61, p less than 0.001). A small but marginally significant number of cases acquired cytoplasmic granules at relapse, and 50 cases underwent a shift in periodic acid-Schiff reactivity that slightly favoured positive to negative. Shifts in immunophenotype were relatively rare, although shifts in cases with a pre-B phenotype to early pre-B ALL or vice versa occurred in about a third of pre-B cases. Loss of HLA-DR or the common ALL antigen occurred in 20 and 11% of cases, respectively. Of the 116 cases with analyzable karyotypes at diagnosis and relapse, 36 (31%) showed a change in karyotypes at relapse, usually from normal to pseudodiploid or hyperdiploid. Cytogenetic evidence for the emergence of a new clone after initial diagnosis was found in only one case. Analysis of the correlation of clinical and lymphoblast biologic features with event-free survival after an initial marrow relapse failed to demonstrate any prognostic significance for the changes identified in this study. T-cell immunophenotype proved to be the only factor significantly related to the outcome of retrieval therapy. ",0
414,1534822,Mls-1a-induced peripheral tolerance to host minor histocompatibility antigens in radiation bone marrow chimeras. Modification of T cell repertoire associated with active suppression and permanent presentation of host antigens,"Minor histocompatibility Ag (mHAg) can be responsible for the development of graft vs host reaction (GVHR) after bone marrow transplantation. In a mouse model, B10.D2 donor immunization against Mls-1a prevents lethal GVHR developed by CD4+ T cells against DBA mHAg in irradiated (DBA/2 x B10.D2)F1 hosts. Such F1 hosts become 100% chimeric and show long term survival (LS mice). The cellular mechanisms underlying the tolerance in LS mice was investigated. It was found that a state of tolerance can be induced in thymectomized F1 hosts. Although spleen cells from LS mice are able to initiate lethal GVHR in third-party H-2k-incompatible hosts, no GVHR is observed in secondary hosts incompatible for specific DBA/2 mHAg. Mixed lymphocyte experiments in vitro confirm that T cells from LS mice are unresponsive toward specific DBA/2 mHAg, although they are able to proliferate in response to H-2 or Mls-1a Ag. The responsiveness to Mls-1a correlates with the presence of V beta 6+ cells in LS mice, probably derived from mature T cells present in the donor inoculum. The tolerance in LS mice is not due to the lack of DBA/2 mHAg presentation; instead, permanent presentation of Ag (Ag I and Ag II) previously described as being responsible for lethal GVHR is consistently observed. A significant protection against GVHR is obtained by transferring normal B10.D2 cells together with spleen cells from LS mice, clearly indicating the contribution of active suppression in the state of tolerance; this is further confirmed by in vitro results obtained in limiting dilution assays. It is concluded that tolerance in chimeric LS mice 1) is due to a peripheral (thymus-independent) mechanism; 2) is specific for mHAg; 3) correlates with unresponsiveness of the repertoire to host mHAg, without alteration of the repertoire for H-2 and Mls-1a Ag; and 4) is associated with an active suppression and with a permanent presentation of at least two mHAg responsible for GVHR mortality. ",0
415,1535092,"Experimental Trichosporon infection in persistently granulocytopenic rabbits: implications for pathogenesis, diagnosis, and treatment of an emerging opportunistic mycosis","Disseminated Trichosporon infection, an uncommon but emerging opportunistic mycosis due to Trichosporon beigelii, is frequently difficult to diagnose, refractory to treatment, and associated with a high attributable mortality. Models of disseminated and gastrointestinal Trichosporon infection were developed in persistently granulocytopenic rabbits. The patterns of infection resembled those of clinical disease, including cutaneous lesions, chorioretinitis, renal infection, pulmonary infection, and antigenemia cross-reactive with cryptococcal capsular polysaccharide. Antigenemia, an early manifestation of disseminated Trichosporon infection, originated in vivo from a fibrillar extracellular matrix. Trichosporon organisms disseminated from the gastrointestinal tract to visceral tissue in colonized immunosuppressed rabbits, whereas there was no dissemination from the gastrointestinal tract of otherwise normal rabbits. The antifungal triazoles, fluconazole and SCH 39304, were most active; maximum tolerated doses of amphotericin B and liposomal amphotericin B were ineffective. Trichosporon antigenemia declined in response to antifungal therapy. These findings contribute to improved understanding of the pathogenesis, diagnosis, and treatment of disseminated Trichosporon infection. ",0
416,1535124,Management of chemotherapy-related nausea and vomiting using a serotonin antagonist,"Patients receiving chemotherapy continue to experience nausea and vomiting despite recent strides to understand the physiology of these symptoms and despite current antiemetic therapies. Ondansetron, a serotonin antagonist, has shown to be a safe and effective drug in alleviating nausea and vomiting. This research-synthesis article provides summaries of eight clinical trials completed between 1988 and 1991. It includes a discussion of the pharmacodynamics and pharmacokinetics of ondansetron, suggestions for adverse events, and implications for nursing practice and future research. ",0
417,1535128,Failure of epinephrine to induce severe cardiac arrhythmia in rats with ventricular hypertrophy secondary to aortic pressure overload,"The arrhythmogenic action of epinephrine was studied in 3 groups of rats: 10 rats with mild constriction of the abdominal aorta (group H1), 10 rats with severe constriction (group H2), 10 sham-operated age-matched rats (group C). Blood pressure and ECG were recorded before, during and after 5 min. perfusion of increasing doses of epinephrine (1, 5, 10 and 25 micrograms.kg-1.min.-1). Ventricular arrhythmia was evaluated from the ECG using a modified Lown's grading system. The ventricular hypertrophy index was calculated from the heart/body weight ratio (mg/g). The mean arterial blood pressure was significantly higher in groups H1 and H2 than in the control group. The ventricular hypertrophy was significant in group H2, but not in group H1. There was no significant difference between the amplitudes of the epinephrine-induced hypertensive responses in the 3 groups but the extent of arrhythmia was significantly lower in the animals with high hypertrophy index. ",0
418,1535365,Retinoids are important cofactors in T cell activation,"Murine thymic T cells depleted of antigen-presenting cells proliferate poorly in response to crosslinking anti-CD3 monoclonal antibodies or concanavalin A when cultured in conventional fetal calf serum-containing serum. However, in a serum-free medium formulated to contain, in addition to basic ingredients, insulin, transferrin, albumin, linoleic acid (ITLB), and retinol, proliferation is vigorous. The presence of retinol is critical, because when omitted, cells do not become activated. The subsets of T cells proliferating with the assistance of retinol cofactor are both CD4+ and CD8+ thymic T cells, and CD4+ peripheral T cells. Mature CD8+ T cells of lymph nodes can also be activated in ITLB medium plus retinol, provided that interleukin 2 (IL-2) is added. Retinol needs to be present at the time when T cell receptor triggering is initiated, suggesting that early activation events (G0 to G1 transition) are dependent on retinol. It is currently less clear whether or not subsequent events associated with G1 to S phase transition also require the presence of retinol. 14-hydroxy-retroretinol (14HRR) is a metabolic product of retinol in lymphocytes, and this retinoid effectively supports T cell activation in conjunction with a mitogen in lieu of retinol. Thus, while retinol and its intracellular product, 14HRR, are unable to activate T cells on their own, they are important cofactors. The requirement for retinol in CD3-mediated T cell activation cannot be satisfied by retinoic acid or ILs-1, 2, 4, and 6, and tumor necrosis factor-alpha whereas interferon gamma can substitute for retinol. Our experiments are compatible with the idea that retinol, in the course of cellular activation, is converted to 14HRR, which is needed as intracellular messenger. If substantiated by molecular studies now underway, our data should lead to the description of a new signal pathway distinct from the retinoic acid signal pathway observed in nonlymphoid cells, but perhaps functioning by a similar mechanism, i.e., ligand-assisted transcriptional regulation. ",0
419,1535399,Atrial natriuretic peptide kinetic studies in patients with cardiac dysfunction,"Three studies were performed: (1) a controlled investigation of alpha-human atrial natriuretic peptide (alpha-hANP) total body production and metabolic clearance rates using a bolus infusion technique (controls, patients 1 to 6); (2) a study of alpha-hANP kinetics in cardiac dysfunction patients using a constant infusion method (patients 7 to 14); and (3) a right heart catheterization study to determine the amount of alpha-hANP released into the circulation at the level of the right heart, estimated by the step-up in alpha-hANP concentration between the superior and inferior vena cava and the pulmonary artery, in the patients with left ventricular dysfunction. Baseline venous plasma alpha-hANP was 27.3 +/- 16.5 pg/ml in the controls (mean +/- SD; N = 6), 141.6 +/- 138.0 pg/ml in patients 1 to 6 (P less than 0.05 compared to controls), and 167.5 +/- 145.7 pg/ml in patients 7 to 14. Total body alpha-hANP production rate was markedly elevated in patients 1 to 6 compared to controls (0.45 +/- 0.36 vs. 0.11 +/- 0.06 micrograms/min, P less than 0.05) and was similar to that determined by the continuous infusion technique in patients 7 to 14 (0.62 +/- 0.44 micrograms/min, P = 0.49 compared to patients 1 to 6). alpha-hANP release into the right heart (0.17 +/- 0.11 micrograms/min), however, was significantly lower than total body production rate in the cardiac dysfunction patients, indicating that total body alpha-hANP secretion occurs from sites in addition to drainage into the right heart via the coronary sinus and anterior cardiac veins. Right atrial pressure correlated with the alpha-hANP released into the right heart.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
420,1535661,Structure-activity relationship studies of central nervous system agents. 5. Effect of the hydrocarbon chain on the affinity of 4-substituted 1-(3-chlorophenyl)piperazines for 5-HT1A receptor site,The effect of the hydrocarbon chain of the model 4-substituted 1-(3-chlorophenyl)piperazines 12-31 on their affinity for 5-HT1A receptor sites was investigated. It was found that elongation of the 4-n-alkyl chain strongly increases the 5-HT1A affinity of the investigated compounds. The affinity reaches the maximum (Ki = 2.67 nM) for the n-hexyl derivative 20. It was shown that hydrophobic interactions of N-4 substituents of 1-arylpiperazines significantly contribute to their 5-HT1A affinity. The specific binding constant was defined as the receptor affinity of the protonated species of compounds under physiological conditions. The range of Ki(AH+) = 1 - 3 x 10(-11) M is a specific affinity limit of the investigated class of compounds at the 5-HT1A receptor sites. ,0
421,1535819,Vitamin D status in children with Down's syndrome,"The serum levels of the active Vitamin D metabolites 25-hydroxyvitamin D[25(OH)D], 1,25-dihydroxyvitamin D[1,25(OH)2D] and 24,25 dihydroxyvitamin D [24,25(OH)2D], were studied in 21 children with Down's syndrome (DS) in Cantabria, a northern region of Spain, located at 44 degrees N latitude. Serum calcium, magnesium, phosphate, alkaline phosphatase, parathormone and osteocalcine were also determined. In the DS group, the average values of the three Vitamin D metabolites were comparable to those of an age-matched group both in winter and summer times. No child with DS showed values below the normal range, either in Vitamin D metabolites, or in the other parameters of calcium metabolism. The normal increment of 25(OH)D and 24,25(OH)2 values from March to October was not observed in five children. This anomaly was corrected in three, after adequate rules of sun exposure during summer time were followed. In the other two, the 25(OH)D levels were high throughout the study. This investigation shows that children with DS do not require Vitamin D prescription when appropriate periods of sunlight exposure are provided. ",0
422,1536135,Methodological issues in epidemiologic studies using biologic markers,"""Biologic markers are becoming prominent features of many classical epidemiologic studies. Their existence has also modified the character of some epidemiologic research such that the term """"transitional epidemiologic studies"""" may be warranted. In the latter type of study, collaboration between laboratory and epidemiologic investigators is integral to the research. In this paper, goals, characteristics, and examples of transitional epidemiologic research are presented. Pertinent features are highlighted, including sources of misclassification and confounding, and elements of study design useful in reducing these potential biases. Sample size issues, transformation of variables, and sources of variability acquire enhanced importance. The study examples presented are intended to illustrate the altered substrate for these methodological features in studies using biologic markers. """,0
423,1536243,Eradication of Ureaplasma urealyticum from the amniotic fluid with transplacental antibiotic treatment,"Ureaplasma urealyticum was isolated from the amniotic fluid of a patient with preterm premature rupture of membranes at 24 weeks. A second amniocentesis performed 48 hours later indicated an increase in the number of neutrophils in the amniotic fluid. Treatment with erythromycin, ampicillin, gentamicin, and clindamycin was instituted for a period of 6 days. Amniotic fluid analysis from a third amniocentesis performed 24 hours after discontinuation of antibiotic treatment revealed only a few white blood cells and was negative for microorganisms. The pregnancy continued for 22 days after admission, at which time spontaneous labor began. The neonate survived with no sequelae and had negative blood cultures. Antibiotic treatment was associated with eradication of Ureaplasma urealyticum from the amniotic cavity, pregnancy prolongation, and neonatal survival. ",0
424,1536248,Serial thoracic versus abdominal circumference ratios for the prediction of pulmonary hypoplasia in premature rupture of the membranes remote from term,"The purpose of this study was to evaluate the fetal thoracic versus abdominal circumference ratio in the prediction of pulmonary hypoplasia after preterm premature rupture of the membranes. A standard curve of thoracic versus abdominal circumference ratio versus gestational age was derived from 120 uncomplicated pregnancies. Thoracic versus abdominal circumference ratio and amniotic fluid estimations were obtained serially in 16 women with premature rupture of the membranes at less than 26 weeks' gestation. An abnormal thoracic versus abdominal circumference ratio predicted lethal pulmonary hypoplasia in six infants. A progressive decline in thoracic versus abdominal circumference ratio was identified in all of these patients. Six of eight women with persistent oligohydramnios had abnormal thoracic versus abdominal circumference ratios and lethal pulmonary hypoplasia. Two surviving infants had restriction deformities and pulmonary complications. In the setting of premature rupture of the fetal membranes at less than 26 weeks, serial thoracic versus abdominal circumference ratio measurement is a reliable predictor of pulmonary hypoplasia. Persistent oligohydramnios is ominous because of the risk of restriction deformities and pulmonary complications in the survivors. ",0
425,1542340,"Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The International Marfan Syndrome Collaborative Study","BACKGROUND: The large glycoprotein fibrillin is a structural component of elastin-containing microfibrils found in many tissues. The Marfan syndrome has been linked to the fibrillin gene on chromosome 15, but congenital contractural arachnodactyly, which shares some of the physical features of the syndrome, has been linked to the fibrillin gene on chromosome 5. METHODS: Using specific markers for the fibrillin genes, we performed genetic linkage analysis in 28 families with the Marfan syndrome and 8 families with four phenotypically related disorders--congenital contractural arachnodactyly (3 families), ectopia lentis (2), mitral-valve prolapse syndrome (2), and annuloaortic ectasia (1). RESULTS: Genetic linkage was established between the Marfan syndrome and only the fibrillin gene on chromosome 15, with a maximum lod score of 25.6 (odds for linkage, 10(25.6):1). Ectopia lentis was also linked to the fibrillin gene on chromosome 15, whereas congenital contractural arachnodactyly was linked to the fibrillin gene on chromosome 5. There was no linkage of mitral-valve prolapse to the fibrillin gene on chromosome 5; studies of chromosome 15 were not informative. Annuloaortic ectasia was not linked to either fibrillin gene. CONCLUSIONS: The Marfan syndrome appears to be caused by mutations in a single fibrillin gene on chromosome 15. Diagnosis of the Marfan syndrome by genetic linkage and analysis is now feasible in many families.",0
426,1544619,Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection,"Spontaneous loss of HBsAg is infrequent in adult HBV carriers. Little is known about this serological change in children. In a prospective study of 420 hepatitis B virus-carrier children who were observed for 1 to 12 yr (mean = 4.3 yr), spontaneous loss of HBsAg occurred in 10 patients, with an average incidence of 0.6%/yr. The HBsAg clearance rate was significantly higher in children who had anti-HBe; children who were at an older age on entry; children whose mothers were HBsAg-; or children with severe liver histological changes detected while they were HBeAg+. Children who seroconverted from HBeAg to anti-HBe before the age of 6 or who had a peak serum ALT level above 100 IU/L were more likely to clear HBsAg. In all 10 patients who became HBsAg-, serum hepatitis B virus DNA became undetectable by both spot hybridization and the polymerase chain reaction, suggesting a complete clearance of the virus from serum. After the loss of HBsAg, the anti-HBs levels were higher in the children born to carrier mothers than in those born to noncarrier mothers. These findings suggest that chronic hepatitis B virus-carrier children rarely lose HBsAg, especially if they have been infected during the perinatal period and have mild histological changes. The poor humoral immune response to HBsAg may be a contributing factor in the establishment of carrier status during horizontal infection but may not be primarily involved in the establishment of carrier status during perinatal infection.",0
427,1544627,Enhancement in antioxidant-based hepatoprotective activity of Trolox by its conjugation to lactosylphenylpyranoside,"When Trolox (a polar analog of vitamin E) is conjugated to p-aminophenyl-beta-D-lactopyranoside, the resulting lactosylphenyl Trolox becomes a markedly more stable and effective hepatoprotector than Trolox. In primary rat hepatocytes exposed to xanthine oxidase-hypoxanthine, lactosylphenyl Trolox prolonged cell survival better than did Trolox, mannitol or ascorbate. In rats that underwent 80-min partial hepatic ischemia, infusion of lactosylphenyl Trolox at 2.9 to 5.7 mumol/kg body wt just before reoxygenation salvaged the organ more extensively than did Trolox. Mechanistically, we showed (a) that lactosylphenyl Trolox does not inhibit xanthine oxidase; (b) that lactosylphenyl Trolox effectively scavenges oxyradicals generated with xanthine oxidase and the peroxyl radicals produced with 2,2'-azo-bis(2-amidinopropane) HCl; (c) that both in hepatocytes and in vivo, lactosylphenyl Trolox is distinctly more cytoprotective than either or both of its precursors; and (d) that lactosylphenyl Trolox is amphipathic (i.e., it has both hydrophilic and hydrophobic properties), which enable it to better access and protect the lipid and aqueous milieus of the cell than the lipophile vitamin E and the moderately polar Trolox. Thus there are strong fundamental reasons for lactosylphenyl Trolox being an effective antioxidant-based hepatoprotector.",0
428,1544630,Inhibition by noradrenaline and adrenaline of the increase in glucose and lactate output and decrease in flow after sympathetic nerve stimulation in perfused rat liver: possible involvement of protein kinase C,"In perfused rat liver stimulation of the hepatic nerve plexuses increased via alpha 1-receptors glucose and lactate output decreased flow and caused an overflow of noradrenaline into the hepatic vein. Infusion of noradrenaline and adrenaline also elicited similar metabolic and hemodynamic alterations via alpha 1-receptors, whereas infusion of isoproterenol via beta 2-receptors enhanced glucose output and slightly reduced lactate release without affecting flow. The influence of circulating catecholamines on the nerve stimulation-dependent changes was investigated. Noradrenaline (100 nmol/L) or adrenaline (40 nmol/L) but not isoproterenol (1 mumol/L), which themselves caused about half-maximal alterations, strongly inhibited the nerve stimulation-induced increase in glucose and lactate output and decrease in flow but had no effect on noradrenaline overflow. The protein kinase C activator (4 beta)phorbol 12-myristate, 13-acetate (100 nmol/L) but not its analog (4 alpha)phorbol 12,13-didecanoate (100 nmol/L) strongly inhibited the metabolic and hemodynamic changes caused by nerve stimulation or noradrenaline infusion. The protein kinase C inhibitor H7 (20 mumol/L) partially prevented the inhibition of the nerve actions by noradrenaline. The results lead us to conclude that noradrenaline and adrenaline inhibited the metabolic and hemodynamic nerve actions by means of a mechanism involving protein kinase C rather than presynaptic alpha-receptors or beta-receptors. The catecholamines apparently increased via alpha 1-receptors inositol 1,4,5-trisphosphate, which in turn enhanced cytosolic Ca2+ and thus altered metabolism and in part hemodynamics, and diacylglycerol, which in turn activated protein kinase C and thus feedback inhibited the signal chain from alpha 1-receptors via G proteins to phospholipase C.",0
429,1551643,Effects of amiloride on renal lithium handling in nonazotemic ascitic cirrhotic patients with avid sodium retention,"The reliability of lithium clearance as an index of distal fluid delivery in cirrhosis with ascites and in other clinical conditions characterized by low fractional sodium excretion has not yet been proven. In particular, lithium reabsorption in the amiloride-sensitive segment of the distal tubule, as evidenced in experimental studies, has not been excluded in such clinical conditions. Thus the acute effect of amiloride on renal lithium handling in 15 nonazotemic ascitic cirrhotic patients with avid sodium retention was evaluated after at least 5 days of controlled sodium intake. Renal plasma flow, glomerular filtration rate, fractional sodium excretion, fractional lithium excretion, fractional potassium excretion, fractional excretion of uric acid, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide were evaluated before and for 6 hr after the administration of amiloride (20 mg/os). After amiloride administration a volume replacement scheme was enacted with intravenous amounts of saline solution, determined by the diuretic and natriuretic effect of the drug, to avoid volume depletion. Amiloride induced a prompt and sustained increase in fractional sodium excretion (from 0.28% +/- 0.09% to 1.0% +/- 0.41%, p less than 0.001) and a decrease in fractional potassium excretion (from 9.38% +/- 5.98% to 3.28% +/- 2.24%, p less than 0.0025), whereas it did not affect fractional lithium excretion and fractional excretion of uric acid. No change was observed in renal plasma flow, glomerular filtration rate, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide. It was concluded that lithium is not reabsorbed in the amiloride-sensitive segment of the distal tubule in nonazotemic ascitic cirrhotic patients with avid sodium retention.",0
430,1552911,Geographic variation in the use of breast-conserving treatment for breast cancer,"BACKGROUND: In the past decade there has been an increase in the use of treatment designed to conserve the breast for women with breast cancer. The extent to which such treatment has been adopted in various regions of the country and whether characteristics of hospitals and patients predict its use is not known, however. METHODS: We used national data on Medicare claims for inpatient care provided in 1986 to study 36,982 women 65 to 79 years of age, who had local or regional breast cancer and underwent either mastectomy or breast-conserving treatment (local excision, quadrantectomy, or subtotal mastectomy). Information about the hospitals at which these women were treated was obtained from an American Hospital Association survey. RESULTS: Of the 36,982 women, 12.1 percent had breast-conserving surgery and 87.9 percent had a mastectomy. The frequency of breast-conserving surgery ranged from 3.5 percent to 21.2 percent in various states. The highest rate of use was in the Middle Atlantic states (20.0 percent) and New England (17.2 percent), and the lowest was in the East South Central states (5.9 percent) and the West South Central states (7.3 percent). Breast-conserving treatment was used more often in urban than in rural areas, in teaching hospitals than in nonteaching hospitals, in large hospitals than in small hospitals, and in hospitals with on-site radiation therapy or geriatric services than in others. Most of the geographic variation persisted after adjustment for the characteristics of hospitals and patients for which data were available. CONCLUSIONS: There is substantial geographic variation in the use of breast-conserving surgery, which cannot be explained by differences in hospital characteristics. Hospital characteristics that were independently redictive of greater use of breast-conserving surgery were the size of the metropolitan area, the status of the institution as a teaching hospital, and the availability of radiation therapy and geriatric services.",0
431,1568717,Cellular immune response to HBcAg in mother-to-infant transmission of hepatitis B virus,"Cellular immunity to HBcAg was studied in hepatitis B virus carrier children and neonates born to hepatitis B virus carrier mothers. A significant proliferative response of peripheral blood mononuclear cells to HBcAg was found in 5 of 10 children with elevated ALT levels but in none of the nine HBeAg-positive children with normal ALT levels. HBeAg but not HBsAg was detected in cord blood of 9 of 10 neonates born to HBeAg-positive carrier mothers, suggesting exposure of these neonates to HBeAg in utero. However, cord mononuclear cells from neonates born to HBeAg-positive carrier mothers did not show a significant change in the proportion of suppressor and helper T-cell subsets or proliferative response to HBcAg. Nor did they produce interleukin-2 receptor after being cocultured with HBcAg. The unresponsiveness of peripheral-blood mononuclear cells or cord mononuclear cells to HBcAg was not reversed by CD8+ cell depletion. Although cord blood mononuclear cells from neonates born to carrier mothers positive for antibody to HBeAg also did not respond to HBcAg, we encountered an infant, born to a carrier mother positive for antibody to HBeAg, who contracted acute hepatitis B at 2.5 mo of age. The baby's peripheral-blood mononuclear cells showed a significant proliferative response to HBcAg. These results support the view that transplacental maternal HBeAg probably induces a specific unresponsiveness of helper T cells to HBcAg and HBeAg in the neonates born to HBeAg-positive carrier mothers. This specific helper T cell tolerance could be maintained throughout the early replicative phase of carrier state but might break someday with the appearance of raised ALT level.",0
432,1569974,Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction,"BACKGROUND: Studies of human immunodeficiency virus type 1 (HIV-1) infection have attempted to quantitate the viral load correlate it with the degree of immune deficiency. In one study, only about 1 in 10,000 peripheral-blood mononuclear cells (PBMC) expressed HIV-1, but in other studies, at least 1 in 100 CD4-positive cells was infected and harbored the HIV-1 provirus. METHODS: We developed a new, highly sensitive in situ polymerase-chain-reaction (PCR) method that amplifies selected genetic regions within intact single cells. We used this technique to determine the proportion of PBMC carrying HIV-1 provirus in infected patients in different stages of disease. RESULTS: None of the PBMC from 11 HIV-1--seronegative patients were found to be positive for HIV-1 provirus by the in situ PCR method. In 56 patients infected with HIV-1, the percentage of PBMC with HIV-1 ranged from 0.1 percent to 13.5 percent. The mean percentage of infected mononuclear cells was greater in 13 patients with persistent generalized adenopathy (mean, 6.6 percent) and 19 with the acquired immunodeficiency syndrome (Stages IV-A to IV-C) (4.6 percent) than in 19 patients with asymptomatic HIV-1 infection (0.9 percent) (P less than 0.001). However, in five patients with Kaposi's sarcoma (Stage IV-D), an average of only 1.6 percent of mononuclear cells were infected. CONCLUSIONS: In HIV-1 infection, the proportion of PBMC that are infected appears to be at least 10 times higher than previously described. It is likely that most infected cells contain HIV-1 provirus in a latent or defective form that was not detected in some earlier studies.",0
433,1579137,Asthma in children,"Despite advances in the understanding of asthma, there is still a high rate of morbidity and mortality from this disease in children. Although many factors are involved, a persistent concern is that the overuse of beta-agonists combined with the underuse of antiinflammatory medications leads to increased mortality. The demonstration that airway inflammation is present in mild asthma and the observations that inflammatory stimuli increase airway responsiveness have led to the use of antiinflammatory agents at earlier stages of disease. However, the medications with antiinflammatory activity that are currently available are not effective for all patients. The problems posed by chronic severe asthma in a child despite appropriate use of corticosteroids suggest that our current concepts are overly simplistic. Therefore, health care workers dealing with this disease must maintain an open mind about what constitutes optimal therapy.",0
434,1584257,Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease,"BACKGROUND: Bypass grafting to arteries of the lower leg has become standard surgical management of advanced peripheral vascular disease. Its success depends on identifying suitable distal vessels. Preoperative preparation includes imaging of the arteries of the lower leg, usually by conventional contrast arteriography. An alternative procedure, magnetic resonance (MR) angiography, has been successfully employed in patients with various cardiovascular diseases, but its possible value in patients with peripheral vascular disease has received little attention. METHODS: We used both conventional and MR angiography in preoperative studies of the lower-leg vessels of 23 patients (25 legs) with peripheral arteriosclerosis and arterial insufficiency, and developed independent therapeutic plans based on the information provided by each technique. When the plans differed, the interventional procedure judged more likely to save the limb was performed. The findings of conventional and MR angiography were verified by intraoperative arteriography, postinterventional arteriography, or direct operative exploration. RESULTS: MR angiography detected all vessels identified by conventional angiography, whereas conventional arteriography failed to detect 22 percent of the runoff vessels identified by MR angiography. The detection by MR angiography of vessels not identified by conventional angiography altered the surgical management of the disorders of four patients (17 percent) and guided successful bypass procedures. CONCLUSIONS: MR angiography is a noninvasive technique with greater sensitivity than conventional contrast arteriography for detecting distal runoff vessels in patients with peripheral arterial occlusive disease.",0
435,1592349,Endocrine mechanisms for the formation of sex-related differences in hepatic estrogen receptor content and their significance for the realization of an estrogen effect on angiotensinogen blood level in rats,"The use of a modified, adequate method of quantification of estrogen receptors has permitted us to prove the existence of sex-specific peculiarities in rat liver estrogen reception and their significance for the realization of sex-dependent changes in angiotensinogen plasma level after estrogenization. Endocrine mechanisms for the formation of sex-related differences in hepatic estrogen receptor content in rats were investigated in detail. The investigation shows that androgens have negative regulatory influence on the hepatic estrogen receptor level in rats. Estrogens and adrenal and thyroid hormones do not take part in the regulation of hepatic estrogen receptor content in rats. It has been proven that the decisive role in keeping up a certain estrogen receptor concentration in hepatocytes belongs to pituitary growth hormone. It was shown for the first time that androgens are able to inhibit the stimulatory effect of growth hormone on hepatic estrogen receptors.",0
436,1592350,Changes of hepatic fatty acid metabolism produced by chronic thioacetamide administration in rats,"Hepatic mitochondrial functions related to fatty acid metabolism, including the respiratory control ratio, fatty acid oxidative capacity and carnitine palmitoyltransferase I activity, were studied in vitro with mitochondria isolated from rats treated with thioacetamide for up to 12 wk. The levels of ketone bodies, carnitine, carnitine esters and malonyl-coenzyme A were also determined in liver extracts. Polarography of mitochondrial respiration from succinate or glutamate plus malate showed a lower respiratory control ratio in thioacetamide-treated rats, whereas uncoupled oxygen consumption was not altered. This suggests that the mitochondrial respiratory chain capacity remained intact in the thioacetamide-treated rats. The oxygen consumption associated with palmitoyl-coenzyme A and palmitoyl-L-carnitine oxidation by isolated liver mitochondria was increased by thioacetamide treatment on both a per-mitochondrial protein and a per-total liver basis. The carnitine palmitoyl-transferase I activity; the tissue levels of ketone bodies, carnitine and carnitine esters; and the beta-hydroxybutyrate/acetoacetate ratio were all higher in the livers of thioacetamide-treated animals than in control livers, whereas the hepatic malonyl-coenzyme A level was decreased by thioacetamide. These results indicate the increased diversion of cytosolic long-chain acyl-coenzyme As into the mitochondria for beta-oxidation rather than their esterification and use in lipogenesis. These intrahepatic metabolic changes induced by chronic thioacetamide administration may reflect the whole-body catabolic state and can be seen as adaptive for maintaining energy homeostasis under conditions of impaired glucose tolerance.",0
437,1592354,Reduced activity of the electron transport chain in liver mitochondria isolated from rats with secondary biliary cirrhosis,"Mitochondrial metabolism was studied in liver mitochondria isolated from rats with secondary biliary cirrhosis induced by bile duct ligation for 5 wk. State 3 oxidation rates were decreased in mitochondrial preparations from bile duct-ligated rats as compared with sham-operated control rats by 63% and 42% using beta-hydroxybutyrate and succinate as substrates, respectively. In contrast, when the substrate was ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine state 3 oxidation rates were not affected by bile duct ligation. Oxidation rates after uncoupling with dinitrophenol were decreased for both beta-hydroxybutyrate and succinate as substrates in mitochondria from bile duct-ligated rats. The phosphate potential was reduced in mitochondria from bile duct-ligated rats (12.5 +/- 0.5 vs. 13.6 +/- 0.2 kcal in control and bile duct-ligated rats, respectively; p less than 0.05). The inner mitochondrial membrane of liver mitochondria from rats with secondary biliary cirrhosis contained three times more cholesterol as compared with control rats, whereas the phospholipid composition was essentially unchanged. Mitochondrial protein content expressed per liver (calculated on the basis of activities of mitochondrial enzymes determined in liver homogenate and in isolated mitochondria) was increased by 50% in bile duct-ligated rats as compared with control rats. In conclusion, the function of the electron transport chain in liver mitochondria isolated from rats with secondary biliary cirrhosis is impaired. This decrease could be related to altered lipid composition of the inner mitochondrial membrane.",0
438,1592355,Stereological and functional analysis of liver mitochondria from rats with secondary biliary cirrhosis: impaired mitochondrial metabolism and increased mitochondrial content per hepatocyte,"Mitochondrial and cytosolic functions were studied in vivo and in perfused livers from rats with secondary biliary cirrhosis induced by bile duct ligation for 5 wk and in sham-operated controls. The livers were stereologically analyzed, and mitochondrial and cytosolic functions were related to liver structure. Oxygen consumption by perfused livers expressed per stereologically determined mitochondrial volume was decreased by 49% in bile duct-ligated rats compared with control rats. Glucose production (expressed per mitochondrial volume) was reduced by more than 90% in bile duct ligation, whereas urea production was not affected. Lactate production, a cytosolic function, was increased fivefold in bile duct ligation, and both the lactate/pyruvate and the beta-hydroxybutyrate/aceto-acetate ratios were increased in the liver perfusate of bile duct-ligated rats. In comparison with control rats, the stereologically determined mitochondrial volume fraction per hepatocyte was increased by 28% in bile duct-ligated rats. Activities of mitochondrial enzymes expressed per area of mitochondrial membrane or per mitochondrial volume were either unchanged (ATPase, cytochrome c oxidase and glutamate dehydrogenase) or decreased (monoamine oxidase) in bile duct ligation. Thus in comparison with control rats, mitochondrial metabolism is impaired in perfused livers from bile duct-ligated rats; increased mitochondrial volume per hepatocyte may represent a strategy to maintain hepatic energy metabolism in rats with secondary biliary cirrhosis.",0
439,1603137,Diagnosis and staging of colonic tumors by conventional abdominal sonography as compared with hydrocolonic sonography,"BACKGROUND: Ultrasonic examination has become increasingly important in the diagnosis of diseases of the gastrointestinal tract. In neoplastic diseases of the large intestine, however, the diagnostic value of conventional transabdominal sonography is limited. The purpose of this investigation was to determine whether the evaluation and staging of colonic tumors would be improved by the retrograde instillation of water into the colon in a procedure called hydrocolonic sonography. METHODS: Three hundred patients were examined in a prospective study in which both conventional transabdominal sonography and transabdominal hydrocolonic sonography were performed before the diagnosis was verified by colonoscopy. The indication for the examinations was abdominal pain, diarrhea, weight loss, or the presence of occult blood in a stool specimen. RESULTS: With the instillation of water into the colon, it was possible to display the colon sonographically from the rectosigmoid transition to the cecum in 97 percent of the patients examined. In addition to permitting the evaluation of the colonic lumen, the procedure allowed the five layers of the colonic wall and the connective tissue surrounding the colon to be examined in detail. Only 9 of 29 carcinomas were diagnosed by conventional abdominal sonography (31 percent), whereas hydrocolonic sonography permitted the diagnosis of 28 (97 percent). No polyps could be detected by conventional abdominal sonography, whereas hydrocolonic sonography permitted the diagnosis of 38 of 42 polyps greater than or equal to 7 mm (91 percent) and 3 of 12 polyps less than 7 mm (25 percent). In addition, detailed evaluation of the structure of the bowel wall with hydrocolonic sonography permitted a more precise staging of colonic tumors. CONCLUSIONS: Hydrocolonic sonography, a new diagnostic procedure, can facilitate the diagnosis and staging of colonic tumors.",0
440,1613945,Studies of emergency cardiopulmonary bypass (ECPB) for cardiopulmonary-cerebral resuscitation; (1) Introduction of a portable-percutaneous ECPB system],"The authors have developed an ECPB system, which can be applied quickly, safely and easily under an emergency condition requiring cardiac massage and artificial ventilation. Fundamentally, the ECPB system consists of 3 parts; a portable ECPB apparatus, a pair of percutaneous cannulae and a short circuit connecting an oxygenator with the cannulae. The ECPB apparatus is assembled with commercially available components (i.e., a centrifugal pump, a battery pack, a temperature controller, a compact membrane oxygenator with a heat exchanger, etc) and they are placed on a mobile cart. The circuit is primed with 300 ml of lactated Ringer solution. The priming can be done within 15 minutes via a reservoir. It is also possible to keep the primed circuit to be ready for emergency use at least for a week. The cannulae are placed intravascularly through the femoral artery and vein by using the Seldinger's percutaneous method. In an emergency situation, the arterial and venous cannulations are carried out separately on the both inguinal regions to save time. The tip of the venous cannula is adjusted to be placed near the right atrium under fluoroscopy. Initiation of ECPB via the femoro-femoral V-A cannulae assures instant and stable supply of oxygenated blood to all of the vital organs. At the present time, nothing is more important than a quick supply of oxygenated blood to the brain to ameliorate the post-ischemic brain damage. ",0
441,1613987,Platelet membrane glycoprotein V and clinical significance of plasma GPVf 1 level],"Thrombin hydrolyzes platelet membrane glycoprotein V (GPV) which has leucine rich repetitive modules specifically, and releases GPVf1 (fragment of N terminal in GPV). The GPV related antigen level in plasma will thus reflect activation of platelet in vivo. The ELISA assay to measure the concentration of GPV and GPVf1 in plasma using polyclonal anti-GPV antibody, was established. The concentration of GPV and GPVf1 in plasma by using polyclonal anti-GPV antibody was established. The concentration of GPV related antigen in plasma is significantly higher in patients with thrombosis and correlated well with thrombotic episodes. It was suggested that the measurement of plasma-GPV-related antigen level is a useful marker for the diagnosis of thrombosis or prethrombotic states. ",0
442,1614179,Pregnancy and labor in mucoviscidosis--results of a study in Germany],"Thirty-one pregnancies in 27 women suffering from mucoviscidosis have been studied in Germany, in the period from 1980 to 1991. This analysis is the largest collection of data to date relating to pregnancy and birth with mucoviscidosis after the American-Canadian study of 1980. The German study demonstrated that only women with few weak symptoms became pregnant: typically the pregnant women's mucoviscidosis was diagnosed at an average age of 9.2 years, and 96.5% of the women had a satisfactory pregravid Shwachman-Kulczicki-Score. Only minor complications were observed in these pregnancies, in particular pulmonary exacerbations (in 18 pregnancies) and an insufficient weight gain (average of 7.2 kg). Abortions were induced in five pregnancies and no spontaneous were observed. There were of maternal deaths during pregnancy or childbirth. More than one quarter of the newborns were premature. All the children had normal sweat chloride test results. 21 women could breast-feed successfully. In fifteen cases the mother's state of health deteriorated after pregnancy however only to a minor (ten cases) or moderate degree (four cases). It is noteworthy that of the twenty six infants twenty one were male. In this study we obtained the unexpected result that unaffected heterocygous children of women with mucoviscidosis are mainly male. ",0
443,1614347,Practical medical education in general practice,"The Medical Faculty of the University of Limburg in Maastricht, The Netherlands pays special attention to extramural care. The extramural profile of the Medical Faculty also manifests itself in the curriculum. Since 1978, a 12-week clerkship in practical medical training in general practice (PMT-GP) has been offered to fifth-year students. The general aim is to acquaint students with general medical aspects as well as specific primary care aspects of health care. The programme started in the autumn of 1978 with 24 students and 24 GP teachers. At present more than 100 GP teachers, working in about 70 practices, train 120-130 students a year. The model of the PMT-GP system is characterized by six features: a ratio of one GP teacher to one student; autonomous examination by the student of at least 15 patients a week; daily follow-up discussion on the basis of patient records prepared by the student; opportunities for self-study by the student; one tutorial day a week at the Medical Faculty; intensive contacts between the Faculty and GP teachers. Key activities of the PMT-GP include autonomous contacts with patients, written records and daily follow-up discussions with the GP teacher. ",0
444,1614397,Primary malignant lymphoma of the esophagus--a case report],"We report a rare case of primary malignant lymphoma of the esophagus without extraesophageal involvement. A 69-year-old woman was referred to our hospital because of dysphagia. Esophagogram revealed an irregularly marginal ulceration with stenosis at the abdominal esophagus. Endoscopic study showed an ulcerative lesion at the level of 30 cm from the incisor teeth. Esophagocardiectomy was performed. Resected specimen showed a shallow depressed ulceration, 6.5 x 6.0 cm in size, at the lower esophagus. Microscopic examination revealed malignant lymphoma of diffuse, large cell type. No evidence of involvement was found in the dissected lymph nodes and the bone marrow biopsy specimens. She has been well for 4 years and 6 months postoperatively. ",0
445,1615133,Effects of fenfluramine and para-chloroamphetamine on sexual behavior of male rats,"The present studies have evaluated the effects of pharmacologically induced release serotonin on sexual responses of male rats during exposure to a sexually receptive female rat. Following acute administration of fenfluramine or para-chloroamphetamine (PCA), significant dose-related decreases in copulatory rate and copulatory efficiency, and increases in ejaculatory latency were observed. These effects were not observed when the animals were pretreated with LY53857, a 5-HT1c/2 antagonist. These studies indicate that acute release of serotonin evoked by these releasing agents has inhibitory effects on sexual sexual drive, capacity to achieve erection and threshold for ejaculation, and these effects are mediated by either the 5-HT1c or 5-HT2 receptor. ",0
446,1615377,Cranial fasciitis of childhood: a case report,"Cranial fasciitis of childhood is very rare, only 17 cases having been reported in the literature. We report an additional case of this rare disease. The patient was a 5-year-old boy who complained of left exophthalmos and double vision. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a large epidural mass in the left frontal region that had invaded into the underlying anterior skull base. The tumor showed homogeneous, low density with nonhomogeneous contrast enhancement on the CT scans, and low intensity on the T1-weighted and high intensity on the T2-weighted MRI images. A whitish-pink, elastic, hard tumor was revealed in the epidural space in the left anterior cranial fossa, which was totally excised with curettage of the affected anterior skull base. The origin of the tumor was suspected to be the fibrous connective tissue of the sphenofrontal suture. The histological diagnosis was that of cranial fasciitis. There was no evidence of recurrence 1 year postoperatively. ",0
447,1616370,Primary Sjögren's syndrome preceding the presentation of systemic lupus erythematosus as a benign intracranial hypertension syndrome,"The case is reported of a 41 year old white woman who developed systemic lupus erythematosus (SLE) seven years after primary Sjögren's syndrome and four years after the association of Sjögren's syndrome with Jaccoud's arthritis. The SLE was detected by a benign intracranial hypertension, which is a rare neuro-ophthalmic presentation of lupus. No associated conditions linked to benign intracranial hypertension syndrome were seen in this patient and the hypertension syndrome recurred one year later. ",0
448,1616423,Evidence of cytotoxic T-cell destruction of epidermal cells in human graft-vs-host disease. Immunohistology with monoclonal antibody TIA-1,"A newly described mouse monoclonal IgG1 antibody, TIA-1, binds serine esterase-positive granule membranes of cytotoxic human T cells and is a candidate for an effector molecule involved in T-cell cytolytic mechanisms analogous to those of the perforin system. We performed immunohistologic studies on frozen human skin (n = 5) and lip (n = 21) sections as well as on control frozen sections of tonsils, purified cytolytic T (CD8) cells, and B cells using an indirect immunoperoxidase system. We found a strong association of TIA-1+ cells with CD8+ cells invading the epidermis in lip and skin lesions of graft-vs-host disease in human marrow allograft recipients, as well as a sharp geographic association of TIA+ lymphocytes with CD8+ regions in human tonsil sections. Double staining of CD8 and TIA-1 antigens with fluorescein isothiocyanate and Texas red confirmed that 80% to 90% of the CD8 cells were TIA-1+ in the epidermal infiltrates. Leu-7 activity (natural killer cell) was minimal and found in only three of 17 lip biopsy specimens. These data provide new evidence that direct cytolytic attack by donor T lymphocytes is the mechanism of epithelial target cell killing in human graft-vs-host disease. ",0
449,1616439,Menstrual history in altitude chamber trainees,"Previous studies have determined a higher rate of altitude-induced decompression sickness (DCS) in women than in men. Women are reportedly at higher risk for developing DCS during menses. A study of menstrual history in women completing altitude chamber training without developing DCS has never been accomplished. The purpose of this study was to collect and analyze menstrual history in these women. Thirteen U.S. Air Force Aerospace Physiology Units participated in a USAF-approved survey for 1 year. After completing altitude chamber flights, data on age, day of menstrual cycle (DMC), birth control pill use (BCP), and mean durations of menstrual cycle and menses were collected. There were 508 responses analyzed. There was no differences between mean duration of menstrual cycle and menses in the Yes (Y) and No (N) BCP groups. Y and N BCP groups were equally distributed across the menstrual cycle. Women completing altitude chamber training without developing DCS appear to be evenly distributed across their menstrual cycle, with use of BCPs not affecting their susceptibility to DCS. ",0
450,1616484,Purification and characterization of diaphorases from some Drosophila species,"Diaphorase-1 and diaphorase-2 were isolated from two Drosophila species, D. virilis and D. melanogaster, and purified by gel filtration, affinity chromatography, immunoaffinity chromatography, and ion-exchange chromatography. The molecular weights of both enzymes were the same in each species. The molecular weight of diaphorase-1 was the same under both denaturating and nondenaturating conditions, close to 60,000, indicating a monomeric structure. Sodium dodecyl sulfate (SDS) electrophoresis of the purified diaphorase-2 revealed the presence of a single protein band of 55,000 Da, while the molecular weight of the native enzyme was found to be 67,000. The two diaphorases were further characterized by their pH optima, isoelectric points, and kinetic parameters, and antibodies were raised in rabbits against the purified enzymes from D. virilis. The antibodies showed no cross-reactions but recognized the corresponding diaphorases in D. melanogaster and D. novamexicana as well as D. virilis. The data obtained confirmed the hypothesis of an independent genetic control of diaphorase-1 and diaphorase-2 in Drosophila. ",0
451,1616850,Promotion of hepatic metastases by liver resection in the rat,"In the early period following radical hepatectomy for hepatoma, recurrences in the remaining liver are frequently found. In regenerating liver, implantation and growth of tumour cells released into the portal system during surgical treatment might be promoted. We examined the relationship between liver regeneration and the formation of metastases following hepatic resection. Intraportal injections of rat ascites containing hepatoma AH130 cells at a concentration of 1 x 10(5) cells 0.2 ml-1 were made at various periods following two thirds liver resection in rats. Tumour cell injections immediately at 24 h after surgery resulted in an increased number of hepatic metastases compared with control animals. Tumour cell injections 2 weeks after hepatectomy, however, had no significant difference in effect compared with control rats. In contrast, tumour cells injected immediately after removal of half of the caudate lobe resulted in the same number of metastases as control animals. These results demonstrate that the number of artificially induced hepatic metastases was increased during an initial period of active liver regeneration and was proportional to the volume of hepatectomy. The effect of 5-fluorouracil (5FU) or mitomycin C (MMC) as inhibitors of hepatic regeneration on liver metastasis after hepatectomy was studied. The administration of 5FU (20 mg kg-1) or MMC (0.2 mg kg-1) immediately, 24 and 48 h after hepatectomy resulted in a marked reduction in metastatic lesions. The administration of 5FU caused delays in weight gain and decreases in the wet weight of remaining liver, while MMC had no effect on either. Accordingly, results of 5FU administration may be due to inhibitory effects on liver regeneration whilst that of MMC administration may be due to cytocidal antitumour effect. The effect of OK-432 as an immunoactivator on the implantation and growth of tumour cells in regenerating liver was also studied. Pretreatment with OK-432, 0.5 mg intraperitoneally on 7 consecutive days, had no effect on hepatic metastases. The pathophysiology of liver regeneration may enhance hematogenous hepatic metastasis and release of tumour cells during surgical manipulation may represent an important cause of recurrence following hepatic resection. ",0
452,1616927,Ontogeny of proximal colon basolateral membrane lipid composition and fluidity in the rabbit,"Basolateral membranes from rabbit proximal colon were prepared from isolated colonocytes throughout postnatal maturation, using a modification of published techniques. In suckling (14-20 day) and post-weaning/mature (35-49 day) animals, membranes were purified approx. 10-fold, based upon the enrichment of ouabain-sensitive, sodium-potassium dependent adenosine triphosphatase activity. Membrane lipid analyses demonstrated age-dependent increases in total cholesterol and the cholesterol/phospholipid molar ratio, as well as decreases in phosphatidylethanolamine content and the fatty acid unsaturation index. Fluidity of basolateral membranes and membrane liposomes, determined from fluorescence anisotropy measurements using the lipid probes 1,6-diphenyl-1,3,5-hexatriene and DL-12-(9-anthroyl)stearic acid, demonstrated significant, ontogenic decreases in fluidity; and, additional studies showed that fluidity changes occurred early in the weaning period (by day 24 postnatally). Arrhenius plots of liposome anisotropies suggested a bilayer lipid thermotropic transition temperature of 22 degrees C in sucklings 26 degrees C in mature rabbits. These findings demonstrate that ontogeny of colonic basolateral membranes is associated with significant modulations in lipid composition and fluidity. ",0
453,1617012,Androgenic activity in 15-day-old male rats: role of the maternal pineal gland,"Female Sprague-Dawley rats, exposed to a long (18L:6D) or a short (6L:18D) photoperiod from 21 days of age, were mated when they reached 55 days of age. On Day 2 of gestation, dams were pinealectomized or sham-operated. Pre- and postnatal photoperiods were identical, and offspring were killed at 15 days of age. Maternal pinealectomy had no effect when rats were kept on 18L:6D. Rats born to sham-operated mothers and kept on 6L:18D had higher testicular testosterone and androstenedione content than offspring raised on the long photoperiod. This stimulatory effect of the short photoperiod was blocked by maternal pinealectomy and was not dependent on the offspring's own pineal since it was observed in both sham-operated and neonatally (on Day 5 after birth) pinealectomized rats. When sham-operated mothers housed on 18L:6D were treated daily during pregnancy and lactation by s.c. melatonin injection, there was an increase in the testicular testosterone content of offspring. It was concluded that when rats are maintained on a 6L:18D cycle the maternal pineal gland enhances the testicular testosterone and androstenedione content in 15-day-old offspring. This effect is probably mediated by maternally derived melatonin. At 15 days of age, the pineal of the offspring had no influence on testicular function. ",0
454,1617014,Demonstration of oxytocin release by bovine luteal cells utilizing the reverse hemolytic plaque assay,"Corpora lutea (CL) of a number of species produce oxytocin (OXT). In the present experiments we studied basal, prostaglandin (PG) F2 alpha-stimulated and ascorbate-stimulated OXT release from individual bovine luteal cells utilizing the reverse hemolytic plaque assay (RHPA). Using a mixture of C- and N-terminus-specific antisera against OXT, we were able to demonstrate OXT plaque formation by individual luteal cells. CL consist of two steroidogenic cell types: large luteal cells (LLC), believed to derive from granulosa cells and to produce and secrete OXT, and small luteal cells (SLC), thought to derive from theca cells. To distinguish between these two cell types, we designated cells greater than 20 microns as LLC and those less than 20 microns as SLC. On the basis of this morphological parameter, OXT release from both LLC and SLC was demonstrable. After an incubation period of 15 h, 7% of both cell types formed OXT plaques. PGF 2 alpha and ascorbate increased the size of plaques surrounding both LLC and SLC to more than 200% and 240%, respectively (basal plaque size = 100%). The number of plaque-forming cells increased only slightly in the presence of either PGF 2 alpha or ascorbate in comparison to basal conditions. We suggest that the RHPA can be used to demonstrate peptide release from luteal cells. It is concluded that LLC may be subdivided into functional subclasses because less than 10% of bovine luteal cells release OXT. Known OXT secretagogues increased the amount of OXT released. It appears that not only LLC but also SLC secrete this peptide.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
455,1617113,Histological characteristics of lupus nephritis in F1 mice with chronic graft-versus-host reaction across MHC class II difference,"Renal lesions at the chronic phase of MHC class-II-disparate graft-versus-host reaction (GVHR) were examined. To induce GVHR, C57BL/6 (B6) spleen cells were injected twice into either (B6 x bm12)F1 (class-II-disparate), (B6 x bm1)F1 (class-I-disparate) or (bm1 x bm12)F1 mice (class-I + II-disparate). For comparison, (C57BL/10 x DBA/2)F1 (BDF1) mice injected with DBA/2 spleen cells were also used. (B6 x bm12)F1 and BDF1 recipients showed marked elevation of anti-DNA antibodies, circulating immune complexes (CIC) and the number of immunoglobulin producing cells (IgPC). At 20 weeks after cell injection, severe immune complex glomerulonephritis (ICGN) was observed in (B6 x bm12)F1 recipients, but was far less severe in (bm1 x bm12)F1 recipients and was not observed in (B6 x bm1)F1 recipients. ICGN was also observed in BDF1 recipients at 12 weeks after cell injection. By immunofluorescent microscopy, IC deposition was detected along the capillary loops and also in the mesangial area in (B6 x bm12)F1 recipients, while BDF1 recipients showed only a capillary pattern. By light microscopy, the renal lesion of (B6 x bm12)F1 recipients appeared similar to those of BDF1 recipients. Histologically, (B6 x bm12)F1 recipients serve as a good model for lupus glomerulonephritis induced by class-II-disparate GVHR. ",0
456,1617127,Neonatal exposure to protoporphyrin-activating lighting as a contributing cause of childhood acute lymphocytic leukemia,"While being a relatively rare disease, acute lymphocytic leukemia (ALL) is the leading form of cancer in children in the developed world today. ALL sharply peaks in incidence at ages three to four years. In the United States there have been persistent, unexplained increases in incidence of ALL in the past two decades. We hypothesize that exposure to photosensitizing lighting immediately after birth may be a contributing cause of ALL. Fluorescent lamps and other light sources with strong illumination, around 400 nanometers, are protoporphyrin-activating. Activation of protoporphyrin produces superoxides and free radicals that can induce breaks in DNA. In newborn nurseries in the US, the intensity of lighting has increased five- to 10-fold over the past two decades. Thus, protoporphyrin-activating light may be a contributing cause of childhood ALL. Additional retrospective and prospective studies should be undertaken of the relationship between exposure of newborns to protoporphyrin-activating illumination and the development of childhood ALL, along with in vitro studies of the hematologic effects of fluorescent lighting. Protoporphyrin-activating lighting is clearly not the sole determinant of ALL, but it could be a completely preventable cause. Inexpensive plastic filters could reduce these exposures substantially. ",0
457,1617237,Effects of hypercholesterolemia on monokine-induced smooth muscle cell proliferation,"Macrophage/smooth muscle cell interactions play a role in atherogenesis and foreign body reactions to biomaterials. This study investigates the effect of a hypercholesterolemic diet on the ability of smooth muscle cells (SMCs) to respond to monokines which are produced in response to hypercholesterolemia, biomaterials or both. Peritoneal macrophages were harvested from rabbits fed either a normal (M phi NL) or a 2% cholesterol/6% peanut oil diet (M phi ATH) (plasma cholesterol 2840 vs 42.3 [p less than 0.005]). The macrophages were then cultured in the presence of either 1) polyglactin 910 (PG910), 2) Dacron, or 3) no biomaterial (control), and the media collected and pooled by week for the smooth muscle cell mitogenesis assays. Rabbit aortic smooth muscle cells were harvested and cultured from the same two groups of rabbits (SMCNL or SMCATH), quiesced in serum free media (48 h) followed by addition of the test media and 3H-TdR. The addition of either biomaterial to M phi NL-conditioned media increased 3H-TdR incorporation in both smooth muscle lines as compared to controls. PG910 resulted in significantly higher 3H-TdR incorporation than Dacron (weeks 3-5, p less than 0.005). The addition of either biomaterial to M phi ATH also increased 3H-TdR incorporation in both smooth muscle cell lines, however, the magnitude of the response was decreased as compared to the M phi NL-conditioned media in both cell lines (p less than 0.001 for either SMC line). In contrast to the M phi NL-conditioned media, the addition of Dacron to M phi ATH resulted in the highest level of 3H-TdR incorporation in both cell lines as compared to the media without biomaterial. The SMCNL had a higher response to both the monokines in conditioned media (2-fold) and to fetal bovine serum (3-fold) than the SMCATH (p less than 0.001). Although there is a generalized decrease in release of mitogens active on SMCs from M phi ATH, the M phi ATH exposed to Dacron release increased amounts of mitogenic factors, most active on the SMCATH cell line. A common mode of failure of small diameter Dacron grafts in man is pseudointimal hyperplasia, and it is inviting to postulate that the Dacron/macrophage/smooth muscle cell interactions in this atherosclerotic group of patients plays a role in the pathogenesis of this lesion. ",0
458,1617538,Prevention of vascular injuries in revision total hip replacement,"Iliac-vessel injury from total hip arthroplasty is associated with hemorrhagic complications and an increased death rate. The authors identified seven patients who had severe medial displacement of the acetabular prosthesis and associated vascular injury to the iliac vessels after total hip replacement. One patient had two hip replacements. Preoperative findings included a pelvic mass (three hips), pelvic pain (eight), radiologic evidence of cement in the pelvis (three) and the acetabular prosthesis in the pelvis (eight), computed tomographic evidence of cement in the pelvis and proximity of the prosthesis to the iliac vessels (four), and arteriography showing displacement or compression of the iliac vessels (seven). Operative management in all cases involved medial exposure, mobilization and repair of the iliac vessels before revision of the hip prosthesis. Postoperative complications were deep vein thrombosis (three), in spite of prophylaxis, and occlusion of a vein interposition graft (one) requiring placement of a femoral crossover graft. There were no deaths, amputations or hemorrhagic complications. The authors advocate preoperative identification of patients who have iliac-vessel involvement by their total hip prosthesis and initial medial extraperitoneal exposure and repair of these vessels before removal of the displaced acetabular prosthesis. ",0
459,1617696,Morphological differentiation of endothelial cells co-cultured with astrocytes on type-I or type-IV collagen,"In this study bovine aortic endothelial cells were co-cultured with astrocytes from fetal Wistar Kyoto rats. Endothelial cells growing on type-I collagen, co-cultured with astrocytes, showed various stages of development. Although some cells appeared to be mature, horseradish peroxidase penetrated within 1 min of incubation through the intercellular junctions of these endothelial elements maintained on type-I collagen. In contrast, endothelial cells on type-IV collagen, co-cultured with astrocytes, were well developed; their intercellular junctions were well established, and plasmalemmal vesicles reduced in number. As a result, horseradish peroxidase was unable to penetrate through the endothelial cells grown on type-IV collagen and co-cultured with astrocytes because of the reduced extent of the junctional and vesicular transport. These findings reveal that (1) type-IV collagen is essential for the differentiation of endothelial cells, (2) endothelial cell-astrocyte interactions occur during co-culture, and (3) endothelial permeability depends on astrocyte-produced factors, in addition to type-IV collagen. ",0
460,1618317,Baculovirus expression of mammalian G protein alpha subunits,"Complementary DNAs encoding three subtypes of the alpha subunit (alpha i-1, alpha o and alpha s) of rat guanyl nucleotide regulatory proteins were used to construct recombinant baculoviruses which direct high-level expression of the corresponding proteins in cultured Sf9 insect cells. The expressed proteins were recognized by polyclonal antisera specific for the different alpha chains, and co-migrated with the native proteins from rat brain membranes in immunoblotting analyses. Soluble and particulate forms of all three immunoreactive alpha chains were observed following ultracentrifugation of cell lysates. Biosynthetic radiolabelling of infected cells with [35S]methionine or [3H]myristate showed that both soluble and particulate forms of alpha i-1 and alpha o were myristoylated; in contrast, alpha s did not incorporate myristate. The soluble fractions from cells expressing alpha chains showed high levels of GTP-binding activity over that observed in uninfected cells, or in cells infected with wild-type virus. The peak expression levels observed at 72 h post-infection were highest for alpha o at ca. 400 pmol of GTP-gamma-35S/mg protein, or roughly 2% of the total soluble protein. The results of this work show that the baculovirus system can be employed for high-level production of mammalian G protein alpha chains which retain GTP-binding activity and are appropriately modified by myristoylation. ",0
461,1618346,Phosphoramidon-sensitive endothelin-converting enzyme in vascular endothelial cells converts big endothelin-1 and big endothelin-3 to their mature form,"Incubation of big endothelin-3 (big ET-3(1-41)) with the membrane fraction obtained from cultured endothelial cells (ECs) resulted in an increase in immunoreactive-ET (IR-ET). This increasing activity was markedly suppressed by phosphoramidon, which is known to inhibit the conversion of big ET-1(1-39) to ET-1(1-21). Reverse-phase HPLC of the incubation mixture of the membrane fraction with big ET-3 revealed one major IR-ET component corresponding to the elution position of synthetic ET-3(1-21). When the cultured ECs were incubated with big ET-3, a conversion to the mature ET-3, as well as an endogenous ET-1 generation, was observed. Both responses were markedly suppressed by phosphoramidon. By the gel filtration of 0.5% CHAPS-solubilized fraction of membrane pellets of ECs, the molecular mass of the proteinase which converts big ET-1 and big ET-3 to their mature form was estimated to be 300-350 kDa. Phosphoramidon almost completely abolished both converting activities of the proteinase. We conclude that the above type of phosphoramidon-sensitive metalloproteinase functions as an ET-converting enzyme to generate the mature form from big ET-1 and big ET-3 in ECs. ",0
462,1618362,Evidence of growth retardation in neonates of apparently normal weight,"The aim of this study was to examine the relationship of ponderal index (PI) and the ratio of mid-arm circumference to occipito-frontal circumference (MAC/OFC) to the delivered weight of the child. Measurements were made on 160 singleton neonates with birthweight greater than 2500 g and delivery at 37 weeks or more. Surprisingly, there was a highly significant correlation between PI and birthweight and MAC/OFC and birthweight. We conclude that: (1) values of PI must be evaluated in relation to birthweight, and not against a single absolute standard for the whole normal population; (2) measurement of PI and MAC/OFC may reveal a group of growth-retarded infants amongst infants of apparently 'normal' birthweight; and (3) this group of infants might be a target for the extra care normally accorded to the low birthweight infant. ",0
463,1618405,Corpus luteum defect. Analysis of 30 cases in clinical pregnancy],"Deficient corpus luteum (DCL) is an ovulatory dysfunction little defined but real. It is said that is frequency is 3 and 10% of sterile couples and 30 to 40% of habitual abortion. Is part of the group of ovulatory aberrations together with in situ luteinization and syndrome of not broken luteinized folicle. The diagnosis is based in endometrial morphology and progesterone determination. The objective of this work is to analyze 30 cases of DCL that achieved pregnancy. The diagnosis was done based on low determination of progesterone in serum, biopsy of irregular or indysphase endometrium and all the factors, remaining normal of esterility. Average age of patients was 36 years and for sterility 3.1. Treatment consisted in clomiphen cytrate (CC) administration 100 mg daily of hCG in 21 cases, CC only in eight cases and associated to bromocriptine in one case (concomitant hyper-prolactinemia); 26 pregnancies went to term, seven of them with support of exogenous progesterone the first weeks. There were three abortions and an ectopic one. It is concluded that with a complete study of sterility that only shows low seric progesterone and/or endometrium in dysphase or irregular, the diagnosis of DCL is probable and should be treated first with CC plus hCG. The evolution of pregnancies is normal and according to these results is little acceptable the use of progesterone as a support in pregnancy. ",0
464,1618481,Hepatitis B virus DNA in peripheral-blood mononuclear cells in chronic hepatitis B after HBsAg clearance,"In this study, peripheral-blood mononuclear cells from patients with chronic hepatitis B and spontaneous or therapy-induced disappearance of HBsAg were examined for HBV DNA. Samples were evaluated by in situ hybridization and polymerase chain reaction both before and after clearance of HBsAg. By in situ hybridization, positive signals were observed in 2 of 13 samples collected after HBsAg loss, in 8 of 15 samples before HBsAg loss and in 0 of 4 control patients without serological markers of active or prior HBV infection. When polymerase chain reaction analyses were performed, HBV DNA was detected in 5 of 12 HBsAg-negative samples and 10 of 15 HBsAg-positive samples from the study group. Testing of mononuclear cells after disappearance of HBsAg revealed that two of eight patients were HBV DNA positive by in situ hybridization and by polymerase chain reaction, whereas two additional patients were positive by polymerase chain reaction alone. Mononuclear cell-associated HBV DNA was detected between 2 and 9 mo after the disappearance of circulating HBsAg by in situ hybridization and as long as 4 yr later by polymerase chain reaction. These data indicate that patients who have undergone HBsAg seroconversion may nonetheless harbor HBV DNA in their peripheral-blood mononuclear cells for prolonged periods.",0
465,1618483,Isolation and characterization of the mannose receptor from human liver potentially involved in the plasma clearance of tissue-type plasminogen activator,"Various studies have shown that mannose receptors rapidly eliminate glycoproteins and microorganisms bearing high mannose-type carbohydrate chains from the blood circulation. The purpose of this study was to characterize the mannose receptor in the liver, which in vivo is involved in the rapid clearance of tissue-type plasminogen activator from the circulation. Human liver membranes were solubilized in Triton X-100, and the solution was applied to a tissue-type plasminogen activator Sepharose column. Bound proteins were eluted with ethylenediaminetetraacetate (10 mmol/L). A second, similar purification step rendered a single liver protein of 175,000 daltons. A combination of ligand blotting and a chromogenic assay for tissue-type plasminogen activator demonstrated that the identified liver protein is a mannose receptor because it bound tissue-type plasminogen activator, this tissue-type plasminogen activator binding being fully inhibited by 0.2 mol/L D-mannose. Western-blot analysis revealed that the isolated liver protein is immunologically identical to the human mannose receptor from placenta. Treatment of the liver protein and the placenta mannose receptor with trypsin yielded the same pattern of proteolytic degradation products as identified on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We conclude that the physiologically relevant mannose receptor for tissue-type plasminogen activator clearance isolated from human liver is immunologically and structurally similar to or identical with the human mannose receptor isolated from placenta.",0
466,1618703,Kinetic analysis of combination effect of navelbine (KW-2307) with cisplatin against human lung adenocarcinoma PC-12 cells in culture,"The combination effect of navelbine (NVB, KW-2307), a newly synthesized vinca alkaloid, and cisplatin (CDDP) was compared with that of vindesine (VDS) and CDDP using human lung adenocarcinoma PC-12 cells. The growth-inhibitory activity of NVB or VDS was time-dependent, whereas that of CDDP was AUC (area under the curve)-dependent. When NVB or VDS was used in combination with CDDP simultaneously for 24 h, antagonism was observed in terms of growth-inhibitory activity. However, additive combination effect was observed when NVB or VDS treatment was followed by CDDP treatment. On this treatment schedule, a synergistic combination effect was observed in terms of the cell-killing activity assessed by colony formation assay. The growth-inhibitory activity of NVB or VDS was detected 24 h after the treatment, whereas that of CDDP became significant 72 h after the treatment. NVB and VDS caused cell accumulation in G2M phase at 10 times their IC80 values, and cells with less than diploid DNA content were detected after 24 h at IC80. CDDP caused accumulation of cells in S phase, and the effect became detectable 16 h after the treatment. The DNA histogram of cells treated with NVB or VDS in combination with CDDP was a superposition of those of cells treated with each drug alone. Significant differences in the characteristics of anticellular activity were not detected between NVB and VDS, although NVB inhibited cell growth at a slightly lower concentration than VDS at the short exposure time of 1-8 h. ",0
467,1618738,Effects of low culture temperature on the induction of hsp70 mRNA and the accumulation of hsp70 and hsp105 in mouse FM3A cells,"We have shown that heat shock does not induce the synthesis of hsp70 in FM3A cells maintained at a low culture temperature of 33 degrees C although it does so in cells maintained at 37 degrees C [T. Hatayama et al. (1991) Biochem. Int. 24, 467-474]. In this paper, we show that FM3A cells maintained at 37 degrees C produced hsp70 mRNA during continuous heating at 42 degrees C or during postincubation at either 37 or 33 degrees C after being heated at 45 degrees C for 15 min, whereas cells maintained at 33 degrees C did not produce hsp70 mRNA during continuous heating at 37, 39, 42, or 45 degrees C, or during postincubation after being heated at any temperature. Thus the lack of hsp70 synthesis in cells maintained at 33 degrees C seemed to be due to the absence of hsp70 mRNA induction. Also, hsp70 was accumulated in cells maintained at 37 degrees C during continuous heating at 42 degrees C and during postincubation at 37 degrees C after heat shock at 45 degrees C, but not during postincubation at 33 degrees C. The cellular level of the constitutive hsp73 as well as the mRNA level were both similar in cells maintained at 33 and 37 degrees C. On the other hand, the cellular level of the constitutive hsp105 in cells maintained at 33 degrees C was only half of that in cells maintained at 37 degrees C. These hsp105 levels increased significantly in both types of cells after continuous heating at 39 degrees C. These findings indicate that the culture temperature affects not only the induction of hsp70 mRNA but also the accumulation of hsp70 and hsp105 in the cells. ",0
468,1618996,Decreased hypoglycemic effect of insulin at night in insulin-dependent diabetes mellitus and healthy subjects,"Diurnal variations in insulin-induced hypoglycemia and in plasma counterregulatory hormone concentrations were explored in eight insulin-dependent diabetic and six healthy subjects during a 100-min iv insulin infusion performed at 0300 h and 1500 h. In healthy subjects, plasma glucose concentrations (mean +/- SD) fell by 35 +/- 2% during the daytime test and by 26.5 +/- 2% during the nocturnal test (P less than 0.01). Plasma cortisol, GH, and epinephrine concentrations increased more during the daytime than during the nocturnal test. In contrast, plasma glucagon concentrations rose more during the nocturnal tests. In insulin-dependent diabetes mellitus patients, insulin infusion had to be interrupted in three subjects because plasma glucose fell below 1.9 mmol/L 80 min after the beginning of the test. In the other five patients plasma glucose fell by 34 +/- 5% during the daytime test while no significant decrease in plasma glucose was observed in any of the eight patients during the nighttime test. Counterregulatory hormone concentrations were consistent with the results of plasma glucose, with no change during the nocturnal test and significant increases in cortisol, GH, and epinephrine during the daytime test. These results show that insulin sensitivity is decreased at night in comparison to midafternoon in healthy subjects and that in insulin-dependent diabetes mellitus patients this phenomenon is exaggerated, even in patients with defective counterregulation to hypoglycemia. ",0
469,1619667,Heterogeneity and sampling volume dependence of epicardial adenosine concentrations,"Rapid steady-state estimates of interstitial fluid (ISF) adenosine concentrations (ADOi) in the left ventricular epicardium of anesthetized dogs were obtained by the epicardial porous disc (EPD) method described herein. Because of the high temporal and spatial resolution of this method, it was ideally suited to test the hypothesis that ADOi may vary in these domains. Variance in steady-state EPD solute concentrations was quantified statistically by the coefficient of variation (CV = standard deviation/mean), which we used as an index of heterogeneity. A significant temporal variation in steady-state EPD adenosine concentrations was observed when samples were sequentially collected from one epicardial location (CV = 42.9 +/- 3.5%). When steady-state sample pairs (n = 45) were collected simultaneously from two distinct epicardial locations, a 2.6 +/- 0.3-fold mean difference in their respective adenosine concentrations was measured. About 25% of this variation was inherent in procedural methodology, based on the variability of steady-state EPD concentrations of extracellularly-equilibrated 14C sucrose (CV = 12.7 +/- 1.2%) and the variability of steady-state concentrations of both solutes measured using in vitro preparations (mean CV = 9.7 +/- 1.2%). Thus, we contend that endogenous myocardial ISF adenosine is temporally and perhaps spatially heterogeneous. Our estimates of steady-state ADOi obtained with the EPD method ranged from 0.47 to 0.99 microM. Using modifications of the EPD technique and the epicardial chamber, we also demonstrated that the adenosine concentration in 'steady-state' epicardial samples is reduced when the volume/surface area ratio of the sample buffer is increased. We hypothesize that sampling-induced decreases in steady-state ADOi underlie these observations, because losses of ISF adenosine to high volumes of sample buffer can be greater than the myocardial cells are capable of replacing. However, with the very low volume/surface area ratio of a single EPD (7.5 microliters/cm2), steady-state ADOi may remain constant during sampling, allowing for accurate determinations of ADOi with this method. ",0
470,1619669,Myocardial glycoproteins in diabetes: type VI collagen is a major PAS-reactive extracellular matrix protein,"An investigation of myocardial glycoproteins was undertaken to elucidate the molecules responsible for the periodic acid-Schiff (PAS) reactivity of the increased extracellular matrix of diabetic cardiomyopathy. Perfusion with radiolabeled mannose indicated an enhanced formation of matrix components in the diabetic compared to the normal rat heart. Electrophoretic separation of radiolabeled extracts demonstrated the presence of glycoproteins with Mr values of 205, 142 and 90 kDa which could be separated by Bio-Gel A-5 m filtration. Fractionation of non-perfused hearts resulted in the isolation of only the 205 and 142 kDa components, which were shown by amino acid analyses and collagenase digestion to belong to the collagen family of proteins and by immunoblotting to represent type VI collagen. The carbohydrate content of these rat myocardial type VI collagen subunits, determined from monosaccharide analyses, was 11 and 12%, respectively, and N-glycanase digestion of the 142 kDa chain resulted in a decrease in size of approximately 14 kDa, indicating the presence of asparagine-linked units. Examination of normal and diabetic rat heart sections indicated that the latter contained abundant PAS-positive strands and nodules which corresponded to the distribution of anti type VI collagen reactivity. Moreover, immunoblots showed higher levels of Type VI collagen in diabetic than in normal heart extracts. Type VI collagen therefore appears to represent a major glycoprotein of myocardial extracellular matrix and to be implicated in diabetic cardiomyopathy. ",0
471,1619683,Dietary fat and postmenopausal breast cancer,"Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal. The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa. Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered. After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association. These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer. Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations. ",0
472,1619997,Intracellular free-magnesium levels in vascular smooth muscle and striated muscle cells of the spontaneously hypertensive rat,"In humans with essential hypertension and in spontaneously hypertensive rats (SHR), insulin resistance may be present even in lean individuals. As the basis for this abnormality is unknown, we have used a newly developed fluorophore to measure intracellular free-Mg2+ concentrations in cultured aortic vascular smooth muscle cells and striated muscle cells from SHR and normotensive Wistar Kyoto (WKY) rats. Intracellular free-Mg2+ levels were lower in both striated muscle cells (SHR, 0.423 +/- 0.077 mmol.L-1 v WKY, 0.559 +/- 0.068 mmol.L-1; P less than .001) and vascular smooth muscle cells (SHR, 0.406 +/- 0.067 mmol.L-1 v WKY, 0.625 +/- 0.077 mmol.L-1; P less than .001) from hypertensive animals. This widespread, intrinsic defect in the regulation of intracellular Mg2+ may explain the increased vascular resistance and reduced insulin sensitivity present in hypertension. ",0
473,1620234,Carbachol potentiates isoprenaline-induced mucin secretion by rat submandibular gland,"We studied the effects of carbachol on isoprenaline-induced secretion of 3[H]glucosamine-labeled high molecular weight protein from in vitro fragments of rat submandibular gland. The concentration-response curve for isoprenaline was determined alone and in the presence of one of two concentrations of carbachol. Isobolic interaction indices were calculated from the resulting curves. The role of extracellular calcium on this interaction was assessed by examining the effect of increasing concentrations of [Ca2+]e on secretion induced by a fixed concentration of isoprenaline alone and in the presence of carbachol. Carbachol alone caused a small, but statistically significant, protein secretion. Carbachol markedly shifted the isoprenaline concentration-response curve to the left in a dose-dependent manner. In the absence of extracellular calcium, carbachol did not increase isoprenaline-induced secretion, but secretion increased as the [Ca2+]e was increased. The carbachol-induced increase in secretion reached a maximal level at approximately 2.0 mM [Ca2+]e. We conclude that carbachol's increase of isoprenaline-induced secretion of 3[H]glucosamine-labeled high molecular weight protein is not additive, but is true potentiation. This potentiation requires extracellular calcium, and may be maximal at physiological [Ca2+]e. ",0
474,1620268,4-Bromoacetamidoprocaine: an affinity ligand for brain muscarinic and nicotinic cholinergic receptors,"This study describes the synthesis, receptor binding characteristics, and some behavioral effects of p-bromoacetamidoprocaine (BAP), a new affinity ligand for brain muscarinic and nicotinic cholinergic receptors. The reversible binding of [3H]QNB to rat brain membranes was inhibited in a concentration dependent and saturable manner by both procaine and BAP, with Ki values of 4 x 10(-6) and 3 x 10(-7) M, respectively, and complete inhibition at 1 x 10(-5) M. Both procaine and BAP, although at much concentrations, inhibited the binding of [3H]methylcarbamylcholine in a concentration dependent manner, with Ki values of 5 x 10(-5) and 1 x 10(-5) M, respectively, and complete inhibition for both at 1 x 10(-3) M. Plots of the % irreversible inhibition of [3H]QNB, [3H]nicotine, and [3H]MCC vs [BAP] yielded Ki values of 7 x 10(-8), 1 x 10(-4), and 6 x 10(-5) M, respectively. In behavioral studies BAP was able to antagonize the QNB-induced hyperactivity in mice; however, BAP did not appear to alter nicotine-induced seizure activity or other behavioral effects in mice. A plot of the time course of inhibition by BAP for [3H]QNB binding revealed that the inhibition was almost complete within 10 min exposure at 37 degrees. The findings indicate that BAP is a useful affinity ligand for examining the biochemical and functional characteristics of brain cholinergic receptors, particularly the muscarinic which has an affinity near the nM concentration range. ",0
475,1620610,Generating compatible translation initiation regions for heterologous gene expression in Escherichia coli by exhaustive periShine-Dalgarno mutagenesis. Human glutathione reductase cDNA as a model,"Adaptation of eucaryotic cDNA to heterologous expression was studied by mutating the translation initiation (TI) region upstream (mTI) and downstream (MTI) of the start codon. In the mTI subregion the 8 bases flanking the invariant Shine-Dalgarno motif GG-AG were mutagenized exhaustively, while the MTI subregion was subjected to random silent mutations at the wobble positions. The quality of a given TI sequence was judged on the basis of expressed enzyme activity. Low-yield and high-yield mutants of both TI subregions were selected and recombined systematically. The analysis of these double cartridges gave the following results: 1. As a rule, an unfavourable MTI subregion can be compensated for by mutations in the mTI subregion and vice versa. 2. The compatibility between mTI and MTI subregion is explainable at least in part by a low interaction tendency; a delta G(o)'-value of -10.7 kcal/mol appears to be a physical threshold for heterologous cDNA expression. 3. On the basis of periShine-Dalgarno mutations, the expression yield for different cDNA sequences could be increased by 1 to 2 orders of magnitude. One of these sequences encoded delta(1-15)human glutathione reductase, a mutant lacking the flexible N-terminal extension of the protein. In conclusion, to study and overcome TI region-based expression problems it is worthwhile to start out with a versatile vector containing exhaustive mutations in the periShine-Dalgarno sequences; as a rule the coding MTI subregion can be kept unchanged. ",0
476,1620658,Influence of modified casomorphins on yawning behavior of rats,"Apomorphine-induced yawning was completely suppressed in animals treated with 5 nmol [D-Pro4]casomorphin (CM) (ICV), 10 nmol [D-Phe3]CM (ICV) or 10 nmol [D-Pip4]CM (ICV). The apomorphine-induced yawning was also decreased, by des-Tyr analogs, but only by about 50%. Physostigmine (0.15 mg/kg, IP) induced yawning. The physostigmine-induced yawning was suppressed by 5 nmol [D-Pro4]CM and 10 nmol [D-Phe3]CM. Both [des-Tyr-D-Phe3]CM and [des-Tyr-D-Pip4]CM were without effect, whereas [des-Tyr-D-Pro4]CM increased significantly the physostigmine-induced yawning. The results suggest that dopaminergic transmission can be modulated by beta-casomorphin derivatives, thus resulting in a decrease in yawning. In the case of the des-tyrosine derivatives, we can assume a dopaminergic modulation, too. An increase in serotonergic activity might be supposed for [des-Tyr-D-Pro4]CM. ",0
477,1620919,Long-term results of endoscopic sphincterotomy in the treatment of residual/recurrent choledocholithiasis],"Endoscopic sphincterotomy is widely accepted as the technique of choice in the treatment of residual or recidivant choledocholithiasis since the results obtained with this technique are favorable when compared to biliary surgery in most series. However, the experience of long term follow up of patients with choledocholithiasis in whom this technique would have been applied as the only treatment is still scarce up to date. We have studied 40 patients (mean age 65.6 +/- 11.1 years) with residual or recidivant choledocholithiasis who had undergone endoscopic treatment successfully before the 30th of June 1985, who could be contacted by a mailed questionnaire or by phone by August 1990. The follow up time 70.7 +/- 19.4 months (mean +/- typical deviation). Out of them, 36 (90%) had been asymptomatic up to the contact date (30 cases) or up to death due to causes not related to biliary pathology (6 patients). Out of the 4 remaining patients, 2 presented mild dyspepsia and another patient has probably developed recidivant choledocholithiasis (according to I.V. cholangiography). The fourth patient presented a severe episode of cholangitis and acute pancreatitis, related to a new episode of choledocholithiasis and died 5 and a half years after the endoscopic sphincterectomy. This represents a 2.5% mortality. These long term results of endoscopic sphincterotomy in patients with residual or recidivant choledocholithiasis are an other point in favour of using this technique as the single treatment of choice in patients above 60 years old. ",0
478,1621172,Membranous lipodystrophy. Clinical and electrophysiological observations in the first South African case,"A 37-year-old white man with membranous lipodystrophy (ML), the first case from Africa, is reported. Two years before presentation a diagnosis of presenile dementia of uncertain aetiology had been made. The diagnosis of ML was confirmed on histological examination of bone fragments obtained during surgery for reduction of pathological fractures. Computed tomography of the head showed typical cerebral atrophy and basal ganglia calcification. Electrophysiological observations included normal peripheral and central conduction studies. ",0
479,1621210,Radiation therapy for the esophageal carcinoma: external irradiation versus high-dose rate intraluminal irradiation,"From September 1977 through December 1989, 149 patients with esophageal carcinoma were treated with external irradiation (EI) with or without high-dose rate intraluminal irradiation (HDRII) using remote afterloading system. Two-year relapse-free survival rates were 52% in sage I (n = 23), 24% in stage II (n = 61) and 19% in stage III (n = 65). Two-year survival rates were 66% in complete response (CR) group (n = 65) and 7 to 9% in non-CR group (n = 84). Concerning CR group external irradiation alone (mean +/- S. D.: 66.5 +/- 5.2 Gy) showed higher local control rate than EI (60.0 +/- 0.4 Gy) + HDRII (10 Gy) (30/38 versus 15/27, p = 0.044), especially in ulcerative type (17/19 versus 5/11, p = 0.009). This preliminary result suggests that HDRII is not effective for the local control of the ulcerative lesion as a boost therapy. ",0
480,1621446,Acute ischemia of the lower extremity in an adolescent with Crohn disease],"The authors report a case with a rare form of peripheral ischaemia. A 25-year-old man with Crohn's disease suffers from sudden ischaemia of his right leg. There is no evidence of entrapment of the popliteal artery, of arterial embolism or Buerger's disease. Thrombocytosis in combination with hypercoagulability as described previously in patients with Crohn's disease seems to be the most probable cause. - In this case percutaneous transluminal thrombectomy and thrombolysis were more successful than surgical thrombectomy using balloon catheters. ",0
481,1621546,Carcinoma of the penis. Our experience with 22 cases],"The penis carcinoma is a neoplasia representing 0.7% of all male neoplasias, with an annual incidence between 1 and 2 cases per 100,000 inhabitants/year. The present study compiles the authors' experience in treating 22 patients presenting this neoplasia in the period between 1977-90. The procedures carried out included local resection, partial amputation, radical penectomy with lymphadenectomy plus radiotherapy, and palliative surgery plus radiotherapy all based on staging made following TNM grading. Therapy complications, follow-up, and survival results are explained. There were 5 occasions of spinocellular carcinoma co-existing with other neoplasias: 1 colon adenocarcinoma, 1 prostate carcinoma, 1 cleaved small cell centrocytic diffuse lymphoma, and 2 skin epithelioma in other sites, and relevant literature was reviewed. A background of psoriasis treated with psoralens plus UV was present in 4 cases, and caution was advised towards genital protection in patients undergoing UV radiations whether for therapeutic, recreational or cosmetic reasons. ",0
482,1621674,Tubulointerstitial changes as a major determinant in the progression of renal damage,"Tubulointerstitial injury is an invariant finding in the chronically diseased kidney, irrespective of the type of disease or the compartment in which the disease originates. Such histologic changes are functionally significant in that scores for such damage, rather than glomerular injury, correlate with decline of renal function. This review summarizes (1) clinical evidence attesting to tubulointerstitial changes as an index of functional impairment, (2) mechanisms by which tubulointerstitial injury impairs renal function, and (3) interactions of pathologic processes in the vascular, glomerular, tubular, and interstitial compartments that culminate in tubulointerstitial injury. This report concludes with a review of interstitial fibrosis, a pathologic process regarded as an irreversible outcome from tubulointerstitial injury. ",0
483,1621864,Effect of sinoaortic denervation on pressor responses in pregnant rats,"We tested the hypothesis that augmented arterial baroreflex activity contributes to attenuation of pressor responses in intact pregnant animals by comparing changes in blood pressure and heart rate during infusions of angiotensin II, phenylephrine, and vasopressin in chronically instrumented pregnant and virgin rats approximately 5 wk after sinoaortic denervation (SAD) or sham surgery. Baseline mean arterial pressure was significantly lower in pregnant animals in both the sham-operated (pregnant 91.7 +/- 1.7 mmHg, virgin 103.7 +/- 2.5 mmHg) and SAD states (pregnant 107.3 +/- 4.0 mmHg, virgin 114.1 +/- 4.0 mmHg). Pressor responses to all three agents were significantly blunted in pregnant animals compared with similarly treated virgins, with the magnitude of attenuation similar in both sham and SAD states. Heart rate decreased similarly in reflex-intact pregnant and virgin animals during pressor infusions. These findings suggest that attenuated pressor responses in the pregnant rat are due primarily to mechanisms other than augmentation of arterial baroreflex activity and are consistent with a generalized reduction in vascular sensitivity during gestation. ",0
484,1622035,Strain differences in autotomy in rats undergoing sciatic nerve transection or repair,"The degree of self-mutilation (autotomy) following sciatic nerve injury was assessed in 6 rat strains. Experimental groups included sciatic nerve transection with and without repair and crush lesions. The degree of autotomy was measured using a standard grading system. There were statistically significant differences between the strains in the transected group in terms of both degree of autotomy and the time of onset of its appearance. The repair group showed a shorter mean time of onset, lower maximal scores, and lower percentage of affected animals. Autotomy was absent in the nerve crush group and in all Lewis rats. In experimental studies when the status of the foot is critical (e.g., to evaluate functional walking patterns) Lewis rats appear to be the most appropriate strain to utilize. These results suggest that there are definite strain differences in the degree of autotomy following nerve transection or repair. ",0
485,1622420,Progressive aortic valve inflammation occurring despite apparent remission of relapsing polychondritis,"We describe a patient with relapsing polychondritis in whom aortic valve inflammation developed 3 years after diagnosis, when the polychondritis had been in apparent remission for an extended period of time. Infection and cardiac involvement can be significant complications of relapsing polychondritis. Recommendations for monitoring and treatment of patients with this disease are discussed. ",0
486,1622600,Biosensors based on the energy metabolism of living cells: the physical chemistry and cell biology of extracellular acidification,"The silicon microphysiometer is a biosensor-based instrument that detects changes in the physiological state of cultured living cells by monitoring the rate at which the cells excrete acidic products of metabolism. This paper discusses the chemical and biological factors that determine the performance and applications of such a system. Under typical culture conditions, extracellular acidification is dominated by the excretion of lactic and carbonic acids formed during the energy metabolism, using glucose and glutamine as carbon sources. The maintenance of transmembrane ionic gradients is an important use of energy, as is cell growth. The activation of cellular receptors usually causes transient or sustained increases in acidification rate. The energetic cost of generating second messengers is probably too small to account for either change, so events more distal to the receptor-activation process must be responsible. The opening of ion channels may cause the increases in some cases. In others, changes in intracellular pH and loose coupling between ATP hydrolysis and synthesis may be involved; models for these processes are presented. ",0
487,1623916,Dose proportionality study of loperamide following oral administration of loperamide oxide,"The pharmacokinetics of loperamide, after oral administration of increasing doses (1 to 16 mg) of loperamide oxide, has been investigated in 10 healthy male volunteers, using a randomised cross-over design. Comparison of the maximum plasma loperamide concentration and AUC demonstrated that the bioavailability of loperamide was proportional to the dose of loperamide oxide administered. ",0
488,1624126,Gallium toxicity and adaptation in Pseudomonas fluorescens,"When cultured in a defined citrate medium supplemented with 1 mM gallium (III) Pseudomonas fluorescens ATCC 13525 experienced a lag phase of 40 h with no apparent diminution in cellular yield. Following initial uptake of the metal-ligand complex, gallium was secreted in the spent fluid. This lag phase was abolished either by inoculating the medium with gallium adapted cells or by inclusion of iron (III) (20 microM) in the growth medium. In the culture enriched with both gallium and iron (III), X-ray fluorescence spectra revealed a gradual decrease of gallium from the spent fluid as growth progressed. In a phosphate deficient medium, no cellular multiplication was observed in the presence of gallium. The inhibitory influence mediated by the trivalent metal was reversed by the addition of (20 microM) iron (III). Although bacterial growth was accompanied by an initial decrease in exocellular gallium, a marked increment in the concentration of this metal was observed in the spent fluid at stationary phase of growth. Citrate was not detected in the exocellular fluid at cessation of bacterial multiplication. Electrophoretic analyses revealed numerous variations in the cytoplasmic protein profiles of the control and metal stressed cells. Gallium induced the syntheses of polypeptides with apparent molecular masses of 89 kDa, 50 kDa, 39 kDa, 26 kDa and 12 kDa. ",0
489,1624471,"Isolation, characterization, and physiological role of the pyruvate dehydrogenase complex and alpha-acetolactate synthase of Lactococcus lactis subsp. lactis bv. diacetylactis","The pyruvate dehydrogenase complex of Lactococcus lactis subsp. lactis bv. diacetylactis has a specific activity of 6.6 U/mg and a Km of 1 mM for pyruvate. The specific activities of E2 and E3 in the complex are 30 and 0.36 U/mg, respectively. The complex is very sensitive to NADH inhibition and consists of four subunits: E1 alpha (44 kDa), E1 beta (35 kDa), E2 (73 kDa), and E3 (60 kDa). The L. lactis alpha-acetolactate synthase has a specific activity of 103 U/mg and a Km of 50 mM for pyruvate. Thiamine pyrophosphate (Km = 3.2 microM) and divalent cations are essential for activity. The native enzyme measures 172 kDa and consists of 62-kDa monomers. The role of both enzymes in product formation is discussed in view of NADH inhibition and competition for pyruvate. ",0
490,1624618,Development of dental plaque on the incisor teeth of monkeys (Macaca fascicularis),"Bacterial plaque which had accumulated for 0.5, 1, 2, 4, 7, 14 and 28 days was cultured from the labial surface of one of the central incisor teeth in 15 monkeys (Macaca fascicularis). Each sampling area was defined by a metal well contained within a custom-made removable acrylic block. The number (log10) of the total colony forming units (c.f.u.) increased significantly from 3.40 to 6.02 between 0.5 and 28 days. Similarly the number of streptococci increased from 2.80 to 4.79 during the same period, although when expressed as a percentage of the total c.f.u., the proportions decreased from 34.9 per cent at 1 day to 6.9 per cent at 7 days and then remained at that level. The number of micro-aerophilic actinomyces increased throughout the period of plaque accumulation and comprised 15.3 per cent of the total c.f.u. at 28 days. Neisseriae were infrequently isolated from 0.5- and 1-day-old plaque and were not recovered at more than 1 per cent of the total c.f.u. during any period of plaque accumulation. The fastest doubling time (median) of the total c.f.u. was 1.9 h (range 1.3-18.5 h). The rapid development of dental plaque after tooth cleaning emphasizes the importance of regular and meticulous oral hygiene to control the accumulation of potentially periodontopathic and cariogenic bacteria. ",0
491,1624716,Quality of self-report data: a comparison of older and younger chronically ill patients,"""This study examined age differences in the quality of self-report data in patients with chronic disease conditions (hypertension, diabetes, heart disease, depression). Data are from 2,304 patients in three health care systems in Los Angeles, Chicago, and Boston. Results support the idea that self-report health data can be gathered from older and younger patients without significant decrements in data quality. Specifically, results showed: (1) small decreases in the reliability of multi-item measures with age, primarily occurring in balanced scales; (2) little evidence of differences among age groups in response set or the tendency to respond """"don't know"""" or """"uncertain,"""" although older patients had a greater tendency to respond in a socially desirable manner; (3) higher item nonresponse in older patients; (4) little variation in item nonresponse by type of question or question placement; (5) generally high panel retention in all age groups, supporting the value of repeated follow-up; and (6) similar known-groups validity across age groups. """,0
492,1624965,Epidemiology of diabetes mellitus in southern Italy: a case-finding method based on drug prescriptions,"""The study evaluates whether data concerning drug prescriptions available from the National Health System (NHS) can be used to provide an estimate of the prevalence and pattern of treatment of diabetes in a well defined health district in southern Italy. In Italy virtually all drug prescriptions are obtained through the NHS. For a period of three consecutive months all prescriptions of insulin, hypoglycemic agents and strips for blood and urine testing were monitored in a well defined area near Naples. 2958 cases were thus identified giving a prevalence of drug treated diabetes mellitus of 2.01%; prevalence was higher in females than in males (2.68 vs 1.35%) and increased with age from 0.05% in the age group below 9 years to 13.67 in the age group over 70 years. This case-finding procedure was validated by cross-check with independent sources of cases. To evaluate the sensitivity of the method a list of 820 """"known"""" cases of drug treated diabetes mellitus was obtained from a random sample of local general practitioners (GPs) and diabetic clinics: 73.5% of these cases were also detected through the analysis of drug prescriptions. To evaluate the probability of misclassification a random subsample of 602 cases identified through prescriptions was submitted to the GPs working in the study area, for 517 the diagnosis of diabetes was confirmed, thus yielding a positive predictive value of 85.9%. After correction for sensitivity and probability of misclassification the prevalence of drug treated diabetes in our population was 2.52%. The pattern of prescriptions in this population is also given.(ABSTRACT TRUNCATED AT 250 WORDS) """,0
493,1625146,Recurrent peripheral arterial occlusion by leukemic cells sedimentation in acute promyelocytic leukemia,"A 10-year-old boy presenting with recurrent successive events of peripheral arterial occlusion in both legs, more prominent on the left side, was diagnosed as having acute promyelocytic leukemia. Histological examination of the occluding material showed that it was composed of leukemic blast cells. The boy underwent five operations. Each time the arterial flow was reestablished by removing cylindrical hollow white material obstructing the lumen. However, after the last operation, irreversible ischemia developed, necessitating an above-knee amputation. There was no evidence of disseminated intravascular coagulation. Three months later a right lumbar sympathectomy was performed for relief of causalgic-ischemic pains, with successful results. Preoperative angiography demonstrated irregular narrowing of the right iliac arteries and tibioperoneal trunk stenosis. ",0
494,1625711,Mitral annular calcification and the risk of stroke in an elderly cohort,"BACKGROUND: Previous clinical studies have suggested that there is an association between mitral annular calcification and the risk of stroke, but it is unclear whether this association is independent of the traditional risk factors for stroke. We examined the relation between mitral annular calcification and the incidence of stroke in a population-based study. METHODS: Subjects in the Framingham Study receiving a routine examination underwent M-mode echocardiography to determine the presence and severity (thickness in millimeters) of mitral annular calcification. The incidence of stroke during eight years of follow-up was analyzed with a proportional-hazards model adjusting for the calcification, age, sex, systolic blood pressure, diabetes mellitus, cigarette smoking, atrial fibrillation, and coronary heart disease or congestive heart failure. RESULTS: Among 1159 subjects whose echocardiograms could be assessed for mitral annular calcification and who had no history or current evidence of stroke at the index examination (51 percent of all subjects), the prevalence of mitral annular calcification was 10.3 percent in the men and 15.8 percent in the women. Multivariate analysis demonstrated that the presence of mitral annular calcification was associated with a relative risk of stroke of 2.10 (95 percent confidence interval, 1.24 to 3.57; P = 0.006). There was a continuous relation between the incidence of stroke and the severity of mitral annular calcification; each millimeter of thickening as shown on the echocardiogram represented a relative risk of stroke of 1.24 (95 percent confidence interval, 1.12 to 1.37; P less than 0.001). Furthermore, even when subjects with coronary heart disease or congestive heart failure were excluded from the analysis, subjects with mitral annular calcification still had twice the risk of stroke. CONCLUSIONS: In an elderly, longitudinally followed population-based cohort, mitral annular calcification was associated with a doubled risk of stroke, independently of traditional risk factors for stroke. Whether such calcification contributes causally to the risk of stroke or is merely a marker of increased risk because of its association with other precursors of stroke remains unknown.",0
495,1626208,Effect of erythropoietin on sexual potency in chronic haemodialysis patients. A preliminary study,"Six male dialysis patients were submitted to a Doppler study of the deep penile arteries and intracavernosal injection of 30 mg papaverine under basal conditions before and after erythropoietin therapy. Penile tumescence was recorded after 15 min by measuring the length and the circumference of the penis as well as the erectile angle between the penis and the legs with the patient in standing position. Haematocrit was raised by erythropoietin therapy from 19.3 +/- 4.5 to 31.2 +/- 5.5 within 3 months. Five patients completed the study. We encountered a significant improvement in the frequency of sexual intercourse per month from 1.3 +/- 0.5 to 2.3 +/- 0.8 (p = 0.014). Furthermore, an increase was observed in the penile brachial index (from 0.87 +/- 0.1 to 0.91 +/- 0.1) and in the papaverin induced increase in penile length (4.6 +/- 1.4 cm versus 5.2 +/- 1.1 cm), penile circumference (2.7 +/- 0.14 cm versus 2.7 +/- 0.27 cm) as well as in the erectile angle (61.7 +/- 37.1 versus 80 +/- 23.5 degrees). These changes were not statistically significant. There was a significant correlation between the increase in the erectile angle and the increase in frequency of intercourse (p = 0.04). In conclusion, erythropoietin treatment could improve the sexual potency in uraemic patients under chronic haemodialysis therapy. ",0
496,1626376,Typing of Australian isolates of Treponema hyodysenteriae by serology and by DNA restriction endonuclease analysis,"A total of 91 isolates of Treponema hyodysenteriae which were obtained from 62 piggeries located around Australia were typed by serology and by DNA restriction endonuclease analysis (REA). The isolates fell into eight serogroups, of which groups B and D were the most common. Isolates with different REA patterns were recognised within serogroups, whilst a few isolates with the same REA pattern were placed into different serogroups. Some of the latter isolates were either from the same piggery or from farms with epidemiological links, thus indicating the bacteria may have altered their antigenic properties. A total of 31 different REA patterns were recognised amongst the Australian isolates. These comprised eight major patterns, with four of these being subdivided on the basis of minor differences in banding. Where a number of isolates were obtained from individual piggeries these all had the same REA pattern, and in one piggery isolates with the same pattern were recovered over a five year period. Plasmid bands were observed in 70 of the Australian isolates (77%), and in six of the seven overseas isolates included in the study for comparison. These plasmids did not affect the REA pattern. Of the States from which substantial numbers of isolates were examined, the greatest number of different strains (12 amongst 19 piggeries) were found from Victoria, and there were 10 REA patterns in strains from 24 piggeries in Queensland. Despite the large total number of different strains of T. hyodysenteriae in Australia, only three were found in more than one State. ",0
497,1627154,Trypsin inhibitors of buffalo seminal plasma,"Two trypsin inhibitors from acid-treated buffalo seminal plasma were purified by gel filtration and affinity chromatography. These acid-stable trypsin inhibitors having charge heterogeneity were homogeneous with respect to size as revealed by gel filtration and SDS-PAGE. Gel filtration data suggest molecular weight value of 9,900 Da for inhibitor I and 10,900 Da for inhibitor II. Molecular weight estimated by SDS-PAGE was found to be 10,600 Da and 11,200 Da for inhibitors I and II, respectively. The hydrodynamic properties such as Stokes radii (1.58 nm and 1.62 nm); intrinsic viscosity (2.5725 ml/g and 2.5025 ml/g) and diffusion coefficient (13.499 x 10(-11) m2/sec. and 13.166X10(-11) m2/sec) respectively for inhibitor I and II were determined by analytical gel filtration. These inhibitors were fairly thermostable and could not be stained by PAS reagent. Both the inhibitors were found to inhibit buffalo acrosin but not bovine chymotrypsin. ",0
498,1627267,Gangliosides in bovine milk. Changes in content and distribution of individual ganglioside levels during lactation,"Bovine milk undergoes changes in its ganglioside contents during the different stages of lactation. These contents are higher in colostrum (7.5 mg of lipid-bound NeuAc/kg) than in transitional (2.3 mg) or mature (1.4 mg) milk. The sialic acid content of milk follows a similar profile to that of gangliosides with the highest content during the first few days post partum followed by a gradual decrease towards the end of the period studied. When the individual distribution of gangliosides was examined throughout the course of lactation, several changes were also found. GD3 is the major ganglioside (about 60-70%) found; its content decreases from the first to the fifth day, increasing towards the end of the period considered. GM3, GD3 and GT3, sialyllactosylceramide-containing gangliosides account for 80-90% of the total lipid-bound NeuAc content. The most striking change in the ganglioside pattern was the gradual increase in G3. ",0
499,1627614,Polyunsaturated fatty acid incorporation into plasmalogens in plasma membrane of glioma cells is preceded temporally by acylation in microsomes,"Plasmalogens (1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine) are major phospholipids in many tissues and cells, particularly of neural origin. Using cultured C6 glioma cells and subcellular fractions isolated on Percoll gradients we investigated selectivity for esterification of several polyunsaturated fatty acids (PUFA) in the sn-2 position of plasmalogens compared to [1-14C]hexadecanol, representative of de novo synthesis of the ether-linked sn-1 position. In whole cells at a final concentration of 105 microM PUFA, 2-4 nmol plasmalogen/mg protein was labeled in 4 h and 10-14 nmol in 24 h, representing 8-15% and 35-50%, respectively, of initial plasmalogen mass. Incorporation of label from hexadecanol was lower than PUFA incorporation (20:5(n-3) greater than 20:4(n-6) greater than 18:3(n-3) much greater than 18:2(n-6)) suggesting deacylation-reacylation at the sn-2 position. Plasmalogens accounted for 50% of total cell ethanolamine phospholipids and 75% in plasma membrane. Using a novel, improved method for extraction of subcellular fractions containing Percoll, plasma membrane also was enriched in plasmalogen relative to microsomes (107.4 +/- 5.2 vs. 40.0 +/- 2.9 nmol/mg protein). Selectivity for esterification at the sn-2 position of plasmalogens with respect to chain length and unsaturation of the fatty acyl chain was similar in both subcellular fractions and reflected that of whole cells. Labeling of plasma membrane with PUFA and fatty alcohol lagged behind that of microsomes. Chase experiments in cells prelabeled with [1-14C]18:3(n-3) for 2 h showed no significant reduction of label in plasmalogen of any subcellular fraction although accumulation of label in the microsomal fraction was slowed initially. Reduction of plasmalogen label (40-50%) did occur in microsomes and plasma membrane when cells prelabeled for 24 h were switched to chase medium with or without chase fatty acid. Our data suggest that esterification of PUFA to plasmalogen may occur at the endoplasmic reticulum with subsequent translocation to plasma membrane resulting in accumulation of relatively stable pools of plasmalogen that are not readily accessible for deacylation-reacylation exchange with newly appearing PUFA. Alternatively, deacylation-reacylation may occur in a more stable phospholipid pool within the plasma membrane but would involve a slower process than at the endoplasmic reticulum. ",0
500,1627977,Regional cerebral glucose utilization in chronic organic mental disorders associated with alcoholism,"Localized cerebral utilization rates for glucose (CMRglu) were determined in 10 detoxified patients with alcoholic organic mental disorders and in 7 age-equivalent normal volunteers using [18F]2-fluoro-2-deoxyglucose positron emission tomography. Although gray and white matter CMRglu were not significantly different, normalized CMRglu was increased in the left cerebellar and parietal cortical regions and decreased in the right posterior white matter and anterior temporal regions of alcoholic patients, and the pattern of regional CMRglu differed between the two groups. The results suggest functional disruption of right-sided and frontal brain regions and hyperactivity of cerebellar-cortical connections in alcoholic chronic organic mental disorders. ",0
501,1628148,"The effect of lipopolysaccharide, interleukin-1 and tumour necrosis factor on the hepatic accumulation of 5-hydroxytryptamine and platelets in the mouse","1. Injection of lipopolysaccharide (LPS; 0.5-500 microgram kg-1) into mice induced a dose-dependent, slowly developing increase in hepatic content of 5-hydroxytryptamine (5-HT). This sustained increase could not be attributed to an LPS-induced alteration of the pharmacokinetic handling of 5-HT by stimulation of its uptake or inhibition of its degradation. 2. Regional differences were apparent in the tissue content of histamine and 5-HT between mast cell-deficient (W/Wv) and normal (+/+) mice. LPS administration (0.5 mg kg-1) gave comparable increases in the hepatic level of 5-HT in mast cell-deficient and normal mice. 3. Reserpine pretreatment (1 mg kg-1) selectively reduced 5-HT levels in the blood, spleen, liver, brain and lung of normal mice. Prior treatment with this agent also abolished the LPS (0.5 mg kg-1)-induced hepatic accumulation of 5-HT. 4. Accumulation of 5-HT in the liver by LPS (0.1 mg kg-1) was temporally associated with both a fall in the levels of circulating platelets, and a reduction in the concentration of 5-HT in the blood. The LPS dose-dependent (0.5-500 micrograms kg-1) increase in hepatic 5-HT content was associated with a similar dose-dependent reduction in the circulating levels of 5-HT. 5. Interleukin-1, alpha and beta (10 micrograms kg-1) and tumour necrosis factor alpha (TNF alpha) (1 mg kg-1) significantly enhanced the accumulation of 5-HT within the liver. Administration of TNF alpha (10 micrograms kg-1) potentiated the increase in hepatic 5-HT content seen with IL-1 beta (10 micrograms kg-1). 6. Electron microscopy revealed numerous platelets in the sinusoidal and perisinusoidal Disse spaces within the liver, in animals pretreated with LPS (0.1 mg kg '). The platelets retained their intact structure and showed no evidence of degranulation. 7. These data suggest that the LPS and cytokine-induced mobilization of 5-HT in the liver is associated with the hepatic translocation of platelets. This migration appears to be independent of platelet aggregation. ",0
502,1628171,Rheumatologists and their patients who seek alternative care: an agreement to disagree,"Alternative treatment, such as homoeopathy, acupuncture and spiritual healing, are popular among patients with rheumatic diseases. Rheumatologists are therefore likely to be confronted with patients who make use of less orthodox health care. Patients' and rheumatologists' views on the subject and on the rheumatologists' role, however, have not yet been assessed. A questionnaire on alternative medicine was sent to all 101 practising Dutch rheumatologists (response rate: 70%). After the results had been analysed 17 rheumatologists, seven rejecting alternative medicine and ten accepting it, handed out a questionnaire to a sample of their patients: 1466 patient questionnaires were distributed (response rate: 80%). Of the respondents 43% had visited an alternative practitioner at least once for their rheumatism and 26% in the year before the survey was held. Hand healers, homoeopaths and acupuncturists were most often visited. Rheumatologists, on their part, were not too enthusiastic about these visits. Only patients' visits to spa treatment centres were welcomed by a majority of them; visits of their patients to manipulative therapists, acupuncturists and homoeopaths were judged positively by a large minority, whereas other therapies were strongly disapproved. Nevertheless, most patients informed their rheumatologist about their visiting an alternative practitioner. A surprisingly low percentage of these patients noticed that the rheumatologist did not sympathize with it. Although many patients paid a visit to an alternative practitioner because regular care did not really help them, their satisfaction with the alternative treatment turned out to be less than their satisfaction with the rheumatologists' help.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
503,1628354,Screening for alpha 1-antitrypsin deficiency in neonates],"In a two-year investigation 113,274 children were screened for alpha-1-antitrypsin deficiency. An original and cheap method was used. In children with an alpha-1-antitrypsin values lower than 1.5 g/l the phenotype was assessed. In 120 neonates alpha-1-antitrypsin was assessed by screening and also quantitatively. The physiological range of alpha-1-antitrypsin for neonates is: 1.4-3.32 g/l. A low incidence of alpha-1-antitrypsin in the Czechoslovak population, as compared with investigations abroad, was revealed. The authors discuss the possibility to extend screening from the clinical, ethical and economic aspect to the entire republic. ",0
504,1628657,Evidence for a sialosyl cation transition-state complex in the reaction of sialidase from influenza virus,"The enzyme mechanism of sialidase from influenza virus has been investigated by kinetic isotope methods, NMR, and a molecular dynamics simulation of the enzyme-substrate complex. Comparison of the reaction rates obtained with the synthetic substrate 4-methylumbelliferyl-N-acetyl-alpha-D-neuraminic acid and the [3,3-2H]-substituted substrate revealed beta-deuterium isotope effects for V/Km ranging over 1.09-1.15 in the pH range 6.0-9.5, whereas the effects observed for V in this pH range increased from 0.979 to 1.07. In D2O, beta DV/Km was slightly increased by 2% and 5% at pD 6.0 and 9.5 respectively, while beta DV was unchanged. Solvent isotope effects of 1.74 were obtained for both beta DV/Km and beta DV at pD 9.5, with beta DV/Km decreasing and beta DV remaining constant at acidic pD. 1H-NMR experiments confirmed that the initial product of the reaction is the alpha-anomer of N-acetyl-D-neuraminic acid. Molecular dynamics studies identified a water molecule in the crystal structure of the sialidase-N-acetyl-D-neuraminic acid complex which is hydrogen-bonded to Asp151 and is available to act as a proton donor source in the enzyme reaction. The results of this study lead us to propose a mechanism for the solvent-mediated hydrolysis of substrate by sialidase that requires the formation of an endocyclic sialosyl cation transition-state intermediate. ",0
505,1628778,Ultrasonic decalcification in aortic stenosis. Clinical and doppler echocardiographic results],"Ten elderly patients with aortic valve stenosis and with a small calcified annulus (less than 20 mm) were treated by ultrasonic valve debridement (UVD) while 17 other elderly patients underwent aortic valve replacement (AVR) during the same period. The clinical and doppler results were assessed for a mean follow-up period of 20 months. Patients with significant aortic regurgitation or associated valve disease were excluded. The patients were studied by m-mode, two-dimensional and Doppler echocardiography before, immediately after, and at 6 months interval after the procedure. A successful decalcification was achieved in 8 patients. The valve was replaced in 2 patients because of cusp perforation or unsatisfactory intraoperative result. All patients showed significant postoperative increase in the mobility of the valve cusps, decrease in the amount of calcium, decrease of the aortic mean valve gradient (from 62 +/- 25 to 23 +/- 6 mmHg, p less than 0.001) and increase of the aortic valve area (from 0.49 +/- 0.11 to 1.21 +/- 0.3, p less than 0.001). The mean valve gradient was slightly higher after UVD than after AVR and showed a slight trend to further increase during follow-up, although only one patient had evidence of restenosis. A mild aortic valve insufficiency was present postoperatively in 6 patients. Worsening of insufficiency was noted in 2 patients during the follow-up period and one subject was re-operated on. Surgical ultrasonic debridement of the aortic valve may be effective in selected surgical candidates with small calcified valve and annulus, but subsequent occurrence of aortic insufficiency and restenosis may seriously limit its application. ",0
506,1628829,Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation,"c-myc belongs to a small, yet growing, group of eukaryotic mRNAs that initiate translation inefficiently from a non-AUG codon upstream from a more efficient AUG codon. We have examined the translational regulation of non-AUG-initiated c-myc 1 and AUG-initiated c-myc 2 protein synthesis in avian and mouse cells during proliferation. As lymphoid, erythroid, and embryo fibroblast cells approached high densities in culture, there was a sustained 5- to 10-fold induction in the synthesis of c-myc 1 protein to levels greater than or equal to c-myc 2 protein synthesis. Treatment with conditioned/depleted media from high-density cells was able to reproduce this activation in low-density cells within 5 hr. Additional studies with the conditioned/depleted media revealed that amino acid availability, specifically methionine deprivation, was responsible for this unique translational control. Our results describe a specific and dramatic regulation of dual translational initiation. Furthermore, these results represent a novel translational activation of a specific gene in higher eukaryotes in response to nutrient deprivation. ",0
507,1628854,Tolerance and safety of vitamin E: a toxicological position report,"""From numerous publications on the """"prophylactic"""" and """"therapeutic"""" use of vitamin E, it may be concluded that the toxicity of vitamin E is very low. It has been demonstrated in animal experiments that vitamin E has neither mutagenic, teratogenic nor carcinogenic properties. Based on studies in humans, a daily dosage of 100-300 mg vitamin E can be considered harmless from a toxicological point of view. Using double-blind studies involving a large number of subjects, it has been demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. From a large body of published data, dosage ranges have been deduced which can be characterized as safe for human subjects even where their use extends over a long period of time. It should, however, be noted that oral intake of high levels of vitamin E can exacerbate the blood coagulation defect of vitamin K deficiency caused by malabsorption or anticoagulant therapy. High levels of vitamin E intake are, therefore, contraindicated in these subjects. """,0
508,1629081,Intracellular pH and oxygen chemoreception in the cat carotid body in vitro,"To test the hypothesis that O2 chemoreception in the carotid body (CB) is mediated by cellular acidosis, we simultaneously measured responses of the chemosensory and intracellular pH (pHi) to agents that are known to change pHi and studied the effects of hypoxia and ischemia on these variables in the cat CB. The CB was perfused and superfused in vitro with a modified Tyrode's solution at 36.0 +/- 0.5 degrees C with or without CO2-HCO3- (pH 7.40) and equilibrated at a given PO2. Chemosensory discharges were recorded from the whole carotid sinus nerve. To measure pHi changes, the CB was loaded with the pH-sensitive indicator 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, and the fluorescence (excitation 420-490 nm, emission greater than 515 nm) was detected by an intensified charged coupled device camera with an epifluorescence macroscope. Boluses of Tyrode's solution (0.5 ml, free of CO2-HCO3-) containing sodium acetate or NH4Cl prolonged perfusion of acid Tyrode's solution (pH 7.20-6.50), and boluses of Tyrode's solution with CO2-HCO3- were used. A decrease of fluorescence indicated pHi turning acid, and an increase of fluorescence indicated a change in alkaline pHi. Chemosensory activity varied inversely with the fluorescence change after application of these agents. Interruption of perfusate flow or application of hypoxic perfusate resulted in large increases in chemosensory discharge without any change in the fluorescence. The results indicated that chemosensory responses to brief ischemia and hypoxia were not mediated by a fall of pHi of CB cells, whereas those to CO2 and extracellular acidity were associated with decreases in pHi. ",0
509,1629186,Prostaglandin endoperoxide synthase substituted with manganese protoporphyrin IX. Formation of a higher oxidation state and its relation to cyclooxygenase reaction,"The heme in prostaglandin endoperoxide synthase (PGH synthase) was substituted with Mn(III)-protoporphyrin IX. The resulting enzyme, Mn-PGH synthase, showed full cyclooxygenase activity but only 0.9% of the peroxidase activity of the native iron enzyme. During the reaction with exogenous or endogenously produced hydroperoxides, a spectral intermediate of Mn-PGH synthase was observed. The electronic absorption bands of the resting enzyme at 376, 472, and 561 nm decreased, and the intermediate's bands at 417, around 513, and 625 nm appeared. The rate constant of the formation of the intermediate was about 10(4) M-1.s-1 at 22 degrees C, three orders of magnitude lower than with the iron enzyme. Spectral properties, conditions of formation, and the suppressed formation in the presence of electron donors provide evidence for a higher oxidation state of Mn-PGH synthase, tentatively a Mn(IV) species. This species was assigned to an intermediate in the peroxidase reaction of Mn-PGH synthase, the low activity of which was explained by the rate-limiting slow reaction of Mn-PGH synthase with hydroperoxides. The findings and interpretation are consistent with the published properties of other manganese-substituted peroxidases. Although the cyclooxygenase activity was similar to that of Fe-PGH synthase, the cyclooxygenase reaction of Mn-PGH synthase showed distinct differences in comparison with Fe-PGH synthase. A longer activation phase was observed which resembled the time course of the formation of the higher oxidation state. Glutathione peroxidase with glutathione, a hydroperoxide-scavenging system, inhibited the cyclooxygenase of Mn-PGH synthase at concentrations where the activity of Fe-PGH synthase was not affected. It is demonstrated that Mn-PGH synthase requires higher concentrations of hydroperoxides for the activation of the cyclooxygenase. These findings suggest that the substitution of iron with manganese in PGH synthase does not change the mechanism of the enzyme. The main difference is the much lower rate of the reaction with hydroperoxides which affects both the peroxidase activity and the hydroperoxide-dependent activation of the cyclooxygenase. A reaction scheme for Mn-PGH synthase is proposed analogous to that suggested for Fe-PGH synthase (Karthein, R., Dietz, R., Nastainczyk, W., and Ruf, H. H. (1988) Eur. J. Biochem. 171, 313-320). ",0
510,1629189,Ligand binding specificity of the leukocyte response integrin expressed by human neutrophils,"The ligand binding specificity of the leukocyte response integrin (LRI) expressed by polymorphonuclear leukocyte (PMN) was investigated by examining its interaction with two adhesion motifs within fibrinogen: the alpha chain sequence RGD and the gamma chain sequence KQAGDV. The effect of the hexapeptides KQAGDV, KQRGDV, and KGAGDV on fibrinogen-stimulated phagocytosis, a LRI-dependent function, was examined. Surprisingly, the sequence KGAGDV was most potent for inhibition of fibrinogen-stimulated ingestion; the order of potency of these peptides was KGAGDV greater than KQAGDV greater KQRGDV = GRGDSPA. Latex spheres coated with multivalent KGAGDV bound specifically to PMN and antibodies that recognized either the LRI beta chain (7G2) or an associated protein (IAP)-abrogated bead binding. Various control and anti-beta 1 and anti-beta 2 antibodies did not affect bead binding. Monovalent peptides KGAGDV and KQRGDV were equipotent for inhibition of bead binding to unstimulated PMN (ID50 = 19 microM). In contrast, KGAGDV was more potent than KQRGDV for inhibition of bead binding to N-formylmethionylleucylphenylalanine-stimulated PMN (ID50 = 2.5 microM versus ID50 = 60 microM). A control peptide, KGALEVA, did not inhibit LRI ligand binding or function. These data suggest that the unique amino acid sequence KGAGDV may represent a specific ligand for LRI and that LRI ligand binding specificity may be regulated by the activation state of the cell. ",0
511,1629322,Evaluation of the rapid CORYNE identification system for Corynebacterium species and other coryneforms,"The Rapid CORYNE system for identification of aerobic, nonsporeforming, gram-positive rods was evaluated according to the manufacturer's instructions with 177 organisms. After inoculation with a heavy suspension of growth, strips containing 20 cupules were incubated for 24 h, reagents were added, and the results of 21 biochemical reactions were recorded as numerical profiles. The strains consisted of pathogenic species of the genus Corynebacterium, primarily C. diphtheriae (n = 29), opportunistic species of Corynebacterium including C. jeikeium (n = 75), recognized species of non-corynebacteria such as Gardnerella and Arcanobacterium (n = 51), and Centers for Disease Control (CDC) coryneform groups (n = 22). Results from single tests read after 24 h yielded correct identifications to species level with no additional tests for 26 (89.7%) of the pathogenic species; 64 (85.3%) of the opportunistic organisms; 51 (100%) of the non-corynebacteria, and 8 (36.4%) of the CDC coryneform groups. Supplemental tests produced the correct identification for three additional pathogenic isolates (100% total) and four additional isolates from the opportunistic species (90.6% total). Twelve of the 15 isolates not identified by the system were in the CDC coryneform groups. Four of the six misidentified and one of the unidentified isolates were C. matruchotii, which was not included in the data base. The system is an excellent rapid alternative to conventional biochemical tests. ",0
512,1629519,Distribution to the fetus and major organs of the rat following inhalation exposure to pyrene,"Concentrations of pyrene and total metabolites were determined for individual fetuses and selected maternal organs and tissues immediately and 6 h following a 95-min head-only exposure of pregnant Wistar rats, on gestation day 17, to five levels of pyrene over the range 200-800 mg m-3 as a microcondensation aerosol. The influence of uterine horn, side and position, on distribution to the fetus was assessed. The concentration of both pyrene and its metabolites increased more over the exposure range (eightfold) than did those in the fetus. Concentrations of pyrene or its metabolites in fetal tissues were not found to be related to its position on the uterine horn. There was an unexplained and significant (P less than 0.01) higher concentration of pyrene in fetuses on the right side relative to the left side of the uterine horn for the animals killed immediately following exposure. A comparison of the levels in maternal tissues measured immediately following the exposure and 6 h later showed that there was some redistribution of pyrene and its metabolites to the fat tissues, i.e. levels in the fat increased over the 6 h period following the exposure. Levels in the other tissues diminished during this period. In general, concentrations of pyrene and its metabolites were lowest in the fetal tissues relative to those in the sampled maternal organs and tissues. ",0
513,1629591,Neurogenic pulmonary edema: case reports and review,"Neurogenic pulmonary edema (NPE) is a relatively common though often subclinical complication of a variety of central nervous system insults (trauma, hemorrhage, seizures, etc.) in children and adults. The syndrome probably results from massive centrally mediated sympathetic discharge and generalized vasoconstriction, and often presents in the emergency department (ED). The symptoms are likely to be mistaken for aspiration pneumonia. Treatment consists of ventilatory support, including positive end-expiratory pressure, and aggressive measures to reduce intracranial pressure. We present four cases of NPE and review its recognition and emergent management. ",0
514,1629597,Alexander Fleming: the spectrum of penicillin,"The discovery of penicillin was directly linked to the inhibition by that agent of the growth of colonies of staphylococcus. However, subsequent resistance by this organism to penicillin as well as to a number of other agents has marked the history of staphylococcus in the antibiotic era. One of the most important mechanisms of this resistance has been the production of penicillinase, an enzyme that inactivates penicillin and related antibiotics. Penicillinase is currently termed beta-lactamase, and it is now recognized that there are several types of beta-lactamases produced by various organisms. The ability of staphylococci to produce this enzyme has been countered by the development of penicillinase-resistant agents and the addition of beta-lactamase inhibitors to antibiotics. ",0
515,1639349,Globulin correction of the albumin gradient: correlation with measured serum to ascites colloid osmotic pressure gradients,"The albumin difference or gradient between serum ascites is presumed to be an effective estimate of the colloid osmotic pressure gradient, although this has never been directly demonstrated. The colloid osmotic pressure gradient is controlled by the degree of portal hypertension. Thus the albumin gradient is clinically useful in detecting patients with ascites caused by portal hypertension, although some overlap in such patients' albumin gradients exists compared with those of patients without portal hypertension. Part of this overlap is related to the inverse correlation of the albumin gradient with serum globulin; globulins also contribute to colloid osmotic pressure. The ability to calculate colloid osmotic pressure in serum and ascites with albumin and globulin concentration or to correct the albumin gradient for the impact of globulins might improve the clinical usefulness of the ascitic fluid analysis in determining the presence of portal hypertension in ascitic patients with borderline albumin gradients. Thus we developed equations to calculate colloid osmotic pressure from multivariate discriminate analyses of albumin and globulin concentrations in serial dilution samples of pooled serum and subsequently validated these equations, along with older methods of calculating colloid osmotic pressure. In an initial set of dilution experiments, globulin concentration was closely correlated with the colloid osmotic pressure to albumin concentration ratio (r = 0.956; p less than 0.001). Multivariate discriminate analysis yielded an equation for calculating colloid osmotic pressure from albumin (A) and globulin (G) concentration with a ratio of colloid osmotic pressure to albumin (calculated colloid osmotic pressure = A(1.058G + 0.163A + 3.11) and two other equations.(ABSTRACT TRUNCATED AT 250 WORDS)",0
516,1640952,A randomized comparison of transcervical and transabdominal chorionic-villus sampling. The U.S. National Institute of Child Health and Human Development Chorionic-Villus Sampling and Amniocentesis Study Group,"BACKGROUND: Chorionic-villus sampling is done in early pregnancy to obtain fetal cells for the prenatal diagnosis of genetic and chromosomal defects. Transcervical chorionic-villus sampling has been shown to be safe and effective in national trials. Recently, an alternative transabdominal technique has been suggested as potentially easier and safer. METHODS: From April 1987 through September 1989, we prospectively compared transcervical and transabdominal chorionic-villus sampling in 3999 women with singleton pregnancies in whom the risk of a genetically abnormal fetus was increased. Women between 7 and 12 weeks of gestation underwent ultrasonographic evaluation of placental and uterine position. Those with active vaginal infections, active bleeding, or cervical polyps were excluded. If the obstetrician thought either sampling procedure was acceptable, the woman was asked to consent to random assignment to one of the two procedures. Both groups were followed to determine the outcome of pregnancy and the rate of spontaneous fetal loss after chorionic-villus sampling. RESULTS: Among the 3999 women who entered the study, sampling was attempted in 3873 (97 percent), 1944 of whom had been assigned to undergo transcervical sampling and 1929 to undergo transabdominal sampling. Of these 3873 women, sampling was eventually successful in 3863. Sampling was successful after a single insertion of the sampling instrument in 94 percent of the transabdominal procedures and 90 percent of the transcervical procedures. Among the women with cytogenetically normal pregnancies who had sampling because of maternal age, the rate of spontaneous fetal loss through 28 weeks of pregnancy was 2.5 percent in the transcervical-sampling group and 2.3 percent in the transabdominal-sampling group (difference, 0.26 percent; 95 percent confidence interval, -0.5 to 1.0 percent). CONCLUSIONS: Transabdominal and transcervical chorionic-villus sampling appear to be equally safe procedures for first-trimester diagnosis of fetal abnormalities.",0
517,1640971,"The Supreme Court, liberty, and abortion","While the issue of abortion has fueled a great deal of personal and political debate and controversy in the US, few have actually read the Supreme Court's rulings on Roe v. Wade and Planned Parenthood of Southeastern Pennsylvania v. Casey, which are central to the debate. This essay summarizes both rulings, examines the difference between the 2, and discusses implications for medical practice. Casey is important to states, physicians, and patients. Of central import is the ruling's restriction against states to outlaw abortion before viability. Other measures are, however, included which will complicate record keeping and securing consent. Restrictions against and/or steps required by the physician practicing abortion may also spread to apply to other medical procedures. The essay considers the future of Roe v. Wade. Whether or not a Freedom of Choice Act is ultimately passed in Congress, abortion will continue to divide large segments of the American population. Anti-abortionists will continue to attempt to overthrow women's right of free choice to abortion.",0
518,1648538,Increased tumor necrosis factor-alpha receptor number in chronic hepatitis B virus infection,"Production of the antiviral cytokine, tumor necrosis factor-alpha is increased in chronic hepatitis B virus infection, and clinical studies of tumor necrosis factor-alpha have indicated a proviral effect at higher doses. To determine whether this might be related to abnormal cell surface tumor necrosis factor-alpha receptor expression, binding characteristics of cell surface tumor necrosis factor-alpha receptor on peripheral blood mononuclear cells in chronic hepatitis B virus carriers were studied using radioiodinated recombinant tumor necrosis factor-alpha. The specific binding curves generated were analyzed according to the method of Scatchard to determine cell surface receptor numbers and dissociation constants. A single class of cell surface tumor necrosis factor-alpha receptor was demonstrated on peripheral blood mononuclear cells and mononuclear subsets. The median number (range) of cell surface tumor necrosis factor-alpha receptors on peripheral blood mononuclear cells from controls (n = 11), chronic hepatitis B virus patients seropositive for hepatitis B virus DNA (n = 8) and seronegative for hepatitis B virus DNA (n = 8) were 2,329 (range = 1,538 to 3,133), 3,375 (range = 2,300 to 6,718) (p less than 0.01) and 3,113 (range = 2,229 to 5,246) (p less than 0.05) sites/cell, respectively. They all had similar dissociation constants of 8.4 x 10(-10) mol/L (range = 4.1 to 16.9), respectively. Further dissection of the peripheral blood mononuclear cells showed that this increase in cell surface receptor number was confined to the monocyte fraction (p less than 0.01). Plasma tumor necrosis factor-alpha levels in five patients with increased monocyte cell surface tumor necrosis factor-alpha receptor numbers were also elevated.(ABSTRACT TRUNCATED AT 250 WORDS)",0
519,1650327,Binding and internalization of transforming growth factor-beta 1 by human hepatoma cells: evidence for receptor recycling,"Cellular processing of 125I-labeled transforming growth factor-beta 1 was investigated in the human hepatoma cell lines Hep G2 and Hep 3B. Binding of 125I-transforming growth factor-beta 1 to cell surface receptors was specific, saturable and calcium-independent. Both cell lines exhibited a single class of high-affinity (Kd = 2.2 x 10(-10) mol/L) binding sites (4.5 x 10(3) for the Hep G2 cell; 1.5 x 10(3) for the Hep 3B cell) for both human and porcine transforming growth factor-beta 1. Binding was temperature dependent, time dependent and pH dependent. Cell-bound 125I-transforming growth factor-beta 1 was removed by brief exposure to acidic medium (pH less than 4) but was converted into an acid-resistant state rapidly after shifting the cells to 37 degrees C. Spontaneous dissociation of bound ligand over a 6 hr period at 4 degrees C was less than 10%. Disuccinimidyl suberate was used to covalently label 125I-transforming growth factor-beta 1 to cell-surface binding sites. Labeling of the ligand/receptor complexes was inhibited by unlabeled transforming growth factor-beta 1 but was unaffected by other growth factors. The radiolabeled complexes showed approximate molecular weights of 280,000, 85,000 and 65,000 when run on reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cell-bound 125I-transforming growth factor-beta 1 was internalized and degraded at 37 degrees C, and the products were released into the medium as trichloroacetic acid-nonprecipitable radioactivity. The lysosomotropic base chloroquine and the carboxylic ionphore monensin inhibited degradation and release of 125I-labeled products from the cells.(ABSTRACT TRUNCATED AT 250 WORDS)",0
520,1655605,Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance. The VA Cooperative Study Group (No. 119),"Patients with overt alcoholic liver disease who had participated in a multicenter therapeutic trial and subgroups of controls (i.e., alcoholic patients without liver disease and patients with neither alcoholism nor liver disease) were tested for hepatitis B virus and hepatitis C virus antibodies to determine the prevalence of these antibodies to determine the prevalence of these antibodies and any clinical association in the progression and outcome of alcoholic liver disease. Antibodies to hepatitis B (anti-HBs and/or anti-HBc) were found in 29.2% of patients with alcoholic liver disease, in 26.1% of hospitalized alcoholic patients without liver disease and in 24.2% of hospitalized nonalcoholic patients without liver disease; frequencies were not significantly different from one another. HBsAg was not evaluated because HBsAg+ patients had been excluded from the original trial. The presence of these antibody markers correlated with ethnic origin of and immunoglobulin levels in the patients. In contrast, antibody to hepatitis C, as detected by enzyme immunoassay, was positive in 27.1%, 4.8% and 3.0% of the three groups, respectively, the first differing significantly from the other two. Antibody to hepatitis C virus positivity correlated significantly with clinical severity of the disease and with the presence of histological features that imply chronic viral infection (periportal inflammation, cirrhosis), despite the fact that the supplementary assay for antibody to hepatitis C virus, using recombinant immunoblot assay, reduced the positive rate by 79%.(ABSTRACT TRUNCATED AT 250 WORDS)",0
521,1658648,Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance,"BACKGROUND: Polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) has been treated with plasma exchange, intravenous immune globulin, and chemotherapy, but the effectiveness of these treatments remains uncertain. METHODS: We randomly assigned 39 patients with stable or worsening neuropathy and MGUS of the IgG, IgA, or IgM type to receive either plasma exchange twice weekly for three weeks or sham plasma exchange, in a double-blind trial. The patients who initially underwent sham plasma exchange subsequently underwent plasma exchange in an open trial. RESULTS: In the double-blind trial, the average neuropathy disability score improved by 2 points from base line (from 62.5 to 60.5) in the sham-exchange group and by 12 points (from 58.3 to 46.3) in the plasma-exchange group (P = 0.06). A similar difference was observed in the weakness score, a component of the neuropathy disability score (improvement, 1 and 10 points, respectively; P = 0.07). After treatment the summed compound muscle action potentials of motor nerves were 1.2 mV lower (worse) than at base line in the sham-exchange group and 0.4 mV higher (better) in the plasma-exchange group (P = 0.07). The greater degree of improvement with plasma exchange was equal in magnitude to or greater than the difference between not being able to walk on the heels or toes and being able to perform these activities. Changes in the vibratory detection threshold, summed motor-nerve conduction velocity, and sensory-nerve action potentials did not differ significantly between the treatment groups. In the open trial, in which patients who initially underwent sham exchange were treated with plasma exchange, the neuropathy disability score (P = 0.04), weakness score (P = 0.07), and summed compound muscle action potentials (P = 0.07) improved more with plasma exchange than they had with sham exchange. In both the double-blind and the open trial, those with IgG or IgA gammopathy had a better response to plasma exchange than those with IgM gammopathy. CONCLUSIONS: Plasma exchange appears to be efficacious in neuropathy associated with MGUS, especially of the IgG or IgA type.",0
522,1658650,The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. Varicella Vaccine Collaborative Study Group,"BACKGROUND: The Oka strain of live attenuated varicella vaccine is immunogenic and highly protective, but there has been concern about the risk of zoster after immunization. METHODS: We examined the incidence of zoster, risk factors for it, and measures of immune response in children with leukemia who received the vaccine and in appropriate controls. RESULTS: After a mean follow-up of 4.1 years, zoster was documented in 13 of the 548 vaccinated children with leukemia (2.4 percent). In a subgroup of 96 vaccinated children matched prospectively with 96 children with leukemia who had had natural varicella infections, there were 4 cases of zoster among the vaccinated children and 15 among the controls, for crude incidence rates of 0.80 and 2.46 cases per 100 person-years, respectively (P = 0.01). Of the total of 13 vaccinated children who had zoster, 11 had a skin rash due to varicella-zoster virus, either from the vaccine itself or from breakthrough varicella after household exposure in the period between immunization and the documentation of zoster. In the 268 children who had any type of rash caused by varicella-zoster virus after vaccination, as compared with those who did not have a rash, the relative risk of subsequent zoster was 5.75. For the 21 vaccinated children who received bone marrow transplants, as compared with those who did not, the relative risk of zoster was 7.5. Cell-mediated immunity as assessed by lymphocyte stimulation was lower in 4 children in whom zoster later developed than in 29 controls who had been vaccinated but who did not have zoster (mean stimulation index, 5.1 vs. 23.8; P = 0.0001). CONCLUSIONS: In children with leukemia who receive the live attenuated varicella vaccine, the subsequent incidence of zoster is lower than in children who have natural varicella infections.",0
523,1671846,Quantitation of intrinsic drug-metabolizing capacity in human liver biopsy specimens: support for the intact-hepatocyte theory,"Hepatic drug metabolism is decreased in patients with severe liver disease, but it is unclear to what extent this is due to altered hepatic blood flow or reduced intrinsic metabolic capacity. In this study we quantitated in needle-biopsy specimens the intrinsic capacity of liver tissue from 67 patients with mild liver disease (n = 36), chronic active hepatitis (n = 16) and cirrhosis (n = 15) to metabolize two model compounds in vitro. Hydroxylation of the low-extraction drug bufuralol resulted in the formation of 251 +/- 25 nmol 1'OH-bufuralol/gm wet wt/hr in mildly diseased liver tissue and was significantly (p less than 0.01) reduced in liver tissue exhibiting chronic active hepatitis (166 +/- 23 nmol/gm wet wt/hr) and cirrhosis (124 +/- 21 nmol/gm wet wt/hr). The formation rates of monoethylglycinexylidide, the main metabolite of the high-extraction drug lidocaine, varied widely and were not significantly different among the three groups. To relate the drug-metabolizing capacity to the hepatocyte content of liver tissue, morphometrical study was performed in the biopsy pieces originally submitted. The metabolic activity of each biopsy piece was then related to the fractional volume of hepatocytes it was calculated to contain. In mildly diseased liver tissue 355 +/- 35 nmol 1'OH-bufuralol/ml hepatocytes x hr or 12.4 +/- 1.0 mumol monoethylglycinexylidide/ml hepatocytes x hr- and in cirrhotic liver tissue 306 +/- 49 nmol 1'OH-bufuralol/ml hepatocytes x hr or 15.3 +/- 3.0 mumol monoethylglycinexylidide/ml hepatocytes x hr--were formed, respectively, and these differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)",0
524,1674589,A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. Military Medical Consortium for Applied Retroviral Research,"BACKGROUND: Despite multiple antiviral humoral and cellular immune responses, infection with the human immunodeficiency virus (HIV) results in a progressively debilitating disease. We hypothesized that a more effective immune response could be generated by post-infection vaccination with HIV-specific antigens. METHODS: We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein, gp160, in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2. The vaccine was administered either on days 0, 30, and 120 or on days 0, 30, 60, 120, 150, and 180. HIV-specific humoral and cellular immune responses were measured; local and systemic reactions to vaccination, including general measures of immune function, were monitored. RESULTS: In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160. Seroconversion to selected envelope epitopes was observed, as were new T-cell proliferative responses to gp160. Response was associated with the CD4 cell count determined before vaccination (13 of 16 subjects [81 percent] with greater than 600 cells per milliliter responded, as compared with 6 of 14 [43 percent] with less than or equal to 600 cells per milliliter; P = 0.07) and with the number of injections administered (87 percent of subjects randomly assigned to receive six injections responded, as compared with 40 percent of those assigned to three injections; P = 0.02). Local reactions at the site of injection were mild. There were no adverse systemic reactions, including diminution of general in vitro or in vivo cellular immune function. After 10 months of follow-up, the mean CD4 count had not decreased in the 19 subjects who responded, but it had decreased by 7.3 percent in the 11 who did not respond. CONCLUSIONS: This gp160 vaccine is safe and immunogenic in volunteer patients with early HIV infection. Although it is too early to know whether this approach will be clinically useful, further scientific and therapeutic evaluation of HIV-specific vaccine therapy is warranted. Similar vaccines may prove to be effective for other chronic infections.",0
525,1683682,Antibody responses to Haemophilus influenzae type B vaccines in men with human immunodeficiency virus infection,"BACKGROUND: Persons with human immunodeficiency virus (HIV) infection are at increased risk for serious infections caused by Haemophilus influenzae, yet there are few data on their antibody responses to the H. influenzae type b vaccines. METHODS: We evaluated antibody responses in 248 men who were randomly assigned to receive a single dose of either the H. influenzae type b polysaccharide (PRP) vaccine or the polysaccharide-mutant diphtheria toxoid conjugate vaccine (PRP-CRM). The subjects were stratified into four groups: seronegative men (67 subjects), men with asymptomatic HIV infection (79), men with symptomatic HIV infection (47), and men with the acquired immunodeficiency syndrome (AIDS) (55). RESULTS: Before immunization, the subjects with AIDS had the lowest PRP-antibody titers; 40 percent had titers below the putative protective level (less than 0.15 micrograms per milliliter). In the seronegative subjects, those with asymptomatic HIV infection, and those with symptomatic HIV infection, the PRP-CRM vaccine led to a threefold greater increase in geometric mean antibody titers than did the PRP vaccine (P less than 0.01). However, the subjects with AIDS had a greater antibody response to the PRP vaccine. The antibody response of HIV-seropositive men to the PRP-CRM vaccine correlated significantly with the number of CD4 lymphocytes (r = 0.47, P less than 0.0001, as compared with r = -0.01 for the PRP vaccine). In these HIV-infected men, both vaccines elicited the dominant anti-PRP idiotype described previously in populations not infected with HIV. CONCLUSIONS: Immunization with the PRP-CRM conjugate vaccine early in the course of HIV infection is likely to confer protection against disease caused by H. influenzae type b.",0
526,1696358,Absence of need for amniocentesis in patients with elevated levels of maternal serum alpha-fetoprotein and normal ultrasonographic examinations,"BACKGROUND: Recent improvements in the accuracy of sonographic diagnosis of neural-tube and ventral-wall defects have raised a question about the wisdom of routinely offering amniocentesis to women who have elevated levels of maternal serum alpha-fetoprotein with a structurally normal fetus as determined by ultrasonography. METHODS: We reviewed the ultrasound findings in 51 consecutive fetuses with spina bifida, encephalocele, gastroschisis, or omphalocele that were delivered or aborted at a single hospital, to estimate the sensitivity of ultrasonography for these diagnoses. In all cases, the mothers had undergone prenatal sonography at one facility between 16 and 24 weeks after the last menstrual period. We used these data to calculate the probability of an affected fetus in a women with a given level of maternal serum alpha-fetoprotein and a normal sonogram. RESULTS: These four types of anomalies were correctly identified in all 51 cases, yielding a sensitivity of 100 percent (95 percent confidence interval, 94 to 100 percent). Using the lower limit of this confidence interval, we calculated that the probability of an affected fetus ranges from 0.01 to 0.15 percent for maternal serum alpha-fetoprotein levels ranging from 2.0 to 3.5 times the median, respectively. CONCLUSIONS: This level of risk is less than the reported risk of abortion due to amniocentesis and may lead some women with elevated levels of alpha-fetoprotein to decide not to proceed with amniocentesis.",0
527,1701753,Site-directed mutagenesis of lysine within the immunodominant autoepitope of PDC-E2,"The major autoantigens of PBC have been identified as the four closely related mitochondrial enzymes PDC-E2, BCKD-E2 OGDC-E2 and protein X. A major structural similarity of these enzymes is the presence of one or more lipoyl domains. The immunodominant epitope of each autoantigen has either been postulated or been demonstrated to be located within the lipoate binding region. However, it is not clear whether the binding of lipoic acid to the epitope is necessary for autoantibody recognition. To address this issue we have constructed by oligonucleotide site-directed mutatagenesis three mutants in the lipoyl domain of human PDC-E2. Because lipoic acid is covalently bound to the zeta-amino group of the lysine residue of PDC-E2, the mutants were designed to replace the lysine residue in the lipoyl domain with glutamine, a negatively charged amino acid; histidine, a positively charged amino acid; and tyrosine, an aromatic amino acid. Binding reactivity of sera from patients with PBC were analyzed by enzyme-linked immunosorbent assay, immunoblotting and specific absorption against each of the three mutants and control clones. All data were compared with parallel studies with a control recombinant clone, the liver-specific F alloantigen. We believe the recognition of the lipoyl domain is a reflection of the surface-exposed, hydrophilic and relatively mobile nature of this region of the autoantigen. Further studies on direct assay for the presence of lipoic acid will be needed to clarify these issues.",0
528,1703123,Liver contains heparin-binding growth factors as the major growth factor for cultured fibroblasts,"The presence of heparin-binding growth factors in liver was investigated by measuring the DNA synthesis stimulatory activity of liver extracts using quiescent fibroblasts as target cells. It was found that cytosolic fractions of mouse, rat and human liver, as well as isolated rat hepatocytes, contain a large amount of growth stimulatory activity. Most liver cytosolic activity is due to heparin-binding growth factors, because greater than 90% of the activity bound to a heparin affinity column in the presence of 0.8 mol/L NaCl, and was quantitatively eluted with 2 mol/L NaCl. Purification of these factors from both mouse and rat liver indicated the presence of both heparin-binding growth factor-1 and 2 in liver extracts. The level of the heparin-binding growth factors, as estimated from the biological activity, is approximately 1 microgram/gm mouse liver and 0.1 microgram/gm rat and human liver. Heparin-binding growth factor-1-like factors were 10 times as abundant as heparin-binding growth factor-2-like factors. These data indicate that the cytosolic fractions of mouse, rat and human liver contain heparin-binding growth factors as the primary growth factor for fibroblasts, and heparin binding growth factor-1-like molecules account for most of the cytosolic activity in both mouse and rat liver.",0
529,1705532,Alterations in nuclear scaffold constituents during carbon tetrachloride-induced liver regeneration,"Liver regeneration was induced in rats by treatment with CCl4, which results in substantial regenerative activity with a sharp mitotic response 2 days after intoxication. Closely paralleling the mitotic index, we observed fourfold increases in nuclear scaffold nucleoside triphosphatase, an activity thought to participate in nucleocytoplasmic RNA transport and in the 46 kD putative enzyme and its selective photolabeling. Because previous work has indicated that the 46 kD protein may be proteolytically derived from lamins A/C by cleavage at a tyrosine residue at aa376, we investigated the response of lamin A/C transcripts during this regeneration. Surprisingly, Northern blot analyses after CCl4 administration showed low levels of lamin A/C transcripts (which appeared to be predominantly poly[A]-), and we found a decrease in immunoprecipitable lamins A/C from in vitro translation of poly(A)- selected RNA. To circumvent potential problems with such analyses, we used reverse transcription/polymerase chain reaction amplification of lamin A/C transcripts from total cytoplasmic RNA. These assays showed a transient, comparatively minor increase in lamin A/C transcripts 1 day after treatment, but levels rapidly declined from 1 to 3 days and were decreased at 3 to 5 days. However, nuclear scaffold protease activity, which shows a considerable selectivity for lamins A/C and may be involved in derivation of the 46 kD protein, increased in parallel to the mitotic response and increases in nucleoside triphosphatase, as assessed using a nonspecific (Azocoll) protease assay. Assays with a specific tyrosine-containing substrate (Z-Y-Sbenzyl) showed an increase that mirrored that observed with the nonspecific substrate.(ABSTRACT TRUNCATED AT 250 WORDS)",0
530,1707028,"Expression of insulin-like growth factor II, alpha-fetoprotein and hepatitis B virus transcripts in human primary liver cancer","Insulin-like growth factor II is a fetal growth factor structurally and functionally related to insulin and insulin-like growth factor I. Its mRNA expression is developmentally regulated in human liver, the reexpression of insulin-like growth factor II fetal transcripts being often observed in primary liver cancer. Insulin-like growth factor II and alpha-fetoprotein mRNAs were studied in 16 human primary liver cancers, most of which were highly differentiated. Hepatitis B virus transcripts were also analyzed in the tumors from hepatitis B virus chronic carriers. alpha-Fetoprotein mRNA was detected in only four tumors and in one nontumorous cirrhotic tissue; all these samples also displayed insulin-like growth factor II fetal transcripts. Furthermore, fetal insulin-like growth factor II mRNAs were observed in five tumors and six nontumorous cirrhotic areas not expressing alpha-fetoprotein mRNA. The presence of hepatitis B virus RNA was only observed in tissues not expressing alpha-fetoprotein or fetal insulin-like growth factor II mRNA. In conclusion, fetal insulin-like growth factor II transcripts are more frequently observed than alpha-fetoprotein mRNA in highly differentiated liver cancers and in surrounding cirrhotic areas. The reexpression of fetal insulin-like growth factor II transcripts might then be a marker of early steps of liver cell transformation.",0
531,1710779,Second-trimester maternal serum alpha-fetoprotein levels and the risk of subsequent fetal death,"BACKGROUND: The finding of an elevated level of maternal serum alpha-fetoprotein during the second trimester of pregnancy may indicate that the fetus has died or is about to die. It is uncertain, however, whether the finding is associated with an increased risk of fetal death later in gestation independent of known causes of elevation, such as the presence of neural-tube defects or multiple gestation. METHODS: To address this question, we performed a case-control study of 612 women whose pregnancies ended in fetal death and 2501 women who gave birth to live infants, using reports from California vital statistics for 1987. All the women had signleton pregnancies and alpha-fetoprotein screening in the second trimester. RESULTS: Women with elevated levels of serum alpha-fetoprotein in the second trimester of pregnancy had an increased risk of fetal death, and the risk was increased until term. Women with the highest levels of serum alpha-fetoprotein--greater than or equal to 3.0 times the median value--had a very high risk of fetal death (odds ratio, 10.4; 95 percent confidence interval, 4.9 to 22.0) as compared with women who had normal levels of alpha-fetoprotein. Maternal serum alpha-fetoprotein levels that were 2.0 to 2.9 times the median were also associated with an elevated risk of fetal death (odds ratio, 2.4; 95 percent confidence interval, 1.7 to 3.4). Elevated levels of alpha-fetoprotein were especially likely to be associated with fetal death in cases in which maternal hypertension or placental infarction was also present. CONCLUSIONs. An unexplained elevated level of maternal serum alpha-fetoprotein in the second trimester of pregnancy is associated with an increased risk of subsequent fetal death, up to four to five months after alpha-fetoprotein screening.",0
532,1712337,Studies on mechanisms of augmentation of liver regeneration by cyclosporine and FK 506,"Evidence could not be found of immune modulation of liver regeneration. The powerful immunosuppressive drug FK 506, which augments the response after partial hepatectomy in normal rats, had the same effect in T cell-deficient nude rats. The cytotoxicity of natural killer cells in treated nude rats was not significantly changed by FK 506 therapy. However, the serum of FK 506-treated nude rats increased hepatocyte proliferation when added to third-party hepatocyte cultures, suggesting that FK 506 had induced a serum growth factor in the nude rats or had suppressed an inhibitory factor. A hypothesis was advanced that FK 506 (and cyclosporine) affects hepatic growth by nonimmunological pathways.",0
533,1713648,Psychological stress and susceptibility to the common cold,"BACKGROUND: It is not known whether psychological stress suppresses host resistance to infection. To investigate this issue, we prospectively studied the relation between psychological stress and the frequency of documented clinical colds among subjects intentionally exposed to respiratory viruses. METHODS: After completing questionnaires assessing degrees of psychological stress, 394 healthy subjects were given nasal drops containing one of five respiratory viruses (rhinovirus type 2, 9, or 14, respiratory syncytial virus, or coronavirus type 229E), and an additional 26 were given saline nasal drops. The subjects were then quarantined and monitored for the development of evidence of infection and symptoms. Clinical colds were defined as clinical symptoms in the presence of an infection verified by the isolation of virus or by an increase in the virus-specific antibody titer. RESULTS: The rates of both respiratory infection (P less than 0.005) and clinical colds (P less than 0.02) increased in a dose-response manner with increases in the degree of psychological stress. Infection rates ranged from approximately 74 percent to approximately 90 percent, according to levels of psychological stress, and the incidence of clinical colds ranged from approximately 27 percent to 47 percent. These effects were not altered when we controlled for age, sex, education, allergic status, weight, the season, the number of subjects housed together, the infectious status of subjects sharing the same housing, and virus-specific antibody status at base line (before challenge). Moreover, the associations observed were similar for all five challenge viruses. Several potential stress-illness mediators, including smoking, alcohol consumption, exercise, diet, quality of sleep, white-cell counts, and total immunoglobulin levels, did not explain the association between stress and illness. Similarly, controls for personality variables (self-esteem, personal control, and introversion-extraversion) failed to alter our findings. CONCLUSIONS: Psychological stress was associated in a dose-response manner with an increased risk of acute infectious respiratory illness, and this risk was attributable to increased rates of infection rather than to an increased frequency of symptoms after infection.",0
534,1714871,Export of intracellular HBsAg in chronic hepatitis B virus infection is related to viral replication,"Serum and liver HBsAg bear an inverse relation to each other during the evolution of chronic hepatitis B virus infection and the quantity of HBsAg in tissue rises gradually with time. In this study, intracellular and extracellular levels of HBsAg were measured by radioimmunoassay in primary culture of hepatocytes from 30 patients with chronic hepatitis B virus infection to determine a possible relationship with hepatitis B virus replication. Serum levels of HBsAg correlated with markers of active viral replication (serum hepatitis B virus DNA, p less than 0.005, and tissue HBcAg, p less than 0.02) but inversely with tissue HBsAg (p less than 0.05). In similar fashion, in vitro export of HBsAg was also related to the presence of active viral replication markers (serum hepatitis B virus DNA, p less than 0.02, and tissue HBcAg, p less than 0.05) and negatively with tissue HBsAg (p less than 0.001). Export of HBeAg also correlated positively with markers of active viral replication (serum hepatitis B virus DNA, p less than 0.05 and tissue HBcAg, p less than 0.05). Further experiments indicated that intrahepatic pre-S1 and pre-S2 correlated closely with intrahepatic HBsAg, indicating that a failure to export HBsAg was unlikely to be attributable to deficient intracellular expression of pre-S1 or pre-S2. These data indicate that in vitro primary hepatocyte culture of hepatitis B virus-infected cells provides an accurate reflection of in vivo export of HBsAg and that this is closely related to the presence of active viral replication.",0
535,1727062,Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance,"BACKGROUND: Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS: We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS: After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS: Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.",0
536,1727788,The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-alpha,"D-Galactosamine is an hepatocyte-specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide-induced mediator of shock, tumor necrosis factor-alpha. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute-phase proteins, we postulated that the lipopolysaccharide-sensitizing effect of D-galactosamine could be caused by its inhibition of acute-phase product transcription. We confirmed that the acute-phase response to lipopolysaccharide was attenuated by simultaneous administration of D-galactosamine. However, when the acute-phase response was induced by subcutaneous turpentine 24 hr before D-galactosamine administration, the effect of D-galactosamine on circulating acute-phase reactants was negligible. Furthermore, induction of an a priori acute-phase response protected mice from both D-galactosamine/lipopolysaccharide and D-galactosamine/tumor necrosis factor-alpha-induced death. The turpentine-induced acute-phase response did not decrease endogenous tumor necrosis factor-alpha production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor-alpha. Thus we suggest that the acute-phase response protects against death in D-galactosamine-sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor-alpha release.",0
537,1727798,Ultrastructural identification of light microscopic giant mitochondria in alcoholic liver disease,"Ultrastructural identification of light microscopic giant mitochondria was performed on the same specimens for light and electron microscopic observations. The liver tissue specimens were fixed in OsO4, embedded in epoxy resin, cut 4 microns thick and stained with polychrome. At the beginning of the study a light microscopic observation was made, and a microphotograph was taken. The identification of light microscopic giant mitochondria by conventional microscopy was identified by the occupation rate in liver cells, the negative findings of stainability and the morphological consistency (round, cigar-shaped and granular). The specimens were subsequently embedded again in epoxy resin and cut into ultrathin sections of 400 A. A transillumination electron microscope was used for the observation, and ultrastructural images of light microscopic giant mitochondria revealed that they were crystalloid bodies with a crystalline latticelike structure. The occupation rates within liver cells and the morphological shapes of the crystalloid bodies corresponded with those of light microscopic giant mitochondria. The light microscopic giant mitochondria obviously had different features from those of electron microscopic giant mitochondria and Mallory bodies (Yokoo's type II), although Mallory bodies showed the same staining properties as light microscopic giant mitochondria.",0
538,1729621,Mortality over a period of 10 years in patients with peripheral arterial disease,"BACKGROUND: Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication, and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease, as diagnosed by noninvasive testing. In this study, we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease. METHODS: We examined 565 men and women (average age, 66 years) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques--measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound. We identified 67 subjects with the disease (11.9 percent), whom we followed prospectively for 10 years. RESULTS: Twenty-one of the 34 men (61.8 percent) and 11 of the 33 women (33.3 percent) with large-vessel peripheral arterial disease died during follow-up, as compared with 31 of the 183 men (16.9 percent) and 26 of the 225 women (11.6 percent) without evidence of peripheral arterial disease. After multivariate adjustment for age, sex, and other risk factors for cardiovascular disease, the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 (95 percent confidence interval, 1.9 to 4.9) for deaths from all causes, 5.9 (95 percent confidence interval, 3.0 to 11.4) for all deaths from cardiovascular disease, and 6.6 (95 percent confidence interval, 2.9 to 14.9) for deaths from coronary heart disease. The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease. After the exclusion of subjects who had a history of cardiovascular disease at base line, the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated. Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic. CONCLUSIONS: Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes.",0
539,1732770,"A comparison of nonionic, low-osmolality radiocontrast agents with ionic, high-osmolality agents during cardiac catheterization","BACKGROUND: Nonionic, low-osmolality radiocontrast agents are used frequently because they are believed to be safer than ionic, high-osmolality agents, but they are also more expensive. We conducted a randomized trial to compare the incidence of adverse events after the administration of ionic, high-osmolality and of non-ionic, low-osmolality radiocontrast agents during cardiac angiography. METHODS: We compared the need to treat patients for adverse reactions and the frequency and severity of specific hemodynamic, systemic, and symptomatic side effects in two groups of patients randomly assigned to receive either ionic, high-osmolality or nonionic, low-osmolality radiocontrast material, and also in 366 patients who could not be randomized. RESULTS: Treatment for adverse events was required in 213 of 737 patients who received high-osmolality contrast agents (29 percent) but in only 69 of 753 patients who received nonionic agents (9 percent) (95 percent confidence interval for the percent difference, 15.9 to 23.6 percent). Hemodynamic deterioration and symptoms also occurred more often in the high-osmolality group, as did severe or prolonged reactions (2.9 percent, as compared with 0.8 percent in the nonionic group; P = 0.035). The severe reactions were largely confined to patients with severe cardiac disease. Multivariate analysis showed that the presence of severe coronary disease and unstable angina were predictors of clinically important adverse reactions. If all the patients in our randomized trial had been given nonionic contrast material, the incremental cost per procedure would have been $89. CONCLUSIONS: Nonionic, low-osmolality contrast material is better tolerated during cardiac angiography than ionic, high-osmolality contrast material. Since cost constraints may prevent the universal use of nonionic contrast material, its selective use in patients with severe cardiac disease could be considered.",0
540,1735530,Effect of alpha-tocopherol on hepatic mixed function oxidases in hepatic ischemia/reperfusion,"This study was done to determine the relationship between microsomal lipid peroxidation during hepatic ischemia/reperfusion and alteration in cytochrome P-450-dependent drug metabolism. Rats were pretreated with alpha-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham-ischemic animals. After 1, 5 or 24 hr of reperfusion, liver microsomes were isolated and cytochrome P-450 and mixed function oxidases were studied. In vehicle-treated ischemic rats, serum ALT levels peaked at 5 hr (5,242 +/- 682 U/L) and were significantly reduced by alpha-tocopherol pretreatment (1,854 +/- 229 U/L, p less than 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle-treated ischemic group, but this elevation was prevented by alpha-tocopherol pretreatment. Microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity were both decreased in vehicle-treated ischemic rats to 60% and 70% of sham-ischemic control levels, respectively. Although alpha-tocopherol restored cytochrome P-450 content to the level of sham-ischemic control rats, aminopyrine-N-demethylase activity remained at 76% of control with alpha-tocopherol treatment (p less than 0.01 compared with sham-ischemic control). In contrast to what was seen with cytochrome P-450 and aminopyrine-N-demethylase, aniline p-hydroxylase activity was elevated in the vehicle-treated ischemic rats compared with sham-ischemic control rats. These increases were prevented by alpha-tocopherol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)",0
541,1735535,Changes in transcripts of basement components during rat liver development: increase in laminin messenger RNAs in the neonatal period,"The expression of laminin and type IV collagen messenger RNA in rat liver was investigated in relation to liver development. Levels of messenger RNA for laminin chains A, B1 and B2, and alpha 1 and alpha 2 chains of type IV collagen were studied by Northern-blot and dot-blot analysis. Although the expression of messenger RNAs for laminin B1 and B2 chains was higher in 19-day gestational fetal liver when compared with the adult, the highest level was detected in 15-day newborns. This finding coincides with the final establishment of the mature liver. Laminin A messenger RNA was not detected in the 19-day gestational fetus or in the neonatal period. In contrast, alpha 1-(IV) and alpha 2-(IV) collagen messenger RNAs maintained high levels in the early neonate and then decreased gradually after 15 days. Our findings suggest that during late stages of liver ontogeny the main components of liver basement membrane proteins undergo a significant alteration in their synthesis. The data further suggest that laminin may play a role in the final stages of hepatic differentiation.",0
542,1735539,Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide,"Nitric oxide is a vasodilator tonically secreted by endothelial cells that is involved in the regulation of arteriolar tone. This study, which includes two protocols, was performed to investigate whether nitric oxide plays a role in the pathogenesis of arterial hypotension in cirrhosis with ascites. In protocol 1, the administration of increasing doses (25, 50, 250, 500 and 1,000 micrograms.kg-1.min-1) of the nitric oxide biosynthesis inhibitor N omega-nitro-L-arginine to 18 conscious rats with cirrhosis and ascites produced, at each dose tested, a significantly greater increase in arterial pressure than in 17 conscious control rats. At the lowest dose of N omega-nitro-L-arginine, arterial pressure significantly rose in cirrhotic rats but not in controls. In protocol 2, arterial pressure, estimated renal plasma flow, glomerular filtration rate and sodium excretion were measured in 12 cirrhotic rats with ascites and 10 control rats before and during the sequential infusion of previously selected doses of N omega-nitro-L-arginine (25, 50 and 250 micrograms.kg-1.min-1). Changes in arterial pressure reproduced those observed in protocol 1. In control rats, N omega-nitro-L-arginine caused a decrease in estimated renal plasma flow without affecting glomerular filtration rate or sodium excretion. In contrast, N omega-nitro-L-arginine administration to cirrhotic animals did not produce any appreciable renal vasoconstrictor effect, and it increased glomerular filtration rate and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)",0
543,1738376,Nosocomial transmission of hepatitis B virus associated with the use of a spring-loaded finger-stick device,"BACKGROUND AND METHODS: From June 1989 through March 1990, 26 patients, of whom 23 had diabetes, contracted acute hepatitis B virus (HBV) infection in a hospital in California. All 26 patients and one HBV carrier (also a diabetic) had been admitted to a single medical ward during the six months before the case patients became infected with HBV. To determine the source of the infection, we conducted a retrospective cohort study of the 72 patients with diabetes who had been admitted to the ward from January through December 1989 and a case-control study comparing the 3 nondiabetic patients who contracted hepatitis with 20 nondiabetic controls. RESULTS: The retrospective cohort study of all the patients with diabetes who were admitted to the ward during 1989 found that those who underwent capillary blood sampling by finger stick with a spring-loaded lancet device were more likely to contract HBV infection than those who did not have finger sticks (attack rate, 42 percent vs. 0 percent; P = 0.08). In addition, a dose-response relation was observed between the number of finger sticks received and the frequency of hepatitis B (P = 0.002). The case-control study found that all 3 of the nondiabetic patients who contracted hepatitis underwent finger-stick blood sampling with the device, as compared with none of the 20 nondiabetic controls (P = 0.0006). A review of nursing procedures indicated that the platform of the device was not routinely changed after each use; this finding suggested that contamination of the platform by HBV-infected blood was the mechanism of percutaneous transmission of HBV. CONCLUSIONS: Proper use of finger-stick devices as well as strict adherence to universal precautions to avoid contamination by blood are required to decrease the possibility of transmission of blood-borne pathogens among hospitalized patients.",0
544,1765122,A comparison of pyridoxal 5'-phosphate dependent decarboxylase and transaminase enzymes at a molecular level,"Pyridoxal 5'-phosphate is a coenzyme for a number of enzymes which catalyse reactions at C alpha of amino acid substrates including transaminases, decarboxylases and serine hydroxymethyltransferase. Using the X-ray coordinates for a transaminase, aspartate aminotransferase, and the results of stereochemical and mechanistic studies for decarboxylases and serine hydroxymethyltransferase, an active-site structure for the decarboxylase group is constructed. The structure of the active-site is further refined through active-site pyridoxyllysine peptide sequence comparison and a 3-D catalytic mechanism for the L-alpha-amino acid decarboxylases is proposed. The chemistry of serine hydroxymethyltransferase is re-examined in the light of the proposed decarboxylase mechanism. ",0
545,1765224,Sensitive periods for behavioral toxicity of polychlorinated biphenyls: determination by cross-fostering in rats,"Polychlorinated biphenyls (PCBs) are transferred to developing organisms via the milk rather than through placental barriers. Recent epidemiological data, however, suggest a greater importance of the prenatal exposure period for the development of neuropsychological disorders. The relative effectiveness of pre- and postnatal PCB exposure was compared in a cross-fostering experiment in rats. Female Wistar rats were fed diets containing 0 or 30 mg PCB/kg. After birth half of the litters in each exposure group were nursed by dams of the other condition. Six different congeners were determined in the brains of the offspring at various ages. Internal exposure to higher chlorinated congeners peaked at weaning in groups with postnatal or permanent exposure, whereas the concentration of a low-chlorinated compound was lower at weaning than at birth or at later age stages. Brain tissue levels in prenatally treated rats declined with aging. In two behavioral paradigms, active avoidance learning and retention of a visual discrimination task, prenatally exposed rats exhibited alterations similar to those of permanently treated subjects, while postnatal exposure caused no detectable behavioral changes. These results support the above-mentioned epidemiological studies which related neurodevelopmental deficits in children to prenatal PCB exposure. ",0
546,1766677,Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma,"Studies of second, non-ocular tumours in surviving retinoblastoma patients and their families have reported a higher than expected incidence and lower age at diagnosis of bladder tumours. This suggests that RB mutations may predispose to bladder cancer. To determine whether this gene is involved in the development of sporadic bladder tumours we have examined 162 bladder tumours for evidence of structural alterations to the RB gene. Ninety-four patients were informative with one or more intragenic RB probes, and 28 of these (29%) showed loss of heterozygosity (LOH). Of these, two tumours showed homozygous deletions with the 5' intragenic probe p123M1.8. The probe p68RS2.0, which recognizes a variable number of tandem repeats site in intron 17 of the RB gene, detected new alleles in 5 of 162 tumours, one of which also showed LOH at another polymorphic site within the gene. The 28 tumours with RB LOH were screened with the RB cDNA probes pR3.8 and pR0.9, which revealed two homozygous deletions and one rearrangement. The tumours with RB LOH were also screened for loss of three markers which flank RB, D13S1 which maps proximal and D13S2 and D13S3 which map distal to RB on chromosome 13q. Two tumours showed retention of heterozygosity for flanking markers on one side of RB and another for markers on both sides. These results suggest that RB is the target gene on 13q in these bladder tumours. When RB loss was compared with tumour grade and stage, an association between high tumour grade and RB loss (0.005 greater than P greater than 0.001) and between muscle invasion and RB loss (P greater than 0.001) was found. Twenty-six of the 28 tumours with LOH were muscle-invasive. This represents 56% of invasive tumours. Only 2/48 (4%) superficial tumours showed RB allele loss, and one of these has progressed rapidly to invasive disease. These results show that LOH at the RB locus is a frequent genetic event in bladder tumours and may identify a subset of more aggressive tumours. ",0
547,1766782,A study of schizophrenic outpatients with the Defense Mechanism Test,"Intrapsychic defensive strategies are allegedly expressed on the Defense Mechanism Test through the presentation, at increasing tachistoscopic exposure times, of a picture in which a central figure is threatened by a peripheral person. Several types of perceptual alterations of the stimulus configuration are coded as defenses in the subjective reports. A number of test variables have already been shown to differentiate significantly between nonclinical controls and nonpsychotic psychiatric patients. In the present study, after a review of the pertinent percept-genetic literature, nonpsychotic patients (n = 57) were compared with a group of schizophrenic outpatients in the active phase (n = 21). As predicted, significantly more schizophrenics than controls were coded for projection and regression and for certain variants of these signs. Four subcodings of repression, three of isolation, the sign of reaction formation, and several variants of identification differentiated in the same direction. Reports in which the central figure was too old and changed from a correct to an incorrect sex attribution were highly characteristic of the schizophrenic sample. No defensive variable was significantly linked with nonpsychotic pathology. Two variants, one of regression and one of identification, allowed a correct diagnostic placement for all schizophrenics and for 82.4% of the nonpsychotic patients. The findings, besides being a further clinical validation of the Defense Mechanism Test, provide a preliminary distinction between high- and low-level defenses. It is suggested that they are congruent with an hierarchical model which implies inclusive nonreflexive relationships between classes of mental disorders. ",0
548,1767683,Possible modification of metastasis from adenocarcinoma of the prostate by colchicine: a case report,"Laboratory data indicate that colchicine has an antimetastatic effect in tissue culture and in tumor-transplantation experiments in animals. The present case report reveals a lack of perineural and capsular invasion as well as distant metastases from a large adenocarcinoma of the prostate in a 63-year-old patient who had taken colchicine daily for 25 years prior to lesion discovery. Failure to demonstrate metastasis was unexpected both because of lesion size (estimated volume 4.4 ml) as well as its histopathology (Gleason pattern 3S, grade 6). Colchicine may have inhibited metastasis of activated Ki-ras oncogenes during oncogenesis along neural microtubules in the area because of the known inhibitory effect of this drug on particle transport along the microtubule component of the cytoskeleton. Colchicine at therapeutic doses for gout may simultaneously inhibit metastasis of other types of malignancies in man. ",0
549,1767833,Contribution of adrenergic mechanisms to glucose counterregulation in humans,"To assess the role of adrenergic mechanisms during prolonged hypoglycemia, eight normal subjects were studied on six occasions. In study 1, insulin was infused subcutaneously (15 mU.m-2.min-1 for 12 h), and plasma glucose concentration (PG) decreased from 89 +/- 2 to 50 +/- 1 mg/dl. In study 2 (insulin as in study 1 + propranolol and phentolamine + variable glucose to maintain PG as in study 1), the rate of hepatic glucose production (HGO, [3-3H]glucose) was approximately 30% lower after 1.5 h, and the rate of peripheral glucose utilization (GU) was approximately 15% greater after 5 h. To quantitate the effects of adrenergic mechanisms on glucose counterregulation, in a control study (study 3), glucoregulatory hormone secretion was blocked, and the hormones were reinfused to reproduce study 1. When alpha- and beta-blockade plus variable glucose were superimposed to study 3 (study 4), HGO was approximately 25% lower (after 2 h), and GU was approximately 10% greater (after 6 h) vs. study 3. When glucose was not infused to match PG of study 3 (study 5), severe hypoglycemia developed (PG at 7 h 36 +/- 2 vs. 62 +/- 3 mg/dl). Finally, when glucose was not infused during alpha- and beta-blockade of study 2 (study 6), PG was 49 +/- 3 mg/dl at 7 h vs. 65 +/- 3 mg/dl of the control study (study 1), despite greater secretion of glucagon, growth hormone, and cortisol. It is concluded that adrenergic mechanisms play a key counterregulatory role, even in the presence of appropriate responses of glucagon and that greater increases in glucagon (and other counterregulatory hormones) cannot compensate fully for absent contribution of adrenergic mechanisms to counterregulation. ",0
550,1768490,Monitoring of factor XII activity and granulocyte elastase release during cardiopulmonary bypass,"Monitoring of the influence of cardiopulmonary bypass (CPB) on hematologic parameters is relevant to an improved understanding of the pathophysiology produced, as well as for the development of improved methods. The selection of suitable parameters is highly important. In this study, both contact phase activation and leukocyte response have been studied. Contact activation was determined by a novel assay for the measurement of Factor XII activity (FXIIA), and leukocyte response was measured by the release of granulocyte elastase. Five patients undergoing elective coronary artery surgery using a bubble oxygenator and pulsatile perfusion were studied. A notable feature of this study was the gradual increase of FXIIA during the study period, with granulocyte elastase levels following a similar pattern. Both FXIIA and granulocyte elastase are appropriate parameters for monitoring CPB, and could be useful in studying alternative bypass procedures and antithrombotic agents. ",0
551,1768532,Hydrolysis of substrate analogues catalysed by beta-D-glucosidase from Aspergillus niger. Part II: Deoxy and deoxyhalo derivatives of cellobiose,"The hydrolysis of sixteen mainly deoxy and deoxyhalo derivatives of celloboise catalysed by beta-D-glucosidase from Aspergillus niger has been studied by means of 1H NMR spectroscopy and progress-curve enzyme kinetics in both single-substrate and competition experiments. In the non-reducing ring of cellobiose it was found that the hydroxy groups at positions 2', 3', and 4' are essential for the enzymatic hydrolysis. The primary hydroxy group on 6' in this ring is, although important for the hydrolysis, not essential. The analogues modified at positions 3' and 4' and the 6'-bromo-6'-deoxy derivative were not inhibitors, whereas the 2'-deoxy derivative inhibited the enzymatic hydrolysis of methyl beta-cellobioside to some extent. Of the analogues modified in the reducing ring, some were hydrolysed faster (e.g. the deoxy compounds) and some slower than methyl beta-cellobioside in single-substrate experiments, but all derivatives were hydrolysed at a lower rate than this reference substrate in direct competition and displayed relatively weak inhibitory effects. The results are interpreted qualitatively with respect to changes in the free binding energies of the substrates and catalytic transition states based on the Michaelis-Menten mechanism, and some mechanistic implications of these findings are discussed. ",0
552,1768839,Lysophosphatidylserine-induced activation of mast cells in mice,"Intravenous injection of lysophosphatidylserine (2.5-25 mg/kg) increases the blood histamine level in mice. Lysophosphatidyl-D-serine, alkyl-lysophosphatidylserine and glycerophosphorylserine show little or no activity. As shown by the similar efficacy of the analogue lacking the OH group in the C-2 position of glycerol conversion into phosphatidylserine is not required. The age of mice influences the activity of lysophosphatidylserine. Thus, the increase in blood histamine is greater in adult mice (8-10 weeks) than in young mice (4-6 weeks). In old mice (50-60 weeks) the tolerance to lysophosphatidylserine is reduced. Repeated parenteral administrations induce depletion of histamine stores with concomitant desensitization to lysophosphatidylserine. Well-perfused organs containing connective tissue mast cells (tongue) are more affected. When [3H] histidine is injected into lysophosphatidylserine-treated mice, the highly radioactive histamine detected in the tongue indicates the preservation of histidine decarboxylase activity after degranulation. The data suggest that lysophosphatidylserine specifically activates connective tissue mast cells in mice. ",0
553,1769084,Long-term ECG monitoring (Holter) in a group of healthy 14-to-18-year-old adolescents],"Using 24-hour Holter ECG examinations, the authors assessed ECG changes in a group of 86 healthy students of a Bratislava secondary school. The students were 14-18 years old. Their mean age was 15.8 years. As to ECG changes, the authors evaluated changes of the heart rate, ectopic disorders of the cardiac rhythm and right bundle branch block. Almost in all students the authors detected one or several disorders of the heart rhythm. Extreme changes were recorded in particular in the heart rate, i. e. tachycardia and bradycardia. Sinus arrhythmia was present in 80.2% of the adolescents, right bundle branch block in 57%, and as to ectopic disorders, ventricular extrasystoles were present in 51.2% of the students and supraventricular ones in 34.9%. ",0
554,1769210,The galactan-degrading enzymes in the snail Biomphalaria glabrata,"1. Embryonic snails incorporate from the perivitelline fluid in which they are embedded a polysaccharide, called galactan, which is composed entirely of D-, or D- and L-galactose. In this investigation the p-nitrophenyl-beta-D-galactoside degrading enzyme of Biomphalaria glabrata which was assumed to be involved in the degradation of the galactans was purified almost to homogeneity and its specificity was studied. 2. It has a mol. wt of 135,000 and is composed of two identical subunits. 3. It could be shown that p-nitrophenyl-beta-D-fucoside was hydrolysed eight times faster, but native galactan was neither decomposed nor was it inhibitory for the hydrolysis of p-nitrophenyl-glycosides. 4. Thus, it is most likely that this galactosidase is not involved in the galactan metabolism. 5. However, a membrane-bound enzyme complex was revealed which was able to metabolize the native galactan of Biomphalaria glabrata completely and which showed graded reactivity towards galactans of other species. 6. Since no intermediate degradation products were found it must be assumed that they were metabolized further in the mitochondria. ",0
555,1769657,"The cloned butyrylcholinesterase (BCHE) gene maps to a single chromosome site, 3q26","Human tissues have two distinct cholinesterase activities: acetylcholinesterase and butyrylcholinesterase. Acetylcholinesterase functions in the transmission of nerve impulses, whereas the physiological function of butyryl-cholinesterase remains unknown. An atypical form of butyrylcholinesterase or the absence of its activity leads to prolonged apnea following administration of the muscle relaxant suxamethonium. Inheritance of these butyrylcholinesterase variants is consistent with the enzyme activity being encoded in a single autosomal locus, BCHE (formerly CHE1 and E1), which has been assigned to chromosome 3. Previous in situ hybridization of a BCHE cDNA probe gave evidence of homologous sequences at 3q26 and 16q11-q23, raising the possibility of more than one locus coding for butyrylcholinesterase [H. Soreq, R. Zamir, D. Zevin-Sonkin, and H. Zakut (1987) Hum. Genet. 77: 325-328]. Using a different cDNA probe hybridized in situ to 46,XX,inv(3)(p25q21) metaphase chromosomes, we report here the localization of BCHE to a single autosomal location: 3q26. ",0
556,1770134,CA 125 in peritoneal fluid from patients with endometriosis,"This study was performed to evaluate CA 125 in peritoneal fluid as an indicator of endometriosis. Peritoneal fluid from patients with mostly minimal and mild endometriosis (n = 43) and normal controls (n = 17) was collected at laparoscopy or laparotomy. The median concentration of CA 125 in peritoneal fluid did not differ significantly between patients and controls (79 IU/ml versus 76 IU/ml). In patients with endometriosis, a significantly increasing concentration of CA 125 in peritoneal fluid was seen from the early follicular to the late luteal phase; a similar change was not observed in the controls. In 14 patients, peritoneal fluid was sampled again after treatment with danazol and a significant reduction in median CA 125 concentration (76.5 IU/ml versus 57 IU/ml), peritoneal fluid volume (17.5 ml versus 10.5 ml) as well as reduced endometriosis scores (4 versus 2) were found. In controls, the concentration of CA 125 was about 10 times higher in peritoneal fluid than in serum. As the peritoneal levels of CA 125 did not differ significantly between patients with endometriosis and controls and as the reduction seen after danazol treatment did not correlate with the decrease of endometriotic implants, it is concluded that the monitoring of CA 125 in peritoneal fluid will not be useful in the diagnosis or control of endometriosis. ",0
557,1770176,The ultrastructural diversity of scrapie-associated fibrils isolated from experimental scrapie and Creutzfeldt-Jakob disease,"Several different samples of scrapie-associated fibrils (SAF) were extracted in identical fashion from the brains of golden Syrian hamsters infected with the 263K strain of scrapie agent and NIH Swiss mice infected with the Fujisaki strain of Creutzfeldt-Jakob disease (CJD) agent. Based on a total of over 500 measurements in individual fibrils in different extracts, hamster fibrils were more abundant, thicker and had better defined substructure than mouse fibrils. Hamster protofibrils were usually either twisted helically or in parallel arrays, whereas mouse protofibrils were often twisted, occasionally parallel, or could not be morphologically defined. Thus, SAF preparations from scrapie-affected hamsters can be ultrastructurally distinguished from those of CJD-affected mice, an observation that presumably reflects differences in their respective host-encoded amyloid protein subunits. ",0
558,1770747,Transplantation of the heart-lung complex (the first clinical experience)],"The article deals with experience in the first transplantation of a heart-lung complex in the USSR. The recipient was a 34-year-old male with dilation cardiomyopathy. It was decided to perform the transplantation because the terminal stage of cardiac failure and secondary pulmonary hypertension developed (cardiac index 1.3 l/m, pressure in pulmonary artery 80/50 mm Hg, resistance of pulmonary vessels 10.4 units after Wood). The heart and lung were transplanted from a 19-year-old male who died from a craniocerebral injury. Cyclosporine, metipred , imuran, dopamine in small doses, cardiotonics, and antibiotics were given in the postoperative period; the patient was kept on artificial respiration for 48 hours. For up to 10 days the patient's condition was relatively stable and his consciousness was clear. Bilateral pneumonia developed, however, from which he died on the 12th postoperative day. The article discusses organizational problems and some questions of immunosuppressive therapy, immunological monitoring, and the management of patients after transplantation of a heart-lung complex. ",0
559,1770756,"Acid-base equilibrium, blood gases and glycolysis during modeling of the factors of extravehicular activities]","The effect of factors simulating extravehicular activities (lower barometric pressure, 100% oxygen breathing, physical load on the upper body, head-down body position) on blood gas composition, acid-base equilibrium, and glycolysis end-products was investigated in 17 test subjects. It was found that 5-hour exposure did not change physiological responses to test workloads, when compared to the baseline studies. In the simulation studies, changes in acid-base equilibrium of venous blood were more significant than those of mixed capillary blood. The variations of the parameters under study reflected primarily the effect of hyperoxia on metabolic processes. The head-down position affected the level of variations in gas composition and acid-base equilibrium of venous blood. These changes were transient and rapidly returned to the norm after termination of the exposure. ",0
560,1770964,National survey of problems and competencies among four- to sixteen-year-olds: parents' reports for normative and clinical samples,"We compared parent-reported problems and competencies for national samples of 2,600 4-16-year-olds assessed at intake into mental health services and 2,600 demographically matched nonreferred children assessed in a home interview survey. Parents responded to the ACQ Behavior Checklist, which includes 23 competence items, three competence scales, 216 problem items, eight syndrome scales, Internalizing, Externalizing, and total competence and problem scores. Most items and scales discriminated significantly (p less than .01) between referred and nonreferred samples. There were important sex and age differences in problem patterns, but regional and ethnic differences were minimal. Somewhat more problems and fewer competencies were reported for lower- than upper-socioeconomic-status children. Referral rates were similar in the most urban and rural areas, but they were significantly higher in areas of intermediate urbanization. Correlations of problem scores with those obtained 10 years earlier in a regional survey and with surveys in other countries showed considerable consistency in the rank order of prevalence rates among specific problems. Apparently owing to its more differentiated response scales, the ACQ was susceptible to respondent characteristics that reduced its discriminative power below that of the Child Behavior Checklist. Comparisons of procedures for discriminating between the normal and the clinical range supported the value of a borderline category for children who are neither clearly normal nor clearly deviant. Interview data from the survey sample yielded significantly higher ACQ problem scores for children who had fewer related adults in their homes, those who had more unrelated adults in their homes, those whose biological parents were unmarried, separated, or divorced, those whose families received public assistance, and those whose household or family members had received mental health services. Children who scored higher on Externalizing than Internalizing problems tended to have unmarried, separated, or divorced parents and to come from families receiving public assistance. However, among children whose household or family members had received mental health services, there were greater proportions of both Externalizing and Internalizing patterns than among other children. ",0
561,1771175,Effect of beta-alanyl-L-histidinato zinc on osteoblastic MC3T3-E1 cells: increases in alkaline phosphatase and proliferation,"The effect of beta-alanyl-L-histidinato zinc (AHZ) on bone metabolism was investigated in osteoblastic MC3T3-E1 cells. Cells were cultured for 3 days at 37 degrees C in a CO2 incubator in plastic dishes containing alpha-modified minimum essential medium supplemented with 10% fetal bovine serum. After the cultures, the medium was exchanged for that containing 0.1% bovine serum albumin plus various concentrations of AHZ or zinc sulfate, and the cells were cultured further for appropriate periods of time. The presence of AHZ (10(-6)-10(-4) mol/l) stimulated proliferation of cells. AHZ increased alkaline phosphatase activity in a dose-related manner up to 10(-5) mol/l; the increase was about 2-fold over the control value. Studies on the effect of actinomycin D or cycloheximide treatment indicated that AHZ may enhance de novo synthesis of the enzyme. AHZ also increased deoxyribonucleic acid (DNA) content dose dependently (10(-6)-10(-4) mol/l). This increase was completely blocked by treatment with cycloheximide. The AHZ (10(-5) mol/l)-induced increases in alkaline phosphatase activity and DNA content were entirely abolished by the presence of dipicolinate (10(-4) mol/l), a chelator of zinc, indicating that the effect of AHZ needs zinc. However, AHZ had a potent effect, more than that of zinc sulfate, on alkaline phosphatase activity and DNA content. The present results indicate that AHZ has a direct specific anabolic effect on osteoblastic cells in vitro and that this effect is related to protein synthesis. ",0
562,1771267,Screening radon risks: a methodology for policymakers,"This paper provides an easy-to-use screening methodology to estimate potential excess lifetime lung cancer risk resulting from indoor radon exposure. The methodology was developed under U.S. EPA Office of Policy, Planning, and Evaluation sponsorship of the agency's Integrated Environmental Management Projects (IEMP) and State/Regional Comparative Risk Projects. These projects help policymakers understand and use scientific data to develop environmental problem-solving strategies. This research presents the risk assessment methodology, discusses its basis, and identifies appropriate applications. The paper also identifies assumptions built into the methodology and qualitatively addresses methodological uncertainties, the direction in which these uncertainties could bias analyses, and their relative importance. The methodology draws from several sources, including risk assessment formulations developed by the U.S. EPA's Office of Radiation Programs, the EPA's Integrated Environmental Management Project (Denver), the International Commission on Radiological Protection, and the National Institute for Occupational Safety and Health. When constructed as a spreadsheet program, the methodology easily facilitates analyses and sensitivity studies (the paper includes several sensitivity study options). The methodology will be most helpful to those who need to make decisions concerning radon testing, public education, and exposure prevention and mitigation programs. ",0
563,1771597,Toxicity of sera from individuals with Chagas' disease to cultured rat embryos: role of antibodies to laminin,"In previous studies antilaminin antibodies in the sera of immunized monkeys and rats were found to be toxic to cultured rat embryos. In order to extend these studies to humans, head-fold stage rat embryos were cultured for 48 hours on ten different serum samples from individuals with Chagas' disease. All embryos (n = 20) cultured on these sera were found to be abnormal. Using ELISA, Western immunoblot, and indirect immunofluorescence it could be shown that antibodies in these sera reacted with laminin. That these antilaminin antibodies were, at least in part, responsible for the toxicity was indicated 1) by reduced cultured embryo toxicity for six of seven serum samples after pre-absorption with purified laminin, 2) by demonstrating a relationship between the amount of affinity-purified antilaminin IgG added to control serum for culture and the severity of embryo abnormalities seen at the end of culture, and 3) by the sera's failing to react with other basement membrane proteins, including type IV collagen, fibronectin, osteonectin, and heparan sulfate proteoglycan. ",0
564,1771614,The effect of lysed platelets on neutralization of heparin in vitro with protamine as measured by the activated coagulation time (ACT),"""The effect of lysed platelets on the activated coagulation time (ACT) was studied in heparinized whole blood during titration with protamine. Frozen-thawed washed platelet suspension, or a chromatography fraction thereof, or autologous frozen-thawed platelet-rich plasma was added in various dilutions to freshly drawn blood anticoagulated with 3,000 USP units/l heparin. After a 10 min incubation, the amount of protamine needed to restore the ACT to baseline (""""protamine titration dose"""") was determined. We found that the protamine titration dose decreased in proportion to the amount of lysed platelet material added; expressed as a percentage of the total number of platelets present, each unit increase in lysed platelets produced a 1.7% +/- 0.8 (SD) reduction in the protamine dose needed to normalize the ACT. A heparin activity assay showed that this effect was not due to anti-heparin activity of lysed platelets such as platelet factor 4 (PF4). Our data indicate that the procoagulant activity of platelet membranes reduced the sensitivity of the ACT to heparin. These findings suggest that membranous platelet microparticles may cause an inaccurate calculation, based on the ACT, of a protamine dose to reverse heparin anticoagulation in cardiopulmonary bypass procedures. """,0
565,1772296,Effect of misoprostol on concentrations of prostaglandins in synovial fluid,"The effect of misoprostol, a synthetic analogue of prostaglandin E, on prostaglandin concentrations in synovial fluids was investigated in a randomised placebo controlled, double blind study. The synovial fluid concentrations of prostaglandin E1, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were measured at the beginning and end of a 24 hour period in 25 patients with effusions of the knee joint. During this period the patients were treated with diclofenac (50 mg every eight hours) and either misoprostol (400 micrograms) or placebo every 12 hours. The concentrations of prostaglandin E and 6-keto-prostaglandin F1 alpha were not significantly altered during treatment. There was an unexpected significant reduction in thromboxane B2 concentrations in the group treated with misoprostol (within group analysis). Although the mean concentration with misoprostol was about half the mean concentration with placebo, this difference was not statistically significant in the between group analysis. These results indicate that misoprostol is unlikely to exert a proinflammatory effect or to interfere with the prostaglandin mediated effects of non-steroidal anti-inflammatory drugs. The significant decrease in thromboxane B2 concentrations in the misoprostol treated group suggests that misoprostol may exert an anti-inflammatory effect. ",0
566,1772331,Salicylate binding by human albumin in the presence of a perfluorochemical emulsion,"The binding of 43 and 216 micrograms/ml sodium salicylate by a perfluorochemical emulsion, by human albumin, and by their mixtures, has been examined at ambient room temperature. Sodium salicylate was chosen as a model drug since it is bound by both sites I and II on human albumin. The concentration of free salicylate was determined through standard centrifugation followed by supernatant ultrafiltration. Sodium salicylate was weakly bound by the perfluorochemical emulsion droplets through an interaction with the emulsifiers. This binding was independent of salicylate concentration. Sodium salicylate was also bound by human albumin and the per cent free salicylate was dependent on both drug and albumin concentration. Relative to salicylate binding by 4% human albumin, addition of the emulsion to 4% human albumin resulted in an increase in the per cent free salicylate in all mixtures examined. The addition of equal or greater volumes of the emulsion to 4% human albumin resulted in the direct and/or indirect displacement of albumin bound salicylate in addition to the protein dilution effect. This displacement of albumin bound salicylate was due to the oleic acid component of the emulsion. ",0
567,1772533,Simultaneous delivery of valproic acid and glycine to the brain. Deamination of 2-propylpentylglycinamide by monoamine oxidase B,"2-Propylpentylglycinamide (2-PPG), a branched aliphatic amine derivative, was found to be readily deaminated by rat liver monoamine oxidase B in vitro and in vivo. The deamination leads to production of 2-propyl-1-pentaldehyde, which can be subsequently converted to valproic acid (VPA), and glycinamide, which is then subsequently converted to glycine. Absorption and biotransformation of a single ip dose of 2-PPG into blood as well as transfer of the drug and its metabolite into the brain were rapid processes. Although VPA (an anticonvulsant) and glycine (an inhibitory neurotransmitter) can be detected in the brain following administration of 2-PPG, its anticonvulsant action cannot be determined. 2-PPG at relatively low doses exhibited distinct tremor effects. Furthermore, 2-PPG appeared to potentiate the convulsant effect induced by pentylenetetrazol. ",0
568,1772727,Hematomas and subcutaneous suture techniques in total hip replacement. An ultrasound study,"Thirty-five patients undergoing total hip replacement due to primary arthrosis were randomized into two groups. In one group each subcutaneous suture included a stitch in the fascia; in the other group the fascia was not included in the suture. Ultrasonography examination showed no significant difference in the number of subcutaneous hematomas in each group. Nine subcutaneous and nine deep hematomas were diagnosed by ultrasound in 15 patients. Three patients had a clinical diagnosis of hematoma and in only one of these did ultrasonography support the diagnosis. It appears that the clinical diagnosis of hematomas, even subcutaneous hematomas, is unreliable. Careful hemostasis is recommended. ",0
569,1772849,Molecular mechanics of the formation of cholic acid micelles,"The molecular mechanics of cholic acid micelle formation were simulated using the Sybyl energy minimization program (MAXIMIN2), developed by Tripos Associates, interfaced with micro-Vax. Before energy minimization, the molecular dimensions of the cholic acid dodecamer C24H40O6, in terms of the unit cell axes a, b, and c in the cubic crystal class, had values of 13, 18, and 6.7 A, respectively. After energy minimization, at 9370 kcals/dodecamer, these values had increased to 21.6, 42.8 and 20.9 A. At an energy minimization level of 21,626 kcals/dodecamer, the micelle structure is stabilized by hydrophobic interaction, forming distinct horizontal channels along the b-axis, directing the carboxyl and hydroxyl groups toward the surface. These structural changes remain relatively constant as the process of energy minimization continues, down to the lowest energy level we considered, 9370 kcals/dodecamer. The cholic acid layers are highly dissimilar, forming channels of irregular size and shape in a somewhat helical structure. The carboxyl groups and phenanthrene rings are in a puckered orientation, which permits compact packing of the sandwiched multilayers. From the dimension of the channels, it is apparent that guest molecules, such as phospholipid, cholesterol, or inorganic calcium, can be incorporated into the micelle through more than one channel, forming inclusion complexes, such as gallstones. ",0
570,1773126,Effect of N-acetyl-D-glucosamine on the migration of Brugia pahangi microfilariae into the haemocoel of Aedes aegypti,"Two strains of Aedes aegypti (L.), differing in their susceptibility to Brugia pahangi (Buckley & Edeson), were examined with regard to the effect on the proportion of microfilariae migrating from the mid-gut, of specific carbohydrate supplements in the infecting bloodmeal. N-Acetyl-D-glucosamine (GlcNAc), a sugar also present on the microfilarial sheath, significantly increased the migration rate. This enhancement is greater for the refractory strain of Ae.aegypti. The use of sucrose as a control sugar results in no enhancement of microfilariae migration. It is postulated that the GlcNAc is acting by blocking endogenous gut/peritrophic membrane carbohydrate binding proteins, which would normally inhibit microfilariae migration. Furthermore, there is a significant correlation whereby increasing loads of microfilariae ingested result in decreasing proportions migrating across the mid-gut. ",0
571,1773268,The chest X ray in Q-fever: a report on 69 cases from the 1989 West Midlands outbreak,"Acute and serial chest radiographic appearances of Q-fever in a large UK outbreak in the West Midlands are described. In 69 acute films (taken within 20 days of onset of illness), 10% of films were normal. Appearances in 62 abnormal films were varied and, in contrast to some previous reports, showed no features that might distinguish Q-fever pneumonia from pneumonias of other origins. Analysis of serial films in 47 cases showed that complete radiographic resolution frequently took up to 6 months, longer than has been described previously. Initial appearances deteriorated over the first 2 weeks of radiographic surveillance in 20% of cases. No relationship was found between the extent of radiographic change and the age of the patient or the presence or absence of respiratory symptoms. Age did not affect time to resolution. ",0
572,1773296,"Erectile response to visual erotic stimuli before and after intracavernosal papaverine, and its relationship to nocturnal penile tumescence and psychometric assessment","""Three methods of assessing erectile capacity--nocturnal penile tumescence (NPT), response to visual erotic stimuli (VES) and to intracavernosal papaverine (ICI)--have been assessed in 42 men presenting with erectile dysfunction. There was some overlap but also important differences between the 3 measures. Subjects were divided into """"high"""" and """"low"""" NPT groups. The """"high"""" group produced greater erectile responses to both VES and ICI. The combination of VES and ICI was the best discriminator of the two NPT groups, and may be of diagnostic value, particularly in younger men, reducing the need for repeated injections and higher doses of papaverine. In the """"low"""" NPT group, presumed predominantly organic, the ICI response correlated better than the VES response with NPT. In the """"high"""" NPT group, the opposite applied, suggesting that in """"psychogenic"""" cases, response to ICI may be modified by psychological mechanisms which could be of aetiological importance and which deserve further study. These three methods should be regarded as measuring different aspects of erectile function and not as alternative diagnostic procedures. More research is required before their respective diagnostic values are established. """,0
573,1773441,Characterization of extracellular binding sites for [3H]-staurosporine on capillary endothelial cells,"[3H]-staurosporine, a non-specific protein kinase inhibitor, bound with high affinity and in a reversible manner to specific and saturable binding sites in cultured bovine cerebral cortex capillary endothelial cells. Scatchard analysis revealed the presence of one class of non-interacting binding sites with an equilibrium dissociation constant (KD) of 9.2 nM and Bmax of 19.3 fmol/10(5) cells. The binding of [3H]-staurosporine was fully displaced by unlabelled staurosporine, H-7 and ATP with IC50 values of 6.9 nM, 3 microM and 0.4 microM respectively. Mild trypsinization of cells after [3H]-staurosporine binding revealed the presence of membrane-associated, extracellular binding sites which could be an ecto-protein kinase. ",0
574,1773964,Wilson's disease in Scotland,"The prevalence and clinical features of Wilson's disease in Scotland were investigated. Thirty three cases were identified but adequate information was available on only 28. In 1989, the prevalence rate was 4 per million. Ten patients with a mean (SEM) age of 18 (1.9) years presented with neurological symptoms, 12 patients aged 14 (1.7) years presented with hepatic symptoms, and six patients aged 12 (0.9) years were asymptomatic siblings of patients with Wilson's disease. Nine (56%) of the 16 patients who underwent liver biopsy on presentation were found to have cirrhosis. Penicillamine treatment was stopped in nine patients because of: abnormal peripheral blood count (6), rash (2), and patient's own choice (1). Nineteen patients were alive in 1989 -12 were well, one had chronic liver failure, four chronic neurological disabilities, and two had both chronic liver failure and neurological disabilities. Twelve patients died from: complications of chronic liver failure (2), acute liver failure (4), pneumonia associated with immobility (4), and other causes (2). Several patients who died had received incomplete medical supervision. ",0
575,1774018,Insulin clearance during hypoglycemia in patients with insulin-dependent diabetes mellitus,"Eight male patients with insulin-dependent diabetes mellitus (IDDM) without residual beta-cell function were studied on two occasions in random order. In one experiment hypoglycemia was induced by a constant rate iv infusion of insulin (0.034 U/kg/h) during 150 minutes. At the other occasion an identical infusion of insulin was given, but this time euglycemia was maintained by a variable iv infusion of glucose. Plasma levels of free insulin were almost identical during the two experiments indicating that insulin clearance is not influenced by hypoglycemia in patients with IDDM. ",0
576,1774027,An experimental study on hepatic arterial embolization with 131I-MMC-GM],"We designed a new gelatin microsphere (GM, 65 micron in diameter), which could combine with mitomycin C and 131I. The test in vitro showed that the GM had excellent drug release effect. Hepatic arterial embolization was carried out in 6 dogs with 131I-MMC-GM. The dogs survived from 4 to 28 days before being killed. Scintigraphy indicated that high radioactivity was concentrated in the liver, but was very low in the blood and thyroid. Pathologic study found that the GM was trapped in hepatic arterioles. The GM was eliminated by foreign body giant cells and the lumen of arterioles was occupied by granulations 14-28 days after operation. 131I-MMC-GM is a multiple anticancer agent which can exert triple action of targeting chemotherapy, internal radiotherapy and arterial embolization. ",0
577,1774133,Evaluation of NK and LAK cell activities in neoplastic patients during treatment with morphine,"The cytotoxic activity of Natural Killer (NK) and Lymphokine Activated Killer (LAK) cells in neoplastic patients with or without antalgic treatment was studied. NK cell activity was found reduced in untreated neoplastic patients when compared to healthy subjects. The atalgic treatment with morphine (orally or intrathecally administered) was able to significantly reduce the mean values of NK cell activity found in cancer patients. In three patients the cytotoxicity of NK cells significantly decreased during transfer from oral to intrathecal administration of morphine. In contrast to the NK cell function, the development of LAK cell activity significantly increased in neoplastic patients when compared to healthy controls. Further increments were obtained during treatment with morphine. The oral treatment with morphine was able to determine a higher induction of LAK cells than the intrathecal administration of the drug. Besides providing new knowledge on the effect of morphine on immune system our findings suggest that, in order to include neoplastic patients in clinical trials of adoptive immunotherapy with LAK cells and interleukin-2 (IL-2), the antalgic therapy with oral administration of morphine may represent a better solution than the intrathecal administration of the drug. ",0
578,1774722,Stage I endometrial carcinoma. Role of omental biopsy and omentectomy,"A prospective, routine histologic assessment of the omentum during primary surgery was conducted on 84 women with stage I endometrial carcinoma between February 1986 and June 1989. The purpose of the study was to determine the true incidence of omental involvement in early endometrial cancer and to detect risk variables associated with such metastases. Omental metastases were found in 7 (8.3%) of 84 patients with stage I endometrial carcinoma. A majority of the metastases (five) consisted of microscopic disease. Factors statistically significantly associated with omental metastasis were adnexal spread, cul-de-sac implantation, papillary serous carcinoma, a positive retroperitoneal lymph node and grade 3 tumor. The study indicated that silent metastases to the omentum frequently are neglected clinically in patients with stage I endometrial carcinoma during primary surgery and that a routine omental biopsy should be part of the procedure. Furthermore, for patients with high-risk variables, a complete omentectomy ought to be considered. ",0
579,1774957,Immunoreactivity of leukemic lymphoblasts of T-cell and B-cell precursor origin with monoclonal anti-GD3 and anti-GM3 antibodies,"The glycosphingolipids GD3, GM3, and alpha 2, 3-sialosylparagloboside (SPG) are major gangliosides of lymphoid leukemia cells. The reactivity of two monoclonal anti-ganglioside antibodies, an anti-GD3 (R24) and an antibody cross-reactive to GM3 and SPG (M2590), to blasts of patients with T-cell acute lymphoblastic leukemia (ALL) and B-cell precursor ALL (pre-B-ALL), were compared using indirect immunofluorescence and flow cytometry. Results from 23 patients with T-ALL and eight with pre-B-ALL yielded four subclasses of T-ALL and two subclasses of pre-B-ALL. Blasts from most of the patients with T-ALL were R24+M2590- whereas most of the patients with pre-B-ALL were R24-M2590-. Seven of 23 patients with T-ALL had ganglioside immunophenotypes similar to that of pre-B-ALL, i.e. R24-M2590- or R24-M2590+. These subclasses could not be further characterized by additional cell surface immunophenotypic markers or by gene (immunoglobulin and T-cell receptor) rearrangement analysis. The ratio R24/M2590 was less than 1.0 in all patients with pre-B-ALL, and was greater than 1.0 in all patients with T-ALL who were R24 positive, but was not useful in characterizing the double negative T-ALL subclass. To assess whether cryptogenicity of gangliosides due to cell surface protein could account for the low binding of either R24 or M2590, blasts were treated with trypsin before antibody analysis. Whereas the binding of R24 was unchanged after trypsin treatment, binding of M2590 was increased in a number of samples, particularly in those samples which were originally M2590-positive. The results show that comparative staining of T-ALL and pre-B-ALL cells with both anti-GD3 and anti-GM3/SPG antibodies results in a further subclassification of ALL and provides a quantitative assessment of the expression of tumor-associated gangliosides on the blasts of this disease. ",0
580,1775085,How do androgens affect episodic gonadotrophin secretion in postmenopausal women?,"In the absence of any significant ovarian oestrogen secretion, as in post-menopausal women, the hypothalamic-pituitary axis may still be influenced by the androgens which continue to be produced. The episodic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by postmenopausal women was accordingly assessed following short-term androgen antagonism induced by flutamide, a specific androgen receptor blocker. Blood samples were collected at 10-min intervals for 10 h in nine women before and during flutamide administration (750 mg/day for 6 days) for the determination of gonadotrophin and sex hormone concentrations by radioimmunoassay. On both occasions, 25 micrograms of gonadotrophin-releasing-hormone (GnRH) was injected intravenously 8 h after initiation of the blood collections. Flutamide administration decreased (P less than 0.01 or less) androgen concentrations (testosterone, androstenedione and dehydroepiandrosterone sulphate) in relation to baseline values, but did not alter oestrogen (oestrone and oestradiol) or sex-hormone-binding globulin levels. The LH and FSH pulse characteristics (frequency, amplitude, interpulse interval and transverse mean levels) determined by a cluster algorithm in the gonadotrophin secretory profiles did not differ before and during androgen blockade. By contrast, androgen antagonism increased LH (P less than 0.01) and tended to enhance FSH (P = 0.10) FSH release in response to GnRH stimulation. Hence, short-term androgen receptor blockade with flutamide did not greatly affect episodic gonadotrophin secretion. However, the combined evidence of the enhanced gonadotrophin release observed in response to GnRH stimulation and the unchanged gonadotrophin secretion during androgen antagonism suggests that alterations in the magnitude, but not the frequency, of hypothalamic GnRH release had occurred. Even in the presence of substantial serum androgen concentrations, the gonadotrophin pulse rhythm in hypogonadal women constitutes the maximal-rate GnRH-LH release pattern. ",0
581,1775136,A shared promoter element regulates the expression of three steroidogenic enzymes,"The adrenal cortex of the mouse coordinately expresses three cytochrome P450 enzymes that are required for the biosynthesis of corticosteroids: cholesterol side-chain cleavage enzyme (SCC), steroid 21-hydroxylase (21-OHase), and steroid 11 beta-hydroxylase (11 beta-OHase). Within their 5'-flanking regions, we previously identified six elements containing variations of an AGGTC motif that regulated expression in mouse Y1 adrenocortical cells: 21-OHase elements at -210, -140, and -65; SCC elements at -70 and -40; and an 11 beta-OHase element at -310. We demonstrate here that all six elements interact with the same, or closely related, DNA-binding protein(s). First, these elements all formed complexes of similar mobility in gel shift assays, suggesting that they interacted with protein(s) of similar size. Additional larger complexes were seen with those probes containing exact AGGTCA sequences. Second, competition experiments confirmed that the factor(s) interacting with different elements had closely related or identical recognition specificities. Finally, indistinguishable profiles of shift activities were seen upon fractionation of nuclear proteins over sequential chromatographic columns. Collectively, these results suggest that related elements interact with a shared protein to regulate three essential steroidogenic enzymes. An AGGTCA sequence motif comprises the response element for several members of the nuclear hormone receptor family. Oligonucleotide competitions and specific effects of antisera in gel shift assays implicated chicken ovalbumin upstream promoter-transcription factor in the formation of the larger complexes seen with the elements containing exact AGGTCA sequences. Therefore, this member of the nuclear hormone receptor family also may regulate the expression of the adrenal steroidogenic enzymes. ",0
582,1775168,Dirofilaria immitis superoxide dismutase: purification and characterization,"Superoxide dismutase (SOD) was purified to apparent homogeneity from Dirofilaria immitis, the causative agent of Dog Heartworm disease which is prevalent in the Southeastern United States. The enzyme has a molecular weight of 18,000 under denaturing conditions with an isoelectric point of 5.6. Both values are similar to those found for previously purified helminth SODs. The amino acid analysis shows greater similarity with mammalian SODs than with the published Schistosoma mansoni SOD, probably because the S. mansoni enzyme appears to be an extracellular, not a cytosolic, SOD. Although SOD activity is easily detected in D. immitis homogenates, the hydrogen peroxide scavenging activities of catalase and glutathione peroxidase were below the limits of our assay. This suggests that D. immitis primary defense against oxidants may be SOD. We feel that this line of research may provide valuable insights into a vulnerable area of D. immitis that may be a good target for drug therapy. ",0
583,1824720,The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes,"BACKGROUND: In some highly trained athletes, the thickness of the left ventricular wall may increase as a consequence of exercise training and resemble that found in cardiac diseases associated with left ventricular hypertrophy, such as hypertrophic cardiomyopathy. In these athletes, the differential diagnosis between physiologic and pathologic hypertrophy may be difficult. METHODS: To address this issue, we measured left ventricular dimensions with echocardiography in 947 elite, highly trained athletes who participated in a wide variety of sports. RESULTS: The thickest left ventricular wall among the athletes measured 16 mm. Wall thicknesses within a range compatible with the diagnosis of hypertrophic cardiomyopathy (greater than or equal to 13 mm) were identified in only 16 of the 947 athletes (1.7 percent); 15 were rowers or canoeists, and 1 was a cyclist. Therefore, the wall was greater than or equal to 13 mm thick in 7 percent of 219 rowers, canoeists, and cyclists but in none of 728 participants in 22 other sports. All athletes with walls greater than or equal to 13 mm thick also had enlarged left ventricular end-diastolic cavities (dimensions, 55 to 63 mm). CONCLUSIONS: On the basis of these data, a left-ventricular-wall thickness of greater than or equal to 13 mm is very uncommon in highly trained athletes, virtually confined to athletes training in rowing sports, and associated with an enlarged left ventricular cavity. In addition, the upper limit to which the thickness of the left ventricular wall may be increased by athletic training appears to be 16 mm. Therefore, athletes with a wall thickness of more than 16 mm and a nondilated left ventricular cavity are likely to have primary forms of pathologic hypertrophy, such as hypertrophic cardiomyopathy.",0
584,1829139,Evidence of limited variability of antigen receptors on intrathyroidal T cells in autoimmune thyroid disease,"BACKGROUND: Patients with autoimmune thyroid diseases, including Graves' disease and Hashimoto's disease, have marked lymphocytic infiltration in their thyroid glands. We examined the gene for the variable regions of the alpha-chain of the human T-cell receptor (the V alpha gene) in intrathyroidal T cells to determine whether the infiltration is a secondary heterogeneous immune response or a more restricted, and therefore primary and presumably pathogenetic, reaction to thyroid autoantigens. METHODS: We used the polymerase chain reaction to detect small numbers of T cells expressing the variable region of the V alpha gene. Different oligonucleotides were used to amplify complementary DNA for the 18 known families of the V alpha gene in intrathyroidal T cells from 9 patients with autoimmune thyroid disease. We compared the findings with the results in patients with nonautoimmune thyroid disease as well as those in normal subjects. RESULTS: We found marked restriction in the expression of T-cell-receptor V alpha genes by T cells from the thyroid tissue of patients with autoimmune thyroid disease. An average of only 5 of the 18 V alpha genes were expressed in such samples, as compared with 17 V alpha genes expressed in peripheral-blood T cells from the same patients. No such restriction was found in thyroid tissue from patients with nonautoimmune thyroid disease. The predominantly expressed V alpha genes differed from patient to patient, however, with no clear association with the type of disease. CONCLUSIONS: Intrathyroidal T-cell accumulation in autoimmune thyroid disease is highly restricted and points to the primacy of T cells in causing thyroid disorders. These results present the possibility of using antibodies to the T-cell receptor for the specific inhibition of abnormal T-cell function in autoimmune thyroid disease.",0
585,1831438,Localization of hepatocyte growth factor in human and rat tissues: an immunohistochemical study,"Hepatocyte growth factor is a protein growth factor with a strong mitogenic effect on hepatocytes. Recently, hepatocyte growth factor and hepatocyte growth factor messenger RNA have been extracted from several organs of humans, rats and rabbits. This study was undertaken to comprehensively define and compare the cellular localization of hepatocyte growth factor in human and rat tissues in detail. Paraffin-embedded sections and frozen sections were examined by immunohistochemistry using a polyclonal antiserum to hepatocyte growth factor. The distribution of hepatocyte growth factor was almost identical in humans and rats. Strong or moderate cytoplasmic immunoreactivity for hepatocyte growth factor was present in most surface epithelia, distal tubules and collecting ducts of the kidneys, large neurons, megakaryocytes, granulocytes, exocrine pancreas, salivary glands, prostate, epididymis and trophoblast. Varying degrees of immunoreactivity were observed in endothelial cells, chondrocytes and macrophages. We conclude that hepatocyte growth factor is widely distributed in numerous tissues and cell types independent of their regenerative activity. This suggests that hepatocyte growth factor may have mitogenic and/or trophic effects on multiple cell types in addition to hepatocytes.",0
586,1834940,The diagnostic performance of computer programs for the interpretation of electrocardiograms,"BACKGROUND: Computer programs for the interpretation of electrocardiograms (ECGs) are now widely used. However, a systematic assessment of various computer programs for the interpretation of ECGs has not been performed. METHODS: We undertook a large international study to compare the performance of nine electrocardiographic computer programs with that of eight cardiologists in interpreting ECGs in 1220 clinically validated cases of various cardiac disorders. ECGs from the following groups were included in the sample: control patients (n = 382); patients with left ventricular hypertrophy (n = 183), right ventricular hypertrophy (n = 55), or biventricular hypertrophy (n = 53); patients with anterior myocardial infarction (n = 170), inferior myocardial infarction (n = 273), or combined myocardial infarction (n = 73); and patients with combined infarction and hypertrophy (n = 31). The interpretations of the computer programs and the cardiologists were compared with the clinical diagnoses made independently of the ECGs, and the computer interpretations were compared with those of the cardiologists. RESULTS: The percentage of ECGs correctly classified by the computer programs (median, 91.3 percent) was lower than that of the cardiologists (median, 96.0 percent; P less than 0.01). The median sensitivity of the computer programs was also significantly lower than that of the cardiologists in diagnosing left ventricular hypertrophy (56.6 percent vs. 63.9 percent, P less than 0.02), right ventricular hypertrophy (31.8 percent vs. 46.6 percent, P less than 0.01), anterior myocardial infarction (77.1 percent vs. 84.9 percent, P less than 0.001), and inferior myocardial infarction (58.8 percent vs. 71.7 percent, P less than 0.0001). The median total accuracy level (the percentage of correct classifications) was 6.6 percent lower for the computer programs (69.7 percent) than for the cardiologists (76.3 percent; P less than 0.001). However, the performance of the best programs nearly matched that of the most accurate cardiologists. CONCLUSIONS: Our study shows that some but not all computer programs for the interpretation of ECGs perform almost as well as cardiologists in identifying seven major cardiac disorders.",0
587,1846342,Significance of natural polymerized albumin and its receptor in hepatitis B infection of hepatocytes,"Lack of information regarding the presence of native albumin polymer in serum and its structural similarity to the one produced by glutaraldehyde treatment casts doubt on the postulate that hepatitis B virus attachment to hepatocytes is mediated through polymerized albumin. We used a sandwich enzyme-linked immunosorbent assay with murine monoclonal antibodies raised against glutaraldehyde-polymerized albumin to detect native albumin polymer in human serum and its cross-reactivity with other albumin polymers. Presence of polymerized albumin receptor on the HepG2 cell was studied by radioreceptor assay. Purified hepatitis B virus and synthetic peptide analogous to part of pre-S2 sequence (120-145) were used to study polymerized albumin-dependent attachment of the virus to HepG2 cells. Antibodies raised against pre-S2 peptide were used to inhibit the pre-S2 and hepatitis B virus attachment to HepG2 cells. Glutaraldehyde-treated polymerized albumin was found to be immunologically cross-reactive with native albumin polymer. Its levels were found to be significantly raised in sera of patients with liver diseases. Polymerized albumin has specific saturable receptor on HepG2 cells with two classes of binding sites of different equilibrium dissociation constant (Kd1 = (16 +/- 9.6)pmol/L and Kd2 = (1,019 +/- 172)pmol/L. Albumin monomer was unable to compete for the polymerized albumin receptor sites on HepG2 cells. Anti-pre-S2 antibodies inhibit hepatitis B virus and pre-S2 binding to hepatocyte by 40% and 70%, respectively. Added extraneous polymerized albumin and the antibody against it did not interfere with virus attachment to HepG2 cells.",0
588,1846347,Antibodies in anti-HBe-positive patient sera bind to an HBe protein expressed on the cell surface of human hepatoma cells: implications for virus clearance,"The relevance of the recently described membrane-bound form of the HBe protein for the antiviral immune response was examined. The data show that antibodies in anti-HBe, but not in anti-HBc-positive human sera efficiently bind to the membrane expressed HBe. No evidence was obtained that the HBc can reach the cell surface in a form that can be detected with human antibodies. The findings suggest that the decline of virus titer that is usually observed after seroconversion from HBe to anti-HBe might be the result of an antibody-mediated elimination of infected cells.",0
589,1847350,Differences in glycolytic capacity and hypoxia tolerance between hepatoma cells and hepatocytes,"Viability, glycolytic capacity and energy metabolism under anaerobic conditions were studied in the hepatoma cell lines HTC, FU5 and HepG2 and in rat and human hepatocytes using glucose and fructose as glycolytic precursors. During 6 hr of anaerobic incubation without additional substrate, viability decreased rapidly in FU5 and HTC cells, whereas viability of HepG2 cells was not significantly affected. In all tumor cells, 10 mmol/L glucose prevented hypoxic cell injury almost completely. Lactate formation from glucose was about five times higher than in hepatocytes under these circumstances. ATP content of the tumor cells remained almost constant under anaerobic conditions in the presence of glucose. Ten millimoles per liter of fructose diminished glycolysis in the hepatoma cells compared with glucose, ranging from 87% reduction in HTC cells to 43% reduction in HepG2 cells. Accordingly, ATP content decreased rapidly in the FU5 and slowly in the HepG2 cells. Viability was strongly diminished in the HTC and FU5 cells in the presence of fructose, whereas in the HepG2 cells no effect of fructose on viability was detectable. In contrast to the hepatoma cells, rat and human hepatocytes exhibited higher rates of anaerobic glycolysis in the presence of fructose and thus were able to maintain their viability under these conditions. These differences in glycolytic capacity, energy metabolism and hypoxia tolerance of hepatoma cells compared with hepatocytes may be used for the treatment of liver cancer by isolated liver perfusion and ex situ revision of the organ.",0
590,1847896,Altered density of glomerular binding sites for atrial natriuretic factor in bile duct-ligated rats with ascites,"""The renal response to atrial natriuretic factor is blunted in cirrhosis with ascites. This might be due to alterations of renal receptors for atrial natriuretic factor. Therefore density and affinity of glomerular atrial natriuretic factor binding sites of bile duct-ligated rats with ascites (n = 10) and of sham-operated controls (n = 10) were determined. Glomerular atrial natriuretic factor binding sites were identified to be of the B-(""""biologically active"""") and C-(""""clearance"""") receptor type. Discrimination and quantitative determination of B and C receptors for atrial natriuretic factor were achieved by displacement experiments with atrial natriuretic factor(99-126) or des(18-22)atrial natriuretic factor(4-23), an analogue binding to C receptors only. Density of total glomerular atrial natriuretic factor binding sites was significantly increased in bile duct-ligated rats (3,518 +/- 864 vs. 1,648 +/- 358 fmol/mg protein; p less than 0.05). This was due to a significant increase of C-receptor density (3,460 +/- 866 vs. 1,486 +/- 363 fmol/mg protein; p less than 0.05), whereas density of B receptors was not significantly different in bile duct-ligated rats (58 +/- 11 vs. 162 +/- 63 fmol/mg protein). Affinity of atrial natriuretic factor to its glomerular binding sites did not differ significantly between both groups. These data suggest that an altered glomerular atrial natriuretic factor receptor density could be involved in the renal resistance to atrial natriuretic factor in cirrhosis with ascites.""",0
591,1857391,"The use of angioplasty, bypass surgery, and amputation in the management of peripheral vascular disease","BACKGROUND: Percutaneous transluminal angioplasty has been adopted widely as a treatment for patients with peripheral vascular disease of the lower extremities. However, the effect of this procedure on the overall management of peripheral vascular disease and on the outcomes of patients has not been clearly delineated. In particular, it is not known whether angioplasty has replaced other treatments for peripheral vascular disease. METHODS: To assess the extent to which angioplasty is used and the associated changes in the surgical management of peripheral vascular disease of the lower extremities, we used data on hospital discharges in Maryland to identify all angioplasty procedures, peripheral bypass operations, and lower-extremity amputations performed for peripheral vascular disease in Maryland hospitals between 1979 and 1989. RESULTS: We estimated that from 1979 to 1989 the annual rate of percutaneous transluminal angioplasty for peripheral vascular disease of the lower extremities, adjusted for age and sex, rose from 1 to 24 per 100,000 Maryland residents (P less than 0.0001 by linear regression). Despite this increase in the use of angioplasty, the adjusted annual rate of peripheral bypass surgery also rose substantially, from 32 to 65 per 100,000 (P less than 0.001), whereas the adjusted annual rate of lower-extremity amputation remained stable at about 30 per 100,000. Total charges for hospitalizations during which a peripheral revascularization procedure was performed increased from $14.7 million in 1979 (in 1989 dollars) to $30.5 million in 1989. CONCLUSIONS: In Maryland, the adoption of percutaneous transluminal angioplasty for peripheral vascular disease of the lower extremities has been associated with an increase in the use of peripheral bypass surgery and with no decline in lower-extremity amputations. These results could be due to increased diagnosis of peripheral vascular disease, expanded indications for procedural interventions, or an increased number of repeat procedures performed in patients with peripheral vascular disease of the lower extremities.",0
592,1860694,Kupffer cell prostaglandin-E2 production is amplified during hepatic regeneration,"Prostaglandin-E2 increases in liver tissue after partial hepatectomy and stimulates DNA synthesis in primary cultures of hepatocytes. This study evaluated the capacity of Kupffer cells isolated at various intervals after partial hepatectomy to produce prostaglandin E2 in response to bacterial endotoxin. This stimulator of Kupffer cells is a normal endogenous component of portal venous blood. After partial hepatectomy (6 to 48 hr), when hepatic regeneration rates were greatest, regenerating liver Kupffer cells demonstrated a significantly greater capacity to produce prostaglandin E2 in response to bacterial endotoxin than did equal numbers of Kupffer cells from time-matched, sham-operated control animals. However, by 12 days after partial hepatectomy, when liver mass had been more than 83% restored, regenerating liver Kupffer cell prostaglandin E2 production had decreased to levels produced by sham KC. We postulate that high levels of Kupffer cell-derived prostaglandin E2 provide a critical paracrine signal fundamental to the initiation and control of growth by neighboring hepatocytes during liver regeneration.",0
593,1860695,Facilitated diffusion and sodium-dependent transport of purine and pyrimidine nucleosides in rat liver,"In mammalian cells, nucleoside transport usually is mediated by facilitated diffusion. In addition, a Na(+)-dependent, concentrative nucleoside transport system has been detected in several tissues but not the liver. To further clarify hepatic nucleoside transport mechanisms, we measured the uptake of [2-14C]uridine (2 to 100 mumol/L) and of [8-14C]adenosine (10 to 75 mumol/L) by the isolated perfused rat liver in the presence or absence of extracellular sodium or specific inhibitors of facilitated nucleoside diffusion. Uridine transport and metabolism were monitored by the release of labeled catabolites including 14CO2, which indicated complete degradation of the pyrimidine. Adenosine, uridine and uridine catabolites were measured in the effluent perfusate by reversed-phase high-performance liquid chromatography and a radioactivity flow monitor. The existence of a Na(+)-dependent nucleoside transport system could be inferred from the following observations: (a) Sodium depletion caused a strong inhibition of nucleoside transport reflected by an up to threefold and 15-fold increase in extracellular uridine and adenosine, respectively. The sodium-dependent transport of uridine was saturated when the influent uridine concentration was raised beyond 20 mumol/L. No such saturation was observed for much higher concentrations of adenosine used (10 to 75 mumol/L). (b) Na(+)-free perfusion resulted in a strong suppression of the release of uridine catabolites by the liver. Complete uridine breakdown was depressed to 7% of the amount of 14CO2 released in the presence of sodium and at influent uridine concentrations below 20 mumol/L. (c) Inhibition of uridine (10 mumol/L) transport and degradation was observed after coperfusion with adenosine, deoxyadenosine, guanosine and deoxyguanosine.(ABSTRACT TRUNCATED AT 250 WORDS)",0
594,1870640,Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery,"BACKGROUND: Preterm delivery is the leading cause of neonatal mortality in the United States, but efforts to address the problem are hampered by the inability to predict accurately which pregnancies are at risk. We postulated that damage to the fetal membranes may release fetal fibronectin into the cervix and vagina, giving rise to a biochemical marker for preterm delivery. METHODS: We measured fetal-fibronectin concentrations in cervical and vaginal secretions, amniotic fluid, and maternal plasma with a sensitive immunoassay using the monoclonal antibody FDC-6. Immunohistochemical studies were used to determine the distribution of fetal fibronectin in the placenta and amniochorionic membranes and to ascertain its cell of origin. RESULTS: Women with uncomplicated pregnancies (n = 163) who delivered at term rarely had cervicovaginal fetal-fibronectin concentrations above 0.05 micrograms per milliliter between 21 and 37 weeks of gestation (11 of 267 cervical samples [4 percent] and 9 of 267 vaginal samples [3 percent]. High levels of fetal fibronectin were detected in amniotic fluid and in the cervical or vaginal secretions of 93.8 percent of the women with preterm rupture of membranes (n = 65). Cervical or vaginal fetal fibronectin was also present in 50.4 percent of the women with preterm uterine contractions and intact membranes (n = 117), and its presence identified the women who delivered before term (n = 60) with a sensitivity of 81.7 percent and a specificity of 82.5 percent. In the placenta and membranes, fetal fibronectin was found at points of contact with the uterine wall. CONCLUSIONS: The presence of cervicovaginal fetal fibronectin in the second and third trimesters of pregnancy identifies a subgroup of women who are at high risk for preterm delivery. This phenomenon may reflect the separation of the chorion from the decidual layer of the uterus, with the release of intact or degraded chorionic components of the extracellular matrix into the cervical and vaginal secretions.",0
595,1870651,A randomized trial of treatment options for alcohol-abusing workers,"BACKGROUND: Employee-assistance programs sponsored by companies or labor unions identify workers who abuse alcohol and refer them for care, often to inpatient rehabilitation programs. Yet the effectiveness of inpatient treatment, as compared with a variety of less intensive alternatives, has repeatedly been called into question. In this study, anchored in the work site, we compared the effectiveness of mandatory in-hospital treatment with that of required attendance at the meetings of a self-help group and a choice of treatment options. METHODS: We randomly assigned a series of 227 workers newly identified as abusing alcohol to one of three rehabilitation regimens: compulsory inpatient treatment, compulsory attendance at Alcoholics Anonymous (AA) meetings, and a choice of options. Inpatient backup was provided if needed. The groups were compared in terms of 12 job-performance variables and 12 measures of drinking and drug use during a two-year follow-up period. RESULTS: All three groups improved, and no significant differences were found among the groups in job-related outcome variables. On seven measures of drinking and drug use, however, we found significant differences at several follow-up assessments. The hospital group fared best and that assigned to AA the least well; those allowed to choose a program had intermediate outcomes. Additional inpatient treatment was required significantly more often (P less than 0.0001) by the AA group (63 percent) and the choice group (38 percent) than by subjects assigned to initial treatment in the hospital (23 percent). The differences among the groups were especially pronounced for workers who had used cocaine within six months before study entry. The estimated costs of inpatient treatment for the AA and choice groups averaged only 10 percent less than the costs for the hospital group because of their higher rates of additional treatment. CONCLUSIONS: Even for employed problem drinkers who are not abusing drugs and who have no serious medical problems, an initial referral to AA alone or a choice of programs, although less costly than inpatient care, involves more risk than compulsory inpatient treatment and should be accompanied by close monitoring for signs of incipient relapse.",0
596,1875969,Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease,"BACKGROUND: The treadmill exercise test identifies patients with different degrees of risk of death from cardiovascular events. We devised a prognostic score, based on the results of treadmill exercise testing, that accurately predicts outcome among inpatients referred for cardiac catheterization. This study was designed to determine whether this score could also accurately predict prognosis in unselected outpatients. METHODS: We prospectively studied 613 consecutive outpatients with suspected coronary disease who were referred for exercise testing between 1983 and 1985. Follow-up was 98 percent complete at four years. The treadmill score was calculated as follows: duration of exercise in minutes--(5 x the maximal ST-segment deviation during or after exercise, in millimeters)--(4 x the treadmill angina index). The numerical treadmill angina index was 0 for no angina, 1 for nonlimiting angina, and 2 for exercise-limiting angina. Treadmill scores ranged from -25 (indicating the highest risk) to +15 (indicating the lowest risk). RESULTS: Predicted outcomes for the outpatients, based on their treadmill scores, agreed closely with the observed outcomes. The score accurately separated patients who subsequently died from those who lived for four years (area under the receiver-operating-characteristic curve = 0.849). The treadmill score was a better discriminator than the clinical data and was even more useful for outpatients than it had been for inpatients. Approximately two thirds of the outpatients had treadmill scores indicating low risk (greater than or equal to +5), reflecting longer exercise times and little or no ST-segment deviation, and their four-year survival rate was 99 percent (average annual mortality rate, 0.25 percent). Four percent of the outpatients had scores indicating high risk (less than -10), reflecting shorter exercise times and more severe ST-segment deviation; their four-year survival rate was 79 percent (average annual mortality rate, 5 percent). CONCLUSIONS: The treadmill score is a useful and valid tool that can help clinicians determine prognosis and decide whether to refer outpatients with suspected coronary disease for cardiac catheterization. In this study, it was a better predictor of outcome than the clinical assessment.",0
597,1881416,Correlations between antepartum maternal metabolism and intelligence of offspring,"BACKGROUND: It is not clear to what extent maternal metabolism during pregnancy affects the cognitive and behavioral function of the offspring by altering brain development in utero. To investigate this question, we correlated measures of metabolism in pregnant diabetic and nondiabetic women with the intellectual development of their offspring. METHODS: The study included 223 pregnant women and their singleton offspring: 89 women had diabetes before pregnancy (pregestational diabetes mellitus), 99 had the onset of diabetes during pregnancy (gestational diabetes mellitus), and 35 had normal carbohydrate metabolism during their pregnancy. We correlated measures of maternal glucose and lipid metabolism (fasting plasma glucose levels, hemoglobin A1c levels, episodes of hypoglycemia, episodes of acetonuria, and plasma beta-hydroxybutyrate and free fatty acid levels) with two measures of intellectual development in the offspring--the mental development index of the Bayley Scales of Infant Development, given at the age of two years, and the Stanford--Binet Intelligence Scale, given at the ages of three, four, and five years and expressed as an average of the three scores. RESULTS: After correction for socioeconomic status, race or ethnic origin, and patient group, the children's mental-development-index scores at the age of two years correlated inversely with the mothers' third-trimester plasma beta-hydroxybutyrate levels (r = -0.21, P less than 0.01); the average Stanford-Binet scores correlated inversely with third-trimester plasma beta-hydroxybutyrate (r = -0.20, P less than 0.02) and free fatty acid (r = -0.27, P less than 0.002) levels. No other correlations were significant. Including various perinatal events (e.g., prematurity and acidemia) in the analyses did not alter the results. CONCLUSIONS: Maternal diabetes during pregnancy may affect behavioral and intellectual development in the offspring. The associations between gestational ketonemia in the mother and a lower IQ in the child warrant continued efforts to avoid ketoacidosis and accelerated starvation in all pregnant women.",0
598,1886625,Breast-feeding in 1991,"The author discusses support for the benefits of breastfeeding during the 1st 3-6 months of an infant's life, raises the issues of potentially deleterious and detrimental maternal-infant exchange of infectious diseases and alcohol, and comments on demands faced by working mothers hoping to breastfeed. For developing countries, breastfeeding is an inexpensive, nutritious feeding method, which may be used instead of other potentially contaminated or inadequate substances. Rich in immune components, studies suggest that breast milk reduces infant morbidity and mortality from infectious diseases, and may increase the chances of survival of low-birth-weight infants in both developed and developing countries. Concerns over available feeding alternatives and sanitation being less important in the United States, most physicians still encourage mothers to breastfeed on the basis of its cost-effectiveness, the potential effects on the clinical severity of gastrointestinal infections, the presumed beneficial effects on maternal-infant interactions, the mother's perception of that interaction, and its contributions to the mother's confidence in her maternal capabilities. The author acknowledges the need for concern over HIV and alcohol transmission from mother to child through breast milk, and discusses the ongoing debate while pointing out caveats and qualifications to conclusions. Breastfeeding may be impossible for constrained by the obligations of work. Accordingly, physicians should recognize these limitations, and support political and legislative initiatives to make breastfeeding a practical possibility for all mothers.",0
599,1886634,The transfer of alcohol to human milk. Effects on flavor and the infant's behavior,"BACKGROUND: The amount of alcohol ingested by a breast-fed infant is only a small fraction of that consumed by its mother, but even this small amount may have an effect on the infant. We investigated whether the ingestion of alcohol by a lactating woman altered the odor of her milk and whether exposure to a small amount of alcohol in the mother's milk had immediate effects on the behavior of the infant. METHODS: Twelve lactating women and their infants were tested on two days separated by an interval of one week. On each testing day, the mother expressed a small quantity of breast milk and then drank either orange juice or orange juice containing a small quantity of ethanol (0.3 g per kilogram of body weight). Additional milk samples were obtained at fixed intervals after the ingestion of the beverage and analyzed to determine their ethanol content. The samples were also evaluated by a panel of adults to determine whether any difference in the odor of the milk was detectable after alcohol ingestion. The infants were weighed before and after nursing to assess the amount of milk they ingested, and their behavior during breast-feeding was monitored by videotape. RESULTS: Short-term alcohol consumption by lactating women significantly and uniformly increased the perceived intensity of the odor of their milk as assessed by the panel; this increase in the intensity of the odor peaked 30 minutes to 1 hour after the alcohol was consumed and decreased thereafter. The alteration in the odor of the milk closely paralleled the changes in the concentration of ethanol in the milk (mean range, 0 to 6.9 mmol per liter [0 to 32 mg per deciliter]). The infants sucked more frequently during the first minute of feedings after their mothers had consumed alcohol (67.0 +/- 6.5 sucks, as compared with 58.4 +/- 5.9 sucks for feedings after the consumption of the nonalcoholic beverage; P less than 0.05), but they consumed significantly less milk (120.4 +/- 9.5 ml vs. 156.4 +/- 8.2 ml, P less than 0.001) during the testing sessions in which their mothers drank the alcoholic beverage. CONCLUSIONS: Although the mechanisms underlying this reduction in milk intake remain to be elucidated, this study shows that short-term alcohol consumption by nursing mothers has an immediate effect on the sensory characteristics (odor) of their milk and the feeding behavior of their infants.",0
600,1891008,Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children,"BACKGROUND: Although asthma diagnosed by a physician is known to be related to serum IgE levels, it is not known whether there is a relation between the level of IgE and airway hyperresponsiveness to a methacholine challenge. The characteristics of asymptomatic persons that predispose them to airway hyperresponsiveness are also unknown. METHODS: We studied the relation between the serum total IgE level and airway hyperresponsiveness in the presence or absence of asthma and other atopic diseases in a birth cohort of children. Data from a questionnaire regarding respiratory symptoms, plus measurements of the serum total IgE level and airway responsiveness to inhaled methacholine, were obtained for 562 11-year-olds in New Zealand. RESULTS: The boys had a higher prevalence than the girls of current diagnosed asthma (13 percent vs. 6 percent), current symptoms of wheezing (22 percent vs. 15 percent), and airflow obstruction at base line (6 percent vs. 1 percent) and had a wider distribution of IgE levels, although mean IgE levels (120.8 IU per milliliter in the boys and 98.1 IU per milliliter in the girls) did not differ significantly between the sexes. The prevalence of diagnosed asthma was strongly related to the serum IgE level (P for trend less than 0.0001). No asthma was reported in children with IgE levels less than 32 IU per milliliter, whereas 36 percent of those with IgE levels greater than or equal to 1000 IU per milliliter were reported to have asthma. This relation with the serum IgE level was not explained by a concomitant diagnosis of allergic rhinitis or eczema. Airway hyperresponsiveness to a methacholine challenge also correlated very highly (P less than 0.0001) with the serum IgE level. This relation remained significant even after the exclusion of children with diagnosed asthma (P less than 0.0001) and of all children with a history of wheezing, allergic rhinitis, or eczema (P less than 0.0001). CONCLUSIONS: Even in children who have been asymptomatic throughout their lives and have no history of atopic disease, airway hyperresponsiveness appears to be closely linked to an allergic diathesis, as reflected by the serum total IgE level.",0
601,1898530,Exposure to dioxins and dibenzofurans through the consumption of fish,"BACKGROUND: In some regions, including the Baltic Sea, fatty fish such as salmon and herring contain high levels of polychlorinated dibenzodioxins and dibenzofurans. We investigated human exposure to these potentially toxic substances in relation to the consumption of fish from the Baltic Sea. METHODS: Plasma levels of 10 different dibenzofurans and 7 dioxins were analyzed in three groups of Swedish men: one group with a high intake of fish (fish eaten almost daily; n = 11), one with a moderate intake of fish (about once per week; n = 9), and one with no consumption of fish (usually because of allergy; n = 9). RESULTS: Plasma levels of several of the compounds we measured were higher in the men with a high intake of fish than in those who consumed moderate amounts, and the levels were higher in those who ate moderate amounts of fish than in those who ate none. The median amounts of the most toxic dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) were 8.0 pg per gram of plasma lipid (range, 2.0 to 13) in the high-intake group, 2.6 pg per gram (range, 1.2 to 4.2) in the moderate-intake group, and 1.8 pg per gram (range, 1.0 to 2.5) in the nonconsumers (P = 0.001 and 0.02, respectively). There were consistent and statistically significant associations between the reported amount of fish eaten and the plasma levels of several of the dibenzofurans and dioxins. CONCLUSIONS: Contaminated fish such as those from the Baltic Sea are an important source of exposure to polychlorinated dibenzofurans and dibenzodioxins in persons who eat fish regularly. However, the clinical consequences of such exposure remain uncertain.",0
602,1899082,Expression of specific UDP-glucuronosyltransferase isoforms in carcinogen-induced preneoplastic rat liver nodules,"The expression of specific UDP-glucuronosyltransferase isoforms in 2-acetylaminofluorane-induced rat liver preneoplastic nodules was studied; livers from pair-fed littermates were used as controls. For comparison, liver and kidney from 3-methylcholanthrene-treated or untreated (control) rats were used. Steady-state UDP-glucuronosyltransferase mRNA levels were determined by Northern blot analysis or in situ hybridization of tissue sections using a 30-mer oligonucleotide specific for the 3-methylcholanthrene-inducible UDP-glucuronosyltransferase (which is active toward 4-nitrophenol) or a double-stranded cDNA probe specific for androsterone-UDP-glucuronosyltransferase. For 3-methylcholanthrene-inducible UDP-glucuronosyltransferase, the mRNA level was very low in control liver; there was a 15-fold increase after 3-methylcholanthrene treatment. This mRNA was present at relatively high concentration in the kidney and there was a threefold increase after 3-methylcholanthrene administration. In livers with preneoplastic nodules 1 mo after cessation of carcinogen administration, this mRNA concentration was approximately 15 times greater than in control liver. Similar changes in the level of the 3-methylcholanthrene-inducible UDP-glucuronosyltransferase were also observed by in situ hybridization of tissue sections. Immunocytochemical studies using an antiserum that recognizes the 3-methylcholanthrene-inducible UDP-glucuronosyltransferase showed a marked increase in the concentration of this isoform in preneoplastic nodules compared with the adjacent nonnodular liver.",0
603,1901623,The deteriorating administrative efficiency of the U.S. health care system,"BACKGROUND AND METHODS: In 1983 the proportion of health care expenditures consumed by administration in the United States was 60 percent higher than in Canada and 97 percent higher than in Britain. To assess the effects of recent health policy initiatives on the administrative efficiency of health care, we examined four components of administrative costs in the United States and Canada for 1987: insurance overhead, hospital administration, nursing home administration, and physicians' billing and overhead expenses. Most data were provided by the two nations' federal health and statistics agencies, supplemented by state and provincial data and published sources. Because data on physicians' billing costs were limited, we estimated a range for these costs by two methods that rely on different sources of data. All figures are reported in 1987 U.S. dollars. RESULTS: In 1987 health care administration cost between $96.8 billion and $120.4 billion in the United States, amounting to 19.3 to 24.1 percent of total spending on health care, or $400 to $497 per capita. In Canada, between 8.4 and 11.1 percent of health care spending ($117 to $156 per capita) was devoted to administration. Administrative costs in the United States increased 37 percent in real dollars between 1983 and 1987, whereas in Canada they declined. The proportion of health care spending consumed by administration is now at least 117 percent higher in the United States than in Canada and accounts for about half the total difference in health care spending between the two nations. If health care administration in the United States had been as efficient as in Canada, $69.0 billion to $83.2 billion would have been saved in 1987. CONCLUSIONS: The administrative structure of the U.S. health care system is increasingly inefficient as compared with that of Canada's national health program. Recent health policies with the avowed goal of improving the efficiency of care have imposed substantial new bureaucratic costs and burdens.",0
604,1902283,Chronic respiratory alkalosis. The effect of sustained hyperventilation on renal regulation of acid-base equilibrium,"BACKGROUND: In normal subjects, chronic hyperventilation lowers plasma bicarbonate concentration, primarily by inhibiting the urinary excretion of net acid. The quantitative relation between reduced arterial carbon dioxide tension (PaCO2) and the plasma bicarbonate concentration in the chronic steady state has not been studied in humans, however, and the laboratory criteria for the diagnosis of chronic respiratory alkalosis therefore remain undefined. We wished to provide such reference data for clinical use. Moreover, because chronic hyperventilation paradoxically lowers blood pH still further in dogs with metabolic acidosis, we desired to study the effect of chronic hypocapnia on the plasma bicarbonate concentration (and blood pH) in normal human subjects in whom acidosis had been induced with ammonium chloride. METHODS: Under metabolic-balance conditions, we used altitude-induced hypobaric hypoxia to produce chronic hypocapnia in nine normal young men, five of whom received ammonium chloride daily to cause metabolic acidosis (the mean [+/- SE] steady-state plasma bicarbonate level in these five was 12.0 +/- 0.5 mmol per liter). RESULTS: For each decrease of 1 mm Hg (0.13 kPa) in the PaCO2, the plasma bicarbonate concentration decreased by 0.41 mmol per liter in the subjects who started with a normal plasma bicarbonate concentration and by 0.42 mmol per liter in the subjects with acidosis. In contrast to the findings in previous studies of dogs, hypocapnia increased blood pH similarly in both groups; the blood hydrogen ion concentration decreased by about 0.4 nmol per liter for every decrease of 1 mm Hg (0.13 kPa) in PaCO2. CONCLUSIONS: These results provide reference data for the diagnosis of chronic respiratory alkalosis in humans. Although chronic hypocapnia decreased plasma bicarbonate levels similarly in normal subjects with acidosis and without acidosis, the percent reduction in PaCO2 was always greater than the corresponding percent reduction in the plasma bicarbonate concentration. Therefore, as was not true of the response in dogs, the subjects' blood pH always increased with hyperventilation, regardless of the initial plasma bicarbonate concentration.",0
605,1906044,Differences in the lectin-binding patterns of the periportal and perivenous endothelial domains in the liver sinusoids,"We have studied the distribution patterns of carbohydrate terminals on the endothelial surface of the mouse liver microvasculature. For this purpose, a wide battery of FITC lectins specific to glucose, mannose, galactose, fucose, N-acetyl-neuraminic acid, N-acetyl-galactosamine and N-acetyl-glucosamine residues were incubated on liver cryostat sections or intraportally perfused under physiological conditions. All the resulting hepatic sections were examined under fluorescent microscopy and confocal laser scanning microscopy. With the exception of N-acetyl-galactosamine- and fucose-binding lectins, all the perfused lectins specifically bound to the microvascular wall as confirmed by blocking methods using their corresponding sugars. A wide range of binding was, however, observed among the lectins, and the latter were classified into four groups according to their affinities for the different segments of the hepatic microvasculature: (a) equal affinity for all segments (concanavalin A); (b) different affinities depending on acinar zone (wheat germ agglutinin, Ricinus communis toxin, phytohemagglutinin E, Erythrina cristagalli agglutinin and Pisum sativum agglutinin); (c) preferential binding to the sinusoidal network (Lathyrus odoratus, phytohemagglutinin); and (d) lectins that fail to bind to the hepatic microvasculature (N-acetyl-galactosamine- and fucose-binding lectins). Sinusoidal segment walls in acinar zone 1 expressed a higher concentration of certain lectin-binding carbohydrate residues (N-acetyl-neuraminic acid, N-acetyl-galactosamine, galactose, mannose and glucose) than in acinar zone 3. The labeling patterns obtained through the incubation of liver sections or through in vivo perfusion with the different lectins did not always coincide. Only concanavalin A, wheat germ agglutinin and phytohemagglutinin E lectins proved to be concordant (i.e., they produced identical labeling patterns in both procedures).(ABSTRACT TRUNCATED AT 250 WORDS)",0
606,1908058,Catabolic illness. Strategies for enhancing recovery,"After injury, infection, extensive chemotherapy, and other critical illnesses, both protein and fat are lost from the body. Although minor alterations in body composition are probably of little clinical importance, losses of body protein of 10 percent or more contribute to morbidity and debility. This catabolic response can be modified and recovery can be accelerated by a variety of approaches. First, the inflammatory response can be reduced; second, specific nutrients can be provided to support the patient's tissue requirements during catabolic illness; and third, growth factors can be used to enhance protein synthesis and tissue repair. These approaches, whether used alone or in combination, will reduce the loss of body protein, which should accelerate recovery, shorten the length of hospitalization, and reduce convalescence.",0
607,1916665,Role of extracellular zinc and copper on metallothionein regulation in cultured rat hepatocytes,"Cellular and extracellular metallothionein contents of rat hepatocytes cultured in the presence of albumin (30 mumol/L) with zinc (1, 10, 50 and 100 mumol/L), copper (1, 10 and 50 mumol/L), zinc and copper (1, 10 and 50 mumol/L of each metal) or no metals in the culture medium have been measured by radioimmunoassay. Cellular metallothionein levels increased steadily with culture time regardless of the metal treatment and showed little dependence (only a twofold increase) on extracellular zinc or copper at all metal concentrations and times (up to 3 days) studied. In contrast, the presence of both metals simultaneously in the culture medium strongly increased cellular metallothionein contents, acting synergistically in some cases. Significant extracellular metallothionein was observed when copper or zinc and copper were present in the culture medium, most of which is likely a consequence of cell leakage because no evidence of physiological secretion was observed. Total metallothionein production (cellular and extracellular metallothionein levels) indicated that copper was a better metallothionein inducer than zinc in these experimental conditions. These results indicate that metallothionein regulation in the hepatocyte is different depending on the extracellular metal levels and composition and that attention must be given to metallothionein release from the hepatocyte.",0
608,1916669,Adaptive regulation of hepatic bile salt transport: effects of alloxan diabetes in the rat,"The hepatic transport of bile salts appears to be adaptively regulated by changes in the bile salt pool size and in the flux of bile salt through the liver. The maximum secretory rate of taurocholate increases or decreases when the bile salt pool size is modified by either oral feeding of cholate or taurocholate (up-regulation) or prolonged bile salt depletion through a biliary fistula (down-regulation), respectively. It is not known whether adaptive regulation of hepatic bile salt transport operates under conditions in which the bile salt pool size is modified by endogenous changes in bile acid metabolism. Because experimental diabetes mellitus is associated with alterations in the synthesis of bile acids and total bile salt pool size and composition in the rat, we examined the effects of diabetes mellitus induced by alloxan (5 mg/100 gm body weight, intravenously) and insulin treatment on hepatic bile salt transport and relate the changes to bile salt pool size variations. At 3 days after alloxan injection (DIAB-3 group) both taurocholate maximum secretory rate and pool size were significantly decreased, whereas they were restored to normal values after 6 days of diabetes (DIAB-6 group). Insulinopenic diabetes for 14 days (DIAB-14 group) and for 24 days (DIAB-24 group) resulted in a marked increase of basal bile salt secretory rate (secondary to an increased contribution of cholate conjugates) and an enhanced taurocholate maximum secretory rate compared with control rats (147% and 188% increase, respectively) and with a group (PHARM-control) that received alloxan but did not develop detectable glycosuria (224% and 286% increase, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)",0
609,1922208,Pretransplantation blood transfusion revisited,"BACKGROUND: Blood transfusion before organ transplantation has a beneficial effect on allograft survival; the mechanism of this effect has remained a mystery. In murine models, the presence of common histocompatibility antigens in the blood donor and the recipient favors the induction of allograft tolerance. METHODS: To investigate the effect of HLA compatibility between blood donor and recipient on the induction of allograft tolerance, we determined the relative frequency of cytotoxic T-lymphocyte precursors specific for donor cells before and at several times after blood transfusion in 23 patients awaiting a first renal transplant. We correlated the results with the presence of shared HLA antigens. RESULTS: T-cell nonresponsiveness against donor cells developed after blood transfusion in 10 of the 23 patients. Tolerance developed only if the blood donor and the recipient had one HLA haplotype or at least one HLA-B and one HLA-DR antigen in common (as was observed in 9 of these 10 patients). Tolerance developed relatively late after blood transfusion (one to two months) and was long-lasting. No decline in the T-cell response against donor alloantigens was observed in any of the 13 patients who received transfusions without having HLA-antigen compatibility with the donor. CONCLUSIONS: Blood transfusion in which there is a common HLA haplotype or shared HLA-B and HLA-DR antigens induces tolerance to donor antigens. This finding may lead to the development of new strategies with which to induce tolerance for transplantation after blood transfusion. Perhaps transplant donors will be selected not only by HLA-antigen matching, but also on the basis of acceptable HLA-antigen mismatches associated with T-cell non-responsiveness induced by selected blood transfusion.",0
610,1922224,When physicians treat members of their own families. Practices in a community hospital,"""BACKGROUND: Little is known about the circumstances under which physicians care for family members. We sought to examine current practice and, in particular, to learn how often family members request medical care or treatment, whether physicians accede to such requests, and what concerns, if any, physicians have about caring for their family members. METHODS: In late 1990 we distributed a pretested, structured questionnaire to all members of the active medical staff (physicians with M.D. or D.O. degrees) of a large suburban community teaching hospital. Of 691 eligible members of the medical staff, 465 physicians responded. RESULTS: Of the 465 respondents, 461 (99 percent) reported requests from family members for medical advice, diagnosis, or treatment. A total of 386 (83 percent of the respondents) had prescribed medication for a family member, 372 (80 percent) had diagnosed medical illnesses, 334 (72 percent) had performed physical examinations, 68 (15 percent) had acted as a family member's primary attending physician in the hospital, and 44 (9 percent) had operated on a family member. In addition, 152 (33 percent) reported that they had observed another physician """"inappropriately involved"""" in a family member's care, and 103 (22 percent) had acceded to a specific request about which they felt uncomfortable. CONCLUSIONS: Practicing physicians often attend and treat their family members and diagnose their illnesses. They may often experience some disquiet in doing so. For physicians, complete medical data, proper training, and sound judgment are essential when family members request treatment.""",0
611,1922237,Bone marrow transplantation for sickle cell disease. A study of parents' decisions,"BACKGROUND: Bone marrow transplantation has been shown to cure sickle cell disease, but it carries a 15 percent mortality risk. To determine whether parents would accept this risk to cure their children of sickle cell disease, we interviewed parents of children with sickle cell disease who were being followed in a university hospital clinic. METHODS: We assessed parents' attitudes by using questions based on the standard reference-gamble paradigm. After we gave them descriptions of bone marrow transplantation and graft-versus-host disease (GVHD), the parents were presented with a series of hypothetical situations. In the first situation, bone marrow transplantation was described as offering certain (100 percent) survival with cure of sickle cell disease. In subsequent descriptions, the mortality rate associated with bone marrow transplantation was increased by 5 percent increments. The parents indicated the highest mortality risk at which they would consent to the procedure in order to cure their children. RESULTS: In order to obtain a cure for their children, 36 of 67 parents (54 percent) were willing to accept some risk of short-term mortality, 25 of 67 (37 percent) were willing to accept at least the 15 percent short-term mortality risk we estimate to be the current figure for bone marrow transplantation, and 8 of 67 (12 percent) were willing to accept a short-term mortality risk of 50 percent or more. Nine parents (13 percent) said they would accept both a mortality risk of 15 percent or more and an additional 15 percent risk of GVHD. The parents' decisions were not related to the clinical severity of their children's illness. CONCLUSIONS: At current rates of mortality and morbidity with bone marrow transplantation, a substantial minority of the parents of children with sickle cell disease may consent to bone marrow transplantation for their children. Parental attitudes should be factored into decisions about whether to offer bone marrow transplantation to children with sickle cell disease.",0
612,1922251,A look-back investigation of patients of an HIV-infected physician. Public health implications,"BACKGROUND: Transmission of the human immunodeficiency virus (HIV) to five patients receiving care from an HIV-infected dentist in Florida has recently been reported. Current data indicate that the risk of HIV transmission from health care workers to patients is low. Despite this low risk, programs to notify patients of past exposure to an HIV-infected health care worker are being conducted with increasing frequency. METHODS: We recently conducted an investigation of all the patients cared for by an HIV-infected family physician during a period when he had severe dermatitis caused by Mycobacterium marinum on his hands and forearms. After reviewing the patients' records, we notified 336 patients who had undergone one or more procedures (digital examination of a body cavity or vaginal delivery) placing them at potentially increased risk of HIV infection. The patients were offered tests for HIV infection and counseling. RESULTS: Of the 336 patients, 325 (97 percent) had negative tests for HIV antibody, 3 (1 percent) refused testing, 1 (less than 1 percent) died of a cause unrelated to HIV infection before notification, and the HIV-antibody status of 7 (2 percent) remained unknown. The direct and indirect public health costs of this investigation were approximately $130,000. CONCLUSIONS: The results of this investigation raise important questions about the risk of HIV transmission from health care workers to patients and the usefulness of HIV look-back programs, particularly in the light of recently published recommendations from the Centers for Disease Control. We propose that before a look-back investigation is undertaken, there should be a clearly identifiable risk of transmission of the infection, substantially higher than the risk requiring limitation of an HIV-infected health care worker's practice prospectively.",0
613,1937381,Intraobserver and interobserver variation in the histopathological assessment of liver allograft rejection. The Liver Transplantation Database (LTD) Investigators,"A study to determine the reproducibility of histopathological findings and diagnoses of rejection was carried out on a series of 42 liver allograft needle biopsy specimens by five pathologists practicing at four liver transplant centers. Pathologists from each of the four centers read each slide independently on two different occasions and were asked to assess 12 histopathological features and render a diagnosis. For all histological variables, the intrarater agreement was higher than the interrater agreement. Moderate to excellent agreement occurred among the pathologists about all histological variables thought to be important in establishing the diagnosis of acute rejection (i.e., portal tract inflammation, subendothelial inflammation and bile duct damage). Other variables such as lobular disarray, bile duct proliferation and particularly arteritis, however, were only fairly or poorly reproducible. Surprisingly, the diagnosis of acute rejection was more reproducible than the individual histopathological findings that were thought to be the basis for the diagnosis. The agreement for the diagnosis of chronic rejection, however, varied according to observer. We noted that relatively inexperienced observers within this group had some difficulties agreeing with more experienced observers in establishing a diagnosis of chronic rejection. These findings demonstrate that the histopathological diagnosis of acute cellular liver allograft rejection is highly reproducible within a group of experienced pathologists and that this diagnosis can be pooled in a common data base with confidence.",0
614,1944471,Changes in lipid and lipoprotein levels and body weight in Tarahumara Indians after consumption of an affluent diet,"""BACKGROUND: Major new public health problems occur in developing countries as they become more affluent and change their traditional dietary patterns. To study this phenomenon in microcosm, we substituted an """"affluent"""" diet for the traditional diet of a group of Tarahumara Indians, a Mexican people known to consume a low-fat, high-fiber diet and to have a very low incidence of risk factors for coronary heart disease. METHODS: Thirteen Tarahumara Indians (five women and eight men [including one adolescent]) consumed their traditional diet (2700 kcal per day) for one week, and were then fed a diet typical of affluent societies, which contained excessive calories (4100 kcal per day), total fat, saturated fat, and cholesterol, for five weeks. RESULTS: After five weeks of consuming the affluent diet, the subjects' mean (+/- SE) plasma cholesterol level increased by 31 percent, from 121 +/- 5 to 159 +/- 6 mg per deciliter (3.13 +/- 0.13 to 4.11 +/- 0.16 mmol per liter, P less than 0.001). The increase in the plasma cholesterol level was primarily in the low-density lipoprotein (LDL) fraction, which rose 39 percent, from 72 +/- 3 to 100 +/- 4 mg per deciliter (1.86 +/- 0.08 to 2.59 +/- 0.10 mmol per liter, P less than 0.001). High-density lipoprotein (HDL) cholesterol, usually low in this population, increased by 31 percent, from 32 +/- 2 to 42 +/- 3 mg per deciliter (0.83 +/- 0.05 to 1.09 +/- 0.08 mmol per liter). Consequently, the ratio of LDL to HDL levels changed little (2.25 with the base-line diet and 2.38 with the affluent diet). Plasma triglyceride levels increased by 18 percent, from 91 +/- 8 to 108 +/- 11 mg per deciliter (1.03 +/- 0.09 to 1.22 +/- 0.12 mmol per liter, P less than 0.05), with a significant increase in the very-low-density lipoprotein triglyceride fraction. All the subjects gained weight, with a mean increase of 3.8 kg (7 percent). CONCLUSIONS: When Tarahumara Indians from a population with virtually no coronary risk factors consumed for a short time a hypercaloric diet typical of a more affluent society, they had dramatic increases in plasma lipid and lipoprotein levels and body weight. If sustained, such changes might increase their risk of coronary heart disease.""",0
615,1959856,IgG is associated with the asialoglycoprotein receptor in the human liver,"Various pathophysiological relationships between IgA and the asialoglycoprotein receptor on hepatocytes have been proposed. As a step toward defining these relationships, we purified the receptor from human livers by means of p-aminophenyl beta-D-thiogalactopyranoside-agarose affinity chromatography. Unexpectedly, we found the asialoglycoprotein receptor to be associated specifically with IgG. Evidence for the specific association included the following: (a) IgG, but little IgA or IgM, was associated with asialoglycoprotein receptor that had been bound to asialoorosomucoid in an enzyme-linked immunosorbent assay; (b) the asialoglycoprotein receptor-associated IgG was predominantly IgG2 and IgG4 subclasses, whereas serum IgG is predominantly IgG1; and (c) some asialoglycoprotein receptor was specifically recovered together with IgG from an anti-IgG affinity column. The association of IgG with asialoglycoprotein receptor was not mediated by receptor recognition of carbohydrate moieties because IgG neither bound directly to asialoglycoprotein receptor nor inhibited binding of asialoglycoprotein receptor to asialoorosomucoid in vitro. The association could not be attributed to antigen-antibody interaction either. We conclude that IgG is associated in vitro with the asialoglycoprotein receptor by a mechanism not yet fully defined and speculate that the IgG serves an immunological function.",0
616,1959872,Age-related changes in total protein and collagen metabolism in rat liver,"Liver collagen levels are determined by a balance between synthesis and degradation, processes known to have rapid rates in growing animals. We report age-related changes in liver collagen synthesis and degradation rates, as well as protein synthesis rates, in rats at five ages from 1 to 24 mo. Fractional collagen synthesis rates were determined after injection of [14C]proline with a flooding dose of unlabeled proline and its incorporation as hydroxy-[14C]proline into proteins. Fractional protein synthesis rates were based on the uptake of [14C]proline into proteins. Fractional collagen degradation rates were calculated from the difference between collagen fractional synthesis and deposition rates. Fractional rates of collagen synthesis were similar between 1 mo (23.0% +/- 4.6%/day) and 24 mo (19.6% +/- 3.4%/day) of age. Collagen deposition into the extracellular matrix was extremely low at every age studied; therefore degradation pathways accounted for the bulk of the collagen synthesized. The mean fractional synthesis rate for the total protein pool was unaltered between 1 mo (105.0% +/- 7.2%/day) and 15 mo (89.9% +/- 6.0%/day) of age, after which it increased to 234.9% +/- 33.0%/day (p less than 0.05) by 24 mo of age. These results indicate that liver collagen and total protein synthesis rates were maintained at relatively high levels during development and maturity but that protein synthesis rates were highest in senescent animals.",0
617,1959875,Cell cycle-dependent uptake of putrescine and its importance in regulating cell cycle phase transition in cultured adult mouse hepatocytes,"Previous studies in which investigators have induced the rate of polyamine uptake in vitro have used either inhibitors of polyamine biosynthesis or growth factors that induce cell proliferation. Recently, however, we have described the induction of putrescine uptake in cultured adult mouse hepatocytes and have shown that uptake is independent of both intracellular polyamine levels and proliferation. Although proliferation was not apparent in those studies, data suggested that, after isolation, the cells entered G1 of the cell cycle. In this study, we have examined whether the induction of putrescine uptake is a function of entry into the cell cycle and whether uptake activity is essential for optimal progression into the S phase. Using ribonuclease reductase subunit M1 as a marker of entry into the cell cycle, we have shown that hepatocytes enter G1 during the first 4 hr of culture. Both putrescine uptake and ornithine decarboxylase activity increased as the cells entered G1. Treatment of the cells with retinoic acid (10 to 33 mumol/L) prevented them from entering G1 and also inhibited the induction of the putrescine transporter by up to 90%. In contrast, initiation of G1 to S phase transition markedly down-regulated the activity of the transporter. Thus induction of the putrescine transporter in isolated hepatocytes appears to be a G1-specific event. Culturing the hepatocytes in the presence of 1,1'-bis[3-(1'-methyl-[4,4'-bipyridinium]-1-yl)-propyl]- 4,4'-bipyridinium, a potent competitive inhibitor of putrescine uptake, resulted in a 47% decrease in intracellular putrescine.(ABSTRACT TRUNCATED AT 250 WORDS)",0
618,1959888,"Autoantibody against dihydrolipoamide dehydrogenase, the E3 subunit of the 2-oxoacid dehydrogenase complexes: significance for primary biliary cirrhosis","Autoantibodies in primary biliary cirrhosis recognize mitochondrial 2-oxacid dehydrogenase complexes, particularly the E2 subunits. Reactivity with the E3 subunit, common to each of the enzyme complexes, was sought by immunoblotting, with sera screened at 1:100 instead of the conventional 1:1,000 dilution. This was found in 11 of 29 sera from patients with primary biliary cirrhosis but also in 10 of 40 sera from normal subjects. Two-dimensional immunoblotting and immunoblotting on purified enzymes established that the reactivity was actually with E3 rather than with another component of the 2-oxoacid enzymes of similar molecular weight. Purified antibodies to E3 eluted from an affinity column did not cross-react with other components of the 2-oxoacid enzyme complexes. The antibodies to E3 did not react with the Escherichia coli or yeast E3 subunits, suggesting that they are not stimulated by immune responses against microorganisms. Thus the proposal that reactivity to the shared E3 subunit of the 2-oxoacid enzyme complexes could initiate primary biliary cirrhosis is not reflected at the antibody level.",0
619,1975247,HLA phenotypes and gene polymorphisms in juvenile liver disease associated with alpha 1-antitrypsin deficiency,"Chronic liver disease affects up to 20% of children with alpha 1-antitrypsin deficiency owing to the PiZZ genotype. Previous observations of a familial occurrence and abnormal immune responses to liver antigens in these patients suggests that immunoregulatory genes may be involved in the pathogenesis of liver damage. We have identified HLA phenotypes and class II (HLA-DR) gene polymorphisms in 140 white PiZZ subjects, of whom 92 (83 index patients) had liver disease, and 206 first-degree relatives. DR3* was present in 35 of 75 (46.7%) unrelated patients with liver disease compared with 5 of 28 (17.8%) patients without (p less than 0.01) and 23 of 100 controls (p less than 0.001). DR4 was increased in patients without liver disease; it was present in 17 of 28 (60.7%) compared with 29 of 75 (38.7%) patients with liver disease (p less than 0.05) and 36 of 100 controls (p less than 0.025). Using Southern blot analysis with HLA-DRB and DQB DNA probes, we identified two polymorphisms of DR3, only one (Dw25) of which is raised in PiZZ individuals with liver disease (9 of 55: 16.4%) compared with 1 of 23 (4.4%) without and 2 of 52 (3.9%) controls (p less than 0.05). Analysis of the segregation of HLA haplotypes in 77 families revealed no concordance for liver disease with HLA in those with affected sibships, indicating that, although DR3-Dw25 is associated with liver disease in alpha 1-antitrypsin deficiency, other factors must play a pathogenic role.",0
620,1977080,A pilot study of low-dose zidovudine in human immunodeficiency virus infection,"BACKGROUND: Zidovudine delays the progression of human immunodeficiency virus (HIV) infection but is associated with hematologic toxicity at high doses. Regimens are needed that preserve or enhance efficacy and reduce toxicity. Acyclovir has been reported to potentiate the effect of zidovudine on HIV in vitro. METHODS: We conducted a Phase II open-label, dose-escalating trial to evaluate the clinical and antiviral effects of zidovudine at low (300 mg daily, 28 subjects), medium (600 mg, 24 subjects), and high (1500 mg, 15 subjects) doses, either with or without acyclovir (4.8 g) by random assignment. The subjects had the acquired immunodeficiency syndrome (AIDS)-related complex, but not AIDS. All of them had either HIV p24 antigenemia or plasma viremia and CD4-lymphocyte counts of 200 to 500 per cubic millimeter when they began treatment. RESULTS: Performance scores and fatigue improved the most in the low- and medium-dose zidovudine groups (both P less than or equal to 0.025). Those assigned to low-dose zidovudine gained the most weight and had the greatest improvement in the mean CD4-lymphocyte count (from 321 per cubic millimeter at base line to 412 per cubic millimeter after 12 weeks, P = 0.01). The proportion of subjects in whom HIV antigenemia resolved, the decrease in the level of antigenemia, and the reduction in the plasma virus titers were similar at all three doses. Subjects assigned to receive the low or medium dose who subsequently crossed over to the 1500-mg dose (n = 19) did not have an increase in CD4-cell counts or a decline in levels of HIV antigen, but they did have dose-related toxicity. The addition of acyclovir to zidovudine was well tolerated, but it did not enhance any of zidovudine's antiretroviral effects. CONCLUSIONS: In this pilot study a very low dose of zidovudine (300 mg) had clinical and virologic effects similar to those of higher daily doses (600 and 1500 mg). The minimal effective dose of zidovudine for the treatment of HIV infection has yet to be determined, and further studies of very low daily doses are warranted.",0
621,1984160,The effect of epilepsy or diabetes mellitus on the risk of automobile accidents,"BACKGROUND: Previous studies of possible associations between chronic medical conditions and traffic safety have been inconsistent and subject to bias because of the incomplete identification of affected persons. Recent advances in the diagnosis and management of epilepsy and diabetes mellitus have improved the control of these disorders and suggest a need to reexamine the risk of traffic mishaps among patients with these conditions. METHODS: We conducted a population-based retrospective cohort study of 30,420 subjects 16 to 90 years of age, with and without epilepsy or diabetes mellitus. Subjects included all the licensed drivers in seven contiguous ZIP Code areas in which the Marshfield Clinic and St. Joseph's Hospital, Marshfield, Wisconsin, are the primary sources of medical care. Standardized rates of moving violations and accidents over a four-year period (1985 through 1988) were compared in affected and unaffected cohorts. RESULTS: Standardized mishap ratios for subjects with diabetes were 1.14 for all moving violations (P = 0.23) and 1.32 for accidents (P = 0.01); for subjects with epilepsy the ratios were 1.13 for moving violations (P = 0.26) and 1.33 for accidents (P = 0.04). CONCLUSIONS: We conclude that drivers with epilepsy or diabetes mellitus have slightly increased risks of traffic accidents as compared with unaffected persons. The increases in risk observed in our study were generally smaller than those in previous studies, and we believe they are not great enough to warrant further restrictions on driving privileges.",0
622,1984193,An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987),"BACKGROUND: Phenacetin abuse is known to produce kidney disease; salicylate use is supposed to prevent cardiovascular disease. We conducted a prospective, longitudinal epidemiologic study to examine the effects of these drugs on cause-specific mortality and on cardiovascular morbidity. METHODS: In 1968 we evaluated a study group of 623 healthy women 30 to 49 years old who had evidence of a regular intake of phenacetin, as measured by urinary excretion of its metabolites, and a matched control group of 621 women. Salicylate excretion was also measured. All subjects were examined over a period of 20 years. RESULTS: Life-table analyses of mortality during the 20 years, with adjustment for the year of birth, cigarette smoking, and length of follow-up, revealed significant differences between the groups in overall mortality (study group vs. control group, 74 vs. 27 deaths; relative risk, 2.2; 95 percent confidence interval, 1.5 to 3.3), deaths due to urologic or renal disease (relative risk, 16.1; 95 percent confidence interval, 3.9 to 66.1), deaths due to cancer (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.3), and deaths due to cardiovascular disease (relative risk, 2.9; 95 percent confidence interval, 1.5 to 5.5). The relative risk of cardiovascular disease (fatal or nonfatal myocardial infarction, heart failure, or stroke) was 1.8, and the 95 percent confidence interval 1.3 to 2.6. The odds ratio for the incidence of hypertension was 1.6, and the 95 percent confidence interval 1.2 to 2.1. The effects of phenacetin on morbidity and mortality, with adjustment for base-line salicylate excretion, were similar. In contrast, salicylate use had no effect on either mortality or morbidity. CONCLUSIONS: Regular use of analgesic drugs containing phenacetin is associated with an increased risk of hypertension and mortality and morbidity due to cardiovascular disease, as well as an increased risk of mortality due to cancer and urologic or renal disease. The use of salicylates carries no such risk.",0
623,1985241,Unexplained rabies in three immigrants in the United States. A virologic investigation,"BACKGROUND: Extensive investigation of three patients who died of rabies in the United States failed to reveal any source of exposure to the disease. The three patients had immigrated to the United States from areas in Laos, the Philippines, and Mexico where rabies is endemic. METHODS: We studied rabies viruses isolated from the three patients, other patients with a known source of exposure, and animals in the United States, Thailand (as a proxy for Laos), the Philippines, and Mexico. The viruses were characterized by indirect immunofluorescence and neutralization tests according to their reactions to panels of monoclonal antibodies. Transcribed complementary DNA from these isolates was amplified by the polymerase chain reaction; the DNA product was then analyzed by differential digestion with restriction enzymes. RESULTS: The viral isolate from each of the three patients was a rabies variant with distinctive antigenic or genetic characteristics. For each of the three isolates, identical variants were found in specimens from rabid animals obtained from or near the country in which the patient lived before immigrating to the United States. None of these variants were found among the isolates collected from rabid animals in the United States. CONCLUSIONS: Rabies infection in these three patients did not originate in the United States but resulted from exposures in Laos, the Philippines, and Mexico. Since the three patients had lived in the United States for 4 years, 6 years, and 11 months, our findings suggest that the onset of the clinical manifestations of rabies occurred after long incubation periods.",0
624,1985242,"Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin","BACKGROUND: In both animal and epidemiologic studies, exposure to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD) has been associated with an increased risk of cancer. METHODS: We conducted a retrospective cohort study of mortality among the 5172 workers at 12 plants in the United States that produced chemicals contaminated with TCDD. Occupational exposure was documented by reviewing job descriptions and by measuring TCDD in serum from a sample of 253 workers. Causes of death were taken from death certificates. RESULTS: Mortality from several cancers previously associated with TCDD (stomach, liver, and nasal cancers, Hodgkin's disease, and non-Hodgkin's lymphoma) was not significantly elevated in this cohort. Mortality from soft-tissue sarcoma was increased, but not significantly (4 deaths; standardized mortality ratio [SMR], 338; 95 percent confidence interval, 92 to 865). In the subcohort of 1520 workers with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency, however, mortality was significantly increased for soft-tissue sarcoma (3 deaths; SMR, 922; 95 percent confidence interval, 190 to 2695) and for cancers of the respiratory system (SMR, 142; 95 percent confidence interval, 103 to 192). Mortality from all cancers combined was slightly but significantly elevated in the overall cohort (SMR, 115; 95 percent confidence interval, 102 to 130) and was higher in the subcohort with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency (SMR, 146; 95 percent confidence interval, 121 to 176). CONCLUSIONS: This study of mortality among workers with occupational exposure to TCDD does not confirm the high relative risks reported for many cancers in previous studies. Conclusions about an increase in the risk of soft-tissue sarcoma are limited by small numbers and misclassification on death certificates. Excess mortality from all cancers combined, cancers of the respiratory tract, and soft-tissue sarcoma may result from exposure to TCDD, although we cannot exclude the possible contribution of factors such as smoking and occupational exposure to other chemicals.",0
625,1988335,Localization of epidermal growth factor receptor in hepatocyte nuclei,"Experiments undertaken to investigate the binding of epidermal growth factor by hepatocyte nuclei showed that: (a) isolated nuclei from both normal and regenerating rat liver are capable of binding 125I-epidermal growth factor, (b) the nuclear epidermal growth factor-binding protein is similar in molecular weight to the plasma membrane epidermal growth factor receptor, (c) monoclonal antibodies produced against the plasma membrane epidermal growth factor receptor recognize the nuclear epidermal growth factor receptor and (d) the nuclear receptor has an affinity for epidermal growth factor comparable to that of the plasma membrane receptor, but fewer (approximately 10%) nuclear receptors are available per protein unit compared with the plasma membrane.",0
626,1988344,Detection of cell-CAM 105 in the pericanalicular domain of the rat hepatocyte plasma membrane,"Cell-CAM 105 has been identified as a cell adhesion molecule based on the ability of anti-cell-CAM 105 monospecific Fab fragments to inhibit the reaggregation of rat hepatocytes. Because of its adhesive properties, it was expected that cell-CAM 105 would be present on the lateral cell surface where adhesive interactions predominate. Paradoxically, however, immunofluorescence analysis of frozen sections of rat liver using specific monoclonal antibodies indicated that cell-CAM 105 was present exclusively in the bile canalicular domain of the rat hepatocyte where there is no intercellular adhesion. To more precisely define the in situ localization of cell-CAM 105, immunoperoxidase labeling and electron microscopy were used to examine intact and mechanically dissociated liver tissue. Results showed that when accessibility was provided by mechanical dissociation of perfusion fixed liver tissue, cell-CAM 105 could be detected in the pericanalicular region of lateral membranes. In contrast, when hepatocytes were labeled after incubation in vitro under conditions used during adhesion assays to induce reaggregation, cell-CAM 105 rapidly redistributed to all areas of the plasma membrane. Immunofluorescence analysis of primary hepatocyte cultures further revealed that cell-CAM 105 and two other bile canalicular proteins relocalized to discrete domains reminiscent of bile canaliculi, whereas cell-CAM 105 was also present in areas of intercellular contact. Serial section electron microscopy analysis of well-defined, cross-sectional profiles of bile canaliculi suggested the presence of cell-CAM 105-positive membrane folds that extended along the length of the bile canalicular border. In sections from livers in which calcium-dependent adhesive contacts had been disrupted by treatment with ethylenediamine tetraacetate, intact bile canaliculi were found that remained attached only by these border folds. The implications of these results are discussed with regard to a possible role for cell-CAM 105 in bile canalicular formation.",0
627,1988346,Specificity of the hepatocyte Na(+)-dependent taurocholate transporter: influence of side chain length and charge,"Trihydroxy bile acids with differing nonsterol chain length and charge were synthesized to define the effect of these parameters on the ability to competitively inhibit the Na(+)-dependent uptake of 14C taurocholate into isolated rat hepatocytes. Compounds with long side chains (greater than or equal to 0.8 nm) beyond carbon-17 of the sterol nucleus and carrying a negative charge or no charge were potent inhibitors. Introduction of a positive charge into the side chain weakened inhibition. When the length of the chain beyond carbon-17 fell below about 0.7 nm, charge still influenced inhibitory potency, but the effect was reversed and positively-charged chains yielded slightly greater inhibition than negatively-charged chains. From these results one may postulate a positively-charged cell surface domain extending outward from a point about 0.7 nm from the sterol nucleus receptor region. Up to about 0.7 nm from the sterol nucleus receptor region one might postulate a negative cell surface charge to account for the weaker inhibitory potency of compounds with short negatively-charged chains. Nonetheless, a short chain, regardless of charge, weakened inhibition, suggesting that a long negatively-charged side chain is necessary to orient the sterol moiety for optimal receptor fit. These data confirm that the Na(+)-dependent taurocholate transport site is sensitive to alterations of side chain charge and length and emphasize the importance of structure when designing bile acid analogs to probe taurocholate transport mechanisms.",0
628,1992320,Lifetime use of nursing home care,"BACKGROUND AND METHODS: Despite the growth in the number of Americans in nursing homes, there are only limited data on the total amount of time that people spend in such facilities. We estimate the amount of time the average person spends in nursing homes over his or her lifetime (lifetime nursing home use), using data from the National Mortality Followback Survey of the next of kin of a sample of persons 25 years of age or older who died in 1986. On the basis of these data, we estimated the likelihood that Americans will use nursing home care during the course of their lifetimes and the total duration of such care. Current data on life expectancy were then used to reweight the sample to project lifetime nursing home use for those who became 65 years old in 1990. RESULTS: Of those who died in 1986 at 25 years of age or older, 29 percent had at some time been residents in a nursing home, and almost half of those who entered a nursing home spent a cumulative total of at least one year there. The probability of nursing home use increased sharply with age at death: 17 percent for age 65 to 74, 36 percent for age 75 to 84, and 60 percent for age 85 to 94. For persons who turned 65 in 1990, we project that 43 percent will enter a nursing home at some time before they die. Of those who enter nursing homes, 55 percent will have total lifetime use of at least one year, and 21 percent will have total lifetime use of five years or more. We also project that more women than men will enter nursing homes (52 percent vs. 33 percent), and among them, more women than men will have total lifetime nursing home use of five years or more (25 percent vs. 13 percent). CONCLUSIONS: Our projections indicate that over a lifetime, the risk of entering a nursing home and spending a long time there is substantial. With the elderly population growing, this has important implications for both medical practice and the financing of long-term care.",0
629,1997838,Video display terminals and the risk of spontaneous abortion,"BACKGROUND: The relation between spontaneous abortion and the use of video display terminals (VDTs) is of great public health concern. Previous investigators of this issue have reported inconsistent findings. METHODS: To determine whether electromagnetic fields emitted by VDTs are associated with an increased risk of spontaneous abortion, a cohort of female telephone operators who used VDTs at work was compared with a cohort of operators who did not use VDTs. To obtain reliable estimates of exposure, we determined the number of hours of VDT use per week from company records and measured electromagnetic fields at VDT workstations and, for purposes of comparison, at workstations without VDTs. Operators who used VDTs had higher abdominal exposure to very-low-frequency (15 kHz) electromagnetic fields (workstations without VDTs did not emit very-low-frequency energy). Abdominal exposure to extremely-low-frequency fields (45 to 60 Hz) was similar for both operators who used VDTs and those who did not. Among 2430 women interviewed, there were 882 pregnancies that met our criteria for inclusion in the study. RESULTS: We found no excess risk of spontaneous abortion among women who used VDTs during the first trimester of pregnancy (odds ratio = 0.93; 95 percent confidence interval, 0.63 to 1.38), and no dose-response relation was apparent when we examined the women's hours of VDT use per week (odds ratio for 1 to 25 hours per week = 1.04; 95 percent confidence interval, 0.61 to 1.79; odds ratio for greater than 25 hours per week = 1.00; 95 percent confidence interval, 0.61 to 1.64). There continued to be no risk associated with the use of VDTs when we accounted for multiple pregnancies, conducted separate analyses of early abortion, late abortion, and all fetal losses, or limited our analyses to spontaneous abortions for which a physician was consulted. CONCLUSIONS: The use of VDTs and exposure to the accompanying electromagnetic fields were not associated with an increased risk of spontaneous abortion in this study.",0
630,1999313,Expression of X protein and hepatitis B virus replication in chronic hepatitis,"The X protein can act on the enhancer of hepatitis B virus in an in vitro system and elevate the transcriptional level of hepatitis B virus. However, because no relationship had been reported between X protein expression and hepatitis B virus replication in patients with chronic hepatitis B, we focused on its expression in the liver in comparison with markers of hepatitis B virus replication. Liver biopsy samples and sera from 59 carriers with HBsAg were examined immunohistochemically for X protein using rabbit IgG against recombinant X protein. There was a significant difference in the serum hepatitis B virus DNA level between X protein-positive and -negative patients (p less than 0.001). Serum pre-S1 and pre-S2 antigens were also measured quantitatively by enzyme immunoassay using monoclonal antibodies specific against each antigen. The titers of pre-S1 antigen in patients positive for X protein were significantly higher (p less than 0.001) than those of the X protein-negative patients (3.02 +/- 0.99 vs. 2.00 +/- 0.59, respectively). Similarly, the titers of pre-S2 antigen were 2.98 +/- 0.91 vs. 1.94 +/- 0.54, respectively (p less than 0.001). The rate of positivity of the X protein was higher (38 of 49; 77.6%) in the replicative group (serum HBeAg, serum hepatitis B virus DNA or HBcAg in liver positive) compared with that observed in the nonreplicative group (3 of 10; 30%--serum HBeAg, serum hepatitis B virus DNA and HBcAg in liver negative) (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)",0
631,1999318,Autoantibodies in primary biliary cirrhosis: analysis of reactivity against eukaryotic and prokaryotic 2-oxo acid dehydrogenase complexes,"Six components of the mammalian 2-oxo acid dehydrogenase complexes have previously been identified as M2 autoantigens in primary biliary cirrhosis. In this report, we present data showing that both polypeptide-specific and cross-reacting antibodies are present in patients' sera. Antibodies reacting with E2 of the pyruvate dehydrogenase complex cross-react with protein X but not with any other mammalian antigen. The main immunogenic region on protein X has been localized to within its single lipoyl domain. Polypeptide-specific antibodies bind to E1 alpha and E1 beta of the pyruvate dehydrogenase complex. Antibodies reacting with the E2 polypeptides of the 2-oxoglutarate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex show some cross-reactivity but do not recognize any of the antigens of the pyruvate dehydrogenase complex. Antibodies against the E2 component of the mammalian pyruvate dehydrogenase complex cross-react effectively with the corresponding protein from yeast but not with E2 from Escherichia coli. Antibody titer against mammalian antigens is significantly higher than against the bacterial antigens, arguing against a bacterial origin for primary biliary cirrhosis.",0
632,2005938,Diagnosis of magnesium-induced diarrhea,"BACKGROUND: There is no specific method of diagnosing magnesium-induced diarrhea. Therefore, the frequency and clinical importance of diarrhea caused by magnesium are unknown. The purposes of this study were to establish a method for diagnosing magnesium-induced diarrhea and to apply it to patients with chronic diarrhea. METHODS: We measured fecal output of soluble magnesium and fecal magnesium concentration in 19 normal subjects with formed stools (15 collection periods), with non-magnesium-induced diarrhea (36 collection periods), and with diarrhea induced by magnesium hydroxide alone (11 collection periods) or in combination with phenolphthalein (3 collection periods), and in 359 patients with chronic diarrhea. RESULTS: The upper limits of fecal output of soluble magnesium and fecal magnesium concentration in normal subjects were 14.6 mmol per day and 45.2 mmol per liter, respectively. When normal subjects had diarrhea due to the ingestion of magnesium hydroxide alone or in combination with phenolphthalein, fecal magnesium output was always abnormally high. For each millimole increase in fecal magnesium output, fecal weight increased by approximately 7.3 g. The fecal magnesium concentration was very high when magnesium was the only cause of diarrhea but only moderately elevated when diarrhea was induced by magnesium hydroxide plus phenolphthalein. Biochemical and clinical evidence indicated that excessive ingestion of magnesium was an important cause of chronic diarrhea in 15 of the 359 patients with chronic diarrhea (4.2 percent), if not the only cause. CONCLUSIONS: Quantitative fecal analysis for soluble magnesium is an accurate method of diagnosing magnesium-induced diarrhea. Some patients with chronic diarrhea ingest excessive amounts of magnesium (in antacids or food supplements), and physicians may fail to discover this before embarking on an expensive and invasive diagnostic evaluation.",0
633,2005940,National allocation of cadaveric kidneys by HLA matching. Projected effect on outcome and costs,"BACKGROUND: Although receiving a cadaveric kidney matched at the HLA-A, B, and DR loci enhances graft survival in cyclosporine-treated patients, the value of a national system of kidney allocation based on HLA matching, with the attendant increased likelihood of better matching, is still questioned. Some fear that the costs of a national system are unjustified when only a small fraction of donors would exactly match any of the 16,000 potential recipients anyway. We estimated the effect on graft survival of the use of HLA matching for all allocations of cadaveric kidneys in the United States. METHODS: The graft-survival rates in five mutually exclusive groups of transplants with increasing numbers of HLA mismatches were estimated by partitioning the data for 22,190 first-time recipients of cadaveric kidneys. Overall graft survival was projected as a weighted average with use of the percentages of transplants in the hierarchical groups in recipient waiting pools of various sizes. We compared the benefits and costs of HLA matching in a national system with those of introducing cyclosporine, which was projected to enhance graft survival by 7 percentage points at 10 years. RESULTS: Sharing kidneys nationally on the basis of hierarchical HLA matching was estimated to enhance graft survival by an additional 5 percentage points at 10 years. The anticipated five-year cost of national allocation of kidneys by HLA matching for 7000 recipients, including consideration of the costs of graft removal and dialysis after transplant rejection, would be +4F6.5 million less than the cost of using cyclosporine alone. CONCLUSIONS: The use of an HLA allocation system will not add to the cost of renal transplantation, but it will improve the long-term results to the same extent as cyclosporine. We propose the initiation of a national kidney-sharing system based on hierarchical levels of HLA matches.",0
634,2010158,Determination of hepatitis B virus DNA in serum using the polymerase chain reaction: clinical significance and correlation with serological and biochemical markers,"Sera from 98 patients with various stages of chronic hepatitis B virus infection were studied to determine the clinical significance of hepatitis B virus DNA in serum detected by the polymerase chain reaction. Patients were divided into three groups according to their HBsAg and HBeAg status. Group I (n = 31) had detectable HBsAg and HBeAg, group II (n = 46) had HBsAg but not HBeAg and group III (n = 21) consisted of patients who were once chronic hepatitis B virus carriers but had lost HBsAg during follow-up. Group I patients usually had significant liver disease (raised serum aminotransferases), had higher titers of HBsAg and had been infected with hepatitis B virus for a shorter period than patients in the other two groups. All patients in group I had hepatitis B virus DNA detectable by polymerase chain reaction and 94% had sufficient hepatitis B virus DNA present for detection by dot-blot hybridization. Group II patients had lower mean serum aminotransferase activities and titers of HBsAg than those in group I. Serum hepatitis B virus DNA was detectable by polymerase chain reaction in 78% but in only 30% of group II patients by dot-blot hybridization. Group II patients who did not have hepatitis B virus DNA detectable by polymerase chain reaction had mean serum aminotransferase levels within the normal range and had a younger mean age than those with hepatitis B virus DNA. Group III patients generally had no evidence of active liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)",0
635,2010169,"Extrahepatic bile duct growth in mice repeatedly injected with human normal serum, IgA-deficient serum or purified secretory IgA","Another group of researchers has reported that seven intraperitoneal injections into mice of purified human serum IgA or normal human serum--but not IgA-deficient serum, mouse serum or saline--induced considerable growth of the extrahepatic bile duct epithelium. They stated that heterologous IgA was principally responsible for this effect. We have quantitated this growth by another method: enumeration of total and radiolabeled nuclei of the lumenal and glandular epithelium in transverse duct sections after tritiated thymidine injection and autoradiography. Our data show maximal incorporation between 18 and 24 hr after the last injection, with the highest labeling index in the lumenal epithelium after only three injections and before any duct enlargement. After four to seven injections, thymidine incorporation continued in juxtalumenal glands, together with massive glandular proliferation into the thickening wall and obvious inflammation. These changes were more pronounced in the liver-proximal part of the duct without affecting intrahepatic duct and gallbladder epithelia. Subcutaneous serum injections were less active. We confirm the inactivity of buffered saline, but, unlike previous authors, demonstrate strong activity in purified human milk secretory IgA and in IgA-deficient serum. We suggest that this different approach of quantitating epithelial proliferation will allow comparison of the bile duct growth effects of different, well-characterized human and animal IgA preparations.",0
636,2014037,Ruling out acute myocardial infarction. A prospective multicenter validation of a 12-hour strategy for patients at low risk,"""BACKGROUND: Although previous investigations have suggested that 24 hours is required to exclude acute myocardial infarction in patients who are admitted to a coronary care unit for the evaluation of acute chest pain, we hypothesized that a 12-hour period might be adequate for patients with a low probability of infarction at the time of admission. METHODS: Using a Bayesian model, we developed a strategy to identify candidates for a shorter period of observation from an analysis of a derivation set of 976 patients with acute chest pain who were admitted to three teaching and four community hospitals. In the derivation set, patients whose clinical characteristics in the emergency room predicted a low (less than or equal to 7 percent) probability of myocardial infarction had only a 0.4 percent risk of infarction if they had neither abnormal levels of cardiac enzymes nor recurrent ischemic pain during the first 12 hours of hospitalization. In an independent testing set of 2684 patients from the seven hospitals, 957 admitted patients (36 percent) were classified as candidates for this 12-hour period of observation according to a previously published multivariate algorithm. Few of these patients were actually transferred from a monitored setting at 12 hours. RESULTS: Of the 771 candidates for a 12-hour period of observation who did not have enzyme abnormalities or recurrent pain during the first 12 hours, 4 (0.5 percent) were subsequently found to have acute myocardial infarction, and only 3 (0.4 percent) died after primary cardiac arrests, all of which occurred three to five days after admission. Rates of other major cardiovascular complications were low in the patients who might have been transferred from the coronary care unit after 12 hours with this strategy. In patients with a higher initial risk of infarction, the standard strategy of 24-hour observation identified all but 11 of 739 acute myocardial infarctions (1 percent). CONCLUSIONS: Emergency room clinical data can be used to identify a large subgroup of patients for whom a 12-hour period of observation is normally sufficient to exclude acute myocardial infarction. Patient-specific evaluation and treatment can then proceed without the restrictions imposed by """"rule-out"""" protocols for myocardial infarction.""",0
637,2017226,Renal hemodynamics and the renin-angiotensin-aldosterone system in normotensive subjects with hypertensive and normotensive parents,"BACKGROUND AND METHODS: The kidney is important in blood-pressure regulation, but its role in the development of essential hypertension is still subject to debate. We compared renal hemodynamics, measured in terms of the clearance of para-aminohippuric acid and inulin, and the characteristics of the renin-angiotensin-aldosterone system in three groups of normotensive subjects at different degrees of risk for hypertension: 41 subjects with two normotensive parents, 52 with one normotensive and one hypertensive parent, and 61 with two hypertensive parents. The subjects ranged in age from 7 to 32 years. RESULTS: The mean renal blood flow was lower in the subjects with two hypertensive parents than in those with two normotensive parents (mean difference [+/- SE], 198 +/- 61 ml per minute per 1.73 m2 of body-surface area; P = 0.002). Moreover, both the filtration fraction and renal vascular resistance were higher in the subjects with two hypertensive parents (filtration fraction: mean difference, 3.0 +/- 1.1 percentage points; P = 0.006; renal vascular resistance: mean difference, 2.7 +/- 0.8 mm Hg per deciliter per minute per 1.73 m2; P = 0.006). The subjects with two hypertensive parents had lower plasma concentrations of renin (mean difference, 3.3 +/- 1.6 mU per liter; P = 0.03) and aldosterone (mean difference, 111 +/- 36 pmol per liter; P = 0.003) than those with two normotensive parents. The differences could not be explained by the small differences in blood pressure between the groups. The values in the subjects with one hypertensive and one normotensive parent fell between those for the other two groups. CONCLUSIONS: Renal vasoconstriction is increased and renin and aldosterone secretion is decreased in young persons at risk for hypertension. These findings support the hypothesis that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension.",0
638,2023607,Emergency management of blunt trauma in children,"Apart from the trend to nonoperative treatment of blunt abdominal injuries, based on accurate CT diagnosis, most of the recent and anticipated changes in pediatric trauma are organizational. They include resuscitation and triage before hospitalization, the use of designated trauma centers, resuscitation by trauma teams, noninvasive diagnosis and monitoring, comprehensive pediatric intensive care, the use of objective measures of outcome, and improved rehabilitation programs (Templeton JM: personal communication). The treatment of individual cases is based on simple but well-established principles. The key steps in management are to recognize children with life-threatening injuries (on the basis of the mechanism of injury or a Pediatric Trauma Score less than or equal to 8 or a Revised Trauma Score less than or equal to 11), to support the function of vital organs by establishing and maintaining adequate respiratory gas exchange and circulation, and to identify all important injuries by thorough and ongoing assessment.",0
639,2029993,Bioelectric impedance analysis: experience with male patients with cirrhosis,"""Bioelectric impedance analysis is a new, convenient and portable method used to estimate total body water and to assess body composition in healthy people. We used the tetrapolar bioelectrical impedance analysis method in 58 cirrhotic patients to assess its clinical applicability. Whole-body resistance, reactance and impedance were measured and compared with those of 30 healthy volunteers matched for age and sex. The resistance and impedance values of ascitic cirrhotic patients (resistance = 461 +/- 80 omega; impedance = 462 +/- 80 omega) and nonascitic cirrhotic patients (resistance = 487 +/- 96 omega; impedance = 489 +/- 97 omega) were comparable with the resistance (488 +/- 44 omega) and impedance (491 +/- 44 omega) of controls. However, a significant (p less than 0.05) reduction in whole body reactance was found in patients with ascites and in those without ascites (34 +/- 9 omega vs. 47 +/- 12 omega) as compared with healthy subjects (56 +/- 7 omega). In 10 ascitic patients total body water was determined both before and after paracentesis; the volume of intraperitoneal fluid removed (7.9 +/- 3.8 L) could not be fully accounted for but only detected as an average volume of 1.9 +/- 1.0 L independently of the initial volume of the ascites. Our data clearly demonstrate that tetrapolar bioelectric impedance analysis is not adequate for measuring variations of """"compartmentalized"""" fluid in the abdomen.""",0
640,2029995,Plasma catecholamines in patients with presinusoidal portal hypertension: comparison with cirrhotic patients and nonportal hypertensive subjects,"During a hemodynamic study, plasma catecholamine concentrations were measured in the pulmonary artery and in the hepatic vein in 18 presinusoidal portal hypertensive patients. Results were compared with those in 15 nonportal hypertensive subjects and in 24 cirrhotic patients in good condition (grade A, according to Pugh's classification). Plasma norepinephrine concentrations in the pulmonary artery or in the hepatic vein were not significantly different between nonportal hypertensive subjects (mean +/- S.E.M.: 271 +/- 36 and 83 +/- 11 pg/ml, respectively) and presinusoidal portal hypertensive patients (273 +/- 33 and 84 +/- 11 pg/ml, respectively). These concentrations were, however, elevated in cirrhotic patients (408 +/- 47 and 256 +/- 45 pg/ml, p less than 0.05 in comparison with the two other groups). These differences suggest that increased sympathetic nervous activity in cirrhosis is associated with the presence of liver disease or increase in sinusoidal pressure. Differences in plasma epinephrine concentrations were not significant among the three groups of patients. However, the existence of a significant correlation between pulmonary artery plasma epinephrine concentration and cardiac index (r2 = 0.46, p less than 0.01) in patients with presinusoidal portal hypertension suggests that the adrenal medulla could play a role in the pathophysiology of the hyperkinetic syndrome of these patients.",0
641,2030001,Involvement of cell calcium and transmembrane potential in control of hepatocyte volume,"This study examined the role of hepatocyte calcium and cytoskeleton in activation of hyposmotic stress-induced increases in hepatocyte transmembrane potential and control of cell volume. Hepatocyte transmembrane potential was measured by glass microelectrodes in mouse liver slices before and after exposure to hyposmotic medium. Hepatocytes were loaded with tetramethylammonium by briefly exposing liver slices to nystatin, a cation poreforming antibiotic. Changes in hepatocyte steady-state water volume were determined by changes in intracellular tetramethylammonium activity measured with tetramethylammonium-sensitive, double-barrel micro-electrodes 4 min after exposure to hyposmotic medium. Hyposmotic stress of 74% of the control osmolality (approximately 280 mOsm) hyperpolarized hepatocyte transmembrane potential by 1.83 times the control hepatocyte transmembrane potential, and cell water volume increased by a factor of 1.19. The Ca2+ channel blocker verapamil (100 mumol/L) completely inhibited hyposmotic stress-induced hyperpolarization of hepatocyte transmembrane potential. This inhibitory effect diminished at doses of 37.5 or 50 mumol/L, but even these hyperpolarizations were decreased significantly compared with control. Hyposmotic stress during added verapamil dosage (50 mumol/L) also resulted in 23% greater cell swelling compared with control. Ca(2+)-free medium plus ethylene glycol-bis (beta-aminoethylether)-N,N'-tetraacetic acid (5 mmol/L) inhibited hyposmotic stress-induced increases in hepatocyte transmembrane potential and resulted in 16% greater cell swelling compared with control. Calmodulin inhibitors trifluoperazine (100 mumol/L) and promethazine (100 mumol/L) inhibited the hyperpolarization of hepatocyte transmembrane potential caused by hyposmolality, as did 3,4,5-trimethoxybenzoate 8-(N,N-diethylamino)octyl ester) (50 mumol/L), which inhibits mobilization of Ca2+ from intracellular stores. Cytochalasin B (50 mumol/L), which disrupts microfilaments, also inhibited hyperpolarization of hepatocyte transmembrane potential with osmotic stress.(ABSTRACT TRUNCATED AT 250 WORDS)",0
642,2030718,Smoking and mortality among older men and women in three communities,"BACKGROUND: Although cigarette smoking is the leading avoidable cause of premature death in middle age, some have claimed that no association is present among older persons. METHODS: We prospectively examined the relation of cigarette-smoking habits with mortality from all causes, cardiovascular causes, and cancer among 7178 persons 65 years of age or older without a history of myocardial infarction, stroke, or cancer who lived in one of three communities: East Boston, Massachusetts; Iowa and Washington counties, Iowa; and New Haven, Connecticut. At the time of the initial interview, prevalence rates of smoking in the three communities ranged from 5.2 to 17.8 percent among women and from 14.2 to 25.8 percent among men. During five years of follow-up there were 1442 deaths, 729 due to cardiovascular disease and 316 due to cancer. RESULTS: In both sexes, rates of total mortality among current smokers were twice what they were among participants who had never smoked. Relative risks, as adjusted for age and community, were 2.1 among the men (95 percent confidence interval, 1.7 to 2.7) and 1.8 among the women (95 percent confidence interval, 1.4 to 2.4). Current smokers had higher rates of cardiovascular mortality than those who had never smoked (as adjusted for age and community, the relative risk was 2.0 [95 percent confidence interval, 1.4 to 2.9] among the men and 1.6 [95 percent confidence interval, 1.1 to 2.3] among the women), as well as increased rates of cancer mortality (relative risk, 2.4 [95 percent confidence interval, 1.4 to 4.1] among the men and 2.4 [95 percent confidence interval, 1.4 to 3.9] among the women). In both sexes, former smokers had rates of cardiovascular mortality similar to those of the participants who had never smoked, regardless of age at cessation, whereas the rates for all cancers, as well as smoking-related cancers, remained elevated among men who had once smoked. CONCLUSIONS: Our prospective findings indicate that the mortality hazards of smoking extend well into later life, and suggest that cessation will continue to improve life expectancy in older people.",0
643,2034245,Sensitivity to triazolam in the elderly,"BACKGROUND: Elderly persons frequently appear to be sensitive to the effects of many drugs that depress the central nervous system. We studied the effect of age on the pharmacokinetics and pharmacodynamics of the benzodiazepine hypnotic agent triazolam, now the most frequently prescribed hypnotic drug in the United States. METHODS: Twenty-six healthy young subjects (mean age, 30 years) and 21 healthy elderly subjects (mean age, 69 years) participated in a four-way crossover study. After a single-blind adaptation trial with placebo, each subject received, in random order and in double-blind fashion, single doses of placebo, 0.125 mg of triazolam, and 0.25 mg of triazolam. For 24 hours after the administration of each of the three study medications, plasma triazolam levels were determined and psychomotor performance, memory, and degree of sedation were assessed. RESULTS: Plasma triazolam concentrations increased in proportion to the dose, but the elderly subjects had higher plasma concentrations due to reduced clearance of the drug. The degree of sedation as rated by an observer and the reduction in the subjects' performance on the digit-symbol substitution test were both greater in the elderly than in the young subjects after they were given the same doses. The relation of the plasma triazolam concentration to the degree of impairment was similar for the two groups. As part of the study, information was presented 1 1/2 hours after the administration of the drugs; the subjects' ability to recall the information 24 hours later was impaired by both doses of triazolam, and the percent decrease was similar in the young and elderly groups. CONCLUSIONS: Triazolam caused a greater degree of sedation and greater impairment of psychomotor performance in healthy elderly persons than in young persons who received the same dose. These effects resulted from reduced clearance and higher plasma concentrations of triazolam rather than from an increased intrinsic sensitivity to the drug. On the basis of these results, the dosage of triazolam for elderly persons should be reduced on average by 50 percent.",0
644,2041549,"Recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside","BACKGROUND: Spinal-cord injury is devastating; until recently, there was no medical treatment to improve recovery of the initial neurologic deficit. Studies in animals have shown that monosialotetrahexosylganglioside (GM-1) ganglioside enhances the functional recovery of damaged neurons. METHODS: A prospective, randomized, placebo-controlled, double-blind trial of GM-1 ganglioside was conducted in patients with spinal-cord injuries. Of 37 patients entered into the study, 34 (23 with cervical injuries and 11 with thoracic injuries) completed the test-drug protocol (100 mg of GM-1 sodium salt or placebo intravenously per day for 18 to 32 doses, with the first dose taken within 72 hours of the injury) and a one-year follow-up period. Neurologic recovery was assessed with the Frankel scale (comprising five categories) and the American Spinal Injury Association (ASIA) motor score (a scale of scores from 0 to 100, derived from strength tests of 20 specific muscles, each scored from 0 to 5). RESULTS: There was a significant difference between groups in the distribution of improvement of Frankel grades from base line to the one-year follow-up (improvement of 0, 1, 2, and 3 grades in 13, 4, 1, and 0 patients, respectively, in the placebo group and 8, 1, 6, and 1 patients, respectively, in the GM-1 group; P = 0.034 by the Cochran-Mantel-Haenszel chi-square test). The GM-1-treated patients also had a significantly greater mean improvement in ASIA motor score from base line to the one-year follow-up than the placebo-treated patients (36.9 vs. 21.6 points; P = 0.047 by analysis of covariance with the base-line ASIA motor score as the covariate). An analysis of individual muscle recoveries revealed that the increased recovery in the GM-1 group was attributable to initially paralyzed muscles that regained useful motor strength rather than to strengthening of paretic muscles. CONCLUSIONS: This small study provides evidence that GM-1 enhances the recovery of neurologic function after one year. A larger study must be conducted, however, before GM-1 is considered efficacious and safe in treating spinal-cord injury.",0
645,2046708,Evaluation of screened blood donations for human immunodeficiency virus type 1 infection by culture and DNA amplification of pooled cells,"BACKGROUND: Reports of transmission of the human immunodeficiency virus type 1 (HIV-1) from transfusions of screened blood and reports of silent, antibody-negative HIV-1 infections in persons at high risk continue to foster concern about the safety of the blood supply. Previous estimates of the risk of HIV-1 range from 1 in 38,000 to 1 in 300,000 per unit of blood but are based on either epidemiologic models or the demonstration of seroconversion in recipients. METHODS: We isolated peripheral-blood mononuclear cells from blood that was fully screened and found to be seronegative, combined them into pools of cells from 50 donors, and tested them for HIV-1 by viral culture and the polymerase chain reaction, using protocols specifically adapted for this analysis. RESULTS: The 1530 pools of mononuclear cells were prepared from 76,500 blood donations made in San Francisco between November 1987 and December 1989. Of these pools, 1436 (representing 71,800 donations) were cultured successfully; 873 (43,650 donations) were evaluated by the polymerase chain reaction. Only one pool was confirmed as HIV-1--infected by both methods. After adjustment for sample-based estimates of the sensitivity of the detection systems using culture and the polymerase chain reaction, the probability that a screened donor will be positive for HIV-1 was estimated as 1 in 61,171 (95 percent upper confidence bound, 1 in 10,695). CONCLUSIONS: Silent HIV-1 infections are exceedingly rare among screened blood donors, so the current risk of HIV-1 transmission from blood transfusions, even in high-prevalence metropolitan areas, is extremely low.",0
646,2050320,Hepatitis B virus infection in patients with idiopathic liver disease,"We studied 67 HBsAg-negative Israeli patients (36 negative for all HBV serological markers as group 1 and 31 positive for antibodies to HBs and HBc as group 2) with chronic liver disease and cirrhosis of unknown origin using a rapid, sensitive and specific assay for the detection of low levels of hepatitis B virus in serum. This technique uses a high-affinity monoclonal antibody to HBs against an a domain epitope of HBsAg to capture the virion, followed by hepatitis B virus DNA amplification with the polymerase chain reaction. In addition, 55 subjects without liver disease served as controls: Group 3 (n = 32) was negative for all hepatitis B virus markers; group 4 (n = 23) was positive for antibodies to HBs and HBc. We found 11 individuals in group 1 (31%) and 10 in group 2 (29%) harboring low levels of hepatitis B virus DNA in serum. In contrast, no one in group 3 or group 4 was positive by this technique (p less than 0.0001). Using polymerase chain reaction primers spanning other regions of the hepatitis B virus genome and a method of restriction-fragment analysis of polymerase chain reaction-amplified sequences, we detected significant DNA sequence heterogeneity, suggesting infection with distinct hepatitis B virus strains. DNA extracted from paraffin-embedded liver biopsy specimens of 42 patients from groups 1 and 2 was shown to contain hepatitis B virus DNA by polymerase chain reaction in 11 of 12 patients with circulating virion DNA. More important, 18 additional patients whose sera were negative by HBs-antibody capture/polymerase chain reaction amplification had hepatitis B virus DNA sequences in their livers.(ABSTRACT TRUNCATED AT 250 WORDS)",0
647,2050333,Ethanol-induced changes in hepatic free radical defense mechanisms and fatty-acid composition in the miniature pig,"In the miniature pig, ethanol consumption has been reported to induce alterations in hepatic antioxidant defense capacity, which could result in increased risk of peroxidative damage. However, ethanol may also induce changes in membrane fatty acid composition, which could reduce the risk of peroxidative damage. This study examined lipid peroxidation, antioxidant defense and fatty acid composition in livers from miniature pigs fed ethanol in diets containing 12% of their calories as fat for 20 mo. After 12 and 20 mo of feeding, ethanol-fed pigs had higher hepatic manganese-superoxide dismutase activity, lower hepatic copper concentrations and low hepatic copper-zinc-superoxide dismutase and glutathione peroxidase activities compared with controls. Lipid peroxidation as assessed by thiobarbituric acid reacting substance assay was lower in liver homogenate and mitochondrial and microsomal fractions from ethanol-fed pigs than in controls. The percentage contribution of highly unsaturated fatty acids to total fatty acids in liver homogenates (after 12 mo of feeding) and microsome fractions (after 20 mo of feeding) was lower in the ethanol-fed pigs than in the controls, resulting in a lower peroxidizability index. Ethanol-fed pigs had minimal or no hepatic damage as assessed by histological methods. We suggest that the relative resistance of microsomes to lipid peroxidation is due to the lower peroxidizability index in the ethanol-fed pigs and may account in part for the absence of significant histopathological findings after 20 mo of ethanol feeding.",0
648,2050336,Glucuronidation of bile acids by their high-dose infusion into rats,"We previously reported that high-dose infusion of ursodeoxycholate into rats caused its extensive glucuronidation. In this study, the glucuronidation of various bile acids after high-dose infusion into rats was examined and the effects of coinfusion of bile acids on the glucuronidation of a trace dose of [14C]deoxycholate were also studied. Sixty minutes after infusion of 14C-bile acids at a rate of 1 mumol/min/100 gm, the glucuronidation of the labeled bile acid in the bile was 31%, 15%, 8% and 3% for deoxycholate, ursodeoxycholate, chenodeoxycholate and cholate, respectively. The infusion of a trace dose of [14C] deoxycholate resulted in only 2% glucuronidation, and coinfusion of taurochenodeoxycholate or tauroursodeoxycholate at a rate of 1 mumol/min/100 gm did not change the percentage of glucuronidation of [14C]deoxycholate. However, coinfusion of chenodeoxycholate, ursodeoxycholate or cholate at the same rate markedly increased the percentage of the [14C]deoxycholate-glycuronide in the bile (35%, 18% and 36%, respectively). Thus glucuronidation of bile acids by high-dose infusion into rats occurs predominantly with deoxycholate and is not specific for ursodeoxycholate, and glucuronidation depends on the unconjugated bile acid load, which might be regulated by the capacity of amidation by the liver.",0
649,2052043,"Plasmodium Falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire. A prospective, longitudinal cohort study of 587 children","BACKGROUND: It is uncertain whether Plasmodium falciparum malaria is more frequent or more severe in children with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection and whether P. falciparum infection accelerates the progression of HIV-related disease. METHODS: We conducted a prospective, longitudinal cohort study in Kinshasa, Zaire. Two hundred sixty children 5 to 9 months of age who had been born to HIV-1-seropositive mothers and 327 children of the same age who had been born to seronegative mothers were monitored intensively for malaria over a 13-month period. All episodes of fever were evaluated with blood smears for malaria, and children found to be infected with P. falciparum were treated with a standard regimen of oral quinine. RESULTS: A total of 2899 fevers were evaluated, with 271 cases of malaria identified. No statistically significant differences were found in the incidence, severity, or response to therapy of malaria among four well-defined groups of children: those with the acquired immunodeficiency syndrome (AIDS), those who were HIV-1-seropositive throughout the study, those who were born to HIV-1-seropositive mothers but reverted to seronegative, and those who were seronegative throughout the study. During the 13-month period the incidence of malaria in the 36 children with HIV infection in whom AIDS developed was lower, although not significantly so, than in the 37 in whom AIDS did not. CONCLUSIONS: In this study malaria was not more frequent or more severe in children with progressive HIV-1 infection and malaria did not appear to accelerate the rate of progression of HIV-1 disease.",0
650,2052060,Factor XI deficiency in Ashkenazi Jews in Israel,"BACKGROUND AND METHODS: Severe factor XI deficiency, which is relatively common among Ashkenazi Jews, is associated with injury-related bleeding of considerable severity. Three point mutations--a splice-junction abnormality (Type I), Glu117----Stop (Type II), and Phe283----Leu (Type III)--have been described in six patients with factor XI deficiency. Clinical correlations with these mutations have not been carried out. We determined the relative frequency of the mutations and their association with plasma levels of factor XI clotting activity and bleeding, analyzing the mutations with the polymerase chain reaction and restriction-enzyme digestion. RESULTS: The Type II and Type III mutations had similar frequencies among 43 Ashkenazi Jewish probands with severe factor XI deficiency; these two mutations accounted for 49 percent and 47 percent, respectively, of a total of 86 analyzed alleles. Among 40 of the probands and 12 of their relatives with severe factor XI deficiency, patients homozygous for Type III mutation had a significantly higher level of factor XI clotting activity (mean [+/- SD] percentage of normal values, 9.7 +/- 3.8 percent; n = 13) than those homozygous for Type II mutation (1.2 +/- 0.5 percent, n = 16) or compound heterozygotes with Type II/III mutation (3.3 +/- 1.6 percent, n = 23), as well as significantly fewer episodes of injury-related bleeding. Each of these three groups had a similarly increased proportion of episodes of bleeding complications after surgery at sites with enhanced local fibrinolysis, such as the urinary tract, or during tooth extraction. CONCLUSIONS: Type II and Type III mutations are the predominant causes of factor XI deficiency among Ashkenazi Jews. Genotypic analysis, assay for factor XI, and consideration of the type and location of surgery can be helpful in planning operations in patients with this disorder.",0
651,2057022,Differences in the use of procedures between women and men hospitalized for coronary heart disease,"BACKGROUND AND METHODS: Previous studies at individual hospitals have reported differences in the use of major diagnostic and therapeutic procedures for women and men with coronary heart disease. To assess whether these differences can be generalized, we performed retrospective analyses of coronary angiography and revascularization (coronary-artery bypass surgery or percutaneous transluminal coronary angioplasty) in women and men hospitalized for coronary heart disease in 1987, using abstract data on 49,623 discharges in Massachusetts and 33,159 discharges in Maryland. We used multiple logistic regression to estimate the adjusted odds of the use of a procedure, controlling for principal diagnosis, age, secondary diagnosis of congestive heart failure or diabetes mellitus, race, and insurance status. RESULTS: The adjusted odds of undergoing angiography were 28 percent and 15 percent higher for men than for women in Massachusetts and Maryland, respectively (95 percent confidence intervals for the odds ratios, 1.22 to 1.35 and 1.08 to 1.22). The respective adjusted odds of undergoing revascularization were 45 percent and 27 percent higher for men than for women (95 percent confidence intervals, 1.35 to 1.55 and 1.16 to 1.40). Because these differences could be related to differing thresholds for hospital admission, we performed a second analysis limited to patients with diagnosed acute myocardial infarction (11,865 discharges in Massachusetts and 6894 discharges in Maryland), a group in which all patients would be expected to receive hospital care. The male-to-female odds ratios in both states remained similar in magnitude and were statistically significant for angiography and revascularization. CONCLUSIONS: These findings demonstrate that women who are hospitalized for coronary heart disease undergo fewer major diagnostic and therapeutic procedures than men. These differences may represent appropriate levels of care for men and women, but it is also possible that they reflect underuse in women or overuse in men. Further study should assess the cause of these differences and their effect on patients' outcomes.",0
652,2057023,Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators,"BACKGROUND: Despite the fact that coronary artery disease is the leading cause of death among women, previous studies have suggested that physicians are less likely to pursue an aggressive approach to coronary artery disease in women than in men. To define this issue further, we compared the care previously received by men and women who were enrolled in a large postinfarction intervention trial. METHODS: We assessed the nature and severity of anginal symptoms and the use of antianginal and antiischemic interventions before enrollment in the 1842 men and 389 women with left ventricular ejection fractions less than or equal to 40 percent after an acute myocardial infarction who were randomized in the Survival and Ventricular Enlargement trial. RESULTS: Before their index infarction, women were as likely as men to have had angina and to have been treated with antianginal drugs. However, despite reports by women of symptoms consistent with greater functional disability from angina, fewer women had undergone cardiac catheterization (15.4 percent of women vs. 27.3 percent of men, P less than 0.001) or coronary bypass surgery (5.9 percent of women vs. 12.7 percent of men, P less than 0.001). When these differences were adjusted for important covariates, men were still twice as likely to undergo an invasive cardiac procedure as women, but bypass surgery was performed with equal frequency among the men and women who did undergo cardiac catheterization. CONCLUSIONS: Physicians pursue a less aggressive management approach to coronary disease in women than in men, despite greater cardiac disability in women.",0
653,2057025,Relation between malpractice claims and adverse events due to negligence. Results of the Harvard Medical Practice Study III,"BACKGROUND AND METHODS: By matching the medical records of a random sample of 31,429 patients hospitalized in New York State in 1984 with statewide data on medical-malpractice claims, we identified patients who had filed claims against physicians and hospitals. These results were then compared with our findings, based on a review of the same medical records, regarding the incidence of injuries to patients caused by medical management (adverse events). RESULTS: We identified 47 malpractice claims among 30,195 patients' records located on our initial visits to the hospitals, and 4 claims among 580 additional records located during follow-up visits. The overall rate of claims per discharge (weighted) was 0.13 percent (95 percent confidence interval, 0.076 to 0.18 percent). Of the 280 patients who had adverse events caused by medical negligence as defined by the study protocol, 8 filed malpractice claims (weighted rate, 1.53 percent; 95 percent confidence interval, 0 to 3.2 percent). By contrast, our estimate of the statewide ratio of adverse events caused by negligence (27,179) to malpractice claims (3570) is 7.6 to 1. This relative frequency overstates the chances that a negligent adverse event will produce a claim, however, because most of the events for which claims were made in the sample did not meet our definition of adverse events due to negligence. CONCLUSIONS: Medical-malpractice litigation infrequently compensates patients injured by medical negligence and rarely identifies, and holds providers accountable for, substandard care.",0
654,2066059,"Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis","Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)",0
655,2100984,Universal New York Health Care. A single-payer strategy linking cost control and universal access,"Now that universal access to health care is back on the governmental agenda, elected officials are faced with the dilemma of expanding our present pluralistic system of numerous private and public payers, with its built-in administrative inefficiencies and inflationary pressures, or scrapping the present system of financing and moving to a tax-based scheme like the Canadian Medicare program, an option fraught with political difficulties. There is, however, a third option. The New York State Department of Health has developed a proposal for universal access--Universal New York Health Care, or UNY-Care--that would retain the existing payers, including employer-based insurance coverage, but combine them in a one-payer framework. Providers would no longer have to interact with the many public and private payers, each with its own rules, criteria, and levels of payment. The single payer would serve as the only payer for most health care services and would also negotiate reimbursement rates. The single-payer framework should bring savings in administrative and billing costs and should move government closer to the goal of buying health care services--getting good value for payment rendered--rather than simply paying bills as they are submitted. Although the single-payer strategy could be implemented at either the state or the federal level, it seems ideal as the principal responsibility of the states in a national plan for universal coverage.",0
656,2104666,The increased needs of patients in nursing homes and patients receiving home health care,"To evaluate the effects of Medicare's prospective payment system and Medicaid's preadmission regulations on long-term care, we constructed clinical profiles in 1982 and 1986 of about 500 randomly selected patients from each of three types of facilities: nursing homes with relatively high proportions of Medicare patients (high-Medicare nursing homes; n = 23), traditional nursing homes (n = 19), and home health agencies (n = 18). Data were obtained directly from the care givers on the medical problems, problems requiring skilled nursing, and functional problems of these representative patients from 12 states. For Medicare patients in high-Medicare nursing homes, the prevalence of medical problems and problems requiring skilled nursing increased substantially, whereas the prevalence of functional problems remained relatively unchanged. For example, from 1982 to 1986 there was a marked increase in the frequency of tube feedings (21 to 29 percent), oxygen use (6 to 14 percent), urinary tract infection (7 to 13 percent), and diastolic hypertension (1 to 10 percent), but not difficulty in eating (48 to 51 percent) or speaking (28 to 29 percent). In contrast, in traditional nursing homes there was an increase in the prevalence of functional disability, but virtually no change in that of problems requiring medical and skilled nursing care. In home health care the functional care needs of Medicare patients increased significantly, and there was a slight increase in the prevalence of problems requiring medical and skilled nursing care. We conclude that from 1982 to 1986 the needs of patients in long-term care increased substantially. This trend appears to result from Medicare's prospective payment system, which encourages earlier hospital discharge to long-term care settings, and from Medicaid's policy of de-institutionalization. Meeting this greater need for care will be costly. We require a better system of reimbursing for long-term care and ensuring its quality.",0
657,2108331,Do the poor cost more? A multihospital study of patients' socioeconomic status and use of hospital resources,"There is controversy about whether hospitalized poor patients use more resources and whether hospitals that provide care for the poor therefore merit supplementary payment under per-case prospective payment systems. We previously reported that patients of low socioeconomic status with connective-tissue disease had longer hospital stays and higher costs than patients of higher socioeconomic status at a single hospital. To examine the generalizability of this phenomenon, we interviewed 16,908 (83 percent) of 20,278 consecutive adult patients (excluding obstetrical and psychiatric patients) admitted in 1987 to five Massachusetts hospitals, to obtain information on three direct measures of socioeconomic status (income, occupation, and education). We divided each measure into three strata. Thus, there were 15 comparisons--three measures of socioeconomic status applied to each of five hospitals. After excluding outliers and adjusting for diagnosis-related group (DRG), we found that the patients of the lowest socioeconomic status had hospital stays 3 to 30 percent longer than those of patients of higher status, the differences varying with the hospital and the indicator of socioeconomic status (P less than or equal to 0.05 for 11 of the 15 comparisons). Hospital charges were 1 to 18 percent higher for the patients of lowest socioeconomic status than for those of higher status (P less than or equal to 0.05 for 9 of 15 comparisons). When we adjusted for age, severity of illness, and DRG, the patients of lowest socioeconomic status had longer stays than those of higher status in 14 of 15 comparisons (P less than 0.05 for 7 of the 15) and higher charges in 13 of 15 comparisons (P less than 0.05 for 6 of the 15). The differences between patients of high and low status ranged up to 21 percent for length of stay and 13 percent for charges. Our findings suggest that hospitalized patients of lower socioeconomic status have longer stays and probably require more resources. Supplementary payments to hospitals for the treatment of poor patients merit further consideration.",0
658,2109828,Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy,"Albright's hereditary osteodystrophy is an autosomal dominant disorder characterized by a short stature, brachydactyly, subcutaneous ossifications, and reduced expression or function of the alpha subunit of the stimulatory G protein (Gs alpha) of adenylate cyclase, which is necessary for the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger. We identified a unique Gs alpha protein in erythrocytes from two related patients with Albright's hereditary osteodystrophy and reduced Gs alpha bioactivity. The Gs alpha variant was recognized by a carboxyl terminal-specific Gs alpha antiserum but not by polyclonal antiserums specific for the amino terminus of Gs alpha. To investigate the molecular basis for this structurally abnormal Gs alpha protein, we studied the Gs alpha gene by restriction-endonuclease analysis. DNA from the two patients had an abnormal restriction-fragment pattern when digested with Ncol, which was consistent with loss of an Ncol restriction site in exon 1 of one Gs alpha allele. Amplification of a 260-base-pair region that includes exon 1 of the Gs alpha gene and direct sequencing of the amplified DNA revealed an A-to-G transition at position +1 in one Gs alpha allele from each of the two patients. This mutation converts the initiator ATG (methionine) codon to GTG (valine), blocking initiation of translation at the normal site. Translation of the abnormal Gs alpha messenger RNA would result in the synthesis of a truncated Gs alpha molecule lacking the amino terminus. We conclude that in at least some patients with Albright's hereditary osteodystrophy, the disease is caused by a single-base substitution in the Gs alpha gene and is thus due to an inherited mutation in a human G protein.",0
659,2114350,Vasopressin/nitroglycerin infusion vs. esophageal tamponade in the treatment of acute variceal bleeding: a randomized controlled trial,"Vasopressin infusion and esophageal tamponade are still widely used to arrest variceal bleeding, but no objective evidence exists on the superiority of either of the two procedures. In this study, 108 cirrhotic patients bleeding from varices were included in a prospective, randomized trial to investigate the comparative effectiveness and safety of balloon tamponade (using the Sengstaken-Blakemore tube for esophageal varices and the Linton-Nachlas tube for gastric varices) (n = 52) and intravenous vasopressin infusion (0.4 to 0.8 mu/min) plus intravenous nitroglycerin infusion (40 to 400 micrograms/min) (n = 56). Both treatments were maintained for 24-hr. The hemostatic efficacy according to the intention to treat was 86.5% for tamponade and 66% for pharmacological therapy (p less than 0.01). No significant differences were found with respect to rebleeding during the first 72 hr after treatment, mortality rate or side effects. These results suggest that esophageal tamponade is more effective than vasopressin/nitroglycerin infusion in the treatment of variceal bleeding in cirrhotic patients.",0
660,2136770,Relative increase of T cells expressing the gamma/delta rather than the alpha/beta receptor in ataxia-telangiectasia,"In ataxia-telangiectasia, B-cell and T-cell deficiencies are thought to be due to a defect of rearrangements of immunoglobulin and T-cell receptor genes. T cells recognize antigens through two types of CD3-associated receptors: alpha/beta chains on mature cells and gamma/delta chains mostly on immature cells. We studied 10 patients with ataxia-telangiectasia and found that most had a relative increase of circulating T cells bearing gamma/delta receptors rather than alpha/beta receptors, as compared with normal subjects (P less than 0.001). Patients with other immune deficits, including eight with common variable immunodeficiency, one with Wiskott-Aldrich syndrome, two with hyperimmunoglobulinemia E syndrome, and one with severe combined immunodeficiency, had normal ratios of gamma/delta-bearing to alpha/beta-bearing cells. A marked predominance of gamma/delta-bearing T cells was found in a patient with a primary T-cell defect. The relative increase in gamma/delta-bearing T cells in the patients with ataxia-telangiectasia was largely accounted for by cells that reacted with the monoclonal antibody BB3, an apparently distinct subset of T cells that selectively express the C gamma 1 gene product of the T-cell receptor. Although they had normal ratios of gamma/delta-bearing to alpha/beta-bearing T cells, the patients with common variable immunodeficiency had a significant increase (P = 0.01) in the number of T cells expressing C gamma 2 that reacted with the monoclonal antibody delta-TCS-1. We conclude that the increased ratio of gamma/delta-bearing to alpha/beta-bearing T cells in ataxia-telangiectasia may reflect both a recombinational defect that interferes with T-cell and B-cell gene rearrangements and an inability to repair damage to the DNA.",0
661,2143270,The life expectancy of profoundly handicapped people with mental retardation,"BACKGROUND: The life expectancy of people with mental retardation is shorter than that of the general population. Exact estimates of the length of survival for mentally retarded persons at especially high risk are not available, however. METHODS: We collected data on mortality and other factors for 99,543 persons with developmental disabilities, including mental retardation, who received services from the California Department of Developmental Services between March 1984 and October 1987. Three subgroups were selected on the basis of the four characteristics identified in previous studies as the best predictors of mortality among mentally retarded people (deficits in cognitive function, limitations on mobility, incontinence, and inability to eat without assistance). In all three subgroups, the subjects had severe deficits in cognitive function and were incontinent; the subjects in subgroup 1 (n = 1550) were immobile and required tube feeding; those in subgroup 2 (n = 4513) were immobile but could eat with assistance; those in subgroup 3 (n = 997) were mobile (but not ambulatory) and could eat with assistance. Life tables were generated for each of the three subgroups. RESULTS: Immobile subjects were found to have a much shorter life expectancy than those who could move about. Those who also required tube feeding (subgroup 1) had a very short life expectancy (i.e., four to five additional years). Those who could eat if fed by others (subgroup 2) had an average life expectancy of approximately eight additional years. In contrast, those who were mobile though not ambulatory (subgroup 3) had a life expectancy of about 23 additional years. CONCLUSIONS: Severe mental retardation is associated with a decrease in life expectancy, particularly for those who were immobile.",0
662,2145212,Recombinant gamma-interferon as adjuvant to hepatitis B vaccine in hemodialysis patients,"Patients undergoing long-term hemodialysis are at high risk of acquiring hepatitis B yet tend to have poor rates of response to hepatitis B vaccine. The effect of recombinant human gamma-interferon (2 million units/m2) on the response to a recombinant hepatitis B vaccine was evaluated in a prospective, randomized controlled trial in 81 hemodialysis patients. A similar proportion of both groups of vaccinees ultimately developed antibody to HBsAg including 81% of the 41 recipients of vaccine alone (group I) and 89% of the 40 recipients of vaccine with gamma-interferon (group II). However, the antibody to HBsAg response occurred earlier in recipients of vaccine with gamma-interferon, so that at 4 mo 63% of group I and 88% of group II had antibody to HBsAg (p less than 0.025). Furthermore, titers of antibody to HBsAg tended to be higher in the vaccinees given interferon; the final geometric mean titers were 232 IU/L in group I and 330 IU/L in group II (p = not significant). Retrospective testing for antibody to hepatitis C virus revealed that 21 (26%) hemodialysis patients were seropositive at entry into this trial, but the presence of antibody to hepatitis C virus did not appear to affect the response rate to the hepatitis B vaccine. These results suggest that the effects of gamma-interferon as an adjuvant in increasing the response rate to hepatitis B vaccination deserve further evaluation perhaps most appropriately in persons who have not responded to an initial course of vaccine.",0
663,2168516,Secondary biosynthetic defects in women with late-onset congenital adrenal hyperplasia,"BACKGROUND AND METHODS: Late-onset (non-classic) congenital adrenal hyperplasia is a cause of hirsutism, menstrual disorders, and infertility, but its frequency and the patterns of abnormalities in adrenal hormone secretion are not well understood. We investigated the frequency and ethnic distribution of nonclassic congenital adrenal hyperplasia due to deficiencies of 3 beta-hydroxy-delta 5-steroid dehydrogenase, 21-hydroxylase, or 11 beta-hydroxylase among 170 Israeli Jewish women with these clinical problems. All enzyme defects were identified by comparing the patients' hormonal responses to a 0.25-mg intravenous bolus dose of alpha 1-24-ACTH with those of 26 age-matched normal women. RESULTS: Twenty women (12 percent) had 3 beta-hydroxy-delta 5-steroid dehydrogenase deficiency, 18 (10 percent) 21-hydroxylase deficiency (14 homozygous), and 14 (8 percent) 11 beta-hydroxylase deficiency. All the homozygous women with 21-hydroxylase deficiency also had evidence of a partial deficiency in 11 beta-hydroxylase activity. Similarly, most of the women with 11 beta-hydroxylase deficiency also had evidence of a deficiency in 3 beta-hydroxy-delta 5-steroid dehydrogenase. Among the 118 women with no adrenal biosynthetic defect, 38 had high plasma androgen concentrations, and 80 had normal concentrations. CONCLUSIONS: About one third of Israeli Jewish women with hirsutism, menstrual disorders, or unexplained infertility had nonclassic congenital adrenal hyperplasia. Secondary adrenal biosynthetic defects were frequent in these women and were probably caused by intra-adrenal androgen excess rather than by dual inherited enzymatic deficiencies.",0
664,2170840,Somatostatin-receptor imaging in the localization of endocrine tumors,"BACKGROUND AND METHODS: A number of different tumors have receptors for somatostatin. We evaluated the efficacy of scanning with 123I-labeled Tyr3-octreotide, a somatostatin analogue, for tumor localization in 42 patients with carcinoid tumors, pancreatic endocrine tumors, or paragangliomas. We then evaluated the response to octreotide therapy in some of these patients. RESULTS: Primary tumors or metastases, often previously unrecognized, were visualized in 12 of 13 patients with carcinoid tumors and in 7 of 9 patients with pancreatic endocrine tumors. The endocrine symptoms of these patients responded well to therapy with octreotide. Among 20 patients with paragangliomas, 8 of whom had more than one tumor, 10 temporal (tympanic or jugular), 9 carotid, and 10 vagal tumors could be visualized. One small tympanic tumor and one small carotid tumor were not seen on the scan. CONCLUSIONS: The 123I-labeled Tyr3-octreotide scanning technique is a rapid and safe procedure for the visualization of some tumors with somatostatin receptors. A positive scan may predict the ability of octreotide therapy to control symptoms of hormonal hypersecretion.",0
665,2181310,Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials,"About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.",0
666,2183888,The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing,"DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS, K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11, 12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative frequencies of N-RAS gene mutations in these hematologic disorders was as follows: acute myelogenous leukemia (AML), 15%; acute lymphoblastic leukemia (ALL), 14%; myelodysplastic syndromes, 24%; and myeloid and lymphoid blast crisis of chronic myelogenous leukemia (CML), 3%. No correlation was observed between the presence of mutations and cytologic features or immunophenotype of these malignancies. Mutations involving codons 12 or 13 were equally prevalent, with a glycine to aspartic acid substitution being the most frequently encountered change. A single T-ALL case had a codon 11 mutation resulting in substitution of alanine with threonine. We failed to find mutations in exons 1 and 2 of the K-RAS or Ha-RAS genes in any case except a single AML with a mutation in codon 61 of the K-RAS gene. Also, no mutations were identified in chronic phase of CML, chronic lymphocytic leukemia. Ph1 positive ALL, non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma. These results indicate that RAS mutations, especially those involving exon 1 of the N-RAS gene, are frequent only in a subset of hematologic malignancies. ",0
667,2186274,The effect on test ordering of informing physicians of the charges for outpatient diagnostic tests,"We studied the effect of informing physicians of the charges for outpatient diagnostic tests on their ordering of such tests in an academic primary care medical practice. All tests were ordered at microcomputer workstations by 121 physicians. For half (the intervention group), the charge for the test being ordered and the total charge for tests for that patient on that day were displayed on the computer screen. The remaining physicians (control group) also used the computers but received no message about charges. The primary outcomes measured were the number of tests ordered and the charges for tests per patient visit. In the 14 weeks before the study, the number of tests ordered and the average charge for tests per patient visit were similar for the intervention and control groups. During the 26-week intervention period, the physicians in the intervention group ordered 14 percent fewer tests per patient visit than did those in the control group (P less than 0.005), and the charges for tests were 13 percent ($6.68 per visit) lower (P less than 0.05). The differences were greater for scheduled visits (17 percent fewer tests and 15 percent lower charges for the intervention group; P less than 0.01) than for unscheduled (urgent) visits (11 percent fewer tests and 10 percent lower charges; P greater than 0.3). During the 19 weeks after the intervention ended, the number of tests ordered by the physicians in the intervention group was only 7.7 percent lower than the number ordered by the physicians in the control group, and the charges for tests were only 3.5 percent lower (P greater than 0.3). Three measures of possible adverse outcomes--number of hospitalizations, emergency room visits, and outpatient visits during the study period and the following six months--were similar for the patients seen by the physicians in both groups. We conclude that displaying the charges for diagnostic tests significantly reduced the number and cost of tests ordered, especially for patients with scheduled visits. The effects of this intervention did not persist after it was discontinued.",0
668,2200965,Comparison of magnetic resonance imaging and ultrasonography in staging early prostate cancer. Results of a multi-institutional cooperative trial,"BACKGROUND: In 1987, a cooperative study group consisting of five institutions was formed to determine the relative benefits of magnetic resonance imaging (MRI) and endorectal (transrectal) ultrasonography in evaluating patients with clinically localized prostate cancer (stage Ta or Tb). METHODS: Over a period of 15 months, 230 patients were entered into the study and evaluated with identical imaging techniques. We compared imaging results with information obtained at the time of surgery and on pathological analysis. RESULTS: MRI correctly staged 77 percent of cases of advanced disease and 57 percent of cases of localized disease; the corresponding figures for ultrasonography were 66 and 46 percent (P not significant). These figures did not vary significantly between readers; moreover, simultaneous interpretation of MRI and ultrasound scans did not improve accuracy. In terms of detecting and localizing lesions, MRI identified only 60 percent of all malignant tumors measuring more than 5 mm on pathological analysis and ultrasonography identified only 59 percent. CONCLUSIONS: The MRI and ultrasonography equipment that is currently available is not highly accurate in staging early prostate cancer, mainly because neither technique has the ability to identify microscopic spread of disease. Further evaluation with improved equipment may improve the accuracy of these techniques.",0
669,2202637,Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis,"The histological findings in patients with primary biliary cirrhosis have been well-defined and are often used in the clinical staging of disease. However, it has only been with the development of reagents that phenotypically characterize the lymphoid infiltrate that attempts have been made to correlate pathophysiology with immune effector populations. Indeed, the inflammatory hepatic lesions in primary biliary cirrhosis have been described as containing CD4-positive and CD8-positive T cells. Less clear, however, have been the T cell receptors in these lesions. Further, the data on immunoglobulin deposits in hepatic lesions have been less well-defined; this deficit may be a result of the quality of polyspecific sera and difficulties in background. To address these issues, we have used a battery of well-defined monospecific and polyspecific reagents to phenotypically define the occurrence of lymphoid cells in the livers of patients undergoing transplantation. Furthermore, we have defined these same markers on T cell lines derived from liver, regional lymph node and peripheral blood. The predominant cell type in the mononuclear infiltrate is the CD3+, CD4+ T lymphocyte bearing the T cell receptor alpha beta. T cell lines from the same patients demonstrate similar findings. Of special importance, however, was the detection of CD20+ B cells and Ig+ cells in the lymphoid infiltrate. Indeed, we also readily demonstrated the presence of immunoglobulin on the surface of biliary epithelium. These data suggest that mechanisms involved in the pathophysiology of primary biliary cirrhosis may include both T cell and antibody mechanisms. The results also underscore the need to develop a functional, and not just a phenotypical, assay of the inflammatory infiltrate.",0
670,2202901,A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group,"BACKGROUND: Beta carotene has been associated with a decreased risk of human cancer in many studies employing dietary questionnaires or blood measurements, and it has had protective effects in some animal models of carcinogenesis. METHODS: We tested the possible cancer-preventing effects of beta carotene by randomly assigning 1805 patients who had had a recent nonmelanoma skin cancer to receive either 50 mg of beta carotene or placebo per day and by conducting annual skin examinations to determine the occurrence of new nonmelanoma skin cancer. RESULTS: Adherence to the prescribed treatment was good, and after one year the actively treated group's median plasma beta carotene level (3021 nmol per liter) was much higher than that of the control group (354 nmol per liter). After five years of follow-up, however, there was no difference between the groups in the rate of occurrence of the first new nonmelanoma skin cancer (relative rate, 1.05; 95 percent confidence interval, 0.91 to 1.22). In subgroup analyses, active treatment showed no efficacy either in the patients whose initial plasma beta carotene level was in the lowest quartile or in those who currently smoked. There was also no significant difference between treated and control groups in the mean number of new nonmelanoma skin cancers per patient-year. CONCLUSIONS: In persons with a previous nonmelanoma skin cancer, treatment with beta carotene does not reduce the occurrence of new skin cancers over a five-year period of treatment and observation.",0
671,2203964,A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women,"Background. The effectiveness of calcium in retarding bone loss in older postmenopausal women is unclear. Earlier work suggested that the women who were most likely to benefit from calcium supplementation were those with low calcium intakes. Methods. We undertook a double-blind, placebo-controlled, randomized trial to determine the effect of calcium on bone loss from the spine, femoral neck, and radius in 301 healthy postmenopausal women, half of whom had a calcium intake lower than 400 mg per day and half an intake of 400 to 650 mg per day. The women received placebo or either calcium carbonate or calcium citrate malate (500 mg of calcium per day) for two years. Results. In women who had undergone menopause five or fewer years earlier, bone loss from the spine was rapid and was not affected by supplementation with calcium. Among the women who had been postmenopausal for six years or more and who were given placebo, bone loss was less rapid in the group with the higher dietary calcium intake. In those with the lower calcium intake, calcium citrate malate prevented bone loss during the two years of the study; its effect was significantly different from that of placebo (P less than 0.05) at the femoral neck (mean change in bone density [+/- SE], 0.87 +/- 1.01 percent vs. -2.11 +/- 0.93 percent), radius (1.05 +/- 0.75 percent vs. -2.33 +/- 0.72 percent), and spine (-0.38 +/- 0.82 percent vs. -2.85 +/- 0.77 percent). Calcium carbonate maintained bone density at the femoral neck (mean change in bone density, 0.08 +/- 0.98 percent) and radius (0.24 +/- 0.70 percent) but not the spine (-2.54 +/- 0.85 percent). Among the women who had been postmenopausal for six years or more and who had the higher calcium intake, those in all three treatment groups maintained bone density at the hip and radius and lost bone from the spine. Conclusions. Healthy older postmenopausal women with a daily calcium intake of less than 400 mg can significantly reduce bone loss by increasing their calcium intake to 800 mg per day. At the dose we tested, supplementation with calcium citrate malate was more effective than supplementation with calcium carbonate.",0
672,2210639,Gel filtration and quasielastic light scattering studies of human bile,"Analyses of cholesterol carriers in the extremely variable biliary samples were performed by chromatography under standard conditions. Sephacryl columns were eluted with buffer containing 10 mmol/L sodium cholate, 150 mmol/L sodium chloride, 50 mmol/L Tris(hydroxymethyl)aminomethane-hydrochloride, pH 8.0, and 1.5 mmol/L ethylenediaminetetraacetate. Moderate changes in temperature, flow rate or sample size produced only minor differences in the results. Increments in bile salt concentration in the elution buffer caused progressive disappearance of vesicles and a rise in their cholesterol/phospholipid ratio. Using the standard chromatographic technique, analyses of the same bile gave reproducible results, and comparisons among various biles were possible. Quantitative light scattering measurements of bile showed that the amount of vesicular cholesterol in whole unprocessed bile was similar to that measured by Sephacryl chromatography. Analyses of human gallbladder biles using a high-resolution Sephacryl column showed four cholesterol-containing peaks: vesicles, lamellae, mixed micelles and an undefined carrier. This long chromatographic column separated the lamellar from the micellar peaks (which had merged on the short column). Phospholipid lamellae solubilized most of the biliary cholesterol. These findings were confirmed by ultracentrifugation of bile.",0
673,2210641,Secretion of biliary lipids from the hepatocyte,"A significant amount of biliary cholesterol is carried in unilamellar-phospholipid (lecithin) vesicles, in both supersaturated human hepatic bile and unsaturated rat bile. This fact supports the concept that biliary cholesterol is normally secreted in phospholipid vesicles from the hepatocyte into the canaliculus. The fundamental aspects of biliary lipid secretion relate first to the quantitative determinants of hepatocytic cholesterol secretion into the bile and, second, to the cell biology of this process. There is a tight curvilinear coupling between the rates of bile acids and biliary lipid secretion in all animal species. The hydrophobicity of the bile acid pool may modify this cosecretory mechanism in that more hydrophobic bile acids recruit more phospholipid and cholesterol per mole of bile acid secreted into the bile. The quantitative significance of this effect, however, is relatively minor. In contrast, intrahepatic determinants, such as the rates of hepatic cholesterol esterification and very low density lipoprotein production modulated by dietary factors, may markedly change the amount of cholesterol carried in vesicles into the bile. Recent studies provide strong evidence to support the concept that biliary cholesterol output is also modulated by the amount of free cholesterol available in specific regions of the endoplasmic reticulum for recruitment by the bile acid cosecretory mechanism. The origin of biliary lipids is in the smooth endoplasmic reticulum membranes. The intracellular transport and the canalicular secretory mechanism of the precursor of biliary lipid vesicles is mostly unknown. Two theories related to the cell biology of biliary lipid secretion are discussed in this article, the fusion-budding model and the exocytotic model.",0
674,2210642,Physical chemistry of biliary lipids during bile formation,"""Present concepts suggest that the canalicular secretion of bile salts is monomeric, which in turn drives the hepatic secretion of lecithin and cholesterol presumably as unilamellar vesicles into bile. As biliary lipids are concentrated within the biliary tree and gallbladder, bile salts structurally alter lecithin-cholesterol vesicles to form a variety of metastable aggregates whose structures and phase transformations are predicted by phase equilibria considerations. These structural transformations ultimately result in the dispersion of biliary lipids as thermodynamically stable micelles or micelles plus thermodynamically unstable vesicles in common duct and gallbladder biles. The experiments reviewed herein represent experimental simulations of these processes. We used pure aqueous lipid systems to model the putative stages of biliary lipid aggregation on the basis of interactions of small unilamellar vesicles of lecithin-cholesterol with bile salts as the latter's concentrations were varied from below to well above the critical micellar concentration. With submicellar bile salt concentrations likely to be found within hepatocytes, vesicle structures are not appreciably altered. However, perimicellar bile salt concentrations possibly occurring in canaliculi and bile ductules induce the formation of a hexagonal rodlike phase. On further increases in bile salt concentration, the hexagonal rods (formed from lecithin-rich and cholesterol-poor vesicles) are dissolved into mixed micelles as bile salt concentrations exceed their critical micellar concentrations. In slightly cholesterol-""""supersaturated"""" biles, the rapid dissolution of this intermediate phase results in the formation of cholesterol-supersaturated mixed micelles that, in time, give rise to a new population of cholesterol-rich vesicles that coexist with saturated micelles.(ABSTRACT TRUNCATED AT 250 WORDS)""",0
675,2210645,"Bile acid secretion, bile flow and biliary lipid secretion in humans","The transport of bile acids through the hepatocyte and the effect of this flux of molecules on bile flow, biliary lipid secretion and bile acid biosynthesis are reviewed. Efficient hepatic clearance of bile acids involves several active systems and passive uptake. Formation of coenzyme A derivatives prevents reflux of lipophilic dihydroxy bile acids. Biotransformation of bile acids during hepatocyte transport involves both type I and type II biotransformations. The major type II biotransformation is reamidation of unconjugated bile acids, but sulfation and glucuronidation also occur. The only major type I biotransformation is oxidoreduction, which converts iso- or 3 oxo bile acids to the preferred 3 alpha-hydroxy form and 7 oxo bile acids to their corresponding 7 alpha-hydroxy derivatives. Secretion of bile acids into the canaliculus is concentrative and induces osmotic flow of plasma water and solutes across the paracellular junctions between the space of Disse and the canaliculus. Bile flow in man is characterized by its low volume and by a paucity of bile acid-independent flow when compared with that of other mammals. Bile acid secretion also induces biliary lipid secretion, but some lipid secretion appears to be bile acid independent. The lipid vesicles secreted in human bile have a much higher cholesterol/phospholipid ratio than those of other mammals. During flow down the biliary tree, vesicles are solubilized by bile acid micelles, and Ca++ ions are complexed by bile acid monomers and micelles. However, the biochemical mechanisms and factors regulating biliary lipid secretion in man are poorly understood.",0
676,2210651,Biliary calcium and gallstone formation,"""The purpose of this paper is to present a brief overview of the current status of the field of biliary calcium and the role of calcium in the formation and maturation of gallstones. The study of free Ca+(+) ions in bile by electrochemical potentiometric measurements using Ca+(+)-selective ion-exchange electrodes is a relatively new field, but much progress has been made in the past few years. Using this powerful analytical tool, new concepts and findings have arisen in almost every aspect of biliary calcium. Although the current symposium is targeted primarily toward cholesterol gallstones, there are several areas in which understanding of biliary calcium may significantly contribute to a better understanding of the pathogenesis of cholesterol, as well as """"pigment"""" (calcium salt), gallstones. Five broad areas are considered in relation to biliary calcium: (a) physiology (calcium entry into bile), (b) biophysics (the regulation of biliary free [Ca+(+)] as related to Gibbs-Donnan equilibria, (c) physical chemistry (the physicochemical state of calcium in bile, (d) thermodynamics (calcium solubility in bile), and (e) kinetics (pronucleating and antinucleating factors and metastable states). With more specific reference to cholesterol stones, consideration is also made of (a) the calcium salt """"seed"""" hypothesis in cholesterol stone pathogenesis; (b) the interactions of Ca+(+) with phospholipid-cholesterol vesicles, with consideration of possible structural requirements and (c) thermodynamic and kinetic factors as related to peripheral or """"eggshell"""" calcification of existing cholesterol stones.""",0
677,2210658,Surface chemistry of phospholipid vesicles relevant to their aggregation and fusion,"A general description of those forces that are important in the stability of the lipid bilayer is presented. The analysis focuses on those that may change under conditions in which aggregation or fusion of vesicles or exchange of their molecules may occur. It is that class of membrane forces that is most likely to play a role in the process(es) that leads to the formation of cholesterol crystals in bile, which eventually grow into gallstones. A specific, hypothetical mechanism for cholesterol crystal nucleation based on vesicle fusion is also given. This mechanism is consistent with the principles of surface chemistry outlined.",0
678,2210661,Molecular control of vesicle aggregation and membrane fusion: hypotheses on bile vesicles,"Molecular factors that control the aggregation and fusion of phospholipid vesicles are reviewed. These include membrane composition, vesicle size, various cations, membrane phase state, dehydrating agents and proteins. Several hypotheses are presented for the mechanism by which bile vesicles aggregate and fuse. It is proposed that phase-separated domains of cholesterol in the bile vesicle bilayer mediate the close approach of the vesicles and that molecular packing defects at the domain boundaries mediate hydrophobic interaction between and fusion of apposed membranes. The apposition or fusion of the membranes may provide the third dimension within which the cholesterol domains on apposed or collapsed membranes can begin to form the monohydrate crystal. Other mediators of aggregation and fusion are likely to be proteins that interact hydrophobically with the bile vesicle and diacylglycerol formed in the vesicles by phospholipase C action. Ca2+ is thought to enhance fusion by interacting with bile salts in the membrane or with membrane-associated proteins.",0
679,2210679,Review of hepatic imaging and a problem-oriented approach to liver masses,"We believe that imaging of the liver is complicated. The sporadic appearance of incidental benign lesions and variability in scanning techniques, equipment and artifacts add difficulties to the evaluation of liver masses. Therefore we emphasize the need to define the problem for which the patient is being imaged. This information helps in choosing the procedure of choice and the technique needed to give the most expedient, accurate answer. This will also help apply the lowest risk and most cost-efficient care. Imaging algorithms vary depending on the suspected pathological conditions. Dynamic bolus-enhanced CT is the modality of choice in most situations. Tc99m sulfur-colloid liver-spleen scans are helpful in patients with suspected FNH, and Tc99m-tagged-RBC-SPECT scans are recommended to confirm cavernous hemangiomas. Cysts are easily confirmed by US. Although MRI is competitive with CT, it has not become a primary modality because of cost, availability, patient selection and variability of scanner capabilities among the many manufacturers and models. It is hard to predict what future development of imaging techniques will bring. Many feel that significant advances have plateaued. Time and money will more likely be concentrated on improving image resolution, speed of scanning and ability to transfer this information to sites outside of the radiology department. In addition to faster scanning, we expect to soon have available safe intravenous and enteric contrast agents for MRI. Certainly this will lead to a new round of investigations to compare MRI with CT scanning.",0
680,2215560,Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus,"BACKGROUND: The value of routine measurements of glycosylated hemoglobin (hemoglobin A1c) in the care of patients with diabetes mellitus is uncertain. We undertook this study to determine whether knowledge of hemoglobin A1c values would result in improved metabolic control in a group of patients with insulin-dependent diabetes mellitus (IDDM). METHODS: We randomly assigned 240 patients with IDDM to one of two groups that were comparable in age, sex, duration of diabetes, and initial hemoglobin A1c levels. The patients were followed for a year, and the hemoglobin A1c concentration was measured at three-month intervals. The hemoglobin A1c values were used in assessing glycemic control and modifying therapy in one of the two groups. In the other, care givers were not aware of the hemoglobin A1c levels and relied on blood or urine glucose measurements to monitor treatment. RESULTS: Among the 222 patients still being followed after one year, the mean hemoglobin A1c value decreased significantly--from 10.1 to 9.5 percent (P less than 0.005)--in the group whose hemoglobin A1c level was monitored (n = 115), whereas the initial and one-year values in the control group (n = 107) were 10.0 and 10.1 percent, respectively. The proportion of patients with poor control, defined as those having a hemoglobin A1c value above 10.0 percent, decreased from 46 to 30 percent (P less than 0.01) in the group whose hemoglobin A1c level was monitored but did not change significantly (45 to 50 percent) in the control group. The patients in the group whose hemoglobin A1c level was monitored were seen and their insulin regimens changed more often, but they were hospitalized for acute care of their diabetes less often than those in the control group. A similar decrease in hemoglobin A1c values occurred in the control group in the following year, when their care givers knew their hemoglobin A1c values. CONCLUSIONS: Regular measurements of hemoglobin A1c lead to changes in diabetes treatment and improvement of metabolic control, indicated by a lowering of hemoglobin A1c values.",0
681,2215561,"Coffee, caffeine, and cardiovascular disease in men","BACKGROUND: For many years, an association between coffee consumption and the risk of coronary heart disease has been suspected. Although based on small numbers of end points, a prospective study has suggested a particularly strong association between recent coffee drinking and the incidence of cardiovascular disease. METHODS: We examined prospectively the relation of coffee consumption with the risk of myocardial infarction, need for coronary-artery bypass grafting or angioplasty, and risk of stroke in a cohort of 45,589 U.S. men who were 40 to 75 years old in 1986 and who had no history of cardiovascular disease. RESULTS: During two years of follow-up observation, 221 participants had a nonfatal myocardial infarction or died of coronary heart disease, 136 underwent coronary-artery surgery or angioplasty, and 54 had a stroke. Total coffee consumption was not associated with an increased risk of coronary heart disease or stroke. The age-adjusted relative risk for all cardiovascular disease among participants who drank four or more cups of coffee per day was 1.04 (95 percent confidence intervals, 0.74 to 1.46). Increasing levels of consumption of caffeinated coffee were not associated with higher risks of cardiovascular disease. Higher consumption of decaffeinated coffee, however, was associated with a marginally significant increase in the risk of coronary heart disease (relative risk, 1.63; 95 percent confidence interval, 1.02 to 2.60). Finally, we observed no pattern of increased risk across the subgroups of participants with increasing intakes of caffeine from all sources. Adjustment for major cardiovascular-risk indicators, dietary intake of fats, and cholesterol intake did not materially alter these associations. CONCLUSIONS: These findings do not support the hypothesis that coffee or caffeine consumption increases the risk of coronary heart disease or stroke.",0
682,2215595,"Predicting the appropriate use of carotid endarterectomy, upper gastrointestinal endoscopy, and coronary angiography","BACKGROUND AND METHODS: In a nationally representative population 65 years of age or older, we have demonstrated that about one quarter of coronary angiographies and upper gastrointestinal endoscopies and two thirds of carotid endarterectomies were performed for reasons that were less than medically appropriate. In this paper we examine whether specific characteristics of patients (age, sex, and race), physicians (age, board-certification status, and experience with the procedure), or hospitals (teaching status, profit-making status, and size) predict whether a procedure will be performed appropriately. RESULTS: In general, we found that little of the variability in the appropriateness of care (4 percent or less) could be explained on the basis of standard, easily obtainable data about the patient, the physician, or the hospital. For all three procedures, however, performance in a teaching hospital increased the likelihood that the reasons would be medically appropriate (P = 0.09 for angiography, P = 0.30 for endoscopy, and P less than 0.01 for endarterectomy). In addition, angiographies were more often performed for appropriate reasons in older or more affluent patients (P less than 0.01 for both). Being treated by a surgeon who performed a high rather than a low number of procedures decreased the likelihood of an appropriate endarterectomy by one third, from 40 to 28 percent (P less than 0.01). CONCLUSIONS: Appropriateness of care cannot be closely predicted from many easily determined characteristics of patients, physicians, or hospitals. Thus, for the present, if appropriateness is to be improved it will have to be assessed directly at the level of each patient, hospital, and physician.",0
683,2227804,Chronic ethanol administration impairs receptor-mediated endocytosis of epidermal growth factor by rat hepatocytes,"The effects of chronic ethanol administration on the receptor-mediated endocytosis of epidermal growth factor were studied in isolated rat hepatocytes. In initial experiments, it was demonstrated that significantly less ligand was bound by hepatocytes isolated from rats fed an ethanol liquid diet for 5 to 7 wk than by cells isolated from chow-fed or pair-fed controls. Reduced binding was shown to be primarily caused by a decreased number of surface receptors rather than by changes in receptor affinity. When hepatocytes were incubated at 37 degrees C in the presence of a large saturating concentration of epidermal growth factor (80 nmol/L), intracellular levels of the ligand were significantly lower in cells from the ethanol-fed animals. However, no effect on degradation of the ligand was observed under those conditions. A defect in the initial stages of receptor-ligand internalization was also indicated because less surface-bound ligand was internalized and subsequently degraded in cells from the ethanol-treated rats. When the endocytosis of a lower, more physiological concentration of the growth factor (0.5 nmol/L) was studied, both the uptake of ligand and its degradation were markedly impaired in hepatocytes from the ethanol-fed animals. These results indicate that chronic ethanol administration impairs the receptor-mediated endocytosis of epidermal growth factor by the liver. The major impairment appears to be a reduction of cell surface receptors; however, other steps of the endocytotic pathway also appear to be affected. These altered steps include defective receptor-ligand internalization and changes in intracellular processing of the ligand leading to decreased degradation.",0
684,2227814,A study of the inhibition of adrenaline-induced vasoconstriction in the isolated perfused liver of rabbit,"We have studied the action of a series of vasoactive and antispasmodic agents on the intrahepatic vasoconstriction induced by adrenaline in the isolated perfused liver of rabbits. The arterial and portal venous resistance, oxygen consumption, liver weight and bile flow were investigated. The drugs used were as follows: nonspecific alpha-adrenergic antagonists (DH-ergocristine, dibenamine, phenoxybenzamine), vasodilators with a direct miscellaneous action (theophylline, papaverine, dipyridamole, glucagon, Aiu-cor by Instituto Gentilli, Italy [inosine, ATP, IPI, UTP]) and antispasmodics (piperylone, tropenziline, noraminophenazone). Adrenaline increased arterial and portal venous resistance followed by a diminution of oxygen consumption, liver weight and bile flow. alpha-Adrenergic antagonists inhibited the effects of adrenaline on portal venous resistance and oxygen consumption and especially the effects on hepatic arterial resistance. The most potent agent was phenoxybenzamine. In contrast to alpha-adrenoceptor blockade, the effects of other vasoactive agents were without a sustained influence on hepatic arterial resistance (excepting those of glucagon and dipyridamole). Some of them were effective as antagonists on responses in the portal venous bed (papaverine, Aiu-cor). Moreover, there were drugs exerting an enhancement of the vasoconstrictor responses of hepatic artery to low concentrations of adrenaline with no effect on the portal venous bed (piperylone, tropenziline). Theophylline and noraminophenazone exerted no effect either on the arterial or portal venous bed. No vasodilator agent antagonized the changes of the bile flow after adrenaline administration.",0
685,2227818,Calcium absorption in bone disease associated with chronic cholestasis during childhood,"Fractional absorption of calcium was determined in 9 children aged 4.9 to 16.9 yr with chronic cholestatic liver disease to determine the role of calcium malabsorption in the development of metabolic bone disease. Radiological evidence of rickets was absent in all patients, but bone density, measured by single beam photon absorptiometry of the distal radius, was reduced in eight of nine subjects. Serum calcium and phosphorus concentrations were normal in all except one subject. Serum 25-hydroxyvitamin D concentration was decreased compared with controls in only one of nine patients, but serum 1,25-dihydroxyvitamin D concentrations were diminished in seven of nine subjects. In all subjects, dietary calcium and phosphorus intakes were greater than 80% of the RDA. Fractional absorption of calcium, determined by oral and intravenous administration of stable calcium isotopes, was similar in cholestatic compared with control subjects (37.1% +/- 12.5% vs. 34.0% +/- 16.4%). In the cholestatic subjects, calcium absorption correlated with serum 1,25-dihydroxyvitamin D (r = 0.871, p less than 0.002) but not 25-hydroxyvitamin D concentrations. Calcium balance, assessed by the duplicate diet method, was positive in four of five subjects. Anthropometric measurements were performed to examine the relationship between nutritional status and bone mineral content. Heights of all subjects were less than or equal to the 10th percentile and fat stores and somatic protein stores were less than the 25th percentile in six of nine subjects. We conclude that factors other than calcium malabsorption and decreased serum 25-hydroxyvitamin D concentration contribute to diminished bone mass in children with cholestatic liver disease.",0
686,2233902,Cerebral glucose metabolism in adults with hyperactivity of childhood onset,"BACKGROUND AND METHODS: The cause of childhood hyperactivity (attention deficit-hyperactivity disorder) is unknown. We investigated the hypothesis that cerebral glucose metabolism might differ between normal adults (controls) and adults with histories of hyperactivity in childhood who continued to have symptoms. Each patient was also the biologic parent of a hyperactive child. None of the adults had ever been treated with stimulant medication. To measure cerebral glucose metabolism, we administered 148 to 185 MBq (4 to 5 mCi) of [18F]fluoro-2-deoxy-D-glucose intravenously to 50 normal adults and 25 hyperactive adults while they performed an auditory-attention task. Images were obtained for 30 minutes with a Scanditronix positron-emission tomograph with a resolution of 5 to 6 mm. Whole-brain and regional rates of glucose metabolism were measured with computer assistance by two trained research assistants, working independently, who were blinded to the subjects' status (control or hyperactive). RESULTS: Global cerebral glucose metabolism was 8.1 percent lower in the adults with hyperactivity than in the normal controls (mean +/- SD, 9.05 +/- 1.20 mg per minute per 100 g vs. 9.85 +/- 1.68 mg per minute per 100 g; P = 0.034). In the adults with hyperactivity, glucose metabolism was significantly reduced, as compared with the values for the controls, in 30 of 60 specific regions of the brain (P less than 0.05). Among the regions of the brain with the greatest reductions in glucose metabolism were the premotor cortex and the superior prefrontal cortex. When the seven women with hyperactivity or the six patients with learning disabilities were omitted from the analysis, the results were similar. CONCLUSIONS: Glucose metabolism, both global and regional, was reduced in adults who had been hyperactive since childhood. The largest reductions were in the premotor cortex and the superior prefrontal cortex--areas earlier shown to be involved in the control of attention and motor activity.",0
687,2233904,"A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease","BACKGROUND: Haemophilus influenzae type b is the leading cause of invasive bacterial disease in young children. The capsular polysaccharide vaccine does not protect children at greatest risk (those under the age of 18 months), but a polysaccharide-protein conjugate vaccine has proved to be more immunogenic in this age group. METHODS: We enrolled 114,000 infants in Finland in an open, prospective, randomized trial of a H. influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]). Children born on odd-numbered days were vaccinated at the ages of 3, 4, 6, and 14 to 18 months; those born on even-numbered days formed the control group and received the same vaccine at the age of 24 months. RESULTS: After three doses of the vaccine there were 4 cases of verified bacteremic H. influenzae type b disease in the group receiving early vaccination, as compared with 64 cases in the control group, between the ages of approximately 7 and 24 months. The protective efficacy of the vaccine was thus 94 percent (95 percent confidence interval, 83 to 98). No serious adverse effects were reported. The immune response to the conjugate vaccine was characteristic of a T-cell-dependent response when studied in a cohort of 120 infants. The primary immunization series resulted in a geometric mean concentration of anticapsular antibody of 0.53 micrograms per milliliter at the age of seven months, and the fourth dose evoked an anamnestic response, with a mean antibody concentration of 45.22 micrograms per milliliter. CONCLUSIONS: A new conjugate vaccine consisting of the capsular polysaccharide of H. influenzae type b covalently linked to a protein carrier (PRP-D), administered to infants beginning at the age of 3 months, is highly effective in protecting young Finnish children (7 to 24 months old) against invasive H. influenzae type b infections.",0
688,2233905,Impaired antibody response to Haemophilus influenzae type b polysaccharide and low IgG2 and IgG4 concentrations in Apache children,"BACKGROUND AND METHODS: Because Native American children are at much higher risk for invasive Haemophilus influenzae type b infection than white children, we compared the antibody responses to H. influenzae type b polysaccharide vaccine in healthy Apache and white children. RESULTS: The concentrations of H. influenzae type b antibody after immunization with polysaccharide vaccine were approximately 10-fold lower in 24-month-old Apache children than in whites of a similar age (P less than 0.01). The decreased response involved H. influenzae type b antibodies of the IgG, IgM, and IgA classes. Concentrations of IgG antibody to tetanus toxoid did not differ significantly, and IgG antibodies to diphtheria toxoid were only twofold lower (P = 0.028). Although total IgG, IgM, and IgA levels were higher in two-year-old Apaches than in whites (all P less than 0.001), IgG2 and IgG4 subclasses were lower (both P less than 0.001). Among the Apaches, individual immunoglobulin levels and allotypes were not significantly correlated with their antibody responses to H. influenzae type b polysaccharide. CONCLUSIONS: Apache children have significant impairment of their antibody response to H. influenzae type b polysaccharide and little or no impairment of their antibody responses to protein toxoids. This immunodeficiency may explain the high incidence of H. influenzae type b infection in this population.",0
689,2233949,Frequency and costs of diagnostic imaging in office practice--a comparison of self-referring and radiologist-referring physicians,"BACKGROUND: To assess possible differences in physicians' practices with respect to diagnostic imaging, we compared the frequency and costs of imaging examinations as performed by primary physicians who used imaging equipment in their offices (self-referring) and as ordered by physicians who always referred patients to radiologists (radiologist-referring). METHODS: Using a large, private insurance-claims data base, we analyzed 65,517 episodes of outpatient care by 6419 physicians for acute upper respiratory symptoms, pregnancy, low back pain, or (in men) difficulty urinating. The respective imaging procedures studied were chest radiography, obstetrical ultrasonography, radiography of the lumbar spine, and excretory urography, cystography, or ultrasonography. RESULTS: For all four clinical presentations, the self-referring physicians obtained imaging examinations 4.0 to 4.5 times more often than the radiologist-referring physicians (P less than 0.0001 for all four). For chest radiography, obstetrical ultrasonography, and lumbar spine radiography, the self-referring physicians charged significantly more than the radiologists for imaging examinations of similar complexity (P less than 0.0001 for all three). The combination of more frequent imaging and higher charges resulted in mean imaging charges per episode of care that were 4.4 to 7.5 times higher for the self-referring physicians (P less than 0.0001). These results were confirmed in a separate analysis that controlled for the specialty of the physician. CONCLUSIONS: Physicians who do not refer their patients to radiologists for medical imaging use imaging examinations more frequently than do physicians who refer their patients to radiologists, and the charges are usually higher when the imaging is done by the self-referring physician. From our results it is not possible to determine which group of physicians uses imaging more appropriately.",0
690,2233961,Long-term outcome after surgical repair of isolated atrial septal defect. Follow-up at 27 to 32 years,"BACKGROUND: Atrial septal defects have been surgically correctable for more than 30 years. The long-term survival rates among patients treated in the early era of cardiac surgery are poorly documented, but such data are of critical importance to the future medical care, employability, and insurability of these patients. METHODS: To determine the natural history of surgically corrected atrial septal defects, we studied all 123 patients who underwent repair of an isolated defect (ostium secundum or sinus venosus) at the Mayo Clinic between 1956 and 1960, 27 to 32 years after the procedure. The follow-up status of all patients was determined by written questionnaires and telephone interviews. Hospital records and death certificates were obtained if interim hospitalization or death had occurred. RESULTS: The overall 30-year actuarial survival rate among survivors of the perioperative period was 74 percent, as compared with 85 percent among controls matched for age and sex. The perioperative mortality was 3.3 percent (four deaths). Actuarial 27-year survival rates among patients in the younger two quartiles according to age at operation (less than or equal to 11 years and 12 to 24 years) were no different from rates among controls--97 percent and 93 percent, respectively. In the two older quartiles (25 to 41 years and greater than 41 years), 27-year survival rates were significantly less (P less than 0.001)--84 percent and 40 percent, respectively--than in controls (91 and 59 percent). Independent predictors of long-term survival according to multivariate analysis were age at operation (P less than 0.0001) and systolic pressure in the main pulmonary artery before operation (P less than 0.0027). When repair was performed in older patients, late cardiac failure, stroke, and atrial fibrillation were significantly more frequent. CONCLUSIONS: Among patients with surgically repaired atrial septal defects, those operated on before the age of 25 have an excellent prognosis, but older patients require careful, regular supervision.",0
691,2258143,A biphasic pattern of anti-pre-S responses in acute hepatitis B virus infection,"The clinical relevance of the immune response to the translation products of the pre-S1 and pre-S2 regions of hepatitis B virus was examined by testing sequential serum samples from 17 patients with acute self-limited hepatitis B and from two patients in whom chronic liver disease developed. Anti-pre-S antibodies were determined by enzyme immunoassays based on the inhibition of binding of monoclonal antibodies to epitopes in the pre-S1 and pre-S2 sequence. In acute, self-limited infection, anti-pre-S antibodies appeared in a biphasic pattern. The early antibodies were detected at the time of clinical signs of acute disease when HBsAg and often HBeAg were present, but hepatitis B virus DNA was no longer detectable in serum. Anti-pre-S levels then fell, but subsequently reappeared as the late antibody during the recovery phase, after development of anti-HBe, but before anti-HBs. Anti-pre-S responses were detected in 15 of 17 patients who recovered (88.2%) and in both patients with acute hepatitis B virus infection evolving to chronic liver disease. Although the early antibodies to pre-S1 and pre-S2 proteins appeared at the time of decreasing levels of infectious virus in serum in cases of self-limited infection, these antibodies also were transiently or continuously present with high levels of serum hepatitis B virus DNA in patients in whom chronic hepatitis B infection developed. Thus the anti-pre-S response in acute hepatitis is not a prognostic marker for clinical resolution.(ABSTRACT TRUNCATED AT 250 WORDS)",0
692,2258146,Influence of hepatitis delta virus replication in the presence of hepatitis B virus DNA in peripheral blood mononuclear cells,"The presence of hepatitis B virus DNA was studied in peripheral blood mononuclear cell samples from 259 HBsAg carriers (229 anti-hepatitis delta negative, 30 anti-hepatitis delta positive), 16 anti-HBc-positive HBsAg-negative patients and 30 patients without hepatitis B virus markers. Hepatitis B virus DNA sequences were detected in peripheral blood mononuclear cell from 115 (44.4%) of the chronic HBsAg carriers and from two (12%) of the anti-HBc-positive, HBsAg-negative patients. In anti-hepatitis delta-negative patients, viral DNA was positive in peripheral blood mononuclear cell from 74 (46%) and from 24 (35.5%) with and without serum HBV-DNA, respectively. With respect to anti-hepatitis delta-positive patients, viral DNA was found in peripheral blood mononuclear cell in 8 of 13 (61.5%) of the patients with circulating hepatitis delta virus RNA and in 9 of 17 (53%) of the hepatitis delta virus RNA-negative subjects. Regarding hepatitis B virus DNA in serum and peripheral blood mononuclear cell, 71% (5 of 7) of the patients with serum hepatitis B virus DNA had this marker in peripheral blood mononuclear cell, whereas 52% (12 of 23) of the patients without serum hepatitis B virus DNA had hepatitis B virus DNA in peripheral blood mononuclear cell. A Southern blot analysis was also carried out on peripheral blood mononuclear cell samples from 30 patients. Hepatitis B virus DNA was detected in 16 patients as free forms, in 12 patients as dimers and free forms and as free circular together with free linear forms in the remaining two patients.(ABSTRACT TRUNCATED AT 250 WORDS)",0
693,2288563,Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study,"A decline in mortality from cardiovascular disease over the past 30 years has been well documented, but the reasons for the decline remain unclear. We analyzed the 10-year incidence of cardiovascular disease and death from cardiovascular disease in three groups of men who were 50 to 59 years old at base line in 1950, 1960, and 1970 (the 1950, 1960, and 1970 cohorts) in order to determine the contribution of secular trends in the incidence of cardiovascular disease, risk factors, and medical care to the decline in mortality. The 10-year cumulative mortality from cardiovascular disease in the 1970 cohort was 43 percent less than that in the 1950 cohort and 37 percent less than that in the 1960 cohort (P = 0.04 by log-rank test). Among the men who were free of cardiovascular disease at base line, the 10-year cumulative incidence of cardiovascular disease declined approximately 19 percent, from 190 per 1000 in the 1950 cohort to 154 per 1000 in the 1970 cohort (0.10 less than P less than 0.20 by chi-square test), whereas the 10-year rate of death from cardiovascular disease declined 60 percent (relative risk for the 1950 cohort as compared with the 1970 cohort, 2.53; 95 percent confidence interval, 1.22 to 5.97). Significant improvements were found in risk factors for cardiovascular disease among the men initially free of cardiovascular disease in the 1970 cohort as compared with those in the 1950 cohort, including a lower serum cholesterol level (mean +/- SD, 5.72 +/- 0.98 mmol per liter [221 +/- 38 mg per deciliter], as compared with 5.90 +/- 1.03 mmol per liter [228 +/- 40 mg per deciliter]) and a lower systolic blood pressure (mean +/- SD, 135 +/- 19 mm Hg, as compared with 139 +/- 25 mm Hg), better management of hypertension (22 percent vs. 0 percent were receiving antihypertensive medication), and reduced cigarette smoking (34 percent vs. 56 percent). We propose that these improvements may have had more pronounced effects on mortality from cardiovascular disease than on the incidence of cardiovascular disease in this population. Our data suggest that the improvement in cardiovascular risk factors in the 1970 cohort may have been an important contributor to the 60 percent decline in mortality in that group as compared with the 1950 cohort, although a decline in the incidence of cardiovascular disease and improved medical interventions may also have contributed to the decline in mortality.",0
694,2294437,The long-term effects of exposure to low doses of lead in childhood. An 11-year follow-up report,"To determine whether the effects of low-level lead exposure persist, we reexamined 132 of 270 young adults who had initially been studied as primary school-children in 1975 through 1978. In the earlier study, neurobehavioral functioning was found to be inversely related to dentin lead levels. As compared with those we restudied, the other 138 subjects had had somewhat higher lead levels on earlier analysis, as well as significantly lower IQ scores and poorer teachers' ratings of classroom behavior. When the 132 subjects were reexamined in 1988, impairment in neurobehavioral function was still found to be related to the lead content of teeth shed at the ages of six and seven. The young people with dentin lead levels greater than 20 ppm had a markedly higher risk of dropping out of high school (adjusted odds ratio, 7.4; 95 percent confidence interval, 1.4 to 40.7) and of having a reading disability (odds ratio, 5.8; 95 percent confidence interval, 1.7 to 19.7) as compared with those with dentin lead levels less than 10 ppm. Higher lead levels in childhood were also significantly associated with lower class standing in high school, increased absenteeism, lower vocabulary and grammatical-reasoning scores, poorer hand-eye coordination, longer reaction times, and slower finger tapping. No significant associations were found with the results of 10 other tests of neurobehavioral functioning. Lead levels were inversely related to self-reports of minor delinquent activity. We conclude that exposure to lead in childhood is associated with deficits in central nervous system functioning that persist into young adulthood.",0
695,2294438,Excess mortality in Harlem,"In recent decades mortality rates have declined for both white and nonwhite Americans, but national averages obscure the extremely high mortality rates in many inner-city communities. Using data from the 1980 census and from death certificates in 1979, 1980, and 1981, we examined mortality rates in New York City's Central Harlem health district, where 96 percent of the inhabitants are black and 41 percent live below the poverty line. For Harlem, the age-adjusted rate of mortality from all causes was the highest in New York City, more than double that of U.S. whites and 50 percent higher than that of U.S. blacks. Almost all the excess mortality was among those less than 65 years old. With rates for the white population as the basis for comparison, the standardized (adjusted for age) mortality ratios (SMRs) for deaths under the age of 65 in Harlem were 2.91 for male residents and 2.70 for female residents. The highest ratios were for women 25 to 34 years old (SMR, 6.13) and men 35 to 44 years old (SMR, 5.98). The chief causes of this excess mortality were cardiovascular disease (23.5 percent of the excess deaths; SMR, 2.23), cirrhosis (17.9 percent; SMR, 10.5), homicide (14.9 percent; SMR, 14.2), and neoplasms (12.6 percent; SMR, 1.77). Survival analysis showed that black men in Harlem were less likely to reach the age of 65 than men in Bangladesh. Of the 353 health areas in New York, 54 (with a total population of 650,000) had mortality rates for persons under 65 years old that were at lest twice the expected rate. All but one of these areas of high mortality were predominantly black or Hispanic. We conclude that Harlem and probably other inner-city areas with largely black populations have extremely high mortality rates that justify special consideration analogous to that given to natural-disaster areas.",0
696,2294448,Decline in the risk of myocardial infarction among women who stop smoking,"To assess the relation of smoking cessation to the risk of a first myocardial infarction in women, we compared the smoking habits of 910 patients who had had their first myocardial infarction with those of 2375 controls in a hospital-based case-control study of women from 25 to 64 years of age. The estimate of relative risk among current smokers as compared with women who had never smoked was 3.6 (95 percent confidence interval, 3.0 to 4.4). Among exsmokers overall, the corresponding estimate of relative risk was 1.2 (95 percent confidence interval, 1.0 to 1.7). Among exsmokers, the estimate of relative risk was significantly elevated among women who had stopped smoking less than two years previously (relative risk, 2.6; 95 percent confidence interval, 1.8 to 3.8). Most of the increase in the risk had dissipated among the women who had stopped smoking two to three years previously, and the estimate of relative risk among the women who had not smoked for three or more years was virtually indistinguishable from that among the women who had never smoked. The same pattern of decline was apparent regardless of the amount smoked, the duration of smoking, the age of the women, or the presence of other predisposing factors. These data suggest that in women, as in men, the increase in the risk of a first myocardial infarction among cigarette smokers declines soon after the cessation of smoking and is largely dissipated after two or three years.",0
697,2295470,Extrahepatic replication of duck hepatitis B virus: more than expected,"Replication of duck hepatitis B virus in extrahepatic tissue such as pancreas, kidney and spleen has been well documented. To assess whether there is more widespread extrahepatic virus replication, we assayed brain, heart, lung, thymus, pancreas, kidney, spleen and intestine of 1- to 16-wk-old ducklings for the presence of duck hepatitis B virus DNA and mRNA by blotting and in situ methods. Replicative intermediates and single-stranded duck hepatitis B virus DNA and RNA transcripts were detected in the brain, lung, heart, intestine, kidney, pancreas and spleen. In situ hybridization showed evidence of viral replication in the lung epithelium, germinal center of spleen, acinar cell of pancreas and tubular epithelium of kidney. These data suggest that extrahepatic duck hepatitis B virus replication is more widespread than previously thought. It is yet to be determined whether widespread extrahepatic replication is unique to duck hepatitis B virus infection or is a common feature of other mammalian hepatitis B-like viruses.",0
698,2296271,Cathepsin D and prognosis in breast cancer,"We investigated the possibility that cathepsin D, an estrogen-induced lysosomal protease, might have value as a prognostic factor in breast cancer by studying frozen tissue specimens from 397 patients. We measured the 34-kd mature form of the enzyme by Western blot assay and densitometry. Among 199 patients with node-negative disease, but not among 198 with node-positive disease, high levels of cathepsin D proved to be a significant predictor of reduced disease-free survival (median follow-up, 64 months), either as a continuous variable (log cathepsin D; P = 0.018) or as a dichotomous variable with an optimized cutoff point (P = 0.0001). Results were similar for overall survival (P = 0.009 and 0.0001, respectively). Relating the level of cathepsin D to other prognostic factors in the patients with node-negative disease, we found an association with aneuploidy but none with estrogen or progesterone receptors, tumor size, or the age of the patient. In multivariate analyses, a high level of cathepsin D was the most important independent factor in predicting shorter disease-free and overall survival in patients with node-negative disease. As compared with the risk in women with low levels of cathepsin D, the relative risk of tumor recurrence was 2.6 (95 percent confidence interval, 1.6 to 4.4) and the relative risk of death was 3.9 (95 percent confidence interval, 2.1 to 7.3) among those with high levels of cathepsin D. For disease-free survival, cathepsin D status was predictive of outcome primarily among those with aneuploid tumors; the actuarial five-year recurrence rates of aneuploid tumors were 60 percent among women with high levels of cathepsin D and 29 percent among those with low levels, as compared with 22 percent for all diploid tumors. We conclude that cathepsin D may be an independent predictor of early recurrence and death in node-negative breast cancer.",0
699,2300087,Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma,"Twelve hundred ninety-six patients with resected colon cancer that either was locally invasive (Stage B2) or had regional nodal involvement (Stage C) were randomly assigned to observation or to treatment for one year with levamisole combined with fluorouracil. Patients with Stage C disease could also be randomly assigned to treatment with levamisole alone. The median follow-up time at this writing is 3 years (range, 2 to 5 1/2). Among the patients with Stage C disease, therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41 percent (P less than 0.0001). The overall death rate was reduced by 33 percent (P approximately 0.006). Treatment with levamisole alone had no detectable effect. The results in the patients with Stage B2 disease were equivocal and too preliminary to allow firm conclusions. Toxic effects of levamisole alone were infrequent, usually consisting of mild nausea with occasional dermatitis or leukopenia, and those of levamisole plus fluorouracil were essentially the same as those of fluorouracil alone--i.e., nausea, vomiting, stomatitis, diarrhea, dermatitis, and leukopenia. These reactions were usually not severe and did not greatly impede patients' compliance with their regimen. We conclude that adjuvant therapy with levamisole and fluorouracil should be standard treatment for Stage C colon carcinoma. Since most patients in our study were treated by community oncologists, this approach should be readily adaptable to conventional medical practice.",0
700,2304491,Delayed childbearing and the outcome of pregnancy,"Whether women who delay childbearing are at increased risk for adverse outcomes of pregnancy is of concern because of the growing proportion of first births to older women. We assessed the effect of advancing maternal age on the outcome of pregnancy in first births in a hospital-based cohort study of 3917 private patients who were 20 years of age or older with a singleton gestation. There was a slight elevation in the risk of having a low-birth-weight infant among women who were 35 years of age or older (adjusted odds ratio, 1.3; 95 percent confidence interval, 0.9 to 1.9) as compared with the risk among women 20 to 29 years of age. However, there was no evidence that women between 30 and 34 or those 35 and older had an increased risk of having a preterm delivery or of having an infant who was small for gestational age, had a low Apgar score, or died in the perinatal period. In contrast, even after controlling for sociodemographic and medical risk factors, we found that women who were 35 or older were significantly more likely to have specific antepartum and intrapartum complications and those who were 30 or older were significantly more likely to have both cesarean sections and infants who were admitted to the newborn intensive care unit. This study suggests that although older primiparous women have higher rates of complications of pregnancy and delivery, their risk of a poor neonatal outcome is not appreciably increased.",0
701,2304504,Reduction of plasma cholesterol levels in normal men on an American Heart Association Step 1 diet or a Step 1 diet with added monounsaturated fat,"The design of diets to achieve optimal changes in plasma lipid levels is controversial. In a randomized, double-blind trial involving 36 healthy young men, we evaluated the effects on plasma lipid levels of both an American Heart Association Step 1 diet (in which 30 percent of the total calories were consumed as fat: 10 percent saturated, 10 percent monounsaturated, and 10 percent polyunsaturated fats, with 250 mg of cholesterol per day) and a monounsaturated fat-enriched Step 1 diet (with 38 percent of the calories consumed as fat: 10 percent saturated, 18 percent monounsaturated, and 10 percent polyunsaturated fats, with 250 mg of cholesterol per day). The effects of these diets were then compared with those of an average American diet, in which 38 percent of the total calories were consumed as fat: 18 percent saturated, 10 percent monounsaturated, and 10 percent polyunsaturated fats, with 500 mg of cholesterol per day. The men consumed the average American diet for 10 weeks before random assignment to one of the two Step 1 diets or to continuation of the average diet for an additional 10 weeks. Caloric intake was adjusted to maintain a constant body weight. As compared with the mean (+/- SD) change in the plasma total cholesterol level in the group that followed the average American diet throughout the study (-0.05 +/- 0.36 mmol per liter), there were statistically significant reductions (P less than 0.025) in the plasma total cholesterol level in the group on the Step 1 diet (-0.37 +/- 0.27 mmol per liter) and in the group on the monounsaturated fat-enriched Step 1 diet (-0.46 +/- 0.36 mmol per liter). There were parallel reductions in the plasma low-density lipoprotein cholesterol levels in these two groups. Neither the plasma triglyceride levels nor the high-density lipoprotein cholesterol concentrations changed significantly with any diet. We conclude that enrichment of the Step 1 diet with monounsaturated fat does not alter the beneficial effects of the Step 1 diet on plasma lipid concentrations.",0
702,2308601,Results of single-lung transplantation for bilateral pulmonary fibrosis. The Toronto Lung Transplant Group,"Between November 1983 and August 1989, we performed single-lung transplantation for end-stage pulmonary fibrosis in 20 patients. Nine patients (45 percent) who survived for more than one year form the basis of this report. Before surgery, the nine survivors had severe restrictive lung disease, with a mean (+/- SD) vital capacity (VC) of 43 +/- 9 percent, a forced expiratory volume in one second (FEV1) of 50 +/- 9 percent, and a single-breath diffusing capacity (DLCO) of 36 +/- 9 percent of predicted values. One year after transplantation, the patients' VC had reached 69 +/- 10 percent, FEV1 79 +/- 15 percent, and DLCO 62 +/- 16 percent of predicted values. Relative perfusion to the transplanted lung rose from 63 +/- 14 percent (three days after surgery) to 77 +/- 7 percent within three months and stayed constant or increased slightly thereafter. Before surgery, despite supplemental oxygen at flow rates varying from 1 to 9 liters per minute, none of the patients could exercise beyond stage 1/2 (2.7 km [1.7 miles] per hour, 5 percent grade) on a modified Bruce treadmill-exercise protocol. All eight patients tested one year or more after transplantation achieved at least stage 1 (2.7 km [1.7 miles] per hour, 10 percent grade), and usually a higher stage, without supplemental oxygen. Arterial oxygen tension returned to normal values in most patients (87 +/- 13 mm Hg), and supplemental oxygen, which all patients required before surgery, was no longer needed by any patient after transplantation. We conclude that in carefully selected patients with end-stage pulmonary fibrosis, single-lung transplantation is an effective treatment.",0
703,2314422,A prospective study of obesity and risk of coronary heart disease in women,"We examined the incidence of nonfatal and fatal coronary heart disease in relation to obesity in a prospective cohort study of 115,886 U.S. women who were 30 to 55 years of age in 1976 and free of diagnosed coronary disease, stroke, and cancer. During eight years of follow-up (775,430 person-years), we identified 605 first coronary events, including 306 nonfatal myocardial infarctions, 83 deaths due to coronary heart disease, and 216 cases of confirmed angina pectoris. A higher Quetelet index (weight in kilograms divided by the square of the height in meters) was positively associated with the occurrence of each category of coronary heart disease. For increasing levels of current Quetelet index (less than 21, 21 to less than 23, 23 to less than 25, 25 to less than 29, and greater than or equal to 29), the relative risks of nonfatal myocardial infarction and fatal coronary heart disease combined, as adjusted for age and cigarette smoking, were 1.0, 1.3, 1.3, 1.8, and 3.3 (Mantel-extension chi for trend = 7.29; P less than 0.00001). As expected, control for a history of hypertension, diabetes mellitus, and hypercholesterolemia--conditions known to be biologic effects of obesity--attenuated the strength of the association. The current Quetelet index was a more important determinant of coronary risk than that at the age of 18; an intervening weight gain increased risk substantially. These prospective data emphasize the importance of obesity as a determinant of coronary heart disease in women. After control for cigarette smoking, which is essential to assess the true effects of obesity, even mild-to-moderate overweight increased the risk of coronary disease in middle-aged women.",0
704,2314423,Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome,"Abundant deposition of bronchoalveolar fibrin and fibronectin occurs during the exudative phase of the adult respiratory distress syndrome (ARDS), promoting hyaline-membrane formation and subsequent alveolar fibrosis. To explore the mechanisms that account for the persistence of bronchoalveolar fibrin and fibronectin, we compared the activity of urokinase, which is necessary for plasminogen activation and fibrin degradation, in cell-free bronchoalveolar-lavage fluid from 8 patients with ARDS, 9 patients with acute pulmonary diseases other than ARDS, and 10 normal subjects. The mean level of urokinase activity in the lavage fluid from the patients with ARDS was 0.003 IU per milliliter of fluid (range, 0 to 0.008), which was significantly lower (P = 0.001) than the level in the fluid from either the patients with pulmonary diseases other than ARDS (0.118 IU per milliliter [range, 0.032 to 0.295]) or the normal subjects (0.129 IU per milliliter [range, 0.045 to 0.198]). The lavage fluid from all the patients with ARDS also had antiplasmin activity, which would promote the persistence of fibrin. A true decrease in urokinase activity was confirmed by the failure of the lavage fluid from the patients with ARDS to convert [125I]plasminogen to plasmin. Despite the low urokinase activity, immunochemical assays revealed normal levels of urokinase antigen in the fluid from the patients with ARDS, suggesting the presence of urokinase inhibitors. Inhibitors were demonstrated directly by a fibrin gel-underlay assay that detects complexes of urokinase with inhibitors. Plasminogen-activator inhibitor type 1 was the principal inhibitor identified. We conclude that increased antifibrinolytic activity due to both urokinase inhibitors and antiplasmins in the bronchoalveolar compartment of patients with ARDS contributes to the formation and persistence of hyaline membranes, a key component of alveolar histopathology in ARDS.",0
705,2314446,Proton nuclear magnetic resonance spectroscopy of plasma from healthy subjects and patients with cancer,"To evaluate the ability of proton nuclear magnetic resonance (NMR) spectroscopy to indicate the presence or absence of malignant disease, we analyzed plasma samples from 104 patients with untreated cancer of various types and from 164 healthy controls. All specimens were coded with random numbers, and the investigators were blind to patient category. A statistically significant difference (P less than 0.001) was found between the mean (+/- SD) line widths in the plasma samples from the controls (39.1 +/- 6.7 Hz) and the line widths in plasma from the patients with cancer (35.2 +/- 6.4 Hz). However, the values showed considerable overlap between the two groups. The average line widths in the 54 male (36.0 +/- 7.9 Hz) and the 110 female (40.5 +/- 5.6 Hz) controls were significantly different (P less than 0.001). Differences in the average line width were also found between 34 male controls 40 years old or older (33.9 +/- 6.5 Hz) and 20 younger men (39.6 +/- 8.8 Hz) (P = 0.008) and between 61 female controls 40 or older (38.8 +/- 5.7 Hz) and 49 younger women (42.5 +/- 4.7 Hz) (P less than 0.001). The average line widths in 36 women with cancer (35.5 +/- 6.8 Hz) and their controls matched for age and sex (39.0 +/- 6.3 Hz) were significantly different (P = 0.03) but again showed much overlap. In 29 men with cancer, the line widths were not different from those of controls matched for age and sex. We conclude that proton NMR spectroscopy is not generally reliable for the detection of cancer. Furthermore, our data demonstrate the importance of studying control groups matched for age and sex.",0
706,2320066,Physicians' responses to financial incentives. Evidence from a for-profit ambulatory care center,"Health Stop is a major chain of ambulatory care centers operating for profit. Until 1985 its physicians were paid a flat hourly wage. In the middle of that year, a new compensation plan was instituted to provide doctors with financial incentives to increase revenues. Physicians could earn bonuses the size of which depended on the gross incomes they generated individually. We compared the practice patterns of 15 doctors, each employed full time at a different Health Stop center in the Boston area, in the same winter months before and after the start of the new arrangement. During the periods compared, the physicians increased the number of laboratory tests performed per patient visit by 23 percent and the number of x-ray films per visit by 16 percent. The total charges per month, adjusted for inflation, grew 20 percent, mostly as a result of a 12 percent increase in the average number of patient visits per month. The wages of the seven physicians who regularly earned the bonus rose 19 percent. We conclude that substantial monetary incentives based on individual performance may induce a group of physicians to increase the intensity of their practice, even though not all of them benefit from the incentives.",0
707,2325721,Exposure to bright light and darkness to treat physiologic maladaptation to night work,"Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.",0
708,2328953,Response of fibronectin to liver regeneration after hepatectomy,"The relationship between plasma fibronectin concentration and the regenerative process in liver remnants after hepatectomy was studied in 12 patients and in male Sprague-Dawley rats with and without cirrhosis. Plasma fibronectin levels were reduced immediately after hepatectomy in humans and rats. Patients and rats without cirrhosis displayed preoperative fibronectin levels within 1 mo and 1 wk, respectively, but low fibronectin levels persisted longer in those with cirrhosis. Plasma fibronectin levels correlated well with the degree of hepatic regeneration in the patients with cirrhosis (r = 0.4227; p less than 0.05) and without cirrhosis (r = 0.8148; p less than 0.001), and also with the percentage of change in liver weight during regeneration in the rat with thioacetamide-induced cirrhosis (r = 0.4905; p less than 0.01) or in the rat without cirrhosis (r = 0.6422; p less than 0.001). These results suggest that plasma fibronectin is a useful marker for the detection of regenerating liver.",0
709,2328954,Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: implication for a pathogenetic role in alcoholic liver fibrogenesis,"Transforming growth factor beta has a specific stimulatory effect on collagen formation by hepatic lipocytes, a cell type believed to be a major source of extracellular matrices in the liver. Because monocytes and macrophages are the known sources of transforming growth factor beta, Kupffer cells--resident macrophages in the liver--may also play an important role in liver fibrogenesis by releasing this cytokine and stimulating lipocyte collagen production. The present study tested this hypothesis using Kupffer cells and hepatic lipocytes isolated from a rat model of alcoholic liver fibrosis. Kupffer-cell-conditioned medium derived from the rat liver with alcoholic fibrosis, but not that from pair-fed control animals, significantly stimulated the net collagen formation of lipocytes isolated from the alcohol-fed, pair-fed control and chow-fed animals. Acidification of the Kupffer-cell-conditioned medium potentiated this effect threefold to fourfold, indicating the presence of a latent form. Fractionation of the Kupffer-cell-conditioned medium by high-performance liquid chromatography gel filtration revealed the major peak of the stimulatory activity corresponding to the molecular weight between 20 kD and 30 kD. It was completely inhibited by anti-transforming growth factor beta IgG. Furthermore, Northern blotting and hybridization of Kupffer-cell messenger RNA from alcohol-fed rats with 32P-labeled transforming growth factor beta complementary DNA demonstrated the presence of 2.5 kb messenger RNA for this cytokine. We conclude that: (a) Kupffer cells isolated from the rat liver with alcoholic fibrosis express and release transforming growth factor beta; (b) that this cytokine is largely responsible for the Kupffer-cell-conditioned medium-induced stimulation of collagen formation by hepatic lipocytes; and (c) that this may represent a possible molecular mechanism of lipocyte stimulation during alcoholic liver fibrogenesis.",0
710,2342524,"Collection and transfusion of blood in the United States, 1982-1988","Widespread concern about the safety of the national blood supply, particularly with respect to the human immunodeficiency virus (HIV), has reportedly affected the use of blood products to support patients. To examine these changes, we conducted national surveys of blood collection and transfusion in the United States in 1982, 1984, 1986, and 1987 and made a limited survey of these activities in 1988. Transfusions of whole blood and red cells reached a peak of 12.2 million units in 1986, then declined to 11.6 million units in 1987 and continued to decline in 1988. Transfusions of plasma declined from a peak of 2.3 million units in 1984 to 2.1 million units in 1987. Growth in the use of platelet transfusions (6.4 million units in 1987) also slowed; however, the proportion of platelets transfused as platelets from single donors grew from 11 percent in 1980 to 25 percent in 1987. Donations of autologous blood increased sharply, from less than 30,000 units in 1982 to 397,000 units in 1987, equivalent to 3 percent of the homologous-blood collections. The growth in collections of homologous blood slowed after 1982. The supply of homologous blood reached a peak of 13.4 million units in 1986 and did not grow between 1986 and 1988. These trends in red-cell, plasma, and platelet transfusions appear to have continued through 1988. We conclude that the unprecedented decline in transfusions of whole blood and red cells, coupled with the continued importation of packed red cells from Western Europe and the offsetting effect of autologous predeposits, forestalled serious shortages of blood that could have resulted from the decline in collections of homologous blood. We attribute these changes in blood collection and blood transfusion to the effects of the epidemic of HIV infection.",0
711,2347555,Variable expression of preS1 antigen in serum during chronic hepatitis B virus infection: an accurate marker for the level of hepatitis B virus replication,"The expression of the preS1 antigen of hepatitis B virus in sera from chronic HBsAg carriers was studied using a specific monoclonal antibody F35.25 in an original, double-immunoradiometric assay. The antibody F35.25 recognized an epitope located between amino-acid residues 32 and 53 on the preS1 sequence of the large HBsAg protein. This domain could be involved in the recognition of hepatitis B virus by hepatocyte receptors. PreS1 antigen detection by monoclonal antibody F35.25 closely correlated with the presence of complete virions in the serum of HBsAg carriers, as demonstrated by ultracentrifugation-gradient experiments and electron-microscopical examination. Of the 19 HBsAg carriers with chronic liver disease, preS1 antigen was detected in 17 (90%): all of the 11 HBeAg- and hepatitis B virus-DNA--positive cases (group 1) and six of eight anti-HBe--positive cases with low levels of hepatitis B virus replication (group 2). PreS1 antigen/HBsAg ratios parallel to preS1 antigen titers were significantly higher in the HBeAg-positive group (34% and 1:10(6] than in the anti-HBe--positive group (18% and 1:10(2]. In contrast, preS1 antigen was not detected in 18 (90%) of the 20 HBsAg healthy carriers positive for anti-HBe and negative for serum hepatitis B virus-DNA (group 3). Our results show that in chronic HBsAg carriers the serum expression of preS1 antigen correlates well with the level of hepatitis B virus replication (serum hepatitis B virus-DNA and/or liver HBcAg) and that it may be useful in assessing the clinical importance of the chronic viral infection.",0
712,2347557,Localization of the heme-binding protein in the cytoplasm and of a heme-binding protein-like immunoreactive protein in the nucleus of rat liver parenchymal cells: immunocytochemical evidence of the subcellular distribution corroborated by radioimmunoassay and immunoblotting,"The abundant heme-binding protein of the liver, probably identical with Z-protein or liver fatty acid-binding protein, has an apparent molecular weight of 14,000 Da and is presumably involved in the intracellular transport of a variety of compounds. The cellular and subcellular distribution of HBP in the liver was studied in adult male and female rats by postembedding immunocytochemistry using the protein A-gold technique. By light microscopic examination heme-binding protein is present exclusively in parenchymal cells and not found in the sinusoidal lining cells or other cells in portal tracts. Immunoreactivity for heme-binding protein is uniformly strong throughout the liver lobule in female rats but is markedly reduced in the pericentral region in male animals. By immunoelectron microscopy heme-binding protein immunoreactivity is localized in cytoplasm and nuclear matrix. The mitochondria and peroxisomes and the secretory apparatus are free of the label. In nuclei, gold labeling is confined to the interchromatin region (euchromatin) and nucleoli; condensed chromatin (heterochromatin) and nucleolus-associated chromatin are negative. The subcellular localization was substantiated by radioimmunoassay and immunoblotting of nuclear and cytosolic fractions. Immunoblotting shows that the heme-binding protein-like immunoreactive protein in the nucleus has a slightly larger molecular weight than that in the cytoplasm.",0
713,2348838,Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration,"Paraneoplastic cerebellar degeneration is a rare syndrome that occurs in patients with gynecologic cancer and is characterized by widespread loss of Purkinje cells. To determine whether Purkinje-cell antigens are selectively expressed in the tumors of patients with the syndrome, we examined tumor tissue from 10 patients whose serum contained anti-Purkinje-cell (anti-Yo) antibodies. The origins of the cancers were the breast (five patients), ovary (three), endometrium (one), and fallopian tube (one). We used as controls tumor tissue from 11 patients with ovarian cancer and 10 patients with breast cancer who were neurologically normal. Using immunohistochemical and Western blot analysis, we found that Purkinje-cell antigens were expressed in all the tumors from the 10 patients with paraneoplastic cerebellar degeneration but in none of the tumors from the 21 neurologically normal patients. When IgG from patients with paraneoplastic cerebellar degeneration was affinity-purified to cerebellar Purkinje-cell antigen, immunohistochemical analysis showed that it reacted specifically with the tumor tissue from those patients. We conclude that in patients with paraneoplastic cerebellar degeneration, the anti-Yo antibody results from an immune response to neural antigens expressed by the gynecologic tumors in the patients.",0
714,2365281,Increased prooxidant action of hepatic cytosolic low-molecular-weight iron in experimental iron overload,"In the iron-loaded liver there may be an increase in the putative intracellular transit pool of iron, components of which could be catalytically active in stimulating lipid peroxidation. To study the levels of low-molecular-weight, catalytically active iron in the liver, cytosolic ultrafiltrates were tested in an assay containing rat liver microsomes and NADPH. Malondialdehyde production was used as an index of lipid peroxidation. This assay system was sensitive enough to detect 0.25 mumol/L ferrous iron; progressive but non-linear increases in malondialdehyde were produced as the iron concentration was increased to 5 mumol/L. Ultrafiltrates from hepatic cytosol of iron-loaded rats had greater prooxidant action than did those from controls. When added to the assay, deferoxamine, an iron chelator, completely suppressed the prooxidant action of hepatic ultrafiltrates, showing that this activity is iron-dependent. Deferoxamine administered intraperitoneally to control animals at a dose of 1 gm/kg completely inhibited the prooxidant effect of hepatic ultrafiltrates prepared from rats killed after 1, 2 and 3 hr. Partial inhibition was observed at 4 hr; by 6 hr the inhibitory effect of deferoxamine was completely lost. Administration of deferoxamine (1 gm/kg intraperitoneally, 1 hr before killing) completely inhibited the prooxidant action of hepatic ultrafiltrates in moderately iron-loaded rats and controls but had no protective effect in heavily iron-loaded rats. These results support the concept that iron overload results in an increase in a hepatic cytosolic pool of low-molecular-weight iron that is catalytically active in stimulating lipid peroxidation. This pool can be chelated transiently in vivo by deferoxamine in moderate, but not heavy, iron overload.",0
715,2365294,Inhibition of alpha-ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis,"Sera from patients with primary biliary cirrhosis contain autoantibodies that recognize mitochondrial proteins. Five of the target autoantigens have now been identified as enzymes of three related multienzyme complexes: the pyruvate dehydrogenase complex, the branched chain alpha-ketoacid dehydrogenase complex and the alpha-ketoglutarate dehydrogenase complex. Each complex consists of component enzymes designated E1, E2 and E3. In this report, we confirm that primary biliary cirrhosis sera react with dihydrolipoamide succinyltransferase, the E2 component of alpha-ketoglutarate dehydrogenase complex. Seventy-three of 188 (39%) primary biliary cirrhosis sera reacted with alpha-ketoglutarate dehydrogenase complex-E2 when immunoblotted against purified alpha-ketoglutarate dehydrogenase complex; one of these sera also reacted with the E1 component. In addition, primary biliary cirrhosis sera possessing alpha-ketoglutarate dehydrogenase complex-E2 reactivity specifically inhibited enzyme function of alpha-ketoglutarate dehydrogenase complex. Enzyme activity was not affected by primary biliary cirrhosis sera that contained autoantibodies to pyruvate dehydrogenase complex-E2 and/or branched chain alpha-ketoacid dehydrogenase complex-E2, which lacked alpha-ketoglutarate dehydrogenase complex-E2 reactivity. Furthermore, affinity-purified primary biliary cirrhosis sera against alpha-ketoglutarate dehydrogenase complex-E2 inhibited only alpha-ketoglutarate dehydrogenase complex activity but did not alter enzyme activity of either pyruvate dehydrogenase complex or branched chain alpha-ketoacid dehydrogenase complex. Finally, alpha-ketoglutarate dehydrogenase complex-E2 specific affinity-purified antisera did not react on immunoblot with any component enzymes of pyruvate dehydrogenase complex or branched chain alpha-ketoacid dehydrogenase complex.(ABSTRACT TRUNCATED AT 250 WORDS)",0
716,2365295,Cholesterol and bile acid metabolism in cultures of primary rat bile ductular epithelial cells,"The role of hepatocytes in bile acid and cholesterol metabolism has been extensively studied. By contrast, nothing is known about the role of bile ductular epithelial cells in cholesterol and bile acid metabolism. The purpose of the current studies was to establish whether bile ductular epithelial cells synthesize cholesterol, bile acids or both and to determine whether these cells are capable of metabolizing (hydroxylating, conjugating) bile acids. Bile ductular epithelial cells were isolated from rat liver after ligation of the common bile duct for 6 to 8 wk. Bile ductular epithelial cells were essentially free (greater than 99%) of hepatocytes and were histochemically positive (greater than 80%) for gamma-glutamyl transpeptidase activity. Cholestatic hepatocytes were simultaneously isolated and characterized with regard to their ability to synthesize and metabolize bile acids. Incubation of bile ductular epithelial cells with [14C]-acetate resulted in rapid labeling of cellular cholesterol, suggesting that these cells have a complete cholesterol biosynthetic pathway. The addition of [4-14C]-cholesterol to bile ductular epithelial cells did not lead to detectable synthesis of [14C]-bile acids. [24-14C]-Cholic acid, [24-14C]-deoxycholic acid, [24-14C]-lithocholic acid and [3H]-ursodeoxycholic acid were individually added to bile ductular epithelial cells and incubated for 24 or 48 hr. Bile acid metabolites were extracted and separated by C-18 reverse-phase high-performance liquid chromatography or thin-layer chromatography. Bile ductular epithelial cells conjugated deoxycholic acid, ursodeoxycholic acid and lithocholic acid to glycine and taurine. Surprisingly, no conjugation of cholic acid was detected. Conjugated lithocholic acid was further metabolized to highly polar metabolite(s), possibly beta-muricholic acid.(ABSTRACT TRUNCATED AT 250 WORDS)",0
717,2366833,Estimation of the risk of thrombocytopenia in the offspring of pregnant women with presumed immune thrombocytopenic purpura,"BACKGROUND AND METHODS: The optimal management of immune thrombocytopenic purpura during pregnancy remains controversial because the risk of severe neonatal thrombocytopenia remains uncertain. We studied the outcome of the index pregnancy in 162 women with a presumptive diagnosis of immune thrombocytopenic purpura to determine the frequency of neonatal thrombocytopenia and to determine whether neonatal risk could be predicted antenatally by history or platelet-antibody testing. RESULTS: Two maternal characteristics were identified as predicting a low risk of severe neonatal thrombocytopenia: the absence of a history of immune thrombocytopenic purpura before pregnancy, and the absence of circulating platelet antibodies in the women who did have a history of the condition. Eighteen of 88 neonates (20 percent; 95 percent confidence interval, 13 to 30 percent) born to women with a history of immune thrombocytopenic purpura had severe thrombocytopenia (platelet count less than 50 x 10(9) per liter at birth), as compared with 0 of 74 (0 percent; 95 percent confidence interval, 0 to 5 percent) born to women first noted to have thrombocytopenia during pregnancy (P less than 0.0001). Among the women with a history of immune thrombocytopenic purpura, 18 of 70 neonates (26 percent; 95 percent confidence interval, 16 to 38 percent) born to those with circulating platelet antibodies had severe thrombocytopenia, as compared with 0 of 18 infants (0 percent; 95 percent confidence interval, 0 to 18.5 percent) born to those without circulating antibodies (P less than 0.02). Thus, the risk of severe neonatal thrombocytopenia in the offspring of women without a history of immune thrombocytopenic purpura before pregnancy and of women with a history of the condition in whom circulating platelet antibodies are not detected was 0 percent (95 percent confidence intervals, 0 to 5 and 0 to 18.5 percent, respectively). CONCLUSIONS: The absence of a history of immune thrombocytopenic purpura or the presence of negative results on circulating-antibody testing in pregnant women indicates a minimal risk of severe neonatal thrombocytopenia in their offspring.",0
718,2373482,Computerized measurement of iron in liver biopsies: a comparison with biochemical iron measurement,"The measurement of stainable hepatic iron using a microcomputer image analysis system was compared with standard biochemical measurements of liver iron content in 103 liver biopsy specimens--29 of idiopathic hemochromatosis, 51 of alcoholic liver disease and 23 of various nonalcoholic liver diseases. Sections were stained using Perls' method for iron; the mean area staining positively for iron was measured and expressed as a percentage of the area of biopsy measured. Biochemical (biochemical hepatic iron [mumol/gm dry wt]/age) and morphometrical (morphometrical hepatic iron [%]/age x 100) hepatic iron indices were calculated. Patients in the idiopathic hemochromatosis group had significantly higher biochemical hepatic iron concentrations (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 284 (range = 119 to 631), 21 (range = 2 to 65) and 15 (range = 3 to 31) mumol/gm dry wt, respectively. The biochemical hepatic iron index was also significantly higher (p less than 0.001) in the hemochromatosis group compared with the alcoholic liver disease and nonalcoholic liver disease groups: 5.8 (range = 2.1 to 13.7), 0.4 (range = 0 to 1.6) and 0.4 (range = 0 to 1.1), respectively. Computerized measurements were significantly higher in the hemochromatosis group (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 9.72% (range = 1.50% to 29.26%), 0.13% (range = 0% to 1.20%) and 0.03% (range = 0% to 0.40%), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)",0
719,2373487,Characterization of a phenotypically and functionally distinct subset of large granular lymphocytes (pit cells) in rat liver sinusoids,"""Pit cells, or large granular lymphocytes, with natural tumoricidal activity are found in the sinusoids of normal rat liver. Hepatic large granular lymphocytes are heterogeneous and can be subdivided into two subsets. These subsets were compared with peripheral-blood large granular lymphocytes and were found to differ phenotypically and functionally. Phenotypical differences included lower expression of the asialo-GM1 marker of natural killer cells, lower cellular density and many more small cytoplasmic granules in hepatic large, granular lymphocytes. Low-density hepatic large, granular lymphocytes were five to eight times more cytotoxic than blood large, granular lymphocytes on a per-cell basis as measured against YAC-1 cells and colon carcinoma cells. In addition, hepatic large, granular lymphocytes were able to lyse P-815 target cells, which are resistant to blood natural killer cells. Large, granular lymphocytes isolated from the liver also contained a subset with intermediate phenotypical and functional characteristics, possibly representing a transitional form between blood and """"liver-specific"""" large, granular lymphocytes. The liver thus contains a specific population of highly activated or further differentiated large granular lymphocytes.""",0
720,2374566,Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects,"BACKGROUND: Fatty acids that contain a trans double bond are consumed in large amounts as hydrogenated oils, but their effects on serum lipoprotein levels are unknown. METHODS: We placed 34 women (mean age, 26 years) and 25 men (mean age, 25 years) on three mixed natural diets of identical nutrient composition, except that 10 percent of the daily energy intake was provided as oleic acid (which contains one cis double bond), trans isomers of oleic acid, or saturated fatty acids. The three diets were consumed for three weeks each, in random order. RESULTS: On the oleic acid diet, the mean (+/- SD) serum values for the entire group for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were 4.46 +/- 0.66. 2.67 +/- 0.54, and 1.42 +/- 0.32 mmol per liter (172 +/- 26, 103 +/- 21, and 55 +/- 12 mg per deciliter), respectively. On the trans-fatty-acid diet, the subjects' mean HDL cholesterol level was 0.17 mmol per liter (7 mg per deciliter) lower than the mean value on the diet high in oleic acid (P less than 0.0001; 95 percent confidence interval, 0.13 to 0.20 mmol per liter). The HDL cholesterol level on the saturated-fat diet was the same as on the oleic acid diet. The LDL cholesterol level was 0.37 mmol per liter (14 mg per deciliter) higher on the trans-fatty-acid diet than on the oleic acid diet (P less than 0.0001; 95 percent confidence interval, 0.28 to 0.45 mmol per liter) and 0.47 mmol per liter (18 mg per deciliter) higher on the saturated-fat diet (P less than 0.001; 95 percent confidence interval, 0.39 to 0.55 mmol per liter) than on the oleic acid diet. The effects on lipoprotein levels did not differ between women and men. CONCLUSIONS: The effect of trans fatty acids on the serum lipoprotein profile is at least as unfavorable as that of the cholesterol-raising saturated fatty acids, because they not only raise LDL cholesterol levels but also lower HDL cholesterol levels.",0
721,2381443,Abnormalities of lipoprotein metabolism in patients with the nephrotic syndrome,"BACKGROUND AND METHODS: Patients with the nephrotic syndrome characteristically have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities are uncertain. In this study, we measured serum lipids and apoproteins in 57 patients with the nephrotic syndrome. We also determined the kinetic indexes of low-density lipoprotein (LDL) metabolism in six patients, and again in three of the six after recovery. RESULTS: The patients with the nephrotic syndrome had elevated serum concentrations of cholesterol, triglycerides, and phospholipids, which were confined to the lipoproteins containing apoprotein B. The serum concentrations of high-density lipoproteins and the associated A-I and A-II apoproteins were similar in the patients with the nephrotic syndrome and normal subjects. The relative proportions of lipids and their positive association with the increased serum concentrations of apoproteins B, C-II, C-III, and E suggest quantitative rather than qualitative differences in the lipoproteins. All the patients had lipiduria, which probably reflected the excretion of high-density lipoproteins, although no intact immunoreactive apoprotein A-I was found in urine. Serum albumin concentrations were inversely related to serum lipid concentrations in the patients, the severity of the hypoalbuminemia corresponding to the degree of change in serum lipoprotein concentrations. The kinetic studies of lipoprotein metabolism revealed an overproduction of LDL apoprotein B that returned to normal after recovery. CONCLUSIONS: The elevated serum concentrations of LDL cholesterol, other lipids, and apoprotein B in patients with uncomplicated nephrotic syndrome are due to reversible increases in lipoprotein production.",0
722,2388667,Cyclosporine-induced sympathetic activation and hypertension after heart transplantation,"BACKGROUND: Hypertension is a frequent complication of cyclosporine-induced immunosuppression, but the underlying mechanism is unknown. In anesthetized animals, the administration of cyclosporine increases sympathetic-nerve discharge, which may contribute to hypertension. METHODS: To determine whether cyclosporine-induced hypertension is accompanied by sustained sympathetic neural activation in patients, we recorded sympathetic action potentials using intraneural microelectrodes (in the peroneal nerve) in heart-transplant recipients receiving azathioprine and prednisone alone (n = 5) or in combination with cyclosporine (n = 14). We performed the same studies in eight patients with myasthenia gravis who were receiving cyclosporine and eight who were not, in five patients with essential hypertension, and in nine normal controls. RESULTS: Heart-transplant recipients receiving cyclosporine had higher mean arterial blood pressure (+/- SE) than those not receiving cyclosporine (112 +/- 3 vs. 96 +/- 4 mm Hg; P less than 0.05) and a 2.7-fold higher rate of sympathetic-nerve firing (80 +/- 3 vs. 30 +/- 4 bursts per minute; P less than 0.05). For patients with myasthenia gravis, similar doses of cyclosporine were associated with smaller elevations in mean arterial blood pressure (100 +/- 2 mm Hg, as compared with 91 +/- 4 mm Hg in those not receiving cyclosporine; P less than 0.05) and in the rate of sympathetic-nerve firing (46 +/- 3 bursts per minute, as compared with 25 +/- 4 bursts per minute; P less than 0.05). Sympathetic activity in patients with heart transplants or myasthenia gravis who were not being treated with cyclosporine was no different from that in patients with essential hypertension or in normal controls. CONCLUSIONS: Cyclosporine-induced hypertension is associated with sympathetic neural activation, which may be accentuated by the cardiac denervation that results from heart transplantation.",0
723,2391069,Lack of metabolic effects of cholecystokinin on hepatocytes,"We previously reported that the liver was the major organ that extracts small, biologically active, circulating forms of cholecystokinin. Although our work indicated extensive degradation of cholecystokinin extracted from plasma during its transit across the hepatocyte, it was unclear whether cholecystokinin might also have a physiological effect on this cell before its intracellular degradation. Therefore we tested the hypothesis that cholecystokinin has a direct biological effect on hepatocytes. Using freshly isolated or cultured hepatocytes, we studied whether cholecystokinin-octapeptide alters protein synthesis, affects amino acid transport or influences cytosolic free calcium concentrations. Using liver slices, we also determined the effect of cholecystokinin-octapeptide on cyclic nucleotide levels. Cholecystokinin-octapeptide, up to a concentration of 1 mumol/L, had no effect on the incorporation of radiolabeled amino acids into total hepatocyte protein; in contrast, comparable molar amounts of insulin stimulated protein synthesis by as much as 37% (ED50 = 1.5 x 10(-10) mol/L). Although insulin and glucagon stimulated the transport into hepatocytes of 14C-alpha-aminoisobutyric acid, a nonmetabolizable amino acid analog, cholecystokinin-octapeptide had no affect Cholecystokinin-octapeptide also did not affect either the concentration of calcium in individual hepatocytes, as measured by digitized video microscopy using Fura-2, or the levels of cyclic AMP or cyclic GMP in liver slices. Our results show that cholecystokinin has no effect on protein synthesis, on amino acid transport or on hepatocyte calcium and cyclic nucleotide levels. These and our previous data suggest that the primary outcome of hepatic extraction of cholecystokinin is hormone degradation.",0
724,2391072,"""Demonstration of """"naturally occurring mitochondrial antibodies"""" in family members of patients with primary biliary cirrhosis""","""Sera from 81 healthy family members (including husbands) of 13 patients with primary biliary cirrhosis were tested by Western blotting against the antigen fractions M9 and M2 derived respectively from rat liver and beef heart mitochondria. Fifty-eight (70%) were positive and recognized four major (molecular weights 98 kD, 65 kD, 61 kD, 58 kD) and eight minor determinants (85 kD, 81 kD, 78 kD, 54 kD, 48 kD, 45 kD, 40 kD, 30 kD) labeled alpha-my. Each of the 58 sera recognized at least one of the four major polypeptides. In contrast, only 6% of 80 primary biliary cirrhosis patients had antibodies against one of these epitopes. Sera from 25 patients with different infectious disorders previously shown to react with submitochondrial particles by enzyme-linked immunosorbent assay also recognized at least one of the four major determinants. From these findings it was concluded that these antibodies may belong to the family of natural autoantibodies. Since they reacted with submitochondrial fractions, they were defined as """"naturally occurring mitochondrial antibodies"""". The high incidence of """"naturally occurring mitochondrial antibodies"""" in primary biliary cirrhosis-contact persons may be taken as indirect evidence for a contagious immunogenic agent circulating in the blood of primary biliary cirrhosis-patients. In contrast, the absence of """"naturally occurring mitochondrial antibodies"""" in primary biliary cirrhosis-patients themselves implies that an underlying B-cell defect is responsible for this lack of antibody production. Considering the protective role of naturally occurring antibodies in general, this postulated B-cell defect could be a major factor in the etiopathogenesis of primary biliary cirrhosis.""",0
725,2402262,Location on chromosome 15 of the gene defect causing Marfan syndrome,"""BACKGROUND: Marfan syndrome, """"the founding member"""" of the heritable disorders of connective tissue, is a common autosomal dominant disorder with highly variable clinical manifestations in the skeletal, ocular, and cardiovascular systems. The fundamental defect leading to this disease has escaped definition despite decades of research efforts by several groups of investigators. METHODS AND RESULTS: Using linkage analyses with polymorphic markers of the human genome, we mapped the genetic defect to chromosome 15 in five families with Marfan syndrome. With three polymorphic markers we obtained definitive proof of linkage in these families (lod score = 3.92, theta = 0.0 +/- 0.11). The most probable location of the gene for the disease is currently D15S45 (lod score = 3.32, theta = 0.0 +/- 0.12). CONCLUSIONS: The chromosomal localization of the mutation in Marfan syndrome is a first step toward the isolation and characterization of the defective gene and serves as a diagnostic test in families in which cosegregation of these markers with the disease has been confirmed.""",0
726,2403658,Absence of HIV infection in blood donors with indeterminate western blot tests for antibody to HIV-1,"To determine whether apparently healthy persons who have had repeatedly reactive enzyme immunoassays and an indeterminate Western blot assay for antibody to the human immunodeficiency virus type 1 (HIV-1) are infected with HIV-1 or HIV-2, we studied 99 such volunteer blood donors in a low-risk area of the country. The subjects were interviewed about HIV risk factors. Coded blood specimens were tested again for HIV-1 antibody (by two different enzyme immunoassays, a Western blot assay and a radioimmunoprecipitation assay) and for HIV-2 antibody by enzyme immunoassay, for HIV-1 by the serum antigen test, for HIV-1 by culture, for human T-cell leukemia virus Type I or II antibody by enzyme immunoassay, and for sequences of HIV DNA by the polymerase chain reaction. Of the 99 blood donors, 98 reported no risk factors for HIV-1 infection; 1 donor had used intravenous drugs. After a median of 14 months (range, 1 to 30) from the time of the initial test, 65 subjects (66 percent) were still repeatedly reactive for HIV-1 antibody on at least one immunoassay. In 91 subjects (92 percent) the Western blot results were still indeterminate, whereas in 8 they were negative. No donor met the criteria for a positive Western blot assay for HIV-1, and none had evidence of HIV-1 or HIV-2 infection on culture or by any other test. We conclude that persons at low risk for HIV infection who have persistent indeterminate HIV-1 Western blots are rarely if ever infected with HIV-1 or HIV-2.",0
727,2403660,"The ratio of waist-to-hip circumference, plasma insulin level, and glucose intolerance as independent predictors of the HDL2 cholesterol level in older adults","High plasma levels of HDL2, a subfraction of high-density lipoprotein (HDL) cholesterol, are associated with a reduced risk of coronary heart disease. To investigate the characteristics related to HDL2 cholesterol levels, we measured lipoprotein levels and several metabolic and anthropometric variables in 146 healthy subjects (77 men and 69 women) in the seventh decade of life. The level of HDL2 cholesterol was inversely correlated with the ratio of the waist-to-hip circumference (r = -0.335 for men; r = -0.370 for women; P less than 0.01) and the plasma insulin level (r = -0.400 for men; r = -0.398 for women; P less than 0.001). In a multiple regression model including both sexes, 41 percent of the variance in the HDL2 level was explained by the combined effect of the waist-to-hip ratio (P less than 0.0001), the plasma insulin level (P = 0.0003), and the degree of glucose tolerance indicated by the integrated area under the plasma glucose curve after an oral glucose-tolerance test (P = 0.05). The body-mass index, total percentage of body fat, maximal oxygen uptake, diet, and sex were not significant predictors of the HDL2 level when added to this model, whereas the original variables remained significant predictors. The HDL2 cholesterol level in subjects at the 25th percentile for waist-to-hip ratio was 153 percent of that in subjects at the 75th percentile. We conclude that HDL2 levels are inversely correlated with truncal fat, plasma insulin levels, and the presence of glucose intolerance and are not independently associated with sex or total body fat.",0
728,2406597,Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus,"Because glucose-stimulated insulin secretion is selectively impaired during the development of insulin-dependent diabetes mellitus (IDDM), we tested the possibility that the glucose transporter of pancreatic islet beta cells is a target of the autoimmune process in patients with IDDM. We measured the uptake of 3-O-methyl-beta-D-glucose by dispersed islet cells from rats after a 15-minute incubation with purified IgG from 27 patients with newly diagnosed IDDM, 28 normal subjects, and 5 patients with non-insulin-dependent diabetes mellitus (NIDDM). The IgG fractions from 26 of the 27 patients with IDDM (96 percent), but from none of the 5 patients with NIDDM, reduced the initial rates of 3-O-methyl-beta-D-glucose uptake to at least 1 SD below the mean of the rates observed in the presence of IgG fractions from normal subjects (P less than 0.001). In contrast, the uptake of L-leucine by islet cells was not affected by any of the IgG fractions. The inhibitory activity of IgG from the patients with IDDM was abolished by preincubation with islet cells and membranes from hepatocytes, which contain the same glucose transporter as beta cells, but not with erythrocytes, which do not contain this transporter. We conclude that IgG from patients with IDDM of recent onset, but not from those with NIDDM, inhibits glucose uptake by rat islet cells. The results are consistent with the presence of an antibody against a protein involved in glucose transport by beta cells that would thereby impair glucose-stimulated insulin secretion.",0
729,2406602,"Effects of electronic fetal-heart-rate monitoring, as compared with periodic auscultation, on the neurologic development of premature infants","In a multicenter, randomized clinical trial, we assessed the early neurologic development of 93 children born prematurely whose heart rates were monitored electronically during delivery and compared it with that of 96 children born prematurely whose heart rates were periodically monitored by auscultation. All the children were singletons with cephalic presentation, and all weighed less than or equal to 1750 g at birth. The mental and psychomotor indexes of the Bayley Scales of Infant Development (standardized mean score +/- SD, 100 +/- 16) and a formal neurologic examination were administered at three follow-up visits (at 4, 8, and 18 months of age, corrected for gestational age). At 18 months, the mean mental-development scores in the groups receiving electronic fetal monitoring and periodic auscultation were 100.5 +/- 2.4 and 104.9 +/- 1.8, respectively (P greater than 0.1). The mean psychomotor-development scores in the two groups at 18 months were 94.0 +/- 2.4 and 98.3 +/- 1.8, respectively (P greater than 0.1). The incidence of cerebral palsy was higher in the electronically monitored group--20 percent as compared with 8 percent in the group that was monitored by auscultation (P less than 0.03). In the electronic-fetal-monitoring group (but not in the periodic-auscultation group), the risk of cerebral palsy increased with the duration of abnormal fetal-heart-rate patterns, as assessed by retrospective review (chi 2 trend = 12.71, P less than 0.001). The median time to delivery after the diagnosis of abnormal fetal-heart-rate patterns was 104 minutes with electronic fetal monitoring, as compared with 60 minutes with periodic auscultation. We conclude that as compared with a structured program of periodic auscultation, electronic fetal monitoring does not result in improved neurologic development in children born prematurely.",0
730,2411647,Mitochondrial antibodies in primary biliary cirrhosis: species and nonspecies specific determinants of M2 antigen,"Sera from patients with primary biliary cirrhosis reacted with four major bands in beef heart mitochondria and ATPase extract when analyzed by immunoblot after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These four immunologically reactive bands corresponded to protein bands with molecular weights of about (a) 80,000; (b) 63,000; (c) 56,000; and (d) 43,000 to 46,000. An additional immunoreactive band was found with some high-titered primary biliary cirrhosis sera at 36,000. No association with any ATPase subunits was found, except for band c which migrated between the alpha- and beta-subunit of ATPase. Most ATPase fractions did not contain this band c, indicating that M2 determinants, as defined by immunoblot, are not identical with any ATPase subunit. Species and nonspecies-specific determinants of M2 were identified using mitochondria from rat liver and human heart and liver. Antigenic bands a, c and d were nonspecies-specific. Band b and e occurred only in beef heart. An additional determinant at about 38,000 was detected using human heart and liver mitochondria. Primary biliary cirrhosis sera showed a typical reaction with two protein bands of Escherichia coli, one at about 85,000 to 90,000 and the other at 60,000. Antibodies against both determinants could be absorbed with submitochondrial particles of beef heart showing that E. coli shares cross-reacting determinants with mitochondria. Sera from 56 primary biliary cirrhosis patients were tested using beef heart mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)",0
731,2415435,Hepatocellular carcinoma after thorotrast exposure: establishment of a new cell line (Mz-Hep-1),"A human hepatoma cell line, associated with thorotrast exposure, from an hepatitis B marker-negative patient was established as a permanent cell line (Mz-Hep-1) in tissue culture. Histology of the primary tumor, as well as phase contrast, transmission and scanning electron microscopy of the cultured cells showed typical characteristics of liver cells. Mz-Hep-1 cells secreted complement components (C2, C3, C4), carcinoembryonic antigen, lactate dehydrogenase, chymotrypsin, haptoglobin and retinol-binding protein and expressed HLA-, transferrin-, blood group B-related determinants and complement component C5 and carcinoembryonic antigen on their cell surface. Mz-Hep-1 cells represent the first human hepatoma cell line, which is strongly associated with a carcinogen.",0
732,2432426,Molecular analysis of the high-hemoglobin-F phenotype in Saudi Arabian sickle cell anemia,"Patients from the eastern province of Saudi Arabia who have sickle cell anemia have high circulating levels of fetal hemoglobin (hemoglobin F, 17 percent), and they therefore have a mild form of the disease. To examine the molecular basis of the elevated production of hemoglobin F, we searched for mutations in the promoter regions of the two hemoglobin F gamma-globin genes (G gamma and A gamma). The DNA sequences 450 bp (base pairs) upstream of both the G gamma and A gamma globin genes were normal except for a single-base cytosine-to-thymidine (C----T) substitution at -158 bp 5' to the cap (preinitiation) site of the G gamma-globin gene of the high-hemoglobin-F chromosome. We searched for an association between this -158 C----T substitution and the production of hemoglobin F and G gamma in normal Saudis and Saudis with sickle cell disease or trait. The substitution was present in nearly 100 percent of the patients with sickle cell disease or trait, and in 22 percent of the normal Saudis. Homozygosity for this mutation had no demonstrable effect on hemoglobin F production in the normal Saudi population. We conclude that this mutation is not uniquely responsible for the increase in hemoglobin F in Saudi patients. It may nevertheless have an important role in regulating hemoglobin F production, but its expression is complex and requires interaction with additional factors, such as hemolytic stress or other molecular determinants, possibly linked to the sickle cell gene.",0
733,2438553,Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids,"Patients with allergic rhinitis often have immediate symptoms after antigen challenge (the early-phase response), followed several hours later by a recurrence of symptoms (the late-phase response). Systemic glucocorticosteroids are known to inhibit the late-phase but not the early-phase response. We studied the effect of one week of pretreatment with topical (rather than systemic) glucocorticosteroids on the response to nasal challenge with antigen in a double-blind, randomized, placebo-controlled crossover study of 13 allergic patients who had previously had a dual response to nasal challenge. The patients were challenged with three 10-fold increments of allergen, producing an early response, and were then followed for 11 hours, encompassing the late response, before they were rechallenged with the lowest dose of allergen. We monitored their responses by means of symptom scores and measurements of the levels of histamine, tosyl-L-arginine methyl ester (TAME)-esterase activity, and kinins in nasal lavages. Topical glucocorticosteroids significantly reduced both the symptoms and the levels of histamine, TAME-esterase activity, and kinins in the early, late, and rechallenge allergic reactions. The fact that, in contrast to treatment with systemic glucocorticosteroids, prolonged pretreatment with topical glucocorticosteroids inhibited the early-phase response to antigen suggests that the route and duration of administration affect the mechanisms of action of the steroids. We conclude that inhibition of the early-phase as well as the late-phase response by topical glucocorticosteroids may provide an advantage over treatment with systemic glucocorticosteroids in patients with allergic rhinitis.",0
734,2443435,Uneven copper distribution in the human newborn liver,"The pattern of copper distribution in human newborn liver was investigated by histochemical methods (rhodamine, orcein and rubeanic acid) and by atomic absorption spectroscopy. A significant correlation (p less than 0.005) was found between the degree of histochemical positivity and the copper concentration found by atomic absorption spectroscopy. In the majority of the 30 livers examined (first group), the copper concentration was much higher than that of normal adult liver, although exhibiting striking individual differences. No correlation between the copper content and sex, body weight or gestational age was found. From a second group of five livers, longitudinal tissue slices 0.5 cm thick were partitioned into regular blocks of about 0.5 gm, which were individually analyzed by atomic absorption spectroscopy. Copper appeared unevenly distributed within each liver, with marked differences even between adjacent blocks. However, a consistent tendency of copper to accumulate in the left lobe more than in the right one was evident. Five additional blocks, one for each liver, were further partitioned into 10 small specimens of a final size (0.05 gm), comparable to that of a needle biopsy. Even at this sampling level, consisting of tissue fragments taken from a small tissue area, the copper concentration appeared quite irregularly distributed. These findings may be considered for two different aspects: (a) the biological implications of the pattern of copper accumulation in different lobar and lobular liver compartments and (b) the statistical inference, for diagnostic purposes, of the mean liver copper content from measurements of single percutaneous biopsy specimens.",0
735,2443436,Two different subtypes of antimitochondrial antibodies are associated with primary biliary cirrhosis: identification and characterization by radioimmunoassay and immunoblotting,"Antimitochondrial antibodies from patients with primary biliary cirrhosis react with different mitochondrial polypeptides as demonstrated by Western blots. The IgG fractions of a patient with primary biliary cirrhosis Stage I reacting exclusively with a pair of polypeptides at 48,000 daltons (p 48) on Western blot and from a patient with Stage III primary biliary cirrhosis reacting exclusively with a single 62,000 dalton polypeptide (p 62) were labeled with 125I; two radioimmunoassays were established detecting antimitochondrial antibodies against p 62 and p 48, respectively. Autologous sera blocked the assay, but the two reference sera did not block each other. Fourteen of 40 patients with primary biliary cirrhosis reacted with p 62, 6/40 with p 48 and 20 sera with both antigens. Sera from 200 patients with various hepatic and nonhepatic diseases were negative for anti-p 62 and anti-p 48. This collection of sera included 5 patients with nonhepatic autoimmune disorders, 3 with drug-induced pseudolupus syndrome and 2 with syphilis II, which were positive for antimitochondrial antibodies by immunofluorescence. Mitochondrial autoantigens p 62 and p 48 were both localized on mitoplasts, presumably inner mitochondrial membranes; they were thermolabile, trypsin- and chymotrypsin-sensitive, but resistant to DNAase, RNAase and neuraminidase treatments. In cesium chloride density gradients, p 62 floated at 1.28 gm per cm3 and p 48 at 1.30 gm per cm3. Thus, radioimmunoassays have been developed that specifically detect two distinct primary biliary cirrhosis-specific subtypes of antimitochondrial antibodies: anti-p 62 and anti-p 48. All primary biliary cirrhosis sera were positive for at least one of these antimitochondrial antibodies subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)",0
736,2445642,Antibodies against acetaldehyde-modified protein epitopes in human alcoholics,"Acetaldehyde, the primary metabolite of ethanol, binds covalently to proteins forming condensation products which have been recently shown to be immunogenic. To assess whether an antibody response against acetaldehyde-modified protein epitopes is associated with alcoholic liver disease, the serum immunoreactivity against proteins modified in vitro by acetaldehyde and against the corresponding unmodified proteins was measured by an enzyme-linked immunosorbent assay in 58 alcoholics with varying degrees of liver damage. Alcoholics showed significantly higher titers against protein-acetaldehyde conjugates than against the unmodified protein, independent of the nature of the carrier protein. The highest titers occurred in alcoholic hepatitis patients. Sera of patients with chronic hepatitis of nonalcoholic origin and of healthy controls also reacted with acetaldehyde conjugates, but their titers were significantly lower than those in alcoholic hepatitis patients. Our data support the idea that binding of acetaldehyde to proteins in humans generates antigenic determinants which trigger a corresponding immune response against such epitopes and suggest that this humoral immune response may be implicated in autoantibody formation and liver damage associated with excessive alcohol consumption.",0
737,2448217,A candidate vaccine for hepatitis B containing the complete viral surface protein,"The entire surface protein of hepatitis B virus serotype ayw containing the preS (preS1+preS2) and S domains has been expressed in the yeast Saccharomyces cerevisiae. Yeast containing a recombinant plasmid utilizing a constitutive promoter did not express this gene successfully due to the toxicity of the protein. A plasmid using a regulatable promoter directed expression which initiated late in the exponential phase of growth and resulted in the accumulation of high intracellular levels of the complete surface protein. The purified polypeptide aggregates into a form which, although not comprised of typical 20 nm particles, displays antigenic determinants encoded by the preS1, preS2 and S domains. Immunization of rabbits elicited the formation of antibodies directed against all three domains. This candidate vaccine will be useful for studying the contributions to viral immunity of the host response to the preS1 and preS2 domains.",0
738,2453428,Expression of class I and class II major histocompatibility complex antigens on human hepatocytes,"We analyzed whether normal human hepatocytes, which normally do not display Class II major histocompatibility complex antigens, can be induced to express them in vitro, and whether this induction has an in vivo counterpart in chronic liver diseases. While both alpha- and gamma-interferon induced expression of Class I antigens, only gamma-interferon induced expression of Class II antigens on hepatocytes in vitro. Recombinant interleukin 2 had no effect on major histocompatibility complex antigen expression. Both Class I and Class II antigens could be detected by indirect immunofluorescence on hepatocytes from patients with various forms of chronic liver disease, regardless of etiology. These findings suggest that gamma-interferon produced by T lymphocytes that infiltrate the liver during the course of chronic hepatitis induces Class II major histocompatibility complex antigen expression and may endow the hepatocytes with the capacity to perform accessory (antigen-presenting) cell functions.",0
739,2453802,Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis,"Anti-neutrophil cytoplasmic autoantibodies have been found in patients with systemic arteritis and glomerulonephritis. We studied the disease distribution and antigen specificity of these autoantibodies. Anti-neutrophil cytoplasmic autoantibodies were identified by indirect immunofluorescence microscopy in 27 of 35 patients with idiopathic necrotizing and crescentic glomerulonephritis, in whom the manifestations of disease ranged from injury limited to the kidney to systemic arteritis. The incidence and titers of the autoantibodies did not differ between patients with disease limited to the kidney and those with systemic disease. Anti-neutrophil immunostaining was detected in 5 of 11 patients with lupus nephritis, 4 of 71 patients with other renal diseases, and none of 50 normal controls. This distribution of autoantibodies was confirmed by an enzyme-linked immunosorbent assay (ELISA) using neutrophil lysate as antigen. According to ELISA, anti-neutrophil cytoplasmic autoantibodies were found to be specific for constituents of primary granules. Two types of autoantibodies were identified; one with reactivity with myeloperoxidase on ELISA produced an artifactual perinuclear immunostaining of alcohol-fixed neutrophils, and another with no reactivity with myeloperoxidase on ELISA produced diffuse cytoplasmic immunostaining. The presence of the same serologic marker in patients with kidney-limited and arteritis-associated necrotizing and crescentic glomerulonephritis, including Wegener's granulomatosis and polyarteritis nodosa, suggests that these clinically diverse diseases may have a similar pathogenesis, initiated by autoantibody-mediated activation of neutrophils.",0
740,2469014,Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells,"Chronic beryllium disease is characterized by the accumulation of helper/inducer T cells, macrophages, and granulomas in the lungs. To evaluate the hypothesis that the proliferation of CD4+ (helper/inducer) T cells in the lungs of patients with this disorder is maintained by local activation of beryllium-specific T-cell clones, we studied T cells obtained from peripheral blood and by bronchoalveolar lavage in eight patients and five healthy controls. The proliferation of T cells in response to beryllium in vitro was confined to the CD4+ T cells from the patients and was dependent on the presentation of antigen in the presence of both major histocompatibility complex class II antigens and functional interleukin-2 receptors. T cells from the patients' lungs had a significantly greater response to beryllium than did T cells from their peripheral blood (stimulation index, 103 vs. 5; P less than 0.01). Lines and clones of cells developed from T cells from the patients' lungs showed dose-dependent proliferation in response to beryllium but did not respond to recall antigens or to other metals. Although all beryllium-specific T-cell clones were CD4+ and none were CD8+ (suppressor/cytotoxic), all beryllium-specific clones studied had different rearrangements of T-cell antigen receptors, suggesting that the response to beryllium involved T cells with diverse specificities for beryllium. We conclude that in patients with chronic beryllium disease, beryllium acts as a class II-restricted antigen, stimulating local proliferation and accumulation in the lung of beryllium-specific CD4+ (helper/inducer) T cells. Hence, chronic beryllium disease is a hypersensitivity disease in which beryllium is the specific antigen.",0
741,2472341,Hepatic enzymic zonation: a reevaluation of the concept of the liver acinus,"The distribution pattern of a periportal enzyme (carbamoylphosphate synthetase) and a pericentral enzyme (glutamine synthetase) in human and rat liver has provided an objective parameter to delineate the zonal boundaries of the liver acinus. On sections, the pericental zone (zone 3) is circular and discrete rather than star-like and reticular, as predicted by the acinar concept, whereas the periportal zone (zone 1) is reticular, i.e. contiguous between adjacent acini rather than discrete. Three-dimensionally, the composite of pericentral zones (the pericentral compartment) follows the branching pattern of the terminal hepatic (central) vein, whereas the composite of periportal zones (the periportal compartment) envelops the pericentral compartment as a three-dimensional network (reticulum). This modified concept that is based upon the three-dimensional distribution of hepatocyte-specific enzymes is supported by data from the literature regarding the three-dimensional angioarchitecture of the liver, the perfusion pattern of the liver and the three-dimensional pattern of tissue oxygenation. Hence, a unified concept of the liver architecture that is based upon the observed distribution pattern of blood flow, of gene expression and of metabolism can be established.",0
742,2473022,Antimitochondrial autoantibodies in primary biliary cirrhosis recognize cross-reactive epitope(s) on protein X and dihydrolipoamide acetyltransferase of pyruvate dehydrogenase complex,"Antimitochondrial autoantibodies are characteristically present in sera of patients with primary biliary cirrhosis. The antimitochondrial autoantibodies recognize four major antigens from beef heart mitochondria at relative molecular weights of 74, 56, 52 and 48 kD. In the present study, we report that the 56 kD antigen is the protein X of pyruvate dehydrogenase complex and that it possesses cross-reactive antimitochondrial autoantibody epitope(s) with the 74 kD antigen, the acetyltransferase (E2) of the pyruvate dehydrogenase complex. This was demonstrated by comparing the specificities of primary biliary cirrhosis sera with a protein X-specific rabbit antiserum and by absorbing primary biliary cirrhosis sera with recombinant pyruvate dehydrogenase-E2 fusion protein. In the two-dimensional gel analysis, primary biliary cirrhosis sera and protein X-specific rabbit antiserum reacted to the same two isoelectric point polypeptides at 56 kD molecular weight. The absorption of primary biliary cirrhosis sera with the human recombinant pyruvate dehydrogenase-E2 removed reactivity toward both the 74 and 56 kD antigens. Furthermore, analysis of 82 antimitochondrial autoantibody-positive primary biliary cirrhosis sera by immunoblotting did not reveal any sera which reacted solely against either the 74 or 56 kD antigen. Finally, primary biliary cirrhosis sera recognized protein X from human, bovine and porcine sources but not protein X from rat or mouse origin. The identification of protein X as another major target of the autoimmune response in primary biliary cirrhosis suggests that the pyruvate dehydrogenase complex may have a central role in the induction of this enigmatic disease.",0
743,2473400,Spontaneous release of histamine from basophils and histamine-releasing factor in patients with atopic dermatitis and food hypersensitivity,"Patients with hypersensitivity to food documented by a double-blind, placebo-controlled oral food challenge have been reported to have a high rate of release of histamine from basophils in vitro. To determine whether patients with atopic dermatitis and food hypersensitivity had similar high rates of spontaneous histamine release in vitro, whether dietary elimination of relevant food antigens affected this release, and whether a cytokine, histamine-releasing factor, could account for it, we evaluated 63 patients with atopic dermatitis and food hypersensitivity (38 of whom had eliminated the offending foods from their diets), 20 patients with atopic dermatitis without food hypersensitivity, and 18 normal volunteers. Patients with atopic dermatitis and food hypersensitivity were found to have higher rates of spontaneous release of histamine from basophils than controls (mean +/- SE, 35.1 +/- 3.9 percent vs. 2.3 +/- 0.2 percent; P less than 0.001). Those who had eliminated the offending food allergen from the diet for an extended period had a significantly lower rate of histamine release (3.7 +/- 0.5 percent; P less than 0.001). In patients with atopic dermatitis without food hypersensitivity, the rate (1.8 +/- 0.2 percent) did not differ from that in normal controls. Mononuclear cells from persons with food allergies spontaneously produced a histamine-releasing factor in vitro that provoked the release of histamine from the basophils of other food-sensitive persons, but not from those of normal controls. Patients who adhered to a restricted diet had a decline in the rate of spontaneous generation of the factor by their mononuclear cells. The histamine-releasing factor was found to activate basophils through surface-bound IgE. We conclude that in patients with food hypersensitivity, exposure to the relevant antigens produces a cytokine (histamine-releasing factor) that interacts with IgE bound to the surface of basophils, causing them to release histamine.",0
744,2488072,Menopause and risk factors for coronary heart disease,"Postmenopausal women are believed to have a higher risk of coronary artery disease than premenopausal women. In this study, we prospectively determined changes in coronary risk factors that were attributable to natural menopause in 541 healthy, initially premenopausal women 42 to 50 years of age. After approximately 2 1/2 years, 69 women had spontaneously stopped menstruating for at least 12 months, and 32 women had stopped natural menstruation and received hormone-replacement therapy for a period of at least 12 months. An equal number of age-matched premenopausal women in the study group served as controls. In women who had a natural menopause and did not receive hormone-replacement therapy, serum levels of high-density lipoprotein (HDL) cholesterol declined as compared with those of premenopausal controls (-0.09 vs. 0.00 mmol per liter; P = 0.01), and levels of low-density lipoprotein (LDL) cholesterol increased (+0.31 vs. +0.14 mmol per liter; P = 0.04). In menopausal women who received hormone-replacement therapy, HDL and LDL cholesterol levels did not change, but the levels of triglycerides (+0.42 vs. -0.04 mmol per liter; P less than 0.001), apolipoprotein A-I (+0.18 vs. +0.03 g per liter; P less than 0.01), and apolipoprotein A-II (+0.05 vs. -0.03 g per liter; P less than 0.05) increased as compared with premenopausal controls. Natural menopause did not affect blood pressure, plasma glucose or insulin levels, body weight, the total number of kilojoules consumed in the diet, or the total number of kilojoules expended in physical activity. These results suggest that a natural menopause has an unfavorable effect on lipid metabolism, which may contribute to an increase in the risk of coronary disease. Hormone-replacement therapy may prevent some of these changes.",0
745,2492082,A consumer-choice health plan for the 1990s. Universal health insurance in a system designed to promote quality and economy (2),"We describe the characteristics necessary for a plan for universal health insurance to find broad acceptance. Such a plan must represent incremental, not radical, change; must respect the preferences of voters, patients, and providers; must avoid major disruption in satisfactory existing arrangements; must avoid creating major windfall gains or losses; must avoid large-scale income redistribution; and must not be inflationary. Our proposal would create a framework that would encourage the efficient organization of care. Successful organizations would probably be those that attracted the loyalty and commitment of physicians, integrated insurance and the provision of care, and aligned the interests of doctors and patients toward high-quality, cost-effective care. The proposal's chief potential disadvantage would be its effect on the employment opportunities of low-wage workers, but this effect could be minimized. In addition, we discuss a proposal to mandate coverage by employers of full-time employees, legislation enacted recently in Massachusetts, high-risk pools, and the system followed in Canada, comparing each of these alternatives with our proposal.",0
746,2498660,Federal spending for illness caused by the human immunodeficiency virus,"Is the federal government devoting sufficient resources to fighting the epidemic of human immunodeficiency virus (HIV) infection, and are these resources being spent appropriately? Some observers contend that the amounts have been inadequate, but until now there has been no overall accounting of federal activities and spending to combat the epidemic. We report expenditure data collected from federal agencies for the years 1982 to 1989. In all, $5.5 billion will have been spent on HIV-related illness during this period by the federal government, nearly 60 percent of it by the U.S. Public Health Service. Federal spending on HIV-related illness in 1989 will reach $2.2 billion, representing over one third of all estimated national (public and private) HIV expenditures, and tripling state expenditures. In 1992, federal spending on the epidemic will reach an estimated $4.3 billion. Although sizable, this will be just 1.8 percent of all 1992 federal health dollars. Similarly, in 1992, national (public and private) spending on HIV-related illness will consume roughly 1.6 percent of all health-related costs in the United States. Federal spending for HIV research and prevention is similar to funding for other major diseases, including some conditions, such as cancer and heart disease, that now have a greater impact on mortality.",0
747,2507916,The effect of cyclosporine on the use of hospital resources for kidney transplantation,"Over the past decade the clinical results of kidney transplantation have improved substantially, with much of the benefit being attributed to the introduction in late 1983 of the immunosuppressive drug cyclosporine. To assess the effect of cyclosporine on the use of hospital services, we studied 702 patients who received kidney transplants at the University of California, San Francisco, between July 1982 and June 1986. All services were priced in constant 1985 dollars, and multiple regression analysis was used to adjust for changing patient and hospital characteristics. The introduction of cyclosporine for patients receiving kidneys from cadavers was associated with a significantly shorter adjusted mean postoperative stay (26.4 days as compared with 37.0 for patients not taking the drug; P less than 0.0001) and lower adjusted mean hospital charges ($28,649 as compared with $37,895; P less than 0.0001), although cyclosporine was not associated with changes in the use of services by patients who received transplants from living related donors. Cyclosporine was also associated with a reduction in the use of certain ancillary services, such as laboratory tests and radiographic procedures. In patients without diabetes who received cadaver kidneys, a sequential cyclosporine regimen (in which a combination of antilymphoblast globulin, prednisone, and azathioprine was given before cyclosporine) reduced the use of hospital services even more than did a cyclosporine regimen in which the combination was not given. The results suggest that new medications, such as cyclosporine, that reduce the frequency of complications and improve outcomes may also reduce the use of hospital resources.",0
748,2507917,Absence of anti-human immunodeficiency virus types 1 and 2 seroconversion after the treatment of hemophilia A or von Willebrand's disease with pasteurized factor VIII concentrate,"Patients with hemophilia A or von Willebrand's disease who are treated with concentrated preparations of human factor VIII made from unscreened pooled plasma are at substantial risk of contracting human immunodeficiency virus (HIV) infection. The purpose of this study was to investigate whether by treating such patients with a pasteurized factor VIII concentrate that had been heated in aqueous solution at 60 degrees C for 10 hours, HIV infection could be avoided. Eleven hemophilia centers in the Federal Republic of Germany and two in Austria identified 155 eligible patients who had been treated exclusively with pasteurized factor VIII concentrate and had not received any other blood products. Between February 1979 and December 1986 they received a total of 15,916,260 IU of pasteurized factor VIII. The United States was the source of 80 percent of the plasma from which the concentrate was made. By September 1988, these 155 patients had been screened for antibody to HIV type 1 (anti-HIV-1) with a total of 657 tests; all were negative. Sixty-seven patients were also tested once for antibody to HIV type 2 (anti-HIV-2); all these tests were negative as well. It appears that pasteurization effectively inactivates HIV, even in plasma that is likely to be highly contaminated with the virus.",0
749,2509912,Hospital care for elderly patients with diseases of the circulatory system. A comparison of hospital use in the United States and Canada,"In an effort to determine how lower health care expenditures in Canada as compared with the United States translate into actual hospital services received, we examined discharge rates, lengths of stay, and the case-mix index (calculated from diagnosis-related group weights) for those 65 years of age and older hospitalized with cardiovascular disease in the United States and two Canadian provinces, Manitoba and Ontario, in 1981 and 1985. We expected that the effect of the prospective payment system might be reflected in changes between 1981 and 1985. Discharge rates for medical treatment of cardiovascular diseases were 2.9 percent higher in the United States than in Canada in 1981, but 1.8 percent lower in 1985; however, the case-mix index was 3.0 percent lower in 1981 and 4.8 percent higher in 1985. The case-mix index for combined medical and surgical discharges was 5.0 percent lower in the United States in 1981, but 10.7 percent higher in 1985. U.S. surgical discharge rates were 20 percent lower in 1981, but 20 percent higher in 1985. Rates of coronary bypass surgery were much higher in the United States in both years, but increased rapidly in both countries, particularly among those 75 and older. Elderly Canadians appeared to have access to cardiovascular surgery, with the exception of coronary bypass surgery, and to other hospital care for cardiovascular disease similar to that of elderly people in the United States.",0
750,2512483,The cost to the central nervous system of climbing to extremely high altitude,"To assess the possibility that climbing to extremely high altitude may result in hypoxic injury to the brain, we performed neuropsychological and physiologic testing on 35 mountaineers before and 1 to 30 days after ascent to altitudes between 5488 and 8848 m, and on 6 subjects before and after simulation in an altitude chamber of a 40-day ascent to 8848 m. Neuropsychological testing revealed a decline in visual long-term memory after ascent as compared with before; of 14 visual items of information on the Wechsler Memory Scale, fewer were recalled after ascent by both the simulated-ascent group (a mean [+/- SD] of 10.14 +/- 1.68 items before, as compared with 7.00 +/- 3.35 items after; P less than 0.05) and the mountaineers (12.33 +/- 1.96 as compared with 11.36 +/- 1.88; P less than 0.05). Verbal long-term memory was also affected, but only in the simulated-ascent group; of a total of 10 words, an average of 8.14 +/- 1.86 were recalled before simulated ascent, but only 6.83 +/- 1.47 afterward (P less than 0.05). On the aphasia screening test, on which normal persons make an average of less than one error in verbal expression, the mountaineers made twice as many aphasic errors after ascent (1.03 +/- 1.10) as before (0.52 +/- 0.80; P less than 0.05). A higher ventilatory response to hypoxia correlated with a reduction in verbal learning (r = -0.88, P less than 0.05) and with poor long-term verbal memory (r = -0.99, P less than 0.01) after ascent. An increase in the number of aphasic errors on the aphasia screening test also correlated with a higher ventilatory response to hypoxia in both the simulated-ascent group (r = 0.94, P less than 0.01) and a subgroup of 11 mountaineers (r = 0.59, P less than 0.05). We conclude that persons with a more vigorous ventilatory response to hypoxia have more residual neurobehavioral impairment after returning to lower elevations. This finding may be explained by poorer oxygenation of the brain despite greater ventilation, perhaps because of a decrease in cerebral blood flow caused by hypocapnia that more than offsets the increase in arterial oxygen saturation.",0
751,2521178,HBsAg carrier infants with serum anti-HBc negativity,"A total of 128 HBsAg carrier infants born to HBeAg-positive HBsAg carrier mothers were tested for serum HBsAg, HBeAg, hepatitis B virus DNA and anti-HBc. Ninety-three of them had received hepatitis B vaccination. Anti-HBc had been found to be negative in sera of 12 infants who were HBsAg, HBeAg and hepatitis B virus DNA positive during the follow-up period of 3 to 5 years. Liver damage, as measured by serum ALT levels, was found to be normal among the 12 HBsAg carrier infants with serum anti-HBc negativity, whereas 39.7% of the 116 anti-HBc-positive HBsAg carrier infants had abnormal ALT levels during the follow-up period. Anti-HBe and anti-HBs also were not detected in sera of these anti-HBc-negative HBsAg carrier infants. Thus, HBsAg carrier infants with anti-HBc negativity probably result from immune incompetency of the hepatitis B virus antigens.",0
752,2521688,Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome,"To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.",0
753,2536896,Racial differences in drug response. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites,"To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.",0
754,2541336,Human papillomavirus infection and cervical cancer in Latin America,"To evaluate a possible association between infection with human papillomavirus (HPV) and cervical cancer, we performed a multicenter case-control study in Latin America of 759 cases of invasive cervical cancer and 1467 randomly selected age-matched controls. Demographic, sexual, behavioral, and other clinical data were obtained by interview, and HPV DNA was assayed in cervical-swab specimens with use of filter in situ hybridization. Cervical infection with HPV 16 or 18 or both was strongly associated with cervical cancer. HPV DNA was detected in 62 percent of the cases but only 32 percent of the controls, and the relative risk of cancer increased from 2.1 (95 percent confidence interval, 1.6 to 2.8) to 9.1 (6.1 to 13.6) with hybridization reactions of increasing strength. Although the number of sexual partners, age at first intercourse, number of live births, and Pap-smear history were also significant risk factors, the strong associations between infection with HPV 16 or 18 or both and cervical cancer persisted after we adjusted for these variables. These observations are consistent with the hypothesis that genital infection with HPV 16 or 18 may have a role in the pathogenesis of cervical cancer. Other well-known risk factors were also identified in the study, but they did not affect the association between HPV and cervical cancer.",0
755,2541337,DNA of human papillomavirus type 16 in dysplastic and malignant lesions of the conjunctiva and cornea,"Human papillomaviruses are receiving attention for their role in the pathogenesis of cancer, especially cancer of the anogenital tract. Although strains of human papillomavirus are associated with benign lesions of the conjunctiva, their association with conjunctival dysplastic lesions and carcinomas has remained unclear. We examined a group of neoplastic lesions of the conjunctiva for the presence of DNA sequences for human papillomavirus types 16 and 18, using in vitro gene amplification with the polymerase chain reaction. Tissue specimens of five conjunctival dysplastic lesions and one invasive carcinoma and swab specimens of the mucosa of both corneas of a patient with unilateral corneal dysplasia contained DNA sequences related to human papillomavirus type 16. All dysplastic specimens examined were positive for DNA sequences. Viral DNA was not detected in six control specimens from patients with conjunctival melanoma, papilloma, nevus, or pterygium. We conclude that DNA from human papillomavirus type 16 is present in a substantial percentage of conjunctival premalignant and malignant lesions. It may play a part in the development of conjunctival dysplasia and carcinoma, as it does in cancers of certain other body sites.",0
756,2545589,"Effect of galactose on interaction of N-(2-hydroxypropyl)methacrylamide copolymers with hepatoma cells in culture: preliminary application to an anticancer agent, daunomycin","A series of copolymers were prepared containing 1,2:3,4-di-O-isopropylidene-6-O-methacryloyl-alpha-D-galactopyranose (0 to 99 mol %), methacryoyltyrosinamide and N-(2-hydroxypropyl)methacrylamide (99 to 0 mol %). The effect of galactose content on interaction with hepatoma cells in vitro was studied. Increased galactose content caused increased accumulation of N-(2-hydroxypropyl)methacrylamide copolymers by two human hepatoma cell lines (Hep G2 and SAH), but accumulation by rat and mouse hepatoma (HTC and NCTC) was not galactose dependent. Accumulation of N-(2-hydroxypropyl)methacrylamide copolymers by Hep G2 was shown to be an active process, being inhibited by low temperature and by the metabolic inhibitor 2,4-dinitrophenol. Addition of N-acetylgalactosamine and polymer-galactose to the incubation medium resulted in a concentration-dependent inhibition of accumulation of galactose-containing polymers. Addition of fucose or galactose was without effect at the concentrations used. Polymers bearing galactosamine or fucosylamine residues and, in addition, daunomycin were evaluated for cytotoxicity against Hep G2 and SAH. N-(2-Hydroxypropyl)methacrylamide copolymer-bound daunomycin produced a dose-dependent inhibition of DNA synthesis (measured by incorporation of [3H]thymidine), and the galactose-containing polymer showed greatest inhibition.",0
757,2552313,Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease,"Epstein-Barr virus (EBV) has been associated with serious or fatal lymphoproliferative disease in immunocompromised patients. EBV nuclear protein 2 and latent membrane protein are characteristically expressed in B lymphocytes proliferating in vitro in response to growth transformation by EBV. These two proteins are thought to be effectors of lymphocyte growth since they increase the expression of B-lymphocyte activation (CD23) and cell-adhesion (LFA 3 and ICAM 1) molecules in vitro. Using monoclonal antibody-immune microscopy, we have demonstrated that these two EBV proteins and their associated B-lymphocyte activation or adhesion molecules are expressed in the infiltrating B lymphocytes in immunocompromised patients with EBV lymphoproliferative disease. These monoclonal antibodies should be useful in the early diagnosis of EBV lymphoproliferative disease and in distinguishing it from other B-lymphocyte cancers associated with EBV, such as Burkitt's lymphoma. The finding of EBV nuclear protein 2 and latent membrane protein and their associated activation or adhesion molecules provides a further pathophysiologic link between EBV and the proliferation of B lymphocytes in immunocompromised patients.",0
758,2566116,A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy,"Leber's hereditary optic neuropathy is a maternally inherited disease associated with the late onset of bilateral loss of central vision and cardiac dysrhythmias. The maternal inheritance is explained by the mitochondrial origin of the disease. Analysis of the sequence of a mitochondrial DNA has indicated that a single nucleotide change at position 11778 is associated with this disease. This mutation converts the 340th amino acid of NADH dehydrogenase subunit 4 from an arginine to a histidine and eliminates an SfaNI endonuclease restriction site. A survey of restriction-fragment-length polymorphisms in the mitochondrial DNA of three independent families with this disease (an American black and two white European families) and 10 controls confirmed that this SfaNI site is associated with the disease. A phylogenetic tree for mitochondrial DNA polymorphism and sequence variants from three probands with Leber's disease and four controls was constructed, and the mutation at position 11778 was found to be associated with two mitochondrial DNA backgrounds--an American black mitochondrial DNA and a European mitochondrial DNA. Thus, this mutation must have arisen twice independently. Since the mutation correlated with symptoms of Leber's disease in both cases, these findings indicate that the mutation is a cause of the disease. This genetic analysis has identified the specific point mutation in the mitochondrial DNA that results in Leber's hereditary optic neuropathy.",0
759,2579336,Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type,"Patients with sickle cell anemia vary in the hematologic and clinical features of their disease, in part because of variability in the presence of linked and unlinked genes that modify the expression of the disease. The hemoglobin S gene is strongly linked to three different haplotypes of polymorphic endonuclease-restriction sites of the beta-like gene cluster (genes in the vicinity of the beta-globin gene)--one prevalent in Atlantic West Africa, another in central West Africa, and yet another in Bantu-speaking Africa (equatorial, East, and southern Africa). We have studied the differences in the hematologic characteristics of patients with sickle cell anemia from the first two geographical areas. We find that the Senegalese (Atlantic West Africa) patients have higher levels of hemoglobin F, a preponderance of G gamma chains in hemoglobin F, a lower proportion of very dense red cells, and a lower percentage of irreversibly sickled cells than those from Benin (central West Africa). We interpret these data to mean that the gamma-chain composition and the hemoglobin F level are haplotype linked and that the decrease in the percentage of dense cells and irreversibly sickled cells is secondary to the elevation in the hemoglobin F level. Patients with sickle cell anemia in the New World probably correspond to various combinations of these types, in addition to the still hematologically undefined haplotype associated with sickle cell anemia in the Bantu-speaking areas of Africa.",0
760,2583685,Chronic delta hepatitis: detection of hepatitis delta virus antigen in serum by immunoblot and correlation with other markers of delta viral replication,"To investigate the presence of serum hepatitis delta virus antigen by immunoblot and its correlation with other markers of active viral replication (intrahepatic hepatitis D antigen, IgM antibody to hepatitis D and serum hepatitis D virus RNA), we studied serum samples from 50 patients with chronic hepatitis D virus infection (38 with and 12 without intrahepatic hepatitis D antigen). Of the 38 patients with intrahepatic hepatitis D antigen, 27 (71%) had antigen detectable in serum by immunoblot, whereas only two were reactive by conventional enzyme-linked immunosorbent assay. Thirty-one (82%) patients were also positive for serum hepatitis D virus RNA by spot hybridization and 33 (87%) were positive for IgM anti-hepatitis D virus. All markers were simultaneously present in 24 patients. Circulating hepatitis D antigen was detected in one (8%), IgM anti-hepatitis D in seven (58%) and hepatitis D virus RNA in two (17%) of the 12 patients who had anti-hepatitis D in serum but not detectable hepatitis D antigen in liver. Hepatitis D antigen was not detected in serum of any of the 15 control patients. The results suggest that serum hepatitis D antigen as detected by immunoblot and serum hepatitis D virus RNA are similar in sensitivity for detection of active hepatitis D virus replication during chronic infection and constitute useful, sensitive and noninvasive tests for the diagnosis and monitoring of chronic hepatitis D virus infection.",0
761,2583692,"Interaction of hemopexin, albumin and liver fatty acid-binding protein with protoporphyrin","Equilibrium constants for the binding of protoporphyrin to serum albumin and hemopexin and liver cytosolic fatty acid-binding protein of the rat were determined fluorometrically. The experimental equilibrium constant [10(6) M-1 (mean +/- S.D.)] values were 8.4 +/- 1.3, 10.0 +/- 2.4 and 34.0 +/- 3.0 for albumin, hemopexin and liver fatty acid-binding protein, respectively. Statistical analysis showed the equilibrium constant of binding of protoporphyrin to liver fatty acid-binding protein to be significantly (p less than 0.01) higher than that to albumin and hemopexin. The data suggest that in patients with erythropoietic protoporphyria an equilibrium gradient may exist which favors the uptake by hepatocytes of plasma protoporphyrin as a result of its greater affinity for intracellular liver fatty acid-binding protein.",0
762,2643770,Multicenter study of autologous adrenal medullary transplantation to the corpus striatum in patients with advanced Parkinson's disease,"""In 19 patients with severe Parkinson's disease, we replicated the surgical procedures developed by Madrazo et al. for transplantation of the adrenal medulla to the striatum, and followed them for six months after operation. We monitored their motor function with the use of standardized scales and determined the amount and quality of """"on"""" and """"off"""" time (the hours of the waking day when the antiparkinsonian medications were effective and ineffective, respectively). We found significant improvement in focal areas of motor function. The mean percentage of on time during the day increased from 47.6 percent to 75.0 percent (P = 0.012); the mean percentage of on time without chorea increased from 26.6 percent to 59.2 percent (P = 0.006); the mean severity of off time decreased as assessed by both the Activities of Daily Living subscale of the Unified Parkinson's Disease Scale (P = 0.002) and the Schwab and England scale (P = 0.037). In contrast to the finding of Madrazo et al., however, the dosages of antiparkinsonian medications could not be decreased and postoperative morbidity was substantial. Despite cautious optimism, we conclude that the widespread use of this procedure outside of research centers is premature, since the improvement we found was slighter than in the previous cases.""",0
763,2643774,Changes in the location of death after passage of Medicare's prospective payment system. A national study,"We reviewed age-specific national mortality data for the years 1981 through 1985 to evaluate changes in the location of death among the nation's elderly after implementation of Medicare's prospective payment system (PPS). Although it was unchanged in 1981 and 1982, the percentage of deaths occurring in the nation's nursing homes increased from 18.9 percent in 1982 to 21.5 percent in 1985. The increases in nursing home deaths were greatest between 1983 and 1984, when 33 states showed larger-than-expected increases when compared with a base period before implementation of PPS. These changes were accompanied by a decline in the percentage of deaths that occurred in hospitals. These changes in the location of death were most pronounced in the Midwest, South, and West; they were very small in the Northeast and in states not affected by the PPS. Furthermore, the states with high population enrollments in health maintenance organizations and with large declines in the mean hospital length of stay in 1984 showed the greatest shifts in the location of death. We conclude that Medicare's PPS resulted in the increased transfer of terminally ill patients from hospitals to nursing homes. Further study is required to determine whether such transfer is medically appropriate.",0
764,2644533,Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer,"We compared a single perioperative cycle of adjuvant combination chemotherapy with no adjuvant treatment in a randomized trial (Ludwig Trial V) including 1275 patients with breast cancer who had no axillary-node metastases. The chemotherapy was administered on days 1 and 8, beginning within 36 hours after mastectomy, and consisted of cyclophosphamide, methotrexate, fluorouracil, and leucovorin. At a median follow-up of 42 months, the mean four-year disease-free survival (+/- SE) was 77 +/- 2 percent among the patients who received chemotherapy perioperatively, as compared with 73 +/- 2 percent among the patients who received no adjuvant treatment (hazard ratio, 0.77; 95 percent confidence interval, 0.61 to 0.98; P = 0.04). An advantage was observed for both premenopausal and postmenopausal women. The magnitude of the treatment effect was largest among patients with no or low estrogen-receptor content in the primary tumor. We conclude that chemotherapy modifies the post-operative course of node-negative breast cancer. Further trials to investigate an optimal selection of patients and treatments should be regarded as the best available therapeutic approach.",0
765,2646197,The glutathione S-transferases: an update,"Over the last 15 years, we have passed through an initial period in which multiple forms of GST in various organs and different species were identified and characterized. The focus of current research is to define the role of the numerous isozymes in cell function, to ascertain the relationship between structure and function of different isozymes and to determine how the expression of GST is regulated in different tissues. During these studies, it is expected that new roles for the GST will be proposed, and this family of multifunctional proteins will continue to hold the interest of numerous investigators for many years.",0
766,2648143,Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms,"The occurrence of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation for leukemia is thought to decrease the probability of recurrence. To study this effect (called adoptive immunotherapy) we modified the prophylaxis of GVHD in patients with advanced hematologic neoplasms (mostly leukemia) who received bone marrow transplants. Patients under 30 years of age were randomly assigned to one of three regimens of post-transplantation immunosuppression: Group I (n = 44) received a standard course of methotrexate for 102 days after transplantation, Group II (n = 40) received an abbreviated (11-day) course of methotrexate, and Group III (n = 25) received the standard course of methotrexate plus viable buffy-coat cells from the marrow donors. All 109 patients received cyclophosphamide (60 mg per kilogram of body weight on each of two days), total-body irradiation (2.25 Gy daily for seven days), and unmodified marrow from HLA-identical sibling donors. The frequency of GVHD of Grades II through IV was 25 percent in Group I, 59 percent in Group II, and 82 percent in Group III (P = 0.0001). The incidence of chronic GVHD, however, did not differ significantly among the groups (33, 51, and 44 percent, respectively), nor did the five-year probability of recurrence of disease (38, 45, and 33 percent, respectively). However, mortality from causes other than cancer was 34 percent in Group I, 45 percent in Group II, and 64 percent in Group III (I vs. III, P = 0.024); the deaths were due primarily to infections complicating the course of GVHD. With a median follow-up of 5.1 years (range, 3.9 to 7.4), disease-free survival was 41 percent in Group I, 30 percent in Group II, and 24 percent in Group III (the differences were not statistically significant). We conclude that abbreviating methotrexate prophylaxis or infusing donor buffy-coat cells increased the incidence of acute GVHD and related mortality without altering the incidence of chronic GVHD or the recurrence of malignant disease.",0
767,2659996,The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes,"The microvascular complications of diabetes mellitus may be caused, in part, by poor glycemic control. Diabetic patients who have received renal allografts may have new glomerular lesions that are manifested structurally by increases in mesangial and glomerular volume. Successful pancreas transplantation produces long-term normoglycemia and provides a unique opportunity to evaluate the impact of the normalization of the blood glucose level on the development of the renal lesions typical of diabetes mellitus in transplanted kidneys. We obtained biopsy specimens from the functioning renal allografts of 12 patients with insulin-dependent (Type I) diabetes before successful pancreas transplantation (performed one to seven years after renal transplantation) and repeated the biopsy at least 1.9 years later. In renal biopsy specimens obtained before pancreas transplantation, the mesangial volume was normal or modestly increased and the glomerular basement membrane was moderately thickened. At follow-up, no progression could be detected in any structural measure in the glomerulus. Furthermore, the recipients of pancreas transplants had smaller glomerular volumes than 13 matched diabetic patients who were recipients of renal allografts but who did not undergo pancreas transplantation (mean +/- SD, 1.80 +/- 0.55 vs. 2.47 +/- 0.73 x 10(6) microns 3; P = 0.02) and showed markedly less mesangial expansion (mesangial-volume fraction, 0.19 +/- 0.07 vs. 0.31 +/- 0.10 microns 3 per cubic micrometer; P = 0.004). We conclude that successful pancreas transplantation is associated with significantly less severe diabetic glomerulopathy in kidneys previously transplanted into diabetic patients. These data support the hypothesis that normoglycemia can prevent the progression of diabetic glomerulopathy in humans.",0
768,2664512,Bone marrow transplantation after the Chernobyl nuclear accident,"On April 26, 1986, an accident at the Chernobyl nuclear power station in the Soviet Union exposed about 200 people to large doses of total-body radiation. Thirteen persons exposed to estimated total-body doses of 5.6 to 13.4 Gy received bone marrow transplants. Two transplant recipients, who received estimated doses of radiation of 5.6 and 8.7 Gy, are alive more than three years after the accident. The others died of various causes, including burns (the cause of death in five), interstitial pneumonitis (three), graft-versus-host disease (two), and acute renal failure and adult respiratory distress syndrome (one). There was hematopoietic (granulocytic) recovery in nine transplant recipients who could be evaluated, six of whom had transient partial engraftment before the recovery of their own marrow. Graft-versus-host disease was diagnosed clinically in four persons and suspected in two others. Although the recovery of endogenous hematopoiesis may occur after exposure to radiation doses of 5.6 to 13.4 Gy, we do not know whether it is more likely after the transient engraftment of transplanted stem cells. Because large doses of radiation affect multiple systems, bone marrow recovery does not necessarily ensure survival. Furthermore, the risk of graft-versus-host disease must be considered when the benefits of this treatment are being weighed.",0
769,2664520,Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus,"To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.",0
770,2668761,"Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus","Islet-amyloid deposits, which are a common feature of Type II diabetes mellitus, are derived from the polymerization of a putative hormone identified as IAPP. IAPP is synthesized by normal islet beta cells and probably is cosecreted with insulin. Although the physiologic function of IAPP and its role in the pathogenesis of Type II diabetes mellitus are just beginning to be unraveled, IAPP may play an important part in the development of this most common form of diabetes mellitus by opposing the action of insulin in peripheral tissues. The polymerization of IAPP to form extracellular islet-amyloid deposits may further contribute to the development of Type II diabetes mellitus by destroying islet cells and by disrupting the passage of glucose and hormones to and from them. Substantial evidence indicates that the propensity of IAPP to polymerize and form extracellular amyloid deposits in only certain species (e.g., humans, cats, and raccoons) is directly associated with an intrinsically amyloidogenic part of the molecule--i.e., positions 20 through 29 of IAPP. The inherent amyloidogenicity of IAPP in these species may be further facilitated by increased beta-cell production of IAPP, leading to a high local concentration that predisposes to polymerization. The latter possibility is supported by studies demonstrating that IAPP production by islet beta cells is increased in normoglycemic cats with impaired glucose tolerance. Although increased production of IAPP may initially cause insulin resistance, prolonged overproduction of IAPP may ultimately impair insulin secretion by leading to the progressive deposition of insoluble islet amyloid, a finding apparent in most subjects with overt diabetes. If, as these studies suggest, increased IAPP production is linked to the development of Type II diabetes mellitus, further studies must address the genetic and nongenetic factors that influence this important biologic change in humans and some animal species.",0
771,2668763,The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents,"To clarify the role of sodium intake in the regulation of blood pressure in obese subjects, we measured blood pressure in 60 obese and 18 nonobese adolescents after successive two-week periods of a high-salt diet (greater than 250 mmol of sodium per day) and a low-salt diet (less than 30 mmol per day). When they were changed from a high-salt to a low-salt diet, the obese group had a significantly larger mean change (+/- SE) in mean arterial pressure (-12 +/- 1 mm Hg) than did the nonobese group (+1 +/- 2 mm Hg; P less than 0.001). The variables that best predicted the degree of sodium sensitivity were the fasting plasma insulin level, the plasma aldosterone level while the low-salt diet was being given, the plasma norepinephrine level while the high-salt diet was being given, and the percentage of body weight made up by fat. Fifty-one of the obese adolescents were also studied before and after a 20-week weight-loss program. After the weight-loss program, the 36 subjects who lost more than 1 kg of body weight had a reduced sensitivity of blood pressure to sodium (difference from value during high-salt diet to that during low-salt diet, -1 +/- 1 mm Hg). The blood pressure of the remaining 15 adolescents was still sensitive to sodium intake (-11 +/- 3 mm Hg). These results support the hypothesis that the blood pressure of obese adolescents is sensitive to dietary sodium intake and that this sensitivity may be due to the combined effects of the hyperinsulinemia, hyperaldosteronism, and increased activity of the sympathetic nervous system that are characteristic of obesity.",0
772,2671729,Effect of one-HLA-DR-antigen-matched and completely HLA-DR-mismatched blood transfusions on survival of heart and kidney allografts,"Blood transfusions can influence the survival of organ allografts favorably, in spite of the danger of sensitization. We investigated the influence of HLA compatibility between blood donors and transfusion recipients on the production of HLA antibodies and on graft survival. Among recipients of transfusions who shared one HLA-DR antigen with their respective donors, antibodies developed in 6 of 28 who had received one transfusion, in 2 of 16 who had received three transfusions, and in 4 of 24 who had undergone renal transplantation. Among recipients who were mismatched with their donors for both HLA-DR antigens, the rate of sensitization was significantly higher in all three of these groups (18 of 30, P = 0.02; 12 of 16, P = 0.0007; and 12 of 22, P = 0.001). The survival of kidney allografts among graft recipients who were given transfusions and shared one HLA-DR antigen with their blood donors (81 percent at five years) was significantly higher than among recipients who were given transfusions and were mismatched for both HLA-DR antigens (57 percent; P = 0.02) or among recipients who were not given transfusions (45 percent; P = 0.001). There was no difference in graft survival between patients who received transfusions mismatched for two HLA-DR antigens and those who were not given transfusions. We conclude that allograft survival can be improved by pretransplantation blood transfusion when the transfusion recipients share at least one HLA-DR antigen with their donors. In view of the increased rate of sensitization and the lack of improvement in graft survival, the transfusion of blood mismatched for two HLA-DR antigens appears to be contraindicated in candidates for transplantation.",0
773,2671740,A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension,"It has been suggested that the metabolic side effects of antihypertensive drugs are responsible for their failure to reduce cardiovascular morbidity in patients with hypertension. Therefore, in 50 patients with essential hypertension, we performed a randomized, double-blind, crossover study comparing the effects of carbohydrate and lipid metabolism of captopril (mean [+/- SD] dose, 81 +/- 24 mg per day) and hydrochlorothiazide (40 +/- 12 mg per day) over two four-month treatment periods. Captopril increased the insulin-mediated disposal of glucose, as compared with placebo, from 5.7 +/- 2.4 to 6.3 +/- 2.5 mg per kilogram of body weight per minute (P less than 0.05), whereas hydrochlorothiazide caused a decrease from 6.4 +/- 2.0 to 5.7 +/- 1.9 (P less than 0.01). Captopril had no effect on the basal insulin concentration, but it decreased the late (30- to 90-minute) insulin response to glucose and increased the early (2- to 6-minute) insulin peak. Hydrochlorothiazide increased the basal insulin concentration and the late insulin response to glucose. These findings may be explained by an increase in insulin sensitivity with captopril and a decrease with hydrochlorothiazide. Little or no change was seen in serum lipid or lipoprotein levels during treatment with captopril, whereas hydrochlorothiazide caused significant increases in serum total (5 percent) and low-density lipoprotein (6 percent) cholesterol levels and total (15 percent) and very-low-density lipoprotein (25 percent) triglyceride levels, as compared with placebo (P less than 0.01 for all comparisons). We conclude that hydrochlorothiazide for the treatment of essential hypertension has adverse effects on glucose and lipid metabolism. It is possible, but not proved in this study, that these changes may contribute to the risk for diabetes mellitus and coronary heart disease. In contrast, captopril appears to have beneficial or no effects on glucose and lipid metabolism.",0
774,2677724,Racial differences in aldosterone excretion and plasma aldosterone concentrations in children,"Blacks are more likely to have hypertension, have lower levels of plasma renin activity, and typically consume less potassium than whites. Whether blacks and whites secrete different amounts of aldosterone is less clear. We estimated aldosterone secretion indirectly in 715 children, 249 of whom were black, by measuring their nocturnal rates of urinary excretion of aldosterone. Dietary sodium and potassium intakes were estimated from their excretion rates. The mean (+/- SE) aldosterone-excretion rate was lower in the black children than in the white children (0.045 +/- 0.003 vs. 0.078 +/- 0.004 nmol per micromole of creatinine per kilogram of body weight; P less than 0.001). The potassium-excretion rate was also lower in the black children than in the white children (0.13 +/- 0.01 vs. 0.18 +/- 0.01 mmol per micromole of creatinine per kilogram; P less than 0.001). Aldosterone excretion was highly correlated with potassium excretion (P less than 0.001), but the lower aldosterone-excretion rate in blacks was explained only in part by their lower dietary intake of potassium. Systolic blood pressure was higher in black children (P less than 0.001), as was diastolic pressure (P = 0.037). In a second study of 99 children, the plasma aldosterone level was found to be significantly lower in black children than in white children (230 +/- 30 vs. 400 +/- 30 pmol per liter; P less than 0.001). Plasma renin activity and plasma cortisol levels were the same in both groups. In summary, we found that black children secrete about 40 percent less aldosterone than white children. The role of the lower aldosterone-secretion rate in the genesis of the higher blood pressures observed in black children is not known.",0
775,2677726,Hospital use and mortality among Medicare beneficiaries in Boston and New Haven,"We compared rates of hospital use and mortality in fiscal year 1985 among Medicare enrollees in Boston and New Haven, Connecticut. Adjusted rates of discharge, readmission, length of stay, and reimbursement were 47, 29, 15, and 79 percent higher, respectively, in Boston; 40 percent of Boston's deaths occurred in hospitals as compared with 32 percent of New Haven's. High-variation medical conditions (those for which there is little consensus about the need for hospitalization) accounted for most of these differences. By contrast, discharge rates for low-variation medical conditions (which tend to reflect the incidence of disease) were similar. Inpatient case-fatality rates were lower in Boston than in New Haven (RR = 0.85; 95 percent confidence interval, 0.78 to 0.92), but when all deaths (regardless of place of death) were measured, the mortality rates in Boston and New Haven were nearly identical (RR = 0.99; 95 percent confidence interval, 0.93 to 1.05). We conclude that the lower rate of hospital use by Medicare enrollees in New Haven was not associated with a higher overall mortality rate. Population-based as well as hospital-based statistics are needed to evaluate differences in hospital mortality rates for high-variation medical conditions.",0
776,2677728,"The Supreme Court, privacy, and abortion","Feelings and opinions are strong and divided on both the 1973 US Supreme Court decision on abortion in Roe v. Wade and the Court's 1989 decision in Webster, which signals a retreat from Roe. The state of the law since Roe v. Wade was decided, and the changes presaged by Webster, are described. Although physicians probably know no more than the public about Roe and Webster, they should. Whatever one's position on the morality of abortion, it has become the most commonly performed surgical procedure in the US over the past 2 decades, and the availability of abortion partly justifies other common medical procedures, such as amniocentesis and chorionic villus sampling. Physicians have a central role in counseling pregnant women about their health and the health of their fetuses, and any criminal restrictions state legislatures are allowed to place on the exercise of that role may also be placed on other medical procedures. The abortion debate has returned to the political arena, where it has been consistently impossible to resolve. In states that decide to add restrictions on abortion, physicians and their pregnant patients may find their medical and moral options sharply limited.",0
777,2694165,Methodological issues in adherence to cancer control regimens,"A six-factor model provides a heuristic framework for understanding adherence behavior: (1) effective provider communication; (2) rapport with provider; (3) client's beliefs and attitudes; (4) client's social climate and norms; (5) behavioral intentions; and (6) supports for and barriers to adherence. Four classes of methodological issues are discussed. Recruitment may be affected by the sociodemographics of the target population, biomedical variables, population size and location, and patient sources utilized. Interventions can be structured to maximize enrollment, participation and long-term retention, and adherence to the regimen promoted with behavioral methodology. Measurement of adherence optimally includes multiple measures at multiple time points, a well-defined focus and unit of adherence, well-constructed response options, and multiple sources of information. Sample size calculations and interpretation of clinical trial results are affected by adherence rates. Multivariate analytic techniques, such as structural equation modeling, make it possible to specify models depicting hypothesized structural relationships between different theoretical constructs and to evaluate the plausibility of these models. ",0
778,2694546,Fibroblast spreading in the presence of cytochalasin D: immunoelectron microscopy of the cytoskeleton],"""Spreading of mouse embryo fibroblasts in the presence of cytochalasin D (1 microgram/ml) was studied using scanning electron microscopy, immunofluorescence, and electron microscopy of platinum replicas. Whereas circular lamellae were formed around the cell body during normal spreading, separate processes appeared at the cell periphery during spreading in cytochalasin-containing medium. The processes gradually elongated and branched. Cytoskeletons of fibroblasts spreading in the cytochalasin-containing medium were obtained by Triton X-100 extraction. They contained microtubules, intermediate filaments, actin """"paracrystals"""" looking like short microfilament bundles, and patches of a meshwork-granular material. Immunogold coating of the cytoskeletons with anti-actin antibody showed that some meshwork-granular patches were decorated with gold particles, whereas the others were not. Non-actin patches were usually located on the distal ends of the processes, thus leaving behind the actin cytoskeletal components during the process growth. Another characteristic feature of this unidentified material is its usual association with the substratum and microtubules. These results suggest that the process protrusion during cell spreading in cytochalasin-containing medium may occur not due to actin polymerization as in the control cells, but due to involvement of some other non-actin cytoskeletal components. These components seem to be able to move along microtubules and to bind to the substratum. """,0
779,2694662,Assessment of the vasomotility of epicardial coronary arteries with quantitative coronary angiography,"Quantitative in vivo analysis of the vasomotility of epicardial coronary arteries is based on the measurement of changes of the vessel diameters. Vessel contours can be determined with the help of a precision caliper by the investigator or with computer-assisted geometrical analysis systems applying a contour detection algorithm; the variability of the results from repeated coronary diameter measurements in the identical film frame is comparably low with all systems (less than or equal to 0.12 mm standard deviation). When investigating the influence of an intervention on coronary vasomotility the variability of the measurements can only be kept low by careful standardization of the entire method. Repeated coronary angiograms are performed in identical angiographic projections (mono- or biplane) with standardization of the inspiratory status of the patient and of the rate of contrast material injection (automatic injection pump). For quantitative analysis all coronary segments with a diameter greater than 1 mm which are clearly outlined, free from overlaps, and mainly run parallel to the image plane, are selected by the investigator in preferably end-diastolic cineframes. Whereas with a caliper and with most of the semi-automatic edge detection systems the segment diameter can only be measured at particular sites defined by the investigator, few systems are able to analyze and average the diameter over the entire segment length. The variability of measurements of the minimal diameters of coronary stenoses in different cine frames is particularly high; therefore, only distinct changes of this parameter (e.g. with the CAAS-system greater than 0.24 mm) may be considered significant.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
780,2694910,Management of the ageing dental patient,"Dental care of elderly persons is very similar to that of younger persons but is often modified by a variety of age related and age associated changes. Diseases and the medications taken to treat them often have a direct effect on oral health. Clinical decision-making for the dental care of older adults can be more complex. Dental disease patterns within the ageing population seem to be changing and seem to be expressed differently resulting in more modifying factors which will require actual diagnosis and complicate treatment planning. This paper presents some definitions of geriatric patients with specific applications to dentistry. Using the available data the characteristics and needs of these patients have been described with particular reference to decision-making. Selected management issues have been discussed with particular reference to stress, communication, prevention and premedication. Some concepts in restorative care especially related to root caries were discussed. In prosthodontics the problems related to treatment have been identified and the incremental treatment technique discussed. Issues in the care of older dental patients are not often related to technical problems but are issues related to what is considered appropriate care, necessary treatment, where it should be carried out and the sequence in which it should be completed. ",0
781,2694981,Changes in serum transferrin and iron concentrations in humans suffering from malaria with parasitaemia,"Sera from non-malarial (control) and Plasmodium falciparum-infected (malaria) subjects were assayed for transferrin and iron. The mean serum transferrin concentration in the malaria sera was found to be elevated by 44% above the control value. The mean serum iron was also raised in the malaria sera, but the increase (19%) was found to be well below that of transferrin. The mean saturation of serum transferrin with iron fell from 42 +/- 17% in the control group to 37 +/- 9% in the malaria group. It is suggested that the increase in transferrin concentration in the sera of malaria subjects probably resulted from an increase in the rate of transferrin synthesis, perhaps in response to the raised serum iron and/or the hypoxia which is known to be associated with malaria infection. ",0
782,2694984,A history of sleeping sickness in Kenya,"Gambian sleeping sickness entered what is now Kenya from Uganda in about 1901 and quickly spread along the Kenyan shores and islands of Lake Victoria, reaching Tanzania in 1902. By 1910 the disease had spread 25 miles inland along the Kuja and Migori rivers and their tributaries. Sleeping sickness waxed and waned in these areas despite attempts to control tsetse fly populations by various methods. It was not until 1950, when the use of insecticides (DDT) applied by backpack sprayer proved successful against Glossina fuscipes at Kibigori, that eradication of G. fuscipes and Gambian sleeping sickness seemed possible. Subsequently the Kuja-Migori endemic area was cleared of flies and disease, as well as the South and Central Nyanza lake shores and islands. By 1965 Gambian sleeping sickness had virtually disappeared from Kenya. A more virulent form of the disease, Rhodesian sleeping sickness, may have also spread to Kenya from Uganda, although its appearance in diverse areas of the Gambian disease suggest that local ecological factors may have played a role in enhanced virulence of trypanosomes stocks. The Rhodesian form of sleeping sickness appeared in the Lambwe Valley, South Nyanza, in about 1959, and despite attempts to eradicate this disease it still persists as the only remaining endemic area in Kenya at this time. The usual transmission of Rhodesian sleeping sickness by G. pallidipes in Kenya was altered when an outbreak occurred at Alego, in Central Nyanza, in 1964. It was discovered that G. fuscipes was the vector and that domestic cattle were an important reservoir of infection. Glossina fuscipes was also the vector of Rhodesian sleeping sickness in an outbreak in Samia in 1976 and another along the lakeshore in South Nyanza in 1981. Sleeping sickness has been restricted primarily to the Western and Nyanza Provinces of Kenya (Fig. 1). ",0
783,2695546,Nontraditional areas for the use of pharmacologic preparations based on research on the molecular mechanisms of their action],On the basis of analysis of a number of documents concerning the molecular mechanisms of actions of well-known drugs the first attempt has been made to subdivide their activities into traditional and nontraditional ones. The possibility of application of a number of well-known drugs to nontraditional fields of pharmacology has been demonstrated. ,0
784,2695599,Parallel changes in catabolite repression of haem biosynthesis and cytochromes in repression-resistant mutants of Saccharomyces cerevisiae,"Effects of three mutant genes, CAT1-2d, cat2-1 and hex2-3, on catabolite repression of mitochondrial cytochromes and the first two enzymes of haem biosynthesis were compared. The CAT1-2d mutation gave no resistance to glucose, whereas cat2-1 endowed both cytochromes and 5-aminolaevulinate dehydratase with resistance, but did not alter the effect of glucose on 5-aminolaevulinate synthase. The hex2-3 mutation caused repression resistance of cytochromes and of the two haem biosynthetic enzymes. hex2-3 strains also accumulated intracellular 5-aminolaevulinate. Co-inheritance of the latter traits, sensitivity to maltose inhibition and ability to grow on raffinose in the presence of 2-deoxyglucose, demonstrated that the pleiotropic phenotype is a function of the single gene hex2-3. Revertants which grew on maltose regained sensitivity to deoxyglucose and exhibited normal sensitivity of cytochromes and haem biosynthesis enzymes to repression. Addition of the hex1-18 mutation, which renders cytochromes resistant to repression, to a cat2-1 strain did not produce the same effect on 5-aminolaevulinate synthase as hex2-3. It is concluded that repression patterns of haem and cytochrome biosynthesis are substantially affected by hex2-3 and cat2-1 but not by CAT1-2d. ",0
785,2695643,Premature gonadal failure in female dogs and cats,"Premature gonadal failure has been detected in phenotypically female dogs and cats with defective prenatal germ cell migration (ovarian aplasia), defective prenatal differentiation of the gonadal ridge into ovarian tissue (true hermaphroditism, male pseudohermaphroditism, ovarian dysgenesis in the presence of XO or XXX sex chromosome complements) or defective gamete maturation in the presence of primordial ovarian follicles (lymphocytic oophoritis, thyroid insufficiency). The most common of these is defective gonadal differentiation in animals with true hermaphroditism and failure of gamete maturation in thyroid insufficiency. A common clinical sign of premature gonadal failure in companion animals is failure to show a pubertal oestrus by 2 years of age. Diagnostic evaluation of such animals should include determination of the karyotype, plasma concentrations of LH and FSH and of thyroid hormones, gonadal histology, and gross evaluation of the Müllerian duct system at laparotomy. ",0
786,2695924,The concept of mental illness,"In recent years it has often been suggested that there is no such thing as mental illness. In naive Cartesianism this assertion starts out from the assumption that illness may develop solely from physical causes. Before clarifying what mental illness is, we should ask what is understood by the general notion of 'illness'. A constituent of the general disease concept is an unvoluntary and sufficiently serious disturbance of vital functions that needs to be defined in detail-and not just any region of disease causes or symptoms. The general disease concept can be defined in the context of everyday life and in the social and legal context and be filled with detailed normative and threshold values in the medical context. A society with a humanitarian orientation responds to the incapacity of its members owing to illness with attempts at institutionalization, which find their expression in norms, privileges and duties. Special disease concepts were developed for defining specific diseases and distinguishing them from others. Since solely the general disease concept, on which the distinction between illness and deviations from moral or legal norms is founded, is aetiologically neutral, it can be filled with any explanation model at the physical or at the mental level in the frame of specific disease concepts: e.g. with the one cause--one disease model, with multifactorial models or behavioural dysfunction models. ",0
787,2695952,Amplification of bacterial plasmids without blocking protein biosynthesis,"The effect of amino acids (presence or absence from the growth media) and metal ions on the replication of Escherichia coli plasmids in rel A+ strains was studied. It was found that: (i) The absence of one amino acid from the growth media had no effect on the plasmid copy number in prototrophic E. coli strains: (ii) The presence of only one amino acid in artificial media free of amino acids had a negligible effect on the plasmid copy number for the amino acids Ala, Arg, Glu, His, Leu, Phe, Thr, Trp, and Tyr: (iii) The combination of Met and Thr caused a rise in pBR322 plasmid copy number up to 90-100 plasmid copies per cell: (iv) The Fe3+ concentration had an amplification effect on E. coli plasmids. The pBR322 plasmid copy number for media free of amino acids and supplemented with 0.2-0.4 mM FeCl3 was 60-80 plasmid copies per cell: (v) The combination of Fe3+ with certain amino acids (Ala, Arg, Glu, Leu, Thr, and Trp) leads to a dramatic increase in the plasmid copy number reaching 180-270 plasmid copies per cell for the plasmid pBR322 and 20-24 for the plasmid pR100. ",0
788,2696250,Quantitative image analysis in nuclear cardiology as a decision aid in addition to visual assessment of findings],"Quantitative analysis of nuclear cardiology procedures has stimulated tremendous work in the past and will continue to do so in the future. The impact on routine patient care has grown at a slower pace and should be assessed separately for tissue perfusion and for myocardial contraction. The current status will be presented, focusing on patients with coronary heart disease. In the preinfarct period myocardial scintigraphy with thallium-201 and emission computer tomography (ECT) is the preferred method. The procedure for quantitation includes transfer of all data into a standard polar map and comparing the numbers with a normal, gender-matched data base. The result reveals areas of reduced tracer uptake, color-coded according to the level of significance. Interpretation of these colored polar maps might appear simple, but in fact requires a substantial amount of knowledge to avoid overinterpretation of the results. This has led us to a restricted use of this quantitative tool: following an initial step of reading the original data in terms of short and long axes slices of the left myocardium, the polar map is utilized for verification and for suggestions of any additional lesions. This has to be confirmed by a second reading of the slices, and only this last step defines the lesions to be reported. Quantitation used in this dialectic approach avoids inclusion of artefacts, and at the same time is useful experience for trainees. Furthermore, it allows easy presentation during the clinical conference and statistical analysis of groups.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
789,2696741,Rapid determination of methandrostenolone in equine urine by isotope dilution liquid chromatography-tandem mass spectrometry,"Urine samples were spiked with [17-methyl-2H3]methandrostenolone as internal standard and extracted with a mixture of dichloromethane and cyclohexane. The organic phase was concentrated and injected onto a short octyl-silica column (30 mm x 4.6 mm I.D.) for separation of methandrostenolone and 17-epimethandrostenolone. The effluent from the column was connected to a Sciex TAGA 6000E triple quadrupole mass spectrometer equipped with an atmospheric pressure ion source for sampling of ions generated by a heated pneumatic nebulizer with corona discharge ionization. This ion source produced abundant [M + H]+ ions and a weak fragment ion due to loss of water. The protonated molecular ions at m/z 301 and 304 for methandrostenolone, 17-epimethandrostenolone and the internal standard were transmitted to the second quadrupole for collision-induced dissociation. Quantification was obtained by selected reaction monitoring of three daughter ions. Methandrostenolone and 17-epimethandrostenolone were separated by liquid chromatography, but gave identical mass spectra. The method detection limit by injection of a urine extract corresponding to 2.8 ml urine was 180 pg/ml at the 99% confidence level. The precision (relative standard deviation) was 3% at the 16 ng/ml level and the linear dynamic range was at least 3 orders of magnitude. Screening for unknown metabolites in urine after administration of methandrostenolone to horses and humans was accomplished by a parent ion scan of m/z 121, a fragment corresponding to the intact A-ring of the steroids. ",0
790,2697011,Neurochemical studies of violent and nonviolent suicide,"Considerable data have been reported indicating that there is a relationship between suicide or more serious suicide attempts and alterations in indices of serotonin (5-HT) function in patients. The fact that these data are based on studies of both suicide completers as well as more serious suicide attempters and involve a range of experimental techniques spanning biochemical assays of postmortem brain tissue as well as neuroendocrine challenge tests and platelet studies strengthens this finding. However, whether altered serotonin indices are specifically associated with violent compared to nonviolent suicide remains less clear. The relationship may be with some other aspect of suicidal behavior such as the overall lethality of the suicide method, impulsivity, or degree of planning. Suicide method appears to be related to modeling effects or to the relative availability of different methods of suicide, which argues against a predominant role for biological factors in selecting suicide methods. The relative importance of biological vs. modeling and sociological factors in determining suicide method will require more comprehensive studies in which the contribution of all of these factors is assessed simultaneously in the same patient population. ",0
791,2697183,Human leukocyte antigen (HLA) frequency among patients with nasopharyngeal carcinoma in Taiwan,"In order to assess the association between human leukocyte antigens (HLA) and nasopharyngeal carcinoma (NPC), a total of 10 familial and 10 sporadic NPC patients and 171 unrelated healthy controls were studied. HLA typing was performed using commercial trays which defined 30 specificities of HLA-A, B and C loci and 10 specificities of HLA-D locus according to the method of Tiwari and Terasaki. HLA-A2, B16 and DR1 were found to be higher among patients with NPC than unrelated healthy controls with an odds ratio (OR) and a 95% confidence interval of 5.91 (2.1-16.6), 6.00 (2.0-18.0) and 6.89 (1.3-37.5), respectively. Further analysis showed that A2(+) B16(+) haplotype was significantly associated with a much higher risk of NPC (OR = 15.5) as compared with A2(-) B16(-) haplotype. No difference in frequency distributions of HLA-A, B, C and D antigens was observed between familial and sporadic NPC patients. ",0
792,2697945,Community health services and health care utilization in rural Bangladesh,"The study, which is based on data from two household level health surveys conducted in 1976 and 1987 in the Companiganj area of rural Bangladesh, examines the premise that the utilization of public health care services can be increased by increasing the availability and accessibility of effective medicines to the public and by improving the disease recognition and management by the health practitioners. The results of the study suggest that the availability and accessability of modern effective medicines through the provision of decentralized community-based rural health services, by a well-trained and well-managed field personnel structure, had an incremental impact on the utilization of modern health care from a rural health center and its subcenters. The study further reveals that, in 1976 as well as in 1987, the overwhelming majority of the rural Bangladesh population were using modern Western medical practitioners, although most of these practitioners were informally trained or self-trained without any formal medical degrees or training. It is concluded that the persons responsible for health program planning and health program implementation need to ensure that the access to basic public health care services be made broad enough to cover the majority of the rural population through a system of decentralized curative and preventive services, as well as through a system of adequate training and deployment of health professionals, including training programs to improve the quality of medical services offered by the informal and self-trained practitioners of modern medicines. ",0
793,2698095,"Investments in women, economic development, and improvements in health in low-income countries","Investments in human resources are more likely to have higher rates of return than investments in capital resources like factories, equipment, inventories, and infrastructure.  There are a variety of studies that estimate the ratio of return from primary and secondary schooling to be between 5-40% annually.  The primary factor affecting return is the level of development of the country in question.  Developing countries are able to achieve higher rates of return than already developed countries.  Determining the rates of return on public and private health investments and related research and developments is much harder because the major improvements that have occurred in the past were accompanied by other significant improvements in trade, nutrition, and income.  However, there is a growing body of evidence that suggests that improvements in health were significantly responsible for the economic growth following World War II.  Analysis of education expenditures indicates that the less educated a country's women are, the lower its standard of living.  90% of the intracountry variation in enrollment rates for men and women for 80 countries between 1960-1980 indicate that this is the case.  Studies conducted during the 1970s and 1980s by demographers, economists, anthropologists, and sociologists clearly show a trend in education of women and child mortality.  Every additional year of female education translates to a 5-10% reduction in child mortality.  It is clear that women play a central role in the health determinants of family members.  The education of women is a strong, although not clearly understood, force affecting child mortality, nutrition, health, and school achievement.  Household resources and maternal education must always be determined before any study of health care delivery effectiveness is conducted.  The same is true for any studies of the effectiveness of local family planning expenditures. ",0
794,2698789,Hepatic resection guided by B-mode ultrasonography],"From December 1987 to July, 1988, ultrasonically guided hepatic resection was performed for primary liver cancer in 12 cases and benign liver tumor in 11 cases. No patient died on table and in 30 days after the operation. Among postoperative complications were hepatic coma in one case, pleural effusions in 3 and bile leaks in 2. Our results showed that the intraoperative B-mode ultrasound could not only demonstrate the number, size and boundary of the lesions but also locate the course of the intrahepatic conduit system and its 3-dimensional relation with the lesions. It was, therefore, very helpful in dealing with the intrahepatic blood vessels and biliary ducts. ",0
795,2698894,A clinical trial of intraligamentary anesthesia,"The effectiveness of the periodontal ligament injection in providing anesthesia for routine extractions and the possible mechanisms of action of the periodontal ligament injection in producing dental anesthesia were investigated in a clinical trial. Periodontal ligament injections were administered under strong pressure with lidocaine on 14 teeth, with epinephrine on seven teeth, and with normal saline on another seven teeth. The anesthesia attained was evaluated by: response of the teeth to an electric pulp tester, gingival probing around the teeth, and the ability for teeth to be extracted without pain. The results demonstrated that periodontal ligament injections with lidocaine were effective in providing adequate anesthesia for the performance of dental extractions. Lidocaine periodontal ligament injections were statistically and clinically more effective in attaining anesthesia than were epinephrine or saline injections. Epinephrine periodontal ligament injections resulted in a slight but statistically significant increase in the stimulus necessary to produce a patient response, when the teeth were stimulated with an electric pulp-tester. Saline injections produced no change in response to the stimulus tested. It appears, based on the results of the saline and epinephrine injections, that hydrostatic pressure had no direct effect on the production of anesthesia with the periodontal ligament injection. ",0
796,2698973,Mathematical approach to the problem of early diagnosis in heart failure],"A tool set for early detection of heart failure (HF) and its criteria for mass population survey in the polyclinic setting was developed. A two-stage screening programme was carried out. At the first stage, patients with cardiac abnormalities were detected. At the second stage, the patients underwent a complex instrumental study. Fourteen most informative signs of HF were identified. A programme was developed for analysis of their baseline values and adoption of solutions by applying a procedure for inhomogeneous sequential statistic recognition, significantly promoting the diagnosis by employing diagnostic tables. ",0
797,2699137,Detection of lymph vessel changes in venous diseases of the leg using imaging procedures],"Chronic venous insufficiency reveals both functional correlations with the lymphatic system of the limbs as well as pathological-anatomical. The functional correlation initially consists in an enhancement of function as a manifestation of a compensation mechanism of lymphatic drainage in relation to the insufficient venous system. Finally, if the lymphatics are themselves damaged in their further course, a safety valve insufficiency occurs with resulting lymphostasis. Apart from this participation, regional damages to the lymphatic fascicles play a role in chronic venous insufficiency in trophic disorders, as for example leg ulcer and atrophy. However, these are far less significant for the overall function of lymphatic drainage. As a role, they show a pronounced collateralization, and thus good possibilities of functional compensation. In particular indirect lymphography with water-soluble contrast medium is suitable as imaging technique in diagnostics with regard to the morphology. Isotope lymphography is suitable with regard to investigating the function of lymphatic drainage and for circumscribed local disorders. As native techniques, xeroradiography and computed tomography are very suitable to analyse tissue damage of the cutis and subcutis resulting from chronic venous insufficiency and from lymphostasis and to make indirect inferences from this with regard to the chronicity of this disease process. ",0
798,2699335,An elderly case of Crohn's disease complicated with internal fistula and mass formation with a review of the Japanese literature],"A case of Crohn's disease in the elderly complicated with internal fistula and mass formation was reported. A 62-year-old woman was admitted to National Toyohashi Hospital on August 16, 1986, with complaints of abdominal pain, pyrexia and diarrhea for two months. Physical examination revealed a goose-egg sized mass in the left lower quadrant of the abdomen. Barium meal examination of the small intestine showed strictures and fistula formation of the jejunum. Angiography showed narrowing and irregularity of the vessels. Malignant tumor of the small intestine could not be ruled out, so that an exploratory laparotomy was done on October 14, 1986. At operation, the jejunum, 70 cm from the ligament of Treitz, formed a 5 x 7 cm mass with adhesion and fistula formation. There was a skip lesion at the terminal ileum. Forty cm of the jejunum and 60 cm of the ileum were resected, and both of the resected specimens showed longitudinal ulceration, cobblestone appearance and thickening of the wall. Histological examination showed noncaseating granulomas with epitheliod cells and giant cells in the tunica muscularis. Since the report by Komi et al. in 1970, 13 cases of Crohn's disease in the elderly have been reported in Japan up to 1988. We summarized the characteristic findings of Crohn's disease in the elderly in Japan as follows; 1) Clinical symptoms and radiographic findings were similar to those in younger patients. 2) Small bowel involvement was reported in 54%. 3) Surgery was performed in 46%. 4) Preoperative diagnosis was only made in 46% of the elderly patients.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
799,2699673,Airborne bacteria and viruses,"Coughing, sneezing, talking, bed-making, turning pages of books, etc. all generate microbial aerosols which are carried and dispersed by air movements. Inhalation of these particles may cause allergic responses but whether or not infectious disease ensues depends in part on the viability and infectivity of the inhaled microbes and their landing sites. Desiccation is experienced by all airborne microbes; gram-negative bacteria and lipid-containing viruses demonstrate phase changes in their outer phospholipid bilayer membranes owing to concomitant changes in water content and/or temperature. These changes most likely lead to cross-linking reactions of associated protein moieties principally at mid to high relative humidity (RH). For lipid-free viruses these reactions of their surface protein moieties occur most rapidly at low RH. Radiation, oxygen, ozone and its reaction products and various pollutants also decrease viability and infectivity through chemical, physical and biological modification to phospholipid, protein and nucleic acid moieties. The extent of damage and the degree of repair together with the efficacy of host defence mechanisms largely controls whether the causative microbes take hold and spread disease via the airborne route. At least indoors, where desiccation is the predominant stress, the general reversibility of membrane-phase changes by vapour-phase rehydration when coupled with efficacious microbial enzymatic repair mechanisms under genetic control, virtually ensures the spread of disease by the aerobiological pathway. ",0
800,2699787,Short term effects of ketoconazole in Cushing's syndrome],"The effects of Ketoconazole (600 mg/day) were evaluated in 10 patients with Cushing's syndrome during a mean period of 4.5 weeks (range 1-12). The urinary free cortisol excretion (UFC) decreased by 21 +/- 15% (mean +/- SEM) (p less than 0.01) on day 1; 54 +/- 8% (p less than 0.0001) on day 2; 60 +/- 15% (p less than 0.0001) on day 3 and 87 +/- 3% (p less than 0.0001) on day 8 compared to baseline. Salivary cortisol at 0800 h decreased similarly. On day 3, 7 patients showed normal UFC values and on day 8, only 1 patient, with the ectopic ACTH syndrome, had persistent hypercortisolism. The cortisol decrease was associated with an increase in desoxycorticosterone values (p less than 0.01) and a decrease in dehydroepiandrosterone sulfate (p less than 0.001), delta 4 androstenedione (p less than 0.05) and testosterone (p less than 0.05). No significant variations were observed in ACTH, 11 desoxycortisol, aldosterone, plasma renin activity, corticosteroid-binding globulin and sex hormone-binding globulin. Side effects were few: mild clinical adrenal insufficiency (n = 5), oedema (n = 3) and reversible hepatic toxicity (n = 1). We conclude that Ketoconazole is an effective inhibitor of cortisol and androgens synthesis. It is well tolerated, rapidly effective and its efficacy persists unchanged for at least one month in all forms of Cushing's syndromes. For these reasons Ketoconazole may be a valuable drug for preoperative treatment of Cushing's syndrome. ",0
801,2699928,Neonatal hypoxia and hemocoagulative changes],"Coagulation abnormalities with and without haemorrhagic manifestations have been frequently reported in newborn-infants affected by hypoxia. Particularly in postmature-infants and in those ones with acute asphyxia at birth, respiratory distress syndrome (RDS), intra-uterine growth retardation (IUGR) and cyanotic congenital heart disease (CCHD). A reduction of synthesis or a consumption of blood coagulation factors are the main causes of these abnormalities. The anomalies of platelet number and of their function, of haemostasis global tests, of coagulation factors and physiologic inhibitors levels, of fibrinogenesis and fibrinolysis are examined, including authors' studies and a review of literature too. The authors think platelet count, PT, PTT, fibrinogen, factor V and VIII, and PDF determinations are necessary laboratory investigations for newborn-infants with RDS or acute asphyxia for about the first week of life, because of the risk of consumption coagulopathy. In the other hypoxic newborns (IUGR, CCHD, postmature infants) platelets count, PT, PTT and serum PDF determinations could be enough in order to value any coagulation abnormalities presence. ",0
802,2700430,X-ray examinations in orthodontic diagnostics as a source of ionizing radiation],"Orthodontics increasingly depends on X-ray examinations in the therapy and diagnosis of dento-facial anomalies. In the choice of roentgenologic diagnostic methods attempts are made to select a method that provides maximum information with the least irradiation of the patient. Insufficient knowledge of the biological effects of ionizing radiation may result in undue precaution by the doctor or utter indifference. Therefore, literature data were analyzed to cast more light on the risks of ionizing radiation. The following conclusions have been reached: orthodontists are obligated to expose their patients to a minimal possible radiation; it is not possible to define the safety threshold of X-ray radiation because of unpredictable stochastic effects, although the incidence of damage due to the lowest doses is negligible; the doses of radiation due to orthodontic X-ray examinations are within the range of natural, environmental doses. However, because of their cumulative effects, they should not be underestimated; stomatologic X-ray examinations account for 8 to 25% of all X-ray examinations, yet their contribution to genetically significant doses is the smallest; since the effects of genetically significant doses have not been scientifically elucidated to a sufficient extent, X-ray radiation should be maximally reduced, modern roentgenologic techniques should be used and the safety instructions should be strictly followed; if all safety measures are adhered to, it is not necessary to impose limitations with regard to the performance of orthodontic X-ray examinations; it is important to obtain from the patient history of his previous X-ray examinations; a favorable relationship should exist between medically warranted needs and possible damages to the patient; standardization of orthodontic X-ray diagnosis will facilitate recording of relevant data and the calculation of radiation doses. ",0
803,2700970,Global changes in caries prevalence and dental manpower requirements: 3. The effects on manpower needs,"A Joint Working Group of the WHO and FDI was formed in 1981 to investigate the dramatic decrease in caries in children and young people that had been observed in a number of industrialized countries in the 1970s. The results of this investigation are reported in this series of three articles. Parts 1 and 2 described the assembly and analysis of all available data on the decrease, and identified the widespread availability of fluoride toothpaste as the most probable cause. Inevitably in developed countries with declining caries incidence there will be a decreased need for dental services, and hence a change in the need for dental personnel. This third article will examine the likely effects on staffing needs and outline a suggested methodology for manpower planning. The lack of adequate data makes prediction a precarious procedure, and this review indicates the urgent need for regular dental health monitoring and better manpower planning in all countries. ",0
804,2710203,The case for wider use of testing for HIV infection,"There has been reluctance by the medical establishment and government to promote extensive human immunodeficiency virus (HIV) testing, even though it can be done economically and accurately. There are good arguments for more testing of 1 of the most serious epidemics of a infectious diseases in history. In 1987 there was estimated to be over 1 million people infected with HIV and most of them are unaware of the infection. The current methods to make people with HIV infection aware of the disease are not effective. Many people do not realize that early detection of HIV is important and that it is treatable. Where increased testing has been done there is evidence that unsafe sexual practices have been reduced by those with HIV. Another benefit of early detection of HIV is the identification of candidates for experimental therapies. There are reports that zidovudine is effective immediately after exposure to HIV, and hospitals should offer this treatment free to personnel exposed to blood or body fluids of an infected person. The effectiveness of hospital precautions should be evaluated and routine screening of patients can then be decided. Testing for HIV in the health care system could drive away those infected or who fear they are. Another argument against wider testing is false positive test results, but use of screening with sequential enzyme immunoassays followed by Western blot should rarely produce false positive results. It is a minimum requirement to test all patients that acknowledge sexual contact with homosexual men, any needle sharing, and any multiple unsafe heterosexual contacts. Also, testing of prenatal patients is strongly recommended, since early detection can allow abortion decision to be made, and also further pregnancies can be prevented.",0
805,2716796,Effect of triglyceride levels on methyl and methylene envelope line widths in proton nuclear magnetic resonance spectroscopy of human plasma,"Recent studies have described a relation between the line widths of the methyl and methylene resonance envelopes in the proton nuclear magnetic resonance spectrum of human plasma and the occurrence of cancer. An average line width of less than 33 Hz has been reported to correlate with the presence of cancer, whereas greater line widths have not. In 26 normal volunteers, we found a significant inverse correlation between fasting triglyceride level and plasma spectral line width. We also observed that dietary lipids have measurable effects on spectral line widths. In another sample of seven normal persons (three of whom had elevated plasma triglyceride levels), the line widths of whole plasma varied widely (mean, 35.6 +/- 8.8 Hz); however, the mean line widths of the lipoprotein fractions isolated from those samples differed greatly, but the variance within each fraction was small (very-low-density lipoprotein, 22.0 +/- 1.9 Hz; low-density lipoprotein, 35.0 +/- 2.8; high-density lipoprotein, 28.8 +/- 1.9). The results of this study indicate that the plasma triglyceride level has a profound effect on the average spectral line width of plasma. This effect can be explained by the relative amounts of lipoprotein fractions in whole plasma. Plasma triglyceride concentrations of more than 1.24 mmol per liter (greater than 110 mg per deciliter), whatever the source, produce average plasma methyl and methylene line widths of less than 33 Hz.",0
806,2725598,Low yield cigarettes and the risk of nonfatal myocardial infarction in women,"""Newer brands of cigarettes with reduced yields of nicotine and carbon monoxide have been promoted as being less hazardous than others. We evaluated the effect of smoking """"low yield"""" cigarettes on the risk of nonfatal myocardial infarction in women under 65 years of age. The data were obtained in a case-control study of 910 women with a first myocardial infarction and 2375 hospital controls. The estimated relative risk for current smokers as compared with those who had never smoked increased with the number of cigarettes smoked. The estimated overall relative risk was 3.7 (95 percent confidence interval, 3.0 to 4.7). The estimated risks did not vary according to the nicotine or carbon monoxide yield of the cigarette. The estimated relative risk (4.7) in women who smoked brands with the lowest levels of nicotine (less than 0.40 mg per cigarette) was similar to that (4.2) in smokers of the higher-yield brands (greater than 1.30 mg). For exsmokers, the estimated relative risk was 1.4 (95 percent confidence interval, 1.0 to 1.8). These data suggest that women who smoke low-yield cigarettes do not have a lower risk of a first nonfatal myocardial infarction than women who smoke higher-yield brands. For smokers who wish to reduce their risk, switching to low-yield brands is a poor alternative to quitting.""",0
807,2725599,"Direct measurement of human immunodeficiency virus seroconversions in a serially tested population of young adults in the United States Army, October 1985 to October 1987. Walter Reed Retrovirus Research Group","Direct measurement of the incidence of infection with the human immunodeficiency virus (HIV)--the rate of new HIV infection--is vital if we are to understand better the dynamics of the current epidemic of HIV infection. Because soldiers are periodically and routinely screened for antibody to HIV, it is possible to measure the incidence of HIV infection directly in this large, demographically well-characterized population of young adults. To determine the incidence of HIV infection in this population, we examined test results reported by the U.S. Army's routine antibody-screening programs. During the first two years of the screening programs, the observed incidence of HIV infection was approximately 0.77 per 1000 persons per year. This rate was higher than expected on the basis of previously published estimates of seroprevalence in the Army (approximately 1.50 per 1000). On the basis of this annual incidence, and assuming it to be stable, we estimate that approximately 600 soldiers will become infected with HIV each year. The observed rate in the Army may be lower than the incidence of HIV infection in the corresponding demographic groups within the general U.S. population.",0
808,2733732,Low levels of high-affinity growth hormone-binding protein in African pygmies,"The cause of growth hormone resistance and short stature in African Pygmies in unknown. Low levels of insulin-like growth factor 1 that fail to respond to growth hormone suggest a possible deficiency of growth hormone receptors. The high-affinity growth hormone-binding protein is a fragment of the growth hormone receptor and may be an indicator of the number of receptors in tissues. We measured growth hormone-binding activity in plasma from 20 pygmies and 12 control subjects (7 white Americans and 5 non-Pygmy black Africans of normal stature). Growth hormone binding to the high-affinity binding protein was significantly reduced in the Pygmies as compared with the controls (mean +/- SD, 6.50 +/- 2.33 percent vs. 12.95 +/- 3.95 percent bound per 160 microliters of plasma; P less than 0.001); however, there was substantial overlap between the values for Pygmies and controls. Growth hormone binding to the low-affinity binding protein was similar in Pygmies and control subjects. We conclude that Pygmies have low levels of high-affinity growth hormone-binding protein in their plasma, which may indicate a reduced number of growth hormone receptors in their tissues. The finding may help explain the resistance to growth in Pygmies, but there may be additional reasons, related to the receptors or not, for their short stature.",0
809,2759550,Detection of antibodies against hepatitis B virus polymerase antigen in hepatitis B virus-infected patients,"By the use of a truncated recombinant hepatitis B virus polymerase antigen, we have characterized a series of patient sera for anti-hepatitis B virus polymerase antibodies. Seven of 54 (13%) had antipolymerase antibodies detectable by Western blot analysis, and no close correlation was apparent between the disease status and patient's immune response against hepatitis B virus polymerase antigen. Our results indicate that serologic responses to the viral polymerase are demonstrable but suggest that such antibodies are not likely to be clinically useful as diagnostic or prognostic markers of infection.",0
810,2761577,The absence of a relation between the periconceptional use of vitamins and neural-tube defects. National Institute of Child Health and Human Development Neural Tube Defects Study Group,"Whether taking multivitamins or folate around the time of conception can reduce a woman's risk of having a child with a neural-tube defect is controversial. To investigate this question, we examined the periconceptional use of vitamin supplements by women who had a conceptus with a neural-tube defect (n = 571), women who had had a stillbirth or a conceptus with another malformation (n = 546), and women who had had a normal conceptus (n = 573). Women with conceptuses with neural-tube defects were identified either prenatally or postnatally and were matched to control mothers for gestational age. To minimize recall bias, we interviewed nearly all the women within five months of the diagnosis of a birth defect or the birth of the infant (mean, 84 days); information on vitamin use was obtained by an interviewer who was unaware of the outcome of pregnancy. The rate of periconceptional multivitamin use among the mothers of infants with neural-tube defects (15.8 percent) was not significantly different from the rate among mothers in either the abnormal or the normal control group (14.1 percent and 15.9 percent, respectively). After adjustment for potential confounding factors, the odds ratio for having an infant with a neural-tube defect among women classified as having had full supplementation with multivitamins was 0.95 as compared with the mothers of the abnormal infants (95 percent confidence interval, 0.78 to 1.14) and 1.00 as compared with the mothers of normal infants (95 percent confidence interval, 0.83 to 1.20). There were no differences among the groups in the use of folate supplements. The adjusted odds ratio for having an infant with a neural-tube defect among those receiving the recommended daily allowance of folate was 0.97 as compared with the mothers of abnormal infants (95 percent confidence interval, 0.79 to 1.18) and 0.98 as compared with the mothers of normal infants (95 percent confidence interval, 0.80 to 1.20). We conclude that the periconceptional use of multivitamins or folate-containing supplements by American women does not decrease the risk of having an infant with a neural-tube defect.",0
811,2770793,Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system,"Chronic granulomatous disease, a syndrome of recurrent infections and failure of oxidative microbicidal activity in phagocytes, results from defects in the gene for one of several components of an oxidase system that can undergo activation. To determine the relative prevalence of certain of the genetic variants of this disorder, we used immunoblotting to detect two specific neutrophil cytosolic proteins of 47 and 67 kd recently shown to be required for oxidase activation. Chronic granulomatous disease is usually an X-linked disorder associated with the absence of membrane cytochrome b558. Of our 94 patients with chronic granulomatous disease, however, 36 had a phenotype characterized by autosomal inheritance, normal membrane oxidase components (including cytochrome b558), and functionally defective cytosolic activity in a cell-free oxidase system. We studied 25 of these 36 patients and found that 22 lacked the 47-kd cytosolic protein, and the remaining 3 were missing the 67-kd component. Patients with chronic granulomatous disease whose functional defect was localized to the neutrophil membrane (classic X-linked cytochrome b-negative type and two other rare variants) had normal amounts of both cytosolic components. We estimate that approximately 33 percent of all patients with chronic granulomatous disease are missing the 47-kd cytosolic oxidase component and about 5 percent of patients are missing the 67-kd component. Chronic granulomatous disease caused by a defect in any cytosolic factors other than the 47-kd and 67-kd proteins, if it exists, is apparently rare.",0
812,2777207,Replication of duck hepatitis B virus in primary duck hepatocytes and its dependence on the state of differentiation of the host cell,"Primary duck hepatocytes obtained from Pekin ducks congenitally infected with duck hepatitis B virus were used to monitor expression of viral proteins and replication of viral DNA in cell culture. Duck hepatitis B virus core antigen, duck hepatitis B virus pre-surface antigen and duck hepatitis B virus DNA were detectable for at least 12 days after cell plating. Whereas expression of duck hepatitis B pre-surface antigen was constant during this time, expression of duck hepatitis B core antigen and of viral DNA rapidly declined. This diminished production of viral components in vitro was paralleled by a change of the hepatocytes toward a fibroblast-like morphology. Supplementation of cell culture medium with 2% dimethyl sulfoxide, a solvent known to maintain the differentiated state of cultured cells, retained competence of the cultured hepatocytes to express duck hepatitis B core antigen and duck hepatitis B virus DNA at high levels. In a second set of experiments, duck hepatitis B virus negative hepatocytes were infected with duck hepatitis B virus from serum of congenitally infected ducks. Dimethyl sulfoxide remarkably improved the competence of cultured duck hepatocytes to become productively infected. This function was maintained for at least 12 days postplating.",0
813,2779614,The effect of cigarette smoking on neutrophil kinetics in human lungs,"Neutrophils may play a part in the pathogenesis of the centrilobular emphysema associated with cigarette smoking. The capillary bed of the lungs concentrates neutrophils approximately 100-fold with respect to erythrocytes, producing a large pool of marginated cells. We examined the effect of cigarette smoking on the kinetics of this pool of cells, using 99mTc-labeled erythrocytes to measure regional blood velocity and 111In-labeled neutrophils to measure the removal of neutrophils during the first passage through the pulmonary circulation, their subsequent washout from the lungs, and the effect of local blood velocity on the number of neutrophils retained in each lung region. We observed no difference in these measurements between subjects who had never smoked (n = 6) and smokers who did not smoke during the study (n = 12). However, subjects who did smoke during the study (n = 12) had a significantly slower rate of washout of radiolabeled neutrophils from the lung (0.08 +/- 0.04 of the total per minute, as compared with 0.13 +/- 0.06 in smokers who did not smoke during the experiment and 0.14 +/- 0.08 in non-smokers) (P = 0.02). We also observed an increase in the regional retention of labeled neutrophils with respect to blood velocity in 5 of the 12 subjects who smoked during the study, but in none of the other subjects. We conclude that the presence of cigarette smoke in the lungs of some subjects increases the local concentration of neutrophils, and suggest that the lesions that characterize emphysema may be a result of the destruction of lung tissue by neutrophils that remain within pulmonary microvessels.",0
814,2779617,The natural history of transfusion-associated infection with human immunodeficiency virus. Factors influencing the rate of progression to disease,"Patients infected by the human immunodeficiency virus (HIV) as a result of blood transfusions are unique in that their dates of infection are well defined and their medical conditions before infection are known. To characterize the natural history of transfusion-associated HIV infection, we studied 694 recipients of blood from 112 donors in whom AIDS later developed and from 31 donors later found to be positive for HIV antibody. Of the recipients tested, 85 were seronegative, 116 were seropositive, and 19 had AIDS. Of 101 HIV-seropositive recipients followed for a median of 55 months after infection, 54 had Centers for Disease Control Class IV disease, including 43 with AIDS. Life-table analysis suggested that AIDS will develop in 49 percent of infected recipients (95 percent confidence limits, 36 to 62 percent) within seven years after infection. As compared with recipients without AIDS, the 43 recipients with AIDS had received more transfusions at the time of infection (median, 21 vs. 7; P = 0.01). HIV-infected blood donors in whom AIDS developed were grouped according to whether AIDS developed within 29 months (the median) after donation (Group 1) or 29 or more months after donation (Group 2). As compared with the 31 recipients of blood from Group 2 blood donors, the 31 recipients of blood from Group 1 donors were more likely to have AIDS four years after infection (49 percent vs. 4 percent; P = 0.005) and illnesses resembling acute retroviral syndrome (14 of 24 vs. 5 of 22; P = 0.03). We conclude that most recipients of HIV-infected blood become seropositive, that AIDS develops in about half these recipients within seven years, and that the risk may be higher when AIDS develops in the blood donor soon after donation.",0
815,2785478,Cirrhotics with variceal hemorrhage: the importance of the time interval between admission and the start of analysis for survival and rebleeding rates,"The importance of variable time of entry for analysis of survival following variceal bleeding has recently been disputed. In a study of 194 cirrhotic patients with bleeding esophageal varices in whom 2-day mortality was 3%, statistically significant differences in both survival and rebleeding rates were obtained by shifting the starting point for analysis of survival by 2 weeks following admission to hospital or by 5 days for the analysis of rebleeding. In addition, the curve of hazard function for death or for failure to control bleeding following admission clearly showed that any change in entry time in a study of variceal bleeding would introduce bias and alter survival or rebleeding rates. Thus, the starting point for analysis following variceal hemorrhage is an important confounding variable when calculating both survival and rebleeding. It should always be taken into account, particularly in clinical trials, which are often performed in centers where patients are referred from other hospitals at different times following bleeding.",0
816,2797067,Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes,"The incidence of end-stage renal disease in patients with diabetes mellitus is reportedly higher among blacks than among whites. This finding may be explained by the greater prevalence of diabetes among blacks. The relation of the type of diabetes to the risk of diabetic end-stage renal disease is largely unstudied. We addressed these issues in a study of all the black and white diabetic patients with end-stage renal disease (470 blacks and 861 whites) reported to the Michigan Kidney Registry who began treatment during 1974 through 1983. We also reviewed the medical records of a subpopulation of such patients (284 blacks and 310 whites) who were less than 65 years of age at the start of treatment for end-stage renal disease to determine what type of diabetes they had. In this study, we made use of national data on the prevalence of diabetes. We found that the incidence of diabetic end-stage renal disease was 2.6-fold higher (P less than or equal to 0.0001) among blacks after we adjusted for the higher prevalence of diabetes among blacks, with the excess risk occurring predominantly among blacks with non-insulin-dependent diabetes mellitus (NIDDM). Most black patients with diabetic end-stage renal disease had NIDDM (77 percent), whereas most white patients with diabetic end-stage renal disease had insulin-dependent diabetes mellitus (IDDM) (58 percent) (P less than or equal to 0.0005 for the difference between the races). For both races combined, the risk of diabetic end-stage renal disease during the 10-year period we studied was markedly greater for patients with IDDM (5.8 percent) than for those with NIDDM (0.5 percent). Our results indicate an increased risk of diabetic end-stage renal disease among blacks as compared with whites, particularly blacks with NIDDM. Although the risk of diabetic end-stage renal disease is higher in patients with IDDM, the majority of patients with diabetic end-stage renal disease in the population we studied had NIDDM.",0
817,2797100,The risk of breast cancer after irradiation of the thymus in infancy,"It is well established that exposure to ionizing radiation during or after puberty increases a woman's risk for breast cancer, but it is less clear whether exposure to ionizing radiation very early in life is also carcinogenic. We studied the incidence of breast cancer prospectively in a cohort of 1201 women who received x-ray treatment in infancy for an enlarged thymus gland and in their 2469 nonirradiated sisters. After an average of 36 years of follow-up, there were 22 breast cancers in the irradiated group and 12 among their sisters, yielding an adjusted rate ratio of 3.6 (95 percent confidence interval, 1.8 to 7.3). The estimated mean absorbed dose of radiation to the breast was 0.69 Gy. The first breast cancer was diagnosed 28 years after irradiation. The dose-response relation was linear (P less than 0.0001), with a relative risk of 3.48 for 1 Gy of radiation (95 percent confidence interval, 2.1 to 6.2) and an additive excess risk of 5.7 per 10(4) person-years per gray (95 percent confidence interval, 2.9 to 9.5). We conclude that exposure of the female breast to ionizing radiation in infancy increases the risk of breast cancer later in life.",0
818,2797101,Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis,"The increasing use of mammography to screen asymptomatic women makes it important to know the risk of breast cancer associated with exposure to low levels of ionizing radiation. We examined the mortality from breast cancer in a cohort of 31,710 women who had been treated for tuberculosis at Canadian sanatoriums between 1930 and 1952. A substantial proportion (26.4 percent) had received radiation doses to the breast of 10 cGy or more from repeated fluoroscopic examinations during therapeutic pneumothoraxes. Women exposed to greater than or equal to 10 cGy of radiation had a relative risk of death from breast cancer of 1.36, as compared with those exposed to less than 10 cGy (95 percent confidence interval, 1.11 to 1.67; P = 0.001). The data were most consistent with a linear dose-response relation. The risk was greatest among women who had been exposed to radiation when they were between 10 and 14 years of age; they had a relative risk of 4.5 per gray, and an additive risk of 6.1 per 10(4) person-years per gray. With increasing age at first exposure, there was substantially less excess risk, and the radiation effect appeared to peak approximately 25 to 34 years after the first exposure. Our additive model for lifetime risk predicts that exposure to 1 cGy at the age of 40 increases the number of deaths from breast cancer by 42 per million women. We conclude that the risk of breast cancer associated with radiation decreases sharply with increasing age at exposure and that even a small benefit to women of screening mammography would outweigh any possible risk of radiation-induced breast cancer.",0
819,2811958,The effect on serum cholesterol levels of coffee brewed by filtering or boiling,"Previous reports have indicated that coffee consumption may increase serum cholesterol levels. We studied the effects of coffee prepared by two common brewing methods (filtering and boiling) on serum lipid levels in a 12-week randomized trial involving 107 young adult subjects with normal serum cholesterol levels. After a three-week run-in period during which they all consumed filtered coffee, the participants were randomly assigned to one of three groups receiving four to six cups of boiled coffee a day, four to six cups of filtered coffee a day, or no coffee, for a period of nine weeks. As compared with the change from base line in the filtered-coffee group, the serum total cholesterol level increased after the consumption of boiled coffee by 0.48 mmol per liter (95 percent confidence limits, 0.13 and 0.83), and the low-density lipoprotein cholesterol level increased by 0.39 mmol per liter (95 percent confidence limits, -0.04 and 0.82). There was no significant difference in the change in serum total or low-density lipoprotein cholesterol levels between the filtered-coffee group and the group that drank no coffee. The levels of high-density lipoprotein cholesterol and apolipoproteins were not affected by boiled or filtered coffee. We conclude that drinking filtered coffee does not affect serum lipid levels. The consumption of boiled coffee, however, has an effect on serum cholesterol levels amounting to a mean net increase of 10 percent of the base-line level after nine weeks.",0
820,2811959,A cluster of HIV infection among heterosexual people without apparent risk factors,"Human immunodeficiency syndrome (HIV) epidemiology in Belgium shows that 66% of all acquired immunodeficiency syndrome patients were infected heterosexually. Since 1985, all HIV-seropositive patients in Brussels and Antwerp who have been heterosexually infected have been offered participation in a partner notification program; this article reports the case study of 1 HIV infected male and his 19 identified previous women sexual partners. This report describes the patient's background and the type and frequency of sexual intercourse he had with each partner. The characteristics of each of the sexual partners were also described. An important consideration of this case was that 11 of the tested partners (56%) were HIV seropositive. Several factors were discussed concerning the cause of this high rate of transmission (e.g. high disseminator patient, highly virulent HIV strain, and presence of genital herpes). This study emphasizes the fact that middle class women with low risk sexual practices were infected with AIDS from as little as 1 sexual encounter with this infected individual. To stop a false sense of security among people with few sexual partners, it was advised that a program of partner notification targeted to heterosexuals be implemented along with other public health policies.",0
821,2814544,Are we missing portal vein thrombosis?,"We report a case of portal vein thrombosis which was misdiagnosed as tropical splenomegaly syndrome. This is the first documented case confirmed radiologically at Universiti Hospital, Kuala Lumpur. A discussion on the management of portal vein thrombosis is also described. ",0
822,2814673,Circulating immune complexes in malignant tumors],"Circulating immune complexes are detectable in the patients with carcinomas of the head and neck, stomach, rectum, external genitals, lungs, with Hodgkin's disease, and melanomas. Immunoglobulin levels are abnormal in all the aforementioned conditions. The levels of IgG, IgA, and IgM differ in the patients with high and normal content of immune complexes. IgG elevation is more manifest in the presence of immune complexes. In pulmonary carcinoma, cancer of the head and neck, and Hodgkin's disease the concentrations of immune complexes and IgG correlate. Relationships between the rest immunoglobulin classes and the immune complexes are not so well specified. ",0
823,2815156,Characterization of steroid hormone association with human plasma lipoproteins,"""Partition coefficient analysis, equilibrium dialysis, and computer simulation were used to evaluate associations of twelve steroid hormones (androstanediol, androstenediol, androstenedione, androsterone, dehydroepiandrosterone, dihydrotestosterone, estradiol, estriol, estrone, hydroxyprogesterone, progesterone, and testosterone) with human plasma high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL). It was determined that partitioning of steroid hormones (SH) between the aqueous medium and the surfaces of lipoproteins (LP) was the initial (first order) SH-LP interaction. For some SH, especially dehydroepiandrosterone, significant second order interactions, which may involve chemical conversions, were detected. The first order binding values of the twelve SH with three LP were combined with the corresponding binding values of SH with sex hormone-binding globulin, corticosteroid-binding globulin, and albumin in a 6 X 12 matrix. The computer program TRANSPORT was used to analyze the matrix and determine the distribution of each SH among six different binding agents in the """"normal"""" male. It was concluded that LP are important vehicles for SH conveyance in plasma and may also be important for SH entry into cells. """,0
824,2815825,Effects of trans-sobrerol on drug metabolizing enzymes in the rat,"1. Metabolism of 14C-trans-sobrerol (I) by Sprague-Dawley rat liver microsomes did not result in covalent binding to proteins, lipid peroxidation or cytochrome P-450 destruction. 2. Subacute and chronic treatment of Sprague-Dawley rats with (I) resulted only in an increase in liver cytosolic GSH-S-transferase. 3. Acute treatment of rats with trans-sobrerol or its metabolite, 8-hydroxycarvotanacetone (II) produced considerable GSH depletion, faster in the case of II, in both liver and lung; the original GSH levels were restored within 24 h. No significant increase in lipid peroxidation was found even when GSH was at its lowest level. 4. UDP-glucuronyltransferase and GSH-S-transferase conjugation occurred with trans-sobrerol and some of its metabolites although at low rates. ",0
825,2815915,Resection of a cardiac rhabdomyoma of the right and left ventricular outflow tract],"Rhabdomyomas are benign cardiac tumors often occurring as multiple lesions. We describe an infant with multiple cardiac rhabdomyomas causing severe right-ventricular and left-ventricular outflow tract obstructions. The intracavitary parts of the rhabdomyomas were successfully resected when the patient was 5 weeks old. Echocardiography showed regression in size of the remaining intramural tumors. Since there is only a low growth potential in cardiac rhabdomyomas, surgical management is indicated only in patients with hemodynamic obstruction or significant arrhythmias. Surgery should be primarily directed to relieve hemodynamic obstruction. If complete resection is not possible without damage to vital structures, resection should be restricted to the intracavitary parts of the tumor. ",0
826,2816169,Manifestation of sarcoidosis of the optic nerve],"Under the suspicion of an optic nerve glioma a resection of the optic nerve tumour was carried out in a 58-year-old female patient with an amaurosis on the right side. The diagnosis of the sarcoidosis of the Nervus opticus was only established on the basis of the histological findings obtained in the resected optic nerve. Even after a period of observation of five years no further general pathologic signs of the sarcoidosis appeared, so that it could be assumed that this was the case of an isolated sarcoid affection of the optic nerve. ",0
827,2816238,Displacement of warfarin from human serum proteins by halothane anaesthesia,"The in vitro effects of the halothane metabolite, trifluoroacetic acid, on the binding of warfarin to human serum proteins have been investigated. An increase in the percentage of free warfarin following incubation with different concentrations of trifluoroacetic acid (1 and 4 mmol/l) was observed. In addition, protein binding of warfarin was studied in serum from patients undergoing halothane anaesthesia (1-2.5%; 2.5 h). After 24 h from the end of the halothane anaesthesia, an increase in the percentage of free warfarin was also detected (0.92 +/- 0.06% at 24 h vs 0.60 +/- 0.02% before halothane administration; P less than 0.005). We conclude that halothane anaesthesia may temporarily potentiate the pharmacological effect of warfarin in the postoperative period following anaesthetic procedures. ",0
828,2816239,Isoflurane or halothane for cesarean section: comparative maternal and neonatal effects,"The maternal and neonatal effects of isoflurane and halothane combined with 50% N2O - 50% O2 were compared in 60 healthy parturients undergoing primary or repeat cesarean section. All patients had rapid sequence induction of anesthesia with sodium thiamylal 4 mg/kg followed by succinylcholine for tracheal intubation. Patients were randomly assigned to one of three groups of 20 each (inspired 0.5% isoflurane, 1% isoflurane or 0.5% halothane), combined with 50% N2O and O2. After delivery, 67% N2O in O2 was used, supplemented by butorphanol. Maternal blood loss did not differ significantly among the three groups and none of the patients developed intraoperative awareness. At the time of delivery, maternal plasma epinephrine levels were significantly above preinduction levels in the 0.5% isoflurane group but unchanged in the other two groups. Neonatal status as ascertained by Apgar scores, cord acid base status and the Neurologic and Adaptive Capacity Scores (NACS) was equally good in the three groups of patients. Serum inorganic fluoride concentrations in the mother after anesthesia were not significantly above preanesthetic levels in any of the groups and there was no biochemical evidence of renal toxicity. In all neonates fluoride ion concentrations in the first voided urine sample were less than 7 mumol/l, a value well below that associated with nephrotoxicity. It is concluded that isoflurane is a safe supplement to N2O - O2 mixture for cesarean section and is a safer alternative to halothane in situations when patients receiving beta-adrenergic therapy require cesarean section since halothane might potentiate arrhythmias caused by beta adrenergic agonists. ",0
829,2816365,Involution of lymph node histiocytes in AIDS,"Lymph nodes of human immunodeficiency virus (HIV)-infected patients were studied histologically and immunohistochemically to elucidate the pattern of involution of various histiocytes in AIDS. Specimens consisted of one node with hyperplasia, five with atrophy, and three with severe atrophy. Antibodies such as L25, ID1, My4, 12, anti-Leu 3a, KiM4, OKT6 and anti-S100 protein were used for identification of the histocytes. Another antibody, VAK5, was used to demonstrate HIV antigen. T-zone histiocytes were mildly decreased in the hyperplastic node, but considerably decreased in the atrophic nodes. My4+ sinus histiocytes were unchanged in number and enlarged in the hyperplastic node, but not decreased in the atrophic nodes. Follicular dendritic cells (FDCs), defined by KiM4, were mostly depleted in the atrophic nodes. The T4 antigen was detected in some of the sinus histiocytes of the atrophic nodes. T6-positive cells were not found in any of the nodes. HIV antigen was detected only in FDCs. It is therefore suggested that various histiocytes respond differently to HIV, and that T-zone histiocytes and sinus histiocytes persist up to the late stage of AIDS. ",0
830,2816517,"Effects of transforming growth factor alpha and interleukin-1 on DNA synthesis, collagen synthesis, procollagen mRNA levels, and prostaglandin E2 production in cultured fetal rat calvaria","Transforming growth factor alpha (TGF-alpha) and interleukin-1 (IL-1) have been shown to affect bone metabolism in vitro by prostaglandin-dependent and PG-independent mechanisms. We assessed the effects of the combination of these two agents on [3H]thymidine (TdR) incorporation into DNA, DNA content, [3H]proline incorporation into collagenase-digestible (CDP), noncollagen protein (NCP), and PGE2 production in 21 day fetal rat calvaria cultured for 24-96 h. We also determined whether TGF-alpha plus IL-1 altered procollagen mRNA levels at 96 h. TGF-alpha, 1-30 ng/ml, produced a 41-59% increase in TdR incorporation into DNA, but the effect was partially blocked by human recombinant IL-1. At 96 h TGF-alpha alone or in combination with IL-1 significantly increased the DNA content of calvaria. At 96 h, TGF-alpha inhibited CDP labeling and the addition of IL-1 further enhanced this inhibitory effect. The enhanced inhibitory effect of TGF-alpha plus IL-1 on collagen synthesis was associated with a synergistic increase in prostaglandin accumulation in the medium. Addition of indomethacin blocked PGE2 accumulation and partially reversed the inhibitory effect of TGF-alpha alone or in combination with IL-1 on collagen synthesis. TGF-alpha decreased procollagen mRNA levels by 55%, but the combination of TGF-alpha plus IL-1 decreased procollagen mRNA levels by 82%. Our results show that TGF-alpha and IL-1, which are both produced by certain tumors as well as activated macrophages, appear to act synergistically to increase prostaglandin synthesis and inhibit collagen synthesis in vitro. Thus these agents may have a regulatory role on bone formation in vivo. ",0
831,2816560,"Sports injuries in elderly athletes: a three-year prospective, controlled study","A 3-year prospective, controlled study of sports injuries in elderly athletes (over 60 years of age) treated at an outpatient sports clinic was carried out in order to determine the number, profile, and specific features of these injuries compared with those of young athletes (between 21 and 25 years). During the study period, 57 elderly and 457 young adult athletes visited the clinic. The majority of the patients in both groups were male (83% of the veterans and 85% of the young). Forty-eight veterans (84%) were endurance sportsmen, while only 115 of the young patients (25%) went in for endurance sports. In both groups the knee joint was most frequently affected, in the young athletes (36%) more frequently than in the elderly (21%). In the elderly athletes shoulder (18%) as well as Achilles tendon and calf (20%) complaints were significantly more common than among young athletes (7% and 5%, respectively). Most (70%) of the injuries in the elderly were overuse injuries, but these comprised only 41% in the young. ",0
832,2816859,Aminoglycoside ototoxicity in cystic fibrosis. Evaluation by high-frequency audiometry,"In this study, we sought to determine the clinical usefulness of high-frequency audiometry (8000 to 20,000 Hz) in detecting aminoglycoside-induced increases in pure-tone hearing thresholds before they are noticed in conventionally tested frequencies. We measured hearing thresholds from 250 to 20,000 Hz in 22 patients with cystic fibrosis who were treated with aminoglycosides. The audiograms were age-matched and were compared with those from 13 patients with cystic fibrosis and 38 subjects without cystic fibrosis, all of whom had never received aminoglycoside therapy. In patients with cystic fibrosis who were treated with aminoglycosides (younger than 20 years), there were statistically significant elevations only in frequencies higher than 16,000 Hz. Patients with cystic fibrosis who were treated with aminoglycosides who were 20 years and older had elevated thresholds in all frequencies tested. Patients with cystic fibrosis who were not treated with aminoglycosides did not differ statistically from controls. High-frequency audiometry may serve as a useful measure of elevation in pure-tone hearing thresholds that precede noticeable loss of auditory acuity in patients with cystic fibrosis who are receiving long-term aminoglycoside therapy. ",0
833,2817085,Prognostic value of the immunocytochemical detection of extramural venous invasion in Dukes' C colorectal adenocarcinomas. A preliminary study,"In postsurgical staging of colorectal adenocarcinomas, it is sometimes difficult to determine the range of possible venous spread. Distinguishing between the extramural veins (especially when the neoplastic embolus takes up the whole lumen and the endothelium cannot be identified) and the smallest extramural lymph nodes (when they are completely replaced by metastatic carcinoma, leaving the capsule alone) is also difficult. This work proposes a more precise definition of true venous invasion to improve histopathologic staging. Immunohistochemical techniques employing commercial antibodies against Factor VIII RAG, with and without enzymatic digestion, and UEA I lectin for residual endothelium detection, were applied, as well as antibodies against vimentin, desmin, and alpha sm-1 actin to detect wall components. The immunohistochemical evaluation of colorectal adenocarcinomas, in particular by anti-alpha sm-1 actin antibodies, permitted a reliable morphologic distinction of the true venous invasion. This factor proved to be relevant for survival rate prediction. ",0
834,2817241,Effects of isoflurane on intracranial pressure and cerebral blood flow pressure in coma patients at neurologic intensive care units. Apropos of 12 cases],"Twelve comatose patients treated in a neurological intensive care unit have been given oxygen - Isoflurane gas inhalation to study the effect on Intra Cranial Pressure (I.C.P.) while undergoing tracheal suction. Raised I.C.P. decrease while one per cent Isoflurane is given during suction; but when Isoflurane is introduced especially on higher intracerebral pressure patients (greater than 37 kPa-20 mmHg) cerebral perfusion pressure decrease without change in I.C.P. and this result is correlated to blood pressure fall. Cerebral blood flow has not been measured while Isoflurane was given; other similar studies give different results. Considering these results, Isoflurane must be used carefully and cautiously on suspected elevated I.C.P. patients or patients with hypovolemia or hypertension. ",0
835,2817893,Sugar sequences of allergenically active oligosaccharide alcohols isolated from a large-molecular-size sea squirt antigen termed H-antigen,"O-Glycosidically linked oligosaccharide chains were liberated as oligosaccharide alcohols (HPG-beta 2) by beta-elimination treatment from a glycopeptide fraction (HPG, Mr ca. 10(5)) that was isolated from a Pronase digest of a large-size sea squirt antigen termed H-antigen (Mr 10(6)-2 X 10(7)). After HPG-beta 2 was divided into a neutral (HPG-beta 2-N) and an acidic (HPG-beta 2-A) fraction, 11 neutral saccharitols were isolated from HPG-beta 2-N, and their sugar sequences were determined by methylation/GC-MS, FAB-MS, and/or DI/EI-MS. By skin tests specific to patients with sea squirt allergy, it was found that six saccharitols were allergenically active but five were inactive. Furthermore, active saccharitols were all of branched structure containing two nonreducing terminal GalNAc (t-GalNAc) residues, whereas the inactive saccharitols contained one or no t-GalNAc. Since the allergic reaction in skin should depend on the crosslinking of IgE antibodies by certain allergens carrying two or more epitopes, three types of N-acetylgalactosaminyl disaccharide units, GalNAc1----2Fuc1----, GalNAc1----3/4GalNAc1----, and GalNAc1----3/4GlcNAc1----, were nominated as the major components of the allergy-specific epitopes in the active saccharitols. Such multiplicity of the epitope structures might reflect the polyclonality of the specific IgE antibodies. ",0
836,2818593,Vascular relaxation mediated by hydroxylamines and oximes: their conversion to nitrites and mechanism of endothelium dependent vascular relaxation,"Hydroxylamines (R-NHOH) and oximes (R = NOH) relax rat aortic rings independent of the presence of the endothelium. The relaxation is inhibited by methylene blue, an inhibitor of soluble guanylate cyclase and by hemoglobin, an inhibitor of the endothelium dependent relaxing factor (EDRF). Both the oximes and hydroxylamines generate NO/NO2- ions on treatment with iodine in glacial acetic acid. However, there is no correlation between relaxation and NO/NO2- formation. Compared to hydroxylamines, the oximes are less potent relaxing agents and not efficiently converted to NO/NO2- ions. We suggest that endothelium dependent relaxation is associated with a hydroxylamine like compound and is not directly related to NO. ",0
837,2818708,Fatal and major complications secondary to nasal and sinus surgery,"The purpose of this study was to review 40 major or fatal complications secondary to nasal and sinus surgery that were referred to the author for consultation or other reasons. The most frequent complications were intracranial, which occurred in 13 cases, and resulted in four deaths. Blindness occurred in ten patients (two bilaterally). Three other fatalities resulted from internal carotid artery damage. Three patients died of anesthesia-related problems and one survived malignant hyperthermia. In all, ten patients died as a result of intracranial catastrophe, hemorrhage, or general anesthesia complications. Although some complications are preventable, others may be unavoidable, even in the hands of well-trained, experienced surgeons. ",0
838,2819025,"The effect of combined dietary iron, calcium and folic acid supplementation on apparent 65Zn absorption and zinc status in pregnant rats","In the present study the effect of combined iron, calcium and folic acid supplementation of the diet on 65Zn retention and zinc status was studied in the pregnant rat. Female Wistar rats were fed on a low- (8 micrograms/g) or high- (60 micrograms/g) Zn diet for 14 d and then mated overnight. After mating, half the rats were fed on the low- or high-Zn diet as before, whilst the other half were fed on similar diets supplemented with Fe, Ca and folic acid. The level of supplementation was chosen to reflect proportionately the possible increase in daily intakes of these nutrients by pregnant women. Rats which did not mate successfully were used as non-pregnant controls. On day 18 of pregnancy, each animal was given a meal of the appropriate diet labelled extrinsically with 65Zn, and on day 20 rats were killed. Carcass 65Zn retention was lower in pregnant and non-pregnant rats fed on the supplemented diets compared with those fed on the unsupplemented diets. Rats which consumed the supplemented diets throughout pregnancy had reduced plasma Zn concentrations but femur and fetal Zn concentrations were unaffected. Maternal femur Ca and fetal Fe concentrations were lower in the high-Zn groups compared with rats fed on low-Zn diets. It was concluded that the risk of inducing fetal Zn depletion as a consequence of Fe, Ca and folic acid supplementation during pregnancy appeared to be slight.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
839,2819066,Distamycin paradoxically stimulates the copying of oligo(dA).poly(dT) by DNA polymerases,"Distamycin A, a polypeptide antibiotic, binds to dA.dT-rich regions in the minor groove of B-DNA. By virtue of its nonintercalating binding, distamycin acts as a potent inhibitor of the synthesis of DNA both in vivo and in vitro. Here we report that distamycin paradoxically stimulates Escherichia coli DNA polymerase I (pol I), its large (Klenow) fragment, and bacteriophage T4 DNA polymerase to copy oligo(dA).poly(dT) in vitro. It is found that distamycin increases the maximum velocity (Vmax) of the extension of the oligo(dA) primer by pol I without affecting the Michaelis constant (Km) of the primer. Gel electrophoresis of the extended primer indicates that the antibiotic specifically increases the rate of addition of the first three dAMP residues. Lastly, in the presence of both distamycin and the oligo(dT)-binding protein factor D, which increases the processivity of pol I, a synergistic stimulation of polymerization is attained. Taken together, these results suggest that distamycin stimulates synthesis by increasing the rate of initiation of oligo(dA) extension. The stimulatory effect of distamycin is inversely related to the stability of the primer-template complex. Thus, maximum stimulation is exerted at elevated temperatures and with shorter oligo(dA) primers. That distamycin increases the thermal stability of [32P](dA)9.poly(dT) is directly demonstrated by electrophoretic separation of the hybrid from dissociated [32P](dA)9 primer. It is proposed that by binding to the short primer-template duplex, distamycin stabilizes the oligo(dA).poly(dT) complex and, therefore, increases the rate of productive initiations of synthesis at the primer terminus. ",0
840,2819316,"Head injury, an empirical study: describing long-term productivity and independent living outcome","As part of larger, multivariate study to be reported later, the present research gathered data from a knowledgeable informant, via telephone, concerning productivity and independent living outcomes for 75 subjects who sustained varying degrees of head injury, 4-7 years prior to the follow-up. The severity of the injury was measured using the Glasgow Coma Scale. Eighteen subjects had a severe injury, 24 had a moderate injury and 33 had a mild injury. The outcomes researched included indices of the subjects' ability to live independently and to be productive. In general, the data indicate that the more severe the injury, as measured by the best GCS during the first 24 hours, the more dependent and less productive the subject was at follow-up. This, however, was not invariably the case. Several mildly injured subjects had poor outcomes, while several severely injured subjects had relatively good outcomes at follow-up. ",0
841,2819322,The mode of action of caffeine on catecholamine release from perfused adrenal glands of cat,"1 Adrenaline and noradrenaline secretion induced by caffeine was investigated in the perfused cat adrenal glands. 2 Caffeine (10-80 mM) caused a dose-dependent increase in both adrenaline and noradrenaline secretion when applied for 1 min and 10 min after replacing Ca2+ with 10(-5)M EGTA in the perfusion solution. The ratio of adrenaline to noradrenaline was about 1:1. Mg2+ and/or Ca2+ inhibited the response to caffeine. 3 When caffeine (40 mM) was repeatedly applied in the absence of extracellular Ca2+, the secretory response almost disappeared but only at the second challenge with caffeine. However, the response was partially restored after readmission of Ca2+ (2.2 mM) and was augmented after the readmission of Ca2+ with ouabain (10(-5) M). 4 Caffeine-induced secretion of adrenaline and noradrenaline increased with the increase in the preloaded concentration of Ca2+ and attained a maximum at 16 mM Ca2+. 5 During perfusion with Ca2+-free Locke solution containing hexamethonium (10(-3)M), acetylcholine (10(-4)M) caused increases in both adrenaline and noradrenaline secretions with a ratio of about 1:2. The secretory responses were partially inhibited by preceding stimulation with exposure to caffeine (80 mM). 6 These results suggest that caffeine mobilizes Ca2+ from an intracellular storage site that may not be entirely the same as that linked to muscarinic receptors, and causes an increase in both adrenaline and noradrenaline secretion from cat adrenal chromaffin cells. ",0
842,2819333,The influence of amine metabolizing enzymes on the pharmacology of tyramine in the isolated perfused mesenteric arterial bed of the rat,"1. The pressor response to the infusion of tyramine (Tyr) into the isolated perfused mesenteric arterial bed of the rat has been studied at both a low and a high dose (0.2 and 2.0 mumol) and the effect of monoamine oxidase-A (MAO-A) and semicarbazide-sensitive amine oxidase (SSAO) inhibition was examined. Very little MAO-B activity is found in homogenates of this tissue when Tyr is used as substrate. 2. Inhibition of SSAO by treating rats with 1 mg kg-1 (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroally lamine (MDL 72145) 1 h before dissection, had no significant effect on the maximum pressure attained or the area under the curve (AUC) of the response to both low and high doses of Tyr. Inhibition of MAO-A, by inclusion of 10 microM clorgyline in the perfusing fluid, resulted in no significant potentiation at both low or high doses of Tyr. The inhibition of both these enzymes together substantially increased the AUC of the pressor response. 3. Cocaine (3 microM) significantly potentiated the responses to adrenaline (Ad). At this dose, cocaine significantly reduced the peak height and the AUC of the responses to both doses of Tyr. 4. Inhibition of extraneuronal uptake mechanisms with corticosterone (29 microM) did not potentiate the response to Ad and did not significantly alter the response to Tyr (low dose). 5. The effects of MDL 72145 and clorgyline on the directly acting amine, Ad, were studied. MDL 72145 caused a small but significant increase in the EC50 and in the maximum response to Ad, whilst clorgyline (10 microM) increased the EC50 value slightly and decreased the maximum response. ",0
843,2819919,Baclofen disrupts passive avoidance retention in rats,"Baclofen (Lioresal, Ciba-Geigy) is an analog of the inhibitory neurotransmitter GABA and is used clinically to control spasticity. Recent studies have demonstrated that this compound produces a marked inhibition of synaptically evoked responses in area CA3 of the hippocampal slice, suggesting that this drug could influence behavior mediated by the limbic system. In the present study, male rats of the Fischer-344 strain were trained on a one-trial passive avoidance task and tested for retention 1 week later. After the training trial, separate groups of rats received either 5 or 10 mg/kg/4 ml IP of baclofen or the distilled H2O vehicle immediately, 10 min, or 60 min after training. One week later, the rats that received baclofen immediately after training reentered the test chamber with a significantly higher frequency than controls, although no differences in vacillatory responses were observed between groups. Similar effects were observed following posttrial administration of chlordiazepoxide. In a separate experiment rats were tested for locomotor activity after receiving the same doses of baclofen. Although baclofen decreased activity during a 30-min period after dosing, rats exposed to baclofen showed no significant change in activity relative to controls 1 week later. These data are consistent with the interpretation that baclofen may interfere with memory consolidation or retention. ",0
844,2820449,Lung cancer in males and type of dwelling. An epidemiologic pilot study,"Data from a large case-control study of male lung cancer in northern Sweden were used for a pilot study concerning possible association between type of dwelling (indoor radon) and lung cancer. The study illustrated the possibilities of retrospective assessment of building type and confounding factors of importance as smoking and occupation and can therefore have methodologic value for further investigations. The study suggested that, within the region, increased indoor radon due to building material was not an important cause of lung cancer. Leakage of radon from the ground could, however, not be considered in the present study and the used radon measure was very crude (years in non-wooden houses). ",0
845,2820689,The galactose-specific receptor system in rat liver during development,"The number and distribution of galactose-specific binding sites were investigated in rat liver cells during perinatal development. Ligand binding to hepatocytes, macrophages and endothelial cells was followed with in vitro and in situ experiments by electron microscopy, using lactosylated bovine serum albumin adsorbed onto 5 nm colloidal gold particles as ligand. Binding capacity, starting at a late stage of fetal development, is very low both on the hepatocyte and on the macrophage surface, which show single particles statistically distributed. By contrast, bound particles are absent from fetal endothelial cells, which also lack the typical coated regions. In vivo, experiments at 37 degrees C show that endocytosis occurs to some extent in prenatal life. These results indicate that the expression of galactose-specific receptors' activity on the different liver cell types follows different developmental patterns, which are independently modulated. ",0
846,2821541,Molecular cloning and amino acid sequence of leukotriene A4 hydrolase,"A cDNA clone corresponding to leukotriene A4 hydrolase was isolated from a human lung lambda gt11 expression library by immunoscreening with a polyclonal antiserum. Several additional clones from human lung and placenta cDNA lambda g11 libraries were obtained by plaque hybridization with the 32P-labeled lung cDNA clone. One of these clones has an insert of 1910 base pairs that contains the complete protein-coding region. From the deduced primary structure, leukotriene A4 hydrolase is a 610 amino and protein with a calculated molecular weight of 69,140. No apparent homologies with microsomal epoxide hydrolases were found. RNA blot analysis indicated substantial amounts of a discrete mRNA of approximately equal to 2250 nucleotides in lung tissue and leukocytes. ",0
847,2822506,The response of adenylate cyclase to ACTH in adipocyte membranes of lean and obese mice,"The response of adenylate cyclase to ACTH was examined in adipocyte membranes of lean (+/+) and obese (ob/ob) mice. The data show that the enzyme is more responsive to ACTH in membranes from obese than from lean mice. This is in contrast with the lower responsiveness of adenylate cyclase to catecholamines in the tissue of the obese than the lean mouse. In the obese, adrenalectomy completely abolished the response of cyclase to ACTH and in the lean, corticosterone supplementation augmented the ACTH response. These results show that glucocorticoids play an important role in the activation of adipocyte adenylate cyclase by ACTH and that the heightened response in the obese mouse adipocyte is related to hypercorticoidism. The results further establish that neither the hypercorticoidism nor the hyperinsulinism of the obese mouse is responsible for the impaired response of the adipocyte membranes to catecholamines, since adrenalectomy which corrected both hormonal excesses did not restore the adenylate cyclase response to isoproterenol. ",0
848,2822559,"Biological actions of peptide YY: effects on endocrine pancreas, pituitary-adrenal axis, and plasma catecholamine concentrations in the dog","The present study was designed to gather information on the biological activity of peptide YY (PYY) in conscious dogs. PYY was infused intravenously at a dose of 238 pmol/kg X h, and plasma concentrations of glucose, insulin, pancreatic polypeptide (PP), ACTH, cortisol and catecholamines (norepinephrine-NE; epinephrine-E; dopamine-DA) were subsequently measured. PYY significantly increased plasma insulin levels transiently without effect on plasma glucose, but decreased plasma PP levels during all infusion periods. PYY stimulated both plasma ACTH and cortisol secretion, and this action of PYY was also shared by PP, with PP being less potent in ACTH-cortisol release. PYY further elicited specific changes in plasma catecholamine concentrations, i.e. an increase of NE but not of E, which were in contrast to the effects of insulin-induced hypoglycemia. PP failed to alter plasma insulin and catecholamine concentrations. These results suggest that PYY can affect anterior pituitary hormone secretion, sympathetic nervous outflow and pancreatic endocrine activity in addition to its known actions on gastric and pancreatic secretion in the dog. ",0
849,2822795,"Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man","Both Adrenocorticotrophin (ACTH) and glucocorticoids raise blood pressure in man and animals, but the relationship of this and altered renal function to other cardiovascular variables, and the differences and similarities of the effects of the two agonists have not been fully explained. The present study compares the effects of ACTH (0.5 mg i.m; every 12 h) and cortisol (50 mg orally, every 6 h) in six normal men over a period of 5 days, preceded and followed by control periods of 3 and 2 days, respectively. Plasma cortisol levels were higher during ACTH treatment than during cortisol treatment. Both treatments raised blood pressure significantly and caused a marked antinatriuresis and expansion of extracellular fluid and plasma volume. ACTH also enhanced potassium excretion but this was less obvious for cortisol. Plasma concentrations of atrial natriuretic peptide rose to more than twice the basal level with both treatments. Both treatments markedly altered renal function. They raised glomerular filtration rate (GFR), i.e. inulin clearance (141% with ACTH; 113% with cortisol) although creatinine clearance was not changed, showing this to be an unreliable index during steroid administration. Filtration fraction (FF) also increased during both treatments, and renal blood flow (RBF) fell, although this achieved statistical significance only during cortisol treatment. Effective renal plasma flow [para-amino hippurate (PAH) clearance] remained unchanged while calculated renal vascular resistance increased. Fractional sodium reabsorption also rose but achieved statistical significance only during ACTH treatment. The similarity of response to treatment suggests that cortisol is largely responsible for the effects of ACTH.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
850,2822917,Nonmetastatic gestational trophoblastic neoplasia. Controversies in definition and management,"The difficulties with the current definition of nonmetastatic gestational trophoblastic neoplasia are discussed in relation to the evaluation of length of time, amount of human chorionic gonadotropin elevation and histologic criteria used to make the diagnosis. Evaluation of the patient is described, and the effect of more-sophisticated methods of investigation on staging and on therapy is placed in perspective. More-effective, less-toxic and more-efficient chemotherapy delivery systems are available today. ",0
851,2823598,Cardiorespiratory patterns in viral septicemia,"Viral infections are known to produce hypotension and shock, but the cardiorespiratory patterns associated with viral septic shock have not been described. The clinical course of nine patients who died from overwhelming cytomegalovirus sepsis was reviewed. Viral septicemia was associated with increased cardiac index, decreased systemic vascular resistance index (SVRI), and elevated oxygen delivery. This pattern appeared during early and late stages of shock. In contrast to bacterial sepsis and endotoxemia, the pulmonary vascular resistance index (PVRI) was normal. These results indicate that overwhelming viral infection can produce shock associated with a high cardiac output, low peripheral resistance state similar to that seen with bacterial shock. Relative sparing of the pulmonary circulation in viral shock is consistent with the absence of endotoxemia in these patients. ",0
852,2823722,The changes in serum neuron-specific enolase in patients with small cell lung cancer],"Serum neuron-specific enolase (NSE) was measured in 48 newly diagnosed untreated patients with small cell lung cancer (SCLC) by radioimmunoassay. Serum NSE level elevated (greater than or equal to 15 ng/ml) in 50% of all patients. The positive ratio of NSE in patients with extensive disease (64%) was significantly higher than those in the patients with limited disease (30%) (p less than 0.05). The positive ratio of NSE in the patients with one metastatic site was 50%, that with two or more metastatic sites was 100% (p less than 0.05). No significant correlation was found between serum NSE levels and metastatic site as well as between serum NSE levels and response to the chemotherapy. In the patients with extensive disease, survival time was shorter in the patients with positive NSE levels than the patients with normal NSE levels. These findings indicate that serum NSE may be a useful marker for staging, monitoring and prognosis in patients with SCLC. ",0
853,2823743,Identification of patients at high risk for local recurrence after conservative surgery and radiation therapy for stage I or II breast cancer,"The extent of excision prior to radiation for breast cancer is controversial. Three hundred evaluable patients with invasive ductal carcinoma received radiation therapy after gross tumor excision. The median follow-up was 70 months. Local recurrence was related to the presence of an extensive intraductal component (EIC) in addition to the invasive ductal carcinoma. From operative notes and pathology reports, patients with an EIC were categorized as having discrete masses with the extent of disease confirmed histologically or as having one of five criteria in which the final pathologic findings revealed more intraductal disease than was evident grossly or by frozen section. After ten years of follow-up, the local failure rate of patients without an EIC (193) was 3% compared with 35% for those with an EIC (107). Eight-year recurrence rates were 18% for clearly defined tumors and 71% for tumors in which the intraductal component was detectable only histologically. ",0
854,2823800,Genetic characterization of an Escherichia coli mutant deficient in organophosphonate biodegradation,"An E. coli mutant deficient in organophosphonate biodegradation has been complemented with a cosmid library prepared from a BamHI partial digest of wild-type E. coli W3110. Mutant E. coli SL724, when transformed with cosmid pSL163 and plasmid pSL263, regained the ability to exploit ethylphosphonate as a sole source of phosphorus during growth. In route to complementation, the Tn5 insert of SL724 was subcloned and restriction enzyme mapped. Complementing pSL163 and pSL263 were also characterized via restriction enzyme digests. ",0
855,2823941,Regulation of erythropoietin production in a human hepatoblastoma cell line,"Production of immuno and biologically active erythropoietin was documented to occur in the human hepatoblastoma cell line HepG-2. The expression of the erythropoietin gene was further verified by Northern blot analysis using a single stranded RNA probe. In vitro studies showed that erythropoietin production by these cells was not stimulated by hypoxia or cobalt chloride, but was related to the proliferative activity of the cells in culture. In addition it was found that the secretion of erythropoietin was almost completely abrogated by tunicamycin, an inhibitor of N-linked glycosylation. This effect of tunicamycin was also observed in a permanently transfected cell line that secretes erythropoietin in large quantities. ",0
856,2823982,The reciprocal electrophysiological influence between the nucleus tegmenti pedunculopontinus and the substantia nigra in normal and decorticated rats,"The electrophysiological characteristics of neurons of the nucleus tegmenti pedunculopontinus (PPN), in particular of those projecting to the substantia nigra (SN), and the reciprocal influence between the PPN and SN were investigated in normal and decorticated rats. In intact animals 65 of the 363 PPN recorded neurons (17.9%) were activated antidromically by SN stimulation, 96 (26.3%) were inhibited after stimulation while 43 (11.8%) were activated. In decorticated rats excitatory responses were decreased (4.8%) while antidromic and inhibitory responses did not change substantially. Electrical stimulation of the PPN induced a brief short-latency excitation of SN neurons (26/77, 33.7%) which was not modified by removing the cortex bilaterally 7-10 days prior to the recording session. This excluded the possibility that corticofugal fibers could be involved in the excitatory responses evoked by PPN stimulation in SN neurons. The latency of the antidromic response evoked in PPN cells by SN stimulation ranged from 0.5 to 12.0 ms and the estimated conduction velocity of these PPN output neurons ranged from 1.1 to less than 0.5 m/s. The electrophysiological heterogeneity of PPN cells was supported also by the fact that two types of neurons, both projecting to the SN, could be distinguished on the basis of their spontaneous firing rate and impulse waveform. The first had a low spontaneous activity (0.5-8 spikes/s) with a triphasic impulse which lasted 3-4 ms. The second had a high firing rate (15-20 spikes/s) and its impulse was usually biphasic and not longer than 3 ms.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
857,2824006,Enhanced sensitivity to beta-carboline inverse agonists in rats chronically treated with FG 7142,"The biochemical and behavioural effects of the chronic administration of the beta-carboline inverse agonist FG 7142 were studied in the rat. Repeated administration of FG 7142 (15 mg/kg IP, twice daily for 10 consecutive days) induced sensitization to the effects of this drug, which from proconvulsant became a full convulsant. Thus, myoclonic seizures were observed in 30% and 80% of the animals by the third and the eighth day of treatment, respectively. The sensitization to the convulsant effect of FG 7142 persisted for up to 50 days after withdrawal and was completely prevented by the concurrent administration of the benzodiazepine receptor antagonist Ro15-1788 (15 mg/kg IP, twice a day for 10 days). Moreover, four to twelve days after withdrawal from chronic treatment with FG 7142, an increased sensitivity to the proconvulsant beta CCE and to the convulsant DMCM was observed. In addition, convulsions induced by isoniazid (350 mg/kg, SC) were potentiated in rats chronically treated with FG 7142 at 5 and 20 days after withdrawal. These pharmacological effects were paralleled by a decrease in the density of low affinity GABA receptors in the cerebral cortex and cerebellum. These results are consistent with the view that repeated administration of FG 7142 induces a long-lasting down-regulation of the GABAergic function which results in an increased sensitivity to beta-carboline inverse agonists and isoniazid. The possibility that a concomitant decrease in the responsiveness to benzodiazepines and Ro15-1788 takes place after chronic treatment with FG 7142 is also discussed. ",0
858,2824206,Pyrimidine pathways enzymes in human tumors of brain and associated tissues: potentialities for the therapeutic use of N-(phosphonacetyl-L-aspartate and 1-beta-D-arabinofuranosylcytosine,"The activities of aspartate transcarbamylase (de novo pyrimidine biosynthesis pathway) and of deoxycytidine kinase as well as deoxycytidine deaminase (salvage pyrimidine biosynthesis pathway) were determined in extracts prepared from 40 brain tumors of different types in comparison with extracts from normal nervous tissues. Aspartate transcarbamylase, which is undetectable in normal brain tissue, is present in all tumor samples and in some cases rises to very high activities. Deoxycytidine kinase activity is present in all tissues but its level is generally higher in tumors. Deoxycytidine deaminase is present in all the tissues which were analyzed, although its activity is lower in some of the tumor samples. 1-beta-D-Arabinofuranosylcytosine is a substrate for both deoxycytidine kinase and deaminase in all the samples used except one. These results suggest some potential for the utilization of 1-beta-D-arabinofuranosylcytosine and N-(phosphonacetyl)-L-aspartate in the treatment of brain tumors. ",0
859,2824561,Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas,"Approximately 25% of patients with pituitary adenomas have no clinical or biochemical evidence for excess hormone secretion and are classified as having null cell or nonfunctioning adenomas. To characterize the cell type of these tumors, we analyzed pituitary hormone gene expression in clinically nonfunctioning pituitary adenomas using specific oligonucleotide probes for the messenger (m)RNAs encoding growth hormone, prolactin, ACTH, and the glycoprotein hormone subunits, alpha, luteinizing hormone (LH)beta, follicle-stimulating hormone (FSH)beta, and thyroid-stimulating hormone (TSH)beta. Expression of one or more of the anterior pituitary hormone genes was found in 12/14 (86%) of the patients with clinically classified nonfunctioning adenomas. Expression of one or more of the glycoprotein hormone genes (alpha, LH beta, FSH beta, TSH beta) was identified most commonly (79%) with expression of multiple beta-subunit genes in many cases. Expression of alpha-subunit mRNA was found in each of the adenomas from patients expressing one of the beta-subunit mRNAs and in three patients with no detectable beta-subunit mRNA. Although FSH beta and LH beta mRNAs were found with similar frequencies in nonfunctioning adenomas, expression of FSH beta mRNA was generally much more abundant. TSH beta mRNA was detected in only one adenoma. The levels of glycoprotein hormone subunit mRNAs were variable in different adenomas, but the lengths of the mRNAs and transcriptional start sites for the alpha- and beta-subunit genes were the same in the pituitary adenomas and in normal pituitary. Growth hormone and prolactin gene expression were not observed in the nonfunctioning adenomas, but ACTH mRNA was found in a single case. Immunohistochemistry of the adenomas confirmed production of one or more pituitary hormones in 13/14 (93%) nonfunctioning tumors, with a distribution of hormone production similar to that of the hormone mRNAs. These data indicate that pituitary adenomas originating from cells producing glycoprotein hormones are common, but are difficult to recognize clinically because of the absence of characteristic endocrine syndromes and defective hormone biosynthesis and secretion. ",0
860,2824590,Foods high in fiber and phytobezoar formation,"High-fiber diets are being recommended by government agencies, cancer institutes, and manufacturers of high-fiber foods. Although this recommendation is appropriate for the majority of clients, some persons are prone to form phytobezoars and should not add certain kinds of fiber to the diet. The phytobezoar is a compact mass of fibers, skins, seeds, leaves, roots, or stems of plants that collects in the stomach or small intestine. Other food particles, such as fats, crystals, granules, fibers, and residues of salts, are incorporated into the mass and contribute to the growth of the bezoar. Clients who have undergone surgical procedures for peptic ulcer disease or stomach cancer or who for other reasons, such as diabetic gastroparesis, have a loss of normal pyloric function and decreased gastric acidity are prone to form phytobezoars. Once formed, the bezoar can be disintegrated through surgery, by the use of the Water Pik and enzymes during endoscopy, or by treatment with metoclopramide. The dietitian should advise such clients to avoid identified foods that lead to phytobezoar formation--oranges, persimmons, coconuts, berries, green beans, figs, apples, sauerkraut, brussels sprouts, and potato peel. ",0
861,2824623,Leukocyte interferon for treating first episodes of genital herpes in women,"Women experiencing their first episodes of genital herpes were treated, beginning within three days of the onset of lesions, with 5 X 10(4) units of human leukocyte interferon/kg of body weight for 12 doses over 14 days (total, approximately 3.6 X 10(7) units) or with placebo in equivalent volumes. Life-table analysis revealed quicker healing and significant reductions in the duration of shedding of virus in interferon-treated patients. Maximum daily geometric mean titers of virus and total area of unhealed lesions also decreased more quickly. No statistically significant difference in resolution of pain was seen between the two groups. Interferon had no effect on onset or frequency of subsequent recurrences recorded over one year of follow-up. Moderate, transient neutropenia occurred in 13 of 34 interferon-treated patients. A therapeutic effect of human leukocyte interferon on initial genital herpes was documented, but the clinical usefulness of interferon treatment of genital herpes is limited at this time. ",0
862,2825047,Haemophilus influenzae-induced decreases in lung beta-adrenoceptor function and number coincide with decreases in spleen noradrenaline,"In the guinea-pig intraperitoneal administration of the Gram-negative bacterium Haemophilus influenzae induces a decrease of beta-adrenoceptor number and results in impairment of beta-adrenoceptor function in the peripheral and central airways, respectively. In the present study, the time-course of these events was studied and compared with changes in catecholamines in plasma, in organs involved in immunoregulation (spleen, thymus), and in the heart and the lung. The number of beta-adrenoceptor binding sites in peripheral lung tissue and beta-adrenoceptor function in isolated tracheal spirals were significantly decreased 3 and 4 days after administration of H. influenzae (24-33%). No significant changes were observed at day 1 and day 8. The effects on tracheal beta-adrenergic receptor function were characterized by a decrease of maximal relaxation only, whereas EC50-values were not affected. These data are indicative of an effect on the functional coupling of the receptors to the biochemical events leading to smooth muscle relaxation. No changes were observed in catecholamine concentrations in the lung, heart, and the thymus after H. influenzae-treatment. Plasma noradrenaline, though, was significantly increased at day 1 after H. influenzae. At day 8 plasma noradrenaline had returned to control levels. Interestingly, the effect on spleen noradrenaline was opposite to the effect seen in plasma. A significant decrease in spleen noradrenaline was observed after H. influenzae at days 1, 3, and 8, with a maximum of 42% at day 1. It is suggested that the decrease in spleen noradrenaline may have a causal relationship with the changes in lung beta-adrenoceptors. ",0
863,2825249,Behavior of T1 relaxation time in normal and neoplastic pulmonary tissue. An in vitro study],"The aim of the study was to look for a difference between normal and neoplastic lung tissue by means of Magnetic Resonance Spectroscopy in vitro. A 2.1 Tesla intensity spectrometer was used. From 23 pneumonectomized patients, two samples from the lung were taken immediately after surgery: one from the center of the neoplasm, one from the healthy surrounding tissue; on each of them T1 relaxation time was measured. Twenty patients out of 23 had a higher T1 relaxation time in the pathologic tissue than in the healthy surrounding tissue; only in 3 cases the T1 of neoplastic tissue was lower than that of the healthy tissue. A correlation was also sought between the T1 value and the histologic type of the neoplasm. In epidermoid carcinoma, the T1 relaxation time increased with the malignity of the neoplasm. ",0
864,2825263,Shoulder luxation. A late clinico-radiologic study],"There are various opinions regarding the aetiology and pathogenesis of dislocation of the shoulder. Various aspects of these theories and their clinical significance have been examined in the course of a clinical and radiological follow-up. Crucial to the development of subluxation is the occurrence of trauma. The age of the patient is important in the prognosis: more than 60% of patients under the age of 30 develop recurrent or persistent dislocation. Apart from a congenital disposition and inadequate treatment, accompanying injuries are primarily responsible for the development of persistent dislocation. Late follow-up has shown that radiologically recognisable post-traumatic changes are apparent in at least one-third of the patients. Persistent symptoms are much more common and consist of pain, limitation of movement, weakness and paraesthesia. In evaluating the late results, one should distinguish between objective functional limitation of movement and subjectively felt reduction in function. ",0
865,2830514,Social and economic factors in the choice of lung cancer treatment. A population-based study in two rural states,"We reviewed 1808 hospital charts representing virtually all patients given a diagnosis of non-small-cell lung cancer in New Hampshire and Vermont between 1973 and 1976 and found that the treatment of patients varied according to their marital status, medical insurance coverage, and proximity to a cancer-treatment center. Patients were more likely to be treated with surgery if they were married (odds ratio, 1.67; 95 percent confidence interval, 1.08 to 2.57) or had private medical insurance (1.52; 1.03 to 2.26). Among patients who did not have surgery, those with private insurance were more likely to receive another form of anticancer therapy--either radiation or chemotherapy (1.57; 1.18 to 2.09). Residing farther from a cancer-treatment center was associated with a greater chance of having surgery. Patients 75 years of age and older were less likely to have surgery (0.16; 0.08 to 0.35) or any other tumor-directed therapy (0.32; 0.19 to 0.54). The relation between the type of treatment and a patient's characteristics was not based on apparent differences in tumor stage or functional status, although both these factors were also strongly predictive of the type of treatment. Despite the fact that privately insured and married patients were more aggressively treated, they did not survive longer after diagnosis. We conclude that for non-small-cell lung cancer, socio-economic as well as medical factors determine treatment.",0
866,2839401,Isolation of a human hepatic ferritin receptor,"A human hepatic ferritin receptor has been isolated from human liver and has been purified using affinity chromatography. An affinity constant of 6.0 x 10(8) moles-1 liter was determined for the ferritin receptor. The molecular weight was estimated to be approximately 53,000 by gel electrophoresis. Binding of ferritin to the receptor coupled to a microparticulate support was specific for human liver ferritin with no binding of rat or porcine ferritin. Binding was unaffected by a 100-fold excess of human transferrin, human asialoorosomucoid and bovine albumin. After treatment of the receptor protein with trypsin, binding was not detected. The human hepatic ferritin receptor may play an important role in the uptake of iron into the hepatocyte in physiological and pathological conditions.",0
867,2859523,Prolongation of the disease-free interval in surgically treated rectal carcinoma,"""To assess the effects of postoperative radiation therapy and chemotherapy on tumor recurrence and patient survival, 227 patients (data on 202 of whom were analyzed) who had undergone """"curative"""" surgical resection for rectal adenocarcinoma were prospectively and randomly assigned to one of four treatments: no adjuvant therapy (concurrent controls, 58 patients), postoperative radiotherapy with 4000 or 4800 rad (50 patients), postoperative chemotherapy (fluorouracil and semustine [methyl-CCNU], 48 patients), or a combination of radiation therapy and chemotherapy (46 patients). Five years after the entry of the last patient and with a median follow-up of all survivors for 80 months, the recurrence rate was highest among the control patients (55 per cent) and lowest among the patients receiving a combination of adjuvant radiation and chemotherapy (33 per cent). Time to tumor recurrence differed significantly among the four treatment groups (P less than 0.04); it was significantly prolonged by combined radiation and chemotherapy as compared with resection alone (P less than 0.009). Overall survival did not differ significantly among the treatment groups. The superiority of the combined-modality regimen appeared to be attributable to the effects of radiation therapy and chemotherapy in controlling local and distant recurrences, respectively. We conclude that this study provides evidence supporting the use of postoperative radiation therapy in conjunction with chemotherapy in patients who have had """"curative"""" resection of rectal cancer with involvement of perirectal fat or regional nodes or both (Stages B2 and C).""",0
868,2859524,Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion,"""The early-morning increase in insulin requirements of patients with insulin-dependent diabetes mellitus (IDDM) has been referred to as the """"dawn phenomenon."""" To determine the roles of growth hormone levels and sympathoadrenal activity in this phenomenon, we studied six subjects with IDDM on four occasions during a constant overnight infusion of insulin. In control experiments (infusion of insulin alone), plasma glucose increased from 98 +/- 5 mg per deciliter at midnight to 225 +/- 36 at 8:00 a.m. (P less than 0.001), glucose production increased by 65 per cent (P less than 0.001), and glucose clearance decreased by 50 per cent (P less than 0.001). When nocturnal surges in growth hormone secretion were prevented by infusion of somatostatin plus replacement glucagon, neither plasma glucose levels nor glucose production increased significantly, and glucose clearance did not decrease. When nocturnal surges in growth hormone secretion were simulated by hourly intravenous injections of growth hormone (15 to 100 micrograms) during infusion of somatostatin and glucagon, plasma glucose levels and glucose production increased and glucose clearance decreased to values observed in control experiments. During combined alpha- and beta-adrenergic blockade (phentolamine and propranolol), values for plasma glucose, glucose production, and glucose utilization were not significantly different from those in control experiments. Increases in plasma glucose were significantly correlated with peak plasma growth hormone concentrations (r = 0.58, P less than 0.01). We conclude that nocturnal surges in growth hormone secretion are primarily responsible for the dawn phenomenon in patients with IDDM.""",0
869,2862584,Rearrangement of the gene for the beta chain of the T-cell receptor in T-cell chronic lymphocytic leukemia and related disorders,"Although monoclonal B-cell populations can be identified both by surface-marker analysis and by immunoglobulin-gene rearrangements, this has not been possible with T cells. We have employed cDNA probes that are specific for the entire beta chain of the T-cell receptor, and for its constant and variable regions, to investigate gene rearrangements in T-cell chronic lymphocytic leukemia and related disorders. In three malignant proliferations of helper (T4-positive) T cells, rearrangements of the beta-chain constant-region gene were readily demonstrated. A patient from the Caribbean who had adult T-cell lymphoma and antibody to human T-cell lymphotrophic virus Type I (HTLV-I), a patient with virus-negative chronic lymphocytic leukemia, and a patient with cutaneous T-cell lymphoma (S�zary variant) made up the T4-positive group. Three additional patients with chronic T8 (cytotoxic-suppressor) lymphocytosis and neutropenia were studied; in two; rearrangements were found. In all five patients with constant-region rearrangements, deletions of variable-region restriction fragments were observed as well. The presence of rearrangements of a T-cell receptor gene provides presumptive evidence for the clonal nature of T-cell proliferation and for its neoplastic character.",0
870,2880292,Psychotropic drug use and the risk of hip fracture,"To assess the risk of hip fracture associated with the use of four classes of psychotropic drugs, we performed a case-control study of 1021 patients with hip fractures and 5606 controls among elderly Medicaid enrollees. Persons treated with hypnotics-anxiolytics having short (less than or equal to 24 hours) elimination half-lives had no increased risk of hip fracture. By contrast, a significantly increased risk was associated with current use of hypnotics-anxiolytics having long (greater than 24 hours) elimination half-lives (odds ratio, 1.8; 95 percent confidence interval, 1.3 to 2.4), tricyclic antidepressants (odds ratio, 1.9; 95 percent confidence interval, 1.3 to 2.8), and antipsychotics (odds ratio, 2.0; 95 percent confidence interval, 1.6 to 2.6). The risk increased in relation to the doses of drugs in these three classes. An analysis for possible confounding by dementia did not alter the results. Previous but noncurrent use of drugs in these classes conferred no increase in risk. Although a cause-and-effect relation was not proved, these data support the hypothesis that the sedative and autonomic effects of psychotropic drugs increase the risk of falling and fractures in elderly persons. The results suggest the need for studies of this association in other populations and for evaluation of newer psychotropic drugs with fewer undesirable sedative and autonomic effects.",0
871,2891033,Expression of opioid peptides in tumors,"""We looked for opioid peptides and their precursors in 108 tumors of both neuroendocrine and nonneuroendocrine origin, using a monoclonal """"pan-opioid"""" antibody, 3-E7, which recognizes the tetrapeptide Tyr-Gly-Gly-Phe (the sequence responsible for pharmacologic activity in all known opioid peptides), in conjunction with polyclonal antibodies directed against representative peptides of each of the three precursors (alpha-endorphin, [met]enkephalin-Arg-Gly-Leu, and dynorphin B). Using the avidin-biotin immunoperoxidase technique, we observed consistent cytoplasmic immunoreactivity (at least focally) in all of 15 adrenal pheochromocytomas, all of 6 thyroid medullary carcinomas, and all of 5 pituitary adenomas. Opioid staining was also observed in parathyroid adenomas (8 of 9), pancreatic islet-cell tumors (7 of 10), carcinoid tumors from various sites (18 of 26), and paragangliomas (1 of 2). There was no immunoreactivity in pulmonary small-cell carcinomas, Merkel-cell tumors of skin, neuroblastomas, or any of the non-neuroendocrine tumors examined. The expression of alpha-endorphin, [met]enkephalin-Arg-Gly-Leu, and dynorphin B varied from tumor to tumor; however, positive staining with the """"pan-opioid"""" antibody was found in each tumor containing at least one of the three precursors. Opioid peptide immunoreactivity was also detected in non-neoplastic cells of the adrenal medulla, pancreatic islets, pituitary, intestinal and bronchial mucosa, and intestinal myenteric plexuses. We conclude that opioid expression within tumors is most likely due to enhanced expression of a normal cell product and that opioid peptides are useful markers of neuroendocrine differentiation in many tumors.""",0
872,2893260,Predictive testing for Huntington's disease with use of a linked DNA marker,"The probability of carrying the gene for Huntington's disease can in many cases be estimated in the children of affected persons by identifying a specific DNA marker that is genetically linked to the gene. We studied 47 persons at 50 percent risk of inheriting Huntington's disease who requested a presymptomatic or prenatal genetic-linkage test between September 1986 and January 1988. The participants were given pre-test counseling and psychological and neurologic evaluations. Nineteen persons later voluntarily withdrew from the protocol, including one who would have been excluded anyway, and one person was from a family that was too small to allow testing. Three D4S10 restriction-fragment-length polymorphisms produced by the HindIII, EcoRI, and Bg/I enzymes were used for all tests, and the probability that a subject was a Huntington's disease carrier was calculated. The accuracy of the test was compromised by a 4 percent recombination frequency between D4S10 and the Huntington's disease gene. Fifteen presymptomatic tests and one prenatal test were completed. Four yielded positive results, seven yielded negative results, and five were uninformative; seven persons are awaiting test results. All participants with positive tests experienced intermittent depression, but none required hospitalization, and no suicide threats were reported. Five participants received a diagnosis of Huntington's disease on the basis of the neurologic assessment. We conclude that some persons in the early stages of Huntington's disease may seek presymptomatic testing rather than neurologic evaluations.",0
873,2908867,Differential location of hemopoietic colonies within liver acini of postnatal and phenylhydrazine-treated adult mice,"We have measured the location of embryonic and adult hemopoietic foci in the liver tissue of postnatal and adult phenylhydrazine-treated mice. Differentiation of acinar domains in liver tissue was made possible by carrying out succinate dehydrogenase histochemical reactions on liver cryostat sections. To determine the position of hemopoietic foci within the lobular gradient of the hepatocyte succinate dehydrogenase activity, this enzyme was measured in hepatocytes surrounding both portal and central veins and hemopoietic foci. Then, assuming the periportal succinate dehydrogenase activity value to be 1.00 +/- 0.2, succinate dehydrogenase activity around postnatal hemopoietic foci was 0.65 +/- 0.19, around phenylhydrazine-induced hemopoietic foci 0.83 +/- 0.24 and around central veins 0.44 +/- 0.11. Scaling the portal to central vein distance and taking 1 as the portal vein point and 0 as the central vein point, the relative position of hemopoietic foci, indirectly calculated from succinate dehydrogenase activity values, was 0.35 +/- 0.13 in postnatal livers and 0.73 +/- 0.12 in phenylhydrazine-treated adult livers. Hemopoietic foci frequencies varied according to both the origin and the liver acinar domain: in postnatal liver acini, it was 37.1% in zone 1, 22.8% in zone 2 and 40% in zone 3; in phenylhydrazine-treated adult acini, it was 89.4% in zone 1 and 10.6% in zone 2. Postnatal hemopoietic foci mainly occurred extrasinusoidally, between hepatocytes and reticular-like cells, whereas adult hemopoietic foci were mostly intrasinusoidal and closely associated to macrophage-like cells. Adult hemopoietic colonies",0
874,2908868,Proline-incorporating cells in chronic active liver diseases,"The incorporation of 3H-proline in cells of liver biopsy specimens from patients with chronic active liver diseases has been studied by light and electron microscopic autoradiography. The labeled proline is incorporated by hepatocytes of the external rows of the residual liver lobule, by the cells of the proliferating bile ductule and very actively by the plasma cells localized at the boundary between the inflammatory infiltrate and the liver lobule. These plasma cells, which are often in close contact with the hepatocytes at the edge of the liver lobule, appear to be either negative or positive after the immunohistochemical tests for the k and lambda chains of immunoglobulins. Results are discussed in relation to both the synthesis of collagen and the role of the immunocompetent cells during the process of the piecemeal necrosis.",0
875,2908869,Preferential covalent binding of acetaldehyde to the alpha-chain of purified rat liver tubulin,"Hepatic ethanol oxidation generates the reactive intermediate acetaldehyde, which binds to proteins. Previous work, using bovine brain tubulin as a model protein, has shown that acetaldehyde preferentially formed stable adducts on the alpha-chain of the heterodimeric molecule. This binding resulted in functional impairment of the tubulin/microtubule system as evidenced by a decreased ability of adducted tubulin to form microtubules. Since tubulin/microtubules are believed to be very important cytoskeletal components of the hepatocyte and results with brain tubulin were interesting, our goal was to extend these studies to liver tubulin. We purified tubulin from rat liver by a polymerization-based cycle method followed by phosphocellulose chromatography. We then characterized the covalent binding of [14C]acetaldehyde to liver tubulin. Naturally forming and cyanoborohydride-stimulated stable adducts formed linearly with liver tubulin in a manner almost identical to that with brain tubulin. We also found that the alpha-chain of the native heterodimeric liver tubulin molecule was the preferred site of adduct formation at low acetaldehyde to protein ratios. These results confirm and extend our previous findings with the brain tubulin model and further suggest that the alpha-chain of tubulin may be a preferential site for acetaldehyde-adduct formation during ethanol oxidation in the liver.",0
876,2909875,Malformations due to presumed spontaneous mutations in newborn infants,"We conducted hospital-based surveillance of congenital malformations to determine the rate of apparently spontaneous single mutations leading to recognized phenotypes. Through surveillance of 69,277 infants with gestational ages of at least 20 weeks, we identified 48 infants (0.07 percent) with major malformations, with phenotypes that suggested that the malformations were due to single mutant genes. Family studies suggested that 11 of these infants (10 with autosomal dominant disorders and 1 with an X-linked condition) were affected as the result of a new (spontaneous) genetic mutation. The spontaneous mutation rates per gene were 0.7 x 10(-5) and 1.44 x 10(-5) for the disorders in which one and two infants were affected, respectively. In addition, 5 of the 10 infants with autosomal recessive malformations had negative family histories, but we were unable to infer the presence of spontaneous mutations in these cases. Because the family history was negative in 44.4 percent of the infants with disorders considered due to autosomal or X-linked genes, counseling should include the understanding that genetic disorders often occur unexpectedly among children of healthy parents.",0
877,2911322,"Abnormalities in parathyroid hormone secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis","We investigated the parathyroid hormone-1,25-dihydroxyvitamin D3 (1,25(OH)2D) axis in osteoporosis by administering phosphate to 8 postmenopausal women with osteoporosis (49 to 78 years old) and to 10 normal women matched for age (50 to 74 years). All subjects responded with a similar increase in the serum phosphorus concentration (women with osteoporosis, 1.15 +/- 0.06 to 1.79 +/- 0.09 mmol per liter; controls, 1.14 +/- 0.05 to 1.73 +/- 0.08 mmol per liter) and a fall in the ionized calcium concentration (women with osteoporosis, 1.12 +/- 0.03 to 1.06 +/- 0.03 mmol per liter; controls, 1.17 +/- 0.01 to 1.11 +/- 0.02 mmol per liter). Parathyroid hormone levels rose 2.5-fold in the control group (15.4 +/- 2.2 to 37.9 +/- 6.1 pg per milliliter) but increased by only 43 percent in the group with osteoporosis (14.8 +/- 2.8 to 21.2 +/- 4.1 pg per milliliter), an increase similar to that previously reported in young normal subjects (53 percent). In healthy older and younger subjects, the levels of 1,25(OH)2D did not change; in the subjects with osteoporosis, however, they decreased significantly (50 percent). We conclude that older women require a greater parathyroid hormone stimulus than younger women to maintain vitamin D homeostasis, because of an age-related decline in the formation of 1,25(OH)2D in response to parathyroid hormone, and that in osteoporosis the age-appropriate parathyroid hormone response to the same hypocalcemic signal is diminished. Our results are consistent with the presence of an abnormality in parathyroid hormone secretory function in osteoporosis in addition to the universal decline in 1,25(OH)2D responsiveness associated with aging.",0
878,2913493,Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with mild-to-moderate alcohol withdrawal syndrome,"We compared the effectiveness, safety, and costs of outpatient (n = 87) and inpatient (n = 77) detoxification from alcohol in a randomized, prospective trial involving 164 male veterans of low socioeconomic status. The outpatients were evaluated medically and psychiatrically and then were prescribed decreasing doses of oxazepam on the basis of daily clinic visits. The inpatient program combined comprehensive psychiatric and medical evaluation, detoxification with oxazepam, and the initiation of rehabilitation treatment. The mean duration of treatment was significantly shorter for outpatients (6.5 days) than for inpatients (9.2 days). On the other hand, significantly more inpatients (95 percent) than outpatient (72 percent) completed detoxification. There were no serious medical complications in either group. Outcome evaluations completed at one and six months for 93 and 85 percent of the patients, respectively, showed substantial improvement in both groups at both follow-up periods. At one month there were fewer alcohol-related problems among inpatients and fewer medical problems among outpatients. However, no group differences were found at the six-month follow-up, nor were differences found in the subsequent use of other alcoholism-treatment services. Costs were substantially greater for inpatients ($3,319 to $3,665 per patient) than for outpatients ($175 to $388). We conclude that outpatient medical detoxification is an effective, safe, and low-cost treatment for patients with mid-to-moderate symptoms of alcohol withdrawal.",0
879,2915666,Reduced bone mass in daughters of women with osteoporosis,"To determine whether premenopausal daughters of women with postmenopausal osteoporosis have lower bone mass than other women of the same age, we measured the bone mineral content of the lumbar spine and femoral neck and midshaft, using dual-photon absorptiometry, in 25 postmenopausal women with osteoporotic compression fractures and in 32 of their premenopausal daughters; we then compared the results with those in normal controls. As compared with normal postmenopausal women, women with osteoporosis had lower bone mineral content in the lumbar spine, femoral neck, and femoral midshaft by 33, 24, and 15 percent, respectively (P less than 0.001 for each comparison by the one-tailed t-test). As compared with normal premenopausal women, the daughters of women with osteoporosis had lower bone mineral content at these sites by 7, 5, and 3 percent, respectively (P = 0.03, 0.07, and 0.15, respectively, by the one-tailed t-test). In terms of a standardized score, we calculated that the mean (+/- SEM) relative deficits in bone mineral content in the daughters of women with osteoporosis were 58 +/- 18 percent (lumbar spine) and 34 +/- 16 percent (femoral neck) of the relative deficits in their mothers. We conclude that daughters of women with osteoporosis have reduced bone mass in the lumbar spine and perhaps in the femoral neck; this reduction in bone mass may put them at increased risk for fractures. We also conclude that postmenopausal osteoporosis may result partly from a relatively low peak bone mass rather than from excessive loss of bone.",0
880,2920993,Urea cycle enzyme activities are normal and inducible by a high-protein diet in CCl4 cirrhosis of rats,"We produced moderately severe, inactive micronodular cirrhosis in rats using CCl4 and measured the urea cycle enzyme activities in liver after feeding a 15% casein diet for 1 week and again after a 60% casein diet for 1 week. There was no deficiency of any of the five urea cycle enzymes in cirrhotic livers of rats pair-fed the 15% casein diet. Argininosuccinate synthetase and carbamyl phosphate synthetase activities were lower than in non-pair-fed controls by some baselines. All five enzymes in cirrhotic livers were induced 1.5- to 3-fold by the high-protein diet expressed as units per 100 gm of rat. The level of carbamyl phosphate synthetase activity was lower in the livers of rats pair-fed the 60% casein diet than in control livers based on wet weight, collagen-free protein and DNA, but the activities were equal expressed as units per 100 gm of rat. This example of CCl4-induced cirrhosis in the rat does not serve as a good model for human cirrhosis, in which the urea cycle enzymes are reported to be decreased in activity.",0
881,2920997,Stimulation of DNA synthesis in hepatocytes by Kupffer cells after partial hepatectomy,"The role of Kupffer cells during reparative regeneration of rat liver was investigated with an in vitro experimental model. Conditioned media from primary cultures of Kupffer cells isolated from intact and regenerating liver were added to primary cultures of hepatocytes, and [3H]thymidine incorporation into DNA was studied. Kupffer cell-conditioned media from intact liver and regenerating remnant liver significantly stimulated DNA synthesis in hepatocytes as compared with control media (p less than 0.05). Moreover, the stimulating activity of Kupffer cells prepared from regenerating liver at 6 and 12 hr after partial hepatectomy was significantly higher than that of Kupffer cells from untreated rats (p less than 0.05). The activity was found in serum-free conditioned media. This stimulating activity exponentially increased as the increase of the number of the cultured cells, indicating that the stimulating activity was released directly by cultured Kupffer cells. These results suggest that Kupffer cells stimulate DNA synthesis in hepatocytes by producing and releasing certain factor(s) at an early stage of liver regeneration after partial hepatectomy.",0
882,2925159,Studies on the regulation of cholesterol metabolism by low- and high-density lipoproteins in HepG2 cells,The uptake and degradation of low-density lipoproteins and the esterification and synthesis of cholesterol were poorly down-regulated by low-density lipoproteins in HepG2 cells. Addition of low-density lipoproteins to the cells increased the free and esterified cholesterol in the cells. The heavier fraction of high-density lipoproteins enhanced the degradation of low-density lipoproteins and cholesterol synthesis and decreased acyl CoA:cholesterol acyltransferase activity. Addition of the heavier fraction of high-density lipoproteins also caused a net efflux of cholesterol from HepG2 cells. The lighter fraction did not have any significant effect on cholesterol metabolism or cellular cholesterol level. Neither the lighter nor the heavier fractions of high-density lipoproteins were found to have any specific binding properties to HepG2 cells.,0
883,2925160,"D-glucaro-1,4-lactone: its excretion in the bile and urine and effect on the biliary secretion of beta-glucuronidase after oral administration in rats","This experiment was designed to test the hypothesis that orally administered D-glucaro-1,4-lactone might be excreted in the bile and thus suppress the activity of biliary beta-glucuronidase, which is believed to play a key role in the development of pigment gallstones. D-Glucaro-1,4-lactone, 50 to 2,600 mu moles, was fed to adult Sprague-Dawley rats which had a bile fistula and were kept in metabolic cages for bile and urine collection. A total of 21 feeding experiments were carried out. Quantitation of D-glucaro-1,4-lactone and total D-glucaric acid as the sum of D-glucaric acid and its lactones in the bile and urine involved extraction of bile with tetrahexylammonium chloride, adjustment of pH, boiling and determination of percentage inhibition of beta-glucuronidase activity. The maximal velocity of beta-glucuronidase in the bile was also determined by the enzyme kinetic method. The results showed that 11% of administered D-glucaro-1,4-lactone was excreted in the urine and only 0.2% in the bile, with D-glucaro-1,4-lactone accounting for 20% of the total excreted D-glucaric acid. The concentration and excretory rate of total D-glucaric acid and D-glucaro-1,4-lactone in the urine, but not in the bile, were proportional to the amount of D-glucaro-1,4-lactone fed. The mean concentration of D-glucaro-1,4-lactone in the bile after feeding was 0.06 mM, which was capable of suppression of 75% of beta-glucuronidase activity. Oral administration of D-glucaro-1,4-lactone decreased biliary beta-glucuronidase concentration, slowed bile flow rate and hence decreased biliary beta-glucuronidase secretion.(ABSTRACT TRUNCATED AT 250 WORDS)",0
884,2927477,Controlling AIDS in Cuba. The logic of quarantine,"Cuba has initiated a program to control Acquired Immune Deficiency Syndrome (AIDS) that is designed to limit the spread of infection with the human immunodeficiency virus (HIV) by implementing compulsory elements of the public health tradition. Widespread screening for HIV infection began 3 years ago, and persons identified as infected have been sent to a sanatorium located in a Havana suburb. The program also reflects concern over the marked increase in prevalence of sexually transmitted diseases. Educational effects in Cuba stress that AIDS is not a disease exclusively of homosexuals and can affect any individual. Condoms are recommended for protection. In contrast to virtually every other nation, Cuba has not made education the key focus of its anti-AIDS strategy. Education is relegated to a marginal role. Key to the policy is identifying infected individuals and bringing them under medical control. Cuba's HIV surveillance program has been carried out with use of an enzyme-linked immunosorbent assay (ELISA), Western blot assay, and antigen tests that have been developed domestically. The director of the Cuban AIDS Investigations Laboratory reports that nearly 3 million Cubans have been tested. It is estimated that among the 7 low-infection groups tested in Cuba, between 21 and 53 persons may have been inaccurately considered positive as a result of testing. Cuban authorities have expressed much interest in obtaining commercially available HIV screening kits -- both ELISA and Western blot assays -- as a standard against which to measure their own test. Despite the inevitability of continued viral transmission, Cuba's policy of a modified quarantine certainly will limit the toll of HIV infection markedly yet comes at a great price. For other nations, the imperatives of prevention, however important, are not the only values to be considered in the battle against AIDS.",0
885,2927481,Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence,"Relaxation of the smooth muscle of the corpora cavernosa of the penis is necessary for penile erection. To determine the relation of impaired relaxation to impotence in diabetic patients, we performed an in vitro examination of corpus cavernosum tissue obtained at the time of implantation of a penile prosthesis in 21 diabetic and 42 nondiabetic men with impotence. Contraction was induced in isolated strips of corporal smooth muscle by norepinephrine; then relaxation was assessed with electrical stimulation of autonomic nerves and with the administration of three agents: acetylcholine, which is known to be mediated by endothelium-derived relaxing factor; papaverine; and sodium nitroprusside. The latter two act directly on smooth muscle (i.e., they are endothelium-independent). Autonomically mediated relaxation with electrical stimulation was less pronounced in the smooth muscle from diabetic men (n = 18) than in the smooth muscle from nondiabetic men (n = 24; P = 0.001). The degree of impairment increased with the duration of diabetes (r = 0.61, P = 0.007). Endothelium-dependent relaxation was also impaired, as evidenced by a lower degree of muscle relaxation after the administration of acetylcholine in the tissue from diabetic men (n = 16) than in that from nondiabetic men (n = 22; P = 0.001). The adverse effects of diabetes persisted after we controlled for smoking and hypertension. Endothelium-independent relaxation after the administration of nitroprusside and papaverine was similar in tissue from the diabetic and nondiabetic men. We conclude that diabetic men with impotence have impairment in both the autonomic and the endothelium-dependent mechanisms that mediate the relaxation of the smooth muscle of the corpora cavernosa. These findings may provide a rationale for the treatment of diabetic men with impotence by intracavernosal injection of vasodilators to induce endothelium-independent relaxation of the smooth muscle.",0
886,2931604,The creatine kinase system in normal and diseased human myocardium,"We measured creatine kinase activity, isozyme composition, and total creatine content in biopsy samples of left ventricular myocardium from 34 adults in four groups: subjects with normal left ventricles, patients with left ventricular hypertrophy due to aortic stenosis, patients with coronary artery disease without left ventricular hypertrophy, and patients with coronary artery disease and left ventricular hypertrophy due to aortic stenosis. As compared with specimens of normal left ventricles, those from all patients with left ventricular hypertrophy had lower creatine kinase activity, higher MB creatine kinase isozyme content and activity, and lower creatine content. Specimens from the patients without left ventricular hypertrophy had normal creatine kinase activity, increased MB creatine kinase isozyme content and activity, and decreased total creatine content. The normal ventricles showed almost no MB isozyme content or activity. These data suggest that changes in the creatine kinase system occur in both pressure-overload hypertrophy and coronary artery disease. Patients with myocardial infarction who have mild or no preexisting fixed coronary artery disease or pressure-overload hypertrophy would not be expected to have elevation of serum MB creatine kinase.",0
887,2936958,Determining optimal therapy--randomized trials in individual patients,"Although the treatment of an individual patient in routine clinical practice has been likened to an experiment, the method is so susceptible to bias that we have come to demand multi-patient, double-blind, randomized controlled trials on matters of efficacy. Unfortunately, such trials have not or cannot be carried out for many clinical disorders; even when they have been executed their results may be difficult to extrapolate to individual patients. To resolve this problem, we have begun to use double-blind randomized trials in which a single patient undergoes a series of pairs of treatments, consisting of one active and one placebo or alternative treatment per pair, with the order determined by random allocation. Appropriate treatment targets (signs, symptoms, or laboratory tests) are used as the measure of efficacy, and the trial is continued until efficacy is established or disproved. We describe such a trial, which resulted in a dramatically beneficial modification of treatment in a patient with partially reversible airflow limitation. We have established a clinical service that facilitates the widespread use of the method in our community.",0
888,2945109,How many days of bed rest for acute low back pain? A randomized clinical trial,"Bed rest is usually recommended for acute low back pain. Although the optimal duration of bed rest is uncertain, a given prescription may directly affect the number of days lost from work or other activities. In a randomized trial, we compared the consequences of recommending two days of bed rest (Group I) with those of recommending seven days (Group II). The subjects were 203 walk-in patients with mechanical low back pain; 78 percent had acute pain (less than or equal to 30 days), and none had marked neurologic deficits. Follow-up data were obtained at three weeks (93 percent) and three months (88 percent). Although compliance with the recommendation of bed rest was variable, patients randomly assigned to Group I missed 45 percent fewer days of work than those assigned to Group II (3.1 vs. 5.6 days, P = 0.01), and no differences were observed in other functional, physiologic, or perceived outcomes. For many patients without neuromotor deficits, clinicians may be able to recommend two days of bed rest rather than longer periods, without any perceptible difference in clinical outcome. If widely applied, this policy might substantially reduce absenteeism from work and the resulting indirect costs of low back pain for both patients and employers.",0
889,2946952,"A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease","It has been postulated that dehydroepiandrosterone (DHEA) and its sulfate ester, dehydroepiandrosterone sulfate (DHEAS), the major secretory products of the human adrenal gland, may be discriminators of life expectancy and aging. We examined the relation of base-line circulating DHEAS levels to subsequent 12-year mortality from any cause, from cardiovascular disease, and from ischemic heart disease in a population-based cohort of 242 men aged 50 to 79 years at the start of the study. Mean DHEAS levels decreased with age and were also significantly lower in men with a history of heart disease than in those without such a history. In men with no history of heart disease at base line, the age-adjusted relative risk associated with a DHEAS level below 140 micrograms per deciliter was 1.5 (P not significant) for death from any causes, 3.3 (P less than 0.05) for death from cardiovascular disease, and 3.2 (P less than 0.05) for death from ischemic heart disease. In multivariate analyses, an increase in DHEAS level of 100 micrograms per deciliter was associated with a 36 percent reduction in mortality from any causes (P less than 0.05) and a 48 percent reduction in mortality from cardiovascular disease (P less than 0.05), after adjustment for age, systolic blood pressure, serum cholesterol level, obesity, fasting plasma glucose level, cigarette smoking status, and personal history of heart disease. Our conclusions are limited by the single determination of DHEAS levels, but the data suggest that the DHEAS concentration is independently and inversely related to death from any cause and death from cardiovascular disease in men over age 50.",0
890,2946956,Selective loss of the suppressor-inducer T-cell subset in progressive multiple sclerosis. Analysis with anti-2H4 monoclonal antibody,"The T4+ lymphocyte population includes a subset that induces suppressor T lymphocytes (T8+ cells) and can be distinguished by dual-color fluorescence analysis with anti-2H4 and anti-T4 monoclonal antibodies. To investigate the possible role of these cells in multiple sclerosis, we used anti-2H4 antibody to characterize peripheral-blood lymphocyte subsets in 63 patients with multiple sclerosis that was progressive, stable, or acute (relapsing-remitting). Twenty-three of 37 patients with progressive multiple sclerosis had a selective decrease in the number and percentage of peripheral-blood T cells that induce suppressor cells (T4+2H4+ cells), whereas only 3 of 16 patients with stable disease and 2 of 10 patients in the midst of an acute attack had a significant decrease. These selective decreases of circulating T4+2H4+ cells occurred in only 1 of 34 patient controls with other neurologic diseases and in 2 of 50 healthy controls (P less than 0.0001 by Fisher's exact test). The absolute number of T4+2H4+ cells and the percentage of reactivity in the populations studied were 187 +/- 28 per cubic millimeter and 8.3 +/- 1 percent in patients with progressive multiple sclerosis; 353 +/- 60 per cubic millimeter and 14.5 +/- 2 percent in patients with stable disease; 368 +/- 72 and 14.6 +/- 2.1 percent in patients with acute disease; 402 +/- 64 and 15.6 +/- 2 percent in controls with other neurologic diseases; and 519 +/- 44 and 19.7 +/- 1 percent in healthy controls. Functional studies using a pokeweed mitogen-driven IgG assay demonstrated a correlation between decreased numbers of T4+2H4+ cells and increased production of IgG in vitro. Family studies showed that the 2H4 antigen was not part of an inherited polymorphic antigenic determinant. Our results suggest that in progressive multiple sclerosis decreases in inducers of suppressor T cells may permit the activation of cells reactive with elements of the central nervous system.",0
891,2948896,The pAS vector system and its application to heterologous gene expression in Escherichia coli,"There are numerous proteins of biological interest which cannot be obtained from natural sources in quantities sufficient for detailed biochemical and physical analysis. The limited bioavailability of these molecules has made it impossible to consider their potential utilization as either pharmacological agents and/or targets. One solution to this problem has been the development of recombinant vector systems which are designed to achieve efficient expression of cloned genes in a variety of biological systems. This paper will describe the development and application of a particular set of vectors which have been designed to achieve efficient expression of essentially any gene coding sequence in Escherichia coli. The system utilizes efficient phage-derived transcriptional and translational regulatory signals and provides a strong regulatable promoter, an antitermination mechanism to ensure efficient transcription across any gene insert, high stability and, when appropriate, efficient translation initiation information. In addition, a wide variety of host strains have been developed in order to help control, stabilize and maximize expression of various cloned genes. The system has now been used to express efficiently more than 75 different prokaryotic and eukaryotic gene products. The application of this system to the expression and characterization of several oncogene products will be described.",0
892,2953975,Market and regulatory influences on the availability of coronary angioplasty and bypass surgery in U.S. hospitals,"Using 1983 data on 3720 nonfederal short-term hospitals, we analyzed the influence of local market competition and state regulatory programs on the availability of percutaneous transluminal coronary angioplasty and coronary-artery bypass surgery. The degree of competition for patients with heart disease was measured in terms of the number of hospitals in the local market area that maintained a cardiac catheterization laboratory or facility for open-heart surgery. When the patient case mix and the hospital's teaching role were controlled for, institutions with more than 20 competitors in the local area were 166 percent more likely to offer coronary angioplasty (P less than 0.0001) and 147 percent more likely to offer bypass surgery (P less than 0.0001) than hospitals with no competitors in the local market. Four fifths of the hospitals performing bypass surgery whose annual volume was less than 200 had one or more neighboring hospitals with a facility for open-heart surgery. State rate-regulation programs in New York, New Jersey, Connecticut, Massachusetts, and Maryland significantly reduced the availability of both procedures, with the greatest regulatory effects being observed in the most competitive hospital markets. We conclude that in the period under consideration, competition encouraged and regulation discouraged the proliferation of these cardiac services.",0
893,2956519,Maternal exposure to spermicides in relation to certain birth defects,"Several studies have found no increase in the overall frequency of birth defects in association with the use of spermicides, but the possibility of an increase in specific defects remains. We evaluated this possibility in a large case-control study. Infants with certain malformations (265 with Down's syndrome, 396 with hypospadias, 146 with limb reduction defects, 116 with neoplasms, and 215 with neural-tube defects) were compared with 3442 control infants with a wide variety of other defects. Exposure to spermicides was assessed for three periods: use during the periconceptional period (one month before through one month after the last menstrual period), use during the first trimester (the first four lunar months of pregnancy), and any use during the lifetime. For the five groups of cases and for each interval, the odds ratios were close to 1.0 (range, 0.7 to 1.3); the upper 95 percent confidence bounds were 2.2 or lower. Risks did not increase with the duration of exposure. When each of the active ingredients in currently available spermicides was considered separately, no differences in odds ratios were apparent between the types of spermicides. With the possible exception of a subgroup of cases (limb reduction defects of unknown cause), these results suggest that risks for the five specific birth defects evaluated are not increased by exposure to spermicides.",0
894,2956520,Lack of association between spermicide use and trisomy,"It has been suggested that the maternal use of spermicidal contraceptives increases the frequency of certain congenital anomalies, including trisomy, but this issue is in dispute. This controversy led us to examine whether the use of spermicidal contraceptives is associated with an increased risk of fetal trisomy. A questionnaire concerning contraceptive use was completed by 13,729 women who were undergoing prenatal fetal chromosome studies but were as yet unaware of the results. Most women were at increased risk of having a trisomic fetus because of their advanced age. Of 154 fetuses with trisomy, 98 had trisomy 21. For each woman (case) with an affected fetus, four controls were selected from among women with chromosomally normal fetuses, matched for maternal age and medical center. Cases and controls were compared by matched-sample maximum-likelihood logistic regression, to examine the association between fetal trisomy and four measures of spermicide use: periconceptional use, timing of last use, duration of last use, and total lifetime use. No evidence was found for an association, either when all types of trisomy were combined or when trisomy 21 alone was considered. All point estimates of odds ratios relating spermicidal exposure to trisomy were approximately 1, and an effect greater than a twofold increase was excluded with 95 percent confidence in the combined-trisomy group for all measures of spermicide use.",0
895,2957591,Opsonophagocytic killing antibody to Pseudomonas aeruginosa mucoid exopolysaccharide in older noncolonized patients with cystic fibrosis,"The principal cause of morbidity and mortality in cystic fibrosis is persistent respiratory colonization with mucoid strains of Pseudomonas aeruginosa. To investigate possible mechanisms of resistance to this organism, we studied serum from 16 older (greater than or equal to 12 years) patients not colonized with mucoid P. aeruginosa, 11 older (greater than or equal to 14 years) colonized patients, 10 younger (less than or equal to 11 years) noncolonized patients, and 20 healthy adults. The samples from the older patients not colonized with mucoid P. aeruginosa contained antibody specific to the mucoid-exopolysaccharide antigen, which could mediate bacterial killing in conjunction with complement and white cells (titers of 4 to 80). These opsonophagocytic killing antibodies were not detected in samples from the 20 normal controls (P less than 0.0001 vs. noncolonized older patients) or 9 of 10 younger (less than or equal to 11 years) noncolonized patients (P = 0.0072 vs. noncolonized older patients). Although the patients with chronic colonization had higher titers of serum opsonophagocytic killing antibody than did the older noncolonized patients (P = 0.0005), these antibodies were not specific to the mucoid-exopolysaccharide antigen. We conclude that there is an association between mucoid-exopolysaccharide-specific opsonophagocytic killing antibody and a lack of detectable P. aeruginosa colonization in a subset of older, relatively healthy patients with cystic fibrosis.",0
896,2958399,Enhanced autoreactivity of T-lymphocytes in primary sclerosing cholangitis,"Primary sclerosing cholangitis is a chronic, cholestatic liver disease in which immune mechanisms are thought to play a role in the pathogenesis. We have determined the frequencies and functional phenotypes of autoreactive T-lymphocytes in peripheral blood specimens from patients with primary sclerosing cholangitis and healthy adults as an indicator of autoreactivity in primary sclerosing cholangitis. We found a significant increase in the percentage of autoreactive suppressor/cytotoxic T-lymphocytes that become activated in the T-, non-T-autologous mixed lymphocyte reaction in primary sclerosing cholangitis patients (p less than 0.002). Blastogenesis in autologous mixed lymphocyte reaction cultures from primary sclerosing cholangitis patients was significantly decreased (p less than 0.02), and the magnitude of the decrease correlated directly with the percentage of activated suppressor/cytotoxic T-lymphocytes (r = 0.56, p less than 0.01). The percentage of autoreactive, suppressor T-lymphocytes was increased in autologous mixed lymphocyte reaction cultures from primary sclerosing cholangitis patients (p less than 0.0001); and suppression of mitogen-induced blastogenesis by autologous concanavalin A-treated mononuclear cells was significantly enhanced. These results, which were unrelated to the histologic stage of liver disease and the presence or absence of active colitis, document the presence of an expanded population of T-lymphocytes in the peripheral blood of patients with primary sclerosing cholangitis that became activated on exposure to autologous major histocompatibility antigens in the autologous mixed lymphocyte reaction. We hypothesize that these autoreactive cells may be a marker or may participate as effector cells in cell-mediated autoimmunity in primary sclerosing cholangitis.",0
897,2959863,Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder,"Photodynamic therapy involves light-induced destruction of tumors containing a photosensitizer such as hematoporphyrin derivative. We conducted a collaborative study to evaluate the efficacy of this form of therapy in treating superficial transitional-cell carcinoma of the bladder. Thirty-seven patients were evaluated and 20 were selected for treatment. A total of 50 papillary tumors and 3 areas of carcinoma in situ were treated. All except two tumors were smaller than 2.5 cm. Assessments for treatment response and toxicity were carried out three months after treatment. The initial diagnosis of one patient was revised after the biopsy material was reviewed, and this patient was not included in the analysis. Complete eradication of all tumors was observed in 9 of 19 patients (47 percent), including those with carcinoma in situ. In the remaining 10 of these 19 patients, 13 tumors could not be eradicated (the overall eradication rate was 37 of 50 tumors [74 percent]), but 9 of the 10 patients had a reduction in tumor size, number, or both of 50 percent or more. We conclude that photodynamic therapy is useful in the treatment of superficial transitional-cell carcinoma of the bladder, but controlled trials will be required to define its place in the treatment of cancer.",0
898,2967432,Cigarette smoking and levels of adrenal androgens in postmenopausal women,"An antiestrogenic effect of cigarette smoking has been suggested, principally on the basis of data on premenopausal women. We examined the relation between cigarette smoking and endogenous sex-hormone levels in a population of 233 white, postmenopausal women 60 to 79 years of age. Current cigarette smokers had significantly higher mean plasma levels of the adrenal androgens dehydroepiandrosterone sulfate and androstenedione than nonsmokers. Mean levels for smokers and nonsmokers were 3.1 mumol per liter (116 micrograms per deciliter) and 2.3 mumol per liter (86 micrograms per deciliter), respectively (P less than 0.001), for dehydroepiandrosterone sulfate, and 27.8 nmol per liter (797 pg per milliliter) and 22.5 nmol per liter (643 pg per milliliter), respectively (P = 0.002), for androstenedione. A dose-response relation was apparent for these hormones; mean plasma levels increased concomitantly with cigarette consumption. The differences in hormone levels remained after adjustment for age and body-mass index. Mean levels of estrone, estradiol, testosterone, and sex-hormone-binding globulin did not differ between smokers and nonsmokers. These results suggest that the possible decreased risk of breast and endometrial cancer associated with cigarette smoking may not be mediated through lower levels of endogenous estrogen, at least in postmenopausal women, and they raise questions about the role of androgens in disease mechanisms in older populations.",0
899,2971014,Activation of liver macrophages following phenobarbital treatment of rats,"Phenobarbital is a potent inducer of hepatic cytochrome P-450 and is a tumor promoter in the two-stage model of liver carcinogenesis. In the present studies, we show that phenobarbital also induces an accumulation of activated macrophages in the livers of treated rats. These macrophages are larger and more stellate than resident Kupffer cells and are highly vacuolated. In addition, macrophages isolated from livers of phenobarbital-treated rats display increased phagocytosis of sheep red blood cells, chemotaxis toward the complement fragment C5a and enhanced production of hydrogen peroxide. Biologically active mediators released by activated macrophages have been implicated in tumor promotion as well as in the regulation of cytochrome P-450-mediated drug biotransformation. We propose that the activated macrophages that accumulate in the liver following phenobarbital treatment may contribute, at least in part, to the biological responses to this drug.",0
900,2981406,Circulating activated suppressor T lymphocytes in aplastic anemia,"""We studied the mechanism of hematopoietic suppression in aplastic anemia by means of two-color flow microfluorometric analysis of lymphocyte subpopulations and correlated the results with the occurrence in vitro of hematopoietic suppression and interferon production. In 12 patients with aplastic anemia a striking increase was observed in a population of """"activated"""" suppressor T lymphocytes, which were defined by binding of both anti-Leu-2 and anti-HLA-DR monoclonal antibodies (patients with aplastic anemia, 6.8 +/- 3.2 per cent [mean +/- S.D.]; normal subjects, 1.7 +/- 1.3; patients given multiple transfusions, 2.5 +/- 1.7). Tac antigen expression, another surface marker of lymphocyte activation, was increased on suppressor lymphocytes in all five patients examined (patients with aplastic anemia, 31 +/- 17 per cent; normal subjects, 0.7 +/- 0.24; patients given multiple transfusions, 2.3 +/- 1.2). When Tac+ and Tac- cells were separated in a cell sorter, only Tac+ cells produced interferon. When lymphocytes of patients with aplastic anemia were cocultured with normal bone marrow, only the Tac+ cell fraction showed hematopoietic suppressor activity. In one patient, in vitro elimination of suppressor lymphocytes by use of OKT8 antibody abolished spontaneous interferon production by bone-marrow cells. These results suggest that activated suppressor lymphocytes producing interferon have a role in the pathogenesis of bone-marrow failure, and indicate the usefulness of defined lymphokine and phenotypic markers in the study of aplastic anemia.""",0
901,2983212,Diet and 20-year mortality from coronary heart disease. The Ireland-Boston Diet-Heart Study,"In a prospective epidemiologic study of 1001 middle-aged men, we examined the relation between dietary information collected approximately 20 years ago and subsequent mortality from coronary heart disease. The men were initially enrolled in three cohorts: one of men born and living in Ireland, another of those born in Ireland who had emigrated to Boston, and the third of those born in the Boston area of Irish immigrants. There were no differences in mortality from coronary heart disease among the three cohorts. In within-population analyses, those who died of coronary heart disease had higher Keys (P = 0.06) and modified Hegsted (P = 0.02) dietary scores than did those who did not (a high score indicates a high intake of saturated fatty acids and cholesterol and a relatively low intake of polyunsaturated fatty acids). These associations were significant (P = 0.03 for the Keys and P = 0.04 for the modified Hegsted scores) after adjustment for other risk factors for coronary heart disease. Fiber intake (P = 0.04) and a vegetable-foods score, which rose with increased intake of fiber, vegetable protein, and starch (P = 0.02), were lower among those who died from coronary heart disease, though not significantly so after adjustment for other risk factors. A higher Keys score carried an increased risk of coronary heart disease (relative risk, 1.60), and a higher fiber intake carried a decreased risk (relative risk, 0.57). Overall, these results tend to support the hypothesis that diet is related, albeit weakly, to the development of coronary heart disease.",0
902,2984567,Epstein-Barr virus-associated B-cell proliferations of diverse clonal origins after bone marrow transplantation in a 12-year-old patient with severe combined immunodeficiency,"A 12-year-old boy with severe combined immunodeficiency who had been kept in a gnotobiotic environment since birth received bone marrow from a histoincompatible sibling in an attempt to reconstitute immunologic function. To prevent graft versus host disease, the donor's marrow was treated in vitro with monoclonal antibody and complement to remove alloreactive T cells. Eighty days after transplantation, the patient had a systemic illness characterized by fever, thrombocytopenia, gastrointestinal pain, and bleeding; he died on the 124th post-transplantation day. Postmortem examination revealed multiple tumor-like B-cell proliferations, recipient in origin, in numerous organs. Epstein-Barr virus (EBV) was isolated from the patient's pharyngeal secretions; EBV nuclear antigen was found in spontaneously transformed peripheral-blood lymphocytes, inflammatory cells from peritoneal fluid, and bone marrow cells; and EBV genomes were discovered in all tumor tissues. The donor's serum showed evidence of past EBV infection. Analysis of cellular immunoglobulin and immunoglobulin gene DNA from the tumors indicated both monoclonal and oligoclonal B-cell proliferations. These findings provide evidence for the evolution of EBV-induced polyclonal activation of B cells to oligoclonal B-cell proliferation and finally to monoclonal B-cell lymphoma.",0
903,2993884,Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation,"It has been suggested that there are altered levels of norepinephrine or other neurotransmitters at functionally important receptors in patients with depressive disorders. This hypothesis is difficult to study in the human central nervous system. However, noradrenergic function can be assessed indirectly with peripheral-blood lymphocytes used as a model of the beta-adrenergic receptor complex. We found that drug-free inpatients with endogenous depression had lower isoproterenol-stimulated cyclic AMP levels in intact lymphocytes than did healthy control subjects (3.9 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01). The density and affinity of beta-adrenergic receptors were similar in controls and depressed subjects (beta-receptor number, 5.4 +/- 0.7 and 5.3 +/- 0.8 fmol per 10(6) cells; binding affinity, 106 +/- 7.6 vs. 99.2 +/- 11.4 pM, respectively). When the depressed patients were subdivided by psychomotor manifestations, binding characteristics were indistinguishable among the subgroups. However, a significant reduction in beta-adrenergic responsiveness was observed in patients with psychomotor agitation, as compared with controls (2.6 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01), but not in patients with psychomotor retardation (5.8 +/- 1.1 pmol per 10(6) cells, P less than 0.05). Thus, the desensitization of beta-adrenergic receptors was correlated more closely with the severity of psychomotor agitation than with the overall severity of depression.",0
904,2993886,Rearrangements of genes for the antigen receptor on T cells as markers of lineage and clonality in human lymphoid neoplasms,"The T alpha and T beta chains of the heterodimeric T-lymphocyte antigen receptor are encoded by separated DNA segments that recombine during T-cell development. We have used rearrangements of the T beta gene as a widely applicable marker of clonality in the T-cell lineage. We show that the T beta genes are used in both the T8 and T4 subpopulations of normal T cells and that S�zary leukemia, adult T-cell leukemia, and the non-B-lineage acute lymphoblastic leukemias are clonal expansions of T cells. Furthermore, circulating T cells from a patient with the T8-cell-predominantly lymphocytosis associated with granulocytopenia are shown to be monoclonal. Finally, the sensitivity and specificity of this tumor-associated marker have been exploited to monitor the therapy of a patient with adult T-cell leukemia. These unique DNA rearrangements provide insights into the cellular origin, clonality, and natural history of T-cell neoplasia.",0
905,2995629,Diarrheal illness among infants and toddlers in day care centers. II. Comparison with day care homes and households,"During the second year of a prospective study of diarrheal illness among 0- to 36-month-old children in day care centers in Maricopa County, Arizona, we concurrently studied children of the same age in 30 day care homes and 102 households not using day care. The seasonal pattern of diarrhea, frequency of pathogen isolation, and relative frequency of individual pathogens were similar in the three settings. Giardia lamblia and rotavirus were the most common enteropathogens. Asymptomatic infection was identified in 14% to 21% of infant-toddler contacts of pathogen-positive cases of diarrhea. We compared rates of diarrhea in the three settings using five serial biweekly family-based surveys during the period of highest diarrhea rates. The incidence in infants and toddlers in DCCs (42 cases per 100 child months) was significantly higher than in DCHs (23 cases per 100 child-months) and in households not using day care (27 cases per 100 child-months); the DCH rate did not differ significantly from that in households not using day care. Among household sample children who began using day care during the survey period, the incidence of diarrhea was significantly higher than in household sample children not using day care. ",0
906,2995643,Differential inhibition of alpha adrenoceptor-mediated pressor responses by rat atrial natriuretic peptide in the pithed rat,"Previous investigations have shown that rat atrial natriuretic peptide (r-ANP,5-28, atriopeptin III), antagonizes the effects of various pressor hormones (angiotensin II, vasopressin and norepinephrine) but is ineffective against pressor responses to acute spinal cord stimulation. Because the latter are believed to be mediated by intrajunctional alpha-1 adrenoceptors, whereas the others are thought to involve mainly extrajunctional receptors, we explored the possible specificity of r-ANP for alpha adrenoceptor subtypes, by comparing r-ANP, the calcium channel blocker nifedipine and the vasodilator sodium nitroprusside in their ability to inhibit pressor responses to the alpha-2 and alpha-1 adrenoceptor agonists, clonidine and phenylephrine, in pithed, vagotomized rats. Acute pressor responses to bolus-injected clonidine were dose-dependently attenuated by both r-ANP (up to 21%) and nifedipine (up to 37%), but acute pressor responses to phenylephrine were unaffected. Sodium nitroprusside inhibited pressor responses to clonidine (up to 67%) and phenylephrine equally (up to 66%). Pressor responses during constant infusions of clonidine and phenylephrine were attenuated similarly by r-ANP and nifedipine. This pattern of results, alpha-2 adrenoceptor specificity during immediate pressor responses but not during sustained pressor responses, suggests that r-ANP, like nifedipine, attenuates those adrenoceptor-mediated pressor responses which depend on slow transmembrane calcium fluxes. ",0
907,2997003,Effects of dibutyryl cyclic AMP and gonadotropin-releasing hormone added prior to filter sterilization of the media and variation in oxygen partial pressure on output of human chorionic gonadotropin from term placental explants,"The effect of 2 mM dibutyryl cyclic AMP (dbcAMP) and 10 and 100 micrograms/ml gonadotropin-releasing hormone (GnRH) added prior to filter sterilization and of varying oxygen partial pressure (5, 20, and 95% oxygen) were evaluated using explants from each of 4 placentas on each of 6 days of culture. There were significant differences between placentas on days 1 and 2 of culture (both p less than 0.025), and day 4 (p less than 0.05), but there were no effects of GnRH or varying oxygen partial pressure on output of human chorionic gonadotropin under the conditions evaluated. ",0
908,2997555,"The immunologic effects, kinetics, and use of glucocorticosteroids",This article describes our current understanding of the immunologic effects of glucocorticosteroids and uses this information in an attempt to place the therapeutic dosing of glucocorticosteroids on a more rational basis. ,0
909,2997573,Regulation of beta-endorphin and ACTH in brain by estradiol,"The effect of estradiol on the brain concentration of immunoreactive beta-endorphin (beta-EP) and C-terminal ACTH (CLIP) was studied in ovariectomized rats. Dopamine, a known inhibitor of pituitary intermediate lobe pro-opiomelanocortin (POMC), was examined as a possible mediator of the estradiol induced changes in brain POMC. Animals were treated for 1 or 3 weeks with either 1) saline; 2) silastic estradiol implants; or 3) estradiol implants plus haloperidol 1 mg/kg/day. After one week of treatment no significant change in hypothalamic beta-EP content was noted in any group compared to the control level of 4.13 +/- .33 (SEM) pmoles although in the neurointermediate lobe beta-EP increased from 566 +/- 72 to 942 +/- 73 pmoles after haloperidol (p less than .005). After 3 weeks, however, hypothalamic beta-EP decreased from 3.96 +/- .28 to 2.74 +/- .19 pmoles (p less than .005) and C-terminal ACTH decreased from 3.78 +/- .33 to 2.82 +/- .18 pmoles (p less than .02) in the estradiol treated rats. This estradiol induced decrease in the hypothalamic content of beta-EP and C-terminal ACTH was not blocked by haloperidol. We conclude that estradiol lowers the hypothalamic content of beta-EP and CLIP and that this effect does not appear to be mediated by dopamine. ",0
910,2998022,Recombinants between attenuated and virulent strains of poliovirus type 1: derivation and characterization of recombinants with centrally located crossover points,"Recombinants with a centrally located crossover point were selected from crosses between poliovirus type 1 strains and intertypic (type 3/type 1) recombinants. Two such recombinants were characterized in some detail. In one of them (v1/a1-6), the 5' half of the genome was derived from a virulent type 1 strain, while the 3' half came from an attenuated type 1 strain. The genome of the other recombinant (a1/v1-7) had the reverse organization, with the 5' and 3' halves being derived from the type 1 attenuated and virulent strains, respectively. As deduced from the RNase T1 oligonucleotide maps, the a1/v1-7 genome also had a relatively short centrally located insert of the poliovirus type 3 origin. Both recombinants exhibited ts phenotypes. The RNA phenotypes of the recombinants corresponded to that of the parent donating the 3' half of the genome, v1/a1-6 and a1/v1-7 expressing RNA- and RNA +/- characters, respectively. Despite being a ts RNA- virus, v1/a1-6 proved to be neurovirulent when injected intracerebrally into Cercopithecus aethiops monkeys, although it exhibited a somewhat diminished level of pathogenicity as compared to its virulent type 1 parent. Recombinant a1/v1-7 behaved as an attenuated strain. These data supported our previous conclusion drawn from the experiments with intertypic poliovirus recombinants that the attenuated phenotype of poliovirus depends largely on the structure of the 5' half of its genome, although mutations of the 3' half may alleviate the virulence of the virus to a degree. ",0
911,2998109,Acquired immune deficiency syndrome (AIDS)],"Acquired immune deficiency syndrome (AIDS) is a new disease caused almost certainly by a transmissible agent, which is most likely a retrovirus termed HTLV-III. The disease is mainly spread by sexual, especially homosexual contact. Blood-borne transmission is another recognized form of spreading of the disease; it seems, however, that the disease is not readily spread via casual, non-sexual, or other than blood-borne routes. Although the disease is still concentrated in the major metropolitan areas of the United States, it is now increasingly observed in several countries throughout the world. The basic characteristic of the disease is a profound dysregulation of the immune system as proved by a qualitative and quantitative defect of helper T-lymphocytes as well as by B-cell hyperactivity. Clinical manifestations are those of severe and life-threatening opportunistic infections and unusual neoplasms, particularly Kaposi's sarcoma. The mortality is extremely high and may well approach 100%. Therapeutic efforts include the treatment of opportunistic infections and the search for agents which may reconstitute immunologic competence. ",0
912,2998131,Effects of a 72-hour prostacyclin infusion on the hormone levels in patients with obliterative arterial disease,"Effects of a 72-h prostacyclin (PGI2) infusion (5 ng/kg/min) on hormone levels were studied in 11 patients (5 males, 6 females) suffering from obliterative arterial disease of the lower extremities. ACTH, cortisol, TSH, prolactin (Prl), GH, LH, FSH, T3, T4, calcitonin, parathyroid hormone (PTH), insulin, plasma renin activity (PRA), aldosterone and testosterone levels were measured at -15, 0, 30, 120, 240 min and 24, 48, 72 and 96 h after the infusion. During the first 240 min Prl and GH levels showed an increase that was thought to be either an effect of release of hormones or a consequence of stress. At the same time the thyroid hormones, T3, T4 and calcitonin decreased, presumably owing to an alteration in the blood flow to the thyroid gland. All these hormone levels returned to normal at 24 h in spite of the infusion continuing. PRA increased only during the second half of the infusion. No changes were found in the levels of ACTH, cortisol, TSH, LH, FSH, PTH, insulin, aldosterone and testosterone during the infusion. Five diabetics showed the same hormonal changes as the non-diabetics and their blood sugar levels remained unaffected during and after the procedure. ",0
913,2998175,Cereal dietary fiber consumption and diverticular disease: a lifespan study in rats,"The relationship between consumption of dietary fiber (DF) from white bread, wholemeal bread, or bran and the development of diverticular disease of the colon has been investigated in a lifespan study using 1800 Wistar rats in nine diet groups. Use of the rat as a model for the human condition was validated by demonstration of significant relationships between fiber intake and fecal output and transit time, and the observation of true acquired diverticula, both single and multiple. Significant inverse relationships (mostly with p less than 0.001) were observed between the incidence of diverticula (and prediverticula) and the concentrations of fiber in the diets, measured by the neutral detergent fiber and Southgate methods. The study offers strong support to the Painter-Burkitt view of human diverticular disease as being due to fiber deficiency, if the extrapolation from rat to man is valid. On the same assumption, the amount of additional fiber required to be consumed in order to achieve a substantial reduction in incidence of the disease is very large. Effects of fiber on body weight, food intake, mineral levels, blood composition and properties, mortality, organ weights, and incidence of tumors and lesions are reported. Significantly fewer mammary tumors were found in rats fed the very high fiber stock diet than in those fed the purified diets. ",0
914,2998357,Multiple thyroid hormone binding sites on rat liver nuclear envelopes,"Nuclear envelopes relatively free of plasma membrane contamination were isolated from the male rat liver. Equilibrium binding of T3 to nuclear envelopes occurred after incubation for 3 h at 20 degrees C. Scatchard analysis revealed two classes of binding sites; a high affinity site having a KD of 1.8 nM with a maximum binding capacity of 14.5 pmol/mg protein and a low affinity site having a KD of 152.1 nM with a maximum binding capacity of 346.8 pmol/mg protein. No degradation of the radioligand occurred during incubation with the nuclear envelope. T4, rT3 and Triac competed effectively for the binding of T3 to the high affinity site whereas only T4 competed well for binding to the lower affinity site. The binding site was protease sensitive but not salt extractable. Multiple T3 binding sites having similar affinities have been reported on plasma membranes. An intriguing possibility is that membrane binding sites may be involved in translocation of thyroid hormone across membrane barriers. ",0
915,2998610,High incidence of amplification of the epidermal growth factor receptor gene in human squamous carcinoma cell lines,"Southern blot-hybridization analysis of DNAs from human tumors demonstrated amplification of the epidermal growth factor (EGF) receptor gene in 10 of 12 squamous cell carcinoma cell lines tested and in none of 18 tumor cell lines of nonsquamous cell carcinomas. The degree of amplification in the squamous cells varied from 2- to 50-fold relative to the epidermal keratinocyte. Hybridization analysis of the RNA showed that the amplification of the EGF receptor gene is accompanied with an increase of the 5.6 kilobases of EGF receptor mRNA. Scatchard plot analysis and sodium dodecyl sulfate-polyacrylamide gel analysis of the EGF receptor revealed that the synthesis of the EGF receptor is also greater in the cells with amplified EGF receptor gene. In contrast, Southern blot analysis of DNAs of primary tumors showed that incidence of amplification of the EGF receptor gene in squamous cells (1 of 6) was almost as frequent as in nonsquamous cells (1 of 4). These results show that amplification of the EGF receptor gene is commonly found in various tumors. In addition, our data suggest that primary squamous cell carcinomas with amplified EGF receptor gene may readily adapt to growth in tissue culture. ",0
916,2998828,Diphenylalkylamine calcium antagonists interact with alpha-adrenoceptor binding sites in aortic membranes,"Some interactions of calcium antagonists with [3H]prazosin and [3H]yohimbine binding sites were investigated in bovine aorta membranes. Diphenylalkylamines (flunarizine, cinnarizine and bepridil) acted as competitors of the two ligands with Ki values in the microM range. With the exception of verapamil, reference compounds (nifedipine, Bay-K 8644, diltiazem) and the peripheral benzodiazepine receptor antagonist PK 11195 did not displace the ligands. The apparent affinity of the diphenylalkylamines for alpha-adrenoceptor was consistent with the concentrations producing vasodilatation. ",0
917,2998853,Tyrosinase activity in the uveal tissue of the adult bovine eye,"Tyrosinase activity in crude extracts from various tissues of the adult bovine eye was examined biochemically. Enzyme activity was measured by using L-3,4-dihydroxyphenylalanine (L-DOPA) as substrate and determining colorimetrically by an increase in absorbancy at 400 or 475 nm. Tyrosinase activity was found in the ciliary body, iris, and choroid with the ciliary body having the highest enzyme activity. The enzyme was 1324-fold purified from the crude extract of the ciliary body by ammonium sulfate fractionation, trypsin digestion, followed by chromatography on Sephacryl S-200, hydroxylapatite, and DEAE-cellulose columns. The apparent Km value for L-DOPA was 0.2 mM and the molecular weight of the enzyme was estimated to be 70000 by gel method. The enzyme activity was markedly reduced by phenylthiourea and diethyldithiocarbamate, specific inhibitors of tyrosinase. ",0
918,2998954,Age-related reduction of beta-adrenoceptor sensitivity in rat heart occurs by multiple mechanisms,"Myocardial responsiveness to catecholamines was evaluated by measuring isoproterenol-stimulated adenylate cyclase activities in myocardial particulate fractions from Fischer 344 rats of 3, 12, and 24 months of age. Dose-response curves of isoproterenol revealed a progressive increase in the activation constant (Kact) with advancing age. In addition, the maximal velocity (Vmax) for 12- and 24-month-old groups was about 20-25% lower than for the 3-month-old group. Analysis of receptor-binding data and nonreceptor-mediated enzyme activities suggests that the age-related decrease in Vmax for isoproterenol may result from a loss of myocardial beta-receptors, whereas the increase in Kact is probably due to a deficit in the postreceptor components of the receptor-cyclase complex. ",0
919,2998964,Effect of glycoursodeoxycholate on precipitation of calcium carbonate,"The potential role of bile salts in preventing calcium carbonate precipitation was investigated by studying their interaction of Ca2+ and their inhibitory effects on calcium carbonate formation. Glycochenodeoxycholate micelles bound more calcium than did glycocholate. At bile salt concentrations exceeding 12.5 mM, glycoursodeoxycholate bound calcium as well as glycochenodexycholate did. Similar results for calcium binding were observed in mixed micelles of bile salts and lecithin. In bicarbonate (25 or 50 mM) and CaCl2 (10 mM) solutions, calcium carbonate formation was inhibited by the bile salts. Glycoursodeoxycholate and glycochenodeoxycholate (25 mM) prevented calcium carbonate formation which was delayed by glycocholate. This effect is not due to differences between both series of bile salts for calcium binding since glycoursodeoxycholate or glycochenodeoxycholate (25 mM) more efficiently prevented calcium carbonate precipitation than did 35 mM glycocholate in spite of the same Ca2+ binding. These results suggest that some bile salts may have a specific role in preventing calcium precipitation in bile. The mechanism is unknown. The physical properties of glycoursodeoxycholate and glycochenodeoxycholate do not support a role for CaCO3 precipitation in gallstone calcification during litholytic therapy.",0
920,2998971,Allelic variation adjacent to the human insulin and apolipoprotein C-II genes in different ethnic groups,"We have used DNA probes for the human insulin gene and apolipoprotein C-II (apo C-II) gene to determine the extent of allelic variation in different ethnic groups. The distribution of an apo C-II DNA polymorphism revealed by the restriction endonuclease Taq I showed no significant variation amongst racial groups; in contrast, an insulin gene-related DNA polymorphism showed marked variability. In Japanese, Chinese, and Asian Indian groups there was an increased frequency of homozygosity for the class 1 allele compared to Caucasian groups (P less than 0.001, P less than 0.01, and P less than 0.05, respectively). In Caucasian, Japanese, Chinese, and Asian Indian groups no class 2 allele was observed; but in the Negroid populations (African and West Indian) the class 2 allele frequencies were 0.23 and 0.25 respectively. Possible reasons for this variation in allele distribution are considered in relation to disease associations. ",0
921,2999094,Purification and properties of myo-inositol-1-phosphatase from rat brain,"myo-Inositol-1-phosphatase [EC 3.1.3.25] was purified from a cytosolic fraction of rat brain. The purified enzyme appeared homogeneous on SDS-polyacrylamide gel electrophoresis and its molecular weight was estimated to be 29,000. The molecular weight of the native enzyme was 55,000 as determined by molecular sieve chromatography. These values indicated that the native enzyme was composed of two identical subunits. The isoelectric point of the enzyme was 4.6. The enzyme hydrolyzed inositol-1-phosphate, 2'-AMP, 2'-GMP, beta-glycerophosphate, and alpha-glycerophosphate; the ratio of the reaction rates was 100 : 84 : 73 : 64 : 32. The Km values for inositol-1-phosphate, 2'-AMP, and beta-glycerophosphate were 1.2 X 10(-4) M, 1.9 X 10(-4) M, and 7.7 X 10(-4) M, respectively. Mn2+ and Ca2+ were strong competitive inhibitors against Mg2+, with Ki values of 3 microM and 20 microM, respectively. This result suggests that myo-inositol-1-phosphatase might be regulated by intracellular Ca2+ and/or Mn2+. Li+, which is known to show a therapeutic effect on manic-depressive disease and also to prolong the intrinsic periods of circadian rhythms in various organisms, was a potent uncompetitive inhibitor and inhibited 50% of the activity at 1 mM. The possibility that myo-inositol-1-phosphatase and inositol phospholipid metabolism are involved in circadian rhythm oscillation is discussed in terms of Li actions. ",0
922,2999592,Intra-blood-brain-barrier synthesis of HTLV-III-specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex,"Intra-blood-brain-barrier production of virus-specific antibody is good evidence of infection within the blood-brain barrier. Patients with the acquired immuno-deficiency syndrome (AIDS) have an increased incidence of neurologic abnormalities--i.e., unexplained, diffuse encephalopathy manifested clinically as chronic progressive dementia. To define the role of human T-cell lymphotropic virus Type III (HTLV-III), the etiologic agent of AIDS, in the pathogenesis of neurologic dysfunction, we compared cerebrospinal fluid and serum from patients with neurologic symptoms associated with AIDS and the AIDS-related complex for the presence of antibodies directed against HTLV-III. Antibodies directed against HTLV-III antigens were detected by four immunologic tests: a fixed-cell immunofluorescence assay, an enzyme-linked immunosorbent assay, immunoblots of viral lysates, and immunoprecipitation of cellular lysates. All patients were seropositive, and 22 of 23 (96 per cent) had HTLV-III-specific antibodies in their cerebrospinal fluid. Unique oligoclonal IgG bands were detected in the cerebrospinal fluid, and the rate of IgG synthesis within the blood-brain barrier was elevated. In eight of nine patients tested, the enzyme-linked immunosorbent assay showed that the percentage of HTLV-III-specific IgG in cerebrospinal fluid was higher than in serum, suggesting that HTLV-III infection of neurologic tissue occurs in the majority of patients with neurologic disease associated with AIDS or its related complex.",0
923,3000116,In vitro insulin action on different ATPases of erythrocyte membranes in normal and diabetic rats,"The in vitro effect of porcine insulin on Na+ + K+, Ca2+- and Mg2+-ATPases of the rat erythrocyte membrane of normal and alloxan-induced diabetic rats was investigated. Na+ + K+- and Ca2+-stimulated enzyme activities were significantly decreased in diabetic rats in comparison to normal animals. The specific activities of both these ATPases in the latter group were markedly reduced on pre-incubating the ghosts with insulin. Similar treatment of the erythrocyte membranes of diabetic animals, however, resulted in a significant increase of these activities. These qualitatively different effects of the hormone in the two groups increased progressively with hormone concentration and duration of pre-incubation. Mg2+-stimulated ATPase activity was not significantly affected in diabetes or by insulin. ",0
924,3000137,Psychiatric effects of cannabis use,"""That cannabis use may provoke mental disturbances is well known to Scandinavian psychiatrists today. A review of the psychiatric aspects of cannabis use is given, and the clinical signs of 70 cases of cannabis psychoses collected in Sweden are described. The bluntness and """"amotivation"""" following chronic cannabis use are discussed. Anxiety reactions, flashbacks, dysphoric reactions and an abstinence syndrome are all sequels of cannabis use. Three risk groups begin to emerge: a) Young teenage cannabis users who lose some of their capacity to learn complex functions and who flee from reality to a world of dreams. With its sedative effect, cannabis could modify such emotions as anger and anxiety and slow down the liberation process of adolescence. b) Heavy daily users, often persons who cannot cope with depression or their life circumstances. c) Psychiatric patients whose resistance to relapses into psychotic reactions might be diminished according to the psychotropic effects of cannabis. """,0
925,3000433,Protein and lipid structural transitions in cytochrome c oxidase-dimyristoylphosphatidylcholine reconstitutions,"The thermotropic behavior of the mitochondrial enzyme cytochrome c oxidase (EC 1.9.3.1) reconstituted in dimyristoylphosphatidylcholine (DMPC) vesicles has been studied by using high-sensitivity differential scanning calorimetry and fluorescence spectroscopy. The incorporation of cytochrome c oxidase into the phospholipid bilayer perturbs the thermodynamic parameters associated with the lipid phase transition in a manner analogous to other integral membrane proteins: it reduces the enthalpy change, lowers the transition temperature, and reduces the cooperative behavior of the phospholipid molecules. Analysis of the dependence of the enthalpy change on the protein:lipid molar ratio indicates that cytochrome c oxidase prevents 99 +/- 5 lipid molecules from participating in the main gel-liquid-crystalline transition. These phospholipid molecules presumably remain in the same physical state below and above the transition temperature of the bulk lipid, thus providing a more or less constant microenvironment to the protein molecule. The effect of the phospholipid bilayer matrix on the thermodynamic stability of the cytochrome c oxidase complex was examined by high-sensitivity differential scanning calorimetry. Detergent (Tween 80)-solubilized cytochrome c oxidase undergoes a complex, irreversible thermal denaturation process centered at 56 degrees C and characterized by an enthalpy change of 550 +/- 50 kcal/mol of enzyme complex. Reconstitution of the cytochrome c oxidase complex into DMPC vesicles shifts the transition temperature upward to 63 degrees C, indicating that the phospholipid bilayer moiety stabilizes the native conformation of the enzyme. The lipid bilayer environment contributes approximately 10 kcal/mol to the free energy of stabilization of the enzyme complex. The thermal unfolding of cytochrome c oxidase is not a two-state process.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
926,3000534,Modification of dental pain and cutaneous thermal sensitivity by physical exercise in man,"The effect of physical exercise on dental pain thresholds, the release of pituitary stress hormones and thermal sensitivity of skin was tested in healthy human subjects. Different levels of exercise (100-300 W) at different pedal frequencies were produced by a cycle ergometer. Thermal limen (the interval between warm and cool thresholds) determined from glabrous hand, hairy forearm and leg was used as a parameter of thermal sensitivity. In all subjects the heart rate and blood pressure were increased with increasing work load. Dental pain thresholds were elevated at high work loads with a concomitant activation of pituitary stress hormone (especially growth hormone) release. Thermal limens at all 3 sites were increased work load, too, independent of the pedal frequency. The increase of thermal limen was most marked in the leg and least in the glabrous hand. The results indicate that physical exercise produces a non-segmental, load-dependent decrease of pain and thermal sensitivity with a concomitant activation of pituitary stress mechanisms. The magnitude of modification varies with skin region. Activation of inhibitory mechanisms at spinal levels via muscle and proprioceptive afferents, in a way suggested by the gate control theory of pain mechanisms, seems to have only a minor, if any, contribution to the present findings, since a higher pedal frequency did not produce a more marked decrease of sensitivity. ",0
927,3000587,Serial culture of single adult human prostatic epithelial cells in serum-free medium containing low calcium and a new growth factor from bovine brain,"Primary cultures of epithelial cells from human prostate acini proliferate in defined medium. However, the limited availability of human tissue and the lack of knowledge of the conditions required for clonal growth and serial culture of epithelial cells have limited progress in the study of human prostate cell biology. Here we report conditions that permit the proliferation of single epithelial cells from normal, benign hyperplastic, and carcinomatous prostate through three to four serial passages, which represents at least seven to nine cumulative doublings of the cell populations. Primary cultures were prepared from prostatic acini. Monolayers resulting from the outgrowth of epithelial cells from acini were harvested and dissociated into suspensions of single cells which gave rise to discrete colonies in subsequent culture. The requirements for successful serial culture were (a) a low calcium concentration, (b) the presence of a growth factor that is concentrated in bovine neural tissue, (c), detachment of the epithelial cells with collagenase, and (d) harvest of cells before the cell concentration reached 6000 cells/cm2 of culture surface. Suspensions of single cells were successfully stored between subcultures in 10% dimethylsulfoxide with 5% fetal bovine serum and revived after storage for up to 2 months in liquid nitrogen. ",0
928,3000642,Enhancement by norepinephrine of automaticity in sheep cardiac Purkinje fibers exposed to hypoxic glucose-free Tyrode's solution: a role for alpha-adrenoceptors?,"A period of drive in the presence of norepinephrine (NE) may be followed by the induction or acceleration of spontaneous activity. Experiments were carried out in sheep cardiac Purkinje fibers to determine whether the effects of NE on automaticity were modified during superfusion with hypoxic glucose-free Tyrode's solution and to assess the possible contribution of alpha-adrenergic influences on automaticity under these conditions. The following results were obtained: Low concentrations of NE (10(-7) and 3 X 10(-7)M) were able to induce automaticity after a period of drive in normal oxygenated (97% O2, 3% CO2) Tyrode's solution. Superfusion with hypoxic (97% N2, 3% CO2) glucose-free Tyrode's solution enhanced NE-induced automaticity. Practolol, in concentrations able to block the effects of NE in normal oxygenated solution, did not counteract the effects of NE in hypoxic glucose-free solution. Yohimbine, but not prazosin, antagonized the effects of NE in hypoxic glucose-free solution. At the same concentration, yohimbine did not affect transmembrane potentials or automaticity induced by isoproterenol. It is concluded that alpha-adrenergic responsiveness appears to be enhanced during superfusion in vitro with hypoxic glucose-free solution, and that alpha-adrenoceptors belonging to the alpha 2-subtype in sheep cardiac Purkinje fibers might influence abnormal automaticity, possibly through an effect on oscillatory potentials. ",0
929,3001244,Identification of protein phosphatase 1 in synaptic junctions: dephosphorylation of endogenous calmodulin-dependent kinase II and synapse-enriched phosphoproteins,"A calcium/calmodulin-dependent protein kinase termed CaM-kinase II is a major component of synaptic junctions from forebrain and constitutes approximately 12% of total synaptic junction protein. CaM-kinase II phosphorylates at least seven polypeptides that are enriched in synaptic junctions, of which two represent the 50- and 60-kilodalton subunits of the protein kinase. In this report the nature of endogenous protein phosphatases which dephosphorylate each of the seven synaptic junction phosphoproteins was examined. Assays of synaptic junctions and other subcellular fractions from rat forebrain for type-1 and type-2 protein phosphatases revealed that protein phosphatase 1 (PrP-1) was specifically enriched in synaptic junctions with respect to cytosolic fractions. The activity of type-2 protein phosphatases was very low in synaptic junctions. Homogeneous PrP-1 from rabbit skeletal muscle was found to dephosphorylate each of the seven phosphoproteins in synaptic junctions. Inhibitors-1 and -2 were found to inhibit endogenous protein phosphatase activity by 70 to 80%. Since inhibitors-1 and -2 are specific inhibitors of PrP-1, these results indicate that this enzyme accounts for the majority of endogenous protein phosphatase activity in synaptic junctions. Approximately 15% of the protein phosphatase activity in synaptic junctions was type 2A, whereas PrP-2B and PrP-2C accounted for little, if any, of the activity toward endogenous or exogenous phosphoproteins. These results indicate that PrP-1 may be important in controlling the state of phosphorylation of synaptic junction proteins. ",0
930,3001394,Tension development in frog skeletal muscle induced by silver ions,"In single fibers of frog toe muscles placed in a Cl- free MOPS solution containing 1.8 mM Ca2+, tension developed slowly in the presence of very low concentrations of Ag+. This tension was not blocked by the administration of Co2+ or Ni2+. On the other hand, two types of transient tensions developed with the application of 5 microM Ag+, in fibers pretreated with 0-Ca2+ MOPS solution, containing either 2 mM Co2+ or 1mM Ni2+, for 10 min. In the presence of divalent cations or TTX, the first repetitive twitch-like contraction disappeared, indicating this tension is induced by action potentials repeatedly generated by the lack of divalent cations. The 2nd subsequent transient tension was caused by 5 microM Ag+ in the presence of various kinds of divalent cations, or TTX. After reversion to the resting tension, the fiber was contracted by adding more than 0.1 mM of Ca2+ or 25 mM caffeine to the external medium. Even when placed in a Ca2+-free solution containing 3 mM EGTA and 3 mM Mg2+ for 30 min, the fiber still developed an appreciable tension in response to 5 microM Ag+. These findings suggest that a transient development of the Ag+-induced tension does not require the presence of external Ca2+. A specific sulfhydryl reagent, pCMPS, did not contract the muscle fiber. Therefore, Ag+ may develop tension by mediating unknown chemical reaction(s) other than the sulfhydryl group on T-tubular membrane proteins. ",0
931,3001579,Evidence for excitatory actions of histamine on supraoptic neurons in vitro: mediation by an H1-type receptor,"The effects of histamine on the firing of supraoptic neurosecretory neurons in the rat were examined in vitro using acutely prepared, hypothalamo-neurohypophysial explants perifused with an artificial cerebrospinal fluid. Extracellular action potentials meeting the criteria of antidromic invasion from neurohypophysial stalk stimulation were recorded from 135 neurons in the tuberal portion of the supraoptic nucleus, which lies superficially along the tuber cinereum and consists of mostly vasopressin-containing neurons. Units could be classified as slow/silent (76.3%), phasic (21.5%) or continuous (2.2%) on the basis of their spontaneous activity. Histamine applied briefly to the perifusate excited approximately one-third of the slow silent neurons and approximately two-thirds of the phasic neurons, with a wide range (10(-3)-10(-9)) in the effective concentration across neurons. The H1-receptor agonists 2-pyridylethylamine and 2-thiazolylethylamine mimicked these excitations in 10 of 12 and 3 of 6 neurons tested, respectively. The H2-receptor agonists dimaprit (4 neurons) and impromidine (5 neurons) failed to excite any of the tested neurons previously excited by histamine. The H1-receptor antagonist promethazine antagonized histamine's excitatory effect in 8 of 9 cells, while the H2-receptor antagonist cimetidine had little effect on the 9 cells tested. Histamine also modified bursts of activity induced in some slow/silent neurons by antidromic stimulation without having an observable effect in the absence of an antidromic burst. In 10 of 18 neurons histamine produced an elongation of burst duration and a modest increase in intraburst firing rate when applied during an antidromically evoked burst. In an additional 5 of 17 neurons, which had neither previously responded to histamine nor shown an antidromically-evoked burst, the pairing of histamine application and antidromic shocks resulted in an antidromically evoked burst. The effects of histamine on evoked bursts also appeared to be mediated by an H1-receptor. Histamine's excitation of supraoptic neurons is thus dependent on the electrical activity expressed by the neuron at the time of testing. Conductances activated by depolarization of the neuron may be modified by histamine or this compound may alter the threshold for burst generation. Considered with data showing H1-receptor localization and histamine-immunoreactive fibers within the supraoptic nucleus, the present results, as well as those showing the potency of centrally applied histamine in releasing vasopressin, suggest histamine may act physiologically by altering the electrical activity of vasopressin-secreting neurons. ",0
932,3001668,Relationship of ACTH1-39-immunostained fibers and magnocellular neurons in the paraventricular nucleus of rat hypothalamus,Dual antigen immunocytochemical staining procedures were used in the same tissue section to determine the distribution of ACTH immunostained fibers and varicosities within the magnocellular and parvocellular divisions in the paraventricular nucleus (PVN) of rat hypothalamus and elucidate its anatomical relationship to vasopressin (VP) and oxytocin (OXY)-containing neurons. Double immunostained preparations using glucose oxidase-antiglucose oxidase complex combined with PAP complex to visualize two antigens with contrasting colors in the same tissue section were employed. ACTH-immunoreactive (ir) fibers were distributed throughout the periventricular stratum and the parvocellular component of the PVN; in the latter area fibers were particularly dense in the ventral medial portion of the medial parvocellular division. Dual immunostained sections revealed a close anatomical association between opiocortin fibers and oxytocin and vasopressin parvocellular neurons. ACTH immunostained fibers were present in the anterior and medial magnocellular component of PVN and in the ventral medial portion of the posterior magnocellular division; these immunoreactive fibers were in intimate proximity to oxytocin-ir perikarya. The very close approximation between the ACTH-ir fibers and oxytocin-containing cell bodies suggests potential cell to cell communication between the two peptidergic systems in PVN. Few ACTH immunostained fibers were seen in the dorsal lateral portion of the posterior magnocellular division in which vasopressinergic neurons predominate. The present anatomical study supports pharmacological and physiological studies which indicate that opioids can influence the activity of magnocellular PV neurons. This study also elucidates an anatomical relationship between opiocortins (ACTH1-39) and parvocellular PV neurons which suggests that the opiocortin system may play a role in the regulation of both the neuroendocrine and autonomic activities of specific PV neurons. ,0
933,3001716,Independent segregation of two antigenic specificities (VP3 and VP7) involved in neutralization of rotavirus infectivity,"Antiserum prepared against the M37 strain of rotavirus, recovered from an asymptomatic newborn infant in Venezuela, neutralized two prototype human rotaviruses that define two separate serotypes: serotype 1 (Wa) and serotype 4 (ST3). Thus, the M37 strain is a naturally occurring intertypic rotavirus. Analysis of reassortant viruses produced during coinfection in vitro indicated that the observed dual serotype specificity of M37 resulted from sharing a related outer capsid protein, VP3, with the ST3 virus and another related outer capsid protein, VP7, with the Wa virus. Analysis of single (VP3)-gene-substitution reassortants indicated that VP3 was as potent an immunogen as VP7. In addition, direct evidence was obtained that the serotype specificity of neutralizing antibody elicited by VP3 can differ from the serotype specificity of neutralizing antibody elicited by VP7, indicating the need for a dual system of rotavirus classification in which the neutralization specificity of both VP3 and VP7 outer capsid proteins are identified. ",0
934,3001784,"The effects of Org 2766 on the performance of sham, neocortical, and hippocampal-lesioned rats in a food search task","""The behavioral effects of an ACTH4-9 variant, Org 2766, given for one week postoperatively at a dose of 1 microgram/rat daily, were evaluated in animals given hippocampal, neocortical, or """"sham"""" lesions. After the week during which the injections were given, the animals were tested for 5 days in a food-search task in which food was hidden in two recessed holes in the floor. On the next day the ability of the rats to find food in these same two baited holes was tested in the presence of 14 additional holes that were not baited. On the following day, the animals were tested again, this time with all 16 holes baited. To assess the long-term effects of Org 2766 treatment, the animals were tested once again 2-3 months later in the same apparatus with 16 empty holes. In general, rats with lesions restricted to the neocortex were severely impaired in the task and were unaffected by prior treatment with Org 2766. Animals with hippocampal damage quickly learned the task and were hyperactive. During the test session with 16 baited holes they showed differential behavioral changes suggesting attentional deficits not seen in """"sham"""" operated rats. These deficits were attenuated by prior Org 2766 treatment, whereas the lesion-induced hyperactivity was not. Treatment with Org 2766 impaired all aspects of performance of """"sham"""" operated animals. """,0
935,3001785,Delta-9-tetrahydrocannabinol potentiates the disruptive effects of phencyclidine on repeated acquisition in monkeys,"Patas monkeys acquired a different four-response chain each session by responding sequentially on three keys or levers in the presence of four discriminative stimuli (geometric forms or numerals). The response chain was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. Each day there were four 15-min sessions, with a 10-min intersession interval. Cumulative dose-effect curves for phencyclidine were obtained by giving an IM injection before each of the four sessions; successive injections increased the cumulative dose by 1/4 log-unit steps. When phencyclidine was administered alone, overall response rate decreased and percent errors increased with increasing doses. When delta-9-tetrahydrocannabinol (THC) was administered PO before the first session at a dose that was ineffective when given alone, the phencyclidine dose-effect curves for both rate and accuracy tended to shift to the left. After pretreatment with a higher dose of THC, which decreased rate in one of three subjects without affecting accuracy when given alone, the rate-decreasing and error-increasing effects of phencyclidine were generally even more pronounced. The results indicate that THC potentiates the disruptive effects of phencyclidine on complex operant behavior in monkeys. ",0
936,3002027,Polyomavirus-transformed FR 3T3 rat cells are able to form metastases in syngeneic rats,"A series of polyomavirus-transformed FR 3T3 rat cell lines were tested for their tumorigenic and metastatic properties after subcutaneous inoculation of syngeneic Fisher rats. All of them grew into tumors, which appeared with variable latency periods; the TD50 varied from cell line to cell line. Eight of the 18 transformants that were inoculated gave rise to metastases, always localized in the lung. The capacity to form metastases, though at a low frequency, was also conferred on FR 3T3 cells upon transformation with a recombinant plasmid encoding only the middle-T protein. Fibroblast-like cells were predominantly observed upon histological examination of the metastases. Culture cell lines were derived from independent tumors and metastases induced by two transformants with low and high metastatic potentials, respectively. Metastasis-derived cell lines exhibited metastatic potentials similar to those of the respective original transformants. All the tumor- and metastasis-derived cell lines synthesized the same early viral polypeptides as the respective original transformants; in contrast, the viral DNA integrations evolved during tumor and metastasis formation. ",0
937,3002146,Effects of dietary supplementation with selenomethionine on the teratogenic effect of ionizing radiation in mice,"Female C3H mice were fed a standard pellet diet (containing 0.2 ppm Se and 30 ppm vit. E) or the same diet supplemented with 0.8 ppm (low dose) or 3.4 ppm (high dose) of selenomethionine for 10 weeks. After mating with males receiving the standard diet the mice were subjected, on the 9th day of pregnancy, to whole body roentgen irradiation of 1.75 Gy. On day 18 of gestation the frequency of resorptions, mortality and the incidence of fetal malformations were studied. Supplementation with Se-methionine resulted in a significant but dose-independent decrease (p less than 0.005) of the number of malformed fetuses from 62 per cent in the irradiated controls to 47 per cent in the low Se-group and high Se-group, respectively. In addition, the number of total malformations as well as fetal resorptions were significantly decreased in a dose-independent manner in the supplemented groups. The decrease in fetal malformations occurred proportionally for all the major malformations observed, i.e. short or kinked tail, rib and vertebral malformations, coloboma and deformation of retina and iris. Glutathione peroxidase activity in whole blood of Se-methionine fed mice was significantly increased. Thus, Se-rich diet may result in scavenaging of radiation-induced hydroperoxides. ",0
938,3002214,Response of cattle persistently infected with noncytopathic bovine viral diarrhea virus to vaccination for bovine viral diarrhea and to subsequent challenge exposure with cytopathic bovine viral diarrhea virus,"Nine steers persistently infected with noncytopathic bovine viral diarrhea (BVD) virus were allotted into 3 groups (3 cattle/group). Cattle in group A were vaccinated with a modified-live BVD virus vaccine of porcine cell origin, cattle in group B with a modified-live BVD virus vaccine of bovine cell origin, and cattle in group C with a killed BVD virus vaccine of bovine cell origin. Detrimental effects due to vaccination were not seen. Six weeks after vaccination, the steers were challenge exposed with a cytopathic BVD virus. All steers developed mucosal disease after challenge exposure, produced antibodies that neutralized various isolates of BVD virus, and remained persistently infected until death. Steers given killed virus vaccine had a minimal neutralizing-antibody response and developed mucosal disease as quickly as reported for challenge-exposed, nonvaccinated, persistently infected cattle. Steers given modified-live virus vaccines had higher neutralizing-antibody response and longer intervals from challenge exposure to development of mucosal disease. The specificity of the neutralizing-antibody response differed between groups of vaccinated cattle. ",0
939,3002367,Measurement of the potential activity of the type-1 and type-2 protein phosphatases in the crude tissue extract,"Although activation and conversion of the inactive/latent high-molecular-weight phosphatases to the Mr = approximately 35,000 catalytic subunits can be achieved by several procedures including freezing/thawing in 0.2 M 2-mercaptoethanol and digestion by proteolytic enzymes, strong indications have been obtained that they are distinct stimulating processes. For instance, when pig brain extracts were treated with trypsin, the type-1 phosphatase could be stimulated approximately 40 fold while the type-2 phosphatase was not slightly modified. Conversely, when the same crude extracts were treated with freezing/thawing in 2-mercaptoethanol, the type-2 phosphatase could be stimulated approximately 10 fold but surprisingly the type-1 species was not slightly influenced. It is suggested that hormonal study on the activity changes of the type-1 and type-2 phosphatase in a crude extract can be made possible by the selective using of these two triggers. ",0
940,3002492,Synthetic oligodeoxyribonucleotides as tools in molecular genetics: the characterization of the CYC1 (iso-1-cytochrome c encoding) locus of Saccharomyces cerevisiae,"""The use of synthetic oligodeoxyribonucleotides as tools for the isolation, characterization and mutagenesis of eukaryote genes has played a major role in the molecular definition of the CYC1 locus of Saccharomyces cerevisiae, which is the structural gene for the apoprotein of iso-1-cytochrome c. Thus, the possibility of using a synthetic oligodeoxyribonucleotide as a probe to identify and monitor the isolation of a specific gene was first established by model studies which defined the melting temperatures (TmS) for duplexes of oligonucleotides of different lengths and base compositions. This led to the isolation of the CYC1 locus using a synthetic 13 nucleotide probe. A more convenient strategy for determination of DNA sequences by the Sanger method was provided by using synthetic oligodeoxyribonucleotides as primers with denatured double-strand plasmid DNA as template. By this means, the sequence of the CYC1 locus was determined by """"walking"""" along the gene without isolating restriction fragments of the DNA or separating DNA strands. Synthetic oligodeoxyribonucleotides, used as primers for reverse transcriptase with mRNA as template, were also used to precisely define the 5'- and 3'-ends of the iso-1-cytochrome c mRNA. Yet another application of synthetic oligodeoxyribonucleotides is their use as specific mutagens after in vitro incorporation into double-stranded DNA. In the case of iso-1-cytochrome c, this mutagenic strategy is being used to define the role of conserved amino-acids in cytochrome function.(ABSTRACT TRUNCATED AT 250 WORDS) """,0
941,3002687,A B-cell hybridoma product inhibiting antibody secretion via 5'-nucleotidase,"A mouse spleen cell/plasmacytoma fusion designed to generate hybridomas making monoclonal antibodies to human lymphocyte 5'-nucleotidase yielded three hybridomas secreting material which inhibited about 50% of human and mouse lymphocyte ecto 5'-nucleotidase activity. The inhibition proved not to be due to antibody but to material of molecular weight 44,000 +/- 7,000 which was not part of an immunoglobulin molecule, although it may be related to a B cell Fc gamma receptor. In a haemolytic plaque assay this material inhibited the production of IgG but not IgM antibody by spleen cells of mice immunized with dinitrophenylated keyhole limpit haemocyanin. By contrast, IgG production by pokeweed mitogen-stimulated human tonsillar lymphocytes (assessed by reverse haemolytic plaque assay) was partially inhibited only by ascitic fluid of one of the hybridomas. The factor was called BAN (B cell anti 5'-nucleotidase). The suppressive action of BAN on IgG production was blocked by antibodies against 5'-nucleotidase suggesting that the lymphocyte enzyme may be acting as a BAN receptor. ",0
942,3002828,Embryonic myosin heavy chain as a differentiation marker of developing human skeletal muscle and rhabdomyosarcoma. A monoclonal antibody study,"Hybridoma cell lines were obtained from the fusion of NS-O myeloma cells with spleen cells of mice immunized with bovine fetal skeletal myosin. A stable hybridoma clone, BF-G6, produced immunoglobulin G1 k antibodies reacting specifically with embryonic-type myosin heavy chains present in fetal but not in neonatal or adult human skeletal muscle, as determined by enzyme immunoassay and immunoblot analysis. Fetal but not adult skeletal muscle fibers were stained by this monoclonal antibody in indirect immunofluorescence assays; smooth muscle cells and cardiac muscle cells, as well as non-muscle cells were also unreactive. Solid tumors of infants and children were tested for reactivity with BF-G6 by immunofluorescence and immunoperoxidase staining. Embryonic myosin heavy chain was expressed in rhabdomyosarcomas but not in other types of tumor, except for Wilms' tumor. Rhabdomyosarcoma cells isolated from a bone marrow metastasis and grown in vitro for several months were also labelled by BF-G6. Embryonic myosin heavy chain can thus be used as a specific differentiation marker of normal and neoplastic skeletal muscle tissue. ",0
943,3002950,Pure mucinous carcinomas of breast: morphologic features and prognostic correlates,"Fifty-three pure mucinous carcinomas of breast were studied, with long-term follow-up evaluation (average, 15 years) for 37. The mean age of the patients was 63 years. Long-term survival (Kaplan-Meier method) was 68 per cent, excluding non-tumor-related deaths. Median survival for the patients with fatal carcinomas was 11.3 years. Fatal and disseminated carcinomas were best predicted by the presence of axillary metastases and by tumor cellularity and size. Only five of the patients had axillary metastases at mastectomy, but in four of these five patients distant metastases developed later. The diameters of all ten of the fatal and disseminated carcinomas were at least 2.5 cm, while 17 of the 27 long-term survivors had smaller tumors. All ten of the fatal and disseminated carcinomas had cellularity of more than 10 per cent, while 12 of 27 long-term survivors had less cellular tumors. Tumor cellularity did not correlate with tumor size; these features were entirely independent. Thus, in contrast to the findings of some prior studies with shorter follow-up periods, pure mucinous carcinomas were seen to be slowly growing, but fully malignant, tumors warranting standard breast carcinoma treatment. ",0
944,3002980,Central adrenergic receptor control of renal function in conscious hypertensive rats,"The role of central nervous system alpha-adrenergic and beta-adrenergic receptors in the increased renal sympathetic nerve activity and antinatriuresis resulting from environmental stress (air stress) in conscious spontaneously hypertensive rats (SHR) was examined. Intracerebroventricular administration of the alpha 2-adrenergic receptor agonist clonidine (1, 5, and 15 micrograms) prevented the effects of air stress on renal sympathetic nerve activity and urinary sodium excretion. Clonidine, 5 and 15 micrograms, lowered baseline mean arterial pressure and renal sympathetic nerve activity and increased baseline urine flow rate and urinary sodium excretion; clonidine, 1 micrograms, had no effect on these baseline levels. Intravenous administration of 5 micrograms, but not 1 microgram of clonidine, abolished the renal responses to air stress. Intracerebroventricular administration of alpha 2-adrenergic receptor antagonists (yohimbine, rauwolscine) reversed the effects of clonidine, alpha 2-adrenergic receptor blockade alone, alpha 1-adrenergic receptor blockade (20 micrograms prazosin), or combined alpha 1-adrenergic and alpha 2-adrenergic receptor blockade (30 micrograms phenoxybenzamine) had no effect on the renal sympathetic nerve activity or antinatriuretic responses to air stress. Intracerebroventricular, but not intravenous, administration of the beta 2-adrenergic receptor antagonist ICI 118551 (30 micrograms) prevented the increased renal sympathetic nerve activity and antinatriuretic responses to air stress. In contrast, intracerebroventricular administration of the beta 1-adrenergic receptor antagonist atenolol (30 micrograms) had no effect on the renal responses to air stress. These results indicate that the increased renal sympathetic nerve activity and antinatriuresis resulting from environmental stress in conscious SHR can be prevented by pharmacological stimulation of central alpha 2-adrenergic receptors or by blockade of central beta 2-adrenergic receptors. ",0
945,3002999,The design of a pentavalent 99mTc-dimercaptosuccinate complex as a tumor imaging agent,"In our search for a technetium-tumor seeking agent, the chemical characteristic of polynuclear Ga-citrate attracted our attention. On this basis, we selected the ligand dimercaptosuccinic acid (DMS) and appropriate labeling conditions in the design of 99mTc(V)-DMS. Chemical characterization was performed by thin layer chromatography, electrophoresis, Sephadex column chromatography and spectrophotometric studies at the chemical concentration (99Tc). Biodistribution in mice bearing Ehrlich ascites tumor and scintigraphic images in VX-2 tumor-bearing rabbit, indicated the great applicability of 99mTc(V)-DMS as a new tumor imaging agent. Its distinctive characteristic, different from the kidney imaging agent (99mTc-DMSA) is demonstrated and the biological implication of hydrolytic polynucleation of pentavalent technetium, through an anionic specie Tc(V)O3-(4), in the tumor cell is discussed. ",0
946,3003086,Evidence for the existence of multiple alpha 1-acid glycoprotein genes in the mouse,"Three alpha 1-acid glycoprotein (AGP) cDNA clones have been isolated from a mouse liver library. Restriction enzyme mapping and sequencing of these cDNAs have shown that two, pMAGP2 and pMAGP3, are virtually identical, whereas the third, pMAGP4, differs significantly both in sequence and restriction enzyme sites. The sequences are 91% identical and differ from each other by single base differences exclusively. No frameshifts are observed, and no termination codons are generated by the single base differences. We interpret these data to indicate that there are at least two distinct AGP genes in the mouse and that two species of AGP mRNA are formed by the transcription of these genes in the liver. Based on the large number of single amino acid substitutions previously observed in human AGP (Schmid, K., Kaufmann, H., Isemura, S., Bauer, F., Emura, J., Motoyama, T., Ishiguro, M., and Nanno, S. (1973) Biochemistry 12, 2711-2724), we propose that at least two functional AGP genes may also exist in humans. ",0
947,3003097,Hormone-stimulated polyphosphoinositide breakdown in rat liver plasma membranes. Roles of guanine nucleotides and calcium,"Calcium-sensitive inositide release in a purified rat liver plasma membrane preparation is increased by calcium-mobilizing hormones in the presence of guanine nucleotides. Vasopressin-stimulated inositide release is evident in the presence of GTP or its nonhydrolyzable analogs guanyl-5'-yl imidodiphosphate and guanosine 5'-(3-O-thio)triphosphate (GTP gamma S). The stimulation of inositide release by (-)-epinephrine (alpha 1), angiotensin II, or vasopressin in the presence of either 1 microM or 10 microM GTP gamma S correlates with the number of receptors present for each hormone. The guanine nucleotide and hormonal stimulation is evident on both inositol trisphosphate production and phosphatidylinositol bisphosphate degradation. Ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (1 mM) completely abolishes stimulation by guanine nucleotides and hormone. Prior treatment of plasma membranes with cholera toxin or islet activating protein or prior injection of animals with islet activating protein does not affect stimulation of inositide release by GTP gamma S or GTP gamma S plus vasopressin. Stimulation by GTP gamma S is dependent upon magnesium and is inhibitable by guanosine 5'-(2-O-thio) diphosphate. Inositide release from the plasma membrane exhibits half-maximal stimulation by calcium at approximately 100 nM free calcium in the presence of 1.5 mM MgCl2 and at approximately 10 microM free calcium in the presence of 10 mM MgCl2. Addition of guanine nucleotides decreases the requirement for calcium and also increases the activity at saturating calcium. The results presented suggest that calcium-mobilizing hormones stimulate polyphosphoinositide breakdown in rat liver plasma membranes through a novel guanine nucleotide binding protein. ",0
948,3003398,Dissociation of newly synthesized Sendai viral proteins from the cytoplasmic surface of isolated plasma membranes of infected cells,"The interaction of Sendai viral proteins with the membranes of infected cells during budding of progeny virions was studied. BHK cells infected with Sendai virus were labeled with [35S]methionine, and the plasma membranes were purified on polycationic polyacrylamide beads. The isolated membranes were incubated with various agents which perturb protein structure to dissociate viral proteins from the membranes. Incubation of membranes with thiocyanate and guanidine removed both the M and nucleocapsid proteins. Urea (6 M) removed the nucleocapsid proteins but removed M protein only in the presence of 0.1 or 1.0 M KCl. In contrast, high salt concentrations alone eluted only the M protein, leaving the nucleocapsid proteins completely membrane bound. About 65% of the M protein was eluted in the presence of 4 M KCl. The remaining membrane-associated M protein was resistant to further extraction by 4 M KCl. Thus, M protein forms two types of interaction with the membrane, one of them being a more extensive association with the membrane than the other. ",0
949,3003815,Characterization of biological properties of synthetic and biological leukotriene B3,"Leukotriene B3 was chemically synthesized and its ability to aggregate rat polymorphonuclear leukocytes (PMN) and to enhance chemokinesis of human leukocytes demonstrated. In both these assays the potency of synthetic leukotriene B3 was marginally less than that of leukotriene B4. Rat PMN incubated with leukotriene A3 were very inefficient in the enzymatic conversion of this epoxide to leukotriene B3. However, the leukotriene B3 produced was able to aggregate rat PMN. These results suggest that unlike leukotriene B5, the proinflammatory properties of leukotriene B3 are similar to those of leukotriene B4. However, since the enzymatic conversion of leukotriene A3 to leukotriene B3 is extremely poor it seems unlikely that leukotriene B3 itself has any major role in vivo. ",0
950,3004186,Alterations in cardiovascular structure and function with advancing age,"The greatest difficulty in studying the effects of aging on cardiovascular structure and function lies in separating the effects of aging itself from those of the inextricably entwined disease processes and life-style changes that accompany aging. Age-related stiffening of the arterial tree results in an increased systolic blood pressure, which appears to impose a greater load on the heart. Probably as an adaptive mechanism to maintain normal wall stress, a modest age-associated concentric left ventricular hypertrophy develops, which approximates 30% between ages 25 and 80. The decrease in mitral valve E-F slope and increase in the left atrial dimension, which are seen with advancing age, may be construed as the consequences of a thicker-walled, less compliant left ventricle. Systolic left ventricular function, measured at rest either by echocardiography or radionuclide techniques, is unaffected by aging. Aerobic exercise capacity, whether measured as total work performance or maximal oxygen consumption declines with age, although in subjects who maintain a high level of physical activity, the decline appears to be approximately half of the 10% per decade decrease seen in sedentary persons. An age-related decline in maximal exercise heart rate has been a universal finding. Although several studies over the past 4 decades have found cardiac output to decrease with age, both at rest and during exercise, a recent study of subjects carefully screened to exclude latent coronary artery disease found no such decline in cardiac output. In these subjects, the age-related decline in maximal heart rate and systolic emptying at peak exercise was offset by an increased utilization of the Frank-Starling mechanism. An attractive hypothesis for explaining the hemodynamic profile of a decreased maximum heart rate, increased preload and decrease in ejection fraction at maximal effort, despite elevated norepinephrine levels, is an age-associated, diminished end-organ responsiveness similar to beta-adrenergic blockade. ",0
951,3004194,Wilms' tumor detection in patients with sporadic aniridia. Successful use of ultrasound,"Eleven patients with sporadic aniridia have been followed up for periods of time ranging from eight months to ten years. The initial renal evaluation included an intravenous pyelogram and ultrasound. Ultrasound evaluation was then performed every four to six months until 8 years of age. After 8 years of age, evaluation was performed every six to 12 months. Two of 11 patients were found to have Wilms' tumors. Ultrasound was sensitive enough to find small lesions prior to extension from the kidney. Ultrasound evaluation permits early detection without repeated radiation, sedation, or contrast and offers an easy technique for follow-up of patients with sporadic aniridia who have a high likelihood of developing a Wilms' tumor. ",0
952,3004328,Development of methods to measure virus inactivation in fresh waters,"This study concerns the identification and correction of deficiencies in methods used to measure inactivation rates of enteric viruses seeded into environmental waters. It was found that viable microorganisms in an environmental water sample increased greatly after addition of small amounts of nutrients normally present in the unpurified seed virus preparation. This burst of microbial growth was not observed after seeding the water with purified virus. The use of radioactively labeled poliovirus revealed that high percentages of virus particles, sometimes greater than 99%, were lost through adherence to containers, especially in less turbid waters. This effect was partially overcome by the use of polypropylene containers and by the absence of movement during incubation. Adherence to containers clearly demonstrated the need for labeled viruses to monitor losses in this type of study. Loss of viral infectivity in samples found to occur during freezing was avoided by addition of broth. Finally, microbial contamination of the cell cultures during infectivity assays was overcome by the use of gentamicin and increased concentrations of penicillin, streptomycin, and amphotericin B. ",0
953,3004546,Pharmacokinetics of enalapril in normal subjects and patients with renal impairment,"The pharmacokinetics of enalaprilat were studied after administration of single and multiple doses of enalapril maleate to people with normal and impaired renal function. Renal impairment was associated with higher serum concentrations of enalaprilat, longer times to peak concentrations, slower decline of serum concentrations and with reduced urinary elimination. Urinary elimination of enalaprilat was closely related to renal function. In patients with severe renal impairment (GFR values below 30 ml min-1 1.73 m-2) significantly smaller doses of enalapril maleate will be required than in patients with normal or less severely impaired renal function. ",0
954,3004600,A 200 kDa surface glycoprotein of human fibroblasts encoded by a gene on chromosome 11 is regulated by cyclic AMP,"A gene mapped to the long arm of human chromosome 11 was previously characterized to code for a cell-surface glycoprotein of an apparent molecular mass of 200 kDa in fibroblasts. We now report that this surface protein is expressed in an increased amount when human fibroblasts or human X Chinese-hamster hybrid cells containing human chromosome 11 are treated with 1 mM dibutyryl cyclic AMP. A detailed analysis of this phenomenon of induction was performed using a long-established, stable cell line of human X Chinese-hamster hybrid cells, J1 clone, which contained human chromosome 11 and expressed the 200 kDa glycoprotein of human origin. It was shown that the 200 kDa protein of J1 cells was inducible with 1 mM dibutyryl cyclic AMP, 10 mM unmodified cyclic AMP, 0.2 mM 8-para-chlorophenylthio cyclic AMP or 1 nM cholera toxin. Induction was potentiated by the addition of a phosphodiesterase inhibitor, Ro 20-1724. These results are consistent with the finding in human fibroblast, confirming that human fibroblasts express a 200 kDa glycoprotein on their surface which is regulated by intracellular concentrations of cyclic AMP. The regulation may be at the level of transcription since the addition of actinomycin D prevented the induction. ",0
955,3004621,Assessment of malignancy potential in so-called interval mammary carcinomas,"Forty-two so-called interval cancers of the breast were studied. The mammograms were reviewed and the tumors were classified as 14 'unrecognized', 9 'observer error', 1 'technical error' and 18 'true' interval cancers. By using a scoring system based upon histologic differentiation, axillary nodal status, estrogen receptor level, and nuclear DNA content, eight ductal carcinomas with high malignancy potential were identified. All of these tumors belonged to the group 'true' interval cancer. The data indicate that the mammographic subgroup 'true' interval cancer identifies the highly malignant tumors. However, even this strictly selected subgroup is heterogeneous since it also includes some tumors with low malignancy potential. ",0
956,3004711,Characterization of acquired epipodophyllotoxin resistance in a Chinese hamster ovary cell line: loss of drug-stimulated DNA cleavage activity,"Recent evidence indicates that type II DNA topoisomerases mediate epipodophyllotoxin-induced DNA damage and may be intrinsic to the drug's antitumor effects. Using an epipodophyllotoxin-resistant cell line, we have now further defined the relationship between DNA damage and cell death and delineated the significance of certain drug-enzyme interactions. When compared to wild-type cells, the mutant Chinese hamster ovary cell line, VpmR-5, exhibits marked resistance to both the cytotoxic and DNA cleavage activities of etoposide (VP-16). Steady-state concentrations of radiolabeled VP-16 are identical in both cell lines. Catalytic activity in crude nuclear extracts from wild-type and VpmR-5 cells is equal and is equally sensitive to inhibition by VP-16. However, using an assay that specifically measures generation of 5' protein-linked breaks in 32P-labeled 3' DNA, we have found that DNA cleavage activity in nuclear extract from the VpmR-5 line is profoundly resistant to stimulation by VP-16. Further, a somatic cell hybrid line of VpmR-5 cells and drug-sensitive EOT-3 cells exhibits recovery of VP-16 sensitivity in concert with reconstitution of DNA cleavage activity. These data indicate that stimulation of enzyme-mediated DNA cleavage, rather than loss of normal topoisomerase function, is responsible for epipodophyllotoxin-induced cytotoxicity. ",0
957,3004903,Studies on the glycoprotein nature of the thyrotropin receptor: interaction with lectins and purification of the bovine protein with the use of Bandeiraea (Griffonia) simplicifolia I affinity chromatography,"The TSH receptor from Triton-solubilized bovine microsomal membranes was found to bind to a substantial extent to columns of the immobilized lectins Bandeiraea (Griffonia) simplicifolia I, Ricinus communis I, wheat germ, and Concanavalin A, whereas it was not retained by Dolichos biflorus. Elution of TSH receptor activity from these lectins could be achieved with the appropriate saccharides in all cases except Concanavalin A. The most extensive adsorption of the receptor occurred on B. simplicifolia I-agarose (84%), and the terminal alpha-D-galactosyl specificity of this interaction was substantiated by its susceptibility to alpha-galactosidase treatment. Whereas TSH itself was not bound to this immobilized lectin, a complex of this hormone with its receptor did interact and could be eluted with methyl-alpha-D-galactoside. Purification (800-fold) of the bovine TSH receptor was achieved by a combination of TSH and B. simplicifolia I affinity chromatographies. Polyacrylamide gel electrophoresis of the purified TSH receptor after radioiodination revealed three major components with apparent mol wt of 316,000, 115,000, and 54,000. ",0
958,3004927,"Effect of o,p'-DDD on cortisol metabolism in Cushing's syndrome of various etiology","Effects of o,p'-DDD on parameters of cortisol metabolism were studied in 3 patients with Cushing's syndrome (ectopic ACTH-syndrome, Cushing's disease, and adrenal cancer). Before o,p'-DDD treatment, plasma cortisol, urinary 17OHCS, and urinary free cortisol were elevated in all patients. These parameters correlated well with each other in ectopic ACTH-syndrome and Cushing's disease. However, in adrenal cancer, urinary 17OHCS did not correlate with either plasma cortisol or urinary free cortisol, while the latter two parameters did. During o,p'-DDD, urinary 17OHCS rapidly declined in a patient with ectopic ACTH syndrome and a patient with Cushing's disease before plasma cortisol or urinary free cortisol decreases. Consequently the positive correlations of urinary 17OHCS with the other parameters were lost. In a case of adrenal cancer, urinary 17OHCS again did not correlate with plasma cortisol or urinary free cortisol. In these conditions, plasma cortisol and urinary free cortisol still significantly correlated. The present results demonstrated the limit of urinary 17OHCS as the index of the cortisol secretion rate both in some cases of adrenal cancer and in patients taking o,p'-DDD. It is suggested that urinary free cortisol should be utilized as a more accurate index for the cortisol secretion rate in such circumstances. ",0
959,3005270,Heart myosin light chain 2 gene. Nucleotide sequence of full length cDNA and expression in normal and hypertensive rat,"We have isolated and characterized a cDNA recombinant plasmid (pRLC429) specific for the rat heart myosin light chain 2 (MLC2). The cDNA insert consists of 446 base pairs, including a 72-base pair segment of the 3'-untranslated region. Additional 5'-sequence, not present in plasmid pRLC429, was obtained by primer extension of the cDNA. The extended cDNA sequence combined with the plasmid pRLC429 sequence provided the codon information for the entire MLC2 polypeptide and partial sequences for the 3'- and 5'-noncoding regions of MLC2 mRNA. The predicted amino acid sequence for rat heart MLC2 showed a high homology with the sequences available for the chicken (83%) and human heart (80%) MLC2s. However, the homology between rat heart MLC2 and its counterpart in rat skeletal muscle is relatively low (67%). On the basis of the nuclease S1 protection assay with uniformly labeled single-stranded pRLC429 DNA, subcloned into M13mp18 phage vector, we conclude that the rat atrial muscle also contains MLC2 of the ventricular type. In an attempt to ascertain whether structural variants of MLC2 are expressed in hypertrophic heart muscle, we examined the RNAs from spontaneously hypertensive rat where there is a natural progression of hypertrophy associated with an increase in blood pressure. The RNA isolated from 7-, 13-, and 18-week-old spontaneously hypertensive rat hearts protected the same length DNA against S1 nuclease as was observed with RNAs from the age-matched normal rat hearts, suggesting that there is a single MLC2 gene transcript expressed in both the normal and hypertrophic heart muscle cells. ",0
960,3005306,Purification and characterization of the human platelet alpha 2-adrenergic receptor,"Human platelet alpha 2-adrenergic receptors have been purified approximately 80,000-fold to apparent homogeneity by a five-step chromatographic procedure. The overall yield starting from the membranes is approximately 2%. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radioiodinated protein from purified receptor preparations shows a single major band of Mr 64,000. The specific binding activity of the alpha 2-adrenergic receptor after four chromatographic steps is 14.5 nmol/mg protein. This value is consistent with the expected theoretical specific activity (15.6 nmol/mg) for a protein with a molecular mass of 64,000 daltons if it is assumed that there is one ligand-binding site/receptor molecule. The purified protein can be covalently labeled with the alkylating alpha-adrenergic ligand, [3H]phenoxybenzamine. This labeling is specific, and it shows that the Mr 64,000 protein contains the ligand binding site of the alpha 2-adrenergic receptor. In addition, the competitive binding of ligands to the purified receptor protein shows the proper alpha 2-adrenergic specificity. The alpha 2-adrenergic receptor contains an essential sulfhydryl residue. Thus, exposure of the purified receptor to the sulfhydryl-specific reagent, phenylmercuric chloride, resulted in an 80% loss of binding activity. This loss of binding activity was prevented when exposure to phenylmercuric chloride was done in the presence of alpha 2-adrenergic ligands, and it was reversed by subsequent exposure to dithiothreitol. Partial proteolysis of purified alpha 2-adrenergic receptors was obtained with Staphylococcus aureus V-8 protease, alpha-chymotrypsin, and papain. In a comparison with purified beta 2-adrenergic receptors, no common partial proteolytic products were found. ",0
961,3005423,Hepatitis B virus DNA in mononuclear cells and analysis of cell subsets for the presence of replicative intermediates of viral DNA,"To determine whether peripheral blood mononuclear cells (PBMCs) contain replicating forms of hepatitis B virus (HBV) DNA and to define which cell subset may be permissive for viral replication, we analyzed the PBMC DNA from 14 carriers positive for hepatitis B surface antigen (HBsAg) by Southern blot hybridization. HBV-related DNA, which was present exclusively in an extrachromosomal state, was found in the PBMCs of all five hepatitis B e antigen (HBeAg)-positive and three of nine HBeAg-negative carriers. Serum-associated HBV DNA was detected only in those HBsAg carriers whose PBMCs contained HBV DNA forms resembling replicative intermediates (1.0-3.2 kilobase pairs in the EcoRI digests). Analysis of PBMC subsets revealed that replicating forms of the HBV genome were present primarily in monocytes. Low levels of hybridization also were detected in B cells, whereas the T cell fraction (which contained natural killer cells) appeared to be devoid of these replicating forms. ",0
962,3005546,Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation,"The effect of platelet-activating factor (acetyl glyceryl ether phosphorylcholine; PAF), a potent inflammatory mediator, on airway responsiveness was studied. In six dogs airway responsiveness was determined by measuring the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance (RL) by 5 cm H2O X L-1 X s, before and after inhalation of PAF (1 mg). PAF caused a 2.3-fold increase in RL (P less than .001) that lasted approximately 30 min. Airway hyperresponsiveness was maximal at 3 hr (mean 3.7-fold increase, P less than .001), persisted at 6 hr (P less than .005) and disappeared by 24 hr. Inhalation of 0.9% NaCl had no effect on RL or on responsiveness. PAF caused an 8-fold increase in neutrophil recovery in bronchoalveolar lavage fluid at 3 hr. OKY-046, a thromboxane synthetase inhibitor, inhibited PAF-induced bronchoconstriction and hyperresponsiveness but did not alter the increase in neutrophil recovery. We tested the specificity of the effect of OKY-046 on the release of cyclooxygenase products from canine neutrophils in vitro; OKY-046 suppressed PAF-induced generation of thromboxane and caused a small increase in prostaglandin F2 alpha release. The studies suggest that the airway hyperresponsiveness induced by PAF may depend on thromboxane generation. ",0
963,3005860,The AIDS epidemic: multidisciplinary trouble,"The author presents an overview of the diversity of issues involved in the acquired immunodeficiency syndrome (AIDS) epidemic. The 1st round of AIDS cases has severely strained both human and societal resources in the US. To appreciate the economics of the problem, its is useful to think of evey case of AIDS as costing the same as a heart transplant. The anticipated doubling in numbers of patients diagnosed in the next year will have far more than twice the impact of the 1st wave on the health care industry, especially in the cities where the majority of cases are concentrated. Progress in the area of biomedical science has been spectacular in terms of the speed with which the virus was isolated and blodd screening techniques were developed. Problematic, however, has been the antigenic variation of the AIDS virus. It is possible that monoclonal technology will help to identify on parts of antigenic molecules that pervade the immune response to many variants and might be effective in neutralization. On the scientific level, there is cause of concern regarding a vaccin for AIDS, since the cellular receptor that the virus requires to initiate infection is the receptor for the T-cell antigen. On the practical level, the logistics of testing such a vaccine are complex. The largest hope for intervention may rest in understanding the role of various co-factors in determining whether a person remains asymptomatic or develops the disease. At present, however, preventive medicine appears to be the solution.",0
964,3005862,Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders,"Patients with the acquired immunodeficiency syndrome (AIDS) acquire undifferentiated B-cell lymphomas that are similar to African Burkitt's lymphoma and contain Epstein-Barr virus (EBV). Using an in vitro assay system that measures a complex of cellular responses to EBV-infected lymphocytes, we found that B cells from 7 patients with AIDS and from 10 patients with AIDS-related disorders produced abnormally low numbers of immunoglobulin-secreting cells (P less than 0.001 as compared with normal controls) and that T-cell suppression, which was greater than 80 percent in EBV-seropositive normal controls, was absent. Instead, the patients' T cells markedly increased immunoglobulin production induced by EBV. In further studies, we determined that the mean frequency of circulating EBV-infected B cells capable of spontaneous outgrowth in vitro was 13 per 10(6) B cells in 7 patients with AIDS and 21 per 10(6) B cells in 10 patients with AIDS-related disorders--figures that were significantly higher than the mean in normal controls (P less than 0.001). Thus, patients with AIDS or AIDS-related disorders may be predisposed to the development of EBV-containing lymphomas, because they have a profound defect of T-cell immunity to EBV and abnormally high numbers of EBV-infected B cells in the circulation.",0
965,3006073,Translation of open reading frame E5 of bovine papillomavirus is required for its transforming activity,"A series of mutations in open reading frame (ORF) E5 of bovine papillomavirus type 1 has been constructed to determine whether this putative gene is required for in vitro oncogenic transformation by viral DNA. Frameshift mutations at either of two different positions located exclusively in ORF E5 cause a substantial reduction in the ability of the cloned viral DNA to induce the appearance of transformed foci of mouse C127 cells. A genetic mapping experiment with one of the mutants indicates that this characteristic transformation defect is actually due to the constructed mutation in ORF E5. Analysis of 10 different mutants with sequence changes at a single position in the ORF showed that there is an exact correspondence between transformation-competence and the ability of the 3' half of ORF E5 to be correctly translated. The transformation defect of an ORF E5 frameshift mutant can be suppressed by a second mutation that restores the correct reading frame to most of the ORF, but not by one that restores the reading frame near the 3' end of the ORF. These results constitute strong genetic evidence that translation of ORF E5 is required for efficient transformation of mouse C127 cells by bovine papillomavirus DNA. Wild-type ORF E5 has the potential to encode a short hydrophobic protein or polypeptide domain. ",0
966,3006164,Dynamic CT of lymphoma manifestations of the liver and spleen],"Fourteen patients with lymphoma involving the liver and/or spleen were examined by dynamic CT. Lymphoma lesions show little enhancement with respect to the spleen and usually also when compared with liver tissue. On two occasions there was a definite increase in density during the arterial phase and dynamic CT could not distinguish the lesions from tumours of hepatic origin. One circumscribed lymphomatous lesion of the liver and six splenic infiltrates were only visible during the first few seconds after a bolus of contrast material had been injected. Dynamic CT does not usually differentiate diffuse involvement of the liver and spleen. In this situation, lack of a trabecular structure of the spleen during the arterial phase and a low peak of the time-density curve may suggest diffuse infiltration. ",0
967,3006408,"Antibodies to measles, smallpox, influenza and arenaviruses in schizophrenic patients]","The levels of hemagglutinating antibodies to measles, smallpox, influenza viruses and of complement-fixing antibody to lymphocytic choriomeningitis, Takaribe, Amapari viruses were studied, in the blood sera of 77 schizophrenics and 44 normal donors. The investigation revealed definite differences. The schizophrenic patients had a statistically significant elevation in the titres of anti-smallpox antibodies. A certain increase in levels of antibodies to the measles virus was observed. There were no considerable differences in titres of antibodies to arenaviruses and influenza virus. A relationship between antibody production, on the one hand, and the severity and course of the disease and also the age of those examined, on the other, was noted. ",0
968,3006502,Ontogeny of pepsin secretory response to secretagogues in isolated rat gastric glands,"By use of isolated gastric glands from rats at various ages, we demonstrated that full-term neonate and 1-day-old rats showed no response to cholecystokinin octapeptide (CCK-OP), carbachol, or Ca2+ ionophore. The same glands, however, were responsive to dibutyryl cAMP. A mature response was not found until the pups were 2 days old. Injection of hydrocortisone into newborn rats led to an increase in pepsinogen concentrations in gastric glands and also an increased responsiveness to CCK-OP, carbachol, and Ca2+ ionophore A23187 24 h after administration. Hydrocortisone thus caused precocious maturation of both pepsinogen accumulation and pepsinogen secretory responsiveness of gastric glands in rat pups. ",0
969,3006555,Infection control and the pregnant health care worker,"Health care workers may be exposed to a variety of infectious agents in the workplace. The pregnant health care worker presents additional concerns because of the potential risk of infection to the developing fetus. Health care workers often misunderstand the basic elements of infection transmission. The result of this misinformation is that personnel are most often concerned about the agents that are least transmissible. To develop an infection control program that is rational and workable, the infection control practitioner must have a thorough understanding of the mechanisms of disease transmission. With this foundation, an infection control program for the pregnant health care worker will rarely involve transfer to alternative assignments or work restriction based on pregnancy alone. The approach outlined in this article stresses a more generic approach to infection control by isolating the disease and not the employee. ",0
970,3010110,Screening to reduce transmission of sexually transmitted diseases in semen used for artificial insemination,"The practice of artificial insemination by donor semen is increasing in the United States. Many sexually transmitted organisms are found in semen, but screening procedures for the detection of these agents in donor semen have not been standardized. Sexually transmitted organisms have been transmitted during artificial insemination by donor, and such transmission can cause local, disseminated, or fatal disease in the recipient woman and may harm the fetus or newborn. Therefore, screening of both the donor and the donated semen is necessary to avoid infectious complications. Because semen samples cannot be evaluated completely on the day of donation, the use of fresh semen for artificial insemination should be discouraged. Until accurate, rapid diagnostic tests are available, only frozen semen that has been appropriately screened should be used.",0
971,3020404,Human papillomavirus in clinically and histologically normal tissue of patients with genital cancer,"To study the association of human papillomavirus (HPV) and herpes simplex virus (HSV) with genital cancer, we collected specimens of cervical, vulvar, endometrial, and vaginal tumors at the time of operation in patients with cancer. In some patients, matched internal-control (histologically normal) tissue was also collected. DNA extracted from the tissue was probed with radiolabeled HPV type 16 DNA, HPV type 18 DNA, and cloned fragments of HSV type 2 DNA. Hybridization to the HindIIIa clone of HSV-2 was detected in only 1 cervical tumor and 1 vulvar tumor (9 percent) among the 22 tumors tested. However, DNA sequences hybridizing to HPV-16 were detected in 21 of 25 tumors (84 percent) and in 8 of 11 (73 percent) of the DNA samples from clinically and histologically normal, paired, internal-control tissues from the patients with cancer. HPV-16 DNA was found in one of nine normal cervixes (11 percent) of women without genital neoplastic disease or abnormal cytology. HPV-18 DNA was detected in only 2 of 24 tumors (8 percent), 1 cervical and 1 vulvar. Our results show a strong association between the presence of HPV-16 genomes and genital tumors and between HPV-16 genomes and histologically normal tissue within 2 to 5 cm of the tumors. The implications of these findings remain to be explored.",0
972,3024002,Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction,"Levels of apolipoprotein B, the protein component of low-density lipoproteins, correlate with the risk of coronary heart disease. We examined whether genetic variation in apolipoprotein B is associated with myocardial infarction by studying apolipoprotein B-gene restriction-fragment-length polymorphisms in 84 patients with myocardial infarction and an equal number of matched controls. Southern blot analysis with apolipoprotein B-gene probes, performed after DNA was digested with the endonucleases XbaI and EcoRI, revealed alleles that we designated as X1, X2, and X3 and as R1 and R2, respectively. Similar studies with the endonuclease MspI revealed alleles of many different sizes (the difference was due to an insertion-deletion polymorphism), which we grouped as larger and smaller alleles and designated as ID1 and ID2, respectively. The frequencies of the X1, R1, and ID1 alleles were all significantly higher (P less than 0.01) in the cases than in the controls. None of the alleles, however, was significantly associated with variation in levels of low-density lipoprotein cholesterol or apolipoprotein B, and the functional importance of these alleles is therefore uncertain. Nonetheless, in addition to quantitative variation in apolipoprotein B levels in plasma, genetic variation at the apolipoprotein B locus may be a new and independent risk factor for myocardial infarction.",0
973,3027557,Evidence of an endogenous digitalis-like factor in the plasma of patients with acromegaly,"Evidence suggests that plasma-volume expansion leads to the release of a digitalis-like factor, which is thought to act on the renal tubular cells and cause natriuresis. We postulated that this factor might be present in patients with acromegaly (in whom plasma volume is elevated) and might return to normal levels when the disease was treated successfully. We measured the ability of plasma extracts from patients with acromegaly to inhibit the binding of ouabain to the sodium pump in normal red cells and to inhibit the enzymatic activity (sodium-potassium-ATPase) of the sodium pump in membrane preparations from normal kidneys. In 21 patients with active acromegaly, the mean (+/- SE) level of ouabain-binding inhibition (1.56 +/- 0.38) was higher (P less than 0.01) than that in either 11 successfully treated patients (0.18 +/- 0.05) or in 27 normal controls (0.19 +/- 0.03). The inhibition of sodium-potassium-ATPase activity by plasma was also greater in patients with active acromegaly (38.1 +/- 6.8 percent) than in successfully treated patients (18.4 +/- 5.6 percent, P less than 0.05) or controls (21.1 +/- 2.7 percent, P less than 0.05). Significant correlations were found between plasma volume and ouabain-binding inhibition in 23 patients (r = 0.72, P less than 0.01) and sodium-potassium-ATPase inhibition in 19 patients (r = 0.62, P less than 0.01). Pituitary adenomectomy decreased plasma volume and the inhibition by plasma of ouabain binding. We conclude that an endogenous digitalis-like factor is present in the plasma of patients with chronic volume expansion due to acromegaly. These results are consistent with the hypothesis that this natriuretic factor may have a physiologic role in water and sodium homeostasis.",0
974,3029592,Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung,"""We conducted a prospective, randomized study to clarify the role of radiotherapy of the primary tumor in limited small-cell cancer of the lung. After stratification for sex and for performance score based on the ability to ambulate, patients were randomly assigned to receive initial radiotherapy plus chemotherapy, delayed radiotherapy plus chemotherapy, or chemotherapy alone. The chemotherapy consisted of cyclophosphamide, etoposide (VP-16-213), and vincristine, with doxorubicin subsequently replacing etoposide in alternate cycles 7 through 18. Chemotherapy was given every three weeks for 18 months. The radiotherapy comprised 4000 rad in four weeks, followed by a 1000-rad """"boost"""" directed against residual disease. All patients received prophylactic whole-brain radiation. The patients enrolled totaled 426, and 399 were evaluable. There was a statistically significant difference in the frequency of complete responses in favor of the two radiotherapy regimens (P = 0.0013). Failure-free survival was also longer with these two regimens (P less than 0.001), as was the interval before treatment failure in the chest (P less than 0.001) and overall survival (P = 0.0099). As expected, toxic effects--chiefly neutropenia--were also increased. The addition of radiotherapy of the primary tumor to combination chemotherapy improved both complete-response rates and survival, with increased but acceptable toxicity.""",0
975,3033502,Pituitary tumors containing cholecystokinin,"We found small amounts of cholecystokinin in the normal human adenohypophysis and therefore examined pituitary tumors from 87 patients with acromegaly, Cushing's disease, Nelson's syndrome, prolactinoma, or inactive pituitary adenomas. Five adenomas associated with Nelson's syndrome contained increased amounts of cholecystokinin, the concentrations being extremely high in two: 8281 and 13,453 pmol per gram as compared with less than 30 pmol per gram in normal pituitary glands. The cholecystokinin concentrations were moderately increased in adenomas from another 12 patients, of whom 5 had Cushing's disease and 7 acromegaly with adenomas containing ACTH. The cholecystokinin peptides from the tumors were smaller and less sulfated than cholecystokinin from normal pituitary glands. We conclude that ACTH-producing pituitary cells may also produce an altered form of cholecystokinin.",0
976,3041218,Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung,"To define the role of cellular oncogenes in human cancers, we studied the prevalence of mutational activation of ras oncogenes in untreated non-small-cell lung cancer. Genomic DNA was extracted from 39 tumor specimens obtained by thoracotomy and was examined for activating point mutations in codons 12, 13, and 61 of the H-ras, K-ras, and N-ras genes. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. The K-ras gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No ras gene mutations were observed in 15 squamous-cell carcinomas, 10 large-cell carcinomas, 1 carcinoid, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small-cell carcinoma. An approximately 20-fold amplification of the unmutated K-ras gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. We conclude that mutational K-ras activation may be an important early event in the pathogenesis of adenocarcinoma of the lung but that amplification of ras genes or mutational activation of H-ras or N-ras does not play a major part in non-small-cell lung cancer.",0
977,3041279,Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2),"Thousands of studies have been conducted of the functioning of the many neurotransmitter systems in order to explore the biologic basis of major depressive disorder. Instead of reviewing this literature exhaustively, we have attempted to propose a model that accommodates the clinical observation that chronic stress early in life in vulnerable persons predisposes them to major depression with contemporary observations of the potential consequences of repeated central nervous system exposure to effectors of the stress response. This model accords with current clinical judgment that major depression is best treated with a combination of psychopharmacologic agents and psychotherapy. Accordingly, whereas psychopharmacologic intervention may be required to resolve an active episode of major depression and to prevent recurrences, psychotherapy may be equally important to lessen the burden of stress imposed by intense inner conflict and counterproductive defenses.",0
978,3045553,Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus,"We compared a high-carbohydrate diet with a high-fat diet (specifically, a diet high in monounsaturated fatty acids) for effects on glycemic control and plasma lipoproteins in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) receiving insulin therapy. The patients were randomly assigned to receive first one diet and then the other, each for 28 days, in a metabolic ward. In the high-carbohydrate diet, 25 percent of the energy was in the form of fat and 60 percent in the form of carbohydrates (47 percent of the total energy was in the form of complex carbohydrates); the high-monounsaturated-fat diet was 50 percent fat (33 percent of the total energy in the form of monounsaturated fatty acids) and 35 percent carbohydrates. The two diets had the same amounts of simple carbohydrates and fiber. As compared with the high-carbohydrate diet, the high-monounsaturated-fat diet resulted in lower mean plasma glucose levels and reduced insulin requirements, lower levels of plasma triglycerides and very-low-density lipoprotein cholesterol (lower by 25 and 35 percent, respectively; P less than 0.01), and higher levels of high-density lipoprotein (HDL) cholesterol (higher by 13 percent; P less than 0.005). Levels of total cholesterol and low-density lipoprotein (LDL) cholesterol did not differ significantly in patients on the two diets. These preliminary results suggest that partial replacement of complex carbohydrates with monounsaturated fatty acids in the diets of patients with NIDDM does not increase the level of LDL cholesterol and may improve glycemic control and the levels of plasma triglycerides and HDL cholesterol.",0
979,3045557,Results and policy implications of the resource-based relative-value study,"""The resource-based relative-value scale (RBRVS) is a measure of relative levels of resource input expended when physicians produce services and procedures. It is a function of the physician's work input, the opportunity cost of specialty training, and the relative practice costs for each specialty. This paper presents resource-based relative values (RBRVs) for selected procedures of four major specialties--family practice, internal medicine, general surgery, and thoracic and cardiovascular surgery. We compare RBRVs with current charges and find several general patterns. Invasive procedures are typically compensated at more than double the rate of evaluation-and-management services, when both consume the same resource inputs. Imaging and laboratory procedures fall between invasive and evaluation-and-management services. We analyze the financial implications of the RBRVS by developing a simple model and simulating the effects of an RBRVS-based fee schedule on physicians' revenues in various specialties. We use Medicare data to perform the simulation under the """"budget-neutral"""" assumption. Results show that an RBRVS-based fee schedule affects specialties differently. The average family practitioner could receive 60 percent more revenue from Medicare, whereas the average ophthalmologist could lose 40 percent of current revenues. The effects on other specialties fall between these two.""",0
980,3047035,Different mechanisms decrease hepatic collagen and albumin production in fasted rats,"Weight loss is correlated with a specific decrease in collagen synthesis in extrahepatic tissues, mainly through modulation of mRNA levels. Here, we investigated the response to weight loss in the rat liver. Male rats were either fed ad libitum or fasted for 92 hr; fasted animals lost approximately 20% of their initial body weight. Following i.p. injection of [5-3H]proline, hepatic collagen was extracted and de novo collagen production was measured. There was a decrease in the specific radioactivities of purified hepatic collagen (-75%) and albumin (-70%) relative to total hepatic protein, indicating that production of both of these proteins was specifically decreased. In fasted animals, the absolute hepatic collagen production was markedly decreased (-60%), while changes in absolute hepatic protein production were small (-15%). Using hybridization with specific DNA probes, we found that fasting causes about a 70% decrease in albumin mRNA, but the quantities of hepatic procollagen alpha 1(I) and alpha 2(I) mRNAs were unchanged. These results are consistent with regulation of albumin production during fasting by modulation of mRNA levels. The inhibition of hepatic collagen production in fasted animals, however, appears to be modulated at a posttranscriptional level or may result from increased degradation. This response differs from the pretranslational regulation of collagen synthesis in extrahepatic tissues during fasting. Furthermore, our results suggest that decreased body weight could be a potentially complicating variable in studies of collagen metabolism and fibrogenesis in the liver.",0
981,3050523,"Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (2)","This article has analyzed the pathogenesis of sodium and water retention in several circumstances. The initiator of retention has been proposed to be either a fall in cardiac output (e.g., low-output cardiac failure and vasoconstrictor hypovolemic nephrotic syndrome) or peripheral arterial vasodilatation (e.g., high-output cardiac failure, cirrhosis, arteriovenous fistula, and pregnancy). In the only state discussed, in which the kidney is diseased and not merely responding to extrarenal reflexes--i.e., nephrotic syndrome--intrarenal mechanisms may predominate and lead to expansion of the arterial vascular tree and suppression of the renin-angiotensin-aldosterone system (i.e., hypervolemic nephrotic syndrome). Otherwise, when kidneys are healthy, either a fall in cardiac output or peripheral arterial vasodilatation may diminish arterial vascular filling and thereby initiate a series of hemodynamic and hormonal events that result in renal sodium and water retention (Fig. 7). Finally, the approach presented in this article should be considered to be a vantage point from which to evaluate states of sodium and water retention, but not to be an exclusive position.",0
982,3054549,Increased insulin concentrations in nondiabetic offspring of diabetic parents,"Insulin resistance is thought by many to be the primary defect that results in non-insulin-dependent diabetes mellitus (NIDDM). An implication of this theory is that prediabetic persons have higher serum insulin levels than normal subjects. We assessed serum insulin concentrations in a cohort of 1497 nondiabetic Mexican Americans, a population at high risk for NIDDM, according to whether their parents or siblings had diabetes. It was assumed that prediabetic persons would be more likely to have strong family histories of diabetes. We found a stepwise increase in fasting insulin levels in nondiabetics with neither, one, or both parents with diabetes (69.8, 77.8, and 94.6 pmol per liter, respectively; P = 0.002). Similar results were observed for insulin sum (the total of insulin concentrations in the fasting state and at 30, 60, and 120 minutes after a 75-g oral glucose load). The differences in insulin sums according to family history remained statistically significant in analyses of covariance, which controlled for variations in body-mass index, body-fat distribution, and level of blood glucose. Subjects without diabetes who had a diabetic sibling had higher fasting concentrations of insulin than subjects without a diabetic sibling (83.2 vs. 69.6 pmol per liter), but the difference was not statistically significant. We conclude that prediabetic persons, who would be expected to be more numerous in kindreds with progressively stronger family histories of diabetes, have hyperinsulinemia. This supports the insulin-resistance hypothesis.",0
983,3059187,Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex,"Two hundred eighty-one patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex were enrolled in a double-blind, placebo-controlled trial of the efficacy and safety of orally administered zidovudine (azidothymidine or AZT). Significant clinical benefits and adverse experiences have been reported from this trial. Because neuropsychiatric dysfunction is often associated with human immunodeficiency virus (HIV) infection, a brief affective and neuropsychological examination was administered over 16 weeks of the trial to evaluate any changes in neuropsychological function that occurred with drug administration. Patients receiving zidovudine, particularly those with AIDS, showed improved cognition as compared with patients receiving placebo. There were no changes in affective symptoms. The zidovudine recipients also had a statistically significant reduction in the intensity of symptomatic distress during the trial that may account in part for the observed cognitive changes. Some improvement in various cognitive measures was also seen in patients with AIDS-related complex. The results of this study suggest HIV-associated cognitive abnormalities may be partially ameliorated after the administration of zidovudine.",0
984,3081805,Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia,"Decreased plasma high-density-lipoprotein (HDL) cholesterol and apolipoprotein A-I levels have been associated with premature coronary artery disease. We identified a PstI restriction-endonuclease site flanking the human apolipoprotein A-I gene at its 3' end that is polymorphic. The absence and presence of this site, as determined by genomic blotting analysis of PstI-digested chromosomal DNA with the use of an apolipoprotein A-I gene probe, were associated with 3.3-kb and 2.2-kb hybridization bands, respectively. The 3.3-kb band appeared in 4.1 percent of 123 randomly selected control subjects and in 3.3 percent of 30 subjects with no angiographic evidence of coronary artery disease. In contrast, among 88 patients who had severe coronary disease before the age of 60, as documented by angiography, the 3.3-kb band occurred in 32 percent (P less than 0.0001). It was also found in 8 of 12 index cases (P less than 0.0001) of kindreds with familial hypoalphalipoproteinemia. In the two patient groups, the allele frequencies of the site that produced the 3.3-kb band were 17 and 42 percent, respectively, as compared with an allele frequency of only 2 percent in the control populations. Within kindreds with familial hypoalphalipoproteinemia and among first-degree relatives of patients with coronary artery disease, the 3.3-kb band was associated with decreased HDL cholesterol levels. Among all patients with coronary artery disease, 58 percent had HDL cholesterol levels below the 10th percentile of normal values; however, this frequency increased to 73 percent when patients with the 3.3-kb band were considered. These findings indicate that the polymorphism in the region between the apolipoprotein A-I and apolipoprotein C-III genes may be a useful marker for the risk of premature coronary artery disease and familial hypoalphalipoproteinemia.",0
985,3084160,Use of nucleic acid probes for the detection of sexually transmitted infectious agents,"Deoxyribonucleic acid sequences specific for a pathogen of interest can be isolated from a variety of microorganisms. Such DNA probes can be exploited to detect infectious agents directly in infected patient material despite the presence of large numbers of other organisms and host DNA. This technology is dependent upon the recognition of a specific nucleotide sequence present in DNA extracted from a clinical sample by a radiolabeled or nonisotopically labeled DNA probe. We have isolated several DNA probes for the detection of pathogenic Neisseria which include a plasmid species unique to the gonococcus, as well as several cloned genes that detect both the gonococcus and the meningococcus. In addition, we characterized a unique plasmid of Chlamydia trachomatis that has proved to be quite useful as a DNA probe for the detection of this pathogen in cervical secretions and, by in situ hybridization, in Papanicolaou smears. Deoxyribonucleic acid hybridization as a diagnostic tool is still in its infancy. It holds a number of advantages over conventional methods of pathogen detection and serves as an alternative, as well as a complement, to available immunologic methods. ",0
986,3084262,Binding of estrogen receptor from N-nitrosomethylurea-induced rat mammary tumors to nuclei,The binding of the cytoplasmic estrogen receptor (ERc) from N-nitrosomethylurea (NMU)-induced rat mammary tumors to the nucleus using a cell-free system is described. All tumors studied were estrogen-receptor-positive and most of them were hormone-dependent. Sixty-two percent of all tumors investigated (n = 134) decreased in size more than 30% 4-5 days after ovariectomy. Brief heating of the cytosol loaded with tritiated estradiol induced activation of the ERc measured by an increase of nuclear binding activity. Temperature-dependent activation was evident in every case. The optimal time and temperature of activation were 15-60 min at 30 degrees C. After denaturation of the ERc by heating for 20 min at 56 degrees C only small parts of free estradiol could be bound to nuclei. Mg2+ ions and EDTA inhibited the nuclear binding of the receptor. The nuclear binding assay was performed for 1 hr at 0-4 degrees C. After this time the activated ERc was bound nearly maximally to nuclei. Under optimized conditions 50-60% of the ERc could be bound to nuclei maximally. Using the same medium for the preparation of crude and purified nuclei the binding of the receptor to both kinds of nuclei was similar. Na2MoO4 prevented the activation of the ERc from NMU-tumors completely but did not influence the binding of the previously activated receptor to nuclei. ,0
987,3084328,"Subchronic oral toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the guinea pig: comparisons with a PCB-containing transformer fluid pyrolysate","""In contrast to the well-characterized acute toxicity of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in the guinea pig, the effects of prolonged po exposure in this species are unknown. The present report describes the results of administration to guinea pigs of 2,3,7,8-TCDD in the feed at levels of 0, 2, 10, 76, or 430 ppt for up to 90 days. Additional aims were to examine recovery following prolonged 2,3,7,8-TCDD exposure in the guinea pig and to generate data to facilitate comparison of the previously reported toxicity of a transformer fluid pyrolysate with that of pure 2,3,7,8-TCDD. Animals receiving 430 ppt 2,3,7,8-TCDD exhibited body weight loss, thymic atrophy, liver enlargement, and 60% mortality by Day 46 (males) and by Day 60 (females), when surviving animals in this group were sacrificed. Total 2,3,7,8-TCDD consumption was approximately 1.3 and 1.9 micrograms/kg, respectively. Animals receiving 76 ppt 2,3,7,8-TCDD for 90 days (total 0.44 microgram/kg) exhibited a decreased rate of body weight gain and increased relative (to body) liver weights. Male animals also displayed a reduction in relative thymus weights and elevated serum triglycerides, while females exhibited hepatocellular cytoplasmic inclusion bodies and lowered serum alanine aminotransferase activities. Toxic effects were generally similar to those observed after acute 2,3,7,8-TCDD administration. No dose-related alterations were seen in animals receiving either 10 ppt (total 0.06 micrograms/kg) or 2 ppt (total 0.01 micrograms/kg) for 90 days, establishing a no-observed-effect level of approximately 0.65 ng 2,3,7,8-TCDD/kg/day. In the recovery study, groups of guinea pigs were administered 430 ppt 2,3,7,8-TCDD for 11, 21, or 35 days and then allowed to recover for an additional 79, 69, or 55 days, respectively. Treatment-related mortality in each group was 0, 10, and 70%, respectively, by Day 90. An effective LD50 of 0.8 microgram 2,3,7,8-TCDD/kg for prolonged exposure was calculated on the basis of these results, a value lower than those previously reported from this laboratory for acute exposure. The results also suggested a possible lowering of the body weight """"set point"""" following 2,3,7,8-TCDD exposure. Comparison of the present findings with those previously reported for a transformer fluid pyrolysate containing a mixture of polychlorinated aromatic species indicated both a greater variety of toxic effects and flatter dose-response relationships for the pyrolysate in the guinea pig. """,0
988,3084382,Isolation and characterization of protective T cells induced by Listeria monocytogenes,"Rats convalescing from a recent infection with Listeria monocytogenes generate T cells which can protect recipient rats against a challenge infection with that organism. Using monoclonal antibodies that react with some but not all rat peripheral T cells, the T-cell mediators of acquired resistance to infection (TCRI) were isolated by panning and characterized by using a fluorescence-activated cell sorter. Many L. monocytogenes-immune TCRI were relatively large cells as judged by their light-scattering properties. That finding accords with previously reported cytokinetic data and velocity sedimentation analyses which revealed that the majority of L. monocytogenes-immune TCRI are lymphoblasts. In the current investigation, the surface antigenic profile of these mediator T cells was revealed as W3/25+ OX8+ OX4+ RT6.1-. That phenotype is identical to that of L. monocytogenes-induced prekiller cells which are formed as part of the animal's cell-mediated response to infection. Like prekiller cells and their differentiated counterparts, L. monocytogenes-immune TCRI adhere preferentially to monolayers of syngeneic fibroblasts. The results indicate that L. monocytogenes-immune TCRI belong to a minor subset of peripheral T cells which also contains T cells that have the cytotoxic potential by which L. monocytogenes-induced prekiller cells have been defined. ",0
989,3084749,Immunologic aspects of surface infections in the lung,"The hallmark of cystic fibrosis is progressive bronchopulmonary damage associated with chronic infection with Pseudomonas aeruginosa, leading to respiratory failure and, ultimately, death. P. aeruginosa is an essentially nonvirulent organism in an immunocompetent host, but it has been shown to colonize the respiratory tract progressively in more than 80% of patients with CF. Patients with CF do not exhibit any evidence of immunologic compromise, and the infection is limited to the mucosal surfaces of the respiratory tract. Thus, P. aeruginosa in bronchopulmonary disease is a unique chronic mucosal infection resulting in a progressive pathologic process. It is therefore conceivable that locally induced alteration in the pulmonary mucosal defense is a major mechanism underlying the development of lung disease in patients with CF. An understanding of immunologic homeostasis in the mucous membranes and in the bronchopulmonary epithelium should provide a better perspective on the factors contributing to the acquisition and chronicity of P. aeruginosa infection in the lower respiratory tract and the development of progressive pulmonary damage unique to CF. ",0
990,3084975,Psychiatric consultation in somatization disorder. A randomized controlled study,"The per capita expenditure for health care of patients with multiple physical symptoms but no apparent physical disease (somatization disorder) is up to nine times the average per capita amount. We conducted a randomized controlled trial to determine whether psychiatric consultation would reduce the medical costs of these patients, without effecting a substantial change in patient outcome. Thirty-eight patients were randomly assigned to treatment or control groups and studied prospectively for 18 months. Treatment consisted of a psychiatric consultation and suggestions on management given to primary physicians. After nine months, the control group was crossed over to receive treatment with the same intervention. After the psychiatric consultation, the quarterly health care charges in the treatment group declined by 53 percent (P less than 0.05). In contrast, the charges in the control group showed wide variations but no overall change. The quarterly charges in the control group were significantly higher than those in the treatment group (P less than 0.05). After the control group was crossed over to receive treatment, their quarterly charges declined by 49 percent (P less than 0.05). The reductions in expenditures in both groups were due largely to decreases in hospitalization. We conclude that psychiatric consultation in the care of patients with somatization disorder reduced subsequent health care expenditures without inducing changes in health status or patients' satisfaction with their health care.",0
991,3085669,Selective labeling of functional groups on membrane proteins or glycoproteins using reactive biotin derivatives and 125I-streptavidin,"Amino groups, sulfhydryl groups or oxidation-induced aldehydes on erythrocyte membrane proteins and/or glycoproteins, were reacted with biotinyl N-hydroxysuccinimide ester (BNHS), 3-(N-maleimido-propionyl) biocytin (MPB) or biocytin hydrazide (BCHZ), respectively. The detergent-lysed biotinylated samples were subjected to SDS-polyacrylamide gel electrophoresis, and the proteins were transferred onto nitrocellulose membranes. The blot was then incubated with a solution containing 125I-streptavidin, and processed for autoradiography. The advantages of this approach over previously reported procedures for labeling the three functional groups include the following: extremely high sensitivity; short exposure times of autoradiograms and relatively low levels of radioactivity; single-step radiolabeling procedures subsequent to processing and handling of gels and no background labeling in control samples. ",0
992,3086016,Immunologic complexity of lymphoblastic lymphoma,"""Twelve patients with a histologic diagnosis of lymphoblastic lymphoma (LBL) were studied immunologically using the methodologic refinement of comparative serial section immunochemistry. By this means, we demonstrate complex LBL phenotypic profiles, revealing 3 major immunologic subtypes: immature T cell, 7 cases; intermediate or mature T cell, 3 cases; immature B cell (pre-pre-B), 2 cases. This phenotypic diversity challenges the basic belief that all LBL are the same. Our immature T-cell cases with frequent simultaneous Leu 2/3/6/9/CALLA/Tdt expression correspond to cortical thymic phenotypes; our mature T-cell phenotypes with Leu 9/la expression and absent L6/Tdt correspond either to medullary thymocytes or post-thymic T cells; our pre-pre-B phenotypes with simultaneous Tdt/CALLA/B4 expression correspond to common acute lymphocytic leukemia (ALL) phenotypes. Mature T-LBL phenotypes are similar to """"novel"""" peripheral T-cell lymphoma phenotypes. Scant or absent Tdt expression in mature LBL is not an isolated antigenic change but a complete phenotypic profile difference from immature T-LBL. The major T- and B-cell phenotypes of LBL might have therapeutic significance. Treatment among LBL phenotypes may need to vary as with acute lymphocytic leukemia phenotypes. Further study is needed; in the meantime, comparative serial section immunotyping promises substantial utility in revealing the immunologic complexity of the lymphomas. """,0
993,3086174,Pharmacologic evaluation of various metabolites and analogs of valproic acid: teratogenic potencies in mice,"A number of metabolites of the anticonvulsant drug valproic acid (VPA) as well as related substances were tested in regard to their teratogenicity in the mouse following single sc injections of 600 mg/kg on Day 8 of gestation. VPA was highly teratogenic at this dose level and over 60% of live fetuses had neural tube defects (exencephaly). Homologous compounds with shorter or longer alkyl chains were less teratogenic. Substitution of the alpha-H atoms in related branched carboxylic acids by methyl or ethyl groups abolished the teratogenic response. Introduction of a double bond in the omega-position of VPA (4-en-VPA) did not change the teratogenicity of VPA, while omega-2 double bond (2-en-VPA) abolished teratogenicity. The other VPA metabolites tested as well as two straight-chain acids (n-octanoic acid and 4-pentenoic acid) and the two clinically used substances valpromide (valproic acid amide) and ethosuximide did not induce neural tube defects, although some of them induced slightly increased resorption rates and fetal weight retardation. The serum protein binding capacities of the various compounds did not correlate with the teratogenic response. Also the concentrations reached in the gestational material did not predict the teratogenicity of the substances tested. Our results indicate that the teratogenicity of the class of compounds studied represents a more specific effect than the anticonvulsant activity which could lead to the development of alternative antiepileptic drugs with low embryotoxic potential. ",0
994,3086277,"Ureidopenicillins, aztreonam, and thienamycin: efficacy as single-drug therapy of severe infections and potential as components of combined therapy","The ureidopenicillins (piperacillin, mezlocillin, and azlocillin), aztreonam, and thienamycin are new broad-spectrum beta-lactams with more potent antibacterial activity than the older cephalosporins and penicillins. However, therapy of severe infections with the ureidopenicillins alone is limited by the potential for emergence of resistant organisms, while monotherapy with aztreonam does not provide adequate coverage for Gram-positive aerobic organisms and anaerobes. In combination therapy with the aminoglycosides, the ureidopenicillins may be preferred to carbenicillin or ticarcillin in the treatment of Pseudomonas aeruginosa infections and in institutions with a high prevalence of carbenicillin or ticarcillin-resistant organisms. Double beta-lactam therapy with piperacillin plus either latamoxef (moxalactam) or ceftazidime may be advantageous in patients for whom aminoglycoside toxicity is a concern. Thienamycin is the most promising of the new beta-lactams for single-agent therapy of severe infections but may also be associated with the emergence of resistant P. aeruginosa during monotherapy. In febrile granulocytopenic patients or other severely ill patients at risk of severe P. aeruginosa infections, thienamycin or another antipseudomonal beta-lactam should be combined with an aminoglycoside. ",0
995,3086312,Isolation and properties of a phosphatidylcholine-specific phospholipase C from bull seminal plasma,"A phospholipase C which hydrolyzes [14C]phosphatidylcholine has been purified 1782-fold from 70% ammonium sulfate extract of bull seminal plasma. Purification steps included acid precipitation, chromatography on DEAE-Sephacel, concanavalin A, octyl-Sepharose 4B and Ultrogel AcA 34. The final step provided homogeneous phospholipase C as determined by polyacrylamide gel electrophoresis. The enzyme comprised two subunits, Mr 69,000 and Mr 55,000, respectively. The enzyme had an optimum at pH 7.2 and pI 5.0. EDTA, Cd2+, Pb2+, Ni2+, Fe2+, and Zn2+ inhibited phospholipase C activity. Km and Vmax on p-nitrophenyl phosphorylcholine and phosphatidylcholine substrates were 20 mM and 17 mumol/min/mg of the purified enzyme and 100 microM and 18 mumol/min/mg of the purified enzyme, respectively. The enzyme appeared to be localized in the acrosome as judged by the binding of anti-phospholipase C to the acrosome. This phospholipase C, unlike other known phospholipases (C), did not hydrolyze [1-14C]phosphatidylinositol. The testicular extract of the guinea pig contained inactive phospholipase C which was activated on incubation with acrosin and trypsin but not chymotrypsin. ",0
996,3086940,Glutathione peroxidase is neither required nor kinetically competent for conversion of 5-HPETE to 5-HETE in rat PMN lysates,"In the 5-lipoxygenase pathway for arachidonic acid metabolism, reduction of 5-hydroperoxyeicosatetraenoic acid (5-HPETE) to 5-hydroxyeicosatetraenoic acid (5-HETE) is catalyzed by an activity different from glutathione peroxidase. Glutathione peroxidase here refers to the nonspecific peroxidase that catalyzes the reduction by glutathione of cumene hydroperoxide and a variety of other peroxides including 5-HPETE. This enzyme is inhibited by mercaptosuccinic acid. Preparations of the 15,000xg supernatant from lysed rat peritoneal polymorphonuclear leukocytes were the source of these activities. Thus, when glutathione peroxidase is inhibited to less than 0.5% of its normal activity by mercaptosuccinic acid, 5-HPETE is reduced as efficiently as in the absence of mercaptosuccinate. In lysate preparations from which endogenous glutathione has been removed, reduction of 5-HPETE is still observed but only in the presence of added reducing agents, e.g., 0.2 mM glutathione. When endogenous glutathione peroxidase is not inhibited, reduction of 5-HPETE occurs at a rate greater than 15-fold faster than can be accounted for by this activity. We conclude, therefore, that the glutathione peroxidase in rat PMNs is not kinetically competent to account for reduction of 5-HPETE. There is a distinct peroxidase that catalyzes this reaction. The 5-HPETE peroxidase can utilize glutathione as reducing agent but is not inhibited by mercaptosuccinate, and additional results indicate that it is inactivated during turnover. ",0
997,3089896,Leucine metabolism in stable cirrhosis,"Alterations in protein and amino acid metabolism have been postulated to explain the frequent observations of muscle wasting and decreased plasma branched-chain amino acid concentrations in cirrhosis. In order to investigate the changes in protein metabolism, we have measured the rates of leucine turnover and oxidation in six stable, biopsy-proven cirrhotics and six age and sex-matched healthy control subjects after an overnight fast, using [1-13C]leucine tracer. Following a primed constant-rate infusion of [1-13C]leucine, the 13C enrichments of plasma leucine and expired CO2 were used to estimate leucine turnover and oxidation, respectively. Fat-free body mass was estimated from the measurements of total body water as quantified by H2[18O] tracer dilution. The rates of CO2 production and oxygen consumption were measured hourly during the study period, using open-circuit respiratory calorimetry. Urinary urea, ammonia and total nitrogen excretion rates were quantified from timed urine samples. Even though the plasma leucine levels were lower in cirrhotics as compared with controls (100.5 +/- 17.1 vs. 138.3 +/- 20.4 mumoles per liter, mean +/- S.D., p less than 0.001), the rates of leucine turnover were not significantly different in the two groups (89.4 +/- 19.0 vs. 87.8 +/- 19.0 mumoles per kg X hr). In contrast, the rates of leucine oxidation were significantly reduced in cirrhosis (8.1 +/- 2.5 vs. 12.7 +/- 3.1 mumoles per kg X hr, p less than 0.01). When all subjects were considered, the leucine oxidation rate was correlated with plasma leucine concentration (r = 0.62, p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)",0
998,3095640,Prospective payment for psychiatry--feasibility and impact,"""Although 15 diagnosis-related groups (DRGs) have been proposed for psychiatric hospital patients, psychiatric hospitals are currently exempt from the DRG prospective payment system. We investigated the ability of the psychiatric DRGs to predict the hospital length of stay and costs by retrospectively analyzing the charts of 8816 randomly selected patients from 32 psychiatric hospitals throughout the United States. In addition, we developed other grouping systems to see whether they would have been better predictors of length of stay. We found that grouping the patients in the 15 psychiatric DRGs reduced the total variance in length of stay by only 3.9 percent. Furthermore, our best alternative grouping--based on major diagnostic categories, whether the patient was transferred from another facility, age, and psychiatric complications and comorbidities--reduced the variance by only 7.8 percent. We conclude that DRGs do not adequately predict length of stay or costs in psychiatric hospitals. We identified factors other than diagnosis that predicted the length of stay better, but all the models we tested would create large financial """"winners"""" and """"losers"""" and thus introduce inappropriate incentives into the care of patients in psychiatric hospitals.""",0
999,3109761,Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart,"Changes in cytosolic free calcium concentration during myocardial ischemia were measured by 19F NMR in 5FBAPTA-loaded perfused rat hearts. The hearts were perfused with Krebs-Henseleit buffer containing 5 microM of the acetoxymethyl ester of 5FBAPTA, which was hydrolyzed by cytosolic esterases to achieve cytosolic concentrations of 5FBAPTA of 0.12 to 0.65 mM. Cytosolic free calcium concentrations were calculated as the product of the ratio of peak areas for bound and free 5FBAPTA in the NMR spectra and the dissociation constant (708 nM). The basal cytosolic calcium concentration, measured in potassium or magnesium arrested hearts, was 252 nM, and the time-average calcium concentration in beating hearts was 630 nM. Following the onset of total ischemia, there was no immediate substantial change in cytosolic calcium despite a rapid decline in creatine phosphate and ATP and a marked increase in inorganic phosphate as monitored by 31P NMR, but by 10 minutes, there was a substantial increase in free calcium concentration. The ratio of peak areas of bound and free 5FBAPTA returned to the preischemic value during reperfusion, and there was no detectable loss of 5FBAPTA from the heart. Creatine phosphate was also restored to its preischemic level during reperfusion. These results indicate that cytosolic free calcium increases during ischemia and is not immediately associated with lethal injury. This increase in cytosolic calcium may activate degradative enzymes that eventually could compromise myocyte viability. ",0
1000,3109809,Late-phase reaction and tear fluid cytology in the rat ocular anaphylaxis,"Tear fluid cytology is described for the early and late phases of ocular anaphylaxis in actively immunized Sprague-Dawley rats. Tears were collected from both eyes of the rats before challenge and at 1, 2, 4, 6, 8, 10, 12, 24, and 48 h after topical challenge with di-DNP-lysine in one eye and PBS in the fellow eye. Results showed a statistically significant increase in the Aggregate Cell Rating, which represents the aggregate scores in neutrophil, eosinophil, lymphocyte, and atypical epithelial cell levels, in antigen-treated vs control eyes. This report is the first to use a cytologic study of tear film to detect the late phase of ocular anaphylaxis in the rat. Cytology of the tear film could be applied to the study of allergic conjunctivitis in both animals and humans. ",0
1001,3110037,Detection of drug residues on the hands of subjects by surface sampling and ion mobility spectrometry,"This paper deals with the detection of drug residues on the hands of human subjects. The results demonstrate that detectable amounts of particulate matter are transferred to the hands by brief contact with drug tablets. A sampling and analysis method has been developed, and is based on the aspirating and trapping of drug microparticles on a filter plug, to be followed by thermal desorption directly into an ion mobility spectrometer. The technique is suited for initial field screening in clinical and forensic applications. The major drugs detected were diazepam, amitriptyline, codeine, acetaminophen, nitroglycerin, and delta 9-tetrahydrocannabinol (delta 9-THC). ",0
1002,3110730,Neisseria meningitidis bacteremia in children: quantitation of bacteremia and spontaneous clinical recovery without antibiotic therapy,"""The relationship between the magnitude of bacteremia due to Neisseria meningitidis and the clinical diagnosis was determined for 43 children who had fever in the presence or absence of focal signs of infection. Bacteremia was quantitated by the previously described procedure using heparinized blood (0.2 to 1.0 mL). Additionally, blood was cultured by means of the radiometric Bactec technique. Seventeen patients had meningitis, 12 had meningococcemia, 13 had unsuspected or """"occult"""" bacteremia, and five had other diagnoses. """"Occult"""" bacteremia was diagnosed initially in four patients, but subsequently meningitis was diagnosed. All 13 patients with 500 or more organisms per milliliter had meningitis or meningococcemia in contrast to 12 (55%) of 22 patients with less than 500 organisms per milliliter (P less than or equal to .0035). Only 18 (42%) of these patients bacteremic with N meningitidis presented with petechiae or purpura. All 13 children with occult bacteremia were sent home after blood cultures were obtained; six of the 13 received a regimen of oral amoxicillin for otitis media. At reexamination (interval 16 to 119 hours) four had meningitis, seven were clinically improved (afebrile, negative blood culture, without invasive disease), and two were still mildly febrile with negative blood culture. Three of these bacteremic children experienced spontaneous clinical and bacteriologic resolution without antibiotic treatment. This has not been previously reported. """,0
1003,3111064,The effect of extreme temperatures on hematologic and biochemical indicators in heifers],The study was aimed at finding the effect of low and high temperatures on some biochemical parameters in heifers. Thirty half-sister heifers were used as the experimental material. The animals were divided into two groups. The experimental group including 16 heifers was kept loose on deep litter in an open barn with no thermal insulation. The control heifers (n = 14) were kept in a thermally insulated house. Blood was collected at extreme temperatures: above 30 degrees C and below -5 degrees C. An insignificant decrease of haemoglobin and haematocrit was recorded in the blood collected at low and high temperatures from the heifers kept in the open barn; a reduction of cholesterolaemia and total lipaemia was recorded at high temperatures. High and low temperatures significantly increased the concentration of free amino acids; the differences between the experimental and control group being from 36 to 76 mumol per litre. The content of 3.5-cyclic adenosine monophosphate was increased insignificantly at extreme temperatures. Hyperglycaemia was recorded in the heifers at high temperatures and at the beginning of the winter season. At low temperatures the concentration of thyroxine was found to be increased in the blood of the experimental animals: 120 nmol per litre and 161 nmol per litre vs. 95 nmol and 116 nmol in the control group. ,0
1004,3112160,Expression of cDNAs for G proteins in Escherichia coli. Two forms of Gs alpha stimulate adenylate cyclase,"Complementary DNAs that encode two forms of the alpha subunit (Gs alpha) of the guanine nucleotide-binding protein responsible for stimulation of adenylate cyclase (Gs) have been inserted into plasmid vectors for expression in Escherichia coli. Following transformation of either of these plasmids into E. coli K38, Gs alpha accumulates to 0.4-0.8 mg/liter (approximately 0.1% of total protein), as judged by immunoblot analysis with specific antisera. Based on deduced amino acid sequence, the two cDNAs should encode proteins with molecular weights of 44,500 and 46,000, respectively (Robishaw, J.D., Smigel, M. D., and Gilman, A. G. (1986) J. Biol. Chem. 261, 9587-9590). Expression of these cDNAs in E. coli yields proteins that co-migrate on sodium dodecyl sulfate-polyacrylamide gels with the Gs alpha subunits from S49 lymphoma cell membranes, with apparent molecular weights of 45,000 and 52,000, respectively. Low levels of activity are detected in the 100,000 X g supernatant after lysis and fractionation of E. coli expressing either form of Gs alpha. Partial purification of Gs alpha from E. coli lysates yields preparations in which significant and stable activity can be assayed. Both forms of Gs alpha migrate through sucrose gradients as soluble, monodisperse species in the absence of detergent. As expressed in E. coli, both forms of Gs alpha can reconstitute isoproterenol-, guanine nucleotide-, and fluoride-stimulated adenylate cyclase activity in S49 cyc-cell membranes to approximately the same degree and can be ADP-ribosylated with [32P]NAD+ and cholera toxin. However, based on the specific activity of purified rabbit liver Gs, only 1-2% of the Gs alpha expressed in E. coli appears to be active. Incubation of partially purified fractions of recombinant Gs alpha with guanosine 5'-(3-O-thio)triphosphate and resolved beta gamma subunits isolated from purified bovine brain G proteins results in a 7-10-fold increase in Gs activity. Incubation of bovine brain beta gamma with recombinant Gs alpha also leads to a dramatic increase in observed levels of cholera toxin-catalyzed [32P]ADP-ribosylation. ",0
1005,3112365,Effects of N-ethylmaleimide on arginine vasopressin-induced responses in an established smooth muscle cell line,"We have previously reported that 8-arginine vasopressin (AVP) stimulates phosphatidylinositol turnover and Ca++ mobilization in rat aortic smooth muscle cells (A10). In the present study, N-ethylmaleimide (NEM) was used to further characterize the putative guanine nucleotide binding protein that transduces the V1 receptor effects on phosphatidylinositol turnover and Ca++ efflux in these cells. Pretreatment of the cells with low concentrations of NEM did not affect the basal levels of the inositol phosphates and Ca++ efflux but significantly inhibited the AVP-induced increases. NEM pretreatment did not significantly affect [3H]AVP binding to intact cells. Guanyl-5'-yl imidodiphosphate reduced the apparent binding affinity of AVP to cell membranes. NEM pretreatment abolished this guanyl-5'-yl imidodiphosphate effect. AVP stimulated a specific GTPase activity in cell membranes; this effect was also abolished by NEM pretreatment. The results suggest that in A10 cells a guanine nucleotide binding protein sensitive to NEM couples vasopressin receptors to phospholipase C. ",0
1006,3112774,Analysis of the role of cysteine residues in isopenicillin N synthetase activity by site-directed mutagenesis,"The predicted amino acid sequences of isopenicillin N synthetase from both Cephalosporium acremonium and Penicillium chrysogenum have two cysteine residues in analogous positions (Cys-106 and Cys-255 in the C. acremonium numbering). To examine the role of these cysteine residues in the activity of the C. acremonium enzyme, we used site-directed in vitro mutagenesis to change these cysteine residues to serine residues. Mutation of Cys-255 reduces specific activity approximately equal to 50%, whereas mutation of Cys-106 or mutation of both Cys-106 and Cys-255 reduces specific activity about 97%. This suggests that the cysteines are important but not essential for IPNS activity. Alkylation of IPNS also almost completely inactivated the enzyme, but residual activity could have been due to incomplete alkylation. Atomic substitution via genetic manipulation in this case is a more accurate means of assessing the role of sulfhydryl moieties in enzyme activity. ",0
1007,3112933,Selective modulation of the CD4 molecular complex by Pseudomonas aeruginosa alkaline protease and elastase,"The binding of monoclonal antibodies against CD4 was specifically inhibited by treatment of human CD4+ cells with either alkaline protease (AP) or elastase (Ela), purified from Pseudomonas aeruginosa. Binding of antibodies against CD3 (pan T), CD5 (pan T), CD8 (T suppressor/cytotoxic), HLA-ABC, HLA-DR, HLA-DQ, HLA-DP/DR, and beta 2 microglobulin was not inhibited by AP or Ela. Heat-inactivation of the proteases at 65 degrees C for 20 min or treatment with the metal chelator EDTA abolished the inhibitory activity of both proteases. These findings may serve to develop novel immunological methods for the isolation and study of the lymphocyte CD4 structure, which plays an important part in the immune response. ",0
1008,3113290,Pupillary diameter and ventilatory CO2 sensitivity after epidural morphine and buprenorphine in volunteers,"The aim of this study was to correlate pupillary diameter with respiratory depression for 20 hr after epidural administration of morphine or buprenorphine. Pupillary diameter and the ventilatory sensitivity to CO2 were measured in six healthy volunteers at various times (0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 20 hr) in two sessions, separated by at least 1 week, at which either epidural morphine, 4 mg, or epidural buprenorphine, 0.15 mg, was administered randomly in a double-blind manner. Three of the six volunteers received 0.3 mg buprenorphine epidurally in a third session. Pupillary diameter was measured with a modified Essilor pupillometer. The ventilatory CO2 sensitivity was measured by a modified Read rebreathing technique. The ventilatory parameters measured were mouth occlusion pressure during the first 0.1 sec of inspiration (P0.1), end-tidal CO2 (PETCO2), tidal volume (VT) and respiratory rate (RR). Slopes of the linear regression lines (P0.1/CO2, VT/CO2, VE/CO2, and RR/CO2) and the intercept values of the regression lines and PETCO2 = 7.2 kPa (P0.1:7.2, VT:7.2, VE:7.2, and RR:7.2) were calculated. Pupillary diameter after epidural morphine was smallest at the second hour and had returned to normal after eight hours. After epidural buprenorphine there were two periods of miosis, one at 1-3 hr, the other at 10 hr. With epidural morphine, a statistically significant correlation (P less than 0.05) was found between pupillary diameter and VE/CO2, VE:7.2, P0.1:7.2, and VT:7.2. With epidural buprenorphine 0.15 mg a significant correlation was found between pupillary diameter and VE:7.2 and P0.1:7.2. With epidural buprenorphine 0.3 mg the correlations between pupillary diameter and VE:CO2, VE:7.2, and P0.1:7.2 were significant.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1009,3113691,In vitro release of hypothalamic corticoliberine in the rat: incubation of slices from the whole hypothalamus],"An experimental system allowing both the incubation and rapid transfert of rat hypothalamic slices has been developed in order to approach the regulation of CRF secretion. The release of CRF has been quantified by a specific radioimmunoassay. Under basal conditions, immunoreactive CRF release reached an optimum of 96.2 +/- 10.4 pg/3 hypothalami/20 min. A depolarizing concentration of KCl (56 mM) or veratridine (50 microM) applied for 20 min. induced a 222 and 257% increase, respectively, in CRF release. The in vitro CRF values released under basal and stimulated conditions are comparable to those of other hypothalamic neuropeptides. Furthermore, in vitro CRF release from the hypothalamus is in the same order of magnitude as in vivo CRF secretion estimated by hypophysial portal blood collection or median eminence push-pull cannulation. ",0
1010,3113912,Determination of nitrates in plasma,"Because of the high efficacy of existing nitrates, alternative dosage formulations have been developed rather than new compounds. These new formulations challenge the analyst to develop analytical methods with lower sensitivity and higher precision. Isosorbide dinitrate is analysed in the presence of its major metabolites isosorbide 2-mononitrate and isosorbide 5-mononitrate. The present method is an improvement over previously published methods. It is not possible to analyse glyceryl trinitrate and its major metabolites 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate with the necessary sensitivity in one chromatogram. A 2-step procedure is therefore applied. The extraction procedures, the gas chromatographic conditions, imprecision and inaccuracy of the methods, the lower limits of quantitation, sample chromatograms and applications of all methods are described in detail. Thus, the possibilities of modern analytical methods in the determination of nitrates in the lower picogram region are demonstrated. ",0
1011,3113983,Bepridil and valproate retard Na+ reactivation in Myxicola,"Two drugs were examined, each causing a similar specific modification of Na+ channel inactivation gating when internally applied to voltage-clamped Myxicola giant axons. Bepridil is an antianginal-antiarrhythmic agent with vasodilator and direct cardiac inotropic effects. Sodium valproate has anticonvulsant activity and causes use-dependent inhibition of repetitive firing in CNS neurons. Bepridil and sodium valproate caused a dose-dependent decrease in maximum Na+ conductance (KD = 25 microM for bepridil; KD = 0.5 mM for valproate). More importantly, at half-maximal blocking concentrations both drugs shifted steady state Na+ inactivation in the hyperpolarizing direction (by 30 mV for bepridil; 15 mV for valproate) and slowed the recovery of Na+ channels from inactivation (by 300% for bepridil; 60% for valproate). There was no effect on the K+ conductance, voltage-dependence of Na+ activation, or the time-dependence of inactivation of conducting channels. Neither produced non-inactivating Na+ current during long depolarizing steps. ",0
1012,3122046,"Artificial feeding--solid ground, not a slippery slope","Decisions about artificial feeding arouse more controversy than those involving any other life-sustaining treatment. Because food and water are generally considered basic elements of humane care, representing love and concern for the helpless, it is often thought that they must always be provided. In a landmark decision, the Supreme Judicial Court of Massachusetts ruled that a feeding tube could be removed from a patient in a persistent vegetative state if this was consistent with his previously expressed wishes. The case of Paul E. Brophy, Sr., is part of an emerging medical and legal consensus on the withholding of artificial feeding from adult patients. The view is growing that tube and intravenous feeding should be likened to other medical interventions and not to the routine provision of nursing care or comfort. Competent patients have the right to refuse such feeding. Feeding can also be stopped incompetent patients who have earlier stated such a wish.",0
1013,3123929,Accuracy of diagnostic coding for Medicare patients under the prospective-payment system,"""Reimbursement of hospitals by Medicare under the prospective-payment system is based on patients' diagnoses as coded at discharge. During the period October 1984 through March 1985, we studied the accuracy of the coding for diagnosis-related groups (DRGs) in hospitals receiving Medicare reimbursement. We used a two-stage cluster method to sample 7050 medical records from 239 hospitals that were stratified according to size. Using blinded techniques with reliability checks, medical-record specialists reabstracted the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to assign correct DRGs to discharged patients. The correct DRGs were then compared with those originally assigned by the physician and the hospital administration. The study revealed an error rate of 20.8 percent in DRG coding. Errors were distributed equally between physicians and hospitals. Small hospitals had significantly higher error rates. Previous studies had found that errors occurred randomly, so that half the errors benefited the hospital financially and half penalized the hospital. The present study found that a statistically significant 61.7 percent of coding errors favored the hospital. These errors caused the average hospital's case-mix index--a measure of the complexity of illness of the hospital's patients--to increase by 1.9 percent. As a result, hospitals received higher net reimbursement from Medicare than was supportable by the medical records. We conclude that """"creep"""" does occur in the coding of DRGs, resulting in overpayment to hospitals for patients covered by Medicare.""",0
1014,3127713,"The effects of regulation, competition, and ownership on mortality rates among hospital inpatients","We examined the influence of the regulation of hospital rates, state certificate-of-need programs, competition, and hospital ownership on mortality rates among inpatients receiving care under Medicare for 16 selected clinical conditions that were studied as a group. Data were obtained from the records of 214,839 patients who received care in 981 hospitals in 45 states from July 1, 1983, through June 30, 1984. We found significant associations between higher mortality rates among inpatients and the stringency of state programs to review hospital rates (P less than or equal to 0.05), the stringency of certificate-of-need legislation (P less than or equal to 0.01), and the intensity of competition in the marketplace, as measured by enrollment in health maintenance organizations (P less than or equal to 0.05). Hospitals in the states with the most stringent review procedures for hospital rates had ratios of actual to predicted death rates that were 6 to 10 percent higher than those of hospitals in states with less stringent rate-review programs (P less than or equal to 0.001). Hospitals in the states with the most stringent procedures for reviewing applications for certificates of need had ratios of actual to predicted death rates that were 5 to 6 percent higher than those of hospitals in states with less stringent certificate-of-need procedures (P less than or equal to 0.05). There was no statistically significant association between mortality rates among inpatients and either the type of hospital ownership or the number of hospitals competing in the market area. Additional analyses, which examined alternative explanations for these findings, failed to change the results. These findings raise serious concerns about the welfare of patients who are admitted to hospitals in highly regulated areas and those admitted to hospitals in relatively competitive markets. They suggest that it is important to incorporate quality-assurance procedures and systems to monitor patients' outcomes into public and private programs designed to contain costs or promote competition, or both.",0
1015,3129660,Private cost containment. The effects of utilization review programs on health care use and expenditures,"Utilization review has been regarded as one of the most promising approaches to the containment of health care costs. We analyzed insurance claims data on 222 groups of employees and dependents for 1984 and 1985 to evaluate the effects of utilization review programs instituted by a large private insurance carrier. The utilization review programs we studied were compulsory; patients who did not follow established utilization review procedures were subject to financial penalties. Controlling for employee characteristics, health care market area factors, and benefit-plan features, we found that utilization review reduced admissions by 12.3 percent, inpatient days by 8.0 percent, hospital expenditures by 11.9 percent, and total medical expenditures by 8.3 percent. When only groups that had relatively high admission rates before adopting utilization review were analyzed, it was found that they had a 34 percent reduction in patient days and a 30 percent reduction in hospital expenditures. The savings-to-cost ratio of utilization review for groups overall was highly favorable--approximately 8 to 1. Private utilization review programs of the type we studied appear to be effective in reducing hospital use and decreasing medical expenditures. This study did not address the possible effects of such programs on the health status of patients.",0
1016,3140013,Evidence of an altered pattern of breathing during exercise in recipients of heart-lung transplants,"Recipients of heart-lung transplants represent an unusual opportunity to study the regulation of ventilation, because the neural pathways between the lungs and the central nervous system are disrupted in these patients. We compared the ventilation response in seven recipients of heart-lung transplants who had normal pulmonary function and seven recipients of heart transplants, all of whom performed incremental bicycle ergometry. The level of ventilation in recipients of heart-lung transplants was similar to that in heart-transplant recipients for equivalent levels of carbon dioxide production. Arterial pH and partial pressure of carbon dioxide at maximal exercise were normal and not significantly different in the two groups, also suggesting that levels of ventilation were appropriate in both groups. However, the rate of the rise in respiratory rate for increasing levels of ventilation was significantly lower in recipients of heart-lung transplants than in heart-transplant recipients, and the initial increase in tidal volume was more rapid in the former group than in the latter. Thus, recipients of heart-lung transplants have an appropriate level of ventilation during exercise as the result of a disproportionate increase in tidal volume at a reduced respiratory rate. We speculate that intrapulmonary receptors are important in regulating the pattern, but not the absolute level, of ventilation during exercise.",0
1017,3173436,Ethical considerations of human investigation in developing countries: the AIDS dilemma,"In the efforts to develop a vaccine for human immunodeficiency virus (HIV), attention has focused on sub-Saharan Africa, where large populations at risk for HIV infection could be studied easily. Cross cultural bioethics must be examined to address the ethical implications and cultural obstacles of such research. Autonomy and informed consent are difficult to achieve in cultures with limited personal choice. In some cultures, individual personhood is secondary to social relationships in the tribe or village. Language barriers, illiteracy, and the lack of knowledge about modern science all make it difficult to adequately inform participants. While the Helsinki Declaration emphasizes that a subject's well-being takes precedence over the interests of science and society, health policy decisions in nonautonomous populations often place state interests over the individual. Political sensitivities have been aroused by attempts to attribute the origin of AIDS to western or central Africa, leading political controversy and discrimination against Africans. Foreign researchers often exclude African participation once they have obtained the body fluid samples for study. Without joint collaboration and education, human research in developing countries can easily become exploitative. Justice dictates that research subjects be chosen for scientific reasons, not due to easy availability or ability to be manipulated. In vaccine development, Africans should not experience a disproportionate amount of risk without an equal share in the benefits. Furthermore, malnutrition, malaria, tuberculosis, and many other diseases present more urgent health problems to the developing world than AIDS. The health care priorities of the developing nations must be considered.",0
1018,3185622,"Handgun regulations, crime, assaults, and homicide. A tale of two cities","To investigate the associations among handgun regulations, assault and other crimes, and homicide, we studied robberies, burglaries, assaults, and homicides in Seattle, Washington, and Vancouver, British Columbia, from 1980 through 1986. Although similar to Seattle in many ways, Vancouver has adopted a more restrictive approach to the regulation of handguns. During the study period, both cities had similar rates of burglary and robbery. In Seattle, the annual rate of assault was modestly higher than that in Vancouver (simple assault: relative risk, 1.18; 95 percent confidence interval, 1.15 to 1.20; aggravated assault: relative risk, 1.16; 95 percent confidence interval, 1.12 to 1.19). However, the rate of assaults involving firearms was seven times higher in Seattle than in Vancouver. Despite similar overall rates of criminal activity and assault, the relative risk of death from homicide, adjusted for age and sex, was significantly higher in Seattle than in Vancouver (relative risk, 1.63; 95 percent confidence interval, 1.28 to 2.08). Virtually all of this excess risk was explained by a 4.8-fold higher risk of being murdered with a handgun in Seattle as compared with Vancouver. Rates of homicide by means other than guns were not substantially different in the two study communities. We conclude that restricting access to handguns may reduce the rate of homicide in a community.",0
1019,3185647,Diminished perception of inspiratory-resistive loads in insulin-dependent diabetics,"Diabetes mellitus is known to be associated with impaired perception of sensory input from organs such as the heart. To determine whether diabetics have a diminished ability to perceive respiratory sensations, we compared the abilities of patients with insulin-dependent diabetes (n = 17) and nondiabetic controls (n = 13) to detect inspiratory-resistive loads. The subjects were evaluated as they breathed through a tube-manifold apparatus with resistance that was varied randomly. They indicated whenever they perceived increased resistance to inspiration. The threshold for detecting added inspiratory resistance was expressed as a fraction of the background resistance of the subject plus that of the apparatus. This fraction, known as the Weber fraction, was 0.53 +/- 0.19 (mean +/- SD) in diabetics with neuropathy, 0.38 +/- 0.24 in diabetics without neuropathy, and 0.29 +/- 0.15 in nondiabetic controls. The differences in the mean value of the Weber fraction among the three groups were significantly different from zero (F = 4.57, P less than 0.025). There was not a significant correlation between the Weber fraction and age, degree of autonomic dysfunction, pulmonary function, cigarette smoking, or degree of diabetic control. The Weber fraction correlated with the duration of diabetes (r = 0.57, P less than 0.02). We conclude that patients with insulin-dependent diabetes may have an impaired ability to perceive inspiratory-resistive loads. This increased threshold for the perception of respiratory sensations may lead to delayed recognition of pulmonary disease in diabetics.",0
1020,3185649,The differential effect of prenatal care on the incidence of low birth weight among blacks and whites in a prepaid health care plan,"Black infants are born with low birth weights (less than 2500 g) and very low birth weights (less than 1500 g) at twice the rate of white infants. We investigated the effect of prenatal care delivered in a health maintenance organization on the birth weights of black and white infants at normal risk for low birth weight. Using birth certificates for all children born in 1978 in the California Kaiser-Permanente hospitals, we studied data on more than 31,000 black and white newborns whose mothers' ages and levels of education were comparable. The data show that black mothers used prenatal care less extensively and had a higher incidence of infants with low birth weights (8.4 vs. 3.6 percent) and very low birth weights (2.0 vs. 0.7 percent) than white mothers. The difference in the use of prenatal care, however, accounted for less than 15 percent of the difference in the incidence of low birth weight. The rates of low birth weight, very low birth weight, and preterm birth (less than 260 days' gestation) decreased with increasing levels of prenatal care for both blacks and whites. However, increasing levels of care were associated with a greater reduction among black infants than among white infants in low birth weight, very low birth weight, and low birth weight at term (greater than or equal to 260 days' gestation). When we compared mothers who received adequate care with those who received inadequate care, the relative risk of giving birth to a very-low-birth-weight infant was reduced 3.6-fold (95 percent confidence interval, 2.0 to 6.6) for black mothers and 2.1-fold (confidence interval, 1.3 to 3.4) for white mothers; the relative risk of giving birth to a low-birth-weight infant at term was reduced 3.4-fold (95 percent confidence interval, 2.2 to 5.4) for black mothers and 1.6-fold (confidence interval, 1.1 to 2.3) for white mothers. We conclude that even in a population of women at low risk for giving birth to low-birth-weight infants, prenatal care is more beneficial for blacks than for whites.",0
1021,3185675,A successful program to lower cesarean-section rates,"Despite the consensus that national cesarean-section rates are excessive, they continue to rise. Currently, approximately one of every four deliveries is by cesarean section. We developed an initiative to reduce the number of cesarean deliveries to a rate of 11 percent of all deliveries at our inner-city hospital. Participation by attending physicians was voluntary and not linked to any sanction. The program included a stringent requirement for a second opinion, objective criteria for the four most common indications for cesarean section, and a detailed review of all cesarean sections and of individual physicians' rates of performing them. During the first two years of the program, the cesarean-section rate fell from 17.5 percent of 1697 deliveries in 1985 to 11.5 percent of 2301 deliveries in 1987 (P less than 0.05). The proportion of infants with five-minute Apgar scores lower than 7 increased from 3 percent in 1985 to 4.9 percent in 1987 (P less than 0.05), but neither the fetal mortality rate (11.9 per 1000) nor the neonatal mortality rate (11.2 per 1000) in 1987 differed significantly from the rates in 1985. A single maternal death, unrelated to cesarean delivery, occurred during the study. Rates of both primary and repeat cesarean sections decreased, although only the decline in the rate of primary cesarean sections, from 12 to 6.8 percent, was statistically significant (P less than 0.05). During the same period, operative vaginal deliveries (i.e., forceps deliveries and midpelvic procedures) declined from 10.4 to 4.3 percent (P less than 0.05) of total deliveries. We conclude that an initiative within an obstetrics department can reduce cesarean-section rates substantially without adverse effects on the outcome for mother or infant.",0
1022,3200267,The sounds of the hospital. Paging patterns in three teaching hospitals,"To examine the influence of hospital paging systems on residency training, nursing services, and patient care, we asked medical interns (first-year residents) in three teaching hospitals to keep logs of pages they received during a three-day period. Thirty-one logs from 26 interns were completed; a total of 1206 pages were recorded on 91 days (1095 hours). Interns were paged an average of once an hour; on 24 occasions, interns were paged five or more times an hour. The majority of pages (65 percent) occurred when interns were engaged in patient care. Only 34 percent of the pages were judged both to require a response within one hour and to result in a change in patient care. Twenty-four percent were clinically indicated and required a response within one hour but did not result in a change in patient care. Sixteen percent of pages resulted in a change in patient care or were clinically indicated but could have been postponed for more than an hour. An additional 26 percent of pages neither resulted in a change in clinical management nor were clinically indicated. Reducing the number of unnecessary pages and postponing nonurgent ones could result in as much as a 42 percent decrease in disruptions of patient care and more rest for interns.",0
1023,3200277,Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception,"Whether pregnant women with insulin-dependent diabetes mellitus have an increased risk of spontaneous abortion is controversial. To address this question, we enrolled 386 women with insulin-dependent diabetes and 432 women without diabetes before or within 21 days after conception and followed both groups prospectively. Sixty-two diabetic women (16.1 percent) and 70 control women (16.2 percent) had pregnancy losses (odds ratio, 0.99; 95 percent confidence interval, 0.67 to 1.46). After adjustment for known risk factors for spontaneous abortion, the rate was still not significantly higher in the diabetic group (odds ratio, 0.91; 95 percent confidence interval, 0.59 to 1.40). Nonetheless, among the diabetic women, most of whom had good metabolic control, those who had spontaneous abortions had higher fasting and postprandial glucose levels in the first trimester than those whose pregnancies continued to delivery (P = 0.01 for fasting glucose levels and P = 0.005 for postprandial levels). In the small subgroup of diabetic women with poor control, who had elevated values for glycosylated hemoglobin in the first trimester, each increase of 1 SD above the normal range was associated with an increase of 3.1 percent in the rate of pregnancy loss (95 percent confidence interval, 0.6 to 5.6). We conclude that diabetic women with good metabolic control are no more likely than nondiabetic women to lose a pregnancy, but that diabetic women with elevated blood glucose and glycosylated hemoglobin levels in the first trimester have a significantly increased risk of having a spontaneous abortion.",0
1024,3200278,Assessing patients' capacities to consent to treatment,"The right of patients to accept or refuse recommended treatment requires careful reassessment when their decision-making capacities are called into question. Patients must be informed appropriately about treatment decisions and be given an opportunity to demonstrate their highest level of mental functioning. The legal standards for competence include the four related skills of communicating a choice, understanding relevant information, appreciating the current situation and its consequences, and manipulating information rationally. Since competence is a legal concept and can be formally determined only in court, the clinical examiner's proper role is to gather relevant information and decide whether an adjudication of incompetence is required. Treatment for impairment of mental functioning can sometimes restore patients' capacities, making it unnecessary to deprive them of their decision-making powers.",0
1025,3262199,A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity,"To study the role of infection in prematurity, we studied the demographic and obstetrical characteristics, chorioamnionic cultures, and placental histologic features of women who delivered prematurely and compared these findings with those in women who delivered at term. Microorganisms were isolated from the area between the chorion and the amnion (chorioamnion) in 23 of 38 placentas (61 percent) from women with preterm labor who delivered before 37 weeks' gestation and in 12 (21 percent) of 56 placentas from women without preterm labor who delivered at term (odds ratio, 5.6; 95 percent confidence interval, 2.1 to 15.6). The most frequent isolates from the placentas of those whose infants were delivered prematurely were Ureaplasma urealyticum (47 percent) and Gardnerella vaginalis (26 percent). The recovery of any organism from the chorioamnion was strongly associated with histologic chorioamnionitis (odds ratio, 7.2; 95 percent confidence interval, 2.7 to 19.5) and with bacterial vaginosis (odds ratio, 3.2; 95 percent confidence interval, 1.1 to 6.6). When multiple logistic regression was used to control for demographic and obstetrical variables, premature delivery was still related to the recovery of organisms from the chorioamnion (odds ratio, 3.8; 95 percent confidence interval, 1.5 to 9.9) and with chorioamnionitis (odds ratio, 5.0; 95 percent confidence interval, 1.6 to 15.3). The proportion of placentas with evidence of infection was highest among those who delivered at the lowest gestational age. We conclude that infection of the chorioamnion is strongly related to histologic chorioamnionitis and may be a cause of premature birth.",0
1026,3275896,Effect of transplantation on the Medicare end-stage renal disease program,"The Medicare end-stage renal disease program has received considerable attention as a model of government funding for high-cost medical treatment. This paper examines how the program has been influenced by renal transplantation. In the past decade, the number of kidney transplantations has increased substantially, and the success rate of these procedures has improved. From 1980 to 1985, the number of transplantations increased by 10 percent per year. During that time, the survival rates for grafts from cadavers and living related donors increased by 7 and 3 percent, respectively, in part because of the introduction of cyclosporine. As a result, the fastest-growing group of beneficiaries of the Medicare end-stage renal disease program are those with functioning grafts. As of the end of 1985, these patients accounted for 18 percent of all beneficiaries and 32 percent of all beneficiaries less than 55 years of age. In the youngest groups, transplantation has reached a level sufficient to reduce the absolute numbers of patients on dialysis, beginning in 1983. Increases in transplantation are not evenly distributed among subgroups of beneficiaries. Relatively few patients 65 years of age and older receive transplants; blacks receive transplants at a rate roughly half that among whites, but the rate is increasing. Because the costs of maintaining patients with functioning grafts are only one third of those for patients on dialysis and because the quality of life is usually much better, renal transplantation is causing a convergence of the best clinical and economic outcomes for patients with end-stage renal disease.",0
1027,3276589,Long-term culture of hepatocytes: effect of hormones on enzyme activities and metabolic capacity,"(i) Hepatocytes isolated from adult rats were cultured for 2 to 3 weeks on collagen in a modified, serum-free Waymouth medium containing fatty acids and varying concentrations of glucocorticoid, insulin and glucagon. (ii) In the presence of all three hormones, it was possible to maintain the content of DNA, the activity of glucokinase, pyruvate kinase, hexokinase and lactate dehydrogenase at initial levels for 2 to 3 weeks. The activity of glucokinase and pyruvate kinase was affected by the concentration of insulin. (iii) The activity of alcohol dehydrogenase was stable for 3 days and declined to about 25% of the initial level after 2 weeks of culture, irrespective of the presence of hormones. (iv) Maintenance of albumin secretion was dependent on the presence of glucocorticoid, and glucocorticoid and insulin showed an additive or, at some time points, a synergistic effect on its secretion. (v) The content of cytochrome P-450 could be kept at 65% of the initial level, provided that a relatively high concentration of dexamethasone was present (10(-6) M). (vi) In the absence of hormones, urea synthesis was 70% of initial levels throughout the experimental period. With insulin and glucocorticoid present, a high concentration of glucagon (10(-8) M) was required to maintain the synthesis of urea at this level. (vii) It is concluded that hepatocyte cultures as described in the present study may be a useful, well-defined system for long-term metabolic, pharmacologic and toxicologic studies.",0
1028,3277055,Seroprevalence of human immunodeficiency virus among childbearing women. Estimation by testing samples of blood from newborns,"Attempts to predict the course of the epidemic of acquired immunodeficiency syndrome (AIDS) have been hampered by the lack of an objective, practical way to estimate the prevalence of infection with the human immunodeficiency virus (HIV) in the general population. Testing for the prevalence of HIV infection in women should be a sensitive means to track the epidemic and to study the potential for perinatal transmission. Antibodies in maternal blood are contained in neonatal blood specimens routinely collected on absorbent paper for other purposes, such as screening for phenylketonuria; we therefore tested for HIV antibody in these specimens. Analysis of batches of individually blinded specimens from selected hospitals protected the anonymity of the mothers and babies and was cost efficient. Using the newborn's blood as an indicator of the mother's serologic status, we concluded that 1 of every 476 women (2.1 per 1000) giving birth in Massachusetts was positive for HIV antibody by immunofluorescence assay or enzyme-linked immunosorbent assay, both confirmed by immunoblot (Western blot) testing. The prevalence of HIV infection varied according to the type and location of the maternity hospitals; rates of seropositivity were highest in inner-city hospitals (8.0 per 1000), lower in mixed urban and suburban hospitals (2.5 per 1000), and lowest in suburban and rural hospitals (0.9 per 1000). This method is useful for collecting data needed to plan and evaluate prevention strategies and to predict the health care resources that will be needed to care for women and children who contract AIDS. Because other states have newborn screening programs similar to the Massachusetts program, this approach can be used for national surveillance of AIDS in women.",0
1029,3283553,Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes,"In fasting nondiabetic subjects, insulin is secreted in regular pulses every 12 to 15 minutes, but patients with non-insulin-dependent diabetes lack regular oscillatory insulin secretion. To investigate whether abnormal insulin oscillations are an early feature of diabetes, we studied 10 minimally glucose-intolerant first-degree relatives of patients with non-insulin-dependent diabetes and 10 controls matched for age and obesity. We performed a time-series analysis of fasting plasma insulin levels in blood samples obtained at 1-minute intervals for 150 minutes. Fasting plasma glucose levels were higher in the relatives than in the controls (mean +/- SD, 5.4 +/- 0.7 vs. 4.4 +/- 0.3 mmol per liter). Autocorrelation of pooled data showed no regular oscillatory activity in the relatives but a 13-minute cycle in the controls (r = 0.23, P less than 0.001). Similarly, Fourier transform analysis showed no significant peak in the relatives but the expected significant peak at 13 to 14 minutes in the controls (P less than 0.05). First-phase (0 to 10 minutes) insulin secretory responses to glucose administered intravenously were not significantly impaired in the relatives (geometric mean, 188 pmol per liter [26.2 mU per liter]; range of SD, +103 to -67 pmol per liter [+14.4 to -9.3 mU per liter]), as compared with the controls (geometric mean, 231 pmol per liter [32.2 mU per liter]; range of SD, +131 to -83 pmol per liter [+18.2 to -11.6 mU per liter]). We conclude that abnormal oscillatory insulin secretion may be an early phenomenon in the development of non-insulin-dependent diabetes.",0
1030,3292364,Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis,"An antinuclear immunofluorescence pattern displaying a thin ring confined to the nuclear envelope was assessed in sera from 38 patients with primary biliary cirrhosis and in sera from a control group of 277 patients with other antinuclear antibody-positive diseases. This rim-like antinuclear reactivity was present in sera from 20 primary biliary cirrhosis patients (52.6%) but in only two patients from the control group (0.7%) (p less than 0.001). Furthermore, this autoantibody was present in three of four primary biliary cirrhosis patients without antimitochondrial antibodies. Presence of this rim-like pattern in primary biliary cirrhosis did not correlate with the presence of associated autoimmune diseases nor with other clinical, biochemical, nor histological features of the disease. The antigenic specificity of sera displaying this antinuclear immunofluorescence pattern was characterized by Western blot analysis using an antigenic extract containing nuclear envelope proteins purified from rat liver. Sixteen of the 20 positive sera showed a common pattern of reactivity with a set of nuclear envelope-associated proteins approximately 200 kD in size. In conclusion, sera from primary biliary cirrhosis patients showing a rim-like fluorescent nuclear pattern have antinuclear autoantibodies that react specifically with components of the nuclear envelope. The high specificity of these new autoantibodies in primary biliary cirrhosis indicate that they might be a serological marker of the disease, particularly useful in patients without antimitochondrial antibodies.",0
1031,3292913,Thromboxane biosynthesis and platelet function in type I diabetes mellitus,"It has been speculated that platelet activation may contribute to the evolution of vascular complications in patients with Type I diabetes mellitus. To address this hypothesis, we measured the plasma and urinary metabolites of thromboxane, presumably of platelet origin, and of prostacyclin, derived from endothelial cells, in addition to more conventional indexes of platelet function. Urinary excretion of the metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between diabetics with or without retinopathy and nondiabetic controls. Furthermore, measurement of platelet granule constituents, the aggregation responses to ADP or arachidonic acid, and levels of serum thromboxane B2 failed to discriminate between the groups. The institution of tight diabetic control with multiple daily injections of insulin failed to alter either urinary metabolite excretion or plasma levels of 11-dehydro-thromboxane B2. Conversely, insulin-induced hypoglycemia failed to alter the concentrations of plasma or urinary thromboxane metabolites in nondiabetic volunteers, despite a mean 60-fold increase in plasma epinephrine. These studies suggest that platelet activation does not precede the development of microvascular complications in patients with Type I diabetes who lack clinical evidence of macrovascular disease and have normal renal function. Furthermore, it is unlikely that platelet activation due to intermittent hypoglycemia contributes to the reportedly accelerated development of retinopathy in such patients, when they are subject to tight diabetic control.",0
1032,3295541,High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma,"""Adult patients with advanced non-Hodgkin's lymphoma in whom conventional chemotherapy has failed are seldom cured thereafter. We studied 100 such patients with intermediate-grade or high-grade non-Hodgkin's lymphoma who were subsequently treated with high-dose chemotherapy (61 patients) or high-dose chemotherapy plus total-body irradiation (39 patients), with bone marrow transplantation used for hematologic support. Thirty-four patients had disease that had been refractory to primary chemotherapy, and 66 patients had had a complete remission with primary chemotherapy but later relapsed. Before autologous bone marrow transplantation and high-dose chemotherapy, the 66 relapsed patients had also received conventional salvage chemotherapy; 22 had had no response or had had disease progression (a response termed """"resistant relapse""""), and 44 patients had responded partially or completely (a response termed """"sensitive relapse""""). After high-dose therapy and bone marrow transplantation, the actuarial three-year disease-free survival was zero in the refractory group, 14 percent in the resistant-relapse group, and 36 percent in the sensitive-relapse group. Patients who had had a complete remission in response to initial chemotherapy had a higher disease-free survival rate than those who had not (P less than 0.001), and patients with sensitive relapse had a higher disease-free survival rate than those with resistant relapse (P less than 0.003). These results should be considered in the planning or interpretation of trials of salvage chemotherapy in adults with non-Hodgkin's lymphoma.""",0
1033,3301615,"Interaction of human liver connective tissue cells, skin fibroblasts and smooth muscle cells with collagen gels","Interactions of liver connective tissue cells, skin fibroblasts and smooth muscle cells with collagen gels in vitro were studied and compared. Liver connective tissue cells showed the lowest rate of migration into the gel and the highest speed of gel contraction, reflecting their high adhesiveness to the substrate as compared to the other cell lines studied. The analysis of their ultrastructural morphology showed that liver connective tissue cells and smooth muscle cells developed cytoskeletal and cytoplasmic organelle polarities, in response to the contact with gel surface. This polarity was lost when cells were embedded in the gel. Skin fibroblasts did not show this characteristic, neither on top nor in the gel. Although liver connective tissue cells have been recognized as analogous to smooth muscle cells, they represent a defined cell population, present in fibrotic livers, with specific behavior and with particular relationship to the extracellular matrix.",0
1034,3309656,Transmission of the human immunodeficiency virus,"The accumulated data strongly support the conclusion that transmission of HIV occurs through blood, sexual activity, and perinatal events. Nevertheless, the fear of transmission by other routes may continue to increase with the anticipated increase in the number of cases of AIDS over the next few years. An unrealistic requirement for absolute certainty about the lack of transmission by other routes persists, despite the knowledge that it is not scientifically possible to prove that an event cannot occur. It remains difficult to believe that a virus that is spreading rapidly and may cause a cruel, frightening, and fatal disease is not highly contagious and easily transmitted. The available data indicate that HIV transmission is not highly efficient in a single or a few exposures, unless one receives a very large inoculum. The widespread dissemination of HIV is more likely the result of multiple, repeated exposures over time by routes of transmission that are strongly related to personal and cultural patterns of behavior--particularly, sexual activity and the use of drugs. Isolated transmission events should be placed in full perspective by examining the results of population-based studies that provide rates of risk. It is from these studies that rational approaches and public policy should be developed.",0
1035,3336380,Effect of nicotine chewing gum in combination with group counseling on the cessation of smoking,"We studied the effectiveness of chewing gum containing nicotine, in combination with group counseling, for subjects who were attempting to stop smoking. We used the Horn-Russell scale, based on a smoking questionnaire, to measure dependence on cigarettes; 173 smokers were grouped as highly dependent on nicotine or as having medium to low degrees of dependence. In a randomized double-blind study, the 60 highly dependent smokers were given gum containing 4 mg of nicotine (n = 27) or 2 mg of nicotine (n = 33), and the 113 smokers with medium or low dependence were given gum containing 2 mg of nicotine (n = 60) or a placebo gum (n = 53). All smokers took part in group counseling. In the highly dependent group, abstinence from cigarettes was chemically verified after six weeks, one year, and two years; 81.5 percent, 44.4 percent, and 33.3 percent of the subjects given gum containing 4 mg of nicotine were abstinent after those follow-up periods; the rates of abstinence were 54.5 percent, 12.1 percent, and 6.1 percent, respectively, for the subjects given gum containing 2 mg of nicotine. In the group with medium or low dependence, the rates of abstinence after the same periods were 73.3 percent, 38.3 percent, and 28.3 percent for the subjects given gum containing 2 mg of nicotine and 41.5 percent, 22.6 percent, and 9.4 percent for those given placebo gum. The differences in outcomes were significant at the 5 percent level for all comparisons, with the exception of the 2-mg nicotine gum versus the placebo gum at one year. This study indicates that the effectiveness of nicotine gum is not due to a placebo effect and that it is related to dose. The use of nicotine gum in appropriate doses should be helpful to persons who are attempting to stop smoking.",0
1036,3336400,Differences in platelet enzyme activity between alcoholics and nonalcoholics,"Blood platelets are an accessible tissue that reflects the activity of many enzymes found in the brain. To investigate the possible effect on such enzymes of long-term consumption of large quantities of ethanol, we assayed the activities of two enzymes, monoamine oxidase and adenylate cyclase, in platelet membranes of men with alcoholism and controls matched for sex and age. We also compared these two groups in terms of the inhibition of platelet monoamine oxidase activity by ethanol in vitro (400 mM), and in terms of the stimulation of adenylate cyclase activity by various agents. There was no significant difference in monoamine oxidase activity between the alcoholics and the controls. However, the inhibition of monoamine oxidase by ethanol was significantly higher in the platelets of alcoholics. The basal activity of adenylate cyclase was the same in platelets from the alcoholics and the controls, but the platelet adenylate cyclase activity after stimulation with guanine nucleotide, cesium fluoride, or prostaglandin E1 was significantly lower in alcoholics. These differences were not associated with age, race, smoking, or illicit drug use, and there was no significant correlation with the duration of problems with alcohol. The changes were long-lasting; cesium fluoride-stimulated adenylate cyclase activity was lower in alcoholic subjects who had abstained from alcohol for one to four years. Discriminant analysis showed that the use of values for the inhibition of monoamine oxidase activity by ethanol and cesium fluoride-stimulated adenylate cyclase activity correctly classified 75 percent of the alcoholics and 73 percent of the controls. These measures may be of value either as indexes of excessive alcohol consumption or as an indication of a predisposition to alcoholism.",0
1037,3336411,Human immunodeficiency virus infection among patients attending clinics for sexually transmitted diseases,"To assess the prevalence and associated risk factors for human immunodeficiency virus (HIV) infection in patients attending inner-city clinics for sexually transmitted diseases in Baltimore, we screened 4028 patients anonymously, of whom 209 (5.2 percent) were seropositive for HIV. HIV-seropositivity rates were higher among men (6.3 percent) than women (3.0 percent) (P less than 0.001) and among blacks (5.0 percent) than whites (1.2 percent) (P less than 0.02). Among men, but not women, HIV seroprevalence increased markedly and steadily up to the age of 40. In men, HIV seropositivity was independently associated with increased age, black race, a history of homosexual contact, and the use of parenteral drugs. In women, a history of parenteral drug use or of being a sexual partner of a bisexual man or parenteral drug user were independently predictive of HIV seropositivity. In men, HIV seropositivity was also associated with a history of syphilis or a reactive serologic test for syphilis, and in women, with a history of genital warts. Since these associations were independent of the type and number of reported sexual partners, they raise the possibility that sexually transmitted diseases that disrupt epithelial surfaces may be important in the transmissibility of HIV. In addition, on a self-administered questionnaire, one third of HIV-infected men and one half of infected women did not acknowledge previous high-risk behavior for HIV exposure. These data suggest that patients at clinics for sexually transmitted diseases represent a group at high risk for HIV infection, and that screening, counseling, and intensive education should be offered to all patients attending such clinics.",0
1038,3336412,Nodular and diffuse types of lymphocyte predominance Hodgkin's disease,"The nodular form of lymphocyte predominance Hodgkin's disease has been shown to be immunophenotypically distinct from the histologically diffuse form and from other types of Hodgkin's disease. We undertook a clinicopathological study of 73 cases to determine whether any clinical differences between the nodular and diffuse subtypes could be discerned. Patients with the diffuse form (n = 41) tended to have a course similar to that of other types of Hodgkin's disease; there were few relapses and only two deaths due to Hodgkin's disease. In contrast, patients with the nodular form (n = 32) had significantly more relapses, which were independent of stage or treatment and equally distributed up to 10 years after initial therapy. Despite the frequent relapses, patients with the nodular form had an indolent course, and there was only one death due to Hodgkin's disease. There were seven fatal second cancers and two non-neoplastic treatment-related deaths, equally distributed between the nodular and diffuse groups. We conclude that nodular lymphocyte predominance Hodgkin's disease may have important clinical as well as immunophenotypic differences from other forms of Hodgkin's disease, and that patients with this condition should be followed carefully because of the possibility of late relapse.",0
1039,3338699,Correlation between the biliary excretion of ouabain and the lateral mobility of hepatocyte plasma membrane proteins in the rat--the effects of age and spironolactone pretreatment,"The biliary excretion of intravenously injected ouabain and the diffusion constant of the lateral mobility of hepatocyte plasma membrane proteins were examined in control (saline-treated) and spironolactone-treated Wistar male rats of different ages (4, 14 to 15 and 24 months old). The biliary excretion of ouabain progressively decreased with age in control rats, the first 10-min biliary recovery in 24-month-old animals being one-third that of the youngest rats (4-month-old). The oral administration of spironolactone for 4 days (10 mg per 100 gm body weight on the first day and 20 mg per 100 gm body weight for the successive 3 days) caused a marked increase in the biliary recovery of ouabain in all age groups. Similarly, the average lateral diffusion constant of hepatocyte plasma membrane proteins as measured by fluorescence recovery after photobleaching showed a linear decrease with age, as was previously observed with F-344 rats of both sexes. Markedly and significantly (30 to 40%) higher diffusion constants were observed in rats pretreated with spironolactone for all three age groups, compared with the respective control values of corresponding ages. The parallelism between ouabain excretion and protein diffusion (i.e., a decrease with age and an increase with spironolactone pretreatment) suggests that the lateral mobility of proteins in the hepatocyte plasma membrane is a candidate mechanism for regulating ouabain excretion through the liver into the bile, most probably by regulating the hepatic uptake process for ouabain.",0
1040,3338721,S-adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis,"We have measured the activity S-adenosyl-L-methionine synthetase in liver biopsies from a group of controls (n = 17) and in 26 cirrhotics (12 alcoholic and 14 posthepatic). The activity of this enzyme was markedly reduced in the group of cirrhotics (285 +/- 32 pmoles per min per mg protein) when compared with that observed in controls (505 +/- 37 pmoles per min per mg protein). No differences in S-adenosyl-L-methionine synthetase was observed between both groups of cirrhotics. Similarly, a marked reduction in the activity phospholipid methyltransferase was also observed in liver biopsies from the same group of cirrhotics (105 +/- 12 pmoles per min per mg protein) when compared with the control subjects (241 +/- 13 pmoles per min per mg protein). Again, no difference in the activity of this enzyme was observed between both groups of cirrhotics. These results indicated a marked deficiency in the metabolism of S-adenosyl-L-methionine in cirrhosis.",0
1041,3340105,Pulmonary hazards of smoking marijuana as compared with tobacco,"To compare the pulmonary hazards of smoking marijuana and tobacco, we quantified the relative burden to the lung of insoluble particulates (tar) and carbon monoxide from the smoke of similar quantities of marijuana and tobacco. The 15 subjects, all men, had smoked both marijuana and tobacco habitually for at least five years. We measured each subject's blood carboxyhemoglobin level before and after smoking and the amount of tar inhaled and deposited in the respiratory tract from the smoke of single filter-tipped tobacco cigarettes (900 to 1200 mg) and marijuana cigarettes (741 to 985 mg) containing 0.004 percent or 1.24 percent delta 9-tetrahydrocanabinol. As compared with smoking tobacco, smoking marijuana was associated with a nearly fivefold greater increment in the blood carboxyhemoglobin level, an approximately threefold increase in the amount of tar inhaled, and retention in the respiratory tract of one third more inhaled tar (P less than 0.001). Significant differences were also noted in the dynamics of smoking marijuana and tobacco, among them an approximately two-thirds larger puff volume, a one-third greater depth of inhalation, and a fourfold longer breath-holding time with marijuana than with tobacco (P less than 0.01). Smoking dynamics and the delivery of tar during marijuana smoking were only slightly influenced by the percentage of tetrahydrocanabinol. We conclude that smoking marijuana, regardless of tetrahydrocannabinol content, results in a substantially greater respiratory burden of carbon monoxide and tar than smoking a similar quantity of tobacco.",0
1042,3340117,Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia,"Water intoxication is a serious problem in many patients with chronic psychiatric illness. In an effort to determine the mechanism of this disorder, we investigated the osmoregulation of water intake and antidiuretic function in psychiatric patients with polydipsia and hyponatremia and in matched controls with psychiatric illness but neither polydipsia nor hyponatremia. We found that a water load suppressed plasma osmolality and vasopressin and urine osmolality in both groups, but that urinary dilution and free water clearance were impaired in the patients with hyponatremia, even though plasma levels of vasopressin and solute clearance were similar in the two groups. Moreover, during water loading and infusion of hypertonic saline, the plasma level of vasopressin was higher at any given plasma osmolality in the test patients than in the controls, indicating a downward resetting of the osmostat. Patients' estimates of the amount of water they desired were shown to correlate significantly with the amount of water consumed and, at any given level of plasma osmolality, appeared to be higher in the test patients than in the controls. We conclude that psychiatric patients with polydipsia and hyponatremia have unexplained defects in urinary dilution, the osmoregulation of water intake, and the secretion of vasopressin.",0
1043,3340127,Energy expenditure and intake in infants born to lean and overweight mothers,"We investigated the contributions of low energy expenditure and high energy intake to excessive weight gain in infants born to overweight mothers. The subjects were infants of 6 lean and 12 overweight mothers, recruited soon after birth. Total energy expenditure and metabolizable energy intake were measured with a new doubly labeled water method over a period of seven days when the infants were 3 months of age, and the postprandial metabolic rate was measured by indirect calorimetry when the infants were 0.1 and 3 months of age. The results were related to weight gain in the first year of life. No significant difference was observed between infants who became overweight by the age of one year (50 percent of infants born to overweight mothers) and those who did not, with respect to weight, length, skinfold thicknesses, metabolic rate at 0.1 and 3 months of age, and metabolizable energy intake at 3 months. However, total energy expenditure at three months of age was 20.7 percent lower in the infants who became overweight than in the other infants (means +/- SE, 256 +/- 27 and 323 +/- 12 kJ per kilogram of body weight per day; P less than 0.05). This difference could account for the mean difference in weight gain. These data suggest that reduced energy expenditure, particularly on physical activity, was an important factor in the rapid weight gain during the first year of life in infants born to overweight mothers.",0
1044,3340131,Transfusion-transmitted AIDS reassessed,"This editorial traces the recommendations of the Food and Drug Administration with respect to reducing transmission of AIDS by transfusions of blood. Next the findings of a research study which appears in the same issue of this journal are reviewed. In this study, the authors describe 7 persons with negative HIV-antibody tests who donated blood but later had detectable HIV antibodies. The authors estimate the number of blood components that test negative but carry infection that are collected annually in the US. Their estimate of the current risk may be overly pessimistic. Newer, more accurate tests should be implemented as soon as clinical trials have established their efficacy and practicality. While tests are being validated, the education of donors must be intensified and focused. Although continued vigilance over the safety of the blood supply is essential, the risks of HIV transmission by transfusion should be kept in perspective. The risk of acquiring HIV infection through transfusion is low compared with the odds of death from influenza, abortion after the 14th week, and car accidents. The measures instituted to protect patients from acquiring HIV infection through blood transfusions have greatly improved the safety of the nation's blood supply. It is safer than it has ever been, but the slight risks that still remain can be reduced at this time only by intensified and appropriately focused education of blood donors and by more circumspect ordering of blood components by physicians.",0
1045,3344006,Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature,"It has been suggested that complete catch-up growth is achieved with treatment in patients with juvenile acquired hypothyroidism. We tested this assumption by examining long-term growth in 18 girls (mean [+/- SD] age, 11.4 +/- 2.7 years; bone age, 6.2 +/- 3.1 years) and 6 boys (age, 10.6 +/- 4.7 years; bone age, 6.4 +/- 2.7 years) with severe primary hypothyroidism (serum thyroxine level 1.1 +/- 0.3 micrograms per deciliter [13 +/- 4 nmol per liter]). At diagnosis, heights were 4.04 +/- 0.5 and 3.15 +/- 0.4 SD below the mean heights for age of normal girls and boys, respectively. The patients were treated with levothyroxine (3.4 +/- 0.3 micrograms per kilogram of body weight per day) to maintain normal thyroid function. During the first 18 months of therapy, the children's skeletal maturation exceeded the maturation expected for their statural growth, regardless of whether or not they were undergoing pubertal development. Predictions of decreased adult height were based on these observations. At maturity, girls and boys stood approximately 2 SD below normal adult stature, at 149 +/- 5.0 cm and 168 +/- 5.1 cm, respectively. Heights at maturity were also lower than midparental heights (P less than 0.01) and lower than pre-illness standard-deviation scores for height (P less than 0.01). The deficit in adult stature was significantly related to the duration of hypothyroidism before treatment (P less than 0.01). We conclude that despite treatment, prolonged juvenile acquired hypothyroidism results in a permanent height deficit related to the duration of thyroxine deficiency before treatment.",0
1046,3344019,"""Neonatologists judge the """"Baby Doe"""" regulations""","The federal regulations now in effect governing the treatment of severely handicapped infants--the so-called Baby Doe regulations--are based on the 1984 amendments to the Child Abuse Prevention and Treatment Act; these regulations require that, except under certain specified conditions, all newborns receive maximal life-prolonging treatment. We sent questionnaires to the 1007 members of the Perinatal Pediatrics Section of the American Academy of Pediatrics to determine their views on the Baby Doe regulations and on whether the regulations had affected their practices; 494 of the members (49 percent) responded. Of the respondents, 76 percent believed that the current regulations were not necessary to protect the rights of handicapped infants; 66 percent believed that the regulations interfered with parents' right to determine what course of action was in the best interest of their children; and 60 percent believed that the regulations did not allow adequate consideration of infants' suffering. In responding to the three hypothetical cases of severely handicapped newborns, up to 32 percent of the respondents said that maximal life-prolonging treatment was not in the best interests of the infants described but that the Baby Doe regulations required such treatment. The responding neonatologists' concerns about the current Baby Doe regulations were similar to those expressed by the United States Supreme Court in rejecting an earlier set of Baby Doe regulations. This similarity suggests that the current Baby Doe regulations should be reevaluated.",0
1047,3347221,Genetic and environmental influences on premature death in adult adoptees,"To assess genetic and environmental influences on adult mortality, we followed 960 families that included children born during the period 1924 through 1926 who were placed early in life with adoptive parents unrelated to them. We evaluated the risks of dying from all causes or from specific groups of causes between the ages of 16 and 58 years for adoptees with a biologic or adoptive parent who died of the same cause before the age of either 50 or 70. We compared these risks with the adoptees' risk of dying from the same causes between the ages of 16 and 58 when either the biologic or adoptive parents were still alive at the ages of 50 and 70. The death of a biologic parent before the age of 50 resulted in relative risks of death in the adoptees of 1.71 (95 percent confidence interval, 1.14 to 2.57) for all causes, 1.98 (1.25 to 3.12) for natural causes, 5.81 (2.47 to 13.7) for infections, 4.52 (1.32 to 15.4) for cardiovascular and cerebrovascular causes, and 1.19 (0.16 to 8.99) for cancers. The death of an adoptive parent resulted in relative risks of death in the adoptees that were close to unity for all causes, natural causes, and infections, 3.02 (0.72 to 12.8) for vascular causes, and 5.16 (1.20 to 22.2) for cancers. A similar but weaker pattern was observed when either a biologic or adoptive parent died before the age of 70. We conclude that premature death in adults has a strong genetic background--especially death due to infections and vascular causes.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1048,3352673,Why there will be little or no physician surplus between now and the year 2000,"Most observers think that by the year 2000 there will be a considerable surplus of physicians in the United States. In this paper we present a new framework for estimating the future balance between supply and demand with respect to physicians' services. Our analysis suggests that even if competitive medical plans serve approximately half the population by the year 2000, there will probably be little or no physician surplus. Moreover, if a slight surplus should occur, it is likely to be largely erased by increased involvement of physicians in administrative activities and a variety of nontraditional clinical activities that currently occupy little of a physician's time. Our prediction of little or no surplus could be altered appreciably, however, by two forces that would have opposite effects: an acceleration of technological change would increase demand beyond our projections, whereas widespread rationing of beneficial services would constrain the demand for physicians' services.",0
1049,3356406,"Elevation of acetylpolyamine levels in mouse tissues, serum and urine after treatment with radical-producing drugs and lipopolysaccharide","Polyamines and acetylpolyamines were analyzed in the liver, spleen, lung, kidney, serum and urine by high-performance liquid chromatography on a column of cation-exchange resin after administering various cytotoxic substances to male mice. All of the compounds tested more or less affected the tissue levels of polyamines, including putrescine, spermidine, spermine and acetylpolyamines (N1-acetylspermidine and N1-acetylspermine). It was found that they were classified into two groups of substances: one group (including radical-producing drugs and lipopolysaccharide) which elevated the tissue levels of N1-acetylspermidine, especially in the liver, while another group of drugs (such as D-galactosamine and DL-ethionine) had little effect on the acetylpolyamine levels. When the acetylpolyamine levels rose, the levels of spermidine and spermine declined, and then putrescine levels were elevated. N1-Acetylspermine was detected only when N1-acetylspermidine levels were very high after treatment with radical-producing drugs and lipopolysaccharide. Halogenated carbon, such as carbon tetrachloride and halothane, elevated the levels of acetylpolyamines especially in the liver, while paraquat elevated them in all tissues examined.",0
1050,3356417,Regulation of bile acid synthesis. I. Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat,"Bile acid synthesis is thought to be regulated by a negative feedback mechanism which is presumably dependent upon the flux of bile acids in the enterohepatic circulation. To characterize further the role of bile acids in regulation of bile acid synthesis, we have administered pure taurine or glycine conjugates of ursodeoxycholic acid or cholic acid to chronic bile fistula rats by continuous intraduodenal infusion, thus simulating restoration of the enterohepatic circulation. The effects of these bile salt infusions on bile acid synthesis, biliary cholesterol and phospholipid secretion and on the activities of the hepatic microsomal enzymes cholesterol 7 alpha-hydroxylase and HMG-CoA reductase were evaluated. Because the rate of biliary bile salt secretion in rats with intact exteriorized enterohepatic circulation averaged 27.1 +/- 1.4 mumoles per 100 gm rat per hr, infusion rates for bile fistula studies were chosen to match (24 to 36 mumoles per 100 gm rat per hr) or exceed (48 mumoles per 100 gm rat per hr) this physiological flux. Infusion of tauroursodeoxycholic acid for 48 hr at 24 and 48 mumoles per 100 gm rat per hr failed to suppress cholic acid synthesis. Bile flow and biliary cholesterol and phospholipid secretion exhibited small, dose-dependent increases with tauroursodeoxycholic acid infusions. No suppression of cholesterol 7 alpha-hydroxylase or HMG-CoA reductase activity was observed. By contrast, taurocholic acid inhibited synthesis of chenodeoxycholate and its metabolites alpha- and beta-muricholate by 10% (NS), 66% (p less than 0.05) and 75% (p less than 0.05) at infusion rates of 24, 36 and 48 mumoles per 100 gm rat per hr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1051,3367961,Inequities in health services among insured Americans. Do working-age adults have less access to medical care than the elderly?,"To determine whether groups other than the elderly and the uninsured have difficulty obtaining access to medical care, we studied 7633 adults nationwide. As we expected, the insured had much greater access than the uninsured, but among the insured there were substantial disparities in access to care. Insured adults of working age were 3.5 times as likely (95 percent confidence interval, 2.7 to 4.4) as the elderly to have needed supportive medical services (including medications and supplies) but not to have received them, and 3.4 times (2.3 to 4.4) as likely to have had major financial difficulties because of illness. Among insured, working-age adults, the poor were 4.4 times (3.5 to 5.3) as likely as those who were not poor to have needed supportive services but not to have received them, and 5.2 times (3.6 to 6.8) as likely to have had major financial problems because of illness. Apart from insurance status and income, blacks were 1.7 times (1.1 to 2.2) as likely as whites to have needed supportive services but not to have received them. Hispanics with a medical illness were 2.2 times (1.3 to 3.2) as likely as whites not to have seen a physician within the past year. We conclude that insured, working-age adults have less access to medical care than the elderly, and that poor, black, or Hispanic persons in this group are at risk for even greater problems with access to care. Current policy strategies are unlikely to improve the ability of these groups to obtain care.",0
1052,3371878,Induction of heat shock proteins in short-term cultured hepatocytes derived from normal and chronically griseofulvin-treated mice,"Freshly isolated mouse hepatocytes were tested with respect to the induction of heat shock (stress) proteins by elevated temperature, sodium arsenite and ethanol treatment. With heat, arsenite and ethanol treatments, the synthesis of a protein with a molecular weight of 68 kD (heat shock protein 68) was predominantly elevated; arsenite and ethanol exerted their effects on heat shock protein synthesis in a dose-dependent manner. Hepatocytes derived from livers of chronically griseofulvin-pretreated mice differed in their response from normal hepatocytes in that ethanol was ineffective in these cells. These results indicate that different modes and pathways of the stress response exist, depending on the nature of the inducing agent but also on pretreatment conditions. In vivo, pathologic alterations of cells and organs (e.g., in the course of chronic diseases) can, therefore, be expected to modulate the stress response.",0
1053,3371879,Ethinylestradiol stimulates a biliary cholesterol-phospholipid cosecretion mechanism in the hamster,"""The mechanism of ethinylestradiol-induced biliary secretion of excess cholesterol, a potential causative factor of cholesterol gallstones, is not yet known. It might be related to altered bile acid metabolism, since the rate of cholesterol and phospholipid secreted into bile is thought to be influenced by the hydrophobicity of the bile acid species secreted. We therefore studied the effect of ethinylestradiol on bile acid metabolism and on secretory relationships between taurocholate and cholesterol/phospholipids in bile. Litter-matched Syrian female hamsters (80 to 100 gm body weight) were injected subcutaneously with either 0.2 ml per day corn oil (controls) or a pharmacologic dose of 5 mg per kg per day ethinylestradiol in corn oil (EE-hamsters; n = 6) for 5 days. On Day 6, bile was collected for 60 min (basal secretory rate) via a bile duct fistula after exclusion of the gallbladder. Then, a graded infusion of taurocholate was given for 110 to 130 min. Secretory rates (nmoles.min-1.-1 liver) for bile acids, cholesterol and phospholipids were determined and their mutual """"linkage coefficients"""" (nmoles of secretory increment per 1 nmole of bile acid secreted) calculated by linear regression analysis. EE-hamsters had higher (p less than 0.02) basal secretory rates of cholesterol (0.71 +/- 0.21 vs. 0.45 +/- 0.10) and phospholipids (5.74 +/- 1.04 vs. 4.21 +/- 0.73) than controls at comparable bile flow and bile salt secretion rates. Cholic acid pool size and the fractional composition of bile acid species in bile were similar.(ABSTRACT TRUNCATED AT 250 WORDS)""",0
1054,3391504,In vitro hepatitis B virus suppression of erythropoiesis is dependent on the multiplicity of infection and is reversible with anti-HBs antibodies,"Exposure of human bone marrow mononuclear cells to hepatitis B virus results in the suppression of the in vitro growth of several hematopoietic progenitor cells. We studied the degree of inhibition of erythroid progenitor cells that results as a function of the time of exposure of mononuclear cells to hepatitis B virus and the ratio of virus to mononuclear cells, the multiplicity of infection. With an overnight incubation of mononuclear cells with hepatitis B virus-containing sera, a multiplicity of infection of greater than one virus per mononuclear cell is required to observe significant inhibition of erythroid colony formation. This multiplicity of infection effect is also observed with purified Dane particles. Exposure of mononuclear cells to an increasing number of Dane particles results in a dose-dependent suppression of erythroid colony formation with significant inhibition observed with a multiplicity of infection of virus to mononuclear cells as low as 5:1. Murine monoclonal antibodies to HBsAg completely neutralize the hepatitis B virus-mediated inhibition of CFU-E while control antibodies do not. Purified HBsAg has no effect on colony formation. In conclusion, the hepatitis B virus-mediated inhibition of erythrogenesis in vitro provides a basis for understanding the bone marrow depression observed during hepatitis B virus infections and may provide an in vitro model for examining hepatitis B virus infection.",0
1055,3391506,The effect of retinol on Ito cell proliferation in vitro,"""Hepatic sinusoidal fat-storing Ito cells are felt to represent the primary storage site for hepatic vitamin A and may be important collagen-producing effector cells during hepatic fibrogenesis. The cirrhotic liver generally has a decreased vitamin A content with increased numbers of """"transitional"""" myofibroblasts adjacent to developing fibrous bands. It has been suggested that Ito cells """"transform"""" into these myofibroblasts. The in vivo loss of Ito cell vitamin A can be simulated in vitro as Ito cells spontaneously lose their vitamin A lipid droplets during primary culture. The current study evaluated Ito cell proliferation in vitro with respect to vitamin A content and the extracellular collagen matrix. The cells were grown on a Type I or Type IV collagen matrix to simulate the types of collagens presumed to be present in the space of Disse. Initially it was observed that freshly isolated Ito cells begin to proliferate several days after isolation coincident with the decline of the vitamin A lipid droplets and a decrease in cellular retinyl palmitate. The proliferation rate for passaged Ito cells was similar on either matrix (on Type I collagen: T 1/2 = 2.2 +/- 1.1 days, n = 16; on Type IV collagen: T 1/2 = 3.3 +/- 1.4 days, n = 4; p less than 0.11). This proliferation rate remained constant through Cell Generation 16 and was similar to the rate for primary Ito cells in culture. To evaluate the possibility that primary Ito cell proliferation is causally related to the loss of vitamin A, Ito cells were re-exposed to an increased concentration of retinol in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)""",0
1056,3391512,Diet composition and surgical technique influence the postoperative recovery of portacaval shunted rats,"In a series of experiments, rats were subjected to end-to-side portacaval shunts using either suture or nonsuture surgical procedures. Rats were maintained on cereal-based or purified diets in pellet form. All rats recovered preoperative body weights within the experimental periods; however, recovery of preoperative body weight was influenced by surgical technique and diet composition. Portacaval shunted rats fed a cereal-based diet required a longer period of time (14 days) to reattain preoperative body weights when compared to portacaval shunted rats fed a purified diet (7 days). Once preoperative body weight was recovered, growth rates of portacaval shunted rats were parallel to those of sham-operated controls. Rats with a suture-portacaval shunt appeared most sensitive to the feeding of a cereal-based diet. All portacaval shunted rats and sham controls fed a purified diet regained preoperative body weights within 7 days after surgery. Sham controls fed either a cereal-based or purified diet recovered preoperative body weights within an average of 4 days. Suture-portacaval shunted rats consuming a pellet form cereal-based diet showed a low feed efficiency which could be reversed by feeding a pellet form purified diet. Rats subjected to a nonsuture glue-portacaval shunt and fed a cereal-based diet showed 50% lower feed efficiencies than did glue-portacaval shunted rats fed a purified diet. Portacaval shunted rats decreased their consumption of cereal-based diets but not of purified diets postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1057,3391515,Feedback regulation of bile acid synthesis in the rat by dietary vs. intravenous cholate or taurocholate,"The regulation of bile acid synthesis was studied (i) in intact or colectomized rats receiving cholate or taurocholate as a dietary supplement and (ii) in experiments using chow-fed animals with a graded intravenous or intraduodenal taurocholate infusion. After the 2-week diet period a bile fistula was established and rates of taurocholate, tauromuricholate and taurochenodeoxycholate secretion were quantitated by high-performance liquid chromatography. During the infusion experiments taurocholate production was calculated from the difference in specific activity of [14C]taurocholate between infusate and bile, whereas tauromuricholate and taurochenodeoxycholate synthesis was derived directly from their secretion rates after pool depletion. Both the 0.5% cholate and taurocholate diet suppressed tauromuricholate and taurochenodeoxycholate secretion nearly totally, but only cholate led to a prolonged inhibition taurocholate synthesis. The diets stimulated total bile acid secretion and expanded the total bile acid pool size 2- to 3-fold, but they also prompted a dramatic increase in the biliary secretion of taurodeoxycholate. In contrast, colectomized animals did not secrete taurodeoxycholate following the cholate diet and, despite a comparable increase in bile acid pool size, tauromuricholate and taurochenodeoxycholate secretion was inhibited to a lesser extent. In addition, the rate of bile acid secretion and synthesis was significantly enhanced when compared to that of intact rats. To determine whether taurocholate affected bile acid synthesis directly, the bile acid was infused intravenously or intraduodenally at varying rates up to 300 mumoles per kg per hr for 54 hr, i.e. a rate exceeding normal total bile acid secretion in these acute bile fistula animals nearly 3-fold.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1058,3391520,"The epidemiology of gallstone disease in Rome, Italy. Part II. Factors associated with the disease. The Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO)","The epidemiological associations of gallstone disease were evaluated in a population of 2,325 civil servants (1,244 men and 1,081 women) in Rome, Italy, which was enrolled in a cross-sectional survey on cholelithiasis. Participants were screened for the presence of gallstones by gallbladder ultrasonography, completed a questionnaire on family and personal history and underwent a physical examination and blood chemistry. Statistically significant associations were established by univariate analysis of the age-standardized data and by step-wise multiple logistic regression. At univariate analysis, increasing age, serum triglycerides and number of cigarettes smoked per day, and decreasing high-density lipoprotein-cholesterol were the conditions associated with the presence of gallstones in men. Age and parity were the correspondent associations in women. After controlling by multiple logistic regression, a different pattern of associated conditions emerged. In men, only age and serum triglycerides showed a significant positive association with gallstones, which was independent of other variables. In women, the presence of gallstones was independently associated with increasing age, number of pregnancies, body mass index and serum triglycerides, and with decreasing total (and low-density lipoprotein) cholesterol. The latter association was curvilinear in shape. The conditions associated with a history of cholecystectomy differed from those observed in subjects with gallstones, with the exceptions of age, in both sexes, and high serum triglycerides, in women. Fasting blood glucose levels were higher in women with a history of cholecystectomy than in those with or without gallstones, both at univariate and multiple logistic regression analyses.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1059,3393171,Stomach cancer after partial gastrectomy for benign ulcer disease,"We followed for 25 to 33 years 6459 patients who had undergone partial gastrectomy for benign ulcer disease to determine the incidence of stomach cancer. The overall risk was no different from that among sex- and age-matched controls from the Swedish Cancer Registry (standardized incidence ratio = 0.96; 95 percent confidence limits, 0.78 and 1.16). However, when the patients were classified according to the duration of follow-up after operation, sex, surgical procedure, diagnosis at the time of operation, and age at operation, differences in risk were observed between the subgroups. After adjustment for potential confounding variables, the average adjusted risk increased 28 percent (adjusted standardized incidence ratio = 1.28; 95 percent confidence limits, 1.11 and 1.49) for each successive five-year interval after operation. The adjusted risk was greater among women than men (adjusted standardized incidence ratio = 1.96; 95 percent confidence limits, 1.18 and 3.24). Patients who had undergone a Billroth I anastomosis had a lower crude risk, both overall (standardized incidence ratio = 0.40; 95 percent confidence limits, 0.20 and 0.71) and after we controlled for other confounding variables (adjusted standardized incidence ratio = 0.27; 95 percent confidence limits, 0.12 and 0.62), than did those who had undergone a Billroth II procedure. The adjusted risk of stomach cancer was greater among patients operated on for gastric ulcer than among those operated on for duodenal ulcer (adjusted standardized incidence ratio = 2.21; 95 percent confidence limits, 1.45 and 3.35). Risk decreased with increased age at operation. Between successive strata of age at operation (less than 39, 40 to 49, 50 to 59, and greater than or equal to 60 years of age), the adjusted risk decreased on the average by about half (adjusted standardized incidence ratio = 0.52; 95 percent confidence limits, 0.41 and 0.66).",0
1060,3393195,Reticuloendothelial clearance in cystic fibrosis and other inflammatory lung diseases,"To examine the possible pathophysiologic role of circulating immune complexes in patients with cystic fibrosis and other inflammatory lung diseases, we studied the reticuloendothelial clearance of IgG-sensitized autologous erythrocytes in 15 patients with cystic fibrosis, 6 with chronic obstructive lung disease not related to cystic fibrosis, 7 with immunodeficiencies, 5 with systemic lupus erythematosus, 4 who had previously undergone a splenectomy, and 10 normal subjects. Patients with chronic inflammation and recurrent infections (i.e., those with cystic fibrosis, chronic obstructive lung disease, and immunodeficiencies) had significantly faster clearance rates (P less than 0.05, less than 0.01, and less than 0.005, respectively) than normal subjects. In contrast, patients with systemic lupus erythematosus (a classic immune complex-mediated disease) and those who had undergone a splenectomy had delayed clearance. The accelerated reticuloendothelial clearance in patients with chronic inflammatory pulmonary disease associated with cystic fibrosis was similar to that observed in stimulated laboratory animals. The rapid clearance rate may account for the rareness of septicemia in such patients despite chronic, persistent local bacterial infection.",0
1061,3405252,An epidemiologic study of mortality among bereaved parents,"To study the health consequences of parental bereavement, we compared the mortality in two groups of bereaved Israeli parents with that in the general population. One cohort comprised the parents of all 2518 soldiers 18 to 40 years of age who were killed during the Yom Kippur War in 1973. The second consisted of the parents of 1128 men 18 to 30 years of age who died in accidents between 1971 and 1975. Both groups were followed through 1983. The comparison population was the entire population of Jewish Israelis for which sex-, age-, and calendar year-specific mortality rates were available. The 10-year age-adjusted life-table mortality was higher among fathers whose sons died in accidents rather than in war (P = 0.045), but mortality did not differ significantly between the two groups of mothers. Overall, we found no excess mortality among the bereaved parents as compared with the general population. The standardized mortality ratios for the fathers and mothers of sons killed at war were 0.91 and 0.90, respectively; for fathers and mothers whose sons died by accident, they were 1.04 and 0.91, respectively. None were significantly different from unity. There was no consistent evidence of an elevated risk of death, early or late, after the loss. Widowed and divorced parents who lost a son did have increased mortality, which was statistically significant in mothers. Our findings provide no support for the hypothesis that the loss of an adult son is associated with increased short-term or long-term mortality in married parents.",0
1062,3405254,Changes in pulmonary mechanics after the administration of surfactant to infants with respiratory distress syndrome,"We assessed pulmonary mechanics in 35 premature infants with respiratory distress syndrome just before and one hour after the administration of 90 mg of surfactant to each infant. Transpulmonary pressure was measured between the airway opening and an esophageal balloon with use of a differential transducer, and flow rates were measured by a pneumotachometer. Values for pulmonary mechanics were then calculated by microcomputer processing. The administration of surfactant produced a large decrease (56 percent) in the mean (+/- SEM) ratio of alveolar to arterial oxygen, from 7.1 +/- 0.5 to 3.1 +/- 0.2 (P less than 0.0001)--a change that indicates improvement in gas exchange. Associated changes in pulmonary mechanics were not demonstrable when 10 of the infants were studied during continuous mechanical ventilation. However, in the 25 infants examined during spontaneous breathing with continuous positive airway pressures (identical airway pressures before and after treatment), large and consistent improvements in pulmonary mechanics were found after the administration of surfactant. Tidal volume increased by 32 percent (P less than 0.03), minute ventilation by 38 percent (P less than 0.02), dynamic compliance by 29 percent (P less than 0.004), and inspiratory flow rates by 54 percent (P less than 0.01). We conclude that significant improvement in pulmonary mechanics results from surfactant-replacement therapy for respiratory distress syndrome, but that these mechanical changes are apparent only during spontaneous respiration and can be masked if measurements are made during mechanical ventilation.",0
1063,3405266,Diagnosis of sickle cell anemia and beta-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes,"We have developed a simple and rapid nonradioactive method for detecting genetic variation and have applied it to the diagnosis of sickle cell anemia and beta-thalassemia. The procedure involves the selective amplification of a segment of the human beta-globin gene with oligonucleotide primers and a thermostable DNA polymerase, followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes covalently labeled with horseradish peroxidase. The hybridized probes were detected with a simple colorimetric assay. We demonstrated the usefulness of this method in a retrospective analysis of two pregnancies at risk for beta-thalassemia and one at risk for sickle cell anemia, as well as in an analysis of nine DNA samples simulating three family sets.",0
1064,3412383,Use of the automatic external defibrillator in the management of out-of-hospital cardiac arrest,"""The automatic external defibrillator is a simple device that can be used by nonprofessional rescuers to treat cardiac arrest. In 1287 consecutive patients with out-of-hospital cardiac arrest, we assessed the results of initial treatment with this device by firefighters who arrived first at the scene, as compared with the results of standard defibrillation administered by paramedics who arrived slightly after the firefighters. Of 276 patients who were initially treated by firefighters using the automatic defibrillator, 84 (30 percent) survived to hospital discharge (expected rate according to a logistic model, 17 percent; P less than 0.001), as compared with 44 (19 percent) of 228 patients when fire-fighters delivered only basic cardiopulmonary resuscitation and the first defibrillation was performed after the arrival of the paramedic team. Few patients with conditions other than ventricular fibrillation survived. In a multivariate analysis of characteristics that influenced survival after ventricular fibrillation, a better survival rate was related to a witnessed collapse (odds ratio, 3.9; 95 percent confidence interval, 2.0 to 7.6), younger age (odds ratio, 1.2; 95 percent confidence interval, 1.0 to 1.4), the presence of """"coarse"""" (higher-amplitude) fibrillation (odds ratio, 4.2; 95 percent confidence interval, 1.6 to 11.0), a shorter response time for paramedics (odds ratio, 1.4; 95 percent confidence interval, 1.0 to 2.1), and initial treatment by firefighters using an automatic external defibrillator (odds ratio, 1.8; 95 percent confidence interval, 1.1 to 2.9). These findings support the widespread use of the automatic external defibrillator as an important part of the treatment of out-of-hospital cardiac arrest, although the overall impact of the use of this device on community survival rates is still uncertain.""",0
1065,3417224,Free amino acids in plasma and skeletal muscle of patients with liver cirrhosis,"Free amino acids were measured under postabsorptive conditions in plasma and intracellular water of skeletal muscle obtained by needle biopsy in nine healthy controls and 14 subjects suffering from clinically stable liver cirrhosis. The aromatic amino acids phenylalanine and tyrosine in cirrhotics were elevated to the same extent in plasma and in muscle water. Branched-chain amino acids were uniformly reduced in plasma, but in muscle water only valine was significantly lower (222 +/- 92 mumoles per kg intracellular water vs. 368 +/- 82, p less than 0.001), while isoleucine (142 +/- 63 vs. 103 +/- 30), leucine (223 +/- 88 vs. 226 +/- 36) and branched-chain amino acids as a whole (589 +/- 186 vs. 681 +/- 88) were normal or elevated with an increased muscle:plasma ratio (3.12 +/- 2.03 vs. 1.41 +/- 0.37, p less than 0.05 for isoleucine; 3.00 +/- 1.28 vs. 1.85 +/- 0.27, p less than 0.025 for leucine; 2.24 +/- 0.64 vs. 1.69 +/- 0.13, p less than 0.05 for total branched-chain amino acids. Our data show that, in cirrhosis, plasma concentrations of branched-chain amino acids do not reflect their levels in muscle cellular water; only the intracellular pool of valine is severely depleted. This suggests that higher amounts of valine supplementation may be useful in nutritional treatment of liver cirrhosis. The elevated muscle:plasma gradients for branched-chain amino acids may result from abnormalities in their transport through muscle-plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1066,3417233,Delta infection in asymptomatic carriers of hepatitis B surface antigen: low prevalence of delta activity and effective suppression of hepatitis B virus replication,"We examined the prevalence of serum anti-delta antibody among 769 intravenous drug abusers in Taiwan. delta infection was found extremely common in the HBsAg-positive carriers with drug abuse, because 128 (85%) of 151 carriers were positive for anti-delta. However, most of antibody titers were low (less than 1:5,000). By molecular hybridization, delta RNA genomes were detectable in only five (4%) of 128 asymptomatic carriers positive for anti-delta. The results suggested that most of them had previous, instead of ongoing, delta infection. We also studied the serum markers reflecting hepatitis B virus replication in these carriers and a control group. Hepatitis B e antigen was positive in only 12 (10%) of 115 anti-delta positive carriers in contrast to 22 (23%) of 95 age- and sex-matched HBsAg-positive, anti-delta negative volunteers donating blood (p less than 0.025). Furthermore, in contrast to the close association between HBeAg and hepatitis B virus DNA generally present in HBsAg carriers (concordance in this series: 79%), among the 12 HBeAg-positive subjects of the delta infected group, only two, or 17%, had serum hepatitis B virus DNA (p less than 0.003). Such suppressing effects did not require a simultaneous presence of the delta agent, as shown by the lack of delta RNA genomes in the serum by sensitive assay. We conclude that although delta superinfection is common in the asymptomatic HBsAg carriers with intravenous drug abuse in the nonendemic area of Taiwan, continuous delta activities are uncommon in them. In addition, the previous delta infection probably exerts effective suppression on the hepatitis B virus replication in these HBsAg carriers.",0
1067,3422337,Transmission of human immunodeficiency virus (HIV) by blood transfusions screened as negative for HIV antibody,"Since early 1985, blood donations in the United States have been screened for antibody to human immunodeficiency virus (HIV). To identify instances of HIV transmission by antibody-negative donations, we investigated 13 persons seropositive for HIV who had received blood from 7 donors who were screened as negative for HIV antibody at the time of donation. Twelve of the 13 recipients had no identifiable risk factors for HIV infection other than the transfusions they had received. On evaluation 8 to 20 months after transfusion, HIV-related illnesses had developed in three recipients, and the acquired immunodeficiency syndrome had developed in one. All seven donors were found to be infected with HIV. On interview, six reported a risk factor for HIV infection, and five had engaged in high-risk activities or had had an illness suggestive of acute retroviral syndrome within the four months preceding their HIV-seronegative donation. Thus, these donors had apparently been infected only recently, and so were negative at the time of blood donation according to available antibody tests. We conclude that there is a small but identifiable risk of HIV infection for recipients of screened blood. To minimize this risk, the reasons for deferral of donation need to be communicated more effectively to blood donors who are at high risk of HIV infection, and new assays that detect HIV infection earlier should be evaluated for their effectiveness in screening donated blood.",0
1068,3463861,The inheritance of Gilles de la Tourette's syndrome and associated behaviors. Evidence for autosomal dominant transmission,"We examined specific genetic hypotheses about the mode of transmission of Gilles de la Tourette's syndrome, by performing segregation analyses in 30 nuclear families identified through 27 index cases. Because data from earlier family studies had suggested that chronic tics and obsessive-compulsive disorder may be alternative phenotypic expressions of the diathesis of Tourette's syndrome, we used three diagnostic schemes to specify affected family members (Tourette's syndrome only; Tourette's syndrome or chronic tics; and Tourette's syndrome, chronic tics, or obsessive-compulsive disorder). The estimates of penetrance for the genotypes AA, Aa, and aa (A denotes the abnormal allele) in the analyses of subjects with Tourette's syndrome, chronic tics, or obsessive-compulsive disorder were 1.000, 1.000, and 0.002, respectively, for male subjects and 0.709, 0.709, and 0.000 for female subjects. These results predict that approximately 10 percent of all patients are phenocopies. We conclude that our analyses provide strong support for the hypothesis that obsessive-compulsive disorder is etiologically related to Tourette's syndrome and chronic tics in these families, and that Tourette's syndrome is inherited as a highly penetrant, sex-influenced, autosomal dominant trait.",0
1069,3466033,Recommended infection-control policies for patients with human immunodeficiency virus infection. An update,"HIV is not readily transmitted to health care workers, even after accidental parenteral exposure to infected blood. Existing guidelines for reducing exposure to blood and other body fluids will protect workers who care for patients infected with this pathogen. New infection-control guidelines for patients with AIDS are therefore not required. Awareness of the potential for nosocomial transmission of HIV has resulted in a renewed respect for the principles and practice of infection control. The procedures that the task force recommended to prevent contact with body fluids will reduce exposure not only to HIV but also to other potentially contagious pathogens in the health care environment. Implementation and enforcement of these guidelines for all patients could greatly reduce the incidence of nosocomial and occupationally acquired infections.",0
1070,3477695,Long-term evaluation of HIV antigen and antibodies to p24 and gp41 in patients with hemophilia. Potential clinical importance,"To investigate the relation between human immunodeficiency virus (HIV) antigenemia and clinical manifestations of HIV infections, we studied 96 patients with hemophilia who were positive for HIV antibody, for a median of 34 months. Every 4 to 10 months a clinical and laboratory examination was performed and serum samples were tested for three HIV markers: HIV antigen, antibody to p24, and antibody to gp41. Twenty-two subjects (23 percent) were found to be positive for HIV antigen: 8 were positive upon entry and remained so (Group 1), and 14 became positive during the study, 4 to 26 months after HIV antibody appeared (seroconversion), 13 of whom remained positive for HIV antigen (Group 2). Most subjects positive for HIV antigen had low or undetectable titers of antibody to p24, whereas the antibody titer to gp41 remained high. In Group 2, patients with low p24 antibody titers had further decreases in their titers before or at the time HIV antigen appeared. Once present, HIV antigen persisted and tended to increase in concentration. In contrast to Group 3 (negative for HIV antigen, low anti-p24 titer) and 4 (negative for HIV antigen, high anti-p24 titer), the groups positive for HIV antigen had significantly higher incidences of acquired immunodeficiency syndrome (P = 0.05), immunodeficiency-related infections (P less than 0.001), and immune thrombocytopenia (P = 0.001), and had more severe disease as measured by the Walter Reed staging system (P less than 0.001). In this study, HIV antigen appeared to be a better predictive marker of HIV-related complications than the absolute T4+ count. These results suggest that HIV antigenemia indicates a poor clinical prognosis.",0
1071,3491317,Endoscopic sclerotherapy versus portacaval shunt in patients with severe cirrhosis and acute variceal hemorrhage. Long-term follow-up,"In a continuation of a trial for which preliminary results were reported in the Journal two years ago, a total of 64 patients with Child Class C cirrhosis and variceal hemorrhage requiring six or more units of blood were randomly assigned to receive either a portacaval shunt (32 patients) or endoscopic sclerotherapy (32 patients). The duration of initial hospitalization and the total amount of blood transfused during hospitalization were significantly less in the patients receiving sclerotherapy (P less than 0.001). There was no difference in short-term survival (50 percent of the sclerotherapy group were discharged alive, as compared with 44 percent of the shunt-surgery group). Both groups were followed for a mean of 530 days after randomization. Rebleeding from varices, the duration of rehospitalization for hemorrhage, and transfusions received after discharge were all significantly greater in the sclerotherapy group (P less than 0.001). Forty percent of the sclerotherapy-treated patients discharged alive (7 of 16 patients) ultimately required surgical treatment for bleeding varices, despite a mean of 6.1 treatment sessions. Health care costs and long-term survival did not differ significantly between the groups (P greater than 0.05). We conclude that although endoscopic sclerotherapy is as good as surgical shunting for the acute management of variceal hemorrhage in poor-risk patients with massive bleeding, sclerotherapy-treated patients in whom varices are not obliterated and bleeding continues should be considered for elective shunt surgery.",0
1072,3494198,Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema,"In patients with alpha 1-antitrypsin deficiency, the development of emphysema is believed to be caused by the unchecked action of proteases on lung tissue. We evaluated the feasibility, safety, and biochemical efficacy of intermittent infusions of alpha 1-antitrypsin in the treatment of patients with alpha 1-antitrypsin deficiency. Twenty-one patients were given 60 mg of active plasma-derived alpha 1-antitrypsin per kilogram of body weight, once a week for up to six months. After a steady state had been reached, the group had trough serum levels of alpha 1-antitrypsin of 126 +/- 1 mg per deciliter as compared with 30 +/- 1 mg per deciliter before treatment, and serum anti-neutrophil elastase capacities of 13.3 +/- 0.1 microM as compared with 5.4 +/- 0.1 microM. The alpha 1-antitrypsin level in the epithelial-lining fluid of the lungs was 0.46 +/- 0.16 microM before treatment, and the anti-neutrophil elastase capacity was 0.81 +/- 0.13 microM. Six days after infusion, alpha 1-antitrypsin levels (1.89 +/- 0.17 microM) and anti-neutrophil elastase capacities (1.65 +/- 0.13 microM) in the lining fluid were significantly increased (P less than 0.0001). Because of the chronicity of the disorder and the lack of sensitive measures of lung destruction, the clinical efficacy of this therapy could not be studied rigorously. No changes in lung function were observed in our patients over six months of treatment. The only important adverse reactions to the 507 infusions were four episodes of self-limited fever. This study demonstrates that infusions of alpha 1-antitrypsin derived from plasma are safe and can reverse the biochemical abnormalities in serum and lung fluid that characterize this disorder. Together with lifetime avoidance of cigarette smoking, replacement therapy with alpha 1-antitrypsin may be a logical approach to long-term medical treatment.",0
1073,3511382,Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy,"Plasma exchange has been reported to be efficacious in chronic inflammatory demyelinating polyradiculoneuropathy. We performed a prospective double-blind trial in which patients with static or worsening disease were randomly assigned to plasma exchange (n = 15) or to sham exchange (n = 14) for three weeks. After three weeks, we observed statistically significant differences in combined measurements of nerve conduction (total, motor, proximal, velocity, and amplitude) favoring patients who had received plasma exchange. Improvement to a greater degree than for any patient receiving sham exchange was detected in the neurologic-disability score in five patients (P = 0.025) and in subset scores for weakness and reflex in four patients (P less than 0.057). We conclude that for some patients with chronic inflammatory demyelinating polyradiculoneuropathy, plasma exchange has an ameliorating effect on neurologic dysfunction and nerve conduction, but in others no improvement is observed. Because plasma was replaced with normal serum albumin, a humoral factor or factors may have a role in the neurologic deficit of this disorder.",0
1074,3511385,Diagnosis of Creutzfeldt-Jakob disease by Western blot identification of marker protein in human brain tissue,"We tested purified preparations of brain tissue from 39 patients with Creutzfeldt-Jakob disease, Gerstmann-Str�ussler-Scheinker syndrome, or kuru, and from 32 patients with a variety of nonspongiform degenerative diseases, with the use of Western blots against an antiserum to a similarly purified fraction made from scrapie-infected hamster brain. Positive reactions occurred in 81 percent of the 31 specimens from the patients with Creutzfeldt-Jakob disease (and in all of the 7 specimens that were stored frozen for less than one year), in 3 of the 4 specimens from the patients with kuru, in 3 of the 4 specimens from the patients with Gerstmann-Str�ussler-Scheinker syndrome, and in none of the specimens from the patients with other neurologic degenerative disorders, including familial or sporadic Alzheimer's disease; dementia associated with myoclonus, motor neuron disease, or parkinsonism; and acquired-immunodeficiency-syndrome encephalopathy. Immunologic testing has thus begun to provide a useful and rapid adjunct to neuropathological examinations and animal-transmission experiments for the diagnosis of the spongiform encephalopathies.",0
1075,3515183,Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism,"Hyporeninemic hypoaldosteronism is an important cause of hyperkalemia and is characterized by low renin secretion. We found that prostacyclin, a potent vasodilator and renin secretagogue, was markedly reduced--as reflected by its stable urinary metabolite 6-keto-prostaglandin F1 alpha--in seven patients with hyporeninemic hypoaldosteronism as compared with seven matched controls with renal insufficiency and as compared with 12 normal volunteers (mean +/- SE, 42 +/- 7 vs. 185 +/- 37 and 164 +/- 20 ng per gram of creatinine, respectively; P less than 0.001). In contrast, renal prostaglandin E2 excretion was similar in all three groups. A low-dose infusion of calcium or norepinephrine (known stimulants of prostacyclin) increased renal prostacyclin release in normal subjects and controls with renal insufficiency. Neither agonist, however, increased the low basal prostacyclin excretion in the patients (49.6 +/- 11 [basal] vs. 62 +/- 20 [norepinephrine] and 47.5 +/- 16 [calcium]; P greater than 0.8). To evaluate the functional importance of the altered prostacyclin production, we studied the responses of renal blood flow and blood pressure to the calcium infusion. The calcium infusion did not alter blood pressure or renal blood flow in the normal subjects or the controls with renal insufficiency. In contrast, the same dose of calcium in the patients with hyporeninemic hypoaldosteronism produced a rise in mean blood pressure (from 91 +/- 6 to 104 +/- 8 mm Hg, P less than 0.05) and a fall in renal blood flow (from 673 +/- 58 to 560 +/- 42 ml per minute per 1.73 m2, P less than 0.05). These results indicate that a deficiency of prostacyclin could explain the low active-renin concentration and altered vasomotor tone seen in hyporeninemic hypoaldosteronism.",0
1076,3519419,"Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism","""It is now widely accepted that the various pharmacologic and addictive consequences of alcohol consumption are related to the tissue concentration of ethanol or its metabolic products. The oxidative metabolism of ethanol in liver is principally catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes exist in multiple molecular forms, and genetic models have been proposed to account for the multiplicity of isoenzymes. Alcohol dehydrogenase subunits are encoded at five different gene loci, and genetic polymorphism occurs at two alcohol dehydrogenase loci. Variant isoenzymes produced at the two polymorphic alcohol dehydrogenase loci account for the differences in enzyme electrophoretic patterns observed among individuals. Some of these variant isoenzymes exhibit widely different kinetic properties, and this may account for the 2- to 3-fold variation in alcohol elimination rate among individuals. Since the protein sequence of several of the alcohol dehydrogenase subunits has been determined and several of the alcohol dehydrogenase genes has been cloned, some of the structural changes which give rise to differences in catalytic and electrophoretic properties are now known. Genetic polymorphism also occurs at the aldehyde dehydrogenase gene locus which encodes the mitochondrial low Km for acetaldehyde aldehyde dehydrogenase isoenzyme. The variant isoenzyme exhibits little or no catalytic activity. Individuals with this """"null"""" variant have higher than normal blood acetaldehyde levels and exhibit an alcohol-flush reaction which appears to be a deterrent to heavy drinking and alcoholism.(ABSTRACT TRUNCATED AT 250 WORDS)""",0
1077,3526148,Immunity to malaria and naturally acquired antibodies to the circumsporozoite protein of Plasmodium falciparum,"A candidate Plasmodium falciparum sporozoite vaccine, R32tet32, which includes 32 tetrapeptide repeats derived from the circumsporozoite protein of P. falciparum, has been developed on the basis of the hypothesis that antibodies to the repeat region of this protein will protect against sporozoite infection. The results of two in vitro assays, the circumsporozoite precipitation reaction and the inhibition of sporozoite invasion into hepatoma cells, are thought to indicate protective immunity. We therefore tested serum samples from persons living in a hyperendemic malarious area of Indonesia for antibodies against R32tet32 and for their ability to produce circumsporozoite precipitation and to inhibit sporozoite invasion of hepatoma cells. The prevalence and mean titer of antibody against R32tet32 increased with the age of the subjects, whereas the prevalence of P. falciparum infection in the community decreased. Only serum samples with IgG or IgM R32tet32 antibody titers greater than or equal to 1/800 had precipitation activity and invasion-inhibiting activity of more than 75 percent. When the serum samples were fractionated by affinity chromatography, only the fractions containing purified human antibody to R32tet32 were found to contain this activity. These data support the hypotheses that antibodies to the circumsporozoite protein are important in reducing the prevalence of malaria with increasing age among persons in areas in which malaria is endemic and that vaccine-elicited antibody to the circumsporozoite repeat region will protect against infection with P. falciparum sporozoites.",0
1078,3526153,Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls,"Leukotrienes C4 and D4 may serve as chemical mediators in asthma. Although patients with asthma are known to be hyperresponsive to the bronchoconstrictive effects of histamine and methacholine, whether the same is true for the leukotrienes is controversial. We compared the airway responses to methacholine and to leukotrienes C4 and D4 in 12 asthmatic patients and 6 controls. We found that the patients were more responsive to the leukotrienes than the controls, and we observed a linear correlation between airway response to methacholine and that to leukotriene C4 (r = 0.68, P less than 0.01) and D4 (r = 0.79, P less than 0.001). However, relative to the airway response to methacholine, the response to the leukotrienes was much greater in the controls than in the patients. Furthermore, the asthmatic subjects who were most responsive to methacholine had the lowest relative airway response to both leukotrienes. Thus, the patients with the greatest airway responsiveness to methacholine paradoxically showed the lowest relative airway response to the leukotrienes. In contrast, this difference in relative airway responses has not been observed between methacholine and other bronchoconstrictor mediators, such as histamine. Although no adequate explanation for these observations has yet emerged, our data suggest that leukotrienes C4 and D4 are unique bronchoconstrictors with a possible role in the pathogenesis of asthma.",0
1079,3531859,Platelet activation in unstable coronary disease,"Pathological and clinical studies have suggested that platelets have a role in the pathogenesis of unstable angina and myocardial infarction. However, the relation of platelet activation to episodic ischemia in patients with unstable angina is unknown. We assessed the biosynthesis of thromboxane and prostacyclin as indexes of platelet activation in patients with stable and unstable coronary disease by physicochemical analysis of metabolites in plasma and urine. Prostacyclin biosynthesis was markedly elevated in patients with acute myocardial infarction and correlated with plasma creatine kinase (r = 0.795; P less than 0.001). The largest rise in thromboxane synthesis was observed in patients with unstable angina, in whom 84 percent of the episodes of chest pain were associated with phasic increases in the excretion of thromboxane and prostacyclin metabolites. However, 50 percent of such increases were not associated with chest pain, possibly reflecting silent myocardial ischemia. These data indicate that platelet activation occurs during spontaneous ischemia in patients with unstable angina. The increment in prostacyclin biosynthesis during such episodes may be a compensatory response of vascular endothelium that limits the degree or effects of platelet activation. If so, biochemically selective inhibition of the synthesis or action of thromboxane A2 would be desirable in the treatment of unstable angina. In contrast, thromboxane inhibitors or antagonists would not be expected to be effective in patients with chronic stable angina, in whom there was no increase in the formation of thromboxane A2.",0
1080,3531862,Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis,"We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.",0
1081,3543674,Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results,"Systemically disseminated cutaneous T-cell lymphoma is generally resistant to chemotherapy and radiotherapy. We tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links DNA. After oral administration of methoxsalen, a lymphocyte-enriched blood fraction was exposed to ultraviolet A (1 to 2 J per square centimeter) and then returned to the patient. The combination of ultraviolet A and methoxsalen caused an 88 +/- 5 percent loss of viability of target lymphocytes, whereas the drug alone was inactive. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 +/- 10 weeks (mean +/- SD). The responding group included 8 of 10 patients with lymph-node involvement, 24 of 29 with exfoliative erythroderma, and 20 of 28 whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the infused damaged cells may have restricted the activity of the abnormal T cells. This preliminary study suggests that extracorporeal photochemotherapy is a promising treatment for widespread cutaneous T-cell lymphoma.",0
1082,3547127,Current trends in cigarette advertising and marketing,"""Because the nation's health is so greatly influenced by cigarette smoking, this report examines current trends in cigarette advertising and marketing. According to the Federal Trade Commission, total cigarette advertising and promotional expenditures reached $2.1 billion in 1984. From 1974 through 1984, total expenditures increased approximately sevenfold, or threefold after adjustment according to the consumer price index. In 1985, cigarette advertising expenditures accounted for 22.3 percent, 7.1 percent, and 0.8 percent of total advertising expenditures in outdoor media, magazines, and newspapers, respectively. When all products and services were ranked according to national advertising expenditures, cigarettes were first in the outdoor media, second in magazines, and third in newspapers. The proportion of total cigarette advertising and promotional expenditures devoted to promotional activities has increased steadily, from 25.5 percent in 1975 to 47.6 percent in 1984. The proportion of expenditures for cigarettes yielding 15 mg or less of """"tar"""" has increased substantially and has consistently exceeded the domestic market share of these cigarettes. The fastest growing markets are discounted cigarettes and brands containing 25 cigarettes per pack. Several advertising campaigns have targeted women, minorities, and blue-collar workers. The study of these marketing trends should assist health officials in identifying and predicting patterns of cigarette use and in developing health promotion programs that counteract the influence of advertising by incorporating similar, effective techniques.""",0
1083,3553947,Yellow professionalism. Advertising by physicians in the Yellow Pages,"""We compared the specialty listings of physicians in the Yellow Pages of the 1983 Hartford, Connecticut, telephone book with the board certifications in specialties of the American Board of Medical Specialties as listed in the American Medical Association directory or the Marquis Directory of Medical Specialists. There were 1179 listings by 946 physicians under 61 specialty headings in the Yellow Pages. We found that a mean of 12 percent of """"specialists"""" listed in the Yellow Pages were not board-certified in a specialty, although they had had ample opportunity to obtain board certification. We conclude that specialty advertising in the Yellow Pages is potentially misleading to consumers and that member boards of the American Board of Medical Specialties should consider ways to diminish this possible misrepresentation.""",0
1084,3557302,Ultracentrifugal isolation of vesicular carriers of biliary cholesterol in native human and rat bile,"We have utilized ultracentrifugation of native bile-Metrizamide density gradients to isolate a vesicular transport system of biliary lipids in both man and rat. We identified vesicular structures by electron microscopy. Fresh bile specimens were obtained from bile fistula rats (unsaturated bile) and from patients 1 week after bile duct surgery (supersaturated bile). Metrizamide was dissolved in bile (33% w/v), and continuous density gradients were performed with undiluted bile (density limits = 1.020 to 1.300 gm per ml). The relative distribution of biliary cholesterol, phospholipid and bile salt was studied as a function of the density of the fractions. Approximately 50% of total rat biliary cholesterol and between 61 and 90% of human biliary cholesterol was concentrated in the lightest fractions of the gradients (density less than 1.060 gm per ml). In contrast, less than 20% of bile salts was present in fractions with densities lower than 1.060 gm per ml. The highest amounts of bile salts and phospholipids of the bile-Metrizamide density gradients were found in the density range of 1.075 to 1.100 gm per ml in both human and rat bile. More than 80% of biliary proteins was found in fractions with densities greater than 1.075 gm per ml, and only 2% was found in the cholesterol-rich fraction with density less than 1.060 gm per ml in both species. When bile salt concentration was raised in rat bile from 38 to 97 mM by adding taurocholate, the low density cholesterol-rich fraction almost disappeared. Electron microscopy of negatively stained preparations of the fractions with density less than 1.060 gm per ml showed 40 to 120 nm vesicles, which were not apparent in the other fractions. Similar vesicles were demonstrated also in fresh rat bile and within the canaliculi after acute depletion of the bile salt pool (biliary bile salt concentration of 3.45 mM; total biliary lipid concentration of 0.25 gm%). The structure of these vesicles was shown in thin sections of liver specimens. They appeared as internal cavities surrounded by a single, continuous 6-nm-thick bilayer. These studies demonstrate that a high proportion of biliary cholesterol is transported in vesicles in human supersaturated native bile and that vesicular carriers are also responsible for the transport of a significant amount of biliary cholesterol in unsaturated rat bile. The presence of vesicles in unsaturated hepatic bile strongly supports the thesis that biliary lipids may be secreted as vesicles from the hepatocyte into the canaliculi.",0
1085,3557303,Bile salts induce calcium uptake in vitro by human erythrocytes,"At high concentrations, bile salts induce hemolysis by comicellization of lipid components of the cell membrane. However, bile salts are also associated with hemolysis at lower concentrations by mechanisms which have not been characterized. To investigate the possibility that bile salts promote calcium uptake by red blood cells and that bile salt-associated hemolysis is, in part, calcium-mediated, calcium uptake by red blood cells was measured in the presence of individual bile salts, and hemolysis dependence upon calcium availability was examined. Washed human red blood cells with or without ATP depletion were incubated with 1 mM CaCl2 and tracer amounts of 45CaCl2 in the presence of selected bile salts at concentrations (0.01 to 0.3 mM) reported to be below critical micellar concentrations. Calcium uptake (defined for the purposes of this study as 45Ca retained in red blood cells) was monitored over 5 hr, after which hemolysis and membrane phospholipid content were determined. The presence of bile salts stimulated calcium uptake 4- to 25-fold--the magnitude of which was partly related to the lipid solubility of the bile salts. ATP depletion or exposure to trifluoperazine, procedures which inhibit calcium pump activity in red blood cells, enhanced bile salt-induced calcium uptake relative to controls. The percentage of associated hemolysis (2 to 14%) at the end of 5 hr correlated directly with the observed calcium uptake. Removal of calcium from the extracellular space reduced hemolysis in the presence of bile salts to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1086,3557307,An extrahepatic bile duct growth factor: in vivo effect and preliminary characterization,"Rabbit sera injected intraperitoneally into BALB/c mice were noted to produce a considerable and selective enlargement of extrahepatic bile ducts. The gallbladder, intrahepatic ducts, liver and other organs showed no stimulation of growth. Duct enlargement leading to widening of its outer diameter which, on average, was 3.6 times that of normal, was due entirely to an increased number of epithelial cells with prominent proliferation of intramural glandular components. There was no evidence of inflammatory bile duct injury, fibrosis or obstruction. All of the above changes were reversible and regressed slowly after discontinuation of injections. The bile duct growth-promoting factor was detected in sera of many animal species including humans and birds. Host response to this factor was determined by the number of injections and appeared to be strain-related since it was not observed in C57BL or C3H mice. The sex and age of the donor or recipient were not of any relevance to the growth response. In order to isolate and characterize the bile duct growth factor, rabbit serum was separated into various fractions, and the effect of each fraction was tested in the animal model. Proteins in the 33 to 65% ammonium sulfate precipitate of whole rabbit sera had activity equal to that of native sera. Activity was abolished by treating this serum fraction with 1% sodium dodecyl sulfate plus proteinase K, suggesting that the bile duct growth factor is a protein. Lipids extracted from whole sera using chloroform: methanol or ultracentrifugation were devoid of activity.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1087,3561456,Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development,"In a prospective cohort study of 249 children from birth to two years of age, we assessed the relation between prenatal and postnatal lead exposure and early cognitive development. On the basis of lead levels in umbilical-cord blood, children were assigned to one of three prenatal-exposure groups: low (less than 3 micrograms per deciliter), medium (6 to 7 micrograms per deciliter), or high (greater than or equal to 10 micrograms per deciliter). Development was assessed semiannually, beginning at the age of six months, with use of the Mental Development Index of the Bayley Scales of Infant Development (mean +/- SD, 100 +/- 16). Capillary-blood samples obtained at the same times provided measures of postnatal lead exposure. Regression methods for longitudinal data were used to evaluate the association between infants' lead levels and their development scores after adjustment for potential confounders. At all ages, infants in the high-prenatal-exposure group scored lower than infants in the other two groups. The estimated difference between the overall performance of the low-exposure and high-exposure groups was 4.8 points (95 percent confidence interval, 2.3 to 7.3). Between the medium- and high-exposure groups, the estimated difference was 3.8 points (95 percent confidence interval, 1.3 to 6.3). Scores were not related to infants' postnatal blood lead levels. It appears that the fetus may be adversely affected at blood lead concentrations well below 25 micrograms per deciliter, the level currently defined by the Centers for Disease Control as the highest acceptable level for young children.",0
1088,3561457,Benzene and leukemia. An epidemiologic risk assessment,"To assess quantitatively the association between benzene exposure and leukemia, we examined the mortality rate of a cohort with occupational exposure to benzene. Cumulative exposure for each cohort member was estimated from historical air-sampling data and, when no sampling data existed, from interpolation on the basis of existing data. The overall standardized mortality ratio (a measure of relative risk multiplied by 100) for leukemia was 337 (95 percent confidence interval, 154 to 641), and that for multiple myeloma was 409 (95 percent confidence interval, 110 to 1047). With stratification according to levels of cumulative exposure, the standardized mortality ratios for leukemia increased from 109 to 322, 1186, and 6637 with increases in cumulative benzene exposure from less than 40 parts per million-years (ppm-years), to 40 to 199, 200 to 399, and 400 or more, respectively. A cumulative benzene exposure of 400 ppm-years is equivalent to a mean annual exposure of 10 ppm over a 40-year working lifetime; 10 ppm is the currently enforceable standard in the United States for occupational exposure to benzene. To examine the shape of the exposure-response relation, we performed a conditional logistic-regression analysis, in which 10 controls were matched to each cohort member with leukemia. From this model, it can be calculated that protection from benzene-induced leukemia would increase exponentially with any reduction in the permissible exposure limit.",0
1089,3574401,Diffusing capacity for carbon monoxide as a predictor of gas exchange during exercise,"In patients with pulmonary disease, the diffusing capacity for carbon monoxide has been used to predict abnormal gas exchange in the lung. However, abnormal values for arterial blood gases during exercise are likely to be the most sensitive manifestations of lung disease. We compared the single-breath diffusing capacity for carbon monoxide at rest with measurements of gas exchange during exercise, including arterial oxygen tension, the alveolar-arterial difference in oxygen tension, the arterial-end-tidal difference in carbon dioxide tension, and the dead-space/tidal-volume ratio in 276 current and former shipyard workers. Sixteen workers had a diffusing capacity for carbon monoxide below 70 percent of predicted; one or more measurements of gas exchange during exercise were abnormal in 14. In contrast, of 96 men who had abnormal gas exchange during exercise, only 14 had a diffusing capacity for carbon monoxide below 70 percent of predicted. Neither the type nor the degree of abnormality in gas exchange could be predicted from the diffusing capacity. We conclude that diffusing capacity for carbon monoxide at rest is a specific but insensitive predictor of abnormal gas exchange during exercise and that, if indicated, measurements of arterial blood gases should be obtained during exercise.",0
1090,3574414,Geographic variations in mortality from motor vehicle crashes,"Using a new technique to study the mortality associated with motor vehicle crashes, we calculated population-based death rates of occupants of motor vehicles during the period 1979 through 1981 and mapped them according to county for the 48 contiguous states of the United States. Mortality was highest in counties of low population density (r = 0.57; P less than 0.0001) and was also inversely correlated with per capita income (r = 0.23; P less than 0.0001). Death rates varied more than 100-fold; for example, Esmeralda County, Nevada, with 0.2 residents per square mile (2.6 km2), had a death rate of 558 per 100,000 population, as compared with Manhattan, New York, with 64,000 residents per square mile and a death rate of 2.5 per 100,000. Differences in road characteristics, travel speeds, seat-belt use, types of vehicles, and availability of emergency care may have been major contributors to these relations.",0
1091,3614286,Statistical problems in the reporting of clinical trials. A survey of three medical journals,"Reports of clinical trials often contain a wealth of data comparing treatments. This can lead to problems in interpretation, particularly when significance testing is used extensively. We examined 45 reports of comparative trials published in the British Medical Journal, the Lancet, or the New England Journal of Medicine to illustrate these statistical problems. The issues we considered included the analysis of multiple end points, the analysis of repeated measurements over time, subgroup analyses, trials of multiple treatments, and the overall number of significance tests in a trial report. Interpretation of large amounts of data is complicated by the common failure to specify in advance the intended size of a trial or statistical stopping rules for interim analyses. In addition, summaries or abstracts of trials tend to emphasize the more statistically significant end points. Overall, the reporting of clinical trials appears to be biased toward an exaggeration of treatment differences. Trials should have a clearer predefined policy for data analysis and reporting. In particular, a limited number of primary treatment comparisons should be specified in advance. The overuse of arbitrary significance levels (for example, P less than 0.05) is detrimental to good scientific reporting, and more emphasis should be given to the magnitude of treatment differences and to estimation methods such as confidence intervals.",0
1092,3614304,Gastrointestinal absorption of calcium from milk and calcium salts,"Whether ingested calcium is absorbed more efficiently from freely water-soluble calcium salts than from poorly soluble salts is unclear. It is also unknown whether calcium is absorbed better from dairy products than from calcium salts. Using a method by which the net absorption of calcium can be accurately measured after a single dose, we studied eight healthy fasting subjects after they took a 500-mg dose of calcium from each of five calcium salts with various degrees of water solubility and from milk. The order of administration of the agents given was randomly determined. The mean (+/- SEM) net calcium absorption, in decreasing order of the solubility of the salts, was 32 +/- 4 percent from calcium acetate, 32 +/- 4 percent from calcium lactate, 27 +/- 3 percent from calcium gluconate, 30 +/- 3 percent from calcium citrate, and 39 +/- 3 percent from calcium carbonate. The differences in absorption were not statistically significant according to analysis of variance. On the basis of in vitro solubility experiments in acid mediums, we hypothesize that acid dissolution in the gastrointestinal tract may be responsible for the similar absorption of calcium from salts with widely different water solubilities. Calcium absorption from whole milk (31 +/- 3 percent) was similar to absorption from calcium salts. We conclude that calcium absorption from carbonate, acetate, lactate, gluconate, and citrate salts of calcium, and from whole milk, is similar in fasting healthy young subjects. Further study will be required to determine whether the results would be different in older subjects, with a higher dose of calcium, or if the calcium was ingested with food.",0
1093,3627181,Circulating erythroid progenitors in the anemia of prematurity,"We studied erythropoiesis in infants with the anemia of prematurity by counting the number of colonies derived from erythroid burst-forming units (BFU-E) in the blood of 11 premature infants before they received transfusions. Colony growth in blood from the infants was compared with growth in blood from adults and umbilical-cord blood from term infants, in the presence of erythropoietin, 0 to 2000 mU per milliliter. Addition of increasing concentrations of erythropoietin resulted in a stepwise increase in the number of colonies derived from BFU-E (P less than 0.0005) of all three groups of subjects. Cultures stimulated with 2000 mU of erythropoietin yielded 28.1 +/- 7.6, 88.0 +/- 19.4, and 121.0 +/- 22.5 bursts (mean +/- SE) per 10(5) cells plated in blood from adults, blood from premature infants, and cord blood, respectively. Although more BFU-E-derived colonies appeared when 200 or 2000 mU were present per milliliter in cultures of the infants' blood and cord blood, the intrinsic responsiveness of BFU-E to erythropoietin was similar in all groups. Although the mean hematocrit was 26 percent, mean serum erythropoietin concentrations (+/- SD) in the infants (20.7 +/- 10.0 mU per milliliter) were not significantly different from those in the adult controls (24.0 +/- 6.5). We conclude that progenitor cells committed to erythroid differentiation are present during the anemia of prematurity, and that the intrinsic responsiveness of the circulating BFU-E pool to erythropoietin is normal. These results implicate inadequate production of erythropoietin as the cause of the anemia of prematurity and suggest that recombinant erythropoietin might provide a therapeutic alternative to transfusion for symptomatic babies with this condition.",0
1094,3627184,Risk factors accounting for racial differences in the rate of premature birth,"In a hospital-based cohort of 8903 black and white women, we investigated medical and socioeconomic risk factors that may explain the known increase in premature births among black women. Among the medical conditions examined, only the maternal hematocrit level (or some related factor) explained a substantial proportion (60 percent) of the increased rate of premature births to black women. Four economic, demographic, and behavioral predictors of prematurity were also examined: age less than 20 years, single marital status, receiving welfare support, and not having graduated from high school. The number of these socioeconomic risk factors occurring in a woman was strongly predictive of premature birth of her infant, regardless of the particular risk factors present. The presence of any one factor was associated with a moderate increase in the risk of prematurity (7.0 percent as compared with 4.6 percent with no risk factors present); the presence of two or more characteristics was associated with a much higher risk (11.2 percent). When the number of these four risk factors pertaining to an individual woman was taken into account, race was no longer a significant predictor of premature birth (odds ratio, 1.22; 95 percent confidence interval, 0.94 to 1.59). When both the maternal hematocrit level and the number of the four socioeconomic risk factors were taken into account, essentially all of the racial variation in prematurity was explained, with the odds ratio for prematurity among blacks being 1.03 (95 percent confidence interval, 0.79 to 1.35). We conclude that the racial difference in the rate of premature birth is attributable to specific medical and socioeconomic characteristics.",0
1095,3627185,Racial differences in low birth weight. Trends and risk factors,"To identify the risk factors responsible for differences in birth weight between blacks and whites, we investigated the effects of four maternal characteristics (age, parity, marital status, and education) on rates of very low birth weight (less than 1500 g) and moderately low birth weight (between 1500 and 2500 g). Using 1983 national data, we found that the black:white rate ratio was 3.0 for very low birth weight and 2.3 for moderately low birth weight. The four maternal factors had directionally similar but quantitatively different effects on very low and moderately low birth weight among blacks and whites. Furthermore, the racial differences in infants' birth weights were greater among low-risk than among high-risk mothers, especially for very low birth weight (black:white ratios of 3.4 and 1.7, respectively). We also examined secular trends in the rates of low birth weight among blacks and whites. Between 1973 and 1983, births of infants with moderately low birth weights decreased more among whites than among blacks, whereas births of infants with very low birth weights increased among blacks and decreased among whites. Fifteen percent of the decline in the rate of moderately low birth weight among whites could be attributed to favorable changes in maternal characteristics (primarily an increase in educational level). Among blacks, adverse changes in maternal characteristics (primarily an increase in births to unmarried women) accounted for 35 percent of the increase in the rate of very low birth weight. The adverse effects of childbearing by teenagers on the outcome of pregnancy among blacks appear to have been overemphasized. The persistence of large racial differences in birth weight, even among mothers at low risk, emphasizes the need for specific targeted interventions to achieve further improvements in infant health.",0
1096,3627197,The impact of televised movies about suicide. A replicative study,"Gould and Shaffer studied suicides by teenagers in the New York City area before and after three fictional films about suicide were televised, and presented evidence suggesting that the films were followed by a significant increase in teenage suicides. Using their methods, we studied teenage suicides in California and Pennsylvania before and after the television broadcast of the same three films. In these states, there was no evidence of an increase in teenage suicides after the films were shown. This remained true when data for New York from the study of Gould and Shaffer were combined with our data from California and Pennsylvania. We conclude that it is premature to be concerned about possibly fatal effects of fictional televised films about suicide.",0
1097,3653851,Acinar redistribution and heterogeneity in transport of the organic cation rhodamine B in rat liver,"We studied a possible acinar heterogeneity in the transport of organic cations, using rhodamine B as model compound. Employing perfusions of isolated rat livers in the ante- and retrograde mode and quantitative fluorescence microscopy, Zones 1 and 3 were shown to be equally efficient in taking up rhodamine B. Ten minutes after injection in an antegrade perfusion, 95% of the dose was localized in the portal half of the acinus. Fifty minutes later, however, the amount of rhodamine B in Zone 1 had been reduced to 23%; 30 and 31% were in Zones 2 and 3, respectively, and the medium concentration was doubled. Thus, unchanged rhodamine B appeared to be transported downstream within the liver, either via the medium or directly from cell to cell, finally resulting in a relatively higher rhodamine B concentration in Zone 3. To obtain additional data, we designed a perfusion setup in which the zones could be studied separately. In both zones, the amount excreted into the medium was about 30 times the amount excreted into bile. Intracellular sequestration of rhodamine B and the rate constant for sinusoidal secretion were higher in Zone 3, while the sinusoidal uptake rates were equal; biliary excretion was higher in Zone 1. Acinar distribution changed with time because rhodamine B, primarily accumulated in Zone 1, was secreted into the sinusoids and taken up again by downstream cells. The finally higher rhodamine B concentration in Zone 3 was caused by a zonal heterogeneity in intracellular sequestration and sinusoidal secretion of rhodamine B.",0
1098,3657865,An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A,"We report the development of a rapid nonradioactive technique for the genetic prediction of human disease and its diagnostic application to hemophilia A. This method is based on enzymatic amplification of short segments of human genes associated with inherited disorders. A novel feature of the procedure is the use of a heat-stable DNA polymerase, which allows the repeated rounds of DNA synthesis to proceed at 63 degrees C. The high sequence specificity of the amplification reaction at this elevated temperature permits restriction-site polymorphisms, contained in the amplified samples, to be analyzed by visual inspection of their digestion products on polyacrylamide gels. By means of this method, we have performed carrier detection and prenatal diagnosis of hemophilia in two families with use of the factor VIII intragenic polymorphisms identified by the restriction enzymes BclI and XbaI. Predictions can be made directly from chorionic villi, without previous DNA extraction, and fetal sex can be determined by amplification of sequences specific for the Y chromosome. Specific amplification of genomic sequences with heat-stable DNA polymerase is applicable to the diagnosis of a wide variety of inherited disorders. These include diseases diagnosed by restriction-site variation, such as Duchenne's muscular dystrophy and sickle cell anemia, those due to a collection of known mutations, such as beta-thalassemia, and those due to gene deletion, such as alpha-thalassemia.",0
1099,3657890,Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas,"One of the most common karyotypic abnormalities is the t(14;18) translocation, which is found in many lymphomas that have a characteristic follicular morphology. Recent molecular studies have shown that this chromosomal translocation results in the juxtaposition of the candidate proto-oncogene bcl-2 (B-cell leukemia-lymphoma) on chromosome 18 with the immunoglobulin heavy-chain locus on chromosome 14. However, because performing accurate cytogenetic studies in solid hematolymphoid neoplasms is difficult, knowledge of the prevalence of the t(14;18) translocation and, by association, the extent of bcl-2 involvement in human lymphomas is limited. We used a number of chromosome-18 DNA probes to analyze various subtypes of Hodgkin's and non-Hodgkin's lymphomas and test for structural abnormalities near or within the bcl-2 gene. Molecular features of the t(14;18) translocation were found in virtually all follicular neoplasms and about 28 percent of diffuse large-cell lymphomas. No changes in bcl-2 were found in several other subtypes of Hodgkin's and non-Hodgkin's lymphomas, including those previously suggested to originate from follicular-center cells and those about which cytogenetic data have been difficult to obtain. Our findings suggest a close pathogenetic relation between bcl-2 and a large group of non-Hodgkin's lymphomas, both with and without a follicular morphology. The methods employed in this study may be useful in improving the accuracy of diagnosis and subclassification of malignant lymphomas.",0
1100,3679088,Increase in the number of fenestrae in mouse endothelial liver cells by altering the cytoskeleton with cytochalasin B,"Endothelial cells of the hepatic sinusoid isolated from mice livers and maintained in culture display typical fenestrae grouped in sieve plates. Treatment with cytochalasin B led to no significant change in the mean diameter of the fenestrae but to an increase in their number and in the porosity of the cells (percentage of the cellular surface opened by the fenestrae) which attained up to 300% of that of the controls. Scanning electron microscopic observations of Triton-extracted cells revealed that these modifications were related to an alteration of the cytoskeleton. The effect of cytochalasin B could be reversed; 3 hr after removal of the drug, the cells recovered their original aspect with sieve plates scattered over their surface. These observations demonstrate that endothelial fenestrae are inducible structures and that the cytoskeleton seems to be involved in their formation.",0
1101,3683459,The course and prognosis of different forms of chronic airways obstruction in a sample from the general population,"We examined the course and prognosis in subjects selected from the general population who had chronic airflow obstruction at the time of their enrollment in a longitudinal epidemiologic study. Mortality and the rate of change in lung function were analyzed in relation to the initial clinical characteristics of the subjects. Twenty-seven subjects with symptoms and signs of asthma (Group I) had a higher survival rate and a much lower rate of decline in pulmonary function than the 45 subjects in Group III, whose clinical characteristics were more compatible with an emphysematous form of chronic obstructive pulmonary disease (COPD). The 10-year mortality among subjects in Group III (non-atopic smokers without a history of asthma) was close to 60 percent, whereas it was only 15 percent in Group I (atopic subjects or nonsmokers with known asthma). The mean overall rate of decline in forced expiratory volume in one second was 70 ml per year in Group III but less than 5 ml per year in Group I. Forty-five patients (Group II) who did not clearly fit into either Group I or III had intermediate values for survival and decline in pulmonary function. Previous data on mortality from COPD and the rate of progression of the condition, although compatible with our findings in patients who had an emphysematous form of disease, are not applicable to those with an asthmatic-bronchitic form. Better control of the progression of asthmatic bronchitis with therapy may explain its more favorable prognosis.",0
1102,3683463,Smoking and women: tragedy of the majority,"""An increasing number of women are becoming victims of their smoking habit. A broader cross-section of women, other than the very rich and the """"indecent,"""" began to smoke in the 1920s, and over the past 50 years tobacco advertising has linked smoking with women's emancipation and achievement of equality with men. The marketing efforts directed to women include special packaging for feminine appeal, """"designer"""" cigarettes, and offering discounted women's products with the purchase of a particular brand of cigarettes. Sponsorship of sporting events coupled with sports themes in cigarette advertisements associates smoking with enhanced physical capacity--a deception. The marketing experts promote smoking as a way of remaining slim in a culture obsessed with thinness. The woman who smokes today is a heavier smoker, on average, with the percentage of women smoking more than 25 cigarettes/day almost doubling from 13% in 1965 to 23% in 1985. Women start smoking at younger and younger ages. 84% of women smokers who are now 28-37 years began to smoke before age 20 as compared with 42% of those now 58-67 years. Today more young women than young men smoke. In addition to the risk of lung cancer, women who smoke also have sex-specific risks, such as those pertaining to a women's reproductive organs and processes. When smoking is of long duration, it appears to increase the risks of intraepithelial neoplasia of the cervix and of invasive cervical cancer. An antiestrogen effect of smoking may provide the explanation for why smoking women reach menopause 1-2 years earlier than nonsmokers. The same mechanism, which has been supported by several case-control studies, may increase postmenopausal osteoporotic fractures, particularly among nonobese women. Possibly the worst consequences of smoking by women are its effects on reproduction and on children. Both a dose-response depressant effect of smoking on fetal development and birth weight have been confirmed. Smoking also reduces fertility, increases the rate of spontaneous abortion of chromosomally normal fetuses, and increases the incidence of abruptio placentae, placenta previa, bleeding during pregnancy, and premature rupture of the membranes. A growing body of evidence also suggests that smoking during pregnancy has longterm effects on children. Those organizations at work to promote the rights of women might consider devoting some attention to help women stop smoking.""",0
1103,3683469,Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease,"Coronary-artery thrombosis may be important in the pathogenesis of unstable angina at rest. To study this possibility, we measured the serum concentrations of fibrin-related antigen, D dimer (the principal breakdown fragment of fibrin), and fibrin monomer (an intermediate product of fibrin formation) in the serum of five groups of subjects. These included 10 healthy controls, 10 controls with noncardiac pain, and three groups of 10 patients each with chronic stable angina, unstable angina at rest, or acute myocardial infarction. The concentration of fibrin-related antigen (normal range, 48 to 184 ng per milliliter) was normal in the control patients with noncardiac pain (63 to 202 ng per milliliter) and in patients with chronic stable angina (95 to 186), but it was increased in patients with unstable angina (401 to 2507) or acute myocardial infarction (470 to 1930) (P less than 0.001). D dimer concentrations in patients with unstable angina (178.3 to 310.6 ng per milliliter) or acute myocardial infarction (103.9 to 321.6) were higher than those in patients with chronic stable angina (28.6 to 52.1), in controls with noncardiac pain (44.7 to 53.1), and in healthy controls (40.4 to 50.3) (P less than 0.001). Concentrations of fibrin monomer were highest in patients with acute myocardial infarction (247.5 to 571.3 ng per milliliter) (P less than 0.001), intermediate in those with unstable angina (54.7 to 241.7) (P less than 0.001), and normal (normal range, 14.5 to 19.8 ng per milliliter) in controls with noncardiac pain (12.0 to 18.4). and patients with chronic stable angina (10.7 to 17.6). These findings suggest the presence of an active thrombotic process in patients with unstable angina at rest or acute myocardial infarction. The data do not prove that the coronary arteries were the site of the thrombotic process, but the observations are consistent with the hypothesis that thrombus formation may have an important role in the pathogenesis of these conditions.",0
1104,3696187,Financial incentives for physicians in HMOs. Is there a conflict of interest?,"Do financial incentives used by health maintenance organizations (HMOs) to restrain the use of health care resources represent a conflict of interest between physicians' concern about their income and their concern about patients? To explore the contractual obligations of primary care physicians in HMOs, I mailed a survey to all 595 HMOs known to be in operation as of June 1986. In all, 302 of 595 HMOs (51 percent) responded. Sixty-seven percent of plans with capitation-based arrangements and 82 percent of plans with fee-for-service arrangements withhold a percentage of their physicians' income against potential deficits, but only 21 percent of plans with salaried physicians do so. Thirty percent of HMOs have other penalties in addition to this withholding. Eighteen percent of HMOs base the return of the withheld amount on the experience of individual physicians rather than on the collective experience of a group of physicians. For-profit HMOs are less likely to use salary-based payment, more likely to withhold a percentage of income, and more likely to base the return of this withheld amount on the experience of individual physicians. Most HMOs have mechanisms for sharing surpluses with participating physicians. I conclude that contractual arrangements in HMOs vary widely. Certain financial incentives, especially when used in combination, suggest conflicts of interest that may influence physicians' behavior and adversely affect the quality of care.",0
1105,3710429,Hemodynamic studies in long- and short-term portal hypertensive rats: the relation to systemic glucagon levels,"It is not known whether the hyperdynamic state which has been observed in several experimental models and in patients with portal hypertension reflects a temporary phase during the evolution of the portal hypertensive syndrome or is an expression of a permanent steady state. A hemodynamic study was performed in a group of rats with long-standing portal hypertension induced by portal vein constriction performed 6.2 +/- 0.1 months earlier. A group of rats matched by age and weight with short-term (20.7 +/- 0.9 days) portal hypertension and a group of long-term (6.2 +/- 0.1 months) sham-operated rats were used as controls. Cardiac output and regional blood flows were measured using a radioactive microsphere technique. Arterial blood levels of glucagon, a known vasodilator that was implicated in the etiology of the hyperdynamic circulation, were also measured. Portal pressure in long- and short-term portal hypertensive groups (12.3 +/- 0.4 and 13.7 +/- 0.4 mm Hg; not statistically significant) was higher than in the sham group (9.0 +/- 0.3 mm Hg; p less than 0.01). Cardiac output in the long-term portal hypertensive rats was similar to the sham-operated group and lower than in the short-term portal hypertensive group (19.4 +/- 1.0 and 20.6 +/- 1.5 vs. 32.7 +/- 2.0 ml X min-1 X 100 gm body weight-1; p less than 0.01). Portal venous inflow in the long-term portal hypertensive group was also similar to the sham group and lower than in the short-term portal hypertensive group (4.51 +/- 0.36 and 4.58 +/- 0.39 vs. 6.72 +/- 0.48 ml X min-1.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1106,3710432,"Cytosolic bile acid binding protein in rat liver: radioimmunoassay, molecular forms, developmental characteristics and organ distribution","Rat liver efficiently extracts bile acids from the portal blood and rapidly excretes them into bile. Little is known about the process by which bile acids traverse the liver cell from the sinusoidal to the canalicular membrane. In order to begin to define this process, we recently identified a pair of similar monomeric (33 kilodalton) cytosolic bile acid binding proteins (bile acid binders I and II, J. Biol. Chem. 1983; 258:3602-3607, Abstract). These bile acid binders have comparable binding affinities for bile acid as the YaYa and YaYc members of the family of glutathione S-transferases, the previously recognized cytoplasmic bile acid binding protein. We now report the establishment of a sensitive and specific radioimmunoassay which equally detects both bile acid binders I and II. Specificity of the antiserum was verified by the co-purification of bile acid binder immunoreactivity with the bile acid binders. Liver contained the greatest concentration of bile acid binder, where it constituted 0.33% of the total cytosolic proteins. Phenobarbital administration and lithocholate feeding had no significant effect on hepatic bile acid binder content. Examination of the ontogeny of bile acid binder revealed a rapid increase after birth to near adult levels by Day 14. In summary, we have established a sensitive radioimmunoassay for the bile acid binders. Its localization mainly in liver and its increase after birth parallel bile acid transport in the liver.",0
1107,3713748,The cost implications of academic group practice. A randomized controlled trial,"We evaluated the reorganization of a general medical clinic into several group practices, using equivalent groups of patients and physicians in a randomized controlled trial. The group practice, unlike the traditional clinic, provided decentralized registration, clinic coverage five days a week, and telephone coverage at night and on weekends. Residents worked in small groups with an attending physician, nurse practitioner, and receptionist. All financial activity involving a sample of 2299 patients was followed during the 11-month intervention. The total hospital charges per patient were 26 percent lower for the patients seen in the group practice than for those seen in the traditional clinic (P = 0.003). This difference was primarily attributable to inpatient charges, which were 27 percent lower per patient hospitalized (P = 0.004). The mean length of stay was 8.3 days among group-practice patients and 10.5 days among traditional-clinic patients (P = 0.011). We conclude that organizational changes to improve outpatient access and to integrate inpatient and outpatient services can decrease medical charges.",0
1108,3724796,Death-scene investigation in sudden infant death,"We conducted death-scene investigations in 26 consecutive cases in which a presumptive diagnosis of sudden infant death syndrome (SIDS) was made and the infants were brought to the emergency room of the Kings County Hospital Center between October 1983 and January 1985. In six cases, we observed strong circumstantial evidence of accidental death. In 18 other cases, we discovered various possible causes of death other than SIDS, including accidental asphyxiation by an object in the crib or bassinet, smothering by overlying while sharing a bed, hyperthermia, and shaken baby syndrome. This study suggests that many sudden deaths of infants have a definable cause that can be revealed by careful investigation of the death scene and that the extremely high rate of SIDS (4.2 per 1000 live births) reported in the population of low socioeconomic status served by Kings County Hospital Center should be questioned.",0
1109,3724804,Familial dependence of the resting metabolic rate,"Human obesity is known to be a familial disorder. We studied 130 nondiabetic adult southwestern American Indians (74 men and 56 women) from 54 families to determine whether the resting metabolic rate, as measured by indirect calorimetry, is a familial trait that is independent of individual differences in fat-free mass (estimated mass of metabolically active tissue), age, and sex. We found that most of the variance in the resting metabolic rate (83 percent, P less than 0.0001) was accounted for by three covariates--fat-free mass, age, and sex--and that fat-free mass was the most important determinant. Family membership accounted for an additional 11 percent (P less than 0.0001) of the variance in the resting metabolic rate. Thus, resting metabolic rate is a familial trait in this population, and it is independent of differences in fat-free mass, age, and sex. We also found that persons from families with lower resting metabolic rates were no more obese than persons from families with higher metabolic rates. This finding may be partly explained by the close correlation between fat-free mass and percentage of body fat (r = 0.81, P less than 0.0001), which indicates that the resting metabolic rate, as adjusted for fat-free mass, is already partly adjusted for obesity. Only prospective studies will elucidate whether the familial dependence of the resting metabolic rate is a contributing mechanism to the familial predisposition to obesity.",0
1110,3732995,Strain-related patterns of biliary excretion and hepatic distribution of copper in the rat,"Biliary copper excretion was studied in male, bile-cannulated rats of the inbred strains Fischer, Brown Norway, WAG/Rij and Lewis. After intravenous injection of 10, 30 and 50 micrograms copper per 100 gm body weight, two patterns of copper excretion were observed; their profiles varied with the copper dose and the strain of the rats used. The lowest amounts of copper were excreted by Fischer rats, the highest by WAG/Rij rats; this was related to the effect of the copper dose on both patterns. The subcellular distribution of copper in the liver was studied in Fischer and Brown Norway rats after doses of 50, 100, and 200 micrograms per 100 gm body weight. Brown Norway rats accumulated more copper in the liver, although the copper concentration was the same in both strains 1 hr after injection of all doses. Fischer rats accumulated proportionally more copper in lysosomal and nuclear mitochondrial fractions whereas Brown Norway rats accumulated proportionally more copper in the cytosol. Gel filtration of liver supernatants revealed that the amount of copper accumulating in the protein presumed to be metallothionein was 2 to 3 times higher in Brown Norway rats, whereas in the Fischer rats more copper eluted in the void volume fraction. We conclude that both biliary copper excretion and copper distribution in the liver are under genetic control. Because of its low copper excretion and reduced binding of copper to metallothionein the Fischer rat, compared to other strains, may be a suitable model for studying the involvement of the liver in copper intoxication.",0
1111,3732998,Multivariate analysis of prognostic factors in fulminant hepatitis B,"We assessed prognostic factors in 115 patients with serologically defined fulminant hepatitis B. The diagnosis in each case was based on the finding of IgM antibody to the hepatitis B core antigen in serum. Multivariate analysis showed that factor V level (p less than 0.001), patient's age (p = 0.001), absence of detectable HBsAg by radioimmunoassay (p = 0.06) and serum alpha-fetoprotein concentration (p = 0.07) were independent predictors of survival. The survival rate in the 21 patients in whom HBsAg was not detected was 47%, which was significantly higher than the survival rate of 17% observed in the 94 HBsAg-positive patients (p = 0.006). In patients with fulminant hepatitis B, the absence of HBsAg in serum as detected by radioimmunoassay has an independent, favorable prognostic value.",0
1112,3733001,Noninvasive measurement of the pressure of esophageal varices using an endoscopic gauge: comparison with measurements by variceal puncture in patients undergoing endoscopic sclerotherapy,"Measurements of variceal pressure with a noninvasive endoscopic pressure gauge and by direct variceal puncture were performed in 20 cirrhotic patients with portal hypertension in the course of the first session of therapeutic sclerotherapy following an episode of variceal bleeding. Endoscopic gauge measurements of the pressure of esophageal varices gave similar values (15.5 +/- 2.7 mm Hg) than measurements by variceal puncture (15.4 +/- 2.4 mm Hg; not statistically significant), and there was a highly significant linear correlation between both measurements (r = 0.9, p less than 0.001). Azygos blood flow, that was markedly increased in these patients (852 +/- 399 ml per min), was directly related to variceal pressure (r = 0.73, p less than 0.01). Variceal pressure was significantly lower than portal pressure (18.8 +/- 5.0 mm Hg) (p less than 0.05), indicating that measurements of variceal pressure cannot substitute measurements of portal pressure. The study demonstrates that the noninvasive endoscopic gauge technique allows an accurate estimation of variceal pressure in patients with portal hypertension. This technique may provide additional useful information in the evaluation of portal hypertension as well as on the mechanism of variceal bleeding.",0
1113,3736618,Oral-contraceptive use and the risk of breast cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development,"To investigate the effect of individual formulations of oral contraceptives on the risk of breast cancer in women, we analyzed case-control data from the Cancer and Steroid Hormone Study of the Centers for Disease Control. The cases were 4711 women 20 to 54 years old with newly diagnosed breast cancer who were selected from eight population-based cancer registries. The controls were 4676 women selected by random-digit dialing of the population of each area covered by a registry. As compared with women who had never used oral contraceptives, women who had used them had a relative risk of breast cancer of 1.0. Among women who used only one oral-contraceptive formulation, this estimate of relative risk did not change appreciably according to the formulation used. Neither the type of estrogen nor the type of progestin contained in oral contraceptives used was associated with an increased risk of breast cancer. The duration of oral-contraceptive use and the time since last use did not influence the risk. These findings provide further support for the contention that oral-contraceptive use does not increase the risk of breast cancer in women.",0
1114,3736630,Optic-nerve degeneration in Alzheimer's disease,"Alzheimer's disease is a dementing disorder of unknown cause in which there is degeneration of neuronal subpopulations in the central nervous system. In postmortem studies, we found widespread axonal degeneration in the optic nerves of 8 of 10 patients with Alzheimer's disease. The retinas of four of the patients were also examined histologically, and three had a reduction in the number of ganglion cells and in the thickness of the nerve-fiber layer. There was no retinal neurofibrillary degeneration or amyloid angiopathy, which are typically seen in the brains of patients with Alzheimer's disease. The changes we observed in the patients with Alzheimer's disease were clearly distinguishable from the findings in 10 age-matched controls and represent a sensory-system degeneration that occurs in Alzheimer's disease. Study of the retina in patients with this disease may be helpful diagnostically, and isolation of the affected ganglion cells may facilitate molecular analysis of the disorder.",0
1115,3748073,The impact of suicide in television movies. Evidence of imitation,"Increasing evidence suggest that imitative behavior may have a role in suicide among teenagers. We studied the variation in the numbers of suicides and attempted suicides by teenagers in the greater New York area two weeks before and two weeks after four fictional films were broadcast on television in the fall and winter of 1984-1985. The mean number of attempts in the two-week periods after the broadcasts (22) was significantly greater than the mean number of attempts before the broadcasts (14; P less than 0.05), and a significant excess in completed suicides, when compared with the number predicted, was found after three of the broadcasts (P less than 0.05). We conclude that the results are consistent with the hypothesis that some teenage suicides are imitative and that alternative explanations for the findings, such as increased referrals to hospitals or increased sensitivity to adolescent suicidal behavior on the part of medical examiners or hospital personnel, are unlikely to account for the increase in attempted and completed suicides.",0
1116,3755800,"The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis","Although corticosteroids are effective in the treatment of hypercalciuria and hypercalcemia in chronic sarcoidosis, complications of their long-term use frequently limit therapy. We studied the efficacy of chloroquine in two patients with sarcoidosis who were unable to tolerate the dosage of corticosteroids required to control hypercalciuria and prevent the formation of renal stones. Over a three-year period, each patient received a 6-month and a 10-month course of oral chloroquine phosphate (500 mg per day) while continuing to receive corticosteroids at a fixed dose. Chloroquine therapy was associated with a significant reduction in levels of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and urinary calcium. We observed a direct correlation between serum 1,25-(OH)2D levels and 24-hour urinary calcium excretion, supporting the hypothesis that excessive serum 1,25-(OH)2D is responsible for the hypercalciuria in sarcoidosis. Serum levels of 25-hydroxyvitamin D (25-(OH)D) did not change with therapy, suggesting that chloroquine may act by inhibiting the conversion of 25-(OH)D to 1,25-(OH)2D. Current dosage guidelines and ophthalmologic-surveillance techniques, which allow chloroquine to be administered with little risk of retinopathy, should permit an expanded role for this agent in the treatment of the calcium abnormalities of sarcoidosis.",0
1117,3758936,"Phagocytosis, an unrecognized property of murine endothelial liver cells","Impairment of the phagocytic capacities of Kupffer cells, as is found in Frog Virus 3 hepatitis of mice, allows the endothelial liver cells to take up intravenously inoculated latex particles of 1.0 micron diameter. In vitro experiments with cultivated endothelial cells isolated by collagenase perfusion of the liver and purified by centrifugal elutriation demonstrate that uptake occurs via a typical mechanism of phagocytosis involving pseudopodia. Ingestion of latex is inhibited by incubation of the cells at 4 degrees C and by treatment with cytochalasin B, whereas colchicine has no effect. These results demonstrate that: the Kupffer cells are not the only cells of the hepatic sinusoid capable of phagocytosis; and under conditions where the phagocytosis in Kupffer cells is impaired, the endothelial cells may participate in the clearance of large particles from the blood.",0
1118,3758947,Simultaneous passive and active immunization against hepatitis B: noninterference of hepatitis B immune globulin with the anti-HBs response to reduced doses of heat-inactivated hepatitis B vaccine,"The effect of simultaneous administration of hepatitis B immune globulin on the antibody response to a low dose of heat-inactivated hepatitis B vaccine was investigated in 175 health care workers. Subjects were divided into four groups: Groups I and II received 3 monthly injections of a reduced dose (0.6 microgram) of a heat-inactivated hepatitis B vaccine (the usual dose being 3 micrograms) along with 500 IU of hepatitis B immune globulin simultaneously with the first injection of vaccine; Groups III and IV received the vaccine only. In addition, Groups I and III received a final booster injection with 0.6 microgram of the vaccine 8 months after the initial injection. Anti-HBs passively acquired from hepatitis B immune globulin did not interfere with the development of an active antibody response to the vaccine: the anti-HBs conversion rates were similar in persons treated with the combined regimen (89%) as in those who received the vaccine only (91%). At 3 and 5 months after the first injection, however, anti-HBs titers in the recipients of vaccine alone were slightly but statistically significantly higher than those of persons who received both hepatitis B immune globulin and vaccine; but at 8 months, this difference was no longer statistically significant. After a booster inoculation at 8 months, the geometric mean titer of anti-HBs increased 7- to 8-fold in antibody-positive vaccinees, regardless of whether hepatitis B immune globulin had been given earlier. Moreover, 6 of 13 nonresponders to the initial three vaccine injections developed anti-HBs after the booster inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1119,3758949,The in vitro production of antibodies to mitochondrial antigens by peripheral blood mononuclear cells from patients with primary biliary cirrhosis,"Peripheral blood mononuclear cells from 7 patients with primary biliary cirrhosis and 7 healthy control subjects were studied for their ability to produce antibodies to mitochondrial antigens in vitro. Peripheral blood mononuclear cells were collected by lymphapheresis and cultured with or without pokeweed mitogen for 10 days. The culture supernatants were then tested for antibodies to mitochondrial antigens by both immunofluorescence microscopy and a microtiter ELISA. Peripheral blood mononuclear cells from 5 of 7 patients with primary biliary cirrhosis but from none of the healthy controls produced antibodies to mitochondrial antigens spontaneously (without pokeweed mitogen stimulation). In contrast, peripheral blood mononuclear cells from 6 of 7 patients with primary biliary cirrhosis and from 6 of 7 control subjects synthesized detectable levels of antibodies to mitochondrial antigens after stimulation with pokeweed mitogen. In general, peripheral blood mononuclear cells from the primary biliary cirrhosis patients produced higher titers of antibodies to mitochondrial antigens in culture than cells from healthy controls. Furthermore, the antibodies to mitochondrial antigens reactivity produced by peripheral blood mononuclear cells of primary biliary cirrhosis patients exhibited a specificity for the M2 mitochondrial antigen which is present on the inner membrane of mitochondrial cristae and which is closely associated with a mitochondrial ATPase activity. In contrast, the antibodies to mitochondrial antigens reactivity produced by peripheral blood mononuclear cells of healthy controls appeared to be directed at a broader range of mitochondrial antigens. These findings indicate that, inpatients with primary biliary cirrhosis, there is a marked expansion of B lymphocyte clones that produce an antibody to a specific mitochondrial antigen.",0
1120,3762619,Relation of glucose tolerance to complications of pregnancy in nondiabetic women,"An increase in fetal and maternal complications has been documented in cases of gestational diabetes, but the glucose levels that predict an increased risk have not been clearly defined. We evaluated the frequency of several neonatal complications (macrosomia, congenital anomalies, perinatal mortality, and prematurity) and maternal complications (toxemia, cesarean section, or both) in relation to glucose tolerance in 249 women in the third trimester of pregnancy. None of the women had previous evidence of diabetes, and all had normal results on an oral glucose-tolerance test, according to accepted criteria. On the basis of their two-hour plasma glucose levels, women were divided into three groups: A (glucose less than 100 mg per deciliter), B (glucose 100 to 119 mg per deciliter), and C (glucose 120 to 164 mg per deciliter). The higher two-hour plasma glucose levels were associated with a significant increase in the incidence of macrosomia (9.9, 15.5, and 27.5 percent in Groups A, B, and C, respectively), congenital abnormalities (0.7, 3.5, and 5.0 percent), and toxemia, cesarean section, or both (19.9, 25.9, and 40.0 percent). A significant correlation between the infant's weight and the mother's two-hour plasma glucose level was also observed. These data indicate that even limited degrees of maternal hyperglycemia, which are currently considered to be within the normal range, may affect the outcome of pregnancy.",0
1121,3773954,"Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide","""In the hope of reducing the adverse health consequences of smoking, physicians frequently advise their patients who cannot quit to smoke fewer cigarettes. Habitual smokers may compensate for the reduced number of cigarettes, however, by taking in more smoke per cigarette. We measured the intake of tar (estimated as mutagenic activity of the urine), nicotine, and carbon monoxide during short-term cigarette restriction. With a reduction from an average of 37 cigarettes to an average of 5 cigarettes per day, the intake of tobacco toxins per cigarette increased roughly threefold and daily exposure to tar and carbon monoxide declined only 50 percent. We conclude that smoking fewer cigarettes may reduce exposure to toxins and related adverse health consequences. However, consistent with a tendency to maintain intake of nicotine, the magnitude of the benefit is much less than expected. Whether """"oversmoking"""" persists during long-term restriction of cigarettes requires further investigation.""",0
1122,3773965,The prevalence of cancer. Estimates based on the Connecticut Tumor Registry,"Cancer incidence and mortality do not fully reflect the effect of cancer. To estimate the number of persons alive who have a history of cancer, we derived prevalence rates based on data from the Connecticut Tumor Registry. We did not attempt to distinguish between people who had been cured of cancer and those who still had the disease. In 1982 the age-adjusted prevalence rates of cancer among males and females were 1,789 and 2,222, respectively, per 100,000. Age-specific prevalence rates were highest among the elderly; 12 percent of men and 11 percent of women over 70 had previously been given a diagnosis of cancer. Breast cancer in females and prostate cancer in males were the two most prevalent malignant diseases. We estimate that about 5 million persons alive in the United States today have at one time received a diagnosis of cancer.",0
1123,3785295,Acute cardiac events temporally related to cocaine abuse,"""The increasingly widespread use of cocaine in the United States has been accompanied and perhaps exacerbated by the misconception that the drug is not associated with serious medical complications. In particular, the potential for cocaine to precipitate life-threatening cardiac events needs to be reemphasized. We report the clinical and pathological findings in seven people in whom nonintravenous """"recreational"""" use of cocaine was temporally related to acute myocardial infarction, ventricular tachycardia and fibrillation, myocarditis, sudden death, or a combination of these events. We also review data on 19 previously reported cases of cocaine-related cardiovascular disorders. Analysis of all 26 patients indicated the following findings: the cardiac consequences of cocaine abuse are not unique to parenteral use of the drug, since nearly all the patients took the drug intranasally; underlying heart disease is not a prerequisite for cocaine-related cardiac disorders; seizure activity, a well-documented noncardiac complication of cocaine abuse, is neither a prerequisite for, nor an accompanying feature of, cardiac toxicity of cocaine; and the cardiac consequences of cocaine are not limited to massive doses of the drug. Although the pathogenesis of cardiac toxicity of cocaine remains incompletely defined, available circumstantial evidence suggests that cocaine has medical consequences that are equal in importance to its well-documented psychosocial consequences.""",0
1124,3804202,Effects of adenine arabinoside on serum and intrahepatic replicative forms of duck hepatitis B virus in chronic infection,"Adenine arabinoside is an antiviral agent which has been used in a number of clinical studies for the treatment of chronic infections with hepatitis B virus. In order to better understand its effects and mode of action, we treated ducks chronically infected with duck hepatitis B virus with a 2-week course and monitored the effects of the drug on viral replication by studying duck hepatitis B virus DNA in liver and serum using molecular biological techniques. We found the drug to be effective in ducks only at much higher doses than those used in humans. At high doses, adenine arabinoside had a dose-related inhibitory effect on viral replication during treatment, but there was a rapid return toward baseline values soon after the cessation of treatment. The supercoiled form of viral DNA was found to be most resistant to adenine arabinoside therapy, and the drug had a disproportionate inhibitory effect on viral plus (noncoding) strand synthesis. We conclude that adenine arabinoside likely exerts its effect in hepadna virus infections predominantly through inhibition of viral DNA polymerase. On the basis of our current study and previous trials in hepatitis B virus-infected patients, we predict that adenine arabinoside will not efficiently eliminate viral replication in chronic hepadna virus infection, when used as the sole therapeutic modality. Adenine arabinoside may have a role to play as an adjunct to immunomodulation or interferon therapy in chronic hepatitis B virus infection in man.",0
1125,3804206,The effect of changes in the fluid state of rat liver plasma membrane on the transport of taurocholate,"The fluidity of basolateral and canalicular rat liver plasma membranes was compared with respect to their response to the membrane perturbants ethanol and calcium. The relation between membrane fluidity and taurocholate transport, a liver plasma membrane function mediated by carrier proteins, was also examined. Membrane fluidity was measured by fluorescence polarization using 1,6-diphenyl-1,3,5-hexatriene as a probe. Uptake of [3H]taurocholate into basolateral rat liver plasma membrane and canalicular rat liver plasma membrane vesicles was measured by a rapid Millipore filtration technique. Anisotropy values were found to be significantly lower for the basolateral rat liver plasma membrane (0.2287 +/- 0.0014) than for the canalicular rat liver plasma membrane (0.2612 +/- 0.0012), indicating that basolateral rat liver plasma membranes are more fluid than canalicular rat liver plasma membranes. Ethanol produced a concentration-dependent effect on lipid fluidity and inhibition of taurocholate uptake, in both membrane preparations. Pretreatment of the membrane with calcium increased the rigidity of both membrane preparations. However, the change in the anisotropy with calcium was only slight in the more rigid canalicular rat liver plasma membrane, while the change in anisotropy was greater and associated with a decrease in taurocholate uptake in the basolateral rat liver plasma membrane. Both the effects of ethanol and calcium were more pronounced in basolateral rat liver plasma membrane than in canalicular rat liver plasma membrane. These results indicate that the fluid state of the hydrophobic bilayer of liver plasma membrane lipids play an important role in regulating bile acid transport in both sinusoidal and canalicular domains.",0
1126,3804213,Development of molecular hybridization technology to evaluate albumin and procollagen mRNA content in baboons and man,"We have developed the methodology for evaluating the effects of pathophysiological conditions on the molecular mechanisms of hepatic protein synthesis and fibrogenesis in baboons and man. Total RNA was extracted from percutaneous liver biopsies of five baboons who were chronically fed an ethanol-rich liquid diet, their pair-fed controls and from humans with a variety of liver abnormalities. Chronic alcohol administration in baboons with liver fibrosis and normal serum albumin levels increased in vitro protein synthesis as measured by [35S]methionine incorporation, albumin mRNA content and Type I procollagen mRNA content. There was no difference in the beta-actin (a constitutive protein) mRNA content. In humans, serum albumin levels correlated with albumin mRNA content as indicated by the intensity of dot blot hybridization and Type I procollagen mRNA levels correlated with the activity of liver fibrosis. The use of RNA-DNA hybridization to investigate procollagen mRNA from human biopsies appears to be a valuable tool for evaluating the potential for collagen synthesis and the future course of liver disease. Besides the use of RNA-DNA hybridization, we describe other methodologies which are useful in delineating the levels of gene expression responsible for hepatic mRNA regulation in normal liver and disease states in man. The use of molecular techniques to evaluate human liver disease provides an opportunity to develop clinically relevant information while at the same time offering the additional advantage of providing fundamental knowledge about fibrogenesis.",0
1127,3807962,Delineation of the extent of coronary atherosclerosis by high-frequency epicardial echocardiography,"Postmortem studies suggest that coronary angiography does not always accurately delineate the extent of coronary-artery disease. We examined this problem in living human hearts by performing high-frequency epicardial echocardiography at the time of cardiac surgery. The ratio of the diameter of the lumen of the coronary artery to the thickness of its wall was used to quantify the severity of coronary lesions. In 11 patients with no angiographic evidence of coronary disease anywhere in the coronary tree, the mean (+/- SEM) ratio was 5.9 +/- 0.3. In 21 patients with angiographic disease at the site evaluated by echocardiography, the mean ratio was lower (2.3 +/- 0.2, P less than 0.05), reflecting encroachment into the arterial lumen by atherosclerotic plaque. In 15 patients with arterial segments that were angiographically normal but with arterial stenoses elsewhere in the coronary tree, the mean ratio was 4.1 +/- 0.3, with marked overlap with the values in the patients who had angiographic disease at the site of the echocardiographic evaluation. These results demonstrate, in living human hearts, that diffuse coronary atherosclerosis is often present when coronary angiography reveals only discrete stenoses. This finding suggests that coronary angiography may underestimate the severity and extent of coronary disease.",0
1128,3807975,Comparisons of national cesarean-section rates,"Our study of cesarean rates in 19 industrialized countries of Europe, North America, and the Pacific revealed sharp differences in rates, ranging from a low of 5 (Czechoslovakia) to a high of 18 (United States) per 100 hospital deliveries in 1981. Differences in cesarean rates according to maternal age, parity, and complications of pregnancy and childbirth reflected national differences in obstetrical practice. For example, the percentage of mothers who had a vaginal birth after a previous cesarean section was only 5 in the United States as compared with 43 in Norway, where the cesarean rate was half that in the United States. Despite the wide range of cesarean rates, almost all the countries studied have had consistent increases over the past decade, and the annual rate of increase for all countries appears to be converging. The steady pace of increase in developed countries, combined with comparable or even higher rates of cesarean delivery now being reported in less developed countries, underscores the need for the medical community to consider the appropriateness of this continued rise in the number of cesarean deliveries.",0
1129,3807992,Factors prognostic of unprovoked seizures after febrile convulsions,"We evaluated the risk of unprovoked seizures after febrile convulsions and the factors prognostic of them in a cohort of 687 children who had an initial febrile seizure while residing in Rochester, Minnesota. Overall, children with febrile convulsions had a fivefold excess of unprovoked seizures, and the risk until the age of 25 was 7 percent. The risk ranged from 2.4 percent among children with simple febrile convulsions to 6 to 8 percent among children with a single complex feature--i.e., focal or prolonged seizures or repeated episodes of febrile convulsions with the same illness. For children with any two of the complex features, the risk was 17 to 22 percent, and for those with all three features, 49 percent. The occurrence of subsequent partial unprovoked seizures was strongly associated with all three of the complex features, whereas the occurrence of subsequent unprovoked seizures of generalized onset was associated with the number of febrile convulsions and a family history of unprovoked seizures. These results are consistent with the view that the increased risk of generalized-onset unprovoked seizures reflects a predisposition to both simple febrile convulsions and generalized-onset unprovoked seizures. The association between complex febrile convulsions and partial seizures, on the other hand, may reflect either a causal association or the presence of preexisting brain disease that is responsible for both the complex febrile seizures and later partial seizures.",0
1130,3821810,Hypocalciuria in preeclampsia,"We studied 40 women in the third trimester of pregnancy to determine whether alterations in serum calcium levels or in urinary calcium excretion would distinguish patients with preeclampsia from normal pregnant women or women with other forms of gestational hypertension. Our population included 10 normal pregnant women, 5 pregnant women with transient hypertension, 6 with chronic hypertension, 7 with chronic hypertension and superimposed preeclampsia, and 12 with preeclampsia. The serum levels of ionized calcium, phosphate, and 1,25-dihydroxyvitamin D were not different among the various groups. In contrast, the mean (+/- SD) 24-hour urinary calcium excretion in the patients with preeclampsia or hypertension with superimposed preeclampsia was significantly lower (42 +/- 29 and 78 +/- 49 mg) than that in normal pregnant women (313 +/- 140 mg per 24 hours), women with transient hypertension (248 +/- 139 mg per 24 hours), or women with chronic hypertension (223 +/- 41 mg per 24 hours) (P less than 0.0001). The hypocalciuria in the women with preeclampsia was associated with a decreased fractional excretion of calcium. Although the mean creatinine clearance was reduced in the women with preeclampsia, the range of values overlapped with those in the other groups. In contrast, we observed little or no overlap with respect to calcium excretion. We conclude that preeclampsia is associated with hypocalciuria due to increased tubular reabsorption of calcium. Measurement of calcium excretion may be useful in distinguishing preeclampsia from other forms of gestational hypertension.",0
1131,3873009,Fecal blood levels in health and disease. A study using HemoQuant,"We tested HemoQuant, a quantitative assay of fecal blood based on the fluorescence of heme-derived porphyrin, in 106 healthy volunteers, 170 patients with gastrointestinal symptoms but with normal diagnostic studies, 44 patients with gastrointestinal cancer, 75 patients with benign polyps, and 374 patients with a variety of other benign gastrointestinal lesions, including ulcers and erosions. In 98 per cent of the healthy volunteers, fecal hemoglobin concentrations were less than 2 mg per gram of stool. Levels were similarly low in stools from patients with symptoms and normal studies and in patients with relatively minor benign lesions. Within these groups, levels were slightly higher in those who had ingested red meat or aspirin. The fecal hemoglobin concentration was higher in patients with gastrointestinal cancer than in any other group, and 97 per cent of those with colorectal cancer had levels above 2 mg per gram. The sensitivity of HemoQuant was significantly greater than that of the guaiac test Hemoccult, particularly when heme was degraded or stools were dry. Intestinal degradation of heme to porphyrin can be measured separately by HemoQuant, and was greater when bleeding was from proximal lesions rather than distal ones. We conclude that HemoQuant is a more sensitive measure of gastrointestinal bleeding than Hemoccult, and that its capacity to measure degraded heme may be useful in indicating the anatomic site of bleeding.",0
1132,3880598,The contribution of low birth weight to infant mortality and childhood morbidity,"The low-birth-weight infant remains at much higher risk of mortality than the infant with normal weight at birth. In the neonatal period, when most infant deaths occur, the proportion of low-birth-weight infants, especially those with very low weight, is the major determinant of the magnitude of the mortality rates. Furthermore, differences in low-birth-weight rates account for the higher neonatal mortality rates observed in some groups, particularly those characterized by socioeconomic disadvantages. Much of the recent decline in neonatal mortality can be attributed to increased survival among low-birth-weight infants, apparently as a result of hospital-based services. The application of these services is currently considered cost-effective, although whether this will continue to be true in the future is unclear because of the increased survival of very tiny infants. Although low-birth-weight infants remain at increased risk of both postneonatal mortality and morbidity in infancy and early childhood, the risk is substantially smaller than that of neonatal death. In addition, these adverse later outcomes have not offset the gains achieved in the neonatal period. Nonetheless, the increased survival of high-risk infants raises concern about their future requirements for special medical and educational services and about the stress on their families. Despite increased access to antenatal services, only moderate declines in the proportion of low-birth-weight infants has been observed, and almost no change has occurred in the proportion of those with very low weight at birth. In addition, in many areas of the country the birth-weight-specific neonatal mortality rates are similar for groups at high and low risk of neonatal death. In view of these findings, continuation of the current decline in neonatal mortality and reduction of the mortality differentials between high- and low-risk groups require the identification and more effective implementation of strategies for the prevention of low-weight births.",0
1133,3880867,High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison,"It has been claimed that high-dose vitamin C is beneficial in the treatment of patients with advanced cancer, especially patients who have had no prior chemotherapy. In a double-blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement. On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy.",0
1134,3881672,Increased expression of an adhesion-promoting surface glycoprotein in the granulocytopenia of hemodialysis,"To identify the mechanisms accounting for hemodialysis-induced granulocytopenia, we undertook quantitative kinetic studies of a granulocyte-adhesion-promoting surface glycoprotein (Mo1). In eight patients undergoing maintenance hemodialysis, there was a fivefold increase in the mean cell-surface expression of Mo1 within 15 minutes after the start of dialysis with a new cuprophane membrane. The peak increase in surface Mo1 coincided with the maximal drop in neutrophil count and with the peak rise in the plasma levels of the complement-activation products C5a desArg and C3a desArg. During dialysis on a membrane being reused for the fifth time, no significant complement activation, no increase in Mo1 expression, and no change in neutrophil count were seen. C5a desArg (but not C3a desArg) induced a comparable increase in Mo1 expression on normal granulocytes in vitro at concentrations similar to those measured in vivo. Chemotactic peptide-induced granulocyte aggregation (a reflection of increased cell-to-cell adhesiveness) was specifically blocked by mouse monoclonal antibodies to Mo1 in vitro. These data suggest that the increased expression of Mo1 on granulocytes in vivo is in part mediated by C5a (and C5a desArg). The quantitative increase in granulocyte-surface Mo1 may provide a mechanism for initiating leukoaggregation, sequestration of granulocytes, and neutropenia during hemodialysis.",0
1135,3897864,Clinical prediction rules. Applications and methodological standards,"The objective of clinical prediction rules is to reduce the uncertainty inherent in medical practice by defining how to use clinical findings to make predictions. Clinical prediction rules are derived from systematic clinical observations. They can help physicians identify patients who require diagnostic tests, treatment, or hospitalization. Before adopting a prediction rule, clinicians must evaluate its applicability to their patients. We describe methodological standards that can be used to decide whether a prediction rule is suitable for adoption in a clinician's practice. We applied these standards to 33 reports of prediction rules; 42 per cent of the reports contained an adequate description of the prediction rules, the patients, and the clinical setting. The misclassification rate of the rule was measured in only 34 per cent of reports, and the effects of the rule on patient care were described in only 6 per cent of reports. If the objectives of clinical prediction rules are to be fully achieved, authors and readers need to pay close attention to basic principles of study design.",0
1136,3917302,Creutzfeldt-Jakob disease prion proteins in human brains,"Creutzfeldt-Jakob disease is caused by a slow infectious pathogen, or prion. We found that purified fractions from the brains of two patients with Creutzfeldt-Jakob disease contained protease-resistant proteins ranging in apparent molecular weight from 10,000 to 50,000. These proteins reacted with antibodies raised against the scrapie prion protein PrP 27-30. Rod-shaped particles were found in the brain tissue of the patients that were similar to those isolated from rodents with either scrapie or experimental Creutzfeldt-Jakob disease. After being stained with Congo red dye, the protein polymers from patients with Creutzfeldt-Jakob disease exhibited green birefringence when examined under polarized light. Our findings suggest that the amyloid plaques found in the brains of patients with Creutzfeldt-Jakob disease may be composed of paracrystalline arrays of prions similar to those in prion diseases in laboratory animals.",0
1137,3920134,Pharmacokinetic-hemodynamic interactions between vasopressin and nitroglycerin: comparison between intravenous and cutaneous routes of nitrate delivery,"Addition of nitroglycerin (NTG) improves the hemodynamic response to vasopressin and may thus be useful in the treatment of gastrointestinal hemorrhage. We studied in the rat the influence of vasopressin on the disposition of a constant intravenous infusion of NTG and the cutaneous absorption of NTG ointment. The effect of NTG on the pharmacokinetics of vasopressin was also determined. Animals were divided into four groups: control, NTG, vasopressin and vasopressin + NTG. Infusions (or ointments) were maintained for 70 min; cardiac output and regional blood flows were determined with the microsphere technique. Both intravenous and cutaneous NTG resulted in similar hemodynamic responses. Vasopressin caused generalized vasoconstriction, while the addition of NTG reversed the deleterious systemic hemodynamic effects of vasopressin. Addition of vasopressin to NTG did not alter NTG systemic clearance nor did NTG affect vasopressin clearance. Of note, the systemic clearance of NTG was directly correlated with the cardiac output (r = 0.804), supporting a model of NTG distribution where blood vessels and/or extrahepatic tissues are the site of elimination of the drug. The marked reduction in skin blood flow by vasopressin did not decrease the steady-state plasma concentration of NTG nor the estimated cutaneous absorption rate of NTG ointment, indicating that cutaneous blood flow is not an important determinant in the absorption of NTG ointment. The skin is an appropriate route of delivery for NTG when combined with vasopressin.",0
1138,3923351,Spontaneous alteration of idiotype in a monoclonal B-cell lymphoma. Escape from detection by anti-idiotype,"The surface immunoglobulin of B-cell neoplasms provides a specific point of attack for potential antibody therapy. The capacity of anti-idiotype antibody to home to the target neoplasm requires that the idiotype be unique and that it be expressed by every cell in the neoplastic clone. We describe the evolution of an altered idiotype in a follicular lymphoma that resulted in escape from laboratory detection by monoclonal anti-idiotype antibody. This was not due to the emergence of a second (biclonal) lymphoma, since all the neoplastic cells were otherwise identical both phenotypically and genotypically, as determined by flow cytometry and genomic DNA (Southern blot) hybridization, respectively. All cells expressed the same B-cell immunotype and bore a constant amount of IgMk. The demonstration of a single configuration of immunoglobulin-gene DNA confirmed monoclonality and established that the change in idiotype was not a result of new gene rearrangements but was more likely due to somatic mutation of the variable region--a process presumed to occur naturally in B cells. These data demonstrate the lability of idiotype expression and define a mechanism by which B-cell neoplasms may become unresponsive to anti-idiotype therapy.",0
1139,3925334,Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification,"Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.",0
1140,3925337,Is the teaching hospital an endangered species?,"""The nonmunicipal teaching hospital faces some special challenges in adapting to the increasingly austere fiscal environment in which all hospitals must operate. However, except in a few instances, such developments as constraints on Medicaid expenditures do not appear to be notably more serious for teaching hospitals than for their community counterparts. The teaching hospitals most closely connected with medical schools provide more charity care and carry more bad debt than community hospitals. But other teaching hospitals have about the same burden as their community counterparts. The most serious problem facing teaching hospitals results from new bases of prospective reimbursement, some of which do not adequately compensate hospitals that treat more """"difficult"""" cases--that is, more expensive cases. Competitive providers of health care such as health maintenance organizations promise to reduce admissions at all types of hospitals; whether this reduction will selectively affect teaching hospitals is not yet clear. By contrast, the fiscal state of municipal teaching hospitals is far more precarious than that of their nonmunicipal counterparts. The ability of these institutions to maintain high-quality patient care and teaching programs is in considerable jeopardy.""",0
1141,3940313,Teaching clinical medicine in the ambulatory setting. An idea whose time may have finally come,"""A resurgence of general interest in teaching clinical medicine in ambulatory-care settings has occurred for several reasons, including changes in the case mix in teaching hospitals, the new responsibilities of house officers and attending physicians brought about by the current payment systems for health care, the increased expectations of patients that medical care will be """"personal,"""" the progressive limitations imposed on the education of medical students by the shorter lengths of stay sought by hospitals under the diagnosis-related-groups system of payment, and the growing need for well-trained primary care physicians that has resulted from the increase in medical care organizations. In this paper, I review earlier attempts to emphasize ambulatory care, to identify the pitfalls that new efforts in this direction should avoid. I also compare inpatient and ambulatory-care teaching to provide a basis for understanding the educational goals that can be achieved more easily in each setting. In addition, I suggest major changes in the flow and use of clinical-practice funds and hospital payments so that they can become possible sources of the financing and organization of an expanded effort to teach clinical medicine in ambulatory-care settings.""",0
1142,3941694,Increased 24-hour energy expenditure in cigarette smokers,"We studied the effect of smoking on energy expenditure in eight healthy cigarette smokers who spent 24 hours in a metabolic chamber on two occasions, once without smoking and once while smoking 24 cigarettes per day. Diet and physical exercise (30 minutes of treadmill walking) were standardized on both occasions. Physical activity in the chamber was measured by use of a radar system. Smoking caused an increase in total 24-hour energy expenditure (from a mean value [+/- SEM] of 2230 +/- 115 to 2445 +/- 120 kcal per 24 hours; P less than 0.001), although no changes were observed in physical activity or mean basal metabolic rate (1545 +/- 80 vs. 1570 +/- 70 kcal per 24 hours). During the smoking period, the mean diurnal urinary excretion of norepinephrine (+/- SEM) increased from 1.25 +/- 0.14 to 1.82 +/- 0.28 micrograms per hour (P less than 0.025), and mean nocturnal excretion increased from 0.73 +/- 0.07 to 0.91 +/- 0.08 micrograms per hour (P less than 0.001). These short-term observations demonstrate that cigarette smoking increases 24-hour energy expenditure by approximately 10 percent, and that this effect may be mediated in part by the sympathetic nervous system. The findings also indicate that energy expenditure can be expected to decrease when people stop smoking, thereby favoring the gain in body weight that often accompanies the cessation of smoking.",0
1143,3945247,Delayed effects of the military draft on mortality. A randomized natural experiment,"To study the effect of military service during the Vietnam era on subsequent mortality, we analyzed a randomized natural experiment, the military draft lottery of 1970 to 1972. Between 1974 and 1983, there were 14,145 deaths among California and Pennsylvania men whose dates of birth were in the years for which the draft lottery was held. The group of men with birth dates that made them eligible for the draft had a higher mortality rate than the group with birth dates that exempted them from the draft: suicide was increased by 13 percent (P = 0.005 by two-tailed test), death from motor-vehicle accidents by 8 percent (P = 0.03), and total mortality by 4 percent (P = 0.03). Only 26 percent of the men who were eligible for the draft actually entered the military. If military service (rather than draft eligibility) was the actual risk factor, suicide and death from motor-vehicle accidents would have to have been increased by 86 percent and 53 percent among men who served in the military, to produce the increased risk that we observed among all draft-eligible men. A separate analysis that compared the causes of death in veterans and nonveterans yielded similar estimates: veterans were 65 percent and 49 percent more likely to die from suicide and motor-vehicle accidents, respectively. We conclude that the most likely explanation for these findings is that military service during the Vietnam War caused an increase in subsequent deaths from suicide and motor-vehicle accidents.",0
1144,3945267,Relation between complications of type I diabetes mellitus and collagen-linked fluorescence,"""Nonenzymatically glycosylated proteins gradually form fluorescent cross-linked protein adducts--a process termed """"browning."""" The rate of this reaction increases with the glucose concentration. Assaying for the presence of browning products in long-lived proteins should therefore provide information on long-term metabolic control. We measured collagen-linked fluorescence typical for nonenzymatic browning in skin-biopsy specimens from 41 subjects with longstanding Type I diabetes and from 25 controls. Fluorescence correlated with age and (weakly) with the duration of diabetes. Mean age-adjusted fluorescence values were twice as high in diabetic subjects as in control subjects (P less than 0.0001) and increased with the severity of retinopathy, nephropathy, and arterial and joint stiffness. The correlation was significant for retinopathy (r = 0.42; P less than 0.01), arterial stiffness (r = 0.41; P less than 0.01), joint stiffness (r = 0.34; P less than 0.05), and the sum of all complications (r = 0.47; P less than 0.01). Fluorescence also correlated with systolic (r = 0.42; P less than 0.01) and diastolic (r = 0.36; P less than 0.05) blood pressures. If one can assume that the fluorescence results from a browning product of glucose, our data suggest that there is an overall correlation between the severity of diabetic complications and cumulative glycemia over many years.""",0
1145,3945268,Pregnancy during residency,"""To identify possible barriers to women physicians who wish to combine parenting with medical careers, we studied 56 of 64 pregnancies from the past 10 years in 63 of 66 Harvard-affiliated residency programs. Pregnancies during residency were common (one in eight married women in 1983) and were usually planned (77 percent). Most institutions were unprepared for pregnancies among members of the house staff; four fifths of the programs had no maternity-leave policy. No one quit a residency program because of pregnancy, and pregnancy rarely affected achievement of board certification. Whether the pregnant women found pregnancy during residency a """"pleasant"""" experience was determined largely by whether the program director was supportive, whether the issue of pregnancy was openly discussed within the program, and whether the woman was permitted to return to work on a part-time basis for the first weeks after maternity leave. We conclude that pregnancy within residency programs should be expected and planned for and that if proper arrangements are made, it need not be a major problem for either the training program or the pregnant resident.""",0
1146,3945293,Transfers to a public hospital. A prospective study of 467 patients,"In recent years there has been a dramatic increase in the number of patients transferred to public hospitals in the United States. We prospectively studied 467 medical and surgical patients who were transferred from the emergency departments of other hospitals in the Chicago area to Cook County Hospital and subsequently admitted. Eighty-nine percent of the transferred patients were black or Hispanic, and 81 percent were unemployed. Most (87 percent) were transferred because they lacked adequate medical insurance. Only 6 percent of the patients had given written informed consent for transfer. Twenty-two percent required admission to an intensive care unit, usually within 24 hours of arrival. Twenty-four percent were in an unstable clinical condition at the transferring hospital. The proportion of transferred medical-service patients who died was 9.4 percent, which was significantly higher than the proportion of medical-service patients who were not transferred (3.8 percent, P less than 0.01). There was no significant difference in the proportion of deaths on the surgical service between patients who were transferred and those who were not (1.5 vs. 2.4 percent). We conclude that patients are transferred to public hospitals predominantly for economic reasons, in spite of the fact that many of them are in an unstable condition at the time of transfer.",0
1147,3957237,Pericanalicular location of hepatocyte lysosomes and effects of fasting: a morphometric analysis,"Lysosomes constitute a small proportion of hepatocyte volume, but they play a key degradative role, particularly during catabolic states such as nutritional deprivation. Our preliminary observations in hepatocytes suggested that fasting may alter the distribution of lysosomes, which are thought to congregate about the biliary canaliculus. The current study aimed to provide, in both fed and fasted rats, a quantitative morphometric analysis of lysosomes in the immediate pericanalicular and successively more distant regions. We selected three regions of radius 0 to 2 (region 1), 2 to 4 (region 2) and 4 to 6 micron (region 3) about the bile canaliculus and compared lysosomal numerical and volume densities. In fed rats, numerical and volume densities of both primary and secondary lysosomes were 5 to 10 times greater in region 1 than in region 3. After a 72-hr fast, this gradient was lost due largely to a reduced number of primary and secondary lysosomes in region 1. Our calculations suggest that during fasting, lysosomes are redistributed away from the bile canaliculus towards the more distant cytoplasm rather than being lost from the cell, for example, into bile. The number of overt macroautophagic vacuoles was not altered by fasting. We estimate that, in fed rats, there are approximately 270 lysosomes per hepatocyte, and that 43% of lysosomes are contained in the immediate pericanalicular region 1, which comprises only 7 to 8% of the cytoplasmic volume. The reason for this pericanalicular concentration of lysosomes and the mechanism of the redistribution with fasting remain to be determined.",0
1148,3960080,Do seizures in children cause intellectual deterioration?,"We studied whether the occurrence of seizures in childhood affected intellectual performance. We compared the full-scale IQs at seven years of age of children who had experienced one or more nonfebrile seizures with the IQs of their seizure-free siblings who were tested at the same age in a large longitudinal study. Among 98 children with seizures, the mean score on IQ tests at seven years was not significantly different from the mean score of their siblings. Mental retardation was more common among the children with seizures, but the excess was accounted for by children who had neurologic abnormalities before the first seizure. We also examined the IQ before and after the onset of seizures in 62 children whose first seizure occurred in the interval between psychometric examinations given at four and seven years of age. The IQ at seven years in the children with seizures did not differ significantly from that in controls matched for IQ (as determined at the four-year assessment), sex, race, and socioeconomic status. Thus, in both the sibling-control comparison and the comparisons made between controls and subjects before and after the onset of seizures, the occurrence of nonfebrile seizures was not associated with a significant change in full-scale IQ.",0
1149,3960081,The use of ambulatory testing in prepaid and fee-for-service group practices. Relation to perceived profitability,"To examine the influence of method of payment on ambulatory testing by internists, we compared the rate at which patients with uncomplicated hypertension were tested by 10 doctors practicing in large fee-for-service groups with that by 17 doctors in large prepaid groups. We examined the use of individual tests and asked the doctors in the fee-for-service groups what they believed about the profitability and costs of tests. After correcting for the patient's age, sex, duration of disease, and severity of disease as measured by pretreatment blood pressure, and for the doctor's year of medical school graduation, we found that 50 percent more electrocardiograms were obtained among patients in fee-for-service practices (0.69 per patient per year vs. 0.45, P = 0.006), and 40 percent more chest radiographs (0.49 vs. 0.35, P = 0.11). Fee-for-service doctors believed that both tests were associated with high profit and costs. These results suggest that the use of certain high-profit, high-cost tests is higher in large fee-for-service groups than in large prepaid groups. Although the generalizability of conclusions based on this limited study must be considered tentative, the findings suggest that it may be appropriate to consider changing the payments for tests as part of a more general reform of the fee schedules.",0
1150,3967853,"Quantitative analysis of major, minor and trace elements in gallbladder bile of patients with and without gallstones","The concentration of 25 major, minor and trace elements in human bile was determined by inductively coupled plasma atomic emission spectrometry. Gallbladder bile was obtained during surgery from patients with cholesterol gallstones, pigment stones and with no biliary tract abnormalities (controls). Comparison of the concentration of elements (microgram per gram of solids) did not reveal any significant differences among the three patient groups. The in vitro nucleation time was not related to the concentration of any element measured.",0
1151,3969086,Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis,"To study pancreatic protein and water secretion in 28 patients with cystic fibrosis and 21 controls matched for pancreatic acinar function as defined by trypsin secretion, we used a quantitative-marker perfusion technique and continuous intravenous secretin-pancreozymin stimulation. Regardless of the level of pancreatic acinar function, secretions from the patients contained significantly higher concentrations of protein than those from the controls. Total protein output and albumin:protein ratios were not increased in secretions from the patients, but their fluid secretion was significantly decreased at any level of pancreatic function. A significant linear correlation was found between protein and volume secretion in the patients (r = 0.86, P less than 0.001), most of whom had a fluid output of less than 4.2 ml per kilogram of body weight per hour. No such relation was found in the control subjects, whose flow was always above 4.2 ml per kilogram per hour. We conclude that fluid secretion in patients with cystic fibrosis may be a rate-limiting factor in protein output and that a limited flow of hyperconcentrated protein secretions may predispose to protein precipitation and ductal obstruction in the pancreas.",0
1152,3974651,The long-term pulmonary sequelae of prematurity: the role of familial airway hyperreactivity and the respiratory distress syndrome,"Respiratory distress syndrome of the newborn, prematurity, and familial airway hyperreactivity may contribute to long-term pulmonary sequelae. We assessed the role of each by testing pulmonary function and airway reactivity in 11 prematurely born children who survived the respiratory distress syndrome and in 11 prematurely born children who had no neonatal respiratory disease, each of whom was paired with a sibling born at term. The subjects were between 7 and 12 years of age when studied. Airway reactivity was also assessed in their mothers. The group who had had the respiratory distress syndrome had higher ratios of residual volume to total lung capacity and lower values for forced expiratory volume in one second than did their siblings or normal controls (P less than 0.01). Expiratory flow was decreased in both groups born prematurely (P less than 0.02) and was related to neonatal exposure to oxygen (r = -0.71, P less than 0.02). The incidence of airway hyperreactivity was elevated in all groups, including the mothers. These data suggest that long-term pulmonary sequelae of the respiratory distress syndrome of the newborn are related to the disease, its treatment, or both, and to airway hyperreactivity. In prematurely born children without neonatal lung disease, the sequelae are related to airway hyperreactivity. The possibility of a relation between familial airway hyperreactivity and premature birth is suggested.",0
1153,3979959,Aldehyde dehydrogenase in alcoholic subjects,"Hepatic aldehyde dehydrogenase activity is depressed in alcoholic liver disease and may account for the observation that alcoholics develop high blood acetaldehyde concentrations following ethanol. To determine whether this is a specific defect in alcoholics, aldehyde dehydrogenase was studied in liver tissue obtained from three groups of subjects. Group I comprised 30 patients with alcoholic liver disease, Group II consisted of eight subjects with liver disease unrelated to alcohol abuse and Group III was a control group of 10 individuals with no significant liver disease. Mean hepatic aldehyde dehydrogenase activity was significantly lower in Group I than in Groups II or III [4.9 +/- 0.6 (mean +/- S.E.), compared to 10.2 +/- 1.8 and 12.4 +/- 1.1 nmoles of acetaldehyde oxidized per min X mg of protein, respectively]. Aldehyde dehydrogenase activity in Group II was relatively well maintained. Aldehyde dehydrogenase activity was found in cytosolic and mitochondrial fractions of liver homogenates. In alcoholic subjects, cytosolic aldehyde dehydrogenase activity was not more depressed than was mitochondrial aldehyde dehydrogenase. Isoelectric focusing demonstrated a single mitochondrial isoenzyme and a single cytosolic isoenzyme in most cases in Group III. In contrast, multiple cytosolic isoenzymes were consistently found in liver tissue from Group I subjects. These findings suggest that depressed aldehyde dehydrogenase activity in alcoholic subjects is not a consequence of liver disease.",0
1154,3997067,Age-related changes in the endocytic capacity of rat liver Kupffer and endothelial cells,"There are many indications that the functional capacity of the reticuloendothelial system (RES) declines with age. The aim of this study was to investigate the cellular basis of age-related changes in the clearance function of the RES. The experiments were focused mainly on Kupffer and endothelial cells of the liver which represent a major part of the RES and are primarily responsible for clearance of colloidal material from the circulation. The clearance capacity of the RES was tested clinically and experimentally by intravenous injection of colloids, such as radiolabeled heat-aggregated colloidal albumin. Age-related changes in the endocytosis of 125I-labeled colloidal albumin (CA) in rats were determined by clearance and organ distribution of different doses of intravenously injected CA, uptake of CA by Kupffer and endothelial liver cells in vivo as determined after isolation of the cells from injected rats and kinetic studies on CA uptake by Kupffer cells in culture. The results show that, at a low dose, the clearance of CA is primarily determined by liver blood flow. At a higher saturating dose, plasma clearance and uptake by the liver are not significantly decreased with age. Endocytosis by endothelial cells, which accounts for about 60% of that of the whole liver, is also unchanged with age. In contrast, a significant decrease in endocytic capacity was observed for Kupffer cells in vivo. This age-related functional decline was also observed in Kupffer cells which were isolated from rats of different ages and maintained in culture.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1155,3997077,Increased serum antibody levels against cow's milk proteins in children with chronic liver disease,"We measured IgG, IgM and IgA antibodies to cow's milk proteins: alpha-casein, alpha-lactalbumin, bovine serum albumin, beta-lactoglobulin-a and beta-lactoglobulin-b in the sera of 29 pediatric patients with liver disease. IgG antibodies to bovine serum albumin, beta-lactoglobulin-a and beta-lactoglobulin-b and IgA antibodies to alpha-casein were elevated in most of the patients compared to age-matched controls. We postulate that, in patients with liver disease either increased intestinal uptake resulting in increased humoral response, or decreased hepatic clearance of food antigens intensifying a humoral response to these foreign antigens, may occur.",0
1156,4000196,Influence of prognosis on decisions regarding the care of newborns with myelodysplasia,"Treatment of newborns with myelodysplasia (meningomyelocele and related disorders) continues to be a controversial subject. We have used a consistent plan of care and have employed the same prognostic criteria over the period from 1965 to 1982 to address the needs of 212 affected newborns. A good prognosis and early surgical care were given to 42 per cent of 53 newborns during the period 1965 to 1970, to 58 per cent of 65 newborns from 1971 to 1976, and to 71 per cent of 94 newborns from 1977 to 1982. Of the newborns with an initially poor prognosis, 19 per cent of 31 received early surgery between 1965 and 1970, as compared with 33 per cent of 27 between 1971 and 1976 and 52 per cent of 27 between 1977 and 1982. Life-table analyses of survival in the three periods revealed significant improvement over time in the survival of newborns receiving early surgical care, regardless of the initial prognosis (log-rank statistic = 8.240, P = 0.016) and in comparison to recipients of supportive care alone (log-rank statistic = 5.975, P = 0.05). We conclude that early surgery permits the survival of an increasing percentage of patients with myelodysplasia.",0
1157,4010752,Racial and socioeconomic disparities in childhood mortality in Boston,"We examined racial and income-related patterns of mortality from birth through adolescence in Boston, where residents have high access to tertiary medical care. Childhood mortality was significantly higher among black children (odds ratio, 1.24; P less than 0.05) and low-income children (odds ratio, 1.47; P less than 0.001). Socioeconomic effects varied for different age groups and causes of death. The largest relative disparity occurred in the neonatal and postneonatal periods, and the smallest in adolescence. Of the total racial differential in neonatal mortality (6.88 deaths per 1000 live births), 51.2 per cent occurred in premature infants, 13.4 per cent in term infants who were small for their gestational age, and 25.9 per cent in neonates who were both premature and small for their age. Black neonatal mortality was elevated at all income levels. Beyond the neonatal period, mortality from respiratory disease, fire, and homicide had strong inverse relationships with income, and mortality from injuries to the occupants of motor vehicles was directly related to income. These data suggest that despite access to tertiary medical services, substantial social differentiation in mortality may exist throughout childhood. Equity in childhood survival will probably require policies that emphasize preventive goals.",0
1158,4018727,Liver disease activity and hepatitis B virus replication in chronic delta antigen-positive hepatitis B virus carriers,"Delta antigen is currently thought to reflect superinfection of the liver with a defective RNA virus (delta agent), requiring helper function from hepatitis B virus for its replication. To assess the influence of delta agent on hepatitis B virus replication in patients persistently infected with both viruses and showing chronic liver disease, we measured serum and liver hepatitis B virus DNA in HBsAg-positive chronic liver disease patients who were either positive or negative for delta antigen in the liver. Hepatitis B virus DNA was assayed in the serum of 21 patients with delta antigen-positive/HBsAg-positive chronic liver disease and in 21 patients with delta antigen-negative/HBsAg-positive chronic liver disease matched for HBeAg/anti-HBe status and underlying liver histology. HBcAg and delta antigen in liver was determined by immunofluorescence or immunoperoxidase staining. In delta antigen-positive/HBsAg-positive chronic liver disease, serum hepatitis B virus DNA was detected transiently in 4 of 21 cases (19%) and was present in these patients at low levels (trace to 2+). In contrast, 9 of 21 (43%) delta antigen-negative/HBsAg-positive chronic liver disease patients were serum hepatitis B virus DNA positive, and five of these had high serum hepatitis B virus DNA levels (3+ to 4+). Serum HBsAg and anti-HBc titers were significantly lower in delta antigen-positive cases and correlated with reduced amount of HBcAg in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1159,4018738,Portal venous bile acids in cholesterol gallstone disease: effect of treatment with chenodeoxycholic and cholic acids,"We determined the serum concentrations of cholic, chenodeoxycholic and deoxycholic acids in portal and peripheral venous blood in 9 gallstone-free patients and 39 patients with cholesterol gallstones during standardized cholecystectomy. An accurate and specific gas chromatographic-mass spectrometric technique was used. The portal venous concentration of total bile acids was similar in gallstone-free and untreated gallstone patients (n = 20); there was no evidence of a reduced hepatic uptake of bile acids in the latter. Treatment with cholic acid (n = 10) was associated with a 70% increase in cholic acid and normal concentration of total bile acids. In chenodeoxycholic acid-treated patients (n = 9), the portal venous concentration of this bile acid was increased 3-fold; total bile acids were increased about 60%. The estimated hepatic uptake of cholic acid was slightly decreased during chenodeoxycholic acid treatment. The results indicate that neither bile acid inflow to the liver nor hepatic bile acid uptake is reduced in fasting patients with cholesterol gallstones, and treatment with chenodeoxycholic acid increases fasting inflow of bile acids to the liver. The latter may contribute to unsaturation of fasting hepatic bile during treatment with chenodeoxycholic acid.",0
1160,4018739,The intrahepatic biliary epithelium in the guinea pig: is hepatic artery blood flow essential in maintaining its function and structure?,"To determine whether hepatic artery blood flow is essential in maintaining the function and structure of bile ductules/ducts, the acute effects of hepatic artery ligation on bile secretion and hepatic ultrastructure were examined in anesthetized, bile duct-cannulated guinea pigs. Sixty minutes after hepatic artery ligation, spontaneous bile flow (5.08 +/- 0.4 microliter per min per gm liver) was virtually the same as that before hepatic artery ligation (5.31 +/- 0.3 microliter per min per gm), as were the choleretic effects of 10 CU per kg per 30 min secretin (7.14 +/- 0.9 vs. 7.21 +/- 0.9 microliter per min per gm), 300 micrograms per kg per 30 min glucagon (6.72 +/- 0.9 vs. 6.59 +/- 0.8 microliter per min per gm) and 60 mumoles per kg per 30 min glycochenodeoxycholate (6.43 +/- 0.6 vs. 6.45 +/- 0.6 microliter per min per gm). The failure of hepatic artery ligation to affect bile secretory function could not be attributed to the existence of collateral arterial blood flow to the liver. First of all, hepatic artery ligation resulted in diminishing significantly hepatic venous, but not portal, oxygen content. More importantly, in isolated guinea pig livers, perfused through the portal vein alone, secretin, glucagon and glycochenodeoxycholate produced changes in bile flow and composition similar to those seen in vivo. Electron microscopy showed no major ultrastructural changes of hepatic parenchyma and biliary epithelium 2 hr after hepatic artery ligation, or 2 hr after perfusing the liver through the portal vein alone save for some portal edema in the latter instance.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1161,4022047,Comparison of a quantitative treadmill exercise score with standard electrocardiographic criteria in screening asymptomatic young men for coronary artery disease,"A computer-derived treadmill exercise score that quantifies the electrocardiographic response to exercise has been reported to have a high sensitivity (87 per cent) and specificity (92 per cent) in patients with a high prevalence of coronary artery disease. To test its accuracy in young, asymptomatic men with a low prevalence of coronary artery disease, we evaluated the responses of 377 military officers (mean age, 36.6 years) by two independent methods. According to standard electrocardiographic criteria, 45 of the subjects (12 per cent) had positive tests, whereas the treadmill exercise score indicated that only 3 (less than 1 per cent) had positive tests. Since two of these three had left ventricular hypertrophy and met only the criteria for the latter without associated coronary artery disease, the treadmill exercise score predicted that only 1 of 377 subjects would have clinically important coronary artery disease. Coronary arteriography, performed in 10 persons with the most positive scores on standard treadmill tests and the highest scores for risk factors, showed that nine subjects did not have coronary artery disease and that one had single-vessel disease (the same subject who the treadmill score predicted would have mild disease). The treadmill exercise score appears to improve the diagnostic specificity of exercise electrocardiography and may be more useful than values on standard stress tests in screening asymptomatic populations for coronary artery disease.",0
1162,4029888,Changes of hepatitis B virus DNA in liver and serum caused by recombinant leukocyte interferon treatment: analysis of intrahepatic replicative hepatitis B virus DNA,"Twenty patients with HBeAg-positive chronic liver disease were given large doses of recombinant leukocyte interferon for 4 weeks. Changes of hepatitis B virus DNA in livers and sera were analyzed by the molecular hybridization technique in paired biopsies obtained before and 2 weeks after treatment. Serum hepatitis B virus DNA was examined before, during and after the treatment until 4 weeks post-interferon. Analysis of hepatic hepatitis B virus DNA revealed species that appeared to represent various forms of replicative hepatitis B virus DNA, i.e., relaxed circular, linear, supercoiled and single-stranded hepatitis B virus DNA, respectively. No evidence of integration of hepatitis B virus DNA in genomic DNA was obtained. Of 15 cases which were positive for hepatic hepatitis B virus DNA before treatment and in which paired biopsies were obtained, hepatic hepatitis B virus DNA became negative in 4, decreased in 5 and unchanged in 6. Among several types of replicative viral DNA in liver tissue, supercoiled hepatitis B virus DNA tended to remain after other forms were reduced. A close correlation between hepatic and serum hepatitis B virus DNA was found in 37 liver biopsy samples and corresponding sera. These results indicate that interferon treatment reduces serum hepatitis B virus levels by inhibiting viral replication in the liver and that persistence or reappearance of hepatitis B virus in serum after interferon is associated with replication.",0
1163,4029897,The effect of 3-palmitoyl-(+)-catechin on Kupffer cells in guinea pig liver,We report a morphometric study on the effect of 3-palmitoyl-(+)-catechin on phagocytic activity of latex particles by Kupffer cells in guinea pig liver. We found an increase in the density of latex particles in Kupffer cells of animals treated with 3-palmitoyl-(+)-catechin. The volume and density of Kupffer cells of treated animals increased (p less than 0.01); there was no significant difference in surface density of the plasma membrane. None of the parameters measured was altered in endothelial cells. These results show that 3-palmitoyl-(+)-catechin produces morphological and functional changes in Kupffer cells.,0
1164,4033706,The effect of dietary protein on the clearance of allopurinol and oxypurinol,"A decrease in dietary protein is known to depress renal plasma flow and creatinine clearance. Using a randomized crossover design, we investigated the pharmacokinetics of allopurinol and its principal metabolite, oxypurinol, after oral administration of 600 mg of allopurinol in six normal subjects receiving a high-protein (268 g per day) or low-protein (19 g per day) diet. For allopurinol, the area under the curve of plasma concentration versus time increased by a factor of 1.45 (P less than 0.02), the renal clearance decreased by 28 per cent (P less than 0.02), and the ratio of the clearance of allopurinol to that of creatinine (fractional excretion) was unchanged between the low-protein and high-protein diets. For oxypurinol, the area under the curve increased nearly three-fold (P less than 0.02), the renal clearance decreased by 64 per cent (P less than 0.02), the fractional excretion decreased by 49 per cent (P less than 0.02), and the plasma oxypurinol half-life increased nearly threefold from 17.3 +/- 1.5 (mean +/- S.E.M.) to 49.9 +/- 2.9 hours (P less than 0.02) during the low-protein diet, as compared with the high-protein diet. We conclude that with the low-protein diet, the absorption, metabolism, and excretion of allopurinol were minimally altered but the total-body clearance of oxypurinol was greatly reduced because of a large increase in the net renal tubular reabsorption of oxypurinol.",0
1165,4039792,"Consequences of unremitting middle-ear disease in early life. Otologic, audiologic, and developmental findings in children with cleft palate","To learn whether chronic otitis media with effusion during early life has lasting otologic, audiologic, or developmental consequences, we evaluated 24 closely matched pairs of children with repaired palatal clefts whose treatment had been equivalent except with regard to persistent otitis media during early life. One group had undergone early (mean age, 3.0 months) myringotomy with placement of tympanostomy tubes, followed by assiduous monitoring and an aggressive treatment program to maintain ventilation in the middle ear. The other group had undergone initial myringotomy later (mean age, 30.8 months) or not at all (two subjects) and presumably had had continuous middle-ear effusion throughout most or all of the first few years of life. Eardrum scarring was equal in both groups. Hearing acuity and consonant articulation were impaired in both groups, but hearing acuity was less impaired (P = 0.05 to 0.10) and consonant articulation significantly less impaired (P = 0.03) in the group undergoing early myringotomy. Mean verbal, performance, and full-scale IQs and scores on psychosocial indexes were normal in both groups and did not differ significantly between the groups. These findings support the hypothesis that early, longstanding otitis media may result in impairment of hearing and of speech, but they do not support the hypothesis that cognitive, language, and psychosocial development are adversely affected.",0
1166,4047105,Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. A prospective study,"Antiepileptic medications were discontinued in 88 children with epilepsy of various causes who had been free of seizures for two to four years. The subjects were then followed for six months to five years (mean, 22 months). Sixty-six (75 per cent) remained free of seizures. Electroencephalographic characteristics, type of seizure, and age at onset were important in predicting outcome. Specific electroencephalographic features (such as the presence or absence of slowing or spikes) were more predictive than simple classification of an electroencephalogram as normal or abnormal. A history of complex partial seizures that had been controlled for two years carried a relatively favorable prognosis (P less than 0.05), whereas a history of atypical febrile seizures carried a poor prognosis (P less than 0.05). The variable of a younger age at onset was also associated with a better outcome (P less than 0.05), but only if accompanied by electroencephalographic slowing. Altogether, six variables (the interaction of age at onset with electroencephalographic slowing, electroencephalographic spikes, atypical febrile seizures, complex partial seizures, electroencephalographic slowing, and electroencephalographic change) were statistically significant (P less than 0.05) in predicting outcome. We conclude that in most children with epilepsy who have been free of seizures for two or more years, antiepileptic medications can safely be discontinued, and that it is possible to predict reasonably well which children will remain free of seizures.",0
1167,4058491,The role of changing clinical practices in the rising costs of hospital care,"""To assess whether changes in clinical practice have contributed to rising hospital costs, we studied 2011 patients who were hospitalized at the University of California, San Francisco, in 1972, 1977, or 1982. For most of the 10 diagnoses studied, there was little change in total use of services by patients. In-hospital survival did not differ during the decade, and length of stay, numbers of special-care days, and use of laboratory services generally remained the same or declined. Only for patients with acute myocardial infarction did the use of imaging procedures increase substantially (e.g., cardiac catheterization was provided to 2 per cent of patients in 1977 and 40 per cent in 1982). Contrary to conventional wisdom, """"little-ticket"""" procedures, such as laboratory tests, did not contribute to rising costs, and new imaging techniques were commonly substituted for older, more invasive procedures. The primary causes of rising costs were the provision of surgery to patients admitted for acute myocardial infarction, delivery, or respiratory distress syndrome of the newborn and the provision of other intensive treatments for the critically ill.""",0
1168,4058511,Rational remuneration,"""Physicians face the end of a phase of unrealistic and unprecedented prosperity fostered by unrestrained third-party remuneration policies. The cost of that phase, along with inflation and the use of expensive technology, has created an economic crisis. I urge my colleagues to take the initiative to address this crisis with other affected groups in the private sector by working to develop guidelines to restrain abuses, promote cost effectiveness, simplify administration, and increase fairness in the remuneration system. Remuneration scales should reflect variations among specialties in terms of skill, stress, and time involved, but should avoid unmeasurable and unverifiable differences within each category of service. Slowness and ineptitude should no longer be rewarded under the guise of """"complexity."""" In the long run, standardized fees will be fair and will simplify the payment process greatly. Reasonable remuneration for agency-subsidized services can be derived in several ways, and once the median remuneration for various services has been established in each specialty, existing relative-value scales can be applied for other cases in that specialty. These measures would effect substantial savings in health care costs without incurring bureaucratic interference or impairing the quality of service. Moreover, they would allow distribution deficiencies to be remedied by permitting a response to market forces--i.e., higher payments would be made in underserved areas.""",0
1169,4058532,Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer,"We studied the frequency and distribution of proliferating epithelial cells lining colonic crypts in 10 subjects at high risk for familial colonic cancer, before and after oral supplementation of their conventional diets with 1.25 g of calcium as calcium carbonate. Patterns of cell proliferation were defined by dividing the colonic crypt into longitudinal compartments and comparing the numbers and fractions of tritiated thymidine--labeled epithelial cells in the various compartments. Before dietary supplementation with calcium, the profile of proliferating epithelial cells in the colonic crypts was comparable to that previously observed in subjects who had had familial colonic cancer. Two to three months after supplementation had been started, proliferation was significantly reduced and the profile of the colonic crypts approached that previously observed in subjects at low risk for colonic cancer. Our findings indicate that oral calcium supplementation induces a more quiescent equilibrium in epithelial-cell proliferation in the colonic mucosa of subjects at high risk of colon cancer, similar to that observed in subjects at low risk.",0
1170,4069159,The risk of myocardial infarction after quitting smoking in men under 55 years of age,"""We assessed the effect of quitting cigarette smoking on the incidence of nonfatal myocardial infarction in men under the age of 55 in a case-control study of 1873 men with first episodes of myocardial infarction and 2775 controls. For """"current"""" smokers (men who had smoked in the previous year) as compared with those who had never smoked, the estimated relative risk of myocardial infarction, adjusted for age, was 2.9 (95 per cent confidence interval, 2.4 to 3.4). Among exsmokers (those who had last smoked at least one year previously), the relative-risk estimate declined to a value close to unity for those who had abstained for at least two years; the estimate was 2.0 (1.1 to 3.8) for men who had abstained for 12 to 23 months, and the estimates were about 1.0 for men who had abstained for longer intervals. The results were unchanged by allowance for multiple potential confounding factors. A similar pattern was apparent among exsmokers who had smoked heavily for many years; among those predisposed to a myocardial infarction because of family history, hypertension, or other risk factors; and among those with no apparent predisposition. The results suggest that the risk of myocardial infarction in cigarette smokers decreases within a few years of quitting to a level similar to that in men who have never smoked.""",0
1171,4189456,Immunofluorescent examination of biopsies from long-term renal allografts,"Immunofluorescent examination of open renal biopsies revealed clear-cut glomerular localization of immunoglobulins not related clearly to the quality of donor-recipient histocompatibility in 19 of 34 renal allografts. The biopsies were obtained 18 to 31 months after transplantations primarily from related donors with a variable quality of histocompatibility match. IgG was the predominant immunoglobulin class fixed in 13 biopsies, and IgM in six. The pattern of immunoglobulin deposition was linear, connoting anti-GBM antibody in four of the 19; it was granular and discontinuous, connoting antigen-antibody-complex deposits, in 13. An immune process may affect glomeruli of renal allografts by mechanisms comparable to those that cause glomerulonephritis in native kidneys. The transplant glomerulonephritis may represent a persistence of the same disease that originally destroyed the host kidneys or the consequence of a new humoral antibody response to allograft antigens.",0
1172,4696247,Regulating abortions,"The lack of clinical guidelines in the regulation of abortion following the Supreme Court's decision allowing abortion is discussed. Regarding first trimester abortions, the Court merely stipulated that the procedure must be performed by a licensed physician. Although few would disagree that adequate social services and contraceptive counseling should accompany abortion procedures, there is no legal guarantee that they would be provided. Recently, the Advisory Committee on Abortion of the Massachusetts Medical Society proposed guidelines to ensure that high standards of medical care are followed in abortion cases, upon which final action is pending. It is urged that the medical profession act to establish guidelines for the care of abortion patients, not only to ensure the health and well-being of the woman, but also to demonstrate that the medical profession is capable of acting responsibly in the regulation of its own practice.",0
1173,5025778,Genital-tract cancers in adolescents and young adults,"In a review of the California Tumor Registry from 1950-1969, which records 1/3 of all cancer cases in California, there was an increase in the number of cancers of the vagina, corpus uteri, prostate, testis, and bladder (male) for the 10-19 year old age group. There was no increase in cancers of the vulva, ovary, cervix, breast, stomach, colon, rectum, and bladder (female). However, for the 20-24 year old age group, cancer of the vulva and testis increased from 1962-1969. The increases are compatible with other observations which indicate a possible association between stilbesterol and other cervical sites besides the vagina. There is a need for cancer surveillance to determine disease patterns and stimulate examination of existing data.",0
1174,5454764,Medicalized sex,"In response to criticism on his article about evaluation of a program for preventing adolescent pregnancies, the author replies that the moral and ethical considerations are indeed important. However, since teenage pregnancies do abound, the physician must take the responsibility for helping to prevent unwanted pregnancies among the adolescent population. The question is not whether such pregnancies should be prevented but which approach is most appropriate and effective for their prevention.",0
1175,5556579,Transplacental carcinogenesis by stilbestrol,"This editorial argues the cause-and-effect relationship between in utero exposure to diethylstilbestrol (DES) and incidence of vaginal adenocarcinoma among young women. It is conjectured that the mechanism by which DES induces tumors is a result of transplacental carcinogenesis; i.e., DES causes a malignant change in any fetal cell of future vaginal tissue, resulting in a genetic defect which may not be realized until puberty, when endogenous hormone production acts as a promoter of the malignancy initiated by DES exposure during gestation. If this theory is correct, local progestational therapy may arrest future adenocarcinoma cases. Though it is obvious that DES therapy must be avoided in the future in the population of pregnant women, of more concern is the presence of residual DES in foodstuffs, particularly livestock meat. A ban of such diet supplementation of human foodstuffs is called for.",0
1176,6094330,Activity and regulation of low density lipoprotein receptors in a human hepatoblastoma cell line,"The responsiveness of low density lipoprotein (LDL) binding and uptake was measured in a human hepatoblastoma cell line, Hep G2. These cells exhibited both saturable, high-affinity and nonsaturable low-affinity components similar to that described for LDL binding in other mammalian cells. In addition, receptor-mediated uptake of [125I]LDL was dependent on the presence of Ca++ and required intact lysine residues in LDL as evidenced by abolition of binding following reductive methylation of LDL. The receptor activity was rapidly responsive to changes made in LDL concentrations in the medium, up-regulating by 200% in the absence of LDL, and down-regulating by 56% in the presence of LDL, both changes occurring within 2 hr. Cholesterol synthesis was estimated by measuring 3-hydroxymethylglutaryl coenzyme A reductase activity. The activity of this enzyme was also found to increase rapidly in the absence of LDL and decrease rapidly in the presence of LDL in the media. The human cell line Hep G2 possesses an active and responsive receptor for LDL and provides a useful model for the study of lipoprotein uptake and metabolism in intact human liver.",0
1177,6104292,X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity,"We studied several members of a family with an X-linked form of cutis laxa; the affected males have mild skin laxity, a characteristic facies, skeletal abnormalities, structural abnormalities of the genitourinary tract, and low serum copper levels. The activity of lysyl oxidase, a copper-dependent enzyme involved in cross-link formation in collagen, was decreased in skin-biopsy specimens (13 to 26 per cent of normal) and in culture medium from cells to two affected males (15 to 20 per cent of normal). Immunoreactive lysyl oxidase from skin of both patients was virtually undetectable by immunodiffusion assay. The amounts of lysyl-derived aldehydes (the product formed in collagen and elastin by lysyl oxidase) and of cross-links formed from these products were decreased in dermal fibroblasts in culture. Collagen extractability from these cells was increased in culture. These findings suggest that lysyl oxidase deficiency provides the biochemical basis of the X-linked form of cutis laxa.",0
1178,6104293,Occupational rituals in patient management,"The social practices surrounding diagnosis and management decisions are analyzed from a sociological perspective as occupational rituals. These rituals are part of rounds and conferences, and they assist physicians in managing uncertainty, making treatment decisions, and evaluating outcomes. Physicians use eight key strategies to manage uncertainty: hedged assertions, probability reasoning, a focus on uncertainty as a research problem, requests for consultations, Socratic teaching, deciding not to decide, gallows humor, and hyperrealism. Clinical experience and scientific evidence are used in treatment decisions. The manner in which decisions are made at rounds allows physicians to dramatize the seriousness with which they take their responsibilities to patients. Two major rituals for evaluating outcomes of treatment decisions, grand rounds and the mortality and morbidity conference, provide a forum for dramatizing success and failure, respectively. Occupational rituals allow physicians to discuss their problems. The capacity of modern medicine to process clinical data threatens to obviate these rituals.",0
1179,6128298,H2-receptor antagonists and hepatic drug disposition,"The effect of four H2-receptor antagonists (cimetidine, burimamide, oxmetidine, and ranitidine) on antipyrine elimination was studied in the isolated perfused rat liver. The first three drugs are substituted imidazoles, whereas ranitidine contains a furanyl nucleus. Isolated livers were perfused using a 100-ml, recycling, constant flow circuit for 4 hr. Antipyrine elimination was studied with or without an H2-receptor antagonist present. In all experiments, antipyrine concentrations declined monoexponentially. In control experiments (no other drug present), antipyrine clearance was 32.5 +/- 0.9 ml per hr. This was greatly reduced in the presence of cimetidine (clearance = 10.1 +/- 0.8 and 5.8 +/- 1.5 ml per hr after 1 and 5 mg doses, p less than 0.01) and burimamide (4.5 +/- 0.6 and 3.0 +/- 1.7 ml per hr, p less than 0.001). By contrast, neither oxmetidine nor ranitidine significantly altered antipyrine pharmacokinetics. These results indicate that the inhibitory effect on hepatic mixed-function oxidases is rapid in onset, independent of H2-receptor antagonist activity, and is not an inevitable consequence of the presence of an imidazole nucleus.",0
1180,6135989,Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study,"We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups. Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality.",0
1181,6143260,Correlation of platelet calcium with blood pressure. Effect of antihypertensive therapy,"Intracellular free calcium has been implicated in vascular smooth-muscle contraction and in the pathophysiology of essential hypertension. We studied free-calcium levels in blood platelets, which have many features in common with vascular smooth-muscle cells. With use of an intracellularly trapped fluorescent dye, the free-calcium concentration in platelets was found to be elevated in 9 patients with borderline hypertension and 45 patients with established essential hypertension, who were compared with 38 normotensive subjects. There was a close correlation between the free-calcium level and both systolic and diastolic blood pressure (n = 92; r = 0.883 for systolic pressure and 0.931 for diastolic pressure; P less than 0.001 for both). Antihypertensive treatment with calcium-entry blockers (n = 15), beta-adrenoceptor blockers (n = 12), or a diuretic (n = 6) resulted in a reduction in free calcium, and this correlated with the fall in blood pressure (P less than 0.001). The intracellular free-calcium concentration in platelets may be determined by the same humoral or pharmacologic factors that determine the height of blood pressure.",0
1182,6150438,Bone-marrow transplantation in the Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI). Biochemical and clinical status 24 months after transplantation,"A 13-year-old girl with the severe form of the Maroteaux-Lamy syndrome (mucopolysaccharidosis Type VI, arylsulfatase B deficiency) has had successful reconstitution with bone marrow from her HLA-MLC-matched sister who had normal arylsulfatase B activity. Full engraftment has been present for 24 months. The following biochemical and clinical changes have occurred: arylsulfatase B activity in peripheral lymphocytes and granulocytes increased to normal levels, and the activity in serial liver-biopsy specimens increased from about 3 per cent of the mean normal level 43 days after transplantation to about 16 per cent at 600 days. Urinary excretion of acid mucopolysaccharide decreased. Ultrastructural evidence of accumulated dermatan sulfate was no longer detectable in bone-marrow cells; in peripheral-blood lymphocytes, granulocytes, or platelets; or in Ito cells of liver. Twenty-four months after engraftment, hepatosplenomegaly was substantially decreased and cardiopulmonary function was normal. Visual acuity and joint mobility were also improved. The patient returned to school and continued to perform well in academic studies. Thus, bone-marrow transplantation provided a source of enzymatically normal cells, which have altered the metabolic and clinical course of the disease.",0
1183,6163985,"Galactosyltransferase isoenzyme II in the detection of pancreatic cancer: comparison with radiologic, endoscopic, and serologic tests","We assessed the value of several serologic markers in detecting pancreatic carcinoma in a prospective study of 270 patients. The sensitivity and specificity of galactosyltransferase isoenzyme II (GT-II), carcinoembryonic antigen (CEA), alpha-fetoprotein, ferritin, C1q binding, and ribonuclease were determined. GT-II was the most sensitive (67.2 per cent) and specific (98.2 per cent) for discriminating between benign and malignant disease and was more sensitive and specific than CEA, the next most useful marker. Sensitivity was 64 per cent for ultrasound, 79.4 per cent for computerized body tomography (CBT), and 92.8 per cent for endoscopic retrograde cholangiopancreatography (ERCP). As a single test, only ERCP was more sensitive than GT-II, but more sensitive diagnoses resulted when GT-II was combined with ultrasound (92 per cent), CBT (88 per cent), or ERCP (100 per cent). Serum GT-II may be useful both by itself and in combination with imaging techniques in distinguishing benign from malignant pancreatic disease; however, this test does not discriminate between pancreatic carcinoma and other gastrointestinal neoplasms.",0
1184,6169614,The delta agent: HBsAg particles with delta antigen and RNA in the serum of an HBV carrier,The hepatitis B virus-associated delta antigen was detected in the serum of a young female drug addict with acute hepatitis and a previous history of hepatitis B surface antigen carrier. Delta antigen was associated with a 35- to 37-nm subpopulation of hepatitis B surface antigen particles which banded at a density of 1.25 gm per cm3 of CsCl and contained a small RNA of approximately 5.5 X 10(5) molecular weight. This report demonstrates that delta antigen is associated with a unique subpopulation of hepatitis B surface antigen particles and small RNA in human serum.,0
1185,6183586,5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia,"5-Azacytidine is a cytidine analogue that is capable of activating repressed genes in tissue-culture cells and has been shown to increase hemoglobin-F production in anemic baboons. This drug was administered to a patient with severe beta-thalassemia in an attempt to stimulate hemoglobin-F production. After seven days of 5-azacytidine treatment, gamma-globin synthesis increased approximately sevenfold, temporarily normalizing the patient's unbalanced globin synthesis. Erythropoiesis became more effective, leading to a temporary increase in the absolute reticulocyte count (from 5000 to 22,000 per cubic millimeter) and in hemoglobin concentration (from 8.0 to 10.8 g per deciliter). Hypomethylation of bone-marrow DNA near both the gamma-globin and epsilon-globin genes was directly demonstrated. At the time of peak drug effect, about 7000 gamma-globin messenger RNA molecules were present per erythroid bone-marrow cell, in contrast to 10 to 15 epsilon-globin messenger RNA molecules per cell. 5-Azacytidine selectivity increases gamma-globin synthesis and therefore provides a new approach to the treatment of severe beta-thalassemia. Further studies will be required to evaluate the efficacy, risks, and long-term toxicity of 5-azacytidine (or related compounds) before this approach can be used as a therapy for patients with disorders of hemoglobin synthesis.",0
1186,6188954,Chronological trend in blood lead levels between 1976 and 1980,"Analysis of a chronological trend in data from the second National Health and Nutrition Examination Survey indicated that average blood lead levels in the United States dropped approximately 37 per cent (5.4 micrograms per deciliter) from February 1976 through February 1980. There was no evidence that this trend was due to errors in laboratory measurement or to the design of the survey. The trend was present even after accounting for differences in race, sex, age, region of the country, season, income, and degree of urbanization. Changes in exposure to lead in paint or in the diet are unlikely explanations of the trend. However, the correlation of blood lead levels with the lead level in gasoline was highly significant (P less than 0.001) overall and in population subgroups defined by race, sex, and age. Although strong correlation does not prove cause and effect, the most likely explanation for the fall in blood lead levels is a reduction in the lead content of gasoline during this period.",0
1187,6207091,Serum alpha-L-fucosidase: a new marker for the diagnosis of primary hepatic carcinoma?,"alpha-L-fucosidase, a lysosomal enzyme which catabolizes fucoproteins, was studied in sera from 30 controls, 32 patients with primary hepatic carcinomas, 24 patients with secondary metastatic liver carcinomas and 36 patients with cirrhosis. Serum alpha-L-fucosidase was increased in primary hepatic carcinomas (145.5 +/- 12 nkat per liter) with a high statistical significance versus controls (51.4 +/- 4.5 - p less than 10(-7], secondary metastatic liver carcinomas (58.9 +/- 6.4 - p less than 10(-5] and cirrhotics (71.3 +/- 6 - p less than 10(-5). A level exceeding 110 was a useful marker for the diagnosis of primary hepatic carcinoma with 75% sensitivity and 90% specificity.",0
1188,6215583,A genetic defect in the binding of protein 4.1 to spectrin in a kindred with hereditary spherocytosis,"Indirect evidence suggests that the genetic defect in hereditary spherocytosis lies in the erythrocyte membrane skeleton, a submembranous meshwork of proteins (principally spectrin, actin, and protein 4.1) responsible for membrane shape and structural stability. To test this premise we systematically assayed the interactions of spectrin, the major skeletal protein, in six kindreds with autosomal dominant hereditary spherocytosis. In one these kindreds, enhancement of spectrin-actin binding by protein 4.1 was reduced, owing to a 39 +/- 4 per cent decrease (mean +/- S.D) in the binding of normal protein 4.1 by spectrin, in all of four members with the disorder. The defective spectrin was separated into two populations by affinity chromatography on immobilized normal protein 4.1. One population (41 +/- 2 per cent) lacked the ability to bind 4.1, but the other functioned normally. Presumable, the nonfunctional spectrin was the product of the autosomal dominant gene responsible for the hereditary spherocytosis in this kindred.",0
1189,6221192,Immunodeficiency in female sexual partners of men with the acquired immunodeficiency syndrome,"Because the current outbreak of acquired immunodeficiency syndrome (AIDS) among previously healthy adults may be caused by a transmissible biologic agent, and because it may be preceded by immunologic abnormalities with or without a prodromal illness, we studied seven female sexual partners of male patients with the syndrome. The male patients were all drug abusers. One of the seven women was found to have the full-blown syndrome, a second had an illness consistent with the prodrome of AIDS (generalized lymphadenopathy, lymphopenia, and a decreased ratio of helper to suppressor T cells), and four others had generalized lymphadenopathy or lymphopenia, with or without a decreased ratio of helper to suppressor T cells. Only one woman had no abnormalities. These findings suggest that AIDS may be transmitted between heterosexual men and women.",0
1190,6224088,Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome,"We studied B-lymphocyte function in 12 homosexual male patients with the acquired immunodeficiency syndrome, 5 healthy homosexual men, and 12 heterosexual controls. In comparison with the heterosexual controls, the patients were found to have elevated numbers of cells spontaneously secreting immunoglobulin, decreased B-cell proliferative responses to T-cell-independent B-cell mitogens, and qualitatively deficient helper T cells. The hyperactive spontaneous B-cell responses as well as the refractoriness to signals for T-cell-independent B-cell activation were highly suggestive of an in vivo polyclonal activation of B cells and may have been responsible for the manifestations of B-cell hyperreactivity, such as hypergammaglobulinemia, seen in these patients. We conclude that the scope of immune dysfunction in the acquired immunodeficiency syndrome involves B cells as well as T cells.",0
1191,6231483,Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation,"Prostacyclin is a potent vasodilator and platelet inhibitor produced by vascular endothelium. Endogenous production of prostacyclin under physiologic conditions is extremely low, far below the capacity of vascular tissue to generate this substance in response to stimulation in vitro. This may reflect a low frequency or intensity of stimulation of prostacyclin production. We postulated that if prostacyclin does act as an endogenous platelet-inhibitory agent, it should be produced in greater amounts in a clinical setting in which platelet-vascular interactions are likely to be increased. To test this hypothesis, we examined prostacyclin biosynthesis in patients with severe atherosclerosis and evidence of platelet activation in vivo. Excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha, a major urinary prostacyclin metabolite, was significantly higher in 9 patients with severe atherosclerosis and evidence of platelet activation (251 to 1859 pg per milligram of creatinine) than in 54 healthy volunteers (45 to 219 pg per milligram of creatinine; P less than 0.001). This difference represented an alteration in biosynthesis rather than in metabolism, since the fractional conversion of infused prostacyclin to the dinor metabolite was identical in both groups. Prostacyclin production may be low in healthy persons because there is almost no stimulus for its production but enhanced in patients with severe atherosclerosis as a consequence of platelet interactions with endothelium or other vascular insults. These observations are compatible with a role for prostacyclin as a local regulator of platelet-vascular interactions.",0
1192,6235163,Hepatitis B vaccination in Down's syndrome and other mentally retarded patients,"""The immune response after vaccination with H-B-VAX (20 micrograms, Months 0, 1 and 6) was investigated in 23 Down's syndrome patients and compared to that in 30 other mentally retarded patients and 32 staff members. About 90% of Down's syndrome and other mentally retarded patients and 100% of staff members had anti-HBs at Month 9, but anti-HBs less than 10 IU per liter were found in 6/23 (26.1%) of Down's syndrome, 7/30 (23.3%) of other mentally retarded patients, in contrast to 2/32 (6.2%) of staff members. No differences in anti-HBs response with regard to sex and age were observed in staff members, but geometric mean titers of anti-HBs were lower in older Down's syndrome and other mentally retarded patients, and in male Down's syndrome patients. Supplementary vaccination is necessary in these individuals to obtain """"protective levels"""" of anti-HBs.""",0
1193,6237261,Is percutaneous coronary angioplasty less expensive than bypass surgery?,Percutaneous transluminal coronary angioplasty is widely considered to be an acceptable and less expensive alternative to bypass surgery in carefully selected patients. We compared expenditures related to cardiac care for 79 unselected patients undergoing coronary angioplasty with expenditures for 89 unselected patients undergoing elective coronary bypass surgery without a previous attempt at angioplasty. All the patients had single-vessel disease. The mean aggregate one-year monetary outlay was 15 per cent lower in the angioplasty group than in the bypass-surgery group. A major component of the expense of angioplasty was the treatment of restenosis in the 33 per cent of patients in this group in whom this late complication occurred. We conclude that percutaneous transluminal coronary angioplasty has potential for reducing expenditures for cardiac revascularization and that a further reduction may be obtainable when the rates of restenosis are improved.,0
1194,6243170,The use of lithium carbonate to reduce infection and leukopenia during systemic chemotherapy,"To investigate whether lithium ameliorates the infectious complications that accompany systemic chemotherapy, we studied 45 patients with small-cell bronchogenic carcinoma receiving combination chemotherapy and radiation therapy. Twenty received lithium carbonate, and 25 received no additional therapy. Control subjects experienced more days with neutropenia than the lithium-treated group (2.17 days per 100 patient-days vs. 0.29), more severe febrile episodes (seven patients vs. one patient), more days hospitalized with fever and neutropenia (1.92 per 100 patient-days vs. 0.18), and more infection-related deaths (five vs. none). Infection-free survival was significantly longer in the lithium-treated group than in controls (P less than 0.05). Delay in subsequent chemotherapy was longer (P less than 0.01) and the number of dose reductions greater (P less than 0.01) in the control group. For both leukocytes and neutrophils, the first cycle nadir, mean of all treatment nadirs, and the lowest nadir observed during treatment were significantly higher in the lithium group. Mean mid-cycle monocyte counts were greater in the lithium group (P less than 0.05) and correlated with concurrent serum lithium levels (rs = 0.74, P less than 0.05). We believe that lithium carbonate shows promise as a means of lowering the risk of infection among patients receiving cytotoxic therapy.",0
1195,6246425,Sustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure,"Eight patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were given captopril (seven patients) or teprotide (one patient). All had dyspnea, edema, elevated pulmonary wedge pressure (28.0 +/- 2.6 mm Hg), low cardiac index (1.6 +/- 0.1 liters per minute per square meter), and elevated levels of serum creatinine (2.3 +/- 0.2 mg per deciliter [203.3 +/- 17.7 mumol per liter]), blood urea nitrogen (48 +/- 5 mg per deciliter [17.1 +/- 1.8 mmol of urea per liter]), plasma renin activity (21 +/- 7 ng of angiotensin I per milliliter per hour), plasma angiotensin II (271 +/- 51 pg per milliliter), and plasma aldosterone (65 +/- 14 ng per deciliter). After one week of therapy, all indexes improved. Creatinine and p-aminohippurate clearances were also increased (P less than 0.01). Improvement was sustained (more than six months) and was associated with a statistically significant increase in the cardiac ejection fraction (12 +/- 3 to 26 +/- 7 per cent). With a mean follow-up of seven months, the New York Heart Association Functional Class has been reduced from IV to II, and the number of days of hospitalization to less than 10 per cent of that before captopril therapy. We conclude that captopril reduces afterload in advanced congestive heart failure and induces sustained improvements in clinical status and renal function.",0
1196,6248785,Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium,"It has been suggested that the reported association between estrogen use and endometrial cancer may have been biased because estrogens provoke uterine bleeding in women with otherwise asymptomatic disease. To evaluate this hypothesis we compared 149 patients with endometrial cancer and 402 control subjects with other conditions with reference to the time when they had last used conjugated estrogens. In women who had last used conjugated estrogens two or more years previously and who had taken them for at least five years, the rate-ratio estimate was 3.3 (95 per cent confidence interval, 1.4 to 8.0) relative to women who had never used them. Uterine bleeding, and hence the diagnosis of otherwise asymptomatic cancer, cannot be attributed to estrogen use that ceased in the distant past. Our results suggest that such use has a residual effect on the risk of endometrial cancer; this effect is not accounted for by biased selection of cases according to estrogen use.",0
1197,6269982,Granuloma collagenase and EDTA-sensitive neutral protease production in hepatic murine schistosomiasis,"Mice infected with Schistosoma mansoni represent a model for study of hepatic fibrosis in humans. Production of trypsin-activatable inactive collagenase and EDTA-sensitive neutral protease was measured in the culture medium in which granuloma explants or primary cultures were maintained. Collagenase production was maximal in granulomas obtained from liver of mice 8 weeks postinfection and was inhibited by Actinomycin D or cycloheximide, and enhanced by lymphocyte factor(s) or heparin. Isolated schistosome eggs did not release these enzymatic activities but did release EDTA-insensitive protease activity. Both enzymes were separated by ion-exchange chromatography and purified to homogeneity. Isolated collagenase had an isoelectric point of 6.2 and molecular weight of 60,000 and had the functional characteristics of a tissue collagenase. The specific activity of collagenase was 33 units per mg protein at an optimum pH 7.5 and lacked proteolytic activity against noncollagenous protein substrates. Isolated EDTA-sensitive neutral protease had specific caseinolytic activity of 150 units per mg protein and gelatinolytic activity of 300 units per mg protein at an optimum pH 7.5; the enzyme lacked activity against undenatured collagen. Isoelectric point was pH 6.0. Protease activity was inhibited by known inhibitors of collagenases. Production and activation of EDTA-sensitive neutral protease and collagenase accompany increased collagen synthesis and content in the liver of mice 8 weeks postinfection with S. mansoni cercariae. Continued accumulation of liver collagen under these conditions suggests an insufficiency in collagenase activity relative to the increase in collagen synthesis.",0
1198,6270552,Autonomic abnormalities and autoantibodies to beta-adrenergic receptors,"""We identified autoantibodies to beta 2-adrenergic receptors in the plasma of three apparently normal subjects, four patients with allergic asthma, one subject who was """"preallergic"""" (at risk of allergy), and one patient with cystic fibrosis. Although these antibodies appeared to be heterogeneous, they shared the ability to affect binding of [125]protein A to calf-lung membranes, to inhibit beta-adrenergic ligand binding to calf-lung bet-adrenergic receptors, and to precipitate solubilized calf-lung beta-adrenergic receptors in an indirect immunoprecipitation assay. The presence of autoantibodies to beta-adrenergic receptors in these subjects correlates with abnormal autonomic responsiveness characterized by alpha-adrenergic and cholinergic hypersensitivity and beta-adrenergic hyposensitivity. These findings suggest that autoantibodies to beta-adrenergic receptors may play a part in the development of ment of autonomic abnormalities.""",0
1199,6276746,Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. Comparison with conventional therapy,"We assessed the rates of vertebral fracture in patients with postmenopausal osteoporosis. Forty-five patients were not treated (91 person-years of observation); 59 were treated conventionally, with calcium (alone or combined with estrogen) or vitamin D or both (218 years); and 61 were treated with sodium fluoride combined with conventional therapy (251 years). The fracture rate (per thousand person-years) was 834 in untreated patients, 419 in those given calcium with or without vitamin D, 304 in those given fluoride and calcium with or without vitamin D, 181 in those given estrogen and calcium with or without vitamin D, and 53 in those given fluoride, estrogen, and calcium with or without vitamin D. It was reduced in all treatment groups (P less than 0.001 for calcium and P less than 1 x 10(-6) for other combinations); fluoride (one years of treatment) and estrogen (but not vitamin D) independently reduced the rate from that observed with calcium alone (P less than 0.001). The combination of calcium fluoride, and estrogen was more effective than any other combination (P less than 0.001). These results provide grounds for optimism about the efficacy of combinations of available agents with sodium fluoride for fracture in postmenopausal osteoporosis.",0
1200,6295907,Effect of chronic ethanol feeding on hepatic collagen in the monkey,"The effect of chronic ethanol feeding was determined on parameters of hepatic collagen metabolism in the monkey. Four monkeys of the species Macaca radiata received a nutritionally adequate diet containing 50% of the calories as ethanol, while four others were pair-fed a diet in which ethanol was isocalorically substituted by carbohydrate. Liver biopsies were obtained at 3, 12, and 24 months, and the animals were killed between 40 and 48 months after initiation of the diets. The ethanol-fed animals developed various degrees of fatty infiltration, but no necrosis, inflammation, or fibrosis. The amount and distribution of collagen Types I, III, and IV demonstrated by immunohistochemical techniques was not altered after ethanol feeding. No changes were found in hepatic protein-bound hydroxyproline or in collagen prolyl hydroxylase activity at the various time intervals. Liver free proline and the incorporation of labeled proline into protein-bound hydroxyproline by liver slices were not altered after 40 to 48 months of ethanol feeding. This study shows that prolonged feeding of ethanol together with an adequate diet results in fatty infiltration but not deposition or alteration of hepatic collagen metabolism.",0
1201,6310394,Central-nervous-system lymphoma related to Epstein-Barr virus,"We have studied five cases suggesting a relation between Epstein-Barr virus infection and primary lymphoma of the central nervous system. A 48-year-old man had primary lymphoma of the central nervous system in the absence of systemic lymphoma or immunosuppression. Development of the tumor was associated with serologic evidence suggesting a recent primary infection with Epstein-Barr virus. DNA preparations from tumor tissue, but not from adjacent normal brain tissue, contained Epstein-Barr virus genomes when hybridized with a probe consisting of the BamHI K fragment of Epstein-Barr virus strain FF41. Evaluation of serum samples from four additional patients with central-nervous-system lymphoma revealed patterns of Epstein-Barr virus-specific antibody that were suggestive of an ongoing infection with EBV. Our results suggest induction of the lymphoma by Epstein-Barr virus.",0
1202,6310395,Sodium-potassium-ATPase activity is influenced by ethnic origin and not by obesity,"Previous investigations have suggested that red-cell ouabain binding (an indirect measure of sodium-potassium-ATPase activity) is lower in severely obese patients than in normal controls. We now confirm that ouabain binding measures sodium-potassium-ATPase activity, and we demonstrate that the level of this activity is genetically determined. The activity of this enzyme differs in various ethnic and racial groups, relatively high levels being encountered in non-Jewish white subjects, particularly those with some Scandinavian ancestry. On the other hand, black, Asian, and Jewish white subjects have lower sodium-potassium-ATPase activity. In contrast, no difference was found in red-cell sodium-potassium-ATPase activity between severely obese and normal persons, nor could we confirm a putative effect of food intake on the level of the red-cell enzyme. We suggest that in most earlier studies in which differences were found between normal and severely obese persons, those differences could have been due to differences in the ethnic origins of the obese and control populations.",0
1203,6312312,Occupational risk for primary cytomegalovirus infection among pediatric health-care workers,"The risk of acquiring cytomegalovirus (CMV) from infected infants concerns pediatric health-care workers, particularly those who may be pregnant. We determined the prevalence of CMV antibody, and thus of past infection, in groups of medical students and house staff, nurses, and physicians, and in groups of pregnant and nonpregnant young women in the community. Although age, sex, and race influenced the results, occupation did not. We then estimated the exposure of the health-care workers by determining the prevalence of CMV infection in three groups of asymptomatic infants for whom they provided care; CMV was shed in urine or saliva of 1.6 per cent of newborns, 13 per cent of premature infants hospitalized for over a month, and 5 per cent of older infants seen in outpatient settings. When we determined the incidence of primary infection in the adult groups by retesting the seronegative members about two years later, we found that the annual attack rates in the medical students (0.6 per cent), house staff (2.7 per cent), and nurses (3.3 per cent) were not higher than in young women in the community (2.5 per cent during pregnancy and 5.5 per cent between pregnancies). We conclude that although pediatric health-care workers frequently and unknowingly care for infants shedding CMV, this occupational contact confers no greater risk than that faced by young women in the community at large.",0
1204,6323983,Epstein-Barr virus replication in oropharyngeal epithelial cells,"Despite the well-established tropism of the Epstein-Barr virus (EBV) for human B lymphocytes, the cell type within the oropharynx capable of allowing EBV replication has never been conclusively identified. Using in situ cytohybridization, we demonstrated EBV DNA in oropharyngeal epithelial cells from 10 of 12 patients with infectious mononucleosis. In duplicates of specimens found to contain cell-associated EBV DNA, we detected EBV RNA in two of four samples, using a biotin-labeled EBV DNA probe, thereby confirming the intracellular location of the viral genome. In 20 of 28 throat washings analyzed, cytohybridization results and assays for cell-free infectious virus were in agreement. In seven of the eight remaining specimens, cytohybridization identified intracellular EBV DNA in the absence of detectable extracellular virus. We conclude that the oropharyngeal epithelial cell may be the target cell type that is productively infected in infectious mononucleosis.",0
1205,6330548,"Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria","""In previous studies, we observed increases in the circulating concentration and production rate of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in a large majority of patients with the syndrome of absorptive hypercalciuria. In the present study, the hypothesis that 1,25-(OD)2D production might be relatively autonomous in this syndrome was tested by fashioning a suppression test in which patients were challenged with a short-term increase in dietary calcium intake. We found that contrary to our hypothesis, the circulating concentration of 1,25-(OH)2D was remarkably sensitive to calcium intake in 15 patients with absorptive hypercalciuria (mean decrease, from 74 to 49 pg per milliliter, P less than 0.001). When this challenge was prolonged for two weeks, however, patients with absorptive hypercalciuria had evidence of an apparent """"escape"""" phenomenon, in which the circulating concentration of 1,25-(OH)2D rebounded toward its initial level and the renal tubular phosphate threshold fell markedly. These findings provide evidence for disordered control of renal phosphate handling and 1,25-(OH)2D production in absorptive hypercalciuria and suggest a linked rather than a cause-and-effect relation between these two abnormalities.""",0
1206,6330549,Idiopathic hyperaldosteronism. A possible role for aldosterone-stimulating factor,"To test the hypothesis that idiopathic hyperaldosteronism is secondary to increased adrenal stimulation by aldosterone-stimulating factor, we measured the latter in seven patients with idiopathic hyperaldosteronism and in four patients who had undergone surgical removal of an aldosterone-producing adenoma. In the patients with hyperaldosteronism, plasma aldosterone concentrations (mean +/- 1 S.E.) were 38 +/- 10 and 78 +/- 19 ng per deciliter in the supine and upright position, respectively (P less than 0.01). Supine plasma aldosterone-stimulating factor was 81 +/- 5 ng per deciliter in 15 normal subjects and 185 +/- 10 (P less than 0.01) in the patients with idiopathic hyperaldosteronism. After removal of an aldosterone-producing adenoma, plasma aldosterone-stimulating factor was normal. The supine value in each patient with idiopathic hyperaldosteronism was above the normal range (61 to 91 ng per deciliter) and increased to 290 +/- 59 ng per deciliter after four hours of upright posture. Twenty-four hour urinary excretion of aldosterone-stimulating factor was 424 +/- 35 ng (normal, 145 +/- 3; P less than 0.01) by affinity chromatography and high-pressure liquid chromatography, and it was not suppressed after two days of treatment with dexamethasone (0.5 mg orally every six hours). At the end of 48 hours, plasma concentrations were 248 +/- 40 ng per deciliter. Plasma cortisol and ACTH concentrations were under 2 micrograms per deciliter and under 40 pg per milliliter, respectively. We conclude that increased secretion of aldosterone-stimulating factor may be the cause of idiopathic hyperaldosteronism.",0
1207,6338385,The therapeutic efficacy of hemodialysis in schizophrenia,"Prompted by previous reports of substantial clinical improvement in most schizophrenic patients given hemodialysis for their psychiatric condition, we studied the efficacy of hemodialysis in 15 schizophrenic outpatients, under double-blind, controlled conditions. The patients were randomly assigned to either a real-sham or sham-real sequence of dialysis treatment. Results of repeated measurement and other analyses of data on symptoms and behavior that were collected before study treatment, at crossover, and at the end of treatment revealed no difference between the effects of real and sham dialysis. These results provide important experimental evidence of the lack of therapeutic efficacy of hemodialysis in schizophrenia.",0
1208,6350877,The infant seat as treatment for gastroesophageal reflux,"""Positioning in the infant seat (""""chalasia chair"""") for treatment of infants with gastroesophageal reflux is presumed to have a beneficial effect. We undertook a controlled, prospective study of such positioning to evaluate this purported benefit. Nine infants with documented gastroesophageal reflux participated in 18 paired two-hour postprandial trials in an infant seat and in the horizontal prone position. Distal esophageal pH monitoring demonstrated longer exposure to gastroesophageal reflux while infants were in the seat than when they were prone (28.2 +/- 6.4 per cent vs. 12.8 +/- 3.7 per cent of total time with pH less than 4.0, P = 0.023), a difference due largely to more episodes (16.0 +/- 2.4 vs. 10.1 +/- 2.3 per two-hour postprandial period, P = 0.002). We conclude that the infant seat, rather than being therapeutic in gastroesophageal reflux in children under six months of age, is actually detrimental, when compared with simply placing an infant prone.""",0
1209,6352448,A prospective randomized study of two sclerotherapy techniques for esophageal varices,"In a study designed to compare the efficacy and safety of two techniques of injection sclerotherapy, 40 patients (30 with cirrhosis and 10 with portal vein block) were randomly allocated to the sheath or free-hand technique. Although the former was associated with significantly less bleeding within the first 24 hr of injection (p less than 0.05) but more postinjection pain (p less than 0.05) and esophageal stricture, there was a trend toward earlier obliteration of varices. This was most marked over the first three courses of injection, and although frequency of rebleeding was not significantly less, none of the 11 episodes in the sheath group were fatal, compared to 5 of 15 bleeds in those injected by the free-hand technique (p less than 0.05).",0
1210,6355845,Diagnosis of human lymphoma with monoclonal antileukocyte antibodies,"Two monoclonal antibodies have been produced that react with antigens present on human white cells. These reagents differ from other monoclonal antibodies of similar specificity in that the antigens they recognize are resistant to conventional tissue-fixation and embedding procedures. These reagents can therefore be used in immunocytochemical staining of paraffin-embedded tissue sections. We assessed the practical usefulness of this technique in the histopathological diagnosis of human lymphoid neoplasms by staining a wide range of routine surgical biopsy specimens of normal and neoplastic tissue (gathered from five institutions), using an indirect immunoperoxidase technique. In all 40 cases of non-Hodgkin's lymphoma, positive labeling of neoplastic cells was obtained with one or both antibodies. In contrast, no staining of neoplastic cells was observed in 60 samples of nonlymphoid neoplasms. We conclude that many of the difficulties encountered by histopathologists in distinguishing between lymphoid and nonlymphoid neoplasms may be overcome by immunohistologic labeling with monoclonal antibodies such as the ones we have studied.",0
1211,6355851,Does free care improve adults' health? Results from a randomized controlled trial,"Does free medical care lead to better health than insurance plans that require the patient to shoulder part of the cost? In an effort to answer this question, we studied 3958 people between the ages of 14 and 61 who were free of disability that precluded work and had been randomly assigned to a set of insurance plans for three or five years. One plan provided free care; the others required enrollees to pay a share of their medical bills. As previously reported, patients in the latter group made approximately one-third fewer visits to a physician and were hospitalized about one-third less often. For persons with poor vision and for low-income persons with high blood pressure, free care brought an improvement (vision better by 0.2 Snellen lines, diastolic blood pressure lower by 3 mm Hg); better control of blood pressure reduced the calculated risk of early death among those at high risk. For the average participant, as well as for subgroups differing in income and initial health status, no significant effects were detected on eight other measures of health status and health habits. Confidence intervals for these eight measures were sufficiently narrow to rule out all but a minimal influence, favorable or adverse, of free care for the average participant. For some measures of health in subgroups of the population, however, the broader confidence intervals make this conclusion less certain.",0
1212,6363250,Ultrastructural studies of fibroblasts transfected with hepatitis B virus DNA,"Cultured 3T3 mouse fibroblasts transfected with cloned hepatitis B virus genome and DNA coding for methotrexate-resistant dihydrofolate reductase, produce and secrete significant amounts of hepatitis B surface antigen (HBsAg). Ultrastructural morphometry revealed that fibroblasts transfected with hepatitis B virus DNA contained significantly more lysosomes than did fibroblasts transfected with the gene coding for methotrexate resistance or normal fibroblasts. Although abundant HBsAg was found in the cytoplasm of transfected fibroblasts by immunologic methods, HBsAg particles were not detected by electron microscopy. Immunoelectron microscopy localized HBsAg to the nuclear envelope, rough endoplasmic reticulum, and endoplasmic cisternae. These findings suggest that the transfected cells produce mainly nonparticulate HBsAg or that they have a defect in intracisternal packaging of HBsAg into particles.",0
1213,6373549,Long-term co-cultures of adult human hepatocytes with rat liver epithelial cells: modulation of albumin secretion and accumulation of extracellular material,"High yields of viable human hepatocytes were obtained by enzymatic perfusion of the left hepatic lobe of kidney donors and cultured alone or with an epithelial cell line derived from rat liver. In conventional cultures, human hepatocytes did not survive more than 2 to 3 weeks and by Day 8 decreased their ability to secrete albumin. When co-cultured, they survived for more than 2 months and secreted high levels of albumin even in a serum-free medium. This long-term survival appeared to correlate with production of an extracellular material which is rich in Type III collagen. In vitro phenotypic alterations of parenchymal cells were reversed by addition of rat liver cells and were characterized by recovery of cuboidal morphology, increased albumin secretion and a shift from Type I to Type III collagen deposition. Rat liver epithelial cells could not be replaced by nonhepatic epithelial cells. These observations suggest that when adult human hepatocytes are maintained in a culture which closely resembles their in vivo environment, they are capable of continuing to actively express specific cell functions.",0
1214,6384002,"Anatomy, visualization and sampling of the biliary tree in animals and man","Difficulties in obtaining proper bile samples are due to inaccessibility of the biliary tree and to distortions induced by sampling methods. One must be cognizant of the effects of diet on bile secretion and gallbladder motility. Experimental methods which interrupt the enterohepatic circulation or alter the intestinal migrating myoelectric complex induce spurious changes in bile flow and composition. Biliary tract pressure-flow relationships must be maintained or the gallbladder will be made functionless. Dead space errors lead to distortions unless studies are performed in the steady state, or dead space is measured and corrections are applied. Surgery has major effects on some parameters of interest, and animals should be allowed to recover when these are studied. The effect of the mixing of bile with other secretions in the duodenum must be considered when using bile-rich duodenal fluid. For some parameters of bile secretion, mixing is unimportant but for others, special precautions for handling bile and interpreting results are required.",0
1215,6384004,Chemistry and enterohepatic circulation of bile acids,"A brief review is given of the chemistry of bile acids, emphasizing the relationship between chemical structure, physical properties and enterohepatic cycling of the major primary and secondary bile acids. Features of the enterohepatic circulation of primary and secondary bile acids in man are summarized. The effects of bile acid feeding on the composition of the enterohepatic circulation in man are reviewed. Methods for characterizing the enterohepatic circulation of bile acids in man are tabulated.",0
1216,6384006,"Size of bile salt micelles: techniques, problems and results","The current state of the knowledge of the size and the aggregation numbers of micelles formed in solutions of bile salts was evaluated. The experimental techniques considered include static light scattering, sedimentation equilibrium, membrane osmometry, sedimentation velocity and translational diffusion. The theoretical background of each method is briefly discussed, the working equations are summarized, and the limitations of each technique are enumerated. Various interaction parameters and their effects on the measured micellar size are discussed. A brief survey of the recent experimental results from the author's laboratory is presented.",0
1217,6387483,Glucose counterregulation and waning of insulin in the Somogyi phenomenon (posthypoglycemic hyperglycemia),"To determine the roles of glucose counterregulation and the waning of insulin action in the development of posthypoglycemic hyperglycemia (the Somogyi phenomenon), we studied changes in plasma glucose and glucose turnover in five patients with insulin-dependent diabetes mellitus (IDDM) after subcutaneous injection of insulin under conditions in which hypoglycemic glucose counterregulation and the waning of insulin action were allowed to occur or were prevented. In control experiments, in which both glucose counterregulation and insulin waning were allowed to occur, plasma glucose levels decreased from 94 +/- 3 to 47 +/- 7 mg per deciliter and then increased to 289 +/- 20 mg per deciliter at 12 hours because of a marked increase in glucose production. When the waning of insulin action was prevented by insulin infusion, glucose production increased less (P less than 0.01), but marked rebound hyperglycemia still occurred (188 +/- 26 mg per deciliter at 12 hours). When both insulin waning and glucose counterregulation were prevented by infusion of both glucose and insulin, glucose production did not increase, and rebound hyperglycemia did not occur. We conclude that hypoglycemia can cause rebound hyperglycemia in the absence of insulin waning in patients with IDDM, and that this results primarily from an excessive increase in glucose production due to activation of glucose counterregulatory systems.",0
1218,6389303,Detection of reovirus type 3 in the porta hepatis of an infant with extrahepatic biliary atresia: ultrastructural and immunocytochemical study,"This report describes immunocytochemical and ultrastructural methods which led to the identification of Reovirus type 3 (Reo-3) in the porta hepatis of a patient with extrahepatic biliary atresia. The study indicates that Reo-3 antigenic sites are demonstrable by the avidin-biotinylated complex peroxidase method following formalin fixation and paraffin embedding, but are destroyed by freezing and thawing prior to fixation. Deparaffinization of the block and subsequent rembedding in epon-araldite did not alter immunoperoxidase staining. This procedure offered the advantage of higher light microscopic resolution of semithin (1 micron) sections and assisted in the selection of specific areas for ultrastructural studies. Localization of Reo-3 in extrahepatic biliary atresia was confined to a biliary remnant in which there were acutely inflammed, partially necrotic microscopic ducts. Electron microscopic examination of the immunoreactive sites revealed virus-like particles similar in appearance to Reo-3 particles in infected tissue culture cells. The observations presented here support previously reported serologic data which have shown an association between Reo-3 infection and extrahepatic biliary atresia.",0
1219,6390207,Effectiveness of a geriatric evaluation unit. A randomized clinical trial,"We randomly assigned frail elderly inpatients with a high probability of nursing-home placement to an innovative geriatric evaluation unit intended to provide improved diagnostic assessment, therapy, rehabilitation, and placement. Patients randomly assigned to the experimental (n = 63) and control (n = 60) groups were equivalent at entry. At one year, patients who had been assigned to the geriatric unit had much lower mortality than controls (23.8 vs. 48.3 per cent, P less than 0.005) and were less likely to have initially been discharged to a nursing home (12.7 vs. 30.0 per cent, P less than 0.05) or to have spent any time in nursing home during the follow-up period (26.9 vs. 46.7 per cent, P less than 0.05). The control-group patients had substantially more acute-care hospital days, nursing-home days, and acute-care hospital readmissions. Patients in the geriatric unit were significantly more likely to have improvement in functional status and morale than controls (P less than 0.05). Direct costs for institutional care were lower for the experimental group, especially after adjustment for survival. We conclude that geriatric evaluation units can provide substantial benefits at minimal cost for appropriate groups of elderly patients, over and above the benefits of traditional hospital approaches.",0
1220,6402699,Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever,"To clarify the mechanisms underlying the loss of body protein during fever and sepsis, we incubated rat muscles with highly purified human leukocytic pyrogen. This polypeptide, which appears identical to interleukin-1, is released by leukocytes and signals the onset of fever in the hypothalamus. In muscles incubated at 37 degrees C, leukocytic pyrogen stimulated net protein degradation by 62 to 118 per cent (P less than 0.001). Proteolysis increased, but rates of muscle-protein synthesis did not change. The pyrogen also dramatically stimulated muscle synthesis of prostaglandin E2, which promotes protein breakdown in this tissue. Addition of indomethacin with leukocytic pyrogen prevented prostaglandin E2 synthesis and abolished the increase in proteolysis. The acceleration of protein breakdown induced by pyrogen was also blocked by Ep-475, an inhibitor of lysosomal thiol proteases. When muscles were incubated at 39 degrees C to mimic fever, protein breakdown increased, but addition of leukocytic pyrogen caused a further marked increase in proteolysis and prostaglandin E2 production. Thus, human leukocytic pyrogen can act on skeletal muscle to stimulate intralysosomal proteolysis by increasing the production of prostaglandin E2. These findings suggest that cyclooxygenase inhibitors may be useful in the treatment of negative nitrogen balance in fever. In addition, the release of prostaglandin E2 induced by leukocytic pyrogen may account for the myalgia that accompanies fever.",0
1221,6405272,Economic evaluation of neonatal intensive care of very-low-birth-weight infants,"We evaluated the economic aspects of neonatal intensive care of very-low-birth-weight infants, using outcomes and costs of care before and after the introduction of a regional neonatal-intensive-care program. Neonatal intensive care increased both survival rates and costs. For newborns weighing 1000 to 1499 g, the cost (in 1978 Canadian dollars) was $59,500 per additional survivor, $2,900 per life-year gained, and $3,200 per quality-adjusted life-year gained; intensive care resulted in a net economic gain when figures were undiscounted but a net economic loss when future costs, effects, and earnings were discounted at 5 per cent per annum. For infants weighing 500 to 999 g, the corresponding costs were $102,500 per additional survivor, $9,300 per life-year gained, and $22,400 per quality-adjusted life-year gained; intensive care resulted in a net economic loss. By every measure of economic evaluation, the impact of neonatal intensive care was more favorable among infants weighing 1000 to 1499 g than among those weighing 500 to 999 g. A judgment concerning the relative economic value of neonatal intensive care of very-low-birth-weight infants requires a comparison with other health programs.",0
1222,6410239,Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease,"This study was designed to determine whether the plasma level of apolipoprotein A-I is a better discriminator of angiographically documented coronary-artery disease than the level of high-density-lipoprotein (HDL) cholesterol in male subjects. The level of plasma apolipoprotein A-I in 83 patients with coronary-artery disease was 96.7 +/- 4.2 mg per deciliter (mean +/- S.E.M.), which was significantly lower (P less than 0.0001) than the level in 25 patients without coronary-artery disease (146.9 +/- 2.1 mg per deciliter). The levels of HDL cholesterol were also lower (P less than 0.0001) in patients with coronary-artery disease (31.9 +/- 1.5 mg per deciliter) than in those without it (45.9 +/- 2.3 mg per deciliter). A stepwise discriminant analysis, however, indicated the superiority of apolipoprotein A-I over HDL cholesterol in detecting coronary-artery disease. Furthermore, a linear discriminant analysis suggested that although HDL cholesterol by itself was a discriminator of coronary-artery disease, it did not provide a substantial increase in discriminatory value over that provided by apolipoprotein A-I; in contrast, apolipoprotein A-I levels added discriminatory value to the information obtained by measuring HDL cholesterol alone. We conclude that apolipoprotein A-I by itself is more useful than HDL cholesterol for identifying patients with coronary-artery disease.",0
1223,6417538,Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms,"Immunoglobulin genes in their germ-line form are separated DNA subsegments that must be joined by means of recombinations during B-cell development. Individual immunoglobulin-gene rearrangements are specific for a given B cell and its progeny. We show that the detection of such gene rearrangements by Southern hybridization provides a sensitive marker for both clonality and B-cell lineage within lymphoid tissues lacking expression of definitive surface phenotypes. We have used these genetic markers in three ways: to establish a diagnosis of lymphoma in a neoplastic disorder of uncertain cell type, to show that some lymphomas that were previously classified as being of T-cell type in fact contain monoclonal B cells, and to detect clonal B-cell populations within lymphomatous tissues of uncertain immunotype and within an atypical lymphofollicular hyperplasia having no other clonal surface markers. These sensitive and unique indicators of clonality located directly at the DNA level are capable of providing insights into the cellular origin, early detection, and natural history of neoplasia.",0
1224,6417539,Yogurt--an autodigesting source of lactose,"Large quantities of yogurt are consumed by some lactase-deficient population groups. We used breath hydrogen measurements to determine whether lactase-deficient subjects absorbed lactose in yogurt better than lactose in milk. Ingestion of 18 g of lactose in yogurt resulted in only about one third as much hydrogen excretion as a similar load of lactose in milk or water, indicating a much better absorption of lactose in yogurt. Ingestion of yogurt also resulted in fewer reports of diarrhea or flatulence than did a similar quantity of lactose ingested in milk or a water solution. The enhanced absorption of lactose in yogurt appeared to result from the intraintestinal digestion of lactose by lactase released from the yogurt organisms. This autodigesting feature makes yogurt a well-tolerated source of milk for lactase-deficient persons and may explain the widespread consumption of yogurt by lactase-deficient population groups.",0
1225,6419110,Mortality among diabetic patients using continuous subcutaneous insulin-infusion pumps,"Because of concern about deaths among diabetic patients using continuous subcutaneous insulin-infusion pumps, we conducted an investigation to determine whether the number of such deaths was excessive. By October 1982 we had identified 35 deaths among the estimated 3500 diabetic patients using pumps in the United States. The observed number of deaths was not greater than the expected number calculated from age-specific death rates for conventionally treated patients with Type I diabetes. The causes of death were not unusual, with two exceptions. One death was associated with malfunction of the device, and the other was attributed to acute bacterial endocarditis that arose from an abscess at the catheter-insertion site. Patients who died had high rates of autonomic neuropathy (66 per cent) and renal disease (39 per cent with serum creatinine levels above 5 mg per deciliter). We conclude that the use of continuous subcutaneous insulin-infusion pumps is not associated with excess mortality. However, certain types of patients may be at greater risk for death, and physicians should take great care in selecting patients for pump therapy.",0
1226,6422299,Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome,"To examine the cellular immune defect that predisposes patients with the acquired immunodeficiency syndrome (AIDS) to opportunistic infections, we tested T lymphocytes from 16 patients for the capacity to secrete macrophage-activating products (lymphokines) including gamma interferon. Mononuclear cells from 10 of 11 patients did not generate an effective lymphokine in response to mitogen, and 11 of 16 produced subnormal levels of gamma interferon (less than 300 U per milliliter). In addition, upon stimulation with specific microbial antigen, cells from none of 14 patients generated active lymphokines, and cells from 13 to 14 completely failed to secrete gamma interferon. However, the antimicrobial function of monocytes from the patients was intact, and once stimulated with normal lymphokines or gamma interferon alone, macrophages derived from patients' monocytes responded with enhanced and effective intracellular antimicrobial activity. These results suggest that impaired lymphokine production may predispose patients with AIDS to opportunistic infections, and they provide a rationale for using gamma interferon as immunotherapy.",0
1227,6427612,Biclonal B-cell lymphoma,"The cells of most tumors are considered to be genetically homogeneous because they are assumed to represent a single clone descended from one abnormal cell. We have discovered three cases of B-cell lymphoma for which this generalization is not true. In each case, the tumor was composed of two subpopulations of cells, each expressing a different immunoglobulin molecule. Antibodies directed against these immunoglobulins were used to separate the two cell subpopulations of each tumor on a fluorescence-activated cell sorter. DNA extracted from the original tumor and the two fractionated subpopulations was analyzed to determine the configuration of immunoglobulin genes. Differences were found in the arrangement of DNA in at least one immunoglobulin gene for each of the two subpopulations. Thus, biclonality of these tumors was revealed by examination of both protein markers (cell-surface immunoglobulin) and DNA markers (immunoglobulin-gene rearrangements). Our results indicate that the incidence of biclonal B-cell lymphoma may be higher than previously recognized, possibly as high as 10 per cent of all B-cell lymphomas. Furthermore, our findings may have important implications for the diagnosis and therapy of lymphoid cancers.",0
1228,6434390,Prolonged maintenance of active cytochrome P-450 in adult rat hepatocytes co-cultured with another liver cell type,"The cytochrome P-450 content promptly fell in adult rat hepatocytes cultured in conventional conditions whereas no obvious change was detected over a 10-day period when these cells were co-cultured with another rat liver epithelial cell type. A concomitant maintenance of the amino-pyrine N-demethylase activity and a high aflatoxin B1-induced cytotoxicity was observed, and addition of phenobarbital to the culture medium produced about a 2-fold increase in cytochrome P-450 level. These results indicate that when placed in co-culture, adult hepatocytes remain differentiated for several days and suggest that such a co-culture system is an appropriate model for pharmacotoxicological studies.",0
1229,6436706,Impaired growth hormone responses to growth hormone-releasing factor in obesity. A pituitary defect reversed with weight reduction,"To investigate whether the impaired growth hormone secretion associated with obesity is a result of a hypothalamic or a pituitary disorder and whether it is a cause or a consequence of obesity, we studied plasma growth hormone responses to growth hormone-releasing factor in morbidly obese patients before gastrointestinal surgical therapy, in formerly obese subjects who had lost considerable weight postoperatively, and in non-obese controls. Growth hormone secretion was also assessed in response to insulin-induced hypoglycemia (in seven patients preoperatively and four postoperatively). In patients studied preoperatively, growth hormone responses to growth hormone-releasing factor were markedly impaired (P less than 0.001 as compared with controls), whereas in patients studied postoperatively they were partially restored to normal (P less than 0.05 as compared with those studied preoperatively). Growth hormone responses to insulin-induced hypoglycemia were similarly diminished in obese patients studied before operation (P less than 0.02). The growth hormone response to growth hormone-releasing factor was inversely correlated with the percentage of ideal body weight (P less than 0.01) and directly correlated with the growth hormone response to insulin (P less than 0.01). The impaired responsiveness to growth hormone-releasing factor suggests that the diminished response to insulin hypoglycemia is mediated by an impaired pituitary response to endogenous growth hormone-releasing factor. The reversibility of the defect after weight reduction suggests that it is a consequence rather than a cause of obesity.",0
1230,6438505,Circulating monoclonal B lymphocytes in non-Hodgkin's lymphoma,"""Using a sensitive flow cytometric method (""""kappa-lambda analysis""""), we have found monoclonal B lymphocytes in the blood of 71 of 91 patients with non-Hodgkin's lymphoma. The presence of the B lymphocytes was independent of the histologic subclassification of the patient's disease. When we performed simultaneous analysis of the surface light-chain type in tumor tissue obtained by biopsy, the apparent light-chain type of the blood monoclonal cells corresponded with that of the tumor in 21 of 23 patients (P = 0.03). There was no correlation of the presence of these cells in the blood with morphologic evidence of bone-marrow involvement by lymphoma, but there was a strong correlation with clinical staging. Studies performed during prolonged clinical remission showed that whereas 16 of 25 patients with nodular non-Hodgkin's lymphoma had persistence of monoclonal lymphocytes, none of the 14 patients with diffuse histiocytic lymphoma in remission had these findings (P less than 0.005). Our analysis for B-cell clonal excess demonstrates the persistence of circulating monoclonal lymphocytes during complete remission in patients with forms of lymphoma that have a high probability of relapse, but we did not find these cells in patients in remission from categories of lymphoma in which prolonged remission is associated with cure. It is possible that the circulating monoclonal lymphocytes in patients with lymphoma are malignant cells, and their disappearance or persistence after remission may have prognostic importance.""",0
1231,6453293,Activation of leukemic pro-suppressor cells to become suppressor-effector cells. Influence of cooperating normal T cells,"We studied the suppressor activity and surface-membrane antigens of immunoregulatory neoplastic T cells from a child with acute lymphoblastic leukemia and hypogammaglobulinemia. The neoplastic T cells were potent inhibitors of immunoglobulin production by pokeweed-mitogen-stimulated normal B cells when radiosensitive cooperative normal T cells were present. Preculturing the leukemic cells with normal T cells or soluble factors allowed them to mediate suppression without the need for cooperating T cells. While acquiring new functional capabilities, approximately 95 per cent of the leukemic cells displayed an antigen (OKT-3) that is found on mature normal T cells; 77 per cent displayed an antigen (Tac) that is found on normal activated immunoregulatory effector cells but not on thymocytes or circulating T cells that are precursors of these effector cells. The results suggest that a population of leukemic prosuppressor cells can be induced to undergo both functional and antigenic differentiation by the influence of normal T cells.",0
1232,6454846,Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity,"Using the monoclonal antibodies OKT4 and OKT8, we determined the proportions of helper and suppressor T cells in patients with sarcoidosis and high-intensity alveolitis, patients with sarcoidosis and low-intensity alveolitis, patients with idiopathic pulmonary fibrosis (IPF), and normal controls. In controls and patients with IPF, the ratio of helper to suppressor T cells was 1.8:1 in lungs and blood. In contrast, this ratio was 10.5:1 in lungs (P less than 0.001) and 0.8:1 in blood (P less than 0.05) in patients with sarcoidosis and high-intensity alveolitis. The ratio of helper to suppressor T cells was not higher in the lungs or blood of patients with sarcoidosis and low-intensity alveolitis; on the contrary, because of the higher proportions of suppressor cells, the ratio of helper to suppressor cells was lower in both lungs and blood. In studies of function, lung T cells from patients with sarcoidosis and high-intensity alveolitis released monocyte chemotactic factor (a lymphokine critical to granuloma formation) and polyclonally activated B cells to produce immunoglobulins. We conclude that one determinant of lung injury in sarcoidosis in the presence of large numbers of lung helper T cells, which are important in granuloma formation.",0
1233,6472399,The incidence of primary cardiac arrest during vigorous exercise,"To examine the risk of primary cardiac arrest during vigorous exercise, we interviewed the wives of 133 men without known prior heart disease who had had primary cardiac arrest. Cases were classified according to their activity at the time of cardiac arrest and the amount of their habitual vigorous activity. From interviews with wives of a random sample of healthy men, we estimated the amount of time members of the community spent in vigorous activity. Among men with low levels of habitual activity, the relative risk of cardiac arrest during exercise compared with that at other times was 56 (95 per cent confidence limits, 23 to 131). The risk during exercise among men at the highest level of habitual activity was also elevated, but only by a factor of 5 (95 per cent confidence limits, 2 to 14). However, among the habitually vigorous men, the overall risk of cardiac arrest--i.e., during and not during vigorous activity--was only 40 per cent that of the sedentary men (95 per cent confidence limits, 0.23 to 0.67). Although the risk of primary cardiac arrest is transiently increased during vigorous exercise, habitual vigorous exercise is associated with an overall decreased risk of primary cardiac arrest.",0
1234,6472421,Sex differences in the effect of diabetes mellitus on lipoprotein triglyceride and cholesterol concentrations,"We studied sex differences in the serum lipid abnormalities associated with diabetes mellitus in 111 patients with insulin-dependent diabetes and 270 patients with non-insulin-dependent diabetes, who were compared with 586 nondiabetic controls. Relative to control levels, the increases in triglycerides were 17 to 34 mg per deciliter greater in diabetic women than in diabetic men. The median low-density-lipoprotein cholesterol concentration in non-insulin-dependent diabetics was 1 to 4 mg per deciliter lower than the control level in women and 16 to 22 mg per deciliter lower in men, and was 30 mg per deciliter higher than control in insulin-dependent diabetic women and similar to control in insulin-dependent diabetic men. The decrease in median high-density-lipoprotein cholesterol in non-insulin-dependent diabetics was 2 to 7 mg per deciliter greater in women than in men, and the increase in high-density-lipoprotein cholesterol in insulin-dependent diabetics was 3 mg per deciliter less in women than in men. We conclude that diabetes has a greater adverse effect on triglyceride and lipoprotein cholesterol concentrations in diabetic women than in diabetic men, and that this may explain the greater increase in risk of arteriosclerosis in diabetic women.",0
1235,6479853,Acetaldehyde stimulates collagen and noncollagen protein production by human fibroblasts,"The mechanisms responsible for the increased hepatic collagen deposition in alcoholic cirrhosis remain unknown. The question of whether ethanol or acetaldehyde has a direct effect on collagen and noncollagen protein production was investigated in human fibroblasts with no detectable activity of alcohol dehydrogenase to distinguish the effects of these metabolites. To eliminate environmental factors, protein production by confluent human skin, fetal and hepatic fibroblasts was studied after three passages. Cells were labeled with [5-3H]proline for 4 hr in the presence of 0.2 mM ascorbate alone or with addition of either ethanol (50 mM) or acetaldehyde (0 to 300 microM). Rates of protein production were calculated from the radioactivities of collagenase-sensitive and collagenase-resistant proteins. Skin fibroblasts from alcoholic individual either with cirrhosis or without liver disease have comparable rates of collagen and noncollagen protein production. Acetaldehyde, in a concentration found in the liver during ethanol abuse, significantly increased collagen production by human skin fibroblasts (up to 140%), fetal fibroblasts (up to 240%) and hepatic fibroblasts (up to 70%) but the addition of ethanol had no significant effect on basal collagen production. The effect of acetaldehyde was dose-related and affected noncollagen protein production in a similar manner. Acetaldehyde did not cause changes in either proline transport or the specific activity of the proline precursor pool. This newly recognized stimulation of collagen production by acetaldehyde may be a possible mechanism of fibrogenesis in alcoholic individuals.",0
1236,6479858,Pneumococcal vaccination: the response of patients with alcoholic liver cirrhosis,"Patients with cirrhosis have an increased risk of dying from pneumococcal pneumonia. Their immunological response to pneumococcal vaccination is not known. We compared the antibody response to challenge with a 14-valent purified pneumococcal polysaccharide vaccine in 15 patients with biopsy-proven alcoholic liver cirrhosis, 10 healthy volunteers and 10 patients with chronic obstructive pulmonary disease. Preimmunization levels for Danish type 1 pneumococcal polysaccharide were lower among cirrhotics than patients with chronic obstructive pulmonary disease. Four and 12 weeks after immunization, no significant differences were found in antibody concentrations between the three groups. We conclude that patients with alcoholic cirrhosis can produce an adequate antibody response to pneumococcal polysaccharide antigen.",0
1237,6479869,Bile salt structure and phase equilibria in aqueous bile salt and bile salt-lecithin systems,"""The hydrophilic-hydrophobic balance of bile salt monomers can be readily quantified by their elution sequence during reverse-phase high-performance liquid chromatography. Such studies have demonstrated that subtle variations in bile salt structure have profound effects on the hydrophilic-hydrophobic balance of this important family of detergent-like molecules. The common trihydroxy bile salt, cholate, is more hydrophilic than dihydroxy bile salts with alpha-oriented OH groups. In contrast, dihydroxy bile salts with one equatorial OH function are more hydrophilic than cholate. Hydrophilic bile salts have, in general, higher critical micellar concentrations than do hydrophobic bile salts and their primary micelles polymerize less readily to form secondary micelles either with increasing bile salt concentrations or with increases in ionic strength. Hydrophilic bile salts also disperse lecithin into mixed micelles at a slower rate than do hydrophobic bile salts. The structure of mixed bile salt-lecithin micelles is more complex than previously believed and varies with bile salt-to-lecithin ratio. These micelles are disc-like in which bile salts saturate the lecithin bilayer """"core"""" presumably as reverse micelles, as well as coating the perimeter as a bilayered """"ribbon"""". The ratio of bile salt to lecithin in the bilayer and the intermicellar monomeric bile salt concentration (critical micellar concentration) determines the macroscopic phase limit. With the common bile salt species, the lecithin-to-bile salt phase limit does not correlate closely with the hydrophilic-hydrophobic balance of the bile salt monomers.(ABSTRACT TRUNCATED AT 250 WORDS)""",0
1238,6479870,Dynamic laser light scattering studies of the micelle to vesicle transition in model and native bile,"Using quasielastic light scattering, we investigated the formation of vesicles produced spontaneously by diluting a mixed micellar solution of bile salt and lecithin beyond the micellar phase boundary. The vesicles were nearly monodisperse, and their size varied between 120 to 500 A depending upon the dilution conditions. A systematic study of the dependence of the vesicle size upon the bile salt and lecithin concentration was made and interpreted in terms of a simple equilibrium model. Likewise, the particle size distribution in native bile obtained from the dog was studied. A comparison of the dilution effect on native bile and on model bile of identical biliary lipid composition provides unambiguous evidence for micellar aggregates and the occurrence of a micelle to vesicle transition in native bile.",0
1239,6479871,Liquid crystalline phase formation by cholesterol in aqueous fatty acid salt solutions,"The interaction of cholesterol with fatty acid salt solutions was investigated as a potential method for gallstone dissolution. In the presence of sodium oleate or laurate, crystalline cholesterol was rapidly converted into a lamellar liquid crystalline phase. Analysis of the mesophase showed that it contained approximately equimolar amounts of the lipid components, although water was the major constituent. The rate of conversion of cholesterol to mesophase was determined from a compressed disc immersed in a stirred solution, as if it were a simple dissolution process. The apparent rate of solubilization was independent of oleate concentration in the 2.5 to 10% range and was approximately 200 times faster than micellar dissolution of cholesterol in 5% sodium cholate. A mechanism is proposed in which the rate-limiting step in mesophase formation is dispersion of liquid crystalline fragments into the bulk medium.",0
1240,6479872,Aqueous bile salt-lecithin-cholesterol systems: equilibrium aspects,"""Cholesterol is solubilized by bile salt and bile salt-lecithin micelles without appreciable alteration in preexisting micellar size or structure. In dilute (approximately 3 gm per dl) model bile, but not in concentrated (approximately 10 gm per dl) systems, supramicellar concentrations of cholesterol are also solubilized in """"stable"""" microdispersions of small lecithin-cholesterol vesicles (approximately 200 to 400 A in radius). Under physical-chemical conditions of physiological importance, the micellar solubilities of cholesterol are influenced by the total lipid concentrations, lecithin-to-bile salt ratio and bile salt species. The hydrophilic-hydrophobic balance of the bile salt monomer also influences the number and composition of precipitate phases coexisting in equilibrium with saturated micelles. When diluted below the critical micellar concentration (more correctly, the intermicellar concentration) of the bile salt species, the systems no longer contain micelles, but cholesterol remains dispersed in unilamellar liposomes that form spontaneously from the mixed micellar concentrations of the biliary lipids.""",0
1241,6479873,Metastability behavior of supersaturated bile,"Major discrepancies exist between both the degree (or cholesterol excess limit) and duration of metastable cholesterol supersaturation in concentrated model biles and native human gallbladder bile. The comparatively reduced metastability of in vitro model systems suggests that a stabilizing factor is absent in these more concentrated systems. In contrast, the metastable supersaturation behavior of the dilute model and hepatic biles is similar particularly with respect to their markedly prolonged metastability, i.e., nucleation time. These observations suggest that changes in the lipid component alone (e.g., structural alterations resulting from dilution) could account for the similarity. The structural component in hepatic biles and in comparable dilute model systems appears to be small unilamellar vesicles which have an unusual duration of metastability and a high capacity for cholesterol transport. In this sense, metastability properties characteristic of pure micellar systems are neither observed nor to be expected in human hepatic bile and are only partially responsible for metastability in gallbladder bile.",0
1242,6479875,Dissolution rate of cholesterol in monooctanoin,"Monooctanoin is used clinically for dissolution of common bile duct cholesterol gallstones. A number of factors influencing the dissolution rate of cholesterol monohydrate in this solvent were investigated. Water increased cholesterol dissolution rate in a manner inconsistent with previous solubility measurements. Dissolution rate increased approximately 50% in the presence of 10 to 15% water in monooctanoin. Further studies on viscosity, the effect of polymers and temperature showed that the solvent viscosity had a dominating influence on dissolution rate. This was thought to be caused by the interaction of cholesterol with the solvent in the dissolving surface layer which caused a decrease in the diffusion coefficient (and dissolution rate) of cholesterol. Reducing viscosity and increasing temperature were identified as possible approaches for increasing cholesterol gallstone dissolution rate in monooctanoin.",0
1243,6479876,Factors influencing cholesterol nucleation in bile,"Dilution induces structural alterations (i.e., vesicle formation) in the lipid particles of supersaturated human hepatic bile and in dilute model bile systems of comparable composition. These alterations strikingly increase both the degree and duration of metastable supersaturation. Concentrated normal human gallbladder bile also shows an increased but less striking degree and duration of metastability compared to comparable model biles. These differences, particularly with respect to gallbladder bile, cannot be attributed solely to compositional or lipid structural differences between native and model systems. They imply that additional factors are responsible for metastability. Furthermore, recent data suggest that biliary proteins may be involved. A limited number of these unidentified proteins have been shown to have the capacity to prolong metastability in supersaturated in vitro model systems. Thus, these recombined systems more nearly resemble the behavior of native bile. The mechanism of the nucleation inhibitory effect of these proteins is not clearly established.",0
1244,6479877,Evidence for a nucleation defect in bile from gallstone patients,"When modern methods of estimating cholesterol saturation in bile were first applied to human bile samples, it seemed that a clear distinction could be made between normal and abnormal biles on the basis of cholesterol saturation. Supersaturation of bile with cholesterol appeared to be the only critical defect required for stone formation. A variety of evidence has now accumulated which indicates that a nucleation defect is also important. Chief among these observations is the fact that gallbladder bile from stone patients nucleates cholesterol crystals more rapidly than equally saturated gallbladder bile from controls. To determine whether the gallbladder contributes to the nucleation defect, hepatic and gallbladder bile nucleation times have been compared. Although the former is more supersaturated, the latter nucleates faster suggesting that the gallbladder is important. In another study, the nucleation times of crystal-free abnormal bile, normal bile and a mixture of the two were obtained. The mixture nucleated as rapidly as the abnormal bile even when the abnormal bile contributed only 5% of the volume of the mixture. This indicated that a nucleating factor is added to abnormal bile in the gallbladder.",0
1245,6479888,Effect of nuclear hydroxy substituents on aqueous solubility and acidic strength of bile acids,"The aqueous solubility and thermodynamic dissociation constants of a representative series of bile acids with varying numbers and configuration of nuclear hydroxyl substituents were determined. The pKa values were calculated by extrapolating pKa' values determined in solutions of aqueous methanol of different mole fractions at 25 degrees C. All bile acids had the same acidic strength in water, indicating that the pattern of hydroxyl nuclear substituents does not affect the acidic strength probably because of the distance between the hydroxyl and ionizing groups. In contrast, aqueous solubility was dependent on the number, position and orientation of the hydroxyl groups. The solubility values ranged from 5 X 10(-8) M (0.05 microM) for 3 alpha-hydroxy-5 beta-cholanoic acid (lithocholic acid) to 1.67 X 10(-3) M (1,670 microM) for 3 alpha,7 beta,12 alpha-trihydroxy-5 beta-cholanoic acid (ursocholic acid). The hydroxy groups notably affect solubility by forming hydrogen bonds with water but also by reducing, according to their orientation, hydrophobicity of the steroid nucleus.",0
1246,6479891,Bile salt micelles: nuclear magnetic resonance spectroscopy and crystallographic studies,Studies of bile salt structure using nuclear magnetic resonance (NMR) and X-ray crystallography have suggested that micellar association of bile salts is a function of side chain length and of packing of the side chain and the steroid nucleus. Lanthanide NMR probe analysis has been used to determine the structure of what is probably the monomer of the bile salt glycocholate. These approaches to the structural chemistry of bile salt intra- and intermolecular interactions are providing the basis for the design of artificial bile salt-like compounds for use in the study and treatment of human gallstone disease.,0
1247,6493273,The association of smoking with cardiomyopathy,"We investigated the possibility that smoking has an association with ventricular wall-motion abnormalities that is independent of its known association with coronary occlusion. We studied 4763 men between the ages of 35 and 74 who had diagnostic coronary angiography and ventriculography. We considered three kinds of wall-motion abnormalities: hypokinesis in one to four ventricular segments, hypokinesis in five to six ventricular segments (diffuse hypokinesis), and akinetic or dyskinetic wall motion in at least one segment. Among men younger than 55, the relative risk of diffuse hypokinesis was 2.78 (1.1 to 6.99) for heavy smokers as compared with nonsmokers. Adjusting for the degree of coronary occlusion or eliminating subjects with a history of myocardial infarction did not change this relative risk. Among men who were 55 or older the relative risk (odds ratio for heavy smokers as compared with nonsmokers) was not significant (0.55 to 2.28). Regardless of age the relative risk of akinesis or dyskinesis, adjusted for coronary stenosis, was significant: 1.84 (1.28 to 2.65) for men under 55 and 1.57 (1.12 to 2.19) for men 55 or older. These results suggest that smoking is related to both cardiomyopathy and transmural myocardial infarction and that the relationships are largely separate from the association of smoking with coronary stenosis.",0
1248,6493284,Exercise radionuclide ventriculographic responses in hypertensive patients with chest pain,"The effectiveness of exercise-treadmill testing in diagnosing coronary-artery disease in hypertensive patients is limited by a high rate of false positivity. Exercise radionuclide ventriculography, however, relies on different criteria (ejection fraction and wall motion), and we have evaluated this procedure in 37 hypertensive and 109 normotensive patients with chest pain, using coronary arteriography as an indicator of coronary disease. In the hypertensive cohort there was no difference in the ejection fraction at rest between the 17 patients with coronary disease and the 20 without it. Neither group had a significant mean (+/- S.E.M.) change in ejection fraction from rest to exercise (-1.9 +/- 2 and - 1.4 +/- 1 per cent, respectively). A wall-motion abnormality developed during exercise in 5 of the 17 hypertensive patients with coronary disease (29 per cent) and in 4 of the 20 without it (20 per cent) (P = not significant). In the normotensive cohort, however, the peak-exercise ejection fractions were significantly different. The 71 patients with coronary disease had a mean decrease of 3.6 +/- 1 per cent, in contrast to the patients without coronary disease, who had an increase of 6 +/- 1 per cent (P less than 0.001). An exercise-induced wall-motion abnormality was seen in 35 of the 71 patients with coronary disease (48 per cent), as compared with 3 of the 38 without it, (8 per cent) (P less than 0.001). We conclude that exercise radionuclide ventriculography is inadequate as a screening test for coronary atherosclerosis in hypertensive patients with chest pain.",0
1249,6500514,Morphologic features of the liver in abetalipoproteinemia,"Liver tissue of a newly diagnosed 30-year-old patient with abetalipoproteinemia was studied by light and electron microscopy. Despite accumulation of large quantities of lipid droplets in hepatocytes, the lobular architecture remained intact, and there was no fibrosis. Acanthocytes were readily identified in sinusoids by scanning electron microscopy. Profiles of rough endoplasmic reticulum, smooth endoplasmic reticulum and Golgi apparatus appeared normal by transmission electron microscopy. Lipid droplets were not bound to membranes and were not associated with the endoplasmic reticulum or Golgi apparatus. In abetalipoproteinemia, these morphological features are consistent with defective apolipoprotein B synthesis. This prevents assembly of lipoproteins that can be secreted through the normal intracellular communicating tubular network and, consequently, fat accumulates in the cytoplasm of the hepatocytes.",0
1250,6537987,Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction,"Tissue-type plasminogen activator is a naturally occurring, clot-selective activator of fibrinolysis. We recently reported that human tissue-type plasminogen activator isolated from a Bowes-melanoma-tissue-culture supernate lysed coronary thrombi in dogs without depleting circulating fibrinogen or alpha 2-antiplasmin, in contrast to the case with streptokinase and urokinase. In the present study coronary thrombolysis, confirmed angiographically, was induced within 19 to 50 minutes with intravenous or intracoronary tissue-type plasminogen activator in six of seven patients with evolving myocardial infarction. Circulating fibrinogen, plasminogen, and alpha 2-antiplasmin were not depleted by this agent, in contrast to the case in the two patients subsequently given streptokinase. In the one patient in whom lysis was not inducible with tissue-type plasminogen activator, it was also not inducible with streptokinase. These observations indicate that clot-selective coronary thrombolysis can be induced in patients with evolving myocardial infarction by means of tissue-type plasminogen activator, without concomitant induction of a systemic lytic state. Definition of its therapeutic benefit must await greater availability of the agent and the performance of appropriate clinical trials.",0
1251,6574315,Long-term marrow culture reveals chromosomally normal hematopoietic progenitor cells in patients with Philadelphia chromosome-positive chronic myelogenous leukemia,"We found that when marrow cells from four patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia were maintained in culture for two to four weeks, a previously undetectable population of chromosomally normal hematopoietic cells (including erythroid, granulopoietic, and pluripotent progenitors) became readily demonstrable in three cases. Time-course studies showed that in such cultures the dominant Philadelphia chromosome-positive population rapidly disappeared, in contrast to coexisting chromosomally normal progenitors, which remained detectable for periods of two to three months. Long-term marrow cultures thus offer a new approach to the assessment of a suppressed but functionally intact population of chromosomally normal hematopoietic stem cells in patients with chronic myelogenous leukemia.",0
1252,6586630,Quantitative microscopy comparison of peroxisome proliferation by the lipid-regulating agent gemfibrozil in several species,"Peroxisome proliferation, a well-documented subcellular reaction which follows the administration of hypolipidemic agents, has been well studied in rodents. However, quantitative studies of this phenomenon in other species of laboratory animals are not readily available even though these species are commonly used as predictors of tolerance or safety in humans. The quantitative stereologic studies reported here compared the effects of the new hypolipidemic agent gemfibrozil on hepatic peroxisomes of monkeys, dogs, hamsters and rats of both sexes under several treatment schedules. Gemfibrozil was administered to rats at 300 mg per kg per day for 1 year in the diet; to hamsters at 400 mg per kg per day for 2 weeks by diet admixture; to dogs at 300 mg per kg per day in gelatin capsules for 1 year; and to monkeys at 300 mg per kg day for 3 months by gavage. These dose levels were selected on the basis of tolerance from preliminary studies in each species. At the end of each experimental interval, liver samples were processed for quantitative microscopy. Peroxisomes from male rats were enlarged and the number of peroxisomes per cell were increased 7-fold over controls, resulting in a 20-fold increased peroxisome volume per cell. Statistically, significant increases also occurred in female rats and the difference between treated and controls was 3-fold for both number and volume of peroxisomes per cytoplasmic unit volume. In hamsters, peroxisomes were proliferated and were of significantly smaller size to the extent that the volume of cytoplasm occupied by peroxisomes was not significantly changed. In dogs, the number of peroxisomes per cell was increased and the volume fraction was significantly increased in females only. The number of peroxisomes in young monkeys did not change after treatment, and the peroxisome volume was decreased in males and increased in females. Aged monkeys had increased number of peroxisomes per hepatocyte with increased volume fraction. These results indicate significant differences in the magnitude and direction of peroxisome changes, reflecting species-dependent organelle response to hypolipidemic agents. The order of susceptibility of peroxisome proliferation in laboratory animals is dog less than monkey less than hamster less than rat.",0
1253,6607203,Relationship between expression of hepatitis B virus antigens in isolated hepatocytes and autologous lymphocyte cytotoxicity in patients with chronic hepatitis B virus infection,"Previous studies demonstrated that peripheral blood lymphocytes are cytotoxic to autologous hepatocytes in patients with chronic hepatitis B virus infection. We examined whether cytotoxicity is specifically directed against hepatocytes expressing HBsAg or HBcAg. Viral antigens were detected by immunofluorescence in isolated hepatocytes before and after exposure to T and non-T lymphocytes from 28 patients with chronic HBV infection in an autologous cytotoxicity assay. There was significant reduction in the percentage of HBcAg-positive hepatocytes after exposure to T lymphocytes and, to a lesser extent, after exposure to non-T cells; hepatocytes expressing HBsAg were not affected. Other studies showed that many hepatocytes containing HBcAg have IgG of anti-HBc specificity bound to their nuclei. In the present study, there was significant association between the presence of HBcAg and nuclear IgG in isolated hepatocytes. The ratio between the percentages of HBcAg-positive and IgG-positive hepatocytes (reflecting the proportion of hepatocytes containing free-core antigen) correlated significantly with reduction in HBcAg-positive liver cells after exposure to T cells, but not to non-T cells. These results suggest that hepatocytes in which viral replication is occurring and which express core determinants are susceptible to cell-mediated cytotoxicity and that T-cell cytolysis may be modulated by anti-HBc which is bound to hepatocytes.",0
1254,6621624,How many miles to the doctor?,"""We used detailed information from 16 states to determine the distance that residents of outlying areas (or of towns of less than 25,000, outside metropolitan areas) must travel to receive various types of medical care. For both 1970 and 1979, we found that approximately 80 per cent of such residents lived within 10 miles' driving distance of some physician and 98 per cent lived within 25 miles. Most of the remaining 2 per cent lived in areas so sparsely settled that physicians will not find them economically attractive as practice locations. During the 1970s, the distance of members of the studied population from medical and surgical specialists was substantially reduced. The greatest improvement occurred for the specialties that had the largest percentage increase in their numbers. As the physician pool expands further during the 1980s, geographic access to specialty care for rural and small-town residents should show a further notable improvement. However, this improvement may not suffice to meet what some consider the """"medical need"""" of those who are geographically isolated or economically deprived.""",0
1255,6656849,Use of single voided urine samples to estimate quantitative proteinuria,"""Quantitation of urinary protein excretion is used extensively for diagnostic and prognostic purposes and to assess the effects of therapy. The method most commonly used to measure urinary protein relies on 24-hour urine collections, which are time consuming, cumbersome, and often inaccurate. We reasoned that the urinary protein/creatinine ratio in a single voided urine sample should correlate well with the quantity of protein in timed urine collections. In a study of 46 specimens we found an excellent correlation between the protein content of a 24-hour urine collection and the protein/creatinine ratio in a single urine sample. The best correlation was found when samples were collected after the first voided morning specimen and before bedtime. We conclude that the determination of the protein/creatinine ratio in single urine samples obtained during normal daylight activity, when properly interpreted by taking into consideration the effect of different rates of creatinine excretion, can replace the 24-hour urine collection in the clinical quantitation of proteinuria. In the presence of stable renal function, a protein/creatinine ratio of more than 3.5 (mg/mg) can be taken to represent """"nephrotic-range"""" proteinuria, and a ratio of less than 0.2 is within normal limits.""",0
1256,6690930,Breast cancer and cigarette smoking,"It has been suggested that cigarette smoking may reduce the incidence of breast cancer, perhaps by as much as 20 per cent. To evaluate the relation between breast-cancer risk and smoking, we studied 2160 women with breast cancer and 717 controls who had been admitted to the hospital for cancer of the ovary, cancer of the colon or rectum, malignant melanoma, or lymphoreticular cancers. As compared with women who had never smoked, the estimated relative risk of breast cancer was 1.1 for current smokers of any amount (95 per cent confidence interval, 0.9 to 1.3), and 1.0 (0.8 to 1.3) for heavy smokers (15 or more cigarettes per day). Allowance for all identified potential confounding factors did not materially alter the results. There was no indication that age at commencement of smoking was related to the risk, nor was there evidence of an effect of smoking within the categories of age at first pregnancy or age at menopause. The data provide evidence against the hypothesis that smoking may reduce the incidence of breast cancer by 20 per cent.",0
1257,6690939,Medical students trained abroad and medical manpower. Recent trends and predictions,"Physicians trained in foreign medical schools, including U.S. citizens, are once again playing a larger part in the provision of medical are in this country. After a decrease in the numbers of such physicians from 1977 through 1980, the number of foreign nationals entering the National Resident Matching Program increased by 312 per cent, and the number of U.S. citizens from foreign schools increased by 273 per cent. U.S. graduates of foreign medical schools participating in Fifth Pathway programs appear to benefit from their extra year of clinical training by being more successful in the National Resident Matching Program and having a higher pass rate on state licensing examinations. These increases in physicians trained in foreign medical schools, together with an increasing number of students graduating from U.S. medical schools, have resulted in an insufficient total number of first-year postgraduate positions, regardless of the specialty, to accommodate all physicians seeking a first-year residency. Since the number of residency positions will probably not expand to meet applicant demand, an increase in the pool of physicians with neither residency training nor licenses to practice medicine is likely. Alien foreign medical-school graduates and U.S. students who go abroad to study medicine can no longer take for granted residency training and practice in the United Stages.",0
1258,6690951,Effect of esophageal emptying and saliva on clearance of acid from the esophagus,"We studied clearance of acid from the esophagus and esophageal emptying in normal subjects. A 15-ml bolus of 0.1 N hydrochloric acid (pH 1.2) radiolabeled with [99mTc]sulfur colloid was injected into the esophagus, and the subject swallowed every 30 seconds. Concurrent manometry and radionuclide imaging showed nearly complete emptying of acid from the esophagus by an immediate secondary peristaltic sequence, although esophageal pH did not rise until the first swallow 30 seconds later. Esophageal pH then returned to normal by a series of step increases, each associated with a swallow-induced peristaltic sequence. Saliva stimulation by an oral lozenge shortened the time required for acid clearance, whereas aspiration of saliva from the mouth abolished acid clearance. Saliva stimulation or aspiration did not affect the virtually complete emptying of acid volume by the initial peristaltic sequence. We conclude that esophageal acid clearance normally occurs as a two-step process: (1) Virtually all acid volume is emptied from the esophagus by one or two peristaltic sequences, leaving a minimal residual amount that sustains a low pH, and (2) residual acid is neutralized by swallowed saliva.",0
1259,6693067,Correlation between liver histology and markers of hepatitis B virus replication in infected patients: a study by in situ hybridization,"Liver sections from 18 patients positive for hepatitis B surface antigen (HBsAg), and from 12 negative patients, were examined for the presence of hepatitis B virus (HBV) DNA using an in situ hybridization assay that would identify only those hepatocytes containing more than 10 to 15 HBV genome equivalents per cell. Such cells are likely to be undergoing active viral replication, rather than latent infection. The findings were correlated with results of tissue immunofluorescence for HBV antigens and the presence of serum hepatitis B e antigen (HBeAg), together with histologic assessment of each liver. HBV DNA detected in the above assay was predominantly cytoplasmic; it was associated with the presence of hepatitis B core antigen (HBcAg) in hepatocytes and HBeAg in serum, and to a lesser extent with cirrhosis and immunosuppression, but not with the presence of HBsAg in hepatocytes, nor with histological evidence of disease activity judged by the presence of piece-meal necrosis and lobular and portal tract inflammation. These findings support the view that liver HBcAg and serum HBeAg are markers of virus replication, and demonstrate that active liver disease in HBsAg-positive patients may occur with or without such markers of replication. It is proposed that alternative mechanisms for hepatocyte injury may apply in different chronic HBV patients, one related to virus replication and one dependent on immunological factors.",0
1260,6694672,Weight gain after cessation of cigarette smoking. A possible role for adipose-tissue lipoprotein lipase,"Cigarette smokers weigh less than nonsmokers and gain weight when they stop smoking. Increased activity of lipoprotein lipase in adipose tissue in some smokers may represent a compensatory response to their reduced body weight. Consequently, we hypothesized that the enzyme's activity may be related to the rate at which smokers gain weight when they stop smoking. To test this hypothesis, we measured body weight and fasting lipoprotein lipase activity in adipose tissue in 15 cigarette smokers before they stopped smoking. The changes in body weight during the first two weeks of abstinence were correlated with the base-line lipase activity in these smokers (r = 0.82, P less than 0.0002). This relation remained significant in the 12 subjects who were still abstinent at three weeks (r = 0.63, P less than 0.03). These results suggest that lipoprotein lipase activity in adipose tissue has a counterregulatory role in the maintenance of body weight and adipose-tissue mass in smokers. The higher the level of lipase activity when the weight-reducing influences of cigarettes cease, the greater the rate at which weight is gained during the first three weeks of abstinence.",0
1261,6694673,Prospective study of alcohol consumption and cancer,"The relation between alcohol consumption and the subsequent occurrence of the five most frequent cancers in Japanese men in Hawaii (cancer of the stomach, colon, rectum, lung, and prostate) was analyzed in a prospective study of 8006 subjects. Information on alcohol consumption was obtained through interviews in the mid-1960s, and the cohort has been followed since then. The analysis, which was adjusted for the effects of age and cigarette smoking, revealed a positive association between consumption of alcohol and rectal cancer, accounted for primarily by an increased risk in men whose usual monthly consumption of beer was 500 oz (15 liters) or more (relative risk, 3.05; P less than 0.01, as compared with those who did not drink beer). A significant positive relation between alcohol consumption and lung-cancer incidence was also found, accounted for primarily by an increased risk among subjects who consumed larger amounts of wine or whiskey, as compared with the risks among nonconsumers of these beverages (relative risk, 2.19, [P = 0.03] and 2.62 [P less than 0.01], respectively). No significant relation between alcohol consumption and the incidence of the other three cancers was found.",0
1262,6694706,Homozygosity of chromosome 13 in retinoblastoma,"We studied the frequency of chromosome 13 homozygosity in tumor tissue obtained directly from eyes harboring retinoblastomas. The data indicate that approximately half of all retinoblastomas are homozygous for large portions of 13q, that the homozygosity occurs in vivo and not as an event secondary to culture of the tumor cells, that chromosome 13 homozygosity is not correlated with the degree of histopathologic differentiation of the tumor, and that the homozygosity occurs in both sporadic and hereditary retinoblastomas. The development of chromosome 13 homozygosity may represent a fundamental event in the oncogenesis of a considerable number of retinoblastomas. This finding may have implications for the genetic counseling of patients with hereditary retinoblastoma. It may also be important in understanding the mechanism of oncogenesis of other tumors, especially hereditary tumors.",0
1263,6700669,Importance of raised growth hormone levels in mediating the metabolic derangements of diabetes,"To evaluate the importance of the raised levels of growth hormone that characterize poor diabetic control, we gave growth hormone for 21 to 45 hours in the form of hourly 100-micrograms pulses to 14 diabetics being treated by insulin pump. Insulin-pump settings and meals were kept constant. Mean 24-hour levels of growth hormone (+/- S.E.M.) rose from 8 +/- 1 to 16 +/- 2 ng per milliliter--values identical to those observed in 12 other patients with poorly controlled diabetes (17 +/- 3 ng per milliliter). Plasma glucose concentrations doubled within 8 to 10 hours and remained elevated until growth hormone was discontinued (fasting glucose level rose from 86 +/- 11 to 204 +/- 17 mg per deciliter at 18 hours and to 240 +/- 20 mg per deciliter at 42 hours). The hyperglycemia was due mainly to a marked stimulation of hepatic glucose production that occurred without changes in levels of free insulin or glucagon. Levels of circulating free fatty acids, ketones, and branched-chain amino acids were also increased. The moderate elevations in growth hormone levels that occur in poorly controlled diabetes can themselves reproduce the whole spectrum of abnormal metabolic fuel concentrations that are associated with poor diabetic control, despite optimized insulin treatment. Thus, hypersecretion of growth hormone may be the cause as much as the consequence of poor diabetic control.",0
1264,6700691,Lack of association between genital mycoplasmas and infertility,"We studied the relation between colonization with Mycoplasma hominis and Ureaplasma urealyticum, and the results of infertility studies in 205 women with involuntary infertility of at least one year's duration. Isolation of M. hominis (but not of U. urealyticum) was significantly (P = 0.002) more common in patients with a history of pelvic inflammatory disease. However, no relation could be shown between these genital mycoplasmas and any of the following: evidence of prior pelvic inflammatory disease as determined by hysterosalpingography and laparoscopy; cervical inflammation; numbers and motility of spermatozoa on postcoital test; pyosemia; quality of cervical mucus; whether the cause of infertility was related to male or female factors, both, or neither; and occurrence and outcome of subsequent pregnancy. Mycoplasmas were cultured from only 10 of 203 endometrial biopsy specimens (4.9 per cent), and in no instance was inflammation associated with this finding. Out studies do not support a role for genital mycoplasmas in the cause of infertility.",0
1265,6708989,Aluminum intoxication from aluminum-containing phosphate binders in children with azotemia not undergoing dialysis,"Aluminum intoxication developed in three infants with azotemia who were not undergoing dialysis and who had been treated with aluminum hydroxide from the first month of life. Biopsies of the iliac crest demonstrated the presence of severe osteomalacia and massive deposition of aluminum in the bone. Serum aluminum levels were significantly (P less than 0.001) higher in these 3 infants and in 1 other, all of whom received more than 100 mg of elemental aluminum per kilogram of body weight per day (mean +/- S.D., 371.0 +/- 178.9 ng per milliliter [13.75 +/- 6.6 mumol per liter] ) than they were in 8 older children with azotemia who were not undergoing dialysis and who received less than 100 mg of elemental aluminum per kilogram per day (27.0 +/- 18.6 ng per milliliter [1.0 +/- 0.68 mumol per liter] ), 7 such children who did not receive aluminum hydroxide (20.28 +/- 9.2 ng per milliliter [0.75 +/- 0.34 mumol per liter] ), and 16 children with normal renal function (21.04 +/- 4.9 ng per milliliter [0.78 +/- 0.18 mumol per liter] ). In all the children with azotemia who were treated with aluminum hydroxide, there was a positive correlation (r = 0.90; P less than 0.01) between the serum aluminum level and the daily dose of elemental aluminum. These studies indicate that gastrointestinal absorption of aluminum can lead to aluminum intoxication in children with azotemia, and that infants may be particularly susceptible to this complication of therapy.",0
1266,6717539,Cognitive function and age at repair of transposition of the great arteries in children,"To assess the effect of the duration of chronic hypoxemia on cognitive function, we studied 38 children with d-transposition of the great arteries and an intact ventricular septum who underwent corrective surgery at six months to six years of age (median, 1.6 years). Tests included the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) in 33 children and the visual-association and auditory-association subtests of the Illinois Test of Psycholinguistic Abilities in 38 and 37 children, respectively. When controlled for social index, age at repair was inversely associated with the WPPSI intelligence-quotient score (P less than 0.01), the visual-association subtest score (P less than 0.01), and the auditory-association subtest score (P less than 0.1). In contrast, age at repair correlated poorly with cognitive function in children with ventricular septal defect, an acyanotic congenital heart defect. These data suggest that postponing repair of a cyanotic congenital heart disease, such as transposition of the great arteries, is associated with progressive impairment of cognitive function.",0
1267,6724509,Liver ultrastructure in mitochondrial urea cycle enzyme deficiencies and comparison with Reye's syndrome,The liver ultrastructural findings in two girls with partial carbamyl phosphate synthetase I (CPS) deficiency and their heterozygote parents and two siblings with ornithine transcarbamylase (OTC) deficiency are described. Liver ultrastructure in the four patients with inherited deficiencies of urea cycle enzymes showed minimal alterations with essentially normal mitochondria when biopsy was performed during periods of good control of their hyperammonemia. Mitochondrial ultrastructure was also essentially normal in the heterozygotes for carbamyl phosphate synthetase I deficiency. These findings are in contrast to the marked alterations in mitochondrial ultrastructure found in the study of two cases of Reye's syndrome in which severe depression of ornithine transcarbamylase and carbamyl phosphate synthetase I activities was noted.,0
1268,6727978,Influence of sickle hemoglobinopathies on growth and development,"To determine the influence of hemoglobinopathy on growth and development, we examined the height, weight, and sexual maturation of 2115 patients 2 to 25 years old who had homozygous sickle-cell disease (SS), SC disease (SC), sickle beta+ thalassemia (S beta+), or sickle beta O thalassemia (S beta O). Using regression analysis of these cross-sectional data to generate growth and maturation curves for each hemoglobinopathy, we found that the curves for all hemoglobinopathy groups were significantly different from published norms for black subjects (P less than 0.001), and that subjects with SS and S beta O were consistently smaller and less sexually developed than those with SC and S beta+ (P less than 0.001). For both sexes and all hemoglobinopathies, low weight was more pronounced than short height and was most apparent in subjects over the age of seven. The median age of the female subjects who had attained at least Tanner Stage V was 17.3 years for those with SS, 17.2 years for S beta O, 16.0 years for SC, and 16.5 years for S beta+; among male subjects the corresponding values were 17.6, 18.8, 16.6, and 16.6 years. Discriminant analysis of menarche status, weight, age, and hemoglobinopathy revealed that the influences of age and weight on menarche were similar regardless of hemoglobinopathy. This relationship suggests a constitutional rather than a primary endocrinologic cause of sexual immaturity in patients with hemoglobinopathies.",0
1269,6738600,Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers,"To examine the role of heritable factors in insulin-dependent diabetes mellitus (IDDM), we studied the incidence of IDDM in the offspring of patients with the disease who were identified by the medical records of the Joslin Diabetes Center from 1928 to 1939. We found 187 survivors who, after the diagnosis of IDDM, had produced 419 offspring for whom information about diabetes status was available. By the age of 20, 6.1 per cent of the offspring of the 88 men had diabetes; in contrast, only 1.3 per cent of the offspring of the 99 women had the disease by the age of 20 (P less than 0.05). Daughters and sons of the men with IDDM were affected equally (there were insufficient numbers of affected offspring of diabetic women to permit determination of whether the sexes were equally affected). We conclude that IDDM is transmitted less frequently to the offspring of diabetic women than to those of diabetic men. More study is required to determine whether this difference reflects a genetic mechanism or, instead, selective perinatal loss of the affected offspring of diabetic mothers.",0
1270,6738616,Muscarinic cholinergic receptors on skin fibroblasts in familial affective disorder,"Cultured human skin fibroblasts possess muscarinic receptors with the properties of specific binding, saturability, pharmacologic specificity, inhibition of norepinephrine-stimulated adenylate cyclase, and increased binding after incubation with an antagonist. The number of binding sites appears to be a stable characteristic of each cell line. We studied fibroblasts from 18 patients with a major affective disorder and found that they had a higher density of binding sites than cells from 12 normal controls. Fibroblasts from 18 relatives who had histories of major or minor affective disorder also had a higher density, and those from five normal relatives were similar to controls. These results, although still preliminary, suggest that increased cholinergic-receptor density may be associated with vulnerability to affective disorders in some familial cases.",0
1271,6738641,C5a-inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever,"Normal peritoneal fluid contains an inhibitor of neutrophil chemotaxis that acts by antagonizing the complement-derived chemotactic anaphyllatoxin C5a. The inhibitor resembles a substance previously described in synovial fluids and is a protein with a molecular weight of approximately 40,000 as determined by gel filtration. In contrast, levels of inhibitory activity in peritoneal fluids from five patients with familial Mediterranean fever were decreased to less than 10 per cent of those found in normal subjects. Gel filtration of peritoneal and synovial fluids from these patients did not yield any fraction with inhibitory activity. We suggest that C5a-inhibitor deficiency in joint and peritoneal fluids from patients with familial Mediterranean fever may have a role in the pathogenesis of the inflammatory attacks characteristic of this disease.",0
1272,6745862,Studies on the secretion of serum proteins from rat hepatoma cells,"We have used crossed immunoelectrophoresis to identify and establish the relative amounts of serum proteins secreted by a differentiated cell line (Fao) derived from a Reuber H35 rat hepatoma. Our results show that these cells secrete at least 15 plasma proteins. Ten of these: albumin, alpha 1-antitrypsin, alpha 1-lipoprotein, alpha 1-macroglobulin, alpha 1-antichymotrypsin, GC-globulin (transcalciferin), fibronectin, hemopexin, transferrin and the C3 component of complement have been identified. To examine the feasibility of using the Fao cell line as a model for studies on the regulation of hepatic protein secretion, we measured the relative amounts of 10 serum proteins secreted into the growth medium after exposure of these cells to dibutyryl cyclic AMP, hydrocortisone and a combination of both compounds. We also examined the effects of growth temperature (33.5 degrees, 37 degrees and 39 degrees C) and the removal of fetal calf serum from the growth medium on the relative amounts of these proteins secreted. We found that the rates of secretion of most of the serum proteins were altered by one or more of the treatments used in these experiments. In addition, detectable levels of secretion of three serum proteins, fibronectin and two unidentified, occurred only under certain of the experimental conditions. These results demonstrate that the pattern of proteins secreted from Fao cells can be experimentally altered and indicate that this cell line may be a useful model for studies on the control of hepatic protein secretion.",0
1273,6749207,Fibrinogen as a risk factor for stroke and myocardial infarction,"To study the possible risk factors for cardiovascular disease, we collected data on plasma levels of coagulation factors, blood pressure, serum cholesterol, and smoking in a random sample of 792 men 54 years of age. During 13.5 years of follow-up, myocardial infarction occurred in 92 men, stroke in 37, and death from causes other than myocardial infarction or stroke in 60. The blood pressure, degree of smoking, serum cholesterol, and fibrinogen level measured at the base-line examination proved to be significant risk factors for infarction by univariate analyses during follow-up, and blood pressure and fibrinogen were risk factors for stroke. Fibrinogen and smoking were strongly related to each other. The relation between fibrinogen and infarction, and between fibrinogen and stroke, became weaker when blood pressure, serum cholesterol, and smoking habits were taken into account, but was still significant for stroke. Although causality cannot be inferred from these data, it is possible that the fibrinogen level plays an important part in the development of stroke and myocardial infarction.",0
1274,6749228,Psychosocial influences on mortality after myocardial infarction,"Psychosocial interviews with 2320 male survivors of acute myocardial infarction, participants in the beta-Blocker Heart Attack Trial, permitted the definition of two variables strongly associated with an increased three-year mortality risk. With other important prognostic factors controlled for, the patients classified as being socially isolated and having a high degree of life stress had more than four times the risk of death of the men with low levels of both stress and isolation. An inverse association of education with mortality in this population reflected the gradient in the prevalence of the defined psychosocial characteristics. High levels of stress and social isolation were most prevalent among the least-educated men and least prevalent among the best-educated. The increase in risk associated with stress and social isolation applied both to total deaths and to sudden cardiac deaths and was noted among men with both high and low levels of ventricular ectopy during hospitalization for the acute infarction.",0
1275,6770270,"Estrogen use in postmenopausal women--costs, risks, and benefits","The cost effectiveness of estrogen use in postmenopausal women was analyzed with use of data from the medical and epidemiologic literature. Risks of endometrial cancer, uterine bleeding, and gallbladder disease were weighed against benefits associated with relief of menopausal symptoms and with prevention of osteoporosis and consequent fractures. Net effects on life expectancy are probably small in either direction, although they are likely to be positive in women with existing osteoporosis or prior hysterectomy. Treatment appears to be relatively cost effective in menopausal women with prior hysterectomy or osteoporosis but does not appear to be cost effective as a prophylactiv measure in asymptomatic women with intact uteri. For women with menopausal symptoms and intact uteri, the decision to prescribe estrogens for the individual patient and the cost effectiveness of estrogen use at the societal level depend critically on the subjective values assigned to symptomatic relief.",0
1276,6785648,"Cost effectiveness of clinical diagnosis, venography, and noninvasive testing in patients with symptomatic deep-vein thrombosis","Until the past decade, physicians were content to base therapeutic decisions on the clinical diagnosis of deep-vein thrombosis. Subsequently, numerous studies demonstrated that clinical diagnosis of this condition is nonspecific. Although many now use objective methods to diagnose venous thrombosis, their relative cost and effectiveness have not been adequately studied. We performed a cost-effectiveness analysis of 516 patients with clinically suspected venous thrombosis who were evaluated by clinical diagnosis, venography, and the less invasive combination of impedance plethysmography and leg scanning. We used this analysis to rank these alternative approaches in terms of both cost and effectiveness. The results indicate that clinical diagnosis is cost ineffective. Venography is cost effective--more so when applied as an outpatient investigation. Impedance plethysmography plus leg scanning is a practical, less invasive alternative to outpatient venography. The cost of inpatient diagnosis is likely to remain the major cost; thus, emphasis should be placed on outpatient diagnostic procedures.",0
1277,6789205,Evaluation of neonatal-intensive-care program,"Within the past 15 years, regional neonatal-intensive-care programs have been introduced and have expanded rapidly. The efficacy of some of the individual interventions that constitute neonatal intensive care has been validated in randomized, controlled clinical trials. It is therefore generally assumed that neonatal-intensive-care programs that incorporate these maneuvers are effective in reducing death and disability. However, the overall effectiveness of these programs has not been tested experimentally. Moreover, much of the non-experimental evidence supporting their value is based on the experience of referral units and does not measure the impact on the populations they serve. A definitive economic evaluation of neonatal intensive care has not yet been reported, despite the high cost of such programs. We conclude that neonatal-intensive care programs require further evaluation with rigorous scientific methods.",0
1278,6792540,Heterogeneity of human prekallikrein deficiency (Fletcher trait): evidence that five of 18 cases are positive for cross-reacting material,"We studied the plasma of 18 patients with a functional deficiency of plasma prekallikrein (Fletcher trait). Samples from 13 subjects contained less than 1 per cent of normal levels of prekallikrein antigen recognized by a specific antiserum (cross-reacting-material negative [CRM-]). In the five other subjects, however, nonfunctional material immunologically indistinguishable from normal prekallikrein was detected by radioimmunoassays at concentrations of 13 to 30 per cent (CRM+ variant). None of the plasma samples contained detectable circulating anticoagulants against prekallikrein. On immunodiffusion against antiserum to kallikrein, each of the five CRM+ samples formed a single precipitin line of complete identity with normal plasma or purified prekallikrein. On immunoelectrophoresis, the precipitin line had the same mobility as that for normal prekallikrein. These studies demonstrate the molecular heterogeneity of human prekallikrein deficiency and show that persons with the CRM+ variant have a nonfunctional form of prekallikrein in their plasma.",0
1279,6793493,Attenuation of the ethanol-induced hepatic redox change after chronic alcohol consumption in baboons: metabolic consequences in vivo and in vitro,"Acute ethanol administration results in increased hepatic NADH/NAD+ ratio and inhibition of galactose elimination, tricarboxylic acid cycle activity, and fatty acid oxidation. To determine how this redox change is affected by chronic alcohol consumption and to assess the resulting metabolic consequences, we studied baboons which were fed alcohol as 50% of their total calories. Redox changes were evaluated through measurement of galactose elimination in vivo and lactate/pyruvate ratios in liver slices in vitro. The metabolic consequences of these changes were assessed through measurement of CO2 production and fatty acid oxidation in liver slices and hepatic lipid accumulation. Chronic alcohol feeding resulted in attenuation of inhibition of galactose elimination, increase in the lactate/pyruvate ratio, and decrease in fatty acid oxidation which were caused by acute ethanol administration. These metabolic adaptations were associated with reduced accumulation of hepatic fat.",0
1280,6795503,Tidal volume and frequency dependence of carbon dioxide elimination by high-frequency ventilation,"Six patients with chronic respiratory failure received mechanical ventilation with tidal volumes less than or equal to the dead-space volume, at frequencies of 30 to 900 breaths per minute. The rate of elimination of carbon dioxide from the ventilator system during a brief trial of high-frequency ventilation accurately predicted the long-term effectiveness of a given combination of frequency and tidal volume. Below frequencies of about 200 breaths per minute, the volume of carbon dioxide eliminated from these patients was most strongly related to the product of frequency and tidal volume; at higher frequencies, carbon dioxide elimination was determined by the tidal volume and was independent of frequency. These results suggest that although the effectiveness of high-frequency ventilation is primarily a function of the product of tidal volume and frequency, above a critical frequency the mechanical characteristics of the lung reduce gas transport by limiting the volume transmitted to the periphery of the lung.",0
1281,6798442,Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers,"""Four members (from four generations) of a family with a mild bleeding disorder and intermittent thrombocytopenia had decreased plasma levels of properties related to factor VIII/von Willebrand factor (FVIII/VWF), an absence of high-molecular-weight forms of FVIII/VWF in the plasma (but normal multimeric structure in the platelets), and increased ristocetin-induced platelet aggregation, as in Type IIB von Willebrand's disease. However, unlike the abnormality in FVIII/VWF in Type IIB disease, the basic defect in this family was in their platelets, which absorbed FVIII/VWF high-molecular-weight multimers at lower concentrations of ristocetin than did normal platelets. In addition, either in platelet-rich plasma or suspended in buffer, their platelets were aggregated by unmodified normal human FVIII/VWF without ristocetin. Since the abnormalities of plasma FVIII/VWF in this family may be secondary to the platelet abnormalities, the term """"pseudo-von Willbrand's disease"""" may be suitably descriptive of their disorder.""",0
1282,6801516,Increased ureagenesis and impaired nitrogen use during infusion of a synthetic amino acid formula: a controlled trial,"""In a controlled trial conducted to assess the biologic value of High Nitrogen Vivonex, we compared this """"elemental"""" diet with predigested protein--Product MJ7041--and with solid food during eight-day balance periods. Each formula was evaluated in three patients with malabsorption and one without it, by measuring apparent absorption of nitrogen and energy, nitrogen balance, and blood and urinary urea nitrogen. Overall energy and nitrogen absorption in the patients with malabsorption was better with either special diet than with solid food; net intestinal uptake of Vivonex tended to be higher but not consistently so in al patients. However, nitrogen balance differed consistently during the three diets; with solid food and MJ7041, retention of absorbed nitrogen was respectively, nine and 16 times greater than with Vivonex. Moreover, institution of each Vivonex period led to a prompt increase in urea nitrogen--a trend quickly reversed by the alternative diets. Although the mechanism for the impairment of nitrogen use caused by High Nitrogen Vivonex is unknown, its low biologic value and tendency to cause azotemia should be kept in mind.""",0
1283,6804866,Cost effectiveness of lead screening,"Lead-screening programs may reduce childhood disabilities, but at what cost? Through a review of the literature, we performed a cost-effectiveness analysis in which the costs, savings, and health benefits of two lead-screening strategies--employing either a free erythrocyte protoporphyrin assay or blood lead measurement--were compared with each other and with a strategy of no screening in a population of three-year-old children. When the prevalence of lead poisoning among the children screened is 7 per cent or more, we estimate that free erythrocyte protoporphyrin screening averts morbidity and results in net savings: It is both better and cheaper than no screening. At prevalences below 7 per cent, the net positive costs from screening and early treatment must be weighed against the noneconomic benefits of improved quality of life and considered in relation to other investments that could be made to benefit society. At all prevalence rates, free erythrocyte protoporphyrin screening is more cost effective than blood lead screening.",0
1284,6810170,"Indications for use of hepatitis B vaccine, based on cost-effectiveness analysis","To formulate indications for the use of hepatitis B vaccine, we examined the cost effectiveness of three strategies: vaccinating everyone; screening everyone and vaccinating those without evidence of immunity; and neither vaccinating nor screening, but passively immunizing those with known exposure. Estimates of the hepatitis attack rate, prevalence of immunity, and frequency of known exposure were made for three representative populations: homosexual men, surgical residents, and the general population of the United States. Screening followed by vaccination of homosexual men and vaccination without prior screening of surgical residents would result in savings of medical costs. Neither screening nor vaccination is the lowest-cost strategy for the general population. Vaccination of susceptible persons will save medical costs for populations with annual attack rates above 5 per cent. Vaccination may be considered cost effective (or cost saving when indirect costs are included) for populations with attack rates as low as 1 to 2 per cent.",0
1285,6823245,Social environment and cancer mortality in men,"The relationship between cancer mortality in men and the social environment of neighborhoods is examined. Qualities of the social environment considered include demographic composition, marital status, nature of housing, and family structure. Data are from death certificates from the Division of Health Statistics of the Massachusetts Department of Public Health for the years 1972 and 1973.",0
1286,6832713,Hepatic free fatty acids in alcoholic liver disease and morbid obesity,"Alcoholic liver disease is characterized by the accumulation of fat and inflammatory changes in the liver. Because free fatty acids, the precursors of triglycerides, can damage biological membranes, accumulation of free fatty acids in the liver might be in part responsible for the functional and morphological changes seen in alcoholic liver disease. We, therefore, determined the hepatic lipid composition in biopsies from 31 patients with alcoholic liver disease, 18 patients with morbid obesity, and 5 patients without evidence of liver disease. Free fatty acids were found in all liver biopsies. Patients with morbid obesity or alcoholic liver disease had significantly higher fatty acid and triglyceride levels than did controls (p less than 0.01). Patients with alcoholic liver disease had significantly higher fatty acid levels than did patients with morbid obesity (p less than 0.05), while there was no difference in the triglyceride concentrations between these two groups. The distribution of the fatty acids in the free fatty acid fraction differed significantly from that in the triglyceride fraction indicating a preferential incorporation of unsaturated fatty acids into triglycerides. This difference in the distribution pattern was lost in patients with the most severe forms of alcoholic liver disease. The data are consistent with the hypothesis that accumulation of free fatty acids in patients with alcoholic liver disease may be responsible for or contribute to the observed functional and morphological damages.",0
1287,6835270,Cardiovascular disease and vasectomy. Findings from two epidemiologic studies,"We performed two epidemiologic studies using routine abstracts of medical records to test the hypothesis that vasectomy may predispose men to cardiovascular disease. In a case-control study 1512 men who were under 55 years of age and had a history of myocardial infarction, stroke, or hypertension were matched with 3024 controls with other conditions; 2.4 per cent of the cases and 2.7 per cent of the controls were identified as having undergone vasectomy (risk ratio, 0.9; 95 per cent confidence limits, 0.6 to 1.3). In a cohort study data covering a mean period of 6 1/2 years after surgery were available on 1764 men who had had a vasectomy and on three comparison cohorts of men who had had other minor surgical procedures. There was no evidence of an increased risk of cardiovascular disease associated with vasectomy. There is no consistent evidence from our studies to support the hypothesis that in the short term vasectomy predisposes young men to cardiovascular disease.",0
1288,6835306,The value of the autopsy in three medical eras,"To determine whether advances in diagnostic procedures have reduced the value of autopsies, we analyzed 100 randomly selected autopsies from each of the academic years 1960, 1970, and 1980 at one university teaching hospital. In all three eras about 10 per cent of the autopsies revealed a major diagnosis that, if known before death, might have led to a change in therapy and prolonged survival; another 12 per cent showed a clinically missed major diagnosis for which treatment would not have been changed. Among 1980 autopsies, renal disease and pulmonary embolus were less common causes of death than before, but systemic bacterial, viral, and fungal infections increased significantly and were missed clinically 24 per cent of the time. The introduction of radionuclide scans, ultrasound, and computerized tomography as diagnostic procedures did not reduce the use of conventional tests in patients who subsequently died and were studied by autopsy. Over-reliance on these new procedures occasionally contributed directly to missed major diagnoses. We conclude that advances in diagnostic technology have not reduced the value of the autopsy, and that a goal-directed autopsy remains a vital component in the assurance of good medical care.",0
1289,6843610,Perturbation of sodium-lithium countertransport in red cells,"The rate of sodium-lithium countertransport in red cells is thought to be determined by inheritance and to be constant over years in a given person. We have found that the rate is influenced acutely by ultrafiltration and by hemodialysis. In seven patients with endstage renal disease secondary to essential hypertension, the mean rate of sodium-lithium countertransport (+/- S.E.M.) was reduced from 0.18 +/- 0.02 to 0.09 +/- 0.01 mmol per liter of cells per hour (P less than 0.02) by ultrafiltration and from 0.22 +/- 0.03 to 0.12 +/- 0.03 mmol per liter per hour (P less than 0.001) by hemodialysis. When patients' red cells obtained before dialysis were incubated with plasma obtained afterward, the rate of countertransport fell, and when red cells obtained after dialysis were incubated with plasma obtained beforehand, the rate returned to normal. Whereas the rate in red cells from normal subjects was reduced after incubation in post-dialysis plasma from patients, predialysis plasma from the same patients had no such effect. We conclude that the rate of the countertransport system of red cells is dependent on a dialyzable plasma factor.",0
1290,6848933,Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy,"We studied the relation in Pima Indians between obesity in children and diabetes during pregnancy in their mothers. Sixty-eight children of 49 women who had had diabetes during pregnancy had a higher prevalence of obesity than 541 children of 134 women who subsequently had diabetes (prediabetics) or than 1326 children of 446 women who remained nondiabetic. At 15 to 19 years of age, 58 per cent of the offspring of diabetics weighed 140 per cent or more of their desirable weight, as compared with 17 per cent of the offspring of nondiabetics and 25 per cent of those of prediabetics (P less than 0.001). Obesity in the offspring was directly related to maternal diabetes, since the association was not substantially confounded by maternal obesity. The findings strongly suggest that the prenatal environment of the offspring of diabetic women results in the development of obesity in childhood and early adulthood.",0
1291,6848934,Absence of cytochrome b-245 in chronic granulomatous disease. A multicenter European evaluation of its incidence and relevance,"The heme-containing protein cytochrome b-245 has been proposed as a primary component of the microbicidal oxidase system of phagocytes that normally generates superoxide-free radicals but when defective is associated with chronic granulomatous disease. We measured this cytochrome in granulocytes from 27 patients with chronic granulomatous disease and from 64 members of their families. It was undetectable in all 19 of the men in whom the defect appeared to be located on the X chromosome. Female relatives who were heterozygous carriers had reduced concentrations of the cytochrome and variable proportions of cells that were unable to generate superoxide; these two characteristics were closely related (r = 0.93 in the 16 mothers and 0.85 in all 24 carriers, P less than 0.001). In contrast, in all eight patients (seven women) with a probable autosomal recessive inheritance the cytochrome was present but nonfunctional. The properties tested, including midpoint potential, carbon monoxide binding, and organelle distribution, were normal, but the cytochrome did not undergo reduction on cellular stimulation. Thus, absence or malfunction of the cytochrome b-245 may be the causal molecular defect in chronic granulomatous disease, implicating it in the microbicidal oxidase system.",0
1292,6855851,Left ventricular function and rapid release of creatine kinase MB in acute myocardial infarction. Evidence for spontaneous reperfusion,"Intracoronary thrombolysis during acute myocardial infarction in human beings is associated with rapid release of creatine kinase and improvement of the cardiac ejection fraction. To examine the phenomenon of spontaneous coronary-artery recanalization, we studied the release of creatine kinase MB and sequential radionuclide ventriculograms in 52 patients with transmural myocardial infarction. Patients were divided into two groups according to whether the release of creatine kinase MB (time from base-line to peak serum level) was rapid (n = 24) or slow (n = 28). Patients with slow release had no significant change in global or regional ejection fraction from the time of admission to discharge. However, global ejection fraction in patients with rapid release improved from 0.38 +/- 0.09 (mean +/- S.D.) to 0.48 +/- 0.08 (P less than 0.001). The regional ejection fraction of Q-wave regions also improved, from 0.33 +/- 0.11 to 0.43 +/- 0.13 (P less than 0.001). A negative correlation (r = -0.52, P less than 0.001) existed between time to peak enzyme level and degree of improvement in ejection fraction. With increasing left ventricular damage, patients with rapid release had greater increments in creatine kinase MB than comparable patients with slow release (P = 0.03), suggesting enzyme washout. These data are consistent with the idea that spontaneous reperfusion, leading to altered enzyme release and improvement in ventricular function, is not uncommon after acute myocardial infarction.",0
1293,6888441,Longitudinal study of the effects of maternal smoking on pulmonary function in children,"We investigated the effects of maternal cigarette smoking on pulmonary function in a cohort of children and adolescents observed prospectively for seven years. A multivariate analysis revealed that after correction for previous forced expiratory volume in one second (FEV1), age, height, change in height, and cigarette smoking in the child, or adolescent, maternal cigarette smoking significantly lowered the expected average annual increase in FEV1 (P = 0.015). On the basis of this analysis, it is estimated that if two children have the same initial FEV1, age, height, increase in height, and personal cigarette-smoking history, but the mother of one has smoked throughout the child's life whereas the mother of the other has not, the difference in the change in FEV1 over time in the exposed child, as compared with that in the unexposed child, will be approximately 28, 51, and 101 ml after one, two, and five years, respectively, or a reduction of 10.7, 9.5, and 7.0 per cent, respectively, in the expected increase. These results suggest that passive exposure to maternal cigarette smoke may have important effects on the development of pulmonary function in children.",0
1294,6888443,Use of statistical analysis in the New England Journal of Medicine,"A sorting of the statistical methods used by authors of the 760 research and review articles in Volumes 298 to 301 of The New England Journal of Medicine indicates that a reader who is conversant with descriptive statistics (percentages, means, and standard deviations) has statistical access to 58 per cent of the articles. Understanding t-tests increases this access to 67 per cent. The addition of contingency tables gives statistical access to 73 per cent of the articles. Familiarity with each additional statistical method gradually increases the percentage of accessible articles. Original Articles use statistical techniques more extensively than other articles in the Journal. Research studies based on a longitudinal design make heavier use of statistics than do those using a cross-sectional design. The tabulations in this study should aid clinicians and medical investigators who are planning their continuing education in statistical methods, and faculty who design or teach courses in quantitative methods for medical and health professionals.",0
1295,6895205,"Proline trapping in granulomas, the site of collagen biosynthesis in murine schistosomiasis","Proline, a critical substrate for collagen synthesis, is increased in liver undergoing fibrosis. In mice with schistosomiasis, the incorporation of proline into collagen occurs within liver granulomas. To study the interaction of liver cells and granulomas in the development of fibrosis, we assayed the enzymes that catalyze the formation and degradation of proline in isolated granulomas and liver. Two sequential enzymes involved in the formation of proline from arginine are ornithine-delta-aminotransferase and delta-pyrroline-5-carboxylate (P5C) reductase. Activities of both these enzymes in granulomas were approximately 10% of those in liver, expressed on the basis of DNA content. The enzymes involved in degradation of proline are proline oxidase and P5C dehydrogenase; both are present in liver cells. In isolated granulomas, activity of proline oxidase was minimal, and P5C dehydrogenase activity was absent. These findings suggest that the metabolism of proline within granulomas differs greatly from that in liver cells. Earlier studies showed that exogenous proline enters granulomas and is rapidly incorporated into collagen. The combined findings raise the possibility that granulomas serve as a proline trap. Proline can enter this compartment and can be incorporated into collagen; however, proline within granulomas cannot readily be diverted into other pathways by degradation.",0
1296,6931286,Heterozygous expression of X-linked mental retardation and X-chromosome marker fra(X)(q27),"Males affected by one form of X-linked retardation possess the X-chromosomal marker fra(X)(q27) and are physically normal except for macro-orchidism. To relate possession of the marker X to phenotypic expression in female heterozygotes, we investigated 128 mildly retarded (IQ, 55 to 75) school-girls in Sydney, New South Wales, Australia. Seventy-two girls had no physical abnormalities and of these, five (7 per cent) carried the marker X. Investigation of relatives revealed retarded males in four of the five families. Pedigree and chromosomal analysis identified a further 18 heterozygotes; six were regarded as intellectually or educationally retarded. We conclude that expression of the X-linked mutation in female carriers contributes to mild mental retardation of girls, that those who are physically normal should be screened for the marker X, and that their relatives should be investigated in order to identify additional females with a high risk of conceiving affected males.",0
1297,6965517,The effect of lithium on murine hematopoiesis in a liquid culture system,"Lithium carbonate has been shown to increase granulocyte production. We studied the effect of lithium on murine hematopoiesis in a liquid culture system providing for the prolonged growth of stem cells and their progeny. After one week of incubation, lithium, at a supernatant concentration of 1 mmol per liter, increased murine pluripotent stem cells (CFU-S, or colony-forming units in spleen) to 232 per cent of control values (P less than 0.001), granulocyte-monocyte progenitor cells (CFU-C, or colony-forming units in culture) to 218 per cent of control values (P less than 0.0001), granulocytes to 125 per cent of control values (P less than 0.01), and megakaryocytes to 246 per cent of control values (P less than 0.001). These increases were associated with transient elevations in colony-stimulatory activity. Prolonged exposure to lithium (three to 12 weeks) was associated with a dose-dependent progressive depletion of stem cells and their progeny. Lithium enhancement of granulopoiesis may be explained by primary stimulation of the pluripotent stem cell. Prolonged proliferative stress induced by lithium when the stem-cell reserve is limited may be associated with diminished replicative potential of the stem cells and rapid depletion of cells.",0
1298,6981575,The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study,"The gradient between wedged and free hepatic venous pressures was measured in patients with alcoholic cirrhosis before and 1, 3, and 9 months after continuous oral administration of propranolol at doses reducing the heart rate by 25% or after administration of a placebo. The gradient between wedged and free hepatic venous pressures decreased throughout the duration of propranolol administration, and it did not significantly change in the patients receiving placebo. Since the gradient between wedged and free hepatic venous pressures closely reflects portal venous pressure in alcoholic cirrhosis, it is concluded that continuous oral administration of propranolol produced sustained reduction in portal venous pressure in these patients.",0
1299,6986552,A randomized clinical trial of the Leboyer approach to childbirth,"To examine the effects of the Leboyer method of delivery, we randomly assigned 56 women to either a Leboyer or a conventional delivery and used a variety of clinical and behavioral measures to assess the outcome in mother and child. No differences were noted in maternal or newborn morbidity, in infant behavior in the first hour of life, at 24 or 72 hours post partum, or at eight months of age; or in maternal perceptions of her infant and the experience of giving birth, except that eight months after delivery, mothers who had used the Leboyer method were more likely to say that the event had influenced their child's behavior (P = 0.05). Women who expected a Leboyer delivery had shorter active labors (P = 0.03), suggesting that psychologic factors (expectations) influence physical outcomes in perinatal medicine. Our results suggest that the Leboyer procedure has no advantage over a gentle, conventional delivery in influencing infant and maternal outcomes.",0
1300,6987518,Increased insulin receptors after exercise in patients with insulin-dependent diabetes mellitus,"Physical exercise is known to improve glucose tolerance and diminish insulin requirements in patients with well-controlled diabetes mellitus. To ascertain whether these effects of exercise are associated with alterations in insulin receptors, we studied [125I]insulin binding to erythrocytes and monocytes in athletically untrained young men with insulin-treated diabetes during three hours of postprandial bicycle exercise (nine patients) and two hours of exercise during fasting (eight patients). Compared with control periods, postprandial exercise, as well as exercise during fasting, significantly increased insulin binding to erythrocytes and monocytes at an insulin-tracer concentration of 34 pmol per liter. We suggest that similar changes occur in working muscle cells and contribute to the improved glucose tolerance induced by exercise.",0
1301,7001229,"Control of blood sugar in insulin-dependent diabetes: comparison of an artificial endocrine pancreas, continuous subcutaneous insulin infusion, and intensified conventional insulin therapy","""We compared the ability of closed-loop intravenous insulin infusion (i.e., an artificial """"pancreas""""), open-loop continuous subcutaneous insulin infusion, and intensified conventional insulin therapy (preprandial injections of regular insulin, with injection of long-acting zinc-suspension insulin before breakfast) to bring the hyperglycemia of insulin-dependent diabetic subjects to a level comparable to that of normal, nondiabetic subjects. The mean circadian levels of plasma glucose, mean amplitude of glycemic excursions, and M values (defined in Methods) did not significantly differ among the three regimens. Although these levels in the diabetic subjects approximated those in the normal subjects, the levels of plasma insulin, mean amplitude of glycemic excursions, and M values were significantly higher than those in normal subjects (P < 0.01). Therefore, at least on a short-term basis, all three regimens can produce comparable, nearly normal levels of blood sugar in such patients; moreover, closed-loop devices can be used to determine insulin requirements for conventional therapy.""",0
1302,7015139,Treatment of primary breast cancer with chemotherapy and tamoxifen,"We studied the possibility that the addition of tamoxifen to L-phenylalanine mustard combined with 5-fluorouracil enhances the benefit from the latter two drugs that has been observed in women with primary breast cancer and positive axillary nodes. Recurrence of disease was reduced at two years in patients given the three-drug regimen whose tumor estrogen-receptor levels were greater than or equal to 10 fmol. Among patients greater than or equal to 50 years old treatment failure was significantly reduced (P less than 0.001): by 51 per cent in those with one to three positive nodes and by 64 per cent in those with four or more. Higher receptor levels were associated with a greater probability of disease-free survival. Patients less than or equal to 49 years old were less responsive: those with one to three positive nodes received no benefit from tamoxifen at any receptor level, whereas those with four or more appeared to have reduced treatment failure associated with higher receptor levels. This adjuvant chemotherapy is not indicated in patients less than or equal to 49 years old whose tumor receptor levels are below 10 fmol; there is a suggestion of benefit in patients greater than or equal to 50 years old whose levels are low.",0
1303,7024808,PaperChase: a computer program to search the medical literature,"This report describes PaperChase, a computer program that permits users to search medical literature by author's name, journal of publication, title word, or medical subject heading (MeSH term), as indexed by the National Library of Medicine. PaperChase was installed in the medical library of Beth Israel Hospital in Boston, with a data base of 400,000 references--nearly all the articles shelved there. During the first year of operation, 1032 medical students, house officers, practicing physicians, and other library users, without formal instruction or user's manual, conducted 8459 searches and displayed 399,821 references, 97,769 of which they selected for printing. Among users who conducted an initial search, 49 per cent returned to complete five or more searches, and 14 per cent returned to complete 20 or more. The large number of satisfied users and the low installation and operating costs suggest that PaperChase could be a valuable means of providing widespread computerized bibliographic retrieval.",0
1304,7024811,Clinical and immunologic effects of fractionated total lymphoid irradiation in refractory rheumatoid arthritis,"Ten patients with refractory rheumatoid arthritis were given 3000 rad of fractionated total lymphoid irradiation in an uncontrolled therapeutic trial. Total lymphoid irradiation was associated with objective evidence of considerable clinical improvement in eight patients and with reduced blood lymphocyte counts in all 10. On completion of irradiation, there was an abrogation of lymphocyte reactivity in vitro in the patients with clinical responses, but abnormal antibody activities characteristic of rheumatoid arthritis and normal components of humoral immunity were not suppressed. Partial recrudescence of arthritis occurred shortly after a year after the completion of irradiation and was paralleled by a restitution of lymphocyte concentrations and responsiveness to mitogens to levels similar to those observed before irradiation. These data provide further evidence of T-cell involvement in the pathogenesis of rheumatoid arthritis and demonstrate that total lymphoid irradiation can induce temporary relief, but they do not ascertain whether the natural history of this disease was altered.",0
1305,7026404,Muscle protein breakdown in liver cirrhosis and the role of altered carbohydrate metabolism,"The rates of muscle protein breakdown, as estimated by the urinary excretion of 3-methylhistidine, were assessed in 30 cirrhotics and 15 controls on a strictly controlled diet. 3-Methylhistidine excretion was increased in cirrhotics irrespective of the etiology of the disease, and correlated with basal glucagon levels and with the insulin/glucagon ratio. In nine cirrhotics and nine age- and sex-matched controls, similar correlations were found between 3-methylhistidine and the areas under 24-hr glucagon or insulin/glucagon curves. A larger amount of 3-methylhistidine was excreted during the nighttime than during the daytime, when glucagon secretion was suppressed and the insulin/glucagon ratio was increased. It is concluded that muscle protein catabolism is increased in cirrhotics, possibly as a result of hyperglucagonemia or the reduced insulin/glucagon ratio. These data agree with the clinical observation of a progressive reduction in lean body mass which becomes evident in an advanced stage of the disease.",0
1306,7027040,Effect of the hemodialysis prescription of patient morbidity: report from the National Cooperative Dialysis Study,"This report summarizes morbidity in 151 patients in a cooperative trial designed to evaluate the clinical effects of different dialysis prescriptions. Four treatment groups were divided along two dimensions: dialysis treatment time (long or short), and blood urea nitrogen (BUN) concentration averaged with respect to time (TACurea) (high or low). Dietary protein was not restricted. There was no difference in mortality between the groups. Withdrawal of patients from the high-BUN groups for medical reasons was significantly greater than withdrawal from the low-BUN groups. Hospitalization was also greater in the high-BUN groups, but dialysis treatment time had no significant effects. The data indicate that the occurrence of morbid events is affected by the dialysis prescription. Increased morbidity appears to accompany prescriptions associated with a relatively high BUN. Conversely, morbidity may be decreased by prescriptions associated with more efficient removal of urea if the dietary intake of protein and other nutrients is adequate.",0
1307,7030903,Hepatitis B virus DNA in the sera of HBsAg carriers: a marker of active hepatitis B virus replication in the liver,"Sera and liver biopsies from 30 Italian patients, carriers of HBsAg for at least 3 years, were examined for markers of hepatitis B virus (HBV) infection by serological assays and immunofluorescence. Biopsies were analyzed for HBcAg, HBsAg, and delta antigen by immunofluorescence; sera were assayed for HBsAg/anti-HBs, HBcAg/anti-HBc, HBeAg/anti-HBe, delta/anti-delta, HBV-specific DNA polymerase activity and the presence of HBV DNA. HBcAg, HBeAg, and DNA polymerase tests were positive in the sera of 71, 86, and 57%, respectively, of carriers with intrahepatic HBcAg. HBV DNA was detected in 100% of patients expressing HBcAg in the liver with a strong correlation between the concentration of serum DNA and the intensity of HBcAg immunofluorescence in the liver. HBV DNA was detected in the sera of 63% of carriers with intrahepatic delta where the other markers of HBV replication (HBeAg, DNA polymerase) were undetectable. The assay for serum HBV DNA appears to be an excellent noninvasive method for detecting active replication of HBV in HBsAg carriers.",0
1308,7040956,Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study,"Eight hundred twelve men with presumed acute myocardial infarction and left ventricular filling pressure of at least 12 mm Hg participated in a randomized double-blind placebo-controlled trial to assess the efficacy of a 48-hour infusion of sodium nitroprusside. The mortality rates at 21 days (10.4 per cent in the placebo group and 11.5 per cent in the nitroprusside group) and at 13 weeks (19.0 per cent and 17.0 per cent, respectively) were not significantly affected by treatment. The efficacy of nitroprusside was related to the time of treatment: the drug had a deleterious effect in patients whose infusions were started within nine hours of the onset of pain (mortality at 13 weeks, 24.2 per cent vs. 12.7 per cent; P = 0.025) and a beneficial effect in those whose infusions were begun later (mortality at 13 weeks, 14.4 per cent vs. 22.3 per cent; P = 0.04). Nitroprusside should probably not be used routinely in patients with high left ventricular filling pressures after acute myocardial infarction. However, the results in the patients given late treatment suggest that those with persistent pump failure might receive sustained benefit from short-term nitroprusside therapy.",0
1309,7042506,Effect of dihydrotestosterone on rat liver alcohol dehydrogenase activity,"Castration was previously demonstrated to result in an increase in liver alcohol dehydrogenase and in rates of ethanol elimination in male rats. In this study, the effect of dihydrotestosterone, which is a more potent androgen than testosterone in the rat, was determined on liver alcohol dehydrogenase and ethanol elimination in the castrated rat. Dihydrotestosterone was found to be a substrate of liver alcohol dehydrogenase in the reductive direction and a competitive inhibitor of ethanol oxidation by the enzyme. Also, the administration of a single dose of dihydrotestosterone inhibited liver alcohol dehydrogenase 4 hr after the injection, but this effect was not persistent at later intervals following injection. This transient in vivo inhibition of liver alcohol dehydrogenase was associated with a delay in ethanol elimination. The microsomal ethanol-oxidizing enzyme system was found to play no role in the changes in ethanol elimination observed after castration and dihydrotestosterone administration since its activity remained unchanged. These studies provide further evidence of an effect of androgenic steroids on liver alcohol dehydrogenase activity and ethanol metabolism.",0
1310,7042507,The liver: an integral part of the enteric mucosal immune system,The inclusion of the liver and biliary tract as an integral part of the enteric mucosal immune defense has come about in the past 5 years as a result of experimental studies in laboratory animals. The importance of secretory IgA and IgA immune complexes in the generation of an immune response and their participation in the immune exclusion of potentially pathogenic molecules and organisms are areas of active investigation. The transport of IgA and IgA immune complexes by the liver from serum to bile may provide another means of immune-mediated host defense against enteric pathogens.,0
1311,7048091,"Internist-1, an experimental computer-based diagnostic consultant for general internal medicine","""Internist-I is an experimental computer program capable of making multiple and complete diagnoses in internal medicine. It differs from most other programs for computer-assisted diagnosis in the generality of its approach and the size and diversity of its knowledge base. To document the strengths and weaknesses of the program we performed a systematic evaluation of the capabilities of INTERNIST-I. Its performance on a series of 19 clinicopathological exercises (Case Records of the Massachusetts General Hospital) published in the Journal appeared qualitatively similar to that of the hospital clinicians but inferior to that of the case discussants. The evaluation demonstrated that the present form of the program is not sufficiently reliable for clinical applications. Specific deficiencies that must be overcome include the program's inability to reason anatomically or temporally, its inability to construct differential diagnoses spanning multiple areas, its occasional attribution of findings to improper causes, and its inability to explain its """"thinking"""".""",0
1312,7050715,Medicare's nursing-home benefit: variations in interpretation,"The use of skilled-nursing facilities by Medicare beneficiaries as measured in days of care per thousand elderly persons varies considerably from one state to another. To explore the possibility that this variation reflects differences in the administrative interpretation of rules governing coverage, we developed nine hypothetical cases and presented them by telephone to claims reviewers in fiscal intermediaries and professional standards review organizations. Cases were designed to illuminate the reviewers' use of discretion. We observed marked differences both in the reviewers' decisions to cover or not cover patients and in the reasoning behind their decisions. Three of the 18 reviewers decided to cover very few cases; almost half the reviewers decided to cover most of the cases, but not the same ones. In only two cases did the 18 reviewers approach consensus. This variation is a reflection of the complexity of Medicare's coverage rules and its decentralized administration. To reduce variation, we recommend more centralized review with oversight by Medicare's central office rather than by its 10 regional offices. This oversight should include the training of reviewers in a way that focuses on complex cases to improve the consistency of judgment.",0
1313,7053465,Changing patterns of graduate medical education,"Postgraduate medical education underwent substantial change during the 1970s: medical-school classes grew, the internship year was eliminated, and the numbers of M.D.s entering primary-care specialties increased. The purpose of this study is to develop a planning model of graduate medical education that can project the impact of these and other changes on the numbers and specialty mix of physicians completing training. The model is applied to an analysis of trends in graduate medical education and to the probable consequences of policy recommendations made by the Graduate Medical Education National Advisory Committee (GMENAC). The results show that the trend toward increasing percentages of M.D.s entering primary-care specialties from 1970 to 1976 changes to no increase from 1976 to 1980. Thus, the GMENAC policy recommendation to increase primary care further is not likely to occur spontaneously in the near future.",0
1314,7053487,Hemodynamic characterization of tolerance to long-term hydralazine therapy in severe chronic heart failure,"We performed hemodynamic studies in 11 patients with severe chronic heart failure whose symptoms had returned to their pretreatment status after 37 +/- 15 weeks (mean +/- S.E.M.) of therapy with the vasodilator hydralazine. The cardiac index increased from 1.85 to 3.47 liters per minute per square meter of body-surface area, and systemic vascular resistance decreased from 1748 to 754 dyn . sec. cm-5 (both p less than 0.01) during initial hydralazine administration but returned to pretreatment values on repeat evaluation; withdrawal of the drug produced no hemodynamic deterioration. Responsiveness to hydralazine could not be restored by doubling the oral dose or by intravenous administration; tolerance was associated with fluid retention in five patients but was not reversed by intensive diuresis. In contrast, the responses to nitroprusside evaluated before and after the development of hydralazine tolerance were unaltered; other oral vasodilators were still effective. We conclude that drug-specific tolerance may account for the lack of clinical improvement in some patients with severe heart failure who receive long-term treatment with hydralazine.",0
1315,7053489,Rural health care: opportunities for established group practices,"Many rural areas of the United States are considered medically underserved. At the core of this underservice is a lack of physicians. Physicians are not attracted to rural areas for a variety of personal and professional reasons. We explore the role of established group practices (EGPs) in dealing with these barriers, by using a model of small associated group practices (AGPs) created in rural communities in association with a larger EGP located elsewhere. We also describe the use of this model by the Lovelace Medical Foundation in New Mexico in creating three rural group practices and planning a fourth.",0
1316,7054069,The effect of portal diversion on the early stages of liver carcinogenesis in the rat,"The effect of portal diversion by ameroid constriction was studied in the carcinogenic process in the rat after initiation of foci by diethylnitrosamine and after the establishment of putative preneoplastic nodules. Portal diversion or portal diversion plus partial hepatectomy did not act to promote or select for the development of nodules. Furthermore, portal diversion did not alter the natural history of established nodules. These results suggest that vascular factors are not important at these early stages of the carcinogenic process in the rat liver.",0
1317,7054709,A protocol for selecting patients with injured extremities who need x-rays,"To help curb excessive radiography, we developed a protocol for selecting patients with injured extremities who need x-ray examination, and we tested the protocol prospectively in 848 patients to determine its safety and effectiveness. Strict adherence to the protocol would have reduced x-ray usage by 12 per cent for upper extremities and 19 per cent for lower extremities. The actual reductions were 5 per cent and 16 per cent, respectively, since further reductions were limited by patient's demands for x-ray examinations. One fracture in 287 were missed, but the treatment was appropriate and the outcome satisfactory. By eliminating superfluous x-ray procedures, the protocol could reduce charges by $79 million to $139 million nationwide, without compromising quality of care or increasing malpractice liability. Nevertheless, even the best protocol cannot eliminate all negative x-ray studies. These results should serve as a stimulus for judicious use of radiography, but also as a warning to avoid overzealous cost-containment strategies that would reduce x-ray usage to below a safe threshold.",0
1318,7057823,The nature of suffering and the goals of medicine,"The question of suffering and its relation to organic illness has rarely been addressed in the medical literature. This article offers a description of the nature and causes of suffering in patients undergoing medical treatment. A distinction based on clinical observations is made between suffering and physical distress. Suffering is experienced by persons, not merely by bodies, and has its source in challenges that threaten the intactness of the person as a complex social and psychological entity. Suffering can include physical pain but is by no means limited to it. The relief of suffering and the cure of disease must be seen as twin obligations of a medical profession that is truly dedicated to the care of the sick. Physicians' failure to understand the nature of suffering can result in medical intervention that (though technically adequate) not only fails to relieve suffering but becomes a source of suffering itself.",0
1319,7070578,Modifications in energy metabolism during the development of chick glial cells and neurons in culture,"Developmental changes in lactate dehydrogenase (LDH), enolase, hexokinase (HK), malate dehydrogenase (MDH), and glutamate dehydrogenase (GDH) activities were measured in cultures of pure neurons and glial cells prepared from brains of chick embryos (8 day-old for neurons, 14 day-old for glial cells) as a function of cellular development with time in culture. The modifications observed in culture were compared to those measured in brain extracts during the development of the nervous tissue in the chick embryo and during the post-hatching period. A significant increase of MDH, GDH, LDH, and enolase activities are observed in neurons between 3 and 6 days of culture, whereas simultaneously a decrease of HK values occurs. In the embryonic brain between 11 and 14 days of incubation, which would correspond for the neuronal cultures to day 3 through 6, modifications of MDH, GDH, HK, and enolase levels are similar to those observed in neurons in culture. Only the increase of LDH activity is less pronounced in vivo than in cultivated cells. The evolution of the tested enzymatic activities in the brain of the chick during the period between 7 days before and 10 days after hatching is quite similar to that observed in cultivated glial cells (prepared from 14 day-old embryos) between 6 and 18 days of culture. All tested activities increased in comparable proportions. The modifications of the enzymatic profile indicate that some maturation phenomena affecting energy metabolism of neuronal and glial elements in culture, are quite similar to those occuring in the total nervous tissue. A relationship between the development of the energy metabolism of the brain and differentiation processes affecting neuroblasts and the glial-forming cells is discussed. ",0
1320,7070826,A standardized evaluation of psychosocial factors in chronic pain,"A number of psychosocial factors are generally considered to be important in exacerbating and maintaining chronic pain problems. However, standardized and reliable methods of evaluating these factors are needed. We have developed such an evaluation system, called the Psychosocial Pain Inventory (PSPI), and have obtained normative data from a large sample of chronic pain patients. Scores on the PSPI were approximately normally distributed and had good inter-rater reliability. Patients with high PSPI scores were more likely to be considered exaggerating their symptoms during their physical examinations, but they did not show less evidence of an organic basis for pain. Significant correlations were obtained between PSPI scores and some measures from the McGill Pain Questionnaire, but scores on the PSPI were essentially unrelated to personality disturbance as measured by the Minnesota Multiphasic Personality Inventory (MMPI). The PSPI and MMPI appear to provide different types of information that can be used in a complementary way in evaluating pain patients. Results of a small pilot study suggest that high scores on the PSPI predict poor response to medical treatment for pain. ",0
1321,7071025,"Fibrosing alveolitis. Causes, characteristics, and consequences","Fibrosing alveolitis may be cryptogenic (idiopathic) or secondary to a wide variety of disease processes. In almost all cases, acute and subacute inflammatory lesions progress to fibrosis and finally to a terminal state called honeycomb lung. Diagnosis is based on clinical and radiologic findings together with demonstration of typical pathologic changes on lung biopsy. The biopsy specimen should be large and taken from less severely involved lung areas to increase the probability that early, more specific lesions will be harvested. Prednisone is usually recommended for specific therapy. Therapy is a factor in duration of survival, although patient response varies. ",0
1322,7072182,Comparative studies of the contamination of vegetable food products by carcinogenic polycyclic aromatic hydrocarbons in the USSR and East Germany],"The content of benz(a)pyrene (BP) in the soil of the agricultural regions of the USSR, away from the intense sources of industrial wastes ranges within 1-10 microgram/kg and depends on the soil type. In the vicinity of the industrial enterprises, the BP content in the soil may be tens thousand times higher. The baseline natural content of BP in the green parts of the vegetables constitutes 1-5 microgram/kg, while in the grain, seeds and fruit it is 10-100 times lower. In the vicinity of the sources of industrial wastes, the BP content in the green parts of the vegetables, in the grain, seeds and fruit was found to be drastically increased. There is a correlation between the BP content in the potato tubers and the soil where the potato is grown. ",0
1323,7072387,How many times has your child had an accident?],"Anamnestic data on frequency, type and place of accidents of children attending the nursery school, the 4th and 8th grade education. Evaluation of a questionnaire to the parents. According to an analysis of 21,560 parental questionnaires which includes information on accidents of their children, 31% of the children attending the nursery school (5 years), 48% of those of the 4th (10 years) and 61% of those of the 8th (14 and 15 years) grade education had suffered an accident once or several times, girls significantly less often than boys. The most frequent types of accidents were open injuries and fractures. Accidents among younger children happened mostly at home, those of the older more frequently at school and at sport. No relationship was found between the rate of accidents and eyesight. ",0
1324,7072491,A suspected new canine storage disease,"This paper describes three cases of what is probably a new form of storage disorder. The affected animals were English Springer Spaniels and they had developed progressive neurological signs when 2-3 years old. They had gross enlargement of the vagi and of the spinal nerves supplying the brachial plexus. By light microscopy in these nerves these were massive amounts of endoneurial loose fibrous tissue with dispersion of nerve fibres and many foamy phagocyte-like cells. In the central nervous system there was very severe cytoplasmic vacuolation of most neurones and neuroglia, perivascular phagocyte-like cells, loss of myelin, loss of Purkinje cells, numerous spheroids, hypertrophic astrocytes and fibrous astrocytosis. There was also foamy cytoplasmic vacuolation of renal convoluted tubules and pancreatic exocrine parenchyma and numerous foamy phagocyte-like cells in lymph node and lung. On ultrastructural examination membrane bound vacuoles were present in the cytoplasm of affected neurones and phagocyte-like cells. Most of the vacuoles were empty, some contained amorphous materials and some, in neurones, contained stacks of curved or straight lamellae. It is suggested that the stored material could be an oligosaccharide. ",0
1325,7072516,High density lipoprotein composition versus heredity for acute myocardial infarction in middle-aged males,"The levels of high density lipoprotein (HDL) cholesterol and apolipoprotein AI (Apo AI) were determined in 299 men, 48 years of age. We found a significant negative correlation between HDL cholesterol and serum triglyceride concentrations and a significant correlation between serum triglyceride concentration and the Apo AI/HDL cholesterol ratio. A history of acute myocardial infarction (AMI) was significantly more common than expected among the fathers of men with a low HDL cholesterol level. We also found a relationship between AMI among fathers and high Apo AI level in sons, although this relationship was not as strong as that between AMI among fathers and low HDL cholesterol in sons. No significant relationship was found between AMI among mothers and HDL cholesterol or Apo AI in sons. ",0
1326,7072665,Enhanced gastroduodenal motility in children,"Metoclopramide hydrochloride was administered to nine children for the treatment of gastric stasis (N=6) and unexplained vomiting (N=3). One additional patient with gastric stasis displayed no response to the test dose of metoclopramide. Both the  frequency and apparent forcefulness of the gastric and duodenal waves increased with the administration of metoclopramide in the nine patients receiving treatment. Eight clinical aspects were monitored, with improvement seen in all during therapy; the rates of both improvement and freedom from symptoms were time dependent. After one month, the median rate of improvement in individual symptoms was 86%, and the median rate of freedom from symptoms was 54%. Only two of the nine patients became totally asymptomatic within the month. However, sustained improvement was maintained after discontinuance of metoclopramide administration. Within the administered dosages and within the study population, metoclopramide was found to be safe. ",0
1327,7073241,Hepatic free choline and betaine and the utilization of dietary protein in the choline-deficient rat,"In the rat, exclusion of choline from a carbohydrate-rich, 10% casein diet, resulted in a drastic reduction of betaine in the liver. The amount of unesterified choline was not lowered to the same extent. Both unesterified choline and total lipids in the liver were increased by rats fed a choline-deficient diet supplemented with 0.5% L-methionine compared to rats given an unsupplemented choline-deficient diet. The amount of betaine was low in both groups compared to choline-supplemented rats. Dietary choline deficiency lowered the biological value of casein only slightly. Statistically significant effects were seen only in some of the experiments when potato starch was used as the carbohydrate source but not when maize starch was used. The choline-deficient potato starch diet gave rise to a more severe liver fattening that the corresponding maize starch diet. ",0
1328,7074302,Pupil studies in depressed patients: an investigation of the mechanism of action of desipramine,"Six depressed patients were treated routinely with desipramine, a relatively selective noradrenergic uptake blocking drug. After 0, 1 and 3 weeks' treatment, pupillary responses to tyramine, phenylephrine and pilocarpine were measured using a photographic techniques. Both 1 and 3 weeks' treatment significantly inhibited tyramine and phenylephrine-induced mydriasis, but did not inhibit pilocarpine-induced miosis; in fact the longer treatment enhanced miosis due to pilocarpine. Resting pupil size was significantly increased after 1 and 3 weeks' treatment. The findings can be explained by the known ability of desipramine to block noradrenaline uptake and alpha adrenoceptors: they provide no evidence of muscarinic receptor blockade or of a slowly developing adaptation at alpha adrenoceptors. ",0
1329,7074363,Impaired brain development of the diabetes insipidus Brattleboro rat,"The Brattleboro homozygous diabetes insipidus (HOM-DI) mutant rat, incapable of synthesizing the neuropeptide vasopressin, has an impaired body growth of which the severity depends upon the conditions of reproduction. The comparison of homogeneously genotyped litters of HOM-DI and heterozygous (HET-DI) control pups, delivered and nursed by HOM-DI females, was regarded to be the only experimental design that practically excludes other influences on growth differences than the mutation itself. In this breeding scheme the postnatal growth of the HOM-DI brain is impaired, and the weight deficit persists into adulthood. Regionally, the neonatal development of cerebellum and medulla oblongata is most affected, and only slightly that of the cerebral cortex. The other separately isolated parts of the the brain seem to be unaffected (olfactory bulbs, hypothalamus, hippocampus, colliculi and thalamus plus basal ganglia). Cerebellum appeared to be the most consistently affected brain area of the HOM-DI Brattleboro rat since, unlike in the case of cerebral cortex and medulla oblongata, the weight deficit persisted throughout life. Olfactory bulb growth, on the other hand, appeared to continue after the first month of life, resulting in an increased weight at day 180. Water content of cerebral cortex and cerebellum of HOM-DI adults appeared slightly higher and might be explained by the generation of different brain water regulation systems for HET- and HOM-DI Brattleboro rats. Protein and DNA estimations of cerebral cortex, cerebellum and olfactory bulbs of male brains during development and in adulthood reflect the differences as found for weight, indicating no obvious changes in cell densities. It is concluded after comparison with other types of brain growth malformations, that the HOM-DI Brattleboro brain has its own particular etiology. The possible involvement of the action of vasopressin is postulated and discussed. ",0
1330,7074531,Intestinovesical fistula in a patient with chronic lymphocytic leukemia: case report and literature review,"A case of intestinovesical fistula secondary to leukemic infiltration is described. The patient was known to have chronic lymphocytic leukemia and had been receiving chemotherapy fo ten months. She presented complaining of nausea, vomiting and vague abdominal pain. She initially denied genitourinary tract symptoms, although admitting urinalysis revealed pyuria, hematuria and bacteriuria. Urine cultures repeatedly grew E. coli despite broad spectrum antibiotic therapy. She eventually developed fecalant material in her urine and pneumaturia. Cystoscopy revealed a fistulous tract. At surgery an ileovesical fistula was found and histopathology showed lymphocytic leukemic infiltration. Intestinovesical fistulas are uncommon. Congenital, traumatic, inflammatory and solid neoplastic etiologies are well established in the literature. No previous cases have been attributed to hematologic malignancies. Since higher remission rates and longer periods of remission are being achieved with chemotherapy, and since fistula symptomatology may present quite subtly, awareness of this association may expedite diagnosis. ",0
1331,7074990,"Development of diltiazem, a calcium antagonist: coronary vasodilating and antihypertensive actions","We found that the coronary vasodilating action resides in novel 1,5-benzothiazepine derivatives. The calcium antagonistic property of diltiazem has been demonstrated in vascular and visceral smooth muscles as well as in cardiac ventricular muscle. Although the vasodilating action of diltiazem was the most potent in coronary and vertebral artery, it also dilates other peripheral arteries including renal artery. Antihypertensive action of diltiazem has been shown in several experimental models, such as SHR, renal hypertensive and DOCA/saline rats. Diuretic effect of diltiazem was observed in SHR. Following chronic administration of diltiazem to SHR, the increment of blood pressure was significantly lowered without changing body fluid. In addition, hypotensive action of diltiazem by i.c.v. was observed only at a very high dose. We assume that the vasodilating action of diltiazem is primarily involved in the mechanism responsible for its antihypertensive action. ",0
1332,7075162,Computer systems for facilitating management of the critically ill,"The Shock Research Unit has applied computer technology to the care of the critically ill and injured patient since 1961. The requirements for patient monitoring were initially explored with a process control computer (IBM) 1710). In the current system, a Xerox Sigma-5 computer is utilized for monitoring EKG, hemodynamic, respiratory, and biochemical signals. Electronic preprocessing increases the efficiency and speed of data acquisition and signal analysis. Provisions are made for recording narrative data as part of a commitment to evolve an automated patient record. Bedside displays include both tabular and graphic summaries of patient status and trends. A computer accessible archive of patient files is maintained. Clinical operation of the system has been facilitated by automation of afferent and efferent functions including flushing of catheters, servo-calibration of pressure measuring systems, automated urine collection and disposal, and computer controlled infusion of fluids and medications. We anticipate the continuing development of automated afferent and efferent components for feedback control of ventilators by automated sampling and measurement of arterial blood gases and infusion of fluids and medications in response to changes in monitored hemodynamic variables. Such automation, together with medical intelligence for priority alarms and interpretive displays, hold promise of increasingly potent and cost-effective systems to facilitate and improve care of the critically ill or injured patient. ",0
1333,7075741,Effects of sphingolipids on erythroblastic maturation in the mouse,The changes effected by injection of an extract of phospholipids obtained from the plasma of normal human donors (PLE) or an emulsion of commercially available sphingolipids on erythropoiesis in the mouse were studied. The parameters followed were 59Fe uptake by the erythroid tissue and the number of circulating reticulocytes. It was found that in the 12--24-h period following administration of PLE or purified sphingomyelin a significant increase in 59Fe uptake by circulating RBC an by their hemic fraction takes place. This change was associated with a higher 59Fe utilization by the bone marrow and with an increase in the number of circulating reticulocytes. ,0
1334,7076116,A combination of chenodeoxycholic acid and ursodeoxycholic acid is more effective than either alone in reducing biliary cholesterol saturation,"The effects on biliary lipids of 10 mg per kg per day of chenodeoxycholic acid (CDCA), 10 mg per kg per day of ursodeoxycholic acid (UDCA), and their equimolar combination (5 mg per kg per day of each), all administered for 45 to 60 days, were investigated in 18 patients with gallstones in a double-blind study with a balanced latin square design. The molar percentage of cholesterol in bile (initial value 9.7 +/- 2.2) was significantly lower after UDCA (5.4 +/- 1.3) and the combination (5.2 +/- 1.2) than after CDCA (7.2 +/- 1.7). Nevertheless, when the ability to solubilize cholesterol was calculated, taking into account the percentage of biliary UDCA, then the differences in cholesterol saturation induced by UDCA alone and the combination also became considerable (saturation index: 0.94 +/- 0.12 as compared to 0.81 +/- 0.12). The total bile acid pool increased significantly after treatment with CDCA and the combination, but not after UDCA. Lithocholic acid was increased significantly only by treatment with CDCA. Diarrhea was observed in five patients with hypertransaminasemia and in four patients after CDCA, whereas both UDCA and the combination were well-tolerated. We conclude that the administration of a combination of equimolar doses of CDCA and UDCA can be recommended for medical treatment of gallstones since it has greater effects on bile cholesterol saturation than either alone, is better tolerated than CDCA, and is less expensive than UDCA.",0
1335,7076211,Unilateral white matter necrosis following carotid endarterectomy,"The authors report the first known example of hypoxic-ischemic white matter necrosis limited to one cerebral hemisphere. The patient was a 63-year-old man who developed signs of a stroke following a myocardial infarct after a left carotid endarterectomy and died seven days later. At autopsy, extensive necrosis of centrum semiovale was found only in the cerebral hemisphere supplied by the endoarterectomized carotid artery. A recent thrombus was found at the site of the endarterectomy, and the right common carotid artery was completely occluded by an old thrombus. This observation probably is explained by a well-established collateral blood supply to the right cerebral hemisphere, which protected it from the effects of the hypotension that accompanied the myocardial infarct. ",0
1336,7076727,Qualitative and quantitative differences in spreading of human fibroblasts on various protein coats. Modulation by treatment of the cells with amines,"In contrast to established cell lines, normal human skin fibroblasts spread on their own fibronectin. The present investigation has examined whether human fibroblasts, like established cell lines, would be capable of spreading on substrata coated with proteins with different reactivity towards the cell surface. Coverslips were coated with human serum, fibronectin, alpha 2 macroglobulin-trypsin, a polyspecific anti-fibroblast antibody and a polyspecific anti-calf-serum antibody. The attachment of the cells to these substrate was of the same extent. Spreading was examined qualitatively using phase, interference contrast and reflection contrast optics on live cells, as well as scanning electron microscopy on fixed cells. To quantitate the maximum degree of cell spreading a semi-automated system was used, which measured the cell perimeter on a large number of cells. The distributions of the degree of cell spreading on the five substrata were compared statistically. The qualitative and quantitative differences observed on the various substrata could be further differentiated by adding various amines to the cells during 60 min spreading or during a 30 min preincubation before spreading. No strict correlation could be found between the effect of the amines on attachment or on spreading and their presumed effects on cellular transglutaminases. The results clearly indicate that the spreading of human fibroblasts can be modulated by the nature of the substratum and that, by using quantitative methods, these differences in behaviour can be measured accurately. ",0
1337,7076984,Bactericidal capacity of polymorphonuclear leukocytes from patients receiving theophylline therapy,"The capacity of polymorphonuclear leukocytes (PMNs) to kill Staphylococcus aureus strains 502 A was studied in 25 patients receiving theophylline therapy and in normal healthy controls. A significant difference in PMN bactericidal capacity was found between controls and patients with serum theophylline levels higher than 8 micrograms/ml, as determined by high-pressure liquid chromatography. The bactericidal capacity of PMNs from both the patient and control populations was reduced in the presence of theophylline levels above 8 micrograms/ml. In addition, a transient but significant drug-independent reduction was found in the bactericidal capacity of transient but significant drug-independent reduction was found in the bactericidal capacity of PMNs from patients receiving theophylline. ",0
1338,7077337,Effects of a single intravenous glucocorticoids dose on biogenic amine levels in cat lumbar spinal cord,"The effects of a single large intravenous dose of methylprednisolone on the steady state levels of dopamine, norepinephrine, and 5-hydroxytryptamine in cat lumbar spinal cord, as a function of dose (15, 30, or 90 mg/kg) and time (1 or 24 h) after administration, were examined by high performance liquid chromatography with electrochemical detection. Methylprednisolone produced a dose-related increase in the levels of dopamine and 5-hydroxytryptamine, but not norepinephrine, measured at 1 h. The effect of the single glucocorticoid dose was biphasic, however, as measurement of the three amines at 24 h showed each to be depressed below the levels found in untreated animals. The possible mechanistic basic and the significance of these glucocorticoid effects are discussed. ",0
1339,7077528,Accumulation of cimetidine by kidney cortex slices,"The mechanisms involved in the excretion of the histamine H2-receptor antagonist cimetidine are as yet incompletely understood. The purpose of this study was to examine the interaction of cimetidine with incubated slices of dog kidney cortex. The results of time and concentration-dependent experiments by using 3H-labeled cimetidine demonstrated that the drug was accumulated without metabolism against a concentration gradient by a saturable process. Inhibition of uptake by cyanide and by incubation under a nitrogen atmosphere indicated energy dependence. Uptake of cimetidine by active cationic transport was likely inasmuch as both cyanine 863 and quinine blocked accumulation. However, a probenecid-sensitive component, accounting for about 20% of steady-state accumulation, also was identified. The lack of inhibitory action of p-aminohippuric acid and the cationic nature of the cimetidine molecule suggest the probenecid-sensitivity was not related to the renal organic anion mechanism. Further, probenecid inhibition was not due to a generalized cellular toxicity because maximally inhibitory concentrations of probenecid did not interfere with uptake of the cation tetraethylammonium. ",0
1340,7077896,Ca-binding capacity and the membrane structure of the erythrocytes in certain types of experimental hypertension in rats],"The authors studied the microstructure of erythrocyte membrane (using polarization method of fluorescent probes) and its Ca-binding property in rats with spontaneous, renal and DOCA-salt hypertension. Rats with spontaneous hypertension showed increased microviscosity of erythrocyte membrane and decrease in its property of binding Ca ions, which is not recorded in renal and DOCA-salt hypertension. Salt overload exerted no influence on both parameters studied. ",0
1341,7077992,Limits and possibilities of optical keratoprosthesis. A clinical and histopathological report (author's transl)],"The author reports on the experience with 75 cases of optical keratoprosthesis performed since 1967. The keratoprosthesis were carried out either by intracorneal anchoring or according to Strampelli as osteo-odonto-keratoprosthesis. Short-term improvement (up to one year) was achieved in 25% of the cases, there was a improvement (up to 14 years) in eight patients. The operation had to repeated in 30%. The keratoprosthesis is anchored under a firmly attached flap of oral mucosa transplanted to the cornea after cataract operation. Common complications are glaucoma, hypotony syndrome, extrusion of the implant, development of a retroprosthetic membrane and retinal detachment. Only in cases of severe damage to the cornea after alkali or acid burns, trauma, or pemphigoid and failure of previous keratoplasties is a keratoprosthesis indicated. The degree of improvement usually depends on the pre-existing damage to the eye. The possibilities of keratoprosthesis are limited and functional improvement is frequently only of short duration. Intensive counseling and patient care are essential pre-requisites. ",0
1342,7078427,Impaired renal mevalonate metabolism in nephrotic syndrome: a stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia,"Increased hepatic lipogenesis in the nephrotic syndrome is not adequately explained by hypoalbuminemia. In this disorder an enhanced delivery of the cholesterol precursor mevalonic acid (MVA) to the liver may be an unidentified stimulus to cholesterogenesis. Since the kidneys are the major site of mevalonate excretion and metabolism by either the sterol or nonsterol shunt pathways, an impairment of any of these metabolic alternatives could result in redistribution of mevalonate to the liver. Male Sprague-Dawley rats rendered nephrotic by puromycin aminonucleoside had their kidneys perfused with Krebs-Henseleit-bicarbonate buffer containing albumin, glucose and 5-14C-MVA. The number five carbon label was utilized so that any 14CO2 produced would represent mevalonate shunt pathway activity. The isolated perfused kidney was used to eliminate confounding variables. In eight control kidneys perfused for 2 hr 62 +/- 2% of the MVA was removed from the perfusate compared to 50 +/- 2% in five nephrotic kidneys (p less than .006). Urinary MVA recovery was 22 +/- 2% in controls. 15 +/- 1% in nephrotics (p less than .05). The incorporation of 14C into renal tissue lipids was not different in the two groups. Recovery of 14CO2 was two times greater in controls than in nephrotics (p less than .006). Inulin clearance per gram of kidney and sodium reabsorption were similar for the two groups. Isolated perfused kidneys from nephrotic rats metabolize MVA abnormally such that less is excreted, less is oxidized, and more is available for recirculation to the liver. This occurs independently of hypoalbuminemia, a change in glomerular filtration rate, or an overt histo-pathologic lesion. These events create an environment for increased hepatic cholesterol synthesis. ",0
1343,7078607,Comparison of Indium-111 platelet scintigraphy and two-dimensional echocardiography in the diagnosis of left ventricular thrombi,"In a study comparing indium-111 platelet scintigraphy and two-dimensional echocardiography as methods of identifying left ventricular thrombi, the results obtained with both techniques were verified at surgery or autopsy in 53 patients--34 with left ventricular aneurysms, and 19 with mitral-valve disease. Left ventricular thrombi were found at surgery or autopsy in 14 of the patients with aneurysms and in none of those with mitral-valve disease. Thirteen of 53 echocardiograms (25 per cent) were technically inadequate and excluded from the analysis. In the group with aneurysms, the sensitivity of scintigraphy in detecting thrombi was 71 per cent, and that of echocardiography was 77 per cent. The specificity of scintigraphy was 100 per cent, and that of echocardiography was 93 per cent. We conclude that indium-111 platelet scintigraphy and two-dimensional echocardiography have useful and complementary roles in the detection of left ventricular thrombi. Both these noninvasive techniques can be used to monitor therapy.",0
1344,7079815,Hyponatremia in adrenal insufficiency: review of pathogenetic mechanisms,"The pathophysiology of hyponatremia in adrenal insufficiency has been a subject of intense controversy. The controversy centers on whether the inability of the kidney to maximally dilute the urine is secondary to increased levels of antidiuretic hormone (ADH) or is independent of ADH. Review of the pertinent studies allows us to conclude that (1) in prolonged glucocorticoid deficiency, plasma ADH levels are elevated because of decreased effective circulating blood volume; (2) in mineralocorticoid deficiency, plasma ADH levels may also be elevated, but in this case because of decreased absolute circulating blood volume; (3) in both instances the elevated ADH levels impair the ability to dilute the urine; and (4) in both glucocorticoid and mineralocorticoid deficiency hemodynamic changes may also contribute, independently of ADH, by limiting delivery of tubular fluid to the diluting site. ",0
1345,7079883,The sick cilia syndrome],"The incidence of bronchiectasis should decrease because of improved immunization, but certain defects would still cause the malady. Fifteen consecutive patients with bronchiectasis were examined for ciliary defects by examining the nasal mucosae with an electron microscope and measuring the clearance of technetium-99m from the lung with a gamma camera. Three patients were found to have defects. Compound cilia, disorganization of the tubular structure, vacuolization and deficient inner dynein arms were observed. In one patient a loss of cell membranes which returned to normal after 4 months, was observed. Ciliary abnormalitites can either be anatomical or physiological and 'sick cilia' should be considered as a cause of bronchiectasis. ",0
1346,7079928,The effect of immunosuppression on the patency and structure of canine vein allografts in the venous system,The effect of immunosuppression on allogeneic femoral vein grafts placed into the venous system of dogs was studied. Autologous vein grafts demonstrated clear patency and few histologic changes up to four weeks after operation. Allogeneic vein grafts in dogs not receiving immunosuppression showed thrombosis in all instances within less than four weeks. Standard immunosuppression therapy reduced the thrombosis rate to 25 per cent at four weeks in dogs with femoral vein allografts. Only mild histologic changes were observed in these grafts. ,0
1347,7080156,"Prevalence and incidence of onchocerciasis as baseline data for evaluation of vector control in San Vicente Pacaya, Guatemala","The aim of this study was to estimate the incidence rate of onchocerciasis as measured by skin biopsy during field surveys carried out in San Vicente Pacaya, Guatemala from 1977 through 1979. The age standardized prevalence rates for males and females were 44.6% and 19.9%, respectively, in 1979. There were annual incidence rates of 0.08 and 0.04 for males and females, respectively. The incidence rates seem to increase with age. Since the effect of false negatives will be greater in females than in males, these rates should be interpreted cautiously. Extremely high reversion rates (proportion of negatives in a later examination among positives at the first examination by skin biopsy) were observed; these figures might be explained mainly by false negatives due to the skin biopsy. However, it is suspected that some of the apparent reversion rates may also have been influenced by other factors, e.g., sex difference. ",0
1348,7080200,"Presence of supposed growth factors in a serum fraction with a molecular weight of the components from 100,000 to 200,000 D]","Growth of cell culture BHK-21 in the presence of different fractions of bovine serum has been studied. Growth-promoting activity of the fraction with molecular weight of 100 000 daltons increased with the concentration of this fraction in the medium, but did not reach the activity level of the whole serum. The intensity of cell proliferation similar to that in the presence of the whole serum was achieved due to the combined action of the serum fraction with molecular weight of 100 000 - 200 000 daltons, containing the supposed growth factors and a fraction with low-molecular components of 14 000 daltons. When tested individually, neither of these two fractions showed similar effect. ",0
1349,7080217,Composition and metabolism of high-density lipoproteins in normal rabbits of different ages and in experimental atherosclerosis],"It is shown that peculiarities of high-density lipoproteids metabolism in old rabbits as compared with young ones in norm are represented by an increase in the activity of lecithincholesterol acyltransferase (EC 2.3.1.4.3) in blood plasma and in time of half-removal of labelled high-density 3H lipoproteids by a decrease in the activity of cholesterol-7 alpha-monooxigenase in the liver. The content of cholesterol esters in the composition of high-density lipoproteids increases with ageing. Under experimental atherosclerosis the decomposition of high-density lipoproteids intensifies, the activity of cholesterol-7 alpha-monooxigenase increases and that of lecithincholesterol acyltransferase is inhibited equally in uneven-aged rabbits. The content of free cholesterol increases and that of cholesterol esters decreases in the high-density lipoproteid composition. ",0
1350,7095747,Polycystic liver disease: a study of cyst fluid constituents,"""Cyst fluid from a patient with polycystic liver disease was obtained by needle aspiration using ultrasound guidance. The constituents of the fluid resembled the """"bile salt-independent"""" fraction of human bile and supports the hypothesis that such cysts are lined by a functioning, secretory bile duct epithelium.""",0
1351,7110242,A controlled evaluation of the risk of bacterial endocarditis in persons with mitral-valve prolapse,"The absence of controlled evidence and the high prevalence of mitral-valve prolapse have created substantial uncertainty about whether this condition is an important risk factor for bacterial endocarditis. We evaluated this risk in a case-control study of hospital inpatients who had undergone echocardiography and who lacked any known cardiovascular risk factors for endocarditis, apart from mitral-valve prolapse and isolated mitral-regurgitant murmurs. Thirteen (25 per cent) of 51 patients with endocarditis had mitral-valve prolapse, as compared with 10 (seven per cent) of the 153 matched controls without endocarditis. For the 51 matched case-control sets, the odds ratio (8.2; 95 per cent confidence interval, 2.4 to 28.4) indicated a substantially higher risk of endocarditis for people with mitral-valve prolapse than for those without it. This association remained statistically significant when parenteral drug abuse and routine antibiotic prophylaxis preceding dental work and other forms of instrumentation were taken into account. Furthermore, the risk may be higher than is indicated by this study, since 46 per cent of the controls underwent echocardiography for clinically suspected mitral-valve prolapse, suggesting an overrepresentation of mitral prolapse in the control group. The results support the contention that mitral-valve prolapse is a significant risk factor for bacterial endocarditis.",0
1352,7118068,Hepatitis B virus and HLA antigen display in the liver during chronic hepatitis B virus infection,"an analysis of the expression of the histocompatibility antigens in the livers of patients with chronic hepatitis B virus infection and normal subjects has demonstrated an increased expression of HLA-A, B, C antigens on the hepatocytes of patients with a low level of viral replication (HBe antibody positive) as compared with patients who exhibit a high level of viral replication (HBe antigen positive) and controls. This increase in the expression of histocompatibility antigens on the hepatocytes was associated with a decrease in the membrane expression of viral antigens by the same cells. These differences in the density of HLA and viral antigen display may influence the efficiency of T-cell cytolysis of hepatitis B virus-infected hepatocytes.",0
1353,7118071,Hypothesis: metabolic activity of the colonic bacteria influences organ injury from ethanol,"Incubation of human fecal homogenates with ethanol (0.078 gm per dl) resulted in accumulation of increased quantities of higher alcohols and other unidentified metabolites when compared with homogenates incubated without ethanol. Studies in rats demonstrated nearly perfect equilibration between blood and colonic luminal ethanol suggesting that the colonic flora in alcoholics is chronically exposed to ethanol concentrations in the range used in the homogenate experiments. The higher alcohols produced by the homogenates were rapidly absorbed from the colon. We hypothesize that, when exposed to ethanol, the colonic flora produced toxic compounds which are absorbed and influence the body's response to ingested ethanol. Individual differences in this bacterial metabolism may account for the wide individual differences in susceptibility to ethanol-related organ injury.",0
1354,7141391,"The mechanism of biliary excretion of alpha 1-acid glycoprotein in the rat: evidence for a molecular weight-dependent, nonreceptor-mediated pathway","The transport of human alpha 1-acid glycoprotein from the circulation to the bile has been studied in the rat. Biliary excretion was proportional to the i.v. injected dose, and the percentage excreted remained constant. The amount excreted in the bile (over 4 hr) was inversely related to the rate of hepatic (hepatocyte) uptake and the galactose receptor which is specific for asialo glycoproteins was not involved. Reinjection of the glycoprotein excreted in bile resulted in a similar proportion of the dose being reexcreted, suggesting that a subset of the glycoprotein is not selected for excretion in bile. Transit times from blood to bile for glucagon, insulin, alpha 1-acid glycoprotein, fetuin, albumin, and carcinoembryonic antigen were directly related to their molecular weights. Removal of sialic acid from the asialo glycoproteins did not affect these transit times. Possible mechanisms for the biliary excretion of alpha 1-acid glycoprotein are discussed.",0
1355,7141398,Pigment gallstone disease: Summary of the National Institutes of Health--international workshop,"This report summarizes the proceedings of the first National Institutes of Health--International Workshop on Pigment Gallstone Disease. The meeting held at the University of Pennsylvania in May, 1981 consisted of eight sessions in which the following aspects of pigment gallstone disease were discussed: (a) classification; (b) epidemiology; (c) radiographic assessment; (d) gallstone composition; (e) composition of bile; (f) pathogenesis; (g) animal models, genetics, and computer analysis, and (h) medical treatment. The interaction of participants interested in various aspects of pigment stone disease was stimulating. This workshop should be a major stimulus for future studies in this relatively neglected, but important area of biliary tract lithiasis.",0
1356,7144866,Magnetic-susceptibility measurement of human iron stores,"We made direct noninvasive magnetic measurements of hepatic iron stores with a specially designed superconducting quantum-interference-device (SQUID) susceptometer in 20 normal subjects and in 110 patients with liver disease, iron deficiency, hereditary hemochromatosis, or transfusional iron overload. Magnetic in vivo measurements of liver non-heme iron were closely correlated with chemical in vitro measurements in liver-biopsy specimens (r = 0.98, P less than 10(-5) up to 115 mumol per gram of liver tissue (wet weight) or more. Magnetically determined storage-iron concentrations were below 6.0 mumol per gram in iron-deficient patients and normal men and premenopausal women, but they were raised (9.7 to 31.4 mumol) in 12 of 67 patients with liver disease and were greatly increased (22.9 to 117.7 mumol) in patients with untreated hereditary hemochromatosis or transfusional iron overload. Magnetic measurements of iron stores provide a new quantitative technique for early detection of hereditary hemochromatosis and for rapid evaluation of treatment regimens for transfusional iron overload.",0
1357,7207565,Blood pressure in acute and chronic vasopressin excess: studies of malignant hypertension and the syndrome of inappropriate antidiuretic hormone secretion,"We studied 29 patients with malignant hypertension and 28 patients with the syndrome of inappropriate antidiuretic hormone secretion to assess the relation of plasma vasopressin to blood pressure in states of acute and chronic vasopressin excess. In the patients with malignant hypertension, vasopressin levels were elevated (13 +/- 2 pg per milliliter. [+/- S.E.M.]) but did not correlate with arterial pressure; however, in normal volunteers, blood pressure did not rise when vasopressin was increased beyond these levels through infusion of the peptide. In the patients with inappropriate antidiuretic hormone secretion, blood pressure was not elevated, but vasopressin was raised (39 +/- 7 pg per milliliter) and did not correlate with systolic or diastolic pressure. These data do not support the concept that an acute or chronic excess of vasopressin makes an important contribution to the regulation of blood pressure.",0
1358,7278884,Quality of institutional participation in multicenter clinical trials,"""We studied the relation between an institution's degree of participation in a multicenter clinical trial and the quality of its participation. The quality of participation was judged on the basis of the percentage of patients entered into the trial who were in fact eligible, who were treated in accordance with the protocol, and for whom the appropriate forms were received. Those who satisfied these criteria were termed """"valid"""" patients. Institutions were divided into two groups, """"major participants"""" and """"minor participants,"""" according to the number of patients they entered in the trial. In a detailed analysis of a multicenter trial of chemotherapy for soft-tissue sarcoma, we found that major participants had a significantly higher percentage of valid patients than did minor participants (81 per cent vs. 39 per cent) and that the minor participants were actually detrimental to the study from both scientific and administrative viewpoints. These results suggest that institutions should not participate in multicenter studies unless they can enter some predetermined minimal number of patients per year.""",0
1359,7286888,Protection by antibiotics against experimental focal cholangitis produced in mice by a schistosomicidal isothiocyanate,"Oral administration to mice of high doses of 4-isothiocyano-4'nitrodiphenylamine (amoscanate), a potent antischistosomal drug, produced focal necrotizing lesions of the large intrahepatic and extrahepatic bile ducts and the gallbladder. Coadministration of erythromycin and, to a somewhat lesser degree, of paromomycin, markedly reduced the effects of amoscanate on the biliary tract. These results suggest that amoscanate may be converted to a cholangiotoxic product by one or several constituents of the enteric bacterial flora. Since erythromycin does not affect the antischistosomal activity of amoscanate, coadministration of an antibacterial agent can reduce toxic effects of a drug while full chemotherapeutic activity is maintained. The possibility of toxic effects of metabolites of xenobiotics produced by intestinal bacteria deserves attention and the experimental production of focal intrahepatic and extrahepatic cholangitis by such drug metabolites suggests a possible mechanism in human bile diseases.",0
1360,7290153,Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes,"We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 19 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responders' thymic cells, irradiated to abrogate antibody production and suppression (P less than 0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P less than 0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.",0
1361,7308986,Effect of chronic alcohol intake on hepatic fibrosis and granulomas in murine schistosomiasis mansoni,"In consideration of the vast prevalence of schistosomiasis and heavy alcohol consumption in many parts of the world, the possibility of an interaction between these two conditions inducing liver disease was studied in mice infected with Schistosoma mansoni. Alcohol consumption significantly reduced by 25% the mean granuloma diameter and by about 60% the extent of fibrous tissue deposition determined chemically as hydroxyproline. DNA, as an expression of the inflammatory and cellular components of the granulomatous reaction in the infected animals, was also significantly reduced by alcohol consumption. These results indicate the need for epidemiological studies in the clinical manifestations and course of schistosomiasis in human alcoholics.",0
1362,7308989,Biliary excretion of sulfobromophthalein compounds in normal and mutant Corriedale sheep. Evidence for a disproportionate transport defect for conjugated sulfobromophthalein,"Biliary excretion of dye was evaluated in three normal and one mutant Corriedale sheep (characterized by depressed biliary transport of many organic anions) during infusion of unconjugated sulfobromophthalein (BSP) and its preformed glutathione conjugate (BSP-GSH). Maximal dye excretion rates in bile in normal sheep were higher when BSP-GSH rather than BSP was administered. In confirmation of earlier studies, dye excretion in bile was markedly depressed in the mutant animal. However, movement of unconjugated BSP from liver cells into bile remained relatively intact whereas transport of conjugated BSP compounds was virtually absent. Preservation of unconjugated dye entry into bile suggests the presence of a transport mechanism for unconjugated BSP which is preserved in mutant sheep and is distinct from that involved in BSP-GSH excretory transport. Renal clearance of conjugated BSP compounds was greater than of unconjugated BSP and clearance values were comparable in the normal and mutant sheep. Thus, no excretory defect comparable to that present in liver was identifiable in the kidney.",0
1363,7350497,Cholera--a possible endemic focus in the United States,"In September and October 1978, after a case of cholera had been discovered in southwestern Louisiana, 10 more Vibrio cholerae O-Group 1 infections were detected in four additional clusters. All 11 infected persons had recently eaten cooked crabs from five widely separated sites in the coastal marsh, and a matched-triplet case-control study showed a significant relation between cholera and eating such crabs (P = 0.007). V. cholerae O1 was isolated from estuarine water, from fresh shrimp, from a leftover cooked crab from a patient's refrigerator, and from sewage in six towns, including three without identified cases. All isolates in Louisiana and an isolate from a single unexplained case in Texas in 1973 were biotype El Tor and serotype inaba; they were hemolytic and of a phage type unique to the United States--suggesting that the organism persisted undetected along the Gulf Coast for at least five years.",0
1364,7351926,"Relation of diet to high-density-lipoprotein cholesterol in middle-aged marathon runners, joggers, and inactive men","We investigated the effect of diet on high-density-lipoprotein (HDL) cholesterol in 59 healthy middle-aged marathon runners, 85 joggers, and 74 inactive men. Marathon runners and joggers reported eating less red meat (P less than 0.0001), bacon (P less than 0.05), and sausage (P less than 0.01) than did the inactive men, although meat consumption was not significantly correlated with HDL. Results suggest that HDL differences (marathon runners, 65 mg per deciliter; joggers, 58 mg per deciliter; inactive men, 43 mg per deciliter) among the three groups were primarily the result of distance run, not dietary factors. Distance run was also the best predictor of the HDL:total cholesterol ratio and of total cholesterol (a negative correlation), and it was second only to weight in predicting triglyceride levels.",0
1365,7351974,Ventilatory control in parents of victims of sudden-infant-death syndrome,"""Since a defective ventilatory-control mechanism may have a role in the sudden-infant-death syndrome (SIDS), and hereditary factors influence the degree of ventilatory drive, we measured ventilatory responsiveness to carbon dioxide with and without increased airway resistance in 12 parents of SIDS victims and 12 control parents matched for age and size. Ventilatory response (delta VI/delta PCO2) and """"respiratory drive"""" (delta P100/delta PCO2) were measured both with and without added resistance to inspiratory flow. SIDS parents had significantly lower ventilatory response with added resistance (P less than 0.05) and without it (P less than 0.01) and significantly lower respiratory drive with added resistance (P less than 0.001) and without it (P less than 0.05). Control parents had significantly increased respiratory drive when the resistance was added (P less than 0.005), whereas SIDS parents did not. The data suggest that a low ventilatory response to carbon dioxide and a diminished compensatory response to increased airway resistance may increase a potential parent's risk of having a child susceptible to SIDS.""",0
1366,7354778,Small-airways dysfunction in nonsmokers chronically exposed to tobacco smoke,"We evaluated the effect of long-term passive smoking (involuntary inhalation of tobacco smoke by nonsmokers) and long-term voluntary smoking on specific indexes of pulmonary function in 2100 middle-aged subjects. Regardless of sex, nonsmokers chronically exposed to tobacco smoke had a lower forced mid-expiratory flow rate (FEF 25 to 75 per cent) and forced end-expiratory flow rate (FEF 75 to 85 per cent) than nonsmokers not exposed (P less than 0.005). In addition, values in passive smokers were not significantly different from those in light smokers and smokers who did not inhale (P less than 0.005). When we looked at the extent to which smoke exposure is related to graded abnormality, we found that nonsmokers in smoke-free working environments have the highest scores on the spirometric tests; passive smokers, smokers who do not inhale, and light smokers score similarly and significantly lower; and heavy smokers score the lowest (P less than 0.005). We conclude that chronic exposure to tobacco smoke in the work environment is deleterious to the nonsmoker and significantly reduces small-airways function.",0
1367,7354809,Increased sodium-lithium countertransport in red cells of patients with essential hypertension,"This paper describes experiments showing that one of the pathways of sodium transport across the red-cell membrane, sodium-lithium countertransport, is faster in patients with essential hypertension than in control subjects. This transport system accepts only sodium or lithium and is not inhibited by ouabain. The maximum rate of transport shows inherited differences. The mean maximum rate of sodium-lithium countertransport was found to be 0.55 +/- 0.02 (mean +/- S.E.M.) mmol (liter of red cells X hour)(-1) in a group of 36 patients with essential hypertension and 0.24 +/- 0.02 in 26 control subjects (P less than 0.001). The first-degree relatives of eight patients with essential hypertension and 10 control subjects had mean maximum rates of sodium-lithium countertransport of 0.54 +/- 0.05 and 0.23 +/- 0.02, respectively. Five patients with secondary hypertension had normal mean maximum rates of sodium-lithium countertransport. The relation between heritability of red-cell sodium-lithium countertransport and essential hypertension should be investigated further.",0
1368,7360176,On the readability of surgical consent forms,"A great deal of attention has been paid to ensuring that surgical consent forms have valid content, but little effort has been made to ensure that the average patient can read and understand them. Five representative surgical consent forms were analyzed with two standardized readability tests. The readability of all five was approximately equivalent to that of material intended for upper-division undergraduates or graduate students. Four of the five forms were written at the level of a scientific journal, and the fifth at the level of a specialized academic magazine. I suggest that few consent forms currently in use could pass readability tests. The implication of these findings is that thousands of persons may be undergoing surgery each year on the basis of inadequate consent. The problem has a reasonably simple solution: analysis of all consent forms for readability, and rewriting of those found excessively difficult.",0
1369,7366635,The threshold approach to clinical decision making,"""The physician's estimate of the probability that a patient has a particular disease is a principal factor in the determination of whether to withhold treatment, obtain more data by testing, or treat without subjecting the patient to the risks of further diagnostic tests. Using the concepts of decision analysis, we have derived expressions for two threshold probabilities involved in this choice: a """"testing"""" threshold and a """"test-treatment"""" threshold. Values can be assigned to these thresholds from data on the reliability and potential risks of the diagnostic test and the benefits and risks of a specific treatment. Treatment should be withheld if the probability of disease is smaller than the testing threshold, and treatment should be given without further testing if the probability of disease is greater than the test-treatment threshold. The test should be performed (with treatment depending on the test outcome) only if the probability of disease is between the two thresholds. The method exposes important principles of decision making and helps the clinician develop a rational, quantitative approach to the use of diagnostic tests.""",0
1370,7383128,Sounding board. The politics of contraception: the view from Beijing,"""Since China contains 1/4 of the world's population, what happens there with regard to limitation of fertility has significance for the whole world. Over the past decade, much has changed in China insofar as politics and the practice of birth control are concerned. At present, China is the only Communist country to support and practice an antinatalist policy, and, in fact, maintains the most stringent antinatalist policy in the world. The national aim has become the 1-child family, and there are strong incentives (food, health care, etc,) towards this end. To achieve this, China has directed much technical effort towards contraceptive production. Original Chinese products have been the paper pill in which the steroids are absorbed on water-soluble paper and Anordrin, a synthetic steroid known as the """"vacation pill."""" A significant contribution also by the Chinese is a male contraceptive pill derived from gossypol. This particular contraceptive has been associated with serious side effects and it remains to be seen whether this work will result in a useful antifertility agent for men. The author suggests that it is now time to encourage collaboration between Western and Chinese researchers, especially since the Chinese have taken the initiative in enlisting interaction with foreign scientific groups, especially with the Special Programme of Research, Development, and Research Training in Human Reproduction of WHO. WHO is presently setting up 2 institutes of research on methods to control fertility in Shanghai and Beijing and Chinese scientists are involved in the WHO task forces on IUDs, orals, and postcoital and plant agents. Clearly, China is placing tremendous emphasis on fertility control and it seems that the U.S. and the Washington politicians in particular could learn from politicians in Beijing.""",0
1371,7402220,Thiazides and acute cholecystitis,"An association between acute cholecystitis and the use of thiazide-containing drugs was observed during routine screening of data from a case-control drug-surveillance program. Evaluation of this relation among 419 patients with acute cholecystitis and 1676 control patients yielded a relative risk estimate of 2.0 for subjects who had used thiazides in the month before admission, as compared with subjects who had never used these drugs (95 per cent confidence interval, 1.4 to 2.7). There was a significant trend of increasing relative risk with increasing duration of use (P < 0.01), and the estimate for subjects who had used thiazides for five or more years was 2.9. The association was not explained by confounding due to the indications for thiazide use, such as hypertension, or other factors, such as obesity or the use of other drugs. No single epidemiologic study can eliminate chance or bias as an explanation for an association; the relation found here should be regarded as a hypothesis that requires independent confirmation.",0
1372,7412851,The new medical-industrial complex,"""The most important health-care development of the day is the recent, relatively unheralded rise of a huge new industry that supplies health-care services for profit. Proprietary hospitals and nursing homes, diagnostic laboratories, home-care and emergency-room services, hemodialysis, and a wide variety of other services produced a gross income to this industry last year of about $35 billion to +40 billion. This new """"medical-industrial complex"""" may be more efficient than its nonprofit competition, but it creates the problems of overuse and fragmentation of services, overemphasis on technology, and """"cream-skimming,"""" and it may also exercise undue influence on national health policy. In this medical market, physicians must act as discerning purchasing agents for their patients and therefore should have no conflicting financial interests. Closer attention from the public and the profession, and careful study, are necessary to ensure that the """"medical-industrial complex"""" puts the interest of the public before those of its stockholders.""",0
1373,7421945,Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen,"We interviewed 327 women who had been 50 to 74 years of age when treated for fracture of the hip of lower forearm, to determine their use (or lack of use) of estrogen preparations. Their responses were compared with those in a random sample of 567 women who were of similar age and from the same region. The risk of fracture was 50 to 60 per cent lower in women who had used these drugs for six years or longer than in women who hadnot used them (95 per cent confidence interval of relative risk, 0.3 to 0.6); those using them for shorter periods received less benefit, if any. A decreased risk of fracture was clearly evident only in women still taking estrogens and evident at either common daily dose (0.625 and 1.25 mg). In conjunction with the finding that estrogens can retard the development of osteoporosis in postmenopausal women, our data argue that lowering of the risk of hip and forearm fractures must be weighed as a benefit of long-term estrogen use.",0
1374,7432433,Dose-response effect of adjuvant chemotherapy in breast cancer,"We retrospectively analyzed the role of the dose level of CMF (cyclophosphamide, methotrexate, and fluorouracil) in postoperative adjuvant chemotherapy for breast cancer and in chemotherapy for metastatic breast cancer. There was a clear dose-response effect, indicating that CMF was useful only when given in a full or nearly full dose (greater than or equal to 85 per cent of the planned dose). Those given adjuvant therapy with 12 cycles of CMF at this dose level had a five-year relapse-free survival of 77 per cent, as compared with 45 per cent of patients treated only with radical mastectomy (P = 0.0001). In contrast, a subgroup receiving less than 65 per cent of the planned dose had a five-year survival without relapses of 48 per cent and a five-year survival with relapses of 67 per cent. These results are similar to those observed in a control group. With each dose level, the results at five years were influenced by the number of axillary lymph nodes involved but not by menopausal status. Our findings indicate that it is necessary to administer combination chemotherapy at a full dose to achieve clinical benefit.",0
1375,7442730,"Diet, serum cholesterol, and death from coronary heart disease. The Western Electric study","Over twenty years ago, we evaluated diet, serum cholesterol, and other variables in 1900 middle-aged men and repeated the evaluation one year later. No therapeutic suggestions were made. Vital status was determined at the 20th anniversary of the initial examination. Scores summarizing each participant's dietary intake of cholesterol, saturated fatty acids, and polyunsaturated fatty acids were calculated according to the formulas of Keys and Hegsted and their co-workers. The two scores were highly correlated, and results were similar for both: there was a positive association between diet score and serum cholesterol concentration at the initial examination, a positive association between change in diet score and change in serum cholesterol concentration from the initial to the second examination, and a positive association prospectively between mean base-line diet score and the 19-year risk of death from coronary heart disease. These associations persisted after adjustment for potentially confounding factors. The results support the conclusion that lipid composition of the diet affects serum cholesterol concentration and risk of coronary death in middle-aged American men.",0
1376,7442740,Estrogens and endometrial cancer,"Retrospective case-control studies attempt to determine the relation of estrogens to endometrial cancer. However, the case group in such studies is a source of bias in that while the cases have undergone examinations for presence of cancer, the controls have not. A woman who does not receive estrogen can have an asymptomatic cancer that can remain undetected. As a solution to this bias, the authors designed a different case-control sampling procedure in which both controls and cases are chosen from patients given intraendometrial examinations. However, other investigators have rejected this method and have continued to use the conventional procedure without doing anything to avoid the overt bias in the case group. Shapiro et al (August 28 issue) presented the results of their conventional case/control groups with some new statistical tactics but the bias still remains. The bias cannot be eliminated until satisfactory sources of other data become available. Clinicians and pathologists are urged to evaluate the epidemiologist's basic assumption that all endometrial cancer cases can be detected clinically during the patient's lifetime: such assumption can be examined without using case-control studies, and new research may provide answers to the unresolved questions.",0
1377,7442756,Opsonic requirements for intravascular clearance after splenectomy,"We investigated the opsonic requirements for intravascular clearance of pneumococci in guinea pigs and of sensitized erythrocytes in human beings after splenectomy. The impaired clearance of injected pneumococci in splenectomized guinea pigs was corrected by immunization. This improvement in clearance was due to increased hepatic sequestration of organisms. There was a significant delay in antibody-mediated clearance of autologous erythrocytes sensitized with IgG (P < 0.001), although the rate of complement-mediated clearance in splenectomized patients was normal. A fourfold increase in sensitizing antibody resulted in a significant improvement in clearance that was due to increased hepatic sequestration (P < 0.005). One patient who had an intact spleen and who had previously received Thorotrast (thorium oxide) had impaired antibody-mediated clearance despite increased sensitization. These observations suggest that, after splenectomy the remaining macrophages of the reticuloendothelial system require increased amounts of antibody to mediate efficient intravascular clearance of opsonized particles.",0
1378,7442758,A practice plan in a municipal teaching hospital: a model for the funding of clinical faculty,"Academic-practice plans have become increasingly important as a source of financial support for the faculty of academic centers. We describe the planning, implementation, and development of one such plan in a municipal hospital, a major affiliate of a medical school. The incorporated practice plan is nonprofit and is owned and governed by physicians. Its success during the eight years of its existence has resulted in growth of the faculty, the development of innovative ambulatory-care programs, and increased financial stability of the hospital. Although such problems as payment for teaching costs and academic advancement for primary-care physicians remain, it is clear that academic-practice plans can support the clinical, teaching, and research goals of academic physicians.",0
1379,7442770,Physical activity and employment status of patients on maintenance dialysis,"Existing data on the clinical outcome of maintenance dialysis for end-stage kidney disease focus mainly on the duration of life. We surveyed 18 dialysis centers to gain a broader overview of the current status of 2481 patients on dialysis, irrespective of the type or location of dialysis. The results suggest that 12 per cent of dialysis patients are diabetics and that 53 per cent are 50 years of age or older. There was considerable variation among centers in the degree of rehabilitation; nevertheless, only 60 per cent of the nondiabetic patients and 23 per cent of the diabetic patients were capable of a level of physical activity beyond that of caring for themselves. Only one quarter of the patients worked outside the home, whereas one third worked at home. These results suggest that a larger proportion of dialysis patients than previously suspected are severely debilitated. There is a need for improved data on the quality and length of life of patients on maintenance dialysis.",0
1380,7477116,Teratogenicity of high vitamin A intake,"BACKGROUND: Studies in animals indicate that natural forms of vitamin A are teratogenic. Synthetic retinoids chemically similar to vitamin A cause birth defects in humans; as in animals, the defects appear to affect tissues derived from the cranial neural crest. METHODS: Between October 1984 and June 1987, we identified 22,748 pregnant women when they underwent screening either by measurement of maternal serum alpha-fetoprotein or by amniocentesis. Nurse interviewers obtained information on the women's diet, medications, and illnesses during the first trimester of pregnancy, as well as information on their family and medical history and exposure to environmental agents. We obtained information on the outcomes of pregnancy from the obstetricians who delivered the babies or from the women themselves. Of the 22,748 women, 339 had babies with birth defects; 121 of these babies had defects occurring in sites that originated in the cranial neural crest. RESULTS: For defects associated with cranial-neural-crest tissue, the ratio of the prevalence among the babies born to women who consumed more than 15,000 IU of preformed vitamin A per day from food and supplements to the prevalence among the babies whose mothers consumed 5000 IU or less per day was 3.5 (95 percent confidence interval, 1.7 to 7.3). For vitamin A from supplements alone, the ratio of the prevalence among the babies born to women who consumed more than 10,000 IU per day to that among the babies whose mothers consumed 5000 IU or less per day was 4.8 (95 percent confidence interval, 2.2 to 10.5). Using a smoothed regression curve, we found an apparent threshold near 10,000 IU per day of supplemental vitamin A. The increased frequency of defects was concentrated among the babies born to women who had consumed high levels of vitamin A before the seventh week of gestation. CONCLUSIONS: High dietary intake of preformed vitamin A appears to be teratogenic. Among the babies born to women who took more than 10,000 IU of preformed vitamin A per day in the form of supplements, we estimate that about 1 infant in 57 had a malformation attributable to the supplement.",0
1381,7477194,Cancer in the parents of children with cancer,"BACKGROUND: Certain types of cancer in children and young adults have been linked with an increased risk of cancer in close relatives. However, the relation between childhood cancer and familial risk remains to be fully assessed in population-based studies. METHODS: We conducted a nationwide study in Denmark of 11,380 parents of children with cancer. The children were identified from records in the Danish Cancer Registry; their parents were identified from population registers. The occurrence and rate of cancer in the parents were determined with use of the Cancer Registry's files and compared with national incidence rates for various categories of tumor. RESULTS: Overall, 1445 cancers were diagnosed in the parents, as compared with 1496 expected from national incidence rates, to yield standardized incidence ratios of 1.0 (95 percent confidence interval, 0.9 to 1.0) for all parents, 1.0 for mothers, and 0.9 for fathers. The lower rate of cancer among fathers reflected their lower standardized incidence ratio for lung cancer (0.8; 95 percent confidence interval, 0.6 to 0.9), as calculated from 144 observations. CONCLUSIONS: Genetic determinants are important in several types of childhood cancer, but the genetic susceptibility to tumors does not generally extend to the parents of children with cancer, nor do the patterns of incidence point to the influence of shared environmental factors. Thus, cancer in children should not be viewed as a general marker for an increased risk of cancer in the patients' parents.",0
1382,7477221,A national survey of the arrangements managed-care plans make with physicians,"BACKGROUND: Despite the growth of managed care in the United States, there is little information about the arrangements managed-care plans make with physicians. METHODS: In 1994 we surveyed by telephone 138 managed-care plans that were selected from 20 metropolitan areas nationwide. Of the 108 plans that responded, 29 were group-model or staff-model health maintenance organizations (HMOs), 50 were network or independent-practice-association (IPA) HMOs, and 29 were preferred-provider organizations (PPOs). RESULTS: Respondents from all three types of plan said they emphasized careful selection of physicians, although the group or staff HMOs tended to have more demanding requirements, such as board certification or eligibility. Sixty-one percent of the plans responded that physicians' previous patterns of costs or utilization of resources had little influence on their selection; 26 percent said these factors had a moderate influence; and 13 percent said they had a large influence. Some risk sharing with physicians was typical in the HMOs but rare in the PPOs. Fifty-six percent of the network or IPA HMOs used capitation as the predominant method of paying primary care physicians, as compared with 34 percent of the group or staff HMOs and 7 percent of the PPOs. More than half the HMOs reported adjusting payments according to utilization or cost patterns, patient complaints, and measures of the quality of care. Ninety-two percent of the network or IPA HMOs and 61 percent of the group or staff HMOs required their patients to select a primary care physician, who was responsible for most referrals to specialists. About three quarters of the HMOs and 31 percent of the PPOs reported using studies of the outcomes of medical care as part of their quality-improvement programs. CONCLUSIONS: Managed-care plans, particularly HMOs, have complex systems for selecting, paying, and monitoring their physicians. Hybrid forms are common, and the differences between group or staff HMOs and network or IPA HMOs are less extensive than is commonly assumed.",0
1383,7477222,The growth of medical groups paid through capitation in California,"BACKGROUND: In California, it is common for health maintenance organizations (HMOs) to contract with large medical groups that are paid through capitation and are responsible for managing a full spectrum of medical services. METHODS: We studied six large medical groups in California--Bristol Park Medical, Friendly Hills HealthCare Network, HealthCare Partners Medical Group, Mullikin Medical Centers, Palo Alto Medical Foundation, and San Jose Medical Group--that are paid through capitation and that are growing as a result of contracts with managed-care organizations. We conducted interviews and obtained data on factors such as patient enrollment, capitation and other revenue, numbers of days spent by enrollees in the hospital, and numbers of visits to physicians per enrollee. RESULTS: Between 1990 and 1994, the number of HMO enrollees whose care was paid for through capitation in the six medical groups increased by 91 percent, from 398,359 to 759,474. In 1994, the mean number of hospital days per 1000 HMO enrollees ranged from 120 to 149 for non-Medicare patients and from 643 to 936 days for Medicare patients. By comparison, in 1993 the mean numbers of hospital days per 1000 HMO enrollees not covered by Medicare were 232 for California and 297 for the United States; for HMO enrollees covered by Medicare, the numbers were 1337 for California and 1698 for the United States. In 1994, the average annual number of visits to physicians for HMO patients in the six groups not covered by Medicare ranged from 3.1 to 3.9; for Medicare patients, it ranged from 7.2 to 9.3; these rates were slightly lower than statewide and national rates. Four of the groups have sold their assets (such as facilities, supplies, equipment, and patients' charts) to outside investors; the physicians remain employed by physician-owned professional corporations. CONCLUSIONS: Medical groups paid through capitation offer a model for the status of physicians in managed-care systems that differs from the employee status offered by staff-model HMOs and the subcontractor status offered by HMOs that negotiate directly with individual physicians. Despite their growth, such medical groups in California face substantial challenges, such as obtaining the financial assets necessary to sustain rapid growth.",0
1384,7489972,Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation,"An increased release of nitric oxide (NO), a powerful vasodilating agent, has been proposed to play a role in the pathogenesis of vasodilation and hyperdynamic circulation associated with advanced cirrhosis. We evaluated NO synthase (NOS) activity in peripheral leukocytes of 12 cirrhotic patients and 9 healthy subjects together with plasma endotoxin levels and systemic hemodynamic (by a noninvasive echocardiographic method). NOS activity was evaluated by (1) measuring the capacity of isolated polymorphonuclear cells (PMNs) and monocytes to convert [3H]arginine to [3H]citrulline; (2) measuring the ability of neutrophils and monocytes to inhibit thrombin-induced platelet aggregation and to increase guanosine 3'-5'-cyclic monophosphate content in coincubated platelets, an expression of NO release from these cells. Both neutrophils and monocytes from cirrhotic patients produced significantly higher amounts of [3H]citrulline than cells obtained from healthy subjects (P < .001 and P < .02 for neutrophils and monocytes, respectively) and were more effective than control cells in inhibiting platelet aggregation (P < .05 and P < .001, respectively for 2 x 10(6) cells) and in increasing guanosine 3'-5'-cyclic monophosphate content in coincubated platelets (P < .05 and P < .001, respectively). The anti-aggregating activity expressed by leukocytes has a pharmacological profile similar to that described for NO, because it increased after addition of superoxide dismutase, a superoxide anion scavenger, and markedly decreased after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine-methyl ester (L-NAME). Cirrhotic patients had significantly higher plasma endotoxin levels (P < .001) and cardiac index (P < .01) when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1385,7489998,Endothelium-dependent vascular hyporesponsiveness without detection of nitric oxide synthase induction in aortas of cirrhotic rats,"The present experiments were designed to test if induction of nitric oxide synthase (NOS) plays a role in the systemic vasodilation observed in hepatic cirrhosis. Because endotoxin levels are elevated in cirrhosis, and endotoxin stimulates inducible nitric oxide synthase (iNOS) expression in several cell lines, aortas of carbon tetrachloride-induced cirrhotic rats with ascites were evaluated for iNOS expression. Endotoxin-treated rats were studied as positive controls. Phenylephrine contraction was decreased in aortic rings with endothelium from both endotoxin-treated and cirrhotic rats as compared with controls. However, after endothelium denudation, the reduced contractility persisted in endotoxin-treated rats but disappeared in cirrhotic rats. L-Nitro-arginine-methylester (L-NAME), a nonselective inhibitor of NOS, potentiated the phenylephrine contraction of aortic rings with and without endothelium from endotoxin-treated rats but only rings with endothelium from cirrhotic rats. Moreover, aminoguanidine (AG), a preferential inhibitor of iNOS, did not affect phenylephrine contraction of rings with or without endothelium from cirrhotic rats but reversed the blunted response in endotoxin-treated rats. Northern analysis detected iNOS RNA (mRNA) expression in aortas of endotoxin-treated rats but did not detect it from cirrhotic rats. In summary, although several previous studies provide evidence for in vivo overproduction of nitric oxide in cirrhosis, the present results do not support iNOS induction as the source of nitric oxide in aortas of cirrhotic rats. Rather, because the aortic vascular hyporesponsiveness in cirrhosis is endothelium-dependent, overexpression or overstimulation of the endothelial constitutive isoform of NOS appears to be involved.",0
1386,7491134,Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States,"""BACKGROUND: In the United States, transmission of the human immunodeficiency virus (HIV) by blood transfusion occurs almost exclusively when a recently infected blood donor is infectious but before antibodies to HIV become detectable (during the """"window period""""). We estimated the risk of HIV transmission caused by transfusion on the basis of the window period associated with the use of current, sensitive enzyme immunosorbent assays and recent data on HIV incidence among blood donors. METHODS: We analyzed demographic and laboratory data on more than 4.1 million blood donations obtained in 1992 and 1993 in 19 regions served by the American National Red Cross, as well as the results of HIV-antibody tests of 4.9 million donations obtained in an additional 23 regions. RESULTS: We estimated that, in the 19 study regions, 1 donation in every 360,000 (95 percent confidence interval, 210,000 to 1,140,000) was made during the window period. In addition, it is estimated that 1 in 2,600,000 donations was HIV-seropositive but was not identified as such because of an error in the laboratory. We estimated that 15 to 42 percent of window-period donations were discarded because they were seropositive on laboratory tests other than the HIV-antibody test. When these results were extrapolated to include the additional 23 Red Cross service regions, there was a risk of one case of HIV transmission for every 450,000 to 660,000 donations of screened blood. If the Red Cross centers are assumed to be representative of all U.S. blood centers, among the 12 million donations collected nationally each year an estimated 18 to 27 infectious donations are available for transfusion. CONCLUSIONS: The estimated risk of transmitting HIV by the transfusion of screened blood is very small and nearly half that estimated previously, primarily because the sensitivity of enzyme immunosorbent assays has been improved.""",0
1387,7491139,Familial aggregation of low birth weight among whites and blacks in the United States,"BACKGROUND: Studies have shown that the birth weight of infants is correlated with the birth weights of their siblings and their mothers. We investigated whether the birth weights of mothers and index children were jointly associated with the risk of low birth weight in the siblings of the index children. METHODS: We used data on the live-birth cohort of the 1988 National Maternal and Infant Health Survey. The analysis included 1691 white and 1461 black mothers, each of whom had two or more live-born, singleton children. Multiple logistic regression with generalized-estimation equations was used to assess the risk of low birth weight among an index child's siblings. Four groups were studied: that in which neither the mother nor the index child had low birth weight (group 1), that in which only the mother had low birth weight (group 2), that in which only the index child had low birth weight (group 3), and that in which both the mother and the index child had low birth weight (group 4). There was adjustment for other maternal and infant covariates. RESULTS: Among white siblings in groups 1, 2, 3, and 4, 3.6, 8.3, 21.2, and 38.9 percent, respectively, had low birth weight, as compared with 8.0, 19.0, 31.1, and 57.1 percent of black siblings. When group 1 was used as the reference group, the adjusted odds ratios (and 95 percent confidence intervals) for low birth weight in groups 2, 3, and 4 were 2.5 (1.4 to 4.3), 6.8 (4.7 to 9.8), and 15.4 (9.2 to 25.5), respectively, among white siblings and 2.6 (1.8 to 3.8), 4.7 (3.5 to 6.4), and 13.9 (9.2 to 20.9) among black siblings. These associations were consistently found for birth weights below 1500 g and those ranging from 1500 to 2499 g in both races and after stratification for the mother's age, parity, education, cigarette-smoking status, and weight and height before pregnancy and the infant's sex. CONCLUSIONS: Although selection and recall biases cannot be excluded with certainty, our data suggest a strong familial aggregation of low birth weight among both whites and blacks in the United States.",0
1388,7494564,Blood pressure and end-stage renal disease in men,"BACKGROUND: End-stage renal disease in the United States creates a large burden for both individuals and society as a whole. Efforts to prevent the condition require an understanding of modifiable risk factors. METHODS: We assessed the development of end-stage renal disease through 1990 in 332,544 men, 35 to 57 years of age, who were screened between 1973 and 1975 for entry into the Multiple Risk Factor Intervention Trial (MRFIT). We used data from the national registry for treated end-stage renal disease of the Health Care Financing Administration and from records on death from renal disease from the National Death Index and the Social Security Administration. RESULTS: During an average of 16 years of follow-up, 814 subjects either died of end-stage renal disease or were treated for that condition (15.6 cases per 100,000 person-years of observation). A strong, graded relation between both systolic and diastolic blood pressure and end-stage renal disease was identified, independent of associations between the disease and age, race, income, use of medication for diabetes mellitus, history of myocardial infarction, serum cholesterol concentration, and cigarette smoking. As compared with men with an optimal level of blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg), the relative risk of end-stage renal disease for those with stage 4 hypertension (systolic pressure > or = 210 mm Hg or diastolic pressure > or = 120 mm Hg) was 22.1 (P < 0.001). These relations were not due to end-stage renal disease that occurred soon after screening and, in the 12,866 screened men who entered the MRFIT study, were not changed by taking into account the base-line serum creatinine concentration and urinary protein excretion. The estimated risk of end-stage renal disease associated with elevations of systolic pressure was greater than that linked with elevations of diastolic pressure when both variables were considered together. CONCLUSIONS: Elevations of blood pressure are a strong independent risk factor for end-stage renal disease; interventions to prevent the disease need to emphasize the prevention and control of both high-normal and high blood pressure.",0
1389,7507464,Ito cell heterogeneity: desmin-negative Ito cells in normal rat liver,"The presence of desmin is used to identify Ito cells in rat liver and to evaluate the purity of separated and cultured Ito cells. Heterogeneity of the normal Ito cell population has been suggested; this could include variations in the content of cytoskeletal components. For these reasons we decided to reevaluate the use of desmin staining as a phenotypical marker of Ito cells in normal rat liver. Our approach was to combine desmin staining with identification of vitamin A (autofluorescence), lipid droplets (Sudan III), vimentin, laminin and tenascin, using cryostat sections: Immunofluorescence, double-immunofluorescence or immunoperoxidase techniques were used. All the techniques described corroborate the existence of desmin-negative Ito cells, mainly located in pericentral areas. In fact, lobular desmin-positive cells showed uneven distribution because they were more frequent in periportal than in pericentral areas. On the contrary, Ito cells identified on the basis of morphological criteria or positivity for laminin were evenly distributed. Double immunofluorescence confirmed this observation, showing nearly complete codistribution of laminin and desmin in periportal areas. Outside this area, positivity for desmin was observed only in about 50% of laminin-positive cells. Our observations suggest that desmin cannot be viewed as a phenotypical marker but rather is a differentiation marker of Ito cells, possibly indicating a specific functional state.",0
1390,7509771,Structure and localization of the IGFBP-1 gene and its expression during liver regeneration,"Insulin-like growth factor-binding protein-1s are important modulators of the insulin-like growth factors that may have both positive and negative effects on the ability of insulin-like growth factors to stimulate cell growth. The IGFBP-1 gene is one of the most highly induced immediate-early genes after partial hepatectomy. The IGFBP-1 gene is also expressed at a high level during fetal liver development and in response to nutritional changes and diabetes. Therefore it may have important roles in liver growth and metabolism. To begin to examine the regulation of this gene, we cloned and sequenced the entire mouse IGFBP-1 gene. Its structure is highly similar to that of the human gene, and, in addition to the exonic regions, the two genes are highly conserved in specific regions in the promoter and first intron. Analysis of this conservation allows us to predict important regulatory sites that define the tissue specific and insulin-mediated regulation of the gene and identify potential sites that might be important for the transcriptional induction during liver regeneration. The mouse gene is located on mouse chromosome 11; it is found at the boundary between regions in the mouse genome homologous to human chromosomes 22 and 7. We found IGFBP-1 mRNA in both parenchymal and nonparenchymal RNA after partial hepatectomy. Using in situ hybridization of IGFBP-1 mRNA in regenerating rat liver tissue, we demonstrated IGFBP-1 transcripts in several cell types. We found that IGFBP-1 gene induction after partial hepatectomy is paralleled by protein expression.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1391,7511127,"Role of Na,K-ATPase in regulating acidification of early rat liver endocytic vesicles","Endocytic vesicles are acidified by an electrogenic proton pump and a parallel chloride conductance; however, acidification might be decreased if electrogenic transporters, such as Na,K-ATPase, that increase vesicle interior-positive membrane potential were also present. We examined this issue in early rat liver endosomes using ion substitution and inhibitors to alter Na,K-ATPase activity. These early endosomes, labeled for 2 min with the fluorescent fluid-phase marker fluorescein isothiocyanate-dextran, consistently acidified faster than endosomes similarly labeled for a 10-min period. In chloride-free media initial rates of acidification of early endosomes were faster in K+ media than in Na+ medium, although addition of K+ to Na+ or Na+ to K+ media to allow Na,K-ATPase to function did not decrease the rate of acidification. In chloride-containing media, rates were the same regardless of cation composition. The Na,K-ATPase inhibitor vanadate was prepared from orthovanadate by several methods, all of which inhibited liver ATPase activity. Two hundred mumol/L vanadate, prepared Cl(-)-free, tended to decrease rates of acidification in all media tested and these effects achieved statistical significance in Cl(-)-free media containing 150 mmol/L K+ or mixtures of Na+ and K+ and in 145 mmol/L KCl/5 mmol/L NaCl medium. Vanadate stocks pH-adjusted with hydrogen chloride increased rates of acidification in sodium gluconate buffers, probably as a result of the effects of the included Cl-. Five mmol/L ouabain (loaded into vesicles by endocytosis) and the membrane-permeable analog strophanthidin (2 mmol/L) both markedly inhibited endosome acidification, regardless of buffer ion composition. Collectively, these results suggest that Na,K-ATPase does not regulate acidification of rat liver early endocytic vesicles, that vanadate may modestly inhibit endosome acidification and that ouabain at high concentrations may inhibit acidification from the vesicle interior face.",0
1392,7519163,Involvement of annexin I and annexin II in hepatocyte proliferation: can annexins I and II be markers for proliferative hepatocytes?,"Annexin is the name of a new family of Ca(2+)-dependent membrane-binding proteins. Eleven types of its related proteins have been reported to date. Among those, annexin I and annexin II have been reported to possess many biological functions in vitro. Its actual role in vivo, however, is yet unknown. The involvement of annexin I and annexin II in the proliferation processes of hepatocytes was examined in the following aspects: (a) hepatocyte proliferation after carbon tetrachloride-induced liver damage, (b) hepatocyte regeneration after partial hepatectomy and (c) postnatal development of hepatocytes. These results showed collectively that annexin I and annexin II were increased in proliferative (or regenerative) hepatocytes, suggesting that both proteins play a certain role in the proliferation event. Furthermore, annexin I- and annexin II-positive hepatocytes always show a wider distribution than that of proliferating cell nuclear antigen or cytokeratin 7-positive hepatocytes, indicating that annexin I and annexin II may be useful markers for detecting not only actively proliferating hepatocytes but also hepatocytes in preproliferative and postproliferative stages.",0
1393,7521314,Heterogeneity of combinatorial human autoantibodies against PDC-E2 and biliary epithelial cells in patients with primary biliary cirrhosis,"The polyclonal nature of antimitochondrial autoantibodies and the limited success of generating human monoclonal antibodies have made analysis of fine specificity and antibody heterogeneity difficult to define. The major autoantigen of primary biliary cirrhosis is the E2 component of the pyruvate dehydrogenase pathway (PDC-E2). To address the relative importance of the region(s) in the PDC-E2 inner lipoyl domain to antibody binding, we report herein detailed profiles of 12 PDC-E2-specific antigen-binding fragments, SP1 through SP12, derived by screening of a combinatorial immunoglobulin library (derived from a primary biliary cirrhosis patient) with full-length native PDC-E2. All antigen-binding fragments are IgG isotypes and include a similar number of lambda- and kappa-chains. The antigen-binding fragments react specifically to PDC-E2 with high affinity (kappa a = 10(-7) to 10(-10) mol/L-1) and recognize a conformational epitope in the inner lipoyl domain of PDC-E2. Furthermore, the antibodies demonstrate substantial heterogeneity in recognition of different recombinant PDC-E2 fragments and differential recognition patterns against mutant constructs of the human PDC-E2 inner lipoyl domain (amino acid residues 91 to 227). In addition, five of the antigen-binding fragment clones (SP1, 3, 4, 8 and 12) demonstrate different staining patterns on biliary epithelial cells of patients with primary biliary cirrhosis but not control liver disease; some antigen-binding fragments specifically stained the apical region of biliary epithelium, a pattern distinct from that of typical mitochondrial staining. The response to the inner lipoyl domain is not, however, monospecific, and there is much more heterogeneity in fine specificity than could be accounted for by arbitrary reshuffling of variable immunoglobulin heavy and light chains into unnatural combinations.",0
1394,7521938,Transmissibility of Pseudomonas cepacia infection in clinic patients and lung-transplant recipients with cystic fibrosis,"BACKGROUND: In patients with cystic fibrosis, infection with Pseudomonas cepacia is associated with poor outcomes. However, the extent of person-to-person transmission and the source of P. cepacia infection after lung transplantation are not well defined. Using DNA-based typing systems, we sought to determine the genetic relatedness of P. cepacia infection at one cystic fibrosis center. METHODS: We analyzed 65 P. cepacia isolates gathered over a period of eight years at a single cystic fibrosis center from 17 clinic patients and from 5 patients who underwent double-lung transplantation. The isolates were analyzed by ribotyping and chromosomal fingerprinting based on pulsed-field gel electrophoresis. RESULTS: Analyses of serial isolates revealed that each clinic patient and transplant recipient harbored a different P. cepacia clone that was persistent. In the transplant recipients, the preoperative and postoperative isolates were identical. In the two patients with disseminated infection after lung transplantation, isolates from multiple sites were identical and indicated clonal expansion of the previous respiratory P. cepacia strain. Pulsed-field gel electrophoresis proved both more discriminative and more practical than ribotyping as a means of defining the genetic relatedness of the P. cepacia isolates. CONCLUSIONS: Our serial analyses in patients with cystic fibrosis at one center found distinct strains of P. cepacia persistently infecting each patient and no evidence of person-to-person transmission of this organism. P. cepacia infection after lung transplantation was due to the persistence of the strain present before transplantation.",0
1395,7523266,Undulin RNA and protein expression in normal and fibrotic human liver,"We have analyzed the distribution, gene expression and cellular origin of undulin, a large extracellular matrix glycoprotein associated with mature collagen fibrils, in human liver by immunohistochemistry, Northern-blot analysis and in situ hybridization. In normal liver, undulin was distributed as densely packed fibers in portal tract stroma, and as fine fibers along sinusoids, and around central veins. Undulin ribonucleic acid expression was low in normal liver, and confined to mesenchymal cells of portal tract stroma, vessel walls and perisinusoidal space. In fibrotic liver, undulin deposition and gene expression were enhanced in fibrotic stroma and areas of fibrogenesis identified by the presence of active septa and inflammatory infiltrate. Undulin gene expression in fibrotic liver was exclusively localized in mesenchymal cells that could be identified by staining for vimentin, and partially for alpha-smooth muscle actin as (myo)fibroblasts, and possibly fat-storing cells. These data suggest that undulin is a constituent of the hepatic extracellular matrix of normal human liver, and that it participates in the rearrangement of connective tissue occurring in hepatic fibrosis.",0
1396,7523269,Expression of the c-myc protooncogene product in cells infected with the hepatitis delta virus,"The intrahepatic accumulation of the c-myc protooncogene product was observed on immunofluorescence in each of six patients with chronic hepatitis delta virus infection who exhibited the hepatitis D antigen in their livers. The c-myc product was stained in the same nuclei that contained the hepatitis D antigen. C-myc was not observed in acute hepatitis D or in cases of chronic hepatitis delta virus infection without expression of the hepatitis D antigen. The protooncogene product was detected in only 1 of 32 viral and nonviral liver disorders unrelated to hepatitis delta virus. To confirm these observations, we transfected HBsAg-positive (PCL/PRF/5) and HBsAg-negative (HepG2) transformed liver cell lines with a plasmid containing a hepatitis delta virus cDNA trimer under the control of the SV40 early enhancer/promoter sequences. Whereas baseline c-myc expression was barely detectable in mock-transfected PLC/PRF/5 or HepG2 cells, strong c-myc nuclear fluorescence was observed when these same cells were transfected with the hepatitis D antigen expression vector. Similar results were obtained after infection of HeLa cells with a recombinant vaccinia virus expressing the hepatitis D antigen. Detection of c-myc mRNA sequences by means of in situ hybridization suggested that the c-myc product accumulation was not due to increased amounts of its mRNA. The c-myc protein accumulates selectively in the livers of patients with chronic hepatitis delta virus infection and in the same nuclei that contain the hepatitis D antigen. The expression of c-myc in hepatitis D antigen-containing cells does not require the presence of hepatitis B virus infection.",0
1397,7523271,Influence of viral quasispecies on effectiveness of interferon therapy in chronic hepatitis C patients,"The quasispecies nature of hepatitis C virus genome distribution is most evident in hypervariable regions of the putative envelope 2 domain. Eight patients with chronic hepatitis C treated with interferon-alpha were studied as to heterogeneity of the hypervariable regions to clarify the implications of quasispecies. More than 10 recombinant clones generated from polymerase chain reaction-amplified products of the hypervariable regions were sequenced. The sets of clones derived from long-term responders before interferon therapy showed a significantly lower (p < 0.05) degree of sequence complexity of the hypervariable region 1 quasispecies than those from short-term ones or non-responders. The values of nucleotide diversity (the average number of nucleotide differences per site between two randomly chosen sequences) in hypervariable region 1 before interferon therapy were also significantly lower (p < 0.05) for long-term responders (mean, 2.31 x 10(-2)). In some cases, nucleotide diversity decreased remarkably during interferon therapy, whereas the values remained unchanged in other cases. In one interesting case, a short-term response was first noted with the nucleotide diversity decreasing from 13.98 x 10(-2) to 0.21 x 10(-2); namely, the diversity of the quasispecies was significantly reduced, and then a long-term response was observed after an additional course of interferon therapy. Thus, the degree of quasispecies' complexity and diversity of hypervariable region 1 was closely correlated with the responsiveness to interferon therapy in chronic hepatitis C patients, and thus may have some influence on interferon efficacy.",0
1398,7531172,Detection of Gp210 autoantibodies in primary biliary cirrhosis using a recombinant protein containing the predominant autoepitope,"Autoantibodies against nuclear pore membrane glycoprotein gp210 have been identified in between 10% and 25% of patients with primary biliary cirrhosis (PBC). These antibodies may be useful in diagnosing PBC and in identifying subgroups of patients. Because previous detection procedures relied on the need to purify hydrophobic proteins and perform immunoblotting, the aim of the present study was to develop a simple assay to detect gp210 autoantibodies. A recombinant polypeptide containing glutathione-S-transferase (GST) fused to the region of gp210 that contains its predominant autoepitope(s) was expressed in bacteria. This fusion protein was purified by glutathione-Sepharose chromatography and used in an enzyme-linked immunosorbent assay (ELISA). The ELISA was reproducible in detecting gp210 autoantibodies in serum samples from patients with PBC. Compared with immunoblotting, the ELISA was 93% sensitive and 96% specific for the detection of gp210 autoantibodies. In conclusion, autoantibodies against gp210 can be easily and reliably detected in patients with PBC by an ELISA that uses a purified recombinant polypeptide.",0
1399,7533126,Nitric oxide is released in regenerating liver after partial hepatectomy,"The induction of hepatic nitric oxide synthase (NOS) and the biosynthesis of nitric oxide (NO) were studied in liver after partial hepatectomy (PH). NOS activity in the liver remnant was observed 4 to 6 hours after PH, and no differences were evidenced between the proximal and distal surgical areas. The form of NOS expressed in liver was independent of calcium and calmodulin, and the messenger RNA levels were first detected 2 hours after hepatectomy using a probe corresponding to the cytokine-induced macrophage NOS. The seric concentration of nitrites remained unchanged after hepatectomy, whereas the content in nitrates and in S-nitrosylated proteins progressively increased in parallel with the NOS activity. The spectra of hemoglobin in the 400-to 460-nm region failed to exhibit the characteristic shift caused by the formation of the nitrosyl-hemoglobin complex, suggesting that NO was rapidly metabolized in liver. Treatment of the animals with substrate analogue NOS inhibitors blocked the pattern of DNA ploidy elicited after hepatectomy, suggesting a role for NO in the regenerative process. Peritoneal resident macrophages were used as an alternative reporter cell system for the assessment of NOS expression. Incubation ex vivo of peritoneal macrophages from animals that underwent hepatectomy induced the expression of NOS in a cytokine-modulated fashion, suggesting that macrophages were primed as a result of the hepatectomy. When peritoneal macrophages from control rats were incubated with the sera of animals that underwent hepatectomy, a time-dependent induction of NOS was observed, with a maximal induction corresponding to sera collected 2 hours after PH. These results indicate that NO might be involved in the control of early responses after PH.",0
1400,7544757,Downregulation of phorbol 12-myristate 13-acetate-induced tumor necrosis factor-alpha and interleukin-1 beta production and gene expression in human monocytic cells by human alpha-fetoprotein,"We previously identified a specific receptor of alpha-fetoprotein (AFP) on human monocytes. Although AFP alters many immune cell functions, the effect of AFP on monocyte cytokine production is unknown. Because tumor necrosis factor--alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are important cytokines in immunoregulation, we investigated whether AFP could modulate TNF-alpha and IL-1 beta production in U937, a human monocytic cell line. Our results showed that U937 cells secreted TNF-alpha and IL-1 beta in response to either phorbyl 12-myristate 13-acetate (PMA) or IFN-gamma + LPS. In contrast, AFP significantly suppressed PMA-induced TNF-alpha and IL-1 beta production by U937 cells in a time and dose dependent fashion. Pretreatment of U937 cells with AFP resulted in maximal inhibition of PMA-stimulated TNF-alpha and IL-1 beta production by 58% and 67% respectively. AFP also inhibited interferon-gamma plus lipopolysaccharide (IFN-gamma + LPS)-induced TNF-alpha and IL-1 beta production. Furthermore, Northern blot analysis showed that AFP suppressed PMA-mediated TNF-alpha and IL-1 beta messenger RNA (mRNA) expression. PMA-induced prostaglandin E2 (PGE2) production by U937 cells was enhanced by AFP. Pretreatment with indomethacin, a cyclooxygenase inhibitor, reversed AFP-inhibited TNF-alpha production by 78%. Thus, we conclude that AFP downregulates TNF-alpha and IL-1 beta production via a PGE2-dependent mechanism.",0
1401,7557846,Expression of transforming growth factor alpha in the liver before and after interferon alfa therapy for chronic hepatitis B,"""The effect of interferon alfa (IFN-alpha) therapy on the expression of transforming growth factor alpha (TGF-alpha) in the liver during chronic hepatitis B was investigated. Serial liver biopsy specimens were evaluated from 35 patients who had participated in a randomized, controlled trial of recombinant human IFN-alpha for the treatment of chronic hepatitis B. Percutaneous liver biopsy specimens obtained before and 1 year after entry in the trial were sectioned and stained with a monoclonal antibody to TGF-alpha in an avidin-biotin-peroxidase-complex system. The expression of TGF-alpha in each section was evaluated blindly (with respect to treatment group and order of biopsies) and was numerically scored. There was no significant difference in TGF-alpha expression before or after therapy between 13 patients receiving daily IFN-alpha, 13 receiving alternate-day IFN-alpha, and 9 receiving no therapy. Sustained clearance of HBV-DNA and DNA polymerase activity occurred in 8 of 26 treated patients (""""responders""""); the 18 other patients were """"nonresponders."""" Expression of TGF-alpha before IFN-alpha therapy was significantly higher in responders than in nonresponders; after IFN-alpha therapy, TGF-alpha expression decreased significantly among responders compared with nonresponders and untreated controls. Thus, the level of expression of TGF-alpha in the liver, which was correlated with the severity of inflammation in the liver in this study, appeared to be predictive of the response to IFN-alpha therapy in chronic hepatitis B, with a higher level of expression indicating a greater likelihood that the patient would respond.""",0
1402,7557879,Differential expression of A and B laminin chains during rat liver regeneration,"We have studied the distribution and expression of laminin during rat liver regeneration by immunofluorescence and immunoblotting using affinity-purified laminin antibodies. Laminin was localized on sinusoidal surfaces in normal and regenerating hepatic parenchyma, but enhanced expression was detected during regeneration from 6 hours to 7 days after a partial hepatectomy. A and B laminin chains were specifically detected by Western blotting in highly purified plasma membrane fractions derived from the sinusoidal domain of hepatocytes. Analysis of laminin expression in whole homogenates from hepatectomized rats showed a differential expression of A and B laminin chains during regeneration: The A chain showed a progressive increase, whereas the B chain exhibited an early, prereplicative increase and then gradually declined to control levels at the end of restorative growth. The results suggest differential temporal requirements for A and B laminin chains during hepatic growth and tissue formation.",0
1403,7565970,The influence of smoking cessation on the prevalence of overweight in the United States,"BACKGROUND: The proportion of U.S. adults 35 to 74 years of age who were overweight increased by 9.6 percent for men and 8.0 percent for women between 1978 and 1990. Since the prevalence of smoking declined over the same period, smoking cessation has been suggested as a factor contributing to the increasing prevalence of overweight. METHODS: To estimate the influence of smoking cessation on the increase in the prevalence of overweight, we analyzed data on current and past weight and smoking status for a national sample of 5247 adults 35 years of age or older who participated in the third National Health and Nutrition Examination Survey, conducted from 1988 through 1991. The results were adjusted for age, sociodemographic characteristics, level of physical activity, alcohol consumption, and (for women) parity. RESULTS: The weight gain over a 10-year period that was associated with the cessation of smoking (i.e., the gain among smokers who quit that was in excess of the gain among continuing smokers) was 4.4 kg for men and 5.0 kg for women. Smokers who had quit within the past 10 years were significantly more likely than respondents who had never smoked to become overweight (odds ratios, 2.4 for men and 2.0 for women). For men, about a quarter (2.3 of 9.6 percentage points) and for women, about a sixth (1.3 of 8.0 percentage points) of the increase in the prevalence of overweight could be attributed to smoking cessation within the past 10 years. CONCLUSIONS: Although its health benefits are undeniable, smoking cessation may nevertheless be associated with a small increase in the prevalence of overweight.",0
1404,7566000,"Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein","BACKGROUND: The epsilon 4 allele of apolipoprotein E has been associated with an increased risk of late-onset Alzheimer's disease. In a cohort of elderly subjects we prospectively investigated the relation between the apolipoprotein E genotype, dementia, and the accumulation of beta-amyloid protein in the cerebral cortex. METHODS: Autopsy involving neuropathological analysis and DNA analysis of frozen blood samples were performed in 92 of 271 persons who were at least 85 years of age, who had been living in Vantaa, Finland, on April 1, 1991, and who had died between that time and the end of 1993. All subjects had been tested for dementia. Apolipoprotein E genotyping was done with a solid-phase minisequencing technique. The percentage of the cortex occupied by methenamine silver-stained plaques was used as an estimate of the extent of beta-amyloid protein deposition. RESULTS: The frequency of the epsilon 4 allele was significantly higher in the subjects with Alzheimer's disease than in the subjects without dementia (30 percent vs. 8 percent, P < 0.001). There was a greater accumulation of beta-amyloid protein in the brain and more neurofibrillary tangles in the subjects with the epsilon 4 allele than in those without it (P < 0.001). The deposition of beta-amyloid protein varied according to the genotype in both the subjects with dementia and those without dementia: it was lowest in those with the epsilon 2/epsilon 3 genotype, intermediate in those with the epsilon 3/epsilon 3 genotype, and highest in those with the epsilon 3/epsilon 4 genotype. A single subject had the epsilon 4/epsilon 4 genotype and had dementia. CONCLUSIONS: The epsilon 4 allele of apolipoprotein E is significantly associated with Alzheimer's disease. Even in elderly subjects without dementia, the apolipoprotein E genotype is related to the degree of deposition of beta-amyloid protein in the cerebral cortex.",0
1405,7590658,Inhibition of nitric oxide synthesis in the forearm arterial bed of patients with advanced cirrhosis,"Increased vascular production of nitric oxide (NO) may contribute to the peripheral vasodilation and hyperdynamic state complicating advanced liver cirrhosis. In this study, we examined the effect on forearm blood flow of local brachial artery infusion of noradrenaline (NA) and NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO-synthase, in 10 alcoholic ascitic cirrhotic patients (patients with decompensated alcohol-induced liver disease: DALD group) and 10 patients with well-compensated alcohol-induced liver disease (CALD group). Forearm blood flow was measured by venous occlusion plethysmography. As compared with the CALD group, the DALD group had higher cardiac index and forearm blood flow as well as lower systemic blood pressure and vascular resistance. Infusions of NA and L-NMMA produced similar reduction in resting blood flow in the CALD group. However, in the DALD group, NA was significantly less effective than L-NMMA. The forearm vasoconstrictor response to NA was also significantly reduced in the DALD group when compared with the CALD group. In the DALD group, NA decreased forearm blood flow by 21.0 +/- 6.2% and increased vascular resistance by 37.2 +/- 12.3%, whereas respective changes in the CALD group were 41.8 +/- 6.2% (P < .01) and 77.8 +/- 9.9% (P < .02). In contrast, L-NMMA induced greater forearm vasoconstriction in the DALD group than in the CALD group. In decompensated patients, L-NMMA decreased forearm blood flow by 50.4 +/- 2.7% and increased vascular resistance by 115.9 +/- 14.4%, whereas changes in compensated patients were 38.2 +/- 4.9% (P < .05) and 77.4 +/- 16.2% (NS), respectively. These results are consistent with the hypothesis that increased vascular synthesis of NO contributes to the high dynamic state of patients with advanced cirrhosis.",0
1406,7590659,Systemic hypotension and diuresis by L-arginine in cirrhotic patients with ascites: role of nitric oxide,"To investigate the role of nitric oxide in renal function and hemodynamics in cirrhotic patients with ascites, L-arginine (30 g in 300 mL of distilled water), a substrate for nitric oxide synthase, was infused into six cirrhotic patients with ascites, and the effects were compared with those of saline infusion. Healthy controls (n = 5) were also studied under the same conditions. In the patients, L-arginine infusion significantly decreased systolic and diastolic blood pressures while markedly increasing urinary flow and urinary sodium excretion; no significant changes were seen with saline infusion. In controls, only diastolic blood pressure was decreased by L-arginine infusion, whereas urinary flow and urinary sodium excretion were increased by both L-arginine and saline infusion. In both groups, a similar increase of plasma atrial natriuretic factor (ANF) was seen with L-arginine and saline infusions; endothelin and catecholamines were not affected by either infusion. In both groups, plasma levels of vasopressin were increased by L-arginine infusion. In the cirrhotic patients, urinary excretions of cyclic guanosine monophosphate (cGMP) and nitrates/nitrites (NOx) were significantly increased by L-arginine infusion, whereas no significant changes were seen with saline infusion. In controls, only the excretion of cGMP was increased by L-arginine infusion. In summary, L-arginine infusion induces diuresis and natriuresis accompanied by increased excretions of cGMP and NOx in cirrhotic patients with ascites. This differs from the response in controls, where the increase in urinary sodium excretion is not accompanied by an increase in markers of increased nitric oxide synthesis.",0
1407,7590663,Hepatic sinusoidal endothelial cells can store and metabolize serum immunoglobulin,"Sinusoidal inclusion-containing endothelial cells in the liver were investigated with particular interest in their capacity of metabolizing immunoglobulin. Formalin-fixed deparaffinized liver specimens were used for immunohistochemistry, and pronase digestion was proved to be effective for antigen retrieval of immunoglobulin. The inclusions in sinusoidal endothelial cells were strongly immunostained with anti-immunoglobulin (Ig)G, IgA, and IgM antibodies in predigested sections. The complements were not identified immunohistochemically in the inclusions even after pronase treatment. Two women with autoimmune liver disease, who initially represented high levels of serum gamma globulin and abundant inclusion-containing endothelial cells, were studied. The subsequent biopsy after effective corticosteroid therapy demonstrated significant histological improvement as well as the disappearance of inclusion-containing endothelial cells (ICECs). During and after treatment, their serum gamma globulin levels were drastically reduced. In conclusion, the hepatic sinusoidal endothelial cells can take up serum immunoglobulin, probably through a receptor-mediated pathway, and its excessive storage results in the formation of cytoplasmic inclusions that are easily recognized by a light microscope. The stored immunoglobulin may be degraded in the cytoplasm, and the inclusions would disappear in association with the reduction of sinusoidal gamma globulin content. In other words, the intralobular density of inclusion-containing endothelial cells is a morphological predictor for the serum gamma globulin level.",0
1408,7590680,The role of transjugular intrahepatic portosystemic shunt for treatment of portal hypertension and its complications: a conference sponsored by the National Digestive Diseases Advisory Board,"TIPS is a new and exciting modality for treatment of portal hypertension and its complications. Indications for TIPS remain to be better defined in terms of efficacy and cost-benefit in relationship to other established modes of therapy of portal hypertension. Prospective, randomized controlled trials are needed for these comparisons. Until the role of TIPS in the routine management of the complications of portal hypertension is better defined, TIPS should be used only in situations in which conventional medical and endoscopic therapies have failed.",0
1409,7601417,Sp1 binding activity increases in activated Ito cells,"Ito cells are the primary cell type in the liver responsible for increased type I collagen production observed during fibrogenesis. After a fibrogenic stimulus, Ito cells change from their normal quiescent state to an activated state. In this study, we examined the expression of the alpha 1(I) collagen gene in Ito cells that were freshly isolated from normal rat liver (quiescent) and Ito cells that were activated by culture on plastic. Northern blots showed that alpha 1(I) collagen messenger RNA levels were low in freshly isolated Ito cells and Ito cells cultured on plastic for up to 4 days, but were induced after 7 days in culture. To determine the location of important transcriptional regulatory elements within the 5'-flanking region of the alpha 1(I) collagen gene, transient transfections using various portions of the alpha 1(I) collagen gene promoter linked to the luciferase gene were performed in cultured Ito cells. As in fibroblast cells, only 220 base pairs (bp) of immediate 5'-flanking sequence of the collagen alpha 1(I) gene was necessary for efficient expression of the reporter gene. Deoxyribonuclease I footprinting analysis and mobility shift assays showed dramatic differences in the DNA binding proteins that interact with the 220 base pair promoter region of the alpha 1(I) collagen gene between freshly isolated and activated Ito cells. Sp1 binding activity was greatly increased in activated Ito cells, as was binding activity for CCAAT binding factor (CBF), a transcription factor previously shown to interact with the alpha 2(I) collagen gene promoter. The increased Sp1 binding activity to the alpha 1(I) collagen gene promoter involves a posttranscriptional event, as shown by Northern and Western blots. Therefore, we show that activated Ito cells have a different pattern of transcription factor binding activity interacting with the alpha 1(I) collagen gene promoter compared with quiescent Ito cells, including increased Sp1 binding activity, and that this may contribute to the increase in alpha 1(I) collagen gene expression during fibrosis.",0
1410,7601421,Sulfation of acetaminophen by the perfused rat liver: the effect of red blood cell carriage,"Acetaminophen uptake and conversion in the perfused rat liver to acetaminophen sulfate was studied with the multiple indicator dilution technique (MID). Because acetaminophen is avidly bound to red blood cells and not albumin, a pre-equilibrated MID dose containing the noneliminated references (51Cr-labeled red blood cells [RBC, a vascular reference], [58Co]EDTA [a small molecular weight interstitial reference that does not enter cells], and D2O [a cellular reference]) and [3H]-acetaminophen was introduced into the portal vein of the single-pass perfused rat liver (1 mg/L acetaminophen) under varying conditions of hematocrit, with observation of timed outflow profiles in the hepatic venous blood. The [3H]acetaminophen curve exhibited an early high peak, paralleling that for red cells and varying with hematocrit, followed by a prolonged decline, with the late appearance of acetaminophen sulfate product; the early peak disappeared when red cells were absent from the dose and perfusate. Analysis demonstrated a slow release of acetaminophen from the red blood cells and rapid liver cell entry, so that red cell binding was displayed as a red cell carriage effect that reduced the rate of liver cell entry and hence of sulfation of [3H]-acetaminophen. The liver cells exhibited a concomitant very low permeability to product acetaminophen sulfate, leading to protracted product outflow curves. An inferred slow efflux-mediated storage phenomenon for product was found to evolve as a result.",0
1411,7601422,The role of Kupffer cells in the differentiation process of hepatic natural killer cells,"Pit cells, or hepatic natural killer (NK) cells, present in rat liver sinusoids, represent an organ-associated NK cell population, with a higher level of activation and a different morphology when compared with peripheral blood NK cells. These cells are the result of an influx of peripheral blood NK cells in the liver microenvironment, followed by an activation or differentiation process toward the highly activated phenotype. In this work we investigated the role of Kupffer cells in this differentiation process of NK cells in the liver sinusoids. In vivo elimination of Kupffer cells with the macrophage cytotoxic drug dichloromethylene diphosphonate induced a decrease in number of hepatic NK cells that paralleled that of Kupffer cells. This effect was further investigated in vitro. Kupffer cell-conditioned medium appeared to enhance the viability, tumor-cytotoxic activity, and adherence of hepatic NK cells to liver endothelial cells in vitro. We conclude therefore that Kupffer cells, present in the microenvironment of the liver sinusoids, play an essential role in the differentiation process of peripheral blood NK cells to the highly activated hepatic NK cell population.",0
1412,7609751,Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns,"BACKGROUND: Because visceral obesity predicts insulin resistance, we studied whether alterations in the gene encoding for the beta 3-adrenergic receptor in visceral fat are associated with insulin resistance. METHODS: We studied the frequency of a cytosine-to-thymidine mutation that results in the replacement of tryptophan by arginine at position 64 (Trp64Arg) of the beta 3-adrenergic receptor by restriction-enzyme digestion with BstOl in 335 subjects from western Finland, 207 of whom were nondiabetic and 128 of whom had non-insulin-dependent diabetes mellitus (NIDDM). We also determined the frequency of the mutation in 156 subjects from southern Finland. Sensitivity to insulin was measured by the hyperinsulinemic-euglycemic clamp technique in 66 randomly selected nondiabetic subjects. RESULTS: In the subjects from western Finland, the frequency of the mutated allele was similar in the nondiabetic subjects and the subjects with NIDDM (12 vs. 11 percent). The mean age of the subjects at the onset of diabetes was lower among those with the mutation than those without it (56 vs. 61 years, P = 0.04). Among the nondiabetic subjects, those with the mutation had a higher ratio of waist to hip circumference (P = 0.02), a greater increase in the serum insulin response after the oral administration of glucose (P = 0.05), a higher diastolic blood pressure (82 vs. 78 mm Hg, P = 0.01), and a lower rate of glucose disposal during the clamp study (5.3 vs. 6.5 mg [29 vs. 36 mumol] per kilogram of body weight per minute; P = 0.04) than the subjects without the mutated allele. In an analysis of sibling pairs, the siblings with the mutation generally had higher waist:hip ratios (P = 0.05) and higher responses of blood glucose and serum insulin after the oral administration of glucose than their siblings without the mutation (P = 0.02 and P = 0.005, respectively). CONCLUSIONS: The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM:",0
1413,7616988,A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. AIDS Clinical Trials Group,"BACKGROUND: The clinical benefits of zidovudine remain unproved in patients with asymptomatic human immunodeficiency virus (HIV) infection when CD4 cell counts exceed 500 per cubic millimeter. We compared zidovudine therapy given immediately with deferred therapy in such subjects. METHODS: Beginning in 1987, subjects with asymptomatic HIV infection and 500 or more CD4 cells per cubic millimeter were randomly assigned to receive placebo or zidovudine (either 500 or 1500 mg per day, starting immediately). In 1989, the study was modified so that open-label treatment with 500 mg of zidovudine per day (deferred therapy) was offered when CD4 cell counts fell below 500 per cubic millimeter. The study end points included overall survival, survival free of the acquired immunodeficiency syndrome (AIDS), toxic effects, and changes in CD4 cell counts. RESULTS: There were 1637 subjects who could be evaluated: 547 in the deferred-therapy group, 549 in the group receiving 500 mg of zidovudine immediately, and 541 in the 1500-mg group. The subjects were followed for up to 6.5 years (group medians, 4.8, 4.8, and 4.9, respectively). There was no significant difference in AIDS-free survival in the deferred-therapy group as compared with the low-dose or high-dose groups (81 cases of progression to AIDS or death vs. 81 and 74, respectively; P = 0.95 and P = 0.13) or in overall survival (51 deaths vs. 47 and 46; P = 0.25 and P = 0.16). The decline in CD4 cells was slower in both immediate-therapy groups than in the deferred-therapy group (P < 0.001 for both). Adverse effects were uncommon, and before the study modification their incidence was similar among the treatment groups, but severe anemia and granulocytopenia were more frequent in the 1500-mg group than in the deferred-therapy group (P < 0.001). CONCLUSIONS: In asymptomatic, HIV-infected adults with 500 or more CD4 cells per cubic millimeter, treatment with zidovudine slows the decline in the CD4 cell count but does not significantly prolong either AIDS-free or overall survival. These results do not encourage the routine use of zidovudine monotherapy in this population.",0
1414,7623903,Metabolic effects of metformin in non-insulin-dependent diabetes mellitus,"BACKGROUND: The metabolic effects and mechanism of action of metformin are still poorly understood, despite the fact that it has been used to treat patients with non-insulin-dependent diabetes mellitus (NIDDM) for more than 30 years. METHODS: In 10 obese patients with NIDDM, we used a combination of isotope dilution, indirect calorimetry, bioimpedance, and tissue-balance techniques to assess the effects of metformin on systemic lactate, glucose, and free-fatty-acid turnover; lactate oxidation and the conversion of lactate to glucose; skeletal-muscle glucose and lactate metabolism; body composition; and energy expenditure before and after four months of treatment. RESULTS: Metformin treatment decreased the mean (+/- SD) glycosylated hemoglobin value from 13.2 +/- 2.2 percent to 10.5 +/- 1.6 percent (P < 0.001) and reduced fasting plasma glucose concentrations from 220 +/- 41 to 155 +/- 28 mg per deciliter (12.2 +/- 0.7 to 8.6 +/- 0.5 mmol per liter) (P < 0.001). Although resting energy expenditure did not change, the patients lost 2.7 +/- 1.3 kg of weight (P < 0.001), 88 percent of which was adipose tissue. The mean (+/- SE) rate of plasma glucose turnover (hepatic glucose output and systemic glucose disposal) decreased from 2.8 +/- 0.2 to 2.0 +/- 0.2 mg per kilogram of body weight per minute (15.3 +/- 0.9 to 10.8 +/- 0.9 mumol per kilogram per minute) (P < 0.001), as a result of a decrease in hepatic glucose output; systemic glucose clearance did not change. The rate of conversion of lactate to glucose (gluconeogenesis) decreased by 37 percent (P < 0.001), whereas lactate oxidation increased by 25 percent (P < 0.001). There were no changes in the plasma lactate concentration, plasma lactate turnover, muscle lactate release, plasma free-fatty-acid turnover, or uptake of glucose by muscle. CONCLUSIONS: Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis. It also seems to induce weight loss, preferentially involving adipose tissue.",0
1415,7635416,"Effect of upright posture and physical exercise on endogenous neurohormonal systems in cirrhotic patients with sodium retention and normal supine plasma renin, aldosterone, and norepinephrine levels","It is well known that sodium retention occurs in a significant proportion of patients with cirrhosis despite normal supine plasma levels of renin, aldosterone (ALDO), and norepinephrine (NE). The current study was performed to assess whether this subset of patients also present normal activity of the renin-aldosterone and sympathetic nervous systems during upright posture in sitting position and moderate physical exercise. Nine healthy controls, 14 patients with compensated cirrhosis and 10 patients with cirrhosis, ascites, sodium retention, and normal supine plasma renin activity (PRA) and ALDO and NE concentration were sequentially studied after 60 minutes in supine rest, 30 minutes in sitting position, and 30 minutes of cycloergometric exercise (3-METs). Sitting position and exercise were associated with similar stimulation of the renin-aldosterone and sympathetic nervous systems in the three groups of subjects. Consequently, cirrhotic patients with ascites showed values of PRA and plasma concentration of ALDO and NE similar to healthy subjects and patients with compensated cirrhosis during supine rest (renin: 1.4 +/- 0.3, 0.8 +/- 0.2, and 0.8 +/- 0.3 ng/mL; aldosterone: 24.3 +/- 4.7, 20.2 +/- 3.9 and 21.4 +/- 3.4 ng/dL; norepinephrine: 252 +/- 23, 250 +/- 16, and 255 +/- 23 pg/mL), sitting position (renin: 2.1 +/- 0.5, 1.1 +/- 0.3, and 1.6 +/- 0.4; aldosterone: 32.2 +/- 7.3, 23.7 +/- 5.3, and 26.2 +/- 4.5; norepinephrine: 356 +/- 38, 401 +/- 63, and 420 +/- 35), and exercise (renin: 2.9 +/- 0.8, 1.6 +/- 0.4, and 2.2 +/- 0.5; aldosterone: 43 +/- 6.4, 34.9 +/- 8.5, and 38.2 +/- 5.3; norepinephrine: 481 +/- 35, 499 +/- 54, and 534 +/- 48).(ABSTRACT TRUNCATED AT 250 WORDS)",0
1416,7635434,Transport characteristics of three fluorescent conjugated bile acid analogs in isolated rat hepatocytes and couplets,"The transport properties of three different synthetically prepared fluorescent conjugated bile acid analogs (FBA), all with the fluorophore on the side chain, were determined using isolated rat hepatocytes and hepatocyte couplets. The compounds studied were cholylglycylamidofluorescein (CGamF), cholyl(N epsilon-nitrobenzoxadiazolyl [NBD])-lysine (C-NBD-L), and chenodeoxycholyl-(N epsilon-NBD)-lysine (CDC-NBD-L). When hepatocytes were incubated at 37 degrees C with 0.3 mumol/L of FBA and 0.15 mol/L of Na+, cell fluorescence increased linearly with time at a rate (U/min) of 7.8 +/- 0.5 for CGamF, 7.2 +/- 0.3 for C-NBD-L, and 13.7 +/- 1.0 for CDC-NBD-L (mean, +/- SE; n = 40 to 90). Uptake was concentration dependent for concentrations less than 20 mumol/L and was saturable. The Michaelis constant (Km) value (mumol/L) for CGamF was 10.8, for C-NBD-L was 3.8, and for CDC-NBD-L was 3.0. In the absence of Na+, the uptake rate was decreased by 50% for CGamF and by 38% for C-NBD-L; but uptake of CDC-NBD-L was unchanged and thus Na+ independent. Cellular uptake of all three derivatives was specific to hepatocytes and was absent in several nonhepatocyte cell lines. For CGamF and C-NBD-L, both Na(+)-dependent and Na(+)-independent uptake was inhibited by 200-fold excess concentrations of cholyltaurine, dehydrocholyltaurine, and cholate, but for CDC-NBD-L, these nonfluorescent bile acids did not inhibit initial uptake. The intracellular fluorescence of CGamF was strongly pH dependent at an excitation wavelength of 495 nm, but pH independent at 440 nm excitation. In contrast, intracellular fluorescence of C-NBD-L and CDC-NBD-L was pH independent. All three FBA were secreted into the canalicular space of approximately 50% to 60% of couplets. Cellular adenosine triphosphate (ATP) depletion with either CN- or atractyloside inhibited secretion of all three FBA. The multispecific organic anion transporter (MOAT) inhibitor, chlorodinitrobenzene, blocked secretion of fluorescent MOAT substrates at a concentration of 1 mumol/L. At this concentration it did not affect secretion of the three FBA. At higher concentrations, chlorodinitrobenzene partially inhibited the canalicular secretion of CGamF but not the other two FBA. In conclusion, all three FBA are secreted by canalicular membrane bile acid transporters, but the sinusoidal uptake characteristics of CGamF and C-NBD-L are more similar than those of CDC-NBD-L to the transport properties of cholyltaurine. Therefore, C-NBD-L appears to be the best of the three for studies of conjugated trihydroxy-bile acid transport in hepatocytes.",0
1417,7637745,Association of weight loss and weight fluctuation with mortality among Japanese American men,"BACKGROUND: Weight loss and fluctuations in weight have been associated with increased risks of death from cardiovascular disease and from all causes. The clinical and public health implications of these associations are unclear. METHODS: We examined the long-term relation of weight change and fluctuation in weight with mortality over a 6-year period in 6537 middle-aged Japanese American men enrolled in the Honolulu Heart Program, a prospective study (mean follow-up, 14.5 years). RESULTS: Men who had a weight loss of 4.5 kg or more or who had large fluctuations in weight (or both) over a six-year period were, on average, in poorer health than their peers whose weight was more stable. After the exclusion of subjects who died during the first five years of follow-up and after adjustment for confounding factors, a weight loss of more than 4.5 kg was associated with the risk of death from all causes, with the exception of death from cancer. The subjects whose weight fluctuated the most had a significantly higher risk of death from cardiovascular causes (relative risk, 1.41; 95 percent confidence interval, 1.03 to 1.93), death from noncardiovascular and noncancerous causes (relative risk, 1.53; 95 percent confidence interval, 1.12 to 2.10), and death from all causes (relative risk, 1.25; 95 percent confidence interval, 1.05 to 1.48). However, the associations of weight loss and variation in weight with death from cardiovascular causes and from noncardiovascular and noncancerous causes were not found among healthy men who had never smoked. CONCLUSIONS: The associations between weight loss or fluctuation and mortality were partially explained by confounding factors and by the presence of preexisting disease. However, weight loss and weight fluctuation were unrelated to death among healthy men who had never smoked. Thus, concern about the health hazards of weight loss and variation may not be applicable to otherwise healthy people.",0
1418,7643881,"Race, sex, drug use, and progression of human immunodeficiency virus disease","BACKGROUND: The rates of progression of human immunodeficiency virus (HIV) infection and survival have been reported to differ among sociodemographic groups. It is unclear whether these differences reflect biologic differences or differences in access to medical care. METHODS: We measured disease progression and survival in a cohort of 1372 patients seropositive for HIV who were treated at a single urban center (median follow-up, 1.6 years). We calculated the rates of survival for the entire cohort and the rates of progression to the acquired immunodeficiency syndrome (AIDS) or death among the 740 patients who presented without AIDS. We used Cox proportional-hazards analysis to examine factors associated with progression to AIDS and death. RESULTS: Progression to AIDS or death was associated with a CD4 cell count of 201 to 350 per cubic millimeter (relative risk, 2.0; P < 0.001), the presence of symptoms at base line (relative risk, 2.0; P < 0.001), prior antiretroviral therapy (relative risk, 1.7; P = 0.003), and older age (relative risk per year of age, 1.02; P = 0.03). However, there was no relation between disease progression and sex, race, injection-drug use, income, level of education, or insurance status. In the entire cohort, a lower CD4 cell count, a diagnosis of AIDS, older age, and the receipt of antiretroviral therapy before enrollment were associated with an increased risk of death, whereas the use of prophylaxis against pneumocystis pneumonia, zidovudine use after enrollment, and having a job at base line were associated with lower risks of death. There was no significant difference in survival between men and women, blacks and whites, injection-drug users and those who did not use drugs, or patients whose median annual incomes were $5,000 or less and those whose incomes were more than $5,000. CONCLUSIONS: Among patients with HIV infection who received medical care from a single urban center, there were no differences in disease progression or survival associated with sex, race, injection-drug use, or socioeconomic status. Differences found in other studies may reflect differences in the use of medical care.",0
1419,7650752,Brain distribution of four rat homologues of the Drosophila dunce cAMP phosphodiesterase,"We have analyzed the brain distribution of the rat cAMP-specific phosphodiesterases (rPDEIV) which are closely related to the defective gene products of the drosophila melanogaster learning and memory mutant dunce. PCR analysis of rat brain cDNA was performed on the four known dunce-like cAMP PDE rat isogenes (rPDE-IV-A, -B, -C, -D). High expression of three of these isogenes (rPDEIV-A, -B, -D) highlighted their involvement in regulation of cAMP in the brain. Specific probes for all four isogenes were then used for in situ hybridization of rat brain sections. Distinct but overlapping expression patterns were observed for rPDEIV-A, rPDEIV-B, and rPDEIV-D. Abundant expression of these subtypes was observed in the olfactory system, the hippocampus and the cerebellum, while no specific signals could be detected in most areas of the brain for the subtype rPDEIV-C. ",0
1420,7651408,A heat shock transcription factor with reduced activity suppresses a yeast HSP70 mutant,"Strains carrying deletions in both the SSA1 and SSA2 HSP70 genes of Saccharomyces cerevisiae exhibit pleiotropic phenotypes, including the inability to grow at 37 degrees C or higher, reduced growth rate at permissive temperatures, increased HSP gene expression, and constitutive thermotolerance. A screen for extragenic suppressors of the ssa1 ssa2 slow-growth phenotype identified a spontaneous dominant suppressor mutation, EXA3-1 (R.J. Nelson, M. Heschl, and E.A. Craig, Genetics 131:277-285, 1992). Here we report that EXA3-1 is an allele of HSF1, which encodes the heat shock transcription factor (HSF). Strains containing the EXA3-1 allele in a wild-type background exhibit a 10- to 15-fold reduction in HSF activity during steady-state growth conditions as well as a delay in the accumulation of the SSA4, HSP26, and HSP104 mRNAs after a heat shock. EXA3-1-mediated suppression is the result of a single amino acid substitution of a highly conserved residue in the HSF DNA-binding domain which drastically reduces the ability of HSF to bind to heat shock elements as evaluated by band shift analysis. Together, these results indicate that the poor growth of ssa1 ssa2 strains is the result, at least in part, of the overproduction of a deleterious heat shock protein(s). This conclusion is supported by the fact that the levels of at least some heat shock proteins are reduced in ssa1 ssa2 cells containing the EXA3-1 allele. Surprisingly, strains containing the EXA3-1 allele in a wild-type HSP70 background grow early as well as the wild-type strain over a wide temperature range, displaying only a slight reduction in growth rate at 37 degrees Celsius, indicating that cells contain significantly more HSF activity than is require for growth under steady-state conditions. ",0
1421,7651472,Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease,"BACKGROUND: In patients with acute exacerbations of chronic obstructive pulmonary disease, noninvasive ventilation may be used in an attempt to avoid endotracheal intubation and complications associated with mechanical ventilation. METHODS: We conducted a prospective, randomized study comparing noninvasive pressure-support ventilation delivered through a face mask with standard treatment in patients admitted to five intensive care units over a 15-month period. RESULTS: A total of 85 patients were recruited from a larger group of 275 patients with chronic obstructive pulmonary disease admitted to the intensive care units in the same period. A total of 42 were randomly assigned to standard therapy and 43 to noninvasive ventilation. The two groups had similar clinical characteristics on admission to the hospital. The use of noninvasive ventilation significantly reduced the need for endotracheal intubation (which was dictated by objective criteria): 11 of 43 patients (26 percent) in the noninvasive-ventilation group were intubated, as compared with 31 of 42 (74 percent) in the standard-treatment group (P < 0.001). In addition, the frequency of complications was significantly lower in the noninvasive-ventilation group (16 percent vs. 48 percent, P = 0.001), and the mean (+/- SD) hospital stay was significantly shorter for patients receiving noninvasive ventilation (23 +/- 17 days vs. 35 +/- 33 days, P = 0.005). The in-hospital mortality rate was also significantly reduced with noninvasive ventilation (4 of 43 patients, or 9 percent, in the noninvasive-ventilation group died in the hospital, as compared with 12 of 42, or 29 percent, in the standard-treatment group; P = 0.02). CONCLUSIONS: In selected patients with acute exacerbations of chronic obstructive pulmonary disease, noninvasive ventilation can reduce the need for endotracheal intubation, the length of the hospital stay, and the in-hospital mortality rate.",0
1422,7652109,Form and magnitude of beta-sympathetic and parasympathetic influences on pulse transit time,"In this study, we examined autonomic influences on pulse transit time measured from the R-wave of the electrocardiogram (R-PTT). Six subjects received three doses each of isoproterenol and atropine. Isoproterenol produced a significant linear decrease in R-PTT, a significant linear increase in heart rate (HR), and a significant linear decrease in diastolic blood pressure (DBP). Atropine produced a significant linear decrease in R-PTT and significant linear increases in HR and DBP. The R-PTT shortening effect of isoproterenol may reflect positive inotropic effects of beta-sympathetic myocardial stimulation. The R-PTT shortening effect of atropine may reflect reduction of parasympathetic inhibition of ventricular myocardial activity. However, possible vascular contributions to these effects remain to be determined. Nonetheless, the results encourage further examination of R-PTT in research concerning autonomic regulation of cardiovascular activity. ",0
1423,7652125,The role of social relations in health promotion,"In considering new paradigms for the prevention and treatment of disease and disability, we need to incorporate ways to promote social support and develop family and community strengths and abilities into our interventions. There is now a substantial body of evidence that indicates that the extent to which social relationships are strong and supportive is related to the health of individuals who live within such social contexts. A review of population-based research on mortality risk over the last 20 years indicates that people who are isolated are at increased mortality risk from a number of causes. More recent studies indicate that social support is particularly related to survival postmyocardial infarction. The pathways that lead from such socioenvironmental exposures to poor health outcomes are likely to be multiple and include behavioral mechanisms and more direct physiologic pathways related to neuroendocrine or immunologic function. For social support to be health promoting, it must provide both a sense of belonging and intimacy and must help people to be more competent and self-efficacious. Acknowledging that health promotion rests on the shoulders not only of individuals but also of their families and communities means that we must commit resources over the next decade to designing, testing, and implementing interventions in this area. ",0
1424,7652141,Effects of psychiatric consultation on medical consumption in medical outpatients with abdominal pain,"A randomized controlled clinical trial was conducted in an outpatient clinic of internal medicine to test the hypothesis that a protocol of cooperation and communication between internist and general practitioner, sustained with psychiatric consultation, would reduce medical consumption in a group of medical outpatients with abdominal pain (N = 106). A reduction in medical consumption could not be demonstrated. However, a great variation in protocol adherence was found, partly related to the severity of the psychological problems. There is some evidence that the protocol, if restricted to cases with more severe psychiatric comorbidity, might reduce medical consumption. ",0
1425,7652184,The 5-lipoxygenase pathway in cultured human intestinal epithelial cells,"Leukotrienes (LTs), the 5-lipoxygenase (5-LOX) metabolites of arachidonic acid, have roles in many biological processes relevant to the gastrointestinal tract, including intestinal inflammation. We screened two well-known human intestinal epithelial cell lines, HT29 and Caco-2, for evidence of LT-associated enzyme transcripts and LT synthesis. Northern blot analysis of total RNA from both intestinal lines demonstrated high levels of transcripts for LTA4 hydrolase, a multisubstrate enzyme that converts the 5-LOX metabolite, LTA4, to LTB4. With total RNA, the 5-LOX transcript was detected only in HT29. Caco-2 failed to show 5-LOX message even with poly A-containing RNA, although the transcript could be amplified with the polymerase chain reaction. Messenger RNA for FLAP, the 5-lipoxygenase-activating protein, was detectable in both cell lines, but only with poly A-containing RNA. In a sonicated cell preparation, HT29, but not Caco-2, revealed detectable levels of 5-HETE and LTB4. These results suggest that certain intestinal epithelial cells possess a limited capacity to synthesize LTs. ",0
1426,7652587,Effects of intracerebroventricular administration of norepinephrine on paraventricular neurosecretory cells],"Extracellular electrical activities of paraventricular nucleus (PVN) cells were recorded in anaesthetized adult rats by using glass microelectrodes. After antidromical identification of the magnocellular neurosecretory cells, the effects of intracerebroventricular (i.c.v.) injection of norepinephrine (NE) on such cells were observed. Of 49 neurons of antidromic stimulation, phasic, fast continuous and slowly irregularly. firing units constituted 42.9%, 36.7%, and 20.4% of the total population respectively. With i.c.v. injection, NE inhibited the activity of most phasically firing units, but enhanced that of most fast continuous and slowly irregular firing units. The inhibition effect of NE could be partially antagonized by i.c.v. injection of phentolamine (2 micrograms/microliters), showing that the effect is possibly mediated by alpha-receptor. The above findings indicate that NE plays different roles in different PVN magnocellular neurons having different patterns of firing activity. ",0
1427,7652921,Pediatric organ donation: impact of medical examiner refusal,"To examine the national Pediatric Intensive Care Unit (PICU) experience regarding Medical Examiner (ME) refusal of organ procurement from potential donors. To review our experience regarding PICU mortalities, organ donation, and impact of the ME on the organ donation process. National survey of PICU directors requesting demographics, type of ME system, perceptions of ME responsiveness to organ donation, and data regarding potential donors and their outcomes. Also, a retrospective chart review of all PICU deaths from 1990 to 1992 at a tertiary care center, noting the number of potential organ donors, ME cases, those harvested, rejected, and reason for rejection. PICU directors selected from a list of Pediatric Section members of the Society of Critical Care Medicine. The response rate was 59%. The chart review was performed in a 1000-bed hospital with a 12-bed PICU. PICU directors' perceptions of ME responsiveness to organ donation were not determined by size of PICU, area served, type of hospital, ME system, or means of contacting the ME. ME refusal accounted for 15% and 16% of total refusals in the survey and chart review, respectively. Family refusal accounted for 49% and 28% in these same groups. Survey respondents' hints and suggestions to decrease denial and increase organ donation focused on improved communication (61% and 33%), and education (16% and 55%). ME refusal does impact on pediatric organ donation, but not as significantly as family refusal. Increased organ procurement in ME-related cases will require improved communication between MEs, physicians, and the Organ Procurement Organizations (OPOs). ",0
1428,7653116,Participation of monocytes and macrophages in canine glomerular disease,"The presence of monocytes/macrophages (MPs) in renal glomeruli was investigated in 86 dogs with different types of glomerulopathies. The identification of MPs in tissue sections was based on cytological criteria and the immunohistochemical demonstration of lysozyme. The highest numbers of MPs in glomeruli were observed in focal and diffuse mesangial proliferative glomerulonephritis (MesPGN), diffuse endocapillary proliferative glomerulonephritis (DEPGN), and diffuse mesangiocapillary glomerulonephritis (DMCGN). In cases of minor glomerular abnormalities (MGA), focal and segmental hyalinosis and sclerosis (FGS), diffuse membranous glomerulonephritis (DMemGN), and diffuse sclerosing glomerulonephritis (DSGN) the presence of glomerular MPs was low. Particularly in MesPGN, the number of MPs was correlated with glomerular hypercellularity and, additionally in DMCGN, with the degree of proteinuria. The results of this study suggest that MPs may be involved in functional and morphological alterations in different types of canine glomerulopathies. ",0
1429,7653141,The effect of Clostridium tetani cultures on immunization with tetanus anatoxin in an experiment],"The paper presents the data on the study, carried out on 383 guinea pigs, of the action of C.tetani cultures on immune reactions of the animals after the injection of tetanus toxoid. The state of the humoral and cell-mediated immunity of the animals (in the hemagglutination inhibition test, the neutralization test, the enzyme-linked immunosorbent assay and the skin allergic test with tetanin), as well as their resistance to challenge with C.tetani. The inhibiting effect of C.tetani on primary immune response to tetanus toxoid and their stimulating effect on secondary immune response have been established. This fact may be used for enhancing the quality of antitetanus preparations, such as toxoid and serum, as well as for working out tactical approaches for the rapid prevention of tetanus. ",0
1430,7653666,Neuromodulation of ion transport in porcine distal colon: NPY reduces secretory actions of leukotrienes,"Electrical transmural stimulation (ETS) was used to examine the neuroregulation of electrolyte transport in the porcine distal colon. ETS of the colonic mucosa-submucosa mounted in Ussing chambers produced rapid and transient increases in short-circuit current (Isc) that were inhibited 36% by serosal bumetanide, suggesting that a portion of the response may be attributed to Cl secretion. ETS actions were dependent upon stimulus intensity and frequency and were inhibited by tetrodotoxin and omega-conotoxin. Prazosin and pyrilamine had no effect on the mucosal responses to ETS, whereas atropine reduced the responses by 32%. Neuropeptide Y (NPY) also reduced the mucosal responses to ETS up to 60% (half-maximal effective concentration = 17 nM). In addition, the effects of leukotriene C4, previously shown to stimulate Cl secretion via a neuronal pathway, were also inhibited by NPY. These results indicate that cholinergic submucosal neurons play a role in the regulation of epithelial ion transport and that NPY acts as an inhibitory neuromodulator, particularly on leukotriene-sensitive neurons in the porcine distal colon. ",0
1431,7653870,Acute grey mercury ointment poisoning],"The clinical picture of poisonings with gray mercury ointment in 56 patients after its cutaneous applications is described. The patients developed gastrointestinal disorders, nephro- and hepatopathies, fever, and dermatitis. The concentration of mercury in the blood was as high as 800 micrograms/liter. The principal agent in conservative therapy is unithiol as an antidote. In grave and medium-severe poisonings hemoperfusion is the most effective modality; early administration of this measure helps appreciably alleviate the course of the disease and prevent the complications most hazardous for life (acute renal failure, etc.). ",0
1432,7654015,Activity of platinum drugs against melanoma cell lines: is it modulated in vitro in the presence of tamoxifen?,"Cisplatin and carboplatin have been used against human malignant melanoma as single agents and in combination. Tamoxifen is used in the treatment of breast cancer, but has no significant activity against human malignant melanoma. Tamoxifen, however, has been promoted as a modulator in some drug regimens. The addition of tamoxifen to cisplatin or carboplatin has been reported to enhance their activity against the human melanoma cell line T-289. We investigated whether tamoxifen potentiates, in vitro, the activity of cisplatin and carboplatin against C32, G361 and StMl11a melanoma cell lines. Tamoxifen alone at clinically achievable concentrations of 0.1 and 1.0 microM (168 hrs exposure) had no significant effect on growth. No chemopotentiation of the activity of cisplatin or carboplatin was observed with the addition of tamoxifen (0.1 and 1.0 microM). The platinum drugs were added for 1 hr (serially diluted from 100.0 microM). Against the G361 line there was a trend towards chemopotentiation of cisplatin by 0.1 microM of tamoxifen. However, this did not reach statistical significance. Tamoxifen (5.0 and 10.0 microM) produced some inhibitory activity, and a trend towards synergy with cisplatin was observed. However, these concentrations are not clinically feasible. Previous reports detecting synergistic interaction between tamoxifen (0.1 and 1.0 microM), and the platinum compounds against the T-289 melanoma cell line cannot be supported in our in vitro system. ",0
1433,7654021,"The cytotoxicity of [(N-alkyl-1H,3H-1-oxoisoindoline-5-yl-oxyl alkanoates and related benzamides in murine and human tissue cultured cell lines","Substituted oxoisoindolines are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L1210, Tmolt-3, and HeLa-S3. In general these agents were not active against the solid cell growth, i.e. KB, skin, HCT-8 ileum, colon, bronchogenic lung, osteosarcoma and glioma. The mode of action of the derivatives involves inhibition of de novo purine synthesis of Tmolt-3 cells, which reduces DNA and RNA syntheses. Purine synthesis was reduced by compound 16 at both regulatory enzymes, i.e. PRPP amido transferase, IMP dehydrogenase and dihydrofolate reductase. The agent lowered d(GTP) and d(CTP) pool levels, further reducing DNA synthesis. DNA strand scission was evident after incubation with Compound 16 for 24 hr at 100 microM and some undefined interaction between the drug and the nucleoside bases appeared to occur, lowering DNA synthesis and causing cell death. ",0
1434,7654290,Epidemiology of trichinosis in Chile. Prevalence study by immunodiagnostic reactions],"In the period 1983-1994 a series of seroepidemiological surveys, by using immunodiagnostic tests for trichinosis, was carried out in 138 localities and health institutions from the 13 regions of the country. Thus, a total of 12,882 randomly selected persons, with different sex and age distribution, were submitted to precipitin test and indirect hemagglutination test for trichinosis. One hundred and ninety one (1.5%) persons resulted positive for trichinosis. Higher rates of infection were observed in central and southern Chile. No differences of positivity, according to age sex, but constant increase parallel to age of the individual were detected. The general prevalence rate of infection of 1.5% is in a reasonable accordance with the prevalence of 2.0% found in human corpses in 1992. ",0
1435,7654580,Eosinophilic folliculitis: a self-limiting illness in patients being treated for haematological malignancy,"Eosinophilic folliculitis is a recognized skin manifestation of human immunodeficiency virus (HIV) disease. Five cases of eosinophilic folliculitis occurring in HIV-negative patients treated for haematological malignancy are reported. In four cases this self-limiting, pruritic eruption, affecting the head and upper trunk, occurred 3 months after bone marrow transplantation, and the fifth case was a patient undergoing chemotherapy for Waldenström's macroglobulinaemia. This suggests that eosinophilic folliculitis is a consequence of disturbances of immune function, and is not specific for HIV infection. ",0
1436,7655165,First evidence of human meconium glycoasparagines,"During a systematic study of carbohydrate material present in human meconium, in addition to the previously described mucins, glycolipids and free oligosaccharides, we have now characterized a significant quantity of free glycoasparagines. These glycoasparagines have been isolated from human meconium by a combination of ion-exchange, concanavalin A (ConA)-affinity and high-performance liquid (HPLC) chromatographies. Their structures have been established by 400 MHz 1H-NMR spectroscopy. These compounds are related to N-acetyllactosaminic type structures and are based on the common core: [formula: see text] These glycoasparagines are probably derived from both protease and partial exoglycosidase hydrolysis of fetal gastrointestinal N-glycosyl proteins. Their structures are discussed in the context of the known catabolic pathways of N-glycans. ",0
1437,7655201,Effects of Nd:YAG microexplosions on heparin-coated PMMA intraocular lenses],"""Surface modification of intraocular lenses (IOL) have improved the quality of cataract surgery. Heparin surface-modified (HSM) IOL are implanted for special indications (e.g., recurrent uveitis, cataract surgery for children, preoperative synechia) because of decreased postoperative inflammatory reactions and higher long-term biocompatibility. Nevertheless, secondary cataract, precipitates and fibrinous membranes appear. The YAG laser is used for treatment. PMMA intraocular lenses with or without a heparin monolayer were exposed to Nd:YAG laser. The experiment was performed under BSS using different energy levels and distances to the IOL. The heparin monolayer was stained with toluidin blue. Subsequently, the surface of the intraocular lenses was examined with light and scanning electron microscopy. The YAG laser marks of HSM IOL and PMMA IOL showed no morphological differences. Microexplosions and pressure waves of the Nd:YAG laser cleared parts of the heparin monolayer in the area of the laser spots dependent on energy distance to the IOL. Even """"breakdown"""" behind the HSM IOL without any PMMA lesion shown circular destruction of the heparin monolayer. The heparin surface defect of HSM IOL after YAG laser treatment should be taken into consideration, because a decreased heparin effect in vivo could be possible. """,0
1438,7655383,Use of cryopreserved bone marrow in allogeneic bone marrow transplantation,"Use of cryopreserved donor bone marrow may facilitate scheduling of allogeneic bone marrow transplantation (BMT) by affording independence of a fixed time for bone marrow donation. The potential risk of damage to hematopoietic stem cells by cryopreservation resulting in delayed engraftment or graft failure has to be taken into account, however. To address these issues, the outcome of 19 matched related BMT (1992-94) performed with cryopreserved donor bone marrow was analyzed and compared with 19 related BMT (1990-93) receiving fresh donor bone marrow (control group). Time to engraftment of patients receiving cryopreserved bone marrow was not different from the control group (ANC > 0.2 x 10(9)/l 15.5 +/- 3.8 days vs 15.8 +/- 5.0 days; ANC > 0.5 x 10(9)/l 17.3 +/- 4.1 days vs 17.9 +/- 5.0 days, respectively). We did not find the previously described trend toward a lower incidence of acute GVHD in patients receiving cryopreserved bone marrow compared with patients receiving fresh bone marrow (acute GVHD > or = II 78 vs 64%). Furthermore, the two groups did not differ in the incidence of chronic GVHD (55 vs 38%) or day 100 survival (74 vs 68%). We conclude that in allogeneic BMT cryopreserved bone marrow cells can be safely used without jeopardising or prolonging time to engraftment. ",0
1439,7655482,Evaluation and management of foot and ankle disorders: present problems and future directions,"""Recent research has raised serious concerns regarding the reliability and validity of the evaluation and treatment scheme proposed by Root et al. Although the Root et al theory is widely referenced in the physical therapy literature and commonly taught in continuing education courses, current issues of concern include: 1) measurement technique reliability, 2) the criteria proposed for normal foot alignment, and 3) the position of the subtalar joint between midstance and heel-off during walking. The intent of this paper is to review these three problem areas which have been identified with the Root et al theory as well as to propose the use of a """"tissue stress model"""" which the authors have found to be an effective alternative for evaluating and treating foot disorders. """,0
1440,7655699,The effects of a new generation of H1 antihistamines (cetirizine and loratadine) on histamine release and the bronchial response to histamine in atopic patients,"The effects of two selective H1 receptor blockers, cetirizine and loratadine, in comparison with placebo, on basophil histamine release and the bronchial response to histamine were assessed. The studies were performed in a group of 18 patients with pollinosis and 22 with atopic asthma. Both tests were performed before and after medication. Histamine release from isolated basophils was evaluated by Shore's method using anti-IgE and pollen antigen as stimulants. The bronchial provocation tests were performed by Ryan's method. The results were expressed as PC20FEV1. It was shown that both drugs significantly inhibited basophil histamine release induced by anti-igE or specific allergen. It was also found that these drugs effectively reduced the bronchial response to histamine challenge. These findings confirm the beneficial clinical effect of a new generation of selective H1 blockers in the treatment of IgE-mediated allergic diseases, and also the possible role of these drugs in the therapy of atopic asthma. ",0
1441,7655895,Monoclonal antibodies identifying chick gonadal cells,"1. The aim of the present study was to raise monoclonal antibodies (MAbs) which discriminate gonadal cell types in chickens. 2. A panel of 180 MAbs was generated, from which 14 were chosen for their specificity. 3. These MAbs were characterised immunohistologically on frozen sections of embryonic, newly-hatched and adult, male and female, left gonads. 4. Three of these MAbs are described: AGC5, AGC7, and AGC13 which recognise respectively germinal epithelial cells, supporting cells and germ cells. 5. These MAbs may be useful in following the developmental pathways in the chicken gonad and analysing the interactive role(s) taking place between gonadal stromal cells and primordial germ cells. ",0
1442,7655967,"""A new """"closed"""" in situ vein bypass technique results in a reduced wound complication rate""","""This prospective randomised multicentre trial was conducted to test whether a new """"closed"""" technique for in situ vein bypass would result in a lower frequency of wound complications, without negative effects on patency rates and without an intolerable increase in residual arteriovenous fistulae compared to the conventional """"open"""" technique. We have developed a new """"closed"""" technique using a co-axial catheter embolisation system for intra-operative coil embolisation of side branches, in order to avoid long incisions. In four centres and 95 patients, 97 in situ bypasses were performed: 47 """"closed"""" and 50 """"open"""". Randomisation was stratified for below knee femoropopliteal bypasses (60) and femorocrural bypasses (37). Indications were disabling intermittent claudication (29), restpain (26) or ulcers and/or necrosis (42). Postoperative mortality was 2% (one in the """"closed"""", one in the """"open"""" group). A total number of 16 (34%) wound complications (grade 1, 2 and 3) occurred in the closed group compared to 36 (72%) in the open group (p < 0.05). Deep wound complications (grade 2) occurred in six patients (13%) of the """"closed"""" group, compared to 15 (30%) in the """"open"""" group. In both groups, three patients (6%) developed deep wound complications including the bypass area (grade 3). In the """"closed"""" group, 20 patients needed additional treatment for arteriovenous fistulae, compared to four in the """"open"""" group. One-year patency rates did not show a statistically significant difference: primary patency rates were 65% and 61% and secondary patency rates were 86% and 76% respectively for the """"closed"""" and """"open"""" group. These results indicate that a """"closed"""" technique reduces wound complication rate, without negative effects on the short term patency rates. The """"closed"""" technique results in an increased number of postoperative treatments for residual arteriovenous fistulae. """,0
1443,7655995,Histaminergic modulation of hormonal control in the exocrine guinea-pig pancreas,The effects of histamine upon secretin- or cholecystokinin (CCK)-evoked exocrine pancreatic secretion were investigated in the anaesthetised guinea pig. Histamine (0.1 mumol/kg/min) induced a slight increase in pancreatic juice flow and total protein release compared to saline controls. Secretin (0.5 pmol/kg/min) and CCK-8 (0.75 pmol/kg/min) evoked marked time course increases in both the rate of pancreatic juice flow and total protein output in the anaesthetised guinea pig. Administration of either secretin or CCK-8 simultaneously with histamine elevated the exocrine pancreatic secretion compared to the smaller response obtained when administered separately. These results indicate that histamine may play an important physiological role in modulating the hormonal control of exocrine guinea pig pancreas. ,0
1444,7656614,The varied manifestation of pulmonary artery agenesis in adulthood,"""Unilateral pulmonary artery agenesis (UPAA), a rare congenital anomaly that is frequently associated with other cardiovascular abnormalities, is usually diagnosed in childhood. Most patients who have no associated cardiac anomalies have only minor or absent symptoms and survive into adulthood. The conditions of such patients are frequently misdiagnosed in adulthood. In this report, we describe six patients with UPAA in whom the diagnosis was first established in adulthood. The varied clinical presentation of these patients is reviewed and the relative effectiveness of a variety of diagnostic tests is compared. During the period January 1987 through December 1990, six male patients, aged 17 to 20 years, were found to have UPAA at the time of their medical screening for enrollment into the armed forces. The diagnosis was based on history, clinical and imaging examinations, including chest radiography, ventilation-perfusion lung scan, digital subtraction angiography (DSA), computed tomography (CT), and magnetic resonance imaging (MRI). In four of the patients, the UPAA was on the left side and in two it was on the right. A right aortic arch was present in three patients and other cardiovascular anomalies were found in three. Pulmonary function studies showed a mild restrictive pattern in four. In contrast to previous reports, the ventilation scan showed a diminished """"wash in"""" and """"equilibrium"""" phase without a delayed """"wash out"""" phase on the affected side in all patients. Selective bronchography through the fiberoptic bronchoscope revealed ipsilateral mixed-type bronchiectasis in two of four patients studied, a finding of clinical significance that has not been described previously. In all cases, the diagnosis was made by DSA. CT of the thorax (n = 6) and MRI (n = 4) were diagnostic in all cases in which they were performed, but added no significant information. UPAA is frequently misdiagnosed in adulthood and is often not considered in the differential diagnosis of the unilateral hyperlucent lung. Clinicians and radiologists should be aware of the possibility of undiagnosed cases in adults, with many atypical characteristics. """,0
1445,7656706,The diagnosis and treatment of benign esophagotracheo-bronchial fistula: a report of 26 cases],"Twenty six patients with esophagotracheal fistula or esophagobronchial fistula were treated from 1960 to 1991. There were 18 males and 8 females with age ranging from 19 to 69. Trauma and complication of esophageal diverticulum were the main causes of fistula. Among 23 patients surgically treated, 10 underwent direct repair, and 13 either closure of esophageal defect or tracheal or bronchial defect. The concomitant procedures were permanent tracheostomy, tracheal resection and reconstruction, pulmonary resection, thoracoplasty esophagectomy, and esophagogastric anastomosis. All patients resumed normal eating. Complications included paralysis of recurrent nerves, empyema, injury and ligation of subclavian artery, dehiscence of tracheal anastomosis, and contralateral pneumohydrothorax in each patient. Prognosis of 3 nonsurgical treatments of fistulas was poor. Surgical intervention should be done as soon as the diagnosis is established in order to minimize pulmonary complication. ",0
1446,7656711,Primary non-Hodgkin's malignant lymphoma of bone in 5 patients],"The authors report here 5 cases of primary non-Hodgkin's malignant lymphoma of bone. All bones of the body can be involved, but the commonly inflicted ones are pelvis and femur. This kind of lymphoma possesses no special clinical features and X-ray manifestation, so it is very difficult to be diagnosed and easily misdiagnosed. The diagnosis can be made with the following 5 items: (1) local significance; (2) X-ray manifestation; (3) bone origination; (4) the no proof of originating from other tissues; and (5) pathological examination. This kind of lymphoma is mainly treated with radiotherapy, and adjuvant surgical treatment and chemotherapy are sometimes given. ",0
1447,7656820,The effect of retinoic acid on cell membrane and metastatic ability of mouse forestomach carcinoma cells],"We studied the effect of all-trans-retinoic acid (RA) on the expression of several surface lectin receptors and cell membrane fluidity of mouse forestomach carcinoma cell line (MFC) in vitro. The results showed that cells treated with RA manifested decreased expression of lectin receptors, increased membrane fludity and reduced spontanous metastasis. These rusults suggest that the effect of RA on tumor cell membrane may be one of the mechanisms involved in the alternation of cell metastatic phenotype. ",0
1448,7657028,Elevated levels of authentic plasma hydroperoxides in NIDDM,"Using a precise technique for measuring authentic plasma lipid hydroperoxides (ROOHs), we show that individuals with non-insulin-dependent diabetes mellitus (NIDDM) have higher levels of ROOH than do control subjects. ROOHs were measured by the ferrous oxidation with xylenol orange assay coupled with the selective ROOH reductant triphenylphosphine. Formation of the ferric xylenol orange complex was determined at 560 nm and calibrated against H2O2. For 22 individuals with NIDDM, a concentration of 9.04 +/- 4.3 mumol/l (mean +/- SD) ROOH was recorded. This concentration was higher (P < 0.0005 by separate-variance t test) than that of plasma ROOHs from control subjects (3.76 +/- 2.48 mumol/l). There was no difference between concentrations of plasma malondialdehyde measured as thiobarbituric acid-reactive material (TBARM) in NIDDM or control subjects (1.00 +/- 0.70 vs. 1.21 +/- 0.62 mumol/l, respectively; P > 0.1). A trend to lower vitamin E levels in the NIDDM group (9.03 +/- 3.31 vs. 10.31 +/- 5.02 micrograms/ml in control subjects) failed to achieve significance at the 95% confidence level. Plasma ROOHs in the diabetic group did not correlate with total plasma cholesterol, triglyceride, fasting glucose, HbA1, vitamin E, or TBARM levels. These data indicate that measurement of authentic ROOHs shows NIDDM to be associated with oxidative stress, which may be unrelated to abnormalities in lipid metabolism and glycemic control. ",0
1449,7657052,Sham feeding increases glucose tolerance by a mechanism independent of insulin secretion in normal subjects,"The effect of sham feeding on glucose metabolism was studied in eleven normal subjects. At random, one intravenous glucose tolerance test (25 g glucose/4 min) was preceded by 15 minutes of pure sham feeding (the sight and smell of a meal but not the taste) which continued for the first 15 minutes after the intravenous glucose load. Pancreatic polypeptide increased significantly during sham feeding and decreased significantly in response to the glucose injection. The glucose disappearance rate was significantly improved from 1.56 +/- 0.22 to 2.07 +/- 0.33 min-1 when the glucose tolerance test was preceded by sham feeding (p = 0.02). Incremental areas of plasma insulin, plasma C-peptide, and insulin secretion rates were not significantly influenced by sham feeding. We conclude that sham feeding by the sight and smell of food improves glucose tolerance in normal subjects without alteration in insulin secretion. ",0
1450,7657155,Vitamin D3 intoxication in naked mole-rats (Heterocephalus glaber) leads to hypercalcaemia and increased calcium deposition in teeth with evidence of abnormal skin calcification,"Naked mole-rats have no access to obvious sources of vitamin D and therefore have an impoverished vitamin D status. In an investigation into the effects of vitamin D supplementation, inadvertently supraphysiological doses of 130,000 times the normal dose of vitamin D were administered. Within 5 days animals appeared lethargic, with reduced food intake. All but one of the seven animals were killed and blood was collected. Plasma vitamin D metabolites 25(OH)D and 1,25(OH)2D and calcium were determined. Both vitamin D metabolite concentrations exceeded the upper limits of sensitivity of the assays (> 100 ng/ml 25(OH)D and > 210 pg/ml 1,25(OH)2D). Active calcium uptake in the intestine was evident along with concomitant increases in calcium concentration in plasma, bone, and teeth. The remaining animal survived, but showed scab-like formations in the skin around the lower jaw and along the nipple line. X-ray analyses revealed calcium deposition in these cornified regions, although there was no evidence of metastatic calcification in other tissues. Deposition of excess calcium in skin that is regularly sloughed off and in teeth that are continuously worn down and replaced may reduce the vitamin D-induced hypercalcaemia and thus alleviate the effects of vitamin D intoxication. ",0
1451,7657284,Human myofibroblastlike cells obtained by outgrowth are representative of the fibrogenic cells in the liver,"During human fibrogenesis, myofibroblastlike cells proliferate and are the main source of fibrosis components. We have used cultured myofibroblastlike cells obtained by outgrowth from explants of human liver to study the expression of extracellular matrix (ECM) components and matrix-metalloproteinase-2 (MMP-2) These cells contained types I, III, IV, and V procollagen messenger RNAs (mRNAs). They also expressed mRNAs for laminin B1 chain and for cellular and plasma fibronectin. The corresponding proteins were detected by immunocytochemistry. MMP-2 expression was shown by Northern blot and gelatin zymography. Because transforming growth factor beta 1 (TGF beta 1) is considered an important mediator in liver fibrogenesis, we examined its effect on expression of ECM components by cultural human myofibroblastlike cells. TGF beta 1 increased collagen mRNAs steady-state levels and total collagen secretion in the culture medium. It also increased fibronectin mRNA levels but had no effect on laminin mRNA or MMP-2 expression. In summary, cultured human myofibroblastlike cells express those ECM components that accumulate during hepatic fibrogenesis, indicating the usefulness of this model to study mechanisms of human liver fibrogenesis. In addition to the mitogenic effect of TGF beta 1 on human myofibroblastlike cells, we now demonstrate its stimulation of ECM accumulation in these cells, thus emphasizing the central role of TGF beta 1 and myofibroblastlike cells in the pathophysiology of human hepatic fibrosis.",0
1452,7657289,Iron-responsive element-binding protein in hemochromatosis liver and intestine,"""Iron-responsive element-binding protein (IRE-BP) activity was studied in liver and intestinal samples of hemochromatosis and control patients using a short 32P-IRE-RNA probe on """"retardation"""" nondenaturing polyacrylamide gels. IRE-BP activity was assessed in liver biopsy specimens in 36 patients--16 hemochromatosis homozygotes, 4 hemochromatosis heterozygotes, 6 patients with secondary iron overload, and 10 control patients with normal hepatic iron concentrations. Intestinal IRE-BP activity was assessed in 14 hemochromatosis homozygotes and 16 normal subjects. Endogenous IRE-BP activity was determined from 32P retarded on the gel, and total IRE-BP activity was assessed after reducing tissue samples with 2-mercaptoethanol. Hepatic endogenous IRE-BP activity was inversely related to hepatic iron concentration (r = .59, P < .0002). Mean hepatic endogenous IRE-BP activity in the hemochromatosis homozygotes, 0.25 +/- 0.04 pmol/mg protein, was significantly decreased compared with values in the normal controls, 0.45 +/- 0.06 pmol/mg protein, P < .05. Hepatic total IRE-BP was also significantly decreased in the hemochromatosis patients by gel retardation assay and Western blotting with anti-IRE-BP antibody. Intestinal endogenous IRE-BP activity, total IRE-BP activity, and iron concentration did not significantly differ between hemochromatosis patients and normal control subjects. This suggests that both endogenous IRE-BP activity and the total amount of the protein are downregulated in the liver by tissue iron. Intestinal IRE-BP activity that regulates intestinal transferrin receptor expression is normal in hemochromatosis and appropriate for the intracellular iron concentration.""",0
1453,7657291,Organellar clusters formed by mitochondrial-rough endoplasmic reticulum associations: an ordered arrangement of mitochondria in hepatocytes,"Our objective was to determine if mitochondrial-rough endoplasmic reticulum (mt-RER) associations provide for an ordered arrangement of mitochondria in the cell. If such an ordered arrangement exists, it might be manifested by grouping of mitochondria according to size and biochemical properties. Liver homogenate was subjected to rate zonal centrifugation for fractionating mitochondrial clusters. These clusters were then examined for morphological and biochemical characteristics. Scanning electron microscopy (SEM) showed that (1) mitochondria were held together in clusters by rough endoplasmic reticulum, (2) clusters consisted of mitochondria of comparable size, and (3) a 45-fold difference in average mitochondrial volume existed between the organelles of the fastest and slowest sedimenting clusters. Transmission electron microscopy (TEM) affirmed that all of the organellar clusters examined were mitochondria associated with rough endoplasmic reticulum. Cytochrome oxidase and mitochondrial DNA were found to be proportional to mitochondrial volume, indicating that these components were synthesized in proportion to increases in volume. Conversely, succinic dehydrogenase and ornithine carbamoyl transferase were increased disproportionately (2.9-fold and six-fold, respectively) with increase in mitochondrial volume. It is evident from this biochemical heterogeneity that clusters composed of larger mitochondria differ functionally from clusters of smaller mitochondria. The size-ordered arrangement suggests that this organization is in some way related to the biogenesis of hepatocyte mitochondria. It is also conjectured that the biochemical heterogeneity is a consequence of addition of selected proteins (e.g., succinic dehydrogenase and carbamoyl transferase) to mitochondria in a developmental process as they mature into larger organelles.",0
1454,7657293,Mucin-vesicle interactions in model bile: evidence for vesicle aggregation and fusion before cholesterol crystal formation,"Nucleation of cholesterol monohydrate crystals from bile is a critical step in the formation of cholesterol gallstones. Measurement of nucleation in model bile system and the characteristics of the initial nucleus have proven elusive. In this study we have used three separate physical chemical techniques to examine vesicle aggregation and fusion, including dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescent biochemical assays. These assays enabled us to quantify the effect of biliary proteins, such as gallbladder mucin, on vesicle fusion and aggregation. In the absence of mucin, fusion is a relatively slow process occurring over 24 hours, whereas physiological concentrations of mucin are able to accelerate almost complete fusion of vesicles within 6 hours. Vesicle fusion and aggregation as characterized by TEM result in the formation of aggregates of multilamellar vesicles and giant fusion bodies associated with a background of mucin. These mucin-vesicle aggregate bodies may represent true nuclei and precede cholesterol monohydrate crystal nucleation. In future studies, these vesicle fusion assays can be used to quantitatively examine the effect of putative pro- and anti-nucleating proteins on the earliest steps of cholesterol crystal nucleation.",0
1455,7657350,Urinary calcium excretion in patients with pregnant hypertension syndrome],"We observed the urinary calcium in 103 patients in the third trimester of pregnancy and the relation between the 24 hour calcium excretion and the calcium/creatinine ratio of a single void urine sample. The study population included 75 normal pregnant women and 28 pregnant woman with pregnant hypertension syndrome. The 24 hour urinary calcium excretion in the patients with pregnant hypertension syndrome was significantly lower (0.70 +/- 0.36 mmol/L) than that in normal pregnant women (4.00 +/- 1.90 mml/L) P < 0.0005. The 24 hour calcium excretion correlated well with the calcium to creatinine ratio of a single void morning urine sample in the two groups. We conclude that the urinary calcium excretion can be used as an indicator for pregnant hypertension syndrome. The 24 hour urinary calcium excretion can be estimated from a single void urine sample. Pregnant hypertension syndrome is associated with hypocalciuria, probably due to increased tubular reabsorption of calcium. ",0
1456,7657389,Retinoic acid receptors and retinoid binding proteins in endometrial adenocarcinoma: differential expression of cellular retinoid binding proteins in endometrioid tumours,"Retinoic acid is apparently required for the normal differentiation of reproductive epithelium. Cellular abnormalities in retinoid homeostasis could be a factor in the development of endometrial malignancy. We have thus investigated the expression of nuclear retinoic acid receptors (RARs and RXRs) and cellular binding proteins for retinol (CRBP) and retinoic acid (CRABP) in endometrial adenocarcinoma of the endometrioid histological subtype. Ten grade I, II grade 2 and 10 grade 3 tumour samples, as well as 4 samples of severe atypical precancerous endometrial hyperplasia, were studied. No significant difference in expression of RAR-beta was detected in tumour samples compared with normal epithelial cells. RAR-gamma was significantly elevated in grade 1 and 2 carcinomas, but this may be due to greater stromal cell involvement in these lower grade tumours. There was significant elevation of CRBP I mRNA in tumour samples. Furthermore, although undetectable in normal endometrial epithelium, CRABP I was expressed in 3/II grade 2 and 9/10 grade 3 carcinomas, with expression being significantly higher where the primary tumour had invaded more than 50% of the total myometrial thickness. Analysis of 2 epithelial-like endometrial adenocarcinoma cell lines supported the idea that CRABP I expression is characteristic of poorly differentiated endometrial adenocarcinoma. Our data suggest that alterations in mechanisms of retinoid homeostasis are a feature of endometrial adenocarcinoma and may contribute to the severity of disease. ",0
1457,7659636,Incontinentia pigmenti: late sequelae and genotypic diagnosis: a three-generation study of four patients,"Late cutaneous signs of incontinentia pigmenti (IP) are often subtle and misdiagnosed. We focus on these somewhat confusing clinical markers in a family, and on the genotypic diagnosis based on DNA analysis. An infant was born with a typical IP rash. Dermatologic examination of the women in her family revealed that her mother, her maternal aunt, and her grandmother had subtle skin signs reminiscent of IP. The four family members proved to be informative for DNA markers in the Xq28 region. Familial cases of IP are sometimes missed due to the lack of recognition of some late skin signs that are not always hyperpigmented streaks. Subtle, faint, hypochromic or atrophic lesions in a linear pattern may occur. Thus an accurate diagnosis of the women in a particular family also requires anamnestic data and recognition of extracutaneous anomalies. When a clinical diagnosis has been made, DNA marker analysis allows us to offer a prenatal diagnosis with minimal risk of error in case of further pregnancy. However, early testing of chorionic villus samples does not allow one to predict the severity of the disease in an affected fetus. ",0
1458,7659768,Subjective and cardiovascular responses to nicotine combined with alcohol in male and female smokers,"Nicotine and alcohol are often consumed concurrently by smokers. Each drug alone produces significant subjective and cardiovascular responses, but the effects of the two drugs in combination have rarely been examined. Smokers who were moderate alcohol drinkers (n = 18, 9 males and 9 females) participated in four sessions, involving acute administration of nicotine/placebo and alcohol/no alcohol. Subjects abstained overnight from tobacco and alcohol prior to each session. Nicotine (20 micrograms/kg per presentation) or placebo was administered by measured-dose nasal spray every 30 min for 2 h following consumption of diet tonic water with or without alcohol (0.5 g/kg). Subjective (visual analog scales, Profile of Mood States, Addiction Research Center Inventory) and cardiovascular (heart rate, systolic and diastolic blood pressure) responses were assessed after each nicotine/placebo administration. Nicotine increased head rush, dizzy, and most stimulant effects (i.e. jittery, tension, and arousal and decreased fatigue and relaxed), while alcohol increased intoxication, head rush, dizzy, and jittery, with no other stimulant effects. Nicotine and alcohol generally produced additive subjective and cardiovascular effects when consumed together, although nicotine attenuated sedating and intoxicating effects of alcohol alone. Furthermore, there were several interaction effects on subjective measures involving gender. Nicotine plus alcohol tended to attenuate some subjective effects due to one drug or the other alone in men but enhanced the effects of either alone in women. These findings indicate that nicotine and alcohol generally have additive subjective and cardiovascular effects, but that men and women differentially respond on some subjective measures to the combination of alcohol and nicotine. ",0
1459,7659804,Eclampsia: 8-year experience],"Eighty-one cases of eclampsia were managed from april 1985 to may 1993 with an incidence of 1.0 in 1.000 deliveries, at the Department of Obstetric, Gynecology and Neonatology of Barros Luco-Trudeau Hospital, Santiago, Chile. 84.6% of patients were primipara and 45.7% were less than 20 years of age. Convulsions occurred during pregnancy in 61.7% of patients, during labor 22.2% and 16.1% post partum. Eleven cases (13.6%) had convulsions while receiving magnesium sulfate therapy. Prior to convulsion 21.3% of patients showed blood pressure below 140/100 mmHg. 25.9% of patients had normal urine protein. Cesarean section was performed in 75.3%, and the most frequent indication was poor cervical conditions. Fetal distress respiratory and the intrauterine growth retardation were the most frequent neonatal morbidity. Perinatal mortality was 13.2%. Maternal mortality was 3.7%. ",0
1460,7660022,"Sociodemographic conditions and nutritional status of children under 1 year old in peripherical areas of Guadalajara, México]","A random population sample was studied with a view to determining the proportion of children of less than on year of age whose weight is less than the minimum adequate weight (MAW) for their age, as well as to identifying factors of a socio-demographic nature that could be associated with this problem and the socio-sanitary importance of these factors. The sample studied was of children of less than one year of age, born between 05/01/1990 and 04/30/1991, whose mothers were entitled to the services of the Mexican Institute of Social Security, in Tlaquepaque and Tonalá, municipalities adjacent to the Metropolitan Zone of Guadalajara, the second most important city in Mexico. The ponderal assessment of the infants was performed on the basis of tables which the Latin-American Perinatology Center had developed for this purpose. Through the use of logistic regression, Odds Ratios (OR) were estimated, with 90% confidence intervals (CI). The model thus prepared was adjusted by means of the H* statistics. Likewise, the population's attributable risk (PAR) was calculated, as well as the probability that a child would not reach the MAW for its age, in the presence or absence of particular risk factors. The results indicate that nearly one fifth of the infants studied do not reach MAW.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1461,7660341,Comparative study of the effects of different glucocorticosteroids on eosinophil survival primed by cultured epithelial cell supernatants obtained from nasal mucosa and nasal polyps,"Supernatants from epithelial cell cultures enhance eosinophil survival in vitro, this effect being abrogated by previous incubation of eosinophils with glucocorticosteroids. This property has resulted in the development of an in vitro test to compare the potency of these drugs. A comparative study was performed with dexamethasone, methylprednisolone, deflazacort, and budesonide. Human epithelial cell conditioned media (HECM) was generated from cultured epithelial cells obtained from healthy nasal mucosa and polyps. Eosinophils isolated from the peripheral blood were incubated with different corticosteroids for one hour before the addition of HECM. The inhibitory potency of the four steroids on the eosinophil survival index was compared using the concentration of steroid causing 50% inhibition (IC50). Eosinophil survival was increased by HECM from both healthy nasal mucosa and polyps. All four steroids blocked HECM-induced eosinophil survival in a dose-dependent manner. On healthy nasal mucosa methylprednisolone was the least potent (IC50 = 536 nM), deflazacort (IC50 = 264 nM) was twice as potent as methylprednisolone, while budesonide and dexamethasone were approximately nine times as potent (both IC50 = 58 nM). When potency was evaluated on the promoting effects of the HECM obtained from nasal polyps, the inhibitory potencies were lower and consequently the IC50 values were higher when compared with HECM generated from healthy nasal mucosa: methylprednisolone (IC50 = 546 nM), deflazacort (IC50 = 390 nM), dexamethasone (IC50 = 76 nM), and budesonide (IC50 = 78 nM). The potencies of glucocorticosteroids can be compared by evaluating their effects on the survival of eosinophils previously primed by supernatants obtained from epithelial cell culture. The different effects of steroids on eosinophils primed by HECM obtained from healthy nasal mucosa compared with HECM obtained from nasal polyps suggest that polyps might represent more active tissue which is relatively resistant to treatment with corticosteroids. ",0
1462,7660832,"Electrophysiological characterization of a novel class III antiarrhythmic agent, GLG-V-13 in the mammalian heart","GLG-V-13, a novel 3,7-diheterabicyclo[3.3.1]nonane, was examined both in vivo and in vitro in order to characterize its electrophysiological, haemodynamic and inotropic properties. Left ventricular epicardial monophasic action potential (MAP), surface ECG and mean arterial blood pressure (MBP) were recorded in six pentobarbital-anaesthetized, artificially ventilated and thoracotomized guinea-pigs. When studied in an intravenous dose interval ranging between 0.5 micrograms/kg and 500 micrograms/kg, GLG-V-13 dose-dependently lengthened the MAP duration (p < 0.05 at doses above 5 micrograms/kg), the atrioventricular conduction time (p < 0.05 at doses above 1 microgram/kg) and the RR interval (p < 0.05 at doses above 25 micrograms/kg). At the highest dose (500 micrograms/kg) these variables were increased by 30%, 13% and 23%, respectively. Only minor effects were noted on intraventricular conduction time (QRS interval) and MBP. In rabbit atrial and papillary muscle preparations, GLG-V-13 (0.32 to 3.2 mg/l) did not exert negative inotropic action. In 10 intact anaesthetized mongrel dogs, left ventricular endocardial MAP at 90% repolarization (MAP90) was measured during atrial pacing before and after administration of GLG-V-13, 3 and 6 mg/kg i.v., respectively. ",0
1463,7661114,"Muscle thickness, measured with ultrasound, may be an indicator of lean tissue wasting in multiple organ failure in the presence of edema","Multiple organ failure (MOF) is accompanied by muscle wasting, but changes in body composition are frequently obscured by fluid retention (edema), mainly in superficial and visceral tissue. There is a need to assess body composition and changes in body composition in these circumstances independently of edema. A relation was sought between fat-free (lean tissue) mass [calculated from body weight and skinfold thicknesses and measured by using dual-energy X-ray absorptiometry (DXA)] and muscle thickness (measured using ultrasound at a variety of sites accessible in an unconscious supine subject) to determine which sites correlated best with lean body mass. The three best sites were midbiceps, midforearm anteriorly, and midthigh anteriorly: R2 for the simple sum of the three sites correlated with fat-free mass from skinfold thicknesses was 71.1%, and with lean tissue mass from DXA was 76.1%. Serial measurements of both muscle thickness and midupper-arm circumference in nine patients with MOF showed a complete dissociation; in all nine there was a significant negative correlation of muscle thickness with time (P < 0.05) but changes in arm circumference were random. Only one patient showed a significant negative correlation with time, seven showed no change, and one other showed a significant increase. The muscle thicknesses that correlate best with lean body mass are measured over the biceps, anterior forearm, and anterior thigh. Monitoring muscle thicknesses at these three sites identifies wasting in edematous patients as it is happening. ",0
1464,7661523,Retest stability of the tinnitus handicap questionnaire,"The test-retest stability of the Tinnitus Handicap Questionnaire was assessed for a sample of 32 tinnitus patients. The questionnaire is a self-report measure that quantifies the physical, emotional, and social consequences of tinnitus (factor 1), the interfering effects of tinnitus on the hearing ability of the patient (factor 2), and the patients' view of tinnitus (factor 3). Retest stability estimates were obtained in order to determine the applicability of using the questionnaire as an outcome measure following tinnitus management. High test-retest correlations emerged for factors 1 and 2, whereas factor 3 yielded inadequate retest reliability. Therefore, it is recommended that only factors 1 and 2 be used for documenting changes in self-perceived tinnitus handicap following medical, surgical, or rehabilitative intervention. ",0
1465,7661686,Surgical antibiotic prophylaxis and Clostridium difficile toxin positivity,"To examine a possible relationship between prophylactic antibiotic therapy (PAT) and the development of Clostridium difficile toxin (CDT) positivity. Retrospective case-control study. Tertiary care medical center in New York, NY. A total of 357 patients, admitted from November 1992 to April 1994, with positive. CDT assays. Of these, 23 patients (6%) received only PAT for elective surgical procedures. Thirty-nine patients were matched as controls for age, sex, and surgical procedure. Both CDT positivity and inappropriate use of PAT. Appropriate PAT was used in 26 (42%) of 62 patients (17% cases, 56% controls). The Mantel-Haenszel estimator for the summary odds ratio for the development of CDT positivity from inappropriate use of PAT was 5.1 (95% confidence interval, 1.10 to 23.64). Main duration between the operation and the final antibiotic dose was significantly longer in the CDT-positive group compared with the control group (3.1 vs 1.7 days, P < .05). The length of hospital stay was significantly longer in the CDT-positive group compared with the control group (16.5 vs 10.2 days, P < .05). The prolonged use of PAT in elective surgical cases increases the risk of developing CDT positivity. The appropriate use of PAT could significantly reduce health costs by eliminating unnecessary doses of antibiotics, by decreasing the rate of CDT positivity, and by shortening the hospital stay. Restrictive policies may need to be implemented to prevent further antibiotic misuse. ",0
1466,7661849,"Ubiquitin in homeostasis, development and disease","Ubiquitin is the most phylogenetically conserved protein known. This 8,500 Da polypeptide can be covalently attached to cellular proteins as a posttranslational modification. In most cases, the addition of multiple ubiquitin adducts to a protein targets it for rapid degradation by a multisubunit protease known as the 26S proteasome. While the ubiquitin/26S proteasome pathway is responsible for the degradation of the bulk of cellular proteins during homeostasis, it may also be responsible for the rapid loss of protein during the programmed death of certain cells, such as skeletal muscle during insect metamorphosis. In addition, alterations in the expression and regulation of ubiquitin may play significant roles in pathological disorders. For example, dramatic increases in ubiquitin and ubiquitin-protein conjugates are observed in a wide variety of neurodegenerative disorders, including Alzheimer's disease. Patients suffering from the autoimmune disease systemic lupus erythematosus generate antibodies reacting with ubiquitin and ubiquitinated histones. At present, it is not known whether these changes in ubiquitin expression and regulation initiate pathological changes in these diseases or if they are altered as a consequence of these disorders. ",0
1467,7661911,Adverse outcome of nonoperative management of intimal injuries caused by penetrating trauma,"""The objective of this study was to determine adverse outcomes associated with the nonoperative management of intimal injuries. A five-year retrospective review of 118 patients admitted with soft signs of vascular injury to two level I trauma centers was conducted. All injuries evaluated were isolated penetrating injuries. The number of major arteries at risk were 16 axillary, 31 brachial, 36 common femoral, 22 superficial femoral, and 13 deep femoral. Twenty-three angiographic abnormalities were identified in 23 limbs. Seven injuries were categorized as """"minor"""" intimal flaps and treated with observation alone. The remainder were explored during operation. During the follow-up period, six of the seven patients treated without operation returned to either the outpatient clinic or emergency department with acute onset of pain or paresthesia in the previously injured limb. The following abnormalities were identified with angiography: one axillary artery thrombosis, one brachial artery pseudoaneurysm, two common femoral thromboses, two superficial femoral artery/superficial femoral vein fistulas, and one deep femoral artery pseudoaneurysm. All the abnormalities were repaired with operation. The benign nature of intimal injury identified with angiography may be overemphasized. The results of long-term follow-up in patients with this type of injury must be reviewed before """"observation alone"""" can be recommended as standard treatment. """,0
1468,7662599,Antianginal efficacy and safety of controlled-delivery diltiazem QD versus an equivalent dose of immediate-release diltiazem TID,"Controlled-delivery once-daily diltiazem (qd), 180 mg and 360 mg, was assessed in two multicenter, randomized, double-blind, placebo-controlled trials using a 3 x 3 Latin square design. Both studies compared the controlled-delivery dosage form to the same total daily dose of immediate-release diltiazem administered three times daily (tid) and to placebo. The primary measure of efficacy was the time to termination of the exercise tolerance test (ETT) at 2, 8, and 24 hours after the morning dose. There were no significant differences in time to ETT termination between the qd and tid formulations at any time, except at 24 hours with 180 mg qd versus 60 mg tid. The comparison to placebo showed that diltiazem 180 mg qd, 360 mg qd, and 120 mg tid significantly lengthened the time to ETT termination (p < 0.05) at all time points, while diltiazem 60 mg tid did not differ from placebo at any time point. The qd formulation also increased the time to 1-mm ST-segment depression and reduced the number of angina attacks and the amount of nitroglycerin used when compared to placebo. No new or unusual adverse events were noted. Diltiazem controlled-release capsules administered once daily are safe and effective for the treatment of patients with chronic stable angina. ",0
1469,7662773,Cytokine-induced release of plasminogen activator inhibitor-1 by human mesothelial cells,"To see what effect the inflammatory cytokines tumour necrosis factor (TNF), interleukin 1 (IL-1), and interleukin 6 (IL-6) had, both alone and in combination, on the production of plasminogen activator inhibitor 1 (PAI-1) by human mesothelial cells. Laboratory study. University hospital, UK. Six cell cultures of human mesothelial cells. Concentrations of PAI-1 in conditioned media and cell lysates after culture for 24 hours. TNF, IL-1, and IL-6 all significantly increased the amount of PAI-1 in the media compared with controls (81%, p < 0.05; 77%, p < 0.05; and 60%, p < 0.05, respectively). TNF and IL-1 together produced significantly more release than each cytokine alone (190%, p < 0.05) and a combination of the three increased release even further (290%, p < 0.05). The presence of endotoxin did not significantly affect the release of PAI-1. Inflammatory cytokines mediate the release of PAI-1 by mesothelial cells, and so may affect the deposition of fibrin within the peritoneal cavity. ",0
1470,7663862,Changes of arterial oxygen tension in supine position during one-lung anesthesia],"One-lung ventilation during anesthesia (one-lung anesthesia) in patients under lateral decubitus position to help performing intra-thoracic surgical procedures was well known to have larger alveolar-to-arterial oxygen tension difference and lower arterial oxygen tension (PaO2) as compared to two-lung ventilation. In the present study, we investigate the changes of arterial oxygen tension in the supine position during one-lung anesthesia. Forty-two patients of palmar hyperhidrosis, ASA class I-II, scheduled to receive bilateral transthoracic endoscopic sympathectomy were studied. After anesthetic induction (fentanyl, thiopental, and succinylcholine), a 35 (for female) or 37 (for male) French left-sided Robertshaw double-lumen endobronchial tube was intubated. Anesthesia was maintained with isoflurane 1.0-1.5% and 50% O2-N2O. They were changed to isoflurane 1.5-2.0% and 100% O2 during one-lung ventilation. Once the surgical operation is completed, they were changed to 100% O2 and two-lung ventilation. Arterial blood gases were measured at 4 phases: 5 min after endobronchial intubation (two-lung ventilation), 5 min after left one-lung ventilation, 5 min after right one-lung ventilation, and 5 min after accomplishing operation (two-lung ventilation). The results showed PaO2 were significantly lower in left and right one-lung ventilation with 100% O2 as compared with that obtained from two-lung ventilation with 50% O2 5 min after endobronchial intubation (p < 0.05). Furthermore, right one-lung ventilation had a lower PaO2 than left one-lung ventilation (p < 0.05). We conclude that arterial oxygen tension can be safely maintained during one-lung anesthesia with pure oxygen in healthy patients lying in a supine position. ",0
1471,7664542,Current and prospective therapies for hepatic fibrosis,"The prospects for new, effective treatments for hepatic fibrosis are real. Currently there are several drugs being evaluated in clinical trials, including polyunsaturated lecithin and prostaglandins. In addition, the authors' (J.F.T. and D.A.B.) knowledge of the pathophysiology of hepatic fibrosis has increased dramatically during the past few years. These advances are being incorporated into novel therapies for hepatic fibrogenesis such as TGF-beta antagonists. Hopefully, definitive treatments for hepatic fibrosis will become available in the near future. ",0
1472,7664693,A cytosolic protein tyrosine kinase activity is induced by follicle stimulating hormone and insulin like growth factor-I in human granulosa cells,"Follicle stimulating hormone (FSH) induces estradiol (E2) production in rat, porcine and human granulosa cells with a concomitant increase in cAMP. In human granulosa cells insulin like growth factor-I (IGF-I) induces E2 production without cAMP accumulation. In the current study we report that IGF-I and FSH effects on aromatase activity both involve activation of a cytosolic soluble protein tyrosine kinase (CytPTK). This FSH and IGF-I stimulated CytPTK activity was blocked by AG-82 (a tyrosine kinase inhibitor) and by staurosporine (STS) (a non specific protein kinase inhibitor) at concentrations which inhibited E2 production. These new findings strengthen the concept of fail-safe mechanism in E2 production in human granulosa cells by an involvement of tyrosine kinase(s) activity downstream of cAMP formation and protein kinase A (PKA) activation. ",0
1473,7664847,Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells,"There is indirect, contradictory evidence both for increased and reduced synthesis of the endothelium-derived vasodilator, nitric oxide, in the pulmonary circulation during acute hypoxia. Therefore, we decided to directly measure the effect of acute hypoxia on nitric oxide production by cultured pulmonary endothelium. Because increases in the intracellular free calcium concentration are known to initiate nitric oxide synthesis, we also studied cytosolic calcium levels. We measured the accumulation of the stable nitric oxide metabolite, nitrite, in the fluid used to superfuse the cultured bovine pulmonary artery endothelial cells at an oxygen tension (PO2) of either 20.3 (normoxia) or 4.9 kPa (hypoxia) (152 or 37 mmHg). Intracellular calcium levels were measured with dual-excitation microfluorimetry after loading the cells with the fluorescent calcium indicator, fura 2. Basal NO synthesis, measured as nitrite accumulation over 10 min, was significantly higher under hypoxic than normoxic conditions (8.3 +/- 2.2 versus 4.6 +/- 0.8 nM). Hypoxia transiently increased cytosolic calcium concentration (from 113 +/- 10 to 231 +/- 45 nM). Ryanodine and thapsigargin (which deplete intracellular calcium stores), but not the removal of extracellular calcium, inhibited the hypoxic increase in cytosolic calcium, indicating that it resulted primarily from release of intracellular calcium. Bradykinin-elicited NO synthesis was potentiated by hypoxia. Bradykinin-induced increase in cytosolic calcium was not inhibited by hypoxia. We conclude that hypoxia acutely increases cytosolic calcium levels and basal and bradykinin-stimulated nitric oxide synthesis in pulmonary artery endothelium. ",0
1474,7664974,Detection of c-mos related products in the dogfish (Scyliorhinus canicula) testis,"The objective of the present paper was to do a comparative study to assess somatic versus germ cell localization of c-mos products in the testis. In mouse and amphibian oocytes, c-mos activity is necessary for meiotic maturation. Lack of c-mos expression has been reported in somatic cells of male and female gonads while transcripts have been found in germ cells of testis and ovary. Using a v-mos probe, we report here the detection of a c-mos related transcript (1.7 kb) in the dogfish Scyliorhinus canicula testis. Western blot analysis detects two proteins of 106 and 32 kDa. A specific immunostaining was exclusively localized in the interstitial tissue while the germinal compartment was completely negative. In conclusion, our results indicate for the first time the presence of c-mos products in an elasmobranch species and, moreover, their presence in somatic testicular cells rather than germ cells. Therefore, this finding in an ancient vertebrate indicates that c-mos activity does not have a direct universal role in the regulation of spermatogenesis. ",0
1475,7665115,Diathermic loop treatment of subclinical cervical infection by human papilloma virus (HPV). Short-term effectiveness],"Multiple modalities of treatment have been employed since cervical subclinical papillomavirus (SPI) were discovered, with various degrees of success. The objective of this report is to assess the efficacy of the removal of cervical SPI by mean of LEEP in office conization. During the period from January 1992 and December 1993, 49 patients with histologically proven HPV infection were treated at the Private Colposcopic Clinic with LEEP. Patients ages ranged from 20 to 49 years old with average 36.1 years, mostly were parous woman. Satisfactory specimens suitable for histologic examination was obtained and in all cases margins of excisions appeared histologically clear of HPV infections patients discomfort was none or minimal in 45 patients (91.8%) and moderate in 4 (8.1%). There were 5 cases (10.2%) of postoperative haemorrhage and 3 cases (6.1%) of minimal cervical infections. The mean base of cone biopsy was 1.43 cm, and ranged from 1.0 to 3.0 cm. The overall cure rate of LEEP was 98% because there was only one confirmed case of treatment failures by loop conization. We concluded that this term results are satisfactory. ",0
1476,7665460,Genetic analysis of the modABCD (molybdate transport) operon of Escherichia coli,"DNA sequence analysis of the modABCD operon of Escherichia coli revealed the presence of four open reading frames. The first gene, modA, codes for a 257-amino-acid periplasmic binding protein enunciated by the presence of a signal peptide-like sequence. The second gene (modB) encodes a 229-amino-acid protein with a potential membrane location, while the 352-amino-acid ModC protein (modC product) contains a nucleotide-binding motif. On the basis of sequence similarities with proteins from other transport systems and molybdate transport proteins from other organisms, these three proteins are proposed to constitute the molybdate transport system. The fourth open reading frame (modD) encodes a 231-amino-acid protein of unknown function. Plasmids containing different mod genes were used to map several molybdate-suppressible chlorate-resistant mutants; interestingly, none of the 40 mutants tested had a mutation in the modD gene. About 35% of these chlorate-resistant mutants were not complemented by mod operon DNA. These mutants, designated mol, contained mutations at unknown chromosomal location(s) and produced formate hydrogenlyase activity only when cultured in molybdate-supplemented glucose-minimal medium, not in L broth. This group of mol mutants constitutes a new class of molybdate utilization mutants distinct from other known mutants in molybdate metabolism. These results show that molybdate, after transport into cells by the ModABC proteins, is metabolized (activated?) by the products of the mol gene(s). ",0
1477,7665582,Synergistic effects of growth factors on the regulation of smooth muscle cell scavenger receptor activity,"Rabbit smooth muscle cells (SMC) express types I and II scavenger receptors (ScR) that are up-regulated by platelet secretion products. In the current studies we investigated the effect of growth factors secreted by platelets on ScR activity in rabbit and human SMC. Platelet-derived growth factor (PDGF BB) and transforming growth factor beta 1 (TGF-beta 1) at 10 ng/ml increased ScR activity in rabbit SMC (by approximately 4- and 2-fold, respectively) but not in human SMC. Epidermal growth factor (EGF) or insulin-like growth factor I (IGF-I) alone had little effect on SMC ScR activity. The growth factors had synergistic effects on ScR activity and on types I and II ScR mRNA expression. In rabbit SMC, PDGF BB, EGF, and TGF-beta 1 together stimulated ScR activity 12-fold. In human SMC, EGF and TGF-beta 1, together with either IGF-I or PDGF BB, stimulated receptor activity approximately 7-fold. Growth factor-mediated induction of ScR activity in rabbit and human SMC was blocked by the tyrosine kinase inhibitor tyrphostin 47, whereas the induction of ScR activity in rabbit but not human SMC was blocked by the protein kinase C inhibitor MDL.29,152. Studies using neutralizing antibodies demonstrated that TGF-beta 1 is the predominant factor in in vitro preparations of platelet secretory products which regulates ScR activity. The growth factors that act synergistically in regulating ScR activity in vitro are all present in atherosclerotic lesions, where they are produced by macrophages, endothelial cells, SMC, and platelets. The data suggest that these growth factors may regulate ScR activity in SMC in vivo and contribute to foam cell formation. ",0
1478,7665726,Neuronal organization of the cochlear nuclei in alligator lizards: a light and electron microscopic investigation,"""The organization of neurons and fibers in the cochlear nuclei of the alligator lizard (Gerrhonotus multicarinatus) was examined with light and electron microscopy. In this species, much is known about the anatomy and physiology of the inner ear including the cochlear nerve, but little is known about the synaptic connections of cochlear fibers on second-order neurons. These data will help to develop general principles addressing the cellular organization of the vertebrate auditory system. Subdivisions of the cochlear nuclei were defined on the basis of their histologic appearance and neuronal composition. Neuron classes were proposed from their light microscopic and ultrastructural features. Nucleus magnocellularis medialis consists of a homogeneous population of neurons called """"lesser ovoid"""" cells. Nucleus magnocellularis lateralis consists of """"greater ovoid"""" and """"small"""" cells. Nucleus angularis lateralis consists of """"spindle"""" cells. Lastly, nucleus angularis medialis contains a population of large neurons called """"duckhead"""" and """"multipolar"""" cells, and a population of smaller neurons called """"bulb"""" and """"agranular"""" cells. These neuron populations are differentially innervated by tectorial and free-standing cochlear fibers that are associated with separate frequency ranges. All neuronal populations except agranular cells were observed to receive synaptic input from cochlear nerve fibers. In nucleus magnocellularis medialis and nucleus angularis medialis, primary afferents form both chemical and electrical synapses with resident neurons. These observations imply that acoustic information is synaptically processed in fundamentally distinct ways in the cochlear nuclei of alligator lizards and distributed along separate neural circuits. Thus, the characteristic structural and functional dichotomy of the alligator lizard inner ear is extended to central auditory pathways by way of cochlear nerve projections. """,0
1479,7666245,Cholesterol consumption alters hepatic sphingomyelin metabolism in rats,"The hypothesis that cholesterol consumption alters hepatic sphingomyelin homeostasis was tested. Rats were fed a purified diet with or without added cholesterol (1 g/100 g) for up to 21 d. In accordance with previous work, cholesterol consumption significantly increased hepatic, whole plasma and VLDL cholesterol concentrations. Dietary cholesterol also raised the amount of sphingomyelin in the VLDL fraction, which was associated with a decrease in hepatic sphingomyelin concentrations. We suggest that the increase in hepatic VLDL secretion after cholesterol consumption imposed an increase in the demand for sphingomyelin in the liver because this phospholipid is a structural component of VLDL. Determination of the activity of two key enzymes of sphingomyelin homeostasis revealed that cholesterol consumption reduced the activity of acid sphingomyelinase in the liver but did not affect that of serine palmitoyltransferase. These enzyme data indicate that the extra sphingomyelin needed after cholesterol loading results from a decrease in the rate of its catabolism in the liver. ",0
1480,7666339,Clinical significance of late peak formation of creatine kinase in patients with acute anterior myocardial infarction after successful reperfusion],"Generally, the time from the onset of acute myocardial infarction (MI) to peak serum creatine kinase (CK) activity is short in patients with acute MI after successful reperfusion. However, in some patients peak CK is observed more than 16 hours after the onset of acute MI despite successful reperfusion. To elucidate the clinical characteristics of patients with late peak CK, CK activity was examined in 55 patients (mean age: 57.5 +/- 10.2 years) with initial acute anterior MI after successful reperfusion. All patients had coronary reflow (TIMI grade 3) within 6 hours after onset of acute MI and no subsequent reocclusion for at least 14 days. The patients were classified into two groups: group E, 41 patients with peak CK observed within 16 hours of onset of acute MI (mean 8.7 hours), and group L, 14 patients with peak CK observed after more than 16 hours (mean 18.7 hours). Although there were no significant differences in the time elapsed between the two groups, the mean peak CK was significantly lower in group L than in group E (2,179 +/- 861 vs 5,379 +/- 2,569 mU/ml, p < 0.01). Well-developed collateral supplies to the infarcted area before reperfusion were observed more frequently in group L (79% vs 24%, p < 0.01). The sum of ST elevation in all leads before reperfusion was lower in group L (12 +/- 7 vs 20 +/- 12 mm, p < 0.01) and additional ST elevation during reperfusion was not observed in group L (0% vs 56%, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1481,7666376,Comparison of arterial potassium and ventilatory dynamics during sinusoidal work rate variation in man,"1. The mechanisms underlying the exercise hyperpnoea have been difficult to define. Recently it has been suggested that exercise ventilation (VE) changes in proportion to changes in arterial potassium concentration ([K+]a). Similar VE and [K+]a time courses following work rate changes have been cited as supporting evidence. This study compared [K+]a and VE dynamics during moderate exercise in man. 2. We observed VE and gas exchange responses in five healthy men to sinusoidal work rate variation between 25 and approximately 105 W. Tests of approximately 30 min duration were performed at sinusoidal periods of 9, 6 and 3 min and in the steady state. In each test, during two or three sine periods, arterial blood was sampled (24 per test) and analysed for [K+] and blood gases. Response amplitude and phase (relative to work rate) were determined for each variable. 3. [K+]a fluctuated in response to sinusoidal work rate forcing with mean-to-peak amplitude averaging 0.15 mmol 1(-1). However, among tests, VE amplitude and phase were not highly correlated with [K+]a (r = 0.36 and 0.67, respectively). Further, average [K+]a amplitude in the 9 and 6 min sinusoidal studies tended to exceed the steady-state amplitude, while average VE amplitude fell progressively with increasing forcing frequency. The dissimilar dynamics of [K+]a and VE seem inconsistent with a major role for [K+]a as a proportional controller of ventilation during non-steady state moderate exercise in man. 4. Among tests, VE and CO2 output (VCO2) amplitude and phase were closely correlated (r = 0.87 and 0.94, respectively). Further, arterial CO2 pressure (Pa,CO2) and arterial pH(pHa) did not fluctuate significantly in ten of twenty and thirteen of twenty studies, respectively. In tests where sinusoidal fluctuation was detected, amplitude averaged 1.1 mmHg and 0.008 units, respectively. Thus VE demonstrated a close dynamic coupling to CO2 output, with consequent tight regulation of Pa,CO2 and pHa. ",0
1482,7666816,Serum lipids and lipoproteins in postmenopausal women receiving transdermal oestrogen in combination with a levonorgestrel-releasing intrauterine device,"To compare the effects of a non-oral combination of a transdermal oestradiol patch (50 micrograms daily) and an intrauterine device (IUD) releasing 20 micrograms of levonorgestrel daily on the serum pattern of lipids and lipoproteins with an established oral regimen of a daily dose of 2 mg of estradiol and 1 mg of noretisterone acetate. An open, randomized study comprised of 40 healthy, early postmenopausal women. During 1 year the concentration of total cholesterol decreased 5.0% in the LNg-IUD group and 10.6% in the oral therapy group; HDL cholesterol decreased 10.9% and 12.8%, respectively, and HDL2 cholesterol decreased 18.1% and 26.9%, respectively. LDL cholesterol values did not change in the LNg-IUD group, whereas a 10.3% decrease was observed in the oral therapy group. Triglyceride values did not change in either group. There were no significant differences in the serum lipoprotein changes between the groups during the treatment. The use of a non-oral regimen of hormone replacement therapy has been advocated to minimize the effect of steroids on the liver. Its effects on the serum pattern of lipids and lipoproteins, however, did not differ significantly from those induced by a continuous oral treatment regimen. ",0
1483,7666874,"The effectiveness of vaccination against influenza in healthy, working adults","BACKGROUND: Although influenza causes substantial morbidity and mortality in all age groups, current recommendations emphasize annual immunization for people at high risk for complications of influenza. We conducted a double-blind, placebo-controlled trial of vaccination against influenza in healthy, working adults. METHODS: In the fall of 1994, we recruited working adults from 18 to 64 years of age from in and around the Minneapolis-St. Paul area and randomly assigned them to receive either influenza vaccine or placebo injections. The primary study outcomes included upper respiratory illnesses, absenteeism from work because of upper respiratory illnesses, and visits to physicians' offices for upper respiratory illnesses. The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses. RESULTS: We enrolled a total of 849 subjects. Baseline characteristics were similar in the two groups. During the follow-up period, consisting of the 1994-1995 influenza season (December 1, 1994, through March 31, 1995), those who received the vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo (105 vs. 140 episodes per 100 subjects, P < 0.001), 43 percent fewer days of sick leave from work due to upper respiratory illness (70 vs. 122 days per 100 subjects, P = 0.001), and 44 percent fewer visits to physicians' offices for upper respiratory illnesses (31 vs. 55 visits per 100 subjects, P = 0.004). The cost savings were estimated to be $46.85 per person vaccinated. CONCLUSIONS: Vaccination against influenza has substantial health-related and economic benefits for healthy, working adults.",0
1484,7666875,Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy,"BACKGROUND: Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma. METHODS: We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE were measured. The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels. RESULTS: Serum total IgE levels were strongly correlated (r = 0.65, P < 0.01) in pairs of siblings concordant for bronchial hyperresponsiveness (defined as a > or = 20 percent decrease in the forced expiratory volume in one second produced by histamine [threshold dose, < or = 16 mg per milliliter]), suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels (r = 0.04, P > 0.10). Analyses of pairs of siblings showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436 (P < 0.001 for a histamine threshold value of < or = 16 mg per milliliter). CONCLUSIONS: This study demonstrates that a trait for an elevated level of serum total IgE is coinherited with a trait for bronchial hyperresponsiveness and that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q. These findings are consistent with the existence of one or more genes on chromosome 5q31-q33 causing susceptibility to asthma.",0
1485,7667162,Predictors of future antihypertensive use in patients with mildly elevated blood pressure,"We prospectively identified predictors of future antihypertensive use in untreated persons age 18-65 years who had elevated diastolic blood pressures of 90-104 mm Hg or systolic blood pressures of at least 140 mm Hg. Data were derived from two independent cohorts completing household surveys conducted in 1981-1984 and 8 years later, as part of the Pawtucket Heart Health Program. Demographics, self-reported health behaviors and beliefs, and physiologic measurements were obtained. Drug use was determined through structured interviews. Analysis of covariance and logistic regression were performed. In the 492 subjects, independent baseline predictors of future antihypertensive use (p < 0.05) included female gender, older age, diastolic blood pressure elevation, self-perceived high blood pressure, and self-reported salt limitation. Antihypertensive use for previously untreated mild hypertension is diverse. Older women with diastolic elevations who are health conscious are most likely to be treated. ",0
1486,7667219,Terminal chronic kidney failure: treatment by dialysis. Confirmations and controversies after 35 years of experience],"""There are currently more than 500,000 people on long-term renal dialysis throughout the world, some have been treated for more than 20 years. Despite this major success in the treatment of chronic renal failure, many unsolved problems remain, often leading to controversial debate. Should dialysis be """"adequate"""" or """"optimal""""? To answer this question results are evaluated on the basis of mid-term and long-term survival rates, morbidity and quality of life criteria including psychological tolerance. While the need for a reliable vascular access and an appropriate dialysis system is obvious for haemodialysis, debate has focused on the optimal dialysis time; total weekly duration under 10-11 hours is sometimes advocated. Nephrologists have emphasized that peritoneal dialysis frees patients from the risk of vascular puncture and the need for anticoagulation while providing better haemodynamic stability. The higher morbidity and risk of infectious complications are however major drawbacks of peritoneal dialysis. Both techniques may require use of recombinant human erythropoietin and daily protein intake of about 1.2 g/kg body weight is mandatory. Despite all the progress made in dialysis concepts and technical applications, several factors may lead to """"inadequate"""" dialysis in some patients. Some, such as insufficient blood flow, are subject to corrective measures, others are cost-related. What is the optimal duration of a dialysis session? How often should dialysers be reused? Are bio-compatible membranes or systems for producing sterile haemodialysis fluid cost-effective? Finally, our understanding of the uraemic toxicity syndrome is still insufficient for a totally satisfactory treatment of renal failure. Further advances in technology and in our understanding of the pathophysiology of renal function and dialysis are needed to reduce morbidity of patients treated for end-stage chronic renal failure and improve their quality of life. """,0
1487,7667404,Peripheral 3-hydroxybutyrate and food intake in a model of dietary-fat induced obesity: effect of vagotomy,"We have examined the effect of peripheral 3-hydroxybutyrate injections on food intake and the contribution of the vagus nerve in the resistance to dietary fat-induced obesity in a rodent model. S 5B/Pl rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to reverse light cycle. Food intake was measured for 24 h following the injection of 3-hydroxybutyrate, lactate, or glycerol (all 5 mMol/kg0.75, SC) at the onset of dark. Three-hydroxybutyrate reduced food intake (p < 0.0001) in S 5B/Pl rats only. Lactate reduced food intake slightly (p < 0.009) in both strains and glycerol had no effect on food intake. In a second experiment, S 5B/Pl and Osborne-Mendel rats were adapted to a high-fat diet and were then subjected to either selective hepatic vagotomy or sham operation. Vagotomy had no effect on weight gain of Osborne-Mendel rats but allowed weight gain in S 5B/Pl rats (p < 0.0001). Even in vagotomized S 5B/Pl rats, however, blood 3-hydroxybutyrate levels were inversely associated (r = -0.50) with food intake. These data suggest that the hepatic vagus nerve may contribute to the resistance of S 5B/Pl rats to dietary-fat induced obesity, but the data do not rule out a strictly central role for the regulation of food intake by 3-hydroxybutyrate in this strain. ",0
1488,7667436,Effects of extraneous stimuli on social cue perception in schizophrenia,"Competing hypotheses that explain the effects of emotionally arousing, extraneous auditory stimuli on the social cue perception of schizophrenic patients were examined in this study: (1) extraneous arousing stimuli enhance patients' cue perception; (2) extraneous stimuli distract patients, and cue perception is diminished. Twenty-five patients with DSM-III-R diagnoses of schizophrenia completed a cue-perception task in which half of the videotaped vignettes included in the task were presented with simultaneous extraneous stimuli and half were not. Item difficulty and consistency across extraneous stimuli conditions were matched on standardization and cross-validation samples. Results showed that schizophrenic subjects were significantly more sensitive to cues when exposed to extraneous stimuli, thereby supporting the first hypothesis. This effect was also observed in a subgroup of schizophrenic subjects who demonstrated a distraction decrement on another test of short-term recall. The presence of extraneous stimuli interacted with perception of abstract cues; that is, schizophrenic subjects were particularly better at perceiving abstract cues when extraneous stimuli were presented simultaneously. Future research needs to determine characteristics of extraneous stimuli that enhance cue perception. ",0
1489,7667833,Thrombolytic treatment with tissue-type plasminogen activator (t-PA) containing liposomes in rabbits: a comparison with free t-PA,"In this study, we aimed at improving the therapeutic index of tissue-type Plasminogen Activator (t-PA) as thrombolytic agent in the treatment of myocardial infarction. Liposome-encapsulated t-PA was tested in a rabbit jugular vein thrombosis model: administration of free t-PA (t-PA) as a bolus injection in the ear vein was compared to a similar administration of liposomal t-PA (t-PA-lip), liposomal t-PA in plasminogen-coated liposomes (Plg-t-PA-lip), a mixture of free t-PA and empty liposomes (t-PA+ empty lip) and a saline-blank (blank) in terms of thrombolytic activity and side effects. Liposomal t-PA (t-PA-lip/Plg-t-PA-lip) showed a significantly better thrombolysis efficiency than equimolar doses of free t-PA (t-PA/ t-PA+ empty lip): about 0.24 mg/kg of liposomal t-PA practically equalled the lysis-activity of a dose of free t-PA of 1.0 mg/kg (t-PA1mg/kg). On the other hand, liposome encapsulation did not affect the systemic activation of alpha 2-antiplasmin and plasminogen by t-PA. We conclude that for this model an improvement in thrombolytic efficacy of t-PA is achieved by liposome encapsulation of t-PA. As t-PA-lip and Plg-t-PA-lip -treatment induced similar results, targeting of liposomal t-PA by coupled glu-Plg remains a topic to be optimized in future studies. ",0
1490,7668011,Current status of malaria prevention with drugs],"""Malaria chemoprophylaxis does not rely on causal aspects but is based on suppression of clinical symptoms after infection has taken place. Chloroquine remains the standard for infection against the """"benign"""" forms of malaria. Due to the widespread chloroquine-resistance of Plasmodium falciparum a chemoprophylaxis will consist of mefloquine or chloroquine combined with proguanil. The decision to take a chemoprophylaxis is based on the knowledge of risk of malaria transmission, effectiveness and side effects of the drugs, and compliance of the traveller. Emergency self-treatment may be helpful in various situations. """,0
1491,7668422,Accidental subdural extra-arachnoid catheterization during epidural analgesia in obstetrics],"The authors describe a case of accidental catheterization of the subdural extra-arachnoid space during epidural analgesia for labour. The epidural catheter had been inserted at the L3-L4 interspace without any problem. A severe hypotension occurred 90 min after the onset of analgesia. A T4 upper sensory level was associated with a complete motor blockade. Total spinal anaesthesia was suspected but ruled out because of delayed onset of analgesia. Extensive epidural anaesthesia was also eliminated as the local anaesthetic dose (15 mL of bupivacaine 0.125%) was not excessive for this patient. After delivery, a water-soluble contrast medium (10 mL of Omnipaque 180) was injected through the catheter and subsequent radiograph of spine showed subdural spread of the contrast medium. This complication might occur more frequently than usually thought and may be life-threatening. Anaesthetic management is discussed in the case of Caesarean section during labour. ",0
1492,7668813,Fluorescent in situ hybridization assessment of chromosome copy number in gestational trophoblastic disease,"The concurrence of congenital trisomy 8 mosaicism and gestational trophoblastic disease in a forty-two-year-old Gravida IV, Para IV female has been described. In contrast to other cases in the literature, this patient had no additional confounding chromosomal abnormalities other than trisomy 8. To the best of our knowledge, this was the only reported case of constitutional trisomy 8 mosaicism associated with gestational trophoblastic disease, a rare gynecological disease entity in and by itself. The present report describes fluorescent in situ hybridization (FISH) studies for assessing chromosome 8 copy number on various patient tissues. The results of the FISH studies are compared with each other and with the original cytogenetic studies. It is concluded that the overall frequency of trisomy 8 cells is lower in the FISH studies using archival material than in the original conventional cytogenetic studies. This is true for the uterus and lung tissues with a metastatic tumor. The possible reasons for the somewhat different frequencies found between conventional cytogenetics via GTG-banding and interphase cytogenetics via FISH are discussed. ",0
1493,7668832,Genotype-phenotype correlation in adult-onset acid maltase deficiency,"We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult-onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(-13T --> G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Deterioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of alpha-glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of alpha-glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years. ",0
1494,7668916,A comparative study of experimental caecal amoebiasis and the evaluation of amoebicides,"Caecal amoebiasis models (mouse, hamster and rat) were compared for amoebic infection and chemotherapeutic evaluation using a pathogenic strain of Entamoeba histolytica of human origin. Caecal infection in the hamster was of the acute type, with a large number of amoebae in the caecal tissue, whereas the amoebae in rats were seen in the lumen, on the mucosal surface. Amoebic lesions in the mouse caecum were of moderate severity. The mouse model responded to both metronidazole (tissue amoebicide) and diloxanide furoate (luminal amoebicide), whereas the hamster model only responded well to metronidazole and the rat model only to diloxanide furoate. Using the mouse as a primary screening model, a new oxadiazole compound, BTI 2405E, was found to have tissue and luminal amoebicidal activity. In rodent caecal models, a single dose of BTI 2405E was found to be more effective than one of metronidazole or diloxanide furoate. The mouse model appears to be the most useful for primary screening of anti-amoebic compounds. ",0
1495,7669117,The effect of the geometry of the tibia on prediction of the cruciate ligament forces: a theoretical analysis,"This paper attempts to highlight the importance of the tibial geometry in the prediction of forces along the cruciate ligaments. A two-dimensional model of the knee which comprises the femur, the tibia and the cruciates was used. The model was subjected to an external antero-posterior force and an external axial compressive force. The analysis showed that, with a flat tibial plateau, the tension arising along either cruciate as a result of the application of an external antero-posterior force is determined solely by the inclination of the ligament to the direction of that force; it is independent of the magnitude of the external axial compressive force. A curved tibial plateau modifies the tension along either cruciate, and in the absence of an axial compressive load on the joint small changes in the geometry of the tibial surface cause slight changes (increase/decrease) in the tension. However, these changes can become considerable when a large axial compressive load is applied on the joint. A concave tibial plateau, where the tangent to the surfaces at the point of contact is inclined to the direction of the same external antero-posterior force by 7.8 degrees, can reduce the tension along either cruciate to zero, if a sufficiently large axial compressive load is applied on the joint. It was shown that the convexity of the lateral tibial plateau can provide an important protective function for the posterior cruciate ligament (PCL) at extreme positions of flexion. The analysis showed that the PCL should experience a larger force than that experienced by the anterior cruciate ligament (ACL) and hence explain why the former should be the stronger of the two. Finally, a hypothesis is proposed suggesting that bone remodelling may occur in the tibiae of the older people, causing them to become more concave with age and as a consequence provides greater protection to the cruciates in the aged, in order to compensate for decreasing strength in the older person. ",0
1496,7669179,Central and peripheral analgesic agents: chemical strategies for limiting brain penetration in kappa-opioid agonists belonging to different chemical classes,"Over the past decade there has been great interest by the pharmaceutical industry in the development of novel analgesics which act by activation of central kappa-opioid receptors. However, in view of the spectrum of unwanted CNS effects associated with such agents, recent efforts have been focused on peripherally-selective compounds with limited ability to cross the blood-brain barrier (BBB). In this review, the authors consider the chemical strategies and associated synthetic procedures employed by various research groups to produce hydrophilic compounds with retained kappa-opioid agonist activity. Physico-chemical (clogP, delta logP) and biological methods (antinociception following administration by peripheral and central routes; ex-vivo binding to detect plasma and brain levels of the drugs) utilized to assess brain penetration are described and compared. Overall, in-vivo ratios correlate better with delta logP values than with clogP. ",0
1497,7669180,Effect of alteration of the heterocyclic nucleus of ILV on its isoform selectivity for PKC. Palladium catalyzed route to benzofuran analogues of ILV,"A palladium catalyzed route for the preparation of several benzofuran analogues of the PKC activator indolactam V (ILV) is described together with the ability of these compounds to activate the isoforms of PKC. The benzofuran analogues of ILV are shown to activate PKC with a slightly different pattern of isotype selectivity than ILV or 7-n-octyl-ILV. Moreover, in an examination of the effect of stereochemistry at the C-14 center of the teleocidins on PKC binding activity, a clear preference for R-stereochemistry at the C-14 center was found, thus providing additional verification of previously published structural correlations between the families of PKC activators. ",0
1498,7669260,Adverse effects of monobactams and carbapenems,"Monobactams and carbapenems are 2 classes of beta-lactam antibiotics that were introduced in the 1980s. This review considers the monobactam aztreonam and the carbapenems imipenem and meropenem. Imipenem is administered together with cilastatin, which inhibits the enzymatic breakdown of imipenem in the kidney. The antibacterial activities of these drugs are quite different from older beta-lactams. Aztreonam is directed towards aerobic Gram-negative bacteria, especially Pseudomonas aeruginosa, while imipenem and meropenem are active against both aerobic and anaerobic Gram-positive and Gram-negative bacteria. Thus, these drugs should be reserved for patients who have a special need for them. They are also structurally different from older beta-lactams and possess different adverse drug reaction profiles. It was initially suggested that aztreonam would be less immunogenic than previous beta-lactams because reactive breakdown products acting as haptens are less likely to be formed. Clinical reports now support this assumption, and, in particular, cross hypersensitivity between aztreonam and other beta-lactams seems to be rare which makes the drug a useful therapeutic alternative. However, hypersensitivity to aztreonam does occur. The predominant concern in terms of adverse reactions to imipenem/cilastatin is the increased tendency to cause seizures compared with other beta-lactams. The risk of producing a seizure is highly associated with inadequate dose adjustment in relation to kidney function. If appropriate care is taken, seizures occur in less than 1% of patients treated. However, it is possible that concomitant administration of other drugs with neurotoxic profiles (e.g. theophylline and cyclosporin) given in overdose, may increase the risk of seizures.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1499,7669358,The efficacy of two comprehensive perinatal programs on reducing adverse perinatal outcomes,"Through the collaboration among University of California at Berkeley School of Public Health, Samuel Merritt College, and a private nonprofit, community-based medical center, the adequacy of two perinatal programs was assessed based on the pregnancy outcomes of teenaged Medi-Cal clients. Historical data from June 1991 to June 1992 were compiled on the pregnancy outcomes of 312 Medi-Cal clients, 12-18 years of age, delivering at the study medical center in Oakland, California. The effect of enrollment in two special perinatal programs, Comprehensive Perinatal Services Program (CPSP) and a school-based program, the Comprehensive Teenage Pregnancy and Parenting Program (CTAPPP), on the occurrence of adverse perinatal outcomes was examined. Adverse perinatal outcomes were defined as the occurrence of one of the following: low birthweight (< 2,500 grams), gestational age less than 37 weeks, or admission to the neonatal intensive care unit (NICU), not related to congenital syphilis. The percentage of teens experiencing adverse perinatal outcomes was 10.9% at the study hospital. No significant association was observed between CTAPPP enrollment and reduced adverse perinatal outcomes, but CPSP enrollment was associated with reduced adverse perinatal outcomes. This association persisted after controlling for potential confounders, including substandard prenatal care, which were also found to be risk factors for adverse perinatal outcomes. Enrollment in both programs simultaneously was not associated with a reduction in adverse outcomes. The significant association between CPSP enrollment and reduced adverse perinatal outcomes indicates that a more comprehensive prenatal program may be beneficial in improving birth outcomes, specifically among high-risk teenage populations.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1500,7669541,Targeting adult smokers through a multi-ethnic public school system,"""In a unique approach to utilizing an existing intervention, """"opportunistic"""" and targeted school-based strategies were used to enroll 446 adults into a tailored preventive health program featuring a health screening and smoking-cessation intervention. Implemented through a public school district serving a multi-ethnic low-to-middle income urban community, subjects in this randomized trial were interviewed at enrollment and at three-, six-, and 12-month follow-up, and rescreened at 12 months, to assess changes in smoking-related knowledge, attitudes, and practices. Using conservative assumptions, self-reported ever-quit rates and continuous abstinence rates of 57.5% and 2.6%, respectively, were achieved across groups; point-prevalence abstinence rates were 13.2%, 12.9%, and 10.3% at three, six, and 12 months. The study examines issues relevant to smoking status and stages of change in this population. The role of the school in increasing access to needed health programming in underserved communities is explored. """,0
1501,7669644,"Malignancy-associated multicentric reticulohistiocytosis: a clinical, histological and immunophenotypic study","The clinical, histopathological, and immunophenotypic characteristics of four cases of malignancy-associated multicentric reticulohistiocytosis (MMR) and one case each of diffuse cutaneous reticulohistiocytosis (DCR) and isolated reticulohistiocytoma (IR), are reviewed. In all four cases of MMR the cutaneous lesions and joint manifestations were judged to be concurrent with the diagnosis of malignancy. Malignancies observed included one case each of pancreatic adenocarcinoma, squamous cell carcinoma of the lung, metastatic melanoma and intraperitoneal grade 4 mucinous adenocarcinoma of uncertain origin. Histologically, all six cases demonstrated the typical changes of a diffuse histiocytic and multinucleated giant cell infiltrate with ground-glass cytoplasm, predominantly in the upper dermis. Immunohistochemical investigation revealed strong cytoplasmic staining with KP-1 (CD68) in all six cases. Prominent membrane staining was noted with leucocyte common antigen (CD45) in four cases (three MMR and one IR), and CD3 in four cases (three MMR and one IR). Weak membrane staining with Leu 22 (CD43) was noted in two MMR cases. UCHL-1 (CD45RO), L26 (CD20), S-100 and BerH2 stains were all uniformly negative. A prominent number of perilesional factor XIIIa-positive dermal dendrocytes were noted in the single case of IR, in contrast with the other five cases. We conclude that MMR, DCR and IR are histopathologically and immunohistochemically similar. The pattern of immunoreactivity observed is consistent with a monocyte-macrophage origin of the infiltrating tumour cells. We emphasize the paraneoplastic association of multicentric reticulohistiocytosis, which we have observed in four of 13 such cases (31%) evaluated at our institution. ",0
1502,7669648,Treatment of urticaria pigmentosa using interferon alpha,"Long-term treatment with interferon alpha (IFN-alpha) has recently been shown to reduce the bone marrow infiltrate and cutaneous lesions in systemic mast cell disease. We therefore administered this cytokine to six patients with urticaria pigmentosa for up to 12 months, using subcutaneous injections of 5 x 10(6) U, initially five times, and subsequently three times a week. The generally well-tolerated therapy resulted in marked improvement of the cutaneous symptoms, especially in three of the patients who suffered from very severe pruritus. Two of the patients with bone marrow infiltration showed normal findings after treatment. However, in none of the patients was there any change in the skin lesions, or decrease in the degree of cutaneous mast cell infiltration, as evidenced by light and electron microscopic examination. These findings indicate that IFN-alpha is highly effective in the control of symptoms, but otherwise does not influence the cutaneous lesions of urticaria pigmentosa. ",0
1503,7669825,"Immunoendocrine aspects of major depression. Relationships between plasma interleukin-6 and soluble interleukin-2 receptor, prolactin and cortisol","Recently, a complete bidirectional circuit between the immune and neuroendocrine systems has been documented. Previous reports from this laboratory have shown that there are complex reciprocal relationships between immune and hypothalamic-pituitary-adrenal (HPA)-axis function in major depression. To further examine the immune-endocrine relationships, this study investigates plasma baseline cortisol and prolactin secretion in relation to plasma interleukin-6 (IL-6) and soluble IL-2 receptor (sIL-2R) levels in 34 healthy controls and 56 major depressed patients. There were significant positive correlations between IL-6 or sIL-2R and plasma cortisol in major depressed subjects and in the combined group of major depressed and healthy subjects. There were also significant positive correlations between plasma prolactin and sIL-2R concentrations in major depressed subjects and in the combined groups of normal and major depressed subjects. ",0
1504,7670560,Chronic intramedullary infusion of prostaglandin E2 stimulates bone formation both in the bone marrow and in the periosteum,"Prostaglandin E2 (PGE2) has a potent bone resorbing activity in vitro, but some recent studies have shown that PGE2 stimulates bone formation in vivo. The effects of PGE2 on the bone are therefore still controversial. We attempted to reveal the effects of PGE2 on bone in vivo more directly; we injected PGE2 continuously into the bone marrow and onto the periosteum and examined the local effects of PGE2 histologically or by bone densitometry. Following PGE2 infusion into the bone marrow, new bone was formed in the bone marrow around the infused site and following PGE2 infusion onto the periosteum, extensive periosteal bone formation was observed. Bone mineral content was also increased significantly in the PGE2 infused bones. The administration of cyclic AMP did not mimic the effects of PGE2. In contrast to in vitro experiments, the in vivo effect of PGE2 is predominantly to produce bone. ",0
1505,7670804,"Results of microbiological examination of 12,064 blood cultures in patients with suspected bacteremia]","During 1991 to 1993 12,064 blood cultures from patients with suspected bacteraemia were examined in a newly established Microbiology Department of the Brno-Bohunice Faculty Hospital. A total of 1,790 (14.8%) blood cultures were positive, 746 (6.2%) were contaminated. The incidence of positive blood cultures was 7.1/1,000 patients admitted in 1991, 10.0/1,000 in 1993. From the positive blood cultures 853 different microbes were isolated: 486 gram-negative bacteria (56.9%), 315 gram-positive ones (36.9%), 9 anaerobes (1.1%) and 44 yeasts (5.2%). In 69 cases (3.8%) more than one agent was recovered from one blood culture. The most frequently isolated microbes were gram-negative non-fermenting rods other than P. aeruginosa (15.7%), E. coli (12.1%), S. aureus (11.4%) and coagulase-negative staphylococci (10.1%). From direct inoculation of blood 22.6% blood cultures were positive, and another 55.3% positive after 1-day growth in broth. In 1993 there were 306 patients with positive blood cultures; in those blood for the culture was collected during the first 48 hours after admission: in 76 (32.7%) admitted to medical wards, in 7 (9.6%) to surgical wards. The mortality of patients with positive blood cultures was 23.5%. ",0
1506,7670851,Removal and efflux of copper from Cu-metallothionein as Cu/tetrathiomolybdate complex in LEC rats,"Tetrathiomolybdate (TTM) removes copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of LEC rats (Long-Evans rats with a cinnamon-like coat color). The first step in the removal of Cu from Cu-MT has been shown to form a complex between MT and TTM through (MT)-S-Cu-S-(TTM) bridges (referred to as MT/TTM complex). Additional TTM was demonstrated to remove Cu from MT/TTM complex as the second step to form Cu/TTM complex by liberating MT. The Cu/TTM complex binds specifically to albumin in serum and to high molecular weight proteins in the absence of albumin, and is assumed to be a form of Cu for efflux by the treatment with TTM. ",0
1507,7670999,Presence of the long and the short forms of Bcl-X in several human and murine tissues,"Bcl-X protein, which is related to Bcl-2, is present essentially in the nervous system and the immune system, under 2 different forms: Bcl-XL, like Bcl-2, is able to prevent apoptotic death of cultured lymphocytes; in contrast, Bcl-XS, which differs from the former one by a deletion of 63 amino acids in the region of greatest homology between Bcl-XL and Bcl-2, is unable to prevent this apoptotic death and even counteracts the protective effect of Bcl-2. It has been reported that the adult nervous system contains exclusively the RNA encoding Bcl-XL whereas the immune system would contain exclusively the RNA encoding Bcl-XS. We show here, by using reverse transcription coupled to PCR, that adult rat brain contains not only the RNA encoding Bcl-XL but also the RNA encoding Bcl-XS. Similarly we show that human lymphocytes, whether infected or not by the HIV, contain both forms of Bcl-X messenger RNA (mRNA). Furthermore we have observed that both forms of mRNA are present in adult rat liver and in cultured mouse hepatocytes. All these results have been confirmed by hybridizing the PCR products transferred to a nylon membrane with a probe specific of Bcl-XL or a non discriminative probe. ",0
1508,7671255,p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells,"To study the pathways associated with genomic instability in cancer, we examined UV-induced and spontaneous mutagenesis in clonal cell lines expressing human papillomavirus (HPV) proteins, either high-risk (HPV16) E6 or E7 or low-risk (HPV11) E6, in comparison to the parental RKO cells, a colon carcinoma cell line expressing only normal p53. High-risk E6 and E7 bind and functionally inactivate tumor suppressor proteins p53 and Rb, respectively, and both disrupt the G1 arrest in response to DNA damage. Low-risk HPV E6 proteins bind p53 with much lower affinity than high-risk E6 and fail to mediate p53 degradation or to disrupt the G1 checkpoint. We found that cells expressing HPV16 E6 had reduced survival and increased mutagenesis at the hprt locus when treated with low doses of UV. However, this analysis was complicated by the unexpected observation of a very high background of spontaneous mutagenesis in the unirradiated cells expressing the HPV16 E6 gene. Fluctuation analysis revealed a 5-fold elevated mutation rate in the cells expressing HPV16 E6. HPV11 E6 conferred a 2-fold elevation in the mutation rate, but HPV16 E7 had no effect. The increased spontaneous mutagenesis, therefore, appeared to be mediated by p53 inactivation and to be independent of Rb (which acts downstream of p53 in the G1 arrest pathway following DNA damage). Taken together, these findings suggest that the effect of p53 inactivation on spontaneous mutagenesis is manifested at the level of DNA repair, recombination, or coupling of transcription with one of these processes instead of by an alteration in G1 arrest. ",0
1509,7671642,Insulin treatment affects the behaviour of Tetrahymena pyriformis and T. malaccensis,"Populations of Tetrahymena pyriformis and T. malaccensis were treated with insulin, then washed and treated again 24 h later. The ethograms of controls, treated, washed and retreated populations were drawn. Statistical analysis showed that T. pyriformis was affected by insulin more severely than T. malaccensis. In T. pyriformis the effects of the 'memory' of the first treatment seem to be more relevant than those of the first and second treatments themselves. On the contrary in T. malaccensis treatments with insulin per se seem to affect the behaviour more strongly than the memory of the first treatment itself. These results are discussed in detail in the context of previous work. ",0
1510,7671978,"Double-blind, placebo-controlled, randomized, crossover trial of high-dose methylprednisolone in patients with chronic progressive form of multiple sclerosis","A double-blind, placebo-controlled, randomized crossover trial of high-dose methylprednisolone (MP) was performed in 35 patients with a primarily chronic progressive form of multiple sclerosis as defined clinically according to Poser's criteria. At time 0 of every course of treatment (1 g MP administered i.v. daily for 5 days followed by oral prednisone tapering over 4 days, or placebo) and at 10, 30 and 90 days thereafter, each patient underwent psychometric tests and was clinically tested according to Kurtzke's Expanded Disability Status Scale (EDSS). The disability pattern of most patients who were treated with placebo either worsened or did not change. A statistically significant improvement (p < 0.001) of EDSS in MP-treated patients was recorded. The improvement mainly concerned the pyramidal, cerebellar and sensitive disorders; it was already evident at the first clinical follow-up and lasted for 3 months from the beginning of the treatment. No frequent and/or important side effects were detected throughout the trial. ",0
1511,7672462,A long perspective on childhood multiple sclerosis,"Twenty-eight patients, all of whom developed multiple sclerosis before 16 years of age and all from a well-defined geographical population (Grampian, north-eastern Scotland) were retrospectively studied. Age at presentation, presenting features and interval between first and second attacks are discussed. Follow-up ranged from three to 47 years and adult categorisation was applied to outcome. This suggested that on the whole, childhood-onset multiple sclerosis is a less aggressive disease than its adult counterpart. ",0
1512,7672529,Idiopathic acute pancreatitis and sarcoidosis,"Pancreatic involvement is rare in sarcoidosis. We describe a 30-year-old man who had two episodes of acute pancreatitis within one month with no current aetiology. Diagnosis of sarcoidosis was based on the presence of bilateral mediastinal adenopathies, alveolar lymphocytosis on bronchoalveolar lavage and biopsy of an enlarged lymph node showing multiple granulomas. This case and five others previously reported in the literature suggest the diagnosis of sarcoidosis should be considered in apparently acute idiopathic pancreatitis. ",0
1513,7672699,Cisplatin-based chemotherapy in dysgerminoma of the ovary: thirteen-year experience at the Institut Gustave Roussy,"Twelve patients with dysgerminoma of the ovary were treated with various cisplatin-based chemotherapy regimens. Chemotherapy was delivered as primary postoperative treatment in 6 patients. All of them are free of disease 18 to 180 months after initiation of chemotherapy. Six other patients received chemotherapy as part of the salvage treatment for recurrent disease. Three failures were observed: one toxic death, one primary failure, and one subsequent relapse. Three patients remain free of disease 50 to 95 months after initiation of chemotherapy. The role of chemotherapy in early- and advanced-stage dysgerminoma of the ovary is reviewed. ",0
1514,7673057,A review of the significance of animal food products as potential pathways of human exposures to dioxins,"The polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are groups of compounds with similar chemical and toxicological properties. Carcinogenicity was considered the most serious toxic end point when setting previous regulatory policies, but recent concerns have focused on the possible endocrine-disrupting activities of the dioxins. Toxicity is related to the 2,3,7,8 pattern of chlorine substitution, a pattern that also leads to chemical and metabolic stability. Dioxins are practically insoluble in water and concentrate in lipids of biological systems, leading to low background concentrations in fat of the general human population. Major environmental sources of dioxins are emissions from industrial chlorination processes and combustion of materials containing chlorine. Inhalation and water have been ruled out as significant exposure pathways, which suggests that food is the primary source. Pathways of entry into food chains are atmospheric transport of emissions and their subsequent deposition on plants, soils, and water. The major food sources seem to be fat-containing animal products and some seafoods. This conclusion is based on evaluations of potential environmental pathways involving dioxins and related compounds. Generally, dioxins and other lipophilic compounds are not taken up and translocated by plants, so residues in foods and feeds derived from seeds should be negligible. Animals on high-roughage diets, or those that ingest contaminated soil, are the most likely to accumulate dioxin residues from the environment. The conclusion that animal products are a major source of human exposure requires verification by appropriate food sampling programs and animal metabolism studies. If it is desirable to reduce human exposure to dioxins via the food supply, reduction of sources would be a more effective strategy than changing agricultural practices and food consumption patterns. ",0
1515,7673058,Effects of energy source and food flavor on conditioned preferences in sheep,"Livestock and range managers would have a powerful tool to direct utilization and modify plant communities if animals could be conditioned to eat specific foods or plants. We attempted to condition preferences for a low-quality forage through nutrient loading. Sheep were fed licorice or orange-flavored straw pellets then were gavaged with glucose or propionate (.381 Mcal, which amounted to approximately 13% of the daily maintenance energy requirement) or water. Four groups of ewes (n = 4) were arranged in a cross-blocked design such that each group received a unique energy/flavor combination: 1) propionate+licorice, 2) propionate+orange, 3) glucose+licorice, or 4) glucose+orange. On alternate days, each group received the other flavor plus water to create an internal control. At the end of 8 d of conditioning, preference for the two flavors was measured by two-choice preference tests. A second trial was conducted for 4 d in which the energy level was doubled to .762 Mcal. Low energy levels of either glucose or propionate did not create significant preferences. Propionate at the low-level caused satiety but at the high level conditioned an aversion to both flavors. This high level of propionate apparently caused malaise that was then associated with the taste of the flavors. The high level of glucose conditioned a preference. The high glucose treatment increased rumen microbial mass, the nutrients of which would have been absorbed in the lower gastrointestinal tract, and may have indirectly provided the positive nutrient feedback required to form a preference. There was a flavor preference for orange that was independent of the energy supplements. ",0
1516,7673152,p21ras as a common signaling target of reactive free radicals and cellular redox stress,"Reactive free radicals have been implicated in mediating signal transduction by a variety of stimuli. We have investigated the role of p21ras in mediating free radical signaling. Our studies revealed that signaling by oxidative agents which modulate cellular redox status, such as H2O2, hemin, Hg2+, and nitric oxide was prevented in cells in which p21ras activity was blocked either through expression of a dominant negative mutant or by treating with a farnesyltransferase inhibitor, as assessed by NF-kappa B binding activity. Furthermore, the NF-kappa B response to these oxidative stress stimuli was found to be enhanced when cells from the human T cell line, Jurkat, were pretreated with L-buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis. We directly assayed p21ras and mitogen-activated protein kinase activities in Jurkat cells and found both of these signaling molecules to be activated in cells treated with the redox modulating agents. Blocking glutathione synthesis made cells 10- to 100-fold more sensitive to these agents. Finally, using recombinant p21ras in vitro, we found that redox modulators directly promoted guanine nucleotide exchange on p21ras. This study suggests that direct activation of p21ras may be a central mechanism by which a variety of redox stress stimuli transmit their signal to the nucleus. ",0
1517,7673401,Spontaneous 24-hour growth hormone profiles in prepubertal small for gestational age children,"To evaluate spontaneous GH secretion in terms of both secretory rate and pulsatile pattern in prepubertal children born small for gestational age (SGA) and still short (below -2 SD scores) at or after 2 yr of age, 24-h GH profiles were investigated in 106 such patients (75 boys and 31 girls; mean age, 7.3 +/- 0.3 yr), 14 of whom (10 boys and 4 girls) had Silver-Russell syndrome. The 24-h secretion of GH was compared with that in 2 reference populations of prepubertal children born at an appropriate size for gestational age (AGA): 179 short healthy children (143 boys and 36 girls; mean age, 10.2 +/- 0.2 yr) and 73 children of normal stature (54 boys and 19 girls; mean age, 10.4 +/- 0.3 yr). Plasma GH concentrations from the 24-h profiles were transformed to GH secretion rates by means of a deconvolution technique. For the SGA children, the mean GH secretion rate was 0.3 U/24 h, with a positive correlation with age, whereas for the reference groups it was higher, 0.5 U/24 h for the short children (P < 0.05) and 0.7 U/24 h for the children of normal stature (P < 0.001). Interestingly, the GH secretion rate correlated positively with weight for height, expressed as the SD score, in girls born SGA (r = 0.40; P < 0.05), whereas an inverse correlation was found for the short AGA girls (r = -0.44; P < 0.05). The mean baseline GH level in the SGA children correlated negatively with age (r = -0.53; P < 0.01), with the highest values found for children younger than 6 yr of age. On the average, 8 GH peaks/24-h period were found in all groups of children, and using Fourier time-series analyses, a similar rhythmicity was found in all groups. In the SGA group, the children younger than 6 yr of age had more GH peaks with lower amplitudes than the older children. It is concluded that children born SGA and still short at or after 2 yr of age spontaneously secrete less GH than healthy children of short stature born AGA. Both of these subgroups of prepubertal short children, however, secrete less GH than children of normal height. This finding might in part explain the growth failure in SGA children. Moreover, in the youngest SGA children (2-6 yr of age) there was another pattern of GH secretion, with a high basal GH level, a low peak amplitude, and a high peak frequency.(ABSTRACT TRUNCATED AT 400 WORDS) ",0
1518,7673700,T cell recognition of the immunodominant Sendai virus NP324-332/Kb epitope is focused on the center of the peptide,"The CTL response to Sendai virus in C57BL/6 mice is directed almost exclusively to a single H-2Kb-restricted epitope derived from the virus nucleoprotein, NP324-332 (FAPGNYPAL). We have previously shown that the repertoire of T cells elicited by this epitope following primary Sendai virus infection is very diverse. The current experiments were undertaken to determine how a diverse array of TCR are able to interact with a single class I epitope. Crystallographic analysis of NP324-332 bound to Kb has shown that the side chains of peptide residues F1, G4, N5, and A8 protrude toward the solvent and are potentially available for recognition by the TCR. Notably, the N5 residue protrudes prominently from the peptide-binding site due to its localization on a bulge in the center of NP324-332. To determine the importance of these residues for T cell recognition, we analyzed the response of a large panel of hybridomas to NP324-332 analogues substituted at these four positions. The data suggested that there is dominant recognition of the central G4 and N5 residues at the center of the peptide. However, individual hybridomas exhibited distinct patterns of fine specificity for residues F1 and A8, in that they were dependent on one, both, or neither of these residues for recognition of NP324-332. These data are consistent with a critical role for the G4 and N5 residues in governing NP324-332/Kb recognition by T cells and may have implications for T cell recognition of class-I restricted epitopes in general. ",0
1519,7674171,Evaluation of tissue adhesives in closure of scleral tunnel incisions,"Using a biomechanical wound strength model, we compared the efficacy of cyanoacrylate and fibrin glues used to close scleral tunnel incisions. Scleral tunnel incisions were made in four groups of rabbits: (1) traditional self-sealing incision, (2) modified non-self-sealing incision, (3) method 2, closed with cyanoacrylate glue, or (4) method 2, closed with fibrin glue. Overall, Groups 1 and 4 showed the least clinical reaction, the slightest decrease in intraocular pressure (which recovered to baseline by day 7), and the most significant recovery of postoperative astigmatism. Initially, the bursting pressure in Groups 1 and 3 was statistically the highest (P < .005). By day 3, wound strengths in Groups 1 and 4 were comparable. Bursting pressure decreased in Groups 2 and 3 by day 7. Our results indicate that clinical responses, intraocular pressure, induced astigmatism, and ultimately wound strength were comparable in fibrin-glue-closed scleral pocket and sutureless self-sealing cataract incisions. Although cyanoacrylate glue cures immediately and initially demonstrates a strong adhesive quality, it causes a severe inflammatory response that inhibits subsequent collagen remodeling. Fibrin tissue adhesives may have an application as adjunctive means of closing scleral tunnel incisions. ",0
1520,7674449,Bacteriology of chronic suppurative otitis media: ofloxacin susceptibility,"Fifty-four patients with active chronic suppurative otitis media (CSOM) were prospectively studied for the bacteriology and their in vitro antibiotic susceptibility to ofloxacin. Thirty-nine patients (72%) had positive cultures. The commonest organism was Pseudomonas sp., which was found in 18 (33%) patients. The second commonest organism was Staphylococcus aureus, which was found in 15 (28%) patients. Bacteroides sp. was found only in 3 (6%) patients, and all were in association with the aerobes. Of all 42 aerobes found, 35 (83%) were susceptible to ofloxacin. The in vitro susceptibility results indicate that ofloxacin can be an effective antibiotic in the treatment of active CSOM. ",0
1521,7675260,Acute cocaine poisoning in a body packer. Clinical case],"""This report takes into consideration the complications due to """"body packers"""" cocaine absorption. In particular we report a clinical case in which severe dysrhythmias occurred. We think an early insertion of a pacemaker able to rid ectopic focus by overdriving is essential by comparison with an effective anti-dysrhythmic therapy. We also examine the cocaine metabolites values in the patient's serum and urine. """,0
1522,7675406,Osteoporosis of pregnancy: long-term follow-up of patients and their offspring,"The usual course of osteoporosis of pregnancy is complete resolution without recurrence. We report the 10-year follow-up of two patients with osteoporosis of pregnancy and their offspring. A 30-year-old woman presented with right hip pain at 30 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. A dual-energy x-ray absorptiometry performed on the 11-year-old daughter of this pregnancy showed osteopenia. A 26-year-old woman presented with left hip pain at 16 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. Dual-energy x-ray absorptiometry performed on the 13-year-old daughter of this pregnancy showed osteopenia. Osteoporosis of the hip discovered during pregnancy may not be a transient process and should prompt a search for osteopenia in both mother and offspring. ",0
1523,7675426,A case report of inflammatory pseudotumor of the urinary bladder,"A case of an inflammatory pseudotumor of the urinary bladder in a 46-yr-old man is presented. This rare, benign, and presumed non-neoplastic, reactive lesion must be differentiated from sarcomas of the urinary bladder. In the present case, we could demonstrate an inflammatory and reactive nature for the pseudotumor. Histologically, the presence of many Brunn's nests with infiltration of inflammatory cells and proliferation of capillaries in the myxoid stroma indicated a chronic inflammatory background for this lesion. It is apparent from morphology and immunohistochemistry findings that the proliferating spindle-shaped cell is of mesenchymal origin and not malignant in nature. These findings suggest that chronic inflammation can induce an overreaction of the bladder wall resembling tumor formation. ",0
1524,7675427,The function of the p53 gene suppressor in carcinogenesis],"The alteration of the p53 gene or protein seems to be the most frequent alteration in the human malignancies. It plays a significant role in the regulation of the physiological cell division. The genetic impairments caused by a series of exogenous or endogenous agents induce the activation of the p53 which results in the G1-S arrest to ensure the opportunity for repair to correct the alteration or in apoptosis when the repair is not able to cope with the mutation. Eventually, the p53 is anticarcinogenic because of its genom guarding function. The investigation of the behavior of this gene and protein is fruitful in solving problems of preventive, diagnostic and therapeutic work. ",0
1525,7675579,"Coincident timing by nondisabled, mentally retarded, and traumatic brain-injured individuals under varying target-exposure conditions","Coincident timing by 15 nondisabled individuals, 15 mentally retarded and 15 traumatically brain injured was measured under varying target-exposure conditions. Absolute constant error, constant error, and variable error were analyzed in separate repeated-measures analyses of variance for early performance (first block of practice), late performance (last block of practice), and retention (last block of retention). Subjects with mental retardation displayed the least accurate and most variable coincident-timing responses. Nondisabled subjects were most influenced by target-exposure time; subjects with traumatic brain injury were most influenced by target-viewing distance; and subjects with mental retardation were most influenced by a combination of target velocity and target-viewing distance. Subjects with mental retardation displayed a too-early response bias, while nondisabled subjects tended to have a too-late response bias. Individuals with traumatic brain injury had a variable response bias. ",0
1526,7675741,The burgeoning problem of latex sensitivity. Surgical gloves are only the beginning,"Awareness of latex sensitization is increasing in both the medical and the general community. Nonimmunologic irritant contact dermatitis, often found on the hands of healthcare workers who wear latex gloves, is the most common feature of sensitivity. The exact latex antigen(s) to blame have not been clearly delineated, but risk factors have been established that can be used to identify persons susceptible to a hypersensitivity reaction. The severity of a reaction depends on the route of exposure; mucosal and visceral exposure poses the greatest risk of reaction. Thus, patients requiring multiple operations and procedures, such as those with spina bifida or congenital urinary tract anomalies, are at high risk. Persons in high-risk groups should be referred for appropriate evaluation and testing, advised to avoid exposure to latex-derived products, and told to carry self-injectable epinephrine. ",0
1527,7675957,Reduced proconvulsant activity of caffeine in rats after a series of electroconvulsive seizures,"A variety of neurotransmitter receptor changes occur after a course of electroconvulsive seizures (ECS) in rats, including an increased density of adenosine A1 sites. Adenosine antagonism has been related to the proconvulsant action of methylxanthines such as caffeine. We determined tonic-clonic seizure duration in rats given ECS with caffeine (0-175 mg/kg, IP) after a course of one or six daily ECS. A single day of ECS did not affect the dose-dependent proconvulsant action of caffeine. After six daily ECS, the proconvulsant action of caffeine was reduced. After nine daily ECS, an A1 antagonist (8-cyclopentyl-1,3-dipropylxanthine) and an A2A antagonist (1-allyl-3,7-dimethyl-8-p-sulfophenylxanthine) showed reduced proconvulsant activity. The results suggest that the reduced proconvulsant action of caffeine after chronic ECS depends on adenosine antagonism. ",0
1528,7676091,Conditioning factors in intrapulmonary gas trapping during controlled mechanic ventilation in anesthesia],"To establish a relation between intrapulmonary gas trapping (Vat) generated by controlled ventilation during anesthesia and the factors that are likely to condition such trapping: flow volume (VT), expiratory time (te), compliance (C), resistance (R) and a time constant in either the anesthetized patient (tau) or under conditions of forced expiration in respiratory function testing (TC 25/50). Thirty patients undergoing surgery with general anesthesia were ventilated following 3 different patterns with te of 2.66, 2 and 1.33 sec, respectively. We measured Vat, C, R and tau for each pattern. Correlation coefficients were figured and line regressions were drawn for Vat and the conditioning factors. We also figured the correlation between mean Vat and calculated Vat based on TC 25/50. Intrapulmonary gas trapping occurred in 93% of patients and increased significantly as te decreased. Correlations between Vat and the factors were as follows: r=0.76 for tau, r=0.62 for C, r=0.62 for R, r= 0.13 for VT and r2 = -0.92 for te/tau. The correlation coefficient of tau and TC 25/50 was 0.92. The results obtained indicate that Vat depends above all on the ratio of te to tau and that trapping can be prevented by applying a te that is greater than 3 tau. ",0
1529,7676129,Neurologic manifestations following accidental exposure to pyralene and its thermal degradation products],"After five young women were exposed to pyralene and its thermal degradation products all developed a rich functional syndrome which could be explained by the traumatic effect of the accident. Nevertheless, in 3 of the women, abnormal somesthetic evoked potentials were observed including 2 with neurological lesions detectable radiologically. Polychlorobiphenyl derivates are toxic for the peripheral nervous system as has been observed in several recent exposure situations. Inversely, any effect on the central nervous system is still under debate. ",0
1530,7676242,Amoxicillin and clavulanic acid versus amoxicillin plus gentamicin in the empirical initial treatment of urinary tract infections in hospitalized patients],"We compared the fixed combination amoxicillin plus clavulanic acid with that of amoxicillin plus gentamicin in the empirical initial treatment of severe urinary tract infections. The study included 87 hospitalized patients (51 women and 36 men, mean age 58 +/- 22 years) with acute uncomplicated pyelonephritis (n = 48) or with complicated urinary tract infections (n = 39). 80 patients (92%) had fever and 31 patients (36%) positive blood cultures. 45 patients were randomly assigned to amoxicillin plus clavulanic acid and 42 to amoxicillin plus gentamicin. Overall, 18 patients (21%) were infected with organisms resistant in vitro to amoxicillin plus clavulanic acid, whereas no pathogen was isolated with resistance to amoxicillin plus gentamicin (p < 0.0001). At the end of the empirical treatment (4.2 +/- 1.5 days after the start), significant bacteriuria was present in 6/39 patients (15%) assigned to amoxicillin plus clavulanic acid, compared to 0/34 patients assigned to amoxicillin plus gentamicin (p < 0.05). The clinical response was satisfactory in both groups, and the time from start of therapy to resolution of fever was 2.2 +/- 1.4 days in the amoxicillin plus clavulanic acid group and 2.3 +/- 1.7 days in the amoxicillin plus gentamicin group. Although the in-vitro resistance did not result in a lower clinical efficacy of amoxicillin plus clavulanic acid compared to amoxicillin plus gentamicin in our relatively small sample of patients, the data indicate that the antimicrobial activity of amoxicillin plus clavulanic acid is inadequate to cover the spectrum of causative agents in hospitalized patients with pyelonephritis or complicated urinary tract infections. Amoxicillin plus clavulanic acid should therefore not be used in the initial empirical treatment of these infections. ",0
1531,7676399,Diet therapy of immunocompromised patients as exemplified in HIV-infection],"Presently, there is no special nutrition for HIV-infected patients; however, there exist preliminary data suggesting that immunonutrition may have benefits in patients with AIDS. Nutritional assessment and nutritional counseling are mandatory in every patient with HIV infection. Both strategies are part of supportive care and should be done as early as possible during the course of the disease. There is evidence that improving the nutritional state will also improve the prognosis of the patients. ",0
1532,7676500,Variations of the lymphocytotoxicity test. An evaluation of sensitivity and specificity,"Multiple variations of the basic lymphocytotoxicity test have been reported to increase test sensitivity. Although these modifications are used routinely in crossmatch tests, as required by federal regulation, there has been no methodical assessment of the relative sensitivities and specificities of these techniques with the exception of the well-studied antiglobulin method. We have performed such a comparison and found that these modifications do not, uniformly, increase test sensitivity. We also observed that the effect of a technique modification on test sensitivity as measured by overall lymphocytotoxic antibody titer does not reflect, necessarily, the effect on HLA-specific antibody. It is widely believed that the antiglobulin method is the most sensitive of the lymphocytotoxicity techniques. We observed that while the antiglobulin method increased overall test sensitivity dramatically, we achieved a comparable level of sensitivity by either substituting B cells for T cells or doubling both the serum and the complement incubation times. However, no other technique modification detected as many HLA antibody specificities as did the antiglobulin method. The data presented here provide useful guidelines for selecting techniques for HLA typing, antibody screening, and cross-matching. ",0
1533,7676730,"Progression of subclinical atherosclerosis in 6 years. Ultrasound evaluation of the average, combined femoral and carotid bifurcation intima-media thickness","The intima-media complex thickness (IMT) was evaluated in 472 asymptomatic subjects in a 6-year follow-up study. Four age groups were included (40-45, 46-50, 51-55 and 56-60) with the aim of obtaining a random equal number of men and women sample. The baseline IMT ranged from 0.42 to 2.12 mm (mean 0.63 mm, SD 0.14 mm). In 4.66% subjects completing the 6-year follow-up, the IMT decreased by more than 0.1 mm and in 18% there was no significant IMT change (> 0.1 mm). In the remaining individuals (77.33%) the IMT increased by at least 0.1 mm. The IMT increase in the 56-60 age group was significantly higher than in the remaining age groups (p < 0.02). A significantly higher percentage of smokers was also observed in the 56-60 age group (p < 0.05). However, the IMT increase in the smoker subgroups was not significantly different from the mean IMT increase observed in the whole group or from the IMT increase observed in the non-smoker group. Blood pressure variations were not associated with change of IMT over six years. The main difference between the four groups was an average weight 5.7% higher in the oldest age group at the end of the study (4.44% higher at inclusion). In conclusion the increase in IMT appeared to be greater in older subjects and the effect of smoking did not apparently affect IMT increase. The method of IMT measurements is able to demonstrate the age-related evolution of intima-media in a population. ",0
1534,7676917,Characterization of Vibrio anguillarum strains isolated from diseased fish in Finland,"Characterization of V. anguillarum strains (n = 109) isolated from diseased salmonids was performed. Eight O serovars were found among the strains. Serovar O1 was predominant (90%), while serovars O2, O3, O5, O8, O9, and a new serovar Va NT2, were represented by 1 or 2 strains. Two strains remained non-typeable. One of these was cross-reactive with several antisera, but had a LPS profile identical to that of serovar O8. All serovars showed specific LPS profiles. All but 1 of the O1 strains had a plasmid comparable in size to the pJM1 virulence plasmid, while plasmids of different sizes were found in O2, Va NT2 and the non-typeable strains. Apart from a single strain resistant to tetracycline, all the strains were sensitive to oxolinic acid, tetracycline, and trimethoprim-sulfonamides. By their biochemical and antigenic properties strains causing vibriosis among salmonids in Finland closely resemble Scandinavian strains. Predominance of the serovars O1 and O2 suggests that commercial vaccines containing these serovars should afford sufficient protection against vibriosis in Finland. ",0
1535,7677112,Studies using immobilized platelet glycoproteins for detection of platelet alloantibodies,"The utility of an enzyme linked immunoassay for the detection of platelet alloantibodies to isolated platelet glycoproteins employing commercially available monoclonal antibodies was studied. The authors established the usefulness of the assay for antibodies to platelet alloantigens (APAA) by testing its sensitivity and specificity under different conditions and using a variety of alloantibodies from patients with immune mediated thrombocytopenia. The authors were able to specifically detect a variety of antibodies to platelet alloantigens on different platelet glycoproteins. These antibodies had specificity for HPA-1a (PIA1), HPA-3 (Bak) and HPA-5 (Br). These results show that the APAA is easily adaptable for routine diagnostic testing in hospital laboratories using commercially available monoclonal antibodies and for the diagnosis of alloimmune mediated thrombocytopenic conditions. ",0
1536,7677232,Immune tolerance and protection against allergic sensitization,"Recent studies in our laboratory have focused on the nature of the primary T-cell response to inhaled allergens in the regional lymph nodes (RLN) draining the upper airways, in immunologically naive mice and rats. In general terms, the first detectable response involves activation of allergen-specific interleukin 4 (IL-4) secreting CD4+ Th-0/Th-2 cells, which triggers (at least in genetically high-immunoglobulin E (IgE)-responders) an initial burst of IgE antibody synthesis. This is followed by a rapidly expanding interferon gamma (IFN-gamma) response in the RLN, which terminates IL-4 secretion and IgE production. We have presented evidence that the initial source of IFN-gamma in this response is a population of major histocompatibility complex (MHC) class I restricted CD8+ T-cells, which respond specifically to the allergen. The initial activation of these CD8+ T-cells requires a source of exogenous IL-2, which appears to be supplied by the Th-0/Th-2 cells, which are themselves eventually suppressed by the cytokine products of the CD8+ T-cells. It is hypothesized that the IFN-gamma-rich milieu created by the allergen-specific CD8+ T-cells eventually selects for allergen-specific Th-1 cells, which, with chronic stimulation, eventually outgrow the CD8+ population and become dominant in the allergen-specific T-cell memory pool. Our most recent experiments have identified a previously covert but highly potent effector cell subset within the CD8+ T-cell population, in the form of allergen-specific TcR1 (gamma/delta) T-cells. Less than 500 of these cells, purified by positive sorting, are required to regulate the CD4 T-cell response in adult mice or rats, in adoptive transfer experiments.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1537,7677469,Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study,"""There has been an National Institutes of Health consensus meeting concerning the management of patients with """"asymptomatic"""" primary hyperparathyroidism, yet there is no clear definition of this condition. The authors, therefore, documented the clinical manifestations and frequencies of these manifestations in unselected patients with primary hyperparathyroidism and determined whether these clinical manifestations resolved after parathyroidectomy. The authors studied 152 unselected consecutive patients with primary hyperparathyroidism and 132 control patients with nontoxic thyroid disorders who were treated by parathyroidectomy or thyroidectomy, respectively, between January 1986 and June 1991. All patients received a questionnaire during their initial office visits and the same questionnaire again after their operations. Patients were also questioned about their perception of the success of the operation. Eighty percent of the parathyroid patients and 70.5% of the thyroid patients completed the questionnaires, and the mean follow-up time was 20 months. Only 7 (4.6%) patients with primary hyperparathyroidism had no symptoms, and 26 (17.1%) had no associated conditions despite 74.3% of these patients having serum calcium levels less than 12 mg/dL. Symptoms including fatigue, exhaustion, weakness, polydipsia, polyuria, nocturia, joint pain, bone pain, constipation, depression, anorexia, nausea, heartburn, and associated conditions, including nephrolithiasis, and hematuria occurred more often in patients with primary hyperparathyroidism than in the thyroid control patients (p < 0.05). After parathyroidectomy, only eight (5.3%) patients failed to have any improvement in symptoms or associated conditions. Fifty-seven percent of the parathyroid patients versus 30% of the thyroid patients felt better overall after the operation, strength subjectively improved in 29% of parathyroid patients versus 13% in thyroid patients; thirty-seven percent of the parathyroid patients versus 13% of the thyroid patients claimed they were less depressed. When examined thoroughly, few patients with primary hyperparathyroidism were asymptomatic or without associated conditions, and most patients experienced subjective improvement after successful parathyroidectomy. """,0
1538,7678126,Current methods of mutation detection,"Mutation detection is important in all areas of biology. Detection of unknown mutations can involve sequencing of kilobases of DNA, often in many patients. This has lead to the development of methods to screen DNA for mutations as well as methods to detect previously described mutations. This review discusses current methods used for such purposes with special emphasis on genetic diseases of humans. However, savings can be made by similar means in other areas of biology where repetitive or extensive sequencing for comparative purposes needs to be done. This review covers the methods used for detection of unknown mutations, namely the ribonuclease, denaturing gradient-gel electrophoresis, carbodiimide, chemical cleavage, single-strand conformation polymorphism, heteroduplex and sequencing methods. Once mutations have been defined they can be searched for repeatedly by methods referred to as diagnostic methods. Such methods include allele-specific oligonucleotide hybridization, allele-specific amplification, ligation, primer extension and the artificial introduction of restriction sites. We can now choose from a range of excellent methods, but the choice will usually depend on the background of the laboratory and/or the application in hand. Screening methods are evolving to more satisfactory forms, and the diagnostic methods can be automated to screen whole populations inexpensively. ",0
1539,7678185,Lead poisoning in children,"In October 1991, the Centers for Disease Control issued new recommendations lowering the acceptable blood lead level. This change was based on data indicating that irreversible adverse neurodevelopmental effects occur in children with chronic low-level exposure to lead. The primary source of lead poisoning is still lead-based paint, particularly in older urban housing. Other sources of lead poisoning are also common. Almost all U.S. children are considered at risk of lead poisoning and should be screened for lead poisoning. Parents should be provided with information about potential sources of lead during routine well-child visits. Multidisciplinary efforts should be made to reduce all lead exposure. Oral chelation therapy on an outpatient basis is now available to treat less severe cases of lead poisoning. ",0
1540,7678188,Successful treatment of ongoing intestinal allograft rejection permits recovery of graft structure and function,"Acute rejection episodes often complicate clinical small bowel transplantation, which prompted us to investigate whether such episodes can be reversed and the intestinal graft salvaged. Inbred Lewis rats that received fully allogeneic Brown-Norway small bowel allografts were treated with cyclosporin A (10 mg/kg) for 5 days, and the drug was then discontinued. Clinical and histologic signs of acute rejection developed, and the animals were subsequently treated with FK 506 (2 mg/kg) on days 14, 16, and 18. Survival was significantly prolonged (201.7 +/- 46.8 days) when compared with animals that were not administered FK 506 (16.5 +/- 0.8 days) or allograft recipients that received no immunosuppressive therapy (10.8 +/- 0.7 days). The histologic changes and functional impairment due to rejection that were observed prior to the start of the FK 506-therapy were reversed. However, biopsy specimens of all animals exhibited features of chronic rejection. This study provides evidence that acute rejection of intestinal allografts can be successfully treated with a short course of FK 506. ",0
1541,7678261,Involvement of immediate-early gene expression in the synergistic effects of steel factor in combination with granulocyte-macrophage colony-stimulating factor or interleukin-3 on proliferation of a human factor-dependent cell line,"Steel factor (SLF) synergizes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) to stimulate proliferation of human factor-dependent cell line, MO7e. To elucidate molecular mechanisms underlying this synergism, induction of immediate-early genes was studied. Treatment of MO7e cells with SLF, GM-CSF, and IL-3 induced/enhanced expression of c-fos, junB, egr-1, and c-myc genes. SLF treatment of MO7e cells led to higher expression of c-fos, junB, and egr-1 genes than did treatment with GM-CSF or IL-3. However, GM-CSF and IL-3 had more prolonged effects on enhancement of the c-myc gene than SLF. Using optimal dosages for cell proliferation, induction of c-fos and junB was greater than additive with SLF plus GM-CSF or IL-3, as compared with each factor alone. Using suboptimal amounts of SLF with optimal GM-CSF or IL-3, induction of c-fos, junB, egr-1, and c-myc genes was greater than additive. De novo protein synthesis was not required for greater induction of these immediate-early genes by the combination of SLF plus GM-CSF. Based on nuclear run-on and actinomycin D experiments, the data suggest that the synergistic effects of SLF plus GM-CSF on the induction of immediate-early genes may be mediated in part at the level of transcription and mRNA stabilization for c-fos, at the level of mRNA stabilization for junB, and at the level of transcription for egr-1. ",0
1542,7678366,The heterogeneity of the mesostriatal dopaminergic system as revealed in normal and parkinsonian monkeys,"The present immunohistochemical study has shown that the mesostriatal DA system in primates is a highly heterogeneous entity composed of several subsystems displaying variable degrees of vulnerability to MPTP. These subsystems were shown to affect the expression of neuropeptide in the striatofugal neurons in a manner that varies according to the location of the cell bodies in the various striatal territories. Also, a distinct subset of DA neurons in the SN/VTA complex was found to specifically innervate GPi and to be relatively resistant to the neurotoxic effect of MPTP. Furthermore, DA neurons expressing calbindin were found to be much less severely affected than other DA neurons in the SN/VTA complex of PD monkeys. Therefore, in contrast to the situation in other neurodegenerative disorders, such as Alzheimer's and Huntington's diseases, calbindin can be used as a marker for a specific subpopulation of DA neurons that are less prone to degeneration in Parkinson's disease. ",0
1543,7678417,"Selection of a mutant cell line based on differential expression of glycosphingolipid, utilizing anti-lactosylceramide antibody and complement","""A mouse mammary carcinoma mutant cell line showing a characteristic alteration of glycosphingolipid (GSL) composition, but with unchanged protein glycosylation pattern, was isolated. Parent cell line FM3A/F28-7 is characterized by the predominance of lactosylceramide (LacCer) and virtual absence of more complex GSLs. Mutant cell line FUA169 was isolated after treatment of F28-7 cells with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine and incubation with anti-LacCer monoclonal antibody T5A7 and complement. FUA169 cells were characterized by a dramatic reduction in LacCer and by the presence of a major ganglioside identified as GM3. They also showed high activity of CMP-sialic acid:LacCer 2,3-sialosyltransferase, whereas F28-7 cells had no detectable activity of this enzyme. In contrast to the difference in GSL pattern, F28-7 and FUA169 showed identical protein glycosylation patterns, as evidenced by """"Western blotting"""" with various lectins and surface labeling with galactose oxidase/NaB3H4 and periodate/NaB3H4. Thus, FUA169 is identified as a glycosylation mutant with regard to GM3 expression and will be useful for studies of the functional role of GM3. Growth of FUA169 cells, relative to F28-7 cells, showed greater temperature sensitivity and greater inhibitability based on restriction of growth factors, particularly insulin. """,0
1544,7678427,Multiclonal synovial T cell response to Yersinia enterocolitica in reactive arthritis: the Yersinia 61-kDa heat-shock protein is not the major target antigen,"The T cell response to bacterial antigens plays a major role in the pathogenesis of reactive arthritis (ReA) following enteric infections with Yersinia enterocolitica. To study the antigen specificity of the T cells at the site of inflammation, the response of cloned T cells from the synovial fluid of 2 patients with ReA to partially purified antigens of Yersinia enterocolitica was determined. The clones showed different patterns of response to various fractions, indicating a multiclonal response to Yersinia antigens, and these specificities differed in the 2 patients. Some T cells were specific for Y. enterocolitica; some cross-reacted with other enterobacteria. Proteins of 14 and 19 kDa could be identified as target antigens for the T cell clones, but no clone could be unequivocally found that reacted with the highly purified Yersinia 61-kDa heat shock protein. Thus, the inflammatory T cell response in the synovial fluid in ReA is multiclonal and not predominantly directed against the bacterial heat shock 61-kDa protein. ",0
1545,7678490,Characterization of human autoantibodies reactive to gastric parietal cells,"Human sera from autoimmune gastritis patients containing autoantibodies to gastric parietal cells were analyzed by immunological methods. Enzyme linked immuno-sorbent assay demonstrated that all nine sera reacted with pig gastric vesicles enriched in H+/K(+)-ATPase (gastric proton pump). Immunoblotting experiments indicated that the alpha subunit of the H+/K(+)-ATPase was the major antigen in the vesicles with two of the sera reacting strongly. We further characterized the specificity of the antibodies using partial sequences of the pig alpha subunit fused with truncated TrpE (anthranilate synthase). The antibodies from autoimmune gastritis patients reacted differently to the two fusion proteins (Met-1 to Ala-79, and Arg-606 to Ile-964), indicating that each patient sera contains a mixture of autoantibodies recognizing different epitopes with variable contents. ",0
1546,7678800,Endogenous galanin modulates the gonadotropin and prolactin proestrous surges in the rat,"Galanin (GAL) has recently emerged as an important neuroendocrine regulator which participates in the control of several pituitary and hypothalamic hormones. Our earlier observation that GAL stimulates LHRH release from nerve terminals of the median eminence as well as basal LH and LHRH-induced LH secretion from pituitary cells in vitro prompted us to evaluate whether endogenous GAL plays a role in regulation of the physiologically occurring preovulatory surges of gonadotropins and PRL. Proestrous female rats were passively immunized against GAL using a high affinity sheep antirat GAL serum (FMS-FJL 17-5). Animals were implanted during diestrus with indwelling atrial cannulae. On the expected day of proestrus, rats received 1 ml of either normal sheep serum or GAL antiserum (GAL-AS), iv, 1 h before blood sampling started. Blood samples (0.5 ml) were collected at hourly intervals from 1400-2300 h, and plasma levels of LH, FSH, and PRL measured by RIA. At several time intervals after GAL-AS administration, the maximum binding ability of the rat plasma was evaluated using standard saturation assays. High neutralizing levels of immunoglobulins were present throughout the experimental period. GAL passive immunization blunted the LH preovulatory surge by 30%. Although maximum LH levels were unaffected by the treatment, the area under the secretory curve and LH levels at 1700, 1900, and 2000 h were significantly reduced. Conversely, FSH secretion was not significantly altered for either maximum FSH levels or area under the curve. However, FSH levels were significantly diminished in GAL-AS-treated rats at 1700 h. GAL passive immunization selectively reduced the plateau phase of the preovulatory surge of PRL. No significant differences were observed in the initiation of the surge or maximum PRL levels, whereas PRL levels were significantly reduced from 1700 to 2200 h. In addition, the area under the PRL curve was diminished in GAL-AS-treated animals by 40%. In conclusion, our results clearly demonstrate that endogenous GAL is involved in control of the preovulatory surges of LH and PRL without altering the FSH surge. In addition, they provide, for the first time, evidence of an important role for endogenous GAL in the regulation of physiological events leading to ovulation. ",0
1547,7678847,Differential induction of prostaglandin E2-dependent and -independent immune suppressor cells by tumor-derived GM-CSF and M-CSF,"Both prostaglandin E2 (PGE2)-dependent (indomethacin-sensitive) and PGE2-independent (indomethacin-insensitive) suppressor cell activities that inhibited mitogenic T cell blastogenesis appeared in the bone marrow and spleen of mice on days 20 to 30 following transplantation of NFSA fibrosarcoma molecularly expressing mRNA for both macrophage (M) and granulocyte-macrophage (GM) colony-stimulating factors (CSFs). The present study was done to characterize the two different suppressor cells isolated from NFSA tumor-bearing mice and to verify a role of CSFs in the induction of suppressor cells in vitro. Whereas PGE2-releasing suppressor cells were found in bone marrow and spleen cells isolated from tumor-bearing mice, indomethacin-insensitive suppressor cells in both tissues were localized predominantly in adherent cell fractions. An increase in Mac-1+ and Mac-2+ spleen cell populations with two to three times larger cell volumes was observed, and both showed strong PGE2-releasing capacity and indomethacin-sensitive suppressor cell activity. However, after elimination of Mac-1+ or Mac-2+ cells, bone marrow cells still showed higher PGE2-releasing capacity and indomethacin-sensitive suppressor activity. The in vitro cultures of normal bone marrow and spleen cells with NFSA cell conditioned medium (NFSA-CM) induced heterogeneous mixtures of indomethacin-sensitive and - insensitive suppressor cells like those observed in cultures with the combination of M-CSF and GM-CSF. However, cultures with either GM-CSF or M-CSF resulted in the induction of indomethacin-sensitive suppressor cells by GM-CSF and of indomethacin-insensitive suppressor cells by M-CSF. In addition, NFSA-CM pretreated with anti-GM-CSF antibody induced indomethacin-insensitive suppressor cells in in vitro cultures of bone marrow and spleen cells. These results suggest that two distinctly different suppressor cells developed under hemopoiesis of myelomonocytic lineage cells are regulated differentially by the two macrophage growth factors, M-CSF and GM-CSF. ",0
1548,7679755,Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy,"Current bias would conclude that elevation of serum prostate specific antigen (PSA) after radical prostatectomy infers failure of the procedure. Since April 1987 preoperative and postoperative serum PSA levels have been obtained on 226 patients who underwent radical perineal prostatectomy for presumed organ confined prostate cancer (stage T1-2N0M0). Clinical failure as defined by elevation of serum acid phosphatase, biopsy proved local recurrence or evidence of malignant disease on bone scan has occurred in 3.9% of the patients with organ confined, 7.0% with specimen confined and 13.2% with margin positive disease. However, when a PSA elevation of greater than 0.5 ng./ml. was used as an indicator of failure the failure rate became 9.8% for the organ confined group, 39.4% for the specimen confined group and 66.0% for margin positive group. Of the patients who failed clinically the interval from initial elevation of postoperative PSA to clinical detection of failure ranged from 2 to 28 months (median 16). Among the patients with an elevated postoperative PSA level but who have not clinically failed followup ranged from 4 to 46 months (median 23). A total of 11 patients had no evidence of failure at greater than 36 months despite the elevated postoperative serum PSA level. These PSA elevations in patients who undergo supposed curative therapy are distressing. However, at this time the majority of these patients have not failed. In the clinically cured patient biochemical evidence of failure may not be sufficient to change the treatment course. ",0
1549,7680331,"A study of the genetic polymorphism of human inter-alpha-trypsin-inhibitor (ITI) in the Han population, Chengdu, China","Phenotypes of inter-alpha-trypsin-inhibitor (ITI) have been determined by isoelectric focusing on polyacrylamide gels followed by immunofixation. The phenotype frequencies of ITI in the Han population in Chengdu, P.R. China have been investigated using this method. In addition, family studies have been conducted in 21 families. The results show that ITI is polymorphic in the Han population in Chengdu, China. The allele frequencies are as follows: ITI*1 = 0.5763. ITI*2 = 0.4107, ITI*3 = 0.0130. ITI is thus a new and promising genetic marker that can be used in the field of forensic haematogenetics. ",0
1550,7687978,Levamisole and interferon in children with chronic hepatitis B,"To evaluate the possible usefulness of simultaneous administration of levamisole and interferon, we randomly allocated 38 children with chronic hepatitis B to receive either 10 MU/m2 interferon-alpha-2a, three times a week for 6 mo (group 1, n = 20) or 90 mg/m2 of levamisole for 45 days, together with 10 MU/m2 of interferon-alpha-2a, three times a week for 6 mo (group 2, n = 18). At the end of the follow-up period (15 mo), no significant differences were observed between the groups with respect to loss of hepatitis B virus DNA and HBeAg from serum and normalization of serum ALT levels. During therapy, a significant increase in the serum levels of ALT and soluble interleukin-2 receptor was observed in both groups but was higher in patients from group 2. The combination of levamisole with interferon was associated with severe side effects. In summary, the combination of levamisole with interferon in children with chronic hepatitis B does not improve the results obtained with interferon alone.",0
1551,7687982,Effect of short-term ethanol treatment on voltage-dependent calcium channels in Kupffer cells,"Kupffer cells, the resident hepatic macrophages, are activated by calcium, and several reports indicate that their function (e.g., phagocytosis and cytokine production) is altered by ethanol. We recently found that Kupffer cells contain L-type voltage-dependent Ca2+ channels. The purpose of this study, therefore, was to evaluate the effect of short-term ethanol treatment on voltage-dependent Ca2+ channels in Kupffer cells. Kupffer cells were isolated from rats 2 hr after intragastric administration of ethanol (5 gm/kg intragastrically). Cytosolic free calcium concentration of cultured Kupffer cells was measured with the fluorescent Ca2+ indicator fura-2. In Kupffer cells isolated from control rats, partial replacement of extracellular Na+ by K+ caused an increase in cytosolic free calcium concentration in a concentration-dependent manner (half-maximal effect was observed with 81 mmol/L K+), presumably because of membrane depolarization. Acute ethanol treatment in vivo shifted the concentration-response curve for K+ to the right (half-maximal effect was observed with 94 mmol/L K+) and reduced the maximal elevation of cytosolic free calcium concentration by means of K+. Significantly, the dihydropyridine-type calcium channel agonist BAY K 8644 (1 mumol/L) shifted the concentration-response curve for K+ to the left in control and ethanol-treated groups (half-maximal effect was observed with 61 and 77 mmol/L K+, respectively). Moreover, the dihydropyridine-type calcium channel blocker nitrendipine (10 mumol/L) prevented the increase in cytosolic free calcium concentration in both groups. When extracellular Ca2+ was omitted from the incubation medium, the increases in cytosolic free calcium concentration due to depolarization were prevented completely. However, direct addition of ethanol to the cell cultures was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1552,7691707,Induction of apoptosis by transforming growth factor-beta 1 in the rat hepatoma cell line McA-RH7777: a possible association with tissue transglutaminase expression,"We report here that transforming growth factor-beta 1 induces cell death in the Morris hepatoma cell line McA-RH7777. We assessed the type of cell death induced by transforming growth factor-beta 1 in this hepatoma cell line on the basis of morphological and biochemical characteristics. Dying cells, which detached from the cell monolayer, showed morphological characteristics of apoptosis (programmed cell death) such as chromatin condensation, nuclear disintegration and cellular fragmentation into clusters of eosinophilic globules. DNA isolated from these cells showed a ladder pattern consisting of multimers of 180 to 190 bp, indicating extensive DNA cleavage into oligonucleosomal units by an endogenous endonuclease. Treatment of the dead cells with detergents and chaotropic agents resulted in formation of insoluble shells, so-called apoptotic bodies, suggesting extensive cross-linking of cell proteins by tissue transglutaminase. Furthermore, increased amounts of cytosolic tissue transglutaminase, which has been recognized as a possible marker of apoptosis, and extensive cross-linking of cytokeratin polypeptides was demonstrated in TGF-beta 1-treated hepatoma cells on immunoblot analysis. These results provide strong evidence that the cell death induced by TGF-beta 1 in McA-RH7777 hepatoma cells is mainly apoptotic. It also suggests that a specific induction of the cytosolic tissue transglutaminase may be involved in the TGF-beta 1-induced pathways of apoptotic cell death in McA-RH7777 hepatoma cells.",0
1553,7693568,HLA B44-restricted cytotoxic T lymphocytes recognizing an epitope on hepatitis C virus nucleocapsid protein,"Cytotoxic T lymphocytes have been reported to be involved in the immune clearance of virus-infected cells and in the pathogenesis of viral infection. We studied the cytotoxic T lymphocyte response to the putative nucleocapsid protein of hepatitis C virus in patients with chronic hepatitis C. Cytotoxic T lymphocytes specific for hepatitis C virus nucleocapsid protein were generated from peripheral blood lymphocytes by means of repeated stimulation with a synthetic hepatitis C virus nucleocapsid protein peptide. The cytotoxic T lymphocytes were CD8 positive and recognized an epitope in hepatitis C virus nucleocapsid protein residues 81 to 100 in association with a human leukocyte antigen class I molecule, B44. The peptide-induced cytotoxic T lymphocytes recognized target cells synthesizing hepatitis C virus nucleocapsid protein endogenously, though less efficiently than peptide-pulsed target cells. The human leukocyte antigen B44-restricted cytotoxic T lymphocyte response was observed in three of five patients with chronic hepatitis C and a human leukocyte antigen B44 molecule but in neither of two hepatitis C virus-negative healthy individuals with human leukocyte antigen B44 molecules. The results demonstrate the presence of hepatitis C virus-specific cytotoxic T lymphocytes in the peripheral blood of patients with chronic hepatitis C and provide a strategy to study the role of cytotoxic T lymphocytes in the viral clearance and the pathogenesis of hepatitis C virus infection.",0
1554,7694896,Lipoylated and unlipoylated domains of human PDC-E2 as autoantigens in primary biliary cirrhosis: significance of lipoate attachment,"Approximately 95% of patients with primary biliary cirrhosis have antimitochondrial antibodies against the E2 component of the pyruvate dehydrogenase complex (E2p). Immunodominant sites on E2p have been localized to the inner lipoyl domain, which serves as a covalent attachment site for the essential cofactor, lipoic acid. However, it is not clear whether the presence of lipoic acid is necessary for autoimmune recognition of human E2p. To facilitate further studies on the inner lipoyl domain and to assess the importance of lipoic acid in antibody binding, we used the previously cloned human E2p cDNA in the construction and high-level expression in Escherichia coli of a subgene encoding the domain. Purification and analysis of the gene product revealed that both lipoylated and unlipoylated forms of the intact domain are generated. Immunoblotting, enzyme-linked immunosorbent assay inhibition experiments and antibody affinity measurements using isolated lipoylated and unlipoylated domains demonstrated that the presence of the lipoyl residue is crucial for effective recognition by primary biliary cirrhosis patients' autoantibodies, which have a higher relative affinity for the lipoylated form. Contrary to some previous suggestions, these results indicate that antibodies in primary biliary cirrhosis patients' sera bind most effectively to a unique peptide-cofactor conformation in the lipoyl domain of the human E2p polypeptide. Moreover, the availability of large amounts of human lipoyl domain will permit further studies into the role of the antigen (if any) in disease pathogenesis.",0
1555,7700288,"Medicare coverage, supplemental insurance, and the use of mammography by older women","BACKGROUND: On January 1, 1991, the Medicare program began offering reimbursement for screening mammography every two years. This study examined the use of mammography in women covered by Medicare during the first two years that the screening benefit was offered. METHODS: Medicare bills for 1991 and 1992 from a nationally representative sample of 4110 women 65 years of age or older were examined to determine the degree of compliance with recognized guidelines for screening mammography and the extent to which the use of mammography was associated with having supplemental insurance, which shields patients from the out-of-pocket costs associated with using Medicare benefits. RESULTS: A total of 36.9 percent of older U.S. women had mammography during the first two years of the Medicare benefit for screening mammography. Only 14.4 percent of the women lacking supplemental insurance had mammography, as compared with 44.7 percent of those with employer-sponsored supplemental insurance, 40.1 percent of those with self-purchased supplemental insurance, and 23.9 percent of those with Medicaid supplemental insurance. These differences persisted in the stratified and multivariate analyses. As compared with women lacking supplemental insurance, women with employment-based supplemental insurance were more likely to undergo mammography (adjusted odds ratio, 3.03; 95 percent confidence interval, 2.17 to 4.23), as were women with self-purchased supplemental insurance (adjusted odds ratio, 2.97; 95 percent confidence interval, 2.13 to 4.15) and women with Medicaid supplemental insurance (adjusted odds ratio, 1.99; 95 percent confidence interval, 1.30 to 3.07). CONCLUSIONS: The use of mammography was substantially below recommended levels during the first two years of Medicare coverage for screening mammography. Women lacking supplemental health insurance were at particularly high risk of failing to undergo mammography. Requiring copayments for preventive services is an obstacle to the effective mass screening of older women for breast cancer.",0
1556,7700310,Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without HIV infection,"BACKGROUND: Herpesvirus-like DNA sequences have recently been found in lesions from patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). It is not known whether these sequences are also present in classic Kaposi's sarcoma or in the Kaposi's sarcoma that occurs in homosexual men who are seronegative for the human immunodeficiency virus (HIV). METHODS: We analyzed DNA in tissue samples from patients with AIDS-associated Kaposi's sarcoma, patients with classic Kaposi's sarcoma, and HIV-seronegative homosexual men with Kaposi's sarcoma. We also analyzed DNA in samples of uninvolved tissue from these patients and in control tissue from healthy subjects. All samples were tested blindly by polymerase chain reaction (PCR) with specific primers to amplify KS330(233), a herpesvirus-like DNA sequence. RESULTS: The KS330(233) PCR product was found in 20 of 21 tissue samples (95 percent) from the patients with Kaposi's sarcoma, including 10 of the 11 samples from the patients with AIDS-associated Kaposi's sarcoma, all 6 samples from the patients with classic Kaposi's sarcoma, and all 4 samples from the HIV-negative homosexual men with Kaposi's sarcoma. Only 1 of the 21 control samples (5 percent) was positive (odds ratio, 400; 95 percent confidence interval, 19 to 17,300). Of the 14 samples of uninvolved skin from the patients with Kaposi's sarcoma, 3 were positive for KS330(233). Representative PCR-product sequences were more than 98 percent identical for the three types of Kaposi's sarcoma, suggesting that all three are caused by the same agent. CONCLUSIONS: The same herpesvirus-like DNA sequences are present in AIDS-associated Kaposi's sarcoma, classic Kaposi's sarcoma, and the Kaposi's sarcoma that occurs in HIV-negative homosexual men. Therefore, this presumably new human herpesvirus is not solely an opportunistic infection in patients with AIDS, and the three forms of Kaposi's sarcoma may be caused by the same infectious agent.",0
1557,7700311,Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas,"BACKGROUND: DNA fragments that appeared to belong to an unidentified human herpesvirus were recently found in more than 90 percent of Kaposi's sarcoma lesions associated with the acquired immunodeficiency syndrome (AIDS). These fragments were also found in 6 of 39 tissue samples without Kaposi's sarcoma, including 3 malignant lymphomas, from patients with AIDS, but not in samples from patients without AIDS. METHODS: We examined the DNA of 193 lymphomas from 42 patients with AIDS and 151 patients who did not have AIDS. We searched the DNA for sequences of Kaposi's sarcoma-associated herpesvirus (KSHV) by Southern blot hybridization, the polymerase chain reaction (PCR), or both. The PCR products in the positive samples were sequences and compared with the KSHV sequences in Kaposi's sarcoma tissues from patients with AIDS. RESULTS: KSHV sequences were identified in eight lymphomas in patients infected with the human immunodeficiency virus. All eight, and only these eight, were body-cavity-based lymphomas--that is, they were characterized by pleural, pericardial, or peritoneal lymphomatous effusions. All eight lymphomas also contained the Epstein-Barr viral genome. KSHV sequences were not found in the other 185 lymphomas. KSHV sequences were 40 to 80 times more abundant in the body-cavity-based lymphomas than in the Kaposi's sarcoma lesions. A high degree of conservation of KSHV sequences in Kaposi's sarcoma and in the eight lymphomas suggests the presence of the same agent in both lesions. CONCLUSIONS: The recently discovered KSHV DNA sequences occur in an unusual subgroup of AIDS-related B-cell lymphomas, but not in any other lymphoid neoplasm studied thus far. Our finding strongly suggests that a novel herpesvirus has a pathogenic role in AIDS-related body-cavity-based lymphomas.",0
1558,7700313,Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage,"BACKGROUND: It has been hypothesized that the pathogenesis of diseases induced by cigarette smoking involves oxidative damage by free radicals. However, definitive evidence that smoking causes the oxidative modification of target molecules in vivo is lacking. We conducted a study to determine whether the production of F2-isoprostanes, which are novel products of lipid peroxidation, is enhanced in persons who smoke. METHODS: We measured the levels of free F2-isoprostanes in plasma, the levels of F2-isoprostanes esterified to plasma lipids, and the urinary excretion of metabolites of F2-isoprostanes in 10 smokers and 10 nonsmokers matched for age and sex. The short-term effects of smoking (three cigarettes smoked over 30 minutes) and the effects of two weeks of abstinence from smoking on levels of F2-isoprostanes in the circulation were also determined in the smokers. RESULTS: Plasma levels of free and esterified F2-isoprostanes were significantly higher in the smokers (242 +/- 147 and 574 +/- 217 pmol per liter, respectively) than in the nonsmokers (103 +/- 19 and 345 +/- 65 pmol per liter; P = 0.02 for free F2-isoprostanes and P = 0.03 for esterified F2-isoprostanes). Smoking had no short-term effects on the circulating levels of F2-isoprostanes. However, the levels of free and esterified F2-isoprostanes fell significantly after two weeks of abstinence from smoking (250 +/- 156 and 624 +/- 214 pmol per liter, respectively, before the cessation of smoking, as compared with 156 +/- 67 and 469 +/- 108 pmol per liter after two weeks' cessation; P = 0.03 for free F2-isoprostanes and P = 0.02 for esterified F2-isoprostanes). CONCLUSIONS: The increased levels of F2-isoprostanes in the circulation of persons who smoke support the hypothesis that smoking can cause the oxidative modification of important biologic molecules in vivo.",0
1559,7705789,Response of plasma and tissue endothelin-1 to liver ischemia and its implication in ischemia-reperfusion injury,"This study was designed to investigate the changes in plasma and tissue endothelin-1/endothelin-2 (ET) after liver ischemia and to assess the protective effect of anti-ET 1/ET 2 monoclonal antibody (ET antibody) against ischemia-reperfusion injury. The ET levels in the liver tissue, hepatic venous blood of the ischemic and non-ischemic sides, and in the portal venous blood were measured before and after partial liver ischemia for 1 hour in the adult dog. The ET levels in the liver tissue and hepatic venous blood on the ischemic side increased slightly during ischemia and markedly after reperfusion, whereas those on the nonischemic side showed no significant increases. The ET levels in the portal venous blood peaked at 1 to 3 hours after ischemia, which was significantly higher than the levels in the hepatic venous blood on the ischemic side and which correlated with the portal venous pressure elevated because of the partial liver clamping. The administration of antibody (2 mg/kg, intravenous) before reperfusion resulted in a significant inhibition of the postreperfusion elevations of serum-glutamic-oxaloacetic transaminase (GOT), S-glutamic pyruvic transaminase (GPT), and the indocyanine green (ICG) dye retention rate. In conclusion, ET was produced both in the liver tissue exposed to ischemia and in the vascular endothelium of the portal bed exposed to portal congestion. The ET released from the vascular endothelium, including the liver and the portal bed, was found to be a possible factor of ischemia-reperfusion injury.",0
1560,7705803,Insulin secretion and plasma levels of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 [7-36 amide] after oral glucose in cirrhosis,"A blunted initial insulin secretory response may contribute to oral glucose intolerance in cirrhosis. Oral glucose is a better stimulant to insulin secretion than intravenous (IV) glucose in part because of release of gut peptides, notably glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1 [7-36 amide]). Because impaired release of or resistance to these gut peptides could explain impaired insulin secretion after oral glucose, we measured insulin secretion, plasma GIP, and GLP-1 [7-36 amide] levels, basally and after 75 g oral glucose, in 10 cirrhotics and 10 controls. Insulin secretion was calculated from a two-compartment analysis of serum C-peptide levels using kinetic parameters derived from IV injection of recombinant human C-peptide. C-peptide metabolic clearance rate, and the fractional rate constants for C-peptide (using the two-compartment model) were not significantly different, but the volume of the central compartment was 15% greater in cirrhotics (P < .01). Fasting blood glucose levels were similar (cirrhotics, 4.9 +/- 0.2; controls, 4.6 +/- 0.1 mmol/L) but serum insulin was six times higher in cirrhotics (P < .001). Cirrhotics had higher fasting GIP (215 +/- 72 vs. 42 +/- 18 pmol/L) and GLP-1 [7-36 amide] levels (25 +/- 3 vs. 16 +/- 1 pmol/L) (both P < .05). After oral glucose, blood glucose levels were significantly higher in cirrhotics. The timing of the gut peptide response to oral glucose was similar in the two groups, but peak levels of both peptides were approximately x2 higher in the cirrhotics.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1561,7705805,Heparan sulfate proteoglycan expression in normal human liver,"Because increasing evidence implicates heparan sulfate proteoglycans (HSPGs) as essential cofactors in receptor-growth factor interactions, in cell-cell recognition systems, and in cell-matrix adhesion processes and yet little is known about their cellular distribution pattern and cellular sources in liver tissue, we used monoclonal antibodies specific for the core proteins of syndecan1, 2, 3, 4, glypican, and perlecan to investigate their immunohistochemical expression in normal adult human liver biopsy specimens. Syndecan1 was expressed in sinusoidal endothelial cells, whereas the endothelium of the portal tract vessels was negative. Hepatocytes showed a membranous staining pattern of the sinusoidal and intercellular domain. Bile duct epithelial cells showed basolateral membrane positivity. Immunoreactivity for syndecan2 was seen in mesenchymal cells, accentuated around bile ducts. Syndecan3 showed intense staining of hepatic arterial and portal venous endothelial cells, of mesenchymal cells, and of Ito cells. Immunohistochemistry for syndecan4 showed a granular staining pattern of hepatocytes at their bile canalicular pole. Glypican showed weak positivity in portal tract mesenchymal cells and clear positivity in nerve bundles. Perlecan was present in Disse's space, in endothelial cells, in basement membranes surrounding bile ducts and vessels, in vessel walls, and in mesenchymal cells. The highly differential expression of these HSPGs in the different cell compartments of the liver, as well as in basement membranes and in Disse's space, suggests that each of these proteoglycans has a specific function in the interplay of cells, matrix molecules, growth factors, and proteinases.",0
1562,7737630,Effects of hepatocyte growth factor on the growth and metabolism of human hepatocytes in primary culture,"The effect of recombinant human hepatocyte growth factor (h-rHGF), a potent mitogen for hepatocytes, was investigated in primary cultures of human hepatocytes. Here, we describe a series of experiments to investigate the kinetics of its mitogenic action, as well as its metabolic effects on cultured human hepatocytes. The h-rHGF is a potent signal for initiating DNA synthesis in human hepatocytes, with maximal stimulatory effects at 10 ng/mL (0.1 pmol/L). The kinetics of DNA synthesis showed a lag of about 48 to 72 hours, followed by a maximum at 96 hours. At least 48 hours of continuous exposure to h-rHGF are required to initiate DNA synthesis in quiescent human hepatocytes. Cell cycle analysis by flow cytometry showed that most of quiescent 2c cells have left G0/G1 and entered the cell cycle (S and G2/M phases) by 96 hours of continuous exposure to h-rHGF. When compared with other growth factors, h-rHGF was a much more potent mitogen. The effects of 10 ng/mL (0.1 pmol/L) h-rHGF on DNA synthesis were only achieved by 1.5 pmol/L epidermal growth factor (EGF), 0.1 mumol/L insulin, or 1 mumol/L glucagon. It is noteworthy that the effect of h-rHGF was potentiated by glucagon but not by insulin or EGF. The stimulatory effect of HGF on DNA synthesis was gradually inhibited by h-rHGF transforming growth factor beta (TGF-beta) in the range 1 to 10 ng/ml. The HGF also influenced the expression of other hepatic genes.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1563,7739683,Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes,"BACKGROUND: Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert-Eaton syndrome. The calcium-channel subtype that is responsible is not known. METHODS: We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex. RESULTS: P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti-P/Q-type calcium-channel antibodies were found in serum from all 32 patients with Lambert-Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with Lambert-Eaton syndrome without cancer. Anti-N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert-Eaton Syndrome. Lower titers of anti-P/Q-type and anti-N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma. CONCLUSIONS: The high frequency of P/Q-type calcium-channel antibodies found in patients with Lambert-Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.",0
1564,7760871,New neuromuscular blocking drugs,"The new nondepolarizing neuromuscular blocking drugs have specific advantages over succinylcholine. Rocuronium has an onset of action that is almost as rapid as that of succinylcholine and may be useful in patients with residual gastric contents. This drug may replace vecuronium, since the two agents are otherwise similar. The onset of action of mivacurium is similar to that of atracurium, but recovery from the blockade is more rapid (if the plasma cholinesterase level is normal), making mivacurium useful for short procedures. Although pipecuronium and doxacurium have minimal effects on the cardiovascular system, their long and variable onset and duration of action limit their usefulness. The need for either drug is questionable. There is still a need, however, for a nondepolarizing drug that has an onset of action as rapid as that of succinylcholine but a duration of action similar to that of mivacurium, with no adverse cardiovascular effects and clearance from the body that is independent of organ function.",0
1565,7768508,Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis,"Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 +/- 70; no ascites, 597 +/- 48; controls, 331 +/- 25 fmol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = -.56, P < .0001) and systemic vascular resistance (r = -.69, P = .014) and directly with cardiac index (r = .74, P < .01). The chronic administration of the NO synthesis inhibitor NG-nitro-L-arginine-methyl-ester (L-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in L-NAME-treated control rats (86 +/- 14 vs. 89 +/- 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after L-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation.",0
1566,7768516,Prostanoid secretion by rat hepatic sinusoidal endothelial cells and its regulation by exogenous adenosine triphosphate,"We investigated the secretory profiles of prostanoids in two types of nonparenchymal cell from the rat liver, sinusoidal endothelial cells and Kupffer cells, in primary culture both under basal conditions and after stimulation with adenine nucleotides. Prostaglandin (PG) E2 was the main prostanoid secreted by both types of hepatic nonparenchymal cell in the basal and adenosine triphosphate (ATP)-stimulated states. Time- and concentration-dependent effects of ATP-mediated PGE2 secretion were noted in sinusoidal endothelial cells, whereas the profile of the relative potencies of individual nucleotides was consistent with the presence of P2y and P1 purinergic receptors. In Kupffer cells, the regulation of prostanoid secretion by adenine nucleotides was essentially the same as that in sinusoidal endothelial cells except that adenosine did not stimulate prostanoid secretion and that prostanoid secretion differed somewhat; Kupffer cells secreted relatively more PGF2 alpha and less 6-keto-PGF1 alpha than sinusoidal endothelial cells in the presence of ATP, suggesting the presence of only P2y receptors. In summary, PGE2 is the main prostanoid secreted by hepatic nonparenchymal cells and its secretion may be stimulated by adenine nucleotides and adenosine.",0
1567,7800006,"Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy","BACKGROUND: Inadequate reconstitution of CD4+ T lymphocytes is an important clinical problem complicating chemotherapy, human immunodeficiency virus infection, and bone marrow transplantation, but relatively little is known about how CD4+ T lymphocytes regenerate. There are two main possibilities: bone marrow-derived progenitors could reconstitute the lymphocyte population using a thymus-dependent pathway, or thymus-independent pathways could predominate. Previous studies have suggested that the CD45RA glycoprotein on CD4+ T lymphocytes is a marker for progeny generated by a thymus-dependent pathway. METHODS: We studied 15 patients 1 to 24 years of age who had undergone intensive chemotherapy for cancer. The absolute numbers of CD4+ T lymphocytes in peripheral blood and the expression of CD45 isoforms (CD45RA and CD45RO) on these lymphocytes were studied serially during lymphocyte regeneration after the completion of therapy. Radiographic imaging of the thymus was performed concomitantly. RESULTS: There was an inverse relation between the patients' ages and the CD4+ T-lymphocyte counts six months after therapy was completed (r = -0.92). The CD4+ recovery correlated quantitatively with the appearance of CD45RA+CD4+ T lymphocytes in the blood (r = 0.64). There was a higher proportion of CD45RA+CD4+ T lymphocytes in patients with thymic enlargement after chemotherapy than in patients without such enlargement (two-sided P = 0.015). CONCLUSIONS: Thymus-dependent regeneration of CD4+ T lymphocytes occurs primarily in children, whereas even young adults have deficiencies in this pathway. Our results suggest that rapid T-cell regeneration requires residual thymic function in patients receiving high-dose chemotherapy.",0
1568,7802867,Protein synthesis in the developing rat liver: participation of initiation factors eIF-2 and eIF-2B,"We studied the decline in protein synthesis in the developing liver in suckling rats (4 to 10 days) and adult rats (2 mo). The rate of protein synthesis was measured with a cell-free system and compared with the activity of two initiation factors, eukaryotic initiation factor-2 and eukaryotic initiation factor-2B, and with casein kinase II, which phosphorylates both factors in vitro. The specific activity of the three parameters decreased in adult rats compared with suckling rats and in parallel to the rate of protein synthesis. Quantification of eukaryotic initiation factor-2 in the ribosomal salt wash and in the postmicrosomal supernatant showed that both the specific activity and the levels of eukaryotic initiation factor-2, are much higher in the ribosomal salt wash fractions than in postmicrosomal supernatants, but no differences were found between the two age groups. The eukaryotic initiation factor-2/ribosome ratio was higher in adult rats than in suckling rats, and this parameter seems to be inversely proportional to the rate of protein synthesis. The phosphorylation state of eukaryotic initiation factor-2 alpha, as determined by isoelectric focusing followed by protein immunoblotting, revealed very low and equal levels of phosphorylation in the two animal groups. The lack of changes in eukaryotic initiation factor-2 levels and phosphorylation status suggests that a decrease in the activity or levels of eukaryotic initiation factor-2B could be responsible for the decrease in eukaryotic initiation factor-2 activity and account for, at least in part, the differences observed in the rates of protein synthesis.",0
1569,7806151,Hemodynamic characteristics of the intrahepatic portal vascular bed over an extended flow range: a study in the isolated perfused rat liver,"The relationship between the perfusion pressure (P) and resistance (R) of the intrahepatic portal vascular bed was determined in isolated rat liver preparations perfused with fresh, heparinized rat blood (hematocrit 30%), with rat blood containing a vasodilator agent (sodium nitroprusside, 1 X 10(-3) mol/L), or with 2.5% bovine serum albumin in Krebs-Henseleit buffer (BSA-KH). Pressure-flow curves were constructed over an extended range of portal venous inflow (0 to 70 mL.min-1, corresponding to a flow rate per gram liver wet weight, Q, of approximately 0 to 7 mL.min-1.g-1). Subsequent analysis showed that two mathematical expressions adequately described the data over the full range of flow. Thus, the pressure-flow curve could be represented by (a) the sum of a linear plus a hyperbolic function, i.e., P = Q.R' + Pmax.Q/(Q + Km), where R', Pmax, and Km are constants, or (b) by the simple equation G = C.P, where G is the conductance (Q/P), and C is a conductivity constant. The values of R', Pmax, Km, and C were significantly different under each of the circumstances investigated, but the form of the curve was not altered. Hence, it is proposed that these parameters can be used to describe the fundamental hemodynamic properties of the portal vascular bed of the isolated rat liver. The results are discussed in terms of the microvascular recruitment and distensible resistance vessel models of the hepatic microcirculation.",0
1570,7806169,Anti-liver cytosolic antigen type 1 (LC1) antibodies in childhood autoimmune liver disease,"Antibodies to liver cytosol antigen type 1 (anti-LC1), which recognize a 60-kd peptide contained in the liver cytosolic fraction, have been reported to define a subset of autoimmune hepatitis (AIH) either negative for other autoantibodies or positive for anti-liver kidney microsomal antibody type 1 (LKM-1) and to be best detected in immunodiffusion. To analyze the prevalence of anti-LC1 in childhood liver disease, we have tested the sera of 95 patients using immunoblot, indirect immunofluorescence, and immunodiffusion. Fifteen children had smooth muscle antibody (SMA) and/or anti-nuclear antibody (ANA)-positive AIH, 13 had anti-LKM-1-positive AIH, 14 had autoimmune sclerosing cholangitis (ASC) (all SMA and/or ANA positive), and 53 had non-autoimmune liver disease (10 had alpha 1-anti-trypsin deficiency [alpha 1-ATD], 11 had Wilson's disease [WD], 14 had Alagille's syndrome, and 18 had chronic hepatitis B virus [HBV] infection). Twenty healthy children were studied as controls. Anti-LC1 positivity in immunodiffusion and strong reactivity in immunoblot were found in 4 LKM-1- and 2 SMA/ANA-positive patients with AIH and in 1 patient with ASC, but in none of the patients with other liver diseases nor in controls. A weak 60-kd band was detected by immunoblot in 6 more patients with AIH (2 were LKM-1- and 4 were SMA/ANA-positive) and 6 patients with ASC, all anti-LC1-negative by immunofluorescence and immunodiffusion. No distinct clinical features characterized the anti-LC1-positive patients.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1571,7806174,Metabolism of cholesterol and low- and high-density lipoproteins in primary biliary cirrhosis: cholesterol absorption and synthesis related to lipoprotein levels and their kinetics,"Cholesterol absorption, elimination, and synthesis, and low-density lipoprotein (LDL) and high density lipoprotein (HDL) kinetics were studied in patients with mild to severe primary biliary cirrhosis (PBC) (n = 16) to show how this cholestatic disease modified cholesterol and lipoprotein metabolism as compared with healthy controls (n = 50). Serum total and lipoprotein cholesterol and triglyceride levels were similar in the two groups, but in PBC, especially in severe forms, very low density lipoprotein (VLDL) was rich in apoprotein (apo) B and cholesterol and low in triglycerides, whereas LDL was rich in triglycerides and low in esterified cholesterol, and HDL was enriched by surface lipids, phospholipids, and free cholesterol. In severe PBC, the fractional catabolic rate (FCR) for LDL apo B was reduced. The transport rate (TR) for LDL apo B was unaffected and it tended to correlate with the LDL apo B and LDL cholesterol levels in PBC, whereas in the controls the LDL apo B concentration was regulated by both the FCR and TR, and LDL cholesterol was regulated only by FCR. FCR for apo A-I in HDL was unaltered in PBC, but TR for apo A-I was reduced in the severe cases. Cholesterol absorption efficiency was significantly reduced in PBC (14.5 +/- 3.0% in severe PBC and 34.0 +/- 2.5% in mild PBC vs. 47.4 +/- 1.4% in the controls, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)",0
1572,7807908,The detoxifying action of peritoneal dialysis in experimental acute diffuse peritonitis],The use of fatty substances (cod-liver oil and fatty emulsions) in association with streaming and dropping dialyzing solutions injection every 4 h have permitted to increase the peritoneal dialysis duration at the acute common peritonitis up to 5 days (the method was proposed by A. A. Shalimov and V. I. Shaposhnikov in 1970). The experiment done on 47 dogs have confirmed the peritoneal dialysis promotion of homeostasis indexes normalization due to the pronounced detoxication effect. ,0
1573,7808200,Radiotherapy for cancer of the larynx: review of a community hospital experience,"Records of 106 patients with squamous cell carcinoma of the larynx treated with radiation therapy (RT) at Washington Adventist Hospital between 1976 and 1988 were analyzed for patterns of failure and survival, with a minimum of five-year follow-up. In patients treated with RT alone, initial local control rate was 72% for tumors involving supraglottic larynx and 90% for glottic larynx; in postoperative RT patients, the rate was 65% in the supraglottic and 67% in the glottic larynx group. The laryngeal preservation rate in patients treated with RT alone was 87% in those with early lesions (T1 and T2) and 63% in those with advanced tumors (T3 and T4). The overall five-year determinate survival rates of the RT-only group and the postoperative RT group were 90% and 57%, respectively. In patients with advanced tumors (stages III and IV), survival rates were comparable for RT alone and postoperative RT (56% and 52%, respectively). ",0
1574,7808485,Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection,"BACKGROUND: In most subjects infected with human immunodeficiency virus type 1 (HIV-1), clinical or laboratory evidence of immunodeficiency develops within 10 years of seroconversion, but a few infected people remain healthy and immunologically normal for more than a decade. Studies of these subjects, termed long-term survivors, may yield important clues for the development of prophylactic and therapeutic interventions against the acquired immunodeficiency syndrome. METHODS AND RESULTS: We studied 10 seropositive subjects who remained asymptomatic with normal and stable CD4+ lymphocyte counts despite 12 to 15 years of HIV-1 infection. Plasma cultures were uniformly negative for infectious virus. However, particle-associated HIV-1 RNA was detected in four subjects with a sensitive branched-DNA signal-amplification assay, whereas in five others the levels of HIV-1 RNA were too low to detect. Infectious HIV-1 was detected in peripheral-blood mononuclear cells (PBMC) of three subjects by standard limiting-dilution cultures, and infectious virus was recovered from another subject with use of a CD8-depleted culture. The other six subjects had no detectable infectious virus in their PBMC. A quantitative polymerase-chain-reaction assay revealed that all subjects had detectable but low titers of viral DNA in PBMC. Overall, the viral burden in the plasma and PBMC of long-term survivors was orders of magnitude lower than that typically found in subjects with progressive disease. There was no in vitro evidence of resistance by host CD4+ lymphocytes to HIV-1 infection. However, long-term survivors had a vigorous, virus-inhibitory CD8+ lymphocyte response and a strong neutralizing-antibody response. In two subjects the kinetics of viral replication were consistent with the presence of a substantially attenuated strain of HIV-1. CONCLUSIONS: Subjects who remain asymptomatic for many years despite HIV-1 infection have low levels of HIV-1 and a combination of strong virus-specific immune responses with some degree of attenuation of the virus.",0
1575,7808572,Stiff-man syndrome. Report of 4 cases],"Four patients are presented who exhibited progressive muscular rigidity in both legs, the thoracolumbar, paraspinal and the abdominal muscles. In only one patient, there was an initial involvement of the shoulder girdle muscles. Electromyography in all four patients at rest recorded continuous electric activity resembling an interference pattern. Following sudden exteroceptive stimuli the activity increased in amplitude and density this corresponded clinically to painful spasms. All patients had oligoclonal banding in CSF. In the serum and CSF of three patients IgG subtype autoantibodies were detected. These have been found to be directed against GABAergic nerve terminals in the rat and human cerebellum and, more specifically, to glutamic acid decarboxylase. All patients improved on clonazepam. Trials of intermittent high-dose methylprednisolone administration gave relief from rigidity in one patient and permitted reduction of clonazepam in another. Intravenous immunoglobulins however had no effect in one patient. ",0
1576,7809000,Leucine aminopeptidase activity in adults of Pomphorhynchus laevis (Acanthocephala): a histochemical study,"In frozen sections of the acanthocephalan Pomphorhynchus laevis, which is a frequent intestinal parasite of cyprinid and salmonid fishes, leucine aminopeptidase (APase) was localized histochemically in outer parts of the presomal bulbus as well as in all layers and most nuclei of the metasomal body wall. Enzyme activity visualized at pH 6.5 using L-leucyl-4-methoxy-2-naphtylamide as the substrate was also associated with ovarian balls, immature larvae, and the testes. The results are discussed with respect to the possible function of APases and the proposed sites of amino acid uptake in tissues of P. laevis. ",0
1577,7809029,Multimerization behaviour of single chain Fv variants for the tumour-binding antibody B72.3,"A systematic study has been performed on the relationship between linker length, relative orientation of variable domains, multimerization behaviour and antigen binding activity for single chain Fvs (scFvs) of the tumour-binding antibody B72.3. Thirteen scFv variants with linkers comprising up to six repeats of the motif Gly-Gly-Gly-Gly-Ser were studied. All these scFvs showed a tendency to form dimers or higher molecular weight species, and this tendency decreased with increasing linker length. The dimers and higher molecular weight forms may arise from head to tail intermolecular association of VH and VL domains. For each linker length, scFvs with the organization VL-linker-VH showed greater binding activity than those with the organization VH-linker-VL. In fact, for the latter organization only the variant with a 30 amino acid linker showed good binding activity, suggesting that (i) for B72.3 the C-terminus of VH or the N-terminus of VL makes a structural contribution to antigen binding, and (ii) shorter linkers interfere with this contribution. Antigen binding studies on scFvs should be interpreted with caution because of their tendency to multimerize. Such multimerization can be minimized by using linkers longer than those in common use. ",0
1578,7809108,Characteristics of peptide and major histocompatibility complex class I/beta 2-microglobulin binding to the transporters associated with antigen processing (TAP1 and TAP2),"The transporter proteins associated with antigen processing (TAP proteins) transport antigenic peptides across the endoplasmic reticulum membrane where they can assemble with newly synthesized major histocompatibility complex (MHC) class I/beta 2-microglobulin (beta 2m) dimers. We have shown previously that TAP possesses a peptide-recognition site with broad specificity and that MHC class I/beta 2m dimers physically associate with TAP. Here, we further characterize the nature of the peptide-binding site on TAP, and the site of interaction of TAP with MHC class I/beta 2m dimers. TAP photoaffinity labeling experiments revealed that both TAP1 and TAP2 are photolabeled by two distinct photopeptide analogues, suggesting that elements of both TAP1 and TAP2 compose the peptide-recognition site. TAP photolabeling analysis on transfectant cell lines that express TAP1 and TAP2 both individually and together revealed that efficient formation of the peptide-binding site occurs only when TAP1 and TAP2 are coexpressed, which correlates with the finding that peptide translocation via TAP occurs only in the presence of both TAP1 and TAP2. These data strongly support the notion that TAP functions as a heterodimer. MHC class I/beta 2m dimers were shown to associate with individual TAP1 chains but were not detectable with individual TAP2 chains. This result suggests that the site of interaction for MHC class I/beta 2m dimers with TAP is on TAP1. ",0
1579,7809163,Ablation of islet endocrine cells by targeted expression of hormone-promoter-driven toxigenes,"Ontogenic relationships between the different types of endocrine cells in the islets of Langerhans were explored by generating transgenic mouse embryos in which cells transcribing the glucagon, insulin, or pancreatic polypeptide genes were destroyed through the promoter-targeted expression of the diphtheria toxin A chain. Embryos lacking glucagon- or insulin-containing cells did not exhibit alterations in the development of the nontargeted islet cell types, whereas embryos lacking pancreatic polypeptide gene-expressing cells also lacked pancreatic insulin- and somatostatin-containing cells. These results show that neither glucagon nor insulin gene-expressing cells are essential for the differentiation of the other islet endocrine-cell types. These results also suggest that pancreatic polypeptide gene-expressing cells are indispensable for the differentiation of islet beta and delta cells because the former produce a necessary paracrine or endocrine factor and/or operate through a cell-lineage relationship. ",0
1580,7809801,Common bile duct stones after laparoscopic cholecystectomy and its treatment. The role of ultrasound and intravenous and intraoperative cholangiography,"In the present work we recount our experience in handling common bile duct stones (CBDS) in our first 100 cases of laparoscopic cholecystectomy. In the first 50 cases our diagnostic procedures involved the use of ultrasound exploration and intravenous cholangiotomography 48 h before laparoscopic surgery. We found three cases of residual CBDS. One of the cases was treated by means of ERCP. The other two cases were resolved by carrying out a transparietohepatic cholangiography after the ERCP procedure failed. After this experience, we changed our strategy, introducing the intraoperative cholangiography in the cases with an unclear diagnosis. With this new approach, no residual CBDS occurred in the following 50 cases. These findings demonstrate the following: (1) In our hands, intravenous cholangiography is not more effective than ultrasound exploration in resolving dubious cases. (2) These dubious cases are more effectively diagnosed by means of selective intraoperative cholangiography. (3) When CBDS is treated by transparietohepatic cholangiography it proves to be less uncomfortable for the patient than ERCP and, as we found, even more efficient in removing the stones, although our experience is based on only two cases. ",0
1581,7809895,WHO strategies to reduce childhood mortality in developing countries],"In 1990, world political leaders decided to make an effort to reduce childhood mortality in developing countries. One of several formulated goals was to reduce childhood mortality by one third compared with the figures for 1990. The child health programmes, which include vaccination, diarrhoeal and respiratory infection programmes, have already managed to reduce the mortality from common childhood diseases significantly. WHO is primarily an organization with technical cooperative aspirations, but still needs all possible available professional and economic support, in order to reduce childhood mortality even further. ",0
1582,7809921,Inhibition of leukotriene B4 synthesis does not prevent development of acute renal failure following storage and transplantation,"Compound BW B70C, a selective 5-lipoxygenase inhibitor was tested for its ability to reduce inflammatory damage in an in vivo rabbit model of renal storage and transplantation. Kidneys were stored at 0-2 degrees C for 48 hr prior to autografting. In controls, renal vein LTB4 levels rose significantly after 30 min reperfusion but fell after 2 hr to baseline. TxB2 levels remained at baseline for the 6 hr measured. 6-k-PGF1 alpha levels rose significantly after 1 hr of reperfusion and remained elevated thereafter. Histology after 6 hr reperfusion showed moderate-to-severe cortical edema and mild congestion. Infused colloidal carbon was retained in the perivascular area in a narrow band at the corticomedullary junction, indicating a zone of vascular permeability. At 3 days after transplant, kidneys exhibited widespread tubular necrosis and calcification but little inflammation. Serum creatinine and urea peaked between days 3 and 5. 3/6 rabbits showed no symptoms of renal failure after 3 weeks. Pretreatment with BW B70C prevented the increase in LTB4 but had little effect on TxB2 and 6-k-PGF1 alpha levels. Histology showed no amelioration of cortical edema at 6 hr and congestion and hemorrhage were exacerbated. BW B70C had no effect on either colloidal carbon retention or distribution but did significantly reduce tubular necrosis and calcification at day 3. There was very little inflammatory infiltrate. BW B70C treatment did not improve the long-term viability of transplanted kidneys: 2/6 rabbits showed no symptoms of renal failure after 3 weeks. These data indicate that inhibition of LTB4 synthesis by BW B70C does not prevent the development of acute renal failure following 48 hr hypothermic storage and transplantation. ",0
1583,7809996,Ochronotic arthropathy: structural and ultrastructural features,"Fragments of articular cartilage and synovial membrane in a case of ochronosis were studied by light microscopy (LM), polarized light, and transmission electron microscopy (TEM). Granular and/or shard-shaped pigments were observed in the synovia, cartilage, and subchondral tissue, and dispersed pigment was also seen in the synovial fluid. Zones of the articular cartilage surface showed small erosions near shards, and sometimes, when the degenerative process was in an advanced stage, a substitutive fibrosis of the cartilage edge was demonstrated. LM and TEM observations of the samples studied revealed an alteration of collagen fibrils that appeared wavy and sometimes fragmented with loss of periodicity. They were always mixed with the dispersed pigment. A peculiar finding that characterized this ochronotic case was the complete absence of inflammatory infiltrates or signs of monocyte-macrophage activation. These structural and ultrastructural observations suggest that the pigment deposition in the articular surfaces was due to the synovial fluid circulation and partially to subchondral blood flow, which transports and stores the ochronotic pigments in the synovia and cartilage. These etiopathologic elements associated with the mechanical pathogenesis naturally present in the joints can contribute to the explanation of the pathogenesis and origin of ochronotic arthropathy. ",0
1584,7810402,Influence of management technology and parturition on antibody levels in cows with bovine leukosis,"Sera from 97 Holstein-Friesian cows kept in isolation (herd I) were tested on 9 occasions with an interval of 90 days. The cows had previously given a positive reaction with bovine leukaemia virus antigen in the agar gel immunodiffusion (AGID) test. During the period of loose housing (at tests 1-3) 0-3 cows per test (0-3.1%) gave a negative reaction. When the same animals were kept in the tie-in system (at tests 4-7) the number of negative reactors varied between 9 and 26 (16.9-20.1%). Twenty-eight cows of herd II were tested serologically by the AGID test on a total of 9 occasions from day 60 before term up to postpartum day 90. The lowest antibody level was obtained at calving, when 7 cows gave a negative result in the AGID test. In three cows the decline of antibody level was so pronounced that their serum was negative even after postpartum day 60. One cow was negative even at the end of the test period (on postpartum day 90). The variation in serum antibody level was demonstrable also by ELISA; however, by that test none of the animals gave a negative result. The antibody level demonstrable in the milk reached its peak at calving and then it underwent a gradual decline; however, it did not drop below the detectability limit by the end of the test period. It is concluded that in bovine leukosis infected herds the performance of the AGID test is extremely impaired by the use of the tie-in housing system, as well as by a combined effect of tying in and parturition. Therefore, during the leukosis eradication and qualification of herds kept in a tie-in system, ELISA is the method that can be used, instead of AGID, with satisfactory efficacy even for the testing of sera. ",0
1585,7810640,cAPK mediates placental renin secretion stimulated by beta-adrenoceptor activation,"Previous studies have indicated that activation of placental beta-adrenoceptors stimulates renin secretion, whereas basal secretion is extremely low. This response is potentiated by inhibition of types III and IV phosphodiesterases, implicating a role for adenosine 3',5'-cyclic monophosphate (cAMP). Described are experiments aimed at defining the regulatory influence of cAMP and cAMP-dependent protein kinase (cAPK) isotypes in renin secretion. Human placental explants were cultured with dobutamine, a beta 1-agonist, and cAPK activity, renin, and cAMP concentrations were determined. After 48 h of incubation, media concentrations of renin and cAMP increased and were positively correlated. Tissue cAPK activity was positively correlated with renin secretion associated with dobutamine. Renin secretion was measured in response to substituted cAMP analogues selective for a unique cAMP binding site (site A or B) for cAPK regulatory subunits. A fivefold stimulation of renin secretion by the type II site B activators occurred, whereas a threefold increase was seen with a type I site B analogue. Site A-selective analogues for cAPK types I and II produced no stimulation. Dobutamine-induced renin secretion was attenuated by selective inhibitors of cAPK regulatory and catalytic subunits. These findings indicate that placental renin secretion associated with beta-adrenoceptor activation is correlated with cAMP generation and mediated predominantly by the type II isoform of cAPK. ",0
1586,7810718,Skeletal muscle phosphate metabolism abnormalities in volume-overload experimental heart failure,"We studied skeletal muscle phosphate metabolism abnormalities to examine their contribution at an early stage of congestive heart failure (CHF) in rats with aortocaval fistula (ACF) 4 wk after the procedure. In a group of 26 rats (13 with ACF and 13 sham operated), we assessed the degree of CHF. The ACF produced a significant rise in heart weight and plasma atrial natriuretic peptide. In a second group of 26 rats (13 ACF and 13 sham operated), we performed 31P-magnetic resonance spectroscopy in the gastrocnemius muscle during motor activity produced by electrical stimulation. The rate of phosphocreatine depletion, expressed by its initial slope, was higher in the ACF rats compared with controls (0.078 +/- 0.01 vs. 0.041 +/- 0.007; P < 0.03). pH and ATP decreased and phosphodiesters increased in all rats during electrical stimulation, with no difference between ACF rats and controls. The kinetics of phosphocreatine recovery were not different between ACF rats and controls. Together with previous studies, our present results suggest that muscle metabolism abnormalities in CHF may vary according to the experimental model and may be observed early in the course of the disease. ",0
1587,7810779,An analysis of rotator cuff repair,"Fifty-four patients who had surgery to repair a chronic rotator cuff tear (54 shoulders) were followed for an average of 25.9 months (range, 16 to 43). Forty-nine of 54 patients had at least 20 months of followup. The average age of the male patients (N = 37) was 52 (range, 24 to 80) and of the female patients (N = 17) was 56 (range, 38 to 72). All of these patients received a functional evaluation based on the Shoulder and Elbow Surgery Society classification system. Forty-eight patients had an individual examination and 33 patients had an isokinetic strength evaluation. There were 43 patients (80%) with a satisfactory functional result and 11 (20%) with an unsatisfactory result. Unsatisfactory results were associated with large and massive tears and decreased postoperative range of motion. Good functional results were obtained by open repair and subacromial decompression for rotator cuff tear. Arthroscopic evaluation and treatment did not affect the functional outcome, but it did increase costs by about $2000 per patient. Arthroscopy is useful to define tear size, which may affect the surgical approach, but the arthroscopic treatment of glenohumeral problems did not alter the functional result. The routine use of arthroscopy before rotator cuff repair is costly, not effective, and therefore not recommended. ",0
1588,7811179,Sleep apnea in patients with hemispheric stroke,"Sleep pattern and breathing in humans are altered following cerebrovascular accidents involving the brainstem. Sleep apnea is a well-established complication of stroke involving the brainstem. On the other hand, the effect of cerebral stroke on sleep and breathing has not been well defined. The diffuse cerebral symptoms such as cognitive deficits, depression or fatigue, after hemispheric stroke mimic those present in patients with sleep apnea. To define the breathing pattern in patients with stroke involving cerebral hemispheres without brainstem lesion and without the prior history of sleep-disordered breathing, we studied 10 patients within 1 year of their stroke. The data collected during polysomnography from the stroke patients were compared with a group of subjects matched for age, body mass index, presence of hypertension, and smoking history without stroke. Patients with stroke had an abnormal sleep architecture with significantly lower slow wave sleep and rapid eye movement (REM) sleep when compared with controls. Sleep was fragmented because of the presence of increased respiratory disturbances. Stroke patients had a respiratory disturbance index of 52 +/- 10 events per hour when compared with 3 +/- 1 in controls (p < .05). Majorities of respiratory events were obstructive apneas and were associated with arterial oxygen desaturations and arousals. The pathogenic mechanism of sleep-disordered breathing in patients with hemispheric stroke seems to be related to the physiological effect of sleep on already compromised upper airway muscle control. Patients with stroke and diffuse cerebral symptoms should be investigated for the possibility of sleep-disordered breathing. ",0
1589,7811210,Service-mix provided to patients in Australian private practice,"Service-mix can reflect changes in demographic factors, oral health, patient demand and treatment philosophies. The aim of this study was to compare service-mix by patient age in 1988 with baseline data from 1983. A weighted, stratified random sample of dentists in Australia was surveyed by mailed questionnaire in 1983 and again in 1988. Service-mix was dominated by restorative, diagnostic and preventive areas. Comparing 1988 with 1983, there were significant increases for diagnostic, preventive, advanced restorative, orthodontic and general areas. Patterns across patient age groups and between years indicated younger patients were being provided with increased preventive services (patients aged 5-11, 25-44 years) and decreased restorative services (patients aged 5-11, 12-17 years), while older patients were being provided with reduced prosthodontic services (patients aged 25-44, 45-64 years), but increased restorative services (patients aged 45-64, 65+ years) and advanced restorative services (patients aged 25-44, 45-64 years). These patterns of service-mix have implications for dental education, research and service delivery. ",0
1590,7811280,"Cardiac myocyte differentiation induced by 3,5,3'-triiodo-L-thyronine (T3) in P19 teratocarcinoma cells is accompanied by preferential binding of RGG(T/A)CA direct repeats spaced by 4 base pairs in the DNA","""When treated with T3, P19 cells differentiate into ultrastructurally proven cardiac myocytes and express the cardiac ventricular specific marker ventricular myosin light chain 2V. This differentiation is irreversibly induced in culture during the first 48 hrs of exposure to T3. We studied the binding of P19-indigenous transcription factors of the Steroid-Thyroid-Retinoic superfamily of nuclear receptors to oligonucleotide response elements bearing direct, inverted and palindromic repeats of the consensus sequence RGG(T/A)CA. Electrophoretic mobility shift assays showed a preference in T3-treated P19 cells for binding RGG(T/A)CA """"half sites"""" in direct repeat orientation separated by 4 base pairs. The specificity of binding was confirmed in competition experiments. This finding suggests that target genes bearing thyroid response elements spaced by 4 base pairs in their promoter regions play an important role in the cardiac differentiation induced by T3 in P19 teratocarcinoma cells. """,0
1591,7811370,Comparison between pharmacologic actions of rabbit bile and bear bile],"In our experiment it was observed that many pharmacologic actions of the rabbit bile were similar to those of bear bile. It was also demonstrated that the effects of the rabbit bile were more obvious than those of bear bile in positive inotropic action, sedation, antitussive action, antihistaminic action and so on. ",0
1592,7812027,Intravariceal pressure measurement in cirrhotic patients: is it a reliable technique?,"""The aim of the present study is to evaluate in both """"in vitro"""" and clinical conditions the reliability of the method for measuring the oesophageal varices pressure by means of a sclerosing needle. The perfusion system was validated """"in vitro"""", comparing the tracings obtained with two different perfusion apparatus, with two different perfusional agents and with the needle either completely or partially inserted in a venous catheter perfused with saline solution, either in the same direction as the flow or the opposite one. The clinical validation was conducted on 14 cirrhotic patients with II to IV grade oesophageal varices according to Dagradi's classification. During endoscopy, the intravariceal and oesophageal pressures were measured using a sclerosing needle, perfused with hydrosoluble contrast medium. Once the intravariceal pressure measurement was completed, an X-ray film of the chest was performed. The data were evaluated considering the absence of visible contrast medium as evidence of correct intravariceal needle position, and the presence of a roundish image as evidence of paravariceal insertion of the needle. The presence of respiratory oscillations and intravariceal pressure values were verified in manometric tracings and were compared with radiological findings. The """"in vitro"""" tests showed no differences in the pressure recording obtained using different pumps, different perfusion agents and with different manners of inserting the needle. Only twenty-eight of the manometric recordings were considered adequate for evaluation in clinical conditions.(ABSTRACT TRUNCATED AT 250 WORDS) """,0
1593,7812083,"Effect of insulin-induced hypoglycemia, 2-deoxyglucose-induced glucose cytopenia, and hyperglycemia on cardiovascular tone in normal and diabetic rats","We studied the metabolic and cardiovascular responses to insulin-induced hypoglycemia, 2-deoxyglucose-induced glucose cytopenia, and hyperglycemia in normal rats and in rats with streptozocin-induced diabetes. Insulin (2.0 U/kg) was infused intravenously into normal and 4-week diabetic rats, and the cardiovascular responses were monitored for 90 minutes. Insulin infusion decreased plasma glucose and mean arterial pressure by the same relative degree in both groups of animals. Heart rate was significantly decreased only in the diabetic rats. The injection of 2-deoxyglucose was followed by an increase in plasma glucose in both normal and diabetic rats. Heart rate was increased in normal rats, and both mean arterial pressure and heart rate decreased in the diabetic animals. Hyperglycemia induced by infusion of glucose increased plasma glucose and insulin and decreased mean arterial pressure and heart rate in both groups of animals. We concluded that acute insulin or insulin-induced hypoglycemia decreases cardiovascular tone in normals and, to a significantly greater extent, in diabetic rats and that while 2-deoxyglucose-induced glucose cytopenia increases cardiovascular tone in normal rats, it elicits a hypotensive response in diabetic ones. Glucose-induced hyperglycemia is associated with a decrease in cardiovascular tone in both groups of animals. ",0
1594,7812226,Litigation and chronic facial pain,"Clinical studies have suggested that the presence of litigation in chronic pain syndromes may complicate diagnostic and treatment strategies. In addition, psychosocial factors may be prevalent in such cases. The present study explored the possible correlation in the facial pain population between patients in litigation and psychological disturbance as measured by the Minnesota Multiphasic Personality Inventory. Beck Depression Inventory and Wahler Symptom Checklist scores also were compared. One hundred eleven patients diagnosed with chronic facial pain were asked if they currently were involved in litigation related to their medical complaints. The result revealed that 18% of the 111 patients were in litigation at the time of their initial visit. The Minnesota Multiphasic Personality Inventory profiles showed that 45% of the litigation patients had four or more clinical scales above 70 (significantly elevated) on the Minnesota Multiphasic Personality Inventory. In contrast, only 18% of the patients who were not in litigation had four or more scales above the 70 criteria. Beck and Wahler scores also were more elevated for the litigation group. The results of the study indicate that chronic facial pain patients in litigation may present with more psychological disturbance as compared to those patients not in litigation. ",0
1595,7812271,Diphosphoryl lipid A derived from the lipopolysaccharide (LPS) of Rhodobacter sphaeroides ATCC 17023 is a potent competitive LPS inhibitor in murine macrophage-like J774.1 cells,"Pentaacyl diphosphoryl lipid A derived from the nontoxic lipopolysaccharide (LPS) of Rhodobacter sphaeroides ATCC 17023 (RsDPLA) did not induce tumour necrosis factor-alpha nor interleukin-6 release in the murine macrophage-like cell line J774.1. However, it effectively inhibited the induction of these two cytokines by LPS of Salmonella minnesota Re mutant R595 (ReLPS) in a concentration-dependent manner. Maximal inhibition and half-maximal inhibition occurred when the ReLPS to RsDPLA mass ratio was 1:30 and 1:1, respectively. A binding study was performed in the presence of serum to determine whether RsDPLA is competing with ReLPS for LPS binding sites on J774.1 cells. This assay allows the determination of LPS binding to J774.1 cells via a mechanism involving CD14, a receptor for complexes of LPS with LPS binding protein (LBP), and its possible inhibition. The results show that RsDPLA strongly inhibits the binding of 125I-labelled ReLPS to J774.1 cells. Maximal and one-half maximal inhibition of binding occurred when the ReLPS to RsDPLA mass ratios were 1:2.5 and 1:0.5, respectively. It was found that the inhibition of binding by RsDPLA was much stronger than that by unlabelled ReLPS. These results suggest that RsDPLA is competing with ReLPS for CD14-dependent recognition of LPS on J774.1 cells. ",0
1596,7812411,Measurement of 13CO2 in expired air as an index of compliance to a high carbohydrate diet naturally enriched in 13C,"The aim of this study was to determine whether breath 13CO2 measurements could be used to assess the compliance to a diet containing carbohydrates naturally enriched in 13C. The study was divided into two periods: Period 1 (baseline of 4 days) with low 13C/12C ratio carbohydrates. Period 2 (5 days) isocaloric diet with a high 13C/12C ratio (corn, cane sugar, pineapple, millet) carbohydrates. Measurements were made of respiratory gas exchange by indirect calorimetry, urinary nitrogen excretion and breath 13CO2 every morning in post-absorptive conditions, both in resting state and during a 45-min low intensity exercise (walking on a treadmill). The subjects were 10 healthy lean women (BMI 20.4 +/- 1.7 kg/m2, % body fat 24.4 +/- 1.3%), the 13C enrichment of oxidized carbohydrate and breath 13CO2 were compared to the enrichment of exogenous dietary carbohydrates. At rest the enrichment of oxidized carbohydrate increased significantly after one day of 13C carbohydrate enriched diet and reached a steady value (103 +/- 16%) similar to the enrichment of exogenous carbohydrates. During exercise, the 13C enrichment of oxidized carbohydrate remained significantly lower (68 +/- 17%) than that of dietary carbohydrates. The compliance to a diet with a high content of carbohydrates naturally enriched in 13C may be assessed from the measurement of breath 13CO2 enrichment combined with respiratory gas exchange in resting, postabsorptive conditions. ",0
1597,7813085,"Apolipoprotein AI, AII, and AIV isoforms in plasma determined by automated isoelectric focusing with PhastSystem and immunofixation","Distinct genetic variants of apolipoprotein (apo) AI have been shown to influence concentrations of high-density lipoprotein (HDL) cholesterol. The genetic polymorphism of apo AIV may modulate HDL-cholesterol, plasma triglycerides, and lipoprotein(a) concentrations. There is evidence for an antagonizing role of apo AII in reverse cholesterol transport. Since genetic polymorphisms and variants of these apolipoproteins are detectable by isoelectric focusing (IEF), we developed a rapid and easy automated method for IEF analysis of apos AI, AII, and AIV on self-made or commercially available gels, using the PhastSystem. Diluted plasma or serum samples (1 microL) are applied automatically onto the gel and IEF is carried out for 35-45 min. Afterwards, the apo A bands are precipitated by specific polyclonal antibodies and visualized by automated silver staining. This rapid procedure is suitable as a routine or screening method for IEF analysis of these major HDL apolipoproteins. ",0
1598,7813118,Potassium channel openers and other regulators of KATP channels,"1. Interest in ATP-sensitive K (KATP) channels first arose when it was shown that hypoglycaemic sulphonylureas, such as glibenclamide, closed these channels in pancreatic beta-cells to cause insulin release. The demonstration that certain smooth muscle relaxants (K channel openers) may exert their actions through opening a similar channel in vascular smooth muscle fueled further investigation of these channels and their physiological role in a variety of tissue types, including various types of smooth muscle, cardiac and skeletal muscle and neural and endocrine organ function. 2. The K channel openers have a variety of potential therapeutic applications, including disorders of smooth muscle hyperreactivity, such as hypertension, and a great deal of research has focused on this field. More recently, attention has turned to the cardiac actions of these compounds and this area is discussed in detail. One of the current problems is the lack of selectivity of KATP channel regulators. However, there have been a number of recent encouraging reports suggesting that, under certain pathophysiological conditions, the action of the K channel openers may be enhanced, conferring upon them some degree of selectivity. 3. A number of endogenous regulators of these channels have been identified, particularly in the category of endogenous openers of these channels. At present though, the physiological role of these channels and the endogenous regulators identified, is unclear. 4. It is evident that, although advances have been made, much work is still required to increase our understanding and ultimately to allow selective pharmacological manipulation of these channels to become a therapeutic reality. ",0
1599,7813182,Oral health status and treatment needs in different age groups in two regions of Tanzania,"The present study was conducted in two regions of Tanzania, where development of oral health services is supported by the Danish International Development Agency (Danida). The study comprised 6035 subjects in five age groups (5-6 yr, 12 yr, 18 yr, 35-44 yr, 55+ yr). Data were collected using WHO's survey methodology. Dental caries affected the primary dentition of one third to one fourth of the 5-6-yr-olds and mean dft was less than 1.0 in both regions. DMFT for 12-yr-olds was also low (< 1.5 DMFT), but was higher in older age groups, mainly due to more missing teeth. The F-component was negligible in all age groups. Treatment need was mainly simple fillings and extractions. Most periodontal sextants in all age groups were affected by bleeding or calculus. Periodontal pockets were rare and loss of teeth limited. It is concluded that the oral health situation in Tanzania is better than that foreseen in the goals for oral health in Tanzania in the year 2002. On the basis of these findings and the severe economic constraints prevailing within the health services in Tanzania, a revision of The National Plan for Oral Health seems urgent. A realistic estimate of the cost and the possible sources of funding of the plan is mandatory. ",0
1600,7813346,"Factors related to frequency, type, and outcome of anal fistulas in Crohn's disease","Relation of clinical factors to frequency, type, and, in particular, outcome of anal fistulas in Crohn's disease was studied. One hundred twelve patients seen in this hospital between January 1972 and June 1993 who suffered from Crohn's disease were included in the study. Those 35 (31 percent) with anal fistulas were re-examined or interviewed and asked about their perianal symptoms and anal control. Rectal involvement of Crohn's disease was associated with an increased incidence of anal fistula (49 vs. 17 percent; P < 0.01), especially high ones (82 vs. 17 percent; P < 0.01). Ten of 18 patients with low fistulas underwent fistulotomy; all 10 fistulas healed, but slowly (mean healing time, 7.5 months), and 4 of them recurred. Of eight low fistulas managed by drainage alone, four healed. Finally, 11 of 18 patients with low fistulas had their fistulas heated. Fourteen of 17 patients with high fistulas were primarily treated by drainage and 3 by local surgery. Finally, only three patients had healed fistulas--two after simple drainage and one after local surgery, and seven patients had to undergo proctectomy. Only two patients with low fistulas required proctectomy. Eight patients (33 percent) of those 24 with fistulas in whom anal continence could be assessed, 5 with local surgery and 3 with drainage alone, reported minor defects in anal control. Fistulotomy is a justifiable option with satisfactory results for low symptomatic anal fistulas associated with Crohn's disease, although healing may be delayed and some fistulas will recur. Outcome of high fistulas is less satisfactory, and proctectomy is ultimately required in a number of patients; therefore, for high fistulas a conservative approach is primarily recommended. ",0
1601,7813350,Results of rectocele repair. A prospective study,"This study was designed to evaluate the results of rectocele repair and parameters that might be useful in selecting patients for this operation. Twenty-five patients with symptom-giving rectoceles were prospectively evaluated with a standardized questionnaire, physical examination, defecography, colon transit studies, anorectal manometry, and electrophysiology. Patients underwent posterior colporrhaphy and perineorrhaphy. They were followed postoperatively (mean, 1.0 year) with the same questionnaire, physical examination, defecography, anorectal manometry, and electrophysiology. Constipation had improved postoperatively in 21 of 24 constipated patients (88 percent). At postoperative follow-up 13 patients (52 percent) had no constipation symptoms, 8 (32 percent) had occasional symptoms, and 4 (16 percent) had symptoms more than once per week. Four patients with rectocele at preoperative defecography, but not at physical examination, had favorable outcomes following surgery. The majority of patients not using vaginal digitalization preoperatively had improved with respect to constipation. All patients with pathologic transit studies had various degrees of constipation postoperatively. Constipation was not improved in two of five patients with preoperative paradoxic sphincter reaction. Rectocele is one cause of constipation that can be treated with good results. Preoperative use of vaginal digitalization is not mandatory for a good postoperative result. Defecography is an important complement to physical examination. Patients with pathologic transit study might have a less favorable outcome of rectocele repair with respect to constipation. More studies about the significance of paradoxic sphincter reaction in these patients are indicated. ",0
1602,7813599,Endocrine characterization of the new dopamine autoreceptor agonist roxindole,"Roxindole (5-Hydroxy-3-(4-phenyl-1,2,3,6-tetrahydropyridil-(1)-butyl)-indol) is a newly developed compound with a high dopamine autoreceptor agonistic potency at D2 receptors. Evaluation of roxindole for clinical purposes in psychiatric patients revealed that the substance has contrary to expectation merely negligible antipsychotic but considerable antidepressive effects. Interestingly it is nearly devoid of any side effects. To further characterize the endocrine effects, 1 mg roxindole was applied at 09:00 to 6 male volunteers and the effects compared to placebo. From 08:00 to 13:00 blood samples were drawn every 30 min. No effect on adrenocorticotropin and cortisol secretion was observed, neither mean plasma concentrations nor area values differed significantly. 90 min after roxindole administration an enhanced release of growth hormone could be observed, comparison of mean hormonal concentration revealed statistical significance (p < 0.05). Also the area values differed significantly (roxindole vs. placebo mean +/- SD 18.1 +/- 17.1 vs. 7.7 +/- 8.0 micrograms x h/l; p < 0.05). After roxindole also a pronounced reduction of prolactin plasma levels from 5.3 +/- 1.4 micrograms/l to 1.1 +/- 0.4 microgram/l within 150 min could be observed. Mean plasma concentrations (p < 0.05) and area values differed significantly (roxindole vs. placebo mean +/- SD 14.8 +/- 13.5 vs. 34.4 +/- 18.1; p < 0.05). Roxindole had no effect on blood pressure parameters and heart rate. The major findings of the present exploratory study are, that roxindole has potent effects on the facilitation of growth hormone secretion and the inhibition of prolactin release. Both findings are complementary and point also to interesting postsynaptic dopamine receptor agonistic effects. ",0
1603,7813622,Molecular characterization of a type I serine-threonine kinase receptor for TGF-beta and activin in the rat pituitary tumor cell line GH3,"GH3 pituitary tumor cells have surface receptors for transforming growth factors-beta (TGF-beta s) and activins/inhibins. GH3 cell mRNA was screened by a novel reverse transcriptase-polymerase chain reaction technique with primers for receptor serine-threonine kinases. We isolated rat homologs of previously identified clones for type I (ALK-2 and ALK-5) and type II (ActRII, TGF-beta RII) activin and TGF-beta receptors, together with a novel clone, whose full-length version was isolated from a GH3 cell cDNA library. Named B1, it encodes a 505-amino-acid protein belonging to the family of type I receptor serine/threonine kinases. The kinase domain of B1 exhibits 90% identity to that of the TGF-beta type I receptor. B1 mRNA is expressed not only in pituitary cells but also in all other cells and tissues examined. B1 protein can be expressed on the cell surface, but cannot bind ligand unless a type II receptor is also present. When coexpressed with the type II receptors specific for TGF-beta or activin, B1 can be efficiently cross-linked to either ligand, suggesting that it can form heteromeric complexes with both type II receptor subunits. ",0
1604,7813623,"Thiophosphorylated RCM-lysozyme, an active site-directed protein tyrosine phosphatase inhibitor, inhibits G2/M transition during mitotic cell cycle and uncouples MPF activation from G2/M transition","Microinjection of thiophosphotyrosylated RCM-lysozyme (TRCML), a potent and specific inhibitor of protein tyrosine phosphatases (PTPs) into sea urchin (Lytechinus pictus) eggs prior to fertilization inhibited the first zygotic cell division in a concentration-dependent fashion. Microinjection of TRCML at varying times after fertilization indicated that at least one site of action is late in the first cell cycle near the G2/M boundary. In order to further study the mechanism for the TRCML effect, a cell-free cell cycling system prepared from electrically activated Xenopus eggs was used. The addition of TRCML to cycling extracts delayed the entrance and progression of extracts through mitosis, as indicated by the inhibition of chromatin condensation, nuclear envelope breakdown, M-phase-promoting factor (MPF) inactivation, and cyclin degradation. Surprisingly, TRCML did not inhibit MPF activation. These results suggest that (1) the target(s) of TRCML lies in late G2- or early M-phase before the onset of metaphase, (2) TRCML uncouples MPF activation from progression through M-phase, and (3) there is a potential involvement of a novel PTP(s) in the control of the cell cycle which may act either downstream of the MPF activation or alternatively in an additional but essential mitotic pathway that is parallel to the MPF activation pathway. ",0
1605,7814105,Caries prevalence in Belgium and The Netherlands,"A list of epidemiological caries studies performed since 1980 in Belgium and The Netherlands was compiled by a literature search and analysed with respect to study design, methods of clinical investigation and the availability of dmft (DMFT) data. The percentages of caries-free 6-year-old children in The Netherlands and Belgium are currently similar. In The Netherlands the data suggest a halt in the decline of caries prevalence since the mid 1990s among 6-year-olds. According to WHO criteria, 12-year-old children in The Netherlands now have a very low caries experience. Children in Belgium belong to the moderate caries experience category. Recent data from the two countries indicate a further decrease in caries prevalence of 12-year-olds during the last decade. Caries prevalence data of adults in Belgium are not available. In The Netherlands the average DMFT-score in the older age groups has hardly changed since 1970. Changes in percentages of edentates in the period 1980-1990 probably reflect part of the changes in oral health status of Dutch adults. The intervention of many methodological problems and confounding factors, such as cultural differences, limit national and international comparisons of caries prevalence data sets. ",0
1606,7814381,Saccharomyces cerevisiae CNE1 encodes an endoplasmic reticulum (ER) membrane protein with sequence similarity to calnexin and calreticulin and functions as a constituent of the ER quality control apparatus,"We have used a polymerase chain reaction strategy to identify in the yeast Saccharomyces cerevisiae genes of the mammalian calnexin/calreticulin family, and we have identified and isolated a single gene, CNE1. The protein predicted from the CNE1 DNA sequence shares some of the motifs with calnexin and calreticulin, and it is 24% identical and 31% similar at the amino acid level with mammalian calnexin. On the basis of its solubility in detergents and its lack of extraction from membranes by 2.5 M urea, high salt, and sodium carbonate at pH 11.5, we have established that Cne1p is an integral membrane protein. However, unlike calnexins, the predicted carboxyl-terminal membrane-spanning domain of Cne1p terminates directly. Furthermore, based on its changed mobility from 76 to 60 kDa after endoglycosidase H digestion Cne1p was shown to be N-glycosylated. Localization of the Cne1p protein by differential and analytical subcellular fractionation as well as by confocal immunofluorescence microscopy showed that it was exclusively located in the endoplasmic reticulum (ER), despite the lack of known ER retention motifs. Although six Ca(2+)-binding proteins were detected in the ER fractions, they were all soluble proteins, and Ca2+ binding activity has not been detected for Cne1p. Disruption of the CNE1 gene did not lead to inviable cells or to gross effects on the levels of secreted proteins such as alpha-pheromone or acid phosphatase. However, in CNE1 disrupted cells, there was an increase of cell-surface expression of an ER retained temperature-sensitive mutant of the alpha-pheromone receptor, ste2-3p, and also an increase in the secretion of heterologously expressed mammalian alpha 1-antitrypsin. Hence, Cne1p appears to function as a constituent of the S. cerevisiae ER protein quality control apparatus. ",0
1607,7814914,Interruption of enteral feedings in head injured patients,"This study was undertaken to determine differences between caloric intake and requirements of critically ill, enterally fed, neurosurgical and neurotrauma patients and to determine the nature and frequency of interruptions in enteral feedings in this same population. This descriptive, prospective study was conducted in a surgical intensive care unit (ICU) in a university teaching hospital. The sample consisted of 52 mechanically ventilated, critically ill patients with a mean age of 48.96 years who were receiving enteral nutrition for at least two days. Basal energy requirements, daily nutritional intake and enteral feeding interruption characteristics were recorded for a total of 586 study days. Underfeeding due to interruptions occurred in the majority of patients for the first eight days following initiation of enteral feeding. Reasons for underfeeding were interruptions of continuous tube feedings due to medication administration via the feeding tube (31%), feeding tube displacement (27%), surgery (12%), ileus (9%), radiologic studies (9%), airway management (8%), bedside procedures (3%) and agitation (1%). The frequency of these enteral feeding interruptions may indicate inadequate nutritional support, highlighting the importance of performing daily nutritional monitoring to prevent malnutrition. ",0
1608,7815494,Modulation of the trans-suppression activity of hepatitis C virus core protein by phosphorylation,"We previously demonstrated that the core protein of hepatitis C virus (HCV) can suppress gene expression and replication of hepatitis B virus (HBV) in a human hepatoma cell line (HuH-7). In this study, we have characterized the phosphorylation property of HCV core protein and examined the effect of phosphorylation on its suppressive activity of HBV. Our results indicated that both the full-length HCV core protein (22 kDa) and its processed or degraded forms (14 to 18 kDa) were phosphorylated in insect cells. As demonstrated by using the glutathione S-transferase fusion protein expression system and in vitro transcription and translation system, the phosphorylation of HCV core protein was carried out by protein kinase A (PKA) and protein kinase C (PKC) in vitro. In both kinase reactions, it was determined that the phosphorylated amino acid was a serine residue. The potential phosphorylated sites in core protein were identified as residues Ser-53 and Ser-116 for PKA and Ser-53 and Ser-99 for PKC. Comparison of the phosphorylation intensities of the wild type and Ser mutants suggested that Ser-99 and Ser-116 were the major phosphorylation sites for PKC and PKA, respectively. The phosphorylation of Ser-99 and Ser-116, but not Ser-53, in HCV core protein was essential for the suppressive activity of HCV core protein on HBV gene expression and replication in HuH-7 cells. Mutation of the former two serine residues to alanine or aspartate residues led to a drastic loss of the inhibitory effects of HCV core protein on HBV gene expression (both transcription and antigen production) and pregenomic RNA encapsidation, as well as the release of HBV virus particles. In contrast, the Ser-53 mutant conferred the same level of suppressive activity as the wild type did. This property is in accordance with the observation that Ser-99 and Ser-116 are the predominant phosphorylation sites in the HCV core construct. All serine mutants (including those with mutations in PKA, PKC, and both kinase recognition sites) of HCV core protein retained the ability to translocate into the nucleus. Furthermore, wild-type HCV core protein diminished its suppressive activity when cells were treated with PKA or PKC inhibitor. In conclusion, HCV core protein is a phospho-protein and in HuH-7 cells, its trans suppression of HBV gene expression and replication is positively regulated by PKA and PKC. The role of phosphorylation in the control of trans-suppressive activity cannot be reproduced by introducing an acidic residue.(ABSTRACT TRUNCATED AT 250 WORDS) ",0
1609,7824000,Recent advances in radiation oncology,"Radiotherapy remains an important component of the management of malignant disease. Especially when combined with cytotoxic chemotherapy, limited surgical excision, or both, irradiation has been shown to control disease in the primary site and regional nodes without the need for surgical extirpation as frequently as in past years. New developments in three-dimensional treatment planning and the precise delivery of high-dose radiation promise to increase the benefit of radiation treatment. Finally, molecular studies of the cell's response to radiation and the phenomena of DNA damage and repair are providing explanations for heretofore unexplained radiobiologic observations. Such research is laying the groundwork for targeted manipulation of the cell's response to radiation, which will be tested in the near future.",0
1610,7843705,Whole-body and segmental bioelectrical parameters in chronic liver disease: effect of gender and disease stages,"The aim of this study was to examine and compare whole-body and segmental impedance measurements in control subjects and patients with progression of liver disease and to investigate whole-body and segmental bioelectrical changes occurring during dehydration therapy or paracentesis. Males have lower resistance (R) and reactance (Xc) values than females in measurements both of the whole body and of the arm, leg, and trunk. This is not true in patients. In the three groups of patients, whole-body R and Xc were lower in each increased disease stage, suggesting that stage has a significant main effect on impedance measurements. The lower extremities were the segment most influenced by the progression of liver disease. The sum of the arm and leg R was only slightly lower than the value of whole-body resistance. The trunk has a meager influence on this parameter, as is clearly shown by the absence of variations before and immediately after paracentesis. In edematous cirrhotic patients without ascites treated with diuretics, our data also showed a significant correlation (r = .81; SEE = 1.2) between changes in body weight (BW) and in the bioelectrical evaluation of total body water (TBW). The association of a prevalent increment of Xc (approximately 40%) with a reduction of extracellular water is the most significant bioelectrical event during dehydration therapy. All these findings show that impedance measurements have a low sensitivity in detecting the volume of ascites in cirrhotic patients, whereas Xc has a clinical use in monitoring changes in extracellular water (EW).",0
1611,7843712,Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population,"The major histocompatibility complex class II alleles at the HLA-DPB1 locus were investigated in 32 German Caucasoid patients with primary biliary cirrhosis (PBC) and compared with those from 47 normal control patients using molecular genotyping techniques. The second exon of the HLA-DPB1 gene was amplified by polymerase chain reaction (PCR) and hybridized with 25 sequence-specific oligonucleotides (SSOs) to assign the HLA-DPB1 alleles on the basis of known sequence variations, according to the protocols of the Eleventh International Histocompatibility Workshop. A strong association of PBC was found with the allele HLA-DPB1*0301. The allele HLA DPB1*0301 was present in 50% (16 of 32) of the patients with PBC compared with 13% (6 of 47) of normal controls (P corrected < .015), whereas the other HLA-DPB1 alleles showed no significant differences in both groups. The relative risk (RR) estimate for the allele HLA-DPB1*0301 was 6.8 (95% confidence limits: 2.27 to 20.57). In summary, this study clearly demonstrates an association of PBC with the HLA-DPB1*0301 allele in German Caucasoids and may add new data to the immunogenetic background of PBC, suggesting a contribution of the HLA-DPB1 gene to the genetic susceptibility of the disease.",0
1612,7843715,Effect of functional grade and etiology on in vivo hepatic phosphorus-31 magnetic resonance spectroscopy in cirrhosis: biochemical basis of spectral appearances,"Hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) was undertaken in 85 patients with histologically proven cirrhosis of varying etiologies and functional severity. Reference data were acquired from 16 healthy volunteers who had no history or evidence of liver disease or alcohol abuse. In vivo hepatic 31P MR spectra were acquired with pulse angle 45 degrees and repetition times (TR) of 5 and 0.5 seconds. Peak area ratios of phosphomonoesters (PME), inorganic phosphate (Pi), and phosphodiesters (PDE) relative to beta ATP, and of PME relative to PDE were calculated from spectra acquired at TR 5 seconds. Estimates of saturation effects for individual resonances were obtained by dividing the peak height at TR 5 seconds by that at TR 0.5 seconds to yield a T1-related signal height ratio (SHR). When compared with reference values, the patients with liver disease showed a significantly higher PME/ATP (P < .0001), PME/PDE (P < .0001), PME SHR (P < .001), and Pi SHR (P < .02), and a lower PDE/ATP (P < .001) and PDE SHR (P < .001). The magnitude of these changes increased significantly and progressively with increasing functional impairment. In patients with compensated cirrhosis spectral appearances varied with etiology; thus, patients with postviral cirrhosis showed a significantly higher Pi/ATP; those with alcoholic cirrhosis, a significantly lower PDE/ATP; and those with cirrhosis secondary to primary sclerosing cholangitis, a significantly lower Pi/ATP than the healthy volunteers or other etiological groups. However, spectral appearances did not vary with etiology in patients with decompensated disease. In vitro 31P MRS of perchloric extracts of samples of liver tissue obtained from 10 patients with cirrhosis at transplant hepatectomy showed increases in levels of the soluble PME metabolites, phosphorylcholine and phosphorylethanolamine, and reductions in the levels of the soluble PDE metabolites, glycerophosphorylcholine and glycerophosphorylethanolamine. These changes suggest regenerative activity in cirrhotic livers. The increases in soluble phosphomonoesters in the aqueous extracts accounted for the increased PME/ATP ratio seen in the in vivo spectra, and might account for the increase in PME SHR. The reduction in soluble phosphodiesters in the aqueous extracts did not entirely account for the reduction PDE/ATP ratio seen in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)",0
1613,7854377,A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease,"BACKGROUND: In a previous study, men with a history of myocardial infarction were found to have an increased prevalence of homozygosity for the deletional allele (D) of the angiotensin-converting-enzyme (ACE) gene. The D allele is associated with higher levels of ACE, which may predispose a person to ischemic heart disease. We investigated the association between the ACE genotype and the incidence of myocardial infarction, as well as other manifestations of ischemic heart disease, in a large, prospective cohort of U.S. male physicians. METHODS: In the Physicians' Health Study, ischemic heart disease as defined by angina, coronary revascularization, or myocardial infarction developed in 1250 men by 1992. They were matched with 2340 controls according to age and smoking history. Zygosity for the deletion-insertion (D-I) polymorphism of the ACE gene was determined by an assay based on the polymerase chain reaction. Data were analyzed for both matched pairs and unmatched samples, with adjustment for the effects of known or suspected risk factors by conditional and nonconditional logistic regression, respectively. RESULTS: The ACE genotype was not associated with the occurrence of either ischemic heart disease or myocardial infarction. The adjusted relative risk associated with the D allele was 1.07 (95 percent confidence interval, 0.96 to 1.19; P = 0.24) for ischemic heart disease and 1.05 (95 percent confidence interval, 0.89 to 1.25; P = 0.56) for myocardial infarction, if an additive mode of inheritance is assumed. Additional analyses assuming dominant and recessive effects of the D allele also failed to show any association, as did the examination of low-risk subgroups. CONCLUSIONS: In a large, prospectively followed population of U.S. male physicians, the presence of the D allele of the ACE gene conferred no appreciable increase in the risk of ischemic heart disease or myocardial infarction.",0
1614,7854380,The cost effectiveness of preoperative autologous blood donations,"BACKGROUND: Since the recognition that human immunodeficiency virus is transmissible by blood transfusion there has been increasing public and professional support for autologous blood donations before elective surgery. Autologous blood donation is, however, a more expensive process than the donation of allogeneic blood by community volunteers. Furthermore, there have been recent improvements in the safety of the volunteer blood supply. METHODS: We used a decision-analysis model to assess the cost effectiveness of donating autologous blood for four surgical procedures. Cost data were collected from the observation of transfusion practice at the University of California, Los Angeles, in 1992. Estimates of the risks of transfusion-associated diseases and the costs of treating them came from the medical literature. Cost effectiveness was expressed in dollars per quality-adjusted year of life saved. We performed sensitivity analyses of the variables in our model and examined the effect of strategies suggested to reduce costs. RESULTS: Substituting autologous for allogeneic blood resulted in little expected health benefit (0.0002 to 0.00044 quality-adjusted year of life saved) at considerable additional cost ($68 to $4,783 per unit of blood). The additional cost of autologous blood was primarily a function of the discarding of units that were donated but not transfused and of a more labor-intensive donation process. The cost-effectiveness ratios ranged from $235,000 to over $23 million per quality-adjusted year of life saved. CONCLUSIONS: Given the improved safety of allogeneic transfusions today, the increased protection afforded by donating autologous blood is limited and may not justify the increased cost.",0
1615,7870142,Screening for colorectal cancer,"In the past few years, knowledge of the clinical, biologic, and molecular genetic characteristics of colorectal cancer has greatly increased. Although the most cost-effective approach remains to be identified, screening for colorectal cancer can decrease mortality due to this disease by detecting cancers at earlier stages and allowing the removal of adenomas, thus preventing the subsequent development of cancer. Molecular studies that have helped define the genetic basis for this disease hold great promise for the development of better and more powerful methods to identify populations at risk. Individually, these technological, clinical, and basic-science advances are exciting; together, they promise to move us closer to the goal of substantially reducing mortality due to colorectal cancer.",0
1616,7875674,Ex vivo hepatic gene transfer in mouse using a defective herpes simplex virus-1 vector,"A defective amplicon herpes simplex virus-1 (HSV-1) vector, HSVlac, was used to transfer an E. coli lacZ reporter gene into primary hepatocytes. The lacZ gene was driven by the HSV immediate early (IE) 4/5 promoter. Use of the HSVlac vector resulted in highly efficient gene transfer. Because difficulties in culturing primary hepatocytes impose limitations in ex vivo gene therapy, we sought to determine whether use of the HSVlac vector could simplify gene transfer. Therefore, we incubated HSVlac with primary hepatocytes in suspension and found that the lacZ gene was still transferred with great rapidity and efficiency. To examine lacZ expression in transduced hepatocytes in vivo, we used a mouse hepatocyte transplantation system. In congeneic recipients of primary hepatocytes transduced with HSVlac in suspension, the lacZ gene was expressed in liver and spleen up to 2 weeks. However, survival of transplanted hepatocytes, as well as persistence of HSVlac genome in recipient organs, was demonstrated for up to an 11-week duration of the experiment. These findings suggest that in vivo regulation of the HSV IE4/5 promoter was responsible for the short-term expression of lacZ, which should be overcome by the use of liver-specific promoters. Therefore, our results indicate the feasibility of hepatic gene transfer with a defective HSV-1 vector.",0
1617,7875683,Expression of SPARC in normal and fibrotic livers,"SPARC (secreted protein, acidic and rich in cysteine)--also known as osteonectin, BM-40, and 43K glycoprotein--is secreted by endothelial cells and fibroblasts in response to culture shock. SPARC has been found in association with tissues undergoing cell proliferation, migration, and extracellular matrix remodeling. We demonstrate that normal livers from humans, rats, and mice express substantial levels of SPARC messenger RNA (mRNA). Moreover, when compared with control specimens, significantly increased levels of SPARC mRNA were found in fibrotic livers from two animal models of liver disease: murine schistosomiasis and carbon tetrachloride-induced fibrosis in rats. Fibrotic human livers also had markedly increased levels of SPARC mRNA in comparison with normal livers. We also detected an increased production of SPARC protein in the liver of animals treated with carbon tetrachloride. By immunocytochemical analysis, SPARC protein was apparent in freshly isolated Ito cells. Hybridization studies showed Ito cells to be the main source of SPARC mRNA. Extracts from a Kupffer-endothelial cell fraction exhibited traces of SPARC transcript, but expression of SPARC mRNA was absent in extracts from freshly isolated hepatocytes. These studies demonstrate the increased expression of SPARC--a protein that modulates cell shape and disrupts cell-matrix interactions--during the initial stages of hepatic fibrosis.",0
1618,7885430,Longevity and Medicare expenditures,"BACKGROUND: In the United States, the elderly account for over one third of health care spending. The total population over the age of 65 is projected to increase, as is life expectancy beyond the age of 65. We studied current patterns of Medicare expenses according to age at death and the possible effect of future demographic changes on Medicare spending. METHODS: We used data from the Medicare program to estimate lifetime Medicare expenses for a sample of 129,166 beneficiaries, 65 or older, who died in 1989 and 1990, according to age at death. Spending for nursing home care not covered by Medicare was excluded. (Nursing home costs represent about 20 percent of total health care spending for the elderly and increase with age.) Through simulation, we assessed the lifetime payments by Medicare for enrollees who turned 65 in 1990 and those who will do so in 2020. RESULTS: Estimated lifetime Medicare payments (in 1990 dollars) ranged from $13,044 for persons who died at 65 years of age, to $56,094 for those who died at 80, to $65,633 for those who died at 101 or older. The payments associated with an additional year of life and the average annual payments over an enrolle's lifetime both decreased as the age at death increased. The estimated 7.9 percent increase in life expectancy beyond 65 years that will have taken place between 1990 and 2020 (19.1 years past the age of 65 in 2020, as compared with 17.7 years in 1990) was associated with an estimated increase of 2.0 percent in lifetime Medicare payments. Of the estimated $98 billion increase in total lifetime payments (in 1990 dollars) from the 1990 group to the 2020 group, 74.3 percent was due to the larger size of the original birth cohort who will reach the age of 65 in 2020, 22.5 percent to an increase in the proportion of that birth cohort projected to survive to 65 years of age, and 3.2 percent to improved life expectancy beyond 65. CONCLUSIONS: The effect on Medicare spending of increased longevity beyond the age of 65 may not be great. Total Medicare payments will be more substantially affected by the expected increase in the absolute number of elderly people.",0
1619,7898526,"The epidemiology of tuberculosis among foreign-born persons in the United States, 1986 to 1993","BACKGROUND: One third of the world's population is infected with Mycobacterium tuberculosis, and in the developed countries immigration is a major force that sustains the incidence of tuberculosis. We studied the effects of immigration on the epidemiology of tuberculosis and its recent resurgence in the United States. METHODS: We analyzed data from the national tuberculosis reporting system of the Centers for Disease Control and Prevention. Since 1986 reports of tuberculosis have included the patient's country of origin. Population estimates for foreign-born persons were derived from special samples from the 1980 and 1990 censuses. RESULTS: The proportion of persons reported to have tuberculosis who were foreign-born increased from 21.6 percent (4925 cases) in 1986 to 29.6 percent (7346 cases) in 1993. For the entire eight-year period, most foreign-born patients with tuberculosis were from Latin America (43.9 percent; 21,115 cases) and Southeast Asia (34.6 percent; 16,643 cases). Among foreign-born persons the incidence rate was almost quadruple the rate for native residents of the United States (30.6 vs. 8.1 per 100,000 person-years), and 55 percent of immigrants with tuberculosis had the condition diagnosed in their first five years in the United States. CONCLUSIONS: Immigration has had an increasingly important effect on the epidemiology of tuberculosis in the United States. It will be difficult to eliminate tuberculosis without better efforts to prevent and control it among immigrants and greater efforts to control it in the countries from which they come.",0
1620,7904979,Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients,"Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the principal enzymes responsible for the oxidation of ethanol, are polymorphic at the ADH2, ADH3 and ALDH2 loci in human beings. Our previous studies have shown that, compared with nonalcoholic individuals, Chinese alcoholic patients without liver disease had significantly lower frequencies of the ADH2*2 and ADH3*1 alleles, which encode high maximum velocity beta 2- and gamma 1-ADH subunits, respectively, as well as a lower frequency of the ALDH2*2 allele, which encodes an enzymatically inactive subunit. The data strongly suggest that genetic variation in both ADH and ALDH may influence drinking behavior and the risk of alcoholism developing through acetaldehyde formation. To further investigate the possible role of acetaldehyde in the pathogenesis of alcoholic liver disease, we determined the ADH and ALDH genotype frequencies in patients with alcohol-related cirrhosis (n = 27), viral hepatitis-related cirrhosis (n = 29) and gastric and duodenal ulcer without relevance to alcohol (n = 30). We developed a new restriction fragment length polymorphism method to genotype the mutant and normal ALDH2 alleles by using polymerase chain reaction-directed mutagenesis, which proved to be simpler and faster than the conventional detection methods that use hybridization with allele-specific oligonucleotide probes. We found that the frequencies of the alleles ADH2*2 (57%), ADH3*1 (78%) and ALDH2*2 (9%) in the alcoholic cirrhotic patients were significantly lower than those in the healthy controls and in the patients with cirrhosis from viral hepatitis and with gastric and duodenal ulcer.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1621,7906387,Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma,"BACKGROUND: The origin and molecular pathogenesis of parathyroid carcinoma are unknown. This life-threatening cause of primary hyperparathyroidism cannot be reliably distinguished from its benign counterpart on the basis of histopathological features alone. Because the PRAD1, or cyclin D1, gene, a cell-cycle regulator, has been implicated in a subgroup of benign parathyroid tumors, we examined the possibility that another cell-cycle regulator with possible functional links to PRAD1, the retinoblastoma tumor-suppressor gene (RB), might be involved in the molecular pathogenesis of parathyroid carcinoma. METHODS: Parathyroid carcinomas from 9 patients and adenomas from 21 were studied for evidence of tumor-specific loss of RB gene DNA (allelic loss) by analysis of four DNA polymorphisms and for evidence of altered expression oF RB protein by immunohistochemical staining. RESULTS: All of 11 specimens from 5 patients with parathyroid carcinoma and informative DNA patterns and 1 of 19 specimens from 19 patients with parathyroid adenoma and informative DNA patterns lacked an RB allele. Fourteen of 16 specimens (88 percent) from the nine patients with carcinoma had abnormal expression of RB protein (a complete or predominant absence of nuclear staining for the protein). None of the 19 adenomas, including the tumor with loss of an RB allele, had unequivocally abnormal staining for RB protein. CONCLUSIONS: Inactivation of the RB gene is common in parathyroid carcinoma and is likely to be an important contributor to its molecular pathogenesis. The presence of such inactivation may help to distinguish benign from malignant parathyroid disease and may have useful diagnostic, prognostic, and therapeutic implications.",0
1622,7908410,c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer,"BACKGROUND: The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. METHODS: Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. RESULTS: Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression. No further information was gained by adding the data on S-phase fraction or p53 accumulation to the analysis. There was no clear evidence of a dose-response effect in patients with minimal or no c-erbB-2 expression. CONCLUSIONS: There is a significant dose-response effect of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil in patients with overexpression of c-erbB-2 but not in patients with no c-erbB-2 expression or minimal c-erbB-2 expression. Overexpression of c-erbB-2 may be a useful marker to identify the patients who are most likely to benefit from high doses of adjuvant chemotherapy.",0
1623,7908719,Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary report,"BACKGROUND: Studies conducted in vitro and in animals suggest that cytokine signals to monocytes or macrophages by interferon gamma are important in the containment and clearance of disseminated nontuberculous mycobacterial infections. METHODS: We studied seven patients with refractory, disseminated nontuberculous mycobacterial infections who were not infected with the human immunodeficiency virus. Three patients were from a family predisposed to the development of Mycobacterium avium complex infections; four patients had idiopathic CD4+ T-lymphocytopenia. Their infections were culture- or biopsy-proved, involved at least two organ systems, and had been treated with the maximal tolerated medical therapy. Cellular proliferation, cytokine production, and phagocyte function were assessed in peripheral-blood cells. Interferon gamma was administered subcutaneously two or three times weekly in a dose of 25 to 50 micrograms per square meter of body-surface area in addition to antimycobacterial medications. Clinical effects were monitored by cultures, biopsies, radiographs, and in one patient a change in the need for paracentesis. RESULTS: In response to phytohemagglutinin, the production of interferon gamma by mononuclear cells from the patients was lower than in normal subjects (P < 0.001), whereas stimulation with ionomycin and phorbol myristate acetate led to normal production of interferon gamma in the patients. Within eight weeks of the start of interferon gamma therapy, all seven patients had marked clinical improvement, with abatement of fever, clearing of many lesions and quiescence of others, radiographic improvement, and a reduction in the need for paracentesis. CONCLUSIONS: Interferon gamma in combination with conventional therapy may be effective for some cases of refractory disseminated nontuberculous mycobacterial infection.",0
1624,7909915,The pharmacology and use of H1-receptor-antagonist drugs,"The second-generation H1-antagonist drugs are supplanting their predecessors in the treatment of allergic rhinoconjunctivitis and chronic urticaria. Their use can be justified mainly on the basis of a more favorable risk-benefit ratio, because they are less toxic to the central nervous system. Future research into H1 antagonists should include additional dose-response studies in patients with allergic disorders, especially children and the elderly; objective studies of adverse effects; studies of topical mucosal application of H1 antagonists; and studies of H1-antagonist enantiomers and active metabolites. With the cloning of the gene encoding the H1 receptor and increased understanding of the precise structural requirements for H1-receptor activity, H1 antagonists with an even more favorable therapeutic index may be developed.",0
1625,7910662,The management of hyperthyroidism,"Although effective treatments for hyperthyroidism are available, none is perfect. Particularly with respect to Graves' disease, what is needed is a therapy directed at modulating the disease process itself rather than merely reducing the synthesis and secretion of thyroid hormones in the hope that the underlying Graves' disease will remit. Greater understanding of the pathogenesis of Graves' disease, resulting from cloning of the thyrotropin receptor and better knowledge of the interactions between these receptors or other thyroid antigens and the immune system, may lead to such treatment. Broad-spectrum immunosuppression, with all its side effects, is not the answer; more focused therapies to inhibit the immune response to specific thyroid antigens may represent the treatment of the future. Meanwhile, radioiodine therapy is the most effective and convenient method of achieving long-term control of hyperthyroidism, although at the cost of hypothyroidism in many patients.",0
1626,7927205,Effects of protein kinase C and cytosolic Ca2+ on exocytosis in the isolated perfused rat liver,"Both protein kinase C and cytosolic Ca2+ are involved in the regulation of exocytosis in a number of cell types. However, the relative importance of each of these for apical exocytosis in the hepatocyte is unknown. To investigate this, we studied the effects of protein kinase C and Ca2+ agonists on horseradish peroxidase excretion in the isolated perfused rat liver. Vasopressin increased both horseradish peroxidase concentration and net horseradish peroxidase excretion in bile, and these effects were abolished by the protein kinase C inhibitor H-7. The protein kinase C activator phorbol dibutyrate also increased both net excretion and the concentration of biliary horseradish peroxidase. In contrast, the Ca2+ ionophore A23187 and the Ca2+ mobilizing agent 2,5'-di(tertbutyl)-1,4-benzohydroquinone both had minimal effects on horseradish peroxidase concentration and inhibited the rate of horseradish peroxidase excretion. These results suggest that protein kinase C stimulates apical exocytosis in the hepatocyte, whereas increased Cai2+ per se does not influence exocytosis and inhibits excretion only transiently by reducing bile flow.",0
1627,7927221,"Fetal bile acid metabolism during infancy: analysis of 1 beta-hydroxylated bile acids in urine, meconium and feces","Fetal bile acids (1 beta-hydroxylated, 6 alpha-hydroxylated and unsaturated bile acids), especially 1 beta, 3 alpha,7 alpha, 12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid (CA-1 beta-ol), have been detected in urine and feces early in life. To investigate whether a fetal pathway of bile acid synthesis exists in infancy, we measured the concentrations of bile acids in the urine, meconium and feces from normal newborns and infants by means of gas chromatography-mass spectrometry. The mean ratio of total bile acids to creatinine in urine increased between birth and 7 days and then gradually decreased; however, the concentration of total bile acids in urine remained significantly higher than that in adult urine until 3 mo of age. The main urinary bile acid was CA-1 beta-ol, and substantial amounts of fetal bile acids were detected in urine until 3 mo of age. The ratio of cholic acid to chenodeoxycholic acid was abnormally low in meconium (mean, 0.44; range, 0.19 to 0.74), and hyocholic acid constituted 19.3% of total bile acids. The mean total bile acid content of feces decreased between birth and 7 days of age and thereafter increased. The mean percentage of fetal bile acids in feces decreased after birth, but substantial amounts were present in feces until 1 mo of age.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1628,7927231,Human combinatorial autoantibodies and mouse monoclonal antibodies to PDC-E2 produce abnormal apical staining of salivary glands in patients with coexistent primary biliary cirrhosis and Sj�gren's syndrome,"An increase in the incidence of Sj�gren's syndrome in patients with primary biliary cirrhosis has been noted. Indeed, primary biliary cirrhosis has been described as a ductal disease with involvement not only of the biliary tract but of epithelial ductal cells in other organs. We have previously reported the development of a panel of mouse monoclonal antibodies directed at PDC-E2, the major autoantigen of primary biliary cirrhosis. One such antibody, C355.1, but none of the other monoclonal antibodies, reacted not only with mitochondria but also with the apical region of biliary epithelium of patients with primary biliary cirrhosis but not in similar specimens from patients with other liver disease or normal human liver. In addition, we have reported the development of human combinatorial antibodies specific for PDC-E2; these reagents also reacted uniquely with the biliary epithelium of patients with primary biliary cirrhosis. In this paper, we have performed a similar study and have compared the staining of monoclonal antibody C355.1 and a human combinatorial antibody, SP4, with control monoclonal antibodies with respect to their reactivity of salivary glands in 9 patients with primary biliary cirrhosis associated with Sj�gren's syndrome, 11 patients with Sj�gren's syndrome alone and 7 control patients. Interestingly, the apical region of the salivary gland epithelial cells of approximately 50% of patients with coexisting primary biliary cirrhosis and Sj�gren's syndrome had a staining pattern similar to that seen in primary biliary cirrhosis biliary epithelium. In contrast, we did not observe this reactivity in any patient with Sj�gren's syndrome alone or in any control patient.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1629,7927240,Heat shock response in the liver: expression and regulation of the hsp70 gene family and early response genes after in vivo hyperthermia,"Heat shock response in cultured cells has been studied extensively; however few data are available on heat shock response in an intact organ of a living animal. In this study we analyzed the kinetics of expression of the heat shock protein 70 gene family (heat shock protein 70, heat shock cognate protein 73 and glucose-regulated protein 78) in the liver of the thermally stressed rat. New synthesis of heat shock protein 70 and heat shock cognate protein 73 was shown in liver slices pulse labeled in vitro with 35S-methionine. Accumulation of heat shock protein 70 and heat shock cognate protein 73 proteins was shown in total cellular extracts. 32P-labeled complementary DNA probes encoding heat shock protein 70, heat shock cognate protein 73 and glucose-regulated protein 78 were used to show that the levels of the corresponding messenger RNAs increase as a fraction of total RNA and in polysomes at different extents and with different kinetics. The induction of heat shock protein 70 and heat shock cognate protein 73 messenger RNAs reflected the increase in the synthesis of the corresponding proteins. Run-on transcription analysis indicated that the expression of heat shock protein 70 and heat shock cognate protein 73 genes was mainly regulated at the transcriptional level. On the contrary, both transcriptional and posttranscriptional regulatory mechanisms can explain the induction of the glucose-regulated protein 78 gene.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1630,7927260,Expression of hepatocyte growth factor in normal and carbon tetrachloride-treated monkeys,"We examined hepatocyte growth factor-producing organs in normal and carbon tetrachloride-treated Japanese monkeys, a species more related to human beings than rats, by measuring hepatocyte growth factor protein and hepatocyte growth factor mRNA in various tissues. Hepatocyte growth factor protein and hepatocyte growth factor mRNA levels were determined by use of an enzyme-linked immunosorbent assay for human hepatocyte growth factor and Northern-blot analysis using human hepatocyte growth factor cDNA as a probe, respectively. Although very slight amounts of hepatocyte growth factor protein were found in various organs of normal monkeys, the hepatocyte growth factor protein levels were remarkably increased only in the livers and spleens of carbon tetrachloride-treated monkeys. Hepatocyte growth factor mRNA was distinctly detected in the livers, spleens, lungs, intestinal tracts, adrenal glands and aortas of normal monkeys. After the administration of carbon tetrachloride, the hepatocyte growth factor mRNA levels in the liver, spleen and gastrointestinal tract were markedly increased; the level in the lung was unchanged, differing from the findings in rats; and the levels in adrenal gland and aorta were unaltered. These results indicate that the liver is an important hepatocyte growth factor-producing organ in monkeys during liver regeneration and that hepatocyte growth factor induced in the liver may stimulate hepatocyte proliferation by way of a paracrine mode.",0
1631,7927266,Mechanism of activation of the Na+/H+ exchanger by arginine vasopressin in hepatocytes,"Arginine vasopressin has been shown to activate the Na+/H+ exchanger in hepatocytes by calcium/calmodulin-dependent processes. Whether this activation also involves protein kinase C and is associated with changes in the intracellular pH setpoint was investigated in this study. Changes in pHi and intracellular Ca++ concentration were measured with the fluorescent probes BCECF and quin-2, respectively. Intracellular pH recovery rate was calculated from time-dependent changes in intracellular pH in hepatocytes acid-loaded with sodium propionate. Arginine vasopressin, phorbol myristate acetate and thapsigargin stimulated intracellular pH recovery but did not increase basal intracellular pH. Arginine vasopressin and thapsigargin, but not phorbol myristol acetate, increased intracellular Ca++ concentration. The protein kinase C inhibitors staurosporine and calphostin C inhibited arginine vasopressin- and phorbol myristol acetate-induced, but not thapsigargin-induced, intracellular pH recovery. Neither staurosporine nor calphostin C affected arginine vasopressin- and thapsigargin-induced increases in intracellular Ca++ concentration, and no inhibitor affected basal intracellular pH recovery. Arginine vasopressin, phorbol myristol acetate and thapsigargin increased intracellular pH dependency of intracellular pH recovery without affecting intracellular pH setpoint. These results indicate that the activation of the Na+/H+ exchanger by arginine vasopressin is mediated both by Ca++/calmodulin and protein kinase C and may be due to enhanced interaction of H+ with the internal modifier site of the exchanger.",0
1632,7927269,The Mallory body: theories on development and pathological significance (Part 2 of a literature survey),"Drawing on data from a previously published literature survey on the clinical and experimental epidemiology of the Mallory body, we discuss current theories on its development in a pro et contra manner. Conclusions have been largely left open to the interpretations of the reader because many are still speculative. The main results of this study characterize Mallory bodies as stereotypical histological byproducts to diverse hepatic injuries (mostly alcohol associated) of questionable pathogenic importance. The temporal characteristics of Mallory bodies cast doubt on their role in hepatic neoplasia both as a disease marker and a causative agent, and prognosis studies suggest that they may be considered preterminal markers in some nonalcoholic liver diseases but remain prognostically unimportant in most studies on alcoholic patients. By similar line of inquiry, no consistent relationships may be found with disease severity or duration in alcoholic liver diseases. The roles of vitamin A deficiency and protein-calorie malnutrition are circumstantial. Drugs known to have calcium-antagonist properties and the physiological characteristics of the stress-response protein ubiquitin support the concept of defective protein systems in Mallory body pathogenesis. Disproportionate hepatic copper accumulation seems both epidemiologically and topographically associated with Mallory bodies, but these connections are largely unsupported by exposure studies. Many arguments still downplay the importance of uncoordinated changes in hepatic oxygen delivery and consumption, but ischemia-reperfusion studies suggest a role of oxygen-derived free radicals in the liver injuries under scrutiny. Finally, the role of Mallory bodies in the control system of hepatocyte function is addressed, and indirect evidence lends credence to a cybernetic approach in future study designs. It is reasonable to assume that different elements of a multifactorial setting operate with varying intensity over time as this may account for some of the controversies that exist. In conclusion, the biological significance of Mallory bodies is still mystery. It is not known whether Mallory bodies represent an epiphenomenon or play a role themselves in the initiation and continuation of liver damage.",0
1633,7935635,Vasoactive intestinal peptide-receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors,"BACKGROUND: Intestinal adenocarcinomas and various endocrine tumors express large numbers of high-affinity receptors for vasoactive intestinal peptide (VIP). We have evaluated the usefulness of scanning with VIP labeled with iodine-123 for tumor localization in patients with gastrointestinal tumors. METHODS: Radioiodinated VIP was purified by high-pressure liquid chromatography and administered as a single intravenous bolus injection (300 pmol [1 microgram]). Scanning with radiolabeled VIP was compared with computed tomography and scanning with somatostatin analogues in 79 patients with colorectal cancer, pancreatic carcinoma, gastric cancer, carcinoid tumor, or insulinoma. RESULTS: Visualization of gastrointestinal tumors and metastases was obtained with radiolabeled VIP. Binding of the labeled peptide by primary tumors and metastases was visible shortly after the injection and was still demonstrable at 24 hours. In patients with colorectal adenocarcinomas, primary or recurrent tumors were visualized in 10 of 10, liver metastases in 15 of 18, lung metastases in 2 of 3, and lymph-node metastases in 4 of 4. Primary pancreatic adenocarcinomas were visualized by imaging in 10 of 12 patients, and liver metastases were seen in 7 of 7. Primary or recurrent gastric adenocarcinomas were visualized in 5 of 5 patients, and liver metastases were seen in 2 of 2 patients. VIP scans were positive in 9 of 10 patients with carcinoid tumors and in 4 of 4 patients with insulinomas. Some tumors with positive VIP scans were also visualized with somatostatin analogues (4 of 17 colorectal adenocarcinomas, 8 of 9 carcinoids, and 2 of 2 insulinomas). In vitro binding studies confirmed the presence of VIP receptors on gastrointestinal tumors. CONCLUSIONS: Scanning with radiolabeled VIP can visualize intestinal tumors and metastases that express receptors for VIP.",0
1634,7935683,Accumulation of nuclear p53 and tumor progression in bladder cancer,"BACKGROUND: We have previously demonstrated a strong association between nuclear accumulation of p53 protein, as determined by immunohistochemical analysis, and mutations in the p53 gene. The purpose of this study was to determine the relation between nuclear accumulation of p53 and tumor progression in transitional-cell carcinoma of the bladder. METHODS: Histologic specimens of transitional-cell carcinoma of the bladder (stages Pa, noninvasive disease, to P4, disease with direct extension into adjacent organs or structures) from 243 patients who were treated by radical cystectomy were examined for the immunohistochemical detection of p53 protein. Nuclear p53 reactivity was then analyzed in relation to time to recurrence and overall survival. RESULTS: The detection of nuclear p53 was significantly associated with an increased risk of recurrence of bladder cancer (P < 0.001) and with decreased overall survival (P < 0.001). In patients with cancer confined to the bladder, the rates of recurrence for stage P1, P2, and P3a tumors that had no detectable nuclear p53 reactivity at five years were 7, 12, and 11 percent, respectively, as compared with 62, 56, and 80 percent, respectively, for tumors that had p53 immunoreactivity. Similar results were obtained when the presence or absence of p53 in the nuclei of the tumor cells was studied in relation to overall survival. In a multivariable analysis stratified according to grade, pathological stage, and lymph-node status, nuclear p53 status was an independent predictor (and in cancer confined to the bladder, the only independent predictor) of recurrence and overall survival (P < 0.001). CONCLUSIONS: In patients with transitional-cell carcinoma confined to the bladder, an accumulation of p53 in the tumor-cell nuclei detected by immunohistochemical methods predicts a significantly increased risk of recurrence and death, independently of tumor grade, stage, and lymph-node status. Patients with transitional-cell carcinoma confirmed to the bladder that demonstrates nuclear p53 reactivity should be considered for protocols of adjuvant treatment.",0
1635,7969300,Variability in radiologists' interpretations of mammograms,"BACKGROUND: Despite the proved value of mammography in screening for breast cancer, its efficacy depends on radiologists' interpretations. The variability in such interpretations is not well understood. METHODS: Using a technique of stratified random sampling, we selected 150 mammograms obtained in 1987: 27 from women with histopathologically confirmed breast cancer and 123 from women with no evidence of breast cancer after three years of follow-up examinations. Ten radiologists, who were unaware of the diagnoses and research hypothesis, each interpreted the 150 mammograms. Disagreement was analyzed within pairs of the 10 radiologists, as well as for the group of 150 women as a whole. RESULTS: The diagnostic consistency between pairs of radiologists was moderate, with a median weighted percentage of agreement of 78 percent (weighted kappa, 0.47). The frequency of the radiologists' recommendations for an immediate workup ranged from 74 to 96 percent for mammograms from the women with cancer and from 11 to 65 percent for films from the women without cancer. A substantial disagreement in management recommendations--in which one radiologist recommended routine follow-up and another recommended a biopsy for the same patient--occurred in 3 percent of the pairwise comparisons but in 25 percent of the comparisons for the group of women as a whole. When two or more radiologists recommended a biopsy for the same patient, a disagreement in the stated location (right or left breast) occurred in 2 percent of the pairwise comparisons among the radiologists but in 9 percent of comparisons for the group of women as a whole. Because some disagreement was likely, given that 10 radiologists read each film, the pairwise comparison is a more conservative estimate of disagreement. CONCLUSIONS: Although mammography is of value in screening women for breast cancer, radiologists can differ, sometimes substantially, in their interpretations of mammograms and in their recommendations for management. Efforts to improve accuracy and reduce variability in interpretation may increase the effectiveness of mammography in detecting early breast cancers.",0
1636,7982658,Phenobarbital induction of alpha 1-acid glycoprotein in primary rat hepatocyte cultures,"The serum level of rat alpha 1-acid glycoprotein is significantly increased by treatment with phenobarbital, and in vivo studies have shown that phenobarbital seems to act mainly at the transcriptional level. To show the direct mediating effect of phenobarbital on alpha 1-acid glycoprotein gene expression, we investigated the ability of primary cultured rat hepatocytes to respond to in vitro phenobarbital administration. Phenobarbital increased both alpha 1 acid glycoprotein secretion and corresponding mRNA levels in primary rat hepatocytes cultured on matrigel. Used in combination with interleukin-1, interleukin-6 and dexamethasone, phenobarbital had an additive or synergistic effect on alpha 1-acid glycoprotein synthesis. These results show that (a) phenobarbital acts directly on hepatocytes by increasing alpha 1-acid glycoprotein gene expression and (b) this effect is mediated by a specific mechanism independent of pathways involved in alpha 1-acid glycoprotein induction by interleukin-1, interleukin-6 and glucocorticoids.",0
1637,7982659,"Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells","During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy-methylglutaryl-coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle alpha-actin. Simvastatin (0.1 to 10 mumol/L) induced a marked dose-dependent decrease of [3H]thymidine incorporation in human Ito cells, whether stimulated by human serum or by purified growth factors. Simvastatin-induced inhibition of DNA synthesis was confirmed by nuclear autoradiography and was not explained by a cytotoxic effect. The growth inhibitory effect of simvastatin was specifically due to inhibition of hydroxy-methylglutaryl-coenzyme A reductase because it was overcome by addition of mevalonic acid, the product of the enzymatic reaction. The reduction in [3H]thymidine incorporation was not affected by supplementation of culture medium with purified cholesterol-low-density lipoprotein or isopentenyl adenine. It was partially reversed by addition of farnesol. These results show that simvastatin decreases the growth of human Ito cells, independently of its effect on cholesterol synthesis. This decrease may be due in part either to reduced farnesylation of proteins involved in growth factor signaling pathway or to inhibition of N-linked protein glycosylation. Whether this effect exists in vivo and could thus lead to a parallel decrease of fibrosis deposition within the liver requires further study.",0
1638,7982660,Ursodeoxycholate protects oxidative mitochondrial metabolism from bile acid toxicity: dose-response study in isolated rat liver mitochondria,"The effect of ursodeoxycholate and tauroursodeoxycholate on the toxicity of lipophilic bile acids (chenodeoxycholate and lithocholate) on the function of the electron transport chain was investigated in isolated rat liver mitochondria. At a concentration of 30 mumol/L, both chenodeoxycholate and lithocholate reduced state 3 oxidation rates and respiratory control ratios of L-glutamate, succinate and duroquinol. In contrast, ADP/O ratios of these substrates and oxidative metabolism of ascorbate were not significantly affected. Ursodeoxycholate did not impair mitochondrial oxidative metabolism up to concentrations of 100 mumol/L; at 300 mumol/L, however, it decreased state 3 oxidation rates and respiratory control ratios of L-glutamate, succinate and duroquinol. Tauroursodeoxycholate had no significant inhibitory effect on state 3 oxidation rates of L-glutamate and succinate at concentrations up to 300 mumol/L. When ursodeoxycholate (final concentration, 30 mumol/L or 100 mumol/L) was added to mitochondrial incubations containing chenodeoxycholate or lithocholate, the toxic effects of lipophilic bile acids on mitochondrial oxidative metabolism were partially reversed. However, 300 mumol/L ursodeoxycholate, in combination with chenodeoxycholate or lithocholate, exhibited greater toxicity compared with incubations containing only the individual bile acids. In contrast to ursodeoxycholate, tauroursodeoxycholate did not reduce the toxic effects of chenodeoxycholate or lithocholate on mitochondrial metabolism. Ursodeoxycholate (100 mumol/L) significantly decreased the incorporation of chenodeoxycholate into mitochondrial membranes, whereas the decrease in lithocholate incorporation was not statistically significant. These studies demonstrate that ursodeoxycholate, but not tauroursodeoxycholate, decreases the toxicity of lipophilic bile acids on the function of the electron but increases bile acid-induced mitochondrial toxicity at higher concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1639,7990860,Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS,"BACKGROUND: Children with the acquired immunodeficiency syndrome (AIDS) have an unusually high incidence of smooth-muscle tumors (leiomyomas and leiomyosarcomas) in addition to malignant lymphomas. We tested the hypothesis that the smooth-muscle tumors in these children are associated with the Epstein-Barr virus (EBV). METHODS: Tissue specimens of five leiomyosarcomas and two leiomyomas from six children with AIDS were studied for evidence of the human immunodeficiency virus (HIV) and EBV by in situ hybridization and quantitative polymerase chain reaction (PCR). Comparison specimens included samples of leiomyosarcoma and leiomyoma from HIV-negative children. EBV clonality of leiomyosarcomas was determined by Southern blot analysis with oligonucleotide probes for EBV terminal-repeat fragments. Tumor specimens were tested by immunoperoxidase staining for infiltration by B lymphocytes and expression of the EBV receptor. Serologic testing for EBV was performed. RESULTS: In situ hybridization showed EBV genomes in all muscle cells of the five leiomyosarcomas and the two leiomyomas from the six HIV-infected children. Quantitative PCR demonstrated strikingly high levels of EBV in tumor tissue, with as many as 4.3 genome copies per cell. Two colonic leiomyosarcomas obtained from different sites at different times from one patient contained different episomal EBV clones, signifying the presence of distinct monoclonal EBV-related tumors. We found biclonal EBV infection in the leiomyosarcoma of another patient. No EBV was detected in normal muscle or tumor specimens from HIV-negative patients. Immunostaining for the EBV receptor was strongly positive in six of the seven leiomyomas and leiomyosarcomas from the patients with AIDS. CONCLUSIONS: EBV can infect smooth-muscle cells, at least in patients with AIDS, and it may contribute to the pathogenesis of leiomyomas and leiomyosarcomas in children with AIDS. EBV seems to play no part in smooth-muscle tumors in HIV-negative children.",0
1640,7993412,Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods,"BACKGROUND: The incidence of tuberculosis and drug resistance is increasing in the United States, but it is not clear how much of the increase is due to reactivation of latent infection and how much to recent transmission. METHODS: We performed DNA fingerprinting using restriction-fragment-length polymorphism (RFLP) analysis of at least one isolate from every patient with confirmed tuberculosis at a major hospital in the Bronx, New York, from December 1, 1989, through December 31, 1992. Medical records and census-tract data were reviewed for relevant clinical, social, and demographic data. RESULTS: Of 130 patients with tuberculosis, 104 adults (80 percent) had complete medical records and isolates whose DNA fingerprints could be evaluated. Isolates from 65 patients (62.5 percent) had unique RFLP patterns, whereas isolates from 39 patients (37.5 percent) had RFLP patterns that were identical to those of an isolate from at least 1 other study patient; the isolates in the latter group were classified into 12 clusters. Patients whose isolates were included in one of the clusters were inferred to have recently transmitted disease. Independent risk factors for having a clustered isolate included seropositivity for the human immunodeficiency virus (HIV) (odds ratio for Hispanic patients, 4.31; P = 0.02; for non-Hispanic patients, 3.12; P = 0.07), Hispanic ethnicity combined with HIV seronegativity (odds ratio, 5.13; P = 0.05), infection with drug-resistant tuberculosis (odds ratio, 4.52; P = 0.005), and younger age (odds ratio, 1.59; P = 0.02). Residence in sections of the Bronx with a median household income below $20,000 was also associated with having a clustered isolate (odds ratio, 3.22; P = 0.04). CONCLUSIONS: In the inner-city community we studied, recently transmitted tuberculosis accounts for approximately 40 percent of the incident cases and almost two thirds of drug-resistant cases. Recent transmission of tuberculosis, and not only reactivation of latent disease, contributes substantially to the increase in tuberculosis.",0
1641,8008027,A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group,"BACKGROUND: People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer. METHODS: We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo; beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations. RESULTS: Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location. CONCLUSIONS: The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.",0
1642,8015568,Allelic loss of chromosome 18q and prognosis in colorectal cancer,"BACKGROUND: Colorectal cancer occurs in approximately 150,000 people each year in the United States. Prognostic assessment influences the treatment of patients with colorectal cancer, including decisions about adjuvant therapy. We evaluated chromosome 18q allelic loss, a genetic event associated with tumor progression, as a prognostic marker for this disease. METHODS: We developed procedures to examine the status of chromosome 18q with microsatellite markers and DNA from formalin-fixed, paraffin-embedded tumors. Allelic loss of chromosome 18q was assessed in 145 consecutively resected stage II or III colorectal carcinomas. RESULTS: Among patients with stage II disease, the five-year survival rate was 93 percent in those whose tumor had no evidence of allelic loss of chromosome 18q and 54 percent in those with allelic loss; among patients with stage III disease, survival was 52 and 38 percent, respectively. The overall estimated hazard ratio for death in patients whose tumor had chromosome 18q allelic loss was 2.83 (P = 0.008) according to univariate analysis. Furthermore, chromosome 18q allelic loss remained a strong predictive factor (hazard ratio for death, 2.46; 95 percent confidence interval, 1.06 to 5.71; P = 0.036) after adjustment for all other evaluated factors, including tumor differentiation, vein invasion, and TNM stage. CONCLUSIONS: The status of chromosome 18q has strong prognostic value in patients with stage II colorectal cancer. The prognosis in patients with stage II cancer and chromosome 18q allelic loss is similar to that in patients with stage III cancer, who are thought to benefit from adjuvant therapy. In contrast, patients with stage II disease who do not have chromosome 18q allelic loss in their tumor have a survival rate similar to that of patients with stage I disease and may not require additional therapy.",0
1643,8015569,Dietary n-3 polyunsaturated fatty acids and smoking-related chronic obstructive pulmonary disease. Atherosclerosis Risk in Communities Study Investigators,"BACKGROUND: Fish contain n-3 polyunsaturated fatty acids, principally eicosapentaenoic acid and docosahexaenoic acid, which are known to interfere with the body's inflammatory response and may be of benefit in chronic inflammatory conditions. METHODS: We studied the relation between the dietary intake of n-3 fatty acids and chronic obstructive pulmonary disease (COPD) in 8960 current or former smokers participating in a population-based study of atherosclerosis. Intake of fatty acids was estimated with a dietary questionnaire. The presence of COPD was assessed by a questionnaire on respiratory symptoms and by spirometry. Three case definitions of COPD were used: symptoms of chronic bronchitis (667 subjects), physician-diagnosed emphysema reported by the subject (185 subjects), and spirometrically detected COPD (197 subjects). RESULTS: After control for pack-years of smoking, age, sex, race, height, weight, energy intake, and educational level, the combined intake of eicosapentaenoic acid and docosahexaenoic acid was inversely related to the risk of COPD in a quantity-dependent fashion. The adjusted odds ratio for the highest quartile of intake as compared with the lowest quartile was 0.66 for chronic bronchitis (95 percent confidence interval, 0.52 to 0.85; P < 0.001 for linear trend across the range of intake values), 0.31 for physician-diagnosed emphysema (95 percent confidence interval, 0.18 to 0.52; P for linear trend, 0.003), and 0.50 for spirometrically detected COPD (95 percent confidence interval, 0.32 to 0.79; P for linear trend, 0.007). CONCLUSIONS: A high dietary intake of n-3 fatty acids may protect cigarette smokers against COPD.",0
1644,8015571,The cost of a successful delivery with in vitro fertilization,"BACKGROUND: The use of in vitro fertilization has engendered considerable debate about who should have the procedure, whether health insurance should cover the cost, and if so, to what extent. We investigated the cost of a successful delivery with in vitro fertilization. METHODS: We calculated the cost per successful delivery with in vitro fertilization (defined as at least one live birth) for a general population of couples undergoing in vitro fertilization and for two subgroups: couples with a diagnosis of tubal disease (who have a better chance of success), and couples in which the woman is over the age of 40 years and the man has a low sperm count (who have a lower chance of success). Information on charges per cycle of in vitro fertilization was obtained from six facilities across the country; delivery rates with this procedure were estimated from the literature. RESULTS: On average, the cost incurred per successful delivery with in vitro fertilization increases from $66,667 for the first cycle of in vitro fertilization to $114,286 by the sixth cycle. The cost increases because with each cycle in which fertilization fails, the probability that a subsequent effort will be successful declines. Sensitivity analyses indicated that the cost per delivery ranges from $44,000 to $211,940. For couples with a better chance of successful in vitro fertilization (i.e., those with a diagnosis of tubal disease), it costs $50,000 per delivery for the first cycle and $72,727 for the sixth. For couples in which the woman is older and there is a diagnosis of male-factor infertility, the cost rises from $160,000 for the first cycle to $800,000 for the sixth. CONCLUSIONS: The debate about insurance coverage for in vitro fertilization must take into account ethical judgments and social values. But analyses of costs and cost effectiveness help elucidate the economic implications of using in vitro fertilization and thus inform the policy discussion.",0
1645,8015572,The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence,"BACKGROUND: Although the medical complications associated with multiple-gestation pregnancies have been well documented, little is known about the effects of such pregnancies on the use of health care resources and the associated costs. This is an important issue because of the increasing use of assisted-reproduction techniques, which commonly result in multiple-gestation pregnancies. METHODS: We determined hospital charges and the use of assisted-reproduction techniques (such as induction of ovulation, in vitro fertilization, and gamete intrafallopian transfer) for 13,206 pregnant women (11,986 with singleton pregnancies, 1135 with twin pregnancies, and 85 with more than two fetuses) who were admitted for delivery to Brigham and Women's Hospital, Boston, in 1986 through 1991 and their 14,033 neonates (11,671 singletons, 2144 twins, and 218 resulting from higher-order multiple gestations). RESULTS: After we controlled for variables known to affect hospital charges, the predicted total charges to the family in 1991 for a singleton delivery were $9,845, as compared with $37,947 for twins ($18,974 per baby) and $109,765 for triplets ($36,588 per baby). Assisted-reproduction techniques were used in 2 percent of singleton, 35 percent of twin, and 77 percent of higher-order multiple-gestation pregnancies; such procedures were approximately equally divided between induction of ovulation alone and in vitro fertilization or gamete intrafallopian transfer. CONCLUSIONS: Multiple-gestation pregnancies, a high proportion of which result from the use of assisted-reproduction techniques, dramatically increase hospital charges. If all the multiple gestations resulting from assisted-reproduction techniques, dramatically increase hospital charges. If all the multiple gestations resulting from assisted-reproduction techniques had been singleton pregnancies, the predicted savings to the health care delivery system in the study hospital alone would have been over $3 million per year. Although assisted reproduction provides tremendous benefits to families with infertility, the increased medical risks entailed by multiple-gestation pregnancies and the associated costs cannot be ignored. We suggest that more attention be paid to approaches to infertility that reduce the likelihood of multiple gestation.",0
1646,8018138,A comparison of active compression-decompression cardiopulmonary resuscitation with standard cardiopulmonary resuscitation for cardiac arrests occurring in the hospital,"BACKGROUND: Recent studies have demonstrated improved cardiopulmonary circulation during cardiac arrest with the use of a hand-held suction device (Ambu CardioPump) to perform active compression-decompression cardiopulmonary resuscitation (CPR). The purpose of this study was to compare active compression-decompression with standard CPR during cardiac arrests in hospitalized patients. METHODS: All patients over the age of 18 years who had a witnessed cardiac arrest while hospitalized at our center were enrolled in this trial; they were randomly assigned according to their medical-record numbers to receive either active compression-decompression or standard CPR. The study end points were the rates of initial resuscitation, survival at 24 hours, hospital discharge, and neurologic outcome. Compressions were performed according to the recommendations of the American Heart Association (80 to 100 compressions per minute; depth of compression, 3.8 to 5.1 cm [1.5 to 2 in.]; and 50 percent of the cycle spent in compression). RESULTS: Sixty-two patients (45 men and 17 women) with a mean age (+/- SE) of 68 +/- 2 years were entered into the trial. Sixty-two percent of the patients who underwent active compression-decompression were initially resuscitated, as compared with 30 percent of the patients who received standard CPR (P < 0.03); 45 percent of the patients who underwent active compression-decompression survived for at least 24 hours, as compared with 9 percent of patients who underwent standard CPR (P < 0.004). Two of the 62 study patients survived to hospital discharge; both were randomly assigned to receive active compression-decompression. Neurologic outcome, as measured by the Glasgow coma score, was better with active compression-decompression (8.0 +/- 1.3) than with standard CPR (3.5 +/- 0.3; P < 0.02). CONCLUSIONS: In this preliminary study, we found that, as compared with standard CPR, active compression-decompression CPR improved the rate of initial resuscitation, survival at 24 hours, and neurologic outcome after in-hospital cardiac arrest. Larger trials will be required to assess the potential benefit in terms of long-term survival.",0
1647,8020877,Effects of anisotonic exposure on duck hepatitis B virus replication,"In cultured hepatocytes from in vivo duck hepatitis B virus-infected ducks the effect of medium osmolarity on viral replication was studied. A 10-day exposure to hypotonic media (277 mOsm/L due to removal of 26 mmol/L NaCl) lowered the duck hepatitis B virus DNA content of cells and of the medium by about 50%, whereas hyperosmotic exposure (421 mOsm/L by addition of 46 mmol/L NaCl) increased it about four-fold compared with normotonic standard incubation medium (329 mOsm/L). The tissue levels of viral RNA transcripts increased during the 10 days of hypertonic exposure but decreased only slightly after hypoosmotic treatment. Western-blot analysis for the production of viral pre-S/S proteins revealed a marked stimulation of viral protein synthesis in hypertonic media, whereas hypotonic exposure inhibited it. Conversely, total cellular protein synthesis as assessed from [3H]leucine incorporation into acid-precipitable material decreased during hyperosmotic exposure but increased during hypoosmotic exposure. We noted a comparable increase of duck hepatitis B virus DNA when raffinose (80 mmol/L) was added to hypotonic or normotonic media, without change in the NaCl concentrations. This suggests that the effects of anisotonicity on viral replication were not due to alterations of Na+ or Cl- activity in the incubation media, but might reflect changes of cellular volume. The effects of anisotonicity on viral replication were only seen after exposure of more than 8 hr of the cells to anisotonicity. The findings suggest that the cellular volume is an important determinant for duck hepatitis B virus replication, yet the underlying molecular mechanisms remain elusive.",0
1648,8020888,Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents,"We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology.",0
1649,8022443,Septic abortion,"Abortion-related deaths, which account for 47% of total maternal mortality in the world, result primarily from sepsis and are widespread in developing countries where abortion is illegal or inaccessible. Septic abortion offers opportunities for prevention on the primary, secondary, and tertiary level of medial care. Primary prevention of septic abortion encompasses the provision of effective contraception, provision of safe and legal abortion in cases of contraceptive failure, and appropriate medical management of abortion. Secondary prevention involves the prompt diagnosis of endometriosis and effective treatment to avert more serious infection. The diagnosis of septic abortion should be considered when women of reproductive age present to health facilities with vaginal bleeding, lower abdominal pain, and fever. Tertiary prevention is aimed at avoiding the serious complications of postabortal infection, including hysterectomy and death. Women with high fever, pelvic peritonitis, and tachycardia should undergo uterine evacuation and parental antibiotic therapy. Supportive care for cardiovascular system and other organs may be essential. The medical technology needed to avert serious complications and deaths from septic abortion is available. Lacking is a political commitment on the part of many governments and health care agencies to address this avoidable contributor to maternal morbidity and mortality.",0
1650,8022446,The difficult issue of second-trimester abortion,"In the US, 10.2% of legal abortions are performed at 13-20 weeks and an additional 1% occur at 21 weeks gestation or beyond. These second-trimester abortions account for about 140,000 procedures per year. Dilatation and evacuation; instillation of saline, urea, or medication into the amniotic cavity; and intravenous prostaglandin administration are the approaches available for these procedures. At present, intravaginal prostaglandin E is the most commonly used mid-trimester abortion method; new research suggests that intravaginal misoprostol may confer advantages. Since teenagers are the population group most likely to delay abortion until the second trimester, priority should be given to making abortion services more accessible and removing requirements such as parental consent. Most beneficial would be a preventive approach that decreases the number of unintended pregnancies among adolescents through school-based sex education programs and access to free, effective contraceptive methods. Problematic is the reluctance on the part of many obstetricians and gynecologists to perform abortions due to a lack of technical training or moral objections. These practitioners should be mandated to fulfill their obligation to meet the needs of their patients, regardless of their personal views on the abortion issues.",0
1651,8028618,Management of infections caused by antibiotic-resistant Streptococcus pneumoniae,"The increasing resistance of S. pneumoniae to antimicrobial agents is a cause for concern. Although a number of therapeutic strategies are possible, local patterns of resistance must be considered. It is essential to determine the susceptibility of individual strains to penicillin and other antimicrobial agents that could be used for therapy. Communication between the clinician and the laboratory is vital to determine the best therapeutic options. The recent recognition of cephalosporin-resistant strains emphasizes the need to determine susceptibility to cephalosporins. Clinical laboratories should be aware of the recently proposed changes in the definition of cephalosporin resistance, and clinicians need to be aware of how these changes affect the choice of antibiotic therapy. Until pneumococcal disease can be effectively prevented, we can expect resistant pneumococcal infections to continue to pose therapeutic difficulties.",0
1652,8041418,The risk of dying in alcohol-related automobile crashes among habitual drunk drivers,"BACKGROUND: Reports suggest that people who drive while intoxicated by alcohol may do so repeatedly. We hypothesized that persons arrested for driving while impaired might be at increased risk for death in an alcohol-related motor vehicle crash. To evaluate this possibility, we studied the deaths of drivers in alcohol-related motor vehicle accidents in North Carolina over a 10-year period. METHODS: We compared drivers who died in motor vehicle crashes from 1980 through 1989 and who had blood alcohol concentrations of at least 20 mg per deciliter (4.3 mmol per liter), referred to as the case drivers, with those who died in crashes but had blood alcohol concentrations below 20 mg per deciliter, referred to as the control drivers. We identified case drivers and control drivers through the state Medical Examiner System. We then searched North Carolina driver-history files for the five years before each death to identify arrests for driving while impaired. RESULTS: We linked a total of 1646 case drivers and 1474 control drivers to their driver-history files. Case drivers were more likely than control drivers to have been arrested for driving while impaired (26 percent vs. 3 percent). After we controlled for potential confounding variables, case drivers 21 to 34 years of age were 4.3 times more likely (95 percent confidence interval, 2.7 to 6.8) than control drivers to have been arrested for driving while impaired; case drivers 35 years of age or older were 11.7 times more likely (95 percent confidence interval, 6.8 to 20.1). The strength of the association appeared to increase with the number of prior arrests. Case drivers were also more likely than the general population of currently licensed drivers to have been arrested. CONCLUSIONS: Arrests for driving while impaired substantially increase the risk of eventual death in an alcohol-related crash. Aggressive intervention in the cases of people arrested for driving while impaired may decrease the likelihood of a future fatal alcohol-related crash.",0
1653,8045495,A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies,"The evaluation of hepatic fibrosis on histological sections is of great interest for the staging and follow-up of chronic liver disease. Because no reliable scoring system is yet available, we have designed a semiquantitative scoring system in which the four main sites of fibrotic deposit--centrilobular vein, portal tract and perisinusoidal space, together with width and number of septa when present--are analyzed. These different items have been previously settled from comparison with morphometric measurements to evaluate surface density of total collagen performed on the same liver needle biopsy specimens stained with picro-sirius. The score has been tested on samples from 200 consecutive patients with various liver diseases and compared with the surface density of total collagen and Knodell scoring system. For observer variation study, the features by three independent pathologists were coded on 20 cases. There was a good interobserver (Kendall's tau-b = 0.75) and intraobserver (tau-B = 0.73) reproducibility. Each component of the fibrosis scoring system and total collagen surface density were significantly linearly related (one-way polynomial analysis, p < 10(-4); the correlation between semiquantitative scoring system and surface density of total collagen was 0.73 (p < 10(-5). Our semiquantitative scoring system, simple and reproducible, describes both liver architecture and fibrotic deposit. It is better related to morphometric measurement of fibrosis than each of its constituents or than the fibrosis item of the Knodell scoring system. It represents a reliable and convenient method for fibrosis evaluation, which is mandatory for clinical use.",0
1654,8058076,Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma,"BACKGROUND: In a previous study, we found that two years of treatment with an inhaled corticosteroid, budesonide, was more effective than treatment with an inhaled beta 2-agonist, terbutaline, in patients with newly diagnosed, generally mild asthma. We continued this study for a third year to investigate whether the steroid dose could be reduced or discontinued and what effect crossover of patients from beta 2-agonist therapy to corticosteroid therapy would have. METHODS: A total of 37 patients treated for two years with inhaled budesonide at a dose of 1200 micrograms per day were randomly assigned to treatment with 400 micrograms of budesonide per day (19 patients) or placebo (18 patients) in a double-blind manner. Another 37 patients, who had received terbutaline during the first two years, were crossed over in an open-label manner to treatment with 1200 micrograms of budesonide per day during the third year. RESULTS: Treatment with the reduced dose of budesonide was sufficiently effective in 74 percent of the patients to maintain bronchial responsiveness at a level similar to that achieved with the higher dose. In contrast, improvement was maintained in only 33 percent of the patients receiving placebo, and the differences in pulmonary function between the steroid and placebo groups were significant (for forced expiratory volume in one second, P = 0.007; for bronchial responsiveness to histamine, P = 0.025; and for peak expiratory flow in the morning, P = 0.040). The condition of patients who were crossed over from terbutaline therapy to treatment with 1200 micrograms of budesonide per day improved. However, the degree of improvement in these patients appeared to be less than in those who were treated with budesonide at the beginning of the three-year study. CONCLUSIONS: Early treatment with inhaled budesonide results in long-lasting control of mild asthma. Maintenance therapy can usually be given at a reduced dose, but discontinuation of treatment is often accompanied by exacerbation of the disease.",0
1655,8065403,Equitable allocation of HLA-compatible kidneys for local pools and for minorities,"BACKGROUND: The methods used to allocate cadaveric kidneys in the United States have been criticized as being unfair to minorities because of an over-emphasis on HLA matching. We evaluated a new HLA-matching method that might alleviate this problem. METHODS: We used data from the United Network for Organ Sharing (UNOS) Kidney Transplant Registry to evaluate and project the outcome of cadaveric kidney transplantation. An HLA-matching method based on compatibility at 10 key amino acid residues of HLA-A and B molecules and a limited number of HLA-DR types was evaluated with use of the HLA types of the patients currently on the national waiting list and waiting lists in Los Angeles and Birmingham, Alabama. RESULTS: With national kidney sharing, the projected 10-year rate of graft survival for transplants in which there were no HLA-A, B, or DR mismatches was 66 percent, as compared with 39 percent for transplants with more than two HLA-A, B, or DR mismatches. With local sharing, 43 percent of patients could be fully matched, and they had a projected 10-year graft-survival rate of 50 percent. When one HLA-DR mismatch was allowed, the projected 10-year graft survival was 46 percent, and 67 percent of patients waiting locally could receive such grafts. Even in Alabama, where 68 percent of the patients on the waiting list are black, 48 percent of waiting patients could obtain a matched kidney. CONCLUSIONS: Inserting two new HLA-matching categories into the UNOS point system for cadaveric kidney allocation would increase the number of patients for whom matches could be found in local pools.",0
1656,8065404,The impact of HLA mismatches on the survival of first cadaveric kidney transplants,"BACKGROUND: The benefits of HLA-A, B, and DR matching of cadaveric kidney grafts and recipients remain controversial when viewed from the perspective of social equity and graft survival. METHODS: We estimated graft survival using proportional-hazards techniques, adjusting for patient and donor characteristics, for a series of 30,564 Medicare patients receiving a first cadaveric kidney transplant between 1984 and 1990. The effects of minimal achievable HLA mismatches and maximal matching on graft survival were estimated by simulated allocation of a sample of organs to a sample of 20,000 candidates for transplantation. RESULTS: The adjusted one-year graft survival was 84.3 percent for grafts with no mismatches and 77.0 percent for grafts with four mismatches. National rationing of donor organs to achieve minimal mismatching and maximal matching could potentially decrease the average number of HLA mismatches from 3.6 to 1.2, with a corresponding increase in the number of matches. As a consequence, projected five-year graft survival could potentially increase from 58.5 percent to 62.9 percent. This would be associated with a decrease in the proportion of kidneys allocated to black recipients from 22.2 to 15.0 percent. CONCLUSIONS: Under ideal circumstances, a policy of maximal matching of cadaveric renal transplants would increase five-year graft survival by a comparatively small 4.4 percentage points, but the actual benefit is likely to be smaller.",0
1657,8065407,The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community,"BACKGROUND: Despite recommendations for annual vaccination against influenza, more than half of elderly Americans do not receive this vaccine. In a serial cohort study, we assessed the efficacy and cost effectiveness of influenza vaccine administered to older persons living in the community. METHODS: Using administrative data bases, we studied men and women over 64 years of age who were enrolled in a large health maintenance organization in the Minneapolis-St. Paul area. We examined the rate of vaccination and the occurrence of influenza and its complications in each of three seasons: 1990-1991, 1991-1992, and 1992-1993. Outcomes were adjusted for age, sex, diagnoses indicating a high risk, use of medications, and previous use of health care services. RESULTS: Each cohort included more than 25,000 persons 65 years of age or older. Immunization rates ranged from 45 percent to 58 percent. Although the vaccine recipients had more coexisting illnesses at base line than those who did not receive the vaccine, during each influenza season vaccination was associated with a reduction in the rate of hospitalization for pneumonia and influenza (by 48 to 57 percent, P < or = 0.002) and for all acute and chronic respiratory conditions (by 27 to 39 percent, P < or = 0.01). Vaccination was also associated with a 37 percent reduction (P = 0.04) in the rate of hospitalization for congestive heart failure during the 1991-1992 season, when influenza A was epidemic. The costs of hospitalization for all types of illness studied were lower in the vaccinated group during 1991-1992 (range of reduction, 47 to 66 percent; P < 0.005) and for acute and chronic respiratory conditions and congestive heart failure in 1990-1991 (reductions of 37 percent and 43 percent, respectively; P < or = 0.05). Direct savings per year averaged $117 per person vaccinated (range, $21 to $235), with cumulative savings of nearly $5 million. Vaccination was also associated with reductions of 39 to 54 percent in mortality from all causes during the three influenza seasons (P < 0.001). CONCLUSIONS: For elderly citizens living in the community, vaccination against influenza is associated with reductions in the rate of hospitalization and in deaths from influenza and its complications, as compared with the rates in unvaccinated elderly persons, and vaccination produces direct dollar savings.",0
1658,8076922,Changes of alpha 1-adrenergic receptors in human liver during intraabdominal sepsis,"We studied changes in alpha 1-adrenergic receptors in human liver plasma membranes during intraabdominal sepsis using [3H]prazosin as a radioligand. Human liver tissues were obtained from nonseptic patients undergoing elective abdominal surgery (control group) and from patients with sepsis requiring laparotomy as a therapeutic measure (septic group). Septic patients were further divided into three subgroups on the basis of septic severity scores: mild sepsis (< 21), moderate sepsis (22 to 32) and severe sepsis (> 33). Plasma membranes were prepared by means of sucrose gradient centrifugation and were purified fivefold on the basis of the enrichment of the activity of the marker enzyme, 5'-nucleotidase. [3H]prazosin-binding studies show that the maximal binding capacity was increased by 49.6% (p < 0.01) in mild sepsis, relatively unchanged in moderate sepsis and decreased by 33.4% (p < 0.05) in severe sepsis (in femtomoles per milligram: 193.7 +/- 5.7 for control [n = 6], 289.8 +/- 23.4 for mild sepsis [n = 4], 192.3 +/- 16.3 for moderate sepsis (n = 4), 129.1 +/- 18.3 for severe sepsis [n = 5]). We found a significant inverse correlation (r = 0.85, p < 0.01) between changes in the densities of alpha 1-adrenergic receptors and septic severity scores. These data indicate that alpha 1-adrenergic receptors in human liver plasma membranes undergo dynamic changes during the development of sepsis--that is, the receptor number increased in mild sepsis, returned to a normal level in moderate sepsis and finally decreased in severe sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1659,8076924,Metabolism and effect of 7-oxo-lithocholic acid 3-sulfate on bile flow and biliary lipid secretion in rats,"Significant amounts of oxo and sulfated bile acids are excreted in the urine of patients with cholestatic liver diseases, but these bile acid species are found only in traces in bile. Several possible explanations for this finding include poor canalicular secretion, rapid biotransformation by oxidoreduction and extrahepatic sulfation of oxo bile acids. To assess the physiological actions and hepatic metabolism of oxo and sulfated bile acids, we synthesized 7-oxo-lithocholic acid 3-sulfate, examined the effect of intravenous infusion of this bile acid (5.0 mumol/min/kg body wt) on bile flow and biliary lipid secretion in Sprague-Dawley rats with a bile fistula and compared this effect with that of the unconjugated analog, 7-oxo-lithocholic acid, and the primary bile acid conjugate, chenodeoxycholic acid 3-sulfate. Bile flow and bile acid secretion increased immediately after infusion of all three bile acids. The highly polar 7-oxo-lithocholic acid 3-sulfate significantly reduced the biliary secretion of phospholipids (p < 0.05) and cholesterol (p < 0.05), but by contrast the more hydrophobic analog, 7-oxo-lithocholic acid, caused a significant increase in the biliary phospholipids (p < 0.001) and cholesterol (p < 0.01) secretion. Infusion of chenodeoxycholic acid 3-sulfate also resulted in an increase in secretion of biliary cholesterol and phospholipids, but the magnitude of the change was less than that induced by 7-oxo-lithocholic acid infusion. Biliary lipid secretion was inversely related to the polarity of the infused bile acid.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1660,8076926,Papaverine inhibits bile acid excretion in isolated perfused rat liver,"We investigated the effects of papaverine on bile acid excretion into bile in the presence of infusions of taurocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid and taurodehydrocholic acid in a single-pass, isolated perfused rat liver model. Although continuous infusion of papaverine (1.6 mumol/min) did not reduce bile acid excretion in the presence of low-dose (1.0 mumol/min) infusions of taurocholic acid or tauroursodeoxycholic acid, papaverine significantly inhibited biliary excretion of bile acids in the presence of low-dose taurochenodeoxycholic acid (-50%) and high-dose (3.0 mumol/min) taurocholic acid (-54%), tauroursodeoxycholic acid (-37%) and taurodehydrocholic acid (-31%). During continuous infusion of taurocholic acid (3 mumol/min), a 15-min infusion of papaverine (3.2 mumol/min) reduced bile acid excretion significantly; however, total uptake of bile acid was slightly decreased by the papaverine infusion. Bile acid excretion increased over the baseline value after the papaverine infusion was stopped and then returned to baseline. These results suggest that papaverine does not affect the uptake phase of bile acids at the sinusoidal membrane but may affect the intracellular transport phase or the excretory phase at the bile canalicular membrane. When taurocholic acid was infused at a constant rate of 3 mumol/min for 20 min without papaverine and then stopped, bile acid excretion decreased gradually and was nearly zero by 52 min. Cumulative bile acid excretion in the 52 min after the end of the infusion reached 3.3 +/- 0.2 mumol/gm liver and represented the storage capacity of the liver.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1661,8078532,The molecular basis of thyroid hormone action,"Progress has been made in understanding the molecular basis of a number of clinical manifestations of thyroid disease, yet many questions remain. Why are there two thyroid hormone-receptor genes? Is the function of each of the two receptors indeed unique? How T3 receptors interact with other nuclear proteins and DNA-binding sites and how these interactions are influenced by T3 is incompletely understood. The developmental regulatory role of T3 receptor alpha 1 and its non-T3-binding alpha 2 variant needs to be defined. Most T3-regulated processes, especially those related to metabolism, muscle contraction, and brain development, function in concert with a number of other regulatory factors. The therapeutic applications of knowledge gained about the basic mechanisms of thyroid hormone action should ultimately extend beyond thyroid disease to processes regulated or influenced by T3; these include cardiac function, lipid metabolism, pituitary hormone secretion, and neural development.",0
1662,8084356,Hospital readmission rates for cohorts of Medicare beneficiaries in Boston and New Haven,"BACKGROUND: Geographic variations in the use of hospital services are associated with differences in the availability of hospital beds. There continues to be uncertainty about the extent to which unmeasured case-mix differences explain these findings. Previous research showed that the number of occupied beds per capita in Boston was substantially higher than the number of occupied beds per capita in New Haven, Connecticut, and that overall rates of hospital utilization were higher for Boston residents than for New Haven residents. METHODS: We used Medicare claims data to study cohorts of Medicare beneficiaries 65 years of age or older and residing in Boston or New Haven who were initially hospitalized for one of five indications (acute myocardial infarction, stroke, gastrointestinal bleeding, hip fracture, or potentially curative surgery for breast, colon, or lung cancer). Residents of Boston or New Haven who were discharged between October 1, 1987, and September 30, 1989, were enrolled in the cohort corresponding to the earliest such admission and followed for up to 35 months. RESULTS: The relative rate of readmission in Boston as compared with New Haven was 1.64 (95 percent confidence interval, 1.53 to 1.76) for all cohorts combined, with a similarly elevated rate for each of the five clinical cohorts and each age, sex, and race subgroup examined. Hospital-specific readmission rates varied substantially among the hospitals in Boston and were higher than those in New Haven. No relation was found between mortality (during the first 30 days after discharge or over the entire study period) and either community or hospital-specific readmission rates. CONCLUSIONS: Regardless of the initial cause of the admission, Medicare beneficiaries who were initially hospitalized in Boston had consistently higher rates of readmission than did Medicare beneficiaries hospitalized in New Haven. Differences in the severity of illness are unlikely to explain these findings. One possible explanation is a threshold effect of hospital-bed availability on decisions to admit patients.",0
1663,8096066,Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection,"BACKGROUND: In the United States there have been recent outbreaks of multidrug-resistant tuberculosis. These outbreaks have primarily involved persons infected with the human immunodeficiency virus (HIV). METHODS: We collected clinical information on 17 patients seen at a New York City hospital who had repeatedly positive cultures for Mycobacterium tuberculosis. Analysis of restriction-fragment--length polymorphisms (RFLPs) was performed on serial isolates of M. tuberculosis obtained from these patients. RESULTS: Six patients had isolates that remained drug-susceptible, and the RFLP patterns of these isolates did not change over time. Eleven patients had isolates that became resistant to antimicrobial agents. The RFLP patterns of the isolates from six of these patients remained essentially unchanged (two strains showed one additional band) despite the development of drug resistance. In five other patients, however, the RFLP patterns of the isolates changed dramatically at the time that drug resistance was detected. The change in the RFLP pattern of the isolate from one patient appeared to be the result of contamination during processing in the laboratory. In the remaining four patients, all of whom had advanced HIV disease, the clinical and microbiologic evidence was consistent with the presence of active tuberculosis caused by a new strain of M. tuberculosis. CONCLUSIONS: Resistance to antituberculous drugs can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant. Exogenous reinfection with multidrug-resistant M. tuberculosis can occur either during therapy for the original infection or after therapy has been completed.",0
1664,8119680,Coinfection study of precore mutant and wild-type hepatitis B-like virus in ducklings,"The precore mutant hepatitis B virus often emerges from a mixed infection with combined wild-type and precore mutant viruses. Nevertheless, the precore mutant does not seem to be an evolutionarily favored strain. To investigate the interaction between wild-type and precore mutant hepadnaviruses in an animal model of perinatal transmission, we used an e antigen-defective mutant duck hepatitis B virus with mutations inside the stem-loop structure of precore messenger RNA for this coinfection study. Thirty 1-day-old ducklings were infected with wild-type duck hepatitis B virus, precore mutant virus or both viruses. The amounts of viremia and the distribution of viruses were analyzed by spot hybridization, polymerase chain reaction, restriction fragment length polymorphism, cloning and sequencing. We found that all the ducklings became chronic carriers of duck hepatitis B virus. The precore mutant replicate was less active than wild-type duck hepatitis B virus, and it could be overgrown by wild-type virus during the course of coinfection. These results demonstrated that wild-type duck hepatitis B virus might become the predominant species in a situation similar to the perinatal cotransmission in human beings. This might at least in part explain why the prototype virus could prevail for years.",0
1665,8119699,Deficiency of bile acid transport and synthesis in oval cells from carcinogen-fed rats,"Freshly isolated oval cells, which we obtained from the livers of rats fed a choline-deficient/DL-ethionine-supplemented diet, did not transport bile acids. Compared with freshly isolated rat hepatocytes they took up only negligible amounts of [3H]taurocholate or [14C]cholate. The cells bound small amounts of radioactive bile acids. This portion of the total cell-associated radioactivity was enhanced on membrane permeabilization. In contrast to cultured liver parenchymal cells from untreated rats, no bile acid synthesis was detected in cultured oval cells. Cultured oval cells also lost the ability to conjugate exogenously added cholate (100 mumol/L) with taurine or glycine. However, when liver parenchymal cells were isolated from carcinogen-fed rats, bile acid uptake was diminished compared with that in hepatocytes from control animals. In particular, the maximum values of taurocholate and cholate uptake were decreased by 75% and 50%, respectively, whereas the Michaelis-Menten constant values were not altered. The study demonstrates that (a) oval cells lack typical liver parenchymal cell-specific properties such as bile acid uptake, bile acid synthesis and conjugation of bile acids with taurine/glycine and therefore do not contribute to bile acid dependent bile formation (b) proliferating in livers of rats fed a choline-deficient/DL-ethionine-supplemented diet are part of the bile duct epithelial cell compartment); and (c) bile acid uptake is reduced in liver parenchymal cells of rats fed a choline deficient/DL-ethionine-supplemented diet, and this effect is due to a decrease in transport capacity without a decrease in transport affinity.",0
1666,8119704,Blood-to-lymph migration of small lymphocytes through the liver of the sheep,"The process of lymphocyte migration is required for the systemic dissemination of immunological memory and immune surveillance. We report here experiments to quantitate the normal traffic of lymphocytes that occurs from blood to lymph through the liver and hepatic node in the sheep. Comparisons were made with known lymphocyte homing pools. Individual afferent hepatic lymphatics had cell outputs of 1.4 +/- 0.1 x 10(6) cells/hr, suggesting that the total combined lymphocyte output from the liver was no greater than about 1 x 10(7) cells/hr. The lymphocyte output in efferent hepatic lymph was 6.2 +/- 0.4 x 10(7) cells/hr, comparable to the cell outputs recorded from other lymph nodes of similar size. When the specificity of lymphocytes homing through the liver or hepatic node was examined, we found similarities to both the peripheral lymph node and intestinal lymph node homing patterns. Migration into afferent hepatic lymph was found to be different from that into intestinal or subcutaneous efferent lymph, and the kinetics of migration into hepatic afferent lymph was faster than that observed into efferent compartments. Intravenously injected endotoxin was found to alter the normal lymph flow through the liver tissue and the hepatic node; it appeared to enhance the migration of macrophages out of the liver by way of the afferent lymph. These studies suggest unique features of lymphocyte traffic through the liver and the need for further experiments on hepatic lymphocyte traffic, particularly in pathological states with substantial mononuclear cell infiltration.",0
1667,8119706,Artificial bile inhibits bile salt-induced gallbladder glycoprotein release in vitro,"The more hydrophobic bile salts cause rapid release of preformed gallbladder mucin and other glycoproteins by gallbladder explants in vitro, whereas the less hydrophobic bile salts elicit a lesser response. This study was designed to determine (a) whether this short-term effect was matched by a sustained increase in glycoprotein secretion over 24 hr and (b) whether it occurred when bile salts were presented in model biles rather than aqueous solution. Although 3 mmol/L taurodeoxycholate in aqueous solution increased release of preformed gallbladder glycoprotein to 843% of control values after 30 min incubation (p < 0.001), no significant increase was observed after 24 hr. The more prolonged exposure also reduced precursor uptake by 32% (p < 0.05) and inhibited synthesis of new glycoprotein by 24% (p < 0.05). Moreover, the stimulatory effect of taurodeoxycholate on release of gallbladder glycoprotein was much reduced when it was presented in model biles rather than in aqueous solution. Nor was there any difference between the effects of more hydrophobic vs. less hydrophobic bile salts when presented in model biles. Aqueous solutions of the more hydrophobic bile salts induce a rapid release of gallbladder glycoprotein in vitro but do not produce a sustained increase in glycoprotein secretion. Their effect is liable to be prevented in vivo by interaction between bile salts and the other lipids in gallbladder bile.",0
1668,8133856,Immune mechanisms of cardiac disease,"It is evident that cellular infiltration can affect cardiac structure and function in a variety of disease states. Myocardial contractility can be impaired by cell-mediated injury or local release of cytokines. The study of immune cardiac disease has entered a period of rapid expansion that should be characterized by delineation of the mechanisms by which immune cells and factors localize in the myocardium, modulate myocyte function, and remodel myocardial architecture (Fig. 2). This new knowledge should result in the ability to target specifically both the pathways by which cardiac contractility is impaired by chronic inflammation and the sustained immune reactivity to cardiac antigens that underlies chronic myocardial inflammation. Nonspecific therapeutic interventions directed at congestive heart failure, currently the only acceptable approach to the treatment of immune myocarditis, should then serve a more ancillary function in the context of the use of rationally designed drugs. Such drugs could, for example, be specifically targeted to inhibiting the trafficking of leukocytes into the heart or the effects of their subsequent activation within the myocardium.",0
1669,8135917,Effect of laboratory variation in the prothrombin-time ratio on the results of oral anticoagulant therapy,"BACKGROUND: Patients receiving long-term anticoagulant therapy may be subject to unnecessary risks of bleeding or thromboembolism because of variability in the commercial thromboplastins used to determine prothrombin time and consequent uncertainty about the actual intensity of anticoagulation. METHODS: We explored the effect of this uncertainty on the benefits and risks of anticoagulation in patients with prosthetic heart valves, using models of thromboembolic and hemorrhagic complications as a function of the intensity of anticoagulation, with quality-adjusted life expectancy and average variable costs used to describe outcomes. RESULTS: Anticoagulation provides a striking benefit for patients whose treatment is conducted within the recommended range of the international normalized ratio (INR)--i.e., 2.5 to 3.5--but if uncertainty about the laboratory results causes the intensity of anticoagulation to fall outside this range, the gain becomes smaller. Uncertainty about the true intensity of anticoagulation may reduce the potential gain in life expectancy, adjusted for quality of life, by more than half and may increase the ratio of costs to effectiveness to almost five times the optimal value. Variability in the intensity of anticoagulation is even greater if older recommendations advocating a higher level of anticoagulation are followed. CONCLUSIONS: Uncertainty about the sensitivities of the commercially available thromboplastins used in the United States can have important clinical and economic effects. This problem could be eliminated if clinical laboratories uniformly reported the intensity of anticoagulation as the INR, by adjusting prothrombin-time ratios for variability in thromboplastins.",0
1670,8138269,Effects of different bile salts on steady-state mRNA levels and transcriptional activity of cholesterol 7 alpha-hydroxylase,"Cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the bile acid synthesis pathway, is down-regulated by taurocholate by way of negative feedback control at the level of gene transcription. The molecular basis of regulation of cholesterol 7 alpha-hydroxylase by other hydrophobic bile salts and under more physiological conditions is not known. The aim of this study was to investigate the molecular basis of regulation of cholesterol 7 alpha-hydroxylase by several naturally occurring bile salts in rats with intact enterohepatic circulation. Male Sprague-Dawley rats were pair-fed for 14 days normal chow (control), cholestyramine (5% of diet), cholic acid (1%), chenodeoxycholic acid (1%) or deoxycholic acid (0.25%). When rats were killed, livers were harvested and HMG-CoA reductase specific activity and cholesterol 7 alpha-hydroxylase specific activities, steady-state mRNA levels and transcriptional activity were determined and compared with those of control rats fed normal chow. Compared with results in paired controls, cholestyramine feeding led to an approximate threefold increase in HMG-CoA reductase specific activity. Feeding of hydrophobic bile salts profoundly decreased the specific activity of HMG-CoA reductase. Cholestyramine led to a three-fold increase in cholesterol 7 alpha-hydroxylase specific activity, steady-state mRNA levels and gene transcriptional activity. The feeding of cholic (1%), chenodeoxycholic (1%) and deoxycholic acid (0.25%) led to significant decreases in cholesterol 7 alpha-hydroxylase specific activities (62%, 84% and 97%, respectively), steady-state mRNA levels (72%, 29% and 61%, respectively) and transcriptional activities (44%, 43% and 54%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)",0
1671,8138271,"Hepatocyte growth factor in transgenic mice: effects on hepatocyte growth, liver regeneration and gene expression","Attention has recently been focused on hepatocyte growth factor as a major candidate factor in liver regeneration because it is the most potent known mitogen for hepatocytes in vitro. However, hepatocyte growth factor also displays diverse activities in vitro as scatter factor, as an epithelial morphogen, as a pluripotent mitogen and as a growth inhibitor. Consequently, we developed transgenic mice that expressed hepatocyte growth factor under the control of albumin regulatory sequences to examine its in vivo role in hepatocyte growth. Hepatocytes of these mice expressed increased levels of hepatocyte growth factor as an autocrine growth factor. Hepatocyte growth factor was a potent stimulus for liver repair; the livers of hepatocyte growth factor-transgenic mice recovered completely in half the time needed for their normal siblings after partial hepatectomy. This transgenic model also enabled us to study the chronic effects of hepatocyte growth factor expression. During several months of observation, the labeling index of hepatocytes in albumin-hepatocyte growth factor mice was doubled, and liver DNA content was increased compared with that in wild-type mice. To identify intermediate signaling pathways for hepatocyte growth factor that might regulate this increased growth response, we examined transgenic mice for changes in expression of genes that are known to be regulated during liver regeneration. We found that levels of c-myc and c-jun mRNA were increased in the hepatocyte growth factor-transgenic mice. In additional experiments the increased c-myc expression was the consequence of increased transcription rates as seen in nuclear run-on and myc-CAT reporter gene experiments. We conclude that hepatocyte growth factor increases growth and repair processes when expressed for long periods in the liver and that c-myc and c-jun may be important intermediaries in the hepatocyte growth response caused by hepatocyte growth factor.",0
1672,8152444,Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma,"BACKGROUND: Many deaths from attacks of asthma may be preventable. However, the difficulty in preventing fatal attacks is that not all the pathophysiologic risk factors have been identified. METHODS: To examine whether dyspnea and chemosensitivity to hypoxia and hypercapnia are factors in fatal asthma attacks, we studied 11 patients with asthma who had had near-fatal attacks, 11 patients with asthma who had not had near-fatal attacks, and 16 normal subjects. Their respiratory responses to hypoxia and hypercapnia, determined by the standard rebreathing technique while the patients were in remission, were assessed in terms of the slopes of ventilation and airway occlusion pressure as a function of the percentage of arterial oxygen saturation and end-tidal carbon dioxide tension, respectively. The perception of dyspnea was scored on the Borg scale during breathing through inspiratory resistances ranging from 0 to 30.9 cm of water per liter per second. RESULTS: The mean (+/- SD) hypoxic ventilatory response (0.14 +/- 0.12 liter per minute per percent of arterial oxygen saturation) and airway occlusion pressure (0.05 +/- 0.05 cm of water per percent of arterial oxygen saturation) were significantly lower in the patients with near-fatal asthma than in the normal subjects (0.60 +/- 0.35, P < 0.001, and 0.16 +/- 0.08, P < 0.001, respectively) and the patients with asthma who had not had near-fatal attacks (0.46 +/- 0.29, P = 0.003, and 0.15 +/- 0.09, P = 0.004). The Borg score was also significantly lower in the patients with near-fatal asthma than in the normal subjects, and their lower hypoxic response was coupled with a blunted perception of dyspnea. CONCLUSIONS: Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose patients to fatal asthma attacks.",0
1673,8175146,"Effects of ethanol feeding on liver, kidney and jejunal membranes of micropigs","The micropig model of chronic alcoholism was used to study the relationship of lipid composition and physical properties in three different tissue membranes from the same animals. Ethanol feeding reduced membrane anisotropy, as measured with the diphenylhexatriene probe, in liver plasma and kidney brush-border membranes but not in jejunal brush-border membranes. Preincubation with ethanol reduced anisotropy in each of the three control membranes, whereas all three membranes from the ethanol-fed group were relatively tolerant to the acute effect of ethanol. In liver and kidney membranes, ethanol feeding increased levels of linoleic (18:2 omega 6) acid and decreased levels of arachidonic (20:4 omega 6) and docosahexaenoic (22:6 omega 3) acids and their specific double-bond positions, consistent with reduced activities of delta 6 and delta 5 fatty acid desaturases. In liver and kidney membranes, anisotropy parameters and the acute effect of ethanol correlated inversely with levels of linoleic acid and directly with levels of arachidonic and docosahexaenoic acids and their specific double bonds. Levels of docosahexaenoic acid correlated with the acute effect of ethanol in all three membranes. Phospholipid fatty acid profiles were similar in jejunal brush-border membranes and terminal bile samples, suggesting that the effects of ethanol on jejunal fatty acids and physical properties are modulated by intraluminal biliary phospholipids. The effect of ethanol on anisotropy could not be attributed to changes in membrane cholesterol/phospholipid ratios. These studies affirm the value of this new animal model of chronic alcoholism and provide comprehensive evidence for the central role of fatty acid desaturation in the membrane-associated effects of ethanol exposure.",0
1674,8177244,Risk factors for hip fracture in black women. The Northeast Hip Fracture Study Group,"BACKGROUND: Although more than 1 percent of black women 80 years of age or older have hip fractures each year, little is known about risk factors for hip fracture in these women. METHODS: We carried out a case-control study involving 144 black women admitted with a first hip fracture to 1 of 30 hospitals in New York and Philadelphia. The control were 218 black women living in the community who were matched to the case patients according to age and ZIP Code or telephone exchange and 181 hospitalized black women matched according to age and hospital. Information was obtained through personal interviews and was studied by multivariable logistic-regression analysis. RESULTS: When the case patients were compared with the control subjects from the community, the women in the lowest quintile for body-mass index had a markedly increased risk of hip fracture as compared with the women in the highest quintile (odds ratio, 13.5; 95 percent confidence interval, 4.2 to 43.3). Postmenopausal estrogen therapy for one year or more was protective for women under 75 years of age (odds ratio, 0.1; 95 percent confidence interval, < 0.1 to 0.5). Factors associated with an increased risk of hip fracture included a history of stroke (odds ratio, 3.1; 95 percent confidence interval, 1.2 to 8.1), use of aids in walking (odds ratio, 5.6; 95 percent confidence interval, 2.7 to 11.5), and consumption of seven or more alcoholic drinks per week (odds ratio, 4.6; 95 percent confidence interval, 1.5 to 14.1). The results were similar when the case patients were compared with the hospitalized control subjects. CONCLUSIONS: Among black women thinness, previous stroke, use of aids in walking, and alcohol consumption are associated with an increased risk of hip fracture. Postmenopausal estrogen therapy protects against hip fracture in women under 75 years of age.",0
1675,8177246,The anatomy of the posterior communicating artery as a risk factor for ischemic cerebral infarction,"BACKGROUND: After the occlusion of an internal carotid artery the principal source of collateral flow is through the arteries of the circle of Willis, but the size and patency of these arteries are quite variable. Study of the anatomy of the collateral pathways in patients with internal-carotid-artery occlusion with or without infarction in the watershed area of the deep white matter may identify patterns that afford protection from ischemic infarction. METHODS: Using conventional magnetic resonance imaging and three-dimensional phase-contrast magnetic resonance angiography, we evaluated 29 consecutive patients (32 hemispheres at risk) with angiographically proved occlusion of the internal carotid artery. Four collateral pathways to the occluded vessel were evaluated: the proximal segment of the anterior cerebral artery, the posterior communicating artery, the ophthalmic artery, and leptomeningeal collateral vessels from the posterior cerebral artery. RESULTS: Only features of the ipsilateral posterior communicating artery were related to the risk of watershed infarction. The presence of posterior communicating arteries measuring at least 1 mm in diameter was associated with the absence of watershed infarction (13 hemispheres, no infarcts; P < 0.001). Conversely, there were 4 watershed infarcts in the 6 hemispheres with posterior communicating arteries measuring less than 1 mm in diameter and 10 infarcts in the 13 hemispheres with no detectable flow in the ipsilateral posterior communicating artery. CONCLUSIONS: A small (< 1 mm in diameter) or absent ipsilateral posterior communicating artery is a risk factor for ischemic cerebral infarction in patients with internal-carotid-artery occlusion.",0
1676,8177268,Linkage of the angiotensinogen gene to essential hypertension,"BACKGROUND: The renin-angiotensin system is a powerful pressor system with a major influence on salt and water homeostasis. Angiotensinogen (also called renin substrate) is a key component of this system; it is cleaved by renin to yield angiotensin I, which is then cleaved by angiotensin-converting enzyme to yield angiotensin II. The observation that plasma angiotensinogen levels correlate with blood pressure and track through families suggests that angiotensinogen may have a role in essential hypertension. We therefore investigated whether there is linkage between the angiotensinogen gene on chromosome 1q42-43 and essential hypertension. METHODS: Samples of DNA from 63 white European families in which two or more members had essential hypertension were tested for linkage of the angiotensinogen gene to this disorder. Affected cousins, nephews, nieces, and half-siblings were included when possible. To test for linkage, we used as a marker a dinucleotide-repeat sequence flanking this gene, and we employed the affected-pedigree-member method of linkage analysis. Two molecular variants of the angiotensinogen gene, one encoding threonine instead of methionine at position 235 (M235T) and the other encoding methionine rather than threonine at position 174 (T174M), were also tested for possible association with essential hypertension. RESULTS: We found significant linkage (t = 5.00, P < 0.001) and association (chi-square = 53.3, P < 0.001) of the angiotensinogen-gene locus to essential hypertension in the 63 multiplex families. This linkage was consistently maintained in the subgroup of subjects with diastolic pressure above 100 mm Hg and in the subgroups classified according to sex. It has been proposed previously that T174M and M235T are associated with essential hypertension. However, we found no association in our population between either polymorphism and this disorder. CONCLUSIONS: This study provides strong and consistent support for the linkage to essential hypertension of regions within or close to the angiotensinogen gene. Precisely how mutations in this region may result in hypertension remains to be determined.",0
1677,8188168,Distribution of pyruvate dehydrogenase dihydrolipoamide acetyltransferase (PDC-E2) and another mitochondrial marker in salivary gland and biliary epithelium from patients with primary biliary cirrhosis,"Previous studies in which quantitative immunofluorescence was used have shown that certain biliary epithelial cells in liver with primary biliary cirrhosis show increased levels of pyruvate dehydrogenase dihydrolipoamide acetyltransferase compared with controls. This study was designed to determine whether the increase in intensity of pyruvate dehydrogenase dihydrolipoamide acetyltransferase in biliary epithelial cells is accounted for by an increase in the number of mitochondria in the same cells. A double-antibody staining technique was used with antibodies specific for pyruvate dehydrogenase dihydrolipoamide acetyltransferase and another mitochondrial inner membrane marker, recognized by the mouse monoclonal antibody MCA151A. Distribution of the antigens was studied in sections of liver and salivary gland, an additional site that is frequently involved in primary biliary cirrhosis. Confocal microscopy was used to quantify the intensity of fluorescence resulting from binding of fluorochrome-labeled antibody. In both liver and salivary glands MCA151A binding was similar in normal and sections with primary biliary cirrhosis and corresponded to the predicted distribution of mitochondria in these tissues. In the liver staining was less intense in biliary epithelial cells than in hepatocytes. In salivary gland binding of both antibodies was predominantly localized to duct cells, with those forming striated ducts, known to be rich in mitochondria, being most intensely stained. There was high coincidence of the two antigens in salivary glands (p < 0.01) and in biliary epithelial cells from normal liver (p = 0.01). However, in liver with primary biliary cirrhosis, despite high coincidence between the antigens on hepatocytes, biliary epithelial cells showed high intensity of pyruvate dehydrogenase dihydrolipoamide acetyltransferase but not MCA151A.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1678,8188173,Renin and angiotensinogen mRNA expression in the kidneys of rats subjected to long-term bile duct ligation,"Activation of antinatriuretic systems such as the renin-angiotensin system, is of major importance in the pathogenesis of sodium retention in cirrhosis. In this study, we studied the intrarenal renin-angiotensin system by measuring renin and angiotensinogen mRNA expression in the kidney of rats subjected to long-term bile duct ligation in a phase before the development of ascites, when sodium retention is already present. Experiments were performed in sham-operated and bile duct-ligated rats 3 wk after surgery. Balance studies showed lower sodium excretion and greater sodium retention in the bile duct-ligated rats compared with the control animals. Plasma renin activity (4.41 +/- 1.01 ng Angiotensin I/ml/hr in the bile duct-ligated group vs. 4.20 +/- 0.74 in the controls) and plasma renin concentration were not different between the two groups. However, plasma renin substrate was significantly decreased in bile duct-ligated animals. Total kidney renin mRNA was significantly higher in the bile duct-ligated animals (0.83 +/- 0.14 densitometric units vs. 0.44 +/- 0.04 in the controls), as determined on Northern-blot analysis and densitometric quantitation. Angiotensinogen mRNA expression in the kidneys of bile duct-ligated rats was significantly decreased (0.09 +/- 0.01 densitometric units) compared with that of the controls (0.21 +/- 0.03). These results indicate that sodium-retaining, nonascitic bile duct-ligated rats show abnormalities of the intrarenal renin angiotensin system that precede changes in plasma renin activity. Our data suggest that the intrarenal renin angiotensin system may participate in the initiation of the renal pathophysiological abnormalities present in bile duct-ligated rats.",0
1679,8188176,Effect of irradiation on hepatic natural killer cells,"The rat liver contains a population of natural killer cells consisting of two morphologically and functionally different subsets, a low-density and a high-density fraction. In this work we describe the influence of low-dose radiation on hepatic natural killer activity. The effect on the cytotoxicity against YAC-1 lymphoma and CC531 colon adenocarcinoma tumor cells was measured in chromium-51 assays, and morphological changes were analyzed by means of electron microscopy. The low-density natural killer fraction showed increased cytotoxicity against YAC-1 which was associated with an increased binding of natural killer cells to the YAC-1 tumor cells shortly after irradiation. These phenomena were paralleled by an increased number of multivesicular bodies and cytoplasmic granules with an electron-lucent halo. In contrast, the other hepatic natural killer cell fraction, the high-density natural killer cells, did not show increased cytotoxicity, binding or morphological alterations. The radiation-stimulated lysis of YAC-1 cells was also observed when in vivo irradiated cells were isolated and tested immediately for in vitro lysis of YAC-1 cells. Sixteen hours after in vitro or in vivo irradiation, the cytotoxicity of hepatic natural killer cells against YAC-1 was no longer enhanced. The cytolysis of and binding of hepatic natural killer cells to CC531 colon adenocarcinoma cells was not stimulated by in vitro irradiation. From these experiments, we conclude that low-dose radiation stimulates the cytotoxicity of hepatic low-density natural killer cells against YAC-1 lymphoma cells immediately after irradiation as the result of enhanced binding of the cells to the tumor cells, in addition to the synthesis of new cytotoxic granules.",0
1680,8190153,Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate,"BACKGROUND: In normal subjects, a low level of metabolic acidosis and positive acid balance (the production of more acid than is excreted) are typically present and correlate in degree with the amount of endogenous acid produced by the metabolism of foods in ordinary diets abundant in protein. Over a lifetime, the counteraction of retained endogenous acid by base mobilized from the skeleton may contribute to the decrease in bone mass that occurs normally with aging. METHODS: To test that possibility, we administered potassium bicarbonate to 18 postmenopausal women who were given a constant diet (652 mg [16 mmol] of calcium and 96 g of protein per 60 kg of body weight). The potassium bicarbonate was given orally for 18 days in doses (60 to 120 mmol per day) that nearly completely neutralized the endogenous acid. RESULTS: During the administration of potassium bicarbonate, the calcium and phosphorus balance became less negative or more positive--that is, less was excreted in comparison with the amount ingested (mean [+/- SD] change in calcium balance, +56 +/- 76 mg [1.4 +/- 1.9 mmol] per day per 60 kg; P = 0.009; change in phosphorus balance, +47 +/- 64 mg [1.5 +/- 2.1 mmol] per day per 60 kg; P = 0.007) because of reductions in urinary calcium and phosphorus excretion. The changes in calcium and phosphorus balance were positively correlated (P < 0.001). Serum osteocalcin concentrations increased from 5.5 +/- 2.8 to 6.1 +/- 2.8 ng per milliliter (P < 0.001), and urinary hydroxyproline excretion decreased from 28.9 +/- 12.3 to 26.7 +/- 10.8 mg per day (220 +/- 94 to 204 +/- 82 mumol per day; P = 0.05). Net renal acid excretion decreased from 70.9 +/- 10.1 to 12.8 +/- 21.8 mmol per day, indicating nearly complete neutralization of endogenous acid. CONCLUSIONS: In postmenopausal women, the oral administration of potassium bicarbonate at a dose sufficient to neutralize endogenous acid improves calcium and phosphorus balance, reduces bone resorption, and increases the rate of bone formation.",0
1681,8196728,Diuretic therapy for hypertension and the risk of primary cardiac arrest,"BACKGROUND: The results of trials of the primary prevention of coronary heart disease have suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes. In contrast, treatment with low doses of thiazide reduces the risk of coronary heart disease. METHODS: To examine the association between thiazide treatment for hypertension and the occurrence of primary cardiac arrest, we conducted a population-based case-control study among enrollees of a health maintenance organization. The case patients were 114 persons with hypertension who had a primary cardiac arrest from 1977 through 1990. The control patients were a stratified random sample of 535 persons with hypertension. The patients' treatment was assessed with the use of a computerized pharmacy data base. Records of their ambulatory care were reviewed to determine other clinical characteristics. RESULTS: The risk of primary cardiac arrest among patients receiving combined thiazide and potassium-sparing diuretic therapy was lower than that among patients treated with a thiazide without potassium-sparing therapy (odds ratio, 0.3; 95 percent confidence interval, 0.1 to 0.7). As compared with low-dose thiazide therapy (25 mg daily), moderate-dose therapy (50 mg daily) was associated with a moderate increase in risk (odds ratio, 1.7; 95 percent confidence interval, 0.7 to 4.5), and high-dose therapy (100 mg daily) was associated with a larger increase in risk (odds ratio, 3.6; 95 percent confidence interval, 1.2 to 10.8) (P value for trend, 0.02). The addition of a potassium-sparing drug to low-dose thiazide therapy was associated with a reduced risk of cardiac arrest (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.5). CONCLUSIONS: Both the dose of thiazide drugs and the addition of potassium-sparing drugs influence the risk of primary cardiac arrest. These results may explain the differences in the effect of antihypertensive therapy on mortality from coronary heart disease in previous clinical trials.",0
1682,8202100,Sotalol,"Sotalol is a novel antiarrhythmic agent combining beta-adrenergic-antagonist actions with the ability to increase cardiac repolarization and refractoriness. The drug's electrophysiologic and clinical profile is different from that of conventional beta-receptor antagonists. As compared with other antiarrhythmic agents, sotalol prevents recurrences of arrhythmia in a higher proportion of patients, particularly among those presenting with ventricular tachycardia and aborted sudden cardiac death. The net hemodynamic effect of sotalol is the result of a balance between the depressant effects due to beta-receptor blockade and an action that tends to increase contractility. Although initially marketed in the United States for treatment of life-threatening ventricular arrhythmias, sotalol also has demonstrated efficacy in many patients with supraventricular arrhythmias. As with all drugs that prolong the QT interval, the syndrome of torsade de pointes is a serious potential adverse effect.",0
1683,8202106,Transient increase in the risk of breast cancer after giving birth,"BACKGROUND: The effect of pregnancy on the risk of breast cancer is not clear. We tested the hypothesis that the risk of breast cancer increases transiently after pregnancy but then falls to a level below that of age-matched nulliparous women. METHODS: We conducted a case-control study of a nationwide cohort in Sweden, using a computerized record linkage between the Cancer Registry and the Fertility Registry. The study subjects were women born from 1925 through 1960 who were resident citizens of Sweden at the time of the 1960 census. A total of 12,666 patients with breast cancer were compared with 62,121 age-matched control subjects. We used conditional logistic regression to estimate odds ratios for the development of breast cancer at different ages, according to maternal age at first delivery (in uniparous as compared with nulliparous women) and age at second delivery (in biparous as compared with uniparous women). RESULTS: Uniparous women were at higher risk of breast cancer than nulliparous women for up to 15 years after childbirth and at lower risk thereafter. The excess risk was most pronounced among women who were older at the time of their first delivery (odds ratio 5 years after delivery among women 35 years old at first delivery, 1.26; 95 percent confidence interval, 1.10 to 1.44). Women who had two pregnancies had a less striking increase in risk. CONCLUSIONS: Pregnancy has a dual effect on the risk of breast cancer: it transiently increases the risk after childbirth but reduces the risk in later years. In women with two pregnancies, the short-term adverse effect is masked by the long-term protection imparted by the first pregnancy. A plausible biologic interpretation is that pregnancy increases the short-term risk of breast cancer by stimulating the growth of cells that have undergone the early stages of malignant transformation but that it confers long-term protection by inducing the differentiation of normal mammary stem cells that have the potential for neoplastic change.",0
1684,8208269,Diabetes and the risk of pancreatic cancer,"BACKGROUND: Diabetes and pancreatic cancer are known to be associated, but the cause of the association and whether diabetes is a risk factor for pancreatic cancer remain controversial. METHODS: A total of 720 patients with pancreatic cancer and 720 control patients from 14 Italian centers were enrolled in the study. All subjects were interviewed personally and in detail about their clinical history. The diagnosis of diabetes was based on criteria recommended by the American Diabetes Association. RESULTS: One hundred sixty-four patients with pancreatic cancer (22.8 percent) and 60 controls (8.3 percent) had diabetes. In the majority of the patients with pancreatic cancer (56.1 percent), diabetes was diagnosed either concomitantly with the cancer (in 40.2 percent), or within two years before the diagnosis of cancer (in 15.9 percent). The association between the two conditions was significant (odds ratio, 3.04; 95 percent confidence interval, 2.21 to 4.17). However, when only patients with diabetes of three or more years' duration were considered, the association was no longer significant (odds ratio, 1.43; 95 percent confidence interval, 0.98 to 2.07). All the patients with pancreatic cancer whose diabetes had been diagnosed before the cancer had non-insulin-dependent diabetes; all but one of the control patients with diabetes had the non-insulin-dependent form of the disease. CONCLUSIONS: Diabetes in patients with pancreatic cancer is frequently of recent onset and is presumably caused by the tumor. Diabetes is not a risk factor for pancreatic cancer.",0
1685,8225223,Parallel decrease of Na(+)-taurocholate cotransport and its encoding mRNA in primary cultures of rat hepatocytes,"We investigated the molecular mechanism underlying the progressive loss of Na(+)-dependent bile salt uptake in primary cultured rat hepatocytes. A specific cDNA probe was used to quantitate the levels of mRNA encoding the Na(+)-taurocholate-cotransporting polypeptide at various culture times. Hepatocytes were cultured on collagen in the presence of insulin (10(-7) mol/L), dexamethasone (10(-7) mol/L) and 10% fetal calf serum for up to 72 hr. During this time period the dissociation constant of Na(+)-dependent taurocholate uptake remained stable (19 to 39 mumol/L), whereas the maximum velocity values decreased from 100% at 3 hr to 55%, 22% and 4% at 24, 48 and 72 hr, respectively. Concomitantly the levels of the Na(+)-taurocholate-cotransporting polypeptide mRNA also decreased from 100% at 3 hr to 41%, 24% and 4% at the later time points. In contrast, Northern hybridization with complementary DNA probes for three common housekeeping gene products revealed a 1.8- to 3.4-fold increase in the levels of mRNA encoding the alpha-subunit of the Na+K(+)-ATPase, beta-actin and glycerol-3-phosphate dehydrogenase. These data indicate that the loss of Na(+)-dependent bile salt uptake in primary cultures of rat hepatocytes is caused by decreased levels of its specific mRNA. Hence the studies further confirm that without specific measures (primary) cultured rat hepatocytes reverse their liver-specific phenotype to a more fetal pattern of gene expression.",0
1686,8225228,"Membrane-associated C-reactive protein on rat liver macrophages is synthesized within the macrophages, expressed as neo-C-reactive protein and bound through a C-reactive protein-specific membrane receptor","We could recently show that rat liver macrophages (Kupffer cells) express a membrane-bound form of C-reactive protein on their surface. Because it is removed by washing the cells in buffers containing Ca(++)-chelators, membrane-bound C-reactive protein is a peripheral protein rather than an integral part of the Kupffer cell membrane. This Kupffer cell membrane-bound C-reactive protein is identical to the galactose-specific particle receptor previously characterized. We now present evidence that Kupffer cells do not acquire soluble serum C-reactive protein but synthesize their own membrane-bound C-reactive protein. By RNA-RNA in situ hybridization, it was found that hepatocytes are not the only sort of liver cells synthesizing C-reactive protein, but C-reactive protein-specific mRNA is present also in Kupffer cells. During acute-phase response C-reactive protein mRNA is found in increased amounts within liver macrophages too. Furthermore, by labeling experiments with antisera against native, pentameric soluble serum C-reactive protein and monoclonal antibodies against a neoepitope present on C-reactive protein subunits only, we could establish that the membrane-bound C-reactive protein expressed on the liver macrophage is not the pentameric molecule of soluble serum C-reactive protein, but rather consists of C-reactive protein subunits. Finally, we present evidence that liver macrophages contain a binding protein in their plasma membrane, with an apparent molecular weight of 59 to 61kD, specific for C-reactive protein and similar to the one previously isolated from macrophage cell lines.",0
1687,8232489,Control of chemotherapy-induced emesis,"The development of antiemetic drugs has been one of the most rewarding areas of oncologic research, since therapeutic advances in this area can result in immediate improvement in the quality of life for patients undergoing chemotherapy. Antiemetic therapy has progressed dramatically during the past decade and a half. Fifteen years ago, patients receiving cisplatin for the first time had a median of 12 vomiting episodes within the first 24 hours, whereas now more than 50 percent of such patients have no vomiting episodes at all. Theoretical and clinical challenges remain, however, in the effort to control chemotherapy-induced emesis. The mechanisms of anticipatory vomiting and delayed vomiting are still not understood, and consistently effective therapeutic approaches to these problems have yet to be developed.",0
1688,8244279,"""Cholesterol carriers in human bile: are """"lamellae"""" involved?""","""Cholesterol, a highly insoluble molecule, is transported in bile by specialized lipid aggregates. On the basis of extensive correlations between laboratory-prepared model biles and surgically harvested native biles, it has become generally accepted that biliary cholesterol is solubilized by simple and mixed micelles, single bilayered (unilamellar) vesicles and, under certain conditions, multilamellar vesicles (liposomes or liquid crystals) all composed of bile salts, lecithin and cholesterol in different proportions. Current concepts suggest that in lithogenic biles multilamellar vesicles result from aggregation and fusion of unilamellar vesicles and are a principal source from which cholesterol precipitates to form gallstones. Recent reports now challenge the prevailing paradigm by proposing that the principal cholesterol-carrying particles in human biles are not micelles but are """"lamellae"""" composed of stacked membrane-like bilayers of lipids. In this article, we provide a critical overview of the experiments that led to the established views of biliary cholesterol transport and to the newer lamellae hypothesis. The principal evidence for lamellae stems from negative-stain electron microscopy, an artifactprone technique when used to study lipid-rich fluids such as bile. We show that lamellar structures represent both the electron microscopic analog of multilamellar vesicles in supersaturated biles that presage the nucleation of cholesterol crystals and an electron microscopic artifact of fossilized mixed micelles that are in fact very tiny (2 to 4 nm in radius) by state-of-the-art noninvasive techniques. We argue further that the lamellae nomenclature improperly equates two fundamentally distinct physical-chemical mechanisms for cholesterol solubilization and dispersion in bile on the basis of identically appearing electron microscopic images.""",0
1689,8247037,Lack of immune responsiveness to bovine serum albumin in insulin-dependent diabetes,"BACKGROUND: Epidemiologic studies have implicated the ingestion of cow's milk in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Moreover, in a recent study, 100 percent of patients with new-onset IDDM had antibodies against bovine serum albumin (BSA), with a majority directed against a 17-amino-acid BSA peptide (ABBOS). Cellular immune mechanisms are thought to be the principal mediators of pancreatic beta-cell destruction in IDDM. METHODS: We measured the responses of peripheral-blood mononuclear cells to BSA and ABBOS or serum IgG anti-BSA antibodies (by particle-concentration fluorescence immunoassay) in 71 patients with IDDM, 55 subjects at various degrees of risk for IDDM, 36 patients with other autoimmune disorders (chronic autoimmune thyroiditis, rheumatoid arthritis, and systemic lupus erythematosus), and 48 normal subjects. RESULTS: The responses of peripheral-blood mononuclear cells to BSA or ABBOS were positive in 2 of 24 patients with new-onset IDDM, 1 of 25 first-degree relatives of patients with IDDM who were negative for islet-cell antibodies, 2 of 30 first-degree relatives of patients with IDDM who were positive for islet-cell antibodies, 1 of 28 patients with established IDDM, and 1 of 29 normal subjects. Similarly, anti-BSA antibodies were not detected significantly more often in patients with new-onset IDDM (3 of 31, 10 percent) than in normal subjects (1 of 37, 3 percent; P = 0.32). However, many patients with autoimmune disease and subjects at increased risk for IDDM had anti-BSA antibodies (frequency, 10 to 31 percent). CONCLUSIONS: Anti-BSA antibodies may reflect a general defect in the process of immunologic tolerance associated with a predisposition to autoimmunity rather than immunity specific to beta cells. The absence of cellular immunity to BSA and ABBOS in IDDM does not support a role for this antigen in the pathogenesis of the disorder.",0
1690,8247072,Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup,"BACKGROUND: The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results. METHODS: The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size. RESULTS: Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned for one or more of their scheduled colonoscopies. Five asymptomatic early-stage colorectal cancers (malignant polyps) were detected by colonoscopy (three at three years, one at six years, and one at seven years). No symptomatic cancers were detected. The numbers of colorectal cancers expected on the basis of the rates in the three reference groups were 48.3, 43.4, and 20.7, for reductions in the incidence of colorectal cancer of 90, 88, and 76 percent, respectively (P < 0.001). CONCLUSIONS: Colonoscopic polypectomy resulted in a lower-than-expected incidence of colorectal cancer. These results support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent colorectal cancer.",0
1691,8259187,Lactation and a reduced risk of premenopausal breast cancer,"BACKGROUND: The evidence of an association of lactation with a reduction in the risk of breast cancer among women has been limited and inconsistent. The effect of lactation appears to be confined to premenopausal women with a history of long lactation, but most studies of this relation have been limited in statistical power. We conducted a multicenter, population-based, case-control study with a sample large enough for us to describe more precisely the association between lactation and the risk of breast cancer. METHODS: Patients less than 75 years old who had breast cancer were identified from statewide tumor registries in Wisconsin, Massachusetts, Maine, and New Hampshire. Controls were randomly selected from lists of licensed drivers if the case subjects were less than 65 years old, and from lists of Medicare beneficiaries if they were 65 through 74 years old. Information on lactation, reproductive history, and family and medical history was obtained by means of telephone interviews. After the exclusion of nulliparous women, 5878 case subjects and 8216 controls remained for analysis. RESULTS: After adjustment for parity, age at first delivery, and other risk factors for breast cancer, lactation was associated with a slight reduction in the risk of breast cancer among premenopausal women, as compared with the risk among women who were parous but had never lactated (relative risk, 0.78; 95 percent confidence interval, 0.66 to 0.91); the relative risk of breast cancer among postmenopausal women who had lactated, as compared with those who had not, was 1.04 (95 percent confidence interval, 0.95 to 1.14). With an increasing cumulative duration of lactation, there was a decreasing risk of breast cancer among premenopausal women (P for trend < 0.001) but not among postmenopausal, parous women (P for trend = 0.51). A younger age at first lactation was significantly associated with a reduction in the risk of premenopausal breast cancer (P for trend = 0.003). As compared with parous women who did not lactate, the relative risk of breast cancer among women who first lactated at less than 20 years of age and breast-fed their infants for a total of six months was 0.54 (95 percent confidence interval, 0.36 to 0.82). CONCLUSIONS: There is a reduction in the risk of breast cancer among premenopausal women who have lactated. No reduction in the risk of breast cancer occurred among postmenopausal women with a history of lactation.",0
1692,8277950,Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children,"BACKGROUND: Both dietary sucrose and the sweetener aspartame have been reported to produce hyperactivity and other behavioral problems in children. METHODS: We conducted a double-blind controlled trial with two groups of children: 25 normal preschool children (3 to 5 years of age), and 23 school-age children (6 to 10 years) described by their parents as sensitive to sugar. The children and their families followed a different diet for each of three consecutive three-week periods. One diet was high in sucrose with no artificial sweeteners, another was low in sucrose and contained aspartame as a sweetener, and the third was low in sucrose and contained saccharin (placebo) as a sweetener. All the diets were essentially free of additives, artificial food coloring, and preservatives. The children's behavior and cognitive performance were evaluated weekly. RESULTS: The preschool children ingested a mean (+/- SD) of 5600 +/- 2100 mg of sucrose per kilogram of body weight per day while on the sucrose diet, 38 +/- 13 mg of aspartame per kilogram per day while on the aspartame diet, and 12 +/- 4.5 mg of saccharin per kilogram per day while on the saccharin diet. The school-age children considered to be sensitive to sugar ingested 4500 +/- 1200 mg of sucrose per kilogram, 32 +/- 8.9 mg of aspartame per kilogram, and 9.9 +/- 3.9 mg of saccharin per kilogram, respectively. For the children described as sugar-sensitive, there were no significant differences among the three diets in any of 39 behavioral and cognitive variables. For the preschool children, only 4 of the 31 measures differed significantly among the three diets, and there was no consistent pattern in the differences that were observed. CONCLUSIONS: Even when intake exceeds typical dietary levels, neither dietary sucrose nor aspartame affects children's behavior or cognitive function.",0
1693,8277951,Islet amyloid polypeptide in patients with pancreatic cancer and diabetes,"BACKGROUND: The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked insulin resistance that declines after tumor resection. Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro. In this study, we examined the relation between IAPP and diabetes in patients with pancreatic cancer. METHODS: We measured IAPP in plasma from 30 patients with pancreatic cancer, 46 patients with other cancers, 23 patients with diabetes, and 25 normal subjects. IAPP immunoreactivity and IAPP messenger RNA were studied in pancreatic cancers, pancreatic tissue adjacent to cancers, and normal pancreatic tissue. RESULTS: Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P < 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes. Among the patients with pancreatic cancer, the concentrations were 25.0 +/- 8.7 pmol per liter in the 7 patients with diabetes who required insulin, 31.4 +/- 12.6 pmol per liter in the 11 patients with diabetes who did not require insulin, and 12.2 +/- 2.4 pmol per liter in the 9 patients with normal glucose tolerance (3 patients had impaired glucose tolerance; their mean plasma IAPP concentration was 11.7 +/- 5.5 pmol per liter). Plasma IAPP concentrations decreased after surgery in the seven patients with pancreatic cancer who were studied before and after subtotal pancreatectomy (28.9 +/- 16.4 vs. 5.6 +/- 3.4 pmol per liter, P = 0.01). Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P < 0.001). In samples from the patients with both pancreatic cancer and diabetes, immunostaining for IAPP was reduced in islets of pancreatic tissue surrounding the tumor; in situ hybridization studies suggested that transcription occurred normally in these islets. CONCLUSIONS: Plasma IAPP concentrations are elevated in patients with pancreatic cancer who have diabetes. Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients.",0
1694,8285929,A preliminary report comparing magnetic resonance coronary angiography with conventional angiography,"BACKGROUND: The ability to assess the patency of coronary arteries by noninvasive means would represent an important advance. We have developed a magnetic resonance imaging (MRI) coronary angiographic technique that permits the display of areas of abnormal coronary blood flow. We have compared this method with conventional contrast angiography for the identification of coronary-artery stenoses. METHODS: MRI coronary angiography was performed with an electrocardiographically gated sequence in 39 subjects, 33 to 84 years of age, who were scheduled for elective cardiac catheterization with coronary angiography. Sequential overlapping transverse and oblique sections were acquired during periods of breath-holding and were displayed as cine loops for analysis. MRI and conventional angiographic data were compared in a blinded manner. The four major epicardial coronary arteries were classified by MRI coronary angiography as being normal (or having only minimal irregularities) or as having disease that was moderately severe to severe. RESULTS: The sensitivity and specificity of MRI coronary angiography, as compared with conventional angiography, for correctly identifying individual vessels with > or = 50 percent angiographic stenoses were 90 percent and 92 percent, respectively. The corresponding positive and negative predictive values were 0.85 and 0.95, respectively. The sensitivity and specificity of the technique were 100 percent and 100 percent, respectively, for the left main coronary artery, 87 percent and 92 percent for the left anterior descending coronary artery, 71 percent and 90 percent for the left circumflex coronary artery, and 100 percent and 78 percent for the right coronary artery. CONCLUSIONS: MRI coronary angiography provides a new approach to evaluating the patency of coronary arteries. These preliminary data suggest that this technique may provide a noninvasive means of evaluating patients with known or suspected coronary artery disease. At its current stage of development, this procedure may be most helpful for excluding clinically important stenoses in patients referred for diagnostic contrast angiography.",0
1695,8289849,A randomized study of the effects of aerobic exercise by lactating women on breast-milk volume and composition,"BACKGROUND: The potential risks and benefits of regular exercise during lactation have not been adequately evaluated. We investigated whether regular aerobic exercise had any effects on the volume or composition of breast milk. METHODS: Six to eight weeks post partum, 33 sedentary women whose infants were being exclusively breast-fed were randomly assigned to an exercise group (18 women) or a control group (15 women). The exercise program consisted of supervised aerobic exercise (at a level of 60 to 70 percent of the heart-rate reserve) for 45 minutes per day, 5 days per week, for 12 weeks. Energy expenditure, dietary intake, body composition, and the volume and composition of breast milk were assessed at 6 to 8, 12 to 14, and 18 to 20 weeks post partum. Maximal oxygen uptake and the plasma prolactin response to nursing were assessed at 6 to 8 and 18 to 20 weeks. RESULTS: The women in the exercise group expended about 400 kcal per day during the exercise sessions but compensated for this energy expenditure with a higher energy intake than that recorded by the control women (mean [+/- SD], intake, 2497 +/- 436 vs. 2168 +/- 328 kcal per day at 18 to 20 weeks; P < 0.05). Maximal oxygen uptake increased by 25 percent in the exercising women but by only 5 percent in the control women (P < 0.001). There were no significant differences between the two groups in maternal body weight or fat loss, the volume or composition of the breast milk, the infant weight gain, or maternal prolactin levels during the 12-week study. CONCLUSIONS: In this study, aerobic exercise performed four or five times per week beginning six to eight weeks post partum had no adverse effect on lactation and significantly improved the cardiovascular fitness of the mothers.",0
1696,8289851,Hyperandrogenism in polycystic ovary syndrome. Evidence of dysregulation of 11 beta-hydroxysteroid dehydrogenase,"BACKGROUND: Hyperandrogenemia is the hallmark of the polycystic ovary syndrome, yet the relative contributions of the adrenal cortex and ovary to the overproduction of androgen remain unclear. To identify possible causes of adrenocortical overactivity, we studied the metabolism of adrenal and ovarian steroid hormones in women with this disorder. METHODS: We measured 24-hour urinary excretion of steroid hormone metabolites by high-resolution capillary gas chromatography in 65 women with the polycystic ovary syndrome and 45 normal women matched for body-mass index. RESULTS: After adjustment for body-mass index, the urinary excretion of testosterone and androstenedione metabolites was 1.9 times higher in the women with the syndrome than in the normal women, and the excretion of dehydroepiandosterone metabolites (C19 steroid sulfates) and cortisol metabolites was 1.5 and 1.3 times higher, respectively (P < 0.01 for all comparisons). The affected women also had significantly higher ratios of 11-oxo (oxygenated) metabolites to 11-hydroxy metabolites of cortisol (1.4 times higher, P < 0.001) and of 11-oxo to 11-hydroxy metabolites of corticosterone (1.8 times higher, P < 0.001). In the group with the polycystic ovary syndrome, 55 percent of the nonobese women and 24 percent of the obese women had ratios above the upper limit of normal; the ratios in the obese women did not differ significantly from those in the nonobese women. CONCLUSIONS: Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.",0
1697,8292133,Administrative costs in U.S. hospitals,"BACKGROUND: Previous estimates of administrative costs in U.S. hospitals have been based on figures for California, and nationwide extrapolation has been controversial. If the costs of bureaucracy are high, major policy reforms may yield substantial savings. METHODS: We obtained detailed data on hospital expenses for fiscal year 1990 from reports submitted to Medicare by 6400 hospitals. We calculated each hospital's administrative costs by summing expenses in the following Medicare cost-accounting categories: administrative and general, nursing administration, central services and supply (excluding the purchase cost of supplies), medical records and library, utilization review, and the salary costs of the employee benefits department. We classified costs in most other categories as clinical. Some small categories of expenses (e.g., gift shop) were excluded from both our clinical and administrative groupings, and for others (e.g., plant operations), a proportional share was allocated between the two groupings. RESULTS: Nationwide, administration accounted for an average of 24.8 percent of each hospital's spending in fiscal 1990. Average hospital administrative costs ranged from 20.5 percent in Minnesota to 30.6 percent in Hawaii. Administrative salaries accounted for 22.4 percent of the average hospital's salary costs. Administrative costs were similar in states with high and low rates of enrollment in health maintenance organizations (HMOs). CONCLUSIONS: Hospital administrative costs in the United States are higher than previous estimates and more than twice as high as those in Canada. Greater enrollment in HMOs, with more competitive bidding by hospitals for managed-care contracts, an important element of proposed managed-competition health care reforms, does not seem to lower hospital administrative costs.",0
1698,8294086,T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections,"Twenty-nine patients with chronic hepatitis C and 15 asymptomatic hepatitis C virus antibody-positive subjects who clinically recovered from hepatitis C virus infection were studied for their peripheral blood lymphomononuclear cell proliferative response to hepatitis C virus structural and nonstructural antigens (core, envelope, nonstructural 4 and nonstructural 5) expressed in yeast as superoxide dismutase fusion proteins, in an initial attempt to define some of the features of the virus-specific immune response. Hepatitis C virus core was the most immunogenic antigen for human leukocyte antigen class II-restricted T cells in both groups of patients studied, and the proliferative response to it was the most vigorous and the most frequently expressed in comparison with the other antigens tested. The specificity of the results was supported by the lack of response to hepatitis C virus antigens by healthy uninfected controls and confirmed by recognition of recombinant core proteins of different origin (yeast and baculovirus) by polyclonal T-cell lines produced by T-cell stimulation with yeast-derived core. Each of the antigens tested was able to induce significant although variable levels of proliferative response, indicating that all can be immunogenic at the T-cell level. Significant proliferative responses to core, nonstructural 4 and nonstructural 5 antigens were more frequently detected in subjects who were able to eradicate infection than in patients with chronic hepatitis C, although the difference was statistically not significant. No difference was observed between the two groups of patients with respect to the response to the putative envelope antigens.",0
1699,8294098,Transforming growth factor-beta 1 and mannose 6-phosphate/insulin-like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat,"These studies investigate the role of transforming growth factor-beta 1, a potent inhibitor of epithelial cell proliferation and stimulator of extracellular matrix biosynthesis, during intrahepatic bile duct hyperplasia and biliary fibrosis. These pathogenic responses were induced in rats by common bile duct ligation. Bile duct cell replication, measured by the bromodeoxyuridine labeling index, was significantly increased 24 hr after common bile duct ligation. This response diminished to baseline by 1 wk. Liver collagen content, determined by quantification of hydroxyproline, was increased significantly after 1 wk of common bile duct ligation, and by 4 wk was increased by a factor of 4. Immunohistochemistry revealed low levels of TGF-beta 1 in normal intrahepatic bile duct epithelium. In contrast, the bile duct epithelium in bile duct-ligated rats stained strongly positive for transforming growth factor-beta 1 at 1 and 4 wk after ligation. These results suggest that transforming growth factor-beta 1 may play a role in both the termination of the bile duct epithelial cell proliferative response and the induction of fibrogenesis after common bile duct ligation. In addition, the mannose 6-phosphate/insulin-like growth factor II receptor was up-regulated in hyperplastic bile duct epithelium 1 and 4 wk after ligation. Because the mannose 6-phosphate/insulin-like growth factor-II receptor has been shown to facilitate the proteolytic activation of transforming growth factor-beta 1, these results suggest that the bile duct epithelium may also be involved in the activation of transforming growth factor-beta 1.",0
1700,8294100,Modulation of the asialoglycoprotein receptor in human hepatoma cells: effect of glucose,"The hepatic receptor for asialoglycoproteins was found to be modulated by the glucose concentration in the medium of the human hepatoma cell line HepG2. The surface binding of asialoorosomucoid, a well-documented ligand for this receptor, increased from 20 ng/mg of cellular protein to about 40 ng/mg as the glucose concentration was increased from 10 to 50 mg/dl. The up-modulating effect of glucose was mimicked by pyruvate, a product of glucose metabolism, and abolished by both 2-deoxyglucose, an inhibitor of glucose metabolism, and by cycloheximide, an inhibitor of protein synthesis. Scatchard plot analysis indicated a rise in the number of binding sites and a twofold increase in binding affinity. In contrast, the binding of antibody remained unchanged with respect to alterations in glucose concentration, an indication that the actual number of receptors remained constant in face of an increased number of binding sites. Specificity of the glucose effect was shown by the binding of insulin and transferrin to their respective receptors, which was unaffected by the high glucose concentration that increased asialoorosomucoid binding. The repression of receptor binding seen with cells grown in biotin-deprived medium was reversed by increasing the glucose concentration of the medium. In this case, binding was restored to a level sixfold to sevenfold higher than that of the control cells grown in dialyzed serum. The stimulatory effect of glucose was shown to be independent of and significantly greater than that of cyclic GMP, a known regulator of receptor expression of biotin-deficient HepG2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1701,8294105,In vivo response of hepatocytes to growth factors requires an initial priming stimulus,"Although growth factor effects have been studied in cultured hepatocytes, little information exists as to whether these factors can trigger hepatocyte replication in vivo. In this study we infused epidermal growth factor, transforming growth factor-alpha and hepatocyte growth factor directly into the portal vein of rats for 24 hr to see whether they could induce DNA synthesis in normal livers or in livers subjected to one-third hepatectomy. Infusion of transforming growth factor-alpha or epidermal growth factor at doses up to 80 micrograms/24 hr had little effect on hepatic DNA synthesis in normal liver, whereas the monomeric and heterodimeric forms of hepatocyte growth factor generally produced increases of less than threefold in hepatic DNA synthesis. In contrast, after one-third hepatectomy infusion of epidermal growth factor, transforming growth factor-alpha or hepatocyte growth factor produced dose-dependent increases in hepatic DNA synthesis. At a dose of 40 micrograms/24 hr, epidermal growth factor increased DNA synthesis threefold, whereas transforming growth factor-alpha or hepatocyte growth factor increased DNA synthesis to greater than six times that in rats that had undergone hepatectomy alone. Furthermore, infusion of these growth factors, with or without one third-hepatectomy, induced the expression of transforming growth factor-alpha mRNA in the liver. The pattern of protooncogene expression induced by one-third hepatectomy was studied to determine the effect of this procedure in sensitizing the liver to the growth factors. Compared with the well-characterized two-thirds hepatectomy system, there was a similar but smaller increase in c-myc expression but no induction of c-jun expression.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1702,8302344,Physician profiling. An analysis of inpatient practice patterns in Florida and Oregon,"BACKGROUND: Physician profiling is a method of cost control that focuses on patterns of care instead of on specific clinical decisions. It is one cost-control method that takes into account physicians' desire to curb the intrusion of administrative mechanisms into the clinical encounter. To provide a concrete example of profiling, we analyzed the inpatient practice patterns of physicians in Florida and Oregon. METHODS: Data for 1991 from Medicare's National Claims History File were used to profile 12,720 attending physicians in Florida and 2589 in Oregon. For each attending physician, we determined the total relative value of all physicians' services delivered during each patient's hospital stay. Relative value was measured in relative-value units (RVUs), according to the resource-based relative-value scale used by Medicare in determining payments to physicians. The mean number of RVUs per admission was then adjusted for the physician's case mix according to the patients' assigned diagnosis-related groups. The influence of the physician's specialty and of selected types of services (such as imaging and endoscopy) was also examined. RESULTS: Florida physicians used markedly more resources, on average, than their colleagues in Oregon (46 vs. 30 case-mix-adjusted RVUs per admission). The difference was apparent for all specialties and all types of service. To illustrate the profiling data potentially available to the medical staffs of individual hospitals, we examined specific data on individual attending physicians and for various types of service for three hospitals' staffs. Despite similar overall profiles that fell below the national mean, each staff had a different practice pattern and would require different efforts to improve efficiency. CONCLUSIONS: In an effort to encourage further debate, we have described one method of physician profiling. Profiling data help identify and characterize differences in practice style to which individual physicians or hospital staffs can respond. Because profiling is not based on rigid rules, it is a cost-containment strategy that can easily accommodate legitimate exceptions; it is therefore preferable to methods in which the appropriateness of each clinical decision is judged separately.",0
1703,8321259,Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia,"BACKGROUND: Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial. METHODS: The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed. RESULTS: The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [+/- SE], 87 +/- 13 vs. 96 +/- 2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system. CONCLUSIONS: Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy.",0
1704,8321261,The relation between health insurance coverage and clinical outcomes among women with breast cancer,"BACKGROUND: Women without private health insurance are less likely than privately insured women to be screened for breast cancer, and their treatment may differ after cancer is diagnosed. In this study we addressed two related questions: Do uninsured patients and those covered by Medicaid have more advanced breast cancer than privately insured patients when the disease is initially diagnosed? And, for each stage of disease, do uninsured patients and patients covered by Medicaid die sooner after breast cancer is diagnosed than privately insured patients? METHODS: We studied 4675 women, 35 to 64 years of age, in whom invasive breast cancer was diagnosed from 1985 through 1987, by linking New Jersey State Cancer Registry records to hospital-discharge data. We compared the stage of disease and stage-specific survival among women with private insurance, no insurance, and Medicaid coverage through June 1992. We also estimated the adjusted risk of death for these groups, using proportional-hazards regression analysis to control for age, race, marital status, household income, coexisting diagnoses, and disease stage. RESULTS: Uninsured patients and those covered by Medicaid presented with more advanced disease than did privately insured patients (P < 0.001 and P = 0.01, respectively). Survival was worse for uninsured patients and those with Medicaid coverage than for privately insured patients with local disease (P < 0.001 for both comparisons) and regional disease (P < 0.001 for both comparisons), but not distant metastases. The adjusted risk of death was 49 percent higher (95 percent confidence interval, 20 to 84 percent) for uninsured patients and 40 percent higher (95 percent confidence interval, 4 to 89 percent) for Medicaid patients than for privately insured patients during the 54 to 89 months after diagnosis. CONCLUSIONS: The more frequent adverse outcomes of breast cancer among women without private health insurance suggest that such women would benefit from improved access to screening and optimal therapy.",0
1705,8332153,Preventive care for women. Does the sex of the physician matter?,"BACKGROUND: Emphasis on ensuring women's access to preventive health services has increased over the past decade. Relatively little attention has been paid to whether the sex of the physician affects the rates of cancer screening among women. We examined differences between male and female physicians in the frequency of screening mammograms and Pap smears among women patients enrolled in a large Midwestern health plan. METHODS: We identified claims for mammography and Pap tests submitted by primary care physicians for 97,962 women, 18 to 75 years of age, who were enrolled in the health plan in 1990. The sex of the physician was manually coded, and the physician's age was obtained from the state licensing board. After identifying a principal physician for each woman, we calculated the frequency of mammography and Pap smears for each physician, using the number of women in his or her practice during 1990 as the denominator. Using unconditional logistic regression, we also calculated the odds ratio of having a Pap smear or mammogram for women patients with female physicians as compared with those with male physicians, controlling for the physician's and the patient's age. RESULTS: Crude rates for Pap smears and mammography were higher for the patients of female than male physicians in most age groups of physicians. The largest differences between female and male physicians were in the rates of Pap smears among the youngest physicians. For the subgroup of women enrolled in the health plan for a year who saw only one physician, after adjustment for the patient's age and the physician's age and specialty, the odds ratio for having a Pap smear was 1.99 (95 percent confidence interval, 1.72 to 2.30) for the patients of female physicians as compared with those of male physicians. For women 40 years old and older, the odds ratio for having a mammogram was 1.41 (95 percent confidence interval, 1.22 to 1.63). For both Pap smears and mammography, the differences between female and male physicians in screening rates were much more pronounced in internal medicine and family practice than in obstetrics and gynecology. CONCLUSIONS: Women are more likely to undergo screening with Pap smears and mammograms if they see female rather than male physicians, particularly if the physician is an internist or family practitioner.",0
1706,8340071,Effect of propylthiouracil on the ethanol-induced increase in liver oxygen consumption in awake rats,"It has been postulated that the beneficial effects of the antithyroid drug propylthiouracil in the treatment of alcoholic liver disease depend primarily on the action of propylthiouracil in suppressing the increase in hepatic oxygen consumption induced by ethanol. The evidence for this effect of propylthiouracil is derived from studies in which liver oxygen consumption has been determined in in vitro preparations. In our study the effects of ethanol and propylthiouracil on liver oxygen consumption were assessed in vivo in an unrestrained and unanesthetized rat model, where liver blood flow and hepatic vein and portal vein oxygen content can be measured. Data show that the liver oxygen consumption increased in rats treated with ethanol-containing liquid diets for 4 to 6 wk, both on withdrawal of alcohol (30%, p < 0.01), and after readministration of ethanol (50%, p < 0.01). Single-dose ethanol administration increased portal tributary blood flow without affecting hepatic arterial blood flow in both controls and rats withdrawn from long-term ethanol treatment. Long-term ethanol administration per se had no effect on portal tributary blood flow; however, hepatic arterial blood flow was increased by 38% (p < 0.01). Treatment with propylthiouracil for 5 days resulted in complete suppression of the increase in liver oxygen consumption induced by long-term ethanol administration. Propylthiouracil treatment also attenuated the increase in portal tributary blood flow after the administration of a single dose of ethanol. These determinations were made 24 hr after the last dose of propylthiouracil.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1707,8341513,Late argon laser suture lysis after mitomycin C trabeculectomy,"Argon laser suture lysis has been effectively used in the early post-operative period to enhance filtration after trabeculectomy. The most substantial reductions in intraocular pressure (IOP) occur when laser suture lysis is performed during the first 2 postoperative weeks, and virtually no effect has been reported after the fourth postoperative week. Mitomycin C, used as adjunct therapy, improves the success rate of trabeculectomy in high-risk eyes and may change the time course for effective suture lysis. The authors used late laser suture lysis in five high-risk patients after mitomycin C trabeculectomy. The mean patient age was 66.8 +/- 15.7 years, and laser suture lysis was performed an average of 13 +/- 5.8 weeks (range, 7-21 weeks) after surgery. The mean IOP before suture lysis was 20.2 +/- 3.8 mmHg. The average IOP reduction immediately after suture lysis was 11.4 +/- 3.9 mmHg. The average IOP 3 to 4 months after laser suture lysis was 9.4 +/- 3.4 mmHg. The authors postulate that adjunctive mitomycin C therapy markedly delays wound healing and appears to extend the period that laser suture lysis is clinically effective. ",0
1708,8341756,Aspergillosis complicating the grafted skin and free muscle flap in a diabetic,"A case of infected diabetic foot ulcer was reconstructed by a free muscle flap overlaid with a skin graft. Primary cutaneous aspergillosis involving the grafted skin and the transplanted muscle was described. The patient presented with an indurated grey-yellow plaque or black eschar in the wound without purulent discharge. Biopsies and cultures demonstrated A. flavus as the etiologic agent without evidence of systemic dissemination. Early diagnosis necessitates a high index of suspicion in immunocompromised patients with unusual cutaneous manifestation. Treatment consisted of aggressive debridement, systemic and local antifungal therapy, and delayed grafting. We concluded that primary cutaneous aspergillosis may occur at the reconstructed wound in an immunocompromised diabetic, and that it is a rare complication requiring prompt diagnosis and treatment. ",0
1709,8359794,"Secretion of soluble chemotactic factors, including interleukin-6: a mechanism for the recruitment of CD8-positive T lymphocytes to human liver allografts during rejection","In 35 patients receiving first liver transplants we assessed the chemotactic responsiveness of peripheral blood lymphocytes to bile, the subset composition of the responding population and the ability of peripheral blood lymphocytes to produce chemotactic factors. In 13 patients in whom acute rejection developed, lymphocyte chemotaxis in vitro was significantly greater in bile sampled 1 or 2 days after transplantation and before episodes of acute rejection than in bile sampled when rejection was clinically apparent or after steroid therapy during stable graft function. The chemotactic factors present showed preferential activity for CD8-positive T cells. Bile sampled during the same posttransplant periods from 11 patients who did not exhibit rejection showed significantly less chemotactic activity. In vitro cultured peripheral blood lymphocytes from patients in whom rejection developed produced lymphocyte chemotactic factors that induced a similar pattern of chemotactic responsiveness with preferential activity for CD8-positive T cells. Separate culture of purified CD4-positive and CD8-positive T cells obtained from patients in whom rejection developed showed that CD4-positive cells produced the factor(s). Analysis of the subset responses of normal peripheral blood lymphocytes to a variety of chemotactic cytokines showed interleukin-6 to have specificity similar to that observed with chemotactic bile, mixed peripheral blood lymphocyte culture supernatants and supernatants of CD4-positive T cells. Chemotactic activity was reduced by 45% to 90% in five chemotactic bile samples and three peripheral blood lymphocyte culture supernatants by treatment with affinity purified interleukin-6 monoclonal antibody.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1710,8359795,Development of human peribiliary capillary plexus: a lectin-histochemical and immunohistochemical study,"""We investigated the development of human intrahepatic peribiliary capillary plexus by lectin-histochemistry and immunohistochemistry, using 40 fetal livers of various gestational ages, 52 postnatal livers of various ages, and 10 adult livers. In the earliest developmental stage of intrahepatic bile ducts (""""the stage of ductal plate""""), no vasculatures were found around the ductal plate, but progenitor vascular cells positive for von Willebrand factor, Ulex europaeus agglutinin I and succinylated wheat germ agglutinin appeared in the mesenchyme of the portal tracts. In """"the stage of biliary cell migration into the mesenchyme,"""" the progenitor vascular cells transformed into capillaries positive for von Willebrand factor, Ulex europaeus agglutinin I, and succinylated wheat germ agglutinin. In """"the stage of bile duct formation,"""" capillaries began to surround the bile ducts (immature peribiliary capillary plexus). The capillaries of the immature peribiliary capillary plexus proliferated and formed premature peribiliary capillary plexus around 40 wk of gestation in large bile ducts and around 6 wk after birth in small bile ducts. The former was composed of inner and outer layers, whereas the latter consisted of scattered capillaries without layer formation. The premature peribiliary capillary plexus continued to proliferate in the postnatal life and reached an adult and mature state around 15 yr. These data suggest that endothelial cells of capillaries of peribiliary capillary plexus derive from mesenchyme at the earliest stage of bile duct development and that the development and maturation of peribiliary capillary plexus progress parallel to those of the intrahepatic bile ducts.""",0
1711,8359796,Visualization of the uptake and processing of oxidized low-density lipoproteins in human and rat liver,"The interaction of oxidized human low-density lipoproteins with human and rat liver was analyzed by light and electron microscopy. At the light microscopic level oxidized low-density lipoprotein was visualized by the fluorescent dye 1,1' dioctadecyl 3,3,3',3' tetramethyl indocarbocyanine perchlorate, whereas at the electron microscopic level, an indirect immunolabeling procedure was used that detected the apoprotein B of the oxidized low-density lipoprotein. In rats, oxidized low-density lipoprotein was administered intravenously, and uptake by human liver was studied by perfusion of tissue blocks. Both in human and in rat liver, fluorescently labeled oxidized low-density lipoprotein was mainly found to become concentrated in Kupffer cells and, to a lesser extent, in endothelial cells. In both species the cell association of fluorescently labeled oxidized low-density lipoprotein could be inhibited by preadministration of polyinosinic acid, indicating a scavenger receptor-mediated process. At the electron microscopic level, oxidized low-density lipoprotein was found to bind mainly to areas of the plasma membrane of the Kupffer cells without clathrin coating, although binding to coated regions was also noticed. Internalization of the ligand occurred through coated vesicle formation and through membrane folding of interacting lamellipodia and wormlike structures. No indication for phagocytosis of aggregated oxidized low-density lipoprotein particles was noticed. After internalization, the immunoreactive oxidized low-density lipoprotein was detected in relatively electron-lucent endosomes and, subsequently, in lysosomes. Endothelial cells internalized oxidized low-density lipoprotein solely through coated pits, after which the particles were transferred through endosomes into lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1712,8371727,A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery,"BACKGROUND: Hypothermic circulatory arrest is a widely used support technique during heart surgery in infants, but its effects on neurologic outcome have been controversial. An alternative method, low-flow cardiopulmonary bypass, maintains continuous cerebral circulation but may increase exposure to known pump-related sources of brain injury, such as embolism or inadequate cerebral perfusion. METHODS: We compared the incidence of perioperative brain injury after deep hypothermia and support consisting predominantly of total circulatory arrest with the incidence after deep hypothermia and support consisting predominantly of low-flow cardiopulmonary bypass in a randomized, single-center trial. The criteria for eligibility included a diagnosis of transposition of the great arteries with an intact ventricular septum or a ventricular septal defect and a planned arterial-switch operation before the age of three months. RESULTS: Of 171 patients with D-transposition of the great arteries, 129 (66 of whom were assigned to circulatory arrest and 63 to low-flow bypass) had an intact ventricular septum, and 42 (21 assigned to circulatory arrest and 21 to low-flow bypass) had a ventricular septal defect. After adjustment for diagnosis, assignment to circulatory arrest as compared with low-flow bypass was associated with a higher risk of clinical seizures (odds ratio, 11.4; 95 percent confidence interval, 1.4 to 93.0), a tendency to a higher risk of ictal activity on continuous electroencephalographic (EEG) monitoring during the first 48 hours after surgery (odds ratio, 2.5; 95 percent confidence interval, 1.0 to 6.4), a longer recovery time to the first reappearance of EEG activity (only in the group with an intact ventricular septum, P < 0.001), and greater release of the brain isoenzyme of creatine kinase in the first 6 hours after surgery (P = 0.046). Analyses comparing durations of circulatory arrest produced results similar to those of analyses comparing treatments. CONCLUSIONS: In heart surgery in infants, a strategy consisting predominantly of circulatory arrest is associated with greater central nervous system perturbation in the early postoperative period than a strategy consisting predominantly of low-flow cardiopulmonary bypass. Assessment of the effect of these findings on later outcomes awaits follow-up of this cohort.",0
1713,8381380,"Patterns of antibodies to hepatitis C virus in patients with chronic non-A, non-B hepatitis and their relationship to viral replication and liver disease","Patients with hepatitis C virus infection may have circulating antibodies to various structural and nonstructural antigens of the virus. To assess whether the antibody profile is related to epidemiological or clinical features of chronic infection or to viral replication, sera from 172 consecutive patients with biopsy-proven chronic non-A, non-B hepatitis were studied for antibodies to nonstructural and structural hepatitis C virus antigens and for serum hepatitis C virus RNA with the polymerase chain reaction using primers derived from the 5' noncoding region. Three subgroups could be identified on the basis of their seroreactivity to hepatitis C virus: 133 cases (77.3% [group A]) were positive on first- and second-generation assays and had antibodies to C100-3 and to C22, C33c or both identified on recombinant immunoblot assay; 23 cases (13.4% [group B]) were positive only on second-generation assay and reacted with C22, C33c or both but not with C100-3; and 26 cases (9.3% [group C]) were negative for all hepatitis C virus antibodies. Mean age and sex distributions were similar among the three groups; a history of transfusion was more frequent among cases in group B (p = 0.06). These patients also had the highest serum aminotransferase values (p = 0.001). Liver histological studies showed active necroinflammatory changes in 69.2% of patients in group A and 52.2% of those in group B but only in 25% of cases in group C. Serum hepatitis C virus RNA was frequently detected in patients of groups A and B, independent of their recombinant immunoblot assay profiles.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1714,8384316,Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators,"BACKGROUND: Most epidemiologic studies of cardiovascular disease in postmenopausal women suggest that estrogen-replacement therapy has a protective effect. The effects of the use of estrogen combined with progestin are less well studied. METHODS: To examine the associations of hormone-replacement therapy with concentrations of plasma lipids and hemostatic factors, fasting serum concentrations of glucose and insulin, and blood pressure, we studied 4958 postmenopausal women participating in a population-based investigation. Using cross-sectional data, we classified the women into four groups according to their use of hormone-replacement therapy: current users of estrogen alone, current users of estrogen with progestin, nonusers who had formerly used these hormones, nonusers who had never used them. RESULTS: Current users had higher mean levels of high-density lipoprotein cholesterol, its subfractions high-density lipoprotein2 and high-density lipoprotein3, and apolipoprotein A-I than nonusers and lower mean levels of low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), fibrinogen, antithrombin III, and fasting serum glucose and insulin. However, current users of estrogen alone had higher triglyceride, factor VII, and protein C levels than either nonusers or current users of estrogen with progestin. After making certain assumptions, we estimated that the findings, if causal, would translate into a reduction of 42 percent in the risk of coronary heart disease in users of hormones as compared with nonusers. Women using estrogen with progestin would have an even greater estimated benefit. CONCLUSIONS: A randomized trial is needed to eliminate possible selection biases in our observational study that are related to the prescription of replacement hormones. Nevertheless, hormone-replacement therapy appears to be associated with a favorable physiologic profile, which probably mediates its protective effects on cardiovascular disease. The use of estrogen combined with progestin appears to be associated with a better profile than the use of estrogen alone.",0
1715,8386694,Regulation of glycogen phosphorylase activity in isolated human hepatocytes,"Hepatocytes were isolated from human liver tissue by a two-step perfusion technique. They were treated with vasopressin, angiotensin, ATP and phenylephrine, which are known to be Ca(2+)-mediated glycogenolytic agents in rat liver tissue, and as a control, they were treated with the cyclic AMP-mediated hormones glucagon and isoproterenol. All agonists induce a time-dependent activation of glycogen phosphorylase. Glucagon and isoproterenol induce a somewhat higher degree of phosphorylase activation compared with vasopressin, angiotensin, ATP and phenylephrine, which all increase inositol tris-phosphate levels and have no effect on the cyclic AMP levels. The total activity of glycogen phosphorylase (a + b), amounting to 30 to 35 mU/mg protein, is found to be much lower than that found in rat liver tissue. Because only minor differences could be found, we conclude that the regulation of glycogen phosphorylase in human liver tissue is basically the same as that found in rat liver tissue.",0
1716,8387945,Characterization of hepatitis C virus structural proteins with a recombinant baculovirus expression system,"We cloned and expressed the sequences encoding the structural proteins of the hepatitis C virus in a baculovirus eukaryotic expression system. Four recombinant constructs expressed sufficient hepatitis C virus-specific proteins in insect cell culture to allow analysis of protein cleavage, glycosylation and immunoreactivity. Using immunoblot analysis, we detected a 22-kD protein corresponding to the hepatitis C virus capsid protein cleaved from a larger precursor. Recombinant constructs encoding the presumptive envelope (E1) protein produced products ranging from 30 to 35 kD, whereas constructs encoding the presumptive E2/NS1 protein expressed products ranging in size from 68 to 73 kD. The recombinant envelope proteins were glycosylated, as shown by sensitivity to endoglycosidase F digestion, whereas the capsid was not. We examined the immunoreactivity of these recombinant proteins using sera from 50 patients chronically infected with HCV. Forty-seven of 50 of these sera contained antibodies against the capsid, 14 (28%) also had antibodies against E1 and at least 5 (10%) had antibody against E2/NS1. Forty-seven of 50 sera (94%) were viremic, as determined on hepatitis C virus polymerase chain reaction. The three sera that were hepatitis C virus polymerase chain reaction negative did not have envelope antibodies, whereas all sera that had envelope antibodies were also hepatitis C virus polymerase chain reaction positive. Thus antibodies to baculovirus-expressed hepatitis C virus structural proteins, including E1 and E2/NS1, are found in the presence of viremia.",0
1717,8387950,Tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells,"Tumor necrosis factor mediates most biological activities of endotoxin and also, in part, mediates endotoxin-induced disturbances in lipid metabolism. In this study, the effect of tumor necrosis factor on low-density lipoprotein receptor activity was investigated in cells of HepG2, a well-differentiated human hepatoma cell line. Pretreatment of the cells with tumor necrosis factor leads to enhanced binding, uptake and degradation of 125I-labeled low-density lipoprotein. This effect of tumor necrosis factor was dose and time dependent. Tumor necrosis factor-stimulated enhancement of low-density lipoprotein binding occurred at all stages of cell growth. However, addition of an excess of unlabeled low-density lipoprotein, to down-regulate low-density lipoprotein receptors before exposure to tumor necrosis factor of the cells, completely abolished the effects of tumor necrosis factor. Competition experiments using unlabeled low-density lipoprotein and blockage experiments with a monoclonal low-density lipoprotein receptor antibody showed that tumor necrosis factor-stimulated low-density lipoprotein binding takes place through stimulation of low-density lipoprotein receptors. Comparison of the kinetics of specific low-density lipoprotein binding in the unstimulated cells and in the tumor necrosis factor-stimulated cells indicated that tumor necrosis factor caused a 30% increase in maximum velocity with no significant change in Michaelis constant, suggesting that tumor necrosis factor increases the number of low-density lipoprotein receptors on the cells rather than changing binding affinity. Preincubation of the cells with cycloheximide or actinomycin D totally abolished the up-regulatory effect of tumor necrosis factor on low-density lipoprotein receptors. Tumor necrosis factor did not stimulate proliferation of HepG2 cells, as judged by cell protein determination or by [3H]thymidine incorporation. In conclusion, this study suggests that tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells by stimulation of de novo synthesis of receptors, independent of cell growth.",0
1718,8392027,Adenylate cyclase activity in microdissected rat liver tissue: periportal to pericentral activity gradient,"Adenylate cyclase activity was measured in microdissected samples from lyophilized cryostat sections of rat liver by means of an improved assay. Livers were obtained from adult Sprague-Dawley rats fasted for 22 hr. Adenylate cyclase activities, basal and those elicited by various agents, were determined in dissected samples from periportal and pericentral regions of the classic liver lobule. In all samples, enzyme activity was strongly stimulated by glucagon, cholera toxin, guanosine-5'-O-(3-thiotriphosphate), sodium fluoride and forskolin. The beta-adrenergic agonist isoproterenol produced very weak, if any, enzyme stimulation. Angiotensin II did not inhibit the activity elicited by lithium chloride and GTP at high concentrations, and pertussis toxin did not enhance the GTP-stimulated activity. We observed a periportal-to-pericentral gradient for basal and agent-stimulated activities.",0
1719,8406361,Zonal distribution of protein-acetaldehyde adducts in the liver of rats fed alcohol for long periods,"Acetaldehyde, a highly reactive intermediate of alcohol metabolism, has been shown to form adducts with liver proteins in rats fed alcohol for long periods. In this report, the zonal distribution of liver protein-acetaldehyde adducts that formed in vivo was studied by means of histoimmunostaining. Rats were pair-fed alcohol-containing and alcohol-free AIN'76 liquid diets for 2 or 11 wk before they were killed and subjected to whole body perfusion with paraformaldehyde. Each liver was cut into 60-microns-thick slices. Slices were first treated with 10% hydrogen peroxide to eliminate endogenous peroxidase activity. They were then incubated sequentially with rabbit antihemocyanin-acetaldehyde adduct, goat antirabbit serum IgG and rabbit peroxidase-antiperoxidase complex. The liver slices were stained with diaminobenzidine and counterstained with methylgreen. In the livers of rats fed alcohol for 2 wk, peroxidase activity was evident in the perivenous zone but not the periportal zone. No staining was obtained when the primary antibody had been preabsorbed with immobilized hemocyanin-acetaldehyde adduct or if the liver slices were incubated with the unimmunized rabbit IgG. Slight staining of the perivenous zone was seen in the livers of control rats, presumably because of minimal protein-acetaldehyde adduct formation emanating from endogenous acetaldehyde. When rats were fed alcohol for longer periods (e.g., 11 wk), protein-acetaldehyde adducts were still seen predominantly in the perivenous zone, but the distribution pattern was more diffuse than that observed in the livers of rats fed alcohol for only 2 wk. More liver cells produced protein-acetaldehyde adducts when rats were fed the alcohol-containing diet supplemented with cyanamide.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1720,8406363,Regulation of iron metabolism in HepG2 cells: a possible role for cytokines in the hepatic deposition of iron,"In chronic inflammation it is reported that serum iron is depleted and hepatic iron is increased because of reticuloendothelial system iron blockade. However, recent studies indicate that hepatic parenchymal cells increase the uptake of transferrin-bound iron after in vivo stimulation with bacterial lipopolysaccharide, suggesting that endotoxemia itself or lipopolysaccharide-induced production of inflammation-related cytokines may also be responsible for this phenomenon. In this study the actions of inflammation-related cytokines on the synthesis of iron-binding proteins (transferrin and ferritin) and transferrin receptor and the uptake of transferrin-bound iron were investigated in a human hepatoblastoma cell line, HepG2, which is the most commonly used cell line for examining the regulation of hepatic protein synthesis by cytokines. The cells were exposed to interleukin-1 beta, interleukin-6 or tumor necrosis factor-alpha separately for 24 hr. In each cytokine treatment group, the level of transferrin, which is secreted into the conditioned medium, was found to be decreased compared with that of untreated cells. On the other hand, the biosynthesis of ferritin was markedly elevated after the same treatment. This increase in ferritin by cytokine treatment was diminished when deferoxamine was used concomitantly to deplete intracellular chelatable iron. After stimulation with interleukin-1 beta, interleukin-6 or tumor necrosis factor-alpha, 59Fe-labeled transferrin uptake into the cells was increased by 36%, 48%, or 18%, respectively, and this uptake was inhibited by the addition of excess unlabeled transferrin. A binding study with 125I-labeled diferric transferrin revealed that the three cytokines increased the number of transferrin receptors on the cell surface by 1.15-fold to 1.35-fold.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1721,8413409,Treatment of acute lymphoblastic leukemia. 30 years' experience at St. Jude Children's Research Hospital,"""BACKGROUND: Therapy for childhood lymphoblastic leukemia has evolved during the past three decades, but key questions about what are the least toxic, most effective forms of treatment remain unanswered because of the lack of comprehensive follow-up information. METHODS: To assess long-term outcome in the series of clinical trials conducted at St. Jude Hospital, we compared the results of treatment typical of four eras: exploratory combination chemotherapy (era 1, 1962 to 1966; 91 patients), regimens for the control of meningeal leukemia (era 2, 1967 to 1979; 825 patients), limited intensification of therapy (era 3, 1979 to 1983; 428 patients), and extended intensification of therapy (era 4, 1984 to 1988; 358 patients). (""""Intensification"""" refers to strategies of systemic chemotherapy that are more aggressive than conventional ones.) The major end points were survival and event-free survival; we also calculated the relative risk of treatment failure and the rate of relapse or death after treatment ended (post-treatment failure rate). RESULTS: The probability of event-free survival improved significantly in each successive era (P < 0.001 by the log-rank test), reaching 71 percent in era 4. There was a decrease of approximately 50 percent in the risk of treatment failure from one era to the next in each subgroup of patients defined according to different combinations of the leukocyte count, race, age, and sex. Leukemia appeared to be eradicated in patients who remained in complete remission for three years or more after treatment in era 4. The incidence of death due to nonleukemic causes remained 4 to 6 percent despite the trend toward more intensive treatment. An estimated 765 patients (45 percent) are long-term survivors; most of them (80 percent) have no health problems related to leukemia or its treatment. CONCLUSIONS: The development and successful application of preventive therapy for meningeal leukemia, followed by the intensification of systemic chemotherapy, has progressively improved the rate of cure of childhood lymphoblastic leukemia, with relatively few adverse sequelae.""",0
1722,8413410,Pretransplantation burden of leukemic progenitor cells as a predictor of relapse after bone marrow transplantation for acute lymphoblastic leukemia,"BACKGROUND: We developed a test to discern small numbers of residual leukemic progenitor cells in the bone marrow of patients with acute lymphoblastic leukemia (ALL) in remission. Preliminary studies revealed that before undergoing bone marrow transplantation such patients differed in their burden of leukemic progenitor cells. These observations suggested that the burden of these cells might influence the risk of relapse after transplantation. METHODS: The number of residual leukemic progenitor cells before bone marrow transplantation was determined for 83 patients with high-risk ALL. We combined multiparameter flow cytometry and cell sorting with assays for leukemic progenitor cells in a quantitative method for the detection of minimal residual disease. RESULTS: The count of leukemic progenitor cells in bone marrow specimens from patients in remission varied markedly between patients, ranging from 0 to 12,546 cells per million mononuclear cells, or from 0 to 1.255 percent (median, 51 leukemic progenitor cells per million mononuclear cells, or 0.005 percent). Patients whose count of leukemic progenitor cells exceeded the median value had a higher likelihood of relapse than did patients with values below the median (relapse rate at one year, 100 percent vs. 41 percent; P < 0.001). There was a statistically significant inverse relation between the leukemic progenitor-cell content of bone marrow before transplantation and the duration of remission after transplantation (P < 0.001). The estimated risk of relapse for patients with > or = 51 leukemic progenitor cells per million mononuclear cells was more than 3.5 times the risk for patients with lower counts, after adjustment for the effects of other covariates (P = 0.005). CONCLUSIONS: The count of residual leukemic progenitor cells is a powerful predictor of relapse after autologous bone marrow transplantation, particularly among male patients. Its measurement may be useful for analyzing and improving the treatment of patients with high-risk ALL in remission.",0
1723,8413431,A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients,"BACKGROUND: Impedance plethysmography performed serially over a one-week period has been shown to be an effective diagnostic strategy for patients with clinically suspected acute deep-vein thrombosis. Compression ultrasonography has a high sensitivity and specificity for the detection of proximal-vein thrombosis. The clinical value of repeated ultrasonography in the management of symptomatic deep-vein thrombosis is unknown. METHODS: We conducted a randomized trial in 985 consecutive outpatients with clinically suspected deep-vein thrombosis to compare the diagnostic value of serial impedance plethysmography (494 patients) and serial compression ultrasonography (491 patients). We compared the positive predictive values of both tests for the diagnosis of venous thrombosis, using contrast venography as a reference. The frequencies of venous thromboembolism during a six-month follow-up period were also compared in patients with repeatedly normal results in order to evaluate the safety of withholding anticoagulant therapy from such patients. RESULTS: The positive predictive value of an abnormal ultrasonogram was 94 percent (95 percent confidence interval, 87 to 98 percent), whereas the predictive value of impedance plethysmography was 83 percent (95 percent confidence interval, 75 to 90 percent) (P = 0.02). In patients with repeatedly normal results, the incidence of venous thromboembolism during the six-month follow-up period was 1.5 percent (95 percent confidence interval, 0.5 to 3.3 percent) for serial compression ultrasonography, as compared with 2.5 percent (95 percent confidence interval, 1.2 to 4.6 percent) for serial impedance plethysmography. CONCLUSIONS: In making the diagnosis of deep-vein thrombosis in symptomatic outpatients, serial compression ultrasonography is preferable to impedance plethysmography, in view of its superior performance in detecting venous thrombosis.",0
1724,8413454,Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. The Investigators of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2),"BACKGROUND: The overall rate of mortality due to ischemic heart disease is known to increase progressively with age. We evaluated the relation between the mortality rate and age in patients with first myocardial infarctions treated with thrombolytic therapy. METHODS: We studied 9720 patients with first infarctions who had been enrolled in the GISSI-2 trial. (This trial compared the efficacy of tissue plasminogen activator with that of streptokinase in patients with myocardial infarction.) Of these, only 35 percent had a history of angina. The relation between age and mortality during hospitalization and during the six months after discharge was determined by unadjusted and adjusted analyses. RESULTS: The in-hospital mortality rate was 1.9 percent among patients 40 years old or younger, but it increased to 31.9 percent among those more than 80 years old; however, values for indicators of infarct size did not increase with age. Autopsies were performed in 20 percent of the 772 patients who died in the hospital; the findings showed that the frequency of cardiac rupture increased from 19 percent among patients 60 years old or younger to 86 percent among those more than 70 years old. The mortality rate for the first six months after hospital discharge also increased significantly with age. After adjustment for confounding variables, older age continued to be significantly associated with a higher risk of in-hospital and post-discharge death. When age was introduced into a multivariate model as a continuous variable, the risk of death was estimated to increase by about 6 percent per year for both in-hospital and six-month mortality rates. CONCLUSIONS: In patients with first myocardial infarctions who received thrombolytic therapy, age was a powerful independent predictor of both in-hospital and post-discharge mortality rates. The exponential, age-related increase in the mortality rate did not appear to be explained by larger infarcts.",0
1725,8416266,Association between polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus,"BACKGROUND: The storage of glucose as glycogen in skeletal muscle is frequently impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their nondiabetic relatives. Despite an intensive search for candidate genes associated with NIDDM, no data have been available on the gene coding for the key enzyme of this pathway, glycogen synthase. METHODS AND RESULTS: Using a human complementary DNA probe, the restriction enzyme Xbal, and Southern blot analysis, we identified two polymorphic alleles, A1 and A2, in the glycogen synthase gene. The gene was localized to chromosome 19. The A1A2 or A2A2 genotype was found in 30 percent of 107 patients with NIDDM but in only 8 percent of 164 nondiabetic subjects without a family history of NIDDM (P < 0.001). The diabetic patients with the A2 allele had a stronger family history of NIDDM (P = 0.019), a higher prevalence of hypertension (P = 0.008), and a more severe defect in insulin-stimulated glucose storage (P = 0.001) than the diabetic patients with the A1 allele. The concentration of the glycogen synthase protein in biopsy specimens of skeletal muscle from the patients with the A2 allele was normal, however, suggesting that expression of the gene was unaltered. The Xbal polymorphism was due to a change of a single base in an intron. CONCLUSIONS: The Xbal polymorphism of the glycogen synthase gene identifies a subgroup of patients with NIDDM characterized by a strong family history of NIDDM, a high prevalence of hypertension, and marked insulin resistance.",0
1726,8417381,Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer,"BACKGROUND: Smoking is a risk factor for several cancers and may also limit the efficacy of treatment. In this study, we evaluated the influence of cigarette smoking during radiation therapy on the efficacy of treatment in patients with head and neck cancer. METHODS: Using a questionnaire, we obtained information on smoking behavior at base line and weekly during therapy in 115 patients with head and neck cancer who were treated with radiation therapy with or without fluorouracil. The side effects of therapy were evaluated weekly, and response was assessed 13 weeks after treatment was completed. The main outcomes measured were treatment response and survival. RESULTS: The prognostic variables were similar among the patients who smoked and those who did not smoke during treatment. The 53 patients who continued to smoke during radiation therapy had a lower rate of complete response (45 percent vs. 74 percent, P = 0.008) and poorer two-year survival (39 percent vs. 66 percent, P = 0.005) than the 62 patients who did not smoke or who had quit before treatment. Among the nonsmoking patients, mortality was influenced by the length of time between quitting and treatment, with a risk reduction (relative to that for patients who continued to smoke) of 40 percent for patients who had quit less than 12 weeks before diagnosis and of 70 percent for patients who had quit more than 1 year before diagnosis. After adjustment for other variables with proportional-hazards regression analysis, smoking remained an independent prognostic factor (P = 0.002), with a relative risk of 2.5 (95 percent confidence interval, 1.4 to 4.4) favoring the patients who abstained from smoking. The results could not be explained by the type of chemotherapy received, the presence of coexisting morbid conditions, differences in the side effects of radiation, or the number of interruptions of treatment. CONCLUSIONS: Patients with head and neck cancer who continue to smoke during radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy.",0
1727,8418405,"Unconventional medicine in the United States. Prevalence, costs, and patterns of use","BACKGROUND: Many people use unconventional therapies for health problems, but the extent of this use and the costs are not known. We conducted a national survey to determine the prevalence, costs, and patterns of use of unconventional therapies, such as acupuncture and chiropractic. METHODS: We limited the therapies studied to 16 commonly used interventions neither taught widely in U.S. medical schools nor generally available in U.S. hospitals. We completed telephone interviews with 1539 adults (response rate, 67 percent) in a national sample of adults 18 years of age or older in 1990. We asked respondents to report any serious or bothersome medical conditions and details of their use of conventional medical services; we then inquired about their use of unconventional therapy. RESULTS: One in three respondents (34 percent) reported using at least one unconventional therapy in the past year, and a third of these saw providers for unconventional therapy. The latter group had made an average of 19 visits to such providers during the preceding year, with an average charge per visit of $27.60. The frequency of use of unconventional therapy varied somewhat among socio-demographic groups, with the highest use reported by nonblack persons from 25 to 49 years of age who had relatively more education and higher incomes. The majority used unconventional therapy for chronic, as opposed to life-threatening, medical conditions. Among those who used unconventional therapy for serious medical conditions, the vast majority (83 percent) also sought treatment for the same condition from a medical doctor; however, 72 percent of the respondents who used unconventional therapy did not inform their medical doctor that they had done so. Extrapolation to the U.S. population suggests that in 1990 Americans made an estimated 425 million visits to providers of unconventional therapy. This number exceeds the number of visits to all U.S. primary care physicians (388 million). Expenditures associated with use of unconventional therapy in 1990 amounted to approximately $13.7 billion, three quarters of which ($10.3 billion) was paid out of pocket. This figure is comparable to the $12.8 billion spent out of pocket annually for all hospitalizations in the United States. CONCLUSIONS: The frequency of use of unconventional therapy in the United States is far higher than previously reported. Medical doctors should ask about their patients' use of unconventional therapy whenever they obtain a medical history.",0
1728,8419814,Rapid serologic testing with immune-complex-dissociated HIV p24 antigen for early detection of HIV infection in neonates. Southern California Pediatric AIDS Consortium,"BACKGROUND: Serologic detection of human immunodeficiency virus (HIV) infection in neonates is complicated by the presence of immune complexes, consisting of passively transferred maternal antibodies and HIV antigens. A new, rapid assay has been designed to disrupt these immune complexes in order to permit the detection of a specific HIV antigen. We evaluated the efficacy of this assay in detecting HIV infection in neonates. METHODS: We measured p24 antigen in blood samples from both infected and uninfected children of HIV-infected mothers. The samples were treated with glycine hydrochloride to dissociate the immune complexes, followed by neutralization with TRIS-hydrochloric acid. A commercial HIV p24 antigen assay was then used, with an optical density greater than 0.120 at a wavelength of 450 nm defined as indicating a positive result. RESULTS: Of eight cord-blood samples from neonates with proved HIV infection, five were positive for immune-complex-dissociated p24 antigen. For two other neonates the first postnatal sample, obtained on days 12 and 18, was positive. There was no follow-up sample for the eighth neonate. Of 22 uninfected neonates, 20 were negative on the cord-blood assay. Two neonates had positive cord-blood samples, but the first postnatal sample was negative. Thus, the tests with early postnatal samples identified the HIV-infection status correctly for all 29 children who could be evaluated. In a separate group of 78 children (median age, 188 weeks), the specificity of the test was 100 percent and the sensitivity 81 percent. CONCLUSIONS: The immune-complex-dissociated HIV p24 antigen assay is a rapid, simple serologic test that may be of value in diagnosing HIV infection in neonates born to HIV-infected women.",0
1729,8419815,Sympathetic-nerve activity during sleep in normal subjects,"BACKGROUND: The early hours of the morning after awakening are associated with an increased frequency of events such as myocardial infarction and ischemic stroke. The triggering mechanisms for these events are not clear. We investigated whether autonomic changes occurring during sleep, particularly rapid-eye-movement (REM) sleep, contribute to the initiation of such events. METHODS: We measured blood pressure, heart rate, and sympathetic-nerve activity (using microneurography, which provides direct measurements of efferent sympathetic-nerve activity related to muscle blood vessels) in eight normal subjects while they were awake and while in the five stages of sleep. RESULTS: The mean (+/- SE) amplitude of bursts of sympathetic-nerve activity and levels of blood pressure and heart rate declined significantly (P < 0.001), from 100 +/- 9 percent, 90 +/- 4 mm Hg, and 64 +/- 2 beats per minute, respectively, during wakefulness to 41 +/- 9 percent, 80 +/- 4 mm Hg, and 59 +/- 2 beats per minute, respectively, during stage 4 of non-REM sleep. Arousal stimuli during stage 2 sleep elicited high-amplitude deflections on the electroencephalogram (called K complexes), which were frequently associated with bursts of sympathetic-nerve activity and transient increases in blood pressure. During REM sleep, sympathetic-nerve activity increased significantly (to 215 +/- 11 percent; P < 0.001) and the blood pressure and heart rate returned to levels similar to those during wakefulness. Momentary restorations of muscle tone during REM sleep (REM twitches) were associated with cessation of sympathetic-nerve discharge and surges in blood pressure. CONCLUSIONS: REM sleep is associated with profound sympathetic activation in normal subjects, possibly linked to changes in muscle tone. The hemodynamic and sympathetic changes during REM sleep could play a part in triggering ischemic events in patients with vascular disease.",0
1730,8419819,Sexual harassment in medical training,"BACKGROUND: Sexual harassment has become a national concern and one that is increasingly recognized in the field of medicine. Although there are reports of the sexual harassment of medical trainees, there is little information on the prevalence of this problem and whether it is adequately addressed by training institutions. METHODS: Surveys with descriptions and examples of sexual harassment were mailed to 133 internal medicine residents in a university training program. The residents were asked to report anonymously whether they had encountered sexual harassment during medical school or residency, the frequency and type of harassment, its effect on them, whether they chose to report it to a person in authority, and the factors that influenced this decision. RESULTS: Surveys were returned by 82 residents (response rate, 62 percent), 33 women and 49 men. Twenty-four women (73 percent) and 11 men (22 percent) reported that they had been sexually harassed at least once during their training. The women were more likely than the men to have been physically harassed, and the women's harassers were of higher professional status. Among those harassed, 19 of the women (79 percent) and 5 of the men (45 percent) thought that the experience created a hostile environment or interfered with their performance at work, but only 2 women and no men reported their experiences to an authority. The women cited a lack of confidence that they would be helped as the main reason for not reporting the experience, whereas men most commonly said that they had dealt with the problem without the need for outside assistance. CONCLUSIONS: Many medical trainees encounter what they believe to be sexual harassment during medical school or residency, and this often creates a hostile learning and work environment. Training institutions need to address the adverse effects this may have on medical education and patient care.",0
1731,8428720,Induction of cytochrome P-4502E1 in the human liver by ethanol is caused by a corresponding increase in encoding messenger RNA,"The propensity of centrilobular liver damage to develop in alcohol abusers after exposure to various hepatotoxins, including ethanol itself, has been linked to the induction by ethanol of P-4502E1, a microsomal P-450 enzyme that bioactivates these agents to reactive metabolites. Whereas long-term ethanol consumption elicits a marked increase in hepatic P-4502E1 content, the molecular mechanism by which ethanol produces this effect is the subject of controversy in animals, and it has not been elucidated in human beings. Possible mechanisms include increased enzyme synthesis stemming from elevated 2E1 messenger RNA levels, enhanced translation of preexisting messenger RNA or stabilization of P-4502E1 protein. To determine which, if any, of these mechanisms underlies P-4502E1 induction in human beings, we examined the effects of ethanol intake on the hepatic intralobular distribution of P-4502E1 messenger RNA and the corresponding protein. Liver sections derived from needle biopsy specimens were obtained from five recently drinking alcoholics (last drink no more than 36 hr before) and eight control subjects (five abstaining alcoholics [last drink 96 hr or more before] and three nondrinkers). In situ hybridization of these liver sections with a human P-4502E1 complementary DNA probe was used to localize P-4502E1 messenger RNA transcripts. Quantitative image analysis of hybridized sections from control subjects revealed that P-4502E1 transcript content in perivenular (zone 3) hepatocytes was significantly higher (p < 0.05) than in midzonal (zone 2) and periportal (zone 1) cells (18.3 +/- 1, 9.5 +/- 2 and 3.1 +/- 2 arbitrary density units, respectively; mean +/- S.E.M.). In recent drinkers, acinar regions containing P-4502E1 transcripts were elevated 2.9-fold compared with those in controls (32.8% +/- 7% vs. 11.2% +/- 2%; p < 0.01), with this messenger RNA increase occurring mainly in perivenular cells (29.6 +/- 3 vs. 18.3 +/- 1 units; p < 0.01). P-4502E1 protein distribution, assessed by the immunohistochemical staining of liver sections with P-4502E1 antibodies, was found to be analogous to that of the messenger RNA in control subjects (the level in perivenular cells was greater than that in midzonal cells, which was greater than that in periportal cells), whereas recent drinkers exhibited marked elevations in enzyme content in both perivenular and midzonal hepatocytes. Moreover, cellular levels of P-4502E1 protein and messenger RNA were significantly correlated (rs = 0.79; p < 0.001) in all patients.(ABSTRACT TRUNCATED AT 400 WORDS)",0
1732,8428721,Portal hypertension in lymphoproliferative and myeloproliferative disorders: hemodynamic and histological correlations,"The pathogenesis of portal hypertension in patients with lymphoproliferative and myeloproliferative disorders is not fully understood. We investigated 20 patients with myeloproliferative disease and 47 patients with lymphoproliferative disease. Transvenous liver biopsies and hepatic vein pressure gradient measurements were performed in all patients, and portal vein blood flow was measured by pulsed Doppler sonography in 31 of these patients and in 22 normal volunteers. The hepatic vein pressure gradient was significantly higher in patients with hepatic infiltrates, fibrosis or both than in patients without hepatic lesions (8.3 +/- 5.0 mmHg vs. 4.1 +/- 2.3 mmHg; p < 0.01). Portal vein blood flow was significantly higher in patients with hematological disease than in normal volunteers (31.2 +/- 15.5 ml/min.kg vs. 14.2 +/- 4.6 ml/min.kg;p < 0.01). In 81.8% of patients with hepatic infiltrates, fibrosis or both and increased portal vein blood flow, the hepatic vein pressure gradient was greater than 6 mm Hg. Although we saw a significant correlation between splenic vein blood flow and portal vein blood flow (n = 20; p < 0.01), we found no significant correlation between splenic vein blood flow and hepatic vein pressure gradient or spleen size. Hepatic infiltration and fibrosis appear to be major determinants of increased hepatic vein pressure gradient, probably because they increase intrahepatic vascular resistance. The role of increased splenic blood flow is probably not determinant. However, because portal pressure was not measured directly in this study, the incidence of portal hypertension may have been underestimated.",0
1733,8429854,Geographic variation in expenditures for physicians' services in the United States,"BACKGROUND: The national volume-performance standard recently implemented by Medicare does not account for geographic variation in expenditures for physicians' services. To study this variation, we examined expenditures for physicians' services in all metropolitan areas in the United States. METHODS: We used Medicare claims data for 1989 to measure rates of service use for beneficiaries living in the 317 U.S. metropolitan statistical areas (MSAs). The variables investigated were rates of admission to the hospital, payments to physicians for inpatient care per admission and per beneficiary, payments to physicians for outpatient care per beneficiary, and overall payments to physicians per beneficiary. Expenditures were measured in terms of allowed charges as adjusted to reflect prevailing charges in each MSA. Rates of use were adjusted for age and sex, with the exception of the variable for payments to physicians for inpatient care per admission, which was adjusted for case mix. RESULTS: Expenditures for the delivery of physicians' services to Medicare beneficiaries varied markedly among MSAs, with those for the areas with the lowest and the highest rates differing at least twofold on each measure. The measures for specific areas varied in parallel: areas with high rates of admission tended to have high levels of payment to physicians for inpatient care per admission, and areas with high payments for inpatient services tended to have high payments for outpatient services. Expenditures were not related to the number of physicians per capita but were lower in MSAs with a high proportion of primary care practitioners. The variation persisted when the 25 largest MSAs were examined; for total payments to physicians per beneficiary, there was a twofold difference between the area with the lowest rate and that with the highest, San Francisco ($872) and Miami ($1,874). The states with the highest overall payments to physicians per beneficiary were Florida, Louisiana, and Michigan. CONCLUSIONS: The marked variation among metropolitan areas in payments to physicians underscores the lack of consensus among physicians about which services are required. Moreover, the practice style in a given community appears to be influenced not by the aggregate supply of physicians but rather by the mixture of primary care physicians and specialists.",0
1734,8433729,Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus,"BACKGROUND AND METHODS: Non-insulin-dependent diabetes mellitus (NIDDM) is a genetically heterogeneous disorder. Maturity-onset diabetes of the young, a form of NIDDM with an early age of onset and autosomal dominant inheritance, can result from mutations in glucokinase, a key enzyme of glucose metabolism in beta cells and the liver. We studied 32 French families with maturity-onset diabetes of the young as well as 21 families with late-onset NIDDM to determine the frequency and clinical features of mutations of glucokinase. Fasting plasma glucose concentrations and oral glucose-tolerance tests were used to determine metabolic status. DNA was isolated from lymphocytes, and DNA polymorphisms in the glucokinase gene were tested for linkage with diabetes. Individual exons of the glucokinase gene from one affected member in each family were amplified by the polymerase chain reaction and screened for mutations by analysis of the conformation-dependent polymorphisms of single-stranded DNA and by DNA sequencing. RESULTS: We found substantial evidence of linkage between the glucokinase locus and maturity-onset diabetes of the young but not between this locus and late-onset NIDDM: Sixteen mutations were identified in 18 of the 32 families with maturity-onset diabetes of the young, but none were found in families with late-onset NIDDM: They included 10 mutations that resulted in an amino acid substitution, 3 that resulted in the synthesis of a truncated protein, and 3 that affected RNA processing. The affected subjects with glucokinase mutations usually had mild hyperglycemia that began during childhood, whereas in subjects with maturity-onset diabetes of the young not due to glucokinase mutations, hyperglycemia usually appeared after puberty. CONCLUSIONS: Mutations in glucokinase are the primary cause of hyperglycemia in a substantial fraction of French patients with maturity-onset diabetes of the young and result in a relatively mild form of NIDDM that can be diagnosed in childhood.",0
1735,8441426,The effect of varying levels of outdoor-air supply on the symptoms of sick building syndrome,"BACKGROUND: The sick building syndrome is the term given to a constellation of symptoms reported by workers in modern office buildings, hypothesized to occur when the supply of outdoor air is reduced, because of the accumulation of contaminants arising from within the building. We undertook this study to determine the effect of changing the supply of outdoor air in four office buildings on the symptoms reported by workers and their perception of the indoor environment. METHODS: Within each of three consecutive two-week blocks, the ventilation systems in each building were manipulated, in random order, to deliver to the indoor environment an intended 20 or 50 ft3 (0.57 or 1.4 m3) of outdoor air per minute per person for one week at a time. Each week, the participants, unaware of the experimental intervention, reported symptoms and the indoor environment was thoroughly evaluated. RESULTS: Of 1838 eligible workers in the four buildings, 1546 (84 percent) participated in the study. The supply of outdoor air averaged 7 percent and 32 percent in the ventilation systems and 30 and 64 ft3 (0.85 and 1.8 m3) per minute per person in the work sites at the lower and higher ventilation levels, respectively. These changes in the supply of outdoor air were not associated with changes in the participants' ratings of the office environment or in symptom frequency (crude odds ratio, 1.0; 95 percent confidence interval, 0.9 to 1.1). After work-site measures of ventilation, temperature, humidity, and air velocity were included in the regression analysis, the adjusted odds ratio was also 1.0 (95 percent confidence interval, 0.8 to 1.2). CONCLUSIONS: Increases in the supply of outdoor air did not appear to affect workers' perceptions of their office environment or their reporting of symptoms considered typical of the sick building syndrome.",0
1736,8444414,Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases,"To evaluate the diagnostic significance of neutrophil cytoplasmic antibodies in chronic liver diseases, we assessed the prevalence of neutrophil cytoplasmic antibodies in autoimmune liver diseases, in particular in primary sclerosing cholangitis, autoimmune chronic active hepatitis and primary biliary cirrhosis, and we also determined the specificity of perinuclear-pattern neutrophil cytoplasmic antibodies for these autoimmune liver diseases by testing sera from patients with nonautoimmune chronic liver diseases. Neutrophil cytoplasmic antibodies were detected in 79% of sera from patients with primary sclerosing cholangitis (n = 24), in 88% of sera from patients with autoimmune chronic active hepatitis (n = 24) and in 28% of sera from patients with primary biliary cirrhosis (n = 25). The presence of neutrophil cytoplasmic antibodies in these diseases correlated significantly (p < 0.008) with the presence of cirrhosis. Neutrophil cytoplasmic antibodies were not detected in nonautoimmune liver diseases. All neutrophil cytoplasmic antibody-positive sera produced a perinuclear fluorescence pattern on ethanol-fixed granulocytes. On neutrophils fixed with paraformaldehyde, a granular cytoplasmic immunofluorescence pattern was observed, demonstrating the cytoplasmic nature of the antigen or antigens involved. Further characterization studies showed that neutrophil cytoplasmic antibodies in autoimmune liver diseases are not directed against myeloperoxidase, proteinase 3 or elastase, the neutrophil cytoplasmic antibody specificities associated with necrotizing vasculitis, glomerulonephritis or both. On Western blots neutrophil cytoplasmic antibodies in autoimmune liver diseases showed reactivity with either lactoferrin, a 67/66-kD protein combination or a 40-kD polypeptide. Reactivity with either of these proteins was observed in sera from patients with primary sclerosing cholangitis (38%), autoimmune chronic active hepatitis (17%) and primary biliary cirrhosis (20%).(ABSTRACT TRUNCATED AT 250 WORDS)",0
1737,8446136,Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. The National Polyp Study Workgroup,"BACKGROUND: The identification and removal of adenomatous polyps and post-polypectomy surveillance are considered to be important for the control of colorectal cancer. In current practice, the intervals between colonoscopies after polypectomy are variable, often a year long, and not based on data from randomized clinical trials. We sought to determine whether follow-up colonoscopy at three years would detect important colonic lesions as well as follow-up colonoscopy at both one and three years. METHODS: Patients were eligible if they had one or more adenomas, no previous polypectomy, and a complete colonoscopy and all their polyps had been removed. They were randomly assigned to have follow-up colonoscopy at one and three years or at three years only. The two study end points were the detection of any adenoma, and the detection of adenomas with advanced pathological features (defined as those > 1 cm in diameter and those with high-grade dysplasia or invasive cancer). RESULTS: Of 2632 eligible patients, 1418 were randomly assigned to the two follow-up groups, 699 to the two-examination group and 719 to the one-examination group. The percentage of patients with adenomas in the group examined at one and three years was 41.7 percent, as compared with 32.0 percent in the group examined at three years (P = 0.006). The percentage of patients with adenomas with advanced pathological features was the same in both groups (3.3 percent). CONCLUSIONS: Colonoscopy performed three years after colonoscopic removal of adenomatous polyps detects important colonic lesions as effectively as follow-up colonoscopy after both one and three years. An interval of at least three years is recommended before follow-up colonoscopy after both one and three years. An interval of at least three years is recommended before follow-up examination after colonoscopic removal of newly diagnosed adenomatous polyps. Adoption of this recommendation nationally should reduce the cost of post-polypectomy surveillance and screening.",0
1738,8446139,Use of multiple drugs among adolescents who use anabolic steroids,"BACKGROUND: Because adolescent users of anabolic steroids are concerned with increasing muscle size and strength, they may be unique among substance users and unlikely to use other drugs. Alternatively, if the factors that cause the use of anabolic steroids are similar to those associated with the use of other substances, adolescents who use anabolic steroids would be expected to report use of other drugs as well. METHODS: We administered a questionnaire based on the 1989 Secondary School Health Risk Survey and the 1990 Youth Risk Behavior Survey of the Centers for Disease Control and Prevention to 1881 students enrolled in compulsory health-science classes (mean [+/- SD] age, 14.9 +/- 1.0 years) in the Richmond County, Georgia, school system. RESULTS: A higher percentage of boys (6.5 percent) than girls (1.9 percent, P < or = 0.001) reported using anabolic steroids without a doctor's prescription. Among ninth-grade students only, 5.4 percent of boys and 1.5 percent of girls reported using anabolic steroids (P < or = 0.001). Among users of anabolic steroids, 25 percent reported sharing needles to inject drugs. The frequency of anabolic-steroid use was significantly (P < 0.001) associated with the frequency of use in the previous 30 days of cocaine (r = 0.44), injectable drugs, alcohol (r = 0.23), marijuana (r = 0.42), cigarettes (r = 0.25), and smokeless tobacco (r = 0.40). On the basis of multiple regression analysis, the use of marijuana, shared needles, smokeless tobacco, and cocaine accounted for 33 percent of the variation in anabolic-steroid use among the ninth-grade students. CONCLUSIONS: In our study, adolescent users of anabolic steroids were likely to use other drugs as well, and many were sharing needles.",0
1739,8446140,Assessing the implementation of physician-payment reform,"BACKGROUND: The Medicare program fundamentally changed its system of payment for physicians' services in 1992. Controversy over the new Medicare fee schedule has focused on three issues: the adequacy of the conversion factor used to translate resource-based relative-value units into fees; the ability of the new payment system to capture differences in work between surgeons and physicians in other specialties; and the allocation of practice expenses across services. METHODS: Using a standard service in each specialty, we developed simulation methods to assess the implementation of physician-payment reform. With these methods we calculated the potential net income for each specialty, as generated by different payment scenarios, including the Medicare fee schedule. RESULTS: We found that Medicare's current monetary-conversion factor yields an unreasonably low level of income for most specialties. Furthermore, the Medicare fee schedule misallocates practice expenses; invasive services are reimbursed for more than actual expenses, and medical services are reimbursed for less. Thus, physicians continue to be paid more generously for invasive services. Finally, the Medicare fee schedule does recognize the wide differences in the intensity of work performed by physicians in various specialties. CONCLUSIONS: The misallocation of practice expenses in the Medicare fee schedule results in serious underpayment for medical services. We think it likely that physicians compensate by performing more lucrative services, such as diagnostic tests. Even if legislation is passed to deal with the misallocation of expenses, the current conversion factor still produces unreasonably low levels of payment overall, which could dissuade those considering a career in medicine from entering the field. Finally, the simulation method we developed can be used as a tool for fee negotiations.",0
1740,8450873,Starvation in the modern world,"Nutritionists, including those involved in famine relief, have learned in the last 25 years that certain deficiency diseases arise from the high protein foods used to rehabilitate starving populations. Other, sometimes inappropriate relief foods starving populations. Other, sometimes inappropriate relief foods include unprocessed or inappropriate grains and unfortified dry skimmed milk. Yet, relief workers do not always receive the most appropriate food for distribution to certain populations. Millions of dollars are appropriated to protect relief supplies for starving people in Somalia, but money is not spent to develop and evaluate simple foods that might save the lives of starving people. There are several items relief agencies and governments should consider when deciding on the most appropriate foods to prevent starvation in famine situations. During kwashiorkor, intestinal mucous produce grossly defective cells, resulting in considerable lactose malabsorption. Thus, using milk to rehabilitate people, especially children, poses a considerable hazard. High carbohydrate diets to rehabilitate starving people can cause gross edema and fatal congestive heart failure. Generally, clinically apparent vitamin or mineral deficiencies do not occur during famines, because the amount of vitamins or minerals needed to small to maintain a very shrunken body. Yet, when the body demand increases as a result of a rehabilitation diet poor in vitamins and minerals but high in protein or calories, clinical deficiency symptoms emerge, e.g., pellagra in Mozambique. Common food combinations used in relief situations consists of corn, soy, and milk fortified with vitamins and minerals (Bal'ahar mixture, India). Both mixtures require the addition of vegetable oils to make it easier for infants and small children to digest the mixtures.",0
1741,8450876,A defective visual pathway in children with reading disability,"BACKGROUND: The possibility that reading disability in children is associated with visual problems is in dispute. We sought to test the existence of this association by using electrophysiologic techniques to measure the processing of visual information in the magnicellular and parvicellular visual pathways of the brain. METHODS: Visual evoked potentials were measured with scalp electrodes in children 8 to 11 years old who were normal readers and in those with reading disability. The potentials were measured for targets with low (0.5 cycle per degree of visual angle) and high (4.5 cycles per degree) spatial frequency, surrounded by either a steady background or a uniform-field flickering 12 times per second. A flickering field normally reduces the amplitude and increases the latency of a transient potential evoked by a low-spatial-frequency target, which preferentially excites the magnicellular visual pathway, but has little effect on the response to a high-spatial-frequency target. RESULTS: With a steady background, the latencies of the early components (N1 and P1) of the visual evoked potentials were longer in the reading-disabled children than in the normal readers when the low-spatial-frequency target was used, but not when the high-spatial-frequency target was used. In normal readers, the flickering background increased the latency and reduced the amplitude of the early components, whereas in the reading-disabled children only the amplitude was affected. No differences were observed in either group with the high-spatial-frequency target. CONCLUSIONS: The pattern of results suggests that the response of the magnicellular visual pathway is slowed in reading-disabled children, who do not, however, have a general slowing of the visual response. The possibility that there is a cause-and-effect relation between these findings and reading disability will require further study.",0
1742,8464434,The occurrence of sleep-disordered breathing among middle-aged adults,"BACKGROUND: Limited data have suggested that sleep-disordered breathing, a condition of repeated episodes of apnea and hypopnea during sleep, is prevalent among adults. Data from the Wisconsin Sleep Cohort Study, a longitudinal study of the natural history of cardiopulmonary disorders of sleep, were used to estimate the prevalence of undiagnosed sleep-disordered breathing among adults and address its importance to the public health. METHODS: A random sample of 602 employed men and women 30 to 60 years old were studied by overnight polysomnography to determine the frequency of episodes of apnea and hypopnea per hour of sleep (the apnea-hypopnea score). We measured the age- and sex-specific prevalence of sleep-disordered breathing in this group using three cutoff points for the apnea-hypopnea score (> or = 5, > or = 10, and > or = 15); we used logistic regression to investigate risk factors. RESULTS: The estimated prevalence of sleep-disordered breathing, defined as an apnea-hypopnea score of 5 or higher, was 9 percent for women and 24 percent for men. We estimated that 2 percent of women and 4 percent of men in the middle-aged work force meet the minimal diagnostic criteria for the sleep apnea syndrome (an apnea-hypopnea score of 5 or higher and daytime hypersomnolence). Male sex and obesity were strongly associated with the presence of sleep-disordered breathing. Habitual snorers, both men and women, tended to have a higher prevalence of apnea-hypopnea scores of 15 or higher. CONCLUSIONS: The prevalence of undiagnosed sleep-disordered breathing is high among men and is much higher than previously suspected among women. Undiagnosed sleep-disordered breathing is associated with daytime hypersomnolence.",0
1743,8469251,A comparison of outcomes in men 11 years after heart-valve replacement with a mechanical valve or bioprosthesis. Veterans Affairs Cooperative Study on Valvular Heart Disease,"BACKGROUND: Mechanical heart valves are durable but thrombogenic, and their use requires that the patient receive anticoagulants. In contrast, bioprosthetic valves are less thrombogenic, but they have limited durability because of tissue deterioration. METHODS: To compare the outcomes of patients who receive these two types of valves, we randomly assigned 575 men scheduled to undergo aortic-valve or mitral-valve replacement to receive either a mechanical or a bioprosthetic valve. The primary end points were death from any cause and any valve-related complication. RESULTS: During an average follow-up of 11 years, there was no difference between the two groups in the probability of death from any cause (11-year probability for mechanical valves, 0.57; for bioprostheses, 0.62; P = 0.57) or in the probability of any valve-related complication (0.65 and 0.69, respectively; P = 0.39). There was a much higher rate of structural valve failure among patients who received bioprosthetic valves (11-year probability, 0.15 for the aortic valves and 0.36 for the mitral valves) than among those who received mechanical valves (no valve failures; P < 0.001). However, this difference was offset by a higher rate of bleeding complications among patients with mechanical valves than among those with bioprosthetic valves (11-year probability, 0.42 and 0.26, respectively; P < 0.001) and by a greater frequency of peri-prosthetic valvular regurgitation among patients with mechanical mitral valves than among those with mitral bioprostheses (11-year probability, 0.17 and 0.09, respectively; P = 0.05). CONCLUSIONS: After 11 years, the rates of survival and freedom from all valve-related complications were similar for patients who received mechanical heart valves and those who received bioprosthetic heart valves. However, structural failure was observed only with the bioprosthetic valves, whereas bleeding complications were more frequent among patients who received mechanical valves.",0
1744,8477966,Augmented glucose use and pentose cycle activity in hepatic endothelial cells after in vivo endotoxemia,"Glucose use and pentose cycle activity were determined in freshly isolated rat hepatic endothelial cells 3 hr after an intravenous injection of Escherichia coli lipopolysaccharide (0.1 mg/kg body weight), by use of [1-14C]glucose, [6-14C]glucose and [2-3H]glucose. Lipopolysaccharide treatment in vivo increased glucose use fivefold, whereas glucose oxidation in the pentose cycle was elevated from 0.2 to 1.5 nmol/hr/10(7) cells. In vitro incubation of endothelial cells from saline- and lipopolysaccharide-treated animals in the presence of phorbol 12-myristate 13-acetate (10(-6) mol/L) increased pentose cycle activity twofold and eightfold, respectively. Phorbol 12-myristate 13-acetate caused only a 40% to 60% increase in glycolysis in both groups. Addition of t-butyl hydroperoxide (0.5 mmol/L), a substrate for glutathione peroxidase, caused a 24-fold and 16-fold increase in the glucose flux through the pentose cycle in cells from saline- and lipopolysaccharide-treated rats, respectively. Oxidation of glucose through the Krebs cycle was also increased several-fold after t-butyl hydroperoxide administration. Depletion of cellular glutathione by N-ethylmaleimide (0.1 mmol/L) inhibited the phorbol 12-myristate 13-acetate-induced or t-butyl hydroperoxide-induced increase in the pentose cycle activity with no marked effects on glycolysis. Diphenyleneiodonium (0.1 mmol/L), an inhibitor of superoxide and nitric oxide synthesis inhibited the phorbol 12-myristate 13-acetate-induced increased pentose cycle activity with no effects on the t-butyl hydroperoxide-induced response.(ABSTRACT TRUNCATED AT 250 WORDS)",0
1745,8491453,Futile cycling between 4-methylumbelliferone and its conjugates in perfused rat liver,"Futile cycling between 4-methylumbelliferone and its sulfate and glucuronide conjugates was examined in the single-pass perfused rat liver preparation. The steady-state hepatic extraction ratio of 4-methylumbelliferone was found to be high (0.97) at a low input concentration of 0.005 mumol/L (tracer), with a net 4-methylumbelliferyl sulfate/4-methylumbelliferyl glucuronide ratio of about 5:1; at 63 mumol/L the steady-state extraction ratio had remained constant despite a shift from net sulfation to net glucuronidation. At higher input 4-methylumbelliferone concentrations, saturation was evidenced by a decreased steady-state extraction ratio and reduced net sulfation and net glucuronidation. Because 4-methylumbelliferyl sulfate and 4-methylumbelliferyl glucuronide deconjugation would result in an intracellular accumulation of 4-methylumbelliferone, the phenomenon was monitored with a shift in tracer [3H]4-methylumbelliferone metabolism from sulfation to glucuronidation with increased intracellular 4-methylumbelliferone concentration. When 4-methylumbelliferyl sulfate (0 to 890 mumol/L) or 4-methylumbelliferyl glucuronide (0 to 460 mumol/L) was delivered simultaneously with tracer [3H]4-methylumbelliferone to the rat liver, notable desulfation of 4-methylumbelliferyl sulfate (18% to 38% rate in) but little deglucuronidation of 4-methylumbelliferyl glucuronide (1.2% to 2.1% rate in) was observed. With 4-methylumbelliferyl sulfate, 4-methylumbelliferone and 4-methylumbelliferyl glucuronide were readily found as metabolites, whereas with 4-methylumbelliferyl glucuronide, levels of the metabolites, 4-methylumbelliferone and 4-methylumbelliferyl sulfate, were much reduced. 4-Methylumbelliferyl sulfate and not 4-methylumbelliferyl glucuronide shifted tracer [3H]4-methylumbelliferone metabolism from [3H]4-methylumbelliferyl sulfate to [3H]4-methylumbelliferyl glucuronide formation in a concentration-dependent fashion. The steady-state extraction ratio for 4-methylumbelliferyl sulfate (0.1 to 0.3) was comparatively higher than that for 4-methylumbelliferyl glucuronide (0.05), and it was found to increase with concentration, an observation explained by the nonlinear protein binding of 4-methylumbelliferyl sulfate. Biliary excretion rates for 4-methylumbelliferone and 4-methylumbelliferyl sulfate were proportional to their input or net formation rates, regardless of whether 4-methylumbelliferone, 4-methylumbelliferyl glucuronide or 4-methylumbelliferyl sulfate was administered. By contrast, the excretion rate of 4-methylumbelliferyl glucuronide when administered was only 1/25 the excretion of 4-methylumbelliferyl glucuronide formed from 4-methylumbelliferone and 4-methylumbelliferyl sulfate. The extent of choleresis paralleled the excretion patterns of preformed and formed 4-methylumbelliferyl glucuronide; bile flow was normal with 4-methylumbelliferyl glucuronide administration and was markedly enhanced with increased 4-methylumbelliferone or 4-methylumbelliferyl sulfate administration. The data suggest the presence of a transmembrane barrier for entry of 4-methylumbelliferyl glucuronide and not 4-methylumbelliferyl sulfate or 4-methylumbelliferone into hepatocytes.(ABSTRACT TRUNCATED AT 400 WORDS)",0
1746,8510687,Educational status and active life expectancy among older blacks and whites,"BACKGROUND AND METHODS: Persons of low socioeconomic status are known to have reduced life expectancy. In a study of the relation of socioeconomic status to disability-free or active life expectancy among older persons, we analyzed prospectively gathered data on 2219 blacks and 1838 whites who were 65 years of age or older in the Piedmont region of North Carolina. We defined disability as the inability to perform independently one or more basic functional activities such as walking, bathing, dressing, eating, and using the toilet. For subgroups defined by sex, race, and education, statistical models were used to estimate, for persons at each year of age, the probability of transition from not being disabled or being disabled at base line to not being disabled, being disabled, or having died one year later. These transition probabilities were then entered into increment-decrement life tables to generate estimates of total, active, and disabled life expectancy (with total life expectancy equal to active life expectancy plus disabled life expectancy). RESULTS: Sixty-five-year-old black men had a lower total life expectancy (11.4 years) and active life expectancy (10 years) than white men (total life expectancy, 12.6 years; active life expectancy, 11.2 years), although the differences were reduced after we controlled for education. The estimates for 65-year-old black women (total life expectancy, 18.7 years; active life expectancy, 15.9 years) were similar to those for white women. Black men and women 75 years old and older had higher values for total life expectancy and active life expectancy than whites, and the differences were larger after stratification for education. Education had a substantially stronger relation to total life expectancy and active life expectancy than did race. At the age of 65, those with 12 or more years of education had an active life expectancy that was 2.4 to 3.9 years longer than the values for those with less education in all the four subgroups defined by sex and race. Overall, the subgroups with longer total life expectancy and active life expectancy also lived more years with a disability. CONCLUSIONS: Among older blacks and whites, the level of education, a measure of socioeconomic status, has a greater effect than race on total life expectancy and active life expectancy.",0
1747,8514264,Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance,"Improvements in the prevention or control of rejection of the kidney and liver have been largely interchangeable (1, 2) and then applicable, with very little modification, to thoracic and other organs. However, the mechanism by which anti rejection treatment permits any of these grafts to be �accepted� has been an immunological enigma (3, 4). We have proposed recently that the exchange of migratory leukocytes between the transplant and the recipient with consequent long-term cellular chimerism in both is the basis for acceptance of all whole-organ allografts and xenografts (5). Although such chimerism was demonstrated only a few months ago, the observations have increased our insight into transplantation immunology and have encouraged the development of alternative therapeutic strategies (6).",0
1748,8531973,Compensation to a department of medicine and its faculty members for the teaching of medical students and house staff,"BACKGROUND: Changes in the organization and financing of health care threaten to alter the prevailing system of financing the teaching of medical students and residents. Little information is available from private medical schools and teaching hospitals about the extent of teaching by faculty members or the mechanisms and levels of reimbursement for teaching. METHODS: We surveyed faculty members in the Department of Medicine at Columbia-Presbyterian Medical Center to ascertain the extent of their teaching activities. A standard number of hours was assigned to each activity, and the total number of teaching hours was calculated for each faculty member. Teaching of fellows and in continuing medical education programs was excluded. We also determined how much money the Department of Medicine received in payment for faculty members' teaching activities, and the sources of this compensation. RESULTS: In the 1992-1993 academic year, the 188 full-time faculty members spent a total of 46,086 hours teaching (mean [+/- SD], 245 +/- 178 hours per faculty member); 10,780 hours (23.4 percent) were spent teaching medical students, and 35,306 hours (76.6 percent) teaching house staff. Eighty percent of faculty members taught for 137 or more hours each. In a multivariate analysis including faculty rank, subspecialty division, years since graduation from medical school, sex, and tenure or clinical track, senior faculty members (P = 0.02), members of certain subspecialty divisions (P < 0.001), and women (P = 0.05) contributed more than the average number of teaching hours. An additional 56 non-full-time faculty members contributed a total of 5684 hours. The net reimbursement to the department for teaching totaled $965,808, or about $16 per hour of teaching by full-time faculty members, after the cost of fringe benefits was excluded. CONCLUSIONS: Faculty members of the department of medicine at a major medical center contribute a large number of hours teaching medical students and house staff. This effort is poorly compensated. Cost-containment efforts have the potential to jeopardize fragile social contracts at academic health centers whereby the faculty participates in teaching by contributing unreimbursed or underreimbursed time.",0
1749,8538705,"A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine","BACKGROUND: Because of concern about safety and efficacy, no pertussis vaccine has been included in the vaccination program in Sweden since 1979. To provide data that might permit the reintroduction of a pertussis vaccine, we conducted a placebo-controlled trial of two acellular and one whole-cell pertussis vaccines. METHODS: After informed consent was obtained, 9829 children born in 1992 were randomly assigned to receive one of four vaccines: a two-component acellular diphtheria-tetanus-pertussis (DTP) vaccine (2566 children), a five-component acellular DTP vaccine (2587 children), a whole-cell DTP vaccine licensed in the United States (2102 children), or (as a control) a vaccine containing diphtheria and tetanus toxoids (DT) alone (2574 children). The vaccines were given at 2, 4, and 6 months of age, and the children were then followed for signs of pertussis for an additional 2 years (to a mean age of 21/2 years). RESULTS: The whole-cell vaccine was associated with significantly higher rates of protracted crying, cyanosis, fever, and local reactions than the other three vaccines. The rates of adverse events were similar for the acellular vaccines and the control DT vaccine. After three doses, the efficacy of the vaccines with respect to pertussis linked to a laboratory-confirmed case of pertussis or contact with an infected household member with paroxysmal cough for > or = 21 days was 58.9 percent for the two-component vaccine (95 percent confidence interval, 50.9 to 65.9 percent), 85.2 percent for the five-component vaccine (95 percent confidence interval, 80.6 to 88.8 percent), and 48.3 percent for the whole-cell vaccine (95 percent confidence interval, 37.0 to 57.6 percent). CONCLUSIONS: The five-component acellular pertussis vaccine we evaluated can be recommended for general use, since it has a favorable safety profile and confers sustained protection against pertussis. The two-component acellular vaccine and the whole-cell vaccine were less efficacious.",0
1750,8538706,Cohort studies of fat intake and the risk of breast cancer--a pooled analysis,"BACKGROUND: Experiments in animals, international correlation comparisons, and case-control studies support an association between dietary fat intake and the incidence of breast cancer. Most cohort studies do not corroborate the association, but they have been criticized for involving small numbers of cases, homogeneous fat intake, and measurement errors in estimates of fat intake. METHODS: We identified seven prospective studies in four countries that met specific criteria and analyzed the primary data in a standardized manner. Pooled estimates of the relation of fat intake to the risk of breast cancer were calculated, and data from study-specific validation studies were used to adjust the results for measurement error. RESULTS: Information about 4980 cases from studies including 337,819 women was available. When women in the highest quintile of energy-adjusted total fat intake were compared with women in the lowest quintile, the multivariate pooled relative risk of breast cancer was 1.05 (95 percent confidence interval, 0.94 to 1.16). Relative risks for saturated, monounsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was little overall association between the percentage of energy intake from fat and the risk of breast cancer, even among women whose energy intake from fat was less than 20 percent. Correcting for error in the measurement of nutrient intake did not materially alter these findings. CONCLUSIONS: We found no evidence of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk even among women whose energy intake from fat was less than 20 percent of total energy intake. In the context of the Western lifestyle, lowering the total intake of fat in midlife is unlikely to reduce the risk of breast cancer substantially.",0
1751,8538709,Relationships between academic institutions and industry in the life sciences--an industry survey,"BACKGROUND: Despite growing acceptance of relationships between academia and industry in the life sciences, systematic, up-to-date information about their extent and the consequences for the parties involved remains scarce. We attempted to collect information about the prevalence, magnitude, commercial benefits, and potential risks of such relationships by surveying a representative sample of life-science companies in the United States to determine their relationships with academic institutions. METHODS: We collected data by telephone from May through September 1994 from senior executives of 210 life-science companies (of 306 companies surveyed; response rate, 69 percent). The sample contained all Fortune 500 companies in the fields of agriculture, chemicals, and pharmaceuticals; all international pharmaceutical companies with sales volumes similar to those of the Fortune 500 companies; and a random sample of non-Fortune 500 companies in the life sciences drawn from multiple commercial and noncommercial directories. Both the survey instrument and the survey methods resembled those of our 1984 study of 106 biotechnology companies, allowing us to assess the evolution of relationships between academia and industry over the past decade. RESULTS: Ninety percent of companies conducting life-science research in the United States had relationships involving the life sciences with an academic institution in 1994. Fifty-nine percent supported research in such institutions, providing an estimated $1.5 billion, or approximately 11.7 percent of all research-and-development funding received that year. The agreements with universities tended to be short-term and to involve small amounts, implying that most such relationships supported applied research or development. Over 60 percent of companies providing support for life-science research in universities had received patents, products, and sales as a result of those relationships. At the same time, the companies reported that their relationships with universities often included agreements to keep the results of research secret beyond the time needed to file a patent. From 1984 to 1994, the involvement of industry with academic institutions has increased, but the characteristics of the relationships have remained remarkably stable. CONCLUSIONS: After more than a decade of sustained interaction, universities and industries seem to have formed durable partnerships in the life sciences, although the relationships may pose greater threats to the openness of scientific communication than universities generally acknowledge. However, industrial support for university research is much smaller in amount than federal support, and companies are unlikely to be able to compensate for sizable federal cutbacks.",0
1752,8550049,Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR,"Autoantibodies from rare patients with primary biliary cirrhosis (PBC) recognize LBR, or lamin B receptor, an integral membrane protein of the inner nuclear membrane. Human LBR has a nucleoplasmic, amino-terminal domain of 208 amino acids followed by a carboxyl-terminal domain with eight putative transmembrane segments. Autoantibodies against LBR from four patients with PBC recognized the nucleoplasmic, amino-terminal domain but not the carboxyl-terminal domain. Immunoblotting of smaller fusion proteins demonstrated that these autoantibodies recognized a conformational epitope(s) contained within the stretch of amino acids from 1 to 60. These results, combined with those of previous studies, show that autoepitopes of nuclear membrane proteins are located within their nucleocytoplasmic domains and that autoantibodies from patients with PBC predominantly react with one domain of a protein antigen. This work also provides further characterization of anti-LBR antibodies that have found utility as reagents in cell biology research.",0
1753,8552144,Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS,"BACKGROUND: Clinical trials of antiretroviral drugs can take years to complete because the outcomes measured are progression to the acquired immunodeficiency syndrome (AIDS) or death. Trials could be accelerated by the use of end points such as changes in CD4+ lymphocyte counts and plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA and beta 2-microglobulin, but there is uncertainty about whether these surrogate measures are valid predictors of disease progression. METHODS: We analyzed data from the Veterans Affairs Cooperative Study on AIDS, which compared immediate with deferred zidovudine therapy. Patients' plasma levels of HIV-1 RNA and beta 2-microglobulin were measured in stored plasma. RESULTS: Among the 129 patients in the immediate-treatment group, 34 had disease that progressed to AIDS, as compared with 57 of the 141 patients in the deferred-treatment group (P = 0.03). Progression to AIDS correlated strongly with base-line CD4+ lymphocyte counts (P = 0.001) and plasma levels of HIV-1 RNA (P < 0.001), but not with base-line levels of beta 2-microglobulin (P = 0.14). A decrease of at least 75 percent in the plasma level of HIV-1 RNA over the first six months of zidovudine therapy accounted for 59 percent of the benefit of treatment, defined as the absence of progression to AIDS (95 percent confidence interval, 13 to 112 percent). Plasma beta 2-microglobulin levels and CD4+ lymphocyte counts explained less of the effect of treatment. A 75 percent decrease in the plasma HIV-1 RNA level plus a 10 percent increase in the CD4+ lymphocyte count could explain 79 percent of the treatment effect (95 percent confidence interval, 27 to 145 percent). CONCLUSIONS: Treatment-induced changes in the plasma HIV-1 RNA level and the CD4+ lymphocyte count, taken together, are valid predictors of the clinical progression of HIV-related disease and can be used to assess the efficacy of zidovudine and possibly other antiretroviral drugs as well.",0
1754,8591843,Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C,"Tumor necrosis factor alpha (TNF-alpha) is a cytokine with pleiotropic properties that is induced in a variety of pathological situations including viral infections. In this work, we analyzed the expression of TNF-alpha gene in patients with chronic hepatitis C. Serum TNF-alpha levels were found to be elevated in all chronic hepatitis C patients including those cases presenting sustained biochemical remission of the disease after interferon therapy. Untreated patients with chronic hepatitis C showed increased TNF-alpha messenger RNA (mRNA) levels in the liver and mononuclear cells as compared with healthy controls. After completion of treatment with interferon, patients experiencing sustained complete response showed values of TNF-alpha mRNA, both in the liver and in peripheral mononuclear cells, within the normal range, significantly lower than patients who did not respond to interferon and than those with complete response who relapsed after interferon withdrawal. Pretreatment values of TNF-alpha mRNA were lower in long-term responders to interferon than in cases who failed to respond to the treatment. Values of TNF-alpha mRNA in the liver or in mononuclear cells were higher in specimens with positive hepatitis C virus (HCV) RNA than in those samples where the virus was undetectable. Neither the intensity of the liver damage nor the amount of HCV RNA in serum or in cells showed correlation with the levels of TNF-alpha transcripts in peripheral mononuclear cells but it was found that high TNF-alpha values were associated with genotype 1b. In conclusion, there is an enhanced expression of TNF-alpha in HCV infection. High levels of this cytokine may play a role in the resistance to interferon therapy.",0
1755,8591845,The effect of mannitol and secretin on the biliary transport of urate in humans,"No evidence is available on the transport of biliary urate and the possible role of choleretic agents in the regulation of biliary urate elimination in humans. To test this hypothesis we studied the following: (1) 45 cholecystomized patients to determine urate levels in hepatic bile and gallbladder bile, and (2) 13 cholecystomized patients fitted with T-tubes to determine the effects of secretin injection (either 70 U of porcine secretin or 0.02 mg.kg-1 of synthetic human secretin, as a single dose) and/or mannitol infusion (5 cm3.min-1 for 90 minutes) on biliary urate excretion. In the latter group, samples of bile and serum were analyzed for urate under basal state and after the administration of both agents. In our first approach, results showed that urate concentrations present in hepatic as well as in gallbladder bile were much lower than the corresponding values in serum (P < .001). The mean gallbladder bile urate concentration was not significantly increased over the concentration in hepatic bile. When compared with basal state values, procine and synthetic secretin induced a significant increase in mean urate clearance (P < .001) because of a significant increase in mean bile flow (P < .001), whereas the mean biliary urate concentration significantly decreased (P < .001) with a concomitant decrease in the mean serum urate concentration (P < .02). Mannitol also induced a significant increase in the mean urate clearance (P < .002) because of a significant increase in the mean biliary urate concentration (P < .01) with a concomitant decrease in the mean serum urate concentration (P < .01) and without changes in the mean bile flow (P > .05). Therefore, it appears that a substantial amount of urate is eliminated by biliary route. The load of biliary urate excreted may be modified by mannitol and secretin and possibly other factors, a finding that could have an application in some pathological conditions associated with decreased renal urate excretion.",0
1756,8591848,"Isolated polycystic liver disease as a distinct genetic disease, unlinked to polycystic kidney disease 1 and polycystic kidney disease 2","Polycystic liver disease (PLD) is proven to occur either sporadically or in association with autosomal dominant polycystic kidney disease (ADPKD), whereas the existence of an isolated (i.e., without any kidney cyst) familial form is disputed. We describe a family with definitely isolated PLD transmitted through three generations and exclude the linkage of the disease to the genetic markers of PKD1 and PKD2, the two main loci responsible for ADPKD. These findings strongly support the existence of PLD as a genetic disease distinct from the known forms of ADPKD.",0
1757,8591850,Carcinoembryonic antigen and blood group-related carbohydrate antigens in glycoproteins in human bile in hepatolithiasis. Japanese Study Group of Hepatolithiasis,"We investigated whether carbohydrate antigens on biliary glycoproteins and carcinoembryonic antigen (CEA) are related to hepatolithiasis. CEA, ABO, and Lewis blood group-related antigens, as well as sialyl-Tn antigen in hepatic bile, were analyzed by Western blotting in samples from 12 patients with hepatolithiasis and 37 with other biliary diseases (choledocholithiasis, 13; cholecystolithiasis, 5; acute cholecystitis, 2; cholangiocarcinoma, 5; common bile duct carcinoma, 4; pancreatic carcinoma, 6; and metastatic carcinoma of liver, 2). CEA was positive on mucinous glycoprotein in six patients (50%) with hepatolithiasis and one case (17%) with pancreatic carcinoma. CEA was also positive on a glycoprotein of approximately 200 kd in eight patients (67%) with hepatolithiasis and two (33%) with pancreatic carcinoma. Lewis X was detected on the mucinous glycoprotein in almost all samples, as well as on glycoproteins of approximately 180 kd in all hepatolithiasis samples and approximately half of those from patients with other diseases. Sialyl-Tn antigen was detected on mucinous glycoprotein in four (80%) with cholangiocarcinoma, two (50%) with common bile duct carcinoma, and all pancreatic carcinoma samples. Mucinous glycoprotein and glycoproteins containing CEA and Lewis X antigens are enriched in hepatic bile of hepatolithiasis, and they may be closely related to the formation of intrahepatic calculi. Sialyl-Tn antigen in biliary mucinous glycoprotein will be a good marker of biliary and pancreatic carcinoma, and probably for cholangiocarcinoma complicated with hepatolithiasis.",0
1758,8591854,Norepinephrine reverses the effects of activin A on DNA synthesis and apoptosis in cultured rat hepatocytes,"Activin A, an autocrine factor produced by hepatocytes, inhibits mitogen-stimulated DNA synthesis and induces apoptotic death of cultured rat hepatocytes. Several lines of evidence indicate that norepinephrine (NE), as a comitogenic growth factor, alters the balance between growth stimulation and inhibition and acts as a trigger for the initiation of hepatocyte proliferation. In the present study, we examined whether NE modulated the effects of activin A on rat hepatocytes in primary culture. Activin A, at a concentration of 10(-9) mol/L, blocked the effect of epidermal growth factor (EGF) on DNA synthesis, that was assessed by measuring [3H] thymidine incorporation and nuclear labeling, almost completely, and NE reversed the inhibitory effect of activin A on DNA synthesis. This effect of NE was dose-dependent, being significant at concentrations of 10(-6) mol/L and above, but was overcome by higher concentrations of activin A, and was attenuated by prazosin, but not by yohimbine or propranolol. NE exerted its effect during the first 24 hours of culture, but was ineffective when added after 24 hours. EGF augmented the release of follistatin, an activin-binding protein known to block the action of activin A, by hepatocytes and NE did not affect the amount of follistatin they released. In addition to inhibiting DNA synthesis by hepatocytes cultured with EGF, activin A induced death of hepatocytes cultured in the absence of EGF. The nuclear morphology of cells cultured with activin A alone was strikingly changed compared with untreated control cells and marked identation of the nuclear membranes and moderate chromatin condensation were observed. Fragmentation of DNA was also observed, suggesting that activin A induced apoptosis, and activin-mediated cell death was prevented significantly by NE. These results indicate that NE, acting on alpha 1-adrenergic receptors, attenuates the effects of activin A on DNA synthesis by and apoptosis of cultured rat hepatocytes.",0
1759,8592525,Inhaled nitric oxide for high-altitude pulmonary edema,"BACKGROUND: Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. When administered by inhalation, nitric oxide, an endothelium-derived relaxing factor, attenuates the pulmonary vasoconstriction produced by short-term hypoxia. METHODS: We studied the effects of inhaled nitric oxide on pulmonary-artery pressure and arterial oxygenation in 18 mountaineers prone to high-altitude pulmonary edema and 18 mountaineers resistant to this condition in a high altitude laboratory (altitude, 4559 m). We also obtained lung-perfusion scans before and during nitric oxide inhalation to gain further insight into the mechanism of action of nitric oxide. RESULTS: In the high-altitude laboratory, subjects prone to high-altitude pulmonary edema had more pronounced pulmonary hypertension and hypoxemia than subjects resistant to high-altitude pulmonary edema. Arterial oxygen saturation was inversely related to the severity of pulmonary hypertension (r=-0.50, P=0.002). In subjects prone to high-altitude pulmonary edema, the inhalation of nitric oxide (40 ppm for 15 minutes) produced a decrease in mean (+/-SD) systolic pulmonary-artery pressure that was three times larger than the decrease in subjects resistant to such edema (25.9+/-8.9 vs. 8.7+/-4.8 mm Hg, P<0.001). Inhaled nitric oxide improved arterial oxygenation in the 10 subjects who had radiographic evidence of pulmonary edema (arterial oxygen saturation increased from 67+/-10 to 73+/-12 percent, P=0.047), whereas it worsened oxygenation in subjects resistant to high-altitude pulmonary edema. The nitric oxide-induced improvement in arterial oxygenation in subjects with high-altitude pulmonary edema was accompanied by a shift in blood flow in the lung away from edematous segments and toward nonedematous segments. CONCLUSIONS: The inhalation of nitric oxide improves arterial oxygenation in high-altitude pulmonary edema, and this beneficial effect may be related to its favorable action on the distribution of blood flow in the lungs. A defect in nitric nitric oxide synthesis may contribute to high-altitude pulmonary edema.",0
1760,8592529,The costs of visits to emergency departments,"BACKGROUND: Many visits to emergency departments are for minor medical problems, and these visits are criticized as being expensive and economically inefficient. This study examines the marginal costs (the extra costs for an additional visit) of emergency department visits. METHODS: Monthly data on the costs of hospital and physicians' services from 1991 through 1993 were obtained from a sample of six community hospitals in Michigan. The data were analyzed with ordinary least-squares regression techniques to determine the ratio of marginal to average costs. Average and marginal costs were then determined for 24,010 visits during 12 randomly selected weeks in 1993. A visit by an individual patient was the unit analysis, and visits were classified as nonurgent, semiurgent, or urgent according to explicit criteria. Costs and charges were determined for all visits and were classified according to the degree of urgency. RESULTS: For all emergency department visits, the average charge was $383, the average cost was $209, and the marginal cost was $88 (42 percent of the average cost). Thirty-two percent of the visits were classified as nonurgent, 26 percent as semiurgent, and 42 percent as urgent. For nonurgent visits, the average charge was $124, the average cost was $62, and the marginal cost was only $24. For semiurgent visits, the average charge was $312, the average cost was $159, and the marginal cost was $67. For urgent visits, the average charge was $621, the average cost was $351, and the marginal cost was $148. CONCLUSIONS: The true costs of nonurgent care in the emergency department are relatively low. The potential savings from a diversion of nonurgent visits to private physicians' offices may therefore be much less than is widely believed.",0
1761,8592548,Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E,"BACKGROUND: Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease, and persons with two copies of the epsilon 4 allele appear to have an especially high risk of dementia. Positron-emission tomography (PET) has identified specific regions of the brain in which the rate of glucose metabolism declines progressively in patients with probable Alzheimer's disease. We used PET to investigate whether these same regions of the brain are affected in subjects homozygous for the epsilon 4 allele before the onset of cognitive impairment. METHODS: Apolipoprotein E genotypes were established in 235 volunteers 50 to 65 years of age who reported a family history of probable Alzheimer's disease. Neurologic and psychiatric evaluations, a battery of neuropsychological tests, magnetic resonance imaging, and PET were performed in 11 epsilon 4 homozygotes and 22 controls without the epsilon 4 allele who were matched for sex, age, and level of education. An automated method was used to generate an aggregate surface-projection map that compared regional rates of glucose metabolism in the two groups. RESULTS: The epsilon 4 homozygotes were cognitively normal. They had significantly reduced rates of glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease. They also had reduced rates of glucose metabolism in additional prefrontal regions, which may be preferentially affected during normal aging. CONCLUSIONS: In late middle age, cognitively normal subjects who are homozygous for the epsilon 4 allele for apolipoprotein E have reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer's disease. These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease. PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.",0
1762,8594427,Identification of a Brazil-nut allergen in transgenic soybeans,"BACKGROUND: The nutritional quality of soybeans (Glycine max) is compromised by a relative deficiency of methionine in the protein fraction of the seeds. To improve the nutritional quality, methionine-rich 2S albumin from the Brazil nut (Betholletia excelsa) has been introduced into transgenic soybeans. Since the Brazil nut is a known allergenic food, we assessed the allergenicity of the 2S albumin. METHODS: The ability of proteins in transgenic and non-transgenic soybeans, Brazil nuts, and purified 2S albumin to bind to IgE in serum from subjects allergic to Brazil nuts was determined by radioallergosorbent tests (4 subjects) and sodium dodecyl sulfate-polyacrylamide-gel electrophoresis (9 subjects) with immunoblotting and autoradiography. Three subjects also underwent skin-prick testing with extracts of soybean, transgenic soybean, and Brazil nut. RESULTS: On radioallergosorbent testing of pooled serum from four subjects allergic to Brazil nuts, protein extracts of transgenic soybean inhibited binding of IgE to Brazil-nut proteins. On immunoblotting, serum IgE from eight of nine subjects bound to purified 2S albumin from the Brazil nut and the transgenic soybean. On skin-prick testing, three subjects had positive reactions to extracts of Brazil nut and transgenic soybean and negative reactions to soybean extract. CONCLUSIONS: The 2S albumin is probably a major Brazil-nut allergen, and the transgenic soybeans analyzed in this study contain this protein. Our study show that an allergen from a food known to be allergenic can be transferred into another food by genetic engineering.",0
1763,8596546,A preliminary study of growth hormone in the treatment of dilated cardiomyopathy,"BACKGROUND: Cardiac hypertrophy is a physiologic response that allows the heart to adapt to an excess hemodynamic load. We hypothesized that inducing cardiac hypertrophy with recombinant human growth hormone might be an effective approach to the treatment of idiopathic dilated cardiomyopathy, a condition in which compensatory cardiac hypertrophy is believed to be deficient. METHODS: Seven patients with idiopathic dilated cardiomyopathy and moderate-to-severe heart failure were studied at base line, after three months of therapy with human growth hormone, and three months after the discontinuation of growth hormone. Standard therapy for heart failure was continued throughout the study. Cardiac function was evaluated with Doppler echocardiography, right-heart catheterization, and exercise testing. RESULTS: When administered at a dose of 14 IU per week, growth hormone doubled the serum concentrations of insulin-like growth factor I. Growth hormone increased left-ventricular-wall thickness and reduced chamber size significantly. Consequently, end-systolic wall stress (a function of both wall thickness and chamber size) fell markedly (from a mean [+/-SE] of 144+/-11 to 85+/-8 dyn per square centimeter, P<0.001). Growth hormone improved cardiac output, particularly during exercise (from 7.4+/-0.7 to 9.7+/-0.9 liters per minute, P=0.003), and enhanced ventricular work, despite reductions in myocardial oxygen consumption (from 56+/-6 to 39+/-5 ml per minute, P=0.005) and energy production (from 1014+/-100 to 701+/-80 J per minute, P=0.002). Thus, ventricular mechanical efficiency rose from 9+/-2 to 21+/-5 percent (P=0.006). Growth hormone also improved clinical symptoms, exercise capacity, and the patients' quality of life. The changes in cardiac size and shape, systolic function, and exercise tolerance were partially reversed three months after growth hormone was discontinued. CONCLUSIONS: Recombinant human growth hormone administered for three months to patients with idiopathic dilated cardiomyopathy increased myocardial mass and reduced the size of the left ventricular chamber, resulting in improvement in hemodynamics, myocardial energy metabolism, and clinical status.",0
1764,8596596,Hyperinsulinemia as an independent risk factor for ischemic heart disease,"BACKGROUND: Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. However, it has not been determined whether plasma insulin levels are independently related to ischemic heart disease after adjustment for other risk factors, including plasma lipoprotein levels. METHODS: In 1985 we collected blood samples from 2103 men from suburbs of Quebec City, Canada, who were 45 to 76 years of age and who did not have ischemic heart disease. A first ischemic event (angina pectoris, acute myocardial infarction or death from coronary heart disease) occurred in 114 men (case patients) between 1985 and 1990. Each case patient was matched for age, body-mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. After excluding men with diabetes, we compared fasting plasma insulin and lipoprotein concentrations at base line in 91 case patients and 105 controls. RESULTS: Fasting insulin concentrations at base line were 18 percent higher in the case patients than in the controls (P<0.001). Logistic-regression analysis showed that the insulin concentration remained associated with ischemic heart disease (odds ratio for ischemic heart disease with each increase of 1 SD in the insulin concentration, 1.7; 95 percent confidence interval, 1.3 to 2.4) after adjustment for systolic blood pressure, use of medications, and family history of ischemic heart disease. Further adjustment by multivariate analysis for plasma triglyceride, apolipoprotein B, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations did not significantly diminish the association between the insulin concentration and the risk of ischemic heart disease (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3). CONCLUSIONS: High fasting insulin concentrations appear to be an independent predictor of ischemic heart disease in men.",0
1765,8598840,Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass,"BACKGROUND: Homozygous carries of the D allele of the angiotensin-converting-enzyme (ACE) gene have been reported to be at increased risk for various cardiovascular disorders, including left ventricular hypertrophy. We investigated the potential role of the ACE gene in influencing left ventricular mass. METHODS: Quantitative echocardiographic data and DNA samples were available for 2439 subjects from the Framingham Heart Study. ACE genotypes were determined by an assay based on the polymerase chain reaction. (The D allele of the ACE gene contains a deletion, whereas the I [insertion] allele does not.) Left ventricular mass and the prevalence of left ventricular hypertrophy, adjusted for clinical covariates, were analyzed according to genotype. Genetic linkage between the ACE locus and left ventricular mass was evaluated by quantitative analysis of pairs of siblings. RESULTS: The ACE genotype was associated neither with left ventricular mass nor with the prevalence of left ventricular hypertrophy. Mean (+/-SE) left ventricular mass (adjusted for sex) among subjects carrying the DD, DI, and II genotypes was 165+/-1.6, 165+/-1.3, and 166+/-2.0 g, respectively (P=0.90). The prevalence of left ventricular hypertrophy among the three genotype groups was 15.6 percent, 13.6 percent, and 15.6 percent, respectively (P=0.36), and the adjusted relative risk of left ventricular hypertrophy associated with the DD genotype was 1.10 (95 percent confidence interval, 0.86 to 1.19). Linkage analysis in 759 pairs of siblings using both the ACE D/I marker and a microsatellite polymorphism at the neighboring locus for the human growth hormone gene failed to support any role of ACE in influencing left ventricular mass. CONCLUSIONS: The ACE genotype showed no association with echocardiographically determined left ventricular mass, nor did it confer an increased risk of left ventricular hypertrophy. We found no appreciable role of the ACE gene in influencing left ventricular mass.",0
1766,8602181,Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women,"BACKGROUND: The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that oxidative modification of low-density lipoprotein may promote atherosclerosis. METHODS: We studied 34,486 postmenopausal women with no cardiovascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease. RESULTS: In analyses adjusted for age and dietary energy intake, vitamin E consumption appeared to be inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend, 0.004). There was little evidence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementation and the duration of supplement use could not be definitely addressed. Intake of vitamins A and C did not appear to be associated with the risk of death form coronary heart disease. CONCLUSIONS: These results suggest that in postmenopausal women the intake of vitamin E from food is inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease.",0
1767,8602183,Kaposi's sarcoma-associated herpesvirus DNA sequences in prostate tissue and human semen,"BACKGROUND: Sequences of novel herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), have been indentified in Kaposi's sarcoma tissue, but it is not known whether the virus is transmitted by sexual contact. METHODS: Using the polymerase chain reaction (PCR), we searched for KSHV DNA sequences in ejaculates from 43 healthy men and tissue from the urogenital tract or prostate of 100 immunocompetent adults. RESULTS: In an unblinded analysis, we identified KSHV DNA sequences in 2 of 20 tissue specimens from the urinary tract (10 percent; 15 men and 5 women), 3 of 46 specimens from the female genital tract (6.5 percent), 4 of 18 specimens from the glans or foreskin (22 percent), 7 of 16 specimens from the prostate (44 percent), and 30 or 33 ejaculates (91 percent). By contrast, such sequences were present in 1 of 18 samples of normal skin (5.5 percent) and 1 of 14 samples of peripheral-blood mononuclear cells (PBMCs; 7.1 percent). Ejaculates and PBMC samples from each of 10 study subjects were analyzed in a blinded, coded fashion, along with PBMCs and biopsy specimens of normal skin from 4 and 8 other patients, respectively. This analysis confirmed the presence of KSHV DNA sequences in semen. Viral DNA was not found in the sperm heads but was present in the fraction of the ejaculates that contained urothelial and other types of cells. Point mutations were found in PCR products amplified from both prostate tissue and sperm samples. CONCLUSIONS: KSHV infects a large proportion of healthy adults and is probably transmitted by sexual contact.",0
1768,8602185,Cost-effectiveness analysis in a setting of budget constraints--is it equitable?,"BACKGROUND: One of the promises of cost-effective analysis is that it can demonstrate how to maximize health benefits attainable within a specific limited budget. Many people argue, however, that when there are budget limitations, the use of cost-effectiveness analysis leads to health care policies that are inequitable. METHODS: We asked prospective jurors, medical ethicists, and experts in medical decision making to choose between two screening tests for a population at low risk for colon cancer. One test was more cost effective than the other but because of budget constraints was too expensive to be given to everyone in the population. With the use of the more effective test for only half the population, 1100 lives could be saved at the same cost as that of saving 1000 lives with the use of the less effective test for the entire population. RESULTS: Fifty-six percent of the prospective jurors, 53 percent of the medical ethicists, and 41 percent of the experts in medical decision making recommended offering the less effective screening test to everyone, even though 100 more lives would have been saved by offering the more expensive test to only a portion of the population. Most of the study participants justified this recommendation on the basis of equity. A smaller number stated either that it was not politically feasible to offer a test to only half the population or that the additional benefit of the more expensive test (100 more lives saved) was too small to justify offering it to only a portion of the public. CONCLUSIONS: People place greater importance on equity than is reflected by cost-effectiveness analysis. Even many experts in medical decision making -- those often responsible for conducting cost-effectiveness analyses -- expressed discomfort with some of its implications. Basing health care priorities on cost effectiveness may not be possible without incorporating explicit considerations of equity into cost-effectiveness analyses or the process used to develop health care policies on the basis of such analyses.",0
1769,8609947,High-density lipoprotein cholesterol and other risk factors for coronary heart disease in female runners,"BACKGROUND: Official guidelines from the Centers for Disease Control and Prevention assert that the majority of health benefits from physical activity are obtained by walking 2 miles (3.2 km) briskly most days of the week (the energy equivalent of running 8 to 12 km per week). The objective of our study was to examine the dose-response relation in women between risk factors for coronary heart disease, particularly the concentration of high-density lipoprotein (HDL) cholesterol, and vigorous exercise at levels that exceed the official guidelines. METHODS: The number of kilometers run per week reported by 1837 female recreational runners in a national cross-sectional survey was compared with medical data provided by the women's physicians. RESULTS: In these cross-sectional data, plasma HDL cholesterol concentrations were higher by an average (+/- SE) of 0.133 +/- 0.020 mg per deciliter (0.003 +/- 0.0005 mmol per liter) for every additional kilometer run per week, an amount nearly identical with that previously reported for men (0.136 +/- 0.006 mg per deciliter [0.004 +/- 0.0002 mmol per liter] per kilometer per week). Among women who ran less than 48 km per week, mean plasma HDL concentrations were significantly higher with each 16-km increment in distance. Women who ran more than 64 km per week had significantly higher mean concentrations of HDL cholesterol than did women who ran less than 48 km per week. They were also significantly more likely to have HDL cholesterol concentrations greater than 100, 90, or 80 mg per deciliter (2.6, 2.3, or 2.1 mmol per liter) than were women running less than 64 km per week. HDL cholesterol concentrations increased significantly in relation to the number of kilometers run per week in premenopausal women who were not using oral contraceptives and in postmenopausal women, whether they were receiving estrogen-replacement therapy or not. CONCLUSIONS: Substantial increases in HDL cholesterol concentrations were found in women who exercised at levels exceeding current guidelines; higher HDL cholesterol concentrations could provide added health benefits to these women.",0
1770,8609949,The role of black and Hispanic physicians in providing health care for underserved populations,"BACKGROUND: Patients who are members of minority groups may be more likely than others to consult physicians of the same race or ethnic group, but little is known about the relation between patients' race or ethnic group and the supply of physicians or the likelihood that minority-group physicians will care for poor or black and Hispanic patients. METHODS: We analyzed data on physicians' practice locations and the racial and ethnic makeup and socioeconomic status of communities in California in 1990. We also surveyed 718 primary care physicians from 51 California communities in 1993 to examine the relation between the physicians' race or ethnic group and the characteristics of the patients they served. RESULTS: Communities with high proportions of black and Hispanic residents were four times as likely as others to have a shortage of physicians, regardless of community income. Black physicians practiced in areas where the percentage of black residents was nearly five times as high, on average, as in areas where other physicians practiced. Hispanic physicians practiced in areas where the percentage of Hispanic residents was twice as high as in areas where other physicians practiced. After we controlled for the racial and ethnic makeup of the community, black physicians cared for significantly more black patients (absolute difference, 25 percentage points; P < 0.001) and Hispanic physicians for significantly more Hispanic patients (absolute difference, 21 percentage points; P < 0.001) than did other physicians. Black physicians cared for more patients covered by Medicaid (P = 0.001) and Hispanic physicians for more uninsured patients (P = 0.03) than did other physicians. CONCLUSIONS: Black and Hispanic physicians have a unique and important role in caring for poor, black, and Hispanic patients in California. Dismantling affirmative-action programs as is currently proposed, may threaten health care for both poor people and members of minority groups.",0
1771,8617419,"Hyperinsulinemia in preascitic cirrhosis: effects on systemic and renal hemodynamics, sodium homeostasis, forearm blood flow, and sympathetic nervous activity","Insulin has been shown to be vasodilatory and antinatriuretic and to stimulate sympathetic nervous activity independent of hypoglycemia in healthy normal subjects. It is hypothesized that hyperinsulinemia, which is commonly observed in cirrhosis, may in part be responsible for the systemic vasodilatation, sympathetic activation, and sodium retention in these patients. The aims of this study, in preascitic cirrhotics, were as follows: (1) to document baseline hyperinsulinemia and its effects on sodium handling, forearm and renal circulations, and sympathetic nervous activity; (2) to determine if pharmacological increases in plasma insulin levels would result in an exaggeration of these physiological effects. Seven male, nonobese, well-compensated, preascitic cirrhotic patients were studied, after being maintained on a 150 mmol sodium per day diet for 7 days, firstly at baseline level, followed by increasing doses of insulin from 10 to 1,200 mU/m2/min using the euglycemic clamp technique. Systemic and renal hemodynamics, urinary sodium excretion, plasma norepinephrine, and forearm blood flow (FBF) were measured at the end of baseline and each hyperinsulinemic period. Baseline measurements in the cirrhotics, when compared with our laboratory standards obtained from a comparable group of male healthy normals, showed significant hyperinsulinemia (P=.01), associated with significantly higher FBF (P=.02), and glomerular filtration rate (GFR) (P=.02), as well as significantly reduced urinary volume (P=.04) and fractional excretion of sodium (P=.04). Insulin infusions in the cirrhotics produced no further sodium retention, but further forearm vasodilatation occurred at doses > or = 10 mU/m2/min. In contrast, there was no further renal vasodilatation except at very high pharmacological levels of insulin together with an unchanged GFR, natriuresis, and diuresis. Hyperinsulinemia produced no significant effects on the sympathetic nervous activity. In conclusion, these results suggest that hyperinsulinemia may be implicated in the glomerular hyperfiltration and sodium retaining tendency of preascitic cirrhotic patients with glucose intolerance. The ability of the kidneys to escape from the sodium retaining effects may serve as an in-built physiological regulatory mechanism on sodium homeostasis.",0
1772,8617439,Induction of rat liver parenchymal cell apoptosis by hepatic myofibroblasts via transforming growth factor beta,"The induction of apoptosis of rat liver parenchymal cells (PC) by transforming growth factor beta (TGF-beta)-expressing transforming fat-storing cells (FSC), i.e., myofibroblasts (MFB), was studied under culture conditions and compared with the apoptotic effect of human recombinant TGF-beta1. MFB were obtained by subculture of FSC. The TGF-beta concentration in the conditioned medium of myofibroblast (MFBcM) determined with the Mink cell proliferation inhibition assay was <0.25 ng/mL/24 in the native medium, but 1.9 ng/mL24 h after transient acidification. MFBcM added in various dilutions and for different times to PC monolayers induced progressive cell detachment from the plastic support and increase of lactate dehydrogenase (LDH) activity in the medium. The reduction of mitochondrial dehydrogenase activity in PC (XTT or WST-1 test) was an early sign of MFBcM-induced functional impairment of PC. Short term exposure of PC with MFBcM for 3 hours was sufficient to induce the deleterious effects on PC, but neither native (nonactivated) MFBcM nor conditioned medium of untransformed FSC (FSCcM), in which TGF-beta was not detectable, were able to impair function and viability of PC. Activated MFBcM increased strongly (up to 21-fold) the concentration of oligonucleosomal DNA fragments both in the adherent and detached fraction of PC. Internucleosomal DNA fragments (DNA ladder) were demonstrated by electrophoresis of extracted DNA on agarose gels and by in situ end-labeling of DNA breaks (TUNEL reaction) only in MFBcM-exposed PC. MFBcM-treated PC exhibited intense fluorescence after staining with DNA-binding dye Hoechst 33342 and an increased number of cells with fragmented nuclei. All these criteria point to MFBcM-generated apoptosis of cultured PC, which were found to be very similar to those induced by human recombinant TGF-beta1. The exclusive role of active TGF-beta in MFBcM as mediator of the apoptotic effects of MFB was proven by preincubation of the conditioned medium with human recombinant latency-associated peptide, which reversed completely MFBcM induced reduction of the XTT-test and the MFBcM-generated increase of oligonucleosomal DNA fragments. Partial reversibility was reached by preincubation of the medium with recombinant soluble type II TGF-beta receptor. The data let us conclude that transformed FSC, i.e., MFB in damaged liver, could participate in the mechanisms of PC apoptosis by paracrine loops involving TGF-beta.",0
1773,8617444,Involvement of calcium in macrophage leukotriene release during experimental cirrhosis,"The aim of the present study was to assess the mechanism of 5-lipoxygenase metabolites (LT) secretion by peritoneal macrophages in rats wih CC14 induced cirrhosis. After stimulation with calcium ionophore A23187 or opsonized zymosan, [3H] arachidonic acid labeled macrophages from cirrhotic rats presented a significantly greater secretion of LT than macrophages from healthy controls. In addition, the phorbol ester TPA (protein kinase C activator) increased LT production only in macrophages from cirrhotic animals and not in controls. Although Ca2+ is thought to be involved in 5 lipoxygenase activation, the role of Ca2+ in LT production was studied. The use of a Ca2+-free medium as well as the addition of TMB-8 (an inhibitor of intra-cellular Ca2+ movements and of plasma membrane Ca2+ fluxes) resulted in a fall in LT production greater for macrophages from cirrhotic animals than for controls. The measurement of cytosolic Ca2+ concentration by cytofluorimetry showed that Fluo-3 loaded macrophages from cirrhotic rats had a greater cytosolic CA2+ concentration than macrophages from control animals both in basal conditions and after A23187 stimulation. Study of 45Ca2+ uptake suggest, that extra-cellular Ca2+ is implicated in the elevated cytosolic Ca2+ observed in macrophages from cirrhotic animals as compared to healthy controls. The greater Ca2+ concentration observed in macrophages from cirrhotic rats was not related to a difference in phospholipase C activation because inositol phosphate production did not differ between macrophages from healthy and cirrhotic animals. Taken together these results suggest that as compared to healthy animals, the greater LT production during cirrhosis could be dependent upon a difference in 5-lipoxygenase activation related to a rise in cytosolic Ca2+ concentration independently of inositol phosphates generation.",0
1774,8618604,Prediction of the need for intensive care in patients who come to emergency departments with acute chest pain,"BACKGROUND: Patients who come to the emergency department with chest pain are a heterogeneous group. Some have ischemic heart disease that may lead to serious complications, whereas others have minor disorders. We performed a study to identify clinical factors that predict which patients will have complications requiring intensive care. METHODS: We first studied 10,682 patients with acute chest pain at seven hospitals between 1984 and 1986 (derivation set) to identify potential clinical predictors of the development of major complications. We then validated these predictors in a separate set of 4676 patients at one hospital between 1990 and 1994 (validation set). RESULTS: In the derivation set of patients, we identified the following set of clinical features, which, if present in the emergency department, were associated with an increased risk of complications: ST-segment elevation or Q waves on the electrocardiogram thought to indicate acute myocardial infarction, other electrocardiographic changes indicating myocardial ischemia, low systolic blood pressure, pulmonary rales above the bases, or an exacerbation of known ischemic heart disease. On the basis of these criteria, the patients in the validation set were stratified into four groups, with the risk of major complications in the first 12 hours ranging from 0.15 to 8 percent. After 12 hours, the probability of a major complication could be updated on the basis of whether the patient had already had a complication of major severity, a complication of intermediate severity, or a myocardial infarction (independent relative risks, 18.9, 7.7 and 4.0, respectively, as compared with patients without prior complications or myocardial infarction). CONCLUSIONS: The risk of major complications in patients with acute chest pain can be estimated on the basis of the clinical presentation and new clinical observations made during the hospital course. These estimates of risk help in making rational decisions about the appropriate level of medical care for patients with acute chest pain.",0
1775,8621151,Vasoactive intestinal peptide in cirrhotic rats: hemodynamic effects and mesenteric arterial receptor characteristics,"Vasoactive intestinal peptide (VIP) blood levels in cirrhosis are elevated, but its hemodynamic and receptor characteristics remain unclarified. We aimed to quantify VIP receptor characteristics in mesenteric arteries, plasma VIP concentration by radioimmunoassay (RIA), and the hemodynamic effects of VIP infusion in bile duct-ligated (BDL) cirrhotic and sham-operated control rats. Mesenteric arterial membranes were prepared by ultracentrifugation, and receptor characteristics were studied using 125I-labeled VIP as a radioligand. For the hemodynamic study, there were four groups: cirrhotic and sham-operated rats were infused with either VIP (50 ng/kg/min for 15 minutes) or equivolumic isotonic saline. Regional blood flows were measured in conscious rats with radioactive microspheres. Receptor studies showed high- and low-affinity binding sites for VIP, which had similar equilibrium dissociation constants (binding affinities) and receptor densities for both the cirrhotic and control rats. Plasma VIP concentrations were significantly elevated in the cirrhotic rats. In both cirrhotic and sham-operated rats, VIP infusion produced plasma levels approximately twofold to threefold increased over the basal levels observed in cirrhotic rats. In cirrhotic rats, VIP infusion did not affect any hemodynamic parameter, whereas in the sham-operated rats VIP infusion significantly increased the mesenteric visceral blood flow. These results show that the hyporesponsiveness to VIP in cirrhotic rats is not attributable to receptor downregulation, implying postreceptor alterations. This suggests that VIP may not play a major role in the maintenance of splanchnic hyperemia in cirrhosis.",0
1776,8621159,"Kupffer cell depletion by liposome-delivered drugs: comparative activity of intracellular clodronate, propamidine, and ethylenediaminetetraacetic acid","Macrophages such as Kupffer cells in the liver are multifunctional cells. They are involved in host defense mechanisms and have a regulatory role in many biomedical processes. Their selective depletion, using liposome-encapsulated drugs, forms a widely accepted approach to studying their functional aspects in vivo. We have compared the Kupffer cell-depleting activities of liposome-encapsulated clodronate, propamidine, and ethylenediaminetetraacetic acid (EDTA) for this purpose. These molecules represent the drug families of bisphosphonates, diamidines (or aromatic polyamidines), and polyaminopolycarboxylic acid-chelating agents, respectively. The Kupffer cell-depleting activity of the liposome-encapsulated antimicrobial drug propamidine exceeded that of clodronate by about a factor of 10. EDTA appeared to be inefficacious for depletion of Kupffer cells in the rat.",0
1777,8628356,Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. The Women and Infants Transmission Study,"BACKGROUND: A substantial proportion of perinatally acquired infections with the human immunodeficiency virus type 1 (HIV-1) occur at or near delivery, which suggests that obstetrical factors may have an important influence on transmission. We evaluated the relation of such factors and other variables to the perinatal transmission of HIV-1. METHODS: The Women and Infants Transmission Study is a prospective, observational study of HIV-1-infected women who were enrolled during pregnancy and followed with their infants for three years after delivery. We studied obstetrical, clinical, immunologic, and virologic data on 525 women who delivered live singleton infants whose HIV-1-infection status was known as of August 31, 1994. RESULTS: Among mothers with membranes that ruptured more than four hours before delivery, the rate of transmission of HIV-1 to the infants was 25 percent, as compared with 14 percent among mothers with membranes that ruptured four hours or less before delivery. In a multivariate analysis, the presence of ruptured membranes for more than four hours nearly doubled the risk of transmission (odds ratio, 1.82; 95 percent confidence interval, 1.10 to 3.00; P = 0.02), regardless of the mode of delivery. The other maternal factors independently associated with transmission were illicit-drug use during pregnancy (odds ratio, 1.90; 95 percent confidence interval, 1.14 to 3.16; P = 0.01), low antenatal CD4+ lymphocyte count (<29 percent of total lymphocytes) (odds ratio, 2.82; 1.67 to 4.76; P<0.001), and birth weight <2500 g (odds ratio, 1.86; 1.03 to 3.34; P = 0.04). CONCLUSIONS: The risk of transmission of HIV-1 from mother to infant increases when the fetal membranes rupture more than four hours before delivery.",0
1778,8628359,The influence of the wider use of surfactant therapy on neonatal mortality among blacks and whites,"BACKGROUND: Surfactant therapy reduces morbidity and mortality among premature infants with the respiratory distress syndrome (RDS). Fetal pulmonary surfactant matures more slowly in white than in black fetuses, and therefore RDS is more prevalent among whites than among blacks. We reasoned that the increased use of surfactant after its approval by the Food and Drug Administration (FDA) in 1990 might have reduced neonatal mortality more among whites than among blacks. METHODS: We merged vital-statistics information for all 1563 infants with very low birth weights (500 to 1500 g) born from 1987 through 1989 or in 1991 and 1992 to residents of St. Louis with clinical data from the four neonatal intensive care units in the St. Louis area; we then compared neonatal mortality during two periods, one before and one after the FDA's approval of surfactant for clinical use (1987 through 1989 and 1991 through 1992). RESULTS: The use of surfactant increased by a factor of 10 between 1987 through 1989 and 1991 through 1992. The neonatal mortality rate among all very-low-birth-weight infants decreased 17 percent, from 220.3 deaths per 1000 very-low-birth-weight babies born alive (in 1987 through 1989) to 183.9 per 1000 (in 1991 through 1992; P = 0.07). This decrease was due to a 41 percent reduction in the mortality rate among white newborns with very low birth weights (from 261.5 per 1000 to 155.5 per 1000; P = 0.003). In contrast, among black infants, the mortality rate for very-low-birth-weight infants did not change significantly (195.6 per 1000 and 196.8 per 1000). The relative risk of death among black newborns with very low birth weights as compared with white newborns with similar weights was 0.7 from 1987 through 1989 and 1.3 from 1991 through 1992 (P = 0.02). The differences in mortality were not explained by differences in access to surfactant therapy, by differences in mortality between black and white infants who received surfactant, or by differences in the use of antenatal corticosteroid therapy. CONCLUSIONS: After surfactant therapy for RDS became generally available, neonatal mortality improved more for white than for black infants with very low birth weights.",0
1779,8649495,"A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Fran�ais du My�lome","BACKGROUND: The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy. METHODS: Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation. RESULTS: The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P < 0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 percent in the conventional-dose group (P = 0.01); the overall estimated rate of survival for five years was 52 percent in the high-dose group and 12 percent in the conventional-dose group (P = 0.03). Treatment-related mortality was similar in the two groups. CONCLUSIONS: High-dose therapy combined with transplantation improves the response rate, eventfree survival, and overall survival in patients with myeloma.",0
1780,8663855,The use of Medicare home health care services,"BACKGROUND: Medicare's home health care program, consisting primarily of home visits by nurses and health aides, was conceived as a means to facilitate hospital discharge. Because home health care is now one of the fastest-growing categories of Medicare expenditures, we analyzed Medicare claims data to determine current patterns of use. METHODS: We used 1993 data from Medicare's National Claims History File to examine the temporal relation between home visits and hospital discharge, as well as the number of months Medicare enrollees received home health care. To determine whether home visits replaced hospital services, we calculated population-based utilization rates, adjusted for age and sex, for enrollees living in the 310 U.S. metropolitan statistical areas and determined whether the areas with higher rates of home health care also had lower admission rates or shorter lengths of stay. Finally, we compared the geographic variation in use of home health care with that of other Medicare services. RESULTS: Roughly 3 million Medicare enrollees received over 160 million home health care visits in 1993. Seventy-eight percent of the visits either occurred more than a month after hospital discharge (35 percent) or were not associated with any inpatient care during the previous six months (43%). Home health care often represented a long-term intervention: 61 percent of the visits were to enrollees who received home health care for six months or more. We could find no evidence that home health care was substituted for hospital care; the metropolitan statistical areas with higher rates of home health care did not have fewer hospital admissions or shorter lengths of stay. There was more geographic variation in the use of home health care than in the use of other major categories of Medicare services (e.g., hospital admissions and physicians' services). Five states (all in the South) had more than 9000 visits per 1000 enrollees, and 14 states had fewer than 3000 visits per 1000 enrollees. CONCLUSIONS: Home health care visits are used primarily to provide long-term care. There is no evidence that services provided at home replace hospital services, and the dramatic geographic variation in home visits suggests a lack of consensus about their appropriate use.",0
1781,8663882,Effect of economic reforms on child growth in urban and rural areas of China,"BACKGROUND: Beginning in 1978, China implemented economic reforms to transform the economy to a free-market system. We compared the effect of the reforms on the growth of children in urban and rural areas. METHODS: Using data from five large cross-sectional surveys conducted between 1975 and 1992, we examined the trends in height for age of children two to five years of age in urban and rural areas. Mean height for age was expressed as the height in centimeters adjusted to a reference value of 99.1 cm for a 42-month-old boy. RESULTS: Height increased before and during the economic reforms. In 1975, the average height of children in periurban rural areas was about 3.5 cm less than that of children in urban areas. Between 1975 and 1985, the average height of children in periurban rural areas increased by 2.0 cm, as compared with 1.3 cm in urban children. Between 1987 and 1992, the average height of both urban and rural children increased, but the net increase for rural children was only one fifth that for urban children (0.5 vs. 2.5 cm). In a 1990 survey of seven provinces, the rural mean height was 92.5 cm, as compared with the urban mean of 96.9 cm and the reference value of 99.1 cm; 38 percent of rural children had moderate stunting of growth and 15 percent had severe stunting, as compared with 10 percent and 3 percent of urban children, respectively. Differences in height between rural and urban children were greater in provinces in which the average height of children was lower. CONCLUSIONS: Despite an overall improvement in child growth during the economic reforms in China, the improvement has not been equitable, as judged by increased differences in height between rural and urban children and increased disparities within rural area.",0
1782,8666334,Interleukin 1 beta markedly stimulates nitric oxide formation in the absence of other cytokines or lipopolysaccharide in primary cultured rat hepatocytes but not in Kupffer cells,"To investigate whether a single inflammatory cytokine could stimulate nitric oxide formation in the absence of other cytokines or lipopolysaccharide (LPS), NO was measured by the redox chemiluminescence method in primary cultured rat hepatocytes and in rat Kupffer cells. Interleukin (IL) 1 beta, but neither IL-6, tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), nor LPS stimulated NO formation in a dose-dependent manner and induced half-maximal effects at 30 pmol/L. Maximal stimulation was achieved at 12 to 16 hours after the addition of 1I nmol/L of IL-1 beta, and was 50- to 60-fold above basal levels in rat hepatocytes. The combined effect of these cytokines with LPS or IFN-gamma on NO formation was also examined. Neither LPS nor IFN-gamma affected the IL-1 beta-induced NO formation. TNF-alpha, however, stimulated IL-1 beta-induced NO formation, while IL-6 inhibited it, although independently these cytokines had no effect on NO formation. None of the cytokines tested stimulated NO formation in cultured rat Kupffer cells. In hepatocytes, the NO formation induced by IL-l beta was blocked by both the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) and by IL-1 receptor antagonist (IL-1ra). Furthermore, IL-1 beta markedly increased NOS activity, and this increase in activity was accompanied by the expression of inducible NOS (iNOS) messenger RNA (mRNA). This study clearly demonstrated that IL-1 beta markedly stimulates NO formation in hepatocytes, in the absence of other cytokines or LPS.",0
1783,8672166,Postmenopausal estrogen and progestin use and the risk of cardiovascular disease,"BACKGROUND: Estrogen therapy in postmenopausal women has been associated with a decreased risk of heart disease. There is little information, however, about the effect of combined estrogen and progestin therapy on the risk of cardiovascular disease. METHODS: We examined the relation between cardiovascular disease and postmenopausal hormone therapy during up to 16 years of follow-up in 59,337 women from the Nurses' Health Study, who were 30 to 55 years of age at base line. Information on hormone use was ascertained with biennial questionnaires. From 1976 to 1992, we documented 770 cases of myocardial infarction or death from coronary disease in this group and 572 strokes. Proportional-hazards models were used to calculate relative risks and 95 percent confidence intervals, adjusted for confounding variables. RESULTS: We observed a marked decrease in the risk of major coronary heart disease among women who took estrogen with progestin (multivariate adjusted relative risk, 0.39; 95 percent confidence interval, 0.19 to 0.78) or estrogen alone (relative risk, 0.60; 95 percent confidence interval, 0.43 to 0.83), as compared with women who did not use hormones [corrected]. However, there was no significant association between stroke and use of combined hormones (multivariate adjusted relative risk, 1.09; 95 percent confidence interval, 0.66 to 1.80) or estrogen alone (relative risk, 1.27; 95 percent confidence interval, 0.95 to 1.69). CONCLUSIONS: The addition of progestin does not appear to attenuate the cardioprotective effects of postmenopausal estrogen therapy.",0
1784,8675150,The hepatocyte growth factor regulates the synthesis of acute-phase proteins in human hepatocytes: divergent effect on interleukin-6-stimulated genes,"Our study addressed the role of the human hepatocyte growth factor (HGF), a potent mitogen for mature rat and human hepatocytes, in the regulation of specific hepatic genes. The experimental evidence obtained in primary cultured human hepatocytes indicates that HGF regulates the synthesis of plasma proteins in a dose-response fashion. It stimulates the synthesis of the negative acute-phase proteins albumin, transferrin, and fibronectin, decreases that of alpha1-antichymotrypsin (ACT) and haptoglobin, and stimulates that of alpha2-macroglobulin (AMG), which in man is insensitive to inflammatory mediators. HGF had no effect on C-reactive protein (CRP) synthesis. These effects differ from those elicited by interleukin-6 (IL-6). The effects of HGF on fibrinogen and alpha1-antitrypsin were, however, similar to those induced by IL-6. The effects of HGF were also observed at the messenger RNA (mRNA) level. Time-course induction experiments showed that the effects of HGF on protein synthesis were delayed by about 48 to 72 hours, in contrast with the 12-hour lag found after IL-6 stimulation. Although the presence of glucocorticoids was not absolutely necessary for HGF to affect plasma protein synthesis, it moderately extended the effects. In pulse-chase experiments, it was found that the action of HGF was not due to an alteration of the rate of secretion of the proteins. The effects of HGF on the synthesis of albumin, transferrin, fibronectin, alpha1-antichymotrypsin, and haptoglobin could be counteracted by the simultaneous presence of IL-6 in the incubation media. A clear additive effect was observed only in the case of fibrinogen. No interaction was observed in the cases of CRP and AMG. The results of this study indicate that the effects of HGF on human hepatocytes may not simply be limited to its mitogenic activity, but that it also regulates hepatic-specific genes and antagonizes, in part, the action of IL-6.",0
1785,8675183,Effect of tumor necrosis factor alpha on intrahepatic bile duct epithelial cell of rat liver,"Tumor necrosis factor alpha (TNF-alpha), which is primarily produced by macrophages, is a cytokine with various biological activities. Macrophage infiltration often accompanies experimental cholangitis in rats, and chronic cholangitis in humans. The pathophysiologic significance of TNF-alpha in cholangitis is not known. We used cultured, polarized intrahepatic bile duct epithelial cells (IBDECs) from rat liver to determine whether TNF-alpha directly affects the organization of IBDEC monolayers. The addition of recombinant TNF-alpha (rTNF-alpha) to culture media at concentrations from 10 to 200 U/mL lacked cytotoxicity to the IBDECs as judged by trypan blue exclusion and lactate dehydrogenase (LDH) release. rTNF-alpha transiently reduced transepithelial electrical resistance in a dose-dependent manner. During this decrease in resistance, the cellular tight junctions became leaky, allowing horseradish peroxidase (HRP) penetration. rTNF-alpha, at concentrations up to 200 U/mL, did not detach IBDECs from Matrigel, an artificial basement membrane. Electron microscopy and immunohistochemistry for F-actin showed a well-preserved cell structure and organization of IBDECs. Results suggest that TNF-alpha is nontoxic to IBDECs, and that it increases the permeability of tight junctions. TNF-alpha may thus disturb the barrier function of the bile duct.",0
1786,8675188,Evidence that interference with binding to hepatic cytosol binders can inhibit bile acid excretion in rats,"We previously identified that Y' bile acid binders (3alpha-hydroxysteroid dehydrogenases) interact with bile acids in intact rat hepatocytes using [3beta-3H, C24-14C]bile acids and that indomethacin, a competitive inhibitor of 3alpha-hydroxysteroid dehydrogenase, inhibits 3H-loss from the C3-position of bile acids as well as inhibits hepatic bile acid removal and excretion. To study the kinetics of these inhibitory effects, glycocholate transport was studied in the absence and presence of indomethacin in the single-pass perfused rat liver. Indomethacin decreased net hepatic glycocholate uptake in the perfused liver, which was confirmed in isolated hepatocytes and basolateral liver plasma membrane vesicles. However, indomethacin markedly increased the sinusoidal efflux and decreased the biliary excretion of glycocholate in the perfused liver. These observations indicate that the effect of indomethacin to delay biliary glycocholate excretion is related to either intracellular or canalicular glycocholate transport. The latter possibility seemed unlikely because indomethacin did not inhibit electrogenic or adenosine triphosphate (ATP)-dependent glycocholate uptake by canalicular liver plasma membrane vesicles. Thus, the current data support an important role for binding of bile acids to cytosolic proteins in overall hepatic transport and suggest that specific interference with cytosolic binding can interfere with the excretion of bile acids.",0
1787,8675189,Biosynthesis and degradation of hyaluronan by nonparenchymal liver cells during liver regeneration,"Hepatic stellate cells (HSC) and endothelial cells of the liver sinusoids synthesize and degrade hyaluronan, respectively. The roles of these cell types in the biosynthesis and degradation of hyaluronan were studied during regeneration following partial hepatectomy. Pure cultures of HSC and liver endothelial cells (LEC) were obtained from regenerating liver at different stages using a Nycodenz gradient followed by discontinuous Percoll gradient. The HSC that established 3 or 4 days after partial hepatectomy synthesized large amounts of hyaluronan when cultured in the presence of fetal calf serum (FCS) or platelet-derived growth factor B-chain homodimer (PDGF)-BB. These cells, as well as LEC, expressed active PDGF beta-receptors. Furthermore, the ability of LEC to degrade hyaluronan was decreased at early stages of liver regeneration. The increased synthesis of hyaluronan by HSC and the failure of LEC to catabolize the polysaccharide resulted in elevated hyaluronan concentrations in the blood.",0
1788,8678931,An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation,"BACKGROUND: To avert major hemorrhage, physicians need to know the lowest intensity of anticoagulation that is effective in preventing stroke in patients with atrial fibrillation. Since the low rate of stroke has made it difficult to perform prospective studies to resolve this issue, we conducted a case-control study. METHODS: We studied 74 consecutive patients with atrial fibrillation who were admitted to our hospital from 1989 through 1994 after having an ischemic stroke while taking warfarin. For each patient with stroke, three controls with nonrheumatic atrial fibrillation who were treated as outpatients were randomly selected from the 1994 registry of the anticoagulant-therapy unit (222 controls). We used the international normalized ratio (INR) to measure the intensity of anticoagulation. For the patients with stroke, we used INR at admission; for the controls, we selected the INR that was measured closest to the month and day of the matched case patient's hospital admission. RESULTS: The risk of stroke rose steeply at INRs below 2.0. At an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, was 2.0 (95 percent confidence interval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percent confidence interval, 2.4 to 4.6); and at an INR of 1.3, it was 6.0 (95 percent confidence interval, 3.6 to 9.8). Other independent risk factors were previous stroke (odds ratio, 10.4; 95 percent confidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio, 2.95; 95 percent confidence interval, 1.3 to 6.5), hypertension (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7), and current smoking (odds ratio, 5.7; 95 percent confidence interval, 1.4 to 24.0). CONCLUSIONS: Among patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 or greater. Since previous studies have indicated that the risk of hemorrhage rises rapidly at INRs greater than 4.0 to 5.0, tight control of anticoagulant therapy to maintain the INR between 2.0 and 3.0 is a better strategy than targeting lower, less effective levels of anticoagulation.",0
1789,8690395,Inhibition of viral replication by genetically engineered mutants of the duck hepatitis B virus core protein,"The hepatitis B virus (HBV) nucleocapsid consists of 240 viral core proteins that are arranged in a highly symmetrical structure, HBV replication can only take place inside intact nucleocapsids. In the present study, we investigated whether genetically engineered core mutants can inhibit viral replication by interfering with the formation of intact nucleocapsids. Using the duck hepatitis B virus (DHBV) model, a series of core protein mutants was generated. Polymerase chain reaction-amplified fragments from the bacterial lacZ gene expressing up to 282 amino acids were added either to the amino- or carboxy-terminus of the DHBV core protein. In addition, carboxy-terminal extensions were generated by fusing the DHBV core protein with the DHBV small surface protein or various fragments of the viral polymerase. Finally, the green fluorescent protein (GFP) was fused in-frame to the carboxy-terminus of the DHBV core protein. In this chimeric protein, GFP is still functional and can act as a reporter molecule. The various core protein mutants were tested for their potential antiviral activity by cotransfection with a replication-competent DHBV construct into the avian hepatoma cell line LMH. Carboxy-terminal, but not amino-terminal, DHBV core mutants inhibited DHBV replication by up to 90% at an effector-to-target ratio of 1:10, thus displaying a dominant negative phenotype. Antiviral activity was species-specific and caused by posttranslational interference with viral replication. The DHBV core-GFP fusion protein should be an ideal tool to assess the antiviral potential of dominant negative core proteins in vivo.",0
1790,8690403,Differences in the mechanisms of uptake and endocytosis of small and large chylomicron remnants by rat liver,"Initial binding and subsequent endocytosis of small and large chylomicron remnants by rat liver were compared. Small and large chylomicrons were obtained from mesenteric lymph of glucose- or fat-fed rats, respectively. The low-density lipoprotein (LDL) receptor was up- and down-regulated as shown by LDL receptor messenger RNA (mRNA). The rate of removal of small chylomicron remnants by isolated perfused rat livers followed closely the activity of the LDL receptor. When mRNA was undetectable, the uptake was as low as that of lymphatic small chylomicrons. In contrast, the uptake of large chylomicron remnants into perfused rat livers was unaffected by changes of the LDL-receptor activity, but significantly reduced after livers were flushed with heparin or heparinase. Large chylomicron remnants were cleared from plasma much faster than small chylomicron remnants, but were more slowly internalized into hepatocytes. Both, small and large chylomicron remnants entered the pathway of receptor-mediated endocytosis as shown by electron microscopy and analysis of isolated endosomes. Yet, large chylomicron remnants were taken up into the compartment of uncoupling of receptors and ligands and multivesicular bodies at a much slower rate. This was independent of the activity of the LDL receptor and the heparin-releasable binding site. From these findings it is concluded that large chylomicron remnants initially bind rapidly to surface components other than the LDL receptor, one of which may be hepatic lipase. Yet, the consecutive internalization is slow. In contrast, small chylomicron remnants are removed at a slower rate from plasma, binding predominantly to the LDL receptor, but are more readily taken up into endosomes.",0
1791,8690406,Interferon gamma down-regulates cytochrome P450 3A genes in primary cultures of well-differentiated rat hepatocytes,"Administration of interferons of both the gamma and alfa/beta classes down-regulates hepatic cytochrome P450 (CYP) genes when administered to humans or rats. In male rats, interferons decrease expression of CYP3A2 at a pretranslational level, but because interferons also release other cytokines in vivo, it is unclear whether this is a direct effect on hepatocytes. We therefore examined the effects of rat recombinant interferon gamma (IFN-gamma) on CYP3A2, other 3A genes, and 2C11 in stable primary cultures of male rat hepatocytes. Hepatocytes were cultured on matrigel in Williams' E, and messenger RNAs (mRNAs) for 3A2, 3A1-like CYPs, and 2C11 mRNA were determined by RNase protection assays. CYP3A and 2C11 proteins were immunoquantified, and their catalytic activities were estimated by testosterone hydroxylation pathways. In control cells, 3A2 mRNA decreased initially but then recovered, and stable levels (15% of freshly isolated cells) were attained between days 3 and 7. Phenobarbital increased 3A2 mRNA to 60-120% values of freshly isolated cells, and mRNA for 3A1-like CYPs were increased 20-fold. In both control and phenobarbital-treated hepatocytes, rat recombinant IFN-gamma (33 U/mL) reduced mRNA for 3A2 and 3A1-like CYPs, as well as 3A protein and testosterone 6 beta-hydroxylase activity. Interferon had no effect on CYP2C11 at mRNA or protein levels in untreated cells, although a reduction in 2C11 protein was evident in phenobarbital-treated cultures. It is concluded that interferon directly alters expression of constitutive and inducible CYP3A genes in well-differentiated male rat hepatocytes in culture, but has no effect on constitutive expression of CYP2C11.",0
1792,8690407,Interferon gamma protects against hepatic tumor growth in rats by increasing Kupffer cell tumoricidal activity,"An increasing number of hepatic resections are being performed as potentially curative surgery for malignant liver neoplasms. Hepatectomy and subsequent liver regeneration produce a local environment that enhances growth of microscopic residual tumor. To determine if pretreatment with murine interferon gamma (IFN-gamma) can protect against such enhanced tumor growth, Buffalo rats were randomized to receive a 3-day treatment of IFN-gamma (50,000 U/qD intraperitoneally) or saline. Groups then underwent intrasplenic injection of 10(6) Morris hepatoma cells, followed 1 hour later by sham (control) or partial hepatectomy (PH) of 70%. PH significantly enhanced tumor growth within the liver (control, 8 +/- 3 nodules per liver; PH, 73 +/- 12 nodules per liver; P < .001). This enhancement was attenuated by prior administration of IFN-gamma IFN-gamma/PH, 16 +/- 3; P < .001 vs. PH). Growth factor release and liver regeneration were not affected significantly by pretreatment with IFN-gamma. The effect of IFN-gamma on tumor growth is associated with a significant enhancement of Kupffer cell (KC)-mediated tumoricidal activity (percentage of specific lysis, 55 +/- 10% control, 78 +/- 11% IFN-gamma, P < .01) but not lymphocyte-mediated tumoricidal activity. Because microscopic residual disease may be present after hepatectomies for cancer, IFN-gamma may be useful agent in retarding growth of residual tumors.",0
1793,8690412,Development of the ornithine cycle in rat liver: zonation of a metabolic pathway,"Ammonia-fixation in mammalian livers is, via the ornithine cycle and glutamine synthetase, strictly compartmentalized, occurring in a wide upstream periportal compartment and in the very last downstream pericentral hepatocytes, respectively. This conclusion is based on the well-known distribution patterns of carbamoyl phosphate synthetase I (CPS) and glutamine synthetase in the developing and adult liver. To determine to what extent the expression patterns of the ornithine cycle enzymes are coordinated with that of CPS, we investigated the patterns of expression of the individual messenger RNAs (mRNAs) of the ornithine cycle pathway in developing and adult rat liver. Our results show that, within the liver, all mRNAs of the ornithine cycle pathway are zonated. The patterns of expression of the different mRNAs match almost perfectly, with variations only in the steepness of the gradients of the mRNAs, suggesting that, in the rat, common regulatory factors are involved in the establishment of the zonation pattern.",0
1794,8703170,Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia,"BACKGROUND: An activating mutation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) was recently found in a patient with Jansens's metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism associated with hypercalcemia and normal or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of this unusual disorder, we analyzed genomic DNA from six additional patients with Jansen's disease. METHODS: Exons encoding the PTH-PTHrP receptor were amplified by the polymerase chain reaction (PCR), and the products were analyzed by gel electrophoresis or direct nucleotide-sequence analysis. Nucleotide changes were confirmed by restriction-enzyme digestion of genomic DNA or the PCR products. RESULTS: The previously reported mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but not in DNA from their healthy relatives or 45 unrelated normal subjects. A novel missense mutation that changes a threonine in the receptor's sixth membrane-spanning region to proline (T410P) was identified in another patient but not in 62 normal subjects. In two patients with radiologic evidence of Jansen's metaphyseal chondrodysplasia but less severe hypercalcemia, no receptor mutations were detected. In COS-7 cels expressing PTH-PTHrP receptors with the T410P or H223R mutation, basal cyclic AMP accumulation was four to six times higher than in cells expressing wild-type receptors. CONCLUSIONS: The expression of constitutively active PTH-PTHrp receptors in kidney, bone, and growth-plate chondrocytes provides a plausible genetic explanation for mineral-ion abnormalities and metaphyseal changes in patients with Jansen's disease.",0
1795,8707247,"The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue","Little is known about the alterations of metabolic organization of the human liver tissue in chronic liver diseases. We therefore compared the distribution of the following zonal metabolic markers in 10 samples of normal liver tissue, 10 samples of fibrotic tissue, and 22 samples of cirrhotic tissue: (a) the enzymatic activities of glucose-6-phosphatase (G6P), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), nicotinamide-adenine-dinucleotide-phosphate [NAPH] dehydrogenase (ND), beta-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine synthetase (GLS); and (c) albumin messenger RNA (mRNA). The normal human hepatic lobule was characterized by the periportal predominance of G6P and SDH enzymatic activities and albumin mRNAs, the perivenous predominance of ND and GDH, the restriction of GLS to a small perivenous compartment, and the predominanc of beta-HBDH at the contact of both portal tracts and centrilobular veins. In fibrosis, the overall metabolic organization of the normal liver tissue was retained. The expression of periportal markers predominated around enlarged portal tracts and that of perivenous markers around residual centrilobular veins. GLS was constantly detected at the contact of centrilobular veins. In cirrhotic nodules, no zonation was observed for most enzymatic activities or for albumin. Only G6P usually predominated at the periphery of the nodules. GLS was constantly undetectable. No difference accordingly to the etiology of the underlying disease was observed. In conclusion, the normal human hepatic lobule presents a marked metabolic zonation, preserved in fibrotic lesions, but lost in cirrhotic nodules. The alterations of the metabolic organization observed in cirrhosis might contribute to the pathogenesis of some of the metabolic disorders associated with advanced liver disease.",0
1796,8707252,S-adenosyl-L-methionine prevents disruption of canalicular function and pericanalicular cytoskeleton integrity caused by cyclosporin A in isolated rat hepatocyte couplets,"Isolated rat hepatocyte couplets were used to study the effect of S-adenosyl-L methionine (SAMe) treatment on disruption of canalicular function caused by cyclosporin A (CyA). Canalicular function was assessed by counting the percentage of couplets that were able to accumulate the fluorescent cholephile choly-lysyl-fluorescein (CLF) into the canalicular vacuole between the two cells, i.e., canalicular vacuole accumulation (CVA). Cotreatment with 1 mmol/L SAMe prevented the inhibition of canalicular vacuole accumulation caused by CyA (75 nmol/L and 100 nmol/L), whereas treatment with it after CyA was unsuccessful. SAMe prevented the dose dependent reduction caused by CyA (5 nmol/L-1 mumol/L) both on CVA and on retention of CLF preaccumulated within the canaliculus, the effect on retention being complete. No difference in intracellular content of reduced glutathione (GSH) between the control and any dose level of the immunosuppressor, with or without SAMe treatment was observed, suggesting that changes in intracellular reduced GSH levels are not involved in the effects of SAMe. F-actin was stained with fluorescein-isothiocyanate phalloidin and fluorescence measurements were performed by confocal microscopy. The ratio of the percanalicular area fluorescence/total couplet fluorescence, indicative of F-actin distribution, significantly decreased with CyA. However, cotreatment of CyA with SAMe protected the integrity of the pericanalicular cytoskeleton, suggesting that this beneficial effect on canalicular function may maintain canalicular contractions and/or preserve tight junction function. Results are discussed in relation to possible involvement of the transmethylation pathway, modifications in membrane fluidity, effects on bile acid transport, and of inhibition of uptake of CyA. They suggest that SAMe could be a good candidate for protecting against CyA-induced membrane dysfunction.",0
1797,8707258,Liver cell uptake and degradation of soluble immunoglobulin G immune complexes in vivo and in vitro in rats,"Immune complexes were formed between dinitrophenylated human serum albumin (DNP-HSA) and polyclonal rabbit immunoglobulin G (IgG) anti-DNP antibodies at antibody excess. The antigen was labelled with isotope (125I-tyramine-cellobiose) or fluorochrome, (6-[fluorescein-5-(and-6)-carboxamido] hexanoic-acid, succinimidyl ester). The radiolabelled antigen, native or antibody complexed, was given intravenously to rats. Radioactivity was measured in various organs at 1 hour following injection. The liver was the main site for removal of the antigen as well as of the immune complexes. Within the liver, immune complexes were mainly associated with nonparenchymal liver cells, the total recovery from Kupffer cells being about 10 times greater than from the liver endothelial cells. The uncomplexed radiolabelled antigen was readily degraded by both cells types. After IgG complexing, the degradation decreased, both in Kupffer cells and in liver endothelial cells. In vitro experiments with isolated liver cells, showed that IgG complexing increased antigen uptake to about the same extent in Kupffer cells and in liver endothelial cells. The degradation of both antigen and immune complexes was less efficient in vitro than in vivo. Immune complex uptake in vitro was shown also by confocal fluorescence microscopy in Kupffer cells and in liver endothelial cells. Also in vitro, only minor uptake was found in the hepatocytes. We conclude that both liver endothelial cells and Kupffer cells are involved in the hepatic handling of soluble IgG immune complexes, but we found no evidence for substantial uptake by hepatocytes.",0
1798,8707267,The polymeric immunoglobulin receptor is the major calmodulin-binding protein in an endosome fraction from rat liver enriched in recycling receptors,"Rat liver endosomes contain one major high-affinity calmodulin-binding protein (CaMBP) that now has been identified as the polymeric immunoglobulin receptor (pIgR). In isolated endosomes pIgR was enriched in the receptor-recycling compartment (RRC); lesser enrichment was found in 'early' endosome (CURL) and much less in 'late' endosome fractions (multivesicular bodies, MVB). The distribution of the major CaMBP, shown by Western blotting or by overlay with I125-calmodulin in the isolated fractions, was consistent with rapid accumulation of I125-immunoglobulin A (IgA) in RRC and CURL after intravenous injection into rats. The receptor was also found in sinusoidal plasma membranes but not in cell fractions containing apical (bile canalicular) or lateral plasma membrane domains of the hepatocyte. The interaction of pIgR with calmodulin was shown by direct binding assays and by affinity chromatography. Thus, calmodulin is the first cytoplasmic protein shown to interact with the pIgR. We postulate that calmodulin regulates pIgA trafficking in rat liver. In addition, the receptor recycling fraction emerges as an endosomal subcompartment involved in pIgA transport via pIgR.",0
1799,8707269,Altered lipid metabolism in apolipoprotein E-deficient mice does not affect cholesterol balance across the liver,"Adaptation of cholesterol and bile acid synthesis and of biliary cholesterol secretion represent key metabolic responses to maintain cholesterol homeostasis and have been suggested to be influenced by apolipoprotein E (apoE) phenotype in humans. We have investigated hepatic metabolism and secretion of cholesterol into bile in homozygous apoE-deficient (apoE -/-) mice fed normal lab chow. Plasma cholesterol levels were 10 times higher in apoE (-/-) mice than in controls (+/+); triacylglycerol levels were only minimally affected. Hepatic cholesterol (+56%) and triacylglycerol (+232%) contents were significantly increased in apoE (-/-) mice, whereas those of cholesteryl ester and of phospholipids were similar in both groups. Lipid accumulated predominantly in periportal areas of apoE (-/-) livers. Hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) messenger RNA (mRNA) level and activity were reduced by 45% and 50%, respectively, in apoE (-/-) mice. In contrast, plasma lathosterol/cholesterol ratios, indicative for whole-body cholesterol synthesis, were fourfold increased in these mice. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was similar in livers of both groups. Despite the marked changes in hepatic cholesterol metabolism, neither hepatic bile acid synthesis, bile acid pool size and composition, nor hepatic cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase mRNA levels differed between apoE (-/-) and (+/+) mice. In addition, biliary cholesterol secretion was unaffected in the knock-out mice. Our results show that lack of apoE leads to marked changes in hepatic cholesterol metabolism without altering cholesterol balance across the liver. The data are compatible with increased peripheral cholesterol biosynthesis in apoE-deficient mice.",0
1800,8707289,Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies,"""The detection of antimitochondrial autoantibodies (AMAs) is critical in the diagnosis of primary biliary cirrhosis (PBC). However, conventional laboratory assays to detect AMA are dependent on the time-consuming method of immunofluorescence microscopy, a method often plagued by problems of nonspecificity. AMAs react against mitochondrial autoantigens including the E2 components of the pyruvate dehydrogenase complex (PDC-E2), the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the 2-oxo-glutarate dehydrogenase complex (OGDC-E2). Interestingly, the immunodominant epitopes of PDC-E2, BCOADC-E2, and OGDC-E2 are all conformational lipoate binding sites, but antibodies against them do not cross-react. Although 80% to 90% of sera from patients with PBC react to PDC-E2, approximately 10% patients with PBC react only to BCOADC-E2 and/or OGDC-E2. We have taken advantage of our epitope-mapping studies of the E2 components of PDC, BCOADC, and OGDC, and constructed a """"designer"""" hybrid clone, designated as pML-MIT3, that coexpresses the immunodominant epitopes within the three distinct lipoyl domains. We examined a total of 321 sera, including 186 sera from patients with PBC, to test the immunoreactivity of pMIT3. Of 186 sera from patients with PBC, 152 sera (81.7%) reacted with recombinant fusion protein of PDC-E2, whereas 171 sera (91.9%) showed positive reactivities when probed by immunoblotting against the recombinant fusion protein expressed from the pML-MIT3 clone. Of 34 PBC sera that did not react with recombinant PDC-E2, 18 sera contained BCOADC-E2-specific AMA and 1 serum possessed only OGDC-E2-specific AMA. We also developed an enzyme-linked immunosorbent assay (ELISA), using affinity-purified recombinant fusion protein of pML-MIT3 clone as the antigen source, to quantify specific AMAs in patients with PBC. None of the 135 control sera from patients with primary sclerosing cholangitis (PSC), chronic autoimmune hepatitis (CAH), systemic lupus erythematosus (SLE), or healthy volunteers showed significant reactivity against pML-MIT3 recombinant fusion protein in the ELISA assay. Our results indicate that an ELISA using recombinant, cloned autoantigen of pML-MIT3 is a powerful and very specific method for the detection of AMA.""",0
1801,8778600,"Meningococcal disease in Los Angeles County, California, and among men in the county jails","BACKGROUND: From January through March 1993, there were 54 cases of meningococcal disease in Los Angeles County, California, of which 9 occurred among men incarcerated in the county's jail system, which was 40 percent above capacity at the time. Several of the 45 patients from the community had had contact with men recently released from a county jail. METHODS: We interviewed patients from the community (n=42) and neighborhood controls matched with the patients for age, race, and ethnic group (n=84) about potential exposures. We collected and cultured pharyngeal swabs for Neisseria meningitidis from men entering the central jail (n=162), men leaving the central jail (n=379), members of the jail staff (n=121), and patients at a community health center (n=214). Meningococcal isolates were identified by serotyping and multilocus enzyme electrophoresis. RESULTS: The presence of community-acquired meningococcal disease was strongly associated with exposure to a person who had been in or worked at one of the county jails (multivariate matched odds ratio, 18.5; 95 percent confidence interval, 3.8 to 90.8; P<0.001). Pharyngeal carriage of meningococcus was significantly more frequent among men released from jail (19 percent) or entering jail (17 percent) than among workers at the jails (3 percent) or community residents seen at the clinic (1 percent). Among men entering jail, those who had previously been incarcerated were more often carriers than those who had not (21 percent vs. 7 percent, P=0.03). Of the isolates from nine community residents with serogroup C meningococcal disease, eight were the same strain as that isolated from the eight inmates with serogroup C disease. CONCLUSIONS: In this outbreak of meningococcal disease in Los Angeles County, nearly half of community residents with the disease had contact with persons who had been in a county jail. The high rates of carriage among recidivists and released inmates suggests that the men became meningococcal carriers while in jail.",0
1802,8778601,Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network,"BACKGROUND: Inhaled beta-agonists are the most commonly used treatment for asthma, but data suggest that regularly scheduled use of these agents may have deleterious effect on the control of asthma. We compared the effects of regularly scheduled use of inhaled albuterol with those of albuterol used only as needed in patients with mild chronic, stable asthma. METHODS: In a multicenter, double-blind study, we randomly assigned 255 patients with mild asthma to inhale albuterol either on a regular schedule (126 patients) or only as needed (129 patients). The patients were followed for 16 weeks. RESULTS: The primary outcome indicator, peak expiratory air flow measured in the morning, did not change significantly during the treatment period in the scheduled (416 liters per minute after the run-in period and 414 liters per minute after the treatment period) or the as-needed (424 liters per minute at both times) treatment groups (P=0.71). There were no significant differences between the two groups in peak flow variability, forced expiratory volume in one second, the number of puffs of supplemental albuterol needed, asthma symptoms, asthma quality-of-life score, or airway responsiveness to methacholine. The statistically significant differences between the groups in evening peak flow and in the short-term bronchodilator response to inhaled albuterol were small and judged to be clinically unimportant. CONCLUSIONS: In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis.",0
1803,8781313,Hepatitis B virus carriers without precore mutations in hepatitis B e antigen-negative stage show more severe liver damage,"Hepatitis B e antigen (HBeAg) is considered to be a major target for the immune response in chronic hepatitis B. The G-->A mutation at nucleotide 1896 may mediate viral escape by creating a TAG stop codon in the precore region, thus preventing HBeAg production. This mutation frequently evolves during HBe seroconversion if thymine, but rarely if cytosine, is present in position 1858. Applying a combination of polymerase chain reaction (PCR) and restriction enzyme action, we have studied the relation of the TAG mutation and the nucleotide (nt) 1858 variants to liver damage assessed by histology activity index (HAI) scoring in 175 chronic hepatitis B virus (HBV) carriers. A TAG mutation was found in 68 of 71 (96%) of HBeAg-negative carriers infected with a T-1858 strain, but not in any of 33 carriers infected exclusively with a C-1858 strain. Four patients showed a mutation of the precore start codon, and 2 had a TAA stop mutation at codon 2. HBeAg-positive infection with a mixture of wild-type and TAG mutant virus indicated active liver damage, because 8 of 9 (89%) of such patients had a Knodell HAI greater than or equal to 8. In HBeAg-negative stage, both inflammation and fibrosis were more pronounced in carriers infected with wild-type HBV compared with precore mutants. C-1858 strains were associated with more inflammation and fibrosis compared with T-1858 strains. C-1858 strains were found in 71% of northern European, 17% of southern European, 31% of African, 2% of Middle Eastern, and 10% of Far Eastern carriers. Analysis of these variants and mutants may prove useful for clinical evaluation and choice of therapy, and may be facilitated by the methods described.",0
1804,8781325,Immunogenicity of biliary epithelium: investigation of antigen presentation to CD4+ T cells,"The intrahepatic biliary epithelium is susceptible to extensive T-cell-mediated damage during primary biliary cirrhosis, primary sclerosing cholangitis, and hepatic allograft rejection. During these processes, human intrahepatic biliary epithelial cells (HIBEC) become activated and express high levels of the lymphocyte adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and lymphocyte-associated antigen (LFA)-3, and of class II MHC antigens. It follows that activated HIBEC may also play a direct role in the activation of antigen-specific CD4+ T lymphocytes. The capacity of class II MHC antigen-expressing HIBEC to present antigen and induce specific proliferation of CD4+ T cells was examined in this study. Lines of purified HIBEC were activated by culture with the proinflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor a and were mixed in coculture with allogeneic CD4+ T cells. The result of interaction between these cells was assessed by measurement of lymphoproliferation and IL-2 production. Class II MHC antigen-expressing HIBEC failed to induce either lymphoproliferation or IL-2 production. However, both of these parameters of T-cell activation were positive in cocultures when a costimulation signal was delivered to T cells by adding bivalent anti-CD28 antibodies. The antigen-specific activation of these T cells was further enhanced by the addition of a cross-linking secondary antibody that caused CD28 receptor aggregation. The failure of cytokine-stimulated HIBEC to induce T-cell activation is consistent with the observation that HIBEC do not express the costimulatory CD28 ligands B7-1 or B7-2 at either mRNA or protein levels. It may be concluded that HIBEC are unlikely to play a direct role in activation of antigen-specific CD4+ T lymphocytes within the inflamed liver.",0
1805,8781326,"Bile ductule formation in fetal, neonatal, and infant livers compared with extrahepatic biliary atresia","The cell of origin of intrahepatic bile ducts during fetal development remains a subject of controversy, although there has been recent evidence that they form from hepatocytes. However, the origin of neoductules and ducts in the setting of liver disease has not been extensively investigated in humans. Using anticytokeratins characteristic of hepatocytes and bile ducts, we repeated earlier studies of fetal development to compare ductule formation in normal developing and newborn livers with the ductules formed during extrahepatic biliary atresia. We utilized an antibody to proliferating cell nuclear antigen (PCNA) staining to determine which cells were in active DNA synthesis (S phase) during fetal development and liver disease progression. The results indicated that hepatocytes undergo a phenotypic switch (metaplasia) to form ductular cells during fetal development. There was no ductular cell replication in the fetal livers. In contrast, both bile ductular metaplasia and proliferation were observed in biliary atresia. Therefore, both a limiting plate phenotypic switch to ductules and replication of ductular cells play a role in the increase in the ductules seen in the progression to biliary cirrhosis. Bile ductular proliferation in biliary atresia, however, was less than that seen in hepatocytes, whereas the number of bile ductules increased and the relative proportion of hepatocytes diminished as the accompanying periductular fibrosis progressed to cirrhosis.",0
1806,8782499,The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies,"BACKGROUND: There is no practical and reliable premortem test for Creutzfeldt-Jakob disease and the related transmissible spongiform encephalopathies. Two proteins, designated 130 and 131, which have been detected in low concentrations in cerebrospinal fluid from patients with Creutzfeldt-Jakob disease, appear to be sensitive and specific markers for the disease. Attempts to identify these proteins, however, have been unsuccessful. We hypothesized that they may be present in the normal brain. METHODS: We detected proteins 130 and 131 in normal human brain, partially sequenced their amino acids, and found that they matched the brain protein known as 14-3-3. We then developed a simple, rapid immunoassay for this protein and tested it in cerebrospinal fluid samples from 71 humans and 30 animals with spongiform encephalopathies and in control samples from 186 humans and 94 animals. RESULTS: The immunoassay detected the 14-3-3 protein in cerebrospinal fluid from 68 of the 71 patients with Creutzfeldt-Jakob disease (96 percent, 95 percent confidence interval, 92 to 99 percent). Among 94 patients with other dementias, the specificity was 96 percent. If one excludes the three patients with dementia who had strokes within one month before testing, the specificity was 99 percent. The test was positive in 12 of 24 patients with viral encephalitis. In animals the sensitivity of the assay was 87 percent and the specificity was 99 percent. CONCLUSION: In patients with dementia, a positive immunoassay for the 14-3-3 brain protein in cerebrospinal fluid strongly supports a diagnosis of Creutzfeldt-Jakob disease. This finding, however, does not support the use of the test in patients without clinically evident dementia.",0
1807,8793929,The effect of legislative requirements on the use of breast-conserving surgery,"BACKGROUND: We studied the effect of state legislation requiring the disclosure of options for the treatment of breast cancer on the use of breast-conserving surgery in clinical practice. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results registry provided data on women from 30 through 79 years of age who underwent breast-conserving surgery or mastectomy for local or regional breast cancer from 1983 through 1990. We examined the trend over time in use of breast-conserving surgery among patients in four sites (Connecticut, Iowa, Seattle, and Utah) where there were no state laws specifically requiring the disclosure of options for the treatment of breast cancer by physicians. For four additional sites (Detroit, Atlanta, New Mexico, and Hawaii) that had such legislation, we determined whether the rate of breast-conserving surgery after the legislation was different from the expected rate. RESULTS: An attorney rated the legislation as giving most direction to physicians in Michigan, followed by Hawaii, Georgia, and New Mexico. The rate of breast-conserving surgery was up to 8.7 percent higher than expected in Detroit for six months after the passage of the Michigan law (P<0.01). The rate was up to 13.2 percent higher than expected in Hawaii for 12 months after that state's law was passed (P<0.05) and up to 6.0 percent higher than expected in Atlanta for 3 months after the passage of the Georgia law (P<0.01). After these transient increases, the surgery rates reverted to the expected levels. No significant effect was detected in New Mexico, where only a resolution without legal force was passed. CONCLUSION: Legislation requiring physicians to disclose options for the treatment of breast cancer appeared to have only a slight and transient effect on the rate of use of breast-conserving surgery.",0
1808,8813039,The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team,"BACKGROUND: We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175. METHODS: The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype. RESULTS: After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome. CONCLUSIONS: Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.",0
1809,8841988,Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis,"The cause of selective degeneration of motor neurons in the ventral horn of the spinal cord associated with amyotrophic lateral sclerosis (ALS) has still not been elucidated. Recently, so-called oxidative stress has been suggested to be a significant factor in the pathogenesis of this disease. We measured the antioxidant actions of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and cytochrome c oxidase (CO) of the human spinal cord in patients with ALS in comparison with those in control patients. Total SOD activity in spinal cord transections from patients with sporadic ALS was not significantly different from the controls in ventral, lateral, or dorsal regions, although enzymic activity was relatively higher in the ventral compared with the dorsal region. GSH-Px activity in the spinal cord of ALS patients was not very different from that in the control tissue. In contrast, CO activity was significantly reduced in all three regions of the spinal cord in patients with ALS, although the reduction was more marked in the ventral region. These results suggest that reactive oxygen species may attack the mitochondrial respiratory chain, leading eventually to the degeneration of vulnerable motor neurons in the spinal cord, even though no obvious changes in the activity of antioxidant enzymes are detectable. ",0
1810,8841996,Downregulation of muscarinic M2 receptors linked to K+ current in cultured guinea-pig atrial myocytes,"1. Desensitization of muscarinic K+ current (IK(ACh)) was studied in cultured atrial myocytes from guinea-pig hearts using whole-cell voltage clamp. 2. Three different types of desensitization could be identified. A fast component which upon rapid superfusion with ACh resulted in a partial relaxation of IK(ACh) within a few seconds to a plateau which was maintained in the presence of ACh. Recovery from this type of desensitization paralleled the decay of IK(ACh) after washout of the agonist. A second type of desensitization was observed within minutes. This was reversed around 10 min after washout of ACh. Both types were heterologous with regard to the A1 receptor and the novel phospholipid (Pl) receptor, both of which activate IK(ACh) via the same signalling pathway. 3. A third type of desensitization (downregulation) occurred upon exposure of the cultures for 24-48 h to the muscarinic agonist carbachol (CCh). The level of downregulation depended on the concentration of CCh (0.1 microM < or = [CCh] < or = 10 microM). No recovery was observed within 5 h after washout of CCh. Thereafter sensitivity to ACh slowly returned (half-time (t1/2), approximately 20 h). 4. Downregulation by CCh (0.1-5 microM) was characterized by an increase in EC50 for ACh with no reduction in maximum IK(ACh). With 5 microM CCh, EC50 was increased from 0.1 to 3.7 microM. At 10 microM CCh EC50 was increased to 15 microM and maximal current that could be evoked by ACh was reduced to 15%. 5. Downregulation by CCh was homologous with regard to A1 and Pl receptors. Maximum IK(ACh), assayed by a saturating concentration of Pl, was not reduced in downregulated cells, suggesting a mechanism localized at the M2 receptor. 6. The changes in the concentration-response curves can be accounted for by assuming an excess of M2 receptors relative to the subsequent component of the signalling pathway. 7. As the intact heart is under tonic vagal control, downregulation is likely to contribute to controlling the sensitivity of the heart to vagal activity in situ. ",0
1811,8842155,Cloning and molecular analysis of cDNAs encoding three sucrose phosphate synthase isoforms from a citrus fruit (Citrus unshiu Marc.),"Three partial cDNA clones (pSPS1, pSPS2 and pSPS3) encoding sucrose phosphate synthases (SPS) were isolated by Reverse Transcription (RT)-PCR using first-strand cDNA prepared from the leaf or fruit of citrus (Citrus unshiu Marc.). The nucleotide and deduced amino acid sequences of the three clones showed significant similarities to SPS previously isolated in other plants. A full-length, cDNA clone, CitSPS1, was isolated from a fruit (juice sacs and pulp segment) cDNA library using one (pSPS1) of the three partial clones as a probe. The 3539-bp CitSPS1 clone coded for a 1057-amino acid polypeptide with a predicted molecular mass of 117.8 kDa. The amino acid sequence deduced from the CitSPS1 clone showed homology with SPS from maize (55.8% identity) and spinach (74.0% identity). Genomic Southern blot analysis suggested that CitSPS1 clone represents a lowcopy-number gene. RNA blot analysis of leaf, flower and fruit showed that CitSPS1 and pSPS2 were expressed in all organs. However, the levels of expression of CitSPS1 in young leaves, flowers and immature fruits were low, but high in mature leaves, and fruit. pSPS2 transcripts were barely detectable in young leaves and immature fruits, low in mature leaves, and high in flowers and mature fruits. pSPS3 transcripts were only detected in young and in mature leaves. ",0
1812,8842508,"Electrophysiologic mechanisms of adverse effects of class I antiarrhythmic drugs (cibenzoline, pilsicainide, disopyramide, procainamide) in induction of atrioventricular re-entrant tachycardia","We evaluated the electrophysiological mechanisms of adverse effects of class I antiarrhythmic drugs (cibenzoline in seven patients, pilsicainide in two, and disopyramide in two, and procainamide in three) in the induction of orthodromic atrioventricular re-entrant tachycardia (AVRT). In 14 patients (10 males, 4 females; mean age 37 +/- 18 years) who had inducible AVRT despite the administration of class I drugs, electrophysiological effects of class I antiarrhythmic drugs were evaluated using programmed electrical stimulation techniques. In 4 out of 6 patients with a manifest accessory pathway, class I drugs induced unidirectional conduction block of the accessory pathway (antegrade conduction block associated with preserved retrograde conduction) and enhanced the induction of AVRT with atrial extrastimulation. In eight patients with a concealed accessory pathway, the outward or inward expansion of the tachycardia induction zone was observed in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs. During ventricular extrastimulation, the induction of bundle branch re-entry after class I drugs initiated the AVRT in patients with either manifest or concealed accessory pathways. We conclude that the adverse effects of class I drugs are mainly due to induction of unidirectional retrograde conduction of the manifest accessory pathway and the greater prolongation of the retrograde conduction time of the concealed accessory pathway than the refractory period, regardless of the sub-classification of class I drugs. ",0
1813,8842686,Effects of oxotremorine and pilocarpine on striatal acetylcholine release as studied by brain dialysis in anesthetized rats,"1. The effects of oxotremorine and pilocarpine on striatal acetylcholine (ACh) release were investigated using brain microdialysis techniques in urethan-anesthetized rats. 2. Oxotremorine (0.1 and 0.5 mg/kg, IV), a preferential M2 agonist, dose-dependently decreased ACh release in the striatum. On the other hand, pilocarpine, at 5 mg/kg (IV), showed a tendency to decrease ACh release in the striatum but, at 7.5 and 10 mg/kg (IV), significantly enhanced release in a dose-dependent manner. 3. The effect of oxotremorine was blocked by scopolamine (0.1 mg/kg, IV) but not by pirenzepine (10 mg/kg, IV), a selective M1 antagonist. 4. Pilocarpine (10 mg/kg, IV) enhancement of striatal ACh release was not affected by 10 mg/kg pirenzepine, but 5 mg/kg pilocarpine significantly increased ACh release in scopolamine (0.1 mg/kg)-pretreated rats without affecting the release by itself. 5. These results suggest that oxotremorine-induced decrease in striatal ACh release is due to stimulation of presynaptic M2 autoreceptor, and that the increase of striatal ACh release by pilocarpine is mediated by mechanism(s) other than effects on muscarinic ACh receptors. ",0
1814,8843144,High-performance liquid chromatographic assay for the quantitation of L-arginine in human plasma,"L-Arginine is metabolized to nitric oxide by nitric oxide synthase, and abnormalities in nitric oxide production have been implicated in the pathogenesis of some diseases involving the vasculature. Thus, there has been interest in the effects of pharmacologic doses of L-arginine in patients with cardiovascular and renal diseases. To study the disposition of exogenous doses, an HPLC method was developed to analyze plasma samples for L-arginine. The assay involves precolumn derivatization of arginine with naphthalenedicarboxaldehyde and cyanide followed by HPLC with UV detection. Only a simple deproteinization of the plasma samples was required. The derivatized arginine was stable (less than 5% degradation in 20 h), facilitating batch sample processing and analysis in an autosampler. Calibration curves were generated in Ringer's lactate solution instead of plasma to correct for endogenous plasma L-arginine. Recovery in plasma, compared to Ringer's solution (n = 4), was 103%. Mean intraday assay precision (n = 6), expressed as coefficient of variation, was 3.4%. Interassay precision (n = 6) was 7%. The assay was applied for the quantitation of L-arginine in plasma samples from a normal subject who had been given a single oral (10 g) and a single intravenous dose (30 g) of exogenous L-arginine. ",0
1815,8843287,Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system,"Macrolide-resistant Streptococcus pyogenes isolates from Finland, Australia, and the United Kingdom and, more recently, Streptococcus pneumoniae and S. pyogenes strains from the United States were shown to have an unusual resistance pattern to macrolides, lincosamides, and streptogramin B antibiotics. This pattern, referred to as M resistance, consists of susceptibility to clindamycin and streptogramin B antibiotics but resistance to 14- and 15-membered macrolides. An evaluation of the macrolide-lincosamide-streptogramin B resistance phenotypes among our streptococcal strains collected from 1993 to 1995 suggested that this unusual resistance pattern is not rare. Eighty-five percent (n = 66) of the S. pneumoniae and 75% (n = 28) of the S. pyogenes strains in our collection had an M phenotype. The mechanism of M resistance was not mediated by target modification, as isolated ribosomes from a pneumococcal strain bearing the M phenotype were fully sensitive to erythromycin. Further, the presence of an erm methylase was excluded with primers specific for an erm consensus sequence. However, results of studies that determined the uptake and incorporation of radiolabeled erythromycin into cells were consistent with the presence of a macrolide efflux determinant. The putative efflux determinant in streptococci seems to be distinct from the multicomponent macrolide efflux system in coagulase-negative staphylococci. The recognition of the prevalence of the M phenotype in streptococci has implications for sensitivity testing and may have an impact on the choice of antibiotic therapy in clinical practice. ",0
1816,8843455,"Human papillomavirus expression in oral mucosa, premalignant conditions, and squamous cell carcinoma: a retrospective review of the literature","The literature of human papillomavirus detection in normal oral mucosa and oral lesions associated with the dysplastic progression of epithelium was reviewed to help define the role of this virus in the development of oral squamous cell carcinoma. All available data from published studies were analyzed by chi-square test for association between the human papillomavirus and age, gender, race, DNA type, location, lesional dysplastic progression, method of detection, tissue preservation, and use of tobacco and alcohol. Human papillomavirus was identified with increasing frequency in normal oral mucosa (13.5%), benign leukoplakia (14.8%), intraepithelial neoplasia (18.5%), squamous carcinoma (26.2%), and verrucous carcinoma (27%). It was detected in oral squamous cell carcinoma significantly (p < 0.005) more often (37.1%; 122 of 329) in studies that used a high sensitivity assay (polymerase chain reaction) than studies that used moderate sensitivity assays (25.2%; 84 of 334) (e.g., Southern blot hybridization) and low sensitivity assays (16.9%; 61 of 362) (e.g., immunohistochemistry, in situ hybridization). Human papillomavirus DNA was detected significantly more often (p < 0.001) in frozen oral squamous cell carcinoma (51.6%; 115 of 223) than paraffin-embedded tissue (21.7%; 136 of 628). High-risk human papillomaviruses (2, 16, 18) were detected in 81.4% of OSCCs that contained the virus compared with low-risk human papillomavirus genotypes (6, 11) in 17.9% of oral squamous cell carcinoma that contained the human papillomavirus (p < 0.001). In studies that analyzed the use of chemical cofactors, the use of tobacco and alcohol (87.3%) was associated more often with oral squamous cell carcinoma than the presence of human papillomavirus (51.3%), however, the difference was not significant. High-risk human papillomavirus genotypes have a significant association with oral squamous cell carcinoma. However, the presence of this virus in a high proportion of oral normal mucosa makes the virus alone a poor prognosticator of progression to malignancy. ",0
1817,8843674,Kinetic study on the cis-trans isomerization of peptidyl-proline dipeptides,"The equilibrium and kinetic parameters of cis-trans interconversion of dipeptides containing peptidyl-proline moiety were investigated using the in-column incubation method with both CZE and HPLC and the ad hoc dissolution method. The use of the latter was possible because the conformational make-up of the solid peptides, and consequently of their ad hoc solution, was sufficiently different from that of the solution at equilibrium. This method with 1H-NMR and CZE analyses yielded very similar results for the cis-trans isomerization of Phe Pro in aqueous sodium borate, pH 8.4, at 10 degrees C with an average value of 0.34 and 6.6 x 10(-5) s-1 for the equilibrium and rate constant, respectively. The in-column incubation method is performed by CZE or HPLC so that the conformers are separated in the first half of the column and then incubated in column where they interconvert and reach equilibrium. Subsequent separation in the second half of the column yielded four peaks. Thus by measuring the conformer composition as a function of the reaction time, the rate constant can be evaluated. The forward rate constant of 1.42 x 10(-4) s-1 determined by the CZE in-column incubation method for Phe-Pro isomerization at 10 degrees C was twice of the value obtained by the ad hoc dissolution method. It is believed that the inner wall of fused-silica capillaries has a catalytic effect on the isomerization. Computer simulation was also employed to gain further insight on the catalytic activity of the capillary inner wall on such isomerization. Whereas the experimental and simulation profiles of Phe-Pro in aqueous borate buffer, pH 8.4, with a 37 cm long capillary were in excellent agreement, a four times faster interconversion rate had to be used to match the experimental profile obtained with a 57 cm long capillary under otherwise identical conditions. The catalytic effect of the octadecyl silica stationary phase on the isomerization was confirmed by the in-column incubation method with HPLC. The overall rate of the cis-trans isomerization of Phe-Pro, which entails the reaction both on the stationary phase and in the mobility phase, was about six times faster at 0 degree C than the rate measured by NMR in free solution using the mobile phase containing 65% (v/v) sodium phosphate, pH 6.5, and 35% (v/v) methanol. The results presented here serve as a caveat that the effect of the wall in CZE or the stationary phase in HPLC on the reaction cannot be ignored. ",0
1818,8843680,Fluorescence-based polymerase chain reaction-single-strand conformation polymorphism analysis of p53 gene by capillary electrophoresis,"Mutation of the p53 gene plays an important role in neoplastic progression in human tumorigenesis. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) techniques are now available for the detection of point mutations. The original method using polyacrylamide gel electrophoresis is disadvantageous, particularly for clinical tests and for analysis of large numbers of samples. Therefore, using an automated capillary electrophoresis (CE) technique with a molecular-sieving polymer solution, we have devised a completely automatic fluorescence-based PCR-SSCP system (CE-FSSCP) for the differential detection of point mutations that dose not require SSCP with radioisotopes and polyacrylamide gels. The automatic CE-FSSCP system was developed for reproducible operations in the denaturation of double-stranded DNA and electrophoresis of single-stranded DNA. The detection system consists of a 100 W I2 lamp and photomultiplier. We performed CE-FSSCP with a 2% linear polyacrylamide polymer solution containing 5% glycerol. Four tissue specimens of lung tumors with mutations in exon 7 of the p53 gene were found to have mutant alleles; six-base-pair deletion at codons 247-248, a one-base-pair deletion at codon 260, a one-base-pair deletion at codon 244 and a GGC to CGC substitution at codon 244. We expect this technique to prove useful for the clinical DNA diagnosis of human cancers, determination of the therapeutic effect of anticancer agents and for the study of the molecular aspects of the mechanisms involved in the pathogenesis of human cancers. ",0
1819,8843810,Post-malaria neurological syndrome,"Neurological signs and symptoms are common in malaria, but observations in Vietnam and Thailand have pointed to a discrete transient neurological syndrome after recovery from severe infections. A prospective study of the post-malaria neurological syndrome (PMNS) was conducted at two centres in Vietnam over four years. Criteria for inclusion were recent symptomatic malaria infection with parasites cleared from blood (and in cases of cerebral malaria full recovery of consciousness), and development of neurological or psychiatric symptoms within two months after the acute illness. Half of the patients with severe falciparum malaria had been taking part in a randomised trial of antimalarials. Of 18,124 patients with falciparum malaria treated (1176 of whom had severe infections) 19 adults and three children had subsequent PMNS; in one patient it followed uncomplicated malaria and in 21 it followed severe malaria. The overall incidence (95% confidence interval) of PMNS after falciparum malaria at the main study centre was 1.2 per 1000 (0.7 to 1.8 per 1000) and relative risk (95% CI) for developing PMNS after severe versus uncomplicated falciparum malaria was 299 (40 to 2223). 13 patients had an acute confusional state or psychosis, six had one or more generalised convulsions, two had generalised convulsions followed by a long period of acute confusion, and one developed a fine tremor. At the time of PMNS diagnosis all patients were aparasitaemic. The syndrome was self-limiting, median duration 60 h (range 24-240). PMNS was associated with the use of oral mefloquine. In the randomised trial 4.4% (10/228) of patients with severe malaria who received mefloquine after parenteral treatment developed PMNS compared with 0.5% (1/210) of those who received quinine; relative risk 9.2 (95% CI 1.2 to 71.3, p = 0.012). Mefloquine is not the only risk factor for PMNS but it is a strong one. Where an effective alternative drug is available, mefloquine should not be used after treatment of severe malaria. ",0
1820,8843941,Characterization of Vitis vinifera L. glutamine synthetase and molecular cloning of cDNAs for the cytosolic enzyme,"Grapevine (Vitis vinifera L.) glutamine synthetase (GS) was analysed into two distinct classes of isoforms; one of them was present in both leaf and root tissues while the other one showed leaf specificity. Western blot analysis revealed that grapevine GS consists of three types of polypeptides of distinct size and differential tissue specificity. Two structurally distinct cDNA clones, pGS1;1 and pGS1;2, encoding grapevine GS were isolated from a cell suspension library and characterized. Both clones contained open reading frames encoding for polypeptides of 356 amino acids with a predicted molecular mass of about 39 kDa. Although the coding sequences of pGS1;1 and pGS1;2 were 84% similar, their 5'- and 3'-untranslated sequences showed only 40% similarity. The coding sequences of the two clones and the derived amino acid sequences showed higher homology to cytosolic than to chloroplastic GSs of other higher plants indicating that the cDNAs isolated encode for cytosolic isoforms of grapevine GS. Southern blot analysis suggested the existence of more than two GS genes in the grapevine genome. In northern blots both clones were hybridized to mRNAs of about 1.4 kb that are differentially expressed in the various tissues. Supply of nitrate or ammonium in the cell suspension culture medium, as a sole nitrogen source, resulted in differential response of the pGS1;1- and pGS1;2-related genes. ",0
1821,8843948,Identification of an immediate-early salicylic acid-inducible tobacco gene and characterization of induction by other compounds,"Tobacco genes that are induced in response to salicylic acid (SA) treatment with immediate-early kinetics were identified by differential mRNA display. Detailed analysis of IS10a, one cDNA clone identified by this method, revealed induction within 30 min of treatment, with a peak of expression at 3 h, that decayed rapidly thereafter. Treatment with the protein synthesis inhibitor, cycloheximide (CHX), also caused induction of IS10a mRNA to comparable levels, but the IS10a mRNA continued to accumulate after 3 h of induction. In combination, CHX and SA led to a superinduction of IS10a mRNA levels that was also sustained. Half-maximal induction was evident at ca. 100-150 microM SA. In addition to SA, induction of IS10a occurred to varying degrees upon treatment with acetylsalicylic acid, benzoic acid, 2,4-dichlorophenoxyacetic acid, methyl jasmonate, and hydrogen peroxide, whereas treatment with other compounds had no effect. The proteins encoded by IS10a and a second highly homologous cDNA show sequence similarity to UDP-glucose: flavonoid glucosyltransferases. ",0
1822,8844087,Experiences and attitudes concerning genetic testing and insurance in a Colorado population: a survey of families diagnosed with fragile X syndrome,"This study examined the relationship between diagnosis, experience with insurance underwriting, and perceptions of difficulties with insurance in genetically tested families. Discrimination was strictly defined as the misuse of genetic information in underwriting. Forty-eight families received a survey and thirty-nine (81%) responded. No insurance cancellations were reported although many families believed that it happened often. The fear evidenced by the respondents was out of proportion to the experiences and 66% of the families reported moderate to moderate to extreme worry over losing health insurance. Genetic counselors and others involved in caretaking of diagnosed families must expand their roles to assist in providing access to local resources and information concerning insurance issues and other social issues. Addressing medical issues alone will not provide the assistance these families require. ",0
1823,8844093,Severe mental retardation and macroorchidism without mutation in the FMR1 gene,"""Only one missense mutation, an Ile304Asn, has been reported in the fragile X gene (FMR1). This mutation is located in the second KH domain of FMR1, and has led to the discovery of the function of the FMR1 gene product as an RNA-binding protein. The patient carrying this mutation has profound mental retardation, macroorchidism, and an """"acromegalic"""" face with prominent supraorbital ridges, enlarged jaw, heavy brow ridges, thick lips, and a broad nose. We have studied the possible involvement of FMR1 in two maternal half-brothers with a phenotype similar to that of the patient with the Ile304Asn mutation. Both brothers had an identical number of CGG repeats in the normal size-range, and shared the same maternal Xq27 haplotype. Southern blot analysis with two overlapping FMR1 cDNA clones, spanning the total FMR1 open reading frame, showed no major deletions, insertions, or gross rearrangements. Single-strand conformation pattern (SSCP) analysis of the KH domains showed no aberrant patterns. The total open reading frame of the FMR1 gene was cloned and sequenced, but no mutation was found. Northern blot analysis showed mRNA in the normal size-range, and immunocytochemistry on individual lymphocytes indicated that FMRP, the protein product of FMR1, was present. In conclusion, it is unlikely that FMR1 plays a role in the phenotype of this patient. Other genes may be responsible for the combination of mental retardation and macroorchidism. """,0
1824,8844429,High-performance liquid chromatography using on-line solid-phase extraction: determination of furosemide in human serum,"An on-line solid-phase extraction technique based on column switching (heart-cutting) was developed for direct injection analysis of furosemide in human serum. In order to minimize the influence of deterioration in pre-treatment column efficiency, which was caused by protein precipitation with repeated injections of serum, furosemide was completely enriched at the top of the analytical column by ion-pair formation with tetra-n-butylammonium ion during heart-cutting. The robustness of the established on-line solid-phase extraction system was confirmed under routine conditions. As a result, almost comparable chromatograms could be obtained even though 50 repeated injections of a 100-microliter volume of serum were carried out using one pre-treatment column. The linearity of the calibration curves was demonstrated by the correlation coefficient which was greater than 0.99999 (5-1000 ng/ml). The relative errors and C.V. of quality control samples were within 4.00 and 5.88%, respectively (furosemide concentrations: 5, 100 and 1000 ng/ml). ",0
1825,8844431,Analytical procedure for the determination of 1-octacosanol in plasma by solvent extraction and capillary gas chromatography,"A simple and rapid method for the determination of 1-octacosanol in plasma, based on an improved Folch extraction technique and capillary gas chromatography, has been developed taking into account the analytical criteria for the pharmacokinetic studies. The procedure was validated in the range of 50-2000 ng/ml. Despite the complexity of the obtained fingerprints, the efficiency and the separation power of GC allowed the determination of 1-octacosanol in plasma samples. The high recoveries (94.5-98.7%) and precision (1.8-5.8%) obtained are in accordance with the established validation criteria. The validity of this method for pharmacokinetic purposes was shown using an endovenous experiment in animals. ",0
1826,8844508,Structure of allotransplanted ganglia and regenerated neuromuscular connections in crayfish,"In adult crayfish, Procambarus clarkii, motoneurons to a denervated abdominal superficial flexor muscle regenerate long-lasting and highly specific synaptic connections as seen from recordings of excitatory postsynaptic potentials, even when they arise from the ganglion of another crayfish. To confirm the morphological origins of these physiological connections we examined the fine structure of the allotransplanted tissue that consisted of the third abdominal ganglion and the nerve to the superficial flexor muscle (the fourth ganglion and the connecting ventral nerve cord were also included). Although there is considerable degeneration, the allotransplanted ganglia display intact areas of axon tracts, neuropil, and somata. Thus in both short (6-8 weeks) and long (24-30 weeks) term transplants approximately 20 healthy somata are present and this is more than the five axons regenerated to the host muscle. The principal neurite and dendrites of these somata receive both excitatory and inhibitory synaptic inputs, and these types of synaptic contacts also occur among the dendritic profiles of the neuropil. Axon tracts in the allotransplanted ganglia and ventral nerve cord consist largely of small diameter axons; most of the large axons including the medial and lateral giant axons are lost. The transplanted ganglia have many blood vessels and blood lacunae ensuring long-term survival. The transplanted superficial flexor nerve regenerates from the ventral to the dorsal surface of the muscle where it has five axons, each consisting of many profiles rather than a single profile. This indicates sprouting of the individual axons and accounts for the enlarged size of the regenerated nerve. The regenerated axons give rise to normal-looking synaptic terminals with well-defined synaptic contacts and presynaptic dense bars or active zones. Some of these synaptic terminals lie in close proximity to degenerating terminals, suggesting that they may inhabit old sites and in this way ensure target specificity. The presence of intact somata, neuropil, and axon tracts are factors that would contribute to the spontaneous firing of the transplanted motoneurons. ",0
1827,8844753,Itraconazole responsive tinea capitis in an HIV-infected child,"Tinea capitis has not been reported to be a prevalent or serious affliction in pediatric patients infected with the human immunodeficiency virus (HIV). We report tinea capitis due to Microsporum canis in a boy infected with HIV. After failing conventional therapy, he was treated successfully with a four-week course of itraconazole. His immunologic status improved during therapy. The possible relationship of this response to the ultimate resolution of disease is discussed. ",0
1828,8844909,"Temporomandibular pain and dysfunction syndrome. History, physical examination, and treatment","A stepwise method for treating TMPDS is presented. Step 1-start patient on a regimen of chloroethane or chlorofluorocarbon spray and exercise. Step 1A--if a clicking joint is the chief complaint, start with click exercise. Step 1B--if restricted mouth opening is the chief complaint, start with range of motion exercise; employ exercises sequentially, not simultaneously. Step 2--if pain is moderate to severe, start with amitriptyline 10 mg at bedtime, increasing the dose in 10-mg increments to 40 mg. Step 3--for nonresponders, add injections of tender points with lidocaine and consider a trial of a different tricyclic. Step 4--for nonresponders, consider a trial of tender point injections combining dexamethasone with local anesthetic. Start by injecting the three most painful tender points with 0.5 mL of a solution of 1 mg of dexamethasone combined with two thirds bupivacaine and one third lidocaine to reach the desired volume. Repeat injections, varying the sites as required. Do this once weekly for 4 to 6 weeks for an adequate trial. This regimen can be continued for an extended period of time with appropriate precautions in place. The value of judgment-free psychosocial support cannot be overemphasized. Patients with TMPDS are faced with long-term problems of pain management. An understanding clinician can provide the sustained support required to prevent the cycle of ever more invasive treatments with their potential for harm. ",0
1829,8844961,Studies of mechanoreceptors in skin of the snout of the echidna Tachyglossus aculeatus,"The echidna Tachyglossus aculeatus, together with the platypus, belongs to the monotremes, a group of mammals with a number of reptilian characteristics. A structure unique to the skin of monotremes is the push rod-a compacted column of epidermal cells that is 20 microns wide and 100 microns long with its tip at the skin surface, and that is able to move relatively independently of adjacent tissue. At the base of each push rod is a cluster of encapsulated nerve endings. Push rods are common in skin of the snout and have been postulated to have a mechanosensory function. Experiments were carried out on four anesthetized echidnas with the aim of determining the function of push rods. Recordings made from the infraorbital nerve, which supplies the skin of the upper jaw, yielded responses from a total of 46 afferents. Two were electroreceptors; the others were mechanoreceptors. Within the group of mechanoreceptors with rapidly adapting responses, three responded to high-frequency vibration and resembled pacinian corpuscles. There were 26 slowly adapting (SA) mechanoreceptors, which, based on the regularity of their discharge, could be divided into two groups: SA I or Merkel type, and SA II or Ruffini type. SA I receptors had very discrete receptive fields with diameters of 100 microns. The receptive fields of two SA I receptors were marked, and after histological processing, one was seen to lie near two push rods. It is concluded that mechanoreceptor responses in the echidna's snout skin resemble those in other mammals in many aspects. We could not unequivocally associate responses to mechanical stimulation with the push rods. ",0
1830,8845240,The fine structure of dexamethasone-induced growth hormone cells in the anterior pituitary gland of the rat fetus,"The effect of synthetic glucocorticoid, dexamethasone (DEX), on the fine structure of the fetal growth hormone (GH) cell was examined in rats on Days 17-19 of gestation by the protein A-gold method of immuno-electron microscopy. GH cells appeared on Day 19 in the control fetuses. The DEX-induced GH cells of Day 17 fetuses displayed more immature features than those of Day 18, which closely resembled GH cells found in the control fetus on Day 19. Cytological changes which indicate increased secretory activity such as the development of the rough endoplasmic reticulum or enlargement of the Golgi complex, and an accumulation of secretory granules were evident only in the DEX-treated fetuses on Day 19. It is concluded that DEX not only accelerates the development of GH cells, as observed on Day 17 or 18, but also brings them to a functionally stimulated state by Day 19. ",0
1831,8845258,Radiation-induced skin injury after percutaneous transluminal coronary angioplasty. Case report,"A 58-year-old man underwent percutaneous transluminal coronary angioplasties in June 1992 and May 1993. Approximately 3 weeks after the last procedure, a cutaneous lesion developed into an ulcer over the right scapular region. The ulcer failed to heal with conservative treatment; therefore, surgical excision was performed. The localization and the course of the development indicated injury caused by radiation, and this was confirmed by the histologic examination. To avoid such injury in interventional procedures with long fluoroscopic time, several precautions should be taken. These include continuous surveillance of the X-ray dosage, the use of different projections to avoid exposure to one skin area throughout the whole procedure, keeping the irradiated area as small as possible, and good planning of the procedure. ",0
1832,8845381,High-ionic strength interference of ribosomal inhibition produced by aminoglycoside antibiotics,"A protein synthesis cell-free system capable of performing with similar efficiencies in different ionic conditions has been developed for the halotolerant marine bacterium Vibrio costicola. The system has been used to test the effect of ionic strength on the interference produced by thirty translation inhibitors with different structural, functional, and domain specificities. In general, at high ionic strengths, the inhibition of protein synthesis produced by polycationic antibiotics like the aminoglycosides is much less pronounced than the inhibition obtained at low ionic strengths, while non-aminoglycosidic antibiotics show similar inhibitory activities at both high and low ionic conditions. These results strongly suggest that competition between polycationic antibiotics and cations at high concentrations in the media is responsible for the lack of inhibition by aminoglycoside antibiotics at high ionic strengths, rather than a lack of binding sites. ",0
1833,8845499,Increased ERCP rate following the introduction of laparoscopic cholecystectomy,"Over the past 5 years there has been a remarkable change in the manner in which symptomatic gallstones are surgically managed. In this study we reviewed the experience of a large HMO to determine the relationship between the rate of increase of ERCP and that of cholecystectomy. All individuals enrolled in US Healthcare's HMO-PA, in the region of southeastern Pennsylvania from 1988 through 1993, were included in the analysis. Using the HMO claims database, patients who underwent an open or laparoscopic cholecystectomy during the study period were identified. We then identified those patients who had a pre- or post- operative ERCP. Over the study period, there has been a substantial increase in cholecystectomies per 1000 members-from 1.37 in 1988 to 2.16 (p < 0.0001) in 1993. In our study population there were 1261 ERCPs performed in 979 patients with an average of 1.3 ERCPs per patient during the study period. The ERCP rate per 1000 members has increased from 0.16 to 0.56 (p < 0.0001) from 1988 to 1993, at the same time that the cholecystectomy rate was substantially increasing. The correlation for the ERCP and cholecystectomy rates from 1988 to 1993 was 0.994 (p < 0.0001). Since the introduction of laparoscopic cholecystectomy in 1989-1990, many more ERCPs are now being performed. It is necessary to determine the implications related to the rapid diffusion of laparoscopic cholecystectomy, including the effect that this technology has had on other older and stable technologies such as ERCP. Our results describe the dramatic effect that laparoscopic cholecystectomy has had on the utilization of ERCPs. ",0
1834,8845567,Lactate production of mammalian intestinal and vascular smooth muscles under aerobic and hypoxic conditions,"Lactate liberation from thoracic aortas and intestinal smooth muscles of the guinea pig, rabbit and rat, as well as coronary arteries of the dog were determined'under aerobic and hypoxic conditions (95% N2 instead of O2). In all smooth muscles tested, the lactate liberation was inhibited in the presence of oxygen, being known as the Pasteur effect. The rates of lactate release from guinea pig aortas and taenia caeci under hypoxia were approximately 10 times greater than those under aerobic conditions. The rate of lactate release from other smooth muscles tested were 3-4 times greater under hypoxic than aerobic conditions. The extent of Pasteur effect was not affected by a removal of adventitial layer from the rabbit aorta nor by the different size of the dog coronary arteries. These results suggest that taenia caeci and aortas of the guinea pig intrinsically possess a strong regulatory system in the glycolytic activity, being highly sensitive to the presence of oxygen. ",0
1835,8845572,The role of chemotherapy in the treatment of multiple myeloma,"Plasma cell neoplasms often present in an asymptomatic, stable phase. Treatment should not be started until manifestations, such as bone pain, increased susceptibility to infections, renal failure, anaemia and weight loss, announce that the disease has progressed to the MM phase. Conventional therapy with melphalan and prednisone results in objective improvement in about 50% of patients and improves median survival to about 32 months from the start of treatment. Induction therapy should be continued until the M-protein reaches a stable plateau that lasts for at least 4 months. Maintenance therapy with melphalan prolongs the duration of the initial response, but does not improve overall survival, in comparison with patients receiving no maintenance therapy, because survival following relapse is shortened in those receiving maintenance melphalan. In two randomized clinical trials, maintenance treatment with interferon alpha prolonged remissions durations and overall survival of MM patients who responded to induction chemotherapy. Second-line treatment for MM patients who are primary refractory to melphalan, and for those who respond initially and then relapse with refractory disease, is outlined. Although long-term control is possible for a minority of patients, it is unlikely that MM can be cured with currently available chemotherapeutic agents. We need to learn more about the basic biology of the disease. ",0
1836,8845740,Regulation of intracellular [Ca2+] and GABA release by presynaptic GABAB receptors in rat cerebrocortical synaptosomes,"In this study we determined the changes in the intracellular free Ca2+ concentration, associated with the inhibitory modulation of the exocytotic release of GABA by GABAB receptor activation in rat cerebrocortical synaptosomes. We observed that SK&F 97541 and (-)baclofen both act as agonists of the presynaptic GABAB receptors in modulating GABA release and Ca2+ influx due to KCl (10 mM) depolarization, but SK&F 97541 is more potent than (-)baclofen in modulating both Ca2+ influx and GABA release. Thus, activation of GABAB receptors by either SK&F97541 (10 microM) or by (-)baclofen (100 microM) caused about 18% inhibition of the increase in [Ca2+]i, due to KCl depolarization, and inhibited the [3H]GABA release by about 30%. The pharmacological similarities of the GABAB receptor activation in producing inhibition of both calcium channel mediated influx of Ca2+ and transmitter release suggest that presynaptic inhibition of GABA release by GABAB receptor activation may result, at least in part, from inhibition of Ca2+ influx through P-type (or possibly Q-type) Ca2+ channels, sensitive to omega-Agatoxin IVA (200 nM). Furthermore, modulation of GABA release of GABAB receptors was abolished by preincubation with pertussis toxin, suggesting that a pertussis toxin sensitive G protein may be the coupling factor between GABAB receptors and the voltage-dependent Ca2+ channels associated with the exocytotic release of GABA in rat cerebrocortical nerve terminals. ",0
1837,8845760,Xylanase homology modeling using the inverse protein folding approach,"Xylanase has been used in wood pulp bleaching in an effort to reduce chlorine release into the environment and pollution associated with paper production. The three-dimensional structure of xylanase is important to enable better understanding of the enzyme mechanism and to help design a more thermostable xylanase mutant. At the time this work was begun, there was no sequence homologous protein available for traditional sequence-based homology modeling. In order to circumvent this problem, the inverse protein folding approach was undertaken to find a suitable template structure. Model structures of Bacillus circulans xylanase were built based on the data-base search results of related proteins. The model structures were refined and compared to the recently solved xylanase X-ray crystal structure. The overall structural similarity between the theoretical model and experimental structure demonstrate the usefulness of this approach. Disagreement in folding topology, however, warrants further research into the inverse protein folding approach. ",0
1838,8845864,"Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor","The interactions in vitro of LY307640 with the cytochromes P450 (P450s) were studied using human liver microsomes, specific inhibitors of the P450s, and cDNA expressed enzymes. The kinetics of formation of the two major oxidative metabolites, desmethyl LY307640 and LY307640 sulfone, were determined using two human liver microsomal samples. The kinetic data indicated that high and low affinity sites were present for the production of both metabolites of LY307640. The Km(apparent) and Vmax(apparent) for desmethyl LY307640 formation by microsomes from human liver E (HL-E) for the high affinity site were 18.8 +/- 4.4 microM and 402 +/- 52 pmol product/min/mg protein. The high affinity site Km(apparent) and Vmax(apparent) for LY307640 sulfone formation by microsomes from HL-E were 4.4 +/- 2.1 microM and 81.8 +/- 18 pmol product/min/mg protein. The rates of desmethyl LY307640 and LY307640 sulfone formation by the high affinity site were determined using 14 human liver microsomal samples characterized for P450 marker catalytic activities and immunoquantified levels of the P450s. Rates of formation of desmethyl LY307640 significantly correlated with the immunoquantified levels of CYP 2C19 and the ability of the microsomes to 4'-hydroxylate S-mephenytoin. LY307640 sulfone formation significantly correlated with the immunoquantified levels of CYP 3A and the ability of the microsomes to 1'-hydroxylate midazolam. Inhibition studies and use of expressed cytochrome P450 systems confirmed the correlation data demonstrating that CYP 2C19 catalyzed the formation of desmethyl LY307640 and CYP 3A and catalyzed LY307640 sulfone formation. Further, LY307640 competitively inhibited S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation as did the structurally related compound, omeprazole. For the inhibition of S-mephenytoin 4'-hydroxylation and midazolam 1'-hydroxylation, LY307640 had higher Ki(apparent) values than that of omeprazole. These studies demonstrate that the high affinity enzymes which catalyze the formation of the desmethyl and sulfone metabolites of LY307640 are, respectively, CYP 2C19 and CYP 3A. In addition, the inhibition data suggest that LY307640 has less potential to inhibit the metabolism of CYP 2C19 substrates compared to omeprazole, and that LY307640 and omeprazole have a similarly low potential to inhibit the metabolism of CYP 3A substrates. ",0
1839,8846315,The content of macro- and trace elements in the cardiac muscle of adult and old rats after stressor influence],"Experiments with adults (8-10 months) and old (20-24 months) male rats have permitted establishing that the stress-induced damage caused an increase in the Ca, Na content and a decrease in the K, Mg, Cu, Zn, Fe content in the cardiac muscle of experimental animals. It is important that there are certain peculiarities in changes in the heart of adult and old rats. Changes in the heart of adult animals after the stress were similar to age changes in control old animals. This confirms the V. V. Frol'kis opinion about the development of the stress-age-syndrome in old animals. The stress-induced damage causes more important changes in the content of macro- and microelements in the heart of old rats. ",0
1840,8846342,Lateral photo-color therapy in the combined ambulatory treatment of mental disorders],"""The feasibility was studied of modifying clinical effects of psychopharmacotherapy with the aid of lateral photo-colour therapy. It was shown that direct """"left hemispheric"""" lightings work towards quick reduction of depressive and anxious symptomatology, weakness, hypoasthenic disorders. Clinical time course of a whole complex of senesthopathic and hysteric signs is characterized by quantitatively variable sensitivity to direct lightings, that of problems of initiating sleep and supervalual and hypochondriacal disorders--to reverse lightings. Multimodality treatment in psychoasthenic and paranoiac-hypochondriac clinico-psychopathologic radicals failed to show superiority to an individually adequate psychopharmacotherapy. """,0
1841,8846761,Nutritional status and food security: winter nutrition monitoring in Sarajevo 1993-1994,"To monitor nutritional status and food security throughout the winter of 1993-1994 in order to provide early warning of any deterioration, identify the nutritionally vulnerable and so enable humanitarian agencies to respond appropriately. Four different household groups were prospectively followed: residents, refugees in collective centres, refugees in private accommodation and elderly living alone (either residents or refugees). Four local communities were purposively selected and two collective centres were randomly selected. Households were randomly selected within each community and collective centre. An additional sample of all elderly inhabitants of the old people's home were nutritionally assessed only. Monitoring was implemented in the besieged city of Sarajevo. 143 households with 90 children (< 18 years), 230 adults (18-59 years), and 94 elderly (60 + years) members, and 40 elderly inhabitants of the old people's home were monitored. Every month from December 1993 to March 1994, information on household food security was collected through structured questionnaires. All subjects were weighed and their heights measured. Weight for age Z scores in children (six months to 12 years) and body mass index (BMI) in adults and the elderly were calculated. While the nutritional status of adults and children consistently remained normal, high levels of undernutrition were detected among the elderly ranging from 16% to 21% (BMI < 18.5). Between December 1993 and February 1994, adults lost an average of 260 grams in weight (paired t test p = 0.005). Indicators of household food security (food stocks per person, market food prices and access to food aid) showed negative trends during the same time period. Whilst there was no nutritional disaster in Sarajevo over the winter 1993-1994, there were signs that capacity to cope was weakening in some groups. The elderly were identified as the most nutritionally vulnerable due to sickness, cold, stress and problems related to food preparation. The most food insecure group were refugees in collective centres who were highly dependent on food aid, were less likely to have relatives outside Sarajevo to support them, had fewer possessions to sell and were least likely to have gardens. ",0
1842,8846842,Altered vasoactivity in the early diabetic eye: measured in the isolated perfused rat eye,"The effect of 4 weeks streptozotocin-induced diabetes on ocular vascular resistance responses to noradrenalin (NA), adrenalin (A), phenylephrine (PHE), isoproterenol (ISOP), prostaglandin F2 alpha (PGF2 alpha). 5-hydroxytryptamine (5-HT) and angiotensin II (ANG II), was determined using a newly-developed, isolated, arterially-perfused rat eye preparation, by comparing responses from control and diabetic eyes. After extensive preliminary experiments to establish optimum parameters, the ophthalmic artery of enucleated control and diabetic rat eyes was cannulated and the retinal and uveal vasculature perfused at a constant flow with Na(+)-Krebs solution after streptozotocin-induced diabetes had been established for 4 weeks. The eyes were maintained in an environment-controlled organ bath. Perfusion pressure was monitored as increasing log M concentrations of agonists were added to the perfusate. Total ocular resistance could be calculated from knowledge of flow and pressure. In control eyes, NA, A, PHE, PGF2 alpha, and 5-HT all produced dose-dependent increases in total vascular resistance, with the following order of potency: NA = A > 5-HT > PHE = PGF2 alpha at 10(-4) M. The ocular circulation was not sensitive to isoproterenol and angiotensin II. In diabetic eyes responses to NA, A, PGF2 alpha and 5-HT were altered. Diabetic responses to NA and A had lower thresholds with larger resistance increases at low concentrations. However, the rate of increase in resistance with concentration was more gradual in diabetic eyes so that at 10(-4) M control responses were larger. Diabetic resistance responses to PGF2 alpha had the same threshold as in control eyes, but were greater in magnitude with an earlier peak at 10(-4) M. In contrast diabetic resistance responses to 5-HT were reduced, peaked at a lower resistance at 10(-4) M, but had the same threshold as those in the control eye. Basal vascular resistances in control: 3.14 +/- 0.32 mmHg min microliter-1 (n = 28), and diabetic eyes: 3.44 +/- 0.19, mmHg min microliter-1 (n = 36), were not significantly different. Vasoactivity in the early diabetic eye is disturbed with the effective balance between different agonists altered in favour of catecholamines at physiological concentrations. This may be related to the early changes in blood flow and oxygen distribution already reported in the rat eye, as well as changes to autonomic function. The isolated perfused rat eye is a valuable technique for investigating such vascular reactivity in animal models of retinal disease. ",0
1843,8846846,Age-dependent cleavage at the C-terminal region of lens beta B2 crystallin,"A previous study has demonstrated that in vivo, the peptide bonds at the C-terminal region of the alpha-A crystallins were cleaved in an age-dependent manner, between the two hydroxyl-containing amino acids in the sequence -PS(T)S (Takemoto, 1995). Bovine beta B2 crystallin also contains the sequence-PSS at its C-terminus. To determine if this specific site of cleavage occurred in other lens proteins besides alpha-A crystallin, beta B2 crystallin was prepared from total proteins of young versus adult bovine lens fiber cells. After cleavage by cyanogen bromide, the C-terminal fragments were characterized by mass spectrometry. The results showed that peptide cleavage also occurred between the two hydroxyl-containing amino acids in the sequence -PSS of beta B2 crystallin from older fiber cells, demonstrating that age-dependent cleavage of this peptide bond occurs in multiple proteins of the aging lens. ",0
1844,8847099,Characterization of a voltage-dependent potassium channel in squid Schwann cells reconstituted in planar lipid bilayers,"An affinity column prepared with noxiustoxin (NTx), a K+ channel blocker from the venom of the Mexican scorpion Centruroides noxius, was used to purify a functional channel from a detergent extract of Schwann cell membrane of the giant axon of the squid Loligo vulgaris. The purified protein was reconstituted as a functional unit in a planar lipid bilayer and tested with a sequence of potentials to obtain information about single-channel amplitude and kinetics. The reconstituted channel showed delayed rectifier behavior with a slope conductance of 10 pS under 5:1 asymmetric KCl concentrations and a clear tendency to open under negative potentials. The zero-current potential was +36mV, which fitted well with the Nernst equation for the CIS/TRANS K(+)-concentration ratio of 5:1. The channel also showed a strong sensitivity to tetraethylammonium and its activity was inhibited by NTx, as expected from the purification procedure. The behavior of this protein in the presence of 0.5 mM ATP (cis side) was also tested, significantly increasing current fluctuations across the membrane. In order to compare the modulation of the Schwann cell K+ channel with that of the axonal K+ channel, a purified protein from the squid axon membrane was also tested in the presence of ATP. This 10-11 pS, delayed rectifier channel from the squid giant axon (Prestipino et al., FEBS Lett. 250:570-574, 1989) was also tested in the presence of ATP and showed a similar rise in activity. ",0
1845,8847135,"Expression of estrogen, progesterone and epidermal growth factor receptors in primary and metastatic breast cancer","The prognostic value of epidermal growth factor receptor (EGFR) expression and its biological role in estrogen receptor-positive (ER+) and ER-negative (ER-) primary breast cancer is controversial. In this study, distributions of ER, progesterone receptor and EGFR have been established using immunohistochemistry in both primary breast tumors and their matched axillary lymph node metastases of 26 patients or their matched distant metastases of 2 patients. In addition, 5 patients with bilateral breast cancer were studied. ER+ tumor cells were detected in 22 (69%) and EGFR+ tumor cells were detected in 11 (34%) primary breast carcinomas. Expression of ER and EGFR was inverse regarding the individual tumor cells in both primary tumors and metastases. Relationship of EGFR expression with poorly differentiated and large breast tumors was observed. Furthermore, primary tumors with a predominant lobular component were ER+ and, with one exception, EGFR-. Invasive ductal carcinomas were more frequently EGFR+. No apparent differences in receptor expression were observed between primary tumors and lymph node metastases or chronously or metachronously occurring bilateral breast cancers. Only one ER+ primary tumor showed a switch to EGFR expression in the involved lymph node. Our study shows that a shift in receptor phenotype between primary tumors and lymph node metastases is a rare event and, thus, additional analyses of involved lymph nodes will not likely serve as a better predictor for response to anti-estrogen therapy. We conclude that expression of EGFR is not a prerequisite for development of metastases. ",0
1846,8847499,The ATP-binding and ATPase activities of human papillomavirus type 16 E1 are significantly weakened by the absence of prolines in its ATP-binding domain,"The E1 protein of human papillomavirus (HPV) type 16 is the only known papillomavirus E1 which does not contain any proline residues in the phosphate-loop (P-loop) of its ATP-binding site. To ascertain whether this feature influences the activities of HPV-16 E1, we generated a mutant HPV-16 E1 (E1Pro) in which prolines are inserted in place of alanines in this site, making the P-loop identical to its bovine papillomavirus type 1 counterpart. Glutathione S-transferase (GST) fusion proteins (GSTE1wt and GSTE1Pro) were produced, purified and used to assay for ATP-binding ability, ATPase activity and ability to complex with the HPV-16 E2 protein. The results show that the lack of prolines in the P-loop, which is unique to HPV-16 E1, significantly weakens its ATP-binding and ATPase activities without affecting its ability to complex with the HPV-16 E2 protein. ",0
1847,8847511,A region of the coronavirus infectious bronchitis virus 1a polyprotein encoding the 3C-like protease domain is subject to rapid turnover when expressed in rabbit reticulocyte lysate,"In order to investigate the mechanisms involved in the processing of infectious bronchitis virus polyproteins, several candidate regions of the genome have been cloned and expressed in vitro. During these studies it was observed that the translation product encoded by one of these clones (pKT205) was poorly expressed. Biochemical and genetic analyses revealed that the basis for the poor expression was a post-translational event involving ubiquitination of the protein and degradation by an ATP-dependent system operating in the reticulocyte lysate used for the in vitro expression. Two independently acting regions which conferred instability were identified, one of which mapped to the predicted 3C protease domain, contained within the 5' end of the clone, while the other, more C-terminal region, was effective in conferring instability upon a heterologous protein to which it had been transferred. These regions may influence the stability of the authentic viral protein(s) in vivo and hence allow for the control of their expression and/or function at the level of proteolysis by cellular protease(s). ",0
1848,8847710,Some aspects of the role of cytochrome P-450 isozymes in the N-oxidative transformation of secondary and tertiary amine compounds,"Indirect evidence of the participation of cytochrome P-450 (P-450) in the microsomal N-oxygenation of secondary and tertiary nitrogen functions is presented by studies employing diagnostic modifiers of the hemoprotein system as well as antibodies directed toward the diverse P-450 isoforms and NADPH-cytochrome P-450 reductase. Experiments with recombinant hemoproteins or P-450 isozymes directly purified from the tissues of various animal species support the results obtained by the inhibitor assays. Although the intermediacy of aminium radicals is thought to be restrictive to P-450-catalyzed N-oxygenation of secondary and tertiary amine groups bearing accessible hydrogens on the alpha-carbon, numerous exceptions to this rule are documented. It is proposed that aminium radicals partition between oxygen rebound and alpha-hydrogen abstraction to yield a finite level of N-oxygenated product in all P-450-mediated amine oxidations, the partition ratio depending on the amine structure and particular P-450 isozyme operative. In some instances, N-oxygenation appears to proceed by peroxidatic mechanisms. The relative contribution of P-450 to the N-oxygenation of secondary and tertiary amines in crude preparations or live animals, where competition with the flavin-containing monooxygenase (FMO) occurs, seems to be a function of the relative amounts and catalytic capacities of the two enzyme systems. Both parameters are species and tissue dependent. Accordingly, the extent to which P-450 contributes to total N-oxidative turnover of the amine substrates varies from minor to major. ",0
1849,8847789,HELP syndrome and anesthetic management],"From January 1990 to December 1994, 24 parturients were diagnosed as having HELLP syndrome alone or combined with preeclampsia/eclampsia among 8,224 patients who were delivered at our institution. They consisted of 14 primiparous and 10 multiparous patients. Mean maternal age was 28.9 +/- 3.3 and gestational age was 34.8 +/- 5.6 weeks. Of 24 parturients, 8 had vaginal delivery and the remaining 16 were delivered by caesarean section. Serious maternal morbidity included eclampsia (n = 3), preeclampsia (n = 18), renal failure (n = 5), hydrothorax (n = 4), and DIC (n = 1). There was no maternal death. There were 3 intrauterine fetal deaths and two neonatal deaths. Perinatal deaths were 2 (0.9%, 2/26). Three caesarean sections were performed under general anesthesia, and 13 under spinal anesthesia. In cases with apparent bleeding tendency, spinal and epidural anesthesia should be avoided. In providing general anesthesia, hypertension should be controlled, and the uterus is preferably dilated before the delivery and contracted there-after. ",0
1850,8847792,Evaluation of postoperative pain in spinal surgery--usefulness of the administration of local anesthetics into the peridural cavity],Analgesic effects of perioperative administration of local anesthetics into the peridural cavity were examined in 21 patients with cervical or lumbar vertebral diseases. Sufficient analgesic effects were obtained particularly in patients with lumbar vertebral disease. Administration of local anesthetics was also effective for postoperative sleep on the day of operation. No postoperative neurological side effects were observed. These findings suggest that peridural administration of local anesthetics during spinal surgery is very useful. ,0
1851,8847868,MCI-154-induced relaxation in vascular smooth muscles of guinea pig,"We investigated the vasorelaxant effects of MCI-154, a cardiotonic agent designed to target thin filaments in cardiac muscles in intact and skinned vessels from guinea pigs. In normal Krebs-Henseleit solution, MCI-154 (10(-7)-10(-4) M) inhibited the contractions induced by angiotensin II, (Ang II), endothelin-1 (ET-1), phenylephrine, and phorbol 12-myristate 13-acetate (PMA) in a concentration-dependent manner in guinea pig aorta. In Ca(2+)-free solutions, ET-1 and PMA caused slowly developing and sustained contractions in guinea pig aorta, whereas phenylephrine and caffeine induced transient contractions due to Ca2+ release from the sarcoplasmic reticulum (SR). MCI-154 (10(-7)-10(-4) M) inhibited the contractile responses to ET-1 and PMA. MCI-154 also reduced the contraction induced by Ca2+ release from phenylehrine- and caffeine-sensitive Ca2+ store sites. On the other hand, the relaxation response to MCI-154 was not affected by the presence of methylene blue, a guanylate cyclase inhibitor or by the removal of endothelial cells. MCI-154 decreased the Ca(2+)-activated tension development in saponin-treated skinned fibers from guinea pig femoral arteries. The effects of MCI-154 were not potentiated in the presence of protein kinase A (PKA), whereas those of cyclic AMP were potentiated, possibly because of lack of protein kinase A. The present experiments demonstrate that MCI-154 inhibits vascular contraction when the contractions are produced by any of three mechanisms: protein kinase C (PKC) activation, Ca2+ mobilization from store sites, or sensitization of contractile elements by Ca2+. ",0
1852,8848015,Evidence for the coupling of Gq protein to D1-like dopamine sites in rat striatum: possible role in dopamine-mediated inositol phosphate formation,"The role of G proteins in mediating the coupling of D1 dopamine receptors to inositol phosphate formation was investigated in rat brain striatum. Pertussis toxin-activated ADP-ribosylation ( > or = 95%) did not affect the ability of the D1 agonist SKF38393 to stimulate the generation of inositol phosphates in striatal slices. Stimulation of striatal membranes with dopamine in the presence of [35S]GTP gamma S or [alpha-32P]GTP increased guanine nucleotide binding to G alpha s, G alpha i, and G alpha q in a concentration-dependent fashion. The activation of G alpha s and G alpha q was mimicked by the D1 agonist SKF38393 and blocked by the D1 antagonist SCH23390. In contrast, the D2/3 dopamine receptor agonist quinpirole stimulated guanine nucleotide binding to G alpha i, and dopamine-stimulated activation of G alpha i was attenuated by the D2 antagonist I-sulpiride. Furthermore, antisera directed against G alpha s or G alpha q but not G alpha i, G alpha o, or G alpha z precipitated specific D1-like binding sites labeled with [3H]SCH23390. The D1-like receptors that coprecipitated with G alpha s-but not with G alpha q can be recognized by a specific D1 dopamine receptor antibody. The data provide evidence to suggest that in addition to coupling to Gs/adenylyl cyclase, D1-like dopamine sites that couple to Gq may mediate dopamine-stimulated formation of inositol phosphates in the rat striatum. ",0
1853,8848230,Glutamate N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists administered into the brain stem depress the renal sympathetic reflex discharges evoked by single shock of somatic afferents in anesthetized rats,"The involvement of glutamate receptors in the central transmission of somatosympathetic reflexes was studied by examining, in anesthetized rats, the effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, and CNQX, a non-NMDA receptor antagonist, on two reflex components, the A- and C-reflexes evoked in the left sympathetic renal nerve by a single shock to the left tibial nerve. The A-reflex elicited by myelinated A fiber stimulation and the C-reflex elicited by unmyelinated C fiber stimulation were depressed, in a dose-dependent manner, following administration of either MK-801 or CNQX into the cisterna magna (i.c.m.). Intrathecal (i.t.) administration of MK-801 did not have any effect on either A- or C-reflexes, while i.t. administration of CNQX had a slight effect on the A-reflex (significantly on the A-reflex only when treated with the highest dose of 100 ng) and the C-reflex. These results indicate that both NMDA and non-NMDA receptors, stimulated by glutamate released possibly as a neurotransmitter, are involved in the central transmission pathways of somatosympathetic reflexes at the level of the brain stem, but not the spinal cord. ",0
1854,8848490,Effect of anabolic steroids on behavior and physiological characteristics of female mice,"Adult female mice were exposed to a combination of four anabolic-androgenic steroids for 9 weeks at doses that were either one or five times the androgenic maintenance level for male mice. Relative to control females, steroid treatment depressed gonadotropin secretion and increased both dry body weight and fat content but without an increase in food intake. Steroid treatment depressed spontaneous use of a running wheel and open-field activity, and it increased aggressiveness. It also eliminated a behavior related to encounters between the sexes--the rejection of genital inspection. There was no effect of steroid treatment on the time required to recover from 10 h of enforced running on a treadmill. Overall, regardless of the test or measure, there was little or no difference in the effect of the high and low dose of steroids. This indicates a threshold of response below the low dose used in these studies, which itself is probably well below that used by many female athletes and body builders. ",0
1855,8848594,Relationship between the fall in growth hormone secretion at birth and the onset of nonshivering thermogenesis is independent of beta adrenergic stimulation,"At the time of birth, many rapid metabolic changes occur including the initiation of nonshivering thermogenesis and a rapid fall in growth hormone concentrations. To evaluate the interaction between these events 5 fetal sheep were studied at 135-144 days' gestation. The fetuses were first cooled 2.22 +/- 0.19 degrees C by circulating cold water through a coil placed around the fetal thorax and then ventilated with oxygen through an exteriorized tracheostomy tube to raise fetal arterial PO2 above 67.5 +/- 14.1 Torr. An hour later the beta adrenergic agonist isoproterenol was infused intravenously for 90 min. The fetuses were then separated from the placenta by occluding the umbilical cord. After 60 min the cooling and then the isoproterenol infusion were stopped and the responses monitored. Basal plasma free fatty acid (FFA 35 +/- 5 microEq L-1) and growth hormone (GH 141 +/- 12 ng mL-1) concentrations were not significantly altered by cooling alone, but oxygenation modestly increased plasma FFA to 237 +/- 55 microEq L-1 (P < 0.01) while GH concentrations fell to 58 +/- 27 ng mL-1 (P < 0.05). Isoproterenol administration did not significantly affect either FFA or GH concentrations. Occlusion of the umbilical cord caused a rapid nearly threefold increase in plasma FFA concentrations to 903 +/- 71 microEq L-1 (P < 0.01) and a fall in the same proportions in GH concentrations to 16 +/- 2 ng mL-1 (P < 0.005). Maximal fetal oxygen consumption was 24.2 +/- 4.4 mL kg-1 min-1. Cessation of cooling induced a significant fall in plasma FFA to 480 +/- 58 microEq L-1 (P < 0.01) and rise in GH concentrations to 46 +/- 5 ng mL-1 (P < 0.01). Following the withdrawal of isoproterenol, the fall in plasma FFA and rise in GH concentrations continued while the fetal oxygen uptake fell to 6.4 +/- 1.7 mliter kg-1 mL-1 (P < 0.01). During the study the variation in plasma GH was inversely correlated with changes in FFA concentrations (R = 0.77, P < 0.001). This study confirms that the major factors initiating nonshivering thermogenesis at birth are: sympathetic stimulation from cutaneous cooling, which was not significantly enhanced by isoproterenol; adequate oxygenation; and removal of placental inhibitor(s). The findings are in agreement with a causal relationship between the initiation of nonshivering thermogenesis and consequent rise in FFA concentrations and the rapid fall in circulating GH concentrations after birth in the lamb, independent of beta adrenergic stimulation. ",0
1856,8848600,Fetal and maternal plasma lipids in chronically catheterized mares in late gestation: effects of different nutritional states,"The effects of different nutritional states on plasma lipid concentrations have been examined in pregnant mares and their fetuses. Maternal and fetal arterial catheters were inserted into 12 pony mares between 244-303 days' gestation (term 320-360 days) and observations made from 5 days following the insertion of catheters. After recovery from surgery maternal and fetal arterial samples were withdrawn from 7 mares with normal feeding patterns (Group IA), from four of these mares at the end of a 30 h fast and 3 h later following refeeding (Group IB) and six mares who failed to re-establish normal feeding patterns (Group II). The fatty acid concentrations and composition of the plasma free fatty acid (FFA), triacylglycerol and phospholipid fractions were analysed. Maternal FFA, triacylglycerol and phospholipid concentrations were significantly raised in the fasted (Group IB) and under-fed (Group II) mares. Fetal concentrations of FFA and phospholipid increased significantly in the group of under-fed (Group II) mares but not in the fasted (Group IB) mares. In the fetal plasma the proportions of polyunsaturated fatty acids derived from essential fatty acids in the FFA and phospholipid fractions were much higher than those in the mare. In the fasted (IB) and under-fed (II) groups the relative amounts of the polyunsaturated fatty acids in each fraction remained unchanged (P > 0.05). These results show a short fast or prolonged undernutrition result in raised maternal plasma lipid concentrations which in turn can effect the total amount of lipid in the fetal circulation. However any increases in polyunsaturated fatty acids in the fetus (e.g. in Group II) are unlikely to come from the maternal circulation; likely sources of these fatty acids are the placenta or fetal tissues. ",0
1857,8848678,Retinoblastoma: clinical and molecular diagnostic aspects],"Retinoblastoma, a tumor of the immature retina concerns babies and young infants in particular. They make up for 14% of malignomas in the first years of life. There are two types of retinoblastoma: In the first two alleles of the gene Rb1 must be inactivated sequentially in the same retinoblast cell until this may escape control. In this case the retinoblastoma is always unilateral and unifocal. This is explained by the lower frequency of two mutations in one retinoblast. The other type, however, is inherited: One allele Rb1 is inactivated in all cells of the organism by mutation. The probability that a second mutation arrives in different retinoblasts is thus high. In this case bilateral multifocal tumors develop. Characterization of the Rb1 gene has permitted identification or at least determination of a haplotype in persons at risk. This knowledge is decisive for early recognition of babies at risk and for genetic counselling. ",0
1858,8855174,"Long-term ganciclovir chemotherapy for congenital duck hepatitis B virus infection in vivo: effect on intrahepatic-viral DNA, RNA, and protein expression","Long-term antiviral chemotherapy using the nucleoside analogue ganciclovir was undertaken with the aim of eliminating hepadnaviral covalently closed circular (CCC) DNA from the livers of ducks that were congenitally infected with the duck hepatitis B virus (DHBV). Twenty-four weeks of ganciclovir therapy caused a substantial reduction in viremia, intrahepatic viral DNA replicative intermediates, and viral core proteins. Unfortunately, ganciclovir therapy did not substantially affect CCC DNA or viral RNA levels, and the treatment resulted in an increase in the intrahepatic expression of the viral envelope proteins, pre-S and S. By the completion of therapy, the viral envelope proteins had assembled into large aggregates within the cytoplasm of most hepatocytes. Viral replication in the bile duct epithelial cells and in the extrahepatic sites was likewise not affected by long-term ganciclovir therapy. In conclusion, 24 weeks of ganciclovir therapy decreased most viral replication markers within the liver, except for those of viral CCC DNA, RNA, and envelope proteins. Long-term therapeutic strategies using nucleoside analogs such as ganciclovir should be used with caution in chronic hepatitis B virus (HBV) infection. The careful monitoring of serum and hepatic markers of viral replication may therefore be important to avoid possible toxic consequences, such as the selective accumulation of viral proteins.",0
1859,8855177,T- and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and in healthy anti-hepatitis C virus--positive blood donors without viremia,"As the host's immune response may determine the course of hepatitis C virus (HCV) infection, we studied the humoral and cellular immune responses to HCV-related antigens in subjects with different outcomes of HCV infection. Lymphoproliferative responses and circulating antibodies to a panel of HCV core- and E1-related 25-mer peptides were examined in 10 healthy anti-HCV-seropositive blood donors (group A) and in 29 patients with chronic hepatitis C (group B). In addition, cellular recognition of recombinant HCV proteins (core, NS3, NS4A, NS5A, NS5B) were investigated. In group A, stronger T-cell responses were detected against both HCV proteins (core, P = .03; NS4, P = .005; NS5B, P = .03) and peptides. Proliferation was induced by the same peptides in each group, defining at least five distinctive epitopes within core (amino acids [aa] of 20-44, aa 39-63, aa 79-103, aa 118-152 and aa 148-172) and three regions within E1(aa 198-252, aa 308-372, and aa 368-392). Subjects with strong T-cell responses had low or no detectable levels of peptide-specific antibodies, and vice versa. In particular, T-cell responses were more common in group A; B-cell responses were more common in group B. From our data, we conclude that a benign course of HCV infection may be the consequence of the effective activation of T-helper lymphocytes.",0
1860,8855201,Fe-nitrilotriacetic acid--binding proteins associated with rat liver plasma membranes,"The uptake of nontransferrin-bound iron by hepatocytes is known to occur and may contribute to the deposition of iron and resulting injury during hemochromatosis. To examine the proteins that may function in the transport of nontransferrin-bound iron, the properties of FeNTA-binding to rat liver basolateral plasma membranes were characterized. The binding of 55FeNTA to purified liver basolateral plasma membranes was measured using a simple centrifugation assay. The binding activity could be solubilized with 0.1% octylglucoside; apparent molecular weight Mapp approximately 210 kd for the binding complex was determined by gel filtration chromatography. Immobilized metal affinity chromatography was used to further purify binding protein(s) from rat liver plasma membranes and at least six polypeptides were identified by silver staining. If associated in a stoichiometric complex, the molecular mass of these proteins would predict a size of approximately 227 kd in fairly close agreement with the gel filtration experiments. The characterization of FeNTA-binding proteins associated with basolateral membranes is the first step towards understanding elements responsible for the uptake of nontransferrin-bound iron by the liver.",0
1861,8890099,Mutations in the mu heavy-chain gene in patients with agammaglobulinemia,"BACKGROUND: Most patients with congenital hypogammaglobulinemia and absent B cells are males with X-linked agammaglobulinemia, which is caused by mutations in the gene for Bruton's tyrosine kinase (Btk); however, there are females with a similar disorder who do not have mutations in this gene. We studied two families with autosomal recessive defects in B-cell development and patients with presumed X-linked agammaglobulinemia who did not have mutations in Btk. METHODS: A series of candidate genes that encode proteins involved in B-cell signal-transduction pathways were analyzed by linkage studies and mutation screening. RESULTS: Four different mutations were identified in the mu heavy-chain gene on chromosome 14. In one family, there was a homozygous 75-to-100-kb deletion that included D-region genes, J-region genes, and the mu constant-region gene. In a second family, there was a homozygous base-pair substitution in the alternative splice site of the mu heavy-chain gene. This mutation would inhibit production of the membrane form of the mu chain and produce an amino acid substitution in the secreted form. In addition, a patient previously thought to have X-linked agammaglobulinemia was found to have an amino acid substitution on one chromosome at an invariant cysteine that is required for the intrachain disulfide bond and, on the other chromosome, a large deletion that included the immunoglobulin locus. CONCLUSIONS: Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in humans. This implies that an intact membrane-bound mu chain is essential for B-cell development.",0
1862,8890103,The postwar hospitalization experience of U.S. veterans of the Persian Gulf War,"BACKGROUND: Since the Persian Gulf War ended in 1991, many veterans of that conflict have reported diverse, unexplained symptoms. To evaluate the health of Gulf War veterans, we studied their postwar hospitalization experience and compared it with that of other military personnel serving at the same time who did not go to the Persian Gulf. METHODS: Using a retrospective cohort approach and data from Department of Defense hospitals, we studied hospitalizations of 547,076 veterans of the Gulf War who were serving in the Army, Navy, Marine Corps, and Air Force and 618,335 other veterans from the same era who did not serve in the Persian Gulf. Using multivariate logistic-regression models, we analyzed risk factors for hospitalization both overall and in 14 broad diagnostic categories during three periods from August 1991 through September 1993 (a total of 45 specific comparisons). RESULTS: After the war, the overall odds ratio for hospitalization of the Gulf War veterans was not higher than that of the other veterans, even after adjustment for selection effects related to deployment. In 16 of the 42 comparisons involving specific diagnoses, the risk of hospitalization among Gulf War veterans differed significantly from that among other veterans. Among these 16 comparisons, Gulf War veterans were at higher risk in 5: neoplasms (largely benign) during 1991, diseases of the genitourinary system during 1991, diseases of the blood and blood-forming organs (mostly forms of anemia) during 1992, and mental disorders during both 1992 and 1993. The differences were not consistent over time and could be accounted for by deferred care, postwar pregnancies, and postwar stress. CONCLUSIONS: During the two years after the Persian Gulf War, there was no excess of unexplained hospitalization among Americans who remained on active duty after serving in that conflict.",0
1863,8900086,The association between birthplace and mortality from cardiovascular causes among black and white residents of New York City,"BACKGROUND: Life expectancy is shorter and mortality from cardiovascular disease higher among blacks than among whites in the United States. We studied whether place of birth was associated with mortality from cardiovascular causes among non-Hispanic black and white residents of New York City. METHODS: We linked mortality records from 1988 through 1992 with 1990 U.S. census data for New York City. Mortality data for blacks born in the U.S. South and Northeast and in the Caribbean were compared with those for whites born in the Northeast. RESULTS: Among blacks, the rates of overall mortality and mortality from cardiovascular causes exceeded those among whites. Among persons born in the Northeast, the rates of death from cardiovascular disease for white men (285 per 100,000), as compared with black men (299), and for white women (155), as compared with black women (165), were similar. However, Southern-born black men and women both had mortality from cardiovascular disease that was substantially higher than that of their counterparts born in the Northeast, and Caribbean-born blacks had rates substantially lower than their Northeastern-born counterparts. The differences among the groups in the rates of death from coronary heart disease were greater than those for death due to stroke or hypertension. In each category defined by age and sex, Caribbean-born blacks had significantly lower rates of death from coronary heart disease than did whites. Black men who were 25 to 44 years of age and were born in the South had a rate of death from coronary heart disease that was 30 percent higher than that of Northeastern-born blacks, and four times that of Caribbean-born blacks of the same sex and age. CONCLUSIONS: The higher rate of mortality from cardiovascular causes among blacks, as compared with whites, in New York City masks substantial variation among blacks based on their place of birth.",0
1864,8903368,Use of dominant negative mutants of the hepadnaviral core protein as antiviral agents,"""Chronic hepatitis B virus (HBV) infection is a major cause of acute and chronic liver diseases. We have recently described HBV and woodchuck hepatitis virus (WHV) dominant negative (DN) core mutants that were capable of inhibiting wild-type viral replication by 95%. These mutants may represent a potent class of antiviral agents that act as """"intracellular immunogens."""" To facilitate their potential use in animal model systems, we now have studied the duck HBV (DHBV) and placed the DN mutant constructs in recombinant retroviral and adenoviral expression vectors. Transient expression of the DHBV molecular equivalent of the WHV and HBV DN constructs inhibited wild-type DHBV replication by 98%. Recombinant retroviral and adenoviral vectors containing the HBV and DHBV DN complementary DNAs (cDNAs) were used to transiently and stably transduce hepatoma-derived cell lines constitutively expressing replicating wild-type virus. These investigations show that the DN core mutants were powerful inhibitors of HBV and DHBV replication when delivered intracellularly and appear as promising antiviral agents for gene therapy of persistent viral infection of the liver.""",0
1865,8903369,The clinical significance of changes in genetic heterogeneity of the hypervariable region 1 in chronic hepatitis C with interferon therapy,"We examined changes in the hypervariable region 1 of the hepatitis C virus (HCV) RNA that occurred with interferon therapy in 33 patients with chronic hepatitis C to assess the clinical significance of this region. The 33 patients had HCV genotype 1b and were classified into three groups based on serum aminotransferase levels during and after therapy with alpha interferon; long-term responders (n = 9), short-term responders (n = 11), and nonresponders (n = 13). Changes in the genetic heterogeneity of the hypervariable region 1 were determined by using nonisotopic polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). HCV RNA levels were evaluated by reverse transcriptase PCR and branched DNA probe assays. Changes in sequences were determined by cloning and sequencing analysis. Before therapy, the long-term responders had significantly lower degrees of heterogeneity and lower viral levels than nonresponders. There were no significant differences between short-term and nonresponders. With interferon therapy, viral levels and degree of heterogeneity decreased to a greater extent among long-term and short-term responders than among nonresponders. Sequencing analysis showed that the three groups had similar clone numbers initially, but long-term responders had rather homogeneous viral populations, whereas short-term and nonresponders had heterogeneous populations, but that there were no nucleotide sequences or amino acid alignments that were specific for any group before, during, and 6 months after therapy. Approximately half of short-term and nonresponders received a second course of interferon 7 to 10 months after the initial therapy; all showed an identical response to the second course of therapy regardless of interim changes in the heterogeneity of hypervariable region 1. These findings suggest that (1) patients who were nonresponders or short-term responders had mixed viral populations that had differing sensitivities to interferon, (2) the changes in the hypervariable region 1 (HVR 1) did not affect responsiveness to interferon, and (3) the lower heterogeneity in the HVR 1 was associated with a long-term response to interferon only when the viral levels were low.",0
1866,8903405,"Long-term alcohol intake enhances ADP-ribosylation of the multifunctional enzyme, phosphoglucomutase, in rat liver","Adenosine diphosphate (ADP)-ribosylation is a posttranslational protein modification that, in turn, alters several regulatory proteins in mammalian cells. We demonstrated that long-term alcohol intake enhanced the ADP-ribosylation of a 58-kd protein in rat liver plasma membranes. To assess the biological significance of this phenomenon, we partially purified the 58-kd acceptor protein from solubilized rat liver homogenates by two sequential preparative high-pressure liquid chromatographies. Microsequencing revealed that it was phosphoglucomutase (PGM) (EC 5,4,2,2). This enzyme underwent negligible auto ADP-ribosylation, but the ADP-ribosylation was remarkably increased by adding rat liver plasma membranes. The extent of the increase was greater in alcohol-fed rats than in pair-fed controls, suggesting enhanced enzyme activities toward ADP-ribosylation of PGM after chronic alcohol consumption. Several important enzymes are ADP-ribosylated, after which their activities are modified. The results of this study showed that PGM is a novel substrate for ADP-ribosylation in the liver and that the ADP-ribosylation is increased after chronic alcohol consumption. In view of the variety of roles of PGM in the liver (carbohydrate metabolism and Ca2+ homeostasis), specific roles of this modification in terms of the effects of alcohol on hepatocytes may deserve further investigation.",0
1867,8929264,The DCC protein and prognosis in colorectal cancer,"BACKGROUND: Allelic loss of chromosome 18q predicts a poor outcome in patients with stage II colorectal cancer. Although the specific gene inactivated by this allelic loss has not been elucidated, the DCC (deleted in colorectal cancer) gene is a candidate. We investigated whether the expression of the DCC protein in tumor cells is a prognostic marker in colorectal carcinoma. METHODS: The expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II and III colorectal carcinomas. The Cox proportional-hazards model was used to adjust for covariates including age, sex, tumor site, degree of tumor differentiation, and use of adjuvant therapy. RESULTS: The expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). CONCLUSIONS: DCC is a prognostic marker in patients with stage II or stage III colorectal cancer. In stage II colorectal carcinomas, the absence of DCC identifies a subgroup of patients with lesions that behave like stage III cancers. These findings may thus have therapeutic implications in this group of patients.",0
1868,8929266,Participation of life-science faculty in research relationships with industry,"BACKGROUND: Recent research on academic-industrial research relationships in the life sciences has examined their frequency, benefits, risks, and evolution from the standpoint of industrial sponsors of research. We collected information on the extent and effects of academic-industrial research relationships from the standpoint of faculty members who participate in them. METHODS: We used a mailed questionnaire to collect data between October 1994 and April 1995 from 2052 faculty members (of 3169 eligible respondents; response rate, 65 percent) in the life sciences at the 50 U.S. universities receiving the most research funding from the National Institutes of Health. RESULTS: Twenty-eight percent of the respondents received research support from industry. Faculty members receiving industrial funds had more peer-reviewed articles published in the previous three years, participated in more administrative activities in their institutions or disciplines, and were more commercially active than faculty members without such funding. However, faculty members receiving more than two thirds of their research support from industry were less academically productive than those receiving a lower level of industrial support, and their articles were less influential than those by researchers with no industrial support. Faculty members with industrial support were significantly more likely than those without industrial support to report that trade secrets had resulted from their work (14.5 percent vs. 4.7 percent, P<0.001) and that they had taken commercial considerations into account when choosing research topics (35 percent vs. 14 percent, P<0.001). CONCLUSIONS: Faculty members with industrial research support are at least as productive academically as those without such support and are more productive commercially. However, faculty members who have research relationships with industry are more likely to restrict their communication with colleagues, and high levels of industrial support may be associated with less academic activity without evidence of proportional increases in commercial productivity.",0
1869,8938173,Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis,"Peripheral blood mononuclear cells (PBMC) of patients with autoimmune hepatitis (AIH) and controls were studied for their proliferative response to six overlapping synthetic peptides covering the 33-amino acid immunodominant region of cytochrome P450IID6, the main target antigen of LKM-1 antibody-positive type II AIH. PBMC from 8 of 8 type II AIH patients (100%), 6 of 12 LKM-1 antibody-negative type I AIH patients (50%), but only 4 of 31 patients with chronic hepatitis C (12.9%) reacted with a 23-amino acid LKM peptide and mainly with a shorter 18-amino acid LKM peptide. Follow-up showed that LKM-specific T-cell responses decreased after immunosuppression had started. Fine specificity, HLA restriction, and cytokine release of LKM-specific T cells were analyzed with 16 CD4+ peptide-specific T-cell lines and 21 CD4+ T-cell clones isolated and expanded from blood and liver tissue of six AIH patients. Activated LKM-specific T cells released interferon gamma (IFN-gamma) but no or little interleukin-4. In three AIH patients, PBMC showed specific recognition of autologous LKM-specific T cells, suggesting the presence of a regulatory T-cell network. These T cells also showed the CD4+ phenotype and secreted large amounts of IFN-gamma. Furthermore, it was assessed that the regulatory T-cell response is clonotypic. To conclude, we describe a major T-cell epitope in AIH that was recognized by Th1 helper cells isolated from blood and liver tissue. This autoreactive T-cell response correlated widely with disease activity and LKM-1 antibody status and seemed to be regulated by anticlonotypic T cells.",0
1870,8938183,The role of adhesion molecules in the recruitment of hepatic natural killer cells (pit cells) in rat liver,"Previous studies showed that blood large granular lymphocytes (LGL), which possess natural killer (NK) activity, develop within rat liver sinusoids into high-density (HD) and subsequently into low-density (LD) pit cells which show an increasing level and spectrum of tumor cytotoxicity. In this study, we investigated the role of adhesion molecules, such as CD2, CD11a, CD18, and CD54 in the recruitment of pit cells to the liver. Immunostaining for electron microscopy, and two color flow cytometry showed that most pit cells expressed CD2, CD11a, CD18, and CD54. After intravenous injections into rats with anti-CD2, anti-CD11a, and anti-CD18 antibodies, the number of pit cells per square millimeter in frozen sections of liver tissue decreased. Treatment of rats with zymosan increased the number of pit cells fivefold, whereas subsequent treatment with anti-adhesion-molecule antibodies resulted in approximately 60% lower number of pit cells. Anti-CD54, supposed to block CD54 expression on sinusoidal endothelial cells, also decreased the number of pit cells. The number of blood LGL was, however, not affected by these antibodies. These results indicate that blocking of CD2, CD11a, CD18, and CD54 antigens on blood LGL and/or liver endothelium decreased the number of pit cells in the liver. These adhesion molecules therefore play an important role in the recruitment of pit cells in the liver.",0
1871,8938187,Transverse movement of spin-labeled phospholipids in the plasma membrane of a hepatocytic cell line (HepG2): implications for biliary lipid secretion,"The redistribution of spin-labeled phospholipid analogs across the plasma membrane of HepG2 cells, either in suspension or grown as monolayers, was investigated. After incorporation into the outer membrane leaflet spin-labeled aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) moved rapidly to the inner monolayer, whereas the analog of phosphatidylcholine (PC) disappeared more slowly from the outer leaflet. The fast, inward movement of the aminophospholipids was abolished after adenosine triphosphate (ATP)-depletion of cells, suggesting the presence of an aminophospholipid translocase in the plasma membrane of these cells. Compared with human red blood cells, the activity of the aminophospholipid translocase is two orders of magnitude higher in HepG2 cells. From these data, a transverse phospholipid asymmetry can be inferred with the aminophospholipids mainly concentrated on the inner monolayer and the choline-containing phospholipids on the outer leaflet. The relevance of the enrichment of PC in the outer membrane leaflet for the formation and composition of the bile is discussed.",0
1872,8948562,The pathophysiology and genetics of congenital lipoid adrenal hyperplasia,"BACKGROUND: Congenital lipoid adrenal hyperplasia results in severe impairment of steroid biosynthesis in the adrenal glands and gonads that is manifested both in utero and postnatally. We recently found mutations in the gene for the steroidogenic acute regulatory protein in four patients with this syndrome, but it was not clear whether all patients have such mutations or why there is substantial clinical variation in these patients. METHODS: We directly sequenced the gene for steroidogenic acute regulatory protein in 15 patients with congenital lipoid adrenal hyperplasia from 10 countries. Identified mutations were confirmed and recreated in expression vectors, transfected into cultured cells, and assayed for the presence and activity of steroidogenic acute regulatory protein. RESULTS: Fifteen different mutations in the gene for steroidogenic acute regulatory protein were found in 14 patients; the mutation Gln258Stop was found in 80 percent of affected alleles from Japanese and Korean patients, and the mutation Arg182Leu was found in 78 percent of affected alleles from Palestinian patients. We developed diagnostic tests for these and eight other mutations. Thirteen of the 15 mutations were in exons 5, 6, or 7, and all rendered the steroidogenic acute regulatory protein inactive in functional assays. Some mutants with amino acid replacements were capable of normal mitochondrial processing, indicating that the activity of steroidogenic acute regulatory protein is not associated with its translocation into mitochondria. Steroidogenic cells lacking the protein retained low levels of steroidogenesis. This explains the secretion of some steroid hormones by the ovaries after puberty before affected cells accumulate large amounts of cholesterol esters. CONCLUSIONS: The congenital lipoid adrenal hyperplasia phenotype is the result of two separate events, an initial genetic loss of steroidogenesis that is dependent on steroidogenic acute regulatory protein and a subsequent loss of steroidogenesis that is independent of the protein due to cellular damage from accumulated cholesterol esters.",0
1873,8960473,A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection,"BACKGROUND: Genetic differences in immune responses may affect susceptibility to mycobacterial infection, but no specific genes have been implicated in humans. We studied four children who had an unexplained genetic susceptibility to mycobacterial infection and who appeared to have inherited the same recessive mutation from a common ancestor. METHODS: We used microsatellite analysis, immunofluorescence studies, and sequence analysis to study the affected patients, unaffected family members, and normal controls. RESULTS: A genome search using microsatellite markers identified a region on chromosome 6q in which the affected children were all homozygous for eight markers. The gene for interferon-gamma receptor 1 maps to this region. Immunofluorescence studies showed that the receptor was absent on leukocytes from the affected children. Sequence analysis of complementary DNA for the gene for interferon-gamma receptor 1 revealed a point mutation at nucleotide 395 that introduces a stop codon and results in a truncated protein that lacks the transmembrane and cytoplasmic domains. CONCLUSIONS: Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferon-gamma. The interferon-gamma pathway is important in the response to intracellular pathogens such as mycobacteria.",0
1874,8985259,Simultaneous determination of plasma mevalonate and 7alpha-hydroxy-4-cholesten-3-one levels in hyperlipoproteinemia: convenient indices for estimating hepatic defects of cholesterol and bile acid syntheses and biliary cholesterol supersaturation,"The high prevalence of cholesterol gallstone disease in hypertriglyceridemic patients may be associated with frequent metabolic defects in cholesterol and bile acid syntheses and in the concomitant formation of bile supersaturated with cholesterol. This study had the two aims: 1) to assess whether the defects as well as the degree of biliary cholesterol supersaturation in patients with hyperlipoproteinemia (HLP) can be estimated by the simultaneous determination of plasma mevalonate (MVL) and 7alpha-hydroxy-4-cholesten-3-one (C4); and 2) to assess the possible application of an estimated cholesterol saturation index ([CSI]E) as a means of evaluating the clinical effects of simvastatin on biliary lipid composition. Biliary cholesterol supersaturation was observed in patients with both IIa and IV HLP types. Consistent with the high activity and steady-state messenger RNA level of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, plasma MVL was significantly higher in 86 patients with HLP (38 type IIa, 44.1 +/- 2.4 nmol/L and 48 type IV, 56.7 +/- 2.3; P < .01) than in 41 normolipidemic subjects (34.2 +/- 1.5), closely correlating with the molar percentage of cholesterol in bile (r = .61, P = .0001; n = 86). On the other hand, consistent with the high activity and messenger RNA level of cholesterol 7alpha-hydroxylase, plasma C4 was significantly higher in patients with HLP (type IIa, 28.8 +/- 2.3 nmol/L and type IV, 38.3 +/- 2.7; P < .01) than in normolipidemic subjects (17.4 +/- 1.5). Plasma C4 was closely correlated with plasma MVL (r = .40, P = .0001; n = 86), but was inversely correlated with the molar percentage of bile acids in bile (r = .49, P = .0001; n = 86). Assuming that cholesterol supersaturation in patients with HLP may be governed by both an enhanced cholesterol secretion (closely reflected by plasma MVL) and a decreased secretion of bile acids (closely reflected by plasma C4), the multivariate linear regression-analyses revealed that an index defined as estimated CSI ([CSI]E) (%) in patients with HLP was given by the following equation using plasma MVL and C4 (nmol/L): [CSI]E = 1[MVL] + 0.7[C4] + 44.4. Biliary cholesterol supersaturation in patients treated with simvastatin improved in a manner parallel to the time course of decreases in plasma MVL and C4. The [CSI]E before and at the end of treatment were correlated with biliary CSI. These results indicate that defects of hepatic cholesterogenesis, and bile acid synthesis, and the degree of biliary cholesterol supersaturation in patients with HLP can be estimated exactly by the simultaneous determination of plasma MVL and C4; furthermore [CSI]E may be adopted for clinical use as a convenient index of biliary CSI.",0
1875,8985275,Alcoholism and alcoholic organ damage and genetic polymorphisms of alcohol metabolizing enzymes in Chinese patients,"It is still not clear why some alcoholic patients acquire certain organ-specific complications of alcoholism whereas other alcoholic patients acquire different ones. As we know the liver alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P4502E1 (P4502E1) are polymorphic at the ADH2, ADH3, and ALDH2 loci and the 5'-flanking region of the P4502E1. The aim of this study was to investigate the differences between Chinese alcoholic patients with cirrhosis and acute pancreatitis by studying the genetic polymorphisms of ADH2, ADH3, ALDH2, and P4502E1. Genotyping of ADH2, ADH3, ALDH2, and P4502E1 was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods on peripheral white blood cell DNA from 75 alcoholic cirrhotic patients, 48 acute alcoholic pancreatitis patients, 19 heavy drinkers without liver disease or pancreatitis, and 235 controls. The results showed that the frequencies of the alleles ADH2*1 and ALDH2*1 in the alcoholic cirrhotic patients were significantly higher than those in the nonalcoholic controls. In acute alcoholic pancreatitis patients, only the frequency of allele ALDH2*1, not ADH2*1 was significantly higher than in the nonalcoholic controls. The allele frequency of ADH2*1 in acute pancreatitis patients was significantly lower (P < .01) than in alcoholic cirrhotic patients. The daily amount of alcohol consumption was significantly lower in patients with acute pancreatitis than in patients with cirrhosis (P < .0005). The genotype distributions of P4502E1, detected by RsaI and PstI, were not different among alcoholic cirrhotic patients, alcoholic pancreatitis patients, heavy drinker, and nonalcoholic controls. In conclusion, ALDH2*1 is the most important alcohol metabolizing gene affecting predisposition to alcoholism whereas the ADH2*2 gene may influence susceptibility to acute alcoholic pancreatitis. The patients with alcohol-induced cirrhosis and with alcohol-induced acute pancreatitis are of two different subpopulations.",0
1876,8985277,Effect of nitric oxide on iron-mediated oxidative stress in primary rat hepatocyte culture,"An iron-mediated oxidative stress caused by an increase of the intracellular pool of low molecular weight complex of iron (LMWC) can be observed with iron overloading or ethanol metabolism. The aim of this study was to determine whether nitric oxide (NO) behaved as a pro-oxidant or an antioxidant in such an iron-mediated oxidative stress in rat hepatocytes. The cells were set up in primary cultures and incubated with lipopolysaccharide (LPS) and gamma-interferon (IFN) for 18 hours to induce NO synthase and to trigger NO production. Then 20 micromol/L iron or 50 mmol/L ethanol were added. Oxidative stress was evaluated by measuring lipoperoxidation using two markers: malondialdehyde (MDA) and conjugated dienes. Simultaneously, NO production was followed by the quantitation of nitrites in the culture medium, dinitrosyl iron complexes (DNICs) and mononitrosyl iron complexes (MNICs) in intact hepatocytes. DNIC and MNIC, evaluated by electron paramagnetic resonance (EPR), corresponded to NO bound to iron-containing molecules and to free NO, respectively. In cultures preincubated with LPS and IFN before iron or ethanol addition, a net decrease of lipid peroxidation induced by either NO, iron, or ethanol was noted. Moreover, an elevation of iron-bound NO and a decrease of free NO were observed in these cultures compared with the cultures incubated with only LPS and IFN. These data support the idea that there is a relationship between the changes of NO pool and the inhibition of oxidative stress. In addition, using N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, NO was shown to be involved in the inhibition of oxidative stress induced by iron or ethanol. Addition of the chelator of LMWC iron, deferiprone, was followed by the inhibition of the increase of iron-bound NO and the reincrease of lipid peroxidation extent, which was as high as in cultures incubated only with LPS and IFN. Thus LMWC iron appeared to be involved also in the inhibition of oxidative stress induced by NO. All the results favor the conclusion that NO acts as an antioxidant in iron-mediated oxidative stress in rat hepatocytes. NO reacted with LMWC iron to form inactive iron complexes unable to induce oxidative stress in rat hepatocytes. Thus NO played a critical role in protecting the liver from oxidative stress.",0
1877,8988885,"A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group","BACKGROUND: The candidate vaccines against malaria are poorly immunogenic and thus have been ineffective in preventing infection. We developed a vaccine based on the circumsporozoite protein of Plasmodium falciparum that incorporates adjuvants selected to enhance the immune response. METHODS: The antigen consists of a hybrid in which the circumsporozoite protein fused to hepatitis B surface antigen (HBsAg) is expressed together with unfused HBsAg. We evaluated three formulations of this antigen in an unblinded trial in 46 subjects who had never been exposed to malaria. RESULTS: Two of the vaccine formulations were highly immunogenic. Four subjects had adverse systemic reactions that may have resulted from the intensity of the immune response after the second dose, which led us to reduce the third dose. Twenty-two vaccinated subjects and six unimmunized controls underwent a challenge consisting of bites from mosquitoes infected with P. falciparum. Malaria developed in all six control subjects, seven of eight subjects who received vaccine 1, and five of seven subjects who received vaccine 2. In contrast, only one of seven subjects who received vaccine 3 became infected (relative risk of infection, 0.14; 95 percent confidence interval, 0.02 to 0.88; P<0.005). CONCLUSIONS: A recombinant vaccine based on fusion of the circumsporozoite protein and HBsAg plus a potent adjuvant can protect against experimental challenge with P. falciparum sporozoites. After additional studies of protective immunity and the vaccination schedule, field trials are indicated for this new vaccine against P. falciparum malaria.",0
1878,8988896,Propagation of a human herpesvirus from AIDS-associated Kaposi's sarcoma,"BACKGROUND: Although unique DNA sequences related to gammaherpesviruses have been found in Kaposi's sarcoma lesions, it is uncertain whether this DNA encodes a virus that is able to reproduce. METHODS: We isolated and propagated a filterable agent whose DNA sequences were found to be identical to those of the Kaposi's sarcoma-associated herpesvirus (KSHV). We obtained early-passage spindle cells from skin lesions of patients with the acquired immunodeficiency syndrome (AIDS) who had Kaposi's sarcoma and cultured them with cells of the human embryonal-kidney epithelial-cell line 293. We characterized the virus according to its effects on cellular morphology and viral replication and its appearance on electron microscopy. RESULTS: KSHV was cytotoxic to 293 cells and was detected by the polymerase chain reaction (PCR) in infected cells but not uninfected ones. Cytotoxicity and positive PCR signals were consistently maintained with viral titers of 1 million per milliliter, for about 20 serial infections of 293 cells. The viral copy number was relatively low (1 to 10 copies per cell). Viral replication was confirmed by Southern blot analysis of DNA isolated from the enriched nuclear fraction of infected cells and by a semiquantitative PCR using dilutions of the lysates of infected cells to detect the 233-bp viral DNA fragment originally described in association with Kaposi's lesions. Electron microscopy revealed herpesvirus-like particles in about 1 percent of cells from infected cultures, as compared with none in cells from uninfected cultures. CONCLUSIONS: A herpesvirus with DNA sequences identical to those of KSHV can be propagated from skin lesions of patients with AIDS-associated Kaposi's sarcoma.",0
1879,9017942,Racial variation in the use of coronary-revascularization procedures. Are the differences real? Do they matter?,"BACKGROUND: Studies have reported that blacks undergo fewer coronary-revascularization procedures than whites, but it is not clear whether the clinical characteristics of the patients account for these differences or whether they indicate underuse of the procedures in blacks or overuse in whites. METHODS: In a study at Duke University of 12,402 patients (10.3 percent of whom were black) with coronary disease, we calculated unadjusted and adjusted rates of angioplasty and bypass surgery in blacks and whites after cardiac catheterization. We also examined patterns of treatment after stratifying the patients according to the severity of disease, angina status, and estimated survival benefit due to revascularization. Finally, we compared five-year survival rates in blacks and whites. RESULTS: After adjustment for the severity of disease and other characteristics, blacks were 13 percent less likely than whites to undergo angioplasty and 32 percent less likely to undergo bypass surgery. The adjusted black:white odds ratios for receiving these procedures were 0.87 (95 percent confidence interval, 0.73 to 1.03) and 0.68 (95 percent confidence interval, 0.56 to 0.82), respectively. The racial differences in rates of bypass surgery persisted among those with severe anginal symptoms (31 percent of blacks underwent surgery, vs. 45 percent of whites, P<0.001) and among those predicted to have the greatest survival benefit from revascularization (42 percent vs. 61 percent, P<0.001). Finally, unadjusted and adjusted rates of survival for five years were significantly lower in blacks than in whites. CONCLUSIONS: Blacks with coronary disease were significantly less likely than whites to undergo coronary revascularization, particularly bypass surgery - a difference that could not be explained by the clinical features of their disease. The differences in treatment were most pronounced among those predicted to benefit the most from revascularization. Since these differences also correlated with a lower survival rate in blacks, we conclude that coronary revascularization appears to be underused in blacks.",0
1880,9041098,Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women,"BACKGROUND: Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. METHODS: In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. RESULTS: PAI-1 levels were inversely associated with D-dimer levels at base line (r= -0.540, P=0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (+/-SD) plasma levels of PAI-1 from 32+/-34 ng per milliliter to 14+/-10 ng per milliliter (P<0.001) and from 31+/-29 ng per milliliter to 15+/-11 ng per milliliter (P=0.003), respectively; there was a significant inverse correlation between pretreatment PAI-1 levels and the degree of reduction in these levels during therapy (r= -0.631, P<0.001 for conjugated estrogen; r = -0.507, P=0.004 for combined therapy). The degree of reduction in PAI-1 levels was associated with increases in D-dimer levels both when conjugated estrogen was given alone (r= -0.572, P=0.001) and when combined hormone therapy was given (r= -0.541, P=0.002). Transdermal estradiol caused no significant changes in PAI-1 levels from base-line values. CONCLUSIONS: Conjugated estrogen, alone or combined with progestin therapy, reduced PAI-1 levels by approximately 50 percent in postmenopausal women and was associated with enhanced systemic fibrinolysis. These findings may partly explain the protective effect of hormone-replacement therapy with respect to coronary artery disease.",0
1881,9049198,Regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1/Sdi1) gene expression in hepatic regeneration,"WAF1/Cip1/Sdi1 (p21) is the prototype of a family of proteins that inhibit cyclin-dependent kinases and regulate cell cycle progression in eukaryotic cells. In addition to normal cell cycle progression, p21 is involved in growth suppression mediated by p53 and transforming growth factor beta (TGFbeta), differentiation, and apoptosis. To gain insight into the possible involvement of p21 in liver cell growth, the expression and regulation of the p21 gene was evaluated in rodent models of liver regeneration and specimens of human liver diseases. Little p21 mRNA was detected in normal liver tissue. After growth stimulation in vivo by 70% partial hepatectomy (PH), the p21 transcript was upregulated in a biphasic manner, with enhanced expression during G1 phase and following S phase. The induction of p21 after PH was regulated primarily at the post-transcriptional level and was due to enhanced mRNA stability. Inhibition of protein synthesis with cycloheximide rapidly induced p21 expression, primarily by post-transcriptional stabilization of the transcript. Hepatic p21 mRNA was also induced by dietary protein deprivation in normal mice. Expression of the p21 gene after PH was similar in p53-deficient (p53 -/-) and wild-type mice, but was p53-dependent following protein deprivation. Primary hepatocytes in culture demonstrated increased p21 expression after treatment with hepatocyte growth factor, TGFbeta, and activin A. p21 mRNA was upregulated in human liver diseases, suggesting a possible role in hepatic growth regulation in pathologic states. The present study demonstrates that p21 is regulated by p53-dependent and -independent pathways in the liver, and is influenced by both mitogenic and growth inhibitory stimuli.",0
1882,9049226,The predominance of hepatitis delta virus genotype I among chronically infected Italian patients,"The sera of 46 Italian patients with chronic hepatitis delta virus (HDV) infection were analyzed for HDV RNA by polymerase chain reaction (PCR) amplification. Genetic analysis of sequences amplified from two regions of the HDV genome indicated that all HDV RNA-positive patients (98%) were infected with HDV genotype I. In Italy, infection with this genotype appeared to be associated with a broad spectrum of chronic disease. No subtypes of HDV genotype I were identified, nor were genetic variations clearly associated with different disease patterns; however, clustering of some sequences suggested correlations with geography and transmission route. Italian HDV genotype I sequences were more diverse than those from east Asia and North America, suggesting that HDV genotype I was likely introduced to Italy earlier and/or from multiple sources as compared to those areas. All sequences analyzed were predicted to fold into the unbranched rod structure typical of HDV RNA. Within this structure, three conserved features were identified, including sequences around the RNA editing site and the polyadenylation signal site. We conclude that in Italy, where HDV infection has been endemic, the overwhelmingly predominant genotype of HDV is genotype I.",0
1883,9049229,Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection,"Hepatitis C virus (HCV) genotype 1b and high pretreatment virus load are predictive factors of poor response to interferon therapy in patients with chronic hepatitis C. To further examine the factors predicting the response to interferon in patients with genotype 1b infection, we analyzed 110 consecutive patients with HCV who were treated with a total of 624 million units of lymphoblastoid interferon alfa. Thirty-six patients (33%) were responders, while the remaining 74 patients (67%) were nonresponders. Multivariate analysis showed that a high virus titer (assessed by serum core protein level, P = .0021) and the presence of more than two amino acid substitutions in the interferon sensitivity-determining region (ISDR) (P = .0036) correlated significantly with the response to interferon therapy. Because mutations analyzed by direct sequencing of polymerase chain reaction (PCR) products may reflect artifacts of direct sequencing, we further analyzed quasispecies of HCV in this region by cloning and sequencing. Although PCR-based analysis of responders with multiple amino acid substitutions in the ISDR showed the presence of a small amount of wild-type strain in their serum, the results obtained by direct sequencing and cloning were essentially the same. A longitudinal study of quasispecies in 2 patients who showed a dramatic change in the virus titer showed no conversion from wild type to mutant or vice versa. Our results indicate that amino acid substitutions and virus load are independent predictors of the response to interferon therapy. The ability of some patients with no mutation in the ISDR or high virus load to eliminate the virus suggests the presence of other unidentified factors, host or viral, that influence the response to interferon therapy.",0
1884,9049230,Analysis of genotypes and amino acid residues 2209 to 2248 of the NS5A region of hepatitis C virus in relation to the response to interferon-beta therapy,"In chronic hepatitis C virus (HCV) infection, genotypes other than genotype 1b of HCV (HCV-1b) and low serum HCV-RNA levels are known to be associated with favorable outcome of interferon alfa (IFN-alpha) therapy. In addition, we recently reported a close correlation between the number of mutations in amino acid sequences 2209 to 2248 of the nonstructual protein 5A gene (NS5A2209-2248) of HCV-1b and the response to IFN-alpha. In the present study, we analyzed these viral factors in relation to the efficacy to IFN-beta, another type I IFN. The pretreatment sera of 40 patients treated with IFN-beta intravenously at 6 MU daily for 42 days were studied. HCV genotypes, serum HCV-RNA levels, and the amino acid sequence of NS5A2209-2248 in HCV-1b were determined. A sustained complete response to IFN therapy occurred in none of the ten patients with the wild-type HCV-1b who had an NS5A2209-2248 sequence identical to the prototype HCV-1b and in none of the six patients with the intermediate-type HCV-1b that had 1 mutation. In contrast, complete responses occurred in the following: 4 of 6 patients with the mutant-type HCV-1b that had five to ten mutations; 6 of 13 patients with genotype 2a of HCV (HCV-2a); and 2 of 5 patients with genotype 2b of HCV (HCV-2b). Among patients with the mutant-type HCV-1b or genotype 2 of HCV (HCV-2) the rate of complete response was significantly higher (12 of 24 vs. 0 of 16 patients, P < .001) and HCV-RNA levels were significantly lower (4.5 [4.0-6.5] vs. 6 [4.5-6.5] log copies/mL, median [range]; P < .001) compared with patients with the wild- or the intermediate-type HCV-1b. Patients with the mutant-type HCV-1b or HCV-2 whose HCV-RNA levels were lower than 6 log copies/mL had a complete response rate of 75% (12 of 16 patients) in contrast to 0% (0 of 24 patients) of the others (P < .001). These results indicate that the mutant-type HCV-1b or HCV-2 are sensitive to IFN-beta as well as IFN-alpha. In conclusion, the determination of HCV genotypes, NS5A2209-2248 of HCV-1b and serum HCV-RNA levels may facilitate the selection of patients with a high likelihood of response to IFN-beta.",0
1885,9096579,Regulation of fecal bile acid excretion in male golden Syrian hamsters fed a cereal-based diet with and without added cholesterol,"The objective of these studies was to investigate the comparative physiology and regulation of bile acid metabolism in the male Golden Syrian hamster by measuring the rate of fecal bile acid excretion and bile acid pool size in animals fed a cereal-based diet either alone, or with added cholesterol or cholestyramine. In group-housed hamsters fed only the plain diet fecal bile acid excretion in animals at 6, 10, and 15 weeks of age averaged 11.0, 8.0, and 6.9 mumol/d per 100 g body weight (bw), respectively. Pool size, measured by subtracting from the total amount of bile acid washed out over 12 hours of biliary diversion the amount of bile acid excreted in the stools over the same period, equalled 17.8 mumol/100 g bw in 15-week-old hamsters fed the plain diet. Hence, under basal conditions, these animals turned over about 38% of their bile acid pool daily. In hamsters fed a diet with 3% cholestyramine for 18 days, fecal bile acid excretion averaged 20.6 mumol/d per 100 g bw, and the pool size contracted to 5.8 mumol/100 g bw. In matching animals fed a diet containing 0.12% cholesterol for 30 days, hepatic cholesterol levels increased from 1.9 +/- 0.1 to 12.6 +/- 0.7 mg/g, fecal bile acid excretion increased marginally from 5.8 to 8.0 mumol/day per 100 g bw, while pool size was unchanged (16.6 mumol/100 g bw). When the cholesterol content of the diet was raised to 1.0%, hepatic cholesterol levels reached 66.5 +/- 2.6 mg/g, but bile acid excretion remained at 8 mumol/d per 100 g bw. These data define some of the basal features of bile acid metabolism in the hamster, and substantiate the view that the marked cholesterolemic response of this species may relate partly to a limited ability to convert dietary cholesterol to bile acid.",0
1886,9096587,Gap junctions and growth control in liver regeneration and in isolated rat hepatocytes,"The hepatocytes in the mature normal liver are tightly coupled through gap junctions, except during compensatory hyperplasia (regeneration) after partial hepatectomy when the gap junctions become down-regulated. The significance of this down-regulation has been a long-standing enigma. The present study of hepatocytes in primary culture and in the regenerating liver aimed at defining the relationship, if any, between hepatocyte gap junctional communication and proliferation. Gap junctional down-regulation in the regenerating liver appeared to be a specific phenomenon because desmosomes and the surface contact area between neighboring hepatocytes remained constant. All agents and conditions (dexamethasone in vivo; dexamethasone, cyclic adenosine monophosphate, serum, and high cell density in vitro) delaying gap junctional down-regulation also increased the lag before the cells reached competence to enter S phase. This raised the possibility that hepatocyte DNA replication was inhibited through preservation of gap junctions. However, we disproved this assumption by showing that the DNA replication (more specifically the G1/S transition rate constant) was inhibited even in hepatocytes completely devoid of gap junctional communication. The teleological advantage of linking gap junctional down-regulation to hepatocyte G1 progression therefore may not be to trigger DNA replication but to ensure that proliferating hepatocytes and hepatocytes responsible for liver-specific metabolic functions maintain separate pools of metabolites and signaling molecules.",0
1887,9099660,The effect of bedside case presentations on patients' perceptions of their medical care,"""BACKGROUND: Concern that case presentations at the bedside may make patients uncomfortable has led many residency programs to move presentations to the conference room. We performed a randomized, controlled trial of the effect of these two approaches on patients' perceptions of their care. METHODS: The study patients were adults admitted to the general medical service of a teaching hospital. Four house-staff """"firms"""" (each comprising teams of physicians) were randomly assigned to make their case presentations during morning rounds either at the patient's bedside or in a conference room for one week, to switch to the alternate site for a second week, and to return to the initial site for a third week. To assess patients' perceptions, a questionnaire was administered within 24 hours of admission. RESULTS: During the three weeks of the study, 95 patients had bedside presentations and 87 patients had conference-room presentations. When the former were compared with the latter, the patients with bedside presentations reported that their doctors spent more time with them on morning rounds (10 vs. 6 minutes, P<0.001). The patients with bedside presentations were also somewhat more likely to report favorable perceptions of their inpatient care (range of adjusted odds ratios, 1.12 to 2.17), although none of the associations were statistically significant. Better-educated patients were less likely to report that physicians used confusing terminology and explained tests and medications inadequately than were patients who had not completed high school. CONCLUSIONS: These data suggest that from the patient's perspective, bedside case presentations are at least as good as conference-room presentations, and perhaps preferable. When physicians make presentations at the bedside of less well educated patients, they should be especially careful to avoid medical jargon and to explain fully their plans for inpatient care.""",0
1888,9110908,Effects of cardiac sympathetic innervation on coronary blood flow,"BACKGROUND: The role of cardiac sympathetic nerves in regulating coronary blood flow is controversial. We sought to determine the degree to which cardiac efferent sympathetic signals modulate coronary blood flow. The heterogeneous sympathetic reinnervation in transplanted hearts provides a model for studying the vasomotor responses to adrenergic stimulation in reinnervated and denervated coronary territories of the same heart. METHODS: We studied 14 cardiac-transplant recipients who had normal coronary arteries and no evidence of rejection and 8 normal subjects. We used positron-emission tomography with [(11)C]hydroxyephedrine, an analogue of norepinephrine, to delineate sympathetic innervation. Using [(13)N]ammonia, we measured myocardial blood flow at rest, during adenosine-induced hyperemia, and in response to sympathetic stimulation induced by cold pressor testing. RESULTS: In the transplant recipients, the uptake of [(11)C]hydroxyephedrine was greater in the territory served by the left anterior descending artery (0.15+/-0.01) than in those served by the right coronary artery (0.07+/-0.01, P<0.001) or the circumflex artery (0.09+/-0.01, P<0.001). The basal flow was similar in all three regions, as was the percent increase in flow during hyperemia. However, the increase in flow in response to cold pressor testing was higher in the territory of the left anterior descending artery (46+/-10 percent) than in those of the right coronary artery (16+/-5 percent, P=0.01) or the circumflex artery (23+/-6 percent, P=0.06), although the changes in hemodynamics and levels of circulating catecholamines were similar. No such regional differences were observed in the normal subjects. CONCLUSIONS: Increases in coronary blood flow in response to sympathetic stimulation correlated with the regional norepinephrine content in the cardiac sympathetic-nerve terminals. These findings suggest that cardiac adrenergic signals play an important part in regulating myocardial blood flow.",0
1889,9113929,Physical activity and the risk of breast cancer,"BACKGROUND: Because physical activity may affect hormonal concentrations and energy balance, we decided to investigate whether everyday exercise is related to the risk of breast cancer. METHODS: During 1974 to 1978 and 1977 to 1983, a total of 25,624 women, 20 to 54 years of age at entry, enrolled in health surveys and answered questionnaires about leisure-time and work activity. RESULTS: During a median follow-up of 13.7 years, we identified 351 cases of invasive breast cancer among the 25,624 women in the cohort. Greater leisure-time activity was associated with a reduced risk of breast cancer, after adjustments for age, body-mass index (the weight in kilograms divided by the square of the height in meters), height, parity, and county of residence (relative risk, 0.63; 95 percent confidence interval, 0.42 to 0.95), among women who exercised regularly, as compared with sedentary women (P for trend=0.04). In regularly exercising women, the reduction in risk was greater in premenopausal women than in postmenopausal women, and greater in younger women (<45 years at study entry) than in older women (> or =45 years) (relative risk, 0.38; 95 percent confidence interval, 0.19 to 0.79). In stratified analyses the risk of breast cancer was lowest in lean women (body-mass index, <22.8) who exercised at least four hours per week (relative risk, 0.28; 95 percent confidence interval, 0.11 to 0.70). The risk was also reduced with higher levels of activity at work, and again there was a more pronounced effect among premenopausal than postmenopausal women. CONCLUSIONS: Physical activity during leisure time and at work is associated with a reduced risk of breast cancer.",0
1890,9113931,High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis,"BACKGROUND: Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS: Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS: We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS: In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.",0
1891,9134874,"Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection","BACKGROUND: In infants and children with maternally acquired human immunodeficiency virus type 1 (HIV-1) infection, treatment with a single antiretroviral agent has limited efficacy. We evaluated the safety and efficacy of a three-drug regimen in a small group of maternally infected infants. METHODS: Zidovudine, didanosine, and nevirapine were administered in combination orally to eight infants 2 to 16 months of age. The efficacy of antiretroviral treatment was evaluated by serial measurements of plasma HIV-1 RNA, quantitative plasma cultures, and quantitative cultures of peripheral-blood mononuclear cells. RESULTS: The three-drug regimen was well tolerated, without clinically important adverse events. Within four weeks, there were reductions in plasma levels of HIV-1 RNA of at least 96 percent (1.5 log) in seven of the eight study patients. Over the 6-month study period, replication of HIV-1 was controlled in two infants who began therapy at 2 1/2 months of age. Plasma RNA levels were reduced by 0.5 to 1.5 log in five of the other six infants. CONCLUSIONS: Although further observations are needed, it appears that in infants with maternally acquired HIV-1 infection, combined treatment with zidovudine, didanosine, and nevirapine is well tolerated and has sustained efficacy against HIV-1.",0
1892,9141417,"APF/CBP, the small, amphipathic, anionic protein(s) in bile and gallstones, consists of lipid-binding and calcium-binding forms","Two very similar small anionic, amphipathic proteins, a phospholipid-binding apoprotein (anionic polypeptide fraction [APF]) and a calcium-binding polypeptide (CBP), are found abundantly in bile and all types of gallstones. The often disparate properties among various preparations of APF/CBP could reflect different sources and separation procedures, leading to partly degraded and/or denatured protein and varied association of bile salts, lipids, bile pigments, and detergents. The present study presents new methods for isolation and purification of APF/CBP, and characterizes the preparations thus obtained. It was found that isolation by selective precipitation of proteins from fresh T-tube bile by added calcium chloride, followed by demineralization with ethylenediaminetetraacetic acid (EDTA), removal of salts, lipids, and some pigment by Sephadex LH-20, and serial ultrafiltration yields the purest preparations. Though free of lipids, bile salts, detergents, and most pigments, these new preparations all show the same 7-kd and 12-kd bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the same major peaks on hydrophobic high-performance liquid chromatography (HPLC), and retain the self-associative, lipid- and calcium-binding functions, typical of older preparations obtained by potentially denaturative procedures. The varied properties among APF/CBP preparations are thus apparently related mainly to their content of different proportions of two major components, lipid-binding APF and calcium-binding CBP. Immunologic cross-reactions indicate common epitopes, and amino acid analyses are also similar, suggesting that APF and CBP may have the same polypeptide backbone, but differ because of posttranslational modification(s). Sufficiently pure APF and CBP have now been obtained to permit possible structural identification by sequencing and molecular biological techniques, though such attempts have thus far been unsuccessful.",0
1893,9141428,The effect of changes in hepatocyte membrane potential on immediate-early proto-oncogene expression following partial hepatectomy in rats,"The stimulus responsible for inducing hepatocytes to enter the cell cycle following partial hepatectomy (PHx) remains to be identified. One suggested candidate is the change in hepatocyte membrane potential (PD) that occurs immediately following PHx. To test this possibility, we monitored changes in hepatocyte PD and immediate-early proto-oncogene expression in rats pretreated with saline or gamma aminobutyric acid (GABA), an amino-acid neurotransmitter that hyperpolarizes isolated hepatocytes. Intraperitoneal injections of saline or GABA (500 microg/g body weight) were administered to adult, male Sprague-Dawley rats 1 hour prior to 70% PHx. Rats were sacrificed and the livers excised at various times until 180 minutes post-PHx for messenger RNA (mRNA) and protein analyses. In additional groups of saline- and GABA-treated rats, PD changes were recorded continuously from -260 to 180 minutes post-PHx. Serum GABA concentrations were determined by ion-exchange chromatography with orthopthaldehyde fluorescence detection. Hepatocyte PD's were recorded in situ by intracellular microelectrodes with an Axoprobe-1A amplifier. Steady-state levels of c-fos, c-jun, jun-B, and c-myc transcripts and proteins were documented by Northern blots of poly(A)-enriched RNA derived from resected livers and Western blots of total nuclear protein, respectively. Serum GABA concentrations remained unchanged in saline-treated controls but increased 10- to 20-fold above baseline values in GABA-treated rats. In saline-treated controls, hepatocyte depolarization occurred immediately and was maintained throughout the 180 minutes post-PHx period (PD pre-PHx, -36.8 +/- 5.1; 15 minutes post-PHx, -27.5 +/- 5.7; and 180 minutes post-PHx, -28.3 +/- 4.4 mV, mean +/- SD); whereas in GABA-treated rats, hepatocyte PD remained unchanged (-37.0 +/- 1.1; -36.4 +/- 3.1 and -39.2 +/- 2.7 mV, respectively). Despite abrogation of hepatocyte PD changes, proto-oncogene mRNA and protein levels in saline- and GABA-treated rats were either similar or, in the case of c-fos and c-jun, increased five- to sevenfold in GABA-treated rats. The results of this study indicate the following: 1) hepatocytes depolarize immediately post-PHx and remain depolarized throughout the priming phase of the cell cycle; 2) elevated serum GABA concentrations prevent PHx-induced hepatocyte depolarization; and 3) depolarization is not the stimulus responsible for priming hepatocytes into replicative competence.",0
1894,9141433,Ectopic expression of the calcium-binding protein parvalbumin in mouse liver endothelial cells,"To elucidate the physiological role of the Ca2+ binding protein parvalbumin, we have generated transgenic mice carrying the full-length complementary DNA (cDNA) of rat parvalbumin under the control of the heavy-metal inducible metallothionein IIA promoter. Immunohistochemical and biochemical methods have been used to detect the presence of ectopic parvalbumin expression in different tissues. Here we show the expression of parvalbumin in endothelial cells lining the liver sinusoids in situ and after isolation in vitro. The hemodynamic effects of endothelin 1, a peptide hormone mediating potent vasoconstriction via calcium signalling, were investigated in the mouse liver perfused in situ. Vasoconstriction, thought to be mediated by the Ito cell, was not affected in the transgenic animals, whereas microvascular exchange, probed with the multiple indicator dilution technique, was markedly decreased in normal mice but virtually not affected in the transgenic animals. This suggests that ectopically expressed parvalbumin is involved in the regulation of Ca2+ signals in the sinusoidal endothelial cells. This animal model could be of interest to those working on the physiology of liver circulation.",0
1895,9141440,"Hrp12, a novel heat-responsive, tissue-specific, phosphorylated protein isolated from mouse liver","Previous studies from this laboratory identified a 28-kd nonreducible protein, liver-derived immunoinhibitory factor (LDIF) from the mouse liver. Isolation of this protein resulted in the co-purification of another unique protein called heat responsive protein 12 kd (Hrp12). In contrast to LDIF, Hrp12 was totally reducible to a protein of 12 kd suggesting a dimer. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) purification, followed by sequencing of an in situ cyanogen bromide digest of membrane bound Hrp12, yielded an internal 20-amino acid polypeptide. Degenerate oligonucleotides made from this peptide were used to screen a murine liver complementary DNA (cDNA) library. A 1240-bp cDNA clone was obtained with an internal 521-bp open reading frame (ORF). Sequence analysis of the 173-amino acid ORF of mouse Hrp12 showed a high degree of homology with a 99 amino acid rat liver-kidney perchloric acid-soluble protein (LKPS) and a 136-amino acid perchloric acid soluble rat protein (PSP). Transcripts for Hrp12 were mainly restricted to the liver and kidney in mouse and man. The protein was estimated to be approximately 0.8% of the total liver-soluble cytosolic protein. A zoo-blot probed at moderate stringency with labeled cDNA revealed a strong conservation of the gene in all of the mammalian species tested. Analysis of the protein structure of Hrp12 revealed motifs predicted to be targets for protein kinase C (PKC). More importantly, purified mouse Hrp12 could be phosphorylated in vitro with PKC. The protein had significant similarity to DnaK heat shock protein (Hsp)70 and contained a 54-amino acid stretch with sequence similarity to Hsp90. This prompted us to investigate the heat shock response of Hrp12. Isolated hepatocytes and hepatoma cells were exposed to different heat shock temperatures (39.5 degrees C, 42.5 degrees C, and 44.5 degrees C); and then total RNA was extracted and Northern analysis carried out. The message for this novel protein responded atypically to heat shock. Although the steady-state level of the message increased after heat shock, a marked oscillatory pattern was superimposed on it. In contrast, the steady-state levels of Hsp90 and Hsp70 messenger RNA (mRNA) were found to respond to heat shock in the expected manner. Finally, the amount of Hrp12 protein was also found to increase after heat shock in a manner that was consistent with heat-responsive proteins.",0
1896,9141444,Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis,"""Membranoproliferative glomerulonephritis (MPGN) may be a component of a generalized vasculitis as well as a component of the clinical expression of type-II mixed cryoglobulinemia (MC). Several studies have established a striking association between hepatitis C virus (HCV) infection and MC. The potential role of HCV in the pathogenesis of MPGN, which occurs in almost half of the cases of MC patients, has not been fully investigated, and the demonstration of HCV proteins as the antigenic constituent of the glomerular immune deposits has remained elusive. Kidney biopsy specimens were obtained from 12 HCV RNA, antibody to HCV (anti-HCV)-positive patients with MPGN and type-II MC, and from 8 controls (3 HCV RNA, anti-HCV-negative patients with MPGN and MC and 5 with noncryoglobulinemic """"idiopathic"""" MPGN). Murine monoclonal antibodies developed against c22-3, E2/NS1, c33c, c100-3, and NS5 proteins were used to detect HCV-related antigens by indirect immunohistochemistry. Acid electroelution of tissue sections was performed to enhance the sensitivity of the immunohistochemical method. Specific HCV-related proteins were detected in glomerular and tubulo-interstitial vascular structures in 8 (66.7%) HCV-positive MC patients and in none of the HCV RNA, anti-HCV-negative controls. HCV immunoreactive deposits displayed the following two major patterns: 1) a linear, homogeneous deposition along glomerular capillary walls, including endothelial cells and sub-endothelial spaces; and 2) a granular bead-like appearance with distinct deposits in mesangial and paramesangial cells. Immunoglobulin G (IgG) and M (IgM) and C3 fraction deposition in adjacent kidney sections displayed features comparable with those found for HCV deposits. Patients with granular deposits showed more pronounced renal impairment and severe proteinuria. These findings indicate that in MC patients with HCV-associated MPGN, kidney deposits consist of HCV-containing immune complexes that are likely to play a direct pathogenetic role in the renal damage.""",0
1897,9154766,Measurements of serum m�llerian inhibiting substance in the evaluation of children with nonpalpable gonads,"BACKGROUND: M�llerian inhibiting substance, produced constitutively by the prepubertal testes, promotes involution of the m�llerian ducts during normal male sexual differentiation. In children with virilization and nonpalpable gonads, only those with testicular tissue should have detectable serum concentrations of m�llerian inhibiting substance. METHODS: We measured serum mullerian inhibiting substance in 65 children with virilization at birth and nonpalpable gonads (age at diagnosis, 2 days to 11 years) and serum testosterone in 54 of them either after the administration of human chorionic gonadotropin or during the physiologic rise in testosterone that occurs in normal infants. RESULTS: The mean (+/-SD) serum mullerian inhibiting substance concentration in the 17 children with no testicular tissue was 0.7+/-0.5 ng per milliliter, as compared with 37.5+/-39.6 ng per milliliter in the 48 children with testes (P<0.001). In the latter group, the mean values in the 14 children with abnormal testes and the 34 with normal testes were 11.5+/-11.8 and 48.2+/-42.1 ng per milliliter, respectively (P< 0.001). The sensitivity and specificity of the serum m�llerian inhibiting substance assay for detecting the absence of testicular tissue were 92 percent and 98 percent, respectively, as compared with 69 percent and 83 percent for the measurement of serum testosterone. Furthermore, measurement of serum mullerian inhibiting substance was more sensitive than serum testosterone measurement for the identification of children with abnormal testes (67 percent vs. 25 percent), whereas the specificity of the two tests was similar. CONCLUSIONS: Measurements of serum mullerian inhibiting substance can be used to determine testicular status in prepubertal children with nonpalpable gonads, thus differentiating anorchia from undescended testes in boys with bilateral cryptorchidism and serving as a measure of testicular integrity in children with intersexual anomalies.",0
1898,9180090,Absence of association between insurance copayments and delays in seeking emergency care among patients with myocardial infarction,"""BACKGROUND: The requirement of copayments for emergency care is thought to control costs by reducing """"inappropriate"""" visits to the emergency department. However, requiring copayments may lead to adverse outcomes if patients delay seeking care for emergency conditions. To determine whether such requirements are associated with delays in seeking care, we examined the length of time from the onset of symptoms to arrival at the hospital among patients with myocardial infarction who did or did not have required insurance copayments. METHODS: All patients were enrolled in a single health maintenance organization (HMO) and presented with myocardial infarction at 1 of 19 hospitals in King County, Washington, from 1989 through 1994. There were 602 patients whose health insurance required a copayment for emergency department care (range, $25 to $100) and 729 patients with no copayment requirement. Data on the time to presentation were obtained from a review of ambulance and hospital records. RESULTS: The median length of time from the onset of symptoms to arrival at the hospital, as adjusted for age, sex, and race, was 135 minutes for the copayment group and 137 minutes for the group with no copayment (95 percent confidence interval for the difference, -19 to +16 minutes). There was no significant association between the presence or absence of a copayment requirement and the time to arrival at the hospital after adjustment for calendar year, income, educational level, cardiac history, or clinical symptoms. Since some patients may be unaware of their copayment requirement, we performed a subgroup analysis of data on patients who had a previous visit to the emergency department with the same copayment status - that is, of patients who were likely to know about their copayment. This analysis also showed no significant association between the requirement for a copayment and delays in seeking treatment. CONCLUSIONS: For privately insured patients in this HMO, the requirement of modest, fixed copayments for emergency services did not lead to delays in seeking treatment for myocardial infarction.""",0
1899,9185745,"Effect of ileal autotransplantation on cholesterol, bile acids, and biliary lipids in pigs with proximal small bowel resection","Our major aim was to investigate the consequences of ileal autotransplantation in pigs with proximal small intestinal resection on biliary lipids and metabolism of bile acids. Biliary lipid secretion rates and bile acid absorption were assessed by measuring dietary and biliary lipids, fractional cholesterol absorption, and fecal excretion of cholesterol and bile acids. In addition, serum bile acids and cholesterol, biliary and fecal bile acid species, and ileal villus height were determined after resection of the proximal 75% of the jejunoileum (n = 15) and autotransplantation of the remaining ileum with systemic venous drainage (n = 15) or transection (n = 5). Autotransplantation further increased fecal excretion of neutral and acidic steroids and serum concentration of bile acids after proximal resection (P < .05 for all); autotransplantation significantly decreased serum cholesterol, ileal villus height, fractional bile acid and cholesterol absorption, and biliary molar percentage of total and primary bile acids, whereas biliary secretion of bile acids, enriched by secondary bile acids, and cholesterol remained unchanged. At 14 weeks, ileal villus height, fractional bile acid and cholesterol absorption, biliary molar percentage of bile acids, and proportion of secondary biliary bile acids were altered by transplantation from the respective postresection values of 864 +/- 22 microm, 97.9 +/- 0.6%, 26.9 +/- 3.9%, 91.8 +/- 1.2% and 9.2 +/- 1.3% to 428 +/- 21 microm, 91.1 +/- 1.5%, 9.5 +/- 1.1%, 83.9 +/- 1.4% and 52.5 +/- 3.5% (P < .005 for all). Posttransplantation biliary bile acid secretion correlated positively with fractional reabsorption (r = .70) and biliary molar percentage (r = .73) of bile acids and ileal villus height (r = .65; P < .01 for all). Decreased absorption efficiency and biliary molar percentage of bile acids, increased biliary secondary bile acids, and short ileal villi point to bacterial overgrowth-induced bile acid malabsorption, which with decreased absorptive area may contribute to malabsorption of other lipids after ileal autotransplantation. Compensatory increase in cholesterol synthesis in the pigs with autotransplanted ileum appeared sufficient for constant biliary secretion of cholesterol and bile acids.",0
1900,9185755,Assessment of the role of activin A and transforming growth factor beta in the regulation of AML12 cell growth,"The present study was conducted to determine the role of two autocrine factors, activin A and transforming growth factor beta (TGF-beta), in the growth regulation of AML12 hepatocytes. We overexpressed truncated type II activin and/or TGF-beta receptors in AML12 cells. In AML12 cells overexpressing truncated type II activin receptors (AML-tAR cells), the inhibitory effect of activin A on DNA synthesis was completely blocked. AML-tAR cells proliferated faster than parental cells, both in the presence and absence of epidermal growth factor (EGF). However, AML-tAR cells could not grow in soft agar. Follistatin augmented EGF-induced DNA synthesis in AML12 cells, whereas it was ineffective in AML-tAR cells. In AML12 cells overexpressing truncated type II TGF-beta receptor (AML-tTR cells), the inhibitory effect of TGF-beta on DNA synthesis was blocked. AML-tTR cells proliferated faster than parental cells, both in the presence and absence of EGF, but at a slower rate than that of AML-tAR cells. AML-tTR cells did not grow in soft agar. The growth rate of cells overexpressing both types of truncated receptors was identical to that of AML-tAR cells, and these cells did not grow in soft agar. These results indicate that both activin A and TGF-beta act as autocrine inhibitors of DNA synthesis in AML12 cells, and that the blocking of the actions of two factors does not lead to transformation. Activin A is a predominant autocrine factor in these cells.",0
1901,9185767,"Cholesterogenesis, lipogenesis, cholesterol degradation to bile acids, and histopathology of the liver in LA/N-cp obese rats","Various lipid parameters were determined in lean control and LA/NIH-corpulent (LA/N-cp) rats, a normotensive strain showing metabolic characteristics associated with human Type IV hyperlipidemia. Hepatic and plasma total cholesterol, high density lipoproteins (HDL) cholesterol and triglycerides were significantly higher in the obese group than in the control group. Depending upon whether the data were expressed as per gram tissue or per organ, the rates of de novo fatty acid synthesis in the liver and adipose tissue were higher by 61% to 127% (P < .05) and 79% to 355% (P < .05), respectively, in the obese group compared with the lean control group. Similarly, hepatic rate of cholesterol synthesis was higher by 46% to 107% (P < .05) in the obese animals compared with the lean ones. In vivo hepatic rate of HDL2 cholesterol degradation to bile acids was lower in the obese group by 48% to 63% (P < .05). This was confirmed in the perfused liver in spite of the fact that cholesterol uptake from HDL2 was 3- to 4-fold higher in the obese group. These changes in lipid parameters of the obese animals were neither caused by hyperphagia because they were pair-fed with the control group nor caused by increased rate of food consumption because they were meal-fed. At the same time, all these lipid parameters were 17% to 20% higher in ad libitum-fed obese than in pair-fed obese group. Histopathological evaluation of the livers in the obese and control groups also showed prominent lipid droplets in the cytoplasm of the obese liver but not in the lean control liver. Thus, the possible causes of obesity in the LA/N-cp obese rats are higher synthetic rates of lipids coupled with lower rate of degradation of cholesterol to bile acids.",0
1902,9187066,Postmenopausal hormone therapy and mortality,"BACKGROUND: Postmenopausal hormone therapy has both benefits and hazards, including decreased risks of osteoporosis and cardiovascular disease and an increased risk of breast cancer. METHODS: We examined the relation between the use of postmenopausal hormones and mortality among participants in the Nurses' Health Study, who were 30 to 55 years of age at base line in 1976. Data were collected by biennial questionnaires beginning in 1976 and continuing through 1992. We documented 3637 deaths from 1976 to 1994. Each participant who died was matched with 10 controls alive at the time of her death. For each death, we defined the subject's hormone status according to the last biennial questionnaire before her death or before the diagnosis of the fatal disease; this reduced bias caused by the discontinuation of hormone use between the time of diagnosis of a potentially fatal disease and death. RESULTS: After adjustment for confounding variables, current hormone users had a lower risk of death (relative risk, 0.63; 95 percent confidence interval, 0.56 to 0.70) than subjects who had never taken hormones; however, the apparent benefit decreased with long-term use (relative risk, 0.80; 0.67 to 0.96, after 10 or more years) because of an increase in mortality from breast cancer among long-term hormone users. Current hormone users with coronary risk factors (69 percent of the women) had the largest reduction in mortality (relative risk, 0.51; 95 percent confidence interval, 0.45 to 0.57), with substantially less benefit for those at low risk (13 percent of the women; relative risk, 0.89; 95 percent confidence interval, 0.62 to 1.28). CONCLUSIONS: On average, mortality among women who use postmenopausal hormones is lower than among nonusers; however, the survival benefit diminishes with longer duration of use and is lower for women at low risk for coronary disease.",0
1903,9187068,Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia,"BACKGROUND: Recombinant human granulocyte colony-stimulating factor PO1 CA-20180ilgrastim) hastens the recovery from neutropenia after P30 CA-21765emotherapy, but its role in the management of childhood leukemia is unclear. METHODS: We randomly assigned 164 patients with acute lymphoblastic leukemia (age range, 2 months to 17 years) to receive placebo or G-CSF (10 microg per kilogram of body weight per day subcutaneously), beginning one day after the completion of remission-induction therapy and continuing until the neutrophil count was greater than or equal to 1000 per cubic millimeter for two days. The clinical and laboratory effects of this therapy were documented for 21 days. The area under the plasma G-CSF concentration-time curve was measured on days 1 and 7 in both groups. RESULTS: Responses to the growth factor could be assessed in 148 patients (73 in the G-CSF group and 75 in the placebo group). G-CSF treatment did not significantly lower the rate of hospitalization for febrile neutropenia (58 percent in the G-CSF group vs. 68 percent in the placebo group; relative risk, 0.85; 95 percent confidence interval, 0.59 to 1.16), increase the likelihood of event-free survival at three years (83 percent in both groups), or decrease the number of severe infections (five in the G-CSF group vs. six in the placebo group). Patients treated with G-CSF had shorter median hospital stays (6 days vs. 10 days, P=0.011) and fewer documented infections (12 vs. 27, P=0.009). The median total costs of supportive care were similar in the G-CSF and placebo groups ($8,768 and $8,616, respectively). Among patients who did not have febrile neutropenia during the first week of G-CSF or placebo injections, higher systemic exposure to the growth factor on day 7 was significantly related to a lower probability of subsequent hospitalization (P=0.049). CONCLUSIONS: G-CSF treatment had some clinical benefit in children who received induction chemotherapy for acute lymphoblastic leukemia, but it did not reduce the rate of hospitalization for febrile neutropenia, prolong survival, or reduce the cost of supportive care.",0
1904,9214466,Extramedullary hematopoiesis in the adult mouse liver is associated with specific hepatic sinusoidal endothelial cells,"In previous work, two anatomically distinct-liver sinusoid endothelial cells (LEC): LEC-1 and LEC-2, have been described. We also reported that extramedullary hepatic hematopoiesis occurs only in close contact with LEC-1, suggesting that these cells may provide the microenvironment necessary for the maintenance and growth of hematopoietic cells. In the present work, we studied the capacity of LEC-1 and LEC-2 to maintain in vitro hematopoiesis. LEC-1 and LEC-2 were isolated and cloned from livers of adult mice. Bone marrow cells (BM) enriched with primitive hematopoietic progenitors were isolated from day-2, post-5-FU-treated mice (5-FUBMC). LEC-1 supported the maintenance and differentiation of hematopoietic progenitors for more than 6 weeks in vitro. In contrast, LEC-2 cells poorly supported the proliferation of hematopoietic cells for only two weeks of the co-culture. LEC-1 and 5-FUBMC cocultures showed cobblestone-area formation and the presence of hematopoietic progenitors that are able to form colonies (CFC) in the adhering fraction after six weeks of coculture. LEC-1 co-cultures treated with a cocktail of cytokines (stem cell factor, interleukin [IL]1alpha, IL-3, and Epo) showed that megakaryocyte (CFU-Mk) and erythrocyte progenitors (BFU-e) were present during the entire period of the culture. Granulocyte-macrophage progenitors (CFU-GM) were present only during the first three weeks of the culture. These results suggest that LEC-1, but not LEC-2, provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of primitive hematopoietic cells. This could explain the anatomical restriction of hematopoietic cells for growing in LEC-1 domains during liver extramedullary hematopoiesis.",0
1905,9214467,"Transferrin receptor recycling in rat hepatocytes is regulated by protein phosphatase 2A, possibly through effects on microtubule-dependent transport","To understand the regulation of receptor-mediated endocytosis in hepatocytes, we have used two specific inhibitors of serine-threonine protein phosphatases (PP), microcystin (MCYST) and okadaic acid (OKA) as probes to alter protein phosphorylation in hepatocytes. We have then examined the impact of these changes on the specific binding and uptake of transferrin (Tf) in hepatocytes. The measurement of PP activity in hepatocyte lysates showed that OKA and MCYST shared a common inhibition of protein phosphatase 2A (PP2A). Our results showed that both OKA (250 nmol/L) and MCYST (500 nmol/L) significantly reduced Tf uptake at steady state (P < or = .05). The measurement of Tf internalization after 15 minutes in protein phosphatase inhibitor-pretreated cells revealed that the initial uptake was also significantly reduced. Binding studies showed that pretreatment with either of the phosphatase inhibitors did not result in significant changes in the K(d) for Tf binding to transferrin receptor (TfR). Additionally, no significant changes in the number of TfR in the plasma membrane were observed in phosphatase inhibitor-pretreated cells. The treatment of hepatocytes with nocodazole (NOC), which results in microtubule disassembly and inhibition of microtubule-based vesicle transport, caused comparable reductions in initial and steady state levels of transferrin accumulation. The changes in transferrin accumulation by both phosphatase inhibitors and nocodazole were accompanied by redistribution of the microtubule-anchored Golgi apparatus and lysosomal network from the perinuclear region to the cell periphery. Our data show that the regulation of Tf uptake by receptor-mediated endocytosis is mediated by PP2A and additionally may occur through regulation of microtubule-based vesicle transport.",0
1906,9219701,Pregnancy loss in the antiphospholipid-antibody syndrome--a possible thrombogenic mechanism,"BACKGROUND: The mechanisms of vascular thrombosis and pregnancy loss in the antiphospholipid-antibody syndrome are unknown. Levels of annexin V, a phospholipid-binding protein with potent anticoagulant activity, are markedly reduced on placental villi from women with this syndrome. Hypercoagulability in such women may therefore be due to the reduction of surface-bound annexin V by antiphospholipid antibodies. To test this idea, we studied how antiphospholipid antibodies affect levels of annexin V on cultured trophoblasts and human umbilical-vein endothelial cells and how they affect the procoagulant activity of these cells. METHODS: We isolated IgG fractions from three patients with the antiphospholipid-antibody syndrome and from normal controls. These antibodies were incubated with cultured BeWo cells (a placental-trophoblast cell line), primary cultured trophoblasts, and human umbilical-vein endothelial cells. Annexin V on the cell surfaces was measured by an enzyme-linked immunosorbent assay. The coagulation times of plasma overlaid on the cells were also determined. RESULTS: Trophoblasts and endothelial cells exposed to antiphospholipid-antibody IgG as compared with control IgG had reduced levels of annexin V (trophoblasts, 0.37 +/- 0.02 vs. 0.85 +/- 0.12 ng per well, P=0.02; endothelial cells, 1.6 +/- 0.04 vs. 2.1 +/- 0.05 ng per well, P=0.001). Also, trophoblasts and endothelial cells exposed to antiphospholipid-antibody IgG had faster mean (+/- SE) plasma coagulation times than cells exposed to control IgG (trophoblasts, 8.7 +/- 2.0 vs. 21.3 +/- 2.9 minutes, P=0.02; endothelial cells, 9.8 +/- 0.8 vs. 14.2 +/- 1.2 minutes, P=0.04). CONCLUSIONS: Antiphospholipid antibodies reduce the levels of annexin V and accelerate the coagulation of plasma on cultured trophoblasts and endothelial cells. The reduction of annexin V levels on vascular cells may be an important mechanism of thrombosis and pregnancy loss in the antiphospholipid-antibody syndrome.",0
1907,9252137,"Possible involvement of pertussis toxin-sensitive G protein in hepatocyte growth factor-induced signal transduction in cultured rat hepatocytes: pertussis toxin treatment inhibits activation of phospholipid signaling, calcium oscillation, and mitogen-activated protein kinase","Treatment of primary cultured rat hepatocytes with hepatocyte growth factor (HGF) gives rise to inositol phosphate formation, cytosolic calcium oscillation, activation of mitogen-activated protein (MAP) kinase and phospholipase D (PLD), and arachidonic acid release, leading to DNA synthesis. Pretreatment of cultured hepatocytes with pertussis toxin (PT), which is known to adenosine diphosphate-ribosylate Gi and Go guanine nucleotide -binding proteins and to inhibit their functions, partially inhibited HGF-induced [3H]thymidine incorporation in a concentration-dependent manner. These results suggest that HGF-mediated DNA synthesis of hepatocytes is partly regulated via PT-sensitive guanine nucleotide-binding protein. Therefore, the effects of PT treatment on HGF-induced signal-transduction pathways were investigated. HGF-induced MAP kinase activation and arachidonic acid release were decreased by PT treatment, whereas PLD activation was diminished by PT to the level of unstimulated control. PT also interfered with HGF-induced inositol phosphate formation and cytosolic calcium oscillation. These results suggest that both PT-sensitive and PT-insensitive pathways are involved in HGF-induced signaling.",0
1908,9252140,Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells,"During the course of liver fibrogenesis, myofibroblast-like cells (MFLC), mostly derived from hepatic stellate cells, proliferate and synthesize excessive amounts of extracellular matrix components. Pentoxifylline (PTX) elicits antiproliferative and antifibrogenic effects in human dermal fibroblasts. The aim of this study was to test the effects of PTX on the proliferation and the synthesis of collagen and gelatinase A in cultured human hepatic MFLC. MFLC were obtained by outgrowth from human liver explants. PTX markedly reduced serum-driven cell proliferation, as assessed by nuclear autoradiography experiments and measurement of actual cell growth. Growth inhibition was totally reversed after removal of the drug. PTX also affected collagen synthesis, as measured by [3H]hydroxyproline incorporation into proteins. Synthesis of secreted collagen was reduced by 24% and 67% at concentrations of 100 microg/mL and 500 microg/mL, respectively. This was associated with a decrease in type I and III procollagen messenger RNA (mRNA), indicating an effect at a pretranslational level. In contrast, PTX did not affect either gelatinase A activity released in culture medium or the expression of its specific mRNA. In conclusion, PTX exhibits potent antiproliferative and antifibrogenic effects toward hepatic MFLC. These results suggest that PTX might have therapeutic implications in chronic liver disease.",0
1909,9252141,Cell growth and differentiation of a novel mouse Ito (fat-storing) cell line transformed by a temperature-sensitive mutant of simian virus 40,"A novel mouse Ito (fat-storing) cell line (A640-IS) was established by transformation with a temperature-sensitive mutant of simian virus 40 (SV40) and the relationships between the expression of SV40 large T antigen and the growth, differentiation, and functions of A640-IS cells were investigated. A640-IS cells expressed large T antigen when cultured at 33 degrees C. At this temperature, the cells grew actively, assumed a fibroblastic shape, and showed few Ito cell characteristics. In contrast, when large T-antigen expression was inhibited by culture at 39 degrees C, the cells did not grow but differentiated into Ito cells as assessed by both morphological and functional characteristics. Expression of the transcription factor SCL (stem cell leukemia), which plays a role in the development and differentiation of blood cells, was observed at both 33 degrees C and 39 degrees C, although expression was greater at 33 degrees C. Therefore, opposite patterns of cell growth and the functions of differentiated cells occurred at 33 degrees C and 39 degrees C in this novel Ito cell line. Transforming growth factor beta1 stimulated A640-IS cells to produce fibronectin, collagen type III, and laminin. This unique Ito cell line provides a useful model to address important questions regarding the nature of these cells.",0
1910,9252153,Different intrahepatic distribution of phosphatidylglycerol and phosphatidylserine liposomes in the rat,"Liposomes with diameters of 200 to 400 nm containing phosphatidylserine (PS) or phosphatidylglycerol (PG) were injected intravenously into rats. Two hours after injection, 75% of the injected dose of PS liposomes was found in the liver and only 10% found in the spleen, while 35% of the PG liposomes was found in the liver and as much as 40% was found in the spleen. Cell-isolation experiments revealed the following remarkable difference in the intrahepatic distribution between the two liposome formulations: the PS liposomes distributed in about equal amounts to Kupffer cells and hepatocytes, despite their size (200-400 nm) exceeding that of the endothelial fenestrae (average 150 nm), whereas the PG liposomes were only taken up by the Kupffer cells and not at all by the hepatocytes. Double-label studies, using liposomes in which the lipid-moiety was radio labeled with [3H]cholesteryloleylether ([3H]CE) and the water phase with [14C]sucrose, showed that the liposomes were taken up as intact particles. These observations were confirmed through electron microscopy by determining the in situ localization of liposome-encapsulated colloidal gold particles in thin sections of liver and spleen. The differences in organ distribution are ascribed to differences in opsonization patterns of the two liposomal surfaces. For the difference in intrahepatic distribution, we offer the following two explanations: the exploitation of the blood cell-mediated forced sieving concept and the indication of a PS-specific pharmacological effect on the dimensions of the fenestrations.",0
1911,9262495,The effect of calcium supplementation on bone density during lactation and after weaning,"BACKGROUND: Women may lose bone during lactation because of calcium lost in breast milk. We studied whether calcium supplementation prevents bone loss during lactation or augments bone gain after weaning. METHODS: We conducted two randomized, placebo-controlled trials of calcium supplementation (1 g per day) in postpartum women. In one trial (the study of lactation), 97 lactating and 99 nonlactating women were enrolled a mean (+/-SD) of 16+/-2 days post partum. In the second trial (the study of weaning), 95 lactating women who weaned their infants in the 2 months after enrollment and 92 nonlactating women were enrolled 5.6+/-0.8 months post partum. The bone density of the total body, lumbar spine, and forearm was measured at enrollment and after three and six months. RESULTS: The bone density of the lumbar spine decreased by 4.2 percent in the lactating women receiving calcium and by 4.9 percent in those receiving placebo and increased by 2.2 and 0.4 percent, respectively, in the nonlactating women (P<0.001 for the effect of lactation; P= 0.01 for the effect of calcium). After weaning, the bone density of the lumbar spine increased by 5.9 percent in the lactating women receiving calcium and by 4.4 percent in those receiving placebo; it increased by 2.5 and 1.6 percent, respectively, in the nonlactating women (P<0.001 for the effects of lactation and calcium). There was no effect of either lactation or calcium supplementation on bone density in the forearm, and there was no effect of calcium supplementation on the calcium concentration in breast milk. CONCLUSIONS: Calcium supplementation does not prevent bone loss during lactation and only slightly enhances the gain in bone density after weaning.",0
1912,9262496,Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma,"BACKGROUND: Mutations of the p53 gene are associated with a poor prognosis in several types of cancer. We investigated the prognostic importance of p53 mutations in patients with aggressive B-cell lymphoma. METHODS: We examined the relation between the presence or absence of a detectable p53 mutation in lymphoma cells and the response to chemotherapy and overall survival in 102 previously untreated patients with aggressive B-cell lymphoma. Mutations of the p53 gene were identified by polymerase-chain-reaction-mediated analysis of single-strand conformation polymorphisms and by direct sequencing. RESULTS: Of 102 cases of aggressive B-cell lymphoma, 22 (22 percent) involved p53 mutations. The rate of complete remission was significantly lower in patients with a tumor carrying a p53 mutation (6 of 22 patients, 27 percent) than in those with the wild-type p53 gene (61 of 80 patients, 76 percent) (P<0.001). Overall survival was significantly lower among patients with p53 mutations than among those with the wild-type p53 gene; the Kaplan-Meier estimates of survival at five years were 16 percent and 64 percent, respectively (P<0.001). Multivariate analysis incorporating prognostic factors from the international prognostic index demonstrated that p53 mutations had independent effects on the rates of complete remission and survival. When we categorized patients according to the international prognostic index, we found no effect of p53 mutations in patients in the groups at high-intermediate and high risk. However, these mutations were significantly associated (P< 0.001) with low rates of complete remission (33 percent vs. 91 percent) and survival (27 percent vs. 81 percent at five years) in the groups at low and low-intermediate risk. CONCLUSIONS: Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.",0
1913,9287230,"Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency","BACKGROUND: Major-histocompatibility-complex (MHC) class II deficiency is an autosomal recessive primary immunodeficiency disease in which MHC class II molecules are absent. It is a genetically heterogeneous disease of gene regulation resulting from defects in several transactivating genes that regulate the expression of MHC class II genes. The mutations responsible for MHC class II deficiency are classified according to complementation group (a group in which the phenotype remains uncorrected in pairwise fusions of cells). There are three known complementation groups (A, B, and C). METHODS: To elucidate the genetic defect in patients with MHC class II deficiency that was not classified genetically, we performed direct complementation assays with the three genes known to regulate the expression of MHC class II genes, CIITA, RFX5, and RFXAP, and the relevant mutations were identified in each patient. RESULTS: Mutations in the RFXAP gene were found in three patients from unrelated families, and the resulting defect was classified as belonging to a novel complementation group (D). Transfection with the wild-type RFXAP gene restored the expression of MHC class II molecules in the patients' cells. CONCLUSIONS: Mutations in a novel MHC class II transactivating factor, RFXAP, can cause MHC class II deficiency. These mutations abolish the expression of MHC class II genes and lead to the same clinical picture of immunodeficiency as in patients with mutations in the other two MHC class II regulatory genes.",0
1914,9303480,A new rat bile ductular epithelial cell culture model characterized by the appearance of polarized bile ducts in vitro,"The rat treated with bile duct ligation (BDL) and furan is a unique animal model of massive bile ductular hyperplasia in which normal liver parenchyma is largely replaced with well-differentiated proliferated bile ductules. We have now developed a simple cell isolation procedure to obtain and culture viable bile ductular epithelial cells in high numbers and with a high degree of purity from the livers of BDL/furan-treated rats. Primary monolayer cell cultures were readily established when the isolated bile ductular epithelial cells were cultured in plastic tissue culture wells coated with rat tail tendon type I collagen plus bovine plasma fibronectin. Under these conditions, epidermal growth factor (EGF) was mitogenic for the cultured cells, and they retained phenotypic features typical of hyperplastic bile ductular epithelium but did not show evidence of ductal morphogenesis in vitro. In contrast, when the isolated bile ductular cells were cultured for 7 to 16 days in the presence of 25 ng EGF/mL and 10% fetal bovine serum on type I collagen gels, they formed into branching ductal structures whose ultrastructural features very closely resembled those of polarized hyperplastic bile ductules/ducts in vivo. Histological preparations of these gel cultures further showed that numerous ductal structures with defined lumens were present. Phenotypically, these ductal structures were completely surrounded by a thickened basement membrane that was strongly immunoreactive for laminin. Like their in vivo biliary cell counterparts, the epithelial cells comprising these ductal structures in culture also exhibited strong immunocytochemical staining reactions for cytokeratins 8 and 19, for glutathione S-transferase pi 7, and for luminal gamma-glutamyl transpeptidase, but they did not express immunoreactive albumin or alpha-fetoprotein. Occasional epithelial cells of the ductal structures, when examined in 10-day-old primary gel culture, showed strong nuclear staining for incorporated 5-bromo-2'deoxyuridine, indicating active cell proliferation. Our results support the development of a novel biliary epithelial cell culture model that has the potential of serving as a powerful tool for investigation of factors that regulate hyperplastic bile ductular morphogenesis, cell proliferation, and polarized cell functions in a structural form in vitro that mimics that of hyperplastic bile ductules induced in vivo.",0
1915,9303485,Ki-67 expression during rat liver regeneration after partial hepatectomy,"Antibodies to the cell-cycle-associated Ki-67 protein have been widely used for more than a decade as markers of proliferative cells. The prototype antibody Ki-67 reacted only with snap-frozen human tissue, but a novel antibody, MIB-1, was able to detect the Ki-67 antigen in paraffin wax-embedded human tissue. The ability of MIB-5, a novel antibody reactive with the rat equivalent Ki-67 protein, to immunohistochemically detect cycling parenchymal and littoral cells in the regenerating rat liver is reported. Rats underwent a standard two-thirds partial hepatectomy (PH), and groups of three animals were killed at intervals for up to 192 hours after PH. DNA synthesis was monitored by flash labeling with bromodeoxyuridine, and the response was as expected with a significant upsurge in hepatocyte labeling at 16 to 17 hours after PH. On the other hand, MIB-5 labeled a relatively constant percentage of hepatocytes (4%-8%) during the first 16 hours after PH, before a large proportion became labeled, also at 17 hours. The temporal pattern of MIB-5 labeling was similar to that of bromodeoxyuridine labeling, although, as expected, MIB-5 indices were higher. Semiquantification of Ki-67 messenger RNA (mRNA) levels by reverse-transcription polymerase chain reaction showed modest (fourfold to fivefold) increases in abundance during the first 12 hours after PH, but then levels increased dramatically to be at least 15-fold those of intact liver at 36 hours after PH. Much higher than normal levels of Ki-67 mRNA persisted throughout the period of study and even at 96 hours after PH they were still ninefold greater than normal. This study has shown the usefulness of the MIB-5 antibody to monitor proliferation in the rat liver, and furthermore, the pattern of expression of both the mRNA and the protein suggest that the Ki-67 protein, with hitherto unknown function, is more abundant in DNA synthesis and mitosis than in the early or even very late first G1 phase.",0
1916,9303490,Up-regulation of type I procollagen C-proteinase enhancer protein messenger RNA in rats with CCl4-induced liver fibrosis,"Using a polyclonal antibody raised against a liver stellate cell (LSC) line derived from a rat CCl4-cirrhotic liver, we isolated 14 clones from a complementary DNA library prepared with total RNA extracted from the same cell line, with nucleotide sequences homologous to that of the type I procollagen C-proteinase enhancer protein (PCPE) gene. The longest PCPE insert of 1,530 base pairs contained an open reading frame coding for 468 amino acids. PCPE cDNA recognized by Northern blot a 1.7-kilobase messenger RNA (mRNA) in total RNA extracted from freshly isolated and early passaged LSC, LSC lines derived from normal (NFSC) and cirrhotic (CFSC) rat livers, and various LSC clones derived from CFSC. The expression of PCPE mRNA was increased threefold in CFSC compared with NFSC. PCPE mRNA was not detected in total rat liver, freshly isolated hepatocytes, or endothelial or Kupffer cells. However, the expression of PCPE mRNA was induced in fibrotic livers of rats treated with CCl4. PCPE mRNA expression in LSC was up-regulated by transforming growth factor beta1 (TGF-beta1) and down-regulated by tumor necrosis factor alpha (TNF-alpha), similar to the changes in alpha1 (1) procollagen mRNA induced by these cytokines. PCPE was not detectable in liver biomatrix proteins obtained from normal liver. However, PCPE was increased in liver biomatrix proteins from cirrhotic livers and was proportional to the amount of collagen. These data suggest that PCPE may play an important role in the processing of type I collagen during liver fibrogenesis, and that TGF-beta1 and TNF-alpha regulate its expression.",0
1917,9303496,Intercellular adhesion molecule-1 and CD18 are involved in neutrophil adhesion and its cytotoxicity to cultured sinusoidal endothelial cells in rats,"The expression of several adhesion molecules is increased on the hepatic sinusoidal endothelial cells (SECs) in various liver diseases. The objective of this study is to assess the roles of intercellular adhesion molecule 1 (ICAM-1) and of CD18 in the interaction between the neutrophils (polymorphonuclear leukocytes [PMNs]) and SECs and in the injury to SECs mediated by PMNs. Rat PMNs was perfused on SECs stimulated with tumor necrosis factor alpha (TNF-alpha) using an in vitro flow system. The number of adhered PMNs to SECs and that of PMNs migrated under SECs was counted and the effects of anti-ICAM-1, anti-CD18, and dexamethasone were studied. We also define the effect of these antibodies on the SEC injury mediated by PMNs stimulated with phorbol 12-myristate 13-acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP). TNF-alpha significantly increased the adhesion of PMNs to SECs (322 +/- 26 cells/mm2) compared with controls (194 +/- 22 cells/mm2). Anti-ICAM-1 and anti-CD18 significantly inhibited the adhesion of PMNs (131 +/- 10 and 51 +/- 30 cells/mm2, respectively). These antibodies also decreased the migration rate of PMNs (6.0% and 7.9%, respectively) compared with controls (migration rate, 21.2%). The SEC injury induced by PMA- and fMLP-activated PMNs was prevented by anti-ICAM-1 and anti-CD18. The adhesion of PMNs induced by TNF-alpha was inhibited by the treatment with dexamethasone (160 +/- 20 cells/mm2) via a down-regulation of ICAM-1 expression on SECs. The interactions between ICAM-1 and CD18 appeared to be important in the adhesion and the migration of PMNs to SECs. The injury to SECs was induced by the close interaction between the activated PMNs and SECs mediated via ICAM-1 and CD18.",0
1918,9303499,Hepatic ICG removal in the pig depends on plasma protein and hematocrit: evidence of sinusoidal binding disequilibrium and unstirred water layer effects,"The influence of binding protein concentration and hematocrit on hepatic uptake of indocyanine green (ICG) was studied in anesthetized pigs during constant infusion of ICG. By exchange transfusions, we either substituted plasma protein with dextran 70 (n = 8) or changed hematocrit (n = 8). Intrinsic hepatic clearance of ICG, K, was calculated from plasma flow rate and concentrations in peripheral artery and liver vein after correction for extrahepatic distribution. By analyzing the relative change of K versus either the protein dilution factor or the change in plasma volume fraction (1-hct), we evaluated four current models for hepatic uptake of protein-bound substances even though a number of model parameters were unknown (parameter-free testing). Protein dilution factors (unitless) of 0.506 +/- 0.027, 0.673 +/- 0.011, and 0.749 +/- 0.028 were associated with inverse K ratios of 0.621 +/- 0.025, 0.758 +/- 0.021, and 0.817 +/- 0.013. These data rejected the traditional hypothesis that ICG uptake is proportional to the unbound concentration. They were compatible with development of binding disequilibrium along the sinusoidal lumen, an unstirred water layer close to the hepatocyte surface, or facilitated uptake from the bound pool. A plasma volume ratio [(1-hct2)/(1-hct1)] of 1.14 +/- 0.02 was associated with a K ratio of 1.07 +/- 0.02 (P = .01). Only sinusoidal binding disequilibrium predicted this finding, whereas an additional unstirred water layer effect could not be excluded. The observations could be simulated by a model that included both of these effects. Thus, neither the relative changes of K nor the absolute K values required the assumption of facilitated uptake from the bound pool. The parameter-free design presented may be useful with other ligands in intact animals.",0
1919,9303503,Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat,"The sialomucin CD34 is expressed on human and mouse hematopoietic stem cells and is used as an important marker for isolating the hematopoietic stem/progenitor cells. The involvement of hepatic stem cells in liver regeneration under certain conditions in adult rats is now well supported. The objective of the present research was to explore the idea that CD34 might also be expressed on hepatic stem cell progeny. Polymerase chain reaction (PCR)-based cloning of rat CD34 was partially accomplished. During the hepatic stem cell activation (2-acetylaminofluorene/partial hepatectomy [AAF/PH] model), the CD34 transcripts were increased and reached the peak level between 9 and 12 days after partial hepatectomy when the progenitor cells (e.g., oval cells, early hepatocytes in basophilic foci, and intestinal type of cells) are most abundant. Both in situ hybridization and immunohistochemistry, using anti-mouse CD34 antibody, which recognizes the cytoplasmic domain, clearly showed the expression of CD34 on oval cells as well as on endothelial cells of large hepatic vessels. In addition, bile ductular epithelial (BDE) cells both in the AAF/PH model and in normal liver expressed CD34, suggesting a close relationship between BDE cells and the hepatic stem-cell compartment. Taken together, the data indicate that CD34 would, similar to its role in the hematopoietic system, be an important probe for characterizing the cellular biology of the hepatic stem-cell compartment.",0
1920,9303515,Effects of interferon treatment on the antiviral T-cell response in hepatitis C virus genotype 1b- and genotype 2c-infected patients,"The viral genotype may influence the response to interferon (IFN) treatment in chronic hepatitis C virus (HCV) infection. To characterize potential mechanisms responsible for this effect, we assessed whether IFN modulation of HCV-specific T-cell responses differs in patients infected by different genotypes. The T-cell response to HCV core protein was sequentially analyzed before and during IFN treatment in two groups of patients chronically infected with HCV genotype 1b (eight patients) or 2c (eight patients). Overlapping 20 mer peptides corresponding to the amino acid sequence of the prevalent viral population identified in the serum of each patient were used for the analysis of the T-cell proliferative response to avoid possible problems caused by amino acid differences between infecting virus and HCV proteins used in vitro. Recombinant HCV core antigen was used in parallel. The level of viremia was monitored by competitive polymerase chain reaction (PCR). The T-cell response to HCV peptides and recombinant core protein detected throughout the follow-up was significantly more vigorous in genotype 2c- than in genotype 1b-infected patients. This difference was the result of a greater enhancement of the T-cell response caused by IFN treatment in genotype 2c- compared with genotype 1b-infected patients. The different IFN modulatory effect on T cells from genotype 1b- and genotype 2c-infected patients illustrates an aspect of the virus-host interaction, which may contribute toward the explanation of why different genotypes differ in responsiveness to IFN treatment.",0
1921,9305669,Management of hepatitis C: a national survey of gastroenterologists and hepatologists,"A survey on the management of hepatitis C virus (HCV) infection was conducted by the American Digestive Health Foundation among United States physicians who are most familiar with the disease. The two-page survey was completed by 57% of a random sample of 2,500 members of the American Gastroenterological Association and the American Association for the Study of Liver Diseases. Analysis was limited to the 1,249 responses from physicians who spent at least 1 day per week in patient care. These physicians frequently managed patients with HCV, and nearly three quarters treated patients with interferon. To prevent transmission, the large majority of physicians recommended measures to avoid blood exposures, were uncertain or disagreed about the importance of sexual contact, and did not caution patients about casual contact. More than 70% of physicians told their patients to stop or minimize alcohol consumption. In the management of a patient with antibody to HCV but normal serum aminotransferase activities, 87% of physicians would have ordered a supplemental test, and if HCV were confirmed, 46% would have obtained a liver biopsy, but only 15% would have treated the patient with interferon. For a patient with chronic HCV infection and elevated serum aminotransferase activities, more than 90% of physicians would have obtained a liver biopsy and approximately 60% would have treated with interferon. Physicians who are most familiar with the management of patients with HCV generally agreed with the recommendations of the Consensus Development Conference Panel regarding prevention of transmission, minimizing alcohol consumption, and managing patients with typical presentations. Controversies remain regarding some issues of general management, the value of molecular testing, and the need to treat certain patients with interferon.",0
1922,9328313,Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells,"Liver stellate cells (SCs) play central roles in both the storage of retinol and the development of liver fibrosis. The present study is aimed to understand the mechanism by which retinoic acid (RA, an active metabolite of retinol) enhances hepatic fibrosis in rats. We tested the effect of 9-cis-RA on several aspects in vitro rat SC cultures, including the activity of cellular plasminogen activator (PA), messenger RNA (mRNA), and protein levels of transforming growth factor-beta (TGF-beta) mRNA level of type-I procollagen, and the activity of type-I collagenase. Employing the rat liver fibrosis model produced by porcine serum, we also estimated the effect of oral administration of a stable RA analog on the progression of the fibrosis, as well as on hepatic TGF-beta contents. In vitro SC cultures, 9-cis-RA enhanced cellular PA and plasmin levels thereby induced plasmin-mediated activation of latent TGF-beta. Active TGF-beta generated self-stimulated its synthesis as well as that of collagen and suppressed the production of collagenase in an autocrine manner. In in vivo rat models, an RA analog accelerated the porcine serum-induced fibrosis by enhancing TGF-beta contents and, thus, collagen levels in the liver, although the RA analog alone was not fibrogenic. These results suggest that RA exacerbated liver fibrosis, at least in part, by inducing the activation and production of latent TGF-beta in liver SCs.",0
1923,9328315,Flow cytometric analysis of vesicular pH in rat hepatocytes after ethanol administration,"We examined the effect of ethanol administration on intravesicular pH in intact hepatocytes by applying a flow cytometric technique to detect fluorescein-isothiocyanate-dextran (FITC-dextran) in acidic vesicles. Rats were pair-fed liquid diets containing either ethanol or isocaloric carbohydrate for 1 to 5 weeks. Our study showed that ethanol administration increased the in situ pH of hepatic lysosomes by 0.15 to 0.2 pH units. This pH increase was sufficient to cause a significant reduction in lysosomal protein degradation. Long-term ethanol administration also caused a significant alkalinization of hepatic endosomes, and this increased pH was sustained over the course of vesicular acidification in hepatocytes incubated in vitro. Direct exposure of hepatocytes from rats fed control diet to either 25 mmol/L ethanol or 50 micromol/L colchicine also brought about a rapid alkalinization of acidic vesicles in a manner that resembled that seen in hepatocytes from ethanol-fed rats. These same treatments augmented the vesicular alkalinization already present in cells from ethanol-fed animals. Although ethanol administration had no effect on the content of the hepatic mannose-6-phosphate/IGFII receptor, the results indicate that sustained alkalinization of endosomes could have important functional consequences by impairing M-6-P/IGFII receptor recycling, thereby disrupting the delivery of newly synthesized hydrolases to lysosomes. This decreased complement of hydrolases within lysosomes together with alkalinization of the intralysosomal compartment would result in an overall decrease in lysosomal proteolysis.",0
1924,9328323,"Induction of cMrp/cMoat gene expression by cisplatin, 2-acetylaminofluorene, or cycloheximide in rat hepatocytes","The human multidrug-resistance-associated protein (MRP), a member of the adenosine triphosphate (ATP)-binding cassette transporter superfamily, is frequently overexpressed in tumor cells resistant to antineoplastic drugs. In the rat, two Mrp isoforms have been identified, Mrp and cMrp. cMrp, also called Mrp2 or cMoat (canalicular multispecific organic anion transporter), is expressed in the canalicular membrane of rat hepatocytes and mediates the excretion of glucuronate, sulfate, and glutathione conjugates into bile. We investigated the expression of cMrp and Mrp in rat hepatocytes in primary culture. Treatment with the chemical carcinogen 2-acetylaminofluorene (2-AAF), the antineoplastic drug cisplatin, and the protein-synthesis inhibitor cycloheximide led to a dose-dependent and time-dependent increase in cmrp gene expression. A 347-base pair cmrp complementary DNA (cDNA) probe served to demonstrate the induction of cmrp messenger RNA (mRNA) with 40 micromol/L 2-AAF, 5 micromol/L cisplatin, or 5 micromol/L cycloheximide. An analogous response was obtained for the increase in cMrp protein. Mrp mRNA was below the detection limit in Northern blots of RNA from liver and hepatocyte cultures, in contrast to rat testis mRNA which served as a positive control. Immunofluorescence microscopy of cultured hepatocytes was used to visualize cMrp in the plasma membrane. Treatment with 2-AAF led to a marked increase in the immunofluorescence signal confirming the cMrp-inducing potency of 2-AAF. In conclusion, the inducing effect of the compounds studied may reflect a general inducibility of hepatic cMrp by a variety of cytotoxic, carcinogenic, and chemotherapeutic agents which is likely to be of relevance for the acquisition of multidrug resistance during chemotherapy and in the process of chemical carcinogenesis in the liver.",0
1925,9328331,Molecular features of the hepatitis B virus nucleocapsid T-cell epitope 18-27: interaction with HLA and T-cell receptor,"The strength of the cytotoxic T lymphocyte (CTL) response is believed to influence the final outcome of hepatitis B virus (HBV) infection. Among the different CTL epitopes so far identified, the sequence 18-27 of the HBV nucleocapsid antigen is widely recognized by CTL of HLA-A2-positive patients with acute self-limited HBV infection, and represents the main component of a peptide-based therapeutic vaccine aimed at stimulating the antiviral CTL response in patients with chronic hepatitis B. In the present study, we further analyzed the features of this important HBV region by the following: 1) defining the contribution of individual residues of the epitope to the interaction with the T-cell receptor (TCR) and with the HLA-A0201 molecule; 2) assessing the antigenicity of this viral region in the context of the different HLA-A2 subtypes; and 3) testing whether this sequence can stimulate not only HLA-class I but also HLA class II restricted T-cell responses. A clear hierarchy was observed in the ability of individual residues to act as TCR or HLA binding sites. Furthermore, the sequence HBc18-27 was able to be recognized by specific CTL when presented in the context of different HLA-A2 subtypes. Finally, this HBV region was also found to stimulate HLA class II restricted T-cell responses. These data further increase the potential coverage and efficacy of therapeutic vaccines based on the HBc18-27 sequence.",0
1926,9345078,"Falls, injuries due to falls, and the risk of admission to a nursing home","BACKGROUND: Falls warrant investigation as a risk factor for nursing home admission because falls are common and are associated with functional disability and because they may be preventable. METHODS: We conducted a prospective study of a probability sample of 1103 people over 71 years of age who were living in the community. Data on demographic and medical characteristics, use of health care, and cognitive, functional, psychological, and social functioning were obtained at base line and one year later during assessments in the participants' homes. The primary outcome studied was the number of days from the initial assessment to a first long-term admission to a skilled-nursing facility during three years of follow-up. Patients were assigned to four categories during follow-up: those who had no falls, those who had one fall without serious injury, those who had two or more falls without serious injury, and those who had at least one fall causing serious injury. RESULTS: A total of 133 participants (12.1 percent) had long-term admissions to nursing homes. In an unadjusted model, the risk of admission increased progressively, as compared with that for the patients with no falls, for those with a single noninjurious fall (relative risk, 4.9; 95 percent confidence interval, 3.2 to 7.5), those with multiple noninjurious falls (relative risk, 8.5; 95 percent confidence interval, 3.4 to 21.2), and those with at least one fall causing serious injury (relative risk, 19.9; 95 percent confidence interval, 12.2 to 32.6). Adjustment for other risk factors lowered these ratios to 3.1 (95 percent confidence interval, 1.9 to 4.9) for one noninjurious fall, 5.5 (95 percent confidence interval, 2.1 to 14.2) for two or more noninjurious falls, and 10.2 (95 percent confidence interval, 5.8 to 17.9) for at least one fall causing serious injury, but the association between falls and admission to a nursing home remained strong and significant. The population attributable risk of long-term admission to a nursing home for these three groups (the proportion of admissions directly attributable to the three categories of falls) was 13 percent, 3 percent, and 10 percent, respectively. CONCLUSIONS: Among older people living in the community falls are a strong predictor of placement in a skilled-nursing facility; interventions that prevent falls and their sequelae may therefore delay or reduce the frequency of nursing home admissions.",0
1927,9362374,Mechanisms of intrathymic tolerance induction to isolated rat hepatocyte allografts,"Intrathymic injection of alloantigen in young adult rats is capable of mediating long-lived transplantation tolerance. In this study, we use a well-defined model of isolated hepatocyte transplantation to define the mechanisms of intrathymic induced tolerance. The recipient rats are Nagase analbuminemic rats (NAR) that are deficient in albumin, to allow for following transplant acceptance using metabolic and genetic markers. Tolerance to allogeneic hepatocyte transplants could be mediated by intrathymic injection of live allogeneic splenocytes, lethally irradiated splenocytes, or isolated hepatocytes. Intrathymic injection of live allogeneic splenocytes, but not of hepatocytes or irradiated splenocytes, resulted in donor microchimerism in peripheral lymphoid organs, with preferential expansion of CD4-positive T cells in the recipient spleens. Tolerance could be adoptively transferred from tolerant animals to naive recipients, but only from those animals that had been inoculated with intrathymic donor splenocytes. We conclude that donor microchimerism is found after intrathymic inoculation of live splenocytes, but is not required for tolerance induction and that microchimerism is not an absolute requirement for the generation of regulatory cells.",0
1928,9385127,The effect of different diagnostic criteria on the prevalence of dementia,"BACKGROUND: There are several widely used sets of criteria for the diagnosis of dementia, but little is known about their degree of agreement and their effects on estimates of the prevalence of dementia. METHODS: We examined 1879 men and women 65 years of age or older who were enrolled in the Canadian Study of Health and Aging and calculated the proportion given a diagnosis of dementia according to six commonly used classification systems: the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), third edition (DSM-III), the third edition, revised of the DSM (DSM-III-R), the fourth edition of the DSM (DSM-IV), the World Health Organization's International Classification of Diseases (ICD), 9th revision (ICD-9) and 10th revision (ICD-10), and the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). The degree of concordance among classification schemes and the importance of various factors in determining diagnostic agreement or disagreement were examined. RESULTS: The proportion of subjects with dementia varied from 3.1 percent when we used the criteria of the ICD-10 to 29.1 percent when the DSM-III criteria were used. The six classification systems identified different groups of subjects as having dementia; only 20 subjects were given a diagnosis of dementia according to all six systems. The classifications based on the various systems differed little according to the patients' age, sex, educational level, or status with respect to institutionalization. The factors that most often caused disagreement in diagnosis between DSM-III and ICD-10 were long-term memory, executive function, social activities, and duration of symptoms. CONCLUSIONS: The commonly used criteria for diagnosis can differ by a factor of 10 in the number of subjects classified as having dementia. Such disagreement has serious implications for research and treatment, as well as for the right of many older persons to drive, make a will, and handle financial affairs.",0
1929,9392695,Alcohol consumption and mortality among middle-aged and elderly U.S. adults,"BACKGROUND: Alcohol consumption has both adverse and beneficial effects on survival. We examined the balance of these in a large prospective study of mortality among U.S. adults. METHODS: Of 490,000 men and women (mean age, 56 years; range, 30 to 104) who reported their alcohol and tobacco use in 1982, 46,000 died during nine years of follow-up. We compared cause-specific and rates of death from all causes across categories of base-line alcohol consumption, adjusting for other risk factors, and related drinking and smoking habits to the cumulative probability of dying between the ages of 35 and 69 years. RESULTS: Causes of death associated with drinking were cirrhosis and alcoholism; cancers of the mouth, esophagus, pharynx, larynx, and liver combined; breast cancer in women; and injuries and other external causes in men. The mortality from breast cancer was 30 percent higher among women reporting at least one drink daily than among nondrinkers (relative risk, 1.3; 95 percent confidence interval, 1.1 to 1.6). The rates of death from all cardiovascular diseases were 30 to 40 percent lower among men (relative risk, 0.7; 95 percent confidence interval, 0.7 to 0.8) and women (relative risk, 0.6; 95 percent confidence interval, 0.6 to 0.7) reporting at least one drink daily than among nondrinkers, with little relation to the level of consumption. The overall death rates were lowest among men and women reporting about one drink daily. Mortality from all causes increased with heavier drinking, particularly among adults under age 60 with lower risk of cardiovascular disease. Alcohol consumption was associated with a small reduction in the overall risk of death in middle age (ages 35 to 69), whereas smoking approximately doubled this risk. CONCLUSIONS: In this middle-aged and elderly population, moderate alcohol consumption slightly reduced overall mortality. The benefit depended in part on age and background cardiovascular risk and was far smaller than the large increase in risk produced by tobacco.",0
1930,9397987,Presence of distinct AP-1 dimers in normal and transformed rat hepatocytes under basal conditions and after epidermal growth factor stimulation,"Activation of the transcriptional regulator AP-1, a dimeric complex formed of various combinations of Fos and Jun proteins, is a key step in the cellular response to mitogens. Because different dimers are believed to display different regulatory functions, we hypothesized that transformed cells that lack normal growth constraints might display AP-1 dimers that are different from those of normal cells. We therefore compared in primary and transformed rat hepatocytes (1) the composition of AP-1 dimers under basal conditions and (2) AP-1 induction by epidermal growth factor (EGF). Under basal conditions, AP-1 contained predominantly Jun homodimers in both cell types. However, whereas normal hepatocytes contained only JunD, both JunD and JunB were present in the AP-1 complex of 7777 cells. EGF treatment triggered almost identical programs of fos and jun gene activation at the messenger RNA (mRNA) level in both cell types, with an early accumulation of c-fos, c-jun, and junB mRNAs, but no change in junD mRNA levels. In both cell types, c-Fos and Fra-1 proteins increased after EGF treatment, but differences in the induction of Jun proteins were noted, with an increase of c-Jun in hepatocytes and an increase of JunB in 7777 cells. In both cell types, activation of AP-1 DNA binding activity by EGF was accompanied by the recruitment of Fra-1 into AP-1, detected earlier in 7777 cells than in hepatocytes, and with the transient appearance of c-Fos in 7777 cells only. Finally, EGF activated AP-1-dependent transcription in 7777 cells but not in hepatocytes. These data indicate important differences in the functional activity of AP-1 in transformed hepatocytes.",0
1931,9414324,The effect of age on the association between body-mass index and mortality,"BACKGROUND: The effect of age on optimal body weight is controversial, and few studies have had adequate numbers of subjects to analyze mortality as a function of body-mass index across age groups. METHODS: We studied mortality over 12 years among white men and women who participated in the American Cancer Society's Cancer Prevention Study I (from 1960 through 1972). The 62,116 men and 262,019 women included in this analysis had never smoked cigarettes, had no history of heart disease, stroke, or cancer (other than skin cancer) at base line in 1959-1960, and had no history of recent unintentional weight loss. The date and cause of death for subjects who died were determined from death certificates. The associations between body-mass index (defined as the weight in kilograms divided by the square of the height in meters) and mortality were examined for six age groups in analyses in which we adjusted for age, educational level, physical activity, and alcohol consumption. RESULTS: Greater body-mass index was associated with higher mortality from all causes and from cardiovascular disease in men and women up to 75 years of age. However, the relative risk associated with greater body-mass index declined with age. For example, for mortality from cardiovascular disease, the relative risk associated with an increment of 1 in the body-mass index was 1.10 (95 percent confidence interval, 1.04 to 1.16) for 30-to-44-year-old men and 1.03 (95 percent confidence interval, 1.02 to 1.05) for 65-to-74-year-old men. For women, the corresponding relative risk estimates were 1.08 (95 percent confidence interval, 1.05 to 1.11) and 1.02 (95 percent confidence interval, 1.02 to 1.03). CONCLUSIONS: Excess body weight increases the risk of death from any cause and from cardiovascular disease in adults between 30 and 74 years of age. The relative risk associated with greater body weight is higher among younger subjects.",0
1932,9420339,The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group,"BACKGROUND: The high-density lipoprotein (HDL) cholesterol concentration is inversely related to the risk of coronary artery disease. The cholesteryl ester transfer protein (CETP) has a central role in the metabolism of this lipoprotein and may therefore alter the susceptibility to atherosclerosis. METHODS: The DNA of 807 men with angiographically documented coronary atherosclerosis was analyzed for the presence of a polymorphism in the gene coding for CETP. The presence of this DNA variation was referred to as B1, and its absence as B2. All patients participated in a cholesterol-lowering trial designed to induce the regression of coronary atherosclerosis and were randomly assigned to treatment with either pravastatin or placebo for two years. RESULTS: The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations (mean [+/-SD], 2.29+/-0.62 microg per milliliter for the B1B1 genotype vs. 1.76+/-0.51 microg per milliliter for the B2B2 genotype) and lower HDL cholesterol concentrations (34+/-8 vs. 39+/-10 mg per deciliter). In addition, we observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group (decrease in mean luminal diameter: 0.14+/-0.21 mm for the B1B1 genotype, 0.10+/-0.20 mm for the B1B2 genotype, and 0.05+/-0.22 mm for the B2B2 genotype). This association was abolished by pravastatin. Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers (representing 16 percent of the patients taking pravastatin). CONCLUSIONS: There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes. This common DNA variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis.",0
1933,9420342,Conflict of interest in the debate over calcium-channel antagonists,"BACKGROUND: Physicians' financial relationships with the pharmaceutical industry are controversial because such relationships may pose a conflict of interest. It is unknown to what extent industry support of medical education and research influences the opinions and behavior of clinicians and researchers. The recent debate over the safety of calcium-channel antagonists provided an opportunity to examine the effect of financial conflicts of interest. METHODS: We searched the English-language medical literature published from March 1995 through September 1996 for articles examining the controversy about the safety of calcium-channel antagonists. Articles were reviewed and classified as being supportive, neutral, or critical with respect to the use of calcium-channel antagonists. The authors of the articles were asked about their financial relationships with both manufacturers of calcium-channel antagonists and manufacturers of competing products (i.e., beta-blockers, angiotensin-converting-enzyme inhibitors, diuretics, and nitrates). We examined the authors' published positions on the safety of calcium-channel antagonists according to their financial relationships with pharmaceutical companies. RESULTS: Authors who supported the use of calcium-channel antagonists were significantly more likely than neutral or critical authors to have financial relationships with manufacturers of calcium-channel antagonists (96 percent, vs. 60 percent and 37 percent, respectively; P<0.001). Supportive authors were also more likely than neutral or critical authors to have financial relationships with any pharmaceutical manufacturer, irrespective of the product (100 percent, vs. 67 percent and 43 percent, respectively; P< 0.001). CONCLUSIONS: Our results demonstrate a strong association between authors' published positions on the safety of calcium-channel antagonists and their financial relationships with pharmaceutical manufacturers. The medical profession needs to develop a more effective policy on conflict of interest. We support complete disclosure of relationships with pharmaceutical manufacturers for clinicians and researchers who write articles examining pharmaceutical products.",0
1934,9425939,Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis,"The effects of chronic hepatitis C virus (HCV) infection, in the absence of cirrhosis, on patients' quality of life was assessed using the short form 36 (SF36) symptomatology questionnaire. Patients with chronic hepatitis C were polysymptomatic and had significant reductions in their SF36 scores for all of the modalities tested. Patients with chronic hepatitis B virus (HBV) infection showed a reduction in the SF36 scores that assessed mental functions, but they had no decrease in the scores that measured physical symptoms, indicating that the symptoms associated with chronic HCV infection are qualitatively different from those associated with chronic HBV infection. Patients with chronic HCV infection who had used intravenous drugs in the past had the greatest impairment in quality-of-life scores, but the reduction in quality-of-life scores was still found in patients who had never used drugs. The reduction in quality of life could not be attributed to the degree of liver inflammation or to the mode of acquisition of the infection. Hence, chronic infection with HCV per se gives rise to physical symptoms that reduce the quality of life of infected patients.",0
1935,9435330,A computer-assisted management program for antibiotics and other antiinfective agents,"BACKGROUND AND METHODS: Optimal decisions about the use of antibiotics and other antiinfective agents in critically ill patients require access to a large amount of complex information. We have developed a computerized decision-support program linked to computer-based patient records that can assist physicians in the use of antiinfective agents and improve the quality of care. This program presents epidemiologic information, along with detailed recommendations and warnings. The program recommends antiinfective regimens and courses of therapy for particular patients and provides immediate feedback. We prospectively studied the use of the computerized antiinfectives-management program for one year in a 12-bed intensive care unit. RESULTS: During the intervention period, all 545 patients admitted were cared for with the aid of the antiinfectives-management program. Measures of processes and outcomes were compared with those for the 1136 patients admitted to the same unit during the two years before the intervention period. The use of the program led to significant reductions in orders for drugs to which the patients had reported allergies (35, vs. 146 during the preintervention period; P<0.01), excess drug dosages (87 vs. 405, P<0.01), and antibiotic-susceptibility mismatches (12 vs. 206, P<0.01). There were also marked reductions in the mean number of days of excessive drug dosage (2.7 vs. 5.9, P<0.002) and in adverse events caused by antiinfective agents (4 vs. 28, P<0.02). In analyses of patients who received antiinfective agents, those treated during the intervention period who always received the regimens recommended by the computer program (n=203) had significant reductions, as compared with those who did not always receive the recommended regimens (n= 195) and those in the preintervention cohort (n = 766), in the cost of antiinfective agents (adjusted mean, $102 vs. $427 and $340, respectively; P<0.001), in total hospital costs (adjusted mean, $26,315 vs. $44,865 and $35,283; P<0.001), and in the length of the hospital stay days (adjusted mean, 10.0 vs. 16.7 and 12.9; P<0.001). CONCLUSIONS; A computerized antiinfectives-management program can improve the quality of patient care and reduce costs.",0
1936,9443925,Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group,"BACKGROUND: Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption, but the balance between its long-term risks and benefits remains unclear. Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear. METHODS: We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age. An additional 435 women who were prepared to receive a combination of estrogen and progestin were randomly assigned to one of the above treatments or open-label estrogen-progestin. The main outcome measure was the change in bone mineral density of the lumbar spine, hip, distal forearm, and total body measured annually for two years by dual-energy x-ray absorptiometry. RESULTS: The women who received placebo lost bone mineral density at all measured sites, whereas the women treated with 5 mg of alendronate daily had a mean (+/-SE) increase in bone mineral density of 3.5+/-0.2 percent at the lumbar spine, 1.9+/-0.1 percent at the hip, and 0.7+/-0.1 percent for the total body (all P<0.001). Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density. Alendronate did not increase bone mineral density of the forearm, but it slowed the loss. The responses to estrogen-progestin were 1 to 2 percentage points greater than those to the 5-mg dose of alendronate. Alendronate was well tolerated, with a safety profile similar to that of placebo or estrogen-progestin. CONCLUSIONS: Alendronate prevents bone loss in postmenopausal women under 60 years of age to nearly the same extent as estrogen-progestin.",0
1937,9449729,Objective estimates of the probability of death from burn injuries,"BACKGROUND: Over the past 20 years, there has been remarkable improvement in the chances of survival of patients treated in burn centers. A simple, accurate system for objectively estimating the probability of death would be useful in counseling patients and making medical decisions. METHODS: We conducted a retrospective review of all 1665 patients with acute burn injuries admitted from 1990 to 1994 to Massachusetts General Hospital and the Shriners Burns Institute in Boston. Using logistic-regression analysis, we developed probability estimates for the prediction of mortality based on a minimal set of well-defined variables. The resulting mortality formula was used to determine whether changes in mortality have occurred since 1984, and it was tested prospectively on all 530 patients with acute burn injuries admitted in 1995 or 1996. RESULTS: Of the 1665 patients (mean [+/-SD] age, 21+/-20 years; mean burn size, 14+/-20 percent of body-surface area), 1598 (96 percent) lived to discharge. The mean length of stay was 21+/-29 days. Three risk factors for death were identified: age greater than 60 years, more than 40 percent of body-surface area burned, and inhalation injury. The mortality formula we developed predicts 0.3 percent, 3 percent, 33 percent, or approximately 90 percent mortality, depending on whether zero, one, two, or three risk factors are present. The results of the prospective test of the formula were similar. A large increase in the proportion of patients who chose not to be resuscitated complicated comparisons of mortality over time. CONCLUSIONS: The probability of mortality after burns is low and can be predicted soon after injury on the basis of simple, objective clinical criteria.",0
1938,9462630,"Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension","The present study is aimed at characterizing the portal, splanchnic, and systemic circulatory effects of F-180, a new long-acting analog of vasopressin (VP) with selective effect on the vascular (V1) receptor, both in normal rats and in portal-hypertensive animals. In preliminary vasopressor tests, F-180 was 18 times more potent than terlipressin (TP) (164 +/- 10 IU x mmol(-1) vs. 9.2 +/- 1.2 IU x mmol(-1)) and four times less potent than arginine VP (614 +/- 25 IU x mmol(-1)). F-180 had negligible antidiuretic potency, resulting in vascular selectivity (V1/V2) of 858 compared with 1.0 for VP and 2.2 for TP. In portal-hypertensive rats with partial portal vein ligation (PPVL), the vasopressor effect of F-180 was 19 times that of TP on a molar basis (ED50 F-180: 0.54 vs. TP: 10.02 nmol x kg(-1)). At low doses (0.405 nmol x kg(-1)), F-180 significantly reduced portal pressure (PP) (-13.8% +/- 6.7%) and superior mesenteric artery blood flow (SMABF) (-25.6% +/- 4.5%), whereas TP at 8.10 nmol x kg(-1) was required to achieve comparable splanchnic effects; however, this dose caused a significantly greater increase in mean arterial pressure (MAP) than F-180 at 0.405 nmol x kg(-1) (28.2% +/- 2.7% vs. 8.9% +/- 2.7% at 20 minutes; P < .05). F-180 at 0.405 nmol x kg(-1) had effects on PP and SMABF similar to a 30-minute intravenous infusion of VP at 10 mU x kg(-1) in PPVL rats, but VP caused a significantly greater elevation in systemic vascular resistance (SVR) and MAP, and more pronounced reduction in cardiac index (P < .05).",0
1939,9462639,ICE-like protease (caspase) is involved in transforming growth factor beta1-mediated apoptosis in FaO rat hepatoma cell line,"Transforming growth factor-beta1 (TGF-beta1) arrests growth and/or stimulates apoptosis of a variety of cells. The biochemical pathways involved in the apoptotic processes, however, remain poorly defined. TGF-beta1 induces DNA fragmentation together with morphological changes, which are characteristic of apoptosis in the FaO rat hepatoma cell line. Histones were remarkably enriched in lysates of these cells during TGF beta1-induced apoptosis. We identified U1-70 kd as a death substrate which is cleaved following TGF-beta1 treatment. The tetrapeptide caspase inhibitor carbobenzoxy-valyl-alanly-aspartyl-(beta-O-methyl)-fluoromethyl ketone (ZVAD-FMK) prevented TGF beta1-induced apoptotic DNA fragmentation and cleavage of the U1-70 kd protein, showing that caspase(s) are involved in TGF beta1-mediated apoptosis. To identify specific caspases involved in apoptosis induced by TGF-beta1 in FaO cells, proteolytic activation of several of these caspases and their substrates were studied as a function of time following TGF beta1-treatment. TGF beta1-treatment induced the progressive proteolytic processing of caspase-2 (ICH-1L/Nedd-2), whereas caspase-1 itself did not show any cleavage from the precursor. Pretreatment with ZVAD-FMK abrogated the maturation of caspase-2 and blocked the apoptotic progress. These results suggest that caspase-2, but not caspase-1, may play a crucial role in TGF beta1-induced apoptosis in these cells.",0
1940,9462659,Compatible organic osmolytes in rat liver sinusoidal endothelial cells,"Compatible organic osmolytes, such as betaine and taurine are involved in the regulation of Kupffer cell (KC) function, but nothing is known about osmolytes in liver endothelial cells. This was investigated here by studying the effect of aniso-osmotic exposure of rat liver sinusoidal endothelial cells (SEC) on osmolyte transport and the messenger RNA (mRNA) levels for the transport systems for betaine (BGT1), taurine (TAUT), and myo-inositol (SMIT). Compared with normo-osmotic exposure (305 mosmol/L), hyperosmotic exposure (405 mosmol/L) of SEC led to an increase in the mRNA levels for these transport systems and simultaneously to a stimulation of betaine, taurine, and myo-inositol uptake, which led to an increase of cell volume. Conversely, hypo-osmotic exposure decreased osmolyte uptake. When hyperosmotically pre-exposed SEC were loaded with betaine, taurine, or myoinositol, hypo-osmotic stress stimulated the efflux of these osmolytes from the cells. Studies on osmolyte tissue levels revealed that taurine was an important compatible organic osmolyte under normo-osmotic conditions and predominantly released following hypo-osmotic stress. Conversely, following hyperosmotic exposure, the increase in cellular betaine and myo-inositol exceeded that of taurine. In lipopolysaccharide (LPS)-treated SEC, hyperosmotic exposure markedly raised the mRNA levels for cyclo-oxygenase-2 (COX-2), but not for inducible nitric oxide synthase (iNOS). The increase of COX-2 mRNA levels was counteracted by betaine and taurine and, to a lesser extent, by myo-inositol. The findings indicate that SEC use taurine, betaine, and myo-inositol as compatible organic osmolytes.",0
1941,9462666,Full-length complementary DNA of hepatitis C virus genome from an infectious blood sample,"We constructed a full-length complementary DNA (cDNA) clone of hepatitis C virus (HCV) from a blood sample of an HCV carrier. The blood from the carrier was eventually transfused to a patient who later developed typical posttransfusion hepatitis C. It was also shown to be infectious to chimpanzees. We obtained 12 overlapping cDNA fragments altogether, covering the entire HCV genome. By subcloning and sequencing, clones considered to constitute the major population were selected. We could also detect 98 base pairs of extra sequences at the 3' end of the genome. After confirming the overlapping sequences, we combined the fragments to make a full-length cDNA. The HCV population in the donor was heterogeneous, as determined by their nucleotide sequences of the hypervariable region in envelope protein, but a few virus clones were selected in the recipient after transmission. The similar convergence of the virus population was previously observed when the same blood sample was injected into a chimpanzee. Interestingly, virus clones isolated during the acute phase in the recipient and the chimpanzee had sequences in the hypervariable region identical to that of the full-length cDNA clone. The full-length cDNA clone of HCV constructed in this study may originate from infectious virus clones.",0
1942,9468466,Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia,"BACKGROUND: The rate of clearance of antileukemic agents differs by a factor of 3 to 10 among children with acute lymphoblastic leukemia. We hypothesized that the outcome of treatment would be improved if doses were individualized to prevent low systemic exposure to the drugs in patients with fast drug clearance. METHODS: We stratified and randomly assigned 182 children with newly diagnosed acute lymphoblastic leukemia to postremission regimens that included high-dose methotrexate and teniposide plus cytarabine. The doses of these drugs were based on body-surface area (in the conventional-therapy group) or the rates of clearance of the three medications in each patient (in the individualized-treatment group). In the individualized-treatment group, doses were increased in patients with rapid clearance and decreased in patients with very slow clearance. RESULTS: Patients who received individualized doses had significantly fewer courses of treatment with systemic exposures below the target range than did patients who received conventional doses (P<0.001 for each medication). Among the patients with B-lineage leukemia, those who received individualized therapy had a significantly better outcome than those given conventional therapy (P=0.02); the mean (+/-SE) rates of continuous complete remission at five years were 76+/-6 percent and 66+/-7 percent, respectively. There was no significant difference between treatments for patients with T-lineage leukemia (P=0.54). In a proportional-hazards model, the time-dependent systemic exposure to methotrexate, but not to teniposide or cytarabine, was significantly related to the risk of early relapse in children with B-lineage leukemia. CONCLUSIONS: Adjusting the dose of methotrexate to account for the patient's ability to clear the drug can improve the outcome in children with B-lineage acute lymphoblastic leukemia.",0
1943,9475763,Expression of Bcl-x in erythroid precursors from patients with polycythemia vera,"BACKGROUND: Deregulating the expression of Bcl-xL, an inhibitor of apoptosis, in an erythropoietin-dependent erythroblast cell line averts apoptosis induced by the withdrawal of erythropoietin. Since in polycythemia vera an abnormal clone of erythroid progenitors is independent of erythropoietin, we investigated whether the endogenous expression of Bcl-xL was deregulated in these cells. METHODS: Erythroid colonies from patients with polycythemia vera and normal subjects were cultured in the presence and absence of erythropoietin and assessed by immunocytochemical and flow-cytometric analysis with anti-Bcl-x antibodies that recognize the two species of Bcl-x (Bcl-xL and Bcl-xS). Reverse-transcriptase-polymerase-chain-reaction analysis was used to determine which one of the two species was responsible for anti-Bcl-x staining. Bone marrow mononuclear cells from 8 healthy bone marrow donors, 14 patients with polycythemia vera, 19 patients with other myeloproliferative syndromes, and 12 patients with secondary erythrocytosis were analyzed by flow cytometry with antibodies against Bcl-x and glycophorin A, an erythroid marker. RESULTS: Erythroid cells from patients with polycythemia vera survived in vitro without erythropoietin, and this finding correlated with the expression of Bcl-x protein (Bcl-xL messenger RNA was the main species of Bcl-x found), even in mature erythroblasts that normally do not express Bcl-x. The mean (+/-SD) percentage of cells positive for both glycophorin A and Bcl-x in the 14 patients with polycythemia vera (21.8+/-3.6 percent) was significantly higher than that in 8 normal donors (6.62+/-1.58 percent), 12 patients with secondary erythrocytosis (6.87+/-1.95 percent), 9 patients with essential thrombocythemia (3.81+/-0.97 percent), and 10 patients with chronic myeloid leukemia (2.7+/-0.41 percent). CONCLUSIONS: Deregulated expression of Bcl-x may contribute to the erythropoietin-independent survival of erythroid-lineage cells in polycythemia vera and thereby contribute to the pathogenesis of this disease.",0
1944,9486993,The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension,"BACKGROUND: It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study. METHODS: The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension. RESULTS: Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8). CONCLUSIONS: In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.",0
1945,9500699,Interleukin 1beta-stimulated production of nitric oxide in rat hepatocytes is mediated through endogenous synthesis of interferon gamma,"The multiple interlocking regulatory mechanisms that underlie induction of hepatocyte inducible nitric oxide synthase (iNOS) expression are largely unknown. Although previous work has indicated the requirement for multiple proinflammatory cytokines to induce hepatocyte NO production, investigators have recently shown that interleukin-1beta (IL-1beta) alone can initiate iNOS expression. In contrast, interferon gamma (IFN-gamma) serves as the sole initiating factor in other cell systems. On the basis of the known ability of IL-1beta to induce transcription and translation of the IFN family of genes, we hypothesized that IL-1beta-mediated hepatocyte expression of iNOS is dependent on endogenous IFN-gamma synthesis. In a system of rat hepatocytes in primary culture, IL-1beta induced production of both NO and IFN-gamma. Using in situ hybridization and immunoblot analysis, IFN-gamma messenger RNA (mRNA) and protein were detected in hepatocytes exposed to IL-1beta. Inhibition of NO synthesis using the competitive substrate inhibitor N-monomethyl-L-arginine (100 micromol/L) did not alter the extent of IL-1beta-mediated IFN-gamma synthesis. In contrast, anti-IFN-gamma antibody or inhibition of IFN-gamma mRNA translation by addition of antisense IFN-gamma oligodeoxynucleotide probes resulted in undetectable levels of NO metabolites and iNOS protein. Repletion of IFN-gamma to the system restored NO production to levels noted in the presence of IL-1beta alone. Transient transfection analysis using a rat hepatocyte iNOS promoter-reporter gene plasmid construct showed that IL-1beta-induced promoter activation was abolished in the presence of anti-IFN-gamma or antisense IFN-gamma. Again, addition of IFN-gamma to the system restored activity of the iNOS promoter. Parallel experiments examining IL-1beta-mediated endogenous hepatocyte IL-1beta and TNF-alpha synthesis indicated no role for these cytokines in the induction of iNOS expression by IL-1beta. It is concluded that IL-1beta-mediated hepatocyte synthesis of NO is dependent on the simultaneous endogenous synthesis of IFN-gamma.",0
1946,9500708,Betaine as an osmolyte in rat liver: metabolism and cell-to-cell interactions,"Betaine was recently identified as an osmolyte in rat liver macrophages (Kupffer cells [KCs]) and sinusoidal endothelial cells (SECs). Betaine interferes with KC functions, such as phagocytosis, cytokine, and prostaglandin syntheses. As betaine is derived from choline, the present study was undertaken to evaluate osmosensitivity and cell heterogeneity of choline metabolism in rat liver. In the perfused rat liver after in vivo prelabeling with [14C]-choline, hypoosmotic stress induced a radioactivity release into the perfusate which was identified as [14C]-betaine by high-performance liquid chromatography (HPLC) analysis and which was inhibited by the anion exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Choline metabolism was studied in cultured liver parenchymal cells, (PCs), KCs, and SECs. Choline was taken up by all but betaine formation from choline was only detectable in PCs and not in KCs and SECs. Betaine formation in PCs was not stimulated by hyperosmolarity; rather, betaine has a role as an osmolyte in KCs and SECs but is of minor importance in PCs, as evidenced by only minor hyperosmolarity-induced betaine uptake. Thus, liver PCs can produce and release betaine derived from choline, and, thereby, possibly supply the osmolyte important for KC and SEC cell function. This may be another example for cell-to-cell interaction in the liver.",0
1947,9500710,"Intracellular distribution of the Wilson's disease gene product (ATPase7B) after in vitro and in vivo exogenous expression in hepatocytes from the LEC rat, an animal model of Wilson's disease","In patients with Wilson's disease, both copper incorporation into ceruloplasmin and excretion of this metal into bile are impaired. These conditions are caused by a genetic defect in the Wilson's disease gene (ATP7B). To investigate the Wilson's disease gene protein (ATPase7B) in hepatocytes, we constructed an expression plasmid carrying full-length complementary DNA for human Wilson's disease gene and attempted to express the gene in hepatocytes of LEC rats, an animal model of Wilson's disease. Transfection of hepatocytes, either in vitro or in vivo, was done using a newly developed cationic liposome containing 1,4-bis(3-(N-hexadecyl) aminopropyl) piperazine. Immunological analyses of human ATPase7B with specific monoclonal antibodies showed human ATPase7B to be a membrane protein with a molecular mass of 155 kd. Analysis of human ATPase7B expressed in hepatocytes from LEC rats suggested that this protein is present in the trans-Golgi network and at the plasma membrane, a distribution pattern similar to that of Menkes' disease protein (ATPase7A). These findings suggest that these two putative copper-transporting P-type ATPases function similarly at the cellular level. Cotransfection and coexpression of the human Wilson's disease gene and ceruloplasmin gene in cultured hepatocytes indicate that the distribution of ceruloplasmin is always accompanied by ATPase7B at the perinuclear region, but that part of ATPase7B localizes irrespective of the distribution of ceruloplasmin. Based on these investigations, we propose that ATPase7B exists in the trans-Golgi network and transports copper into this compartment. This seems to ensure an appropriate delivery of copper to the apoceruloplasmin. On the other hand, part of ATPase7B that is not accompanied by ceruloplasmin in the perinuclear region and at the plasma membrane seems to contribute to efflux of this metal from the hepatocytes. Thus the distribution patterns of ATPase7B in hepatocytes may explain the dual roles of this P-type ATPase in hepatocytes.",0
1948,9500714,Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver,"Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXa, iron, and carbon monoxide. The HO-system consists of two isoenzymes, namely HO-2 and the inducible isoform HO-1, also referred to as heat shock protein (hsp) 32. Although both parenchymal and non-parenchymal liver cells participate in heme metabolism, the expression pattern of the isoenzymes in normal and stress exposed liver is unknown. To study this, rats underwent either endotoxin (lipopolysaccharide [LPS]) challenge, hemorrhagic hypotension, glutathione (GSH) depletion, or cobalt chloride injection, all known to provoke oxidative stress. HO-2 messenger RNA (mRNA) and protein were constitutively expressed in hepatocytes, Kupffer/endothelial-, and stellate (Ito-) cell enriched fractions. Although both non-parenchymal cell fractions expressed HO-1 transcripts, HO-1 immunoreactive protein was restricted to Kupffer cells in the normal liver. In contrast to HO-2, a significant increase in HO-1 on the whole organ level was noted by hemorrhagic hypotension, GSH depletion, and cobalt chloride injection. However, the distinct stress models led to a strikingly different cell-type specific and sublobular expression pattern of HO-1 gene expression. HO-1 was inducible in sinusoidal lining cells (hemorrhagic hypotension, LPS challenge), in periportal (cobalt chloride), or pericentral (GSH depletion, hemorrhagic hypotension) hepatocytes. The blockade of protein translation before hemorrhage by cycloheximide reduced upregulation of HO-1/hsp32 mRNA significantly (65.4% reduction, P < .05), whereas the inducibility of hsp70 transcript was maintained. In addition to transcriptional regulation, HO-1 seems to be subject to posttranscriptional control in particular in non-parenchymal cells.",0
1949,9504948,Ethical issues in studies in Thailand of the vertical transmission of HIV,"This article, written by a resident of Thailand, argues that placebo-controlled trials of treatments to prevent maternal-fetal transmission of HIV infection are sometimes justified in settings where treatment is otherwise totally unavailable because at least half of those involved would likely benefit. However, different developing countries have different levels of resources, and efforts should be made to perform equivalency studies as an alternative to placebo-controlled trials, especially those involving zidovudine, which is a standard of care in developed countries. When placebo-controlled trials of short-course zidovudine began in Thailand in 1994, zidovudine was not being routinely offered to patients because of financial constraints and a lack of the necessary treatment infrastructure. As time passed, situations changed (in 1996 efforts began to procure zidovudine for impoverished mothers), and a trial that seemed ethical in 1994 could be considered unethical in 1997. Thus, in 1997, one placebo-controlled trial of short-term zidovudine therapy was terminated early but another, sponsored by the US Centers for Disease Control and Prevention, is slated for completion in 1998. This decision to complete the trial led to local and international controversy because the affected women were not informed about treatment options. Another unjustified and unethical study sponsored by the US Walter Reed Army Institute of Research in Lampang seeks to determine the natural history of perinatal HIV infection and only recently offered women and newborns zidovudine treatment.",0
1950,9516219,Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators,"BACKGROUND AND METHODS: National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. RESULTS: Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid. CONCLUSIONS: The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.",0
1951,9516228,Progress and problems in the fight against AIDS,"The provision of double-nucleoside therapy against HIV/AIDS in Europe and North America is most likely responsible for the observed marked declines in AIDS-related morbidity and mortality in 1995 and 1996, while the addition of protease inhibitors resulted in further benefit in late 1996 and 1997. The number of inpatients with AIDS has decreased while the number of outpatients has increased, reflecting major improvements in the treatment of HIV infection. However, simpler treatments are needed and much remains to be learned about how to safely apply these new biomedical tools against HIV/AIDS, including the nature of therapy-related long-term complications. Furthermore, funds are still needed for ongoing research and prevention. For the average AIDS patient in developing countries, highly active antiretroviral therapy is an inaccessible dream, and merely a diversion for developing country health ministries from more pressing concerns which threatens more cost-effective programs against HIV, such as the targeted distribution of condoms or the treatment of sexually transmitted diseases which facilitate the spread of HIV. Since nothing will likely bridge this gap between poor and rich countries, only prevention and a vaccine will likely make a real difference for the poor in the battle against HIV/AIDS.",0
1952,9535665,Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women,"BACKGROUND: Osteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Ialpha1, a bone-matrix protein. METHODS: We determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 1778 postmenopausal women using a polymerase-chain-reaction-based assay. We then related the genotypes to bone mineral density and the occurrence of osteoporotic fractures in these women. RESULTS: As compared with the 1194 women with the SS genotype, the 526 women with the Ss genotype had 2 percent lower bone mineral density at the femoral neck (P=0.003) and the lumbar spine (P=0.02); the 58 women with the ss genotype had reductions of 4 percent at the femoral neck (P= 0.05) and 6 percent at the lumbar spine (P=0.005). These differences increased with age (P=0.01 for modification by age of the effect of COLIA1 on femoral-neck bone density, and P=0.004 for modification of the effect on lumbar-spine bone density). Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures (relative risk per copy of the s allele, 1.5; 95 percent confidence interval, 1.1 to 2.1). CONCLUSIONS: The COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.",0
1953,9535669,"Aging, health risks, and cumulative disability","BACKGROUND: Persons with lower health risks tend to live longer than those with higher health risks, but there has been concern that greater longevity may bring with it greater disability. We performed a longitudinal study to determine whether persons with lower potentially modifiable health risks have more or less cumulative disability. METHODS: We studied 1741 university alumni who were surveyed first in 1962 (average age, 43 years) and then annually starting in 1986. Strata of high, moderate, and low risk were defined on the basis of smoking, body-mass index, and exercise patterns. Cumulative disability was determined with a health-assessment questionnaire and scored on a scale of 0 to 3. Cumulative disability from 1986 to 1994 (average age in 1994, 75 years) or death was the measure of lifetime disability. RESULTS: Persons with high health risks in 1962 or 1986 had twice the cumulative disability of those with low health risks (disability index, 1.02 vs. 0.49; P<0.001). The results were consistent among survivors, subjects who died, men, and women and for both the last year and the last two years of observation. The onset of disability was postponed by more than five years in the low-risk group as compared with the high-risk group. The disability index for the low-risk subjects who died was half that for the high-risk subjects in the last one or two years of observation. CONCLUSIONS: Smoking, body-mass index, and exercise patterns in midlife and late adulthood are predictors of subsequent disability. Not only do persons with better health habits survive longer, but in such persons, disability is postponed and compressed into fewer years at the end of life.",0
1954,9537449,p21Ras downstream effectors are increased in activity or expression in mouse liver tumors but do not differ between ras-mutated and ras-wild-type lesions,"Mouse liver tumors frequently harbor activating ras gene mutations. Downstream effector molecules of p21Ras include Raf-1 kinase which mediates external signals via kinase signaling pathways to nuclear transcription factors including c-Fos and c-Jun. Mouse liver tumors with differing ras-mutational status were analyzed for alterations in Ras/Raf-1 signal transduction. Tumors were characterized with respect to the presence of base substitutions in the 3 known hot-spot positions at codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras. Ha-ras codon 61 or Ki-ras codon 13 mutations, but no N-ras mutations, were detected in 23 out of 33 tumors analyzed, while no ras-mutations were found in 10 of the tumors. There was no significant difference in the expression of p21RaS proteins between ras-mutated tumors and tumors without detectable ras mutations. To allow for determination of Raf-1 kinase activity in tumors, a sensitive and specific assay was developed for measurements with tissue homogenates. Raf-1 kinase activity was increased about four-fold in liver tumors as compared with normal liver tissue. No significant differences in kinase activity, however, were evident between ras-mutated and ras-wild-type tumors. The same was true with respect to the levels of c-fos and c-jun mRNAs. Moreover, there were no significant differences in cell division (5-bromo-2'-deoxyuridine-labeling indices) of hepatocytes from ras-mutated and ras-wild-type tumors. The similar degree of constitutive activation of the Ras/Raf-1 signaling pathway in liver tumors, with and without detectable ras mutations, suggests that other molecules within the signaling pathway may substitute for ras-mutations during oncogenic conversion of ras-wild-type hepatocytes.",0
1955,9537456,Re-treatment with interferon alfa of patients with chronic hepatitis C,"Treatment of patients with chronic hepatitis C has had limited success because of relapses and nonresponse to interferon alfa therapy (currently the only established therapeutic agent). A retrospective study was done to determine the efficacy of re-treatment with interferon and the predictors of response in patients who failed to achieve sustained response after one standard course of interferon therapy (3 million units three times a week for 24 weeks). One hundred and eleven patients (47 relapsers and 64 nonresponders), mean age 45 years, were included in the study. Eighteen relapsers and 13 nonresponders received a higher dose (5 MU), and 11 relapsers and 6 nonresponders received a longer duration (48 weeks) of interferon therapy. The remaining patients received the same regimen as the first treatment. Eighty-one percent and 23% of relapsers and nonresponders, respectively, had an end-of-treatment response, and 19% and 3% of the corresponding patient groups had a sustained response to re-treatment. Two patients with breakthrough during their first treatment were the only nonresponders with sustained response after re-treatment. Sustained response was observed only in patients who received an increased dose or duration of interferon therapy. No predictor of sustained response was found. In conclusion, sustained response to re-treatment with interferon was only observed with augmentation of dose or duration of therapy in some relapsers and patients who had breakthrough. Established predictors of response to interferon in naive patients, in particular serum hepatitis C virus RNA and genotype, were not associated with sustained response to re-treatment.",0
1956,9554857,Topical treatment with nerve growth factor for corneal neurotrophic ulcers,"BACKGROUND: Corneal neurotrophic ulcers associated with impairment of sensory innervation of the cornea may lead to loss of vision, and there is no effective treatment for these ulcers. We evaluated the effects of nerve growth factor in patients with this disorder. METHODS: Twelve patients (14 eyes) with severe neurotrophic corneal ulcers associated with corneal anesthesia were treated with topical nerve growth factor 10 times daily for two days and then 6 times daily until the ulcers healed. Treatment continued for 2 weeks after the ulcers healed, and the patients were then followed for up to 12 months. The evolution of the corneal disease during treatment and follow-up was evaluated by slit-lamp examination, photography, fluorescein-dye testing, and tests of corneal sensitivity and best corrected visual acuity. RESULTS: Corneal healing began 2 to 14 days after the initiation of treatment with nerve growth factor, and all patients had complete healing of their corneal ulcers after 10 days to 6 weeks of treatment. Corneal sensitivity improved in 13 eyes, and returned to normal in 2 of the 13 eyes. Corneal integrity and sensitivity were maintained during the follow-up period (range, 3 to 12 months). Best corrected visual acuity increased progressively during treatment and follow-up in all patients. There were no systemic or local side effects of treatment. CONCLUSIONS: In this preliminary, uncontrolled study, topically applied exogenous nerve growth factor restored corneal integrity in patients with corneal neurotrophic ulcers.",0
1957,9562581,"Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Fran�ais d'Immunoth�rapie","BACKGROUND: Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment. METHODS: Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis. RESULTS: Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases. CONCLUSIONS: Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment.",0
1958,9562589,Accidental nuclear war--a post-cold war assessment,"BACKGROUND: In the 1980s, many medical organizations identified the prevention of nuclear war as one of the medical profession's most important goals. An assessment of the current danger is warranted given the radically changed context of the post-Cold War era. METHODS: We reviewed the recent literature on the status of nuclear arsenals and the risk of nuclear war. We then estimated the likely medical effects of a scenario identified by leading experts as posing a serious danger: an accidental launch of nuclear weapons. We assessed possible measures to reduce the risk of such an event. RESULTS: U.S. and Russian nuclear-weapons systems remain on a high-level alert status. This fact, combined with the aging of Russian technical systems, has recently increased the risk of an accidental nuclear attack. As a conservative estimate, an accidental intermediate-sized launch of weapons from a single Russian submarine would result in the deaths of 6,838,000 persons from firestorms in eight U.S. cities. Millions of other people would probably be exposed to potentially lethal radiation from fallout. An agreement to remove all nuclear missiles from high-level alert status and eliminate the capability of a rapid launch would put an end to this threat. CONCLUSIONS: The risk of an accidental nuclear attack has increased in recent years, threatening a public health disaster of unprecedented scale. Physicians and medical organizations should work actively to help build support for the policy changes that would prevent such a disaster.",0
1959,9571252,Emergence of multidrug-resistant Salmonella enterica serotype typhimurium DT104 infections in the United States,"BACKGROUND: Strains of salmonella that are resistant to antimicrobial agents have become a worldwide health problem. A distinct strain of Salmonella enterica serotype typhimurium, known as definitive type 104 (DT104), is resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline and has become a major cause of illness in humans and animals in Europe, especially the United Kingdom. METHODS: To characterize typhimurium DT104 infections in the United States, we analyzed data collected by local and state health departments and public health laboratories between 1979 and 1996 in national surveys of the antimicrobial-drug resistance of salmonella. Selected typhimurium isolates with the five-drug pattern of resistance were phage typed. RESULTS: The prevalence of typhimurium isolates with the five-drug pattern of resistance increased from 0.6 percent in 1979-1980 to 34 percent in 1996. In 1994-1995, such isolates were identified in samples from 36 of the 46 surveillance sites (78 percent). Thirty-nine of 43 typhimurium isolates with the five-drug pattern of resistance identified in 1994-1995 and 1996 were phage type DT104 or a closely related phage type. CONCLUSIONS: Multidrug-resistant typhimurium DT104 has become a widespread pathogen in the United States. More prudent use of antimicrobial agents in farm animals and more effective disease prevention on farms are necessary to reduce the dissemination of multidrug-resistant typhimurium DT104 and to slow the emergence of resistance to additional agents in this and other strains of salmonella.",0
1960,9580648,Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients,"BACKGROUND: Epstein-Barr virus (EBV) is associated with various malignant and benign lymphoproliferative disorders. It also efficiently transforms human B lymphocytes in vitro. The latent membrane protein 1 (LMP1) of EBV-infected cells plays a central part in this process by mimicking members of the family of tumor necrosis factor (TNF) receptors, thereby transmitting growth signals from the cell membrane to the nucleus through cytoplasmic TNF-receptor-associated factors (TRAFs). I sought evidence of LMP1-mediated signal transduction through TRAFs in tumor tissue from patients with post-transplantation lymphoproliferative disease and non-Hodgkin's lymphomas related to the acquired immunodeficiency syndrome (AIDS). METHODS: The association of LMP1 with TRAF-1 or TRAF-3 in tumor tissue was studied with double-immunofluorescence microscopy and immunoprecipitation assays. Evidence of LMP1-TRAF signaling was sought with an electrophoretic mobility shift assay for the nuclear factor-kappaB (NF-kappaB) transcription factor. RESULTS: Tumors from eight patients with post-transplantation lymphoproliferative disease, two patients with AIDS-associated non-Hodgkin's lymphoma, and three patients with endemic Burkitt's lymphoma were analyzed. Tumors from six of the patients with post-transplantation lymphoproliferative disease were positive for EBV and expressed LMP1; two samples were EBV-negative. Tumors from both patients with AIDS-associated non-Hodgkin's lymphoma were EBV-positive and expressed LMP1, whereas tumors from all three patients with Burkitt's tumors were positive for EBV but negative for LMP1. Double-immunofluorescence microscopy showed that LMP1 localized with and immunoprecipitated with TRAF-1 and TRAF-3 in all eight of the EBV-positive, LMP1-positive samples. An electrophoretic mobility shift assay revealed activated NF-kappaB in all eight EBV-positive, LMP1-positive samples as well, but not in either of the EBV-negative, LMP1-negative samples or in the three EBV-positive, LMP1-negative samples. CONCLUSIONS: LMP1-mediated signaling through the TRAF system has a role in the pathogenesis of the EBV-positive lymphomas that arise in immunosuppressed patients.",0
1961,9581677,"Inhibition of establishment and growth of mouse liver metastases after treatment with interferon gamma and beta-1,3-D-glucan","The purpose of this study was to investigate the combined antitumor effect of aminated beta-1,3-D-glucan (AG) and interferon-gamma (IFN-gamma) in an experimental liver metastasis model. Liver metastases were established by inoculation of C-26 colon carcinoma cells into the superior mesenteric vein of syngeneic mice. Treatment of mice started 24 hours after inoculation of tumor cells by daily intravenous injections of either AG, IFN-gamma, or a combination of both for a duration of 6 days. The resultant liver metastases were then quantified after an additional period of 11 days. Combination of IFN-gamma and AG inhibited the growth of liver metastases almost entirely. IFN-gamma was also very efficient, while AG alone did not exert any significant antitumor effect. These results, along with histological studies from mice receiving AG and IFN-gamma, indicated that activation and recruitment of liver macrophages may be a part of the mechanism responsible for the inhibition of metastatic growth observed in this study.",0
1962,9581678,Glutathione protects metastatic melanoma cells against oxidative stress in the murine hepatic microvasculature,"Calcein-labeled B16 melanoma (B16M) cells were injected intraportally, and in vivo video microscopy was used to study the distribution and damage of cancer cells arrested in the liver microvasculature over a period of 4 hours. The contribution of glutathione (GSH)-dependent antioxidant machinery to the possible oxidative stress-resistance mechanism of B16M cell was determined by in vitro incubation with the selective inhibitor of GSH synthesis L-buthionine (S,R)-sulphoximine (BSO) before B16M cell injection in untreated and 0.5-mg/kg lipopolysaccharide (LPS)-treated mice. In addition, untreated and LPS-treated isolated syngeneic hepatic sinusoidal endothelial cells (HSE) were used to determine in vitro their specific contribution to B16M cell damage. Trauma inherent to intrasinusoidal lodgement damaged 35% of B16M cells in both normal and LPS-treated mouse liver. The rest of the arrested B16M cells remained intact in normal liver for at least 4 hours, although their damaged cell percentage significantly (P < .05) increased since the second hour in normal mice injected with BSO-treated cells and since the first hour in LPS-treated mice given untreated cells. Recombinant human interleukin-1 receptor antagonist (rHuIL-1-Ra) given to mice 15 minutes before LPS significantly (P < .05) abrogated B16M cell damage. On the other hand, 40% of the B16M cells co-cultured with unstimulated HSE and 70% of the co-cultured with LPS-treated HSE became sensitive to endothelial cell-mediated damage after BSO treatment. These results demonstrate that a high intracellular level of GSH protects B16M cells from possible in vivo and in vitro sinusoidal cell-mediated oxidative stress, contributing to the mechanism of metastatic cell survival within the hepatic microvasculature.",0
1963,9581689,Chylomicrons alter the hepatic distribution and cellular response to endotoxin in rats,"Chylomicrons (CM) can bind endotoxin (lipopolysaccharide [LPS]), forming CM-LPS complexes, and protect against endotoxic shock and death in rodent models of gram-negative sepsis. The liver appears to play a central role in this process, as demonstrated by the increased uptake of LPS by this organ. We examined the effect of CM on the uptake and cellular response to injected 125I-LPS by hepatocytes and hepatic nonparenchymal cells. Whereas CM increased the uptake of LPS by both hepatocytes and Kupffer cells, the increase was proportionately greater in hepatocytes than Kupffer cells. Importantly, CM-LPS complexes inhibited inducible nitric oxide synthase (iNOS) mRNA expression and NO production in Kupffer cells and endothelial cells, reducing mRNA levels by 45% to 50% as compared with LPS alone. CM-bound LPS also reduced NO production by hepatocytes in response to cytokine stimulation. Lastly, CM-LPS complexes yielded a concentration-dependent inhibition of LPS-induced tumor necrosis factor alpha (TNF-alpha) production by Kupffer cells in vitro. These data indicate that the mechanism by which CM protect against endotoxicity may involve an increased uptake of LPS by hepatocytes. Moreover, uptake of CM-bound LPS by liver cells attenuates the capacity of these cells to respond to proinflammatory stimulation. These results highlight important anti-inflammatory properties of CM.",0
1964,9581695,"Efficacy of thymosin alpha1 in patients with chronic hepatitis B: a randomized, controlled trial","Thymosin alpha1 (Talpha) is an immune modifier that has been shown in a pilot study to be effective for chronic hepatitis B; this requires confirmation. Ninety-eight patients with clinicopathologically proven chronic hepatitis B were randomly allocated to 3 groups: 1) group A received a 26-week course of Talpha with a 1.6-mg subcutaneous injection two times a week (T6 group); 2) group B received the same regimen as group A, but Talpha therapy extended for 52 weeks (T12 group); and 3) group C served as a control group and was followed up for 18 months without specific treatment (T0 group). The three groups were comparable in clinicohistological features at entry. The complete virological response rate (clearance of serum hepatitis B virus [HBV] DNA and hepatitis B e antigen [HBeAg]) was higher in group A (40.6%) and group B (26.5%) than in group C (9.4%) (group A vs. group C: P=.004; group B vs. group C: P=.068) when assessed 18 months after entry, although complete response rates among these three groups were similar when first assessed at the end of therapy. There was a trend for complete virological response to increase or accumulate gradually after the end of Talpha therapy. None of the responders lost hepatitis B surface antigen. Blinded histological assessment showed a significant improvement in treated patients, particularly in lobular necroinflammation and scores excluding fibrosis. No significant side effects were observed. These results suggest that a 26-week course of Talpha therapy is effective and safe in patients with chronic hepatitis B.",0
1965,9614257,Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy,"BACKGROUND: Children with high-risk acute lymphoblastic leukemia (ALL) who have a slow response to initial chemotherapy (more than 25 percent blasts in the bone marrow on day 7) have a poor outcome despite intensive therapy. We conducted a randomized trial in which such patients were treated with either an augmented intensive regimen of post-induction chemotherapy or a standard regimen of intensive post-induction chemotherapy. METHODS: Between January 1991 and June 1995, 311 children with newly diagnosed ALL who were either 1 to 9 years of age with white-cell counts of at least 50,000 per cubic millimeter or 10 years of age or older, had a slow response to initial therapy, and entered remission at the end of induction chemotherapy were randomly assigned to receive standard therapy (156 children) or augmented therapy (155). Those with lymphomatous features were excluded. Event-free survival and overall survival were assessed from the end of induction treatment. RESULTS: The outcome at five years was significantly better in the augmented-therapy group than in the standard-therapy group (Kaplan-Meier estimate of event-free survival [+/-SD]: 75.0+/-3.8 vs. 55.0+/-4.5 percent, P<0.001; overall survival: 78.4+/-3.7 vs. 66.7+/-4.2 percent, P=0.02). The difference between treatments was most pronounced among patients one to nine years of age, all of whom had white-cell counts of at least 50,000 per cubic millimeter (P<0.001). Risk factors for an adverse event in the entire cohort included a white-cell count of 200,000 per cubic millimeter or higher (P=0.004), race other than black or white (P<0.001), and the presence of a t(9;22) translocation (P=0.007). The toxic effects of augmented therapy were considerable but manageable. CONCLUSIONS: Augmented post-induction chemotherapy results in an excellent outcome for most patients with high-risk ALL and a slow response to initial therapy.",0
1966,9620315,"Immunoreactivity of porcine heart dihydrolipoamide acetyl- and succinyl-transferases (PDC-E2, OGDC-E2) with primary biliary cirrhosis sera: characterization of the autoantigenic region and effects of enzymatic delipoylation and relipoylation","Analysis of the primary structure of the lipoyl domain of the dihydrolipoamide acetyltransferase (PDC-E2) component of the porcine pyruvate dehydrogenase complex (PDC) reveals a high degree of homology with M2 antigen and human PDC-E2. The porcine PDC-E2 and the dihydrolipoamide succinyltransferase (OGDC-E2) component of the porcine 2-oxoglutarate dehydrogenase complex (OGDC) were identified as mitochondrial autoantigen with sera from patients with primary biliary cirrhosis (PBC). Immunodominant regions (autoepitopes) on the porcine-PDC-E2 component have been mapped to two regions around Lys-46 (outer lipoyl domain) and Lys-173 (inner lipoyl domain), which contained covalently bound lipoic acid prosthetic group. When these lipoyl domains were cleaved at Asp-45 or Asp-172 with endoproteinase Asp-N, the autoantigenicities of the two domains completely disappeared; this suggested the requirement of Asp-45 or Asp-172 residues for the immunoreaction with PBC sera. In addition, a single 14-amino acid epitope peptide histidine-substituted at Asp-172 did not exhibit competitive inhibition of autoantigen binding. Fragmentation of lipoyl domain of the porcine PDC-E2 by limited proteolysis and BrCN-cleavage after alkylation resulted in rapid loss of autoantigenicity. Enzymatic delipoylation and relipoylation of the complexed and free PDC-E2 and OGDC-E2 components did not influence immunoreactivity with PBC sera.",0
1967,9620318,Diet and gallstones in Italy: the cross-sectional MICOL results,"Fifteen thousand nine hundred ten men and 13,674 women (age, 30-69 years) were enrolled in an epidemiological survey of the general population, between December 1984 and April 1987. Each participant was submitted to ultrasonography (US) of the gallbladder and completed a food-frequency questionnaire, covering 38 food items. A common portion size was identified and subjects were asked how often each item was consumed. Nutrient intake was computed by multiplying the intake frequency and nutrient content per portion for each item, and then by summing the product over all foods. Each nutrient intake was adjusted for energy intake. Alcohol intake was calculated by summing the consumption of wine, beer, and liquor. Having excluded subjects aware of having gallstones (GS) or previously submitted to cholecystectomy (to avoid prothopatic bias), 787 males and 1,014 females with GS and 14,272 males and 10,836 females without GS were available for analysis. Relative risks (RR) of GS were computed by quintiles of nutrient intake. The overnight fasting period was calculated as the difference between the specified time of dinner and the time of the next meal (breakfast or lunch). A significant negative association was found between RR of GS and total energy intake for males (chi2 for trend = 8.37; P = .004), fiber intake for females (chi2 = 5.45; P = .02), and daily alcohol consumption for males (chi2 = 10.86; P = .001). A positive association was observed between RR of GS and carbohydrate (chi2 = 5.95; P = .01 for males; chi2 = 9.39; P = .002 for females) and protein intake only for males (chi2 = 10.92; P = .01). Prevalence of GS was higher among subjects who had an overnight fasting period of over 12 hours than subjects with that of less than 12 hours. (RR: 1.35; 95% CI: 1.01-1.80 for males; RR: 1.28; 95% CI: 1.03-1.60 for females). These data do not confirm that high energy intake is associated with an increased risk of GS. Factors protecting against GS comprise: low carbohydrate (males and females) and protein (males) intakes, high fiber (females) and moderate alcohol intake (males) consumption, and a shorter overnight fasting period for both sexes.",0
1968,9620335,Hepatic stellate cells are not subjected to oxidant stress during iron-induced fibrogenesis in rodents,"Oxidant stress plays a key role in hepatic fibrogenesis. This study was undertaken to assess whether, during iron overload-associated liver fibrosis in vivo, oxidant stress occurs in hepatic stellate cells (HSC) during active fibrogenesis. Gerbils were treated with iron-dextran, and, after hepatic fibrosis developed, livers were subjected to various combination of in situ hybridization and immunocytochemistry analyses. In iron-treated animals, no specific accumulation of ferritin protein was found in collagen mRNA-expressing cells. Moreover, the activity of the iron regulatory protein, the main sensor of cellular iron status, was unchanged in HSC from iron-treated animals. Although a significant amount of malondialdehyde-protein adducts was detected in gerbil liver during fibrogenesis, accumulation of these lipid peroxidation by-products was restricted to iron-laden cells adjacent to activated HSC. In cultured gerbil HSC, iron, aldehydes, and other pro-oxidants were able to enhance the expression of an oxidant stress-responsive gene, heme oxygenase (HO), with no change in collagen mRNA accumulation. In keeping with these findings, we found that, in vivo, activation of HO gene was present in iron-filled nonparenchymal cell aggregates, but absent in HSC. In conclusion, the data indicate that during iron overload-associated fibrogenesis, HSC are not directly subjected to oxidant stress, but are likely to be activated by paracrine signals arising in neighboring cells.",0
1969,9620346,Broadly reactive antibodies to hypervariable region 1 in hepatitis C virus-infected patient sera: relation to viral loads and response to interferon,"To clarify the nature of serum anti-hypervariable region 1 (HVR1) antibodies in patients infected with hepatitis C virus (HCV), we assessed the reactivity of 21 patients' sera with 42 HVR1 proteins by Western blot. HVR1 was expressed as fusion proteins with glutathione S-transferase (GST). The patients' sera reacted with variable percentages of the HVR1 proteins, and always reacted with HVR1 proteins of the different genotype. In the genotype-1b-infected patients, the percentage of genotype-1b HVR1 proteins reactive with serum correlated significantly with viral loads; the sera reactive with the higher percentages of HVR1 proteins contained the larger viral loads. In addition, it was significantly lower in the responders of interferon (IFN) therapy than in nonresponders. The competition assays indicated that multiple fractions of anti-HVR1 antibodies with different specificity in a serum reacted with different HVR1 proteins, and that, additionally, a single fraction of antibodies often reacted with more than one HVR1 protein through a similar amino acid sequence. In conclusion, serum anti-HVR1 antibodies were broadly reactive by the mechanism of both the cross-reactivity of a single fraction of anti-HVR1 antibodies with more than one HVR1 protein and the presence of multiple fractions of anti-HVR1 antibodies with different specificity in a serum. In genotype-1b-infected patients, the broad reactivity of serum anti-HVR1 antibodies correlated with viral loads and response to IFN. Further studies are necessary to elucidate the correlation among the broad reactivity of sera with multiple HVR1 proteins and clinical features of chronic hepatitis C patients.",0
1970,9620351,Molecular basis for persistent hepatitis B virus infection in the liver after clearance of serum hepatitis B surface antigen,"Hepatitis B virus (HBV) DNA has been detected by polymerase chain reaction (PCR) in the liver of patients with resolved chronic HBV infection and sustained clearance of hepatitis B surface antigen (HBsAg) from serum. However, it is unknown whether the virus is transcriptionally active at this time or if the covalently closed circular (CCC) replicative intermediate of HBV DNA can still be detected. Therefore, hepatic nucleic acid extracts from seven patients who had cleared serum HBsAg were assessed by (PCR) for either reverse-transcribed HBV RNA, or an intact direct repeat region of the HBV genome indicative of the CCC replicative intermediate of HBV DNA. HBV transcripts were detected in four of seven patients in the study group, whereas an intact direct repeat region of the HBV genome was detected in three. Evidence for viral transcription and replication was more frequently detected in patients who had recently cleared serum HBsAg, but HBV RNA was also detected in one patient 5 years after HBsAg clearance, and an intact direct repeat region of HBV DNA was detected in another subject at nearly 4 years after resolution of disease. Therefore, hepatic HBV transcription may be associated with replicative intermediates of persistent HBV DNA in patients who have cleared HBsAg from serum, suggesting that, on occasion, HBV may not be in a latent state but undergoing low-level replication.",0
1971,9624194,Hospitalization costs associated with homelessness in New York City,"BACKGROUND: Homelessness is believed to be a cause of health problems and high medical costs, but data supporting this association have been difficult to obtain. We compared lengths of stay and reasons for hospital admission among homeless and other low-income persons in New York City to estimate the hospitalization costs associated with homelessness. METHODS: We obtained hospital-discharge data on 18,864 admissions of homeless adults to New York City's public general hospitals (excluding admissions for childbirth) and 383,986 nonmaternity admissions of other low-income adults to all general hospitals in New York City during 1992 and 1993. The differences in length of stay were adjusted for diagnosis-related group, principal diagnosis, selected coexisting illnesses, and demographic characteristics. RESULTS: Of the admissions of homeless people, 51.5 percent were for treatment of substance abuse or mental illness, as compared with 22.8 percent for the other low-income patients, and another 19.7 percent of the admissions of homeless people were for trauma, respiratory disorders, skin disorders, and infectious diseases (excluding the acquired immunodeficiency syndrome [AIDS]), many of which are potentially preventable medical conditions. For the homeless, 80.6 percent of the admissions involved either a principal or a secondary diagnosis of substance abuse or mental illness -- roughly twice the rates for the other patients. The homeless patients stayed 4.1 days, or 36 percent, longer per admission on average than the other patients, even after adjustments were made for differences in the rates of substance abuse and mental illness and other clinical and demographic characteristics. The costs of the additional days per discharge averaged $4,094 for psychiatric patients, $3,370 for patients with AIDS, and $2,414 for all types of patients. CONCLUSIONS: Homelessness is associated with substantial excess costs per hospital stay in New York City. Decisions to fund housing and supportive services for the homeless should take into account the potential of these services to reduce the high costs of hospitalization in this population.",0
1972,9647874,Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol,"BACKGROUND: Guidelines established by the National Cholesterol Education Program (NCEP) promote exercise and weight loss for the treatment of abnormal lipoprotein levels. Little is known, however, about the effects of exercise or the NCEP diet, which is moderately low in fat and cholesterol, in persons with lipoprotein levels that place them at high risk for coronary heart disease. METHODS: We studied plasma lipoprotein levels in 180 postmenopausal women, 45 through 64 years of age, and 197 men, 30 through 64 years of age, who had low high-density lipoprotein (HDL) cholesterol levels (< or =59 mg per deciliter in women and < or =44 mg per deciliter in men) and moderately elevated levels of low-density lipoprotein (LDL) cholesterol (>125 mg per deciliter but <210 mg per deciliter in women and >125 mg per deciliter but <190 mg per deciliter in men). The subjects were randomly assigned to aerobic exercise, the NCEP Step 2 diet, or diet plus exercise, or to a control group, which received no intervention. RESULTS: Dietary intake of fat and cholesterol decreased during the one-year study (P<0.001), as did body weight, in women and men in either the diet group or the diet-plus-exercise group, as compared with the controls (P<0.001) and the exercise group (P<0.05), in which dietary intake and body weight were unchanged. Changes in HDL cholesterol and triglyceride levels and the ratio of total to HDL cholesterol did not differ significantly among the treatment groups, for subjects of either sex. The serum level of LDL cholesterol was significantly reduced among women (a decrease of 14.5+/-22.2 mg per deciliter) and men (a decrease of 20.0+/-17.3 mg per deciliter) in the diet-plus-exercise group, as compared with the control group (women had a decrease of 2.5+/-16.6 mg per deciliter, P<0.05; men had a decrease of 4.6+/-21.1 mg per deciliter, P<0.001). The reduction in LDL cholesterol in men in the diet-plus-exercise group was also significant as compared with that among the men in the exercise group (3.6+/-18.8 mg per deciliter, P<0.001). In contrast, changes in LDL cholesterol levels were not significant among the women (a decrease of 7.3+/-18.9 mg per deciliter) or the men (10.8+/-18.8 mg per deciliter) in the diet group, as compared with the controls. CONCLUSIONS: The NCEP Step 2 diet failed to lower LDL cholesterol levels in men or women with high-risk lipoprotein levels who did not engage in aerobic exercise. This finding highlights the importance of physical activity in the treatment of elevated LDL cholesterol levels.",0
1973,9657092,Development of pseudointima and stenosis after transjugular intrahepatic portasystemic shunts: characterization of cell phenotype and function,"The clinical utility of transjugular intrahepatic portasystemic shunts (TIPS) is frequently complicated by the ingrowth of tissue into the stent lumen, causing stent stenosis. These studies were undertaken to define the cellular and matrix components of the pseudointima, define the phenotype and function of the mesenchymal cells in the pseudointima and maintain them in culture, and to study the differences between stenotic and nonstenosed stents. A total of 35 stents were evaluated. TIPS pseudointima were examined histologically, by immunohistochemistry and in situ hybridization to determine the cellular and connective tissue constituents. Mesenchymal cells were grown from tissue within the TIPS and around it, and their phenotype was studied and compared with control smooth muscle cells and fibroblasts. Masson's trichrome staining of histological sections demonstrated that TIPS tissue was composed of collagen and palisades of mesenchymal cells and was lined by an endothelium. Immunostaining demonstrated strong and uniform alpha-smooth muscle staining in TIPS mesenchymal cells and peri-TIPS cells. Type I procollagen mRNA expression was demonstrated in mesenchymal cells in and around the stent by in situ hybridization. TIPS mesenchymal cells secreted less radiolabeled fibronectin, and far more type III, relative to type I, collagen compared with peri-TIPS cells. TIPS cells also expressed high levels of type III procollagen mRNA compared with peri-TIPS cells. There was no difference between stenotic stents and nonstenosed stents with respect to clinical features, time from stenting, gross morphology, histology, presence of bile fistulae, and cell phenotype. However, smooth muscle cells (SMC) from stenotic stents demonstrated both greater cell proliferation and collagen I and III secretion compared with those from nonstenosed stents. These data demonstrate that TIPS stenosis results from an accumulation of collagen and proliferation of SMC within the stent lumen.",0
1974,9657094,Increased cerebrovascular resistance in cirrhotic patients with ascites,"Studies assessing regional hemodynamics in patients with cirrhosis and ascites have shown vasodilation in the splanchnic circulation and vasoconstriction in the renal circulation and in the brachial and femoral artery vascular territories. The aim of this study was to assess the cerebral vascular resistance in cirrhotic patients with ascites. The resistive index in the middle cerebral artery (an index of the cerebral vascular resistance) and in a renal interlobar artery were measured by Doppler ultrasonography in 7 healthy subjects: 13 patients with compensated cirrhosis and 24 patients with ascites (13 with renal failure). The arterial blood pressure and the activity of the renin-angiotensin and sympathetic nervous systems, as estimated by plasma renin activity and plasma norepinephrine concentration, respectively, were also measured. The resistive index in the middle cerebral artery was significantly increased in patients with ascites (0.68 +/- 0.05, mean +/- SD) as compared with patients without ascites (0.60 +/- 0.01, P < .05) and with healthy patients (0.52 +/- 0.01, P < .01). Renal resistive index was also increased in patients with ascites (0.77 +/- 0.01) compared with the other two groups (0.68 +/- 0.02 and 0.62 +/- 0.00, respectively; P < .001). The resistive index in the middle cerebral artery showed a direct correlation with renal resistive index (r = .73, P < .01), plasma renin activity (r = .61, P < .01), and norepinephrine (r = .53, P < .01). The resistive index in the middle cerebral artery showed an inverse correlation with mean arterial pressure (r = -.45, P < .01). These results indicate that in patients with cirrhosis and ascites there is a cerebral vasoconstriction which is probably related with the arterial hypotension and the overactivity of vasoconstrictor systems.",0
1975,9657113,Cytokine and hepatitis B virus DNA co-immunizations enhance cellular and humoral immune responses to the middle but not to the large hepatitis B virus surface antigen in mice,"Genetic immunization is a potentially useful strategy to prevent or treat hepatitis B virus (HBV) infection. We have previously shown that HBV envelope proteins are highly immunogenic using this technique. The large envelope protein (LHBs), however, induced significantly weaker humoral and cellular immune responses when compared with the middle envelope protein (MHBs). We studied the effect of co-immunizations with cytokine DNA expression constructs encoding for interleukin (IL)-2 and (GM-CSF) on the immunogenicity of LHBs at the B-and T-cell level. Co-immunizations of mice with plasmids encoding for MHBs and IL-2 or GM-CSF increased anti-HBs responses, helper T-cell proliferative activity, and cytotoxic T lymphocyte (CTL) killing. In contrast, co-immunizations of plasmids encoding for LHBs and IL-2 or GM-CSF had no effect on humoral and cellular immune responses. LHBs did not inhibit the production or secretion of IL-2 and GM-CSF. In addition, IL-2, tumor necrosis factor alfa (TNF-alpha), and interferon gamma (IFN-gamma) had no suppressive effect on HBV envelope protein expression in vitro. Based on these data, MHBs, but not LHBs, genetic immunization can be augmented by IL-2 or GM-CSF cytokines.",0
1976,9657118,Modulation of immune responses to hepatitis C virus envelope E2 protein following injection of plasmid DNA using single or combined delivery routes,"Different delivery routes of plasmid DNA may result in the induction of differential humoral and cellular immunity. We have studied the influence of two main routes of plasmid injection, performed intramuscularly and intraepidermally using a gene gun, for the induction of immune responses specific to hepatitis C virus (HCV) envelope protein E2. Three plasmids expressing different immunogenic domains of E2 (amino acids [aa] 384443, aa 504-555, and aa 384-746) were injected into BALB/c mice according to five different protocols using various combinations of intramuscular (i.m.) or intraepidermal (i.e.) primary and booster injections. Seroconversion rates, antibody titers and isotypes, epitope recognition, and T-helper (Th) release cytokine profiles were analyzed. Antibody titers and epitope recognition were linked to either or both the nature of the immunogen expressed and the delivery route chosen. In all cases, the lowest antibody titers were obtained using single i.m.-based protocols. Independently of the antibody titers generated, only some specific i.e.-combined delivery routes induced antibodies able to recognize determinants located in the N-terminal of E2 (aa 384411 and aa 411437) and mimicked by synthetic peptides. By contrast, the antibody isotypes and the splenic cytokine production identified were independent of the plasmids used and the delivery route implemented. All conditions resulted in Th-1 like responses suggested by the exclusive detection of IgG2a and 2b antibodies and the production of interferon gamma (INF-gamma) but no interleukin-4 (IL-4). Overall, our results suggest that the combination of i.m. and i.e. delivery routes provides the most efficient way to induce a broad immune response against HCV-E2.",0
1977,9673299,A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. Recombinant Outer-Surface Protein A Lyme Disease Vaccine Study Consortium,"BACKGROUND: Lyme disease is a multisystem inflammatory disease caused by infection with the tick-borne spirochete Borrelia burgdorferi and is the most common vector-borne infection in the United States. We assessed the efficacy of a recombinant vaccine consisting of outer-surface protein A (OspA) without adjuvant in subjects at risk for Lyme disease. METHODS: For this double-blind trial, 10,305 subjects 18 years of age or older were recruited at 14 sites in areas of the United States where Lyme disease was endemic; the subjects were randomly assigned to receive either placebo (5149 subjects) or 30 microg of OspA vaccine (5156 subjects). The first two injections were administered 1 month apart, and 7515 subjects also received a booster dose at 12 months. The subjects were observed for two seasons during which the risk of transmission of Lyme disease was high. The primary end point was the number of new clinically and serologically confirmed cases of Lyme disease. RESULTS: The efficacy of the vaccine was 68 percent in the first year of the study in the entire population and 92 percent in the second year among the 3745 subjects who received the third injection. The vaccine was well tolerated. There was a higher incidence of mild, self-limited local and systemic reactions in the vaccine group, but only during the seven days after vaccination. There was no significant increase in the frequency of arthritis or neurologic events in vaccine recipients. CONCLUSIONS: In this study, OspA vaccine was safe and effective in the prevention of Lyme disease.",0
1978,9673308,"Partial-birth abortion, Congress, and the Constitution","""In the US, a new antiabortion strategy of using legislative and judicial forums to change the rhetoric of abortion rather than using abortion rhetoric to change the law arose out of disappointment when the 1992 Casey decision failed to overturn Roe. This new approach is crystallized by the 1995 introduction of federal legislation (vetoed by the President) to ban so-called """"partial-birth"""" abortions. Opponents to this late-term procedure undertaken to preserve a women's life or health distinguish intact dilatation and extraction from induced labor to terminate a nonviable pregnancy (failing to recognize the lack of ethical difference) and make inaccurate political statements linking the abortion procedure to infanticide. When the ban was reintroduced to Congress in 1997, the previously silent American Medical Association agreed to support the bill if two """"physician-friendly"""" amendments were added, but the American College of Obstetricians and Gynecologists made it clear that it is """"inappropriate, ill advised, and dangerous"""" for legislative bodies to intervene into medical decision-making. The new version of the bill shifted the focus to all abortions after viability unless they are necessary to protect the mother from grievous harm to her physical (not mental) health, thus limiting the reach of the Roe decision. Clinton vetoed this bill also. Such legislation would be unlikely to prevent even one abortion, and its importance rests in its view of the proper role of government in regulating health care. This follows previous efforts to reframe the abortion debate by creating a dichotomy that marginalizes either women or fetuses and shifts the focus to another issue.""",0
1979,9695991,Effects of long-term ursodeoxycholate administration on expression levels of secretory low-molecular-weight phospholipases A2 and mucin genes in gallbladders and biliary composition in patients with multiple cholesterol stones,"Group IIA phospholipase A2 (PLA2), a secretory low-molecular-weight PLA2, may play a critical role in the process of gallbladder mucosal inflammation in multiple cholesterol stones, which in turn may produce biliary pronucleating proteins as well as mucin. On the other hand, ursodeoxycholate (UDC) decreases biliary levels of various pronucleating proteins, possibly because of its membrane-protective effects on the inflamed gallbladder mucosa. To elucidate that beneficial effect of UDC, the expression levels of low-molecular-weight PLA2s, group IIA PLA2 (PLA2-IIA), and group V PLA2 (PLA2-V), and mucin core polypeptide genes in the gallbladders were studied for UDC-treated patients and untreated patients with multiple cholesterol stones. Furthermore, the results were correlated with alterations in biliary composition. With long-term administration of UDC, the PLA2-IIA protein mass (2.7 +/- 0.5 vs. 5.0 +/- 0.4 ng/mg x protein [mean +/- SEM]; P < .01) and steady-state mRNA level, as well as the PLA2-V mRNA level, were significantly decreased in the gallbladders, where the prostaglandin E2 (PGE2) level was concomitantly decreased (190.7 +/- 27.9 vs. 393.6 +/- 55.3 pg/mg x protein; P < .01). In the gallbladder bile, the immunoradiometrically determined PLA2-IIA levels were significantly decreased in the UDC-treated patients (43 +/- 4 ng/dL; P < .01) in comparison with untreated patients (78 +/- 6 ng/dL). Significant decreases were similarly found for total protein, mucin, and free arachidonate concentrations, as well as nucleation activity in the bile. The degree of the changes was found to be rather small in solitary stones. In contrast to the decreased mucin concentration, however, there were no significant changes in the expression levels of mucin core polypeptide genes (MUC1-MUC6) between the UDC-treated and untreated patients. Long-term UDC administration was observed to lower the increased PLA2-IIA protein mass and mRNA level, as well as the PLA2-V mRNA level, in the gallbladders of patients with multiple cholesterol stones, which in turn may be of therapeutic importance in improving the gallbladder mucosal inflammation. Effects of UDC on secretory low-molecular-weight PLA2s as inflammatory mediators may relate to the reported efficacy of UDC treatment in cholesterol gallstone disease.",0
1980,9696007,Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver,"Recent advances have implicated the importance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in the regulation of liver growth. Therefore, we studied how dexamethasone, a well-known inhibitor of these cytokines, influences the proliferation of different hepatic cell populations. As we expected, dexamethasone pretreatment suppressed the expression of both TNF and IL-6 after partial hepatectomy and significantly reduced the proliferative response of the hepatocytes. Furthermore, the proliferative response of hepatocytes could be rescued by IL-6 administration. Dexamethasone also severely diminished the induction and expansion of oval cells induced by the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) protocol but did not have any effect on the proliferation of the bile duct cells stimulated by bile duct ligation. The differential inhibition of these two morphologically very similar cell types may be used to characterize divergent regulatory mechanisms responsible for the proliferative response of oval cells and adult bile epithelial cells.",0
1981,9696011,Infiltrating CD45RC- T cells are associated with immunologic unresponsiveness induced by donor class I major histocompatibility complex antigens in rats,"It has previously been shown that a single intravenous injection of freshly heparinized donor-specific blood transfusion (DST) before transplantation significantly prolongs the survival of fully allogeneic ACI (RT1a)-to-LEW(RT1(1)) rat hepatic allografts. Additionally, we have shown that pretreatment of LEW rats with PVG.r1 blood, which shares only the RT1.A major histocompatibility complex (MHC) region with ACI, significantly prolongs the survival of ACI hepatic allografts. In this study, we report the cellular identity of hepatic allograft leukocyte infiltrates following transplantation. Fluorescence-activated cell sorting (FACS) analysis revealed that CD4+ T cells infiltrating liver allografts could be divided into two subsets, CD45RC- CD4+ and CD45RC+ CD4+ T cells, and that the ratio of CD45RC- CD4+/CD45RC+ CD4+ T cells was significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood as compared to untreated allografts. Further, CD8+ T cells that accumulated in the liver grafts could be similarly divided into two subsets, and the ratio of CD45RC- CD8+/CD45RC+ CD8+ T cells was also significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that CD45RC- CD4+ T cells harvested from hepatic allografts pretreated with PVG.r1 blood expressed interleukin-4 (IL-4) and interleukin-10 (IL-10), but not interleukin-2 (IL-2) or interferon-gamma (IFN-gamma). In contrast, CD45RC- CD8+ T cells from hepatic allografts pretreated with PVG.r1 blood expressed IL-4, IL-10, and IFN-lambda, but not IL-2. These results indicate that the CD45RC leukocyte common antigen could be used to differentiate CD4+ and CD8+ T cells following pretreatment with DST or PVG.r1 blood. Persistent infiltration of CD45RC- CD4+ and CD45RC- CD8+ T cells, capable of secreting Th2-type cytokines may prevent allograft rejection by causing immunologic unresponsiveness.",0
1982,9696013,Effect of tumor necrosis factor alpha and intercellular adhesion molecule-1 expression on immunogenicity of murine liver cells in mice,"""Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been implicated in the pathogenesis of various inflammatory liver disease states, including viral and autoimmune hepatitis as well as liver allograft rejection. Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine known to up-regulate adhesion molecules as well as major histocompatibility complex (MHC) class I expression, and has been demonstrated to be important in the rejection of vascularized organ allografts. The current studies address the effect of TNF-alpha and the role of ICAM-1 expression on liver cell immunogenicity in vitro in mixed lymphocyte hepatocyte culture (MLHC), in vitro in mixed lymphocyte liver nonparenchymal cell culture (MLNPC), in vivo in hepatocyte sponge matrix allografts (HC-SMA), and in vivo in liver nonparenchymal cell sponge matrix allografts (NPC-SMA). Purified allogeneic hepatocytes (HC) and liver nonparenchymal cells (NPC) under naive, unstimulated conditions demonstrated different profiles of MHC antigen and adhesion molecule expression, but both liver cell populations stimulated the proliferation and development of allospecific cytotoxic effectors in vitro and in vivo. Despite significant up-regulation of MHC class I and ICAM-1 on both HC and liver NPCs by in vivo treatment with TNF-alpha, the immunogenicity of TNF-alpha-stimulated liver cells was not appreciably different from naive, unstimulated liver cells. In contrast, ICAM-1-negative HC and NPCs were significantly less immunogenic both in terms of lymphocyte proliferative responses and the generation of allospecific cytolytic effectors. These results suggest that constitutive expression of ICAM-1 enhances the immunogenicity of """"donor"""" liver cells but is not absolutely required to elicit immune responses to allogeneic liver cells. Further studies to determine the role of adhesion molecule expression on trafficking of host immune cells to the liver and the role of adhesion molecule expression by host cells are required to clarify their role in immune responses to liver cells.""",0
1983,9696023,DNA ribonucleases that are active against intracellular hepatitis B viral RNA targets,"DNA ribonucleases directed against direct repeat 1 (DR1) and polyadenylation signal regions of hepatitis B virus (HBV) messages were prepared with phosphorothioate modifications and varying arm lengths. DNA ribonucleases modified throughout the entire molecule and in the target binding arms were completely protected from degradation after incubation with serum. DNA ribonuclease modified only at the 5' and 3' termini remained 92.9% intact after incubation. Molecules with no modification were degraded to 67.6% under the same conditions. However, modification of the entire molecule and in the recognition arms resulted in 99.8% and 98.4% inactivation of cleavage activity, respectively. Modification of only the termini resulted in retention of 20% to 40% of original activity. Lengthening each terminally modified arm from 9 to 11 nucleotides increased cleavage efficiency almost 10-fold. In Huh 7 cells, DR1-directed DNA ribonucleases with terminal modifications significantly suppressed HBV-luciferase fusion gene expression up to 48% of control. In contrast, DNA ribonucleases had no effect on a control construct lacking any HBV target sequences. Moreover, inactivated mutant and HCV-directed DNA ribonucleases had no significant effects on the HBV target. We conclude that resistance of DNA ribonucleases to degradation can be enhanced through phosphorothioate modification. Cleavage activity can be retained by limiting modification to the termini and lengthening the recognition arms. Such DNA ribonucleases can be made to specifically cleave target HBV RNA and substantially inhibit intracellular viral gene expression.",0
1984,9718375,Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization,"BACKGROUND: In vitro fertilization is associated with a high risk of multiple births, which is a direct consequence of the number of embryos transferred. However, other factors that contribute to the risk are not well defined. METHODS: Using the data base established by the Human Fertilization and Embryology Authority in the United Kingdom, we studied the factors associated with an increased risk of multiple births in 44,236 cycles in 25,240 women. The factors included the woman's age, the cause and duration of infertility, previous attempts at in vitro fertilization, previous live births, number of eggs fertilized, and number of embryos transferred. RESULTS: Older age, tubal infertility, longer duration of infertility, and a higher number of previous attempts at in vitro fertilization were all associated with a significantly decreased chance of a birth and of multiple births. Previous live birth was associated with an increased chance of a birth but not of multiple births. The higher the number of eggs fertilized, the higher the likelihood of a live birth. When more than four eggs were fertilized, there was no increase in the birth rate for women receiving three transferred embryos as compared with those receiving two, but there was a considerable increase in the rate of multiple births when three were transferred (odds ratio, 1.6; 95 percent confidence interval, 1.5 to 1.8). CONCLUSIONS: Among women undergoing in vitro fertilization, the chances of a live birth are related to the number of eggs fertilized, presumably because of the greater selection of embryos for transfer. When more than four eggs are fertilized and available for transfer, the woman's chance of a birth is not diminished by transferring only two embryos. Transferring more embryos increases the risk of multiple births.",0
1985,9731548,"Effect of the prokinetic agent, erythromycin, in the Richardson ground squirrel model of cholesterol gallstone disease","Impaired gallbladder motility and delayed intestinal transit contribute to cholesterol gallstone formation by impeding the enterohepatic circulation of bile salts and causing gallbladder stasis. The therapeutic value of erythromycin, a prokinetic motilin analog, was evaluated in an animal model of gallstone formation. Eighty ground squirrels were fed either a trace- (control) or a high- (1%) cholesterol diet. Half of each diet group received either erythromycin stearate or placebo orally twice daily for 4 weeks. Biliary lipid secretion and bile salt pool size were determined via common duct cannulation. Gallbladder contractile response to cholecystokinin (CCK) was studied in vitro. Intestinal transit was evaluated in vivo by 51Cr marker. In the placebo-treated group, fed the high- versus the trace-cholesterol diet, bile salt secretion decreased (trace-cholesterol + placebo, 21.0 +/- 1.8 nmol/min/g liver vs. high-cholesterol + placebo, 9.3 +/- 1.4 nmol/min/g liver), cholesterol saturation index (CSI) doubled (trace-cholesterol + placebo, 0.61 +/- 0.06 vs. high-cholesterol + placebo, 1.30 +/- 0.04), nucleation time shortened (trace-cholesterol + placebo, > 21 days vs. high-cholesterol + placebo, 6.4 +/- 1.0 days), cholesterol crystals formed, gallbladder contractility diminished, and intestinal transit was delayed (each P < .05). Erythromycin treatment of animals on the high-cholesterol diet restored gallbladder contractility and intestinal transit to control levels, increased bile salt secretion, reduced the total bile salt pool, lowered the cholesterol saturation of bile, lengthened the nucleation time, and so reduced crystal formation (each P < .05). Erythromycin enhances gallbladder motility and hastens intestinal transit, promoting more rapid enterohepatic cycling of bile salts. This increases bile salt secretion, improves cholesterol solubility, and reduces crystal development.",0
1986,9731577,Dissection of human humoral immune response against hepatitis C virus E2 glycoprotein by repertoire cloning and generation of recombinant Fab fragments,"Demonstration of antibodies inhibiting key viral functions is the basis for the design of an effective vaccine. Dissection of the human antibody response by repertoire cloning may be a powerful means to address this issue. In this study, a panel of human monoclonal recombinant Fab fragments specific for hepatitis C virus (HCV) E2 envelope protein was generated. The selection procedure was designed to select for cross-genotype reactive antibodies. Sequences coding five different human recombinant Fabs specific for the HCV/E2 protein were cloned and characterized. The ability of the cloned antibody fragments to inhibit adhesion of recombinant envelope E2 protein to target cells was assayed. While affinity of the different antibody fragments appeared similar, activity in inhibiting E2 binding to target cells varied considerably from one Fab fragment to another. Two Fabs were not able to inhibit E2 binding at high concentration (40 microg/mL), while three other Fab clones were active in neutralizing 50% of the E2 binding at concentrations ranging from 3 to 0.35 microg/mL.",0
1987,9744970,High-level chloramphenicol resistance in Neisseria meningitidis,"BACKGROUND: Neisseria meningitidis is nearly always susceptible to the penicillins, the cephalosporins, and chloramphenicol. Between 1987 and 1996, however, chloramphenicol-resistant strains were isolated from 11 patients in Vietnam and 1 in France. METHODS: The minimal inhibitory concentration of chloramphenicol was determined for the 12 isolates. The isolates were analyzed by monoclonal-antibody-based serotyping and subtyping, pulsed-field gel electrophoresis, and multilocus enzyme electrophoresis. Bacterial DNA was analyzed by hybridization, the polymerase chain reaction, and sequencing to identify the resistance gene and determine the origin of the resistance. RESULTS: The isolates were resistant to chloramphenicol (minimal inhibitory concentration, > or =64 mg per liter) and produced an active chloramphenicol acetyltransferase. All 12 strains belonged to serogroup B but had a high degree of diversity, and 10 could not be typed with the use of monoclonal antibodies. The nucleotide sequence of the resistance gene and the flanking regions was identical to that of an internal portion of transposon Tn4451 that carries the catP gene in Clostridium perfringens. Moreover, this gene was located in the same genomic site in the chloramphenicol-resistant isolates. CONCLUSIONS: The high-level chloramphenicol resistance that we describe in N. meningitidis isolates is of great concern, since in developing countries, chloramphenicol given intramuscularly is the standard therapy for meningococcal meningitis. The resistance to chloramphenicol is due to the presence of the catP gene on a truncated transposon that has lost mobility because of internal deletions, and the transformation of genetic material between strains of N. meningitidis probably played an important part in the dissemination of the gene.",0
1988,9753708,The sentinel node in breast cancer--a multicenter validation study,"""BACKGROUND: Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. METHODS: We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. """"Hot spots"""" representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. RESULTS: The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status of the axillary nodes was 97 percent (392 of 405); the specificity of the method was 100 percent, the positive predictive value was 100 percent, the negative predictive value was 96 percent (291 of 304), and the sensitivity was 89 percent (101 of 114). The sentinel nodes were outside the axilla in 8 percent of cases and outside of level 1 nodes in 11 percent of cases. Three percent of positive sentinel nodes were in nonaxillary locations. CONCLUSIONS: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient.""",0
1989,9753710,Obesity associated with a mutation in a genetic regulator of adipocyte differentiation,"BACKGROUND: There is increasing evidence of genetic factors leading to obesity, but the exact genes involved have not been defined. Peroxisome-proliferator-activated receptor gamma2 (PPARgamma2) is a transcription factor that has a key role in adipocyte differentiation, and therefore mutations of the gene for this factor might predispose people to obesity. METHODS: We studied 358 unrelated German subjects, including 121 obese subjects (defined as those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 29). We evaluated these subjects for mutations in the gene for PPARgamma2 at or near a site of serine phosphorylation at position 114 that negatively regulates the transcriptional activity of the protein, using a polymerase-chain-reaction-based assay coupled with specific endonuclease digestion. The activity of the mutation identified was analyzed by retroviral transfection and overexpression in murine fibroblasts. RESULTS: Four of the 121 obese subjects had a missense mutation in the gene for PPARgamma2 that resulted in the conversion of proline to glutamine at position 115, as compared with none of the 237 subjects of normal weight (P=0.01). All the subjects with the mutant allele were markedly obese, with body-mass-index values ranging from 37.9 to 47.3, as compared with a mean of 33.6 in the other obese subjects. Overexpression of the mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at position 114 was defective, as well as to accelerated differentiation of the cells into adipocytes and greater cellular accumulation of triglyceride than with the wild-type PPARgamma2. These effects were similar to those of an in vitro mutation created directly at the Ser114 phosphorylation site. CONCLUSIONS: A Pro115Gln mutation in PPARgamma2 accelerates the differentiation of adipocytes and may cause obesity.",0
1990,9755224,Cryptosporidium parvum is cytopathic for cultured human biliary epithelia via an apoptotic mechanism,"While the clinical features of sclerosing cholangitis secondary to opportunistic infections of the biliary tree in patients with acquired immunodeficiency syndrome (AIDS) are well known, the mechanisms by which microbial pathogens such as Cryptosporidium parvum associated with this syndrome actually cause disease are obscure. We established an in vitro model of biliary cryptosporidiosis employing a human biliary epithelial cell line. Using morphological and biochemical techniques, we examined the interaction of C. parvum with cultured human cholangiocytes. When the apical plasma membrane of polarized, confluent monolayers of human biliary epithelial cells was exposed to C. parvum oocysts that had been excysted in vitro, sporozoites attached to and invaded the cells in a time-, dose-, temperature-, and pH-dependent manner. The infectious process was both plasma membrane domain- and cell-specific, because no attachment or invasion occurred when the basolateral membrane of cholangiocytes was exposed to the parasite, or when a human hepatocyte cell line (HepG2) was used. Time-lapse video microscopy and scanning electron microscopy (SEM) showed that sporozoite attachment was rapid, involved extensive cholangiocyte membrane ruffling, and culminated in parasite penetration into a tight-fitting vacuole formed by invagination of the plasma membrane similar to those found in naturally occurring infection in vivo. Transmission electron microscopy (TEM) showed that C. parvum organisms formed parasitophorus vacuoles and were able to undergo a complete reproductive cycle, forming both asexual and sexual reproductive stages. Unexpectedly, direct cytopathic effects were noted in infected monolayers, with widespread programmed cell death (i.e., apoptosis) of biliary epithelial cells as assessed both morphologically and biochemically beginning within hours after exposure to the organism. The novel finding of specific cytopathic invasion of biliary epithelia by C. parvum may be relevant to the pathogenesis and possible therapy of the secondary sclerosing cholangitis seen in AIDS patients with biliary cryptosporidiosis.",0
1991,9755227,Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats,"Increased intrahepatic resistance in cirrhotic livers is in part caused by increased vascular tone. Several morphological abnormalities have been described in the sinusoidal endothelial cells of cirrhotic livers, but the functional impact of these abnormalities on the intrahepatic vascular tone has not been studied. The aim of this study was to investigate the intrahepatic endothelial function and the role of nitric oxide (NO) with regard to vascular tone in cirrhotic livers. Isolated rat liver perfusions were performed in cirrhotic rats (induced by chronic carbon tetrachloride inhalation) and weight-matched normal controls. After preconstricting the intrahepatic microcirculation with methoxamine (10(-4) mol/L), response to cumulative doses of receptor-mediated endothelial agonist, acetylcholine (10(-7) mol/L-10(-5) mol/L), was obtained. In another series, response to the receptor-independent endothelial agonist, calcium ionophore A23187 (10(-7) mol/L and 3 x 10(-7) mol/L), was obtained in the absence and presence of Nomega-nitro-L-arginine (NNA) and indomethacin. In a third series of rats, nitrate and nitrite production was measured in the perfusate of perfused normal and cirrhotic livers. There was significantly less vasorelaxation in cirrhotic livers as compared with normal livers in response to acetylcholine and calcium ionophore A23187 (P < .0001). The impaired vasorelaxation was a result of a decrease in both NO-mediated and non-NO-mediated components of vasorelaxation. Cirrhotic livers from ascitic rats had significantly less vasorelaxation as compared with livers from nonascitic rats (P < .005). There was significantly less production of nitrates and nitrites in cirrhotic livers (P < .05). The liver microcirculation of cirrhotic livers is characterized by endothelial dysfunction that results in impaired release of endothelial relaxing factors including NO.",0
1992,9755246,Neither intestinal sequestration of bile acids nor common bile duct ligation modulate the expression and function of the rat ileal bile acid transporter,"The regulatory responses of bile acid (BA) transport in the terminal ileum to perturbations in BA homeostasis are complex, and conflicting results have been reported by different investigators. These studies were designed to examine the response of this system to a reduction in ileal bile salt concentrations at both a functional and molecular level. Common bile duct ligation (BDL) or feeding of a novel bile acid-binding compound, GT31-104HB, for 7 days were used to reduce ileal apical membrane bile salt flux. Apical bile acid transport function was assessed by examining sodium-dependent uptake of [3H]-taurocholate (TC) into brush border membrane vesicles (BBMV). Expression of the apical sodium-dependent bile acid transporter (ASBT) and the ileal lipid-binding protein (ILBP) were assessed by Western blotting with quantitation using [125I]-labeled secondary antibody and a phosphorimager. Neither common BDL nor intestinal sequestration of BA led to a change in ileal bile acid transport function or the expression of the ASBT or the ILBP. These results indicate that a reduction in presentation of bile salts to the apical surface of the terminal ileum does not modulate the expression of the genes involved in their transport.",0
1993,9755254,Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus,"A novel transient mechanism for studying hepatitis B virus (HBV) gene expression and replication using recombinant HBV baculovirus to deliver the HBV genome to HepG2 cells was generated. In HBV baculovirus infected HepG2 cells, HBV transcripts, and intracellular and secreted HBV antigens are produced; replication occurs as evidenced by the presence of high levels of intracellular replicative intermediates and protected HBV DNA in the medium. Density-gradient analysis of extracellular HBV DNA indicated that the DNA was contained predominantly in enveloped HBV virions. Covalently closed circular (CCC) DNA is present indicating that, in this system, HBV core particles are capable of delivering newly synthesized HBV genomes back into the nuclei of infected cells. HBV gene expression is driven exclusively from endogenous promoters. Levels of HBV gene expression and replication can be achieved in HBV baculovirus-infected HepG2 cells which far exceed levels found in HepG2 2.2.15 cells. HBV baculovirus infection of HepG2 cells lends itself readily to experimental manipulation as follows: 1) HBV expression can be initiated any time relative to seeding of HepG2 cells; 2) levels of HBV replication can be regulated over a wide range simply by changing the baculovirus multiplicity of infection; 3) HBV replication is readily detectable by one day post infection with HBV baculovirus and persists at least through day eleven post infection; and (4) the transient nature of the infection can be extended and/or enhanced by superinfecting the cultures. We conclude that infection of HepG2 cells by HBV recombinant baculovirus represents a simple to use and highly flexible system for studying the effects of antivirals and/or cytokines on HBV production and for understanding HBV replication and pathogenesis at the molecular level.",0
1994,9770560,Benefit of a favorable cardiovascular risk-factor profile in middle age with respect to Medicare costs,"BACKGROUND: People without major risk factors for cardiovascular disease in middle age live longer than those with unfavorable risk-factor profiles. It is not known whether such low-risk status also results in lower expenditures for medical care at older ages. We used data from the Chicago Heart Association Detection Project in Industry to assess the relation of a low risk of cardiovascular disease in middle age to Medicare expenditures later in life. METHODS: We studied 7039 men and 6757 women who were 40 to 64 years of age when surveyed between 1967 and 1973 and who survived to have at least two years of Medicare coverage in 1984 through 1994. Men and women classified as being at low risk for cardiovascular disease were those who had the following characteristics at the time they were initially surveyed: serum cholesterol level, <200 mg per deciliter (5.2 mmol per liter); blood pressure, < or =120/80 mm Hg; no current smoking; an absence of electrocardiographic abnormalities; no history of diabetes; and no history of myocardial infarction. We compared Medicare costs for the 279 men (4.0 percent) and 298 women (4.4 percent) who had this low-risk profile with those for the rest of the study group, who were not at low risk. Health Care Financing Administration charges for services to Medicare beneficiaries were used to estimate average annual health care costs (total costs, those for cardiovascular diseases, and those for cancer). RESULTS: Average annual health care charges were much lower for persons at low risk - the total charges for the men at low risk were less than two thirds of the charges for the men not at low risk ($1,615 less); for the women at low risk, the charges were less than one half of those for the women not at low risk ($1,885 less). Charges related to cardiovascular disease were lower for the low-risk groups of men and women than for those not at low risk (by $979 and $556, respectively), and charges related to cancer were also lower (by $134 and $189). CONCLUSIONS: People with favorable cardiovascular risk profiles in middle age had lower average annual Medicare charges in older age. Having optimal status with respect to major cardiovascular risk factors may result not only in greater longevity but also in lower health care costs.",0
1995,9780337,Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program,"BACKGROUND: The requirements with respect to HLA compatibility and the relative importance of matching for individual class I and class II HLA alleles in the transplantation of hematopoietic stem cells from unrelated donors have not yet been established. METHODS: We performed retrospective DNA typing of alleles at 11 polymorphic loci of HLA genes in 440 recipients of hematopoietic stem cells from unrelated donors who were serologically identical with their respective recipients for HLA-A, B, and DR antigens. Of these recipients, 80 percent had leukemia; the rest had lymphoma, marrow failure, or a congenital disorder. RESULTS: Multivariate analysis showed that incompatibility for HLA-A alleles and incompatibility for HLA-C alleles were independent risk factors for severe acute graft-versus-host disease (GVHD) (HLA-A, P=0.006; HLA-C, P=0.001). Mismatching of HLA-A, but not of HLA-C, alleles was an independent risk factor for death (P<0.001). Matching [corrected] of HLA-C alleles was a significant risk factor for relapse of leukemia (P=0.035). HLA-B disparity was a significant risk factor for both GVHD and death in the univariate analysis, but not in multivariate analysis. Disparities in class II HLA alleles of the DRB1, DQA1, DQB1, DPA1, and DPB1 loci were not identified as significant risk factors for acute GVHD or death in the multivariate analysis. CONCLUSIONS: Genomic typing of class I HLA alleles adds substantially to the success of transplantation of hematopoietic stem cells from unrelated donors, even if the donors are serologically identical to their recipients with respect to HLA-A, B, and DR antigens.",0
1996,9791144,Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects,"BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin. In this study, a specific bradykinin-receptor antagonist, icatibant acetate (HOE 140), was used to determine the contribution of bradykinin to the short-term effects of ACE inhibition on blood pressure and plasma renin activity in both normotensive and hypertensive subjects. METHODS: We compared the hemodynamic, renal, and endocrine effects of captopril alone (25 mg), captopril plus icatibant (100 microg per kilogram of body weight), the angiotensin II subtype 1-receptor antagonist losartan (75 mg), and placebo in 20 subjects with normal blood pressure and 7 subjects with hypertension. The subjects were studied while they were salt depleted (i.e., in balance on a diet in which they were allowed 10 mmol of sodium per day). The drugs were administered on four separate study days in a single-blind, randomized fashion. RESULTS: The coadministration of icatibant significantly attenuated the hypotensive effect of captopril (maximal decrease in mean arterial pressure for all subjects combined, 10.5+/-1.0 mm Hg, as compared with 14.0+/-1.0 mm Hg for captopril alone; P=0.001), in such a way that the decrease in blood pressure after the administration of captopril plus icatibant was similar to that after the administration of losartan (maximal decrease in mean arterial pressure, 11.0+/-1.7 mm Hg). Icatibant did not alter the renal hemodynamic response to captopril, but it significantly altered the change in plasma renin activity in response to ACE inhibition (-0.4+/-0.4 ng of angiotensin I per milliliter per hour, as compared with 2.0+/-0.7 ng per milliliter per hour for captopril alone; P=0.007). The magnitude of these effects was similar in both the normotensive and the hypertensive subjects, as well as in both the black subjects and the white subjects. CONCLUSIONS: These data confirm that bradykinin contributes to the short-term effects of ACE inhibition on blood pressure in normotensive and hypertensive persons and suggest that bradykinin also contributes to the short-term effects of ACE inhibition on the renin-angiotensin system.",0
1997,9794898,Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis,"We describe two patients with liver kidney microsomal antibody type 1 (LKM1)-positive autoimmune hepatitis (AIH) with associated endocrinopathies. The first patient had insulin-dependent diabetes (IDDM), and the second patient had Addison's disease and hypoparathyroidism, and is also positive for islet cell antibodies, without overt diabetes. To account for the existence of multiple endocrinopathy in these patients, we investigated whether there is sequence similarity between the target of LKM1 antibodies, cytochrome P4502D6 (CYP2D6), and other human proteins, and if so, whether this structural similarity produces a detectable cross-reactive immune response. Our database search identified two proteins, carboxypeptidase H, an autoantigen in insulin-dependent diabetes, and 21-hydroxylase, the major autoantigen in Addison's disease, that share sequence similarity to the second major LKM1 epitope on CYP2D6. We tested the reactivity of sera from these patients to the homologous regions of the three autoantigens using an enzyme-linked immunosorbent assay (ELISA). The cut-off for positivity was established by testing sera from 22 healthy children. To determine the significance of reactivity to the peptide homologues of the three autoantigens, we investigated 16 additional patients with LKM1 AIH and 20 children with chronic hepatitis B virus infection as pathological controls. We found that reactivity to the second major epitope of CYP2D6 is significantly associated with reactivity to the homologous regions of carboxypeptidase H (CPH) and 21-hydroxylase (21-OHase) in patients with LKM1 AIH, and that this simultaneous recognition is cross-reactive. We suggest that a cross-reactive immune response between homologous autoantigens may contribute to the development of multiple endocrinopathies in LKM1 AIH.",0
1998,9794919,"Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B","The polarized rat hepatoma/human fibroblast hybrid cell line, WIF-B, forms apical vacuoles into which cholephilic substances are secreted. We studied expression, localization, and function of the apical conjugate export pump, Mrp2, in WIF-B cells. Mrp2, the apical isoform of the multidrug resistance protein, alternatively termed canalicular Mrp (cMrp) or canalicular multispecific organic anion transporter (cMoat), is a 190-kd membrane glycoprotein mediating adenosine triphosphate (ATP)-dependent transport of glucuronides, glutathione S-conjugates, and other amphiphilic anions across the hepatocyte canalicular membrane into bile. Expression of the rat mrp2 gene in WIF-B cells was shown by reverse-transcription polymerase chain reaction (PCR), followed by sequencing of the amplified 789-bp fragment. Immunoblotting, using antibodies reacting with the amino-terminal or with the carboxyl-terminal sequence of rat Mrp2, detected the 190-kd glycoprotein in WIF-B cell homogenates. Immunofluorescence microscopy localized Mrp2 to the apical membrane domain. Preloading of WIF-B cells with a membrane-permeable ester of the calcium-dependent fluorescent indicator, Fluo-3, was followed by Mrp2-mediated secretion of the amphiphilic anion, Fluo-3, into the apical vacuoles. This transport was potently inhibited by cyclosporin A added to the culture medium. Direct measurements of ATP-dependent transport into Mrp2-containing plasma membrane vesicles in comparison with Mrp2-deficient vesicles established that Fluo-3 is transported by Mrp2 with a Km value of 3.7 micromol/L. Our results indicate that the polarized WIF-B cells express the rat ortholog of the apical conjugate-transporting ATPase, Mrp2. The function of Mrp2 as well as the action of inhibitors can thus be analyzed by use of the fluorescent amphiphilic anion, Fluo-3.",0
1999,9794921,Copper resistant human hepatoblastoma mutant cell lines without metallothionein induction overexpress ATP7B,"Mutant human hepatoblastoma cell lines resistant to copper toxicity were isolated from mutagenized HuH7. Two copper resistant cell lines (CuR), CuR 23 and CuR 27, had reduced basal expression of metallothionein (MT) messenger RNA (mRNA) and exhibited minimal or no increase in resistance to cadmium or zinc toxicity. Copper uptake, efflux of newly transported copper, glutathione content, and efflux rate were comparable with HuH7, whereas holoceruloplasmin synthesis and secretion were slightly decreased. Subcellular distribution of copper at steady-state showed an increase in organelle and membrane fractions with a reduction in cytosol. Expression of ATP7B mRNA was fivefold increased, and ATP7B protein approximately threefold increased in both CuR 23 and 27. Another cell line, CuR 41, showed increased basal expression of MT and ATP7B mRNA but not ATP7B protein, and resistance to cadmium and zinc toxicity. Copper uptake in CuR 41 was comparable with HuH7, but initial rates of efflux of copper and glutathione were reduced. The synthesis of holoceruloplasmin but not ceruloplasmin peptide was markedly diminished in CuR 41. Subcellular distribution of copper showed an increase in cytosolic and decreased organelle and membrane-associated copper. These data suggest that cellular resistance to copper toxicity was achieved in two independent cell lines without MT induction and that the induction of ATP7B may lead to the enhanced intracellular sequestration of copper by organelles.",0
2000,9794922,Defective nonoxidative leucine degradation and endogenous leucine flux in cirrhosis during an amino acid infusion,"The metabolic fate of leucine's first and second carbon may be different depending on the tissue in which leucine is metabolized, as well as the prevailing hormonal milieu of that tissue. However, previous studies of leucine kinetics in humans have used only leucine labeled (as tracer) at the first carbon position. Because cirrhosis is associated with factors (such as insulin resistance and altered fuel substrate utilization) that may influence how leucine is degraded, the kinetics of leucine's first and second carbon using a simultaneous infusion of [1-14C] leucine and [2-13C] leucine were studied in the postabsorptive state and during an amino acid infusion in 6 stable cirrhotic patients and 6 matched controls. The data were normalized for different body compartments that were quantified from the dilution of H2 [180] and bromide. The body cell mass, but not body weight or fat-free body mass, was decreased in cirrhosis (P < .001). In response to the amino acid infusion, total leucine appearance from proteolysis and leucine's incorporation into protein increased significantly in both groups, but were higher in cirrhotic patients. Endogenous protein breakdown decreased in normals but remained unchanged in cirrhosis. These alterations in leucine metabolism became more prominent when data were expressed based on the body cell mass rather than on body weight. The oxidation of leucine's first carbon (C1) was decreased in cirrhosis, but the oxidation of leucine's second carbon (C2) did not differ between groups during both the postabsorptive period and the amino acid infusion, while nonoxidative leucine degradation [the difference between the oxidation of leucine's (C1) and (C2)] was also decreased in cirrhosis. In addition, there was a positive correlation between nonoxidative leucine degradation (which represents leucine incorporation into fat), and the respiratory quotient obtained from indirect calorimetry (r = .87; P < .001). These data suggest that the extent of leucine carbon oxidation is dependent on whether fat or carbohydrate is the prevailing fuel substrate. In addition, cirrhotic patients have decreased nonoxidative leucine degradation and are unable to suppress endogenous protein breakdown normally in response to amino acid administration. These abnormalities may contribute to the diminished fat stores and body cell mass commonly observed in cirrhosis.",0
2001,9819448,Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness,"BACKGROUND: Mutations in the GJB2 gene cause one form of nonsyndromic recessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance of the 30delG mutant allele of GJB2. We assessed the contribution of mutations in GJB2 to the prevalence of the condition among Ashkenazi Jews. METHODS: We tested for mutations in GJB2 in DNA samples from three Ashkenazi Jewish families with nonsyndromic recessive deafness, from Ashkenazi Jewish persons seeking carrier testing for other conditions, and from members of other ethnic groups. The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions. RESULTS: Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence interval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservation of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. CONCLUSIONS: The high frequency of carriers of mutations in GJB2 (4.76 percent) predicts a prevalence of 1 deaf person among 1765 people, which may account for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggest that this site is a hot spot for recurrent mutations.",0
2002,9819451,Primary care physicians' experience of financial incentives in managed-care systems,"BACKGROUND: Managed-care organizations' use of financial incentives to influence the practice of primary care physicians is controversial. We studied the prevalence and effects of these incentives. METHODS: We surveyed a probability sample of primary care physicians practicing in the largest urban counties in California in 1996. The physicians were asked about the types of incentives they encountered, the amount of income that was keyed to incentives, their experience of pressure in their practices, and the ways in which such pressure affected patient care. RESULTS: Data were analyzed for 766 physicians involved in managed-care systems. Thirty-eight percent of these physicians reported that their arrangements with the managed-care system included some type of incentive in the form of a bonus. Fifty-seven percent of the physicians reported that they felt pressure from the managed-care organization to limit referrals (17 percent said they believed such pressure compromised patient care), and 75 percent felt pressure to see more patients per day (24 percent believed such pressure compromised patient care). The physicians who reported that their financial arrangements included an incentive based on referrals were more likely than others to have felt pressured to limit referrals in a manner that compromised care (adjusted odds ratio 2.5; 95 percent confidence interval, 1.2 to 5.0), and physicians with an incentive based on productivity were more likely to have felt pressure to see more patients that they believed compromised care (adjusted odds ratio, 2.1; 95 percent confidence interval, 1.2 to 3.8). The physicians whose health care systems used incentives keyed to productivity were less likely than others to be very satisfied with their practices (adjusted odds ratio, 0.4; 95 percent confidence interval, 0.2 to 0.6), whereas those whose systems included incentives related to the quality of care or patients' satisfaction were more likely to be very satisfied (adjusted odds ratio, 1.8; 95 percent confidence interval, 1.1 to 3.0). CONCLUSIONS: Many managed-care organizations include financial incentives for primary care physicians that are indexed to various measures of performance. Incentives that depend on limiting referrals or on greater productivity apply selective pressure to physicians in ways that are believed to compromise care. Incentives that depend on the quality of care and patients' satisfaction are associated with greater job satisfaction among physicians.",0
2003,9828212,Growth-related expression of the ectonucleotide pyrophosphatase PC-1 in rat liver,"Plasma cell differentiation antigen-1 (PC-1) is a 5'-ectonucleotide pyrophosphatase that has been implicated in various processes including insulin- and nucleotide-mediated signaling and cell growth. We show here that the expression of both PC-1 mRNA and protein in rat liver and in hepatoma cells is strictly growth-related. Thus, the level of PC-1 in FAO hepatoma cells increased with the cell density. PC-1 was not expressed in the neonatal rat liver, but gradually appeared in the first weeks of age, to reach adult levels around the weaning period. Furthermore, PC-1 protein and mRNA largely disappeared from the liver within 24 hours following a hepatectomy of 70%, but re-appeared in the later phases (3-15 days) of the ensuing regeneration period. An equally rapid loss of PC-1 protein and mRNA could also be provoked in normal livers by the administration of the translational inhibitor, cycloheximide, but the transcriptional inhibitors, actinomycin D and alpha-amanitin, did not show these effects. Nuclear run-on assays revealed that the loss of PC-1 mRNA after hepatectomy or after the administration of cycloheximide was not caused by a decreased transcription of the PC-1 gene, suggesting that the level of PC-1 is controlled by an mRNA-stabilizing protein that is lost after hepatectomy and has a high turnover.",0
2004,9828215,Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation In vitro,"Activation of local tissue macrophages (Kupffer cells) and of quiescent hepatic stellate cells (HSCs) to a myofibroblast phenotype are two key events in liver inflammation and fibrosis. It is known that products of activated macrophages may activate stellate cells. We have hypothesized that the products of activated HSCs may also modulate the activity of Kupffer cells. The cytokine interleukin-10 (IL-10), produced by lymphocytes and macrophages, has profound inhibitory actions on macrophages. Normal rat and mouse HSCs that differentiate in vivo and in vitro to activated myofibroblasts were isolated by enzyme perfusion and density centrifugation with or without centrifugal elutriation, confirmed by vitamin A autofluorescence and positive immunostaining for the myofibroblast markers desmin and smooth muscle actin (SMA). Conditioned media and lysates from these cells were found to down-regulate lipopolysaccharide (LPS)-induced tumor necrosis factor- (TNF-) secretion by the mouse macrophage line RAW 267.4. In highly purified preparations of rat HSCs, messenger RNA (mRNA) for IL-10 was detected by reverse-transcription polymerase chain reaction (RT-PCR), from the time of isolation to up to 120 days of culture on plastic. Long-term cultures of unstimulated mouse HSCs secreted IL-10 protein as detected by immunoblotting and specific enzyme-linked immunosorbent assay (ELISA). IL-10 protein was undetectable by immunohistochemistry in mouse HSCs for the first 3 days in culture. After this, the percentage of IL-10-positive cells increased to 45% at day 7 and 100% by day 14, and expression of IL-10 continued in long-term cultures of up to 120 days. The expression of IL-10 by the stromal cells that govern the fibrotic process in the liver may have important implications for the regulation of inflammation and fibrosis in the liver.",0
2005,9828227,"Nitric oxide and guanosine 3',5'-cyclic monophosphate stimulate bile secretion in isolated rat hepatocyte couplets, but not in isolated bile duct units","Nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cGMP) have recently been shown to stimulate bile acid-independent bile flow in the isolated perfused rat liver (IPRL). However, the cellular origin and mechanisms of this choleresis have not yet been determined. To address these questions, we examined the effects of NO and cGMP on bile secretion in isolated rat hepatocyte couplets (IRHC) and in isolated bile duct units (IBDU), both of which are isolated cell systems in which cell polarity is maintained and secretion can be measured directly. Changes in the area of the canalicular and ductular lumens were determined in IRHC and IBDU, respectively, as indicators of the rate of fluid secretion using video microscopy. In addition, Cl-/HCO3- exchanger activity in IBDU was evaluated by measuring changes in intracellular pH (pHi) after Cl- removal/readmission by microfluorometric methods. In the presence of HCO3-, both the NO donor, S-nitroso-acetyl-penicillamine (SNAP), and the cell-permeant cGMP analogue, dibutyryl cGMP (DBcGMP), stimulated canalicular bile secretion (P <.05), as did the cell-permeant cAMP analogue, dibutyryl cAMP (DBcAMP) (P <.05). Removal of HCO3- from the buffer completely abolished the choleretic effects of DBcGMP, but had no effect on NO-induced choleresis. In contrast, secretion in IBDU was not stimulated following incubations with SNAP or DBcGMP over 30 minutes, whereas DBcAMP and secretin, a cholangiocyte secretagogue and cAMP agonist, both had a marked effect on ductular secretion over this same time interval (P <.05). SNAP also had no effect on Cl-/HCO3- exchanger activity in IBDU, and inhibition of endogenous NO synthesis by NG-monomethyl-L-arginine (L-NMMA) did not alter secretin-induced stimulation of ductular bile secretion and Cl-/HCO3- exchanger activity. In summary, NO and cGMP stimulate bile secretion exclusively at the the level of hepatocytes, whereas cAMP mediates choleresis at both hepatocyte and bile duct levels. These findings may have important implications for the regulation of ductular bile secretion by hormones and neuropeptides, as well as under pathological conditions with increased hepatic NO synthesis.",0
2006,9828228,"Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine monophosphate","Na+/taurocholate (Na+/TC) cotransport in hepatocytes is mediated primarily by Na+/TC cotransporting polypeptide (Ntcp), and cyclic adenosine monophosphate (cAMP) stimulates Na+/TC cotransport by inducing translocation of Ntcp to the plasma membrane. The aim of the present study was to determine if Ntcp is a phosphoprotein and if cAMP alters Ntcp phosphorylation. Freshly prepared hepatocytes from rat livers were incubated with carrier-free 32PO4 for 2 hours, followed by incubation with 10 micromol/L 8-chlorophenylthio adenosin 3':5'-cyclic monophosphate (CPT-cAMP) for 15 minutes. Subcellular fractions isolated from 32P-labeled hepatocytes were subjected to immunoprecipitation using Ntcp antibody, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography to determine if Ntcp is phosphorylated. Ntcp immunoprecipitated from plasma membranes isolated from nonlabeled hepatocytes was subjected to immunoblot analysis using anti-phosphoserine, anti-phosphothreonine, or anti-phosphotyrosine antibody to determine whether Ntcp is a serine, threonine, or tyrosine phosphoprotein. Hepatocytes were loaded with bis-(2-amino-5-methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid (MAPTA), a Ca2+ buffering agent, and the effect of CPT-cAMP on TC uptake, cytosolic [Ca2+], and ntcp phosphorylation and translocation was determined. In addition, the effect of cAMP on protein phosphatases 1 and 2A (PP1/2A) was determined in homogenates and plasma membranes obtained from CPT-cAMP-treated hepatocytes. Phosphorylation study showed that phosphorylated Ntcp is detectable in plasma membranes, and cAMP treatment resulted in dephosphorylation of Ntcp. Immunoblot analysis with phosphoamino antibodies revealed that Ntcp is a serine/threonine, and not a tyrosine, phosphoprotein, and cAMP inhibited both serine and threonine phosphorylation. In MAPTA-loaded hepatocytes, CPT-cAMP failed to stimulate TC uptake, failed to increase cytosolic [Ca2+], and failed to induce translocation and dephosphorylation of Ntcp. cAMP did not alter the activity of PP1/2A in either homogenates or in plasma membranes. Taken together, these results suggest that Ntcp is a serine/threonine phosphoprotein and is dephosphorylated by cAMP treatment. Activation of PP1/2A is not involved in cAMP-mediated dephosphorylation of Ntcp. Both translocation and dephosphorylation of Ntcp may be involved in the regulation of hepatic Na+/TC cotransport.",0
2007,9828233,Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro,"To determine whether adefovir is active against lamivudine-resistant hepatitis B virus (HBV), the inhibition constants of adefovir diphosphate and lamivudine triphosphate for wild-type and mutant human HBV DNA polymerases, which contain amino acid substitutions associated with lamivudine resistance, were compared. Recombinant wild-type and mutant human HBV DNA polymerases were expressed and substantially purified using a baculovirus expression system and immunoaffinity chromatography. HBV DNA polymerase mutants M552I, M552V, and L528M/M552V showed resistance to lamivudine triphosphate with inhibition constants (Ki) increased by 8.0-fold, 19.6-fold, and 25.2-fold compared with that of wild-type HBV DNA polymerase. However, these mutants remained sensitive to adefovir diphosphate with the inhibition constants increasing by 1.3-fold and 2.2-fold or decreasing by 0.79-fold. The L528M single mutation, identified in patients with increasing HBV DNA levels during therapy with famciclovir, also remained sensitive to adefovir diphosphate with the inhibition constant increased by only 2.3-fold.",0
2008,9854115,Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy,"BACKGROUND: Highly active antiretroviral therapy can effectively decrease the levels of human immunodeficiency virus type 1 (HIV-1) virions in peripheral plasma and seminal fluid of infected men. Whether the genital tract of HIV-1-infected men who are receiving highly active antiretroviral therapy and who have no detectable virus in the peripheral plasma harbors replication-competent virus is not known. METHODS: We collected peripheral-blood and semen samples from seven men with HIV-1 infections who were receiving highly active antiretroviral therapy and who had no detectable viral RNA (fewer than 50 copies per milliliter) in plasma and analyzed the samples for cell-associated proviral DNA using a quantitative polymerase-chain-reaction assay. Replication-competent viruses were evaluated by cell-coculture assays. Proviral DNA and replication-competent virus obtained from peripheral-blood and seminal cells were also analyzed by sequencing relevant viral genes. RESULTS: Despite the long-term suppression of HIV-1 RNA in the plasma of the seven men, proviral DNA was detected in seminal cells in four. Replication-competent viruses were recovered from peripheral-blood cells in three men and from the seminal cells in two of these three men. The viruses recovered from the seminal cells had no genotypic mutations suggestive of resistance to antiretroviral drugs and were macrophage-tropic, a feature that is characteristic of HIV-1 strains that are capable of being sexually transmitted. CONCLUSIONS: In HIV-1-infected men who are receiving highly active antiretroviral therapy and who have no detectable levels of viral RNA in plasma the virus may be present in seminal cells and therefore may be capable of being transmitted sexually.",0
2009,9862843,Effects of chronic ethanol administration on rat liver proteasome activities: relationship with oxidative stress,"We previously reported that ethanol elicits an increased protein oxidation in the liver of rats receiving chronic ethanol by continuous intragastric infusion (Tsukamoto-French method). This accumulation of oxidized proteins could result from a decrease in the cytosolic proteolysis, related specifically to alkaline protease and its major components, the proteasomes. Because several studies suggest that intracellular proteolysis depends on the severity of oxidative stress, we investigated the cytosolic proteolytic activity under two chronic ethanol treatment paradigms associated with varying degrees of oxidative stress. For 4 weeks, male rats received chronic ethanol by continuous intragastric infusion or by oral administration (10% ethanol ad libitum as sole drinking fluid). A significant decrease was evident for alkaline protease activity as well as for sodium dodecyl sulfate (SDS)-activated latent 20S proteasome (chymotrypsine-like [ChT-L] and peptidylglutamyl peptide hydrolase [PGPH] activities) in the liver of rats receiving ethanol by continuous intragastric infusion. Free radical production and related processes appeared to be contributing events in proteolysis inhibition, because phenethyl isothiocyanate (PIC), an inhibitor of cytochrome P4502E1 (CYP2E1), reduced the inhibition of the ethanol-related ChT-L activity. Moreover, the lipid peroxidation level was inversely correlated with ChT-L activity. In contrast, no such changes were observed in ChT-L and PGPH activities or in cellular free radical targets following the oral ad libitum consumption of 10% ethanol. It appears, thus, that only the alcohol treatment paradigm associated with an overt oxidative stress produced a significant inhibition of the proteasome activity. The mechanisms of proteasome inhibition could involve the formation of an endogenous inhibitor such as protein aggregates or aldehyde-derivative peptides. Whatever the mechanism, the inhibition of cytosolic proteolysis and the subsequent accumulation of damaged proteins may be involved in the oxidatively challenged alcoholic livers and play a pathogenic role in experimental alcoholic liver disease.",0
2010,9862858,The protective role of adenosine in inducing nitric oxide synthesis in rat liver ischemia preconditioning is mediated by activation of adenosine A2 receptors,"This study aims to determine if the protective role of adenosine in liver ischemic preconditioning is mediated by the activation of adenosine receptors and to ascertain which of these receptors is implicated in the process. Administration of adenosine A1 and A2 receptor antagonists to preconditioned animals indicates that hepatic preconditioning is mediated by the activation of adenosine A2 receptors. Propentofylline (an inhibitor of adenosine transport into cells) in the preconditioned group, subjected to previous administration of an adenosine A2 receptor antagonist, prevented the negative effect of the latter on the protection offered by preconditioning. An increase of NO production was detected just immediately after hepatic preconditioning, and the administration of an adenosine A2 receptor antagonist to the preconditioning group prevented this increase, thus abolishing the protective effect of preconditioning. However, the administration of a NO donor to the preconditioned group subjected to previous administration of the adenosine A2 receptor antagonist was able to maintain the preconditioning effects. In conclusion, these results indicate that, in preconditioning, the protective effect of adenosine could be a result of an increase in extracellular adenosine. This in turn would induce the activation of adenosine A2 receptors, which, by eliciting an increase in NO generation, would protect against the injury associated with hepatic ischemia-reperfusion.",0
2011,9862866,Growth hormone inhibits rat liver alpha-1-acid glycoprotein gene expression in vivo and in vitro,"The gene encoding alpha-1-acid glycoprotein (AGP), one of the major acute-phase proteins, is positively controlled at the transcriptional level by cytokines (interleukin-1 [IL-1], IL-6, and tumor necrosis factor alpha) and glucocorticoids. Here, we show that growth hormone (GH) treatment of isolated rat hepatocytes in vitro reduces AGP messenger RNA (mRNA) expression. AGP gene expression remained inducible by IL-1, IL-6, and phenobarbital (PB) in GH-treated hepatocytes. Interestingly, the repressive effect of GH on AGP gene expression was also observed in vivo: liver AGP mRNA content was strongly increased in hypophysectomized rats, and GH treatment of these animals led to a decrease in mRNA to levels lower than those in untreated control animals. Moreover, the inhibitory effect of GH mainly occurs at the transcriptional level and can be observed as little as 0.5 hours after GH adding in vitro to isolated hepatocytes. These results show negative regulation of AGP gene expression and strongly suggest that GH is a major endogenous regulator of constitutive AGP gene expression. Moreover, transfection assays showed that the region of the AGP promoter located at position -147 to -123 is involved in AGP gene regulation by GH. Furthermore, GH deeply modifies the pattern of nuclear protein binding to this region. GH treatment of hypophysectomized rats led to the release of proteins of 42 to 45 and 80 kd and to the binding of proteins of 48 to 50 and 90 kd.",0
2012,9869669,Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer,"BACKGROUND: We performed a multi-institutional randomized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer. METHODS: Preoperative chemotherapy for patients randomly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil. Surgery was performed two to four weeks after the completion of the third cycle; patients also received two additional cycles of chemotherapy after the operation. Patients randomly assigned to the immediate-surgery group underwent the same surgical procedure. The main end point was overall survival. RESULTS: Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery. After a median possible study time of 55.4 months, there were no significant differences between the two groups in median survival: 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery (P=0.53). At one year, the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone; at two years, survival was 35 percent and 37 percent, respectively. The toxic effects of chemotherapy were tolerable, and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery. There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma. Weight loss was a significant predictor of poor outcome (P=0.03). With the addition of chemotherapy, there was no change in the rate of recurrence at locoregional or distant sites. CONCLUSIONS: Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus.",0
2013,9869676,Self-referral of patients for electron-beam computed tomography to screen for coronary artery disease,"As the availability of electron-beam CT increases, it is appropriate to question the balance among medical science, patient care, and profits. Broadening patients' sense of empowerment and promoting their autonomy are worthy goals within medicine. Breast-cancer screening with mammography is an example of a radiographic test used successfully in a diagnostic program based on self-referral. But the lessons of such a program, in which the distinction between the disease and the disease-free state is more easily recognized than is the case for age-dependent calcific arterial changes, are not easily extrapolated to screening for coronary disease. Currently, we are facing the possibility that market forces may increase interest in electron-beam CT beyond what is justified by its potential medical benefit. Well-designed clinical trials are required to define fully the appropriate indications for and limitations of electron-beam CT. Such trials will eventually clarify the medical applications of the technique and determine its suitability as a screening procedure for cardiovascular disease. Until then, the use of electron-beam CT, like that of all tests in medicine, should be based on a clearly defined rationale and should be coupled with a medical evaluation by a physician.",0
2014,9878014,The Ariel Project: A prospective cohort study of maternal-child transmission of human immunodeficiency virus type 1 in the era of maternal antiretroviral therapy,"In a prospective cohort study, clinical and biologic factors that contribute to maternal-child transmission of human immunodeficiency virus type 1 (HIV-1) were studied. HIV-infected pregnant women and their infants were evaluated prospectively according to a standardized protocol. Of 204 evaluable women, 81% received zidovudine during their pregnancy. The infection rate among the 209 evaluable infants was 9.1%. By univariate analysis, histologic chorioamnionitis, prolonged rupture of membranes, and a history of genital warts were significantly associated with transmission. Additional factors associated with transmission that approached significance included a higher maternal virus load at delivery and the presence of cocaine in the urine. In a logistic regression model, histologic chorioamnionitis was the only independent predictor of transmission. Despite a significantly higher transmission rate at one site, no unique viral genotype was found at any site. Thus, chorioamnionitis was found to be the major risk factor for transmission among women receiving zidovudine. ",0
2015,9878638,A comparison of two antimicrobial-impregnated central venous catheters. Catheter Study Group,"BACKGROUND: The use of central venous catheters impregnated with either minocycline and rifampin or chlorhexidine and silver sulfadiazine reduces the rates of catheter colonization and catheter-related bloodstream infection as compared with the use of unimpregnated catheters. We compared the rates of catheter colonization and catheter-related bloodstream infection associated with these two kinds of antiinfective catheters. METHODS: We conducted a prospective, randomized clinical trial in 12 university-affiliated hospitals. High-risk adult patients in whom central venous catheters were expected to remain in place for three or more days were randomly assigned to undergo insertion of polyurethane, triple-lumen catheters impregnated with either minocycline and rifampin (on both the luminal and external surfaces) or chlorhexidine and silver sulfadiazine (on only the external surface). After their removal, the tips and subcutaneous segments of the catheters were cultured by both the roll-plate and the sonication methods. Peripheral-blood cultures were obtained if clinically indicated. RESULTS: Of 865 catheters inserted, 738 (85 percent) produced culture results that could be evaluated. The clinical characteristics of the patients and the risk factors for infection were similar in the two groups. Catheters impregnated with minocycline and rifampin were 1/3 as likely to be colonized as catheters impregnated with chlorhexidine and silver sulfadiazine (28 of 356 catheters [7.9 percent] vs. 87 of 382 [22.8 percent], P<0.001), and catheter-related bloodstream infection was 1/12 as likely in catheters impregnated with minocycline and rifampin (1 of 356 [0.3 percent], vs. 13 of 382 [3.4 percent] for those impregnated with chlorhexidine and silver sulfadiazine; P<0.002). CONCLUSIONS: The use of central venous catheters impregnated with minocycline and rifampin is associated with a lower rate of infection than the use of catheters impregnated with chlorhexidine and silver sulfadiazine.",0
2016,9878643,Geographic variations in utilization rates in Veterans Affairs hospitals and clinics,"BACKGROUND: In the United States, geographic variation in hospital use is common. It is uncertain whether there are similar geographic variations in the health care system of the Department of Veterans Affairs (VA), which differs from the private sector because it predominantly serves men with annual incomes below $20,000, has a central system of administration, and uses salaried physicians. Thus, it might be less likely to have geographic variations. METHODS: We used VA data bases to obtain information on patients treated for eight diseases (chronic obstructive pulmonary disease, pneumonia, congestive heart failure, angina, diabetes, chronic renal failure, bipolar disorder, and major depression). We analyzed their use of hospital and outpatient services by assessing the risk-adjusted numbers of hospital days (the average number of days a patient spent in the hospital per 12 months of follow-up, regardless of the number of hospital stays), hospital-discharge rates, and clinic-visit rates from 1991 through 1995 for the entire system and within the 22 geographically based health care networks. RESULTS: We found substantial geographic variation in hospital use for all eight cohorts of patients and all the years studied. Variations in the numbers of hospital days per person-year among the networks were greatest among patients with chronic obstructive pulmonary disease (ranging from a factor of 2.7 to a factor of 3.1) during a given year and smallest among patients with angina (ranging from a factor of 1.5 to a factor of 2.1). Levels of hospital use were highest in the Northeast and lowest in the West. The variation in the rates of clinic visits for principal medical care among the networks ranged from a factor of approximately 1.6 to a factor of 4.0; variations in the rates were greatest among patients with chronic renal failure and smallest among patients with chronic obstructive pulmonary disease. There was no clear geographic pattern in the rates of outpatient-clinic use. CONCLUSIONS: There are significant geographic variations in the use of hospital and outpatient services in the VA health care system. Because VA physicians are unable to increase their income by changing their patterns of practice, our findings suggest that their practice styles are similar to those of other physicians in their geographic regions.",0
2017,9878845,"The Gas1 glycoprotein, a putative wall polymer cross-linker","The yeast cell wall, which for years has been regarded as a static cellular component, has been revealed to be dynamic in its structure and composition and complex in its enzymatic activity. The S. cerevisiae cell wall is composed of beta-1,3/beta-1,6-glucans, mannoproteins, and chitin, which are assembled into an extracellular matrix essential for maintenance of cell integrity. Gas1p, a glycoprotein anchored to the outer leaflet of the plasma membrane through a glycosylphosphatidylinositol, plays a key role in cell wall assembly. Loss of Gas1p leads to several morphogenetic defects and to a decrease in the amount of cross-links between the cell wall glucans. These defects in turn trigger a compensatory response that guarantees cell viability. Several Gas1p homologs have been isolated from Candida species and S. pombe. The Gas1p family also includes two plant proteins with endo-beta-1,3-glucanase activity. Sequence comparisons reveal that Gas1p family proteins have a modular organization of domains. The genetic and molecular analyses reviewed here suggest that Gas1p could play a role as a polymer cross-linker, presumably by catalyzing a transglycosylation reaction. ",0
2018,9879059,Mutagenesis of the human 5-HT1B receptor: differences from the closely related 5-HT1A receptor and the role of residue F331 in signal transduction,"We have used a combination of sequence comparisons, computer-based modeling and site-directed mutagenesis to investigate the molecular interactions involved in ligand binding and signal transduction of the human 5-HT1B receptor. Two amino acid residues, S212 in transmembrane region (TM) V and F331 in TM VI, were replaced by alanines. These amino acids are conserved in many G protein-coupled receptors and therefore likely to be important for receptor function. The mutant receptors were expressed in Chinese hamster ovary cells. The 5-HT-like agonist 5-carboxamido-tryptamine (5-CT) bound with 15-fold lower affinity to the S212A mutant as compared to wild-type receptor and the antagonist methiothepin bound with 17-fold lower affinity to the F331A mutant. No reduction in the affinity of 5-HT was seen for the S212A mutant, although an equivalent mutation in the 5-HT1A receptor resulted in a 100-fold reduction of 5-HT binding. The inhibition of forskolin-stimulated cyclic AMP production by 5-HT was significantly reduced in cells expressing the F331A mutant, even though the endogenous ligand 5-HT bound with somewhat increased affinity. Methiothepin acted as an inverse agonist and increased the forskolin-stimulated cyclic AMP production at both the wild-type receptor and the mutants, and the effect was stronger on the F331A mutant. These results suggest that F331 is involved in the conformational changes necessary for signal transduction. ",0
2019,9879522,"Normalization of periodontal tissues in osteopetrotic mib mutant rats, treated with CSF-1","The osteopetrotic mib mutation in rats causes defects in the skeletal bone tissue in young animals. These defects, i.e. slow bone remodelling, changes in both crystallinity and mineral content, are transient and undergo normalization, even without any treatment in 6-wk-old animals. Treatment with CSF-1 (colony stimulating factor-1) accelerates the normalization process in skeletal bones. The periodontal tissues around the apices of incisors show abnormalities caused by the slow remodelling process of the mandible bone tissue, the deficiency of osteoclasts and their abnormal morphology, as well as the disorganization of periodontal ligament fibres. In contrast to the skeletal tissues, these abnormalities would not undergo spontaneous normalization. Under treatment with colony stimulating factor 1 (CSF-1), the primitive bone trabeculae of mandible are resorbed and the normalization of the number of osteoclasts and their cytology occurs. The organization of the periodontal ligament fibres is partially restored, resembling the histological structure of the normal one. ",0
2020,9879555,Canine leishmaniasis due to Leishmania infantum MON-1 in northern Morocco,"A seroprevalence study of canine leishmaniasis was carried out in five provinces in northern Morocco: Taounate, Al Hoceima, Zouagha Moulay Yacoub, Chefchaouen and Ouezzane. 55 localities have been concerned and a total of 1,013 dogs were screened, which represents almost 100% of the canine census. Of the screened dogs: 87 showed antibody titer > or = 100 when tested by IFAT (seroprevalence of 8.6%) and were distributed in 83 asymptomatics (without clinical symptoms) and four symptomatics (with one or several symptoms of leishmaniasis) with important variations according to the locality. Relative frequency of asymptomatic dogs was observed (8.2%), and the seroprevalence increased in middle altitude (500 m < altitude < 1,000 m) and high altitude (> or = 1,000 m). Parasites isolated from dogs were identified as L. infantum MON-1 by isoenzyme profile and Rsal digestion. ",0
2021,9879623,Survey of 50 years of veterinary remedy provision in the Netherlands],"This article gives an overview of a half century of veterinary product provision in the Netherlands, and describes the availability of veterinary products from 1945 and onwards. The development of antibiotics, sulfonamides, anthelmintics, endocrine products, vaccines, and other product groups is discussed briefly. The importance of the research carried out by leading pharmaceutical companies in collaboration with the Faculty of Veterinary Medicine Utrecht and other governmental research institutes is stressed. This article also emphasizes the importance of good and responsible product information for veterinarians. The introduction of the veterinary drug law in 1986 has had great consequences for the industry, distributors, and wholesalers as well as for practising veterinarians. ",0
2022,9879796,Treatment of major depression associated with smoking cessation,"A number of clinicians have reported cases of major depression associated with smoking cessation. We report here a case of major depression in a 27-year-old woman who abruptly reduced cigarette consumption from 35 to 8 cigarettes per day during the baseline period. A multi-component behavioural programme was applied to stop smoking, together with pharmacotherapy and Beck's cognitive therapy for depression. Twelve months after ending treatment, the patient was still abstaining from smoking, and she showed no signs of depressive symptomatology. ",0
2023,9880357,Myo-inositol-dependent sodium uptake in ice plant ,"In salt-stressed ice plants (Mesembryanthemum crystallinum), sodium accumulates to high concentrations in vacuoles, and polyols (myo-inositol, D-ononitol, and D-pinitol) accumulate in the cytosol. Polyol synthesis is regulated by NaCl and involves induction and repression of gene expression (D.E. Nelson, B. Shen, and H.J. Bohnert [1998] Plant Cell 10: 753-764). In the study reported here we found increased phloem transport of myo-inositol and reciprocal increased transport of sodium and inositol to leaves under stress. To determine the relationship between increased translocation and sodium uptake, we analyzed the effects of exogenous application of myo-inositol: The NaCl-inducible ice plant myo-inositol 1-phosphate synthase is repressed in roots, and sodium uptake from root to shoot increases without stimulating growth. Sodium uptake and transport through the xylem was coupled to a 10-fold increase of myo-inositol and ononitol in the xylem. Seedlings of the ice plant are not salt-tolerant, and yet the addition of exogenous myo-inositol conferred upon them patterns of gene expression and polyol accumulation observed in mature, salt-tolerant plants. Sodium uptake and transport through the xylem was enhanced in the presence of myo-inositol. The results indicate an interdependence of sodium uptake and alterations in the distribution of myo-inositol. We hypothesize that myo-inositol could serve not only as a substrate for the production of compatible solutes but also as a leaf-to-root signal that promotes sodium uptake. ",0
2024,9880423,New look at epiphrenic diverticula,"Twenty-five patients with epiphrenica diverticula were studied to clarify the mechanism for esophageal regurgitation and to evaluate methods of treatment. Esophagogastroduodenoscopy, esophageal motility, and cineradiographic studies were performed. With probes in the tubular esophagus and diverticula of two patients, motility and cineradiographic studies were performed simultaneously to correlate symptoms and pressure changes with movement of diverticular and esophageal contents. Nineteen patients were operated, and six relatively asymptomatic patients were not. There was no operative mortality, and the one esophageal fistula that occurred healed spontaneously. Results were excellent or good in 10 operated patients followed long term after resection or imbrication of the diverticula. Eight patients did not undergo myotomy. Results in four of these patients followed long term were excellent. Retrograde movement of diverticular contents into the esophagus depends on pouch volume and a pressure gradient between the pouch and the tubular esophagus after an esophageal contraction wave in the tubular esophagus has dissipated. The height of esophageal reflux and resulting symptoms depend on these factors and the lower esophageal sphincter pressure (LESP). Asymptomatic patients with an epiphrenic diverticulum do not require operation. Resection or imbrication of a diverticulum are the operative methods of treatment. We prefer the abdominal approach when this is possible. Myotomy in contraindicated when gastroesophageal reflux exists or the LESP is below normal. ",0
2025,9880604,A pair of reciprocally inhibitory histaminergic sensory neurons are activated within the same phase of ingestive motor programs in Aplysia,"Previous studies have shown that each buccal ganglion in Aplysia contains two B52 neurons, one in each hemiganglion. We now show that there are two B52 neurons in a single buccal hemiganglion and four cells in an animal. We also show that the B52 neurons are histamine-immunoreactive and use reverse phase HPLC to show that the histamine-immunoreactive substance is authentic histamine. Previous studies have shown that the B52 neurons make numerous inhibitory synaptic connections with neurons active during the radula closing/retraction phase of ingestive motor programs. A computational model of the Aplysia feeding central pattern generator has, therefore, suggested that the B52 neurons play a role in terminating closing/retraction. Consistent with this idea we show that both B52 neurons fire at the beginning of radula opening/protraction. We also show that both B52 neurons are sensory neurons. They are depolarized when a flap of connective tissue adjacent to the buccal commissural arch is stretched. During ingestive feeding this is likely to occur at the peak of closing/retraction as opening/protraction begins. In the course of this study we compare the two ipsilateral B52 neurons and show that these cells are virtually indistinguishable; e.g., they use a common neurotransmitter, make the same synaptic connections, and are both sensory as well as premotor neurons. Nevertheless we show that the B52 neurons are reciprocally inhibitory. Our results, therefore, strikingly confirm theoretical predictions made by others that neurons that inhibit each other will not necessarily participate in antagonistic phases of behavior. ",0
2026,9880660,Towards the cloning of genes underlying murine QTLs,"""Many quantitative trait loci (QTLs), including those for ethanol-related traits, have been mapped in the mouse. In light of rapidly developing tools and resources, we briefly review the strategy for identifying the genes underlying these QTLs. We note that positional cloning will soon be a matter of testing candidate genes rather than discovering genes; therefore, we describe a """"congenic test"""" to support that a candidate gene is indeed a QTL. Considering the rapid development of congenics and mutants, we also identify four areas of investigation-phenotypes, ethanol specificity, environment, and gene interactions-that might be exploited during the course of positional cloning to gain insights into QTL pathways. In particular, we note that multiple mutants of nearly every major neurotransmitter pathway have now been made. These mutants are not only useful for phenotypic tests, but also could be used to conduct """"gene dependence"""" tests of QTLs. We also consider potential applications for the very recently developed ability to clone mice. """,0
2027,9880775,Artificial liver: review and Cedars-Sinai experience,"During the past decade, whole organ transplantation has become the only clinically effective method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is restricted by shortage of organ donors, high cost, relatively high morbidity, and need for life-long immunosuppression. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to utilization of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Recently, advances in hepatocyte isolation and culture techniques, improved understanding of hepatocyte-matrix interactions, availability of new biomaterials, improved hollow-fiber technology, and better understanding of flow and mass transport across semipermeable membranes have resulted in the development of a new generation of liver assist devices. Some of these devices, including the one developed by the authors, are currently being tested in the clinical setting. In this paper, the past experience with liver support systems is reviewed, the present status of the field is critically examined, and the results of a phase I clinical trial with the bioartificial liver, utilizing primary porcine hepatocytes, are summarized. ",0
2028,9880937,Resistance of bovine and porcine Pasteurella to florfenicol and other antibiotics],"The resistance pattern of 221 (89 bovine, 132 porcine) pasteurella strains isolated in 1996 against 16 antibiotics or chemotherapeutics was determined by agar diffusion. Pasteurella haemolytica showed a higher level of resistance compared to Pasteurella multocida; porcine strains were more resistant than bovine strains. Over 90% of porcine Pasteurella multocida were sensible to penicillin G, ampicillin, cephalothin, polymyxin B, enrofloxacin, chloramphenicol and florfenicol. In addition, bovine strains were at least 90% sensible to oxacillin, erythromycin, gentamycin and sulfmethoxazole-trimethoprim. More than 90% of porcine Pasteurella haemolytica were classified as sensible to polymyxin B, enrofloxacin und florfenicol; bovine strains to cephalothin, neomycin und chloramphenicol as well. In 1996, 2 years after the chloramphenicol ban for food rendering animals, only 6.3% of bovine pasteurella strains proved to be resistant against chloramphenicol compared to a 16.27% fraction in 1994. The mean MIC-values of florfenicol against pasteurella spp. were nearly the same in bovine and porcine isolates with 0.53 microgram/ml and 0.52 microgram/ml respectively. Pasteurella haemolytica, however, showed higher MIC-values (0.68 microgram/ml in bovine, 0.70 microgram/ml in porcine isolates) than Pasteurella multocida with 0.47 microgram/ml in bovine and 0.51 microgram/ml in porcine strains. No isolate had a MIC of florfenicol greater than 1.0 microgram/ml, all pasteurella strains were classified sensible to florfenicol. ",0
2029,9881087,A case of untreatable progressive bladder carcinoma effectively treated by single administration of tegafur and uracil],"Bloody urine was grossly observed and multinodular shadow confirmed in both lungs of an 81-year-old male, who had been referred to our department. The diagnosis was bladder cancer (TCC, G3, T4N3M1) from detailed examination. With his advanced age and lowered ADL, the family did not wish for aggressive treatment, so no combination multidrug chemotherapy was attempted. Instead he was given 300 mg/day UFT per os. After 4 weeks administration, the metastatic focus decreased and tended to contract; at the same time gross observation revealed no more bloody urine. Moreover, following 7 weeks of administration, the bladder tumor disappeared, the lung metastatic focus showed overall shrinkage of over 50%, the lymph node metastasis also was more than 50% less, and the case was considered to be PR. The literature reveals UFT was efficacious in only 2 other cases of progressive bladder carcinoma. Since UFT has fewer complications, such as myelosuppression, among antitumor agent, it is considered worth trying in cases where intensive treatment is not feasible. ",0
2030,9881118,Effects of couples' characteristics on contraceptive use in sub-Saharan Africa: the Ghanaian example,"Using data from the 1988 Ghana Demographic and Health Survey, this study examines couples' demographic and socioeconomic characteristics in the context of their attitudes towards family planning, and the impact of these factors on the use of contraceptives. The characteristics of the husbands and their influence on wives' behaviour illustrate the role of intra-household relations between men and women and their effect on fertility-related behaviour in patriarchal African societies. Compared to elsewhere in the Third World, Africa has one of the lowest contraceptive use rates.  Recent studies suggest that gender relations in many parts of the continent may be responsible for such low use of modern contraception.  The 1988 Ghana Demographic and Health Survey collected data on background characteristics, contraceptive knowledge and use, attitudes toward family planning, marriage, fertility, and fertility preferences from 4488 reproductive-age women and 1010 of their husbands.  Relative to their spouses, men tended to be older, better educated, and more likely working in agriculture.  83% of men and 73% of women indicated their acceptance of mass media family planning messages, while 20% of husbands and 16% of wives reported using some form of contraception.  A larger percentage of men and women over age 26 reported using contraception compared to respondents under age 26.  The level of contraception use increased with the level of education for both sexes, although the level of use was inversely related to the difference in age between spouses.  Periodic abstinence was the most widely used method, followed by oral contraception.  Communication between spouses was an important predictor of family planning use. ",0
2031,9881458,Light-induced cGMP-phosphodiesterase activity in intact rat retinal rod cells as revealed by rapid-freezing enzyme cytochemistry,"Cyclic guanosine monophosphate (cGMP)-phosphodiesterase (PDE) in the outer segment of vertebrate retinal rod cells is one of key enzymes mediating phototransduction. We report here on light-induced PDE activity in intact rat retinal rod cells processed by rapid-freezing enzyme cytochemistry, a new morphological technique that is a combination of rapid-freezing, freeze-substitution fixation, and subsequent enzyme cytochemistry. This technique quickly immobilizes and preserves both enzyme activity and the cell ultrastructure in a state approximating living conditions; consequently, it has proved useful for cytochemical detection of light-induced PDE activity. Using this technique we observed that the catalytic site of PDE molecules in rapid-frozen outer segments was predominantly located in the extradiscal spaces; PDE activity was significantly greater in light than in darkness; and illumination elicited marked increases in PDE activity in dark-adapted cells. Light-induced PDE activity was first cytochemically detected after 3 s of illumination and reached a peak within 5 s, at which time it was in virtually the same as that seen in fully light adapted cells. In addition, cytochemical guanosine triphosphatase (GTPase) activity in dark-adapted cells, as well as corresponding PDE activity, increased in a time-dependent manner with illumination duration; this acceleration in GTPase activity closely paralleled the PDE activity. Thus, our results suggest, in part, the existence of reciprocal regulation of PDE and activated transducin alpha subunit, thereby modulating light adaptation in rod cells. ",0
2032,9881719,EMS and UV-light-induced colony sectoring and delayed mutation in Chinese hamster cells,"To review studies of mutagen-induced colony sectoring which demonstrate that UV light and EMS produce delayed mutational events in Chinese hamster ovary cells. Since the late 1940s, it has been known that the treatment of a single bacterial or yeast cell with mutagenic agents produces complete mutant colonies (pures) and colonies composed of both mutant and non-mutant cell types (mosaics) with various sectored patterns. A similar sectoring phenomenon has been observed in Chinese hamster ovary cells (CHO) using the DNA alkylating agent ethyl methane sulphonate (EMS) or ultraviolet light. However, unlike bacteria and yeast, a significant fraction of CHO mutant colonies contained sectors of less than 1/2; i.e. 1/4, 1/8 and 1/16 sectors, suggesting a delayed production of mutations. Using various colony-replating approaches, it was found that these mutagenic agents produced the ratio of mutant to wild-type cells expected for a delayed mutational process which produces mutant events for at least 12-14 cell divisions following treatment. This delayed mutation phenomenon was observed at both the glucose-6-phosphate dehydrogenase (G6PD) and hypoxanthine guanine phosphoribosyltransferase (HGPRT) loci. Various mutational mechanisms for the production of delayed mutations are discussed. These studies suggest that mutagens such as UV light and EMS induce long-term alterations in mammalian cells that act to increase the 'apparent' spontaneous mutation frequency. This delayed mutational decrease in stability of the genome may explain the accumulation over time of the multiple genetic changes observed in malignant tumours. ",0
2033,9881860,Ventral subiculum regulates hypothalamo-pituitary-adrenocortical and behavioural responses to cognitive stressors,"The hippocampus plays an important role in central stress integration. The present study tests the hypothesis that the ventral subiculum, as a principal source of hippocampal efferents, is involved in co-ordination of hypothalamo-pituitary-adrenocortical and behavioural responses to cognitively-processed information. Basal hypothalamo-pituitary-adrenocortical activation appears to be normal in ventral subiculum lesion rats, as basal corticosterone and adrenocorticotropic hormone secretion, anterior pituitary pro-opiomelanocortin and type 1 corticotropin-releasing hormone receptor messenger RNA expression, adrenal and thymus weight, and splenic mitogen activity are not affected by lesion. Lesions of the ventral subiculum induce glucocorticoid hypersecretion following restraint stress or open field exposure, whereas responses to ether inhalation are unaffected. Interestingly, ventral subiculum lesion does not affect fast glucocorticoid negative feedback inhibition of restraint-induced adrenocorticotropic hormone release. Corticotropin-releasing hormone immunoreactivity is increased in the hypothalamic paraventricular nucleus of ventral subiculum lesion rats, and is differentially depleted by acute stress exposure (relative to sham-lesion rats). However, ventral subiculum lesion does not affect basal and stress-induced corticotropin-releasing hormone, arginine vasopressin and cFOS messenger RNA expression in paraventricular nucleus neurons. Behavioural analysis reveals that ventral subiculum lesion rats are hyper-responsive to open field exposure, showing decreased total ambulation and reduced incidence of central square entry. The results suggest that the ventral subiculum plays a specific role in integrating cognitively-processed stimuli (e.g., restraint and open field exposure) into appropriate neuroendocrine and behavioural responses to stress. Enhanced stress-induced glucocorticoid secretion and increased corticotropin-releasing hormone biosynthesis are likely due to removal of oligosynaptic inhibitory input to the paraventricular nucleus subsequent to ventral subiculum lesion. ",0
2034,9882026,Review article: olestra and its gastrointestinal safety,"Olestra is a fat substitute made from sucrose and vegetable oil. Olestra is neither digested nor absorbed, and therefore adds no calories or fat to the diet. Because the gut is the only organ that is exposed to olestra, the potential for olestra to affect gastrointestinal structure and function, and the absorption of nutrients from the gut, has been investigated. Histological evaluations performed after long-term feeding studies have shown no indications that olestra causes injury to the gastrointestinal mucosa. Olestra is not metabolized by the colonic microflora, and has no meaningful effects on the metabolic function of these organisms. Studies of gastrointestinal transit have shown that the consumption of olestra with food does not affect gastric emptying, or small or large bowel transit times. Olestra does not affect the absorption of macronutrients, water-soluble vitamins or minerals. It causes a dose-responsive decrease in the availability of the fat-soluble vitamins A, D, E and K; however, this potentially adverse effect is offset by the addition of vitamins to olestra-containing foods. Olestra has no consistent effect on the amount of total bile acids excreted in the faeces, and therefore probably has no significant effect on bile acid absorption. The occurrence of gastrointestinal symptoms, including diarrhoea, loose stools, gas and abdominal cramping, after consumption of olestra under ordinary snacking conditions is comparable to that following consumption of triglyceride-containing snacks. ",0
2035,9882396,Design and synthesis of fluorogenic trypsin peptide substrates based on resonance energy transfer,"An assay based on new internally quenched fluorogenic peptide substrates with the general structure 4-(4-dimethylaminophenylazo)benzoic acid (DABCYL)-Gly-Pro-Ala-Xaa-Leu-Ala-Ile-Gly-5-(2-aminoethylamino++ +)naphtha lene-1-sulfonic acid (EDANS), where Xaa = Arg, Lys, has been developed to measure proteolytic activity of trypsin and similar proteases. The kinetic parameters for the tryptic hydrolysis of DABCYL-Gly-Pro-Ala-Arg-Leu-Ala-Ile-Gly-EDANS are Km = 34 microM, kcat = 40 s-1, and kcat/Km = 1.17 x 10(6) M-1 s-1. The substrates offer two advantages over common substrates. First they are very sensitive. Applications to chemically modified trypsin and engineered variants show the ability to detect traces of proteolytic activity. In addition, these substrates are adapted to the S'-specificity of the investigated protease. These features and the prospect of miniaturization makes the assay suitable for applications to high-throughput screening. ",0
2036,9882702,Constitutive activation of the human bradykinin B2 receptor induced by mutations in transmembrane helices III and VI,"We report that mutation of specific residues in the human B2 bradykinin (BK) receptor induces its marked constitutive activation, evaluated through inositol phosphate production in COS-7 cells expressing the wild-type or mutant receptors. We provide evidence for a strikingly high constitutive activation of the B2 receptor induced by alanine substitution of the Asn113 residue, located in the third transmembrane domain. These results are reminiscent of our previous finding that mutation of the homologous Asn111 residue induces constitutive activation of the AT1 angiotensin II receptor. BK overstimulation of the constitutively activated mutant N113A receptor was also observed. Phe replacement of the Trp256 residue, fairly conserved in transmembrane domain VI of G protein-coupled receptors, also induced a less prominent but significant constitutive activation. Interestingly, the peptidic HOE 140 compound and an original nonpeptidic compound LF 16 0335, which both behaved as inverse agonists of the wild-type receptor expressed in COS-7 cells, became potent and efficient agonists of the two constitutively activated mutant N113A and W256F receptors. These parallel changes observed for two chemically unrelated series can serve as a basis for future studies of structure-function relationships and modeling of activation processes, based on a detailed analysis of the network of helix-helix interactions, which stabilize the inactive receptor conformation and undergo rearrangements on transition to activated states. ",0
2037,9882818,Bladder infiltration of mesenteric panniculitis],"Mesenteric panniculitis is a rare, recently accepted clinical entity which is characterized by the presence of an unspecific inflammatory process in the fat tissue of the gut mesentery. A usually intermittent abdominal pain is the most frequent symptom, whereas urological involvement is exceptional. This paper contributes a new case of mesenteric panniculitis in a 72-year old male patient who initially presented with signs and symptoms of intestinal obstruction resulting from mesenteric tumoration, and affecting a segment of the terminal ileum which, during growth, infiltrated the apex of the bladder leading to its resection. The ultimate diagnosis was histologic. Brief review of the clinical features, as well as the diagnostic and therapeutic procedures. ",0
2038,9882884,Diagnostic strategy in abdominal injuries],"There is persistent controversy concerning the management of patients with abdominal trauma. The major point is to determine whether or not the abdominal trauma is penetrating. In rare cases (shock, abdominal gunshot wound, peritonitis, evisceration, digestive tract bleeding and abdominal stab out of place) urgent laparotomy remains mandatory. In the other cases, although some centers recommend serial abdominal exams for asymptomatic patients, with the risk of delayed laparotomy, most authors prefer a more aggressive approach. In the case of anterior penetrating abdominal trauma, diagnostic peritoneal lavage, which is an over sensitive method, could be replaced by laparoscopy, which allows both diagnosis and treatment. Triple-contrast CT scan is the first-line diagnostic modality in penetrating back and flank trauma. ",0
2039,9882894,Extracranial cephalic schwannomas. Apropos of 13 cases],"The authors report a series of 13 extracranial cephalic schwannomas, treated between 1981 and 1998. Schwannomas are rare and benign tumors derived from Schwann cells. Cephalic sites represent 2.5% of all schwannomas. Their diagnosis is often delayed, because symptoms mainly consist of compression disorders. There is a female predominance. The age distribution is homogeneous. There are no risk factors. There is no predominant side. The orbit and jugular foramen are the most frequent sites. The trigeminal nerve is usually involved. CT scan and magnetic resonance imaging (MRI) specify the topography and characteristics of the tumor and can contribute to the diagnosis. Macroscopically, schwannoma is a well-demarcated, ovoid or spherical, brownish tumor, off-centered from the nerve. It is composed of soft, easily fragmented tissue. The diagnosis is often obvious on microscopic examination and rarely requires immunohistochemical confirmation. The only treatment is surgical. It consists enucleation after opening the epineurium, using on operating microscope, without disruption of the nerve. Total excision ensures recovery. The authors have observed only one recurrence (first patient operated without microscope). Compression disorders regress completely. Nerve injuries have a variable prognosis. Malignant transformation is exceptional. Type II neurofibromatosis must be excluded in young patients. ",0
2040,9883233,A new operative method to treat high teat stenoses in dairy cows,"To evaluate in a pilot study an alternative technique using theloscopic surgery in the management of proximal teat stenoses of dairy cows. The study included three lactating dairy cows (mean age 3.5 years) with a stenotic fibrous lesion in the proximal region of a teat. The lesions were suspected to be of traumatic origin and the diagnoses were confirmed by ultrasonography. For surgery, the cows were sedated and the base of the teat anaesthetized. The resectoscope was introduced through an incision in the teat cistern. The surgical area was continuously irrigated with saline solution and the stenotic lesions electroresected. Haemorrhage was controlled whenever possible by electrocoagulation. In two cows, the procedure was successful and resulted in normal milk flow. One of the two cows was slaughtered soon after the operation for reasons unrelated to udder health. The other cow could be milked normally at a follow-up examination 4 months later and on ultrasonography, there was no recurrence of the stenotic lesions. In both cows, there was no evidence of concurrent intramammary infection. In the third cow, the procedure had to be discontinued because of severe intraoperative haemorrhage. Video-assisted theloscopic electroresection of fibrotic teats is a promising, novel and minimally invasive technique for the surgical correction of the glandular part of the cistern. It should be considered as an alternative to conventional surgical methods in valuable dairy cows. ",0
2041,9883451,Two cases of cerebral aneurysm detected after recanalization of the middle cerebral artery],"Two cases of aneurysm incidentally detected after recanalization of middle cerebral artery (MCA) occlusion are reported. Patient 1 was a 62-year-old male with sudden onset of left hemiparesis. We performed emergent intravascular surgery. The initial cerebral angiography revealed occlusion at the M1 portion of the right MCA. After partial recanalization with a microcatheter, carotid angiography revealed a right M1-M2 junction aneurysm. Due to the risk of aneurysmal rupture, the thrombolytic procedure was stopped. Follow up angiography after 1 month revealed complete recanalization of the right MCA and a persistent aneurysm. Patient 2 was a 65-year-old male with left hemiparesis. The initial cerebral angiography revealed occlusion at the M1 portion of the right MCA. After 1 month follow-up cerebral angiography revealed spontaneous recanalization of the right MCA and an incidental aneurysm at the M1-M2 junction. Neck clipping of the aneurysm was performed. When using a microcatheter or microballoon catheter to treat arterial occlusion, surgeons should consider the possibility of a rupture of a hidden aneurysm. ",0
2042,9883781,Recruitment to a school-based adult smoking-cessation program: do gender and race/ethnicity make a difference?,"""Recruitment to interventional research, clinical trials, and community-based health programs remains a central public health challenge, particularly among low-income and multi-ethnic populations. Utilizing existing community institutions and """"opportunistic"""" communication channels within these settings for recruitment seems an optimal strategy for overcoming barriers to participation. However, such institutions frequently serve heterogeneous populations, and little is known regarding intra-community variations in program uptake. This paper reports the gender and race/ethnic differences in subject characteristics and enrollment patterns among 435 Latino and African American participants in a smoking-cessation program delivered through one such community institution, an inner-city school district in Los Angeles County. Enrollees were more likely to be female and Latino. Recruitment strategies tailored specifically to this program were more effective then recruitment through channels such as regular school activities, particularly among African Americans. Intragroup variations need to be carefully considered in the design and implementation of such programs if they are to receive acceptance and to succeed. """,0
2043,9883962,Possible salmonella osteomyelitis of spine following laser disc decompression,"We report a case of chronic discitis and vertebral osteomyelitis that we believe was caused by Salmonella typhimurium following laser decompression of the L4/5 disc for symptomatic disc protrusion in a 50-year-old Asian man. The infection was successfully treated with intravenous ceftriaxone combined with oral ciprofloxacin. We believe this to be the only report of such a complication following this procedure, which is generally without infective complications. ",0
2044,9884065,In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum,"We investigated the effect of the cannabinoid agonist (+)WIN-55212-2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical field stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or coincubated, reduced twitch responses to a similar degree (85%). (+)WIN-55212-2 concentration-dependently inhibited twitch responses (IC50 73 nM), but had no additive effect with atropine or TTX. The cannabinoid CB1 receptor antagonist SR 141716 (pA2 8.2), but not the CB2 receptor antagonist, SR 144528, competitively antagonized twitch inhibition by (+)WIN-55212-2. Atropine but not (+)WIN-55212-2 or TTX prevented carbachol-induced tonic contraction. These results provide functional evidence of the existence of prejunctional cannabinoid CB1-receptors in the human ileum longitudinal smooth muscle. Agonist activation of these receptors prevents responses to electrical field stimulation, presumably by inhibiting acetylcholine release. SR 141716 is a potent and competitive antagonist of cannabinoid CB1 receptors naturally expressed in the human gut. ",0
2045,9884111,Acute cocaine effects on stereotype and defense: an ethoexperimental approach,"Cocaine administration to laboratory animals may produce locomotor hyperactivity and stereotypies that include sniffing and rearing, in addition to anxiety-like effects. A time-sampling study of the effects of 3, 10 or 30 mg/kg cocaine (i.p.) over time following injection indicated early enhancement of locomotion and crouching, with the latter most increased in low- and intermediate-dose cocaine groups, with increased rearing and standing during the second hour of the test period. Additional analyses at 30-60 min post-injection suggested qualitative changes in rearing, with high dose animals showing more, but shorter, rears, and a higher frequency of sniffing. The high dose cocaine enhancement of sniffing was strongly associated with rear and stand behaviors, but also occurred while the animal was crouching. This pattern of changes, with initial crouching/freezing and locomotion (flight?), followed by rearing, standing, and sniffing behaviors similar to those seen in risk assessment suggests that cocaine, particularly at high doses, may elicit defense. An additional study using only saline or the high (30 mg/kg) dose indicated that cocaine produced more sniffing regardless of the direction from which the air stream entered the test cage (i.e. top or bottom). However, cocaine animals oriented their sniffing behaviors toward the incoming air, with reliably more sniffs up in cages with the air stream entering from the top, and more sniffs down, when the air stream entered through a wire mesh cage bottom. Controls showed the same pattern, but their sniff orientation differences were not reliable. These results indicate that the sniffing that follows acute high dose cocaine administration is appropriately oriented toward relevant environmental stimuli, a factor disconsonant with the interpretation of sniffing as a stereotypical behavior, but one that is in agreement with the view that it may reflect a risk assessment component of the defense pattern. ",0
2046,9884163,Comparison of alcohol-preferring and nonpreferring selectively bred rat lines. II. Operant self-administration in a continuous-access situation,"Several rat lines have been developed using preference/nonpreference and daily ethanol intake in the homecage as criteria for selective breeding. Using these lines, behavioral and neural factors that may underlie the genetic basis for the control of ethanol consumption have been examined. In this paper, we report data from eight of these selected lines: the Alcohol-Preferring (P) and Alcohol-Nonpreferring (NP), the Alcohol-Accepting (AA) and Alcohol-Nonaccepting (ANA), and the High Alcohol Drinking (HAD1 and HAD2) and Low Alcohol Drinking (LAD1 and LAD2) rats. All lines were tested using operant procedures and the same protocols for both the ethanol self-administration initiation and measurement of continuous-access ethanol consumption. During continuous access, the animals were housed in operant chambers with access to 10% (v/v) ethanol after responses on one lever, food pellets (45 mg) after responses on a second lever, and water in a drinking tube that was connected to a drinkometer circuit. Under these procedures, both similarities and differences among the selected lines on continuous-access operant ethanol intake were observed. For example, overall total homecage ethanol drinking was similar for the AA and both HAD lines. When examined in the operant continuous-access situation, however, the AA rats displayed a different consumption pattem, compared with the HAD lines. Data suggest that the frequency of drinking bouts was a primary factor in the phenotypic homecage selection of the preferring lines that was revealed by the use of the continuous-access operant procedure. In general, data suggest that genes related to ethanol preference and intake in homecage continuous-access situations may not be identical to those related to ethanol's reinforcing function in operant continuous-access conditions. Because ethanol consumption appears to be controlled by different drinking patterns across lines, the selected lines provide for a variety of models to understand how varying genotypes can impact ethanol consumption. ",0
2047,9884212,Determination of roquefortine C in blue cheese using on-line column-switching liquid chromatography,"A method is described for the determination of roquefortine C in (blue) cheese. After liquid liquid extraction with a mixture of hydrochloric acid and methanol, and filtration, an aliquot is analysed using column-switching reversed-phase liquid chromatography. The recovery of roquefortine C in Fetta cheese is about 85%, the calibration curve is linear from 10 to 2500 ng g(-1) (r2 = 0.998), and the detection limit is about 10 ng g(-1). In different batches of Danish Blue concentrations of 1000-2000 ng g(-1) of roquefortine C are found. As regards the stability of roquelfortine C its half-life in diffuse daylight is ca. 50 min, while after irradiation with ultraviolet light, it is about 10 min. ",0
2048,9884414,Hypertension as an etiopathological factor in the development of cerebral atrophy in hemodialyzed patients,"Twenty-five patients on long-term regular hemodialysis treatment (RDT) at our dialysis unit who underwent diagnostic cerebral computed tomography (CCT) participated in a study aimed at clarifying the pathogenesis of cerebral atrophy occasionally found at their original scan. The upper age limit was 55 years to exclude the physiological involutive brain changes occurring with age. Cerebral atrophy (CA), as defined morphologically (enlargement of cerebral sulci or an increased Evan's Index), was detected in all cases. Seventeen patients underwent magnetic resonance imaging (MRI) to define possible white matter changes more accurately. No significant correlation was found between the degree of atrophy and the following uremia-altered hematoseric parameters: creatinine, hematocrit, cholesterol, triglyceridemia, albumin, PTH, calcium, inorganic phosphate. There was no correlation between degree of atrophy and number of months the patients had been on RDT or time that passed between the finding of a creatinine clearance <30 ml/min and the start of RDT. Very high correlations were found between the degree of CA and predialytic blood pressure values, and between CA and the duration of hypertension (n = 13, r = 0.66, p < 0.013). Thus, hypertension seems to be an early cause of cerebral parenchymal damage in RDT patients, and should be promptly corrected. ",0
2049,9884819,Myxofibrosarcoma of soft tissues: cytomorphologic analysis of a series,"Within the English literature, myxofibrosarcoma is a recently described entity. Although the histopathologic features have been reported, the cytomorphologic spectrum of myxofibrosarcoma has been far less documented. The cytologic findings of six fine-needle aspiration biopsy specimens (five primaries, one local recurrence) from six patients are described. The patients' ages ranged from 26-77 yr; there were four women and two men. The aspiration biopsy specimens ranged from slightly to markedly cellular. Although a myxoid granular to filamentous background was observed at least focally in all cases, the volume of the myxoid material was inversely proportional to the cellularity and grade of the tumor. Individual tumor cells were round to spindled, often displaying a wide range of cell shapes and sizes. Nuclei were generally large, pleomorphic, and hyperchromatic, frequently containing prominent nucleoli. Cytoplasm ranged from scant to dense and tapering. Multinucleated tumor giant cells were occasionally observed. In general, low- and intermediate-grade myxofibrosarcomas were more easily recognized in cytologic preparations. In contrast, high-grade myxofibrosarcoma was more difficult to specifically subtype and not easily distinguished from other adult pleomorphic sarcomas. ",0
2050,9884820,Cytodiagnostic patterns of metaplastic breast carcinoma in aspiration samples: a study of 14 cases,"Metaplastic breast carcinomas (MBCs) are not only uncommon neoplasms but also show a myriad of cytomorphologic patterns in aspiration samples. These tumors comprise less than 5% of breast malignancies and have an uncertain prognosis. In this study, the fine-needle aspiration cytologic features of 14 MBCs with the identification of two distinct malignant cell populations are presented, based on which a definitive diagnosis was possible in 12 of the 14 cases. In the remaining 2 cases the diagnosis of MBC was substantiated after study of cell blocks from the aspirate, which were made in all the cases. Furthermore, the diagnosis of MBC was also confirmed subsequently on tissue examination. The various combinations of patterns included malignant ductal, squamous, and sarcomatous (including heterologous) elements and multinucleated osteoclastic giant cells. As a result of this study, it was felt that if malignant breast aspirates on careful examination show two or more distinct neoplastic elements, the diagnosis of MBC may be possible. ",0
2051,9884856,'Out-of-hospital cardiac arrests' treated by the West Midlands Ambulance Service over a 2-year period,"We aimed to determine whether our results were any better or worse than other published reports and to examine the efficacy of the West Midlands Ambulance Service (WMAS) policy of applying cardiopulmonary resuscitation (CPR) and manual ventilation to all unwitnessed cardiac arrests in preference to immediate defibrillation. All cardiac arrests were studied from October 1994 to September 1996. In all unwitnessed arrests, crews undertook CPR and manually ventilated the lungs via a mask or an endotracheal tube with a bag and valve or a mechanical resuscitator using an FIO2 of 1 or 0.21 for at least 2 min before defibrillation was attempted. There were 3403 diagnosed cardiac arrests but, in these, the diagnosis was not certain. CPR and advanced life support (ALS) were applied in 3380 patients and return of spontaneous circulation (ROSC) was obtained in 554, giving a success rate of 16.4%. A total of 364 patients were accepted into hospital, 90 patients died in A&E but 274 patients were admitted to ICU/CCU. Seventy died within 24 h, 69 died after 24 h and 135 were discharged alive and well without cerebral damage. The final success to discharge rate was 49.27%. Of those discharged, 69 had a circulatory arrest period of more than 4 min but in only 10 was a bystander available to start CPR. The European Resuscitation Council Guidelines recommending immediate defibrillation for unwitnessed arrests are not supported by these results. The apparent lack of cerebral damage and the percentage success suggests that resuscitation considerations should be as brain orientated as they are heart orientated. The elapsed time periods reported challenge several shibboleths. ",0
2052,9885190,The Rhizobium etli metZ gene is essential for methionine biosynthesis and nodulation of Phaseolus vulgaris,"A mutant strain (CTNUX23) of Rhizobium etli carrying Tn5 unable to grow with sulfate as the sole sulfur source was isolated and characterized. Sequence analysis showed that Tn5 is inserted into a metZ (O-succinylhomoserine sulfhydrylase)-homologous gene. The CTNUX23 mutant strain had a growth dependency for methionine, although cystathionine or homocysteine, but not homoserine or O-succinylhomoserine, allowed growth of the mutant. RNase protection assays showed that the metZ-like gene had a basal level of expression in methionine- or cysteine-grown cells, which was induced when sulfate or thiosulfate was used. The metZ gene was cloned from the parent wild-type strain, CE3, and the resulting plasmid pAR204 relieved, after transformation, the methionine auxotrophy of both strains CTNUX23 of R. etli and PAO503(metZ) of Pseudomonas aeruginosa. Unlike strain CE3 or CTNUX23 (pAR204), strain CTNUX23 showed undetectable levels of O-succinylhomoserine sulfhydrylase activity. Strain CTNUX23 was unable to produce flavonoid-inducible lipo-chitin oligosaccharides (Nod factors) or to induce nodules or nodulelike structures on the roots of Phaseolus vulgaris, unless methionine was added to the growth medium. These data and our previous results support the notion that cysteine or glutathione, but not methionine, is supplied by the root cells to bacteria growing inside the plant. ",0
2053,9887163,A reappraisal of private employers' role in providing health insurance,"BACKGROUND: In 1996, according to official figures, 61 percent of Americans received health insurance through employers. However, this estimate includes persons who relied primarily on government insurance such as Medicare, workers whose employers arranged their insurance but contributed nothing toward the premiums, and government employees whose private coverage was paid for by taxpayers. METHODS: To estimate the number of persons whose principal health insurance was paid for in whole or in part by employers in the private sector and the number receiving government-funded insurance, we analyzed data from the March 1997 Current Population Survey. Approximately 130,000 persons representative of the noninstitutionalized U.S. population were sampled. We considered people to be covered principally by health insurance paid for by private-sector employers if they had no public insurance coverage and were covered by insurance from a non-governmental employer who paid all or part of their premiums. Those who were covered by Medicaid, Medicare, insurance resulting from former or current military service, or the Indian Health Service were considered to be receiving government insurance. RESULTS: In 1996, 43.1 percent of the population (90 percent confidence interval, 42.7 to 43.5 percent) depended principally on health insurance paid for by private-sector employers, 34.2 percent (90 percent confidence interval, 33.8 to 34.6 percent) had publicly funded insurance, 7.1 percent (90 percent confidence interval, 6.8 to 7.6 percent) purchased their own coverage, and 15.6 percent (90 percent confidence interval, 15.3 to 15.9 percent) were uninsured. In only six states was more than half the population covered principally by health insurance paid for by private-sector employers. CONCLUSIONS: Current definitions of health insurance overemphasize the role of private employers and underestimate the extent to which government pays for health insurance.",0
2054,9895396,Dietary fiber and the risk of colorectal cancer and adenoma in women,"BACKGROUND: A high intake of dietary fiber has been thought to reduce the risk of colorectal cancer and adenoma. METHODS: We conducted a prospective study of 88,757 women, who were 34 to 59 years old and had no history of cancer, inflammatory bowel disease, or familial polyposis, who completed a dietary questionnaire in 1980. During a 16-year follow-up period, 787 cases of colorectal cancer were documented. In addition, 1012 patients with adenomas of the distal colon and rectum were found among 27,530 participants who underwent endoscopy during the follow-up period. RESULTS: After adjustment for age, established risk factors, and total energy intake, we found no association between the intake of dietary fiber and the risk of colorectal cancer; the relative risk for the highest as compared with the lowest quintile group with respect to fiber intake was 0.95 (95 percent confidence interval, 0.73 to 1.25). No protective effect of dietary fiber was observed when we omitted, adjustment for total energy intake, when events during the first six years of follow-up were excluded, or when we excluded women who altered their fiber intake during the follow-up period. No significant association between fiber intake and the risk of colorectal adenoma was found. CONCLUSIONS: Our data do not support the existence of an important protective effect of dietary fiber against colorectal cancer or adenoma.",0
2055,9895397,Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network,"BACKGROUND: Induction of superovulation with gonadotropins and intrauterine insemination are frequently used to treat infertility. We conducted a large, randomized, controlled clinical trial of these treatments. METHODS: We studied 932 couples in which the woman had no identifiable infertility factor and the man had motile sperm. The couples were randomly assigned to receive intracervical insemination, intrauterine insemination, superovulation and intracervical insemination, or superovulation and intrauterine insemination. Treatment continued for four cycles unless pregnancy was achieved. RESULTS: The 231 couples in the group treated with superovulation and intrauterine insemination had a higher rate of pregnancy (33 percent) than the 234 couples in the intrauterine-insemination group (18 percent), the 234 couples in the group treated with superovulation and intracervical insemination (19 percent), or the 233 couples in the intracervical-insemination group (10 percent). Stratified, discrete-time Cox proportional-hazards analysis showed that the couples in the group treated with superovulation and intrauterine insemination were 3.2 times as likely to become pregnant as those in the intracervical-insemination group (95 percent confidence interval, 2.0 to 5.3) and 1.7 times as likely as those in the intrauterine-insemination group (95 percent confidence interval, 1.2 to 2.6). The couples in the intrauterine-insemination group and in the group treated with superovulation and intracervical insemination were nearly twice as likely to conceive as those in the intracervical-insemination group. CONCLUSIONS: Among infertile couples, treatment with induction of superovulation and intrauterine insemination is three times as likely to result in pregnancy as is intracervical insemination and twice as likely to result in pregnancy as is treatment with either superovulation and intracervical insemination or intrauterine insemination alone.",0
2056,9918941,CCAAT/enhancer binding protein alpha (C/EBPalpha) is an important mediator of mouse C/EBPbeta protein isoform production,"Both CCAAT/enhancer binding protein alpha (C/EBPalpha) and C/EBPbeta are intronless, yet can create various N-terminally truncated protein products with distinct DNA binding and transactivation potentials. These proteins can be generated via two distinct mechanisms, one translational and the other post-translational. In the translational mechanism, there is alternative translational start site selection of the different AUG codons present in the single messenger RNA (mRNA) species via a process of leaky ribosome scanning. Additionally, a post-translational method of isoform formation, through specific proteolytic cleavage of the full length protein has also been described. In this manuscript, we present evidence that the production of C/EBPbeta protein isoforms in the neonatal mouse liver is regulated by C/EBPalpha. In C/EBPalpha knockout mice, the predominant C/EBPbeta proteins are the larger 38- and 35-kd isoforms, whereas wild-type animals primarily possess the smaller 21- and 14-kd isoforms. These C/EBPalpha-dependent differences are liver specific, not present in lung or adipose tissues, and present at day 18 of development. Additionally, we show that induction of C/EBPalpha expression leads to an increase in the production of the 21-kd C/EBPbeta isoform in cell culture studies. As the various C/EBPbeta protein isoforms have different transcriptional capabilities, it is important to understand the regulation of the production of these isoforms. Our observations suggest a novel role for the C/EBPalpha transcription factor in this process.",0
2057,9920951,A controlled trial of exercise rehabilitation after heart transplantation,"BACKGROUND: In patients who have received a cardiac transplant, the denervated donor heart responds abnormally to exercise and exercise tolerance is reduced. The role of physical exercise in the treatment of patients who have undergone cardiac transplantation has not been determined. We assessed the effects of training on the capacity for exercise early after cardiac transplantation. METHODS: Twenty-seven patients who were discharged within two weeks after receiving a heart transplant were randomly assigned to participate in a six-month structured cardiac-rehabilitation program (exercise group, 14 patients) or to undergo unstructured therapy at home (control group, 13 patients). Each patient in the exercise group underwent an individualized program of muscular-strength and aerobic training under the guidance of a physical therapist, whereas control patients received no formal exercise training. Cardiopulmonary stress testing was performed at base line (within one month after heart transplantation) and six months later. RESULTS: As compared with the control group, the exercise group had significantly greater increases in peak oxygen consumption (mean increase, 4.4 ml per kilogram of body weight per minute [49 percent] vs. 1.9 ml per kilogram per minute [18 percent]; P=0.01) and workload (mean increase, 35 W [59 percent] vs. 12 W [18 percent]; P=0.01) and a greater reduction in the ventilatory equivalent for carbon dioxide (mean decrease, 13 [20 percent] vs. 6 [11 percent]; P=0.02). The mean dose of prednisone, the number of patients taking antihypertensive medications, the average number of episodes of rejection and of infection during the study period, and weight gain did not differ significantly between the groups. CONCLUSIONS: When initiated early after cardiac transplantation, exercise training increases the capacity for physical work.",0
2058,9920954,"""Do """"America's Best Hospitals"""" perform better for acute myocardial infarction?""","""BACKGROUND: """"America's Best Hospitals,"""" an influential list published annually by U.S. News and World Report, assesses the quality of hospitals. It is not known whether patients admitted to hospitals ranked at the top in cardiology have lower short-term mortality from acute myocardial infarction than those admitted to other hospitals or whether differences in mortality are explained by differential use of recommended therapies. METHODS: Using data from the Cooperative Cardiovascular Project on 149,177 elderly Medicare beneficiaries with acute myocardial infarction in 1994 or 1995, we examined the care and outcomes of patients admitted to three types of hospitals: those ranked high in cardiology (top-ranked hospitals); hospitals not in the top rank that had on-site facilities for cardiac catheterization, coronary angioplasty, and bypass surgery (similarly equipped hospitals); and the remaining hospitals (non-similarly equipped hospitals). We compared 30-day mortality; the rates of use of aspirin, beta-blockers, and reperfusion; and the relation of differences in rates of therapy to short-term mortality. RESULTS: Admission to a top-ranked hospital was associated with lower adjusted 30-day mortality (odds ratio, 0.87; 95 percent confidence interval, 0.76 to 1.00; P=0.05 for top-ranked hospitals vs. the others). Among patients without contraindications to therapy, top-ranked hospitals had significantly higher rates of use of aspirin (96.2 percent, as compared with 88.6 percent for similarly equipped hospitals and 83.4 percent for non-similarly equipped hospitals; P<0.01) and beta-blockers (75.0 percent vs. 61.8 percent and 58.7 percent, P<0.01), but lower rates of reperfusion therapy (61.0 percent vs. 70.7 percent and 65.6 percent, P=0.03). The survival advantage associated with admission to top-ranked hospitals was less strong after we adjusted for factors including the use of aspirin and beta-blockers (odds ratio, 0.94; 95 percent confidence interval, 0.82 to 1.08; P=0.38). CONCLUSIONS: Admission to a hospital ranked high on the list of """"America's Best Hospitals"""" was associated with lower 30-day mortality among elderly patients with acute myocardial infarction. A substantial portion of the survival advantage may be associated with these hospitals' higher rates of use of aspirin and beta-blocker therapy.""",0
2059,9920955,Effects of admission to a teaching hospital on the cost and quality of care for Medicare beneficiaries,"BACKGROUND AND METHODS: We studied the effects of admission to a teaching hospital on the cost and quality of care for patients covered by Medicare (age, 65 years old or older). We used data from the National Long Term Care Survey and merged them with Medicare claims data. We selected the first hospitalization for hip fracture (802 patients), stroke (793), coronary heart disease (1007), or congestive heart failure (604) occurring between January 1, 1984 and December 31, 1994, and calculated all Medicare payments for inpatient and outpatient care during the six-month period after admission. Survival was assessed through 1995. Hospitals were classified as major or minor teaching hospitals (with minor hospitals defined as those in which the number of residents per bed was less than the median number for all teaching hospitals) or as private nonprofit, government (i.e., public), or private for-profit hospitals. RESULTS: Medicare payments for the six-month period after hospitalization were highest for patients initially admitted to teaching hospitals for the treatment of hip fracture, stroke, or coronary heart disease and for patients initially admitted to for-profit hospitals for the treatment of congestive heart failure. As compared with payments to for-profit hospitals, payments to major teaching hospitals for hip fracture were significantly higher, payments to government hospitals for coronary heart disease were lower, and payments to government and nonprofit hospitals for congestive heart failure were lower. After adjustment for patients' characteristics and social subsidies, major teaching hospitals had the lowest mortality rates (hazard ratio for death, 0.75, as compared with for-profit hospitals; 95 percent confidence interval, 0.62 to 0.91). For individual conditions, the only significant survival advantage associated with admission to major teaching hospitals was for hip fractures (hazard ratio, 0.54, as compared with for-profit hospitals; 95 percent confidence interval, 0.37 to 0.79). CONCLUSIONS: Although admission to a major teaching hospital may be associated with increased costs to the Medicare program, overall survival for patients with the common conditions we studied was better at these hospitals, especially for patients with hip fractures.",0
2060,9929522,Cocaine and tobacco use and the risk of spontaneous abortion,"BACKGROUND: Cigarette smoking and cocaine use may be risk factors for spontaneous abortion, but data supporting such a link are limited. METHODS: We studied the associations between cocaine and tobacco use and spontaneous abortion among pregnant adolescents and women (age range, 14 to 40 years) who sought care at an inner-city emergency department. A total of 400 adolescents and women had spontaneous abortions either at study entry or during follow-up (which lasted until 22 weeks' gestation), and 570 adolescents and women remained pregnant past 22 weeks' gestation. Cocaine use was measured at base line by self-reports and analysis of urine and hair samples. Cigarette smoking was measured by self-reports and urine analysis. RESULTS: The adolescents and women in both groups were predominantly black and of lower socioeconomic status. Among those who had spontaneous abortions, 28.9 percent used cocaine on the basis of hair analysis and 34.6 percent smoked on the basis of a urine cotinine assay, as compared with 20.5 percent and 21.8 percent, respectively, of the adolescents and women who did not have spontaneous abortions. The presence of cocaine in hair samples was independently associated with an increase in the occurrence of spontaneous abortion (odds ratio, 1.4; 95 percent confidence interval, 1.0 to 2.1) after adjustment for demographic and drug-use variables. However, the use of cocaine as measured by self-reports and by urine analysis was not. The presence of cotinine in urine was also independently associated with an increased risk of spontaneous abortion (odds ratio, 1.8; 95 percent confidence interval, 1.3 to 2.6). Twenty-four percent of the risk of spontaneous abortion could be related to cocaine or tobacco use. CONCLUSIONS: Cocaine and tobacco use were common in our study population and were associated with a significant risk of spontaneous abortion.",0
2061,10021470,Effect of growth hormone treatment on adult height of children with idiopathic short stature. Genentech Collaborative Group,"BACKGROUND: Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown. METHODS: We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups. RESULTS: In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls. CONCLUSION: Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children.",0
2062,10021471,Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency,"BACKGROUND: Since 1968 it has been known that bone marrow transplantation can ameliorate severe combined immunodeficiency, but data on the long-term efficacy of this treatment are limited. We prospectively studied immunologic function in 89 consecutive infants with severe combined immunodeficiency who received hematopoietic stem-cell transplants at Duke University Medical Center between May 1982 and September 1998. METHODS: Serum immunoglobulin levels and lymphocyte phenotypes and function were assessed and genetic analyses performed according to standard methods. Bone marrow was depleted of T cells by agglutination with soybean lectin and by sheep-erythrocyte rosetting before transplantation. RESULTS: Seventy-seven of the infants received T-cell-depleted, HLA-haploidentical parental marrow, and 12 received HLA-identical marrow from a related donor; 3 of the recipients of haploidentical marrow also received placental-blood transplants from unrelated donors. Except for two patients who received placental blood, none of the recipients received chemotherapy before transplantation or prophylaxis against graft-versus-host disease. Of the 89 infants, 72 (81 percent) were still alive 3 months to 16.5 years after transplantation, including all of the 12 who received HLA-identical marrow, 60 of the 77 (78 percent) who were given haploidentical marrow, and 2 of the 3 (67 percent) who received both haploidentical marrow and placental blood. T-cell function became normal within two weeks after transplantation in the patients who received unfractionated HLA-identical marrow but usually not until three to four months after transplantation in those who received T-cell-depleted marrow. At the time of the most recent evaluation, all but 4 of the 72 survivors had normal T-cell function, and all the T cells in their blood were of donor origin. B-cell function remained abnormal in many of the recipients of haploidentical marrow. In 26 children (5 recipients of HLA-identical marrow and 21 recipients of haploidentical marrow) between 2 percent and 100 percent of B cells were of donor origin. Forty-five of the 72 children were receiving intravenous immune globulin. CONCLUSIONS: Transplantation of marrow from a related donor is a life-saving and life-sustaining treatment for patients with any type of severe combined immunodeficiency, even when there is no HLA-identical donor.",0
2063,10051459,Anti-idiotypic antibodies to anti-PDC-E2 in primary biliary cirrhosis and normal subjects,"Anti-idiotypic antibodies may regulate the immune system and influence pathogenic autoimmunity. We investigated idiotype-anti-idiotype interactions in sera of patients with primary biliary cirrhosis (PBC), normal subjects and animals immunized with pyruvate dehydrogenase complex (PDC) or its derivatives. IgG autoantibody to the E2 subunit of PDC (PDC-E2) was derived by affinity-purification from sera of 12 patients with PBC, and F(ab)2 was prepared (anti-PDC-E2-F[ab]2). This was used as a reactant by enzyme-linked immunosorbent assay (ELISA) with sera from patients with PBC, normal subjects, or immunized animals. Results were that IgG antibody to anti-PDC-E2-F(ab)2 was detectable at low concentration in 12 PBC sera (mean optical density [OD] +/- SD: 1.02 +/- 0.26), and also in 19 normal sera (mean OD +/- SD: 0.97 +/- 0. 35) using a serum dilution of 1:20; background OD was 0.09 to 0.10, whereas antisera from animals immunized with PDC or PDC-E2 were nonreactive. There was a significant inverse correlation (r = -.59, P =.04) between the levels of anti-PDC-E2 in PBC sera (but not normal sera), and anti-idiotypic antibody reactive with anti-PDC-E2-F(ab)2. Anti-idiotypic antibody existed as a complex with anti-PDC-E2, because the removal of anti-PDC-E2 from serum resulted in decreased reactivity to anti-PDC-E2-F(ab)2. Reactivity between PDC-E2 and anti-PDC-E2 from PBC serum was not inhibited by normal sera, indicating that anti-idiotypic antibody from normal sera with anti-PDC-E2 reacts with the framework of F(ab) rather than the paratope. The conclusions are that PBC and normal sera contain IgG class anti-idiotypic antibodies to anti-PDC-E2, the characteristic autoantibody in PBC. Anti-PDC-E2 in immunized animals does not contain an idiotype cross-reactive with human anti-PDC-E2. Anti-idiotypic antibody in PBC is complexed with anti-PDC-E2 and in part accounts for immune complexes demonstrable in PBC. Anti-idiotypic antibody in PBC may regulate levels of anti-PDC-E2.",0
2064,10051465,"Carbohydrate-deficient transferrin, a sensitive marker of chronic alcohol abuse, is highly influenced by body iron","Carbohydrate-deficient transferrin (CDT), a microheterogeneous form of serum transferrin (Tf), has been proposed as the most reliable marker of chronic alcohol consumption, although unexplained false-positive and -negative results have been reported. We investigated whether body iron influenced CDT serum levels by studying alcohol abusers with or without iron overload and nonabusers with iron deficiency or iron overload caused by genetic hemochromatosis (GH). In alcohol abusers, CDT was significantly lower in the presence of iron overload than in the absence (24.6 +/- 16.5 U/L vs. 33.3 +/- 11.7 U/L; P <.01), with false-negative results almost exclusively in patients with iron overload. Similarly, in nonabusers with GH, CDT was lower than in normal controls (9.6 +/- 2. 2 U/L vs. 15.7 +/- 3.3 U/L; P <.0001), whereas, patients with iron deficiency anemia had significantly higher levels than controls (28. 1 +/- 5.8 U/L vs. 15.7 +/- 3.3 U/L; P <.0001). In nonabusers, iron supplementation therapy significantly decreased CDT levels in patients with iron deficiency anemia (33.7 +/- 6.6 U/L vs. 21.7 +/- 5.2 U/L; P =.0007), while iron-depletion treatment significantly increased CDT levels in patients with GH (9.7 +/- 2.0 U/L vs. 14.7 +/- 4.0 U/L; P =.001). Alcohol abusers had a significant relationship between liver iron concentration (LIC) and the reciprocal of CDT (r =.65; P <.0001), while in nonabusers, there was a significant correlation between Tf and CDT (r =.72; P <.0001). In conclusion, CDT serum levels are markedly affected by the patient's iron status, with iron overload reducing its sensitivity in alcohol abusers and iron deficiency its specificity in nonabusers. CDT can be considered a reliable marker of alcohol abuse only when iron stores are normal.",0
2065,10051479,Peroxynitrite formation during rat hepatic allograft rejection,"The role of nitric oxide (NO) on tissue injury of hepatic allografts during rejection remains controversial. We investigated inducible nitric oxide synthase (iNOS) expression and formation of peroxynitrite in ACI rat liver grafts implanted in recipients. Animals were divided into four experimental groups: group I, isografts; group II, untreated hepatic allografts; group III, allografts treated with FK506; and group IV, allografts pretreated with donor-specific blood transfusion (DST). Serum nitrite/nitrate, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) concentrations increased significantly in group II rats after transplantation but were significantly lower in groups I, III, and IV. The numbers of macrophages that reacted with an antimacrophage iNOS monoclonal antibody as well as iNOS messenger RNA (mRNA) levels in liver specimens were also much lower in groups I, III, and IV as compared with group II. Immunostaining and Western blot analysis showed prominent tissue nitrotyrosine expression in untreated hepatic allografts, but not in allografts treated with FK506 or donor-specific blood. These results suggest that one of the mechanisms by which production of NO results in injury in rat hepatic allografts may be because of its reaction with superoxide to form peroxynitrite.",0
2066,10051498,Hepatitis B virus X protein transactivates the inducible nitric oxide synthase promoter,"The capability of hepatitis B virus (HBV) to increase the transcription of the human hepatic inducible nitric oxide synthase (iNOS) by transactivating its promoter has been studied. We have observed by reverse-transcription polymerase chain reaction (RT-PCR) that although the mRNA for the iNOS was almost undetectable in the human hepatoblastoma cell line, HepG2, it was constitutively expressed in the 2.2.15 cell line (a derivative of the HepG2 that produces complete HBV particles). Transfection of HepG2 and 2.2.15 cells with the p1iNOS-CAT plasmid (containing a 1.1-kb fragment of the iNOS promoter) resulted in an increase in chloramphenicol acetyl transferase (CAT) activity in 2.2.15 cells. Similar results were observed when HepG2 and Chang liver cell lines were cotransfected with the p1iNOS-CAT plasmid and the complete HBV genome. It was shown that pX was responsible for the transactivation by cotransfection of HepG2 cells with the p1iNOS-CAT and plasmids expressing the HBV-encoded pX protein, core antigen, and e antigen. Cotransfection of HepG2 cells with the pX expression plasmids and a series of deletion mutants of the 1.1-kb iNOS promoter fragments established that transactivation by pX depends on the presence of at least one nuclear factor-kappaB (NF-kappaB) binding site. This was further confirmed by cotransfecting cells with a plasmid expressing the NF-kappaB inhibitor, IkappaB.",0
2067,10051504,Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells,"Oxidative stress plays a key role in liver fibrosis. Both inflammatory cells and activated Kupffer cells produce H2O2, an oxidant involved in the activation of hepatic stellate cells (HSC). Increased production of reactive oxygen intermediates (ROIs) in fibrotic livers is associated in part with the up-regulation of transforming growth factor beta (TGF-beta), and this cytokine enhances collagen production by cultured HSC. However, the possible link between oxidative stress and the molecular mechanisms by which TGF-beta induces collagen gene expression in HSC remains to be elucidated. To address this question, we investigated whether H2O2 is a mediator of TGF-beta-elicited alpha1(I) collagen gene (col1a1) up-regulation. We demonstrated that TGF-beta induces the accumulation of H2O2, and that this oxidant is, in turn, directly involved in up-regulating the expression of the col1a1 gene. While the addition of H2O2 to HSC induced the expression of alpha1(I) procollagen mRNA, catalase, an H2O2 enzyme scavenger, abrogated TGF-beta-mediated col1a1 gene up-regulation. We transfected HSC with chimeric plasmids driven by different segments of the mouse col1a1 promoter and mapped a cis-acting element (-370 to -344) essential for TGF-beta responsiveness. We further showed that TGF-beta induced the activation and binding of a C/EBPbeta-containing transcriptional complex to this sequence, an effect that was also mimicked by the addition of H2O2. Taken together, these data demonstrate a direct connection between TGF-beta-mediated accumulation of H2O2 and the up-regulation of col1a1 gene in HSC.",0
2068,10094941,Generation of monoclonal antibodies to murine bile duct epithelial cells: identification of annexin V as a new marker of small intrahepatic bile ducts,"Biliary epithelial cells (BECs) are distributed along the length of both the extrahepatic and intrahepatic biliary tree, but have distinctly different phenotypes and functions according to their anatomical location. It has been reasoned that the distinct appearance of pathogenic lesions in different biliary diseases may be associated with the expression of distinct proteins. These data prompted us to immunize rats with cultured murine BECs with the objective of determining if there are unique antigens on BECs. Of the 45 monoclonal antibodies (mAbs) produced, 12 mAbs (MBEC 1-12) were selected for detailed study based on their classification into three major groups. These groups included four antibodies (MBEC 1-4) that reacted in a staining pattern typical of mucin. A second group of mAbs, MBECs 5 to 8, reacted strongly along the biliary tract and by immunoblot analysis, reacted with several bands ranging from 44 kd to 64 kd. These antibodies were considered as markers of pan BECs and their staining pattern proved similar to that of a control polyclonal pan-cytokeratin. The final group of mAbs, MBECs 9 to 12, recognized a 36-kd antigen using lysates of murine BECs. These antibodies also predominantly stained small peripheral bile ducts. The reactive antigen was purified by immunoprecipitation and microsequenced; the peptides sequenced showed 100% homology with murine annexin V. The identification of annexin V with predominantly intrahepatic bile ducts, is of significant interest because of the multiple roles of annexin V, including that of membrane cytoskeletal interactions during transport and apoptosis.",0
2069,10094962,"Determination of the chelatable iron pool of isolated rat hepatocytes by digital fluorescence microscopy using the fluorescent probe, phen green SK","""The intracellular pool of chelatable iron is considered to be a decisive pathogenetic factor for various kinds of cell injury. We therefore set about establishing a method of detecting chelatable iron in isolated hepatocytes based on digital fluorescence microscopy. The fluorescence of hepatocytes loaded with the fluorescent metal indicators, phen green SK (PG SK), phen green FL (PG FL), calcein, or fluorescein desferrioxamine (FL-DFO), was quenched when iron was added to the cells in a membrane-permeable form. It increased when cellular chelatable iron available to the probe was experimentally decreased by an excess of various membrane-permeable transition metal chelators. The quenching by means of the ferrous ammonium sulfate + citrate complex and also the """"dequenching"""" using 2,2'-dipyridyl (2,2'-DPD) were largest for PG. We therefore optimized the conditions for its use in hepatocytes and tested the influence of possible confounding factors. An ex situ calibration method was set up to determine the chelatable iron pool of cultured hepatocytes from the increase of PG SK fluorescence after the addition of excess 2,2'-DPD. Using this method, we found 9.8 +/- 2.9 micromol/L (mean +/- SEM; n = 18) chelatable iron in rat hepatocytes, which constituted 1.0% +/- 0.3% of the total iron content of the cells as determined by atomic absorption spectroscopy. The concentration of chelatable iron in hepatocytes was higher than the one in K562 cells (4.0 +/- 1.3 micromol/L; mean +/- SEM; n = 8), which were used for comparison. This method allowed us to record time courses of iron uptake and of iron chelation by different chelators (e.g., deferoxamine, 1,10-phenanthroline) in single, intact cells.""",0
2070,10094969,Expression of hepatitis C virus NS5B protein: characterization of its RNA polymerase activity and RNA binding,"The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is considered to possess RNA-dependent RNA polymerase (RdRp) activity and to play an essential role for the viral replication. In this study, we expressed the NS5B protein of 65 kd by a recombinant baculovirus. With the highly purified NS5B protein, we established an in vitro system for RdRp activity by using poly(A) as a template and a 15-mer oligo(U) (oligo(U)15) as a primer. Optimal conditions of temperature and pH for primer-dependent polymerase activity of the NS5B were 32 degrees C and pH 8.0. The addition of 10 mmol of Mg2+ increased the activity. The importance of three motifs conserved in RdRp among other positive-strand RNA viruses was confirmed by introduction of an Ala residue to every amino acid of the motifs by site-directed mutagenesis. All mutants lost RdRp activity, but retained the RNA binding activity, except one mutant at Thr287/Asn291. Deletion mutant analysis indicated that the N-terminal region of NS5B protein was critical for the RNA binding. Inhibition of RdRp activity by (-)beta-L-2', 3'-dideoxy-3'-thiacytidine 5'-triphosphate (3TC; lamivudine triphosphate) and phosphonoacetic acid (PAA) was observed after screening of nucleoside analogs and known polymerase inhibitors. These data provide us not only important clues for understanding the mechanism of HCV replication, but also a new target of antiviral therapy.",0
2071,10094977,"Quantitative antibody responses to structural (Core) and nonstructural (NS3, NS4, and NS5) hepatitis C virus proteins among seroconverting injecting drug users: impact of epitope variation and relationship to detection of HCV RNA in blood","To gain insight into the natural history of hepatitis C virus (HCV), 13 human immunodeficiency virus (HIV)-seronegative injecting drug users were studied who seroconverted for HCV as determined by third-generation enzyme-linked immunosorbent assay, showed an ensuing antibody response to HCV, and were not treated with any antiviral drugs during follow-up. Subjects included 13 untreated HIV-negative individuals, of whom 5 (38.5%) apparently cleared HCV and were polymerase chain reaction (PCR)-negative in at least 3 consecutive samples, 3 (23.1%) showed transient viremia and were PCR-negative in 1 sample during the study period, and the other 5 (38.5%) showed persistent viremia. Viremia was determined longitudinally by reverse-transcription PCR (RT-PCR) and quantified by branched DNA (bDNA). HCV genotypes were determined on serial samples during follow-up. Quantitative antibody levels to core, NS3, NS4, and NS5 were determined using the Chiron RIBA HCV-titering Strip Immunoblot Assay, which is based on HCV genotype 1. The antibody responses to core, NS3, NS4, and NS5 were erratic. In individuals infected with HCV genotype 1, significantly higher median antibody responses to core (P =.02) and to NS4 (P =.04) were found as compared with those infected with other genotypes, showing a significant impact of HCV genotype specificity of the assay. In groups infected with HCV genotype 1, significantly higher median NS3 antibody titers (2.61 relative intensity [RI] vs. 0.38 RI; P =.003) were found in the individuals with persistent viremia than in those with apparent resolution of HCV RNA in blood. In groups infected with genotypes other than genotype 1, significantly higher median NS3 antibody titers (0.89 RI vs. 0.03 RI; P =.0004) and NS5 antibody titers (1.86 RI vs. 0.01 RI; P =.006) were found in the individuals with persistent viremia than in those with apparent resolution of HCV RNA in blood. Individuals with viral persistence had higher HCV-RNA loads with higher antibody responses as compared with individuals with apparent viral clearance from blood. Apparent viral clearance from blood was observed in an unexpectedly high percentage (38.5%), associated with a significant decrease of antibodies to NS3, independent of HCV genotype, as compared with individuals with persistent viremia (P <.005). Apparent viral clearance from blood with gradual loss of antibodies to various HCV proteins, independent of HCV genotype, was observed in 4 of the 5 individuals within approximately 1 year after HCV seroconversion, whereas 1 of these individuals apparently cleared the virus from blood, with complete seroreversion.",0
2072,10099139,The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies,"BACKGROUND: To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. METHODS: North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. RESULTS: The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. CONCLUSIONS: The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.",0
2073,10202164,Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer,"BACKGROUND AND METHODS: We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. RESULTS: Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. CONCLUSIONS: The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.",0
2074,10210707,Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma,"BACKGROUND: Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. The identification of a common precursor of the two types of lymphoma would show definitively that Reed-Sternberg cells originate from B cells. METHODS: We studied lymphomas from two patients, one with a composite lymphoma (classic Hodgkin's disease and a follicular lymphoma in the same lymph node) and the other with a T-cell-rich B-cell lymphoma that was followed by classic Hodgkin's disease. Single Reed-Sternberg cells and non-Hodgkin's lymphoma cells from frozen sections were micromanipulated. The rearranged immunoglobulin variable-region genes (V genes) of the heavy and light chains were amplified by the polymerase chain reaction from genomic DNA and sequenced. RESULTS: In both patients, the Reed-Sternberg cells were related clonally to the non-Hodgkin's lymphoma B cells. The V genes carried somatic mutations (a hallmark of germinal-center B cells and their descendants). In both patients, some somatic mutations were shared by the Reed-Sternberg and non-Hodgkin's lymphoma cells, whereas other somatic mutations were found exclusively in one or the other cell type. CONCLUSIONS: In two patients with classic Hodgkin's disease and non-Hodgkin's B-cell lymphoma, we identified a common B-cell precursor, probably a germinal-center B-cell, for both lymphomas. This finding suggests that the two types of lymphoma underwent both shared and distinct transforming events and provides proof of the B-cell derivation of Reed-Sternberg cells in classic Hodgkin's disease.",0
2075,10216124,Inhibition of rat hepatocyte proliferation by transforming growth factor beta and glucagon is associated with inhibition of ERK2 and p70 S6 kinase,"Stimulation of hepatocyte proliferation by epidermal growth factor (EGF) and insulin is inhibited by transforming growth factor beta (TGF-beta) and by glucagon. It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70(S6k)), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SB 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated whether the inhibition of proliferation by TGF-beta involves these protein kinase cascades. Culture of hepatocytes with TGF-beta for 16 hours decreased the stimulation by EGF of ERK2 and p70(S6k) (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH2-terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70(S6k) (by approximately 50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-beta were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-beta may be in part mediated by inhibition of ERK2 and p70(S6k), but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-beta are not elicited in response to short-term treatment.",0
2076,10216130,"After portal branch ligation in rat, nuclear factor kappaB, interleukin-6, signal transducers and activators of transcription 3, c-fos, c-myc, and c-jun are similarly induced in the ligated and nonligated lobes","Several studies have emphasized the involvement of transcription factors, cytokines, and proto-oncogenes in initiating the regenerative process after partial hepatectomy. To assess whether these events do specifically occur in a cellular system undergoing regeneration, we studied the induction of nuclear factor kappaB (NFkappaB), interleukin-6 (IL-6), signal transducers and activators of transcription 3 (Stat3), c-fos, c-myc, c-jun, after portal branch ligation (PBL), which produces atrophy of the deprived lobes (70% of the liver parenchyma), whereas the perfused lobes undergo compensatory regeneration. Nuclear extracts and total RNA were prepared from control livers as well as from atrophying and regenerating lobes at 0.5, 1, 2, 5, and 8 after PBL. NFkappaB and Stat3 induction were studied by electrophoretic mobility shift assays and Western blotting. IL-6 and proto-oncogenes expressions were assessed by reverse transcription polymerase chain reaction and Northern blotting, respectively. Assays were also performed after a sham operation. NFkappaB and Stat3 protein expression and DNA binding were rapidly and similarly induced in nuclear extracts from the atrophying and regenerating lobes. IL-6 was elevated in both lobes from 1 to 8 hours after PBL as well as c-fos, c-myc, and c-jun during the first 2 hours. IL-6 and Stat3 but not NFkappaB were also elevated after a sham operation. These findings suggest that the cellular and molecular changes occurring early in a regenerating liver are nonspecific, possibly stress-induced, cellular responses. They do not indicate the future evolution towards atrophy or regeneration.",0
2077,10217502,Multiple haem-utilization loci in Helicobacter pylori,"To identify genes responsible for the utilization of haem as an iron source in Helicobacter pylori, a siderophore synthesis mutant of Escherichia coli was transformed with an ordered cosmid library of H. pylori NCTC 11638. Four independent cosmids were found that were able to complement this mutant on iron-restrictive solid media containing different haem compounds as the sole source of iron. Hybridization experiments revealed that the four cosmids contained unrelated DNA fragments. No major differences were observed in the growth of the four transformants on iron-restrictive solid media to which different haem compounds had been added. None of the cosmids could confer the ability to use haem as an iron source to an E. coli aroB tonB mutant, which means that transport of iron and/or haem across the outer membrane requires a functional TonB protein. Further characterization of the cosmids revealed that one of them was also able to complement E. coli aroB hemA, indicating that the haem molecule is taken up as a whole by this haem-biosynthesis mutant. Expression of this haem-uptake system could not be repressed by excess iron. Another cosmid expressed two polypeptides in E. coli which were specifically immunoreactive with a polyclonal antiserum raised against whole cells of H. pylori. The production of these proteins appeared to be iron repressible. One of these proteins has the same molecular mass as a previously described 77 kDa haem-binding iron-repressible outer-membrane protein (IROMP) of H. pylori. ",0
2078,10217513,Immunohistochemical demonstration of exocytosis-regulating proteins within rat molar dentinal tubules,"No morphologically defined synaptic structures have so far been detected between nerve terminals and the dentine-producing odontoblasts. Recent studies of the molecular mechanisms in neuronal exocytosis have identified several proteins that participate in synaptic-vesicle exocytosis. By localizing these proteins with immunohistochemical methods, information about the capacity for synaptic exocytosis should be obtained. Here, antibodies directed against some of the exocytosis-related proteins were used to investigate whether they are present in nerve fibers within the dentinal tubules in rat molars. Antibodies against synaptosome-associated protein of 25 kDa, Rab 3, synaptotagmin and synapsin all produced a punctuate staining pattern, suggesting that the proteins are accumulated in bouton-like elements. The results demonstrate that a set of exocytosis-related proteins is accumulated in the dentinal tubules, most probably within the intradentinal nerves. This finding is consistent with the hypothesis that intradentinal nerves can mediate efferent signals. ",0
2079,10217614,Multimodality nuclear medicine imaging in three-dimensional radiation treatment planning for lung cancer: challenges and prospects,"The purpose of this study was to determine the utility of quantitative single photon emission computed tomography (SPECT) lung perfusion scans and F-18 fluorodeoxyglucose positron emission computed tomography (PET) during X-ray computed tomography (CT)-based treatment planning for patients with lung cancer. Pre-radiotherapy SPECT (n = 104) and PET (n = 35) images were available to the clinician to assist in radiation field design for patients with bronchogenic cancer. The SPECT and PET scans were registered with anatomic information derived from CT. The information from SPECT and PET provides the treatment planner with functional data not seen with CT. SPECT yields three-dimensional (3D) lung perfusion maps. PET provides 3D metabolic images that assist in tumor localization. The impact of the nuclear medicine images on the treatment planning process was assessed by determining the frequency, type, and extent of changes to plans. Pre-radiotherapy SPECT scans were used to modify 11 (11%) treatment plans; primarily altering beam angles to avoid highly functioning tissue. Fifty (48%) SPECT datasets were judged to be 'potentially useful' due to the detection of hypoperfused regions of the lungs, but were not used during treatment planning. PET data influenced 34% (12 of 35) of the treatment plans examined, and resulted in enlarging portions of the beam aperture (margins) up to 15 mm. Challenges associated with image quality and registration arise when utilizing nuclear medicine data in the treatment planning process. Initial implementation of advanced SPECT image reconstruction techniques that are not typically used in the clinic suggests that the reconstruction method may influence dose response data derived from the SPECT images and improve image registration with CT. The use of nuclear medicine transmission computed tomography (TCT) for both SPECT and PET is presented as a possible tool to reconstruct more accurate emission images and to aid in the registration of emission data with the planning CT. Nuclear medicine imaging techniques appear to be a potentially valuable tool during radiotherapy treatment planning for patients with lung cancer. The utilization of accurate nuclear medicine image reconstruction techniques and TCT may improve the treatment planning process. ",0
2080,10218091,Immunological basis for the therapy of multiple sclerosis,"Much progress is currently being made in different areas of clinical and experimental multiple sclerosis (MS) research, including epidemiology and genetics, immunological mechanisms, possible role of infectious agents, imaging, clinical trials and development of new therapeutic agents. This article reviews some principles of MS pathogenesis and immunotherapy. ",0
2081,10218251,Acupuncture as a treatment modality for back problems,"Concepts of acupuncture in traditional Chinese medicine are presented for clarity and contrast to Western medical concepts. Various acupuncture techniques and methods are discussed including dry needling, electroacupuncture, acupuncture using hypodermic needles, and injecting various solutions into the acupuncture sites. Potential complications and precautions are also presented. A type of chronic back pain is discussed that is possibly associated with a radiculopathically induced, hypersensitivity myofascial syndrome that presents as a fibromyalgia-like syndrome. Effective acupuncture treatment for the described chronic fibromyalgia-like syndrome is discussed. ",0
2082,10218495,The induction of GSH synthesis by nanomolar concentrations of NO in endothelial cells: a role for gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase,"Nitric oxide protects cells from oxidative stress through a number of direct scavenging reactions with free radicals but the effects of nitric oxide on the regulation of antioxidant enzymes are only now emerging. Using bovine aortic endothelial cells as a model, we show that nitric oxide, at physiological rates of production (1-3 nM/s), is capable of inducing the synthesis of glutathione through a mechanism involving gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase. This novel nitric oxide signalling pathway is cGMP-independent and we hypothesize that it makes an important contribution to the anti-atherosclerotic and antioxidant properties of nitric oxide. ",0
2083,10218775,Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression,"Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. A progressive deficit was observed after a diabetes duration of six to eight weeks, which reached a maximum after 12 weeks of diabetes and remained stable thereafter. Next, long-term potentiation was examined in the dentate gyrus and in the CA3-field after 12 weeks of diabetes. Both were found to be impaired compared to controls. Finally, long-term depression was examined in the CA1-field of the hippocampus after 12 weeks of diabetes and found to be enhanced in slices from diabetic rats compared to controls. Changes in synaptic plasticity were observed in hippocampal slices from streptozotocin-diabetic rats. Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways. ",0
2084,10218792,Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study,"In situ hybridization histochemistry was used to show the distribution of messenger RNA for central cannabinoid CB 1 receptors in dorsal root ganglia of the rat. CB1 messenger RNA was highly expressed in neuronal subpopulations of rat dorsal root ganglia. The phenotypes of neurons that express messenger RNA for CB1 were subsequently examined by combining a 35S-labeled ribonucleotide probe for CB1 messenger RNA with digoxigenin-labeled riboprobes for preprotachykinin A (substance P precursor), alpha-calcitonin gene-related peptide and preprosomatostatin (somatostatin precursor) messenger RNAs. Qualitative examination revealed expression of CBI messenger RNA predominantly in medium-and large-sized cells distributed throughout the dorsal root ganglia. The majority of neurons expressing substance P messenger RNA were CB1 messenger RNA negative and smaller in size than the CB1 messenger RNA-positive cells. Only 13% of substance P messenger RNA-positive cells expressed CB1 messenger RNA. A similar degree of co-localization was observed with alpha-calcitonin gene-related peptide: 10% of cells expressing messenger RNA for this neuropeptide were CB1 messenger RNA positive. Co-localization of CB1 and somatostatin messenger RNAs was observed in less than 0.5% of somatostatin messenger RNA-positive cells. The data suggest that subpopulations of neurons in rat dorsal root ganglia are capable of synthesizing cannabinoid receptors and inserting them on terminals in the superficial dorsal horn. These findings provide anatomical evidence for cannabinoid modulation of primary afferent transmission. Although an anatomical basis for cannabinoid-mediated suppression of release of neurogenic peptides from nociceptive primary afferents is provided, our results demonstrate that the majority of CB messenger RNA-positive neurons in the dorsal root ganglia contain transmitters and/or neuromodulators other than the neuropeptides examined herein. ",0
2085,10219209,A mentoring program for underrepresented-minority students at the University of Rochester School of Medicine,"Mentoring underrepresented-minority (URM) students poses a special challenge because most medical schools have few URM faculty and many non-URM faculty hesitate to be mentors for URM students. Some medical students perform less well in the clinical years than would be expected from their pre-clinical performances. One factor is some students' difficulty in adapting to the culture of medicine, which mentors can help students overcome. The University of Rochester School of Medicine created the Medical Student Mentoring Program to address the needs of URM students and non-URM faculty who could be mentors. The program, offered in 1995-96 and 1996-97, trained mentors, created a bicultural support group for URM students, and provided structured mentoring. Interviews were conducted with faculty and students to identify critical areas that influence the success of URM students in their clinical years; URM faculty, residents, and advanced students shared their experiences with the program students at reflection group meetings. Mentors participated in an initial orientation. Of the 42 students eligible during 1995-1997, 30 participated and were assigned to 15 mentors. At the end of the program's first year, the students and mentors gave their reactions, and although there were some differences in their viewpoints, overall they considered the program useful. Non-URM faculty appreciated the support and guidance that allowed them to mentor URM students more effectively. The program ran formally for two years, and some of the mentoring relationships continued into the third year. Loss of funding and change in administrative leadership contributed to the ending of this program. Mentoring continues to be a priority at the medical center, and a new mentoring program has been developed for URM and non-URM medical students. ",0
2086,10219360,Tuberculous peritonitis: fatality associated with delayed diagnosis,"We describe a fatal case of tuberculous peritonitis and review the literature on the diagnostic modalities available to diagnose this entity. We suspect a delayed diagnosis resulted in the death of our patient. Today, the prompt diagnosis of an unknown ascitic process involves laparoscopy. A patient with unknown large volume ascites is the easiest and safest to laparoscope. Using a mini laparoscope, a bedside procedure with instantaneous return can be done. The newer noninvasive tests like determination of ascites fluid adenosine deaminase activity and polymerase chain reaction may be helpful in the prompt diagnosis of peritoneal tuberculosis. We recommend that patients with clinical presentation suggestive of peritoneal tuberculosis have either an aggressive diagnostic workup using high-yield tests or a trial of antituberculous therapy. ",0
2087,10219896,"IL-1beta, IL-6 and TNF-alpha in synovial fluid of patients with non-gonococcal septic arthritis","Interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are the main proinflammatory cytokines responsible for the inflammatory process and cartilage destruction of inflammatory arthropathies. The present study sequentially measured the concentrations of these cytokines and their proportions of detectable levels in the synovial fluid (SF) of 23 patients with non-gonococcal (GC) septic arthritis before and after treatment. Persistently high concentrations and proportions of IL-6 and TNF-alpha were found up to day 7 of treatment, while SF IL-1beta concentration declined significantly after day 7 (p = 0.036). SF IL-1beta and TNF-alpha correlated with each other significantly and with SF WBC counts (p < 0.01). Positive correlations between SF IL-1beta concentration and joint effusion (p < 0.01) and between SF TNF-alpha concentration and joint tenderness (p < 0.001) were observed. SF IL-1beta and TNF-alpha were significantly higher in patients with local complications of septic arthritis. In conclusion, high levels of IL-1beta, IL-6 and TNF-alpha were detected in SF of patients with non-GC septic arthritis. Only IL-1beta decreased significantly after day 7 of treatment, but IL-6 and TNF-alpha concentrations were persistently high. SF IL-1beta and TNF-alpha may be useful in predicting the outcome and complications of patients with this disease. ",0
2088,10220138,Mitochondrial deafness mutations reviewed,"The first molecular defect for nonsyndromic hearing loss was identified in 1993, and was a mitochondrial mutation. Since then a number of inherited mitochondrial DNA (mtDNA) mutations have been implicated in hearing loss, and acquired mtDNA mutations have been proposed as one of the causes of the hearing loss associated with aging, presbyacusis. These molecular findings have raised as many questions as they have answered, however, since the pathophysiology between the mutations and the clinical phenotype remains poorly understood. This mini-review will, after a short background review of mitochondrial genetics, (1) outline the different mtDNA mutations associated with inherited syndromic, nonsyndromic, and ototoxic hearing loss, (2) summarize the data on acquired mtDNA mutations and their possible association with presbyacusis, (3) describe the biochemical consequences of the inherited mtDNA mutations, (4) suggest the clinical implications of the identification of these mutations, and (5) discuss the penetrance and tissue specificity of the hearing associated mtDNA mutations. ",0
2089,10220259,An analysis of errors in blood component transfusion records with regard to quality improvement of data acquisition and to the performance of lookback and traceback procedures,"Quality assurance of blood transfusion covers institutions, personnel, and procedures involved in preparing, issuing, and using blood components. The accuracy of data related to blood component transfusions is a tool for quality control in the transfusion service. A study of the accuracy of data records of the transfusion service at the University Hospital of Erlangen, Germany, between June 1994 and May 1996 was carried out. All returned blood component transfusion report forms were examined for discrepancies between primary data records and clinical transfusion reports. Blood components (n = 49,224) from allogeneic and autologous donations, packed red cells, fresh-frozen plasma, and platelet components that had been issued for transfusion were included in this evaluation. For 27.3 percent of all components issued, no transfusion report was returned to the blood bank. For the remaining 35,786 units, errors were found in 3.8 percent of the records. For 1.24 percent of all components, discrepant information related to the recipient's identity or the component's status was found; this affected the feasibility of lookback or traceback searches. A remarkably high frequency of discrepancies exists between computerized blood bank records and the information recorded on returned blood transfusion forms. The processes of data acquisition and entry must be included in quality assurance efforts in transfusion medicine. ",0
2090,10220271,"Safety issues of plateletpheresis: comparison of the effects of two cell separators on the activation of coagulation, fibrinolysis, and neutrophils and on the formation of neutrophil-platelet aggregates","Although many donors undergo repeated plateletpheresis, data on the consequences of plateletpheresis for the donor's health remain scarce. Thus, the effect of plateletpheresis on the activation of coagulation, fibrinolysis, and neutrophils was investigated. Part 1: Sixteen healthy men were randomly assigned to undergo plateletpheresis on a cell separator (AMICUS, Fenwal Baxter; or MCS 3p, Haemonetics). The effects of plateletpheresis on plasma levels of prothrombin fragment (F(1+2)), D-dimer, plasmin-plasmin inhibitor (PPI) complexes, and plasminogen activator inhibitor (PAI-1); on the activation of neutrophils (% L-selectin+); and on the frequency of platelet-neutrophil aggregates (% CD41+ neutrophils) were compared. Part 2: Ten healthy men received infusions of ACD-A and placebo without apheresis in a randomized, double-blind crossover study to control for the pharmacologic effects of citrate. Part 1: No change in F(1+2) occurred (p>0.05), which indicated that plateletpheresis did not enhance coagulation. Levels of D-dimer, PPI, and PAI-1 decreased over time on the AMICUS (p<0.001). Plateletpheresis did not activate neutrophils (p>0.05), but it decreased the percentage of CD41+ neutrophils (p<0.003). An approximately 80-percent drop in mononuclear cells was observed in the extracorporeal circulation of the AMICUS (p<0.001 vs. baseline and p = 0.005 vs. MCS 3p), and circulating lymphocyte and monocyte counts decreased concomitantly. Part 2: Infusion of ACD-A slightly decreased D-dimer levels (p<0.05), and both infusions decreased the circulating lymphocyte counts. Plateletpheresis can be regarded as safe with respect to the activation of coagulation or neutrophils. The consequences for the donor's health of the decrease in D-dimer, PPI, and PAI-1 may deserve further investigation. ",0
2091,10220371,Genetic basis in plants for interactions with disease-suppressive bacteria,"Plant health depends, in part, on associations with disease-suppressive microflora, but little is known about the role of plant genes in establishing such associations. Identifying such genes will contribute to understanding the basis for plant health in natural communities and to new strategies to reduce dependence on pesticides in agriculture. To assess the role of the plant host in disease suppression, we used a genetic mapping population of tomato to evaluate the efficacy of the biocontrol agent Bacillus cereus against the seed pathogen Pythium torulosum. We detected significant phenotypic variation among recombinant inbred lines that comprise the mapping population for resistance to P. torulosum, disease suppression by B. cereus, and growth of B. cereus on the seed. Genetic analysis revealed that three quantitative trait loci (QTL) associated with disease suppression by B. cereus explained 38% of the phenotypic variation among the recombinant inbred lines. In two cases, QTL for disease suppression by B. cereus map to the same locations as QTL for other traits, suggesting that the host effect on biocontrol is mediated by different mechanisms. The discovery of a genetic basis in the host for interactions with a biocontrol agent suggests new opportunities to exploit natural genetic variation in host species to enhance our understanding of beneficial plant-microbe interactions and develop ecologically sound strategies for disease control in agriculture. ",0
2092,10220763,An analysis of 6 Leber mutations in 31 individuals with optic atrophy. A study of its transmission in 5 families],"Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder that represents the most frequent cause of visual loss among otherwise healthy young men. We have screened for the most important LHON mutations (primary mutations) and several other previously described mutations (secondary mutations) in 31 Spanish patients suffering from optic atrophy. These individuals fulfilled the clinical criteria for LHON. We have compared the mutation frequencies obtained with those reported in several other countries. We have also followed the segregation of the disease and its associated LHON mutations in five families. The screening has been performed by PCR followed by restriction enzyme digestions and electrophoretic separation. 67.75% of the patients did not harbour any of the studied mutations, whereas 16.13% showed one mutation and the remaining 16.13% carried two Leber mutations in their mitochondrial DNA. The three primary mutations as well as G15257A were the changes most frequently detected (30% each of them). There were no significant differences among the compared populations in terms of frequencies of the primary mutations. In contrast, our patients showed a significantly higher rate of 15257 mutation. The incidence of primary LHON mutations among the Spanish patients is not statistically different from those observed in other Caucasian populations. Transmission of the mutation to the progeny is not necessarily linked to the transmission of the disease. This fact complicates genetic counselling and makes prenatal diagnosis almost impossible for this disease. ",0
2093,10221099,Epstein-Barr virus in a donor kidney as a cause of non-Hodgkin lymphoma],"A 22-year-old male who had received a kidney transplant from his father (HLA haploidentical), presented with fever and malaise. After transplantectomy was performed because of rejection, the patient developed abdominal pain due to perforation of the small intestine. Non-Hodgkin's lymphoma was found in both the transplant and the small bowel. The patient had suffered a primary Epstein-Barr virus (EBV) infection, probably transferred through the transplanted kidney. DNA analysis showed that the lymphoma was of patient origin. After withdrawal of immunosuppressive therapy, no recurrence of the lymphoma was seen. EBV is a well-known aetiologic agent of non-Hodgkin's lymphomas arising in the immunocompromised patient. ",0
2094,10221660,"Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats","Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation. ",0
2095,10221826,p53 expression in gastric mucosa with Helicobacter pylori infection,"Expression of p53 was examined immunohistochemically in the Japanese monkey model with Helicobacter pylori infection of the gastric mucosa to investigate the association between H. pylori infection and gastric carcinogenesis for a period of 4 years. In the course of these observations, from 3 years after H. pylori inoculation, nuclear staining for p53 was seen in the glandular cells of the mucosa infected with H. pylori, especially in the neck region of the glands. There was a gradual increase in the number of immunopositive cases among the infected animals. Three years after inoculation, three out of six cases, and 4 years after inoculation, four out of six cases exhibited positive staining for p53. Before inoculation, and up to 2 years after inoculation, the infected group showed no immunoreaction for p53. The non-infected group likewise displayed no immunostaining for p53 through 4 years of observation. These results suggest that p53 alterations occur in the H. pylori-infected gastric mucosa and that H. pylori infection may play an important role in gastric carcinogenesis. ",0
2096,10222348,Single-nucleotide polymorphisms in intron 2 of CYP21P: evidence for a higher rate of mutation at CpG dinucleotides in the functional steroid 21-hydroxylase gene and application to segregation analysis in congenital adrenal hyperplasia,"Intron 2 of CYP21, the functional steroid 21-hydroxylase gene contains several single-nucleotide polymorphisms (SNPs). We tested the hypothesis that intron 2 of the pseudogene, CYP21P, might also be polymorphic and provide markers for segregation analysis of this region of the genome, including observable markers for segregation analysis of CYP21 gene deletions. A comparison of SNPs in both genes might provide insights into the rates of mutation in these duplicated genes. After amplification with PCR, we examined restriction site polymorphisms in intron 2 of CYP21P in 24 members of the parental generation of the Centre d'Etude du Polymorphisme Humain families and selected offspring. Intron 2 of CYP21P contains frequent SNPs around nucleotide 398 and nucleotide 509, which can be typed by PCR/restriction enzyme digestion with HaeIII. Of the 48 CYP21P alleles examined, 44 could be characterized unambiguously. Of these 44 alleles, 4 were deleted, and the frequencies of restriction at the polymorphic HaeIII sites were 20 of 40 at nucleotide 398 and 30 of 40 at nucleotide 509. Both polymorphisms result from C-->T transitions that occur at CpG dinucleotides. The frequencies of C at these nucleotides in CYP21P are significantly higher than at the corresponding nucleotides in CYP21 of the same individuals (P <0.01). These data suggest that these CpG dinucleotides are more frequently mutated in CYP21 than in CYP21P, and that several mutations at CpG dinucleotides in the coding regions of CYP21 might result from CpG instability rather than the more usually proposed mechanism of gene conversion. These frequent SNPs provide useful markers for studying both allelic segregation of CYP21, particularly for chromosomes with known CYP21 deletions, and for investigating the origin of these polymorphisms. ",0
2097,10222765,Advances in understanding of clinical presentations and molecular mechanisms of triplet repeat diseases],"Triplet repeat diseases are diseases caused by unstable expansion of trinucleotide repeats in the causative genes. Identification of the causative genes has made it possible to understand the clinical presentations and molecular mechanisms of neurodegeneration caused by expanded triplet repeat diseases. In the triplet repeat diseases caused by expansion of CAG trinucleotide repeats, the CAG repeats code for polyglutamine stretches. Evidences, which indicate that proteins with expanded polyglutamine stretches result in aggregate formation and induce apoptosis, are accumulating, and it is expected that development of therapeutic measures for triplet repeat diseases will become a reality in the near future. ",0
2098,10222852,Improving physical functioning in the elderly dialysis patient: relevance of physical therapy,"Compromised physical functioning is characteristic of medically complicated patients on dialysis, but many of these deficits can be addressed by rehabilitation. This article describes the benefits and limitations of a 3-month physical therapy pilot program at an inner-city hemodialysis clinic. Program results indicate the difficulties in keeping patients participating in such a program, but, for those patients who did regularly participate, on-site physical therapy consultation was valuable in assisting staff to identify exercise regimens that were consistent with individual patients' needs and addressed their functional difficulties. ",0
2099,10223773,The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron,"Ondansetron is an antiemetic agent metabolized by cytochrome P450 (CYP) enzymes. Rifampin (INN, rifampicin) is a potent inducer of CYP3A4 and some other CYP enzymes. We examined the possible effect of rifampin on the pharmacokinetics of orally and intravenously administered ondansetron. In a randomized crossover study with 4 phases and a washout of 4 weeks, 10 healthy volunteers took either 600 mg rifampin (in 2 phases) or placebo (in 2 phases) once a day for 5 days. On day 6, 8 mg ondansetron was administered either orally (after rifampin and placebo) or intravenously (after rifampin and placebo). Ondansetron concentrations in plasma were measured up to 12 hours. The mean total area under the plasma concentration-time curve [AUC(0-infinity)] of orally administered ondansetron after rifampin pretreatment was reduced by 65% compared with placebo (P < .001). Rifampin decreased the peak plasma concentration of oral ondansetron by about 50% (from 27.2+/-3.0 to 13.8+/-1.5 ng/mL [mean +/- SEM]; P < .001]) and the elimination half-life (t1/2) by 38% (P < .01). The bioavailability of oral ondansetron was reduced from 60% to 40% (P < .01) by rifampin. The clearance of intravenous ondansetron was increased 83% (from 440+/-38.4 to 805+/-44.6 mL/min [P < .001]) by rifampin. Rifampin reduced the t1/2 of intravenously administered ondansetron by 46% (P < .001) and the AUC(0-infinity) by 48% (P < .001). Rifampin considerably decreases the plasma concentrations of ondansetron after both oral and intravenous administration. The interaction is most likely the result of induction of the CYP3A4-mediated metabolism of ondansetron. Concomitant use of rifampin or other potent inducers of CYP3A4 with ondansetron may result in a reduced antiemetic effect, particularly after oral administration of ondansetron. ",0
2100,10224143,"Differential display identification of plunc, a novel gene expressed in embryonic palate, nasal epithelium, and adult lung","We have identified a novel gene transcript of approximately 1.1 kilobases in length that is expressed in the presumptive nasal epithelium of the mouse embryo. In situ hybridization analysis shows discrete regions of expression associated with the palate, nasal septum, and nasal conchae. This transcript is also expressed strongly in the trachea and bronchi of the adult lung. Screening of a mouse heart cDNA library yielded several overlapping clones to give a continuous sequence of 1113 bases, containing an open reading frame of 278 codons comprising the complete mRNA. No significant homologies with known genes were observed at the nucleotide level; limited amino acid homology with two salivary gland-specific proteins was noted. A search for functionally significant protein motifs revealed consensus sequences for N-glycosylation, protein kinase C and casein kinase phosphorylation, and a leucine zipper. Additionally, we observed a unique amino acid sequence pattern, consisting of the residues Gly-(Leu/Pro/Gln)-(Pro/Leu)-Leu-Pro-Leu, repeated four times near the amino-terminal portion of the protein with two amino acid residues separating the repeats. Based on these observations, we propose that we have identified a new gene, which we call plunc (for palate, lung, and nasal epithelium clone; GenBankTM accession number U69172). ",0
2101,10224338,"Influence of sub-minimum inhibitory concentrations of cefodizime on the phagocytosis, intracellular killing and oxidative bursts of human polymorphonuclear leukocytes","It is generally recognized that sub-minimum inhibitory concentrations (sub-MICs) of antibiotics are still capable of interfering with some bacterial virulence parameters, thus facilitating host neutrophilic defenses such as phagocytosis, killing and oxidative bursts. This study investigated the interaction of Escherichia coli with these neutrophilic functions after pretreatment with various sub-MICs of cefodizime. E. coli exposed to 1/2 to 1/8 MICs of cefodizime showed the extensive production of long and very long filaments that interfere with the precise measurement of phagocytic and killing parameters. Our analysis was consequently extended to the activity of 1/16 to 1/64 MICs. The interesting finding was that, although phagocytosis was unaffected, killing was significantly increased in one strain at 1/16 MIC and in another at 1/32 MIC while in the last strain it was unaffected. Oxidative bursts were not modified by any of the sub-MICs. The knowledge that these sub-MICs are still effective in increasing bacteria killing, correlated with the pharmacokinetic curve of a common single dose of cefodizime 1 g i.m., showed that the killing effects of sub-MICs may last for as long as 12 h after the activity of the MIC value. This integrated information extends our knowledge of the ultimate efficacy of an antibiotic and provides further information for optimizing scheduling. ",0
2102,10224603,"Basic aspects of prematurity prevention and results achieved by a suitable, simple program","""An urgent task for modern obstetrics is to reduce the number of unwanted very early prematures. Long-term impairments of these infants still occur too frequently. Ascending genital infections, particularly before 32 gestational weeks, are the most significant cause of prematurity. The best chance of preventing early prematurity is to employ a prophylactic screening program, preferably including self-pH-measurement by all pregnant patients and paying attention to all other important risk factors. The results of this """"Prenatal Care Self-Examination"""" program are encouraging. The rate of very small prematures, with a birth weight of less than 1,500 g, in all 1,120 multigravidae who have taken part in this program is clearly lower, at 1.3%, than in immediate previous pregnancies when it was 7.8%. The rate of extremely small infants of less than 1,000 g amounted to 0.9%, compared with 3.9% in previous pregnancies. Results from a prospective study recently presented confirm in a convincing way what can be achieved in an entire city. In Erfurt, with 208,000 inhabitants and about 1,500 deliveries per year, all in the one maternity department in this city, 16 practitioners taking care of the pregnant patients, i.e. nearly one half of them in Erfurt, motivated their patients to take part in our prematurity prevention program with its """"Prenatal Care Self-Examination"""", where the patients themselves measured their vaginal pH twice a week. The results are very interesting. In the group of 1,842 patients without prenatal self-examination activity, the frequency of very early prematures--i.e. less than 32 weeks gest.--was 3.3% (n = 61). In the group of 314 patients who performed prenatal self-examinations, the corresponding frequency was only 0.3% (n = 1). This is an eleven-fold, and significantly lower rate. On account of such positive results, a definitive step has been made with regard to practicability and efficiency of prevention of very early premature birth. """,0
2103,10341273,Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy,"BACKGROUND AND METHODS: Although potent antiretroviral therapy can control infection with human immunodeficiency virus type 1 (HIV-1), a long-lived reservoir of infectious virus persists in CD4+ T cells. We investigated this viral reservoir by measuring the levels of cell-associated viral DNA and messenger RNA (mRNA) that are essential for HIV-1 replication. Approximately every 6 months, we obtained samples of peripheral-blood mononuclear cells from five men with long-standing HIV-1 infection who had had undetectable levels of plasma HIV-1 RNA for 20 months or more during treatment with potent antiretroviral drugs. RESULTS: Before treatment, plasma levels of HIV-1 RNA correlated with the levels of cell-associated unintegrated HIV-1 DNA and unspliced viral mRNA. After treatment, plasma levels of HIV-1 RNA fell by more than 2.7 log to undetectable levels. The decrease in cell-associated integrated and unintegrated HIV-1 DNA and mRNA occurred in two phases. The first phase occurred during the initial 500 days of treatment and was characterized by substantial decreases in the levels of DNA and mRNA, but not to undetectable levels. The concentrations of cell-associated unintegrated viral DNA, integrated proviral DNA, and unspliced viral mRNA decreased by 1.25 to 1.46 log. The second phase occurred during the subsequent 300 days or more of treatment and was characterized by a plateau in the levels of HIV-1 DNA and unspliced mRNA. After an initial rapid decline, the ratio of unspliced to multiply spliced viral mRNA (a measure of active viral transcription) stabilized and remained greater than zero at each measurement. CONCLUSIONS: Despite treatment with potent antiretroviral drugs and the suppression of plasma HIV-1 RNA to undetectable levels for 20 months or more, HIV-1 transcription persists in peripheral-blood mononuclear cells. Unless the quasi-steady state levels of HIV DNA and mRNA eventually disappear with longer periods of therapy, these findings suggest that HIV-1 infection cannot be eradicated with current treatments.",0
2104,10347122,Formation of 4-hydroxynonenal adducts with cytochrome c oxidase in rats following short-term ethanol intake,"This study addresses the role of the lipid peroxidation product, 4-hydroxynonenal (HNE), in ethanol-related damage of cytochrome c oxidase (COX) in vivo. It utilizes an animal model with acute ethanol exposure in which HNE levels in liver mitochondria are strikingly increased. Pregnant female Sprague-Dawley rats were administered 5 doses of ethanol (4 gm/kg, po at 12-hour intervals) beginning on day 17 of gestation and were sacrificed on day 19. Controls were pair-fed and received dextrose isocaloric to ethanol. Mitochondria were isolated from maternal and fetal livers and COX activities were measured spectrophotometrically. Compared with the pair-fed controls, COX activity was decreased with exposure to ethanol by 25% in maternal rats and 43% in fetal rats (P<.05). Western Blot with an HNE-Histidine antibody showed enhanced formation of HNE adducts with COX from ethanol-exposed rats, which was more pronounced in fetal than in adult livers. The HNE adducts were mainly with subunit IV of COX. The cause and effect relationship between HNE adduct formation and COX inhibition was examined in vitro by incubating purified COX with HNE. COX inhibition was accompanied by concentration-dependent HNE adduct formation that was consistent with those found in in vivo ethanol-exposed samples. These results suggest that the ethanol-related decreases in COX activity found in liver mitochondria could be attributable to HNE adduct formation with the enzyme complex. This could be an important mechanism by which modification of proteins occur in in vivo oxidative stress.",0
2105,10347129,"""The """"early-sorting"""" endocytic compartment of rat hepatocytes is involved in the intracellular pathway of caveolin-1 (VIP-21)""","The sinusoidal plasma membrane of the hepatocyte is organized into functional and structural microdomains whose origin, maintenance, and functioning are closely related with the endocytic compartment. Three different subcellular fractions, from rat liver, containing caveolin-1, the structural protein of caveolae, were morphologically and biochemically characterized. A caveolae-enriched plasma membrane fraction (CEF), contains large membrane structures surrounding attached internal plasmalemmal vesicles; the receptor-recycling compartment (RRC), contains tubules and vesicles with similar morphology to the internal vesicles observed by electron microscopy in CEF; and finally, caveolin-1 was also detected in early-sorting endosomes (CURL, compartment of uncoupling receptors and ligands). In this study, we show that following an intravenous administration of retinol-binding protein (RBP), there was a redistribution of caveolin-1 from the plasma membrane (CEF) to intracellular endocytic compartments (RRC and early-sorting endosomes). Thus, these results indicate that, in the hepatocyte, caveolae are dynamic structures actively interacting with the endocytic compartment.",0
2106,10347131,Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy,"In a recent phase II clinical study, 13 chronic hepatitis B-infected patients treated daily with 30 mg adefovir dipivoxil for 12 weeks displayed a median 4.1-log10 decrease in plasma hepatitis B virus (HBV)-DNA levels. The decline of viral load during therapy displayed a biphasic kinetic profile that was modeled to determine the efficacy of inhibition of viral production, as well as kinetic constants for the clearance of free virus and the loss of infected cells. Viral production was suppressed with an efficacy of 0.993 +/- 0.008, indicating that only 0.7% of viral production persisted during therapy. The initial, faster phase of viral load decline reflects the clearance of HBV particles from plasma with a half-life of 1.1 +/- 0.3 days, translating to a 48% daily turnover of the free virus. The second, slower phase of viral load decline closely mirrors the rate-limiting process of infected cell loss, with a half-life of 18 +/- 7 days. The duration of therapy required to completely eliminate the virus from plasma or suppress it to levels sufficient to induce seroconversion is a function of the half-life of the free virus, the half-life of infected cells, and the efficacy of inhibition of virus production from infected cells. These quantitative analyses provide a more detailed picture of the dynamics of HBV infection and therapy, and can be used to compare the efficacy of various doses and inhibitors of HBV replication for the treatment of HBV infections.",0
2107,10352166,Use of alternative medicine by women with early-stage breast cancer,"BACKGROUND: We analyzed the use of alternative medicine by women who had received standard therapy for early-stage breast cancer diagnosed between September 1993 and September 1995. METHODS: A cohort of 480 patients with newly diagnosed early-stage breast cancer was recruited from a Massachusetts statewide cohort of women participating in a study of how women choose treatment for cancer. Alternative medical treatments, conventional therapies, and health-related quality of life were examined. RESULTS: New use of alternative medicine after surgery for breast cancer was common (reported by 28.1 percent of the women); such use was not associated with choices about standard medical therapies after we controlled for clinical and sociodemographic variables. A total of 10.6 percent of the women had used alternative medicine before they were given a diagnosis of breast cancer. Women who initiated the use of alternative medicine after surgery reported a worse quality of life than women who never used alternative medicine. Mental health scores were similar at base line among women who decided to use alternative medicine and those who did not, but three months after surgery the use of alternative medicine was independently associated with depression, fear of recurrence of cancer, lower scores for mental health and sexual satisfaction, and more physical symptoms as well as symptoms of greater intensity. All groups of women reported improving quality of life one year after surgery. CONCLUSIONS: Among women with newly diagnosed early-stage breast cancer who had been treated with standard therapies, new use of alternative medicine was a marker of greater psychosocial distress and worse quality of life.",0
2108,10361253,Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance,"Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non-professional antigen-presenting cells (APC) and deleted by activation-induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non-professional APC to up-regulate their expression of Bcl-2-related anti-apoptotic proteins, which inhibit the CD95 pro-apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation-induced up-regulation of Bcl-2-related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation. ",0
2109,10361324,Vascular surgical society of great britain and ireland: perioperative renal function following endovascular repair of abdominal aortic aneurysm with suprarenal and infrarenal stents ,"BACKGROUND: Endovascular repair (EVR) of abdominal aortic aneurysm (AAA) is feasible for selected patients. Placing an uncovered stent across the origins of the renal arteries may improve fixation and seal of the proximal end of the stent-graft. However, this has potential for problems (e.g. renal artery stenosis or microembolization). This study aimed to evaluate the short-term effect of a suprarenal stent on the function of the individual kidney. METHODS: In 30 patients undergoing EVR for AAA, renal function was assessed before and after operation by 99mTc-radiolabelled diethylenetriamine penta-acetate radionuclide renography and daily measurement of serum creatinine levels. Eleven patients had infrarenal stent-grafts using an aorta uni-iliac system (group 1); 19 patients had the device with an uncovered suprarenal stent (modified Gianturco Z stent), ten of which were aorta uni-iliac and nine bifurcated systems (group 2). Individual kidney function was expressed as the whole kidney transit time (WKTT). In addition, glomerular filtration rate (GFR) was measured from serial blood samples following renography. RESULTS: [Table: see text] CONCLUSION: No result reached statistical significance. Placing an uncovered stent over the origins of the renal arteries does not appear to impair kidney function in the short term. ",0
2110,10361567,Reviewer bias against the unconventional? A randomized double-blind study of peer review,"To test the hypothesis that there is a reviewer bias against publication of a test of an unconventional drug. Randomized, controlled, double-blind study of peer review. Convenience sample of 291 medical doctors from a wide variety of specialties drawn from a list of conference participants. Reviewers were randomly assigned to receive one of two versions of a manuscript. Version M related to an in-vitro experiment on a mainstream drug (Metoprolol). The otherwise identical version V used a highly unconventional drug (beef spleen cell extract) for the same experiment. Reviewers were asked to complete a standardised evaluation sheet including visual analogue scales (VASs) on a set of predefined quality criteria. All participants were debriefed after completion of the study. The response rate was 61%. There were no significant differences in VAS ratings between the two versions of the manuscript. Ratings covered the entire range of the VASs. In the present setting, there was no evidence for a reviewer-bias against testing an unconventional drug. The low inter-rater reliability, however, suggested inadequate validity of peer review. ",0
2111,10361697,"Regiospecific synthesis of pyrido[3,4-b]- and pyrido[4,3-b]carbazole-5,11-dione derivatives. Evaluation of their in vitro antifungal or antiprotozoological activities","Hetero Diels-Alder reactions between 2- or 3-bromocarbazolequinones 1a or 1b and azadiene 5 afford regiospecifically pyrido[3,4-b]- and pyrido[4,3-b]carbazole-3,5,11-triones 6a and 6b. The regiochemistry of the cycloadditions is controlled by the position of the bromine atom at C-2 or C-3 of the bromoquinone. The corresponding N- and O-methyl derivatives 7 and 8 are prepared. Structural assignment of the regioisomers is made by 1H-NMR nuclear Overhauser effect difference experiments performed on a diacetoxy derivative of pyrido[4,3-b]carbazole 9b. The in vitro antifungal and antiprotozoological activities of some prepared derivatives have been evaluated against Candida albicans, Candida krusei, Cryptococcus neoformans and Trichomonas vaginalis. None of the tested compounds have shown significant activity towards the yeasts or protozoa. ",0
2112,10361723,Glucose 1- and 2-oxidases from fungal strains: isolation and production of monoclonal antibodies,"Monoclonal antibodies (Mabs) against purified glucose 2-oxidase (EC 1.1.3.10) from Coriolus versicolor were raised by hybridoma technology using Sp2/0 myeloma cells as a fusion partner. Hybrid growth was observed in 42% of culture wells and 30% of these (i.e. 30 culture wells) contained anti-glucose 2-oxidase activity. Three positive wells containing hybrid cell lines were selected and cloned twice by the limiting dilution method and two hybridoma clones (E1A5 and E1A6) secreting Mabs were selected at random for purification and characterisation purposes. Both cell lines secreted Mabs of IgM class which were purified by gel filtration chromatography on a Sephacryl S-200 column with a final recovery of 80% and a purification factor of 16. The purified preparations were apparently homogeneous on native PAGE running with a M(r) of 950 kDa. Mabs were highly specific for glucose 2-oxidase as determined by Western blotting. These Mabs also crossreacted with glucose 1- and 2-oxidases from other fungal sources (Phanerochaeta chrysosporium, Penicillium amagasakiense and Aspergillus niger) as determined by Western blotting and by ELISA. Both glucose 1- and 2-oxidases from C. versicolor, P. chrysosporium, P. amagasakiense and A. niger were purified by hydrophobic interaction chromatography on Sepharose 4B-triazine dye with a recovery of enzyme activity in the range 85-92%. Purified preparations of glucose oxidases from fungal strains were apparently homogeneous on native PAGE. Glucose 2-oxidases were more hydrophobic than glucose 1-oxidases as determined by their chomatographic behaviour on Sepharose 4B-Cibacron Red G-E which could be used to study their roles in lignin biodegradation. ",0
2113,10361745,Surgical reconstruction of the external nose: personal experience],"Because of the ensuring malformations, most often vascular in nature, malignant tumors of the nasal pyramid often require partial or total exeresis of the nasal structures. These tumors are most commonly basal cell carcinoma (85-90%) and squamous cell carcinoma (7-8%). A recent epidemiological survey performed in Italy showed that, in this country, such carcinomas account for approximately 13% of all malignant cutaneous neoplasms of the head and neck region. This work presents the author's personal experience in 8 cases of partial, subtotal and total reconstruction of the nose, performed over 5 years of clinical activity. The cases include 8 patients (4 males and 4 females, age range 48-95 years, mean age 77.3 years): 7 cases of malignant cutaneous nasal tumors (5 basal cell, 1 squamous cell and 1 basal-squamous cell carcinoma) and 1 case of iatrogeneous perforation through the entire thickness of the right nasal wall, approximately 7-8 mm in diameter, the outcome of sclerotizing treatments initiated 30 years before for angioma. On the whole, including the case of iatrogeneous nasal perforation the following procedures were used: 7 frontal fascio-cutaneous flaps and 1 nasal-genienic flap associated with a median of upper lip muscle. As regards the frontal flaps, in 5 cases a variation was used where the inset base was set more medially and with dimensions different from up-and-down Converse flaps. In 2 other cases a median frontal flap was used. Except for one case of partial necrosis of the flap, healed by subsequent surgery, complications were not particularly important from the clinical point of view and occurred in the broadest exeresis, where reconstruction of the structures adjacent to the nose and the mucosa lining proved necessary. On the whole, considering the initial stages of the lesions and the often advanced age of the patients, the surgical treatment gave good results from the oncological, aesthetic and functional points of view. ",0
2114,10361812,Effect of dietary fiber on the nutritional utilization of proteins and minerals],"In the last years, many experimental studies performed in humans and in animals show the relationship between dietary fibre (DF) and lipemia. All agree that fibre supplements are recommendable as a complement during treatments with hypocholesterolemic drug. Nevertheless dietary fibre interacts with the absorption of some nutrients in the diet, and thus on one hand the consumption in adequate amounts may induce the desired effect of lipemia but on the other it may not be advisable from other viewpoints. ",0
2115,10361896,Gastrointestinal tract evaluation in patients with iron deficiency anemia,"Iron deficiency anemia is the most common form of anemia encountered in clinical practice and is an extremely common manifestation of chronic occult gastrointestinal bleeding. Current evidence suggests that a large proportion of men and postmenopausal women with iron deficiency anemia harbor significant gastrointestinal tract pathological lesions as the source of blood loss. As such, the evaluation of patients with iron deficiency anemia is generally focused on the gastrointestinal tract. Importantly, the diagnosis of iron deficiency anemia should be firmly established before an extensive evaluation is undertaken. Management strategies for patients with iron deficiency anemia are reviewed; an important general point is that clinical features (ie, symptoms) may help direct specific investigation. The role of small-intestinal investigation in patients with iron deficiency anemia is controversial and should probably be reserved for patients with iron deficiency anemia and persistent gastrointestinal symptoms or those who fail to respond to appropriate therapy. The treatment and prognosis of patients with iron deficiency anemia and the majority of gastrointestinal tract lesions are straightforward. However, patients with vascular ectasias as the source of blood loss can represent a true management challenge. ",0
2116,10361960,Moclobemide and fluoxetine for panic disorder. International Panic Disorder Study Group,"An international, multicentre, double blind parallel group study compared the tolerability and efficacy of moclobemide with the selective serotonin reuptake inhibitor (SSRI) fluoxetine for panic disorder. SSRIs have been shown effective for panic. The target dose of moclobemide was 450 mg and of fluoxetine was 20 mg. There were two consecutive studies. An eight week study of acute adverse events, tolerability and efficacy was followed by a long-term extension study to 1 year. The efficacy data showed no significant difference between moclobemide and fluoxetine. Both had acute efficacy, with 63% moclobemide and 70% fluoxetine patients (ns) panic free at 8 weeks. Both agents were well tolerated to 8 weeks, but moclobemide had fewer severe adverse events (5) than fluoxetine (9). There were no severe adverse events in the extension phase with either drug, and almost all patients completing 1 year extension treatment (moclobemide 61 patients, fluoxetine 65) were much or very much improved. These data suggest moclobemide and fluoxetine are tolerated and effective for both acute panic treatment and maintenance therapy. ",0
2117,10362190,"Prevalence, characteristics and prognostic value during long-term follow-up of nonsustained ventricular tachycardia after myocardial infarction in the thrombolytic era","The purpose of this study was to determine the prevalence, characteristics and the predictive value of nonsustained ventricular tachycardia (VT) for subsequent death and arrhythmic events after acute myocardial infarction (AMI). Nonsustained VT has been linked to an increased risk for sudden death in coronary patients. It is unknown whether this parameter can be used for selection of high-risk patients to receive an implantable defibrillator for primary prevention of sudden death in patients shortly after AMI. In 325 consecutive infarct survivors, 24-h Holter monitoring was performed 10+/-6 days after AMI. All patients underwent coronary angiography, determination of left ventricular function and assessment of heart rate variability (HRV). Mean follow-up was 30+/-22 months. There was a low prevalence (9%) of nonsustained VT shortly after AMI. Nonsustained VT together with depressed left ventricular ejection fraction (LVEF) was found in only 2.4% of patients. During follow-up, 25 patients reached one of the prospectively defined end points (primary composite end point of cardiac death, sustained VT or resuscitated ventricular fibrillation; secondary end point: arrhythmic events). Kaplan Meier event probability analyses revealed that only HRV, LVEF and status of the infarct-related artery were univariate predictors of death or arrhythmic events. The presence of nonsustained VT carried a relative risk of 2.6 for the primary study end point but was not a significant predictor if only arrhythmic events were considered. On multivariate analysis, only HRV, LVEF and the status of the infarct artery were found to be independently related to the primary study end point. There is a low prevalence of nonsustained VT shortly after AMI. Only 2% to 3% of all infarct survivors treated according to contemporary guidelines demonstrate both depressed LVEF and nonsustained VT. The predictive value of nonsustained VT for subsequent mortality and arrhythmic events is inferior to that of impaired autonomic tone, LVEF or infarct-related artery patency. Accordingly, the use of nonsustained VT to select patients for primary implantable cardioverter/defibrillator prevention trials shortly after AMI appears to be limited. ",0
2118,10362276,Biophysical shunt theory for neuropsychopathology: neuroimmunological causality for the suicide condition,"This article describes a working hypothesis of the nature of the 'suicide condition' (SC). The authors contend that the SC emerges as a specialized result of two-phase impairment in the neuroimmunological 'inherited schematic representation' (ISR) involving: (a) the formation of a 'microcellular suicide' phenomenon; and (b) the establishment of a 'macro-organismic suicide' program. Our hypothesis, unlike earlier ones, is based on scientific evidence spanning diverse clinical diagnostic areas indicating that the SC is induced by a local histoincompatibility across distinct tissue structures and/or a remodeling of one or more neurimmunological ISR designs due to biophysical ion shunt bypass and neglect, whereas a normal neuroimmunological ISR complex produces an all-embracing organismic histocompatible tissue-syntonic-to-ego-syntonic expression. The presence of abnormal 'microcellular suicide' assemblies leads to cell syntonic-to-cell dystonic transformation and initiates the first modification phase by contaminating certain neurimmunological ISR programs which in turn trigger the onset of partial ego syntonic-to-ego-dystonic conversion. This is translated by the self-conscious experience as partial self-to-alien tissue translocation. These formations accumulate at a rate, arriving at the second phase in SC establishment when they reach a magnitude resolution that surpasses the organismic suicide threshold level and increase the amount of ego-syntonic-to-ego-dystonic inclusion. This is then translated by the self-conscious experience as a 'foreseeable and inescapable death' that is based on severe self-to-alien multiorgan substitution. The latter overcomes the rules and regulations prescribed by impulse-induced inner events, regardless of outer psychosocial events, and leads to an irrevocable drive to suicide. ",0
2119,10362492,Determination of a putative phosphate-containing peptide in calreticulin,"Calreticulin is an abundant endo/sarcoplasmic reticulum (ER/SR) protein that may carry out multiple functions inside cells. Except for calreticulin, all of the major ER/SR Ca2+-binding proteins are substrates for protein kinase CK2 in vitro, which led us to hypothesize that native calreticulin might exist in the phosphorylated form. To investigate this possibility, we purified calreticulin from cardiac microsomes and verified its identity by immunoblot analysis and sequencing of tryptic peptides. Purified calreticulin, like cardiac calsequestrin, contained endogenous phosphate as determined by a Malachite green assay for phosphate. Previous analyses of cardiac calsequestrin have localized phosphate to a single tryptic peptide containing serine phosphate on sites phosphorylated by protein kinase CK2. Using a similar procedure, we analyzed calreticulin tryptic peptides with Malachite green, localizing phosphate binding to a single calreticulin peptide 367LKEEEEDKK. As this peptide contains no phosphorylatable residues, our results suggest that calreticulin may tightly bind phosphate or a phosphate-containing molecule at this site. ",0
2120,10362523,A HMG-CoA reductase inhibitor improved regression of atherosclerosis in the rabbit aorta without affecting serum lipid levels: possible relevance of up-regulation of endothelial NO synthase mRNA,"We determined the role of Fluvastatin: HMG-CoA reductase inhibitor on the regression of atherosclerosis following removal of dietary cholesterol. Male rabbits fed a 0.5% cholesterol diet for 12 weeks were divided into three groups: A1, hypercholesterolemic; A2, fed a regular diet for an 12 additional weeks; and A3, fed a regular diet with fluvastatin (2 mg/kg/day). Fluvastatin treatment (A3) did not affect serum lipid levels compared with A2. However, it decreased the atherosclerotic area in the aortic arch and decreased total and esterified cholesterol concentrations in the descending aorta. Tone-related basal NO release in the thoracic aorta was larger in A3 than in A2. eNOS mRNA in vessel was determined by competitive RT-PCR assay. It increased in A1, compared with normal aorta and decreased in A2; however, it did not decrease in A3. This is the first report of a decrease in eNOS mRNA in atherosclerosis after removal of dietary cholesterol and a reversal of it by a HMG-CoA reductase inhibitor, which may contribute to the regression of atherosclerosis. ",0
2121,10362591,Choline uptake across the ventricular membrane of neonate rat choroid plexus,"The uptake of [3H]choline from the cerebrospinal fluid (CSF) side of the rat neonatal choroid plexus was characterized in primary cultures of the choroidal epithelium grown on solid supports. Cell-to-medium concentration ratios were approximately 5 at 1 min and as high as 70 at 30 min. Apical choline uptake was facilitated; the Km was approximately 50 microM. Several organic cations (e.g., hemicholinium-3 and N1-methylnicotinamide) inhibited uptake. The reduction or removal of external Na+ or the addition of 5 mM LiCl had no effect on uptake. However, increasing external K+ concentration from 3 to 30 mM depolarized ventricular membrane potential (-70 to -15 mV) and reduced uptake to 45% of that for the control. Treatment with 1 mM ouabain or 2 mM BaCl2 reduced uptake 45%, and intracellular acidification reduced uptake to approximately 90% of that for controls. These data indicate that the uptake of choline from CSF across the ventricular membrane of the neonatal choroidal epithelium is not directly coupled to Na+ influx but is sensitive to plasma membrane electrical potential. ",0
2122,10362693,End-systolic myocardial stiffness is a load-independent index of contractility in stage 24 chick embryonic heart,"Cardiac morphogenesis and function are interrelated during cardiovascular development. We evaluated the effects of acute alteration of loading condition to chick embryonic ventricular contractility using end-systolic myocardial stiffness based on the incremental elastic modulus concept. End-systolic stress-strain relations including geometric factor and end-systolic myocardial stiffness were determined from the simultaneous measurement of ventricular pressure and chamber dimension in the following four groups of stage 24 White Leghorn chick embryos: volume infusion (n = 9), conotruncal occlusion (n = 9), calcium suffusion (n = 10), and verapamil suffusion (n = 8). The end-systolic stress-strain relationship was linear in each embryo. There was no correlation between end-systolic myocardial stiffness and end-systolic stress. End-systolic myocardial stiffness increased with calcium suffusion (P < 0.05 vs. volume infusion). The geometric factor increased after verapamil suffusion (P < 0.05). End-systolic myocardial stiffness normalized by geometric factor was not changed by alteration of preload or afterload, increased after calcium suffusion, and decreased after verapamil administration (P < 0.05). These results suggest that normalized end-systolic myocardial stiffness is a load-independent index of ventricular contractility in the developing embryonic chick ventricle. ",0
2123,10362820,"Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men","BACKGROUND: The sale of cigars in the United States has been increasing for the past six years. Cigar smoking is a known risk factor for certain cancers and for chronic obstructive pulmonary disease (COPD). However, unlike the relation between cigarette smoking and cardiovascular disease, the association between cigar smoking and cardiovascular disease has not been clearly established. METHODS: We performed a cohort study among 17,774 men 30 to 85 years of age at base line (from 1964 through 1973) who were enrolled in the Kaiser Permanente health plan and who reported that they had never smoked cigarettes and did not currently smoke a pipe. Those who smoked cigars (1546 men) and those who did not (16,228) were followed from 1971 through the end of 1995 for a first hospitalization for or death from a major cardiovascular disease or COPD, and through the end of 1996 for a diagnosis of cancer. RESULTS: In multivariate analysis, cigar smokers, as compared with nonsmokers, were at higher risk for coronary heart disease (relative risk, 1.27; 95 percent confidence interval, 1.12 to 1.45), COPD (relative risk, 1.45; 95 percent confidence interval, 1.10 to 1.91), and cancers of the upper aerodigestive tract (relative risk, 2.02; 95 percent confidence interval, 1.01 to 4.06) and lung (relative risk, 2.14; 95 percent confidence interval, 1.12 to 4.11), with evidence of dose-response effects. There appeared to be a synergistic relation between cigar smoking and alcohol consumption with respect to the risk of oropharyngeal cancers and cancers of the upper aerodigestive tract. CONCLUSIONS: Independently of other risk factors, regular cigar smoking can increase the risk of coronary heart disease, COPD, and cancers of the upper aerodigestive tract and lung.",0
2124,10362822,A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer,"""BACKGROUND: In patients with cancer, symptoms of limbic and brain-stem dysfunction may result from a paraneoplastic disorder. Paraneoplastic limbic or brain-stem encephalitis occurs more frequently with testicular cancer than with most other cancers. We sought antineuronal antibodies that might be used in a diagnostic test for this syndrome. METHODS: Immunohistochemical and immunoblotting techniques were used to detect serum and cerebrospinal fluid antibodies. Serologic screening of a complementary DNA library and Northern blotting were used to clone the target antigen and determine which tissues expressed it. RESULTS: Of 13 patients with testicular cancer and paraneoplastic limbic or brain-stem encephalitis (or both), 10 had antibodies in serum and cerebrospinal fluid against a 40-kd neuronal protein. These antibodies were used to clone a gene that we call Ma2, which codes for a protein (Ma2) that was recognized by serum from the 10 patients, but not by serum from 344 control subjects. Ma2 was selectively expressed by normal brain tissue and by the testicular tumors of the patients. Ma2 shares homology with Ma1, a """"brain-testis-cancer"""" gene related to other paraneoplastic syndromes and tumors. CONCLUSIONS: The serum of patients with subacute limbic and brain-stem dysfunction and testicular cancer contains antibodies against a protein found in normal brain and in testicular tumors. Detection of these antibodies supports the paraneoplastic origin of the neurologic disorder and could be of diagnostic importance.""",0
2125,10363171,Surgical stress induces a marked and sustained increase of adrenal androgen secretion in postmenopausal women,"We analyzed the secretion of adrenal androgens in response to surgical stress in eight (8) postmenopausal women. ACTH, cortisol (F) and adrenal androgens, such as dehydroepiandrosterone (DHEA), delta 4-androstendione (delta 4-A), dehydroepiandrosterone sulfate (DHEA-S) and testosterone (T) were measured at 08:00 and 20:00 hr the day before and for three consecutive days after operation, as well as at 0, 15, 30, 60, 120 minutes during cholocystectomy. Basal levels of ACTH, F, DHEA, delta 4-A, DHEA-S and T were found within the normal range for this age group before surgery. During surgery the ACTH was significantly increased, reaching a peak value at 30 min after surgery initiation. F, DHEA and delta 4-A were significantly increased during and after surgery, returning to pre-surgery levels by the third day post-surgery. DHEA-S levels did not increase during surgery but was found significantly increased the day after surgery, returning to presurgical levels two days later. We conclude that surgical stress can induce adrenal androgen hypersecretion during and within the early days post-surgery. Because the adrenal androgens levels are declining and respond suboptimally to exogenous corticotropin releasing hormone (CRH) or ACTH bolus injection in aging women, it is conceivable that this remarkable response of adrenal androgens to surgical stress is probably of biological significance and conceivably mediated by a CRH/ACTH-independent mechanism. ",0
2126,10363176,"A safe, effective in vivo gene therapy for melanoma using tyrosinase promoter-driven cytosine deaminase gene","This study was designed to develop a safe, effective gene therapy for disseminated melanoma. We constructed retroviral vectors containing a tyrosinase promoter-cytosine deaminase expression cassette (Tyr/CD), and demonstrated that the tyrosinase promoter conferred a selective expression of cytosine deaminase (CD) gene in B16 melanoma cells, especially when the Tyr/CD cassette inserted in 3'LTR region of a retroviral vector. In vivo gene therapy for the intraperitoneally disseminated melanoma using Tyr/CD retrovirus-producing cells and 5-fluorocytosine (5-FC) showed that retroviruses produced in situ were capable of infecting tumor xenografts and bone marrow cells in animal model, and survival rates were prolonged significantly as compared with those treated with CD2 retrovirus-producing cells and 5-FC. Importantly, the treatment-related bone marrow suppression was not observed in the former treatment, while profound bone marrow suppression was observed in the latter treatment. In vivo gene therapy using retrovirus-producing cells containing suicide gene under the control of a tissue-specific promoter and 5-FC administration is safer and more effective for the treatment of disseminated melanoma, as compared with retrovirus-producing cells containing the gene under the control of a universal promoter and 5-FC. ",0
2127,10363287,A proposal for application and scoring of the Clock Drawing Test in Alzheimer's disease],"The Clock Drawing Test (CDT) has been used in recent years as a simple neuropsychological instrument to assess cognitive deterioration associated with dementia, even though uniform operative criteria with respect to its application and scoring have not been established. To present application normatives and establish the most relevant psychometric criteria of the CDT in a sample of healthy subjects (HS) and patients with Alzheimer's disease (AD). 56 patients were selected of which 35 were female and 21 were male. The patients' mean age was 72.7 with a standard deviation of 7.64. All of whom where probable AD patients according to the NINCDS-ADRDA criteria at stage 1 CDR. The group of HS was made up of 56 control subjects (34 female, 22 male) with a mean age of 72.14 and a standard deviation of 7.2. The CDT was applied in both its command (COM) and copy (COP) experimental conditions. The main psychometric parameters analysed in the studied series showed the following values: internal consistency (Cronbach's alpha coefficient 0.9029); cut off point CT COM 6 with 92.80, sensitivity; false negatives (FN) 7.2 with a specificity rating 93.48; false positive (FP) 6.52 with 93.16 efficacy; cut off point CT COP 8 with 73.11 sensitivity; FN 26.89 with 90.58 specificity; FP 9.42 with 82.49 efficacy. The CDT can be used to discriminate between HS and those in the initial stages of AD in the given sample using the established application and scoring criteria. ",0
2128,10363292,A system of multidimensional behavior assessment. A scale for parents of children from 6 to 11 years of age. Colombian version],"Behavioral Assessment System for Children (BASC) has demonstrated to be useful in the diagnosis of Attention Deficit Disorder (ADD). A randomized sample of 120 children, 6 to 11-year-old, participants from the school of the city of Medellín, Colombia, was selected. The sample was stratified by sex and two socioeconomic status (SES). Parents were asked to answer the BASC Parent Rating Scale (PRS) 6-11, authorized Spanish version. Cronbach's alpha coefficient was 0.85 for the clinical scale (9 items). It was 0.75 for the Adaptive Scale (3 items). A scale designed with 4 items to assess ADD (hyperactivity, attention problems, aggression, and conduct problems) showed an alpha coefficient of 0.82. Male children scored significantly higher than female (ANOVA, p < 0.05) in hyperactivity, conduct problems, and atypicality. Children from low SES scored significantly higher than children of high SES on the most of clinical measures (p < 0.05) and lower on the three adaptive measures. Cluster analysis selecting six clusters found a prevalence of 61.6% for normal male children. In the total sample there were a 4% at risk of DDA type II (inattentive) and 14% at risk of DDA type I (combined). BASC PRS (6-11) showed reliability and validity to assessing the behavior in Spanish speaking Colombian children. ",0
2129,10363746,The survival and well-being of patients treated for Cushing's syndrome,"The main aim of the study was to evaluate the survival, well-being and working capacity of patients treated for Cushing's syndrome. The study was carried out by retrospectively analysing patient records from years 1981-94. Follow-up time was extended from the time of diagnosis to the end of 1996. A questionnaire dealing with symptoms prior to and after therapy, and the quality of life estimated on a Visual Analogue Scale (VAS) was sent to all surviving patients. The study was performed in a university hospital. Survival, subjective well-being, working capacity before and after treatment and disappearance of symptoms after treatment of Cushing's syndrome. During the follow-up time 10 patients died out of a total of 74. The overall standardized mortality ratio (SMR) was 168% (95% CI 81-309%). The SMR of patients with pituitary disease was 267% (89-525%), and in patients with adrenal adenoma it was 135% (16-489%). Forty-six per cent of the surviving patients stated that they felt fully recovered from the disease, but the proportion of patients having persisting symptoms after treatment was also noteworthy. The mean VAS score (range 0-100) was 19 (SD 14) before treatment and 82 (SD 18) after treatment (P<0.001). After treatment, 81% of the patients were able to return to work, 11% retired because of disability, 5% retired because of age and 3% were on sick-leave at the time of answering the questionnaire. During the follow-up time, 42% of the patients with pituitary disease suffered a relapse. However, the effect of the relapse on well-being was not significant. The mortality risk of patients treated for Cushing's disease was not significantly increased compared with that of the general population. Many symptoms persisted even years after therapy. After clinical recovery, working ability was not always regained. ",0
2130,10363802,Evaluation of gallium-68 tris(2-mercaptobenzyl)amine: a complex with brain and myocardial uptake,"Previous research into development of a gallium-radiolabeled agent that crosses the blood-brain barrier has met with limited success. In this study, we focused our attention on a Ga(III) complex of a 4-coordinate amine trithiolate tripod ligand, tris(2-mercaptobenzyl) amine (S3N). The Ga(III) S3N complex is small, neutral, and lipophilic, meeting the requirements for a potential brain imaging agent. The Ga-68 complex was easily formed with a radiochemical purity of >95%. In vitro stability of the Ga-S3N complex, determined in rat serum incubated at 37 degrees C, was greater than 95% intact at 2 h by silica gel and reversed-phase radio-thin layer chromatography. Biodistribution studies conducted in female Sprague-Dawley rats showed the complex cleared rapidly from the blood with initial high liver uptake followed by rapid washout. Significant uptake was observed in the brain, with brain:blood ratios increasing from 0.11 at 2 min postinjection to 3.8 at 60 min postinjection. Uptake was also observed in the heart going from a heart:blood ratio of 2.3 at 2 min postinjection to 11 at 60 min postinjection. Molecular mechanics were used to determine the coordination number, and demonstrated that the Ga(III) complex prefers to be 4-coordinate. Imaging studies with 68Ga-S3N in a Nemestrina macaque showed significant brain uptake, similar to other lipophilic agents. The extraction of 68Ga-S3N into the brains of both rodents and primates, higher than any 68Ga agent reported in the literature, suggests that this compound may have potential as a brain imaging agent for positron emission tomography. ",0
2131,10363814,Restoration of decaying long-term potentiation in the hippocampal formation by stimulation of neuromodulatory nuclei in freely moving rats,"Induction of long-term potentiation within the hippocampal formation can be modulated by afferent influences from a number of subcortical structures known to be involved in hippocampal-dependent learning and memory. This study performed on freely moving rats investigated the effects of stimulation of the noradrenergic locus coeruleus nucleus and the serotonergic dorsal raphe nucleus on spontaneously decaying posttetanic long-term potentiation in the dentate gyrus and the hippocampal CA1 area, respectively. High-frequency electrical stimulation of the locus coeruleus or the dorsal raphe elicited a well-expressed behavioural reaction of exploratory or defensive type, respectively, but did not significantly alter transmission at perforant path-dentate gyrus or Schaffer collateral-CA synapses, when delivered either before tetanic stimulation of the perforant path or the Schaffer collaterals or long (hours and days) after previously induced long-term potentiation had completely decayed. However, when locus coeruleus or dorsal raphe stimulation was delivered with the same parameters during a limited time (minutes and hours) after marked or even complete decay of tetanus-induced long-term potentiation at perforant path-dentate gyrus or Schaffer collateral-CA1 synapses, the potentiation was partially or entirely restored but never increased beyond the initial level of potentiation. In CA1, stimulation of ipsilateral and contralateral Schaffer collaterals demonstrated that the restoration of previously existing long-term potentiation by dorsal raphe stimulation was input-specific, occurring, like tetanus-induced potentiation, only in the pathway which had previously been tetanized. These findings suggest that the noradrenergic locus coeruleus and the serotonergic dorsal raphe can influence not only induction, but also spontaneous decay of long-term potentiation in the hippocampal formation. Since hippocampal long-term potentiation is thought to play a role in certain kinds of learning and memory, and association of tetanic stimulation with activation of ascending neuromodulatory systems is required for full expression of long-term potentiation, the restoration of hippocampal long-term potentiation by activation of a neuromodulatory system alone may serve as a mechanism of associative reminder which may underlie facilitation of memory retrieval after a period of forgetting, as has been observed in trained rats under similar conditions. ",0
2132,10363854,Economic and resource utilization analysis of outpatient management of fever and neutropenia in low-risk pediatric patients with cancer,"To measure resource allocation in outpatient management of fever and neutropenia in low-risk pediatric patients with cancer and its impact on their families. A prospective clinical trial was conducted. Eligible patients received a single dose of intravenous (IV) antibiotics and were observed for several hours in clinic. Patients were randomly assigned to continue either IV or oral antibiotics and were seen daily as outpatients. Charges were calculated based on the number of resources used and Medicare/Medicaid reimbursement schedules. A questionnaire was used to measure the impact of outpatient treatment on the family. Seventy-three episodes of fever and neutropenia were studied. The median duration of treatment was 4 days. Eighty-six percent of the episodes were managed without hospitalization. The median calculated charge was $1840. The median calculated charge for patients receiving oral antibiotics was $1544 and was significantly less than the $2039 median charge for outpatients treated with IV antibiotics. The estimated charge for comparable inpatient treatment was $4503. Nearly all families preferred outpatient care, and few reported a loss of work hours or increased child care expenses. Outpatient treatment of low-risk episodes of fever and neutropenia is substantially less costly than inpatient care and is preferred by most families. ",0
2133,10363967,Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2,"Transfection of multidrug resistance proteins (MRPs) MRP1 and MRP2 in human ovarian carcinoma 2008 cells conferred a marked level of resistance to short-term (1-4 h) exposure to the polyglutamatable antifolates methotrexate (MTX; 21-74-fold), ZD1694 (4-138-fold), and GW1843 (101-156-fold). Evidence for MRP-mediated antifolate efflux relies upon the following findings: (a) a 2-3.3-fold lower accumulation of [3H]MTX and subsequent reduced formation of long-chain polyglutamate forms of MTX; (b) reversal of MTX resistance by probenecid in both transfectants, and (c) ATP-dependent uptake of [3H]MTX in inside-out vesicles of MRP1 and MRP2 transfectants. This report provides a mechanistic basis for resistance to polyglutamatable antifolates through an MRP-mediated drug extrusion. ",0
2134,10364174,Interaction of granulocyte colony-stimulating factor (G-CSF) with its receptor. Evidence that Glu19 of G-CSF interacts with Arg288 of the receptor,"Granulocyte colony-stimulating factor (G-CSF) forms a tetrameric complex with its receptor, comprising two G-CSF and two receptor molecules. The structure of the complex is unknown, and it is unclear whether there are one or two binding sites on G-CSF and the receptor. The immunoglobulin-like domain and the cytokine receptor homologous module of the receptor are involved in G-CSF binding, and Arg288 in the cytokine receptor homologous module is particularly important. To identify residues in G-CSF that interact with Arg288, selected charged residues in G-CSF were mutated to Ala. To clarify whether there are two binding sites, a chimeric receptor was created in which the Ig domain was replaced with that of the related receptor gp130. This chimera bound G-CSF but could not transduce a signal, consistent with failure of dimerization and loss of one binding site. The G-CSF mutants had reduced mitogenic activity on cells expressing wild-type receptor. When tested with the chimeric receptor, all G-CSF mutants except one (E46A) showed reduced binding, suggesting that Glu46 is important for interaction with the Ig domain. On cells expressing R288A receptor, all the G-CSF mutants except E19A showed reduced mitogenic activity, indicating that Glu19 of G-CSF interacts with Arg288 of the receptor. ",0
2135,10364209,Phosphorylation of the myosin-II light chain does not regulate the timing of cytokinesis in fission yeast,"Proper coordination of cytokinesis with chromosome separation during mitosis is crucial to ensure that each daughter cell inherits an equivalent set of chromosomes. It has been proposed that one mechanism by which this is achieved is through temporally regulated myosin regulatory light chain (RLC) phosphorylation (Satterwhite, L. L., and Pollard, T. D. (1992) Curr. Opin. Cell Biol. 4, 43-52). A variety of evidence is consistent with this model. A direct test of the importance of RLC phosphorylation in vivo has been done only in Dictyostelium and Drosophila; phosphorylation of the RLC is essential in Drosophila (Jordan, P., and Karess, R. (1997) J. Cell Biol. 139, 1805-1819) but not essential in Dictyostelium (Ostrow, B. D., Chen, P., and Chisholm, R. L. (1994) J. Cell Biol. 127, 1945-1955). The Schizosaccharomyces pombe myosin light chain Cdc4p is essential for cytokinesis, but it was unknown whether phosphorylation played a role in its regulation. Here we show that the S. pombe myosin light chain Cdc4p is phosphorylated in vivo on either serine 2 or 6 but not both. Mutation of either or both of these sites to alanine did not effect the ability of Cdc4p to bind the type II myosin Myo2p, and cells expressing only these mutated versions of Cdc4p grew and divided normally. Similarly, mutation of Ser-2, Ser-6, or both residues to aspartic acid did not affect growth or division of cells. Thus we conclude that phosphorylation of Cdc4p is not essential in vivo for the function of the protein. ",0
2136,10364261,Effects of mutations of a phosphorylation site in an exposed loop in acidic fibroblast growth factor,"Acidic fibroblast growth factor (aFGF) contains a phosphorylation site recognized by protein kinase C. A non-mitogenic mutant growth factor is devoid of this phosphorylation site. We have changed amino acids in and close to the phosphorylation site and studied the consequences of this for binding of the growth factor to high affinity receptors as well as to heparin. We have also studied the ability of the mutants to stimulate DNA synthesis and cell proliferation as well as phosphorylation of mitogen-activated protein kinase and the ability of the growth factor mutants to be transported to the nucleus. The results indicate that while the mutations strongly affect the ability of the growth factor to bind to heparin, they do not affect much the binding to the specific FGF receptors, activation of mitogen-activated protein kinase or transport of the growth factor to the nucleus. The mutations affect to various extents the ability of the growth factor to stimulate DNA synthesis and to induce cell multiplication. We find that phosphorylation of aFGF is not required for mitogenic activity. The data suggest that altered interaction of the growth factor with a cellular component different from the receptor, possibly a component in the nucleus, is the reason for the different mitogenicity of the different growth factor mutants. ",0
2137,10364294,Use of major histocompatibility complex class I/peptide/beta2M tetramers to quantitate CD8(+) cytotoxic T lymphocytes specific for dominant and nondominant viral epitopes in simian-human immunodeficiency virus-infected rhesus monkeys,"To evaluate the impact of the diversity of antigen recognition by T lymphocytes on disease pathogenesis, we must be able to identify and analyze simultaneously cytotoxic T-lymphocyte (CTL) responses specific for multiple viral epitopes. Many of the studies of the role of CD8(+) CTLs in AIDS pathogenesis have been done with simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies have frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M presented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present study we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes: the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodeficiency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The frequency of CD8(+) CTLs specific for the p11C,C-M, p68A, and p41A epitopes was quantitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/beta2m complexes. All SHIV-infected Mamu-A*01(+) rhesus monkeys tested had a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In contrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac Pol p68A and HIV-1 Env p41A epitopes, and these responses were detected at very low frequencies. Thus, the p11C,C-M-specific CD8(+) CTL response is dominant and the p41A- and p68A-specific CD8(+) CTL responses are nondominant. These results indicate that CD8(+) CTL responses to dominant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8(+) CTL responses to nondominant epitopes, due to the low frequency of these epitope-specific cells, may be difficult to detect and quantitate by this approach. ",0
2138,10364656,Bacterial colonization of ureteral stents,"The aim of this study was to assess the frequency of bacterial stent colonization and stent-associated bacteriuria, and to evaluate the significance of urinary cultures for identification of colonizing microorganisms. A total of 93 ureteral stents from 71 patients were examined: 9 patients with permanent ureteral stenting due to malignant ureteral obstruction (27 stents), and 62 patients with temporary ureteral stents (66 stents). Bacteriuria and bacterial stent colonization were found in all patients with permanent stents. In patients with temporary stents, colonized stents were found in 69.3% (43/62), mainly in combination with sterile urine (45.2%, 28/62). Mean indwelling times did not differ between patients with sterile urine and sterile stents (11.8 days) and patients with sterile urine and colonized stents (11.2 days). Prophylactic antibiosis in 42/62 temporarily stented patients did not reduce colonization rates compared to patients without antibiotics (70 vs. 65%). Enterococci were the bacteria most frequently cultured from urine and stents. In the present study, ureteral stent colonization rates were 100% in permanently and 69.3% in temporarily stented patients. Antibiotic prophylaxis did not prevent stent colonization and should not be routinely administered. Since urinary cultures correctly identified all colonizing microorganisms in only 21%, removal/replacement and bacteriologic evaluation of ureteral stents may be necessary in case of urosepsis. ",0
2139,10364674,Screening for mutations in the promoter and the coding region of the IGFBP1 and IGFBP3 genes in Silver-Russell syndrome patients,"In the present study we sought to identify genetic variation in genes for insulin-like growth factor binding proteins 1 and 3 (IGFBP1, IGFBP3) in 7p12-13 which through alteration of protein function or level of expression might contribute to the manifestation of Silver-Russell syndrome. Genomic DNA samples from 49 Silver-Russell syndrome (SRS) patients and from unaffected controls were investigated by single-strand conformation analysis. Overlapping polymerase chain reaction fragments covered the whole coding sequences as well as the 5' untranslated region of the IGFBP1 and IGFBP3 genes. We detected 3 new polymorphisms in the transcribed sequence of IGFBP1, one amino acid polymorphism in exon 1 of IGFBP3 and four variants in its promotor region and in intron 1. They all occurred in similar frequencies in SRS patients and in controls. Thus, paternally inherited mutations in the promoter and coding regions of IGFBP1 and IGFBP3 genes play neither a major nor a minor role in the etiology of SRS. The newly detected polymorphisms in the coding region are powerful tools for analysis of imprinting status and for detection of possible changes in the imprinting patterns of the two genes. ",0
2140,10364763,Adrenal hemorrhage diagnosed by ultrasonically-guided biopsy,"Adrenal hemorrhage in adults is an uncommon disease and is usually associated with systemic diseases, trauma or anticoagulation. When adrenal hemorrhage is discovered in chronic course without any suggestive clinical settings, it is difficult to distinguish adrenal hemorrhage correctly before surgical resection. We present a case of adrenal hemorrhage which was incidentally detected as an adrenal mass and was successfully treated in a conservative way based upon histopathological findings obtained by ultrasonically guided biopsy. ",0
2141,10364810,The role of inflammation in the pathogenesis and prognosis of unstable angina],"Unstable angina is a clinical syndrome which results from the unstabilization of the coronary atherosclerothic plaque, leading to its ulceration or rupture and to the formation of superimposed thrombus. The mechanism underlying plaque unstabilization is a subject of intense basic research. In the last few years, new knowledge has emerged that relates inflammation in the atherosclerothic lesion with its gradual growth and development, as well as with its sudden transformation into a complicated plaque causing unstable angina or myocardial infarction. In this article we will review the evidence that links inflammation with the pathogenesis of unstable angina and its prognosis. ",0
2142,10364814,Differences in the clinical presentation and prognosis of unstable angina and non-Q wave infarction],"At present it is generally accepted that unstable angina and non-Q-wave myocardial infarction have a common underlying pathophysiology, however, clinical presentation and outcome of these syndromes depend on the location, grade and duration of myocardial ischemia. The most important difference between both syndromes is the myocardial necrosis from non-Q myocardial infarction, which may carry a higher risk death and reinfarction rate and for that reason a worse prognosis than unstable angina. Some studies suggest that the effect of antithrombotic treatment can be different in both syndromes. Nevertheless the differences do not achieve significance in most of these studies. ",0
2143,10365189,Predictors of change in frequency of crack cocaine use in a street-recruited sample,"Crack cocaine users are at high risk for HIV, with higher frequency crack users engaging in higher rates of HIV-related sexual risk behaviors. This study will assess the variables impacting changes in crack use frequency. Out-of-treatment crack users were street recruited in East Harlem, NY. Subjects (n = 727) were 33% female, 91% minority, and 28% reported recent drug injecting. Baseline and 6-month follow-up interviews were administered. There was a significant reduction in crack use over time (p < .0001). Subjects were categorized according to five groups, based on their change in level of crack use between the two interviews, to predict those who stopped, maintained, or changed their level of use. Discriminant analyses identified six variables as the best predictors of the five groups, including having been in drug treatment since baseline and having been a drug injector (both related to reduced levels of crack use). The overall reduction in crack use for the sample masked the fact that important subgroups remained at high use levels or increased their use. The identification of subgroups who may be most resistant to reducing drug use can be helpful in developing more effective interventions. ",0
2144,10365223,"The utility of rapid qualitative determination of troponin T, the MB fraction of creatine phosphokinase and myoglobin in acute ischemic coronary syndromes]","The objective of our study was to validate the diagnostic utility of cardiac troponine T in acute ischemic syndromes, and also in cases of difficult diagnosis. We analyzed its concordance and compare them with conventional enzymatic quantitative methods. We determined sensitivity, specificity, positive and negative predictive values and likelihood ratio. Kappa index was used to know the concordance grade between T troponin and the positive or negative results of the quantitative enzymatic curve. Stochastic significance was valued by Chi square of Mcnemar test. In seventy patients who arrived to the hospital with chest pain who were assigned to five different groups. The sensitivity in quantitative markers was higher than qualitative methods, however the specificity, likelihood ratio was lower. In the total group the concordance analysis between qualitative and quantitative markers was adequate, (kappa index 0.65 p < 0.05). This study suggest that the rapid bedside qualitative test by cardiac Troponin T is a good diagnostic marker compared with conventional quantitative markers to evaluate chest pain in acute ischemic syndromes. ",0
2145,10365312,Independent and combined effects of L-arginine and diazepam on ammonium chloride-induced convulsions in rats,"The independent and combined effects of L-arginine (840 mg/kg) and diazepam (0.75 mg/kg) pretreatment (30 min) were tested on ammonium chloride (400 mg/kg)-induced convulsions in rats. Ammonia concentrations were determined in blood and brain regions (cerebral cortex, brain stem and cerebellum) 30 min after L-arginine or diazepam treatment. Ammonia concentrations were measured at the time of induction of convulsions by ammonium chloride in L-arginine, diazepam or saline pretreated animals. L-arginine and not diazepam decreased ammonia concentrations in control as well as in ammonium chloride-treated animals. However, both the compounds suppressed convulsions elicited by ammonium chloride. Protection produced concurrently by these agents was much greater than that produced by them independently. It is concluded that convulsions caused by hyperammonemic condition can be suppressed either by preventing a rise in brain ammonia to toxic level or by anticonvulsant agents having a GABA potentiating action. A much greater protection can be achieved if agents having these properties are administered concurrently. ",0
2146,10365721,Effect of pharmaceutical services on adherence to criteria-for-use guidelines in the operating room,"Guidelines for the use of neuromuscular blocking agents (NMBAs) and sedatives during two- to four-hour surgical procedures were developed, and the effect of pharmacy presence on adherence to the guidelines was determined. Differences in cost per dose of the NMBAs pancuronium bromide, cisatracurium besylate, and vecuronium bromide were determined. Pancuronium was designated as the first-line agent in the NMBA guidelines, cisatracurium as the second-line agent, and vecuronium as the third-line agent. In the sedative guidelines, lorazepam was the first-line agent, midazolam was the second-line agent, and propofol was the third-line agent. Pharmacy presence in the operating room was provided during January 1997. The pharmacist made a preliminary decision about the most appropriate agent and encouraged guideline adherence. Cost and adherence data were compared with data for November 1996 and March 1997. During January, the NMBA guidelines were followed 75% of the time and the sedative guidelines were followed 15% of the time; the corresponding rates for March were 40% and 12%. Compared with November 1996, a saving of $5.61 per case was observed in January in the NMBA category and a saving of $2.77 was observed in March; between January and March, there was an increase of $2.84 per case. Pharmacy presence in the OR was associated with better adherence to criteria-for-use guidelines for NMBAs and sedatives; NMBA cost savings associated with implementation of the guidelines were higher when a pharmacist was present. ",0
2147,10365904,"The relationship between in vivo emptying of the gallbladder, biliary pain, and in vitro contractility of the gallbladder in patients with gallstones: is biliary colic muscular in origin?","This study sought to determine whether there is a positive correlation between gallbladder emptying, biliary pain, and in vitro contractility. Ultrasound measurements were carried out on 25 gallstone patients. The response of gallbladder strips to 1.75*10(-11) to 5.25*10(-7) M cholecystokinin-8 was recorded. In a second study 23 patients filled in pain questionnaires, and in vitro studies were again carried out. Of five patients with no gallbladder emptying, four had in vitro contraction. Overall, a significant, positive linear correlation was found (P < 0.0001). In the second study in vitro contractility showed a positive linear correlation with pain. Gallbladder emptying correlates with contractility. However, since most 'non-contractors' can contract, we suggest the term 'non-emptying' or 'emptying' to describe gallbladder dynamics. The positive correlation between pain and contractility suggests that biliary pain has a muscular component. ",0
2148,10365982,"Essential fatty acids as determinants of lipid requirements in infants, children and adults","Essential fatty acids (EFA) are the indispensable component of the lipid supply beyond the provision of energy as a fuel for oxidation. They serve as dietary precursors for the formation of prostanoids and other eicosanoids thus are of great significance in health and modulation of disease conditions. Eicosanoids are powerful autocrine and paracrine regulators of cell and tissue functions: thrombocyte aggregation, inflammatory reactions and leukocyte functions, vasoconstriction and vasodilatation, blood pressure, bronchial constriction, and uterine contraction. Recent attention has focused on the effect of n-3 and n-6 long chain EFAs in normal fetal development. Results from human infant studies suggest that n-3 fatty acids are needed for optimal development of visual and brain function. Human milk is the best and only time proven source of fat and dietary essential fatty acids for infant feeding. International recommendations for n-3 and n-6 EFA dietary intake are reviewed and suggested intakes for long chain EFAs are provided. ",0
2149,10366179,Assessment and control for confounding by indication in observational studies,"""In the evaluation of pharmacologic therapies, the controlled clinical trial is the preferred design. When clinical trial results are not available, the alternative designs are observational epidemiologic studies. A traditional concern about the validity of findings from epidemiologic studies is the possibility of bias from uncontrolled confounding. In studies of pharmacologic therapies, confounding by indication may arise when a drug treatment serves as a marker for a clinical characteristic or medical condition that triggers the use of the treatment and that, at the same time, increases the risk of the outcome under study. Confounding by indication is not conceptually different from confounding by other factors, and the approaches to detect and control for confounding--matching, stratification, restriction, and multivariate adjustment--are the same. Even after adjustment for known risk factors, residual confounding may occur because of measurement error or unmeasured or unknown risk factors. Although residual confounding is difficult to exclude in observational studies, there are limits to what this """"unknown"""" confounding can explain. The degree of confounding depends on the prevalence of the putative confounding factor, the level of its association with the disease, and the level of its association with the exposure. For example, a confounding factor with a prevalence of 20% would have to increase the relative odds of both outcome and exposure by factors of 4 to 5 before the relative risk of 1.57 would be reduced to 1.00. Observational studies have provided important scientific evidence about the risks associated with several risk factors, including drug therapies, and they are often the only option for assessing safety. Understanding the methods to detect and control for confounding makes it possible to assess the plausibility of claims that confounding is an alternative explanation for the findings of particular studies. """,0
2150,10366461,Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro,"Ovarian cancer cells frequently metastasize by implanting onto the peritoneal mesothelial surface of the abdominal cavity. Although the CD44 molecule expressed by ovarian cancer cells is known to partly mediate this process, the role of other adhesion proteins such as beta1-integrins has been previously difficult to demonstrate using the 4B4 anti-beta1 neutralizing antibody. In view of the widespread expression of beta1-integrins in ovarian cancer, however, we have further examined the potential role of this class of molecules in ovarian cancer cell implantation through the use of an alternative anti-beta1 neutralizing antibody, MAB13. We now report that MAB13 is capable of inhibiting the binding of three separate human ovarian cancer cell lines (36M2, CAOV-3, SKOV-3) to mesothelium (mean 37 +/- 4% inhibition, n = 21, P < 0.001). An additive inhibitory effect was observed when MAB13 was combined with anti-CD44 antibody (clone 515) (mean 63 +/- 3% inhibition, n = 19, P < 0.001), suggesting that binding occurs through two independent pathways involving both beta1-integrins and CD44. Because fibronectin is an extracellular matrix ligand recognized by many types of integrins and is abundantly expressed on mesothelial cells, the inhibitory effects of MAB13 and 4B4 on ovarian cancer cell binding to fibronectin were directly compared. MAB13 inhibited ovarian cancer cell binding to fibronectin to a significantly greater degree than did 4B4, suggesting that the discordant effects of these two antibodies on mesothelial adhesion may be partly related to their differential ability to neutralizing fibronectin-mediated binding. Studies using anti-alpha5 neutralizing antibody demonstrated that the alpha5beta1 fibronectin receptor contributes to approximately 50% of integrin-mediated binding of 36M2 and CAOV-3 cells (which express the alpha5 chain in 54 and 58% of cells, respectively). Since the RGD sequence of fibronectin is a known recognition site for many types of integrins, including alpha5beta1 and alphanubeta3, we performed binding in the continued presence of both anti-alpha5 and RGD peptide in order to exclude other types of fibronectin-integrin interactions. The addition of RGD peptides at concentrations known to be capable of blocking fibronectin binding resulted in no additional inhibitory effect over that observed with anti-alpha5 antibody alone, suggesting that alpha5beta1 was the major receptor responsible for fibronectin-mediated ovarian cancer binding to mesothelium. These data demonstrate that ovarian cancer cell binding to peritoneal mesothelium is mediated by several adhesion pathways and that simultaneous inhibition of both beta1-integrin and CD44 function may be necessary in order to significantly limit the intraabdominal spread of this tumor in vivo. ",0
2151,10366610,Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation,"Hyperkalaemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia are three autosomal dominant skeletal muscle disorders linked to the SCN4A gene encoding the alpha-subunit of the human voltage-sensitive sodium channel. To date, approximately 20 point mutations causing these disorders have been described. We have identified a new point mutation, in the SCN4A gene, in a family with a hyperkalaemic periodic paralysis phenotype. This mutation predicts an isoleucine-to-phenylalanine substitution at position 1495 located in the transmembrane segment S5 in the fourth homologous domain of the human alpha-subunit sodium channel. Introduction of the I1495F mutation into the wild-type channels disrupted the macroscopic current inactivation decay and shifted both steady-state activation and inactivation to the hyperpolarizing direction. The recovery from fast inactivation was slowed, and there was no effect on channel deactivation. Additionally, a significant enhancement of slow inactivation was observed in the I1495F mutation. In contrast, the T704M mutation, a hyperkalaemic periodic paralysis mutation located in the cytoplasmic interface of the S5 segment of the second domain, also shifted activation in the hyperpolarizing direction but had little effect on fast inactivation and dramatically impaired slow inactivation. These results, showing that the I1495F and T704M hyperkalaemic periodic paralysis mutations both have profound effects on channel activation and fast-slow inactivation, suggest that the S5 segment maybe in a location where fast and slow inactivation converge. ",0
2152,10366616,The supporting-cell antigen: a receptor-like protein tyrosine phosphatase expressed in the sensory epithelia of the avian inner ear,"After noise- or drug-induced hair-cell loss, the sensory epithelia of the avian inner ear can regenerate new hair cells. Few molecular markers are available for the supporting-cell precursors of the hair cells that regenerate, and little is known about the signaling mechanisms underlying this regenerative response. Hybridoma methodology was used to obtain a monoclonal antibody (mAb) that stains the apical surface of supporting cells in the sensory epithelia of the inner ear. The mAb recognizes the supporting-cell antigen (SCA), a protein that is also found on the apical surfaces of retinal Müller cells, renal tubule cells, and intestinal brush border cells. Expression screening and molecular cloning reveal that the SCA is a novel receptor-like protein tyrosine phosphatase (RPTP), sharing similarity with human density-enhanced phosphatase, an RPTP thought to have a role in the density-dependent arrest of cell growth. In response to hair-cell damage induced by noise in vivo or hair-cell loss caused by ototoxic drug treatment in vitro, some supporting cells show a dramatic decrease in SCA expression levels on their apical surface. This decrease occurs before supporting cells are known to first enter S-phase after trauma, indicating that it may be a primary rather than a secondary response to injury. These results indicate that the SCA is a signaling molecule that may influence the potential of nonsensory supporting cells to either proliferate or differentiate into hair cells. ",0
2153,10366681,Effects of cyanide and hypoxia on membrane currents in neurones acutely dissociated from the rostral ventrolateral medulla of the rat,"Previous reports suggested that some neurones located in the rostral ventrolateral medulla (RVL) can act as fast oxygen sensors which enhance the sympathetic activity and blood pressure independent of peripheral chemoreceptors. The aim of this study was to compare hypoxic responses of different subpopulations of RVL neurones to ascertain whether the hypoxic sensitivity is restricted to one group of these neurones. Whole-cell patch-clamp recordings were made from acutely dissociated neurones obtained from RVL of P13-P19 rats. Short-lasting hypoxia (1-2 min) was evoked by pressure injection of NaCN or lowering pO2. Cells projecting to the upper thoracic segments were retrogradely labelled with fluorescent beads. Catecholaminergic (CA) or non-catecholaminergic (non-CA) neurones were identified using single-cell reverse-transcription polymerase chain reaction (RT-PCR) or immunocytochemistry. Recordings were made from 38 neurones (26 spinally-projecting, 12 non-spinal) using Cs+/TEA or K+-containing pipettes. In most of the cells tested with slow depolarising ramp commands (78%; including spinally-projecting and non-spinal neurones, as well as CA and non-CA neurones), NaCN or hypoxia evoked a reversible increase of the sustained inward current. Extracellular application of 1 mM Co2+ or 25 nM TTX revealed three components of the hypoxia-sensitive inward current which resembled the persistent sodium (INaP), low threshold calcium (LVA Ca2+) and high threshold calcium (HVA Ca2+) currents. The NaCN or hypoxia induced increase of the current could also be observed during step commands. Recordings with K+-containing pipettes during similar depolarising ramps revealed, in addition, a reversible increase of IK in 78% of tested cells (in all four types of examined neurones). These results are consistent with the concepts that RVL neurones can act as a central oxygen sensor. However, in contrast to the previously published data demonstrating that in pentobarbital anaesthetised rats only the barosensitive and spinally projecting cells were affected by a short-lasting hypoxia, our findings obtained with dissociated RVL neurones indicate that sensitivity to hypoxia is widely distributed within this part of the medulla oblongata. ",0
2154,10366730,The affinity and kinetics of inhibition of cysteine proteinases by intact recombinant bovine cystatin C,"Recent studies have shown that the bovine cysteine proteinase inhibitor, cystatin C, is synthesized as a preprotein containing a 118-residue mature protein. However, the forms of the inhibitor isolated previously from bovine tissues had shorter N-terminal regions than expected from these results, and also lower affinity for proteinases than human cystatin C. In this work, we report the properties of recombinant, full-length bovine cystatin C having a complete N-terminal region. The general characteristics of this form of the inhibitor, as reflected by the isoelectric point, the far-ultraviolet circular dichroism spectrum, the thermal stability and the changes of tryptophan fluorescence on interaction with papain, resembled those of human cystatin C. The affinity and kinetics of inhibition of papain and cathepsins B, H and L by the bovine inhibitor were also comparable with those of the human inhibitor, although certain differences were apparent. Notably, the affinity of bovine cystatin C for cathepsin H was somewhat weaker than that of human cystatin C, and bovine cystatin C bound to cathepsin L with about a four-fold higher association rate constant than the human inhibitor. This rate constant is comparable with the highest values reported previously for cystatin-cysteine proteinase reactions. The full-length, recombinant bovine cystatin C bound appreciably more tightly to proteinases than the shorter form characterized previously. Digestion of the recombinant inhibitor with neutrophil elastase resulted in forms with truncated N-terminal regions and appreciably decreased affinity for papain, consistent with the forms of bovine cystatin C isolated previously having arisen by proteolytic cleavage of a mature, full-length inhibitor. ",0
2155,10366790,Recurrent mutations in the iron regulatory element of L-ferritin in hereditary hyperferritinemia-cataract syndrome,"Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder characterized by bilateral cataracts and increased serum and tissue L-ferritin, in the absence of iron overload. The deregulation of ferritin production is caused by heterogeneous mutations in the iron regulatory element (IRE) of L-ferritin that interfere with the binding of iron regulatory proteins. We have identified several patients from three unrelated Italian families with HHCS. Iron parameters were assessed by standard methods. The IRE element of L-ferritin was amplified by PCR using appropriate primers and directly sequenced. Ferritin levels ranged from 918 microg/L to 2490 microg/L in the patients studied. In one family bilateral cataracts were diagnosed early in life, whereas in the others cataracts were diagnosed around 40-50 years. The female proband of family 3 presented with a severe iron deficiency anemia, which was unrecognized because of the increased ferritin values. Sequencing of the IRE element of L-ferritin in the probands of the three families identified three different nucleotide substitutions (+32 GAE A, +40 AAE G and +39 CT) in the IRE of L-ferritin. These mutations have already been reported in unrelated subjects of different ethnic origins. Our findings are consistent with recurrent mutations associated with HHCS and underline the importance of this syndrome in the differential diagnosis of unexplained hyperferritinemia. In addition, the findings highlight the role played by transferrin saturation in the diagnosis of iron deficiency in these patients. ",0
2156,10366792,An Italian national multicenter study for the definition of reference ranges for normal values of peripheral blood lymphocyte subsets in healthy adults,"Reference ranges are necessary in clinical chemistry and hematology to compare an observed value and to provide meaningful information. The aim of this multicenter study was the definition of reference ranges of the relative and absolute numbers of lymphocyte subsets by evaluating a large cohort of healthy adults and by using a standard protocol to reduce the variability in both sample preparation methodology and flow cytometer operation. Other aims of this study were the evaluation of the influence of sex, age, obesity, smoking, sport and some methodological variables on lymphocyte subsets and the comparison of differential white blood cell values obtained by flow cytometry and those obtained by hematology counters. Blood samples from 1311 healthy adults (blood donors and volunteers chosen according to the Italian law for donor selection) were analyzed to study, by flow cytometry, the immunophenotype of lymphocyte subsets and their distribution in terms of percentages and absolute values. Pre-analytical and analytical phases were performed according to the guidelines of the International Federation of Clinical Chemistry (IFCC) and the Italian Group of Cytometry (GIC). T cells were defined by the expression of CD3; T subpopulations by the coexpression of CD4 or CD8 or HLA-DR; B-lymphocytes were identified by the expression of CD19 while natural killer lymphocytes were identified by positivity of CD16 and/or CD56 without CD3. We calculated, for each laboratory and for all data collected, the frequency distribution percent values and absolute values of each lymphocyte subset. The influence of age, sex, smoking, obesity and sport was calculated by the t-test. The influence of some methodological variables was calculated by the t-test and multiple regression test. Fifty-three flow cytometry laboratories at different institutions in Italy participated in this study. Data was obtained from 1311 healthy adults aged from 18 to 70; 968 phenotype analyses (74%) were considered eligible for statistical analysis. Significant results were found as regards sex, smoking and some methodological variables (quantity of sample, washing procedures, brand of monoclonal antibodies and kind of instruments used). The comparison between hematology counters and cytometers showed no difference for any of the parameters considered. The large number of cases, the different kinds of laboratories and their distribution throughout the country make our sample representative of the Italian adult population. The standardization criteria of pre-analytical and analytical phases (the most important issues in evaluating reference values for an indicator) assured good reproducibility among laboratories so that the obtained reference ranges may be useful for interlaboratory comparison of results. Instruments and the brand of monoclonal antibodies may represent an inevitable cause of variability. ",0
2157,10367010,Breakfast and mental health,"The objective of the present investigation was to study the relationship between breakfast consumption and subjective reports of mental health and health-related behaviours in a general population sample (126 subjects aged between 20 and 79 years). Individuals who consumed a cereal breakfast each day were less depressed, less emotionally distressed and had lower levels of perceived stress than those who did not eat breakfast each day. Those who consumed breakfast had a healthier lifestyle than the others in that they were less likely to be smokers, drank less alcohol and had a healthier diet. However, the relationship between cereal breakfast consumption and mental health did not reflect these differences in the smoking, alcohol consumption and diet. In conclusion, there is an association between breakfast consumption and well-being which cannot entirely be accounted for by differences in other aspects of diet or smoking and alcohol consumption. Further intervention studies are now needed to establish whether causal relationships and mechanisms underlie the associations seen in this study. ",0
2158,10367448,Quantification of the morphological features of a full microvascular network,"Investigations into the changes that occur in microvasculature following the surgical procedure called delay have brought about the need for a computer system capable of quantifying the morphological features of a full microvascular network in terms of average vessel length, diameter, and tortuosity. Both the formulaic conventions that have been developed to measure these quantities as well as their implementation in the form of a HP-9000/UNIX based computer software system that we developed specifically for this purpose are discussed. Reliability studies performed using the final system to measure the microcirculatory network of a mouse latissmus dorsi muscle (LDM) showed 95% confidence intervals within 5% of means and coefficients of variability within 7% of means for all quantities measured in large (150-300 microns), medium (50-150 microns), and small (< 50 microns) diameter vessels. These variations were significantly smaller than the changes that were observed in a preliminary study comparing these microvascular network parameters before and after delay in the hairless mouse LDM, showing the proposed quantification methods to be well suited to the study of the microvascular changes following delay. It is hoped that the formulaic conventions, implementation process and reliability data will provide a useful comparison for other researchers interested in measuring similar features of microcirculatory networks. ",0
2159,10367978,Health status of a population of infants born before 26 weeks gestation derived from routine data collected between 21 and 27 months post-delivery,"This retrospective study was designed: (a) to determine the extent to which routine data sources in the UK can provide data relating to the later health status of selected groups of infants; and (b) to use such an approach to describe the outcome of a geographically defined population of infants born before 26 weeks gestation. All infants of less than 26 weeks gestation admitted for neonatal intensive care during the period 1/1/91 and 31/12/93 whose mother's address at the time of birth was within the boundaries of the Trent Health Region were included. Health status was assessed against a previously described simple scheme and using information from existing sources only. During the 3-year period 249 infants of less than 26 weeks gestation were admitted for intensive care. Of these 66 (26.5%) survived to be discharged from the neonatal service. A further seven infants died before the age of 2 years. Of the remaining 59 four were lost to follow up (three could not be traced; one was living abroad). Of the 55 infants reviewed, 36 demonstrated no features, pre-defined in the classification scheme, of severe disability. However, only 30 children appeared to be considered entirely normal. Infants born before 26 weeks gestation and admitted for neonatal intensive care had, approximately, a 12% chance of normal survival to 2 years. A slightly smaller proportion of infants survived with significant disability. Existing routine data sources could be adapted to provide useful public health information about the outcome of 'high risk' groups of infants. ",0
2160,10368351,Detection of changes in lung tissue properties with multiple-indicator dilution,"We evaluated the potential utility of a group of indicators, each of which targets a particular tissue property, as indicators in the multiple-indicator dilution method to detect and to identify abnormalities in lung tissue properties resulting from lung injury models. We measured the pulmonary venous outflow concentration vs. time curves of [14C]diazepam, 3HOH, [14C]phenylethylamine, and a vascular reference indicator following their bolus injection into the pulmonary artery of isolated perfused rabbit lungs under different experimental conditions, resulting in changes in the lung tissue composition. The conditions included granulomatous inflammation, induced by the intravenous injection of complete Freund's adjuvant (CFA), and intratracheal fluid instillation, each of which resulted in similar increases in lung wet weight. Each of these conditions resulted in a unique pattern among the concentration vs. time outflow curves of the indicators studied. The patterns were quantified by using mathematical models describing the pulmonary disposition of each of the indicators studied. A unique model parameter vector was obtained for each condition, demonstrating the ability to detect and to identify changes in lung tissue properties by using the appropriate group of indicators in the multiple-indicator dilution method. One change that was particularly interesting was a CFA-induced change in the disposition of diazepam, suggestive of a substantial increase in peripheral-type benzodiazepine receptors in the inflamed lungs. ",0
2161,10368367,Airway remodeling in asthma amplifies heterogeneities in smooth muscle shortening causing hyperresponsiveness,"Although airway remodeling and inflammation in asthma can amplify the constriction response of a single airway, their influence on the structural changes in the whole airway network is unknown. We present a morphometric model of the human lung that incorporates cross-sectional wall areas corresponding to the adventitia, airway smooth muscle (ASM), and mucosa for healthy and mildly and severely asthmatic airways and the influence of parenchymal tethering. A heterogeneous ASM percent shortening stimulus is imposed, causing distinct constriction patterns for healthy and asthmatic airways. We calculate lung resistance and elastance from 0.1 to 5 Hz. We show that, for a given ASM stimulus, the distribution of wall area in asthmatic subjects will amplify not only the mean but the heterogeneity of constriction in the lung periphery. Moreover, heterogeneous ASM shortening that would produce only mild changes in the healthy lung can cause hyperresponsive changes in lung resistance and elastance at typical breathing rates in the asthmatic lung, even with relatively small increases in airway resistance. This condition arises when airway closures occur randomly in the lung periphery. We suggest that heterogeneity is a crucial determinant of hyperresponsiveness in asthma and that acute asthma is more a consequence of extensive airway wall inflammation and remodeling, predisposing the lung to produce an acute pattern of heterogeneous constriction. ",0
2162,10368382,"Effects of omega-agatoxin IVA, a P-type calcium channel antagonist, on the development of spinal neuronal hyperexcitability caused by knee inflammation in rats","Both N- and P-type high-threshold calcium channels are located presynaptically in the CNS and are involved in the release of transmitters. To investigate the importance of P-type calcium channels in the generation of inflammation-evoked hyperexcitability of spinal cord neurons, electrophysiological recordings were made from wide-dynamic-range neurons with input from the knee joint in the anesthetized rat. The responses of each neuron to innocuous and noxious pressure onto the knee and the ankle were continuously assessed before and during the development of an inflammation in the knee joint induced by the injections of K/C into the joint cavity. The specific antagonist at P-type calcium channels omega-agatoxin was administered into a 30-microl trough on the spinal cord surface above the recorded neuron. In most neurons the application of omega-agatoxin before induction of inflammation slightly enhanced the responses to pressure onto the knee and ankle or left them unchanged. Two different protocols were then followed. In the control group (13 rats) only Tyrode was administered to the spinal cord during and after induction of inflammation. In these neurons the responses to mechanical stimuli applied to both the inflamed knee and to the noninflamed ankle showed a significant increase over 4 h. In the experimental group (12 rats) omega-agatoxin was applied during knee injection and in five 15-min periods up to 180 min after kaolin. This prevented the increase of the neuronal responses to innocuous pressure onto the knee and to innocuous and noxious pressure onto the ankle; only the responses to noxious pressure onto the knee were significantly enhanced during development of inflammation. Thus the development of inflammation-evoked hyperexcitability was attenuated by omega-agatoxin, and this suggests that P-type calcium channels in the spinal cord are involved in the generation of inflammation-evoked hyperexcitability of spinal cord neurons. Finally, when omega-agatoxin was administered to the spinal cord 4 h after the kaolin injection, i.e., when inflammation-evoked hyperexcitability was fully established, the responses to innocuous and noxious pressure onto the knee were reduced by 20-30% on average. The shift in the effect of omega-agatoxin, from slight facilitation or no change of the responses before inflammation to inhibition in the state of hyperexcitability, indicates that P-type calcium channels are important for excitatory synaptic transmission involved in the maintenance of inflammation-evoked hyperexcitability. ",0
2163,10368788,Burden of hereditary diseases in residents of the Mari El Republic],"A summary of the medical genetic studies of the Marii El population is presented. A total of 276,900 people, 110,894 and 166,006 urban and rural inhabitants, respectively, were examined. Regarding the ethnic composition, the studied population was mostly Mari (61.96%) and Russian (32.04%). Medical genetic examination revealed 480 subjects from 260 families with autosomal dominant (AD) diseases, 234 subjects from 184 families with autosomal recessive (AR) diseases, and 49 subjects from 41 families with x-linked diseases. Segregation analysis revealed a good agreement between the expected and observed segregation frequencies for families with AR and AD diseases and allowed the frequency of hereditary diseases in the urban and rural, as well as the Russian and Mari, populations, to be estimated. The total frequency of AD diseases in Maris was approximately twice as high as in Russians (1.99 and 0.97%, respectively); substantial differences between district populations were found. The total frequency of AR diseases was also two times higher in Maris than in Russians (1.00 and 0.54%, respectively). The frequencies of AR and AD diseases in different districts were correlated with the levels of random and local inbreeding, population size, and the index of maximum selection. ",0
2164,10368861,Circadian rhythm of stereotyped complex behaviours in rats in environmental lead exposure,"1. Stereotyped complex behaviours are present in a number of psychotic illnesses, neurological diseases and even can be generated in response to chemical environment (e.g., drugs or toxins). 2. The circadian rhythm of complex behaviours such as, rearing, preening, scratching and biting/licking was evaluated in an open-field situation in rats exposed to lead (2% lead acetate in drinking water for 30 days). 3. The circadian rhythm of rearing patterns showed depressions from 2 to 14 hr on day 3 and 13, and from 2-6 hr on day 23 (it elevated at 10 hr), whereas increased pattern was apparent at all test periods (except at 6 hr) on day 30. 4. Increased responses of circadian rhythm of preening behaviour were obtained at 18 hr (with decrease at 22 hr) on day 3, at 6 and 14-22 hr on day 13 and, at all the test periods on day 23 (except at 6 hr) and on day 30. 5. The rhythmic patterns of the scratching behaviour showed elevations at each test period as observed on day 3, 13, 23 and 30. The responses in lead-intoxicated rates, however, showed depressions in the light-period and augmentations in the dark-period. 6. The biting/licking behaviours indicated increased patterns of the circadian rhythm attaining a parabolic response, which were inconsistent to the scratching behaviour patterns. Amongst lead-intoxicated rats this behaviour exhibited depressed responses in light-period, whereas in dark-period it showed elevations. ",0
2165,10368910,Child-directed speech produced by mothers with symptoms of depression fails to promote associative learning in 4-month-old infants,"Child-directed (CD) speech segments produced by 20 mothers who varied in self-reported symptoms of depression, recorded during a structured play interaction with their 2- to 6-month-old infants, were used as conditioned stimuli with face reinforcers in a conditioned attention paradigm. After pairings of speech segments and faces, speech segments were assessed for their ability to increase time spent looking at a novel checker-board pattern (summation test) using 225 4-month-old infants of nondepressed mothers. Significant positive summation, an index of associative learning, was obtained in groups of infants tested with speech produced by mothers with comparatively fewer self-reported symptoms of depression (Beck Depression Inventory or BDI < or = 15). However, significant positive summation was not achieved using speech samples produced by mothers with comparatively more symptoms of depression (BDI > 15). These results indicate that the CD speech produced by mothers with symptoms of depression does not promote associative learning in infants. ",0
2166,10369084,Analyzing prognostic factors in breast cancer using a multistate model,"In breast cancer clinical research, an important goal is to analyze how factors are seen to affect the disease process. Meanwhile, the disease progression is not fully modelled using standard analysis since transitions between intermediate events such as local-regional recurrences (LRR) or metachronous contralateral breast cancer (MCBC) are not considered. In the present study, the progression of disease was modelled using a multistate model. By this approach, we assessed transitions during the course of the disease and studied prognostic factors for each transition. The model was applied to 6,185 patients with unilateral ductal invasive breast cancer, clinical stage I through III, treated between 1981 and 1988 at the Curie Institute. At first diagnosis, high clinical stage, high histological grade, positive lymph nodes, and age less than 40 years were associated with increased risks of LRR, metastases, or death. Except age, the same factors remained predictive for metastases or death following LRR. Chemotherapy for the first cancer was associated with a decreased risk for developing MCBC. As the time interval from diagnosis of the primary tumor to that of a local or contralateral recurrence increased, the risk of metastases or death decreased. Nodal status for the first tumor and clinical stage for the contralateral tumor increased the risk of metastases or death following MCBC. Conversely, the risk decreased for patients who received adjuvant hormone therapy following MCBC. In conclusion, the multistate model offers us a much more appropriate way to study prognostic factors for each transition in breast cancer disease. ",0
2167,10369614,Positive impact of a follow-up phone call to community pharmacies in a medicaid drug utilization program,"To evaluate the impact of including community pharmacists in strategies to alter excessive prescribing of antiulcer medications (AUMs) in a statewide drug utilization review (DUR) program. Mailing educational materials to physicians is a common intervention strategy of retrospective DUR programs. However, pharmacists are typically left out of this process, ignoring a possibly influential healthcare provider. Patients without gastroesophageal reflux disease who received > or = 1.0 normalized therapeutic equivalents (e.g., 1.0 NTE = ranitidine 300 mg/d or omeprazole 20 mg/d) for five of six prior months were included. The pharmacists and physicians of these patients were divided into one of three geographically distinct groups: group 1 physicians received mailed materials only (pharmacists were not contacted); group 2 physicians and pharmacists received mailed materials only; and group 3 physicians and pharmacists received mailed materials, and the pharmacists were contacted by phone. Mean NTE and AUM costs were analyzed six months before and six months following the intervention. One hundred thirty-eight, 329, and 248 patients were included in G1, G2, and G3, respectively. There was a 12.4%, 8.0%, and 14.0% reduction in NTE for G1, G2, and G3, respectively. G1 AUM cost decreased 7.7% ($7710); G2 decreased 6.8% ($14 037); G3 decreased 20.5% ($26722). The total decrease in AUM cost for the entire cohort from before to after the intervention was $48469 (p < 0.05) in the six months following the intervention. A follow-up phone call to pharmacists in a statewide DUR intervention enhances the effectiveness of DUR interventions under the conditions studied. Enlisting the support of community pharmacists may improve the cost savings of these interventions. ",0
2168,10369661,Molecular basis of glutathione synthetase deficiency and a rare gene permutation event,"Glutathione synthetase (GS) catalyses the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner. Malfunctioning of GS results in disorders including metabolic acidosis, 5-oxoprolinuria, neurological dysfunction, haemolytic anaemia and in some cases is probably lethal. Here we report the crystal structure of human GS (hGS) at 2.1 A resolution in complex with ADP, two magnesium ions, a sulfate ion and glutathione. The structure indicates that hGS belongs to the recently identified ATP-grasp superfamily, although it displays no detectable sequence identity with other family members including its bacterial counterpart, Escherichia coli GS. The difficulty in identifying hGS as a member of the family is due in part to a rare gene permutation which has resulted in a circular shift of the conserved secondary structure elements in hGS with respect to the other known ATP-grasp proteins. Nevertheless, it appears likely that the enzyme shares the same general catalytic mechanism as other ligases. The possibility of cyclic permutations provides an insight into the evolution of this family and will probably lead to the identification of new members. Mutations that lead to GS deficiency have been mapped onto the structure, providing a molecular basis for understanding their effects. ",0
2169,10369850,Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2,"BACKGROUND: The detection of pheochromocytomas in patients at risk for these tumors, such as patients with von Hippel-Lindau disease or multiple endocrine neoplasia type 2 (MEN-2), is hindered by the inadequate sensitivity of commonly available biochemical tests. In this study we evaluated measurements of plasma normetanephrine and metanephrine for detecting pheochromocytomas in patients with von Hippel-Lindau disease or MEN-2. METHODS: We studied 26 patients with von Hippel-Lindau disease and 9 patients with MEN-2 who had histologically verified pheochromocytomas and 50 patients with von Hippel-Lindau disease or MEN-2 who had no radiologic evidence of pheochromocytoma. Von Hippel-Lindau disease and MEN-2 were diagnosed on the basis of germ-line mutations of the appropriate genes. The plasma concentrations of normetanephrine and metanephrine were compared with the plasma concentrations of catecholamines (norepinephrine and epinephrine) and urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid. RESULTS: The sensitivity of measurements of plasma normetanephrine and metanephrine for the detection of tumors was 97 percent, whereas the other biochemical tests had a sensitivity of only 47 to 74 percent. All patients with MEN-2 had high plasma concentrations of metanephrine, whereas the patients with von Hippel-Lindau disease had almost exclusively high plasma concentrations of only normetanephrine. One patient with von Hippel-Lindau disease had a normal plasma normetanephrine concentration; this patient had a very small adrenal tumor (<1 cm). The high sensitivity of measurements of plasma normetanephrine and metanephrine was accompanied by a high level of specificity (96 percent). CONCLUSIONS: Measurements of plasma normetanephrine and metanephrine are useful in screening for pheochromocytomas in patients with a familial predisposition to these tumors.",0
2170,10369852,The relation between funding by the National Institutes of Health and the burden of disease,"BACKGROUND: The Institute of Medicine has proposed that the amount of disease-specific research funding provided by the National Institutes of Health (NIH) be systematically and consistently compared with the burden of disease for society. METHODS: We performed a cross-sectional study comparing estimates of disease-specific funding in 1996 with data on six measures of the burden of disease. The measures were total mortality, years of life lost, and number of hospital days in 1994 and incidence, prevalence, and disability-adjusted life-years (one disability-adjusted life-year is defined as the loss of one year of healthy life to disease) in 1990. With the use of these measures as explanatory variables in a regression analysis, predicted funding was calculated and compared with actual funding. RESULTS: There was no relation between the amount of NIH funding and the incidence, prevalence, or number of hospital days attributed to each condition or disease (P=0.82, P=0.23, and P=0.21, respectively). The numbers of deaths (r=0.40, P=0.03) and years of life lost (r=0.42, P=0.02) were weakly associated with funding, whereas the number of disability-adjusted life-years was strongly predictive of funding (r=0.62, P<0.001). When the latter three measures were used to predict expected funding, the conclusions about the appropriateness of funding for some diseases varied according to the measure used. However, the acquired immunodeficiency syndrome, breast cancer, diabetes mellitus, and dementia all received relatively generous funding, regardless of which measure was used as the basis for calculating support. Research on chronic obstructive pulmonary disease, perinatal conditions, and peptic ulcer was relatively underfunded. CONCLUSIONS: The amount of NIH funding for research on a disease is associated with the burden of the disease; however, different measures of the burden of disease may yield different conclusions about the appropriateness of disease-specific funding levels.",0
2171,10369988,Optimized preoperative planning of calcaneal fractures using spiral computed tomography,"The aim of this study was the evaluation of spiral-CT examinations in preoperative planning of calcaneal fractures supported by 3D reconstructions after electronic disarticulation. We examined 45 patients with 47 calcaneal fractures with diagnostic spiral-CT examinations in a prospective study. In addition to the conventional axial slices and sagittal reconstructions, 3D reconstructions prior to and after electronic disarticulation were performed and rated by orthopaedic surgeons and radiologists. The following diagnostic criteria were rated: involvement of articular facets, number of fragments and hindfoot deformities. Axial slices were considered to be the gold standard, because not all patients underwent surgical treatment. Axial slices showed involvement of 90 articular facets (100 %). Three-dimensional reformations after electronic disarticulation depicted 82 fractures (82 of 90, 91 %), sagittal reconstructions 63 fractures (63 of 90, 70 %). Three-dimensional reconstructions without electronic disarticulation showed five fractures (5 of 90, 5.5 %). The number of fragments was demonstrated best on sagittal reconstructions (two, three or four fragments); five fragments were diagnosed best on axial slices, and 3D reconstruction without electronic disarticulation showed only a very small number of fragments, due to overlaying bones. Hindfoot deformities (lateralisation, varus deformation, shortening) were demonstrated best on axial slices, except in terms of showing height reduction, which was demonstrated better on sagittal and 3D reconstructions. Three-dimensional reconstructions after electronic disarticulation support a clear understanding of the 3D position of the fragments and of their displacement in comparison with 3D reconstruction without electronic disarticulation, which is essential for an effective surgical reduction. Due to the potential manipulation of surface-oriented 3D reconstructions, regardless of whether electronic disarticulation is used, this imaging technique should not be considered in an isolated framework. Three-dimensional images without electronic disarticulation are superfluous in any case. ",0
2172,10370113,Hox C6 expression during development and regeneration of forelimbs in larval Notophthalmus viridescens,"""A central theme concerning the epimorphic regenerative potential of urodele amphibian appendages is that limb regeneration in the adult parallels larval limb development. Results of previous research have led to the suggestion that homeobox containing genes are """"re-expressed"""" during the epimorphic regeneration of forelimbs of adult Notophthalmus viridescens in patterns which retrace larval limb development. However, to date no literature exists concerning expression patterns of any homeobox containing genes during larval development of this species. The lack of such information has been a hindrance in exploring the similarities as well as differences which exist between limb regeneration in adults and limb development in larvae. Here we report the first such results of the localization of Hox C6 (formerly, NvHBox-1) in developing and regenerating forelimbs of N. viridescens larvae as demonstrated by whole-mount in situ hybridization. Inasmuch as the pattern of Hox C6 expression is similar in developing forelimb buds of larvae and epimorphically regenerating forelimb blastemata of both adults and larvae, our results support the paradigm that epimorphic regeneration in adult newts parallels larval forelimb development. However, in contrast with observations which document the presence of Hox C6 in both intact, as well as regenerating hindlimbs and tails of adult newts, our results reveal no such Hox C6 expression during larval development of hindlimbs or the tail. As such, our findings indicate that critical differences in larval hindlimb and tail development versus adult expression patterns of this gene in these two appendages may be due primarily to differences in gene regulation as opposed to gene function. Thus, the apparent ability of urodeles to regulate genes in such a highly co-ordinated fashion so as to replace lost, differentiated, appendicular structures in adult animals may assist, at least in part, in better elucidating the phenomenon of epimorphic regeneration. """,0
2173,10370221,"Effect of ethanol/propylene glycol on the in vitro percutaneous absorption of aspirin, biophysical changes and macroscopic barrier properties of the skin","The effect of the solvent systems ethanol (EtOH), propylene glycol (PG) and combinations thereof was examined on the in vitro percutaneous absorption of the antithrombotic, aspirin, through porcine epidermis. Biophysical changes in the stratum corneum lipids were studied through the use of Fourier transform infrared (FTIR) spectroscopy. Macroscopic barrier properties of the epidermis were examined through the use of in vitro transepidermal water loss (TEWL). The flux of aspirin increased with increasing concentrations of EtOH in the solvent systems. The maximum flux of aspirin was achieved by 80% EtOH in combination with 20% PG beyond which (i.e. 100% EtOH) there was no increase in the flux. FTIR spectroscopic study was enacted in order to determine the biophysical properties of the stratum corneum when the solvents were applied. The FTIR spectra of the stratum corneum treated with 80% EtOH/20% PG showed a maximum decrease in absorbance for the asymmetric and symmetric C&z. sbnd;H peaks, which suggests a greater loss of the lipids in the stratum corneum layers. In vitro TEWL studies allowed an investigation into the macroscopic barrier integrity properties of the stratum corneum. The TEWL results indicated that each of the solvent systems significantly enhanced (P<0.05) in vitro TEWL in comparison to the control. In conclusion, 80% EtOH/20% PG enhanced the percutaneous absorption of aspirin by perturbing the macroscopic barrier integrity of the stratum corneum and through a loss of stratum corneum lipids. ",0
2174,10370397,Different effects of temocapril and cadralazine on electrocardiographic voltages and left ventricular mass in patients with essential hypertension,"To assess whether electrocardiographic variables are useful to detect the regression of left ventricular (LV) mass after long-term antihypertensive treatment, we related electrocardiographic voltages to echocardiographic variables before and after treatment with an ACE inhibitor, temocapril (TEM), or direct vasodilator, cadralazine (CAD). Twenty-one patients with essential hypertension were treated with either TEM (n = 11) or CAD (n = 10) for one year. LV mass index (LVMI) by echocardiography and Sokolow-Lyon voltage (SV1 + RV5), Cornell voltage (RaVL + SV3) and RV5 + RV6 by standard 12-lead electrocardiographic voltages were determined before and after treatment. Both drugs decreased blood pressure to the same extent. Both Sokolow-Lyon voltage and RV5 + RV6 tended to decrease in the ACE group (40.0 +/- 9.4 to 37.2 +/- 9.4 mm and 44.7 +/- 13.5 to 41.7 +/- 11.7 mm, respectively, N.S.), but not in the CAD group (38.4 +/- 6.8 to 39.7 +/- 7.7 mm and 42.9 +/- 10.4 to 46.8 +/- 11.2 mm, respectively, N.S.). LVMI decreased in the ACE group (-24 +/- 22 g/m2), whereas it increased in the CAD group (37 +/- 27 g/m2, p < 0.01). Change in LVMI was correlated with the changes in RV5 + RV6 and Sokolow-Lyon voltage (r = 0.73, p < 0.01 and r = 0.70, p < 0.01, respectively), but not with that in Cornell voltage. These results indicated that the changes in voltage criteria of RV5 + RV6 and Sokolow-Lyon are useful to assess the change in LVM after antihypertensive treatment in patients with essential hypertension although voltage variables in electrocardiogram were not sensitive to detect changes in LVMI. ",0
2175,10370671,Use of transcatheter arterial infusion of anticancer agents with lipiodol to prevent recurrence of hepatocellular carcinoma after hepatic resection,"Hepatectomy has been accepted as a reliable cure for primary hepatocellular carcinoma (HCC). However, the residual liver recurrence rate after hepatectomy remains high. To improve the prognosis after hepatectomy for HCC, repeated post-operative transcatheter arterial infusions of anticancer drugs and lipiodol (TAI) was given. This study evaluates the efficacy of this treatment for preventing residual liver recurrence after hepatectomy. TAI after hepatectomy was performed in 24 (TAI group) of 65 cases showing tumor invasion such as infiltration to the capsule, intraportal spread, and intrahepatic metastasis. In TAI, a mixture of Mitomycin C (MMC) and Adriamycin (ADM) is administered with lipiodol via the hepatic artery. The recurrence and survival rates of the TAI (n = 24) and non-TAI (n = 41) groups were compared to evaluate the efficacy of TAI after hepatectomy. The TAI group had a lower cumulative residual liver recurrence rate than the non-TAI group (p < 0.01). Division of residual liver recurrence cases into two groups according to the duration of recurrence showed that the rate of recurrence within 1 year after hepatectomy was lower in the TAI group (10.0%) (1/10) than in the non-TAI group (48.4%) (15/31) (p = 0.07). Also, the cumulative survival rate in the TAI group was significantly higher (p < 0.05). The morbidity rate was 16.6%. Bilomas occurred without infection in 2 cases, and liver abscess in one. TAI may be an effective surgical adjuvant against residual liver recurrence, and we suggest that its effectiveness results from suppression of intrahepatic micrometastases rather than multicentric carcinogenesis. ",0
2176,10370883,"Utilization of a self-contained psychometry-oriented device, for study of affective and cognitive function of a subject]","""We appraised the possibility to use the Psycho-Log 24, an ambulatory, adapted to chronopsychometry device, which realizes simplified questionnaires and performance test adaptable to each subject; this device has dimensions like a pocketbook; its storage capacity is compatible with a long time use. 9 adult volunteers (8 healthy subjects and 1 depressive patient) participated to this study. All of them effected reaction times (TRS) during 3 to 31 days at the rate of at least 4 sessions/day; some of them completed mental calculations (CM), letters cancellations (BRL) and auto-estimation scales (from 1 to 9 items, also measured by a classic method). For TRS and all the subjects, the frequencies histograms calculated by hour and on a 24 h scale, showed a bimodal variation, with a major peak suggesting a circadian rhythm. 5 subjects had different time for the daily best performances of each hand (shifted from 5 to 12 h). In the healthy adults, for BRL and CM, the best performances in speed and precision are shifted and could be related to the """"fatigue"""" auto-estimated peaks. There is a significant correlation between auto-estimations by Psycho-Log and the classic method. The coherence between the auto-estimations of the depressive subject is strong during the remission stage, and lower during the relapse stage. The used method seems an effective mean to know the temporal structure of the cognitive and affective functions of a subject, and to estimate the preserving of this structure; the method first could constitute an exploratory mean for an objective evaluation of the drugs effects and patients quality of life, secondly could be implicated in researches with diagnosis target. """,0
2177,10370994,A new method of three-dimensional computer assisted reconstruction of the developing biliary tract,"A three-dimensional (3-D) computer assisted reconstruction of the biliary tract was performed in human and rat embryos at Carnegie stage 23 to describe and compare the biliary structures and to point out the anatomic relations between the structures of the hepatic pedicle. Light micrograph images from consecutive serial sagittal sections (diameter 7 mm) of one human and 16 rat embryos were directly digitalized with a CCD camera. The serial views were aligned automatically by software. The data were analysed following segmentation and thresholding, allowing automatic reconstruction. The main bile ducts ascended in the mesoderm of the hepatoduodenal ligament. The extrahepatic bile ducts: common bile duct (CD), cystic duct and gallbladder in the human, formed a compound system which could not be shown so clearly in histologic sections. The hepato-pancreatic ampulla was studied as visualised through the duodenum. The course of the CD was like a chicane. The gallbladder diameter and length were similar to those of the CD. Computer-assisted reconstruction permitted easy acquisition of the data by direct examination of the sections through the microscope. This method showed the relationships between the different structures of the hepatic pedicle and allowed estimation of the volume of the bile duct. These findings were not obvious in two-dimensional (2-D) views from histologic sections. Each embryonic stage could be rebuilt in 3-D, which could introduce the time as a fourth dimension, fundamental for the study of organogenesis. ",0
2178,10371393,"""The heritability of alcoholism symptoms: """"indicators of genetic and environmental influence in alcohol-dependent individuals"""" revisited""","""There is consistent evidence from twin and adoption studies implicating genetic factors in the etiology of alcoholism, yet few studies have examined the role of genetic influences on individual symptoms of alcoholism. In a previous study of 113 male twins, Johnson et al. (1996a) identified 7 alcoholism symptoms that were more """"genetic"""" and 14 that were more """"environmental"""" (that is, non-genetic) in their etiology by examining symptom concordances among monozygotic and dizygotic twin pairs. The present study represents an attempt to replicate the results of this previous study and extend them by estimating the contribution of genetic factors to the variation in liability for different alcoholism symptoms. Subjects were 3356 male twin pairs from the Vietnam Era Twin Registry. Lifetime histories of alcoholism symptoms were assessed by a structured psychiatric telephone interview. The results of the previous study were not replicated. The correlations between symptom classifications as genetic and non-genetic in the present and previous study were nonsignificant and ranged from -0.27 to 0.11. However, within the present study the correlation between symptom classifications as genetic and non-genetic was statistically significant across random split-half subsamples (r = 0.59); nine alcoholism symptoms were consistently classified as genetic and six symptoms as non-genetic in their etiology. Model-fitting analyses applied to different alcoholism symptoms yielded heritability estimates ranging from 0.03 to 0.53 with broad and overlapping confidence intervals around these estimates, ranging from 0.00 to 0.65. The results of this study highlight the difficulty of identifying more or less heritable phenotypes in twin research, and suggest that it may not be possible to identify specific alcoholism symptoms that are more genetic in their etiology than others. Nevertheless, there appears to be potentially important variation in the relative magnitude of genetic influences for individual alcoholism symptoms, and exploring these differences may lead to further insights into the nosology and etiology of alcohol-related problems. """,0
2179,10371503,"Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy","The size of the pool of resting CD4+ T cells containing replication-competent HIV in the blood of patients receiving intermittent interleukin (IL)-2 plus highly active anti-retroviral therapy (HAART) was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4+ T cells in three patients receiving IL-2 plus HAART, despite the fact that large numbers of resting CD4+ T cells were cultured. Lymph node biopsies were done in two of these three patients and virus could not be isolated. These results indicate that the intermittent administration of IL-2 with continuous HAART may lead to a substantial reduction in the pool of resting CD4+ T cells that contain replication-competent HIV. ",0
2180,10371535,Brain regions associated with episodic retrieval in normal aging and Alzheimer's disease,"To examine patterns of brain activation during verbal episodic retrieval in normal elderly subjects and patients in an early phase of AD. It is established that 1) a profound episodic memory impairment is a cardinal symptom of AD; and 2) some of the earliest brain changes in this disease occur in regions critical to episodic memory, such as the hippocampus and neighboring regions. Yet, it remains largely unknown whether the episodic memory deficit seen in AD is paralleled by concomitant alterations in brain activity during actual task performance in these or other brain areas. Using PET, blood flow was assessed in normal elderly subjects and patients with early AD during two retrieval conditions involving completion of word stems: baseline and cued recall. The patients with AD showed a marked performance deficit in cued recall, although the two groups were indistinguishable in the baseline task condition. Both groups showed bilateral activity in orbital and dorsolateral prefrontal cortex, left precuneus, and right cerebellum, as well as decreased activity in distinct left temporal regions during cued recall. The normal elderly alone activated the left parietal cortex and the left hippocampal formation during episodic retrieval. By contrast, AD-related increases in activity during cued recall were observed in the left orbital prefrontal cortex and left cerebellum. The similar patterns of activations in the two groups suggest that a large distributed network involved in episodic memory retrieval functions relatively normally in early AD. Those retrieval activations seen in the normal elderly, as opposed to the patients, may reflect AD-related failures in semantic processing and successful recollection of the target information, respectively. Finally, the AD-related increases in activity were interpreted in terms of compensatory reactions to the difficulties in performing the episodic memory task. ",0
2181,10372507,GABA-ergic neurons and the neurobiology of schizophrenia and other psychoses,"""There are a number of disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) that are characterised by having psychotic symptoms as the defining feature [17]. The narrowest definition of psychosis is restricted to delusions or prominent hallucinations, with the hallucinations occurring in the absence of insight into their pathological nature. Schizophrenia is the most prevalent form of psychosis, but this may also occur due to other medical conditions (e.g., Prader-Willi syndrome, epilepsy), in the early post-partum period, at menopause, and as a result of drug use. This article attempts to draw together an underlying causation across the various forms of psychotic disorder and, by integrating this with what is known about the genetics, neuroanatomy and neuropharmacology of the positive symptoms in schizophrenia, produce a broader understanding. At the cellular level, gamma-aminobutyric acid (GABA)-ergic interneurons are a common feature in psychotic states, and are a principal focus for serotonin and dopamine innervations, as well as playing an important role in cortical development. At the systems level, prefrontal and medial temporal cortices are implicated with activity levels out of synchrony in schizophrenics. How these vast areas of disparately functioning cortical networks are """"bound"""" together to provide coherent conscious experiences is again a function of GABA-ergic interneurons. These interneurons have highly divergent inhibitory projections to large numbers of pyramidal neurons and are themselves synchronised by the ascending dopamine and serotonin innervations. """,0
2182,10372654,Complex regulation of prothymosin alpha in mammary tumors arising arising in transgenic mice,"Expression of prothymosin alpha (PTA) has been related to cell proliferation, both normal and pathological. PTA has also been proposed to be a target of the c-myc protooncogene. To study PTA mRNA levels during pathological cell growth, and especially the effect of the activation of specific oncogenes on PTA expression, we have studied its expression in tumors that arise in transgenic mice. We found high PTA levels in mammary tumors arising in c-myc, c-neu, and v-ras transgenic mice. Levels of this protein were variable between different tumors, and there is a differential regulation of PTA respect to other putative c-myc target genes, such as Ornithine Decarboxylase (ODC). Furthermore, expression of PTA is not absolutely dependent of c-myc expression, as shown by MYC depletion experiments performed with antisense oligonucleotides. We conclude that regulation of PTA in these tumors is complex and depends on more than a single activated oncogene. ",0
2183,10372898,The role of botulinus toxin type A in treatment--with special reference to children,"Although botulinum toxin A was first introduced to treat strabismus and blepherospasm it is now used in an increasing number of conditions, many in the field of pediatrics. Its action results from a prevention of the release of acetylcholine from nerve terminals. A number of studies recording the effects of the toxin in the treatment of spastic cerebral palsy are reviewed, and although these can be criticized, there seems to be no doubt that it can be of benefit. It is few side effects, but it may reveal an underlying weakness. Other disadvantages are its cost and the need for repeated injections. It can be used for the relief of rigidity, although the effects in the extrapyramidal form of cerebral palsy are not so dramatic. Also it can be beneficial in some forms of dystonia, rarely if this is generalized, but certainly if it is focal, and especially if there is accompanying pain. There are several conditions seen in children, such as strabismus, blepherospasm and tremors, in which this form of treatment will rarely be indicated; but they will be mentioned. An exception may be spasmodic torticollis during adolescence if it does not respond to other therapy, as it is so disabling. Botulinum toxin can be used to block the discharges from cholinergic sympathetic and parasympathetic terminals. Focal hyperhidrosis can be very distressing among older children, and the use of the toxin should sometimes be considered in this and other autonomic disorders. ",0
2184,10372904,Comparison between semiquantitative interictal Tc-99m HMPAO SPECT and clinical parameters in children with partial seizures,"The aim of the present study was to correlate between clinical parameters (age, age of onset, frequency and duration of seizures) and semiquantitative interictal SPECT parameters in children with partial seizures. We obtained 30 patients who had hypoperfusion in interictal SPECT, retrospectively. All patients underwent a detailed clinical examination, electroencephalography (EEG) investigation and brain computerized tomography (CT) and/or magnetic resonance imaging (MRI). Single photon emission computerized tomography (SPECT) studies were evaluated visually and by calculating semiquantitative parameters (the degree (asymmetry index, AI) and extent (number of ROI) of hypoperfusion). Visual analysis detected ipsilateral hypoperfusion in 23 (76%) patients with a unilateral focus and contralateral hypoperfusion in seven patients. We found an inverse correlation between the age at onset of seizure (r = -0.40, P = 0.025), frequency of seizures(but positive correlation; r = 0.77, P = 0.000) and AI. Number of ROIs showed a moderate correlation with the frequency of seizures (r = 0.67, P = 0.000), while correlation of the age at onset of seizures was not significant. This study performed in pediatric patients also suggested that either SPECT parameters may be used for correlating with clinical parameters. ",0
2185,10373016,"Facial development and type III collagen RNA expression: concurrent repression in the osteopetrotic (Toothless,tl) rat and rescue after treatment with colony-stimulating factor-1","The toothless (osteopetrotic) mutation in the rat is characterized by retarded development of the anterior facial skeleton. Growth of the anterior face in rats occurs at the premaxillary-maxillary suture (PMMS). To identify potential mechanisms for stunted facial growth in this mutation we compared the temporospatial expression of collagen I (Col I) and collagen III (Col III) RNA around this suture in toothless (tl) rats and normal littermates by in situ hybridization of specific riboprobes in sagittal sections of the head. In normal rats, the suture is S shaped at birth and becomes highly convoluted by 10 days with cells in the center (fibroblasts and osteoblast progenitors) expressing Col III RNA and those at the periphery (osteoblasts) expressing no Col III RNA but high amounts of Col I RNA throughout the growth phase (the first 2 postnatal weeks). In the mutant PMMS, cells were reduced in number, less differentiated, and fewer osteoblasts were encountered. Expression of Col I RNA was at normal levels, but centrosutural cells expressed Col III RNA only after day 6 and then only weakly. A highly convoluted sutural shape was never achieved in mutants during the first 2 postnatal weeks. Treatment of tl rats with the cytokine CSF-1 improved facial growth and restored cellular diversity and Col III RNA expression in the PMMS to normal levels. Taken together, these data suggest that normal facial growth in rats is related to expression of Col III RNAby osteoblast precursors in the PMMS, that these cells are deficient in the tl mutation and are rescued following treatment with CSF-1. ",0
2186,10373070,Incidence and outcome of Clostridium difficile infection following autologous peripheral blood stem cell transplantation,"A retrospective evaluation of 200 consecutive recipients of autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence and outcome of infection with Clostridium difficile. The diagnosis was confirmed in 14 patients with diarrhea (15 episodes) at a median of 33 days after stem cell infusion. Five patients were neutropenic at the time of diagnosis. Every individual had adverse known risk factors such as recent or current use of antibiotic, corticosteroid and antiviral therapy, recent administration of myeloablative chemotherapy and numerous, prolonged periods of hospitalization. Diarrhea, frequently hemorrhagic, was the most common presenting feature along with fever, abdominal cramps and abdominal distention. Diagnosis was established by the stool-cytotoxin test. Response to standard treatment with oral vancomycin or metronidazole was prompt despite the presence of several adverse prognostic features in these patients. There was only one instance of relapse which was also treated successfully. Several transplant-related variables such as age, sex, underlying malignancy, myelo-ablative regimen, duration of neutropenia, and prophylactic use of oral ampicillin underwent statistical analysis but failed to be predictive of C. difficile infection in such a setting. Finally, C. difficile is not uncommon after autologous PBSCT and must be included in the differential diagnosis in any such patient with diarrhea. ",0
2187,10373103,The effect of activity on the waking temperature rhythm in humans,"""Nine healthy female subjects were studied when exposed to the natural light-dark cycle, but living for 17 """"days"""" on a 27h day (9h sleep, 18h wake). Since the circadian endogenous oscillator cannot entrain to this imposed period, forced desynchronization between the sleep/activity cycle and the endogenous circadian temperature rhythm took place. This enabled the effects of activity on core temperature to be assessed at different endogenous circadian phases and at different stages of the sleep/activity cycle. Rectal temperature was measured at 6-minute intervals, and the activity of the nondominant wrist was summed at 1-minute intervals. Each waking span was divided into overlapping 3h sections, and each section was submitted to linear regression analysis between the rectal temperatures and the total activity in the previous 30 minutes. From this analysis were obtained the gradient (of the change in rectal temperature produced by a unit change in activity) and the intercept (the rectal temperature predicted when activity was zero). The gradients were subjected to a two-factor analysis of variance (ANOVA) (circadian phase/ time awake). There was no significant effect of time awake, but circadian phase was highly significant statistically. Post hoc tests (Newman-Keuls) indicated that gradients around the temperature peak were significantly less than those around its trough. The intercepts formed a sinusoid that, for the group, showed a mesor (+/-SE) of 36.97 (+/-0.12) and amplitude (95% confidence interval) of 0.22 degrees C (0.12 degrees C, 0.32 degrees C). We conclude that this is a further method for removing masking effects from circadian temperature rhythm data in order to assess its endogenous component, a method that can be used when subjects are able to live normally. We suggest also that the decreased effect of activity on temperature when the endogenous circadian rhythm and activity are at their peak will reduce the possibility of hyperthermia. """,0
2188,10373305,Novel strategy yields candidate Gsh-1 homeobox gene targets using hypothalamus progenitor cell lines,"We describe the successful application of a strategy that potentially provides for an efficient and universal screen for downstream gene targets. We used the promoter of the Gsh-1 homeobox gene to drive expression of the SV40 T-antigen gene in transgenic mice. We have previously shown that the Gsh-1 homeobox gene is expressed in discrete domains of the ganglionic eminences, diencephalon, and hindbrain during brain development. Gsh-1-SV40 T transgenic mice showed cellular hyperplasia in regions of the brain coincident with Gsh-1 expression. The Gsh-1-SV40 T transgene was introduced, by breeding, into Gsh-1 homozygous mutant mice, and Gsh-1 -/- cell lines were made. Clonal cell lines were generated and analyzed by Northern blot hybridizations and Affymetrix GeneChip probe arrays to determine gene expression profiles. The results indicate that the cell lines remain representative of early developmental stages. Further, immunocytochemistry showed uniformly high levels of nestin expression, typical of central nervous system progenitor cells, and the absence of terminal differentiation markers of neuronal cells. One clonal cell line, No. 14, was then stably transfected with a tet-inducible Gsh-1 expression construct and subcloned. The starting clone 14, together with the uninduced and induced subclones, provided cell populations with varying levels of Gsh-1 expression. Differential display and Affymetrix GeneChip probe arrays were then used to identify transcript differences that represent candidate Gsh-1 target genes. Of particular interest, the drm and gas1 genes, which repress cell proliferation, were observed to be activated in Gsh-1-expressing cells. These observations support models predicting that homeobox genes function in the regulation of cell proliferation. ",0
2189,10373365,Molecular characterization of a protease secreted by Erwinia amylovora,"A protease with a molecular mass of 48 kDa is secreted by the fire blight pathogen Erwinia amylovora in minimal medium. We characterized this activity as a metalloprotease, since the enzyme was inhibited by EDTA and o -phenanthroline. A gene cluster was determined to encode four genes connected to protease expression, including a structural gene (prtA) and three genes (prtD, prtE, prtF) for secretion of the protease, which are transcribed in the same direction. The organization of the protease gene cluster in E. amylovora is different from that in other Gram-negative bacteria, such as Erwinia chrysanthemi, Pseudomonas aeruginosa and Serratia marcescens. On the basis of the conservative motif of metalloproteases, PrtA was identified to be a member of the metzincin subfamily of zinc-binding metalloproteases, and was confirmed to be the 48 kDa protease on gels by sequencing of tryptic peptide fragments derived from the protein. The protease is apparently secreted into the external medium through the type I secretion pathway via PrtD, PrtE and PrtF which share more than 90% identity with the secretion apparatus for lipase of S. marcescens. A protease mutant was created by Tn 5 -insertions, and the mutation localized in the prtD gene. The lack of protease reduced colonization of an E. amylovora secretion mutant labelled with the gene for the green fluorescent protein (gfp) in the parenchyma of apple leaves. ",0
2190,10373423,A large non-immunized human Fab fragment phage library that permits rapid isolation and kinetic analysis of high affinity antibodies,"We report the design, construction, and use of the first very large non-immunized phage antibody library in Fab format, which allows the rapid isolation and affinity analysis of antigen-specific human antibody fragments. Individually cloned heavy and light chain variable region libraries were combined in an efficient two-step cloning procedure, permitting the cloning of a total of 3.7 x 10(10) independent Fab clones. The performance of the library was determined by the successful selection of on average 14 different Fabs against 6 antigens tested. These include tetanus toxoid, the hapten phenyl-oxazolone, the breast cancer-associated MUC1 antigen, and three highly related glycoprotein hormones: human chorionic gonadotropin, human luteinizing hormone, and human follicle-stimulating hormone. In the latter category, a panel of either homone-specific or cross-reactive antibodies were identified. The design of the library permits the monitoring of selections with polyclonal phage preparations and to carry out large scale screening of antibody off-rates with unpurified Fab fragments on BIAcore. Antibodies with off-rates in the order of 10(-2) to 10(-4) s-1 and affinities up to 2.7 nM were recovered. The kinetics of these phage antibodies are of the same order of magnitude as antibodies associated with a secondary immune response. This new phage antibody library is set to become a valuable source of antibodies to many different targets, and to play a vital role in target discovery and validation in the area of functional genomics. ",0
2191,10373426,Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin,"The effects of acylation-stimulating protein (ASP) and insulin on free fatty acid (FFA) release from isolated human fat cells and the signal transduction pathways to induce these effects were studied. ASP and insulin inhibited basal and norepinephrine-induced FFA release by stimulating fractional FFA re-esterification (both to the same extent) and by inhibiting FFA produced during lipolysis (ASP to a lesser extent than insulin). Protein kinase C inhibition influenced none of the effects of ASP or insulin. Phosphatidylinositol 3-kinase inhibition counteracted the effects of insulin but not of ASP. Phosphodiesterase 3 (PDE3) activity was stimulated by ASP and insulin, whereas PDE4 activity was slightly increased by ASP only. Selective PDE3 inhibition reversed the effects of both ASP and insulin on fractional FFA re-esterification and lipolysis. Selective PDE4 inhibition slightly counteracted the ASP but not the effect of insulin on fractional FFA re-esterification and did not prevent the action of ASP or insulin on lipolysis. Thus, ASP and insulin play a major role in regulating FFA release from fat cells as follows: insulin by stimulating fractional FFA re-esterification and inhibiting lipolysis and ASP mainly by stimulating fractional FFA re-esterification. For both ASP and insulin these effects on FFA release are mediated by PDE3, and for ASP PDE4 might also be involved. The signaling pathway preceding PDE is not known for ASP but involves phosphatidylinositol 3-kinase for insulin. ",0
2192,10373528,Upstream stimulatory factor regulates major histocompatibility complex class I gene expression: the U2DeltaE4 splice variant abrogates E-box activity,"The tissue-specific expression of major histocompatibility complex class I genes is determined by a series of upstream regulatory elements, many of which remain ill defined. We now report that a distal E-box element, located between bp -309 and -314 upstream of transcription initiation, acts as a cell type-specific enhancer of class I promoter activity. The class I E box is very active in a neuroblastoma cell line, CHP-126, but is relatively inactive in the HeLa epithelial cell line. The basic helix-loop-helix leucine zipper proteins upstream stimulatory factor 1 (USF1) and USF2 were shown to specifically recognize the class I E box, resulting in the activation of the downstream promoter. Fine mapping of USF1 and USF2 amino-terminal functional domains revealed differences in their abilities to activate the class I E box. Whereas USF1 contained only an extended activation domain, USF2 contained both an activation domain and a negative regulatory region. Surprisingly, the naturally occurring splice variant of USF2 lacking the exon 4 domain, U2DeltaE4, acted as a dominant-negative regulator of USF-mediated activation of the class I promoter. This latter activity is in sharp contrast to the known ability of U2DeltaE4 to activate the adenovirus major late promoter. Class I E-box function is correlated with the relative amount of U2DeltaE4 in a cell, leading to the proposal that U2DeltaE4 modulates class I E-box activity and may represent one mechanism to fine-tune class I expression in various tissues. ",0
2193,10373621,Complementary DNA Encoding nm23/NDP Kinase Gene from the Korean Tiger Shark Scyliorhinus torazame,": A new tumor suppressor gene, snm23, homologous to the gene for human nucleoside diphosphate kinase nm23/NDP was first cloned from Korean tiger shark (Scyliorhinus torazame) skin lambda ZAP-II complementary DNA library. The gene (named snm23) containing the tumor metastasis suppressor protein was sequenced. The nucleotide and deduced amino acid sequences of snm23 revealed an open reading frame of 450 bp that corresponded to a protein of 150 amino acid residues, with a calculated molecular mass of 16.8 kDa. Sequence comparison of snm23 with nm23/NDP kinases was performed. In order to determine tissue specificity, reverse transcription-polymerase chain reaction was used. The expression of snm23/NDP kinase was detected in tissues from skin, cartilage, and liver of Korean tiger shark. ",0
2194,10373673,Metallothionein expression and zinc levels in invasive ductal breast carcinoma,"Metallothioneins (MTs) and zinc are both known to promote progression of tumors in human cancers. A close relationship exists between MT and zinc, as synthesis of the former has been reported to be induced by the latter. To assess the relationship between MT and zinc content in breast cancer tissues, we analysed MT expression by immunohistochemistry and tissue zinc levels by atomic absorption spectrometry (AAS) in invasive ductal breast cancers and adjacent benign breast tissues. We observed overexpression of MT in breast cancer tissues and noted that zinc content in breast cancer tissues was twice that of benign breast tissues. The nuclear fraction obtained by subcellular fractionation of breast cancer tissues was found to have a higher zinc content than the plasma membrane and cytosolic fractions. Contrary to expectations, we found a significant inverse correlation of MT expression with zinc levels in breast cancer tissues, suggesting that whilst both synergistically influence growth and survival of tumor cells, they may also have divergent roles in carcinogenesis. ",0
2195,10373999,Is telephone counselling a useful addition to physician advice and nicotine replacement therapy in helping patients to stop smoking? A randomized controlled trial,"The authors evaluated the incremental efficacy of telephone counselling by a nurse in addition to physician advice and nicotine replacement therapy in helping patients to stop smoking. The trial was conducted at the University of Ottawa Heart Institute. A total of 396 volunteers who smoked 15 or more cigarettes daily were randomly assigned to either of 2 groups: usual care (control group) and usual care plus telephone counselling (intervention group); the groups were stratified by sex and degree of nicotine dependence. Usual care involved the receipt of physician advice on 3 occasions, self-help materials and 12 weeks of nicotine replacement therapy. Telephone counselling was provided by a nurse at 2, 6 and 13 weeks after the target quit date. Point-prevalent quit rates were determined at 52 weeks after the target quit date. The point-prevalent quit rates at 52 weeks did not differ significantly between the control and intervention groups (24.1% v. 23.4% respectively). The quit rates did not differ significantly at the secondary measurement points of 4, 12 and 26 weeks. Brief physician assistance, along with nicotine replacement therapy, can help well-motivated smokers to quit. Three additional sessions of telephone counselling by a nurse were ineffective in increasing quit rates. This form of assistance may be useful in the absence of physician advice or when self-selected by patients. ",0
2196,10374019,The results of autogenous tibial periosteal transplants for full thickness cartilage defects in the knee joints of pigs,"An experimental study was conducted to demonstrate macroscopic and microscopic healing of full thickness cartilage defects with mature stable hyaline cartilage after autogenous tibial periosteal transplants in the knee joints of pigs. Similar full thickness osteochondral defects were created in the medial femoral condyles of both knees in 10 healthy young adult pigs. Periosteal transplants were performed on the left knees and the right knees used as controls. The pigs were sacrified in two groups at 6 weeks and 3 months. The knees were inspected for healing and stability of the graft. Microscopic sections were taken and evaluated using a histological score developed by O'Driscoll. Macroscopically, almost all defects with periosteal grafts healed with a translucent bluish-white colour indicating articular cartilage formation. There was good restoration of the bony contour and filling of the defects were superior to controls. Histologically, we were able to demonstrate immature hyaline cartilage which matured at 3 months. The newly formed tissue was stable and well-incorporated. It had almost complete bonding to the adjacent articular margin, good reconstitution of the osteochondral junction and a well maintained structural integrity. We concluded that periosteal transplants in the knee of a pig model healed with mature stable hyaline cartilage. ",0
2197,10374407,"Effect of mild hypothermia on the changes of cerebral blood flow, brain blood barrier and neuronal injuries following reperfusion of focal cerebral ischemia in rats","To compare the effects of mild hypothermia induced in different time courses on rats subjected to 3 hours (h) of ischemia followed by 3 h or 72 h of reperfusion. Eighty male Sprague-Dawley rats were divided into three mild hypothermic (MHT, 32 +/- 0.2 degrees C) groups, including intra-ischemia (MHTi), intra-reperfusion (MHTr), and intra-ischemia/reperfusion (MHTi + r) group, and one normothermic group (NT, 37 +/- 0.2 degrees C) as the control. Reversible focal ischemia was carried out in rats with suture model. The cortical blood flow was measured during 3 h of ischemia followed by 3 h of reperfusion. The permeability of brain blood barrier (BBB) was estimated after 3 h of reperfusion. The infarct volume was measured at 72 h after reperfusion to determine the effects of MHT. The acute post-ischemic hyperperfusion and delayed hypoperfusion in ischemic perifocal region and sustained hypoperfusion in ischemic core were inhibited in MHTi + r and MHTi rats (P < 0.05). MHTi + r protection on post-ischemic progressive hypoperfusion in the perifocal region was more effective than that of MHTi (P < 0.05). The BBB disruption and the infarct volume were significantly reduced in both MHTi and MHTi + r groups (P < 0.05), especially in the MHTi + r rats. This study demonstrates that MHTi + r has more substantial protective effects on reducing ischemia/reperfusion injury than MHTi. It may inhibit post-ischemic hyperperfusion and delayed or sustained hypoperfusion in ischemic perifocal regions, and reduce brain blood barrier disruption in the cortex region. ",0
2198,10374505,Hodgkin's disease with concurrent infection of toxoplasmosis],"Hodgkin's disease (HD) is a specific type of malignant lymphoma characteristic of local and general lymphadenectasis. Aquired toxoplasmosis (AT) is one kind of lymphoadenopathy without fever and fatigue. When the two diseases coexist, clinical and pathological misdiagnosis may be made. This is the first male case of toxoplasmosis and Hodgkin's disease in China, diagnosed by surgical removal of the major part of the cervical and supraclavicular masses, detection of blood anti-toxoplasma gondii antibody, PCR analysis of toxoplasma gondii DNA, and pathological, ultrastructural and immunohistochemical studies of the tumour tissues. The patient treated by radiation and chemotherapy was abated. ",0
2199,10374556,The role of CDDP on cytotoxicity of TILs obtained from colorectal tumors],The effects of intravenous injection of cisplatin (CDDP) and the incubated with CDDP in vitro on the epitopes and cytotoxicity of TIL obtained from eight colorectal tumor patients were detected respectively by flow cytometer. There was a significant increase in CD3+/CD8+ subset in TIL in patients receiving intravenous injection of CDDP. And the cytotoxicity of these TILs increased significantly. The cytotoxities were positively correlated with the amount of CD3+/CD8+ subset in TIL. Raji cells incubated with CDDP in vitro showed increased susceptibility to TIL induced lysis. ,0
2200,10374651,Four behavioural syndromes of schizophrenia: a replication in a second inner-London epidemiological sample,"In a previous large epidemiological survey of patients with strictly defined schizophrenia in the London borough of Camden, we extracted four behavioural syndromes (Social withdrawal, Thought disturbance, Anti-social behaviour and Depressed behaviour) by factor analysis of MRC Social Behaviour Schedule (SBS) data. These syndromes had significant differential relationships to symptoms assessed using the Manchester Scale (MS), symptom-derived syndromes, and social functioning variables. A second inner-London epidemiological survey of schizophrenia in South Westminster using identical methodology found the same four behavioural syndromes with identical core component items. The same four behavioural syndromes were extracted, whether applying strict Feighner diagnostic criteria (n=112) or broader DSM-III-R criteria (n=198). The four syndromes extracted from the Feighner positive sample showed relationships to symptoms and social functioning variables similar to those found in the original Camden study. However, the symptom-derived factors were not the same and did not conform to the three recognised symptom-based syndromes of schizophrenia. This successful replication suggests that assessment of the four behavioural syndromes of schizophrenia offers a different perspective on disability and a potentially relevant measure in clinical practice, clinical trials and studies of the neuropsychology and pathophysiology of schizophrenia. ",0
2201,10374951,Effect of C-terminal deletions in the movement protein of cowpea chlorotic mottle virus on cell-to-cell and long-distance movement,"In order to elucidate the function of the C-terminal region of cowpea chlorotic mottle bromovirus (CCMV) movement protein (MP) in cell-to-cell movement, a set of deletions ranging from 10 to 80 amino acids (deltaMP10, deltaMP20, deltaMP33, deltaMP43, deltaMP60 and deltaMP80) was engineered into the MP gene encoded by the biologically active clone C3/deltaCP-EGFP, a variant of CCMV RNA3 that contained wild-type (wt) MP and the enhanced green fluorescent protein (EGFP) gene in place of the coat protein (CP). The effect of each MP deletion on cell-to-cell movement was examined in three susceptible host plants: Chenopodium quinoa, Nicotiana benthamiana and cowpea (Vigno sinensis cv. Black Eye). The results indicate that, except for mutant deltaMP43, infections resulting from the deletion mutants remained subliminal. Interestingly, infections resulting from inoculating mutant deltaMP43, which lacked the 43 most C-terminal amino acids, spread rapidly between cells and the number of infected cells expressing EGFP approached that of control inoculations made with C3/deltaCP-EGFP. To verify whether the presence of wt CP altered the movement behaviour of these mutants, each MP deletion was also incorporated into the genetic background of wt CCMV RNA3 (pCC3) and inoculated independently to all three hosts. The results suggest that the overall movement process exhibited by each MP mutant is influenced profoundly by the presence of CP and the particular host plant tested. ",0
2202,10375403,GroEL-assisted and -unassisted refolding of mature and precursor adrenodoxin: the role of the precursor sequence,"We have performed refolding studies on a [2Fe-2S] protein, adrenodoxin (Adx), and its precursor form, preadrenodoxin. In vitro, mature Adx is expressed as a soluble active form in Escherichia coli, but precursor Adx is expressed in inclusion bodies. Both mature and precursor Adx refolded spontaneously from their denatured forms and the recovery levels of enzyme activities were 40 and 37% for mature and precursor Adx, respectively. Furthermore, the interaction between GroEL- and Gdn-HCl-denatured mature and precursor forms was investigated. In the case of mature Adx, the activity was increased in the presence of either GroEL, GroES, or bovine serum albumin and the refolding of mature Adx is a nonspecific process. However, the GroEL-mediated reaction is specific for precursor Adx under the experimental conditions used here. A higher electron transfer activity is obtained after ATP addition to the GroEL-containing refolding mixture, and GroEL-precursor complexes were found by gel chromatography studies. Our observation suggests that the small single-domain protein Adx (mature form) folded independently of the chaperonin GroEL. The contribution of the chaperonin complexes to the folding is toward the aggregation-sensitive precursor Adx, which in vitro folded 1.3- to 1.4-fold slower than mature Adx. This demonstrates that the presequence is responsible for the formation of inclusion bodies and for the in vitro recognition motif for GroEL binding. ",0
2203,10375851,Epidemiologic survey of tongue lesions and analysis of the etiologic factors involved],"The prevalence of tongue lesions, and relationships with different systemic diseases, according to the international literature of epidemiologic studies were reviewed. The data were compared with a Hungarian investigation of 5034 individuals, between 1992 and 1995 in Budapest. Tongue lesions were found in 22.76% of the examined individuals. The ratio was similar in women (51%) and men (49%). Fissured tongue was found in 21.49%, geographic tongue in 2.21%, atrophic tongue in 0.12% and central papillar atrophy in 0.70%. These data agree in general with the epidemiological data found in the international literature. Some rare tongue alterations were also investigated. Lingua indentata was found in 1.49% and hypertrophy of papillae foliatae was found in 0.20%. The relationship with different systemic diseases was the following: In diabetes mellitus tongue lesions were found in 29.03%, in hypertension in 28.63%, connected to heart- and vascular diseases in 25.15%, to haematologic diseases in 17.54%. Tongue lesions were found in 23.86% in the case of liver disease, in 22.38% in gastrointestinal diseases and in 20.69% associated to tumors. In the case of Candida's infection tongue alterations were found in 41.6%, in smokers in 23.72%. Tongue lesions caused complaints rarely, only in 2.27%. The recognition of tongue lesions may be helpful in the early diagnosis of systemic diseases. ",0
2204,10376177,Transesophageal echocardiography for the evaluation and management of patients with cerebral ischemia,"To prevent recurrent strokes and transient ischemic attacks, considerable attention is devoted to investigating the etiology of acute cerebral ischemia in the large subpopulation of patients without an easily identifiable cause. In general, transthoracic echocardiography is an insensitive tool for the evaluation of patients with cerebral ischemia, unless clinical signs and/or symptoms of cardiac disease are present. Transesophageal echocardiography (TEE), because of its increased sensitivity for aortic arch atheromata, atrial septal pathology, left atrial thrombi, and valvular abnormalities, is the preferred cardiac imaging modality, especially in young patients, older patients with hypertension or systemic atherosclerosis, and patients with prosthetic heart valves. This paper reviews the prognostic and therapeutic impact of TEE in patients with cerebral ischemia, specifically focusing on the ability of information obtained by this technique to alter patient management and improve risk stratification. ",0
2205,10376242,Changes in plasma and milk concentrations of glucose and IGF-1 in response to exogenous growth hormone in lactating goats,"Exogenous growth hormone was administered subcutaneously to five lactating goats during the post-peak period of lactation. Milk yields increased significantly by approximately 20% in response to growth hormone. Blood and milk samples were taken in the periods before, during and after growth hormone treatment. The concentrations of glucose in milk increased significantly by approximately 50% in the period following growth hormone treatment at a time corresponding to the increase in milk yield. There was a transient increase in plasma glucose concentrations immediately following growth hormone treatment before either milk glucose concentrations or milk yields were increased. Both free and total IGF-1 concentrations in plasma increased slowly following growth hormone treatment. The increase in plasma IGF-1 corresponded to the increase in milk yields and milk glucose concentrations. Concentrations of IGF-1 in milk increased more rapidly than those in plasma, rising by approximately 150% following growth hormone treatment, and were starting to decline by the time that milk yield and milk glucose concentrations were at their maximum. As milk glucose concentrations have been shown previously to reflect changes in the intracellular concentration of glucose, the results indicate that part of the mechanism by which growth hormone stimulates milk production is by increasing the intracellular availability of glucose for lactose synthesis. The results also suggest that changes occur in the concentrations of IGF-1 in the environment of the mammary gland before changes are observed in the general circulation, and that these are reflected in the changed concentrations in milk. ",0
2206,10376391,Talc--a standard drug in the treatment of malignant pleural effusion],"Currently, talc is the most effective and widely-used agent for chemical pleurodesis in the treatment of both malignant pleural effusion and pneumothorax. Its popularity has been growing due to the low incidence of side effects, low cost and higher success rate in comparison with other agents (tetracyclines, bleomycin, Corynebacterium parvum). The guidelines for talc pleurodesis are summarized and the history of the Corynebacterium parvum as an agent for chemical pleurodesis is mentioned. Its production in the Czech Republic has been halted due to the increased interest in the talc as a chemical sclerosant. ",0
2207,10376899,Influence of sotalol on the time constant of isovolumic left ventricular relaxation in anesthetized dogs,"To determine the effects of various doses of sotalol on myocardial relaxation in healthy dogs. 12 healthy adult mixed-breed dogs anesthetized with thiopental and alpha-chloralose. Left ventricular pressure (LVP), aortic pressure, and aortic flow velocity were measured. The time constant of isovolumic relaxation (tau) was determined by means of linear regression of the natural logarithm of LVP and by means of direct measurement from the LVP-versus-time curve. Sotalol was administered IV at cumulative doses of 1, 2, 4, and 8 mg/kg to 6 dogs; the other 6 were used as controls. Mean systolic aortic pressure was used to assess afterload, and maximal rate of increase in LVP versus time (dP/dt) was used as an index of contractility. After administration of the first dose of sotalol, tau was increased significantly, and maximum dP/dt was decreased significantly, compared with baseline values. Administration of additional doses of sotalol did not result in any additional change in tau, but maximum dP/dt increased, and maximum dP/dt after administration of the final dose of sotalol was significantly higher than maximum dP/dt after administration of the first dose. There were no significant changes in mean systolic aortic pressure. In healthy dogs, sotalol did not have any negative effect on myocardial relaxation beyond those attributable to its beta-blocking properties, despite an increase in intracellular ionized calcium concentration, as suggested by an increase in maximum dP/dt after an initial decrease. ",0
2208,10376900,Biosafety of Brucella abortus strain RB51 for vaccination of mature bulls and pregnant heifers,"To determine shedding and colonization profiles in mature sexually intact bulls and pregnant heifers after vaccination with a standard calfhood dose of Brucella abortus strain RB51 (SRB51). 6 sexually mature 3-year-old Jersey bulls and 7 mixed-breed heifers in midgestation. Bulls and pregnant heifers were vaccinated IM with the standard calfhood dose of 3x10(10) colony-forming units of SRB51. After vaccination, selected body fluids were monitored weekly for vaccine organism shedding. Pathogenesis was monitored in bulls by weekly breeding soundness examination and, in heifers, by delivery status of the calf. Vaccine organism colonization was assessed by obtaining select tissues at necropsy for bacterial culture. Serologic analysis was performed by use of numerous tests, including complement fixation, an SRB51-based ELISA, and immunoblot analysis. After vaccination, none of the vaccinated bulls or heifers shed SRB51 in their secretions. Results of breeding soundness examination for bulls were normal as was delivery status of the pregnant heifers (6 live births, 1 dystocia). At necropsy, SRB51 was not recovered from any of the selected tissues obtained from bulls, heifers, or calves; however, serologic analysis did detect SRB51-specific antibodies in all cattle. Vaccination with the standard calfhood dose of SRB51 administered IM was not associated with shedding or colonization in sexually mature bulls or pregnant heifers. Also, under conditions of this study with small numbers of animals, IM vaccination with SRB51 does not appear to cause any reproductive problems when administered to sexually mature cattle. ",0
2209,10376909,Pulmonary distribution of aerosolized technetium Tc 99m pentetate after administration of a single dose of aerosolized albuterol sulfate in horses with recurrent airway obstruction,"To determine whether pulmonary distribution of aerosolized technetium Tc 99m pentetate is improved after inhalation of a single dose of albuterol sulfate in horses susceptible to recurrent airway obstruction (heaves). 6 horses with heaves and 4 horses with normal respiratory tract function. Images were obtained during ventilation of horses at baseline (maximal change in pleural pressure during tidal breathing [deltaPpImax] >15 cm H2O) and after aerosolized albuterol sulfate (360 microg) administration, with a 24-hour washout period between experiments. The deltaPpImax was determined prior to the baseline scan, prior to albuterol sulfate administration, and 5 minutes after albuterol sulfate administration. Images were assessed by visual inspection (semi-quantitative scoring system) and histogram analysis. Images obtained from horses with heaves had nonuniform pulmonary distribution of radionuclide characterized by poor penetration in peripheral lung fields and excess deposition in large airways. Histogram analysis of images of the caudal portions of the lungs revealed nonuniform radionuclide deposition in horses with heaves and uniform radionuclide deposition in control horses. Administration of a single dose of aerosolized albuterol sulfate improved pulmonary distribution of aerosolized radiolabeled pentetate suspension in horses with heaves but did not alter pulmonary distribution in clinically normal horses. Precedent bronchodilator administration may improve pulmonary distribution of aerosolized, surface-active anti-inflammatory preparations. ",0
2210,10376987,Clinico-pathological and treatment-related factors influencing survival in parotid cancer,"One hundred and three patients with primary parotid cancer treated surgically at the Christie Hospital, Manchester (1952-1992), were analysed to assess the influence on survival of prognostic and treatment-related factors. Thirty-seven patients were treated by surgery alone (SG), 66 received post-operative radiation (SG+RT). Median follow-up was 12 years, minimum 5 years. The 10-year disease-specific survival rates for stage I, II and III/IV were 96%, 61% and 17% respectively (P < 0.0001). The various histological types segregated into three survival patterns: low-, intermediate-and high-grade with 10-year survival rates of 93%, 41% and 50% respectively (P < 0.0001). On multivariate analysis, the factors influencing risk of cancer death in order of importance were: tumour size > 4 cm (P < 0.001), presence of nodes (P = 0.001), histology of adenoid cystic carcinoma (P = 0.01), high-tumour grade (P = 0.02) and perineural involvement (P = 0.01). Neither the extent of surgery nor the operator influenced outcome. Overall, adjuvant RT significantly reduced locoregional recurrence (SG+RT 15% vs SG 43%; P = 0.002) but not survival, although on subanalysis, there was a trend to improved survival with large cancers and high-grade tumours. Long-term survival is determined primarily by tumour characteristics, namely clinical stage and grade. Post-operative RT contributes significantly to locoregional control and probably confers some survival advantage in high-risk patients. ",0
2211,10376989,Knockout of the glutamate dehydrogenase gene in bloodstream Trypanosoma brucei in culture has no effect on editing of mitochondrial mRNAs,"Glutamate dehydrogenase (GDH) was shown previously to bind the 3' oligo[U] tail of the mitochondrial guide RNAs (gRNAs) of Leishmania tarentolae, apparently in the dinucleotide pocket (Bringaud F, Stripecke R, Frech GC, Freedland S, Turck C, Byrne EM, Simpson L. Mol. Cell. Biol. 1997; 17:3915-3923). Bloodstream Trypanosoma brucei cells in culture represent a good system to investigate the genetic effects of knocking out kinetoplastid nuclear genes to test a role in RNA editing, since editing of several mitochondrial genes occurs but is dispensable for viability (Corell RA, Myler P, Stuart K. Mol. Biochem. Parasitol. 1994; 64:65-74 and Stuart K. In: Benne R, editor. RNA editing--the alteration of protein coding sequences of RNA. New York: Ellis Horwood, 1993:25-52). Both GDH alleles of bloodstream T. brucei in culture were replaced by drug resistant markers without any effect on viability. The ratios of edited to unedited mRNAs for several cryptogenes were assayed by primer extension analysis. The steady state abundances of these edited RNAs were unaffected by the double knockout. This evidence suggests that GDH may not play a role in the editing reaction in bloodstream trypanosomes in culture, but this conclusion is tentative since there could be redundant genes for any biological function. We employed a double allelic replacement technique to generate a tetracycline inducible conditional expression of an ectopic copy of the deleted gene in bloodstream trypanosomes in culture. We used this strategy for genes encoding mitochondrial proteins which are not required during this stage of the life cycle, but as a general strategy it should be appropriate for generation of conditional null mutants for essential genes as well. ",0
2212,10377032,Human sperm proteome: immunodominant sperm surface antigens identified with sera from infertile men and women,"The objective of this study was to identify those immunodominant sperm antigens recognized by antisperm antibodies (ASA) in the serum samples of infertile men and women. High-resolution two-dimensional gel electrophoresis was employed to separate human sperm proteins using isoelectric focusing or nonequilibrium pH gradient electrophoresis, followed by PAGE. Serum samples from 15 infertile male subjects and 6 infertile female subjects that contained ASA as assayed by the immunobead binding test (IBT) were analyzed by Western blotting followed by enhanced chemiluminescence (ECL). Serum samples from 10 fertile subjects (5 males and 5 females) that were ASA negative by IBT were used as controls. The ECL blots were analyzed by computer scanning to compare the immunoreactivity between serum samples from fertile and infertile subjects and to identify the antigens unique to the sera of the infertile subjects; 98 sperm auto- and iso-antigenic protein spots were recognized by sera from infertile males and females but not from fertile subjects. Based on vectorial labeling with 125I at the sperm surface, a subset of 6 auto- and iso-antigens was identified as possibly relevant to antibody-mediated infertility. ",0
2213,10377229,New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: chemistry and pharmacological evaluation,"A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS. ",0
2214,10377266,Induction of gadd153 mRNA by nutrient deprivation is overcome by glutamine,"The growth arrest and DNA damage-inducible (gadd) genes are co-ordinately activated by a variety of genotoxic agents and/or growth-cessation signals. The regulation of gadd153 mRNA was investigated in renal proximal tubular epithelial cells (LLC-PK1) cultured in a nutrient- and serum-deprived medium. The addition of glutamine alone to LLC-PK1 cells cultured in Earl's balanced salt solution (EBSS) is sufficient to suppress gadd153 mRNA expression, and the removal of only glutamine from Dulbecco's modified Eagle's medium (DMEM) is also sufficient to induce gadd153 mRNA expression. Consistent with these findings, the inhibition of glutamine utilization with acivicin and 6-diazo-5-oxo-l-norleucine (DON) in cells grown in a glutamine-containing medium effectively induces gadd153 expression. Glutamine can be used as an energy source in cultured mammalian cells. However, it is unlikely that deficits in cellular energy stores (ATP) are coupled to gadd153 mRNA expression, because concentrations of ATP, UTP and GTP are all elevated in EBSS-exposed cells, and the addition of alpha-oxoglutarate to cells grown in EBSS has no effect on gadd153 mRNA expression. In contrast, concentrations of CTP decline substantially in EBSS and glutamine-deprived DMEM-cultured cells. Glutamine also serves as a precursor for the synthesis of protein and DNA. The addition of glutamine to cells grown in EBSS partly restores CTP concentrations. The addition of pyrimidine ribonucleosides (cytidine and uridine) to LLC-PK1 cells also restores CTP concentrations, in a manner commensurate with their relative abilities to overcome gadd153 expression. Finally, glutamine does not completely suppress DNA damage-induced gadd153 expression, suggesting that multiple signalling pathways lead to the expression of gadd153 mRNA under conditions of nutrient deprivation and DNA damage. ",0
2215,10377406,A functional bone morphogenetic protein system in the ovary,"""Bone morphogenetic proteins (BMPs) comprise a large group of polypeptides in the transforming growth factor beta superfamily with essential physiological functions in morphogenesis and organogenesis in both vertebrates and invertebrates. At present, the role of BMPs in the reproductive system of any species is poorly understood. Here, we have established the existence of a functional BMP system in the ovary, replete with ligand, receptor, and novel cellular functions. In situ hybridization histochemistry identified strong mRNA labeling for BMP-4 and -7 in the theca cells and BMP receptor types IA, IB, and II in the granulosa cells and oocytes of most follicles in ovaries of normal cycling rats. To explore the paracrine function of this BMP system, we examined the effects of recombinant BMP-4 and -7 on FSH (follicle-stimulating hormone)-induced rat granulosa cytodifferentiation in serum-free medium. Both BMP-4 and -7 regulated FSH action in positive and negative ways. Specifically, physiological concentrations of the BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. These effects were dose- and time-dependent. Furthermore, the BMPs increased granulosa cell sensitivity to FSH. Thus, BMPs have now been identified as molecules that differentially regulate FSH-dependent estradiol and progesterone production in a way that reflects steroidogenesis during the normal estrous cycle. As such, it can be hypothesized that BMPs might be the long-sought """"luteinization inhibitor"""" in Graafian follicles during their growth and development. """,0
2216,10377496,The consumption of cassava is not responsible for the etiology of endemic goiter in rural areas in Senegal],"An epidemiological study of iodine deficiency disorders (IDD) was carried out in West Senegal and Casamance. Five hundred and eighty five households were selected in 3 areas with a high prevalence of goiter. We assessed the relative impact of iodine deficiency (estimated by mean iodine excretion in the urine of family members) and cassava consumption (mean frequency of consumption by the household). Cassava consumption, even if on a regular basis, neither caused nor increased goiter formation in this area of West Africa. This was probably due to the local method of cassava root preparation, which reduces the amount of cyanogenic compounds consumed. Iodine deficiency was principally responsible for goiter formation. Therefore, the commercial availability of iodine-supplemented salt should lead to the eradication of IDD from Senegal in the near future. ",0
2217,10377534,Immune responses to Dermatophilus congolensis infections,"Complex mechanisms underly the establishment of dermatophilosis, an exudative and proliferative skin disease of ruminants. This multicomponent system involves the bacterium Dermatophilus congolensis, transmission by various routes including flies, host genetic factors and immunosuppression by Amblyomma variegatum ticks. Here, Nick Ambrose and colleagues summarize recent evidence for an association between A. variegatum and severe chronic dermatophilosis in cattle. Breed-based differences in resistance to dermatophilosis are probably related to immunity to ticks or resistance to the immunosuppressive effects of ticks. Immunity to dermatophilosis might involve non-classic responses mediated by CD1 antigen presentation and gammadelta T cells. Progress towards vaccination is further complicated by strain-specific acquired immunity to D. congolensis. ",0
2218,10377957,Influence of dietary selenium and vitamin E on the levels of fatty acids in brain and liver tissues of lambs,"In this study, the effects of dietary vitamin E, selenium, and their combination on the levels of fatty acid composition of the brain and liver tissues were examined. In brain tissue, the amounts of most fatty acids increased in vitamin E, combination and selenium groups compared with control group values. While the proportions of myristic, pentadecanoic, palmitic, linoleic, and total saturated fatty acids were decreased in vitamin E, Se and combination groups, eicosapentaenoic, total unsaturated and MUFA were increased in the same groups. In addition, the proportions arachidonic, eicosapentaenoic, total unsaturated, omega 6 and MUFA in the combination group were higher than in the control group. In liver tissue, the amounts of myristic, pentadecanoic, palmitic, eicosedienoic, eicosapentaenoic, docosahexaenoic, omega 3 and PUFA were higher in the combination group than in the control group. Also the proportions of eicosapentaenoic, docosahexaenoic acids in supplemented groups were higher than those in the control group. We conclude that dietary vitamin E and selenium have an influence on the levels of fatty acids in the brain and liver. ",0
2219,10378277,The crystal structure of human S-adenosylmethionine decarboxylase at 2.25 A resolution reveals a novel fold,"S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical regulatory enzyme of the polyamine synthetic pathway, and a well-studied drug target. The AdoMetDC decarboxylation reaction depends upon a pyruvoyl cofactor generated via an intramolecular proenzyme self-cleavage reaction. Both the proenzyme-processing and substrate-decarboxylation reactions are allosterically enhanced by putrescine. Structural elucidation of this enzyme is necessary to fully interpret the existing mutational and inhibitor-binding data, and to suggest further experimental studies. The structure of human AdoMetDC has been determined to 2.25 A resolution using multiwavelength anomalous diffraction (MAD) phasing methods based on 22 selenium-atom positions. The quaternary structure of the mature AdoMetDC is an (alpha beta)2 dimer, where alpha and beta represent the products of the proenzyme self-cleavage reaction. The architecture of each (alpha beta) monomer is a novel four-layer alpha/beta-sandwich fold, comprised of two antiparallel eight-stranded beta sheets flanked by several alpha and 3(10) helices. The structure and topology of AdoMetDC display internal symmetry, suggesting that this protein may be the product of an ancient gene duplication. The positions of conserved, functionally important residues suggest the location of the active site and a possible binding site for the effector molecule putrescine. ",0
2220,10378386,Variable histological expression of dystrophinopathy in two females,"We report two carriers of Xp21 muscular dystrophy with unusual clinical manifestations and striking variability of dystrophin deficiency within the same muscle biopsy. The first patient was a 60-year-old nun with recent onset of cramps and proximal weakness, mimicking an acquired myopathy. Muscle biopsy disclosed slight alterations in one sample and severe dystrophic changes in another; dystrophin was absent in 7% fibers in the former specimen and in 60% in the second. X inactivation was skewed with 90% cells inactivating the same X chromosome. The second patient was a 17-year-old girl with hyperCKemia, learning disability and a family history of X-linked muscular dystrophy. Muscle biopsy displayed slight fiber size variability and some internal nuclei; dystrophin was absent only in one muscle fiber. A second sample with the same morphological features demonstrated dystrophin deficiency with mosaic distribution. The pattern of X inactivation was normal. These cases emphasize the variability of histopathological changes and dystrophin deficiency in Xp21 muscular dystrophy carriers and the risk of sampling errors in muscle biopsy. ",0
2221,10378401,Iodine deficiency in Turkey,"Turkey is an iodine deficiency area. The overall goitre prevalence is thought to be 30%, and most epidemiological studies give figures compatible with mild to moderate iodine deficiency. However, it is suspected that there are regions where iodine deficiency might be more severe than previously known. In this study the goitre prevalence and iodine status in a mountain village in Central Anatolia were investigated and the results compared to those of an urban area with mild iodine deficiency. Parameters of iodine status in the mountainous region showed severe iodine deficiency comparable to that in Central Africa. It seems that there are regions in Turkey where current programmes of salt iodization will be inadequate to correct the problem of iodine deficiency. Our observations suggest that regional variations in iodine status may impede the success of salt iodization programmes, which alone may not be adequate for correction of the problem country-wide. Alternative sources of iodine should be considered in addition to expanded and more efficient salt iodization programmes. ",0
2222,10378685,Murine B-cell and T-cell epitopes of the allergen Hev b 5 from natural rubber latex,"Hev b 5, a proline-rich acidic protein with a predominantly random secondary structure, is a major allergen in natural rubber latex and a candidate for specific immunotherapy of latex allergy. As a first step in the identification of candidate peptides for immunotherapy, we have begun to identify the B-cell and T-cell epitopes of Hev b 5 in BALB/c mice. The mice were immunized with a Hev b 5 fusion protein. The B-cell epitopes were determined by the SPOTS method using overlapping octamers or by ELISA inhibition using a series of overlapping 20-mers. The T-cell epitopes were determined by the proliferation and cytokine release of splenocytes cultured in the presence of the 20-mers. Potential antibody binding regions included residues in regions 1-38, 55-74, 109-128 and 132-151. Examination of the binding sequences for common motifs suggested enhanced antibody binding to the KXEE or KEXE sequences, where X is empty, threonine or alanine. Splenocyte stimulation and cytokine release suggest T-cell epitopes with the regions 1-20, 37-56, 73-101 and 109-146. Since they may contain major T-cell epitopes but do not exhibit significant antibody binding, peptide regions 38-48 and 75-101 are candidates for specific immunotherapy to Hev b 5 in the BALB/c mouse model. ",0
2223,10378809,Acalculous gallbladder pain: a largely unrecognised entity,"To study the presentation for and outcome of cholecystectomy in patients with acalculous gallbladder pain. Sixty-six consecutive patients with prospective documentation underwent cholecystectomy for putative acalculous gallbladder pain between December 1988 to April 1995. The diagnosis was made on clinical grounds, but in the majority, a CCK oral cholecystogram was performed. Outcomes were assessed by postal questionnaire mailed in October 1995 or by the last recorded follow- up. Fifty-eight females and eight males, with a median age of 37.5 years had experienced abdominal pain, usually with associated nausea, for a median of three years. Preoperative investigations were non-contributory, with the exception of the CCK oral cholecystogram which was regarded as abnormal in all instances. At a median follow-up of 40 months, 48 patients (72.7%) described their symptoms as either totally relieved or much improved by cholecystectomy. Though the pathophysiology remains poorly understood, there is clearly a group of patients who suffer from gallbladder pain in the absence of gallstones and who benefit from cholecystectomy. ",0
2224,10378945,Electromyogram-controlled functional electrical stimulation for treatment of the paralyzed upper extremity,"Spinal cord lesions at level C5 to C6 lead to loss of hand functions and lesions at C4 to additional deficits of arm functionality. The presented dual channel surface stimulator with dual channel electromyogram (EMG) measurement was developed to investigate control strategies for an EMG-controlled implantable stimulation system and serves in addition as a therapy device for patients with partial innervation but weak muscle force. Four different control strategies for stimulation amplitude are available. The amplitude can be preset manually or can follow the preprocessed EMG signals proportionally. The shoulder control program allows proportional control of both stimulation channels with one EMG channel while the second EMG channel serves as the channel selector. Finally, a special feedback training program triggers a stimulation burst when EMG activity is detected. During a 2 year patient study, 18 patients from 2 hospitals and 1 rehabilitation center performed the feedback training. Almost all patients obtained an improvement of functionality. Apart from muscle strengthening, the feedback effect led to an improvement of proprioception and supported relearning of motions. For the documentation of the training status, functional muscle test (British Medical Research Council) and measurements of power, angle, torque, muscle fatigue, and EMG were performed. Obviously, EMG triggered stimulation provides several advantages compared to conventional passive electrical stimulation. ",0
2225,10379105,Maxillary sinus augmentation prior to placement of endosseous implants: A histomorphometric analysis,"""The aim of this prospective study was to histomorphometrically evaluate at various time intervals the mineralization stage and process of an allogeneic-xenogeneic bone graft used in sinus augmentation procedures. One biopsy was taken from 20 patients at either 6, 8, 10, or 12 months after sinus augmentation. Immediately following the biopsy, an endosseous implant was placed into the biopsy site. This protocol provided 4 groups of 5 patients each, based on healing time following sinus augmentation. Using backscattered electron image analysis, the specimens were histomorphometrically analyzed to determine the volume fractions of residual cancellous bone, newly formed bone, soft tissue, bovine hydroxyapatite, and """"remineralized"""" freeze-dried demineralized bone allograft (rDFDBA). """"Remineralization"""" of DFDBA particles was observed in a few areas in all specimens. Polarized light microscopy showed that only the 12-month biopsies had a predominance of lamellar bone formation. The area within the biopsies that represented the residual alveolar ridge consisted of 32.6% +/- 8.6% (mean +/- SD) of bone. In the grafted area of the biopsies the volume fraction of newly formed bone at 12 months (20.7% +/- 8.3%) was significantly higher (P < .05, analysis of variance) than at 6 months (8.1% +/- 3.0%). There was no statistically significant difference between newly formed bone in the inferior, central, and superior grafted areas in all 4 time intervals. This prospective study indicates that the mineralization process of an allogeneic-xenogeneic sinus graft is incomplete 6 months after the sinus augmentation procedure. New bone formation increased up to 12 months postaugmentation; however, it remained lower than the volume of residual bone. """,0
2226,10379177,Application of the principles of the systemic approach to interpretation of the pathogenesis of traumatic shock and traumatic disease],Experimental and clinical studies for many years led the authors to the conclusion that systemic approach seems most adequate for current interpretation of pathogenesis of traumatic disease (TD) and its component--traumatic shock (TS). It seems valid to assess TD and TS severity and dynamics by the proportion of pathological and adaptive reactions. Drugs should be used for maintenance and stimulation of adaptive reactions. Strong correlations of dynamics and severity of TD and TS enable prediction of TD course and outcome in acute period by time criterion (+)-T and distinguish three degrees of TD severity as well as evaluation of probability of favorable or unfavorable (lethal) outcome. ,0
2227,10379325,The vascularization of the os calcaneum and the clinical consequences,"This study was conducted to analyze extraosseous and intraosseous vascularization of the os calcaneum and to elucidate possible clinical manifestations. The arteries of 13 lower leg and foot specimens of human cadavers were injected with a polymer and subjected to maceration or were embedded in plastic. The examination revealed that 45% of the bone is vascularized via medial arteries and 45% via lateral arteries, whereas the remaining 10% is supplied by the sinus tarsi artery. From the medial side, two or three vessels branch off the posterior tibial artery, penetrate the calcaneus below the sustentaculum, and supply the medial part of the posterior joint. The lateral calcaneal artery normally is a branch from the posterior tibial artery. In two of 13 specimens, this lateral supply comes from the peroneal artery. The medial and lateral intraosseous arterial supply for the calcaneus is equal. Inside the bone there is a water-shed zone where the medial and lateral arterial supply meet in the midline. Only 10% of the blood flow is supplied by vessels in the sinus tarsi. Clinically, interruption of the lateral calcaneal artery during the conventional lateral surgical approach for a calcaneus fracture may result in ischemic bone necrosis. The lateral calcaneal artery could supply a local microvascular flap to cover soft tissue defects of the heel. A compartment syndrome after a calcaneus fracture may be caused by bleeding from the medial calcaneal arteries into the quadratus plantae compartment. ",0
2228,10379874,Identification and mapping of novel tumor suppressor loci on 6p in diffuse large B-cell non-Hodgkin's lymphoma,"Allelic deletions have been thought to be indicators of the presence of tumor suppressor genes (TSGs). As indicated by this allelotype study using 39 highly informative microsatellite markers distributed among all autosomal chromosomes, frequent loss of heterozygosity (LOH) has been found at 6p in B-cell non-Hodgkin's lymphoma. To identify the commonly deleted regions (CDRs), we performed fine deletion mapping using 26 highly polymorphic microsatellite markers on 6p. The most frequent LOH occurred at D651721, where 9 of 18 of the informative cases (50%) had allelic losses. Seventeen of 32 cases (53%) exhibited LOH at least at one locus on 6p. Ten of these 17 cases showed interstitial deletions, and their LOH patterns indicated two CDRs on 6p; one between D6S1721 and D6S260 (at 6p23-24), and the other between D6S265 and D6S291 (at 6p21). The genetic distance of both CDRs was 6 cM. The CDKN1A (p21) gene is reported to be located within the interval of the CDR at 6p21, but no mutation of the gene was found in these 32 patients. These data suggested that these two loci might harbor novel putative TSGs responsible for the pathogenesis of malignant lymphoma. We have constructed a contig of yeast artificial chromosome (YAC) clones spanning the most frequent CDR at 6p23-24. This YAC contig can be used for fine physical mapping of the region and cloning of candidate TSGs. ",0
2229,10379955,The fungicide carbendazim induces meiotic micronuclei in the spermatids of the rat testis,"Whether the fungicide carbendazim affects the meiotic spermatocytes and consequently induces chromosome aberrations in the spermatids was determined in the adult rat testis using the micronucleus test. Round spermatids containing micronuclei (MN) were significantly increased in number at stages I and V on days 1 and 4.5 after treatment with carbendazim (100 mg/kg), respectively (p<0.05). Immunocytochemistry indicated that approximately 68% of the carbendazim-induced MN contained kinetochores. These results suggest that carbendazim induces chromosome aberrations in spermatids with a high incidence of aneuploidy. ",0
2230,10380229,"The hydrophilic, protease-sensitive terminal domains of eucaryotic DNA topoisomerases have essential intracellular functions","The amino-terminus of eucaryotic DNA topoisomerase I and the carboxy-terminus of eucaryotic DNA topoisomerase II contain sequences that are enriched in charged amino acid residues, hyper-sensitive to protease digestion, not required for the in vitro topoisomerase activities, able to tolerate insertion and deletion mutations, and thus may have a disordered structure. In an interesting contrast to the catalytically essential core domain, the sequences in these terminal hydrophilic domains are not conserved among the topoisomerases from different species. However, many lines of evidence, including those presented here, demonstrate that the topoisomerase tail domains have critical intracellular functions. The biological functions of the amino-terminus of topoisomerase I include the nuclear import and targeting to the transcriptionally active loci. The carboxy-terminus of topoisomerase II also contains the sequences necessary for nuclear localization and possibly sequences necessary for other critical functions. ",0
2231,10380527,Recurrent thrombosis of the venous supply of the upper extremity],"The incidence of DVT in axillo-subclavian district is rather low. Up-to-date reports show however it is progressively increasing, owing to the widespread diffusion of intravenous prosthetic devices. While the opportunities of a correct diagnosis are becoming various, particularly because of the development of echo color-Doppler and imaging techniques, there is indecision for the treatment: the question is about a medical and a surgical therapy. Neither the former nor the latter are well established. This case report is about a 61-year-old woman affected by a recurrent DVT of the subclavian and axillary veins, who never underwent operation and/or handling of the venous district. Clinical tests didn't show any well determinate cause of thrombosis. It was decided not to treat the patient surgically, so a medical therapy was undertaken. Now she is completely recovered. ",0
2232,10380565,Prevalence of intestinal helminthiasis in 100 municipalities in Venezuela (1989-1992)],"A total of 113,254 individuals from 100 venezuelan municipalities were studied by mean of Kato-Katz coprological examination and the geohelminth prevalences were established. The national prevalences of T. trichiura, A. lumbricoides and Anquilostomideos were 32.6%, 26.9% and 5.6% respectively+. For T. trichiura the highest values were obtained for the following municipalities: Arévalo González (54.6%) in Miranda state, Urama (76.9%) in Carabobo state and Punta de Piedra (78.4%) in Sucre state. For A. lumbricoides the highest values were determined in Punta de Piedra (63%), Tunapuy (61.9%) in Sucre state and Arévalo González (62.7%) in Miranda state. For hookworm the highest values were detected in El Amparo (39.5%) and San Camilo (35.9%) in the state of Apure. In relation to the age, the highest prevalence of Ascariosis and Trichuriosis were determined in pre-school and school children and for hookworm in adolescents and adults. A high variability between the municipalities belonging to the same state for the three geohelminths was observed. ",0
2233,10380819,The rationale for early diagnosis of cancer--the example of breast cancer,"The main advantage of early diagnosis of cancer is the reduction of tumor size at initial treatment and thereby an increase in the proportion of patients without distant dissemination. This benefit is illustrated by the example of breast cancer. A model of its natural history was built using data extracted from the files of over 4000 patients followed in the same institution for 20 to 35 years. The model was used to quantify the impact of tumor size, histologic grade, and lymph node involvement on the probability of distant spread. The relationships were found to be highly significant. The model also and unexpectedly revealed that the tumors progress while they grow; avoiding histologic progression is therefore another advantage of early diagnosis. The model showed that residual tumor can be a nidus for distant dissemination, and that consistency between the prediction of the model and the results of post-operative radiotherapy is satisfactory. Conversely to what is often stated, the benefits of post-operative radiotherapy appear to be greater for small tumors, even in the absence of lymph node involvement, than for large ones. The model could be used to help improve screening strategies, but more data are required, in particular for the young age range. ",0
2234,10380840,The distribution of YKL-40 in osteoarthritic and normal human articular cartilage,"YKL-40, also called human cartilage glycoprotein-39, is a major secretory protein of human chondrocytes in cell culture. YKL-40 mRNA is expressed by cartilage from patients with rheumatoid arthritis, but is not detectable in normal human cartilage. The aim was to investigate the distribution of YKL-40 in osteoarthritic (n=9) and macroscopically normal (n=5) human articular cartilage, collected from 12 pre-selected areas of the femoral head, to discover a potential role for YKL-40 in cartilage remodelling in osteoarthritis. Immunohistochemical analysis showed that YKL-40 staining was found in chondrocytes of osteoarthritic cartilage mainly in the superficial and middle zone of the cartilage rather than the deep zone. There was a tendency for high number of YKL-40 positive chondrocytes in areas of the femoral head with a considerable biomechanical load. The number of chondrocytes with a positive staining for YKL-40 was in general low in normal cartilage. The present findings, together with previous observations, suggests that YKL-40 may be of importance in cartilage remodelling/degradation of osteoarthritic joints. ",0
2235,10381104,Pharmacodynamics of levofloxacin and ciprofloxacin against Streptococcus pneumoniae,"An in-vitro pharmacokinetic model was used to compare the pharmacodynamics of levofloxacin and ciprofloxacin against four penicillin-susceptible and four penicillin-resistant Streptococcus pneumoniae. Logarithmic-phase cultures were exposed to the peak concentrations of levofloxacin or ciprofloxacin observed in human serum after 500 mg and 750 mg oral doses, human elimination pharmacokinetics were simulated, and viable bacterial counts were measured at 0, 1, 2, 4, 6, 8, 12, 24 and 36 h. Levofloxacin was rapidly and significantly bactericidal against all eight strains evaluated, with eradication of six strains occurring despite area under the inhibitory curve over 24 h (AUIC24) values of only 32-64 SIT(-1) x h (serum inhibitory titre over time). The pharmacodynamics of ciprofloxacin were more variable and the rate of bacterial killing was consistently slower than observed with levofloxacin. Ciprofloxacin eradicated five strains despite having an AUIC24 of only 44 SIT(-1) x h. These data suggest that the increased potency of levofloxacin and more favourable pharmacokinetics compared with ciprofloxacin provide enhanced pharmacodynamic activity against S. pneumoniae. Furthermore, these data suggest that the minimum AUIC required for clinical efficacy against and eradication of S. pneumoniae with levofloxacin and ciprofloxacin may be well below the 125 SIT(-1) x h identified by other studies. ",0
2236,10381644,Truncated products of the vestigial proliferation gene induce apoptosis,"The vestigial (vg) gene in D. melanogaster, whose mutant phenotype is characterized by wing atrophy, encodes a novel nuclear protein involved in cell proliferation. The original vg mutant (vgBG) displays massive apoptosis in the wing imaginal disc. Here we tested the hypothesis that the vg mutant phenotype could be due: (i) to lack of cell proliferation in null mutants due to the absence of the Vg product and, (ii) to apoptosis in vgBG and other mutants due to the presence of a major Vg truncated product. In agreement with our hypothesis no cell death was observed in null vg mutants, and the anticell death baculovirus P35 product is unable to rescue the mutant phenotype caused by absence of the Vg product. In addition, expression of the antiproliferative gene dacapo, the homolog of p21, induces a mutant wing phenotype without inducing cell death. In contrast the wing phenotype of the original vg mutant could be reproduced by the ectopic expression of the reaper cell death gene when expressed by vg regulatory sequences. In agreement with the hypothesis, the classic vg mutant spontaneously displays an increase in reaper expression in the wing disc and its phenotype can be partially rescued by the P35 product. Finally, we showed that ectopic expression of a truncated Vg product is able on its own to induce ectopic cell death and reaper expression. Our results shed new light on the function of the vg gene, in particular, they suggest that the normal and truncated products affect vg target genes in different ways. ",0
2237,10381761,Pituitary adenylate cyclase-activating peptide as a neurotransmitter in the canine ileal circular muscle,"Pituitary adenylate cyclase-activating peptide (PACAP)1-27, PACAP1-38, and vasoactive intestinal peptide (VIP) initiated dose-dependent contractions of canine ileal circular muscle after intra-arterial injection in vivo or ex vivo. PACAP1-27- and VIP-induced contractions approached the tissue maximum; VIP was 100-fold less potent. PACAP1-38 was more potent than VIP. PACAP1-27 contractions in vivo were unaffected by hexamethonium, reduced equally by atropine or atropine plus hexamethonium, and abolished by tetrodotoxin (TTX), suggesting that PACAP released acetylcholine and another excitatory neurotransmitter from postganglionic cholinergic enteric nerves. In myenteric plexus-free circular muscle strips, PACAP1-27 at 10(-9) M and PACAP1-38 or VIP at 10(-7) M increased [3H]acetylcholine release during nerve stimulation, suggesting the locus of one postganglionic site at which PACAP1-27 acts. All agonists inhibited nerve-mediated contractions in vivo with a potency rank order similar to that for excitation. Inhibition of nitric oxide (NO) synthetase or TTX decreased the duration and amplitude of PACAP1-27- but not PACAP1-38-induced inhibition. Inhibition of NO synthetase abolished VIP-induced inhibition, but TTX did not. Submaximal contractions to acetylcholine were amplified by PACAP1-27 or VIP before TTX and inhibited after TTX. Thus, both PACAP molecules and VIP directly inhibit and indirectly excite smooth muscle contractions. PACAP1-27 and VIP also release NO. The functional potency differences between PACAP1-27 and VIP suggest PAC1 receptors mediate all responses, likely through the stimulation of adenylate cyclase. ",0
2238,10381797,Stimulation of epithelial sodium channel activity by the sulfonylurea glibenclamide,"The amiloride-sensitive epithelial sodium channel (ENaC) contributes to the regulation of the sodium balance and blood pressure because it mediates a rate-limiting step in sodium transport across the epithelium of the distal nephron. The activity of ENaC is regulated by hormones, such as aldosterone and vasopressin, and by other intracellular or extracellular factors, but the mechanisms of these regulations are not yet well understood. It has been proposed that ENaC may be regulated by an associated ATP-binding cassette protein such as the cystic fibrosis conductance regulator or the K channel-associated sulfonylurea receptor. Glibenclamide, a known inhibitor of sulfonylurea receptor and cystic fibrosis conductance regulator, induced a dose-dependent and reversible stimulation (of the order of 40-50%) of the amiloride-sensitive current in oocytes expressing Xenopus ENaC, with a K1/2 of 45 +/- 5 microM. A similar effect was observed in oocytes expressing human ENaC, but not rat ENaC. Measurements performed with various combinations of rat and Xenopus subunits indicated that several subunits are involved in this effect. Glibenclamide also increased the transepithelial Na transport by the A6 Xenopus kidney cell line. Single-channel current recordings showed a doubling of the number of the open channels when glibenclamide was applied locally to the extracellular surface of the cell membrane. These results support the hypothesis of the existence of an associated ATP-binding cassette-type regulatory protein associated with the epithelial sodium channel. ",0
2239,10381927,"Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats","To investigate the role of the cholinergic system in regulation of cholangiocyte functions, we evaluated the effects of vagotomy on cholangiocyte proliferation and secretion in rats that underwent bile duct ligation (BDL rats). After bile duct ligation (BDL), the vagus nerve was resected; 7 days later, expression of M3 acetylcholine receptor was evaluated. Cholangiocyte proliferation was assessed by morphometry and measurement of DNA synthesis. Apoptosis was evaluated by light microscopy and annexin-V staining. Ductal secretion was evaluated by measurement of secretin-induced choleresis, secretin receptor (SR) gene expression, and cyclic adenosine 3',5'-monophosphate (cAMP) levels. Vagotomy decreased the expression of M3 acetylcholine receptors in cholangiocytes. DNA synthesis and ductal mass were markedly decreased, whereas cholangiocyte apoptosis was increased by vagotomy. Vagotomy decreased ductal secretion. Forskolin treatment prevented the decrease in cAMP levels induced by vagotomy, maintained cholangiocyte proliferation, and decreased cholangiocyte apoptosis caused by vagotomy in BDL rats. Cholangiocyte secretion was also maintained by forskolin. Vagotomy impairs cholangiocyte proliferation and enhances apoptosis, leading to decreased ductal mass in response to BDL. Secretin-induced choleresis of BDL rats was virtually eliminated by vagotomy in association with decreased cholangiocyte cAMP levels. Maintenance of cAMP levels by forskolin administration prevents the effects of vagotomy on cholangiocyte proliferation, apoptosis, and secretion. ",0
2240,10382187,"The Index of Nausea, Vomiting, and Retching: a new format of the lndex of Nausea and Vomiting","To determine the reliability of the Index of Nausea, Vomiting, and Retching (INVR), a new format of the Rhodes Index of Nausea and Vomiting Form 2 (INV-2). A parallel form study was conducted at a large, Midwestern teaching hospital and a cancer center. Convenience sample of 159 subjects: 40 obstetrical, 60 oncological, 59 medical/surgical. Two instruments, the INVR and the INV-2, were administered approximately 30-60 minutes apart. One-half of the subjects completed the INVR first, and the other half completed the INV-2 first. Equivalency measures of reliability correlation coefficients for both instruments. A high rate of agreement was found in the responses between the two forms. In cases of clear disagreement, the responses to the INVR were more frequently consistent than the responses to the original form. INVR has tested reliability and is more user friendly for the patient and the healthcare provider. Nurses have a focal role in managing symptoms. Managing nausea, vomiting, and retching requires excellent assessment skills of the patient's personal symptom experience and knowledge of pharmacology. Efficient, cost-saving assessments require accurate self-report instruments that permit patients to quantify their symptom experiences. The INVR can provide a scientific base from which to prescribe and teach patients and may improve their quality of life. Reliable and valid self-reporting instruments are essential for managing these adverse symptoms. ",0
2241,10382232,Effects of interleukin-1 beta on DNA synthesis in rat alveolar type II cells in primary culture,"Proliferation of alveolar type II cells is critical for restoration of the integrity of alveolar epithelium in alveolar injuries caused by a number of different aetiologies. Because effects of inflammatory cytokines on the proliferation of alveolar type II cells are not clear, we investigated the effects of interleukin-1 beta (IL-1 beta) on [3H]-thymidine incorporation into DNA in rat alveolar type II cells in primary culture. Interleukin-1 beta enhanced the [3H]-thymidine incorporation dose and time dependently. The increase of [3H]-thymidine incorporation was observed in parallel with increased number of rat alveolar type II cells. The effect of IL-1 beta on [3H]-thymidine incorporation was additive to effects of growth factors which were known to act as mitogenic factors for type II cells. Anti-interleukin-1 beta antibody or IL-1 receptor antagonist partially inhibited the effects of IL-1 beta on [3H]-thymidine incorporation. Their combination completely inhibited the effects of IL-1 beta. In the absence of IL-1 beta, the combination inhibited the [3H]-thymidine incorporation to a level under that in the control. Isolated alveolar type II cells were immunocytochemically stained positive with anti-IL-1 beta antibody. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed the presence of the mRNA for IL-1 beta in cultured alveolar type II cells. These results demonstrate that exogenous IL-1 beta stimulates DNA synthesis in alveolar type II cells and that the cells also produce IL-1 beta endogenously and suggest that endogenous IL-1 beta may mediate basal DNA synthesis of alveolar type II cells. ",0
2242,10382460,"Divergent backgrounds, unified goals: continuing education program for multinational nurses in a hospital in the Middle East","This article reports continuing education as one strategy used to resolve the competence issues of multinational nurses working in Saudi Arabia. Four categories of Staff Nurses (I, II, III, and IV), N = 111, recruited from eight countries participated in a study that describes the outcomes of a training session for nurses at one hospital in Dammam. An average of 12 to 13 nurses attended 1-day courses over a 9-day period to address urgent policies and procedures selected from the hospital's guidelines for patient care. Results from pretests and posttests completed by the participants yielded information that echo differences of the nurses in terms of country of origin and possibly educational background, rather than their recruitment status with which the employers determine remuneration and responsibilities. The findings suggest ways to ensure that future nurses derive more benefit, and that recruiters and employers reconsider the criteria used for recruitment and placement. ",0
2243,10382476,Satisfaction with midwife-managed care in different time periods: a randomised controlled trial of 1299 women,"To compare women's satisfaction with midwife-managed care with 'shared care' over three different time periods. Randomised controlled trial. Glasgow Royal Maternity Hospital, Glasgow, UK. 1299 women experiencing normal pregnancy (consent rate: 82%). Six hundred and forty-eight women were randomised to midwife-managed care and 651 to 'shared care'. Three self-report questionnaires were sent to women's homes. The questionnaires examined: satisfaction with antenatal care at 34-35 weeks' gestation, and satisfaction with intrapartum, hospital- and home-based postnatal care at seven weeks postnatally. The third questionnaire reviewed satisfaction with intrapartum care seven months after delivery. Women in both groups were satisfied. However, women in the midwife-managed group were more highly satisfied in relation to the dimensions examined: relationships with staff, information transfer, choices and decisions, and social support. The differences between the two groups were evident for all time periods (i.e. antenatal, intrapartum and postnatal periods) and were sustained at seven-month follow-up. This is illustrated in the mean scores for relationships with staff, as measured at 34-35 weeks' gestation (possible range -2; very negative attitudes to 2; very positive attitudes). Women in the midwife-managed group scored a mean of 1.22 compared to 0.74 for the 'shared care' group (mean diff: 0.48; 95% CI: 0.42 to 0.55). While women in both groups were more likely to make positive rather than negative comments in open-ended questions, the midwife-managed group were more likely to make positive comments whereas the 'shared care' group were more likely to make negative comments. Midwife-managed care for healthy pregnant women which is integrated into existing services improves satisfaction with antenatal, intrapartum and postnatal care. ",0
2244,10382586,Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: the German BABYDIAB study,"Islet autoantibodies precede the clinical onset of Type I (insulin-dependent) diabetes mellitus. The cumulative development of such autoantibodies in infants followed from birth and in particular infants with high-risk HLA genotypes is poorly defined, but such information is essential to design trials to prevent islet autoimmunity. HLA genotypes were determined in offspring of parents with Type I diabetes who were followed from birth for at least 2 years (median follow-up: 3.1 years) and who were characterised for the expression of insulin, GAD65, IA-2 and islet cell autoantibodies at birth, 9 months, 2 and 5 years of age. The HLA genotypes DRB1*03/04(DQB1*57non-Asp) and DRB1*04/04(DQB1*57non-Asp) were present in 7.1% and 5.0% of offspring of parents with Type I diabetes. The frequency of both genotypes was increased in offspring who developed islet autoantibodies within the first 2 years of life (27.3% vs 5.5%, odds ratio 6.3 [p = 0.002] and 22.7% vs 4.2%, odds ratio 6.6 [p = 0.003]) and half of all offspring who developed antibodies had these genotypes. Other genotypes were not associated with an increase in risk. By life-table analysis, the cumulative risk of developing islet autoantibodies by the age of 2 years was 20% (95% CI 9.4,30.6) for offspring carrying either the DRB1*03104(DQB1*57non-Asp) or the DRB1*04/04(DQB1*57non-Asp) genotype compared with 2.7% (95% CI 1.2,4.2) for offspring without these genotypes (p < 0.0001). These data show that early appearance of islet autoantibodies is remarkably frequent for DR3/4 heterozygous and DR4/4 homozygous offspring and indicate that primary prevention could be considered once available in an offspring cohort selected for these genotypes. ",0
2245,10383010,Low levels of dehydroascorbic acid in uraemic serum and the partial correction of dehydroascorbic acid deficiency by haemodialysis,"Vitamin C is currently considered a potent water-soluble antioxidant and it appeared reasonable to study the metabolic changes of vitamin C in uraemia and during haemodialysis. We measured the levels of ascorbic, dehydroascorbic and diketogulonic acids in sera of uraemic patients before and during haemodialysis, using the 2,4-dinitrophenylhydrazine method. The results indicate that the levels of ascorbic and dehydroascorbic acids in uraemic sera are low in comparison with controls, but the levels of diketogulonic acid are higher than in healthy persons. The comparison of ratios between levels of these substances in uraemic sera and in normal sera indicate that the oxidation of ascorbic acid to dehydroascorbic in uraemia proceeds much slower than in controls. We propose that uraemic patients are characterized by pronounced deficiency of dehydroascorbic acid. A marked decrease of ascorbic and diketogulonic acid plasma levels, and a pronounced increase of dehydroascorbic acid levels during haemodialysis was observed. Ratios between plasma levels of ascorbic and dehydroascorbic acids following haemodialysis are the same as in healthy persons. Uraemic patients are characterized by marked deficiency of dehydroascorbic acid and this deficiency can be partially corrected by haemodialysis. ",0
2246,10383126,Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay,"MYC gene overexpression was identified recently as a downstream step at the end of the Wnt/APC/beta-catenin pathway dysregulation observed in colorectal cancer (T-C. He et al., Science (Washington DC), 281: 1509-1512, 1998). It thus appears that an excess of c-myc protein is a primary cause of numerous cancers. In breast cancer, MYC has been studied mostly at the DNA level because of the poor quality of available antibodies against the protein product. The renewed interest in MYC calls for a sensitive and accurate method for analyzing MYC overexpression in breast tumors. We have developed a real-time quantitative reverse transcription-PCR assay based on TaqMan fluorescence methodology to quantify the MYC mRNA copy number. We validated the method on a large series of breast tumors. MYC gene overexpression was observed in 29 of 134 (22%) breast tumor RNAs, ranging from 3.2 to 19 times the level in normal breast tissues. These data imply that dysregulated MYC gene expression is potentially involved in the pathogenesis of breast cancer, especially by favoring local cell proliferation. We also found that MYC gene overexpression was rarely due to an increased MYC gene copy number in breast cancer. This new, simple, rapid, and semiautomated method will be useful for screening cancer patients for MYC overexpression and will prove a powerful tool in large, randomized, prospective, cooperative group trials and in the MYC-based therapy project. ",0
2247,10383621,Optic flow illusion and single neuron behaviour reconciled by a population model,"Radial patterns of optic flow contain a centre of expansion that indicates the observer's direction of self-movement. When the radial pattern is viewed with transparently overlapping unidirectional motion, the centre of expansion appears to shift in the direction of the unidirectional motion [Duffy, C.J. & Wurtz, R.H. (1993) Vision Res., 33, 1481-1490]. Neurons in the medial superior temporal (MST) area of monkey cerebral cortex are thought to mediate optic flow analysis, but they do not shift their responses to parallel the illusion created by transparent overlap. The population-based model of optic flow analysis proposed by Lappe and Rauschecker replicates the illusory shift observed in perceptual studies [Lappe, M. & Rauschecker, J.P. (1995) Vision Res., 35, 1619-1631]. We analysed the behaviour of constituent neurons in the model, to gain insight into neuronal mechanisms underlying the illusion. Single model neurons did not show the illusory shift but rather graded variations of their response specificity. The shift required the aggregate response of the population. We compared the model's predictions about the behaviour of single neurons with the responses recorded from area MST. The predicted distribution of overlap effects agreed with that observed in area MST. The success of the population-based model in predicting the illusion and the neuronal behaviour suggests that area MST uses the graded responses of single neurons to create a population response that supports optic flow perception. ",0
2248,10383699,Origin of hyperplastic epithelial cells in idiopathic collapsing glomerulopathy,"Glomerular epithelial cell hypertrophy and hyperplasia are listed as the primary criteria for the diagnosis of collapsing glomerulopathy (CG), a distinct variant of focal segmental glomerulosclerosis. However, the extent of podocyte phenotypic alterations that occur in CG, and the origin of the hyperplastic epithelial cells remain to be established. Renal biopsy materials from seven out of three patients with CG were studied by serial section analysis for immunohistochemistry and electron microscopy. Markers for podocytes (PHM5 and synaptopodin), parietal epithelial cells (PECs: cytokeratin) and macrophages (CD68) were used for the immunohistochemistry. Multiple ultrathin sections from a total of 15 glomeruli, including some from patients with CG, were examined by electron microscopy. Glomerular adhesions occurred in 71% of the serially sectioned glomeruli taken from patients with CG. Hyperplastic epithelial cells were immunonegative for podocyte markers and CD68, but invariably immunopositive for cytokeratin. Electron microscopy revealed that detachment of the podocytes from involved glomerular capillary walls was extensive. Many of the detached podocytes appeared to be necrotic and apoptotic. In contrast, junctional complexes of desmosomes and zonula adherens connected hyperplastic epithelial cells to each other. Cilia were also often observed. The results of our ultrastructural and immunohistochemical study suggest that the hyperplastic epithelial cells observed in cases of CG are derived from PECs. Our results raise the possibility that PECs play a general role in covering glomerular tufts from which the podocytes have disappeared. ",0
2249,10383747,Long-term culture of murine epidermal keratinocytes,"The production of transgenic and null mice with skin abnormalities makes it increasingly important to establish cultures of mouse epidermal keratinocytes for in vitro studies. This requires that each cell line be derived from a single mouse and that the cells be carried for multiple passages. Freezing the cells would also be advantageous by allowing comparison of keratinocytes from several mouse lines at the same time. Mouse keratinocytes, however, have been exceedingly difficult to grow as primary cultures, and subculturing these cells has been virtually impossible until now. We describe a gentle dissociation method and a highly supplemented fibroblast conditioned medium that allows us to grow and subculture total mouse keratinocytes for up to 19 subcultures, allowing an increase in cell number of greater than 10 logs. Epidermal keratinocytes from newborn mice were grown on collagen IV coated dishes in murine fibroblast conditioned medium with 0.06 mM calcium and added growth factors. The cells could be passaged, frozen as viable stocks, and induced to differentiate. Morphologically the cultured keratinocytes demonstrated a pattern characteristic of basal cells. Stratified cultures which made mouse keratin 1 and profilaggrin through passage 10 were induced by purging the monolayer cultures of growth factors, then adding medium with 0.15 mM calcium; expression of mouse keratin 1 and profilaggrin was lost by passage 15. The methods explained in detail here should be of great interest to investigators who are now trying to analyze skin phenotypes and expression of markers of epidermal differentiation of their transgenic or knockout mice. ",0
2250,10383963,Analysis of peptidoglycan structure from vegetative cells of Bacillus subtilis 168 and role of PBP 5 in peptidoglycan maturation,"The composition and fine structure of the vegetative cell wall peptidoglycan from Bacillus subtilis were determined by analysis of its constituent muropeptides. The structures of 39 muropeptides, representing 97% of the total peptidoglycan, were elucidated. About 99% analyzed muropeptides in B. subtilis vegetative cell peptidoglycan have the free carboxylic group of diaminopimelic acid amidated. Anhydromuropeptides and products missing a glucosamine at the nonreducing terminus account for 0.4 and 1.5%, respectively, of the total muropeptides. These two types of muropeptides are suggested to end glycan strands. An unexpected feature of B. subtilis muropeptides was the occurrence of a glycine residue in position 5 of the peptide side chain on monomers or oligomers, which account for 2.7% of the total muropeptides. This amount is, however, dependent on the composition of the growth media. Potential attachment sites for anionic polymers to peptidoglycan occur on dominant muropeptides and account for 2.1% of the total. B. subtilis peptidoglycan is incompletely digested by lysozyme due to de-N-acetylation of glucosamine, which occurs on 17.3% of muropeptides. The cross-linking index of the polymer changes with the growth phase. It is highest in late stationary phase, with a value of 33.2 or 44% per muramic acid residue, as determined by reverse-phase high-pressure liquid chromatography or gel filtration, respectively. Analysis of the muropeptide composition of a dacA (PBP 5) mutant shows a dramatic decrease of muropeptides with tripeptide side chains and an increase or appearance of muropeptides with pentapeptide side chains in monomers or oligomers. The total muropeptides with pentapeptide side chains accounts for almost 82% in the dacA mutant. This major low-molecular-weight PBP (DD-carboxypeptidase) is suggested to play a role in peptidoglycan maturation. ",0
2251,10384116,CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway,"The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection. ",0
2252,10385375,Posttraumatic intestinal stenosis presenting as a perforation: report of a case,"A 78-year-old woman was admitted to the hospital after falling into a ditch approximately 1 m deep and sustaining a blunt abdominal trauma with a left femur fracture. On the tenth day after admission, symptoms of a small bowel obstruction occurred. A nasogastric tube was inserted, and the symptoms thus improved. She sometimes complained of abdominal pain during the 12 months after the fall, but recovered with conservative management. The next year, she was readmitted to the hospital for a pin extraction of the left femur bone. During this admission, 15 months since her admission after her fall, she again complained of abdominal pain. Abdominal pain increased with a muscular defense, and abdominal X-rays revealed free air. She was referred to our hospital with a diagnosis of perforative peritonitis, and emergency surgery was performed. Upon laparotomy, circumferential stenoses of the small bowel were recognized in the proximal segments about 40cm, 80cm, and 100cm from the ileocecal region. In addition, a perforation and prominent dilatation of the bowel segment was observed just proximal to the stenosis about 100cm from the ileocecal region. She underwent a small intestinal resection at two sites. There were no findings of an intestinal specific ulcer, such as Crohn's disease, intestinal tuberculosis, or malignancy, based on the results of a histopathological examination. ",0
2253,10385557,Secretion of activin A in recurrent epithelial ovarian carcinoma,"Activin A is a dimeric protein, composed of two beta-A subunits, that belongs to the TGF-beta family of growth factors. Most primary epithelial ovarian tumors (96%) synthesize and secrete activin protein in vitro and preliminary studies show that serum levels of activin are frequently elevated in women with epithelial ovarian cancer. Our objectives were to expand on studies of serum activin A levels in women with epithelial ovarian cancer and to determine whether levels of activin A correlate with the clinical course of disease. Preoperative serum activin A levels were measured in 41 patients with epithelial ovarian cancer. In addition, serum activin A levels were measured in all available postoperative samples from the subset of these patients (n = 26) who had an elevated preoperative serum activin A level. Medical record information was used to compare each patient's serum levels of activin A to the clinical course of disease. Seventy-two percent of the stage III and IV patients (26/36), and none (0/5) of the stage I patients, had an elevated preoperative serum activin level. In postoperative samples, activin A levels were increased with persistent or recurrent (n = 9) stage III or IV ovarian cancer. Activin A levels dropped postoperatively and remained at or below the control level in patients in remission. Serum activin A levels correlate with recurrent or persistent disease in patients with epithelial ovarian cancer. ",0
2254,10385636,"In situ nucleic acid detection of PDC-E2, BCOADC-E2, OGDC-E2, PDC-E1alpha, BCOADC-E1alpha, OGDC-E1, and the E3 binding protein (protein X) in primary biliary cirrhosis","The characteristic serological feature of primary biliary cirrhosis (PBC) is the presence of antimitochondrial antibodies (AMAs), and the major proteins recognized by AMAs are subunits of the 2-oxo acid dehydrogenase complexes (2-OADC), including the E2 components of the pyruvate dehydrogenase complex (PDC), the 2-oxo-glutarate dehydrogenase complex (OGDC), the branched-chain 2-oxoacid dehydrogenase complex (BCOADC), the E3 binding protein (E3BP or protein X) and the E1a component of mammalian PDC. Previous work has postulated that either E3BP, or a molecule cross-reactive with the PDC-E2 molecule, is uniquely expressed on the surface of biliary epithelial cells in PBC. To address this issue, we performed in situ hybridization for all of the major 2-OADC components at the mRNA level, including PDC-E2, BCOADC-E2, OGDC-E2, PDC-E1a, BCOADC-E1a, OGDC-E1, and E3BP using 13 PBC and 9 control livers using 7 mitochondrial antisense probes. In both PBC and controls, the expression of all 2-OADC component mRNA studied herein were found in hepatocytes and infiltrating mononuclear cells, without significant differences. Interestingly, however, despite published data on immunohistochemical staining, interlobular bile ducts including the injured bile ducts in PBC were generally negative or only faintly positive, with the exception of 1 bile duct in 1 of 13 cases of PBC and 1 of 9 control liver specimens. Moreover, confocal microscopic examination and image analysis revealed that the mRNA signal intensity of each of the 2-OADC components in the bile ducts of PBC was relatively lower in comparison with control liver diseases. These data suggest that continuous enhanced synthesis of the 2-OADC components is not likely to be occurring in the biliary epithelial cells in PBC, and that an increase of PDC-E2 or E3BP immunoreactivity in PBC is caused by exogenous imported or cross-reactive molecules.",0
2255,10385640,Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: a mouse model of primary biliary cirrhosis,"The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by autoreactive responses to a highly conserved self-antigen, pyruvate dehydrogenase complex (PDC). We recently reported the development of PBC-like lesions in SJL mice sensitized with PDC and have named this model disease experimental autoimmune cholangitis (EAC). In the present study, the breakdown of tolerance to PDC has been investigated in animals sensitized for EAC. Splenic mononuclear cells from SJL mice sensitized with bovine heart PDC (bPDC) in adjuvant showed T-cell proliferative and mixed Th1/Th2 cytokine secretory responses following in vitro stimulation with bPDC. Despite the likelihood of extensive sequence homology with mouse PDC (there is a greater than 95% sequence identity between rat and human PDC-E2 subunits), bPDC was highly immunogenic inducing significant T- and B-cell responses in the absence of any form of adjuvant. The multi-subunit quaternary structure of intact PDC was critical for this immunostimulatory activity because no response was produced by sensitization with monomeric recombinant PDC-E2 inner lipoyl domain. Mice sensitized with bPDC and CFA developed, within 2 weeks of sensitization, high-titer antibody responses reactive with bPDC that were fully cross-reactive with the murine homologue. Breakdown of T-cell tolerance to self-PDC took significantly longer, not being seen until 20 weeks postsensitization; a similar length of time to that previously shown to be required for EAC lesion development. Conclusions drawn from these data may have important implications for our understanding, and therapeutic manipulation, of PBC in humans.",0
2256,10385993,Proteolytic activity in relation to seasonal cambial growth and xylogenesis in Pinus banksiana,"Proteolytic activity in the cambial zone and developing xylem of Pinus banksiana Lamb. was investigated over an annual cycle of growth and dormancy. Highest proteolytic activity was associated with the most active period of primary-wall radial expansion of cambial derivatives, in early spring, before protoplasmic autolysis was initiated in developing earlywood. Three pH maxima of proteolytic activity, near pH 3.0, 6.5 and 9.5, were observed at that time. In general, activities measured at pH values below 7.0 were greater than those determined above pH 7.0 at all stages in the annual cycle, in both cambial zone and developing xylem, although elevated activity at alkaline pH was also observed during springtime growth. Polyvinylpolypyrollidone (PVP) treatment markedly enhanced pH 7.5 but not pH 4.0 proteolytic activity in the cambial zone, but not in developing xylem, indicating the presence of PVP-binding proteinase regulators in the cambium. By fractionation and effector studies total proteolysis was determined to comprise interactions between serine, cystine, aspartate and metallo-proteases having MWs, by gel chromatography, between 10 and 100 kDa. The observations point to a complex regulatory mechanism controlling the presence and catalytic rates of the distinct types of proteases in the cambial region throughout an annual cycle of growth and dormancy. ",0
2257,10386075,Validation of health-related quality of life instruments,"The development of instruments to quantitate health-related quality of life (HRQOL) includes taking the appropriate and, in fact, essential steps to ensure that the designated tool measures what it purports to measure and does it accurately and reliably. Such steps are not only critical in the development of appropriate tools, but, when clearly presented, also serve to prove to the reader (and reviewers) that the instrument is a legitimate one. Key to the development of any HRQOL instrument are three fundamental concepts: validity, reliability, and responsiveness. Validity proves that the instrument measures what it claims to measure. Reliability proves that the results are reproducible in a stable setting. Responsiveness proves that the instrument is sensitive enough to record important differences or changes. Each of these principles is discussed, including some examples of the application of these principles in previously published HRQOL studies. The studies referenced are excellent examples of the methods used in the creation of a HRQOL scale, and the reader is strongly encouraged to review these in their entirety to fully grasp the concepts.",0
2258,10386076,Strategies and pitfalls in quality of life research,"QOL research is an important element of outcomes research and can provide an important adjunct to clinical trials in hepatology. The principles of QOL research are similar to all outcomes research methods. Pitfalls in QOL research include poor study design, choosing the wrong instrument, and inadequate interpretation of design. These pitfalls can be avoided with a well-thought-out strategy including a well-designed hypothesis to test, a validated instrument, careful data collection and analysis, and collaboration with biostatisticians and experts in health-utility research when necessary. QOL research is best suited to questions where survival differences between the two groups studied are modest or to balance economic outcomes, but it can be a useful part of virtually any clinical question.",0
2259,10386080,Meta-analysis: when and how,"Systematic reviews have a central role in evidence-based medicine. The quantitative systematic review, also known as meta-analysis, provides a logical structure for quantifying evidence and for exploring bias and diversity in research systematically. It is essential that clinicians, educators, and researchers understand the methods that comprise this research tool, particularly the basic step-by-step process, and know when numerical pooling of data is appropriate. The essay describes how systematic reviews are best conducted and when statistical pooling of data is appropriate. Systematic reviews are scientific investigations with planned methods that use original studies as subjects and synthesize the results of multiple studies using strategies to limit bias and random error. This process requires judgments to be made explicit, and should be question driven, protocol based, reproducible, and comprehensive in scope. Meta-analysis provides a framework for research synthesis, increases power and precision, provides an overall estimate and range of effect, and identifies greater-than-expected variability among study results (heterogeneity). Meta-analysis does not remove subjectivity from the process of synthesis, identify sources of variability among studies, or obviate the need for sound, compassionate clinical reasoning. Statistical heterogeneity should be anticipated and welcomed. It forces a consideration of clinical heterogeneity as well as variation in study protocol and quality. Statistical tests for homogeneity are insensitive and do not indicate sources of heterogeneity, making such consideration imperative. The most common and popular measures of efficacy for a meta-analysis are the standardized difference between two means, the relative risk, and the odds ratio. An additional measure, the number needed to treat, with its 95% confidence interval is the most clinically useful measure of the effects of an intervention and is useful for comparing the relative effectiveness of different interventions for the same condition. Important parts of meta-analysis and sensitivity and subgroup analyses are best considered a priori and should be used to explore heterogeneity and to test for publication bias and variation in study quality.",0
2260,10386082,Using outcomes data to identify best medical practice: the role of policy models,"Increasingly, physicians are attempting to incorporate best evidence into their clinical decision making. However, best evidence takes a variety of forms, including clinical trials, cohort studies, administrative data, and patient preference data. Incorporating multiple data sources in a way that informs complex clinical decisions is a substantial analytical challenge. One approach to this challenge is to develop a simulation/decision model that explicitly represents the natural history of disease and the impact of treatments on that natural history. The model should be requisite--that is, sufficient in form to address the decision problem--but not overly complex. Such a model can be of value because it (1) allows a variety of viewpoints to be considered, (2) incorporates the best scientific evidence, and (3) permits sensitivity analyses to evaluate the impact of alternative clinical scenarios and uncertainty in model inputs. The Stroke Prevention Policy Model (SPPM) illustrates this approach. The SPPM is a simulation model designed to predict the best among various treatment alternatives for preventing strokes. Similar models can be applied to treatment outcomes for liver disease.",0
2261,10386168,Coexistence of lowered mood and cognitive impairment of elderly people in five birth cohorts,"The prevalences of lowered mood and cognitive impairment, and their combination were investigated in 1993 random subjects of five birth cohorts (at age of 65, 70, 75, 80 and 85 years). The frequency of a high Zung-score (> 45), indicating depressive symptoms, in the five age groups was 11%, 13%, 20%, 16%, and 36%, respectively. The corresponding figures for a low MMSE-score (Mini Mental State Examination < 24) were 11%, 9%, 25%, 46%, and 60%; the respective frequencies of subjects fulfilling both criteria simultaneously were 2%, 3%, 8%, 12% and 24%, respectively. Overall, about 30% of the subjects with a low MMSE-score had a high Zung-score. However, more than half of the old subjects (over 75 years) with a high Zung-score also had low MMSE-scores. The data indicate that the combination of impaired cognition and lowered mood doubles in frequency by five-year intervals after the age of 70 years in the general aged population, and that this condition is present in one of four subjects at the age of 85 years. ",0
2262,10386600,Skp2 induction and phosphorylation is associated with the late G1 phase of proliferating rat hepatocytes,"The changes in phosphoproteins purified with the affinity peptide p9CKShs1 were analyzed from extracts of regenerating rat livers in order to define some G1 and G1/S regulations characteristic of mature hepatocytes stimulated to proliferate. We observed a 47 kDa phosphoprotein that occurred first at the end of G1 before peaking in the S phase. P47 was also found to be phosphorylated in late G1 in primary hepatocyte cultures stimulated with mitogens. P47 was still phosphorylated in extracts depleted of Cdc2, but to a lesser extent after Cdk2 depletion. This phosphoprotein was identified as Skp2. (i) P47 shared the same electrophoretic mobility than Skp2, a cell cycle protein essential for S phase entry in human fibroblasts; (ii) Skp2, like P47, started to be expressed and was highly phosphorylated during the G1/S transition of hepatocytes stimulated to proliferate in vivo and in vitro; (iii) P47 was specifically immunoprecipitated by an antibody directed against Skp2. In addition, cyclin A/Cdk2 complexes from regenerating liver clearly interacted with Skp2. This is the first demonstration that Skp2 is induced and phosphorylated in the late G1 and S phase of hepatocytes in vivo in regenerating liver as well as in vitro in mitogen-stimulated hepatocytes. ",0
2263,10386649,Correlation between gamma-ray-induced G2 arrest and radioresistance in two human cancer cells,"The correlation between radioresistance and gamma-ray-induced G2 arrest was examined in two human cancer cell lines, HeLa (cervical carcinoma) and MeWo (melanoma). Cellular radioresistance was examined by a colony formation assay and Hoechst 33342 staining. G2 arrest induced by gamma-rays was examined by flow cytometry, and the accumulation of cyclin B1 and cdc2 proteins was analyzed using Western blotting. HeLa was more resistant (10% survival dose[D10] = 10 Gy) than MeWo (D10 = 4 Gy) to gamma-rays. In HeLa, cell cycle analysis showed that G2 arrest was induced 10 or 24 h after irradiation of 10 or 4 Gy, respectively. In contrast, no clear G2 arrest in MeWo was observed after irradiation. Western blot analysis showed that cell cycle regulators, cyclin B1 and cdc2, were accumulated in HeLa but not in MeWo. The accumulation of cyclin B1 and cdc2 reached peak levels 24-34 h after irradiation of 10 Gy, and 24 h after irradiation of 4 Gy. In addition, Hoechst staining revealed similar increase in apoptotic bodies with time after irradiation in HeLa and MeWo at isosurvival doses. Radioresistance of these human cancer cells is closely correlated with gamma-ray-induced G2 arrest, and cyclin B1 and cdc2 are possible regulators of G2 arrest. ",0
2264,10386966,Regulation of tyrosine hydroxylase gene expression by muscarinic agonists in rat adrenal medulla,"Tyrosine hydroxylase (TH) gene expression in the adrenal medulla is regulated by numerous stimuli via transsynaptic mechanisms. The adrenal chromaffin cell receptors that mediate this transsynaptic response remain unidentified. In this report we demonstrate that the muscarinic acetylcholine receptor agonist bethanechol stimulates the TH gene transcription rate in both innervated and denervated adrenal glands. Hence, this muscarinic response is not dependent on transsynaptic influences, suggesting that agonist occupation of adrenal chromaffin cell muscarinic receptors is sufficient to activate intracellular signaling pathways that stimulate the TH gene. When bethanechol is administered repeatedly over a 3-h interval (four injections spaced 1 h apart), TH mRNA levels are increased two- to threefold at 6 and 12 h after the initial injection of drug. It is surprising that this induction of TH mRNA does not lead to increases in TH activity or TH protein level. These results are consistent with the hypothesis that both transcriptional and posttranscriptional mechanisms must be regulated to induce TH protein and that muscarinic agonists activate only a subset of these mechanisms. ",0
2265,10387140,Preliminary observations on the use of midodrine hydrochloride in the treatment of refractory neurocardiogenic syncope,"Recurrent episodes of neurocardiogenic syncope that occur without warning are a common cause of recurrent syncope that can be identified during head upright tilt table testing. While the use of beta blockers, theophyllines, fludrocortisone, disopyramide, and serotonin reuptake inhibitors can be useful in the prevention of episodes, some patients are either unresponsive to or poorly tolerant of these agents. We investigated the use of the peripheral alpha stimulating agent midodrine in preventing both tilt-induced and spontaneous neurocardiogenic syncope. Twenty-five patients (16 women, 9 men, mean age 30 +/- 23 years) with severe recurrent syncope and a positive head upright tilt table study (refractory to or intolerant of standard therapies) were placed on midodrine 5-10 mg orally three times per day, (two patients required 15 mg/day). Of these, twelve became asymptomatic and five had a marked reduction in symptoms. We conclude that midodrine may be an effective therapy in patients with recurrent neurocardiogenic syncope refractory to other forms of therapy. ",0
2266,10388193,Ethical issues for otolaryngology and surgery in the elderly,"""Clinical ethics is an intrinsic aspect of medical practice. Concerns for ethical conduct arise in the management of medical benefits, patient preferences, quality of life, and the relationship between patient care and its attendant familial, social, economic, and legal circumstances. Ethical concerns in surgical practice are central to the essence of the Hippocratic doctrine, """"First do no harm."""" In caring for our patients, particularly in light of the modern practice of medicine, we often use the risk-benefit calculus. The range of ethical concerns for the otolaryngologist who deals with the elderly and infirm covers many diverse situations. Superimposed over this spectrum is the idea of patient autonomy, which is considered to be a cardinal issue in any ethical discussion. Furthermore, increasing medical care costs have created a debate regarding the rationing of healthcare. Ethicists continue the discussion as to whether age should be a decisive factor in the rationing of this care. Definitions of """"heroic"""" and """"extraordinary"""" assume greater significance, and controversies of language become pivotal when the comprehension and cognitive orientation of the patient are compromised by disease and senescence. """,0
2267,10388518,Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture,"The trace fatty acid conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis when fed prior to carcinogen during pubertal mammary gland development or during the promotion phase of carcinogenesis. The following studies were done to investigate possible mechanisms of these effects. Using a physiological model for growth and differentiation of normal rat mammary epithelial cell organoids (MEO) in primary culture, we found that CLA, but not linoleic acid (LA), inhibited growth of MEO and that this growth inhibition was mediated both by a reduction in DNA synthesis and a stimulation of apoptosis. The effects of CLA did not appear to be mediated by changes in epithelial protein kinase C (PKC) since neither total activity nor expression nor localization of PKC isoenzymes alpha, beta II, delta, epsilon, eta, or zeta were altered in the epithelium of CLA-fed rats. In contrast, PKCs delta, epsilon, and eta were specifically upregulated and associated with a lipid-like, but acetone-insoluble, fibrillar material found exclusively in adipocytes from CLA-fed rats. Taken together, these observations demonstrate that CLA can act directly to inhibit growth and induce apoptosis of normal MEO and may thus prevent breast cancer by its ability to reduce mammary epithelial density and to inhibit the outgrowth of initiated MEO. Moreover, the changes in mammary adipocyte PKC expression and lipid composition suggest that the adipose stroma may play an important in vivo role in mediating the ability of CLA to inhibit mammary carcinogenesis. ",0
2268,10388622,"Surface ultrastructure of pit organ, spectacle, and non pit organ epidermis of infrared imaging boid snakes: A scanning probe and scanning electron microscopy study","Boid snakes possess unique infrared imaging pit organs. The ultrastructure of the surfaces of these organs scatter or reflect electromagnetic radiation of specific wavelengths. Pit organ epidermal surfaces of boid snakes are covered with arrays of pore-like structures called micropits. In order to determine the dimensions of this complicated surface structure, we have performed the first ultrastructural analysis on snake epidermis by high-resolution microscopy techniques. Using scanning probe microscopy and scanning electron microscopy, we found that the epidermis of pit organ, maxillary non pit organ, spectacle, and ventral scales contain arrays of micropits. These scale surfaces also contain major surface features of overlapping plate-like structures. Pit organ micropits averaged 319 nm in diameter and 46 nm in depth and were spaced an average of 808 nm from each other. These micropits were significantly deeper, of greater diameter, and spaced at greater distances apart than those of the other scales. Plate structures of the pit organs had a mean distance between plates of 3.5 microm and a mean plate step height of 151 nm. These differences serve to strengthen the argument that arrays of micropit and plate surface structures function as spectral filters or anti-reflective coatings with respect to incident electromagnetic radiation. ",0
2269,10388842,A method for computational combinatorial peptide design of inhibitors of Ras protein,"A computational combinatorial approach is proposed for the design of a peptide inhibitor of Ras protein. The procedure involves three steps. First, a 'Multiple Copy Simultaneous Search' identifies the location of specific functional groups on the Ras surface. This search method allowed us to identify an important binding surface consisting of two beta strands (residues 5-8 and 52-56), in addition to the well known Ras effector loop and switch II region. The two beta strands had not previously been reported to be involved in Ras-Raf interaction. Second, after constructing the peptide inhibitor chain based on the location of N-methylacetamide (NMA) minima, functional groups are selected and connected to the main chain Calpha atom. This step generates a number of possible peptides with different sequences on the Ras surface. Third, potential inhibitors are designed based on a sequence alignment of the peptides generated in the second step. This computational approach reproduces the conserved pattern of hydrophobic, hydrophilic and charged amino acids identified from the Ras effectors. The advantages and limitations of this approach are discussed. ",0
2270,10388986,Increased urinary atrial natriuretic peptide-like immunoreactivity excretion but decreased plasma atrial natriuretic peptide concentration in patients with hyperosmolar-hyperglycemic nonketotic syndrome,"This study was undertaken to measure urinary atrial natriuretic peptide-like immunoreactivity (ANP-LI) and plasma ANP concentration in patients with hyperosmolar-hyperglycemic nonketotic syndrome (HHNS) to investigate the change of renal ANP-LI and cardiac ANP synthesis in volume-depleted diabetic patients. The urine ANP-LI:creatinine ratio, plasma ANP level, and plasma renin activity (PRA) were measured in 12 patients with HHNS during the acute stage and after recovery, in 28 oral hypoglycemic agent (OHA)-treated type 2 diabetic patients, and in 23 normal subjects. ANP and PRA were measured by radioimmunoassay. These HHNS patients had severe hyperglycemia and hyperosmolality as well as increased blood urea nitrogen, creatinine, and PRA levels, as compared with normal subjects and OHA-treated type 2 diabetic patients. In these patients, the urinary ANP-LI:creatinine ratio (11.69 +/- 2.11 pmol/mmol) was significantly increased in comparison with the normal group (1.78 +/- 0.11 pmol/mmol) and OHA-treated diabetic patients (2.43 +/- 0.45 pmol/mmol), whereas plasma ANP concentration (5.12 +/- 0.72 pmol/l) was significantly lower than the corresponding values of the normal group (7.39 +/- 0.85 pmol/l) and OHA-treated diabetic patients (8.43 +/- 1.05 pmol/l). All of these abnormalities were significantly ameliorated after insulin, fluid, and electrolyte replacement. Our data show that urinary ANP-LI was significantly increased, whereas plasma ANP concentration was decreased, in the face of raised PRA in HHNS patients. This study indicates that renal ANP-LI substances and cardiac ANP may exhibit different responsiveness in diabetic patients with HHNS. ",0
2271,10389143,Interactive modulation by dopamine and serotonin neurons of receptor sensitivity of the alternate neurochemical system,"Ontogenetic dopaminergic denervation of rat forebrain is associated with latent supersensitization of dopamine (DA) receptors that is unmasked only by a priming process entailing repeated DA agonist treatments. Similar denervation supersensitivity holds for serotonin (5-HT) and most other neurochemical systems. Because DA and 5-HT neurons compete for target sites in the brain and mimic or replicate actions of the others, we investigated the modulatory influence of DA neurons on 5-HT receptor sensitivity; and role of 5-HT neurons in modulating DA receptor sensitivity. In these studies rats were lesioned with the DA neurotoxin 6-hydroxydopamine (6-OHDA, i.c.v.; desipramine pretreatment) or 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, i.c.v.; desipramine pretreatment) either at 3 days after birth or in adulthood. Responses to DA and 5-HT agonists were determined in several behavioral paradigms in adulthood. In assessing oral responses to agonists, we found that the D1 agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 38393) profoundly induced activity if rats were lesioned neonatally with 6-OHDA, but not if rats were co-lesioned as neonates or as adults with 5,7-DHT. The D2 agonist quinpirole induced profound oral activity, but only if rats were lesioned as neonates with 5,7-DHT; or if rats were lesioned with both 6-OHDA (neonatally administered) and 5,7-DHT (adult stage). In all rats lesioned as neonates with 6-OHDA, the 5-HT2 agonist m-chlorophenylpiperazine produced enhanced activity, regardless of 5,7-DHT treatment. These findings demonstrate that DA neurons modulate receptor sensitivity status of both DA and 5-HT receptors; and 5-HT neurons do so similarly. This phenomenon is pertinent to animal models of human disorders and in the syndrome spectrum and treatment approach of human neurodegenerative disorders (e.g. parkinsonism, tardive dyskinesia), developmental disorders (e.g. hyperkinetic activity) and psychiatric disorders. ",0
2272,10389174,Age-dependent changes in memory and mushroom bodies in the Drosophila mutant vermilion deficient in the kynurenine pathway of tryptophan metabolism,"Evolutionary conservation of homologous genes that cause related phenotypes in humans and Drosophila help to unravel genes implicated in polygenic human diseases. Among them are neurodegenerative disorders, such as Huntington, Parkinson, Alzheimer and HIV-induced diseases. They are characterized by a late onset disturbances of memory, changes in volumetric indices of the brain structures involved in memory formation, synaptic and glial pathology, and altered content of the intermediates of the kynurenine pathway, the endogenous modulators of the NMDA receptors. This pathway in conserved in insects, rodents and humans. We, therefore, studied the effects of aberrant tryptophan metabolism on memory, brain plasticity, synaptic and glial immunoreactivity in the Drosophila mutants vermilion (no kynurenines) and cinnabar (excess of neuroprotective kynurenic acid) over the life time. The mutant vermilion demonstrated gradual decline of 3-th memory performance and complete memory failure on the 28th day of life in a paradigm of conditioned courtship suppression. A drastic increase in the volume of the calyces of the mushroom bodies, and a decay in immunochemical staining of this brain structure with antibodies to synaptic protein csp and glia, precede the age-dependent memory defect and develop from the 12th day of adult life. ",0
2273,10389567,Recent experiences with hexadimethrine for neutralizing heparin after cardiopulmonary bypass,"Hexadimethrine bromide was used for the neutralization of heparin during cardiac surgery in the late 1950s. For some years, this institution has used it for patients who may be allergic to protamine. In view of the recent renewal of interest in hexadimethrine, we present four cases outlining its use during cardiac procedures in such patients. Other drugs for reversing the action of heparin such as heparinase or platelet factor IV are not yet widely available. ",0
2274,10390045,Perceptions of soil-eating and anaemia among pregnant women on the Kenyan coast,"""After a clinical study at Kilifi District hospital had shown a high prevalence of geophagy among pregnant women, and a strong association of geophagy, anaemia and iron depletion, 52 pregnant women from the same hospital, and 4 traditional healers from the surroundings of Kilifi in Kenya were interviewed on the topic of soil-eating and its perceived causes and consequences. The findings were substantiated by results from an earlier anthropological study on maternal health and anaemia in the same study area. Most of the pregnant women (73%) ate soil regularly. They mainly ate the soil from walls of houses, and their estimated median daily ingestion was 41.5 g. They described soil-eating as a predominantly female practice with strong relations to fertility and reproduction. They made associations between soil-eating, the condition of the blood and certain bodily states: pregnancy, lack of blood (upungufu wa damu), an illness called safura involving """"weak"""" blood, and worms (minyolo). The relationships the women described between soil-eating and illness resemble to some extent the causalities explored in biomedical research on soil-eating, anaemia and intestinal worm infections. However the women did not conceptualise the issue in terms of the single causal links characteristic of most scientific thought. Instead, they acknowledged the existence of multiple links between phenomena which they observed in their own and other women's bodies. The women's ideas about soil-eating and their bodies shows the significance of both social and cultural context on the ways in which women derive knowledge from, and make sense of their bodily states. The cultural associations of soil-eating with blood, fertility and femininity exist alongside knowledge of its links to illness. Our findings show that soil-eating is more than just a physiologically induced behaviour; it is a rich cultural practice. """,0
2275,10390128,The clinical potential of cyclooxygenase-2-specific inhibitors,"Emerging evidence suggests that cyclooxygenase-2 (COX-2) has diverse physiologic and pathophysiologic functions. It is expressed constitutively in the developing kidney and brain, playing a role in their proper maturation and function. Further, COX-2 expression may be up-regulated at certain sites: in the kidney during sodium restriction; in the microglia of cognitive centers within the hippocampus and cortex in Alzheimer's disease; and in intestinal adenomas and colon tumors. On the basis of COX-2 expression in Alzheimer's disease and colon cancer, COX-2-specific inhibitors may find clinical utility in the prevention or treatment of these conditions. Despite this apparently optimistic outlook for future uses of COX-2 inhibitors, most of the findings supporting this perspective are based on in vitro and in vivo models and must be rigorously corroborated in human studies, some of which are already planned. ",0
2276,10390252,Cost of chickenpox in Canada: part I. Cost of uncomplicated cases,"The purpose of this study was to assess the direct medical costs and productivity losses associated with uncomplicated chickenpox (no hospitalization) in Canada. A total of 179 otherwise healthy 1- to 9-year-old children with active chickenpox were recruited from schools, day care centers, and physician offices in 5 provinces. Direct medical (physician contacts, medication, and diagnostic tests) and nonmedical (personal expenses including child care) resources expended during the illness were determined by caregiver interview. Productivity losses attributable to the disease were determined by assessing caregiver time lost from work and daily activities. Unit costs for all resources were obtained from sources in 2 provinces, and per-patient treatment costs were determined from the patient, Ministry of Health, and societal perspectives. From a societal perspective, the per-case cost for children from 1 to 4 years of age and from 5 to 9 years of age was $370.2 and $236.5, respectively. Direct medical costs accounted for 10% of the total costs in both groups. The largest cost driver in patient care was caregiver productivity losses, which amounted to $316.5 in the younger age group and to $182.7 in the older age group. Based on an estimated yearly incidence of 344 656 cases of uncomplicated chickenpox in Canada, the total annual societal burden of the disease can be estimated at $109.2 million, with a cost to the Ministry of Health of $11.2 million. Chickenpox is one of the last common childhood diseases prevalent in Canada, and the uncomplicated disease, despite its rather benign course, imparts a large annual economic burden. ",0
2277,10390606,Succinimide and saccharin-based enzyme-activated inhibitors of serine proteases,"The inhibition of human leukocyte elastase (HLE), and other serine proteases, by succinimide and saccharin-based compounds is reviewed. The succinimide compounds are unique in that the inactivating species is generated within the enzyme active site via a molecular rearrangement. The related saccharin derivatives also inactivate serine proteases by an enzyme-activated mechanism. Those factors effecting the potency, selectivity and stability of these important classes of inhibitor are discussed. ",0
2278,10391069,"Effect of Staphylococcus aureus extract on the expression of L-selectin and LFA-1, in neutrophils from patients with allergic bronchial asthma]","Messier L-selectin and LFA-1 in neutrophils from moderate and non atopic asthma patients, before and after stimuli with and without Sa (Staphylococcus aureus). Design Trial; experimental. We studied neutrophils from 12 moderate and non atopic asthma patients and 12 healthy subjects before and after stimuli with and without Sa. The neutrophyls adhesion molecules, CD 62-L and CD 11 a was measured by citometric flow assays. The median of CD 62-L molecule expression increase with the stimuli in non atopic asthma patients from 2444 (CI 1966, CS 3627, RC 1661) to 6285.5 (CI 5243, CS 7203, RC 1960), and the median of CD 11 a molecule expression decrease with the stimuli in non atopic asthma patients from 9910.5 (CI 9765, CS 9961, RC 196) to 7670 (CI 7125, CS 8291, RC 1166). The median of CD 11 a molecule expression increase with the stimuli in healthy subjects from 593 (CI 361, CS 929, RC 568) to 1113 (CI 910, CS 1240, RC 330) and the median of CD 11 a molecule expression decrease with the stimuli in healthy subjects from 9850 (CI 9741, CS 9898, RC 157) to 9808.5 (CI 9693, CS 9890, RC 197) [CI. Inferior Cuartil, CS. Superior Cuartil, RC.-Cuartil Range]. ",0
2279,10391441,Corticotropic-releasing hormone and serotonin interact in the human brainstem: behavioral implications,"The objective of this human post mortem study was to determine whether neurons which synthesize corticotropic-releasing hormone and serotonin form circuits implicated in the pathophysiology of major depression and suicide. For the first time, a sensitive, dual immunocytochemical procedure was used to identify circuits formed by corticotropic-releasing hormone-synthesizing and serotonergic cell groups. Corticotropic-releasing hormone-immunoreactive varicose fibers and puncta with morphological characteristics of terminals were labeled in the midline raphe, periventricular gray and pontine parabrachial complex, on single-labeled tissues processed immunocytochemically with a rabbit antibody to rat/human corticotropic-releasing hormone. Presumptive synaptic interactions with monoaminergic neurons were demonstrated with dual labeling techniques. Corticotropic-releasing hormone-immunoreactive terminals apposed neuronal somata and primary dendrites of serotonergic neurons in the pontine raphe. Serotonergic neurons were immunolabeled with a mouse antibody to phenylalanine hydroxylase, an enzyme with substantial sequence homology to tryptophan hydroxylase. Interactions in the lateral parabrachial nucleus were suggested by precise overlap of corticotropic-releasing hormone and serotonergic terminal fields. Corticotropic-releasing hormone projections were confirmed to noradrenergic neurons containing neuromelanin in the locus ceruleus. Maps of corticotropic-releasing hormone fiber trajectories suggest that these pathways may derive from the forebrain and, locally, from the human homologue of Barrington's nucleus--a neurochemically specialized division of the laterodorsal tegmental complex. Chemosensory functions were predicted by novel evidence for corticotropic-releasing hormone- and monoaminergic neurovascular and subependymal fiber plexuses. In conclusion, corticotropic-releasing hormone may influence the activity of two major monoaminergic cell systems implicated in the stress-diathesis model of mental illness, through neural and humoral mechanisms. ",0
2280,10395631,Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group,"BACKGROUND AND METHODS: Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1-infected and 365 of whom were not) who had known CMV status and were born to HIV-1-infected women and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age. RESULTS: At birth the frequency of CMV infection was similar in the HIV-1-infected and HIV-1-uninfected infants (4.3 percent and 4.5 percent, respectively), but the HIV-1-infected infants had a higher rate of CMV infection at six months of age (39.9 percent vs. 15.3 percent, P=0.001) and continued to have a higher rate of CMV infection through four years of age (P=0.04). By 18 months of age, the infants with both infections had higher rates of HIV-1 disease progression (70.0 percent vs. 30.4 percent, P=0.001), CDC class C symptoms or death (52.5 percent vs. 21.7 percent, P=0.008), and impaired brain growth or progressive motor deficits (35.6 percent vs. 8.7 percent, P=0.005) than infants infected only with HIV-1. In a Cox regression analysis, CMV infection was associated with an increased risk of HIV-1 disease progression (relative risk, 2.59; 95 percent confidence interval, 1.13 to 5.95). Among children infected with HIV-1 alone, but not among those infected with both viruses, children with rapid progression of HIV-1 disease had higher mean levels of HIV-1 RNA than those with slower or no progression of disease. CONCLUSIONS: HIV-1-infected infants who acquire CMV infection in the first 18 months of life have a significantly higher rate of disease progression and central nervous system disease than those infected with HIV-1 alone.",0
2281,10421640,The immunobiology of bile and biliary epithelium,"Long thought to be just a simple pipe involved in the delivery of bile from hepatocytes to the gallbladder and intestine, bile ducts are now regarded as highly dynamic structures consisting of cell populations involved in formation, transport and modification of bile by both secretory and absorptive processes. In fact, both bile and biliary epithelium appear to have active immunologic roles in both innate and adaptive immune responses. These roles are becoming increasingly clear as techniques have been developed allowing for the study of bile and biliary epithelial cells (BECs) in mucosal immunity. Bile is actively involved in the transport of immunoglobulin to the intestine, while BECs secrete chemokines and cytokines and serve to localize the immune response by expressing critical cell adhesion molecules. Evidence suggests that BECs may also function as professional antigen-presenting cells (APC) and, in the process, contribute to the modulation of inflammatory reactions. Bile ducts and, in particular, BECs, are the primary site of damage in several immunologically mediated liver diseases. Progress in these important areas has been rapid and forms the basis of this review.",0
2282,10421655,MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells,"Fibrosis occurs in most chronic liver injuries and results from changes in the balance between synthesis and degradation of extracellular matrix components. In fibrotic livers, there is a markedly increased activity of matrix metalloproteinase 2 (MMP2), a major enzyme involved in extracellular matrix remodeling. We have previously shown that hepatic stellate cells secrete latent MMP2 and that MMP2 activation occurs in coculture of hepatic stellate cells and hepatocytes concomitantly with matrix deposition. In the present work we investigated the effects of various extracellular matrix components and concanavalin A, an inducer of immune-mediated liver injuries, on MMP2 activation in cultured human hepatic stellate cells. Collagen I induced a dose-dependent MMP2 activation, which was not blocked by both actinomycin and cycloheximide. Collagen VI, laminin, and a reconstituted basement membrane (matrigel) were ineffective in inducing activation. Specific antibodies against the subunits of alpha2beta1 integrins, the major collagen I receptor, induced partial inhibition of MMP2 activation. Treatment of cells with concanavalin A resulted in a marked activation of MMP2 that correlated with the proteolytic processing of MT1-MMP, the MMP2 activator, from a Mr=60 kd toward a Mr=43 kd polypeptide. Actinomycin and cycloheximide inhibited the MMP2 activation induced by concanavalin A. Recombinant tissue inhibitor of metalloproteinase-2 and the MMP inhibitor BB-3103, but not PMSF, blocked MMP2 activation induced by collagen I or concanavalin A, and MT1-MMP processing to its Mr-43 kd form. These results suggest that the accumulation of collagen I may specifically contribute to the remodeling of extracellular matrix in fibrotic livers by inducing MMP2 activation.",0
2283,10421668,Quasispecies of hepatitis C virus in serum and in three different parts of the liver of patients with chronic hepatitis,"Hepatitis C virus (HCV) has been known to infect hosts as a quasispecies. Several reports have shown this using serum samples, but there is little information about quasispecies in the liver. In this study, we evaluated quasispecies in serum and in 3 different parts of the liver in 8 patients with varying severity of chronic hepatitis C by calculating nucleotide diversity, entropy, type of substitution and by phylogenetic analysis. Nucleotide diversity of HCV was different in each sample and ranged from 0.37% +/- 0.31% to 4.10% +/- 1.06%. However, the degree of HCV diversity in serum correlated with that in the liver in each patient (P <.01). Common HCV clones were found both in serum and liver samples in all 6 noncirrhotic patients, but all serum clones were different from the clones from the 2 cirrhotic livers. Phylogenetic analysis showed that the degree of genetic diversity of HCV among the 3 liver samples was significantly high in the 4 patients with fibrosis. These genetic compartmentalizations of HCV did not depend on the type of substitution or the viral load of each liver sample. HCV quasispecies within the liver may be closely related to the viral life cycle and the pathogenesis of persistent infection of HCV.",0
2284,10421893,"Influence of juvenile hormone and mating on oogenesis and oviposition in the codling moth, cydia pomonella ","Oogenesis in the codling moth, Cydia pomonella, and the role of juvenile hormones (JHs) were addressed. Rudimentary ovarian structures were recognisable in day 3-4 pupae, when haemolymph JH was still undetectable by coupled gas chromatography-mass spectrometry in the selected ion mode (GC-MS/SIM). The presence of developing oocytes was observed by light microscopy on day 8, coincident with very low JH titres (0.74 +/- 0.05 ng/ml JH II). Chorionation was only evident upon emergence, following an increase in JH in the pharate adult (0h old: 4.71 +/- 0.34 ng/ml JH II). Analysis of haemolymph from virgin and mated females indicated that JH II was predominant, with approximately equal and lower quantities of JHs I and III (3.3- to 5.0-fold less). When pupae or newly emerged adults were treated with JH homologues, no alteration in ovarian protein content was apparent, but the JH mimetic, fenoxycarb, depressed the number of oocytes filling >/= 50% follicular volume. Chorion deposition was stimulated by JHs I, II, or III (10 &mgr;g), but not by fenoxycarb (0.05 &mgr;g, 10 &mgr;g). Mating provided correct stimuli for enhanced choriogenesis and egg laying, and, since haemolymph JH titres were concomitantly elevated (approximately 2-fold), it was postulated that the rise in JH elicited both these events. Application of JHs to virgin females, however, could not mimic mating; only increases in choriogenesis were induced: JH-treatment of virgins (or mated insects) significantly decreased oviposition rates over 24 and 48 h and markedly reduced the life-time total number of eggs. Arch. Copyright 1999 Wiley-Liss, Inc. ",0
2285,10421902,Nano-electrospray tandem mass spectrometry for the analysis of neurosteroid sulphates,"Neurosteroids are synthesised in the central and peripheral nervous system or are derived from peripheral sources, and act in the nervous system. In the present study we have evaluated the potential for using nano-electrospray (nano-ES) tandem mass spectrometry (MS/MS) for the structural analysis and detection of neurosteroids, in particular, steroid sulphates found in brain. Complete structural information can be obtained from 1 ng (3 pmol) of steroid sulphate, while fragment ions characteristic of the sulphate ester group can be obtained from only 3 pg (10 fmol) of sample. These values correspond to the expected quantities of steroid sulphates (e.g. pregnenolone sulphate) in about 100 mg and 300 microg of brain, respectively. Deuterated neurosteroid sulphates added to homogenised rat brain have been successfully analysed by nano-ES-MS/MS at a level of 50 pg/mg of brain. ",0
2286,10421922,Extracorporeal liver assist devices in acute liver failure],"The acute liver failure (ALF) is a complex syndrome resulting from loss of synthetic and metabolic functions of the liver. Despite recent advances in intensive care medicine patients with severe ALF have a very high mortality and the orthotopic liver transplantation still remains the only proven effective treatment of ALF. Numerous attempts have been made to improve survival by using various extracorporeal support techniques, but none of these therapeutic approaches was able to increase the survival rate. Liver support systems based on detoxification procedures only could not influence the deleterious course of the disease. It is certain that an ideal liver support system should be capable to fulfil the liver's essential synthetic and metabolic functions as well as detoxification and excretion. Over the last years the development of hybrid liver assist devices has aimed at replacing these liver functions and therefore might give an advantage over earlier systems based on detoxification techniques only. This article gives a short review of the various liver support systems and focuses then on the hybrid liver support systems, their construction and the remaining problems after the first clinical applications. ",0
2287,10422088,Effects of total parenteral nutrition on endotoxin translocation and extent of the stress response in burned rats,"Postburn endotoxin translocation has been well documented. However, the relationship between the secretion of catabolic hormones, degree of endotoxin translocation, and intestinal atrophy has not been previously demonstrated. In this experiment, modulation of the secretion of catabolic hormones according to the route of nutrient administration was examined in burned animals. A total of 55 rats, with and without a burn injury, were orally or parenterally fed. Urinary excretion of epinephrine and norepinephrine (U-EN) of each rat was measured for 48 h after burn injury as an indicator of the stress response. Evaluations of intestinal atrophy and endotoxin contents in the liver and spleen were also done 48 h after burn injury. U-EN after burn injury in rats administered total parenteral nutrition (TPN) was higher than in those fed orally. Endotoxin translocation and intestinal atrophy after thermal injury were also augmented by TPN. A significant positive correlation between U-EN and endotoxin content of the liver, and a negative correlation between U-EN and weight of the intestine, were observed. TPN enhances the stress response after burn injury. An increase in endotoxin translocation and intestinal atrophy by TPN are closely related to enhancement of the stress response. ",0
2288,10422536,The XRCC2 and XRCC3 repair genes are required for chromosome stability in mammalian cells,"The irs1 and irs1SF hamster cell lines are mutated for the XRCC2 and XRCC3 genes, respectively. Both show heightened sensitivity to ionizing radiation and particularly to the DNA cross-linking chemical mitomycin C (MMC). Frequencies of spontaneous chromosomal aberration have previously been reported to be higher in these two cell lines than in parental, wild-type cell lines. Microcell-mediated chromosome transfer was used to introduce complementing or non-complementing human chromosomes into each cell line. irs1 cells received human chromosome 7 (which contains the human XRCC2 gene) or, as a control, human chromosome 4. irs1SF cells received human chromosome 14 (which contains the XRCC3 gene) or human chromosome 7. For each set of hybrid cell lines, clones carrying the complementing human chromosome recovered MMC resistance to near-wild-type levels, while control clones carrying noncomplementing chromosomes remained sensitive to MMC. Fluorescence in situ hybridization with a human-specific probe revealed that the human chromosome in complemented clones remained intact in almost all cells even after extended passage. However, the human chromosome in noncomplemented clones frequently underwent chromosome rearrangements including breaks, deletions, and translocations. Chromosome aberrations accumulated slowly in the noncomplemented clones over subsequent passages, with some particular deletions and unbalanced translocations persistently transmitted throughout individual subclones. Our results indicate that the XRCC2 and XRCC3 genes, which are now considered members of the RAD51 gene family, play essential roles in maintaining chromosome stability during cell division. This may reflect roles in DNA repair, possibly via homologous recombination. ",0
2289,10422586,Molecular genetics of carbapenem antibiotic biosynthesis,"Carbapenems are potent beta-lactam antibiotics with a broad spectrum of activity against both Gram positive and Gram negative bacteria. As naturally produced metabolites, they have been isolated from species of Streptomyces, Erwinia and Serratia. The latter two members of the Enterobacteriaceae have proved to be genetically amenable and a growing body of research on these organisms now exists concerning the genes responsible for carbapenem biosynthesis and the regulatory mechanisms controlling their expression. A cluster of nine carbapenem (car) genes has been identified on the chromosome of Erwinia carotovora. These genes encode the enzymes required for construction of carbapenem and the proteins responsible for a novel beta-lactam resistance mechanism, conferring carbapenem immunity in the producing host. Although sharing no homology with the well known enzymes of penicillin biosynthesis, two of the encoded proteins are apparently similar to enzymes of the clavulanic acid biosynthetic pathway implying a common mechanism for construction of the beta-lactam ring. In addition, a transcriptional activator is encoded as the first gene of the carbapenem cluster and this allows positive expression of the remaining downstream genes in response to a quorum sensing, N-acyl homoserine lactone, signalling molecule. ",0
2290,10422623,Effect of defibrillation on hemodynamics during cardioverter defibrillator implantation],"This study evaluated the influences of induced ventricular fibrillation and defibrillation on the hemodynamics in patients with malignant ventricular arrhythmias during cardioverter defibrillator implantation. A total of 15 patients were analyzed, divided into 2 groups based on ventricular contractility. Group A included 6 patients with preoperative left ventricular fractional shortening < or = 0.20 and Group B consisted of 9 patients with fractional shortening > 0.20. Mean blood pressure, cardiac output, pulmonary capillary wedge pressure, and left ventricular stroke work index were measured before and after ventricular fibrillation and defibrillation. In addition, end-systolic wall stress and rate-corrected mean velocity of circumferential fiber shortening were obtained from transesophageal echocardiography. In Group B, measured 30 sec after defibrillation, mean blood pressure, cardiac output, and left ventricular stroke work index increased significantly (p < 0.05), whereas only pulmonary capillary wedge pressure indicated a significant increase (p < 0.001) after defibrillation in Group A. Throughout 5 repeated ventricular fibrillations and defibrillations. Group A showed consistently lower postoperative values than preoperative values for mean blood pressure, cardiac output and left ventricular stroke work index. In contrast, in Group B, the postoperative values were constantly higher than preoperative values. Although end-systolic wall stress decreased after defibrillation in both groups, the magnitude of decrease was significantly greater in Group A than in Group B (p < 0.01). While rate-corrected mean velocity of circumferential fiber shortening increased after defibrillation in both groups, the difference of rate-corrected mean velocity of circumferential fiber shortening between Groups A and B was statistically significant at beats one and 2 following defibrillation (p < 0.05) where Group A indicated a more drastic increase than Group B. In both groups, post-defibrillation end-systolic wall stress and rate-corrected mean velocity of circumferential fiber shortening gradually approached the preoperative values as beats proceeded. These results suggest that repeated defibrillations in patients with poor ventricular contractility potentially deteriorates hemodynamics, presumably because the left ventricle is often intolerant to abrupt arterial collapse by ventricular fibrillation and to subsequent rapid preload increase after defibrillation. ",0
2291,10423088,Endothelial dysfunction in hypertension,"Hypertension is an important risk factor for the development of atherosclerosis and endothelial dysfunction may be a key mechanism. The nitric oxide mediated vasodilator function of the endothelium has been widely studied as a test of endothelial integrity in patients with hypertension and impaired basal and muscarinic agonist stimulated components of nitric oxide mediated vascular tone have been found in coronary, forearm and cutaneous resistance vessels and in coronary and forearm conduit vessels. The underlying abnormalities of these changes are unknown but it is likely to be a secondary phenomenon due to increased blood pressure. However, endothelial dysfunction as assessed by response to muscarinic agonists does not occur in all patients and antihypertensive therapy so far has been mostly unable to reverse it. Although widely used the response to acetylcholine has some shortcomings and it remains to be established what parameter best reflects endothelial dysfunction. The relationship of such abnormalities to the present or future atherosclerosis needs to be defined. ",0
2292,10423207,Transplant pharmacists' opinions on generic product selection of critical-dose drugs,"Factors considered important by transplant pharmacists in decisions about generic product selection and in defining critical-dose drugs, as well as transplant pharmacists' attitudes about bioequivalence testing, were studied. Surveys, completed by telephone and fax in 1997, were used to assess pharmacists' role at solid-organ transplant centers, factors the pharmacists considered important for generic product selection, and pharmacists' attitudes about the FDA guidelines on bioequivalence testing. Surveys were completed by 59 pharmacists. The factors considered important by pharmacists for inclusion of generic products on the formulary were safety (97% of respondents), clinical consequences (97%), efficacy (92%), and bioequivalence (92%). Nearly all the pharmacists (95%) expressed a belief that generic products of some critical-dose drugs should not be dispensed. Only 12% of the respondents said they thought that the FDA guidelines on bioequivalence testing were appropriate for critical-dose drugs, and 92% thought that bioequivalence testing for this category of drugs should be conducted in actual patients. Efficacy, safety, the presence of a narrow therapeutic index, bioequivalence, and clinical consequences were identified by transplant pharmacists as important factors in decisions about generic product selection; current FDA guidelines for establishing bioequivalence were viewed as possibly not appropriate for critical-dose drugs. ",0
2293,10423295,Testes-specific transgene expression in insulin-like growth factor-I transgenic mice,"Insulin-like growth factor-I (IGF-I) is a low molecular weight peptide that mediates the cell proliferating actions of growth hormone. Evidence exists indicating that IGF-I is produced by various cell types and this growth factor has been implicated in a variety of reproductive processes. To investigate the effect of IGF-I over-expression on reproductive systems, we generated three independent lines of transgenic mice harbouring a human IGF-I cDNA (hIGF-I) under the control of a Cytomegalovirus immediate early (CMV) promoter. The CMV promoter was used in an attempt to direct expression of IGF-I into a variety of tissues both reproductive and non-reproductive. Yet expression of the foreign hIGF-I gene, determined by Northern blot, was found to occur only in the testicular tissues of the male mice, apparently due to methylation of the transgene in all the tissues tested except the testes, which demonstrate transgene hypomethylation. Evaluation of the transgene expression during testicular development revealed that expression begins between 10 and 15 days of development, coinciding with the appearance of the zygotene and pachytene primary spermatocytes during early spermatogenesis, therefore indicating germ line expression of the transgene. Extensive study of the CMV-hIGF-I transgenic lines of mice has revealed that the effects of the transgene expression do not extend beyond the testicular tissues. No significant differences (P > 0.05) in the IGF-I serum levels, growth rates, or testicular histology have been observed between transgenic and non-transgenic male siblings. The ability of transgenic males to produce offspring also appears unaffected. Evaluation of the IGF binding protein (IGFBP) levels in the testicular tissues of CMV-hIGF-I transgenic mice by Western ligand blot revealed an increase in the concentration of testicular proteins with molecular weights corresponding to IGFBP-2 and IGFBP-3. These results suggest that the testicular over-expression of IGF-I induces increased IGFBP localization in this tissue. Inhibition of IGF activity by the IGFBPs would explain the lack of a dramatic physiological effect in the CMV-hIGF-I transgenic mice, despite the presence of elevated testicular IGF-I. The observation that testis specific IGF-I overexpression induces localization of IGFBPs in this tissue confirms the existence of a well regulated testicular IGF system and supports the convention that this growth factor plays an important role in testicular function. ",0
2294,10423572,Chemiluminescent detection of catecholamines by generation of hydrogen peroxide with imidazole,"A novel detection method for catecholamines using imidazole was investigated using a chemiluminescence coupled flow injection system. Imidazole catalysed decomposition of catecholamines to generate hydrogen peroxide, then the hydrogen peroxide was detected by chemiluminescence. The optimal condition for generation of hydrogen peroxide from a catecholamine was to incubate the catecholamines (53 pmol) in an imidazole solution (50 mmol/L, pH 9.0, 1.0 mL) at 60 degrees C for 30 min. Peroxide-was detected by peroxyoxalate chemiluminescence, and the rank order of the light emission intensities was as follows; dopamine (100%) >epinephrine (78%) >L-DOPA (62%) >norepinephrine (58%) >deoxyepinephrine (51%) >isoproterenol (43%) >dihydroxybenzylamine (25%). The light intensities of the reaction mixtures (corresponding to 1.06 pmol catecholamines) varied depending on the chemiluminescence (CL) detection reaction, and the rank order of the light intensity was as follows; luminol CL catalysed with horseradish peroxidase (HRP) (371%) >peroxyoxalate chemiluminescence (100%) >luminol CL catalysed with ferrycyanide (62%) >lucigenin CL (15%) >pyrogallol CL (0.8%) >purpurogallin CL (0.4%) >luminol CL (0.3%). The luminol CL reaction catalysed by HRP is recommended for the detection of peroxide in this method for catecholamines. ",0
2295,10423607,The prescription Drug User Fee Act of 1992 and the new drug development process,"The Prescription Drug User Fee Act of 1992 (PDUFA) authorizes the US Food and Drug Administration (FDA) to levy user fees on manufacturers who submit applications to the agency. Revenues are dedicated to the achievement of a set of specific performance goals, documented by the FDA Commissioner and referenced in the Act. The FDA currently credits PDUFA with the agency's success in reducing new drug review times and eliminating the formidable new drug application (NDA) backlog. To provide an independent assessment of PDUFA's impact on the new drug development process, the Tufts Center for the Study of Drug Development established an annual user fee survey of over 50 major pharmaceutical and biotechnology firms with operations in the United States. As of December 31, 1996, survey data have been collected for fiscal years 1994, 1995, and 1996. Data from a cohort of user fee drugs approved in 1993-1996 were compared with data from all non-user fee drugs approved in 1990-1992. Whereas the mean approval phase (NDA submission to approval) for the user fee drugs was considerably shorter than that for the non-user fee drugs (14.5 versus 31.0 months, respectively), the mean clinical phase (investigational new drug application filing to NDA submission) was somewhat longer (88.0 versus 81.1 months, respectively). As a result, the total time from the start of clinical testing to drug approval (total phase) was only marginally shorter for the user fee drugs (102.0 versus 112.1 months, respectively). These results highlight the need for efforts to reduce lengthy drug development times. ",0
2296,10423735,Seroprevalence of anti-human parvovirus B19 antibodies in patients attending a centre for sexually transmitted diseases,"The aim of this study was to establish the serological prevalence of anti-human Parvovirus B19 (HP-B19) antibodies in a group of 321 patients attending a Centre for Sexually Transmitted Diseases (STDs) and epidemiologically examine whether this virus may also be sexually transmitted. For this purpose, the serum prevalence of anti-HP-B19 evaluated in STD patients (39%) was compared with that of 164 healthy blood donors (10%, p < 0.001), using commercially available ELISA methods detecting the anti-VP1 reactivity of the sera. The same STD patients were also analyzed for serum reactivities against 4 STD-causing microorganisms, namely T. pallidum (TPHA), HBV (HBcAb), HCV (HCV-Ab) and HIV (HIV-Ab), to observe possible associations with the serum anti-HP-B19 reactivity. These tests were also carried out with commercially available kits. The results suggest that the serum anti-HP-B19 antibody prevalence in patients with STDs is increased, also independently of their intravenous drug addition and varies with the reactivity pattern determined. In addition, as expected for a STD, the anti-HP-B19 prevalence is increased in homobisexual patients compared with heterosexuals. ",0
2297,10423745,Effect of novel biosurfactants on biodegradation of polychlorinated biphenyls by pure and mixed bacterial cultures,"A study was conducted to determine the potential positive effect of novel biosurfactants on the enhancement of Aroclor 1248 metabolization in both in vitro and in situ experiments. Among two lipopeptides tested the highest activity was found in experiments with a hydrolytically opened form of lichenysin A. Lichenysin A itself did not enhance the degradation activity of chosen microorganism-degraders and in most cases inhibited their PCB mineralization rates. Glucolipid surfactant from marine bacterium Alcanivorax borkumensis showed in several tests a strong enhancing effect on microbial metabolization of Aroclor 1248 congeners. Biosurfactants appeared to act very specifically, i.e. depending on strain and concentration used. Experiments set up with soil samples did not give a clear answer whether bioemulsifiers applied at low concentration could sufficiently increase the rates of biodegradation in situ. Only A. borkumiensis glucose lipid caused the most marked enhancement of Aroclor 1248 metabolization in soil microcosm. We suggest that taking into account the specificity of surface- and biological activities of various biosurfactants they may promote the mineralization of sorbed PCBs in polluted soils, when the optimized biosurfactant-degrader combination is used. ",0
2298,10424151,Disappearance of globus pallidus hyperintensity in a patient with portal-systemic encephalopathy after occlusion of the shunt vessel],"A 67-year-old woman was admitted to our hospital with confusion and asterixis on January 23, 1994. She had had the same symptoms repeatedly. On admission she was disorientated, and had slurred speech and asterixis. Laboratory data showed hyperammonemia (84 micrograms/dl) with a poor ICG hepatic clearance (ICG15min = 32%), although hepatic failure did not exist. Abdominal ultrasonography, CT scan and liver biopsy showed no evidence of cirrhosis. Celiac arteriography revealed a large shunt vessel connecting the portal vein to the left renal vein. A 1.5 T magnetic resonance imaging (MRI) demonstrated a bilateral and symmetrical hyperintensity of the globus pallidus in the T1-weighted images. Portal-systemic encephalopathy recurred repeatedly in spite of the conservative therapy, and there was no evidence of the portal hypertension. Therefore, the operative procedure of ligation of the shunt vessel was done on February 21, 1995. After the operation, blood ammonia level and ICG hepatic clearance were normalized. She became free from encephalopathy. Twenty-seven months after the operation, the hyperintensity of the globus pallidus in the T1-weighted images completely disappeared. There have been several reports describing that the globus pallidus alterations on the T1-weighted images in patients with liver cirrhosis, manganese intoxication and portal-systemic encephalopathy. To our knowledge, this is the first case that the hyperintense signal of the basal ganglia in a patient with portal-systemic encephalopathy disappeared completely after occlusion of the shunt vessel. ",0
2299,10424380,Recolonisation pattern of mutans streptococci after suppression by three different modes of chlorhexidine gel application,"Clinical studies have shown conflicting results for the reduction of approximal caries when chlorhexidine gel has been applied either in trays or by flossing. To investigate whether these modes of treatment affect the colonization of mutans streptococci (MS) differently, we quantified MS in saliva and on various tooth surfaces before and after a single chlorhexidine gel application. Twenty-one schoolchildren (15-16 yr old), with high numbers of salivary MS, were randomised into three groups. The subjects were treated with a 1% chlorhexidine gel applied either by: 1) interdental flossing; 2) individually designed mouth trays; or 3) a combination of polishing and flossing. Analysis of saliva and of dental plaque from 12 sites over an 8-wk period showed a greater reduction of both salivary MS counts and total number of colonised sites in the tray group than in the flossing group. The effect on MS in the polishing-flossing group approached that obtained in the tray group. In the interdental areas, more sites had no detectable MS (score 0) after tray treatment than after flossing, whereas the reduction of heavily colonised sites (scores 3+/-4) was higher in the flossing group. The reappearance of sites with score 3+/-4 after the gel treatment was more rapid in the flossing group than in the other two groups. In conclusion, the results showed a transient reduction of MS colonisation by all three methods, and that the application of the chlorhexidine gel both in mouth trays or as a combination of polishing and flossing was more effective in reducing the MS population than flossing alone. ",0
2300,10424985,Condyle position as a predictor of temporomandibular joint internal derangement,"The significance of the position of the mandibular condyle in the glenoid fossa remains a controversial subject. This study evaluated the relationship between condyle position and disk displacement. Fifty-two asymptomatic volunteers and 130 symptomatic patients underwent linear tomography and bilateral temporomandibular joint magnetic resonance scans. There was a higher prevalence of distal condyles in symptomatic patients with disk displacement compared with asymptomatic volunteers (P <.05). Distally positioned condyles identified joints with disk displacement with reduction, disk displacement without reduction, or a symptomatic normal joint with a sensitivity of 0.64, 0.56, and 0.33, respectively. Distally positioned condyles identified joints with disk displacement with reduction, disk displacement without reduction, or a symptomatic normal joint with a specificity of 0.56, 0.65, and 0.55, respectively. There were more distal condyles in symptomatic subjects with disk displacement, but the reliability of a distal condyle to predict the presence or absence of disk displacement was low. ",0
2301,10432327,The association between for-profit hospital ownership and increased Medicare spending,"BACKGROUND AND METHODS: The rate of conversion to for-profit ownership of hospitals has recently increased in the United States, with uncertain implications for health care costs. We compared total per capita Medicare spending in areas served by for-profit and not-for-profit hospitals. We used American Hospital Association data to categorize U.S. hospital service areas as for-profit (meaning that all beds in the area were in for-profit hospitals), not-for-profit (all beds were in not-for-profit hospitals), or mixed in 1989, 1992, and 1995. We then used data from the Continuous Medicare History Sample to calculate the 1989, 1992, and 1995 spending rates in each area, adjusting for other characteristics known to influence spending: age, sex, race, region of the United States, percentage of population living in urban areas, Medicare mortality rate, number of hospitals, number of physicians per capita, percentage of beds in hospitals affiliated with medical schools, percentage of beds in hospitals belonging to hospital chains, and percentage of Medicare beneficiaries enrolled in health maintenance organizations. RESULTS: Adjusted total per capita Medicare spending in the 208 areas where all hospitals remained under for-profit ownership during the study years was greater than in the 2860 areas where all hospitals remained under not-for-profit ownership ($4,006 vs. $3,554 in 1989, $4,243 vs. $3,841 in 1992, and $5,172 vs. $4,440 in 1995; P<0.001 for each comparison). Mixed areas had intermediate spending rates. Spending in for-profit areas was greater than in not-for-profit areas in each category of service examined: hospital services, physicians' services, home health care, and services at other facilities. The greatest increases in per capita spending between 1989 and 1995 were for hospital services (a mean increase of $395 in for-profit areas and $283 in not-for-profit areas, P=0.03 for the comparison between for-profit and not-for-profit areas) and home health care (an increase of $457 in for-profit areas and $324 in not-for-profit areas, P<0.001). Between 1989 and 1995, spending in the 33 areas where all hospitals converted from not-for-profit to for-profit ownership grew more rapidly than in the 2860 areas where all hospitals remained under not-for-profit ownership ($1,295 vs. $866, P=0.03). CONCLUSIONS: Both the rates of per capita Medicare spending and the increases in spending rates were greater in areas served by for-profit hospitals than in areas served by not-for-profit hospitals.",0
2302,10441601,Integrated screening for Down's syndrome based on tests performed during the first and second trimesters,"BACKGROUND: Both first-trimester screening and second-trimester screening for Down's syndrome are effective means of selecting women for chorionic-villus sampling or amniocentesis, but there is uncertainty about which screening method should be used in practice. We propose a new screening method in which measurements obtained during both trimesters are integrated to provide a single estimate of a woman's risk of having a pregnancy affected by Down's syndrome. METHODS: We used data from published studies of various screening methods employed during the first and second trimesters. The first-trimester screening consisted of measurement of serum pregnancy-associated plasma protein A in 77 pregnancies affected by Down's syndrome and 383 unaffected pregnancies and measurements of nuchal translucency obtained by ultrasonography in 326 affected and 95,476 unaffected pregnancies. The second-trimester tests were various combinations of measurements of serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in 77 affected and 385 unaffected pregnancies. RESULTS: When we used a risk of 1 in 120 or greater as the cutoff to define a positive result on the integrated screening test, the rate of detection of Down's syndrome was 85 percent, with a false positive rate of 0.9 percent. To achieve the same rate of detection, current screening tests would have higher false positive rates (5 to 22 percent). If the integrated test were to replace the triple test (measurements of serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin), currently used with a 5 percent false positive rate, for screening during the second trimester, the detection rate would be higher 85 percent vs. 69 percent), with a reduction of four fifths in the number of invasive diagnostic procedures and consequent losses of normal fetuses. CONCLUSIONS: The integrated test detects more cases of Down's syndrome with a much lower false positive rate than the best currently available test.",0
2303,10441602,Long-term clinical efficacy of grass-pollen immunotherapy,"BACKGROUND: Pollen immunotherapy is effective in selected patients with IgE-mediated seasonal allergic rhinitis, although it is questionable whether there is long-term benefit after the discontinuation of treatment. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of the discontinuation of immunotherapy for grass-pollen allergy in patients in whom three to four years of this treatment had previously been shown to be effective. During the three years of this trial, primary outcome measures were scores for seasonal symptoms and the use of rescue medication. Objective measures included the immediate conjunctival response and the immediate and late skin responses to allergen challenge. Cutaneous-biopsy specimens obtained 24 hours after intradermal allergen challenge were examined for T-cell infiltration and the presence of cytokine-producing T helper cells (TH2 cells) (as evidenced by the presence of interleukin-4 messenger RNA). A matched group of patients with hay fever who had not received immunotherapy was followed as a control for the natural course of the disease. RESULTS: Scores for seasonal symptoms and the use of rescue antiallergic medication, which included short courses of prednisolone, remained low after the discontinuation of immunotherapy, and there was no significant difference between patients who continued immunotherapy and those who discontinued it. Symptom scores in both treatment groups (median areas under the curve in 1995, 921 for continuation of immunotherapy and 504 for discontinuation of immunotherapy; P=0.60) were markedly lower than those in the group that had not received immunotherapy (median value in 1995, 2863). Although there was a tendency for immediate sensitivity to allergen to return late after discontinuation, there was a sustained reduction in the late skin response and associated CD3+ T-cell infiltration and interleukin-4 messenger RNA expression. CONCLUSIONS: Immunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity.",0
2304,10462381,"Deficient assembly and function of gap junctions in Trf1, a trafficking mutant of the human liver-derived cell line HuH-7","The Trf1 cell line, selected from the human hepatoma cell line HuH-7, manifests altered trafficking of various plasma membrane proteins. In particular, there is a striking loss of State 2 asialoglycoprotein receptors. This cell line is shown here to also manifest defects in function and assembly of gap junctions comprising connexin43 (Cx43). No alteration of Cx43 expression or phosphorylation was apparent. Nevertheless, immunostaining of Cx43 revealed that fewer and smaller gap junctions were present at appositional membrane areas in Trf1 cells as compared with parental HuH-7. This correlated with a significant attenuation in gap junction-mediated communication between Trf1 cells as demonstrated by markedly decreased dye transfer and their reduced ability to propagate mechanically evoked Ca(2+) waves. Isoelectric focusing (IEF) of Cx43 in HuH-7 cells indicated that the pIs of this protein were significantly lower than that predicted from its amino acid sequence; no differences in pI were evident in Cx43 from Trf1 cells and the HuH-7 cell line. The effects of the Trf1 mutation on assembly and function of gap junctions indicate that this mutation influences trafficking of Cx43. Connexins differ in several respects from other membrane proteins thus far analyzed in Trf1 mutants: gap junctions localize exclusively to the lateral cell surface; they are not glycoproteins; and they do not play a role in endocytic pathways. The disruption of trafficking of Cx43 by this mutation suggests that the Trf1 phenotype is a defect at a common point along the trafficking pathway of cell-surface proteins, irrespective of their ultimate destination on the cell surface or their glycosylation profile.",0
2305,10462383,Persistent activation of nuclear factor-kappaB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IkappaB family proteins,"Rat hepatic stellate cells (HSC) cultured in serum-containing medium underwent a rapid (3-hour) classical induction of p50:p65 and p65:p65 nuclear factor-kappaB (NF-kappaB) dimers. Subsequent culturing was associated with prolonged expression of active p50:p65 and persistent induction of a high-mobility NF-kappaB DNA binding complex consisting of potentially novel Rel-like protein(s). Formation of the latter complex was competed for by specific double-stranded oligonucleotides, was up-regulated by treatment of HSCs with tumor necrosis factor alpha (TNF-alpha), and was maintained at basal levels of expression by a soluble HSC-derived factor. An NF-kappaB-responsive CAT reporter gene was highly active in early cultured HSCs but was also trans-activated at a lower but significant level in longer-term cultured cells and could be completely suppressed by expression of dominant negative IkappaB-alpha. Physiological significance of the lower persistent NF-kappaB activities was also demonstrated by the ability of long-term cultured HSCs to support the activity of the NF-kappaB-dependent human intercellular adhesion molecule-1 (ICAM-1) promoter. Freshly isolated HSCs expressed high levels of IkappaB-alpha and IkappaB-beta. Culture activation was accompanied by a long-term reduction in levels of IkappaB-alpha with no detectable expression in the nuclear fraction of cells, under these conditions p50:p65 was detected in the nucleus. IkappaB-beta expression was transiently reduced and, upon replenishment, was associated with appearance of a lower-mobility IkappaB-beta antibody-reactive species. Bcl3 expression was absent in freshly isolated HSC but was induced during culturing and became a persistent feature of the activated HSC. Inhibition of NF-kappaB DNA binding activity by gliotoxin was associated with increased numbers of apoptotic cells. We suggest that activation of NF-kappaB in cultured HSC is required for expression of specific genes associated with the activated phenotype such as ICAM-1 and may be antiapoptotic for rat HSCs.",0
2306,10477778,The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation,"BACKGROUND: Point mutations in the factor V gene (factor V Leiden) and the prothrombin gene (the substitution of A for G at position 20210) are the most common causes of inherited thrombophilia. Whether or not factor V Leiden increases the risk of recurrent deep venous thrombosis is controversial, and there is no information on the risk of recurrence among carriers of both mutations. METHODS: We studied a retrospective cohort of 624 patients who were referred for a first episode of deep venous thrombosis. After excluding 212 patients with other inherited or acquired causes of thrombophilia, we compared 112 patients who were heterozygous carriers of factor V Leiden with 17 patients who were heterozygous for both factor V Leiden and the prothrombin mutation and 283 patients who had neither mutation. The relative risk of recurrent deep venous thrombosis was calculated with use of a proportional-hazards model. RESULTS: Patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.6; P=0.76). In contrast, patients who were heterozygous for both factor V Leiden and the prothrombin mutation had a higher risk of recurrent thrombosis than did carriers of factor V Leiden alone (relative risk, 2.6; 95 percent confidence interval, 1.3 to 5.1; P=0.002). When the analysis was restricted to patients with spontaneous recurrences (i.e., ones that occurred in the absence of transient risk factors for venous thrombosis), the risk among carriers of both mutations, as compared with carriers of factor V Leiden alone, remained high (relative risk, 3.7; 95 percent confidence interval, 1.7 to 7.7; P<0.001), particularly if the first event had also been spontaneous (relative risk, 5.4; 95 percent confidence interval, 2.0 to 14.1; P<0.001). In contrast, the risk of recurrence in the presence of transient risk factors was similar among carriers of both mutations and carriers of factor V Leiden alone. CONCLUSIONS: The risk of recurrent deep venous thrombosis is similar among carriers of factor V Leiden and patients without this mutation. Carriers of both factor V Leiden and the G20210A prothrombin mutation have an increased risk of recurrent deep venous thrombosis after a first episode and are candidates for lifelong anticoagulation.",0
2307,10498490,A mechanism of central sleep apnea in patients with heart failure,"BACKGROUND: Breathing is controlled by a negative-feedback system in which an increase in the partial pressure of arterial carbon dioxide stimulates breathing and a decrease inhibits it. Although enhanced sensitivity to carbon dioxide helps maintain the partial pressure of arterial carbon dioxide within a narrow range during waking hours, in some persons a large hyperventilatory response during sleep may lower the value below the apneic threshold, thereby resulting in central apnea. I tested the hypothesis that enhanced sensitivity to carbon dioxide contributes to the development of central sleep apnea in some patients with heart failure. METHODS: This prospective study included 20 men who had treated, stable heart failure with left ventricular systolic dysfunction. Ten had central sleep apnea, and 10 did not. The patients underwent polysomnography and studies of their ventilatory response to carbon dioxide. RESULTS: Patients who met the criteria for central sleep apnea had significantly more episodes of central apnea per hour than those without central sleep apnea (mean [+/-SD], 35+/-24 vs. 0.5+/-1.0 episodes per hour). Those with sleep apnea also had a significantly larger ventilatory response to carbon dioxide than those without central sleep apnea (5.1+/-3.1 vs. 2.1+/-1.0 liters per minute per millimeter of mercury, P=0.007), and there was a significant positive correlation between ventilatory response and the number of episodes of apnea and hypopnea per hour during sleep (r=0.6, P=0.01). CONCLUSIONS: Enhanced sensitivity to carbon dioxide may predispose some patients with heart failure to the development of central sleep apnea.",0
2308,10498633,Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis,"Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH. Prime candidates at present are those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines. The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorphic sites in the interleukin-10 (IL-10) gene promoter (positions -1082, -819, and -592), and 2 polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) promoter (positions -308 and -238) in type 1 AIH. The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL-1B and IL-10 alleles, genotypes, or haplotypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF*2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB1*0301. This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.",0
2309,10498651,CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells,"""Hepatic stellate cells (HSCs) are a major source of extracellular matrix, which, during fibrogenesis, undergo a process of """"activation"""" characterized by increased proliferation and collagen synthesis. Oxidative stress can stimulate HSC proliferation and collagen synthesis in vitro. Cytochrome P4502E1 (CYP2E1) is an effective producer of reactive oxygen species. To study how intracellular oxidative stress modulates alpha 2 collagen type I (COL1A2) gene induction, a rat HSC line (HSC-T6) was transfected with human CYP2E1 complementary DNA in the sense and antisense orientation and with empty vector, and stable cell lines were generated. The cells expressing CYP2E1 displayed elevated production of reactive oxygen species and showed a 4-fold increase in COL1A2 messenger RNA (mRNA) levels; expression of this mRNA among different clones appeared to correlate with the level of CYP2E1. COL1A2 expression was decreased by vitamin E treatment or transfection with manganese superoxide dismutase, and was further increased after treatment with L-buthionine sulfoximine (BSO) to lower GSH levels. Thus, CYP2E1-dependent oxidative stress plays a major role in the elevation of COL1A2 mRNA levels in this system. Nuclear run-on assay showed a 3-and-a-half-fold increase in COL1A2 transcription in the cells expressing CYP2E1; stabilization of COL1A2 mRNA was also observed. These results indicate that under oxidative stress conditions, COL1A2 mRNA expression is regulated both transcriptionally and through mRNA stabilization. The CYP2E1-expressing HSC appear to be a valuable model for the sustained generation of reactive oxygen species and may allow the elucidation of signaling pathways responsible for oxidant stress-mediated collagen gene induction.""",0
2310,10498653,The structural and functional polarity of the hepatic human/rat hybrid WIF-B is a stable and dominant trait,"WIF-B cells were generated previously to obtain a good in vitro model expressing the structural and functional polarity of hepatocytes. Here we tested the stability and the strength of the WIF-B polarized phenotype. WIF-B cells stayed polarized and formed functional bile canaliculi even after 3 months in culture or after injection in nude mice and culture of the resulting tumors. WIF-B was subcloned and 10,000 colonies were examined; all (except for 3) were composed of bile canaliculi forming cells. Some subclones were characterized; the polarized ones presented the same properties and karyotype as the WIF-B cells; the 3 unpolarized subclones had a lower level of E-cadherin and different karyotypes. WIF-B cells were fused with their nonpolarized hepatic parental cells. The polarity state of the resulting FWIF hybrids was studied from day 11 to day 38 after fusion, by immunolocalization of hepatocyte domain-specific plasma membrane proteins. Most FWIF colonies (>80%) were composed of polarized cells. Soon after fusion these cells were exclusively polarized as simple epithelial cells. The percent of colonies containing cells expressing the typical hepatocyte polarity increased with time and reached 80% at day 38. This result confirms the two-step polarization process previously described for WIF-B. Chromosomally complete FWIF hybrids were examined several months after fusion. As shown by the study of bile acid transport and by confocal analysis of the localization of membrane domain markers, FWIF cells expressed a functional and fully polarized hepatic phenotype. In conclusion, polarity is a stable and dominant trait of WIF-B.",0
2311,10498662,Cost-effectiveness analysis of hepatitis A vaccination strategies for adults,"""Our objective in this study was to determine the cost-effectiveness of hepatitis A vaccination strategies in healthy adults in the United States. We constructed a decision model simulating costs and health consequences for otherwise healthy adults with respect to hepatitis A prevention. Three strategies were compared: (1) no intervention, (2) vaccination against hepatitis A, and (3) testing for antibodies to hepatitis A and vaccinating those without antibodies. Costs and probabilities were obtained from the published literature. One- and two- way sensitivity analyses were performed. Under baseline conditions, the """"test"""" strategy cost $230,100 per life-year saved compared with the """"no intervention"""" strategy. The incremental cost-effectiveness of the """"vaccination"""" strategy compared with the """"test"""" strategy was $20.1 million per life-year saved. The """"test"""" strategy was cost-effective when the hepatitis A case fatality rate exceeded 17% (baseline 2.7%). The """"vaccination"""" strategy was cost-effective when 1 dose of vaccine cost $7 or less (baseline $57). Under baseline conditions, neither the """"test"""" nor the """"vaccination"""" strategies are considered cost-effective according to current standards. Large changes in hepatitis A incidence, mortality rates, or vaccine cost are required for either of the intervention strategies to approach potentially cost-effectiveness. Such conditions may occur in areas in which hepatitis A is endemic, and/or under mass-vaccination scenarios.""",0
2312,10515361,"Evaluation of sodium bicarbonate, chloride, or sulfate with a coccidiostat in corn-soy or corn-soy-meat diets for broiler chickens","During the period from January to June, combined-sex broiler chickens were inoculated with coccidia via drinking water at 14 d of age. In a completely randomized design (eight replicate pens; 88 chicks per pen) using built-up litter, experimental diets contained monensin plus 0.20% dietary sodium bicarbonate (SBC), which provided 0.054% sodium and 0.144% bicarbonate. Treatment with SBC significantly improved coccidial lesion score, 45-d body weight, and feed efficiency compared with monensin alone. In a 2 x 5 factorial trial using built-up litter pens (eight replicate pens; 88 chicks per pen) vs. each ionophore alone, 0.20% dietary SBC with monensin significantly improved body weight, uniformity, and feed efficiency; 0.20% SBC with halifuginone, lasalocid, monensin, or salinomycin significantly reduced mortality; and 0.20% SBC with lasalocid, monensin, or salinomycin significantly increased breast meat yield. In a 2x4 factorial trial (12 replicate pens; 88 chicks per pen) on built-up litter, corn-soy and corn-soy-meat diets (higher potassium, lower chloride) with monensin were evaluated using 0.054% sodium from SBC, NaCl, or sodium sulfate decahydrate (SSD). With both diet types, SBC (0.20%) or NaCl (0.139% extra) significantly improved weight uniformity, feed efficiency, mortality, and breast meat yield; however, the SSD results were closer to controls. In a 21-d battery brooder test using similar diets and design (2x4 factorial; 4 replicate pens; 10 chicks per pen), SBC and NaCl significantly reduced coccidial lesion scores; SSD produced a significant, but weaker effect. Extra NaCl significantly increased water intake (approximately 37%), water excretion (approximately 27%), and litter moisture (approximately 22%) with both diet types. The SSD did not affect water intake. ",0
2313,10515815,"Neutrophil A2A adenosine receptor inhibits inflammation in a rat model of meningitis: synergy with the type IV phosphodiesterase inhibitor, rolipram","Bacterial meningitis is a disease worsened by neutrophil-induced damage in the subarachnoid space. In this study, the A2A adenosine receptors on human neutrophils were characterized, and the role of A2A receptors on the trafficking of leukocytes to the cerebrospinal fluid and on blood-brain barrier permeability (BBBP) was assessed in a rat meningitis model. Neutrophils bind the A2A selective antagonist, 125I-ZM241385 (Bmax=843 receptors/neutrophil; KD=0.125 nM). A selective A2A receptor agonist, WRC-0470 (2-cyclohexylmethylidene-hydrazinoadenosine; 0.03-1 microM), alone and synergistically with the type IV phosphodiesterase inhibitor, rolipram, increased neutrophil [cAMP]i and reduced cytokine-enhanced neutrophil adherence, superoxide release, and degranulation. These effects of WRC-0470 were reversed by ZM241385 (100 nM). In a lipopolysaccharide-induced rat meningitis model, WRC-0470 (0-0.9 microgram/kg/h), with or without rolipram (0-0.01 microgram/kg/h), inhibited pleocytosis and reduced the lipopolysaccharide-induced increase in BBBP, indicative of decreased neutrophil-induced damage. ",0
2314,10519898,Racial differences in the treatment of early-stage lung cancer,"BACKGROUND: If discovered at an early stage, non-small-cell lung cancer is potentially curable by surgical resection. However, two disparities have been noted between black patients and white patients with this disease. Blacks are less likely to receive surgical treatment than whites, and they are likely to die sooner than whites. We undertook a population-based study to estimate the disparity in the rates of surgical treatment and to evaluate the extent to which this disparity is associated with differences in overall survival. METHODS: We studied all black patients and white patients 65 years of age or older who were given a diagnosis of resectable non-small-cell lung cancer (stage I or II) between 1985 and 1993 and who resided in 1 of the 10 study areas of the Surveillance, Epidemiology, and End Results (SEER) program (10,984 patients). Data on the diagnosis, stage of disease, treatment, and demographic characteristics of the patients were obtained from the SEER data base. Information on coexisting illnesses, type of Medicare coverage, and survival was obtained from linked Medicare inpatient-discharge records. RESULTS: The rate of surgery was 12.7 percentage points lower for black patients than for white patients (64.0 percent vs. 76.7 percent, P<0.001), and the five-year survival rate was also lower for blacks (26.4 percent vs. 34.1 percent, P<0.001). However, among the patients undergoing surgery, survival was similar for the two racial groups, as it was among those who did not undergo surgery. Furthermore, analyses in which adjustments were made for factors that are predictive of either candidacy for surgery or survival did not alter the influence of race on these outcomes. CONCLUSIONS: Our analyses suggest that the lower survival rate among black patients with early-stage, non-small-cell lung cancer, as compared with white patients, is largely explained by the lower rate of surgical treatment among blacks. Efforts to increase the rate of surgical treatment for black patients appear to be a promising way of improving survival in this group.",0
2315,10534353,The impact of diagnosis of hepatitis C virus on quality of life,"The aim of this study was to examine the effects of diagnosis of hepatitis C virus (HCV) infection on quality of life in a cohort admitted to Fairfield Infectious Diseases Hospital with acute hepatitis from 1971 to 1975. Sera stored from the original admission were tested for antibody to HCV. Systematic approaches were used to locate anti-HCV-positive individuals and outcomes assessed by the Short Form 36 (SF-36) scale and a study-specific questionnaire as well as clinical review. Study subjects' SF-36 scores were compared with Australian population norms. Anti-HCV and HCV-RNA positive individuals (n = 15) aware of their serostatus rated significantly worse on 7 of 8 SF-36 scales compared with population norms. However, HCV-seropositive and RNA-positive individuals unaware of their HCV serostatus (n = 19) scored significantly worse in only 3 scales. Those aware of their serostatus did not differ sociodemographically, clinically, virologically, or serologically from those who were unaware, nor was there a link between quality of life (QOL) scores and objective measures of ill health. All subjects had injected drugs in the past. In conclusion, HCV-RNA and anti-HCV-positive individuals in our study have significantly poorer subjective health status 26 years after original infection compared with population norms. QOL measures were significantly worse for HCV-seropositive individuals aware of their serostatus compared with those unaware. We feel that the reduced QOL in the diagnosed group may be partially an effect of labeling and that the impact of the diagnostic process per se on QOL in individuals with HCV requires further evaluation.",0
2316,10547408,The economic implications of HLA matching in cadaveric renal transplantation,"BACKGROUND: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria is controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. METHODS: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. RESULTS: Average Medicare payments for renal transplant recipients in the three years after transplantation increased from 60,436 dollars per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to 80,807 dollars for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P<0.001). By three years after transplantation, the average Medicare payments were 64,119 dollars for transplantations of kidneys with less than 12 hours of cold ischemia time and 74,997 dollars for those with more than 36 hours (P<0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings (4,290 dollars per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold ischemia time were considered. CONCLUSIONS: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold ischemia time were greater than the advantages of optimizing HLA matching.",0
2317,10559448,Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention,"BACKGROUND AND METHODS: Periconceptional administration of folic acid can reduce a woman's risk of having a fetus or infant with a neural-tube defect. As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 microg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy. RESULTS: Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the northern region and 1.0 per 1000 in the southern region. Among the fetuses or infants of the women with periconceptional use of folic acid, the rates were 1.0 per 1000 in the northern region and 0.6 per 1000 in the southern region. The greatest reduction in risk occurred among the fetuses or infants of a subgroup of women in the northern region with periconceptional use who took folic acid pills more than 80 percent of the time (reduction in risk, 85 percent as compared with the fetuses or infants of women who registered before their last menstrual period and who took no folic acid; 95 percent confidence interval, 62 to 94 percent) [corrected]. In the southern region the reduction in risk among the fetuses or infants of women with periconceptional use of folic acid was also significant (reduction in risk, 41 percent; 95 percent confidence interval, 3 to 64 percent). CONCLUSIONS: Periconceptional intake of 400 microg of folic acid daily can reduce the risk of neural-tube defects in areas with high rates of these defects and in areas with low rates.",0
2318,10572155,The effect of patients' preferences on racial differences in access to renal transplantation,"BACKGROUND: In the United States, black patients undergo renal transplantation less often than white patients, but few studies have directly assessed the association between race and patients' preferences with respect to transplantation. METHODS: To assess preferences with respect to transplantation and experiences with medical care, we interviewed 1392 (82.9 percent) of 1679 eligible patients with end-stage renal disease (age range, 18 to 54 years) approximately 10 months after they had begun maintenance treatment with dialysis. Participants were selected from a stratified random sample of patients undergoing dialysis in four regions of the United States (Alabama, southern California, Michigan, and the mid-Atlantic region of Maryland, Virginia, and the District of Columbia) in 1996 and 1997. Patients were followed until March 1999. RESULTS: The interviews were conducted with 384 black women, 354 white women, 337 black men, and 317 white men. Black patients were less likely than white patients to want a transplant (76.3 percent of black women reported such a preference, vs. 79.3 percent of white women, and 80.7 percent of black men vs. 85.5 percent of white men), and they were less likely to be very certain about this preference (58.3 percent vs. 65.3 percent and 64.1 percent vs. 75.7 percent, respectively; P<0.01 for each comparison with both sexes combined). However, much larger differences were evident in rates of referral for evaluation at a transplantation center (50.4 percent for black women vs. 70.5 percent for white women, and 53.9 percent for black men vs. 76.2 percent for white men; P<0.001 for each comparison) and placement on a waiting list or transplantation within 18 months after the start of dialysis therapy (31.3 percent for black women vs. 56.5 percent for white women, and 35.3 percent for black men vs. 60.6 percent for white men; P<0.001). These racial differences remained significant after adjustment for patients' preferences and expectations about transplantation, sociodemographic characteristics, the type of dialysis facility, perceptions of care, health status, the cause of renal failure, and the presence or absence of coexisting illnesses. CONCLUSIONS: In the United States, the preferences and expectations with respect to renal transplantation among patients with end-stage renal disease differ according to race. These differences, however, explain only a small fraction of the substantial racial differences in access to transplantation. Physicians should ensure that black patients who desire renal transplantation are fully informed about it and are referred for evaluation.",0
2319,10573510,Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma,"Our previous immunohistochemical study on intrahepatic bile duct tumors showed that invasive cholangiocarcinoma (ICC) with a poor outcome expressed MUC1 mucin but was negative for MUC2 mucin, whereas bile duct cystadenocarcinoma (BDCC) with a favorable outcome was MUC1 negative and MUC2 positive. In the present study, ICC was further subdivided into 2 subtypes: intraductal growth type and/or periductal infiltrating type (ICC-IP) and mass forming type (ICC-M). The survival of patients with BDCC or ICC-IP is significantly better than that of patients with ICC-M. We examined these subtypes (ICC-IP and ICC-M) and BDCC for their expression of MUC1 mucins of different glycoforms. ICC-M showed significantly higher MUC1 expression rates (90%, 95%, and 85% positive rates as measured with the DF3, MY.1E12, and MUC1-Glycoprotein antibodies, respectively) than BDCC and ICC-IP (14% and 33%, 58% and 58%, and 0% and 50% positive respectively, as measured by the same antibodies). In contrast, BDCC (86% positive) and ICC-IP (67% positive) showed significantly higher MUC2 expression rates than ICC-M (25% positive) as measured with the anti-MRP antibody. Thus, the immunohistochemical staining pattern of ICC-IP resembled the pattern of BDCC more than they resembled ICC-M. In general, MUC1 expression is associated with poor patient outcome, irrespective of the glycosylation status. In particular, high expression of more sialylated forms of MUC1 mucins was correlated with poor survival. In contrast, expression of non-sialylated MUC2 mucin is a favorable prognostic indicator. These results suggest that ICC-IP is a different entity from ICC-M. This reclassification may have value in determining prognosis and treatment method.",0
2320,10573520,Role for tumor necrosis factor alpha receptor 1 and interleukin-1 receptor in the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin,"Peroxisome proliferators (PPs) cause rodent liver enlargement and tumors. In vitro, PPs induce rat and mouse hepatocyte DNA synthesis and suppress apoptosis, a response mimicked by exogenous tumor necrosis factor alpha (TNFalpha). Here, we determine the role of TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), and nuclear factor kappa beta (NFkappaB) in the response of mouse hepatocytes to the PP, nafenopin. Nafenopin (50 micromol/L) induced DNA synthesis as measured by bromodeoxyuridine (BrdU) incorporation, suppressed cell death as measured by Hoechst 33258 staining, induced peroxisomal beta-oxidation as measured by cyanide insensitive palmitoyl CoA oxidation (PCO) and caused activation of nuclear factor kappa beta (NFkappaB) as determined by electrophoretic mobility gel shift assay (EMSA). The induction of DNA synthesis and the suppression of apoptosis in response to nafenopin was abrogated completely by blocking antibodies to TNFR1 but not to TNFR2. In contrast, the induction of peroxisomal beta-oxidation by nafenopin was not blocked by the anti-TNFR1 antibody. Next, we evaluated the response of hepatocytes to interleukin-1 (IL-1), another proinflammatory cytokine. IL-1alpha (2.5 ng/mL) and, to a lesser extent, IL-1beta (5 ng/mL), shared the ability of TNFalpha to induce DNA synthesis and suppress apoptosis. In addition, anti-IL-1 receptor, type 1/p80 (IL-1R) antibodies were able to abrogate the response to nafenopin. IL-1alpha was still able to perturb hepatocyte growth in the presence of the anti-TNFR1 antibody suggesting that IL-1alpha acts independently rather than by elaborating TNFalpha. In summary, these data provide additional evidence for a role for hepatic cytokines in the perturbation of hepatocyte growth by PPs such as nafenopin.",0
2321,10573525,Kupffer cell-independent acute hepatocellular oxidative stress and decreased bile formation in post-cold-ischemic rat liver,"The purpose of this study was to examine distribution and time history of oxidative stress during the hyperacute period of reperfusion in the liver grafts undergoing cold ischemia and to investigate roles of Kupffer cells as a potential oxidant source. Rat livers were harvested at 4 degrees C in University of Wisconsin solution and followed by reperfusion with Krebs-Henseleit buffer under monitoring bile excretion. To investigate oxidative changes, laser-confocal microfluorography was performed in reperfused livers preloaded with dichlorodihydrofluorescein diacetate succinimidyl ester, a fluorescence precursor sensing intracellular hydroperoxide generation. Livers undergoing the 16-hour cold storage displayed an impaired recovery of bile acid-dependent bile output concurrent with a marked increase in hydroperoxide generation in hepatocytes, which occurred as early as 5 minutes after the onset of reperfusion, whereas the status of lobular perfusion was well maintained. Pretreatment with liposome-encapsulated dichloromethylene diphosphonate, a Kupffer cell-depleting reagent, did neither alter the reperfusion-induced periportal oxidative changes nor improve the recovery of bile output in the graft. On the other hand, EPCK, a hepatotropic antioxidant composed of vitamin E phosphate ester bound to vitamin C, not only diminished the oxidative changes but also improved the reduction of bile acid-dependent bile output. Furthermore, the reagent was capable of inhibiting H(2)O(2)-induced oxidative stress in cultured hepatocytes. These results suggest that hepatocytes constitute a major site of the oxidative insult triggered through Kupffer cell-independent mechanisms and serve as an important cellular component to be protected by antioxidant therapeutics.",0
2322,10607812,Improved clinical outcome after widespread use of coronary-artery stenting in Canada,"BACKGROUND: The introduction and refinement of coronary-artery stenting dramatically changed the practice of percutaneous coronary revascularization in the mid-1990s. We analyzed one-year follow-up data for all percutaneous coronary interventions performed in a large, unselected population in Canada to determine whether the use of coronary stenting has been associated with improved outcomes. METHODS: Prospectively collected data on all percutaneous coronary interventions performed on residents of British Columbia, Canada, between April 1994 and June 1997 were linked to province-wide health care data bases to provide the date of the following end points: subsequent target-vessel revascularization, myocardial infarction, and death. Baseline characteristics and procedural variables were identified and Kaplan-Meier survival curves were generated for 9594 procedures divided into seven groups, one for each sequential half-year period. RESULTS: The overall burden of coexisting illnesses remained stable throughout the study period. A large increase in the rate of coronary stenting (from 14.2 percent in the period from April to June 1994 to 58.7 percent in the period from January to June 1997) was associated with a significant reduction in the rate of adverse cardiac events at one year (from 28.8 percent to 22.8.percent; adjusted relative risk, 0.79; 95 percent confidence interval, 0.69 to 0.90; P<0.001). This reduction in adverse events was exclusively due to a large reduction in subsequent target-vessel revascularization (from 24.4 percent to 17.0 percent; adjusted relative risk, 0.72; 95 percent confidence interval, 0.62 to 0.83; P<0.001) without significant changes in the overall rates of myocardial infarction (5.4 percent, P=0.28) or death (3.9 percent, P=0.65). CONCLUSIONS: The need for target-vessel revascularization during one year of follow-up decreased after percutaneous coronary intervention during the mid-1990s. The reduction was coincident with the introduction and subsequent widespread use of coronary stenting.",0
2323,10613720,Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study,"Patients with primary sclerosing cholangitis (PSC) have a significantly increased risk of developing cholangiocarcinoma (CCA). Risk factors for developing such a complication are not well defined. We conducted a multicenter, case-control study to determine the risk factors and possible predictors for CCA in patients with PSC. The demographic, clinical, and laboratory features of 26 PSC patients with CCA diagnosed over a 7-year period at eight academic centers were compared with 87 patients with PSC but no CCA (controls). There was no statistically significant difference in demographics, smoking, signs or symptoms or complications of PSC, indices of disease severity (Mayo Risk score or Child-Pugh score), frequency or duration or complications of inflammatory bowel disease (IBD), frequency of biliary surgery, or therapeutic endoscopy between the two groups. Alcohol consumption was significantly associated with CCA in patients with PSC (odds ratio: 2.95; 95% CI: 1.04-8.3). Serum carbohydrate antigen 19-9 (CA 19-9) was significantly higher in patients with CCA than those without (177 +/- 89 and 61 +/- 58 U/mL, respectively; P =.002). A serum CA 19-9 level > 100 U/mL had 75% sensitivity and 80% specificity in identifying PSC patients with CCA. In conclusion, alcohol consumption was a risk factor for having CCA in PSC patients. The indices of severity of liver disease were not associated with CCA in patients with PSC. Serum CA 19-9 appeared to have good ability to discriminate PSC patients with and without CCA.",0
2324,10613730,Heterogeneity of growth potential of adult rat hepatocytes in vitro,"Nearly pure populations of small hepatocytes (SHs), parenchymal hepatocytes (PHs), and nonparenchymal cells (NPCs) were prepared from the adult rat, and cocultures of hepatocytes and NPCs were reconstituted from them first to obtain the direct evidence that NPCs promote the growth of hepatocytes and second to compare the growth potential between SHs and PHs. SHs and PHs underwent multiple divisions when cocultured with NPCs, whereas neither SHs nor PHs formed colonies at 10 days when cultured alone. Stellate cells in the NPCs were shown to be responsible for this growth promotion. SHs showed a higher growth capacity than PHs. To clearly show the relationship between the growth potential and the size of hepatocytes, SHs and PHs were further fractionated by a fluorescence-activated cell sorter, because the size distribution of SHs and PHs was half overlapped. SHs produced 2 cell populations, SH-R2 and SH-R3. The former showed a greater extent of granularity and autofluorescence than the latter. In contrast, PHs produced only 1 population (PH-R2), which corresponded to the SH-R2. The size of hepatocytes of SH-R3 was smaller (17.1 +/- 0.2 microm) than those of SH-R2 (22.6 +/- 0.5 microm) and PH-R2 (24.1 +/- 0.1 microm) and there was not a significant overlap in the size distribution between the 2 groups. The hepatocytes of SH-R3 were highly replicative and 4 or 5 times higher in their growth potential than those of SH-R2 and PH-R2. We concluded that the growth potential of hepatocytes is heterogeneous and is correlated with their size and the extent of their granularity and autofluorescence.",0
2325,10613735,Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells,"Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic actions of acetaldehyde and the induction of an oxidative stress response. However, the mechanisms responsible for these activities, and the possible connections between oxidative stress and acetaldehyde-induced fibrosis are not well understood. In this communication we investigated the molecular mechanisms whereby acetaldehyde induces mouse alpha1(I) procollagen (col1a1) gene expression in cultured hepatic stellate cells. Transfection assays using reporter plasmids driven by different segments of the col1a1 promoter localized an acetaldehyde-responsive element (AcRE) between nucleotides -370 and -345. We also show that acetaldehyde enhances binding of a CCAAT/enhancer binding protein-beta (C/EBPbeta)-containing complex to this element, and that this effect is due, at least in part, to an increase in the concentration of nuclear p35C/EBPbeta protein. Although this element overlaps to a previously described transforming growth factor beta1 (TGF-beta1)-responsive element, the stimulatory effect of acetaldehyde is not mediated through this cytokine, because addition of neutralizing anti-TGF-beta1 antibodies does not prevent acetaldehyde-elicited col1a1 up-regulation. On the other hand, this effect is blocked by the addition of catalase, an H(2)O(2) scavenger. Moreover, this ethanol metabolite stimulates production of H(2)O(2) in stellate cells. Thus, these results suggest that acetaldehyde-induced col1a1 up-regulation is mediated, at least in part, through H(2)O(2). Altogether, these data suggest that the -370 to -344 region of the col1a1 gene is a point of convergence of the action of numerous extracellular stimuli that ultimately leads to col1a1 up-regulation. In addition, we have established a direct connection between oxidative stress and enhanced col1a1 expression induced by acetaldehyde.",0
2326,10613749,In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance,"Several mutations (V521L, P525L, L528M, T532S, and V555I) in the gene for hepatitis B virus (HBV) polymerase have been identified in HBV isolated from patients that displayed break-through viremia during famciclovir treatment. To determine whether these mutations cause phenotypic resistance to famciclovir, we compared the inhibition constants (K(i)) of penciclovir triphosphate (PCVTP, the active metabolite of famciclovir) for recombinant wild-type and mutant HBV polymerases containing these mutations. In in vitro enzymatic assays, the V555I mutation displayed the most resistance (with K(i) increased by 6.2-fold) to PCVTP. The V521L and L528M mutations showed moderately decreased sensitivity to PCVTP (K(i) increased by >3-fold). We also analyzed the cross-resistance profiles of these variants for adefovir and lamivudine, two other antiviral agents that also inhibit DNA replication by HBV polymerase. All 5 famciclovir-associated mutations were sensitive to adefovir diphosphate (ADVDP) in in vitro enzymatic assays (<2.3-fold decreased sensitivity). The V521L, L528M, and T532S mutations were also sensitive to lamivudine triphosphate (LAMTP); however, the P525L and V555I mutations displayed moderately decreased sensitivity to LAMTP in enzymatic assays (3.6-fold decreased sensitivity). The lamivudine-resistant mutations M552I, M552V, and L528M+M552V, which were previously shown to display 8- to 25-fold resistance to LAMTP, were less resistant (< or = 3.1-fold) to PCVTP.",0
2327,10615079,Underrepresentation of patients 65 years of age or older in cancer-treatment trials,"BACKGROUND: Studies have documented the underrepresentation of women and blacks in clinical trials, and their recruitment is now federally mandated. However, little is known about the level of participation of elderly patients. We determined the rates of enrollment of patients 65 years of age or older in trials of treatment for cancer. METHODS: We analyzed data on 16,396 patients consecutively enrolled in 164 Southwest Oncology Group treatment trials between 1993 and 1996 according to sex, race (black or white), and age under 65 years or 65 or older. These rates were compared with the corresponding rates in the general population of patients with cancer, derived from the 1990 U.S. Census and from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program for the period from 1992 through 1994. Fifteen types of cancer were included in the analysis. RESULTS: The overall proportions of women and blacks enrolled in Southwest Oncology Group trials were similar to or the same as the estimated proportions in the U.S. population of patients with cancer (women, 41 percent and 43 percent; blacks, 10 percent and 10 percent, respectively). In contrast, patients 65 years of age or older were underrepresented overall (25 percent vs. 63 percent, P<0.001) and in trials involving all 15 types of cancer except lymphoma. The underrepresentation was particularly notable in trials of treatment for breast cancer (9 percent vs. 49 percent, P<0.001). The findings were similar when data on patients who were 70 years of age or older were analyzed, when 15 trials that excluded older patients were eliminated from the analysis, and when community-based enrollment was analyzed separately from enrollment at academic centers. CONCLUSIONS: There is substantial underrepresentation of patients 65 years of age or older in studies of treatment for cancer. The reasons should be clarified, and policies adopted to correct this underrepresentation.",0
2328,10648764,Influenza and the rates of hospitalization for respiratory disease among infants and young children,"BACKGROUND: Young children may be at increased risk for serious complications from influenzavirus infection. However, in population-based studies it has been difficult to separate the effects of influenzavirus from those of respiratory syncytial virus. Respiratory syncytial virus often circulates with influenzaviruses and is the most frequent cause of hospitalization for lower respiratory tract infections in infants and young children. We studied the rates of hospitalization for acute respiratory-disease among infants and children during periods when the circulation of influenzaviruses predominated over the circulation of respiratory syncytial virus. METHODS: For each season from October to May during the period from 1992 to 1997, we used local viral surveillance data to define periods in Washington State and northern California when the circulation of influenzaviruses predominated over that of respiratory syncytial virus. We calculated the rates of hospitalization for acute respiratory disease, excess rates attributable to influenzavirus, and incidence-rate ratios for all infants and children younger than 18 years of age who were enrolled in either the Kaiser Permanente Medical Care Program of Northern California or the Group Health Cooperative of Puget Sound. RESULTS: The rates of hospitalization for acute respiratory disease among children who did not have conditions that put them at high risk for complications of influenza (e.g., asthma, cardiovascular diseases, or premature birth) and who were younger than two years of age were 231 per 100,000 person-months at Northern California Kaiser sites (from 1993 to 1997) and 193 per 100,000 person-months at Group Health Cooperative sites (from 1992 to 1997). These rates were approximately 12 times as high as the rates among children without high-risk conditions who were 5 to 17 years of age (19 per 100,000 person-months at Northern California Kaiser sites and 16 per 100,000 person-months at Group Health Cooperative sites) and approached the rates among children with chronic health conditions who were 5 to 17 years of age (386 per 100,000 person-months and 216 per 100,000 person-months, respectively). CONCLUSIONS: Infants and young children without chronic or serious medical conditions are at increased risk for hospitalization during influenza seasons. Routine influenza vaccination should be considered in these children.",0
2329,10648768,Distribution of research awards from the National Institutes of Health among medical schools,"BACKGROUND: Previous studies have demonstrated that a small number of the 125 medical schools in the United States receive a disproportionately large share of the research awards granted by the National Institutes of Health (NIH). We assessed whether the distribution of NIH research awards to medical schools changed between 1986 and 1997. METHODS: We used NIH data to rank medical schools in each year from 1986 to 1997 according to the number of awards each school received (as a measure of each school's activity in research, also referred to as research intensity). The proportion of awards received by schools ranked 1 to 10, 11 to 30, 31 to 50, and 51 or lower in research activity was then calculated, and changes over time were examined. We also examined changes in the distribution of awards and changes in award amounts according to the type of department, the type of academic degree held by the principal investigator, and the awarding institute. RESULTS: Between 1986 and 1997, the proportion of research awards granted by the NIH to the 10 most research intensive medical schools increased slightly (from 24.6 percent of all awards to 27.1 percent), whereas the 75 least research intensive medical schools (those ranked 51 or lower) received proportionately fewer awards (declining from 24.3 percent to 21.8 percent). The increased proportion of awards to top-10 schools consisted primarily of increases in awards to clinical departments, awards to physicians, and awards from highly competitive NIH institutes. Basic-science departments received a smaller proportion of awards than clinical departments, both in 1986 and in 1997. CONCLUSIONS: Research funded by the NIH is becoming more concentrated in the medical schools that are most active in research.",0
2330,10655250,Increased activity of guanosine 3'-5'-cyclic monophosphate phosphodiesterase in the renal tissue of cirrhotic rats with ascites,"A possible defect of guanosine 3'-5'-cyclic monophosphate (cGMP) content in the renal tissue caused by an increased activity of cGMP phosphodiesterase (PDE) has, so far, not been evaluated in the pathogenesis of renal resistance to endogenous natriuretic peptides (ENP) in cirrhosis with ascites. To test this hypothesis the activity of cGMP-PDE and the concentration of cGMP were evaluated in vitro in the renal tissue of 10 control rats and 10 cirrhotic rats with ascites before and after the intravenous (IV) administration of Zaprinast (Sigma, St. Louis, MO), a specific cGMP-PDE inhibitor (30 microgram/kg/min). Moreover, the effects of the intravenous administration of Zaprinast (15 microgram/kg/min and 30 microgram/kg/min) on renal plasma flow (RPF), glomerular filtration rate (GFR), and urinary sodium excretion (U(Na)V) were evaluated in 10 conscious control rats and 10 conscious cirrhotic rats with ascites. The effects of Zaprinast on plasma renin activity (PRA) was also evaluated in 10 control rats and in 10 cirrhotic rats with ascites. Finally, the effect of Zaprinast on RPF, GFR, and U(Na)V were evaluated in 10 cirrhotic rats after the IV administration of the ENP-receptor antagonist, HS-142-1. The renal content of cGMP was reduced in cirrhotic rats because of increased activity of cGMP-PDE. Zaprinast inhibited cGMP-PDE activity and increased the renal content of cGMP in these animals. The inhibition of cGMP-PDE was associated with an increase in RPF, GFR, and U(Na)V and a reduction in PRA. HS-142-1 prevented any renal effect of Zaprinast in cirrhotic rats. In conclusion, an increased activity of the cGMP-PDE in renal tissue contributes to the renal resistance to ENP in cirrhosis with ascites.",0
2331,10655255,"Effects of the histamine H(1) receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis","To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portal-systemic encephalopathy, we examined the effects of histamine H(1) receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H(1) receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H(1) receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [(3)H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H(1) receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H(1) receptors in both sham- and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H(1) receptor-mediated mechanism.",0
2332,10655274,Reduced hepatitis B virus surface antigen-specific Th1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen-specific antibodies in the trimera mouse,"In chronic hepatitis B virus (HBV) infection weak antiviral immune responses are associated with viral persistence. We studied possible immune deficits underlying the lack of serum antibodies of such patients against the HBV surface antigen (HBsAg) in a novel human/mouse chimeric model. A hepatitis B surface antigen (HBs) vaccination of Balb/c mice engrafted with peripheral blood mononuclear cells (PBMC) of naturally HBV-immunized donors induced high frequencies of human HBsAg-specific B and T helper 1 (Th1) cells. These responses were associated with high serum anti-HBs antibody levels of the subclasses immunoglobulin G1 (IgG1) and IgG2 that are driven by interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). In contrast, PBMC of chronic HBV carriers transplanted into the chimera failed to produce anti-HBs antibodies after vaccination with HBsAg and exhibited a deficit of antigen-specific Th1 cells. A possible influence of HBsAg or viremia was excluded by the lack of viral replication in such chimera. The observed T-cell defect was specific for HBsAg, as the B- and T-cell responses to tetanus toxoid (TT) were fully retained. Thus, our study shows that viral persistence in chronic HBV carriers is associated with an HBsAg-specific Th1 cell defect, which likely is responsible for the insufficient neutralizing anti-HBs-antibody response and is not reversed by HBs vaccination. Alternative approaches to induce HBs-specific Th1 cell responses might represent a future therapeutic option.",0
2333,10655528,A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group,"BACKGROUND AND METHODS: Type 1 diabetes mellitus is now classified as autoimmune (type 1A) or idiopathic (type 1B), but little is known about the latter. We classified 56 consecutive Japanese adults with type 1 diabetes according to the presence or absence of glutamic acid decarboxylase antibodies (their presence is a marker of autoimmunity) and compared their clinical, serologic, and pathological characteristics. RESULTS: We divided the patients into three groups: 36 patients with positive tests for serum glutamic acid decarboxylase autoantibodies, 9 with negative tests for serum glutamic acid decarboxylase antibodies and glycosylated hemoglobin values higher than 11.5 percent, and 11 with negative tests for serum glutamic acid decarboxylase antibodies and glycosylated hemoglobin values lower than 8.5 percent. In comparison with the first two groups, the third group had a shorter mean duration of symptoms of hyperglycemia (4.0 days), a higher mean plasma glucose concentration (773 mg per deciliter [43 mmol per liter]) in spite of lower glycosylated hemoglobin values, diminished urinary excretion of C peptide, a more severe metabolic disorder (with ketoacidosis), higher serum pancreatic enzyme concentrations, and an absence of islet-cell, IA-2, and insulin antibodies. Immunohistologic studies of pancreatic-biopsy specimens from three patients with negative tests for glutamic acid decarboxylase autoantibodies and low glycosylated hemoglobin values revealed T-lymphocyte-predominant infiltrates in the exocrine pancreas but no insulitis and no evidence of acute or chronic pancreatitis. CONCLUSIONS: Some patients with idiopathic type 1 diabetes have a nonautoimmune, fulminant disorder characterized by the absence of insulitis and of diabetes-related antibodies, a remarkably abrupt onset, and high serum pancreatic enzyme concentrations.",0
2334,10666428,Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy,"BACKGROUND: Among patients with type 1 diabetes mellitus, intensive therapy (with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [hemoglobin A1c]) markedly reduces the risk of microvascular complications as compared with conventional therapy. To assess whether these benefits persist, we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial (DCCT). METHODS: At the end of the DCCT, the patients in the conventional-therapy group were offered intensive therapy, and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended, and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year, approximately half of whom were from each treatment group. RESULTS: The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT (average, 9.1 percent and 7.2 percent, respectively) narrowed during follow-up (median during 4 years, 8.2 percent and 7.9 percent, respectively, P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the intensive-therapy group than in the conventional-therapy group (odds reduction, 72 percent to 87 percent, P<0.001). The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group. CONCLUSIONS: The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least four years, despite increasing hyperglycemia.",0
2335,10706556,Activation of nuclear factor kappaB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis,"The hepatitis C virus (HCV) core protein is a multifunctional protein. It may bind to the death domain of tumor necrosis factor receptor 1 (TNFR1) and to the cytoplasmic tail of lymphotoxin-beta receptor, implying that it may be involved in the apoptosis and anti-apoptosis signaling pathways. In vitro studies have been inconclusive regarding its ability to inhibit or enhance TNF-alpha-induced apoptosis. To address this issue, electrophoretic mobility shift assay (EMSA) and immunohistochemical studies were used to show the activation of nuclear factor kappaB (NF-kappaB) in HCV-infected liver tissues and in HCV core-transfected cells. The activation of NF-kappaB was correlated with the apoptosis assays. The results showed that NF-kappaB activation could be shown in HCV-infected livers and HCV core-transfected cells. The data of EMSA correlated with those of immunohistochemical studies, which revealed a higher frequency of NF-kappaB nuclear staining in HCV-infected than in normal livers. NF-kappaB activation conferred resistance to TNF-alpha-induced apoptosis in HCV core-transfected cells. Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate sensitized them to TNF-alpha-induced apoptosis. These findings suggest that HCV infection may cause anti-apoptosis by activation of NF-kappaB and implicate a mechanism by which HCV may evade the host's immune surveillance leading to viral persistence and possibly to hepatocarcinogenesis.",0
2336,10706564,A new step toward standardization of serum hepatitis C virus-RNA quantification in patients with chronic hepatitis C,"The need to improve efficacy of antiviral therapy for chronic hepatitis C has prompted the development of quantitative assays, which allows the assessment of viral load before therapy. The aim of our study was to evaluate the clinical relevance of 3 serum HCV-RNA quantitative assays in 87 patients with chronic hepatitis C, the noncommercially available SuperQuant assay (National Genetic Institute), recently used in large international controlled trials, the most early and widely used Quantiplex HCV RNA v2.0 assay (branched DNA [bDNA] v2.0; Bayer Diagnostics, Puteaux, France), and the new generation Cobas Amplicor HCV Monitor assay (COBAS v2.0; Roche Diagnostics Systems, Meylan, France), which is a semiautomated reverse transcription-polymerase chain reaction (RT-PCR) assay. The level and range of quantification were similar between all assays and a strong correlation was observed over all HCV genotypes among the assays. Recent publications have suggested that the baseline cut-off level of 2 x 10(6) copies/mL, as determined by the SuperQuant assay, is able to discriminate between patients with low viral load from those with high viral load and can be used to predict responses to therapy. Because all 3 assays use different testing technologies we examined how many of our patients fell above this defined cut-off level when tested by the other assays; of 22 patients measured below 2 x 10(6) copies/mL with the SuperQuant assay, 17 of 22 and 19 of 22 patients were eligible with the bDNA v2. 0 and the COBAS v2.0 assays, respectively (P >.05). Our results indicate that the 2 commercial assays can be used to determine treatment schedules in patients with chronic hepatitis C, providing a flexibility in multicenter controlled trials by offering better accessibility of test results.",0
2337,10706571,Inhibition of hepatitis C virus (HCV)-RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozymes,"Ribozymes are catalytic RNA molecules that can be designed to cleave specific RNA sequences. To investigate the potential use of synthetic stabilized ribozymes for the treatment of chronic hepatitis C virus (HCV) infection, we designed and synthesized hammerhead ribozymes targeting 15 conserved sites in the 5' untranslated region (UTR) of HCV RNA. This region forms an internal ribosome entry site that allows for efficient translation of the HCV polyprotein. The 15 synthetic ribozymes contained modified nucleotides and linkages that stabilize the molecules against nuclease degradation. All 15 ribozymes were tested for their ability to reduce expression in an HCV 5' UTR/luciferase reporter system and for their ability to inhibit replication of an HCV-poliovirus (HCV-PV) chimera. Treatment with several ribozymes resulted in significant down-regulation of HCV 5' UTR/luciferase reporter expression (range 40% to 80% inhibition, P <.05). Moreover, several ribozymes showed significant inhibition (>90%, P <.001) of chimeric HCV-PV replication. We further show that the inhibitory activity of ribozymes targeting site 195 of HCV RNA exhibits a sequence-specific dose response, requires an active catalytic ribozyme core, and is dependent on the presence of the HCV 5' UTR. Treatment with synthetic stabilized anti-HCV ribozymes has the potential to aid patients who are infected with HCV by reducing the viral burden through specific targeting and cleavage of the viral genome.",0
2338,10706572,The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States,"Because chronic liver disease may develop many years after acute hepatitis C virus (HCV) infection, the past incidence of acute infections is a major determinant of the future burden of HCV-associated complications. We estimated past incidence of acute HCV infection using national seroprevalence data and relative age-specific incidence data from a sentinel counties surveillance system. Projections of the future prevalence of HCV-infected patients were derived from models that included an 85% drop in HCV infection incidence as observed for reported cases in the early 1990s. The models showed a large increase in the incidence of HCV infections from the late 1960s to the early 1980s. The degree of increase was dependent on the assumed rate of antibody loss; a model with 2.5% annual antibody loss showed annual incidence increasing from 45,000 infections (95% confidence interval [95% CI]: 0-110,000) in the early 1960s to 380,000 infections (95% CI: 250,000 to 500, 000) in the 1980s. Projections showed that although the prevalence of HCV infection may be declining currently because of the decline in incidence in the 1990s, the number of persons infected for >/=20 years could increase substantially before peaking in 2015. If the incidence of new HCV infections does not increase in the future, persons born between 1940 and 1965 will be at highest lifetime risk of acquiring the infection.",0
2339,10706897,Cigarette smoking and invasive pneumococcal disease. Active Bacterial Core Surveillance Team,"BACKGROUND: Approximately half of otherwise healthy adults with invasive pneumococcal disease are cigarette smokers. We conducted a population-based case-control study to assess the importance of cigarette smoking and other factors as risk factors for pneumococcal infections. METHODS: We identified immunocompetent patients who were 18 to 64 years old and who had invasive pneumococcal disease (as defined by the isolation of Streptococcus pneumoniae from a normally sterile site) by active surveillance of laboratories in metropolitan Atlanta, Baltimore, and Toronto. Telephone interviews were conducted with 228 patients and 301 control subjects who were reached by random-digit dialing. RESULTS: Fifty-eight percent of the patients and 24 percent of the control subjects were current smokers. Invasive pneumococcal disease was associated with cigarette smoking (odds ratio, 4.1; 95 percent confidence interval, 2.4 to 7.3) and with passive smoking among nonsmokers (odds ratio, 2.5; 95 percent confidence interval, 1.2 to 5.1) after adjustment by logistic-regression analysis for age, study site, and independent risk factors such as male sex, black race, chronic illness, low level of education, and living with young children who were in day care. There were dose-response relations for the current number of cigarettes smoked per day, pack-years of smoking, and time since quitting. The adjusted population attributable risk was 51 percent for cigarette smoking, 17 percent for passive smoking, and 14 percent for chronic illness. CONCLUSIONS: Cigarette smoking is the strongest independent risk factor for invasive pneumococcal disease among immunocompetent, nonelderly adults. Because of the high prevalence of smoking and the large population attributable risk, programs to reduce both smoking and exposure to environmental tobacco smoke have the potential to reduce the incidence of pneumococcal disease.",0
2340,10717013,Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue diseases,"BACKGROUND: The postulated relation between silicone breast implants and the risk of connective-tissue and autoimmune diseases has generated intense medical and legal interest during the past decade. The salience of the issue persists, despite the fact that a great deal of research has been conducted on this subject. To provide a stronger quantitative basis for addressing the postulated relation, we applied several techniques of meta-analysis that combine, compare, and summarize the results of existing relevant studies. METHODS: We searched data bases and reviewed citations in relevant articles to identify studies that met prestated inclusion criteria. Nine cohort studies, nine case-control studies, and two cross-sectional studies were included in our meta-analyses. We conducted meta-analyses of the results of these studies, both with and without adjustment for confounding factors, and a separate analysis restricted to studies of silicone-gel-filled breast implants. Finally, we estimated the annual number of new cases of connective-tissue disease that could be attributed to breast implants. RESULTS: There was no evidence that breast implants were associated with a significant increase in the summary adjusted relative risk of individual connective-tissue diseases (rheumatoid arthritis, 1.04 [95 percent confidence interval, 0.72 to 1.51]; systemic lupus erythematosus, 0.65 [95 percent confidence interval, 0.35 to 1.23]; scleroderma or systemic sclerosis, 1.01 [95 percent confidence interval, 0.59 to 1.73]; and Sj�gren's syndrome, 1.42 [95 percent confidence interval, 0.65 to 3.11]); all definite connective-tissue diseases combined (0.80; 95 percent confidence interval, 0.62 to 1.04); or other autoimmune or rheumatic conditions (0.96; 95 percent confidence interval, 0.74 to 1.25). Nor was there evidence of significantly increased risk in the unadjusted analyses or in the analysis restricted to silicone-gel-filled implants. CONCLUSIONS: On the basis of our meta-analyses, there was no evidence of an association between breast implants in general, or silicone-gel-filled breast implants specifically, and any of the individual connective-tissue diseases, all definite connective-tissue diseases combined, or other autoimmune or rheumatic conditions. From a public health perspective, breast implants appear to have a minimal effect on the number of women in whom connective-tissue diseases develop, and the elimination of implants would not be likely to reduce the incidence of connective-tissue diseases.",0
2341,10733550,Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and toll-like receptor 4,"Lipopolysaccharide (LPS) binding protein (LBP) is a key serum factor that mediates LPS activation of mononuclear cells. In the presence of LBP, 1/1,000 the concentration of LPS is sufficient to activate peripheral blood monocytes. Previous studies with Kupffer cells have shown a variable effect of serum on LPS activation of these cells and led to the conclusion that, unlike extrahepatic mononuclear cells, Kupffer cells do not respond to LPS in an LBP-dependent fashion. Because there are multiple components in serum other than LBP that might affect LPS activation, these reports with serum are difficult to interpret. To investigate the specific role of LBP in LPS activation of Kupffer cells, we produced a functional recombinant rat LBP using a baculovirus expression system, which we used to selectively examine the role of LBP's on Kupffer-cell function. Isolated Kupffer cells exposed to increasing concentrations of LPS (0, 1, 10 ng/mL) showed a dose-dependent increase in TNF-alpha production, which was augmented and accelerated by the presence of LBP. The effects of LBP on Kupffer cell activation by LPS are dependent on a functional Toll-like receptor 4 (Tlr 4) because Kupffer cells from C3H/HeJ mice failed to respond to LPS in the presence of LBP. LBP plays an important role in mediating Kupffer cell activation by LPS, and these effects are dependent on the presence of functioning Tlr 4.",0
2342,10738048,Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study,"BACKGROUND: Previous research has suggested that thiazide diuretics and beta-blockers may promote the development of type 2 diabetes mellitus. However, the results of previous studies have been inconsistent, and many studies have been limited by inadequate data on outcomes and by potential confounding. METHODS: We conducted a prospective study of 12,550 adults 45 to 64 years old who did not have diabetes. An extensive health evaluation conducted at base line included assessment of medication use and measurement of blood pressure with a random-zero sphygmomanometer. The incidence of new cases of diabetes was assessed after three years and after six years by measurement of serum glucose concentrations while the subjects were fasting. RESULTS: After simultaneous adjustment for age, sex, race, education, adiposity, family history with respect to diabetes, physical-activity level, other health-related behavior, and coexisting illnesses, subjects with hypertension who were taking thiazide diuretics were not at greater risk for the subsequent development of diabetes than were subjects with hypertension who were not receiving any antihypertensive therapy (relative hazard, 0.91; 95 percent confidence interval, 0.73 to 1.13). Likewise, subjects who were taking angiotensin-converting-enzyme inhibitors and calcium-channel antagonists were not at greater risk than those not taking any medication. In contrast, subjects with hypertension who were taking beta-blockers had a 28 percent higher risk of subsequent diabetes (relative hazard, 1.28; 95 percent confidence interval, 1.04 to 1.57). CONCLUSIONS: Concern about the risk of diabetes should not discourage physicians from prescribing thiazide diuretics to nondiabetic adults who have hypertension. The use of beta-blockers appears to increase the risk of diabetes, but this adverse effect must be weighed against the proven benefits of beta-blockers in reducing the risk of cardiovascular events.",0
2343,10749960,The effect of previous coronary-artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction. Bypass Angioplasty Revascularization Investigation Investigators,"BACKGROUND: Acute myocardial infarction in patients with diabetes is associated with high mortality. We studied whether previous revascularization by coronary-artery bypass grafting (CABG), as compared with percutaneous transluminal coronary angioplasty (PTCA), influences the prognosis in such patients. METHODS: We classified all patients eligible for the Bypass Angioplasty Revascularization Investigation who underwent coronary revascularization within three months after entry into the study according to whether they had diabetes and whether they had undergone CABG, either initially or after PTCA. The protective effect of CABG with regard to mortality in the presence and in the absence of subsequent spontaneous Q-wave myocardial infarction was estimated with the use of Cox regression models. RESULTS: Among the 641 patients with diabetes and the 2962 without diabetes, the cumulative five-year rates of death were 20 percent and 8 percent, respectively (P<0.001), and the five-year rates of spontaneous Q-wave myocardial infarction were 8 percent and 4 percent (P<0.001). CABG greatly reduced the risk of death after spontaneous Q-wave myocardial infarction in the patients with diabetes (relative risk, 0.09; 95 percent confidence interval, 0.03 to 0.29). Among patients with diabetes who had undergone CABG but did not have spontaneous Q-wave myocardial infarctions, the corresponding relative risk of death was 0.65 (95 percent confidence interval, 0.45 to 0.94). Among the patients without diabetes, no protective effect of CABG was evident. CONCLUSIONS: Among patients with diabetes, previous coronary bypass surgery, as compared with coronary angioplasty, has a highly favorable influence on prognosis after acute myocardial infarction and a smaller beneficial effect among patients who do not have infarction. These findings should influence the type of coronary revascularization procedure selected for patients with diabetes who have multivessel coronary artery disease.",0
2344,10749964,Differences between men and women in the rate of use of hip and knee arthroplasty,"BACKGROUND: Previous studies suggest that, for some conditions, women receive fewer health care interventions than men. We estimated the potential need for arthroplasty and the willingness to undergo the procedure in both men and women and examined whether there were differences between the sexes. METHODS: All 48,218 persons 55 years of age or older in two areas of Ontario, Canada, were surveyed by mail and telephone to identify those with hip or knee problems. In these subjects, we assessed the severity of arthritis and the presence of coexisting conditions by questionnaire, documented arthritis by examination and radiography, and conducted interviews to evaluate the subjects' willingness to undergo arthroplasty. The potential need for arthroplasty was defined by the presence of severe symptoms and disability, the absence of any absolute contraindications to surgery, and clinical and radiographic evidence of arthritis. The estimates of need were then adjusted for the subjects' willingness to undergo arthroplasty. RESULTS: The overall response rates were at least 72 percent for the questionnaires and interviews. As compared with men, women had a higher prevalence of arthritis of the hip or knee (age-adjusted odds ratio, 1.76; P<0.001) and had worse symptoms and greater disability, but women were less likely to have undergone arthroplasty (adjusted odds ratio, 0.78; P<0.001). Despite their equal willingness to have the surgery, fewer women than men had discussed the possibility of arthroplasty with a physician (adjusted odds ratio, 0.63). The numbers of people with a potential need for hip or knee arthroplasty were 44.9 per 1000 among women and 20.8 per 1000 among men. After adjustment for willingness to undergo the procedure, the numbers were 5.3 per 1000 for women and 1.6 per 1000 for men. CONCLUSIONS: There is underuse of arthroplasty for severe arthritis in both sexes, but the degree of underuse is more than three times as great in women as in men.",0
2345,10760310,Relation of race and sex to the use of reperfusion therapy in Medicare beneficiaries with acute myocardial infarction,"BACKGROUND: There are few reports describing the combined influence of the race and sex of a patient on the use of reperfusion therapy for acute myocardial infarction. METHODS: To determine the relation of race and sex to the receipt of reperfusion therapy for myocardial infarction in the United States, we reviewed the medical records of 234,769 Medicare patients with myocardial infarction. From these records we identified 26,575 white or black patients who met strict eligibility criteria for reperfusion therapy. We then performed bivariate and multivariate analyses of prevalence ratios to determine predictors of the use of reperfusion therapy in four subgroups of patients categorized according to race and sex: white men, white women, black men, and black women. RESULTS: Among eligible patients, white men received reperfusion therapy with the highest frequency (59 percent), followed by white women (56 percent), black men (50 percent), and black women (44 percent). After adjustment for differences in demographic and clinical characteristics, white women were as likely as white men to receive reperfusion therapy (prevalence ratio, 1.00; 95 percent confidence interval, 0.98 to 1.03). Likewise, black women were as likely as black men to receive reperfusion therapy (prevalence ratio, 1.00; 95 percent confidence interval, 0.89 to 1.13). However, black women were significantly less likely to receive reperfusion therapy than white men (prevalence ratio, 0.90; 95 percent confidence interval, 0.82 to 0.98), as were black men (prevalence ratio, 0.85; 95 percent confidence interval, 0.78 to 0.93). CONCLUSIONS: After adjustment for differences in clinical and demographic characteristics and clinical presentation, differences according to sex in the use of reperfusion therapy are minimal. However, blacks, regardless of sex, are significantly less likely than whites to receive this potentially lifesaving therapy.",0
2346,10781620,Ceftriaxone-resistant salmonella infection acquired by a child from cattle,"BACKGROUND: The emergence of resistance to antimicrobial agents within the salmonellae is a worldwide problem that has been associated with the use of antibiotics in livestock. Resistance to ceftriaxone and the fluoroquinolones, which are used to treat invasive salmonella infections, is rare in the United States. We analyzed the molecular characteristics of a ceftriaxone-resistant strain of Salmonella enterica serotype typhimurium isolated from a 12-year-old boy with fever, abdominal pain, and diarrhea. METHODS: We used pulsed-field gel electrophoresis and analysis of plasmids and beta-lactamases to compare the ceftriaxone-resistant S. enterica serotype typhimurium from the child with four isolates of this strain obtained from cattle during a local outbreak of salmonellosis. RESULTS: The ceftriaxone-resistant isolate from the child was indistinguishable from one of the isolates from cattle, which was also resistant to ceftriaxone. Both ceftriaxone-resistant isolates were resistant to 13 antimicrobial agents; all but one of the resistance determinants were on a conjugative plasmid of 160 kb that encoded the functional group 1 beta-lactamase CMY-2. Both ceftriaxone-resistant isolates were closely related to the three other salmonella isolates obtained from cattle, all of which were susceptible to ceftriaxone. CONCLUSIONS: This study provides additional evidence that antibiotic-resistant strains of salmonella in the United States evolve primarily in livestock. Resistance to ceftriaxone, the drug of choice for invasive salmonella disease, is a public health concern, especially with respect to children, since fluoroquinolones, which can also be used to treat this disease, are not approved for use in children.",0
2347,10793165,Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency,"BACKGROUND: Immune function can be restored in infants with severe combined immunodeficiency by transplantation of unfractionated bone marrow from HLA-identical donors or T-cell-depleted marrow stem cells from haploidentical donors, with whom there is a single haplotype mismatch, without the need for chemotherapy before transplantation or prophylaxis against graft-versus-host disease. The role of the thymus in this process is unknown. METHODS: We analyzed the phenotypes of circulating T cells and the proliferative responses of peripheral-blood mononuclear cells to phytohemagglutinin in 83 patients with severe combined immunodeficiency who received allogeneic marrow transplants without T-cell ablation from related donors over an 18-year period. We also tested for the presence of episomes of T-cell antigen receptors (extrachromosomal DNA circles formed during intrathymic T-cell development) to assess thymus-dependent T-cell reconstitution. RESULTS: Before and early after transplantation, the numbers of circulating T cells were low, with a predominance of mature CD45RO+ T cells (primarily resulting from the transplacental transfer of maternal cells); T-cell antigen-receptor episomes were undetectable in peripheral-blood mononuclear cells. In 73 of the infants, thymus-derived T cells expressing CD45RA and T-cell antigen-receptor episomes were detected within three to six weeks after transplantation. The mean (+/-SD) value for thymus-dependent T-cell antigen-receptor episomes peaked (at 7311+/-8652 per microgram of peripheral-blood mononuclear-cell DNA) 1 to 2 years after transplantation and declined to low levels (less than 100 episomes per microgram of DNA) within 14 years, as compared with a gradual decline from birth to the age of about 80 years in normal subjects. CONCLUSIONS: The vestigial thymus in infants with severe combined immunodeficiency is functional and can produce enough T cells after bone marrow transplantation to provide normal immune function.",0
2348,10796878,ATP depletion in rat cholangiocytes leads to marked internalization of membrane proteins,"Intrahepatic bile ducts (BD) are a critical target of injury in the postischemic liver. Decreased vascular perfusion causes characteristic changes in the morphology of the ductular epithelia including a loss of secondary membrane structures and a decrease in plasma membrane surface area. Using adenosine triphosphate (ATP) depletion of cultured normal rat cholangiocytes (NRC) to model ischemic ducts, the present studies examined the fate of apical membrane proteins to determine whether membrane recycling might contribute to rapid functional recovery. Apical proteins, including gamma-glutamyl transpeptidase (GGT), Na(+)-glucose cotransporter (SGLT1), and apically biotinylated proteins, were not shed into the luminal space during ATP depletion. Instead, labeling of surface proteins after ATP depletion showed a significant decrease in GGT and SGLT1, consistent with membrane internalization. Similarly, z-axis confocal microscopy of biotinylated apical proteins also showed protein internalization. During ATP recovery, SGLT1 transport activity remained profoundly depressed even after 24 hours of recovery, indicating that the function of the internalized apical proteins is not rapidly recovered. These studies suggest that the membrane internalization in ATP-depleted cholangiocytes is a unidirectional process that contributes to prolonged functional deficits after restoration of normal cellular ATP levels. This sustained decrease in transport capacity may contribute to the development of ductular injury in postischemic livers.",0
2349,10796885,Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts,"Activation of hepatic stellate cells (HSCs) is the key step in liver fibrogenesis. Increased transforming growth factor beta (TGF-beta) expression and extracellular matrix production in patients with hepatic fibrosis and experimental models of liver fibrogenesis support implication of TGF-beta in the pathogenesis of this disease. However, a causative role for TGF-beta during transdifferentiation of HSCs has not been delineated in molecular detail. Using a rat cell culture model of HSC transdifferentiation, we analyzed TGF-beta signal transduction and identified changes between stellate cells and their transdifferentiated phenotype. Fully transdifferentiated myofibroblasts, opposed to HSCs, were not inhibited in proliferation activity on treatment with TGF-beta1. Furthermore, stimulation of alpha2 (I) collagen and Smad7 messenger RNA (mRNA) expression by TGF-beta1 was achieved in stellate cells but not in myofibroblasts. Northern and Western blot analyses indicated significant expression of TGF-beta receptors I and II in both cell types. In contrast, [(125)I]-TGF-beta1 receptor affinity labeling displayed strongly reduced types I, II, and III receptor presentation at the cell surface of myofibroblasts. Moreover, myofibroblasts did not display DNA-binding SMAD proteins in electrophoretic mobility shift assays with a CAGA box. These data indicate that stellate cells are responsive to TGF-beta1 treatment and transduce a signal that may play an important role in liver fibrogenesis. Myofibroblasts display decreased availability of surface receptors for TGF-beta, which could be based on autocrine stimulation. However, lack of activated SMAD complexes with DNA-binding activity and absence of alpha2 (I) collagen transcription inhibition by latency-associated peptide (LAP)/anti-TGF-beta antibody raise the possibility of TGF-beta signaling independent receptor down-regulation in myofibroblasts.",0
2350,10796888,Molecular mechanisms of tumor necrosis factor alpha-stimulated leukocyte recruitment into the murine hepatic circulation,"To date, much of the adhesion work in the liver has been restricted to sinusoids and postsinusoidal venules. However, selectins have been localized on the portal (presinusoidal) venules and these vessels have been shown to be important in metastasis of tumors. The purpose of this study was to characterize the leukocyte-endothelial interactions within the 3 compartments of the hepatic microvasculature under baseline conditions and in response to tumor necrosis factor alpha (TNF-alpha). Mice deficient in P-selectin or both E- and P-selectin were compared with wild-type (C57Bl/6, wild type) mice. Animals were injected with murine TNF-alpha (15 microg/kg intraperitoneally [IP]) and the liver was examined by fluorescence intravital microscopy 4 hours later. Under baseline conditions, leukocyte flux in the portal venules was 1.42 +/- 0.42 cells/min. Leukocyte flux in the portal venules of wild-type mice increased 8-fold in response to 4 hours of TNF-alpha stimulation. This was reduced by 50% in the P-selectin-deficient mice but was not reduced further by either the addition of an E-selectin antibody (9A9, 100 microg intravenously [IV]) to these mice or in mice deficient in both E- and P-selectin. In P-selectin-deficient mice, the addition of an antibody against alpha(4)-integrin (R1-2, 75 microg IP) reduced rolling to baseline. But in the E- and P-double-selectin-deficient mice the addition of an antibody against L-selectin (Mel 14, 3 microg/kg IV) had no effect on TNF-alpha-induced recruitment. Similar responses were seen in the central venules, however, in the sinusoids the increased number of stationary leukocytes seen in response to 4 hours of TNF-alpha stimulation in the wild-type mice was not reduced in P-selectin-deficient mice with or without the alpha(4)-integrin antibody. These data suggest that leukocytes can use alpha(4)-integrin independent of the selectins in the venules. Within the sinusoids, however, inhibition of E-selectin, P-selectin, and alpha(4)-integrin was insufficient to reduce leukocyte recruitment.",0
2351,10796895,Reactivity of 13 in vitro expressed hepatitis B surface antigen variants in 7 commercial diagnostic assays,"The primary marker of current hepatitis B infection is the surface antigen (HBsAg), however HBsAg negativity does not exclude hepatitis B viremia. HBsAg variants can be responsible for such diagnostic failures. Here 13 different HBsAg variants were cloned, variant protein produced in a mammalian expression system, and tested using 7 commercial HBsAg diagnostic assays. Of 12 variants analyzed, 6 samples displayed similar reactivity to the positive control (containing standard HBsAg sequence) in most of the assays, but 6 samples, containing various mutations throughout the entire major hydrophilic region (MHR), showed reduced reactivity. It was found that the loss of cysteine at amino acid (aa) 124 in 1 sample affected the secretion as well as the reactivity of HBsAg in the expression system. Thus, not all assays are equally able to detect HBsAg variants, implying that, to attain an acceptable level of sensitivity, the antibody repertoire of the current assays should be extended.",0
2352,10805825,"Mortality from pneumonia in children in the United States, 1939 through 1996","BACKGROUND AND METHODS: Pneumonia remains an important cause of childhood deaths throughout the world, but in developed countries, the mortality rate is decreasing. We reviewed death records for children in the United States from 1939 through 1996. A plot of the annual rates of change in the number of deaths from pneumonia was used to generate hypotheses about the influence of various events and interventions. We used data from the National Hospital Discharge Survey, the Medicaid program, and published reports to test these hypotheses. RESULTS: During the 58-year study period, the number of children who died from pneumonia declined by 97 percent, from 24,637 in 1939 to 800 in 1996. During the same period, the rate of mortality from other causes declined by 82 percent. There were steep declines in the mortality rates for pneumonia from 1944 to 1950, although the rate increased among older children in 1957, and there were sustained declines in all age groups from 1966 to 1982. From 1966 to 1982, the mortality declined by an average of 13.0 percent annually, and these decreases coincided with increases in the proportion of poor children covered by Medicaid, increases in rates of hospitalization for pneumonia, a narrowing of the gap between the mortality rate for black children and the rate for white children, and a convergence between the mortality rate in the South and the rates in the other three census regions. CONCLUSIONS: Since 1939, the rate of mortality from pneumonia in children in the United States has declined markedly. We hypothesize that the steep declines in the late 1940s are attributable to the use of penicillin, that the peak in 1957 was due to the influenza A pandemic, and that the sustained decline from 1966 through 1982 may be attributable in part to improved access to medical care for poor children.",0
2353,10805827,The effect of longevity on spending for acute and long-term care,"BACKGROUND: The proportion of the population made up of elderly persons in the United States is projected to increase from 13 percent of the population in 2000 to 20 percent by 2030. The implications for health care expenditures may be profound, because elderly persons use health care services at a greater rate than younger persons. We estimated total expenditures for acute and long-term care from the age of 65 years until death and in the last two years of life. METHODS: We combined data from Medicare, the National Mortality Followback Survey, and the National Medical Expenditure Survey to estimate total national expenditures for health care according to the age at death. We also simulated expenditures with the use of projected demographic characteristics of two cohorts: people turning 65 in 2000 and those turning 65 in 2015. RESULTS: Total expenditures (in 1996 dollars) from the age of 65 years until death increase substantially with longevity, from $31,181 for persons who die at the age of 65 years to more than $200,000 for those who die at the age of 90, in part because of steep increases in nursing home expenditures for very old persons. Spending in the last two years of life also increases with longevity, but a reduction in Medicare expenditures ($37,000 for persons who die at the age of 75 years and $21,000 for those who die at the age of 95) moderates the effect of the increase in nursing home expenditures ($6,000 for those who die at the age of 75 years and $32,000 for those who die at the age of 95). Health care spending for women is consistently higher than that for men, after adjustment for the increased longevity of women. Simulations show that increased longevity after the age of 65 years has a relatively small effect on the anticipated increase in spending, especially for services covered by Medicare, from 2000 to 2015. The effects of the larger number of people born in 1950 than in 1935 and the larger number of people surviving to the age of 65 years are much more important. CONCLUSIONS: In the United States, the effect of longevity on expenditures for acute care differs from its effect on expenditures for long-term care. Acute care expenditures, principally for hospital care and physicians' services, increase at a reduced rate as the age at death increases, whereas expenditures for long-term care increase at an accelerated rate. Increases in longevity after the age of 65 years may result in greater spending for long-term care, but the increase in the number of elderly persons has a more important effect on total spending.",0
2354,10824072,Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation,"BACKGROUND: Despite extensive training of citizens of Seattle in cardiopulmonary resuscitation (CPR), bystanders do not perform CPR in almost half of witnessed cardiac arrests. Instructions in chest compression plus mouth-to-mouth ventilation given by dispatchers over the telephone can require 2.4 minutes. In experimental studies, chest compression alone is associated with survival rates similar to those with chest compression plus mouth-to-mouth ventilation. We conducted a randomized study to compare CPR by chest compression alone with CPR by chest compression plus mouth-to-mouth ventilation. METHODS: The setting of the trial was an urban, fire-department-based, emergency-medical-care system with central dispatching. In a randomized manner, telephone dispatchers gave bystanders at the scene of apparent cardiac arrest instructions in either chest compression alone or chest compression plus mouth-to-mouth ventilation. The primary end point was survival to hospital discharge. RESULTS: Data were analyzed for 241 patients randomly assigned to receive chest compression alone and 279 assigned to chest compression plus mouth-to-mouth ventilation. Complete instructions were delivered in 62 percent of episodes for the group receiving chest compression plus mouth-to-mouth ventilation and 81 percent of episodes for the group receiving chest compression alone (P=0.005). Instructions for compression required 1.4 minutes less to complete than instructions for compression plus mouth-to-mouth ventilation. Survival to hospital discharge was better among patients assigned to chest compression alone than among those assigned to chest compression plus mouth-to-mouth ventilation (14.6 percent vs. 10.4 percent), but the difference was not statistically significant (P=0.18). CONCLUSIONS: The outcome after CPR with chest compression alone is similar to that after chest compression with mouth-to-mouth ventilation, and chest compression alone may be the preferred approach for bystanders inexperienced in CPR.",0
2355,10824074,Association between early-onset Parkinson's disease and mutations in the parkin gene,"BACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.",0
2356,10824077,The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators,"BACKGROUND: There is an inverse relation between mortality from cardiovascular causes and the number of elective cardiac procedures (coronary angioplasty, stenting, or coronary bypass surgery) performed by individual practitioners or hospitals. However, it is not known whether patients with acute myocardial infarction fare better at centers where more patients undergo primary angioplasty or thrombolytic therapy than at centers with lower volumes. METHODS: We analyzed data from the National Registry of Myocardial Infarction to determine the relation between the number of patients receiving reperfusion therapy (primary angioplasty or thrombolytic therapy) and subsequent in-hospital mortality. A total of 450 hospitals were divided into quartiles according to the volume of primary angioplasty. Multiple logistic-regression models were used to determine whether the volume of primary angioplasty procedures was an independent predictor of in-hospital mortality among patients undergoing this procedure. Similar analyses were performed for patients receiving thrombolytic therapy at 516 hospitals. RESULTS: In-hospital mortality was 28 percent lower among patients who underwent primary angioplasty at hospitals with the highest volume than among those who underwent angioplasty at hospitals with the lowest volume (adjusted relative risk, 0.72; 95 percent confidence interval, 0.60 to 0.87; P<0.001). This lower rate, which represented 2.0 fewer deaths per 100 patients treated, was independent of the total volume of patients with myocardial infarction at each hospital, year of admission, and use or nonuse of adjunctive pharmacologic therapies. There was no significant relation between the volume of thrombolytic interventions and in-hospital mortality among patients who received thrombolytic therapy (7.0 percent for patients in the highest-volume hospitals vs. 6.9 percent for those in the lowest-volume hospitals, P=0.36). CONCLUSIONS: Among hospitals in the United States that have full interventional capabilities, a higher volume of angioplasty procedures is associated with a lower mortality rate among patients undergoing primary angioplasty, but there is no association between volume and mortality for thrombolytic therapy.",0
2357,10853001,Genetic and environmental factors in age-related nuclear cataracts in monozygotic and dizygotic twins,"BACKGROUND: Age-related cataracts are a major public health problem. The relative importance of genes and environment in the causation of nuclear cataracts, the most common form of age-related cataracts, is not known. METHODS: We studied 506 pairs of female twins (226 monozygotic and 280 dizygotic) who were 50 to 79 years old (mean, 62). The amount of nuclear cataract in the right and left eyes was determined objectively by analysis of Scheimpflug lens photographs (yielding three measures) and subjectively with use of the Oxford Clinical Cataract Classification and Grading System (yielding one measure). All eight measures (four in each eye) were subsequently combined in one summary measure of nuclear cataract for each woman. A univariate maximum-likelihood model was used to estimate the variance of the genetic and environmental contributions to each of the measures. RESULTS: The different measures of cataract formation were highly correlated (correlation coefficients, 0.71 to 0.94). The mean scores were similar for the right and left eyes and for monozygotic and dizygotic twins. Quantitative genetic modeling of each of the nuclear-cataract scores invariably resulted in a best-fitting model that involved additive genetic effects, unique environmental effects, and age. The common environmental and dominant genetic effects could be removed from the models without significant loss of fit. The overall heritability in the combined nuclear-cataract score (the proportion of the variance explained by genetic factors) was 48 percent (95 percent confidence interval, 42 to 54 percent); age accounted for 38 percent of the variance (95 percent confidence interval, 31 to 44 percent) and unique environmental effects for 14 percent (95 percent confidence interval, 12 to 18 percent). CONCLUSIONS: Genetic effects are important even in such a clearly age-related disease as nuclear cataract, explaining almost 50 percent of the variation in the severity of this disease.",0
2358,10861321,"Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue","BACKGROUND: Continuous intravenous infusion of epoprostenol (prostacyclin) is an effective treatment for primary pulmonary hypertension. This approach requires the insertion of a permanent central venous catheter, with the associated risk of serious complications. Recently, aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS: We evaluated the effects of aerosolized iloprost on exercise capacity and hemodynamic variables over a one-year period in patients with primary pulmonary hypertension. RESULTS: Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a daily dose of 100 or 150 microg for at least one year. The mean (+/-SD) distance covered in the six-minute walk test increased from 278+/-96 m at base line to 363+/-135 m after 12 months (P<0.001). During the same period, the mean pulmonary arterial pressure before the inhalation of iloprost declined from 59+/-10 mm Hg to 52+/-15 mm Hg (P=0.006), cardiac output increased from 3.8+/-1.4 liters per minute to 4.4+/-1.3 liters per minute (P=0.02), and pulmonary vascular resistance declined from 1205+/-467 dyn x sec x cm(-5) to 925+/-469 dyn x sec x cm(-5) (P<0.001). The treatment was generally well tolerated, except for mild coughing, minor headache, and jaw pain in some patients. CONCLUSIONS: Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.",0
2359,10861325,"Randomized, controlled trials, observational studies, and the hierarchy of research designs","BACKGROUND: In the hierarchy of research designs, the results of randomized, controlled trials are considered to be evidence of the highest grade, whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects. We used published meta-analyses to identify randomized clinical trials and observational studies that examined the same clinical topics. We then compared the results of the original reports according to the type of research design. METHODS: A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of randomized, controlled trials and meta-analyses of either cohort or case-control studies that assessed the same intervention. For each of five topics, summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual randomized, controlled trials and the individual observational studies. RESULTS: For the five clinical topics and 99 reports evaluated, the average results of the observational studies were remarkably similar to those of the randomized, controlled trials. For example, analysis of 13 randomized, controlled trials of the effectiveness of bacille Calmette-Gu�rin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 (95 percent confidence interval, 0.34 to 0.70) among vaccinated patients, as compared with an odds ratio of 0.50 (95 percent confidence interval, 0.39 to 0.65) from 10 case-control studies. In addition, the range of the point estimates for the effect of vaccination was wider for the randomized, controlled trials (0.20 to 1.56) than for the observational studies (0.17 to 0.84). CONCLUSIONS: The results of well-designed observational studies (with either a cohort or a case-control design) do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.",0
2360,10869296,DNA-Based immunization produces Th1 immune responses to hepatitis delta virus in a mouse model,"Hepatitis delta virus (HDV) superinfection is one of the major causes of fulminant hepatitis in endemic areas of hepatitis B virus (HBV) infection. Currently, there is no effective treatment or vaccine against HDV superinfection. DNA-based immunization is a promising antiviral strategy to prevent or treat persistent viral infections. In this study, we investigated the immunological effects of DNA vaccines against HDV in BALB/c mice. Plasmid (pD) encoding large hepatitis D antigen (L-HDAg), or plasmid (pS/pD) coexpressing hepatitis B surface antigen (HBsAg) and L-HDAg, were injected into mice intramuscularly. The seroconversion rate, anti-HBs levels, anti-HDV titers, T-cell proliferation responses, and T-helper (Th)-release cytokine profiles were analyzed. Mice immunized with plasmids, pS/pD or pD, produced low, but significant, titers of anti-HDV antibodies. In contrast, pS/pD induced much stronger anti-HBs titers in the immunized animals. Interestingly, splenic lymphocytes derived from pS/pD-inoculated mice demonstrated significant proliferation responses to recombinant HBsAg and HDAg, and resulted in a Th1-like immune response as suggested by the production of interferon gamma (INF-gamma) and interleukin-2 (IL-2), but not IL-4. The splenic lymphocyte derived from the pD-inoculated mice showed a similar Th1 response to the stimulation of HDAg, but not to HBsAg. In conclusion, our results suggest that DNA vaccines against HDV can induce significant cellular immune responses with a Th1 preference. HBV and HDV coimmunization can be performed by DNA vaccines. These results are promising for the future development of prophylactic and therapeutic HDV vaccines.",0
2361,10882763,Treatment of acute myocardial infarction and 30-day mortality among women and men,"BACKGROUND: Previous studies have suggested that women with acute myocardial infarction receive less aggressive therapy than men. We used data from the Cooperative Cardiovascular Project to determine whether women and men who were ideal candidates for therapy after acute myocardial infarction were treated differently. METHODS: Information was abstracted from the charts of 138,956 Medicare beneficiaries (49 percent of them women) who had an acute myocardial infarction in 1994 or 1995. Multivariate analysis was used to assess differences between women and men in the medications administered, the procedures used, the assignment of do-not-resuscitate status, and 30-day mortality. RESULTS: Among ideal candidates for therapy, women in all age groups were less likely to undergo diagnostic catheterization than men. The difference was especially pronounced among older women; for a woman 85 years of age or older, the adjusted relative risk was 0.75 (95 percent confidence interval, 0.68 to 0.83). Women were somewhat less likely than men to receive thrombolytic therapy within 60 minutes (adjusted relative risk, 0.93; 95 percent confidence interval, 0.90 to 0.96) or to receive aspirin within 24 hours after arrival at the hospital (adjusted relative risk, 0.96; 95 percent confidence interval, 0.95 to 0.97), but they were equally likely to receive beta-blockers (adjusted relative risk, 0.99; 95 percent confidence interval, 0.95 to 1.03) and somewhat more likely to receive angiotensin-converting-enzyme inhibitors (adjusted relative risk, 1.05; 95 percent confidence interval, 1.02 to 1.08). Women were more likely than men to have a do-not-resuscitate order in their records (adjusted relative risk, 1.26; 95 percent confidence interval, 1.22 to 1.29). After adjustment, women and men had similar 30-day mortality rates (hazard ratio, 1.02; 95 percent confidence interval, 0.99 to 1.04). CONCLUSIONS: As compared with men, women receive somewhat less aggressive treatment during the early management of acute myocardial infarction. However, many of these differences are small, and there is no apparent effect on early mortality.",0
2362,10882764,Primary prevention of coronary heart disease in women through diet and lifestyle,"BACKGROUND: Many lifestyle-related risk factors for coronary heart disease have been identified, but little is known about their effect on the risk of disease when they are considered together. METHODS: We followed 84,129 women participating in the Nurses' Health Study who were free of diagnosed cardiovascular disease, cancer, and diabetes at base line in 1980. Information on diet and lifestyle was updated periodically. During 14 years of follow-up, we documented 1128 major coronary events (296 deaths from coronary heart disease and 832 nonfatal infarctions). We defined subjects at low risk as those who were not currently smoking, had a body-mass index (the weight in kilograms divided by the square of the height in meters) under 25, consumed an average of at least half a drink of an alcoholic beverage per day, engaged in moderate-to-vigorous physical activity (which could include brisk walking) for at least half an hour per day, on average, and scored in the highest 40 percent of the cohort for consumption of a diet high in cereal fiber, marine n-3 fatty acids, and folate, with a high ratio of polyunsaturated to saturated fat, and low in trans fat and glycemic load, which reflects the extent to which diet raises blood glucose levels. RESULTS: Many of the factors were correlated, but each independently and significantly predicted risk, even after further adjustment for age, family history, presence or absence of diagnosed hypertension or diagnosed high cholesterol level, and menopausal status. Women in the low-risk category (who made up 3 percent of the population) had a relative risk of coronary events of 0.17 (95 percent confidence interval, 0.07 to 0.41) as compared with all the other women. Eighty-two percent of coronary events in the study cohort (95 percent confidence interval, 58 to 93 percent) could be attributed to lack of adherence to this low-risk pattern. CONCLUSION: Among women, adherence to lifestyle guidelines involving diet, exercise, and abstinence from smoking is associated with a very low risk of coronary heart disease.",0
2363,10911004,Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen,"BACKGROUND: Registry data on patients with type 1 diabetes mellitus who undergo pancreatic islet transplantation indicate that only 8 percent are free of the need for insulin therapy at one year. METHODS: Seven consecutive patients with type 1 diabetes and a history of severe hypoglycemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus, and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium, and transplanted immediately by means of a percutaneous transhepatic portal embolization. RESULTS: All seven patients quickly attained sustained insulin independence after transplantation of a mean (+/-SD) islet mass of 11,547+/-1604 islet equivalents per kilogram of body weight (median follow-up, 11.9 months; range, 4.4 to 14.9). All recipients required islets from two donor pancreases, and one required a third transplant from two donors to achieve sustained insulin independence. The mean glycosylated hemoglobin values were normal after transplantation in all recipients. The mean amplitude of glycemic excursions (a measure of fluctuations in blood glucose concentrations) was significantly decreased after the attainment of insulin independence (from 198+/-32 mg per deciliter [11.1+/-1.8 mmol per liter] before transplantation to 119+/-37 mg per deciliter [6.7+/-2.1 mmol per liter] after the first transplantation and 51+/-30 mg per deciliter [2.8+/-1.7 mmol per liter] after the attainment of insulin independence; P<0.001). There were no further episodes of hypoglycemic coma. Complications were minor, and there were no significant increases in lipid concentrations during follow-up. CONCLUSIONS: Our observations in patients with type 1 diabetes indicate that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass.",0
2364,10915723,A Rho-specific exchange factor Ect2 is induced from S to M phases in regenerating mouse liver,"The ect2 oncogene was originally identified as a transforming complementary DNA (cDNA) from mouse epithelial cells in an expression cloning approach and encodes a product related to Rho-specific exchange factors and yeast cell cycle regulators. To explore the potential role of ect2 in the cell cycle, we examined the expression of the ect2 proto-oncogene in a liver regeneration model in mice after partial (two thirds) hepatectomy. We found that the expression of the ect2 transcript and protein were markedly elevated with the onset of DNA synthesis and remained elevated during G2 and M phases. The timing of ect2 expression matched that of proliferating cell nuclear antigen (PCNA) and partially overlapped cell division cycle 2 (Cdc2) expression. In situ hybridization analysis showed that ect2 was expressed at a high level in cells undergoing mitosis in regenerating liver. Moreover, expression of a dominant negative or an oncogenic mutant of ect2 in cultured mouse hepatocytes resulted in a large increase in the number of binucleated cells. These findings showed that Ect2 is expressed in a cell cycle-dependent manner during liver regeneration, and suggest that it has an important role in the regulation of cytokinesis.",0
2365,10915743,Human homologue of maid: A dominant inhibitory helix-loop-helix protein associated with liver-specific gene expression,"The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key regulators in numerous developmental processes. The class I HLH proteins, such as E12 are ubiquitously expressed. Class II HLH proteins, such as MyoD, are expressed in a tissue-specific manner. Class I and II heterodimers can bind to E-boxes (CANNTG) and regulate lineage commitments of embryonic cells. In an attempt to identify partners for the E12 protein that may exert control during liver development, we performed the yeast 2-hybrid screen using an expression complementary DNA library from human fetal liver. A novel dominant inhibitory HLH factor, designated HHM (human homologue of maid), was isolated and characterized. HHM is structurally related to the Id family and was highly expressed in brain, pituitary gland, lung, heart, placenta, fetal liver, and bone marrow. HHM physically interacted with E12 in vitro and in mammalian cells. Comparison of the dominant inhibitory effects of HHM and Id2 on the binding of E12/MyoD dimer to an E-box element revealed a weaker inhibition by HHM. However, HHM but not Id2 specifically inhibited the luciferase gene activation induced by hepatic nuclear factor 4 (HNF4) promoter. The HHM was transiently expressed during stem-cell-driven regeneration of the liver at the stage in which the early basophilic foci of hepatocytes started to appear. These results suggest that HHM is a novel type of dominant inhibitory HLH protein that might modulate liver-specific gene expression.",0
2366,10915746,Specific detection of minus-strand hepatitis C virus RNA by reverse-transcription polymerase chain reaction on PolyA(+)-purified RNA,"A full-length complementary DNA (cDNA) clone of the hepatitis C virus (HCV) genome was used to prepare full-length plus- and minus-strand RNA. The minus-strand RNA, which contains a polyA(+) tract complementary to the polyU tract found in the plus strand (genomic) RNA, but not the plus strand RNA, was captured with a commercial polyA(+)-tract isolation system. After elution, the minus strand was amplified by reverse-transcription polymerase chain reaction (RT-PCR). The combination of this procedure and RT-PCR using rTth resulted in an unprecedented level of discrimination of 10 logs(10). HCV minus-strand RNA isolation was unaffected by the addition of an excess of 10(4) of plus strands or by the addition of cellular RNA, and although the polyA(+) isolation step removed 99. 99% of plus strands, there was no loss of minus-strand signal. Minus-strand RNA was detected in RNA extracted from 4/4 liver samples and 4/8 peripheral blood mononuclear cells (PBMC) samples examined. Because the titer of plus-strand HCV RNA in any sample makes a significant contribution to false, random, and self-priming, removal of the plus strand in this manner results in the most accurate method yet devised to confirm the replication of HCV in a population of cells.",0
2367,10915750,Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer,"To clarify the effects of hepatitis C virus (HCV) infection on hepatocytes, we analyzed and compared the induction of intracellular signals by HCV and hepatitis B virus (HBV) proteins. We examined the influence of 7 HCV (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) and 4 HBV (precore, core, polymerase, and X) proteins on 5 well-defined intracellular signaling pathways associated with cell proliferation, differentiation, and apoptosis by use of a reporter assay. Viral protein-expression vectors were cotransfected into mammalian cells with reporter vectors having a luciferase gene driven by the following inducible cis-enhancer elements: the cyclic adenosine monophosphate response element, the serum response element (SRE), and the binding sites for nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1), and serum response factor (SRF). In addition, the activation of signals by HCV proteins was examined in a reporter plasmid having a natural interleukin-8 (IL-8) promoter upstream of a luciferase gene. Of 11 HCV and HBV proteins, HCV core had the strongest influence on intracellular signals, especially NF-kappaB-, AP-1-, and SRE-associated pathways. HCV core's activation level exceeded that of HBV X protein, a well-characterized transactivator of these signals. Moreover, HCV core activated the IL-8 promoter through NF-kappaB and AP-1. For the other proteins, HCV NS4B showed signal activation, but signals were activated at a lesser extent. The luciferase reporter assay, a recently introduced technique, helped in the elucidation of molecular events underlying the inflammatory and proliferation process in the liver induced by HCV.",0
2368,10954761,"Siblings, day-care attendance, and the risk of asthma and wheezing during childhood","BACKGROUND: Young children with older siblings and those who attend day care are at increased risk for infections, which in turn may protect against the development of allergic diseases, including asthma. However, the results of studies examining the relation between exposure to other children and the subsequent development of asthma have been conflicting. METHODS: In a study involving 1035 children followed since birth as part of the Tucson Children's Respiratory Study, we determined the incidence of asthma (defined as at least one episode of asthma diagnosed by a physician when the child was 6 to 13 years old) and the prevalence of frequent wheezing (more than three wheezing episodes during the preceding year) in relation to the number of siblings at home and in relation to attendance at day care during infancy. RESULTS: The presence of one or more older siblings at home protected against the development of asthma (adjusted relative risk for each additional older sibling, 0.8; 95 percent confidence interval, 0.7 to 1.0; P=0.04), as did attendance at day care during the first six months of life (adjusted relative risk, 0.4; 95 percent confidence interval, 0.2 to 1.0; P=0.04). Children with more exposure to other children at home or at day care were more likely to have frequent wheezing at the age of 2 years than children with little or no exposure (adjusted relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.8; P=0.01) but were less likely to have frequent wheezing from the age of 6 (adjusted relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0; P=0.03) through the age of 13 (adjusted relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). CONCLUSIONS: Exposure of young children to older children at home or to other children at day care protects against the development of asthma and frequent wheezing later in childhood.",0
2369,10960444,Expression and antitumor effects of TRAIL in human cholangiocarcinoma,"Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2L has been recently identified as important in promoting programmed cell death in breast and colon adenocarcinomas. In this study, we investigated the expression and therapeutic potential of TRAIL in cholangiocarcinoma, one of the most devastating human hepatic malignancies. Expression of TRAIL receptors was determined in 13 patients with resectable intrahepatic cholangiocarcinoma. Cellular effects of TRAIL in promoting apoptosis of human cholangiocarcinoma cells were analyzed after exposure to recombinant protein, as well as following transfection with a cDNA expression construct. In vivo effects of TRAIL on tumor growth were investigated after subcutaneous injection of cholangiocarcinoma cells into nude mice. Analysis of 13 clinical and tissue samples revealed that TRAIL receptors containing the death domain were present in all cholangiocarcinomas as well as paired normal hepatic tissues derived from surgically resected margins. In contrast, 7 tumors did not express the TRAIL decoy receptors lacking the death domain; such receptors were detectable in all of the normal hepatic tissue counterparts. Recombinant TRAIL induced extensive programmed cell death in cholangiocarcinoma cell lines lacking decoy receptor expression. Transfection of the ectodomain of TRAIL also induced cellular apoptosis; this effect was abolished by introduction of the generalized lymphoproliferative disease-like mutation in the TRAIL protein. Finally, in vivo administration of recombinant TRAIL substantially inhibited subcutaneous tumor growth of human cholangiocarcinoma cells. Induction of apoptosis in tumor cells is possible with a biologically active TRAIL, and suggests that this cytokine is a promising antitumor agent against human cholangiocarcinoma.",0
2370,10960445,Epidermal growth factor impairs the cytochrome C/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway,"Transforming growth factor beta (TGF-beta)-mediated apoptosis is one of the major death processes in the liver. We have previously shown that epidermal growth factor (EGF) is an important survival signal for TGF-beta-induced apoptosis in fetal hepatocytes (Fabregat et al., FEBS Lett 1996;384:14-18). In this work we have studied the intracellular signaling implicated in the protective effect of EGF. We show here that EGF activates p42 and p44 mitogen-activated protein kinases (MAPK). However, mitogen extracellular kinase (MEK) inhibitors do not block the survival effect of EGF. EGF also activates phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB/AKT) in these cells. The presence of PI 3-kinase inhibitors blocks the protective effect of EGF on cell viability, DNA fragmentation, and caspase-3 activity. We have found that TGF-beta disrupts the mitochondrial transmembrane potential (DeltaPsi(m))( )and activates the release of cytochrome c, this effect being blocked by EGF, via a PI 3-kinase-dependent pathway. A detailed study on bcl-2 superfamily gene expression shows that TGF-beta produces a decrease in the messenger RNA (mRNA) and protein levels of bcl-x(L), an antiapoptotic member of this family, capable of preventing cytochrome c release. EGF is able to maintain bcl-x(L) levels even in the presence of TGF-beta. PI 3-kinase inhibitors completely block the protective effect of EGF on TGF-beta-induced bcl-x(L )down-regulation. We conclude that PI 3-kinase mediates the survival effect of EGF on TGF-beta-induced death by acting upstream from the mitochondrial changes, i.e., preventing bcl-x(L) down-regulation, cytochrome c release, and activation of caspase-3.",0
2371,10960457,Antibodies against hepatitis C virus-like particles and viral clearance in acute and chronic hepatitis C,"We recently described the efficient assembly of hepatitis C virus (HCV) structural proteins into HCV-like particles (HCV-LPs) in insect cells. These noninfectious HCV-LPs have similar morphologic and biophysical properties as putative virions isolated from HCV-infected humans and can induce a broadly directed immune response in animal models. The HCV envelope proteins of HCV-LPs are presumably presented in a native, virion-like conformation and may therefore interact with antienvelope antibodies directed against conformational epitopes. In this study, HCV-LPs were used as capture antigens in an enzyme-linked immunosorbent assay (ELISA) to detect and quantify antibodies against HCV structural proteins in patients with acute and chronic hepatitis C. High titers of anti-HCV-LP antibodies were detected in patients chronically infected with HCV genotypes 1 to 6. In contrast to individuals with chronic hepatitis C, patients with acute self-limited hepatitis C displayed only a transient and weak seroreactivity against HCV-LPs. Patients with chronic HCV infection successfully treated with interferon demonstrated a gradual decline of anti-HCV-LP titers during or subsequent to viral clearance. Sustained interferon responders were characterized by significantly higher pretreatment levels of anti-HCV-LP antibodies as compared with nonresponders (P =.0001). In conclusion, HCV infection is associated with limited humoral immunity against the envelope proteins present on the HCV-LPs. An HCV-LP-based ELISA may be a useful diagnostic tool to distinguish acute hepatitis C from chronic HCV infection with exacerbation, and to predict viral clearance in response to interferon.",0
2372,11050037,"Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens","The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: group A (170)ExDK(173) and group B (168)EIExD(172). (170)E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas (173)K and (168)E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an EIExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vbeta in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vbeta in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.",0
2373,11050050,Immunologic considerations for therapeutic strategies utilizing allogeneic hepatocytes: hepatocyte-expressed membrane-bound major histocompatibility complex class I antigen sensitizes while soluble antigen suppresses the immune response in rats,"Understanding the immunologic effects of hepatocytes is critical because of the potential to use these cells for bioartificial livers, as a vehicle for gene transfer, and as a means to induce donor-specific immunosuppression in organ transplantation. However, this understanding is complicated by the fact that hepatocytes express membrane-bound and soluble forms of major histocompatibility complex (MHC) class I antigen, each with the potential to induce different immune responses. In the present study we first determined the immunologic effect of normal donor-derived hepatocytes in a rat heart transplant model. We then used ex vivo hepatocyte gene transfer to examine the immunologic effects of different forms of hepatocyte-expressed MHC class I antigen. Results showed that intrasplenic injection of purified, donor-strain-specific hepatocytes into recipients primes alloimmunity, as evidenced by acceleration of heart allograft rejection. Interestingly, injection of autologous hepatocytes transfected ex vivo with DNA encoding only membrane-bound donor MHC class I antigen (RT1.A(a)) also accelerated allograft rejection. However, hepatocytes transfected to express only secreted donor MHC antigen prolonged transplant survival. Limiting-dilution analysis of lymphocytes from animals treated with hepatocytes producing only secreted alloantigen showed an antigen-specific reduction in cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) precursors. Further analysis of CTL populations by flow cytometry revealed a relatively high percentage of nonviable cells, implying that soluble antigen promotes allospecific CTL death. In summary, this study suggests that hepatocyte-expressed MHC class I molecules have opposing immunologic effects, with the membrane-bound antigen inducing immunologic sensitization, and the soluble antigen promoting donor-specific immunosuppression.",0
2374,11096167,The effect of fecal occult-blood screening on the incidence of colorectal cancer,"BACKGROUND: Both annual testing for fecal occult blood and biennial testing significantly reduce mortality from colorectal cancer. However, the effect of screening on the incidence of colorectal cancer remains uncertain, despite the diagnosis and removal of precancerous lesions in many persons who undergo screening. METHODS: We followed the participants in the Minnesota Colon Cancer Control Study for 18 years. A total of 46,551 people, most of whom were 50 to 80 years old, were enrolled between 1975 and 1978 and randomly assigned to annual screening, biennial screening, or usual care (the control group). Those assigned to the screening groups were asked to prepare and submit two samples from each of three consecutive stools for guaiac-based testing. Those with at least one positive slide in the set of six were offered a diagnostic examination that included colonoscopy. Screening was conducted between 1976 and 1982 and again between 1986 and 1992. Study participants have been followed with respect to newly diagnosed cases of colorectal cancer and deaths. Follow-up has been more than 90 percent complete. RESULTS: During the 18-year follow-up period, we identified 1359 new cases of colorectal cancer: 417 in the annual-screening group, 435 in the biennial-screening group, and 507 in the control group. The cumulative incidence ratios for colorectal cancer in the screening groups as compared with the control group were 0.80 (95 percent confidence interval, 0.70 to 0.90) and 0.83 (95 percent confidence interval, 0.73 to 0.94) for the annual-screening and biennial-screening groups, respectively. For both screening groups, the number of positive slides was associated with the positive predictive value both for colorectal cancer and for adenomatous polyps at least 1 cm in diameter. CONCLUSIONS: The use of either annual or biennial fecal occult-blood testing significantly reduces the incidence of colorectal cancer.",0
2375,11096168,Folic acid antagonists during pregnancy and the risk of birth defects,"BACKGROUND: Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. METHODS: We compared data on exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs for 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects with data for 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use. RESULTS: The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs. CONCLUSIONS: Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects.",0
2376,11096170,Conflict-of-interest policies for investigators in clinical trials,"""BACKGROUND: There is substantial concern that financial conflicts of interest on the part of investigators conducting clinical trials may compromise the well-being of research subjects. METHODS: We analyzed policies governing conflicts of interest at the 10 medical schools in the United States that receive the largest amount of research funding from the National Institutes of Health. These institutions are Baylor College of Medicine, Columbia University College of Physicians and Surgeons, Harvard Medical School, Johns Hopkins University School of Medicine, the University of Pennsylvania School of Medicine, the University of California at Los Angeles School of Medicine, the University of California at San Francisco School of Medicine, the University of Washington School of Medicine, Washington University School of Medicine at St. Louis, and Yale University School of Medicine. RESULTS: All 10 universities required that faculty members disclose financial interests to university officials. Only four required disclosure by all members of the research staff. Five universities required disclosure of all financial interests, even though federal regulations specify a threshold for disclosure. Six universities required disclosure to the institutional review board as well as to a committee on conflicts of interest or a university official. Four universities had stricter requirements for investigators conducting clinical trials than required by federal regulations. One university prohibited investigators from having stock, stock options, consulting agreements, or decision-making positions involving a company that sponsored the research. A second university prohibited researchers from trading stock or stock options in a company that sponsored the research or sold the product or device under study. Two universities ordinarily did not allow faculty members to participate in clinical research if they had what federal regulations refer to as a """"significant"""" financial interest in the company owning the product or device being studied, but exceptions were allowed. CONCLUSIONS: Policies governing conflicts of interest at leading medical schools in the United States vary widely. We suggest that university-based investigators and research staff be prohibited from holding stock, stock options, or decision-making positions in a company that may reasonably appear to be affected by the results of their clinical research. Of the 10 medical schools we studied, only 1 had a policy that was close to this standard.""",0
2377,11106717,The risk of menstrual abnormalities after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group,"BACKGROUND: The existence of a post-tubal-ligation syndrome of menstrual abnormalities has been debated for decades. We used data from the U.S. Collaborative Review of Sterilization to determine whether the likelihood of persistent menstrual abnormalities was greater among women who had undergone tubal sterilization than among women who had not. METHODS: A total of 9514 women who underwent tubal sterilization and 573 women whose partners underwent vasectomy were followed in a multicenter, prospective cohort study for up to five years by means of annual telephone interviews. All women were asked the same questions about six characteristics of their menstrual cycles in the presterilization and follow-up interviews. Multiple logistic-regression analysis was used to assess the risk of persistent menstrual changes. RESULTS: The women who had undergone sterilization were no more likely than those who had not undergone the procedure to report persistent changes in intermenstrual bleeding or the length of the menstrual cycle. They were more likely to have decreases in the number of days of bleeding (odds ratio, 2.4; 95 percent confidence interval, 1.1 to 5.2), the amount of bleeding (odds ratio, 1.5; 95 percent confidence interval, 1.1 to 2.0), and menstrual pain (odds ratio, 1.3; 95 percent confidence interval, 1.0 to 1.8) and to have an increase in cycle irregularity (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3). Among women who had had very heavy bleeding at base line, women who had undergone sterilization were more likely than women who had not undergone the procedure to report decreased bleeding (45 percent vs. 33 percent, P=0.03). CONCLUSIONS: Women who have undergone tubal sterilization are no more likely than other women to have menstrual abnormalities.",0
2378,11114315,Familial aggregation of Parkinson's disease in Iceland,"BACKGROUND: The role of genetics in early-onset Parkinson's disease has been established, but whether there is a genetic contribution to the more common, late-onset form remains uncertain. METHODS: We reviewed the medical records and confirmed the diagnosis of Parkinson's disease in 772 living and deceased patients in whom the disease had been diagnosed during the previous 50 years in Iceland. With the use of an extensive computerized data base containing genealogic information on 610,920 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than random members of the population (control subjects). RESULTS: Patients with Parkinson's disease, including a subgroup of 560 patients with late-onset disease (onset at >50 years of age), were significantly more related to each other than were subjects in matched groups of controls, and this relatedness extended beyond the nuclear family. The risk ratio for Parkinson's disease was 6.7 (95 percent confidence interval, 4.3 to 9.6) for siblings, 3.2 (95 percent confidence interval, 1.2 to 7.8) for offspring, and 2.7 (95 percent confidence interval, 1.6 to 3.9) for nephews and nieces of patients with late-onset Parkinson's disease. CONCLUSIONS: Late-onset Parkinson's disease has a genetic component as well as an environmental component.",0
2379,11114317,Association of the California Tobacco Control Program with declines in cigarette consumption and mortality from heart disease,"BACKGROUND: The California Tobacco Control Program, a large, aggressive antitobacco program implemented in 1989 and funded by a voter-enacted cigarette surtax, accelerated the decline in cigarette consumption and in the prevalence of smoking in California. Since the excess risk of heart disease falls rapidly after the cessation of smoking, we tested the hypothesis that this program was associated with lower rates of death from heart disease. METHODS: Data on per capita cigarette consumption and age-adjusted rates of death from heart disease in California and the United States from 1980 to 1997 were fitted in multiple regression analyses. The regression analyses included the rates in the rest of the United States and variables that allowed for changes in the rates after 1988, when the tobacco-control program was approved, and after 1992, when the program was cut back. RESULTS: Between 1989 and 1992, the rates of decline in per capita cigarette consumption and mortality from heart disease in California, relative to the rest of the United States, were significantly greater than the pre-1989 rates, by 2.72 packs per year per year (P = 0.001) and by 2.93 deaths per year per 100,000 population per year (P<0.001). These rates of decline were reduced (by 2.05 packs per year per year, [P=0.04], and by 1.71 deaths per year per 100,000 population per year, [P=0.031) when the program was cut back, beginning in 1992. Despite these problems, the program was associated with 33,300 fewer deaths from heart disease between 1989 and 1997 than the number that would have been expected if the earlier trend in mortality from heart disease in California relative to the rest of the United States had continued. The diminished effectiveness of the program after 1992 was associated with 8300 more deaths than would have been expected had its initial effectiveness been maintained. CONCLUSIONS: A large and aggressive tobacco-control program is associated with a reduction in deaths from heart disease in the short run.",0
2380,11117976,Prognosis of cancers associated with venous thromboembolism,"BACKGROUND: Little is known about the prognosis of cancer discovered during or after an episode of venous thromboembolism. METHODS: We linked the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files to obtain data on the survival of patients who received a diagnosis of cancer at the same time as or after an episode of venous thromboembolism. Their survival was compared with that of patients with cancer who did not have venous thromboembolism (control patients), who were matched in terms of type of cancer, age, sex, and year of diagnosis. RESULTS: Of 668 patients who had cancer at the time of an episode of deep venous thromboembolism, 44.0 percent of those with data on the spread of disease (563 patients) had distant metastasis, as compared with 35.1 percent of 5371 control patients with data on spread (prevalence ratio, 1.26; 95 percent confidence interval, 1.13 to 1.40). In the group with cancer at the time of venous thromboembolism, the one-year survival rate was 12 percent, as compared with 36 percent in the control group (P<0.001), and the mortality ratio for the entire follow-up period was 2.20 (95 percent confidence interval, 2.05 to 2.40). Patients in whom cancer was diagnosed within one year after an episode of venous thromboembolism had a slightly increased risk of distant metastasis at the time of the diagnosis (prevalence ratio, 1.23 [95 percent confidence interval, 1.08 to 1.40]) and a relatively low rate of survival at one year (38 percent, vs. 47 percent in the control group; P<0.001). CONCLUSIONS: Cancer diagnosed at the same time as or within one year after an episode of venous thromboembolism is associated with an advanced stage of cancer and a poor prognosis.",0
2381,11124824,Differential role of I kappa B kinase 1 and 2 in primary rat hepatocytes,"Nuclear factor-kappa B (NF-kappa B) protects hepatocytes from undergoing apoptosis during embryonic development and during liver regeneration. Activation of NF-kappa B is mediated through phosphorylation of its inhibitor, I kappa B, by a kinase complex that contains 2 I kappa B kinases. We analyzed the differential role of I kappa B kinase 1 (IKK1) and I kappa B kinase 2 (IKK2) in tumor necrosis factor alpha (TNF-alpha)- and interleukin-1 beta (IL-1 beta)-mediated NF-kappa B activation in primary rat hepatocytes. Maximal induction of IKK activity was observed 5 minutes after TNF-alpha and 15 minutes after IL-1 beta treatment, and activated IKK was able to phosphorylate GST-I kappa B (1-54) and GST-p65 (354-551), but not a GST-p65 (354-551) substrate with a serine-to-alanine substitution at position 536. Infection with an adenovirus containing catalytically inactive IKK2K44M (Ad5IKK2dn) completely blocked both TNF-alpha- and IL-1 beta-induced GST-I kappa B and GST-p65 phosphorylation, I kappa B degradation, and NF-kappa B DNA binding. Adenovirally transduced, catalytically inactive IKK1K44M (Ad5IKK1dn) reduced IKK activity and NF-kappa B DNA binding only slightly. Accordingly, Ad5IKK2dn induced apoptosis in 75% (+/-6%) of hepatocytes after 12 hours of TNF-alpha, which was accompanied by activation of caspases 3 and 8, nuclear fragmentation, and DNA laddering. In contrast, Ad5IKK1dn led to 21% (+/-2%) apoptosis in TNF-alpha-treated hepatocytes after 12 hours and comparatively low activity of caspases 3 and 8. Furthermore, Ad5IKK2dn completely blocked the induction of inducible nitric oxide synthase (iNOS), whereas Ad5IKK1dn had no influence on the expression of iNOS. Thus, IKK2 is the main mediator for cytokine-induced NF-kappa B activation in primary hepatocytes and protects against TNF-alpha-induced apoptosis, whereas IKK1 kinase activity is not required for NF-kappa B activation.",0
2382,11124832,"Hepatitis C virus core protein enhances the activation of the transcription factor, Elk1, in response to mitogenic stimuli","Mitogen-activated protein kinase (MAPK) pathways play key roles in cell proliferation, transformation of mammalian cells, and the stress response. We and other investigators showed that hepatitis C virus (HCV) core protein has an oncogenic potential, but its mechanism has remained unknown. We previously demonstrated that the MAPK-extra-cellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway and its downstream target, the serum response element (SRE), is activated in BALB/3T3 cells producing HCV core protein. To elucidate the precise mechanism by which HCV core protein activates the MEK-ERK pathway, we transiently expressed HCV core protein in several cell lines and studied the signal transduction of the pathway, using Gal4-Elk1 luciferase assay, in vitro kinas assay of MAPK, and Western blotting analysis. We discovered that, in the presence of mitogenic signal, HCV core protein enhanced Elk1 activation working downstream of MEK without affecting ERK activity and Elk1 phosphorylation. Our data suggest that HCV core protein may activate Elk1 through a pathway alternative to the typical phosphorylation cascade. These findings might give new insights into the role of HCV in hepatocarcinogenesis.",0
2383,11124839,A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group,"Clinical and molecular virological differences were evaluated in 50 Japanese patients chronically infected with HBV of genotype B and C who were matched for age and sex as well as the severity of liver disease in a case-control study. Hepatitis B e antigen (HBeAg) was significantly less frequent (16% vs. 42%, P <.01), whereas antibody to HBeAg (anti-HBe) was significantly more common (84% vs. 56%, P <. 01) in genotype B than C patients. The predominance of mutants with G-to-A mutation at nucleotide (nt) 1896 in the precore region (A1896) over the wild-type was comparable between genotype B and C patients (60% and 62%, respectively), and it correlated with anti-HBe. The double mutation in the basic core promoter (A-to-T at nt 1762 and G-to-A at nt 1764), however, was significantly more frequent in genotype C than B patients (58% vs. 16%, P <.01), and it did not correlate with anti-HBe or HBeAg. By the multiple logistic regression analysis, the double mutation in the basic core promoter (T1762/A1764) was significantly associated with genotype C [odds ratio (OR), 9.3; 95% confidence interval (CI), 3.4-25.1]], age > or = 35 years (OR, 5.5; CI, 1.5-20.5), and more advanced liver disease (OR, 4.1; CI, 1.6-10.2), but it was not associated with sex, HBeAg, HBV DNA, or the precore mutation (A1896). These results suggest a role of the double mutation in the basic core promoter in association with genotype C and a longer duration of infection in the aggravation of chronic hepatitis B.",0
2384,11124843,Hepatitis C virus infection in a community in the Nile Delta: risk factors for seropositivity,"""The purpose of this study was to identify risk factors for hepatitis C virus (HCV) infection in a rural village in the Nile Delta with a high prevalence of antibodies to HCV (anti-HCV). One half of the village households were systematically selected, tested for anti-HCV, and interviewed: 973 of 3,999 (24.3%) subjects were anti-HCV-positive (reflecting prior HCV infection but not necessarily current liver disease), with nearly equal prevalence among males and females. Anti-HCV prevalence increased sharply with age among both males and females, from 9.3% in those 20 years of age and younger to >50% in those older than 35, suggesting a cohort effect with reduced transmission in recent years. Multivariate regression was used to estimate independent effects of risk factors on seropositivity. Among those over 20 years of age, the following risk factors were significantly associated with seropositivity: age (P <.001); male gender (odds ratio [OR] = 2.5, 95% CI = 1.3-4.7); marriage (OR = 4.1, 2.4-6.9); anti-schistosomiasis injection treatment (OR = 2.0, 1.3-2.9); blood transfusion (OR = 1.8, 1.1-2.9), invasive medical procedure (surgery, catheterization, endoscopy, and/or dialysis) (OR = 1.5, 1.1-1.9); receipt of injections from """"informal"""" health care provider (OR = 1.3, 1.0-1.6); and cesarean section or abortion (OR = 1.4, 1.0-1.9). Exposures not significantly related to anti-HCV positivity in adults included: history of, or active infection with, Schistosoma mansoni, sutures or abscess drainage, goza smoking in a group, and shaving by community barbers. Among those 20 years old or younger, no risk factors were clearly associated with anti-HCV positivity; however, circumcision for boys by informal health care providers was marginally associated with anti-HCV (OR = 1.7, 1.0-3.0). Prevention programs focused primarily on culturally influenced risks in rural Egyptian communities are being implemented and evaluated.""",0
2385,11136263,Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients,"BACKGROUND: Colonization and infection with vancomycin-resistant enterococci have been associated with exposure to antibiotics that are active against anaerobes. In mice that have intestinal colonization with vancomycin-resistant enterococci, these agents promote high-density colonization, whereas antibiotics with minimal antianaerobic activity do not. METHODS: We conducted a seven-month prospective study of 51 patients who were colonized with vancomycin-resistant enterococci, as evidenced by the presence of the bacteria in stool. We examined the density of vancomycin-resistant enterococci in stool during and after therapy with antibiotic regimens and compared the effect on this density of antianaerobic agents and agents with minimal antianaerobic activity. In a subgroup of 10 patients, cultures of environmental specimens (e.g., from bedding and clothing) were obtained. RESULTS: During treatment with 40 of 42 antianaerobic-antibiotic regimens (95 percent), high-density colonization with vancomycin-resistant enterococci was maintained (mean [+/-SD] number of organisms, 7.8+/-1.5 log per gram of stool). The density of colonization decreased after these regimens were discontinued. Among patients who had not received antianaerobic antibiotics for at least one week, 10 of 13 patients who began such regimens had an increase in the number of organisms of more than 1.0 log per gram (mean increase, 2.2 log per gram), whereas among 10 patients who began regimens of antibiotics with minimal antianaerobic activity, there was a mean decrease in the number of enterococci of 0.6 log per gram (P=0.006 for the difference between groups). When the density of vancomycin-resistant enterococci in stool was at least 4 log per gram, 10 of 12 sets of cultures of environmental specimens had at least one positive sample, as compared with 1 of 9 sets from patients with a mean number of organisms in stool of less than 4 log per gram (P=0.002). CONCLUSIONS: For patients with vancomycin-resistant enterococci in stool, treatment with antianaerobic antibiotics promotes high-density colonization. Limiting the use of such agents in these patients may help decrease the spread of vancomycin-resistant enterococci.",0
2386,11136265,Outcome of myocardial infarction in Veterans Health Administration patients as compared with medicare patients,"BACKGROUND: Some have the opinion that patients cared for in Veterans Health Administration (VHA) hospitals receive care of poorer quality than those cared for in non-VHA institutions. To assess the quality of care in VHA hospitals, we compared the outcome of acute myocardial infarction among patients in VHA and non-VHA institutions while controlling for potential confounders, including coexisting conditions and severity of illness. METHODS: We studied 2486 veterans discharged from 81 VHA hospitals and 29,249 Medicare patients discharged from 1530 non-VHA hospitals, restricting our samples to men at least 65 years of age who were discharged with confirmed acute myocardial infarction. We compared coexisting conditions, severity of illness, and 30-day and 1-year mortality in the two samples. RESULTS: VHA patients were significantly more likely than Medicare patients to have a recorded history of hypertension (64.3 percent vs. 57.3 percent), chronic obstructive pulmonary disease or asthma (30.9 percent vs. 23.5 percent), diabetes (34.8 percent vs. 29.0 percent), stroke (20.4 percent vs. 14.2 percent), or dementia (7.2 percent vs. 4.8 percent) (P<0.001 for all comparisons). According to both multivariate logistic regression and an analysis using 2265 matched pairs of VHA and Medicare patients, there were no significant differences in 30-day or 1-year mortality. The matched-pairs analysis found that the difference in mortality at 30 days (the mortality rate among Medicare patients minus the mortality rate among VHA patients), averaged over the 5-year age groups, was -0.8 percent (95 percent confidence interval, -2.8 percent to 1.3 percent), and the difference in mortality at 1 year was -1.3 percent (95 percent confidence interval, -3.9 percent to 1.3 percent). CONCLUSIONS: VHA patients had more coexisting conditions than Medicare patients. Nevertheless, we found no significant difference in mortality between VHA and Medicare patients, a result that suggests a similar quality of care for acute myocardial infarction.",0
2387,11136953,Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group,"BACKGROUND: The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension. METHODS: A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order. RESULTS: Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during the DASH diet (P<0.01). The effects of sodium were observed in participants with and in those without hypertension, blacks and those of other races, and women and men. The DASH diet was associated with a significantly lower systolic blood pressure at each sodium level; and the difference was greater with high sodium levels than with low ones. As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension. CONCLUSIONS: The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially, with greater effects in combination than singly. Long-term health benefits will depend on the ability of people to make long-lasting dietary changes and the increased availability of lower-sodium foods.",0
2388,11172139,Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers,"BACKGROUND: In recipients of allogeneic hematopoietic-cell transplants, peripheral-blood cells mobilized with the use of filgrastim (recombinant granulocyte colony-stimulating factor) engraft more rapidly than bone marrow. However, the relative effects of these techniques on the rates of acute and chronic graft-versus-host disease, overall survival, and disease-free survival have not been determined in randomized studies. METHODS: Between March 1996 and July 1999, 172 patients (12 to 55 years of age) with hematologic cancer were randomly assigned to receive either bone marrow or filgrastim-mobilized peripheral-blood cells from HLA-identical relatives for hematopoietic rescue after the treatment of hematologic cancer with high doses of chemotherapy, with or without radiation. RESULTS: The recovery of both neutrophils and platelets was faster with peripheral-blood cells than with marrow (P<0.001 for both comparisons). The cumulative incidence of grade II, III, or IV acute graft-versus-host disease at 100 days was 64 percent with peripheral-blood cells and 57 percent with marrow (hazard ratio, 1.21; 95 percent confidence interval, 0.81 to 1.81; P=0.35). The cumulative incidence of chronic graft-versus-host disease was 46 percent with peripheral-blood cells and 35 percent with marrow (hazard ratio, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54). The estimated overall probability of survival at two years was 66 percent with peripheral-blood cells and 54 percent with marrow (hazard ratio for death, 0.62; 95 percent confidence interval, 0.38 to 1.02; P=0.06). The rate of disease-free survival at two years was 65 percent with peripheral-blood cells and 45 percent with marrow (hazard ratio for relapse or death, 0.60; 95 percent confidence interval, 0.38 to 0.95; P=0.03). CONCLUSIONS: In patients given high-dose chemotherapy, with or without radiation, for the treatment of hematologic cancer, allogeneic peripheral-blood cells used for hematopoietic rescue restore blood counts faster than allogeneic bone marrow, without increasing the risk of graft-versus-host disease.",0
2389,11172143,Are patients' office visits with physicians getting shorter?,"BACKGROUND: Many believe that managed care creates pressure on physicians to increase productivity, see more patients, and spend less time with each patient. METHODS: We used nationally representative data from the National Ambulatory Medical Care Survey (NAMCS) of the National Center for Health Statistics and the American Medical Association's Socioeconomic Monitoring System (SMS) to examine the length of office visits with physicians from 1989 through 1998. We assessed the trends for visits covered by a managed-care or other prepaid health plan (prepaid visits) and non-prepaid visits for primary and specialty care, for new and established patients, and for common and serious diagnoses. RESULTS: Between 1989 and 1998 the number of visits to physicians' offices increased significantly from 677 million to 797 million, although the rate of visits per 100 population did not change significantly. The average duration of office visits in 1989 was 16.3 minutes according to the NAMCS and 20.4 minutes according to the SMS survey. According to both sets of data, the average duration of visits increased by between one and two minutes between 1989 and 1998. The duration of the visits increased for both prepaid and nonprepaid visits. Nonprepaid visits were consistently longer than prepaid visits, although the gap declined from 1 minute in 1989 to 0.6 minute in 1998. There was an upward trend in the length of visits for both primary and specialty care and for both new and established patients. The average length of visits remained stable or increased for patients with the most common diagnoses and for those with the most serious diagnoses. CONCLUSIONS: Contrary to expectations, the growth of managed health care has not been associated with a reduction in the length of office visits. The observed trends cannot be explained by increases in physicians' availability, shifts in the distribution of physicians according to sex, or changes in the complexity of the case mix.",0
2390,11172144,Acute pharyngitis,"The primary care physician needs to identify those patients with acute pharyngitis who require specific antimicrobial therapy and to avoid unnecessary and potentially deleterious treatment in the large majority of patients who have a benign, self-limited infection that is usually viral. In most cases, differentiating between these two types of infection can be accomplished easily if the physician considers the epidemiologic setting, the history, and the physical findings, plus the results of a few readily available laboratory tests. When antimicrobial therapy is required, the safest, narrowest-spectrum, and most cost-effective drugs should be used. Despite agreement on these principles by expert advisory committees, data from national surveys of ambulatory care indicate that antimicrobial agents continue to be prescribed indiscriminately for upper respiratory infections.",0
2391,11172152,A molecular marker for chloroquine-resistant falciparum malaria,"BACKGROUND: Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. METHODS: To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. RESULTS: The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P<0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1). CONCLUSIONS: This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.",0
2392,11172153,Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics,"BACKGROUND: Cerebral edema is an uncommon but devastating complication of diabetic ketoacidosis in children. Risk factors for this complication have not been clearly defined. METHODS: In this multicenter study, we identified 61 children who had been hospitalized for diabetic ketoacidosis within a 15-year period and in whom cerebral edema had developed. Two additional groups of children with diabetic ketoacidosis but without cerebral edema were also identified: 181 randomly selected children and 174 children matched to those in the cerebral-edema group with respect to age at presentation, onset of diabetes (established vs. newly diagnosed disease), initial serum glucose concentration, and initial venous pH. Using logistic regression we compared the three groups with respect to demographic characteristics and biochemical variables at presentation and compared the matched groups with respect to therapeutic interventions and changes in biochemical values during treatment. RESULTS: A comparison of the children in the cerebral-edema group with those in the random control group showed that cerebral edema was significantly associated with lower initial partial pressures of arterial carbon dioxide (relative risk of cerebral edema for each decrease of 7.8 mm Hg [representing 1 SD], 3.4; 95 percent confidence interval, 1.9 to 6.3; P<0.001) and higher initial serum urea nitrogen concentrations (relative risk of cerebral edema for each increase of 9 mg per deciliter [3.2 mmol per liter] [representing 1 SD], 1.7; 95 percent confidence interval, 1.2 to 2.5; P=0.003). A comparison of the children with cerebral edema with those in the matched control group also showed that cerebral edema was associated with lower partial pressures of arterial carbon dioxide and higher serum urea nitrogen concentrations. Of the therapeutic variables, only treatment with bicarbonate was associated with cerebral edema, after adjustment for other covariates (relative risk, 4.2; 95 percent confidence interval, 1.5 to 12.1; P=0.008). CONCLUSIONS: Children with diabetic ketoacidosis who have low partial pressures of arterial carbon dioxide and high serum urea nitrogen concentrations at presentation and who are treated with bicarbonate are at increased risk for cerebral edema.",0
2393,11172333,Increased activity in the biliary Con A-binding fraction accounts for the difference in crystallization behavior in bile from Chilean gallstone patients compared with Dutch gallstone patients,"Chile has one of the highest prevalences of cholesterol gallstone disease in the world. Recent data indicate that this is partly caused by genetic (Indian) factors. However, the causal factors inducing increased gallstone formation have not been elucidated. The aim of this study was to compare biliary composition and cholesterol crystallization in bile from patients of high and moderate risk areas (Chile and The Netherlands) for gallstone disease. Bile was sampled at cholecystectomy from 30 Chilean and 26 Dutch gallstone patients. The Con A-binding fraction (CABF) was extracted from fresh native bile samples by incubation with Con A-sepharose. Reconstitution of the CABF to the Con A-extracted native bile induced almost full recovery of crystallization confirming the validity of this technique. There was no difference between the two groups regarding sex and age. Chilean bile nucleated significantly faster (3.5 +/- 0.6 vs. 7.9 +/- 1.5 days) despite the fact that Dutch bile had a significantly higher cholesterol saturation index (CSI) (1.6 vs. 1.2, P = .01). The total lipid content was not different. Chilean bile contained more total protein (5 vs. 2.9 mg/mL, P = .008). IgG, IgM, Haptoglobin and alpha-1-acid glycoprotein were not different between the two groups. IgA, though, was significantly higher in the Chilean samples (0.44 vs. 0.19 mg/mL, P < .001). Extraction of CABF increased crystal observation time (COT) and decreased crystal growth in both groups. However, the effects were much more pronounced in the Chilean samples. Compared with Dutch bile, Chilean bile crystallizes much faster despite a lower CSI. Chilean bile contains an increased content of Con A-binding nucleation promoting activity.",0
2394,11207350,Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction,"BACKGROUND: A polymorphism in the gene for alcohol dehydrogenase type 3 (ADH3) alters the rate of alcohol metabolism. We investigated the relation among the ADH3 polymorphism, the level of alcohol consumption, and the risk of myocardial infarction in a nested case-control study based on data from the prospective Physicians' Health Study. METHODS: We identified 396 patients with eligible newly diagnosed cases of myocardial infarction among men in the Physicians' Health Study. Of these patients, 374 were matched with 2 randomly selected control subjects each and the remaining 22 with 1 control each (total, 770 controls). The ADH3 genotype (gamma1gamma1, gamma1gamma2, or gamma2gamma2) was determined in all subjects. We examined the relations among the level of alcohol intake, the ADH3 genotype, and plasma high-density lipoprotein (HDL) levels in this study population and in a similar cohort of women. RESULTS: As compared with homozygosity for the allele associated with a fast rate of ethanol oxidation (gamma1), homozygosity for the allele associated with a slow rate of ethanol oxidation (gamma2) was associated with a reduced risk of myocardial infarction (relative risk, 0.65; 95 percent confidence interval, 0.43 to 0.99). Moderate alcohol consumption was associated with a decreased risk of myocardial infarction in all three genotype groups (gamma1gamma1, gamma1gamma2, and gamma2gamma2); however, the ADH3 genotype significantly modified this association (P=0.01 for the interaction). Among men who were homozygous for the gamma1 allele, those who consumed at least one drink per day had a relative risk of myocardial infarction of 0.62 (95 percent confidence interval, 0.34 to 1.13), as compared with the risk among men who consumed less than one drink per week. Men who consumed at least one drink per day and were homozygous for the gamma2 allele had the greatest reduction in risk (relative risk, 0.14; 95 percent confidence interval, 0.04 to 0.45). Such men also had the highest plasma HDL levels (P for interaction = 0.05). We confirmed the interaction among the ADH3 genotype, the level of alcohol consumption, and the HDL level in an independent study of postmenopausal women (P=0.02). CONCLUSIONS: Moderate drinkers who are homozygous for the slow-oxidizing ADH3 allele have higher HDL levels and a substantially decreased risk of myocardial infarction.",0
2395,11221608,Absence of cardiac toxicity of zidovudine in infants,"BACKGROUND: Some evidence suggests that perinatal exposure to zidovudine may cause cardiac abnormalities in infants. We prospectively studied left ventricular structure and function in infants born to mothers infected with the human immunodeficiency virus (HIV) in order to determine whether there was evidence of zidovudine cardiac toxicity after perinatal exposure. METHODS: We followed a group of infants born to HIV-infected women from birth to five years of age with echocardiographic studies every four to six months. Serial echocardiograms were obtained for 382 infants without HIV infection (36 with zidovudine exposure) and 58 HIV-infected infants (12 with zidovudine exposure). Repeated-measures analysis was used to examine four measures of left ventricular structure and function during the first 14 months of life in relation to zidovudine exposure. RESULTS: Zidovudine exposure was not associated with significant abnormalities in mean left ventricular fractional shortening, end-diastolic dimension, contractility, or mass in either non�HIV-infected or HIV-infected infants. Among infants without HIV infection, the mean fractional shortening at 10 to 14 months was 38.1 percent for those never exposed to zidovudine and 39.0 percent for those exposed to zidovudine (mean difference, ?0.9 percentage point; 95 percent confidence interval, ?3.1 to 1.3 percentage points; P=0.43). Among HIV-infected infants, the mean fractional shortening at 10 to 14 months was similar in those never exposed to zidovudine (35.4 percent) and those exposed to the drug (35.3 percent) (mean difference, 0.1 percentage point; 95 percent confidence interval, ?3.7 to 3.9 percentage points; P=0.95). Zidovudine exposure was not significantly related to depressed fractional shortening (shortening of 25 percent or less) during the first 14 months of life. No child over the age of 10 months had depressed fractional shortening. CONCLUSIONS: Zidovudine was not associated with acute or chronic abnormalities in left ventricular structure or function in infants exposed to the drug in the perinatal period.",0
2396,11230748,Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus-mediated antisense targeting,"Hepatocyte nuclear factor 4 (HNF4) is a member of the nuclear receptor super-family that has shown activating effects on particular cytochrome P450 (CYP) promoters from several species. However, its role in the regulation of human CYPs in the liver is still poorly understood, as no comprehensive studies in human-relevant models have been performed. In the present study, we have investigated whether HNF4 plays a general role in the expression of 7 major CYP genes in primary cultured human hepatocytes. To this end, we developed an adenoviral vector for efficient expression of HNF4 antisense RNA. Transduction of human hepatocytes with the recombinant adenovirus resulted in a time-dependent increase in the antisense transcript, followed by a concomitant decrease in apolipoprotein C III mRNA (a target gene of HNF4). Specificity was confirmed by showing that increasing levels of HNF4 antisense RNA resulted in the reduction of HNF4 protein, whereas retinoic X receptoralpha-(RXRalpha), the closest homologous member of the nuclear receptor super-family, was unaffected. Analysis of CYP gene expression in human hepatocytes transfected with HNF4 antisense RNA revealed singular behaviors: (1) CYP3A4, CYP3A5, and CYP2A6 showed an important, dose-dependent down-regulation on blockage of HNF4 translation; (2) a moderate inhibition of CYP2B6, CYP2C9, and CYP2D6 expression was observed (40%-45% reduction); (3) the levels of CYP2E1 were not affected even in the absence of this transcription factor. In conclusion, using an original strategy (efficient antisense RNA expression vector), our study shows that HNF4 is a general regulator supporting the expression of major drug-metabolizing CYPs in human hepatocytes.",0
2397,11230757,Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region,"There is currently no universally accepted numbering convention for the antiviral drug-related resistance mutations in the reverse transcriptase (rt) domain of the human hepatitis B virus (HBV) polymerase. The published inconsistencies have resulted from different HBV genotypes. A standardized numbering system for HBV polymerase is proposed. The new system is based on functional observations of HBV surface gene proteins (preS1, preS2, and HBsAg) and on the current convention used for human immunodeficiency virus type 1 (HIV-1) polymerase proteins (protease, rt, and integrase), in which the amino acid numbering restarts at the first codon position of each domain. The HBV polymerase protein can be divided into 4 domains (terminal protein, spacer, rt, ribonuclease H) and each of these can be numbered separately. In this proposal, the HBV rt domain starts with the highly conserved EDWGPCDEHG motif, contains 344 amino acids, and the lamivudine-related resistance mutations are found at amino acid rtL180M (previously amino acid 528, 526, 515, or 525) and rtM204V/I (previously 552, 550, 539, or 549). The new consensus rt domain numbering system is genotype independent and allows investigators to number any previously and newly discovered antiviral-related amino acid change in a standardized manner.",0
2398,11236776,Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors,"""BACKGROUND: The effect on allograft survival of the transplantation of kidneys from living donors without the previous initiation of long-term dialysis is controversial. METHODS: Using data from the U.S. Renal Data System, we performed a retrospective cohort study of 8481 patients who were or who were not treated by long-term dialysis before receiving a kidney transplant from a living donor. The relative rate of allograft failure for patients who received a transplant without previously undergoing long-term dialysis, as compared with patients who underwent long-term dialysis before transplantation, was assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including the transplantation center and median household income. The association between the receipt of a kidney transplant from a living donor without previous dialysis (""""preemptive transplantation"""") and the risk of biopsy-confirmed acute rejection within six months after transplantation was evaluated by conditional logistic-regression analysis, with adjustment for the transplantation center. RESULTS: Transplantation of a kidney from a living donor without previous long-term dialysis was associated with a 52 percent reduction in the risk of allograft failure during the first year after transplantation (rate ratio, 0.48; P=0.002), an 82 percent reduction during the second year (rate ratio, 0.18; P=0.001), and an 86 percent reduction during subsequent years (rate ratio, 0.14; P=0.001), as compared with transplantation after dialysis. The reduction in the rate of allograft failure during the first year was attenuated when adjustment was made for the timing of acute rejection within the first year (rate ratio, 0.69; 95 percent confidence interval, 0.44 to 1.10; P=0.10). Increasing duration of dialysis was associated with increasing odds of rejection within six months after transplantation (P=0.001). CONCLUSIONS: Preemptive transplantation of kidneys from living donors without the previous initiation of dialysis is associated with longer allograft survival than transplantation performed after the initiation of dialysis.""",0
2399,11248159,Expenditures for the care of HIV-infected patients in the era of highly active antiretroviral therapy,"BACKGROUND: The introduction of expensive but very effective antiviral medications has led to questions about the effects on the total use of resources for the care of patients with human immunodeficiency virus (HIV) infection. We examined expenditures for the care of HIV-infected patients since the introduction of highly active antiretroviral therapy. METHODS: We interviewed a random sample of 2864 patients who were representative of all American adults receiving care for HIV infection in early 1996, and followed them for up to 36 months. We estimated the average expenditure per patient per month on the basis of self-reported information about care received. RESULTS: The mean expenditure was $1,792 per patient per month at base line, but it declined to $1,359 for survivors in 1997, since the increases in pharmaceutical expenditures were smaller than the reductions in hospital costs. Use of highly active antiretroviral therapy was independently associated with a reduction in expenditures. After adjustments for the interview date, clinical status, and deaths, the estimated annual expenditure declined from $20,300 per patient in 1996 to $18,300 in 1998. Expenditures among subgroups of patients varied by a factor of as much as three. Pharmaceutical costs were lowest and hospital costs highest among underserved groups, including blacks, women, and patients without private insurance. CONCLUSIONS: The total cost of care for adults with HIV infection has declined since the introduction of highly active antiretroviral therapy. Expenditures have increased for medications but have declined for other services. However, there are large variations in expenditures across subgroups of patients.",0
2400,11274620,Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine,"BACKGROUND: Acute rejection is a serious and frequent complication of renal transplantation, and its diagnosis is contingent on the invasive procedure of allograft biopsy. A noninvasive diagnostic test for rejection could improve the outcome of transplantation. METHODS: We obtained 24 urine specimens from 22 renal-allograft recipients with a biopsy-confirmed episode of acute rejection and 127 samples from 63 recipients without evidence of acute rejection. RNA was isolated from the urinary cells. Messenger RNA (mRNA) encoding the cytotoxic proteins perforin and granzyme B and a constitutively expressed cyclophilin B gene were measured with the use of a competitive, quantitative polymerase chain reaction, and the level of expression was correlated with allograft status. RESULTS: The log-transformed mean (+/-SE) levels of perforin mRNA and granzyme B mRNA, which encode cytotoxic proteins, but not the levels of constitutively expressed cyclophiiin B mRNA, were higher in the urinary cells from the 22 patients with a biopsy-confirmed episode of acute rejection than in the 63 recipients without an episode of acute rejection (perforin, 1.4+/-0.3 vs. -0.6+/-0.2 fg per microgram of total RNA; P<0.001; and granzyme B, 1.2+/-0.3 vs. -0.9+/-0.2 fg per microgram of total RNA; P<0.001). Analysis involving the receiver-operating-characteristic curve demonstrated that acute rejection can be predicted with a sensitivity of 83 percent and a specificity of 83 percent with the use of a cutoff value of 0.9 fg of perforin mRNA per microgram of total RNA, and with a sensitivity of 79 percent and a specificity of 77 percent with the use of a cutoff value of 0.4 fg of granzyme B mRNA per microgram of total RNA. Sequential urine samples were obtained from 37 patients during the first nine days after transplantation; and measurements of the levels of mRNA that encoded cytotoxic proteins identified those in whom acute rejection developed. CONCLUSIONS: Measurement of mRNA encoding cytotoxic proteins in urinary cells offers a noninvasive means of diagnosing acute rejection of renal allografts.",0
2401,11283839,Cholestatic expression pattern of sinusoidal and canalicular organic anion transport systems in primary cultured rat hepatocytes,"To maintain ongoing vectorial bile secretion, hepatocytes localize distinct transport systems at their basolateral and canalicular membrane domains. Here we compare the expression of the basolateral Na(+)-taurocholate cotransporter (Ntcp) and organic anion transporting polypeptides 1 and 2 (Oatp1, Oatp2) and the canalicular bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2) in primary cultured rat hepatocytes. During 72 hours of culturing time the messenger RNA (mRNA) and protein levels of Ntcp and Oatp1 decreased in parallel to 2% to 7% of initial values at 3 hours. Although Oatp2 mRNA exhibited a similar down-regulation to 4%, Oatp2 protein and function were maintained at 25% to 47% of initial values. Furthermore, Bsep and Mrp2 protein levels were maintained at about 50%, while the Mrp2 mRNA showed a transient up-regulation to 154% at 24 and 48 hours. Also, induction of Mrp1 mRNA and protein was observed starting after 24 hours. These results indicate transcriptional down-regulation or decreased mRNA stability of Ntcp and Oatp1, transcriptional and posttranslational regulation of Oatp2, Bsep, and Mrp2 and transcriptional up-regulation of Mrp1 in primary cultured hepatocytes. Furthermore, and most importantly, the observed changes in transporter expression closely resemble the altered transporter phenotypes of cholestatic and proliferating hepatocytes in vivo, thus indicating that primary cultured hepatocytes acquire a cholestatic phenotype, and that the transporter expression might be a suitable differentiation marker for maintenance of hepatocytes in vitro.",0
2402,11283861,Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy,"The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an important objective of immune therapies for chronic hepatitis B. However, amplification of CTL responses in vivo may be ineffective if HBV-specific CD8 cells are either absent or nonresponsive to exogenous stimulation. In this study, we asked whether antiviral treatments able to inhibit viral replication and to reduce viral and antigen load can successfully reconstitute CTL responses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV-specific CTL response before and during lamivudine therapy was studied longitudinally in 6 HLA-A2-positive patients with HBeAg+ chronic hepatitis B. Both HBV-specific cytotoxic T cell activity measured by chromium release assay on peptide stimulation in vitro and CD8+ T cell frequency measured ex vivo by HLA-A2/peptide tetramer staining were significantly augmented by lamivudine therapy. This enhancement followed the reconstitution of CD4 reactivity and the decline of viral load induced by therapy. Our study shows that lamivudine treatment in chronic hepatitis B can restore CTL reactivity, making CTL susceptible to exogenous stimulation. This effect may enhance the probability that T cell-based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection.",0
2403,11297703,Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck,"BACKGROUND: Oncogenic human papillomaviruses (HPVs), especially HPV type 16 (HPV-16), cause anogenital epithelial cancers and are suspected of causing epithelial cancers of the head and neck. METHODS: To examine the relation between head and neck cancers and HPVs, we performed a nested case-control study within a joint Nordic cohort in which serum samples were collected from almost 900,000 subjects. Samples collected at enrollment from 292 persons in whom squamous-cell carcinoma of the head and neck developed, on average, 9.4 years after enrollment and from 1568 matched controls were analyzed for antibodies against HPV-16, HPV-18, HPV-33, and HPV-73 and for cotinine levels as a marker of smoking habits. Polymerase-chain-reaction (PCR) analyses for HPV DNA were performed in tumor tissue from 160 of the study patients with cancer. RESULTS: After adjustment for cotinine levels, the odds ratio for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16 was 2.2 (95 percent confidence interval, 1.4 to 3.4). No increased risk was observed for other HPV types. Fifty percent of oropharyngeal and 14 percent of tongue cancers contained HPV-16 DNA, according to PCR analysis. CONCLUSIONS: HPV-16 infection may be a risk factor for squamous-cell carcinoma of the head and neck.",0
2404,11309635,Cognitive function in postmenopausal women treated with raloxifene,"BACKGROUND: In postmenopausal women, estrogen may have a beneficial effect on cognition or reduce the risk of decline in cognitive function. Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known. METHODS: As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries. The women were randomly assigned to receive raloxifene (60 mg or 120 mg) or placebo daily for three years. We compared the mean scores of the groups on six tests of cognitive function, which were administered at base line and at six months and one, two, and three years. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent. RESULTS: The mean cognitive scores in the three groups of women were similar at base line. The scores improved slightly in all three groups during the three-year study period, with no significant differences among the groups. The risk of decline in the cognitive function, as measured by four of the six tests, did not differ significantly between the two raloxifene groups combined and the placebo group, but there was a trend toward less decline in the combined raloxifene group on the two tests of verbal memory (relative risk, 0.77) and attention, (relative risk, 0.87). Newly reported or worsening hot flashes did not negatively influence test scores or the effect of treatment on test performance. CONCLUSIONS: Raloxifene treatment for three years does not affect overall cognitive scores in postmenopausal women with osteoporosis.",0
2405,11346810,Racial differences in the use of cardiac catheterization after acute myocardial infarction,"BACKGROUND: Several studies have reported that black patients are less likely than white patients to undergo cardiac catheterization after acute myocardial infarction. The role of the race of the physician in this pattern is unknown. METHODS: We analyzed data from the Cooperative Cardiovascular Project, a study of Medicare beneficiaries hospitalized for acute myocardial infarction in 1994 and 1995, to evaluate whether differences between black patients and white patients in the use of cardiac catheterization within 60 days after acute myocardial infarction varied according to the race of their attending physician. RESULTS: Our study cohort consisted of 35,676 white and 4039 black patients with acute myocardial infarction who were treated by 17,550 white and 588 black physicians. Black patients had lower rates of cardiac catheterization than white patients, regardless of whether their attending physician was white (rate of catheterization, 38.4 percent vs. 45.7 percent; P< 0.001) or black (38.2 percent vs. 49.6 percent, P<0.001). We did not find a significant interaction between the race of the patients and the race of the physicians in the use of cardiac catheterization. The adjusted mortality rate among black patients was lower than or similar to that among white patients for up to three years after the infarction. CONCLUSIONS: Racial differences in the use of cardiac catheterization are similar among patients treated by white physicians and those treated by black physicians, suggesting that this pattern of care is independent of the race of the physician.",0
2406,11386265,Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS,"BACKGROUND: From studies of genetic polymorphisms and the rate of progression from human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS), it appears that the strongest susceptibility is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B*3501, the most common HLA-B*35 subtype. We examined subtypes of HLA-B*35 in five cohorts and analyzed the relation of structural differences between HLA-B*35 subtypes to the risk of progression to AIDS. METHODS: Genotyping of HLA class I loci was performed for 850 patients who seroconverted and had known dates of HIV-1 infection. Survival analyses with respect to the rate of progression to AIDS were performed to identify the effects of closely related HLA-B*35 subtypes with different peptide-binding specificities. RESULTS: HLA-B*35 subtypes were divided into two groups according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but can bind several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-PY alleles by only one amino acid residue. CONCLUSIONS: This analysis shows that, in patients with HIV-1 infection, a single amino acid change in HLA molecules has a substantial effect on the rate of progression to AIDS. The different consequences of HLA-B*35-PY and HLA-B*35-Px in terms of disease progression highlight the importance of the epitope specificities of closely related class I molecules in the immune defense against HIV-1.",0
2407,11391531,Induction of Mdr1b expression by tumor necrosis factor-alpha in rat liver cells is independent of p53 but requires NF-kappaB signaling,"The multidrug resistance protein Mdr1b in rats is up-regulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up-regulation of Mdr1b in these models is TNF-alpha-dependent. The mechanism of Mdr1b activation by TNF-alpha is unknown as TNF-alpha can signal through various pathways, including NF-kappaB and p53, transcription factors for which binding sites in the Mdr1b promoter have been identified. We aimed to elucidate the mechanism of up-regulation of Mdr1b by TNF-alpha. We selectively used constructs expressing dominant negative Fas-associated death domain protein (FADD), TNF receptor associated factor-2 (TRAF2) or IkappaB to inhibit pathways downstream of the TNF receptor. Further, the proteasome inhibitor MG-132 was used, which prevents the breakdown of IkappaB. We show a critical role for NF-kappaB in activation of Mdr1b gene expression both in primary rat hepatocytes and in rat hepatoma H-4-II-E cells. Because p53 is up-regulated by TNF-alpha in an NF-kappaB-dependent manner and the Mdr1b promoter contains a p53 binding site, we used liver cells expressing a dominant negative p53 to show that TNF-alpha up-regulation of Mdr1b is independent of functional p53. Using transient transfection assays, we show that Mdr1b up-regulation correlates with activation of the promoter. Mutation of the NF-kappaB site in the Mdr1b promoter prevents its induction by TNF-alpha. In conclusion our results show that activation of the rat Mdr1b gene by TNF-alpha is a result of NF-kappaB signaling and independent of p53.",0
2408,11391538,Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: therapeutic implications,"Previously we have shown that the imino sugar inhibitor of N-linked glycan processing, N-nonyl-deoxynojirimycin (N-nonyl-DNJ), had antiviral activity in the woodchuck model of chronic hepatitis B virus (HBV) infection. In studying the mechanism of action of this compound, it was discovered that imino sugars could inhibit HBV secretion without inhibiting N-linked glycoprocessing. Although N-nonyl-DNJ is an inhibitor of the endoplasmic reticulum (ER) glucosidase, here it is shown that N-nonyl-DNJ retained antiviral activity at concentrations that had no significant impact on ER glucosidase function. Taken together, these results suggested that N-nonyl-DNJ possessed an antiviral activity attributable to a function other than an impact on glycoprocessing. This hypothesis was confirmed by experiments showing that N-nonyl-deoxygalactojirimycin (N-nonyl-DGJ), an alkyl derivative of galactose with no impact on glycoprocessing, retains anti-HBV activity. The data suggest that N-nonyl-DGJ exerts its antiviral action at a point before viral envelopment and may prevent the proper encapsidation of the HBV pregenomic RNA.",0
2409,11419425,"Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization","BACKGROUND: In the setting of percutaneous coronary revascularization, agents in the class known as platelet glycoprotein IIb/IIIa inhibitors have significantly reduced the incidence of death or nonfatal myocardial infarction at 30 days. We assessed whether there are differences in safety or efficacy between two such inhibitors, tirofiban and abciximab. METHODS: Using a double-blind, double-dummy design at 149 hospitals in 18 countries, we randomly assigned patients to receive either tirofiban or abciximab before undergoing percutaneous coronary revascularization with the intent to perform stenting. The primary end point was a composite of death, nonfatal myocardial infarction, or urgent target-vessel revascularization at 30 days. The trial was designed and statistically powered to demonstrate the noninferiority of tirofiban as compared with abciximab. RESULTS: The primary end point occurred more frequently among the 2398 patients in the tirofiban group than among the 2411 patients in the abciximab group (7.6 percent vs. 6.0 percent; hazard ratio, 1.26; one-sided 95 percent confidence interval of 1.51, demonstrating lack of equivalence, and two-sided 95 percent confidence interval of 1.01 to 1.57, demonstrating the superiority of abciximab over tirofiban; P=0.038). The magnitude and the direction of the effect were similar for each component of the composite end point (hazard ratio for death, 1.21; hazard ratio for myocardial infarction, 1.27; and hazard ratio for urgent target-vessel revascularization, 1.26), and the difference in the incidence of myocardial infarction between the tirofiban group and the abciximab group was significant (6.9 percent and 5.4 percent, respectively; P=0.04). The relative benefit of abciximab was consistent regardless of age, sex, the presence or absence of diabetes, or the presence or absence of pretreatment with clopidogrel. There were no significant differences in the rates of major bleeding complications or transfusions, but tirofiban was associated with a lower rate of minor bleeding episodes and thrombocytopenia. CONCLUSIONS: Although the trial was intended to assess the noninferiority of tirofiban as compared with abciximab, the findings demonstrated that tirofiban offered less protection from major ischemic events than did abciximab.",0
2410,11419427,"Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations","BACKGROUND: Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance, predominantly in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer. METHODS: Mutation-specific predictive genetic testing was performed by polymerase-chain-reaction amplification, followed by restriction-enzyme digestion and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopical analysis. RESULTS: Superficial infiltrates of malignant signet-ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were present in 65 of the 140 tissue blocks analyzed, representing in aggregate less than 2 percent of the gastric mucosa. CONCLUSIONS: We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.",0
2411,11431727,Reduced mitochondrial adenosine triphosphate synthesis in skeletal muscle in patients with Child-Pugh class B and C cirrhosis,"Patients with cirrhosis of the liver often complain of tiredness and a lack of strength at physical exercise. Other investigators have found that muscle strength, work capacity, and maximal oxygen consumption are reduced in cirrhosis. We hypothesized that mitochondrial maximal rate of ATP synthesis in skeletal muscle may be impaired in these patients. This was tested with (31)P nuclear magnetic resonance spectroscopy in anterior tibial muscle of cirrhotic patients and healthy controls at rest, during exercise, and subsequent recovery. In patients with Child-Pugh class B and C cirrhosis resting PCr/P(i) ratio (8.3 +/- 1.0; n = 7) was lower than in patients with Child-Pugh class A cirrhosis (12.1 +/- 2.1; n = 7) and controls (11. 7 +/- 1.1; n = 6; P =.03), while the resting P(i)/gammaATP ratio was higher in Child-Pugh class B and C patients (0.43, 0.30, and 0.27, respectively; P =.03). Maximal rate of mitochondrial adenosine triphosphate (ATP) synthesis (V(max)) as calculated from the initial rate of phosphocreatine (PCr) recovery after work was lower in Child-Pugh class B and C cirrhosis (0.189 mmol/L/s +/- 0.034) than in both Child-Pugh class A patients (0.402 mmol/L/s +/- 0.103) and controls (0.425 mmol/L/s +/- 0.064; P =.01). V(max) was significantly correlated to intracellular free [Mg(2+)] obtained from the (31)P nuclear magnetic resonance (NMR) spectra (P =.003). Insufficient oxygen delivery did not seem a likely cause of reduced ATP synthesis in the patients. These findings suggest either a decreased number of mitochondria in skeletal muscle of the cirrhotic patient in Child-Pugh class B and C or a defective mitochondrial function that could be related to low intracellular free [Mg(2+)].",0
2412,11450677,Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection,"BACKGROUND: Tissue remodeling depends on mesenchymal cells (fibroblasts and myofibroblasts) and is a prominent feature of chronic renal-transplant rejection. It is not known whether the mesenchymal cells that participate in remodeling originate locally or from circulating precursor cells. METHODS: We obtained biopsy specimens of renal allografts from six male recipients of an allograft from a female donor, four female recipients of an allograft from a male donor, two male recipients of an allograft from a male donor, and two female recipients of an allograft from a female donor. All the allografts were undergoing chronic rejection. All but two specimens were obtained within six months after transplantation. We used immunohistochemical methods to identify mesenchymal cells with smooth-muscle alpha-actin and in situ hybridization to identify mesenchymal cells with Y-chromosome DNA. RESULTS: No Y-chromosome bodies were identified in the case of the two renal-allograft specimens in which both the donor and the recipient were female. In the case of the two renal-allograft specimens in which both the donor and the recipient were male, approximately 40 percent of mesenchymal cells contained a Y-chromosome body. In the case of the six specimens in which the donor was female and the recipient was male, a mean (+/-SD) of 34+/-16 percent of mesenchymal cells in the neointima, 38+/-12 percent of such cells in the adventitia, and 30+/-7 percent of such cells in the interstitium contained the Y-chromosomal marker, indicating that they originated from the recipient rather than the donor. In the case of the four renal-allograft specimens in which the donor was male and the recipient was female, the respective values were 24+/-15 percent, 33+/-9 percent, and 23+/-8 percent, indicating a persistent population of donor mesenchymal cells. CONCLUSIONS: The presence of mesenchymal cells of host origin in the vascular and interstitial compartments of renal allografts undergoing chronic rejection provides evidence that a circulating mesenchymal precursor cell has the potential to migrate to areas of inflammation.",0
2413,11474660,"Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation","BACKGROUND: Multiparity and the use of oral contraceptives reduce the risk of ovarian cancer, but their effects on this risk in women with a BRCA1 or BRCA2 mutation are unclear. METHODS: We conducted a population-based case-control study of ovarian cancer among Jewish women in Israel. Women were tested for the two founder mutations in BRCA1 and the one founder mutation in BRCA2 that are known to be common among Jews. We estimated the effects of parity and oral-contraceptive use on the risk of ovarian cancer in carriers and noncarriers in separate analyses that included all control women, who did not have ovarian cancer. RESULTS: Of 751 controls who underwent mutation analysis, 13 (1.7 percent) had a BRCA1 or BRCA2 mutation, whereas 244 of 840 women with ovarian cancer (29.0 percent) had a BRCA1 or BRCA2 mutation. Overall, each additional birth and each additional year of use of oral contraceptives were found to lower the risk of ovarian cancer, as expected. Additional births were protective in separate analyses of carriers and noncarriers, but oral-contraceptive use appeared to reduce the risk only in noncarriers; among carriers, the reduction in the odds of ovarian cancer was 12 percent per birth (95 percent confidence interval, 2.3 to 21 percent) and 0.2 percent per year of oral-contraceptive use (-4.9 to 5.0 percent). CONCLUSIONS: The risk of ovarian cancer among carriers of a BRCA1 or BRCA2 mutation decreases with each birth but not with increased duration of use of oral contraceptives. These data suggest that it is premature to use oral contraceptives for the chemoprevention of ovarian cancer in carriers of such mutations.",0
2414,11481615,Hydrogen peroxide mediates vascular cell adhesion molecule-1 expression from interleukin-18-activated hepatic sinusoidal endothelium: implications for circulating cancer cell arrest in the murine liver,"The mechanism of intrasinusoidal arrest of circulating cancer cells, which is a critical step in liver metastasis, appears to be facilitated by tumor-derived proinflammatory factors that increase sinusoidal cell adhesion receptors for cancer cells. However, how this prometastatic microenvironment is up-regulated remains unknown. Using intrasplenically injected B16 melanoma (B16M) cells, we show that the expression of vascular cell adhesion molecule-1 (VCAM-1) significantly increased in hepatic sinusoidal endothelium (HSE) cells over physiologic baseline within the first 24 hours of metastatic cancer cell infiltration in the liver. This correlated with increased in vitro adhesion of B16M cells to HSE cells isolated from B16M cell-injected mice. In vivo VCAM-1 blockade with specific antibodies before B16M cell injection decreased sinusoidal retention of luciferase-transfected B16M cells by 85%, and metastasis development by 75%, indicating that VCAM-1 expression on tumor-activated HSE cells had a prometastatic contribution. Because VCAM-1 expression is oxidative stress-inducible, recombinant catalase was in vivo administered, resulting in a complete abrogation of both VCAM-1 expression and B16M cell adhesion increases in HSE cells isolated from B16M cell-injected mice. Catalase also abrogated the proadhesive response of HSE cells to B16M-conditioned medium (B16M-CM) in vitro, although this did not affect the concomitant release of major proinflammatory cytokines by HSE cells. HSE cells treated with B16M-CM released interleukin (IL)-18 via tumor necrosis factor-alpha (TNF-alpha)-dependent IL-1beta in vitro. In turn, H(2)O(2) production from B16M-CM-treated HSE cells was regulated by IL-18. Thus, liver-infiltrating B16M cells activated their adhesion to HSE through a sequential process involving TNF-alpha-dependent IL-1beta, which induced IL-18 to up-regulate VCAM-1 via H(2)O(2). The pivotal position of H(2)O(2) was further supported by the fact that incubation of HSE cells with nontoxic concentrations of H(2)O(2) directly enhanced VCAM-1-dependent B16M cell adhesion in vitro without proinflammatory cytokine mediation, which emphasizes the key role of oxidative stress in the pathogenesis of liver inflammation and metastasis.",0
2415,11481622,Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine,"Present hepatitis B vaccines use multidose prolonged regimens, which even healthcare workers at risk do not always complete. Moreover, when vaccination is completed there remain some who fail to achieve adequate protection. The protection of adults at risk could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Vaccine-naive adults were randomized to vaccination with either Engerix-B (SmithKline Biologicals, Rixensart, Belgium) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare; Medeva Pharma Plc, Speke, UK). The primary efficacy parameter was the degree of seroprotection 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 304 adults entered the study. Of these, 16 failed to complete the study (9 on Hepacare and 7 on Engerix-B). With the Engerix-B standard (0, 1, 6) regimen, 88% of subjects were protected by month 7, whereas with the triple antigen vaccine a 2-dose regimen (0, 1) provided equivalent protection (91%) within 6 months and a 3-dose (0, 1, 6) regimen was significantly superior (98% seroprotected by 7 months after starting vaccination P <.001). With adults at risk for a suboptimal response (i.e., older adults, the obese, men, and smokers) the triple antigen vaccine produced a greater degree of protection. The vaccines had similar safety profiles. Both vaccines were well tolerated. In healthy normal adults, a triple antigen hepatitis B vaccine containing S and pre-S antigens produced an enhanced immunologic response and was as effective as a 2- and 3-dose regimen.",0
2416,11481625,"A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C","This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared peginterferon alfa-2b (PegIntron) to interferon alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) interferon alfa-2b dose (3 MIU) or the once-weekly (QW) peginterferon alfa-2b (0.5, 1.0, or 1.5 microg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa-2b doses significantly (P < or =.042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with interferon alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 microg/kg peginterferon alfa-2b because of a higher relapse rate among patients treated with 1.5 microg/kg peginterferon alfa-2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa-2b doses decreased liver inflammation to a greater extent than did interferon alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa-2b maintained (0.5 microg/kg) or surpassed (1.0, 1.5 microg/kg) the clinical efficacy of interferon alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 microg/kg peginterferon alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation.",0
2417,11481628,Hepatitis C virus-like particles induce virus-specific humoral and cellular immune responses in mice,"We have recently described the production of hepatitis C virus-like particles (HCV-LPs) in insect cells that resemble the putative virions. Here we evaluate the humoral and cellular immunogenicity of the virus-like particles with or without viral p7 protein, a small viral polypeptide that resides between the structural and nonstructural regions of the HCV polyprotein and whose function has not been defined. Immunized BALB/c mice developed high titers of anti-E2 antibodies and virus-specific cellular immune responses including cytotoxic T lymphocytes and T helper responses with gamma interferon production. The virus-like particles without p7 generated a higher cellular immune response with a more T(H)1 profile than the particles with p7. Immunization of heat-denatured particles resulted in substantially lower humoral and cellular responses, suggesting that the immunogenicity is strongly dependent on particle formation. Administration of CpG oligonucleotide or cationic lipid 3beta-[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol), two potent adjuvants, did not significantly enhance the immunogenicity of HCV-LPs. Our results indicate that HCV-LPs can induce humoral and cellular immune responses and offer a promising approach to vaccine development.",0
2418,11484689,Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia,"BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.",0
2419,11496851,Dysfunction of endothelial protein C activation in severe meningococcal sepsis,"BACKGROUND: Impairment of the protein C anticoagulation pathway is critical to the thrombosis associated with sepsis and to the development of purpura fulminans in meningococcemia. We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions. METHODS: We assessed the integrity of the endothelium and the expression of thrombomodulin and the endothelial protein C receptor in biopsy specimens of purpuric lesions from 21 children with meningococcal sepsis (median age, 41 months), as compared with control skin-biopsy specimens. RESULTS: The expression of endothelial thrombomodulin and of the endothelial protein C receptor was lower in the patients with meningococcal sepsis than in the controls, both in vessels with thrombosis and in vessels without thrombosis. On electron microscopical examination, the endothelial cells were generally intact in both thrombosed and nonthrombosed vessels. Plasma thrombomodulin levels in the children with meningococcal sepsis (median, 6.4 ng per liter) were higher than those in the controls (median, 3.6 ng per liter; P=0.002). Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls. In two patients treated with unactivated protein C concentrate, activated protein C was undetectable at the time of admission, and plasma levels remained low. CONCLUSIONS: In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin-endothelial protein C receptor pathway.",0
2420,11504735,The Hemophilus influenzae Hap autotransporter is a chymotrypsin clan serine protease and undergoes autoproteolysis via an intermolecular mechanism,"The Hemophilus influenzae Hap adhesin is an autotransporter protein that undergoes an autoproteolytic cleavage event resulting in extracellular release of the adhesin domain (Hap(s)) from the membrane-associated translocator domain (Hap(beta)). Hap autoproteolysis is mediated by Ser(243) and occurs at LN1036-7 and to a lesser extent at more COOH-terminal alternate sites. In the present study, we sought to further define the mechanism of Hap autoproteolysis. Site-directed mutagenesis of residues His(98) and Asp(140) identified a catalytic triad conserved among a subfamily of autotransporters and reminiscent of the SA (chymotrypsin) clan of serine proteases. Amino-terminal amino acid sequencing of histidine-tagged Hap(beta) species and site-directed mutagenesis established that autoproteolysis occurs at LT1046-7, FA1077-8, and FS1067-8, revealing a consensus target sequence for cleavage that consists of ((Q/R)(A/S)X(L/F)) at the P4 through P1 positions. Examination of a recombinant strain co-expressing a Hap derivative lacking all cleavage sites (HapDelta1036-99) and a Hap derivative lacking proteolytic activity (HapS243A) demonstrated that autoproteolysis occurs by an intermolecular mechanism. Kinetic analysis of Hap autoproteolysis in bacteria expressing Hap under control of an inducible promoter demonstrated that autoproteolysis increases as the density of Hap precursor in the outer membrane increases, confirming intermolecular cleavage and suggesting a novel mechanism for regulation of bacterial adherence and microcolony formation. ",0
2421,11504855,Trichome distribution in Arabidopsis thaliana and its close relative Arabidopsis lyrata: molecular analysis of the candidate gene GLABROUS1,"GLABROUS1 (GL1) belongs to the large family of MYB transcription factors and is known to play a central role in trichome initiation. We studied trichome distribution and the molecular variation of GL1 in 28 A. thaliana accessions. Trichome density on rosette leaves was highly variable among those accessions. On the molecular level, we detected substantial sequence variation in a 3-kb fragment which included the complete coding region of the GL1 locus (pi = 0.01). Phylogenetic analysis of GL1 indicates the presence of two diverged clades among 28 accessions. Using ANOVA, we show that the phenotypic variation in trichome density cannot be explained by the sequence divergence between the two phylogenetic lineages. Sequence analysis of wild-type Arabidopsis thaliana and Arabidopsis lyrata accessions indicates that all amino acid substitutions are located outside of the conserved helix-turn-helix DNA-binding domains R2 and R3. Using plants of A. thaliana and A. lyrata with either naturally occurring or ethyl methane sulfonate--induced glabrous phenotypes, we demonstrate that the last 14 C-terminal amino acids of the GL1 gene have no major impact on the initiation of trichomes. ",0
2422,11505136,The selective guanylate cyclase inhibitor ODQ reduces multiple organ injury in rodent models of Gram-positive and Gram-negative shock,"An enhanced formation of endogenous nitric oxide contributes to the circulatory failure caused by endotoxin (lipopolysaccharide). Many of the biological actions of nitric oxide are mediated by the guanylate cyclase/cyclic guanosine 3prime;,5'-monophosphate system. We recently discovered that two cell wall components, namely lipoteichoic acid and peptidoglycan of the Gram-positive bacterium Staphylococcus aureus, synergize to cause shock and multiple organ dysfunction syndrome in the rat. Here we investigate the effects of a selective guanylate cyclase inhibitor, 1H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ), on the circulatory failure and multiple organ dysfunction syndrome (kidney, liver, lung) caused by a) coadministration of lipoteichoic acid and peptidoglycan (Gram-positive shock) or b) lipopolysaccharide (Gram-negative shock) in the anesthetized rat. Furthermore, we investigated whether ODQ scavenges superoxide anions and/or hydroxyl radicals. The in vivo portion of the study was a prospective, randomized, controlled animal study. The in vitro portion included a) cultured ventricular myoblasts of the rat, H9c2(2-1) cells, and b) a cell free superoxide anion assay system. University-based research laboratory. Seventy-five anesthetized, male Wistar rats were used for the in vivo study. For the in vivo portion of the study, after surgical preparation, anesthetized rats were observed for 6 hrs. All rats were pretreated and received an intravenous infusion of saline (1.5 mL.kg-1.hr-1), which was maintained throughout the experiment. The rats were assigned to nine groups. Group 1 contained control rats (sham) subjected to 2 mL/kg saline intraperitoneally, 2 hrs before the experiment (n = 7). Group 2 contained control rats (sham) that received 2 mg/kg ODQ intraperitoneally, 2 hrs before the experiment (n = 9). Group 3 contained control rats (sham) that received 2 mL/kg dimethyl sulfoxide, 30% v/v in saline intraperitoneally, as a vehicle for ODQ, 2 hrs before the experiment (n = 6). In group 4 rats, Gram-positive shock was induced by coadministration of lipoteichoic acid (3 mg/kg intravenously) and peptidoglycan (10 mg/kg intravenously) (n = 10). In group 5, rats were pretreated with ODQ (as described previously) before lipoteichoic acid/peptidoglycan (n = 9). In group 6, rats were pretreated with dimethyl sulfoxide (as described previously) before lipoteichoic acid/peptidoglycan (n = 7). In group 7, Gram-negative shock was induced by lipopolysaccharide (6 mg/kg intravenously) (n = 11). In group 8, rats were pretreated with ODQ (as described previously) before lipopolysaccharide (n = 8). In group 9, rats were pretreated with dimethyl sulfoxide (as described previously) before lipopolysaccharide (n = 8). For the in vitro portion of the study, rat cells were preincubated with vehicle (saline and/or dimethyl sulfoxide) and ODQ (0.1 microM to 1 mM) for 2 hrs. The cells then were exposed to H2O2 (1 mM) for 4 hrs at 37 degrees C, after which time cell viability was determined by measuring the mitochondrial-dependent reduction of 3-(4,5-di-methyliazol-2-yl)-2,5-diphenyltetrazolium bromide to blue formazan. Next, an aqueous solution was incubated with ODQ (as described previously), and superoxide anions were produced by using a hypoxanthine/xanthine-oxidase assay. The chemiluminescence assay was used to evaluate any potential antioxidative effects of ODQ. In vivo, administration of lipoteichoic acid/peptidoglycan or lipopolysaccharide resulted within 6 hrs in hypotension, acute renal dysfunction, hepatocellular injury, and lung injury. Pretreatment of rats with ODQ attenuated the renal dysfunction, lung injury, and hepatocellular injury caused by lipoteichoic acid/peptidoglycan or lipopolysaccharide. In vitro, administration of H2O2 (for 4 hrs) to rat cardiomyoblasts decreased mitochondrial respiration attributable to generation of hydroxyl radicals. Pretreatment of cells with ODQ did not abolish this cell injury. In addition, ODQ did not scavenge superoxide anions. These results imply that ODQ, an inhibitor of guanylate cyclase, reduces the multiple organ injury and dysfunction caused by wall fragments of Gram-positive or Gram-negative bacteria in the anesthetized rat. The observed protective effects of ODQ are not attributable to the ability of ODQ to reduce the formation or the effects of superoxide anions or hydroxyl radicals. ",0
2423,11505558,Controlled release from an electrorheological fluid dosage form: experimental results for a prototype system,"A new controlled-release technology that is based on electrorheological fluids (ERF) is described, and a model system is investigated. Humidified starch (duration of humidification is 30-35 minutes) was used as a filler material (approximately 20% w/w) in olive oil to make the ER system, and benzocaine (BZN) was used as the model drug. The average particle size of starch in the olive oil was approximately 200 nm. 1N HCl was used as the receiver medium and BZN was assayed by UV spectroscopy at 226 nm. A series of studies was done at five temperatures (25 degrees, 30 degrees, 35 degrees, 40 degrees, and 45 degrees C) and two external electric fields (E-fields) that were generated by applying potential drops across the diffusion apparatus of 0 V and 290 V. Control studies of BZN release from olive oil without filler showed little or no increase in release rates resulting from application of E-fields. In addition, while reversing the polarity for BZN in olive oil caused differences in release rates, these differences were too small to explain the results obtained for the ER systems. It was found that release of BZN increased significantly with the application of the electric field (approximately 53% increase at 25 degrees C). A plot of the log of the release rate vs 1/T was linear for the 0 V data but deviated from linearity for the 290 V data. The increase in release rates due to the E-field became smaller as the temperature was increased. The results are consistent with (but are not sufficient to prove) the hypothesis that the increased release rate is due to a small amount of ordering of the cornstarch filler particles in response to the applied E-field, which results in a reduction in the tortuosity of the system. ",0
2424,11506344,Genital injury: is it significant? A review of the literature,"The purpose of this review was to critically evaluate the available literature on genital injury in order to facilitate an understanding of its significance in relation to sexual offence trials. Wide variation exists in research objectives, study populations and methodology, hindering interpretation considerably. The most valuable research in this field identifies the range of normal genital findings and those associated with consensual sexual intercourse, to enable interpretation of genital findings in sexual assault victims. However, there are, unfortunately, few studies of this nature. Difficulties arise when examining doctors are not experienced in the genital examination of those other than sexual assault victims, limiting their ability to draw conclusions about genital injury if it is detected. If the methods of genital examination employed are not the same as those used to examine a wide range of non-sexual assault victims, comparison and thus valuable interpretation is further limited. This review of the literature finds that the most appropriate genital examinations and indeed the most legally valuable as far as interpretation is concerned, are done macroscopically by doctors with considerable experience in the examination of normal, diseased and traumatized genitalia, and a sound knowledge of the principles of injury interpretation. A deficiency exists in the literature in relation to macroscopic genital examination findings in consensually sexually active women who have been examined by forensically trained doctors. This deficiency must be addressed before the medicolegal significance of genital injury relating to sexual assault can be accurately interpreted, and before any decision is made to incorporate colposcopy or staining techniques into the routine assessment of sexual assault victims. ",0
2425,11506414,Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease,"The fluorogenic enzyme assay for palmitoyl-protein thioesterase (PPT) has greatly facilitated the diagnosis of infantile neuronal ceroid lipofuscinosis (Santavuori-Haltia disease) and the search for possible new variants with atypical clinical presentation. Here, we present the first cases of adult neuronal ceroid lipofuscinosis with onset in the fourth decade of life due to a profound deficiency of PPT. The causative mutations in the CLN1 gene were the known, deleterious mutation R151X and the novel missense mutation G108R. Patients presented at onset (31 and 38 years), with psychiatric symptoms only. At present (ages 56 and 54 years), visual, verbal, and cognitive losses have progressed and both patients have cerebellar ataxia and cannot walk without support. ",0
2426,11506505,Differences between human breast cell lines in susceptibility towards growth inhibition by genistein,"Genistein is thought to contribute to the putative breast cancer preventive activity of soya. The mechanisms by which it arrests the growth of breast cells are incompletely understood. In order to explore generic features of the modulation of human breast cell growth by genistein, its effects on cell lines MCF-7, ZR-75.1, T47-D, MDA-MB 468, MDA-MB 231 and HBL 100 were compared. Genistein at 1 microM stimulated growth only in MCF-7 cells. At 10 microM it arrested the growth of all 6 cell types, however that of T47-D and HBL 100 cells only in medium with reduced (2%) fetal calf serum. Genistein induced apoptosis in only MDA-MB 468 cells. It arrested cells in the G2 stage of the cell cycle in all cell lines except ZR-75.1. Cells differed in their susceptibility towards inhibition by genistein of phorbol ester-induced proto-oncogene c-fos levels, transcription factor activator protein-1 (AP-1) activity and extracellular signal-regulated kinase (ERK) activity. Genistein augmented anisomycin-induced levels of proto-oncogene c-jun in ZR 75.1 and MCF-7 cells. The results suggest that induction of apoptosis, G2 cell cycle arrest and inhibition of c-fos expression, AP-1 transactivation and ERK phosphorylation may contribute to the growth-inhibitory effect of genistein in some breast cell types, but none of these effects of genistein constitutes a generic mode of growth-arresting action. ",0
2427,11506749,"Efficacy and safety of orally/sublingually, intranasally, and intraperitoneally administered recombinant murine interferon in the treatment of murine encephalomyocarditis virus","Interferons (IFN) have been shown to be effective in protecting animals against lethal viral infections when administered systemically in relatively high doses. Intraperitoneal (i.p.) injection of mice with encephalomyocarditis virus (EMCV) gives rise to a rapidly progressive fatal disease characterized by central nervous system involvement and encephalitis. IFN-alpha has been shown to be effective in protecting mice against lethal EMCV infection when given via parenteral and oral/sublingual routes. The current study was designed to explore the ability of orally/sublingually and intranasally (i.n.) administered IFN-alpha to treat mice infected with EMCV in support of a planned clinical trial to evaluate efficacy of oral IFN-alpha in human viral infections. The primary objective of the study was to determine the efficacy of recombinant murine IFN-alpha (rMuIFN-alpha) in the treatment of mice infected with 100 LD(50) EMCV following oral, i.n., and i.p. administration at doses of 20,000 and 100,000 IU. The results of the current experiment did not indicate protection from infection with EMCV in mice that received IFN by the i.n. or oral/sublingual routes. The negative controls, infection of mice with 100 LD(50) of EMCV followed by treatment with excipient via all three routes, resulted in death of nearly all mice, as expected. The positive control, treatment of EMCV-infected (100 LD(50)) mice with rMuIFN-alpha via the i.p. route, was successful in protecting a significant number of mice from death compared with matched controls. This study points out the need to determine the optimum conditions for administration of oral/sublingual or i.n. IFN to insure maximum efficacy against viral infections. ",0
2428,11507045,Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo,"Hypoxia and acidosis are hallmarks of tumors as well as critical determinants of response to treatments. They can upregulate vascular endothelial growth factor (VEGF) in vitro. However, the relationship between tissue oxygen partial pressure (pO(2))/pH and VEGF transcription in vivo is not known. Thus, we developed a novel in vivo microscopy technique to simultaneously measure VEGF promoter activity, pO(2), and pH. To monitor VEGF expression in vivo, we engineered human glioma cells that express green fluorescent protein (GFP) under the control of the VEGF promoter. These cells were implanted into the cranial windows in severe combined immunodeficient mice, and VEGF promoter activity was assessed by GFP imaging. Tissue pO(2) and pH were determined by phosphorescence quenching microscopy and ratio imaging microscopy, respectively. These techniques have allowed us to show, for the first time, that VEGF transcription in brain tumors is independently regulated by the tissue pO(2) and pH. One week after tumor implantation, significant angiogenesis was observed, with increased GFP fluorescence throughout the tumor. Under hypoxic or neutral pH conditions, VEGF-promoter activity increased, with a decrease in pO(2) and independent of pH. Under low pH or oxygenated conditions, VEGF-promoter activity increased, with a decrease in pH and independent of pO(2). In agreement with the in vivo findings, both hypoxia and acidic pH induced VEGF expression in these cells in vitro and showed no additive effect for combined hypoxia and low pH. These results suggest that VEGF transcription in brain tumors is regulated by both tissue pO(2) and pH via distinct pathways. ",0
2429,11507291,Tl-201 chloride and Tc-99m MIBI accumulation in lung adenocarcinoma in patients with and without distant metastases,"The relation between Tl-201 chloride accumulation by the tumor and its distant metastatic potential were evaluated in patients with lung adenocarcinoma and compared with the same parameters achieved using Tc-99m MIBI. Fifty-six patients with primary lung adenocarcinoma were examined before therapy was begun. They were classified according to the radiologic findings and pathologic diagnosis into two groups: distant metastases and no distant metastases. All patients underwent dual-isotope imaging with Tl-201 chloride and Tc-99m MIBI. Regions of interest were placed over the tumor uptake (T) and contralateral normal lung tissue (N) areas on one transverse view with clearly defined lesions, and the T:N ratio and retention index were calculated. The early and delayed T:N ratios and retention index using Tl-201 chloride SPECT in the distant-metastases group were significantly greater (P < 0.001 to P < 0.05) than were those in the no-distant-metastases group. There was no significant correlation between the T:N ratio and retention index and distant metastatic potential using Tc-99m MIBI SPECT. Tl-201 chloride SPECT may be more effective than Tc-99m MIBI SPECT for evaluating the distant metastatic potential of primary lung adenocarcinoma. ",0
2430,11507838,Corrosion of Cu-xZn alloys in slightly alkaline chloride solutions studied by stripping voltammetry and microanalysis,"The mechanism of corrosion of Cu-xZn alloys (x = 10-40 wt %) in slightly alkaline chloride solutions was investigated by analysing solid reaction products by energy dispersive X-ray analysis (EDS) and dissolved reaction products by differential anodic pulse stripping (DAPS) voltammetry. The corrosion process was studied under open circuit and under potentiostatic conditions at selected potentials. Pure metals were studied comparatively so that an interacting effect of particular metal components in the alloy could be determined. All four Cu-xZn alloys show an improved behaviour compared to pure metals. Under open-circuit condition both components dissolve simultaneously in the solution. With increasing immersion time the preferential, dissolution of zinc in the solution becomes pronounced. It is the highest for Cu-10Zn and the lowest for Cu-30Zn alloy. Under potentiostatic control the dissolution mechanism depends on the electrode potential and changes from exclusive dissolution of zinc to simultaneous dissolution of both components with preferential dissolution of zinc. The latter decreases, as the electrode potential becomes more positive. ",0
2431,11508434,Alternative messenger RNA splicing and enzyme forms of cathepsin B in human osteoarthritic cartilage and cultured chondrocytes,"In previous studies, we suggested that cathepsin B, which is present at sites of cartilage remodeling in osteoarthritis (OA), may act as an antagonist of cartilage repair, an enhancer of the action of metalloproteinases, and a mediator of cartilage neovascularization and mineralization. Alternative splicing of cathepsin B pre-messenger RNA (pre-mRNA) and/or mRNA overexpression is a plausible regulatory mechanism. In the present study, we investigated the abundance of cathepsin B transcripts and the properties of cathepsin B protein in normal and OA cartilage, osteophytes, and cultured chondrocytes. Cathepsin B mRNA splice variants containing the full-length transcript (CB) and the variants lacking either exon 2 (CB[-2]) or lacking exons 2 and 3 (CB[-2,3]) were measured by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot assays and were localized by in situ RT-PCR. Cathepsin B protein was analyzed by electrophoretic, Western blot, and chromatographic methods. The relative content of CB, CB(-2), and CB(-2,3) varied considerably in OA cartilage and osteophytes, with less variation in normal cartilage. The mean cathepsin B mRNA level was significantly higher in OA cartilage and osteophytes than in normal cartilage. Normal cultured chondrocytes attained cathepsin B mRNA levels similar to those in OA cartilage. Enzyme overexpression resulted in the secretion of procathepsin B, followed by activation to the proteolytically active form. The high levels of CB and CB(-2) are consistent with an overproduction of secreted procathepsin B in OA. Up-regulation of chondrocyte cathepsin B, which takes place at both the transcriptional and the translational level, suggests a leading role of the enzyme in the progression of OA. ",0
2432,11508674,Hydrogen sulfide and colonic epithelial metabolism: implications for ulcerative colitis,"Hydrogen sulfide (HS-) impairs the oxidation of butyrate in colonocytes and is found in excess in feces of patients with ulcerative colitis. The possible pathogenic role of HS- in ulcerative colitis was further investigated. To investigate the metabolic effect of free and bound fecal HS-, isolated rat colonocytes were incubated in the presence of butyrate without and with the addition of (1) HS- in water, (2) sterile filtrates of fecal homogenates supplemented and incubated with HS- and known sources of fecal HS- production, and (3) HS- incubated with fecal agents known to bind HS-. Oxidation rates were obtained by quantifying the production of CO2. Total and free HS-, as well as the fecal ability to bind HS-, were determined in health and ulcerative colitis. Compared to the production of CO2 by colonocytes incubated with 2 mmol/liter of butyrate, the further addition of 1.25 and 2.5 mmol/liter of HS- in water reduced the production of CO2 by 57.6+/-10.0 and 98.9+/-1.4%, respectively. However, when adding fecal filtrate of homogenate supplemented with HS- corresponding to 1.25 and 2.5 mmol/liter of HS- in water, the reduction of CO2 production was only 30.7+/-12.0 and 53.2+/-14.0%, respectively. Neither the fecal level of total or free HS- nor the remarkable fecal ability to bind HS- differed in health or quiescent and active ulcerative colitis. Bound HS- had no or little effect on CO2 production. Addition of fecal filtrate of nonsupplemented homogenate to colonocytes significantly reduced the oxidation of butyrate to CO2 about 25%, which could not be ascribed to fecal HS-. In conclusion, fecal HS- has little effect on butyrate oxidation in colonocytes and does not seem to play a pathogenic role for UC by impairing colonic epithelial metabolism. Other fecal agents seem to be more potent metabolic inhibitors than fecal HS-. The role of colonic contents in the pathogenesis of ulcerative colitis remains circumstantial. ",0
2433,11509132,Overexpression of p27(KIP1) induced by Bak gene leads to the arrest in G(1) phase of HCC-9204 cell line],"To explore whether p27(KIP1) plays an important role in prolonging cell cycle in G(1) phase and leading to apoptosis of HCC-9204 cells. A model of Bak-induced cell cycle arrest in G(1) phase and subsequent apoptosis was established. p27(KIP1) was obtained from the model and sequenced afterwards. A zinc inducible p27(KIP1) stable transfectant was constructed. The effects of inducible p27(KIP1) on cell growth and cell cycle arrest were examined in control pMD and pMD-KIP1 transfected HCC-9204 cells. Western blot was performed to evaluate the expression of p27(KIP1). The cell growth was reduced by 35% upon 48h of p27(KIP1) induction with zinc treatment as determined by trypan blue exclusion assay. p27(KIP1) caused cell cycle arrest at 24h after induction, with 40% increase in G(1) population. Bak may induce cell cycle arrest in G(1) phase through up-regulating expression of p27(KIP1). The inducible p27(KIP1)-expressing cells provide a model to assess p27(KIP1) function. ",0
2434,11509278,IL-8 concentration in coronary sinus blood during early coronary reperfusion after ischemic arrest,"Activation of the inflammatory response is an important factor contributing to complications of cardiopulmonary bypass. Increased level of proinflammatory cytokine - IL-8 has been reported during coronary artery bypass grafting (CABG) operations with the use of cardiopulmonary bypass. The aim of this study was to find out whether the heart is the main source of IL-8 during early coronary reperfusion. IL-8 concentration in coronary sinus before clamping and 5, 10, and 15 min after declamping of the aorta as well as in radial artery blood before clamping and 10 min after declamping of the aorta, was assessed in 30 patients undergoing CABG surgery. We observed increase in IL-8 concentration in coronary sinus blood after declamping of the aorta, however no difference between coronary sinus and arterial blood concentration was noted. The median value of IL-8 concentration in coronary sinus blood was 1.85 pg/ml before ischemia and 15.4, 20.3, and 29.3 pg/ml in 5, 10 and 15 min after aortic declamping, respectively. Our additional finding was that there was a negative correlation between IL-8 level and hemoglobin saturation with oxygen in coronary sinus blood 10 min after coronary reperfusion. We conclude that the heart is not the main source of IL-8 in early coronary reperfusion, although coronary reperfusion induces its release. ",0
2435,11510132,Amelioration of NaCl stress in Pisum sativum Linn,"Activity of endogenous auxins and growth inhibitors, gibberellins and cytokinins was observed in the extracts of seedlings of Pisum sativum under NaCl stress. After 6 days of germination, when Pisum sativum seedlings were subjected to low concentration of NaCl (50 mM) or boron (10 ppm) increased the endogenous growth regulating substances. Higher concentration of NaCl (150 mM) decreased endogenous level of growth regulators, length of the root and shoot, and fresh and dry weights of seedlings, whereas boron increased the parameters except endogenous growth regulators. Mitotic index and some abnormalities were observed in the treated plants. SDS-PAGE banding pattern of Pisum sativum seedlings extracted in tris-glycine and tris-HCl showed that lower concentration of NaCl increased the number of protein bands, while the higher concentration decreased these protein bands. Combination of boron and NaCl (150 mM) caused an increase in total number of protein bands compared with the total number of bands recorded by using NaCl (150 mM) alone. ",0
2436,11510180,Differential diagnosis of infective endocarditis and fevers of unrelated genesis],"Case histories of 84 patients with fevers lasting from 2 weeks to 6 months and suspected infective endocarditis (IE) were analyzed. Infective endocarditis was diagnosed in 15 patients. From the viewpoint of IE diagnosis by the DUKE criteria, the major criteria possess the highest diagnostic value. Use of only minor DUKE criteria gave false-positive results in diagnosis of IE in feverish patients with angiitis, hemopoietic diseases, and malignant tumors with remote metastases. The diagnosis of IE should be based on the DUKE criteria, clinical picture, and data of laboratory tests (pericarditis, shift of the leukocytic formula to the left, increased level of circulating immune complexes, high erythrocyte sedimentation rate, etc.). ",0
2437,11510673,"Complaints of foodborne illness in San Francisco, California, 1998","""Foodborne diseases are an important public problem affecting millions of Americans each year and resulting in substantial morbidity and mortality. Many foodborne infections occur in outbreak settings. Outbreaks are often detected by complaints from the public to health authorities. This report reviews complaints received by the San Francisco Department of Public Health involving suspected foodborne illness in 1998. Although such foodborne complaints are commonly received by health officials, we provide the first review of population-based data describing such complaints. We use a broad definition of a foodborne disease outbreak. We judged a complaint to be a """"likely foodborne disease outbreak"""" if it involved more than one person and more than one family; no other common meals were shared recently by ill persons; diarrhea, vomiting, or both was reported; and the incubation period was more than one hour. In 1998, 326 complaints of foodborne illness, involving a total of 599 ill people, were received by the Communicable Disease Control Unit in San Francisco. The complaints involved from 1 to 36 ill persons, with 61% involving one ill person and 25% involving two ill persons. Of the 126 reports involving illness in more than one person, 77 (61%) were judged to be likely foodborne disease outbreaks. Three of these 77 outbreaks had been investigated prior to our review. This project confirms that more foodborne disease outbreaks occur than are reported to state and national outbreak surveillance systems. Our review of the San Francisco system highlights opportunities for gleaning valuable information from the foodborne disease complaint systems in place in most jurisdictions. """,0
2438,11511029,Isolation and morphological characterisation of UHMWPE wear debris generated in vitro,"Wear tests are generally carried out on materials used in prosthetic hip implants, in order to obtain a better understanding of the tribological processes involved and improve the quality control of joint prostheses, directed towards reducing the risk of implant failure of innovative prostheses. Ceramic femoral heads of mixed alumina-zirconia oxides as well as zirconia and alumina single oxide heads were tested against UHMWPE acetabular cups in a hip joint simulator. Polyethylene cups and ceramic femoral heads were mounted in a simulator apparatus moving according to a sinusoidal function, under load and in the presence of bovine calf serum as lubricant. Wear particles were isolated from the bovine calf serum collected during the wear tests. An easy to follow method was used to separate the wear particles from the lubricant. Chemical digestive methods were used to separate the wear particles from the lubricant and the isolated particles were studied using scanning electron microscopy. The morphologies of the polyethylene debris showed considerable differences, both in size and shape of the particles, as a function of the coupled head material. ",0
2439,11511090,Evaluation of glycated insulin in diabetic animals using immunocytochemistry and radioimmunoassay,"Glycated insulin was evaluated in plasma and biological tissues of diabetic animal models by immunocytochemistry (ICC) and a novel radioimmunoassay. Glycated insulin circulated at 0.10 +/- 0.04 ng/ml and 2.20 +/- 0.14 ng/ml in lean and diabetic obese (ob/ob) mice, corresponding to 12.5 and 9.8% total plasma insulin, respectively. The concentration of glycated insulin was elevated 22-fold in obese mice compared to controls (P < 0.001). In the pancreas, glycated insulin was 48 +/- 10 and 83 +/- 4 ng/g wt (P < 0.05) in lean and obese mice, respectively, representing approximately 2% total insulin in the diabetic pancreas (4.60 +/- 0.17 microg/g wt). ICC revealed fluorescent positively stained cells in pancreatic islets from hydrocortisone (HC)-treated diabetic rats. Fasting of HC-treated rats, resulted in 3-fold and 15-fold reductions in plasma glycated insulin (P < 0.01) and insulin (P < 0.001), respectively. Following a 30 min feeding period in these insulin resistant rats, plasma glucose, insulin, and glycated insulin increased (P < 0.001) rapidly with 1.4-, 1.6-, and 2.9-fold elevations, respectively. Injection of HC-treated rats with insulin (50 U/kg) resulted in a rapid 33% decrease of plasma glucose (P < 0.001) and a marked 4-fold increase in plasma insulin (P < 0.01), whereas glycated insulin concentrations remained unchanged. Since glycation of insulin impairs biological activity, physiologically regulated secretion of glycated insulin into the circulation in diabetic animal models suggests a role in the pathogenesis of diabetes. ",0
2440,11511930,A second case of somatic triple mosaicism in the CYBB gene causing chronic granulomatous disease,"The most common form of chronic granulomatous disease (CGD) is caused by mutations in the CYBB gene that is carried on the X-chromosome and give rise to the X-linked form of the disease. The product of this gene is the large subunit of flavocytochrome b558, gp91phox, the catalytic core of the superoxide-generating enzyme, NADPH oxidase. In the overwhelming majority of cases, mutations are family-specific and occur in the exonic regions of the gene or, less frequently, at the intron/exon borders. In addition, there are large, often multi-gene, deletions. Four mutations have also been found in the promoter regions. In contrast, very few intronic mutations have been reported. Here we describe an unusual intronic mutation that causes CGD. The mutation is the insertion of 12 bp in intron XI, accompanied by the deletion of exon 12. Remarkably, the grandmother of this patient is chimeric, carrying a normal allele, the patient's allele, and an allele with a 4-nucleotide insertion at a site adjacent to the patient's insertion, in combination with a 1.5-kb deletion within intron XI. The patient's mother carries a normal allele and the patient's allele. We propose that an initial mutational event during the grandmother's embryogenesis has undergone unsuccessful DNA repair and has resulted in two aberrant alleles, one of which has been inherited by the patient and his mother. Remarkably, in the only two kindreds that have been examined in detail where deletions originating within introns have led to CGD, both families have contained members with triple somatic mosaicism. ",0
2441,11511938,Detection of bacteraemia in critically ill patients using 16S rDNA polymerase chain reaction and DNA sequencing,"To confirm the sensitivity of the polymerase chain reaction (PCR) technique (versus blood cultures) and to gain a better understanding of the incidence of true- and false-positive results when using this technique. Observational study. Fourteen-bed, level 3 intensive care unit. Hundred twenty-six critically ill adult patients. Hundred ninety-seven blood culture and PCR samples taken as clinically indicated for suspected sepsis, according to routine ICU protocol. The PCR product (16SrDNA: 341F-1195R) was sequenced and compared with a database of known species (Genebank) to identify the bacterial nucleic acid. The PCR or blood culture result was classified as a true-positive if there was other microbiological or clinical supporting evidence. ",0
2442,11512050,Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens,"Prior research suggests that high levels of acetylcholine (ACh) in the nucleus accumbens (NAc) are associated with aversive states such as morphine withdrawal, but this has not been tested for nicotine withdrawal. The goal was to test the hypothesis that acute nicotine decreases extracellular ACh and increases extracellular dopamine (DA) in the NAc, while withdrawal from nicotine causes an opposite neurochemical imbalance with high extracellular ACh and low DA. Rats were prepared with a microdialysis probe in the NAc (primarily the shell region). They received one injection of nicotine (0.5 mg/kg, s.c.) or chronic nicotine (9 mg/kg per day via osmotic minipump). Naive animals receiving acute nicotine showed a mild, significant increase in both ACh (122% of baseline) and DA (124%). After chronic nicotine administration for 7 days, the nicotinic antagonist mecamylamine (1.0 mg/kg, s.c.) precipitated withdrawal with the appearance of somatic signs (teeth chattering and shakes/tremors) and a significant increase in extracellular ACh to 125% of baseline, while extracellular DA decreased to 65%. Control groups receiving saline in place of nicotine or mecamylamine did not show these effects. Earlier work suggests that the observed release of accumbens ACh and DA in response to acute nicotine administration may be a factor in nicotine-induced suppression of appetite. ACh release during withdrawal, coupled with the decrease in extracellular DA may play a role in the aversive aspects of nicotine withdrawal that contribute to dependency. ",0
2443,11512229,Use of a portable CT scanner for monitoring ventilated patients in an intensive care unit],"Evaluation of postoperative pulmonary atelectasis using a portable computed tomography (CT) unit. 5 spiral CT-examinations in low-dose technique were performed on each of 10 patients with partial pulmonary atelectasis after coronary bypass surgery. The patients were artificially ventilated using different levels (0 to +15 cm H2O) of positive end-exspiratory pressure (PEEP). The changes in atelectatic volumes were determined for each side. In 6 patients the primary volume of atelectasis was larger on the left side than on the right. Atelectatic volumes decreased with increasing PEEP. Re-expansion of atelectases was significantly (p < 0.01) better with a PEEP of +15 cm H2O. Computed tomography allows visualisation of postoperative atelectasis reliably, even in the low-dose technique. Concordantly, additional therapeutically relevant side findings can be detected compared to conventional chest X-ray. Risky patient transport becomes unnecessary. ",0
2444,11512410,Effect of posterior hypothalamic injection of procaine on the hippocampal theta rhythm in freely moving cats,"Earlier in vivo studies conducted on freely moving and anesthetized rats demonstrated that the posterior hypothalamus (PH) comprises pathways critical for producing the synchronous hippocampal formation (HPC) theta rhythm. In addition, these findings suggested that the frequency of the HPC theta was encoded in the PH and then was fed via the medial forebrain bundle to the medial septum and HPC. In the present study we attempted to verify this hypothesis with use of a different in vivo model--freely moving cats. The microinjection of the local anaesthetic, procaine, into the PH region reversibly suppressed the spontaneous as well as sensory and electrically induced HPC theta. However, in contrast to rats, in freely moving cats microinjection of procaine into the PH reduced the amplitude of the HPC theta but had no effect on theta frequency. We conclude that in freely moving cats the PH region comprises a critical part of the ascending brainstem pathway, for production of the HPC theta rhythm. In contrast to rats, in freely moving cats ascending inputs from the brainstem to the PH contribute mainly to the amplitude of the HPC theta rhythm. ",0
2445,11512434,Change in the pH of aqueous humor after administration of anti-glaucoma agents in rabbits in vivo],"In this contribution the activity of antiglaucomatics--2% pilocarpine (pH 5.98), 0.5% timoptol (pH 6.58) and 0.005% xalatan (pH 6.83) is emphasized from the view of pH values and changes of the pH values of the rabbit aqueous humor in vitro after their application. The rabbit's aqueous humor pH is 7.59--similar to the human healthy eye (7.5-7.6). We observed that these antiglaucomatics decrease the aqueous humor pH to the acid levels in the following order: 2% pilocarpine > 0.5% timoptol > 0.005% xalatan. The most significant decrease was measured immediately after the application. From the view of speed of response and effectivity in time achieving the pH of the normal aqueous humor we constate the following order: 0.005% xalatan > 0.5% timoptol > 2% pilocarpine. The changes in pH of the aqueous humor after application of these antiglaucomatics are directly connect with their physiologic function in the eye. Moreover, they also point out the importance of the pH dependence of the antiglaucomatics applicated into the conjunctival sac in the treatment of the glaucoma disease. ",0
2446,11512438,Personal experience in the treatment of proliferative diabetic retinopathy using an argon laser],"The authors evaluate the results of treatment of proliferative diabetic retinopathy by panretinal photocoagulation with an argon laser in a group of 122 eyes, 89 patients, with a mean follow-up period of 4.7 years. They achieved complete regression of revascularization of 69% eyes, partial regression in 21% eyes. In 10% eyes they treatment failed. The resulting visual acuity was 6/12 and better in 41% eyes, a visual acuity worse than 6/60 was recorded in 11% eyes. It remained unaltered in 70% eyes, deteriorated in 19%. The authors evaluated the success rate of laser photocoagulation in relation to the stage and site of neovascularizations. They found that the poorest reaction to panretinal photocoagulation is obtained in advanced neovascularization of the disc and they remain of the known view that advanced neovascularizations display a certain grade of autonomy which is the cause of a poorer response to panretinal photcogaulation. They confirm former observations that if signs of regression of neovascularization develop early, within 3-6 weeks after the onset of laser photocoagulation this may be considered a prognostically favourable sign. ",0
2447,11512463,Activity of the autonomous nervous system measured based on the variability of heart rate in female urinary incontinence],"To compare the ANS activity, measured by heart rate variability (HRV) in various types of female urinary incontinence (UI). 25 patients were included in this prospective study: 11 presented stress UI without sphincter incompetence, 9 presented mixed UI and 5 presented urge UI. UI without idiopathic detrusor instability (IDI) (n = 11) was compared to UI with IDI (N = 14.). No statistically significant difference was observed for mean age of the patients in the two groups. A 24-hour Holter ECG, under the conditions of the patient's everyday life, provided time and frequency indices (Fourier transform) of HRV, reflecting the sympathetic, parasympathetic and global ANS activity. The global ANS activity of the patients with either mixed UI, urge UI or UI with IDI, was statistically significantly lower (p < 0.05) than that of patients with stress UI. The sympathetic-vagal balance, heart rate, blood pressure, and Ditrovie score were not significantly different between the groups. This preliminary study shows that IDI is associated with a global reduction of ANS activity compared to that of patients without IDI. Modifications of sympathetic, parasympathetic and global ANS activity were also observed between the various types of female UI. ",0
2448,11512571,"Age-period-cohort analysis of lung cancer mortality in Japan, 1960-1995","The mortality data on lung cancer in Japan from 1960 to 1995 was analysed based on an age-period-cohort (APC) model. Though the APC model has an 'identifiable problem' caused by the relationship of age, period and cohort parameters, non-linear components of them revealed their original (separated) effects. They were: (1) non-linear age effects had a peak in 55-59 and 60-64 years old in males and 50-54 in females, (2) non-linear period effects were very small in both genders, (3) non-linear age and period effects were small enough to neglect compared with their linear effects, and (4) there were five parts of trends in Japanese lung cancer mortality in both genders in the non-linear birth cohort effects. The 1961-65 birth cohort effect seemed to increase differently from previous birth years. This trend should be monitored carefully. ",0
2449,11513273,Analysis of wine for penicillin,"This study addresses the question of whether the antibiotic Penicillin, which is produced by the common mold Penicillium notatum, could possibly become a contaminate of wine during the fermentation process. The significance of this study is related to the potential health effects this agent might produce in those consumers who have an allergic response to Penicillin. It has been estimated that between 6% and 8% of the American population is subject to this type of allergic response. A method is developed for the detection of penicillin in wines using high-pressure liquid chromatography. We demonstrate that penicillin G hydrolyzes rapidly in wine with first-order kinetics, and the half-life of this antibiotic is 147 min in a typical commercial wine. An analysis of a number of commercial wines shows no evidence of the presence of penicillin, which should negate the question of any allergic response associated with this potential contaminate. ",0
2450,11513501,"Discovering the person with Alzheimer's disease: cognitive, emotional and behavioural aspects","The person-centred approach to dementia care emerges from a new emphasis on the experience of the person with dementia. The person is seen as attempting to manage and cope with their difficulties, through a variety of coping mechanisms. Some are able to seek to maximize their cognitive capacities, and there are a number of strategies now available to assist in this process. However, the emotional aspects merit increased attention, with more awareness needed of the range of powerful emotions that may be present, and of the possibility of therapeutic interventions to alleviate symptoms of anxiety and depression. Many of the difficult behaviours seen in dementia may be understood more fully with an appreciation of their emotional underpinning, in feelings of anger, fear, insecurity and hopelessness. The interaction between caregiver strain and challenging behaviour also merits further exploration. The person-centred approach has many implications for practice, as well as for research. The perspective of the person with dementia, and outcomes reflecting that perspective, must be represented in research studies in dementia care. Caregivers, whether family members or paid workers, require additional support in order to recognize the person's needs and to meet them in ways which enable the person's identity and full human value to be upheld. ",0
2451,11513596,On the multiple functional roles of the active site histidine in catalysis and allosteric regulation of Escherichia coli glucosamine 6-phosphate deaminase,"The active site of glucosamine-6-phosphate deaminase (EC 3.5.99.6, formerly 5.3.1.10) from Escherichia coli was first characterized on the basis of the crystallographic structure of the enzyme bound to the competitive inhibitor 2-amino-2-deoxy-glucitol 6-phosphate. The structure corresponds to the R allosteric state of the enzyme; it shows the side-chain of His143 in close proximity to the O5 atom of the inhibitor. This arrangement suggests that His143 could have a role in the catalysis of the ring-opening step of glucosamine 6-phosphate whose alpha-anomer is the true substrate. The imidazole group of this active-site histidine contacts the carboxy groups from Glu148 and Asp141, via its Ndelta1 atom [Oliva et al. (1995) Structure 3, 1323-1332]. These interactions change in the T state because the side chain of Glu148 moves toward the allosteric site, leaving at the active site the dyad Asp141-His143 [Horjales et al. (1999) Structure 7, 527-536]. In this research, a dual approach using site-directed mutagenesis and controlled chemical modification of histidine residues has been used to investigate the role of the active-site histidine. Our results support a multifunctional role of His143; in the forward reaction, it is involved in the catalysis of the ring-opening step of the substrate, glucosamine 6-P. In the reverse reaction, the substrate fructose 6-P binds in its open chain, carbonylic form. The role of His143 in the binding of both glucosamine 6-P and reaction intermediates in their extended-chain forms was demonstrated by binding experiments using the reaction intermediate analogue, 2-amino-2-deoxy-D-glucitol 6-phosphate. His143 was also shown to be a critical residue for the conformational coupling between active and allosteric sites. From the pH dependence of the reactivity of the active site histidine to diethyl dicarbonate, we observed a pK(a) change of 1.2 units to the acid side when the enzyme undergoes the allosteric T to R transition during which the side chain of Glu148 moves toward the active site. The kinetic study of the Glu148-Gln mutant deaminase shows that the loss of the carboxy group and its replacement with the corresponding amide modifies the k(cat) versus pH profile of the enzyme, suggesting that the catalytic step requiring the participation of His143 has become rate-limiting. This, in turn, indicates that the interaction Glu148-His143 in the wild-type enzyme in the R state contributes to make the enzyme functional over a wide pH range. ",0
2452,11513723,Development of enzyme-linked immunosorbent assays for the hepatotoxic alkaloids riddelliine and riddelliine N-oxide,"Pyrrolizidine alkaloid-containing plants are widely distributed throughout the world and are particularly common in the genus Senecio. The structural types and concentrations of the alkaloids vary among plant species. In addition, within a species of plant, concentrations vary with environment and location. Many pyrrolizidine alkaloids are toxic and cause poisoning in livestock and in humans. Rapid, sensitive, and specific diagnostic techniques are needed to identify poisoned animals and to determine the particular plants and conditions under which livestock are likely to be poisoned. In this study, two competitive inhibition enzyme-linked immunosorbent assays for riddelliine, riddelliine N-oxide, and other closely related pyrrolizidine alkaloids were developed using polyclonal antibodies. One assay is class specific toward the free base forms of the pyrrolizidine alkaloids; the other assay showed cross-reactivity to both the free base and N-oxide forms of the alkaloids. The assay with the lowest limit of detection had an I(50) of 803.9 pg with a limit of detection of 47.5 pg for riddelliine. Spike and recovery studies for riddelliine in bovine blood ranged from 45 to 74%. The assay that showed cross-reactivity between the N-oxide and free base forms of the pyrrolizidine alkaloids allowed estimation of the total pyrrolizidine alkaloid content in Senecio riddellii in admixture with alfalfa. These findings suggest that these techniques will be excellent tools to diagnose poisoned animals and identify highly toxic plants. ",0
2453,11513735,Ubiquitination is essential for human cytomegalovirus US11-mediated dislocation of MHC class I molecules from the endoplasmic reticulum to the cytosol,"Human cytomegalovirus encodes two glycoproteins, US2 and US11, which cause rapid degradation of MHC class I molecules, thus preventing recognition of virus-infected cells by the immune system. This degradation process involves retrograde transport or 'dislocation' of MHC class I molecules from the endoplasmic reticulum (ER) to the cytosol, where they are deglycosylated by an N-glycanase and degraded by the proteasome. At present it is unknown whether ubiquitination is required for US2- and US11-mediated dislocation and degradation of MHC class I molecules. Here, we show that in E36ts20 hamster cells, which contain a temperature-sensitive mutation in the E1 ubiquitin-activating enzyme, US11-mediated degradation of MHC class I molecules is strongly impaired at the non-permissive temperature, indicating the necessity for ubiquitination in this process. We next addressed the question of whether ubiquitination is a condition for the retrograde movement of MHC class I molecules from the ER to the cytosol, or whether ubiquitination is merely required for recognition of dislocated MHC class I molecules by the proteasome. In the absence of a functional ubiquitin system, complexes of US11 and MHC class I molecules accumulate in the ER. In this state the membrane topology of MHC class I molecules does not significantly change, as judged from proteinase K digestions. Thus the results indicate that a functional ubiquitin system is essential for dislocation of MHC class I molecules from the ER to the cytosol. ",0
2454,11513736,Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide,"Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their physiological actions by binding to natriuretic peptide receptor A (NPRA), a receptor guanylate cyclase (rGC) that synthesizes cGMP in response to both ligands. The family of rGCs is rapidly expanding, and it is plausible that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these peptides, particularly given the low affinity of NPRA for BNP. We have investigated this hypothesis, using a genetically modified (knockout) mouse in which the gene encoding NPRA has been disrupted. Enzyme assays and NPRA-specific Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expression, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon. In contrast, immunoreactive NPRA is not detectable in tissues isolated from NPRA knockout animals and ANP- and BNP-stimulatable GC activities are markedly reduced in all mutant tissues. However, testis and adrenal gland retain statistically significant, high-affinity responses to BNP. This residual response to BNP cannot be accounted for by natriuretic peptide receptor B, or any other known mammalian rGC, suggesting the presence of a novel receptor in these tissues that prefers BNP over ANP. ",0
2455,11513757,Dopaminergic neurons in the brain and dopaminergic innervation of the albumen gland in mated and virgin helisoma duryi (mollusca: pulmonata),"Dopamine was shown to stimulate the perivitelline fluid secretion by the albumen gland. Even though the albumen gland has been shown to contain catecholaminergic fibers and its innervation has been studied, the type of catecholamines, distribution of fibers and the precise source of this neural innervation has not yet been deduced. This study was designed to address these issues and examine the correlation between dopamine concentration and the sexual status of snails. Dopaminergic neurons were found in all ganglia except the pleural and right parietal, and their axons in all ganglia and major nerves of the brain. In the albumen gland dopaminergic axons formed a nerve tract in the central region, and a uniform net in other areas. Neuronal cell bodies were present in the vicinity of the axons. Dopamine was a major catecholamine in the brain and the albumen gland. No significant difference in dopamine quantity was found when the brain and the albumen gland of randomly mating, virgin and first time mated snails were compared. Our results represent the first detailed studies regarding the catecholamine innervation and quantitation of neurotransmitters in the albumen gland. In this study we localized catecholaminergic neurons and axons in the albumen gland and the brain, identified these neurons and axons as dopaminergic, reported monoamines present in the albumen gland and the brain, and compared the dopamine content in the brain and the albumen gland of randomly mating, virgin and first time mated snails. ",0
2456,11513890,Toxicity of cadmium and zinc to Diplostomum spathaceum (Trematoda: Diplostomidae) cercarial survival,"The toxicity of cadmium and zinc at concentrations ranging from 0.1 to 10000 microg/l was investigated with cercariae of Diplostomum spathaceum at three temperatures (12, 20, 25 degrees C) and three levels of water hardness (distilled water, soft water, hard water). Under most environmental conditions survival of cercariae was reduced by increasing metal concentration. Increasing water hardness and decreasing water temperature caused an increase in the survival of both control and metal exposed cercariae. However, with decreasing temperature increased survival of metal-exposed cercariae above the control occurred at a number of low metal concentrations. Differences in the relative toxicity of cadmium and zinc to cercariae was dependent on the environmental conditions of exposure. The two heavy metals demonstrated little toxicity to cercariae during the period of maximum cercarial infectivity (0-5 h). The mechanisms of metal toxicity and their effects on cercarial survival are discussed. ",0
2457,11513972,Hyperosmotic stress activates the insulin receptor in CHO cells,"Stress factors, such as osmotic stress and genotoxic agents, activate stress kinases, whereas growth factors preferentially stimulate the structurally homologous mitogen-activated protein kinases, ERK1/2. Hyperosmolarity also has insulin-mimicking action as reflected by ERK1/2 activation and by the stimulation of glucose uptake in adipocytes. We examined to what extent hyperosmolarity activates components of the insulin receptor (IR) signalling pathway. CHO cells expressing the human IR were treated with 500 mM NaCl or 700 mM sorbitol and the activation of insulin signalling intermediates was studied. Hyperosmolarity induced tyrosine phosphorylation of the IR beta-subunit, and the adaptor proteins p52-Shc, p66-Shc, and IRS1. Furthermore, the stress kinases JNK and p38 were activated. When CHO cells were transfected with a kinase-dead IR (K1030R) mutant, hyperosmolarity did not induce tyrosine phosphorylation of the IR, indicating that hyperosmolarity induced IR autophosphorylation directly, rather than inducing phosphorylation by an exogenous tyrosine kinase. A partially purified and detergent-solubilized IR was not phosphorylated in response to hyperosmolarity, suggesting that hyperosmolarity activates the receptor only when present in the plasma membrane. In cells stably expressing the kinase-dead IR, IRS1 and Shc Tyr phosphorylation was abrogated, indicating that the hyperosmolarity signalling was dependent on an active IR tyrosine kinase. In contrast, the stress kinases p38 and JNK were normally activated by hyperosmolarity in the IR-K1030R mutant. We conclude that, at least in CHO cells, hyperosmolarity signals partially through IR autophosphorylation and subsequent activation of the IR downstream targets. This may be responsible for some of the insulin-mimicking effects of hyperosmolarity. The activation of stress kinases by hyperosmolarity occurs independent of the IR. ",0
2458,11514133,Perceptions of the real and the ideal ward atmosphere among trainees and staff before and after the introduction of a new work rehabilitation model,"Changes in the ward atmosphere of a psychiatric work rehabilitation unit were investigated. Both trainees and staff filled in the Community-Oriented Programs Environment Scale (COPES) before and after a new rehabilitation model was implemented. It was hypothesised that the levels of autonomy and practical orientation would increase from both the trainees' and staff's perspective concerning the real ward atmosphere and that the staff's perceptions of an ideal ward atmosphere would change in the same way. The staff perceived an increased level of autonomy with respect to both the real ward atmosphere and to what constitutes an ideal ward atmosphere, which partly confirmed the hypotheses, but the level of practical orientation was stable. Concerning the staff's estimate of an ideal ward atmosphere, further changes were an increased level of involvement and a decrease in spontaneity, which was not hypothesised, but was not in conflict with the philosophy behind the new model. From the trainee's perspective there was no change of either autonomy or practical orientation. Instead, there was a decrease in personal problem orientation. Compared to an optimal profile, the ward atmosphere was beneficial, before as well as after implementation of the new programme. Differences were found between the staff and the trainees, but they were not large enough to separate the groups according to what is considered an optimal profile. The few changes found support earlier conclusions that the ward atmosphere is a stable phenomenon over time. ",0
2459,11514139,"1,4-Disubstituted imidazoles are potential antibacterial agents functioning as inhibitors of enoyl acyl carrier protein reductase (FabI)","1,4-Disubstituted imidazole inhibitors of Staphylococcus aureus and Escherichia coli enoyl acyl carrier protein reductase (FabI) have been identified. Crystal structure data shows the inhibitor 1 bound in the enzyme active site of E. coli FabI. ",0
2460,11514902,Genotoxic evaluation of the effect of Thuya occidentalys tinctures,"Three tinctures samples from extracts of the popular medicinal plant Thuya occidentalis were tested in vitro through two short term tests for measuring the activity of genotoxic chemicals. Using the Salmonella/mammalian-microsome (Mutatest) assay and the SOS-chromotest (induction of beta-galactosidase in Escherichia coli), none of the extract was effective in inducing mutagenesis or beta-galactosidase synthesis (as an indicator of general and early sign of DNA damage), even with metabolization. ",0
2461,11515294,Coronary surgery after 70 years of age],"Previous reports on coronary artery bypass grafting in elderly patients have not usually addressed the current era of aggressive percutaneous angioplasty. To investigate this important subgroup of patients, we analyzed our recent coronary artery bypass grafting experience with patients 70 years of age or older from May 1988 to August 1993, 158 consecutive patients in this age range (mean age 70.3 years) underwent surgical revascularization at our institution. Overall operative mortality was 4.4% (7/158), with 71.4% (5/7) of deaths due to cardiac causes. Postoperative morbidity occurred in 50.6% (80/158) of patients but was of a serious nature in only 12.0% (19/158). Surgical priority was significantly correlated with operative mortality: 1.6% (2/122) for elective cases and 17.2% (5/29) for urgent or emergency cases (p < 0.01). Univariate analysis isolated the need for postoperative inotropic support or mechanical assistance, perioperative myocardial infarction and reoperation for bleeding as significant risk factors for operative mortality (p < 0.01). Of the patients discharged from the hospital, 144 (95.4%) were followed up for a mean of 23 months (3-62). During the follow-up period there were 3 deaths, all from non cardiac causes, and 92.3% of the patients were in Canadian Cardiovascular Society class I (CCS). These results indicate that, although with somewhat higher morbidity and mortality rates, elderly patients have a very acceptable operative risk in the current era of high-risk coronary artery bypass grafting, particularly if elective revascularization is possible. ",0
2462,11515462,Acute colonic pseudoobstruction: physiopathology and treatment],"The acute colonic pseudo-obstruction is a rare condition. Pathophysiological knowledges, nowadays, are still discussed. Several associated pathological conditions (cardiological, neurological, metabolic) would mainly cause, with different mechanisms, a sympathetic-parasympathetic imbalance. In Authors' experience with 19 patients the sudden onset and the rapid evolution to a serious condition set the difference with a mechanical obstruction. The radiological control was essential to the therapeutic options. The endoscopic decompression was successful in 2 cases; the tube cecostomy was effective in 13; the right emycolectomy was necessary in 1 case with multiple diastasic cecal perforations. Mortality rate: 3 patients (15.70%). ",0
2463,11515699,"The relationship between cannabis use, depression and anxiety among Australian adults: findings from the National Survey of Mental Health and Well-Being","This study aimed to examine the patterns of association between cannabis use, and anxiety and affective disorders, in the general population. Data from the Australian National Survey of Mental Health and Well-Being, a representative survey of Australians aged 18 years and over, were analysed to address the following questions: (1) is there an association between cannabis use, DSM-IV abuse and dependence, and DSM-IV affective and anxiety disorders; (2) if so, is it explained by: demographic characteristics, levels of neuroticism, or other drug use; and (3) does the presence of a comorbid affective or anxiety disorder affect the likelihood of treatment seeking among cannabis users? There was a moderate univariate association between involvement with cannabis use in the past 12 months and the prevalence of affective and anxiety disorders. Among those with DSM-IV cannabis dependence, 14% met criteria for an affective disorder, compared to 6% of non-users; while 17% met criteria for an anxiety disorder, compared to 5% of non-users. These associations did not remain significant after including demographics, neuroticism and other drug use in multiple regressions. Cannabis use did not appear to be directly related to depression or anxiety when account was taken of other drug use. However, the association between heavier involvement with cannabis use and affective and anxiety disorders has implications for the treatment of persons with problematic cannabis use. ",0
2464,11515873,Surgical management of severe truncal insufficiency: experience with truncal valve remodeling techniques,"Truncal valve insufficiency has been a significant short- and long-term risk factor for repair of truncus arteriosus. Recent reports have documented the virtues of truncal valve repair. The purpose of this report is to review our experience with truncal valve repair and illustrate our techniques. Between 1995 and 2000, 8 patients had interventions for severe truncal valve insufficiency at primary repair (3 patients) or in conjunction with conduit replacement (5 patients). One neonate had truncal valve replacement at initial repair early in the experience. The other 7 patients had truncal valve repair, 3 by valvar suture techniques. The remaining 4 patients had leaflet excision and annular remodeling in 3 (coronary reimplantation was required in 2) and commissure resuspension in 1 patient. Trivial to mild truncal valve insufficiency is present in the patients who had leaflet excision and annular remodeling (n = 3) and commissure resuspension (n = 1). Of the 3 patients who had valvar suture truncal valve repair, there was one death and 2 patients required acute valve replacement. The 7 survivors are doing well 1 month to 6 years postoperatively. Truncal valve repair by valvar suture techniques has not been successful in our practice. Truncal valve remodeling by leaflet excision and reduction annuloplasty is an effective method for truncal valve repair. When leaflet excision of a coronary sinus of Valsalva is required, coronary artery translocation can be accomplished. ",0
2465,11516064,Female genital warts: global trends and treatments,"The increasing incidence of human papillomavirus (HPV) infection and HPV-associated conditions such as genital warts in women is a global concern. Genital warts are a clinical manifestation of HPV types 6 and 11, and are estimated to affect 1% of sexually active adults aged between 15 and 49. HPV infection is also strongly associated with cervical cancer, and is prevalent in as many as 99% of cases. The psychological stress of having genital warts is often greater than the morbidity of the disease, and therefore successful treatment is crucial. Current treatments are patient-applied and provider-administered therapies. Imiquimod 5% cream, a patient-applied therapy, is an efficacious treatment with tolerable side-effects and a low recurrence rate, and has the potential to be an effective strategy for the management of genital warts. ",0
2466,11516074,Laser cutting: influence on morphological and physicochemical properties of polyhydroxybutyrate,"Polyhydroxybutyrate (PHB) is a biocompatible and resorbable implant material. For these reasons, it has been used for the fabrication of temporary stents, bone plates, nails and screws (Peng et al. Biomaterials 1996;17:685). In some cases, the brittle mechanical properties of PHB homopolymer limit its application. A typical plasticizer, triethylcitrate (TEC), was used to overcome such limitations by making the material more pliable. In the past few years, CO2-laser cutting of PHB was used in the manufacturing of small medical devices such as stents. Embrittlement of plasticized PHB tubes has been observed, after laser machining. Consequently, the physicochemical and morphological properties of laser-processed surfaces and cut edges of plasticized polymer samples were examined to determine the extent of changes in polymer properties as a result of laser machining. These studies included determination of the depth of the laser-induced heat affected zone by polariscopy of thin polymer sections. Molecular weight changes and changes in the TEC content as a function of distance from the laser-cut edge were determined. In a preliminary test, the cellular response to the processed material was investigated by cell culture study of L929 mouse fibroblasts on laser-machined surfaces. The heat-affected zone was readily classified into four different regions with a total depth of about 60 to 100 microm (Klamp, Master Thesis, University of Rostock, 1998). These results correspond well with the chemical analysis and molecular weight measurements. Furthermore, it was found that cells grew preferentially on the laser-machined area. These findings have significant implications for the manufacture of medical implants from PHB by laser machining. ",0
2467,11516328,Fluorescence properties of albumin blue 633 and 670 in plasma and whole blood,"We have determined the fluorescence characteristics of two long wavelength dyes, albumin blue 633 (AB633) and 670 (AB670), in plasma and blood to evaluate the possibility of making direct fluorescence sensing measurements in blood. Using binding and lifetime measurements we were also able to show that these dyes bind selectively to human serum albumin (HSA) in plasma and blood. By measuring changes in the mean lifetime of AB670 with changes in the HSA concentration, we showed that lifetime-based sensing can be used to monitor HSA concentrations using these albumin blue dyes. Anisotropy measurements for AB633 and AB670 in plasma and blood revealed high anisotropy values for these dyes in these media. Exploiting these high anisotropies, we were also able to determine HSA concentrations in plasma and blood mimics using changes in AB670 anisotropy with HSA concentration. These results show that, apart from being able to make fluorescence measurements directly in plasma and blood, it is possible to sense directly for specific plasma/blood components using fluorescent probes that bind preferentially to them. ",0
2468,11516363,The metabolic toxicities of antiretroviral therapy,"Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities. ",0
2469,11517290,The use of amplified cDNA to investigate the expression of seven imprinted genes in human oocytes and preimplantation embryos,"Imprinted genes are characterized by expression of only one of the two alleles according to its inheritance from the mother or the father. This mono-allelic expression must arise from primary differential epigenetic modification of the parental alleles of the imprinted gene in the spermatozoon and the oocyte. Most of the information on the onset of imprinted gene expression, and on the molecular mechanisms regulating mono-allelic expression, have been derived from studies in the mouse. In this paper, we investigate the expression of seven imprinted genes in human preimplantation development. Due to limitations imposed by the rarity of human embryos available for research, our approach has been to screen amplified cDNA preparations prepared from human unfertilized oocytes and individual embryos at each of the 4-cell, 8-cell and blastocyst stages. Gene-specific primers were used to investigate expression of the imprinted genes by polymerase chain reaction (PCR) analysis of these amplified cDNA. We found that expression is inherently variable in the amplified cDNA from embryo to embryo but the use of several samples at each stage showed that the SNRPN, UBE3A and PEG1 genes are expressed throughout human preimplantation development. This was confirmed by direct analysis by gene-specific reverse transcription-PCR on a limited number of lysed embryos (one gene analysed per embryo). Thus, the amplified cDNA may be used to rapidly identify those imprinted genes expressed in preimplantation development and, hence, those genes amenable to investigation of the epigenetic mechanisms regulating mono-allelic expression. Confirmation of preimplantation expression also identifies those imprinted diseases amenable to preimplantation diagnosis, and the imprinted genes which may be used in assessment of possible perturbations of imprinting following new procedures in assisted reproduction. Our series of single embryo amplified cDNA are established as a valuable resource for comparative studies of gene expression within one embryo and between embryos throughout early human development. The amplified cDNA thus circumvent the need for a continuous supply of human embryos for studies on embryonic gene expression. ",0
2470,11517578,Ultrasonic integrated backscatter in early assessment of myocardial injury during open heart surgery,"The recovery of cyclic variation of ultrasonic integrated backscatter in myocardial ischemia provides early assessment of myocardial injury and is useful in assessing myocardial injury during open heart surgery. We studied 25 patients with valvular disease undergoing cardiac surgery--7 with aortic stenosis, 7 with aortic regurgitation, 6 with mitral stenosis, and 5 with mitral regurgitation. All underwent transesophageal echocardiography (before aortic cross-clamping: T-pre and 60 minutes after aortic declamping: T-60). The short-axis view at the papillary muscle level of the left ventricle was recorded and anterior areas were assessed. The magnitude of cyclic variation at T-pre and T-60 was 9.4 +/- 2.5 dB and 8.8 +/- 3.0 dB, and the ratio was 97 +/- 32%. Fractional shortening at T-pre and at T-60 was 27 +/- 7% and 20 +/- 9%, and the ratio was 79 +/- 44%. Recovery of magnitude was ahead of recovery of fractional shortening. The percent recovery of magnitude at T-60 did not correlate with aortic cross-clamping time (p = 0.91), postoperative peak creatine kinase-MB (p = 0.4), or catecholamine dosage (p = 0.13), but correlated with preoperative left ventricular mass index (p < 0.01). In patients with aortic stenosis, the percent recovery of magnitude at T-60 (66 +/- 4%) was significantly lower than in those with other types of valvular disease. The recovery of magnitude of cyclic variation of ultrasonic integrated backscatter provides early assessment of myocardial injury, particularly in severely hypertrophied hearts, during reperfusion after aortic declamping in open heart surgery. ",0
2471,11517632,Chronic iron overload and toxicity: clinical chemistry perspective,"The content of body iron is regulated primarily by absorption since humans have no physiological mechanism by which excess iron is excreted. This regulation, however, is not absolute. Many factors such as the content of diets, iron doses, life styles, etc. influence iron absorption. In the past, nutrition programs for iron fortification and the ingestion of iron preparations have been widely practiced because of the seriousness of worldwide iron deficiency. Also, we now know that a significant number of asymptomatic people carry the hemochromatosis gene, HFE, indicating that these people have the potential to accumulate excess body iron in their lifetime. Excess body iron can be highly toxic. This toxicity involves many organs leading to a variety of serious diseases such as liver disease, heart disease, diabetes mellitus, hormonal abnormalities, dysfunctional immune system, etc. The tissue damage associated with iron overload is believed to result primarily from free radical reactions mediated by iron. Iron is an effective catalyst in free radical reactions. The diseases associated with iron overload can be managed effectively or prevented. Therefore, early diagnosis of iron overload and appropriate therapy are critical. By providing the necessary laboratory data, clinical chemistry laboratories can play the pivotal role in the management of these health problems. ",0
2472,11518285,The effects of static and intermittent compression on nitric oxide production in articular cartilage explants,"Nitric oxide (NO) production and NO synthase (NOS) expression are increased in osteoarthritis and rheumatoid arthritis, suggesting that NO may play a role in the destruction of articular cartilage. To test the hypothesis that mechanical stress may increase NO production by chondrocytes, we measured the effects of physiological levels of static and intermittent compression on NOS activity, NO production, and NOS antigen expression by porcine articular cartilage explants. Static compression significantly increased NO production at 0.1 MPa stress for 24 h (P < 0.05). Intermittent compression at 0.5 Hz for 6 h followed by 18 h recovery also increased NO production and NOS activity at 1.0 MPa stress (P < 0.05). Intermittent compression at 0.5 Hz for 24 h at a magnitude of 0.1 or 0.5 MPa caused an increase in NO production and NOS activity (P < 0.05). Immunoblot analysis showed stress-induced upregulation of NOS2, but not NOS1 or NOS3. There was no loss in cell viability following any of the loading regimens. Addition of 2 mM 1400 W (a specific NOS2 inhibitor) reduced NO production by 51% with no loss of cell viability. These findings indicate that NO production by chondrocytes is influenced by mechanical compression in vitro and suggest that biomechanical factors may in part regulate NO production in vivo. ",0
2473,11518356,"Activities of plasminogen activator, plasmin and kallikrein in synovial fluid from patients with temporomandibular joint disorders","To measure the activities of plasminogen activator (PA), plasmin and kallikrein, multiple synovial fluid samples were taken from 32 patients with internal derangement (ID) and osteoarthrosis (OA), and nine asymptomatic volunteers. The enzyme activity in synovial fluid from the temporomandibular joint (TMJ) was quantitated by a fluorogenic substrate assay using an enzyme substrate. In fluid samples from the patient group, PA was detected in 24 (31.5%), plasmin in 20 (26.3%) and kallikrein in 53 (96.4%), while none of these enzymes were found in the synovial fluid samples from the control group. There were positive correlations found among PA, plasmin and kallikrein. These results clearly demonstrated increased levels of PA, plasmin and kallikrein activities in the synovial fluid of patients with ID and OA, and suggest that these enzymes may be involved in the pathogenesis of synovitis, as well as the resorption of cartilage and bone in TMJ. ",0
2474,11518518,Alkalinization of acrosome measured by GFP as a pH indicator and its relation to sperm capacitation,"We previously targeted EGFP (a mutant of green fluorescent protein) to the lumen of the mouse sperm acrosome and reported the time course of EGFP release during the acrosome reaction. In the study reported here, we estimated the pH within the mouse sperm acrosome utilizing the pH-dependent nature of EGFP fluorescence. The average intra-acrosomal pH was estimated to be 5.3 +/- 0.1 immediately after sperm preparation, gradually increasing to 6.2 +/- 0.3 during 120 min of incubation in TYH media suitable for capacitation. Spontaneous acrosome reactions were noted to increase concomitantly with acrosomal alkalinization during incubation. We also demonstrated that acrosomal antigens detected by monoclonal antibodies MN7 and MC41 did not dissolve following the acrosome reaction in pH 5.3 media, but dissolved at pH 6.2. These data suggest that acrosomal alkalinization during incubation conducive for sperm capacitation may function to alter acrosomal contents and prepare them for release during the acrosome reaction. ",0
2475,11518693,Cold preservation-warm reoxygenation increases hepatocyte steady-state Ca(2+) and response to Ca(2+)-mobilizing agonist,"Although the role of Ca(2+) in liver transplantation injury has been the object of several studies, direct evidence for alterations in intracellular Ca(2+) homeostasis after cold preservation-warm reoxygenation (CP/WR) has never been presented. We thus investigated the effects of CP/WR on steady-state Ca(2+) and responses to a Ca(2+)-mobilizing agonist. Isolated rat hepatocytes were suspended in University of Wisconsin solution, stored at 4 degrees C for 0, 24, and 48 h, and reoxygenated at 37 degrees C for 1 h. Cytosolic Ca(2+) was measured in single cells by digitized fluorescence videomicroscopy. CP/WR caused a significant increase in steady-state cytosolic Ca(2+), which was inversely proportional to cell viability. Pretreatment of hepatocytes with an agent that protects mitochondrial function attenuated the increase in steady-state cytosolic Ca(2+) and improved hepatocyte viability. Ca(2+) responses to the purinergic agonist ATP also increased significantly as a function of cold storage time. This increase was related to an increase in the size of inositol 1,4,5-trisphosphate-sensitive Ca(2+) stores and subsequent capacitative Ca(2+) entry. Thus CP/WR significantly perturbs steady-state hepatocellular Ca(2+) and responses to Ca(2+)-mobilizing agonists, which may contribute to hepatocyte metabolic dysfunction observed after CP/WR. ",0
2476,11519168,The neuropathogenesis of Borna disease virus infection],"Borna disease virus(BDV) is a noncytolytic, neurotropic RNA virus that causes a disease of the central nervous system(CNS) in several vertebrate species, including horses, sheep, cats and ostriches. Epidemiological studies using peripheral blood or brain samples revealed that BDV can infect humans and that it may be related with certain neuropsychiatric disorders. The unique genetic and biological properties of BDV indicate that BDV develops a persistent infection in the CNS. Furthermore, a line of recent evidences suggests that BDV infection causes direct effects on brain functions in the absence of immunopathology-related brain damage. In this review, we discuss about recent data regarding neuropathogenesis of BDV infections in animals and humans. ",0
2477,11519219,Combined intralesional interferon alpha 2B and oral vitamin E in the treatment of Peyronie's disease,"It has been recently reported that intralesional therapy with alpha interferon 2B resulted in significant improvement of both objective and subjective complaints (penile curvature, pain, plaque size, sexual function) associated with Peyronie's disease. Vitamin E, with its antioxidant properties, may play a role in reducing the inflammatory response. This study was designed to determine the safety and effectiveness of a high dose of alpha INF-2B injected weekly into the Peyronie's plaque combined with oral Vitamin E therapy. Twenty-nine patients with Peyronie's disease were evaluated with penile duplex Doppler for degree of penile curvature, deformity, and plaque size both prior to and after treatment. Each patient then received 4.0 x 10(6) units of alpha INF-2B in 10 cc of normal saline after appropriate local anesthesia. Injections were given once per week directly into the Peyronie's plaque for a period of 10 weeks. Patients also received 400 units of Vitamin E by mouth twice a day. Subjective data was obtained via a questionnaire prior to and at the conclusion of the study. Preliminary results demonstrated improvement of penile curvature in 39% of patients, with one patient experiencing complete resolution. Significant decreases in plaque sizes were noted in 11 of these patients, with softening of the plaques noted in all patients completing the study. Seven patients dropped out of the study prior to completing the 10 weeks: three with severe disease proceeded to surgery, two were lost to follow-up, one had exascerbation of his arthritis symptoms, and one quit secondary to flu-like symptoms. Subjective data from questionnaires revealed improvement in sexual function in those men with decreased curvature and plaque size. Weekly intralesional injections with 4.0 x 10(6) units improved plaque consistency and decreased curvature and plaque size (P < 0.5). Overall subjective sexual performance was reportedly improved. Increased dosage of alpha INF-2B resulted in increased severity of flu-like symptoms when compared to the lower (1 x 10(6) units) biweekly dosage. No significant difference was noted with the addition of oral Vitamin E therapy. ",0
2478,11519625,The impact of familial alcoholism on alcohol reactivity in female social drinkers,"Some individuals may have an inherent reactivity to alcohol that facilitates early development of characteristics associated with alcoholism. Although response to alcohol cues has been used to assess this reactivity, few studies have included women or investigated familial alcoholism as a variable. In this study, 23 female college students were divided into groups according to family history of alcoholism (positive or negative). Alcohol reactivity was measured by salivation, skin temperature, heart rate, mood state, and craving for alcohol following presentation of alcohol-related and neutral cues. Results indicate no correlation between salivary reactivity and alcohol craving, which suggests that these variables tap into different domains of cue reactivity. Findings demonstrate that alcohol cue reactivity can be assessed in female social drinkers and that familial alcoholism may influence salivary reactivity to alcohol-related cues. ",0
2479,11519762,Trends in lung cancer incidence in Sweden with special reference to period and birth cohorts,"Sweden has one of the largest population-based cancer registers in the world that provides an opportunity to examine the trend of lung cancer incidence during a 35-year period. The primary aim of the present study was to estimate the effects of birth cohort, year of diagnosis (period), and age on the time trends of lung cancer incidence rates, and to analyze the gender-specific incidence of different histopathological types of lung cancer. Among men the age-standardized incidence rate increased steadily up to 1982, when a peak of 49 cases per 100,000 person-years was reached. Among women the incidence rate was lower and showed a monotonic increase throughout the observation period. The fastest rate of increase was noted among the youngest women. In women, but not in men, there was a steady increase in risk with each successive birth cohort. For both sexes there were large changes in the histopathological distributions of cases. The most notable was a major increase in adenocarcinomas. The overall age-adjusted incidence rate of lung cancer in Sweden has stabilized in men during the past two decades while rates are still increasing in women. In view of the continued high prevalence of smoking among young women, a future definite increase in the overall number of lung cancer cases in women can be expected. ",0
2480,11519801,Robotic automated clean-up for detection of fumonisins B1 and B2 in corn and corn-based feed by high-performance liquid chromatography,"A high-performance liquid chromatography (HPLC) system with fluorescence detection and an automated on-line solid-phase extraction procedure for fumonisins B1 and B2 in corn and corn-based products is described. Different amounts of strong anion-exchange, C18 and end-capped C18 (C(18 ec)) silicas were tested for sample clean-up. Various HPLC parameters were analyzed. The best methodology was found to be extraction with acetonitrile-water and clean up on C(18 ec) disposable extraction cartridges. The system has the advantage of running in an unattended mode of operation and allows processing of 40 samples without system refuel, performing clean-up, o-phthaldialdehyde derivatization, injection and fumonisin detection by fluorescence detection linked to a computer integrator for automated data processing. Recoveries were performed with corn and corn-based feed samples (n=3) spiked with 0.1, 0.5, 1.0, 5.0 and 10 microg/g. Average recoveries for corn and corn-based feed were, respectively, 92.6 and 88.3% with relative standard deviations (RSDs) of 5.04 and 6.22%, for fumonisin B1 and 91.2 and 89.0% with RSDs of 5.84 and 7.88% for fumonisin B2. Detection limits (S/N=3) for corn and corn-based feed were approximately 0.03 microg/g for fumonisin B1 and 0.05 microg/g for fumonisin B2 ",0
2481,11520011,Anxiety and depression as correlates of self-reported behavioural inhibition in normal adolescents,"In a previous study, Muris, Merckelbach, Wessel, and Van de Ven [Psychopathological correlates of self-reported behavioural inhibition in normal children. Behav. Res. Ther. 37 (1999) 575-584] found that children who defined themselves as high on behavioural inhibition displayed elevated levels of psychopathological symptoms compared to children who defined themselves as low or middle on behavioural inhibition. The present study further examined the relationship between self-reported behavioural inhibition and anxiety disorders and depression symptoms in a large sample of adolescents aged 12-18 years (N=968). Adolescents completed a measure of behavioural inhibition and questionnaires of anxiety and depression. Results indicated that adolescents who classified themselves as high on behavioural inhibition had higher scores of anxiety and depression than adolescents who classified themselves as low or middle on behavioural inhibition. Structural equations modelling was employed to test hypothetical models on the role of behavioural inhibition in childhood anxiety and depression. It was found that a pathway in which behavioural inhibition results in anxiety, which in turn leads to depression, provided the best fit for the data. ",0
2482,11520169,"Distribution of aggrecanase (ADAMts 4/5) cleavage products in normal and osteoarthritic human articular cartilage: the influence of age, topography and zone of tissue","To develop and characterize a polyclonal antiserum (RAM 3.2), which recognizes the neo-C terminal cleavage product generated by the action of aggrecanase (ADAMts 4/5) on the G1-domain of human aggrecan. We also intend to use this antiserum to investigate normal, age-related changes in human articular cartilage. The antiserum was raised in rabbits and its localization in cryosections of normal articular cartilage was investigated by immunohistochemistry. The concentration of the aggrecanase neo-epitope was also investigated in extracts of the tissue using SDS-PAGE and electrophoresis in large pore/agarose gels. The product of aggrecanase action appears to accumulate in the extracellular matrix during normal aging of the tissue. Furthermore, the concentration of the fragment depended on the topographical site on the femoral condyle from which the sample was selected. Electrophoretic and immunohistochemical analysis of the fragment in normal cartilage showed that in immature cartilage it was deposited mainly in the surface layers, whereas in mature samples it was distributed throughout the depth of the tissue. In contrast, immunoreactivity of osteoarthritic cartilage was always less and the distribution was more variable than in normal cartilage of the same age. (1) The proteolytic cleavage of aggrecan by aggrecanase is a normal homeostatic event and much of the neo-C terminal fragment produced by the enzyme is retained in the tissue. (2) The presence of this immunoreactive product in normal cartilage can be used as an indication of aggrecan turnover. (3) That in osteoarthritic cartilage there is a reduction in the concentration of the G1-fragments. ",0
2483,11520263,Six-year trends in productivity and utilization of 73 clinical laboratories: a College of American Pathologists Laboratory Management Index Program study,"To describe longitudinal trends in the efficiency, labor productivity, and utilization of clinical laboratories in the United States. Financial and activity data were prospectively collected from 73 clinical laboratories continuously enrolled in the College of American Pathologists Laboratory Management Index Program from 1994 through 1999. Each laboratory reported quarterly on its costs, labor inputs, and test activity using uniform data definitions. During the 6-year study period, there was a significant increase in laboratory labor productivity (2.1% more tests/full-time equivalent/y; P <.001). Productivity increases were offset by increasing labor expense (1.5%/full-time equivalent/y; P <.001), consumable expense (1.7%/on-site test/y; P =.005), and blood expense, which comprised more than 10% of laboratory expenses by 1999 (4.4% increase/y; P <.001). As a result, overall expense per test showed no significant change in non-inflation-adjusted dollars. Reference laboratory expense per test did not change significantly during the study period; the proportion of tests sent to reference laboratories grew slightly (0.06% increase/y; P <.001). Test volume of the median laboratory grew by 5442 tests per year (2.3% annual increase; P <.001), while the proportion of testing from inpatients declined by 1.7% per year (P <.001). Inpatient test utilization declined on a discharge basis (annual decline of 1.2 tests/inpatient discharge; P <.001) and on a per diem basis (annual decline of 0.08 tests/inpatient day; P =.002). Inpatient laboratory expense declined on a discharge basis (annual decline of $2.40 or 1.3% per discharge; P <.001), but did not change significantly per inpatient day. Most of the reduction in the expense per discharge occurred during 1994-1996. Between 1994 and 1999, clinical laboratories in the United States experienced significant changes in the cost of operations, utilization, and labor productivity. Laboratory administrators who compare local institutional performance with that of peers are advised to use current or forward-trended peer data. Quarter-to-quarter improvement in many measures of laboratory financial activity may not signal a superior operation, as performance of the whole industry appears to be improving. ",0
2484,11526541,"Activation of caspases occurs downstream from radical oxygen species production, Bcl-xL down-regulation, and early cytochrome C release in apoptosis induced by transforming growth factor beta in rat fetal hepatocytes","Most of the morphologic changes that are observed in apoptotic cells are caused by a set of cysteine proteases (caspases) that are activated during this process. In previous works from our group we found that treatment of rat fetal hepatocytes with transforming growth factor beta1 (TGF-beta1) is followed by apoptotic cell death. TGF-beta1 mediates radical oxygen species (ROS) production that precedes bcl-xL down-regulation, loss of mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-3 (Herrera et al., FASEB J 2001;15:741-751). In this work, we have analyzed how TGF-beta1 activates the caspase cascade and whether or not caspase activation precedes the oxidative stress induced by this factor. Our results show that TGF-beta1 activates at least caspase-3, -8, and -9 in rat fetal hepatocytes, which are not required for ROS production, glutathione depletion, bcl-xL down-regulation, and initial cytochrome c release. However, caspase activation mediates cleavage of Bid and Bcl-xL that could originate an amplification loop on the mitochondrial events. An interesting result is that transmembrane potential disruption occurs later than the initial cytochrome c release and is mostly blocked by the pan-caspase inhibitor Z-VAD.fmk, indicating that the decrease in mitochondrial transmembrane potential (Delta(Psi)m) may be a consequence of caspase activity rather than the mechanism by which TGF-beta induces cytochrome c efflux. Finally, although Z-VAD.fmk completely blocks nucleosomal DNA fragmentation, it only delays cell death, which suggests that activation of the apoptotic program by TGF-beta in fetal hepatocytes inevitably leads to death, with or without caspases.",0
2485,11547740,Infection with GB virus C and reduced mortality among HIV-infected patients,"BACKGROUND: The flavivirus GB virus C (GBV-C, also designated hepatitis G virus) was identified in a search for hepatitis viruses, but no disease is currently known to be associated with it. We investigated the relation between coinfection with GBV-C and the long-term outcome in patients infected with the human immunodeficiency virus (HIV). METHODS: A total of 197 HIV-positive patients were followed prospectively beginning in 1993 or 1994. Of these patients, 33 (16.8 percent) tested positive for GBV-C RNA, 112 (56.9 percent) had detectable antibodies against the GBV-C envelope protein E2, and 52 (26.4 percent) had no marker of GBV-C infection and were considered unexposed. We assessed the relation between GBV-C infection and the progression of HIV disease. We also tested 169 GBV-C-positive plasma samples with a quantitative branched-chain DNA (bDNA) assay in order to investigate possible correlations between GBV-C viral load and both the CD4+ cell count and the HIV load. RESULTS: Among the patients who tested positive for GBV-C RNA, survival was significantly longer, and there was a slower progression to the acquired immunodeficiency syndrome (AIDS) (P<0.001 for both comparisons). Survival after the development of AIDS was also better among the GBV-C-positive patients. The association of GBV-C viremia with reduced mortality remained significant in analyses stratified according to age and CD4+ cell count. In an analysis restricted to the years after highly active antiretroviral therapy became available, the presence of GBV-C RNA remained predictive of longer survival (P=0.02). The HIV load was lower in the GBV-C-positive patients than in the GBV-C-negative patients. The GBV-C load correlated inversely with the HIV load (r=-0.33, P<0.001) but did not correlate with the CD4+ cell count. CONCLUSIONS: Coinfection with GBV-C is associated with a reduced mortality rate in HIV-infected patients. GBV-C is not known to cause any disease, but it is possible that its presence leads to an inhibition of HIV replication. However, GBV-C infection could also be a marker for the presence of other factors that lead to a favorable HIV response.",0
2486,11556302,Changing the status of drugs from prescription to over-the-counter availability,"The availability of drugs on an over-the-counter basis, including those previously available only by prescription, provides patients with improved access to effective therapies. Removal of the requirement for prescriptions saves both the health care professional and the patient time. However, the overall effect on health care costs is complex. One such effect may be that costs shift from third-party payers to patients. In addition, short-term cost savings may be offset over the long term by problems due to inappropriate use or suboptimal therapy. Optimal therapy with an over-the-counter drug requires that the consumer diagnose the underlying condition correctly and use the drug in a manner that minimizes risk. Assessment of the ability of patients to use drugs in this manner is a critical component of the regulatory review of over-the-counter drugs. The available data arouse the concern that without the supervision of a health care professional, some patients may not be able to use over-the-counter drugs appropriately for certain diagnoses or chronic conditions or in high-risk situations. On the other hand, the widespread use of over-the-counter aspirin on a long-term basis for cardiovascular-risk reduction illustrates the potential value of increased drug availability for long-term therapy. Advances in technology may facilitate the growth of over-the-counter drug therapy. For example, the wide availability and acceptance of reliable methods for measuring serum cholesterol in nonmedical settings may eventually contribute to the safety and effectiveness of over-the-counter treatments for hyperlipidemia. Thus, the future promises increases in the number of drugs available over the counter and in the variety of indications for their use.",0
2487,11584379,Endothelial cell-mediated uptake of a hepatitis B virus: a new concept of liver targeting of hepatotropic microorganisms,"The liver is a target for many infectious agents, most notably hepatitis viruses. However, several receptor molecules identified so far for hepatitis viruses were found to be ubiquitously expressed and can thus not account for efficient liver targeting. Using a model hepatitis B virus, the duck hepatitis B virus (DHBV), we have obtained data indicating that scavenging liver sinusoidal endothelial cells (LSEC), rather than hepatocytes themselves, play the key role in the initial uptake of viral pathogens into the liver. Experiments with fluorescent viral particles and coated gold particles in test animals, as well as in primary liver cell culture, demonstrated a preferential uptake of the viral substrates into LSEC. Intracellularly, fluorescent virus particles internalized by LSEC colocalized with the DHBV receptor, carboxypeptidase D, suggesting receptor-mediated rescue from lysosomal degradation. To comply with the high efficiency by which hepatitis B viruses infect hepatocytes in vivo, we propose that viruses initially scavenged by LSEC are thereafter released to infect adjacent hepatocytes, the only cells capable of replicating these viruses. Such a model of primary uptake into LSEC may illustrate a general mechanism by which blood-borne hepatotropic agents are targeted to the hepatocytes in the liver.",0
2488,11584382,Woodchuck hepatocytes remain permissive for hepadnavirus infection and mouse liver repopulation after cryopreservation,"Isolated hepatocytes represent a relevant model of the liver and are highly required both for research and therapeutic applications. However, sources of primary liver cells from human beings and from some animal species are limited. Therefore, cryopreservation of hepatocytes could greatly facilitate advances in various research areas. The aim of this study was to evaluate whether cryopreserved primary woodchuck hepatocytes could be used for woodchuck hepatitis B virus (WHV) infection studies, and whether they could maintain their regenerative potential in vivo after thawing. Critical steps for good quality of cryopreserved hepatocytes included the use of University of Wisconsin (UW) solution as a main component of the freezing medium, stepwise reduction of dimethylsulfoxide (DMSO) to avoid osmotic shock, and maintenance of low concentrations of DMSO in the culture medium. After cryopreservation, cell viability was still high (70% to 80%), and 50% to 60% of thawed cells attached to the plates. The appearance of covalently closed circular (ccc)DNA and of WHV-replicative forms a few days after in vitro infection demonstrated that thawed woodchuck hepatocytes were still susceptible to viral infection, thus proving maintenance of a very high hepatocyte-specific differentiation status. Furthermore, transplantation of woodchuck hepatocytes into the liver of urokinase-type plasminogen activator (uPA)/recombination activation gene-2 (RAG-2) mice, a model of liver regeneration, demonstrated that cryopreserved cells retained the ability to divide and to extensively repopulate a xenogenic liver. Notably, in vivo susceptibility to infection with WHV and proliferative capacity of frozen/thawed woodchuck hepatocytes in recipient mice were identical to those observed by transplanting fresh hepatocytes.",0
2489,11586952,Widespread distribution of urinary tract infections caused by a multidrug-resistant Escherichia coli clonal group,"BACKGROUND: The management of urinary tract infections is complicated by the increasing prevalence of antibiotic-resistant strains of Escherichia coli. We studied the clonal composition of E. coli isolates that were resistant to trimethoprim-sulfamethoxazole from women with community-acquired urinary tract infections. METHODS: Prospectively collected E. coli isolates from women with urinary tract infections in a university community in California were evaluated for antibiotic susceptibility, O:H serotype, DNA fingerprinting, pulsed-field gel electrophoretic pattern, and virulence factors. The prevalence and characteristics of an antibiotic-resistant clone were evaluated in this group of isolates and in those from comparison cohorts in Michigan and Minnesota. RESULTS: Fifty-five of the 255 E. coli isolates (22 percent) from the California cohort were resistant to trimethoprim-sulfamethoxazole as well as other antibiotics. There was a common pattern of DNA fingerprinting, suggesting that the isolates belonged to the same clonal group (clonal group A), in 28 of 55 isolates with trimethoprim-sulfamethoxazole resistance (51 percent) and in 2 of 50 randomly selected isolates that were susceptible to trimethoprim-sulfamethoxazole (4 percent, P<0.001). In addition, 11 of 29 resistant isolates (38 percent) from the Michigan cohort and 7 of 18 (39 percent) from the Minnesota cohort belonged to clonal group A. Most of the clonal group A isolates were serotype O11:H(nt) or O77:H(nt), with similar patterns of virulence factors, antibiotic susceptibility, and electrophoretic features. CONCLUSIONS: In three geographically diverse communities, a single clonal group accounted for nearly half of community-acquired urinary tract infections in women that were caused by E. coli strains with resistance to trimethoprim-sulfamethoxazole. The widespread distribution and high prevalence of E. coli clonal group A has major public health implications.",0
2490,11596591,Lack of health insurance and decline in overall health in late middle age,"BACKGROUND: The number of adults in their 50s and 60s in the United States who do not have health insurance is increasing. This group may be particularly vulnerable to the ill effects of being uninsured. METHODS: We conducted a prospective cohort study using files from the Health and Retirement Study, a national survey of adults who were 51 to 61 years old in 1992. We determined the risks of a major decline in overall health and of the development of new physical difficulties between 1992 and 1996 for participants who were continuously uninsured (uninsured in 1992 and in 1994), those who were intermittently uninsured (uninsured either in 1992 or in 1994), and those who were continuously insured. We used logistic regression to determine the independent effects of being uninsured on health outcomes after adjustment for base-line sociodemographic factors, preexisting medical conditions, and types of health-related behavior such as smoking and alcohol use. RESULTS: We analyzed data for 7577 participants. The 717 continuously uninsured participants and the 825 intermittently uninsured participants were more likely than the 6035 continuously insured participants to have a major decline in overall health between 1992 and 1996 (21.6 percent, 16.1 percent, and 8.3 percent of the three groups, respectively; P<0.001 for both comparisons). According to a multivariate analysis, the adjusted relative risk of a major decline in overall health was 1.63 (95 percent confidence interval, 1.26 to 2.08) for continuously uninsured participants and 1.41 (95 percent confidence interval, 1.11 to 1.78) for intermittently uninsured participants, as compared with continuously insured participants. A new difficulty in walking or climbing stairs was also more likely to develop in the continuously or intermittently uninsured participants than in the continuously insured participants (28.8 percent, 26.4 percent, and 17.1 percent of the three groups, respectively; P<0.001 for both comparisons). The adjusted relative risk of such a new physical difficulty was 1.23 (95 percent confidence interval, 1.02 to 1.47) for the continuously uninsured participants and 1.26 (95 percent confidence interval, 1.01 to 1.54) for the intermittently uninsured participants. CONCLUSIONS: The lack of health insurance is associated with an increased risk of a decline in overall health among adults 51 to 61 years old.",0
2491,11639780,The evolution and characteristics of social hygiene in modern Japan],"The purpose of this paper is the clarification of the theory of social hygiene and its conception in modern society. The theory of social hygiene in modern society was mainly formed by the influence of social democracy and the social reform movement. Social hygiene in modern Japan was presented by Germany in the middle Meiji era and prevailed in the Taisho era. Yoshie Fukuhara, Gito Terouka and Teido Kunisaki developed the mainstream of the theory about social hygiene in modern Japan. The principle of social hygiene in Japan was that the target group of social hygienic activities (such as laborers, poor people, consumers of medical service and so on) should establish the idea of self-government and autonomy of their lives. Social supports to the target group were recognized as combining with the idea of self-government and autonomy of lives. Some of those activities influenced by the principle were performed. Particularly, the work of Tetsuo Hoshino was unique in showing the relation between health and human culture. The work has shown that human health is reflected in human cultural activities. Social hygiene was important to the foundation of introduction and evolution of the thoughts of public health, health culture and medical insurance in modern Japan. ",0
2492,11640959,Promotion of neural cell adhesion by electrochemically generated and functionalized polymer films,"""New strategies for spatially controllable cell adhesion have been developed for brain cells from embryonic chicken. They are based on electrochemically active phenol and pyrrole derivatives, and can be used for the selective coverage of electroconductive substrates. Besides mimicking standard laminin-related adhesion promoting mechanisms by means of an electroactive monomer-linked 18-peptide segment from laminin (SRARKQAASIKVAVSADR), electrochemically generated thin (6-30 nm) polymer films of 3-hydroxybenzyl-hydrazine (3HBH) and 2-(3-hydroxyphenyl)-ethanol (2(3HP)E) with and without mechanically entrapped or covalently linked D-lysine have proved to promote cell adhesion in serum-free medium on indium-doped tin oxide (ITO) substrates during the first 6 culturing days in vitro. The effectiveness of the peptide was strongly density-dependent. Unexpectedly, laminin itself or a combination of laminin and poly-D-lysine (PDL) did not promote cell adhesion and neuron differentiation in serum-free cultures on ITO. However, they worked perfectly well on regular polystyrene substrates in serum-free medium or on ITO when medium with serum was used. This finding might suggest that the adhesion efficiency of laminin does not depend only on the kind of medium supplement but also on the type of substrate. In contrast, the adhesion-promoting properties of """"artificial"""" polymeric films seemed to be based on a more direct cell-film interaction, with the film masking the substrate properties. """,0
2493,11640997,Diabetic ketoacidosis in a case of pheochromocytoma,"A 31-year-old woman was admitted to our hospital because of diabetic ketoacidosis (DKA). Ultrasound sonography revealed the existence of the left adrenal tumor and endocrinological examinations established a diagnosis of pheochromocytoma. She had been healthy and there was no evidence for gestational diabetes in her personal history. Characteristic features were not found in her tumor size and the catecholamine levels as compared with typical cases of pheochromocytoma. An overwhelming secretion of catecholamine might suppress insulin secretion, as evidenced by the improvement after the resection of the tumor. However, a significant insulin resistance continued after tumor resection. Obesity and the heterozygosity of beta3-adrenergic receptor gene (Try64Arg) might play a role in insulin resistance, which resulted in DKA at least in part. Literature survey revealed four cases of DKA in the patients with pheochromocytoma including ours, three of which were Japanese. Pancreatic capacity to secrete insulin has been reported to be less than Caucasians, which might be another reason for DKA. Thus, we speculate that both suppressed insulin secretion and insulin resistance deteriorated by obesity or other factor(s) such as abnormality in beta3 adrenergic receptor probably depress beta-cell function resulting in abnormal metabolic imbalance such as DKA. ",0
2494,11640999,A policy analysis of the introduction and dissemination of external peer review (visitatie) as a means of professional self-regulation amongst medical specialists in The Netherlands in the period 1985-2000,"By examining the introduction and dissemination of external peer review through site-visits (visitatie) amongst Dutch medical specialists, this paper sets out to deepen our insight into the dynamics of professional self-regulation and health care policy making. We explore how visitatie has been used in the political process between medical specialists and the state, serving as a strategy in protecting the autonomy of physicians. In the late eighties and early nineties, factors both internal as well as external to the medical profession all together determined the start and spread of visitatie. The conflict between state and doctors over the specialists' income, the introduction of the market oriented policies, new visions on quality assurance, the debate on the future of medical specialistic care and a new legal framework on quality assurance, challenged the medical community to find ways to reconfirm the public's trust in the self-regulating mechanism of the profession. One answer is found in carrying out 300-400 visitaties annually. During the past years, many stakeholders have perceived visitatie as a credible instrument in assuring quality patient care. The dynamics of professionalization and measurable impact of visitatie will determine whether or not it is here to stay. ",0
2495,11641030,The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants,"The aim of the study was to determine the effect of a low oral dose of erythromycin on whole gastrointestinal transit time [WGTT]. Erythromycin [EM] [1.5 mg/kg, 6 hourly] or placebo was given first over 7 days in a double blind randomized crossover study of 21 preterm infants with feed intolerance. Median [range] birth weight was 1420 [690, 2200] g and postconceptual age 32. 5 [20, 36.4] weeks. WGTT was assessed on day 3 of each treatment, by timing the transit of carmine red through the gut. Treatments were compared using Student's paired t test. WGTT was significantly shorter following EM treatment as compared to placebo: mean [SD] 10.16 [4.6] h vs. 15. 9 [7.2] h, p<0.01. Oral low-dose EM significantly shortens WGTT of feed-intolerant preterm infants. ",0
2496,11641248,Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo,"Angiogenesis is an ordered process requiring the inter-play of numerous cellular and humoral factors. Studies over the past 20 years have identified several growth factors, cytokines, and enzymes that promote blood vessel formation. Most have revealed how individual factors promote an angiogenic phenotype in endothelial cells in vitro or contribute to blood vessel formation in vivo. However, the fundamental question that remains unanswered is how the cellular microenvironment contributes to angiogenesis. Fibrocytes are a recently characterized mesenchymal cell type isolated from peripheral blood that rapidly enter subcutaneously implanted wound chambers and sites of tissue injury. Here we describe the induction of an angiogenic phenotype in microvascular endothelial cells in vitro and promotion of angiogenesis in vivo by cultured fibrocytes. Fibrocytes constitutively secrete extracellular matrix-degrading enzymes, primarily matrix metalloproteinase 9, which promotes endothelial cell invasion. In addition, fibrocytes secrete several proangiogenic factors including VEGF, bFGF, IL-8, PDGF, and hematopoietic growth factors that promote endothelial cell migration, proliferation, and/or tube formation. By contrast, they do not produce representative antiangiogenic factors. Finally, both autologous fibrocytes and fibrocyte-conditioned media were found to induce blood vessel formation in vivo using the Matrigel angiogenesis model. ",0
2497,11641776,Cell cycle-independent upregulation of p27Kip1 by p21Waf1 in K562 cells,"Cellular differentiation frequently involves sequential peaks in the expression of cyclin-dependent kinase inhibitors (cdki's). For example, an increase in levels of the cdki p27Kip1 follows upregulation of p21Waf1 in several cell types induced to differentiate by diverse stimuli. In this study, we have investigated whether p21Waf1 expression itself, rather than the differentiating agent, could be increasing p27Kip1 protein levels. We used an inducible p21Waf1 expression vector in a K562 leukemic cell model which we had previously shown to initiate differentiation following p21Waf1 upregulation. The current study reports that p21Waf1 upregulated p27Kip1 protein without altering p27Kip1 mRNA levels. This effect did not depend on G1-phase arrest-the increase in p27Kip1 occurred at all phases of the cell cycle. p21Waf1-expressing extracts inhibited phosphorylation of p27Kip1 on threonine-187, leading to decreased ubiquitination and decreased proteasomal destruction of p27Kip1. In K562 cells, upregulation of p27Kip1 by p21Waf1 during differentiation facilitated an ordered transition between these two cdki's, each of which may distinctly influence the differentiation process. ",0
2498,11641891,Verification of the diagnosis of Buerger's disease in outpatients],"The aim of the paper was to estimate the correctness of thromboangiitis obliterans (TAO) diagnosis in ambulatory patients. 99 patients with initial diagnosis of TAO selected from 3137 outpatients, have been examined in consulting unit for vascular diseases, from 1996 to 1998. Burger's disease has been diagnosed in 26 patients in accordance with Shionoya's criteria. Applying the point scoring system suggested by Papa et al., certain diagnosis could be made in 21 patients and probable on in 3 patients. Of the remaining patients, it is interesting to note that manual examination revealed absence of pulsation at femoral and popliteal arteries in 60% of patients and 42% of patients demonstrated atherosclerosis risk factors. On the other hand superficial thrombophlebitis and Raynaud's phenomenon have been rarely diagnosed in 5 and 18% respectively. ",0
2499,11642119,Differences in individual sensitivity to the antimutagenic effect of retinol in lymphocytes from workers in contact with nickel compounds],"Individual sensitivity to nickel compounds was studied in workers employed in nickel industry. The mutagen sensitivity was inferred from the number of sister chromatid exchanges (SCEs), which was used to characterize the structural alterations of the chromosomes in workers' lymphocytes before and after administration of retinol for a month. The SCE number decreased after retinol administration in nine out of eleven workers. ",0
2500,11642133,Four new mutations and polymorphic variants of the low density lipoprotein receptor in patients with familial hypercholesterolemia in Saint Petersburg],"In a collection of DNA samples from 100 unrelated patients with clinical features of familial hypercholesterolemia (FH), a search for mutations of exons 4 and 10 of the low-density lipoprotein (LDL) receptor gene was performed using heteroduplex and single-strand conformational polymorphism (SSCP) analyses followed by sequencing of amplified DNA fragments. Four new mutations of the LDL receptor gene were identified: C146R (c.499 T > C), A130P (c.451 G > C), G128G (c.477 T > C), and C188Y (c.626 G > A). Mutation A130P was assigned to the same chromosome with allele variant 447C. Two polymorphic sites in exon 10 of the LDL receptor gene (1413G/A and 1545C/T) were found in the Russian population for the first time. Based on the data obtained, familial hypercholesterolemia was confirmed in seven patients. ",0
2501,11642283,Experimental study of materials for patch graft on right ventricular outflow tract under extracorporeal circulation in dogs--comparison between Denacol EX-313-treated bovine jugular vein graft and expanded polytetrafluoroethylene (EPTFE) graft,"A comparison between a bovine jugular vein treated with a hydrophilic polyepoxy compound cross-linker (Denacol), and expanded polytetrafluoroethylene (EPTFE), an artificial material, as a patch graft for the reconstruction of the right ventricular outflow tract under extracorporeal circulation in dogs, as if they had pulmonic stenosis, was made. Hemodynamic and histological examinations were conducted two weeks after the transplantation. Hemodynamic problems were not observed in either the Denacol or EPTFE groups. Macroscopically, organization of new tissue on the graft surface was more marked in the EPTFE group than in the Denacol group, and newly-formed tissue was seen surrounding the border of the graft and burying it in the EPTFE group. In the Denacol group, microscopic findings revealed the presence of inflammatory cells and fibroblasts, and an invasion of the graft by collagen fibers and elastic fibers. In the EPTFE group, there was minimal cellular infiltration of the graft and a thick layer consisting of collagen fibers and fibroblasts was observed around the graft. These results indicated that two weeks after transplantation the graft was better assimilated and organized with blood vasculature in the patch graft in the Denacol group than in the EPTFE group. ",0
2502,11642683,The relationship of personality dimensions as measured by the temperament and character inventory and quality of life in individuals with schizophrenia or schizoaffective disorder living in the community,The influence of personality factors on the appraisal of subjective quality of life in individuals with schizophrenia or schizoaffective disorder is not much investigated. The present study examined this relationship in a sample of 104 patients living in the community. The temperament and character inventory was used to assess personality and the Lancashire quality of life profile was used to assess quality of life. The results showed that lower levels of harm avoidance and higher levels of self-directedness were significantly correlated to a better subjective quality of life. Regression analyses controlling for psychopathology revealed that a higher level of self-directedness was significantly associated with a better subjective quality in all aspects measured and explained the variance in the latter in the range of 4-12%. It is concluded that personality factors are involved in severely mentally ill individuals' assessment of their quality of life and should be accounted for in evaluations of quality of life assessments. The strength and directions of this influence require further studies. ,0
2503,11642910,Inadequacies with the ACOG and AAP statements on managing ethical conflict during the intrapartum period,"[The American College of Obstetricians and Gynecologists] takes the view that respect for the autonomy of the pregnant woman should be almost absolute and [the American Academy of Pediatrics] takes the view that respect for the autonomy of the pregnant woman should be limited or prima facie in character.  ACOG's reading of this central bioethical principle admits of virtually no exceptions, while AAP's reading does allow exceptions....A complete account of obstetric ethics that would apply in clinical practice during the intrapartum period must take into account both negative and positive autonomy-based rights of the pregnant woman and beneficence-based obligations to the at-term fetus -- and to the pregnant woman, as well.  Such an account will be, we believe, more clinically applicable than the accounts offered by ACOG and AAP. ",0
2504,11732000,Patterns of regional sympathetic nerve traffic in preascitic and ascitic cirrhosis,"Overactivity of the sympathetic nervous system and portal hypertension are key factors in the development of ascites in cirrhosis. The sympathoexcitation that characterizes the more advanced stages of liver diseases is less clearly defined in preascitic cirrhosis. We measured sympathetic nerve traffic to skeletal muscle (peroneal nerve) and to skin districts by microneurography in (1) 12 Child class A cirrhotic patients with clinically significant portal hypertension (portal pressure gradient > 10 mm Hg, 14.8 +/- 1.2 mm Hg, mean +/- SEM) but without actual or previous ascites, (2) 16 Child class C cirrhotic patients with tense ascites, and (3) 10 patients with mild congestive heart failure, a condition paradigmatic of a marked sympathetic activation. Muscle sympathetic nerve traffic was markedly increased in Child class C subjects as compared with controls (23.9 +/- 1.6 bursts/min, P <.01) and superimposable to that recorded in heart failure patients (52.9 +/- 4.7 vs. 60.3 +/- 2 bursts/min, P = not significant). Muscle sympathetic nerve traffic was also increased in Child class A subjects (41.6 +/- 2 bursts/min, P <.01 vs. controls) although to a lesser extent (P <.05 vs. Child class C patients). Skin sympathetic nerve traffic was within the normal range in all patients. Neurohormones were all markedly increased in Child class C subjects. Only norepinephrine was increased in Child class A patients. Our data show that sympathetic nerve traffic activation (1) is already detectable in Child class A cirrhosis when clinically significant portal hypertension is present but ascites never developed and (2) is not generalized because although muscle traffic is increased, skin traffic is within normal range. The role of drugs modulating sympathoactivation should be investigated in preascitic cirrhosis.",0
2505,11732008,Notch receptor expression in adult human liver: a possible role in bile duct formation and hepatic neovascularization,"Notch signaling is an evolutionarily conserved mechanism, used to regulate cell fate decisions. Four Notch receptors have been identified in man (Notch-1 to -4). In this study, semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to examine the expression pattern of Notch receptor genes in whole adult human liver and isolated liver cell preparations. All 4 receptors were expressed in the adult liver, with no significant differences in the levels of Notch-1, -2, and -4 messenger RNA (mRNA) between normal and diseased liver. However, Notch-3 expression appeared to be increased in diseased tissue. The distribution of Notch-1 and -4 in normal tissue was similar, with Notch-1 also detectable at low levels in the sinusoidal endothelium. Notch-2 expression was more widely distributed, and detectable in hepatocytes, medium-sized bile ducts, and the sinusoidal endothelium. Notch-3 expression was seen on hepatocytes, with weaker expression detectable in portal veins, hepatic arteries, and the sinusoids. In normal liver tissue Notch-1, -2, and -3 were found to be coexpressed on bile duct epithelium; however, with the exception of Notch-3 in primary sclerosing cholangitis (PSC) livers, expression was absent on proliferating ductules in all disease states examined. Interestingly, the expression of Notch-2 and -3 was associated with numerous small vessels within the portal tract septa of diseased tissue. The absence of Notch receptor expression on proliferating bile ductules and its presence on neovessels suggests that Notch signaling may be important for normal bile duct formation and the aberrant neovascularization seen in diseased liver tissue.",0
2506,11732011,Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope,"The immunogenicity of the Hepatitis C virus (HCV) nonstructural protein 3 (NS3) was investigated using different DNA-based strategies and a preclinical mouse model transgenic for the HLA-A2.1 molecule. Plasmids expressing NS3 either as a wild-type protein, as a fusion with murine lysosome-associated-membrane protein-1 specific sequences, or under the control of the Semliki Forest virus replicase were evaluated in vitro and in vivo. All plasmids were shown to express the expected size protein. These 3 NS3-expressing vaccines induced overall comparable levels of CTLs when measured at different times postvaccination although mice injected with the NS3-LAMP expressing plasmid showed a particularly homogeneous and overall vigorous response (specific lysis ranged from 60% to 90 % for an E:T ratio of 33.3:1 with a mean CTL precursor frequency of 1:2.10(5) cells). Out of the four HLA-A2.1-restricted NS3 epitopes previously described in HCV infected patients (aa 1073-1081, aa 1406-1415; aa 1169-1177 and aa 1287-1296), the NS3-DNA generated CTLs were predominantly targeted at the aa 1073-1081 epitope. Peptide-based immunization showed that the mouse repertoire was intact for all epitopes tested except one (aa 1287-1296). In conclusion, the 3 NS3-DNA vaccines although based on different mode of action, shared a comparable efficacy at inducing CTL. Surprisingly, the breadth of such response was restricted to a single, major epitope.",0
2507,11742045,The effect of group psychosocial support on survival in metastatic breast cancer,"BACKGROUND: Supportive-expressive group therapy has been reported to prolong survival among women with metastatic breast cancer. However, in recent studies, various psychosocial interventions have not prolonged survival. METHODS: In a multicenter trial, we randomly assigned 235 women with metastatic breast cancer who were expected to survive at least three months in a 2:1 ratio to an intervention group that participated in weekly supportive-expressive group therapy (158 women) or to a control group that received no such intervention (77 women). All the women received educational materials and any medical or psychosocial care that was deemed necessary. The primary outcome was survival; psychosocial function was assessed by self-reported questionnaires. RESULTS: Women assigned to supportive-expressive therapy had greater improvement in psychological symptoms and reported less pain (P=0.04) than women in the control group. A significant interaction of treatment-group assignment with base-line psychological score was found (P</=0.003 for the comparison of mood variables; P=0.04 for the comparison of pain); women who were more distressed benefited, whereas those who were less distressed did not. The psychological intervention did not prolong survival (median survival, 17.9 months in the intervention group and 17.6 months in the control group; hazard ratio for death according to the univariate analysis, 1.06 [95 percent confidence interval, 0.78 to 1.45]; hazard ratio according to the multivariate analysis, 1.23 [95 percent confidence interval, 0.88 to 1.72]). CONCLUSIONS: Supportive-expressive group therapy does not prolong survival in women with metastatic breast cancer. It improves mood and the perception of pain, particularly in women who are initially more distressed.",0
2508,11752355,Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation,"BACKGROUND: Successful engraftment of hematopoietic stem cells from unrelated donors is influenced by disparities between the donor and recipient for HLA-A, B, and C alleles. Disparities between HLA sequence polymorphisms that are serologically detectable are termed antigen mismatches, whereas those that can be identified only by DNA-based typing methods are termed allele mismatches. Whether both kinds of polymorphisms are important in transplantation is not known. We tested the hypothesis that allele mismatches that are detectable only at the DNA level are less immunogenic than those that are serologically detectable and thereby are associated with a lower risk of graft failure after hematopoietic-cell transplantation METHODS: We used DNA sequencing to define the HLA-A, B, and C alleles in 471 patients who received bone marrow from unrelated donors for the treatment of chronic myeloid leukemia after myeloablative conditioning therapy. The odds ratios for graft failure were determined for recipients of transplants from donors with a single class I allele mismatch, a single class I antigen mismatch, or two or more class I mismatches, as compared with those with no mismatch RESULTS: A single HLA allele mismatch did not increase the risk of graft failure, whereas a single antigen mismatch significantly increased the risk. The risk was also increased if the recipient was HLA homozygous at the mismatched class I locus or if the donor had two or more class I mismatches CONCLUSIONS: HLA class I antigen mismatches that are serologically detectable confer an enhanced risk of graft failure after hematopoietic-cell transplantation. Transplants from donors with a single class I allele mismatch that is not serologically detectable may be used without an increased risk of graft failure.",0
2509,11752356,"Acetaminophen, aspirin, and chronic renal failure","BACKGROUND: Several epidemiologic studies have demonstrated an association between heavy consumption of nonnarcotic analgesics and the occurrence of chronic renal failure, but it is unclear which is the cause and which is the effect METHODS: In a nationwide, population-based, case-control study of early-stage chronic renal failure in Sweden, face-to-face interviews were conducted with 926 patients with newly diagnosed renal failure and 998 control subjects, of whom 918 and 980, respectively, had complete data. We used logistic-regression models to estimate the relative risks of disease-specific types of chronic renal failure associated with the use of various analgesics RESULTS: Aspirin and acetaminophen were used regularly by 37 percent and 25 percent, respectively, of the patients with renal failure and by 19 percent and 12 percent, respectively, of the controls. Regular use of either drug in the absence of the other was associated with an increase by a factor of 2.5 in the risk of chronic renal failure from any cause. The relative risks rose with increasing cumulative lifetime doses, rose more consistently with acetaminophen use than with aspirin use, and were increased for most disease-specific types of chronic renal failure. When we disregarded the recent use of analgesics, which could have occurred in response to antecedents of renal disease, the associations were only slightly attenuated CONCLUSIONS: Our results are consistent with the existence of exacerbating effects of acetaminophen and aspirin on chronic renal failure. However, we cannot rule out the possibility of bias due to the triggering of analgesic consumption by predisposing conditions.",0
2510,11752357,Cyclooxygenase inhibitors and the antiplatelet effects of aspirin,"BACKGROUND: Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies METHODS: We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily) RESULTS: Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin CONCLUSIONS: The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.",0
2511,11784875,Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer,"BACKGROUND: We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer. METHODS: A total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. RESULTS: The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1. CONCLUSIONS: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.",0
2512,11786962,Regulation of the alpha-fetoprotein gene by the isoforms of ATBF1 transcription factor in human hepatoma,"We investigated mechanisms regulating expression of alpha-fetoprotein (AFP) in 3 human hepatoma cell lines, HuH-7, HepG2, and huH-1, producing high, medium, and low levels of AFP, respectively. The silencer, a negative cis-acting element of the AFP gene, was highly activated in huH-1 and HepG2 to repress AFP enhancer activity by 91%, whereas only 26% repression was observed in HuH-7. To account for the difference in AFP production between HepG2 and huH-1, we investigated the roles of two isoforms of the AT motif-binding factor 1 (ATBF1) transcription factor, ATBF1-A and -B. Cotransfection assays showed that the ATBF1 isoforms regulated the AFP gene differently in HepG2 and huH-1. In huH-1 and HuH-7, both ATBF1 isoforms suppressed strongly enhancer activity and slightly promoter activity. In HepG2, on the other hand, ATBF1-A suppressed the enhancer and promoter activities, but surprisingly, ATBF1-B was found to stimulate enhancer activity while showing no effect on the promoter. Levels of ATBF1-A mRNA were similar in all 3 cell lines, whereas the expression ATBF1-B mRNA varied greatly, with the highest level seen in HepG2 followed by huH-1 and HuH-7. These results suggest that, in HepG2, ATBF1-B may have a dominant negative effect to relieve the transcriptional repression caused by its isoform. In support of this view, we found that the N-terminal region specific to the ATBF1-A molecule possessed transcriptional repressor activity. Thus, the use of the ATBF1 variants as well as the silencer may provide a unique mechanism that contributes to the determination of AFP levels in human hepatoma cell lines.",0
2513,11786978,Cis-preferential recruitment of duck hepatitis B virus core protein to the RNA/polymerase preassembly complex,"Hepadnaviral replication requires the concerted action of the polymerase and core proteins to ensure selective packaging of the RNA pregenome into nucleocapsids. Virus assembly is initiated by cis-preferential binding of polymerase to the encapsidation signal straightepsilon, present on pregenomic RNA. Using the duck hepatitis B virus (DHBV) model, we analyzed how core protein is recruited to the RNA/polymerase preassembly complex. Two sets of trans-complementation assays were performed in cotransfected hepatoma cells. First, a replication-competent DHBV construct was tested for its ability to rescue replication of genomes bearing mutations within the core region. Self-packaging of wild-type pregenomes was more efficient than cross-packaging of core-deficient pregenomes, and this bias was strongly enhanced if mutant pregenomes coded for self-assembly-competent, but packaging-deficient, core proteins. Second, the site of wild-type core protein translation, i.e., pregenomic RNA (cis) or separate messenger RNA (trans), was analyzed for its effect on the phenotype of a previously described dominant-negative (DN) DHBV core protein mutant. This mutant forms chimeric nucleocapsids with wild-type core proteins and blocks reverse transcription within most, but not all, mixed particles. Strikingly, suppression of viral DNA synthesis by the mutant increased 100-fold when wild-type core protein was provided in trans. Our results suggest that recruitment of core protein to the DHBV preassembly complex occurs in a cis-preferential manner. This mechanism may account for the leakiness of DN DHBV core protein mutants targeting reverse transcription.",0
2514,11794217,Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease,"BACKGROUND: Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may help to prevent Alzheimer's disease. The results, however, are inconsistent. METHODS: We studied the association between the use of NSAIDs and Alzheimer's disease and vascular dementia in a prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line, in 1991. To detect new cases of dementia, follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999. The risk of Alzheimer's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records. We defined four mutually exclusive categories of use: nonuse, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use), and long-term use (24 months or more of cumulative use). Adjustments were made by Cox regression analysis for age, sex, education, smoking status, and the use or nonuse of salicylates, histamine Hz-receptor antagonists, antihypertensive agents, and hypoglycemic agents. RESULTS: During an average follow-up period of 6.8 years, dementia developed in 394 subjects, of whom 293 had Alzheimer's disease, 56 vascular dementia, and 45 other types of dementia. The relative risk of Alzheimer's disease was 0.95 (95 percent confidence interval, 0.70 to 1.29) in subjects with short-term use of NSAIDs, 0.83 (95 percent confidence interval, 0.62 to 1.11) in those with intermediate-term use, and 0.20 (95 percent confidence interval, 0.05 to 0.83) in those with long-term use. The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia. CONCLUSIONS: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.",0
2515,11796848,Outcomes in young adulthood for very-low-birth-weight infants,"BACKGROUND: Very-low-birth-weight infants (those weighing less than 1500 g) born during the initial years of neonatal intensive care have now reached young adulthood. METHODS: We compared a cohort of 242 survivors among very-low-birth-weight infants born between 1977 and 1979 (mean birth weight, 1179 g; mean gestational age at birth, 29.7 weeks) with 233 controls from the same population in Cleveland who had normal birth weights. We assessed the level of education, cognitive and academic achievement, and rates of chronic illness and risk-taking behavior at 20 years of age. Outcomes were adjusted for sex and sociodemographic status. RESULTS: Fewer very-low-birth-weight young adults than normal-birth-weight young adults had graduated from high school (74 percent vs. 83 percent, P=0.04). Very-low-birth-weight men, but not women, were significantly less likely than normal-birth-weight controls to be enrolled in postsecondary study (30 percent vs. 53 percent, P=0.002). Very-low-birth-weight participants had a lower mean IQ (87 vs. 92) and lower academic achievement scores (P<0.001 for both comparisons). They had higher rates of neurosensory impairments (10 percent vs. <1 percent, P<0.001) and subnormal height (10 percent vs. 5 percent, P=0.04). The very-low-birth-weight group reported less alcohol and drug use and had lower rates of pregnancy than normal-birth-weight controls; these differences persisted when comparisons were restricted to the participants without neurosensory impairment. CONCLUSIONS: Educational disadvantage associated with very low birth weight persists into early adulthood.",0
2516,11807149,Frequency of uterine contractions and the risk of spontaneous preterm delivery,"BACKGROUND: The measurement of the frequency of uterine contractions has not been useful for reducing the rate of preterm delivery in randomized trials. Nonetheless, ambulatory monitoring of contractions continues to be used in clinical practice. METHODS: We assessed the frequency of uterine contractions as a predictor of the risk of spontaneous preterm delivery before 35 weeks of gestation. We enrolled women with singleton pregnancies between 22 and 24 weeks of gestation. The women used a contraction monitor at home to record contraction frequency twice daily on 2 or more days per week from enrollment to delivery or 37 weeks of gestation. RESULTS: We obtained 34,908 hours of successful monitoring recordings from 306 women. Although more contractions were recorded from women who delivered before 35 weeks than from women who delivered at 35 weeks or later, we could identify no threshold frequency that effectively identified women who delivered preterm infants. The sensitivity and positive predictive value of a maximal hourly frequency of contractions of four or more between 4 p.m. and 3:59 a.m. were 9 percent and 25 percent, respectively, at 22 to 24 weeks and 28 percent and 23 percent at 27 to 28 weeks. Other proposed screening tests, such as digital and ultrasound evaluations of the cervix and assays for fetal fibronectin in cervicovaginal secretions, also had low sensitivity and positive predictive value for preterm labor. CONCLUSIONS: Although the likelihood of preterm delivery increases with an increased frequency of uterine contractions, measurement of this frequency is not clinically useful for predicting preterm delivery.",0
2517,11826398,Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression,"Diabetes has been reported to increase the expression of cytochrome P450 (CYP) 2E1 messenger RNA (mRNA) and protein several-fold, and enhanced expression has been associated with elevated ketone bodies. Primary cultured rat hepatocytes were used to explore ketone body and insulin regulation of CYP2E1 expression. Hydroxybutyrate and acetoacetate (AC), alone or in combination, either failed to affect or decreased CYP2E1 mRNA levels by up to 90% relative to untreated hepatocytes. Insulin produced a concentration-dependent decrease in CYP2E1 mRNA levels, and insulin receptor immunoprecipitation showed a correspondence between receptor phosphorylation and the decrease in CYP2E1 mRNA levels at physiologic levels of insulin. Phosphatase inhibitors decreased CYP2E1 mRNA levels by greater than 95%. The phosphatidylinositol 3-kinase (PI3-kinase) inhibitors wortmannin or LY294002 and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated decrease in CYP2E1 mRNA levels. Geldanamycin, which inhibits Src kinase, also abrogated the insulin-mediated decrease in CYP2E1 mRNA levels. In contrast, the protein kinase C (PKC) inhibitor bisindolylmaleimide, the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, and the p38 mitogen-activated protein (MAP) kinase inhibitor SB202190 did not affect the insulin-mediated decrease in CYP2E1. CYP2E1 mRNA half-life decreased from approximately 48 hours in the absence of insulin to approximately 15 hours at 10 nmol/L insulin, and this decrease was prevented by wortmannin. The half-life of CYP2B mRNA was increased by insulin, whereas that of CYP3A was unaffected. Analysis of CYP2E1 gene transcription using heterogeneous nuclear RNA (hnRNA) showed that insulin suppressed CYP2E1 transcription. In conclusion, these data show involvement of transcriptional and posttranscriptional mechanisms in the insulin-mediated regulation of CYP2E1 and implicate PI3-kinase, p70 S6 kinase, and Src kinase in mediating these effects.",0
2518,11826415,Fine specificity of autoantibodies to soluble liver antigen and liver/pancreas,"Autoantibodies to soluble liver antigen and liver pancreas (SLA/LP) have been described as specific markers for Autoimmune Hepatitis (AIH), occurring in about 20% of patients with AIH. The high degree of specificity for SLA/LP in autoimmune liver disease suggests a possible role in its pathogenesis. This study aims to map the exact epitope(s) recognized by SLA/LP autoantibodies and to assess the role of molecular mimicry between microbial antigens and self-epitopes. Using SLA/LP-reactive sera of 18 individual AIH patients and a pool of 15 patient sera, we found the dominant immune reactivity directed to peptide p395-414 and a less prominent immune response to 2 other epitopes adjacent to the dominant epitope. Immunodominance of peptide p395-414 was confirmed by absorption experiments. The SLA/LP autoantibodies of all tested AIH patients were mainly of the IgG1 type, suggesting that SLA/LP autoantibodies may arise by a common and specific underlying immune stimulus. Based on sequence homologies of the SLA/LP antigenic region with viral proteins, it was hypothesized that molecular mimicry may drive autoimmunity to SLA/LP. However, the homologous virus-derived peptides were not recognized by SLA/LP autoantibodies. Similarly, the only known procaryotic homologue, MJ0610 of Methanococcus jannaschii, was only weakly recognized by SLA/LP-positive sera. Thus, no evidence could be found for molecular mimicry being the causative mechanism for the development of SLA/LP autoantibodies. In conclusion, the exquisite epitope specificity and IgG subtype are evidence for the maturity of the SLA/LP autoantibody response; a specific autoantigen-driven process underlying the immunopathogenesis is likely.",0
2519,11832528,Benefit of atrial pacing in sleep apnea syndrome,"BACKGROUND: Many patients with sleep apnea syndrome have nocturnal bradycardia, paroxysmal tachyarrhythmias, or both, which can be prevented by permanent atrial pacing. We evaluated the effect of using cardiac pacing to increase the heart rate during sleep in patients with sleep apnea syndrome. METHODS: We studied 15 patients (11 men and 4 women; mean [+/-SD] age, 69+/-9 years) with central or obstructive sleep apnea who had received permanent atrial-synchronous ventricular pacemakers for symptomatic sinus bradycardia. All patients underwent three polysomnographic evaluations on consecutive nights, the first night for base-line evaluation and then, in random order, one night in spontaneous rhythm and one in dual-chamber pacing mode with atrial overdrive (basic rate, 15 beats per minute faster than the mean nocturnal sinus rate). The total duration and number of episodes of central or obstructive sleep apnea or hypopnea were analyzed and compared. RESULTS: The mean 24-hour sinus rate during spontaneous rhythm was 57 +/- 5 beats per minute at base line, as compared with 72 +/- 3 beats per minute with atrial overdrive pacing (P<0.001). The total duration of sleep was 321 +/- 49 minutes in spontaneous rhythm, as compared with 331 +/- 46 minutes with atrial overdrive pacing (P=0.48). The hypopnea index (the total number of episodes of hypopnea divided by the number of hours of sleep) was reduced from 9 +/- 4 in spontaneous rhythm to 3 +/-3 with atrial overdrive pacing (P<0.001). For both apnea and hypopnea, the value for the index was 28 +/- 22 in spontaneous rhythm, as compared with 11 +/- 14 with atrial overdrive pacing (P<0.001). CONCLUSIONS: In patients with sleep apnea syndrome, atrial overdrive pacing significantly reduces the number of episodes of central or obstructive sleep apnea without reducing the total sleep time.",0
2520,11832530,Expression of p53 and prognosis in children with malignant gliomas,"BACKGROUND: The prognosis of children with high-grade gliomas is uncertain, even when clinical and histologic findings are considered. We investigated whether mutations in the TP53 gene or the degree of expression of p53 protein in high-grade gliomas is associated with progression-free survival in children with these tumors. METHODS: Paraffin-embedded specimens of malignant gliomas from children treated in the Children's Cancer Group study CCG-945 were assessed by mutational analysis of TP53 (121 specimens) and immunohistochemical analysis of p53 (115 specimens). For mutational studies, areas of tissue that contained malignant glioma were isolated by microdissection, and the DNA was subjected to polymerase-chain-reaction-based amplification and sequencing of TP53 exons 5, 6, 7, and 8. Immunohistochemical analysis was performed with the use of a microwave-enhanced antigen retrieval and an antibody that bound both wild-type and mutant p53. RESULTS: We found a significant association between overexpression of p53 and outcome; this association was independent of histologic features, age, sex, the extent of resection, and tumor location. The rate ( +/- SE) of progression-free survival at five years was 44 +/- 6 percent in the group of 74 patients whose tumors had low levels of expression of p53 and 17 +/- 6 percent in the group of 41 patients whose tumors had overexpression of p53 (P<0.001). A nonsignificant association was observed between mutations in TP53 and outcome. CONCLUSIONS: Overexpression of p53 in malignant gliomas during childhood is strongly associated with an adverse outcome, independently of clinical prognostic factors and histologic findings.",0
2521,11844848,Plasma homocysteine as a risk factor for dementia and Alzheimer's disease,"BACKGROUND: In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. METHODS: A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. RESULTS: Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled. CONCLUSIONS: An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.",0
2522,11844852,Promotion of prescription drugs to consumers,"BACKGROUND: Spending on prescription drugs is the fastest growing component of the health care budget. There is public concern about the possibility that direct-to-consumer advertising of prescription drugs will result in inappropriate prescribing and higher costs of care. Guidelines issued in 1997 by the Food and Drug Administration (FDA) regarding advertising to consumers through electronic media are considered by some to be responsible for unleashing a flood of direct-to-consumer advertising. METHODS: Using data on spending for promotional purposes and sales of prescription drugs, we examined industrywide trends for various types of promotion. We also tracked the relation between promotional efforts and sales over time. Finally, we documented the variation in direct-to-consumer advertising among and within five therapeutic classes of drugs and compared the variation in the intensity of such advertising with variation in the intensity of promotion to health care professionals. RESULTS: Annual spending on direct-to-consumer advertising for prescription drugs tripled between 1996 and 2000, when it reached nearly $2.5 billion. Despite this increase, such advertising accounts for only 15 percent of the money spent on drug promotion and is highly concentrated on a subgroup of products. Within a therapeutic class, there is marked variation in the intensity of direct-to-consumer advertising, and the amount of such advertising for specific products fluctuates over time. The initial surge in direct-to-consumer advertising preceded the 1997 FDA guidelines that clarified the rules for electronic direct-to-consumer advertising, and thus the 1997 guidelines may not have been the most important reason for the overall increase. CONCLUSIONS: Although the use of direct-to-consumer advertising has grown disproportionately to other forms of promotion, it continues to account for a small proportion of total promotional efforts. Nevertheless, physicians must assist patients in evaluating health-related information obtained through direct advertising.",0
2523,11870377,Hepatic arterial buffer response in patients with advanced cirrhosis,"Hepatic arterial buffer response (HABR) is considered an important compensatory mechanism to maintain perfusion of the liver by hepatic arterial vasodilation on reduction of portal venous perfusion. HABR has been suggested to be impaired in patients with advanced cirrhosis. In patients with hepatopetal portal flow, placement of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal venous liver perfusion. Accordingly, patients with severe cirrhosis should have impaired HABR after TIPS implantation. Therefore, the aim of this study was to investigate the effect of TIPS on HABR as reflected by changes in resistance index (RI) of the hepatic artery. A total of 366 patients with cirrhosis (Child-Pugh class A, 106; class B, 168; class C, 92) underwent duplex Doppler ultrasonographic examination with determination of RI and maximal flow velocity in the portal vein before and 1 month after TIPS placement. Portosystemic pressure gradient was determined before and after TIPS placement. In 29 patients with hepatofugal portal blood flow, RI was significantly lower than in 337 patients with hepatopetal flow (0.63 plus minus 0.02 vs. 0.69 plus minus 0.01; P <.001). TIPS induced a significant decrease of the RI in patients with hepatopetal flow (RI, 0.69 plus minus 0.01 before vs. 0.64 plus minus 0.01 after TIPS; P =.001) but not in patients with hepatofugal flow (RI, 0.63 plus minus 0.02 before vs. 0.63 plus minus 0.02 after TIPS; NS). This response was not dependent on the Child-Pugh class. In conclusion, our results suggest that some degree of HABR is preserved even in patients with advanced cirrhosis with significant portal hypertension.",0
2524,11893791,Prevalence of impaired glucose tolerance among children and adolescents with marked obesity,"BACKGROUND: Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents. METHODS: All subjects underwent a two-hour oral glucose-tolerance test (1.75 g [DOSAGE ERROR CORRECTED] of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose. RESULTS: Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance. CONCLUSIONS: Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.",0
2525,11907291,A controlled trial of inpatient and outpatient geriatric evaluation and management,"BACKGROUND: Over the past 20 years, both inpatient units and outpatient clinics have developed programs for geriatric evaluation and management. However, the effects of these interventions on survival and functional status remain uncertain. METHODS: We conducted a randomized trial involving frail patients 65 years of age or older who were hospitalized at 11 Veterans Affairs medical centers. After their condition had been stabilized, patients were randomly assigned, according to a two-by-two factorial design, to receive either care in an inpatient geriatric unit or usual inpatient care, followed by either care at an outpatient geriatric clinic or usual outpatient care. The interventions involved teams that provided geriatric assessment and management according to Veterans Affairs standards and published guidelines. The primary outcomes were survival and health-related quality of life, measured with the use of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), one year after randomization. Secondary outcomes were the ability to perform activities of daily living, physical performance, utilization of health services, and costs. RESULTS: A total of 1388 patients were enrolled and followed. Neither the inpatient nor the outpatient intervention had a significant effect on mortality (21 percent at one year overall), nor were there any synergistic effects between the two interventions. At discharge, patients assigned to the inpatient geriatric units had significantly greater improvements in the scores for four of the eight SF-36 subscales, activities of daily living, and physical performance than did those assigned to usual inpatient care. At one year, patients assigned to the outpatient geriatric clinics had better scores on the SF-36 mental health subscale, even after adjustment for the score at discharge, than those assigned to usual outpatient care. Total costs at one year were similar for the intervention and usual-care groups. CONCLUSIONS: In this controlled trial, care provided in inpatient geriatric units and outpatient geriatric clinics had no significant effects on survival. There were significant reductions in functional decline with inpatient geriatric evaluation and management and improvements in mental health with outpatient geriatric evaluation and management, with no increase in costs.",0
2526,11915030,The MDR phenotype is associated with the expression of COX-2 and iNOS in a human hepatocellular carcinoma cell line,"The presence of multiple drug resistance (MDR1) and angiogenic phenotypes negatively affect patients' prognosis with cancer even when treated with drugs that are not transported by the MDR1 gene product. It is possible to suggest a link between the MDR1 and angiogenic phenotypes. Because prostaglandins (PGs) and nitric oxide (NO) have been proposed to be involved in angiogenesis in vivo, the production of PGs and NO and the behavior of inducible NO synthase (iNOS), cyclooxygenase 1 (COX-1), and inducible cyclooxygenase (COX-2) were studied in parental drug-sensitive (P5) liver cancer cell lines and in P5-derived MDR1 cells P1(0.5). Immunohistochemical evaluation, Northern and Western blot analysis of COX-2 and iNOS, and assessment of cell proliferation were performed in basal conditions and after the exposure to stimulants or to specific inhibitors of COX-2 and iNOS. The messenger RNA and protein levels of COX-2 and iNOS were in basal conditions higher in P1(0.5) cells than the parental P5 cells. The exposure to lipopolysaccharide (LPS) or epidermal growth factor (EGF) determined an increase of PG and NO production in both cell lines and this increase was strongly reduced by COX-2 inhibitors such as celecoxib (CLX) and nimesulide (NIME). The inhibition of NO production by COX-2 inhibitors suggests cross-talk between COX-2 and iNOS pathways. CLX and NIME also inhibited cell proliferation, but only in MDR1 cells. A specific inhibitor of iNOS, N(6)-(1-iminoethyl)-L-lysine, had only a mild effect on cell proliferation in both cell lines. In conclusion, these data support the hypothesis that the MDR1 and angiogenic phenotypes are linked to each other in human liver cancer cell lines.",0
2527,11919305,Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease,"BACKGROUND: Sequence variants in the gene encoding estrogen receptor alpha (ER-alpha) may modify the effects of hormone-replacement therapy on levels of high-density lipoprotein (HDL) cholesterol and other outcomes related to estrogen treatment in postmenopausal women. METHODS: We characterized 309 women with coronary artery disease who were enrolled in the Estrogen Replacement and Atherosclerosis trial with respect to eight previously described and two newly identified ER-alpha polymorphisms, and we examined the association between these polymorphisms and the response of HDL cholesterol and other lipids to treatment with estrogen alone or estrogen plus progestin. RESULTS: After adjustment for age, race, diabetes status, body-mass index, smoking status, alcohol intake, and frequency of exercise, the 18.9 percent of the women who had the IVS1-401 C/C genotype (i.e., with C on both chromosomes in intervening sequence 1 at position 401 before exon 2) had an increase in the HDL cholesterol level with hormone-replacement therapy that was more than twice the increase observed in the other women (13.1 mg per deciliter vs. 6.0 mg per deciliter, P for treatment-by-genotype interaction = 0.004); this effect was limited to changes in the HDL subfraction 3 (HDL3) (P for interaction=0.04). Similar patterns of response were observed for three other highly linked ER-alpha intron 1 polymorphisms close to the IVS1-401 site (range of P values for interaction = 0.07 to 0.005). The pattern of increased response of HDL cholesterol in women with the IVS1-401 C/C genotype was evident in both the women receiving estrogen and those receiving estrogen plus progestin, was preserved across racial and ethnic groups, and was significant among women who were compliant with the study medication (P<0.001). CONCLUSIONS: Postmenopausal women with coronary disease who have the ER-alpha IVS1-401 C/C genotype, or several other closely related genotypes, have an augmented response of HDL cholesterol to hormone-replacement therapy.",0
2528,11932474,Understanding the treatment preferences of seriously ill patients,"BACKGROUND: The questions patients are asked about their preferences with regard to life-sustaining treatment usually focus on specific interventions, but the outcomes of treatment and their likelihood affect patients' preferences. METHODS: We administered a questionnaire about treatment preferences to 226 persons who were 60 years of age or older and who had a limited life expectancy due to cancer, congestive heart failure, or chronic obstructive pulmonary disease. The study participants were asked whether they would want to receive a given treatment, first when the outcome was known with certainty and then with different likelihoods of an adverse outcome. The outcome without treatment was specified as death from the underlying disease. RESULTS: The burden of treatment (i.e., the length of the hospital stay, extent of testing, and invasiveness of interventions), the outcome, and the likelihood of the outcome all influenced treatment preferences. For a low-burden treatment with the restoration of current health, 98.7 percent of participants said they would choose to receive the treatment (rather than not receive it and die), but 11.2 percent of these participants would not choose the treatment if it had a high burden. If the outcome was survival but with severe functional impairment or cognitive impairment, 74.4 percent and 88.8 percent of these participants, respectively, would not choose treatment. The number of participants who said they would choose treatment declined as the likelihood of an adverse outcome increased, with fewer participants choosing treatment when the possible outcome was functional or cognitive impairment than when it was death. Preferences did not differ according to the primary diagnosis. CONCLUSIONS: Advance care planning should take into account patients' attitudes toward the burden of treatment, the possible outcomes, and their likelihood. The likelihood of adverse functional and cognitive outcomes of treatment requires explicit consideration.",0
2529,11948270,Blood levels of long-chain n-3 fatty acids and the risk of sudden death,"BACKGROUND: Experimental data suggest that long-chain n-3 polyunsaturated fatty acids found in fish have antiarrhythmic properties, and a randomized trial suggested that dietary supplements of n-3 fatty acids may reduce the risk of sudden death among survivors of myocardial infarction. Whether long-chain n-3 fatty acids are also associated with the risk of sudden death in those without a history of cardiovascular disease is unknown. METHODS: We conducted a prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians' Health Study. The fatty-acid composition of previously collected blood was analyzed by gas-liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status. RESULTS: Base-line blood levels of long-chain n-3 fatty acids were inversely related to the risk of sudden death both before adjustment for potential confounders (P for trend = 0.004) and after such adjustment (P for trend = 0.007). As compared with men whose blood levels of long-chain n-3 fatty acids were in the lowest quartile, the relative risk of sudden death was significantly lower among men with levels in the third quartile (adjusted relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.87) and the fourth quartile (adjusted relative risk, 0.19; 95 percent confidence interval, 0.05 to 0.71). CONCLUSIONS: The n-3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.",0
2530,11948274,Variations in morbidity after radical prostatectomy,"BACKGROUND: Recent studies of surgery for cancer have demonstrated variations in outcomes among hospitals and among surgeons. We sought to examine variations in morbidity after radical prostatectomy for prostate cancer. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare linked data base to evaluate health-related outcomes after radical prostatectomy. The rates of postoperative complications, late urinary complications (strictures or fistulas 31 to 365 days after the procedure), and long-term incontinence (more than 1 year after the procedure) were inferred from the Medicare claims records of 11,522 patients who underwent prostatectomy between 1992 and 1996. These rates were analyzed in relation to hospital volume and surgeon volume (the number of procedures performed at individual hospitals and by individual surgeons, respectively). RESULTS: Neither hospital volume nor surgeon volume was significantly associated with surgery-related death. Significant trends in the relation between volume and outcome were observed with respect to postoperative complications and late urinary complications. Postoperative morbidity was lower in very-high-volume hospitals than in low-volume hospitals (27 percent vs. 32 percent, P=0.03) and was also lower when the prostatectomy was performed by very-high-volume surgeons than when it was performed by low-volume surgeons (26 percent vs. 32 percent, P<0.001). The rates of late urinary complications followed a similar pattern. Results for long-term preservation of continence were less clear-cut. In a detailed analysis of the 159 surgeons who had a high or very high volume of procedures, wide surgeon-to-surgeon variations in these clinical outcomes were observed, and they were much greater than would be predicted on the basis of chance or observed variations in the case mix. CONCLUSIONS: In men undergoing prostatectomy, the rates of postoperative and late urinary complications are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a high number of such procedures.",0
2531,11981753,"Transport of the sulfated, amidated bile acid, sulfolithocholyltaurine, into rat hepatocytes is mediated by Oatp1 and Oatp2","The uptake of the sulfated bile acid sulfolithocholyltaurine (SLCT) was investigated in isolated rat hepatocytes and in HeLa cells transfected with complementary DNAs (cDNAs) of organic anion transporting polypeptides (Oatps) 1 and 2 cloned from rat liver. In hepatocytes, transport of SLCT was greatly reduced by bromosulfophthalein (BSP), estrone sulfate, the precursor bile acids cholyltaurine and lithocholyltaurine, and 4,4'-diisothiocyanostilbene-2-2'-disulfonic acid (DIDS). However, SLCT transport was insensitive to 4-methylumbelliferyl sulfate, harmol sulfate, digoxin, fexofenadine, and lack of sodium ion. Because the estimation of kinetic constants was enhanced with use of inhibitors, BSP (1-50 micromol/L) was added to isolated rat hepatocytes to assess the various transport components for SLCT uptake. The resulting data showed a nonsaturable pathway and at least 2 pathways of different Michaelis-Menten constants (K(m)) (70 and 6 micromol/L) and similar maximum velocities (V(max)) (1.73 and 1.2 nmol/min/mg protein) and inhibition constants of 0.63 and 10.3 micromol/L for BSP. In expression systems, SLCT was taken up by Oatp1 and Oatp2 expressed in HeLa cells with similar K(m) values (12.6 +/- 6.2 and 14.6 +/- 1.9 micromol/L). These K(m) values were comparable to that observed for the high-affinity pathway in rat hepatocytes. In conclusion, the results suggest that transport of SLCT into rat liver is mediated in part by Oatp1 and Oatp2, high-affinity pathways, a lower-affinity pathway of unknown origin, and a nonsaturable pathway that is compatible with a transport system of high K(m) and/or passive diffusion.",0
2532,11981756,"The p21(Cip1) protein, a cyclin inhibitor, regulates the levels and the intracellular localization of CDC25A in mice regenerating livers","Liver cells from p21(Cip1-/-) mice subjected to partial hepatectomy (PH) progress into DNA synthesis faster than those from wild-type mice. These cells also show a premature induction of cyclin E/cyclin-dependent kinase (CDK) 2 activity. We studied the mechanisms whereby cells lacking p21(Cip1) showed a premature induction of this activity. Whereas the levels of CDK2, cyclin E, and p27(Kip1) were similar in both wild-type and p21(Cip1-/-) mice, those of the activator CDC25A were much higher in p21(Cip1-/-) quiescent and regenerating livers than in wild-type animals. Moreover, p21(Cip1-/-) cells also showed a premature translocation of CDC25A from cytoplasm into the nucleus. The ectopic expression of p21(Cip1) into mice embryo fibroblasts from p21(Cip1-/-) mice decreased the levels of CDC25A and delayed its nuclear translocation. The levels of CDC25A messenger RNA in p21(Cip1-/-) cells were higher than in wild-type cells, suggesting that this increase might be responsible, at least in part, for the high levels of CDC25A protein in these cells. Thus, the results reported here indicate that p21(Cip1) regulates the levels and the intracellular localization of CDC25A. We also found a good correlation between CDC25A nuclear translocation and cyclin E/CDK2 activation. In conclusion, premature translocation of CDC25A to the nucleus might be involved in the advanced induction of cyclin E/CDK2 activity and DNA replication in cells from animals lacking p21(Cip1).",0
2533,11981757,A tamoxifen-inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver,"The spatiotemporal control of somatic mutagenesis in mice is considered a promising step to determine the function of a given gene product in a defined population of cells at any given time during animal life and also to generate better mouse models of human diseases. To introduce defined mutations in a temporally controlled manner in the liver, we established transgenic mice expressing a tamoxifen-inducible Cre recombinase under the control of the transthyretin promoter (TTR-Cre ind). The recombinase activity was examined on 2 different floxed alleles by crossing TTR-Cre ind mice with either the reporter strain ROSA 26 or with homozygous mice carrying floxed catalytic alpha2 subunit of the adenosine monophosphate (AMP)-activated protein kinase gene. By placing 2 mutated hormone-binding domains of murine estrogen receptor (Mer) at both termini of the Cre, we show that the fusion protein is active only on administration of the synthetic estrogen antagonist 4-hydroxytamoxifen (4-OHT) without any background in the absence of the inducing agent. The recombination is specific of the fetal and adult liver, and we show that the efficiency of recombination reached 80% to 100% after treatment with 4-OHT. In conclusion, TTR-Cre ind transgenic mice represent a valuable tool for temporally controlling the desired gene modifications in vivo in the fetal and adult liver. This would certainly help to understand the physiologic functions of genes in the liver, to create various mouse models mimicking human diseases, and to contribute to liver cancer-specific suicide gene therapy studies.",0
2534,11981771,Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism,"Apoptosis plays an important role in the progression of alcohol-induced liver disease to cirrhosis. Oxidative stress is an early event in the development of apoptosis. The major aim of this study was to study the conditions in which oxidative stress occurs in chronic alcoholism and its relationship with apoptosis of hepatocytes. We have found that oxidative stress is associated with chronic ethanol consumption in humans and in rats, in the former independently of the existence of alcohol-induced liver disease. Ethanol or acetaldehyde induces apoptosis in hepatocytes isolated from alcoholic rats, but not in those from control rats. Inhibition of aldehyde dehydrogenase, but not of cytochrome P450 2E1, prevents ethanol-induced cell death. Ethanol-induced apoptosis is caused by increased reactive oxygen species (ROS) driven by increased availability of the reduced form of nicotinamide-adenine dinucleotide (NADH) owing to mitochondrial acetaldehyde metabolism and it is prevented by blocking the opening of mitochondrial permeability transition (MPT) pores with cyclosporine A. Inhibition of nitric oxide (NO) synthase or addition of antioxidant vitamins C and E completely prevented ethanol-induced apoptosis. Mitochondrial oxidative stress, which occurs during chronic alcoholism, renders hepatocytes susceptible to apoptosis. On the other hand, the CD95 ligand expression was up-regulated by acetaldehyde. In conclusion, ethanol induces apoptosis via 2 different pathways: MPT and up-regulation of the expression of CD95-Fas ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms.",0
2535,11986412,Participation in research and access to experimental treatments by HIV-infected patients,"BACKGROUND: Although there is concern that minority groups and women are underrepresented in research involving patients with human immunodeficiency virus (HIV) infection, the available data are inconclusive. METHODS: We used nationally representative data from the HIV Cost and Services Utilization Study to determine the characteristics of the participants and nonparticipants in trials of medications for HIV infection and whether or not patients had access to experimental treatments. A probability sample of 2864 persons, representing all 231,400 adults with known HIV infection who are cared for in the contiguous United States, were interviewed on three occasions between 1996 and 1998. They were asked about participation in clinical research studies of medications and past receipt of experimental medications for HIV. RESULTS: We estimate that 14 percent of adults receiving care for HIV infection participated in a medication trial or study; 24 percent had received experimental medications; and 8 percent had tried and failed to obtain experimental treatments. According to multivariate models, non-Hispanic blacks and Hispanics were less likely to be participating in trials than non-Hispanic whites (odds ratio for participation among non-Hispanic blacks, 0.50 [95 percent confidence interval, 0.28 to 0.91]; odds ratio among Hispanics, 0.58 [95 percent confidence interval, 0.37 to 0.93]) and to have received experimental medications (odds ratios, 0.41 [95 percent confidence interval, 0.32 to 0.54] and 0.56 [95 percent confidence interval, 0.41 to 0.78], respectively). Patients who were cared for in private health maintenance organizations were less likely to participate in trials than those with fee-for-service insurance (odds ratio, 0.43 [95 percent confidence interval, 0.21 to 0.88]). Women were not underrepresented in research trials and had a similar likelihood of receiving experimental treatments. CONCLUSIONS: Among patients with HIV infection, participation in research trials and access to experimental treatment is influenced by race or ethnic group and type of health insurance.",0
2536,12000815,Changes in the transmission of tuberculosis in New York City from 1990 to 1999,"BACKGROUND: Over the past decade, there has been a reduction in the incidence of tuberculosis in New York City and in the United States. However, the reduction has been confined mainly to U.S.-born persons. Understanding the reasons for the lack of reduction among non-U.S.-born persons may lead to new strategies for tuberculosis control. METHODS: We performed DNA fingerprinting with the IS6110 insertion sequence of the organisms isolated from patients with culture-positive tuberculosis in northern Manhattan from 1990 to 1999. The goal was to identify the strains responsible for multiple infections, presumably through recent transmission (clusters of cases), as well as the strains found in only one patient, presumably representing reactivation of latent infection. RESULTS: Of 546 available isolates of Mycobacterium tuberculosis, 261 (48 percent) belonged to a cluster and 285 (52 percent) did not. In multivariate analysis, significant predictors of noncluster status included birth outside the United States (odds ratio for a strain causing a cluster among non-Hispanic foreign-born patients, 0.31; 95 percent confidence interval, 0.14 to 0.66; odds ratio among Hispanic foreign-born patients, 0.51; 95 percent confidence interval, 0.30 to 0.88), age greater than 60 years (odds ratio, 0.37), and diagnosis after 1993 (odds ratio, 0.50). All these characteristics appeared to be associated with reactivation disease rather than with tuberculosis due to recent transmission. Homelessness was associated with clustering (odds ratio, 1.78; 95 percent confidence interval, 0.99 to 3.20) and therefore with recent transmission. CONCLUSIONS: These findings from northern Manhattan suggest that among foreign-born persons, tuberculosis is largely caused by reactivation of latent infection, whereas among U.S.-born persons, many cases result from recent transmission. Strategies for the control and elimination of tuberculosis among foreign-born persons at high risk should be directed toward the treatment of latent tuberculosis infection.",0
2537,12050341,"Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease","BACKGROUND: Both aspirin and clopidogrel reduce the rate of cardiovascular events in patients with coronary heart disease. We estimated the cost effectiveness of the increased use of aspirin, clopidogrel, or both for secondary prevention in patients with coronary heart disease. METHODS: We used the Coronary Heart Disease Policy Model, a computer simulation of the U.S. population, to estimate the incremental cost effectiveness (in dollars per quality-adjusted years of life gained) of four strategies in patients over 35 years of age with coronary disease from 2003 to 2027: aspirin for all eligible patients (i.e., those who were not allergic to or intolerant of aspirin), aspirin for all eligible patients plus clopidogrel for patients who were ineligible for aspirin, clopidogrel for all patients, and the combination of aspirin for all eligible patients plus clopidogrel for all patients. RESULTS: The extension of aspirin therapy from the current levels of use to all eligible patients for 25 years would have an estimated cost-effectiveness ratio of about $11,000 per quality-adjusted year of life gained. The addition of clopidogrel for the 5 percent of patients who are ineligible for aspirin would cost about $31,000 per quality-adjusted year of life gained. Clopidogrel alone in all patients or in routine combination with aspirin had an incremental cost of more than $130,000 per quality-adjusted year of life gained and remained financially unattractive across a wide range of assumptions. However, clopidogrel alone or in combination with aspirin would cost less than $50,000 per quality-adjusted year of life gained if its price were reduced by 70 to 82 percent, to $1.00 and $0.60 per day, respectively. CONCLUSIONS: Increased prescription of aspirin for secondary prevention of coronary heart disease is attractive from a cost-effectiveness perspective. Because clopidogrel is more costly, its incremental cost effectiveness is currently unattractive, unless its use is restricted to patients who are ineligible for aspirin.",0
2538,12063369,Ventricular pacing or dual-chamber pacing for sinus-node dysfunction,"BACKGROUND: Dual-chamber (atrioventricular) and single-chamber (ventricular) pacing are alternative treatment approaches for sinus-node dysfunction that causes clinically significant bradycardia. However, it is unknown which type of pacing results in the better outcome. METHODS: We randomly assigned a total of 2010 patients with sinus-node dysfunction to dual-chamber pacing (1014 patients) or ventricular pacing (996 patients) and followed them for a median of 33.1 months. The primary end point was death from any cause or nonfatal stroke. Secondary end points included the composite of death, stroke, or hospitalization for heart failure; atrial fibrillation; heart-failure score; the pacemaker syndrome; and the quality of life. RESULTS: The incidence of the primary end point did not differ significantly between the dual-chamber group (21.5 percent) and the ventricular-paced group (23.0 percent, P=0.48). In patients assigned to dual-chamber pacing, the risk of atrial fibrillation was lower (hazard ratio, 0.79; 95 percent confidence interval, 0.66 to 0.94; P=0.008), and heart-failure scores were better (P<0.001). The differences in the rates of hospitalization for heart failure and of death, stroke, or hospitalization for heart failure were not significant in unadjusted analyses but became marginally significant in adjusted analyses. Dual-chamber pacing resulted in a small but measurable increase in the quality of life, as compared with ventricular pacing. CONCLUSIONS: In sinus-node dysfunction, dual-chamber pacing does not improve stroke-free survival, as compared with ventricular pacing. However, dual-chamber pacing reduces the risk of atrial fibrillation, reduces signs and symptoms of heart failure, and slightly improves the quality of life. Overall, dual-chamber pacing offers significant improvement as compared with ventricular pacing.",0
2539,12063370,Antiretroviral therapy during pregnancy and the risk of an adverse outcome,"BACKGROUND: Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. METHODS: We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. RESULTS: After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). CONCLUSIONS: As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.",0
2540,12075054,The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma,"BACKGROUND: The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. METHODS: Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. RESULTS: Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators. CONCLUSIONS: DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.",0
2541,12075056,Endothelial function and oxidative stress in renovascular hypertension,"BACKGROUND: It has been reported that renovascular hypertension activates the renin-angiotensin system, leading to an increase in oxidative stress. We sought to determine whether renal-artery angioplasty improves endothelial dysfunction in patients with renovascular hypertension through a reduction in oxidative stress. METHODS: We evaluated the response of forearm blood flow to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after renal-artery angioplasty in 15 subjects with renovascular hypertension and 15 controls without hypertension who were matched for age and sex. Forearm blood flow was measured with the use of a mercury-filled Silastic strain-gauge plethysmograph. RESULTS: The forearm blood flow in response to acetylcholine was less in subjects with renovascular hypertension than in controls, although the forearm blood flow in response to isosorbide dinitrate was similar in the two groups. Angioplasty decreased systolic and diastolic blood pressures, forearm vascular resistance, and urinary excretion of 8-hydroxy-2'-deoxyguanosine and serum malondialdehyde-modified low-density lipoprotein (LDL), indexes of oxidative stress. After angioplasty, the mean (+/-SD) forearm blood flow in response to acetylcholine was increased in the patients with renovascular hypertension (19.3+/-6.8 vs. 29.6+/-7.1 ml per minute per 100 ml, P=0.002). The increase in the maximal forearm blood flow in response to acetylcholine correlated significantly with the decrease in urinary excretion of 8-hydroxy-2'-deoxyguanosine (r=-0.51, P=0.004) and serum malondialdehyde-modified LDL (r=-0.39, P=0.02). Coinfusion of ascorbic acid (vitamin C) augmented the response of forearm blood flow to acetylcholine before angioplasty (P<0.001) but not after angioplasty. CONCLUSIONS: These findings suggest that excessive oxidative stress is involved, at least in part, in impaired endothelium-dependent vasodilatation in patients with renovascular hypertension.",0
2542,12085347,Cyclin kinase inhibitor p21 potentiates bile acid-induced apoptosis in hepatocytes that is dependent on p53,"Prolonged activation of the mitogen-activated protein kinase (MAPK) pathway enhances expression of the cyclin kinase inhibitor p21 that can promote growth arrest and cell survival in response to cytotoxic insults. Bile acids can also cause prolonged MAPK activation that is cytoprotective against bile acid-induced cell death. Here, we examined the impact of bile acid-induced MAPK signaling and p21 expression on the survival of primary mouse hepatocytes. Deoxycholic acid (DCA) caused prolonged activation of the MAPK pathway that weakly enhanced p21 protein expression. When DCA-induced MAPK activation was blocked using MEK1/2 inhibitors, both hepatocyte viability and expression of p21 were reduced. Surprisingly, constitutive overexpression of p21 in p21+/+ hepatocytes enhanced DCA-induced cell killing. In agreement with these findings, treatment of p21-/- hepatocytes with DCA and MEK1/2 inhibitors also caused less apoptosis than observed in wild-type p21+/+ cells. Expression of p21 in p21-/- hepatocytes did not modify basal levels of apoptosis but restored the apoptotic response of p21-/- cells to those of p21+/+ cells overexpressing p21. These findings suggest that basal expression of p21 plays a facilitating, proapoptotic role in DCA-induced apoptosis. Overexpression of p21 enhanced p53 protein levels. In agreement with a role for p53 in the enhanced apoptotic response, overexpression of p21 did not potentiate apoptosis in p53-/- hepatocytes but, instead, attenuated the death response in these cells. In conclusion, our data suggest that overexpression of p21 can promote apoptosis, leading to elevated sensitivity to proapoptotic stimuli.",0
2543,12085351,Repeated fasting stress causes activation of mitogen-activated protein kinases (ERK/JNK) in rat liver,"Mitogen-activated protein kinases (MAPK)-signaling pathways play key roles in cytoplasmic-nuclear signal transmission in response to various extracellular stimuli. In this study, we investigated the effect of repeated fasting stress on activation of the 3 members of the MAPK family, the extracellular signal-regulated kinase (ERK), the c-Jun NH(2)-terminal kinase (JNK), and the p38 mitogen-activated protein kinase (p38 kinase), in rat liver. Immunecomplex kinase assays showed that ERK and JNK were significantly activated in the liver extract from fasted rats whereas p38 kinase showed no activation. In an immunohistochemical study, the phosphorylated and activated form of ERK (p-ERK) was abundantly expressed in pericentral hepatocytes of fasted liver compared with those of the control. On the other hand, the phosphorylated and activated form of JNK (p-JNK) was highly expressed in irregular-shaped cells along the sinusoidal lining of fasted liver. A double immunofluorescent study to identify p-JNK immunoreactive cells revealed them to be Kupffer cells, which are the resident hepatic macrophages. In conclusion, ERK and JNK are selectively activated in distinct cell types of rat liver by repeated fasting stress.",0
2544,12085362,Recipient-derived hepatocytes in liver transplants: a rare event in sex-mismatched transplants,"Bone marrow-derived stem cells have been shown to engraft and populate native tissues during repair and in transplanted animal tissues. Very few studies have been performed in humans to evaluate the possibility of stem cell engraftment in transplanted tissues. In human renal transplants, recipient cells have been demonstrated within vascular and interstitial structures. In a previous study of patients with hepatic transplants, hepatocytes with XY chromosome patterns have been detected in sex-mismatched female to male transplanted livers in a small number of cases. Because of the possibility of Y chromosome microchimerism of females with male offspring, we analyzed the presence of X and Y chromosomes in liver biopsies of 13 patients with sex-mismatched liver transplants (8 female to male, 5 male to female) and long transplant to biopsy intervals (1.2 to 12 years; mean, 4.5 years). We were able to detect recipient-specific sex chromosomal patterns in inflammatory cells by fluorescent in situ hybridization/immunohistochemistry combination within the liver parenchyma but not within hepatocytes. In conclusion, recipient engraftment of stem cells may be an early feature in liver transplant but may be an infrequent persistent feature in long-term grafts.",0
2545,12087137,Oral contraceptives and the risk of breast cancer,"BACKGROUND: It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives. METHODS: We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. RESULTS: The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. CONCLUSIONS: Among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer.",0
2546,12097535,Comparative efficacy of insect repellents against mosquito bites,"""BACKGROUND: The worldwide threat of arthropod-transmitted diseases, with their associated morbidity and mortality, underscores the need for effective insect repellents. Multiple chemical, botanical, and """"alternative"""" repellent products are marketed to consumers. We sought to determine which products available in the United States provide reliable and prolonged complete protection from mosquito bites. METHODS: We conducted studies involving 15 volunteers to test the relative efficacy of seven botanical insect repellents; four products containing N,N-diethyl-m-toluamide, now called N,N-diethyl-3-methylbenzamide (DEET); a repellent containing IR3535 (ethyl butylacetylaminopropionate); three repellent-impregnated wristbands; and a moisturizer that is commonly claimed to have repellent effects. These products were tested in a controlled laboratory environment in which the species of the mosquitoes, their age, their degree of hunger, the humidity, the temperature, and the light-dark cycle were all kept constant. RESULTS: DEET-based products provided complete protection for the longest duration. Higher concentrations of DEET provided longer-lasting protection. A formulation containing 23.8 percent DEET had a mean complete-protection time of 301.5 minutes. A soybean-oil-based repellent protected against mosquito bites for an average of 94.6 minutes. The IR3535-based repellent protected for an average of 22.9 minutes. All other botanical repellents we tested provided protection for a mean duration of less than 20 minutes. Repellent-impregnated wristbands offered no protection. CONCLUSIONS: Currently available non-DEET repellents do not provide protection for durations similar to those of DEET-based repellents and cannot be relied on to provide prolonged protection in environments where mosquito-borne diseases are a substantial threat.""",0
2547,12097536,Absence of association of thrombophilia polymorphisms with intrauterine growth restriction,"BACKGROUND: Previous data have demonstrated associations between thrombophilia polymorphisms in pregnant women and an increased risk of intrauterine growth restriction in their offspring, but this finding remains uncertain. METHODS: We performed a hospital-based case-control study and a family-based study including 493 newborns with intrauterine growth restriction (defined by birth weight below the 10th percentile for gestational age and sex according to Canadian norms) and 472 controls (with birth weight at or above the 10th percentile). We determined the presence or absence in newborns and their parents of the following polymorphisms: methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, factor V Leiden G1691A, and prothrombin G20210A. Mothers were interviewed to obtain information on other risk factors for intrauterine growth restriction. RESULTS: The risk of intrauterine growth restriction was not increased among mothers carrying a polymorphism associated with thrombophilia. In the case-control study, the odds ratios associated with two copies of the variant, after adjustment for newborn genotype and other risk factors, were 1.55 for MTHFR C677T (95 percent confidence interval, 0.83 to 2.90) and 0.49 for MTHFR A1298C (95 percent confidence interval, 0.25 to 0.93); heterozygotes for factor V Leiden had an odds ratio of 1.18 (95 percent confidence interval, 0.54 to 2.55), and heterozygotes for prothrombin G20210A had an odds ratio of 0.92 (95 percent confidence interval, 0.36 to 2.35). These polymorphisms in the newborn were not associated with an increased risk. Newborns who were homozygous for the MTHFR C677T variant had a decreased risk of intrauterine growth restriction (odds ratio after adjustment for mother's genotype and other confounders, 0.52 [95 percent confidence interval, 0.29 to 0.94]). The results of the family-based study supported those of the case-control study. CONCLUSIONS: Our findings do not indicate that there are associations between maternal or newborn polymorphisms associated with thrombophilia and an increased risk of intrauterine growth restriction.",0
2548,12124404,Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure,"BACKGROUND: B-type natriuretic peptide is released from the cardiac ventricles in response to increased wall tension. METHODS: We conducted a prospective study of 1586 patients who came to the emergency department with acute dyspnea and whose B-type natriuretic peptide was measured with a bedside assay. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the B-type natriuretic peptide assay. RESULTS: The final diagnosis was dyspnea due to congestive heart failure in 744 patients (47 percent), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). B-type natriuretic peptide levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea. The diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg per milliliter was 83.4 percent. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg per milliliter was 96 percent. In multiple logistic-regression analysis, measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure. CONCLUSIONS: Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea.",0
2549,12124407,Toll-like receptor 4 polymorphisms and atherogenesis,"BACKGROUND: The ability to mount a prominent inflammatory response to bacterial pathogens confers an advantage in innate immune defense but may signal an increased risk of atherosclerosis. We determined whether recently discovered genetic variants of toll-like receptor 4 (TLR4) that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide are related to the development of atherosclerosis. METHODS: As part of the five-year follow-up in the Bruneck (Italy) Study, we screened 810 persons in the study cohort for the TLR4 polymorphisms Asp299Gly and Thr399Ile. The extent and progression of carotid atherosclerosis were assessed by high-resolution duplex ultrasonography. RESULTS: As compared with subjects with wild-type TLR4, the 55 subjects with the Asp299Gly TLR4 allele had lower levels of certain proinflammatory cytokines, acute-phase reactants, and soluble adhesion molecules, such as interleukin-6 and fibrinogen. Although these subjects were found to be more susceptible to severe bacterial infections, they had a lower risk of carotid atherosclerosis (odds ratio, 0.54; 95 percent confidence interval, 0.32 to 0.98; P=0.05) and a smaller intima-media thickness in the common carotid artery (regression coefficient, -0.07; 95 percent confidence interval, -0.12 to -0.02; P=0.01). CONCLUSIONS: The Asp299Gly TLR4 polymorphism, which attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens, is associated with a decreased risk of atherosclerosis. This finding is consistent with the hypothesis that innate immunity may play a part in atherogenesis.",0
2550,12140298,A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates,"BACKGROUND: Guidelines issued in 1996 in the United States recommend either screening of pregnant women for group B streptococcal colonization by means of cultures (screening approach) or assessing clinical risk factors (risk-based approach) to identify candidates for intrapartum antibiotic prophylaxis. METHODS: In a multistate retrospective cohort study, we compared the effectiveness of the screening and risk-based approaches in preventing early-onset group B streptococcal disease (in infants less than seven days old). We studied a stratified random sample of the 629,912 live births in 1998 and 1999 in eight geographical areas where there was active surveillance for group B streptococcal infection, including all births in which the neonate had early-onset disease. Women with no documented culture for group B streptococcus were considered to have been cared for according to the risk-based approach. RESULTS: We studied 5144 births, including 312 in which the newborn had early-onset group B streptococcal disease. Antenatal screening was documented for 52 percent of the mothers. The risk of early-onset disease was significantly lower among the infants of screened women than among those in the risk-based group (adjusted relative risk, 0.46; 95 percent confidence interval, 0.36 to 0.60). Because women whose providers had no strategy for prophylaxis may have been misclassified in the risk-based group, we excluded all women with risk factors and adequate time for prophylaxis who did not receive antibiotics. The adjusted relative risk of early-onset disease associated with the screening approach in this secondary analysis was similar--0.48 (95 percent confidence interval, 0.37 to 0.63). CONCLUSIONS: Routine screening for group B streptococcus during pregnancy prevents more cases of early-onset disease than the risk-based approach. Recommendations that endorse both strategies as equivalent warrant reconsideration.",0
2551,12143057,Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks,"Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority of patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective for short periods but results in the emergence of drug-resistant HBV in a substantial number of patients within 1 year of therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type and lamivudine-resistant HBV, but it is unclear whether resistance mutations will emerge after long-term therapy with this drug. To determine whether extended treatment with ADV led to the emergence of drug-resistant populations of HBV, we analyzed virus isolated from patients currently enrolled in a long-term open-label study. The reverse transcriptase domain of HBV polymerase was amplified and sequenced from patients that had received a cumulative exposure of up to 60 weeks of ADV. During our analyses, several previously unreported amino acid substitutions were observed in the reverse transcriptase domain of HBV. Importantly, none of the observed mutations occurred in more than 1 patient, nor were they associated with an adefovir-resistant phenotype in vitro. Furthermore, none of the patients from whom these mutant viruses were isolated had evidence of virologic rebound. In conclusion, these results, although based on a limited number of patients, suggest that treatment with ADV does not lead to the emergence of resistant virus after up to 60 weeks of therapy.",0
2552,12151470,Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant,"BACKGROUND: In May 2000, eight persons who had formerly worked at a microwave-popcorn production plant were reported to have severe bronchiolitis obliterans. No recognized cause was identified in the plant. Therefore, we medically evaluated current employees and assessed their occupational exposures. METHODS: Questionnaire responses and spirometric findings in participating workers were compared with data from the third National Health and Nutrition Examination Survey, after adjustment for age and smoking status. We evaluated the relation between exposures and health-related outcomes by analyzing the rates of symptoms and abnormalities according to current and cumulative exposure to diacetyl, the predominant ketone in artificial butter flavoring and in the air at the plant. RESULTS: Of the 135 current workers at the plant, 117 (87 percent) completed the questionnaire. These 117 workers had 2.6 times the expected rates of chronic cough and shortness of breath, according to comparisons with the national data, and twice the expected rates of physician-diagnosed asthma and chronic bronchitis. Overall, the workers had 3.3 times the expected rate of airway obstruction; those who had never smoked had 10.8 times the expected rate. Workers directly involved in the production of microwave popcorn had higher rates of shortness of breath on exertion and skin problems that had developed since they started work than workers in other parts of the plant. There was a strong relation between the quartile of estimated cumulative exposure to diacetyl and the frequency and extent of airway obstruction. CONCLUSIONS: The excess rates of lung disease and lung-function abnormalities and the relation between exposure and outcomes in this working population indicate that they probably had occupational bronchiolitis obliterans caused by the inhalation of volatile butter-flavoring ingredients.",0
2553,12192016,"Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation","BACKGROUND: In women with breast cancer, the role of radical mastectomy, as compared with less extensive surgery, has been a matter of debate. We report 25-year findings of a randomized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy. METHODS: A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative irradiation, or total mastectomy plus axillary dissection only if their nodes became positive. A total of 586 women with clinically positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation. Kaplan-Meier and cumulative-incidence estimates of outcome were obtained. RESULTS: No significant differences were observed among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to disease-free survival, relapse-free survival, distant-disease-free survival, or overall survival. Among women with negative nodes, the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 (95 percent confidence interval, 0.91 to 1.28; P=0.38), and the hazard ratio for death among those who had total mastectomy without radiation as compared with those who underwent radical mastectomy was 1.03 (95 percent confidence interval, 0.87 to 1.23; P=0.72). Among women with positive nodes, the hazard ratio for death among those who underwent total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.06 (95 percent confidence interval, 0.89 to 1.27; P=0.49). CONCLUSIONS: The findings validate earlier results showing no advantage from radical mastectomy. Although differences of a few percentage points cannot be excluded, the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy.",0
2554,12192019,Experiences of Oregon nurses and social workers with hospice patients who requested assistance with suicide,"BACKGROUND: Oregon's 1997 Death with Dignity Act legalizes physician-assisted suicide. To date, information about patients who have requested this option has come from surveys of physicians. Although 78 percent of the 91 Oregonians who have died by assisted suicide were enrolled in hospice programs, there is little information about the experiences of hospice practitioners with these patients. METHODS: In 2001, we mailed a questionnaire to all hospice nurses and social workers in Oregon. RESULTS: Of 545 eligible hospice nurses and social workers, 397 (73 percent) returned the survey, including 71 percent of nurses and 78 percent of social workers. Since November 1997, 179 of the respondents (45 percent) had cared for a patient who requested assistance with suicide. Hospice nurses reported on 82 patients who had received prescriptions for lethal medication. Ninety-eight percent of the nurses had discussed the request with a coworker, and 77 percent of the requests had been presented at a hospice interdisciplinary conference on patient care. A very important reason for the request was to control the circumstances of death. The least important reasons included depression, lack of social support, and fear of being a financial drain on family members. Although the patients were concerned about burdening others, only 11 percent of hospice nurses rated their family caregivers as more burdened than family caregivers for other hospice patients. CONCLUSIONS: Since assisted suicide was legalized in Oregon, many hospice nurses and social workers have provided care for a patient who requested assistance with suicide. They rated desire for control as a very important reason for these requests.",0
2555,12198661,Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex,"Bacterial DNA containing unmethylated CpG dinucleotide motifs is immunostimulatory to mammals, skewing CD4(+) T-cell responses toward the Th1 phenotype. Autoreactive T-cell responses seen in primary biliary cirrhosis (PBC) are typically of the Th1 phenotype, raising the possibility that bacterial DNA might play a role in the generation of pathologic autoimmunity. We therefore studied the effects of CpG motif-containing oligodeoxynucleotides (ODN) on responses to pyruvate dehydrogenase complex (PDC, the autoantigen in PBC) in a murine model. Sensitization of SJL/J mice with non-self-PDC has been shown to result in induction of autoreactive T-cell responses to PDC sharing characteristics with those seen in patients with PBC. Administration of CpG ODN to SJL/J mice at the time of sensitization with PDC resulted in a significant skewing of splenic T-cell response to self-PDC, with significant augmentation of the Th1 cytokine response (interleukin [IL] 2 and interferon [IFN] gamma) and reduction of the Th2 response (IL-4 and IL-10). In fact, CpG ODN seemed to be more effective at biasing the response phenotype and as effective at inducing liver histologic change as complete Freund's adjuvant (CFA), the standard adjuvant used for induction of Th1 responses in murine autoimmune and infectious immunity models. In conclusion, our findings raise the possibility that bacteria play a role in the development of autoimmunity (in PBC at least) through the potential of their DNA to shift the T-cell responses toward the phenotype associated with autoimmune damage. Moreover, this study suggests caution in the therapeutic use of CpG ODN as vaccine adjuvants.",0
2556,12213942,Walking compared with vigorous exercise for the prevention of cardiovascular events in women,"BACKGROUND: The role of walking, as compared with vigorous exercise, in the prevention of cardiovascular disease remains controversial. Data for women who are members of minority racial or ethnic groups are particularly sparse. METHODS: We prospectively examined the total physical-activity score, walking, vigorous exercise, and hours spent sitting as predictors of the incidence of coronary events and total cardiovascular events among 73,743 postmenopausal women 50 to 79 years of age in the Women's Health Initiative Observational Study. At base line, participants were free of diagnosed cardiovascular disease and cancer, and all participants completed detailed questionnaires about physical activity. We documented 345 newly diagnosed cases of coronary heart disease and 1551 total cardiovascular events. RESULTS: An increasing physical-activity score had a strong, graded, inverse association with the risk of both coronary events and total cardiovascular events. There were similar findings among white women and black women. Women in increasing quintiles of energy expenditure measured in metabolic equivalents (the MET score) had age-adjusted relative risks of coronary events of 1.00, 0.73, 0.69, 0.68, and 0.47, respectively (P for trend, <0.001). In multivariate analyses, the inverse gradient between the total MET score and the risk of cardiovascular events remained strong (adjusted relative risks for increasing quintiles, 1.00, 0.89, 0.81, 0.78, and 0.72, respectively; P for trend <0.001). Walking and vigorous exercise were associated with similar risk reductions, and the results did not vary substantially according to race, age, or body-mass index. A brisker walking pace and fewer hours spent sitting daily also predicted lower risk. CONCLUSIONS: These prospective data indicate that both walking and vigorous exercise are associated with substantial reductions in the incidence of cardiovascular events among postmenopausal women, irrespective of race or ethnic group, age, and body-mass index. Prolonged sitting predicts increased cardiovascular risk.",0
2557,12297824,Epidemiology of the American Indians' burden and its likely genetic origins,"""It was not known until recently whether the endemic of cholesterol gallstones among certain southwestern American Indian tribes was unique among this ethnic group. With use of ultrasonography of the gallbladder and standard diagnostic criteria, gallstones are now found in epidemic proportions in 13 diverse American Indian tribes and communities living in Arizona, Oklahoma, and the Dakotas. We speculate that this predisposition is polygenic involving """"thrifty"""" genes that conferred survival advantages when Paleo-Indians migrated from present-day Siberia to the Americas during the last Great Ice Age approximately 50,000 to 10,000 years ago. A reasonable hypothesis is that functioning of these genes promoted more efficient calorie utilization and storage in the form of adipose tissue. Beneficial results would have been operative during the isolation of Paleo-Indians in the Bering Strait land bridge (Beringia) when thrifty genes would have ensured sufficient fat reserves for survival of prolonged winters, successful pregnancy outcomes, and extended lactation periods. The authors' conjoint work on genetics of experimental cholesterol cholelithiasis in inbred mice promises help in pinpointing orthologous genetic loci (LITH genes) in the human genome. Moreover, the shared environments and homogeneity of American Indian tribes and communities should facilitate discovery of the ensembles of their common and rarer cholesterol gallstone genes. It is anticipated that knowledge of expression, polymorphisms, and functionality of LITH genes will help resolve the molecular mechanisms of this complex heterogeneous trait and thereby provide targets for novel therapies to prevent cholesterol cholelithiasis worldwide.""",0
2558,12297826,Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos,"This work shows that hepatic cell lines reproducibly can be derived from E14 embryos of many mouse inbred strains. These bipotential mouse embryonic liver (BMEL) cell lines present a mixed morphology, containing both epithelial and palmate-like cells, and an uncoupled phenotype, expressing hepatocyte transcription factors (HNF1alpha, HNF4alpha, GATA4) but not functions (apolipoproteins, albumin). BMEL cells are bipotential: under inducing conditions they express hepatocyte and bile duct functions. In addition, they can undergo morphogenesis in Matrigel culture to form bile duct units. When returned to basal culture conditions, the differentiated cells revert, within a few days, to an undifferentiated state. The ensemble of markers expressed by BMEL cells implies that they originate from hepatoblasts, the endodermal precursors of the liver. In conclusion, the establishment of a simple and reproducible method to isolate from any mouse embryo bipotential hepatic cell lines that exhibit the properties of transit stem cells provides a novel paradigm for investigation of hepatic cell lineage relationships.",0
2559,12297830,Prevention of bile acid-induced apoptosis by betaine in rat liver,"Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.",0
2560,12324553,Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection,"BACKGROUND: Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. METHODS: A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. RESULTS: A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin. CONCLUSIONS: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.",0
2561,12362006,Hyperbaric oxygen for acute carbon monoxide poisoning,"BACKGROUND: Patients with acute carbon monoxide poisoning commonly have cognitive sequelae. We conducted a double-blind, randomized trial to evaluate the effect of hyperbaric-oxygen treatment on such cognitive sequelae. METHODS: We randomly assigned patients with symptomatic acute carbon monoxide poisoning in equal proportions to three chamber sessions within a 24-hour period, consisting of either three hyperbaric-oxygen treatments or one normobaric-oxygen treatment plus two sessions of exposure to normobaric room air. Oxygen treatments were administered from a high-flow reservoir through a face mask that prevented rebreathing or by endotracheal tube. Neuropsychological tests were administered immediately after chamber sessions 1 and 3, and 2 weeks, 6 weeks, 6 months, and 12 months after enrollment. The primary outcome was cognitive sequelae six weeks after carbon monoxide poisoning. RESULTS: The trial was stopped after the third of four scheduled interim analyses, at which point there were 76 patients in each group. Cognitive sequelae at six weeks were less frequent in the hyperbaric-oxygen group (19 of 76 [25.0 percent]) than in the normobaric-oxygen group (35 of 76 [46.1 percent], P=0.007), even after adjustment for cerebellar dysfunction and for stratification variables (adjusted odds ratio, 0.45 [95 percent confidence interval, 0.22 to 0.92]; P=0.03). The presence of cerebellar dysfunction before treatment was associated with the occurrence of cognitive sequelae (odds ratio, 5.71 [95 percent confidence interval, 1.69 to 19.31]; P=0.005) and was more frequent in the normobaric-oxygen group (15 percent vs. 4 percent, P=0.03). Cognitive sequelae were less frequent in the hyperbaric-oxygen group at 12 months, according to the intention-to-treat analysis (P=0.04). CONCLUSIONS: Three hyperbaric-oxygen treatments within a 24-hour period appeared to reduce the risk of cognitive sequelae 6 weeks and 12 months after acute carbon monoxide poisoning.",0
2562,12362010,State expenditures for tobacco-control programs and the tobacco settlement,"BACKGROUND: Despite controversy surrounding the use of funds arising from settlement agreements with the tobacco industry, little is known about the role of these funds in expenditures for state tobacco-control programs. METHODS: We evaluated state expenditures for tobacco-control programs in fiscal year 2001 in the context of the amount of tobacco-settlement funds received and allocated to tobacco-control programs and in the context of other state-level economic and health data. RESULTS: In 2001 the average state received $28.35 per capita from the tobacco settlement but allocated approximately 6 percent of these funds to tobacco-control programs. The average state dedicated $3.49 per capita (range, $0.10 to $15.47) to tobacco-control programs. The proportion of settlement funds allocated to tobacco-control programs varied from 0 to 100 percent and was strongly related to levels of tobacco-control funding (P<0.001). States with higher smoking rates tended to invest less per capita in tobacco-control programs (P=0.007), as did tobacco-producing states (the mean per capita expenditure was $1.20, as compared with $3.81 in non-tobacco-producing states; P<0.008). In a multivariate analysis, the proportion of the settlement revenue allocated to tobacco-control programs was the primary determinant of the level of total funding; the state tobacco-related health burden was unrelated to program funding. CONCLUSIONS: State health needs appear to have little effect on the funding of state tobacco-control programs. Because only a very small proportion of the tobacco settlement is being used for tobacco-control programs, the settlement represents an unrealized opportunity to reduce morbidity and mortality from smoking.",0
2563,12362011,Evidence of real-world effectiveness of a telephone quitline for smokers,"BACKGROUND: Telephone services that offer smoking-cessation counseling (quitlines) have proliferated in recent years, encouraged by positive results of clinical trials. The question remains, however, whether those results can be translated into real-world effectiveness. METHODS: We embedded a randomized, controlled trial into the ongoing service of the California Smokers' Helpline. Callers were randomly assigned to a treatment group (1973 callers) or a control group (1309 callers). All participants received self-help materials. Those in the treatment group were assigned to receive up to seven counseling sessions; those in the control group could also receive counseling if they called back for it after randomization. RESULTS: Counseling was provided to 72.1 percent of those in the treatment group and 31.6 percent of those in the control group (mean, 3.0 sessions). The rates of abstinence for 1, 3, 6, and 12 months, according to an intention-to-treat analysis, were 23.7 percent, 17.9 percent, 12.8 percent, and 9.1 percent, respectively, for those in the treatment group and 16.5 percent, 12.1 percent, 8.6 percent, and 6.9 percent, respectively, for those in the control group (P<0.001). Analyses factoring out both the subgroup of control subjects who received counseling and the corresponding treatment subgroup indicate that counseling approximately doubled abstinence rates: rates of abstinence for 1, 3, 6, and 12 months were 20.7 percent, 15.9 percent, 11.7 percent, and 7.5 percent, respectively, in the remaining subjects in the treatment group and 9.6 percent, 6.7 percent, 5.2 percent, and 4.1 percent, respectively, in the remaining subjects in the control group (P<0.001). Therefore, the absolute difference in the rate of abstinence for 12 months between the remaining subjects in the treatment and control groups was 3.4 percent. The 12-month abstinence rates for those who made at least one attempt to quit were 23.3 percent in the treatment group and 18.4 percent in the control group (P<0.001). CONCLUSIONS: A telephone counseling protocol for smoking cessation, previously proven efficacious, was effective when translated to a real-world setting. Its success supports Public Health Service guidelines calling for greater availability of quitlines.",0
2564,12374875,Endogenous antimicrobial peptides and skin infections in atopic dermatitis,"BACKGROUND: The innate immune system of human skin contains antimicrobial peptides known as cathelicidins (LL-37) and beta-defensins. In normal skin these peptides are negligible, but they accumulate in skin affected by inflammatory diseases such as psoriasis. We compared the levels of expression of LL-37 and human beta-defensin 2 (HBD-2) in inflamed skin from patients with atopic dermatitis and from those with psoriasis. METHODS: The expression of LL-37 and HBD-2 protein in skin-biopsy specimens from patients with psoriasis, patients with atopic dermatitis, and normal subjects was determined by immunohistochemical analysis. The amount of antimicrobial peptides in extracts of skin samples was also analyzed by immunodot blot analysis (for LL-37) and Western blot analysis (for HBD-2). Quantitative, real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays were used to confirm the relative expression of HBD-2 and LL-37 messenger RNA (mRNA) in the skin-biopsy specimens. These peptides were also tested for antimicrobial activity against Staphylococcus aureus with the use of a colony-forming assay. RESULTS: Immunohistochemical analysis confirmed the presence of abundant LL-37 and HBD-2 in the superficial epidermis of all patients with psoriasis. In comparison, immunostaining for these peptides was significantly decreased in acute and chronic lesions from patients with atopic dermatitis (P=0.006 and P=0.03, respectively). These results were confirmed by immunodot blot and Western blot analyses. Real-time RT-PCR showed significantly lower expression of HBD-2 mRNA and LL-37 mRNA in atopic lesions than in psoriatic lesions (P=0.009 and P=0.02, respectively). The combination of LL-37 and HBD-2 showed synergistic antimicrobial activity by effectively killing S. aureus. CONCLUSIONS: A deficiency in the expression of antimicrobial peptides may account for the susceptibility of patients with atopic dermatitis to skin infection with S. aureus.",0
2565,12395317,PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival,"Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.",0
2566,12395319,Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli,"Cyclin D1 is considered to play a critical role in the progression from G1 to S phase of the cell cycle, and its overexpression is seen in many human tumors. However, previous studies in cell lines have shown that cyclin D1 is not sufficient to trigger cell replication. To directly test the role of cyclin D1 in the progression of the cell cycle, we have examined the proliferative response of hepatocytes to the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in mice with homozygous disruption of the cyclin D1 gene. We found that 24 hours after administration of TCPOBOP, the number of bromodeoxyuridine (BrdU)-positive hepatocytes was significantly reduced in cyclin D1(-/-) (labeling index was 1.9% in knockout mice vs. 9.7% of heterozygous mice); however, no difference in the number of proliferating hepatocytes was found 36 or 72 hours after treatment (labeling index was 16% and 43% in cyclin D1(-/-) mice vs. 20% and 41% of heterozygous mice), indicating that lack of cyclin D1 may transiently delay entry into S phase but is not sufficient to inhibit the response of hepatocytes to mitogenic stimuli. The results also show that although there was no difference in hepatic protein levels of cyclin D2 and D3 between untreated cyclin D1(-/-) and cyclin D1(+/-) mice, messenger RNA (mRNA) and protein levels of cyclin E were much higher in the former. In conclusion, our results show that cyclin D1 is not essential for liver development and hepatocyte proliferation induced by mitogenic stimuli and suggest that overexpression of cyclin E may compensate for the lack of cyclin D1.",0
2567,12395328,Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver,"Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl(4)-treated group (phenobarbital with CCl(4) treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of (3)H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl(4)-treated rats were found to have the smallest vascular space, extravascular albumin space, (3)H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of (3)H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses.",0
2568,12407578,Use and interpretation of virological tests for hepatitis C,"Four virological markers of hepatitis C virus (HCV) infection are used clinically for management of patients with hepatitis C, namely the HCV genotype, HCV RNA, HCV core antigen, and antibody to HCV (anti-HCV). The diagnosis of acute and chronic hepatitis C is based on both anti-HCV detection using enzyme immunoassays (EIA) and HCV RNA detection using a sensitive molecular biology-based technique. Other virological tools, including HCV genotype determination and HCV RNA quantification, are now used to tailor treatment to the individual patient and to determine its efficacy. This article reviews the kinetics of HCV markers during acute and chronic HCV infection, together with current assays and their practical use in the management of HCV-infected patients.",0
2569,12407582,Sexual activity as a risk factor for hepatitis C,"The accumulated evidence indicates that hepatitis C virus (HCV) can be transmitted by sexual contact but much less efficiently than other sexually transmitted viruses, including hepatitis B virus and human immunodeficiency virus (HIV). However, because sex is such a common behavior and the reservoir of HCV-infected individuals is sizable, sexual transmission of HCV likely contributes to the total burden of infection in the United States. Risk of HCV transmission by sexual contact differs by the type of sexual relationship. Persons in long-term monogamous partnerships are at lower risk of HCV acquisition (0% to 0.6% per year) than persons with multiple partners or those at risk for sexually transmitted diseases (0.4% to 1.8% per year). This difference may reflect differences in sexual risk behaviors or differences in rates of exposure to nonsexual sources of HCV, such as injection drug use or shared razors and toothbrushes. In seroprevalence studies in monogamous, heterosexual partners of HCV-infected, HIV-negative persons, the frequency of antibody-positive and genotype-concordant couples is 2.8% to 11% in Southeast Asia, 0% to 6.3% in Northern Europe, and 2.7% in the United States. Among individuals at risk for sexually transmitted diseases (STDs), the median seroprevalence of antibody to HCV (anti-HCV) is 4% (range, 1.6% to 25.5%). HIV coinfection appears to increase the rate of HCV transmission by sexual contact. Current recommendations about sexual practices are different for persons with chronic HCV infection who are in steady monogamous partnerships versus those with multiple partners or who are in short-term sexual relationships.",0
2570,12407596,Prevention and treatment of hepatitis C in injection drug users,"Injection drug users constitute the largest group of persons infected with the hepatitis C virus (HCV) in the United States, and most new infections occur in drug users. Controlling hepatitis C in the U.S. population, therefore, will require developing, testing, and implementing effective prevention and treatment strategies for persons who inject drugs. Fortunately, a substantial body of research and clinical experience exists on the prevention and management of chronic viral diseases among injection drug users. The need to implement interventions to stop the spread of HCV among drug users is critical. The capacity of substance-use treatment programs need to be expanded to accommodate all who want and need treatment. Physicians and pharmacists should be educated in how to provide access to sterile syringes and to teach safe injection techniques, both of which are lifesaving interventions. The treatment of hepatitis C in drug users requires an interdisciplinary approach that brings together expertise in treating hepatitis and caring for drug users. Treatment decisions should be made individually by patients with their physicians, based on a balanced assessment of risks and benefits and the patient's personal values. Physicians should carefully assess, monitor, and support adherence and mental health in all patients, regardless of whether drug use is known or suspected. Research is needed to better understand how best to prevent and treat hepatitis C in substance users. In the meantime, substantial progress can be made if existing knowledge and resources are brought to bear.",0
2571,12407597,Alcohol use and hepatitis C,"Excess alcohol consumption can worsen the course and outcome of chronic hepatitis C. It is important to distinguish between alcohol abuse, which must be treated on its own merits, and the effect of alcohol use on progression, severity, and treatment of hepatitis C. Most studies on the effects of alcohol on hepatitis C have focused on patients with high levels of daily alcohol intake. Indeed, the adverse effects of light and moderate amounts of alcohol intake on hepatitis C virus (HCV) infection have not been clearly shown, and only limited studies have been performed. Sex differences exist in the effect of alcohol on fibrosis as well as on the severity of hepatitis C. Alcohol use has been reported to be associated with lower responses to therapy and, in some studies, higher HCV RNA levels and increased HCV quasi-species. Few studies address the treatment of hepatitis C in the alcoholic individual or determine the effect of continued light or moderate alcohol use on the outcome of treatment response. In summary, many critical questions remain regarding the interactions between alcohol and hepatitis C. Currently, the evidence from the literature shows that heavy alcohol intake worsens the outcome of HCV infection. The literature is inadequate to provide definitive recommendations regarding the effect of light to moderate alcohol use in patients with hepatitis C.",0
2572,12421890,Effects of the amount and intensity of exercise on plasma lipoproteins,"BACKGROUND: Increased physical activity is related to reduced risk of cardiovascular disease, possibly because it leads to improvement in the lipoprotein profile. However, the amount of exercise training required for optimal benefit is unknown. In a prospective, randomized study, we investigated the effects of the amount and intensity of exercise on lipoproteins. METHODS: A total of 111 sedentary, overweight men and women with mild-to-moderate dyslipidemia were randomly assigned to participate for six months in a control group or for approximately eight months in one of three exercise groups: high-amount-high-intensity exercise, the caloric equivalent of jogging 20 mi (32.0 km) per week at 65 to 80 percent of peak oxygen consumption; low-amount-high-intensity exercise, the equivalent of jogging 12 mi (19.2 km) per week at 65 to 80 percent of peak oxygen consumption; or low-amount-moderate-intensity exercise, the equivalent of walking 12 mi per week at 40 to 55 percent of peak oxygen consumption. Subjects were encouraged to maintain their base-line body weight. The 84 subjects who complied with these guidelines served as the basis for the main analysis. Detailed lipoprotein profiling was performed by nuclear magnetic resonance spectroscopy with verification by measurement of cholesterol in lipoprotein subfractions. RESULTS: There was a beneficial effect of exercise on a variety of lipid and lipoprotein variables, seen most clearly with the high amount of high-intensity exercise. The high amount of exercise resulted in greater improvements than did the lower amounts of exercise (in 10 of 11 lipoprotein variables) and was always superior to the control condition (11 of 11 variables). Both lower-amount exercise groups always had better responses than the control group (22 of 22 comparisons). CONCLUSIONS: The highest amount of weekly exercise, with minimal weight change, had widespread beneficial effects on the lipoprotein profile. The improvements were related to the amount of activity and not to the intensity of exercise or improvement in fitness.",0
2573,12444179,Glycoprotein-D-adjuvant vaccine to prevent genital herpes,"BACKGROUND: An effective prophylactic vaccine would help control the spread of genital herpes. METHODS: We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2-seronegative female subjects in Study 2. RESULTS: A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well tolerated and elicited humoral and cellular responses. Overall, the efficacy of the vaccine was 38 percent in Study 1 (95 percent confidence interval, -18 to 68 percent; 15 cases occurred in the vaccine group and 24 in the control group), and efficacy in female subjects was 42 percent in Study 2 (95 percent confidence interval, -31 to 74 percent; 9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in Study 1 was 73 percent (95 percent confidence interval, 19 to 91 percent; P=0.01), and efficacy in Study 2 was 74 percent (95 percent confidence interval, 9 to 93 percent; P=0.02). It was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at base line or in men. CONCLUSIONS: These studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV-2 at base line but not in those who are seropositive for HSV-1 and seronegative for HSV-2. It had no efficacy in men, regardless of their HSV serologic status.",0
2574,12447877,Epidermal growth factor-induced activation of the insulin-like growth factor I receptor in rat hepatocytes,"Insulin-like growth factor I (IGF-I) plays a critical role in the induction of cell cycle progression and survival in many cell types. However, there is minimal IGF-I binding to hepatocytes, and a role for IGF-I in hepatocyte signaling has not been elucidated. The dynamics of IGF-I receptor (IGF-IR) activation were examined in freshly isolated rat hepatocytes. IGF-I did not activate the IGF-IR. However, des(1-3)IGF-I, which weakly binds IGF binding protein-3 (IGFBP-3), induced IGF-IR phosphorylation. IGFBP-3 surface coating was identified by confocal immunofluorescence microscopy. In contrast with the inactivity of IGF-I, epidermal growth factor (EGF) induced the tyrosine phosphorylation of the IGF-IR in parallel with EGF receptor phosphorylation. Transactivation of the IGF-IR by EGF was inhibited by tyrphostin I-Ome-AG538, a tyrosine kinase inhibitor with high specificity for the IGF-IR. Src kinase inhibitors pyrazolopyrimidine PP-1 and PP-2 inhibited transactivation of the IGF-IR by EGF. EGF stimulated the tyrosine phosphorylation of Src, and induced its association with the IGF-IR. EGF-induced phosphorylations of insulin-related substrate (IRS)-1, IRS-2, Akt, and p42/44 mitogen-activated protein kinases (MAPKs) were inhibited variably by I-Ome-AG538. In conclusion, the data show an EGF- and Src-mediated transactivation pathway for IGF-IR activation in hepatocytes, and indicate a role for the IGF-IR in hepatocyte intracellular signaling. The findings also show a role for IGFBP-3 in the inhibition of IGF-I signaling in hepatocytes.",0
2575,12490682,Effect of dialysis dose and membrane flux in maintenance hemodialysis,"BACKGROUND: The effects of the dose of dialysis and the level of flux of the dialyzer membrane on mortality and morbidity among patients undergoing maintenance hemodialysis are uncertain. METHODS: We undertook a randomized clinical trial in 1846 patients undergoing thrice-weekly dialysis, using a two-by-two factorial design to assign patients randomly to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. RESULTS: In the standard-dose group, the mean (+/-SD) urea-reduction ratio was 66.3+/-2.5 percent, the single-pool Kt/V was 1.32+/-0.09, and the equilibrated Kt/V was 1.16+/-0.08; in the high-dose group, the values were 75.2+/-2.5 percent, 1.71+/-0.11, and 1.53+/-0.09, respectively. Flux, estimated on the basis of beta2-microglobulin clearance, was 3+/-7 ml per minute in the low-flux group and 34+/-11 ml per minute in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95 percent confidence interval, 0.84 to 1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95 percent confidence interval, 0.81 to 1.05; P=0.23). The main secondary outcomes (first hospitalization for cardiac causes or death from any cause, first hospitalization for infection or death from any cause, first 15 percent decrease in the serum albumin level or death from any cause, and all hospitalizations not related to vascular access) also did not differ significantly between either the dose groups or the flux groups. Possible benefits of the dose or flux interventions were suggested in two of seven prespecified subgroups of patients. CONCLUSIONS: Patients undergoing hemodialysis thrice weekly appear to have no major benefit from a higher dialysis dose than that recommended by current U.S. guidelines or from the use of a high-flux membrane.",0
2576,12500194,Cytochrome P450 2E1 responsiveness in the promoter of glutamate-cysteine ligase catalytic subunit,"Previous studies have shown cytochrome P450 2E1 (CYP2E1)-dependent transcriptional up-regulation of glutamate-cysteine ligase (GCL). To identify sequences mediating constitutive and induced expression of the catalytic subunit of GCL (GCLC), a series of deletion mutants from the 5'-flanking region (-3,802 to +465) were transfected into control (C34) and CYP2E1-overexpressing (E47) HepG2 cells. Increased luciferase expression, both basal (2- to 3-fold) and following exposure to ethanol, arachidonic acid (AA), or AA plus iron, was detected in E47 cells with the full-length but not shorter reporter vectors. Basal induction was blocked by CYP2E1 inhibitors and catalase. Basal and inducible luciferase expression in E47 cells was blunted by the full-length construct mutated in the ARE4 site. Catalase and diallyl sulfide prevented basal and AA-induced messenger RNA (mRNA) levels of GCLC and the modulatory subunit of GCL (GCLM). Preincubation with low doses of AA increased glutathione (GSH) levels as well as GCLC and GCLM mRNAs, and this protected against H(2)O(2) and menadione toxicity. Primary hepatocytes from pyrazole-injected rats with high levels of CYP2E1 showed an increase in GSH levels as well as GCLC and GCLM mRNAs compared with saline controls, and this was prevented by diallyl sulfide. In conclusion, redox-sensitive elements directing constitutive and induced expression of the GCLC in CYP2E1-expressing cells are present in the ARE4 distal portion of the 5'-flanking region, between positions -3,802 and -2,752, perhaps a reflection of metabolic adaptation to CYP2E1-generated oxidative stress.",0
2577,12500203,"A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial","Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V(2) receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V(2) receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P <.05) and serum sodium (P <.05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use.",0
2578,12501221,Influenza-related hospitalizations among children in Hong Kong,"BACKGROUND: It has been difficult to define the burden of influenza in children because of confounding by the cocirculation of respiratory syncytial virus (RSV). In Hong Kong, China, the influenza and RSV infection seasons sometimes do not overlap, thus providing an opportunity to estimate the rate of influenza-related hospitalization in a defined population, free from the effects of RSV. METHODS: In a retrospective, population-based study, we estimated the influenza-associated excess rate of hospitalization among children 15 years old or younger in the Hong Kong Special Administrative Region from 1997 to 1999. Data from a single hospital with intensive use of virologic analyses for diagnosis were obtained to define and adjust for underestimation of the model. RESULTS: Peaks of influenza and RSV infection activity were well separated in 1998 and 1999 but overlapped in 1997. The adjusted rates of excess hospitalization for acute respiratory disease that were attributable to influenza were 278.5 and 288.2 per 10,000 children less than 1 year of age in 1998 and 1999, respectively; 218.4 and 209.3 per 10,000 children 1 to less than 2 years of age; 125.6 and 77.3 per 10,000 children 2 to less than 5 years of age; 57.3 and 20.9 per 10,000 children 5 to less than 10 years of age; and 16.4 and 8.1 per 10,000 children 10 to 15 years of age. CONCLUSIONS: In the subtropics, influenza is an important cause of hospitalization among children, with rates exceeding those reported for temperate regions.",0
2579,12510040,"Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome","BACKGROUND: Hallervorden-Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase-associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden-Spatz syndrome with and without mutations in PANK2. METHODS: One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations. RESULTS: All patients with classic Hallervorden-Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease led to amino acid changes, those in patients with classic disease more often resulted in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, T2-weighted magnetic resonance imaging (MRI) of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without mutations. CONCLUSIONS: PANK2 mutations are associated with all cases of classic Hallervorden-Spatz syndrome and one third of cases of atypical disease. A specific MRI pattern distinguishes patients with PANK2 mutations. Predicted levels of pantothenate kinase 2 protein correlate with the severity of disease.",0
2580,12519920,Nephron number in patients with primary hypertension,"BACKGROUND: A diminished number of nephrons has been proposed as one of the factors contributing to the development of primary hypertension. METHODS: To test this hypothesis, we used a three-dimensional stereologic method to compare the number and volume of glomeruli in 10 middle-aged white patients (age range, 35 to 59 years) with a history of primary hypertension or left ventricular hypertrophy (or both) and renal arteriolar lesions with the number and volume in 10 normotensive subjects matched for sex, age, height, and weight. All 20 subjects had died in accidents. RESULTS: Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls (median, 702,379 vs. 1,429,200). Patients with hypertension also had a significantly greater glomerular volume than did the controls (median, 6.50x10(-3) mm3 vs. 2.79x10(-3) mm3; P<0.001) but very few obsolescent glomeruli. CONCLUSIONS: The data support the hypothesis that the number of nephrons is reduced in white patients with primary hypertension.",0
2581,12556541,Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes,"BACKGROUND: Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. METHODS: The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. RESULTS: The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). CONCLUSIONS: A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.",0
2582,12571257,Signaling molecules in nonfamilial pulmonary hypertension,"BACKGROUND: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. RESULTS: The expression of angiopoietin-1 messenger RNA and the protein itself and the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.",0
2583,12594313,Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone,"BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. METHODS: Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. RESULTS: A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01). CONCLUSIONS: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.",0
2584,12594315,Detection of pathologic prion protein in the olfactory epithelium in sporadic Creutzfeldt-Jakob disease,"BACKGROUND: Olfactory cortexes and the olfactory tracts are involved in sporadic Creutzfeldt-Jakob disease. We examined peripheral regions of the olfactory sensory pathway, including the olfactory mucosa, to assess whether pathologic infectious prion protein (PrPSc) is deposited in the epithelium lining the nasal cavity. METHODS: We studied nine patients with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease. We obtained the brain, the cribriform plate with the attached olfactory mucosa, and the surrounding respiratory epithelium at autopsy. Control samples of nasal mucosa were obtained post mortem or at biopsy from age-matched control subjects and from control patients with other neurodegenerative diseases. The olfactory and respiratory mucosa and the intracranial olfactory system were analyzed by light microscopy, immunohistochemistry, and Western blotting for pathological changes and for deposition of PrPSc. RESULTS: In all nine patients with sporadic Creutzfeldt-Jakob disease, PrPSc was found in the olfactory cilia and central olfactory pathway but not in the respiratory mucosa. No PrPSc was detected in any of the tissue samples from the 11 controls. CONCLUSIONS: Our pathological and biochemical studies show that PrPSc is deposited in the neuroepithelium of the olfactory mucosa in patients with sporadic Creutzfeldt-Jakob disease, indicating that olfactory biopsy may provide diagnostic information in living patients. The olfactory pathway may represent a route of infection and a means of spreading prions.",0
2585,12601356,Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection,"Spontaneous resolution of hepatitis C virus (HCV) infection is a relatively infrequent event, and these individuals provide a unique opportunity to characterize correlates of protective immunity as an important first step in the development of vaccine candidates. The aim of this study was to directly and comprehensively enumerate HCV-nonstructural protein 3 (NS3) specific CD4(+) and CD8(+) T cells ex vivo from HLA diverse individuals who had been successful in spontaneously resolving HCV infection. We measured interferon gamma (IFN-gamma) production with an ELISPOT assay using magnetic bead-separated CD4(+) or CD8(+) T cells in response to autologous DCs that had been pulsed with 15mer per peptides overlapping by 11 amino acids and spanning all of the NS3 protein (150 total peptides). All subjects with spontaneously recovered HCV infection demonstrated vigorous and multispecific CD4(+) T-cell responses to NS3 peptides, and 6 of 10 subjects demonstrated CD8(+) T-cell responses. More importantly, we identified novel, previously unpredicted antigenic regions, which in most cases elicited high frequencies within a given individual. In conclusion, subjects who have spontaneously eradicated HCV infection up to 35 years earlier demonstrate persistent CD4(+) and CD8(+) T-cell responses specific to NS3. By providing a comprehensive screening of all potential T-cell epitopes contained in the NS3 region, our strategy defines the breadth of the T-cell response and identifies novel, unpredicted specificities.",0
2586,12601359,Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C,"Interferon alfa (IFN-alpha) is an approved therapeutic agent for chronic hepatitis C. To directly characterize the effects of IFN-alpha in humans, we used microarrays to profile gene expression in peripheral blood mononuclear cells (PBMCs) from hepatitis C patients treated with IFN-alpha. Seven patients were studied using two strategies: (1) in vivo: PBMCs were collected immediately before the first dose of IFN-alpha, and 3 and 6 hours after the dose; (2) ex vivo: PBMCs that were collected before the first IFN-alpha dose were incubated with IFN-alpha for 3 and 6 hours. The microarray datasets were analyzed with significance analysis of microarrays (SAM) to identify genes regulated by IFN-alpha. We identified 516 named genes up-regulated at least 2-fold, at a false discovery rate (FDR) of less than 1%. In vivo and ex vivo studies generated similar results. No genes were identified as regulated differently between these 2 experimental conditions. The up-regulated genes belonged to a broad range of functional pathways and included multiple genes thought to be involved in the direct antiviral effect of IFN-alpha. Of particular interest, 88 genes directly relating to functions of immune cells were up-regulated, including genes involved in antigen processing and presentation, T-cell activation, lymphocyte trafficking, and effector functions, suggesting that IFN-alpha up-regulates multiple genes involving different aspects of immune responses to enhance immunity against hepatitis C virus. In conclusion, IFN-alpha-inducible genes can be identified in human PBMCs in vivo as well as ex vivo. Signature changes associated with different treatment outcomes may be found among these genes.",0
2587,12601366,Hepatocyte growth factor activates CCAAT enhancer binding protein and cell replication via PI3-kinase pathway,"Hepatocyte growth factor (HGF), a ligand of c-Met receptor, stimulates activation of cellular kinases via phosphatidylinositol 3-kinase (PI3-kinase). CCAAT/enhancer binding protein (C/EBP) controls cell cycle progression. The present study was designed to determine whether HGF activates C/EBP in association with the S-phase entrance for cell replication and whether PI3-kinase contributes to the activation of C/EBP. Treatment of H4IIE cells, a hepatocyte-derived cell line, with HGF increased protein binding to the C/EBP binding site at an early time. Immunodepletion, subcellular fractionation, and confocal microscopic analyses showed that the HGF-induced C/EBP DNA binding activity depended on nuclear translocation of C/EBP beta. Whereas stable transfection of the p110 catalytic subunit of PI3-kinase enhanced HGF-mediated nuclear translocation of C/EBP beta and DNA binding, stable transfection of p85 subunit or chemical inhibition of PI3-kinase completely blocked C/EBP activation. HGF increased luciferase reporter activity in cells transfected with a mammalian cell expression vector containing -1.65 kilobase rGSTA2 promoter comprising C/EBP response element (pGL-1651). Whereas transfection with pCMV500, a control vector, allowed pGL-1651 to respond to HGF, expression of dominant negative mutant C/EBP completely inhibited the ability of HGF to stimulate the reporter gene expression. Flow cytometric analysis showed that HGF caused an increase in the area of S phase with a reciprocal decrease in that of G(1) phase, suggesting that HGF promoted cell cycle progression to S phase. In conclusion, HGF induces nuclear translocation of C/EBP beta via the PI3-kinase pathway and stimulates C/EBP DNA binding and gene transcription and that the PI3-kinase-mediated C/EBP activation by HGF may contribute to cell replication.",0
2588,12637607,Factors associated with the development of peanut allergy in childhood,"BACKGROUND: The prevalence of peanut allergy appears to have increased in recent decades. Other than a family history of peanut allergy and the presence of atopy, there are no known risk factors. METHODS: We used data from the Avon Longitudinal Study of Parents and Children, a geographically defined cohort study of 13,971 preschool children, to identify those with a convincing history of peanut allergy and the subgroup that reacted to a double-blind peanut challenge. We first prospectively collected data on the whole cohort and then collected detailed information retrospectively by interview from the parents of children with peanut reactions and of children from two groups of controls (a random sample from the cohort and a group of children whose mothers had a history of eczema and who had had eczema themselves in the first six months of life). RESULTS: Forty-nine children had a history of peanut allergy; peanut allergy was confirmed by peanut challenge in 23 of 36 children tested. There was no evidence of prenatal sensitization from the maternal diet, and peanut-specific IgE was not detectable in the cord blood. Peanut allergy was independently associated with intake of soy milk or soy formula (odds ratio, 2.6; 95 percent confidence interval, 1.3 to 5.2), rash over joints and skin creases (odds ratio, 2.6; 95 percent confidence interval, 1.4 to 5.0), and oozing, crusted rash (odds ratio, 5.2; 95 percent confidence interval, 2.7 to 10.2). Analysis of interview data showed a significant independent relation of peanut allergy with the use of skin preparations containing peanut oil (odds ratio, 6.8; 95 percent confidence interval, 1.4 to 32.9). CONCLUSIONS: Sensitization to peanut protein may occur in children through the application of peanut oil to inflamed skin. The association with soy protein could arise from cross-sensitization through common epitopes. Confirmation of these risk factors in future studies could lead to new strategies to prevent sensitization in infants who are at risk for subsequent peanut allergy.",0
2589,12700371,Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter,"BACKGROUND: Despite dramatic declines in children's blood lead concentrations and a lowering of the Centers for Disease Control and Prevention's level of concern to 10 microg per deciliter (0.483 micromol per liter), little is known about children's neurobehavioral functioning at lead concentrations below this level. METHODS: We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders. RESULTS: The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 microg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 microg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 microg per deciliter. CONCLUSIONS: Blood lead concentrations, even those below 10 microg per deciliter, are inversely associated with children's IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.",0
2590,12724481,Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis,"BACKGROUND: Vasodilators are considered to be contraindicated in patients with severe aortic stenosis because of concern that they may precipitate life-threatening hypotension. However, vasodilators such as nitroprusside may improve myocardial performance if peripheral vasoconstriction is contributing to afterload. METHODS: We determined the response to intravenous nitroprusside in 25 patients with severe aortic stenosis and left ventricular systolic dysfunction. Patients were included in the study if they had been admitted to the intensive care unit for invasive hemodynamic monitoring of heart failure and if they had a depressed ejection fraction (<or=0.35), severe aortic stenosis (aortic-valve area, <or=1 cm2), and a depressed cardiac index (<or=2.2 liters per minute per square meter). Patients were excluded if they had hypotension, defined as either the need for intravenous inotropic or pressor agents or a low mean systemic arterial pressure (<60 mm Hg). Patients were enrolled irrespective of other, coexisting valve disease or coronary artery disease. RESULTS: At base line, the mean (+/-SD) ejection fraction was 0.21+/-0.08; the aortic-valve area was 0.6+/-0.2 cm2, with peak and mean gradients of 65+/-37 and 39+/-23 mm Hg, respectively; and the cardiac index was 1.60+/-0.35 liters per minute per square meter. After six hours of therapy with nitroprusside (at which time the dose had been increased to a mean of 103+/-67 microg per minute), the cardiac index had increased to 2.22+/-0.44 liters per minute per square meter (P<0.001 for the comparison with base line). After 24 hours of nitroprusside infusion (dose, 128+/-96 microg per minute), the cardiac index had increased further, to 2.52+/-0.55 liters per minute per square meter (P<0.001 for the comparison with base line). Nitroprusside was well tolerated and had minimal side effects. CONCLUSIONS: Nitroprusside rapidly and markedly improves cardiac function in patients with decompensated heart failure due to severe left ventricular systolic dysfunction and severe aortic stenosis. It provides a safe and effective bridge to aortic-valve replacement or oral vasodilator therapy in these critically ill patients.",0
2591,12759480,Cost effectiveness of lung-volume-reduction surgery for patients with severe emphysema,"BACKGROUND: The National Emphysema Treatment Trial, a randomized clinical trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema, included a prospective economic analysis. METHODS: After pulmonary rehabilitation, 1218 patients at 17 medical centers were randomly assigned to lung-volume-reduction surgery or continued medical treatment. Costs for the use of medical care, medications, transportation, and time spent receiving treatment were derived from Medicare claims and data from the trial. Cost effectiveness was calculated over the duration of the trial and was estimated for 10 years of follow-up with the use of modeling based on observed trends in survival, cost, and quality of life. RESULTS: Interim analyses identified a group of patients with excess mortality and little chance of improved functional status after surgery. When these patients were excluded, the cost-effectiveness ratio for lung-volume-reduction surgery as compared with medical therapy was 190,000 dollars per quality-adjusted life-year gained at 3 years and 53,000 dollars per quality-adjusted life-year gained at 10 years. Subgroup analyses identified patients with predominantly upper-lobe emphysema and low exercise capacity after pulmonary rehabilitation who had lower mortality and better functional status than patients who received medical therapy. The cost-effectiveness ratio in this subgroup was 98,000 dollars per quality-adjusted life-year gained at 3 years and 21,000 dollars at 10 years. Bootstrap analysis revealed substantial uncertainty for the subgroup and 10-year estimates. CONCLUSIONS: Given its cost and benefits over three years of follow-up, lung-volume-reduction surgery is costly relative to medical therapy. Although the predictions are subject to substantial uncertainty, the procedure may be cost effective if benefits can be maintained over time.",0
2592,12774003,Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT,"Nonselective beta-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol + placebo (n = 174) or propranolol + IS-MN (n = 175). There were no significant differences in the 1- and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol + placebo, 8.3% and 10.6%; propranolol + IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n = 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol + IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. In conclusion, propranolol effectively prevents variceal bleeding. Adding IS-MN does not further decrease the low residual risk of bleeding in patients receiving propranolol. However, the long-term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding.",0
2593,12802024,Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease,"BACKGROUND: Faced with unsatisfactory results of treatment for advanced Hodgkin's disease, we investigated three combinations of chemotherapy. METHODS: From 1993 to 1998, 1201 eligible patients 15 to 65 years of age who had newly diagnosed Hodgkin's disease in unfavorable stage IIB or IIIA or stage IIIB or IV were randomly assigned to receive eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP); or increased-dose BEACOPP, each followed by local radiotherapy when indicated. Enrollment in the COPP-ABVD group was stopped in 1996 owing to inferior results. RESULTS: For the final analysis, 1195 of 1201 patients could be evaluated: 260 in the COPP-ABVD group, 469 in the BEACOPP group, and 466 in the increased-dose BEACOPP group; the median follow-up was 72, 54, and 51 months, respectively. The rate of freedom from treatment failure at five years was 69 percent in the COPP-ABVD group, 76 percent in the BEACOPP group, and 87 percent in the increased-dose BEACOPP group (P=0.04 for the comparison of the COPP-ABVD group with the BEACOPP group and P<0.001 for the comparison of the increased-dose BEACOPP group with the COPP-ABVD group and with the BEACOPP group), and the five-year rates of overall survival were 83 percent, 88 percent, and 91 percent, respectively (P=0.16 for the comparison of the COPP-ABVD group with the BEACOPP group, P=0.06 for the comparison of the BEACOPP group with the increased-dose BEACOPP group, and P=0.002 for the comparison of the COPP-ABVD group with the increased-dose BEACOPP group). Rates of early progression were significantly lower with increased-dose BEACOPP than with COPP-ABVD or standard BEACOPP. CONCLUSIONS: Increased-dose BEACOPP resulted in better tumor control and overall survival than did COPP-ABVD.",0
2594,12802026,Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension,"BACKGROUND: It is uncertain whether ambulatory blood-pressure measurements recorded for 24 hours in patients with treated hypertension predict cardiovascular events independently of blood-pressure measurements obtained in the physician's office and other cardiovascular risk factors. METHODS: We assessed the association between base-line ambulatory blood pressures in treated patients and subsequent cardiovascular events among 1963 patients with a median follow-up of 5 years (range, 1 to 66 months). RESULTS: We documented new cardiovascular events in 157 patients. In a Cox proportional-hazards model with adjustment for age, sex, smoking status, presence or absence of diabetes mellitus, serum cholesterol concentration, body-mass index, use or nonuse of lipid-lowering drugs, and presence or absence of a history of cardiovascular events, as well as blood pressure measured at the physician's office, higher mean values for 24-hour ambulatory systolic and diastolic blood pressure were independent risk factors for new cardiovascular events. The adjusted relative risk of cardiovascular events associated with a 1-SD increment in blood pressure was 1.34 (95 percent confidence interval, 1.11 to 1.62) for 24-hour ambulatory systolic blood pressure, 1.30 (95 percent confidence interval, 1.08 to 1.58) for ambulatory systolic blood pressure during the daytime, and 1.27 (95 percent confidence interval, 1.07 to 1.57) for ambulatory systolic blood pressure during the nighttime. For ambulatory diastolic blood pressure, the corresponding relative risks of cardiovascular events associated with a 1-SD increment were 1.21 (95 percent confidence interval, 1.01 to 1.46), 1.24 (95 percent confidence interval, 1.03 to 1.49), and 1.18 (95 percent confidence interval, 0.98 to 1.40). CONCLUSIONS: In patients with treated hypertension, a higher ambulatory systolic or diastolic blood pressure predicts cardiovascular events even after adjustment for classic risk factors including office measurements of blood pressure.",0
2595,12815135,Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography,"BACKGROUND: We compared the diagnostic accuracy of integrated positron-emission tomography (PET) and computed tomography (CT) with that of CT alone, that of PET alone, and that of conventional visual correlation of PET and CT in determining the stage of disease in non-small-cell lung cancer. METHODS: In a prospective study, integrated PET-CT was performed in 50 patients with proven or suspected non-small-cell lung cancer. CT and PET alone, visually correlated PET and CT, and integrated PET-CT were evaluated separately, and a tumor-node-metastasis (TNM) stage was assigned on the basis of image analysis. Nodal stations were identified according to the mapping system of the American Thoracic Society. The standard of reference was histopathological assessment of tumor stage and node stage. Extrathoracic metastases were confirmed histopathologically or by at least one other imaging method. A paired sign test was used to compare integrated PET-CT with the other imaging methods. RESULTS: Integrated PET-CT provided additional information in 20 of 49 patients (41 percent), beyond that provided by conventional visual correlation of PET and CT. Integrated PET-CT had better diagnostic accuracy than the other imaging methods. Tumor staging was significantly more accurate with integrated PET-CT than with CT alone (P=0.001), PET alone (P<0.001), or visual correlation of PET and CT (P=0.013); node staging was also significantly more accurate with integrated PET-CT than with PET alone (P=0.013). In metastasis staging, integrated PET-CT increased the diagnostic certainty in two of eight patients. CONCLUSIONS: Integrated PET-CT improves the diagnostic accuracy of the staging of non-small-cell lung cancer.",0
2596,12815136,Leisure activities and the risk of dementia in the elderly,"BACKGROUND: Participation in leisure activities has been associated with a lower risk of dementia. It is unclear whether increased participation in leisure activities lowers the risk of dementia or participation in leisure activities declines during the preclinical phase of dementia. METHODS: We examined the relation between leisure activities and the risk of dementia in a prospective cohort of 469 subjects older than 75 years of age who resided in the community and did not have dementia at base line. We examined the frequency of participation in leisure activities at enrollment and derived cognitive-activity and physical-activity scales in which the units of measure were activity-days per week. Cox proportional-hazards analysis was used to evaluate the risk of dementia according to the base-line level of participation in leisure activities, with adjustment for age, sex, educational level, presence or absence of chronic medical illnesses, and base-line cognitive status. RESULTS: Over a median follow-up period of 5.1 years, dementia developed in 124 subjects (Alzheimer's disease in 61 subjects, vascular dementia in 30, mixed dementia in 25, and other types of dementia in 8). Among leisure activities, reading, playing board games, playing musical instruments, and dancing were associated with a reduced risk of dementia. A one-point increment in the cognitive-activity score was significantly associated with a reduced risk of dementia (hazard ratio, 0.93 [95 percent confidence interval, 0.90 to 0.97]), but a one-point increment in the physical-activity score was not (hazard ratio, 1.00). The association with the cognitive-activity score persisted after the exclusion of the subjects with possible preclinical dementia at base line. Results were similar for Alzheimer's disease and vascular dementia. In linear mixed models, increased participation in cognitive activities at base line was associated with reduced rates of decline in memory. CONCLUSIONS: Participation in leisure activities is associated with a reduced risk of dementia, even after adjustment for base-line cognitive status and after the exclusion of subjects with possible preclinical dementia. Controlled trials are needed to assess the protective effect of cognitive leisure activities on the risk of dementia.",0
2597,12826639,The quality of health care delivered to adults in the United States,"BACKGROUND: We have little systematic information about the extent to which standard processes involved in health care--a key element of quality--are delivered in the United States. METHODS: We telephoned a random sample of adults living in 12 metropolitan areas in the United States and asked them about selected health care experiences. We also received written consent to copy their medical records for the most recent two-year period and used this information to evaluate performance on 439 indicators of quality of care for 30 acute and chronic conditions as well as preventive care. We then constructed aggregate scores. RESULTS: Participants received 54.9 percent (95 percent confidence interval, 54.3 to 55.5) of recommended care. We found little difference among the proportion of recommended preventive care provided (54.9 percent), the proportion of recommended acute care provided (53.5 percent), and the proportion of recommended care provided for chronic conditions (56.1 percent). Among different medical functions, adherence to the processes involved in care ranged from 52.2 percent for screening to 58.5 percent for follow-up care. Quality varied substantially according to the particular medical condition, ranging from 78.7 percent of recommended care (95 percent confidence interval, 73.3 to 84.2) for senile cataract to 10.5 percent of recommended care (95 percent confidence interval, 6.8 to 14.6) for alcohol dependence. CONCLUSIONS: The deficits we have identified in adherence to recommended processes for basic care pose serious threats to the health of the American public. Strategies to reduce these deficits in care are warranted.",0
2598,12829998,Translational regulation by p38 mitogen-activated protein kinase signaling during human cholangiocarcinoma growth,"The p38 mitogen-activated protein kinase (MAPK) signaling pathway is aberrantly expressed and maintains transformed cell growth in malignant human cholangiocytes. Because cell growth requires and is intimately related to protein synthesis, our aims were to assess the effect of p38 MAPK signaling on protein synthesis during growth of malignant human cholangiocytes. Inhibition of p38 MAPK activity during mitogenic stimulation decreased protein synthesis rates and tumor cell xenograft growth in nude mice. Altered protein synthesis resulted from decreased translational efficiency with impaired initiation of translation. Mitogenic stimulation resulted in phosphorylation of the eukaryotic initiation factor (eIF)-4E. Inhibition of p38 MAPK signaling or functional dysregulation of translation by small interfering double-stranded RNA (siRNA) to eIF-4E decreased anchorage-independent growth of malignant cholangiocytes. In conclusion, these studies identify a relationship between p38 MAPK activity and the regulation of protein synthesis during human cholangiocarcinoma growth. As protein synthesis is intimately linked to cell growth, dysregulation of translation initiation is a mechanism by which cellular p38 MAPK signaling participates in growth regulation of malignant cholangiocytes.",0
2599,12840089,"A multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis","BACKGROUND: The treatment of infants with bronchiolitis is largely supportive. The role of bronchodilators is controversial. Most studies of the use of bronchodilators have enrolled small numbers of subjects and have examined only short-term outcomes, such as clinical scores. METHODS: We conducted a randomized, double-blind, controlled trial comparing nebulized single-isomer epinephrine with placebo in 194 infants admitted to four hospitals in Queens-land, Australia, with a clinical diagnosis of bronchiolitis. Three 4-ml doses of 1 percent nebulized epinephrine or three 4-ml doses of normal saline were administered at four-hour intervals after hospital admission. Observations were made at admission and just before, 30 minutes after, and 60 minutes after each dose. The primary outcome measures were the length of the hospital stay and the time until the infant was ready for discharge. The secondary outcome measures were the degree of change in the respiratory rate, the heart rate, and the respiratory-effort score and the time that supplemental oxygen was required. RESULTS: There were no significant overall differences between the groups in the length of the hospital stay (P=0.16) or the time until the infant was ready for discharge (P=0.86). Among infants who required supplemental oxygen and intravenous fluids, the time until the infant was ready for discharge was significantly longer in the epinephrine group than in the placebo group (P=0.02). The need for supplemental oxygen at admission had the greatest influence on the score for severity of illness and strongly predicted the length of the hospital stay and the time until the infant was ready for discharge (P<0.001). There were no significant changes in the respiratory rate, blood pressure, or respiratory-effort scores from before each treatment to after each treatment. The heart rate was significantly increased after each treatment with epinephrine (P=0.02 to P<0.001). CONCLUSIONS: The use of nebulized epinephrine did not significantly reduce the length of the hospital stay or the time until the infant was ready for discharge among infants admitted to the hospital with bronchiolitis.",0
2600,12867606,Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma,"BACKGROUND: The effectiveness of avoidance of house-dust-mite allergen (Dermatophagoides pteronyssinus 1 [Der p1]) in the management of asthma is uncertain. METHODS: We conducted a double-blind, randomized, placebo-controlled study of allergen-impermeable bed covers involving 1122 adults with asthma. The primary outcomes were the mean morning peak expiratory flow rate over a four-week period during the run-in phase and at six months and the proportion of patients who discontinued inhaled corticosteroid therapy as part of a phased-reduction program during months 7 through 12. Der p1 was measured in mattress dust in a 10 percent random subsample of homes at entry and at 6 and 12 months. RESULTS: The prevalence of sensitivity to dust-mite allergen was 65.4 percent in the group supplied with allergen-impermeable bed covers (active-intervention group) and 65.1 percent in the control group supplied with non-impermeable bed covers. The concentration of Der p1 in mattress dust was significantly lower in the active-intervention group at 6 months (geometric mean, 0.58 microg per gram vs. 1.71 microg per gram in the control group; P=0.01) but not at 12 months (1.05 microg per gram vs. 1.64 microg per gram; P=0.74). The mean morning peak expiratory flow rate improved significantly in both groups (from 410.7 to 419.1 liters per minute in the active-intervention group, P<0.001 for the change; and from 417.8 to 427.4 liters per minute in the control group, P<0.001 for the change). After adjustment for base-line differences (by analysis of covariance), there was no significant difference between the groups in the peak expiratory flow rate at six months (difference in means, active-intervention group vs. control group, -1.6 liters per minute [95 percent confidence interval, -5.9 to 2.7] among all patients [P=0.46] and -1.5 liters per minute [95 percent confidence interval, -6.9 to 3.9] among mite-sensitive patients [P=0.59]). There was no significant difference between the groups in the proportion in whom complete cessation of inhaled corticosteroid therapy was achieved (17.4 percent in the active-intervention group and 17.1 percent in the control group) or in the mean reduction in steroid dose, either among all patients or among mite-sensitive patients. CONCLUSIONS: Allergen-impermeable covers, as a single intervention for the avoidance of exposure to dust-mite allergen, seem clinically ineffective in adults with asthma.",0
2601,12883484,"A liver tolerates a portal antigen by generating CD11c+ cells, which select Fas ligand+ Th2 cells via apoptosis","Administration of an antigen (Ag) per oral route leads to apoptosis of Ag-specific CD4(+) T cells and to development of Th2 cells expressing Fas ligand (FasL) in the liver. We determined whether presentation of an ingested Ag in the liver alone was enough to select these FasL(+)Th2 cells and explored how this selection was achieved in the liver. Ovalbumin (OVA) administered orally was colocalized with class II(+) cells in the periportal and parenchymal area of the liver. On coculture with naive OVA-specific CD4(+) T cells, hepatic CD11c(+) cells from mice fed OVA generated Ag-specific Th2 cells. This was achieved by apoptosis of CD4(+) T cells, decrease of interleukin 12 (IL-12) secretion, and increase of IL-18 secretion by the CD11c(+) cells. Addition of IL-12 to this coculture prevented apoptosis of the CD4(+) T cells, which was associated with up-modulation of IL-2 receptor beta chain expression. Administration of IL-12 to mice fed OVA prevented apoptosis of OVA-specific CD4(+) T cells in the liver. Moreover, adoptive transfer of hepatic CD11c(+) cells from mice fed OVA together with OVA-specific CD4(+) T cells led to development of Th2 cells as well as apoptosis of the transferred CD4(+) T cells in the lymph nodes of the recipient mice on immunization with OVA. In conclusion, presentation of an ingested Ag by hepatic CD11c(+) cells selects Th2 cells resistant to apoptosis in the liver, which is mediated in part by down-regulation of IL-12 secretion by the former cells.",0
2602,12939584,Novel differential gene expression in human cirrhosis detected by suppression subtractive hybridization,"Pathogenic molecular pathways in cirrhotic liver diseases such as hepatitis C virus (HCV), autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are poorly characterized. Differentially expressed genes are often important in disease pathogenesis. Suppression subtractive hybridization (SSH) is a genome-wide approach that enriches for differentially expressed mRNA transcripts. We aimed to make novel observations of differential gene expression in cirrhosis using SSH combined with quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Liver transcriptomes in HCV cirrhosis, AIH cirrhosis, PBC, and nondiseased liver tissue were examined by SSH. Resulting complementary DNA (cDNA) clones were rescreened for differential expression by dot-blot hybridization and then sequenced. Selected gene expression was quantified by real-time RT-PCR. Following SSH, 694 clones were rescreened for differential gene expression, of which 145 were sequenced and found to derive from 89 different genes. Seven clones were homologous only with expressed sequence tag (EST) sequences encoding genes having no known function. Up-regulated expression of four genes was confirmed by real-time RT-PCR: transmembrane 4 superfamily member 3 (tetraspanin CO-029) in all forms of cirrhosis, hedgehog interacting protein (HIP) in AIH cirrhosis and chitinase 3-like-1 (HC gp-39 or ykl-40) and arginine-glutamic acid repeat (RERE) in HCV cirrhosis. RERE gene polymorphisms and splice variants were observed in all tissues examined. Tetraspanin CO-029 up-regulation was primarily localized to bile ductular cells. In conclusion, novel observations of differential gene expression in human cirrhosis were made using SSH as the primary discovery tool. In particular, further studies of the RERE gene and its products in HCV associated liver disease are warranted.",0
2603,12939592,Antibody-selected mimics of hepatitis C virus hypervariable region 1 activate both primary and memory Th lymphocytes,"An ideal strategy that leads to a vaccine aimed at controlling viral escape may be that of preventing the replication of escape mutants by eliciting a T- and B-cell repertoire directed against many viral variants. The hypervariable region 1 (HVR1) of the putative envelope 2 protein that presents B and T epitopes shown to induce protective immunity against hepatitis C virus (HCV), might be suitable for this purpose if its immunogenicity can be improved by generating mimics that induce broad, highly cross-reactive, anti-HVR1 responses. Recently we described a successful approach to select HVR1 mimics (mimotopes) incorporating the variability found in a great number of viral variants. In this report we explore whether these mimotopes, designed to mimic B-cell epitopes, also mimic helper T-cell epitopes. The first interesting observation is that mimotopes selected for their reactivity to HVR1-specific antibodies of infected patients also do express HVR1 T-cell epitopes, suggesting that similar constraints govern HVR1-specific humoral and cellular immune responses. Moreover, some HVR1 mimotopes stimulate a multispecific CD4(+) T-cell repertoire that effectively cross-reacts with HVR1 native sequences. This may significantly limit effects as a T-cell receptor (TCR) antagonist frequently exerted by natural HVR1-variants on HVR1-specific T-cell responses. In conclusion, these data lend strong support to using HVR1 mimotopes in vaccines designed to prevent replication of escape mutants.",0
2604,13679526,Withdrawal of mechanical ventilation in anticipation of death in the intensive care unit,"BACKGROUND: In critically ill patients who are receiving mechanical ventilation, the factors associated with physicians' decisions to withdraw ventilation in anticipation of death are unclear. The objective of this study was to examine the clinical determinants that were associated with the withdrawal of mechanical ventilation. METHODS: We studied adults who were receiving mechanical ventilation in 15 intensive care units, recording base-line physiological characteristics, daily Multiple Organ Dysfunction Scores, the patient's decision-making ability, the type of life support administered, the use of do-not-resuscitate orders, the physician's prediction of the patient's status, and the physician's perceptions of the patient's preferences about the use of life support. We examined the relation between these factors and withdrawal of mechanical ventilation, using Cox proportional-hazards regression analysis. RESULTS: Of 851 patients who were receiving mechanical ventilation, 539 (63.3 percent) were successfully weaned, 146 (17.2 percent) died while receiving mechanical ventilation, and 166 (19.5 percent) had mechanical ventilation withdrawn. The need for inotropes or vasopressors was associated with withdrawal of the ventilator (hazard ratio, 1.78; 95 percent confidence interval, 1.20 to 2.66; P=0.004), as were the physician's prediction that the patient's likelihood of survival in the intensive care unit was less than 10 percent (hazard ratio, 3.49; 95 percent confidence interval, 1.39 to 8.79; P=0.002), the physician's prediction that future cognitive function would be severely impaired (hazard ratio, 2.51; 95 percent confidence interval, 1.28 to 4.94; P=0.04), and the physician's perception that the patient did not want life support used (hazard ratio, 4.19; 95 percent confidence interval, 2.57 to 6.81; P<0.001). CONCLUSIONS: Rather than age or the severity of the illness and organ dysfunction, the strongest determinants of the withdrawal of ventilation in critically ill patients were the physician's perception that the patient preferred not to use life support, the physician's predictions of a low likelihood of survival in the intensive care unit and a high likelihood of poor cognitive function, and the use of inotropes or vasopressors.",0
2605,13945539,"A case of vaccinia necrosum (or progressive vaccinia), with severe hypogammaglobulinaemia, treated with n-methyl isatin beta-thiosemicarbazone (33T57)","A fatal case of vaccinia necrosum treated with antivaccinial gamma globulin and N-methyl isatin beta-thiosemicarbazone (33T57) is described. Histological abnormalities found at necropsy included intranuclear as well as cytoplasmic inclusion bodies, absence of lymphoid germinal centres, grey hepatization, and bronchiolar epithelial hyperplasia. Virus titres were highest in the original skin lesion; virus was also found in the lymph node draining it and in the kidney and the brain. No toxic effects could be clearly attributed to the drug used in treatment. ",0
2606,13971682,Structurally caused freezing point depression of biological tissues,"When investigating the freezing behaviour (by thermal analysis) of the glycerol-extracted adductor muscle of Mytilus edulis it was observed that the temperature of ice formation in the muscular tissue was up to 1.5 degrees C lower than the freezing point of the embedding liquid, a 0.25 N KCl solution with pH = 4.9 with which the tissue had been equilibrated prior to the freezing experiment. A smaller freezing point depression was observed if the pH values of the embedding 0.25 N KCl solution were above or below pH = 4.9. Reasoning from results obtained previously in analogous experiments with artificial gels, the anomalous freezing depression is explained by the impossibility of growing at the normal freezing temperature regular macroscopic crystals inside the gel, due to the presence of the gel network. The freezing temperature is here determined by the size of the microprisms penetrating the meshes of the network at the lowered freezing temperature. This process leads finally to an ice block of more or less regular structure in which the filaments are embedded. Prerequisite for this hindrance of ideal ice growth is a sufficient tensile strength of the filamental network. The existence of structurally caused freezing point depression in biological tissue is likely to invalidate many conclusions reported in the literature, in which hypertonicity was deduced from cryoscopic data. ",0
2607,14341318,SIALADENITIS AND MAJOR SALIVARY GLAND TUMORS IN CHILDREN: EXPERIENCE AT LOS ANGELES CHILDRENS HOSPITAL AND A REVIEW OF THE LITERATURE,"Except for mumps, the benign lesions most frequently seen in the salivary glands of a child are parotitis, hemangioendotheliomas and mixed tumors. Carcinoma and sarcoma are uncommon. Rapid growth and pain are features of malignant change. Chronic parotitis usually subsides under conservative treatment. If operation is necessary, total parotidectomy is advisable. Scout x-ray films and sialangiographic examination are useful in differentiating an inflammatory lesion from a neoplastic growth.The treatment of choice for a non-inflammatory tumor is surgical excision, for most parotid tumors are radioresistant. Small masses should be completely excised for pathological evaluation. Since operation entails risk of damage to the seventh nerve, incisional biopsy may occasionally be indicated in the case of a large diffuse lesion for it is very likely to be benign and operation unnecessary. The risks of seventh nerve damage are magnified in a child as the anatomic structures are smaller and the nerve lies in a more superficial position. ",0
2608,14342505,EXTRACELLULAR RIBONUCLEASE FORMATION IN BACILLUS SUBTILIS AND ITS STIMULATION BY ACTINOMYCIN D,"1. Extracellular ribonuclease is produced linearly for at least 3hr. by washed post-logarithmic-phase cells of Bacillus subtilis suspended in a medium containing maltose (1%) and casein hydrolysate (0.5%). 2. Low concentrations of actinomycin D (less than 2mug./ml.) stimulate ribonuclease formation, the maximum effect being observed with a concentration of 1mug./ml. Concentrations greater than 2mug./ml. are inhibitory. There is no parallel stimulation of alpha-amylase formed under the same conditions, and [(14)C]uracil incorporation into a perchloric acid-insoluble form is inhibited. 3. The actinomycin D-induced stimulation is not due to the presence of an activator, nor is the inhibition due to the release of an inhibitor by the cells. The effect is on the amount of ribonuclease produced in the medium. 4. Extracellular ribonuclease formation is partially inhibited by anaerobiosis, 2,4-dinitrophenol, sodium azide and by chloramphenicol and puromycin. 5. High concentrations of antibiotic do not completely inhibit ribonuclease formation, but a basal amount of enzyme representing 20min. synthesis in an uninhibited system is always produced. This ;antibiotic-insensitive' enzyme could possibly represent preformed enzyme ;in the pipe-line' en route to secretion. 6. The stimulated appearance of ribonuclease in the presence of 1mug. of actinomycin D/ml. is shown to be dependent on enzyme synthesis. The mechanism of this effect is discussed. ",0
2609,14500804,The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis,"BACKGROUND: Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. METHODS: A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. RESULTS: The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. CONCLUSIONS: There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy.",0
2610,14512869,Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice,"In human chronic hepatitis C, alcohol intake is a synergistic factor for the acceleration of hepatocarcinogenesis. Recently, we showed a significant increase of reactive oxygen species (ROS) in hepatitis C virus (HCV) core-transgenic mice fed ethanol-containing diets. Because previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase (GST), which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to the pathogenesis of liver disease of HCV-infected patients with high ethanol consumption.",0
2611,14512876,Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice,"The equilibrium between the production and degradation of collagen is rigorously controlled by a number of growth factors and cytokines. Interferon alfa (IFN-alpha) is now widely used for the treatment of chronic hepatitis C, which can improve serum levels of fibrotic markers and the degree of hepatic fibrosis, not only in patients who responded to therapy but also in those in whom it is ineffective. These findings may suggest that IFN-alpha possesses direct antifibrotic effects in addition to its antiviral activity. However, in contrast to IFN-gamma, which has been shown to suppress collagen gene transcription, little is known about the mechanisms responsible for the antifibrotic effects of IFN-alpha. Here, we report that IFN-alpha, when administered into transgenic mice harboring the alpha2(I) collagen gene (COL1A2) promoter sequence, significantly repressed promoter activation and prevented the progression of hepatic fibrosis induced by carbon tetrachloride injection. Transient transfection assays indicated that IFN-alpha decreased the steady-state levels of COL1A2 messenger RNA (mRNA) and inhibited basal and TGF-beta/Smad3-stimulated COL1A2 transcription in activated hepatic stellate cells (HSC). These inhibitory effects of IFN-alpha on COL1A2 transcription were exerted through the interaction between phosphorylated Stat1 and p300. Blocking of the IFN-alpha signal by overexpressing the intracellular domain-deleted IFN receptor increased basal COL1A2 transcription and abolished the inhibitory effects of IFN-alpha. In conclusion, our results indicate that IFN-alpha antagonizes the TGF-beta/Smad3-stimulated COL1A2 transcription in vitro and suppresses COL1A2 promoter activation in vivo, providing a molecular basis for antifibrotic effects of IFN-alpha.",0
2612,14512882,"Ontogeny, distribution, and possible functional implications of an unusual aquaporin, AQP8, in mouse liver","Aquaporins are channel proteins widely expressed in nature and known to facilitate the rapid movement of water across numerous cell membranes. A mammalian aquaporin, AQP8, was recently discovered and found to have a very distinct evolutionary pathway. To understand the reason for this divergence, here we define the ontogeny and exact subcellular localization of AQP8 in mouse liver, a representative organ transporting large volumes of water for secretion of bile. Northern blotting showed strong AQP8 expression between fetal day 17 and birth as well as at weaning and thereafter. Interestingly, this pattern was confirmed by immunohistochemistry and coincided both temporally and spatially with that of hepatic glycogen accumulation. As seen by reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, fasting was accompanied by remarkable down-regulation of hepatic AQP8 that paralleled the expected depletion of glycogen content. The level of hepatic AQP8 returned to be considerable after refeeding. Immunoelectron microscopy confirmed AQP8 in hepatocytes where labeling was over smooth endoplasmic reticulum (SER) membranes adjacent to glycogen granules and in canalicular membranes, subapical vesicles, and some mitochondria. In conclusion, in addition to supporting a role for AQP8 in canalicular water secretion, these findings also suggest an intracellular involvement of AQP8 in preserving cytoplasmic osmolality during glycogen metabolism and in maintaining mitochondrial volume. AQP8 may have evolved separately to feature these intracellular roles as no other known aquaporin shows this specialization.",0
2613,14512884,Effects of cell proliferation on the uptake of transferrin-bound iron by human hepatoma cells,"The effects of cellular proliferation on the uptake of transferrin-bound iron (Tf-Fe) and expression of transferrin receptor-1 (TfR1) and transferrin receptor-2 (TfR2) were investigated using a human hepatoma (HuH7) cell line stably transfected with TfR1 antisense RNA expression vector to suppress TfR1 expression. At transferrin (Tf) concentrations of 50 nmol/L and 5 micromol/L, when Tf-Fe uptake occurs by the TfR1- and TfR1-independent (NTfR1)-mediated process, respectively, the rate of Fe uptake by proliferating cells was approximately 250% that of stationary cells. The maximum rate of Fe uptake by the TfR1- and NTfR1-mediated process by proliferating cells was increased to 200% and 300% that of stationary cells, respectively. The maximum binding of Tf by both TfR1- and NTfR1-mediated processes by proliferating cells was increased significantly to 160% that of stationary cells. TfR1 and TfR2-alpha protein levels expressed by proliferating cells was observed to be approximately 300% and 200% greater than the stationary cells, respectively. During the proliferating growth phase, expression of TfR1 messenger RNA (mRNA) increased to 300% whereas TfR2-alpha mRNA decreased to 50% that of stationary cells. In conclusion, an increase in Tf-Fe uptake by TfR1-mediated pathway by proliferating cells was associated with increased TfR1 mRNA and protein expression. An increase in Tf-Fe uptake by NTfR1-mediated pathway was correlated with an increase in TfR2-alpha protein expression but not TfR2-alpha mRNA. In conclusion, TfR2-alpha protein is likely to have a role in the mediation of Tf-Fe uptake by the NTfR1 process by HuH7 hepatoma cell in proliferating and stationary stages of growth.",0
2614,14523140,Characteristics of Hodgkin's lymphoma after infectious mononucleosis,"BACKGROUND: Infectious mononucleosis-related Epstein-Barr virus (EBV) infection has been associated with an increased risk of Hodgkin's lymphoma in young adults. Whether the association is causal remains unclear. METHODS: We compared the incidence rates of Hodgkin's lymphoma in two population-based Danish cohorts of patients who were tested for infectious mononucleosis: 17,045 with serologic evidence of having had acute EBV infection, and 24,614 with no such evidence. We combined the cohort of patients who had serologically verified infectious mononucleosis with a cohort of 21,510 Swedish patients with infectious mononucleosis (combined total, 38,555). Biopsy specimens of Hodgkin's lymphomas occurring during follow-up in this combined cohort were tested serologically for the presence of EBV. Using this information, we modeled the relative risk of EBV-negative and EBV-positive Hodgkin's lymphoma in different periods after the diagnosis of infectious mononucleosis and estimated the median incubation time for mononucleosis-related EBV-positive Hodgkin's lymphoma. RESULTS: Only serologically confirmed infectious mononucleosis was associated with a persistently increased risk of Hodgkin's lymphoma. Sixteen of 29 tumors (55 percent), obtained from patients with infectious mononucleosis, had evidence of EBV. There was no evidence of an increased risk of EBV-negative Hodgkin's lymphoma after infectious mononucleosis. In contrast, the risk of EBV-positive Hodgkin's lymphoma was significantly increased (relative risk, 4.0; 95 percent confidence interval, 3.4 to 4.5). The estimated median incubation time from mononucleosis to EBV-positive Hodgkin's lymphoma was 4.1 years (95 percent confidence interval, 1.8 to 8.3). CONCLUSIONS: A causal association between infectious mononucleosis-related EBV infection and the EBV-positive subgroup of Hodgkin's lymphomas is likely in young adults.",0
2615,14573732,Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease,"BACKGROUND: Cellular antioxidant enzymes such as glutathione peroxidase 1 and superoxide dismutase have a central role in the control of reactive oxygen species. In vitro data and studies in animal models suggest that these enzymes may protect against atherosclerosis, but little is known about their relevance to human disease. METHODS: We conducted a prospective study among 636 patients with suspected coronary artery disease, with a median follow-up period of 4.7 years (maximum, 5.4) to assess the risk of cardiovascular events associated with base-line erythrocyte glutathione peroxidase 1 and superoxide dismutase activity. RESULTS: Glutathione peroxidase 1 activity was among the strongest univariate predictors of the risk of cardiovascular events, whereas superoxide dismutase activity had no association with risk. The risk of cardiovascular events was inversely associated with increasing quartiles of glutathione peroxidase 1 activity (P for trend <0.001); patients in the highest quartile of glutathione peroxidase 1 activity had a hazard ratio of 0.29 (95 percent confidence interval, 0.15 to 0.58; P<0.001), as compared with those in the lowest quartile. Glutathione peroxidase 1 activity was affected by sex and smoking status but retained its predictive power in these subgroups. After adjustment for these and other cardiovascular risk factors, the inverse association between glutathione peroxidase 1 activity and cardiovascular events remained nearly unchanged. CONCLUSIONS: In patients with coronary artery disease, a low level of activity of red-cell glutathione peroxidase 1 is independently associated with an increased risk of cardiovascular events. Glutathione peroxidase 1 activity may have prognostic value in addition to that of traditional risk factors. Furthermore, increasing glutathione peroxidase 1 activity might lower the risk of cardiovascular events.",0
2616,14578855,Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis,"The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stress-induced hepatocyte damage. In this context, methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.",0
2617,14578867,Deficiency in virion secretion and decreased stability of the hepatitis B virus immune escape mutant G145R,"Hepatitis B virus with a G145R mutation in the small surface protein is considered the quintessential immune escape mutant because it frequently is found in vaccinated individuals with breakthrough infections and liver transplant recipients under anti-hepatitis B surface antigen (HBsAg) immunoglobulin prophylaxis. Nowadays the prevalence of the variant progressively increases. However, because spread of a virus depends not only on immune pressure but also on the viral phenotype, we investigated the biologic properties of the G145R variant. The G145R mutation was introduced into wild-type (Wt) virus genome by in vitro mutagenesis. After transfection into human hepatoma cells, the DNA, RNA, and protein synthesis and viral secretion ability of the mutant were studied. Furthermore, cotransfection studies were performed with the G145R variant and a Wt virus S-protein expressing construct and vice versa. Production and stability of viral messenger RNAs (mRNAs), DNA, and proteins were not affected by the G145R mutation. In contrast, secretion of mutant virions was reduced significantly. Only 20% of virions were found in the medium of G145R variant-transfected cells compared with Wt virus. Furthermore, mutant virions were more sensitive to detergent treatment suggesting a diminished stability. In cotransfection studies, Wt virus S-protein rescued secretion of mutant virions, whereas mutant S-protein had a transdominant negative effect on secretion of Wt virus. Both mechanisms may support persistence of the defective mutant in a mixed population with Wt virus. In conclusion, the significant defect of the G145R mutant for secretion of infectious virions and the diminished stability of mutant virions may limit global spread of the mutant.",0
2618,14645638,"Lp(a) lipoprotein, vascular disease, and mortality in the elderly","BACKGROUND: As compared with what is known about predictors of vascular events in middle-aged persons, less is known about these events in the elderly. Lp(a) lipoprotein, which plays an important part in atherothrombogenesis, has been associated with an increased risk of vascular disease. We investigated this relation among older U.S. adults. METHODS: In a prospective study of 5888 community-dwelling older adults (65 years of age or older) in the United States, 2375 women and 1597 men who were free of vascular disease provided base-line serum samples for analysis for levels of Lp(a) lipoprotein. These 3972 subjects were followed for a median of 7.4 years to evaluate the development of stroke and to track deaths from vascular causes and all causes. The men and women were divided into quintile groups according to the Lp(a) lipoprotein level at base line. RESULTS: Using Cox proportional-hazards models, we determined the risk associated with each quintile level of Lp(a) lipoprotein, with the lowest quintile serving as the reference group. As compared with those in the lowest quintile, men in the highest quintile had three times the unadjusted risk of stroke (relative risk, 3.00; 95 percent confidence interval, 1.59 to 5.65), almost three times the risk of death associated with vascular events (relative risk, 2.54; 95 percent confidence interval, 1.59 to 4.08), and nearly twice the risk of death from all causes (relative risk, 1.76; 95 percent confidence interval, 1.31 to 2.36). Adjustment for age; sex; the levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; carotid-wall thickness; smoking status; the presence or absence of diabetes and systolic and diastolic hypertension; body-mass index; and other traditional risk factors had little effect on the final assessments. Similar analyses for women, which also included adjustment for estrogen use or nonuse, revealed no such relation. CONCLUSIONS: Among older adults in the United States, an elevated level of Lp(a) lipoprotein is an independent predictor of stroke, death from vascular disease, and death from any cause in men but not in women. These data support the use of Lp(a) lipoprotein levels in predicting the risk of these events in older men.",0
2619,14647055,Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection,"Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCV-specific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P =.001) and scope (14/36 vs. 4/36 pools, P =.002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R = -0.51, P =.049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4(+)CD25(+) regulatory T cells (7.3% chronic vs. 2.5% recovered, P =.002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4(+)CD25(+) regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence.",0
2620,14647063,DNA methylation controls the responsiveness of hepatoma cells to leukemia inhibitory factor,"The related members of the interleukin 6 (IL-6) family of cytokines, IL-6, leukemia inhibitory factor (LIF), and oncostatin M, act as major inflammatory mediators and induce the hepatic acute phase reaction. Normal parenchymal liver cells express the receptors for these cytokines, and these receptors activate, to a comparable level, the intracellular signaling through signal transducer and activator of transcription (STAT) proteins and extracellular-regulated kinase (ERK). In contrast, hepatoma cell lines show attenuated responsiveness to some of these cytokines that is correlated with lower expression of the corresponding ligand-binding receptor subunits. This study tests the hypothesis that the reduced expression of LIF receptor (LIFR) observed in hepatoma cells is mediated by altered DNA methylation. H-35 rat hepatoma cells that have a greatly reduced LIF responsiveness were treated with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase. Surviving and proliferating cells showed reestablished expression of LIFR protein and function. Restriction landmark genomic scanning (RLGS) demonstrated genome-wide drug-induced alterations in DNA methylation status, with striking similarities in the demethylation pattern among independently derived clonal lines. Upon extended growth in the absence of 5-aza-2'-deoxycytidine, the cells exhibit partial reversion to pretreatment patterns. Demethylation and remethylation of the CpG island within the LIFR promoter that is active in normal liver cells correlate with increased and decreased usage of this promoter in H-35 cells. In conclusion, these results indicate that transformed liver cells frequently undergo epigenetic alterations that suppress LIFR gene expression and modify the responsiveness to this IL-6 type cytokine.",0
2621,14657428,IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation,"BACKGROUND: Approximately 10 percent of infants with intrauterine growth retardation remain small, and the causes of their growth deficits are often unclear. We postulated that mutations in the gene for the insulin-like growth factor I receptor (IGF-IR) might underlie some cases of prenatal and postnatal growth failure. METHODS: We screened two groups of children for abnormalities in the IGF-IR gene. In one group of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, we used single-strand conformation polymorphism analysis, followed by direct DNA sequencing of any abnormalities found. A second cohort consisted of 50 children with short stature who had elevated circulating IGF-I concentrations. Complete sequencing of the IGF-IR gene was performed with DNA from nine children. We also studied a control group of 43 children with normal birth weights. RESULTS: In the first cohort, we identified one girl who was a compound heterozygote for point mutations in exon 2 of the IGF-IR gene that altered the amino acid sequence to Arg108Gln in one allele and Lys115Asn in the other. Fibroblasts cultured from the patient had decreased IGF-I-receptor function, as compared with that in control fibroblasts. No such mutations were found in the 43 controls. In the second group, we identified one boy with a nonsense mutation (Arg59stop) that reduced the number of IGF-I receptors on fibroblasts. Both children had intrauterine growth retardation and poor postnatal growth. CONCLUSIONS: Mutations in the IGF-IR gene that lead to abnormalities in the function or number of IGF-I receptors may also retard intrauterine and subsequent growth in humans.",0
2622,14668456,Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection,"BACKGROUND: It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS: In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS: A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS: There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.",0
2623,14681506,Premature coronary-artery atherosclerosis in systemic lupus erythematosus,"BACKGROUND: Premature coronary artery disease is a major cause of illness and death in patients with systemic lupus erythematosus, but little is known about the prevalence, extent, and causes of coronary-artery atherosclerosis. METHODS: We used electron-beam computed tomography to screen for the presence of coronary-artery calcification in 65 patients with systemic lupus erythematosus (mean [+/-SD] age, 40.3+/-11.6 years) and 69 control subjects (mean age, 42.7+/-12.6 years) with no history of coronary artery disease. When calcification was detected, the extent was measured by means of the Agatston score. The frequency of risk factors for coronary artery disease was compared in patients and controls, and the relation between the patients' clinical characteristics and the presence or absence of coronary-artery calcification was examined. RESULTS: The two groups were similar with respect to age, race, and sex. Coronary-artery calcification was more frequent in patients with lupus (20 of 65 patients) than in control subjects (6 of 69 subjects) (P=0.002). The mean calcification score was 68.9+/-244.2 in the patients and 8.8+/-41.8 (P<0.001) in controls. Levels of total, high-density lipoprotein, and low-density lipoprotein cholesterol were not elevated in patients with lupus, but levels of triglycerides (P=0.02) and homocysteine (P<0.001) were. Among patients with lupus, measures of disease activity were similar in those with and those without coronary-artery calcification, but those with calcification were more likely to be older (P<0.001) and male (P=0.008). CONCLUSIONS: In patients with systemic lupus erythematosus, the prevalence of coronary-artery atherosclerosis is elevated and the age at onset is reduced. Early detection of atherosclerosis may provide an opportunity for therapeutic intervention.",0
2624,14695408,The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma,"BACKGROUND: Myeloma cells may secrete factors that affect the function of osteoblasts, osteoclasts, or both. METHODS: We subjected purified plasma cells from the bone marrow of patients with newly diagnosed multiple myeloma and control subjects to oligonucleotide microarray profiling and biochemical and immunohistochemical analyses to identify molecular determinants of osteolytic lesions. RESULTS: We studied 45 control subjects, 36 patients with multiple myeloma in whom focal lesions of bone could not be detected by magnetic resonance imaging (MRI), and 137 patients in whom MRI detected such lesions. Different patterns of expression of 57 of approximately 10,000 genes from purified myeloma cells could be used to distinguish the two groups of patients (P<0.001). Permutation analysis, which adjusts the significance level to account for multiple comparisons in the data sets, showed that 4 of these 57 genes were significantly overexpressed by plasma cells from patients with focal lesions. One of these genes, dickkopf 1 (DKK1), and its corresponding protein (DKK1) were studied in detail because DKK1 is a secreted factor that has been linked to the function of osteoblasts. Immunohistochemical analysis of bone marrow-biopsy specimens showed that only myeloma cells contained detectable DKK1. Elevated DKK1 levels in bone marrow plasma and peripheral blood from patients with multiple myeloma correlated with the gene-expression patterns of DKK1 and were associated with the presence of focal bone lesions. Recombinant human DKK1 or bone marrow serum containing an elevated level of DKK1 inhibited the differentiation of osteoblast precursor cells in vitro. CONCLUSIONS: The production of DKK1, an inhibitor of osteoblast differentiation, by myeloma cells is associated with the presence of lytic bone lesions in patients with multiple myeloma.",0
2625,14695410,The effect of oral sucrose on exercise tolerance in patients with McArdle's disease,"BACKGROUND: Energy metabolism in muscles relies predominantly on the breakdown of glycogen early in exercise. In patients with McArdle's disease, blocked glycogenolysis in muscles results in low exercise tolerance and can lead to muscle injury, particularly in the first minutes of exercise. We hypothesized that ingesting sucrose before exercise would increase the availability of glucose and would therefore improve exercise tolerance in patients with McArdle's disease. METHODS: In a single-blind, randomized, placebo-controlled crossover study, 12 patients with McArdle's disease drank 660 ml of a beverage that had been sweetened with artificial sweeteners (placebo) or with 75 g of sucrose after an overnight fast. Thirty to 40 minutes later, the patients rode a stationary bicycle at a constant workload for 15 minutes while the heart rate, level of perceived exertion, and venous blood glucose levels were monitored. RESULTS: Supplemental sucrose increased the mean plasma glucose level by more than 36 mg per deciliter (2.0 mmol per liter) and resulted in a marked improvement in exercise tolerance in all patients. The mean (+/-SE) heart rate dropped by a maximum of 34+/-3 beats per minute (P<0.001), and the level of perceived exertion fell dramatically when the patients ingested glucose as compared with when they received the placebo. CONCLUSIONS: This study suggests that the ingestion of sucrose before exercise can markedly improve exercise tolerance in patients with McArdle's disease. The treatment takes effect during the time when muscle injury commonly develops in these patients. In addition to increasing the patients' exercise capacity and sense of well-being, the treatment may protect against exercise-induced rhabdomyolysis.",0
2626,14711913,Use of high-cost operative procedures by Medicare beneficiaries enrolled in for-profit and not-for-profit health plans,"BACKGROUND: It is widely believed that for-profit health plans are more likely than not-for-profit health plans to respond to financial incentives by restricting access to care, especially access to high-cost procedures. Until recently, data to address this question have been limited. METHODS: We tested the hypothesis that the rates of use of 12 common high-cost procedures would be lower in for-profit health plans than in not-for-profit plans. Using standardized Medicare HEDIS data on 3,726,065 Medicare beneficiaries 65 years of age or older who were enrolled in 254 health plans during 1997, we compared for-profit and not-for-profit plans with respect to rates of cardiac catheterization, coronary-artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid endarterectomy, reduction of femur fracture, total hip replacement, total knee replacement, partial colectomy, open cholecystectomy, closed cholecystectomy, hysterectomy, and prostatectomy. We adjusted the comparisons for sociodemographic case mix and for characteristics of the health plans other than their tax status, including the plans' location. RESULTS: The rates of carotid endarterectomy, cardiac catheterization, coronary-artery bypass grafting, and percutaneous transluminal coronary angioplasty were higher in for-profit health plans than they were in not-for-profit health plans; the rates of use of other common costly operative procedures were similar in the two types of plan. After adjustment for enrollee case mix and other characteristics of the plans, the for-profit plans had significantly higher rates than the not-for-profit plans for 2 of the 12 procedures we studied and had lower rates for none. The geographic locations of the health plans did not explain these findings. CONCLUSIONS: Contrary to our expectations about the likely effects of financial incentives, the rates of use of high-cost operative procedures were not lower among beneficiaries enrolled in for-profit health plans than among those enrolled in not-for-profit health plans.",0
2627,14724303,Immunoproliferative small intestinal disease associated with Campylobacter jejuni,"BACKGROUND: Immunoproliferative small intestinal disease (also known as alpha chain disease) is a form of lymphoma that arises in small intestinal mucosa-associated lymphoid tissue (MALT) and is associated with the expression of a monotypic truncated immunoglobulin alpha heavy chain without an associated light chain. Early-stage disease responds to antibiotics, suggesting a bacterial origin. We attempted to identify a causative agent. METHODS: We performed polymerase chain reaction (PCR), DNA sequencing, fluorescence in situ hybridization, and immunohistochemical studies on intestinal-biopsy specimens from a series of patients with immunoproliferative small intestinal disease. RESULTS: Analysis of frozen intestinal tissue obtained from an index patient with immunoproliferative small intestinal disease who had a dramatic response to antibiotics revealed the presence of Campylobacter jejuni. A follow-up retrospective analysis of archival intestinal-biopsy specimens disclosed campylobacter species in four of six additional patients with immunoproliferative small intestinal disease. CONCLUSIONS: These results indicate that campylobacter and immunoproliferative small intestinal disease are associated and that C. jejuni should be added to the growing list of human pathogens responsible for immunoproliferative states.",0
2628,14749453,Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia,"BACKGROUND: The diagnosis and treatment of bacterial pneumonia in patients who are receiving mechanical ventilation remain a difficult challenge. The triggering receptor expressed on myeloid cells (TREM-1) is a member of the immunoglobulin superfamily, and its expression on phagocytes is specifically up-regulated by microbial products. The presence of soluble TREM-1 (sTREM-1) in bronchoalveolar-lavage fluid from patients receiving mechanical ventilation may be an indicator of pneumonia. METHODS: We conducted a prospective study of 148 patients receiving mechanical ventilation in whom infectious pneumonia was suspected. A rapid immunoblot technique was used to measure sTREM-1 in bronchoalveolar-lavage fluid. Two independent intensivists who were unaware of the results of the sTREM-1 assay determined whether community-acquired pneumonia and ventilator-associated pneumonia were present or absent. RESULTS: The final diagnosis was community-acquired pneumonia in 38 patients, ventilator-associated pneumonia in 46 patients, and no pneumonia in 64 patients. The presence of sTREM-1 by itself was more accurate than any clinical findings or laboratory values in identifying the presence of bacterial or fungal pneumonia (likelihood ratio, 10.38; sensitivity, 98 percent; specificity, 90 percent). In multiple logistic-regression analysis, the presence of sTREM-1 was the strongest independent predictor of pneumonia (odds ratio, 41.5). CONCLUSIONS: In patients receiving mechanical ventilation, rapid detection of sTREM-1 in bronchoalveolar-lavage fluid may be useful in establishing or excluding the diagnosis of bacterial or fungal pneumonia.",0
2629,14752829,AQP4 transfected into mouse cholangiocytes promotes water transport in biliary epithelia,"Rodent cholangiocytes express 6 of the 11 known channel proteins called aquaporins (AQPs) that are involved in transcellular water transport in mammals. However, clarifying the role of AQPs in mediating water transport in biliary epithelia has been limited in part because of the absence of physiologically relevant experimental models. In this study, we established a novel AQP4-transfected polarized mouse cholangiocyte cell line suitable for functional studies of transepithelial water transport, and, using this model, we define the importance of this AQP in water transport across biliary epithelia. Polarized normal mouse cholangiocytes (NMCs) lacking endogenous AQP4 were transfected stably with functional AQP4 or cotransfected with functional AQP4 and a transport-deficient AQP4 dominant negative mutant using a retroviral delivery system. In transfected NMCs, AQP4 is expressed on both the mRNA and protein levels and is localized at both the apical and basolateral membranes. In nontransfected NMCs, the transcellular water flow, P(f), value was relatively high (i.e., 16.4 +/- 3.2 microm/sec) and likely was a reflection of endogenous expression of AQP1 and AQP8. In NMCs transfected with AQP4, P(f) increased to 75.7 +/- 1.4 microm/sec, that is, by 4.6-fold, indicating the contribution of AQP4 in channel-mediated water transport across MNCs monolayer. In cotransfected NMCs, AQP4 dominant negative reduced P(f) twofold; no changes in P(f) were observed in NMCs transfected with the empty vector. In conclusion, we developed a novel polarized mouse cholangiocyte monolayer model, allowing direct study of AQP4-mediated water transport by biliary epithelia and generated data providing additional support for the importance of AQP4 in cholangiocyte water transport.",0
2630,14762183,Association of cystic fibrosis with abnormalities in fatty acid metabolism,"BACKGROUND: Patients with cystic fibrosis have altered levels of plasma fatty acids. We previously demonstrated that arachidonic acid levels are increased and docosahexaenoic acid levels are decreased in affected tissues from cystic fibrosis-knockout mice. In this study we determined whether humans with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have a similar fatty acid defect in tissues expressing CFTR. METHODS: Fatty acids from nasal- and rectal-biopsy specimens, nasal epithelial scrapings, and plasma were analyzed from 38 subjects with cystic fibrosis and compared with results in 13 obligate heterozygotes, 24 healthy controls, 11 subjects with inflammatory bowel disease, 9 subjects with upper respiratory tract infection, and 16 subjects with asthma. RESULTS: The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency and subjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy control subjects. In nasal tissue, this change reflected an increase in arachidonic acid levels and a decrease in docosahexaenoic acid levels. In cells from nasal mucosa, the ratio of arachidonic to docosahexaenoic acid was increased in subjects with cystic fibrosis (P<0.001), as compared with healthy controls, with values in obligate heterozygotes intermediate between these two groups (P<0.001). The ratio was not increased in subjects with inflammatory bowel disease. Subjects with asthma and those with upper respiratory tract infection had values intermediate between those in subjects with cystic fibrosis and those in healthy control subjects. CONCLUSIONS: These data indicate that alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.",0
2631,14767988,Altered gene expression in acute systemic inflammation detected by complete coverage of the human liver transcriptome,"The goal of the current study was to provide complete coverage of the liver transcriptome with human probes corresponding to every gene expressed in embryonic, adult, and/or cancerous liver. We developed dedicated tools, namely, the Liverpool nylon array of complementary DNA (cDNA) probes for approximately 10,000 nonredundant genes and the LiverTools database. Inflammation-induced transcriptome changes were studied in liver tissue samples from patients with an acute systemic inflammation and from control subjects. One hundred and fifty-four messenger RNAs (mRNA) correlated statistically with the extent of inflammation. Of these, 134 mRNA samples were not associated previously with an acute-phase (AP) response. The hepatocyte origin and proinflammatory cytokine responsiveness of these mRNAs were confirmed by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) in cytokine-challenged hepatoma cells. The corresponding gene promoters were enriched in potential binding sites for inflammation-driven transcription factors in the liver. Some of the corresponding proteins may provide novel blood markers of clinical relevance. The mRNAs whose level is most correlated with the AP extent (P <.05) were enriched in intracellular signaling molecules, transcription factors, glycosylation enzymes, and up-regulated plasma proteins. In conclusion, the hepatocyte responded to the AP extent by fine tuning some mRNA levels, controlling most, if not all, intracellular events from early signaling to the final secretion of proteins involved in innate immunity. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).",0
2632,14767989,PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation,"In fibroblasts, thrombin induces collagen deposition through activation of a G-protein-coupled receptor, proteinase-activated receptor 1 (PAR(1)). In the current study, we examined whether PAR(1) antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (BDL). The current results demonstrated that HSCs express PAR(1), as well as proteinase-activated receptors 2 (PAR(2)) and 4 (PAR(4)), and that all three PARs were up-regulated in response to exposure to growth factor in vitro. Exposure to thrombin and to SFLLRN-(SF)-NH(2), a PAR(1) agonist, and GYPGKF (GY)-NH(2), a PAR(4) agonist, triggered HSC proliferation and contraction, as well as monocyte chemotactic protein-1 (MCP-1) production and collagen I synthesis and release. These effects were inhibited by the PAR(1) antagonist. Administration of this antagonist, 1.5 mg/kg/d, to BDL rats reduced liver type I collagen messenger RNA (mRNA) expression and surface collagen by 63%, as measured by quantitative morphometric analysis. Similarly, hepatic and urinary excretion of hydroxyproline was reduced significantly by the PAR(1) antagonist. In conclusion, PAR(s) regulates HSC activity; development of PAR antagonists might be a feasible therapeutic strategy for protecting against fibrosis in patients with chronic liver diseases.",0
2633,14767997,CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling,"Chronic oxidative stress induced by overexpression of the cytochrome P450 isoform 2E1 (CYP2E1) has been implicated in hepatocyte injury and death. However, the mechanism by which CYP2E1 overexpression may promote cell death is unknown. Acute oxidative stress activates mitogen-activated protein kinases (MAPK), suggesting that chronic oxidant generation by CYP2E1 may regulate cellular responses through these signaling pathways. The effect of CYP2E1 overexpression on MAPK activation and their function in altering death responses of CYP2E1-overexpressing hepatocytes were investigated. Chronic CYP2E1 overexpression led to increased extracellular signal-regulated kinase 1/2 (ERK1/2) activation constitutively and in response to oxidant stress from the superoxide generator menadione. CYP2E1-overexpressing cells were resistant to menadione toxicity through an ERK1/2-dependent mechanism. Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1. However, CYP2E1-overexpressing cells were sensitized to necrotic death from AA and the PUFA gamma-linolenic acid, but not from saturated or monounsaturated fatty acids. Death from PUFA resulted from oxidative stress and was blocked by inhibition of ERK1/2, but not p38 MAPK or activator protein-1 signaling. CYP2E1 expression induced ERK1/2 activation through increased epidermal growth factor receptor (EGFR)/c-Raf signaling. Inhibition of EGFR signaling reversed CYP2E1-induced resistance to menadione and sensitization to AA toxicity. In conclusion, chronic CYP2E1 overexpression leads to sustained ERK1/2 activation mediated by EGFR/c-Raf signaling. This adaptive response in hepatocytes exposed to chronic oxidative stress confers differential effects on cellular survival, protecting against menadione-induced apoptosis, but sensitizing to necrotic death from PUFA.",0
2634,14960743,Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes,"BACKGROUND: Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown. METHODS: We performed hyperinsulinemic-euglycemic clamp studies in combination with infusions of [6,6-(2)H(2)]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton ((1)H) magnetic resonance spectroscopy studies were performed to measure intramyocellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [(2)H(5)]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed (31)P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle. RESULTS: The insulin-stimulated rate of glucose uptake by muscle was approximately 60 percent lower in the insulin-resistant subjects than in the insulin-sensitive control subjects (P<0.001) and was associated with an increase of approximately 80 percent in the intramyocellular lipid content (P=0.005). This increase in intramyocellular lipid content was most likely attributable to mitochondrial dysfunction, as reflected by a reduction of approximately 30 percent in mitochondrial phosphorylation (P=0.01 for the comparison with controls), since there were no significant differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor alpha, interleukin-6, resistin, or adiponectin. CONCLUSIONS: These data support the hypothesis that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.",0
2635,14985484,Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood,"""BACKGROUND: The risk of type 2 diabetes mellitus is increased in people who have low birth weights and who subsequently become obese as adults. Whether their obesity originates in childhood and, if so, at what age are unknown. Understanding the origin of obesity may be especially important in developing countries, where type 2 diabetes is rapidly increasing yet public health messages still focus on reducing childhood """"undernutrition."""" METHODS: We evaluated glucose tolerance and plasma insulin concentrations in 1492 men and women 26 to 32 years of age who had been measured at birth and at intervals of three to six months throughout infancy, childhood, and adolescence in a prospective, population-based study. RESULTS: The prevalence of impaired glucose tolerance was 10.8 percent, and that of diabetes was 4.4 percent. Subjects with impaired glucose tolerance or diabetes typically had a low body-mass index up to the age of two years, followed by an early adiposity rebound (the age after infancy when body mass starts to rise) and an accelerated increase in body-mass index until adulthood. However, despite an increase in body-mass index between the ages of 2 and 12 years, none of these subjects were obese at the age of 12 years. The odds ratio for disease associated with an increase in the body-mass index of 1 SD from 2 to 12 years of age was 1.36 (95 percent confidence interval, 1.18 to 1.57; P<0.001). CONCLUSIONS: There is an association between thinness in infancy and the presence of impaired glucose tolerance or diabetes in young adulthood. Crossing into higher categories of body-mass index after the age of two years is also associated with these disorders.""",0
2636,14999111,Estrogen plus progestin and colorectal cancer in postmenopausal women,"BACKGROUND: Although the Women's Health Initiative (WHI) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group, the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer. We analyzed features of the colorectal cancers that developed and their relation to the characteristics of the participants. METHODS: In the WHI trial, 16,608 postmenopausal women who were 50 to 79 years of age and had an intact uterus were randomly assigned to a combination of conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The main outcome measures were the incidence, stages, and types of colorectal cancer, as determined by blinded central adjudication. RESULTS: There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean +/-SD, 3.2+/-4.1 vs. 0.8+/-1.7; P=0.002) and were more advanced (regional or metastatic disease, 76.2 percent vs. 48.5 percent; P=0.004). In exploratory analyses, women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding (3.8+/-4.3 vs. 0.7+/-1.5 nodes, P=0.006). CONCLUSIONS: Relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer. However, colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo.",0
2637,14999680,Gene expression pattern in hepatic stem/progenitor cells during rat fetal development using complementary DNA microarrays,"To identify new and differentially expressed genes in rat fetal liver epithelial stem/progenitor cells during their proliferation, lineage commitment, and differentiation, we used a high throughput method-mouse complementary DNA (cDNA) microarrays-for analysis of gene expression. The gene expression pattern of rat hepatic cells was studied during their differentiation in vivo: from embryonic day (ED) 13 until adulthood. The differentially regulated genes were grouped into two clusters: a cluster of up-regulated genes comprised of 281 clones and a cluster of down-regulated genes comprised of 230 members. The expression of the latter increased abruptly between ED 16 and ED 17. Many of the overexpressed genes from the first cluster fall into distinct, differentially expressed functional groups: genes related to development, morphogenesis, and differentiation; calcium- and phospholipid-binding proteins and signal transducers; and cell adhesion, migration, and matrix proteins. Several other functional groups of genes that are initially down-regulated, then increase during development, also emerged: genes related to inflammation, blood coagulation, detoxification, serum proteins, amino acids, lipids, and carbohydrate metabolism. Twenty-eight genes overexpressed in fetal liver that were not detected in adult liver are suggested as potential markers for identification of liver progenitor cells. In conclusion, our data show that the gene expression program of fetal hepatoblasts differs profoundly from that of adult hepatocytes and that it is regulated in a specific manner with a major switch at ED 16 to 17, marking a dramatic change in the gene expression program during the transition of fetal liver progenitor cells from an undifferentiated to a differentiated state. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).",0
2638,14999681,Immortalized p19ARF null hepatocytes restore liver injury and generate hepatic progenitors after transplantation,"Primary hepatocytes are blocked in mitotic activity and well-defined culture conditions only allow the limited expansion of these cells. Various genetic modifications have therefore been employed to establish immortalized hepatic cell lines, but, unfortunately, proper hepatocyte cultures conducting a faithful hepatic gene expression program and lacking malignancy are hardly available. Here we report the immortalization of primary hepatocytes isolated from p19(ARF) null mice using the rationale that loss of p19(ARF) lowers growth-suppressive functions of p53 and bypasses cellular senescence without losing genetic stability. The established hepatocytes, called MIM, express liver-specific markers, show a nontumorigenic phenotype, and competence to undergo Fas-mediated apoptosis. Intrasplenic transplantation of GFP-expressing parental MIM cells into Fas-injured livers of SCID mice revealed liver-reconstituting activity. In the regenerated liver, MIM cells localized in small-sized clusters and showed presence in structures comparable to canals of Hering, the site of oval cells. Transplantation of MIM-Bcl-X(L) cells, which are protected against apoptosis, and successive Fas-induced liver damage, enhanced donor-derived liver repopulation by showing differentiation into cholangiocytes and cells expressing markers characteristic of both fetal hepatocytes and oval cells. In conclusion, these data indicate that long-term cultivated p19(ARF) null hepatocytes are capable of generating hepatic progenitor cells during liver restoration, and thus represent a highly valuable tool to study the differentiation repertoire of hepatocytes.",0
2639,14999686,P-selectin suppresses hepatic inflammation and fibrosis in mice by regulating interferon gamma and the IL-13 decoy receptor,"The selectin family of cell adhesion molecules is widely thought to promote inflammatory reactions by facilitating leukocyte recruitment. However, it was unexpectedly found that mice with targeted deletion of the P-selectin gene (PsKO mice) developed unpolarized type 1/type 2 cytokine responses and severely aggravated liver pathology following infection with the type 2-promoting pathogen Schistosoma mansoni. In fact, liver fibrosis, which is dependent on interleukin 13 (IL-13), increased by a factor of more than 6, despite simultaneous induction of the antifibrotic cytokine interferon gamma (IFN-gamma). Inflammation, as measured by granuloma size, also increased significantly in the absence of P-selectin. When infected PsKO mice were treated with neutralizing anti-IFN-gamma monoclonal antibodies, however, granuloma size was restored to wild-type levels; this finding revealed the potent proinflammatory role of IFN-gamma when expressed concomitantly with IL-13. Untreated PsKO mice also exhibited a significant (sixfold) reduction in decoy IL-13 receptor (IL-13 receptor alpha-2) expression when compared with infected wild-type animals. It is noteworthy, however, that when decoy receptor activity was restored in PsKO mice by treatment with soluble IL-13 receptor alpha-2-Fc, the exacerbated fibrotic response was completely inhibited. Thus, reduced expression of the decoy IL-13 receptor mediated by the elevated type 1 cytokine response probably accounts for the enhanced activity of IL-13 in PsKO mice and for the resultant increase in collagen deposition. In conclusion, the current study has revealed the critical role of P-selectin in the progression of chronic liver disease caused by schistosome parasites. By suppressing IFN-gamma and up-regulating the decoy IL-13 receptor, P-selectin dramatically inhibits the pathologic tissue remodeling that results from chronic type 2 cytokine-mediated inflammation.",0
2640,14999702,Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes,"Differences in the composition of the hepatitis C virus (HCV) quasispecies between plasma and blood mononuclear cells (BMC) strongly suggest that BMCs support viral replication. We examined the frequency of such compartmentalization, the cell types involved, the constraints exerted on the different variants, and the role of immunoglobulin-complexed variants. We screened the hypervariable region (HVR1) of HCV isolates from 14 HBsAg- and HIV-seronegative patients with chronic HCV infection. HCV RNA was amplified and cloned from plasma, the immunoglobulin G (IgG)-bound fraction, and total and sorted BMCs (CD19+, CD8+, CD4+, and CD14+ cells). Compartmentalization was estimated using a matrix correlation test. The ratio of nonsynonymous/synonymous substitutions (d(N)/d(S) ratio) was calculated for each compartment. HCV RNA was detected in 3/3 BMC, 11/11 CD19+, 10/11 CD14+, 4/11 CD8+ and 0/11 CD4+ cell samples. HVR1 sequences were significantly different between plasma and at least one cellular compartment in all nine cases analyzed, and between B cells (CD19+) and monocytes (CD14+) in all five available cases. IgG-bound variants were distinct from cellular variants. D(N)/d(S) ratios were similar (n = 3) or lower (n = 6) in cellular compartments compared with plasma and the IgG-bound fraction. In conclusion, HCV compartmentalization is a common phenomenon. B cells and monocytes harbor HCV variants showing a low rate of nonsynonymous mutations, a feature that might contribute to the persistence of HCV infection.",0
2641,14999705,Interfering with capsid formation: a practicable antiviral strategy against hepatitis B virus?,"Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe nonnucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.",0
2642,15042736,Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A report of two cases],"To critically review the past years of research on paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in children and adolescents. Literature on PANDAS published from 1995 onward was systematically reviewed. The review focuses on definition and diagnostic consideration aetiological and therapeutical issues. To illustrate the clinical characteristic of PANDAS authors present two cases of children with a severe course of obsessive-compulsive disorder and Tourette's syndrome. Post-streptococcal autoimmunity has been postulated as an aetiologic factor in the development of childhood-onset obsessive-compulsive disorder, tic disorders including Tourette's disorder. This hypothesis arose from a series of clinical observations including the documentation of obsessive-compulsive symptoms of children affected by Sydenham's chorea, a variant of rheumatic fever characterised by neurological dysfunction and also by concomitant investigations of childhood-onset OCD and Tourette's syndrome. Results of these studies led to the identification of children whose clinical course is characterised by abrupt and dramatic symptom exacerbations which are temporally related to group A beta-hemolytic streptococcal infections. The identification of such a subgroup will allow for testing of the model of pathogenesis as well as development of novel treatment and prevention strategies. Future research are needed to explore the nature of PANDAS and their relationship with different psychiatric disorders in children and adolescents. ",0
2643,15042836,Redox-dependent regulation of gene expression induced by nitric oxide],"Nitric oxide (NO) is a mobile, highly reactive signal molecule, and changes the expression of specific genes in effector cells. Under physiological conditions, NO reacts with molecular oxygen and with reactive oxygen species (ROS) to produce intermediates known as reactive nitrogen species (RNS). The production of NO and RNS in the cell is controlled by hormones, neurotransmitters, cytokines, and growth factors. Hence NO and its derivatives act as secondary paracrinous factors and transmit the signal from NO-producing to neighboring cells. Intracellular reception of NO and RNS is due to Src-related tyrosine protein kinases, G-protein Ras, cytochrome oxidase, and guanylate cyclase. Receptor proteins mostly contain heme, active thiol, or iron-sulfur groups, and are both on the plasma membrane and in internal cell compartments. Many of the NO receptors are the key components of cell regulatory systems controlling the transcription factors AP-1, HIF-1, NF-kappa B, and p53 and the expression of their target genes. A distinguishing feature of NO signaling is that changes in redox potential of the cell switch the NO receptor and, consequently, modify the NO effect. Depending on the ROS level, NO activates different signal transduction pathways to induce (or suppress) different gene sets. The data considered indicate that antioxidants may be used to directionally change the transcriptional response of the cell to NO. ",0
2644,15043329,Absolute CD4 and CD8 counts and CD4-to-CD8 ratios in eight patients with indolent B-cell chronic lymphocytic leukemia,"There are some patients with B-cell chronic lymphocytic leukemia who exhibit an extraordinary natural resistance to this malignancy, which lasts for many years. In this study, we report the T-cell subset values and ratios in eight such patients. Impath (New York, NY) evaluated immunophenotyping by performing flow cytometry. Absolute CD4 and CD8 counts and CD4:CD8 ratios were performed at Memphis Pathology Laboratory, Memphis, Tennessee. CD4 and CD8 counts and CD4:CD8 ratios were normal in all eight patients, in contrast to the suppressor cell proliferation and low helper-suppressor ratios that have been previously reported in other patients with B-cell chronic lymphocytic leukemia. These results require further study to determine their significance. Implications for further study are discussed. ",0
2645,15043392,Severe acute respiratory syndrome: scientific and anecdotal evidence for drug treatment,"Severe acute respiratory syndrome (SARS), caused by a highly infectious novel coronavirus (CoV), predominantly presents with severe pneumonitis leading to respiratory failure and death in approximately 10% of victims. Most cases present, after an incubation of 2 to 11 days, with fever and chills, which are followed by dry cough and dyspnea before the onset of respiratory failure. The management of SARS is controversial, largely due to the lack of data from controlled trials, which were logistically impossible to design or execute at the time of the overwhelming outbreak between March and June 2003. The use of an antiviral is logical although there is no effective agent against SARS-CoV, with the widespread use of ribavirin in 2003 attracting considerable scepticism. The use of ribavirin as a monotherapy in SARS is not recommended. Retrospective data suggest that administration of the anti-HIV drug Kaletra in combination with ribavirin could reduce mortality and incidence of respiratory failure. The use of corticosteroid was based on the similarity between SARS and bronchiolitis obliterans organizing pneumonia. Corticosteroid use is considered important in subsets of patients with SARS. As SARS may still resurge, it is imperative that past experience is analyzed. This review will attempt to address the rationale for pharmacotherapy in SARS using anecdotal and the limited published data. ",0
2646,15043409,Anthrone and oxanthrone C-glycosides from Picramnia latifolia collected in Peru,"Cytotoxicity-based, bioassay-guided fractionation of the chloroform-soluble extracts of both the roots and leaves of Picramnia latifolia led to the isolation of two new anthrone C-glycosides, picramniosides G (1) and H (2), two new oxanthrone C-glycosides, mayosides D (3) and E (4), and a new benzanthrone natural product, 6,8-dihydroxy-10-methyl-7H-benz[de]anthracen-7-one (5), together with 10 known compounds, 6,8-dihydroxy-4-methyl-7H-benz[de]anthracen-7-one (6), nataloe-emodin (7), chrysophanein, chrysophanol, 1,5-dihydroxy-7-methoxy-3-methylanthraquinone, pulmatin, 7-hydroxycoumarin, 7-hydroxy-6-methoxycoumarin, beta-sitosterol, and beta-sitosterol glucoside. The structures of 1-5 were established by spectroscopic methods, including 1D and 2D NMR, HRMS, and CD data interpretation. The cytotoxic activity of all isolates was evaluated in a small panel of human cancer cell lines. Compound 7 exhibited significant in vitro cytotoxic activity in the tested cell lines, but no significant activity was observed with an in vivo hollow fiber model at doses of 6.25, 12.5, 25, and 50 mg/kg/injection. ",0
2647,15043593,Complement activation in prestorage leucocyte-filtered plasma,"Complement activation and generation of pro-inflammatory cytokines occur during storage of blood components. Prestorage leucocyte filtration of platelet concentrates and red cells diminishes the accumulation of leucocyte-derived cytokines during storage, however, transfusion reactions are not eliminated. We investigated inflammatory mediator release during storage of plasma and whole blood and the effect of prestorage leucocyte filtration of plasma. Twenty-four blood units were collected from healthy blood donors and stored for 35 days. Eight units were stored as whole blood, eight units as plasma and eight units as prestorage filtered plasma. Samples were collected weekly for analyses of potassium, leucocytes, free plasma haemoglobin, complement activation (C3a and SC5b-9) and pro-inflammatory cytokines [interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha]. Elevated levels of C3a and SC5b-9 were registered in filtered plasma, from the beginning of storage. C3a levels increased during storage. There was a higher rate of change during storage in C3a (P < 0.01) and SC5b-9 (P < 0.05) in plasma compared with filtered plasma. Interleukin (IL)-8 is released in whole blood. The cytokine levels generated in plasma and filtered plasma were low. Complement activation is present in whole blood, plasma and filtered plasma during storage. Prestorage filtration of plasma activates the complement cascade but does not influence cytokine generation. ",0
2648,15043617,Predicting treatment dose for novel therapies using urea standard Kt/V,"Calculation of urea standard Kt/V (stdKt/V) as a dose measure for guiding novel hemodialysis or hemofiltration therapy prescription is complex since this parameter depends on the magnitude of posttreatment urea rebound. We propose here a two-step procedure for calculating urea stdKt/V from single-pool urea Kt/V values (spKt/V) determined from serum urea concentrations in pretreatment and posttreatment blood samples. First, the dependence of urea stdKt/V on equilibrated Kt/V (eKt/V) was derived from a fixed-volume single-pool model. Second, an empirical equation for predicting urea eKt/V from urea spKt/V values was determined using multiple linear regression and available data during 4-hour hemodialysis, 2-hour hemodialysis, and 2-hour hemofiltration treatments. This empirical (rate/dose) equation is likely more robust for novel therapies than other equations derived from only data during conventional (4-hour) hemodialysis treatments. The combination of these formulas allowed construction of nomograms for calculating urea stdKt/V from spKt/V during novel therapies. These principles were further illustrated by calculating the predicted treatment dose for daily (six times per week) hemofiltration therapy required to achieve a given urea stdKt/V. ",0
2649,15043760,The role of the clinical research coordinator--data manager--in oncology clinical trials,"""The purpose of this study was to determine the standard tasks performed by clinical research coordinators (CRCs) in oncology clinical trials. Forty-one CRCs were anonymously surveyed, using a four-page self-administered questionnaire focused on demographics, qualifications, and professional experience. The survey questions on responsibilities consisted of an ad-hoc 32-item questionnaire where respondents had to rate the frequency of involvement in the listed activities using a 3-point scale. We defined as """"standard"""" a task that was rated as """"in all or nearly all trials"""" by at least half of the respondents. A response rate of 90% (37 out of 41) was achieved after two mailings. Less than half of the respondents had received additional training in oncology, clinical research or Good Clinical Practices (GCP). Overall, all standard tasks performed by CRCs were in the category of """"monitoring activities"""" (those usually performed by a Clinical Research Associate """"CRA"""") and included patient registration/randomization, recruitment follow-up, case report form completion, collaboration with the CRA, serious adverse events reporting, handling of investigator files, and preparing the site for and/or attending audits. CRCs play a key role in the implementation of oncology clinical trials, which goes far beyond mere data collection and/or administrative support, and directly contributes to the gathering of good quality data. """,0
2650,15044357,Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone,"Secretion of GH by pituitary somatotropes is primarily stimulated by the hypothalamic GHRH through the activation of a specific G protein-coupled receptor, GHRH receptor (GHRH-R). GH is also released in response to ghrelin, a peptide produced in the stomach, hypothalamus, and pituitary that activates somatotropes via a distinct G protein-coupled receptor, referred to as the GH secretagogue receptor (GHS-R). Here, we have analyzed the expression of both GHRH-R and GHS-R (by multiplex RT-PCR) in porcine pituitary cell cultures, after acute (4 h) treatment with GHRH or ghrelin as well as with other regulators of somatotropes (somatostatin, dexamethasone). Exposure of cultures to GHRH decreased GHRH-R mRNA content and also diminished GHS-R transcript levels. Likewise, ghrelin down-regulated both GHS-R and GHRH-R expression. Interestingly, administration of the activator of adenylate cyclase, forskolin, decreased GHRH-R mRNA levels but had no effect on GHS-R, thus suggesting a distinct contribution of the various intracellular signals operating in somatotropes to the regulation of the expression of these receptors. Accordingly, an atypical activator of adenylate cyclase in the pig somatotrope is low-dose (10(-13) m) somatostatin, which also suppressed GHRH-R mRNA levels without altering GHS-R expression. Finally, dexamethasone did not modify GHRH-R or GHS-R expression. In summary, our data show for the first time that ghrelin, as well as GHRH, mediates homologous and heterologous down-regulation of their own receptor synthesis. However, our results also indicate that the expression of porcine GHRH-R and GHS-R is regulated by distinct signals that may differ from those reported in other mammalian species. ",0
2651,15044409,What is the most relevant standard of success in assisted reproduction? The importance of informed choice,"Whilst there is a need to emphasize the birth rates of healthy infants when reporting success rates following infertility treatment, is 'the singleton term gestation per cycle started' the most appropriate measure? Although there are many ways to measure the efficacy of medical intervention, none of these exclude from the 'successes' those in whom complications have occurred. The safe delivery of healthy twins at term, while possibly not the ideal outcome, should still be regarded as a treatment success. Although multiple pregnancy, in particular high order multiple pregnancy, continues to be a major problem associated with assisted reproductive treatments and also with ovulation induction, appropriate counselling concerning the risks of twin and triplet pregnancies will allow couples to make informed choices and allow clinicians to continue to individualize treatment plans. ",0
2652,15044465,Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility,"We have examined overexpression of the human epidermal growth factor receptor 2 (HER2) to determine if it modifies the anti-proliferative effect of transforming growth factor (TGF)-beta against MCF-10A human mammary epithelial cells. Exogenous TGF-beta inhibited cell proliferation and induced Smad-dependent transcriptional reporter activity in both MCF-10A/HER2 and MCF-10A/vector control cells. Ligand-induced reporter activity was 7-fold higher in HER2-overexpressing cells. In wound closure and transwell assays, TGF-beta induced motility of HER2-transduced, but not control cells. The HER2-blocking antibody trastuzumab (Herceptin) prevented TGF-beta-induced cell motility. Expression of a constitutively active TGF-beta type I receptor (ALK5(T204D)) induced motility of MCF-10A/HER2 but not MCF-10A/vector cells. TGF-beta-induced motility was blocked by coincubation with either the phosphatidylinositol 3-kinase inhibitor LY294002, the mitogen-activated protein kinase (MAPK) inhibitor U0126, the p38 MAPK inhibitor SB202190, and an integrin beta(1) blocking antibody. Rac1 activity was higher in HER2-overexpressing cells, where both Rac1 and Pak1 proteins were constitutively associated with HER2. Both exogenous TGF-beta and transduction with constitutively active ALK5 enhanced this association. TGF-beta induced actin stress fibers as well as lamellipodia within the leading edge of wounds. Herceptin blocked basal and TGF-beta-stimulated Rac1 activity but did not repress TGF-beta-stimulated transcriptional reporter activity. These data suggest that 1) overexpression of HER2 in nontumorigenic mammary epithelial is permissive for the ability of TGF-beta to induce cell motility and Rac1 activity, and 2) HER2 and TGF-beta signaling cooperate in the induction of cellular events associated with tumor progression. ",0
2653,15044509,Expression of adrenomedullin and its receptors in human salivary tissue,"Adrenomedullin is a multifunctional peptide produced by a wide range of different cells and tissues. This study was designed to investigate whether adrenomedullin is present in human saliva and in salivary glands. It was expected that saliva may contain high concentrations of adrenomedullin, which has antimicrobial activity in vitro, which may have functional implications in the oral cavity. Saliva from the submandibular and parotid glands contained higher concentrations of adrenomedullin than did the circulation, but lower concentrations than in whole saliva. This suggests that oral epithelium may contribute the majority of the adrenomedullin peptide found in saliva. Specific adrenomedullin receptors were found in cell lines from the submandibular (HSG) and parotid (HSY) salivary glands. These findings suggest a paracrine/autocrine role for adrenomedullin in these tissues; however, the concentration of adrenomedullin in saliva was insufficient to suggest a significant antimicrobial action in the healthy oral cavity. ",0
2654,15044570,Reconnaissance study of sunbed use by primary school children in Lanarkshire,"The aim of this study was to swiftly gain insight into anecdotal evidence that primary school children in local schools were using sunbeds. A seven-question questionnaire was conducted by school nurses in 23 primary schools in the Wishaw Local Health Care Co-operative catchment area. Children in primary classes 4 (aged 8-9) and 6/7 (aged 10-11) took part in the classroom surveys. Positive responses were counted by a show of hands by the children. A total of 1405 children took part in the survey. Of these, 48 per cent expressed a desire to use a sunbed and 7 per cent (96 children) had actually used a sunbed in the last 6 months. Of the 96 who professed to using a sunbed, 16 used one regularly, 61 gained access to a sunbed in someone's house, and 21 had used a sunbed in a shop or salon. Twenty-nine (30 per cent) admitted that they had suffered sore skin or sore eyes after sunbed use. This preliminary survey suggests that a significant number of primary school children may be using tanning devices either in the home or on commercial premises. More rigorous research is urgently required to test these findings. The precautionary principle suggests that public action is justified on present evidence. ",0
2655,15044574,How are primary care organizations using financial incentives to influence prescribing?,"Primary care organizations (PCOs) in England are required to run a prescribing incentive scheme. The average payment received by general practitioners (GPs) under these schemes is not known. We conducted a longitudinal (2 year) questionnaire study of all PCOs in London and the south east of England aiming to explore the relationship between the financial incentives, the selection of prescribing indicators and success at remaining within budget. In the second year, the average reward per GP amounted to 1220 pounds (range 470 pounds-4330 pounds). Underspent PCOs made larger incentive scheme payments to their practices as did PCOs that had successfully overturned a first year overspend into a second year underspend. The size of rewards was unrelated to the selection of any particular cost- or quality-based prescribing indicator. We conclude that larger prescribing incentive scheme payments may have contributed to prescribing cost control but their effect on prescribing quality is uncertain. ",0
2656,15044599,Oxytocin receptor gene expression of estrogen-stimulated human myometrium in extracorporeally perfused non-pregnant uteri,"Oxytocin (OT) and the oxytocin receptor (OTR) seem to be less important for uterine contractility-associated disorders of the non-pregnant uterus compared to the pregnant uterus. In the present study, we investigated the mutual dependence of OTR, OT and 17beta-estradiol (E(2)) with regard to the localization of OTR in the non-pregnant uterus. Utilizing our established model for extracorporeal perfusion of the human uterus, we perfused 15 human uteri for 27 h under physiological conditions without oestradiol (group A, n = 5) or with high E(2) stimulation (group B, n = 5) followed by OT stimulation for both groups during the last 3 h of the experiment. Negative controls (n = 5) remained in perfusions for 27 h without any further hormone treatment. Gene expression of the myometrial OTR in both groups was compared using reverse transcriptase triple primer PCR. Stimulation with E(2) and OT led to significantly higher OTR gene expression than stimulation with OT alone. We also showed that concentrations of OTR transcripts increase from the lower uterine segment to the uterine fundus. However, maximum OTR levels of the uterine fundus in group B did not reach concentrations of specimens of third trimester of pregnancy which were used as positive controls. We conclude that our experimental model simulates a situation similiarly to the stimulated non-pregnant uterus in the therapeutic concepts of assisted reproduction. The data presented demonstrate that the dynamics of OTR expression can be modulated by stimulation with E(2) and OT, not only in the pregnant but also in the non-pregnant uterus. ",0
2657,15044641,Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity,"BACKGROUND: We studied the outcomes at school age in children who had participated in a double-blind, placebo-controlled trial of early postnatal dexamethasone therapy (initiated within 12 hours after birth) for the prevention of chronic lung disease of prematurity. METHODS: Of the 262 children included in the initial study, 159 lived to school age. Of these children, 146 (72 in the dexamethasone group and 74 in the control group) were included in our study. All the infants had had severe respiratory distress syndrome requiring mechanical ventilation shortly after birth. In the dexamethasone group, 0.25 mg of dexamethasone per kilogram of body weight was given intravenously every 12 hours for one week, and then the dose was tapered. We evaluated the children's growth, neurologic and motor function, cognition, and school performance. RESULTS: Children in the dexamethasone group were significantly shorter than the controls (P=0.03 for boys, P=0.01 for girls, and P=0.03 for all children) and had a significantly smaller head circumference (P=0.04). Children in the dexamethasone group had significantly poorer motor skills (P<0.001), motor coordination (P<0.001), and visual-motor integration (P=0.02). As compared with the controls, children in the dexamethasone group also had significantly lower full IQ scores (mean [+/-SD], 78.2+/-15.0 vs. 84.4+/-12.6; P=0.008), verbal IQ scores (84.1+/-13.2 vs. 88.4+/-11.8, P=0.04), and performance IQ scores (76.5+/-14.6 vs. 84.5+/-12.7, P=0.001). The frequency of clinically significant disabilities was higher among children in the dexamethasone group than among controls (28 of 72 [39 percent] vs. 16 of 74 [22 percent], P=0.04). CONCLUSIONS: Early postnatal dexamethasone therapy should not be recommended for the routine prevention or treatment of chronic lung disease, because it leads to substantial adverse effects on neuromotor and cognitive function at school age.",0
2658,15044664,Binge status and quality of life after gastric bypass surgery: a one-year study,"This study evaluated gastric bypass surgery outcomes according to presurgical binge eating severity. Adult patients completed assessment questionnaires including the Short Form-36, Gormally Binge Eating Scale (BES), and Beck Depression Inventory (BDI) before and 12 months after surgery. One hundred nine patients (18 men, 91 women) were recruited. Based on their baseline BES scores, patients were non- [n = 52 (48%)], moderate [n = 31 (28%)], or severe [n = 26 (24%)] binge eaters. Although the percentage of excess weight loss was greatest after 12 months in the severe binge eaters, the difference among groups was not significant. Severe binge eaters had higher baseline BDI scores than either non- or moderate binge eaters (p = 0.001). After surgery, BDI scores declined significantly in all groups from the baseline scores but remained higher postoperatively in the severe binge eaters (p = 0.018). BES scores declined significantly (p = 0.000) after surgery within all groups. There was no difference in the Short Form-36 physical component summary scores at baseline among groups. Mental component summary scores were significantly lower in the severe binge eaters (p = 0.001). After surgery, there was no difference among groups in either physical or mental component summary scores. In conclusion, data from the present study suggest that patients have similar outcomes in terms of improved depression scores, binge eating behavior, and health-related quality of life regardless of their binge eating severity before surgery. Patients with the most severe binge eating behavior before surgery showed the most improvement when assessed 12 months after surgery. ",0
2659,15044703,Complex molecular architecture of beet yellows virus particles,"""Closteroviruses possess exceptionally long filamentous virus particles that mediate protection and active transport of the genomic RNA within infected plants. These virions are composed of a long """"body"""" and short """"tail"""" whose principal components are the major and minor capsid proteins, respectively. Here we use biochemical, genetic, and ultrastructural analyses to dissect the molecular composition and architecture of particles of beet yellows virus, a closterovirus. We demonstrate that the virion tails encapsidate the 5'-terminal, approximately 650-nt-long, part of the viral RNA. In addition to the minor capsid protein, the viral Hsp70-homolog, 64-kDa protein, and 20-kDa protein are also incorporated into the virion tail. Atomic force microscopy of virions revealed that the tail possesses a striking, segmented morphology with the tip segment probably being built of 20-kDa protein. The unexpectedly complex structure of closterovirus virions has important mechanistic and functional implications that may also apply to other virus families. """,0
2660,15045261,Determination of chlorinated pesticides and PCB in pine needles - improved method for the monitoring of airborne organochlorine pollutants,"A method to determine organochlorine pollutants in pine needles is described. Fresh, whole needles have been extracted for 48 h in dichloromethane to obtain the epicuticular wax fraction. The remainder has been cut into small pieces and again extracted with dichloromethane to obtain the internal lipids. Prior to gas chromatography, both the wax and the internal lipid extracts have been fractionated on two columns: first a silica gel/silica gel : sulphuric acid 2 : 1 column with dichloromethane as eluent and then a nitrophenyl silica column with hexane as eluent. Three fractions have been collected, fraction 1 containing hexachlorobenzene (HCB), fraction 2 containing polychlorinated biphenyls (PCB) and 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (DDE), and fraction 3 containing the remaining, more polar, organochlorine pesticides. For some pine species, the nitrophenyl silica column has been combined with a short aminopropyl silica column to obtain chromatograms of the PCB fraction free from negative peaks. The precision is in the range of 4-12% relative standard deviation, and the overall recovery is around 65-90%. ",0
2661,15045479,The presence of microscopic hematuria detected by urine dipstick test in the evaluation of patients with renal colic,"Urolithiasis is a common diagnosis in patients presenting at our hospital with flank pain. One of the most important steps in the diagnostic algorithm of renal colic is the presence of hematuria, but this fact has been challenged by authors reporting a negative urinalysis for microscopic hematuria in about 9-18% of such patients. Our aim was to investigate whether the same results are obtained when a sample of urine is tested with a urine dipstick test (UDT) at the time of the initial examination. Data from patients with the clinical diagnosis of renal colic examined at the emergency department of our hospital were reviewed, and the sensitivity of hematuria in urine samples tested by UDT was recorded in a group consisting of patients for whom imaging showed evidence of a stone >3 mm in size. In cases in which UDT was negative, or showed only traces of red blood cells (RBCs), a formal urinalysis was performed. A total of 609 patients were finally included in the study, with a mean age of 49.2 years. Average stone size was 5.8 mm, located mainly in the lower part of the ureter. Dipstick analysis was positive for hematuria in 92.9%. A urinalysis, with a cut-off point of less than three red blood cells per high power field, was used as a means to verify the results of the UDT in 17.8% of cases: in 7.1% of UDT negative patients and 10.7% of patients with traces of blood. The urinalysis was negative in 5.1% of patients, adding only 2% to the diagnostic accuracy of UDT. Therefore, our findings suggest that the sensitivity of a UDT for hematuria in cases of suspected renal colic has a high degree of accuracy when performed at the emergency department, and can be used as a first-line, low cost examination. A microscopic analysis may be useful when the UDT is negative or not clear enough, to verify the results. ",0
2662,15045667,Positive and negative tropic curvature induced by microbeam irradiation of protonemal tip cells of the moss Ceratodon purpureus,"The photoreceptor phytochrome mediates tropic responses in protonemata of the moss Ceratodon purpureus. Under standard conditions the tip cells grow towards unilateral red light, or perpendicular to the electrical vector of polarized light. In this study the response of tip cells to partial irradiation of the apical region was analysed using a microbeam apparatus. The fluence response curve gave an unexpected pattern: whereas a 15-min microbeam with light intensities around 3 micro mol m (-2) s (-1) induced a growth curvature towards the irradiated side, higher light intensities around 100 micro mol m (-2) s (-1) caused a negative response, the cells grew away from the irradiated side. This avoidance response is explained by two effects: the light intensity is high enough to induce photoconversion into the active Pfr form of phytochrome, not only on the irradiated but also on the non-irradiated side by stray light. At the same time, the strong light on the irradiated side acts antagonistically to Pfr. As a result of this inhibition, the growth direction is moved to the light-avoiding side. Such a Pfr-independent mechanism might be important for the phototropic response to distinguish between the light-directed and light-avoiding side under unilateral light. ",0
2663,15046639,Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis,"Genes of the Raf family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Recently, it was shown that activating mutations of BRaf are found with high frequency in human melanomas. The Ras family member most often mutated in melanoma is NRas. The constitutive activation of the Ras/Raf signaling pathway suggests an impact on the clinical course of the tumor. To address this notion, we analyzed tumor DNA from 114 primary cutaneous melanomas and of 86 metastatic lesions obtained from 174 patients for mutations in BRaf (exons 15 and 11) and NRas (exons 1 and 2) by direct sequencing of PCR products and correlated these results with the clinical course. In 57.5% of the tumors either BRaf or NRas were mutated with a higher incidence in metastatic (66.3%) than in primary lesions (50.9%). Although the majority of BRaf mutations affected codon 599, almost 15% of mutations at this position were different from the well-described exchange from valine to glutamic acid. These mutations (V599R and V599K) also displayed increased kinase and transforming activity. Surprisingly, the additional BRaf variants D593V, G465R and G465E showed a complete loss of activity in the  We demonstrate a high - albeit lower than initially anticipated - frequency of activating BRaf mutations in melanoma in the largest series of directly analyzed tumors reported to date. Notably, the clinical course of patients harboring activating BRaf mutations in metastatic melanoma was significantly affected by the presence of a constitutive BRaf activation in these. ",0
2664,15046926,Drug release from starch-acetate microparticles and films with and without incorporated alpha-amylase,"Acetylation of starch considerably decreases its swelling and enzymatic degradation. Thus, starch-acetate (SA) based delivery systems may be suitable for controlled drug delivery. The aim of the present study was to evaluate drug release from the SA microparticles (SA mps) and SA films. The average degree of acetyl substitution (DS) per glucose residue in the starch was either 1.9 (SA DS 1.9) or 2.6 (SA DS 2.6). Timolol (mw 332), calcein (mw 623) and bovine serum albumin (BSA, mw 68,000) were used as model drugs. A continuous timolol release from the both SA mps was observed in phosphate buffer solution (PBS) pH 7.4 (50-days incubation). The release of timolol was faster from the SA DS 1.9 mps than from the SA DS 2.6 mps. Calcein release from both SA mps was continuous in PBS pH 7.4 (5-days incubation). But, calcein release profile from the SA DS 2.6 film in PBS pH 7.4 showed discontinuities. However, the release of calcein from both SA films was continuous in human serum in vitro during the 7-day incubation, i.e. enzymes enhanced calcein release. Thus, alpha-amylase was incorporated into the SA films in order to enhance drug release from the films. However, the effects of incorporation of alpha-amylase on the model macromolecule (BSA) release from the SA films were modest. In conclusion, this study demonstrates the achievement of slow release of different molecular weight model drugs from the SA mps and films as compared to fast release from the native starch preparations. DS of SA, physicochemical properties of a drug and the presence of enzymes can all affect drug release profiles from SA based preparations. ",0
2665,15047468,Improving the interlaboratory variation for creatinine serum assay],"To assess inter-assay variation and accuracy of blood creatinine measurements as well as the effect of the standardization of the calibration procedures on inter-assay variation. Inter-assay variation and accuracy were assessed using 30 frozen human sera and 3 certified reference materials, which were analysed by 17 creatinine assays (colorimetric: 12, enzymatic: 4, HPLC: 1). Usual calibration procedure was compared with two common calibration procedures using either a reference material (404.1 micromol/L), or secondary sera calibrators (69, 115 et 180 micromol/L). Most of the commercially available methods display inaccuracy, > 10% for creatininemia < 150 micromol/L in most cases. For this concentration range, the mean creatininemia was statistically significantly different as a function of the assay used (p < 0.001). Enzymatic assays produced lower results than colorimetric ones for low creatinine levels but higher results for high creatinine levels. Assays being calibrated according to the manufacturer's recommendations, the median dispersion factor was 14% for the 20 samples between 45 and 150 micromol/L, and 8% for the 10 samples between 250 and 350 micromol/L. The calibration procedure modified inter-assay variation significantly (p < 0.001) but we gained little advantage from both common calibration procedures. A significant decrease of inter-assay variation occurred within each technical group (colorimetric or enzymatic) when a common calibration was performed using calibrators which concentration(s) was(were) close to the concentrations to be measured. Inter-assay variation is too high to allow prediction of glomerular filtration rate (GFR) or creatinine clearance from serum creatinine level. Our results highlight the interest of a calibration procedure using several concentrations with at least one between 90 and 150 micromol/L. The marketing of such a calibrator should be considered in order to decrease inter-assay variation in the range of creatinine levels which defines a mild chronic renal failure. Such an approach will certainly reduce inter-assay variation only within each technical group but could allow to include technical group as a co-variable in the algorithms developed for predicting GFR or creatinine clearance. A global transferability will certainly need the correlation of all types of creatinine assays versus a definitive method, whom definition remains uncertain. ",0
2666,15047474,Antiphospholipid antibodies in African women presenting obstetrical complications],"The presence of antiphospholipid antibodies (APL) has been investigated in 68 African women presenting obstetrical complications versus a control group of 22 pregnant healthy women. Patients inclusion criterias were recurrent foetal loss, pre eclampsia, retroplacental haematoma and chronic foetal suffering. Eight of patients (11.8%) had a positive APL diagnosis, versus 0% in controls, using the combination of diluted thromboplastin test and Staclot LA These results argue for the systematic APL screening in African women with obstetrical complications, and could further improve the management of patients at risk. ",0
2667,15047524,In vitro activities of piperacillin against beta-lactamase-negative ampicillin-resistant Haemophilus influenzae,"The in vitro activities of piperacillin (PIP) against beta-lactamase-negative ampicillin (AMP)-resistant (BLNAR) Haemophilus influenzae were compared with those of cefotaxime (CTX) and ceftriaxone (CRO), and the potency of PIP as therapy for meningitis caused by BLNAR is also discussed. PIP showed good activity (MIC at which 90% of strains are inhibited, 0.25 micro g/ml) against 69 BLNAR strains, and its activity was comparable to that of CRO and superior to that of CTX. No significant correlation was observed between the MICs of PIP and CTX or CRO or AMP, whereas a high correlation was observed between the MICs of CTX and CRO. In the killing study, PIP showed potent bactericidal activity compared with those of CTX and CRO. By microscopic examination, PIP caused the formation of a spindle and short filamentous cells with bulges and induced cell lysis in BLNAR strains, while treatment with CTX and CRO resulted in the formation of large, spherical cells without any obvious lysis. The affinity of Bocillin FL, a fluorescent penicillin used for determination of the 50% inhibitory concentration (IC(50)s) for penicillin-binding proteins (PBPs), to PBPs 3a and 3b of BLNAR strains was drastically decreased compared with that to an AMP-susceptible strain (ATCC 33391). In the case of the BLNAR strains, the IC(50)s for PBPs 1a, 1b, and 2 were similar to those for the PBPs of ATCC 33391. Since the affinity of binding to PBPs 3a and 3b of the BLNAR strains decreased drastically, the second targets among the PBPs were PBP 2 for PIP, PBP1 (1a and 1b) for CTX and CRO. In conclusion, PIP showed excellent activities against BLNAR strains in a manner different from those of cephem antibiotics, suggesting that it could be a candidate therapeutic agent for the treatment of meningitis caused by BLNAR strains. ",0
2668,15047818,Protection from bacterial infection by a single vaccination with replication-deficient mutant herpes simplex virus type 1,"Adaptive immune responses in which CD8(+) T cells recognize pathogen-derived peptides in the context of major histocompatibility complex class I molecules play a major role in the host defense against infection with intracellular pathogens. Cells infected with intracellular bacteria such as Listeria monocytogenes, Salmonella enterica serovar Typhimurium, or Mycobacterium tuberculosis are directly lysed by cytotoxic CD8(+) T cells. For this reason, current vaccines for intracellular pathogens, such as subunit vaccines or viable bacterial vaccines, aim to generate robust cytotoxic T-cell responses. In order to investigate the capacity of a herpes simplex virus type 1 (HSV-1) vector to induce strong cytotoxic effector cell responses and protection from infection with intracellular pathogens, we developed a replication-deficient, recombinant HSV-1 (rHSV-1) vaccine. We demonstrate in side-by-side comparison with DNA vaccination that rHSV-1 vaccination induces very strong CD8(+) effector T-cell responses. While both vaccines provided protection from infection with L. monocytogenes at low, but lethal doses, only rHSV-1 vaccines could protect from higher infectious doses; HSV-1 induced potent memory cytotoxic T lymphocytes that, upon challenge by pathogens, efficiently protected the animals. Despite the stimulation of relatively low humoral and CD4-T-cell responses, rHSV-1 vectors are strong candidates for future vaccine strategies that confer efficient protection from subsequent infection with intracellular bacteria. ",0
2669,15047873,Temperature-triggered periodical thermogenic oscillations in skunk cabbage (Symplocarpus foetidus),"The natural occurrence of temperature-triggered and light-independent thermogenic oscillation in the spadix of skunk cabbage, Symplocarpus foetidus, was discovered. The identified thermogenic oscillator had an accurate periodical cycle (ca. 60 min per cycle) that apparently responded to an increase or decrease in the spadix temperature with a threshold of less than 0.9 degrees C. Neither a constant ambient air temperature nor transient changes in the ambient air temperature within 10 min (19 degrees C --> 15 degrees C --> 19 degrees C) induced the temperature oscillation in the spadix. Moreover, the periodical cycles were independent of the weight of the spadix (2.5-9.2 g) and the amplitudes of the temperature oscillations were correlated with the magnitude of the changes in the spadix temperatures. These results imply that periodical temperature oscillations in the spadix of S. foetidus possess a quantitative regulatory process that involves a temperature sensation and subsequent heat production. Based on these results, we propose a time-dependent thermogenic oscillatory model that acts as a precise thermal regulator under dynamic environmental temperature changes. ",0
2670,15047906,The influence of the region between residues 220 and 344 and beyond in Phrixotrix railroad worm luciferases green and red bioluminescence,"To find the regions having a major influence on the bioluminescence spectra of railroad worm luciferases, we constructed new chimeric luciferases switching the fragments from residues 1-219 and from 220-545 between Phrixotrix viviani (PxvGR; lambda(max) = 548 nm) green light-emitting luciferase and Phrixothrix hirtus (PxhRE; lambda(max) = 623 nm) red light-emitting luciferases. The emission spectrum (lambda(max) = 571 nm) and K(M) for luciferin in the chimera PxRE220GR (1-219, PxhRE; 220-545, PxvGR) suggested that the region above residue 220 of PxvGR had a major effect on the active site. However, switching the sequence between the residues 220-344 from PxvGR luciferase into PxhRE (PxREGRRE) luciferase resulted in red light emission (lambda(max) = 603 nm), indicating that the region 220-344 by itself does not determine the emission spectrum. Furthermore, the sequence before residue 220 of the green-emitting luciferase is incompatible for light emission with the sequence above residue 220 of PxhRE. These results suggest that the fragments before and after residue 220, which correspond to distinct subdomains, may fold differently in the green- and red-emitting luciferases, affecting the active site conformation. ",0
2671,15048089,Distinct functional domains of Nbs1 modulate the timing and magnitude of ATM activation after low doses of ionizing radiation,"The ATM kinase is a tumour suppressor and a key activator of genome integrity checkpoints in mammalian cells exposed to ionizing radiation (IR) and other insults that elicit DNA double-strand breaks (DSBs). In response to IR, autophosphorylation on serine 1981 causes dissociation of ATM dimers and initiates cellular ATM kinase activity. Here, we show that the kinetics and magnitude of ATM Ser1981 phosphorylation after exposure of human fibroblasts to low doses (2 Gy) of IR are altered in cells deficient in Nbs1, a substrate of ATM and a component of the MRN (Mre11-Rad50-Nbs1) complex involved in processing/repair of DSBs and ATM-dependent cell cycle checkpoints. Timely phosphorylation of both ATM Ser1981 and the ATM substrate Smc1 after IR were rescued via retrovirally mediated reconstitution of Nbs1-deficient cells by wild-type Nbs1 or mutants of Nbs1 defective in the FHA domain or nonphosphorylatable by ATM, but not by Nbs1 lacking the Mre11-interaction domain. Our data indicate that apart from its role downstream of ATM in the DNA damage checkpoint network, the MRN complex serves also as a modulator/amplifier of ATM activity. Although not absolutely required for ATM activation, the MRN nuclease complex may help reach the threshold activity of ATM necessary for optimal genome maintenance and prevention of cancer. ",0
2672,15048576,Diabetes-induced abnormalities in ER calcium mobilization in primary and secondary nociceptive neurons,"Development of diabetic sensory polyneuropathy is associated with alterations in intracellular calcium homeostasis in primary and secondary nociceptive neurons. We have shown previously that in a model of streptozotocin (STZ)-induced diabetes, the calcium signal is prolonged and calcium release from ryanodine-sensitive calcium stores down-regulated in neurons of the nociceptive system. The aim of the present study was a more detailed characterization of calcium homeostasis in primary (dorsal root ganglia, DRG) and secondary (dorsal horn, DH) nociceptive neurons in STZ-induced diabetes. Fluorescence video-imaging was used to measure free cytosolic [Ca2+] ([Ca2+]i) in lumbar nociceptive neurons of control and streptozotocin-diabetic rats. Resting [Ca2+]i rose progressively in these neurons with the duration of diabetes and calcium mobilization from the endoplasmic reticulum (ER) decreased during diabetes. The amplitude of calcium release from both ryanodine- and IP3-sensitive calcium stores induced by caffeine, ionomycin, ATP or glutamate was significantly (P<0.01) lower in DRG and DH neurons from 6-week STZ-diabetic rats. Diabetes-induced changes in the calcium homeostasis were similar in DRG and DH neurons indicating that they might be general for many types of neurons from the central and peripheral nervous systems. ",0
2673,15048756,POSSUM and P-POSSUM for risk-adjusted audit of patients undergoing emergency laparotomy,"The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) is a scoring system that is used widely to predict 30-day mortality and morbidity rates. The Portsmouth predictor modification (P-POSSUM) was developed to overcome the overprediction of mortality by POSSUM, especially in low-risk patients. In this prospective study, the validity of POSSUM and P-POSSUM was tested in patients undergoing emergency laparotomy in a referral hospital of a developing country. Some 120 patients who underwent emergency laparotomy in a single unit were studied. Predicted morbidity and mortality rates were calculated by POSSUM and P-POSSUM equations using both linear regression and the exponential methods of analysis. These were compared with actual outcomes. When the linear method of analysis was used POSSUM overpredicted morbidity, and there was a significant difference between the observed and predicted values (observed to expected (O : E) ratio 0.68). The prediction was more accurate when the exponential method was used (O : E ratio 0.91). POSSUM also significantly overpredicted mortality when analysed by the linear method (O : E ratio 0.39), but the prediction improved when exponential analysis was used (O : E ratio 0.62). Applying linear and exponential analyses for P-POSSUM, the O : E ratios for mortality were 0.66 and 0.88 respectively. If analysed correctly POSSUM is a good predictor of morbidity and mortality in patients undergoing emergency laparotomy. P-POSSUM predicts mortality equally well. Both equations may be used for risk-adjusted surgical audit of patients undergoing emergency laparotomy. ",0
2674,15048973,About the mechanism of interference of silver staining with peptide mass spectrometry,"The mechanism by which silver staining of proteins in polyacrylamide gels interferes with mass spectrometry of peptides produced by proteolysis has been investigated. It was demonstrated that this interference increases with time between silver staining and gel processing, although the silver image is constant. This suggested an important role of the formaldehyde used in silver staining development in this interference process. Consequently, a formaldehyde-free staining protocol has been devised, using carbohydrazide as the developing agent. This protocol showed much increased peptide coverage and retained the sensitivity of silver staining. These results were however obtained at the expense of an increased background in the stained gels and of a reduced staining homogeneity. ",0
2675,15049165,Demyelinating lesions in cervical spinal cord and disability in multiple sclerosis patients],"In multiple sclerosis (MS) lesions appear both in brain and cervical cord. The aim of this study was to estimate the presence of MRI changes in cervical cord depending on the course, duration of the disease and a disability. Clinical measures included 66 patients suffering from MS, the diagnosis was made according to McDonald's criteria. Patients were aged from 18 to 62 (41 women and 25 men). In patients with relapsing-remitting form (EDSS 1-4) single lesions were seen whereas secondary progressive patients (EDSS 3-7) had diffuse demyelinating lesions and primary progressive patients (EDSS 4-8)--both kinds of changes. It has been shown that the lesions occurred as the disease proceeds. Patients without demyelinating lesions in cervical cord had EDSS from 1 to 3 and the duration of their disease was longer than 10 years (benign MS). The duration of the disease depends on the presence and character of demyelinating lesions in cervical cord to a large extent. That dependence was not noticed in a primary progressive form. In benign MS there were no lesions in cervical cord. ",0
2676,15049199,The problem of specialization in otolaryngology on the turn of the XIX century--Warsaw physician contribution],"The problem of specialization in otolaryngology in the end of the XIX and the beginning of XX century in Warsaw is described in detail. The programmes of specialization and specialistic examinations at that time did not exist. The professional trainings of Warsaw physicians in otolaryngology carried out abroad, especially in Vienna, Berlin, Paris and London are presented. The professional training at Warsaw otolaryngological hospital wards, out-patient clinics, infirmieries and consulting-rooms are stressed in more details. Number of physicians specialized in otolaryngology increased in the beginning of the XX century. The Warsaw physicians wrote many scientific papers and several books, they were also competent teachers of a great number of distinguished otolaryngologists. The achievements of Warsaw doctors at the time of the formation of Polish Otolaryngological Society in 1921 are pointed out. ",0
2677,15049255,The influence of spontaneous posterior vitreous detachment in resolution of diabetic macular edema in NIDDM],"To establish the influence of posterior vitreous detachment on development and resolution of diabetic macular edema in NIDDM. To asses the posterior vitreous detachment role in argon laser treatment of diabetic macular edema. Retrospective study. 68 eyes of 36 patients were involved into the study, 52 eyes (76.5%) with macular edema and 16 eyes (23.5%) without macular edema. Posterior vitreous detachment (PVD) was present in 62.5% of cases without macular edema, and only 30.77% of cases had macular edema. Laser treatment applied in accordance to general standards cased resolution of macular edema in all cases with posterior vitreous detachment. In group with no spontaneous posterior vitreous detachment, macular edema resolved only in 19.23% of cases. Diabetic macular edema is less common in eyes with spontaneous posterior vitreous detachment. This observation shows, that not only vascular factor but also vitreo-macular tractions are responsible for macular pathology in diabetic macular edema. The efficacy of standard argon laser treatment depends also on vitreo-macular relation--presence of PVD, and is more sufficient in eyes with posterior vitreous detachment. ",0
2678,15049256,Neuroendocrine tumors of visual system--Merkel cell carcinoma],"To describe cases of Merkel cell carcinoma. Belonging to the APUD-system tumors, the highly malignant Merkel cell carcinoma affects in 10% the ocular adnexes, 50-60% of the patients develop a metastasis to the lymph nodes, and the five year survival rate is only 38%. 30% of the tumors recur after one year. In the last eight years the Merkel cell carcinoma was diagnosed in four patients and was treated by wide resection, radiotherapy and cytostatic drugs. Histological and immunohistological examination was performed. In three cases the carcinoma was diagnosed in the upper lid and in one case in the eyebrow. Two patients could not be cured. Characteristic is clinical uniform appearance of the tumor as painless, reddish nodule with smooth surface, telangiectatic blood vessels, fast growing and fast leading to metastasis. Furthermore, the histological characteristics of the tumor were found as well as NSE, S100 proteins and neuroendocrine granula, which allow to classify to the APUD--system and to distinguish from the more benign tumors. As neuroendocrine tumor the Merkel cell carcinoma represents a high malignant tumor in ophthalmology. The certain diagnosis is only made by histological and immunohistological examination. A full-thickness resection followed by radiation, should be performed as soon as possible. ",0
2679,15049377,Evolving targets for risk reduction in diabetes,"Recent evidence shows that target low-density lipoprotein cholesterol should be less than 100 mg/dl in patients with diabetes, and that even those with initially low levels benefit from pharmacologic therapy. Recent studies document that blood pressures lower than the previous target of 140/90 mmHg are beneficial, in addition to providing observational evidence against a lower threshold of benefit. Evidence that addresses the effect of blood glucose on macrovascular disease risk in patients with diabetes is reviewed. Finally, recommendations are made regarding systematic changes in healthcare delivery that will facilitate risk reduction strategies in diabetes. ",0
2680,15049554,"Evaluation of genotoxicity of sodium hypochlorite, chlorine dioxide and peracetic acid using plant tests]","The aim of this research was to evaluate the potential genotoxic effects of three drinking water disinfectants by means of in vivo short-term mutagenicity tests using plants. The study was carried out in laboratory using distilled water disinfected with sodium hypochlorite (NaClO), chlorine dioxide (ClO2) and peracetic acid (PAA) at different concentrations both in neutral and acid conditions. Untreated distilled water was used as a negative control. Micronuclei test in Tradescantia pollen cells and chromosomal aberration test in root cells of Allium cepa were the bioassays performed by exposing directly plant bioindicators to treated and untreated distilled water. The Tradescantia/micronuclei test gave positive results in most of the ClO2-treated water samples but only at acid pH. The Allium cepa test showed genotoxicity in NaClO-treated samples at acid pH and in a ClO2-treated sample at pH 7. PAA-treated samples were always nongenotoxic. Since the concentrations tested of free disinfectants are usually present in drinking water for biocidal purposes, genotoxicity of these compounds could be a public health problem. ",0
2681,15050196,Management of osteoporosis in women with peripheral osteoporotic fractures after 50 years of age: a study of practices,"To evaluate practices regarding the management of osteoporosis revealed by low-impact peripheral fractures in women older than 50 years of age. Six orthopedic surgeons prospectively recruited patients presenting with their first low-impact peripheral fracture. Three months after the fracture, each patient's usual primary-care physician provided information on management. The 132 patients (140 fractures) included in the study had a mean age of 73.8 years. Fracture sites in decreasing order of frequency were the wrist (29%), the hip (28%), the ankle (19%), the pelvis, the humerus, and the leg. Data on management by the primary-care physician were available for 106 patients. Fifty patients (50/106, 47%) were given a diagnosis of osteoporosis by their primary-care physician and 38 (38/106, 35%) received medications for osteoporosis. In two-thirds of patients, a valuable opportunity for using the effective treatments available for osteoporosis was lost. Given the high risk of further fractures in this population, our finding is of great concern. ",0
2682,15050840,"Transcriptional immune responses by honey bee larvae during invasion by the bacterial pathogen, Paenibacillus larvae","Honey bee larvae are highly susceptible to the bacterial pathogen Paenibacillus larvae only during the first instar of larval development. Transcript levels were measured for genes encoding two antimicrobial peptides, abaecin and defensin, as well as for two candidates in the immune response cascade (PGRP-LD and masquerade) in control larvae and larvae exposed to the pathogen. Transcripts for all four are present throughout development. This suggests that other physiological or dietary factors may better explain the age-based change in vulnerability to this pathogen. One of these genes, abaecin, shows significant up-regulation 24 h following oral inoculation with P. larvae, precisely when the bacterium surmounts the midgut epithelia of bees. Expression of both antimicrobial peptides varied by 1000-fold across different nestmate bees, indicating an allelic component to their expression. The implications of these results for current hypotheses related to disease tolerance in social insects are discussed, along with implications for breeding bees resistant to this important disease. ",0
2683,15051058,Structure-activity studies for a novel series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones as K(ATP) channel openers,"In search of a novel chemotype of K(ATP) channel openers a series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones was synthesized. It was found that cyclopentanone in the left hand portion of the molecule was 4-fold more potent than cyclohexanone. Introduction of gem-dimethyl groups as well as incorporation of oxygen in the cyclohexanone ring in the left hand portion of the molecule increased the potency 10-fold. In the right hand portion of the molecule, the NH-group of the pyrazolone can be effectively substituted by oxygen increasing the activity 5-fold. Incorporation of a methyl group adjacent to the dihydropyridine (DHP) nitrogen not only significantly boosted activity, but also provided an additional benefit of increased metabolic stability. In vitro tests on the tissue from pig bladder strips provided further confirmation of K(ATP) activity of these compounds. ",0
2684,15051203,Comparison of the clinical diagnosis of diabetic macular edema with diagnosis by optical coherence tomography,"To compare the diagnosis of diabetic macular edema (DME) by stereoscopic slit-lamp biomicroscopic examination of the fundus with a 78-diopter noncontact lens with diagnosis by optical coherence tomography (OCT). Prospective, double-masked, noninterventional diagnostic study. Analysis of slit-lamp biomicroscopic findings compared with OCT measurements. Patients with DME from a private retina practice. Presence or absence of macular thickening. The reference range for this clinic was comparable to reference ranges published from other clinics. The clinical detection of DME was less than detection by OCT. Chance-corrected agreements (kappa statistic) of the 2 methods were 0.63 for the foveal zone and 0.36 to 0.42 for the 4 parafoveal zones. The errors committed in clinical examination were primarily of the type in which clinical examination did not detect DME but OCT did (58%-90%) for the 5 zones analyzed. Reference ranges for OCT seem to be similar for different clinical settings, suggesting the usefulness of OCT in multicenter studies. The current standard of care for DME detection, stereoscopic slit-lamp examination of the fundus, is less sensitive than OCT for detection of DME. Because the principal therapy for DME, focal laser photocoagulation, is mainly sight preserving and not sight restoring, the wider use of OCT may beneficially impact visual disability from DME. ",0
2685,15051380,Abolition of hCAR-dependent cell tropism using fiber knobs of Atadenovirus serotypes,"Most adenoviral vectors use in gene therapy protocols derive from species C. However, expression of the primary receptor (human Coxsackievirus and Adenovirus receptor, hCAR) for these AdV is variable on cancer cells. In vivo targeting of a therapeutic gene to specific cells has then become a major issue in gene therapy. The Ad fiber protein largely determines viral tropism through interaction with specific receptors. Hereto, we constructed a set of HAdV5 vectors carrying chimeric fibers with knob domains from nonhuman AdV, namely from the FAdV-1 (Aviadenovirus), DAdV-1, and BAdV-4 (Atadenovirus). Correspondents viruses were produced using an established new HEK293 cell line, which express the HAdV2 fiber. Recombinant HAdV harboring chimeric fibers constituted of the N-terminal domain of HAdV2, and knob domain of bovine adenovirus type 4 (BAdV-4) demonstrated the greatest reduction in fiber-mediated gene transfer into human cells expressing the hCAR. Moreover, this vector infects with a better efficiency than vector with wild-type fiber, the Chinese Hamster Ovarian (CHO) and SKOV3 cell lines, both from ovarian origin, hamster and human, respectively. These studies support the concept that changing the fiber knob domain to ablate hCAR interaction should result in a de- or retargeted adenoviral vector. The adenoviral vector with the chimeric HAdV2/BAdV-4 fiber lacking hCAR interaction and with an ovarian cell tropism could be a nice candidate to elaborate vectors for ovarian tumor therapy. ",0
2686,15051420,Protection against hydrogen peroxide-induced cytotoxicity in PC12 cells by scutellarin,"The present study investigated the protective actions of the antioxidant scutellarin against the cytotoxicity produced by exposure to H2O2 in PC12 cells. This was done by assaying for MTT (3,(4,5-dimethylthiazole-2-yl)2,5-diphenyl-tetrazolium bromide) reduction and lactate dehydrogenase (LDH) release. Reactive oxygen species (ROS) and Ca2+ in cells were evaluated by fluorescent microplate reader using DCFH and Fura 2-AM, respectively, as probes. Lipid peroxidation was quantified using thiobarbituric acid-reactive substances (TBARS). Mitochondrial membrane potential (MMP) was assessed by the retention of rhodamine123 (Rh123), a specific fluorescent cationic dye that is readily sequestered by active mitochondria, depending on their transmembrane potential. The DNA content and percentage of apoptosis were monitored with flow cytometry. Vitamin E, a potent antioxidant, was employed as a comparative agent. Preincubation of PC12 cells with scutellarin prevented cytotoxicity induced by H2O2. Intracellular accumulation of ROS, Ca2+ and products of lipid peroxidation, resulting from H2O2 were significantly reduced by scutellarin. Incubation of cells with H2O2 caused a marked decrease in MMP, which was significantly inhibited by scutellarin. PC12 cells treated with H2O2 underwent apoptotic death as determined by flow cytometric assay. The percentage of this H2O2-induced apoptosis in the cells was decreased in the presence of different concentrations of scutellarin. Scutellarin exhibited significantly higher potency compared to the antioxidant vitamin E. The present findings showed that scutellarin attenuated H2O2-induced cytotoxicity, intracellular accumulation of ROS and Ca2+, lipid peroxidation, and loss of MMP and DNA, which may represent the cellular mechanisms for its neuroprotective action. ",0
2687,15051479,Herbimycin A inhibits angiogenic activity in endothelial cells and reduces neovascularization in a rat model of retinopathy of prematurity,"The pathogenesis of retinopathy of prematurity involves dysregulated angiogenesis resulting in pre-retinal growth of new vessels. Inhibition of tyrosine kinase-dependent pro-angiogenic signals may provide a rational therapeutic approach to the reduction of pre-retinal neovascularization. Vascular endothelial growth factor stimulates endothelial cell mitogenesis, differentiation and migration, by binding and activating the receptor tyrosine kinases vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2. One of the vascular endothelial growth factor receptor substrates implicated in vascular endothelial growth factor signal transduction is c-Src. The ability of herbimycin A, a c-Src-selective tyrosine kinase inhibitor, to inhibit vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and tube formation was investigated. The ability of the compound to inhibit pathologic angiogenesis was tested in a rat model of retinopathy of prematurity. Exposure of neonatal rats to oxygen concentrations cycling between 10 and 50% induced severe pre-retinal neovascularization in all rats. Some of the eyes of these variable oxygen-exposed rats were herbimycin A-injected or vehicle-injected 1 or 3 days post-oxygen exposure while some eyes were non-injected. All rats were sacrificed for assessment 6 days post-exposure. Herbimycin A inhibited both vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and capillary tube formation in a dose-dependent manner. Injection of herbimycin A into oxygen-treated rats 1 day post-oxygen exposure produced a 63% decrease in pre-retinal neovascularization relative to vehicle (P = 0.0029). There was a 41% decrease in pre-retinal neovascularization in herbimycin-injected eyes relative to vehicle-injected eyes 3 days post-oxygen (P = 0.031). Pre-retinal neovascularization was reduced in vehicle-injected eyes relative to non-injected eyes at both injection times. There were no significant differences in retinal vascular area between any of the experimental groups. Based on the results of this study, herbimycin A inhibits endothelial cell proliferation and tube formation at non-toxic concentrations and reduces pre-retinal neovascularization in a rat model of retinopathy of prematurity. Reduction of angiogenesis by the inhibition of tyrosine kinase activity may be a viable route to the development of effective chemotherapies applicable to eye disease. ",0
2688,15051668,p38 mitogen-activated protein kinase contributes to the diminished aortic contraction by endothelin-1 in DOCA-salt hypertensive rats,"We investigated whether the diminished contractile responsiveness to endothelin-1 (ET-1) is associated with the altered activation of mitogen-activated protein kinase (MAPK) in aortic smooth muscles from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. ET-1 dose-dependently increased contractions in aortic smooth muscle strips, and the contractions were significantly attenuated in tissues from DOCA-salt hypertensive rats compared with those from sham-operated rats. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was elevated by ET-1, with the magnitude and time-course being similar between strips. Although ET-1 also increased the phosphorylation of p38 MAPK in both strips, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. 5-hydroxytryptamine (5-HT) increased vascular contraction and phosphorylation of both MAPK isoforms; these were greater in DOCA-salt hypertensive rats than in sham-operated rats. ET-1 also increased the phosphorylation of caldesmon, an actin-binding protein, in sham-operated and DOCA-salt hypertensive rats. However, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. The phosphorylation of MAPK isoforms and caldesmon elevated by ET-1 was inhibited by PD098059, an inhibitor of ERK1/2 kinase, and SB203580, an inhibitor of p38 MAPK, respectively. These results suggest that ET-1 and 5-HT induce contraction by activating the MAPK pathway in rat aortic smooth muscle and that the diminished responsiveness to ET-1 in the DOCA-salt hypertensive rat may be, in part, mediated by the decrease of caldesmon phosphorylation after the decreased activation of p38 MAPK. ",0
2689,15051860,Manufacture and use of dairy protein fractions,"Fractionation of the mixture of proteins found in milk and whey to form pure, individual dairy protein fractions might allow individuals with special nutritional needs to tailor their diet to improve health. Ion exchange process chromatography was examined for this purpose using selective elution to release separately the proteins bound from whey and produce several protein fractions. Alternatively, bound proteins were released all at once to make a whey protein isolate. Prototype beverages containing these proteins were examined for clarity before and after thermal processing. Beverages containing whey protein isolate were clear at pH 2-7 before heating, but only beverages at pH <or= 3.0 were clear after thermal processing (88 degrees C, 120 s). Beverages at higher pH were made clear after heating by addition of food-grade lauryl sulfate, which prevented aggregation of the denatured proteins formed during thermal processing. Alternatively, thermally processed clear beverages at pH 3-7 were possible using the whey protein glycomacropeptide. Because of the balance between sweetness and acidity, beverages with a pH greater than carbonated soft drinks and juices (pH 2.5-3) might remain palatable using less sugar. Development of high-protein low-carbohydrate beverages might provide health benefits for individuals suffering from diabetes, obesity, and hypercholesterolemia, especially when these beverages contain dairy protein fractions known to be high in essential amino acids and branched-chain amino acids. ",0
2690,15052177,Medical termination of pregnancy at 9-14 weeks gestation. Prospective study of 105 cases in Saint-Laurent-du-Maroni (French Guyana)],"To demonstrate the effectiveness and safety of mifepristone 600mg with misoprostol 800 mg, for termination of pregnancy at 9-14 weeks gestation. This prospective study included 105 women at 9 to 14 weeks gestation given 800 mg of vaginal misoprostol, 2 or 3 days after a single dose of 600 mg of mifepristone for pregnancy termination. Outcomes measures included mean expulsion time, the interval between fotal and placental expulsion, adverse effects, vaginal bleeding, requirement for analgesia, and hospital stay, analyzed by parity and gestational age. Pregnancy termination was successful in 92.4% of the patients without requirement for surgery. The mean time to expulsion was 6 hours. The fetus and placenta were expelled together in 79% of the cases. In 15% the conception products were retained in the cervical canal, and removed with a ring forceps. Additional misoprostol doses were necessary in 33% and analgesia (nalbuphine sublingually, mean dose was 10mg) in 56%. Significant bleeding was observed in 7.5%, leading to curettage in 2 patients. No statistically significant differences were found between the rate of success and term (9-12 versus 12-14) or parity. Combining oral mifepristone and vaginal misoprostol is a successful alternative to surgical termination of pregnancy, even after 9 weeks' gestation. The use of nalbuphine for analgesia improves acceptability; sublingual administration helps avoid invasive procedures. Before 14 weeks gestation, the legal limit for termination of pregnancy in France, the choice between the surgical and medical alternatives should be left to the patient. ",0
2691,15052493,What are the health effects of fat?,"In order to answer the question which health benefits are to be expected from dietary fat, we have to differentiate between different kinds of fat with varying fatty acid composition. Saturated fatty acids are commonly judged to have a negative health impact as they lead to increased serum cholesterol levels and a higher risk of coronary heart disease. Therefore, all recommendations stress the importance to limit the intake of saturated fatty acids. Monounsaturated fatty acids, on the other hand, have a positive impact on the serum lipid profile, lead to decreased LDL-oxidation and favorably influence the metabolism of diabetics. However, it is essential that monounsaturated fatty acids be mainly supplied by plant oils like rape seed or olive oil and not by foods that are simultaneously rich in saturated fatty acids. Concerning polyunsaturated fatty acids, it is important to increase the supply of n-3 fatty acids (ratio of n-6:n-3: about 5:1) as there is substantial evidence for their protective effects. If the fatty acid composition of the diet is optimized, even a total dietary fat content of 35% of total energy intake can be adequate as long as there is enough physical activity and the diet is rich in plant-derived foods like vegetables, fruits, cereals, potatoes, beans and legumes. ",0
2692,15052660,Postnatal development of the eye in the naked mole rat (Heterocephalus glaber),"The naked mole rat (Heterocephalus glaber) is a subterranean rodent whose eyes are thought to be visually nonfunctional and as such is an ideal animal with which to pursue questions in evolutionary developmental biology. This report is the first in-depth study on the development and morphology of the naked mole rat eye. Using standard histological analysis and scanning and transmission electron microscopy, we describe the structural features of the eye. We further report on the morphological changes that accompany the development of this eye from neonate to adult and compare them with those that occur during mouse eye development. We observed numerous abnormalities in the shape and cellular arrangement of the structures of the anterior chamber, with notable malformations of the lens. Cell proliferation and cell death assays were conducted to investigate the possible causes of lens malformation. We found that neither of these processes appeared abnormal, indicating that they were not responsible for the lens phenotype of the mole rat. In order to investigate the process of lens differentiation, we analyzed the expression of gamma-crystallins using Western blots and immunocytochemistry. At birth, levels of gamma-crystallin appear normal, but soon thereafter, the gamma-crystallin expression is terminated. Absence of detectable gamma-crystallins in adults suggests that there is a gradual degradation and loss of these proteins. The evolutionary factors that could be responsible for the eye morphology of the naked mole rat are discussed. A model for abnormal lens differentiation and the role it plays in the morphogenesis of the rest of the eye in the naked mole rats is proposed. ",0
2693,15052778,Remifentanil for intraoperative anesthesia],"To compare the efficacy and safety of remifentanil with fentanyl used for intraoperative anesthesia. Fifty-four patients undergoing modified radical mastectomy or total hysterectomy were randomly assigned to remifentanil group or fentanyl group with 27 cases in each group. Anesthesia was induced with propofol (2 mg/kg) and either remifentanil (2 micrograms/kg) or fentanyl (2.5 micrograms/kg), and was maintained with inhalation of nitrous oxide in oxygen (2:1) and a continuous infusion of either remifentanil (0.2 microgram.kg-1.min-1) or fentanyl (0.03 microgram.kg-1.min-1). Depth of anesthesia, hemodynamic changes, recovery profile of anesthesia, postoperative analgesia and adverse reactions were observed. The number of patients exhibited light depth of anesthesia during tracheal intubation and maintenance in the remifentanil group was significantly fewer than that in the fentanyl group (P < 0.05). Hemodynamic changes during intubation, skin incision, maintenance of anesthesia and extubation in the remifentanil group were significantly smaller than those in the fentanyl group (P < 0.05, P < 0.01). The time to opening eyes on command and the time for extubation after surgery were comparable between the two groups. More patients in the remifentanil group required bolus injection of morphine for postoperative pain relief than those in the fentanyl group (P < 0.05). There was no significant difference between the two groups in the aspect of adverse reactions. The anesthetic and analgesic effects of remifentanil are more potent than those of fentanyl. Remifentanil can offer superior intraoperative hemodynamic stability compared with fentanyl without compromising recovery from anesthesia. ",0
2694,15053071,Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland,"Currently genetic testing for BRCA1 and BRCA2 susceptibility genes is performed throughout Europe and North America. In Poland three founder mutations in BRCA1 account for 14% of all invasive ovarian cancers and oophorectomy is frequently recommended to mutation carriers as a preventive measure. The purpose of the present study was to evaluate patient acceptance of the recommendation for prophylactic oophorectomy in a hereditary cancer clinic. Seventy-two women over the age of 40 and who carried a BRCA1 mutation were advised to undergo prophylactic oophorectomy. After a mean follow-up period of 19 months, 43 of the women (60%) had undergone the procedure. Of the 29 women who had not had an oophorectomy, five indicated that they did not intend to do so, 19 indicated that they intended to have the operation in the near future and five were undecided. In conclusion, preventive oophorectomy is acceptable to most Polish women at high risk of hereditary ovarian cancer and should be among the range of services offered in cancer genetics clinics. ",0
2695,15053368,"Identification of Chlamydophila pneumoniae in an emerald tree boa, Corallus caninus","Tissues were evaluated from emerald tree boas, Corallus caninus, from a collection in which chlamydiosis was diagnosed. To determine the strain of chlamydia infecting these snakes, tissue samples from 5 frozen snakes were tested by a quantitative TaqMan polymerase chain reaction (PCR) test and a PCR sequence analysis test. Of the 22 samples tested, 9 were categorized as either positive or weakly positive with the TaqMan test, and 6 yielded an amplicon using a serial PCR test that amplified a portion of the 23S ribosomal RNA gene. A PCR product suitable for sequencing was obtained from the heart of one of the snakes. Sequence analysis showed that the snake had been infected with Chlamydophila pneumoniae. These findings show that C. pneumoniae can infect emerald tree boas, broadening the range of reptiles known to be infected by this primarily human pathogen. ",0
2696,15053703,Perceived discrimination and substance use in African American parents and their children: a panel study,"The relation between perceived racial discrimination and substance use was examined in a panel of 684 African American families, using the prototype-willingness model of adolescent health risk (F. X. Gibbons, M. Gerrard, & D. Lane, 2003). Discrimination was concurrently and prospectively related to use in the parents and the children (mean age=10.5 years at Wave 1). The discrimination-->use relation in the parents was mediated by distress (anxiety and depression). Among the children, the relation was mediated by distress as well as their risk cognitions (favorability of their risk images and their willingness to use) and the extent to which they reported affiliating with friends who were using substances. Each of these relations with discrimination was positive. In contrast, effective parenting was associated with less willingness and intention to use. Theoretical and applied implications of the results are discussed. ",0
2697,15053988,"Hepatic glucose autoregulation: responses to small, non-insulin-induced changes in arterial glucose","The purpose of this study was to determine whether the sedentary dog is able to autoregulate glucose production (R(a)) in response to non-insulin-induced changes (<20 mg/dl) in arterial glucose. Dogs had catheters implanted >16 days before study. Protocols consisted of basal (-30 to 0 min) and bilateral renal arterial phloridzin infusion (0-180 min) periods. Somatostatin was infused, and glucagon and insulin were replaced to basal levels. In one protocol (Phl +/- Glc), glucose was allowed to fall from t = 0-90 min. This was followed by a period when glucose was infused to restore euglycemia (90-150 min) and a period when glucose was allowed to fall again (150-180 min). In a second protocol (EC), glucose was infused to compensate for the renal glucose loss due to phloridzin and maintain euglycemia from t = 0-180 min. Arterial insulin, glucagon, cortisol, and catecholamines remained at basal in both protocols. In Phl +/- Glc, glucose fell by approximately 20 mg/dl by t = 90 min with phloridzin infusion. R(a) did not change from basal in Phl +/- Glc despite the fall in glucose for the first 90 min. R(a) was significantly suppressed with restoration of euglycemia from t = 90-150 min (P < 0.05) and returned to basal when glucose was allowed to fall from t = 150-180 min. R(a) did not change from basal in EC. In conclusion, the liver autoregulates R(a) in response to small changes in glucose independently of changes in pancreatic hormones at rest. However, the liver of the resting dog is more sensitive to a small increment, rather than decrement, in arterial glucose. ",0
2698,15054441,Trigonelline is not responsible for the acute increase in plasma homocysteine following ingestion of instant coffee,"To determine whether trigonelline contributes to the effect of coffee on homocysteine (Hcy). This was a randomised crossover study. Subjects consumed 50 mg trigonelline, 5 g of instant coffee (approximately 50 mg trigonelline) or water, consumed as a single dose in 100 ml, with 1 week between each treatment. Blood samples were drawn fasting and hourly for 8 h. Urine samples were collected pretreatment and every 2 h for 8 h. Christchurch Clinical Studies Trust, Christchurch, New Zealand. Eight healthy male subjects. Instant coffee raised plasma Hcy concentrations compared with water (P=0.019) and trigonelline (P=0.037). Plasma Hcy concentrations were not different between water and trigonelline treatments (P=0.789). The change in plasma Hcy concentration was higher (mean+/-s.e.) 4 h (0.7+/-0.2 micromol/l, P=0.006), 5 h (0.7+/-0.2 micromol/l, P=0.013) and 7 h (0.7+/-0.2 micromol/l, P=0.024) following coffee consumption. Urinary glycine betaine excretion was increased by coffee but not by trigonelline. Ingestion of instant coffee acutely elevated plasma Hcy; however, trigonelline is not responsible for this rise. Supported by the Health Research Council, the Canterbury Medical Foundation, the Foundation of Research, Science and Technology. ",0
2699,15054677,Distribution of Nevskia ramosa and other rosette-forming neustonic bacteria,"Samples from 27 natural and artificial aquatic environments were analyzed for the presence of rosette-forming bacteria by a combined cultivation and molecular biological approach. Rosette-forming bacteria developed in 20 enrichment cultures with ammonia-free medium under air. Three morphotypes could be distinguished. The most abundant type I resembled Nevskia ramosa and formed hydrophobic, flat, and dichotomously branching rosettes. Type II rosettes were three-dimensional and were observed in 10 enrichments, often together with those of type I. These rosettes were hydrophilic indicating life in the hyponeuston underneath the air-water interface. Rosettes of a third type consisted of hydrophilic slime stalks that were excreted at the cell poles and were observed in only one sample. Using fluorescence in situ hybridization (FISH) with the Nevskia-specific probes NEV177 and NEV656, the presence of Nevskia ramosa was demonstrated in exactly those samples that showed type I rosettes. In a series of most-probable-number experiments, during a calm and sunny weather period 430,000 Nevskia-like bacteria per mL were found in surface samples, while during rainy weather and within the water body the numbers were lower by several orders of magnitude. Five pure cultures isolated from various enrichments were characterized in detail. The two isolates forming type I rosettes were identified as Nevskia ramosa by 16S rDNA analysis. However, comparison by genomic fingerprinting (ERIC-PCR) revealed differences between the two isolates and previously characterized strains. The 16S rDNA of two isolates forming type II rosettes showed 97.6% similarity to that of Pseudomonas fluorescens. The closest relative of the isolate forming type III rosettes was Sphingomonas parapaucimobilis (96.4% sequence similarity of the 16S rRNA sequence). All isolates grew homogeneously submersed if ammonia was added to the medium. Our results indicate that Nevskia ramosa is a widely distributed epineustonic bacterium, which can specifically be deleted by its flat and hydrophobic rosettes on ammonia-free media. ",0
2700,15054696,High resolution MR neurography in patients with cervical radiculopathy],"To image the cervical spinal nerves directly in patients with clinical and radiographic evidence of cervical radiculopathy via high resolution MR neurography by means of a qualitative and quantitative analysis. Twenty symptomatic patients with cervical radiculopathy and five asymptomatic volunteers were examined. A phased-array coil system was used to obtain high-resolution coronal T1-weighted spin echo and coronal/axial short tau inversion recovery (STIR) images of the cervical spine and spinal nerves. On the axial STIR images, nerve/muscle signal intensity ratio of the cervical spinal nerves were measured on both sides and compared with paired samples t test. P values below 0.05 were considered statistically significant (p<0.05). A markedly increased signal in the distal portion of the affected spinal nerves was found. Nerve/muscle signal intensity ratio measurements of the affected spinal nerves showed a significantly increased intensity compared with the noninvolved spinal nerves (p<0.05). In controls, nerve/muscle signal intensity rate was nearly identical on both sides (p>0.05). Magnetic resonance neurography performed with phased-array coils can detect signal abnormalities within compressed cervical spinal nerves in patients with corresponding radicular symptoms and findings. This technique may be helpful especially in evaluating patients with multi-level disc disease of the cervical spine. ",0
2701,15054843,Ectopia lentis phenotypes and the FBN1 gene,"""Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the """"MASS"""" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features [Milewicz et al., 1995: J Clin Invest 95:2373-2378], familial arachnodactyly, Shprintzen-Goldberg syndrome [Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205], and severe progressive kyphoscoliosis [Adès et al., 2002: Am J Med Genet 109:261-270]. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. [1994: Am J Med Genet 53:65-71]. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS [Loeys et al., 2001: Arch Intern Med 161:2447-2454], once in one member of a multi-generation EL kindred, [Körkkö et al., 2002: J Med Genet 39:34-41], and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement [Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362]. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational """"hot-spot"""" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations. """,0
2702,15054866,Study of puupehenone and related compounds as inhibitors of angiogenesis,"Puupehenone, a sesquiterpene produced by certain sponges, was selected in the course of a blind screening for new potential inhibitors of angiogenesis. In our study, we compare the potential anti-angiogenic activities of puupehenone and another 11 related compounds that were either natural products from marine origin or their synthetic derivatives. The effects of these compounds were determined with cell growth and differentiation assays on bovine aorta endothelial cells. Our results show that these compounds are weak inhibitors to cell growth and are not selective for endothelial cells. However, contrary to cell growth, the differentiation of endothelial cells into tubular structures was completely inhibited by 7 of these compounds at concentrations equal or lower than 3 microM. Three of these compounds, isozonarol, 8-epipuupehedione and 8 epi-9,11-dihydropuupehedione, completely inhibited the in vivo angiogenesis in the CAM assay at doses equal or lower than 30 nmol/egg. Further characterisation showed that these 3 terpenes also inhibited endothelial cell production of urokinase and invasion. One compound (8-epipuupehedione) inhibited endothelial cell migration in a dose-dependent manner. The anti-angiogenic properties of the selected compounds, the simplicity of their structures and the feasibility of their synthesis make them attractive drugs for further evaluation in the treatment of angiogenesis-related pathologies. ",0
2703,15054995,Occupational infectious diseases in the Czech Republic],"The authors present a survey on the incidence of occupational infectious and parasitic diseases in the Czech Republic. Between 1996 and 2000, occupational infectious and invasive diseases were diagnosed in 1906 patients. This is about 18% of the total number of diagnosed cases in the period under study. The total number of the diagnosed diseases included 68% of those occurring due to interhuman transmission, 29% of zoonoses and 3% of tropical diseases. The majority of occupational infectious diseases developed in health care workers (66%). This was followed by agriculture, game management and forestry workers (20%). In the group of sick workers, women outnumbered men (74% vs. 26%). The mean age of those affected was 39.2 +/- 11.9, range, 16-79 years. Scabies, viral hepatitis and tuberculosis predominated in the group of transmitted diseases and trichophytoses, erysipeloid and Lyme borreliosis among zoonoses. During the whole period of investigation, scabies occupied the first place among occupational infectious diseases. The increased incidence of diseases is mostly due to epidemics in the general population, and its spread is attributed to a low hygiene and social standards, overcrowding, increased migration that creates a higher risk for the elderly, mentally retarded and immunocompromised subjects. In tropical and subtropical countries, contract workers suffered mostly from malaria, amebiasis and infectious hepatitis A. It was possible to clearly identify occupational infectious and parasitic disease in different working conditions. The results of the survey confirm that infectious and parasitic diseases still create a difficult problem especially among health care and agriculture or forestry workers. ",0
2704,15055299,Toxicological considerations in the application and interpretation of DNA adducts in epidemiological studies,"This chapter will review a variety of issues related to the use of biomarkers in molecular epidemiological studies. It will draw upon experience gained from related mechanistic research in toxicological studies. This includes important methodological issues that impact on the type of assays that can be used and how these issues affect the selection of the method and the biological sample. It will also address issues affecting the use of biomarkers as measures of exposure and effect, and discuss inferences for causality and the selection of target organ versus surrogate tissues. Combining information from toxicological studies can also aid in the interpretation of epidemiological studies, such as tissues with and without strong biological plausibility and relationships between observed DNA adducts and those that arise from endogenous processes. Finally, it will discuss issues related to important pathways of metabolism and implications of genetic polymorphisms. These critical issues affect both the design and interpretation of molecular epidemiological studies. ",0
2705,15055860,Primary prevention of coronary heart disease in general practice: a cross sectional population study,"The aim of this study was to assess the interventions by general practitioners on cardiovascular risk factors among persons without a history of cardiovascular disease attending for a cardiovascular check-up. All inhabitants of three Belgian towns aged between 45 and 64 years were invited for a cardiovascular check-up and blood test. Of all the attending persons without a history of cardiovascular disease (n = 898), 51% received at least one prescription, diet or health advice: 28% for hyperlipidaemia, 23% for physical activity, 22% for caloric intake, 9% for blood sugar, 5% for blood pressure and 4% for smoking. Interventions on lipoproteins, blood sugar and smoking habits were significantly more often proposed to persons with a medium or high cardiovascular risk compared to those at low cardiovascular risk. For persons at low cardiovascular risk, therapeutic lifestyle changes are often not advised, and isolated risk factors often remain untreated. ",0
2706,15055870,Emergency repair of groin herniae: outcome and implications for elective surgery waiting times,"Patients with groin herniae do not always seek medical advice and, when listed for surgery, often wait many months for elective repair. We audited our emergency admissions for complicated groin herniae to establish whether a change in policy for elective surgery could lower their incidence. We performed a retrospective review of all admissions for complicated groin herniae from 1 January 2000 to 31 December 2001. Besides outcome, we recorded patients' awareness of their diagnosis before admission and whether they had been listed for elective surgery. We identified 19 patients (16 men and three women) with an inguinal and 19 (four men and 15 women) with a femoral hernia. Sixteen (42%) knew of their hernia before admission (11 inguinal and five femoral), but only three had been awaiting surgical repair for 1, 7 and 26 weeks, respectively. The median (interquartile range) age was 70 (54-84) years in inguinal and 79 (64-88) years in femoral herniae. Surgery was performed in all but an 84-year-old man who died pre-operatively. Two patients with inguinal and 11 with femoral herniae required a laparotomy (p = 0.006). Bowel resection was necessary in one patient with an inguinal and 12 with femoral herniae (p = 0.001). Complications occurred in 12 cases (31%). Four patients, all with femoral herniae, died post-operatively, for an overall mortality of 13% (5/38). Morbidity and mortality for complicated groin hernia, particularly femoral, remain high. As most patients were elderly and unaware of their diagnosis, reducing waiting times for elective repair is unlikely to influence the incidence of complicated herniae. ",0
2707,15055933,Simulating fecal coliform bacteria loading from an urbanizing watershed,"The fate and transport of fecal coliform bacteria in the urbanizing Polecat Creek watershed, located in Virginia, was simulated using the Hydrological Simulation Program-FORTRAN (HSPF). Both point and nonpoint sources of fecal coliform were included in the simulation. Hydrologic and water quality parameters of HSPF were calibrated and validated using observed data collected from October 1994 to June 2000 at three monitoring stations. The percent errors in total runoff volumes between observed and simulated values ranged from 0.4 to 4.2% for the calibration period, and 0.4 to 6.7% for the validation period. The geometric mean of simulated fecal coliform concentrations at the outlet of the watershed was 10% lower than that of observed values for the calibration period. HSPF moderately under-predicted the geometric mean concentration by 16.4% for one sub-watershed and slightly over-predicted by 7.3% for another. Observed fecal coliform concentrations were compared with the range defined by the minimum and maximum simulated concentrations occurring within a 3-day window centered on the day the water sample was collected. Over 42% of grab sample data collected at the three monitoring sites in the watershed fell within the max min range of simulated concentrations over the 3-days window for the calibration period. For all monitoring sites, 39.5% of the total samples taken during the validation period fell in the range of simulated concentrations over the 3-day window period. Results presented in this study demonstrate that HSPF reasonably represents the hydrology and water quality of an urbanizin watershed and that it could be utilized as a planning tool for future assessment of land use impacts on fecal coliform on in-stream concentrations. ",0
2708,15055965,Determination of refractory elements in used lubricating oil by ICPOES employing emulsified sample introduction and calibration with inorganic standards,"The quantification of trace elements in used lubricating oil is useful for evaluating the wearing of specific components of engines. In the present work, inductively coupled plasma optical emission spectrometry (ICPOES) was used for determining five refractory elements (Ni, Mo, Cr, V and Ti) in lubricating-oil samples. The methodology was developed while aiming at the introduction of such organic samples into the ICP as emulsions. Several nebulization systems were tested with clear advantage for Meinhard K3 coupled with a cyclonic spray chamber. The carbon deposition on the injector tip as well as the plasma background was minimized through careful optimization of the Ar and O2 gas mixture flows into the plasma. The optimization of instrumental and experimental parameters allowed quantification using calibration curves prepared with analyte inorganic standards. An internal standard (Sc) was used to correct the matrix effects and signal fluctuations. The limits of detection (3Sb/m), in the ng g(-1) range were obtained for all five elements. The methodology was validated through an analysis of standard reference materials (SRM 1084a, 1085a and 1085b). Good analyte recoveries (from 92.6 to 104.7%) were achieved. Comparison studies against established ICPOES methodologies (sample acid decomposition or sample direct dilution in an organic solvent) have shown that the proposed methodology present clear advantages in terms of simplicity of sample preparation, overall analysis time, and the use of inorganic standards for calibration instead of expensive metallorganic standards. ",0
2709,15055983,Randomized clinical trial comparing overnight use of two self-directed peroxide tooth whiteners,"To directly compare tooth color change and spatial uniformity of two brush-applied, peroxide-based overnight tooth whiteners in a 2-week randomized clinical trial. 57 adult volunteers were randomly assigned to Crest Night Effects, a 19% sodium percarbonate system packaged in unit dose sachets that when applied, dries to form an adherent film, or Colgate Simply White Night, a paint-on liquid in an applicator bottle at a concentration of 8.7% hydrogen peroxide. Both groups applied their assigned gel on the facial surfaces of the six maxillary anterior teeth for 14 nights. Efficacy was measured objectively as change in L*a*b* tooth color from standard digital images of maxillary teeth, while safety was evaluated by clinical examination and interview. After 14 nights treatment, adjusted mean (SE) change in yellowness (delta b*) was -0.95 (0.092) for the 19% sodium percarbonate film and -0.17 (0.096) for the 8.7% hydrogen peroxide gel, with these groups differing statistically (P < 0.0001). Other individual and composite color parameters also demonstrated significantly greater whitening for the 19% sodium percarbonate film compared to the 8.7% hydrogen peroxide gel after 14 nights use. Only the 19% sodium percarbonate film exhibited significant (P< 0.0001) proximal color improvement (delta b*) after 2 weeks, approximately 98% of that seen on the body of the tooth, providing evidence of proximal bleaching and uniform spatial whitening following use of this barrier-free system. Both products were well-tolerated, with no subjects discontinuing treatment early due to a causal adverse event. ",0
2710,15056117,Cytotoxicity and sealing properties of four classes of endodontic sealers evaluated by succinic dehydrogenase activity and confocal laser scanning microscopy,"The objectives of this study were to evaluate the cytotoxicity and sealing properties of four classes of endodontic sealers (PCS/Kerr, RoekoSeal/Roeko, TopSeal/Dentsply, and EndoREZ/Ultradent). For cytotoxicity testing (MTT method), the materials were either placed immediately in contact with cultured cells or 24 h after setting, then evaluated at three subsequent time points (24 h, 48 h, or 1 wk). For the leakage study, extracted human roots were obturated with acrylic cones and sealers and immersed for 48 h into rhodamine-labeled lipopolysaccharide. The roots were then observed under a confocal laser scanning microscope to estimate (semiquantitatively) the presence of the rhodamine-lipopolysaccharide (LPS) inside the canal. The results showed that cytotoxicity generally increased with time, and that most materials pose significant cytotoxic risks, particularly in the freshly mixed condition. Further, all materials showed significant leakage although there was large variation among teeth. Overall, the silicon-based material (Roeko Seal) was less cytotoxic and more effective in sealing root canals against LPS leakage than other materials. ",0
2711,15056141,Intermittent topical 5-fluorouracil is effective without significant irritation in the treatment of actinic keratoses but prolongs treatment duration,"Controversy exists as to whether treatment of actinic keratoses with intermittent doses of topical 5-fluorouracil is effective in the absence of significant irritation. To evaluate the efficacy and degree of irritation of 5-fluorouracil as a function of its application frequency. A total of 85 actinic keratoses in 53 patients were treated, initially with four applications per week for the first week. After this first week, if intolerable irritation arose, patients were instructed to reduce application frequency to two times per week for the rest of the treatment period. Treatment was completed for 95.4% of the lesions included, with healing of 88.6% of them. The mean time to healing was 7.4 weeks (with four applications weekly) and 10.2 weeks (with two applications). The healing rate was similar in the two groups. Significant correlations (p<0.001) were observed between application frequency and time to healing. Intermittent 5-fluorouracil treatment is effective without causing significant irritation, but time to healing increases with declining application frequency. ",0
2712,15056517,Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits,"Since use of multiple drugs to treat psychiatric patients is increasing, and research on this practice is rare, the authors carried out a retrospective case-control study of multiple versus single antipsychotic treatment in psychiatric inpatients. Inpatient treatment groups receiving either antipsychotic monotherapy or polytherapy were matched in terms of age, sex, diagnostic category, and admission clinical ratings (Global Assessment of Functioning [GAF] and Clinical Global Impression [CGI]), which yielded 70 subject pairs. They were compared in terms of total chlorpromazine-equivalent daily dose, changes in total daily dose, length of hospitalization, incidence of adverse effects, and changes in clinical ratings (CGI, GAF, Positive and Negative Syndrome Scale score) between admission and discharge. Initial doses were closely similar at admission for both treatment groups, but the median total final antipsychotic dose was 78% higher for those receiving antipsychotic polytherapy versus monotherapy. Also, median length of stay in the hospital was 55% (8.5 days) longer, and risk of adverse effects was 56% higher with polytherapy, whereas clinical improvement scores were similar (within 11%) for both treatments. Short-term treatment with multiple antipsychotics was associated with major increases in drug exposure, adverse events, and time in the hospital but with no apparent gain in clinical benefit. These findings require further testing in controlled prospective studies. ",0
2713,15056567,Nutritional manipulation of fetal adipose tissue deposition and uncoupling protein 1 messenger RNA abundance in the sheep: differential effects of timing and duration,"A range of epidemiological and experimental studies have indicated that suboptimal nutrition at different stages of gestation is associated with an increased prevalence of adult hypertension, cardiovascular disease, and obesity. The timing of prenatal nutrient restriction is important in determining postnatal outcomes-including obesity. The present study, aimed to determine the extent to which fetal adiposity and expression of the key thermogenic protein, uncoupling protein (UCP)1, are altered by restriction of maternal nutrient intake imposed during four different periods, starting from before conception. Maternal nutrient intake was restricted from 60 days before until 8 days after mating (periconceptional nutrient restriction; R-C), from 60 days before mating and throughout gestation (R-R), from 8 days gestation until term (C-R), or from 115 days gestation until term. Fetal perirenal adipose tissue (PAT) was sampled near to term at approximately 143 days. UCP1 mRNA, but not protein, abundance in PAT was increased in fetuses in the R-R group (C-C 63 +/- 18; R-C 83 +/- 43; C-R 103 +/- 38; R-R 167 +/- 50 arbitrary units (P < 0.05)). In contrast, the abundance of UCP1 mRNA, but not protein, in fetal PAT was decreased when maternal nutrition was restricted from 115 days gestation. The major effect of maternal nutrient restriction on adipose tissue deposition occurred in the C-R group, in which the proportion of fetal fat was doubled, whereas maternal nutrient restriction from 115 days gestation reduced fetal fat deposition. In conclusion, there are differential effects of maternal and therefore fetal nutrient restriction on UCP1 mRNA expression and fetal fat mass and these effects are dependent on the timing and duration of nutrient restriction. ",0
2714,15056811,Ethyl acrylate risk assessment with a hybrid computational fluid dynamics and physiologically based nasal dosimetry model,"Cytotoxicity in the nasal epithelium is frequently observed in rodents exposed to volatile organic acids and esters by inhalation. An interspecies, hybrid computational fluid dynamics and physiologically based pharmacokinetic (CFD-PBPK) dosimetry model for inhaled ethyl acrylate (EA) is available for estimating internal dose measures for EA, its metabolite acrylic acid (AA), and EA-mediated reductions in tissue glutathione (GSH). Nasal tissue concentrations of AA were previously used as the dose metric for a chronic Reference Concentration (RfC) calculation with this compound. However, EA was more toxic than expected, based on calculated tissue AA concentrations. Unlike AA, EA causes depletion of tissue GSH. We have developed an RfC for EA using tissue GSH depletion in the olfactory epithelium as the primary measure of nasal tissue dose. The hybrid CFD-PBPK model was refined to improve the accuracy of simulations for GSH in rat olfactory tissues. This refined model was used to determine the concentration for continuous human exposures to EA predicted to reduce nasal GSH levels to the same extent as seen in rats exposed to EA at the no-observed-effect level (NOEL). Importantly, AA concentrations in the human nasal olfactory epithelium at the proposed chronic RfC were predicted to be lower than the AA concentrations estimated in the rat at the NOEL. Thus, a chronic RfC based on maintaining GSH in the human nasal olfactory epithelium at levels equivalent to the rat NOEL would also provide an adequate margin of safety with respect to AA concentrations in nasal tissues. ",0
2715,15057114,Normative ethics in sports medicine,"The relationship between a team physician and an athlete differs significantly from the traditional doctor-patient relationship. To better define the ethical norms and ideals in sports medicine, we surveyed the views of practicing team physicians in the Ivy, National Football, and National Hockey Leagues and compared them with responses offered by professional ethicists. Six hypothetical cases were presented, each representing a distinct area of ethical conflict: advertising, conflicting healthcare goals, confidentiality, innovative treatments, enabling dangerous behavior, and treating children. Thirty-one ethicists and 131 team physicians responded to the surveys. Subjects were asked to rate agreement or disagreement with statements that followed the case description. Responses were converted to scores ranging from 0 to 100. A priori, a difference greater than 20 points was set to represent significant disagreement. By that standard, there was agreement between the physicians and ethicists for 18 of 23 statements. We concluded that team physicians and ethicists share many of the same ethical views on common ethical issues in sports medicine. The high degree of variance in the responses in both groups, however, suggests that many unresolved areas remain in the field of ethics in sports medicine. ",0
2716,15057202,West Nile virus: a primer for infection control professionals,"In 1999, an outbreak of human West Nile encephalitis occurred in New York City. During the outbreak, 62 cases of human West Nile virus (WNV) infection were diagnosed, with 7 deaths. This was the first time that human WNV infections were detected in the Western Hemisphere. By 2002, the total number of human cases of WNV that year alone reached 4156, with 284 fatalities. In addition, investigations have shown that WNV can be acquired through organ transplantation, blood transfusion, breast milk, transplacental transmission, and occupational exposure. This article provides an overview of the 2002 WNV epidemic in the United States and reviews the epidemiology of WNV, the clinical presentation of human WNV infection, and the prevention and control of this emerging pathogen. ",0
2717,15057268,A systematic approach to the assessment of known TNF-alpha polymorphisms in Graves' disease,"Single-nucleotide polymorphisms (SNPs) within the tumour necrosis factor alpha (TNF-alpha) gene on chromosome 6p21.3 have been associated with many autoimmune diseases; however, results have been conflicting and accurate allele frequencies have never been established in a UK Caucasian population. The aim of this study was to assess the frequency of 22 known TNF-alpha SNPs in a UK Caucasian control population and investigate association of all polymorphisms with >5% minor allele frequency in a large case-control data set of patients with Graves' disease (GD). Eight of the 22 SNPs had minor allele frequencies >5% and were investigated further. The other 14 SNPs were present in the UK population at frequencies ranging from 0 to 4.7%. A significant increase of the A allele of the -238 SNP was seen in GD patients when compared with control subjects (9.6 vs 6.8%, respectively; P=0.003) and mirrored in the genotype distribution (P=0.009). Furthermore, association of the -238 SNP appears not to be due to linkage disequilibrium of the known HLA-DRB1(*)03 associations with GD. This study has established accurate allele frequencies of TNF-alpha SNPs in a UK population and provides preliminary evidence for association of the TNF-alpha gene with GD. ",0
2718,15057481,"Isolation of carotenoid-deficient mutant from alkylated dibenzothiophene desulfurizing nocardioform bacteria, Gordonia sp. TM414","The dibenzothiophene-desulfurizing nocardioform bacteria, Gordonia sp. TM414, was isolated from oil-contaminated soil. To avoid coloration of the oil layer after the desulfurization reaction, which could decrease the quality of the oil, two colorless knock-out mutants, TPc and TPd, were isolated by using a broad-host-range transposon complex. Genomic sequence analysis revealed that the same gene was disrupted in these mutants and that the transposon-inserted gene was assigned as the gene for phytoene desaturase, crt I. The crt I mutants also showed desulfurization activity comparable to that of the parent strain in a model-oil/aqueous bi-phasic reaction, suggesting that the carotenoid production is not responsible for the bi-phasic desulfurization reaction that requires hydrophobic substrate incorporation from the organic phase. ",0
2719,15057902,HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination,"Variable immune responses to hepatitis B virus (HBV) infection and recombinant HBV vaccines have been associated with polymorphisms in several genes within the human leukocyte antigen (HLA) complex. Analyses of polymerase chain reaction (PCR)-based genotyping data from 164 North American adolescents vaccinated with recombinant HBV products confirmed that HLA-DRB1*07 (relative odds [RO] = 5.18, P <.0001) and human immunodeficiency virus type 1 (HIV-1) infection (RO = 3.91, P <.001) were both associated with nonresponse to full-dose vaccination. Further associations were observed with single nucleotide polymorphisms (SNPs) at the IL2 and IL4 loci along with insertion/deletion variants at the IL12B locus (P =.003-.01). Host genetic associations were independent of one another as well as other HLA (A, B, C, and DQB1) and cytokine gene (IL4R, IL6, IL10, and TNF) variants. Statistical adjustments for nongenetic factors (gender, ethnicity, age, HIV-1 infection, and vaccination protocols) did not substantially alter the strengths of the genetic relationships. The overall distribution pattern of genetic variations was similar between the analyzed vaccinees and additional adolescents (n = 292) from the same cohort. In conclusion, DRB1*07 (or a closely linked allele) and immunoregulatory cytokine gene polymorphisms correlate with variable immune response to recombinant HBV vaccines.",0
2720,15057907,Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation,"Recently, we demonstrated that the cyclooxygenase-2 (COX-2) inhibitor celecoxib acts to significantly suppress the growth of rat C611B cholangiocarcinoma (ChC) cells in vitro. To establish a molecular mechanism for this growth suppression, we investigated the effects of celecoxib on apoptotic signaling pathways in cultured rat C611B ChC cells. Celecoxib and another COX-2 inhibitor, rofecoxib, at 5 microM were almost equally effective in inhibiting prostaglandin E(2) (PGE(2)) production by these cells, but at this low concentration, neither inhibitor suppressed growth or induced apoptosis. Celecoxib at 50 microM induced prominent apoptosis in these cells, whereas rofecoxib at 50 microM was without effect in either suppressing growth or inducing apoptosis. Celecoxib (50 microM) did not alter Bcl-2, Bcl-x(L), or COX-2 protein levels, nor did it inhibit p42/44 mitogen-activated protein kinase (MAPK) phosphorylation; however, it significantly suppressed serine/threonine kinase Akt/PKB (Akt) phosphorylation and kinase activity in cultured C611B cells. This effect, in turn, directly correlated with Bax translocation to mitochondria, cytochrome c release into cytosol, activation of caspase-9 and caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Addition of 25 microM PGE(2) to C611B cell cultures blocked the apoptotic actions of celecoxib. Rofecoxib (50 microM) was without effect in suppressing Akt phosphorylation and caspase-3 activation. In vivo, celecoxib partially suppressed tumorigenic growth of C611B ChC cells. In conclusion, our results indicate that celecoxib preferentially acts in vitro to induce apoptosis in ChC cells through a mechanism involving Akt inactivation, Bax translocation, and cytochrome c release. Our in vivo results further suggest celecoxib might have potential therapeutic or chemopreventive value against ChC.",0
2721,15057914,Kupffer cells alter organic anion transport through multidrug resistance protein 2 in the post-cold ischemic rat liver,"Although Kupffer cells (KCs) may play a crucial role in post-cold ischemic hepatocellular injury, their role in nonnecrotic graft dysfunction remains unknown. This study examined reveal the role of KC in post-cold ischemic liver grafts. Rat livers treated with or without liposome-encapsulated dichloromethylene diphosphonate, a KC-depleting reagent, were stored in University of Wisconsin (UW) solution at 4 degrees C for 8 to 24 hours and reperfused while monitoring biliary output and constituents. The ability of hepatocytes to excrete bile was assessed through laser-confocal microfluorography in situ. Cold ischemia-reperfused grafts decreased their bile output significantly at 8 hours without any notable cell injury. This event coincided with impaired excretion of glutathione and bilirubin-IXalpha (BR-IXalpha), suggesting delayed transport of these organic anions. We examined whether intracellular relocalization of multidrug resistance protein-2 (Mrp2) occurred. Kinetic analyses for biliary excretion of carboxyfluorescein, a fluoroprobe excreted through this transporter, revealed significant delay of dye excretion from hepatocytes into bile canaliculi. The KC-depleting treatment significantly attenuated this decline in biliary anion transport mediated through Mrp2 in the 8-hour cold ischemic grafts via redistribution of Mrp2 from the cytoplasm to the canalicular membrane. Furthermore, thromboxane A(2) (TXA(2)) synthase in KC appeared involved as blocking this enzyme improved 5-carboxyfluorescein excretion while cytoplasmic internalization of Mrp2 disappeared in the KC-depleting grafts. In conclusion, KC activation is an important determinant of nonnecrotic hepatocellular dysfunction, jeopardizing homeostasis of the detoxification capacity and organic anion metabolism of the post-cold ischemic grafts. ",0
2722,15058231,Detection and quantitative determination of modified and/or denatured human serum albumin],"A simple method of quantitative evaluation of modified human serum albumin (SA) was suggested for the use in clinical practice. It is based on the natural ability of modified SA to form complexes with endogenous urea. An SA content, which lost its secondary and tertiary structures, is indirectly predetermined by the quantity of urea bound with protein that is biochemically determined after hydrolysis of the studied sample of partially purified SA. The clinical value of the parameter that is being determined is under discussion. ",0
2723,15058525,Infliximab: lack of efficacy on perforating complications in Crohn's disease,"Infliximab (Remicade), a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-alpha), has emerged as promising therapeutic option in perianal fistulizing Crohn's disease (CD). However, little knowledge exists about its use for the treatment of internal fistulas in CD. We present our experience with infliximab in this situation. Four patients with CD who had internal fistulas (Case 1: entero-enteral and entero-abdominal; Case 2: entero-enteral; Case 3: entero-enteral and parastomal; Case 4: entero-vesical) were treated with 3 infusions of infliximab (5 mg/kg body weight) with intervals of 2 and 4 weeks. In addition, 3 patients had strictures and 2 patients had perianal fistulas. After the three infusions of infliximab (5 mg/kg body weight), internal fistulas remained unchanged in all patients. The perianal fistulas present in 2 cases were healed. Administration of infliximab was safe and well tolerated in all cases. Treatment with 3 infusions of infliximab (5 mg/kg body weight) led to healing of only the perianal fistulas, whereas the internal fistulas were not influenced. We conclude that in these 4 cases, infliximab was well tolerated but not effective for the management of internal fistulas and was no alternative for surgery. ",0
2724,15058879,Preliminary evaluation of a 10-wk. resistance and cardiovascular exercise protocol on physiological and psychological measures for a sample of older women,"A preliminary 10-wk. study was conducted to determine the effect a combined strength and cardiovascular exercise protocol had on both physiological and psychological change in 17 older (M age = 66.8 yr.), formerly sedentary women. The protocol was associated with better adherence than typically found for new and returning exercisers. Significant improvements over 10 wk. were found on Body Mass Index, body fat, resting heart rate, and balance. Significant, positive changes in mean ratings were also found on Physical Self-concept, Total Mood Disturbance, Depression, and Fatigue (small to moderate treatment effect sizes). Although no significant changes were found for rated Tension, Vigor, Anger, and Confusion, mean changes were in the desired direction and rated Tension showed a moderate effect size. The need for replication, including a control group and follow-up, plus continued research on exercise protocols both well-tolerated and effective for older individuals and other specific groups, were discussed. ",0
2725,15058995,Characteristics of immobilized lipase on hydrophobic superparamagnetic microspheres to catalyze esterification,"A novel immobilized lipase (from Candida rugosa) on hydrophobic and superparamagnetic microspheres was prepared and used as a biocatalyst to catalyze esterification reactions in diverse solvents and reaction systems. The results showed that the immobilized lipase had over 2-fold higher activities in higher log P value solvents. An exponential increase of lipase activity against log P of two miscible solvent mixtures was observed for the first time. Both free and immobilized lipase achieved its maximum activity at the range of water activity (a(w)) 0.5-0.8 or higher. At a(w) 0.6, the immobilized lipase exhibited markedly higher activities in heptane and a solvent-free system than did the native lipase. In multicompetitive reactions, the alcohol specificity of the lipase showed a strong chain-length dependency, and the immobilized enzyme exhibited more preference for a longer-chain alcohol, which is different from previous reports. The immobilized lipase showed higher specificities for butyric acid and the medium-chain-length fatty acids (C(8)-C(12)). Then, the immobilized lipase was extended to solvent-free synthesis of glycerides from glycerol and fatty acids. Recovered by magnetic separation, the immobilized lipase exhibited good reusability in repeated batch reaction, indicating its promising feature for biotechnology application. ",0
2726,15059018,Distributed network imaging and electrical impedance tomography of minimally invasive surgery,"Minimally invasive surgery has become highly dependent on imaging. For instance, the effectiveness of cryosurgery in treating cancer is dependent on knowledge of freezing extent, and relies on real-time imaging techniques for monitoring. However, medical imaging is often very expensive and therefore not available to most of the world population. Here we propose the concept of distributed network imaging (DNI) which could make medical imaging and minimally invasive surgery available to all who need these advanced medical modalities. We demonstrate the concept through electrical impedance tomography (EIT) of cryosurgery. The central idea is to develop an inexpensive measurend (data collection hardware) at a remote site and then to connect the measurend apparatus to an advanced image reconstruction server, which can serve a large number of distributed measurends at remote sites, using existing communication conduits (Ethernet, telephone, satellite, etc.). These conduits transfer the raw data from the measurend to the server and the reconstructed image from the server to the measurend. Electrical impedance tomography (EIT) is an imaging modality which utilizes tissue impedance variation to construct an image. The EIT measurend which consists of electrodes, a power supply, and means to measure voltage is inexpensive, and therefore suitable for DNI. EIT is also very well-suited to imaging cryosurgery since frozen tissue impedance is much higher than that of unfrozen tissue. In this study, we first develop numerical models to illustrate the theoretical ability of EIT to image cryosurgery. We begin with a simplified two dimensional model, and then extend the study to the more appropriate three dimensional model. Our simulated finite element phantoms and pixel-based Newton-Raphson reconstruction algorithms were able to produce easily identifiable images of frozen regions within tissue. Then, we demonstrate the feasibility of the DNI concept though a case study using EIT to image an in vitro liver cryosurgery procedure through a modem. We find that the acquired raw data packets are less than 5KB per image and the images, using compression, do not exceed 50KB per image. ",0
2727,15059030,Population genomics of drug response,"Genetic diversity contributes to both disease susceptibility and variability in response to drugs. However, it has proven difficult to isolate genes that underlie common complex disease, and genetic variations that influence clinical responses to drugs remain largely uncovered. The candidate gene approach to uncover genetic variations that contribute to disease susceptibility or variations in response to common drugs has not met expectations. Although the sib-pair linkage approach has certain theoretical advantages in dealing with common/complex disease, success has been slow in coming. Meanwhile family studies including siblings, cousins and second cousins, and studies in well-defined founder populations, have increasingly gained popularity and enabled scientists to map and isolate genes for common complex disease, such as schizophrenia and asthma. The latter method has generated new hope that this approach may also be effective in mapping genes that regulate drug response. Indeed, there is compelling evidence that corticosteroid sensitivity is a mapable trait in patients with asthma. Collectively, these studies support the value of leveraging information available within population-based data systems to map and isolate genes for common complex disease and drug response. ",0
2728,15059054,Youth health research ethics: time for a mature-minor clause?,"Research into adolescent health issues is hampered by absolute requirements for parental consent. Society's recognition of adolescents' autonomy and decision-making capacity has been embodied in the legal recognition of the mature minor's right to make decisions on matters affecting his or her life. Psychological research indicates that young people from 14 years have decision-making capacity. US and UK research ethics guidelines acknowledge the mature-minor principle, but Australian guidelines are out of step with international practice. An absolute requirement for parental consent in Australian research ethics guidelines is potentially unethical if it denies mature adolescents' autonomy and is a barrier to participation, study validity and improved health outcomes through research findings. There are grounds for considering a mature-minor clause in the National Health and Medical Research Council research ethics guidelines, particularly in the context of youth participation in minimal-risk research. ",0
2729,15059232,"Effect of dietary clenbuterol and cimaterol on muscle composition, beta-adrenergic and androgen receptor concentrations in broiler chickens","Illegal dietary supplementation with beta(2)-agonists has been shown to increase protein deposition and decrease fat accretion in domestic animals. In poultry the metabolic and endocrine responses to beta(2)-agonists are not fully elucidated. In this trial the effects of dietary clenbuterol (1 p.p.m.) and cimaterol (1 p.p.m.) on muscle composition and endocrine response of male broiler chickens were studied. Dietary clenbuterol induced a slight, but in general not significant, improvement of zootechnical performances and carcass yields. Chemical composition of muscle was not influenced by dietary treatments, even if a slight improvement of protein content was observed in treated groups. No effects on fatty acid composition of meat were detected. Both clenbuterol and cimaterol treatments caused a downregulation in testicular androgen receptors and in pulmonary, cardiac and central nervous system beta-adrenergic receptors. ",0
2730,15059239,Relationship between dietary unsaturation and vitamin E in poultry,"Vitamin E requirements are linked to dietary polyunsaturated fatty acids (PUFA) content as a result of the protective effect of vitamin E from lipid peroxidation. On the other hand, it has been suggested that dietary PUFA interfere with vitamin E absorption. A 4 x 4 factorial study was planned to assess the effect of dietary vitamin E inclusion level (0, 100, 200 and 400 mg/kg) and degree of unsaturation (15, 34, 45 and 61 g PUFA/kg) on vitamin E apparent absorption and tissue deposition in poultry. A total of 192 female broiler chickens were used. A digestibility balance was carried out between 19 and 23 days of age to calculate apparent absorption of fat and vitamin E. The livers of 96 animals were obtained at 44 days of age for vitamin E determination. Increasing dietary levels of vitamin E reduced its apparent absorption. The more saturated diet reduced fat and vitamin E apparent absorption while PUFA levels from 34 to 61 g/kg did not modify this parameter but reduced the hepatic vitamin E concentration, suggesting a greater systemic use of this vitamin. These results suggest that PUFA do not limit vitamin E absorption, although they may increase its degradation in the gastrointestinal tract. ",0
2731,15059445,Study of biosensor technology on the detection of endotoxin-neutralizing materials],"To explore the application of biosensor technology in the determination of endotoxin-neutralizing materials. After mixing polymyxin B (PMB) with endotoxin in certain concentration, the neutralizing ratio of PMB to endotoxin was assessed by biosensor technique and limulus amebocyte lysate test respectively. The results from the two methods were compared. The neutralizing ratio of PMB to endotoxin as assessed by biosensor technology was 0.35 microg to 1 ng, while that by dynamic turbidimetric and chromogenic limulus amebocyte lysate (LAL) technique was 0.5 mg to 1 ng and 1 mg to 1 ng, respectively. The results obtained by biotechnology were similar to that by biosensor technique. Biosensor technology was an accurate, convenient and rapid method for the determination of potency of endotoxin-neutralizing materials. ",0
2732,15059930,Phosphoinositide-dependent kinase 1 and p21-activated protein kinase mediate reactive oxygen species-dependent regulation of platelet-derived growth factor-induced smooth muscle cell migration,"Smooth muscle cell migration in response to platelet-derived growth factor (PDGF) is a key event in several vascular pathologies, including atherosclerosis and restenosis. PDGF increases intracellular levels of reactive oxygen species (ROS) in vascular smooth muscle cells (VSMCs), but the ROS sensitivity of migration and of the signaling pathways leading to migration are largely unknown. In VSMCs, PDGF dose-dependently increased migration compared with nonstimulated cells, with a maximum increase at 10 ng/mL. Pretreatment with the antioxidant N-acetyl-cysteine, the flavin-containing enzyme inhibitor diphenylene iodonium, or the glutathione peroxidase mimetic ebselen significantly attenuated migration (PDGF alone, 5.0+/-1.1-fold; NAC, 1.8+/-0.2-fold; diphenylene iodonium, 1.4+/-0.3-fold migration; and ebselen, 2.0+/-0.5-fold migration), as did overexpression of catalase. Pretreatment of VSMCs with the Src inhibitor PP1 or dominant-negative Rac adenovirus significantly inhibited migration, but only Src activation was attenuated by ROS inhibitors. Phosphorylation of the Src- and Rac-effector p21-activated protein kinase (PAK) 1 on Thr423 (the phosphoinositide-dependent kinase-1 [PDK1] site) was attenuated by ROS inhibition, and infection of VSMCs with dominant-negative PAK1 adenovirus attenuated migration. Moreover, kinase-inactive K111N-PDK1 inhibited PAK1 phosphorylation on Thr423, and both K111N-PDK1 and Y9F-PDK1 significantly inhibited VSMC migration. PDK1 tyrosine phosphorylation was also ROS dependent. These data indicate that PDGF-induced VSMC migration is ROS dependent and identify the Src/PDK1/PAK1 signaling pathway as an important ROS-sensitive mediator of migration. Such information is critical to understanding the role of ROS in vascular diseases in which migration of VSMCs is an important component. ",0
2733,15060402,Who is portrayed in psychotropic drug advertisements?,"The purpose of our study was to determine who is portrayed in psychotropic drug advertisements across time in three national psychiatric journals. All psychotropic drug advertisements portraying people were collected from the American Journal of Psychiatry, the British Journal of Psychiatry, and the Canadian Journal of Psychiatry at three time intervals (1981, 1991, and 2001). The advertisements were classified according to patient demographics, patient portrayal, and product information. Chi-square analysis was used to test for statistically significant associations among the variables. Fifty-seven percent of the psychotropic drug advertisements featured women, and 88% portrayed white patients. Statistically significant associations were detected between gender and the setting in which the patient was portrayed (chi(2) = 13.54, df = 3, p < 0.004), and gender and role (chi(2) = 29.41, df = 3, p < 0.001). Disproportionate gender representation was most notable in the 2001 time interval in the American Journal of Psychiatry. Women and white patients were overrepresented compared with psychiatric epidemiologic data in all three countries. The effect of these advertisements on physician perception, diagnosis, and prescribing is unknown but may be substantial. Future advertisements for psychotropic drugs should seek more balanced representations of gender and race. ",0
2734,15060457,Contribution of magnetic resonance cholangiopancreatography to the management of patients with suspected common bile duct stones,"To evaluate the value of magnetic resonance cholangiography (MRC) as a systematic first-line investigation in the management of patients with suspected common bile duct stones. Ninety-nine consecutive patients with clinical suspicion of choledocolithiasis were prospectively explored by MRC. All MRCs were interpreted by two radiologists with knowledge of the patient's clinical condition and laboratory results. In case of discrepancy, a third opinion was obtained to reach consensus. The definitive diagnosis was established on the basis of endoscopic exploration of the common bile duct (n=40), clinical and biological follow-up at 6 Months (n=55) or other investigations (n=4). The clinician's level of confidence, management options implemented, and impact of management decisions were used to assess the contribution of MRC. The diagnostic accuracy of MRC for common bile duct stones was also determined. At the observed level of confidence (85.9%), MRC identified a differential diagnosis in 7.1% of patients avoiding unnecessary endoscopic exploration in 59.6%. Systematic first-line MRC enabled appropriate management in 83.8% of patients. The sensitivity, specificity, and positive and negative predictive values of MRC for the diagnosis of common bile duct stones were 95.7%, 98.7%, 95.7% and 98.7%, respectively, with excellent inter-observer agreement (kappa=0.915). Magnetic resonance cholangiography can be used to efficiently screen patients who may need further invasive exploration of the common bile duct. It specifically identifies patients requiring therapeutic ERCP. ",0
2735,15060478,Comorbidity and socioeconomic deprivation: an observational study of the prevalence of comorbidity in general practice,"Although inequalities in health between the most affluent and most deprived individuals in our communities have been well documented, the underlying causes are still not completely understood. There has been recent interest in the contribution of multiple morbidity as one explanatory factor, although there is little evidence as yet regarding this. The few general practice based studies investigating the presence of comorbidity have highlighted its significance. However the relationship between multiple morbidity and deprivation is still relatively under-researched and under-reported in the literature. As a result, the full extent of comorbidity and its implications remains unknown. Some argue, however, that there is now recognition that comorbidity is the rule rather than the exception and that this ought to influence approaches to quality of care. If this is to take place there is an urgent need for a greater understanding of the nature and impact of comorbidity. ",0
2736,15060524,Venous hypertensive myelopathy as a potential mimic of transverse myelitis,"Case report. We describe a patient who developed a myelopathy associated with a noncompressive herniated cervical intervertebral disc at the same level. We provide clinical and radiological evidence that reveals that even though the disc herniation did not compress the spinal cord, it diminished venous blood flow out of the spinal cord, possibly resulting in a venous hypertensive myelopathy (VHM). Baltimore, MD, USA. A 29-year-old woman developed a cervical radiculopathy, followed by a slowly progressive cervical myelopathy associated with a herniated C5-C6 disc. Magnetic resonance imaging showed a noncompressive disc herniation, a swollen spinal cord with increased T2 signal most prominent at the site of the herniated disc, extending several levels above and below the disc. The patient was diagnosed with acute transverse myelitis (ATM) and was started on IV steroids. However, unlike most cases of transverse myelitis, spinal fluid analysis was noninflammatory. In contrast, several features suggested that the patient instead had VHM. We suggest that the disc herniation resulted in impaired drainage of blood from the spinal cord through compression of the venous plexus near the intervertebral foramen. Although the patient did not recover function following high-dose steroid administration, she recovered completely following C5-C6 discectomy and fusion. To our knowledge, this is the first report of likely VHM in the absence of a spinal arteriovenous malformation. We suggest that some patients diagnosed with ATM in the setting of extrinsic spinal column abnormalities may actually have a noninflammatory myelopathy associated with impaired spinal venous drainage. ",0
2737,15060733,Inhibition of vancomycin-resistant enterococcus by continuous-flow cultures of human stool microflora with and without anaerobic gas supplementation,"A continuous-flow competitive exclusion (CFCE) culture model of human stool microflora was used to examine whether supplemental anaerobic gas is necessary for maintenance of anaerobes and inhibition of vancomycin-resistant Enterococcus (VRE). CFCE cultures of human stool microflora were maintained with supplemental nitrogen, without supplemental nitrogen, or with percolated room air. Cultures with or without supplemental nitrogen maintained >9 log(10) CFU mL(-1) of obligate anaerobes and eliminated 10(6) CFU mL(-1) of VRE. When room air was percolated into the culture, anaerobes were detected at < or =2 log(10) CFU mL(-1), and the same VRE inoculum was not eliminated ( P < 0.001). These data demonstrate that human stool CFCE cultures maintain high levels of obligate anaerobes and inhibit VRE without the addition of supplemental anaerobic gas. ",0
2738,15061767,From immune system to health systems--challenges for health research,"There are many similarities between the immune system and health systems. Both are knowledge-based learning systems with an ultimate common objective of maintaining the health of individuals and populations, respectively. The immune system learns from the environment, and knowledge and discovery are key drivers of health systems improvement and improving health status. But discovery goes well beyond immunology, virology and genomics, for example, in the quest to develop new drugs, vaccines and diagnostic tests. New ways must also be discovered to make sure that these products reach the people who need it most. We must discover ways for knowledge to be turned into effective policies, to inform the practice of healthcare and to inform the public and society at large. Only if discovery is seen in its broadest perspective will we be able to reach the goal of health for all. ",0
2739,15061856,Assessing the impact of oral health on the life quality of children: implications for research and practice,"Traditionally, child oral health has been assessed using clinical parameters of disease and deformity. However, there is a growing interest in the psychosocial impact of oral health among children. This commentary outlines the value and need for assessing child oral health-related quality of life (COHQoL). COHQoL has implications for oral health needs assessment (at an individual and population level) and for evaluating outcomes from specific treatments, initiatives and dental services overall. In addition, it could prove to be a useful adjunct tool for evidence-based dentistry research and practice. Theoretical and practical considerations in assessing the complex psychosocial construct of oral health among children are discussed: the use of general versus oral health-specific measures, the development of tools for children, the use of generic versus condition-specific measures, and the measurement of 'positive' oral health. Recommendations for research and practice are presented. ",0
2740,15062604,Pulmonary hypertension as a result of drug therapy,"Pulmonary hypertension, as a result of adverse drug reactions, must be considered as a rare occurrence. With good medicinal chemistry and screening of compounds before entry into man, it should be almost totally avoidable. Life and medicine are a continuing challenge as our exploration of the regions of unknown biology throw up new targets and new mechanisms and may catch us again as the anorectic (anorectic) drug caught our predecessors. ",0
2741,15062608,Pulmonary complications of radiation therapy,"There have been important developments in understanding the difference in pathogenesis and clinical significance between acute or sporadic pneumonitis and late radiation fibrosis. Corticosteroid therapy and other forms of therapy are useful in the treatment of acute pneumonitis. Late radiation fibrosis is refractory to treatment; therefore, minimizing the likelihood of developing it is particularly important. Baseline lung assessments are appropriate in patients who are clinically at risk. A new development is the use of the DVH to compare radiation treatment plans to minimize the volume of normal lung irradiated in patients who are at risk. It is hoped that the study of mechanisms that lead to the development of radiation fibrosis will point the way to possible future therapies. Patients who are included in studies of novel irradiation treatments for lung cancer need, in particular, to be monitored for late radiation lung toxicity. ",0
2742,15062856,"Cartilage link protein interacts with neurocan, which shows hyaluronan binding characteristics different from CD44 and TSG-6","The interaction of neurocan with hyaluronan was qualitatively characterized with alkaline phosphatase fusion proteins secreted by mammalian cells. The wild type neurocan hyaluronan binding domain fused to alkaline phosphatase bound to immobilized hyaluronan under physiological as well as moderately hypertonic conditions, whereas its ability to bind to immobilized chondroitin sulfate dropped rapidly with increasing salt concentration. Strong hyaluronan binding ability was still evident when in both link modules within the hyaluronan binding domain a basic amino acid was mutated, which is well conserved among link modules of hyaluronan binding proteins. A strong enhancement of the binding of neurocan to immobilized hyaluronan was observed after preincubation of the immobilized hyaluronan with cartilage link protein. Moreover, this preincubation mediated also the binding of a fusion protein representing only the immunoglobulin module of neurocan linked to alkaline phosphatase, which showed no binding to immobilized hyaluronan alone. The interaction of the neurocan immunoglobulin module with link protein could also be shown by overlay blot analysis. These observations suggest that the hyaluronan binding characteristics of paired link modules are different from those of single link modules, and that the reported temporal co-expression of cartilage link protein and of neurocan in developing brain implicates the possibility of a cooperative function of these molecules. ",0
2743,15062988,Distinct glutamate receptors govern differential levels of nitric oxide production in a layer-specific manner in the rat cerebellar cortex,"To evaluate roles of nitric oxide (NO) in neural functions, it is critical to know how neural inputs activate neuronal NO synthase in individual sites. Although NMDA receptor-dependent mechanism well explains postsynaptic, robust NO production, this sole mechanism does not explain some aspects of NO production in the brain, such as the low-level production of NO and the mechanism for presynaptic NO production. We hypothesized that the glutamate receptor involved in NO production is site-specific and controls the initial NO concentration in each site. We visualized NO production mediated by NMDA, AMPA and type-1 metabotropic glutamate (mGlu-1) receptors in rat cerebellar slices and granule cells in culture, with an NO-specific fluorescent indicator, diaminofluorescein-2. AMPA receptor, but not NMDA or mGlu-1 receptor, was responsible for NO production at parallel fiber terminals, which was blocked by CNQX, tetrodotoxin or voltage-dependent calcium channel blockers. More numbers of electrical stimulation were required for NO production in the molecular layer than in other layers, suggesting that AMPA receptor activation generates NO at lower concentrations through a remote interaction with NO synthase. Although Purkinje cell does not express NO synthase, we detected NO production in Purkinje cell layer following electrical stimulation in the white matter at 50 Hz, but not at 10 Hz. This NO production was tetrodotoxin-sensitive, suggesting occurrence in the basket cell terminals, and required synergistic activation of mGlu-1 and NMDA receptors. In the granule cell layer, activation of AMPA or mGlu-1 receptor produced NO uniformly, while NMDA receptor activation produced NO in discontinuous areas of this layer. Thus, distinct glutamate receptors, including non-NMDA receptors, govern occurrence and level of NO production in a layer-specific manner. ",0
2744,15063590,Intestinal epithelial tight junctions as targets for enteric bacteria-derived toxins,"The application of a multidisciplinary approach to study bacterial pathogenesis, along with the recent sequencing of entire microbial genomes have made possible discoveries that are changing the way scientists view the bacterium-host interaction. Today, research on the molecular basis of the pathogenesis of infectious diarrheal diseases of necessity transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. Novel multidisciplinary approaches led to the discovery of new bacteria-host cell interactions involving signals regulating intestinal permeability through the modulation of cell cytoskeleton and intercellular tight junctions (TJ). A century ago, TJ were conceptualized as a secreted extracellular cement forming an absolute and unregulated barrier within the paracellular space. Biological studies of the past several decades have shown that TJ are dynamic structures subjected to structural changes that dictate their functional status under a variety of developmental, physiological, and pathological circumstances. To meet the many diverse physiological challenges to which the intestinal epithelial barrier is subjected, TJ must be capable of rapid and coordinated responses. This requires the presence of a complex regulatory system that orchestrates the state of assembly of the TJ multiprotein network. Many pathogenic bacteria exploit this system to accomplish their pathogenic strategies by ultimately modulating intestinal permeability. ",0
2745,15063810,Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors,"Our previously synthesized 37 compounds, which are 2,5,6-substituted benzoxazole, benzimidazole, benzothiazole, and oxazolo(4,5-b)pyridine derivatives, were tested for their eukaryotic DNA topoisomerase II inhibitory activity in cell free system and 28 were found to inhibit the topoisomerase II at an initial concentration of 100 microg/ml. After further testing at a lower range of concentrations, 12 derivatives, which were considered as positive topoisomerase inhibitors, exhibited IC50 values between 11.4 and 46.8 microM. Etoposide was used as the standard reference drug to compare the inhibitor activity. Among these compounds, 2-phenoxymethylbenzothiazole (3f), 6-nitro-2-(2-methoxyphenyl)benzoxazole (1a), 5-methylcarboxylate-2-phenylthiomethylbenzimidazole (3c), and 6-methyl-2-(2-nitrophenyl)benzoxazole (1c) were found to be more active than the reference drug etoposide. Present results point out that, besides the very well-known bi- and ter-benzimidazoles, compounds with single bicycle fused ring systems in their structure such as benzimidazole, benzoxazole, benzothiazole, and/or oxazolopyridine derivatives also exhibit significant topoisomerase II inhibitory activity. ",0
2746,15064542,Common perilla (Perilla frutescens (L.) Britton.) as a perspective immunomodulator],"Common perilla (Perilla frutescens (L.) Britton) is a new perspective annual medicinal dead-nettle family (Lamiaceae Lindl.) plant in Lithuania. Its medicinal raw material and preparations produced of it are characterised by the variety of pharmacological effects: desensitizing, antimicrobial, anti tumorous, and antioxidative. This species was introduced from the East Asia and cultivated in many European, Asian, and North American countries. The common perilla has been cultivated in Lithuania as a decorative plant in parks and squares since 1990. This plant has been introduced in the collection and exposition of medicinal plants in Kaunas Botanical Garden of Vytautas Magnus University since 1998 with the purpose to analyze biological and pharmacological properties of plants and to assess the quality and quantity of the raw herb. It would be reasonable to carry out experimental research on biological qualities and raw material of the common perilla in Lithuania in accordance with the contemporary technologies and requirements of the European Union standards. ",0
2747,15065412,Preliminary study on research method of cell survival rate at procedure of cryopreservation of tissue engineered tendons],"To study the research method of cell survival rate at the procedure of cryopreservation of tissue engineered tendons. In the 4th generation of human fibroblasts, the dead cells were stained with propidium iodine (PI), while the living cells with Hoechst 33342 (Ho). The living cells and dead cells emitted fluorescence of red and blue respectively after they were stimulated by suitable ultra-violet, then flow cytometry was applied to distinguish them. The seeding cells were collected to make them to be the cell suspension of suitable concentration (6.0 x 10(5) cell/ml) before they were divided into two parts. We cryopreserved and defrosted one part three times to kill the cells and did not cryopreserve the other part, then we made cell suspension at different ratios of cryopreserved cell to non-cryopreserved cells. The fluorescence staining and flow cytometry were used to study the correlation between cell ratios of cryopreserved cell to non-cryopreserved cell and the cell survival rates. We compared the cell survival rates between immediate flow cytometry and that 2 hours after fluorescence staining. The results of flow cytometry showed that correlation between the ratio of cryopreservation and the cell survival rate was significant (r = 0.970, P < 0.05), image analysis study also showed the correlation was significant (r = 0.982, P < 0.05). The cell survival rate decreased by use of flow cytometry two hours after fluorescence staining, but there was no significant difference when compared with that of immediate flow cytometry (P > 0.05). We could also observe the cells on the tissue engineered tendons by fluorescence image directly. Flow cytometry and fluorescence image after PI and Ho staining is a good way in study cell survival rate at the procedure of cryopreservation of tissue engineered tendons. ",0
2748,15065421,Analysis of curative result for keloid with integrated methods],"To study the curative effects of keloid by operation combined with postoperative beta radiation and silicone gel sheeting. From 1996 to 2002, 598 patients with keloid (243 males, 355 females, aging 15-55 years with an average of 28.6 years) were treated by integrated therapy. Their disease courses were from 6 months to 6 years. The keloid area ranged from 1.0 cm x 1.5 cm-8.0 cm x 15 cm. First, keloid was removed by operation, and then the wounds were sutured directly (group suture) or covered with skin graft (group graft). In group suture, the operational sites were managed by beta ray radiotherapy 24-48 hours after operation. The total doses of radiation were 12-15 Gy, 5 times 1 week (group suture A) and 10 times 2 weeks (group suture B). Radiotherapy was not taken until stitches were taken out in group graft, and then the same methods were adopted as group suture B. After radiotherapy, silicone gel sheeting was used in 325 cases for 3-6 months. All patients were followed up for 12-18 months. (1) The overall efficacy was 91.3% in group suture A (n = 196), and 95.8% in group suture B (n = 383), respectively. There was significant difference between the two groups (P < 0.01). (2) Radiotherapy was of no effect in 6 cases of group graft (n = 19). (3) Silicone gel sheeting had effectiveness in 185 cases. Silicone gel sheeting had no obvious effect on the overall efficacy, but it could improve the quality of texture and color of skin. By use of integrated methods to treat keloid, if the wound can be sutured directly, skin grafting should not be adopted. The results in group suture B are better than those in group suture A; silicone gel sheeting should be used as possible. ",0
2749,15065807,Capillary electrophoresis in the determination of anionic catecholamine metabolites from patients' urine,"A micellar electrokinetic capillary chromatographic method for determining anionic catecholamine metabolites from patient urine samples was established. The optimum electrolyte solution (pH 10.6) was made of tetraborate and sodium dodecyl sulphate into water. Furthermore, studies were focused to optimize solid-phase extraction clean-up steps to concentrate patient urine samples for identification of catecholamines with UV detection. The water-micelle distribution coefficients (octanol-water partition coefficient, log Pow) for the analytes were determined by conductometric titration. High plate numbers (120,000-200,000/40 cm detection window) and small diffusion coefficients (2.00-3.50 x 10(-6) cm(-2) s(-1)) resulted in high resolution and symmetry of the analyte zones. The standard deviations of the migration times and the peak heights were less than 3 and 7%, respectively. The octanol-water coefficients increased in the order of decreased pKa1 value of the analytes, why separation between structurally related vanillinic mandelic acids could be obtained. Limits of detection and quantification were around 0.05 and 0.1 microg/ml, respectively, except for dopamine. The concentrations of the catecholamine metabolites in the studied patient urines varied from 0.186 to 76.4 microg/ml. The results showed evidences of serious diseases among the patients. ",0
2750,15065839,Prediction equations for normal and low lung function from the Health Survey for England,"""The aim of this study was to derive new spirometric reference equations for the English population, using the 1995/1996 Health Survey for England, a large nationally representative cross-sectional study. The measurements used were the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) of a sample of 6,053 """"healthy"""" (nonsmokers with no reported diagnosis of asthma or respiratory symptoms) White people aged > or = 16 yrs. Multiple regression analysis, with age and height as predictors, was carried out to estimate prediction equations for mean FEV1, FVC and FEV1/FVC, separately for males and females. A method based on smoothing multiple estimates of the fifth percentiles of residuals was used to derive prediction equations for the lower limit of normal lung function. The new equations fit the current English adult population considerably better than the European Coal and Steel Community equations, and the proportions of people with """"low"""" (below the fifth percentile) lung function are closer to those expected throughout the whole adult age range (16 to > 75 yrs). For the age ranges the studies share in common, the new equations give estimates close to those derived from other nonlinear equations in recent studies. It is, therefore, suggested that these newly developed prediction equations be used for the White English population in both epidemiological studies and clinical practice. """,0
2751,15065895,Computational model to evaluate port wine stain depth profiling using pulsed photothermal radiometry,"We report on development of an optical-thermal model to evaluate the use of pulsed photothermal radiometry (PPTR) for depth profiling of port wine stain (PWS) skin. In the model, digitized histology sections of a PWS biopsy were used as the input skin geometry. Laser induced temperature profiles were reconstructed from simulated PPTR signals by applying an iterative, non-negatively constrained conjugate gradient algorithm. Accuracy of the following PWS skin characteristics extracted from the reconstructed profiles was determined: (1) average epidermal thickness (z(epi)), (2) maximum epidermal temperature rise (DeltaT(epi,max)), (3) depth of PWS upper boundary (z(PWS)), and (4) depth of maximum PWS temperature rise (z(PWS,max)). Comparison of the actual and reconstructed profiles from PPTR data revealed a good match for all four PWS skin characteristics. Results of this study indicate that PPTR is a viable approach for depth profiling of PWS skin. ",0
2752,15066291,Comparative study of permanent interstitial prostate brachytherapy post-implant evaluation among seven Italian institutes,"The purposes of this multicentric study are (a) the evaluation of four different commercially available treatment planning systems (TPSs) and (b) to verify whether the dosimetric results are comparable, also when considering the inter-observer variabilities and the different scanning protocols used. This work is to be considered a first step to test the value of multicentric studies based on dosimetric evaluation of the quality of the implants. Four different TPSs were used and the following tests were performed:Comparison of the parameters and mathematical algorithms used; comparison of the dose distributions generated by three different geometries of sources based on 32 dose-points on each source geometry. An octagonal geometric phantom was used to compare volume algorithms and dose-volume histogram (DVH) calculations (V150(Gy), V100(Gy), V50(Gy) and V25(Gy)). Comparison of the post-plan source distribution performed on a prostate-phantom implanted with (125)I seeds. A CT scan of the phantom was obtained at each participating center. Both the geometrical coordinates (with respect to the most caudal one), and the spread of the geometrical distribution, were calculated. The volumes included within different isodoses were also collected. Comparison of the post-plan source distribution performed on an actual patient. Post-plan V100% and D90(Gy) derived from seed distributions obtained by different operators were calculated, using the same target delineation. All the considered TPSs satisfied the AAPM dosimetric parameter recommendations. Point-dose examinations revealed differences smaller than 5%, except for one of the systems. Although the volume algorithm was not the same for all systems, no statistically significant difference was found in the volume measurements. The DVHs also presented differences smaller than 5%, except for one TPS. The distances between the seeds, based on the same CT images, showed a mean SD of 0.13 mm. The mean maximum difference of the position of each seed was 0.36 mm. The most significant errors were made in the cranio-caudal direction (mean maximal difference: 0.44 mm); here the size of the step between slices played an important role. The algorithm of source positioning of the different TPSs may also help explain this difference. The compiled DVHs showed differences smaller than 5%. Post-plans derived from different seed distributions showed a mild dependence upon operators. We obtained a mean value of 97.8 and 152.7 with a percentage of SD of 0.43 and 1.7, respectively, for V100% and D90(Gy). Three-dimensional (3D) geometric reconstructions of seed distributions are slightly dependent upon the operators and the scanning protocols have little effect on the dosimetric evaluation. Some relevant discrepancies were found between one of the TPSs and the other three if few sources were used; increasing the number of seeds those differences became less pronounced. Multicentric studies on the quality of prostate implants based on post-implant dosimetry are feasible, provided an accurate step-wise evaluation of the procedure be performed. ",0
2753,15067170,A web-based federated neuroinformatics model for surgical planning and clinical research applications in epilepsy,"There is an increasing need to efficiently share diverse clinical and image data among different clinics, labs, and departments of a medical center enterprise to facilitate better quality care and more effective clinical research. In this paper, we describe a web-based, federated information model as a viable technical solution with applications in medical refractory epilepsy and other neurological disorders. We describe four such online applications developed in a federated system prototype: surgical planning, image analysis, statistical data analysis, and dynamic extraction, transforming, and loading (ETL) of data from a heterogeneous collection of data sources into an epilepsy multimedia data warehouse (EMDW). The federated information system adopts a three-tiered architecture, consisting of a user-interface layer, an application logic layer, and a data service layer. We implemented two complementary federated information technologies, i.e., XML (eXtensible Markup Language) and CORBA (Common Object Request Broker Architecture), in the prototype to enable multimedia data exchange and brain images transmission. The preliminary results show that the federated prototype system provides a uniform interface, heterogeneous information integration and efficient data sharing for users in our institution who are concerned with the care of patients with epilepsy and who pursue research in this area. ",0
2754,15067329,cDNA microarray analysis with amplified RNA after isolation of intact cellular RNA from neoplastic and non-neoplastic prostate tissue separated by laser microdissections,"Laser microdissection is a valuable tool to prepare pure cell populations from complex tissues for further analyses. Gene expression studies by real-time RT-PCR and cDNA arrays of microdissected tissues are becoming widely used methods. The integrity and quantity of prepared RNA must be proven to ensure reliable results in subsequent applications such as quantitative RT-PCR and cDNA-arrays. In the present study we used RNAlater trade mark protected prostate tissue for laser microdissection of tumor and tumor-free tissues. RNA quality and quantity was assessed using automated capillary gel electrophoresis. By using quantitative real time-RT-PCR before and after mRNA amplification the insulin-like growth factor binding protein-3 (IGFBP-3) gene expression was shown to be down-regulated in three out of five cases and DD3 was up-regulated in cancer tissues in all cases. The up-regulation of DD3 and the down-regulation of IGFBP-3 gene expression in cancer tissue were conserved after RNA amplification. A cDNA microarray also revealed an IGFBP-3 down-regulation in cancer tissue as well as several genes known to be differerentially expressed in prostate cancer. Taken together, we present a novel method for the isolation of intact RNA from laser microdissection-derived prostate cancer tissue useful for downstream applications of real-time RT-PCR and cDNA microarrays. ",0
2755,15067384,Construction of a comparative RFLP map of Echinochloa crus-galli toward QTL analysis of flooding tolerance,"To analyze quantitative trait loci (QTLs) affecting flooding tolerance and other physiological and morphological traits in Echinochloa crus-galli, a restriction fragment length polymorphism (RFLP) map was constructed using 55 plants of the F(2) population ( E. crus-galli var. praticola x E. crus-galli var. formosensis). One hundred forty-one loci formed 41 linkage groups. The total map size was 1,468 cM and the average size of linkage groups was 35.8 cM. The average distance between markers was 14.7 cM and the range was 0-37.2 cM. Early comparisons to the genetic maps of other taxa suggest appreciable synteny with buffelgrass ( Pennisetum spp.) and sorghum ( Sorghum spp.). One hundred ninty-one F(2) plants were used to analyze QTLs of flooding tolerance, plant morphology, heading date, number of leaves, and plant height. For flooding tolerance, two QTLs were detected and one was mapped on linkage group 24. Other traits, including plant morphology, heading date, number of leaves, and plant height were highly correlated. Three genomic regions accounted for most of the mapped QTLs, each explaining 2-4 of the significant marker-trait associations. The high observed correlation between the traits appears to result from QTLs with a large contribution to the phenotypic variance at the same or nearby locations. ",0
2756,15067577,"Interrelations between p73 and p53: a model, neuroblastoma]","Homologies in sequence and gene organization of p53 and their relatives, p73 and p63, suggest similar biological functions. However differences exist between the p53 family members. Indeed in human tumors p53 is often mutated while p63 and p73 are very rarely mutated. In addition, in contrast to p53 which is transcribed in a unique mRNA species spanning all gene exons, each homologue expresses two types of isoforms: some with transactivation domain (TAD) showing tumor suppressive properties, the others deprived of TAD, with oncogenic properties. If p53 responds to immediate genotoxic stress, its homologues participate to the cell homeostasis of specific tissues along their development and differentiation, neuronal tissue for p73, epithelial for p63. However a collaboration between the three p53 family members has been shown to occur in response to cell genotoxic damages. Neuroblastic tumors characterized by a large spectrum of neuronal differentiation constitute a good model to study relationship between p73 and p53 as well as the regulation of their respective expression. ",0
2757,15067896,Obstetrical complications and further schizophrenia of the infant: a new medicolegal threat to the obstetrician?],"Schizophrenia is a multifactorial disease with complex interactions between a genetic liability, possible perinatal complications and exposure to later environmental risk factors in childhood. Maternal influenza infection, wartime-famine-related denutrition and maternal depression or exposure to repeated stress in pregnancy may have a deleterious effect on brain development and neuronal migration. Obstetrical complications which are significantly associated with schizophrenia are bleeding, diabetes, prematurity, fetal growth retardation, Rhesus incompatibility, preeclampsia and congenital malformations. Subjects with onset of schizophrenia before age 22 had more often a history of acute fetal distress (abnormal presentation at birth and complicated cesarean delivery). Obstetrical complications may have a direct negative impact on fetal brain development or may be on the causal pathway between prepartum maternal depression or psychosis, exposure to stress and impaired relation between mother and child consecutive to postnatal depression. ",0
2758,15068062,Functional expression of bcl-2 protein family and AIF in bovine mammary tissue in early lactation,"Cell proliferation and apoptosis were measured in bovine mammary tissue around the time of peak milk production in three heifers, and compared with changes in the expression of bcl-2-related intracellular signals and apoptosis-inducing factor (AIF). Cell proliferation and apoptosis were relatively constant during the study period with no significant change in the incidence of either event. However, the ratio of apoptotic to proliferating cells tended to change from 0.99 on day 45 of lactation to 1.82 on day 63 (P=0.064), suggesting that in the course of the study, a dynamic balance may have been succeeded by net cell loss. Average milk production recorded 6 d after biopsy was correlated with the estimated number of cells (r=0.898; P<0.01) but not with the apoptosis to proliferation ratio (r=-0.224, P>0.05). Turnover of the cell population was associated with relatively constant expression of anti-apoptotic bcl-2. Competitive PCR also indicated expression of bax, in contrast to observations in lactating rodent mammary tissue. Bax expression was relatively low compared with that of bcl-2, but immunohistochemical staining for bax protein, which was not detectable on day 45, was observed on day 53 and, more intensely, on day 60 when the protein appeared to be membrane-associated. A partial coding sequence for bovine AIF was identified and AIF expression was evaluated by in situ hybridization. The results indicated that AIF was expressed in luminal alveolar cells and that, in concert with a change in bax to bcl-2 ratio, they might contribute to signalling of a change in the dynamic balance of the cell population as lactation progresses. ",0
2759,15068119,Lysophosphatidic acid modulates the regenerative responses of human gingival fibroblasts and enhances the actions of platelet-derived growth factor,"Platelet-derived growth factor (PDGF) has been used to promote healing in many in vitro and in vivo models of periodontal regeneration. PDGF is known to interact extensively with another platelet mediator, lysophosphatidic acid (LPA), to enhance regenerative responses in non-oral systems. PDGF and LPA are both liberated by platelets in the blood clot, which is known to be critical in stabilizing early periodontal wound healing. The purpose of this study was to evaluate the basic interactions of LPA with primary human gingival fibroblasts (GF) alone and with PDGF-BB for promoting GF growth and migration, as well as their effects in an in vitro oral wound-healing model. GF regenerative responses were measured using 1 and 10 microM LPA in the absence or presence of 1 or 10 ng/ml PDGF-BB. Cell growth was determined using [3H]thymidine incorporation and cell counting. Migration responses were measured using a microchemotaxis chamber. For the in vitro wound-healing experiments, GF were grown to confluence on glass slides, and a 3 mm wide wound was mechanically inflicted. Percent wound fill on days 4, 6, and 9 was analyzed using computer-assisted histomorphometry. GF exhibited proliferative and chemotactic responses to LPA. These responses were synergistic when LPA and PDGF-BB were present together. LPA on its own did not stimulate statistically significant wound fill, but when combined with PDGF-BB, wound fill was equivalent to the 10% serum positive control group by day 6 (5.5-fold of negative control, [P<0.001]) and again on day 9 (6-fold of negative control, [P<0.001]). These studies provide the first evidence that LPA stimulates human GF regenerative responses and that it interacts positively with PDGF-BB to regulate these actions. The results suggest that LPA needs to be further investigated in the oral system as a factor that should be considered for incorporation when designing new periodontal wound-healing therapies using PDGF. ",0
2760,15068273,Actin and ubiquitin protein sequences support a cercozoan/foraminiferan ancestry for the plasmodiophorid plant pathogens,"The plasmodiophorids are a group of eukaryotic intracellular parasites that cause disease in a variety of economically significant crops. Plasmodiophorids have traditionally been considered fungi but have more recently been suggested to be members of the Cercozoa, a morphologically diverse group of amoeboid, flagellate, and amoeboflagellate protists. The recognition that Cercozoa constitute a monophyletic lineage has come from phylogenetic analyses of small subunit ribosomal RNA genes. Protein sequence data have suggested that the closest relatives of Cercozoa are the Foraminifera. To further test a cercozoan origin for the plasmodiophorids, we isolated actin genes from Plasmodiophora brassicae, Sorosphaera veronicae, and Spongospora subterranea, and polyubiquitin gene fragments from P. brassicae and S. subterranea. We also isolated actin genes from the chlorarachniophyte Lotharella globosa. In protein phylogenies of actin, the plasmodiophorid sequences consistently branch with Cercozoa and Foraminifera, and weakly branch as the sister group to the foraminiferans. The plasmodiophorid polyubiquitin sequences contain a single amino acid residue insertion at the functionally important processing point between ubiquitin monomers, the same place in which an otherwise unique insertion exists in the cercozoan and foraminiferan proteins. Taken together, these results indicate that plasmodiophorids are indeed related to Cercozoa and Foraminifera, although the relationships amongst these groups remain unresolved. ",0
2761,15068289,Binding interaction of gatifloxacin with bovine serum albumin,"The binding of gatifloxacin to bovine serum albumin (BSA) in aqueous solution was studied using fluorescence spectroscopy and absorbance spectra, Further, the interactions influenced by Fe3+ and Cu2+ were also explored in this work. Based on Scatchard's site-binding model and florescence quenching, practical formulas for small molecule ligands to bio-macromolecules have been proposed. The binding parameters were measured according to suggested models, and the binding distance and the transfer efficiency of energy between gatifloxacin and BSA were also obtained in view of the Förster theory of non-radiation energy transfer. The effect of gatifloxacin on the conformation of BSA has also been analyzed using synchronous fluorescence spectroscopy. ",0
2762,15068333,National Hospital Ambulatory Medical Care Survey: 2002 emergency department summary,"This report describes ambulatory care visits to hospital emergency departments (EDs) in the United States. Statistics are presented on selected hospital, patient, and visit characteristics. Selected trends in ED utilization from 1992 through 2002 are also presented. The data presented in this report were collected from the 2002 National Hospital Ambulatory Medical Care Survey (NHAMCS). NHAMCS is part of the ambulatory care component of the National Health Care Survey that measures health care utilization across various types of providers. NHAMCS is a national probability sample survey of visits to emergency and outpatient departments of non-Federal, short-stay, and general hospitals in the United States. Sample data are weighted to produce annual national estimates. During 2002, an estimated 110.2 million visits were made to hospital EDs, about 38.9 visits per 100 persons. From 1992 through 2002, an increasing trend in the ED utilization rate was observed for persons over 44 years of age. In 2002, abdominal pain, chest pain, fever, and cough were the leading patient complaints accounting for nearly one-fifth of all visits. Acute upper respiratory infection was the leading illness-related diagnosis at ED visits. From 1992 through 2002, decreases in ED visit rates were observed for intracranial injuries in children, and increases were found for depression in young adults and arthropathies among middle-aged and elderly patients. There were an estimated 39.2 million injury-related visits during 2002, or 13.8 visits per 100 persons. Diagnostic/screening services, procedures, and medications were provided at 86.8 percent, 43.2 percent, and 75.8 percent of visits, respectively. In 2002, approximately 12 percent of ED visits resulted in hospital admission. On average, patients spent 3.2 hours in the ED. ",0
2763,15068661,Are there sex differences in emotional and biological responses in spousal caregivers of patients with Alzheimer's disease?,"The purpose of this study was to compare emotional and biological responses of men and women who are spousal caregivers of patients with Alzheimer's disease (AD). Quality-of-life measurements, bioinstrumentation data, and immunophenotype assessments were obtained from female and male spousal caregivers of patients with AD. Spousal caregivers (women, n = 45 with average age 69.7; men, n = 16 with average age 71.4 years) completed questionnaires that assessed psychosocial variables. Blood was drawn and lymphocyte subsets (including natural killer [NK] cell number) were determined using flow cytometry. The degree of relaxation was determined measuring muscle tension (EMG) in the frontalis and trapezius muscles, skin conductance, skin temperature, and heart rate. Male spousal caregivers, as compared to female spousal caregivers, had significantly lower levels of stress, depression, caregiver burden (subjective), anxiety, anger-hostility, and somatic symptoms and higher levels of mental health, sense of coherence, NK cell number, and social and physical functioning. There were no statistically significant differences between the 2 groups in social support, coping resources, or T, T suppressor, or activated T cells. Women had more T helper cells and fewer NK cells than men. Men had fewer manifestations of a physiological stress response, as indicated by bioinstrumentation parameters. Unique sex-specific issues need to be considered when strategies are implemented to assist the increasing number of caregivers as our society ages. ",0
2764,15068888,Sample size calculations for Bayesian prediction of bovine viral-diarrhoea-virus infection in beef herds,"We used a Bayesian classification approach to predict the bovine viral-diarrhoea-virus infection status of a herd when the prevalence of persistently infected animals in such herds is very small (e.g. <1%). An example of the approach is presented using data on beef herds in Wyoming, USA. The approach uses past covariate information (serum-neutralization titres collected on animals in 16 herds) within a predictive model for classification of a future observable herd. Simulations to estimate misclassification probabilities for different misclassification costs and prevalences of infected herds can be used as a guide to the sample size needed for classification of a future herd. ",0
2765,15068986,Screening for coronary heart disease: recommendation statement,"This statement summarizes the current U.S. Preventive Services Task Force (USPSTF) recommendations on screening for coronary heart disease and the supporting scientific evidence and updates the 1996 recommendations on this topic. The complete information on which this statement is based, including evidence tables and references, is available in the background article and the systematic evidence review, available through the USPSTF Web site (http://www.preventiveservices.ahrq.gov) and through the National Guideline Clearinghouse (http://www.guideline.gov). The article and the recommendation statement are also available in print through the Agency for Healthcare Research and Quality Publications Clearinghouse (telephone, 800-358-9295; e-mail, ahrqpubs@ahrq.gov). ",0
2766,15069221,Re-thinking accountability: trust versus confidence in medical practice,"In seeking to prevent a reoccurrence of scandals such as that involving cardiac surgery in Bristol, the UK government has adopted a model of regulation that uses rules and surveillance as a way of both improving the quality of care delivered and increasing confidence in healthcare institutions. However, this approach may actually act to reduce confidence and trust while also reducing the moral motivation of practitioners. Accountability in health care is discussed, and it is suggested that openness about the difficult dilemmas that arise when practitioners have a duty to be accountable to more than one audience may be an alternative means of restoring trust. A greater emphasis on the sharing of information between individual health professionals and their patients would increase trust and would allow patients to hold their doctors to account for the quality of care they receive. Concentrating more on developing trust by the sharing of information and less on the futile search for complete confidence in systems and rules may improve the quality of care delivered while also nurturing the moral motivation of professionals upon which the delivery of high quality health care depends. ",0
2767,15069237,Molecular diagnosis and genetic counseling for fragile X mental retardation,"The fragile X syndrome is the most frequent cause of inherited mental retardation. It is caused by a dynamic mutation: the progressive expansion of polymorphic (CGG)n trinucleotide repeats located in the promoter region of the FMRI gene at Xq27.3. The cloning of the FMRI gene and the elucidation of the molecular basis of the fragile X syndrome is of great importance for the diagnosis and understanding of this unusual type of mutation. Although extensively studied, the mechanism behind the transition from stable normal (CGG)n alleles to the carrier state (an unstable premutation) and from premutation to mutation is partially understood. The clinical diagnosis of fragile X mental retardation (FXMR) is not possible as dysmorphic features are subtle. Molecular diagnosis by Southern Blot is the confirmatory test that makes carrier detection and prenatal diagnosis possible. As the risk of recurrence of FXMR is high in the family and carrier relatives, an identification of fragile X positive children, and offering carrier detection and prenatal diagnosis to the families is very important. It is possible by screening mentally retarded children and adults even if there is no family history of mental retardation or typical behavioral or physical features associated with the fragile X phenotype. In this review we have discussed the method for the diagnosis and counseling of the families. The complexities due to premutation and the variable severity of manifestations in carrier females need to be understood while counseling fragile X families. ",0
2768,15069242,Cerebral perfusion pressure management of severe diffuse head injury: effect on brain compliance and intracranial pressure,"Cerebral perfusion pressure management (CPPM) is an accepted modality of treatment of severe diffuse head injury (SDHI). However, CPPM has the potential to cause transcapillary exudation in the presence of a disrupted blood brain barrier and can lead to further increase of intracranial pressure (ICP) and worsening of compliance. This study attempts to evaluate the effect of both transient and prolonged changes in cerebral perfusion pressure (CPP) on ICP and cerebral compliance as measured by the Pressure Volume Index (PVI), and to correlate changes in PVI with outcome at 12 months using the Glasgow Outcome Score. Prospective study in a neurosurgical ICU. Twenty-seven SDHI patients managed using standard protocol to maintain CPP above 70 mmHg. Mean arterial pressure (MAP), ICP and CPP were monitored every half-hour. Daily monitoring of the PVI and ICP was done before, and after the induced elevation of MAP using IV Dopamine infusion. The relationship between CPP, MAP, ICP, PVI and outcome was evaluated. The paired and independent samples T-test, and the Pearson correlation coefficient. CPPM rarely leads to progressive rise in ICP. Maintaining CPP above 70mmHg does not influence ICP or PVI. Transient elevations in CPP above 70mmHg may produce a small rise in ICP. Trend of change in PVI influenced outcome despite similar ICP and CPP. Elevating the CPP above 70mmHg does not either reduce the ICP or worsen the compliance. Monitoring changes in compliance should form an integral part of CPPM. ",0
2769,15069319,Head and neck tumors other than squamous cell carcinoma,"This review deals with classification and treatment of some rare nonsquamous cell carcinomas of the head and neck. Paranasal sinus tumor classification is under evaluation. Contrary to the past, the recent tendency is to build stage classifications on prognostic factors that mainly reflect limitations for adequate surgery, and not simply on dimensional criteria, which are more frequently used in TNM. Among sinonasal tract tumors new pathologic entities have been described. So far, little is known about their natural history and about the need to use pathologic classification to differentiate treatment. Recent advances in radiotherapeutic techniques, such as intensity-modulated radiotherapy, will probably have an impact on future treatment of paranasal sinus tumors. Several molecular targets (c-kit, HER-2/neu, androgen receptors) have been identified in salivary gland cancer. It is interesting to note that among different histotypes there is a trend toward a consistent expression of specific markers in specific cancers, suggesting a possible implication of them in the disease histogenesis. Not surprisingly these findings prompted clinical research with molecular targeted drugs. Nonsquamous cell carcinomas of the head and neck are rare neoplasms. A multidisciplinary team treatment plan is needed, in particular for skull base-located tumors. Salivary gland cancer displays several molecular targets that need to be investigated further. ",0
2770,15069749,Patient care at diagnosis: a planned education approach,The diagnosis of diabetes can have a deep and long-lasting effect on patients' lives. The care and support they receive at this time is of the utmost importance in helping patients to cope with and adjust to their newly diagnosed condition. This article discusses the development of a structured protocol to encompass the emotional and physical care that patients require following a new diagnosis. The protocol will be piloted at the author's primary care trust. ,0
2771,15069910,Physicians' Internet information-seeking behaviors,"Our understanding about the role of the Internet as a resource for physicians has improved in the past several years with reports of patterns for use and measures of impact on medical practice. The purpose of this study was to begin to shape a theory base for more fully describing physicians' information-seeking behaviors as they apply to Internet use and applications for continuing education providers to more effectively support learning. A survey about Internet use and physician information seeking was administered by facsimile transmission to a random sample of 3,347 physicians. Almost all physicians have access to the Internet, and most believe it is important for patient care. The most frequent use is in accessing the latest research on specific topics, new information in a disease area, and information related to a specific patient problem. Critical to seeking clinical information is the credibility of the source, followed by relevance, unlimited access, speed, and ease of use. Electronic media are viewed as increasingly important sources for clinical information, with decreased use of journals and local continuing medical education (CME). Barriers to finding needed information include too much information, lack of specific information, and navigation or searching difficulties. The Internet has become an important force in how physicians deliver care. Understanding more about physician information-seeking needs, behaviors, and uses is critical to CME providers to support a self-directed curriculum for each physician. A shift to increased use of electronic CME options points to new demands for users and providers. Specific information about how physicians create a question and search for resources is an area that requires providers to develop new skills. ",0
2772,15070126,Oligodendroglioma and juvenile pilocytic astrocytoma presenting as synchronous primary brain tumors. Case report with histological and molecular differentiation of the tumors and review of the literature,"Multiple metastatic brain tumors and multifocal primary brain tumors of a single histological type are well described in the literature. The concurrent presence of multiple primary brain tumors with different histological characteristics, however, is very rare. The authors describe the first known case in which an oligodendroglioma and a juvenile pilocytic astrocytoma (JPA) presented as synchronous primary brain tumors in the same patient. This 43-year-old man presented with a 2-month history of progressive headaches, nausea, and vomiting. Magnetic resonance imaging demonstrated an enhancing heterogeneous right medial cerebellar lesion and a larger calcified, nonenhancing, heterogeneous right frontal lesion with surrounding edema and a mass effect. The results of a metastatic workup were unremarkable. The patient underwent an initial right frontotemporal craniotomy and a subsequent suboccipital craniectomy 2 years later for resection of the posterior fossa lesion. Histological examination revealed the frontal and cerebellar lesions to be an oligodendroglioma and JPA, respectively. A molecular analysis detected a deletion of chromosome 1p36 in the oligodendroglioma, but not in the JPA. After the initial operation, the patient received follow-up care for his oligodendroglioma, but eventually required temozolomide for tumor progression. His condition remains stable both neurologically and according to imaging studies. The authors describe the first known case in which a low-grade oligodendroglioma and a JPA presented as synchronous primary brain tumors. They review the literature on multiple primary brain tumors with different histological characteristics and discuss potential mechanisms for the development of these lesions. ",0
2773,15070665,Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients,"Conventional therapies for primary chronic cold agglutinin disease (CAD) are ineffective, but remissions after treatment with the anti-CD20 antibody rituximab have been described in a small, prospective trial and in some case reports. In this study we report on 37 courses of rituximab administered prospectively to 27 patients. Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment. In both groups combined, responses were achieved after 20 of 37 courses, giving an overall response rate of 54%. We observed 1 complete and 19 partial responses. Two nonresponders and 3 patients who experienced relapse received second-line therapy with interferon-alpha combined with a new course of rituximab, and 1 nonresponder and 2 patients who experienced relapse achieved partial responses. Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months. We conclude that rituximab is an effective and well-tolerated therapy for CAD. Histologic and flow cytometric findings suggest that some of the effect may be mediated by mechanisms other than the elimination of clonal lymphocytes. We were unable to predict responses from the hematologic, immunologic, or histologic parameters before therapy. ",0
2774,15070822,Lung function changes in workers exposed to cobalt compounds: a 13-year follow-up,"The objective of the study was to examine the influence of cobalt exposure on lung function changes in workers from a cobalt-producing plant in a health monitoring program implemented between 1988 and 2001. A total of 122 male workers with at least 4 (median = 6) lung function tests (FEV(1) and FVC) during the follow-up period were assessed longitudinally. Cobalt exposure significantly decreased over the follow-up period, as reflected by the measurements in air and urine. The possible association of spirometric changes with cobalt exposure was examined by a random coefficients model, taking into account other potential influential variables, such as smoking, age, previous respiratory illness, exposure to other lung toxicants, or the presence of glutamate in position 69 in the HLA-DP beta-chain, an HLA polymorphism possibly associated with hard-metal-induced lung diseases. The main finding of the follow-up study was that cobalt exposure contributed to a decline in FEV(1) over time, and only in association with smoking. No influence of glutamate in position 69 in the HLA-DP beta-chain polymorphism was detected. Although the amplitude of the additional FEV(1) decrement associated with smoking exposure was relatively small (< 20%) compared with the expected decline in a non-cobalt-exposed smoker, the results indicate that further efforts to reduce cobalt exposure and to encourage workers to quit smoking are still warranted. ",0
2775,15071114,Cognitive correlates of white matter growth and stress hormones in female squirrel monkey adults,"Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18-60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging. ",0
2776,15071302,Pneumococcal psoas pyomyositis associated with complement deficiency,"A 4.5-year-old boy with complement deficiency developed infection of the psoas caused by Streptococcus pneumoniae. Pyomyositis of the psoas muscle is uncommon but should be included in the differential diagnosis of fever and lameness. The most useful diagnostic test is computed tomography guided needle aspiration, and underlying conditions should be sought. ",0
2777,15071322,Positron emission tomography with fluoro-2-deoxy-D-glucose (FDG-PET) in the staging of post transplant lymphoproliferative disorder in lung transplant recipients,"Posttransplantation lymphoproliferative disorder (PTLD) is a histologic heterogeneous disease that complicates 4 to 8% of lung transplant recipients. Disease extent is an important prognostic factor and may affect therapy. Positron emission tomography with fluoro-2-deoxy-D-glucose (FDG-PET) has proven useful for staging high-grade lymphomas but is less accurate for staging low-grade and extranodal lymphoma. This study examined our initial experience using FDG-PET imaging to stage lung transplant recipients with posttransplantation lymphoproliferative disorder. FDG can show foci of uptake, particularly in extrathoracic sites, not seen by conventional imaging, which allows more accurate staging of disease thereby yielding useful prognostic information and guiding therapy. ",0
2778,15071391,Severe bloodstream infections: a population-based assessment,"Although bloodstream infection commonly results in critical illness, population-based studies of the epidemiology of severe bloodstream infection are lacking. We sought to define the incidence and microbiology of severe bloodstream infection (bloodstream infection associated with intensive care unit admission within 48 hrs) and assess risk factors for acquisition and death. Population-based surveillance cohort. Multidisciplinary and cardiovascular surgical intensive care units. All adults with severe bloodstream infection in the Calgary Health Region (population approximately 1 million) during 2000-2002. None. Three hundred forty patients had 342 episodes of severe bloodstream infection (15.7 per 100,000 population/year). Several demographic and chronic conditions were significant risk factors for acquiring severe bloodstream infection (relative risk, 95% confidence interval) including age > or =65 yrs (7.0, 5.6-8.7), male gender (1.3, 1.1-1.6), urban residence (2.4, 1.2-5.6), hemodialysis (208.7, 142.9-296.3), diabetes mellitus (5.9, 4.4-7.8), alcoholism (5.6, 3.8-8.0), cancer (7.5, 5.3-10.3), and lung disease (3.8, 2.6-5.4). The most common etiologies were Staphylococcus aureus, Escherichia coli, and Streptococcus pneumoniae (3.0, 3.0, and 1.9 per 100,000/year, respectively). The case-fatality rate was 142 of 340 (42%) for an annual mortality rate of 6.5 per 100,000. Increased Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.1 per point; 95% confidence interval, 1.1-1.2) and presence of a comorbidity (odds ratio, 2.5; 95% confidence interval, 1.4-4.3) were significant independent predictors of death. Bloodstream infections are commonly severe enough to require management in an intensive care unit and are associated with a high mortality rate. Identification of risk factors for severe bloodstream infection may allow targeting of preventive efforts to individuals at greatest potential benefit. ",0
2779,15072123,Trends in leprosy case detection worldwide since 1985,"Trends in case detection and case detection rate (CDR) since 1985 are described at regional and national levels. Annual case detection by WHO Region was available for 1994-2000. Using different sources, complete time series for case detection were constructed for 1985-1998 for a group of 33 endemic countries cumulatively (top 33), and for 14 individual countries (top 14). Population statistics were used to derive CDRs. India contributed 79% to global case detection in 1998. Africa, the Americas and South-East Asia each contributed about 30% when India is excluded. During 1994-2000, case detection did not decrease in these three WHO Regions. The 33 countries contributed 99% and 98% to global case detection in 1994 and 1998, respectively. Cumulative case detection for the top 33 minus India gradually increased, overall almost doubling. The contribution of the top 14 to case detection of the top 33 hardly changed over time, equalling 96% in 1998 (81% when India is excluded). In terms of annual case detection, Brazil was always ranked second after India; it accounted for 27% of 1998 case detection in the top 33 except India. In 1998, seven of the top 14 countries--including India and Brazil--had CDRs above 2 per 10,000. The CDR did not exceed 1 per 10,000 for the other half. Decreasing tendencies in CDR, either for the whole period or in the 1990s, are observed for four of the top 14 countries (Guinea and three Western Pacific countries: China, Vietnam and the Philippines). In conclusion, there is no general decline in case detection to date, and several important countries still have high CDRs. Prevalence is an irrelevant indicator for monitoring epidemiological changes in leprosy. Trends in the transmission and incidence of leprosy are still completely unclear, necessitating further research. The target to eliminate leprosy as a public health problem, defined as a prevalence of less than 1 per 10,000, is therefore also an inadequate yardstick for decision making on leprosy control. ",0
2780,15072129,"HLA associations in leprosy patients from Mumbai, India","Genetic predisposition to both disease susceptibility and to host immune response has been postulated. In India, about 64% of leprosy prevalence and 78% of new case detection of the worlds estimated 719,330 cases occur. Convincing results have been reported from studies on HLA class II association in leprosy. However data on HLA class I association are limited and inconsistent. The HLA A, B and C allele distribution in 103 leprosy patients and 101 normal healthy control individuals were studied by microlymphocytotoxicity assay. Further 32 multibacillary leprosy patients along with the 67 controls were studied by molecular high-resolution PCR-SSOP technique. The significant results from the present study were: 1) serologically, a significant increase in HLA A2, A11, B40 and Cw7, while a decrease of A28, B12, B15 and Cw3 were observed among the leprosy patients when compared with the controls; 2) molecular subtyping in multibacillary leprosy patients revealed a significant increase in frequency of HLA A*0203, A*0206, A*1102, B*1801, B*4016, B*5110, Cw*0407 and Cw*0703 while a decrease in the frequency of HLA A*0101, A*0211, B*4006, Cw*03031, Cw*04011 and Cw*0602 leprosy patients was observed when compared with the controls; 3) further haplotypes A*1102-B*4006-Cw*1502; A*0203-B*4016-Cw*0703; A*11-B*40 was significantly increased among the multibacillary leprosy patients when compared with the controls. It seems that HLA class I alleles play vital roles in disease association/pathogenesis. ",0
2781,15072149,Ultrasonography of the medial iliac lymph nodes in the dog,"Sixty-one medial iliac lymph nodes of 38 different dogs (eight with adenocarcinoma of the apocrine glands of the anal sac, 13 with multicentric lymphoma, six with multicentric lymphoma but in clinical remission, and 11 control dogs) were evaluated to assess the ability of ultrasound to identify and interrogate these lymph nodes across the different groups and to differentiate these groups using different sonographic parameters. Ultrasound proved to be useful to assess canine medial iliac lymph nodes. An increase in size or number of detected lymph nodes or finding rounder or heterogeneous lymph nodes could differentiate lymph nodes of dogs of the control group from lymph nodes of dogs with lymphoma or an adenocarcinoma of the apocrine glands of the anal sac. Subcategories of malignancy could not be differentiated. More studies need to be performed, both with patients with reactive lymph nodes and also focusing on other canine superficial lymph nodes, before generalizing the results of this study to other areas or diseases. ",0
2782,15072390,Communication strategies to motivate patients to follow doctor's advice],"The growing attention to the preventive aspects of health care has raised the question how to motivate patients to modify potentially health damaging habits such as smoking, alcohol abuse, wrong diet or poor exercise. The present paper examines the theory and the techniques of the motivational interview and proposes practical examples which illustrate how the physician may overcome patient's resistance. The authors describe the principal aspects of the process of motivational change and some of the corresponding attitudes and skills which the physician has to adopt in each phase of this process. The basic assumptions are that the patient is the main agent of change and that the physician's task is to facilitate this process and to sustain the patient's efforts. ",0
2783,15072483,Duplex Doppler sonography in patients with acute renal colic: prospective study and literature review,"To determine the value of duplex Doppler sonography in the diagnosis of acute urinary obstruction. In 46 healthy individuals and 42 patients with urinary obstruction confirmed by intravenous urography, 176 kidneys were examined with duplex Doppler sonography. The mean intra-arterial resistive index value and the difference of mean resistive index values between both kidneys were determined for each person. Resistive index and delta resistive index values were compared with urographic findings in the 42 patients. In the 46 healthy individuals, the mean resistive index and delta resistive index values were 0.59 +/- 0.05 and 0.03 +/- 0.01. In the 14 patients with complete urinary obstruction, these values were 0.70 +/- 0.06 and 0.09 +/- 0.02, whereas in the 28 patients with partial urinary obstruction, these values were 0.64 +/- 0.06 and 0.03 +/- 0.05. Urographic findings and duplex Doppler sonography were correlated in the 42 patients, with a resistive index = 0.65 and delta resistive index = 0.05 as discriminatory thresholds for obstruction. In patients with complete obstruction, the diagnostic sensitivity of these values was 64% and 100% with a specificity of 82% and 89%, respectively. In patients with partial obstruction, the sensitivity of these values was 54% and 46% with a specificity of 82% and 89%, with respect to the control group of healthy individuals. Delta resistive index is a very sensitive and specific parameter in the sonographic diagnosis of complete urinary obstruction but insensitive in partial urinary obstruction. Duplex Doppler sonography is recommended in cases where intravenous urography is contraindicated. ",0
2784,15072619,Ureteral ultrasonic lithotripsy revisited: a neglected tool?,"Ultrasonic lithotripsy was one of the first modalities used for treating renal and ureteral stones. However, in recent years, it has been largely replaced by newer techniques such as laser lithotripsy with rigid as well as flexible ureteroscopes. The aim of this study was to review the results and our current indications for ureteroscopic ultrasonic lithotripsy (UUL). Between October 2000 and May 2002, 340 ureteroscopies were performed for the treatment of ureteral stones in the Rabin Medical Center. Of this series, 9 patients (2.6%) underwent UUL using a semirigid 8F ureteroscope (Wolf) and an Olympus ultrasonic lithotripter (LUS-1) with a 4.5F hollow probe. Four patients had Steinstrasse following shockwave lithotripsy, four had large (1-2-mm) ureteral stones, and one had an impacted calcified ureteral double-J stent. Stones >5 mm were initially fragmented by the holmium laser (550-microm fiber). A double-J stent was placed in all patients. The mean follow-up time was 20 months. The mean operative time was 84 minutes. No intraoperative complications occurred. The mean hospital stay was 3.9 days. Eight patients became stone free after the first procedure, and the other underwent secondary ureteroscopy, which rendered him stone free. Patients in whom UUL is performed are relatively complex stone patients. The use of ultrasonic lithotripsy following, or in combination with, laser or ballistic devices utilizes the unique properties of UUL, which combines stone fragmentation and efficient removal of small fragments. The technique was particularly useful in patients with Steinstrasse or a large stone burden. Thus, UUL has a limited but significant role in the treatment of ureteral stones. ",0
2785,15072973,"A new method to denude the endothelium without damage to media: structural, functional, and biomechanical validation","The intimial thickening that occurs in human and animal atherogenesis can be induced by mechanical injury to the endothelium. The objective of the present study was to develop a new method to induce arterial endothelial injury without damage to the media for future investigations of mechanisms of intimal thickening and atherogenesis. A specifically designed catheter was inserted into the common femoral artery of Wistar rats (n = 9) through an arteriotomic mouth. After application of Tyrode solution containing 0.14 M KCl on the surface of the vessel, the vessel contracted onto the catheter. The catheter was then moved back and forth to scrape away the endothelium. The left common femoral artery of the same rat was subjected to the standard balloon injury model. The two models were evaluated structurally, functionally, and biomechanically. Structurally, we verified that both techniques remove the endothelium, but the balloon method damages the media. Functionally, we examined the contractile response of the artery to [K+] and norepinephrine 2 days after the denudation. We found that the right femoral artery underwent contraction in response to [K+], whereas the left artery did not. Furthermore, neither artery responded to norepinephrine. Biomechanically, we measured the pressure-diameter relationship and the zero-stress state of the vessel and computed the stress-strain relation. The circumferential stretch ratios at 120 mmHg were 1.38 +/- 0.08 for the control, 1.41 +/- 0.08 (P > 0.05) for the new method, and 1.56 +/- 0.09 for the balloon injury (P < 0.05). The opening angles at the zero-stress state were 113 +/- 21 degrees for the control, 102 +/- 18 degrees for the new method (P > 0.05), and 8 +/- 13 degrees for the balloon injury (P < 0.001). In conclusion, the new method removes the endothelium while maintaining the structure, contractile function, and biomechanical properties of the vessel. ",0
2786,15073020,Proteins associated with diseases show enhanced sequence correlation between charged residues,"Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of distant residues in allosteric regulation. Bioinformatic and structural analysis methods have been introduced to infer residues that are correlated. Recently, increasing attention has been paid to obtain the sequence properties that determine the tendency of disease-related proteins (Abeta peptides, prion proteins, transthyretin, etc.) to aggregate and form fibrils. Motivated in part by the need to identify sequence characteristics that indicate a tendency to aggregate, we introduce a general method that probes covariations in charged residues along the sequence in a given protein family. The method, which involves computing the sequence correlation entropy (SCE) using the quenched probability P(sk)(i,j) of finding a residue pair at a given sequence separation, sk, allows us to classify protein families in terms of their SCE. Our general approach may be a useful way in obtaining evolutionary covariations of amino acid residues on a genome wide level. We use a combination of SCE and clustering based on the principle component analysis to classify the protein families. From an analysis of 839 families, covering approximately 500,000 sequences, we find that proteins with relatively low values of SCE are predominantly associated with various diseases. In several families, residues that give rise to peaks in P(sk)(i,j) are clustered in the three-dimensional structure. For the class of proteins with low SCE values, there are significant numbers of mixed charged-hydrophobic (CH) and charged-polar (CP) runs. Our findings suggest that the low values of SCE and the presence of (CH) and/or (CP) may be indicative of disease association or tendency to aggregate. Our results led to the hypothesis that functions of proteins with similar SCE values may be linked. The hypothesis is validated with a few anecdotal examples. The present results also lead to the prediction that the overall charge correlations in proteins affect the kinetics of amyloid formation--a feature that is common to all proteins implicated in neurodegenerative diseases. ",0
2787,15073091,Detection and quantification of heteroplasmic mutant mitochondrial DNA by real-time amplification refractory mutation system quantitative PCR analysis: a single-step approach,"The A3243G mitochondrial tRNA leu(UUR) point mutation causes mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, the most common mitochondrial DNA (mtDNA) disorder, and is also found in patients with maternally inherited diabetes and deafness syndrome (MIDD). To correlate disease manifestation with mutation loads, it is necessary to measure the percentage of the A3243G mtDNA mutation. To reliably quantify low proportions of the mutant mtDNA, we developed a real-time amplification refractory mutation system quantitative PCR (ARMS-qPCR) assay. We validated the method with experimental samples containing known proportions of mutant A3243G mtDNA generated by mixing known amounts of cloned plasmid DNA containing either the wild-type or the mutant sequences. A correlation coefficient of 0.9995 between the expected and observed values for the proportions of mutant A3243G in the experimental samples was found. Evaluation of a total of 36 patient DNA samples demonstrated consistent results between PCR-restriction fragment length polymorphism (RFLP) analysis and real-time ARMS-qPCR. However, the latter method was much more sensitive for detecting low percentages of mutant heteroplasmy. Three samples contained allele-specific oligonucleotide-detectable but RFLP-undetectable mutations. The real-time ARMS-qPCR method provides rapid, reliable, one-step quantitative detection of heteroplasmic mutant mtDNA. ",0
2788,15073134,Trastuzumab (Herceptin) enhances class I-restricted antigen presentation recognized by HER-2/neu-specific T cytotoxic lymphocytes,"Numerous examples from animal models and clinical trials showed that HER-2-derived peptides are naturally processed as a CTL epitope and can be recognized by tumor-specific CTLs in several tumors with HER-2 overexpression. The humanized anti-HER-2 monoclonal antibody, Herceptin, has been designed to specifically antagonize the HER-2 function by directing against the extracellular domain of the HER-2 protein. One of the actions of Herceptin includes the internalization and degradation of HER-2, which might increase the amount of HER-2-derived peptides available for loading to MHC class I. In the present study, we investigated how Herceptin treatment of HER-2-overexpressing targets affects lysis by HER-2-specific CTLs. We showed that Herceptin sensitized HER-2-overexpressing tumors to lysis by HLA-A2-restricted or HLA-A24-restricted CTLs, without any effect of the expression of MHC class I, costimulatory molecules, adhesion molecules, or TAP-1 on the targets. Furthermore, the enhancement of cytolytic activity with Herceptin was inhibited by addition of a specific proteasome inhibitor, lactacystin. These results suggested that Herceptin treatment might enhance the class I-restricted presentation of endogenous HER-2 antigen via the proteasome step, resulting in higher susceptibility of HER-2-overexpressing tumors to lysis by the HER-2-specific CTLs. ",0
2789,15073492,Impact of the renin-angiotensin system on lipid and carbohydrate metabolism,"This review is intended to provide an update of the impact of the renin-angiotensin system on lipid and carbohydrate metabolism and of its relationship with adipose-tissue and skeletal muscle activities. The components of the renin-angiotensin system are fully represented in the adipose tissue and appear to be upregulated in obesity--a condition associated with enhanced circulating angiotensinogen levels. The local renin-angiotensin system plays a role in adipocyte differentiation and possibly in body-fat accumulation. In humans, angiotensin II produced by mature adipocytes appears to inhibit the differentiation of adipocyte precursors, thus decreasing the percentage of small insulin-sensitive adipocytes. In turn, the lipid-storage capacity of adipose tissue could become reduced and triglycerides might accumulate in liver and skeletal muscle, contributing to insulin resistance. Randomized controlled trials indicating that pharmacological renin-angiotensin system blockade improves insulin sensitivity and reduces the risk of type 2 diabetes are in keeping with this possibility. The local renin-angiotensin system in skeletal muscle may affect exercise performance and the individual response to different types of muscular performance. The concept that the local renin-angiotensin system plays a role in body-fat storage and in lipid and carbohydrate metabolism is further supported by genetic studies showing that susceptibility to weight gain and possibly insulin resistance is greater in individuals carrying certain renin-angiotensin system allelic variants associated with alterations in systemic and local angiotensinogen levels and angiotensin-converting enzyme activity. In summary, the aforementioned data imply that the renin-angiotensin system plays a substantial role in obesity, insulin resistance and the associated increase in blood pressure. ",0
2790,15073517,Gender-specific vulnerability for rCBF abnormalities among cocaine abusers,"Fifty abstinent cocaine-dependent patients and 20 healthy controls were evaluated with 99mTc-HMPAO SPECT to examine gender differences in perfusion. Group contrasts with statistical parametric mapping revealed male and female patients exhibited not only different regions, but different types of perfusion abnormality, including decreased perfusion in the anterior cingulate/frontal regions among cocaine-dependent men, and increased perfusion in the posterior cingulate of cocaine-dependent women. The findings suggested that cocaine-dependent men have perfusion deficits previously associated with cocaine withdrawal and impaired response inhibition, whereas, cocaine-dependent women demonstrated perfusion abnormalities consistent with heightened stress responsivity and worse treatment outcome. The possibility of different neural mechanisms underlying relapse in men and women, and the implications for utilizing specialized treatments are discussed. ",0
2791,15073519,Heightened pain and delayed regeneration of galanin axons in diabetic mice,"Galanin peptide in primary sensory neurons may confer analgesia following injury. Its presence in regenerative axon sprouts where pain may be initiated has not been examined. We examined very early outgrowth of peptidergic axon sprouts after sciatic nerve crush in mice with experimental streptozotocin-induced diabetes. Diabetic mice had a retarded wave of outgrowing galanin axons, but those expressing calcitonin gene-related peptide grew normally. Diabetic mice also developed early, then persistent excessive autotomy behaviour, an index of pain behaviour in complete nerve lesions. Diabetes is associated with variations in the early outgrowth of peptide-containing axons. A relative delay in galanin axon outgrowth could contribute to heightened neuropathic pain in diabetes. ",0
2792,15073544,Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei,"The fatty acid synthase inhibitor C75 reduces feeding rapidly and for several days. We investigated brain sites potentially involved in actions of i.p. C75 in mice by examining c-Fos. At 3 h C75 increased numbers of c-Fos-immunoreactive cells in hindbrain feeding-related nuclei, and in the paraventricular nucleus (PVN), lateral aspects of the arcuate nucleus (ARC), and in the central amygdala. At 24 h C75 prevented fasting-induced c-Fos expression in the medial ARC and three of its targets: lateral magnocellular PVN, lateral hypothalamus, and dorsomedial hypothalamus. C75, but not fasting, increased c-Fos in parvocellular PVN. This pattern of results suggests a shift from hindbrain-initiated short-term actions to activation of hypothalamic mechanisms that could mediate the long-term anorectic responses to C75. ",0
2793,15073583,Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability,"ELOVL4 is a member of the fatty acid elongase (ELO) family of genes. Mutations of this gene are responsible for autosomal dominant Stargardt-like macular degeneration. However, the specific role of ELOVL4 in photoreceptor cells and the mechanism by which mutations in ELOVL4 causes macular degeneration are not known. In this study we examined the subcellular localization of wild type (wt) and mutant (mt) ELOVL4 EGFP fusion protein and the potential functional consequence of mtELOVL4 expression on cell viability. Wt and mt ELOVL4 were expressed as EGFP fusion proteins in NIH 3T3 and HEK293 cells. Subcellular localizations of the fusion proteins were determined with a series of organelle-specific markers for endoplasmic reticulum (pDsRed2-ER), mitochondria (pDsRed2-Mito), peroxisomes (pDsRed2-Peroxi), and Golgi (BODIPY TR). Transfected cells were viewed using confocal and episcopic-fluorescence microscopy. Western blot analysis was performed to assess protein expression using an anti-GFP antibody. TUNEL staining was used to quantify apoptotic cell death. In cell transfection studies, wtELOVL4/EGFP fusion protein localized preferentially to the endoplasmic reticulum (ER) and was not found to be discernibly present in mitochondria, peroxisomes, or Golgi. In contrast, the truncated mutant fusion protein (which has no ER retention signal) appeared to be mislocalized to other compartments within transfected cells. Transfected cells expressing mtELOVL4/EGFP fusion protein exhibited induction of apoptotic cell death. Unlike wtELOVL4/EGFP fusion protein, the mtELOVL4/EGFP fusion protein did not localize to the ER but rather appeared to be sequestered elsewhere in an aggregated pattern in the cytoplasm. The apoptosis induced by the mutant ELOVL4 fusion protein may be the mechanism whereby photoreceptor cells degenerate in Stargardt-like macular degeneration. Our study has provided an important in vitro model system for further assessment of ELOVL4 biochemical functions. ",0
2794,15073849,Radical retropubic prostatectomy in Hispanic patients,"Hispanics are the largest minority group in the U.S. Most studies assessing race as a predictor of biochemical disease recurrence after radical retropubic prostatectomy (RRP) have focused on African-American patients. To the authors' knowledge, little has been published to date regarding radical prostatectomy in Hispanic patients. Hispanics represent 29% of the patients in the current study. The authors analyzed the presentation and outcome of Hispanic males managed with radical prostatectomy. In the current study, 1163 RRPs were performed. Patients were categorized by ethnicity as Hispanics, white non-Hispanics, African-Americans, and other ethnicities. African-American and other minority group patients were excluded from the analysis because of the small number in the current series. A comparative analysis of Hispanics and white non-Hispanics was performed. RRP was performed in 1163 patients. Two hundred seven Hispanic and 518 white non-Hispanic patients met the study criteria. The mean follow-up was 46.9 months. Twenty-three percent of the Hispanic patients received neoadjuvant therapy. RRP Gleason scores of 2-6, 7, and 8-10 were found in 45% of patients, 38% of patients, and in 17% of patients, respectively. Lymph node metastases were present in 3%, seminal vesicle invasion in 13%, and extraprostatic extension in 23% of Hispanic patients. Adjuvant hormonal therapy was administered to 6% of the Hispanic patients. The biochemical disease recurrence rate was 12%. The mean time to biochemical disease recurrence was 29.7 months. A comparison between the Hispanic and the white non-Hispanic groups showed no significant differences in the analyzed variables. Hispanic patients managed with radical prostatectomy for prostate carcinoma were found to have similar presentation, pathologic findings, and outcome as the white non-Hispanic patients. ",0
2795,15073902,Evidence of inappropriate use of vancomycin in a university affiliated hospital in Brazil,"To evaluate the appropriateness of use of vancomycin in a University affiliated Hospital in Brazil. One hundred sequential therapeutic courses of vancomycin were retrospectively examined through a chart review. The prescriptions were evaluated in terms of indication, use of critical process indicators, and use of outcome measurements according to an adapted version of the criteria recommended by the American Society of Health-System Pharmacists. The indication for use was appropriate in 39% of the cases. Critical process indicators indicated frequent inappropriate use, mainly in relation to a low frequency of bacterial cultures (54%), infrequent determination of creatinine levels prior to therapy (57%), incorrect dosage (42%), incorrect duration of therapy (63%), and infrequent determination of serum levels of vancomycin (73%). It was impossible to evaluate outcome measurements, since data were not collected in most patients. Larger discrepancies between recommendation and practice were detected in Paediatrics and Paediatric Pneumology Services. The misuse of vancomycin in our hospital is very common according to standard guidelines, demanding new policies of control in order to diminish the possibility of the emergence of multi-resistant strains. ",0
2796,15074031,Radiofrequency ablation in primary and metastatic hepatic tumors],"A number of alternative therapies have been used for the treatment of malignant hepatic tumors. Radiofrequency ablation (RFA) is an evolving technology being used to treat patients with unresectable primary and metastatic hepatic cancers. RFA produces coagulative necrosis of the tumor through local tissue heating. Liver tumors can be treated percutaneously, laparoscopically, or during laparotomy, using ultrasonography to identify tumors and to guide placement of the RFA needle electrode. In general, RFA is a safe, well-tolerated, effective treatment for unresectable hepatic malignancies less than 6.0 cm in diameter. ",0
2797,15074492,The burden of terrorism in Malaysia,"In the peace-loving, moderate and progressive country of Muslim-dominated Malaysia, violence generally is alien to the culture. Terrorism initially took shape during the post-independence, communist era by jungle recalcitrant actions. In recent years, this has been superceded by a more internationally related trend of violence. Only very few incidents were based locally, while the majority were linked to international groups or organizations abroad, including the Kumpulan Mujahidin Malaysia (KMM), Jemaah Islamiyah (JI), and the Abu Sayyaf Group (ASG). Kidnapping with ransom seemed to have been the most commone modus operandi, while killing and robbery accounted for very few of these incidents. The number of victims in each event so far has been small, and smaller for those physically harmed or killed. This pattern of terrorist attacks suggests that the current level of provision of emergency medical services is sufficient to handle such incidents. Recent advances in local emergency medicine also have witnessed the establishment of various teaching and training modules, a pivotal role played by university hospitals and supported by the Ministry of Health. However, the spate of ongoing events of mass destruction such as the conflict in Israel/Palestine, wars in Afghanistan and Iraq, the World Trade Center and Pentagon tragedies of 11 September 2001, and the Bali bombing in Indonesia, remain as great concerns to Malaysians. Both the government and the people of Malaysia abhor such unjustified uses of terror, and take every measure to curtail them. The National Security Council policies of Arahan No. 18 and Arahan No. 20 detail specific roles and responsibilities of various agencies in managing terrorism and disasters respectively, while the use of the stern Internal Security Act that allows indefinite detention without trial, evidently has been an efficient intelligence and security apparatus. With more recent developments of terrorist events regionally and globally, Malaysia continues to face an ongoing threat from such activities. Various measures have been and will be actively undertaken both by government and non-governmental agencies in facing these challenges. ",0
2798,15074602,Molecular inclusion of rofecoxib with cyclodextrin: pharmacological properties in laboratory animals,"Rofecoxib is practically insoluble in water and its prolonged use is associated with the incidence of side effects like gastrointestinal perforations, ulcerations and bleeding. Therefore, an attempt has been made to improve the aqueous solubility of the drug by making an inclusion complex using dimethyl-beta-cyclodextrin (DIMEB). The complexes were prepared by kneading and by the spray drying method. The prepared complexes showed better anti-inflammatory activity and decreased ulcerogenic potential than the pure drug. ",0
2799,15074722,Effect of coexistent scaphotrapezoidal osteoarthrosis on outcome after trapeziectomy,"Scaphotrapezoidal osteoarthrosis can cause persistent pain after trapeziectomy. It has previously been recommended that the scaphotrapezoidal joint should be resected at the time of trapeziectomy to avoid this complication if radiographs show evidence of joint degeneration. We have reviewed the records of 77 patients who had 87 trapeziectomies and assessed their radiographs for the presence and degree of osteoarthrosis. There was evidence of scaphotrapezoidal osteoarthrosis in almost half of the hands. Its presence, however, had no influence on subjective or objective measures of pain, function or power before or after operation, or on outcome. Only one patient required resection of the scaphotrapezoidal joint because of persistent pain. Resection of the joint cannot be recommended as a routine adjunct to trapeziectomy on radiological evidence alone. ",0
2800,15074795,Ammonia emissions from swine houses in the southeastern United States,"Ammonia (NH3) from confined animal feeding operations is emitted from several sources including lagoons, field applications, and houses. This paper presents studies that were conducted to evaluate NH3 emissions from swine finisher and sow animal houses in the southeastern USA. Management and climate variables including animal weight, feed consumption, housing gutter water temperature, total time fans operated per day, house air temperature, house ambient NH3 concentration, and animal numbers were measured to determine their individual and combined effect on NH3 emissions. Ammonia emissions varied on daily and seasonal bases with higher emissions during warmer periods. For finishers, the summertime housing emissions on a per-animal basis were 2.4 times higher than wintertime (7.0 vs. 3.3 g NH3 animal(-1) d(-1)) or 3.2 times higher when compared on an animal unit (AU) basis (1 AU = 500 kg) because of climate and animal size differences between measurement periods. For summertime, the emission factor for the finishing pigs was 7.8 times higher than for sows on an animal basis and 25.6 times higher on an AU basis. Simple models were developed for housing emissions based on (i) all measured factors that were independent of each other and (ii) on three commonly measured management factors. The two models explained 97 and 64%, respectively, of variations in emissions. Ammonia emissions were found to be somewhat less than other studies on the same type housing due to more representative housing concentration measurements and calibration of exhaust fans; thus, emission factors for these type houses will be less than previously thought. ",0
2801,15074810,Incubation time effects on imazaquin desorption as determined by nonequilibrium thin-soil disc flow,"Because organic sorption in soil may never reach equilibrium, a thin-disc flow nonequilibrium method may be helpful in understanding herbicide-soil interactions. This research was conducted to (i) determine the influence of incubation time on imazaquin [2-(4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl)-3-quinolinecarboxylic acid] desorption from soil, (ii) examine the influence of solution flow velocities on desorption, and (iii) elucidate the most appropriate kinetic model to describe imazaquin leaching. Soil at 7.5% moisture w/w was treated with imazaquin and incubated for 24, 72, and 168 h. Treated soil was sealed in an in-line filter apparatus and rinsed with 5.0 mM CaCl2 at 0.33, 0.67, or 1.0 mL min(-1). Effluent was collected as 1.0-mL fractions for a total of 50 mL. Flow was stopped for 24 h. When flow resumed, fractions were collected for an additional 15 mL. After the initial desorption, 79% of the imazaquin incubated for 24 h was leached. Increasing incubation time beyond 24 h reduced imazaquin leaching. After both desorption events, 13% of the initially applied imazaquin remained in the soil incubated for 168 h, compared with 7% with soil incubated for 24 h. Elovich and Freundlich kinetics accounted for 98% of the variance observed in the imazaquin desorption curves. First-order and diffusion kinetics accounted for 91% of the variance. Incubating soil for 72 h before desorption reduced the rate of imazaquin desorption by approximately 12%, compared with the 24-h incubation treatment. Imazaquin desorption was not affected by wash solution flow rate. These data suggest that the kinetics of desorption in prolonged desorption events are limited by transport phenomena (i.e., particle and film diffusion). ",0
2802,15075321,Aromatic residue position on the nonpolar face of class a amphipathic helical peptides determines biological activity,"The apolipoprotein A-I mimetic peptide 4F (Ac-DWFKAFYDKVAEKFKEAF-NH(2)), with four Phe residues on the nonpolar face of the amphipathic alpha-helix, is strongly anti-inflammatory, whereas two 3F analogs (3F(3) and 3F(14)) are not. To understand how changes in helix nonpolar face structure affect function, two additional 3F analogs, Ac-DKLKAFYDKVFEWAKEAF-NH(2) (3F-1) and Ac-DKWKAVYDKFAEAFKEFL-NH(2) (3F-2), were designed using the same amino acid composition as 3F(3) and 3F(14). The aromatic residues in 3F-1 and 3F-2 are near the polar-nonpolar interface and at the center of the nonpolar face of the helix, respectively. Like 4F, but in contrast to 3F(3) and 3F(14), these peptides effectively inhibited lytic peptide-induced hemolysis, oxidized phospholipid-induced monocyte chemotaxis, and scavenged lipid hydroperoxides from low density lipoprotein. High pressure liquid chromatography retention times and monolayer exclusion pressures indicated that there is no direct correlation of peptide function with lipid affinity. Fluorescence studies suggested that, although the peptides bind phospholipids similarly, the Trp residue in 4F, 3F-1, and 3F-2 is less motionally restricted than in 3F(3) and 3F(14). Based on these results and molecular modeling studies, we propose that the arrangement of aromatic residues in class A amphipathic helical molecules regulates entry of reactive oxygen species into peptide-phospholipid complexes, thereby reducing the extent of monocyte chemotaxis, an important step in atherosclerosis. ",0
2803,15075670,Special pharmacokinetics of dipetarudin suggests a potential antitumor activity of this thrombin inhibitor,"Thrombin is a potent mitogen for many tumor cells, suggesting that this enzyme may be involved in tumor genesis and metastasis. Inhibition of thrombin expressed on the surface of tumor cells may improve outcomes in some tumor cases. For this reason, a thrombin inhibitor to be applied in antitumor therapy must have favorable pharmacokinetic attributes to exert its action as long as possible in the extravascular compartment of the extracellular space, with a short action intravascularly, avoiding bleeding and/or other undesirable side-effects. None of the thrombin inhibitors in clinical use has these properties. Here, we report for first time a direct thrombin inhibitor, named dipetarudin that could be very useful in antitumor therapy because of its pharmacokinetic behavior characterized by a rapid distribution in the extravascular space with a slow elimination from this compartment. ",0
2804,15076941,Intravitreous leptin concentrations in patients with proliferative diabetic retinopathy,"Previous studies have demonstrated that leptin is an angiogenic factor, and an increase in intravitreous leptin concentrations in diabetic patients with proliferative diabetic retinopathy (PDR) has also been described. The aim of the present study was to investigate the source of intravitreal leptin and to determine whether it is related to PDR activity. Serum and vitreous fluid samples were obtained simultaneously at the time of vitreoretinal surgery from 25 patients with PDR and 32 nondiabetic patients with nonproliferative ocular diseases (controls). Both groups were matched by age, sex, and body mass index. Leptin levels were determined by ELISA. We did not observe any significant differences in vitreal levels of leptin between diabetic patients with PDR and controls (4.22 [2.6-9.7] versus 3.49 [1.9-9.7] ng/mL; P = not significant). Leptin concentrations were lower in vitreous fluid than in serum samples from diabetic patients with PDR (P < 0.001) and controls (P < 0.001). A direct correlation between serum and vitreous leptin concentrations was detected in diabetic patients with PDR (r = 0.60; P = 0.01) and controls (r = 0.51; P = 0.01). Finally, we did not observe any relationship between intravitreous leptin levels and PDR activity. The intraocular production of leptin is not critically involved in the etiopathogenesis of PDR. In addition, our results suggest that serum diffusion is a relevant source of leptin in vitreous fluid. ",0
2805,15077054,Antioxidative abilities during aging],"Biological aging is associated with increased cellular levels of reactive oxygen species (ROS) as well as the formation and accumulation of oxidized biomolecules. During evolution, organisms developed a highly-efficient and adaptive antioxidant defense system. Antioxidants can generally be divided into two categories: enzymatic and non-enzymatic. During the aging process the activity of antioxidant enzymes, e.g. SOD, CAT, GSH-Px, and GSSG-R, depends on factors such as race, gender, tissue and subcellular localization of enzymes. The age-dependent decrease in antioxidant enzyme activity may be attributed to oxidative modifications of enzymes. During the aging process, ROS may also lead to the induction of some enzyme activity which is explained as an adaptive phenomenon. The decrease in GSH concentration with age can be explained by decreased GSH synthesis and/or increased GSH consumption in the removal of peroxides and xenobiotics. In plasma albumin, ferritin, transferrin, and caeruloplasmin exert protective action. Plasma proteins can inhibit ROS generation and lipid peroxidation by chelating free transition metals. Plasma protein concentrations changes with age. The major exogenous antioxidants, mostly derived from the diet, are vitamin E, C, A, and beta-carotene. During the aging process the level of vitamins may decrease or increase, depending on such factors as diet, and diseases. ",0
2806,15077626,The involvement of cyclic GMP in the photoperiodic flower induction of Pharbitis nil,"The involvement of cGMP in the regulation of the flowering of Pharbitis nil was investigated through exogenous applications of cGMP and chemicals that are able to change the cGMP level and analyses of endogenous cGMP level. Exogenous applications of cGMP and 8-pCPT-cGMP (a cyclic GMP non hydrolyzed analog) to P. nil plants, which were exposed to a 12-h-long subinductive night, significantly increased flowering response. NS-2028 (guanylyl cyclase inhibitor) inhibited flowering when that compound was applied during a 16-h-long inductive night, whereas SNP (guanylyl cyclase activator) increased the flowering when plants were subjected to a 12-h-long subinductive night. The inhibitors of cyclic nucleotides phosphodiesterase (isobutyl-methylxanthine and dipyridamole), which increase the cytosolic cGMP level, promoted the flowering and allowed the length of the dark period necessary for induction of flowering to be reduced. The endogenous cGMP level was also measured after the treatment of P. nil seedlings with those chemicals. Results have clearly shown that compounds that were used in physiological experiments modulated endogenous cGMP level. There was a significant difference in the cyclic GMP level between 16-h-long night conditions and a long night with a night-break. During a long inductive night the oscillation of cGMP was observed with four main peaks in 4, 7, 11, 14 h, whereas a 10 min flash of red light in the middle of the night was able to modify these rhythmical changes in the second half of the long night. These results have shown that there are oscillations in the concentration of cGMP in the night and the biosynthesis and/or deactivation of cGMP is affected by light treatment and therefore it may be involved in the regulation of photoinduction processes in cotyledons. From these combined results, we propose a hypothesis that cGMP is involved in the control of photoperiodic flower induction in Pharbitis nil. ",0
2807,15077720,Acetylcholinesterase concentrations in heparinized blood of Hispaniolan Amazon parrots (Amazona ventralis),"Organophosphate and carbamate pesticides inhibit acetylcholinesterase (AChE) at nerve synapses. Blood samples from 22 Hispaniolan Amazon parrots (Amazona ventralis) were assayed for cholinesterase levels by two different techniques. Using the modified Michel method, the whole-blood cholinesterase activity levels ranged from 0.082 to 0.616 deltapH/hr with a mean value of 0.35 deltapH/hr. A reference range (0.08-0.62 deltapH/hr) for cholinesterase was established in birds. The modified Ellman spectrophotometric method was used to measure AChE activity by adding acetylthiocholine or pseudocholinesterase (plasma cholinesterase) activity by adding butyrylthiocholine. The reference range of the AChE activity using the modified Ellman spectrophotometric method was 0-1.12 micromol/ml/min with a mean of 0.48 micromol/ml/min, and for pseudocholinesterase the range was 0.09-0.98 micromol/ml/min with a mean of 0.53 micromol/ml/min. ",0
2808,15078220,Mechanisms of ATPases--a multi-disciplinary approach,"ATPases are important molecular machines that convert the chemical energies stored in ATP to mechanical actions within the cell. ATPases are among the most abundant proteins with diverse functions involved in almost every cellular pathway. The well characterised ATPases include the various motor proteins responsible for cargo transfers, cell motilities, and muscle contractions; the protein degradation machinery - the proteasome; the ATP synthase, F-ATPase; and the chaperone systems. Other ATPases include DNA helicases and DNA replication complex; proteins responsible for protein/complex disassembly; and certain gene regulators. It is beyond the scope of this review to cover the complete range of ATPases. Instead, we will focus on a few representative ATPases, chosen based on their diverse mechanisms and properties. Furthermore, this review is by no means trying to cover comprehensively the literature for each ATPase nor the historical aspects in each field. We will focus on describing the various techniques being employed to derive the mechanisms and properties of the chosen ATPases. Among them, high and low resolution structural studies combined with biochemical assays seem to be the dominant technical advances adapted to reveal mechanisms for most of the ATPases except the bacterial sigma54 activators, whose mechanism of action is mostly derived from large amount of biochemical studies. A number of them, especially the F-ATPase and motor proteins, have been studied successfully by various single molecule and imaging techniques. We will therefore discuss them in greater details in order to describe the wide range techniques being utilised. ",0
2809,15078224,Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates,"Activated phagocytes release the haem enzyme MPO (myeloperoxidase) and also generate superoxide radicals (O2*-), and hence H2O2, via an oxidative burst. Reaction of MPO with H2O2 in the presence of chloride ions generates HOCl (the physiological mixture of hypochlorous acid and its anion present at pH 7.4). Exposure of glycosaminoglycans to a MPO-H2O2-Cl- system or reagent HOCl generates long-lived chloramides [R-NCl-C(O)-R'] derived from the glycosamine N-acetyl functions. Decomposition of these species by transition metal ions gives polymer-derived amidyl (nitrogen-centred) radicals [R-N*-C(O)-R'], polymer-derived carbon-centred radicals and site-specific strand scission. In the present study, we have shown that exposure of glycosaminoglycan chloramides to O2*- also promotes chloramide decomposition and glycosaminoglycan fragmentation. These processes are inhibited by superoxide dismutase, metal ion chelators and the metal ion-binding protein BSA, consistent with chloramide decomposition and polymer fragmentation occurring via O2*--dependent one-electron reduction, possibly catalysed by trace metal ions. Polymer fragmentation induced by O2*- [generated by the superoxide thermal source 1, di-(4-carboxybenzyl)hyponitrite] was demonstrated to be entirely chloramide dependent as no fragmentation occurred with the native polymers or when the chloramides were quenched by prior treatment with methionine. EPR spin-trapping experiments using 5,5-dimethyl1-pyrroline-N-oxide and 2-methyl-2-nitrosopropane have provided evidence for both O2*- and polymer-derived carbon-centred radicals as intermediates. The results obtained are consistent with a mechanism involving one-electron reduction of the chloramides to yield polymer-derived amidyl radicals, which subsequently undergo intramolecular hydrogen atom abstraction reactions to give carbon-centred radicals. The latter undergo fragmentation reactions in a site-specific manner. This synergistic damage to glycosaminoglycans induced by HOCl and O2*- may be of significance at sites of inflammation where both oxidants are generated concurrently. ",0
2810,15078923,Cross-dressing the virion: the transcapsidation of adeno-associated virus serotypes functionally defines subgroups,"""For all adeno-associated virus (AAV) serotypes, 60 monomers of the Vp1, Vp2, and Vp3 structural proteins assemble via an unknown mechanism to form an intact capsid. In an effort to better understand the properties of the capsid monomers and their role in viral entry and infection, we evaluated whether monomers from distinct serotypes can be mixed to form infectious particles with unique phenotypes. This transcapsidation approach consisted of the transfection of pairwise combinations of AAV serotype 1 to 5 helper plasmids to produce mosaic capsid recombinant AAV (rAAV). All ratios (19:1, 3:1, 1:1, 1:3, and 1:19) of these mixtures were able to replicate the green fluorescent protein transgene and to produce capsid proteins. A high-titer rAAV was obtained with mixtures that included either serotype 1, 2, or 3, whereas an rAAV of intermediate titer was obtained from serotype 5 mixtures. Only mixtures containing the AAV4 capsid exhibited reduced packaging capacity. The binding profiles of the mixed-virus preparations to either heparin sulfate (HS) or mucin agarose revealed that only AAV3-AAV5 mixtures at the 3:1 ratio exhibited duality in binding. All other mixtures displayed either an abrupt shift or a gradual alteration in the binding profile to the respective ligand upon increase of a capsid component that conferred either HS or mucin binding. The transduction of cell lines was used to further evaluate the phenotypes of these transcapsidated virions. Three transduction profiles were observed: (i) small to no change regardless of ratio, (ii) a gradual increase in transduction consistent with titration of a second capsid component, or (iii) an abrupt increase in transduction (threshold effect) dependent on the specific ratios used. Interestingly, an unexpected synergistic effect in transduction was observed when AAV1 helper constructs were combined with type 2 or type 3 recipient helpers. Further studies determined that at least two components contributed to this observed synergy: (i) heparin-mediated binding from AAV2 and (ii) an unidentified enhancement activity from AAV1 structural proteins. Using this procedure of mixing different AAV helper plasmids to generate """"cross-dressed"""" AAV virions, we propose an additional means of classifying new AAV serotypes into subgroups based on functional approaches to analyze AAV capsid assembly, receptor-mediated binding, and virus trafficking. Exploitation of this approach in generating custom-designed AAV vectors should be of significant value to the field of gene therapy. """,0
2811,15078935,Apoptosis of bystander T cells induced by human immunodeficiency virus type 1 with increased envelope/receptor affinity and coreceptor binding site exposure,"Apoptosis of uninfected bystander CD4(+) T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) pathogenesis. The viral and host mechanisms that lead to bystander apoptosis are not well understood. To investigate properties of the viral envelope glycoproteins (Env proteins) that influence the ability of HIV-1 to induce bystander apoptosis, we used molecularly cloned viruses that differ only in specific amino acids in Env. The ability of these strains to induce bystander apoptosis was tested in herpesvirus saimiri-immortalized primary CD4(+) T cells (CD4/HVS), which resemble activated primary T cells. Changes in Env that increase affinity for CD4 or CCR5 or increase coreceptor binding site exposure enhanced the capacity of HIV-1 to induce bystander apoptosis following viral infection or exposure to nonreplicating virions. Apoptosis induced by HIV-1 virions was inhibited by CD4, CXCR4, and CCR5 antibodies or by the CXCR4 inhibitor AMD3100, but not the fusion inhibitor T20. HIV-1 virions with mutant Envs that bind CXCR4 but are defective for CD4 binding or membrane fusion induced apoptosis, whereas CXCR4 binding-defective mutants did not. These results demonstrate that HIV-1 virions induce apoptosis through a CXCR4- or CCR5-dependent pathway that does not require Env/CD4 signaling or membrane fusion and suggest that HIV-1 variants with increased envelope/receptor affinity or coreceptor binding site exposure may promote T-cell depletion in vivo by accelerating bystander cell death. ",0
2812,15079098,Early complications and changes of left ventricular geometry and volume following two types of ventricular reconstruction: compression of scar zone and modified Dor aneurysmectomy],"The aim of the study was to evaluate early complication rate and changes of left ventricular geometry and function after two types of left ventricular reconstruction surgery. The study included 54 patients with ischemic heart disease and left ventricular aneurysm, who underwent coronary artery bypass grafting and left ventricular reconstruction surgery: I group (31 patients) underwent modified Dor aneurysmectomy and II group (23 patients) underwent infarcted wall compression. The study protocol included operative data, early postoperative complications and evaluation of left ventricular function 10(th)-14(th) day after surgery. Early complication rate had tendency to be higher in I group. Among patients with left ventricular ejection fraction <20%, in I group all 6 patients died, including 5 patients who underwent aneurysmectomy combined with mitral and tricuspid anuloplasty and 2 patients who underwent both apical aneurysmectomy and posterior wall compression, in II group - 1 of 3 patients died. Early changes of left ventricular geometry in I group included decrease in left ventricular diameter, volume, mass, as well as reduction of short axis of left atrium, in II group - decrease in left ventricular diameter, mass and both axis of left atrium. Left ventricular ejection fraction had tendency to increase in both groups: in 41.9% of patients in I group and in 56.5% in II group. Following different types of left ventricular reconstruction surgery early postoperative complications rate did not differ, except higher mortality rate in patients with left ventricular ejection fraction <20%, who underwent modified Dor aneurysmectomy combined with other surgical procedures. Early changes of left ventricular geometry and volume differed between patients who underwent different types of left ventricular reconstruction. ",0
2813,15079156,Future prospects for fludarabine-containing regimens in the treatment of hematological cancers,"Developments in the understanding of disease biology and in therapeutic approaches during the last decade have failed to alter the natural history of many human hematological malignancies, including chronic lymphocytic leukemia (CLL). Despite better appreciation of the molecular foundations and phenotypic characteristics of these cancers, improvements to disease classification and prognosis, and the discovery of more effective cytotoxic and biological agents, these disorders remain largely incurable. The development of a new class of cytotoxic agents in the 1980 s, namely the purine analogs, heralded a period of renewed optimism in the treatment of indolent lymphoid leukemias and lymphomas. More recently, monoclonal antibodies that selectively target cell-surface proteins, and agents that target cell-cycle or apoptotic pathways, have been developed and their use alone or in combination promise to have a major impact on the treatment of these conditions. Of these, the anti-CD52 antibody alemtuzumab and the anti-CD20 antibody rituximab have demonstrated the most potential for the treatment of CLL. Further, because of their different mode of action in comparison to conventional cytotoxic agents, combination regimens involving fludarabine and these antibodies are showing particular promise in early trials. The encouraging findings with these combination therapies are moving the intent of therapy from palliation towards cure. This paper reviews the therapeutic application of present and future fludarabine-containing approaches. The strategies that are discussed include fludarabine given with alemtuzumab, rituximab, or other monoclonal antibodies, and the potential benefits of combining fludarabine with more experimental agents such as antisense oligonucleotides, immunotoxins, or radioimmunoconjugates. The successful application of fludarabine plus alemtuzumab, or fludarabine in combination with other cytotoxic agents, as preparative regimens for stem cell transplantation techniques is also covered. ",0
2814,15079178,Growth of exclusively breastfed infants in the first 6 months of life],"To evaluate the growth of exclusively breastfed infants from birth to 6 months of life. This was a longitudinal study of 184 children who received primary care at a public institution (Exclusive Breastfeeding Stimulation Program, PROAME) in Belém, state of Pará, Brazil, between February 2000 and January 2001. A total of 102 children completed the study. All were born at full term with a birth weight greater than or equal to 2,500 g. No events were recorded during the neonatal period and the infants were exclusively breastfed, on demand, since their birth. The infants were followed up monthly, and the weight and length measured at birth and at the end of the first, fourth and sixth months of life were compared to the 50th percentile line of the NCHS growth charts and to other previous studies of Brazilian children who were exclusively breastfed. Growth was adequate for all the children, who doubled their weight before the fourth month of life. Despite a slow-down in weight and height gain after the fourth month, the weight averages at 6 months were greater than the standards used for comparison. The average weight of these exclusively breastfed children was above the 50th percentile of the NCHS curve at 6 months, thus confirming the nutritional advantages of breast milk, especially when the mothers receive guidance regarding the appropriate techniques for breastfeeding. ",0
2815,15079776,Varicose veins are common in patients with coronary artery ectasia. Just a coincidence or a systemic deficit of the vascular wall?,"Coronary artery ectasia (CAE), an uncommon finding during coronary arteriography, has been associated with the presence of aneurysm(s) in other parts of the arterial tree including the abdominal aorta. Varicose veins (VV) or phlebectasias are a common disorder of the superficial leg veins. Correlations between arterial and venous ectasias have not been established. We sought to examine whether there is an association between CAE and VV. CAE was diagnosed in 181 patients out of 7510 eligible patients undergoing coronary arteriography within 33 months. The prevalence of VV was significantly higher among patients with CAE (40%) compared to 200 aged-matched patients with coronary artery disease but without CAE (17%) and to 201 randomly selected subjects from the general population (23%). In multivariate analysis, CAE was found to be significantly and independently associated with VV (RR=3.42, 95% confidence interval (CI) 2.24-5.59, p<0.001). In this study population, VV were more common in patients with CAE than in those without. This association was valid in both univariate and multivariate analysis, suggesting the possible existence of a generalised defect of the entire vascular wall. ",0
2816,15080302,The involvement of natural killer cells in the pathogenesis of severe acute respiratory syndrome,"By using peripheral blood samples from 221 cases of severe acute respiratory syndrome (SARS), 34 of Mycoplasma pneumoniae infection, and 44 healthy adults, we measured the total number of natural killer (NK) and CD158b+ NK cells (CD158b+ NK) using flow cytometric analysis and calculated the percentage of CD158b+ NK cells. The total number of NK and CD158b+ NK cells and the percentage of CD158b+ NK cells were significantly lower in patients with SARS than in those with M. pneumoniae infection (P < .05 for all) and healthy subjects (P < .01, P < .01, P < .05, respectively); in 72 patients with severe SARS than in 149 with mild SARS (P < .05 for all); and in 174 cases of SARS with anti-SARS coronavirus-specific IgG and/or IgM antibodies than in 47 without antibodies (P < .05, P < .01, P < .01, respectively). There were no significant differences for the 3 values among patients with SARS without anti-SARS coronavirus antibody, patients with M. pneumoniae infection, and healthy subjects. The number of NK cells and the expression of CD158b on the surface of NK cells changed in patients with SARS and correlated with disease severity and the presence of anti-SARS coronavirus-specific antibodies; SARS differed from M. pneumoniae infection in pathogenesis involving NK cells. Monitoring the total number of NK and CD158b+ NK cells and the percentage of CDD158b+ NK cells might aid in differentiating SARS from M. pneumoniae infection. ",0
2817,15081122,The novel mouse microphthalmia mutations Mitfmi-enu5 and Mitfmi-bcc2 produce dominant negative Mitf proteins,"Mutations in the microphthalmia-associated transcription factor (Mitf) gene affect the development of different cell types, including melanocytes, osteoclasts, and retinal pigmented epithelial cells of the eye. Many different mutations at the locus are known and since they affect the phenotype to different extents they form an allelic series. The Mitf protein is a member of the Mitf-Tfe subfamily of basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors and binds the 6-bp canonical CAC/TGTG sequence (E box) as either a homodimer or a heterodimer with related proteins. The many Mitf mutations have provided important insights into the in vivo behavior of a bHLH-Zip protein. Here we describe the phenotype of two new semidominant Mitf mutations recovered in recent mutagenic screens, Mitf(mi-enu5) and Mitf(mi-bcc2); determine the molecular lesions involved; and show that the mutant proteins act in a dominant negative fashion in vitro. The novel mutations are phenotypically distinct from previously known Mitf mutations. ",0
2818,15081388,Dimemorfan enhances acetylcholine release from rat hippocampal slices,"Our previous study reported that an antitussive drug, dimemorfan, attenuates cholinergic dysfunction-induced amnesia in mice and acts like a sigma1 receptor agonist. This study further showed that dimemorfan (30 microM), like the putative sigma1 receptor agonist (+)-SKF-10047 (10 microM), significantly enhanced 25 mM KCl-evoked [3H]acetylcholine release from rat hippocampal but not striatal slices, which was antagonized by a sigma1 receptor antagonist haloperidol (0.3 microM). ",0
2819,15082219,"The role of Ca2+ channel modulation in the neuroprotective actions of estrogen in beta-amyloid protein and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cytotoxic models","Physiologically relevant concentrations of 17beta-estradiol (E2) are neuroprotective in both beta-amyloid protein 25-35 (Abeta) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cytotoxicity in SK-N-SH cells. MPTP, but not Abeta, induces apoptosis in this cell line. The L-type calcium channel blocker nifedipine or decreased extracellular Ca(2+) concentration blocked Abeta-induced cell death, but not MPTP-induced cell death. Other blockers selective for different Ca(2+) channel subtypes had no effects on either Abeta or MPTP induced death. Western blot analysis for L-type Ca(2+) channel alpha(1)-subunits demonstrated that Abeta increases the expression of the neuronal alpha(1C) and alpha(1D) subunits of L-type channels. Both E2 and nifedipine inhibit the increase in expression of these by Abeta. MPTP also increases expression of alpha(1C) and alpha(1D), but the increases were not influenced by E2 or nifedipine. These observations suggested that Abeta cytotoxicity in SK-N-SH cells may involve increased availability of calcium to cells, whereas MPTP induced cytotoxicity does not require extracellular Ca(2+). Both cytotoxic models were associated with increased expression of Ca(2+) channel alpha(1) subunits, and neuroprotection associated with inhibition of that increase. These studies reveal that nifedipine, in addition to its direct action of nifedipine on Ca(2+) channels, may also protect neurons from Abeta toxicity through the suppression of the channel protein overexpression. A new action of dihydropyridines (DHPs) may be considered in the regulation of calcium homeostasis. ",0
2820,15082464,A comparison of two intensities of psychosocial intervention for alcohol dependent patients treated with acamprosate,"To compare two levels of psychosocial intervention in combination with acamprosate medication for the treatment of alcohol dependence. Patients (n = 70) were prescribed acamprosate and randomized to Minimal Psychosocial Intervention (MPI) or Extended Psychosocial Intervention (EPI). MPI patients met a psychiatrist for 20-30 min sessions on four occasions during a 6 month period. EPI patients were offered 10-15 sessions with a psychiatric nurse in addition to the visits to the psychiatrist. EPI patients were trained to use behavioural and cognitive coping skills to deal with high-risk situations in line with a manual developed for relapse prevention. Patients were assessed four times during the 24-week study by self-report and laboratory tests. Patients on average reported a decline in days with heavy drinking and in cumulative number of drinking days. No significant differences between patients in MPI and EPI were found with respect to heavy drinking, cumulative number of drinking days, number of days to first drink, or biomarkers of alcohol consumption. Higher age and lower level of education were significant predictors of treatment success. Adding more intensive individual treatments appears to add no extra improvement beyond that obtained by prescribing acamprosate and offering an infrequent consultation with a physician. ",0
2821,15082635,The metabolic syndrome and associated lifestyle factors among South Korean adults,"The importance of managing the metabolic syndrome has been emphasized in the prevention of cardiovascular disease. Although South Koreans have a low prevalence of obesity, little information is available about the prevalence of the metabolic syndrome and its associated risk factors. Data was obtained from individuals aged 20-79 years from the Korean National Health and Nutrition Examination Survey 1998, a cross-sectional health survey of a nationally representative sample of non-institutionalized civilian South Koreans. The prevalence of the metabolic syndrome, as defined by the Third Report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), was determined, and lifestyle factors associated with predisposition to the metabolic syndrome were analysed. Among South Korean adults, the age-adjusted prevalence of the metabolic syndrome was 14.2% for men and 17.7% for women, whereas the age-adjusted prevalence of obesity (body mass index (BMI) >or=30 kg/m(2)) was 1.7% and 3.0% for men and women, respectively. Age, unemployment, higher BMI, and current smoking were associated factors for the metabolic syndrome regardless of gender. Moderate exercise (2-3 sessions/week) in men and light alcohol drinking (<15 g/day) in women decreased the odds of the metabolic syndrome. Metabolic syndrome is present in more than 15% of South Koreans despite a low prevalence of obesity. Higher BMI and current smoking were identified as independent modifiable risk factors of the metabolic syndrome. Weight control and smoking cessation may therefore decrease the prevalence of the metabolic syndrome in South Korean adults. ",0
2822,15082739,Childhood abuse and risk of smoking onset,"To determine the association between childhood abuse and becoming a smoker. Retrospective cohort study. Boston, Massachusetts. 722 women aged 36-45 years who completed the baseline questionnaire for the Harvard study of moods and cycles and the survey of interpersonal relationships. Women who experienced either physical or sexual abuse as a child were 40% more likely to begin smoking compared with women with no history of abuse (95% CI 1.0 to 2.0). Virtually all of this association was confined to sexual abuse (OR = 2.2, 95% CI 1.1 to 4.3) as compared with physical abuse (OR = 0.7, 95% CI 0.7 to 1.6). However, the joint effect of experiencing both physical and sexual abuse as a child led to a 3.5-fold increase in the likelihood of becoming a smoker (95% CI 1.3 to 9.4) compared with women who did not experience any childhood abuse after adjustment for religion, social class, and poverty. Women who experience childhood abuse, even in the absence of depression, are at increased risk of becoming cigarette smokers. ",0
2823,15082868,The post-haemorrhagic vasopressin release into the blood,"The aim of the present study was to compare the influence of the renin-angiotensin and sympathetic system in the process of post-haemorrhagic vasopressin release. A dialysis of the venous blood from the sella turcica region was performed in male rats under anaesthesia. The animals were divided into eight experimental groups: 1). control; 2). bleeding; 3). 20 days after superior cervical ganglionectomy; 4). 20 days after superior cervical ganglionectomy and bleeding; 5). injection of captopril; 6). injection of captopril and bleeding; 7). 20 days after superior cervical ganglionectomy and injection of captopril; 8). 20 days after superior cervical ganglionectomy, injection of captopril and bleeding. The content of vasopressin in dialysates was determined by radioimmunoassay. In control rats the release of vasopressin into dialysates was constant during 180 min of the experiment. Bleeding, as well as, superior cervical ganglionectomy caused an increase in vasopressin release. Captopril did not change vasopressin release in comparison to control group. Furthermore, vasopressin release after both, bleeding and sympathetic denervation performed simultaneously was significantly abolished. We conclude that renin-angiotensin, as well as, sympathetic nervous system are involved in the increased post-haemorrhagic vasopressin release. ",0
2824,15082914,Steroid receptors and cell cycle in normal mammary epithelium,"The ovarian steroids estrogen and progesterone (E(2) and P) are essential for normal mammary gland growth and development; however, the mechanisms by which they influence the proliferative activity of the mammary epithelium remain unclear. Mammary epithelial cells cells expressing the receptors for E(2) and P (ER and PR respectively) are separate from, although often adjacent to, those capable of proliferating, implying that the ovarian steroids act indirectly via paracrine or juxtacrine growth factors to stimulate entry into the cell cycle. A large number of candidate factors have been identified in a variety of different experimental systems, and it appears that transforming growth factor beta may play a role in preventing proliferation of steroid receptor-containing cells. Dysregulation of the strict inverse relationship between ERalpha expression and proliferation is detectable in premalignant human breast lesions, indicating that it might be essential to the tumorigenic process. Challenges for the future include determining which of the candidates identified as being mediators of the effects of E(2) are physiologically and clinically relevant as well as finding out how ERalpha-containing cells become proliferative during tumorigenesis. Answering these questions could greatly increase our understanding of the factors controlling mammary gland development and the processes leading to cancer formation. ",0
2825,15083240,"Epidemiology, clinical features and treatment outcome of Wilms' tumor in Taiwan: a report from Taiwan Pediatric Oncology Group","Taiwan Pediatric Oncology Group (TPOG)-W-91 is the first multi-institutional Wilms' tumor study for children in Taiwan. This clinical trial used a multidisciplinary approach, based on and similar to the National Wilms' Tumor Study 4. The study was conducted to evaluate the epidemiological characteristics and analyze the outcome of Wilms' tumor patients treated with this protocol. Ninety eight children with Wilms' tumor (WT) were analyzed for distributions of age, gender, associated congenital anomalies, tumor sites, histology, tumor weights, and clinical stages. Patients received individualized multimodality treatment based upon the histology of the tumor and clinicopathologic stage. The treatment included surgery, radiotherapy and 2-, 3-, and 4-agent active chemotherapeutic agents. Seventy patients were eligible for analysis of treatment outcome. The endpoints were progression-free and overall survival (PFS, OS). Patients were divided into various subgroups according to the chemotherapy regimen used, tumor stage, age at diagnosis, gender, and tumor weight. The prognostic factors were evaluated and the survival rates of various clinical subgroups were compared using log-rank test. The average annual incidence rate of WT was 2.9 per million children under 15 years of age. The M/F ratio was 1.04. The mean age at diagnosis was 3.7 years. All bilateral tumors occurred in females. Congenital anomalies were present in 17.3% of patients. Anaplastic histology was found in 6 of 98 cases (6.1%). The stage distribution was: I, 43.2%; II, 19.3%; III, 23.9%; IV, 6.8%; and V, 6.8%. The median follow-up time was 89.1 months (range, 1.8 to 128.1 months). The 5-year PFS rate was 0.7841 (SE, 0.0494; 53 of 70 patients) and the 5-year OS rate was 0.886 (SE, 0.038; 63 of 70 patients). Gender was found to be the only significant prognostic variable. This study evaluated the epidemiological characteristics, clinical features, multimodality therapy regimens, and treatment outcome of WT in Taiwan. Data obtained from this study may lead to further improvement in the prognosis of pediatric malignant solid tumor. ",0
2826,15083393,Atypical HHS-syndrome--a rare differential diagnosis of circulatory disorders of the hand],"We report on an acral circulatory disorder of the hand, representing a Hypothenar-Hammer-Syndrome (HHS) with atypical symptoms. The patient suffered from a radial circulatory disorder of his right hand, clinically representing a secondary M. Raynaud. The symptoms occurred after a single severe trauma of the right hand and after using both hands like a hammer. Angiography showed a cork-screw sign of the A. ulnaris at the typical area and an open Arcus palmaris superficialis as well as occlusions of multiple finger arteries. Symptoms improved significantly after lysis. The most important differential diagnosis is endangiitis obliterans according to angiography. If symptoms occur again, histology is recommended to exclude vasculitis. Surgery should be discussed if the HHS is confirmed, since a cork-screw morphology of the A. ulnaris exists as well as perfusion of the fingers mainly via the A. ulnaris. Also a radial circulatory disorder of the hand combined with typical anamnesis may represent a HHS. ",0
2827,15084693,Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia,"BACKGROUND: In patients with acute myeloid leukemia (AML), the presence or absence of recurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the current classification system does not fully reflect the molecular heterogeneity of the disease, and treatment stratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype. METHODS: We used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normal karyotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups with distinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novel supervised learning algorithm to devise a gene-expression-based clinical-outcome predictor, which we then tested using an independent validation group comprising the 57 remaining patients. RESULTS: Unsupervised analysis identified new molecular subtypes of AML, including two prognostically relevant subgroups in AML with a normal karyotype. Using the supervised learning algorithm, we constructed an optimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patients in the independent validation group (P=0.006), including the subgroup of patients with AML with a normal karyotype (P=0.046). In multivariate analysis, the gene-expression predictor was a strong independent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P<0.001). CONCLUSIONS: The use of gene-expression profiling improves the molecular classification of adult AML.",0
2828,15102999,Evidence of airborne transmission of the severe acute respiratory syndrome virus,"BACKGROUND: There is uncertainty about the mode of transmission of the severe acute respiratory syndrome (SARS) virus. We analyzed the temporal and spatial distributions of cases in a large community outbreak of SARS in Hong Kong and examined the correlation of these data with the three-dimensional spread of a virus-laden aerosol plume that was modeled using studies of airflow dynamics. METHODS: We determined the distribution of the initial 187 cases of SARS in the Amoy Gardens housing complex in 2003 according to the date of onset and location of residence. We then studied the association between the location (building, floor, and direction the apartment unit faced) and the probability of infection using logistic regression. The spread of the airborne, virus-laden aerosols generated by the index patient was modeled with the use of airflow-dynamics studies, including studies performed with the use of computational fluid-dynamics and multizone modeling. RESULTS: The curves of the epidemic suggested a common source of the outbreak. All but 5 patients lived in seven buildings (A to G), and the index patient and more than half the other patients with SARS (99 patients) lived in building E. Residents of the floors at the middle and upper levels in building E were at a significantly higher risk than residents on lower floors; this finding is consistent with a rising plume of contaminated warm air in the air shaft generated from a middle-level apartment unit. The risks for the different units matched the virus concentrations predicted with the use of multizone modeling. The distribution of risk in buildings B, C, and D corresponded well with the three-dimensional spread of virus-laden aerosols predicted with the use of computational fluid-dynamics modeling. CONCLUSIONS: Airborne spread of the virus appears to explain this large community outbreak of SARS, and future efforts at prevention and control must take into consideration the potential for airborne spread of this virus.",0
2829,15122750,Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation,"The factors that regulate lymphocyte traffic in chronic hepatitis C (CHC) are not completely defined. Interferon (IFN)-inducible T cell alpha chemoattractant (I-TAC) is a relatively new member of the CXCR3 chemokine ligand family that selectively recruits activated T cells to sites of inflammation. To determine if I-TAC plays a role in CHC, we investigated I-TAC expression in hepatitis C virus (HCV)-infected liver biopsy material. I-TAC messenger RNA (mRNA) levels were significantly increased in HCV-infected liver compared with normal liver, which correlated with both portal and lobular inflammation. I-TAC expression was localized to hepatocytes throughout the liver lobule, with those in close proximity to active areas of inflammation expressing the highest concentration of I-TAC. In vitro, I-TAC mRNA and protein expression was inducible in Huh-7 cells following either IFN-alpha or -gamma stimulation and synergistically with tumor necrosis factor (TNF)-alpha. Furthermore, transfection of Huh-7 cells with either poly(I:C) or HCV RNA representing the HCV subgenomic replicon induced I-TAC mRNA expression. HCV replication was also found to modulate I-TAC expression, with stimulation of Huh-7 cells harboring either the HCV subgenomic or genomic replicon showing significantly increased synergistic effects compared with those previously seen in Huh-7 cells alone with IFN-gamma and TNF-alpha. In conclusion, these results suggest I-TAC, one of the most potent chemoattractants for activated T cells, is produced by hepatocytes in the HCV-infected liver and plays an important role in T cell recruitment and ultimately the pathogenesis of CHC.",0
2830,15122765,Thy1-positive mesenchymal cells promote the maturation of CD49f-positive hepatic progenitor cells in the mouse fetal liver,"Previously, we reported a system to enrich mouse fetal hepatic progenitor cells (HPCs) by forming cell aggregates. In this study, we sorted two cell populations, CD49f(+)Thy1(-)CD45(-) cells (CD49f-positive cells) and CD49f(+/-)Thy1(+)CD45(-) cells (Thy1-positive cells), from the cell aggregates using a flow cytometer. CD49f-positive cells stained positive for endodermal specific markers such as alpha-fetoprotein (AFP), albumin (ALB), and cytokeratin 19 (CK19), and are thus thought to be HPCs. However, Thy1-positive cells were a morphologically heterogeneous population; reverse-transcription polymerase chain reaction (RT-PCR) and immunocytochemical analyses revealed the expression of mesenchymal cell markers such as alpha-smooth muscle actin, desmin, and vimentin, but not of AFP, ALB, or CK19. Therefore, Thy1-positive cells were thought to be of a mesenchymal lineage. When these two cell populations were co-cultured, the CD49f-positive colonies matured morphologically and stored a significant amount of glycogen. Furthermore, real-time RT-PCR demonstrated an increased expression of tyrosine amino transferase and tryptophan oxygenase mRNA, and transmission electron microscopy confirmed that co-cultured cells produced mature hepatocytes. However, when CD49f-positive cells were cultured alone or when the two populations were cultured separately, the CD49f-positive cells did not mature. These results indicate that CD49f-positive cells are primitive hepatic endodermal cells with the capacity to differentiate into hepatocytes, and that Thy1-positive cells promote the maturation of CD49f-positive cells by direct cell-to-cell contact. In conclusion, we were able to isolate CD49f-positive primitive hepatic endodermal cells and Thy1-positive mesenchymal cells and to demonstrate the requirement of cell-to-cell contact between these cell types for the maturation of the hepatic precursors.",0
2831,15175438,Obesity and the metabolic syndrome in children and adolescents,"BACKGROUND: The prevalence and magnitude of childhood obesity are increasing dramatically. We examined the effect of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to insulin resistance and to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial cohort of children and adolescents. METHODS: We administered a standard glucose-tolerance test to 439 obese, 31 overweight, and 20 nonobese children and adolescents. Baseline measurements included blood pressure and plasma lipid, C-reactive protein, and adiponectin levels. Levels of triglycerides, high-density lipoprotein cholesterol, and blood pressure were adjusted for age and sex. Because the body-mass index varies according to age, we standardized the value for age and sex with the use of conversion to a z score. RESULTS: The prevalence of the metabolic syndrome increased with the severity of obesity and reached 50 percent in severely obese youngsters. Each half-unit increase in the body-mass index, converted to a z score, was associated with an increase in the risk of the metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95 percent confidence interval, 1.16 to 2.08), as was each unit of increase in insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95 percent confidence interval, 1.07 to 1.18 for each additional unit of insulin resistance). The prevalence of the metabolic syndrome increased significantly with increasing insulin resistance (P for trend, <0.001) after adjustment for race or ethnic group and the degree of obesity. C-reactive protein levels increased and adiponectin levels decreased with increasing obesity. CONCLUSIONS: The prevalence of the metabolic syndrome is high among obese children and adolescents, and it increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters.",0
2832,15185312,Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1,"Black Americans (blacks) have a high prevalence of chronic hepatitis C virus (HCV) infection and respond poorly to therapy with interferon alfa-based regimens, but they have been underrepresented in clinical trials. The aim of this study was to assess the rate of sustained virological response (SVR) to peginterferon alfa-2a (40 kd) in combination with ribavirin in black patients chronically infected with HCV genotype 1. In a prospective, multicenter, open-label trial, 78 black and 28 white American interferon-na?ve patients were enrolled to receive once weekly subcutaneous injections of 180 microg peginterferon alfa-2a plus oral ribavirin (1000 mg/d for patients weighing less than 75 kg and 1200 mg/d for patients weighing 75 kg or more) for 48 weeks. Pre- and post-treatment liver biopsies were evaluated for necroinflammation and fibrosis. SVR, defined as undetectable (<50 IU/mL) HCV RNA, was 26% in the black group and 39% in the white group. Although the SVR rate was lower in blacks than in whites, the SVR of 26% represents an improvement over previously reported SVR rates from smaller, retrospective studies of black patients. We also observed improvement in fibrosis in 25% of the black patients. No unexpected adverse events occurred. In conclusion, this prospective study evaluating responses of black patients with chronic hepatitis C to peginterferon alfa-2a/ribavirin has demonstrated that treatment can be safely offered to such individuals with reasonable antiviral and histological benefit.",0
2833,15185318,"Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers","The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.",0
2834,15201411,Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease,"BACKGROUND: Liposuction has been proposed as a potential treatment for the metabolic complications of obesity. We evaluated the effect of large-volume abdominal liposuction on metabolic risk factors for coronary heart disease in women with abdominal obesity. METHODS: We evaluated the insulin sensitivity of liver, skeletal muscle, and adipose tissue (with a euglycemic-hyperinsulinemic clamp procedure and isotope-tracer infusions) as well as levels of inflammatory mediators and other risk factors for coronary heart disease in 15 obese women before and 10 to 12 weeks after abdominal liposuction. Eight of the women had normal glucose tolerance (mean [+/-SD] body-mass index, 35.1+/-2.4), and seven had type 2 diabetes (body-mass index, 39.9+/-5.6). RESULTS: Liposuction decreased the volume of subcutaneous abdominal adipose tissue by 44 percent in the subjects with normal glucose tolerance and 28 percent in those with diabetes; those with normal oral glucose tolerance lost 9.1+/-3.7 kg of fat (18+/-3 percent decrease in total fat, P=0.002), and those with type 2 diabetes lost 10.5+/-3.3 kg of fat (19+/-2 percent decrease in total fat, P<0.001). Liposuction did not significantly alter the insulin sensitivity of muscle, liver, or adipose tissue (assessed by the stimulation of glucose disposal, the suppression of glucose production, and the suppression of lipolysis, respectively); did not significantly alter plasma concentrations of C-reactive protein, interleukin-6, tumor necrosis factor alpha, and adiponectin; and did not significantly affect other risk factors for coronary heart disease (blood pressure and plasma glucose, insulin, and lipid concentrations) in either group. CONCLUSIONS: Abdominal liposuction does not significantly improve obesity-associated metabolic abnormalities. Decreasing adipose tissue mass alone will not achieve the metabolic benefits of weight loss.",0
2835,15213739,"Phylogeny based on 16S rDNA and nifH sequences of Ralstonia taiwanensis strains isolated from nitrogen-fixing nodules of Mimosa pudica, in India","Bacterial symbionts present in the indeterminate-type nitrogen (N)-fixing nodules of Mimosa pudica grown in North and South India showed maximum similarity to Ralstonia taiwanensis on the basis of carbon-source utilization patterns and 16S rDNA sequence. Isolates from the nodules of M. pudica from North India and South India showed identical ARDRA (Amplified Ribosomal DNA Restriction Analysis) patterns with Sau3AI and RsaI, but AluI revealed dimorphy between the North Indian and South Indian isolates. Alignment of 16S rDNA sequences revealed similarity of North Indian isolates with an R. taiwanensis strain isolated from M. pudica in Taiwan, whereas South Indian isolates showed closer relatedness with the isolates from Mimosa diplotricha. Alignment of nifH sequences from both North Indian and South Indian isolates with that of the related isolates revealed their closer affinity to alpha-rhizobia, suggesting that nif genes in the beta-rhizobia might have been acquired from alpha-rhizobia via lateral transfer during co-occupancy of nodules by alpha-rhizobia and progenitors of R. taiwanensis, members of the beta-subclass of Proteobacteria. Immunological cross-reaction of the bacteroid preparation of M. pudica nodules showed strong a positive signal with anti-dinitrogenase reductase antibody, whereas a weak positive cross-reaction was observed with free-living R. taiwanensis grown microaerobically in minimal medium with and without NH4Cl. In spite of the expression of dinitrogenase reductase under free-living conditions, acetylene reduction was not observed under N-free conditions even after prolonged incubation. ",0
2836,15213750,Isolation of antibiotic-resistant and antimetabolite-resistant mutants of Frankia strains EuI1c and Cc1.17,"Antibiotic-resistant and antimetabolite-resistant mutants of the nitrogen-fixing symbiotic bacterium Frankia were isolated to provide strains with genetic backgrounds amenable to genetic analysis. The lethal and mutagenic effects of ethyl methanesulfonate (EMS) and UV light on four Frankia strains were investigated. UV irradiation or EMS treatment of strain EuI1c cells resulted in the formation of two different colony types: rough and smooth. The smooth colonies were conditional sporulation mutants. In the case of EMS-induced cells of strain Cc1.17, resistance to lincomycin, ampicillin, and 5-fluorouracil occurred at a frequency of 1 x 10(-5), 1 x 10(-5), and 4 x 10(-5), respectively. The lincomycin-resistant mutants produced a yellow-tan pigment that was released into the growth medium. Resistance to tetracycline and lincomycin with EMS-induced cells of strain EuI1c occurred at a frequency of 3.2 x 10(-3) and 4.7 x 10(-4), respectively. These strains will be useful for the development of genetic methods for Frankia. ",0
2837,15214038,Neonatal tolerance revisited again: specific CTL priming in mouse neonates exposed to small numbers of semi- or fully allogeneic spleen cells,"Neonatal and adult mice mount distinct responses to allogeneic cells. Injection of neonates with fully allogeneic cells results in lethal graft-vs.-host disease (GVHD), whereas injection of semi-allogeneic (F1) cells leads to lifelong tolerance to the alloantigens, often marked by specific CTL non-responsiveness. In contrast, adults injected with the same number of either cell type become primed and develop vigorous anti-donor CTL activity. One possibility for this differential responsiveness may be developmental immaturity in the CTL arm of the immune system. Recent studies have shown that neonates are capable of mounting mature CTL responses, but only in the presence of strong Th1-promoting agents. Here, we demonstrate that neonates are competent to develop vigorous MHC class I-restricted CTL activity in vivo upon exposure to either fully or semi-allogeneic spleen cells. Specific CTL activity was generated using doses of cells approximately tenfold lower than levels used for the induction of GVHD or tolerance. Thus, the present studies demonstrate that mouse neonates are fully mature in their capacity to develop alloreactive CTL activity, as long as the dose of donor cells is low enough. These results have important implications for the known exposure of human fetuses and infants to small numbers of maternal cells. ",0
2838,15214141,Nutritional supplementation for diabetic foot ulcers: the first RCT,"To determine if oral nutritional supplementation improved wound healing in malnourished patients with diabetic foot ulcers when compared with a placebo. This prospective randomised controlled double-blind trial involved patients aged over 60 with diabetes mellitus and a Wagner grade I-II foot ulcer of over four weeks' duration. Patients received either 400 ml (400 kcal) oral nutritional supplementation (n = 26) or 400 ml placebo (n = 27) daily for six months. Patients were followed monthly for six months and after one and two years. A third of the patients were classified as having protein-energy malnutrition at inclusion, with no difference between the two groups. Critical leg ischaemia was more common in the intervention group than in the placebo group (p = 0.008). Nine patients in the intervention group (35%) and four in the placebo group (15%) dropped out of the study (not significant). Of those who completed the study, the wound had healed at six months in eight out of 23 patients (41%) (placebo) and in seven out of 17 (35%) (intervention) (not significant). Twenty-four per cent of patients with protein-energy malnutrition at inclusion had healed at six months compared with 50% of those without it (not significant). This is the first study to evaluate the possible benefits of nutritional supplementation on diabetic foot ulcers. A third of patients were malnourished. We encountered several methodological problems and were unable to demonstrate an improved wound healing rate in these patients. ",0
2839,15214252,Four-month breastfeeding duration in postcesarean women of different cultures in the Israeli Negev,"The objective of the study was to increase breastfeeding initiation and duration rates among postcesarean women by implementing a culturally appropriate breastfeeding intervention. This study was a prospective population-based, controlled evaluation of a breastfeeding intervention consisting of 570 Jewish and Muslim postcesarean women who had delivered healthy, term infants at an Israeli hospital. Women in the control group (n = 264) received standard hospital care and women in the intervention group (n = 306) received early, culturally sensitive, postcesarean breastfeeding guidance. Surveys regarding breastfeeding duration practices were conducted at 10 and 16 weeks postpartum. Overall and exclusive 4-month breastfeeding duration rates were significantly higher for the intervention group as compared to the control group for the Jewish women at 10 and 16 weeks postpartum. Since few Muslim women ceased breastfeeding, only exclusive breastfeeding rates were evaluated. At 10 and 16 weeks, significantly more Muslim women in the intervention group were exclusively breastfeeding as compared to the control group, although rates dramatically declined by 16 weeks. Despite the challenges to breastfeeding posed by cesarean delivery, early and appropriate breastfeeding guidance facilitated successful outcomes for both Jewish and Muslim women. ",0
2840,15214588,An update on Intravenous Regional Anaesthesia of the arm,"""Intravenous Regional Anaesthesia (IVRA) has been first described in 1908 by the german surgeon August KG Bier. Although the technique was easy to perform and effective in giving surgical anaesthesia, the newer plexus block techniques largely replaced in a short time the """"Bier block"""", because of time limitations of IVRA and safety considerations. Throughout the years modifications in procedure and new pharmacologic adjuvants have been shown to prevent toxic reactions to anaesthetics and mitigate limitations of IVRA. This paper rewiews the technique itself, its historical background, procedural modifications to improve its safety and efficiency, pharmacologic adjuvants acting on onset time of anaesthesia and on tourniquet pain, and drugs improving postoperative analgesia and muscle relaxation. The economic side of IVRA is also discussed. """,0
2841,15215142,Substitutions at methionine 220 in the 14alpha-sterol demethylase (Cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs,"Five clinical isolates of Aspergillus fumigatus that exhibited similar patterns of reduced susceptibility to itraconazole and other triazole drugs were analyzed. Sequence analysis of genes (cyp51A and cyp51B) encoding the 14alpha-sterol demethylases revealed that all five strains harbored mutations in cyp51A resulting in the replacement of methionine at residue 220 by valine, lysine, or threonine. When the mutated cyp51A genes were introduced into an A. fumigatus wild-type strain, the transformants exhibited reduced susceptibility to all triazole agents, confirming that the mutations were responsible for the resistance phenotype. ",0
2842,15215413,MITOPRED: a web server for the prediction of mitochondrial proteins,"MITOPRED web server enables prediction of nucleus-encoded mitochondrial proteins in all eukaryotic species. Predictions are made using a new algorithm based primarily on Pfam domain occurrence patterns in mitochondrial and non-mitochondrial locations. Pre-calculated predictions are instantly accessible for proteomes of Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila, Homo sapiens, Mus musculus and Arabidopsis species as well as all the eukaryotic sequences in the Swiss-Prot and TrEMBL databases. Queries, at different confidence levels, can be made through four distinct options: (i) entering Swiss-Prot/TrEMBL accession numbers; (ii) uploading a local file with such accession numbers; (iii) entering protein sequences; (iv) uploading a local file containing protein sequences in FASTA format. Automated updates are scheduled for the pre-calculated prediction database so as to provide access to the most current data. The server, its documentation and the data are available from http://mitopred.sdsc.edu. ",0
2843,15215475,MoViES: molecular vibrations evaluation server for analysis of fluctuational dynamics of proteins and nucleic acids,"Analysis of vibrational motions and thermal fluctuational dynamics is a widely used approach for studying structural, dynamic and functional properties of proteins and nucleic acids. Development of a freely accessible web server for computation of vibrational and thermal fluctuational dynamics of biomolecules is thus useful for facilitating the relevant studies. We have developed a computer program for computing vibrational normal modes and thermal fluctuational properties of proteins and nucleic acids and applied it in several studies. In our program, vibrational normal modes are computed by using modified AMBER molecular mechanics force fields, and thermal fluctuational properties are computed by means of a self-consistent harmonic approximation method. A web version of our program, MoViES (Molecular Vibrations Evaluation Server), was set up to facilitate the use of our program to study vibrational dynamics of proteins and nucleic acids. This software was tested on selected proteins, which show that the computed normal modes and thermal fluctuational bond disruption probabilities are consistent with experimental findings and other normal mode computations. MoViES can be accessed at http://ang.cz3.nus.edu.sg/cgi-bin/prog/norm.pl. ",0
2844,15215481,Long-term survival of children with end-stage renal disease,"BACKGROUND: Although renal-replacement therapy for children with end-stage renal disease has been used for several decades, data on patients' long-term survival are sparse. METHODS: We examined the long-term survival of all children and adolescents who were under 20 years of age when renal-replacement therapy commenced (study period, April 1963 through March 2002), using data from the Australia and New Zealand Dialysis and Transplant Registry. Survival was analyzed with the use of Kaplan-Meier methods and age-standardized mortality rates. Risk factors for death were analyzed with the use of Cox regression analysis with time-dependent covariates. RESULTS: A total of 1634 children and adolescents were followed for a median of 9.7 years. The long-term survival rate among children requiring renal-replacement therapy was 79 percent at 10 years and 66 percent at 20 years. Mortality rates were 30 times as high as for children without end-stage renal disease. Risk factors for death were a young age at the time renal-replacement therapy was initiated (especially for children under 1 year of age, among whom the risk was four times as high as for children 15 to 19 years of age) and treatment with dialysis (which was associated with a risk more than four times as high as for renal transplantation). Overall, a trend toward improved survival was observed over the four decades of the study. CONCLUSIONS: Despite improvement in long-term survival, mortality rates among children requiring renal-replacement therapy remain substantially higher than those among children without end-stage renal disease. Increasing the proportion of children treated with renal transplantation rather than with dialysis can improve survival further.",0
2845,15215543,Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings,"To retrospectively evaluate computed tomographic (CT) features of pleomorphic carcinoma of the lung and to compare these features with pathologic findings. Ten patients (10 men, three women; mean age at diagnosis, 64.1 years; range, 43-75 years) with pleomorphic carcinoma treated from June 2000 to January 2003 were selected from two institutions. Two radiologists retrospectively reviewed CT features, which included size and location of tumor, presence of calcification, attenuation values and internal architecture of the mass, and invasion of pleura and chest wall. Attenuation values of the mass on CT scans were compared with pathologic findings in tumors in available gross specimens. Follow-up CT scans were not routinely obtained except in two patients with progressive pleural effusion and rapid growth of the tumor as seen on serial chest radiographs. On unenhanced CT scans, attenuation of the tumor was similar to that of the surrounding muscle. Calcification within the tumor was visible in one patient. Invasion of chest wall was noted in two patients. Seven patients had pleural invasion. Tumors were located at the lung periphery in nine patients. On contrast material-enhanced CT scans, lesions with the longest diameter larger than 5 cm showed central low-attenuation areas with substantial enhancement in the tumor periphery; in comparison, lesions with the longest diameter smaller than 5 cm showed homogeneous enhancement. Size of two lesions with the longest diameter larger than 5 cm increased rapidly after a follow-up of shorter than 3 weeks. Low-attenuation areas on contrast-enhanced CT scans were found to correspond to areas of myxoid degeneration, necrosis, or hemorrhage in pathologic specimens. Findings of this study suggest that pleomorphic carcinomas of the lung preferentially manifest as large peripheral lung neoplasms with a central low-attenuation area and frequently invade the pleura and chest wall. ",0
2846,15215588,"Biphenyl-inducible promoters in a polychlorinated biphenyl-degrading bacterium, Rhodococcus sp. RHA1","Five transcriptional promoters of biphenyl-degradation genes in Rhodococcus sp. RHA1 were characterized. We newly identified the etbA4 promoter region, which was located adjacent upstream from a ferredoxin reductase gene, etbA4 and a dihydrodiol dehydrogenase gene, bphB2. The etbA4 promoter activity was determined in RHA1 using a promoter probe vector with a luxAB luciferase reporter gene, and was induced by a variety of aromatic compounds as well as the bphA1, ebdA1, etbA1, and etbD1 promoters. All these promoters were induced by aromatic compounds in a closely related heterologous host, R. erythropolis IAM1399 in the presence of RHA1 bphST genes, suggesting that these five promoters are under the control of bphST-coding two-component regulatory system. Sequence comparison of the bphA1 promoter with the ebdA1 and etbA1 promoters, whose transcription starts were determined by primer extension analysis, revealed a consensus sequence centering 42-bp upstream from the transcription start. This consensus was also conserved in the etbA4 and etbD1 promoters, and deletions of the bphA1 promoter affecting the consensus impaired inducible promoter activity. These results suggest that this consensus plays a role in transcription induction and/or the promotion of biphenyl degradation genes in RHA1. ",0
2847,15215600,"Kinetic analysis of a chitinase from red sea bream, Pagrus major","Kinetic analysis was done on the 46-kDa chitinase (EC 3.2.1.14) purified from the stomach of red sea bream, Pagrus major, using glycolchitin and N-acetylchitooligosaccharides (GlcNAc(n), n=2-6) as substrates. High activity was observed at two pHs, such as 2.5 and 9.0, toward glycolchitin as seen in other insect chitinases, and also at both pH 2.5 and 5.0 even toward a short substrate, N-acetylchitopentasaccharide. Allosamidin competitively inhibited chitinase with Ki value of 0.0214 microM at pH 2.5 and 0.0024 microM at pH 9.0 in the reaction of glycolchitin. Substrate inhibition was observed in the reaction of N-acetylchitopentasaccharide. The anomeric forms of the products from N-acetylchitooligosaccharides were analyzed to be beta anomer by the high pressure liquid chromatography (HPLC) method. The data for both beta-anomer formation and allosamidin inhibition suggest that red sea bream chitinase belongs to family 18 of glycosyl hydrolases. This suggestion is also supported by the results for the N-terminal amino acid sequence. ",0
2848,15215881,Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors,"The Global Study of Sexual Attitudes and Behaviors (GSSAB) is an international survey of various aspects of sex and relationships among adults aged 40-80 y. An analysis of GSSAB data was performed to estimate the prevalence and correlates of sexual problems in 13,882 women and 13,618 men from 29 countries. The overall response rate was modest; however, the estimates of prevalence of sexual problems are comparable with published values. Several factors consistently elevated the likelihood of sexual problems. Age was an important correlate of lubrication difficulties among women and of several sexual problems, including a lack of interest in sex, the inability to reach orgasm, and erectile difficulties among men. We conclude that sexual difficulties are relatively common among mature adults throughout the world. Sexual problems tend to be more associated with physical health and aging among men than women. ",0
2849,15216199,Calcium antagonists: A new class of therapeutic agents,"A new class of therapeutic agents, sharing inhibition of the slow calcium channel, will soon be available to the American patient. Selective action of these agents upon the atrioventricular node, the smooth muscle of coronary and peripheral arteries, and the contractility of cardiac muscle opens new vistas in cardiovascular pharmacology. Early release of these agents by the Federal Drug Administration for general use is urged, based upon the already wide and successful experience in the European and South American continents. ",0
2850,15216205,Left ventricular aneurysm: Twenty-year surgical experience with 1572 patients at the Texas Heart Institute,"From January 1958 through December 1979, 1572 patients underwent surgery for left ventricular aneurysm (LVA) in our institution. The series included 1365 men and 207 women, with a ratio of 6.5:1. Ages ranged from 25 to 79 years, with a mean of 54.7 years. Most patients were in NYHA functional Class III or IV, and all had sustained at least one documented myocardial infarction. During the first decade, LVA resection alone was performed, but after the advent of aortocoronary bypass (ACB) surgery, the majority of patients underwent ACB along with LVA resection. Some required additional septoplasty, mitral valve replacement, annuloplasty, or aortic valve replacement. In all groups, the mortality was higher for women than for men. Early deaths were due primarily to acute or progressive myocardial failure secondary to recurrent myocardial infarction. Follow-up information for 6 months to 8 years was obtained by means of questionnaires submitted to patients and referring physicians. Of 475 patients who underwent LVA resection and ACB and who responded, 92.2% were either improved or asymptomatic. ",0
2851,15216450,Non-functioning pituitary adenomas: endocrinological and clinical outcome after transsphenoidal and transcranial surgery,"To study improvement of anterior pituitary function after transsphenoidal and transcranial surgery of non-functioning (NF) pituitary macro- and microadenomas. We retrospectively examined 155 patients with NF adenomas preoperatively and 3 months, 1 year and 2 years postoperatively. 130 patients harboured a macroadenoma, 109 underwent transsphenoidal (group one), 21 transcranial surgery (group two). 25 patients presented a microadenoma (transsphenoidal surgery, group three). Endocrine studies included basal serum levels and dynamic testing of anterior pituitary partial function. Clinical symptoms and hormone replacement therapy were documented. Preoperatively, in group one, two and three, somatotropic function was impaired in 85, 90 and 80 %, gonadotropic in 61, 57 and 24 %, corticotropic in 31, 38 and 28 %, thyreotropic in 32, 38 and 12 % and lactotropic in 22, 38 and 32 % cases, respectively. Pituitary functions did not improve significantly after transsphenoidal or transcranial surgery. Presurgically, 63, 62 and 0 % patients complained about visual impairments, 60, 48 and 40 % about headache, 53, 24 and 36 % about fatigue and 28, 33 and 20 % about disturbance of cycle or potency. After transsphenoidal surgery, impaired vision, headache and fatigue improved within 3 months; after transcranial surgery, only headache improved. Preoperatively, pituitary malfunctions were treated adequately. Postsurgically, more patients received adrenal and thyroid hormone substitution, less patients received sex hormones than examinations proved necessary. Anterior pituitary function of NF adenoma patients did not improve significantly after transsphenoidal or transcranial surgery. After transsphenoidal surgery, most clinical symptoms normalised within 3 months. In some of the patients, substitution was not optimally adjusted to hormonal impairments. ",0
2852,15216454,HIV-1 promotes quiescence in human neural progenitor cells,"The exact mechanism by which human immunodeficiency virus type 1 (HIV-1) produces dementia remains obscure. We have recently found that chemokines can inhibit neural progenitor cell proliferation. We hypothesized that HIV-1 could also inhibit neural progenitor cell proliferation by chemokine receptor signaling. We found that HIV-1 coat proteins that used C-C chemokine receptor 3 or C-X-C chemokine receptor 4 as coreceptors inhibited proliferation of neural progenitor cells in isolated cultures, as well as in hippocampal slices. The cerebrospinal fluid from patients with dementia also inhibited neural progenitor cell proliferation in these culture systems. To obtain an in vivo correlation, we examined hippocampus tissue obtained from patients with dementia at autopsy and found reduced numbers of neural progenitor cells in patients with dementia, compared with patients without dementia. Apolipoprotein E3, but not E4, antagonized the effects of coat proteins. We found reduced phosphorylation of extracellular signal-regulated kinase in neural progenitor cells treated with coat proteins, which may explain the protein's mechanism of action. We conclude that HIV-1 inhibits neural progenitor cell proliferation, which may result in impaired ability to form new memories and learn new tasks. ",0
2853,15216484,Cardiovascular risk in stage 4 and 5 nephropathy,"""Severity of heart disease of almost all types, as well as mortality risk associated with heart disease, increases in step with severity of kidney disease, although not necessarily in a linear fashion. Heart failure is more common and just as lethal as ischemic heart disease in patients with severe chronic kidney disease (CKD). The incidence of nonfatal heart disease in dialysis and transplant populations has now been described in detail. Although standard risk factors for heart disease that are more common among patients with CKD than in the general population do not adequately explain the greatly increased risk of heart disease in patients with severe CKD, neither do as yet identified """"nontraditional"""" risk factors. However, in addition to the factors not common in the general population, such as anemia, hyperphosphatemia, and markers of systemic inflammation, patients with CKD in the modern era may also exhibit excessive thrombotic tendencies. Screening for heart disease in this population relies mainly on dobutamine stress echocardiography or nuclear scintigraphy. The role of electron beam CT (EBCT) scanning is currently controversial. The indications for coronary angiography are the same for patients with CKD as for the general population, but patients with CKD are at greatly increased risk for contrast-associated nephropathy, the least controversial preventive therapy, which consists of isotonic saline and N-acetylcysteine. Finally, patients with CKD do not currently receive adequate medical therapy for prevention and treatment of heart disease. """,0
2854,15216968,"Present state of social participation and associated factors among middle-aged and older people--a survey in Hatoyama Town, Saitama Prefecture]","Many studies have documented that social participation is beneficial for maintaining autonomy and quality of later life. However, little is known about present state of social participation in the Japanese elderly and effective means for its promotion. To establish what factor might promote social participation in later life, this study was performed to examine the present state of social participation and a number of parameters among middle-aged and older people living in a Japanese community. The subjects comprised 1,568 residents aged 55 to 79 years, a 1/3 random sample selected from the total population of this age group in H town, Saitama Prefecture. They were requested to answer the questionnaire delivered by mail. We examined the level of social participation from four aspects: work, social and volunteer activities, individual pursuits and study activities, and analyzed possible associations with demographic, socio-economic, health-, and community-related variables by multiple regression analysis. A total of 964 persons answered the questionnaire (61.5% response rate). Age and gender were associated with each of four social activity domains. Living arrangements (with or without spouse) were independently associated with social and volunteer activity, and study. Educational attainment positively correlated with work and individual pursuits. Residents in a newly constructed town-region were less likely to engage in work, social and volunteer activities, and study than their counterparts living in an older town-region. Those who had a stronger sense of co-living in the community, and who would like to keep their social activity level, were more likely to participate in social and volunteer, as well as study activities and also individual pursuits. People feeling that the municipality should support social activities among residents had a higher level of study activity. These results show that cultivating a sense of co-living in the community among residents and maintaining their motivation are needed for promoting social participation among older residents. To what extent public support should meet potential needs of social participation remains for further study. ",0
2855,15217375,Exposure to interferon-gamma during synaptogenesis increases inhibitory activity after a latent period in cultured rat hippocampal neurons,"Certain disorders of the nervous system may have their origin in disturbances in the development of synaptic connections and network structure that may not become overt until later in life. As inflammatory cytokines can influence synaptic activity in neuronal cultures, we analysed whether cytokine exposure during synaptogenesis can lead to imbalances in a neuronal network. Short-term application of interferon-gamma (IFN-gamma), but not tumour necrosis factor-alpha, during peak synaptogenesis (but not before or after) in Sprague-Dawley rat hippocampal cultures, caused both a decrease in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) and an increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). These effects were only detected in recordings made weeks later. This was not due to a depression of glutamatergic synapses or to a change in the relative number of neurons containing glutamic acid decarboxylase (GAD). There was an increase in the average amplitude of miniature IPSCs, and in GAD-expressing neurons the amplitude of miniature EPSCs were larger as well as the responses to glutamate. This indicates that IFN-gamma-treatment induced increased inhibition via postsynaptic changes. These effects of IFN-gamma treatment were not observed when neuronal nitric oxide synthase was inhibited. Our study therefore shows that exposure to IFN-gamma during a restricted period of development, which coincides with the peak of excitatory synaptogenesis, can cause progressive changes in synaptic activity in the network. Thus, cytokine exposure at a critical period of development may constitute a 'hit-and-run' mechanism for certain nervous system disorders that become manifest after a latency period. ",0
2856,15217599,Assessment of parallel acquisition techniques in adrenal magnetic resonance imaging: does increased temporal resolution significantly improve visualization of adrenal lesions?,"To compare conventional radiofrequency coil reception techniques with parallel coil array acquisition methods in adrenal tissue visualization and to evaluate the dependence of temporal resolution on image quality in adrenal magnetic resonance magnetic resonance (MR) imaging. Using a 1.5 T MR imager, conventional and parallel sampled sequences were acquired in 10 healthy volunteers and 10 patients with adrenal lesions. The imaging protocol consisted of: conventional (TR/TE 4,730/125 ms; FA 150 degrees; NA 1; AT 25 s), and two parallel imaging SMASH techniques (TR/TE 4,090/125 ms; FA 150 degrees; NA 1 resulting in an AT of 12 s, as well as NA 2 resulting in an AT of 24 s) with generalized autocalibration T(2)-weighted turbo spin echo sequences with 5 mm slice thickness, 1.6 mm in-plane resolution, and an acceleration factor 2. Severity of breathing motion and aliasing artifact and overall image quality were rated on five-point scales and evaluated with student's t test; a differential receiver operating characteristic (DROC) analysis was performed. Adrenal gland findings included adenomas, metastases, and hemorrhages. Acceleration of conventional turbo spin echo sequence with one signal average led to an increase in diagnostic power (DROC 0.362) as well as significant improvement in overall image quality (P(Volunteers) =.017; P(Patients) =.042) and reduction of breathing motion artifact in patients (P(Patients) =.012) while improving the temporal resolution. Parallel imaging with two signal averages resulted in further improvement of image quality over conventional imaging (DROC 0.303), (P(Volunteers) =.045; P(Patients) =.022), in the same acquisition time as the conventional method. Parallel acceleration of sequences used for adrenal tissue visualization leads to a significant increase in diagnostic quality by significantly reducing breathing motion artifacts without sacrificing contrast indispensable for adrenal lesion characterization. ",0
2857,15218175,Comparison of the effects of RNase-negative and wild-type classical swine fever virus on peripheral blood cells of infected pigs,"Elimination of the RNase activity of classical swine fever virus (CSFV) glycoprotein E(rns) was previously shown to result in virus attenuation. Specific reduction of B cell numbers in the peripheral blood, a typical symptom of CSFV infection in pigs, was not detected on infection with the RNase-negative mutant C-H346Delta [Meyers et al. (1999). J Virol 73, 10224-10235]. The present report shows that this feature is restricted to this specific virus mutant, and does not represent a general property of RNase-negative CSFV. The effects induced by infection with two other RNase-negative and wild-type (wt) CSFV strains on the composition of peripheral blood cells have been further analysed. For all viruses, not only general leukopenia but also a reduction of different subsets of leukocytes (T-lymphocytes, monocytes and granulocytes) was detected. Similar to the results with B-cells, no significant differences with regard to changes in cell number were determined for RNase-negative mutants and wt virus during the initial phase of infection. Later, the values returned to pre-infection levels for the mutants, but stayed at low levels in the wt virus-infected animals. A major difference was reflected in the virus load of the infected animals, which was dramatically higher for pigs infected with wt CSFV, so that reduction of the virus load represents a further marker for attenuation resulting from RNase destruction. Attenuation was also detectable for the RNase-negative mutant C-W300G, which showed rapid reversion to the wt sequence within the infected pig. The prevention of fatal disease after infection with C-W300G is apparently determined during the short time between infection and reversion, as the virus revertant reisolated from infected pigs was shown to be virulent when used for infection in a follow-up study. Reversion of C-W300G was also detected in tissue culture during passage on swine testis epithelioid cells and porcine transformed kidney (MAX) cells, whereas the mutation was stable when SK6 or 38A1D cells were tested. ",0
2858,15218938,Selective and independent activation of four motor fascicles using a four contact nerve-cuff electrode,"""Any one of the four motor nerves in the cat sciatic nerve could be activated selectively and independently, from threshold to saturation, using a self-sizing spiral cuff electrode containing four radially placed monopolar contacts. These studies were carried out in nine adult cats with acute implants. Of the 36 possible fascicles, 23 fascicles could be activated selectively with current stimuli applied to a single contact and ten of the remaining fascicles could be activated selectively with current stimuli applied to two contacts, """"field steering."""" In three experiments, time constraints precluded attempting selective activation through """"field steering"""" techniques. In eight of the ten cases where """"field steering"""" was used, a positive and a negative current source (anodic steering) were required to achieve the desired fascicle and in the remaining two cases, two negative current sources (cathodic steering) were required. The relative distance from the electrode contacts to each fascicle was well correlated to the order in which each fascicle was activated. In seven experiments, carried out in two animals, selective activation was verified by collision block techniques. The results of these experiments support the hypothesis that selective and independent activation of any of four motor fascicles in the cat sciatic nerve is possible using a four contact self-sizing spiral cuff electrode. Furthermore, in a more general case, these results support the concept of a """"tunable"""" electrode that is capable of """"steering"""" the excitation from an undesirable location to a preferred location. """,0
2859,15219146,Patient flow in hospitals: understanding and controlling it better,"Because waits, delays, and cancellations are so common in healthcare, patients and providers assume that waiting is an inevitable, but regrettable, part of the care process. For years, hospitals responded to delays by adding resources--more beds and buildings or more staff--as the only way to deal with an increasingly needy population. Furthermore, as long as payment for services covered the costs, more construction and more staff allowed for continued inefficiencies in the system. Today, few organizations can afford this solution. Moreover, recent work on assessing the reasons for delays suggests that adding resources is not the answer. In many cases, delays are not a resource problem; they are a flow problem. The Institute for Healthcare Improvement has worked with more than 60 hospitals in the United States and the United Kingdom to evaluate what influences the smooth and timely flow of patients through hospital departments and to develop and implement methods for improving flow. Specific areas of focus include smoothing the flow of elective surgery, reducing waits for inpatient admission through emergency departments, achieving timely and efficient transfer of patients from the intensive care unit to medical/surgical units, and improving flow from the inpatient setting to long-term-care facilities. ",0
2860,15219322,Impact of conventional anesthesia on auditory brainstem responses in mice,"Anesthesia is known to affect the auditory brainstem response (ABR) in animals often used in hearing research. This study describes the differences in ABRs between awake and anesthetized FVB/N mice. Intracranial electrodes connected to a head fixation pedestal were used for click-evoked ABR recordings. This pedestal served to immobilize mice, either awake or under anesthesia, in a 'free' sound field. The presence of myogenic noise in the awake condition obviously increases recording time. However it is demonstrated that recording times can be significantly reduced by increasing the stimulus repetition rate from 23 up to 80 impulses per second. This causes only a small but significant increase in absolute peak latencies in the awake condition, but has no significant effect on the overall ABR-waveform, nor on the ABR-threshold, nor on the ABR interpeak latencies, nor on the absolute peak latencies in the anesthetized condition. Anesthesia with ketamine/xylazine caused a significant prolongation of ABR-peak latencies and interpeak latencies as well as a significant upward shift (8.0+/-1.8 dB) of ABR-thresholds as compared to the awake condition. Under anesthesia the measurement accuracy of peak latencies, interpeak latencies and thresholds decreases. In conclusion, the awake condition is preferable for more accurate measurements of ABR characteristics, in spite of the myogenic noise concomitant with this condition. ",0
2861,15219624,Changes in caffeine consumption as a signal of pregnancy,"The purpose of this prospective study was to examine caffeine consumption and other signals of early pregnancy. One hundred and five pregnant, nonsmoking, coffee drinkers ages 18-40 were enrolled by the ninth week after their last menstrual period (LMP). Participants kept daily diaries of beverage and caffeine consumption and symptoms. Urine samples were collected to assess hormone metabolites. Descriptive statistics were generated. During the first trimester, 96% of subjects decreased or quit drinking coffee, 65% of whom reported a unique aversion to coffee. The mean daily caffeine consumption at LMP from coffee alone was 119 mg (S.D., 105), with a range 1-574 mg. There was a 59% decrease of mean daily consumption of caffeine from coffee between weeks 4 and 6, from 96 to 39 mg. The vast majority of subjects experienced nausea (98%) and appetite loss (93%); vomiting was less prevalent (54%). The most common dietary aversions included meat, coffee, spicy foods, and dairy products. Hormone metabolite patterns are reported. Signals of early pregnancy included an aversion to coffee in addition to nausea and vomiting, which resulted in decreased caffeine consumption. These symptoms often interfered with daily life and lasted beyond the first trimester for many. Consideration should be given that a decrease in caffeine consumption may be a signal for a healthy pregnancy and acting as a confounder. ",0
2862,15220298,Functional magnetic resonance imaging during hypotension in the developing animal,"Hypotension in adult animals recruits brain sites extending from cerebellar cortex to the midbrain and forebrain, suggesting a range of motor and endocrine reactions to maintain perfusion. We hypothesized that comparable neural actions during development rely more extensively on localized medullary processes. We used functional MRI to assess neural responses during sodium nitroprusside challenges in 14 isoflurane-anesthetized kittens, aged 14-25 days, and seven adult cats. Baseline arterial pressure increased with age in kittens, and basal heart rates were higher. The magnitude of depressor responses increased with age, while baroreceptor reflex sensitivity initially increased over those of adults. In contrast to a decline in adult cats, functional MRI signal intensity increased significantly in dorsal and ventrolateral medullary regions and the midline raphe in the kittens during the hypotensive challenges. In addition, significant signal intensity differences emerged in cerebellar cortex and deep nuclei, dorsolateral pons, midbrain tectum, hippocampus, thalamus, and insular cortex. The altered neural responses in medullary baroreceptor reflex sites may have resulted from disinhibitory or facilitatory influences from cerebellar and more rostral structures as a result of inadequately developed myelination or other neural processes. A comparable immaturity of blood pressure control mechanisms in humans would have significant clinical implications. ",0
2863,15220426,Inhibition of severe acute respiratory syndrome virus replication by small interfering RNAs in mammalian cells,"Severe acute respiratory syndrome (SARS) is an acute respiratory infectious disease that spread worldwide in early 2003. The cause was determined as a novel coronavirus (CoV), SARS-associated CoV (SARS-CoV), with a single-stranded, plus-sense RNA. To date, no effective specific treatment has been identified. To exploit the possibility of using RNA interference as a therapeutic approach to fight the disease, plasmid-mediated small interfering RNAs (siRNAs) were generated to target the SARS-CoV genome. The expression of siRNAs from two plasmids, which specifically target the viral RNA polymerase, effectively blocked the cytopathic effects of SARS-CoV on Vero cells. These two plasmids also inhibited viral replication as shown by titer assays and by an examination of viral RNA and protein levels. Thus, our results demonstrated the feasibility of developing siRNAs as effective anti-SARS drugs. ",0
2864,15220491,CT of coronary artery disease,"The socioeconomic importance of heart disease provides considerable motivation for development of radiologic tools for noninvasive imaging of the coronary arteries. Current computed tomographic (CT) techniques combine high speed and spatial resolution with sophisticated electrocardiographic synchronization and robustness of use. Application of these modalities for evaluation of coronary artery disease is a topic of active current research. Coronary artery calcium measurements with different CT techniques have been used for determining the risk of coronary events, but the exact role of this marker for cardiac risk stratification remains unclear pending results of population-based studies. Contrast material-enhanced CT coronary angiography has become an established clinical indication for some scenarios (eg, coronary artery anomalies, bypass patency, surgical planning). With current technology, the accuracy of CT coronary angiography for detection of coronary artery stenoses appears promising enough to warrant pursuit of this application, but sensitivity is still not high enough for routine diagnostic needs. The high negative predictive value of a normal CT coronary angiogram, however, may be useful for reliable exclusion of coronary artery stenosis. The cross-sectional nature of CT may allow noninvasive assessment of the coronary artery wall. Use of contrast-enhanced CT coronary angiography for detection, characterization, and quantification of atherosclerotic changes and total disease burden in coronary arteries as a potential tool for cardiac risk stratification is currently being investigated. ",0
2865,15220666,The role of probiotics in the clinical management of food allergy and atopic dermatitis,"The probiotics are cultures of potentially beneficial bacteria that positively affects host by enhancing the microbial balance and therefore restore the normal intestinal permeability and gut microecology, improve the intestine's immunologic barrier function and reduce the generation of proinflammatory cycochines characteristics of allergic inflammation. The authors made a survey of the most relevant studies concerning the use of probiotics in the food allergy, atopic dermatitis, and in primary prevention of atopy. On the basis of these trials probiotic therapy alleviates allergic inflammation as demonstrated by the control of clinical symptoms and the reduction of local and systemic inflammatory markers. ",0
2866,15221235,The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein,"The influenza-virus M2 protein has proton channel activity required for virus uncoating and maturation of hemagglutinin (HA) through low-pH compartments. The proton channel is cytotoxic in heterologous expression systems and can be blocked with rimantadine. In an independent, rimantadine-resistant function, M2, interacting with the M1 protein, controls the shape of virus particles. These bud from cholesterol-rich membrane rafts where viral glycoproteins and matrix (M1)/RNP complexes assemble. We demonstrate that M2 preparations from influenza virus-infected cells and from a baculovirus expression system contain 0.5-0.9 molecules of cholesterol per monomer. Sequence analyses of the membrane-proximal M2 endodomain reveal interfacial hydrophobicity, a cholesterol-binding motif first identified in peripheral benzodiazepine receptor and human immunodeficiency virus gp41, and an overlapping phosphatidylinositol 4,5-bisphosphate-binding motif. M2 induced rimantadine-reversible cytotoxicity in intrinsically cholesterol-free E. coli, and purified E. coli-expressed M2 functionally reconstituted into cholesterol-free liposomes supported rimantadine-sensitive proton translocation. Therefore, cholesterol was nonessential for M2 ion-channel function and cytotoxicity and for the effect of rimantadine. Only about 5-8% of both M2 preparations, regardless of cholesterol content, associated with detergent-resistant membranes. Cholesterol affinity and palmitoylation, in combination with a short transmembrane segment suggest M2 is a peripheral raft protein. Preference for the raft/non-raft interface may determine colocalization with HA during apical transport, the low level of M2 incorporated into the viral envelope and its undisclosed role in virus budding for which a model is presented. M2 may promote clustering and merger of rafts and the pinching-off (fission) of virus particles. ",0
2867,15221629,Pathological gambling in two patients on dopamine replacement therapy for Parkinson's disease,"""We describe two cases where increases in dopaminergic therapy were initiated by the patients due to perceived deterioration in symptoms of idiopathic Parkinson's disease. Shortly afterwards, both cases also met clinical criteria for pathological gambling. To date, only 29 cases of pathological gambling in patients with Parkinson's disease have been reported. This """"pathological gambling disorder"""" is an addiction-like behavior triggered by excessive dopaminergic drugs and does not respond to standard therapy for pathological gambling. It only responds to an adjustment of Parkinson's disease therapy. """,0
2868,15221796,Novel MC1R variants in Ligurian melanoma patients and controls,"Several variant forms of the melanocortin-1 receptor gene (MC1R) have been associated with red hair, fair skin and an increased risk for melanoma. Their involvement in melanoma susceptibility is apparently linked both to skin sensitivity and to non-pigmentary pathways. We investigated the frequency of the MC1R variants in the Italian region of Liguria, where the occurrence and penetrance of melanoma are low and primary susceptibility is characterized by prevalence of the CDKN2A c.301G>T [p.G101W] founder mutation. Additionally, we attempted to establish the frequency of the red hair/fair skin phenotype in our region. As predicted by anecdotal evidence, the frequency of red hair/phototype I was very low (0.7%). Screening of 17 red-haired individuals and their red-haired relatives, 207 controls and 214 melanoma patients unselected for hair color but all of Ligurian descent, led to the detection of 8 novel substitutions (c.133T>C [p.F45L], c.248C>T [p.S83L], c.332C>T [p. A111V], c.479G>A [p.R160Q], c.637C>T [p.R213W], c.793G>A [p. V265I], c.923C>T [p. T308M], c.943T>C [p.C315R]), 1 novel deletion (c.520_523delGTC [p.V174del]) and 3 novel synonymous variants (c.366G>C [p. V122V], c.684G>A [p. Q228Q], c.726C>T [p.T241T]). Preliminary genotype/phenotype correlation seems to indicate that other genes involved in the regulation of human pigmentation may mask the recessive action of high-penetrance MC1R alleles, thus determining the low frequency of at-risk phototypes and of incidence and/or penetrance of melanoma in Liguria. ",0
2869,15221881,Resistance training exercise and creatine in patients with Charcot-Marie-Tooth disease,"Resistance exercise and creatine supplementation independently improve strength and function in patients with certain neuromuscular diseases. The purpose of this study was to examine the effects of resistance training with and without creatine supplementation on muscle, strength, and function in patients with Charcot-Marie-Tooth (CMT) disease. Twenty patients with CMT consumed 5 g/day creatine or placebo while participating in resistance training for 12 weeks. Energy metabolites, muscle fiber type and size, strength, and timed activities of daily living were measured before and after training. There were no differences between creatine or placebo groups for any outcome. For the groups combined, exercise training increased type I muscle fiber diameter (48.2 +/- 14.2 microm vs. 55.4 +/- 14.8 microm), strength, and activities of daily living (ADL) times. Thus, patients respond to resistance training with muscle fiber adaptations, and improvements in strength and function. Creatine was not beneficial. ",0
2870,15221913,Variability in axillary lymph node dissection for breast cancer,"The axillary nodal status may influence the prognosis and the choice of adjuvant treatment of individual breast cancer patients. The variation in number of reported axillary lymph nodes and its effect on the axillary nodal stage were studied and the implications are discussed. Between 1994 and 1997, a total of 4,806 axillary dissections for invasive breast cancers in 4,715 patients were performed in hospitals in the North-Netherlands. The factors associated with the number of reported nodes and the relation of this number with the nodal status and the number of positive nodes were studied. The number of reported nodes varied significantly between pathology laboratories, the median number of nodes ranged from 9 to 15, respectively. The individual hospitals explained even more variability in the number of nodes than pathology laboratories (range in median number 8-15, P < 0.0001). The number of reported nodes increased gradually during the study period. A decreasing trend was observed with older patient age. A higher number of reported nodes was associated with a markedly increased chance of finding tumor positive nodes, especially more than three nodes. The frequency of node positivity increased from 28% if less than six nodes to 54% if >/=20 nodes were examined, the percentage of tumors with >/=4 positive nodes increased from 4 to 31%. Multivariate analysis confirmed these results. This population-based study showed a large variation in the number of reported lymph nodes between hospitals. A more extensive surgical dissection or histopathological examination of the specimen generally resulted in a higher number of positive nodes. Although the impact of misclassification on adjuvant treatment will have varied, the impact with regard to adjuvant regional radiotherapy may have been considerable. ",0
2871,15221950,Characterization of leukocyte subtypes in chicken inner ear sensory epithelia,"Human hearing and balance require intact inner ear sensory hair cells, which transduce mechanical stimuli into electrical signals that are transmitted to the brain. Loss of hair cells after birth in mammals is irreversible, whereas birds are able to regenerate hair cells after insult and demonstrate ongoing hair cell production in the vestibular epithelia. Leukocytes reside in undamaged sensory epithelia of the avian inner ear and increase in number after trauma, prior to the proliferation of hair cell progenitors. It has been hypothesized that leukocyte-produced growth factors or cytokines may be involved in triggering hair cell regeneration. Little is known about the specific leukocyte subtypes present in avian ear. Immunohistochemistry with a panel of monoclonal antibodies to chicken leukocytes was used to identify leukocyte subtypes in normal posthatch chicken ear sensory epithelia. The responsiveness of the leukocytes to aminoglycoside-induced damage was also observed. Based on immunocytochemical and morphological criteria, we quantified leukocyte subtypes in normal and drug-damaged auditory and vestibular sensory epithelia. Data indicate that lymphocytes (B and T cells) do not reside in normal or drug-damaged ear sensory epithelia at 1-3 days post insult but are present in adjacent nonsensory tissues. The most common leukocytes in inner ear sensory epithelia are ramified cells of the myeloid lineage. Many of these are MHC class II positive, and a small percentage are mature tissue macrophages. An absence of leukocytes in lesioned areas of the auditory sensory epithelium suggests they may not play a critical role in triggering hair cell regeneration. ",0
2872,15222152,How the clinical laboratory and the emergency department can work together to move patients through quickly,"The emergency departments (ED) at many medical centers are experiencing increased crowding and prolonged ED patient length of stay. During periods of heavy patient volume, the ED may go on divert status and be unable to care for new patients except for life-threatening illness. As part of a larger interdepartmental effort to improve ED operations, we implemented an ED satellite laboratory (kiosk) in the ED of Massachusetts General Hospital. The tests performed included cardiac markers, urinalysis, urine pregnancy testing, and whole blood glucose testing. The resulting average test turnaround time decreased by 51.5 minutes (87%) compared with the central laboratory, and physician satisfaction increased markedly. ED patient length of stay decreased by an average of 41 minutes for each patient tested, and the number of ED divert hours has steadily decreased. We therefore have concluded that point-of-care testing in an ED satellite laboratory may improve ED operations and contribute to improved outcomes when implemented as part of a larger interdepartmental effort. ",0
2873,15222429,Comparison of Work Ability Index and cognitive function tests],"The purpose of this study was to evaluate the effect of aging with regard to scores for certain cognitive function tests and WAI (Work Ability Index), and to examine the relationship between cognitive function test scores and work ability as measured by WAI. The subjects were 139 male employees of a factory producing steel plate, and their average age was 48.1 yr (SD 16.4). The WAI and cognitive function tests were conducted and valid scores were obtained from 134 subjects as to WAI, and from 88 subjects as to cognitive function tests. The subjects were divided into two groups: young workers (under 45 yr) and middle-aged to elderly workers (45 yr and over). The WAI scores of the two groups were compared, but no significant differences were observed. Nevertheless, for two WAI items, WAI-2 and WAI-7, the scores of the middle-aged to elderly worker group were significantly higher than those of the young worker group. In contrast, the scores for WAI-3 of the middle-aged to elderly group were significantly lower than those of the young worker group. The cognitive function test scores for the two groups were also compared. The scores for Working Memory test, Tracking test, and Sentence-to-sentence Comparison test of the middle-aged to elderly worker group were significantly lower than those of the younger group. Moreover, for the middle-aged to elderly worker group, the average WAI-3 scores for those with good cognitive function test results and those with poor cognitive function test results were compared, but there were no significant differences. This result shows that deterioration of physical function caused by aging is not related to deterioration of cognitive function caused by aging in the subjects of this study. The reason for this may be that the subjects are blue-collar workers, and thus cognitive functions are less important for their work. ",0
2874,15222513,Etiologies of acute undifferentiated febrile illness in Thailand,"Acute pyrexia of unknown origin (Acute PUO) was reported to affect approximately 200,000-400,000 patients each year reported by the national Annual Epidemiological Surveillance Report. The patients usually present with fever of less than two-week duration and non-specific symptoms such as malaise, myalgia, headache and loss of appetite. Its mortality rate is less than 0.02 percent. It would be interesting to find the etiologies and propose a management plan if the etiologies are discovered. This prospective epidemiologic study aimed to discover the etiologies of acute undifferentiated febrile illness in a tropical region like Thailand. Ten community-based hospitals were chosen as representatives in each part of Thailand to enroll patients into the study. Patients aged over two years old who presented with fever at the participating hospitals during year 1991-1993 were eligible for the study. Entry criteria of acute undifferentiated febrile illnesses (AUFI) included oral temperature over 38.3 degrees C within the last 24 hours, duration of fever ranging from 3-14 days, no specific single organ involvement by history taking and physical examination, normal or non-specific results of the following investigations: complete blood count, thick film for malaria, urinalysis and chest roentgenogram. The patients were hospitalized and a preset diagnostic protocol was performed. Other diagnostic procedures deemed necessary by attending physicians were perform. Patients were followed up within one month after hospital discharge. 1,240 patients were enrolled but only 1,137 case records and results of the serological tests were available for analysis. Etiologies could be found in 471 cases (38.7%). Primary bacteremia was detected in 36 cases (3.2%). E. coli, streptococci, salmonella, Enterobacter spp. and S. aureus were the five most common blood isolates. Serological studies revealed positive results for scrub typhus (7.5%), influenza (6.0%), dengue fever (5.7%), murine typhus (5.3%), enteric fever (1.9%), chikunkunya infection (1.1%), leptospirosis (1.1%) and melioidosis (0.9%). Thirteen cases succumbed (1.1%) in this study. The etiologies in the majority (61.3%) of AUFI remained unknown. Rickettsial infection, influenza and dengue fever are the most common identifiable diseases in a tropical country like Thailand especially during the rainy season. A management guideline for diagnosis and treatment of the AUFI with emphasis on primary bacteremia and antimicrobial-treatable AUFI was proposed. ",0
2875,15223019,Differential expression and localization of CFTR and ENaC in mouse endometrium during pre-implantation,"Interaction between the cystic fibrosis transmembrane conductance regulator (CFTR), a CAMP-activated Cl- channel, and epithelial Na+ channel (ENaC) has been proposed as the major mechanism regulating uterine fluid absorption and secretion. Differential expression of these ion channels may give rise to dynamic changes in the fluid environment affecting various reproductive events in the female reproductive tract. This study investigated the expression and localization of CFTR and ENaC during the pre-implantation period. Semi-quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry were used to study the expression and localization of CFTR and ENaC in uteri collected from mature superovulated female mice. RT-PCR showed maximal ENaC and CFTR expression on day 3 after mating. Maximal immunoreactivity was also observed for both ENaC and CFTR on day 3 after mating. However, ENaC was immunolocalized to the apical membrane of both luminal and glandular epithelia, while CFTR was predominantly found in the stromal cells rather than the epithelial cells. Differential expression and localization of CFTR and ENaC provide a molecular mechanism by which maximal fluid absorption can be achieved immediately prior to implantation, to ensure the immobilization of the blastocyst necessary for implantation. ",0
2876,15223152,Packaging of single DNA molecules by the yeast mitochondrial protein Abf2p: reinterpretation of recent single molecule experiments,"Brewer et al. (Biophys. J. 85 (2003) 2519-2524) have studied the compaction of dsDNA in a double flow cell by observing the extension of stained DNA tethered in buffer solutions with or without Abf2p. They use a Langmuir adsorption model in which one Abf2p molecule adsorbs on one site on the DNA, and the binding constant, K, is given as the ratio of the experimental rates of adsorption and desorption. This paper presents an improved interpretation. Instead of Langmuir adsorption we use the more appropriate McGhee-von Hippel (J. Mol. Biol. 86 (1974) 469-489) theory for the adsorption of large ligands to a one-dimensional lattice. We assume that each adsorbed molecule shortens the effective contour length of DNA by the foot print of Abf2p of 27 base pairs. When Abf2p adsorbs to DNA stretched in the flowing buffer solution, we account for a tension effect that decreases the adsorption rate and the binding constant by a factor of 2 to 4. The data suggest that the accessibility to Abf2p decreases significantly with increasing compaction of DNA, resulting in a lower adsorption rate and a lower binding constant. The kinetics reported by Brewer et al. (Biophys. J. 85 (2003) 2519-2524) lead to a binding constant K=3.6 x 10(6) M(-1) at the beginning, and to K=5 x 10(5) M(-1) near the end of a compaction run, more than an order of magnitude lower than the value K=2.57 x 10(7) M(-1) calculated by Brewer et al. (Biophys. J. 85 (2003) 2519-2524). ",0
2877,15223631,The expression of the aurora-A gene and its significance with tumorgenesis in non-Hodgkin's lymphoma,"Non-Hodgkin's lymphoma (NHL) has a wide biological heterogeneity with various cell origin and biological features. Recent WHO classification of lymphoid neoplasms gives importance to immunological and cytogenetic features in addition to morphologic aspects of tumors. Several investigators have performed NHL subclassification based on other biological features of tumor cells. It is extremely important to clarify the proliferation mechanism of tumor cells, and understanding this mechanism may provide insight not only into the biology of tumors but also into the treatment strategy for NHL. Therefore, research focused on the cell cycle is one of the major approaches to the biology and the oncogenesis of NHL. The Aurora kinase family recently identified from Drosophila melamogaster is believed to be an essential kinase involved in mitotic cell cycles. Several groups have reported that Aurora kinases are overexpressed in some solid tumors, suggesting that Aurora kinases may be involved in tumor survival and proliferation. Here, we focus on the role of Aurora-A kinase in the tumorgenesis of NHL using our recent research data, and discuss the possibility of Aurora-A as a new molecular target of NHL treatment. ",0
2878,15223681,Detection of abnormal proliferation in histologically 'normal' colonic biopsies using FTIR-microspectroscopy,"Abnormal crypt proliferation and development in the colon has been associated with premalignant stages of colon cancer. Conventionally, molecular markers are used to detect abnormal crypt proliferation. In the present work, feasibility studies of FTIR-MSP to distinguish between normal and abnormal crypts from colon biopsies that show normal histopathological features have been undertaken. The results indicate that abnormal crypts show deviations in the pattern of absorbance in the Mid IR region along the crypt height when compared with the normal crypts. The crypts could be empirically classified into three groups such as crypts having a normal absorbance pattern for all biochemical components, crypts with abnormal absorbance pattern for some biochemical components and crypts with completely abnormal absorbance pattern along the height for all or most biochemical components studied by FTIR. The utilization of FTIR-MSP is proposed for diagnosis of abnormal metabolism at the molecular level of histologically completely normal-looking crypts, especially from those biopsies that are taken from sites far away from cancer. This method could give rise to a reduction in false-negative results during examination of biopsies using the conventional histopathological methods. The present method may be complementary to existing methods for precise demarcation of the zone of colostomy prior to colon cancer surgery. ",0
2879,15223740,Threat appraisal and avoidance after traumatic brain injury: why and how often are activities avoided?,"Goldstein emphasized the anxiety-related avoidance of activities after brain injury, but such avoidance has rarely been systematically investigated. This study aimed to compile a list of specific threat appraisals that may lead to avoidance and to obtain data on the frequency with which these appraisals and consequent avoidance occur. Survey. Qualitative methodology was used to obtain an account of threat appraisals. These data were then used to compile two questionnaires that asked about the experience of these appraisals and consequent avoidance. Fifty individuals with a TBI completed the questionnaires. A varied list of threat appraisals was obtained. Appraisals and consequent avoidance were frequent in the sample. Males and those whose TBI resulted from an assault reported more avoidance. A core aim of rehabilitation is to facilitate participation in valued roles and activities. Threat appraisals and avoidance deserve more attention in research and practice because they may constitute a significant obstacle to achieving this. ",0
2880,15223993,Gliclazide at a lower concentration than therapeutic dose increases the sensitivity of insulin secretion to glucose in perfused rat pancreas,"We studied the difference between effects of therapeutic dose and sub-therapeutic dose of gliclazide on the glucose-induced insulin secretion. The normal rat pancreas was isolated and perfused with Krebs-Ringer buffer containing 1-14 mmol/l glucose. Influcences of 0.25 and 2.5 microg/ml gliclazide on the glucose concentration-insulin secretion curve was examined. Gliclazide at 0.25 microg/ml significantly potentiated 5-8 mmol/l glucose-induced insulin secretion (2.5 +/- 0.5 vs 1.0 +/- 0.3 mU for 15 min at 6.5 mmol/l glucose, P<0.01), but did not give influence on either 1-3 or 10-14 mmol/l glucose-induced insulin secretion. The glucose concentration, at which half-maximal insulin secretion was observed, was lower with gliclazide (5.9 mmol/l) than in the control (7.5 mmol/l). Gliclazide at 2.5 microg/ml markedly increased the maximally glucose-stimulated insulin secretion from 3.9 +/- 0.5 mU for 15 min in the control to 6.6 +/- 0.7 mU for 15 min (P<0.01). The half-maximal insulin secretion was observed at a lower glucose concentration (5.0 mmol/l) than in the absence of gliclazide. Gliclazide in sub-therapeutically low dose has different effects on insulin secretion from in therapeutic dose, namely sharpens the insulin secretion sensitivity to glucose with no influence on the maximal insulin secretion. It is possible that low doses of gliclazide might be of interest in some type 2 diabetics whose main pathophysiology is the blunting of insulin secretion response to hyperglycemia. ",0
2881,15224214,Do different osmolar solutions change the epithelial surface of the healthy rabbit cornea?,"We evaluated various osmolar solutions in use for ophthalmic treatment for their effect on the corneal surface. Healthy corneas were exposed to hypoosmolar balanced salt solution (BSS), an isoosmolar solution and hyperosmolar solution Previn. Rinsing solutions--BSS from Opsia, and Previn from Prevor--were provided by the manufacturers. Our laboratory made an iso-corneal solution from an electrolytes and amino acid composition, based on our measurements for osmolarity of human corneas. During final anesthesia, each six healthy rabbit eyes were exposed to 1 drop of the above-mentioned solutions, every second for 120 min. Drops were applied from a height of 2 cm, wetting the corneal surface homogeneously. Surface changes compared to healthy corneas were visible in scanning-electron-microscope images. In grading such changes,we found that balanced salt solution caused changes within the surface appearance, with increased cell-shape changes and microvilli loss. Isoosmolar and Previn solution did not show slightly pronounced nuclei within an intact cellular membrane. Isoosmolar and hyperosmolar rising did not change the microvilli of the corneal-cell surface. Hypoosmolar rinsing changed the surfaces considerably. We believe that, contrary to prevalent opinion, application of hyperosmolar solutions to the healthy eye does not harm corneal surface integrity. Iso-corneal solution and Previn solution did not change the surface of the healthy rabbit cornea. ",0
2882,15235977,Continuous epidural infusion for postoperative mechanical ventilation,"We evaluated in analgesic and sedative effects of continuous epidural infusion of two analgesic regimens in ventilated patients following esophagectomy. Forty-six patients, divided into two treatment groups, received postoperative continuous epidural infusion of morphine, or that of a combination of bupivacaine and morphine. Assessments were made with the following indices: pain relief score, somnolence score, patient ventilator coordination score, and the number of supplemental administrations of analgesics and sedatives. No significant differences occurred in somnolence scores or patient ventilator coordination scores between the two groups, which revealed satisfactory sedation for mechanical ventilation. Patients receiving the combination of bupivacaine and morphine had significantly less pain postoperatively, requiring a smaller number of supplemental administrations of analgesics and sedatives ( P < 0.05). It is concluded that: 1) continuous epidural infusion of analgesics gives potent analgesia and sedation of ventilated patients following esophagectomy; 2) the combination of bupivacaine and morphine gives pain relief superior to morphine alone. ",0
2883,15236187,Lymphotoxin beta receptor signaling induces the chemokine CCL20 in intestinal epithelium,"The follicle-associated epithelium (FAE) that overlies Peyer's patches (PPs) exhibits distinct features compared with the adjacent villus epithelium. Besides the presence of antigen-sampling membranous M cells and the down-regulation of digestive functions, it constitutively expresses the chemokine CCL20. The mechanisms that induce FAE differentiation and CCL20 expression are poorly understood. The aim of this work was to test whether lymphotoxin beta receptor signaling (LTbetaR), which plays a central role in PPs' organogenesis, mediates CCL20 gene expression in intestinal epithelial cells. CCL20, lymphotoxin beta (LTbeta) and LTbetaR expression were monitored during embryonic development by in situ hybridization of mouse intestine. The human intestinal epithelial cell line T84 was used to study CCL20 expression following LTalpha(1)/beta(2) stimulation. In vivo CCL20 expression following agonistic anti-LTbetaR antibody treatment was studied by laser microdissection and quantitative RT-PCR. CCL20 was expressed in the FAE before birth at the time when the first hematopoietic CD4(+)CD3(-) appeared in the PP anlage. LTbetaR was expressed in the epithelium during PP organogenesis, making it a putative target for LTalpha(1)beta(2)signals. In vitro, CCL20 was induced in T84 cells upon LTbetaR signaling, either using an agonistic ligand or anti-LTbeta receptor agonistic antibody. LTalpha(1)beta(2)-induced CCL20 expression was found to be NF-kappaB dependent. LTbetaR signaling up-regulated CCL20 expression in the small intestinal epithelium in vivo. Our results show that LTbetaR signaling induces CCL20 expression in intestinal epithelial cells, suggesting that this pathway triggers constitutive production of CCL20 in the FAE. ",0
2884,15236461,Biodegradable polyphosphoester micelles for gene delivery,"A new biodegradable polyphosphoester, poly[[(cholesteryl oxocarbonylamido ethyl) methyl bis(ethylene) ammonium iodide] ethyl phosphate] (PCEP) was synthesized and investigated for gene delivery. Carrying a positive charge in its backbone and a lipophilic cholesterol structure in the side chain, PCEP self-assembled into micelles in aqueous buffer at room temperature with an average size of 60-100 nm. It could bind and protect plasmid DNA from nuclease digestion. Cell proliferation assay indicated a lower cytotoxicity for PCEP than for poly-L-lysine and Lipofectamine. The IC50 determined by the WST-1 assay was 69.8, 51.6, and 12.1 microg/mL for PCEP, Lipofectamine, and poly-L-lysine, respectively. PCEP efficiently delivered DNA to several cell lines such as HEK293, Caco-2, and HeLa. The highest efficiency was achieved when PCEP/DNA complex was prepared in Opti-MEM with a +/- charge ratio of 1.5-2. The transfection efficiency did not change significantly when the complex was used 3 days after preparation. The addition of chloroquine to the formulation increased transfection efficiency 10- to 50-fold compared to the complex alone. In vivo studies showed a luciferase expression by PCEP/DNA complexes in muscle increasing with time during 3 months, although the expression level was lower than that by direct injection of naked DNA. In addition to biodegradability and lower toxicity, the PCEP micelle carrier offers structural versatility. The backbone charge density and the side chain lipophilicity are two parameters that can be varied through copolymerization and monomer variation to optimize the transfection efficiency. ",0
2885,15236595,Kinetic characterization of thiolate anion formation and chemical catalysis of activated microsomal glutathione transferase 1,"Microsomal glutathione transferase 1 (MGST1) displays the unique ability to be activated, up to 30-fold, by the reaction with sulfhydryl reagents, e.g., N-ethylmaleimide. Analysis of glutathione (GSH) thiolate formation, which occurs upon mixing activated MGST1 with GSH, reveals biphasic kinetics, where the rapid phase dominated at higher GSH concentrations. The kinetic behavior suggests a two-step mechanism consisting of a rapid GSH-binding step (K(D)(GSH) approximately 10 mM), followed by slower formation of thiolate (k(2) approximately 10 s(-1)). The release rate (or protonation of the enzyme GSH thiolate complex) of GS(-) was slow (k(-2) = 0.016 s(-1)), consistent with overall tight binding of GSH. Electrophilic second substrates react rapidly with the E*GS(-) complex, and again, a two-step mechanism is suggested. In comparison to the unactivated enzyme [Morgenstern et al. (2001) Biochemistry 40, 3378-3384], the mechanisms of GSH thiolate formation and electrophile interaction are similar; however, thiolate anion formation is enhanced 30-fold in the activated enzyme, contributing to an increased k(cat) (3.6 s(-1)). Interestingly, in the activated enzyme, thiolate formation and proton release from the enzyme are not strictly coupled, because proton release (as well as k(cat)) was found to be approximately 4 times slower than GSH thiolate formation in an unbuffered system. Solvent kinetic isotope effect measurements demonstrated a 2-fold decrease in the rate constant (k(2)) for thiolate formation and k(cat) (in the reaction with 1-chloro-2,4-dinitrobenzene) for both unactivated and activated MGST1. This indicates that thiolate formation contributes to k(cat) for the activated enzyme, as suggested previously for unactivated MGST1. The stoichiometry of thiolate formation, proton release, and burst kinetics suggested utilization of one GSH molecule per enzyme trimer. ",0
2886,15237006,"Treatment of dysfunctional uterine bleeding: patient preferences for endometrial ablation, a levonorgestrel-releasing intrauterine device, or hysterectomy","To investigate patient preferences for endometrial ablation and a levonorgestrel-releasing intrauterine device (IUD) as alternatives to hysterectomy in the treatment of dysfunctional uterine bleeding. Comparative study based on structured interviews. A large teaching hospital with 500 beds in the Netherlands. Ninety-six patients who were scheduled for endometrial ablation, 25 patients who were scheduled for hysterectomy, and 23 patients who were scheduled for a levonorgestrel-releasing IUD were interviewed. All of the women had dysfunctional uterine bleeding. Patients were asked to state their most significant complaints and their reasons for choosing a particular treatment. Subsequently, the preference for endometrial ablation and a levonorgestrel-releasing IUD as alternatives to hysterectomy was assessed during a structured interview. Women were informed about the advantages and disadvantages of all three treatment options. Patients rated their preferences according to different hypothetical success rates. The success rates after endometrial ablation and levonorgestrel-releasing IUD were varied until patients found an acceptable treatment outcome. Patient preference of endometrial ablation and the levonorgestrel-releasing IUD over hysterectomy. The main reason for the treatment of choice differed between the three groups. Most of the patients in the hysterectomy group wanted a definite solution to their problems, whereas patients in the levonorgestrel-releasing IUD group and in the ablation group put greater emphasis on a minimally invasive intervention with or without a short hospital stay. In women undergoing ablation, 70% of the patients preferred this treatment and the levonorgestrel-releasing IUD to hysterectomy in cases in which the success rate of noninvasive treatment was presumed to be 50%. In women having a levonorgestrel-releasing IUD inserted, 95% of the patients preferred this approach over hysterectomy in cases in which the success rate of this device was presumed to be 50%, whereas 35% of patients preferred ablation over hysterectomy in cases in which the success rate of ablation was presumed to be 50%. In women undergoing hysterectomy, 30% would have opted for ablation and 45% would have opted for a levonorgestrel-releasing IUD in cases in which success rates were 50%. Of patients who opted for hysterectomy, however, 60% stated that they would have preferred a noninvasive treatment if the success rate of this type of treatment were >80%. A majority of the patients who had dysfunctional uterine bleeding and who were scheduled for an endometrial ablation or a levonorgestrel-releasing IUD were inclined to take a risk of 50% likelihood of treatment failure to avoid a hysterectomy. As a consequence, research of treatment for dysfunctional uterine bleeding should focus on this 50% success level. ",0
2887,15237197,Ethical aspects of genetic testing in the workplace,"The European Group on Ethics and New Technologies, which advises the European Commission, has published an opinion paper on ethical aspects of genetic testing in the workplace. The paper goes well beyond the usual ethical issues, presenting a summary of genetic testing in the workplace in the United States and Europe and criteria for appropriate testing. Unlike many other documents on ethics, it pays close attention to the problem of false-positive and false-negative test results. Although no genetic tests are currently appropriate for screening workers or applicants for jobs in which occupational hazards exist, inappropriate testing has occurred and regulations are needed to ensure that only appropriate testing is used in the future. Workers or their representatives should be involved in deciding when and how genetic testing in the workplace is done. ",0
2888,15237261,Is sentinel lymph node biopsy of therapeutic relevance for melanoma?,"It is still unclear whether sentinel lymph node biopsy (SLNB) has an effect on the survival or recurrence-free survival of patients. It would be necessary to compare patients with SLNB (or with selective lymph node dissection in the case of positive SLNB) and patients without SLNB who received only a close clinical and sonographic follow-up. To date, no results from prospective, randomized studies of SLNB are available. Patients with SLNB (n = 283) and patients in clinical stage I and II with close follow-up examinations only (n = 3,514) were studied retrospectively in this investigation with regard to prognostic factors established in the literature: sex, age, tumor thickness, histological tumor type, ulceration and localization. Multivariate analysis did not show an independent significant advantage with regard to survival when SLNB had been performed (p = 0.37). Compared with patients in clinical stage I and II with close follow-up only (n = 2,617),patients in stage I and II with negative SLNB (n = 238) had no significantly lower melanoma-related mortality (p =0.36) but significantly fewer recurrences in the regional lymph node area (p = 0.0015). With regard to survival without distant metastases and disease-specific survival, patients with positive SLNB (n = 33) did not significantly benefit by comparison with patients who developed lymph node metastasis identified clinically or sonographically later during follow-up examinations (n = 246; p =0.89 and p = 0.38, respectively). In the relatively short follow-up period after SLNB, patients for whom SLNB had been performed did not have - on the whole - a prognostic advantage over patients who were subject only to close follow-up monitoring. Patients for whom subclinical lymph node metastases had been removed as the result of a positive SLNB did not have a better prognosis than patients without SLNB who had developed lymph node metastases within the follow-up period [corrected] ",0
2889,15237363,The role of selective digestive decontamination for reducing infection in patients undergoing liver transplantation: a systematic review and meta-analysis,"Selective digestive decontamination (SDD) refers to the use of antimicrobials to reduce the burden of aerobic gram-negative bacteria and/or yeast in the intestinal tract to prevent infections caused by these organisms. Liver transplant patients are highly vulnerable to bacterial infection particularly with gram-negative organisms within the first month after transplantation, and SDD has been proposed as a potential measure to prevent these infections. However, the benefit of this procedure remains controversial. We undertook a systematic review and meta-analysis to determine whether SDD is beneficial in reducing infections overall and those caused by gram-negative bacteria in patients following liver transplantation. All studies that evaluated the efficacy of SDD in liver transplant patients were included. Randomized trials that included liver transplant patients given SDD versus either placebo or no treatment or minimal treatment (e.g., oral nystatin alone), and that provided adequate data to calculate a relative risk ratio, were included in the meta-analysis. Our review shows that most studies found SDD to be effective in reducing gram-negative infection. The nonrandomized and uncontrolled trials also showed benefit with SDD in reducing overall infection; however, the effect on overall infection was limited in the 4 randomized trials, in which the pooled relative risk was 0.88 (95% CI, 0.7-1.1), indicating no statistically significant reduction in infection with the use of SDD. The summary risk ratio for the association between SDD and gram-negative infection was 0.16 (95% CI, 0.07-0.37), indicating an 84% relative risk reduction in the incidence of infection caused by gram-negative bacteria in patients receiving SDD in randomized trials. In conclusion, the available literature supports a beneficial effect of SDD on gram-negative infection following liver transplantation; however, the risk of antimicrobial resistance must be considered. Larger multicenter randomized trials in this patient population to assess the effect of SDD in reducing infection and mortality, while assessing the risk of antimicrobial resistance, are needed. ",0
2890,15237403,Characterization of glyco isoforms in plasma-derived human antithrombin by on-line capillary zone electrophoresis-electrospray ionization-quadrupole ion trap-mass spectrometry of the intact glycoproteins,"The carbohydrate structures of five isoforms of alpha-AT and two isoforms of beta-AT were determined by applying capillary zone electrophoresis (CZE) on-line coupled to electrospray ionization-mass spectrometry (ESI-MS) using an ion-trap analyzer. For the AT preparations gained from a plasma pool at least semiquantitative information on the isoform-distributions could be gained. Unlike to the commonly used approaches starting from enzymatically treated glycoproteins, this approach deals with intact proteins. The high accuracy of the molecular mass determination obtained by the ion-trap analyzer allows one to calculate and ascertain the carbohydrate composition assuming no variations in the protein moiety of AT and to exclude or confirm the presence of the potential post-translational or other modifications. Therefore, the direct coupling of CZE with ESI-MS does not only represent a fast alternative technique to two-dimensional electrophoresis (2-DE) but serves as a method which provides structural information complementary to that gained from peptide mapping methods. ",0
2891,15238082,Inhibition of the proteasome reduces transfer-induced diabetes in nonobese diabetic mice,"Inhibition of the 26S proteasome reduces the severity of several immune-mediated diseases. Here, we report that the proteasome also regulates transfer-induced diabetes in nonobese mice. Treatment of recipient mice with the proteasome inhibitor N(alpha)-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal (MG132) resulted in a 76% reduction in transfer-induced diabetes. The closely related inhibitor carbobenzoxy-l-leucyl-l-leucinal that inhibits calpains but not the proteasome had no protective effect, suggesting that MG132 acted via inhibition of the proteasome. MG132 decreased proliferation of transferred T cells in the pancreatic lymph nodes in vivo and prevented their expansion in a dose-dependent manner in vitro, consistent with a direct effect by MG132 on the T cells. MG132 did not prevent migration of transferred T cells into the islets but reduced the number of mice with severe infiltration. We suggest that MG132 prevents transfer-induced diabetes by directly targeting the autoreactive T cells and lowering their diabetogenic potential. ",0
2892,15238087,Statin drugs do not affect serum complement activation in vitro,"Statin drugs prevent coronary heart disease through anti-inflammatory mechanisms in addition to the well-known reduction of low-density lipoproteins. The complement system plays an essential role in the inflammatory response and has been postulated to be modified by statins. A direct role for statins in complement activation, however, has not been previously investigated. We therefore studied the effect of statins on in vitro complement activation. Pravastatin, atorvastatin and the active metabolite of the latter, ortho-hydroxy atorvastatin, were added to normal human serum and incubated for 1 h in the absence or presence of aggregated immunoglobulin (classical pathway activation) or cobra venom factor (alternative pathway activation). The degree of complement activation, as detected by specific complement-activation products for the classical pathway (C1rs-C1-inhibitor complexes), the combined classical and lectin pathway (C4bc), the alternative pathway (C3bBbP) and the final common pathway (C3bc and TCC), was not affected by pre-incubation of the serum with any of the statins. Statins do not affect complement activation directly, but indirect effects in vivo may well be operative. ",0
2893,15238361,Calcitonin gene-related peptide elevates calcium and polarizes membrane potential in MG-63 cells by both cAMP-independent and -dependent mechanisms,"Published data suggest that the neuropeptide calcitonin gene-related peptide (CGRP) can stimulate osteoblastic bone formation; however, interest has focused on activation of cAMP-dependent signaling pathways in osteogenic cells without full consideration of the importance of cAMP-independent signaling. We have now examined the effects of CGRP on intracellular Ca(2+) concentration ([Ca(2+)](int)) and membrane potential (E(m)) in preosteoblastic human MG-63 cells by single-cell fluorescent confocal analysis using fluo 4-AM-fura red-AM and bis(1,3-dibarbituric acid)-trimethine oxanol [DiBAC(4)(3)] bis-oxonol assays. CGRP produced a two-stage change in [Ca(2+)](int): a rapid transient peak and a secondary sustained increase. Both responses were dose dependent with an EC(50) of approximately 0.30 nM, and the maximal effect (initially approximately 3-fold over basal levels) was observed at 20 nM. The initial phase was sensitive to inhibition of Ca(2+) mobilization with thapsigargin, whereas the secondary phase was eliminated only by blocking transmembrane Ca(2+) influx with verapamil or inhibiting cAMP-dependent signaling with the Rp isomer of adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMPS). These data suggest that CGRP initially stimulates Ca(2+) discharge from intracellular stores by a cAMP-independent mechanism and subsequently stimulates Ca(2+) influx through L-type voltage-dependent Ca(2+) channels by a cAMP-dependent mechanism. In addition, CGRP dose-dependently polarized cellular E(m), with maximal effect at 20 nM and an EC(50) of 0.30 nM. This effect was attenuated with charybdotoxin (-20%) or glyburide (glibenclamide; -80%), suggesting that E(m) hyperpolarization is induced by both Ca(2+)-activated and ATP-sensitive K(+) channels. Thus CGRP signals strongly by both cAMP-dependent and cAMP-independent signaling pathways in preosteoblastic human MG-63 cells. ",0
2894,15238624,Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome,"BACKGROUND: Monochorionic twin pregnancies complicated by severe twin-to-twin transfusion syndrome at midgestation can be treated by either serial amnioreduction (removal of large volumes of amniotic fluid) or selective fetoscopic laser coagulation of the communicating vessels on the chorionic plate. We conducted a randomized trial to compare the efficacy and safety of these two treatments. METHODS: Pregnant women with severe twin-to-twin transfusion syndrome before 26 weeks of gestation were randomly assigned to laser therapy or amnioreduction. We assessed perinatal survival of at least one twin (a prespecified primary outcome), survival of at least one twin at six months of age, and survival without neurologic complications at six months of age on the basis of the number of pregnancies or the number of fetuses or infants, as appropriate. RESULTS: The study was concluded early, after 72 women had been assigned to the laser group and 70 to the amnioreduction group, because a planned interim analysis demonstrated a significant benefit in the laser group. As compared with the amnioreduction group, the laser group had a higher likelihood of the survival of at least one twin to 28 days of age (76 percent vs. 56 percent; relative risk of the death of both fetuses, 0.63; 95 percent confidence interval, 0.25 to 0.93; P=0.009) and 6 months of age (P=0.002). Infants in the laser group also had a lower incidence of cystic periventricular leukomalacia (6 percent vs. 14 percent, P=0.02) and were more likely to be free of neurologic complications at six months of age (52 percent vs. 31 percent, P=0.003). CONCLUSIONS: Endoscopic laser coagulation of anastomoses is a more effective first-line treatment than serial amnioreduction for severe twin-to-twin transfusion syndrome diagnosed before 26 weeks of gestation.",0
2895,15238870,The role of contrast-enhanced ultrasonography for the detection of hepatocellular carcinoma],"The incidence of the hepatocellular carcinoma (HCC) is increasing in Occident, as well as in France. Primary prevention is the only solution for early detection. The combination of ultrasound (US) and alphaFP each 4 to 6 Months dosage has many limitations. The sensitivity of US examination is rather poor (less than 70% for lesions below 2 cm in diameter) and serum alphaFP values remain normal in almost 50% of HCC. US contrast agents (USCAs) with perfluorocarbon gases increase the backscattered signals during all phases of the liver transit, including arterial, portal and delayed phases. Hepatocellular lesions exhibit a specific kinetics with strong enhancement during arterial phase, and rapid wash-out during portal and delayed phases. USCAs increase the detection of HCCs and allow characterization of additional focal lesions found in cirrhotic livers (regenerative and dysplastic nodules, haemangiomas.). Indeed, regenerative nodules contrast uptake is synchronous to the surrounding parenchyma, and usually disappear during portal and delayed phases. However, US in cirrhosis remains a difficult examination, with limitations due to limited access to sub-diaphragmatic localization, attenuation of the ultrasound beam and shortness of the arterial phase. ",0
2896,15239085,Beyond insulin resistance in NASH: TNF-alpha or adiponectin?,"Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor alpha (TNF-alpha) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-alpha activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-alpha and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-alpha and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 microg/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD. ",0
2897,15239090,Effects of antiviral therapy on the cellular immune response in acute hepatitis C,"Spontaneous recovery occurs in a minority of patients with acute hepatitis C but is associated with vigorous and long-lasting cellular immune responses. Treatment-induced recovery can be achieved in the majority of patients who are treated in the acute phase, but the kinetics and mechanisms of viral clearance and immune responsiveness are not known. Both direct antiviral effects and indirect immune-mediated effects, such as immune modulation of Th2 to Th1 responses and prevention of exhaustion of cellular responses by rapid reduction of viral titer, have been proposed. To investigate how early antiviral therapy affects hepatitis C virus (HCV)-specific T cell responses, we performed detailed prospective clinical, virological, and immunological studies on 7 patients with acute hepatitis C who received antiviral therapy and were followed at 2 to 4 week intervals for 1 to 2 years. The total CD4(+) and CD8(+) cell response was analyzed with 600 overlapping HCV peptides and 6 proteins by ex vivo enzyme-linked immunospot (ELISpot), intracellular cytokine staining, and proliferation assays. In contrast to earlier studies with selected HCV epitopes, this extended analysis detected multispecific interferon gamma(+) (IFN-gamma(+)) responses in each patient, even in the absence of T-cell proliferation. After initiation of antiviral therapy (at a mean of 20 weeks after infection), all sustained responders demonstrated gradually decreasing, then nearly absent HCV-specific T-cell responses, whereas the sole patient who developed viral breakthrough after initial HCV control maintained cellular immune responses. In conclusion, a sustained response to antiviral therapy was not associated with a lasting enhancement of HCV-specific T-cell responsiveness in the blood.",0
2898,15239099,Mitochondrial nitric oxide synthase drives redox signals for proliferation and quiescence in rat liver development,"Mitochondrial nitric oxide synthase (mtNOS) is a fine regulator of oxygen uptake and reactive oxygen species that eventually modulates the activity of regulatory proteins and cell cycle progression. From this perspective, we examined liver mtNOS modulation and mitochondrial redox changes in developing rats from embryonic days 17-19 and postnatal day 2 (proliferating hepatocyte phenotype) through postnatal days 15-90 (quiescent phenotype). mtNOS expression and activity were almost undetectable in fetal liver, and progressively increased after birth by tenfold up to adult stage. NO-dependent mitochondrial hydrogen peroxide (H(2)O(2)) production and Mn-superoxide dismutase followed the developmental modulation of mtNOS and contributed to parallel variations of cytosolic H(2)O(2) concentration ([H(2)O(2)](ss)) and cell fluorescence. mtNOS-dependent [H(2)O(2)](ss) was a good predictor of extracellular signal-regulated kinase (ERK)/p38 activity ratio, cyclin D1, and tissue proliferation. At low 10(-11)-10(-12) M [H(2)O(2)](ss), proliferating phenotypes had high cyclin D1 and phospho-ERK1/2 and low phospho-p38 mitogen-activated protein kinase, while at 10(-9) M [H(2)O(2)](ss), quiescent phenotypes had the opposite pattern. Accordingly, leading postnatal day 2-isolated hepatocytes to embryo or adult redox conditions with H(2)O(2) or NO-H(2)O(2) scavengers, or with ERK inhibitor U0126, p38 inhibitor SB202190 or p38 activator anisomycin resulted in correlative changes of ERK/p38 activity ratio, cyclin D1 expression, and [(3)H] thymidine incorporation in the cells. Accordingly, p38 inhibitor SB202190 or N-acetyl-cysteine prevented H(2)O(2) inhibitory effects on proliferation. In conclusion, the results suggest that a synchronized increase of mtNOS and derived H(2)O(2) operate on hepatocyte signaling pathways to support the liver developmental transition from proliferation to quiescence.",0
2899,15239192,Minimally invasive treatment of osteoporotic vertebral compression fracture,"The use of percutaneous vertebroplasty (PV) to treat osteoporotic vertebral fractures is increasing. This investigation assesses the efficacy and safety of PV for refractory pain owing to osteoporotic vertebral compression fractures. A retrospective investigation of PV was conducted with a minimal of 1 year follow up. PV with polymethylmethacrylate (PMMA) was performed on 75 patients with osteoporotic vertebral compression fractures that responded poorly to the conservative therapy. Patients were asked to quantify their degree of pain using Huskisson's visual analogue scale to assess the clinical results. Eighty-seven vertebrae treated using PV in 70 patients were evaluated with a minimal of 1 year follow up. Pain, as assessed on the VAS, decreased from 80+/-16 mm before PV to 36+/-28 mm at 1 month after PV and 30+/-19 mm at the most recent follow up. The reduction in pain from the baseline to 1 month (p=0.031) and to final follow up (p=0.023) were both statistically significant. Sixty-two patients (85.5%) quickly returned to their pre-injury activity level and achieved better quality of life. PV is effective in pain reduction for painful vertebral compression fractures. It provided significant pain relief. Skillful techniques and careful safeguards can minimize the risks of PMMA migration. ",0
2900,15239610,"Effects of AGI-1096, a novel antioxidant compound with anti-inflammatory and antiproliferative properties, on rodent allograft arteriosclerosis","AGI-1096 is a novel phenolic intracellular antioxidant with anti-inflammatory and antiproliferative properties. In vitro, AGI-1096 inhibited the inducible expression of vascular cell adhesion molecule (VCAM)-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 in endothelial cells and tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. It also inhibited serum-stimulated proliferation of aortic smooth-muscle cells. In vivo, AGI-1096 demonstrated anti-inflammatory properties in a murine delayed-type hypersensitivity model. Given these antioxidant, anti-inflammatory and antiproliferative properties, we reasoned that AGI-1096 may be able to prevent chronic allograft arteriosclerosis. This hypothesis was tested in a rodent aortic transplantation model. Donor descending aortas from August-Copenhagen-Irish rats were heterotopically transplanted into Lewis rat abdomens in end-to-end fashion. Animals were assigned to six groups as follows: AGI-1096 0 mg/kg per day (vehicle, n = 10), 10 mg/kg per day (n = 10), 20 mg/kg per day (n = 10), 40 mg/kg per day (n = 10), positive control (cyclosporine A 10 mg/kg per day by oral gavage, n = 10), and isograft negative control (Lewis-to-Lewis, n = 5). AGI-1096 was administrated subcutaneously to recipient animals three days before the surgery and for 90 days thereafter. On day 90, the paraffin-embedded allograft sections were stained with Elastin-van Gieson's stain, and the intima/media (I/M) ratio and luminal narrowing (1%LN) was assessed by digital morphometry. AGI-1096 demonstrated dose-dependent lowering of the I/M ratio and %LN when compared with vehicle controls. This is the first study to show that treatment of allograft recipients with AGI-1096 decreases the incidence of transplant arteriosclerosis. These data suggest that AGI-1096 may be a promising new therapeutic agent for use in clinical transplantation. ",0
2901,15239631,"One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation","Hepatocyte transplantation is emerging as a possible treatment for patients with acute liver failure and liver-based metabolic disorders. With the limited availability of donor tissue, it is important to find new sources of liver tissue for isolation of high-quality hepatocytes. Segment IV with or without the caudate lobe was removed during three split-liver procedures. Hepatocytes were isolated from the tissues using a collagenase perfusion technique under strict sterile conditions. The mean number of hepatocytes that were isolated was 5.14 x 10(8) cells with a mean cell viability of 89%. Two of the hepatocyte preparations were used for cell transplantation in a 1-day-old boy with an antenatal diagnosis of a severe urea cycle defect caused by ornithine transcarbamylase deficiency. The six recipients of split-liver grafts demonstrated no complications related to the removal of segment IV. Segment IV with or without the caudate lobe obtained from split-liver procedures is potentially a good source of high-quality hepatocytes for cell transplantation. ",0
2902,15239659,PDBLIG: classification of small molecular protein binding in the Protein Data Bank,"It is known that proteins can adopt different folds while sharing similar features for recognition of similar substrates or ligands, for example, in the binding sites of enzyme cofactors such as ATP. On the other hand, proteins that have highly flexible binding sites or belong to large and diverse protein families can bind structurally dissimilar ligands, as, for example, in the case of the matrix metalloprotease family. We have developed a database, PDBLIG, that classifies protein domains and ligands. The information stored includes each protein's function, domain class(es), which ligand(s) it binds, and so on. The database can provide valuable knowledge for drug discovery, supporting the answering of questions such as whether the same drug molecule can bind different target protein families and whether these families are related functionally or structurally, which ligand classes (such as metabolites or organic molecules) bind to a particular protein family and whether the ligands are druglike, and which target families bind a wide variety of ligands and whether different ligands are associated with different subfamilies. ",0
2903,15239670,Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity,"HIF (hypoxia-inducible factor) is an alphabeta transcription factor that modulates the hypoxic response in many animals. The cellular abundance and activity of HIF-alpha are regulated by its post-translational hydroxylation. The hydroxylation of HIF is catalysed by PHD (prolyl hydroxylase domain) enzymes and FIH (factorinhibiting HIF), all of which are 2-oxoglutarate- and Fe(II)-dependent dioxygenases. FIH hydroxylates a conserved asparagine residue in HIF-alpha (Asn-803), which blocks the binding of HIF to the transcriptional co-activator p300, preventing transcription of hypoxia-regulated genes under normoxic conditions. In the present paper, we report studies on possible mechanisms for the regulation of FIH activity. Recently solved crystal structures of FIH indicate that it is homodimeric. Site-directed mutants of FIH at residues Leu-340 and Ile-344, designed to disrupt dimerization, were generated in order to examine the importance of the dimeric state in determining FIH activity. A single point mutant, L340R (Leu-340-->Arg), was shown to be predominantly monomeric and to have lost catalytic activity as measured by assays monitoring 2-oxoglutarate turnover and asparagine hydroxylation. In contrast, the I344R (Ile-344-->Arg) mutant was predominantly dimeric and catalytically active. The results imply that the homodimeric form of FIH is required for productive substrate binding. The structural data also revealed a hydrophobic interaction formed between FIH and a conserved leucine residue (Leu-795) on the HIF substrate, which is close to the dimer interface. A recent report has revealed that phosphorylation of Thr-796, which is adjacent to Leu-795, enhances the transcriptional response in hypoxia. Consistent with this, we show that phosphorylation of Thr-796 prevents the hydroxylation of Asn-803 by FIH. ",0
2904,15239675,Laser-capture microdissection: applications in routine molecular dermatopathology,"Advances in molecular pathology with the introduction of the Southern blot technique and the polymerase chain reaction (PCR) have emerged as important tools, which are frequently used in routine dermato-histopathology. Applications for PCR-based diagnostics are particularly helpful for the determination of clonality in cutaneous lymphocytic infiltrates and for detection of infectious agents, such as herpes simplex virus (HSV), varicella zoster virus (VZV), Borrelia burgdorferi, Mycobacteria, Leishmania, and Treponema pallidum. As biopsies are always composed of different cells, the cells of interest are often only a minor population. As a consequence, their specific DNA is diluted by the majority of contaminating cells. Another problem is the time- and labor-intensive DNA extraction, because usually only formalin-fixed, paraffin-embedded tissue is available, which makes molecular diagnostics a time and labor consuming, and consequently a cost-intensive procedure. To overcome these shortcomings and to eventually shorten the time to generate a result, we introduce a laser-capture microdissection (LCM)-based method for the detection of infectious agents and clonality. Only the cells of interest for the particular indication are microdissected (e.g. epidermal cells for HSV and VZV and lymphocytes for clonality analysis) and subjected to PCR amplification. Due to an accelerated DNA-extraction procedure which generates DNA in 5 h (compared to 3-4 days using conventional DNA extraction), we are able to generate a result within one working day. ",0
2905,15240073,Prevalence and characteristics of Escherichia coli O157 from major food animals in Korea,"Escherichia coli O157:H7/NM (E. coli O157) is now recognized as an important cause of diarrhea, hemorrhagic colitis and hemolytic-uremic syndrome worldwide. There have been several cases of human E. coli O157 infection in Korea since it was first isolated from a patient with hemolytic-uremic syndrome in 1998. Meat, other foods, and recreational and drinking water contaminated with animal feces are probably the major sources of the E. coli O157 infection. In this study, we investigated the prevalence of E. coli O157 in fecal and meat samples of cattle, pigs and chicken in Korea from April 2000 to July 2002. Eighty-six (3.03%) of 2843 samples were positive for E. coli O157. Most of the E. coli O157 strains were isolated from fecal samples of beef and dairy cattle from May to October of each year. Of 86 E. coli O157 isolates, 73 were serotype O157:H7 and 13 were serotype O157:NM. Polymerase chain reaction (PCR) analysis of E. coli O157 virulence markers revealed that all O157:H7/NM isolates were positive for EhlyA, eaeA and rfb(O157), and 77 isolates were positive for stx1 and/or stx2. Cytotoxicity analysis revealed that many of the E. coli O157 isolates showed high cytotoxicity on Vero cells. Our data suggest that the majority of Korean E. coli O157 isolates from food animals can cause serious diseases in humans. ",0
2906,15240257,The P450 monooxygenase BcABA1 is essential for abscisic acid biosynthesis in Botrytis cinerea,"""The phytopathogenic ascomycete Botrytis cinerea is known to produce abscisic acid (ABA), which is thought to be involved in host-pathogen interaction. Biochemical analyses had previously shown that, in contrast to higher plants, the fungal ABA biosynthesis probably does not proceed via carotenoids but involves direct cyclization of farnesyl diphosphate and subsequent oxidation steps. We present here evidence that this """"direct"""" pathway is indeed the only one used by an ABA-overproducing strain of B. cinerea. Targeted inactivation of the gene bccpr1 encoding a cytochrome P450 oxidoreductase reduced the ABA production significantly, proving the involvement of P450 monooxygenases in the pathway. Expression analysis of 28 different putative P450 monooxygenase genes revealed two that were induced under ABA biosynthesis conditions. Targeted inactivation showed that one of these, bcaba1, is essential for ABA biosynthesis: DeltaBcaba1 mutants contained no residual ABA. Thus, bcaba1 represents the first identified fungal ABA biosynthetic gene. """,0
2907,15240337,A survey of airborne isocyanate exposure in 13 Swedish polyurethane industries,"Exposure to isocyanates can be harmful to workers by causing different disorders of the airways. The main objectives of this study were to survey the personal 8 h time-weighted average exposure to isocyanates at 13 Swedish plants that handled either polyurethane, diisocyanates or both, including four types of manufacturing processes: moulding, continuous foaming, flame lamination and low or no heating processes. A total of 223 air samples were collected for 111 workers with personal air monitoring using a dry filter method with 1-(2-methoxyphenyl)piperazine (2MP) as derivatization reagent. A further 272 stationary samples were collected, using the 2MP method, a modified 2MP method and an impinger method using dibutylamine in toluene. With the applied strategy, a large number of workers were monitored and four industrial environments were compared regarding the isocyanate exposure. All workers were found to be exposed to isocyanates in the range 0.004-5.2 p.p.b. On average, the personal exposure levels in the different types of manufacturing processes were, in decreasing order: continuous foaming > flame lamination > moulding >> low or no heating processes. However, there were variations in exposure levels in plants with similar processes and also between different shifts performing the same tasks. Isocyanic acid, which could not be sampled by the 2MP method used for personal monitoring, was found by short-term stationary monitoring in levels up to 38 p.p.b. in the flame lamination plants. ",0
2908,15240347,Hormones and the stressed brain,"The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action-in concert-is crucial for individual differences in coping with other individuals, which in turn depend on genetic- and experience-related factors. The actions exerted by cortisol and corticosterone have an enormous diversity. They include the regulation of rapid molecular aggregations, membrane processes, and gene transcription. In the latter transcriptional regulation, the corticosteroid hormones have two modes of operation. One mode is mediated by high-affinity mineralocorticoid receptors (MRs), which control gene networks underlying stabilization of neuronal activity as determinant for the sensitivity to trigger immediate responses to stress organized by corticotrophin-releasing hormone (CRH)-1 receptor. Whereas disturbance of homeostasis is prevented by MR-mediated processes, its recovery is facilitated via the low-affinity glucocorticoid receptors (GRs) that require stress levels of cortisol. GRs promote in coordination with CRH-2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance, and health. Imbalance induced by genetic modification or stressors changes specific neural signaling pathways underlying cognition and emotion. This yin-yang concept in stress regulation is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid-induced stress-related disorders such as severe forms of depression. ",0
2909,15241435,Gene-environment interaction analysis of serotonin system markers with adolescent depression,"We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk. ",0
2910,15241437,BCR-ABL transcripts are early predictors for hematological relapse in chronic myeloid leukemia after hematopoietic cell transplantation with reduced intensity conditioning,"Kinetics of BCR-ABL transcript elimination and its prognostic implications on relapse were analyzed in patients with chronic myeloid leukemia (CML) after reduced intensity hematopoietic cell transplantation (HCT). In all, 19 CML patients were conditioned with 2 Gy total-body irradiation in combination with (n=14) or without (n=3) fludarabine 3 x 30 mg/m(2) (Flu) or 4.5 Gy total lymphoid irradiation (TLI) with Flu and OKT3 3 x 5 mg (n=2) and were treated with cyclosporine (CSP) and mycophenolate mofetil after allogeneic HCT. BCR-ABL transcripts were analyzed by nested RT-PCR and Taqman((R)) RT-PCR on days +28, +56 and +84 after HCT and were evaluated for their association with relapse. Of the 19 patients, 14 achieved sustained remissions of which six had a negative RT-PCR 28 days after HCT. Five patients relapsed +41, +54, +57, +136 and +234 days after HCT. Predictors for relapse were advanced disease stage (P=0.02) and slow reduction of BCR-ABL transcripts at day 28 (P=0.006) and day 56 (P=0.047) post-transplant. We conclude that a complete clearance of BCR-ABL transcripts is achievable within 4 weeks from HCT even after minimal conditioning and that early kinetics of BCR-ABL transcripts significantly correlate with the probability of hematological relapse. ",0
2911,15241448,Allozyme variation and structure of the Canarian endemic palm tree Phoenix canariensis (Arecaceae): implications for conservation,"Electrophoretic analysis of 18 allozyme loci was used to estimate the levels and structuring of genetic variation within and among natural populations of the protected endemic palm species from the Canary Islands (Phoenix canariensis) to evaluate its genetic relationship with the widespread congener P. dactylifera, and to assess comparatively the genetic variation in the populations where the two species coexist with morphologically intermediate plants (mixed populations). Our survey revealed that the within-population component explains roughly 75% of the genetic variation levels detected in P. canariensis (A=1.59; P=41.8; He=0.158), which rank higher than those reported for other species of the Arecaceae. A Principal Component analysis (PCA) based on allele frequencies consistently separates populations of P. canariensis and P. dactylifera, and reveals a close genetic relationship between P. canariensis and the mixed populations. Reduced levels of genetic variation in P. canariensis with respect to P. dactylifera, the fact that the genetic makeup of the Canarian endemic (with no unique alleles) is a subset of that found in P. dactylifera, and the high genetic identity between both species strongly suggest that P. canariensis is recently derived from a common ancestor closely related to P. dactylifera. ",0
2912,15241811,A multimodal behavioral approach to performance anxiety,"Cognitive-behavior therapy (CBT) stresses a trimodal assessment framework (affect, behavior, and cognition [ABC]), whereas the multimodal approach assesses seven discrete but interactive components--behavior, affect, sensation, imagery, cognition, interpersonal relationships, and drugs/biological factors (BASIC I.D.). Only complex or recalcitrant cases call for the entire seven-pronged range of multimodal interventions. Various case illustrations are offered as examples of how a clinician might proceed when confronted with problems that fall under the general heading of performance anxiety. The main example is of a violinist in a symphony orchestra whose career was in serious jeopardy because of his extreme fear of performing in public. He responded very well to a focused but elaborate desensitization procedure. The hierarchy that was eventually constructed contained many dimensions and subhierarchies featuring interlocking elements that evoked his anxiety. In addition to imaginal systematic desensitization, sessions were devoted to his actual performance in the clinical setting. As a homework assignment, he found it helpful to listen to a long-playing record of an actual rehearsal and to play along with the world-renowned orchestra and conductor. The subsequent disclosure by the client of an important sexual problem was dealt with concomitantly by using a fairly conventional counseling procedure. Therapy required 20 sessions over a 3-month period. ",0
2913,15241893,Platelet anti-aggregating triterpenoids from the leaves of Acanthopanax senticosus and the fruits of A. sessiliflorus,"Six triterpenoids, chiisanogenin, chiisanoside, ursolic acid, oleanolic acid, beta-sitosterol and daucosterol, were isolated as the platelet anti-aggregating components from the leaves of Acanthopanax senticosus and the fruits of A. sessiliflorus. Chiisanogenin showed about 50-fold higher potency than acetylsalicylic acid (ASA) on U46619-induced platelet aggregation (IC50o:6.21 microM) and 10-20-fold higher effects than ASA on epinephrine- and arachidonic acid (AA)-induced aggregation (IC50:2.50 and 4.81 microM, respectively). ",0
2914,15242044,A case report of severe laryngeal edema which occured before removal of a laryngeal mask airway],"A 41-year-old woman was scheduled for a partial hip arthroplasty. She was suffering from malignant rheumatoid arthritis for a long time and we recognized her difficult airway. After epidural catheterization, anesthesia was induced with fentanyl, thiopental, and 5% sevoflurane with oxygen. A laryngeal mask airway (LMA ; size 3) was inserted smoothly on third trial after suxamethonium chloride administration. Anesthesia was maintained with fentanyl, vecuronium bromide, sevoflurane with oxygen and epidural anesthesia. No complications were observed during the operation. After reversal of muscle relaxant, spontaneous respiration returned. But inspiratory stridor and chest wall retraction occurred soon, and we found severe epiglottic edema by bronchoscopy. A tracheal tube (ID 5.5 mm) was intubated immediately through the LMA. Twenty hours later the pharyngeal edema was still very severe, and tracheotomy was performed. The edema disappeared three days later. We thought the edema had occurred as a result of blood flow disturbance caused by LMA in narrow pharyngeal space expanding to the epiglottis. It should be kept in mind that severe edema could develop after LMA in malignant rheumatoid arthritis. ",0
2915,15242225,"""Listening to """"felt needs"""": investigating genital prolapse in western Nepal""","The global prevalence of genital prolapse is estimated to be 2-20% in women under age 45. In Nepal, genital prolapse appears to be widespread, but little published evidence exists to buttress this claim. This paper presents findings of two studies, one ethnographic and one clinic-based, in western Nepal. The ethnographic study involved 16 focus group discussions with 120 community members and key informants, and covered community perceptions and women's experience of prolapse and its perceived causes and consequences. The clinic-based study was conducted among 2,072 women who presented with gynaecological complaints and received a diagnosis. One in four of them had genital prolapse, of whom 95% had self-reported the prolapse. The most commonly perceived causes of prolapse were lifting heavy loads, including in the post-partum period. The adverse effects reported included difficulty urinating, abdominal pain, backache, painful intercourse, burning upon urination, white watery discharge, foul-smelling discharge, itching, and difficulty lifting, sitting, walking and standing. The results confirm prolapse as a significant public health problem in western Nepal. We strongly recommend developing systematic, rotational gynaecological clinics in rural districts, the use of a screening checklist and counselling for prevention and early management of genital prolapse by district health workers for family planning and antenatal patients. ",0
2916,15242330,Newer anticonvulsants in the treatment of bipolar disorder,"The anticonvulsants valproate and carbamazepine have efficacy in treating acute mania, but their efficacy in treating acute bipolar depression and preventing mood episodes remains uncertain. Despite this, and given their utility and widespread use, both are widely accepted as standard treatments for bipolar disorder. All the newer anticonvulsants that have become available during the last decade have been or are being assessed to determine their efficacy in the treatment of various phases of bipolar disorder. Among the newer anticonvulsants, some appear to have efficacy in treating core bipolar symptoms, while others have efficacy in treating psychiatric comorbidity such as substance abuse or an anxiety disorder. Lamotrigine is the most widely studied and is effective in treating and preventing bipolar depression, and it is the only anticonvulsant approved by the U.S. Food and Drug Administration as a maintenance treatment for bipolar disorder. Other newer anticonvulsants, levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but further studies are required before they can be recommended for routine use to treat bipolar disorder. Gabapentin and topiramate do not appear to have efficacy in treating acute mania, but their utility in bipolar depression and prevention of mood episodes has not been studied in double-blind trials. Pregabalin has utility in treating generalized anxiety disorder, but it has not been studied in bipolar disorder. Given the success of lamotrigine in treating bipolar disorder, further double-blind controlled trials of the newer anticonvulsants in treating bipolar disorder are warranted. This article summarizes current evidence from trials of anticonvulsants in bipolar disorder and makes recommendations for their clinical use. ",0
2917,15242523,Gene transfer of connexin43 into skeletal muscle,"Cellular cardiomyoplasty using skeletal myoblasts may be beneficial for infarct repair. One drawback to skeletal muscle cells is their lack of gap junction expression after differentiation, thus preventing electrical coupling to host cardiomyocytes. We sought to overexpress the gap junction protein connexin43 (Cx43) in differentiated skeletal myotubes, using retroviral, adenoviral, and plasmid-mediated gene transfer. All strategies resulted in overexpression of Cx43 in cultured myotubes, but expression of Cx43 from constitutive viral promoters caused significant death upon differentiation. Dye transfer studies showed that surviving myotubes contained functional gap junctions, however. Retrovirally transfected myoblasts did not express Cx43 after grafting into the heart, possibly due to promoter silencing. Adenovirally transfected myoblasts expressed abundant Cx43 after forming myotubes in cardiac grafts, but grafts showed signs of injury at 1 week and had died by 2 weeks. Interestingly, transfection of already differentiated myotubes with adenoviral Cx43 was nontoxic, implying a window of vulnerability during differentiation. To test this hypothesis, Cx43 was expressed from the muscle creatine kinase (MCK) promoter, which is active only after myocyte differentiation. The MCK promoter resulted in high levels of Cx43 expression in differentiated myotubes but did not cause cell death during differentiation. MCK-Cx43-transfected myoblasts formed viable cardiac grafts and, in some cases, Cx43-expressing myotubes were in close apposition to host cardiomyocytes, possibly allowing electrical coupling. Thus, high levels of Cx43 during skeletal muscle differentiation cause cell death. When, however, expression of Cx43 is delayed until after differentiation, using the MCK promoter, myotubes are viable and express gap junction proteins after grafting in the heart. This strategy may permit electrical coupling of skeletal and cardiac muscle for cardiac repair. ",0
2918,15242560,Preischemic selenium status as a major determinant of myocardial infarct size in vivo in rats,"Prospective epidemiological studies have shown that the incidence of numerous cardiovascular pathologies is correlated with body selenium status. However, it remains unclear whether selenium status also influences the outcome of myocardial infarction. The aim of the present study was to test whether dietary selenium intake affects myocardial necrosis induced by transient regional ischemia in vivo in rats. For this purpose, male Wistar rats received either a high-selenium (High-Se: 1.5 mg of Se/kg) or a low-selenium (Low-Se: 0.05 mg of Se/kg) diet for 10 weeks. Animals were subjected to 30 min of myocardial ischemia induced by coronary artery ligation followed by 60 min of reperfusion. Pre- and postischemic blood samples were collected for glutathione (GSH and GSSG) determination and for glutathione peroxidase (GSH-Px) assessment. Our results show that high-selenium intake reduces myocardial infarct size (High-Se: 25.16 +/- 1.19% versus Low-Se: 36.51 +/- 4.14%, p < 0.05), preserves postischemic GSH/GSSG ratio (High-Se: 1.37 +/- 0.37 versus Low-Se: 0.47 +/- 0.10, p < 0.05), increases plasma GSH-Px activity, and improves postischemic mean arterial pressure. In conclusion, preischemic body selenium status is a major determinant of the outcome of myocardial ischemia in vivo in rats probably because it influences the cellular redox status. ",0
2919,15282350,Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition,"BACKGROUND: The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. METHODS: Women who had a cumulative lifetime risk of breast cancer of 15 percent or more were screened every six months with a clinical breast examination and once a year by mammography and MRI, with independent readings. The characteristics of the cancers that were detected were compared with the characteristics of those in two different age-matched control groups. RESULTS: We screened 1909 eligible women, including 358 carriers of germ-line mutations. Within a median follow-up period of 2.9 years, 51 tumors (44 invasive cancers, 6 ductal carcinomas in situ, and 1 lymphoma) and 1 lobular carcinoma in situ were detected. The sensitivity of clinical breast examination, mammography, and MRI for detecting invasive breast cancer was 17.9 percent, 33.3 percent, and 79.5 percent, respectively, and the specificity was 98.1 percent, 95.0 percent, and 89.8 percent, respectively. The overall discriminating capacity of MRI was significantly better than that of mammography (P<0.05). The proportion of invasive tumors that were 10 mm or less in diameter was significantly greater in our surveillance group (43.2 percent) than in either control group (14.0 percent [P<0.001] and 12.5 percent [P=0.04], respectively). The combined incidence of positive axillary nodes and micrometastases in invasive cancers in our study was 21.4 percent, as compared with 52.4 percent (P<0.001) and 56.4 percent (P=0.001) in the two control groups. CONCLUSIONS: MRI appears to be more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer.",0
2920,15295048,Loss of Smad3 in acute T-cell lymphoblastic leukemia,"BACKGROUND: The receptors for transforming growth factor beta (TGF-beta) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates--Smad3--in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-beta and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27Kip1 were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-beta on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27Kip1 to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27Kip1 work synergistically to promote T-cell leukemogenesis in mice.",0
2921,15295049,Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells,"BACKGROUND: Increased proliferation of bronchial smooth-muscle cells may lead to increased muscle mass in the airways of patients with asthma. The antiproliferative effect of glucocorticoids in bronchial smooth-muscle cells in subjects without asthma is mediated by a complex of the glucocorticoid receptor and the CCAAT/enhancer binding protein alpha (C/EBPalpha). We examined the signaling pathway controlling the inhibitory effect of glucocorticoids on cell proliferation and interleukin-6 synthesis in bronchial smooth-muscle cells of subjects with asthma and those without asthma. METHODS: Lines of bronchial smooth-muscle cells were established from cells from 20 subjects with asthma, 8 subjects with emphysema, and 26 control subjects. Cell proliferation was determined by means of cell counts and [3H]thymidine incorporation. Signal transduction was studied by means of an electrophoretic DNA mobility-shift assay, a supershift electrophoretic-mobility assay, immunoblotting, use of C/EBPalpha antisense oligonucleotides, and use of a human C/EBPalpha expression vector. Interleukin-6 release was determined by means of an enzyme-linked immunosorbent assay. RESULTS: Glucocorticoids activated the glucocorticoid receptor and inhibited serum-induced secretion of interleukin-6 in bronchial smooth-muscle cells from both subjects with asthma and those without asthma; however, glucocorticoids inhibited proliferation only in bronchial smooth-muscle cells from subjects without asthma. C/EBPalpha protein was detected by immunoblotting in all bronchial smooth-muscle cells from subjects without asthma but not in those with asthma, whereas the protein was expressed in lymphocytes from both groups of subjects. C/EBPalpha antisense oligonucleotides or the glucocorticoid-receptor inhibitor mifepristone reversed the antiproliferative effect of glucocorticoids in bronchial smooth-muscle cells from subjects without asthma. When bronchial smooth-muscle cells from subjects with asthma were transiently transfected with an expression vector for human C/EBPalpha, two forms of the protein were expressed, and subsequent administration of glucocorticoids inhibited cell proliferation. CONCLUSIONS: We hypothesize that a cell-type-specific absence of C/EBPalpha is responsible for the enhanced proliferation of bronchial smooth-muscle cells derived from subjects with asthma and that it explains the failure of glucocorticoids to inhibit proliferation in vitro.",0
2922,15295050,Primary care physicians who treat blacks and whites,"""BACKGROUND: In the United States, black patients generally receive lower-quality health care than white patients. Black patients may receive their care from a subgroup of physicians whose qualifications or resources are inferior to those of the physicians who treat white patients. METHODS: We performed a cross-sectional analysis of 150,391 visits by black Medicare beneficiaries and white Medicare beneficiaries 65 years of age or older for medical """"evaluation and management"""" who were seen by 4355 primary care physicians who participated in a biannual telephone survey, the 2000-2001 Community Tracking Study Physician Survey. RESULTS: Most visits by black patients were with a small group of physicians (80 percent of visits were accounted for by 22 percent of physicians) who provided only a small percentage of care to white patients. In a comparison of visits by white patients and black patients, we found that the physicians whom the black patients visited were less likely to be board certified (77.4 percent) than were the physicians visited by the white patients (86.1 percent, P=0.02) and also more likely to report that they were unable to provide high-quality care to all their patients (27.8 percent vs. 19.3 percent, P=0.005). The physicians treating black patients also reported facing greater difficulties in obtaining access for their patients to high-quality subspecialists, high-quality diagnostic imaging, and nonemergency admission to the hospital. CONCLUSIONS: Black patients and white patients are to a large extent treated by different physicians. The physicians treating black patients may be less well trained clinically and may have less access to important clinical resources than physicians treating white patients. Further research should be conducted to address the extent to which these differences may be responsible for disparities in health care.""",0
2923,15306665,Public-access defibrillation and survival after out-of-hospital cardiac arrest,"BACKGROUND: The rate of survival after out-of-hospital cardiac arrest is low. It is not known whether this rate will increase if laypersons are trained to attempt defibrillation with the use of automated external defibrillators (AEDs). METHODS: We conducted a prospective, community-based, multicenter clinical trial in which we randomly assigned community units (e.g., shopping malls and apartment complexes) to a structured and monitored emergency-response system involving lay volunteers trained in cardiopulmonary resuscitation (CPR) alone or in CPR and the use of AEDs. The primary outcome was survival to hospital discharge. RESULTS: More than 19,000 volunteer responders from 993 community units in 24 North American regions participated. The two study groups had similar unit and volunteer characteristics. Patients with treated out-of-hospital cardiac arrest in the two groups were similar in age (mean, 69.8 years), proportion of men (67 percent), rate of cardiac arrest in a public location (70 percent), and rate of witnessed cardiac arrest (72 percent). No inappropriate shocks were delivered. There were more survivors to hospital discharge in the units assigned to have volunteers trained in CPR plus the use of AEDs (30 survivors among 128 arrests) than there were in the units assigned to have volunteers trained only in CPR (15 among 107; P=0.03; relative risk, 2.0; 95 percent confidence interval, 1.07 to 3.77); there were only 2 survivors in residential complexes. Functional status at hospital discharge did not differ between the two groups. CONCLUSIONS: Training and equipping volunteers to attempt early defibrillation within a structured response system can increase the number of survivors to hospital discharge after out-of-hospital cardiac arrest in public locations. Trained laypersons can use AEDs safely and effectively.",0
2924,15306666,Advanced cardiac life support in out-of-hospital cardiac arrest,"BACKGROUND: The Ontario Prehospital Advanced Life Support (OPALS) Study tested the incremental effect on the rate of survival after out-of-hospital cardiac arrest of adding a program of advanced life support to a program of rapid defibrillation. METHODS: This multicenter, controlled clinical trial was conducted in 17 cities before and after advanced-life-support programs were instituted and enrolled 5638 patients who had had cardiac arrest outside the hospital. Of those patients, 1391 were enrolled during the rapid-defibrillation phase and 4247 during the subsequent advanced-life-support phase. Paramedics were trained in standard advanced life support, which includes endotracheal intubation and the administration of intravenous drugs. RESULTS: From the rapid-defibrillation phase to the advanced-life-support phase, the rate of admission to a hospital increased significantly (10.9 percent vs. 14.6 percent, P<0.001), but the rate of survival to hospital discharge did not (5.0 percent vs. 5.1 percent, P=0.83). The multivariate odds ratio for survival after advanced life support was 1.1 (95 percent confidence interval, 0.8 to 1.5); after an arrest witnessed by a bystander, 4.4 (95 percent confidence interval, 3.1 to 6.4); after cardiopulmonary resuscitation administered by a bystander, 3.7 (95 percent confidence interval, 2.5 to 5.4); and after rapid defibrillation, 3.4 (95 percent confidence interval, 1.4 to 8.4). There was no improvement in the rate of survival with the use of advanced life support in any subgroup. CONCLUSIONS: The addition of advanced-life-support interventions did not improve the rate of survival after out-of-hospital cardiac arrest in a previously optimized emergency-medical-services system of rapid defibrillation. In order to save lives, health care planners should make cardiopulmonary resuscitation by citizens and rapid-defibrillation responses a priority for the resources of emergency-medical-services systems.",0
2925,15306667,Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML,"BACKGROUND: The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal. METHODS: We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors from marrow during several phases of CML and from normal marrow. BCR-ABL, beta-catenin, and LEF-1 transcripts were compared by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay in normal and CML hematopoietic stem cells and granulocyte-macrophage progenitors. Confocal fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter assay were used to detect nuclear beta-catenin in these cells. In vitro replating assays were used to identify self-renewing cells as candidate leukemic stem cells, and the dependence of self-renewal on beta-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the beta-catenin pathway. RESULTS: The granulocyte-macrophage progenitor pool from patients with CML in blast crisis and imatinib-resistant CML was expanded, expressed BCR-ABL, and had elevated levels of nuclear beta-catenin as compared with the levels in progenitors from normal marrow. Unlike normal granulocyte-macrophage progenitors, CML granulocyte-macrophage progenitors formed self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity was reduced by enforced expression of axin. CONCLUSIONS: Activation of beta-catenin in CML granulocyte-macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells.",0
2926,15317891,"Circulating tumor cells, disease progression, and survival in metastatic breast cancer","BACKGROUND: We tested the hypothesis that the level of circulating tumor cells can predict survival in metastatic breast cancer. METHODS: In a prospective, multicenter study, we tested 177 patients with measurable metastatic breast cancer for levels of circulating tumor cells both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. RESULTS: Outcomes were assessed according to levels of circulating tumor cells at baseline, before the patients started a new treatment for metastatic disease. Patients in a training set with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 circulating tumor cells per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P<0.001) and shorter overall survival (10.1 months vs. >18 months, P<0.001). At the first follow-up visit after the initiation of therapy, this difference between the groups persisted (progression-free survival, 2.1 months vs. 7.0 months; P<0.001; overall survival, 8.2 months vs. >18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy. The multivariate Cox proportional-hazards regression showed that, of all the variables in the statistical model, the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival. CONCLUSIONS: The number of circulating tumor cells before treatment is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer.",0
2927,15329426,Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome,"BACKGROUND: Preclinical studies suggest that exogenous surfactant may be of value in the treatment of the acute respiratory distress syndrome (ARDS), and two phase 2 clinical trials have shown a trend toward benefit. We conducted two phase 3 studies of a protein-containing surfactant in adults with ARDS. METHODS: In two multicenter, randomized, double-blind trials involving 448 patients with ARDS from various causes, we compared standard therapy alone with standard therapy plus up to four intratracheal doses of a recombinant surfactant protein C-based surfactant given within a period of 24 hours. RESULTS: The overall survival rate was 66 percent 28 days after treatment, and the median number of ventilator-free days was 0 (68 percent range, 0 to 26); there was no significant difference between the groups in terms of mortality or the need for mechanical ventilation. Patients receiving surfactant had a significantly greater improvement in blood oxygenation during the initial 24 hours of treatment than patients receiving standard therapy, according to both univariate and multivariate analyses. CONCLUSIONS: The use of exogenous surfactant in a heterogeneous population of patients with ARDS did not improve survival. Patients who received surfactant had a greater improvement in gas exchange during the 24-hour treatment period than patients who received standard therapy alone, suggesting the potential benefit of a longer treatment course.",0
2928,15329427,ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia,"BACKGROUND: The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV(H)) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV(H) but lack expression of ZAP-70. METHODS: We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV(H) gene. We then investigated the association between the results and the time from diagnosis to initial therapy. RESULTS: We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV(H) gene (71 percent), but in only 24 of the 143 patients with a mutated IgV(H) gene (17 percent, P<0.001). Among the patients with ZAP-70-positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV(H) gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV(H) gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70-negative CLL cells who had either mutated or unmutated IgV(H) genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV(H) gene and 7.1 years in those with an unmutated IgV(H) gene (P<0.001). CONCLUSIONS: Although the presence of an unmutated IgV(H) gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.",0
2929,15349900,Negative regulation of hepatocellular carcinoma cell growth by signal regulatory protein alpha1,"Signal regulatory protein (SIRP) alpha1 is a member of the SIRP family that undergoes tyrosine phosphorylation and binds SHP-2 tyrosine phosphatase in response to various mitogens. The expression levels of SIRPalpha1 were decreased in HCC tissues, compared with the matched normal tissues. Exogenous expression of wild type SIRPalpha1, but not of a mutant SIRPalpha1 lacking the tyrosine phosphorylation sites, in SIRPalpha1-negative Huh7 human HCC cells resulted in suppression of tumor cell growth both in vitro and in vivo. Treatment of Huh7 transfectants with EGF or HGF induced tyrosine phosphorylation of SIRPalpha1 and its association with SHP-2, which were accompanied by reduced ERK1 activation. Expression of SIRPalpha1 significantly suppressed activation of NF-kappaB and also sensitized Huh7 cells to TNFalpha or cisplatin-induced cell death. In addition, SIRPalpha1-transfected Huh7 cells displayed reduced cell migration and cell spreading in a fashion that was dependent on SIRPalpha1/SHP-2 complex formation. In conclusion, a negative regulatory effect of SIRPalpha1 on hepatocarcinogenesis is exerted, at least in part, through inhibition of ERK and NF-kappaB pathways.",0
2930,15349911,Hepatitis C virus NS5A-regulated gene expression and signaling revealed via microarray and comparative promoter analyses,"Most individuals exposed to hepatitis C virus (HCV) become chronically infected and are predisposed to liver disease. The mechanisms underlying viral persistence and disease progression are unknown. A role for the HCV NS5A protein in viral replication and interferon resistance has been demonstrated. To identify mechanisms affected by NS5A, we analyzed the gene expression of Huh7 cells expressing NS5A and control cells using oligonucleotide microarrays. A set of 103 genes (43 up-regulated, 60 down-regulated) whose expression was modified by at least twofold was selected. These included genes involved in cell adhesion and motility, calcium homeostasis, lipid transport and metabolism, and genes regulating immune responses. The finding of modulated expression of genes related to the TGF-beta superfamily and liver fibrosis was observed. Interestingly, both the tumor necrosis factor and lymphotoxin beta receptors were down-regulated by NS5A. Similar data were obtained following expression of four NS5A mutants obtained from patients who were not responsive or were sensitive to interferon therapy. Through computational analysis, we determined that 39 of the 43 genes up-regulated by NS5A contained one or more nuclear factor kappaB (NF-kappaB) binding sites within their promoter region. Using the Gibbs sampling method, we also detected enrichment of NF-kappaB consensus binding sites in the upstream regions of the 43 coexpressed genes. Activation of NF-kappaB by NS5A was subsequently demonstrated in luciferase reporter assays. Adenovirus-mediated expression of IkappaBalpha reverted NS5A mediated up-regulation of gene expression. In conclusion, this study suggests a role of NS5A and NF-kappaB in HCV pathogenesis and related liver disease. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).",0
2931,15349915,A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D,"""There are two subtypes of hepatitis B virus genotype A (HBV/A) and they are provisionally designated Aa (""""a"""" standing for Africa/Asia) and Ae (""""e"""" for Europe). In a case-control study, 78 HBV/Aa, 78HBV/Ae, and 78HBV/D carriers from several countries were compared. The prevalence of HBe antigen (HBeAg) in serum was significantly lower in carriers of HBV/Aa than in carriers of HBV/Ae (31% vs. 49%; P = .033), with a difference more obvious in the carriers aged 30 years or younger (34% vs. 67%; P = .029). HBV DNA levels in the carriers of HBV/Aa (median, 3.46 log copies/mL; 95% CI, 2.93-3.95) were significantly lower than those of carriers of HBV/Ae (6.09 log copies/mL; 95% CI, 4.24-7.64) or of carriers of HBV/D (5.48 log copies/mL; 95% CI, 4.06-7.02), regardless of the HBeAg status (P < .001). The most specific and frequent substitutions in 54 HBV/Aa isolates were double substitutions for T1809 (100%) and T1812 (96%) immediately upstream of the precore initiation codon, which would interfere with the translation of HBeAg in HBV/Aa infections. They were not detected in 57 HBV/Ae or 61 HBV/D isolates examined. The double mutation in the core promoter (T1762/A1764) was more frequent in both HBV/Aa (50%) and HBV/Ae (44%) than in HBV/D isolates (25%; P < .01), whereas the precore mutation (A1896) occurred in HBV/D isolates only (48%; P < .0001). In conclusion, the clearance of HBeAg from serum may occur by different mechanisms in HBV/Aa, HBV/Ae, and HBV/D infections, which may influence clinical manifestations in the Western countries where both genotypes A and D are prevalent.""",0
2932,15356306,Oral erythromycin and the risk of sudden death from cardiac causes,"BACKGROUND: Oral erythromycin prolongs cardiac repolarization and is associated with case reports of torsades de pointes. Because erythromycin is extensively metabolized by cytochrome P-450 3A (CYP3A) isozymes, commonly used medications that inhibit the effects of CYP3A may increase plasma erythromycin concentrations, thereby increasing the risk of ventricular arrhythmias and sudden death. We studied the association between the use of erythromycin and the risk of sudden death from cardiac causes and whether this risk was increased with the concurrent use of strong inhibitors of CYP3A. METHODS: We studied a previously identified Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. The CYP3A inhibitors used in the study were nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin; each doubles, at least, the area under the time-concentration curve for a CYP3A substrate. Amoxicillin, an antimicrobial agent with similar indications but which does not prolong cardiac repolarization, and former use of erythromycin also were studied, to assess possible confounding by indication. RESULTS: The multivariate adjusted rate of sudden death from cardiac causes among patients currently using erythromycin was twice as high (incidence-rate ratio, 2.01; 95 percent confidence interval, 1.08 to 3.75; P=0.03) as that among those who had not used any of the study antibiotic medications. There was no significant increase in the risk of sudden death among former users of erythromycin (incidence-rate ratio, 0.89; 95 percent confidence interval, 0.72 to 1.09; P=0.26) or among those who were currently using amoxicillin (incidence-rate ratio, 1.18; 95 percent confidence interval, 0.59 to 2.36; P=0.65). The adjusted rate of sudden death from cardiac causes was five times as high (incidence-rate ratio, 5.35; 95 percent confidence interval, 1.72 to 16.64; P=0.004) among those who concurrently used CYP3A inhibitors and erythromycin as that among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications. In contrast, there was no increase in the risk of sudden death among those who concurrently used amoxicillin and CYP3A inhibitors or those currently using any of the study antibiotic medications who had formerly used CYP3A inhibitors. CONCLUSIONS: The concurrent use of erythromycin and strong inhibitors of CYP3A should be avoided.",0
2933,15371575,Talking about death with children who have severe malignant disease,"BACKGROUND: One of the questions faced by the parents of a child who is terminally ill with a malignant disease is whether or not they should talk about death with their child. METHODS: In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer between 1992 and 1997. Among 561 eligible parents, 449 answered a questionnaire, and 429 stated whether or not they had talked about death with their child. RESULTS: None of the 147 parents who talked with their child about death regretted it. In contrast, 69 of 258 parents (27 percent) who did not talk with their child about death regretted not having done so. Parents who sensed that their child was aware of his or her imminent death were more likely to regret not having talked about it (47 percent, as compared with 13 percent of parents who did not sense this awareness in their child; relative risk, 3.7; 95 percent confidence interval, 2.3 to 6.0). The same variable was related to having talked about death (50 percent vs. 13 percent; relative risk, 3.8; 95 percent confidence interval, 2.6 to 5.6), as was being religious (42 percent vs. 25 percent; relative risk, 1.7; 95 percent confidence interval, 1.2 to 2.3). The child's age was related to both having talked about death and the parents' regretting not having talked about it. CONCLUSIONS: Parents who sense that their child is aware of his or her imminent death more often later regret not having talked with their child than do parents who do not sense this awareness in their child; overall, no parent in this cohort later regretted having talked with his or her child about death.",0
2934,15382127,Peptide antibiotic human beta-defensin-1 and -2 contribute to antimicrobial defense of the intrahepatic biliary tree,"Human beta-defensins (hBDs) are important antimicrobial peptides that contribute to innate immunity at mucosal surfaces. This study was undertaken to investigate the expression of hBD-1 and hBD-2 in intrahepatic biliary epithelial cells in specimens of human liver, and 4 cultured cell lines (2 consisting of biliary epithelial cells and 2 cholangiocarcinoma cells). In addition, hBD-1 and hBD-2 were assayed in specimens of bile. hBD-1 was nonspecifically expressed immunohistochemically in intrahepatic biliary epithelium and hepatocytes in all patients studied, but expression of hBD-2 was restricted to large intrahepatic bile ducts in 8 of 10 patients with extrahepatic biliary obstruction (EBO), 7 of 11 with hepatolithiasis, 1 of 6 with primary biliary cirrhosis (PBC), 1 of 5 with primary sclerosing cholangitis (PSC), 0 of 6 with chronic hepatitis C (CH-C), and 0 of 11 with normal hepatic histology. hBD-2 expression was evident in bile ducts exhibiting active inflammation. Serum C reactive protein levels correlated with biliary epithelial expression of hBD-2. Real-time PCR revealed that in all of 28 specimens of fresh liver, including specimens from patients with hepatolithiasis, PBC, PSC, CH-C and normal hepatic histology, hBD-1 messenger RNA was consistently expressed, whereas hBD-2 messenger RNA was selectively expressed in biliary epithelium of patients with hepatolithiasis. Immunobloting analysis revealed hBD-2 protein in bile in 1 of 3 patients with PSC, 1 of 3 with PBC, and each of 6 with hepatolithiasis; in contrast, hBD-1 was detectable in all bile samples examined. Four cultured biliary epithelial cell lines consistently expressed hBD-1; in contrast these cell lines did not express hBD-2 spontaneously but were induced to express hBD-2 by treatment with Eschericia coli, lipopolysaccharide, interleukin-1beta or tumor necrosis factor-alpha. In conclusion, these findings suggest that in the intrahepatic biliary tree, hBD-2 is expressed in response to local infection and/or active inflammation, whereas hBD-1 may constitute a preexisting component of the biliary antimicrobial defense system.",0
2935,15385656,"Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization","BACKGROUND: End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. METHODS: We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. RESULTS: The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1.1 to 1.2), 1.8 with an estimated GFR of 30 to 44 ml per minute per 1.73 m2 (95 percent confidence interval, 1.7 to 1.9), 3.2 with an estimated GFR of 15 to 29 ml per minute per 1.73 m2 (95 percent confidence interval, 3.1 to 3.4), and 5.9 with an estimated GFR of less than 15 ml per minute per 1.73 m2 (95 percent confidence interval, 5.4 to 6.5). The adjusted hazard ratio for cardiovascular events also increased inversely with the estimated GFR: 1.4 (95 percent confidence interval, 1.4 to 1.5), 2.0 (95 percent confidence interval, 1.9 to 2.1), 2.8 (95 percent confidence interval, 2.6 to 2.9), and 3.4 (95 percent confidence interval, 3.1 to 3.8), respectively. The adjusted risk of hospitalization with a reduced estimated GFR followed a similar pattern. CONCLUSIONS: An independent, graded association was observed between a reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization in a large, community-based population. These findings highlight the clinical and public health importance of chronic renal insufficiency.",0
2936,15483282,Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants,"BACKGROUND: In an attempt to reduce the coagulopathic and inflammatory responses seen after cardiopulmonary bypass, the use of fresh whole blood during heart operations has become the standard of care for neonates and infants at many institutions. We compared the use of fresh whole blood with the use of a combination of packed red cells and fresh-frozen plasma (reconstituted blood) for priming of the cardiopulmonary bypass circuit. METHODS: We conducted a single-center, randomized, double-blind, controlled trial involving children less than one year of age who underwent open-heart surgery. Patients were assigned to receive either fresh whole blood that had been collected not more than 48 hours previously (96 patients) or reconstituted blood (104 patients) for bypass-circuit priming. Clinical outcomes and serologic measures of systemic inflammation and myocardial injury were compared between the groups. RESULTS: The group that received reconstituted blood had a shorter stay in the intensive care unit than the group that received fresh whole blood (70.5 hours vs. 97.0 hours, P=0.04). The group that received reconstituted blood also had a smaller cumulative fluid balance at 48 hours (-6.9 ml per kilogram of body weight vs. 28.8 ml per kilogram, P=0.003). Early postoperative chest-tube output, blood-product transfusion requirements, and levels of serum mediators of inflammation and cardiac troponin I were similar in the two groups. CONCLUSIONS: The use of fresh whole blood for cardiopulmonary bypass priming has no advantage over the use of a combination of packed red cells and fresh-frozen plasma during surgery for congenital heart disease. Moreover, circuit priming with fresh whole blood is associated with an increased length of stay in the intensive care unit and increased perioperative fluid overload.",0
2937,15486982,To be or not to be NKT: natural killer T cells in the liver,"Much of the hepatology literature to date has focused on the adaptive, antigen-specific response mediated by classical T-cell populations in both the protection and pathogenesis of liver disease. However, the liver is selectively enriched for cells representative of innate immunity, including natural killer T (NKT) cells. In particular, certain CD1d-reactive T cells are present at much higher frequencies in the liver than in the peripheral blood. Although these cells have previously been defined mostly on the basis of phenotypic markers, recent emerging literature regarding NKT cell populations has revealed considerable functional complexity. This review summarizes the recent literature regarding NKT cells, which may have important roles in a variety of liver diseases. Although there is an abundance of literature on the phenotype, distribution, and function of these cells in mice, much less is known about them in human health or liver diseases.",0
2938,15533851,Combination of isosorbide dinitrate and hydralazine in blacks with heart failure,"BACKGROUND: We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy. METHODS: A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life. RESULTS: The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (-0.1+/-1.9 vs. -0.5+/-2.0, P=0.01; range of possible values, -6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, -5.6+/-20.6 vs. -2.7+/-21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]). CONCLUSIONS: The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.",0
2939,15548776,Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells,"BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.",0
2940,15558739,"Sidechain biology and the immunogenicity of PDC-E2, the major autoantigen of primary biliary cirrhosis","The E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2) is the immunodominant autoantigen of primary biliary cirrhosis. Whereas lipoylation of PDC-E2 is essential for enzymatic activity and predominates under normal conditions, other biochemical systems exist that also target the lysine residue, including acylation of fatty acids or xenobiotics and ubiquitinylation. More importantly, the immunogenicity can be affected by derivatization of the lysine residue, as the recognition of lipoylated PDC-E2 by patient autoantibodies is enhanced compared with octanoylated PDC-E2. Furthermore, our laboratory has shown that various xenobiotic modifications of a peptide representing the immunodominant region of PDC-E2 are immunoreactive against patient sera. The only purported regulatory system that prevents the accumulation of potentially autoreactive PDC-E2 is glutathionylation, in which the lysine-lipoic acid moiety is further modified with glutathione during apoptosis. Interestingly, this system is found in several cell lines, including HeLa, Jurkat, and Caco-2 cells, but not in cholangiocytes and salivary gland epithelial cells, both of which are targets for destruction in primary biliary cirrhosis. Hence, the failure of this or other regulatory system(s) may overwhelm the immune system with immunogenic PDC-E2 that can initiate the breakdown of tolerance in a genetically susceptible individual. In this review the authors survey the data available on the biochemical life of PDC-E2, with particular emphasis on the lysine residue and its known interactions with machinery involved in various posttranslational modifications.",0
2941,15564543,Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia,"BACKGROUND: Data regarding the outcome of cord-blood transplantation in adults are scant, despite the fact that these grafts are increasingly used in adults. METHODS: We compared the outcomes of the transplantation of hematopoietic stem cells from unrelated donors in adults with leukemia who had received cord blood that was mismatched for one HLA antigen (34 patients) or two antigens (116 patients), bone marrow that had one HLA mismatch (83 patients), and HLA-matched bone marrow (367 patients). We used Cox proportional-hazards models to analyze the data. RESULTS: Cord-blood recipients were younger and more likely to have advanced leukemia than were bone marrow recipients, and they received lower doses of nucleated cells. Hematopoietic recovery was slower with transplantation of mismatched bone marrow and cord blood than with matched marrow transplantations. Acute graft-versus-host disease (GVHD) was more likely to occur after mismatched marrow transplantation, and chronic GVHD was more likely to occur after cord-blood transplantation. The rates of treatment-related mortality, treatment failure, and overall mortality were lowest among patients who received matched marrow transplants. Patients who received mismatched bone marrow transplants and those who received mismatched cord-blood transplants had similar rates of treatment-related mortality (P=0.96), treatment failure (P=0.69), and overall mortality (P=0.62). There were no differences in the rate of recurrence of leukemia among the groups. There were no differences in outcome after cord-blood transplantation between patients with one HLA mismatch and those with two HLA mismatches. CONCLUSIONS: HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor.",0
2942,15565659,Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice,"In the injured liver, hepatic stellate cells (HSCs) secrete many different cytokines, recruit lymphocytes, and thus participate actively in the pathogenesis of liver disease. Little is known of the role of HSCs in immune responses. In this study, HSCs isolated from C57BL/10 (H2b) mice were found to express scant key surface molecules in the quiescent stage. Activated HSCs express major histocompatibility complex class I, costimulatory molecules, and produce a variety of cytokines. Stimulation by interferon gamma (IFN-gamma) or activated T cells enhanced expression of these molecules. Interestingly, addition of the activated (but not quiescent) HSCs suppressed thymidine uptake by T cells that were stimulated by alloantigens or by anti-CD3-mediated T-cell receptor ligation in a dose-dependent manner. High cytokine production by the T cells suggests that the inhibition was probably not a result of suppression of their activation. T-cell division was also found to be normal in a CFSE dilution assay. The HSC-induced T-cell hyporesponsiveness was associated with enhanced T-cell apoptosis. Activation of HSCs was associated with markedly enhanced expression of B7-H1. Blockade of B7-H1/PD-1 ligation significantly reduced HSC immunomodulatory activity, suggesting an important role of B7-H1. In conclusion, the bidirectional interactions between HSCs and immune cells may contribute to hepatic immune tolerance.",0
2943,15602022,Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene,"A 30-year-old man who presented with delayed puberty and infertility was found to have hypogonadism associated with an absence of circulating luteinizing hormone. The patient had a homozygous missense mutation in the gene that encodes the beta subunit of luteinizing hormone (Gly36Asp), a mutation that disrupted a vital cystine knot motif and abrogated the heterodimerization and secretion of luteinizing hormone. Treatment with human chorionic gonadotropin increased circulating testosterone, promoted virilization, and was associated with the appearance of normal spermatozoa in low concentrations. This case illustrates the important physiological role that luteinizing hormone plays in male sexual maturation and fertility.",0
2944,15616204,Adiposity as compared with physical activity in predicting mortality among women,"BACKGROUND: Whether higher levels of physical activity can counteract the elevated risk of death associated with adiposity is controversial. METHODS: We examined the associations of the body-mass index and physical activity with death among 116,564 women who, in 1976, were 30 to 55 years of age and free of known cardiovascular disease and cancer. RESULTS: During 24 years of follow-up, 10,282 deaths occurred--2370 from cardiovascular disease, 5223 from cancer, and 2689 from other causes. Mortality rates increased monotonically with higher body-mass-index values among women who had never smoked (P for trend <0.001). In combined analyses of all participants, adiposity predicted a higher risk of death regardless of the level of physical activity. Higher levels of physical activity appeared to be beneficial at all levels of adiposity but did not eliminate the higher risk of death associated with obesity. As compared with women who were lean (i.e., they had a body-mass index lower than 25) and active (they spent 3.5 or more hours exercising per week), the multivariate relative risks of death were 1.55 (95 percent confidence interval, 1.42 to 1.70) for lean and inactive women, 1.91 (95 percent confidence interval, 1.60 to 2.30) for women who were obese (defined as a body-mass index of 30 or higher) but active, and 2.42 (95 percent confidence interval, 2.14 to 2.73) for inactive, obese women. Even modest weight gain during adulthood, independent of physical activity, was associated with a higher risk of death. We estimate that excess weight (defined as a body-mass index of 25 or higher) and physical inactivity (less than 3.5 hours of exercise per week) together could account for 31 percent of all premature deaths, 59 percent of deaths from cardiovascular disease, and 21 percent of deaths from cancer among nonsmoking women. CONCLUSIONS: Both increased adiposity and reduced physical activity are strong and independent predictors of death.",0
2945,15619229,Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases,"Liver tissue engineering using hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation or liver-directed gene therapy to correct various types of hepatic insufficiency. Hepatocytes are not sustained when transplanted under the kidney capsule of syngeneic mice. However, when we transplanted hepatocytes with the extracellular matrix components extracted from Engelbreth-Holm-Swarm cells, hepatocytes survived for at least 140 days and formed small liver tissues. Liver engineering in hemophilia A mice reconstituted 5% to 10% of normal clotting activity, enough to reduce the bleeding time and have a therapeutic benefit. Conversely, the subcutaneous space did not support the persistent survival of hepatocytes with Engelbreth-Holm-Swarm gel matrix. We hypothesized that establishing a local vascular network at the transplantation site would reduce graft loss. To test this idea, we provided a potent angiogenic agent before hepatocyte transplantation into the subcutaneous space. With this procedure, persistent survival was achieved for the length of the experiment (120 days). To establish that these engineered liver tissues also retained their native regeneration potential in vivo, we induced two different modes of proliferative stimulus to the naive liver and confirmed that hepatocytes within the extrahepatic tissues regenerated with activity similar to that of naive liver. In conclusion, our studies indicate that liver tissues can be engineered and maintained at extrahepatic sites, retain their capacity for regeneration in vivo, and used to successfully treat genetic disorders.",0
2946,15619238,Diosgenin-induced biliary cholesterol secretion in mice requires Abcg8,"The plant sterol diosgenin has been shown to stimulate biliary cholesterol secretion in mice without affecting the expression of the adenosine triphosphate-binding cassette transporter heterodimer Abcg5/g8. The aim of this study was to investigate the mechanism of diosgenin-induced cholesterol hypersecretion and to identify the genes involved. Surprisingly, despite its lack of effect on Abcg5/g8 expression in wild-type mice, diosgenin did not stimulate biliary cholesterol secretion in mice deficient for Abcg8. Analysis of the kinetics of cholesterol secretion suggested that diosgenin probably activates a step before Abcg5/g8. To identify potential diosgenin targets, gene expression profiling was performed in mice fed a diosgenin-supplemented diet. Diosgenin feeding increased hepatic expression of genes involved in cholesterol synthesis as well as genes encoding for several cytochrome P450s. No significant change in expression of known cholesterol transporters was found. Comparison with published expression-profiling data for Srebp2-overexpressing mice, another mouse model in which biliary cholesterol secretion is elevated, revealed a number of genes with unknown function that were upregulated in both diosgenin-fed mice and mice overexpressing Srebp2. In conclusion, we found that although Abcg8 is essential for most diosgenin-induced biliary cholesterol hypersecretion, diosgenin probably does not interact directly with Abcg5/Abcg8, but rather increases cholesterol delivery to the heterodimer. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).",0
2947,15635108,Neurologic and developmental disability at six years of age after extremely preterm birth,"BACKGROUND: Birth before 26 weeks of gestation is associated with a high prevalence of neurologic and developmental disabilities in the infant during the first two years of life. METHODS: We studied at the time of early school age children who had been born at 25 or fewer completed weeks of gestation in the United Kingdom and Ireland in 1995. Each child had been evaluated at 30 months of age. The children underwent standardized cognitive and neurologic assessments at six years of age. Disability was defined as severe (indicating dependence on caregivers), moderate, or mild according to predetermined criteria. RESULTS: Of 308 surviving children, 241 (78 percent) were assessed at a median age of six years and four months; 160 classmates delivered at full term served as a comparison group. Although the use of test reference norms showed that cognitive impairment (defined as results more than 2 SD below the mean) was present in 21 percent of the children born extremely preterm (as compared with 1 percent in the standardized data), this value rose to 41 percent when the results were compared with those for their classmates. The rates of severe, moderate, and mild disability were 22 percent, 24 percent, and 34 percent, respectively; disabling cerebral palsy was present in 30 children (12 percent). Among children with severe disability at 30 months of age, 86 percent still had moderate-to-severe disability at 6 years of age. In contrast, other disabilities at the age of 30 months were poorly predictive of developmental problems at 6 years of age. CONCLUSIONS: Among extremely preterm children, cognitive and neurologic impairment is common at school age. A comparison with their classroom peers indicates a level of impairment that is greater than is recognized with the use of standardized norms.",0
2948,15647575,Extended work shifts and the risk of motor vehicle crashes among interns,"BACKGROUND: Long work hours and work shifts of an extended duration (> or =24 hours) remain a hallmark of medical education in the United States. Yet their effect on health and safety has not been evaluated with the use of validated measures. METHODS: We conducted a prospective nationwide, Web-based survey in which 2737 residents in their first postgraduate year (interns) completed 17,003 monthly reports that provided detailed information about work hours, work shifts of an extended duration, documented motor vehicle crashes, near-miss incidents, and incidents involving involuntary sleeping. RESULTS: The odds ratios for reporting a motor vehicle crash and for reporting a near-miss incident after an extended work shift, as compared with a shift that was not of extended duration, were 2.3 (95 percent confidence interval, 1.6 to 3.3) and 5.9 (95 percent confidence interval, 5.4 to 6.3), respectively. In a prospective analysis, every extended work shift that was scheduled in a month increased the monthly risk of a motor vehicle crash by 9.1 percent (95 percent confidence interval, 3.4 to 14.7 percent) and increased the monthly risk of a crash during the commute from work by 16.2 percent (95 percent confidence interval, 7.8 to 24.7 percent). In months in which interns worked five or more extended shifts, the risk that they would fall asleep while driving or while stopped in traffic was significantly increased (odds ratios, 2.39 [95 percent confidence interval, 2.31 to 2.46] and 3.69 [95 percent confidence interval, 3.60 to 3.77], respectively). CONCLUSIONS: Extended-duration work shifts, which are currently sanctioned by the Accreditation Council for Graduate Medical Education, pose safety hazards for interns. These results have implications for medical residency programs, which routinely schedule physicians to work more than 24 consecutive hours.",0
2949,15647578,Risk of fracture after androgen deprivation for prostate cancer,"BACKGROUND: The use of androgen-deprivation therapy for prostate cancer has increased substantially over the past 15 years. This treatment is associated with a loss of bone-mineral density, but the risk of fracture after androgen-deprivation therapy has not been well studied. METHODS: We studied the records of 50,613 men who were listed in the linked database of the Surveillance, Epidemiology, and End Results program and Medicare as having received a diagnosis of prostate cancer in the period from 1992 through 1997. The primary outcomes were the occurrence of any fracture and the occurrence of a fracture resulting in hospitalization. Cox proportional-hazards analyses were adjusted for characteristics of the patients and the cancer, other cancer treatment received, and the occurrence of a fracture or the diagnosis of osteoporosis during the 12 months preceding the diagnosis of cancer. RESULTS: Of men surviving at least five years after diagnosis, 19.4 percent of those who received androgen-deprivation therapy had a fracture, as compared with 12.6 percent of those not receiving androgen-deprivation therapy (P<0.001). In the Cox proportional-hazards analyses, adjusted for characteristics of the patient and the tumor, there was a statistically significant relation between the number of doses of gonadotropin-releasing hormone received during the 12 months after diagnosis and the subsequent risk of fracture. CONCLUSIONS: Androgen-deprivation therapy for prostate cancer increases the risk of fracture.",0
2950,15659724,Effects of moderate alcohol consumption on cognitive function in women,"BACKGROUND: The adverse effects of excess alcohol intake on cognitive function are well established, but the effect of moderate consumption is uncertain. METHODS: Between 1995 and 2001, we evaluated cognitive function in 12,480 participants in the Nurses' Health Study who were 70 to 81 years old, with follow-up assessments in 11,102 two years later. The level of alcohol consumption was ascertained regularly beginning in 1980. We calculated multivariate-adjusted mean cognitive scores and multivariate-adjusted risks of cognitive impairment (defined as the lowest 10 percent of the scores) and a substantial decline in cognitive function over time (defined as a change that was in the worst 10 percent of the distribution of the decline). We also stratified analyses according to the apolipoprotein E genotype in a subgroup of women. RESULTS: After multivariate adjustment, moderate drinkers (those who consumed less than 15.0 g of alcohol per day [about one drink]) had better mean cognitive scores than nondrinkers. Among moderate drinkers, as compared with nondrinkers, the relative risk of impairment was 0.77 on our test of general cognition (95 percent confidence interval, 0.67 to 0.88) and 0.81 on the basis of a global cognitive score combining the results of all tests (95 percent confidence interval, 0.70 to 0.93). The results for cognitive decline were similar; for example, on our test of general cognition, the relative risk of a substantial decline in performance over a two-year period was 0.85 (95 percent confidence interval, 0.74 to 0.98) among moderate drinkers, as compared with nondrinkers. There were no significant associations between higher levels of drinking (15.0 to 30.0 g per day) and the risk of cognitive impairment or decline. There were no significant differences in risks according to the beverage (e.g., wine or beer) and no interaction with the apolipoprotein E genotype. CONCLUSIONS: Our data suggest that in women, up to one drink per day does not impair cognitive function and may actually decrease the risk of cognitive decline.",0
2951,15660394,Fluorescence resonance energy transfer analysis of proapoptotic CD95-EGF receptor interactions in Huh7 cells,"Hyperosmolarity- and CD95 ligand (CD95L)-induced interactions between CD95 (Fas/APO-1) and the epidermal growth factor receptor (EGFR) involve EGFR-catalyzed CD95 tyrosine phosphorylation. Such interactions were studied by means of fluorescence resonance energy transfer (FRET) and CD95 receptor mutagenesis in Huh7 hepatoma cells. In cells cotransfected with EGFR-cyan fluorescent protein and CD95-yellow fluorescent protein, FRET studies showed a rapid, hyperosmolarity-induced, c-Jun-N-terminal kinase-dependent CD95-EGFR association in the cytosol with subsequent microtubule-dependent translocation of the protein complex to the plasma membrane. Inhibition of EGFR tyrosine kinase activity by AG1478 and cyclic adenosine monophosphate had no effect on hyperosmotic CD95-EGFR association in the cytosol but prevented CD95 tyrosine phosphorylation, targeting of the protein complex to the plasma membrane, and formation of the death-inducing signaling complex (DISC). The requirement of EGFR-mediated CD95 tyrosine phosphorylation for hyperosmotic and CD95L-induced CD95 membrane targeting and DISC formation was also shown in CD95 mutagenesis experiments. CD95 mutants with tyrosine-phenylalanine exchanges at positions 232 and 291 failed to translocate to the plasma membrane and to recruit Fas-associated death domain and caspase 8, although these mutants still associated with the EGFR in the cytosol in response to hyperosmolarity and CD95L. Cells transfected with these mutants were also resistant to CD95L-induced apoptosis. Single mutations of tyrosine 91, 232, and 291 failed to inhibit CD95 membrane targeting, DISC formation, or CD95L-induced apoptosis. In conclusion, we identify EGFR-CD95 interaction and phosphorylation of critical CD95 tyrosine residues as important early events in hyperosmotic and CD95L-induced CD95 activation and apoptosis induction.",0
2952,15689585,A clone of methicillin-resistant Staphylococcus aureus among professional football players,"BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of infections outside of health care settings. We investigated an outbreak of abscesses due to MRSA among members of a professional football team and examined the transmission and microbiologic characteristics of the outbreak strain. METHODS: We conducted a retrospective cohort study and nasal-swab survey of 84 St. Louis Rams football players and staff members. S. aureus recovered from wound, nasal, and environmental cultures was analyzed by means of pulsed-field gel electrophoresis (PFGE) and typing for resistance and toxin genes. MRSA from the team was compared with other community isolates and hospital isolates. RESULTS: During the 2003 football season, eight MRSA infections occurred among 5 of the 58 Rams players (9 percent); all of the infections developed at turf-abrasion sites. MRSA infection was significantly associated with the lineman or linebacker position and a higher body-mass index. No MRSA was found in nasal or environmental samples; however, methicillin-susceptible S. aureus was recovered from whirlpools and taping gel and from 35 of the 84 nasal swabs from players and staff members (42 percent). MRSA from a competing football team and from other community clusters and sporadic cases had PFGE patterns that were indistinguishable from those of the Rams' MRSA; all carried the gene for Panton-Valentine leukocidin and the gene complex for staphylococcal-cassette-chromosome mec type IVa resistance (clone USA300-0114). CONCLUSIONS: We describe a highly conserved, community-associated MRSA clone that caused abscesses among professional football players and that was indistinguishable from isolates from various other regions of the United States.",0
2953,15690474,Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy,"Cholangiocarcinomas are devastating cancers that are increasing in both their worldwide incidence and mortality rates. The challenges posed by these often lethal biliary tract cancers are daunting, with conventional treatment options being limited and the only hope for long-term survival being that of complete surgical resection of the tumor. Unfortunately, the vast majority of patients with cholangiocarcinoma typically seek treatment with advanced disease, and often these patients are deemed poor candidates for curative surgery. Moreover, conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival, and although photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, it is not curative. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangiocarcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome. This review focuses on potential preventive targets in cholangiocarcinogenesis, such as inducible nitric oxide synthase, cyclooxygenase-2, and altered bile acid signaling pathways. In addition, molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are described in the context of various clinical and pathological presentations. Moreover, an emphasis is placed on the importance of critical signaling pathways and postulated interactions, including those of ErbB-2, hepatocyte growth factor/Met, interleukin-6/glycoprotein130, cyclooxygenase-2, vascular endothelial growth factor, transforming growth factor-beta, MUC1 and MUC4, beta-catenin, telomerase, and Fas pathways as potential molecular therapeutic targets in cholangiocarcinoma.",0
2954,15723320,Bacterial translocation (BT) in cirrhosis,"""Gut flora and bacterial translocation (BT) play an important role in the pathogenesis of the complications of cirrhosis. Research on the pathogenesis of BT and its clinical significance transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. This review delineates multiple mechanisms involved in the process of BT, with an emphasis on alterations in intestinal flora and mucosal barrier function, particularly immunological defense mechanisms. Current knowledge on the innate and adaptive immune response that allows a """"friendly"""" communication between bacteria and host is summarized, and alterations occurring in cirrhosis that may facilitate BT are discussed. In addition, definition of a """"pathological"""" BT is proposed together with an analysis of the anatomical site and route of BT. Finally, therapeutic approaches for the prevention of BT in experimental and human cirrhosis are reviewed. Future research in the field of BT in cirrhosis will allow the development of new therapeutic targets in the prevention of infections and other complications of cirrhosis.""",0
2955,15726664,Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts,"Fractalkine is a chemokine with both chemoattractant and cell-adhesive functions, and in the intestine it is involved with its receptor CX3CR1 in the chemoattraction and recruitment of intraepithelial lymphocytes. We examined the pathophysiological roles of fractalkine and CX3CR1 in normal and diseased bile ducts. Expression of fractalkine and CX3CR1 were examined in liver tissues from patients with primary biliary cirrhosis (17 cases) and controls (9 cases of primary sclerosing cholangitis, 10 cases of extrahepatic biliary obstruction, 20 cases of chronic viral hepatitis C, and 18 cases of histologically normal livers). Expression of fractalkine in biliary epithelial cells (BECs) in response to cytokine treatments was examined using a human cholangiocarcinoma cell line (HuCC-T1) and human intrahepatic BEC line. The chemotaxis of CX3CR1-expressing monocytes (THP-1) toward fractalkine was assayed using chemotaxis chambers. Fractalkine messenger RNA/protein were expressed on BECs of normal and diseased bile ducts, and their expression was upregulated in injured bile ducts of primary biliary cirrhosis. CX3CR1 was expressed on infiltrating mononuclear cells in portal tracts and on CD3(+), CD4(+), and CD8(+) intraepithelial lymphocytes of injured bile ducts in primary biliary cirrhosis. Fractalkine messenger RNA expression was upregulated in two cultured BECs on treatment with lipopolysaccharide and Th1-cytokines (interleukin 1beta, interferon gamma, and tumor necrosis factor alpha). THP-1 cells showed chemotaxis toward fractalkine secreted by cultured cells. In conclusion, Th1-cytokine predominance and lipopolysaccharide in the microenvironment of injured bile ducts resulting from primary biliary cirrhosis induce the upregulation of fractalkine expression in BECs, followed by the chemoattraction of CX3CR1-expressing mononuclear cells, including CD4(+) and CD8(+) T cells, and their adhesion to BECs and the accumulation of biliary intraepithelial lymphocytes.",0
2956,15728808,"Effectiveness of mass oral cholera vaccination in Beira, Mozambique","BACKGROUND: New-generation, orally administered cholera vaccines offer the promise of improved control of cholera in sub-Saharan Africa. However, the high prevalence of human immunodeficiency virus (HIV) infection in many cholera-affected African populations has raised doubts about the level of protection possible with vaccination. We evaluated a mass immunization program with recombinant cholera-toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in Beira, Mozambique, a city where the seroprevalence of HIV is 20 to 30 percent. METHODS: From December 2003 to January 2004, we undertook mass immunization of nonpregnant persons at least two years of age, using a two-dose regimen of rBS-WC vaccine in Esturro, Beira (population 21,818). We then assessed vaccine protection in a case-control study during an outbreak of El Tor Ogawa cholera in Beira between January and May 2004. To estimate the level of vaccine protection, antecedent rates of vaccination were compared between persons with culture-confirmed cholera severe enough to have prompted them to seek treatment and age- and sex-matched neighborhood controls without treated diarrhea. RESULTS: We assessed the effectiveness of the vaccine in 43 persons with cholera and 172 controls. Receipt of one or more doses of rBS-WC vaccine was associated with 78 percent protection (95 percent confidence interval, 39 to 92 percent; P=0.004). The vaccine was equally effective in children younger than five years of age and in older persons. A concurrently conducted case-control study designed to detect bias compared persons with treated, noncholeraic diarrhea and controls without diarrhea in the same population and found no protection associated with receipt of the rBS-WC vaccine. CONCLUSIONS: The rBS-WC vaccine was highly effective against clinically significant cholera in an urban sub-Saharan African population with a high prevalence of HIV infection.",0
2957,15742390,Direct hepatic fate specification from mouse embryonic stem cells,"The molecules responsible for hepatic differentiation from embryonic stem (ES) cells have yet to be elucidated. Here we have identified growth factors that allow direct hepatic fate-specification from ES cells by using simple adherent monolayer culture conditions. ES cell-derived hepatocytes showed liver-specific characteristics, including several metabolic activities, suggesting that ES cells can differentiate into functional hepatocytes without the requirement for embryoid body (EB) formation, in vivo transplantation, or a coculture system. Most importantly, transplantation of ES cell-derived hepatocytes in mice with cirrhosis showed significant therapeutic effects. In conclusion, this novel system for hepatic fate specification will help elucidate the precise molecular mechanisms of hepatic differentiation in vitro and could represent an attractive approach for developing stem cell therapies for treatment of hepatic disease in humans. Supplementary material for this article can be found on the HEPATOLOGY website ( http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html).",0
2958,15745979,Family-based association between Alzheimer's disease and variants in UBQLN1,"BACKGROUND: Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22. METHODS: We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls. RESULTS: In the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease. CONCLUSIONS: Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.",0
2959,15784668,A potential decline in life expectancy in the United States in the 21st century,"Forecasts of life expectancy are an important component of public policy that influence age-based entitlement programs such as Social Security and Medicare. Although the Social Security Administration recently raised its estimates of how long Americans are going to live in the 21st century, current trends in obesity in the United States suggest that these estimates may not be accurate. From our analysis of the effect of obesity on longevity, we conclude that the steady rise in life expectancy during the past two centuries may soon come to an end.",0
2960,15788495,Hospitalization for mental illness among parents after the death of a child,"""BACKGROUND: The loss of a child is considered one of the most stressful events in the life of a parent. We hypothesized that parental bereavement increases the risk of hospital admission for a psychiatric disorder, especially for affective disorders. METHODS: We studied a cohort of 1,082,503 persons identified from national registers in Denmark who were born between 1952 and 1999 and had at least one child under 18 years of age during the follow-up period, from 1970 to 1999. Parents who lost a child during follow-up were categorized as """"bereaved"""" from the date of death of the child. RESULTS: As compared with parents who did not lose a child, parents who lost a child had an overall relative risk of a first psychiatric hospitalization for any disorder of 1.67 (95 percent confidence interval, 1.53 to 1.83). Bereaved mothers had a higher relative risk of being hospitalized for any psychiatric disorder than bereaved fathers (relative risks, 1.78 [95 percent confidence interval, 1.60 to 1.98] and 1.38 [95 percent confidence interval, 1.17 to 1.63], respectively; P value for interaction, 0.01). The relative risks of hospitalization specifically for affective disorders were 1.91 (95 percent confidence interval, 1.59 to 2.30) and 1.61 (95 percent confidence interval, 1.15 to 2.27) for bereaved mothers and fathers, respectively. Among mothers, the relative risk of being hospitalized for any psychiatric disorder was highest during the first year after the death of the child but remained significantly elevated five years or more after the death. CONCLUSIONS: The risk of psychiatric hospitalization was increased among parents, especially mothers, who lost a child.""",0
2961,15791608,Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment,"Hepatitis C virus (HCV) diminishes health related quality of life (HRQOL), and it is now common to measure HRQOL in clinical trials. We sought to summarize the HRQOL data in HCV, and to establish the minimally clinically important difference (MCID) in HRQOL scores in HCV. We performed a systematic review to identify relevant studies, and converted HRQOL data from each study into clinically interpretable statistics. An expert panel used a modified Delphi technique to estimate the MCID in HCV. We found that patients with HCV scored lower than controls across all scales of the SF-36. Patients achieving sustained virological response (SVR) scored higher across all scales versus patients without SVR, especially in the physical health domains. HRQOL differences did not correspond with differences in liver histology or ALT levels. Based upon the published data, the expert panel concluded that the SF-36 vitality scale was most relevant in patients with HCV, and generated a mean MCID of 4.2 points on this scale. In conclusion, patients with HCV have a clinically significant decrement in HRQOL versus controls, and physical HRQOL improves in patients achieving SVR but not in those without SVR. The data further suggest that traditional outcomes fail to capture the full spectrum of illness related to chronic HCV. A difference of 4.2 points on the SF-36 vitality scale can be used as an estimate of the MCID in HCV, and this value may be used as the basis for power calculations in clinical trials evaluating HRQOL. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html).",0
2962,15793852,A biphasic response of hepatobiliary cholesterol metabolism to dietary fat at the onset of obesity in the mouse,"Human obesity is associated with abnormal hepatic cholesterol homeostasis and resistance to leptin action. Because leptin administration to rodents promotes the biliary elimination of plasma cholesterol, this study was designed to elucidate a pathophysiological role for leptin during the development of obesity. We fed mice diets containing high or low saturated fat contents. Before and after the onset of obesity, we measured downstream targets of leptin action and evaluated plasma, hepatic, and biliary cholesterol metabolism. Although not obese at 28 days, mice fed a high fat diet became hyperleptinemic. Sensitivity to leptin was evidenced by downregulation of both hepatic stearoyl CoA desaturase-1 and fatty acid synthase. Due principally to upregulation of adenosine triphosphate-binding cassette proteins A1 and G5, plasma high density lipoprotein (HDL) cholesterol concentrations increased, as did relative secretion rates of biliary cholesterol. A smaller, more hydrophilic bile salt pool decreased intestinal cholesterol absorption. In this setting, hepatic cholesterol synthesis was downregulated, indicative of increased uptake of plasma cholesterol. After 56 days of high fat feeding, obesity was associated with leptin resistance, as evidenced by marked hyperleptinemia without downregulation of stearoyl CoA desaturase-1 or fatty acid synthase and by upregulation of hepatic cholesterol and bile salt synthesis. Hypercholesterolemia was attributable to overproduction and decreased clearance of large HDL(1) particles. In conclusion, before the onset of obesity, preserved leptin sensitivity promotes biliary elimination of endogenous cholesterol in response to dietary fat. Leptin resistance due to obesity leads to a maladaptive response whereby newly synthesized cholesterol in the liver is eliminated via bile.",0
2963,15814878,"Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia","BACKGROUND: Mutations in TERC, the gene for the RNA component of telomerase, cause short telomeres in congenital aplastic anemia and in some cases of apparently acquired hematopoietic failure. We investigated whether mutations in genes for other components of telomerase also occur in aplastic anemia. METHODS: We screened blood or marrow cells from 124 patients with apparently acquired aplastic anemia and 282 control subjects for sequence variations in the TERT, DKC1, NHP2, and NOP10 genes; an additional 81 patients and 246 controls were examined for genetic variations in TERT. Telomere lengths and the telomerase activity of peripheral-blood leukocytes were evaluated in patients carrying genetic variants. Identified mutations were transfected into telomerase-deficient cell lines to examine their effects and their mechanism of action on telomerase function. RESULTS: Five heterozygous, nonsynonymous mutations (which cause an amino acid change in the corresponding protein) were identified in TERT, the gene for the telomerase reverse transcriptase catalytic enzyme, among seven unrelated patients. Leukocytes from these patients had short telomeres and low telomerase enzymatic activity. In three of these patients, the mutation was also detected in buccal mucosa cells. Family members carrying the mutations also had short telomeres and reduced telomerase activity but no evident hematologic abnormality. The results of coexpression of wild-type TERT and TERT with aplastic anemia-associated mutations in a telomerase-deficient cell line suggested that haploinsufficiency was the mechanism of telomere shortening due to TERT mutations. CONCLUSIONS: Heterozygous mutations in the TERT gene impair telomerase activity by haploinsufficiency and may be risk factors for marrow failure.",0
2964,15829527,Vitamin E and donepezil for the treatment of mild cognitive impairment,"BACKGROUND: Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease. METHODS: In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function. RESULTS: A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers. CONCLUSIONS: Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.",0
2965,15829534,DNA topoisomerase II in therapy-related acute promyelocytic leukemia,"""BACKGROUND: Chromosomal translocations leading to chimeric oncoproteins are important in leukemogenesis, but how they form is unclear. We studied acute promyelocytic leukemia (APL) with the t(15;17) translocation that developed after treatment of breast or laryngeal cancer with chemotherapeutic agents that poison topoisomerase II. METHODS: We used long-range polymerase chain reaction and sequence analysis to characterize t(15;17) genomic breakpoints in therapy-related APL. To determine whether topoisomerase II was directly involved in mediating breaks of double-stranded DNA at the observed translocation breakpoints, we used a functional in vitro assay to examine topoisomerase II-mediated cleavage in the normal homologues of the PML and RARA breakpoints. RESULTS: Translocation breakpoints in APL that developed after exposure to mitoxantrone, a topoisomerase II poison, were tightly clustered in an 8-bp region within PML intron 6. In functional assays, this """"hot spot"""" and the corresponding RARA breakpoints were common sites of mitoxantrone-induced cleavage by topoisomerase II. Etoposide and doxorubicin also induced cleavage by topoisomerase II at the translocation breakpoints in APL arising after exposure to these agents. Short, homologous sequences in PML and RARA suggested the occurrence of DNA repair by means of the nonhomologous end-joining pathway. CONCLUSIONS: Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomerase II poisons.""",0
2966,15830397,A key role for autoreactive B cells in the breakdown of T-cell tolerance to pyruvate dehydrogenase complex in the mouse,"The key immunological event in the pathogenesis of the autoimmune liver disease primary biliary cirrhosis is breakdown of T-cell self-tolerance to pyruvate dehydrogenase complex (PDC). The mechanism resulting in this breakdown of tolerance remains unclear. Mice exposed to self-PDC mount no immune response; however, animals coexposed to self-PDC and PDC of foreign origin (which in isolation induces a cross-reactive antibody but not an autoreactive T-cell response) show breakdown of T-cell as well as B-cell tolerance. This observation raises the possibility that a cross-reactive antibody response to self-PDC can promote breakdown of T-cell tolerance. The aim of this study was to address the hypothesis that breakdown of T-cell tolerance to PDC can be driven by the presence of B cells and/or antibodies cross-reactive with this self-antigen. Naive female SJL/J mice were exposed to self-PDC alone and in the presence of purified splenic B cells from animals primed with foreign PDC (or controls) or purified immunoglobulin (Ig) G from the same animals. Breakdown of T-cell tolerance was assessed by splenic T-cell proliferative response to antigen at 5 weeks. CD4(+) T-cell proliferative responses indicative of breakdown of T-cell tolerance to self-PDC were seen in the majority (7 of 9, 78%) of animals receiving self-PDC together with purified PDC-reactive B cells. Tolerance breakdown was not seen in animals receiving self-PDC with purified anti-PDC IgG or with B cells from animals sensitized with an irrelevant antigen. In conclusion, breakdown of T-cell tolerance to the highly conserved self-antigen PDC may be mediated by high-level presentation of self-derived epitopes by activated cross-reactive B cells.",0
2967,15843669,Familial cancer associated with a polymorphism in ARLTS1,"BACKGROUND: The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene. METHODS: We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant. RESULTS: We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles. CONCLUSIONS: A genetic variant of ARLTS1 predisposes patients to familial cancer.",0
2968,15843670,Clinical practice. Rehabilitation after stroke,"A 66-year-old man was suddenly unable to speak, follow directions, or move his right arm and leg. He received tissue plasminogen activator within 90 minutes. Four days later, his speech was limited to effortful answers of yes or no. He could not walk or use his right arm, and self-care tasks required maximal assistance. What advice would you offer him and his family regarding rehabilitation for his disabilities?",0
2969,15872200,Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer),"BACKGROUND: Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome. METHODS: Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing. RESULTS: Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not. CONCLUSIONS: Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.",0
2970,15888697,Decreased histone deacetylase activity in chronic obstructive pulmonary disease,"BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages. METHODS: HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-transcriptase-polymerase-chain-reaction assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunoprecipitation assay. RESULTS: Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. CONCLUSIONS: Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease.",0
2971,15901861,Asthma as a risk factor for invasive pneumococcal disease,"BACKGROUND: The risk of invasive pneumococcal disease among persons with asthma is unknown. METHODS: We conducted a nested case-control study to examine the association between asthma and invasive pneumococcal disease. The study population included persons 2 to 49 years of age who were enrolled in Tennessee's Medicaid program (TennCare) for more than one year during the study period (1995 through 2002) and who resided in counties participating in a prospective laboratory-based program of surveillance for invasive pneumococcal disease. For each subject with invasive pneumococcal disease, 10 age-matched controls without invasive pneumococcal disease were randomly selected from the same population. TennCare files were queried to identify the presence of coexisting conditions that confer a high risk of pneumococcal disease. For the purpose of our study, asthma was defined by documentation of one or more inpatient or emergency-department diagnoses of asthma, two outpatient diagnoses, or the use of asthma-related medications. High-risk asthma was defined as asthma requiring admission to a hospital or a visit to an emergency department, the use of rescue therapy or long-term use of oral corticosteroids, or the dispensing of three or more prescriptions for beta-agonists within the year before enrollment in the study. RESULTS: A total of 635 persons with invasive pneumococcal disease and 6350 controls were identified, of whom 114 (18.0 percent) and 516 (8.1 percent), respectively, had asthma. Persons with asthma had an increased risk of invasive pneumococcal disease (adjusted odds ratio, 2.4; 95 percent confidence interval, 1.9 to 3.1) as compared with controls. Among those without coexisting conditions, the annual incidence of invasive pneumococcal disease was 4.2 episodes per 10,000 persons with high-risk asthma and 2.3 episodes per 10,000 persons with low-risk asthma, as compared with 1.2 episodes per 10,000 persons without asthma. CONCLUSIONS: Asthma is an independent risk factor for invasive pneumococcal disease. The risk among persons with asthma was at least double that among controls.",0
2972,15917383,Statins and the risk of colorectal cancer,"BACKGROUND: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer. METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available. RESULTS: In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available. CONCLUSIONS: The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.",0
2973,15917385,Academic medical centers' standards for clinical-trial agreements with industry,"BACKGROUND: Although industry sponsors provide approximately 70 percent of the funding for clinical drug trials in the United States, little is known about the legal agreements that exist between industry sponsors and academic investigators. We studied institutional standards regarding contractual provisions that restrict investigators' control over trials. METHODS: We used a structured, cross-sectional mail survey of medical-school research administrators responsible for negotiating clinical-trial agreements with industry sponsors. RESULTS: Of 122 institutions approached, 107 participated. There was a high degree of consensus among administrators about the acceptability of several contractual provisions relating to publications. For example, more than 85 percent reported that their office would not approve provisions giving industry sponsors the authority to revise manuscripts or decide whether results should be published. There was considerable disagreement about the acceptability of provisions allowing the sponsor to insert its own statistical analyses in manuscripts (24 percent allowed them, 47 percent disallowed them, and 29 percent were not sure whether they should allow them), draft the manuscript (50 percent allowed it, 40 percent disallowed it, and 11 percent were not sure whether they should allow it), and prohibit investigators from sharing data with third parties after the trial is over (41 percent allowed it, 34 percent disallowed it, and 24 percent were not sure whether they should allow it). Disputes were common after the agreements had been signed and most frequently centered on payment (75 percent of administrators reported at least one such dispute in the previous year), intellectual property (30 percent), and control of or access to data (17 percent). CONCLUSIONS: Standards for certain restrictive provisions in clinical-trial agreements with industry sponsors vary considerably among academic medical centers. Greater sharing of information about legal relationships with industry sponsors is desirable in order to build consensus about appropriate standards.",0
2974,15918171,A functional polymorphism in the IL-10 promoter influences the response after vaccination with HBsAg and hepatitis A,"The immune response to hepatitis B surface antigen (HBsAg) is mostly genetically determined. Interleukin 10 (IL-10) is a central immunoregulatory cytokine with important effects on B-cells. We have studied the influence of IL-10 promoter polymorphisms on the immune response to HBsAg and hepatitis A vaccination. We vaccinated 202 twin pairs in an open prospective study with a combined recombinant HBsAg/inactivated hepatitis A vaccine. IL-10 promoter polymorphisms were investigated in all individuals and their influence on anti-HBs, and anti-HAV responsiveness was studied. In the multiple regression analysis accounting for smoking, gender, body mass index and age, the ACC haplotype (-1082, -819 and -592) had a strong influence on anti-HBs production. Individuals carrying the ACC haplotype had anti-HBs titres almost twice as high as individuals without this haplotype. In contrast, anti-HAV production was suppressed by the presence of the -1082A allele in comparison with individuals homozygous for the -1082G allele. The contribution of the shared IL-10 promoter haplotype accounted for 27% of the genetic influence on anti-HBs antibody response. In conclusion, genetic variability in the IL-10 promoter is an important modulator of the immune response against hepatitis viral antigens.",0
2975,15930419,Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose,"BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.",0
2976,15941849,Ovarian transplantation between monozygotic twins discordant for premature ovarian failure,"Monozygotic 24-year-old twins presented with discordant ovarian function. One had had premature ovarian failure at the age of 14 years, whereas her sister had normal ovaries and three naturally conceived children. After unsuccessful egg-donation therapy, the sterile twin received a transplant of ovarian cortical tissue from her sister by means of a minilaparotomy. Within three months after transplantation, the recipient's cycles resumed and serum gonadotropin levels fell to the normal range. During the second cycle, she conceived, and her pregnancy progressed uneventfully. At 38 weeks' gestation, she delivered a healthy-appearing female infant.",0
2977,15962311,Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells,"CD4(+)CD25(+) regulatory T cells (Treg) are important mediators of peripheral immune tolerance; however, whether Treg participate also in hepatic immune tolerance is not clear. Therefore, we tested the potential of Treg to suppress stimulation of CD4(+) T cells by liver sinusoidal endothelial cells (LSEC), Kupffer cells (KC), or hepatocytes. In the absence of Treg, all 3 types of liver cells could stimulate CD4(+) T cell proliferation; in the presence of Treg, however, CD4(+) T cell proliferation was suppressed. Interaction with KC even stimulated the expansion of the Treg population; LSEC or hepatocytes, in contrast, could not induce proliferation of Treg. Because liver inflammation can be induced by infection, we tested the potential of liver cells to modify Treg suppressor activity in the presence of microbial signals. In the presence of immune-stimulatory CpG-oligonucleotides, LSEC, KC, and hepatocytes could indeed overcome Treg-mediated suppression; in the presence of lipopolysaccharide (LPS), however, only KC and hepatocytes, but not LSEC, could overcome Treg suppressor activity. Hepatocytes from mice with deficient toll-like receptor-4 signaling failed to abrogate Treg suppression in response to LPS, indicating that overcoming Treg suppressor activity was indeed a response of the liver cell and not of the Treg. In conclusion, Treg can suppress CD4(+) T cell stimulation by liver cells. However, in response to microbial signals, the liver cells can overcome the suppressive activity of Treg. Thus, liver cells may facilitate the transition from hepatic immune tolerance to hepatic inflammation by controlling Treg suppressor activity.",0
2978,15986415,Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort,"Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC.",0
2979,16000354,Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia,"BACKGROUND: We conducted a randomized comparison of hydroxyurea with anagrelide in the treatment of essential thrombocythemia. METHODS: A total of 809 patients with essential thrombocythemia who were at high risk for vascular events received low-dose aspirin plus either anagrelide or hydroxyurea. The composite primary end point was the actuarial risk of arterial thrombosis (myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, or peripheral arterial thrombosis), venous thrombosis (deep-vein thrombosis, splanchnic-vein thrombosis, or pulmonary embolism), serious hemorrhage, or death from thrombotic or hemorrhagic causes. RESULTS: After a median follow-up of 39 months, patients in the anagrelide group were significantly more likely than those in the hydroxyurea group to have reached the primary end point (odds ratio, 1.57; 95 percent confidence interval, 1.04 to 2.37; P=0.03). As compared with hydroxyurea plus aspirin, anagrelide plus aspirin was associated with increased rates of arterial thrombosis (P=0.004), serious hemorrhage (P=0.008), and transformation to myelofibrosis (P=0.01) but with a decreased rate of venous thromboembolism (P=0.006). Patients receiving anagrelide were more likely to withdraw from their assigned treatment (P<0.001). Equivalent long-term control of the platelet count was achieved in both groups. CONCLUSIONS: Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events.",0
2980,16000355,"Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease","BACKGROUND: Lp(a) lipoprotein binds proinflammatory oxidized phospholipids. We investigated whether levels of oxidized low-density lipoprotein (LDL) measured with use of monoclonal antibody E06 reflect the presence and extent of obstructive coronary artery disease, defined as a stenosis of more than 50 percent of the luminal diameter. METHODS: Levels of oxidized LDL and Lp(a) lipoprotein were measured in a total of 504 patients immediately before coronary angiography. Levels of oxidized LDL are reported as the oxidized phospholipid content per particle of apolipoprotein B-100 (oxidized phospholipid:apo B-100 ratio). RESULTS: Measurements of the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels were skewed toward lower values, and the values for the oxidized phospholipid:apo B-100 ratio correlated strongly with those for Lp(a) lipoprotein (r=0.83, P<0.001). In the entire cohort, the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels showed a strong and graded association with the presence and extent of coronary artery disease (i.e., the number of vessels with a stenosis of more than 50 percent of the luminal diameter) (P<0.001). Among patients 60 years of age or younger, those in the highest quartiles for the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels had odds ratios for coronary artery disease of 3.12 (P<0.001) and 3.64 (P<0.001), respectively, as compared with patients in the lowest quartile. The combined effect of hypercholesterolemia and being in the highest quartiles of the oxidized phospholipid:apo B-100 ratio (odds ratio, 16.8; P<0.001) and Lp(a) lipoprotein levels (odds ratio, 14.2; P<0.001) significantly increased the probability of coronary artery disease among patients 60 years of age or younger. In the entire study group, the association of the oxidized phospholipid:apo B-100 ratio with obstructive coronary artery disease was independent of all clinical and lipid measures except one, Lp(a) lipoprotein. However, among patients 60 years of age or younger, the oxidized phospholipid:apo B-100 ratio remained an independent predictor of coronary artery disease. CONCLUSIONS: Circulating levels of oxidized LDL are strongly associated with angiographically documented coronary artery disease, particularly in patients 60 years of age or younger. These data suggest that the atherogenicity of Lp(a) lipoprotein may be mediated in part by associated proinflammatory oxidized phospholipids.",0
2981,16025518,Conventional liver CD4 T cells are functionally distinct and suppressed by environmental factors,"The contribution of intrahepatic conventional T cells to the unique immunologic properties of the liver has not been clearly defined. We isolated bulk and CD4 T cells from mouse liver and compared their functions with each other and with their splenic counterparts. Unlike bulk spleen T cells, bulk liver T cells reacted minimally to allogeneic or antigen-loaded syngeneic dendritic cells. However, after exclusion of natural killer T cells (NKTs) and gammadelta T cells by FACS, liver and spleen CD4 T cells actually proliferated to a similar extent upon allogeneic or antigen-specific stimulation. Liver CD4 T cells were more sensitive to interleukin 2 (IL-2) than were spleen CD4 T cells, but had a similar proliferative potential based on their response to CD3 ligation. In addition, activated liver CD4 T cells produced higher levels of IL-4, IL-5, IL-10, and interferon gamma (IFN-gamma) than did splenic CD4 T cells. Therefore, liver CD4 T cells are intrinsically different from spleen CD4 T cells. In vitro, liver or spleen NKTs and gammadelta T cells suppressed liver and spleen CD4 T-cell proliferation in a dose-dependent fashion. In conclusion, unconventional T cells constrain liver CD4 T-cell function. Our findings have implications for pathological conditions of the liver that involve the response of conventional CD4 T lymphocytes.",0
2982,16034011,"Quality of care in U.S. hospitals as reflected by standardized measures, 2002-2004","BACKGROUND: In July 2002, the Joint Commission on Accreditation of Healthcare Organizations implemented standardized performance measures that were designed to track the performance of accredited hospitals and encourage improvement in the quality of health care. METHODS: We examined hospitals' performance on 18 standardized indicators of the quality of care for acute myocardial infarction, heart failure, and pneumonia. One measure assessed a clinical outcome (death in the hospital after acute myocardial infarction), and the other 17 measures assessed processes of care. Data were collected over a two-year period in more than 3000 accredited hospitals. All participating hospitals received quarterly feedback in the form of comparative reports throughout the study. RESULTS: Descriptive analysis revealed a significant improvement (P<0.01) in the performance of U.S. hospitals on 15 of 18 measures, and no measure showed a significant deterioration. The magnitude of improvement ranged from 3 percent to 33 percent during the eight quarters studied. For 16 of the 17 process-of-care measures, hospitals with a low level of performance at baseline had greater improvements over the subsequent two years than hospitals with a high level of performance at baseline. CONCLUSIONS: Over a two-year period, we observed consistent improvement in measures reflecting the process of care for acute myocardial infarction, heart failure, and pneumonia. Both quantitative and qualitative research are needed to explore the reasons for these improvements.",0
2983,16049209,Perioperative beta-blocker therapy and mortality after major noncardiac surgery,"BACKGROUND: Despite limited evidence from randomized trials, perioperative treatment with beta-blockers is now widely advocated. We assessed the use of perioperative beta-blockers and their association with in-hospital mortality in routine clinical practice. METHODS: We conducted a retrospective cohort study of patients 18 years of age or older who underwent major noncardiac surgery in 2000 and 2001 at 329 hospitals throughout the United States. We used propensity-score matching to adjust for differences between patients who received perioperative beta-blockers and those who did not receive such therapy and compared in-hospital mortality using multivariable logistic modeling. RESULTS: Of 782,969 patients, 663,635 (85 percent) had no recorded contraindications to beta-blockers, 122,338 of whom (18 percent) received such treatment during the first two hospital days, including 14 percent of patients with a Revised Cardiac Risk Index (RCRI) score of 0 and 44 percent with a score of 4 or higher. The relationship between perioperative beta-blocker treatment and the risk of death varied directly with cardiac risk; among the 580,665 patients with an RCRI score of 0 or 1, treatment was associated with no benefit and possible harm, whereas among the patients with an RCRI score of 2, 3, or 4 or more, the adjusted odds ratios for death in the hospital were 0.88 (95 percent confidence interval, 0.80 to 0.98), 0.71 (95 percent confidence interval, 0.63 to 0.80), and 0.58 (95 percent confidence interval, 0.50 to 0.67), respectively. CONCLUSIONS: Perioperative beta-blocker therapy is associated with a reduced risk of in-hospital death among high-risk, but not low-risk, patients undergoing major noncardiac surgery. Patient safety may be enhanced by increasing the use of beta-blockers in high-risk patients.",0
2984,16093464,One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis,"BACKGROUND: Since the use of parathyroid hormone as a treatment for osteoporosis is limited to two years or less, the question of whether antiresorptive therapy should follow parathyroid hormone therapy is important. We previously reported results after the first year of this randomized trial comparing the use of full-length parathyroid hormone (1-84) alone, alendronate alone, or both combined. In the continuation of this trial, we asked whether antiresorptive therapy is required to maintain gains in bone mineral density after one year of therapy with parathyroid hormone (1-84). METHODS: In the data reported here, women who had received parathyroid hormone (1-84) monotherapy (100 microg daily) in year 1 were randomly reassigned to one additional year with either placebo (60 subjects) or alendronate (59 subjects). Subjects who had received combination therapy in year 1 received alendronate in year 2; those who had received alendronate monotherapy in year 1 continued with alendronate in year 2. Bone mineral density at the spine and hip was assessed with the use of dual-energy x-ray absorptiometry and quantitative computed tomography (CT). RESULTS: Over two years, alendronate therapy after parathyroid hormone therapy led to significant increases in bone mineral density in comparison with the results for placebo after parathyroid hormone therapy, a difference particularly evident for bone mineral density in trabecular bone at the spine on quantitative CT (an increase of 31 percent in the parathyroid hormone-alendronate group as compared with 14 percent in the parathyroid hormone-placebo group). During year 2, subjects receiving placebo lost substantial bone mineral density. CONCLUSIONS: After one year of parathyroid hormone (1-84), densitometric gains appear to be maintained or increased with alendronate but lost if parathyroid hormone is not followed by an antiresorptive agent. These results have clinical implications for therapeutic choices after the discontinuation of parathyroid hormone.",0
2985,16107620,"Sex and racial differences in the management of acute myocardial infarction, 1994 through 2002","""BACKGROUND: Although increased attention has been paid to sex and racial differences in the management of myocardial infarction, it is unknown whether these differences have narrowed over time. METHODS: With the use of data from the National Registry of Myocardial Infarction, we examined sex and racial differences in the treatment of patients who were deemed to be """"ideal candidates"""" for particular treatments and in deaths among 598,911 patients hospitalized with myocardial infarction between 1994 and 2002. RESULTS: In the unadjusted analysis, sex and racial differences were observed for rates of reperfusion therapy (for white men, white women, black men, and black women: 86.5, 83.3, 80.4, and 77.8 percent, respectively; P<0.001), use of aspirin (84.4, 78.7, 83.7, and 78.4 percent, respectively; P<0.001), use of beta-blockers (66.6, 62.9, 67.8, and 64.5 percent; P<0.001), and coronary angiography (69.1, 55.9, 64.0, and 55.0 percent; P<0.001). After multivariable adjustment, racial and sex differences persisted for rates of reperfusion therapy (risk ratio for white women, black men, and black women: 0.97, 0.91, and 0.89, respectively, as compared with white men) and coronary angiography (relative risk, 0.91, 0.82, and 0.76) but were attenuated for the use of aspirin (risk ratio, 0.97, 0.98, and 0.94) and beta-blockers (risk ratio, 0.98, 1.00, and 0.96); all risks were unchanged over time. Adjusted in-hospital mortality was similar among white women (risk ratio, 1.05; 95 percent confidence interval, 1.03 to 1.07) and black men (risk ratio, 0.95; 95 percent confidence interval, 0.89 to 1.00), as compared with white men, but was higher among black women (risk ratio, 1.11; 95 percent confidence interval, 1.06 to 1.16) and was unchanged over time. CONCLUSIONS: Rates of reperfusion therapy, coronary angiography, and in-hospital death after myocardial infarction, but not the use of aspirin and beta-blockers, vary according to race and sex, with no evidence that the differences have narrowed in recent years.""",0
2986,16107622,Trends in the quality of care and racial disparities in Medicare managed care,"BACKGROUND: Since 1997, all managed-care plans administered by Medicare have reported on quality-of-care measures from the Health Plan Employer Data and Information Set (HEDIS). Studies of early data found that blacks received care that was of lower quality than that received by whites. In this study, we assessed changes over time in the overall quality of care and in the magnitude of racial disparities in nine measures of clinical performance. METHODS: In order to compare the quality of care for elderly white and black beneficiaries enrolled in Medicare managed-care plans who were eligible for at least one of nine HEDIS measures, we analyzed 1.8 million individual-level observations from 183 health plans from 1997 to 2003. For each measure, we assessed whether the magnitude of the racial disparity had changed over time with the use of multivariable models that adjusted for the age, sex, health plan, Medicaid eligibility, and socioeconomic position of beneficiaries on the basis of their area of residence. RESULTS: During the seven-year study period, clinical performance improved on all measures for both white enrollees and black enrollees (P<0.001). The gap between white beneficiaries and black beneficiaries narrowed for seven HEDIS measures (P<0.01). However, racial disparities did not decrease for glucose control among patients with diabetes (increasing from 4 percent to 7 percent, P<0.001) or for cholesterol control among patients with cardiovascular disorders (increasing from 14 percent to 17 percent; change not significant, P=0.72). CONCLUSIONS: The measured quality of care for elderly Medicare beneficiaries in managed-care plans improved substantially from 1997 to 2003. Racial disparities declined for most, but not all, HEDIS measures we studied. Future research should examine factors that contributed to the narrowing of racial disparities on some measures and focus on interventions to eliminate persistent disparities in the quality of care.",0
2987,16116637,Modeling the current and future disease burden of hepatitis C among injection drug users in Scotland,"Quantitative estimates of the current and future burden of hepatitis C virus (HCV) disease are required to plan a public health response to the HCV epidemic with regard to both prevention and treatment. A forward projection model was used to estimate the numbers of both current and former injecting drug users (IDUs) who acquired HCV and progressed to moderate and severe disease in Glasgow and Scotland during 1960-2030. The model was designed to synthesize information on the incidence and cessation of injecting drug use, the incidence of HCV infection among IDUs, the rate of HCV disease progression, and the annual number of IDUs developing HCV-related decompensated cirrhosis. During 2003, a total of 17,400 and 42,900 HCV-infected IDUs were estimated in Glasgow and Scotland, respectively; this compares with approximately 5,000 and 13,900 diagnosed, respectively, and 13,200 and 32,200 with chronic HCV, respectively. The number of IDUs developing HCV-related decompensated cirrhosis in Scotland is estimated to double between 2000 and 2020. As many as 16% and 27% of former IDUs in 2005 aged 30-39 and 40-49 years, respectively, were estimated to have moderate disease, which highlights the potential benefit of targeting HCV testing at former IDUs who belong to these age groups. In conclusion, the identification and treatment of a larger proportion of former IDUs with HCV disease and education about the importance of minimal alcohol consumption are needed to help achieve a greater impact on the future morbidity and mortality of this disease.",0
2988,16145372,Identification of 2 serum biomarkers of renal cell carcinoma by surface enhanced laser desorption/ionization mass spectrometry,"Surface enhanced laser desorption/ionization mass spectrometry can generate robust information from a small amount of clinical samples such as serum and plasma. In this study we identified novel diagnostic biomarkers of renal cell carcinoma (RCC) by large-scale serum protein profiling using surface enhanced laser desorption/ionization mass spectrometry. Proteomic spectra were generated by a time of flight mass spectrometer from a set of training samples (21 patients with RCC and 24 healthy volunteers) and another set of validation samples (19 patients with RCC, 20 healthy volunteers and 5 patients with pyelonephritis). Information on the peaks (intensity and m/z) was extracted from the mass spectra using newly developed algorithms, and the Mann-Whitney's U test and linear support vector machine were used to identify the peaks distinguishing RCC samples from the controls. Two peaks with molecular masses of 4,151 and 8,968 m/z were selected as significantly more prominent in RCC samples (p <0.01) among the 3,539 peaks in the range of 3,000 to 30,000 m/z obtained from the training samples. Simultaneous recognition of these 2 biomarkers was shown to have a sensitivity of 89.5% for the diagnosis of RCC and an overall specificity of 80.0% (95% [19 of 20] of healthy volunteers and 20% [1 of 5] of patients with pyelonephritis) in the blinded validation samples, and to allow detection of RCC in stage I (UICC) in 88.9% (16 of 18) of the cases. We identified 2 serum biomarkers potentially useful for the early diagnosis of RCC. This finding warrants a further large-scale multi-institutional analysis for clinical evaluation of the diagnostic significance of these biomarkers. ",0
2989,16146099,Increased apoptosis in the adult rat liver after a single dose of adriamycin administration,"The purpose of this study was the evaluation of hepatocytes in the adult rat's liver after adriamycin administration in a single dose. The presented above morphological changes, on tissue, cell and ultrastructural level are the evidence of persistent and irreversible damage of liver tissue via adriamycin. Cells damaged in that way waste away. In the present study cell death touched mainly single cells and necrosis was not observed. It is the evidence of apoptosis--the natural death of cells. ",0
2990,16146578,Fostering critical thinking skills: a strategy for enhancing evidence based wellness care,"""Chiropractic has traditionally regarded itself a wellness profession. As wellness care is postulated to play a central role in the future growth of chiropractic, the development of a wellness ethos acceptable within conventional health care is desirable. This paper describes a unit which prepares chiropractic students for the role of """"wellness coaches"""". Emphasis is placed on providing students with exercises in critical thinking in an effort to prepare them for the challenge of interfacing with an increasingly evidence based health care system. This case study describes how health may be promoted and disease prevented through development of personalized wellness programs. As critical thinking is essential to the provision of evidence based wellness care, diverse learning opportunities for developing and refining critical thinking skills have been created. Three of the learning opportunities are an intrinsic component of the subject and, taken together, contributed over 50% of the final grade of the unit. They include a literature review, developing a client wellness contract and peer evaluation. In addition to these 3 compulsory exercises, students were also given an opportunity to develop their critical appraisal skills by undertaking voluntary self- and unit evaluation. Several opportunities for informal self-appraisal were offered in a structured self-study guide, while unit appraisal was undertaken by means of a questionnaire and group discussion at which the Head of School was present. Formal assessment showed all students capable of preparing a wellness program consistent with current thinking in contemporary health care. The small group of students who appraised the unit seemed to value the diversity of learning experiences provided. Opportunities for voluntary unit and self-appraisal were used to varying degrees. Unit evaluation provided useful feedback that led to substantial changes in unit structure. Students have demonstrated themselves capable of applying critical thinking in construction of evidence based wellness programs. With respect to unit design, selective use of learning opportunities highlighted the desirability of using obligatory learning opportunities to ensure exposure to core constructs while student feedback was found to provide useful information for enriching unit review. It is hoped inclusion of critical thinking learning opportunities in the undergraduate chiropractic curriculum will contribute to the development of an evidence based ethos in chiropractic care. """,0
2991,16146685,Identification of novel genes in the memory response to Brucella infection by cDNA arrays,"This study investigated memory responses in immune mice spleen cells to brucellosis by gene expression utilizing cDNA micro arrays. Out of a total of 1176 cDNA's 21 genes were differentially regulated in three independent experiments, and generally supported a Th1 type immune response. 10 genes were validated by real time PCR, and 3 genes (CD 86, CD 40 L and CD 132) were also analyzed by Flow Cytometry for surface protein expression. We extended these findings by studying the expression of five selected genes (IRF 1, SOCS 1, IL 2 R, IRF 7, and CXCR 4) in two independent groups of Brucella immunized mice. In this study we show the potential application of utilizing gene arrays to identify and establish new correlates of protection against a cell mediated immune response. ",0
2992,16146723,Tissue transglutaminase: from biological glue to cell survival cues,"Tissue transglutaminase (TG2, EC 2.3.2.13) is a ubiquitous enzyme that catalyzes Ca2+-dependent post-translational modification of proteins by inserting highly stable (epsilon-[gamma-glutamyl] lysine) isopeptide bonds or by conjugating polyamines at selected peptide-bound glutamine residues. The TG2-catalyzed cross-linked products (generally high molecular mass scaffold of proteins) are of great physiological significance; they are highly stable and resistant to mechanical, chemical and proteolytic degradation. The accumulation of isopeptide bonds can be observed in skin, hair and during blood clotting and wound healing. In addition to transamidation activity, TG2 also exhibits GTPase activity and in response to certain agonist hormones can serve as a signal transducing G protein. Although predominantly a cytosolic protein, TG2 can translocate to the nucleus with the help of importin alpha-3 protein or to the membranes in association with integrins. Moreover, TG2 can also be secreted outside the cell (by yet unknown mechanism) where it crosslinks proteins of the extracellular matrix (ECM) and promotes cell adhesion and spreading. Another important property of TG2 is that it has high binding-affinity for the ECM component protein, fibronectin and thus can promote interaction between cell surface integrin with fibronectin. In this review, we discuss the implications of increased TG2 expression in drug-resistant and metastatic cancer cells and that how TG2 expression can contribute in the development of these phenotypes. ",0
2993,16146981,Early and late outcome after coronary artery bypass surgery in diabetic patients,"To determine the impact of diabetes on outcome after coronary artery bypass surgery. We matched 866 diabetic patients with non-diabetic controls in regards to gender, age, left ventricular ejection fraction, body mass index, presence of unstable angina and history of myocardial infarction, and day of surgery. The 30-d mortality and morbidity were evaluated with univariate analysis and survival and freedom from cardiac death were assessed with the Kaplan-Meier method. Follow-up time was 69+/-37 months. The 30-d mortality was 2.0% in the diabetic group and 1.0% in the non-diabetic group (p=0.15). Postoperative morbidity did not differ between groups. Cumulative 5- and 10-year survival rates were 89 and 71% in diabetics and 94 and 84% in non-diabetics (p=0.001). During follow-up, there was no difference between groups in regards to repeat revascularization. The 30-d mortality was equally low in diabetic and non-diabetic patients with severe coronary artery disease. However, long-term survival was significantly lower in the diabetic group than in the non-diabetic group. ",0
2994,16147610,The gynaecological management of women on tamoxifen: a national questionnaire survey,"Tamoxifen is the standard adjuvant treatment for women with breast carcinoma, decreasing the incidence of contralateral disease. However, the risk of endometrial cancer is increased. To establish current gynaecological management of women receiving tamoxifen in the United Kingdom we conducted a postal questionnaire of consultant gynaecologists, enquiring about frequency of, and methods used to investigate women on tamoxifen. Ninety-five per cent investigate women on tamoxifen only if they are symptomatic. Pelvic ultrasound and endometrial sampling are used for first-line investigation by 68.7%. Interpreting ultrasound findings, endometrial thickness is the parameter regarded as most important. An endometrial thickness of greater than 5 mm is regarded abnormal by 47.8% of respondents and of 4 mm by 23.6%. As there is no consensus of opinion regarding normal values for endometrial thickness, further data are required to ensure consistency when interpreting ultrasound reports of women on tamoxifen. ",0
2995,16147828,Correlation between visual examination of the cervix and digital examination,"To determine the correlation between visual assessment of the cervix and digital examination. Prospective study of patients presenting to Labor and Delivery. Exclusion criteria were preterm premature ruptured membranes (PPROM) and placenta previa. Visual and digital assessments of cervical dilation, effacement, position, and station of fetal presenting part were made. Correlation between visual and digital examinations was measured using Spearman rank correlation coefficient (COR). A p-value<0.05 was considered significant. The study involved a total of 107 patients at a mean gestational age of 32.3 weeks (range 17-41). Seven patients had ruptured membranes, and 46 were nulliparous. Visual assessment correlated with digital examination for all parameters measured with Spearman rank correlation coefficients between 0.618 and 0.686 (all significant at p<0.001). Correlations between visual and digital assessment of cervical dilation, effacement, station, and position were not as strong (0.291-0.699), but remained significant (p<0.02) in a subgroup of 50 preterm patients<34 weeks gestation. Visual assessment correlates with digital examination of the cervix. This correlation remained significant in a subset of preterm patients with intact membranes. ",0
2996,16147865,"A novel splice variant of human gene NPL, mainly expressed in human liver, kidney and peripheral blood leukocyte","""From the human fetal brain cDNA library constructed by our lab, a novel variant cDNA of a human gene was successfully cloned and identified. Because the gene has been named N-acetylneuraminate pyruvate lyase (NPL), accordingly we term our splice variant NPL_v2. The cDNA of NPL_v2 has a full-length open reading frame (ORF) from the nucleotide position 320 to 1225 that encodes a protein comprising 301 amino acids. SMART analysis showed that our hypothetical protein has one dihydrodipicolinate synthase (DHDPS) domain. Phosphorylation analysis of the deduced protein show that there are five phosphorylation sites including three """"serine"""" and two """"threonine"""" at the region that are not found in other splice variant. RT-PCR experiment revealed that our splice variant of the gene is mainly expressed in human placenta, liver, kidney, pancreas, spleen, thymus, ovary, small intestine and peripheral blood leukocyte. """,0
2997,16147952,Purkinje neuron physiology is altered by the inflammatory factor interleukin-6,"The cytokine interleukin-6 (IL-6) is produced by cells of the central nervous system (CNS) during a variety of neuroinflammatory states, in which it is thought to play a role in neuroprotection and/or neuropathology associated with neurological disease. In addition, CNS expression of IL-6 during non-pathological conditions may also occur, although the conditions for such IL-6 production remain elusive. Expression of IL-6 and its receptor and signal transducing elements by neurons and glia within the cerebellum implicate a role of IL-6 in modulating cerebellar function under normal conditions and in contributing to pathology and pathophysiology within the cerebellum during CNS disease states. Evidence for such a role of IL-6 comes from studies using transgenic mice that chronically express IL-6 within the CNS. These mice exhibit profound cerebellar pathology and significant alterations of Purkinje neuron electrical and synaptic activity. Additional evidence comes from in vitro studies using primary cultures of cerebellar cortex that have been chronically exposed to exogenously applied IL-6. Consistent with the IL-6 transgenic mice, chronic IL-6 treated Purkinje neurons in culture exhibit alterations of endogenous electrophysiological properties as well as changes in intracellular Ca2+ homeostasis and signaling. Despite these changes in Purkinje neuron physiology, chronic IL-6 does not affect the survival or morphology of Purkinje neurons in culture. Thus, by itself, IL-6 is able to modulate key components of cerebellar circuitry during periods of chronic expression, such as during neuroinflammation, and may be an important player in the movement disorders associated with a number of CNS disease states. ",0
2998,16147999,Pyruvate kinase revisited: the activating effect of K+,"For more than 50 years, it has been known that K(+) is an essential activator of pyruvate kinase (Kachmar, J. F., and Boyer, P. D. (1953) J. Biol. Chem. 200, 669-683). However, the role of K(+) in the catalysis by pyruvate kinase has not been totally understood. Previous studies without K(+) showed that the affinity of ADP-Mg(2+) depends on the concentration of phosphoenolpyruvate, although the kinetics of the enzyme at saturating K(+) concentrations show independence in the binding of substrates (Reynard, A. M., Hass, L. F., Jacobsen, D. D. & Boyer, P. D. (1961) J. Biol. Chem. 236, 2277-2283). Here, we explored the kinetics of the enzyme with and without K(+). The results show that without K(+), the kinetic mechanism of pyruvate kinase changes from random to ordered with phosphoenol-pyruvate as first substrate. V(max) with K(+) was about 400 higher than without K(+). In the presence of K(+), the affinities for phosphoenol-pyruvate, ADP-Mg(2+), oxalate, and ADP-Cr(2+) were 2-6-fold higher than in the absence of K(+). This as well as fluorescence data also indicate that K(+) is involved in the acquisition of the active conformation of the enzyme, allowing either phosphoenolpyruvate or ADP to bind independently (random mechanism). In the absence of K(+), ADP cannot bind to the enzyme until phosphoenolpyruvate forms a competent active site (ordered mechanism). We propose that K(+) induces the closure of the active site and the arrangement of the residues involved in the binding of the nucleotide. ",0
2999,16148012,Irradiation-induced translocation of p53 to mitochondria in the absence of apoptosis,"The tumor suppressor protein p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcription-independent mechanisms. Recently, it was shown that during apoptosis p53 can specifically translocate to mitochondria, where it physically interacts with and inactivates prosurvival Bcl-2 proteins. In the present study, we therefore investigated the role of mitochondrial translocation of p53 for the stress response of tumor cells. In various cell lines, DNA damage induced by either ionizing irradiation or topoisomerase inhibitors triggered a robust translocation of a fraction of p53 to mitochondria to a similar extent. Nevertheless, the cells succumbed to apoptosis only in response to topoisomerase inhibitors, but remained resistant to apoptosis induced by ionizing radiation. Irradiated cells became senescent, although irradiation triggered a functional p53 response and induced expression of p21, Bax, and Puma. Interestingly, even the targeted expression of p53 to mitochondria was insufficient to launch apoptosis, whereas overexpression of wild-type p53 induced Bax activation and apoptotic alterations. Together, these results suggest that, in contrast to previous reports, mitochondrial translocation of p53 does not per se lead to cell death and that this might constitute a mechanism that contributes to the resistance of tumor cells to ionizing radiation-induced apoptosis. ",0
3000,16148067,Monitoring of cerebral oxygenation during hypoxic gas management in congenital heart disease with increased pulmonary blood flow,"In the preoperative management of congenital heart disease (CHD) with increased pulmonary blood flow, hypoxic gas management to control pulmonary blood flow is useful. However, the cerebral oxygenation state has rarely been studied, and there is concern about neurologic development. In eight infants with CHD accompanied by increased pulmonary blood flow, hypoxia was induced after a 1-h baseline period in room air (FiO2, 0.21). The infants were simultaneously monitored in both the front-temporal region and the right-brachial region for 90 min using near-infrared spectroscopy (NIRS). The minimum SaO2 (pulse oximetry) after hypoxic gas administration was 80.8 +/- 2.9% when the minimum FiO2 was 16.2 +/- 1.1%. With a decrease in SaO2, oxy-Hb (O2Hb) decreased and total Hb [cHb: O2Hb + deoxy-Hb (HHb)] increased in both regions in the majority of infants. HHb increased in both regions with a decrease in SaO2. The maximum change in the tissue oxygenation index (TOI: O2Hb/cHb x 100) was -8.3 +/- 2.6% in the front-temporal region and -3.6 +/- 2.3% in the right-brachial region. Cerebral oxygenation decreased despite an increase in cerebral blood flow during hypoxic gas management. The change in TOI was < or =10% when the SaO2 was > or =80%. Safer control of SaO2 should be maintained over 80% for hypoxia management in CHD based on the results of the present study. ",0
3001,16148079,"Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex","Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10- and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits. ",0
3002,16148145,Impairment of thymus-dependent responses by murine dendritic cells infected with foot-and-mouth disease virus,"Foot-and-mouth disease virus (FMDV) is a cytopathic virus that experimentally infects mice, inducing a thymus-independent neutralizing Ab response that rapidly clears the virus. In contrast, vaccination with UV-inactivated virus induces a typical thymus-dependent (TD) response. In this study we show that dendritic cells (DCs) are susceptible to infection with FMDV in vitro, although viral replication is abortive. Infected DCs down-regulate the expression of MHC class II and CD40 molecules and up-regulate the expression of CD11b. In addition, infected DCs exhibit morphological and functional changes toward a macrophage-like phenotype. FMDV-infected DCs fail to stimulate T cell proliferation in vitro and to boost an Ab response in vivo. Moreover, infection of DCs in vitro induces the secretion of IFN-gamma and the suppressive cytokine IL-10 in cocultures of DCs and splenocytes. High quantities of these cytokines are also detected in the spleens of FMDV-infected mice, but not in the spleens of vaccinated mice. The peak secretion of IFN-gamma and IL-10 is concurrent with the suppression of Con A-mediated proliferation of T cells obtained from the spleens of infected mice. Furthermore, the secretion of these cytokines correlates with the suppression of the response to OVA, a typical TD Ag. Thus, infection of DCs with FMDV induces suppression of TD responses without affecting the induction of a protective thymus-independent response. Later, T cell responses are restored, setting the stage for the development of a long-lasting protective immunity. ",0
3003,16148148,Novel functions of tyrosine kinase 2 in the antiviral defense against murine cytomegalovirus,"We have recently reported that tyrosine kinase 2 (Tyk2)-deficient mice have a selective defect in the in vivo defense against certain viruses. In our current study we show that Tyk2 is essential for the defense against murine CMV (MCMV). In vivo challenges with MCMV revealed impaired clearance of virus from organs and decreased survival of mice in the absence of Tyk2. Our in vitro studies demonstrate that MCMV replicates to dramatically higher titers in Tyk2-deficient macrophages compared with wild-type cells. We show an essential role of type I IFN (IFN-alphabeta) in the control of MCMV replication, with a prominent role of IFN-beta. MCMV infection leads to the activation of STAT1 and STAT2 in an IFN-alphabeta receptor 1-dependent manner. Consistent with the role of Tyk2 in IFN-alphabeta signaling, activation of STAT1 and STAT2 is reduced in Tyk2-deficient cells. However, lack of Tyk2 results in impaired MCMV-mediated gene induction of only a subset of MCMV-induced IFN-alphabeta-responsive genes. Taken together, our data demonstrate a requirement for Tyk2 in the in vitro and in vivo antiviral defense against MCMV infection. In addition to the established role of Tyk2 as an amplifier of Jak/Stat signaling upon IFN-alphabeta stimulation, we provide evidence for a novel role of Tyk2 as a modifier of host responses. ",0
3004,16148169,LNFPIII/LeX-stimulated macrophages activate natural killer cells via CD40-CD40L interaction,"Lacto-N-fucopentaose III (LNFPIII) is a human milk sugar containing the biologically active Lewis X (LeX) trisaccharide. LNFPIII/LeX is also expressed by immunosuppressive helminth parasites, by bacteria, and on a number of tumor/cancer cells. In this report, we first demonstrate that LNFPIII activates macrophages in vitro as indicated by upregulation of Gr-1 expression on F4/80(+) cells. Further, we investigated the effect of LNFPIII-activated macrophages on NK cell activity. We found that LNFPIII-stimulated F4/80(+) cells were able to activate NK cells, inducing upregulation of CD69 expression and gamma interferon (IFN-gamma) production. The experiments show that NK cell activation is macrophage dependent, since NK cells alone did not secrete IFN-gamma in response to LNFPIII. Furthermore, we found that activation of NK cells by glycan-stimulated macrophages required cell-cell contact. As part of the cell-cell contact mechanism, we determined that CD40-CD40L interaction was critical for IFN-gamma secretion by NK cells, as the addition of anti-CD40L antibodies to the coculture blocked IFN-gamma production. We also demonstrated that LNFPIII-stimulated macrophages secrete prostaglandin E(2), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-alpha) but a very low level of IL-12. Interestingly, addition of anti-TNF-alpha, anti-IL-10, or anti-IL-12 monoclonal antibodies did not significantly alter NK cell activity. Our data show that these soluble mediators are not critical for LNFPIII-stimulated macrophage activation of NK cells and provide further evidence for the importance of cell-cell contact and CD40-CD40L interactions between macrophages and NK cells. ",0
3005,16148212,Contributions of public health to genetics education for health care professionals,"With growing knowledge about the role of genetics in health, genetics education for health care professionals has taken on increasing importance. Many efforts are under way to develop new genetics curricula. Although such efforts are primarily the responsibility of health professional schools and professional societies, the public health system is an important stakeholder, and different sectors of public health have opportunities to enhance educational efforts. These include the development of authoritative information sources about the clinical utility of genetic susceptibility and pharmacogenetic tests, creation of networks that link professionals in underserved regions to educational materials and consultative backup, and sponsorship of forums for multidisciplinary discussion of controversial issues. Public health input can help to ensure an appropriate emphasis on health outcomes as new genomic tests and technologies come into use, thus helping to protect society from the social and medical costs of genetic tests with limited clinical value. ",0
3006,16148247,Natural history of menopause symptoms in primary care patients: a MetroNet study,"The association between changes in menopausal status and menopause-related symptom reporting over the course of the menopause transition is not well understood, especially whether there are any racial differences in this association. To determine (1) the prevalence and the natural history of menopause symptoms among primary care patients approaching, or at menopause; (2) the relationship between self-reported symptoms and menopausal status; and (3) whether this relationship varies in African American and white women. Cross-sectional self-report survey of 342 women aged 40 to 55 years (31.6% African American) were recruited from 8 family practice centers in 2000 and 2001. Among 251 women without surgical menopause, 133 (53.0%) were premenopausal, 72 (28.7%) were peri-menopausal, and 46 (18.3%) were postmenopausal. The most commonly reported symptoms were joint/muscle pain and headache, which did not vary by menopausal status. As many as 28.6% of the women with regular menstruation reported hot flashes, and 18.8% had night sweats; although both symptoms were strongly associated with changes in menopausal status (P < .01). During the natural menopausal transition, white women had increasing trends of nervousness, memory loss, vaginal dryness, loss of sexual interest, hot flashes, and night sweats while African American women only had increasing trend of painful sex and hot flashes. In multivariate analyses, loss of sexual interest was associated with postmenopause status in white but not in African American women. Symptoms are not uncommon among premenopausal women and become more prevalent as the transition through menopause occurs. The prevalence of vasomotor symptoms in premenopausal women may be an under-recognized aspect of the natural history of the menopause transition. African American and white women may present different symptoms through menopause transition. ",0
3007,16148459,Ventilation-induced neutrophil infiltration and apoptosis depend on apoptosis signal-regulated kinase 1 pathway,"Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein (MIP)-2, a functional equivalent of human interleukin-8, neutrophil infiltration, and apoptosis. The mechanisms regulating ventilation-induced cytokine production and lung cell death are unclear. Based on our previous in vitro and in vivo models of lung cell stretch, we hypothesized that high tidal volume ventilation-induced MIP-2 production, neutrophil infiltration, and apoptosis are dependent on the activation of apoptosis signal-regulated kinase 1 (ASK1), the upstream activator of c-Jun N-terminal kinase (JNK). : Prospective, controlled animal experiment. University research laboratory. Male C57BL/6 mice, weighting 20-25 g. C57BL/6 mice were exposed to high tidal volume (30 mL/kg) or low tidal volume (6 mL/kg) mechanical ventilation for 15 mins to 5 hrs. High tidal volume ventilation induced MIP-2 messenger RNA expression, MIP-2 protein production, neutrophil migration into the lung, airway epithelial cell apoptosis, and activation of ASK1, JNK, and activator protein (AP)-1 DNA binding in a dose-dependent and time-dependent manner. ASK1 inhibition with thioredoxin attenuated high tidal volume ventilation-induced MIP-2 messenger RNA expression, MIP-2 protein production, neutrophil migration into the lung, airway epithelial cell apoptosis, activation of JNK, and AP-1 DNA binding. Our data showed that high tidal volume ventilation-induced MIP-2 production, neutrophil sequestration, and apoptotic cell death were dependent, in part, on activation of the ASK1/JNK/AP-1 pathway. ",0
3008,16175599,Hepatitis C virus inhibits intracellular interferon alpha expression in human hepatic cell lines,"The chronicity of hepatitis C virus (HCV) infection raises the question of how HCV is able to persist in hepatic cells. We show that human primary hepatocytes and human hepatic cell lines (Huh7 and HepG2) spontaneously produce interferon (IFN)-alpha that is inhibited in the HCV replicon cells (Huh.8 and FCA-1). Silencing IFN-alpha gene expression by IFN-alpha small interfering RNA (siRNA) in the HCV replicon cells resulted in increased HCV replicon expression. The activation of IFN-alpha expression by interferon regulatory factor (IRF-7) led to the inhibition of HCV replicon expression, whereas the anti-IFN-alpha receptor antibody could partially block IRF-7-mediated HCV replicon inhibition. In addition, the blockade of IFN-alpha receptor by anti-IFN-alpha receptor antibody on the replicon cells increased HCV replicon expression. Among the HCV nonstructural (NS) proteins tested, NS5A is the most potent inhibitor of IFN-alpha expression by the hepatic cells. Investigation of the mechanism of HCV action on IFN-alpha showed that IRF-7-induced IFN-alpha promoter activation was inhibited in the HCV replicon cells. Furthermore, IRF-7 expression was restricted in the HCV replicon cells. In conclusion, we provide direct evidence that HCV undermines the intracellular innate immunity of the target cells, which may account for HCV persistence in hepatic cells.",0
3009,16175622,Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis,"The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper-responsive innate immune system to pathogen-associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age-matched healthy controls and stimulated such cells in vitro with defined ligands for toll-like receptor (TLR) 2 (lipoteichoic acid; LTA), TLR3 (polyIC), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin), and TLR9 (CpG-B). Supernatant fluids from the cultures were analyzed for levels of 5 different pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, IL-8, IL-12p70, and TNF-alpha. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1beta, IL-6, IL-8, and TNF-alpha, compared with controls. In conclusion, monocytes from patients with PBC appear more sensitive to signaling via select TLRs, resulting in secretion of selective pro-inflammatory cytokines integral to the inflammatory response that may be critical in the breakdown of self-tolerance.",0
3010,16177250,Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children,"Staphylococcus aureus has increasingly been recognized as a cause of severe invasive illness. We describe three children who died at our institution after rapidly progressive clinical deterioration from this infection, with necrotizing pneumonia and multiple-organ-system involvement. The identification of bilateral adrenal hemorrhage at autopsy was characteristic of the Waterhouse-Friderichsen syndrome, a constellation of findings usually associated with fulminant meningococcemia. The close genetic relationship among the three responsible isolates of S. aureus, one susceptible to methicillin and two resistant to methicillin, underscores the close relationship between virulent methicillin-susceptible S. aureus and methicillin-resistant S. aureus isolates now circulating in the community.",0
3011,16177975,Evaluation of antinociceptive and antiinflammatory activities of the essential oil (EO) of Ocimum micranthum Willd. from Northeastern Brazil,"The EO of Ocimum micranthum was studied for a possible analgesic effect on the acetic acid induced writhing and formalin test in mice and antioedema activities on the carrageenan and dextran induced paw oedema in rats. The EO demonstrated antinociceptive effects, and pretreatment with naloxone did not reverse the antinociception, indicating that the opioid system is not involved. On the other hand, pretreatment with L-arginine (L-arg) reversed the antinociception, suggesting involvement of the nitric oxide (NO) system. The EO did not present an antioedematogenic effect in the carrageenan and dextran models. ",0
3012,16178200,Construction of the eukaryote expression vector of human soluble tumor necrosis factor receptor],"Human soluble tumor necrosis factor receptor (sTNFR) can interfere with the biological functions of interleukin-1, which may be appropriate to the treatment of periodontitis. The eukaryote expression vector of the human sTNFR gene must be constructed prior to conducting transgene therapy of periodontitis. Both sTNFR gene and plasmid pcDNA 3.1 (+) DNA were digested with Kpn I and Xho I. After purification, the two fragments were ligated by TakaRa DNA Ligation Kit (Ver 2.0). This recombinant DNA was then transformed into E. Coli Competent Cells JM109 and positive clones were selected on the LB agarose plate containing ampicillin (80 microg/ul). Six single clones were indentified by double digestion with kpn I and xho I and two fragments with the size of 5.4 kb and 1.0 kb were produced as expected. The sTNFR gene was successfully inserted into the eukaryote expression vector plasmid pcDNA 3.1 (+) by recombination technology in vitro. ",0
3013,16178341,Exploring nursing values in the development of a nurse-led service,"This article considers the development of nurse-led services as a part of a pilot study and explores the therapeutic nature of the role of the nurse. In particular it suggests a need for reconsideration of the fundamental values of nurse-led care in the context of changing organizational culture. Within the UK there has been pressure from policy makers to extend the role of the specialist nurse and create new nursing roles, shifting the boundaries between professional health groups. The philosophy of nurse-led initiatives has therefore been driven mainly from a service redesign and clinical need standpoint rather than necessarily focusing on enhancing patients' experience and the changes in organizational culture required to achieve this. While several studies have focused on the safety, comparative cost and comparative patient outcomes in nurse-led care in relation to traditional or doctor-led care, little attention has been given to the changing organizational values underlying the nursing role. Exploring this context is essential if new nursing roles are to provide more than relief for bottlenecks in the system and also meet their potential for providing patient centred and innovative models of care. ",0
3014,16179374,Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia,"In chronic lymphocytic leukemia (CLL), chromosomes usually evade detailed cytogenetic analyses because cells poorly respond to the traditionally used set of mitogens. We applied novel technologies, such as stimulation of CLL cells either with CD40 ligand or with a combination of CpG-oligodeoxynucleotides and IL-2, to increase the frequency of metaphase spreads for detailed chromosome analysis in 96 patients with CLL. This approach revealed that translocations occurred in 33 of 96 (34%) of our patients with CLL. The presence of translocations defined a new prognostic subgroup because these patients have significantly shorter median treatment-free survival (24 months vs 106 months; P < .001) and significantly inferior overall survival (OS; median, 94 months) than patients without translocations (346 months; P < .001). In multivariate analysis-including Binet stage, complex karyotype, CD38 expression, and 17p deletions-translocation proved to be the prognostic marker with the highest impact for an unfavorable clinical outcome (P < .001). In summary, we identified a new subgroup of patients with CLL defined by chromosomal trans-locations and poor prognosis. Our data may facilitate the identification of molecular events crucial for transforming activity in this disease and should have implications for risk-adapted clinical management of patients with CLL. ",0
3015,16179409,Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status,"Circulating levels of the orexigenic peptide ghrelin increase during fasting and decrease with refeeding. Exogenous ghrelin administration is a potent stimulus for food intake in rodents and humans. In subjects on fixed feeding schedules, ghrelin increases before each meal, raising the possibility that anticipation of meals, in addition to effects of fasting and feeding, contributes to ghrelin secretion. To distinguish among these regulatory influences, plasma ghrelin profiles were generated in freely fed rats and in meal-fed rats trained to consume their daily calories over a 4-h period in the light phase. In freely feeding rats, plasma ghrelin levels increased to a peak of 778 +/- 95 pg/ml just before the onset of the dark. Similarly, in meal-fed rats anticipating a large meal of either chow or Ensure at their usual feeding time, plasma ghrelin increased steadily over the 2 h preceding the meal to peaks of 2192 +/- 218 and 2075 +/- 92 pg/ml, respectively. When freely fed rats were food deprived for a time equivalent to meal-fed rats, there was no peak of plasma ghrelin. In addition, eating-induced suppression of the ghrelin response differed significantly between meal-fed rats and ad libitum-fed rats receiving meals of similar size. These findings indicate that anticipation of eating, as well as fasting/feeding status, influences pre- and postprandial plasma ghrelin levels in rats. Together, these data are consistent with a role for ghrelin in the regulation of anticipatory processes involved in food intake and nutrient disposition. ",0
3016,16179571,Incidence and clinical features of disease progression in adult moyamoya disease,"The progression of occlusive lesions in the major intracranial arteries was believed to be very rare in adult patients with moyamoya disease. The present study aims to clarify the incidence and clinical features of disease progression in adult moyamoya disease. For the past 15 years, 120 adult Japanese patients were diagnosed with moyamoya disease. Of these, 63 patients were enrolled in this historical prospective cohort study on a total of 86 nonoperated hemispheres. All were followed up with a mean period of 73.6 months. MRI and magnetic resonance angiography were repeated every 6 to 12 months, and cerebral angiography was performed when disease progression was suspected on MRI and magnetic resonance angiography. Disease progression occurred in 15 of 86 nonoperated hemispheres (17.4% per hemisphere) or in 15 of 63 patients (23.8% per patient) during the follow-up period. Occlusive arterial lesions progressed in both anterior and posterior circulations, in both symptomatic and asymptomatic patients, and in both bilateral and unilateral types. Eight of 15 patients developed ischemic or hemorrhagic events in relation to disease progression. Multivariate analysis revealed that the odds ratio conferred by a male patient was 0.20 (95% CI, 0.04 to 0.97). The incidence of disease progression in adult moyamoya disease is much higher than recognized before, and female patients may be at higher risk for it than male patients. Careful follow-up would be essential to prevent additional stroke occurrence in medically treated adult patients with moyamoya disease, even if they are asymptomatic or are diagnosed as having unilateral moyamoya disease. ",0
3017,16179614,TGF-beta-induced apoptosis in endothelial cells mediated by M6P/IGFII-R and mini-plasminogen,"Transforming growth factor-beta (TGF-beta), a key modulator of endothelial cell apoptosis, must be activated from the latent form (LTGF-beta) to induce biological responses. In the present study, we report activation of TGF-beta by functional and physical co-operation of the mannose-6-phosphate/insulin-like-growth-factor-II receptor (CD222) and the urokinase-type plasminogen activator receptor (CD87). We show that endothelial cells express CD222 and CD87 in a membrane complex and demonstrate that the association of these two receptors is essential for the release of active TGF-beta in the transduced mouse fibroblast used as model cells. By contrast, smooth-muscle cells, which express CD222 and CD87 at similar density to endothelial cells but not in complexed form, do not activate TGF-beta. We also have found that mini-plasminogen is a high-affinity ligand for CD222 and is essential for the activation of TGF-beta by the CD87-CD222 complex to induce apoptosis in endothelial cells. This specific mechanism of TGF-beta-mediated apoptosis in endothelial cells is thus a potential novel target to be considered for treatment of pathological vascular disorders (e.g. tumor angiogenesis). ",0
3018,16179785,Biomarkers in patients with gastric inflammation: a systematic review,"The importance of examining the status of gastric inflammation has been acknowledged; the new classification by the updated Sydney system (USS) allows us to evaluate the quantitative status of gastric inflammation. However, this system is based on the histological classification derived from biopsy specimens. Therefore, more convenient, objective and practical biomarkers are recommended. We undertook a systematic review to find out potential biomarkers by summarizing the relationship between biomarkers and grades of inflammation. By a primary search via Medline up to December 2004, we extracted a total of 6,526 papers that described biomarkers for human gastric inflammation. All papers were screened by title and abstract. The authors then retrieved 435 citations for complete review; ultimately 231 were appropriate for inclusion criteria. These papers were subclassified into several categories and summarized by each author. In addition to standard markers such as pepsinogens, we confirmed the close relationship between the levels of several biomarkers including gastrin, interleukin-8, HLA class II molecules, reactive oxygen species, and the histological grades. This review provides valuable information describing the clinical implication of these biomarkers for evaluating the static conditions or dynamic alterations of human gastric inflammation. ",0
3019,16179958,Influence of baclofen on temperature-sensitive neurons in chick hypothalamus,"The effects of the GABA(B)-receptor agonist baclofen on neuronal tonic activity (firing rate) and temperature sensitivity (temperature coefficient, TC) of neurons in the preoptic area/anterior hypothalamus (PO/AH) have been examined in chick brain slices, using extracellular recordings. The tonic activity of both warm-sensitive and cold-sensitive neurons, as well as temperature-insensitive neurons, was significantly inhibited by superfusion with baclofen (1 microM). It is clearly evident from the present study that there was an increasing trend in warm-sensitive neurons and a significant (p<0.05) increase in TC of cold-sensitive neurons. Relatively high percentage (31.5%) of chick PO/AH neurons was determined as cold sensitive by present investigation. Particularly, GABA(B) mechanisms modify temperature sensitivity of the PO/AH neurons and thus modulation of temperature sensitivity in PO/AH is involved in the control of body temperature. ",0
3020,16179977,Lessons learned from the development of a new hybrid strategy for the management of hypoplastic left heart syndrome,"Despite improvements in surgical techniques and perioperative management, the overall results of traditional staged palliation for hypoplastic left heart syndrome (HLHS) remain suboptimal. We report the evolution of a hybrid strategy in 34 patients coupling innovative surgical and transcatheter techniques that requires one open-heart procedure to reach a Fontan completion. Experience has led to modifications in technique, timing of procedures, and follow-up. Current initial palliation is by intraoperative, off-pump, placement of bilateral pulmonary artery bands and a PDA stent. Transcatheter creation of an unrestricted atrial septal defect is performed when necessary. Follow-up includes weekly cardiology assessment, including echocardiography with a surveillance catheterization performed at 6 weeks. At 3-6 months a comprehensive stage 2 procedure (elements of traditional stages 1-3) is performed. At 2 years, transcatheter Fontan completion with a covered stent is performed. Initial hybrid stage 1 was from August 2001 to December 2004 and included 29 newborns (1.8-4.2 kg). There were five hospital deaths and three interstage deaths. Procedural and interstage deaths were eliminated in the latter half of the experience. Comprehensive stage 2 included 18 patients. There were four deaths; two patients who died were brought urgently to operation. Transcatheter Fontan completion included 5 patients (not from the initial 29); there were no deaths and all returned home in 24 hours. With this strategy there is one exposure to cardiopulmonary bypass, aortic cross-clamping, and circulatory arrest. There was a significant learning curve, which is highlighted. This initial experience warrants further investigation to determine whether this hybrid strategy will yield better short- and long-term outcomes. ",0
3021,16180142,Gene expression profiling of jejunal Peyer's patches in juvenile and adult pigs,"Peyer's patches are organized lymphoid tissues of the small intestine that play a critical role in disease resistance and oral tolerance. Peyer's patches in the jejunum contain lymphocytes, dendritic cells, macrophages, villous epithelium, and specialized follicle-associated epithelium. Little is known about the mechanisms and processes by which cells of the Peyer's patches discriminate food nutrients and commensal microflora from pathogenic microbiota. We hypothesize that the jejunal Peyer's patches express genes that mediate and regulate its essential functions. Expression patterns of approximately 2600 cDNAs from a porcine Peyer's patch subtracted library were examined by microarray profiling. Individual mRNAs of interest were further examined by quantitative RT-PCR. Innate immunity-associated genes, including complement 3 and lysozyme, and the genes for epithelial chloride channel and trappin 1 were highly expressed by jejunal Peyer's patch in both juvenile and adult pigs. The growth- and apoptosis-associated genes CIDE-B, GW112, and PSP/Reg I (pancreatic stone protein or regenerating gene) were differentially expressed in juvenile pig Peyer's patches. Many sequences which were highly expressed in jejunal Peyer's patches have previously been described with functions in epithelial cells. Animal-to-animal variation in basal jejunal Peyer's patch gene expression was considerable and reflects the dynamic physiological environment of the gut in addition to genetic, epigenetic, and microbiological variation in the small intestine. ",0
3022,16180796,Pregnancy and labor after combined pancreas-kidney transplantation in Czech Republic],"To inform about the first own experiences and to present opinion on leading pregnancy and delivery after a combined pancreas and kidney transplantation. Case report and review article. Department of Obstetric and Gynecology, 1st Medical Faculty of the Charles University and General Faculty Hospital, Prague. Pregnancies and deliveries after the transplantation of solid organs are not common. Mostly there are experiences with women after kidney transplantation, smaller or no experiences are with women after transplantation of other solid organs. About 25 pancreas transplantation per year are performed in the Czech republic. Two women after the combined kidney and pancreas transplantation were the first in Czech republic to get pregnant spontaneously and delivered by using a chronic immunosupressive. therapy (Prograf, Imuran, Prednison) in 2002 and 2003. These single pregnancies were led as a high-risk pregnancy in Regional Perinatology Center in collaboration with Transplant and Diabetic Center. Both pregnancies were termined from the obstetrical indication before the term by cesarean section. Both children were healthy. The pregnancy of both patients has not affected the function of the transplanted organs and development of both children has been normal. ",0
3023,16180828,Alkaloids from the sponge Monanchora unguifera,"The bioassay-guided fractionation of the cytotoxic crude gum obtained from the Caribbean sponge Monanchora unguifera led to the isolation and characterization of the new compounds batzelladine J (1) and crambescidic acid (2) in addition to known guanidine alkaloids ptilomycalin A (3a), ptilocaulin (4), and isoptilocaulin (5). The structures of the compounds were elucidated by interpretation of the 1D and 2D NMR experiments. The chemotaxonomic implications of these findings are discussed. ",0
3024,16180939,Testing and implementing signal impact analysis in a regulatory setting: results of a pilot study,"Statistical signal detection methods such as proportional reporting ratios (PRRs) detect many drug safety signals when applied to databases of spontaneous suspected adverse drug reactions (ADRs). Impact analysis is a tool that was developed as an aid to prioritisation of such signals. This paper describes a pilot project whereby impact analysis was simultaneously introduced into practice in a regulatory setting and tested in comparison with the existing approach. Impact analysis was run on signals detected during a 26-week period from the UK Adverse Drug Reactions On-line Information Tracking (ADROIT) database of spontaneous ADRs that met minimum criteria (PRR>or=3.0, chi2>or=4.0 and >or=3 reported cases) and related to established drugs (i.e. those that have been available for at least 2 years and no longer carry the 'black triangle' symbol). The current method of signal prioritisation (i.e. the collective judgement at a weekly meeting) was initially performed without knowledge of the findings of impact analysis. Subsequently, the meeting was presented with the findings and, where appropriate, given the opportunity to reconsider the judgement made. The categories arising from the two methods were compared and the ultimate action recorded. Inter-observer variation between scientists performing impact analysis was also assessed. Eighty-six separate signals were analysed by impact analysis, of which 5% were categorised as high priority (A), 14% as requiring further information (B), 31% as low priority (C) and 50% as no action required (D). In general, the new method tended to give a higher level of priority to signals than the existing approach. Overall, there was 59% agreement between the impact analysis and the collective judgement at the meetings (kappa statistic=0.30). There was slightly greater agreement between impact analysis and the final action taken (kappa statistic=0.39), indicating that the findings of an impact analysis had an influence on the outcome. Assessment of inter-observer variation demonstrated that the method is repeatable (kappa statistic for overall category=0.77). Almost 70% of those who participated in the pilot study believed that impact analysis represented an improvement in how signals were prioritised. Impact analysis is a repeatable method of signal prioritisation that tended to give a higher level of priority to signals than the standard approach and which had an influence on the ultimate outcome. ",0
3025,16180951,Effects of problem-oriented willed-movement therapy on motor abilities for people with poststroke cognitive deficits,"Cognitive deficits after stroke are common and interfere with recovery. One purpose of this study was to determine whether the motor abilities of subjects who have poststroke cognitive deficits and who have received problem-oriented willed-movement (POWM) therapy will improve more than the motor abilities of subjects in the reference group who have received neurodevelopmental treatment (NDT). Another purpose of this study was to identify the relationship between cognitive function and motor abilities for both groups. The subjects recruited for this study were 36 men and 11 women with various degrees of poststroke cognitive deficits. A randomized block design was used to assign the subjects to 2 groups. Cognitive function and motor ability were evaluated with the Mini-Mental State Examination and the Stroke Rehabilitation Assessment of Movement (STREAM). Both groups received physical therapy 5 or 6 times per week in 50-minute sessions. The STREAM scores improved after treatment in both groups. Main group effects were found for the lower-extremity (F=4.58, P< .05) and basic mobility (F=27.49, P< .01) subscales of the STREAM. Pretest cognitive function showed a positive relationship with posttest motor ability in the NDT group (r = .446, P< .05). However, the relationship between pretest cognitive function and posttest motor ability had no statistical significance in the POWM group (r = .101, P= .630). These findings suggest that, regardless of a person's cognitive function, POWM intervention is effective in improving lower-extremity and basic mobilities and indicates the need to use relatively intact cognitive function or perceptual function, or both, to improve motor rehabilitation for people with cognitive function deficits. ",0
3026,16181076,Regulation of neurogenesis and angiogenesis in depression,"The characterization of depression as a treatable disease has led to very significant research aimed at understanding disease mechanisms and treatments. Antidepressant therapy, employing chemical and non-chemical antidepressants are quite successful in treatment of the disorder although their mechanism of action is not well understood. Basic research with rodent models is providing vital evidence concerning the molecules and mechanisms involved in antidepressant action. The regulation of neurotrophic and growth factors observed after antidepressant administration is seen as playing an important role in modulating the therapeutic effects of antidepressants. Recently, adult neurogenesis or the birth of new neurons has emerged as a physiological phenomenon necessary for the behavioral response of antidepressant treatment. Equally interesting are correlative associations between neurogenesis and angiogenesis or the birth of new vasculature. Growth factors such as brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) play vital roles in both these phenomena making the interplay of neurogenesis and angiogenesis an exciting avenue of brain research. This review will focus on the research that has led us to this current understanding of antidepressant action in context with the pathophysiology of depression using examples from basic, preclinical and clinical investigations. ",0
3027,16181307,Cytomorphological study of soft tissue neoplasms: role of fluorescent immunocytochemistry in diagnosis,"Exact categorization of soft tissue tumours (STTs) on smears requires application of various ancillary techniques. This study was aimed at evaluating the role of fluorescent immunocytochemistry (FICC) in cyto-diagnosis of 30 STT cases. Thirty cases of soft tissue tumours were included in the present study. All cases were subjected to routine Giemsa and Papanicolaou stain. Extra smears were made and kept for fluorescent immunostaining. A panel of cytoskeletal antibodies, tagged with FITC (Fluorescein isothyocynate), was employed in all these cases. Fluorescent immunostained smears were examined under Zeiss Confocal Laser scanning microscope, using double immunofluorescence (red-green). Finally, all cases were subjected to biopsy and again immunoperoxidase staining. Among the 30 cases in the present study, unaided cytological diagnoses ranged from 'spindle cell' tumour in four (13.3%) cases, benign and malignant spindle cell tumour in 17 (56.6%) cases, to malignant mesenchymal tumour in nine (30%) cases. FICC helped in further correct categorization of 25/30 (83.3%) cases viz. leiomyoma (three), benign neurogenic tumour (six), schwannoma (one), dermatofibrosarcoma protuberans (three), synovial sarcoma (two), rhabdomyosarcoma (two), malignant fibrous histiocytoma (five) and malignant peripheral nerve sheath tumour (three). Aggressive fibromatosis was found to be a missed diagnosis in two cases. Overall concordance between cyto-diagnosis with FICC, and histopathology results was 83.3% (P < 0.05). Fluorescent immunocytochemistry is a significant ancillary technique for making a rapid and specific diagnosis of STT, as required for their timely management. Incorporation of a wide panel of antibody markers with clinico-cytological correlation is recommended in forming an exact diagnosis in these cases. ",0
3028,16181533,Effects of Shenggu injection on mRNA expression of vascular endothelia growth factor in rat osteoblasts in vitro],"To study the effects of Shenggu injection (SGI) on mRNA expression of vascular endothelia growth factor (VEGF) in rat osteoblasts in vitro and to explore its possible molecular mechanisms in promoting fracture healing. Rat osteoblasts cultured in vitro were stimulated with SGI according to the protocol. The expression levels of VEGF mRNA in the cells in every group were examined by reverse-transcriptase ploymerase chain reaction (RT-PCR). When osteoblasts were stimulated with different concentrations of SGI for 5 days, the expression of VEGF mRNA peaked with 1 mg/ml SGI on the 5th day. When treated with 1 mg/ml SGI from the 1st to the 5th day, the expression of VEGF mRNA increased gradually with the increase of culturing time. SGI could promote significantly the expression of VEGF mRNA in rat osteoblasts in vitro. The levels of expression of VEGF mRNA changed along with different concentrations and stimulating time of SGI. ",0
3029,16182195,Anticopper therapy against cancer and diseases of inflammation and fibrosis,"Anticopper drugs that have been developed to treat Wilson's disease, a disease of copper toxicity, include tetrathiomolybdate, zinc, penicillamine, and trientine. Lowering copper levels by a modest amount in non-Wilson's patients with tetrathiomolybdate inhibits angiogenesis, fibrosis and inflammation while avoiding clinical copper deficiency. Through this mechanism tetrathiomolybdate has proven effective in numerous animal models of cancer, retinopathy, fibrosis, and inflammation. Penicillamine has efficacy in rheumatoid arthritis and trientine has efficacy in diabetic neuropathy and diabetic heart disease. If clinical studies support the animal work, anticopper therapy holds promise for therapy of cancer, fibrotic disease and inflammatory and autoimmune diseases. ",0
3030,16182522,Identification by microarray analysis of aspartate aminotransferase and glutamine synthetase as glucocorticoid target genes in a mouse Schwann cell line,"Schwann cells have been identified as targets for glucocorticoids. Besides genes implicated in the myelination process, the target genes of glucocorticoids have not been identified in these cells. For that purpose, we performed microarray analysis on MSC80 (mouse Schwann cells) treated with a synthetic glucocorticoid, dexamethasone. These cells express a functional glucocorticoid receptor (GR), but none of the other steroid receptors. This allowed us to identify genes specifically regulated by GR in the absence of the mineralocorticoid receptor. Among the 5000 genes analyzed, 12 were at least two-fold upregulated and 91 genes were at least two-fold down-regulated upon treatment with dexamethasone. Because of their potential role in Schwann cell homeostasis, we selected, for further analysis, the upregulated genes encoding glutamine synthetase (GS) and cytosolic aspartate aminotransferase (cAspAT). These genes play a crucial role in the glutamate cycle which was shown to be vital in neuron-astrocyte cross-talk in the central nervous system. Their activation was confirmed by semi-quantitative and real-time PCR. A detailed analysis of cAspAT promoter activity revealed that the mechanism of regulation by GR in Schwann cells differs from that in hepatoma cells, suggesting a cell-specific regulation. The transactivation potency of the two Glucocorticoid Responsive Units (GRU) present in the cAspAT promoter seems to be dependent on the levels of the GR in MSC80 cells. Furthermore, we show that an increase in GR levels under certain circumstances could considerably potentiate the effects of glucocorticoids on the cAspAT promoter via synergistic activation of both GRU, To the opposite, an enhancement in GR levels did not further potentiate Dex-activation of the GS promoter, showing a differential mechanism of action of GR in the context of both promoters. ",0
3031,16183008,Relationship of problem-focused coping strategies to changes in quality of life following treatment for early stage breast cancer,"This study examined whether problem-focused coping strategies used by early stage breast cancer patients at the end of treatment could predict changes in quality of life six months later. One hundred forty-six women completed measures of problem-focused coping and quality of life at the end of early stage breast cancer treatment. Quality of life was reassessed six months later. Women who focused more on their symptoms at treatment end experienced less physical and mental quality-of-life improvement six months later. Women more likely to seek out information about their illness experienced greater physical quality-of-life improvement. The relationship of focusing on symptoms with quality of life was broad-based; the relationship of information seeking with quality of life was limited to improvements in physical functioning. Results suggest that focusing on symptoms is a maladaptive approach to illness, but that information seeking may yield benefits to physical recovery. ",0
3032,16183009,The cancer pain experience of Israeli and American patients 65 years and older,"With the aging of the world's population, cancer pain will become an increasingly important health issue. The purpose of this study was to describe the cancer pain experience of Americans (n = 60) and Israelis (n = 39) 65 years and older. Outpatients in teaching hospitals in the U.S. and in Israel completed study questionnaires. Thirty percent of the total variance of worst pain was explained by age, symptom severity, and cancer stage, and 40% of the total variance of pain interference was explained by whether they were American or Israeli, symptom severity, and sense of coherence. Israeli patients had significantly higher scores on worst pain and pain interference, and significantly lower pain management index (PMI) and knowledge and attitudes toward pain and pain control scores. Studies with larger samples and across different cultures are needed to confirm these findings in order to develop culturally appropriate interventions. ",0
3033,16183128,An ophthalmologist's guide to understanding antibiotic susceptibility and minimum inhibitory concentration data,"To address the need to establish appropriate evaluation criteria for analyzing in vitro antibiotic susceptibility based on original data. In vitro laboratory investigation. Bacterial isolates from patients with conjunctivitis. Minimum inhibitory concentrations (MICs), descriptive statistics, antibiotic susceptibility, potency, and statistical analysis. Minimum inhibitory concentrations were determined for 80 bacterial conjunctivitis isolates to moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, and ofloxacin. Using the MIC values, descriptive statistics (median, MIC50, MIC90, mode, range), antibiotic susceptibility, and potency of each antibiotic were calculated for each bacterial group. The data were analyzed statistically using appropriate randomization and nonparametric tests. The descriptive statistics of gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae) followed a consistent trend where the median, MIC50, MIC90, and mode demonstrated the lowest values, in all instances, for moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, and ofloxacin. The descriptive statistics for Haemophilus species (the predominant gram-negative bacteria implicated in conjunctivitis) did not describe any consistent trend. In contrast, antibiotic susceptibility testing did not demonstrate any advantage among the 5 fluorquinolones tested, except for moxifloxacin in the S. aureus fluoroquinolone-resistant group. Potency studies indicated that moxifloxacin and gatifloxacin were the most potent for gram-positive bacteria, whereas gatifloxacin and ciprofloxacin were the most potent for Haemophilus species. In the absence of human clinical trial data to guide care, in vitro susceptibility data should be analyzed with a set of descriptive statistics along with a nonparametric statistical analysis. No single parameter or test should be relied upon in all instances to demonstrate the in vitro superiority of one antibiotic over another. In this study, fourth-generation fluoroquinolones did have some potency advantages over second-generation fluoroquinolones against gram-positive conjunctival bacterial isolates, but not for Haemophilus isolates. ",0
3034,16183159,Studies on the use of NE-4C embryonic neuroectodermal stem cells for targeting brain tumour,"Neural stem cells were suggested to migrate to and invade intracranial gliomas. In the presented studies, interactions of NE-4C embryonic neural stem cells were investigated with C6 and Gl261, LL and U87, glioblastoma cells or with primary astrocytes. Glioma-derived humoral factors did not influence the proliferation of stem cells. NE-4C-derived humoral factors did not alter the proliferation of Gl261 and U87 cells, but increased the mitotic activity of C6 cells and that of astrocytes. In chimera-aggregates, all types of glioma cells co-aggregated with astrocytes, but most of them segregated from stem cells. Complete intercalation of stem and tumour cells was detected only in chimera-aggregates of Gl261 glioma and NE-4C cells. If mixed suspensions of NE-4C and Gl261 cells were injected into the brain, stem cells survived and grew inside the tumour mass. NE-4C stem cells, however, did not migrate towards the tumour, if implanted near to Gl261 tumours established in the adult mouse forebrain. The observations indicate that not all types of stem cells could be used for targeting all sorts of brain tumours. ",0
3035,16183445,The use of intravenous recombinant tissue plasminogen activator in acute ischemic stroke,"We sought to determine the frequency of use of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) in patients presenting to our institution with acute ischemic stroke (AIS). This observational study involved keeping a log of all patients presenting to our institution with symptoms consistent with AIS who were potential candidates for emergency thrombolysis over a 3-year period. The log included brain computed tomography (CT) scan results, whether or not rt-PA was administered, and contraindications to thrombolysis. It also included each patient's time flow through the system, from symptom onset to decision time regarding (and administration of) thrombolytics. Over the 36-month period of the study, there were 142 patients who presented to the Emergency Department (ED) who initially were thought to be potential candidates for thrombolysis for AIS. Ninety-five (68.5%) of these 142 patients had a confirmed diagnosis of AIS. On further clarification of symptom onset, 77 (81%) of these 95 patients with AIS actually presented within 3 h, and 17 (22%) of these 77 patients met criteria for thrombolysis and had no contraindications. All 17 (100%) patients with AIS presenting within 3 h of onset and without contraindications received i.v. rt-PA in the ED. In conclusion, i.v. rt-PA can be administered for AIS within the 3-h window if a hospital is committed to providing this treatment. Thrombolysis remains a treatment for a minority of AIS patients. ",0
3036,16183448,Headache and seizure in a young woman postpartum,"A 19-year-old woman, 8 days postpartum, presented to the Emergency Department (ED) with a chief complaint of headache, decreased vision, and agitation. Past medical history was unremarkable. Physical examination was remarkable only for dry mucous membranes, decreased visual acuity, and trace pedal edema bilaterally. While in the ED, the patient experienced a generalized tonic-clonic seizure. Computed tomography (CT) scan of the head was suspicious for venous infarction. Magnetic resonance imaging (MRI) and MR venography revealed sagittal sinus and left transverse sinus thrombosis. The risk factors, clinical presentation, diagnostic evaluation, and management of cerebral venous thrombosis are reviewed. ",0
3037,16183489,"""""""Radical but conservative"""" is the main goal for ultrasonography-guided liver resection: prospective validation of this approach""","Despite higher blood loss, morbidity, and mortality, rate of major resection is still high in most surgical institutions because of fear of incomplete tumor removal. To verify whether intraoperative ultrasonography (IOUS) minimizes the rate of major hepatectomies while maintaining treatment radicality, we have prospectively validated our policy, based on extensive use of IOUS resection guidance. Ninety-three consecutive patients with liver tumors were prospectively enrolled. There were 61 men and 32 women with a mean age of 65.6 years. Fifty-nine patients had hepatocellular carcinoma and 34 had colorectal cancer liver metastases. Surgical strategy was based on the relationship between the tumor and intrahepatic vascular structures at IOUS. Rates of major and minor resection, mortality, morbidity, and rate of local recurrences were evaluated. There was no hospital mortality; major morbidity occurred in 2.2% of patients and minor complications in 17%. Six (6.5%) patients required blood transfusion. Major resections (two or more segments) were accomplished in 14 patients (15%), and 5 (5.4%) patients had more than three segments removed. Major vascular invasion was present in 16 patients (17%), and contact without infiltration with major vessels was present in another 16; part of the wall of the inferior vena cava was resected in 1 patient. Surgical clearance was achieved in all patients without local recurrence at a mean followup of 18 months (median 13, range 6 to 52 months). This study shows that liver operations performed under IOUS guidance are safe and radical and reduce need for major hepatectomies. ",0
3038,16183613,A new test battery to assess aphasic disturbances and associated cognitive dysfunctions -- German normative data on the aphasia check list,"Aphasia, defined as an acquired impairment of linguistic abilities, can be accompanied by a diversity of neuropsychological dysfunction. Accordingly, the necessity to include cognitive testing in the diagnosis of aphasia is increasingly recognized. Here we present the Aphasia Check List (ACL), a new test battery for the assessment of aphasic and associated cognitive disorders. The language part of the battery provides a differentiated profile of important linguistic abilities. In addition, the ACL includes nonverbal screening tests for three neuropsychological domains: memory, attention, and reasoning. Dysfunctions in these domains have been observed in aphasic patients and can have an impact on language function. The ACL is applicable to patients with language disturbances of different etiologies, different stages of disease, and to patients with mild to severe aphasia. As the entire test duration is only about 30 minutes, the ACL is also economically valuable. It thus presents an adequate starting point in aphasia diagnosis for a wide range of patients. Here we describe the construction of the ACL, and the normative study of its original German version with 154 aphasic patients and 106 healthy comparison subjects. The ACL cognition part revealed additional neuropsychological dysfunction in the aphasia group. We present the patterns of these dysfunctions and their correlations with language deficits. ",0
3039,16183688,Increased arterial wave reflections predict severe cardiovascular events in patients undergoing percutaneous coronary interventions,"Increased arterial wave reflections are associated with the presence and extent of coronary atherosclerosis and with cardiovascular mortality in selected populations. We prospectively evaluated their prognostic value in the short- and long-term following percutaneous coronary interventions (PCIs). We non-invasively quantified wave reflections [expressed as augmentation index corrected for heart rate of 75 b.p.m. (AIx@75)] using applanation tonometry of the radial artery and a validated transfer function to obtain the corresponding aortic values in 262 patients undergoing PCI. During 2-year follow-up, 61 patients reached the primary endpoint [death, myocardial infarction (MI), and restenosis]. Increasing tertiles of Alx@75 were related to the rate of patients reaching the primary endpoint [15.2, 20 and 35.3%, respectively (P = 0.001)], as well as the secondary endpoints total mortality, myocardial infarction and death plus myocardial infarction (RR for the third vs. the first tertile 4.33, 3.25 and 3.46, respectively, P < 0.05). In a multivariable Cox-regression model, AIx@75 added prognostic value above and beyond clinical risk factors, angiographic variables, and medications (RR 1.8, 95%CI 1.18-2.76 per increasing AIx@75-tertile, P < 0.01). Increased arterial wave reflections are independently associated with an increased risk for severe short- and long-term cardiovascular events in patients undergoing PCI. ",0
3040,16183826,Age-related changes in twitch properties of plantar flexor muscles in prepubertal children,"The twitch of the triceps surae muscle (TS), which characterizes the contractile properties independently of volition, differs in amplitude, but not in time course, when evoked in pre or postpubertal children. The aim of the present study was to compare the TS twitch contractile properties in prepubertal children (7 to 11 y). M-wave and twitch were recorded at rest by supramaximal electrical stimulations of the posterior tibial nerve. Twitches were characterized by peak torque (Pt), contraction time (CT), half relaxation time (HRT), and rate of torque development (dPt/dt). Electromechanical delay (EMD) was quantified with regard to the TS M-wave onset. Pt values increased significantly with the age of the prepubertal children but remained lower than that for adult subjects. CT and HRT values did not change with age. Thus, dPt/dt increased significantly between the 7-year-old and the 11-year-old children but remained significantly lower than that for adults. Despite EMD values decreased with age, they remained significantly higher than those of adult subjects. These results confirmed the link between growth processes and the increase in twitch torque for prepubertal children within a limited range of age. However, the time-course characteristics were not affected by age. The increase in dPt/dt and the decrease in the EMD could be used as indirect indicators of changes in contractile kinetics and in musculo-tendinous stiffness with the age of the prepubertal children. The age-related relationships established by this study will serve as reference values for clinical testing of the TS performances in relation to muscle disease or disuse. ",0
3041,16183828,Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls,"Preterm birth might induce permanent changes in vascular structure and function as well as in blood pressure. To elucidate this hypothesis and underlying mechanisms in girls born before term, the authors correlated neonatal data, including estradiol levels, with vascular function and structure and with blood pressure after puberty. In a case-control study design, 34 girls born before term and 32 gender- and age-matched control infants born at term were included. Pulse wave analysis was used to determine aortic pressure profiles and overall arterial compliance. Stiffness of the carotid artery and abdominal aorta was measured with ultrasonography. Pulse wave velocity in the forearm was measured with photoplethysmography. A laser Doppler technique was used to determine skin perfusion before and after transdermal delivery of acetylcholine, an endothelium-dependent vasodilator. It was found that preterm girls had significantly higher brachial and aortic blood pressure, a narrower but less stiff abdominal aorta, and lower peripheral skin blood flow than did control infants. Augmentation index, carotid stiffness, pulse wave velocity, endothelium-dependent vasodilatation, and heart rate were similar in the two groups. In the preterm group, blood pressure and vascular functions showed no association with intrauterine growth retardation or neonatal estradiol levels. In conclusion, preterm girls have higher blood pressure and an increased resistance in the vascular tree after puberty. These findings may have implications for future cardiovascular risk in the growing adult population surviving preterm birth. ",0
3042,16184181,High-dose busulfan and thiotepa followed by autologous stem cell transplantation (ASCT) in previously irradiated medulloblastoma patients: high toxicity and lack of efficacy,"We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma. ",0
3043,16184384,Adaptation of the rheumatoid arthritis quality of life scale for Estonia,"The aim of the study was to adapt the rheumatoid arthritis quality of life scale (RAQoL) for Estonia and assess its psychometric properties. The RAQoL was translated into Estonian using the dual panel method. The translation was assessed for face and content validity by means of interviews with 15 rheumatoid arthritis (RA) patients. Reproducibility and construct validity were estimated using a further sample of 50 patients. Unidimensionality of the final scale was assessed by Rasch analysis. No major problems occurred in translating the instrument, it was well accepted by interviewees. The Estonian RAQoL had good test-retest reliability, internal consistency and ability to discriminate between groups defined by patient-perceived severity. Predicted convergent and divergent validity was demonstrated. Unidimensionality of the instrument was confirmed by excellent fit to the Rasch model. The RAQoL is appropriate for use in clinical studies and trials involving RA patients. ",0
3044,16184513,Abnormal umbilical-portal-hepatic venous system in two siblings: a sign for congenital cholangiodysplasia,"We report on two siblings who presented prenatally with a ductus venosus (DV) that was abnormally located between the middle hepatic vein (mHV) and the proximal inferior vena cava (IVC), and with hepatomegaly. The first case presented with polyhydramnios at 33 weeks and therapeutic amniocentesis resulted in premature delivery soon after admission. The neonate died 19 days later and autopsy revealed congenital cholangiodysplasia. The second fetus presented for routine screening at 19 weeks of gestation and was found to have similar abnormalities of the venous system, suggesting the same origin of disease. Termination of pregnancy was performed and autopsy revealed congenital cholangiodysplasia. Our observations suggest that an abnormal umbilical-portal-hepatic venous system may be associated with a congenital malformation of the liver. ",0
3045,16184992,Magnetic resonance imaging for diagnosing lesions of the triangular fibrocartilage complex,"In a retrospective survey we compared the magnetic resonance imaging (MRI) protocols with the arthroscopic findings for triangular fibrocartilage complex (TFCC) lesions. We found a sensitivity of 0.61 and specificity of 0.88 for MRI. The positive predictive value was 0.85 and the negative predictive value was only 0.68. These values are very similar to those in other recent surveys. These findings and the reviewed publications all indicate that MRI cannot replace arthroscopy. Special coils and MRI-arthrography can significantly enhance the specificity and the sensitivity. A negative MRI is not an endpoint and not a contraindication for further exploration, in particular for arthroscopy. ",0
3046,16185208,The role of alcohol-specific socialization in adolescents' drinking behaviour,"To determine which alcohol-specific socialization practices are related to adolescents' alcohol use, and to investigate whether parents differ in their alcohol-specific socialization towards their children. In a sample of 428 families, both parents and two adolescents (aged 13-16 years) completed a questionnaire at home about alcohol-specific parenting and their own alcohol use. Based on the reports of each family member, three different models of alcohol-specific socialization were formulated: from the perspective of the siblings, the mother and the father. Results of structural equation modelling generally showed the same associations between alcohol-specific socialization and drinking of younger and older adolescents. The strongest association was found for providing alcohol-specific rules. Applying strict rules about alcohol use was negatively related to adolescents' alcohol use; this was also the case for having confidence in the effectiveness of alcohol-specific socialization. Unexpectedly, frequency of communication about alcohol issues was positively associated with alcohol consumption of adolescents. This study is one of the first to examine associations between alcohol-specific socialization and adolescents' drinking using a between- and a within-family design. Results showed strong associations between alcohol-specific socialization (particularly of enforcing rules) and adolescent alcohol use. Although parents strongly differentiated their socialization practices between children, no differences in associations between alcohol-specific socialization and drinking were found between older and younger adolescents. ",0
3047,16185343,Synthetic vascular prosthesis impregnated with genetically modified bone marrow cells produced recombinant proteins,"The aim of this study is to develop an experimental model of small caliber expanded polytetrafluoroethylene (ePTFE) vascular prostheses that produce recombinant proteins by seeding genetically modified bone marrow mesenchymal stem cells (MSC). Beta-galactosidase (beta-gal) cDNA was transduced into rat MSC mediated by an adenovirus vector. The cells were impregnated into the ePTFE vascular prostheses measuring 2 mm in internal diameter and 90 microm in fibril length, followed by 48 h of incubation. The expressions of beta-gal were determined by X-gal staining. The luminal surface of the ePTFE vascular prostheses was covered with the MSC expressing beta-gal. Most of the gene-transduced MSC spread along the fibers forming colonies. These results suggest that small caliber vascular prostheses, in which the inner surface was seeded by genetically modified MSC, produced recombinant proteins. This may be a preliminary model to autocrine functioning vascular prostheses. ",0
3048,16185835,A sudden C3-C4 tetraplegia revealing an intracranial dural arteriovenous draining into the spinal medullary veins],"We report a case of intracranial dural arteriovenous (DAVF) draining into the spinal medullary veins. A 49-year-old woman presented a rapidly progressive ascending myelopathy resulting in a C3-C4 tetraplegia associated with acute respiratory failure at the twelfth hour. MRI revealed swelling of the cervical spinal cord, hyperintensity on T2 and enhancement of enlarged veins on MR angiography. A conventional angiography showed the DAVF with venous drainage into the spinal vein extending to the conus medullaris. After embolization, neurological recovery occurred during the first week, allowing tracheal extubation on day 2. Clinical, radiological and therapeutic aspects of this uncommon pathology are presented. ",0
3049,16185854,Hydatid liver disease revealed by surgical acute abdominal syndrome],"Hepatic hydatid disease is an uncommon surgical emergency. We report an observation and its diagnosis and treatment. An algerian child consulted in emergency unit for appendicitis syndrome. The surgeon discovered an opened hydatid liver cyst. He performed a cystectomy associated with post-operative chemotherapy. Hepatic hydatid disease is frequent in endemic zone. If not complicated, it is often revealed by hepatomegaly. The diagnosis is radiological and mainly serological. Management is medicosurgical. Prognosis depends on early surgical management. Long-time serological and echographic follow-up is required. ",0
3050,16185863,Novel and expanded jadomycins incorporating non-proteogenic amino acids,"Jadomycin B is a secondary metabolite produced, in response to stress, by Streptomyces venezuelae ISP5230 grown in nutrient-deprived media. We present definitive electrospray ionization mass spectrometry data identifying a series of novel jadomycins with non-proteogenic amino acids incorporated into the oxazolone ring of the secondary metabolite, and strengthening evidence for the existence of an aldimine intermediate in the biosynthetic pathway. We also demonstrate that the size of the oxazolone ring can be expanded by incorporating beta-amino acids. ",0
3051,16185951,Mapping of a macular drusen susceptibility locus in rhesus macaques to the homologue of human chromosome 6q14-15,"Rhesus macaques (Macaca mulatta) are a natural model for retinal drusen formation. The present study aimed at clarifying whether chromosomal regions homologous to candidate genes for drusen formation and progression in humans are also associated with a drusen phenotype in rhesus macaques. Some 42 genetic markers from seven chromosomal regions implicated in macular degeneration syndromes in humans were tested for whether they identified homologous, polymorphic sequences in rhesus DNA. This was found to be the case for seven markers, all of which were subsequently screened for the presence of potentially disease-predisposing alleles in 52 randomly chosen adult animals from the Cayo Santiago population of rhesus macaques (Caribbean Primate Research Center, PR, USA). The high drusen prevalence expected in the Cayo Santiago colony was confirmed in our sample in that 38 animals were found to have drusen (73%). Logistic regression analysis revealed that some alleles of the rhesus homologue of anonymous human marker D6S1036 were consistently over-represented among affected animals. Of two candidate genes located in the respective region, allelic variation in one (IMPG1) showed strong association with drusen formation. We conclude that one or more genes located at the rhesus homologue of human 6q14-15 are likely to play a role in retinal drusen formation, a finding that represents a first step towards the identification of genetic factors implicated in macular drusen formation in rhesus macaques. This is an important tool for the separation of genetic and environmental factors which must occur before satisfactory management methods can be developed. ",0
3052,16186034,The out-of body experience: precipitating factors and neural correlates,"Out-of-body experiences (OBEs) are defined as experiences in which a person seems to be awake and sees his body and the world from a location outside his physical body. More precisely, they can be defined by the presence of the following three phenomenological characteristics: (i) disembodiment (location of the self outside one's body); (ii) the impression of seeing the world from an elevated and distanced visuo-spatial perspective (extracorporeal, but egocentric visuo-spatial perspective); and (iii) the impression of seeing one's own body (autoscopy) from this perspective. OBEs have fascinated mankind from time immemorial and are abundant in folklore, mythology, and spiritual experiences of most ancient and modern societies. Here, we review some of the classical precipitating factors of OBEs such as sleep, drug abuse, and general anesthesia as well as their neurobiology and compare them with recent findings on neurological and neurocognitive mechanisms of OBEs. The reviewed data suggest that OBEs are due to functional disintegration of lower-level multisensory processing and abnormal higher-level self-processing at the temporo-parietal junction. We argue that the experimental investigation of the interactions between these multisensory and cognitive mechanisms in OBEs and related illusions in combination with neuroimaging and behavioral techniques might further our understanding of the central mechanisms of corporal awareness and self-consciousness much as previous research about the neural bases of complex body part illusions such as phantom limbs has done. ",0
3053,16186239,Restoration of virulence of escape mutants of H5 and H9 influenza viruses by their readaptation to mice,"Antigenic mapping of the haemagglutinin (HA) molecule of H5 and H9 influenza viruses by selecting escape mutants with monoclonal anti-HA antibodies and subjecting the selected viruses to immunological analysis and sequencing has previously been performed. The viruses used as wild-type strains were mouse-adapted variants of the original H5 and H9 isolates. Phenotypic characterization of the escape mutants revealed that the amino acid change in HA that conferred resistance to a monoclonal antibody was sometimes associated with additional effects, including decreased virulence for mice. In the present study, the low-virulence H5 and H9 escape mutants were readapted to mice. Analysis of the readapted variants revealed that the reacquisition of virulence was not necessarily achieved by reacquisition of the wild-type HA gene sequence, but was also associated either with the removal of a glycosylation site (the one acquired previously by the escape mutant) without the exact restoration of the initial wild-type amino acid sequence, or, for an H5 escape mutant that had no newly acquired glycosylation sites, with an additional amino acid change in a remote part of the HA molecule. The data suggest that such 'compensating' mutations, removing the damaging effects of antibody-selected amino acid changes, may be important in the course of influenza virus evolution. ",0
3054,16186494,Structure and reactivity of hydroxypropylphosphonic acid epoxidase in fosfomycin biosynthesis by a cation- and flavin-dependent mechanism,"The biosynthesis of fosfomycin, an oxirane antibiotic in clinical use, involves a unique epoxidation catalyzed by (S)-2-hydroxypropylphosphonic acid epoxidase (HPPE). The reaction is essentially dehydrogenation of a secondary alcohol. A high-resolution crystallographic analysis reveals that the HPPE subunit displays a two-domain combination. The C-terminal or catalytic domain has the cupin fold that binds a divalent cation, whereas the N-terminal domain carries a helix-turn-helix motif with putative DNA-binding helices positioned 34 A apart. The structure of HPPE serves as a model for numerous proteins, of ill-defined function, predicted to be transcription factors but carrying a cupin domain at the C terminus. Structure-reactivity analyses reveal conformational changes near the catalytic center driven by the presence or absence of ligand, that HPPE is a Zn(2+)/Fe(2+)-dependent epoxidase, proof that flavin mononucleotide is required for catalysis, and allow us to propose a simple mechanism that is compatible with previous experimental data. The participation of the redox inert Zn(2+) in the mechanism is surprising and indicates that Lewis acid properties of the metal ions are sufficient to polarize the substrate and, aided by flavin mononucleotide reduction, facilitate the epoxidation. ",0
3055,16186632,Monoamine oxidase a polymorphism in Brazilian patients: risk factor for late-onset Alzheimer's disease?,"Different studies have attempted to find polymorphisms involved in the serotonergic pathway that could be involved in mood disorders and late-onset Alzheimer's disease (LOAD) symptoms. Here, we compared the frequency of two polymorphisms: monoamine oxidase A (MAOA) and serotonin transporter in LOAD patients versus controls. No evidence of association was observed when these polymorphisms were compared separately; however, the combination of the MAOA allele 1+the short allele of 5-HTTLPR+ApoE-epsilon4 was significantly more frequent in patients than in controls. It reinforces the hypothesis that different genes acting together might play a role in AD susceptibility. Based on these data, we suggest replicating these studies in larger samples of LOAD patients belonging to different ethnic groups. ",0
3056,16186637,National guidelines for the use of antibiotics in hospitalised adult patients: the SWAB guidelines revisited,"Since 1996, the Dutch Working Party on Antibiotic Policy (Stichting Werkgroep AntibioticaBeleid, SWAB) has been developing national guidelines for the use of antibiotics in hospitalised adult patients. As a result of both an inventory of the wishes of the users of these guidelines and the recently developed criteria for evidence-based guideline development, we have revised our format for the development of SWAB guidelines. By involving the members of the relevant professional societies and giving them the opportunity to comment on the guidelines at an early stage, we are aiming for a successful implementation of the guidelines in the hospitals. ",0
3057,16207849,Cost-effectiveness of implantable cardioverter-defibrillators,"BACKGROUND: Eight randomized trials have evaluated whether the prophylactic use of an implantable cardioverter-defibrillator (ICD) improves survival among patients who are at risk for sudden death due to left ventricular systolic dysfunction but who have not had a life-threatening ventricular arrhythmia. We assessed the cost-effectiveness of the ICD in the populations represented in these primary-prevention trials. METHODS: We developed a Markov model of the cost, quality of life, survival, and incremental cost-effectiveness of the prophylactic implantation of an ICD, as compared with control therapy, among patients with survival and mortality rates similar to those in each of the clinical trials. We modeled the efficacy of the ICD as a reduction in the relative risk of death on the basis of the hazard ratios reported in the individual clinical trials. RESULTS: Use of the ICD increased lifetime costs in every trial. Two trials--the Coronary Artery Bypass Graft (CABG) Patch Trial and the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)--found that the prophylactic implantation of an ICD did not reduce the risk of death and thus was both more expensive and less effective than control therapy. For the other six trials--the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I, MADIT II, the Multicenter Unsustained Tachycardia Trial (MUSTT), the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)--the use of an ICD was projected to add between 1.01 and 2.99 quality-adjusted life-years (QALY) and between 68,300 dollars and 101,500 dollars in cost. Using base-case assumptions, we found that the cost-effectiveness of the ICD as compared with control therapy in these six populations ranged from 34,000 dollars to 70,200 dollars per QALY gained. Sensitivity analyses showed that this cost-effectiveness ratio would remain below 100,000 dollars per QALY as long as the ICD reduced mortality for seven or more years. CONCLUSIONS: Prophylactic implantation of an ICD has a cost-effectiveness ratio below 100,000 dollars per QALY gained in populations in which a significant device-related reduction in mortality has been demonstrated.",0
3058,16221779,"Asbestos exposure, pleural mesothelioma, and serum osteopontin levels","BACKGROUND: We investigated the presence of osteopontin in pleural mesothelioma and determined serum osteopontin levels in three populations: subjects without cancer who were exposed to asbestos, subjects without cancer who were not exposed to asbestos, and patients with pleural mesothelioma who were exposed to asbestos. METHODS: A group of 69 subjects with asbestos-related nonmalignant pulmonary disease were compared with 45 subjects without exposure to asbestos and 76 patients with surgically staged pleural mesothelioma. Tumor tissue was examined for osteopontin by immunohistochemical analysis, and serum osteopontin levels were measured by an enzyme-linked immunosorbent assay. RESULTS: There were no significant differences in mean (+/-SE) serum osteopontin levels between age-matched subjects with exposure to asbestos and subjects without exposure to asbestos (30+/-3 ng per milliliter and 20+/-4 ng per milliliter, respectively; P=0.06). In the group with exposure to asbestos, elevated serum osteopontin levels were associated with pulmonary plaques and fibrosis (56+/-13 ng per milliliter) but not with normal radiographic findings (21+/-5 ng per milliliter), plaques alone (23+/-3 ng per milliliter), or fibrosis alone (32+/-7 ng per milliliter) (P=0.004). Serum osteopontin levels were significantly higher in the group with pleural mesothelioma than in the group with exposure to asbestos (133+/-10 ng per milliliter vs. 30+/-3 ng per milliliter, P<0.001). Immunohistochemical analysis revealed osteopontin staining of the tumor cells in 36 of 38 samples of pleural mesothelioma. An analysis of serum osteopontin levels comparing the receiver-operating-characteristic curve in the group exposed to asbestos with that of the group with mesothelioma had a sensitivity of 77.6 percent and a specificity of 85.5 percent at a cutoff value of 48.3 ng of osteopontin per milliliter. Subgroup analysis comparing patients with stage I mesothelioma with subjects with exposure to asbestos revealed a sensitivity of 84.6 percent and a specificity of 88.4 percent at a cutoff value of 62.4 ng of osteopontin per milliliter. CONCLUSIONS: Serum osteopontin levels can be used to distinguish persons with exposure to asbestos who do not have cancer from those with exposure to asbestos who have pleural mesothelioma.",0
3059,16236740,Severe expressive-language delay related to duplication of the Williams-Beuren locus,"The Williams-Beuren syndrome (WBS) locus, at 7q11.23, is prone to recurrent chromosomal rearrangements, including the microdeletion that causes WBS, a multisystem condition with characteristic cardiovascular, cognitive, and behavioral features. It is hypothesized that reciprocal duplications of the WBS interval should also occur, and here we present such a case description. The most striking phenotype was a severe delay in expressive speech, in contrast to the normal articulation and fluent expressive language observed in persons with WBS. Our results suggest that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities.",0
3060,16250048,Human monoclonal antibodies that react with the E2 glycoprotein of hepatitis C virus and possess neutralizing activity,"""Active and/or passive immunoprophylaxis against hepatitis C virus (HCV) remain unachieved goals. Monoclonal antibodies might provide one approach to protection. We derived human monoclonal antibodies from the bone marrow of a patient with a well-controlled HCV infection of 22 years duration. Five distinct antibodies reactive with the E2 glycoprotein of the homologous 1a strain of HCV were recovered as antigen-binding fragments (FAbs). They demonstrated affinity constants as high as 2 nanomolar. """"Neutralization of binding"""" titers paralleled the affinity constants. All five FAbs reacted with soluble E2 protein only in nonreducing gels, indicating that the relevant epitopes were conformational. The FAbs could be divided into two groups, based on competition analysis. Three of the FAbs neutralized the infectivity of pseudotyped virus particles (pp) bearing the envelope glycoproteins of the homologous HCV strain (genotype 1a). The three FAbs also neutralized genotype 1b pp and one also neutralized genotype 2a pp. In conclusion, one or more of these monoclonal antibodies may be useful in preventing infections by HCV belonging to genotype 1 or 2, the most medically important genotypes worldwide.""",0
3061,16250049,Early intrahepatic antigen-specific retention of na?ve CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice,"We have previously shown that na?ve CD8+ T cells recognizing their cognate antigen within the liver are retained and undergo activation in situ, independent from lymphoid tissues. Intrahepatic primary T cell activation results in apoptosis and may play a crucial role in the ability of the liver to induce tolerance. Although adhesion molecules required for intrahepatic retention of T cells that have undergone previous extra-hepatic activation have been characterized, adhesive interactions involved in selective antigen-dependent intrahepatic retention of na?ve CD8+ T cells have not been investigated. By adoptively transferring radiolabeled T cell receptor (TCR)-transgenic CD8+ T cells into recipient animals ubiquitously expressing the relevant antigen, we show that 40% to 60 % of donor antigen-specific na?ve CD8+ T cells were retained in the liver within 1 hour after transfer, despite ubiquitous expression of the antigen. Intravital microscopy showed that most donor na?ve T cells slowed down and were irreversibly retained intrahepatically within the first few minutes after adoptive transfer, strongly suggesting that they were directly activated by liver cells in situ. This process was largely dependent on LFA-1 and ICAM-1, but was independent of blocking with antibodies against VCAM-1, alpha4 integrin, P-selectin, VAP-1, and beta1 integrin. ICAM-2 seemed to play only a minor role in this process. Interestingly, LFA-1 expressed by both donor T cells and liver cells was involved in retention of the antigen-reactive T cells. In conclusion, LFA-1-dependent intrahepatic T cell retention and activation are linked events that may play a crucial role in the establishment of liver-induced antigen-specific tolerance.",0
3062,16250053,Ethanol metabolism alters interferon gamma signaling in recombinant HepG2 cells,"We previously showed that IFNgamma signal transduction was suppressed by ethanol in recombinant HepG2 cells (VL-17A cells), which express alcohol dehydrogenase (ADH) and CYP2E1. We examined the mechanisms by which STAT1 phosphorylation is blocked by ethanol treatment in VL-17A cells. Cells were exposed to 0 or 100 mmol/L ethanol for 72 hours. STAT1 phosphorylation was determined by Western blot after 1 hour IFNgamma exposure. Reduction of STAT1 phosphorylation by ethanol was prevented in the presence of 4MP, DAS, or uric acid, indicating that the oxidative products from ethanol metabolism were partly responsible for suppression of STAT1 phosphorylation. Ethanol exposure decreased STAT1 tyrosine phosphorylation, whereas serine phosphorylation on the protein was unchanged. These effects of ethanol were mimicked by the peroxynitrite (PN) donor, SIN-1, which also blocked tyrosine, but not serine phosphorylation, on STAT1. When cells expressing either ADH (VA-13 cells) or CYP2E1 (E-47 cells) were exposed to ethanol, both ADH- and CYP2E1-generated products reduced STAT1 phosphorylation. In addition, SOCS1, a negative regulator of IFNgamma signaling and which is degraded by the proteasome, was stabilized by ethanol treatment, presumably because of inhibited proteasome activity. Furthermore, SIN-1 treatment elevated SOCS1 levels in VL-17A cells, indicating that PN has a role in SOCS1 elevation. In conclusion, under conditions of ethanol-elicited oxidative stress, PN prevents STAT1 phosphorylation by stabilization of SOCS1, and possibly by nitration of tyrosine residues in STAT1 protein.",0
3063,16251534,Effect of screening and adjuvant therapy on mortality from breast cancer,"BACKGROUND: We used modeling techniques to assess the relative and absolute contributions of screening mammography and adjuvant treatment to the reduction in breast-cancer mortality in the United States from 1975 to 2000. METHODS: A consortium of investigators developed seven independent statistical models of breast-cancer incidence and mortality. All seven groups used the same sources to obtain data on the use of screening mammography, adjuvant treatment, and benefits of treatment with respect to the rate of death from breast cancer. RESULTS: The proportion of the total reduction in the rate of death from breast cancer attributed to screening varied in the seven models from 28 to 65 percent (median, 46 percent), with adjuvant treatment contributing the rest. The variability across models in the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty associated with estimating the benefit of screening. CONCLUSIONS: Seven statistical models showed that both screening mammography and treatment have helped reduce the rate of death from breast cancer in the United States.",0
3064,16282177,Continuous positive airway pressure for central sleep apnea and heart failure,"BACKGROUND: The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial tested the hypothesis that continuous positive airway pressure (CPAP) would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure. METHODS: After medical therapy was optimized, 258 patients who had heart failure (mean age [+/-SD], 63+/-10 years; ejection fraction, 24.5+/-7.7 percent) and central sleep apnea (number of episodes of apnea and hypopnea per hour of sleep, 40+/-16) were randomly assigned to receive CPAP (128 patients) or no CPAP (130 patients) and were followed for a mean of two years. During follow-up, sleep studies were conducted and measurements of the ejection fraction, exercise capacity, quality of life, and neurohormones were obtained. RESULTS: Three months after undergoing randomization, the CPAP group, as compared with the control group, had greater reductions in the frequency of episodes of apnea and hypopnea (-21+/-16 vs. -2+/-18 per hour, P<0.001) and in norepinephrine levels (-1.03+/-1.84 vs. 0.02+/-0.99 nmol per liter, P=0.009), and greater increases in the mean nocturnal oxygen saturation (1.6+/-2.8 percent vs. 0.4+/-2.5 percent, P<0.001), ejection fraction (2.2+/-5.4 percent vs. 0.4+/-5.3 percent, P=0.02), and the distance walked in six minutes (20.0+/-55 vs. -0.8+/-64.8 m, P=0.016). There were no differences between the control group and the CPAP group in the number of hospitalizations, quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after 18 months the divergence favored the CPAP group, yet the overall event rates (death and heart transplantation) did not differ (32 vs. 32 events, respectively; P=0.54). CONCLUSIONS: Although CPAP attenuated central sleep apnea, improved nocturnal oxygenation, increased the ejection fraction, lowered norepinephrine levels, and increased the distance walked in six minutes, it did not affect survival. Our data do not support the use of CPAP to extend life in patients who have central sleep apnea and heart failure.",0
3065,16291981,Randomized trial of lifestyle modification and pharmacotherapy for obesity,"BACKGROUND: Weight-loss medications are recommended as an adjunct to a comprehensive program of diet, exercise, and behavior therapy but are typically prescribed with minimal or no lifestyle modification. This practice is likely to limit therapeutic benefits. METHODS: In this one-year trial, we randomly assigned 224 obese adults to receive 15 mg of sibutramine per day alone, delivered by a primary care provider in eight visits of 10 to 15 minutes each; lifestyle-modification counseling alone, delivered in 30 group sessions; sibutramine plus 30 group sessions of lifestyle-modification counseling (i.e., combined therapy); or sibutramine plus brief lifestyle-modification counseling delivered by a primary care provider in eight visits of 10 to 15 minutes each. All subjects were prescribed a diet of 1200 to 1500 kcal per day and the same exercise regimen. RESULTS: At one year, subjects who received combined therapy lost a mean (+/-SD) of 12.1+/-9.8 kg, whereas those receiving sibutramine alone lost 5.0+/-7.4 kg, those treated by lifestyle modification alone lost 6.7+/-7.9 kg, and those receiving sibutramine plus brief therapy lost 7.5+/-8.0 kg (P<0.001). Those in the combined-therapy group who frequently recorded their food intake lost more weight than those who did so infrequently (18.1+/-9.8 kg vs. 7.7+/-7.5 kg, P=0.04). CONCLUSIONS: The combination of medication and group lifestyle modification resulted in more weight loss than either medication or lifestyle modification alone. The results underscore the importance of prescribing weight-loss medications in combination with, rather than in lieu of, lifestyle modification.",0
3066,16291984,Sildenafil citrate therapy for pulmonary arterial hypertension,"BACKGROUND: Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung. METHODS: In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study. RESULTS: The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m. CONCLUSIONS: Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.",0
3067,16291985,Cost-effectiveness of cervical-cancer screening in five developing countries,"BACKGROUND: Cervical-cancer screening strategies that involve the use of conventional cytology and require multiple visits have been impractical in developing countries. METHODS: We used computer-based models to assess the cost-effectiveness of a variety of cervical-cancer screening strategies in India, Kenya, Peru, South Africa, and Thailand. Primary data were combined with data from the literature to estimate age-specific incidence and mortality rates for cancer and the effectiveness of screening for and treatment of precancerous lesions. We assessed the direct medical, time, and program-related costs of strategies that differed according to screening test, targeted age and frequency, and number of clinic visits required. Single-visit strategies involved the assumption that screening and treatment could be provided in the same day. Outcomes included the lifetime risk of cancer, years of life saved, lifetime costs, and cost-effectiveness ratios (cost per year of life saved). RESULTS: The most cost-effective strategies were those that required the fewest visits, resulting in improved follow-up testing and treatment. Screening women once in their lifetime, at the age of 35 years, with a one-visit or two-visit screening strategy involving visual inspection of the cervix with acetic acid or DNA testing for human papillomavirus (HPV) in cervical cell samples, reduced the lifetime risk of cancer by approximately 25 to 36 percent, and cost less than 500 dollars per year of life saved. Relative cancer risk declined by an additional 40 percent with two screenings (at 35 and 40 years of age), resulting in a cost per year of life saved that was less than each country's per capita gross domestic product--a very cost-effective result, according to the Commission on Macroeconomics and Health. CONCLUSIONS: Cervical-cancer screening strategies incorporating visual inspection of the cervix with acetic acid or DNA testing for HPV in one or two clinical visits are cost-effective alternatives to conventional three-visit cytology-based screening programs in resource-poor settings.",0
3068,16317684,"OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia","The cellular and subcellular localization and mechanism of transport of the heteromeric organic solute transporter (OST) OSTalpha-OSTbeta was examined in human and rodent epithelia. The two subunits of the transporter were expressed together in human small intestine, kidney, and liver, tissues that also express the apical sodium-dependent bile acid uptake transporter ASBT (SLC10A2). Indirect immunofluorescence microscopy localized OSTalpha and OSTbeta to the basolateral membrane of mouse, rat, and human ileal enterocytes, renal proximal tubular cells, and cholangiocytes. Transport in OSTalpha-OSTbeta-expressing Xenopus laevis oocytes was unaffected by depletion of intracellular adenosine triphosphate, or by changes in transmembrane Na(+), K(+), H(+), or Cl(-) concentration gradients. However, the oocytes demonstrated robust substrate efflux and trans-stimulation, indicating that transport occurs by facilitated diffusion. Madin Darby canine kidney cells coexpressing mouse Ostalpha and Ostbeta exhibited enhanced apical to basolateral transport of the major glycine and taurine conjugated bile acid species. In conclusion, the selective localization of OSTalpha and OSTbeta to the basolateral plasma membrane of epithelial cells responsible for bile acid and sterol reabsorption, the substrate selectivity of the transporter, and the facilitated diffusion transport mode collectively indicate that OSTalpha-OSTbeta is a key basolateral transporter for the reabsorption of these important steroid-derived molecules.",0
3069,16371633,Disciplinary action by medical boards and prior behavior in medical school,"BACKGROUND: Evidence supporting professionalism as a critical measure of competence in medical education is limited. In this case-control study, we investigated the association of disciplinary action against practicing physicians with prior unprofessional behavior in medical school. We also examined the specific types of behavior that are most predictive of disciplinary action against practicing physicians with unprofessional behavior in medical school. METHODS: The study included 235 graduates of three medical schools who were disciplined by one of 40 state medical boards between 1990 and 2003 (case physicians). The 469 control physicians were matched with the case physicians according to medical school and graduation year. Predictor variables from medical school included the presence or absence of narratives describing unprofessional behavior, grades, standardized-test scores, and demographic characteristics. Narratives were assigned an overall rating for unprofessional behavior. Those that met the threshold for unprofessional behavior were further classified among eight types of behavior and assigned a severity rating (moderate to severe). RESULTS: Disciplinary action by a medical board was strongly associated with prior unprofessional behavior in medical school (odds ratio, 3.0; 95 percent confidence interval, 1.9 to 4.8), for a population attributable risk of disciplinary action of 26 percent. The types of unprofessional behavior most strongly linked with disciplinary action were severe irresponsibility (odds ratio, 8.5; 95 percent confidence interval, 1.8 to 40.1) and severely diminished capacity for self-improvement (odds ratio, 3.1; 95 percent confidence interval, 1.2 to 8.2). Disciplinary action by a medical board was also associated with low scores on the Medical College Admission Test and poor grades in the first two years of medical school (1 percent and 7 percent population attributable risk, respectively), but the association with these variables was less strong than that with unprofessional behavior. CONCLUSIONS: In this case-control study, disciplinary action among practicing physicians by medical boards was strongly associated with unprofessional behavior in medical school. Students with the strongest association were those who were described as irresponsible or as having diminished ability to improve their behavior. Professionalism should have a central role in medical academics and throughout one's medical career.",0
3070,16374844,Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence,"The authors reviewed 77 published reports available before August 1, 2005 that examined the ability of hematopoietic cells to generate hepatocytes in the liver. A list of these publications and a synopsis of each are available on-line. We interpret the evidence provided by this data set to suggest that one or more types of hematopoietic cells may rarely acquire the hepatocyte phenotype in the liver (frequency < or =10(-4)), although the nature of the hematopoietic cells involved and the mechanisms responsible for acquisition of a hepatocyte phenotype are still controversial. Hematopoietic stem cells do not appear to be direct precursors of hepatocytes, which, instead, can be generated from cells of the macrophage-monocyte lineage. Fusion between hepatocytes and transplanted hematopoietic cells has been substantiated as a mechanism by which hepatocytes that carry a bone marrow tag are generated, but direct transdifferentiation of hematopoietic cells has not been demonstrated. In conclusion, hematopoietic cells contribute little to hepatocyte formation under either physiological or pathological conditions, although they may provide cytokines and growth factors that promote hepatocyte functions by paracrine mechanisms. Cells of the endodermal hepatocyte lineage are far more potent generators of hepatocytes than are hematopoietic cells.",0
3071,16421365,Mucus clearance and lung function in cystic fibrosis with hypertonic saline,"BACKGROUND: Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce defects in mucus clearance and airway defense. Through osmotic forces, hypertonic saline may increase the volume of airway surface liquid, restore mucus clearance, and improve lung function. METHODS: A total of 24 patients with cystic fibrosis were randomly assigned to receive treatment with inhaled hypertonic saline (5 ml of 7 percent sodium chloride) four times daily with or without pretreatment with amiloride. Mucus clearance and lung function were measured during 14-day baseline and treatment periods. RESULTS: Long-term inhalation of hypertonic saline without pretreatment with amiloride (i.e., with placebo pretreatment) resulted in a sustained (> or =8 hours) increase in 1-hour rates of mucus clearance, as compared with those with amiloride pretreatment (14.0+/-2.0 vs. 7.0+/-1.5 percent, respectively; P=0.02) and increased 24-hour rates of mucus clearance over baseline. Furthermore, inhalation of hypertonic saline with placebo improved the forced expiratory volume in one second (FEV1) between the baseline period and the treatment period (mean difference, 6.62 percent; 95 percent confidence interval, 1.6 to 11.7; P=0.02), whereas hypertonic saline with amiloride did not improve FEV1 (mean difference, 2.9 percent; 95 percent confidence interval, -2.2 to 8.0; P=0.23). Forced vital capacity (FVC), the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), and respiratory symptoms also significantly improved in patients treated with hypertonic saline and placebo, whereas the residual volume as a proportion of total lung capacity (RV:TLC) did not change in either group. A comparison of the changes in lung function in the two groups showed no significant difference. In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit. CONCLUSIONS: In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease.",0
3072,16436765,Ethnic and racial differences in the smoking-related risk of lung cancer,"BACKGROUND: There is remarkable variation in the incidence of lung cancer among ethnic and racial groups in the United States. METHODS: We investigated differences in the risk of lung cancer associated with cigarette smoking among 183,813 African-American, Japanese-American, Latino, Native Hawaiian, and white men and women in the Multiethnic Cohort Study. Our analysis included 1979 cases of incident lung cancer identified prospectively over an eight-year period, between baseline (1993 through 1996) and 2001. RESULTS: The risk of lung cancer among ethnic and racial groups was modified by the number of cigarettes smoked per day. Among participants who smoked no more than 30 cigarettes per day, African Americans and Native Hawaiians had significantly greater risks of lung cancer than did the other groups. Among those who smoked no more than 10 and those who smoked 11 to 20 cigarettes per day, relative risks ranged from 0.21 to 0.39 (P<0.001) among Japanese Americans and Latinos and from 0.45 to 0.57 (P<0.001) among whites, as compared with African Americans. However, at levels exceeding 30 cigarettes per day, these differences were not significant. Differences in risk associated with smoking were observed among both men and women and for all histologic types of lung cancer. CONCLUSIONS: Among cigarette smokers, African Americans and Native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans, and Latinos.",0
3073,16440368,Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger,"Canalicular bile is modified along bile ducts through reabsorptive and secretory processes regulated by nerves, bile salts, and hormones such as secretin. Secretin stimulates ductular cystic fibrosis transmembrane conductance regulator (CFTR)-dependent Cl- efflux and subsequent biliary HCO3- secretion, possibly via Cl-/HCO3- anion exchange (AE). However, the contribution of secretin to bile regulation in the normal rat, the significance of choleretic bile salts in secretin effects, and the role of Cl-/HCO3- exchange in secretin-stimulated HCO3- secretion all remain unclear. Here, secretin was administered to normal rats with maintained bile acid pool via continuous taurocholate infusion. Bile flow and biliary HCO3- and Cl- excretion were monitored following intrabiliary retrograde fluxes of saline solutions with and without the Cl- channel inhibitor 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) or the Cl-/HCO3- exchange inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Secretin increased bile flow and biliary excretion of HCO3- and Cl-. Interestingly, secretin effects were not observed in the absence of taurocholate. Whereas secretin effects were all blocked by intrabiliary NPPB, DIDS only inhibited secretin-induced increases in bile flow and HCO3- excretion but not the increased Cl- excretion, revealing a role of biliary Cl-/HCO3- exchange in secretin-induced, bicarbonate-rich choleresis in normal rats. Finally, small hairpin RNA adenoviral constructs were used to demonstrate the involvement of the Na+-independent anion exchanger 2 (AE2) through gene silencing in normal rat cholangiocytes. AE2 gene silencing caused a marked inhibition of unstimulated and secretin-stimulated Cl-/HCO3- exchange. In conclusion, maintenance of the bile acid pool is crucial for secretin to induce bicarbonate-rich choleresis in the normal rat and that this occurs via a chloride-bicarbonate exchange process consistent with AE2 function.",0
3074,16440369,C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells,"We previously demonstrated that formation of complexes between the DNA-binding domains of hepatocyte nuclear factor 6 (HNF6) and forkhead box a2 (Foxa2) proteins stimulated Foxa2 transcriptional activity. Here, we used HepG2 cell cotransfection assays to demonstrate that HNF6 transcriptional activity was stimulated by CCAAT/enhancer-binding protein alpha (C/EBPalpha), but not by the related C/EBPbeta or C/EBPdelta proteins. Formation of the C/EBPalpha-HNF6 protein complex required the HNF6 cut domain and the C/EBPalpha activation domain (AD) 1/AD2 sequences. This C/EBPalpha-HNF6 transcriptional synergy required both the N-terminal HNF6 polyhistidine and serine/threonine/proline box sequences, as well as the C/EBPalpha AD1/AD2 sequences, the latter of which are known to recruit the CREB binding protein (CBP) transcriptional coactivator. Consistent with these findings, adenovirus E1A-mediated inhibition of p300/CBP histone acetyltransferase activity abrogated C/EBPalpha-HNF6 transcriptional synergy in cotransfection assays. Co-immunoprecipitation assays with liver protein extracts demonstrate an association between the HNF6 and C/EBPalpha transcription factors and the CBP coactivator protein in vivo. Furthermore, chromatin immunoprecipitation assays with hepatoma cells demonstrated that increased levels of both C/EBPalpha and HNF6 proteins were required to stimulate association of these transcription factors and the CBP coactivator protein with the endogenous mouse Foxa2 promoter region. In conclusion, formation of the C/EBPalpha-HNF6 protein complex stimulates recruitment of the CBP coactivator protein for expression of Foxa2, a transcription factor critical for regulating expression of hepatic gluconeogenic genes during fasting.",0
3075,16447260,Therapy of hepatitis B -- viral suppression or eradication?,"The practicing clinician is currently faced with a number of treatment options for chronic hepatitis B. Beginning in 1998 with the licensing of lamivudine and subsequently adefovir, the treatment paradigm shifted from 4 to 6 months of conventional alfa interferon to a year of nucleoside analog therapy. However, prolonged treatment with nucleoside analogs is often needed to optimize virological response. Recently, a 48-week regimen of pegylated interferon for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B has been shown to be effective, and long-term nucleoside analog therapy has been demonstrated to maintain viral suppression. These findings have added to the complexity of decision-making and have raised questions about whether a finite course of pegylated interferon or nucleoside analog therapy, with possible long-term maintenance, is better as first-line therapy. Each of these fundamentally different approaches has advantages and limitations, and both have a place in the therapeutic armamentarium against chronic hepatitis B. Long-term therapy with nucleoside analogs, however, raises a number of practical concerns that have not been fully addressed as of yet. I will present evidence in support of the recommendation that antiviral therapy should ideally be directed toward achieving the highest rate of viral clearance with the shortest interval of treatment.",0
3076,16447289,The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule,"The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.",0
3077,16447292,Liver stem cells and prospects for liver reconstitution by transplanted cells,"Although it was proposed almost 60 years ago that the adult mammalian liver contains hepatic stem cells, this issue remains controversial. Part of the problem is that no specific marker gene unique to the adult hepatic stem cell has yet been identified, and regeneration of the liver after acute injury is achieved through proliferation of adult hepatocytes and does not require activation or proliferation of stem cells. Also, there are differences in the expected properties of stem versus progenitor cells, and we attempt to use specific criteria to distinguish between these cell types. We review the evidence for each of these cell types in the adult versus embryonic/fetal liver, where tissue-specific stem cells are known to exist and to be involved in organ development. This review is limited to studies directed toward identification of hepatic epithelial stem cells and does not address the controversial issue of whether stem cells derived from the bone marrow have hepatocytic potential, a topic that has been covered extensively in other recent reviews.",0
3078,16452557,Intensive insulin therapy in the medical ICU,"BACKGROUND: Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown. METHODS: In a prospective, randomized, controlled study of adult patients admitted to our medical ICU, we studied patients who were considered to need intensive care for at least three days. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]). There was a history of diabetes in 16.9 percent of the patients. RESULTS: In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P=0.009) and morbidity was also reduced. CONCLUSIONS: Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data. (ClinicalTrials.gov number, NCT00115479.)",0
3079,16481636,Calcium plus vitamin D supplementation and the risk of colorectal cancer,"BACKGROUND: Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [corrected] twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study. RESULTS: The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P=0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics. CONCLUSIONS: Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.).",0
3080,16496318,Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo,"Hepatic stellate cell activation is a main feature of liver fibrogenesis. We have previously shown that phagocytosis of apoptotic bodies by stellate cells induces procollagen alpha1 (I) and transforming growth factor beta (TGF-beta) expression in vitro. Here we have further investigated the downstream effects of phagocytosis by studying NADPH oxidase activation and its link to procollagen alpha1 (I) and TGF-beta1 expression in an immortalized human stellate cell line and in several models of liver fibrosis. Phagocytosis of apoptotic bodies in LX-1 cells significantly increased superoxide production both in the extracellular and intracellular milieus. By confocal microscopy of LX-1 cells, increased intracellular reactive oxygen species (ROS) were detected in the cells with intracellular apoptotic bodies, and immunohistochemistry documented translocation of the NADPH oxidase p47phox subunit to the membrane. NADPH oxidase activation resulted in upregulation of procollagen alpha1 (I); in contrast, TGF-beta1 expression was independent of NADPH oxidase activation. This was also confirmed by using siRNA to inhibit TGF-beta1 production. In addition, with EM studies we showed that phagocytosis of apoptotic bodies by stellate cells occurs in vivo. In conclusion, these data provide a mechanistic link between phagocytosis of apoptotic bodies, production of oxidative radicals, and the activation of hepatic stellate cells.",0
3081,16496321,Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection,"Dendritic cells (DC) of hepatitis B virus (HBV) carriers have been reported to exhibit functional impairment. Possible explanations for this phenomenon are infection of HBV by DC or alteration of DC function by HBV. We therefore analyzed whether DC support the different steps of HBV infection and replication: uptake, deposition of the HBV genome in the nucleus, antigen expression, and progeny virus release. When HBV genomes were artificially introduced into monocyte-derived DC by adenoviral vectors, low-level expression of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) but no HBV replication was detected. When monocyte-derived DC were subjected to wild-type HBV or a recombinant HBV expressing Renilla luciferase under a non-liver-specific promoter, intracellular HBV DNA was detected in a low percentage of cells. However, neither nuclear cccDNA was formed nor luciferase activity was detected, indicating that either uncoating or nucleocytoplasmic transport were blocked. To verify our observation in the in vivo situation, myeloid and plasmacytoid DC were isolated from blood of high viremic HBV carriers, and analyzed by quantitative polymerase chain reaction (PCR) and electron microscopy. Although circulating DC had in vivo been exposed to more than 10(4) HBV virions per cell, HBV genomic DNA was hardly detected, and no nuclear cccDNA was detected at all. By using electron microscopy, subviral particles were found in endocytic vesicles, but virions were undetectable as were viral capsids in the cytoplasm. In conclusion, circulating DC may take up HBV antigens, but neither support nucleocytoplasmic transport nor replication of HBV.",0
3082,16496333,The influence of T cell cross-reactivity on HCV-peptide specific human T cell response,"Detection of hepatitis C virus (HCV)-specific T cell response after exposure to hepatitis C in anti-HCV-positive or anti-HCV-negative patients has been associated with an ability to successfully control the infection. However, cross-reactivity between common human pathogens and HCV sequences has been demonstrated. The aim of this study was to investigate the impact of T cell cross-reactivity on HCV-specific T cell responses and their detection in HCV infected and non-infected subjects. The magnitude, function, and cross-reactivity of HCV peptide reactive T cells were studied in non-HCV-infected newborns and adults using a broad array of HCV peptides (601 peptides) spanning the entire HCV sequence. Comparisons were made with responses present in recovered and in chronically HCV-infected patients. HCV peptide reactive T cells are detectable in adults irrespective of previous HCV exposure and cross-reactivity between HCV peptides, and sequences of common pathogens, such as human herpes virus 1, can be demonstrated. Furthermore, the comprehensive magnitude of HCV-peptide reactive T cells present in chronically HCV-infected patients is similar and in some cases even lower than that of HCV-peptide reactive T cell response found in HCV-negative adults. In conclusion, the presence of oligo-specific HCV-peptide reactive T cells in humans does not always reflect a demonstration of previous HCV contact, whereas cross-reactivity with other common pathogens can potentially influence the HCV-specific T cell profile. The conspicuous deficit of HCV-peptide-specific T cells found in chronically HCV-infected patients confirms the profound collapse of virus-specific T cell response caused by HCV persistence.",0
3083,16496347,Zonal gene expression in murine liver: lessons from tumors,"Gene expression in hepatocytes within the liver lobule is differentially regulated along the portal to central axis; however, the mechanisms governing the processes of zonation within the lobule are unknown. A model for zonal heterogeneity in normal liver is proposed, based on observations of differential expression of genes in liver tumors from mice that harbor activating mutations in either Catnb (which codes for beta-catenin) or Ha-ras. According to the model, the regulatory control consists of two opposing signals, one delivered by endothelial cells of the central veins activating a beta-catenin-dependent pathway (retrograde signal), the other by blood-borne molecules activating Ras-dependent downstream cascades (anterograde signal). In conclusion, gradients of opposing signaling molecules along the portocentral axis determine the pattern of enzymes and other proteins expressed in hepatocytes of the periportal and pericentral domains of the liver lobule.",0
3084,16499090,Effect of protein kinase C on human melanoma A375-S2 cell death induced by evodiamine],"To study the role of PKC in evodiamine-induced A375-S2 cell death. Ratio of apoptosis induced by evodiamine was determined by TUNEL assay. MTT assay was carried out to assess cytotoxic effect of evodiamine. The influence on expression of ERK, phospho-ERK and Bcl-2 was detected by Western blotting analysis. TUNEL assay indicated that apoptosis was the type of A375-S2 cell death induced by evodiamine treatment for 24 h. Both staurosporine (inhibitor of PKC) and PD98059 (inhibitor of ERK) cooperated with evodiamine to further induce A375-S2 cell death. Evodiamine inhibited PKC activity, down-regulated the expression of ERK, phospho-ERK and Bcl-2, and staurosporine was capable of augmenting these effects induced by evodiamine. PKC lies upstream and exhibits regulatory effect on ERK and Bcl-2 in evodiamine-induced cell death. ",0
3085,16499101,"The leukocytic index of intoxication and some blood parameters in the evaluation of the severity of inflammatory, purulent, and pyodestructive diseases at various sites and in the determination of their prognosis]","The leukocytic index of intoxication (LII), hemoglobin, leukocytes, and lymphocytes were studied in patients with inflammatory, purulent, and pyodestructive diseases of the abdomen, lung, and soft tissues. It was shown that Lll progressively increased and the levels of lymphocytes decreased as the states deteriorated in all groups of patients, particularly in those who died due to ineffective treatment. This all testifies to the diagnostic and predictive value of these parameters and they may be wider used in the treatment of patients with inflammatory, purulent, and pyodestructive diseases at various sites. This is indicated by the values obtained by the end of treatment of patients. ",0
3086,16499438,A PEGylated fibrin patch for mesenchymal stem cell delivery,"A potential therapy for myocardial infarction is to deliver isolated mesenchymal stem cells (MSCs) to the infarcted site. A key issue with this technology is the development of a suitable system for MSC delivery. Our delivery system of interest is a fibrin-based patch used to entrap cells during polymerization. This delivery vehicle has many advantages; however the mechanical properties and the limited capacity for tailoring cell response may restrict its application. We have developed a PEGylated fibrin patch for MSC transplantation by modifying fibrinogen (Fgn) with the benzotriazole carbonate derivative of PEG to create secondary crosslinking. In this study, the chemical PEGylation of fibrinogen was verified by both amine group quantification and SDS-PAGE. The clotting characteristics and physical properties were compared between the fibrin patch and PEGylated fibrin patch. After seeding with porcine MSCs, the cell viability, morphology, and motility in the novel patch were observed. Phenotypic changes in the embedded MSCs were examined using immunohistochemistry and RT-PCR. The optimal molar ratio (PEG:Fgn = 10:1) was determined for loading MSCs in vitro into the PEGylated fibrin patch. The results suggest that our PEGylated fibrin patch increases MSC viability. Furthermore, the PEGylated fibrin causes phenotypic changes in MSCs consistent with endothelial cells. ",0
3087,16499468,Measuring end-of-life care outcomes retrospectively,"Fundamental to measuring both the processes and outcomes of end-of-life care is that one understand the context and distinct differences of that care. Measurement plays an important role in clinical assessment, research, quality improvement, and public accountability. Some of the unique challenges that confront investigators using prospective research designs to assess quality of end-of-life care can be addressed with retrospective approaches or follow-back designs. Retrospective research avoids reliance on the difficult task of prospectively identifying the terminally ill, avoids burdening very sick participants, minimizes missing data because of poor functional status, creates a clear time frame for the purpose of comparing settings of care, and is a cost-effective way to collect population-based data about individuals who have died. This paper reviews research using a retrospective design and analyzes the reliability and validity issues associated with a follow-back design. Although methodological challenges beset both prospective and retrospective data collection, use of both methods in combination or in sequence provides a clearer understanding of the complex, multidimensional issues involved in providing care to dying individuals. ",0
3088,16499568,Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H,"The complement system participates in both innate and acquired immune responses. Deficiencies in any of the protein components of this system are generally uncommon and require specialized services for diagnosis. Consequently, complement deficiencies are clinically underscored and may be more common than is normally estimated. As C3 is the major complement component and participates in all three pathways of activation, it is fundamental to understand all the clinical consequences observed in patients for which this protein is below normal concentration or absent in the serum. C3 deficiencies are generally associated with higher susceptibility to severe infections and in some cases with autoimmune diseases such as systemic lupus erythematosus. Here, we review the main clinical aspects and the molecular basis of primary C3 deficiency as well as the mutations in the regulatory proteins factor I and factor H that result in secondary C3 deficiencies. We also discuss the use of animal models to study these deficiencies. ",0
3089,16499594,Risk factors for reduced areal bone mineral density in young adults with stem cell transplantation in childhood,"Slightly, but significantly, reduced bone mineral density (BMD) has been detected as a late effect after stem cell transplantation (SCT) performed in childhood. The aim of the study was to evaluate the risk factors of reduced BMD after SCT in childhood. We evaluated areal BMD of 16 young adults (six males, 10 females), aged 21 yr (range 15-34) by dual-energy X-ray absorptiometry at the lumbar spine, at the femoral neck, in the total hip, and in the total body. Bone turnover rate was evaluated by markers of bone formation and resorption. Six of the 16 patients had reduced BMD with a Z-score of < or = -1 at least at one measurement site. Factors associated with reduced BMD were prepubertal status at transplant (p = 0.03), delayed pubertal growth (p = 0.03), pubertal onset gonadal hormone insufficiency (p = 0.02), and female sex (p = 0.02). Surprisingly, height in SDs and lumbar spine BMD correlated negatively (p = 0.008) in those with reduced bone mass, indicating that low areal density could not be due the small size of the vertebrae. Bone turnover markers were similar for those with normal and reduced BMD. In conclusion, 38% of the SCT long-term survivors had reduced areal BMD. Prepubertal status at transplant with pubertal onset gonadal hormone insufficiency and female sex predisposed to reduced bone mass after SCT performed in childhood. ",0
3090,16500578,Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline,"Heart failure (HF) is a syndrome characterized by high mortality, frequent hospitalization, reduced quality of life, and a complex therapeutic regimen. Knowledge about HF is accumulating so rapidly that individual clinicians may be unable to readily and adequately synthesize new information into effective strategies of care for patients with this syndrome. Trial data, though valuable, often do not give direction for individual patient management. These characteristics make HF an ideal candidate for practice guidelines. The 2006 Heart Failure Society of America comprehensive practice guideline addresses the full range of evaluation, care, and management of patients with HF. ",0
3091,16501005,Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro,"Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V(max) was 8.0 and 17.0 nmol/min/nmol enzyme and K(m,u) was 0.21 and 0.21 muM, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >or=1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 +/- 9.8 ml/min/mg protein and 6.1 +/- 3.6 ml/min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney. ",0
3092,16501846,Multimodal immunosuppressant therapy in steroid-refractory common variable immunodeficiency sprue: a case report complicating cytomegalovirus infection,"Immunodeficient patients can develop malabsorption, mimicking celiac disease clinically and histologically. Such individuals may also occasionally require immunosuppressive therapy for autoimmune disorders. We have identified a patient with common variable immunodeficiency (CVID)-associated sprue complicated by duodenal cytomegalovirus (CMV) infection following corticosteroid and ancillary immunomodulatory therapy. Ganciclovir and a modification of the immunosuppressant regimen improved both clinical symptoms and villous atrophy. To our knowledge, this is original documentation of duodenal CMV infection secondary to immunomodulatory therapy for steroid-refractory CVID-sprue. ",0
3093,16501932,Development of a process for the production of the anticancer lead compound pleurotin by fermentation of Hohenbuehelia atrocaerulea,"Pleurotin is a naphthoquinone antibiotic originally isolated from Pleurotus griseus. Two pleurotin producing strains of Hohenbuehelia atrocaerulea have been identified, which, on solid substrate fermentation for 2 months yield 1-2 mg/l of the antibiotic. Described here is the lengthy developmental process which resulted in a production protocol being developed which reliably yields pleurotin from liquid fermentation at >300 mg/l. Critical to obtaining this increase in titer was inclusion in the media of an aqueous extract of alder wood. ",0
3094,16503323,Formation of rectus sheath hematoma with antibiotic use and warfarin therapy: a case report,"This case is reported to inform physicians of a case of amoxicillin/clavulanate potassium use in a patient taking warfarin and the subsequent alteration (prolongation) in the international normalized ratio (INR) that resulted in the formation of a rectus sheath hematoma (RSH). A 75-year-old man receiving long-term warfarin therapy developed a lower respiratory tract infection with paroxysmal coughing that was treated with oral amoxicillin 250 mg/clavulanate potassium 125 mg TID for 7 days. In the 3 days after completing antibiotic treatment, he developed increasingly severe lower abdominal pain that was clinically diagnosed as RSH. The patient was admitted to the local hospital for confirmation of the diagnosis and appropriate management. Before this episode, his INR was consistently within therapeutic range (2-3); on admission it had risen to 5.7. His condition was managed conservatively, and he was discharged home 6 days postadmission. This case is reported to highlight the potential interaction between warfarin and amoxicillin/clavulanate potassium and subsequent RSH formation. The potential mechanism of the interaction between amoxicillin/clavulanate potassium and warfarin may be either pharmacokinetic (via metabolism in the cytochrome P4S0 system and preferential metabolism of clavulanate potassium in the liver) or pharmacodynamic (via interference with the production of vitamin K-dependent clotting factors II, VI, IX, and X). This case of RSH in an elderly patient receiving long-term stable warfarin anticoagulation is probably associated with amoxicillin/clavulanate potassium use and paroxysmal coughing. ",0
3095,16503355,Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes,"Cannabinoids have been shown to influence the immune system. However, their immunomodulatory effects have not been extensively studied. In this investigation, we have observed that both primary and Jurkat T cells express a functional cannabinoid receptor 2 (CB(2)). Furthermore, both the synthetic cannabinoids CP55,940 and WIN55,212-2, as well as the CB(2)-selective agonist JWH-015, caused a significant inhibition of the chemokine CXCL12-induced and CXCR4-mediated chemotaxis of Jurkat T cells, as well as their transendothelial migration. Involvement of the CB(2) receptor was further confirmed by partial reversal of the inhibition using the CB(2)-specific antagonist, AM630. Similarly, CP55,940 and JWH-015 inhibited the CXCL12-induced chemotaxis of primary CD4(+) and CD8(+) T lymphocytes. Further investigation of signaling studies to delineate the mechanism of inhibition revealed that cannabinoids enhance CXCL12-induced p44/42 MAP kinase activity. However, enhanced MAP kinase activity was not responsible for the inhibition of chemotaxis. This suggests that cannabinoids differentially regulate CXCR4-mediated migration and MAP kinase activation in T cells. Cannabinoids were also found to downregulate the PMA-enhanced enzyme activity of matrix metalloproteinase-9, which is known to play an important role in transendothelial migration. This study provides novel information regarding cannabinoid modulation of functional effects in T cells. ",0
3096,16503578,Population-response model for vibrotactile spatial summation,"A computational model based on previous physiological and psychophysical data is presented for the human Pacinian (P) psychophysical channel. The model can predict the probability of detection in simple psychophysical tasks, and hence psychometric functions and thresholds. The model simulates stimulating variable and fixed glabrous skin sites with different-sized contactors and includes spatial variation of monkey P-fiber sensitivities. Therefore, it is especially suitable for studying spatial summation, i.e. the improvement of threshold with increasing contactor area. Selective contributions of neural integration (n.i.) and probability summation (p.s.) are also incorporated into the model. Model predictions are compared to psychophysical results of Gescheider et al. (2005). The performance of the model regarding the effects of contactor size is very good. In addition to predicting approximately 3 dB improvement of thresholds when the contactor area is doubled, the model also reveals nonlinear contributions of p.s. and n.i. Furthermore, the model asserts that thresholds are largely governed by neural integration when small contactors are used. These and other findings discussed in the article show that the presented model is a helpful tool for formulating testable hypotheses. Although the model can also simulate some temporal summation effects, simulation results do not conform well to previous data on temporal response properties. Thus, the model needs to be refined in that respect. ",0
3097,16503714,Daptomycin for the treatment of gram-positive bacteremia and infective endocarditis: a retrospective case series of 31 patients,"To evaluate the outcomes in patients with bacteremia and/or infective endocarditis who were treated with daptomycin. Retrospective chart review. A university-affiliated medical center in Chicago, Illinois, and a regional hospital in Fountain Valley, California. Thirty-one inpatients treated with daptomycin for bacteremia and/or infective endocarditis. Patients were given daptomycin 4-6 mg/kg intravenously every 24-48 hours based on the practitioner's discretion and depending on the patient's clinical condition and presence of comorbidities. Primary end points were resolution of signs and symptoms of infection and discharge from the hospital. Methicillin-resistant Staphylococcus aureus ([MRSA] 11 patients) and vancomycin-resistant entercocci ([VRE] 11 patients) were the most common pathogens, whereas 7 patients had methicillin-sensitive S. aureus infection and 1 patient had coagulasenegative Staphylococcus infection. One patient with endocarditis had a negative culture result. Overall, 24 (77%) of the 31 patients achieved clinical resolution and were discharged, including all patients infected with MRSA; 7 patients died, 6 of whom had VRE infection. Duration of treatment for infective endocarditis lasted longer (typically 22-43 days) than that for bacteremia only (< or = 14 days), and no patients discontinued daptomycin because of adverse events. In these patients, daptomycin was safe and well tolerated even for extended durations of treatment. Daptomycin may provide an effective option for treating drug-resistant gram-positive bloodstream infections and endocarditis. ",0
3098,16503738,"Fluarix, inactivated split-virus influenza vaccine","Influenza is a potentially fatal respiratory infection resulting from several influenza virus strains. It causes annual epidemics of disease for which vaccination is the cornerstone of public health policy. The inadequacies of vaccine supply in the US during the 2004 influenza season revealed the deficiencies of current vaccine development and delivery. One outcome of this was the accelerated approval of an inactivated split-virus influenza vaccine, Fluarix. This paper reviews the immunogenicity and reactogenicity of this vaccine, and makes recommendations for the incorporation of Fluarix into the public health framework alongside other similar vaccines. Other directions to explore in an effort to secure future vaccine supply are considered. ",0
3099,16504110,Can electronic search engines optimize screening of search results in systematic reviews: an empirical study,"Most electronic search efforts directed at identifying primary studies for inclusion in systematic reviews rely on the optimal Boolean search features of search interfaces such as DIALOG and Ovid. Our objective is to test the ability of an Ultraseek search engine to rank MEDLINE records of the included studies of Cochrane reviews within the top half of all the records retrieved by the Boolean MEDLINE search used by the reviewers. Collections were created using the MEDLINE bibliographic records of included and excluded studies listed in the review and all records retrieved by the MEDLINE search. Records were converted to individual HTML files. Collections of records were indexed and searched through a statistical search engine, Ultraseek, using review-specific search terms. Our data sources, systematic reviews published in the Cochrane library, were included if they reported using at least one phase of the Cochrane Highly Sensitive Search Strategy (HSSS), provided citations for both included and excluded studies and conducted a meta-analysis using a binary outcome measure. Reviews were selected if they yielded between 1000-6000 records when the MEDLINE search strategy was replicated. Nine Cochrane reviews were included. Included studies within the Cochrane reviews were found within the first 500 retrieved studies more often than would be expected by chance. Across all reviews, recall of included studies into the top 500 was 0.70. There was no statistically significant difference in ranking when comparing included studies with just the subset of excluded studies listed as excluded in the published review. The relevance ranking provided by the search engine was better than expected by chance and shows promise for the preliminary evaluation of large results from Boolean searches. A statistical search engine does not appear to be able to make fine discriminations concerning the relevance of bibliographic records that have been pre-screened by systematic reviewers. ",0
3100,16504226,Studies on the late steps of (+) pisatin biosynthesis: evidence for (-) enantiomeric intermediates,"Pisatin, a 6a-hydroxyl-pterocarpan phytoalexin from pea (Pisum sativum L.), is relatively unique among naturally occurring pterocarpans by virtue of the (+) stereochemistry of its 6a-11a C-C bond. However, pisatin synthesizing pea tissue has an isoflavone reductase, first identified in alfalfa, which acts on the (-) antipode. In order to establish the natural biosynthetic pathway to (+) pisatin, and to evaluate the possible involvement of intermediates with a (-) chirality in its biosynthesis, we administered chiral, tritium-labeled, isoflavanones and pterocarpans to pisatin-synthesizing pea cotyledons and compared the efficiency of their incorporation. Pea incorporated the isoflavanone, (-) sophorol, more efficiently than either its (+) antipode, or the pterocarpans (+) or (-) maackiain. (-) Sophorol was also metabolized by protein extracts from pisatin-synthesizing pea seedlings in a NADPH-dependent manner. Three products were produced. One was the isoflavene (7,2'-dihydroxy-4',5'-methylenedioxyisoflav-3-ene), and another had properties consistent with the isoflavanol (7,2'-dihydroxy-4',5'-methylenedioxyisoflavanol), the expected product for an isoflavanone reductase. A cDNA encoding sophorol reductase was also isolated from a cDNA library made from pisatin-synthesizing pea. The cloned recombinant sophorol reductase preferred (-) sophorol over (+) sophorol as a substrate and produced 7,2'-dihydroxy-4',5'-methylenedioxyisoflavanol. Although no other intermediates in (+) pisatin biosynthesis were identified, the results lend additional support to the involvement of intermediates of (-) chirality in (+) pisatin synthesis. ",0
3101,16504518,Tricyclic pharmacophore-based molecules as novel integrin alphavbeta3 antagonists. Part IV: preliminary control of alphavbeta3 selectivity by meta-oriented substitution,"To establish the in vivo efficacy of alphavbeta3/alphaIIbbeta3 dual antagonists possessing a tricyclic pharmacophore, a corresponding alphavbeta3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain alphavbeta3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for alphavbeta3 over alphaIIbbeta3 for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an alphavbeta3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay. ",0
3102,16504759,SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation,"Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases. Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy. ",0
3103,16504837,QT dispersion: comparison between participants with Type 1 and 2 diabetes and association with microalbuminuria in diabetes,"The interlead variation of QT duration in surface electrocardiogram [ECG; QT dispersion (QTd)] has been shown to predict mortality in both diabetic and general population. Diabetic cardiac autonomic neuropathy (CAN) is a common complication of diabetes, and it is also associated with worse prognosis among the diabetic population. In this study, we investigated the association between QTd duration and CAN, as well as other complications of diabetes in participants with Types 1 and 2 diabetes. A total of 184 patients with either Type 1 (n=63) or 2 (n=121) diabetes, as well as 100 control participants, matched for age and sex with the diabetic individuals, were studied. QT and RR intervals were measured on 12 leads of resting ECG tracing. QTd was calculated semiautomatically using a computer program as the difference between the maximum and the minimum QT in any of the 12 leads. CAN was diagnosed when two out of the four classical tests were abnormal. QTd was not significantly different between controls and patients with either Type 1 or 2 diabetes. Age-adjusted QTd intervals were not significantly different between patients with Types 1 and 2 diabetes (P=.86). For both types of diabetes, no significant differences were found in QTd between patients with and without CAN. Multivariable linear regression analysis, after adjustment for a number of confounding factors, demonstrated a positive association between QTd and duration of diabetes (P=.02) in the group of the patients with Type 1 diabetes. In those with Type 2 diabetes, QTd was associated with age (P=.006) and presence of microalbuminuria (P=.001). In addition, no significant association was found with retinopathy or blood pressure levels. Age-adjusted QTd interval was not different between patients with Types 1 and 2 diabetes. CAN is not associated with QTd interval in both types of diabetes. Furthermore, microalbuminuria was found to be the strongest predictor of QTd in patients with Type 2 diabetes. Because long QTd interval predicts cardiac mortality in participants with diabetes, it is suggested that it may be a useful adjuvant index in the evaluation of cardiovascular risk in participants with Type 2 diabetes and microalbuminuria. ",0
3104,16504891,Transduodenal excision of bleeding periampullary endocrine tumor as a bridge to pancreaticoduodenectomy in a Jehovah's Witness patient,"We discuss the case of a Jehovah's Witness patient who presented with a bleeding endocrine periampullary mass. Transduodenal excision of the ampullary mass was successfully performed as a bridge to pancreaticoduodenectomy in this critically ill patient. The roles of pancreaticoduodenectomy and alternatives to pancreaticoduodenectomy in the emergency setting are reviewed, in particular, for patients who decline transfusion of blood products. The surgical approach to surgery and perioperative anemia in Jehovah's Witness patients is described. Finally, we reviewed the role of transduodenal excision in the management of ampullary tumors and describe its use as a bridge to pancreaticoduodenectomy in a patient with a malignant neoplasm of the ampulla. ",0
3105,16504926,The pharmacokinetics and acute renal effects of oral microemulsion ciclosporin A in normal pigs,"The use of ciclosporin A (CsA) is limited by nephrotoxicity. Anatomic and physiologic similarities to humans make the pig a potential important animal model for research in effects and adverse events of CsA. In a long-term study CsA 10 mg/kg/day for 6 months did not cause deterioration in renal histology or function in pigs. For ideal CsA dosage in future long-term studies of nephrotoxicity we performed this study to describe pharmacokinetics and acute effects on renal function of CsA in normal pigs. Three groups of 5 piglets comprised the material, a control group and 2 groups receiving 5 days treatment with CsA (Neoral) 15 or 30 mg/kg/day, respectively. CsA whole blood concentration (B-CsA) (hourly), renal blood flow, glomerular filtration rate (GFR) and serum creatinine were measured. The area under the curve from time 0 to 12 h was calculated using the Trapezoidal Rule. Pharmacokinetic calculations were performed using the KINFIT non-linear curve fitting module. B-CsA reached peak in median at 0.90 and 0.96 h (633 and 914 ng/ml) in the 15 and 30 mg/kg/day groups, respectively, and median AUC was 5055 and 6275 h ng/ml, respectively. Trough levels were 338 and 475 ng/ml. The distribution of CsA followed a 2-compartment model. Serum creatinine was 111 (control), 112 (15 mg/kg/day) and significantly increased to 168 ìmol/l in 30 mg/kg/day group, which also had a reduction in GFR compared to the other 2 groups. CsA causes acute nephrotoxicity in piglets. The distribution follows a 2-compartment model similar to humans, but higher doses are necessary in pigs. ",0
3106,16504968,Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage,"Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90-topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death. ",0
3107,16505006,Disrupting the enzyme complex regulating O-GlcNAcylation blocks signaling and development,"Although the knowledge that nuclear and cytoplasmic proteins are modified with N-acetylglucosamine has existed for decades, little has been shown as to its function until recently. There are now substantial data highlighting the significance of proper regulation of this modification in multiple cellular processes. Currently, only two enzymes are known that regulate this modification. O-GlcNAc transferase (OGT) modifies protein substrates posttranslationally by adding the N-acetylglucosamine. Bifunctional nuclear/cytoplasmic O-GlcNAcase and acetyl transferase (NCOAT) is responsible for cleaving the modification from target proteins. Here, we demonstrate for the first time an unusual association of these two opposing enzymes into a single O-GlcNAczyme complex. NCOAT and OGT associate strongly through specific domains such that NCOAT accompanies OGT, with histone deacetylases (HDACs), into transcription corepression complexes. Exclusion of NCOAT activities from OGT association blocks proper estrogen-dependent cell signaling as well as mammary development in transgenic mice. This demonstrates that NCOAT is in a strategic position to rapidly counteract OGT and HDAC without requiring its recruitment. ",0
3108,16505175,Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: involvement of Nox2 (gp91phox)-containing NADPH oxidase,"Nonenzymatic glycation that results in the production of early-glycation Amadori-modified proteins and advanced-glycation end products may be important in the pathogenesis of diabetic complications. However, the effects of early-glycated proteins, such as glycated serum albumin (Gly-BSA), are poorly defined. In this study, we investigated the effects of Gly-BSA on reactive oxygen species (ROS) production by cardiomyocytes. Cultured neonatal rat cardiomyocytes were incubated with Gly-BSA or vehicle (bovine serum albumin [BSA]) for up to 48 hours. Gly-BSA dose-dependently increased in situ ROS production (whole-cell dichlorodihydrofluorescein fluorescence), with an optimum effect at 400 microg/mL after 24-hour incubation (152+/-10% versus BSA 100%; P<0.01). Treatment with the NADPH oxidase inhibitor apocynin, a Nox2 (gp91phox) antisense oligonucleotide (Nox2 AS), or the peptide gp91ds-tat significantly reduced Gly-BSA-induced ROS production at 24 hours (68.5+/-2.2%, 61.4+/-8.3%, and 53.2+/-5.4% reduction, respectively). NADPH-dependent activity in cell homogenates was also significantly increased by Gly-BSA at 24 hours (161+/-8% versus BSA) and was inhibited by diphenyleneiodonium, apocynin, NOX2AS, and the protein kinase C inhibitor bisindolylmaleimide I but not by a nitric oxide synthase inhibitor or mitochondrial inhibitors. Furthermore, bisindolylmaleimide I prevented Gly-BSA-stimulated Rac1 translocation, an essential step for NADPH oxidase activation. Gly-BSA-induced increases in ROS were associated with apocynin-inhibitable nuclear translocation of nuclear factor-kappaB and an increase in atrial natriuretic factor mRNA expression. Gly-BSA stimulates cardiomyocyte ROS production through a protein kinase C-dependent activation of a Nox2-containing NADPH oxidase, which results in nuclear factor-kappaB activation and upregulation of atrial natriuretic factor mRNA. These findings suggest that early-glycated Amadori products may play a role in the development of diabetic heart disease. ",0
3109,16505232,Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance,"Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCbeta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCbeta1 and -beta2, but not PKCalpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCbeta1 and -beta2, but not PKCalpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCbeta2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCbeta in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance. ",0
3110,16506245,"""Tyrosine-based """"activatable pro-tag"""": enzyme-catalyzed protein capture and release""","""Protein recovery is often achieved by a series of capture and release steps that often involve chromatographic binding and elution. We report an alternative, non-chromatographic, capture and release approach that employs enzymes and the stimuli-responsive polysaccharide chitosan. We capture our protein using the enzyme tyrosinase that oxidizes accessible tyrosine residues of the protein and """"activates"""" these residues for covalent capture (i.e., conjugation) onto chitosan. Using fusions of green fluorescent protein (GFP) we observed that: (i) enzymatic activation is required for protein capture to chitosan; and (ii) capture is enhanced (approximately five-fold) by engineering the protein to have a penta-tyrosine fusion tag that provides additional accessible tyrosine residues for enzymatic activation. Because the fusion tag appears to be the primary site for capture, and capture requires activation, we designate penta-tyrosine as a """"pro-tag."""" The captured GFP-chitosan conjugate possesses the pH-responsive solubility that is characteristic of chitosan. We exploit this pH-responsive solubility to facilitate purification of the captured protein. Two enzymatic methods were explored to release the captured GFP from the chitosan conjugate. The first method employs enterokinase (EK) to cleave the protein at an engineered EK-cleavage site. The second method employs chitosanase to hydrolyze the chitosan backbone. Using GFP as a model protein, we demonstrated that enzymatic capture and release provides a simple, non-chromatographic means to recover proteins directly from cell lysates. """,0
3111,16506330,Forced organ donation: the presumed consent to organ donation laws of the various states and the United States Constitution,"The issues presented in this Comment pertain to whether there are substantive limits imposed by the Fourteenth Amendment upon the state legislatures which would defeat the recent, tentative steps of many states to pass laws authorizing presumed consent to organ donation. The final and perhaps least effective presumed consent law creates a presumption of consent to organ donation. The potential organ donor makes the choice whether to donate or not during his lifetime. This form of the presumed consent law would probably have the least impact on increasing the number of available donor organs. It permitted the coroner to harvest the eyes and corneas of deceased individuals if the coroner was unaware of objections from either the decedent or the family of the decedent. Presumed consent statutes should be found unconstitutional because they infringe upon a family's property interest in a deceased relative's corpse. However, due to the family's property interest in a relative's deceased body, as set forth in the next section, the result is that presumed consent statutes are unconstitutional. In order to find the presumed consent law unconstitutional, the Court would have to find that either: (a) the Fourteenth Amendment's liberty component included the family's right to determine what happens to a relative's body after death, or (b) that the property component included a vested state law property interest in the dead body. ",0
3112,16506352,Examining the relationship between bone mineral density and fracture risk reduction during pharmacologic treatment of osteoporosis,"Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes the patient to an increased risk for fracture. Elements of bone strength include bone mineralization, architecture, turnover, size, and bone mineral density (BMD). Measurement of BMD is the most readily available, noninvasive method for assessing osteoporotic fracture risk and is used by the World Health Organization for diagnostic purposes. Because low BMD is predictive of increased fracture risk, it was believed that changes in BMD during pharmacologic therapy for osteoporosis would strongly predict observed fracture risk reductions. We examined the relationship between changes in BMD and reduction in fracture risk during pharmacologic therapy in postmenopausal women with osteoporosis. The correlation between BMD increases and fracture risk reduction during treatment is not consistent; larger increases in BMD do not necessarily correlate with greater reductions in fracture risk. Multiple factors, in addition to BMD, appear to contribute to the increased bone strength and decreased fracture risk achieved with approved drug therapies for osteoporosis. Until the exact relationship of these factors is fully understood, clinicians should continue to evaluate drug efficacy for osteoporosis based on the fracture risk reductions from well-designed clinical trials. ",0
3113,16506499,Pediatric congenital atlantoaxial dislocation: differences between the irreducible and reducible varieties,"Clinicoradiological differences and outcome following surgery in pediatric patients (< or = 16 years of age) with congenital irreducible atlantoaxial dislocation (IAAD) and reducible atlantoaxial dislocation (RAAD) were analyzed. Ninety-six patients (57 with IAAD and 39 with RAAD) were categorized as follows: Grade I, no deficits except hyperreflexia or neck pain (six patients); Grade II, minor deficits but independent for activities of daily living (25); Grade III, partially dependent (30); and Grade IV, totally dependent (35). Patients with RAAD underwent direct posterior fusion, and those with IAAD were treated with transoral decompression and posterior fusion. Patients with good outcomes included those who could walk unaided, with improvement in spasticity and weakness, and those who maintained Grade I status. The category of poor outcome included patients with the following conditions: postoperative deterioration or lack of improvement; inability to ambulate regardless of neurological improvement at a minimum follow-up duration of 3 months; or perioperative death. A significantly higher incidence of C-1 assimilation, C2-3 fusion, asymmetrical occiput-C2 facet joints, and basilar invagination were seen in patients with IAAD, and os odontoideum was noted in those with RAAD (p < 0.05). A good outcome was recorded in 35 patients with IAAD and 22 with RAAD, whereas 14 with IAAD and nine with RAAD had a poor outcome (eight patients in each category were lost to follow up). Radiological differences in the anatomy of patients with IAAD and those with RAAD may be due to improper segmentation of the occipital and upper cervical sclerotomes in the former and dysfunction of the transverse ligament in the latter. A significantly better outcome was noted in completely dependent patients with IAAD compared with those with RAAD. Respiratory compromise was an important prognostic factor. ",0
3114,16506841,Effect of flavor compound chemical structure and environmental relative humidity on the binding of volatile flavor compounds to dehydrated soy protein isolates,"Influence of flavor compound chemical structure, including functional group and stereochemistry, and environmental relative humidity (RH) on the binding of volatile flavor compounds to dehydrated soy protein isolates (SPIs) was evaluated by inverse gas chromatography. Binding of selected volatile flavor compounds differed slightly between SPIs of different origins. Results showed that the flavor compound chemical structure greatly determined its binding potential to SPIs. Binding of nonpolar flavor compounds (hydrocarbon) to soy proteins was attributed mainly to nonspecific van der Waals dispersion forces and was not affected by adsorbed water. The more polar flavor compounds (ester, ketone, aldehyde, and alcohol) exhibited both specific (hydrogen bonding, dipole forces) and nonspecific interactions, and their binding with soy proteins was greatly impaired by adsorbed water in the extremely low humidity region (approaching 0% RH). Further water uptake in the 30 to 50% RH region did not significantly affect the binding of polar compounds, although sorption of alcohol compounds (when present at high levels) further increased. ",0
3115,16507082,The impact of sequence divergence and DNA mismatch repair on homeologous recombination in Arabidopsis,"We examined the effects of substrate divergence and DNA mismatch repair (MMR) on recombination in Arabidopsis thaliana. Relative to the frequency observed in plants with a homologous construct (0% divergence), recombination was decreased 4.1-, 9.6-, 11.7- or 20.3-fold, respectively, in lines with constructs containing 0.5%, 2%, 4% or 9% divergence between the recombination substrates. To evaluate the contribution of the MMR system in this decrease, 12 independent reporter lines (two or three lines per reporter construct) were crossed to an AtMSH2 T-DNA insertional mutant. We examined the recombination frequency in progeny homozygous for a reporter T-DNA and homozygous either for the wild type or the mutant allele of AtMSH2. The loss of MMR activity led to a two- to ninefold increase in homeologous recombination and the size of the increase did not seem to correlate with the amount of divergence. Inversely, complementation of the insertional mutant with a wild-type cDNA of AtMSH2 reduced recombination. Our results demonstrate clearly that sequence divergence can dramatically reduce the recombination frequency in plants and that the MMR system plays a part in this decrease. ",0
3116,16507146,Cytokine polymorphisms influence treatment outcomes in SLE patients treated with antimalarial drugs,"Antimalarial agents have been widely used as disease-modifying antirheumatic drugs in the treatment of systemic lupus erythematosus (SLE) and other rheumatological diseases, although their mechanism of action has not yet been fully defined. It is known, however, that effective response to treatment is variable among patients. Thus, the identification of genetic predictors of treatment response would provide valuable information for therapeutic intervention. The aim of the present study was to analyze the effect of antimalarial treatment on tumor necrosis factor (TNF)alpha serum levels and evaluate the possible influence of TNFalpha and IL-10 functional genetic polymorphisms on the response to antimalarial drugs. To this end, TNFalpha serum levels were quantified in 171 SLE patients and 215 healthy controls by ELISA techniques and polymorphisms at positions -1,082 and -308 of the IL-10 and TNFalpha gene promoters were determined by PCR amplification followed by hybridization with fluorescent-labeled allele-specific probes in 192 SLE patients and 343 matched controls. Data were related to clinical features and treatment at the time of sampling and during the course of the disease. Results showed a significantly higher amount of serum TNFalpha in the entire SLE population compared with controls. However, TNFalpha serum levels correlated negatively with the use of antimalarial treatment during at least three months before sampling. Patients under single or combined treatment with these drugs had TNFalpha serum levels similar to healthy controls, whereas untreated patients and those under corticosteroid or immunosuppressive therapies had increased amounts of this cytokine. This suggests, however, that antimalarial-mediated inhibition of TNFalpha was only significant in patients who were genetically high TNFalpha or low IL-10 producers. In addition, evaluation of SLE patients administered antimalarial drugs for three or more years who did not require any other specific SLE treatment indicates that patients with the combined genotype low IL-10/high TNFalpha are the best responders to antimalarial therapy, developing mild disease with a good course under this treatment. In conclusion, we proposed that an antimalarial-mediated downregulation of TNFalpha levels in SLE patients is influenced by polymorphisms at IL-10 and TNFalpha promoters. Our results may thus find important clinical application through the identification of patients who are the most likely to benefit from antimalarial therapy. ",0
3117,16507275,NCCN Task Force Report: Adjuvant Therapy for Breast Cancer,"The National Comprehensive Cancer Network (NCCN) first published the NCCN Breast Cancer Treatment Guidelines in 1996. The Guidelines address the treatment of all stages of breast cancer across the spectrum of patient care and have been updated yearly. Adjuvant therapy for breast cancer has undergone an especially rapid evolution over the past few years. Therefore, the NCCN Breast Cancer Guidelines Panel was supplemented by additional experts to form the Adjuvant Therapy Task Force to provide a forum for an extended discussion and expanded input to the adjuvant therapy recommendations for the Breast Cancer Treatment Guidelines. Issues discussed included methods of risk-stratification for recurrence; how biologic markers such as HER2 status, quantitative estrogen receptor, or genetic markers can be incorporated as prognostic or predictive factors; and how age, menopausal status, and estrogen receptor levels impact benefits from chemotherapy and endocrine therapy. Additionally, the task force discussed the strategies for use of aromatase inhibitors in postmenopausal women and the potential incorporation of trastuzumab into adjuvant therapy of women with HER2/neu positive breast cancer. This supplement summarizes the background data and ensuing discussion from the Adjuvant Task Force meeting. ",0
3118,16507380,Potential drug-drug interaction between interferon alfa-2b and gemfibrozil in a patient with malignant melanoma,"In the United States, patients with high-risk stage II or III melanoma are often treated with adjuvant interferon (IFN) therapy for 1 year after surgery. Adverse events associated with IFN alfa-2b use are primarily constitutional symptoms. However, hypertriglyceridemia requiring treatment has been reported. The aim of this report was to describe a potential drug-drug interaction between IFN alfa-2b and gemfibrozil in a patient with malignant melanoma. The possible mechanism of this potential interaction was examined. This report presents the case of a 43-year-old male patient weighing 101 kg with newly diagnosed stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient presented to the University of California Irvine Medical Center, Orange, California with severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations at week 48 of 104 of adjuvant treatment of malignant melanoma (IFN alfa 11 MU SC TIW in combination with the investigational melanoma vaccine melanoma theraccine 1.25 mL [I mL lysate + 0.25 mL vaccine adjuvant] given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104), and IFN-induced hypertriglyceridemia (gemfibrozil 600 mg PO BID). The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medication. The possible mechanism of this potential IFN alfa-gemfibrozil interaction as related to the cytochrome P450 (CYP) enzyme system was assessed. In this case of a possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID in a patient undergoing treatment for IFN-induced hypertriglyceridemia, the Naranjo Adverse Drug Reactions (ADR) Probability Scale score was 7 (ie, ADR possibly related to treatment). Both IFN and gemfibrozil inhibit the activity of the hepatic enzymes CYP1A2 and CYP2C19. A possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia. ",0
3119,16507494,Diffuse unilateral subacute neuroretinitis in Africa,"Diffuse unilateral subacute neuroretinitis (DUSN) is well known in endemic areas of the southeastern United States, South America, and the northern Midwestern United States. Two different categories of nematodes, according to their length, are related to endemic areas. We report the first case of DUSN caused by a small nematode in Africa. We describe the case of a 12-year-old Senegalese girl who presented a long-standing diffuse unilateral subacute neuroretinitis and in whom the worm could be localized. The length of the unidentified worm measured using the software of the fundus camera was approximately 600 microm. This measurement corresponds to the smaller nematode usually found in patients from the southeastern United States and South America. Diffuse unilateral subacute neuroretinitis can also be observed in patients living in Africa. ",0
3120,16507549,Clinical biomarkers of cardiac injury: cardiac troponins and natriuretic peptides,"Laboratory and clinical medicine groups are actively collaborating and optimizing their individual expertise to potentially prove standardized biomarker assays that will optimize patient care. It is critical as new biomarkers are discovered, that quality specifications be developed prior to approval by regulatory agencies that give supported endorsement for the worldwide marketplace. The laboratory medicine and clinical communities of scientists continues to challenge the biomarker field, working towards developing standard reference materials, and providing quality analytical specifications that, hopefully, will be endorsed by our clinical, in vitro diagnostic and pharmaceutical industry colleagues. This paper will specifically address cardiac troponins and natriuretic peptides. ",0
3121,16507650,"Contrary to adult, neonatal rats show pronounced brain uptake of corticosteroids","Neurotoxic adverse effects after systemic corticosteroid administration are elevated in preterm infants. To test whether this might be related to an immature blood-brain barrier (BBB) that permits corticosteroids to enter the brain and induce neurotoxic effects, this study assessed the differences in brain permeability of triamcinolone acetonide after intratracheal administration to neonatal (10- to 11-day-old) and adult rats. Triamcinolone acetonide (or the phosphate prodrug in the case of neonatal rats) was administered intratracheally to neonatal rats at doses of 2.5, 25, or 50 microg/kg and to adult rats at 100 microg/kg. An ex vivo receptor binding assay was used to monitor the cumulative brain and liver glucocorticoid receptor occupancies over 6 h. Brain and liver receptor occupancies in neonates were similar for the 25 and 50 microg/kg triamcinolone acetonide phosphate (brain/liver receptor occupancy ratio, 1.10 +/- 0.14 and 0.87 +/- 0.13, respectively), whereas some reduction in the brain permeability was seen at the lower dose. After intratracheal administration of 100 microg/kg triamcinolone acetonide to adult rats, receptor occupancies in the brain were significantly lower (brain/liver ratio, 0.21 +/- 0.14; p < 0.001). The study demonstrated that glucocorticoids enter the brain of neonatal rats because of an immature BBB. The results of this study support the hypothesis that neurotoxic adverse effects in preterm infants after systemic corticosteroid administration might be related to an immature BBB. ",0
3122,16507781,Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia,"Current prognostic factors for acute myeloblastic leukemia (AML) are not sufficient to accurately predict the group of patients in the intermediate-risk category who will successfully respond to treatment. Distinct patterns of inherited functional genomic polymorphisms might explain part of these heterogeneous prognoses. We used the allelic discrimination method to identify polymorphisms in GSTT1, SULT1C2, CDA, SXR (drug metabolic pathways), XPD, XPA, XPG, ERCC1, TOP2A (DNA repair), VEGF (angiogenesis), and MDR1 (multidrug resistance) genes in 110 adult patients with intermediate-risk AML, enrolled in the CETLAM-99 prospective trial. A multivariate prognostic model adjusted for age, white blood cell (WBC) count, French-American-British group, cytogenetics, MLL rearrangement, internal tandem duplication of FLT3 (FLT3-ITD), induction courses to achieve complete remission, and germline polymorphisms, was used to detect independent risk factors associated with clinical outcome. This analysis showed an increased risk of refractoriness to chemotherapy in the group of patients with XPA variant alleles (RR = 14; P = .02). In the same model, increased relapse risk was associated with SULT1C2 heterozygosity (RR = 4.1; P = .004), FLT3-ITD (RR 3.3; P = .003), and MDR1 variant alleles (RR = 2.4; P = .02). Adverse prognostic variables for overall survival were XPA (RR = 3.4; P = .02) and MDR1 (RR = 2.1; P = .02) variant alleles, and WBC count (RR = 2.1; P = .02). These findings might be useful in selecting risk-adapted treatment strategies in intermediate-risk AML. ",0
3123,16507832,Delayed versus immediate surgical intervention and prostate cancer outcome,"For prostate cancer patients with small, lower-grade tumors, expectant management with delayed surgical intervention (active surveillance) is a rarely used therapeutic option because the opportunity for cure may be lost. We compared outcomes of 38 patients with small, lower-grade prostate cancer in an expectant management program who underwent delayed surgical intervention at a median of 26.5 months (95% confidence interval [CI] = 17 to 32 months; range = 12.0-73.0 months) after diagnosis with 150 similar patients who underwent immediate surgical intervention at a median of 3.0 months (95% CI = 2 to 4 months; range = 1.0-9.0 months) after diagnosis. Noncurable cancer was defined as adverse pathology associated with a less than 75% chance of remaining disease-free for 10 years after surgery. Noncurable cancer was diagnosed in nine (23%) of the 38 patients in the delayed intervention cohort and in 24 (16%) of the 150 men in the immediate intervention group. After adjusting for age and prostate-specific antigen (PSA) density (i.e., PSA value divided by prostate volume) in a Mantel-Haenszel analysis, the risks of noncurable cancer associated with delayed and immediate intervention did not differ statistically significantly (relative risk = 1.08, 95% CI = 0.55 to 2.12; P = .819, two-sided Cochran-Mantel-Haenszel statistic). Age, PSA, and PSA density were all statistically significantly associated with the risk of noncurable cancer (P = .030, .013, and .008, respectively; two-sided chi-square test). Thus, delayed prostate cancer surgery for patients with small, lower-grade prostate cancers does not appear to compromise curability. ",0
3124,16507906,Emerin-lacking mice show minimal motor and cardiac dysfunctions with nuclear-associated vacuoles,"Emery-Dreifuss muscular dystrophy is an inherited muscular disorder clinically characterized by slowly progressive weakness affecting humero-peroneal muscles, early joint contractures, and cardiomyopathy with conduction block. The X-linked recessive form is caused by mutation in the EMD gene encoding an integral protein of the inner nuclear membrane, emerin. In this study, mutant mice lacking emerin were produced by insertion of a neomycin resistance gene into exon 6 of the coding gene. Tissues taken from mutant mice lacked emerin. The mutant mice displayed a normal growth rate indistinguishable from their littermates and were fertile. No marked muscle weakness or joint abnormalities were observed; however, rotarod test revealed altered motor coordination. Electrocardiography showed mild prolongation of atrioventricular conduction time in emerin-lacking male mice older than 40 weeks of age. Electron microscopic analysis of skeletal and cardiac muscles from emerin-lacking mice revealed small vacuoles, which mostly bordered the myonuclei. Our results suggest that emerin deficiency causes minimal motor and cardiac dysfunctions in mice with a structural fragility of myonuclei. ",0
3125,16507909,Caspase-mediated cleavage of glial fibrillary acidic protein within degenerating astrocytes of the Alzheimer's disease brain,"Recent studies demonstrate roles for activation of caspases and cleavage of cellular proteins within neurons of the Alzheimer's disease (AD) brain. To determine whether a similar role for caspases also occurs within glial cells in AD, we designed a site-directed caspase-cleavage antibody specific to glial fibrillary acidic protein (GFAP), a cytoskeleton protein specifically expressed in astrocytes. In vitro characterization of this antibody using both a cell-free system and a cell model system of apoptosis demonstrated that the antibody (termed GFAP caspase-cleavage product antibody or GFAP-CCP Ab) immunolabeled the predicted caspase-cleavage fragment, but not full-length GFAP, by Western blot analysis. To determine whether caspases cleave GFAP in vivo, tissue sections from control and AD brains were examined by immunohistochemistry using the GFAP-CCP Ab. Two prominent features of staining were evident: immunolabeling of degenerating astrocytes in proximity to blood vessels and staining within plaque-rich regions of the AD brain. Furthermore, co-localization of the GFAP-CCP Ab and an antibody specific to active caspase-3 was demonstrated within damaged astrocytes of the AD brain. These data suggest that the activation of caspases and cleavage of cellular proteins such as GFAP may contribute to astrocyte injury and damage in the AD brain. ",0
3126,16508110,"Crystallization and preliminary X-ray crystallographic analysis of MbtI, a protein essential for siderophore biosynthesis in Mycobacterium tuberculosis","Mycobacterium tuberculosis, the causative agent of tuberculosis, depends on the secretion of salicylate-based siderophores called mycobactins for the acquisition of extracellular iron, which is essential for the growth and virulence of the bacterium. The protein MbtI is thought to be the isochorismate synthase enzyme responsible for the conversion of chorismate to isochorismate, the first step in the salicylate production required for mycobactin biosynthesis. MbtI has been overexpressed in Escherichia coli, purified and crystallized. The crystals diffract to a maximum resolution of 1.8 A. They belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 51.8, b = 163.4, c = 194.9 A, consistent with the presence of either two, three or four molecules in the asymmetric unit. ",0
3127,16508173,Antinociceptive activities of alpha-truxillic acid and beta-truxinic acid derivatives,"Our recent study demonstrated that the dimeric structure of alpha-truxillic acid derivatives played an important role in the expression of their anti-inflammatory activities. In the present report, to investigate the correlation between the structure and anti-inflammatory activity, alpha-truxillic acid (1) and its derivatives (2-6), beta-truxinic acid (7) and its derivatives (8-10) were prepared, and their activities were evaluated in the formalin test. All compounds showed only weak or no activities against the neurogenic pain response, but demonstrated significant activities against the inflammatory pain response induced by formalin. The highest anti-inflammatory activities were observed for alpha-truxillic acid (1) and its derivative 4,4'-dihydroxy-alpha-truxillic acid (2). In addition, alpha-truxillic acid (1) and its derivative, alpha-truxillic acid bis(p-nitrophenyl)ester (5), showed higher anti-inflammatory activities than beta-truxinic acid (7) and the corresponding derivative (10). Furthermore, free carboxylic acids (1, 2) showed higher activities than their dimethyl esters (3, 4) and bis(p-nitrophenyl)ester (5). These results confirmed that the alpha-formation of dimeric structure and the free carboxylic acid were also important for the expression of anti-inflammatory activities. Otherwise, 4,4'-dichloro-beta-truxinic acid (8) had higher activity than its parent compound 7; furthermore, 1,3-dibenzoyl-2,4-di(4-chlorophenyl)cyclobutane (6) also showed strong anti-inflammatory activity. These results suggested that substituents in the phenyl groups were also important for the expression of anti-inflammatory activity. In order to gain information about their activity intensity, the anti-inflammatory activities of 2 and 4,4'-dichlorolated derivatives (6, 8) were compared with that of indomethacin (a nonsteroidal anti-inflammatory drug) in the formalin test. As a result, compounds 2, 6 and 8 showed stronger anti-inflammatory activities than indomethacin. These results suggested that alpha-truxillic acid and beta-truxinic acid derivatives might be developed into a new type of anti-inflammatory drug. ",0
3128,16508512,"""The """"Fistula VAC,"""" a technique for management of enterocutaneous fistulae arising within the open abdomen: report of 5 cases""","Management of intestinal fistulae in open abdominal wounds remains a significant clinical challenge for those caring for patients surviving damage control abdominal operations. Breaking the cycle of tissue inflammation, infection, and sepsis, resulting from leakage of enteric contents, should be a major goal in the approach to these complex patients. We describe a technique utilizing vacuum assisted closure (VAC) which achieves control of enteric flow from fistulae in open abdominal wounds. The fistula-VAC is fashioned from standard sponge supplies, negative pressure pumps, and ostomy appliances. The fistula-VAC was changed every three days prior to split thickness skin grafting, and every five days following grafting. Five patients underwent application of the fistula-VAC. All patients had complete diversion of enteric contents. This enteric diversion allowed for successful skin grafting in all patients. Application of the fistula-VAC should be considered a useful option in treating patients with intestinal fistulae in open abdominal wounds. ",0
3129,16508584,Nocturnal hypertension and impaired sympathovagal tone in Turner syndrome,"Increased blood pressure (BP), night: day BP ratio, and heart rate is seen in Turner syndrome (TS), and an increased risk of ischaemic heart disease and type 2 diabetes, as well as aortic dilatation and dissection. We hypothesized that altered heart rate variability is present in TS in comparison with controls, and can be influenced by hormonal replacement therapy (HRT). We examined the impact of HRT on sympathovagal control of heart rate variability. Patients (n = 8, aged 29.5 +/- 5.3 years; no treatment or HRT) and controls (n = 8, aged 28.5 +/- 4.2 years; no treatment) were examined by short-term spectral analysis (supine-standing), bedside neuropathy tests, and 24-h ambulatory BP. N-terminal pro-brain natriuretic peptide (BNP), renin, aldosterone and urinary albumin excretion was determined. The interaction between position and status (TS or control) was examined for data from spectral analysis. Low-frequency (LF) power, coefficient of component variation of LF (both measures of sympathetic and vagal activity), and the LF: high-frequency (HF) power ratio (a measure of sympathovagal balance) were diminished in TS compared with controls, especially during standing. Systolic and diastolic night ambulatory BP (both P = 0.03), and systolic and diastolic night: day ratio (P = 0.01; P = 0.004) was increased in TS. During HRT diastolic day (P = 0.05) and 24-h diastolic ambulatory BP (P = 0.08) decreased. N-terminal pro-BNP was elevated in TS. Decreased sympathovagal balance or tone and nocturnal hypertension is present in TS, and N-terminal pro-BNP is elevated. HRT did not modulate the sympathovagal tone, but decreased BP. These changes may be linked to the increased cardiovascular risk and possibly the increased risk of aortic dilatation in TS. ",0
3130,16508750,Missense mutations in the BMP15 gene are associated with ovarian failure,"Premature ovarian failure (POF) is an unexplained amenorrhoea (>6 months) with raised levels of gonadotropins (FSH>40 U/L) occurring before the age of 40 years. Recent studies have elucidated the role of oocyte derived growth factors (BMP15 and GDF9) in maintenance of folliculogenesis, granulosa cell (GC) proliferation and overall fertility. Our recently published work showed presence of two rare missense variants in the GDF9 gene associated with ovarian failure (Dixit et al. 2005, Menopause 12:749-754). The present case-control study has been structured to establish the role of BMP15 germline status associated with ovarian failure. Sequence analysis of the coding region of the BMP15 gene was carried out in a cohort of women with POF (n=133), primary amenorrhoea (n=60), and secondary amenorrhoea (n=9) compared with control females (n=197). This study revealed a total of 18 germline variants in the coding region of BMP15 gene, including 16 novel variants. These novel variants include one intronic variant, one 3' flanking variant, one silent variant, and 13 missense variants. Eleven missense variants were present only in cases with complete absence in the control females. The remaining two missense variants viz. c.308A>G (p.Asn103Ser) and c.788_789insTCT (p.Leu263_Arg264insLeu) were present both in the cases and in the controls. The c.788_789insTCT variant was significantly higher in primary amenorrhoea cases than in the controls (Fisher's exact test, P=0.034). Three frequent variants c.-9C>G, c.308A>G, and c.852C>T were chosen for haplotyping. The haplotype G-G-C was found to be significantly associated with ovarian failure (P=0.0075). In a nutshell, the BMP15 gene is highly associated with etiology of ovarian failure. ",0
3131,16509584,Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors,"We extended the previously described dynamic pharmacophore model studies of HIV-1 integrase (IN) by considering more key residues in the active site, including Mg2+. First, we applied a Monte Carlo sampling method to map the complementary features of the IN binding surface. Two types of dynamic pharmacophore models were generated. One considers Mg2+ as part of the IN and therefore as an excluded volume, and the other treats Mg2+ as a positively charged feature, representing a new type of pharmacophore model aimed to identify compounds potentially preventing Mg2+ binding. Second, we validated the models with 385 known active (IC50 < 20 microM) and 235 (IC50 > 100 microM) inactive IN inhibitors. Third, we used the derived models to screen our small molecule database. Twenty-two structurally novel compounds were tested in an in vitro assay specific for IN, and two of them showed IC50 < or = 10 microM for strand transfer reaction. ",0
3132,16510150,Identification of members of the annexin family in the detergent-insoluble fraction of rat Morris hepatoma plasma membranes,"For proteomic analysis, plasma membranes of rat hepatocellular carcinoma Morris hepatoma 7777 were selectively solubilized according to the previously developed method [D. Josic, K. Zeilinger, Methods Enzymol. 271 (1996) 113-134]. If the Triton X100 insoluble pellet is subsequently extracted, several proteins can be solubilized. These proteins can be classified in two groups according to their molecular size. The proteins with apparent molecular weights in SDS-PAGE between 70 and 75 kDa belong to the first group. Smaller proteins, with apparent molecular weights between 30 and 45 kDa, are members of the second group. The main protein of higher molecular weight was also found in the Triton X100 insoluble extract from normal rat liver plasma membranes. This protein was identified as Annexin A6. The proteins from the second group are practically absent in the Triton X100 insoluble extract from rat liver. These proteins are present in relatively high concentrations in plasma membranes of Morris hepatoma 7777. Both groups of detergent-insoluble proteins from Morris hepatoma 7777 were further analyzed with SELDI-TOF and LC electrospray ionization mass spectrometry. From the first group, Annexin A6, together with two other integral plasma membrane proteins, was identified. In the second group of proteins with apparent molecular weights between 30 and 45kDa, further members of the annexin family, Annexins A1, A2, A4, A5 and A7 were identified. The possible role of these low molecular size annexins as potential cancer biomarkers is discussed. ",0
3133,16510657,Early intervention in low birth weight premature infants: results at 18 years of age for the Infant Health and Development Program,"To assess whether improvements in cognitive and behavioral development seen in preschool educational programs persist, we compared those in a multisite randomized trial of such a program over the first 3 years of life (INT) to those with follow-up only (FUO) at 18 months of age. This was a prospective follow-up of the Infant Health and Development Program at 8 sites heterogeneous for sociodemographic characteristics. Originally 985 children were randomized to the INT (n = 377) or FUO (n = 608) groups within 2 birth weight strata: heavier low birth weight (HLBW; 2001-2499 g) and lighter low birth weight (LLBW; < or = 2000 g). Primary outcome measures were the Peabody Picture Vocabulary Test (PPVT-III), reading and mathematics subscales of the Woodcock-Johnson Tests of Achievement, youth self-report on the Total Behavior Problem Index, and high-risk behaviors on the Youth Risk Behavior Surveillance System (YRBSS). Secondary outcomes included Weschler full-scale IQ, caregiver report on the Total Behavior Problem Index, and caregiver and youth self-reported physical health using the Medical Outcome Study measure. Assessors were masked as to study status. We assessed 636 youths at 18 years (64.6% of the 985, 72% of whom had not died or refused at prior assessments). After adjusting for cohort attrition, differences favoring the INT group were seen on the Woodcock-Johnson Tests of Achievement in math (5.1 points), YRBSS (-0.7 points), and the PPVT-III (3.8 points) in the HLBW youth. In the LLBW youth, the Woodcock-Johnson Tests of Achievement in reading was higher in the FUO than INT group (4.2). The findings in the HLBW INT group provide support for preschool education to make long-term changes in a diverse group of children who are at developmental risk. The lack of observable benefit in the LLBW group raises questions about the biological and educational factors that foster or inhibit sustained effects of early educational intervention. ",0
3134,16510892,The representation of taste quality in the mammalian nervous system,"The process by which the mammalian nervous system represents the features of a sapid stimulus that lead to a perception of taste quality has long been controversial. The labeled-line (sparse coding) view differs from the across-neuron pattern (ensemble) counterpoint in proposing that activity in a given class of neurons is necessary and sufficient to generate a specific taste perception. This article critically reviews molecular, electro-physiological, and behavioral findings that bear on the issue. In the peripheral gustatory system, the authors conclude that most qualities appear to be signaled by labeled lines; however, elements of both types of coding characterize signaling of sodium salts. Given the heterogeneity of neuronal tuning functions in the brain, the central coding mechanism is less clear. Both sparse coding and neuronal ensemble models remain viable possibilities. Furthermore, temporal patterns of discharge could contribute additional information. Ultimately, until specific classes of neurons can be selectively manipulated and perceptual consequences assessed, it will be difficult to go beyond mere correlation and conclusively discern the validity of these coding models. ",0
3135,16511321,Crystallization and preliminary X-ray crystallographic analysis of biodegradative threonine deaminase (TdcB) from Salmonella typhimurium,"Biodegradative threonine deaminase (TdcB) catalyzes the deamination of L-threonine to alpha-ketobutyrate, the first reaction in the anaerobic breakdown of L-threonine to propionate. Unlike the biosynthetic threonine deaminase, TdcB is insensitive to L-isoleucine and is activated by AMP. Here, the cloning of TdcB (molecular weight 36 kDa) from Salmonella typhimurium with an N-terminal hexahistidine affinity tag and its overexpression in Escherichia coli is reported. TdcB was purified to homogeneity using Ni-NTA affinity column chromatography and crystallized using the hanging-drop vapour-diffusion technique in three different crystal forms. Crystal forms I (unit-cell parameters a = 46.32, b = 55.30, c = 67.24 A, alpha = 103.09, beta = 94.70, gamma = 112.94 degrees) and II (a = 56.68, b = 76.83, c = 78.50 A, alpha = 66.12, beta = 89.16, gamma = 77.08 degrees) belong to space group P1 and contain two and four molecules of TdcB, respectively, in the asymmetric unit. Poorly diffracting form III crystals were obtained in space group C2 and based on the unit-cell volume are most likely to contain one molecule per asymmetric unit. Two complete data sets of resolutions 2.2 A (crystal form I) and 1.7 A (crystal form II) were collected at 100 K using an in-house X-ray source. ",0
3136,16511590,PPAR gamma and human metabolic disease,"The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARalpha, PPARdelta, and PPARgamma) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARalpha and PPARdelta appear primarily to stimulate oxidative lipid metabolism, while PPARgamma is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARgamma in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARgamma in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome. ",0
3137,16511731,Prophylaxis of bipolar disorder],"Until recently, the psychopharmacological treatment alternatives for bipolar maintenance treatment were limited to lithium, which seems of special usefulness in a classical manifestation of the illness with mood-stabilising and anti-suicidal properties. With atypical features like psychotic symptoms or rapid cycling, lithium seems to be less useful. This led to further research into alternative options as carbamazepine, valproate or lamotrigine as well as atypical neuroleptics, thyroid hormones or innovative substances like omega fatty acids. This article summarises the current state of knowledge on treatment options for maintenance therapy. ",0
3138,16511743,Positron emission tomography (PET) in oncology: a part of medical therapeutic expertise],"""Early inclusion of positron emission tomography (PET) in the stepwise oncological diagnosis improves tumor staging and can make further costly diagnostic and inadequate therapeutic measures superfluous. The advantage of this method, in answering the many questions that arise, has been supported by an extensive literature and analysis of interdisciplinary data. Its use is therefore demanded by doctors working in oncology. Surgeons and radiotherapists demand PET studies before local treatment is started so that patients with advanced-stage cancer are spared invasive local therapeutic measures. Oncologists take advantage of PET""""s potential to administer stage-related chemotherapy and provide evidence of its efficacy. Expensive treatment regimens can be immediately tested for their efficacy and, if ineffective, can be replaced by a more suitable combination of chemotherapeutic agents. For this purpose combined PET and CT can be considered the (future) standard for oncological diagnosis. Manufacturers have already positioned themselves to provide PET only as part of combined PET/CT equipment. If these advances are not used, patients are deprived of optimal treatment. Furthermore, PET provides considerable potential for cost savings by avoiding expensive measures that do not prolong life. Responsible use of these resources within the health service system requires the early use of PET in the staging of diagnostic methods so that therapeutic options can be weighed through interdisciplinary consultation. The patient can thus be given optimal information and included in therapeutic decisions. It is our obligation as doctors to demand from the decision makers that PET equipment be provided for use in accordance with correct indications and to reimburse the costs as is already the case in other parts of Europe. """,0
3139,16511798,Undifferentiated tumor in the ovary of a corn snake (Elaphe guttata guttata),"A 6-year-old intact female corn snake (Elaphe guttata guttata) was presented with a 3-week history of anorexia. Coelomic radiographs revealed a 9 x 4 cm soft tissue opacity suggestive of a right ovarian enlargement. The mass (9 x 5 x 4 cm) was surgically removed, and multiple smears from tissue sections were stained with Diff-Quik. Multiple tissue samples from the mass were collected and fixed in formalin. Cytologic specimens were moderately cellular and contained light pink amorphous background material. The cells were primarily spindle-shaped with moderate to marked anisocytosis and anisokaryosis. Cells sometimes were round to polygonal, and rarely were arranged in small clusters. Macrophages occasionally were observed. Histologic specimens consisted of a highly cellular mass composed of pleomorphic, spindle-shaped cells and, occasionally, round to polygonal cells arranged in irregular fascicles. The neoplastic cells were immunoreactive for cytokeratin (AE1/AE3), smooth muscle actin, and skeletal muscle actin, but did not stain for vimentin or desmin. On the basis of the morphologic and immunohistochemical results, a diagnosis of ovarian undifferentiated carcinoma was made. In this report, we describe the challenges of using immunohistochemistry to diagnose this uncommon type of tumor in reptiles. ",0
3140,16511846,Sclerosing papillary lesion of the breast: a diagnostic pitfall for malignancy in fine needle aspiration biopsy,"Papillary neoplasms of breast constitute a group of lesions that show broad spectrum of morphological changes, ranging from benign to malignant and posing challenges at all diagnostic levels. Some benign papillary lesions may form well-defined solid masses with a dominant sclerosed architecture, known as complex sclerosing papillary lesion or simply sclerosing papilloma. The purpose of this study is to apply the previously published criteria for papillary lesions and to identify the cytomorphologic findings that lead to false-positive diagnosis of these cases. We reviewed the fine needle aspiration biopsies (FNAB) of six histologically proven sclerosing papilloma that were called suspicious or malignant on FNAB. The patient age ranged from 40 to 69, with a mean of (43 +/- 6) yr. Three patients presented with a palpable lump and two patients had history of fibrocystic disease. All six patients had abnormal screening mammograms. FNAB was performed using a 23-gauge syringe attached to a commercial holder. FNA smears were markedly hypercellular with large number of epithelial fragments and papillary clusters, discohesive single cells that are hyperchromatic with mild to moderate nuclear pleomorphism. Bipolar cells were present in all cases, varying from low to abundant. Intraoperative consultation was requested on four cases. Touch preparations were made on two cases and were reported as suspicious based on the cellularity and nuclear atypia. All surgically excised specimens showed sclerosing complex papillary proliferative lesions with epithelial hyperplasia. In conclusion, FNA cytology of this proliferative lesions may be highly cellular and may display cellular atypia similar to breast carcinoma and thus leads to false-positive interpretation. ",0
3141,16511923,Prevalence of neurocognitive dysfunction and other clinical manifestations in disabled patients with systemic lupus erythematosus,"While work disability is common in patients with systemic lupus erythematosus (SLE), it is not known which lupus disease characteristics predispose toward work disability. We examined demographic, clinical, serological, and neuropsychological factors in a group of disabled and nondisabled patients with SLE. Fifty patients meeting American College of Rheumatology criteria for SLE were assessed for work status, disease characteristics, fatigue, anxiety, depressive symptoms, and quality of life. All subjects underwent an abbreviated panel of neuropsychological tests. Subjects who had formal work disability (social security or longterm disability, n = 16) and subjects who self-reported work disability without formal recognition (n = 8) were compared to subjects denying work disability from lupus (n = 26). Education level, African-American race, and SLICC Damage Index score were significantly associated with formal work disability relative to other subjects. Neurocognitive impairment (OR 14.44, 95% CI 3.01, 68.20; p = 0.001), nephritis (OR 3.75, 95% CI 1.01, 13.9; p = 0.048), and discoid lupus (OR 19.93, 95% CI 3.51, 113.3; p = 0.001) were all associated with formal disability. Formally disabled patients had higher fatigue and anxiety scores and more impaired quality of life in many domains relative to nondisabled subjects. Subjects with self-reported work disability also had neurocognitive dysfunction, high fatigue scores, and poor quality of life, but in other respects appeared to have milder disease than formally disabled subjects. Neurocognitive dysfunction and fatigue are 2 manifestations that may contribute materially to work disability in lupus. Other associated factors include low education levels, SLICC Damage Index scores, discoid lupus, nephritis, and possibly African-American race. ",0
3142,16512090,"""""""Fat halo sign of the colon"""": not only in patients with inflammatory bowel disease. An illustrated case-report]""","A 76-year old man was referred for radiological evaluation of recurrent left sided flank pain, micro-haematuria and renal cysts. Computer tomographic findings were colon wall-thickening and submucosal fat (fat halo sign) throughout the entire length of the colon. Fat halo sign is thought to be a reliable marker for inflammatory bowel disease. It has also been reported in patients receiving cytoreductive therapy or in patients with graft-versus-host disease. A relation between short segment fat halo sign and obesity in asymptomatic patients is presumed. None of these conditions apply for this patient without evidence of previous or present gastrointestinal disease. The striking changes of the colon wall are exceptional, although they have to be considered as a normal finding. ",0
3143,16512147,Pasteurella anatipestifer as a cause of mortality in captive wild waterfowl,"An outbreak of Pasteurella anatipestifer infection in young wild waterfowl at the Niska Waterfowl Research Center resulted in losses of approximately 100 Blue and Snow Geese, one White-fronted Goose, five Mandarin Ducks, one Black Duck and one Wood Duck. Clinical signs included diarrhea, paralysis and tremors. Gross lesions were fibrin deposits on serosal surfaces, hemorrhages on the epicardium, consolidation of the lungs, cloudy or flaky deposits on the air sacs, and dark, swollen spleens. Microscopic lesions included fibrinous meningitis, pneumonitis, air saculitis and serositis. Swollen leg and foot joints were seen in some cases. Chloramphenicol treatment seemed to be of benefit in controlling the outbreak. ",0
3144,16512398,Quality of life of patients with old myocardial infarction on prolonged therapy with atenolol],"The purpose of the study was to evaluate the influence of atenolol, a selective, beta1-adrenoblocker, on the quality of life (QL) of patients with old myocardial infarction (MI). The subjects of this 12-month open uncontrolled study were 40 male patients aged 29 to 59 years (mean age 46.8 +/- 1.19) suffering from functional class II-III stable exertional angina, which occurred 6 months after their first large-focal MI. QL was evaluated before and during the course of therapy (after 1, 3, 6, and 12 months) using EORTC QLQ CORE 30, short version of MMPI test, and Spielberg State-Trait Anxiety inventory. The patients received atenolol in effective doses selected on an individual basis (mean day dose was 67.9 +/- 4.2 mg) within one year; the study revealed increase of QL falling in all the categories of EORTC QLQ CORE 30, decrease of reactive and personal anxiety, as well as positive changes in averaged MMPI profile, which reflected lowering of anxiety and depression level in the actual psyche status. ",0
3145,16513083,Bile acid-mediated induction of cyclooxygenase-2 and Mcl-1 in hepatic stellate cells,"In cholestatic liver diseases, bile acids induce hepatocyte apoptosis and thus cause liver injury, but hepatic stellate cells (HSCs) survive in the presence of bile acids. We attempted to analyze anti-apoptotic signaling pathways in HSCs against bile acid-induced apoptosis. In immortalized human HSCs and primarily cultured rat HSCs, bile acid treatment increased the expression levels of cyclooxygenase-2 (COX-2) and Mcl-1. COX-2 induction was found to be due to transcriptional enhancement dependent on p42/44, p38 MAPK, and JNK activation, whereas Mcl-1 induction resulted from bile acid-mediated protein stabilization in a Raf-1-dependent manner. Moreover, the inhibitions of either COX-2 activity by celecoxib or Mcl-1 induction by siRNA transfection rendered HSCs susceptible to bile acid-induced apoptosis. These results imply that the bile acid-mediated inductions of COX-2 and Mcl-1 may lead to HSC survival in cholestatic liver diseases. ",0
3146,16513143,Molecular mechanism of mutagenesis induced by olaquindox using a shuttle vector pSP189/mammalian cell system,"Olaquindox, a quinoxaline 1,4-dioxide derivative from quindoxin, is widely used as an animal growth promoter in China. We tested olaquindox as a mutagen in a SV40-based shuttle vector pSP189 and African green kidney cell (Vero E6 cell line) system to define the safety of olaquindox as a food-additive for animals. When applied at 6.6 microg/ml, olaquindox caused 12 times higher mutation frequency in comparison to untreated controls. More than 70% of base substitutions happened at G:C base pairs featuring G:C to T:A or G:C to A:T conversions. Frequency of point mutations for in vitro modified plasmids was also dramatically increased from the spontaneous background level. Olaquindox-induced mutations did not occur randomly along the supF shuttle vector, but instead, had a hot spot at base pair #155 which accounts for 37% of total mutations. Olaquindox-induced mutations also showed sequence-specificity in which most point mutations occurred at site N in a 5'-NNTTNN-3' sequence while most tandem bases deletion and rearrangement were seen at the 5'-ANGGCCNAAA-3' sequence. We conclude that olaquindox induces DNA mutation, therefore, should not be used as an additive to promote animal growth. ",0
3147,16513159,Human cytomegalovirus infection and T cell immunosenescence: a mini review,"""The mammalian immune system defends the organism against pathogens, and possibly cancer, but is known to become dysregulated with increasing age. This results in greater morbidity and mortality due to infectious disease in old people. The most important changes occur in T cell immunity, manifested sometimes dramatically as altered clonal expansions of cells of limited antigen specificity and a marked shrinkage of the T cell antigen receptor repertoire. At the same time, it was independently reported that CMV seropositivity was associated with many of the same T cell changes that were being identified as biomarkers of immune ageing. It has now become clear that CMV is commonly the driving force behind the oligoclonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. These changes are much less obvious in centenarians and most extreme in people whom longitudinal studies have shown to possess an """"immune risk profile"""". This is a cluster of immunological parameters of which CMV seropositivity is one component and which predicts incipient mortality in an elderly population. Taken together, these findings suggest the hypothesis that persistence of CMV as a chronic antigenic stressor is a major contributor to immunosenescence and associated mortality. """,0
3148,16513280,Babesia--a historical overview,"The history of the genus Babesia is briefly outlined. The classical differences with the main other genus of non-pigment-forming hemoparasites, Theileria, are the absence of extra-erythrocytic multiplication (schizogony) in Babesia and the cycle in the vector tick, which includes transovarial transmission in Babesia but only transstadial transmission in Theileria. Also, the multiplication in the red cell of Babesia, by budding, most often results in two daughter cells (merozoites), while that of Theileria gives four merozoites, often as a Maltese cross. In particular this means that what is still commonly called Babesia microti is not a Babesia and that it would be just as logical to speak of human theileriosis as of babesiosis. The small piroplasm of horses, long known as Babesia equi, is already commonly designated as Theileria equi. However, on molecular grounds, it may be necessary to create a new genus for these parasites. The Babesia species of domestic animals are briefly discussed and presented in a table. ",0
3149,16513608,Low efficacy of 18F-FDG PET for detection of uveal malignant melanoma compared with 123I-IMP SPECT,"Earlier investigations showed that N-isopropyl-p-123I-iodoamphetamine SPECT (123I-IMP SPECT) is useful for the diagnosis of uveal malignant melanoma, whereas the feasibility and usefulness of 18F-FDG PET in uveal malignant melanoma have not yet been established. We compared the usefulness of 123I-IMP SPECT and 18F-FDG PET for the detection of uveal malignant melanoma on the same subjects. Nineteen patients (10 men, 9 women) with suspected uveal malignant melanoma were examined by 123I-IMP SPECT. Thirteen of them were also examined by 18F-FDG PET. 123I-IMP SPECT was performed at 15 min or at 3 and 24 h after intravenous administration of 123I-IMP. In 12 of 19 study patients, 123I-IMP SPECT obtained at 24 h after intravenous administration of 123I-IMP delineated an area of increased uptake in the site corresponding to the ocular tumor. All of the ocular tumors in the 12 123I-IMP SPECT-positive patients were confirmed histopathologically and clinically to be uveal malignant melanoma. The other 7 123I-IMP-SPECT-negative patients have been monitored under the diagnosis of choroidal nevus, choroidal hemangioma, hyperplasia of the pigment epithelium of the retina, or idiopathic inflammatory lesions without any complications. In a total of 13 patients examined by 18F-FDG PET, 9 of whom were 123I-IMP SPECT positive and 4 were negative, only 1 patient showed abnormal uptake of 18F-FDG PET in the site corresponding to the ocular tumor. Therefore, 8 of 9 patients with uveal malignant melanoma showed false-negative results in 18F-FDG PET. The 18F-FDG PET-positive patient with uveal malignant melanoma had the largest tumor mass with a short diameter of 12 mm, a long diameter of 17 mm, and a height of 7 mm. In the other 8 18F-FDG PET-negative patients, the tumors had a dimension of 11 x 13 x 7 mm or less. 123I-IMP SPECT is a sensitive and accurate method for the detection of uveal malignant melanoma, whereas the efficacy of 18F-FDG PET for this purpose is low because of a high incidence of false-negative results. 123I-IMP SPECT is far more superior in comparison with 18F-FDG PET in detecting uveal malignant melanoma. ",0
3150,16513625,Angiostatin overexpression in Morris hepatoma results in decreased tumor growth but increased perfusion and vascularization,"Growth of malignant tumors is dependent on sufficient blood supply. Thus, inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Human angiostatin (hANG) is one of the most potent inhibitors of endothelial cell proliferation, angiogenesis, and tumor growth in vivo. However, its mechanisms operating in vivo are not well understood. To obtain more information about functional changes in the angiogenic process, we established Morris hepatoma (MH3924A) cell lines expressing hANG (hANG-MH3924A). The effects of hANG expression on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) were measured in coculture experiments in vitro. To evaluate changes in tumor perfusion and blood volume, H2 15O and 68Ga-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) were used for PET studies in vivo. Additionally, immunohistologic quantification of vascularization, apoptosis, and proliferation as well as gene array analyses were performed. Our in vitro experiments demonstrate reduced proliferation and increased apoptosis in HUVECs when being cocultured with hANG-MH3924A. In support, tumor growth of hANG-MH3924A is diminished by 95% in vivo. However, tumor perfusion and blood volume are increased in hANG-MH3924A corresponding to an increased microvessel density. Furthermore, hANG-transfected tumors show changes in expression of genes related to apoptosis, stress, signal transduction, and metabolism. hANG expression leads to inhibition of tumor growth, increased apoptosis, and changes in the expression of multiple genes involved in stress reactions, signal transduction, and apoptosis, which indicates a multifactorial reaction of tumors. An enhanced microvessel density is seen as part of these reactions and is associated with increased perfusion as measured by PET. ",0
3151,16513809,Association between reported exposure to road traffic and respiratory symptoms in children: evidence of bias,"Many studies showing effects of traffic-related air pollution on health rely on self-reported exposure, which may be inaccurate. We estimated the association between self-reported exposure to road traffic and respiratory symptoms in preschool children, and investigated whether the effect could have been caused by reporting bias. In a random sample of 8700 preschool children in Leicestershire, UK, exposure to road traffic and respiratory symptoms were assessed by a postal questionnaire (response rate 80%). The association between traffic exposure and respiratory outcomes was assessed using unconditional logistic regression and conditional regression models (matching by postcode). Prevalence odds ratios (95% confidence intervals) for self-reported road traffic exposure, comparing the categories 'moderate' and 'dense', respectively, with 'little or no' were for current wheezing: 1.26 (1.13-1.42) and 1.30 (1.09-1.55); chronic rhinitis: 1.18 (1.05-1.31) and 1.31 (1.11-1.56); night cough: 1.17 (1.04-1.32) and 1.36 (1.14-1.62); and bronchodilator use: 1.20 (1.04-1.38) and 1.18 (0.95-1.46). Matched analysis only comparing symptomatic and asymptomatic children living at the same postcode (thus exposed to similar road traffic) showed similar ORs, suggesting that parents of children with respiratory symptoms reported more road traffic than parents of asymptomatic children. Our study suggests that reporting bias could explain some or even all the association between reported exposure to road traffic and disease. Over-reporting of exposure by only 10% of parents of symptomatic children would be sufficient to produce the effect sizes shown in this study. Future research should be based only on objective measurements of traffic exposure. ",0
3152,16513822,Renal function in juvenile rats subjected to prenatal malnutrition and chronic salt overload,"Dietary sodium may contribute to hypertension and to cardiovascular and renal disease if a primary deficiency of the kidney to excrete sodium exists. In order to investigate whether chronic 1% NaCl in the drinking water changes blood pressure and renal haemodynamics in juvenile Wistar rats subjected to prenatal malnutrition, an evaluation of plasma volume, oxidative stress in the kidney, proteinuria and renal haemodynamics was carried out. Malnutrition was induced by a multideficient diet. Mean arterial pressure, renal blood flow and glomerular filtration rate (GFR) were measured using a blood pressure transducer, a flow probe and inulin clearance, respectively. Plasma volume and oxidative stress were measured by means of the Evans Blue method and by monitoring thiobarbituric acid reactive substances (TBARS) in the kidneys, respectively. Urinary protein was measured by precipitation with 3% sulphosalicylic acid. It was observed that prenatally malnourished rats presented higher values of plasma volume (26%, P < 0.05), kidney TBARS (43%, P < 0.01) and blood pressure (10%, P < 0.01) when compared with the control group. However, they showed no change in renal haemodynamics or proteinuria. Neither prenatally malnourished nor control rats treated with sodium overload presented plasma volume or blood pressure values different from their respective control groups, but both groups presented elevated proteinuria (P < 0.01). The prenatally malnourished group treated with sodium overload presented higher values of kidney TBARS, GFR and filtration fraction (58, 87 and 72% higher, respectively, P < 0.01) than its respective control group. In summary, sodium overload did not exacerbate the hypertension in juvenile prenatally malnourished rats, but induced renal haemodynamic adjustments compatible with the development of renal disease. ",0
3153,16514042,"Dietzia cinnamea sp. nov., a novel species isolated from a perianal swab of a patient with a bone marrow transplant","The taxonomic status of a bacterium isolated from a perianal swab of a patient with a bone marrow transplant was characterized using a polyphasic taxonomic approach. Chemotaxonomic investigations revealed the presence of cell wall chemotype IV, short chain mycolic acids that co-migrated with those extracted from members of the genus Dietzia, and a dihydrogenated menaquinone with eight isoprene units as the predominant menaquinone. Generic assignment was confirmed by 16S rRNA gene sequencing. Comparative analysis of the 16S rRNA gene sequence showed that this isolate constitutes a distinct phyletic line within the genus Dietzia, displaying 97.5-98.7% sequence similarity with Dietzia species with validly published names. The isolate could be distinguished from the type strain of Dietzia maris (1.6% sequence divergence) and other species of the genus Dietzia by DNA-DNA hybridization, as well as by using a set of biochemical tests. Genotypic and phenotypic data show that the strain merits classification as a novel species of the genus Dietzia for which the name Dietzia cinnamea sp. nov. is proposed; the type strain is IMMIB RIV-399T (= DSM 44904T = CCUG 50875T). ",0
3154,16514050,Brief report: assessing adherence to pediatric antiretroviral regimens using the 24-hour recall interview,"Examine the 24-hr Recall Interview (24RI) for assessing children's antiretroviral medication adherence. Caregivers of 54 children with HIV (aged 2-12 years) completed a clinical adherence interview and the 24RI by telephone. Children's viral load and 3-month pharmacy records were obtained. Thirty-seven percent of children missed > or = 1 dose of medicine over 3 days. In 22% of the samples, adherence varied across medications. The 24RI adherence scores (Frequency, Interval, and Dietary Adherence) were moderately reliable across the three interviews. Pharmacy refill rates were significantly related to viral load, and 24RI barriers were marginally significantly related to viral load. The 24RI, with its systematic, cued recall, and decreased focus on adherence, may reduce socially desirable responding compared to other self-report methods, and reporting adherence barriers may indicate adherence difficulty. However, the validity of the 24RI must be improved to make it a useful measure to include in an adherence assessment battery. ",0
3155,16514172,Superoxide formation and interaction with nitric oxide modulate systemic arterial pressure and renal function in salt-depleted dogs,"To determine the role of superoxide (O(2)(-)) formation in the kidney during alterations in the renin-angiotensin system, we evaluated responses to the intra-arterial infusion of an O(2)(-) - scavenging agent, tempol, in the denervated kidney of anesthetized salt-depleted (SD, n=6) dogs and salt-replete (SR, n=6) dogs. As expected, basal plasma renin activity was higher in SD than in SR dogs (8.4 +/- 1.0 vs. 2.3 +/- 0.6 ng angiotensin 1/ml/hr). Interestingly, the basal level of urinary F(2)-isoprostanes excretion (marker for endogenous O(2)(-) activity) relative to creatinine (Cr) excretion was also significantly higher in SD compared to SR dogs (9.1 +/- 2.8 vs. 1.6 +/- 0.4 ng F(2)-isoprostanes/mg of Cr). There was a significant increase in renal blood flow (4.3 +/- 0.5 to 4.9 +/- 0.6 ml/min/g) and decreases in renal vascular resistance (38.2 +/- 5.8 to 33.2 +/- 4.7 mm Hg/ml/min/g) and mean systemic arterial pressure (148 +/- 6 to 112 +/- 10 mm Hg) in SD dogs but not in SR dogs during infusion of tempol at 1 mg/kg/min for 30 mins. Glomerular filtration rate and urinary sodium excretion (U(Na)V) did not change significantly during tempol infusion in both groups of dogs. Administration of the nitric oxide synthase inhibitor nitro-L-arginine (50 mug/kg/min) during tempol infusion caused a reduction in U(Na)V in SR dogs (47% +/- 12%) but did not cause a decrease in SD dogs. These data show that low salt intake enhances O(2)(-) activity that influences renal and systemic hemodynamics and thus may contribute to the regulation of arterial pressure in the salt-restricted state. ",0
3156,16514627,Early healing of flexor tendon insertion site injuries: Tunnel repair is mechanically and histologically inferior to surface repair in a canine model,"Orthopedic injuries often require surgical reattachment of tendon to bone. Tendon ends can be sutured to bone by direct apposition to the bone surface or by placement within a bone tunnel. Our objective was to compare early healing of a traditional surface versus a novel tunnel method for repair of the flexor digitorum profundus (FDP) tendon insertion site in a canine model. A total of 70 tendon-bone specimens were analyzed 0, 5, 10 or 21 days after injury and repair, using tensile and range of motion mechanical testing, histology and densitometry. Ultimate force (a measure of repair strength) did not differ between surface and tunnel repairs at day 0. Both repair types had reduced strength at 10 and 21 days compared to 0 days, indicative of deterioration of suture grasping strength (tendon softening). At 21 days, tendons repaired in a bone tunnel had 38% lower ultimate force compared to surface repairs (p = 0.017). Histological findings were comparable between repair groups at 5 and 10 days but differed at 21 days, when we saw evidence of maturation of the tendon-bone interface in the surface repairs compared to an immature fibrous interface with no evidence of tendon-bone integration in the tunnel repairs. After accounting for bone removed by the tunnel, no difference in bone mineral density or trabecular bone volume existed between surface and tunnel repairs. If the results of our animal study extend to healing of the human FDP insertion, they indicate that FDP tendons should be reattached to the distal phalanx by suture to the cortical surface rather than suture in a bone tunnel. ",0
3157,16515583,Predicting the clinical behavior of ovarian cancer from gene expression profiles,"We investigated whether prognostic information is reflected in the expression patterns of ovarian carcinoma samples. RNA obtained from seven FIGO stage I without recurrence, seven platin-sensitive advanced-stage (III or IV), and six platin-resistant advanced-stage ovarian tumors was hybridized on a complementary DNA microarray with 21,372 spotted clones. The results revealed that a considerable number of genes exhibit nonaccidental differential expression between the different tumor classes. Principal component analysis reflected the differences between the three tumor classes and their order of transition. Using a leave-one-out approach together with least squares support vector machines, we obtained an estimated classification test accuracy of 100% for the distinction between stage I and advanced-stage disease and 76.92% for the distinction between platin-resistant versus platin-sensitive disease in FIGO stage III/IV. These results indicate that gene expression patterns could be useful in clinical management of ovarian cancer. ",0
3158,16515760,Imaging osteoarthritis: magnetic resonance imaging versus x-ray,"Until recently, imaging evaluation of osteoarthritis has relied primarily on conventional radiography. Using radiography in clinical practice or clinical research, however, has been fraught with difficulty. Techniques for reproducibly acquiring serial radiographs of joints have improved considerably over the past several years. However, the greatest promise for advancing knowledge about osteoarthritis and its treatment lies in MRI and its unique ability to examine the joint as a whole organ. In contrast to conventional radiography, MRI can directly visualize the articular cartilage, synovium, menisci, and other intra-articular structures important to the functional integrity of joints. There have been considerable advances in MRI of articular cartilage in particular over the past several years. However, much of this has come from small cross-sectional studies. Larger, longitudinal studies are ongoing, and publications are just emerging. This paper reviews the current status of x-ray and MRI in osteoarthritis and points to where changes might be anticipated in the future. ",0
3159,16516278,Juvenile granulosa cell tumor of the ovary associated with tuberous sclerosis,"Tuberous sclerosis is a neurocutaneous syndrome characterized by benign tumors that can affect many organs. Juvenile granulosa cell tumors of the ovary are rare neoplasms that typically occur in the first three decades of life and have excellent prognosis for early-staged disease. We report the first case of an 8-year-old white female with tuberous sclerosis and juvenile granulosa cell tumor of the ovary. She presented with a 20 x 22 cm pelvic mass and received a right salpingo-oophorectomy. Three months later, she recurred and underwent a left salpingo-oophorectomy, lymphadenectomy, and omentectomy followed by four cycles of Bleomycin, Etoposide, and Cisplatin chemotherapy. She is currently free of disease 8 years after her recurrence. Treatment options and a review of the literature pertaining to juvenile ovarian granulosa cell tumors and tuberous sclerosis are discussed. ",0
3160,16516401,Neoneurogenesis: tumors may initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis,"Malignant tumors frequently release angiogenic factors, which lead to the vascularization of the tumor, a process called neoangiogenesis. This neoangiogenesis provides sufficient nourishment of the tumor when it exceeds a certain size. Recently, a similar mechanism has been postulated for the development of new lymph vessels in tumors, termed lymphangiogenesis. Thus, tumors get access to the circulation and lymph drainage like any other growing or regenerating tissue. Furthermore, it has been hypothesized that neoangiogenesis and lymphangiogenesis support metastasis development. Elaborating on this model, we herein present strong arguments for the new theory that tumors initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis. For this process, we coin the term neoneurogenesis. It is likely that neoneurogenesis further supports the formation of metastases, since the ingrown nerve endings can release neurotransmitters which enhance the metastasis development. Strikingly, the presence of nerve cell markers in tumor tissues has been shown to be a prognostic marker for the course of a cancer disease, and we have recently reported on the metastasis-increasing function of the neurotransmitter norepinephrine in a mouse model. ",0
3161,16516429,Determination of flavonoids in Portulaca oleracea L. by capillary electrophoresis with electrochemical detection,"A general method based on capillary electrophoresis with electrochemical detection (CE-ED) was developed for identification and determination of five flavonoids (kaempferol, apigenin, myricetin, quercetin and luteolin) in plant species. Running buffer, pH and concentration, separation voltage, injection time and detection potential were investigated to acquire the optimum conditions. The working electrode was a 500 microm diameter carbon disc electrode positioned opposite the outlet of capillary. At room temperature, the five flavonoids could be well separated within 21 min in a 60 cm length capillary at a separation voltage of 19.5 kV with 50 mM Na2B4O7-100 mM NaH2PO4 (pH 8.50) as the running buffer. The relationship between peak currents and analyte concentrations was linear over about two orders of magnitude, and the detection limits (S/N=3) were ranging from 0.12 to 0.21 microg/ml for all analytes. The optimized CE-ED method was employed to analyze the above flavonoids in different parts of Portulaca oleracea L. ",0
3162,16516891,Epigallocatechin-3-gallate protects toluene diisocyanate-induced airway inflammation in a murine model of asthma,"Epigallocatechin-3-gallate (EGCG), a major form of tea catechin, has anti-allergic properties. To elucidate the anti-allergic mechanisms of EGCG, we investigated its regulation of matrix metalloproteinase (MMP-9) expression in toluene diisocyanate (TDI)-inhalation lung tissues as well as TNF-alpha and Th2 cytokine (IL-5) production in BAL fluid. Compared with untreated asthmatic mice those administrated with EGCG had significantly reduced asthmatic reaction. Also, increased reactive oxygen species (ROS) generation by TDI inhalation was diminished by administration of EGCG in BAL fluid. These results suggest that EGCG regulates inflammatory cell migration possibly by suppressing MMP-9 production and ROS generation, and indicate that EGCG may be useful as an adjuvant therapy for bronchial asthma. ",0
3163,16516892,"The novel neurotrophin-regulated neuronal development-associated protein, NDAP, mediates apoptosis","""We identified a novel gene and named it, """"neuronal development-associated protein (NDAP)"""". We detected NDAP mRNA presence in most tissues including the brain where it was present in the area from the external granular layer to the multiform layer in the cerebral cortex, and in CA1, CA2, CA3 and the dentate gyrus in the hippocampus. Its expression increased transiently in primary cultures of 2-4 day neurons and 1-2 week astrocytes and was significantly reduced in older cultures. Treatment by the neurotrophin, NT-3, significantly attenuated the decline of NDAP in neurons from days 2 to 10, whereas growth factors such as GDNF and insulin, and high potassium levels did not. To elucidate the effects of neurotrophins, we treated day 5 neurons with NT-3, BDNF or NGF for 48 h. NT-3 and BDNF both inhibited downregulation of NDAP mRNA levels but NGF slightly enhanced the already present downregulation; this effect of NGF was significant when examined in day 3 neurons. To investigate the potential function of NDAP, we over-expressed an NDAP-EGFP fusion protein in 4-week-old astrocytes. The newly expressed NDAP gradually aggregated into membrane-bound structures and eventually led to cell death through apoptosis by 24 h. Significant levels of cell death were also observed in NDAP-EGFP transfected HEK293 cells. Thus maintenance of high NDAP levels may cause apoptosis. The different regulations of NDAP expression by neurotrophins indicate that the expression of NDAP might be a checkpoint for apoptosis during neuronal development. """,0
3164,16517009,Cross-transmission of nosocomial pathogens in an adult intensive care unit: incidence and risk factors,"The incidence and determinants of cross-transmission in an adult intensive care unit (ICU) were examined under normal conditions. Four hundred and thirty patients were followed for 3947 patient-days. Cross-transmitted pathogens were identified by genetic typing. A cross-transmission episode was defined as when two or more patients had indistinguishable isolates and had been treated in the ICU during intervals up to seven days apart. The direction of cross-transmission was confirmed if the incriminated pathogen was isolated from the donor before admission of the recipient; otherwise, both patients could potentially be a donor or a recipient. These patients were excluded from the risk factor analysis. Recipients of pathogens were compared with those who were not involved in cross-transmission. Out of 22 056 examined specimens, 275 isolates were typed and 40 episodes of cross-transmission were detected. The overall incidence of cross-transmission was 10.7 [95% confidence intervals (CI) 7.6-14.5] per 1000 patient-days. In multivariate analysis, those who were nursed in an understaffed environment [odds ratio (OR) = 3.3, 95% CI 1.4-7.8], had a nasogastric tube (OR = 2.9, 95% CI 1.1-7.8) and were ventilated (OR = 2.5, 95% CI 1.1-6.0) for all of their stay, compared with none or part of their stay, showed an increase in the risk of cross-transmission. Repeated bronchoscopy (OR = 5.1, 95% CI 1.04-25) compared with no bronchoscopy and immunosuppresion (OR = 3.9, 95% CI 1.2-12.5) also increased the risk. This study showed that cross-transmission of nosocomial pathogens in the ICU is associated with understaffing, immunosuppression and factors that result in multiple staff/patient contacts, thus emphasizing the importance of hand hygiene. ",0
3165,16517021,Brain regional alterations in the modulation of the glutamate-nitric oxide-cGMP pathway in liver cirrhosis. Role of hyperammonemia and cell types involved,"Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function and alterations in personality and neuromuscular coordination. Hyperammonemia and liver failure result in altered glutamatergic neurotransmission, which contributes to hepatic encephalopathy. Alterations in the function of the glutamate-nitric oxide-cGMP pathway may be responsible for some of the neurological alterations found in hepatic encephalopathy. The function of this pathway is altered in brain from patients died with liver cirrhosis and one altered step of the pathway is the activation of soluble guanylate cyclase by nitric oxide, which is increased in cerebral cortex and reduced in cerebellum from these patients. Portacaval anastomosis and bile duct ligation plus hyperammonemia in rats reproduce the alterations in the activation of soluble guanylate cyclase by NO both in cerebellum and cerebral cortex. We assessed whether hyperammonemia is responsible for the region-selective alterations in guanylate cyclase modulation in liver cirrhosis and whether the alteration occurs in neurons or in astrocytes. Activation of guanylate cyclase by nitric oxide is lower in cerebellar neurons exposed to ammonia (1.5-fold) than in control neurons (3.3-fold). The activation of guanylate cyclase by nitric oxide is higher in cortical neurons exposed to ammonia (8.7-fold) than in control neurons (5.5-fold). The activation is not affected in cerebellar or cortical astrocytes. These findings indicate that hyperammonemia is responsible for the differential alterations in the modulation of soluble guanylate cyclase by nitric oxide in cerebellum and cerebral cortex of cirrhotic patients. Moreover, under the conditions used, the alterations occur selectively in neurons and not in astrocytes. ",0
3166,16517120,A comparison of in vivo and in vitro neuroimaging of 5-HT 1A receptor binding sites in the cat brain,"To validate the cat as a suitable model for positron emission tomography imaging (PET) and to gain further knowledge on the anatomical distribution of the serotonin-1A receptor (5-HT 1A) in the feline brain, we used PET with [18F]MPPF and in vitro autoradiography with [3H]MPPF, [3H]8-OH-DPAT and [3H]paroxetine. PET radioactivity curves with [18F]MPPF were very reproducible in anaesthetized cats, with the highest radioactivity uptakes recorded in the hippocampus, cingulate cortex, septum, infralimbic cortex and raphe nucleus, whereas the lowest were found in the cerebellum. [3H]8-OH-DPAT binding displayed a comparable, albeit lower, regional distribution than with [3H]MPPF. Autoradiography also revealed the presence of 5-HT 1A receptor binding sites in the cortex and in the interpeduncular nucleus, due to its greater sensitivity and spatial resolution compared with PET imaging. The cat constitutes an interesting experimental model for PET imaging, as many physiological concepts have been well established with this animal. Our study also shows the advantages of combining complementary neuroimaging techniques such as in vivo PET imaging and in vitro autoradiography to visualize the distribution of the 5-HT 1A receptors. ",0
3167,16517228,Development and validation of isomer specific RP-HPLC method for quantification of cefpodoxime proxetil,"The present work explains the development and validation of a simple and reliable isomer specific liquid chromatographic method for the quantitative determination of cefpodoxime proxetil (CP) in rat in situ intestinal perfusate samples. Chromatography was carried out by reversed-phase technique on a C-18 column with a mobile phase composed of 20 mM ammonium acetate buffer (pH 5.0) and acetonitrile in the ratio of 62:38 pumped at a flow-rate of 1 ml/min. The detection was carried out at 235 nm and a column temperature of 30 degrees C. The method was evaluated for the various validation parameters, such as linearity, accuracy, precision, LOD, LOQ, specificity, selectivity, and sample stability. The results of intra- and inter-day validation (n = 3) showed the method to be efficient and the same was applied in an in situ permeability study conducted for CP in rats. ",0
3168,16517960,Metabolic mechanisms of stress hyperglycemia,"Stress hyperglycemia has gained the attention of virtually every physician who encounters critically ill patients, with the emergence of clinical data supporting tight glycemic control and intensive insulinization for optimal outcome. In order to effectively manage stress hyperglycemia, newer theories of critical illness and the interactions of the brain, neuroendocrine axis, and immune system need to be explored. Nonlinear physiologic processes, glucose allostasis, immune-neuroendocrine axis activation, and molecular mechanisms of insulin receptor signal transduction contribute to a novel model of stress hyperglycemia. In chronic critical illness, allostatic overload leads to a plurality of organ-system derangements and eventually death. Intervention not only involves insulinization according to neurofuzzy logic but also targeting more proximate events with cognitive/behavioral therapy and hypothalamic releasing factors. ",0
3169,16518133,Somatic augmentation strategies in clozapine resistance--what facts?,"Polypharmacy without evidence-based support is sometimes needed for patients treated with 40% to 70% clozapine who are clozapine nonresponders. Several somatic augmentation strategies are proposed in the scientific literature, with different levels of evidence for safety and efficacy. The purpose of the present study is to review the available literature on the efficacy and safety of clozapine augmentation with somatic agents other than antipsychotics. The following classes of agents are considered: (1) mood stabilizers, (2) antidepressants, (3) electroconvulsive therapy and repetitive transcranial magnetic stimulation, (4) glutamatergic agents, (5)fatty acids supplements, and (6) benzodiazepines. Case controls and small-size clinical trials largely dominate the literature, limiting the power to draw conclusions concerning safety issues and the meaning of negative studies. Moreover, variable definitions of clozapine resistance, heterogeneous outcome measures, and short duration of treatment trials are additional limitations. Generally, adjunctive strategies for clozapine-resistant patients remain based on scarce evidence of efficacy and significant safety concerns. Low-frequency repetitive transcranial magnetic stimulation, fatty acids supplements, and mirtazapine showed good tolerability and some efficacy, but the results need replication. ",0
3170,16518291,Difficulty in diagnosing acute appendicitis in the presence of acute portal vein thrombosis: the role of CT scan. Report of 2 cases],Acute appendicitis can cause of portal vein thrombosis. Diagnosis of appendicitis can be difficult because its symptoms may be masked by those of acute portal vein thrombosis. We report 2 cases of appendicitis associated with acute portal vein thrombosis whose diagnosis was delayed by several months. The delayed diagnosis of acute appendicitis in the presence of acute portal vein thrombosis can be avoided by using spiral-computed tomography and careful investigation of signs of appendicitis. ,0
3171,16518556,Health-related quality of life among chronic stroke survivors attending a rehabilitation clinic,"To assess health-related quality of life (HRQOL) among chronic stroke survivors and factors associated with it. Cross-sectional survey study of patients who had survived one year or more after a stroke. Subjects consisted of stroke patients attending the outpatient clinic of a rehabilitation centre. HRQOL was assessed using the Medical Outcomes 36-Item Short-Form Health Survey (SF-36), functional status using the Modified Barthel Index (MBI), and mood using the Beck's Depression Inventory (BDI). A total of 100 patients (63 men and 37 women, mean age 60.7 +/-10.8 years) were interviewed at an average of 22.2 +/-14.5 months post-stroke. The mean MBI was 88.9 +/-17.9, and the prevalence of depression 24%. 50 percent of patients needed varying degrees of care for their activities of daily living. The SF-36 scores of the patients were comparable to that of the general population except for the domain of physical function, which was much lower (23.9 versus 83.4). Age, sex, post-stroke duration, MBI score and side of hemiplegia were not associated with HRQOL. Depressed patients however had significantly lower SF-36 scores across all domains except for that of physical function and bodily pain (p-value is less than 0.001). A significant proportion of chronic stroke survivors attending the rehabilitation clinic continue to face limitations in their physical activities. In addition, almost 30 percent of these survivors have depression that affects their HRQOL adversely. ",0
3172,16518637,Occurrence of tetraploidy in Nicotiana attenuata plants after Agrobacterium-mediated transformation is genotype specific but independent of polysomaty of explant tissue,"Genotypes of Nicotiana attenuata collected from Utah and Arizona were transformed with 17 different vectors (14 unpublished vectors based on 3 new backbone vectors) using an Agrobacterium-mediated procedure to functionally analyze genes important for plant-insect interactions. None of the 51 T1-T3 transgenic Utah lines analyzed by the flow cytometry were tetraploid, as opposed to 18 of 33 transgenic Arizona lines (55%). Analysis of T0 regenerants transformed with the same vector carrying an inverted repeat (IR) N. attenuata pro-systemin construct confirmed the genotype dependency of tetraploidization: none of the 23 transgenic Utah lines were tetraploid but 31 (72%) of 43 transgenic Arizonas were tetraploid. We tested the hypothesis that the differences in polysomaty of the explant tissues accounted for genotype dependency of tetraploid formation by measuring polysomaty levels in different seedling tissues. Hypocotyls, cotyledons, and roots of Utah and Arizona genotypes contained similar percentages of 4C nuclei (61 and 60; 7 and 5; and 58 and 61%, respectively). Since we used hypocotyls as explant sources and the nonoccurrence of tetraploid Utah transformants does not correspond to the high percentage of 4C nuclei in Utah hypocotyls, we can rule out a direct relationship between tetraploid formation and polysomaty level. We hypothesize that the difference between the Utah and Arizona genotypes results from the failure of polyploid Utah callus to regenerate into fully competent plants. We propose that future work on post-transformation polyploidy concentrate on the processes that occur during callus formation and plant regeneration from callus. ",0
3173,16519314,"Effect of short-term exposure to methyl-tert-butyl ether and tert-butyl alcohol on the hatch rate and development of the African catfish, Clarias gariepinus","Methyl tert-butyl ether (MTBE), a synthetic chemical used as a fuel additive, has been detected more frequently in the environment than previously. In this study, we examine the effects of MTBE (up to 100 mg/L) and its primary metabolite tertbutyl alcohol (TBA) (up to 1,400 mg/L) on the hatch rate and larval development of the African catfish Clarias gariepinus. Exposure to higher MTBE concentrations resulted in deformed eyes, mouthparts, and spinal cord and in increased larval mortality. Methyl tert-butyl ether exposure had no significant impact on egg viability, whereas TBA induced a decline of hatch rate. The MTBE can be regarded as a pollutant with toxicological effects on catfish larvae at concentrations above 50 mg/L. Although such concentrations greatly surpass present-day concentrations found in surface water (0.088 mg/L), concentrations up to 200 mg/L have been detected in groundwater. ",0
3174,16519471,Probing the surface of polymer colloids by conductometric surfactant titration,"This work revisits the use of surfactant titrations for the characterization of latex particle surfaces. Experiments were performed to study the effect of comonomer composition and the effect of acid comonomers, and the technique is applied to the characterization of particle morphology in composite latices for several different systems. It is confirmed that the packing density of surfactant on a polymer surface is a linear function of copolymer composition. Inclusion of acid comonomers has the expected effect of decreasing the amount of surfactant adsorbed on the polymer surfaces. The usefulness of the technique in the determination of particle morphology is demonstrated, in particular toward the detection of thin layers of either seed or second-stage polymer on the particle surface which are not easily detected by other techniques such as transmission electron microscopy (TEM). Finally, it is shown that the use of acid comonomers in composite particles greatly reduces the usefulness of the surfactant titration technique for morphology characterization. A possible explanation for this effect is proposed. ",0
3175,16519545,Trends in outpatient prescription drug use and related costs in the US: 1998-2003,"To present a brief synopsis of trends in the number of prescriptions and retail costs of outpatient drugs dispensed in the US between 1998 and 2003. Data were extracted from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index databases. In 1998, 2.7 billion outpatient prescriptions were dispensed versus 3.6 billion in 2003. This equates to a 33.3% increase over the 6-year period. Of the top 20 most dispensed drugs by volume, 40% were launched in the 1990s or 2000s. Retail costs for the total market of dispensed outpatient prescription drugs were 96.1 billion US dollars in 1998 and 196 billion US dollars in 2003, a 104% increase. Of the top 20 most dispensed drugs by retail cost, all were tradename drugs and were launched in the 1990s or 2000s. These data indicate a large increase in the US over a short time period in dispensed outpatient prescriptions and their associated retail costs. ",0
3176,16519816,"Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology","The Direct Repeat locus of the Mycobacterium tuberculosis complex (MTC) is a member of the CRISPR (Clustered regularly interspaced short palindromic repeats) sequences family. Spoligotyping is the widely used PCR-based reverse-hybridization blotting technique that assays the genetic diversity of this locus and is useful both for clinical laboratory, molecular epidemiology, evolutionary and population genetics. It is easy, robust, cheap, and produces highly diverse portable numerical results, as the result of the combination of (1) Unique Events Polymorphism (UEP) (2) Insertion-Sequence-mediated genetic recombination. Genetic convergence, although rare, was also previously demonstrated. Three previous international spoligotype databases had partly revealed the global and local geographical structures of MTC bacilli populations, however, there was a need for the release of a new, more representative and extended, international spoligotyping database. The fourth international spoligotyping database, SpolDB4, describes 1939 shared-types (STs) representative of a total of 39,295 strains from 122 countries, which are tentatively classified into 62 clades/lineages using a mixed expert-based and bioinformatical approach. The SpolDB4 update adds 26 new potentially phylogeographically-specific MTC genotype families. It provides a clearer picture of the current MTC genomes diversity as well as on the relationships between the genetic attributes investigated (spoligotypes) and the infra-species classification and evolutionary history of the species. Indeed, an independent Naïve-Bayes mixture-model analysis has validated main of the previous supervised SpolDB3 classification results, confirming the usefulness of both supervised and unsupervised models as an approach to understand MTC population structure. Updated results on the epidemiological status of spoligotypes, as well as genetic prevalence maps on six main lineages are also shown. Our results suggests the existence of fine geographical genetic clines within MTC populations, that could mirror the passed and present Homo sapiens sapiens demographical and mycobacterial co-evolutionary history whose structure could be further reconstructed and modelled, thereby providing a large-scale conceptual framework of the global TB Epidemiologic Network. Our results broaden the knowledge of the global phylogeography of the MTC complex. SpolDB4 should be a very useful tool to better define the identity of a given MTC clinical isolate, and to better analyze the links between its current spreading and previous evolutionary history. The building and mining of extended MTC polymorphic genetic databases is in progress. ",0
3177,16519952,Mucosal healing and mucociliary transport change after endoscopic sinus surgery in children with chronic maxillary sinusitis,"The aim of the study was to evaluate the effects of endoscopic sinus surgery for chronic maxillary sinusitis in children by investigating ultrastructure element changes in the sinus mucosa and nasal mucociliary clearance before and after operation. Twenty-five children with chronic maxillary sinusitis scheduled to undergo functional endoscopic sinus surgery and another five controls were enrolled. A saccharin transit test was performed before and after the operation for each subject. Forty specimens of diseased maxillary sinus mucosa were classified into edematous and polypoid types, with 20 specimens in each type. The mucosal specimens were taken from the superolateral wall of each maxillary sinus during surgery and at post-operative follow-up when the mucosal recovery had begun and the symptoms had subsided. The specimens were examined with a scanning electron microscope. A significant increase in number of the submucosal gland openings (GO) was noted for the sinusitis group, of both edematous and polypoid types. In post-operative cases, the number of gland openings decreased, however, it remained higher than for the control group. The number of goblet cells (GC) decreased in the sinusitis cases, and significant difference was not demonstrated compared to postoperative and control groups. After endoscopic sinus surgery, the cilia in both types of antral mucosa were significantly regenerated compared to preoperative variants. Significant differences in postoperative saccharin transit time were demonstrated for both types of antral mucosa compared to the preoperative values. After endoscopic sinus surgery for chronic pediatric sinusitis, the antral mucosa recovered and mucociliary clearance improved for both types of antral mucosa, with improved ventilation and drainage demonstrated for our patients. Based on our specimens, the edematous mucosa appear to regenerate sooner than the polypoid variant, with close post-operative follow-up for more than 2 and 4 months for the edematous and polypoid types of antral mucosa, respectively, necessary to prevent sinusitis relapse. ",0
3178,16520464,"Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia","Purine analogs and alkylators are important agents for treating chronic lymphocytic leukemia (CLL). Early studies combining fludarabine and chlorambucil were abandoned owing to increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive. We previously reported that pentostatin and cyclophosphamide (PC) is active and well-tolerated in patients with relapsed or refractory CLL. Subsequently, we added rituximab, and now report on this three-drug combination. We treated 46 patients with either previously treated CLL (32 patients) or other low-grade B-cell neoplasms (14 patients). Patients received pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2 (PCR). All drugs were administered on the same day (rituximab omitted from cycle 1), and patients received six cycles at 3-week intervals. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median age was 62 years (range, 30 to 80 years). The median number of prior regimens was two (range, one to seven). For CLL patients, there were 24 responses (75%), including eight complete responses (25%). In fludarabine-refractory patients, 75% responded. Toxicity was acceptable, with grade 3/4 infections (including fever of unknown origin) in 28%. The regimen was well tolerated, with 72% of patients receiving the planned treatment at full dose. PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL. ",0
3179,16520510,Community health center integration: experience in the State of Ohio,"In the face of severe financial challenges and demands to improve quality and service to patients, many community health centers (CHCs) have aligned or integrated with other CHCs, physician groups, or hospitals. Yet the nature of and rationale for these organizational decisions are not well understood. Our research applied an organizational theoretical framework to test whether strategic adaptation theory or institutional theory best describes the integration activity of CHCs in Ohio. We collected primary data from case studies of seven CHCs selected for geographic representation and studied December 2000-January 2001. Semi-structured interviews and a case study database supported our chain of evidence. We found that CHC integration activity was substantial (five of seven CHCs integrated) and extremely varied. Consistent with strategic adaptation theory, we determined that CHC integration actions were predominantly center-specific, rational responses to environmental challenges and were initiated to improve operations or financial performance. Rarely did CHCs initiate major organizational change merely to mimic other CHC actions, as might have been expected of highly institutionalized organizations. Understanding the basis for CHCs' strategic decisions while monitoring financial health will remain critical as lawmakers and administrators work to develop policies that both maintain progress made and improve primary care access for the poor, the uninsured, and those with special health care needs served by these important safety net providers. ",0
3180,16520902,"Delivery of viral vectors to tumor cells: extracellular transport, systemic distribution, and strategies for improvement","It is a challenge to deliver therapeutic genes to tumor cells using viral vectors because (i) the size of these vectors are close to or larger than the space between fibers in extracellular matrix and (ii) viral proteins are potentially toxic in normal tissues. In general, gene delivery is hindered by various physiological barriers to virus transport from the site of injection to the nucleus of tumor cells and is limited by normal tissue tolerance of toxicity determined by local concentrations of transgene products and viral proteins. To illustrate the obstacles encountered in the delivery and yet limit the scope of discussion, this review focuses only on extracellular transport in solid tumors and distribution of viral vectors in normal organs after they are injected intravenously or intratumorally. This review also discusses current strategies for improving intratumoral transport and specificity of viral vectors. ",0
3181,16520922,Erythrocyte omega-3 and omega-6 polyunsaturated fatty acids and preeclampsia risk in Peruvian women,"This case-control study was conducted in Lima, Peru, from June 1997 through January 1998 to assess whether alteration in maternal erythrocyte omega-3 (n-3) and omega-6 (n-6) fatty acids was associated with increased risk of preeclampsia. A total of 99 preeclampsia and 100 normotensive pregnant women were included. Maternal erythrocyte n-3 and n-6 fatty acids were determined using capillary gas chromatography/mass spectrometry and expressed as micromolar (mM) concentrations. We employed logistic regression procedures to estimate odds ratios (ORs) and 95% confidence intervals (CIs). n-3 fatty acids were consistently lower in preeclampsia cases than controls. After adjusting for confounders, the corresponding ORs for preeclampsia across decreasing quartiles of sum of long-chain n-3 fatty acids were 1.0, 3.3, 2.4, and 3.3, respectively (P=0.07 for trend). A similar pattern was observed for eicosapentenoic acid (20:5n-3, EPA) and docosahexenoic acid (22:6n-3, DHA). There was no clear evidence of an association between arachidonic acid (20:4n-6, AA) and preeclampsia risk, the ORs in successively lower quartiles were 1.0, 1.1, 1.0, and 1.5 (P=0.48 for trend). A similar pattern was seen for the sum of long-chain n-6 fatty acids. In Peruvian women, low erythrocyte n-3 fatty acids appeared to be associated with an increased risk of preeclampsia. ",0
3182,16521193,Successful laparoscopic management for cholecystoenteric fistula,"Since 1987, laparoscopic cholecystectomy (LC) has been widely used as the favored treatment for gallbladder lesions. Cholecystoenteric fistula (CF) is an uncommon complication of the gallbladder disease, which has been one of the reasons for the conversion from LC to open cholecystectomy. Here, we have reported four cases of CF managed successfully by laparoscopic approach without conversion to open cholecystectomy. During the 4-year period from 2000 to 2004, the medical records of the four patients with CF treated successfully with laparoscopic management at the Chang Gung Memorial Hospital-Taipei were retrospectively reviewed. The study comprised two male and two female patients with ages ranging from 36 to 74 years (median: 53.5 years). All the four patients had right upper quadrant pain. Two of the four patients were detected with pneumobilia by abdominal ultrasonography. One patient was diagnosed with cholecystocolic fistula preoperatively correctly by endoscopic retrograde cholangiopancreatography and the other one was diagnosed as cholecystoduodenal fistula by magnetic resonance cholangiopancreatography. Correct preoperative diagnosis of CF was made in two of the four patients with 50% preoperative diagnostic rate. All the four patients underwent LC and closure of the fistula was carried out by using Endo-GIA successfully with uneventful postoperative courses. The hospital stay of the four patients ranged from 7 to 10 d (median, 8 d). CF is a known complication of chronic gallbladder disease that is traditionally considered as a contraindication to LC. Correct preoperative diagnosis of CF demands high index of suspicion and determines the success of laparoscopic management for the subset of patients. The difficult laparoscopic repair is safe and effective in the experienced hands of laparoscopic surgeons. ",0
3183,16521390,Is now the time to purchase an in-office CAD/CAM device?,"In-office CAD/CAM is a reality. It allows fabrication of tooth-colored inlays and onlays, crowns and veneers in one appointment. It is especially well-suited to dentists who accomplish many single-tooth or single-quadrant restorations. As with any new technology, its cost is high, but using it can be financially feasible. Clinical and basic science investigations have resulted in positive findings on the concept. There are some significant advantages and several disadvantages. In-office CAD/CAM works well for many dentists, but practitioners should evaluate it carefully before accepting it, as it is not for everybody. ",0
3184,16521433,Classical and novel molecular prognostic factors in ovarian cancers],"Development of molecular biology techniques allows at present for a more rapid and more reliable diagnosis of ovarian cancers. Present paper describes genetic alterations which predispose to development of ovarian cancer and mutations which play principal role in pathogenesis of sporadic cases of the disease. Prognostic significance has also been outlined of expression of cyclooxygenase 2, ligands of P-selectin and inhibitors of complement in cells of ovarian cancer as well as their potential therapeutic significance. A separate chapter has been devoted to the potential and achievements gained using DNA microarray techniques. ",0
3185,16521616,Health seeking behaviors of African Americans: implications for health administration,"Disparities in health care and good health between African Americans and other populations while established in the literature are traditionally based on socioeconomic measures of race, income, age, and education (Bailey, 2000; Lillie-Blanton, Brodie, Rowland, Altman and McIntosh, 2000; Ren and Amick, 1996; Watson, 2001; Weinick, Zuvekas, and Cohen, 2000). This study broadens the scope by exploring how sociocultural (poverty, racism, prejudice, and discrimination) and psychosocial factors (perceived health status, the lack of personal efficacy in contributing to decisions about health care. feelings of helplessness, and the lack of trust in the health care providers) relate to health-seeking behaviors of African Americans (Bailey, 1991; Ren and Amick, 1996, Watson, 2001). Interviews were conducted with 111 African American adult patients at a community health center, focusing on health-seeking behaviors, and sociocultural and psychosocial factors. Results suggest that when these negative factors are removed, the health seeking behaviors of African Americans closely mirror the behaviors of the majority population. Subjects did not view themselves in poorer health, fail to seek medical attention when needed, or distrust their primary health care providers. In general, fears associated with health care were attributed to illness rather than health care providers, although a weak linkage was found between patient self-esteem and fear or dislike of future treatment by physicians (adj R2= .362, S.E. =15, F=21, sig. <.001). The study highlights the need for further study in two areas: cultural competency of health care providers, especially those from Asia and Africa who are often assigned to community health centers, and the impact of an accessible community health center on the health seeking behaviors and health status of predominately African American communities. ",0
3186,16521690,Adult granulosa cell tumor of the ovary: 35 cases in a single Korean Institute,"Adult granulosa cell tumor of the ovary is an uncommon neoplasm. The overall prognosis is favorable. The prognostic factors that are related to survival have not been well defined and are discussed in the literature amidst controversy. Thirty-five patients diagnosed with adult granulosa cell tumor of the ovary were reviewed retrospectively. Demographic data, pathologic findings, treatments, and survival times were reviewed and analyzed for prognostic significance. Of the 35 cases, there were 30 cases representing stage I tumors, one case at stage II, four cases at stage III, and no cases at stage IV. The mean overall survival time of all patients was 140.3 months. The 5- and 10-year survival rates were 92.0% and 85.8% respectively. The FIGO stage was the only independent prognostic factor. Despite the small number of patients, the study showed that the less advanced stage is the only favorable prognostic factor of significance. ",0
3187,16523570,The struggle to maintain neutrality in the treatment of patient with pedophilia,"This article explores the ethical concept of neutrality through use of a psychiatric clinical vignette. In this case a psychiatry resident is faced with the treatment of a patient who was found by the FBI to be in possession of child pornography. Although not accused of any other crimes, the patient was a fugitive from the law and requesting treatment for pedophilia. Faced with the pressures of limited resources and anxiety about the patient's dangerousness to others, the resident and his supervisor tried to strike a balance between the ethical principles of neutrality and beneficence. Through this vignette, the importance of neutrality, as well as how it can be compromised by other pressures such as expediency and anxiety, is explored. ",0
3188,16524112,Psychosocial aspects of patients with sexual dysfunction],"Sexual dysfunctions are common among the general population. An essential part of the assignments to specialized sexual medicine care units are from primary care physicians. In 2002 to 2004 for a period of 18 months questionnaires were given to all patients, who attended the special sexual medicine care unit at the University Hospital of Zurich for the first time. At the beginning of their treatment, the patients were questioned about different psychosocial characteristics and aspects of their sexuality. We studied 43 women (48.3%) and 46 men (51.7%). Women were with an average age of 33.8 years 10 years younger than men, 43.5 years. The most common sexual dysfunction in women was lack or loss of sexual desire (51.2%), followed by nonorganic vaginism (20.9%) and orgasm disorders (11.6%), in men erectile dysfunction (50.0%), followed by premature ejaculation (26.1%) and lack or loss of sexual desire (15.2%). The studied subjects showed distinctively lower values in their sense of coherence than men and women in the general population. The patients were much more anxious than people in the average population. The questioned men were also much more depressive than men in the general population and than the examined women. The examined men reported sexual wishes, needs and sexual activities significant more frequently than the examined women. As men and women with sexual dysfunctions are much more anxious than people from the general population, physicians should address sexual themes in the conversations with their patients carefully but actively. ",0
3189,16524416,Endemic fungal infections caused by Cryptococcus neoformans and Penicillium marneffei in patients infected with human immunodeficiency virus and treated with highly active anti-retroviral therapy,"This study compared the clinical presentations of 58 episodes of cryptococcosis in 50 patients and 26 episodes of penicillosis in 25 patients infected with human immunodeficiency virus (HIV) between June 1994 and June 2004, and assessed the safety of discontinuation of secondary prophylaxis for endemic fungal infections in those patients responding to highly active anti-retroviral therapy (HAART). Neurological symptoms were seen more commonly in patients with cryptococcosis, whereas respiratory symptoms, lymphadenopathy, hepatomegaly and/or splenomegaly, and non-thrush-related oral presentations were seen more commonly in patients with penicillosis. Patients with penicillosis were more likely to have abnormal chest radiography results and radiographic presentations of interstitial lesions, cavitations, fibrotic lesions and mass lesions. At the end of the study, maintenance antifungal therapy had been discontinued in 27 patients with cryptococcosis and in 18 patients with penicillosis in whom the median CD4 count had increased to 186 cells/microL (range, 9-523 cells/microL) and 95 cells/microL (range, 15-359 cells/microL), respectively, after HAART. Only one episode of penicillosis recurred (a relapse rate of 1.72/100 person-years; 95% CI, 1.44-2.10/100 person-years) after a median follow-up duration of 35.3 months (range, 2.6-91.6 months). No relapses occurred in patients with cryptococcosis after a median follow-up duration of 22.3 months (range, 1-83.4 months). These findings suggest that there are differences in the clinical presentations between endemic cryptococcosis and penicillosis in patients with HIV infection, and that it is safe to discontinue secondary antifungal prophylaxis for cryptococcosis and penicillosis in patients responding to HAART. ",0
3190,16524533,Valvular heart disease in pregnancy,"Women with valvular disease who are pregnant or planning to conceive require careful evaluation and management. Pregnancy is associated with normal physiologic changes that can aggravate many valvular conditions and may require the initiation or increase of cardiovascular medications to manage fluid overload or arrhythmias. Most women will tolerate pregnancy and delivery without major complication, though some types of valvular heart disease are poorly tolerated and require more intensive management, or even termination of the pregnancy. In addition, patients at risk of thromboembolism and those who have prosthetic cardiac valves require anticoagulation. The decision regarding the choice and intensity of anticoagulation requires careful balance between the individual risks of thrombosis and bleeding in the mother and harm to the fetus. ",0
3191,16524912,Fe-hydrogenase maturases in the hydrogenosomes of Trichomonas vaginalis,"Assembly of active Fe-hydrogenase in the chloroplasts of the green alga Chlamydomonas reinhardtii requires auxiliary maturases, the S-adenosylmethionine-dependent enzymes HydG and HydE and the GTPase HydF. Genes encoding homologous maturases had been found in the genomes of all eubacteria that contain Fe-hydrogenase genes but not yet in any other eukaryote. By means of proteomic analysis, we identified a homologue of HydG in the hydrogenosomes, mitochondrion-related organelles that produce hydrogen under anaerobiosis by the activity of Fe-hydrogenase, in the pathogenic protist Trichomonas vaginalis. Genes encoding two other components of the Hyd system, HydE and HydF, were found in the T. vaginalis genome database. Overexpression of HydG, HydE, and HydF in trichomonads showed that all three proteins are specifically targeted to the hydrogenosomes, the site of Fe-hydrogenase maturation. The results of Neighbor-Net analyses of sequence similarities are consistent with a common eubacterial ancestor of HydG, HydE, and HydF in T. vaginalis and C. reinhardtii, supporting a monophyletic origin of Fe-hydrogenase maturases in the two eukaryotes. Although Fe-hydrogenases exist in only a few eukaryotes, related Narf proteins with different cellular functions are widely distributed. Thus, we propose that the acquisition of Fe-hydrogenases, together with Hyd maturases, occurred once in eukaryotic evolution, followed by the appearance of Narf through gene duplication of the Fe-hydrogenase gene and subsequent loss of the Hyd proteins in eukaryotes in which Fe-hydrogenase function was lost. ",0
3192,16524982,AGRIS and AtRegNet. a platform to link cis-regulatory elements and transcription factors into regulatory networks,"Gene regulatory pathways converge at the level of transcription, where interactions among regulatory genes and between regulators and target genes result in the establishment of spatiotemporal patterns of gene expression. The growing identification of direct target genes for key transcription factors (TFs) through traditional and high-throughput experimental approaches has facilitated the elucidation of regulatory networks at the genome level. To integrate this information into a Web-based knowledgebase, we have developed the Arabidopsis Gene Regulatory Information Server (AGRIS). AGRIS, which contains all Arabidopsis (Arabidopsis thaliana) promoter sequences, TFs, and their target genes and functions, provides the scientific community with a platform to establish regulatory networks. AGRIS currently houses three linked databases: AtcisDB (Arabidopsis thaliana cis-regulatory database), AtTFDB (Arabidopsis thaliana transcription factor database), and AtRegNet (Arabidopsis thaliana regulatory network). AtTFDB contains 1,690 Arabidopsis TFs and their sequences (protein and DNA) grouped into 50 (October 2005) families with information on available mutants in the corresponding genes. AtcisDB consists of 25,806 (September 2005) promoter sequences of annotated Arabidopsis genes with a description of putative cis-regulatory elements. AtRegNet links, in direct interactions, several hundred genes with the TFs that control their expression. The current release of AtRegNet contains a total of 187 (September 2005) direct targets for 66 TFs. AGRIS can be accessed at http://Arabidopsis.med.ohio-state.edu. ",0
3193,16525092,Efficacy of sulfadoxine-pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria in East Timor,"The efficacy of sulfadoxine-pyrimethamine (SP) in East Timor is unknown. We treated 38 individuals with uncomplicated Plasmodium falciparum malaria with SP and monitored the outcome for 28 days. Recrudescent parasitemia, confirmed by genotyping, were detected in three individuals resulting in a late treatment failure rate of 7.9% (95% confidence interval = 1.7-21.4%). The results suggest that SP is still efficacious in treating uncomplicated P. falciparum malaria in East Timor. However, the useful life of SP in East Timor may be limited because 80% of the parasites in our samples were found to already carry double mutations in P. falciparum dihydrofolate reductase (S108N/C59R). The data from this study also highlights that the presence of gametocytes may significantly influence the estimate of SP efficacy determined by genotyping. ",0
3194,16525924,Brain lesions in patient diagnosed of meningitis],"Streptococcus pneumoniae is responsible for most community acquired bacterial meningitis in adults. During the course of meningitis, the development of a new neurological focality can be a sign of an associated complication such as cerebritis. We report a case of pneumococcal meningitis in a 40 year old woman who reported blurred vision one week after hospital admission. Ophthalmologic exploration was normal. Brain MR images showed areas of cerebritis. Cerebritis is a rare complication of pneumococcal meningitis. We discuss the differential diagnosis and the utility of the different imaging techniques. ",0
3195,16526252,Familial obesity as a predictor of child obesity],"Studies carried out in various parts of the world indicate that family obesity significantly affects the incidence of obesity in children. This is especially a characteristic of children whose both parents are obese. The study was conducted using a polling method. Questionnaires were filled out by parents and brothers and sisters, including their body height and weight. The collected data served as the basis for assessing the family nutritional status. Statistical analysis of the results showed that obese children frequently have obese parents, brothers and sisters in regard to normal-weight children. Differences are statistically significant in relation to fathers (p=0.043), i.e. statistically obese schoolchildren have more frequently obese fathers than those of normal nutritional status. Other differences could not be considered significant (p > 0.05). Obese children have more often obese parents, brothers and sisters than normal-weight children. It was found that the nutritional status of moderately and extremely obese children was quite different from that of normal-weight children and that there was a statistically significant dependence between the nutritional status of children and their fathers. This research showed that family obesity is a potential contributing factor to obesity of schoolchildren. ",0
3196,16526307,"Types of studies, power of study and choice of test]","In scientific research different study designs are used to provide answers to different questions (e.g., What is the cause of a disease? Is medication A better than medication B? What is the prevalence of a disease?). Cross-sectional study is appropriate when we are interested in the prevalence of a disease or certain feature, cohort study provides answer to the incidence or relative risk, whereas case-control study is conducted to obtain odds ratio. While these studies are observational, randomized control trial is the only experimental study design which can give answers to questions of causative relationships between variables as where researcher himself or herself assigns subjects to different groups (experimental or control). Power of a study represents the probability of finding a difference that exists in a population. It depends on the chosen level of significance, difference that we look for (effect size), variability of the measured variables, and sample size. Most often sample size is the only element under direct researcher's control. Therefore, methods have been developed to approximate the necessary sample size to obtain the desired power. Choosing appropriate statistical procedure is a complicated task that demands specific knowledge and training. To determine an appropriate statistical procedure, it is important to keep in mind the following characteristics of the study: (1) purpose of the study (description, investigation of differences or associations); (2) type of sample (dependent or independent samples); (3) number of groups (one, two, or more); (4) level of measurement (nominal, ordinal, interval or ratio); and (5) distribution of the data (normal or not). ",0
3197,16526318,Early prognostic factors in patients with acute renal failure requiring dialysis,"Despite improvements in renal therapy and technology, the mortality rate of patients with acute renal failure (ARF) remains high. Because ARF is a heterogeneous syndrome, occurring in patients with diverse etiologies and comorbid conditions, predicting its outcome is difficult. This study aims to identify early clinical and laboratory prognostic factors, including acute-phase reactants such as C-reactive protein (CRP), fibrinogen, and albumin, in ARF patients requiring dialysis. From June 2002 to March 2004, 61 patients with ARF requiring dialysis at Chang Gung Memorial Hospital, Chiayi, were prospectively analyzed. For each patient, the worst values of prognostic variables 24 hr before starting dialysis were prospectively assessed. Oliguria, low plasma fibrinogen levels, hypotension, cardiac disease, and neoplastic disease were statistically significant in predicting hospital mortality. Using Youden's index, the best cut-off value for plasma fibrinogen in predicting mortality was 300 mg/dL with a sensitivity and specificity of 61% and 96%, respectively. Serum CRP and serum albumin were not predictive of hospital mortality. Early prognostic factors in predicting mortality for patients with ARF requiring dialysis identified by multivariate logistic regression were oliguria, low plasma fibrinogen, hypotension, cardiac disease, and neoplastic disease. Serum CRP and albumin were not predictive of hospital mortality, whereas a plasma fibrinogen level < or =300 mg/dL had 61% sensitivity and 96% specificity in predicting mortality. ",0
3198,16527157,Neoadjuvant therapy for operable breast-cancer],"Preoperative or neoadjuvant systemic treatment refers to either the first postdiagnosis systemic treatment that a patient receives or indicates that additional subsequent therapy is intended. Randomized controlled clinical trials have shown that preoperative systemic treatment offers the same disease free survival and overall survival benefits as does adjuvant systemic treatment. Neoadjuvant therapy has been found to increase the breast-conserving surgery rate. This therapy also allows to evaluate the primary tumor response to chemotherapy. Additionally, on the basis of the biologic characteristics of a tumor and differences in the response to systemic treatment, primary systemic treatment should be regarded as a tool that can be used to individualize systemic treatment for patients with breast cancer. However, some issues remain to be resolved, such as the markers that should be assessed before this therapy, as well as the optimal surgical and radiotherapy treatment. ",0
3199,16527260,"Cytochrome P450 expression and metabolic activation of cooked food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in MCF10A breast epithelial cells","The cytochrome P450 expression profile was determined in the MCF10A human breast epithelial cell line, as was the ability of this cell line to catalyze the bioactivation of the cooked food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Using non-quantitative reverse transcription-polymerase chain reaction (RT-PCR), transcripts for CYP1B1, CYP2J2, CYP2R1, CYP2U1, CYP2W1, CYP4B1, CYP4F, CYP4V2, CYP4X1 and CYP4Z1 were detected in both sub-confluent and confluent MCF10A cells. By contrast, CYP1A2 mRNA was detected only in confluent MCF10A cells, while CYP1A1, CYP2S1 and CYP2F1 were detected predominantly or exclusively in sub-confluent cultures. 2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment of confluent MCF10A cells markedly induced microsomal ethoxyresorufin O-deethylase activity and CYP1A1, CYP1A2 and CYP1B1 mRNA levels, as determined by real-time RT-PCR, while treatment with 10(-4)M PhIP had little effect on these P450 transcript levels. Treatment of confluent MCF10A cells with PhIP (10(-4)M) for 24, 48 or 72 h produced time-dependent increases in the amounts of DNA adducts, as measured by (32)P-post-labeling. These results indicate that multiple P450s, including those known to catalyze PhIP N-oxidation, are expressed in MCF10A cells, and that this non-neoplastic human breast epithelial cell line contains sufficient enzymatic machinery to support PhIP bioactivation and generate DNA damage. ",0
3200,16527461,Effects of sustained antibiotic bactericidal treatment on Chlamydia trachomatis-infected epithelial-like cells (HeLa) and monocyte-like cells (THP-1 and U-937),"Chlamydia trachomatis is a human pathogen that causes multiple diseases worldwide. Despite appropriate therapy with existing antichlamydial antibiotics, chronic exacerbated diseases often occur and lead to serious sequelae. Since C. trachomatis has been found to enter a persistent state after exposure to deleterious conditions, the role of persistence in the failure of chlamydial antibiotherapy is questioned. HeLa, THP-1 and U-937 cells were infected with 10(4)C. trachomatis serovar L2 infectious particles. Three days later the infected cells were treated with minimal bactericidal concentrations of doxycycline (DOX), erythromycin (ERY) or tetracycline (TET) for 24 days or 30 days. Antibiotic efficacy was assessed by measuring chlamydial inclusions and infectious particles, by investigating the resumption of chlamydial growth after antibiotic removal and by testing Chlamydia viability using reverse transcriptase polymerase chain reaction targeting unprocessed 16S rRNA, processed 16S rRNA and Omp-1 mRNA. Treatment of infected HeLa cells with the usual antichlamydial antibiotics suppressed chlamydial active growth. The infection remained unapparent. However, 24 days post treatment the bacterium was found to be viable, as proved by continued expression of unprocessed and processed 16S rRNA and Omp-1 mRNA. This inactive unapparent chlamydial state is not infectious, suggesting Chlamydia persistence. Chlamydia trachomatis also developed persistence both in permissive THP-1 and non-permissive U-937 cells. Unlike in HeLa cells, persistent chlamydial infection in THP-1 and U-937 cells was resolved after 30 days of DOX treatment. Of interest, we noticed that only THP-1 and U-937 cells that were persistently infected following their interaction with infected HeLa cells remained capable of transmitting active infection to HeLa cells. These findings suggest that DOX, TET and ERY, usually administered to combat chlamydial diseases, fail to resolve persistent infection occurring during treatment in non-immune HeLa cells. However, in immune THP-1 and U-937 cells, the persistent infection is resolved by therapy with DOX. Epithelial cells could be the reservoir of persistent chlamydial particles. ",0
3201,16527862,Nitric oxide synthase 2 and pressure-overload-induced left ventricular remodelling in mice,"Nitric oxide synthase 2 (NOS2) has been reported to increase in hypertrophied cardiomyocytes; however, whether NOS2 plays a role in the development of hypertrophy is unknown. To investigate the relationship of NOS2 with left ventricular (LV) remodelling and hypertrophy following prolonged pressure overload, we studied 18 male wild-type (WT) and 20 male NOS2-deficient (NOS2-/-) mice before and 7, 14 and 28 days after transverse aortic constriction (TAC) using echocardiography. A subgroup of eight WT and eight NOS2-/- mice were studied 42 days after TAC. Haemodynamic measurements were obtained before killing. Left ventricular size and function were similar for both genotypes at baseline. After TAC for 28 days, both groups developed LV hypertrophy, with echo-derived LV mass increasing from 78 +/- 2 to 147 +/- 10 mg in WT and from 86 +/- 3 to 142 +/- 10 mg in NOS2-/- mice. Twenty-eight days after TAC, LV weight and cardiomyocyte width were also similar in both genotypes. Fractional shortening (FS) decreased on day 7 from 57 +/- 1 to 48 +/- 2% in WT and from 59 +/- 1 to 49 +/- 2% in NOS2-/- mice. Although this decrease in FS was transient in WT mice, it persisted in NOS2-/- mice. Invasively measured parameters of systolic and diastolic function, however, were similar in the two genotypes both 28 and 42 days after TAC. A load-independent index of contractility, Emax, was similar in both strains 42 days after TAC. In conclusion, NOS2 does not appear to have a critical role in the development of LV hypertrophy after chronic pressure overload. ",0
3202,16527988,Novel role for STAT-5B in the regulation of Hsp27-FGF-2 axis facilitating thrombin-induced vascular smooth muscle cell growth and motility,"Previously, we have demonstrated that STAT-3 plays a role in thrombin-induced VSMC motility. To learn more about the role of STATs in the mitogenic and chemotactic signaling events of thrombin, here we have studied the role of STAT-5. Thrombin activated STAT-5 as measured by its tyrosine phosphorylation, DNA binding, and reporter gene activity. Inhibition of STAT-5B, but not STAT-5A, by adenovirus-mediated expression of its respective dominant-negative mutants suppressed thrombin-induced VSMC growth and motility. Thrombin induced the expression of Hsp27 and FGF-2 in a time- and STAT-5B-dependent manner in VSMC. In addition, small interfering RNA-directed depletion of Hsp27 levels or adenovirus-mediated expression of its dominant-negative mutant attenuated thrombin-induced FGF-2 expression, growth, and motility of VSMC. An increased association of STAT-5B with STAT-3 occurred in response to thrombin and adenovirus-mediated expression of dnSTAT-3 suppressed thrombin-induced Hsp27 and FGF-2 induction, DNA synthesis and motility in VSMC. Together, these results indicate that thrombin-induced VSMC growth and motility require STAT-5B/STAT-3-dependent expression of Hsp27 and FGF-2. These observations also suggest that STAT-5B/STAT-3/Hsp27/FGF-2 signaling via its involvement in the regulation of VSMC growth and motility may play an important role in the pathogenesis of vascular diseases such as restenosis after angioplasty. ",0
3203,16528246,Escherichia coli lipopolysaccharide inhibits renin activity in human mesangial cells,"Hyperactivation of systemic renin-angiotensin system (RAS) during sepsis is well documented. However, the behavior of intrarenal RAS in the context of endotoxemia is yet to be defined. The present study evaluates the direct effect of Escherichia coli lipopolysaccharide (LPS) on immortalized human mesangial cell (HMC) RAS. Quiescent HMC were incubated with vehicle or LPS (1-100 microg/ml), and levels of angiotensin I and II (Ang I and II) and their metabolites were analyzed by high-performance liquid chromatography. In addition, angiotensin-converting enzyme (ACE) and renin activity were also investigated. Cell lysate and extracellular medium levels of Ang II were rapidly reduced (1 h) in a time- and concentration-dependent manner, reaching a significant -9 fold-change (P<0.001) after 3 h of LPS incubation. Similar results were obtained for Ang I levels (-3 fold-change, P<0.001). We ruled out Ang I and II degradation, as levels of their metabolic fragments were also significantly decreased by LPS. ACE activity was slightly increased following LPS incubation. On the other hand, renin activity was significantly inhibited, as Ang I concentration elevation following exogenous angiotensinogen administration was blunted by LPS (-60% vs vehicle, P<0.001). Renin and angiotensinogen protein levels were not affected by LPS according to Western blot analysis. Taken together, these data demonstrate for the first time that LPS significantly downregulates HMC RAS through inhibition of renin or renin-like activity. These findings are potentially related to the development of and/or recovery from acute renal failure in the context of sepsis. ",0
3204,16528535,Characterization of an ecto-ATPase activity in Fonsecaea pedrosoi,"In this work, we characterized an ecto-ATPase activity in intact mycelial forms of Fonsecaea pedrosoi, the primary causative agent of chromoblastomycosis. In the presence of 1 mM EDTA, fungal cells hydrolyzed adenosine-5'-triphosphate (ATP) at a rate of 84.6 +/- 11.3 nmol Pi h(-1) mg(-1) mycelial dry weight. The ecto-ATPase activity was increased at about five times (498.3 +/- 27.6 nmol Pi h(-1) mg(-1)) in the presence of 5 mM MgCl2, with values of Vmax and apparent Km for Mg-ATP(2-) corresponding to 541.9 +/- 48.6 nmol Pi h(-1) mg(-1) cellular dry weight and 1.9 +/- 0.2 mM, respectively. The Mg2+-stimulated ecto-ATPase activity was insensitive to inhibitors of intracellular ATPases such as vanadate (P-ATPases), bafilomycin A1(V-ATPases), and oligomycin (F-ATPases). Inhibitors of acid phosphatases (molybdate, vanadate, and fluoride) or alkaline phosphatases (levamizole) had no effect on the ecto-ATPase activity. The surface of the Mg2+ -stimulated ATPase in F. pedrosoi was confirmed by assays in which 4,4'-diisothiocyanostylbene-2,2'-disulfonic acid (DIDS), a membrane impermeant inhibitor, and suramin, an inhibitor of ecto-ATPase and antagonist of P2 purinoreceptors. Based on the differential expression of ecto-ATPases in the different morphological stages of F. pedrosoi, the putative role of this enzyme in fungal biology is discussed. ",0
3205,16529166,Acceptance of screening colonoscopy for the prevention of colorectal cancer],"Morbidity and mortality in colorectal cancer are on the rise. Colonoscopy and polypectomy helps to decrease the incidence of colorectal cancer by 75%. This is the first analysis acceptance of screening colonoscopies in Poland. The study was designed to (1) analyze common reasons for consent or refusal to undergo colonoscopy; (2) review the value of diverse sources of information on colonoscopy; (3) determine whether participation in screening colonoscopy programme was connected with participation in other screening examinations; (4) examine the range of pathologic findings; and (5) detect various pathological findings and their location. Two groups of subjects aged 40-65 years were formed: I--consenting to colonoscopy (n=1000) and II--refusing to undergo the examination (n=200). Subjects aged 40-49 years were included when at least one of their first-degree relatives was previously diagnosed with colorectal cancer. Lack of any sign of cancer was requisite for enrollment. Data was extracted from questionnaires filled before and after the examination. The most common reason for consent to colonoscopy was prophylaxis, while refusal was usually due to fear of pain. The most convincing sources of information on colonoscopy were the media. Persons who undergo screening tests for other cancers were more inclined to undergo screening colonoscopy as well. Bowel preparation was more difficult and more inconvenient than the examination itself. Screening colonoscopies are valuable because they enable detection of cancer and adenomatous polyps in asymptomatic patients. Rectosigmoidoscopy would fail to disclose the pathology in 20% of our subjects found positive by colonoscopy. ",0
3206,16529424,Determination of molecular parameters of linear and circular scleroglucan coexisting in ternary mixtures using light scattering,"A combination of static and dynamic light scattering (SLS and DLS) is applied here to determine molecular parameters for coexisting linear and circular scleroglucan polymers of similar molecular weights, dissolved in water, that is, forming a ternary system. The weight-average molecular weights, M(w), were determined to be 3.2 x 10(5) and 3.9 x 10(5) g/mol for the circular and linear molecules, respectively, whereas the z-average radius of gyration, R(g), was found to be equal to 41 nm for the circular molecules and 136 nm for the linear ones. These values are within a physically reasonable range in view of the heterogeneity of the samples. This study confirms that decomposition of total scattering intensities deduced from the dynamic properties can be used to determine molecular parameters of populations of molecules of equal M(w) but different morphologies present in ternary mixtures. ",0
3207,16529662,Paths of lateral gene transfer of lysyl-aminoacyl-tRNA synthetases with a unique evolutionary transition stage of prokaryotes coding for class I and II varieties by the same organisms,"While the premise that lateral gene transfer (LGT) is a dominant evolutionary force is still in considerable dispute, the case for widespread LGT in the family of aminoacyl-tRNA synthetases (aaRS) is no longer contentious. aaRSs are ancient enzymes, guarding the fidelity of the genetic code. They are clustered in two structurally unrelated classes. Only lysine aminoacyl-tRNA synthetase (LysRS) is found both as a class 1 and a class 2 enzyme (LysRS1-2). Remarkably, in several extant prokaryotes both classes of the enzyme coexist, a unique phenomenon that has yet to receive its due attention. We applied a phylogenetic approach for determining the extent and origin of LGT in prokaryotic LysRS. Reconstructing species trees for Archaea and Bacteria, and inferring that their last common ancestors encoded LysRS1 and LysRS2, respectively, we studied the gains and losses of both classes. A complex pattern of LGT events emerged. In specific groups of organisms LysRS1 was replaced by LysRS2 (and vice versa). In one occasion, within the alpha proteobacteria, a LysRS2 to LysRS1 LGT was followed by reversal to LysRS2. After establishing the most likely LGT paths, we studied the possible origins of the laterally transferred genes. To this end, we reconstructed LysRS gene trees and evaluated the likely origins of the laterally transferred genes. While the sources of LysRS1 LGTs were readily identified, those for LysRS2 remain, for now, uncertain. The replacement of one LysRS by another apparently transits through a stage simultaneously coding for both synthetases, probably conferring a selective advantage to the affected organisms. The family of LysRSs features complex LGT events. The currently available data were sufficient for identifying unambiguously the origins of LysRS1 but not of LysRS2 gene transfers. A selective advantage is suggested to organisms encoding simultaneously LysRS1-2. ",0
3208,16529883,Experimental determination of the diffusion boundary layer width of micron and submicron particles,"""Powder dissolution kinetics have shown that for particles in the so called """"large"""" size regime (more than about 50 microm), the dissolution rate scales as the specific surface area, i.e. rate proportional to d(-1) where d is the particle diameter. This is consistent with an effective diffusion boundary layer width h(EFF) that is constant with respect to particle size. However, for particles in the so called """"small"""" size regime (d less than about 50 microm), the dissolution rate has a stronger dependence than proportional to d(-1) [Bisrat, M., Anderberg, E.K., Barnett, M.I., Nystroem, C., 1992. Physicochemical aspects of drug release. XV. Investigation of diffusional transport in dissolution of suspended, sparingly soluble drugs. Int. J. Pharm., 80, 191-201; Mosharraf, M., Nystroem, C., 1995. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int. J. Pharm., 122, 35-47]. In this regime, Prandtl boundary layer theory predicts an h(EFF) approximately equal to the particle radius or diameter. This paper presents the first experimental determination of h(EFF) for particles less than about 2 microm. The powder dissolution kinetics of six suspensions over the particle diameter range of 5.9 +/- 0.1 to 0.53 +/- 0.05 microm are analyzed to yield h(EFF) values of 8.5 +/- 1.9 to 0.34 +/- 0.14 microm. The theoretical expectation for mass transport, dissolution time proportional to d(2.0), is in good agreement with the experimental results of dissolution time proportional to d(2.3). An understanding of these mass transfer mechanisms allows pharmaceutical scientists to achieve targeted release rates with minimum ensemble instability. """,0
3209,16529887,The chemical composition of essential oil and in vitro antibacterial activities of essential oil and methanol extract of Ziziphora persica Bunge,"This study was designed to examine the chemical composition of essential oil and the in vitro antibacterial activities of essential oil and methanol extracts of Ziziphora persica. The inhibitory effects of essential oil and methanol extracts of Ziziphora persica were tested against 98 laboratory strains belonging to 51 bacteria species by using disc-diffusion assay and micro-broth dilution methods, respectively. GC and GC/MS analyses revealed that the essential oil predominantly contains (+)-pulegone (79.33%), limonene (6.78%) and piperitenone (4.2%). The antibacterial test results showed that both methanol extract and in particular essential oil of Ziziphora persica had antibacterial activity against a number of bacteria tested. The lowest MIC values (7.81microg/ml) were obtained with the essential oil of Ziziphora persica against Bacillus dipsauri, Corynebacterium cystitidis and Corynebacterium flavescens. ",0
3210,16557546,The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro,"Cyclosporin A (CsA) inhibits the in vitro replication of HCV subgenomic replicons. We here report on the potent anti-HCV activity of the non-immunosuppressive cyclosporin DEBIO-025. The 50% effective concentration for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by DEBIO-025 was 0.27 +/- 0.03 microg/mL and for CsA 2.8 +/- 0.4 microg/mL. The concentration that reduced the growth of exponentially proliferating Huh 5-2 cells by 50% was greater than 27 microg/mL for DEBIO-025 and 12 +/- 6 microg/mL for CsA, resulting in a selectivity index of approximately 900 for DEBIO-025 and 40 for CsA. The superior activity of DEBIO-025, as compared with CsA, was corroborated by monitoring HCV RNA levels in Huh 5-2, two other HCV subgenomic replicon-containing cell lines, and by monitoring the luciferase signal and viral antigen production in hepatoma cells that had been infected with an infectious full-length chimeric HCV construct. The combination of interferon alpha 2a with either CsA or DEBIO-025 resulted in an additive to slightly synergistic antiviral activity. DEBIO-025, at concentrations of 0.5 and 1 microg/mL, was able to clear cells from their HCV replicon within three to four passages, whereas treatment with CsA at the same concentrations for seven consecutive passages did not result in clearance of the HCV replicon. In conclusion, DEBIO-025, a compound that is also endowed with potent anti-HIV activity and is well tolerated in animals and humans, may form an attractive new option for the therapy of HCV infections, particularly in HCV/HIV co-infected patients.",0
3211,16598045,Role of COL4A1 in small-vessel disease and hemorrhagic stroke,"Small-vessel diseases of the brain underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. In this report, we show that a mutation in the mouse Col4a1 gene, encoding procollagen type IV alpha1, predisposes both newborn and adult mice to intracerebral hemorrhage. Surgical delivery of mutant mice alleviated birth-associated trauma and hemorrhage. We identified a COL4A1 mutation in a human family with small-vessel disease. We concluded that mutation of COL4A1 may cause a spectrum of cerebrovascular phenotypes and that persons with COL4A1 mutations may be predisposed to hemorrhage, especially after environmental stress.",0
3212,16628626,Genomic response to interferon-alpha in chimpanzees: implications of rapid downregulation for hepatitis C kinetics,"The mechanism of the interferon-alpha (IFN-alpha)-induced antiviral response during hepatitis C virus (HCV) therapy is n o t completely understood. In this study,we examined the transcriptional response to IFN-alpha in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-alpha. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours postinoculation, a time when high levels of circulating pegylated IFN-alpha were still present. The rapid downregulation of the IFN-alpha response may be involved in the transition between the observed phase I and phase II viral kinetics during IFN-alpha therapy in HCV-infected patients. The response to all three forms of IFN-alpha was similar; thus, the reasons for previous failures in antiviral treatment of chimpanzees with human IFN-alpha were not due to species specificity of IFN-alpha. The response to IFN-alpha was partially tissue-specific. A total of 1778 genes were altered in expression by twofold or more by IFN-alpha, with 538 and 950 being unique to the liver or PBMC, respectively. Analysis of the IFN-alpha and IFN-gamma responses in primary chimpanzee and human hepatocytes were compared as well. IFN-alpha and IFN-gamma induced partially overlapping sets of genes in hepatocytes. In conclusion, the response to IFN-alpha is largely tissue-specific, and the response is rapidly downregulated in vivo, which may have a significant influence on the kinetics of antiviral response.",0
3213,16628674,A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus,A single nucleotide polymorphism characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the multidrug resistance protein 2 gene was found in a group of patients with primary biliary cirrhosis. This heterozygous mutation was significantly associated with the presence of pruritus.,0
3214,16641396,Vitamins C and E and the risks of preeclampsia and perinatal complications,"BACKGROUND: Supplementation with antioxidant vitamins has been proposed to reduce the risk of preeclampsia and perinatal complications, but the effects of this intervention are uncertain. METHODS: We conducted a multicenter, randomized trial of nulliparous women between 14 and 22 weeks of gestation. Women were assigned to daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or placebo (microcrystalline cellulose) until delivery. Primary outcomes were the risks of maternal preeclampsia, death or serious outcomes in the infants (on the basis of definitions used by the Australian and New Zealand Neonatal Network), and delivering an infant whose birth weight was below the 10th percentile for gestational age. RESULTS: Of the 1877 women enrolled in the study, 935 were randomly assigned to the vitamin group and 942 to the placebo group. Baseline characteristics of the two groups were similar. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (6.0 percent and 5.0 percent, respectively; relative risk, 1.20; 95 percent confidence interval, 0.82 to 1.75), death or serious outcomes in the infant (9.5 percent and 12.1 percent; relative risk, 0.79; 95 percent confidence interval, 0.61 to 1.02), or having an infant with a birth weight below the 10th percentile for gestational age (8.7 percent and 9.9 percent; relative risk, 0.87; 95 percent confidence interval, 0.66 to 1.16). CONCLUSIONS: Supplementation with vitamins C and E during pregnancy does not reduce the risk of preeclampsia in nulliparous women, the risk of intrauterine growth restriction, or the risk of death or other serious outcomes in their infants. (Controlledtrials.com number, ISRCTN00416244.).",0
3215,16641397,Variant of hepatitis B virus with primary resistance to adefovir,"The reverse-transcriptase inhibitor lamivudine (Zeffix, GlaxoSmithKline) is often used to treat chronic infection with hepatitis B virus (HBV) until resistance develops. Treatment may then be switched to the reverse-transcriptase inhibitor adefovir (Hepsera, Gilead), which has a lower frequency of resistance. Here, we describe three cases of primary adefovir resistance that were sensitive to tenofovir (Viread, Gilead). All three cases involved a rare HBV variant with a valine at position 233 of the reverse-transcriptase domain instead of isoleucine (rtI233V), as in the wild-type virus. This HBV variant also displayed resistance to adefovir and sensitivity to tenofovir in vitro.",0
3216,16672702,Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency,"A four-month-old boy with primary immunodeficiency was found to have a homozygous germ-line mutation of the gene encoding the CD3zeta subunit of the T-cell receptor-CD3 complex. CD3zeta is necessary for the development and function of T cells. Some of the patient's T cells had low levels of the T-cell receptor-CD3 complex and carried the Q70X mutation in both alleles of CD3zeta, whereas other T cells had normal levels of the complex and bore the Q70X mutation on only one allele of CD3zeta, plus one of three heterozygous somatic mutations of CD3zeta on the other allele, allowing expression of poorly functional T-cell receptor-CD3 complexes.",0
3217,16687714,Influence of donor C3 allotype on late renal-transplantation outcome,"BACKGROUND: The complement system has a critical role in both the innate and the adaptive immune responses. In humans, C3 exists as two main allotypes, F (fast) and S (slow), which are known to affect the incidence of inflammatory disease. We conducted a study to address the influence of these alleles on late renal-graft outcome. METHODS: We determined the C3 allotypes of 662 pairs of adult kidney donors and recipients from 1993 through 2002 and then related C3F/S polymorphism status to demographic and clinical outcome data. The median length of follow-up was 3.3 years. RESULTS: Analysis of 513 pairs of white donors and recipients identified 113 C3S/S recipients of a C3S/F or a C3F/F kidney and 179 C3S/S recipients of a C3S/S kidney. Graft survival was significantly better with a C3F/F or C3F/S donor allotype than a C3S/S allotype (P=0.05). The hazard ratio for graft loss of C3S/S kidneys, as compared with C3F/F or C3F/S kidneys, was 2.21 (95 percent confidence interval, 1.04 to 4.72; P=0.04). The graft function of C3F/F or C3F/S donor kidneys was significantly better than that of C3S/S donor kidneys (P<0.001). The effect of the C3F allele was specific to recipients who did not themselves possess this allele. Multivariate analysis excluded effects of other factors known to influence graft outcome. CONCLUSIONS: Expression of C3 alleles by donor renal cells appears to have a differential effect on late graft outcome. Among white C3S/S recipients, receipt of a C3F/F or C3F/S donor kidney, rather than a C3S/S donor kidney, is associated with a significantly better long-term outcome. These findings suggest that the two alleles have functional differences.",0
3218,16729312,Host cell responses induced by hepatitis C virus binding,"Initiation of hepatitis C virus (HCV) infection is mediated by docking of the viral envelope to the hepatocyte cell surface membrane followed by entry of the virus into the host cell. Aiming to elucidate the impact of this interaction on host cell biology, we performed a genomic analysis of the host cell response following binding of HCV to cell surface proteins. As ligands for HCV-host cell surface interaction, we used recombinant envelope glycoproteins and HCV-like particles (HCV-LPs) recently shown to bind or enter hepatocytes and human hepatoma cells. Gene expression profiling of HepG2 hepatoma cells following binding of E1/E2, HCV-LPs, and liver tissue samples from HCV-infected individuals was performed using a 7.5-kd human cDNA microarray. Cellular binding of HCV-LPs to hepatoma cells resulted in differential expression of 565 out of 7,419 host cell genes. Examination of transcriptional changes revealed a broad and complex transcriptional program induced by ligand binding to target cells. Expression of several genes important for innate immune responses and lipid metabolism was significantly modulated by ligand-cell surface interaction. To assess the functional relevance and biological significance of these findings for viral infection in vivo, transcriptional changes were compared with gene expression profiles in liver tissue samples from HCV-infected patients or controls. Side-by-side analysis revealed that the expression of 27 genes was similarly altered following HCV-LP binding in hepatoma cells and viral infection in vivo. In conclusion, HCV binding results in a cascade of intracellular signals modulating target gene expression and contributing to host cell responses in vivo. Reprogramming of cellular gene expression induced by HCV-cell surface interaction may be part of the viral strategy to condition viral entry and replication and escape from innate host cell responses.",0
3219,16729317,Step-by-step progress toward understanding the hepatitis C virus RNA helicase,"Helicases are a ubiquitous class of enzymes involved in nearly all aspects of DNA and RNA metabolism. Despite recent progress in understanding their mechanism of action, limited resolution has left inaccessible the detailed mechanisms by which these enzymes couple the rearrangement of nucleic acid structures to the binding and hydrolysis of ATP. Observing individual mechanistic cycles of these motor proteins is central to understanding their cellular functions. Here we follow in real time, at a resolution of two base pairs and 20 ms, the RNA translocation and unwinding cycles of a hepatitis C virus helicase (NS3) monomer. NS3 is a representative superfamily-2 helicase essential for viral replication, and therefore a potentially important drug target. We show that the cyclic movement of NS3 is coordinated by ATP in discrete steps of 11 +/- 3 base pairs, and that actual unwinding occurs in rapid smaller substeps of 3.6 +/- 1.3 base pairs, also triggered by ATP binding, indicating that NS3 might move like an inchworm. This ATP-coupling mechanism is likely to be applicable to other non-hexameric helicases involved in many essential cellular functions. The assay developed here should be useful in investigating a broad range of nucleic acid translocation motors.",0
3220,16738271,Unintended consequences of caps on Medicare drug benefits,"BACKGROUND: Little information exists about the consequences of limits on prescription-drug benefits for Medicare beneficiaries. METHODS: We compared the clinical and economic outcomes in 2003 among 157,275 Medicare+Choice beneficiaries whose annual drug benefits were capped at 1,000 dollars and 41,904 beneficiaries whose drug benefits were unlimited because of employer supplements. RESULTS: After adjusting for individual characteristics, we found that subjects whose benefits were capped had pharmacy costs for drugs applicable to the cap that were lower by 31 percent than subjects whose benefits were not capped (95 percent confidence interval, 29 to 33 percent) but had total medical costs that were only 1 percent lower (95 percent confidence interval, -4 to 6 percent). Subjects whose benefits were capped had higher relative rates of visits to the emergency department (relative rate, 1.09 [95 percent confidence interval, 1.04 to 1.14]), nonelective hospitalizations (relative rate, 1.13 [1.05 to 1.21]), and death (relative rate, 1.22 [1.07 to 1.38]; difference, 0.68 per 100 person-years [0.30 to 1.07]). Among subjects who used drugs for hypertension, hyperlipidemia, or diabetes in 2002, those whose benefits were capped were more likely to be nonadherent to long-term drug therapy in 2003; the respective odds ratios were 1.30 (95 percent confidence interval, 1.23 to 1.38), 1.27 (1.19 to 1.34), and 1.33 (1.18 to 1.48) for subjects using drugs for hypertension, hyperlipidemia, and diabetes. In each subgroup, the physiological outcomes were worse for subjects whose drug benefits were capped than for those whose benefits were not capped; the odds ratios were 1.05 (95 percent confidence interval, 1.00 to 1.09), 1.13 (1.03 to 1.25), and 1.23 (1.03 to 1.46), respectively, for subjects with a systolic blood pressure of 140 mm Hg or more, a serum low-density-lipoprotein cholesterol level of 130 mg per deciliter or more, and a glycated hemoglobin level of 8 percent or more. CONCLUSIONS: A cap on drug benefits was associated with lower drug consumption and unfavorable clinical outcomes. In patients with chronic disease, the cap was associated with poorer adherence to drug therapy and poorer control of blood pressure, lipid levels, and glucose levels. The savings in drug costs from the cap were offset by increases in the costs of hospitalization and emergency department care.",0
3221,16760444,Major congenital malformations after first-trimester exposure to ACE inhibitors,"BACKGROUND: Use of angiotensin-converting-enzyme (ACE) inhibitors during the second and third trimesters of pregnancy is contraindicated because of their association with an increased risk of fetopathy. In contrast, first-trimester use of ACE inhibitors has not been linked to adverse fetal outcomes. We conducted a study to assess the association between exposure to ACE inhibitors during the first trimester of pregnancy only and the risk of congenital malformations. METHODS: We studied a cohort of 29,507 infants enrolled in Tennessee Medicaid and born between 1985 and 2000 for whom there was no evidence of maternal diabetes. We identified 209 infants with exposure to ACE inhibitors in the first trimester alone, 202 infants with exposure to other antihypertensive medications in the first trimester alone, and 29,096 infants with no exposure to antihypertensive drugs at any time during gestation. Major congenital malformations were identified from linked vital records and hospitalization claims during the first year of life and confirmed by review of medical records. RESULTS: Infants with only first-trimester exposure to ACE inhibitors had an increased risk of major congenital malformations (risk ratio, 2.71; 95 percent confidence interval, 1.72 to 4.27) as compared with infants who had no exposure to antihypertensive medications. In contrast, fetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk (risk ratio, 0.66; 95 percent confidence interval, 0.25 to 1.75). Infants exposed to ACE inhibitors were at increased risk for malformations of the cardiovascular system (risk ratio, 3.72; 95 percent confidence interval, 1.89 to 7.30) and the central nervous system (risk ratio, 4.39; 95 percent confidence interval, 1.37 to 14.02). CONCLUSIONS: Exposure to ACE inhibitors during the first trimester cannot be considered safe and should be avoided.",0
3222,16760445,Single-dose azithromycin for the treatment of cholera in adults,"BACKGROUND: Single-dose azithromycin is effective in the treatment of severe cholera in children, but its effectiveness in adults has not been evaluated. METHODS: We conducted a double-blind, randomized trial comparing the equivalence of azithromycin and ciprofloxacin (each given in a single 1-g dose of two 500-mg tablets) among 195 men with severe cholera caused by Vibrio cholerae O1 or O139. Patients were hospitalized for five days. A stool culture was performed daily. Primary outcome measures were clinical success (the cessation of watery stools within 48 hours after drug administration) and bacteriologic success (the inability to isolate V. cholerae after 48 hours). RESULTS: Therapy was clinically successful in 71 of 97 patients receiving azithromycin (73 percent) and in 26 of 98 patients receiving ciprofloxacin (27 percent) (P<0.001) and bacteriologically successful in 76 of 97 patients receiving azithromycin (78 percent) and in 10 of 98 patients receiving ciprofloxacin (10 percent) (P<0.001). Patients who were treated with azithromycin had a shorter duration of diarrhea than did patients treated with ciprofloxacin (median, 30 vs. 78 hours); a lower frequency of vomiting (43 percent vs. 67 percent); fewer stools (median, 36 vs. 52); and a lower stool volume (median, 114 vs. 322 ml per kilogram of body weight). The median minimal inhibitory concentration of ciprofloxacin for the 177 isolates of V. cholerae O1 was 0.25 mug per milliliter, which was 11 to 83 times as high as that in previous studies at this site. CONCLUSIONS: Single-dose azithromycin was effective in the treatment of severe cholera in adults. The lack of efficacy of ciprofloxacin may result from its diminished activity against V. cholerae O1 strains currently circulating in Bangladesh. (ClinicalTrials.gov number, NCT00229944.).",0
3223,16790697,Condom use and the risk of genital human papillomavirus infection in young women,"BACKGROUND: To evaluate whether the use of male condoms reduces the risk of male-to-female transmission of human papillomavirus (HPV) infection, longitudinal studies explicitly designed to evaluate the temporal relationship between condom use and HPV infection are needed. METHODS: We followed 82 female university students who reported their first intercourse with a male partner either during the study period or within two weeks before enrollment. Cervical and vulvovaginal samples for HPV DNA testing and Papanicolaou testing were collected at gynecologic examinations every four months. Every two weeks, women used electronic diaries to record information about their daily sexual behavior. Cox proportional-hazards models were used to evaluate risk factors for HPV infection. RESULTS: The incidence of genital HPV infection was 37.8 per 100 patient-years at risk among women whose partners used condoms for all instances of intercourse during the eight months before testing, as compared with 89.3 per 100 patient-years at risk in women whose partners used condoms less than 5 percent of the time (adjusted hazard ratio, 0.3; 95 percent confidence interval, 0.1 to 0.6, adjusted for the number of new partners and the number of previous partners of the male partner). Similar associations were observed when the analysis was restricted to high-risk and low-risk types of HPV and HPV types 6, 11, 16, and 18. In women reporting 100 percent condom use by their partners, no cervical squamous intraepithelial lesions were detected in 32 patient-years at risk, whereas 14 incident lesions were detected during 97 patient-years at risk among women whose partners did not use condoms or used them less consistently. CONCLUSIONS: Among newly sexually active women, consistent condom use by their partners appears to reduce the risk of cervical and vulvovaginal HPV infection.",0
3224,16799983,A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B,"Four hundred and eighty Chinese subjects with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were enrolled in a multicenter, double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) 10 mg once daily. There was a significant difference in reduction of serum hepatitis B virus (HBV) DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log10 copies/mL, respectively, P < .001). Further reductions in serum HBV DNA and increases in the proportion of subjects with an HBV DNA level of at most 10(5) copies/mL, with HBV DNA undetectable, and with ALT normalization were observed in ADV-treated subjects at week 52 (median HBV DNA reduction of 4.5 log(10) copies/mL, 67% with HBV DNA <or= 10(5) copies/mL, 28% with HBV DNA undetectable, and 79% with ALT normalization). Subjects who initially received ADV lost some treatment benefit after being rerandomized to the placebo in week 40. Subjects with YMDD mutant HBV at baseline had virological, biochemical, and serological responses to treatment that were similar to those of subjects with wild-type HBV. The incidence of clinically adverse events was similar in nature and severity between the treatment groups, and there was no evidence of renal toxicity. No adefovir-related HBV mutations were identified. In conclusion, treatment with ADV 10 mg daily over 52 weeks was safe and effective in Chinese subjects with HBeAg-positive CHB and did not lead to the emergence of drug resistance. The study is continuing for an additional 4 years with all subjects on open-label ADV 10 mg daily.",0
3225,16822993,Carbon in airway macrophages and lung function in children,"BACKGROUND: Epidemiologic studies indirectly suggest that the inhalation of carbonaceous particulate matter impairs lung function in children. Using the carbon content of airway macrophages as a marker of individual exposure to particulate matter derived from fossil fuel, we sought direct evidence of this association. METHODS: Airway macrophages were obtained from healthy children through sputum induction, and the area of airway macrophages occupied by carbon was measured. Lung function was measured with the use of spirometry. We modeled the exposure to primary particulate matter (PM) that is less than 10 mum in aerodynamic diameter (PM10) at or near each child's home address. Linear regression was used to evaluate associations between carbon content of alveolar macrophages and variables that may affect individual exposure. To determine whether lung function that is reduced for other reasons is associated with an increase in the carbon content of airway macrophages, we also studied children with severe asthma. RESULTS: We were able to assess the carbon content of airway macrophages in 64 of 114 healthy children (56 percent). Each increase in primary PM10 of 1.0 microg per cubic meter was associated with an increase of 0.10 microm2 (95 percent confidence interval, 0.01 to 0.18) in the carbon content of airway macrophages, and each increase of 1.0 microm2 in carbon content was associated with a reduction of 17 percent (95 percent confidence interval, 5.6 to 28.4 percent) in forced expiratory volume in one second, of 12.9 percent (95 percent confidence interval, 0.9 to 24.8 percent) in forced vital capacity, and of 34.7 percent (95 percent confidence interval, 11.3 to 58.1 percent) in the forced expiratory flow between 25 and 75 percent of the forced vital capacity. The carbon content of airway macrophages was lower in children with asthma than in healthy children. CONCLUSIONS: There is a dose-dependent inverse association between the carbon content of airway macrophages and lung function in children. We found no evidence that reduced lung function itself causes an increase in carbon content.",0
3226,16822995,Hospital volume and the outcomes of mechanical ventilation,"BACKGROUND: An increased volume of patients is associated with improved survival in numerous high-risk medical and surgical conditions. The relationship between the number of patients admitted (hospital volume) and outcome among patients with critical illnesses is unknown. METHODS: We analyzed data from 20,241 nonsurgical patients receiving mechanical ventilation at 37 acute care hospitals in the Acute Physiology and Chronic Health Evaluation clinical information system from 2002 through 2003. Multivariate analyses were performed to adjust for the severity of illness and other differences in the case mix. RESULTS: An increase in hospital volume was associated with improved survival among patients receiving mechanical ventilation in the intensive care unit (ICU) and in the hospital. Admission to a hospital in the highest quartile according to volume (i.e., >400 patients receiving mechanical ventilation per year) was associated with a 37 percent reduction in the adjusted odds of death in the ICU as compared with admission to hospitals in the lowest quartile (< or =150 patients receiving mechanical ventilation per year, P<0.001). In-hospital mortality was similarly reduced (adjusted odds ratio, 0.66; 95 percent confidence interval, 0.52 to 0.83; P<0.001). A typical patient in a hospital in a low-volume quartile would have an adjusted in-hospital mortality of 34.2 percent as compared with 25.5 percent in a hospital in a high-volume quartile. Among survivors, there were no significant trends in the length of stay in the ICU or the hospital. CONCLUSIONS: Mechanical ventilation of patients in a hospital with a high case volume is associated with reduced mortality. Further research is needed to determine the mechanism of the relationship between volume and outcome among patients with a critical illness.",0
3227,16850024,Modeling of hyperoxaluric calcium oxalate nephrolithiasis: experimental induction of hyperoxaluria by hydroxy-L-proline,"A number of animal models have been developed to investigate calcium oxalate (CaOx) nephrolithiasis. Ethylene glycol (EG)-induced hyperoxaluria in rats is most common, but is criticized because EG and some of its metabolites are nephrotoxic and EG causes metabolic acidosis. Both oxalate (Ox) and CaOx crystals are also injurious to renal epithelial cells. Thus, it is difficult to distinguish the effects of EG and its metabolites from those induced by Ox and CaOx crystals. This study was performed to investigate hydroxy-L-proline (HLP), a common ingredient of many diets, as a hyperoxaluria-inducing agent. In rats, HLP has been shown to induce CaOx nephrolithiasis in only hypercalciuric conditions. Five percent HLP mixed with chow was given to male Sprague-Dawley rats for 63 days, resulting in hyperoxaluria, CaOx crystalluria, and nephrolithiasis. Crystal deposits were surrounded by ED-1-positive inflammatory cells. Cell injury and death was followed by regeneration, as suggested by an increase in proliferating cell nuclear antigen-positive cells. Both osteopontin (OPN) and CD44 were upregulated. Staining for CD44 and OPN was intense in cells lining the tubules that contained crystals. Along with a rise in urinary Ox and lactate dehydrogenase, there were significant increases in 8-isoprostane and hydrogen peroxide excretion, indicating that the oxidative stress induced cell injury. Thus, HLP-induced hyperoxaluria alone can induce CaOx nephrolithiasis in rats. ",0
3228,16855264,TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program,"BACKGROUND: Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo. METHODS: We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year. RESULTS: Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372. CONCLUSIONS: Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992. [ClinicalTrials.gov]).",0
3229,16855265,Trends in prevalence and outcome of heart failure with preserved ejection fraction,"BACKGROUND: The prevalence of heart failure with preserved ejection fraction may be changing as a result of changes in population demographics and in the prevalence and treatment of risk factors for heart failure. Changes in the prevalence of heart failure with preserved ejection fraction may contribute to changes in the natural history of heart failure. We performed a study to define secular trends in the prevalence of heart failure with preserved ejection fraction among patients at a single institution over a 15-year period. METHODS: We studied all consecutive patients hospitalized with decompensated heart failure at Mayo Clinic Hospitals in Olmsted County, Minnesota, from 1987 through 2001. We classified patients as having either preserved or reduced ejection fraction. The patients were also classified as community patients (Olmsted County residents) or referral patients. Secular trends in the type of heart failure, associated cardiovascular disease, and survival were defined. RESULTS: A total of 6076 patients with heart failure were discharged over the 15-year period; data on ejection fraction were available for 4596 of these patients (76 percent). Of these, 53 percent had a reduced ejection fraction and 47 percent had a preserved ejection fraction. The proportion of patients with the diagnosis of heart failure with preserved ejection fraction increased over time and was significantly higher among community patients than among referral patients (55 percent vs. 45 percent). The prevalence rates of hypertension, atrial fibrillation, and diabetes among patients with heart failure increased significantly over time. Survival was slightly better among patients with preserved ejection fraction (adjusted hazard ratio for death, 0.96; P=0.01). Survival improved over time for those with reduced ejection fraction but not for those with preserved ejection fraction. CONCLUSIONS: The prevalence of heart failure with preserved ejection fraction increased over a 15-year period, while the rate of death from this disorder remained unchanged. These trends underscore the importance of this growing public health problem.",0
3230,16870915,Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence,"BACKGROUND: The optimal level of counseling and frequency of attendance for medication distribution has not been established for the primary care, office-based buprenorphine-naloxone treatment of opioid dependence. METHODS: We conducted a 24-week randomized, controlled clinical trial with 166 patients assigned to one of three treatments: standard medical management and either once-weekly or thrice-weekly medication dispensing or enhanced medical management and thrice-weekly medication dispensing. Standard medical management was brief, manual-guided, medically focused counseling; enhanced management was similar, but each session was extended. The primary outcomes were the self-reported frequency of illicit opioid use, the percentage of opioid-negative urine specimens, and the maximum number of consecutive weeks of abstinence from illicit opioids. RESULTS: The three treatments had similar efficacies with respect to the mean percentage of opioid-negative urine specimens (standard medical management and once-weekly medication dispensing, 44 percent; standard medical management and thrice-weekly medication dispensing, 40 percent; and enhanced medical management and thrice-weekly medication dispensing, 40 percent; P=0.82) and the maximum number of consecutive weeks during which patients were abstinent from illicit opioids. All three treatments were associated with significant reductions from baseline in the frequency of illicit opioid use, but there were no significant differences among the treatments. The proportion of patients remaining in the study at 24 weeks did not differ significantly among the patients receiving standard medical management and once-weekly medication dispensing (48 percent) or thrice-weekly medication dispensing (43 percent) or enhanced medical management and thrice-weekly medication dispensing (39 percent) (P=0.64). Adherence to buprenorphine-naloxone treatment varied; increased adherence was associated with improved treatment outcomes. CONCLUSIONS: Among patients receiving buprenorphine-naloxone in primary care for opioid dependence, the efficacy of brief weekly counseling and once-weekly medication dispensing did not differ significantly from that of extended weekly counseling and thrice-weekly dispensing. Strategies to improve buprenorphine-naloxone adherence are needed. (ClinicalTrials.gov number, NCT00023283 [ClinicalTrials.gov].).",0
3231,16870916,Pay-for-performance programs in family practices in the United Kingdom,"BACKGROUND: In 2004, after a series of national initiatives associated with marked improvements in the quality of care, the National Health Service of the United Kingdom introduced a pay-for-performance contract for family practitioners. This contract increases existing income according to performance with respect to 146 quality indicators covering clinical care for 10 chronic diseases, organization of care, and patient experience. METHODS: We analyzed data extracted automatically from clinical computing systems for 8105 family practices in England in the first year of the pay-for-performance program (April 2004 through March 2005), data from the U.K. Census, and data on characteristics of individual family practices. We examined the proportion of patients deemed eligible for a clinical quality indicator for whom the indicator was met (reported achievement) and the proportion of the total number of patients with a medical condition for whom a quality indicator was met (population achievement), and we used multiple regression analysis to determine the extent to which practices achieved high scores by classifying patients as ineligible for quality indicators (exception reporting). RESULTS: The median reported achievement in the first year of the new contract was 83.4 percent (interquartile range, 78.2 to 87.0 percent). Sociodemographic characteristics of the patients (age and socioeconomic features) and practices (size of practice, number of patients per practitioner, age of practitioner, and whether the practitioner was medically educated in the United Kingdom) had moderate but significant effects on performance. Exception reporting by practices was not extensive (median rate, 6 percent), but it was the strongest predictor of achievement: a 1 percent increase in the rate of exception reporting was associated with a 0.31 percent increase in reported achievement. Exception reporting was high in a small number of practices: 1 percent of practices excluded more than 15 percent of patients. CONCLUSIONS: English family practices attained high levels of achievement in the first year of the new pay-for-performance contract. A small number of practices appear to have achieved high scores by excluding large numbers of patients by exception reporting. More research is needed to determine whether these practices are excluding patients for sound clinical reasons or in order to increase income.",0
3232,16885551,Validation of a rule for termination of resuscitation in out-of-hospital cardiac arrest,"BACKGROUND: We prospectively evaluated a clinical prediction rule to be used by emergency medical technicians (EMTs) trained in the use of an automated external defibrillator for the termination of basic life support resuscitative efforts during out-of-hospital cardiac arrest. The rule recommends termination when there is no return of spontaneous circulation, no shocks are administered, and the arrest is not witnessed by emergency medical-services personnel. Otherwise, the rule recommends transportation to the hospital, in accordance with routine practice. METHODS: The study included 24 emergency medical systems in Ontario, Canada. All patients 18 years of age or older who had an arrest of presumed cardiac cause and who were treated by EMTs trained in the use of an automated external defibrillator were included. The patients were treated according to standard guidelines. Characteristics of diagnostic tests for the prediction rule were calculated. These characteristics include sensitivity, specificity, and positive and negative predictive values. RESULTS: Follow-up data were obtained for all 1240 patients. Of 776 patients with cardiac arrest for whom the rule recommended termination, 4 survived (0.5 percent). The rule had a specificity of 90.2 percent for recommending transport of survivors to the emergency department and had a positive predictive value for death of 99.5 percent when termination was recommended. Implementation of this rule would result in a decrease in the rate of transportation from 100 percent of patients to 37.4 percent. The addition of other criteria (a response interval greater than eight minutes or a cardiac arrest not witnessed by a bystander) would further improve both the specificity and positive predictive value of the rule but would result in the transportation of a larger proportion of patients. CONCLUSIONS: The use of a clinical prediction rule for the termination of resuscitation may help clinicians decide whether to terminate basic life support resuscitative efforts in patients having an out-of-hospital cardiac arrest.",0
3233,16899777,A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer,"BACKGROUND: Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy. METHODS: We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study. RESULTS: The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy. CONCLUSIONS: The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC.",0
3234,16914704,Neonatal MRI to predict neurodevelopmental outcomes in preterm infants,"BACKGROUND: Very preterm infants are at high risk for adverse neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been proposed as a means of predicting neurodevelopmental outcomes in this population. METHODS: We studied 167 very preterm infants (gestational age at birth, 30 weeks or less) to assess the associations between qualitatively defined white-matter and gray-matter abnormalities on MRI at term equivalent (gestational age of 40 weeks) and the risks of severe cognitive delay, severe psychomotor delay, cerebral palsy, and neurosensory (hearing or visual) impairment at 2 years of age (corrected for prematurity). RESULTS: At two years of age, 17 percent of infants had severe cognitive delay, 10 percent had severe psychomotor delay, 10 percent had cerebral palsy, and 11 percent had neurosensory impairment. Moderate-to-severe cerebral white-matter abnormalities present in 21 percent of infants at term equivalent were predictive of the following adverse outcomes at two years of age: cognitive delay (odds ratio, 3.6; 95 percent confidence interval, 1.5 to 8.7), motor delay (odds ratio, 10.3; 95 percent confidence interval, 3.5 to 30.8), cerebral palsy (odds ratio, 9.6; 95 percent confidence interval, 3.2 to 28.3), and neurosensory impairment (odds ratio, 4.2; 95 percent confidence interval, 1.6 to 11.3). Gray-matter abnormalities (present in 49 percent of infants) were also associated, but less strongly, with cognitive delay, motor delay, and cerebral palsy. Moderate-to-severe white-matter abnormalities on MRI were significant predictors of severe motor delay and cerebral palsy after adjustment for other measures during the neonatal period, including findings on cranial ultrasonography. CONCLUSIONS: Abnormal findings on MRI at term equivalent in very preterm infants strongly predict adverse neurodevelopmental outcomes at two years of age. These findings suggest a role for MRI at term equivalent in risk stratification for these infants.",0
3235,16926275,"Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old","BACKGROUND: Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned. METHODS: We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health-AARP cohort who were 50 to 71 years old at enrollment in 1995-1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status. RESULTS: During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated. CONCLUSIONS: Excess body weight during midlife, including overweight, is associated with an increased risk of death.",0
3236,16941698,Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats,"Integrin-linked kinase (ILK) is a multidomain focal adhesion protein implicated in signal transduction between integrins and growth factor receptors. Although its expression is upregulated in pulmonary and renal fibrosis, its role in the development of hepatic fibrosis remains to be determined. Therefore, we considered it important to investigate whether ILK is involved in activation of hepatic stellate cells and thus plays a role in the development of hepatic fibrosis. Immunohistochemical analysis of liver sections obtained from rats with CCl4-induced cirrhosis revealed increased expression and colocalization of ILK and alpha-smooth muscle actin in hepatic stellate cells in perisinusoidal areas. In addition, hepatic stellate cells isolated from fibrotic livers expressed high levels of ILK and alpha-smooth muscle actin, and their expression was sustained in culture. In contrast, hepatic stellate cells (HSCs) isolated from normal rat liver did not express ILK, but its expression was increased when the cells were activated in culture. Our studies also showed that ILK is involved in the phosphorylation of ERK 1/2, p38 MAPK, JNK, and PKB and that selective inhibition of ILK expression by siRNA results in a significant decrease in their phosphorylation. These changes were accompanied by significant inhibition of cell spreading and migration without affecting cell proliferation. In conclusion, ILK plays a key role in HSC activation and could be a possible target for antifibrogenic therapy.",0
3237,16941702,CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus,"Hepatitis C is a major cause of chronic liver disease, with 170 million individuals infected worldwide and no available vaccine. We analyzed the effects of an induced T-cell response in 3 chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. In all animals the specific T-cell response modified the outcome of infection, producing a 10- to 1,000-fold reduction in peak virus titers. The challenge of 2 immunized animals that had been previously exposed to hepatitis C virus resulted in subclinical infections. Immune responses in the third animal, naive prior to immunization, limited viral replication immediately, evidenced by a 30-fold reduction in virus titer by week 2, declining to a nonquantifiable level by week 6. After 10 weeks of immunological control, we observed a resurgence of virus, followed by progression to a persistent infection. Comparing virus evolution with T-cell recognition, we demonstrated that: (i) resurgence was concomitant with the emergence of new dominant viral populations bearing single amino acid changes in the NS3 and NS5A regions, (ii) these mutations resulted in a loss of CD4+ T-cell recognition, and (iii) subsequent to viral resurgence and immune escape a large fraction of NS3-specific T cells became impaired in their ability to secrete IFN-gamma and proliferate. In contrast, NS3-specific responses were sustained in the recovered/immunized animals presenting with subclinical infections. In conclusion, viral escape from CD4+ T cells can result in the eventual failure of an induced T-cell response that initially controls infection. Vaccines that can induce strong T-cell responses prior to challenge will not necessarily prevent persistent HCV infection.",0
3238,16943404,"The value of medical spending in the United States, 1960-2000","BACKGROUND: The increased use of medical therapies has led to increased medical costs. To provide insight into the value of this increased spending, we compared gains in life expectancy with the increased costs of care from 1960 through 2000. METHODS: We estimated life expectancy in 1960, 1970, 1980, 1990, and 2000 for four age groups. To control for the influence of nonmedical factors on survival, we assumed in our base-case analysis that 50 percent of the gains were due to medical care. We compared the adjusted increases in life expectancy with the lifetime cost of medical care in the same years. RESULTS: From 1960 through 2000, the life expectancy for newborns increased by 6.97 years, lifetime medical spending adjusted for inflation increased by approximately 69,000 dollars, and the cost per year of life gained was 19,900 dollars. The cost increased from 7,400 dollars per year of life gained in the 1970s to 36,300 dollars in the 1990s. The average cost per year of life gained in 1960-2000 was approximately 31,600 dollars at 15 years of age, 53,700 dollars at 45 years of age, and 84,700 dollars at 65 years of age. At 65 years of age, costs rose more rapidly than did life expectancy: the cost per year of life gained was 121,000 dollars between 1980 and 1990 and 145,000 dollars between 1990 and 2000. CONCLUSIONS: On average, the increases in medical spending since 1960 have provided reasonable value. However, the spending increases in medical care for the elderly since 1980 are associated with a high cost per year of life gained. The national focus on the rise in medical spending should be balanced by attention to the health benefits of this increased spending.",0
3239,16957145,DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy,"BACKGROUND: Adjuvant cisplatin-based chemotherapy improves survival among patients with completely resected non-small-cell lung cancer, but there is no validated clinical or biologic predictor of the benefit of chemotherapy. METHODS: We used immunohistochemical analysis to determine the expression of the excision repair cross-complementation group 1 (ERCC1) protein in operative specimens of non-small-cell lung cancer. The patients had been enrolled in the International Adjuvant Lung Cancer Trial, thereby allowing a comparison of the effect of adjuvant cisplatin-based chemotherapy on survival, according to ERCC1 expression. Overall survival was analyzed with a Cox model adjusted for clinical and pathological factors. RESULTS: Among 761 tumors, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). A benefit from cisplatin-based adjuvant chemotherapy was associated with the absence of ERCC1 (test for interaction, P=0.009). Adjuvant chemotherapy, as compared with observation, significantly prolonged survival among patients with ERCC1-negative tumors (adjusted hazard ratio for death, 0.65; 95% confidence interval [CI], 0.50 to 0.86; P=0.002) but not among patients with ERCC1-positive tumors (adjusted hazard ratio for death, 1.14; 95% CI, 0.84 to 1.55; P=0.40). Among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66; 95% CI, 0.49 to 0.90; P=0.009). CONCLUSIONS: Patients with completely resected non-small-cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not.",0
3240,17035648,Microscopic-observation drug-susceptibility assay for the diagnosis of TB,"BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on L�wenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for L�wenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used.",0
3241,17035649,A self-regulation program for maintenance of weight loss,"BACKGROUND: Since many successful dieters regain the weight they lose, programs that teach maintenance skills are needed. We developed a maintenance program based on self-regulation theory and tested the efficacy of delivering the program face to face or over the Internet. METHODS: We randomly assigned 314 participants who had lost a mean of 19.3 kg of body weight in the previous 2 years to one of three groups: a control group, which received quarterly newsletters (105 participants), a group that received face-to-face intervention (105), and a group that received Internet-based intervention (104). The content of the programs in the two intervention groups was the same, emphasizing daily self-weighing and self-regulation, as was the frequency of contact with the groups. The primary outcome was weight gain over a period of 18 months. RESULTS: The mean (+/-SD) weight gain was 2.5+/-6.7 kg in the face-to-face group, 4.7+/-8.6 kg in the Internet group, and 4.9+/-6.5 kg in the control group, with a significant difference between the face-to-face group and the control group (2.4 kg; 95% confidence interval [CI], 0.002 to 10.8; P=0.05). The proportion of participants who regained 2.3 kg or more over the 18-month period was significantly higher in the control group (72.4%) than in the face-to-face group (45.7%; absolute difference, 27%; 95% CI, 14 to 39; P<0.001) or the Internet group (54.8%; absolute difference, 18%; 95% CI, 5 to 30; P=0.008). Daily self-weighing increased in both intervention groups and was associated with a decreased risk of regaining 2.3 kg or more (P<0.001). CONCLUSIONS: As compared with receiving quarterly newsletters, a self-regulation program based on daily weighing improved maintenance of weight loss, particularly when delivered face to face. (ClinicalTrials.gov number, NCT00067145 [ClinicalTrials.gov].)",0
3242,17050892,Reduced lung function at birth and the risk of asthma at 10 years of age,"BACKGROUND: Reduced lung function in early infancy has been associated with later obstructive airway diseases. We assessed whether reduced lung function shortly after birth predicts asthma 10 years later. METHODS: We conducted a prospective birth cohort study of healthy infants in which we measured lung function shortly after birth with the use of tidal breathing flow-volume loops (the fraction of expiratory time to peak tidal expiratory flow to total expiratory time [t(PTEF)/t(E)]) in 802 infants and passive respiratory mechanics, including respiratory-system compliance, in 664 infants. At 10 years of age, 616 children (77%) were reassessed by measuring lung function, exercise-induced bronchoconstriction, and bronchial hyperresponsiveness (by means of a methacholine challenge) and by conducting a structured interview to determine whether there was a history of asthma or current asthma. RESULTS: As compared with children whose t(PTEF)/t(E) shortly after birth was above the median, children whose t(PTEF)/t(E) was at or below the median were more likely at 10 years of age to have a history of asthma (24.3% vs. 16.2%, P=0.01), to have current asthma (14.6% vs. 7.5%, P=0.005), and to have severe bronchial hyperresponsiveness, defined as a methacholine dose of less than 1.0 micromol causing a 20% fall in the forced expiratory volume in 1 second (FEV1) (9.1% vs. 4.9%, P=0.05). As compared with children whose respiratory-system compliance was above the median, children with respiratory compliance at or below the median more often had a history of asthma (27.4% vs. 14.8%; P=0.001) and current asthma (15.0% vs. 7.7%, P=0.009), although this measure was not associated with later measurements of lung function. At 10 years of age, t(PTEF)/t(E) at birth correlated weakly with the maximal midexpiratory flow rate (r=0.10, P=0.01) but not with FEV1 or forced vital capacity. CONCLUSIONS: Reduced lung function at birth is associated with an increased risk of asthma by 10 years of age.",0
3243,17058221,The half-life of hepatitis B virions,"The virion half-life of hepatitis B virus (HBV) is currently estimated at approximately 1 day. This estimate has been obtained from drug perturbation experiments with reverse transcriptase inhibitors. However, the analyses of those experiments have not considered the export of virions produced from preformed mature DNA-containing HBV capsids in infected cells. Data from 3 acutely infected chimpanzees indicates that there is approximately 10-fold more total intracellular HBV DNA than HBV DNA in blood, and therefore the half-life of virions for chimpanzees during acute infection is 10-fold shorter at 3.8 hours than the half-life associated with export of total intracellular HBV DNA. Mathematical model simulations duplicating the viral dynamics observed in drug perturbation experiments suggest a half-life of at most 4.4 hours for HBV virions in chronically infected humans, significantly shorter than current estimates, but consistent with the half-lives of virions for hepatitis C virus and HIV. This faster turnover of HBV in blood indicates a correspondingly higher replication rate and risk of mutation against hepatitis B antiviral therapy. In conclusion, we find the half-life of HBV virions is approximately 4 hours, significantly shorter than current estimates of 1 day. This new value is consistent with virion half-life estimates for HIV and hepatitis C virus.",0
3244,17058227,In vivo immune modulatory activity of hepatic stellate cells in mice,"Accumulating data suggest that hepatic tolerance, initially demonstrated by spontaneous acceptance of liver allografts in many species, results from an immune regulatory activity occurring in the liver. However, the responsible cellular and molecular components have not been completely understood. We have recently described profound T cell inhibitory activity of hepatic stellate cells (HSCs) in vitro. In this study, we demonstrate in vivo evidence of immune modulatory activity of HSCs in mice using an islet transplantation model. Co-transplanted HSCs effectively protected islet allografts from rejection, forming a multi-layered capsule, which reduced allograft immunocyte infiltrates by enhancement of apoptotic death. The immune modulation by HSCs appeared to be a local effect, and regulated by inducible expression of B7-H1, an inhibitory molecule of B7 family. This may reflect an intrinsic mechanism of immune inhibition mediated by liver-derived tissue cells. In conclusion, these results may lead to better understanding of liver immunobiology and development of new strategies for treatment of liver diseases.",0
3245,17058232,T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells,"""The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node-activated T cells, liver-activated T cells are short-lived, a mechanism that might contribute to the """"liver tolerance effect."""" Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8(+) T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that na?ve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating na?ve CD8(+) T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion, this study has identified, at the ultrastructural level, a unique type of interaction between na?ve T lymphocytes and liver parenchymal cells in vivo. These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.""",0
3246,17058242,Beyond randomized controlled trials: a critical comparison of trials with nonrandomized studies,"Observational analogs of randomized clinical trials (RCTs) are well accepted in the study of disease risk factors, diagnosis, and prognosis. There is controversy about observational studies when the focus is on the intended benefit due to lack of blinding and poor control for unmeasured confounding. Well-designed randomized clinical trials are costly both in time and money. Therefore, existing databases are used increasingly and are often the only feasible source with which to examine delayed health effects. We reviewed the reasons for possible discrepancies between RCTs and observational studies. There can be different patient populations, differences in therapeutic regimen, control of confounding, follow-up, measuring outcome, and differences arising from the intention-to-treat analysis. Observational studies cannot replace trials, nor do trials make observational studies unnecessary. Both designs are susceptible to particular bias, so neither provides perfect information.",0
3247,17079763,Pay for performance in commercial HMOs,"BACKGROUND: Pay for performance has increasingly become the subject of intense interest and debate, both of which have been heightened as the Centers for Medicare and Medicaid Services moves closer to adopting this approach for Medicare. Although many claims have been made for the effectiveness of this approach, the extent of its national penetration remains unknown. METHODS: We surveyed a sample of 252 health maintenance organizations (HMOs) (response rate, 96%) drawn from 41 metropolitan areas across the nation about use of pay for performance. We determined the prevalence of pay-for-performance programs, detailed the features of such programs, and examined the adoption of pay for performance as a function of the characteristics of both the health plans and markets. RESULTS: More than half the HMOs, representing more than 80% of persons enrolled, use pay for performance in their provider contracts. Of the 126 health plans with pay-for-performance programs, nearly 90% had programs for physicians and 38% had programs for hospitals. Use of pay for performance was statistically associated with geographic region, use of primary care providers (PCPs) as gatekeepers, use of capitation to pay PCPs, and whether the plans themselves received bonuses or penalties according to performance. CONCLUSIONS: Pay for performance is now commonly used by HMOs, especially those that are situated to assign responsibility for a particular patient to a PCP or medical group. As the design of Medicare with pay for performance moves forward, it will be important to leverage the early experience of pay for performance in the commercial market.",0
3248,17093250,Low-carbohydrate-diet score and the risk of coronary heart disease in women,"BACKGROUND: Low-carbohydrate diets have been advocated for weight loss and to prevent obesity, but the long-term safety of these diets has not been determined. METHODS: We evaluated data on 82,802 women in the Nurses' Health Study who had completed a validated food-frequency questionnaire. Data from the questionnaire were used to calculate a low-carbohydrate-diet score, which was based on the percentage of energy as carbohydrate, fat, and protein (a higher score reflects a higher intake of fat and protein and a lower intake of carbohydrate). The association between the low-carbohydrate-diet score and the risk of coronary heart disease was examined. RESULTS: During 20 years of follow-up, we documented 1994 new cases of coronary heart disease. After multivariate adjustment, the relative risk of coronary heart disease comparing highest and lowest deciles of the low-carbohydrate-diet score was 0.94 (95% confidence interval [CI], 0.76 to 1.18; P for trend=0.19). The relative risk comparing highest and lowest deciles of a low-carbohydrate-diet score on the basis of the percentage of energy from carbohydrate, animal protein, and animal fat was 0.94 (95% CI, 0.74 to 1.19; P for trend=0.52), whereas the relative risk on the basis of the percentage of energy from intake of carbohydrates, vegetable protein, and vegetable fat was 0.70 (95% CI, 0.56 to 0.88; P for trend=0.002). A higher glycemic load was strongly associated with an increased risk of coronary heart disease (relative risk comparing highest and lowest deciles, 1.90; 95% CI, 1.15 to 3.15; P for trend=0.003). CONCLUSIONS: Our findings suggest that diets lower in carbohydrate and higher in protein and fat are not associated with increased risk of coronary heart disease in women. When vegetable sources of fat and protein are chosen, these diets may moderately reduce the risk of coronary heart disease.",0
3249,17133482,JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation,"JunD is implicated in the regulation of hepatic stellate cell (HSC) activation and liver fibrosis via its transcriptional regulation of the tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. In the present study we found in vivo evidence of a role for JunD in fibrogenesis. Expression of JunD was demonstrated in alpha-SMA-positive activated HSCs of fibrotic rodents and human livers. The junD-/- mice were protected from carbon tetrachloride-induced fibrosis. The livers of injured junD-/- mice displayed significantly reduced formation of fibrotic crosslinked collagen and a smaller number of alpha-SMA-positive HSCs compared with those of wild-type (wt) mice. Hepatic TIMP-1 mRNA expression in injured junD-/- mice was 78% lower and in culture activated junD-/- HSCs was 50%-80% lower than that in wt mice. In examining the signal transduction mechanisms that regulate JunD-dependent TIMP-1 expression, we found a role for phosphorylation of the Ser100 residue of JunD but ruled out JNK as a mediator of this event, suggesting ERK1/2 is utilized. In conclusion, a signaling pathway for the development of fibrosis involves the regulation of TIMP-1 expression by phosphorylated JunD.",0
3250,17133499,Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial,"""In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon +/- RBV and had Ishak fibrosis scores > or = 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm3 (n = 559); (B) bridging fibrosis with platelet counts < or =125,000/mm3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm3 (n = 198); and (D) cirrhosis with platelet counts < or =125,000/mm3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these """"difficult-to-cure"""" patients.""",0
3251,17135585,Financial relationships between institutional review board members and industry,"BACKGROUND: Little is known about the nature, extent, and consequences of financial relationships between industry and institutional review board (IRB) members in academic institutions. We surveyed IRB members about such relationships. METHODS: We surveyed a random sample of 893 IRB members at 100 academic institutions (response rate, 67.2%). The questionnaire focused on the financial relationships that the members had with industry (e.g., employment, membership on boards, consulting, receipt of royalties, and paid speaking). RESULTS: We found that 36% of IRB members had had at least one relationship with industry in the past year. Of the respondents, 85.5% said they never thought that the relationships that another IRB member had with industry affected his or her IRB-related decisions in an inappropriate way, 11.9% said they thought this occurred rarely, 2.4% thought it occurred sometimes, and 0.2% thought it occurred often. Seventy-eight respondents (15.1%) reported that at least one protocol came before their IRB during the previous year that was sponsored either by a company with which they had a relationship or by a competitor of that company, both of which could be considered conflicts of interest. Of these 78 members (62 voting members and 16 nonvoting members), 57.7% reported that they always disclosed the relationship to an IRB official, 7.7% said they sometimes did, 11.5% said they rarely did, and 23.1% said they never did. Of the 62 voting members who reported conflicts, 64.5% reported that they never voted on the protocol, 4.8% said they rarely did, 11.3% said they sometimes did, and 19.4% said they always did. Most respondents reported that the views of IRB members who had experience working with industry were beneficial in reviewing industry-sponsored protocols. CONCLUSIONS: Relationships between IRB members and industry are common, and members sometimes participate in decisions about protocols sponsored by companies with which they have a financial relationship. Current regulations and policies should be examined to be sure that there is an appropriate way to handle conflicts of interest stemming from relationships with industry.",0
3252,17182987,A randomized trial of diagnostic techniques for ventilator-associated pneumonia,"BACKGROUND: Critically ill patients who require mechanical ventilation are at risk for ventilator-associated pneumonia. Current data are conflicting as to the optimal diagnostic approach in patients who have suspected ventilator-associated pneumonia. METHODS: In a multicenter trial, we randomly assigned immunocompetent adults who were receiving mechanical ventilation and who had suspected ventilator-associated pneumonia after 4 days in the intensive care unit (ICU) to undergo either bronchoalveolar lavage with quantitative culture of the bronchoalveolar-lavage fluid or endotracheal aspiration with nonquantitative culture of the aspirate. Patients known to be colonized or infected with pseudomonas species or methicillin-resistant Staphylococcus aureus were excluded. Empirical antibiotic therapy was initiated in all patients until culture results were available, at which point a protocol of targeted therapy was used for discontinuing or reducing the dose or number of antibiotics, or for resuming antibiotic therapy to treat a preenrollment condition if the culture was negative. RESULTS: We enrolled 740 patients in 28 ICUs in Canada and the United States. There was no significant difference in the primary outcome (28-day mortality rate) between the bronchoalveolar-lavage group and the endotracheal-aspiration group (18.9% and 18.4%, respectively; P=0.94). The bronchoalveolar-lavage group and the endotracheal-aspiration group also had similar rates of targeted therapy (74.2% and 74.6%, respectively; P=0.90), days alive without antibiotics (10.4+/-7.5 and 10.6+/-7.9, P=0.86), and maximum organ-dysfunction scores (mean [+/-SD], 8.3+/-3.6 and 8.6+/-4.0; P=0.26). The two groups did not differ significantly in the length of stay in the ICU or hospital. CONCLUSIONS: Two diagnostic strategies for ventilator-associated pneumonia--bronchoalveolar lavage with quantitative culture of the bronchoalveolar-lavage fluid and endotracheal aspiration with nonquantitative culture of the aspirate--are associated with similar clinical outcomes and similar overall use of antibiotics. (Current Controlled Trials number, ISRCTN51767272 [controlled-trials.com].).",0
3253,17182990,PET of brain amyloid and tau in mild cognitive impairment,"BACKGROUND: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics. METHODS: We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI). RESULTS: Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI. CONCLUSIONS: FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.",0
3254,17187402,"The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT","Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis [corrected]",0
3255,17187418,Regulation of the UGT1A1 bilirubin-conjugating pathway: role of a new splicing event at the UGT1A locus,"UDP-glucuronosyltransferase 1A1 (UGT1A1) is involved in a wide range of biological and pharmacological processes because of its critical role in the conjugation of a diverse array of endogenous and exogenous compounds. We now describe a new UGT1A1 isoform, referred to as isoform 2 (UGT1A1_i2), encoded by a 1495-bp complementary DNA isolated from human liver and generated by an alternative splicing event involving an additional exon found at the 3' end of the UGT1A locus. The N-terminal portion of the 45-kd UGT1A1_i2 protein is identical to UGT1A1 (55 kd, UGT1A1_i1); however, UGT1A1_i2 contains a unique 10-residue sequence instead of the 99-amino acid C-terminal domain of UGT1A1_i1. RT-PCR and Western blot analyses with a specific antibody against UGT1A1 indicate that isoform 2 is differentially expressed in liver, kidney, colon, and small intestine at levels that reach or exceed, for some tissues, those of isoform 1. Western blots of different cell fractions and immunofluorescence experiments indicate that UGT1A1_i1 and UGT1A1_i2 colocalize in microsomes. Functional enzymatic data indicate that UGT1A1_i2, which lacks transferase activity when stably expressed alone in HEK293 cells, acts as a negative modulator of UGT1A1_i1, decreasing its activity by up to 78%. Coimmunoprecipitation of UGT1A1_i1 and UGT1A1_i2 suggests that this repression may occur via direct protein-protein interactions. CONCLUSION: Our results indicate that this newly discovered alternative splicing mechanism at the UGT1A locus amplifies the structural diversity of human UGT proteins and describes the identification of an additional posttranscriptional regulatory mechanism of the glucuronidation pathway.",0
3256,17187425,Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver,"Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. CONCLUSION: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver.",0
3257,17187430,Toll-like receptor-3 and the regulation of intrahepatic immunity: implications for interferon-alpha therapy,"The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.",0
3258,17202453,Dopamine agonists and the risk of cardiac-valve regurgitation,"BACKGROUND: Case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, used in the treatment of Parkinson's disease and the restless legs syndrome, may increase the risk of cardiac-valve regurgitation. METHODS: We used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80 years of age who were prescribed antiparkinsonian drugs between 1988 and 2005. We conducted a nested case-control analysis within this cohort in which each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 control subjects from the cohort, according to age, sex, and year of entry into the cohort. Incidence-rate ratios for cardiac-valve regurgitation with the use of different dopamine agonists were estimated by conditional logistic-regression analysis. RESULTS: Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists. CONCLUSIONS: In this study, use of the dopamine agonists pergolide and cabergoline was associated with an increased risk of newly diagnosed cardiac-valve regurgitation.",0
3259,17229951,Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor,"BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.",0
3260,17256722,Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes,"In liver, most genes are expressed with a porto-central gradient. The transcription factor hepatic nuclear-factor4alpha (HNF4alpha) is associated with 12% of the genes in adult liver, but its involvement in zonation of gene expression has not been investigated. A putative HNF4alpha-response element in the upstream enhancer of glutamine synthetase (GS), an exclusively pericentral enzyme, was protected against DNase-I and interacted with a protein that is recognized by HNF4alpha-specific antiserum. Chromatin-immunoprecipitation assays of HNF4alpha-deficient (H4LivKO) and control (H4Flox) livers with HNF4alpha antiserum precipitated the GS upstream enhancer DNA only from H4Flox liver. Identical results were obtained with a histone-deacetylasel (HDAC1) antibody, but antibodies against HDAC3, SMRT and SHP did not precipitate the GS upstream enhancer. In H4Flox liver, GS, ornithine aminotransferase (OAT) and thyroid hormone-receptor beta1 (TRbeta1) were exclusively expressed in pericentral hepatocytes. In H4LivKO liver, this pericentral expression remained unaffected, but the genes were additionally expressed in the periportal hepatocytes, albeit at a lower level. The expression of the periportal enzyme phosphoenolpyruvate carboxykinase had declined in HNF4alpha-deficient hepatocytes. GS-negative cells, which were present as single, large hepatocytes or as groups of small cells near portal veins, did express HNF4alpha. Clusters of very small GS- and HNF4alpha-negative, and PCNA- and OV6-positive cells near portal veins were contiguous with streaks of brightly HNF4alpha-positive, OV6-, PCNA-, and PEPCK-dim cells. CONCLUSION: Our findings show that HNF4alpha suppresses the expression of pericentral proteins in periportal hepatocytes, possibly via a HDAC1-mediated mechanism. Furthermore, we show that HNF4alpha deficiency induces foci of regenerating hepatocytes.",0
3261,17256726,A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1,"Genetic predisposition to type 1 autoimmune hepatitis (AIH) is linked mainly to HLA class II genes. We previously searched the whole HLA region for AIH susceptibility genes using microsatellite markers and found only HLA-DR/DQ to be a candidate region for this suspected multifactorial disease. As such, the aim of this study was to broaden our search and screen the whole genome for additional genes that might contribute to type 1 AIH susceptibility. Eighty-one patients with type 1 AIH (15 men, 66 women, average age 55.9) and 80 healthy sex- and age-matched Japanese controls were enrolled in this study. We performed a case-control association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. Two markers, one on chromosome 11 (D11S902, Pc = 0.013) and one on chromosome 18 (D18S464, Pc = 0.008), were revealed to have statistically significant associations with AIH. An additional 7 markers (D2S367, D6S309, D9S273, D11S1320, D16S423, D17S938, and D18S68) were also found to be candidate susceptibility regions. In addition, our results showed there were 17 regions that may contain genes of resistance to AIH. No specific markers were detected in HLA-DR4-negative patients, and no differences were seen in the clinical courses of patients (severe versus mild to moderate). CONCLUSION: This first genomewide scan of Japanese AIH patients revealed at least 26 candidate AIH susceptibility or resistance regions other than HLA class II loci. These results also suggested that the products of several genes interact to determine heritable susceptibility to AIH.",0
3262,17256746,Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B,"We studied the long-term efficacy of adefovir dipivoxil (ADV) treatment in 42 HBeAg-negative patients with chronic hepatitis B (CHB) who had developed genotypical lamivudine (LAM) resistance with virological and clinical breakthroughs under long-term LAM treatment. Patients were allocated in 2 treatment groups. In the first (n = 14), LAM was switched to ADV monotherapy whereas in the second (n = 28) ADV was added to LAM. The two groups did not differ in patients' characteristics, all of them having HBV genotype D infection with the precore stop codon mutation. Within 12 months from start of ADV treatment, serum HBV DNA became nondetectable and ALT normalized in 71% and 90% of patients, respectively, with no difference between the 2 arms. Patients with baseline HBV DNA levels less than 10(7) copies/ml experienced a significantly earlier and more frequent decline in serum HBV DNA to nondetectable levels as compared with patients with greater than 10(7) HBV DNA copies/ml at baseline (P = 0.0013) This response has hitherto been maintained (median treatment duration 40 months) in all patients with ADV added to LAM, whereas virological and biochemical breakthroughs due to development of ADV signature resistance mutations occurred in 3 of 14 patients (21%) on ADV monotherapy 15 to 18 months from start of treatment (P = 0.0174). CONCLUSION: Adding ADV to LAM in HBeAg-negative CHB patients with LAM resistance effectively suppresses HBV replication inmost of them and induces biochemical remission that can be maintained in all of them at least for 3 years without any evidence of development of resistance to ADV.",0
3263,17256753,AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers,"We previously reported that peripheral blood mononuclear cells (PBMCs) from patients with primary biliary cirrhosis (PBC) produce significantly higher levels of polyclonal IgM than controls after exposure to CpG. Furthermore, the prevalence and unusually high levels of antimitochondrial antibodies (AMAs) in patients with PBC suggest a profound loss ofB cell tolerance. We have addressed the issue of whether CpG will promote the production ofAMAs and whether new experimental agents that inhibit the lymphocyte potassium channels Kv1.3 and KCa3.1 can suppress CpG-mediated B cell activation and AMA production. PBMCs were stimulated with and without CpG and were subsequently analyzed for phenotype, including expression of TLR9, CD86, and KCa3.1 concurrent with measurements of AMA and responses to a control antigen, tetanus toxoid, in supernatants. Additionally, K+ channel expression on B cells from PBC patients and controls was studied using whole-cell patch-clamp technology. In patients with PBC, CpG induces secretion of AMAs in PBMCs andalso up-regulates B cell expression of TLR9, CD86, and KCa3.1. Additionally, K+ channel blockers suppress secretion of AMA without a reduction of CpG-B-enhanced IgM production. Furthermore, there is diminished up-regulation of TLR9 and CD86 without affecting proliferation of B cells, B cell apoptosis, or viability. CONCLUSION: These data suggest that the hyperresponsiveness of B cells in PBC accelerates B cell-mediated autoimmunity.",0
3264,17256764,Concanavalin A induces autophagy in hepatoma cells and has a therapeutic effect in a murine in situ hepatoma model,"Concanavalin A (ConA), a lectin with mannose specificity that can induce acute hepatic inflammation, was tested for its therapeutic effect against hepatoma. ConA is cytotoxic or inhibitory to hepatoma cells, which is mediated by the autophagic pathway through mitochondria. Once it was bound to cell membrane glycoproteins, the ConA was internalized and preferentially localized onto the mitochondria. The mitochondria membrane permeability changed, and an autophagic pathway including LC3-II generation, double-layer vesicle, BNIP3 induction, and acidic vesicular organelle formation was induced. Either 3-MA or siRNA for BNIP3 and LC3, but neither beclin-1 nor ATG 5, partially inhibited the ConA-induced cell death. In addition to the autophagy induction, ConA is known to be a T cell mitogen. Using an in situ hepatoma model, ConA can exert an anti-hepatoma therapeutic effect, inhibiting tumor nodule formation in the liver and prolonging survival. CONCLUSION: ConA can be considered as an anti-hepatoma agent therapeutically because of its autophagic induction and immunomodulating activity. This dual function of ConA provides a novel mechanism for the biological effect of lectin.",0
3265,17259444,Public reporting and pay for performance in hospital quality improvement,"BACKGROUND: Public reporting and pay for performance are intended to accelerate improvements in hospital care, yet little is known about the benefits of these methods of providing incentives for improving care. METHODS: We measured changes in adherence to 10 individual and 4 composite measures of quality over a period of 2 years at 613 hospitals that voluntarily reported information about the quality of care through a national public-reporting initiative, including 207 facilities that simultaneously participated in a pay-for-performance demonstration project funded by the Centers for Medicare and Medicaid Services; we then compared the pay-for-performance hospitals with the 406 hospitals with public reporting only (control hospitals). We used multivariable modeling to estimate the improvement attributable to financial incentives after adjusting for baseline performance and other hospital characteristics. RESULTS: As compared with the control group, pay-for-performance hospitals showed greater improvement in all composite measures of quality, including measures of care for heart failure, acute myocardial infarction, and pneumonia and a composite of 10 measures. Baseline performance was inversely associated with improvement; in pay-for-performance hospitals, the improvement in the composite of all 10 measures was 16.1% for hospitals in the lowest quintile of baseline performance and 1.9% for those in the highest quintile (P<0.001). After adjustments were made for differences in baseline performance and other hospital characteristics, pay for performance was associated with improvements ranging from 2.6 to 4.1% over the 2-year period. CONCLUSIONS: Hospitals engaged in both public reporting and pay for performance achieved modestly greater improvements in quality than did hospitals engaged only in public reporting. Additional research is required to determine whether different incentives would stimulate more improvement and whether the benefits of these programs outweigh their costs.",0
3266,17287477,GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis,"BACKGROUND: Increased mortality from infection in patients with pulmonary alveolar proteinosis occurs in association with high levels of autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We tested the hypothesis that neutrophil functions are impaired in patients with pulmonary alveolar proteinosis and that GM-CSF autoantibodies cause the dysfunction. METHODS: We studied 12 subjects with pulmonary alveolar proteinosis, 61 healthy control subjects, and 12 control subjects with either cystic fibrosis or end-stage liver disease. We also studied GM-CSF-/- mice and wild-type mice. We evaluated basal neutrophil functions, neutrophil functions after priming by GM-CSF to augment antimicrobial functions, and the effects of highly purified GM-CSF autoantibodies on neutrophil functions in vitro and in vivo. RESULTS: Neutrophils from subjects with pulmonary alveolar proteinosis had normal ultrastructure and differentiation markers but impaired basal functions and antimicrobial functions after GM-CSF priming. GM-CSF-/- mice also had reduced basal neutrophil functions, but functions after GM-CSF priming were unimpaired. The neutrophil dysfunction characteristic of pulmonary alveolar proteinosis was reproduced in a dose-dependent fashion in blood specimens from healthy control subjects after incubation with affinity-purified GM-CSF autoantibodies isolated from patients with pulmonary alveolar proteinosis. The injection of mouse GM-CSF antibodies into wild-type mice also caused neutrophil dysfunction. CONCLUSIONS: The antimicrobial functions of neutrophils are impaired in patients with pulmonary alveolar proteinosis, owing to the presence of GM-CSF autoantibodies. The effects of these autoantibodies show that GM-CSF is an essential regulator of neutrophil functions.",0
3267,17287479,"Religion, conscience, and controversial clinical practices","BACKGROUND: There is a heated debate about whether health professionals may refuse to provide treatments to which they object on moral grounds. It is important to understand how physicians think about their ethical rights and obligations when such conflicts emerge in clinical practice. METHODS: We conducted a cross-sectional survey of a stratified, random sample of 2000 practicing U.S. physicians from all specialties by mail. The primary criterion variables were physicians' judgments about their ethical rights and obligations when patients request a legal medical procedure to which the physician objects for religious or moral reasons. These procedures included administering terminal sedation in dying patients, providing abortion for failed contraception, and prescribing birth control to adolescents without parental approval. RESULTS: A total of 1144 of 1820 physicians (63%) responded to our survey. On the basis of our results, we estimate that most physicians believe that it is ethically permissible for doctors to explain their moral objections to patients (63%). Most also believe that physicians are obligated to present all options (86%) and to refer the patient to another clinician who does not object to the requested procedure (71%). Physicians who were male, those who were religious, and those who had personal objections to morally controversial clinical practices were less likely to report that doctors must disclose information about or refer patients for medical procedures to which the physician objected on moral grounds (multivariate odds ratios, 0.3 to 0.5). CONCLUSIONS: Many physicians do not consider themselves obligated to disclose information about or refer patients for legal but morally controversial medical procedures. Patients who want information about and access to such procedures may need to inquire proactively to determine whether their physicians would accommodate such requests.",0
3268,17301297,Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease,"BACKGROUND: Treatment of acute Kawasaki disease with intravenous immune globulin and aspirin reduces the risk of coronary-artery abnormalities and systemic inflammation, but despite intravenous immune globulin therapy, coronary-artery abnormalities develop in some children. Studies have suggested that primary corticosteroid therapy might be beneficial and that adverse events are infrequent with short-term use. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to determine whether the addition of intravenous methylprednisolone to conventional primary therapy for Kawasaki disease reduces the risk of coronary-artery abnormalities. Patients with 10 or fewer days of fever were randomly assigned to receive intravenous methylprednisolone, 30 mg per kilogram of body weight (101 patients), or placebo (98 patients). All patients then received conventional therapy with intravenous immune globulin, 2 g per kilogram, as well as aspirin, 80 to 100 mg per kilogram per day until they were afebrile for 48 hours and 3 to 5 mg per kilogram per day thereafter. RESULTS: At week 1 and week 5 after randomization, patients in the two study groups had similar coronary dimensions, expressed as z scores adjusted for body-surface area, absolute dimensions, and changes in dimensions. As compared with patients receiving placebo, patients receiving intravenous methylprednisolone had a somewhat shorter initial period of hospitalization (P=0.05) and, at week 1, a lower erythrocyte sedimentation rate (P=0.02) and a tendency toward a lower C-reactive protein level (P=0.07). However, the two groups had similar numbers of days spent in the hospital, numbers of days of fever, rates of retreatment with intravenous immune globulin, and numbers of adverse events. CONCLUSIONS: Our data do not provide support for the addition of a single pulsed dose of intravenous methylprednisolone to conventional intravenous immune globulin therapy for the routine primary treatment of children with Kawasaki disease. (ClinicalTrials.gov number, NCT00132080 [ClinicalTrials.gov].)",0
3269,17301300,Inheritance of a cancer-associated MLH1 germ-line epimutation,"Persons who have hypermethylation of one allele of MLH1 in somatic cells throughout the body (a germ-line epimutation) have a predisposition for the development of cancer in a pattern typical of hereditary nonpolyposis colorectal cancer. By studying the families of two such persons, we found evidence that the epimutation was transmitted from a mother to her son but was erased in his spermatozoa. The affected maternal allele was inherited by three other siblings from these two families, but in those offspring the allele had reverted to the normal active state. These findings demonstrate a novel pattern of inheritance of cancer susceptibility and are consistent with transgenerational epigenetic inheritance.",0
3270,17314339,DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer,"BACKGROUND: RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis, tumor progression, and the response of non-small-cell lung cancer to treatment. METHODS: We developed an automated quantitative determination of the RRM1 protein in routinely processed histologic specimens. In these specimens, we measured the expression of RRM1 and two other proteins that are relevant to non-small-cell lung cancer: the excision repair cross-complementation group 1 (ERCC1) protein and the phosphatase and tensin homologue (PTEN). We compared the results with the clinical outcomes in 187 patients with early-stage non-small-cell lung cancer who had received only surgical treatment. RESULTS: RRM1 expression correlated with the expression of ERCC1 (P<0.001) but not with the expression of PTEN (P=0.37). The median disease-free survival exceeded 120 months in the group of patients with tumors that had high expression of RRM1 and was 54.5 months in the group with low expression of RRM1 (hazard ratio for disease progression or death in the high-expression group, 0.46; P=0.004). The overall survival was more than 120 months for patients with tumors with high expression of RRM1 and 60.2 months for those with low expression of RRM1 (hazard ratio for death, 0.61; P=0.02). Among these 187 patients, the survival advantage was limited to the 30% of patients with tumors that had a high expression of both RRM1 and ERCC1. CONCLUSIONS: RRM1 and ERCC1 are determinants of survival after surgical treatment of early-stage, non-small-cell lung cancer.",0
3271,17326153,Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection,"The functional impairment of HCV-specific T cell responses is believed to be an important determinant of HCV persistence, but the functional T cell defects of patients with chronic hepatitis C (CH-C) are only partially defined. CD8 responses to HLA-A2-restricted epitopes of HCV and other unrelated viruses were studied in 23 HLA-A2-positive patients both ex vivo and after in vitro culture. Degranulation capacity, intracellular perforin, and granzyme-A content and cytokine production (IFN-gamma, TNF-alpha) by HCV- and non-HCV-specific CD8 cells were tested both ex vivo and in vitro, whereas cytolytic activity was studied after 10 days' expansion in vitro. Memory maturation and role of exhaustion were assessed ex vivo by HCV-specific CD8 staining for CD127 and PD-1, and in vitro after peripheral blood mononuclear cells (PBMC) culture in the presence of anti-PD-L1 monoclonal antibodies. IFN-gamma production and cytolytic activity were expressed less efficiently by HCV-specific than by non-HCV specific CD8 cells derived from the same CH-C patients. The amount of stored granzyme-A within single cells was always lower in HCV-specific CD8 cells, which were less efficient also in the release of lytic granules and in the production of TNF-alpha. The CD8 dysfunction was associated with high PD-1 expression by most HCV-specific CD8 cells, and PD-1/PD-L1 blockade by anti-PD-L1 antibodies in vitro was able to improve the HCV-specific CD8 function. CONCLUSION: Our study characterizes CD8 defects that may be important in maintaining HCV persistence; identification of strategies to correct these defects may help to define novel approaches to treat HCV infection.",0
3272,17326190,Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors,"Immunotherapy is often effective only for small tumor burdens and, in many cases, is restricted to subcutaneous tumors. Here, we investigated the antitumor effects of combination therapy with GM-CSF and IL-12 on orthotopic liver tumors with intermediate or large tumor volumes, or on chemically-induced multifocal liver tumors in animals. Adenoviruses encoding GM-CSF or IL-12 were injected intratumorally to animals bearing transplanted tumors, or injected via intrahepatic artery in animals with primary multifocal liver tumors induced by diethylnitrosamine. Our results demonstrated that IL-12, but not GM-CSF, monotherapy displayed significant therapeutic effects, whereas combination therapy with both cytokines displayed synergistic antitumor effects not only on transplanted tumor models with intermediate or large tumor loads, but also on carcinogen-induced multifocal liver tumors. Effector cell analyses, revealed by in vivo cell subset depletion, flow cytometry analysis, and immunohistochemical staining of tumor infiltrates, indicated that NK cells were the prominent antitumor effectors for the IL-12-mediated antitumor activity, whereas CD8+ T cells, NKT cells, and macrophages were more important than NK cells in the combination therapy-mediated antitumor effects. Both IL-12 monotherapy and combination therapy could induce various types of effectors and high levels of IFN-gamma; however, the latter induced much higher levels than the former, which may explain why combination therapy is superior to IL-12 monotherapy. CONCLUSION: Combination therapy with GM-CSF and IL-12 represents a promising immunotherapy strategy for treating orthotopic, widespread liver tumors.",0
3273,17366663,Hypoxic conformance of metabolism in primary rat hepatocytes: a model of hepatic hibernation,"""Following prolonged hypoxia, mammalian cells invoke adaptive mechanisms to enhance oxygen delivery and promote energy conservation. We previously reported that hepatocytes subjected to prolonged moderate hypoxia (PO2 = 20-50 mmHg for > 3 hours) demonstrated a reversible inhibition of cellular respiration with maintenance of cell viability, associated with a decrease in mitochondrial adenosine triphosphate (ATP) synthesis; acute hypoxia (similar PO2 for < 30 minutes) did not induce a similar suppression of respiration and ATP synthesis. In the current study, using an in vitro model of primary rat hepatocytes, we measured the changes in metabolic demand for ATP during hypoxic conformance, and tested whether viability is maintained by preferentially suppressing nonessential processes while sustaining processes essential for maintaining cell homeostasis. In addition, the rate of recovery of oxygen consumption and ATP concentrations following reoxygenation after prolonged and acute hypoxia/anoxia was compared. Oxygen consumption and ATP concentrations decreased during prolonged hypoxia compared with acute hypoxia. However, ouabain-inhibitable respiration did not decrease during prolonged hypoxia, indicating that membrane Na+/K+ ATPase activity, an essential process for cell viability, was maintained. In contrast, ATP-dependent glucuronidation and sulfation of acetaminophen, deemed """"non-essential"""" processes, were decreased significantly compared with normoxic cells. After reoxygenation, cells exposed to prolonged moderate hypoxia demonstrated a more rapid recovery of respiration compared to acute hypoxia/anoxia. CONCLUSION: This """"hepatic hibernation"""" during prolonged moderate hypoxia may represent an anticipatory adaptation that seeks to maintain cell viability while delaying or preventing the onset of lethal hypoxia, and facilitates rapid recovery after the resumption of normoxia.""",0
3274,17377159,NALP1 in vitiligo-associated multiple autoimmune disease,"BACKGROUND: Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated autoimmune and autoinflammatory diseases. The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease. METHODS: We tested 177 single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak for association with disease and identified a strong candidate gene. We then sequenced DNA in and around the gene to identify additional SNPs. We carried out a second round of tests of association using some of these additional SNPs, thus elucidating the association with disease in the gene and its extended promoter region in fine detail. RESULTS: Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system. Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease. CONCLUSIONS: DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders.",0
3275,17393466,Early diagnostic potential for hepatocellular carcinoma using the SELDI ProteinChip system,"Early detection of HCC increases the potential for curative treatment and improves survival. To facilitate early detection of HCC, this study sought to identify novel diagnostic markers of HCC using surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS) ProteinChip technology. Serum samples were obtained from 153 patients with or without HCC, all of whom had been diagnosed with HCV-associated chronic liver disease. To identify proteins associated with HCC, serum samples were analyzed using SELDI-TOF/MS. We constructed an initial decision tree for the correct diagnosis of HCC using serum samples from patients with (n = 35) and without (n = 44) HCC. Six protein peaks were selected to construct a decision tree using this first group. The efficacy of the decision tree was then assessed using a second group of patients with (n = 29) and without (n = 33) HCC. The sensitivity and specificity of this decision tree for the diagnosis of HCC were 83% and 76%, respectively. For a third group, we analyzed sera from seven patients with HCC obtained before the diagnosis of HCC by ultrasonography (US) and from five patients free of HCC for the past 3 years. Use of these diagnostic markers predicted the diagnosis of HCC in six of these seven patients before HCC was clinically apparent without any false positives. CONCLUSION: Serum profiling using the SELDI ProteinChip system is useful for the early detection and prediction of HCC in patients with chronic HCV infection.",0
3276,17393467,ERK2 but not ERK1 plays a key role in hepatocyte replication: an RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes,"The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 have been implicated in various physiological events, and specific targeting of these MAPKs could affect cell proliferation in many cell types. First, to evaluate the potential specific roles of these two MAPKs, we analyzed the mitogenic response in regenerating liver after partial hepatectomy (PH) and in primary culture of hepatocytes isolated from ERK1-deficient mice. We show that ERK1 knockout and wild-type (wt) cells replicate with the same kinetics after PH in liver, in vivo, and in primary cultures of hepatocytes, in vitro. Indeed, Cyclin D1 and Cdk1 appear to be expressed concomitantly in knockout and wt cells, highlighting that hepatocytes progress in the cell cycle independently of the presence of ERK1. Second, we specifically abolished ERK2 expression by RNA interference in mouse and rat hepatocytes. We investigated whether small interfering RNA (siRNA) targeting ERK2 could specifically inhibit its expression and interfere with the process of replication. In ERK1-deficient hepatocytes, silencing ERK2 expression by RNA interference and ERK2 activation by U0126 clearly demonstrate that DNA replication is regulated by an ERK2-dependent mechanism. Furthermore, in rat wt hepatocytes, whereas ERK2 targeting inhibits late G(1) and S phase progression, ERK1 silencing is devoid of any effect on cell proliferation, indicating that ERK1 cannot rescue ERK2 deficiency. CONCLUSION: Our results emphasize the importance of the MAPK cascade in hepatocyte replication and allow us to conclude that ERK2 is the key form involved in this regulation, in vivo and in vitro.",0
3277,17393500,Genetic and catalytic efficiency structure of an HCV protease quasispecies,"The HCV nonstructural protein (NS)3/4A serine protease is not only involved in viral polyprotein processing but also efficiently blocks the retinoic-acid-inducible gen I and Toll-like receptor 3 signaling pathways and contributes to virus persistence by enabling HCV to escape the interferon antiviral response. Therefore, the NS3/4A protease has emerged as an ideal target for the control of the disease and the development of new anti-HCV agents. Here, we analyzed, at a high resolution (approximately 100 individual clones), the HCV NS3 protease gene quasispecies from three infected individuals. Nucleotide heterogeneity of 49%, 84%, and 91% were identified, respectively, which created a dense net that linked different parts of the viral population. Minority variants having mutations involved in the acquisition of resistance to current NS3/4A protease inhibitors (PIs) were also found. A vast diversity of different catalytic efficiencies could be distinguished. Importantly, 67% of the analyzed enzymes displayed a detectable protease activity. Moreover, 35% of the minority individual variants showed similar or better catalytic efficiency than the master (most abundant) enzyme. Nevertheless, and in contrast to minority variants, master enzymes always displayed a high catalytic efficiency when different viral polyprotein cleavage sites were tested. Finally, genetic and catalytic efficiency differences were observed when the 3 quasispecies were compared, suggesting that different selective forces were acting in different infected individuals. CONCLUSION: The rugged HCV protease quasispecies landscape should be able to react to environmental changes that may threaten its survival.",0
3278,17393518,Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial,"Cholesterol biosynthesis is an integral part of HCV RNA replication. Not only does HCV RNA replicate on lipid rafts, but it also requires cholesterol intermediates to replicate. In addition, it has been shown in vitro that several HMG-CoA reductase inhibitors can decrease HCV RNA replication by > or = 1 log. Therefore, we designed a clinical trial to evaluate the effect of atorvastatin on HCV RNA levels. In this prospective clinical trial, where patients served as their own control, 10 HCV-infected patients who required treatment for high cholesterol were given 20 mg atorvastatin per day. Although serum cholesterol and LDL predictably decreased significantly, there was no statistically significant change in week 4 and week 12 HCV RNA levels compared to pretreatment HCV RNA levels by the paired Student t test. It is unclear whether the addition of an HMG-CoA reductase inhibitor to interferon or a more potent inhibitor of cholesterol biosynthesis may be required to inhibit HCV RNA replication in vivo. In conclusion, atorvastatin, and likely all HMG-CoA reductase inhibitors, does not inhibit HCV RNA replication in vivo at conventional doses.",0
3279,17393528,Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding,"""Although both beta-blockade (BB) and endoscopic variceal ligation (EVL) are used for primary prevention of variceal bleeding (VB) in patients with cirrhosis with moderate to large esophageal varices (EVs), the more cost-effective option is uncertain. We created a Markov decision model to compare BB and EVL in such patients, examining both cost-effectiveness (cost per life year [LY]) and cost-utility (cost per quality-adjusted life year [QALY]). Outcomes included cost per LY, cost per QALY, proportions of persons with VB, TIPS, and all-cause mortality. EVL and BB were compared using the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR). When considering only LYs, initial EVL exceeds the benchmark of 50,000 dollars/LY, with an ICER of 98,407 dollars. However, when quality of life (QoL) is considered, EVL is cost-effective compared to BB (ICUR of 25,548 dollars/QALY). In sensitivity analysis, EVL is cost-effective if the yearly risk of EV bleeding is > or = 0.26 (base case 0.15), the relative risk of bleeding on BB is > or = 0.69 (base case 0.58), or if the relative risk of bleeding with EVL is < 0.27 (base case 0.35). The ICUR favored EVL unless the relative risk of bleeding on BB is < 0.46, the relative risk of bleeding with EVL is > 0.46, or the time horizon is < or = 24 months. Whether EVL is """"cost-effective"""" relative to BB therapy for primary prevention of EV bleeding depends on whether LYs or QALYs are considered. If only LYs are considered, then EVL is not cost-effective compared to BB therapy; however, if QoL is considered, then EVL is cost-effective.""",0
3280,17409324,Mutations in VANGL1 associated with neural-tube defects,"Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting. In a protein-protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3. These findings implicate VANGL1 as a risk factor in human neural-tube defects.",0
3281,17429083,Interleukin-1-receptor antagonist in type 2 diabetes mellitus,"BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. RESULTS: At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. CONCLUSIONS: The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].).",0
3282,17442906,Targeted therapy for inherited GPI deficiency,"Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase-encoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM. The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency.",0
3283,17460227,A lethal defect of mitochondrial and peroxisomal fission,"We report on a newborn girl with microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very-long-chain fatty acids. We found a defect of the fission of both mitochondria and peroxisomes, as well as a heterozygous, dominant-negative mutation in the dynamin-like protein 1 gene (DLP1). The DLP1 protein has previously been implicated, in vitro, in the fission of both these organelles. Overexpression of the mutant DLP1 in control cells reproduced the fission defect. Our findings are representative of a class of disease characterized by defects in both mitochondria and peroxisomes.",0
3284,17460228,A national survey of physician-industry relationships,"BACKGROUND: Relationships between physicians and pharmaceutical, medical device, and other medically related industries have received considerable attention in recent years. We surveyed physicians to collect information about their financial associations with industry and the factors that predict those associations. METHODS: We conducted a national survey of 3167 physicians in six specialties (anesthesiology, cardiology, family practice, general surgery, internal medicine, and pediatrics) in late 2003 and early 2004. The raw response rate for this probability sample was 52%, and the weighted response rate was 58%. RESULTS: Most physicians (94%) reported some type of relationship with the pharmaceutical industry, and most of these relationships involved receiving food in the workplace (83%) or receiving drug samples (78%). More than one third of the respondents (35%) received reimbursement for costs associated with professional meetings or continuing medical education, and more than one quarter (28%) received payments for consulting, giving lectures, or enrolling patients in trials. Cardiologists were more than twice as likely as family practitioners to receive payments. Family practitioners met more frequently with industry representatives than did physicians in other specialties, and physicians in solo, two-person, or group practices met more frequently with industry representatives than did physicians practicing in hospitals and clinics. CONCLUSIONS: The results of this national survey indicate that relationships between physicians and industry are common and underscore the variation among such relationships according to specialty, practice type, and professional activities.",0
3285,17464971,Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis,"Measurement of hepatic venous pressure gradient (HVPG) is a standard method for the assessment of portal pressure and correlates with the occurrence of its complications. Liver stiffness measurement (LSM) has been proposed as a noninvasive technique for the prediction of the complications of cirrhosis. In this study, we evaluated the ability of LSM to predict severe portal hypertension compared with that of HVPG in 61 consecutive patients with HCV-related chronic liver disease. A strong relationship between LSM and HVPG measurements was found in the overall population (r=0.81, P<0.0001). However, although the correlation was excellent for HVPG values less than 10 or 12 mm Hg (r=0.81, P=0.0003 and r=0.91, P<0.0001, respectively), linear regression analysis was not optimal for HVPG values>or=10 mm Hg (r2=0.35, P<0.0001) or>or=12 mm Hg (r2=0.17, P=0.02). The AUROC for the prediction of HVPG>or=10 and >or=12 mm Hg were 0.99 and 0.92, respectively and at LSM cutoff values of 13.6 kPa and 17.6 kPa, sensitivity was 97% and 94%, respectively. In patients with cirrhosis, LSM positively correlated with the presence of esophageal varices (P=0.002), although no correlation between LSM and esophageal varices size was detected. The area under the ROC for the prediction of EV was 0.76 and at a LSM cutoff value of 17.6 kPa sensitivity was 90%. CONCLUSION: LSM represents a non-invasive tool for the identification of chronic liver disease patients with clinically significant or severe portal hypertension and could be employed for screening patients to be subjected to standard investigations including upper GI endoscopy and hemodynamic studies.",0
3286,17464989,Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma,"In HCC, inactivation of tumor suppressor genes plays a significant role in carcinogenesis. Apart from deletions and mutations, growing evidence has indicated that epigenetic alterations including aberrant promoter methylation and histone deacetylation are also implicated in inactivation of tumor suppressor genes. The goal of this study was to identify epigenetically silenced candidate tumor suppressor genes in human HCC by comparing the changes in oligonucleotide microarray gene expression profiles in HCC cell lines upon pharmacological treatment with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC). By analyzing the gene expression profiles, we selected tissue factor pathway inhibitor-2 (TFPI-2), a Kunitz-type serine protease inhibitor, for validation and further characterization. Our results showed that TFPI-2 was frequently silenced in human HCC and HCC cell lines. TFPI-2 was significantly underexpressed in approximately 90% of primary HCCs when compared with their corresponding nontumorous livers. TFPI-2 promoter methylation was detected in 80% of HCC cell lines and 47% of human HCCs and was accompanied by reduced TFPI-2 messenger RNA expression. In addition, TFPI-2 expression in HCC cell lines can be robustly restored by combined treatment with 5-Aza-dC and histone deacetylase inhibitor trichostatin A. These findings indicate that TFPI-2 is frequently silenced in human HCC via epigenetic alterations, including promoter methylation and histone deacetylation. Moreover, ectopic overexpression of TFPI-2 significantly suppressed the proliferation and invasiveness of HCC cells. CONCLUSION: Our findings suggest that TFPI-2 is a candidate tumor suppressor gene in human HCC.",0
3287,17465001,The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms,"Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPARgamma (rosiglitazone) or short interfering RNAs for SOCS-7. CONCLUSION: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms.",0
3288,17476011,Use of physicians' services under Medicare's resource-based payments,"BACKGROUND: In 1992, Medicare implemented the resource-based relative-value scale, which established payments for physicians' services based on relative costs. We conducted a study to determine how the use of physicians' services changed during the first decade after the implementation of this scale. METHODS: With the resource-based relative-value scale, Medicare payments are based on the number of relative-value units (RVUs) assigned to physicians' services. The total number of RVUs reflects the volume of physicians' work (the time, skill, and training required for a physician to provide the service), practice expenses, and professional-liability insurance. Using national data from Medicare on physicians' services and American Medical Association files on RVUs, we analyzed the growth in RVUs per Medicare beneficiary from 1992 to 2002 according to the type of service and specialty. We also examined this growth with respect to the quantity and mix of services, revisions in the valuation of RVUs, and new service codes. RESULTS: Between 1992 and 2002, the volume of physicians' work per Medicare beneficiary grew by 50%, and the total RVUs per Medicare beneficiary grew by 45%. The quantity and mix of services were the largest sources of growth, increasing by 19% for RVUs for physicians' work and by 22% for total RVUs. Our findings varied among services and specialties. Revised valuation of RVUs was a key source of the growth in RVUs for physicians' work and total RVUs for evaluation and management and for tests. New service codes were the largest drivers of growth for major procedures (accounting for 36% of the growth in RVUs for physicians' work and 35% of the growth in total RVUs), and the quantity and mix of existing services were the largest drivers of growth for imaging. The growth in RVUs for physicians' work was greatest in cardiology (114%) and gastroenterology (72%). The total growth in RVUs was greatest in cardiology (99%) and dermatology (105%). CONCLUSIONS: In the first 10 years after the implementation of the resource-based relative-value scale, RVUs per Medicare beneficiary grew substantially. The leading sources of growth varied among service types and specialties. An understanding of these sources of growth can inform policies to control Medicare spending.",0
3289,17507703,Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma,"BACKGROUND: Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma. We investigated whether the symptom-driven use of a combination of beclomethasone dipropionate and albuterol (also known as salbutamol) in a single inhaler would be as effective as the regular use of inhaled beclomethasone and superior to the as-needed use of inhaled albuterol. METHODS: We conducted a 6-month, double-blind, double-dummy, randomized, parallel-group trial. After a 4-week run-in, patients with mild asthma were randomly assigned to receive one of four inhaled treatments: placebo twice daily plus 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler as needed (as-needed combination therapy); placebo twice daily plus 100 microg of albuterol as needed (as-needed albuterol therapy); 250 microg of beclomethasone twice daily and 100 microg of albuterol as needed (regular beclomethasone therapy); or 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler twice daily plus 100 microg of albuterol as needed (regular combination therapy). The primary outcome was the morning peak expiratory flow rate. RESULTS: In 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters (88.36% of the predicted value), the morning peak expiratory flow rate during the last 2 weeks of the 6-month treatment was higher (P=0.04) and the number of exacerbations during the 6-month treatment was lower (P=0.002) in the as-needed combination therapy group than in the as-needed albuterol therapy group, but the values in the as-needed combination therapy group were not significantly different from those in the groups receiving regular beclomethasone therapy or regular combination therapy. The cumulative dose of inhaled beclomethasone was lower in the as-needed combination therapy group than in the groups receiving regular beclomethasone therapy or regular combination therapy (P<0.001 for both comparisons). CONCLUSIONS: In patients with mild asthma, the symptom-driven use of inhaled beclomethasone (250 microg) and albuterol (100 microg) in a single inhaler is as effective as regular use of inhaled beclomethasone (250 microg twice daily) and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid. (ClinicalTrials.gov number, NCT00382889 [ClinicalTrials.gov].).",0
3290,17518369,Identification of host genes involved in hepatitis C virus replication by small interfering RNA technology,"Hepatitis C virus (HCV) replication is highly dependent on host cell factors. Identification of these host factors not only facilitates understanding of the biology of HCV infection but also enables the discovery of novel targets for anti-HCV therapy. To identify host genes important for HCV RNA replication, we screened a library of small interfering RNA (siRNA) that targets approximately 4,000 human genes in Huh7-derived EN5-3 cells harboring an HCV subgenomic replicon with the nonstructural region NS3-NS5B from the 1b-N strain. Nine cellular genes that potentially regulate HCV replication were identified in this screen. Silencing of these genes resulted in inhibition of HCV replication by more than 60% and exhibited minimal toxicity. Knockdown of host gene expression by these siRNAs was confirmed at the RNA level and, in some instances, at the protein level. The level of siRNA silencing of these host genes correlated well with inhibition of HCV. These genes included those that encoded a G-protein coupled receptor (TBXA2R), a membrane protein (LTbeta), an adapter protein (TRAF2), 2 transcription factors (RelA and NFkappaB2), 2 protein kinases (MKK7 and SNARK), and 2 closely related transporter proteins (SLC12A4 and SLC12A5). Of interest, some of these genes are members of the tumor necrosis factor/lymphotoxin signaling pathway. CONCLUSION: Findings of this study may provide important information for understanding HCV replication. In addition, these cellular genes may constitute a novel set of targets for HCV antiviral therapy.",0
3291,17518370,The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor,"The purpose of this study was to identify the receptor responsible for endocytosis of denatured collagen from blood. The major site of clearance of this material (at least 0.5 g/day in humans) is a receptor on liver sinusoidal endothelial cells (LSECs). We have now identified an 180-kDa endocytic receptor on LSECs, peptide mass fingerprinting of which revealed it to be the mannose receptor. Challenge of mannose-receptor knockout mice and their cultured LSECs revealed significantly reduced blood clearance and a complete absence of LSEC endocytosis of denatured collagen. Organ analysis of wild-type versus knockout mice after injection of denatured collagen revealed significantly reduced liver uptake in the knockout mice. Clearance/endocytosis of ligands for other receptors in these animals was as that for wild-type mice, and denatured collagen uptake in wild-type mice was not affected by other ligands of the mannose receptor, namely mannose and mannan. Furthermore, unlike that of mannose and mannan, endocytosis of denatured collagen by the mannose receptor is calcium independent. This suggests that the binding site for denatured collagen is distinct from that for mannose/mannan. Mannose receptors on LSECs appear to have less affinity for circulating triple helical type I collagen. CONCLUSION: The mannose receptor is the main candidate for being the endocytic denatured collagen receptor on LSECs.",0
3292,17523162,Bile salt-dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4,"Human ABCB4 (multidrug resistance [MDR]3 P-glycoprotein) is expressed in the canalicular membrane of the hepatocyte. ABCB4 has been shown to be required for phosphatidylcholine (PC) secretion into the bile and to translocate PC across the plasma membrane. To further investigate the function of ABCB4, we established a cell line stably expressing ABCB4 (human embryonic kidney [HEK]/ABCB4). The efflux of phospholipids from HEK/ABCB4 cells was remarkably increased by the addition of taurocholate. In addition, the cholesterol efflux from HEK/ABCB4 cells was also enhanced in the presence of taurocholate. Light scattering measurements suggested that the taurocholate monomer plays an important role in ABCB4-mediated lipid secretion. On the other hand, the efflux of phospholipids and cholesterol was not mediated by ABCB1 (MDR1) even in the presence of taurocholate. Taurocholate promoted the efflux of phospholipids and cholesterol from HEK/ABCB4 cells more efficiently than glycocholate and cholate. ABCB4-K435M and ABCB4-K1075M, Walker A lysine mutants, did not mediate the phospholipid and cholesterol efflux in the presence of taurocholate, suggesting that ATP hydrolysis is essential for the efflux. Verapamil completely inhibited the taurocholate-dependent efflux of phospholipids and cholesterol from HEK/ABCB4 cells. Mass spectrometry revealed that, in the presence of taurocholate, HEK/ABCB4 cells preferentially secreted PC compared to sphingomyelin. PC vesicles induced cholesterol diffusion from cell membrane, but did not accept cholesterol from ABCB4. CONCLUSION: ABCB4 mediates the efflux of phospholipids into the canalicular lumen in the presence of bile salts, and plays a crucial role in bile formation and lipid homeostasis.",0
3293,17526009,Myxovirus-1 and protein kinase haplotypes and fibrosis in chronic hepatitis C virus,"Candidate genes, including myxovirus resistance-1 (Mx1), protein kinase (PKR), transforming growth factor-beta1 (TGF-beta), interleukin-10 (IL-10), and interferon-gamma (IFN-gamma), were evaluated for associations with liver fibrosis in 374 treatment-naive patients with genotype-1 chronic HCV infection [194 Caucasian Americans (CAs) and 180 African Americans (AAs)], using a genetic haplotype approach. Among the 18 haplotypes that occurred with a frequency >or=5% in the cohort overall, the Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T) (abbreviated Mx1-CAGT), and PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak >or= 3 versus <3). These associations persisted after adjustment for potential confounders such as alcohol use, sex, age (which is strongly correlated with the estimated duration of HCV infection [Spearman's correlation coefficient (r(s)) = 0.6)], and race (for Mx1-CAGT: OR = 0.33; 95% CI: 0.16-0.68; P = 0.0027; and for PKR-TGATT: OR = 0.56; 95% CI: 0.32-0.98; P = 0.0405). Population structure was evaluated using the structured association method using data from 161 ancestry-informative markers and did not affect our findings. We used an independent cohort of 34 AA and 160 CA in an attempt to validate our findings, although notable differences were found in the characteristics of the two patient groups. Although we observed a similar protective trend for the Mx1-CAGT haplotype in the validation set, the association was not statistically significant. CONCLUSION: In addition to other factors, polymorphisms in cytokine genes may play a role in the progression of HCV-related fibrosis; however, further studies are needed.",0
3294,17526021,Incidence of non-Hodgkin's lymphoma among individuals with chronic hepatitis B virus infection,"Although hepatitis C virus (HCV) infection has been shown to be associated with development of non-Hodgkin's lymphoma (NHL), few studies have investigated the association between chronic HBV infection and NHL. The purpose of this study was to compare the incidence of NHL between patients with and without chronic hepatitis B virus (HBV) infection. Using automated laboratory result and clinical data from two United States health systems, we identified individuals with chronic HBV infection from January 1, 1995 through December 31, 2001. Using each health system's population-based tumor registry, we identified all cases of NHL diagnosed through December 31, 2002. We excluded any individual with a history of NHL or human immunodeficiency virus (HIV). We fit Cox proportional hazards models to calculate hazard ratios comparing the incidence of NHL between chronic HBV-infected patients (N = 3,888) and patients without HBV (N = 205,203) drawn from the source populations. We identified 8 NHL cases in the chronic HBV infection cohort and 111 cases in the comparison cohort. Patients with chronic HBV infection were 2.8 times more likely to develop NHL than matched comparison patients (adjusted hazard ratio = 2.80, 95% confidence interval = 1.16-6.75), after controlling for age, race, sex, income, Charlson comorbidity index, study site, and HCV infection. CONCLUSION: chronic HBV-infected patients were nearly 3 times more likely to develop NHL than comparison patients.",0
3295,17526025,Redox-dependent and ligand-independent trans-activation of insulin receptor by globular adiponectin,"Adiponectin/ACRP30 is an adipose tissue-derived hormone with antiatherogenic, antidiabetic, and insulin-sensitizing properties. Although the metabolic effects of adiponectin on glucose and lipid metabolism are well known, the signaling pathways triggered by adiponectin receptors remain to be elucidated. We report evidence that in hepatic cells, adiponectin stimulation produces a transient burst of reactive oxygen species (ROS) through activation of the small GTPase Rac1 and 5-lypoxigenase. Furthermore, adiponectin-induced oxidants cause the oxidation/inhibition of protein-tyrosine phosphatase (PTP) 1B, one of the major phosphotyrosine phosphatases involved in the control of insulin receptor phosphorylation. Adiponectin causes increased association of PTP1B to insulin receptor and the oxidation/inhibition of the phosphatase, ultimately provoking the ligand-independent trans-phosphorylation of insulin receptor. We also report evidence that redox signaling plays a key role in both mitogen-activated protein kinase activation and hepatic glucose consumption induced by adiponectin. CONCLUSION: These results point to ROS as critical regulators of the cross-talk between adiponectin and insulin pathways and provide a redox-based molecular mechanism for the insulin-sensitizing function of adiponectin.",0
3296,17538933,Restoration of p53 function: a new therapeutic strategy to induce tumor regression?,"Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.",0
3297,17538966,Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration,"The experimental protocols used in the investigation of stem cell-mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic lineages. Although the protocols are numerous and often used interchangeably across species, a thorough comparative phenotypic analysis of oval cells in rats and mice using well-established and generally acknowledged molecular markers has not been provided. In the present study, we evaluated and compared the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell-mediated liver regeneration-namely, treatment with 2-acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline-deficient, ethionine-supplemented (CDE) diet; a 3,5-diethoxycarbonyl-1,4-dihydro-collidin (DDC) diet; and N-acetyl-paraaminophen (APAP). Reproducibly, oval cells showing reactivity for cytokeratins (CKs), muscle pyruvate kinase (MPK), the adenosine triphosphate-binding cassette transporter ABCG2/BCRP1 (ABCG2), alpha-fetoprotein (AFP), and delta-like protein 1/preadipocyte factor 1 (Dlk/Pref-1) were induced in rat liver treated according to the AAF/PHx and CDE but not the DDC protocol. In mouse liver, the CDE, DDC, and APAP protocols all induced CKs and ABCG2-positive oval cells. However, AFP and Dlk/Pref-1 expression was rarely detected in oval cells. CONCLUSION: Our results delineate remarkable phenotypic discrepancies exhibited by oval cells in stem cell-mediated liver regeneration between rats and mice and underline the importance of careful extrapolation between individual species.",0
3298,17538967,Glucocorticoid signaling synchronizes the liver circadian transcriptome,"Circadian control of physiology is mediated by local, tissue-based clocks, synchronized to each other and to solar time by signals from the suprachiasmatic nuclei (SCN), the master oscillator in the hypothalamus. These local clocks coordinate the transcription of key pathways to establish tissue-specific daily metabolic programs. How local transcriptomes are synchronized across the organism and their relative contribution to circadian output remain unclear. In the present study we showed that glucocorticoids alone are able to synchronize expression of about 60% of the circadian transcriptome. We propose that synchronization occurs directly by the action of glucocorticoids on a diverse range of downstream targets and indirectly by regulating the core clock genes mPer1, Bmal1, mCry1, and Dbp. We have identified the pivotal liver transcription factor, HNF4alpha, as a mediator of circadian and glucocorticoid-regulated transcription, showing that it is a key conduit for downstream targeting. CONCLUSION: We have demonstrated that by orchestrating transcriptional cascades, glucocorticoids are able to direct synchronization of a diverse range of functionally important circadian genes.",0
3299,17554119,"Bacteremia, fever, and splenomegaly caused by a newly recognized bartonella species","Bartonella species cause serious human infections globally, including bacillary angiomatosis, Oroya fever, trench fever, and endocarditis. We describe a patient who had fever and splenomegaly after traveling to Peru and also had bacteremia from an organism that resembled Bartonella bacilliformis, the causative agent of Oroya fever, which is endemic to Peru. However, genetic analyses revealed that this fastidious bacterium represented a previously uncultured and unnamed bartonella species, closely related to B. clarridgeiae and more distantly related to B. bacilliformis. We characterized this isolate, including its ability to cause fever and sustained bacteremia in a rhesus macaque. The route of infection and burden of human disease associated with this newly described pathogen are currently unknown.",0
3300,17559151,Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution,"CD8(+) T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens. CONCLUSION: These data provide insight into the frequency and reproducibility of viral escape from CD8(+) T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens.",0
3301,17582070,Natural history of multiple sclerosis with childhood onset,"BACKGROUND: The course and prognosis of childhood-onset multiple sclerosis have not been well described. METHODS: We used data from 13 adult neurology departments affiliated with the European Database for Multiple Sclerosis (EDMUS) network to identify a cohort of 394 patients who had multiple sclerosis with an onset at 16 years of age or younger and a comparison group of 1775 patients who had multiple sclerosis with an onset after 16 years of age. We determined the initial clinical features, the dates of disease onset, and the occurrence of outcomes, including relapse, conversion to secondary progression, and irreversible disability as measured by scores of 4 (limited walking ability but ability to walk more than 500 m without aid or rest), 6 (ability to walk with unilateral support no more than 100 m without rest), and 7 (ability to walk no more than 10 m without rest while using a wall or furniture for support) on the Kurtzke Disability Status Scale (range, 0 to 10; higher scores indicate more severe disability). RESULTS: For patients with childhood-onset multiple sclerosis, the estimated median time from onset to secondary progression was 28 years, and the median age at conversion to secondary progression was 41 years. The median times from onset to disability scores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively, and the corresponding median ages were 34.6, 42.2, and 50.5 years. In comparison with patients with adult-onset disease, those with childhood-onset disease were more likely to be female than male (female:male ratio, 2.8 vs. 1.8), were more likely to have an exacerbating-remitting initial course (98% vs. 84%), took approximately 10 years longer to reach secondary progression and irreversible disability, and reached these landmarks at an age approximately 10 years younger (P<0.001 for all comparisons). CONCLUSIONS: Patients with childhood-onset multiple sclerosis take longer to reach states of irreversible disability but do so at a younger age than patients with adult-onset multiple sclerosis.",0
3302,17596850,Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management,"Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Approved treatments for chronic hepatitis B include 2 formulations of interferon and 4 nucleos(t)ide analogues (NAs). Sustained viral suppression is rarely achieved after withdrawal of a 48-week course of NA therapy, necessitating long, and in many cases, indefinite treatment with increasing risk of development of drug resistance. Antiviral resistance and poor adherence are the most important factors in treatment failure of hepatitis B. Thus, there is a need to standardize nomenclature relating to hepatitis B antiviral resistance, and to define genotypic, phenotypic, and clinical resistance to NA therapy.",0
3303,17599777,Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus,"Current therapy of chronic hepatitis C is based on the combination of pegylated interferon-alpha and ribavirin. In spite of 50% sustained virological response, therapy is still limited by unsatisfying success rates with genotype 1 infections and adverse side effects. One attempt to increase success rates is triple combination therapy of interferon and ribavirin with amantadine, a drug assumed to interfere with HCV p7 ion channel function. However, results from clinical trials indicate limited efficacy and the antiviral activity is unclear. In contrast, NS3 protease inhibitors have shown potent antiviral effects in clinical trials but rapid selection for drug resistance may limit their benefit. Targeting cellular factors required for HCV is therefore an attractive alternative. In this study, employing a system for production of infectious HCV particles in cell culture, we determined the antiviral effects of amantadine and iminosugar derivatives; the second of which primarily target host cell glucosidases required for folding and maturation of HCV envelope glycoproteins. We found that across a spectrum of HCV isolates and genotypes, amantadine affected neither RNA replication nor the release or infectivity of HCV particles. In agreement, p7 ion channel activity was not affected by amantadine, demonstrating that amantadine is not an HCV-selective antiviral. In contrast, a dose-dependent reduction of virus titers was achieved with iminosugars. Furthermore, HCV was rapidly eliminated from cell culture upon passage in the presence of a long alkyl chain deoxynojirimycin (DNJ). CONCLUSION: Iminosugar derivatives are potential drugs for treatment of HCV infections.",0
3304,17611204,In vitro fertilization with preimplantation genetic screening,"BACKGROUND: Pregnancy rates in women of advanced maternal age undergoing in vitro fertilization (IVF) are disappointingly low. It has been suggested that the use of preimplantation genetic screening of cleavage-stage embryos for aneuploidies may improve the effectiveness of IVF in these women. METHODS: We conducted a multicenter, randomized, double-blind, controlled trial comparing three cycles of IVF with and without preimplantation genetic screening in women 35 through 41 years of age. The primary outcome measure was ongoing pregnancy at 12 weeks of gestation. The secondary outcome measures were biochemical pregnancy, clinical pregnancy, miscarriage, and live birth. RESULTS: Four hundred eight women (206 assigned to preimplantation genetic screening and 202 assigned to the control group) underwent 836 cycles of IVF (434 cycles with and 402 cycles without preimplantation genetic screening). The ongoing-pregnancy rate was significantly lower in the women assigned to preimplantation genetic screening (52 of 206 women [25%]) than in those not assigned to preimplantation genetic screening (74 of 202 women [37%]; rate ratio, 0.69; 95% confidence interval [CI], 0.51 to 0.93). The women assigned to preimplantation genetic screening also had a significantly lower live-birth rate (49 of 206 women [24%] vs. 71 of 202 women [35%]; rate ratio, 0.68; 95% CI, 0.50 to 0.92). CONCLUSIONS: Preimplantation genetic screening did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of advanced maternal age. (Current Controlled Trials number, ISRCTN76355836 [controlled-trials.com].).",0
3305,17625126,Use of health services by previously uninsured Medicare beneficiaries,"BACKGROUND: Previously uninsured adults who enroll in the Medicare program at the age of 65 years may have greater morbidity, requiring more intensive and costlier care over subsequent years, than they would if they had been previously insured. METHODS: We used longitudinal data from the nationally representative Health and Retirement Study to assess self-reported health care use and expenditures from 1992 through 2004 among 5158 adults who were privately insured or uninsured before Medicare coverage began at the age of 65 years. We used propensity-score methods to compare health care use and expenditures for previously insured and uninsured beneficiaries who were similar across numerous characteristics at 59 to 60 years of age and adjusted for differences in supplemental and prescription-drug coverage after 65 years of age. RESULTS: Among 2951 adults with hypertension, diabetes, heart disease, or stroke diagnosed before 65 years of age, previously uninsured adults who acquired Medicare coverage at the age of 65 reported significantly greater increases in the numbers of doctor visits (P<0.001) and hospitalizations (P=0.001) and in total medical expenditures (P=0.02) than did previously insured adults. Significant differential increases were not evident among the 2207 adults without these conditions (P>0.12 for all comparisons). In analyses adjusted for supplemental and prescription-drug coverage, previously uninsured adults with these conditions reported more doctor visits (13% relative difference, P=0.04), more hospitalizations (20% relative difference, P=0.04), and higher total medical expenditures (51% relative difference, P=0.09) from ages 65 to 72 years than did previously insured adults. CONCLUSIONS: The costs of expanding health insurance coverage for uninsured adults before they reach the age of 65 years may be partially offset by subsequent reductions in health care use and spending for these adults after the age of 65, particularly if they have cardiovascular disease or diabetes before the age of 65 years.",0
3306,17634449,Genomewide association analysis of coronary artery disease,"BACKGROUND: Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. METHODS: We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). CONCLUSIONS: We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.",0
3307,17652652,The spread of obesity in a large social network over 32 years,"BACKGROUND: The prevalence of obesity has increased substantially over the past 30 years. We performed a quantitative analysis of the nature and extent of the person-to-person spread of obesity as a possible factor contributing to the obesity epidemic. METHODS: We evaluated a densely interconnected social network of 12,067 people assessed repeatedly from 1971 to 2003 as part of the Framingham Heart Study. The body-mass index was available for all subjects. We used longitudinal statistical models to examine whether weight gain in one person was associated with weight gain in his or her friends, siblings, spouse, and neighbors. RESULTS: Discernible clusters of obese persons (body-mass index [the weight in kilograms divided by the square of the height in meters], > or =30) were present in the network at all time points, and the clusters extended to three degrees of separation. These clusters did not appear to be solely attributable to the selective formation of social ties among obese persons. A person's chances of becoming obese increased by 57% (95% confidence interval [CI], 6 to 123) if he or she had a friend who became obese in a given interval. Among pairs of adult siblings, if one sibling became obese, the chance that the other would become obese increased by 40% (95% CI, 21 to 60). If one spouse became obese, the likelihood that the other spouse would become obese increased by 37% (95% CI, 7 to 73). These effects were not seen among neighbors in the immediate geographic location. Persons of the same sex had relatively greater influence on each other than those of the opposite sex. The spread of smoking cessation did not account for the spread of obesity in the network. CONCLUSIONS: Network phenomena appear to be relevant to the biologic and behavioral trait of obesity, and obesity appears to spread through social ties. These findings have implications for clinical and public health interventions.",0
3308,17654744,Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response,"Chronicity of hepatitis B virus (HBV) infection is characterized by a weak immune response to the virus. CD4+CD25+ regulatory T cells (Treg) are present in increased numbers in the peripheral blood of chronic HBV patients, and these Treg are capable of suppressing the HBV-specific immune response. The aim of this study was to abrogate Treg-mediated suppression of the HBV-specific immune response. Therefore, Treg and a Treg-depleted cell fraction were isolated from peripheral blood of chronic HBV patients. Subsequently, the suppressive effect of Treg on the response to HBV core antigen (HBcAg) and tetanus toxin was compared, and the effect of exogenous tumor necrosis factor alpha (TNF-alpha), interleukin-1-beta (IL-1beta), or neutralizing antibodies against interleukin-10 (IL-10) or transforming growth factor beta (TGF-beta) on Treg-mediated suppression was determined. The results show that Treg of chronic HBV patients had a more potent suppressive effect on the response to HBcAg compared with the response to tetanus toxin. Neutralization of IL-10 and TGF-beta or exogenous IL-1beta had no effect on Treg-mediated suppression of the anti-HBcAg response, whereas exogenous TNF-alpha partially abrogated Treg-mediated suppression. Preincubation of Treg with TNF-alpha demonstrated that TNF-alpha had a direct effect on the Treg. No difference was observed in the type II TNF receptor expression by Treg from chronic HBV patients and healthy controls. CONCLUSION: Treg-mediated suppression of the anti-HBV response can be reduced by exogenous TNF-alpha. Because chronic HBV patients are known to produce less TNF-alpha, these data implicate an important role for TNF-alpha in the impaired antiviral response in chronic HBV.",0
3309,17657819,Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes,"Connective tissue growth factor (CTGF) is important for transforming growth factor-beta (TGF-beta)-induced liver fibrogenesis. Hepatic stellate cells have been recognized as its major cellular source in the liver. Here we demonstrate the induction of CTGF expression in hepatocytes of damaged livers and identify a molecular mechanism responsible for it. CTGF expression was found by immunohistochemistry in bile duct epithelial cells, hepatic stellate cells, and hepatocytes in fibrotic liver tissue from patients with chronic hepatitis B infection. Similarly, CTGF expression was induced in hepatocytes of carbon tetrachloride-treated mice. CTGF expression and secretion were detected spontaneously in a medium of hepatocytes after 3 days of culture, which was enhanced by stimulation with TGF-beta. TGF-beta-induced CTGF expression was mediated through the activin receptor-like kinase 5 (ALK5)/Smad3 pathway, whereas activin receptor-like kinase 1 activation antagonized this effect. CTGF expression in the liver tissue of TGF-beta transgenic mice correlated with serum TGF-beta levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-beta-dependent and intrinsic CTGF expression, indicating that TGF-beta signaling was required. In line with these data, hepatocyte-specific transgenic Smad7 reduced CTGF expression in carbon tetrachloride-treated animals, whereas in Smad7 knockout mice, it was enhanced. Furthermore, an interferon gamma treatment of patients with chronic hepatitis B virus infection induced Smad7 expression in hepatocytes, leading to decreased CTGF expression and fibrogenesis. CONCLUSION: Our data provide evidence for the profibrogenic activity of TGF-beta directed to hepatocytes and mediated via the up-regulation of CTGF. We identify ALK5-dependent Smad3 signaling as the responsible pathway inducing CTGF expression, which can be hindered by an activated activin receptor-like kinase 1 pathway and completely inhibited by TGF-beta antagonist Smad7.",0
3310,17661416,Is waiting time a measure of access to liver transplantation? Is shorter necessarily better?,"BACKGROUND: The Model for End-Stage Liver Disease (MELD) score has been used since February 2002 to allocate livers for transplantation from deceased donors according to medical need. Allocation based on MELD scores should ensure that sicker patients receive transplants first regardless of transplantation center volume. OBJECTIVE: To determine whether the MELD score at transplantation and waiting time of liver transplant recipients differs by transplantation center volume. DESIGN: Analysis of the Organ Procurement and Transplantation Network database. Centers were classified according to the volume of transplantations performed in 2005: high (> or =100 transplantations), medium (50 to 99 transplantations), and low (<50 transplantations). SETTING: Transplantation centers in the United States. PATIENTS: 20,075 transplant recipients between 27 February 2002 and 30 April 2006. MEASUREMENTS: MELD scores and waiting times of liver transplant recipients. RESULTS: Transplant recipients at high-volume centers had lower MELD scores (35.1% with MELD scores < or =18 vs. 22.7% and 27.0% at medium- and low-volume centers, respectively; P < 0.001), and the median MELD score was 22 compared with 24 at both medium- and low-volume centers. Despite having lower MELD scores, recipients at high-volume centers also experienced shorter waiting times (median waiting time, 69 days vs. 98 days and 94 days at medium-and low-volume centers, respectively; P < 0.001). LIMITATIONS: The definition of transplantation center volume was subjective. The recent implementation of MELD precluded analysis of differences in long-term outcomes related to waiting time or center volume. CONCLUSIONS: The MELD scores and waiting time of liver transplant recipients differed by transplantation center volume. High-volume centers have shorter waiting times and perform more transplantations for less sick patients. The reasons for these differences are unclear but warrant further investigation.",0
3311,17668873,Aging in rat causes hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2,"""The process of aging has recently been shown to substantially affect the ability of cells to respond to inflammatory challenges. We demonstrate that aging leads to hepatic hyperresponsiveness to interleukin 1beta (IL-1beta), and we examine the factors that could be responsible for this phenomenon. IL-1beta-induced phosphorylation of c-jun N-terminal kinase (JNK) in hepatocytes isolated from aged rats was 3 times more potent than that in hepatocytes from young rats. Moreover, JNK was activated by substantially lower doses of IL-1beta. These age-related changes in JNK phosphorylation correlated with diminished IL-1beta-induced degradation of interleukin-1 receptor-associated kinase-1 (IRAK-1). Expression levels of IL1beta receptor I, total JNK, IRAK-1, and transforming growth factor-beta-activated kinase-1 (TAK-1) were not affected by aging. However, increased neutral sphingomyelinase activity was observed in hepatocytes from old animals, which we show is caused by induction of the plasma membrane localized neutral sphingomyelinase-2 (NSMase-2). We provide evidence that NSMase-2 is both required and sufficient for the onset of IL-1beta hyperresponsiveness during aging. Overexpression of NSMase-2 in hepatocytes from young rats leads both to a reduction in IRAK-1 degradation and potentiation of JNK phosphorylation, mimicking that seen in hepatocytes from old animals. More importantly, inhibition of NSMase activity in hepatocytes from aged rats using either scyphostatin or short interfering ribonucleic acid (siRNA) leads to reversion to the """"young"""" phenotype of IL-1beta response. CONCLUSION: These results show that the process of aging causes increased basal NSMase-2 activity in hepatocytes, which in turn leads to IRAK-1 stabilization, JNK potentiation, and ultimately IL-1beta hyperresponsiveness.""",0
3312,17668876,Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy,"Hepatitis C virus (HCV) has been known to replicate with extremely varying efficiencies in different host cells, even within different populations of a single human hepatoma cell line, termed Huh-7. Several reports have implicated the retinoic-acid inducible gene I (RIG-I)/ interferon regulatory factor 3 (IRF-3) pathway of the innate antiviral response with differences in host cell permissiveness to HCV. To investigate the general impact of the IRF-3 response onto HCV replication in cell culture, we generated an ample array of stable Huh-7 cell lines with altered IRF-3 responsiveness. Neither blocking IRF-3 activation in various host cells by expression of dominant negative RIG-I or HCV NS3/4A protease nor reconstitution of RIG-I signaling in Huh7.5, a cell clone known to be defective in this pathway, had any impact on HCV replication. Only by overexpressing constitutively active RIG-I or the signaling adaptor Cardif (also known as interferon-beta promoter stimulator 1, mitochondrial anti-viral signaling protein, or virus-induced signaling adaptor), both leading to a stimulation of the IRF-3 pathway in the absence of inducers, was HCV replication significantly inhibited. We therefore assessed the extent of RIG-I- dependent IRF-3 activation by different species of RNA, including full-length HCV genomes and HCV RNA duplexes, and observed strong induction only in response to double-stranded RNAs. CONCLUSION: Based on these findings, we propose a refined model of innate immune escape by HCV involving limited initial induction and stringent subsequent control of the IRF-3 response.",0
3313,17668881,Effect of the interleukin-6 C174G gene polymorphism on treatment of acute and chronic hepatitis C in human immunodeficiency virus coinfected patients,"Hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection poses a difficult therapeutic problem. Response to HCV-specific therapy is variable but might be influenced by host genetic factors, including polymorphisms of cytokine genes. Here, we studied whether interleukin-6 (IL-6) C174G gene polymorphism affects the response to antiviral treatment in HCV-infected HIV-positive subjects. We determined IL-6 genotypes in HIV-positive patients with acute (n = 52) and chronic (n = 60) hepatitis C treated with pegylated interferon-alpha. Two hundred ten HCV monoinfected, 197 HIV monoinfected, and 100 healthy individuals were studied as controls. Patients were classified into high and low producers according to IL-6 genotypes. Rates of sustained virological responses (SVRs) were compared between the IL-6 genotypes. Signal transducer and activator of transcription three phosphorylation was analyzed by Western blot in HCV core-transfected human hepatoma cell line (HUH7) cells. Distribution of IL-6 genotypes did not differ significantly between the study groups. SVR was achieved in 63% of HIV/HCV coinfected patients. Carriers of the IL-6 high producer (HP) genotype had significantly higher SVR rates than patients with an IL-6 low producer genotype (70.1% versus 52%; P < 0.002). This effect was seen in both HIV-positive patients with acute (74% versus 33%; P < 0.05) and chronic (66% versus 33%; P < 0.05) hepatitis C. Multivariate analysis confirmed IL-6 HP carriage as an independent positive predictor for SVR (Odd's ratio 6.1; P = 0.004). This effect corresponds to the in vitro observation that in HCV core-transfected HUH7 cells, IL-6 overcomes the HCV core-mediated inhibition of STAT3 activation. CONCLUSION: Response rates to HCV-specific treatment are higher in HCV/HIV-positive patients carrying the IL-6 HP genotype, which might be because of IL-6 mediated STAT3 activation.",0
3314,17668884,Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers,"In recent years, a large number of groups studied the fate of human stem cells in livers of immunodeficient animals. However, the interpretation of the results is quite controversial. We transplanted 4 different types of human extrahepatic precursor cells (derived from cord blood, monocytes, bone marrow, and pancreas) into livers of nonobese diabetic/severe combined immunodeficiency mice. Human hepatocytes were used as positive controls. Tracking of the transplanted human cells could be achieved by in situ hybridization with alu probes. Cells with alu-positive nuclei stained positive for human albumin and glycogen. Both markers were negative before transplantation. However, cells with alu-positive nuclei did not show a hepatocyte-like morphology and did not express cytochrome P450 3A4, and this suggests that these cells represent a mixed cell type possibly resulting from partial transdifferentiation. Using antibodies specific for human albumin, we also observed a second human albumin-positive cell type that could be clearly distinguished from the previously described cells by its hepatocyte-like morphology. Surprisingly, these cells had a mouse and not a human nucleus which is explained by transdifferentiation of human cells. Although it has not yet been formally proven, we suggest horizontal gene transfer as a likely mechanism, especially because we observed small fragments of human nuclei in mouse cells that originated from deteriorating transplanted cells. Qualitatively similar results were obtained with all 4 human precursor cell types through different routes of administration with and without the induction of liver damage. CONCLUSION: We observed evidence not for transdifferentiation but instead for a complex situation including partial differentiation and possibly horizontal gene transfer.",0
3315,17687131,NXY-059 for the treatment of acute ischemic stroke,"BACKGROUND: The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I (SAINT I) trial, reducing disability when given to patients who had acute ischemic stroke. We sought confirmation of efficacy in a second, larger trial. METHODS: We enrolled 3306 patients with acute ischemic stroke in a randomized, double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms. Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days. We examined scores on neurologic and activities-of-daily-living scales as secondary end points. We also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial hemorrhages. RESULTS: The efficacy analysis was based on 3195 patients. Prognostic factors were well balanced between the treatment groups. Mortality was equal in the two groups, and adverse-event rates were similar. The distribution of scores on the modified Rankin scale did not differ between the group treated with NXY-059 (1588 patients) and the placebo group (1607 patients; P=0.33 by the Cochran-Mantel-Haenszel test; odds ratio for limiting disability, 0.94; 95% confidence interval [CI], 0.83 to 1.06). Analysis of categorized scores on the modified Rankin scale confirmed the lack of benefit: the odds ratio for trichotomization into modified Rankin scale scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 (95% CI, 0.80 to 1.06). There was no evidence of efficacy for any of the secondary end points. Among patients treated with alteplase, there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage. CONCLUSIONS: NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms. (ClinicalTrials.gov number, NCT00061022 [ClinicalTrials.gov].)",0
3316,17699817,A decade of direct-to-consumer advertising of prescription drugs,"BACKGROUND: Evidence suggests that direct-to-consumer advertising of prescription drugs increases pharmaceutical sales and both helps to avert underuse of medicines and leads to potential overuse. Concern about such advertising has increased recently owing to the withdrawal from the market of heavily advertised drugs found to carry serious risks. Moreover, the Food and Drug Administration (FDA) has been criticized for its weak enforcement of laws regulating such advertising. METHODS: We examined industry-wide trends in spending by pharmaceutical companies on direct-to-consumer advertising and promotion to physicians during the past decade. We characterized the drugs for which such advertising is used and assessed the timing of advertising after a drug is introduced. Finally, we examined trends in the FDA's regulation of drug advertising. RESULTS: Total spending on pharmaceutical promotion grew from $11.4 billion in 1996 to $29.9 billion in 2005. Although during that time spending on direct-to-consumer advertising increased by 330%, it made up only 14% of total promotional expenditures in 2005. Direct-to-consumer campaigns generally begin within a year after the approval of a product by the FDA. In the context of regulatory changes requiring legal review before issuing letters, the number of letters sent by the FDA to pharmaceutical manufacturers regarding violations of drug-advertising regulations fell from 142 in 1997 to only 21 in 2006. CONCLUSIONS: Spending on direct-to-consumer advertising has continued to increase in recent years in spite of the criticisms leveled against it. Our findings suggest that calls for a moratorium on such advertising for new drugs would represent a dramatic departure from current practices.",0
3317,17705260,Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9,"Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor beta1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis. Inhibition of HSC chemotaxis by PDGF was blocked by TLR9 antagonists, and was absent in primary HSCs from mice deficient in TLR9 or the TLR adaptor molecule MyD88. Stimulation of TLR9 on HSCs blocked signaling by the PDGF signaling molecule inositol 1,4,5-triphosphate and reduced PDGF-mediated increase in cytosolic Ca(2+). CONCLUSION: DNA from apoptotic hepatocytes acts as an important mediator of HSC differentiation by (1) providing a stop signal to mobile HSCs when they have reached an area of apoptosing hepatocytes and (2) inducing a stationary phenotype-associated up-regulation of collagen production.",0
3318,17705277,Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein beta,"It is believed that adult tissues in mammals lack the plasticity needed to assume new developmental fates because of the absence of efficient pathways of dedifferentiation. However, the well-documented ability of the transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) to activate pancreatic lineage development and insulin production following ectopic expression in liver suggests a surprising degree of residual plasticity in adult liver cells. This study seeks a mechanistic explanation for the capacity of PDX-1 to endow liver cells with pancreatic characteristics and function. We demonstrate that PDX-1, previously shown to play an essential role in normal pancreatic organogenesis and pancreatic beta-cell function and to possess the potential to activate multiple pancreatic markers in liver, can also direct hepatic dedifferentiation. PDX-1 represses the adult hepatic repertoire of gene expression and activates the expression of the immature hepatic marker alpha-fetoprotein. We present evidence indicating that PDX-1 triggers hepatic dedifferentiation by repressing the key hepatic transcription factor CCAAT/enhancer-binding protein beta. Hepatic dedifferentiation is necessary though not sufficient for the activation of the mature pancreatic repertoire in liver. CONCLUSION: Our study suggests a dual role for PDX-1 in liver: inducing hepatic dedifferentiation and activating the pancreatic lineage. The identification of dedifferentiation signals may promote the capacity to endow mature tissues in mammals with the plasticity needed for acquiring novel developmental fates and functions to be implemented in the field of regenerative medicine.",0
3319,17715409,Long-term mortality after gastric bypass surgery,"BACKGROUND: Although gastric bypass surgery accounts for 80% of bariatric surgery in the United States, only limited long-term data are available on mortality among patients who have undergone this procedure as compared with severely obese persons from a general population. METHODS: In this retrospective cohort study, we determined the long-term mortality (from 1984 to 2002) among 9949 patients who had undergone gastric bypass surgery and 9628 severely obese persons who applied for driver's licenses. From these subjects, 7925 surgical patients and 7925 severely obese control subjects were matched for age, sex, and body-mass index. We determined the rates of death from any cause and from specific causes with the use of the National Death Index. RESULTS: During a mean follow-up of 7.1 years, adjusted long-term mortality from any cause in the surgery group decreased by 40%, as compared with that in the control group (37.6 vs. 57.1 deaths per 10,000 person-years, P<0.001); cause-specific mortality in the surgery group decreased by 56% for coronary artery disease (2.6 vs. 5.9 per 10,000 person-years, P=0.006), by 92% for diabetes (0.4 vs. 3.4 per 10,000 person-years, P=0.005), and by 60% for cancer (5.5 vs. 13.3 per 10,000 person-years, P<0.001). However, rates of death not caused by disease, such as accidents and suicide, were 58% higher in the surgery group than in the control group (11.1 vs. 6.4 per 10,000 person-years, P=0.04). CONCLUSIONS: Long-term total mortality after gastric bypass surgery was significantly reduced, particularly deaths from diabetes, heart disease, and cancer. However, the rate of death from causes other than disease was higher in the surgery group than in the control group.",0
3320,17715410,A study of sexuality and health among older adults in the United States,"BACKGROUND: Despite the aging of the population, little is known about the sexual behaviors and sexual function of older people. METHODS: We report the prevalence of sexual activity, behaviors, and problems in a national probability sample of 3005 U.S. adults (1550 women and 1455 men) 57 to 85 years of age, and we describe the association of these variables with age and health status. RESULTS: The unweighted survey response rate for this probability sample was 74.8%, and the weighted response rate was 75.5%. The prevalence of sexual activity declined with age (73% among respondents who were 57 to 64 years of age, 53% among respondents who were 65 to 74 years of age, and 26% among respondents who were 75 to 85 years of age); women were significantly less likely than men at all ages to report sexual activity. Among respondents who were sexually active, about half of both men and women reported at least one bothersome sexual problem. The most prevalent sexual problems among women were low desire (43%), difficulty with vaginal lubrication (39%), and inability to climax (34%). Among men, the most prevalent sexual problems were erectile difficulties (37%). Fourteen percent of all men reported using medication or supplements to improve sexual function. Men and women who rated their health as being poor were less likely to be sexually active and, among respondents who were sexually active, were more likely to report sexual problems. A total of 38% of men and 22% of women reported having discussed sex with a physician since the age of 50 years. CONCLUSIONS: Many older adults are sexually active. Women are less likely than men to have a spousal or other intimate relationship and to be sexually active. Sexual problems are frequent among older adults, but these problems are infrequently discussed with physicians.",0
3321,17761593,Luteinizing hormone beta mutation and hypogonadism in men and women,"Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism. We describe the clinical features of a consanguineous family in which three siblings, two men and one woman, had hypogonadism related to isolated luteinizing hormone deficiency. These subjects have a newly discovered homozygous mutation of a 5' splice site in LHB: IVS2+1G-->C. This mutation disrupts the splicing of messenger RNA (mRNA), generating a gross abnormality in the processing of the luteinizing hormone beta-subunit mRNA, which abrogates the secretion of luteinizing hormone. We also determined that the female phenotype of this LHB mutation is characterized by normal pubertal development, secondary amenorrhea, and infertility.",0
3322,17855668,Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease,"BACKGROUND: Exposure to air pollution from traffic is associated with adverse cardiovascular events. The mechanisms for this association are unknown. We conducted a controlled exposure to dilute diesel exhaust in patients with stable coronary heart disease to determine the direct effect of air pollution on myocardial, vascular, and fibrinolytic function. METHODS: In a double-blind, randomized, crossover study, 20 men with prior myocardial infarction were exposed, in two separate sessions, to dilute diesel exhaust (300 mug per cubic meter) or filtered air for 1 hour during periods of rest and moderate exercise in a controlled-exposure facility. During the exposure, myocardial ischemia was quantified by ST-segment analysis using continuous 12-lead electrocardiography. Six hours after exposure, vasomotor and fibrinolytic function were assessed by means of intraarterial agonist infusions. RESULTS: During both exposure sessions, the heart rate increased with exercise (P<0.001); the increase was similar during exposure to diesel exhaust and exposure to filtered air (P=0.67). Exercise-induced ST-segment depression was present in all patients, but there was a greater increase in the ischemic burden during exposure to diesel exhaust (-22+/-4 vs. -8+/-6 millivolt seconds, P<0.001). Exposure to diesel exhaust did not aggravate preexisting vasomotor dysfunction, but it did reduce the acute release of endothelial tissue plasminogen activator (P=0.009; 35% decrease in the area under the curve). CONCLUSIONS: Brief exposure to dilute diesel exhaust promotes myocardial ischemia and inhibits endogenous fibrinolytic capacity in men with stable coronary heart disease. Our findings point to ischemic and thrombotic mechanisms that may explain in part the observation that exposure to combustion-derived air pollution is associated with adverse cardiovascular events. (ClinicalTrials.gov number, NCT00437138 [ClinicalTrials.gov].).",0
3323,17880014,Metalloproteinase-9 deficiency protects against hepatic ischemia/reperfusion injury,"Leukocyte transmigration across endothelial and extracellular matrix protein barriers is dependent on adhesion and focal matrix degradation events. In the present study we investigated the role of metalloproteinase-9 (MMP-9/gelatinase B) in liver ischemia/reperfusion (I/R) injury using MMP-9-deficient (MMP-9(-/-)) animals and mice treated with a specific anti-MMP-9 neutralizing antibody or with a broad gelatinase inhibitor for both MMP-9 and metalloproteinase-2 (MMP-2/gelatinase A). Compared to wild-type mice, MMP-9(-/-) mice and mice treated with an anti-MMP-9 antibody showed significantly reduced liver damage. In contrast, mice treated with a broad gelatinase inhibitor showed rather inferior protection against I/R injury and were characterized by persistent ongoing liver inflammation, suggesting that MMP-2 and MMP-9 may have distinct roles in this type of injury. MMP-9 was mostly detected in Ly-6G and macrophage antigen-1 leukocytes adherent to the vessel walls and infiltrating the damaged livers of wild-type mice after liver I/R injury. Leukocyte traffic and cytokine expression were markedly impaired in livers of MMP-9(-/-) animals and in livers of mice treated with anti-MMP-9 antibody after I/R injury; however, initiation of the endothelial adhesion cascades was similar in both MMP-9(-/-) and control livers. We also showed that MMP-9-specific inhibition disrupted neutrophil migration across fibronectin in transwell filters and depressed myeloperoxidase (MPO) activation in vitro. CONCLUSION: These results support critical functions for MMP-9 in leukocyte recruitment and activation leading to liver damage. Moreover, they provide the rationale for identifying inhibitors to specifically target MMP-9 in vivo as a potential therapeutic approach in liver I/R injury.",0
3324,17881750,Outcomes at 2 years of age after repeat doses of antenatal corticosteroids,"BACKGROUND: We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment. METHODS: Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neurosensory disability and body size of the children at 2 years of corrected age. RESULTS: Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04). CONCLUSIONS: Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neurosensory disability or body size at 2 years of age. (Current Controlled Trials number, ISRCTN48656428 [controlled-trials.com].).",0
3325,17898097,Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years,"BACKGROUND: It has been hypothesized that early exposure to thimerosal, a mercury-containing preservative used in vaccines and immune globulin preparations, is associated with neuropsychological deficits in children. METHODS: We enrolled 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes. (We did not assess autism-spectrum disorders.) Exposure to mercury from thimerosal was determined from computerized immunization records, medical records, personal immunization records, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We assessed the association between current neuropsychological performance and exposure to mercury during the prenatal period, the neonatal period (birth to 28 days), and the first 7 months of life. RESULTS: Among the 42 neuropsychological outcomes, we detected only a few significant associations with exposure to mercury from thimerosal. The detected associations were small and almost equally divided between positive and negative effects. Higher prenatal mercury exposure was associated with better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination. CONCLUSIONS: Our study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at the age of 7 to 10 years.",0
3326,17914038,Effectiveness of influenza vaccine in the community-dwelling elderly,"BACKGROUND: Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short-term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results. METHODS: Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding. RESULTS: There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant--though lower--reductions in the risks of both hospitalization and death. CONCLUSIONS: During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved.",0
3327,17914040,Effectiveness and safety of drug-eluting stents in Ontario,"BACKGROUND: The placement of drug-eluting stents decreases the frequency of repeat revascularization procedures in patients undergoing percutaneous coronary intervention (PCI) in randomized clinical trials. However, there is uncertainty about the effectiveness of drug-eluting stents, and increasing concern about their safety, in routine clinical practice. METHODS: From the Cardiac Care Network of Ontario's population-based clinical registry of all patients undergoing PCI in Ontario, Canada, we identified a well-balanced cohort of 3751 pairs of patients, matched on the basis of propensity score, who received either bare-metal stents alone or drug-eluting stents alone during an index PCI procedure between December 1, 2003, and March 31, 2005. The primary outcomes of the study were the rates of target-vessel revascularization, myocardial infarction, and death. RESULTS: The 2-year rate of target-vessel revascularization was significantly lower among patients who received drug-eluting stents than among those who received bare-metal stents (7.4% vs. 10.7%, P<0.001). Drug-eluting stents were associated with significant reductions in the rate of target-vessel revascularization among patients with two or three risk factors for restenosis (i.e., presence of diabetes, small vessels [<3 mm in diameter], and long lesions [> or =20 mm]) but not among lower-risk patients. The 3-year mortality rate was significantly higher in the bare-metal-stent group than in the drug-eluting-stent group (7.8% vs. 5.5%, P<0.001), whereas the 2-year rate of myocardial infarction was similar in the two groups (5.2% and 5.7%, respectively; P=0.95). CONCLUSIONS: Drug-eluting stents are effective in reducing the need for target-vessel revascularization in patients at highest risk for restenosis, without a significantly increased rate of death or myocardial infarction.",0
3328,17926378,Excretion of cephaloridine and cephalothin in patients with renal impairment,"Cephaloridine has been shown to possess certain favorable pharmacologic features while retaining the desirable antimicrobial properties of the parent compound, cephalothin. The major advantage of cephaloridine is its relatively greater resistance to metabolic degradation, presumably by the liver. This results in more prolonged blood levels in healthy subjects and a longer half-life in patients with severe renal disease. These features, together with reported enhanced antimicrobial activity and lack of inhibition by serum, suggest that it may replace or substitute for the parent compound, cephalothin, provided further clinical trials indicate that it proves to be an effective agent. Suggestions are given for a modified dosage schedule in uremic patients and during hemodialysis.",0
3329,17926885,Clinical considerations in the use of corticosteroids,"""Factors concerned with the institution of prolonged, nonspecific corticoid therapy are discussed in detail because of the seriousness of the complications that may occur and the magnitude of the clinical problem. Particular attention has been paid to the psychologic effects of ACTH and corticosteroid therapy with reference to the manner in which """"habituation"""" to these agents may complicate the attempt to reduce or discontinue therapy at a later date. A plea is made to reassess regularly the possibility of effecting a reduction in dosage in all patients being maintained for prolonged periods on corticosteroids. Finally, a program is suggested that is based on physiologic concepts that may be employed when complete withdrawal of corticosteroid therapy is contemplated.""",0
3330,17926887,Management of emergencies. I. Management of the unconscious patient,"At the Boston City Hospital, with the arrival of each new generation of interns, a series of lectures is given on the management of medical emergencies. This series has been sponsored by the First and Third (Tufts) Medical Services under the direction of Dr. Fernando Biguria, and all the medical services have taken part. The lectures continue to be among the most popular and valuable conferences held during the year. Because of this, the Journal, has arranged a similar series, many of the articles being written by participants in the Boston City Hospital lecture course, with the hope that they may be helpful to all physicians, but especially to the young men and women who are now eagerly awaiting their internship this July.",0
3331,17928596,Childhood asthma after bacterial colonization of the airway in neonates,"BACKGROUND: Pathological features of the airway in young children with severe recurrent wheeze suggest an association between bacterial colonization and the initiating events of early asthma. We conducted a study to investigate a possible association between bacterial colonization of the hypopharynx in asymptomatic neonates and later development of recurrent wheeze, asthma, and allergy during the first 5 years of life. METHODS: The subjects were children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort who were born to mothers with asthma. Aspirates from the hypopharyngeal region of asymptomatic 1-month-old infants were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Wheeze was monitored prospectively on diary cards during the first 5 years of life. Blood eosinophil count and total IgE and specific IgE were measured at 4 years of age. Lung function was measured and asthma was diagnosed at 5 years of age. RESULTS: Hypopharyngeal samples were cultured from 321 neonates at 1 month of age. Twenty-one percent of the infants were colonized with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms; colonization with one or more of these organisms, but not colonization with S. aureus, was significantly associated with persistent wheeze (hazard ratio, 2.40; 95% confidence interval [CI], 1.45 to 3.99), acute severe exacerbation of wheeze (hazard ratio, 2.99; 95% CI, 1.66 to 5.39), and hospitalization for wheeze (hazard ratio, 3.85; 95% CI, 1.90 to 7.79). Blood eosinophil counts and total IgE at 4 years of age were significantly increased in children colonized neonatally with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms, but specific IgE was not significantly affected. The prevalence of asthma and the reversibility of airway resistance after beta2-agonist administration at 5 years of age were significantly increased in the children colonized neonatally with these organisms as compared with the children without such colonization (33% vs. 10% and 23% vs. 18%, respectively). CONCLUSIONS: Neonates colonized in the hypopharyngeal region with S. pneumoniae, H. influenzae, or M. catarrhalis, or with a combination of these organisms, are at increased risk for recurrent wheeze and asthma early in life.",0
3332,17928597,HER2 and response to paclitaxel in node-positive breast cancer,"BACKGROUND: The status of human epidermal growth factor receptor type 2 (HER2) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy. We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above standard levels, from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide, or from both. METHODS: We randomly selected 1500 women from 3121 women with node-positive breast cancer who had been randomly assigned to receive doxorubicin (60, 75, or 90 mg per square meter of body-surface area) plus cyclophosphamide (600 mg per square meter) for four cycles, followed by four cycles of paclitaxel (175 mg per square meter) or observation. Tissue blocks from 1322 of these 1500 women were available. Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed. RESULTS: No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter. HER2 positivity was, however, associated with a significant benefit from paclitaxel. The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01). Patients with a HER2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status, but paclitaxel did not benefit patients with HER2-negative, estrogen-receptor-positive cancers. CONCLUSIONS: The expression or amplification, or both, of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin (<60 mg per square meter) plus cyclophosphamide in node-positive breast cancer, regardless of estrogen-receptor status. Patients with HER2-negative, estrogen-receptor-positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide.",0
3333,17928599,The quality of ambulatory care delivered to children in the United States,"BACKGROUND: Little is known about the magnitude of deficits in the quality of care delivered to children, since comprehensive studies have been lacking. METHODS: We assessed the extent to which care processes recommended for pediatric outpatients are delivered. Quality indicators were developed with the use of the RAND-UCLA modified Delphi method. Parents of 1536 children who were randomly selected from 12 metropolitan areas provided written informed consent to obtain medical records from all providers who had seen the children during the 2-year period before the date of study recruitment. Trained nurses abstracted these medical records. Composite quality scores were calculated by dividing the number of times indicated care was documented as having been ordered or delivered by the number of times a care process was indicated. RESULTS: On average, according to data in the medical records, children in the study received 46.5% (95% confidence interval [CI], 44.5 to 48.4) of the indicated care. They received 67.6% (95% CI, 63.9 to 71.3) of the indicated care for acute medical problems, 53.4% (95% CI, 50.0 to 56.8) of the indicated care for chronic medical conditions, and 40.7% (95% CI, 38.1 to 43.4) of the indicated preventive care. Quality varied according to the clinical area, with the rate of adherence to indicated care ranging from 92.0% (95% CI, 89.9 to 94.1) for upper respiratory tract infections to 34.5% (95% CI, 31.0 to 37.9) for preventive services for adolescents. CONCLUSIONS: Deficits in the quality of care provided to children appear to be similar in magnitude to those previously reported for adults. Strategies to reduce these apparent deficits are needed.",0
3334,17929296,Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice,"Hepatitis B virus (HBV) infection is one of the most frequent causes of chronic liver disease worldwide. Because recent studies have suggested that Toll-like receptor (TLR)-based therapies may be a promising approach in the treatment of HBV infection, we studied the role of the local innate immune system of the liver as a possible mediator of this effect. Murine nonparenchymal cells, including Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs), were isolated from C57/BL6 wild-type or MyD88(-/-) mice and stimulated by agonists of TLR1 to TLR9. Supernatants were harvested and assayed for their antiviral activity against HBV in HBV-Met cells. No direct antiviral effect of TLR agonists could be observed. In controls (myeloid dendritic cells), TLR1, TLR3, TLR4, TLR7, and TLR9 activation lead to production of antiviral cytokines. By contrast, only supernatants from TLR3-stimulated and TLR4-stimulated KCs and TLR3-stimulated LSECs from wild-type mice were able to potently suppress HBV replication as assessed via Southern blotting. Similar results were found with cells from MyD88(-/-) mice, indicating that the effect was independent of this signaling pathway. Cellular HBV RNA and hepatitis B surface antigen or hepatitis B e antigen levels in supernatants remained unchanged. Using neutralizing antibodies, we demonstrated that the TLR3-mediated effect but not the TLR4-mediated effect is mediated exclusively through interferon-beta. CONCLUSION: Our data indicate that the innate immune system of the liver can control HBV replication after activation by TLR agonists. This has implications for the development of TLR-based therapeutic approaches against HBV.",0
3335,17935227,Gut-derived commensal bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity,"Intraorgan dendritic cells (DCs) monitor the environment and help translate triggers of innate immunity into adaptive immune responses. Liver-based DCs are continually exposed, via gut-derived portal venous blood, to potential antigens and bacterial products that can trigger innate immunity. However, somehow the liver avoids a state of perpetual inflammation and protects central immune organs from overstimulation. In this study, we tested the hypothesis that hepatic interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) activity increases the activation/maturation threshold of hepatic DCs toward innate immune signals. The results show that the liver nuclear STAT3 activity is significantly higher than that of other organs and is IL-6-dependent. Hepatic DCs in normal IL-6 wild-type (IL-6(+/+)) mice are phenotypically and functionally less mature than DCs from IL-6-deficient (IL-6(-/-)) or STAT3-inhibited IL-6(+/+) mice, as determined by surface marker expression, proinflammatory cytokine secretion, and allogeneic T-cell stimulation. IL-6(+/+) liver DCs produce IL-6 in response to exposure to lipopolysaccharide (LPS) and cytidine phosphate guanosine oligonucleotides (CpG) but are resistant to maturation compared with IL-6(-/-) liver DCs. Conversely, exogenous IL-6 inhibits LPS-induced IL-6(-/-) liver DC maturation. IL-6/STAT3 signaling influences the liver DC expression of toll-like receptor 9 and IL-1 receptor associated kinase-M. The depletion of gut commensal bacteria in IL-6(+/+) mice with oral antibiotics decreased portal blood endotoxin levels, lowered the expression of IL-6 and phospho-STAT3, and significantly increased liver DC maturation. CONCLUSION: Gut-derived bacterial products, by stimulating hepatic IL-6/STAT3 signaling, inhibit hepatic DC activation/maturation and thereby elevate the threshold needed for translating triggers of innate immunity into adaptive immune responses. Manipulating gut bacteria may therefore be an effective strategy for altering intrahepatic immune responses.",0
3336,17971179,Inverse correlation between activated protein C generation and carotid atherosclerosis in Type 2 diabetic patients,"Activated protein C (APC) is a key regulator of the clotting system and immune responses. We studied the relationship between the degree of atherosclerosis as measured by the intima-media thickness (IMT) of carotid artery and APC generation in Type 2 diabetic patients. Eighty-seven Type 2 diabetic patients and 35 control subjects participated. APC generation was assessed by the plasma APC-protein C inhibitor complex (APC-PCI) levels and the mean IMT of carotid artery was measured by ultrasonography. The plasma levels of the thrombin-anti-thromobin complex (TAT) and platelet-derived growth factor (PDGF) were measured by enzyme-linked immunoassays. Plasma TAT levels were significantly higher in diabetic patients [2.03 (1.12, 2.56) ng/ml, median (25th, 75th percentile)] compared with control subjects [0.85 (0.55, 2.08) ng/ml, P < 0.01]. Plasma APC-PCI levels were significantly lower in diabetic patients [0.93 (0.74, 1.22) ng/ml], than in control subjects [1.66 (1.25, 2.36) ng/ml, P < 0.001]. The mean IMT was significantly increased in diabetic patients (0.881 +/- 0.242 mm; mean +/- sd) compared with control subjects (0.669 +/- 0.140 mm; P < 0.01). Univariate analysis showed a significant and inverse correlation between plasma APC-PCI levels and mean IMT (r = -0.32, P < 0.005), and multivariate regression analysis confirmed the independent correlation (P < 0.05). Moreover, plasma APC-PCI levels significantly and inversely correlated with plasma PDGF levels in diabetic patients (r = -0.30, P < 0.01). These results suggest that decreased APC generation is associated with vascular atherosclerotic changes in Type 2 diabetic patients. ",0
3337,17971189,"Aerobic fitness, fatness and the metabolic syndrome in children and adolescents","The paediatric obesity epidemic is well documented. Recently, there has also been the emergence of type 2 diabetes and the metabolic syndrome (MetS) among children and adolescents. Although it is well known that obesity is linked to the metabolic syndrome in youth, the role of physical activity and fitness on the metabolic syndrome is unclear. The purpose of this review was to examine the concepts of and associations between fitness, fatness and the MetS in children and adolescents. In general, the association between fatness and the MetS (or components of the MetS) is stronger than those for fitness. Furthermore, the correlation between fatness and the MetS remains significant after controlling for fitness, whereas the correlation between fitness and MetS does not remain significant after controlling for fatness. When subjects are cross-tabulated into categories (fat-fit, etc.), there is good evidence that fitness attenuates the MetS score among fat children and adolescents. The reasons for these observations possibly involve genetics, adipocytokines and mitochondrial function. Further study is needed to understand the role of physical activity and other environmental factors on this phenomena. In addition, longitudinal studies of the fat-fit phenotype are required and should include measurements of the hormonal mileau, adipokines and the oxidative capacity of skeletal muscle during childhood and adolescence. ",0
3338,17971196,Regional radiotherapy versus an axillary lymph node dissection after lumpectomy: a safe alternative for an axillary lymph node dissection in a clinically uninvolved axilla in breast cancer. A case control study with 10 years follow up,"The standard treatment of the axilla in breast cancer used to be an axillary lymph node dissection. An axillary lymph node dissection is known to give substantial risks of morbidity. In recent years the sentinel node biopsy has become common practice. Future randomized study results will determine whether the expected decrease in morbidity can be proven. Before the introduction of the sentinel node biopsy, we conducted a study in which 180 women of 50 years and older with T1/T2 cN0 breast cancer were treated with breast conserving therapy. Instead of an axillary lymph node dissection regional radiotherapy was given in combination with tamoxifen (RT-group). The study group was compared with 341 patients, with the same patient and tumour characteristics, treated with an axillary lymph node dissection (S-group). The treatment groups were comparable, except for age. The RT-group was significantly older than the S-group. The median follow up was 7.2 years. The regional relapse rates were low and equal in both treatment groups, 1.1% in RT-group versus 1.5% in S-group at 5 years. The overall survival was similar; the disease free survival was significant better in the RT-group. Regional recurrence rates after regional radiotherapy are very low and equal to an axillary lymphnode dissection. ",0
3339,17971401,Functional mitral regurgitation after a first non-ST-segment elevation acute coronary syndrome: contribution to congestive heart failure,"Functional mitral regurgitation (MR) is a frequent complication after the acute phase of a myocardial infarction and plays an important role in the development of congestive heart failure (CHF) after a Q-wave myocardial infarction. Nevertheless, until now, the relevance of functional MR after a non-ST-segment elevation acute coronary syndrome (NSTSEACS) has been poorly addressed. Our aim was to assess the relationship between the presence or absence and the severity of functional MR after a first NSTSEACS and the development of CHF. Two hundred and seventy-nine patients discharged from hospital in NYHA functional classes I and II (71.7% men; mean age 66.3 +/- 13.2 years) after a first NSTSEACS were studied. Every patient underwent an echocardiographic study during the first week after the index NSTSEACS and were clinically followed-up. MR was detected in 40.1% patients. Patients were followed-up for a median time of 418 days (inter-quartile range: 295-561). Six patients (3.6%) in the group without MR and 15 patients (13.4%) in the group with MR required hospitalization due to CHF during follow-up. Only MR was found as an independent predictor of CHF development (HR = 1.8; 95% CI = 1.1-3.1; P = 0.02) and CHF development or cardiac death (HR = 2.1; 95% CI = 1.3-3.3; P = 0.01) in the long-term follow-up multivariable Cox regression analysis. There is an increased risk for subsequent CHF in patients with MR after a first NSTSEACS. The risk of CHF is closely related to the MR presence and severity. Thus, the detection of MR by means of Doppler echocardiography after a first episode of NSTSEACS is crucial. ",0
3340,17971544,"Use of preventive care by elderly male veterans receiving care through the Veterans Health Administration, Medicare fee-for-service, and Medicare HMO plans","We compared use of preventive care among veterans receiving care through the Veterans Health Administration (VHA), Medicare fee-for-service (FFS) plans, and Medicare health maintenance organizations (HMOs). Using both the Costs and Use, and Access to Care files of the Medicare Current Beneficiary Survey (2000-2003), we performed a cross-sectional analysis examining self-reported use of influenza vaccination, pneumococcal vaccination, serum cholesterol screening, and serum prostate-specific antigen measurement among male veterans 65 years or older. Veterans' care was categorized as received through VHA, Medicare FFS, Medicare HMOs, VHA and Medicare FFS, or VHA and Medicare HMOs. Veterans receiving care through VHA reported 10% greater use of influenza vaccination (P<.05), 14% greater use of pneumococcal vaccination (P<.01), a nonsignificant 6% greater use of serum cholesterol screening (P=.1), and 15% greater use of prostate cancer screening (P<.01) than did veterans receiving care through Medicare HMOs. Veterans receiving care through Medicare FFS reported less use of all 4 preventive measures (P<.01) than did veterans receiving care through Medicare HMOs. Receiving care through VHA was associated with greater use of preventive care. ",0
3341,17971708,"Characteristics and outcomes of adult patients lost to follow-up at an antiretroviral treatment clinic in johannesburg, South Africa","A significant proportion of those initiating antiretroviral treatment (ART) for HIV infection are lost to follow-up. Causes for discontinuing ART follow-up in resource-limited settings are not well understood. A retrospective analysis was conducted of all adult patients receiving ART at an urban public clinic in Johannesburg, South Africa between April 2004 and June 2005. Patients discontinuing follow-up for at least 6 weeks were identified and further studied, and causes for treatment default were tabulated. Of 1631 adult patients studied, 267 (16.4%) discontinued follow-up during the study period. Gender, ethnicity, and age were not predictive of loss to follow-up. Of those discontinuing follow-up, 173 (64.8%) were successfully traced. Death accounted for 48% (n = 83) of those traced. Characteristics associated with death were older age at ART initiation (P = 0.022), lower baseline CD4 cell count (P = 0.0073), higher initial HIV RNA load (P = 0.024), and loss of weight on ART (P = 0.033). Date of death was known for 71% (n = 59) of patients traced deceased, of whom 83% (n = 49) had died within 30 days of active ART. Common nonmortality losses included relocation or clinic transfer (25.4%) and hospitalization or illness not resulting in death (10.4%). Few cited financial difficulty or medication toxicity as reasons for discontinuing follow-up. Nearly 1 in 6 patients receiving ART in a resource-constrained setting had discontinued follow-up over a 15-month period. Early mortality was high, especially in those with profound immunosuppression. Improving access to care and streamlining patient tracking may improve ART outcomes. ",0
3342,17972658,Social networks: a profile of the elderly who self-neglect,"Self-neglect is an independent risk factor for early mortality in older people and has been linked to depression and the occurrence of mental and physical decline. Sound social networks have been shown to slow the process of decline in the elderly, and currently little is known about the social networks associated with elder self-neglect. The aim of this study was to explore the social networks associated with elder self-neglect compared with a matched-control group. Ninety-one Adult Protective Services-validated cases of elder self-neglect were compared on formal and informal social network factors with 91controls matched for age, race, gender, and socio-economic status. Elders in the self-neglect group were significantly less likely to (1) Live with a spouse, (2) Live with others, (3) Have weekly contact with children or siblings, (4) Visit with neighbors and friends and (5) Participate in religious activities. Less adequate social resources related to family, friends, and religious affiliations are significantly associated with elder self-neglect. ",0
3343,17973160,Evaluation of swallowing in children with vomiting after feeding,"Vomiting after feeding is a symptom of gastroesophageal reflux (GER) and of eosinophilic esophagitis (EE), which are considered to be a cause of infant feeding disorder. The objective of the present study was to evaluate swallowing in children with feeding disorder manifested by vomiting after feeding. Using clinical and videofluoroscopic methods we studied the swallowing of 37 children with vomiting after feeding (mean age=15.4 months), and of 15 healthy children (mean age=20.5 months). In the videofluoroscopic examination the children swallowed a free volume of milk and 5 ml of mashed banana, both mixed with barium sulfate. We evaluated five swallows of liquid and five swallows of paste. The videofluoroscopic examination was recorded at 60 frames/s. Patients had difficulty during feeding, pneumonia, respiratory distress, otitis, and irritability more frequently than controls. During feeding, children with vomiting, choke were irritable, and refused food more frequently than controls, and during the videofluoroscopic examination the patients had more backward movement of the head than controls for both the liquid and paste boluses. There was no difference in the timing of oral swallowing transit, pharyngeal swallowing transit, or pharyngeal clearance between patients and controls. We conclude that children with vomiting after feeding may have difficulties in accepting feeding, although they have no alteration of oral and pharyngeal phases of swallowing. ",0
3344,17973230,Pneumatocele during long-lasting observation of hyper IgE patient],"Hyper IgE syndrome (Job's syndrome) is a rare multiorgan disease characterized by the triad: elevated serum IgE level, recurrent sinopulmonary infections, most often staphylococcal, and cutaneous cold abscesses starting in infancy. We report 21 years old patient with hyper IgE syndrome, diagnosed at age of 6 years on the basis of hyperimmunoglobulinaemia E and recurrent pulmonary and cutaneous infections. Now he was admitted because of pneumonia complicating with pneumatocele, which could not be resolved despite intravenous antibiotics. Surgical intervention was necessary. The postoperative period was complicated by Staphyloccocus aureus sepsis. ",0
3345,17973402,Microfluidic device for the discrimination of single-nucleotide polymorphisms in DNA oligomers using electrochemically actuated alkaline dehybridization,"This work describes an integrated microfluidic (mu-fl) device that can be used to effect separations that discriminate single-nucleotide polymorphisms (SNP) based on kinetic differences in the lability of perfectly matched (PM) and mismatched (MM) DNA duplexes during alkaline dehybridization. For this purpose a 21-base single-stranded DNA (ssDNA) probe sequence was immobilized on agarose-coated magnetic beads, that in turn can be localized within the channels of a poly(dimethylsiloxane) microfluidic device using an embedded magnetic separator. The PM and MM ssDNA targets were hybridized with the probe to form a mixture of PM and MM DNA duplexes using standard protocols, and the hydroxide ions necessary for mediating the dehybridization were generated electrochemically in situ by performing the oxygen reduction reaction (ORR) using O2 that passively permeates the device at a Pt working electrode (Pt-WE) embedded within the microfluidic channel system. The alkaline DNA dehybridization process was followed using fluorescence microscopy. The results of this study show that the two duplexes exhibit different kinetics of dehybridization, rate profiles that can be manipulated as a function of both the amount of the hydroxide ions generated and the mass-transfer characteristics of their transport within the device. This system is shown to function as a durable platform for effecting hybridization/dehybridization cycles using a nonthermal, electrochemical actuation mechanism, one that may enable new designs for lab-on-a-chip devices used in DNA analysis. ",0
3346,17973403,"Gene identification and structural characterization of the pyridoxal 5'-phosphate degradative protein 3-hydroxy-2-methylpyridine-4,5-dicarboxylate decarboxylase from mesorhizobium loti MAFF303099","The function of the mlr6791 gene from Mesorhizobium loti MAFF303099 has been identified. This gene encodes 3-hydroxy-2-methylpyridine-4,5-dicarboxylate decarboxylase (HMPDdc), an enzyme involved in the catabolism of pyridoxal 5'-phosphate (Vitamin B6). This enzyme was overexpressed in Escherichia coli and characterized. HMPDdc is a 26 kDa protein that catalyzes the decarboxylation of 3-hydroxy-2-methylpyridine-4,5-dicarboxylate to 3-hydroxy-2-methylpyridine-5-carboxylate. The KM and kcat were found to be 366 microM and 0.6 s-1, respectively. The structure of this enzyme was determined at 1.9 A resolution using SAD phasing and belongs to the class II aldolase/adducin superfamily. While the decarboxylation of hydroxy-substituted benzene rings is a common motif in biosynthesis, the mechanism of this reaction is still poorly characterized. The structural studies described here suggest that catalysis of such decarboxylations proceeds by an aldolase-like mechanism. ",0
3347,17973561,Altered reproduction in fish exposed to pulp and paper mill effluents: roles of individual compounds and mill operating conditions,"For the last 20 years, studies conducted in North America, Scandinavia, and New Zealand have shown that pulp and paper mill effluents affect fish reproduction. Despite the level of effort applied, few leads are available regarding the factors responsible. Effluents affect reproduction in multiple fish species, as evidenced by decreased gonad size, decreased circulating and gonadal production of reproductive steroids, altered expression of secondary sex characteristics, and decreased egg production. Several studies also have shown that effluent constituents are capable of accumulating in fish and binding to sex steroid receptors/ binding proteins. Studies aimed at isolating biologically active substances within the pulping and papermaking process have provided clues about their source, and work has progressed in identifying opportunities for in-mill treatment technologies. Following comparisons of manufacturing processes and fish responses before and after process changes, it can be concluded that effluent from all types of mill processes are capable of affecting fish reproduction and that any improvements could not be attributed to a specific process modification (because mills normally performed multiple modifications simultaneously). Improved reproductive performance in fish generally was associated with reduced use of molecular chlorine, improved condensate handling, and liquor spill control. Effluent biotreatment has been effective in reducing some effects, but biotreated effluents also have shown no difference or an exacerbation of effects. The role of biotreatment in relation to effects on fish reproduction remains unclear and needs to be resolved. ",0
3348,17973562,Survival rates and blood metal concentrations in two species of free-ranging North American sea ducks,"Populations of several species of North American sea ducks have declined in the past few decades. Exposure to environmental contaminants, particularly metals, has been proposed as one of many possible factors contributing to these declines. Population dynamics are influenced by survival rates and breeding effort. In the present study, we examined the relationships between blood metal concentrations (Cd, Pb, Se, and Hg) and apparent annual survival and recapture probabilities (the latter as a surrogate for breeding effort) in adult females of two sea duck species, the king eider (Somateria spectabilis) and the white-winged scoter (Melanitta fusca), both of which have experienced declines in continental population during in recent years. No support was found for the hypothesis that exposure of white-winged scoters to these metals or of king eiders to Cd, Se, and Pb adversely affected probabilities of apparent annual survival. We detected a weak negative relationship (beta = -0.833) between Hg and annual survival of king eiders, but the 90% confidence interval of the slope estimate overlapped zero (-2.439 to +0.672). Recapture probabilities were unrelated to concentrations of Cd, Se, and Pb in either species. Evidence indicated that Hg concentrations affected recapture probability in white-winged scoters (beta = -194.77; 90% confidence interval, -203.770 to -185.778). Mercury levels were low in both species, and blood samples may not adequately represent long-term exposure to Hg. Therefore, conclusions regarding Hg effects on these birds should be considered with caution. ",0
3349,17973653,Development of a new test for the global fibrinolytic capacity in whole blood,"The development of global tests for the fibrinolytic capacity in blood is hampered by the low base-line fibrinolytic activity in blood, by the involvement of both plasmatic components and blood cells in the fibrinolytic system and by the loss of fibrinolytic activity as a result of the action of plasminogen activator inhibitor-1 (PAI-1). To develop a new test for the global fibrinolytic capacity (GFC) of whole blood samples. Collection of blood in thrombin increased the subsequent generation of fibrin degradation products. This was ascribed to rapid clot formation and concomitant reduction of in vitro neutralization of tissue-type plasminogen activator (tPA) by PAI-1. On the basis of this observation, the following test was designed: blood samples were collected in thrombin with and without aprotinin and clots were incubated for 3 h at 37 degrees C. The GFC was assessed from the difference between the fibrin degradation products in the two sera. The assay was applied to blood samples from patients and healthy subjects. Other hemostasis parameters were determined in plasma samples taken simultaneously. The GFC varied considerably (normal range 0.13-13.6 microg mL(-1)); physical exercise strongly increased the GFC. Statistically significant correlations were found with tPA activity, PAI-1 activity and fibrinogen level. A mixture of antibodies against tPA and urokinase-type plasminogen activator (uPA) completely inhibited the GFC. An inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFI) accelerated fibrinolysis 8-fold. The new test represents a global assessment of the main fibrinolytic factors in plasma and potentially those associated with blood cells. ",0
3350,17973732,A pilot study to prevent hearing loss in farmers,"Determine the feasibility and outcome of a pilot program to increase farm workers' use of hearing protection when performing activities with high noise exposure. The study was a quasi-experimental study. Eight intervention farmers and 17 comparison farmers participated in the study. Before and after the intervention, farmers completed a survey to identify their frequency of use of hearing protection, and their beliefs about hearing loss and use of hearing protection. The intervention consisted of noise assessments, educational sessions, mailed reminders with brochures, and placement of hearing protection on the farm. The intervention was effective in increasing the use of hearing protection 1 and 2 months after the implementation of the program. Hearing loss is a serious problem with farmers, and yet many farmers neglect to protect their hearing with the use of protection. The pilot study findings indicate that efforts to increase the use of hearing protection by farmers can be effective. ",0
3351,17973782,Effect of parental hypertension and/or parental diabetes on hypertension in Taiwanese diabetic patients,"Both type 2 diabetes mellitus (T2DM) and hypertension aggregate in families. It is a common thought that diabetic patients with parental diabetes and/or parental hypertension are more likely to develop hypertension. This study evaluated the separate and joint effects of parental hypertension and parental diabetes on the prevalence of hypertension in patients with T2DM. A total of 89 956 patients from a national cohort were interviewed by telephone. Information about age, sex, onset age of diabetes, body height, body weight, systolic (SBP) and diastolic blood pressure (DBP), smoking, hypertension, and paternal and maternal history of diabetes and hypertension were obtained. Hypertension was defined in two ways: (1) a positive history; or (2) a positive history or a reported SBP > or = 140 mmHg and/or DBP > or = 90 mmHg in patients without a hypertension history. While analysed separately in logistic models, both parental diabetes and parental hypertension were positively associated with hypertension. However, when both were analysed together, only parental hypertension was positively associated with hypertension, with paternal and maternal hypertension exerting a similar effect of an approximately 2.5-fold higher risk. While considering the effect of parental hypertension, both paternal and maternal diabetes was significantly associated with a lower risk of hypertension with odds ratios of approximately 0.8. Parental hypertension was also significantly associated with increased SBP and DBP; and parental diabetes with lower values in multiple linear regression. Parental hypertension is strongly associated with hypertension. However, parental diabetes may be protective if the effect of parental hypertension is considered. ",0
3352,17973925,Monocular deprivation enhances the nuclear signalling of extracellular signal-regulated kinase in the developing visual cortex,"Monocular deprivation (MD) of vision leads to a loss of cortical response to the deprived eye in the early postnatal period (ocular dominance plasticity). The activity of several signal molecules, including extracellular signal-regulated kinase (ERK), has been reported as playing a crucial role in the ocular dominance plasticity. Although pharmacological inhibition of ERK disturbed the ocular dominance plasticity, it remains to be elucidated how the ERK activity is modulated by MD. We herein report the effects of MD on ERK activation in the visual cortex of young and adult rats. Phosphorylated ERK (pERK)-immunopositive cells are mainly distributed in layers II/III of the visual cortex. Following MD, we found a significant decrease in the density of pERK-immunopositive cells in the cortex receiving deprived-eye inputs in both young and adult animals. The amount of pERK protein also decreased in the input-deprived cortex as revealed by Western blotting. Regarding the subcellular localization of pERK, we found a significant increase in the pERK-immunopositive nucleus following MD in young animals. In these animals, the amount of pERK protein in the nuclear fraction of cortical tissue was significantly increased. No up-regulation of the nuclear pERK was observed in adults or following binocular deprivation. These findings suggest that ERK activation may therefore be regulated by different mechanisms between young and adult animals, and MD during the developing period may thus specifically up-regulate the nuclear signalling of ERK. ",0
3353,17973969,Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program,"Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors. ",0
3354,17974359,"Intensifying efforts to reduce child malnutrition in India: an evaluation of the Dular program in Jharkhand, India","The Dular strategy is a unique nutrition initiative initiated by UNICEF India in collaboration with the states of Bihar and Jharkhand. Designed to complement the government's Integrated Child Development Services (ICDS) and build upon its infrastructure, one of the major goals of the Dular program is to capitalize and develop community resources at the grassroots level. The emphasis of the Dular program is on establishing a community-based tracking system of the health status of women and of children 0 to 36 months of age by neighborhood-based local resource persons (LRPs). The main objectives of the Dular program include increased prenatal attendance, improvement in breastfeeding and colostrum delivery, improved nutritional practices, and decreased malnutrition. An impact evaluation of 744 women and children in Jharkhand examined antenatal and birthing practices, colostrum delivery, delivery of breastmilk as first food, reported use of iodized salt, measured iodized salt status, immunization and weight-for-age z-scores (WAZ) of children 0 to 36 months of age, controlling for various measures of socioeconomic status. Differences were found between Dular and non-Dular villages in all major outcomes. Particularly noteworthy is that young children in Dular areas had a 45% lower prevalence of severe malnutrition and were four times more likely to receive colostrum than those in non-Dular villages. Our evaluation results indicate that programmatic overlays to the ICDS program, which focus primary attention on children 0 to 36 months of age and on women, have the potential to transform into a cost-effective instrument for reducing child malnutrition in India, with implications for women and children in India. ",0
3355,17974473,Quantitative approach to dialysis adequacy (Part one)],"A quantitative assessment of dialysis and prescription of dialysis as therapy in every single patient have always been a continuous problem. Numerous efforts have been made to date to determine the kind of therapy for patients on haemodialysis on the basis of simple objective indices instead of clinical and laboratory parameters. Some of these indices have been widely accepted nowadays. Although the main clinical and laboratory parameters have still been currently applied in the assessment of peritoneal dialysis adequacy, serious quantitative approaches are made even in these cases regarding the more accurate therapy. ",0
3356,17974748,Treating attention-deficit/hyperactivity disorder with a stimulant transdermal patch: the clinical art,"Stimulant medications (amphetamine and methylphenidate) are the best-documented treatments for attention-deficit/hyperactivity disorder, but their short pharmacokinetic and behavioral half-lives have historically produced irksome time-course effects. New drug-delivery systems designed to eliminate the need for frequent dosing include the methylphenidate transdermal system, in which the matrix acts as both the drug reservoir and the skin adhesive. The methylphenidate transdermal system patch, in contrast to long-acting oral preparations, requires a paradigmatic shift in clinical thinking, as well as refinement of clinical management skills. For dosing with the methylphenidate transdermal system patch, clinicians must think in terms of a retrievable form of drug delivery (in milligrams per hour) rather than a fixed nonretrievable dose (in milligrams per dose or milligrams per day). Clinicians and patients can determine the optimal clinical dose by controlling 2 variables: (1) patch size (controlling milligrams per hour) and (2) duration of patch wear. The new paradigm is worth learning, because the patch offers several advantages over oral preparations for some patients, chiefly individualized control over effect duration (determined by when the patch is applied in the morning and removed in the afternoon/evening). Taking full advantage of this treatment option requires educating the patient and parents regarding practical elements of daily use. These elements include patch-site selection, application techniques, management of wear time to optimize the daily time course of clinical benefits, and skin hygiene. This article summarizes clinical principles that physicians may find useful in managing this new addition to the attention-deficit/hyperactivity disorder treatment armamentarium. ",0
3357,17974913,"Malignant astrocytic glioma: genetics, biology, and paths to treatment","Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses. ",0
3358,17975001,Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth,"Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb(+/-) mice. Pttg(-/-) pituitary glands exhibit ARF/p53/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary p21 levels in the absence of PTTG were associated with suppressed cyclin-dependent kinase 2 activity, Rb phosphorylation, and cyclin A expression, all required for cell cycle progression. Although senescence-associated beta-galactosidase was enhanced in Pttg-deficient pituitary glands, telomere lengths were increased. DNA damage signaling pathways were activated and aneuploidy was evident in the Pttg-deficient pituitary, triggering senescence-associated genes. To confirm the p21 dependency of decreased proliferation and senescence in the Pttg-null pituitary, mouse embryonic fibroblast (MEF) colony formation was tested in wild-type, Pttg(-/-), Rb(+/-), Rb(+/-)Pttg(-/-), and Rb(+/-)Pttg(-/-)p21(-/-) cells. Rb(+/-)Pttg(-/-) MEFs, unlike Rb(+/-) cells, failed to produce colonies and exhibited high levels of senescence. p21 deletion from Rb(+/-)Pttg(-/-) MEFs enhanced anchorage-independent cell growth, accompanied by a marked decrease in senescence. As cell proliferation assessed by bromodeoxyuridine incorporation was higher in Rb(+/-)Pttg(-/-)p21(-/-) relative to Rb(+/-)Pttg(-/-) pituitary glands, p21-dependent senescence provoked by Pttg deletion may underlie pituitary hypoplasia and decreased tumor development in Rb(+/-)Pttg(-/-) mice. ",0
3359,17975090,Uncultivated Tannerella BU045 and BU063 are slim segmented filamentous rods of high prevalence but low abundance in inflammatory disease-associated dental plaques,"Uncultivated clones BU045 and BU063 and Tannerella forsythia, a 'consensus periodontal pathogen', are the closest known relatives within the genus Tannerella. They have been described to inhabit different ecological niches of the human oral cavity. In this study, fluorescent in situ hybridization (FISH) and immunofluorescence were combined to investigate the prevalence and abundance of BU045 and BU063 in comparison to T. forsythia in plaques from gingivitis, necrotizing ulcerative gingivitis (NUG) and chronic periodontitis. Phylotype-specific FISH probes identified BU045 and BU063 as elongated thin rods with a segmented structure. Two structurally similar and previously unknown, rare phylotypes (127+ and 997+) were also identified due to partial 16S rRNA sequence identity with T. forsythia. In gingivitis, NUG and periodontitis patients, BU045, BU063, 127+, 997+ and T. forsythia were detected with prevalences of 50/83/71/14 and 81%, 100/100/86/17 and 53%, and 100/100/12/0 and 100%, respectively. Supragingivally, colonization density of all five organisms was generally low, rarely exceeding 0.1% of the total biota. In periodontal pocket samples, however, cell numbers of T. forsythia, but not of the uncultivable phylotypes, were greatly elevated. Our data demonstrate that Tannerella phylotypes BU045, BU063, 127+ and 997+ consist of long slim rods with segments, which, with respect to FISH stainability, often behaved as independent units. The phylotypes are frequent but low-level colonizers of various periodontal disease-associated plaques. Their apparent inability to proliferate to high density seems to exclude any relevance for the pathogenesis of periodontal diseases. ",0
3360,17975136,Amplicon mapping and expression profiling identify the Fas-associated death domain gene as a new driver in the 11q13.3 amplicon in laryngeal/pharyngeal cancer,"Amplification of the 11q13 region is a frequent event in human cancer. The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene. To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon. Using array-based comparative genomic hybridization analysis, we detected a region of approximately 1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser(194) phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser(194) phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest. Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit from Taxol-based chemoradiotherapy. ",0
3361,17975719,State policy environment and delayed or forgone care among children with special health care needs,"To evaluate if children with special health care needs (CSHCN) residing in states with more generous public insurance programs were less likely to report delayed or forgone care. We used multilevel modeling to evaluate state policy characteristics after controlling for individual characteristics. We used the 2001 National Survey of CSHCN for individual-level data (N=33,317) merged with state-level data, which included measures of the state's public insurance programs (Medicaid eligibility and enrollment, spending on Medicaid, SCHIP and Title V, and income eligibility levels), state poverty level and provider supply (including pediatric primary care and specialty providers). We also included a variable for state waivers for CSHCN requiring institutional level care. Delayed or forgone care significantly varied among CSHCN between states, net of individual characteristics. Of all the state characteristics studied, only the Medicaid income eligibility levels influenced the risk of experiencing delayed care. CSHCN living in states with higher income eligibility thresholds or more generous eligibility levels were less likely to experience delayed care (OR 0.89(0.80,0.99); P<or=0.05). By analyzing child health policy in the context of individual characteristics that may place a child at risk for delayed care, we determined that improving Medicaid eligibility levels improved the process of care for CSHCN. ",0
3362,17975811,Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance,"Liver sinusoidal endothelial cells (LSEC) are unique organ-resident antigen-presenting cells capable of cross-presentation and subsequent tolerization of na?ve CD8(+) T cells. We investigated the molecular mechanisms underlying this tolerance induction in naive CD8(+) T cells. MHC class I-restricted antigen presentation by LSEC led to initial stimulation of na?ve CD8(+) T cells, which up-regulated CD69, CD25, CD44, and programmed death (PD)-1 and proliferated similar to dendritic cell (DC)-activated CD8(+) T cells. Importantly, cognate interaction with na?ve CD8(+) T cells triggered increased expression of co-inhibitory B7-H1 but not co-stimulatory CD80/86 molecules exclusively on LSEC but not DC. This matured phenotype of B7-H1(high) CD80/86(low) was critical for induction of CD8(+) T cell tolerance by LSEC: B7-H1-deficient LSEC, that failed to interact with PD-1 on stimulated T cells, were incapable of inducing CD8(+) T cell tolerance. Moreover, increased costimulation via CD28 interfered with tolerance induction, indicating that the noninducible low expression levels of CD80/86 on LSEC supported B7-H1-dependent tolerance induction. LSEC-tolerized CD8(+) T cells had a distinctive phenotype from na?ve and activated T cells with CD25(low), CD44(high), CD62L(high). They also expressed the homeostatic cytokine receptors CD127, CD122, and high levels of Bcl-2, indicating survival rather than deletion of tolerant CD8(+) T cells. On adoptive transfer into congenic animals, tolerized CD8(+) T cells failed to show specific cytotoxicity in vivo. CONCLUSION: Cognate interaction of LSEC with na?ve CD8(+) T cells elicits a unique tolerogenic maturation of LSEC and permissiveness of T cells for tolerogenic signals, demonstrating that LSEC-induced tolerance is an active and dynamic process.",0
3363,17975828,Nicotinic acetylcholine receptor-subunit mRNAs in the mouse superior cervical ganglion are regulated by development but not by deletion of distinct subunit genes,"Mice with deletions of nicotinic ACh receptor (nAChR) subunit genes are valuable models for studying nAChR functions. We could previously show in the mouse superior cervical ganglion (SCG) that the absence of distinct subunits affects the functional properties of receptors. Here, we have addressed the question of whether deletions of the subunits alpha5, alpha7, or beta2 are compensated at the mRNA level, monitored by reverse transcription and quantitative real-time polymerase chain reaction. Relative to our reference gene, alpha3, which is expressed in all SCG nAChRs, mRNA levels of beta4 showed little change from birth until adult ages in intact ganglia of wild-type mice. In contrast, alpha4 declined sharply after birth and was barely detectable in adult animals. alpha5, alpha7, and beta2 subunit message levels also declined, though more slowly and less completely than alpha4. The subunits alpha6 and beta3 were detected by conventional polymerase chain reaction at very low levels, if at all, whereas alpha2 was never seen in any of our samples. The developmental profile of nAChR mRNA levels in the three knockout strains did not differ markedly from that of wild-type mice. Likewise, message levels of nAChR subunits were similar in cultures prepared from either wild-type or knockout animals. Our observations indicate a developmental regulation of nAChR subunit mRNAs in the SCG of mice after birth that was not affected by the three knockouts under investigation. ",0
3364,17975997,Endoscopic removal of a molariform supernumerary intranasal tooth (heterotopic polyodontia) in a horse,"A 3-year-old Thoroughbred mare was evaluated because of abnormal upper respiratory tract sounds (that had become apparent during race training) of 3 to 4 months' duration. On initial physical evaluation, there were no abnormal findings. During trotting, an abnormal upper airway expiratory sound was audible. Endoscopic examination revealed a small mass protruding into the right ventral nasal meatus. Radiographic images of the skull revealed no abnormal findings. Computed tomography of the head revealed an abnormal structure in the same location as the mass that was observed during endoscopy. The x-ray attenuation of the mass was identical to that of dental tissue. The mass was surgically removed with endoscopic guidance. On gross examination, the excised mass appeared to be a nearly normal molariform tooth. Histologic examination revealed that it was a well-formed tooth, with no other associated cellular populations. The mass was determined to be a molariform supernumerary intranasal tooth. Six months following discharge from the hospital, the trainer reported that the abnormal respiratory tract sound was no longer audible. During a follow-up endoscopic examination performed at the training facility, no abnormalities were detected. In horses, an intranasal tooth should be considered as a differential diagnosis for expiratory stridor. Clear definitions of heterotopic polyodontia, dentigerous cyst, and temporal teratoma can be used to clinically diagnose these separate anomalies. In the horse of this report, computed tomographic findings contributed to determination of a diagnosis and formulation of a treatment plan. ",0
3365,17976141,Survey regarding the status of senior physicians in German dermatology clinics,"The group of senior physicians/assistant medical directors between chairman and residents is in a major focus regarding current changes in the medical system in Germany. The manifold clinical tasks clearly underline the importance of senior physicians as key players; they are neither so regarded nor paid accordingly. In addition senior physicians are responsible for education of residents. To gain insight into the current situation of senior physicians in dermatology information was acquired by a detailed questionnaire. The return-rate of 44.7% was considerably higher than in comparable surveys. The responses show a high degree of satisfaction with medical work, position and interaction with chairman and staff. Most critical was the increasing administrative work and the low salary. This is the first survey in a medical subspecialty among senior physicians in Germany. After the planned new pay schedule is instituted and restructuring of professorship in academic institutions is completed, the survey will be repeated. ",0
3366,17976187,"Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome","Low-risk myelodysplastic syndrome (MDS) is characterized by cytopenia, mainly anemia, because of ineffective hematopoiesis. Some of the patients with ineffective erythropoiesis, with or without ring sideroblasts in their bone marrow, develop severe anemia requiring frequent blood transfusions and consequently develop iron overload. Excess free iron in cells catalyses the generation of reactive oxygen species (ROS) that cause cell and tissue damage. Using flow cytometry techniques, we compared the oxidative status of red blood cells (RBC), platelets and neutrophils in 14 MDS patients with those of normal donors. The results show that ROS were higher while reduced glutathione (GSH) was lower in their RBC and platelets compared with normal cells. In neutrophils, no difference was found in ROS, while the GSH levels were lower. A correlation (r = 0.6) was found between serum ferritin levels of the patients and the ROS in their RBC and platelets. The oxidative stress was ameliorated by a short incubation with the iron-chelators, the deferrioxamine and deferiprone or with antioxidants such as N-acetylcysteine, suggesting that MDS patients might benefit from treatment with iron-chelators and antioxidants. ",0
3367,17976226,Bispectral index monitoring: appreciated but does not affect drug dosing and hypnotic levels,"Bispectral index (BIS) has been associated with benefits from less-deep anesthesia as well as preventing awareness, albeit not at the same time. We investigated how increasing experience from BIS in clinical practice affect the hypnotic level, drug consumption, as well as subjective opinions on this monitoring. Eight certified registered nurse anesthetists (CRNAs) with previous experience from 88 (46-121) BIS monitored cases anesthetized 80 cases with concealed BIS, followed by 80 cases with available BIS. Additional education and training was followed by yet another 160 patients randomized to open or blindly recorded BIS. BIS levels, anesthetic gas consumption, fentanyl use, and subjective opinions on utility and reliability were investigated. After gaining initial experience from BIS monitoring, the fraction of time with BIS levels of 40-60 did not deteriorate in cases with concealed monitoring and no further improvement was found in subsequent cases with available data from the BIS monitoring, not even after additional training and encouragement to adhere to the 40-60 interval. Compared with the first experience from BIS monitoring the subjective opinions on utility had increased from 33 to 78 mm (100 mm visual analog scales) (P<0.0001). Although BIS became considerably appreciated, growing experience and repeated education had no impact on drug dosing and BIS levels. ",0
3368,17976260,Urea inclusion compounds of enalapril maleate for the improvement of pharmaceutical characteristics,"Urea is a well known adductor for linear organic compounds. In the present study, enalapril maleate, a substituted cyclic organic compound, was successfully included in urea together with a suitable rapidly adductible endocyte (RAE). Formation of the urea inclusion compound was confirmed by Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction. The modified Zimmerschied calorimetric method was used to estimate the minimum amount of RAE required for adduction of enalapril maleate in urea. Urea-enalapril maleate-RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behaviour studied by differential scanning calorimetry. Regression analysis revealed an excellent r(2) value with regard to the influence of the relative proportion of RAE on the heat of decomposition. The inclusion compounds were found to exhibit good content uniformity and improved dissolution profile as demonstrated by increased dissolution efficiency. Studies revealed that urea inclusion may be a promising alternative for the formulation of potent poorly soluble drugs into immediate release products. ",0
3369,17976330,Treatment of symptomatic lower extremity acute deep venous thrombosis: role of mechanical thrombectomy,"Systemic anticoagulation with heparin or its unfractionated derivatives followed by warfarin therapy has been the mainstay of treatment in patients with lower extremity deep venous thrombosis (DVT). Although heparin is an effective treatment modality in preventing thrombus propagation, it provides minimal therapeutic effect in dissolving preexisting venous thrombus. The clinical consequence of DVT, owing in part to loss of venous endothelial and valvular function, is postphlebitic syndrome or chronic venous insufficiency. Current advances in endovascular therapy have resulted in various endovascular thrombectomy systems that can effectively remove a large venous thrombus burden, which may represent a potential advantage of preserving venous valvular function and thereby reduce the likelihood of postphlebitic syndrome. In this article, we review a variety of surgical and interventional methods in venous thrombus removal. Current treatment modalities using mechanical thrombectomy devices and pharmacomechancial thrombectomy strategy are also discussed. ",0
3370,17976621,Diabetic eye examination report,"The purpose of this study was to revise a former American Optometric Association (AOA) Diabetic Eye Examination Report form and create a standard reporting form that could be implemented easily into clinical practice. Ohio Optometric Association (OOA) members were recruited to complete the pilot Diabetic Eye Examination Report (DEER) on 5 consecutive diabetic patients. They were then instructed to send a copy of the completed form to the comanaging physician of the patient's choice. The participating optometrists and comanaging physicians were surveyed regarding the content and format of the pilot DEER. The pilot DEER was revised based on the survey responses and comments from 51 participating optometrists and 75 comanaging physicians, existing diabetic retinopathy examination forms, and a literature review. In general, optometrists and comanaging physicians agreed on the importance of communication (100% in both groups, 51of 51 and 75 of 75). Eighty-eight percent (45 of 51) of optometrists and 95% (71 of 75) comanaging physicians found the form to be an adequate summary. Eighty-seven percent (65 of 75) of comanaging physicians expressed interest in receiving the pilot DEER as a standard communication form concerning their diabetic patients. The new form is now available through the OOA at www.ooa.org as an initiative of Healthy People 2010. In an electronic format, it is possible for the optometrist to type information directly onto the form, making it more professional and legible. Printed forms are also available through the AOA purchasing department. ",0
3371,17976637,Human recombinant Fab fragments with sub-nanomolar affinities for acetylated histones,"Acetylation of lysines at different sites in the N-terminus of core histones is a common mode of chromatin modification; different combinations of such modifications are associated with distinct patterns of gene expression, replication and repair. Antibodies are usually used to identify and localize particular histone modifications and to correlate their presence with transcription or other cellular processes. This requires antibodies of sufficient specificity and affinity for each of the many modifications that have now been observed. In most instances, polyclonal antibodies have been used but monoclonal antibodies can also be effective. Here we report that a phage-displayed repertoire of rearranged antibody genes from splenic B cells from a patient with systemic lupus contain Fab fragments that can bind native acetylated lysine 8 histone H4. This finding represents the first selection of human antibodies specific for acetylated histone and suggests that lupus antibodies may contribute to dissection of the histone code. ",0
3372,17976693,Treatment strategy in fibromyalgia syndrome: where are we now?,"The treatment of the fibromyalgia syndrome (FMS) is not standardized and often ineffective, and the course of disease progression is unpredictable. To highlight the efficacy of the pharmacologic and nonpharmacologic treatments administered to FMS patients. Medline search for articles published between 1983 and 2007, using the keywords fibromyalgia, pharmacologic and nonpharmacologic treatment, and multidisciplinary modalities. Randomized controlled trials (RCTs) indicate that FMS has been treated by a wide range of drugs including antidepressants, opioids, nonsteroidal anti-inflammatory drugs, sedatives, muscle relaxants, and antiepileptic agents. Although the syndrome is now more widely recognized and understood, its treatment remains challenging and some physicians believe that no effective treatment exists. Only a few drugs have been shown to have clear-cut benefits in RCTs. FMS sufferers benefit from exercise and a number of the tested programs have involved more than 1 type of exercise. Two other major approaches are psychophysiologically based therapy, such as electromyography biofeedback, and interventions based on cognitive-behavioral therapy. Twelve controlled clinical studies have provided evidence supporting the efficacy of treatments administered to people with FMS by multidisciplinary teams using multicomponent strategies. It is difficult to draw definite conclusions concerning the most appropriate approach to managing FMS because of the methodological limitations of the available studies and the fact that the heterogeneity and nonstandardized nature of their therapeutic programs make them difficult to compare. An individually tailored multidisciplinary pharmacologic, rehabilitative, and cognitive-behavioral approach currently seems to be the most effective. ",0
3373,17976767,Management of ventricular dysrhythmia secondary to trazodone overdose,"Torsades de pointes (TdP), a life-threatening ventricular dysrhythmia, was recorded in a 30-year-old woman who had taken a deliberate overdose of trazodone. The patient was successfully defibrillated to normal sinus rhythm and given intravenous magnesium sulfate according to Advanced Cardiovascular Life Support guidelines. The patient was discharged and experienced no further complications. ",0
3374,17976994,"Inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamides","The interaction of a series of 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamides with neutrophil-derived serine proteases was investigated. The nature of the amino acid component, believed to be oriented toward the S' subsites, had a profound effect on enzyme selectivity. This series of compounds were found to be potent, time-dependent inhibitors of human neutrophil elastase (HNE) and were devoid of any inhibitory activity toward neutrophil proteinase 3 (PR 3) and cathepsin G (Cat G). The results of these studies demonstrate that exploitation of differences in the S' subsites of HNE and PR 3 can lead to highly selective inhibitors of HNE. ",0
3375,17977030,Evidence from limited proteolysis of a ristocetin-induced conformational change in human von Willebrand factor that promotes its binding to platelet glycoprotein Ib-IX-V,"von Willebrand factor (VWF) does not normally interact with platelets in the bloodstream. Binding to exposed vascular subendothelium, however, enables VWF to interact with the platelet glycoprotein Ib-IX-V complex (GP Ib-IX-V). This change in function may reflect a change in its conformation. Ristocetin also promotes interaction of VWF with GP Ib-IX-V; it thus provides a model for changes in VWF conformation and function that may occur in vivo. The fluid-phase conformation of VWF was evaluated from its susceptibility to proteolytic digestion. Ristocetin markedly altered the pattern of VWF digestion by trypsin, increasing the prevalence of two major proteolytic fragments (109 and 160 kDa), and decreasing that of four fragments (130, 145, 181 and 199 kDa). Vancomycin, a structurally related antibiotic, did not affect the digestion pattern. However, it partially reversed the ristocetin-induced change in digestion. Changes in prevalence of five of the tryptic fragments of VWF with ristocetin and vancomycin correlated closely with changes in VWF binding to GP Ib-IX-V. Heparin also partially inhibited the ristocetin-induced changes in tryptic digestion of VWF. These observations suggest that ristocetin may modulate VWF conformation in such a way as to expose its GP Ib-binding domain and enable it to interact with the platelet. Such modulation also exposes a cryptic site (or sites) for proteolytic cleavage by trypsin. ",0
3376,17977607,The eyes as a mirror of our thoughts: quantification of motor imagery of goal-directed movements through eye movement registration,"It has been suggested that motor imagery possesses a range of useful applications in sport as well as in rehabilitation. Until now, research in this field has been hampered by the lack of an objective method to monitor the subjects' participation in the task. In this present study, a new approach to quantifying motor imagery of goal-directed hand movements by means of eye movement registration is examined. Eye movements of 15 right-handed subjects were recorded using EOG during both physical execution and visual motor imagery of a cyclical aiming task, performed at three different inter-target distances. We found that 89% of subjects made task-related eye movements during imagery with the eyes open and 84% of participants also did so during imagery with the eyes closed. Both the number and amplitude of the eye movements during imagery closely resembled those of eye movements made during physical execution of the task. This indicates that the coupling between neural patterns for eye and hand movements remains intact when hand movements are merely imagined as opposed to being physically executed. Therefore, eye movement recordings may be used as an objective technique to evaluate subjects' compliance, motor imagery ability, and spatial accuracy. ",0
3377,17977970,Human immunodeficiency virus type 1 Vif functionally interacts with diverse APOBEC3 cytidine deaminases and moves with them between cytoplasmic sites of mRNA metabolism,"Vif(IIIB), which has been a standard model for the viral infectivity factor of human immunodeficiency virus type 1 (HIV-1), binds the cytidine deaminase APOBEC3G (A3G) and induces its degradation, thereby precluding its lethal incorporation into assembling virions. Additionally, Vif(IIIB) less efficiently degrades A3F, another potent anti-HIV-1 cytidine deaminase. Although the APOBEC3 paralogs A3A, A3B, and A3C have weaker anti-HIV-1 activities and are only partially degraded by Vif(IIIB), we found that Vif(IIIB) induces their emigration from the nucleus to the cytosol and thereby causes net increases in the cytosolic concentrations and anti-HIV-1 activities of A3A and A3B. In contrast, some other Vifs, exemplified by Vif(HXB2) and Vif(ELI-1), much more efficiently degrade and thereby neutralize all APOBEC3s. Studies focused mainly on A3F imply that it occurs associated with mRNA-PABP1 in translationally active polysomes and to a lesser extent in mRNA processing bodies (P-bodies). A3F appears to stabilize the P-bodies with which it is associated. A correspondingly small proportion of Vif(IIIB) also localizes in P-bodies in an A3F-dependent manner. Stress causes A3A, A3B, A3C, and A3F to colocalize efficiently with Vif(IIIB) and mRNA-PABP1 complexes in stress granules in a manner that is prevented by cycloheximide, an inhibitor of translational elongation. Coimmunoprecipitation studies suggest that Vifs from different HIV-1 isolates associate with all tested APOBEC3s. Thus, Vifs interact closely with structurally diverse APOBEC3s, with effects on their subcellular localization, degradation rates, and antiviral activities. Cytosolic APOBEC3-Vif complexes are predominantly bound to mRNAs that dynamically move between translationally active and storage or processing pools. ",0
3378,17978221,"Streptomyces radiopugnans sp. nov., a radiation-resistant actinomycete isolated from radiation-polluted soil in China","The taxonomic position of an actinomycete isolated from radiation-polluted soil collected in Xinjiang Province, north-west China, was determined by using a polyphasic approach. The isolate, designated strain R97T, had chemical and morphological properties characteristic of streptomycetes. An almost-complete 16S rRNA gene sequence of the isolate was generated and compared with corresponding sequences of representative streptomycetes. The 16S rRNA data not only supported the classification of the strain in the genus Streptomyces but also showed that it represented a distinct phyletic line that was most closely, albeit loosely, associated with three other thermotolerant organisms, namely Streptomyces macrosporus NBRC 14748T, Streptomyces megasporus NBRC 14749T and Streptomyces thermolineatus NBRC 14750T. Strain R97T could be distinguished from these organisms based on a range of phenotypic properties. It is proposed that R97T (=CGMCC 4.3519T=DSM 41901T) be classified as the type strain of a novel species in the genus Streptomyces, Streptomyces radiopugnans sp. nov. The organism was shown to be resistant to 60Co gamma radiation at a dose of 15 kGy. ",0
3379,17978482,Comparison of basal gene expression and induction of CYP3As in HepG2 and human fetal liver cells,"Human fetal liver (HFL) cell culture was initiated from a pool of six normal human liver tissues. The proliferation and viability of HFL cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay, and the cells increased by more than 100-fold by culture for 15 d. The levels of expression of albumin (ALB), hepatocyte nuclear factor 4alpha, hepatocyte growth factor, CYP3A4, CYP3A5, and CYP3A7 mRNAs in HFL cells increased with culture period, while that of alpha-fetoprotein (AFP) mRNA decreased gradually. In HepG2 cells, however, the expression levels of ALB and AFP mRNAs were not changed, and the levels of expression of CYP3A4, CYP3A5, and CYP3A7 mRNAs decreased gradually. The mRNA expression of major CYP isoforms including CYP3As, i.e., CYP1A2, CYP2A6, CYP2B6, CYP2C (2C9 and 2C19), CYP2D6, and CYP2E1, could be detected in HepG2 cells. With the exception of CYP1A2, all of the CYP mRNAs expressed in HepG2 cells were detected in HFL cells. In HFL cells, CYP3A4 and CYP3A7 mRNA expression levels were markedly up-regulated by dexamethasone (DEX), but not by rifampicin (RIF). CYP3A5 mRNA expression was increased to a level 3-fold greater than control by DEX. On the other hand, CYP3A4, CYP3A5, and CYP3A7 mRNA expression levels in HepG2 cells were increased from 2- to 3-fold by treatment with DEX and RIF. Pregnane X receptor mRNA was expressed in HepG2 cells, but not HFL cells. These results indicate that the character of HFL cells with regard to CYP expression was different from that of HepG2 cells. ",0
3380,17978485,Enantioselective dehydroxylation of enterodiol and enterolactone precursors by human intestinal bacteria,"During the course of experiments on the transformation of lignans to phytoestrogenic substances, such as enterodiol (END) and enterolactone (ENL), a previously isolated bacterium, Eubacterium (E.) sp. strain SDG-2, capable of phenolic p-dehydroxylation in the biotransformation of secoisolariciresinol diglucoside to END and ENL, was concluded to be Eggerthella (Eg.) lenta (Eg. sp. SDG-2) on the basis of 16S rRNA gene sequence analysis. The bacterium could transform (+)-dihydroxyenterodiol (DHEND, 3a) to (+)-END (1a), but not for (-)-DHEND (3b) to (-)-END (1b) under anaerobic conditions. By incubation of a mixture of (+)- and (-)-dihydroxyenterolactone (DHENL, 4a and 4b) with Eg. sp. SDG-2, only (-)-DHENL (4b) was converted to (-)-ENL (2b), selectively. On the other hand, we isolated a different bacterium, strain ARC-1, capable of dehydroxylating (-)-DHEND (3b) to (-)-END (1b) from human feces. Strain ARC-1 could transform not only (-)-DHEND (3b) to (-)-END (1b), but also (+)-DHENL (4a) to (+)-ENL (2b). However, the bacterium could not transform (+)-DHEND (3a) and (-)-DHENL (4b). Both bacterial strains demonstrated different enantioselective dehydroxylation. ",0
3381,17978507,Effect of carboxyl-group of D-glutamic acid or gamma-carboxy-D-glutamic acid as N-terminal amino acid of (111)in-diethylenetriaminepentaacetic acid-octreotide on accumulation of radioactivity in kidney,"To establish a strategy for developing (111)In-diethylenetriaminepentaacetic acid ((111)In-DTPA)-octreotide, a diagnostic radiopharmaceutical agent for tumors, with reduced non-specific renal radio-accumulation, the compounds having D-glutamic acid (Glu) or gamma-carboxy-D-glutamic acid (carboxy-Glu) as the N-terminal amino acid were examined for in vivo radio-distribution. Compounds carrying Glu and carboxy-Glu containing one and two negative charges, respectively, showed lower renal radio-accumulation than that carrying D-phenylalanine. It was revealed that the introduction of a negative charge reduces the renal radio-accumulation independently from the number of negative charges. The present result can be a clue for the development of (111)In-DTPA-octreotides with reduced the renal radio-accumulation. ",0
3382,17978884,Transcriptional analysis of a major capsid protein gene from Spodoptera exigua ascovirus 5a,"The major capsid protein (mcp) gene of Spodoptera exigua ascovirus 5a (SeAV-5a) was confirmed by aphidicolin viral DNA replication inhibition analysis to be a late gene. The 5' and 3' ends of mcp gene transcripts have been mapped. Primer extension analyses indicated that transcription of the mcp gene initiates from a cytosine 25 nucleotides (nt) upstream of the translation start codon. Two independent approaches by 3' rapid amplification of cDNA ends (3' RACE) and oligo (dT) cellulose binding assay suggested that SeAV-5a mcp mRNA is polyadenylated. Analyses by 3' RACE also revealed that mcp transcripts terminate at a U, either at 26 or 38 nt downstream of the translation stop codon. The putative 5' transcription control region of the SeAV-5a mcp gene shares similarities with other ascoviruses and Chilo iridescent virus (CIV), containing a conserved TATA-box-like motif (TAATTAAA) and an ATTTGATCTT motif upstream of it. The 3' downstream regions of the mcp gene of all the ascoviruses examined and CIV can form a stem-loop structure, and the ends of the mcp gene transcripts of SeAV-5a are within the predicted stem-loop region. This suggests that the stem-loop structure of the mcp gene might be involved in transcription termination. ",0
3383,17979194,"Role of the IXI/V motif in oligomer assembly and function of StHsp14.0, a small heat shock protein from the acidothermophilic archaeon, Sulfolobus tokodaii strain 7","Small heat shock proteins (sHsps) are one of the most ubiquitous molecular chaperones. They are grouped together based on a conserved domain, the alpha-crystallin domain. Generally, sHsps exist as oligomers of 9-40 subunits, and the oligomers undergo reversible temperature-dependent dissociation into smaller species as dimers, which interact with denaturing substrate proteins. Previous studies have shown that the C-terminal region, especially the consensus IXI/V motif, is responsible for oligomer assembly. In this study, we examined deletions or mutations in the C-terminal region on the oligomer assembly and function of StHsp14.0, an sHsp from an acidothermophilic archaeon, Sulfolobus tokodaii strain 7. Mutated StHsp14.0 with C-terminal deletion or replacement of IIe residues in the IXI/V motif to Ala, Ser, or Phe residues could not form large oligomers and lost chaperone activity. StHsp14.0WKW, whose Ile residues in the IXI/V motif are changed to Trp, existed as an oligomer like that of the wild type. However, it dissociates to small oligomers and exhibits chaperone activity at relatively lowered temperature. Replacement of two Ile residues in the motif to relatively small residues, Ala or Ser, also resulted in the change of beta-sheet rich secondary structure and decrease of hydrophobicity. Interestingly, StHsp14.0 mutant with amino acid replacements to Phe kept almost the same secondary structure and relatively high hydrophobicity despite that it could not form an oligomeric structure. The results show that hydrophobicity and size of the amino acids in the IXI/V motif in the C-terminal region are responsible not only for assembly of the oligomer but also for the maintenance of beta-sheet rich secondary structure and hydrophobicity, which are important for the function of sHsp. ",0
3384,17980518,A novel medium devoid of ruminant peptone for high yield growth of Mycoplasma ovipneumoniae,"Mycoplasma ovipneumoniae is considered an emerging veterinary pathogen causing pneumonia in sheep and goats worldwide. Currently it has not been possible to define a growth medium that yields the maximum growth of M. ovipneumoniae within a short incubation period. Growth yields of M. ovipneumoniae in Eaton's medium are variable and not as consistently high as those seen with other Mycoplasma spp. This study investigated the ability of different M. ovipneumoniae field strains to grow in various media formulations, where PPLO broth was replaced by a vegetable protein source, and comparisons were made in terms of strain viability in Eaton's medium. Studies were also conducted to determine the optimal carbohydrate source for use in the M. ovipneumoniae medium. Generally, it was found that different strains showed good growth in all media tested, with growth yields at 24h in TSB-1 medium higher than those observed with Eaton's medium. Growth yields reached 10(8) to 10(9)cfu ml(-1) within 24h for particular field strains, with all strains achieving this growth level within 48-72h. ",0
3385,17980550,Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms,"Neuropathy is common in patients receiving vinca alkaloids, platinum derivatives, or taxanes. This double-blind, randomized, placebo-controlled study assessed the efficacy of low-dose amitriptyline to relieve chemotherapy-induced symptoms in 44 patients (age 20-65 years) who had neuropathic symptoms (numbness, tingling, pain) with a severity of > or =3/10. They were treated with amitriptyline for eight weeks (10mg/day to start, then dose elevation of 10mg/week up to 50mg/day if tolerated, followed by a stable dose > or =4 weeks). The patients completed a diary twice weekly, noting the intensity of pain, numbness and tingling, global improvement, and adverse effects. Neurological examination was performed at each visit (baseline, four, and eight weeks). The patients assessed both intensity and relief of pain, and overall discomfort. They also completed the Neuropathic Pain Scale and validated measures of anxiety and depression, and quality of life (QoL). The results demonstrated that amitriptyline did not improve sensory neuropathic symptoms, although there was a trend toward global improvement and improved QoL in favor of the amitriptyline group. No statistical significance was reached, probably due to the small number of patients and too low dose of amitriptyline. Amitriptyline was well tolerated. ",0
3386,17980783,Synovial sarcoma of the infratemporal fossa,"A case is reported in which synovial sarcoma (SS) is arising within the infratemporal fossa. Case report and literature review from an academic tertiary referral practice. A 46-year-old white woman presented with a 1-month history of having paresthesias on the left side of her head. There was a sensory deficit at the level of the third division dermatome (V3) of the fifth left cranial nerve. Computed tomography (CT) and magnetic resonance imaging revealed a mass centered in the left infratemporal fossa. Fine needle aspiration (FNA) revealed a spindle cell neoplasm. An endoscopic, transantral biopsy of the mass revealed SS. The SS in the infratemporal fossa was surgically removed en bloc. The patient had postoperative chemoradiotherapy and is free of disease at 1 year from completion of treatment. This is the first reported case from the United States of America of SS located in the infratemporal fossa and the third case to be reported in the English language literature. ",0
3387,17981022,Use of recycled plastic in concrete: a review,"Numerous waste materials are generated from manufacturing processes, service industries and municipal solid wastes. The increasing awareness about the environment has tremendously contributed to the concerns related with disposal of the generated wastes. Solid waste management is one of the major environmental concerns in the world. With the scarcity of space for landfilling and due to its ever increasing cost, waste utilization has become an attractive alternative to disposal. Research is being carried out on the utilization of waste products in concrete. Such waste products include discarded tires, plastic, glass, steel, burnt foundry sand, and coal combustion by-products (CCBs). Each of these waste products has provided a specific effect on the properties of fresh and hardened concrete. The use of waste products in concrete not only makes it economical, but also helps in reducing disposal problems. Reuse of bulky wastes is considered the best environmental alternative for solving the problem of disposal. One such waste is plastic, which could be used in various applications. However, efforts have also been made to explore its use in concrete/asphalt concrete. The development of new construction materials using recycled plastics is important to both the construction and the plastic recycling industries. This paper presents a detailed review about waste and recycled plastics, waste management options, and research published on the effect of recycled plastic on the fresh and hardened properties of concrete. The effect of recycled and waste plastic on bulk density, air content, workability, compressive strength, splitting tensile strength, modulus of elasticity, impact resistance, permeability, and abrasion resistance is discussed in this paper. ",0
3388,17981116,Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes,"Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle- and liver-specific AIF ablation in mice initiates a pattern of OxPhos deficiency closely mimicking that of human insulin resistance, and contrary to current expectations, results in increased glucose tolerance, reduced fat mass, and increased insulin sensitivity. These results are maintained upon high-fat feeding and in both genetic mosaic and ubiquitous OxPhos-deficient mutants. Importantly, the effects of AIF on glucose metabolism are acutely inducible and reversible. These findings establish that tissue-specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity. ",0
3389,17981537,Mechanisms of evasion of complement by Porphyromonas gingivalis,"The complement system is an important host response to invading bacteria. Activation leads to deposition on the bacterial surface of C3b and its' inactivation products and phagocytosis of the opsonised bacteria by host cells. Alternatively the entire complement pathway including terminal components C5b-9 may be activated on the cell surface which gives rise to generation and insertion of the membrane attack complex into the bacterial membrane and cell lysis. Bacterial resistance to complement may be by enzyme digestion of complement components or by the generation or acquisition from the host of cell surface molecules which allow the organism to adopt host complement control proteins. The involvement of surface polysaccharides can be deduced from the very strong association of resistance with the presence of capsule and extended or modified LPS O-antigens in several species. However, in many cases the mechanism is unclear. The proteases of Porphyromonas gingivalis breakdown C3 and C5 and prevent the deposition of C3b on the bacterial cell surface. Greater deposition of both C3b and C5b-9 occurs in protease deficient mutants but mutants do not show loss of resistance to complement mediated lysis. Instead, complement resistance in P. gingivalis is associated with the presence on the cell surface of an anionic branched mannan and appears independent of capsule serotype. ",0
3390,17981551,Adaptation of endothelium to exercise training: insights from experimental studies,"Endothelial dysfunction is one of the hallmarks of cardiovascular disease and serves as a prognostic marker for forecasting the development and outcome of the disease process. Current pharmacological treatment strategies only incompletely repair endothelial dysfunction whereas exercise training corrects this dysfunction, primarily due to improved production and/or bioavailability of nitric oxide, the main endothelium-derived vasodilator. This type of treatment also improves the function of healthy endothelium. The focus of this review is to discuss the underlying biological factors involved in improved endothelial function after exercise training in healthy individuals as well as those with cardiovascular disease or a metabolic syndrome. The ability to sustain the bioavailability of nitric oxide (NO) in the endothelium is probably the most important factor in restoring normal endothelial function by exercise training. ",0
3391,17981769,Studying telomeres in a longitudinal population based study,"Telomeres, the termini of linear chromosomes, consist of large but variable numbers of DNA oligomer repeats embedded in a nucleoprotein complex. In humans, telomere length (TL) is largely genetically determined but also featured by an age dependent attrition. TL has therefore been put forward as a marker for biological aging and was also reported to be associated with aging diseases such as cardiovascular disease. However it remains unclear whether the biomarker value in a particular disease depends on shorter TL at birth or rather if it's a mere reflection of an accelerated telomere attrition during lifetime, or else, if it is a combination of both. While the importance of telomere attrition is supported by cross-sectional evidence associating shorter telomeres with oxidative stress and inflammation, longitudinal studies are required to accurately assess telomere attrition and its presumed link with accelerated aging. In this review we present different models for the biomarker value of TL and discuss the theoretical and methodological considerations of studying TL in a longitudinal population study with a special emphasis on cardiovascular disease. ",0
3392,17981827,Plasma angiogenin levels in acute coronary syndromes: implications for prognosis,"Angiogenin is a member of the ribonuclease superfamily, which has been implicated as a mitogen of endothelial cells and activator of matrix metalloproteinases and plasminogen-activated plasmin pathways. We hypothesized abnormalities of angiogenin levels in acute coronary syndrome (ACS), with prognostic implications for predicting adverse events. We measured plasma angiogenin levels (ELISA) in 396 consecutive patients (63.4% males; mean age 67 years, SD 13) admitted with ACS, who were compared with 44 'disease controls' (patients with stable coronary artery disease) and 76 healthy controls. Clinical follow-up at 6 months was performed for adverse endpoints (cardiovascular death, recurrent ACS, revascularization and heart failure). ACS patients had significantly elevated plasma angiogenin levels compared with both disease controls and healthy controls (P < 0.001). After adjusting for baseline characteristics, raised troponin T levels and electrocardiographic changes, raised angiogenin levels were independently associated with more adverse events at 6 months' follow-up [HR 1.44 (95% CI: 1.10-1.89); P = 0.008]. Plasma angiogenin levels are significantly increased in ACS, and may be involved in the pathogenesis of this condition. High angiogenin levels were predictive of adverse events during follow-up. ",0
3393,17981846,Interventions for adult family carers of people who have had a stroke: a systematic review,"A systematic review of the effectiveness of interventions for adult family carers of people with stroke, and an exploratory examination of the relationship between the conceptual basis of these interventions and their effectiveness. Seventeen electronic databases and grey literature sources were searched, including ASSIA, BNI, Cochrane Library, CINAHL, EMBASE, MEDLINE, PsycINFO, Social Science Citation Index and the Science Citation Index, HMIC and the National Research Register. Authors of unpublished material were contacted for data and additional publications. Reference and citation tracking was performed on included publications. randomized controlled trials of interventions aimed primarily at adult family carers of people post stroke; carers were the primary sample; primary outcomes reported were for carers. Two independent reviewers screened titles and abstracts to identify publications and extract data. Quality assessment was performed to weight study findings. Eight papers were found reporting on six complex, generally heterogeneous, interventions: caregiver training; education and counselling; social problem-solving partnerships, delivered principally by telephone; a psycho-educational telephone support group; a nurse-led support and education programme; and a support programme, delivered either to groups in hospital or individuals during home visits. Half of the interventions were based on stress-coping theories; the remainder did not identify a conceptual basis for the intervention. Some benefits were reported for all interventions, although trials were generally of low quality, preventing firm conclusions being drawn. The presence of a conceptual basis for interventions does not appear to influence effectiveness. ",0
3394,17982062,"Duration of antigen expression in vivo following DNA immunization modifies the magnitude, contraction, and secondary responses of CD8+ T lymphocytes","The duration of Ag expression in vivo has been reported to have a minimal impact on both the magnitude and kinetics of contraction of a pathogen-induced CD8(+) T cell response. In this study, we controlled the duration of Ag expression by excising the ear pinnae following intradermal ear pinnae DNA immunization. This resulted in decreased magnitude, accelerated contraction and differentiation, and surprisingly greater secondary CD8(+) T cell responses. Furthermore, we found delayed and prolonged Ag presentation in the immunized mice; however, this presentation was considerably decreased when the depot Ag was eliminated. These findings suggest that the magnitude and the contraction phase of the CD8(+) T cell response following intradermal DNA immunization is regulated by the duration rather than the initial exposure to Ag. ",0
3395,17982334,The transdermal contraceptive patch: an updated review of the literature,"The transdermal contraceptive patch which contains ethinyl estradiol and norelgestromin has an efficacy similar to current oral contraceptives (OCs). The major advantages include transdermal application and maintenance of adequate hormonal levels for at least 7 days. Side effects are similar to OC except for breast tenderness in the first 2 months of use and skin irritation at the application site. Although concern has been raised about a possible increased risk of venous thromboembolism, current available data comparing the patch to a norgestimate-containing OC ranges from no increase in risk to a 2.4-fold increase. ",0
3396,17982557,Microwave-induced fast decalcification of rat bone for electron microscopic analysis: an ultrastructural and cytochemical study,"Bone decalcification is a time-consuming process. It takes weeks and preservation of the tissue structure depends on the quality and velocity of the demineralization process. In the present study, a decalcification methodology was adapted using microwaving to accelerate the decalcification of rat bone for electron microscopic analysis. The ultrastructure of the bone decalcified by microwave energy was observed. Wistar rats were perfused with paraformaldehyde and maxillary segments were removed and fixed in glutaraldehyde. Half of specimens were decalcified by conventional treatment with immersion in Warshawsky solution at 4 degrees C during 45 days, and the other half of specimens were placed into the beaker with 20 mL of the Warshawsky solution in ice bath and thereafter submitted to irradiation in a domestic microwave oven (700 maximum power) during 20 s/350 W/+/-37 degrees C. In the first day, the specimens were irradiated 9 times and stored at 40 degrees C overnight. In the second day, the specimens were irradiated 20 times changing the solution and the ice after each bath. After decalcification, some specimens were postfixed in osmium tetroxide and others in osmium tetroxide and potassium pyroantimonate. The specimens were observed under transmission electron microscopy. The results showed an increase in the decalcification rate in the specimens activated by microwaving and a reduction of total experiment time from 45 days in the conventional method to 48 hours in the microwave-aided method. ",0
3397,17982655,The ribosomal P0 protein induces a spontaneous immune response in patients with head and neck advanced stage carcinoma that is not dependent on its overexpression in carcinomas,"A typical feature in systemic lupus erythemathosus patients is the presence of autoantibodies to the carboxyl-terminal homologous P proteins (P0, P1, P2) domain (C-22 P0 epitope). In this report we provide evidence for the in vivo immunogenicity of the P0 protein in head and neck cancer patients as well as overexpression by immunohistochemistry of the C-22 P0 epitope in invasive carcinomas (55/57). Overexpression of this epitope was also significantly associated with a number of pathological lesions arising in the head and neck stratified epithelium including acanthosis (8/8), benign tumors (11/11), dysplasia (23/25) and in situ carcinomas (9/9). Intermediate cell layer restricted epitope overexpression was observed in well differentiated carcinomas, while undifferentiated tumors showed overexpression throughout the cell layers. Employing recombinant P proteins, sera from 40 of the 57 carcinoma patients and 39 normal donors, were subjected to immunoblot analysis. Immunity to P0 protein (7/40) was associated with malignancy and with advanced disease stage, but it was not dependent on the C-22 P0 epitope overexpression, although it was the preferential autoantibody target in 4 patients. Increased expression of the C-22 P0 epitope on the surface of pharynx cancer cells following cellular stress in vitro, may imply P0 protein presentation as an in vivo autoantibody target in cancer patients. Evidence for immunity to the P0 protein, as well as overexpression in patients with head and neck carcinoma may be relevant for monitoring cancer progression, in planning immunotherapeutic strategies, and contribute to the understanding of immuno-biological behaviour of head and neck carcinomas. ",0
3398,17982862,"Seroprevalence of toxoplasmosis in pregnant women in Rabat, Morocco]","In Morocco, the seroprevalence of toxoplasmosis in pregnant women living in Rabat, was estimated by analyzing antibodies (IgG, IgM) levels using an ELISA test. The analysis of 2456 serums at the Institut National d'Hygiène showed that the seroprevalence of toxoplasmosis is about 50.6%. According to the questionnaire, the lack of knowledge about this disease and soil contact could be the main causes of toxoplasmosis infection. The use of IgG avidity test has excluded a recent infection in 93.5% of pregnant women with IgM positive sera. ",0
3399,17982916,Characteristics of GABA receptors on the ocellar L-neurons of American cockroach Periplaneta americana,"The ocellar L-neurons of cockroach Periplaneta americana were used in the present study as model systems to investigate the pharmacological properties of the GABA receptors. To do so, a glass microelectrode was impaled into the axon of the L-neurons to record the membrane potential intracellularly and to monitor membrane response to GABA treatment and cercal stimulation by air puff. The traditional GABA and their receptor agonists were introduced through perfusion and/or iontophoresis to monitor their effects on the L-neurons. The GABA receptor antagonists were administered by perfusion to examine if the response of the L-neurons to GABA and/or cercal stimulation was changed. The results revealed that administration of GABA, muscimol and imidazole acetic acid, two GABAA agonists, produced depolarization on the L-neurons. However, treatment of 3-APS and guanidine acetic acid, another two GABAA agonists, evoked hyperpolarization on the L-neurons. Among those tested antagonists, only picrotoxin, GABAA antagonist, antagonize the depolarization induced by GABA and/or cercal stimulation. More interestingly, administration of strychnine, glycine receptor antagonist, largely attenuated the depolarization response of the L-neurons to cercal stimulation. This attenuation caused by strychnine was even stronger than that initiated by varied GABA antagonists. In addition, phaclofen, a GABAB receptor antagonist, showed no antagonistic effect. These results strongly suggest that the characteristics of GABA receptors of the ocellar L-neurons may differ from those in vertebrates. It may be more likely to be a novel GABA receptor. ",0
3400,17983266,Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis,"Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and naïve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ(-) Yersinia pseudotuberculosis (Yptb). YopJ(-) Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis. ",0
3401,17983381,Usefulness of intradermal test and patch test in the diagnosis of nonimmediate reactions to metamizol,"Metamizole is a pyrazolone derivative, and its most common reactions are IgE-mediated reaction and idiosyncratic reactions. Non-immediate reactions are poorly described and there are very few reports on non-immediate reactions to pyrazolones. We evaluated 12 patients (nine men) who consulted for a non-immediate reaction after metamizol administration. We performed cutaneous tests (skin prick tests and immediate and delayed intradermal tests) and epicutaneous tests, and, if necessary, an oral challenge test. All skin prick and intradermal tests, if necessary, were negative in immediate reading. Delayed intradermal tests were positive in six of 10 patients (60%) and epicutaneous tests were positive in four of 11 patients (36%). Three cases (25%), were diagnosed by a positive oral challenge test. Delayed-reading intradermal tests and patch tests are useful tools in the diagnosis of nonimmediate reactions to pyrazolones and should be considered the first step when evaluating these type of reactions. Intradermal test appears to be more sensitive than patch test. The positivity of skin tests suggests an immunological reaction, probably mediated by T lymphocytes, but further studies are required. ",0
3402,17983767,Difference in carotid intima-media thickness between Korean and Japanese men,"Koreans are recently at higher risk for coronary heart disease than are the Japanese. We aimed to evaluate levels of carotid intima-media thickness (IMT) and coronary risk factors in Korean and Japanese men in the post-World War II birth cohort. We conducted a population-based study of 352 randomly selected healthy men 40 to 49 years of age: 102 Koreans in Ansan City, Gyeonggi-do, Korea and 250 Japanese in Kusatsu City, Shiga, Japan. Imaging carotid IMT by ultrasonography and other procedures were standardized. Analyzing blood samples and reading carotid IMT were performed at the University of Pittsburgh. Despite more favorable or similar features in coronary risk factors as compared to Japanese men, the Korean men had a higher crude IMT level than the Japanese men (mean +/- standard error, 0.655+/-0.008 mm vs 0.616+/-0.005 mm, respectively, p<0.0001). The difference in the levels of carotid IMT significantly remained after adjusting for metabolic and conventional risk factors (0.654+/-0.008 mm vs. 0.616+/-0.005 mm, respectively; p<0.0001). Among men 40 to 49 years of age, Koreans had significantly higher levels of carotid IMT than the Japanese. Factors that underlie the different susceptibility to subclinical atherosclerosis need to be explored. ",0
3403,17983768,Biases in the subjective timing of perceptual events: Libet et al. (1983) revisited,"We report two experiments in which participants had to judge the time of occurrence of a stimulus relative to a clock. The experiments were based on the control condition used by Libet, Gleason, Wright, and Pearl [Libet, B., Gleason, C. A., Wright, E. W., & Pearl, D. K. (1983). Time of conscious intention to act in relation to onset of cerebral activities (readiness-potential): The unconscious initiation of a freely voluntary act. Brain 106, 623-642] to correct for any bias in the estimation of the time at which an endogenous event, the conscious intention to perform a movement, occurred. Participants' responses were affected systematically by the sensory modality of the stimulus and by the speed of the clock. Such findings demonstrate the variability in judging the time at which an exogenous event occurs and, by extension, suggest that such variability may also apply to the judging the time of occurrence of endogenous events. The reliability of participants' estimations of when they formed the conscious intention to perform a movement in Libet et al.'s (1983) study is therefore questionable. ",0
3404,17983850,The structure of ghrelin,"The structure of ghrelin, a 28-residue octanoylated peptide hormone, is only known up to the level of primary structure identifying an active core of residues 1-5 or 1-4 including octanoyl-Ser3 as necessary to elicit receptor response. This chapter reviews the results and limitations of experimental and computer modeling studies, which have appeared in the literature. The (1)H NMR spectroscopy experimental studies revealed an unstructured and/or fast interconverting peptide at acidic pH, while molecular dynamics (MD) simulation studies at neutral pH pointed to a stable conformation over a time period of 25 ns in water and in the presence of a lipid bilayer. The significance of these findings is discussed with regards to the pH difference, the timescales accessible to simulation and NMR spectroscopy, and the limitations of computational modeling. MD simulations of ghrelin in the presence of a lipid membrane revealed that the octanoyl side chain did not insert into the lipid bilayer, but instead the peptide bound to the lipid headgroups with residues Arg15, Lys16, Glu17, and Ser18, which are located in a hairpin-like bend in the structure. The implications of these findings with regards to a recently obtained homology model of the ghrelin receptor are discussed. ",0
3405,17983919,Pregnancy rates after conservative treatment for borderline ovarian tumours: a systematic review,"Borderline ovarian tumours account for 10-15% of all ovarian cancers, and there have been numerous studies indicating their excellent long-term prognosis. As this disease commonly affects younger women, the issue of fertility-preserving surgery is increasingly important. A systematic review of the literature, searching the relevant electronic databases was performed analysing conservative surgery, borderline ovarian tumours and pregnancy rates/fertility outcome. Overall, 19 studies met the inclusion criteria. From these studies, 2479 patients had borderline ovarian tumours of which 923 (37%) patients were treated by conservative surgery. Nine studies recorded data regarding pregnancy outcome. A pregnancy rate of 48% was calculated on these data, where recorded, analysing the number of women wanting to conceive and the actual number of pregnancies achieved. The recurrence rate after conservative treatment was 16% with only five recorded disease-related deaths. Knowledge of the pregnancy rates is important to permit appropriate counselling of women diagnosed with this malignancy. ",0
3406,17984161,Role of paroxetine in interferon-alpha-induced immune and behavioural changes in male Wistar rats,"Treatment with pro-inflammatory cytokine, IFNalpha was documented to result in neuropsychiatric complications including depression and treatment with antidepressant, paroxetine could improve the depressive symptoms. Therefore, the effects of IFNalpha on behaviour and cytokine changes in the whole blood culture and in the prefrontal cortex, hypothalamus and hippocampus areas of the brain in wistar rats were investigated with emphasis on the role of paroxetine in the prevention of depressive behaviour induced by pro-inflammatory cytokines. The group of rats treated with IFNalpha (s.c. 50,000 IU/kg for 3 days/week for 5 weeks) was compared with three other groups; 1) saline control group (s.c. normal saline 0.2 ml/kg/day for 7 weeks), 2) paroxetine control group (paroxetine suspension orally 10 mg/kg/day for 7 weeks) and 3) group treated with paroxetine for 2 weeks followed by IFNalpha for 5 weeks. In open filed, the IFNalpha treated rats showed anxiety behaviour compared to the rats from the other groups. There was no significant difference in home cage emergence test, Morris water maze and object recognition test. There is no significant difference in plasma corticosterone between groups. The pro-inflammatory cytokines (TNFalpha, IL1beta and IFNgamma), were significantly higher whereas the anti-inflammatory cytokine, IL10 was lower in the stimulated whole blood culture of IFNalpha treated rats. In the brain, both pro-inflammatory cytokine IL1beta and anti-inflammatory cytokine IL10 were higher in hypothalamus of the IFNalpha treated rats; by contrast the concentration of IL10 was lowest in hippocampus region of this group compared to the other groups. The paroxetine pretreated rats did not show these cytokine changes following IFNalpha treatment. Thus it appears that paroxetine pretreatment prevents the pro-inflammatory changes in blood and brain following IFNalpha treatment in turn prevents the anxiety behaviour. ",0
3407,17984194,Association between foot type and tibial stress injuries: a systematic review,"To systematically review published articles investigating the association between structural foot characteristics and tibial stress injuries, and to suggest possible future avenues of research in this area. Literature was identified, selected and appraised in accordance with the methods of a systematic review. Articles potentially relevant to the research question were identified by searching the following electronic databases: Amed, Cinahl, Index to UK theses, Medline, PubMed, Scopus, Sports discus and Web of science. Duplicates were removed and, based on the title and abstract, the full text of relevant studies were retrieved. Two reviewers independently assessed papers; this formed the basis for the inclusion of the most appropriate trials. From the 479 articles originally identified, nine were deemed appropriate for inclusion in the review. In general, specific data relating to this relationship was limited. Outcomes of the nine investigations were difficult to compare due to differing methods used across studies. Results have proved conflicting, with limited evidence found to implicate any specific foot type as a potential risk factor for tibial stress injuries. No definitive conclusions can be drawn relating foot structure or function to an increased risk of tibial stress injuries. Extremes of foot types are likely to pose an increased risk of tibial stress injuries compared to normal arched feet. ",0
3408,17984198,Development of a fibre size-specific job-exposure matrix for airborne asbestos fibres,"To develop a method for estimating fibre size-specific exposures to airborne asbestos dust for use in epidemiological investigations of exposure-response relations. Archived membrane filter samples collected at a Charleston, South Carolina asbestos textile plant during 1964-8 were analysed by transmission electron microscopy (TEM) to determine the bivariate diameter/length distribution of airborne fibres by plant operation. The protocol used for these analyses was based on the direct transfer method published by the International Standards Organization (ISO), modified to enhance fibre size determinations, especially for long fibres. Procedures to adjust standard phase contrast microscopy (PCM) fibre concentration measures using the TEM data in a job-exposure matrix (JEM) were developed in order to estimate fibre size-specific exposures. A total of 84 airborne dust samples were used to measure diameter and length for over 18,000 fibres or fibre bundles. Consistent with previous studies, a small proportion of airborne fibres were longer than >5 microm in length, but the proportion varied considerably by plant operation (range 6.9% to 20.8%). The bivariate diameter/length distribution of airborne fibres was expressed as the proportion of fibres in 20 size-specific cells and this distribution demonstrated a relatively high degree of variability by plant operation. PCM adjustment factors also varied substantially across plant operations. These data provide new information concerning the airborne fibre characteristics for a previously studied textile facility. The TEM data demonstrate that the vast majority of airborne fibres inhaled by the workers were shorter than 5 mum in length, and thus not included in the PCM-based fibre counts. The TEM data were used to develop a new fibre size-specific JEM for use in an updated cohort mortality study to investigate the role of fibre dimension in the development of asbestos-related lung diseases. ",0
3409,17984210,Duplicate copies of lic1 direct the addition of multiple phosphocholine residues in the lipopolysaccharide of Haemophilus influenzae,"The genes of the lic1 operon (lic1A to lic1D) are responsible for incorporation of phosphocholine (PCho) into the lipopolysaccharide (LPS) of Haemophilus influenzae. PCho plays a multifaceted role in the commensal and pathogenic lifestyles of a range of mucosal pathogens, including H. influenzae. Structural studies of the LPS of nontypeable H. influenzae (NTHI) have revealed that PCho can be linked to a hexose on any one of the oligosaccharide chain extensions from the conserved inner core triheptosyl backbone. In a collection of NTHI strains we found several strains in which there were two distinct but variant lic1D DNA sequences, genes predicted to encode the transferase responsible for directing the addition of PCho to LPS. The same isolates were also found to express concomitantly two PCho residues at distinct positions in their LPS. In one such NTHI isolate, isolate 1158, structural analysis of LPS from lic1 mutants confirmed that each of the two copies of lic1D directs the addition of PCho to a distinct location on the LPS. One position for PCho addition is a novel heptose, which is part of the oligosaccharide extension from the proximal heptose of the LPS inner core. Modification of the LPS by addition of two PCho residues resulted in increased binding of C-reactive protein and had consequential effects on the resistance of the organism to the killing effects of normal human serum compared to the effects of glycoforms containing one or no PCho. When bound, C-reactive protein leads to complement-mediated killing, indicating the potential biological significance of multiple PCho residues. ",0
3410,17984335,Seroprevalence of Entamoeba histolytica infection in HIV-infected patients in China,"Seroprevalence of Entamoeba histolytica infection in HIV-infected individuals from Shanghai city, Anhui province, and Henan province, China, was examined by enzyme-linked immunosorbent assay using crude antigen and a recombinant surface antigen, C-Igl, of the parasite. In 215 HIV-infected individuals, the positive rates for these antigens were 12.1% and 7.9%, respectively; these rates were significantly higher than the rates of 3.1% and 0.5%, respectively, in 191 patients with gastrointestinal symptoms who were not infected with HIV. There was no significant difference in seropositivity to E. histolytica between men and women. Seropositivity in HIV-infected individuals was higher in patients with a CD4(+) T cell count of < 200/microL. This is the first report showing a higher seroprevalence of E. histolytica infection in HIV-infected patients in China. Our results also suggest that HIV infection is a risk factor for infection with E. histolytica. ",0
3411,17984615,A case of octreotide acetate-induced acute pancreatitis],"A 56-year-old man was admitted to our hospital in July 2000 because of epigastralgia and back pain with past history of repeated upper abdominal pain due to acute pancreatitis since 1995. Abdominal computed tomography on admission showed a swelling in the pancreas head and several large pancreatic pseudocysts. He was diagnosed as acute pancreatitis based on abdominal pain, elevated pancreatic enzymes and computed tomography finding, and given 50 microg octreotide subcutaneously for the treatment of pancreatic pseudocysts. Within 3 hours after octreotide injection, he complained of upper abdominal pain and had an elevated serum amylase level. Abdominal pain disappeared after cessation of octreotide injection and the patient was discharged free from abdominal pain. Octreotide might cause acute pancreatitis by inducing spasm of the sphincter of Oddi. Careful check-up of the patients might be needed during treatment with octreotide. ",0
3412,17984654,"Intake of fruit, vegetables, and antioxidants and risk of type 2 diabetes: systematic review and meta-analysis","The public health recommendation is to consume five or more servings of fruit and vegetables daily, but the association between the intake of fruit and vegetables and the risk of type 2 diabetes is unclear. To examine the association between the intake of fruit, vegetables, and antioxidants and the risk of type 2 diabetes, prospective cohort studies were sought, with measures of intakes at baseline and incident diabetes at follow-up. Five cohort studies of fruit and vegetables intake and the risk of diabetes were included, incorporating 167,128 participants and 4858 incident cases of type 2 diabetes, with a mean follow-up of 13 years. The relative risk of type 2 diabetes for consuming five or more servings of fruit and vegetables daily was 0.96 (95% CI, 0.79-1.17, P = 0.96), 1.01 (0.88-1.15, P = 0.88) for three or more servings of fruit, and 0.97 (0.86-1.10, P = 0.59) for three or more servings of vegetables. Nine cohort studies of antioxidant intake and the risk of diabetes were also identified, incorporating 139,793 participants and 8813 incident cases of type 2 diabetes, with a mean follow-up of 13 years. The pooled relative risk was 0.87 (0.79-0.98, P = 0.02) for the highest compared with the lowest antioxidant intake. The consumption of three or more daily servings of fruit or vegetables was not associated with a substantial reduction in the risk of type 2 diabetes. The intake of antioxidants was associated with a 13% reduction in risk, mainly attributed to vitamin E. These results are not supported by randomized, controlled trials of vitamin supplements, therefore the findings might not be causal, and the discrepancy remains unclear. ",0
3413,17985001,Metastatic tumors of the uvea in 38 eyes,"The reported incidence of metastatic uveal tumors has been increasing. The aim of this study is to report the clinical features, management, and prognosis of uveal metastatic tumors seen in a general oncology hospital. The records of 28 patients with uveal metastasis diagnosed between 1999 and 2006 were reviewed retrospectively. Uveal metastatic tumours were detected in a total of 38 eyes, uveal involvement included the iris in 4 eyes and the choroid in 37 eyes. Ten patients (35.7%) had bilateral uveal involvement. The primary cancer site was the breast in 24 patients, the lung in 2 patients, the ovary in 1 patient, and the gastrointestinal tract in 1 patient. While the most common symptom was blurred vision, 14.2% of patients were asymptomatic. Choroidal metastases typically were creamy yellow in color, plateau or dome-shaped, and associated with secondary retinal detachment in 56.8% of eyes. The mean time interval between ocular and systemic diagnosis was 41.07 months. At the time of ocular diagnosis, 75% of patients had systemic metastasis. Eight eyes were treated with chemotherapy and hormone therapy, and external beam radiotherapy was applied to 30 eyes. Lesions commonly responded well to therapy, but 22 patients died as a result of disseminated systemic disease. Patients with uveal metastasis generally present to ophthalmologists with visual symptoms but may be asymptomatic in some cases. Local tumor control can be managed with current therapy, but systemic prognosis is generally poor because of the disseminated stage of the malignant disease. ",0
3414,17985314,"Association of maternal pancreatic function and foetal growth in rats treated with DFU, a selective cyclooxygenase-2 inhibitor","Constitutive (COX-1) and inducible (COX-2) cyclooxygenase isoforms have been detected in various mammalian tissues. Their activity is blocked by non-steroidal anti-inflammatory drugs that may induce various side reactions. The aim of the study was to evaluate the effects of DFU, a selective COX-2 inhibitor, on exocrine and endocrine pancreatic function and the immunoexpression of both COX isoforms in maternal and foetal rat pancreases. The compound was administered to pregnant Wistar rats once daily from the 8th to the 21st day of gestation. Glucose level and amylase activity were determined in the maternal sera. Maternal and foetal pancreases were examined histologically. Immunoexpression of COX-1 and COX-2 was also evaluated. Both biochemical parameters, as well as the histological structure of the pancreas were undisturbed in the dams and their foetuses. The maternal glucose level was found to be an important factor for foetal growth. Strong cytoplasmic COX-1 immunostaining was observed in acinar secretory cells, whereas in islets the immune reaction was weak. Endocrine cells also revealed strong cytoplasmic COX-2 staining in the maternal and foetal pancreases. Acinar cells exhibited nuclear reaction, which was strong in the foetal but weak in the maternal pancreases. No differences in COX immunoexpression were found between the DFU-exposed and the control groups in either mothers or foetuses. It should be stressed that DFU administered throughout mid and late pregnancy in rats did not change maternal or foetal pancreatic morphology or immunoexpression of either of the main COX isoforms in the organ. ",0
3415,17985384,High dose adenosine for suboptimal myocardial reperfusion after primary PCI: A randomized placebo-controlled pilot study,"This study was designed to investigate the influence of high dose intracoronary adenosine on persistent ST-segment elevation after primary percutaneous coronary intervention (PCI). After successful PCI for acute myocardial infarction 40-50% of patients show persistent ST-segment elevation indicating suboptimal myocardial reperfusion. Adenosine has been studied to ameliorate reperfusion and is frequently used in a variety of doses, but there are no prospective studies to support its use for treatment of suboptimal reperfusion. We conducted a blinded, randomized, and placebo-controlled study with high dose intracoronary adenosine in 51 patients with <70% ST-segment resolution (STRes) after successful primary PCI. All patients were treated with stents and abciximab. Immediately after adenosine, significantly more patients showed optimal (>70%) STRes compared with placebo (33% versus 9%, P < 0.05). Mean STRes was higher after adenosine (35.4% versus 23.0%, P < 0.05). In addition, TIMI frame count was significant lower (15.7 versus 30.2, P < 0.005), Myocardial Blush Grade was higher (2.7 versus 2.0, P < 0.05) and resistance index was lower in the adenosine group (0.70 versus 1.31 mm Hg per ml/min, P < 0.005). Intracoronary adenosine accelerates recovery of microvascular perfusion in case of persistent ST segment elevation after primary PCI. ",0
3416,17985675,Are we ready? Evidence of support mechanisms for Canadian health care workers in multi-jurisdictional emergency planning,"Federal, provincial and municipal leaders in Canada have adopted a culture of preparedness with the development and update of emergency plans in anticipation of different types of disasters. As evident during the 2003 global outbreak of Severe Acute Respiratory Syndrome (SARS), it is important to provide support for health care workers (HCWs) who are vulnerable during infectious outbreak scenarios. Here we focus on the identification and evaluation of existing support mechanisms incorporated within emergency plans across various jurisdictional levels. Qualitative content analysis of 12 emergency plans from national, provincial and municipal levels were conducted using NVIVO software. The plans were scanned and coded according to 1) informational, 2) instrumental, and 3) emotional support mechanisms for HCWs and other first responders. Emergency plans were comprised of a predominance of informational and instrumental supports, yet few emotional or social support mechanisms. All the plans lacked gender-based analysis of how infectious disease outbreaks impact male and female HCWs differently. Acknowledgement of the need for emotional supports was evident at higher jurisdictional levels, but recommended for implementation locally. While support mechanisms for HCWs are included in this sample of emergency plans, content analysis revealed few emotional or social supports planned for critical personnel; particularly for those who will be required to work in extremely stressful conditions under significant personal risk. The implications of transferring responsibilities for support to local and institutional jurisdictions are discussed. ",0
3417,17985680,"The use of herbal and other non-vitamin, non-mineral supplements among pre- and post-menopausal women in Ontario","Herbal or other non-vitamin, non-mineral (NVNM) supplements are used by many Canadians, and are of public health significance given potential health effects. The majority of supplement users are women, yet there are limited data on their pattern of use. Ontario women were surveyed about their use of NVNM supplements, including those for women's health, and characteristics associated with use were examined. 3,423 randomly selected Ontario households were telephoned to identify eligible women (25-65 years). Of the 1,741 identified, 800 agreed to participate and were mailed a self-administered questionnaire querying NVNM supplement use and health-related characteristics. Prevalence of use, duration, and reasons for use were calculated; distributions of respondent characteristics were tabulated and associations with supplement use were assessed. 478 women (27%) completed questionnaires; 64% reported ever, and 34% reported current use of NVNM supplements. Echinacea was the most frequently used, followed by evening primrose, garlic, and camomile; supplements were used for less than one year. Alleviation of symptoms and prevention of illness were two primary reasons for taking NVNM supplements. 49% reported ever, and 37% reported current use of supplements for women's health, and for reasons similar to other NVNM supplements. High body mass index (> or =30.0 kg/m2) was associated with more supplement use, and visiting a physiotherapist in the past year was associated with less. Findings suggest a high level of NVNM supplement use among Ontario women, possibly associated with certain health-related characteristics. This has important public health implications considering possible benefits and/or interactions with conventional medications. ",0
3418,17985771,Colonoscopy by a family physician: a case series demonstrating health care savings,"Army community hospitals (ACHs) without gastroenterologists require civilian referrals for colonoscopy. The purpose of this study was to determine whether a colonoscopy-trained, military family physician (FP) saved health care dollars at an ACH by decreasing outside referrals. We present a chart review of all 182 colonoscopies performed by a FP at an ACH from September 2003 to May 2005. The total facility cost was determined using the cost of personnel, lost clinic hours, equipment, supplies, medications, continuing medical education, missed diagnoses, procedure complications, and need for additional studies. The potential referral cost was determined using local civilian colonoscopy billing codes and TRICARE reimbursement rates for 2004. The total facility cost was $53,517.14 ($294.05 per colonoscopy). The total referral cost would have been $156,197.60 ($858.23 per colonoscopy). Using a FP saved the hospital $102,680.46 ($564.18 per colonoscopy). A colonoscopy-trained FP saved significant health care dollars at an ACH. ",0
3419,17986212,Prevalence of methicillin-resistant Staphylococcus aureus among veterinarians: an international study,"Pig farmers and veterinarians in contact with livestock in The Netherlands have a higher risk of methicillin-resistant Staphylococcus aureus (MRSA) carriage than the general population. The objective of this study was to investigate whether this is also true for other professionals in contact with pigs in an international setting. A convenience sample of 272 participants at an international conference on pig health in Denmark was screened for MRSA carriage using combined nose/throat swabs and were asked to complete a questionnaire concerning animal contacts, exposure to known MRSA risk-factors, and the protective measures taken when entering pig farms. In total, 34 (12.5%) participants from nine countries carried MRSA. Thirty-one of these isolates were non-typeable by pulsed-field gel electrophoresis following SmaI digestion of chromosomal DNA. All of the non-typeable isolates belonged to spa types (t011, t034, t108, t571, t567 and t899) that correspond to multilocus sequence type 398. All of the above-mentioned spa types, with the exception of t899, have been isolated previously from either Dutch pigs, pig farmers and/or veterinarians. Protective measures, e.g., masks, gowns and gloves, did not protect against MRSA acquisition. Transmission of MRSA from pigs to staff tending to these animals appears to be an international problem, creating a new reservoir for community-acquired MRSA (CA-MRSA) in humans in Europe, and possibly worldwide. The rise of a new zoonotic source of MRSA could have a severe impact on the epidemiology of CA-MRSA, and may have consequences for the control of MRSA, especially in those countries that maintain a low prevalence by means of search-and-destroy policies. ",0
3420,17986238,Wnt signaling in ovarian tumorigenesis,"Data are emerging implicating Wnt signaling in ovarian tumorigenesis. We sought to review the current literature on the subject and discuss the pathway's potential role as a prognostic marker and therapeutic target. We conducted a systematic literature review of studies investigating the association between Wnt signaling and ovarian cancer. Search strategies included online searching of the MEDLINE database and hand searching of relevant publications and reviews. Additional reports were collected by systematically reviewing all references from retrieved papers. Twenty-nine papers were identified that directly investigate Wnt signaling and ovarian cancer. Mutations in the CTNNB1 gene that codes for beta-catenin, the key effector in the pathway, are directly linked to carcinogenic transformation but are mostly found in ovarian endometrioid adenocarcinomas, a histologic subtype of epithelial ovarian cancer. These mutations, along with others, lead to deregulation of the pathway and transcription of target genes. Differences in various intra- and extracellular components of the Wnt pathway have been demonstrated between normal ovarian and cancer cell lines and between benign tissue and ovarian cancer. These differences implicate Wnt signaling in the molecular events that lead to ovarian cancer development despite the fact that gene mutations are uncommon. The data suggest that Wnt signaling plays a role in ovarian tumorigenesis. The exact mechanisms by which this occurs need to be further elucidated. Wnt signaling is probably involved via multiple, diverse mechanisms. Further research in this area is warranted. ",0
3421,17986305,Sensitive skin is not limited to the face,"Sensitive skin (or reactive or hyper-reactive skin) is defined as skin that reacts by erythema and/or subjective symptoms (pricking, burning, pain, pruritus etc.) to stimuli that are not pathogens in themselves (e.g. wind, heat, cold, water, cosmetics, stress). This phenomenon is very frequent, occurring in about 50% of the European population. Sensitive skin is always reported on the face. The aim of our study was to determine if it can occur in other localizations. We have performed this study in two centres. One was a department of dermatology in a university hospital while the other one was a centre for cosmetological studies. A questionnaire was given to women aged > 15 years. The questions were: Do you have sensitive skin? If yes, in which localization? What are the symptoms and triggering factors? Four hundred subjects were included in the study (200 in each centre). The two populations were similar in terms of age, sex, and most of the results. The mean age was 40 years. Eighty-five per cent of the 400 subjects declared that they had sensitive skin on the face, and 70% had sensitive skin in another area: hands (58%), scalp (36%), feet (34%), neck (27%), torso (23%) or back (21%). Triggering factors included cold (66%), heat (28%), stress (61%), sun exposure (51%), wind (42%), water from a shower (29%) or a swimming pool (40%), soaps (42%), cosmetics (28%) and pollution (18%). Friction from clothes was reported in 28% of cases. Sensitive skin was observed as redness in most cases along with various subjective symptoms. The proportion of subjects presenting with sensitive skin is probably overestimated. However, the main result of this study is that sensitive skin is not restricted to the face but rather it is also present at other localizations, mainly the hands, and often the scalp and feet. ",0
3422,17986579,Debating the influence of self-reports by people living with chronic disease on healthy aging and longevity,"For people living with chronic disease, decision-making in relation to their health and lifestyle choices is an integral aspect to managing the complexity that living with chronic disease brings into their lives. Research findings reveal that people living with chronic disease can self-report what may seem to be appropriate explanations for their health status and seem to be in control of their health in their efforts to master the constraints imposed by their life situation. Precisely because ignoring disease-related changes may actually contribute to disease progression, it is imperative to know whether self-reports are made linking biomedical understandings of their disease with the person's social situation and life events. To understand how to influence choices made by people living with chronic disease to promote healthy aging and longevity, it is imperative for health and social care professionals to learn how to question people's self-reports, given that self-reports are often used as evidence in practice and research to inform clinical solutions. ",0
3423,17986648,A role for altered microtubule polymer levels in vincristine resistance of childhood acute lymphoblastic leukemia xenografts,"The microtubule-depolymerizing drug, vincristine, is effective in the treatment of acute lymphoblastic leukemia (ALL). Although vincristine resistance mechanisms have been extensively characterized in cell lines, their clinical relevance is poorly understood. The aim of the current study was to define clinically relevant mechanisms of vincristine resistance in a panel of childhood ALL xenografts established in immune-deficient (nonobese diabetic/severe combined immunodeficient) mice. We also studied two independent xenograft sublines that were selected by in vivo vincristine exposure. In vitro vincristine sensitivity determined by a stromal coculture, murine bone marrow stromal cell line (MS-5), assay, but not methyl-thiazolyl-tetrazolium metabolic activity assay, significantly correlated (P = 0.05) with the length of the patients' first remission. Investigations into mechanisms of resistance revealed no association with steady-state vincristine accumulation or increased activity and/or expression of ATP-binding cassette transporters, although increased intracellular levels of polymerized tubulin significantly correlated with resistance (r = 0.85; P = 0.0019). Two xenograft sublines selected by in vivo vincristine exposure exhibited a 2-fold increase in polymerized tubulin levels compared with the parental subline (P < 0.05), reflecting their in vivo vincristine resistance. In this study, a vincristine-resistant xenograft with high levels of polymerized tubulin was relatively sensitive to the microtubule-polymerizing drug paclitaxel. These results indicate that the balance between polymerized and nonpolymerized tubulin may be an important determinant of response to Vinca alkaloid-based chemotherapy regimens in childhood ALL. ",0
3424,17986887,Intramedullary stabilization of extraarticular proximal tibial fractures: a biomechanical comparison of intramedullary and extramedullary implants including a new proximal tibia nail (PTN),"To determine in the laboratory whether there are or are not differences between individual geometrical designs of intramedullary and extramedullary devices used for the fixation of extraarticular proximal tibial fractures. Five devices were tested: a newly developed Proximal Tibia Nail (PTN), conventional double-plate osteosynthesis (DPO), the Less Invasive Stabilization System (LISS), an augmented Unreamed Tibial Nail with a T-stabilization-plate (UTN + TSP), and an external fixator (ExFix). A 10-mm defect osteotomy was performed on paired human tibiae, and the proximal and distal ends were potted in polymethylmethacrylate cement (PMMA). Each pair of bones was randomly stabilized with the new PTN in 1 tibia (Groups PTN1 through PTN4) and in 1 of the 4 comparative implants in the corresponding contralateral bone. A biomechanical test of the bone implant construct was then performed with a vertical axial force of 350, 600, and 900 N, a bending moment of 6 Nm and a bidirectional rotational strain of 8 Nm. Displacement of bone fragments was measured and depicted as a force-displacement diagram. For axial loading, significant differences were seen between the PTN 2 group compared to the LISS group (P = 0.016) and the PTN 4 group compared to the ExFix group (P = 0.016). No statistically significant differences were seen for the PTN 1 group compared to the DPO group (P = 0.125) and the PTN 3 group compared to the UTN + TSP group (P = 0.453). The bending stiffness of the PTN 1-4 groups was not significantly different from any of the 4 alternative implants. There was comparable torsional stiffness in all implant groups except for the UTN + TSP group, which was less stable and significantly different from the PTN 3 group (P = 0.016). Given the parameters of this investigation, the new PTN would theoretically provide the same mechanical stability as the DPO in axial loading. Higher stability in axial loading may be present when compared to the LISS or the ExFix. Further clinical investigation of this implant will determine its usefulness among proximal tibial fixation devices. ",0
3425,17986904,The influence of carbohydrate-electrolyte ingestion on soccer skill performance,"To investigate the effect of ingesting a carbohydrate-electrolyte solution (CHO-E), in subjects with reduced carbohydrate stores, during an intermittent shuttle running test (LIST) on soccer passing (LSPT) and shooting (LSST) performance. Sixteen healthy male university soccer players ingested either a 6.4% CHO-E or placebo (PLA) solution during 90 min of the LIST (5 mL x kg(-1) BM before and 2 mL x kg(-1) BM every 15 min of exercise), in a double-blind, randomized, crossover design, with each trial separated by at least 7 d. On the evening before the main trial (17:00 h), subjects performed the glycogen-reducing cycling exercise (approximately 80 min at 70% VO2max). They were then fed a low-carbohydrate evening meal and reported to the laboratory the following morning after a 10-h fast. Blood was collected at rest and after every 30 min of exercise; skill tests were performed before and after the LIST. The change in mean LSST performance from pre- to post-LIST was better in the CHO-E trial (11 +/- 45 vs -16 +/- 42%; P < 0.01) but not significantly different for the LSPT performance (-1 +/- 10% (CHO-E) vs -6 +/- 13% (PLA), P = 0.13). Sprint performance during the LIST was quicker in the CHO-E trial (2.50 +/- 0.13 vs 2.53 +/- 0.13 s, P < 0.01). Plasma glucose was higher in the CHO-E trial after 90 min of exercise (5.2 +/- 0.3 vs 3.9 +/- 0.4 mM, P < 0.01). Ingestion of a carbohydrate-electrolyte solution during exercise enabled subjects with compromised glycogen stores to better maintain skill and sprint performance than when ingesting fluid alone. ",0
3426,17986968,"""""""Towards a Better Life"""": a program of comprehensive rehabilitation for elderly patients following revision hip arthroplasty""","""Introduction. The aim of the research was to evaluate the quality of life of patients recovering from revision hip arthroplasty, who underwent rehabilitation under the """"Towards a Better Life"""" program (TBL). In the TBL Program, appropriate physical exercises, relaxation techniques, seminars, and panel discussions are combined to support general improvement in both physical and psychological condition, thus improving the patients' quality of live.<br /> Material and methods. The effectiveness of the TBL approach was evaluated in a clinical experiment involving 36 patients recovering from revision hip arthroplasty, treated under the standard rehabilitation program in general use at the centers represented by the authors. The patients were divided into two equal groups, matched by age and sex: an experimental group E (n = 18), with patients who received additionally the """"Towards a Better Life"""" Program, and a control group K (n = 18), consisting of patients who did not receive this program. The methods used to evaluate the outcome of rehabilitation included clinical interview and observation, the Medical Outcomes Study (MOS-100) and the Self-Evaluating Quality of Life Scale (QOL). The patients were tested before rehabilitation commenced and re-tested two months later.<br /> Analysis of results. On the Physical Index of the MOS-100 scale considerably greater progress was observed in patients from Group E in terms of reduced pain, increased coordination and fluency of movement, improved respiratory capacity, regulation of blood pressure and pulse, functioning of the digestive system, reduced body weight, and improved walking distance. In this group somewhat greater improvements were noted on the Psychological Index of the MOS-100, especially in cognitive functions (perception and attention) and emotional factors (increased satisfaction with life, reduced anexiety, depression, and irritability). The QOL parameters most sensitive to the difference between the TBL Program and the standard program were pain management, independence and self-care, and especially improved self-image and reduced anxiety. The improvements noted by Group E were in many subtest two or three times higher than in Group K.<br /> Conclusions. The greater improvements recorder by patients participating in the """"Towards a Better Life"""" Program in all measured parameters indicates that the program is highly effective in comparison to the standard model. The patients from Group E were much more satisfied with the results they had achieved in rehabilitation, and attained a higher degree of independence and self-determination. The TBL Program can be used to improve the quality of life of patients recovering from revision hip arthroplasty. """,0
3427,17987318,Post-embryonic pericardial cells of Drosophila are required for overcoming toxic stress but not for cardiac function or adult development,"The Drosophila heart is composed of two cell types: cardioblasts (CB) and pericardial cells (PC). Whereas CBs act to maintain rhythmic contractions, the functions of accessory PCs are not clear. The close association between these two cell types has led to speculation of a cardio-regulatory role for PCs. However, we find that viability and cardiac function are normal in larvae following post-embryonic ablation of PCs by induced cell death. Removal of PCs during the larval instars or before metamorphosis results in viable and fertile adults. Interestingly, such animals have a reduced lifespan and increased sensitivity to toxic chemicals. Thus, although PCs may have an embryonic role in cardiogenesis, they do not appear to play a part later in cardiac function as suggested. However, the role of PCs in the uptake and sequestering of toxins, their sensitivity to toxic stress and the decreased lifespan of animals without PCs indicate the importance of PCs in organismal homeostasis. ",0
3428,17987360,Specific pharmacokinetic interaction between lumefantrine and monodesbutyl-benflumetol in Plasmodium falciparum,"The blood schizontocidal activity of lumefantrine, monodesbutyl-benflumetol (DBB) and a 999:1 combination of both compounds has been investigated in 26 fresh isolates of Plasmodium falciparum from northwestern Thailand, using the WHO standard protocol Mark II for determining the inhibition of schizont maturation. The geometric mean cut-off concentrations of schizont maturation (GMCOC) were 943.2 nM for lumefantrine, 146.3 nM for DBB and 182.2 nM for the 999:1 combination of lumefantrine and DBB. The EC(50) values were 27.3 nM for lumefantrine, 5.7 nM for DBB, and 16.5 nM for the combination, and the EC(90) values 163.1 nM for lumefantrine, 44.1 nM for DBB, and 78.3 nM for the combination. Despite the very low concentration in the combination, DBB exerted significant synergistic activity with lumefantrine that was strongest at the EC(90) and EC(99) levels. Correlation analysis indicates that DBB is the leading determinant for the activity of the combination. ",0
3429,17987750,Clinical and microbiological efficacy of MDT in the treatment of diabetic foot ulcers,"To assess the clinical and microbiological efficacy of maggot debridement therapy (MDT) in the management of diabetic foot ulcers unresponsive to conventional treatment and surgical intervention. Consecutive diabetic patients with foot wounds presenting at the vascular surgery unit and the diabetic foot unit of Alexandria Main University Hospital were selected for MDT. Lucilia sericata medicinal maggots were applied to the ulcers for three days per week. Changes in the percentage of necrotic tissue and ulcer surface area were recorded each week over the 12-week follow-up period. Semiquantitative swab technique was used to determine the bacterial load before and after MDT. The sample comprised 10 patients with 13 diabetic foot ulcers. The mean baseline ulcer surface area was 23.5cm2 (range 1.3-63.1), and the mean percentage of necrotic tissue was 74.9% (range 29.9-100). Complete debridement was achieved in all ulcers in a mean of 1.9 weeks (range 1-4). Five ulcers (38.5%) were completely debrided with one three-day MDT cycle. The mean reduction in ulcer size was significant at 90.2%, and this occurred in a mean of 8.1 weeks (range 2-12). The mean weekly reduction in ulcer size was 16.1% (range 8.3-50). Full wound healing occurred in 11 ulcers (84.6%) within a mean of 7.3 weeks (range 2-10). The bacterial load of all ulcers reduced sharply after the first MDT cycle to below the 10(5) threshold, which facilitates healing. The results highlight the potential benefits of MDT in diabetic wound care in developing countries. MDT was proved to be a rapid, simple and efficient method of treating these ulcers. ",0
3430,17987802,Reactive oxygen species damaged human serum albumin in patients with hepatocellular carcinoma,"The role of reactive oxygen species (ROS) damaged human serum albumin (HSA) in hepatocellular carcinoma (HCC) has been investigated in the present study. HSA was modified by hydroxyl radical. Modification occurred in HSA was characterized by physico-chemical techniques. ROS modified HSA was found to be highly immunogenic in rabbits. The binding characteristics of circulating antibodies in HCC patients against native and ROS-modified HSA were assessed. HCC patients (n = 31) were examined by direct binding ELISA and their results were compared with healthy age-matched controls (n = 22). High degree of specific binding by 77.4% of HCC sera towards ROS-HSA, in comparison to its native analogue (p < 0.05) was observed. Competitive ELISA reiterates the direct binding results. Gel retardation assay further substantiated the enhanced recognition of ROS-HSA by circulating antibodies in HCC patients. The increase in total serum protein carbonyl levels in the HCC patients was largely due to an increase in oxidized albumin. Purified HSA of HCC patients (HCC-HSA) contained higher levels of carbonyls than HSA of normal subjects (normal-HSA) (p < 0.01). HCC-HSA was conformationally altered, with more exposure of its hydrophobic regions. Collectively, the oxidation of plasma proteins, especially HSA, might enhance oxidative stress in HCC patients. ",0
3431,17988007,Functional indicators for assessing zinc deficiency,"Zinc is an essential micronutrient for growth and proper immune function. There is currently no simple recommendation for the assessment of population-level zinc deficiency. Trials of zinc supplementation have shown positive effects of supplementation on clinical outcomes and growth. We reviewed the results of randomized trials of zinc supplementation and correlation studies that assessed infectious diseases, growth, and development outcomes among children under 5 years of age. The results indicate that zinc supplementation decreases the incidence and prevalence of diarrhea and pneumonia, but the use of trial data to make population-level estimates of zinc deficiency is not practical and is difficult to quantify. The data also indicate that zinc supplementation increases growth, especially among children who are stunted. Stunting rates are commonly estimated and can be used to estimate zinc deficiency. Previous recommendations suggest that stunting rates at or above 20% should be indicative of zinc deficiency among children under 5 years of age. This review provides additional data and analysis to support the current recommendation. ",0
3432,17988297,Chronic lymphoid leukaemia: clinico-haematological correlation and outcome in a single institution in Niger Delta region of Nigeria,"Sixty patients were prospectively studied with the aim of analyzing the clinical and laboratory features and outcome of patients diagnosed with chronic lymphocytic leukaemia (CLL) in a major referral center in Niger Delta region of Nigeria for 10 years (1995-2005). The peripheral blood, bone marrow cytology, clinical features and stage at diagnosis were studied. Treatment modalities, response to treatment and survival outcome of the patients were analysed. Sixty patients (15 men and 45 women) were seen, with female preponderance (M : F ratio,1 : 3). The CLL incidence was 36.4% of total leukaemias. The median age was 56 years with peak age group at 51-60 years while 15% were below 40 years. Major clinical findings include lymphadenopathy (91.7%), anaemia (58.3%), abdominal swelling (58.3%), and splenomegaly (50%) with 53 patients (88.3%) presenting as International (Binet) stage B and C while only seven patients (11.7%) were seen in stage A. The least clinical presentation includes Richter's syndrome in 3.3% of cases and herpes Zoster skin manifestations in two patients (3.3%). There was a strong association between the blood counts at diagnosis and outcome of therapy. The 2-year survival for young (<55 years) and older (>55 years) CLL patients was 27.2% and 28.9%, respectively, which is still very poor because of a number of strong limiting factors. CLL is not rare in Southern Nigeria and its presentations are similar to cases seen worldwide. Contrary to existing literature a female predominance was observed in this study with majority of patients seeking medical intervention late. It is therefore recommended that future research into the genetic make up/HLA typing of patients of African descent is needed to clarify some of the differences observed. ",0
3433,17988531,The study of vascular lesion using ultrasound in children with a history of Kawasaki disease],"To explore the endothelial function, carotid artery stiffness index and carotid intima-media thickness in children with a history of Kawasaki disease (KD). A cohort of 204 children was studied, which comprised 51 patients with Kawasaki disease with coronary artery lesion (CAL group), 50 patients with Kawasaki disease with normal coronary arteries (normal coronary arteries group), and 103 healthy age matched children (control group). Their systemic blood pressure, fasting cholesterol concentrations, flow-mediated dilation (FMD) of the brachial artery, carotid artery stiffness index and carotid intima-media thickness (IMT) were compared. FMD of the brachial artery in CAL group (5.2% +/- 1.9%) and normal coronary arteries group (6.8% +/- 2.0%) were significantly lower than that of control group (13.2% +/- 4.1%, both P < 0. 01); carotid artery stiffness index in CAL group (4.0 +/- 0.6) was significantly greater than that of normal coronary arteries group (3.6 +/- 0.6) and control group (3.4 +/- 0.5, P = 0.05, P < 0.01); likewise, IMT in CAL group (0.447 mm +/- 0.024 mm) was significantly higher than that of normal coronary arteries group (0.426 mm +/- 0.016 mm) and control group (0.424 mm +/- 0.016 mm, both P < 0.01). In multiple linear regression analysis, age and patient grouping were significant determinants of carotid artery stiffness index, FMD and IMT. There were significant correlations between carotid artery stiffness index, FMD and IMT in both healthy group and KD group after adjustment of age. There were endothelial dysfunction and increased systemic arterial stiffness and IMT late after the acute phase of Kawasaki disease. flow-mediated dilation of the brachial artery, carotid artery stiffness index combined carotid intima-media thickness can evaluated completely the prognosis of vascular lesion in convalescence after KD. ",0
3434,17988576,The effect of PPS on location of rBCG in bladder cancer cell line T24],"To investigate the effect of polyporus polysaccharide (PPS) on location of green fluorescent recombinant protein BCG in human bladder cancer cell line T24. A green fluorescent protein expressed with rBCG was used as reporter gene, and laser scanning confocal microscopy and flow cytometry(FCM) analysis were performed to examine the alteration of T24 cells stimulated with rBCG or rBCG plus PPS. Green fluorescence (86.335+/-5.856) was observed obviously in the cytoplasm of T24 cells after interaction with rBCG for 24 h. By FCM we found scatter dot signal in SS and FS channel from rBCG groups was stronger that a control at 24 h and 48 h respectively. Meanwhile the population of T24 cells deflected to upper right and the percentage of GFP(+) T24 cells detected in FL1 channel was (8.7+/-1.572)%, (13.8+/-2.31)% (P<0.05 compared to the control) respectively. For rBCG plus PPS groups, the fluorescence intensity increased in the nucleus (72.603+/-1.165), while decreased in the cytoplasm (93.06+/-0.958), thus the nucleus/plasm ratio increased (0.78+/-0.005). Compared to rBCG group (62.832+/-2.909, 105.306+/-6.393, 0.597+/-0.012), the difference was statistically significant (P<0.05). rBCG is able to enter directly into the cytoplasm of T24 cells. ",0
3435,17988613,Prevalence of delirium in patients admitted because of medical conditions],"Delirium is a common problem among people during hospitalization. The aim of the study was to analyze the prevalence and characteristics of delirium among patients admitted by medical conditions. We performed a transversal cohort study in 165 patients admitted to 6 tertiary teaching hospitals. We scored the Barthel index (BI) previously to their admission, and also comorbidity using the Charlson index. Diagnosis of delirium was assessed using the Confusional Assessment Method in this transversal study. There were 101 women (61.2%) and 64 men. The mean (SD) age was 80.3 (12) years. The average of Charlson Index was 2.6 (1.7). Previous and evaluation BI were 71.5 (27) and 40.3 (30) respectively. Forty-two patients (25.4%) had delirium. Poor BI at the evaluation and previous diagnosis of dementia were significant independent variables associated with delirium in the logistic regression analysis. Delirium is frequent in medical hospitalized patients. Previous dementia and low BI at the evaluation among medical patients are associated with delirium. ",0
3436,17988904,Effect of proximal arterial occlusion on the progression of the distal arterial disease,"To test the hypothesis that a proximal arterial occlusion has a protective effect on the progression of distal arterial disease, assessed by distal runoff resistance score (DRRS). One hundred and nineteen patients (median age 64 y, male 96%) with a unilateral iliac and/or femoral arterial occlusion caused by atherosclerosis were analyzed retrospectively. DRRS was assessed on arteriograms of the test limb (with proximal arterial occlusion) and control limb (contralateral limb). Multivariate analysis was performed to determine if a proximal arterial occlusion was an independent risk factor for the development of a difference in the DRRS between the test and control limbs. The clinical features of the subjects were claudication in 85%, ankle brachial index 0.52 (median), diabetes in 30% and smoker in 76%. The upper leg DRRS of the test limb was significantly lower in the iliac occlusion group than in the control limb (1.87+/-1.69 vs 2.85+/-2.75, p=0.032). However, multivariate analysis failed to identify any risk factors associated with the difference in DRRS in both limbs. There was no evidence that a proximal arterial occlusion was associated with a slower progression of distal arterial disease. ",0
3437,17989117,Validation and comparison of reference equations for the 6-min walk distance test,"Exercise impairment as measured by the 6-min walk distance (6MWD) test afflicts many patients with chronic obstructive pulmonary disease (COPD) and is known to predict mortality. Reference equations for the 6MWD in adults have been published but not yet validated. The present authors prospectively followed 1,379 COPD patients for 55+/-30 months and tested the predictive value of the baseline 6MWD in metres, the 6MWD work (kg.m(-1)) and as a percentage of predicted values the 6MWD in meters according to two reference equations. All-cause mortality was the validating outcome. The best threshold values were identified for each of the tests using receiver operating characteristic (ROC) curves. The threshold values obtained were: 350 m for the 6MWD, 25,000 kg.m(-1) for the 6MWD work, and 67 and 54% predicted for the two reference equations. All modalities of the testing were similar at predicting COPD mortality and correlated well with the 6MWD test. In conclusion, all modalities of testing predict mortality in chronic obstructive pulmonary disease equally well. In the 6-min walk distance test, a value <350 m is associated with increased mortality and should be regarded as abnormal. ",0
3438,17989126,Preoperative management of the pheochromocytoma patient,"Pheochromocytomas are rare neuroendocrine tumors with a highly variable clinical presentation, but they most commonly present as spells of headaches, sweating, palpitations, and hypertension. Patients with pheochromocytoma may develop complicated and potentially lethal cardiovascular and other complications, especially in the setting of diagnostic or interventional procedures (e.g. upon induction of anesthesia or during surgery). The serious and potentially lethal nature of such complications is due to the potent effect of paroxysmal release of catecholamines. Because this warrants prompt diagnosis and treatment, the physician should be aware of the clinical manifestations and complications of catecholamine excess and be able to provide proper preoperative management to minimize catecholamine-related pre-, intra-, and postoperative adverse events. The following clinical scenario and discussion aim to enhance the knowledge of the physician regarding the behavior of pheochromocytoma and to outline current approaches to comprehensive preoperative management of patients suffering from this tumor. ",0
3439,17989131,The economic impact of clean indoor air laws,"Clean indoor air laws are easily implemented, are well accepted by the public, reduce nonsmoker exposure to secondhand smoke, and contribute to a reduction in overall cigarette consumption. There are currently thousands of clean indoor air laws throughout the Unites States, and the majority of Americans live in areas where smoking is completely prohibited in workplaces, restaurants, or bars. The vast majority of scientific evidence indicates that there is no negative economic impact of clean indoor air policies, with many studies finding that there may be some positive effects on local businesses. This is despite the fact that tobacco industry-sponsored research has attempted to create fears to the contrary. Further progress in the diffusion of clean indoor air laws will depend on the continued documentation of the economic impact of clean indoor air laws, particularly within the hospitality industry. This article reviews the spread of clean indoor air laws, the effect on public health, and the scientific evidence of the economic impact of implementation of clean indoor air laws. ",0
3440,17989182,Nucleolar targeting of hepatitis delta antigen abolishes its ability to initiate viral antigenomic RNA replication,"Hepatitis delta virus (HDV) is a small RNA virus that contains one 1.7-kb single-stranded circular RNA of negative polarity. The HDV particle also contains two isoforms of hepatitis delta antigen (HDAg), small (SHDAg) and large HDAg. SHDAg is required for the replication of HDV, which is presumably carried out by host RNA-dependent RNA polymerases. The localization and the HDAg and host RNA polymerase responsible for HDV replication remain important issues to be addressed. In this study, using recombinant SHDAg fused with a heterologous nucleolar localization sequence (NoLS) to confine its subcellular localization in nucleoli, we aimed to study the effect of SHDAg subcellular localization on HDV RNA replication. The initiation of genomic RNA synthesis from antigenomic template was hardly detectable when SHDAg was fused with the NoLS motif and localized mainly in nucleoli. In contrast, the initiation of antigenomic RNA synthesis was not affected. Drug treatment to release a SHDAg-NoLS mutant from nucleoli could partially restore the replication of HDV genomic RNA from antigenomic RNA. This also recovered the cointeraction between SHDAg and RNA polymerase II. These data strongly suggest that nuclear polymerase (RNA polymerase II) is involved in the synthesis of genomic RNA and that the synthesis of antigenomic RNA can occur in nucleoli. Our results support the idea that the replication of HDV genomic RNA or antigenomic RNA is likely to be carried out by different machineries in different subcellular localizations. ",0
3441,17989550,The impact of new-generation physicians on the function of academic anesthesiology departments,"Academic departments of anesthesiology have had to adapt a wide variety of clinical and educational work functions to the viewpoints, values and normative expectations of the newer generations of physicians who now present themselves for training as well as for faculty employment. This commentary will elaborate on key points that academic departments must recognize and incorporate into their functional and organizational imperatives in order to remain successful with regard to physician recruitment and retention. Recognition of differences between newer-generation vs. established physician issues and concerns include differences in: learning style, teaching style, approach to clinical schedules and the concept of life-work balance, academic and personal motivation, desire for control of their work experience, effective productivity incentives, as well as communication style issues and implications thereof. The spectrum of physicians who contribute to the impact of these factors on contemporary academic anesthesiology departments include faculty, nonfaculty staff physicians, residents and medical students. Academic departments of anesthesiology which can successfully incorporate the changes and most importantly the functional and organizational flexibility needed to respond to the newer generations' worldview and so-called balanced goals will be able to best attract high-caliber housestaff and future faculty. ",0
3442,17989578,Tactile dysgeusia: a new clinical observation of middle ear and skull base surgery,"""To describe a new clinical observation of """"tactile dysgeusia,"""" a phenomenon associated with otologic and skull base surgery likely caused by injury to the chorda tympani nerve (CTN) or the nervus intermedius (NI) with subsequent aberrant cross-innervation with somatosensory fibers in the surgical field. Descriptive case series. Tertiary university referral center. Eight patients described a sensation of touch-evoked dysgeusia after surgery. Seven patients underwent a variety of middle ear procedures including stapedotomies and mastoidectomies. One patient had a large cerebellopontine angle meningioma excised through a translabyrinthine approach. There were no preoperatively sensory symptoms of any kind. In five of seven patients who had an otologic procedure, the CTN nerve was transected, whereas in the remaining two, the nerve was preserved but stretched. In the meningioma patient, the facial nerve was preserved without clear identification of the NI; the facial nerve function was normal postoperatively. All of the otologic patients experienced symptoms of dysgeusia and sensory alteration triggered by touching various parts of the outer ear. One also has a secondary trigger in the V2 dermatome. In the meningioma patient, taste and sensory alteration was induced by stimulating the ipsilateral V2 and V3 dermatome. In all patients, the symptom was located in the lateral aspect of the ipsilateral hemitongue. Tactile dysgeusia is an unusual complication after otologic and neurotologic procedures. It is likely related to aberrant re-innervation of the special sensory fibers within the CTN nerve or the NI with somatosensory fibers. Postoperative """"tactile dysgeusia"""" may not be so rare; its true incidence could only be ascertained through a more rigorous postoperative assessment. """,0
3443,17990212,Acute resistance exercise reduces heart rate complexity and increases QTc interval,"Acute resistance exercise (RE) has been shown to reduce cardiac vagal control. Whether this would in turn affect QTc interval (an index of ventricular depolarization/repolarization) or heart rate complexity is not known. Heart rate variability (HRV), heart rate complexity (SampEn), and QT interval (rate corrected using Bazett, Fridericia, Hodges, and Framingham) were measured before and 5 min after an acute RE bout in twelve healthy young men. Normalized high frequency power of HRV (an index of cardiac parasympathetic modulation; HF (nu)), and SampEn were reduced following RE (p < 0.05). Bazett corrected QTc interval increased following RE (p < 0.05). Change in HF (nu) from rest to recovery was correlated with both change in SampEn (r = 0.51, p < 0.05) and change in QTc interval for each method of correction (r = - 0.67 to - 0.70, p < 0.05). Acute RE reduced HF spectral power of HRV and this was related to both reduced heart rate complexity and increased QTc length. Thus, during recovery from acute RE, there is prolongation of depolarization and repolarization of the ventricles concomitant with reduced cardiac irregularity, and this may be related to a reduction in cardiac vagal control. ",0
3444,17990308,Modulation of astrocyte P2Y1 receptors by the carboxyl terminal domain of the gap junction protein Cx43,"Gap junction proteins, connexins, provide intercellular channels that allow ions and small signaling molecules to be transmitted to adjacent coupled cells. Besides this function, it is becoming apparent that connexins also exert channel-independent effects, which are likely mediated by processes involving protein-protein interactions. Although a number of connexin interacting proteins have been identified, only little is known about the functional consequences of such interactions. We have previously shown that deletion of the astrocytic gap junction protein, connexin43 (Cx43) causes a right-ward shift in the dose-response curve to P2Y1R agonists and decreased P2Y1R expression levels. To evaluate whether these changes were due to reduced gap junctional communication or to protein-protein interactions, Cx43-null astrocytes were transfected with full-length Cx43 and Cx43 domains, and P2Y1R function and expression levels evaluated. Results indicate that restoration of P2Y1R function is independent of gap junctional communication and that the Cx43 carboxyl terminus spanning the SH3 binding domain (260-280) participates in the rescue of P2Y1R pharmacological behavior (shifting to the left the P2Y1R dose-response curve) without affecting its expression levels. These results suggest that the Cx43 carboxyl-terminus domain provides a binding site for an intracellular molecule, most likely a member of the c-Src tyrosine kinase family, which affects P2Y1R-induced calcium mobilization. It is here proposed that a nonchannel function of Cx43 is to serve as a decoy for such kinases. Such modulation of P2Y1R is expected to influence several neural cell functions, especially under inflammation and neurodegenerative disorders where expression levels of Cx43 are decreased. ",0
3445,17990468,Clinical efficacy of Bannaitong Mdicinal Tea combined with azasetron in preventing and treating chemotherapy induced gastrointestinal reaction],"To observe the effects of Biannaitong Medicinal Tea (BNT) combined with Azasetron in preventing and treating the gastrointestinal reaction induced by chemotherapy. Sixty-four patients underwent chemotherapy with DP regimen (docetaxol + DDP) were randomly assigned to two groups, the treated group and the control group. All patients were given 10 mg Azasetron intravenously 30 min before starting chemotherapy once a day for two successive days, but to patients in the treated group, 300 mL BNT was given orally additionally in the evenings before chemotherapy. The occurrence of adverse reactions, such as antiemetic efficacy constipation, abdominal distention, etc. was observed. The vomiting control rates in the two groups were insignificantly different (87.5% vs 84.4%, P > 0.05), but difference in the complete control rates between them were significant (53.1% vs 43.8% , P < 0.05). And the occurrences of constipation (3.1% vs 59.4%) and abdominal distention (15.6% vs 59.4%) in the two groups were also significantly different (both P <0.05). BNT used in coordination with Azasetron for alleviating vomiting could enhance the antiemetic effect, reduce the adverse effects of chemotherapy, such as constipation, abdominal distension and anorexia, and thus to increase the compliance of patients. ",0
3446,17990492,Metabolic flux profiling of reaction modules in liver drug transformation,"With appropriate models, the metabolic profile of a biological system may be interrogated to obtain both significant discriminatory markers as well as mechanistic insight into the observed phenotype. One promising application is the analysis of drug toxicity, where a single chemical triggers multiple responses across cellular metabolism. Here, we describe a modeling framework whereby metabolite measurements are used to investigate the interactions between specialized cell functions through a metabolic reaction network. As a model system, we studied the hepatic transformation of troglitazone (TGZ), an antidiabetic drug withdrawn due to idiosyncratic hepatotoxicity. Results point to a well-defined TGZ transformation module that connects to other major pathways in the hepatocyte via amino acids and their derivatives. The quantitative significance of these connections depended on the nutritional state and the availability of the sulfur containing amino acids. ",0
3447,17991101,Emergency embolization of multiple splenic artery pseudoaneurysms associated with portal hypertension complicating cystic fibrosis,"Cystic fibrosis (CF) is the most common potentially lethal genetic disease in the white population. Improvements in life expectancy have led to an increasing recognition of hepatobiliary complications from CF. Splenic artery aneurysms are a rare complication of portal hypertension with a high mortality due to their significant potential for rupture, resulting in life-threatening i.p. haemorrhage. The optimum treatment of ruptured splenic artery aneurysms is controversial. This case describes the successful emergency embolization of multiple splenic artery pseudoaneurysms associated with portal hypertension complicating cystic fibrosis. ",0
3448,17991135,Impaired glucose tolerance and risk factors for progression to type 2 diabetes in youth,"Impaired glucose tolerance and impaired fasting glucose represent two potentially reversible prediabetes conditions. Previous reports from various regions across the globe indicate that both conditions may be relatively common in obese children and adolescents. The major factor driving the development of compromised glucose metabolism in obese youth is severe insulin resistance. This severe insulin resistance has been strongly associated with specific patterns of lipid partitioning. Severe obesity along with continued weight gain, specifically in obese youth belonging to ethnic minorities, have been shown to be associated with deterioration of glucose tolerance over short periods of time. As obesity-related insulin resistance in the pediatric age-group is associated with the development of altered glucose metabolism and other elements of the metabolic syndrome, severely obese youth are a high-risk group for the development of type 2 diabetes and may benefit most from preventive interventions such as environmental changes that promote increased physical activity. ",0
3449,17991332,Application of amorphous silicon electronic portal imaging device (a-Si EPID) to dosimetry quality assurance of radiation therapy],"""Due to its good dosimetric properties, amorphous silicon electronic portal imaging device (a-Si EPID), as a rapid two-dimensional dosimetric measurement device, presents an attractive prospect in routine quality assurance (QA) test, dosimetric verification of intensity-modulated radiotherapy treatment (IMRT) and in vivo dose monitoring. This study was to explore the application of a-Si EPID as a detector for dosimetric QA of linear accelerator radiotherapy, and setup the calibration module. The imaging calibration procedure of conventional a-Si EPID was modified for dosimetric measurement by acquiring the traditional """"flush field"""" from integrated subfields to correct the dosimetric responding difference in pixel sensitivity. The energy dependence of the a-Si EPID detectors was analyzed through off-axis dose response curves. Calibrated dose profile obtained with a-Si EPID was compared with the measuring results of ion chamber in a 3-D water phantom. The calibrated dose profiles measured with a-Si EPID showed a deviation within 2% in high dose regions, but dropped much steeply in the penumbra region, as compared with that scanned using ion chamber in water. With the modeling management set up in this research, a-Si EPID can be applied for dosimetric QA of linear accelerator in radiotherapy. """,0
3450,17991484,Development of a new antibody to the human inhibin/activin betaB subunit and its application to improved inhibin B ELISAs,"Inhibin B has emerged as a clinically useful analyte for studies of reproductive function in both men and women. The antibody to the betaB subunit (C5) used in current commercially available assays (DSL and OBI) was raised in this laboratory to a synthetic peptide from the betaB subunit. These assays require pre-treatment of samples with hydrogen peroxide to oxidise two methionines in the epitope to the sulfoxide for full immunoreactivity. It was also claimed that this antibody cross-reacted significantly with inhibin A leading to a 0.5% cross-reaction of inhibin A in the current generation of immunoassays. Both of the above immunoassays required overnight incubation with sample. The development of improved antibodies to the betaB subunit has proved difficult due to the conservation of the betaB subunit between species. We describe the development of new monoclonal antibodies to the betaB subunit, by immunisation of mice with recombinant X. laevis activin B using the RIMMS method of immunisation. The result has been the development of highly specific antibodies in a short time period. One of these antibodies 46A/F is shown to be a highly effective capture antibody in a human inhibin B ELISA, without any sample pre-treatment. The results of the validation of an improved inhibin B assay using 46A/F as the capture antibody are shown, with comparison to one of the commercially available inhibin B assays. Overall, the inhibin B assay is simplified and the performance improved by using this new antibody 46A/F. It was further shown that the cross-reaction of inhibin A in both the OBI and DSL inhibin B ELISAs is ten fold less than previously reported. This can be attributed to the poor quality of recombinant inhibin B available for use as standard in 1996. Although the present generation of inhibin B assays has proved adequate to enable the physiological function of inhibin to be determined and novel clinical applications found, the simplification of the assay made possible by the improved antibody should make possible a new generation of more rapid, sensitive, convenient and robust tools for routine use. ",0
3451,17991623,The impact of acute urinary morbidity on late urinary function after permanent prostate brachytherapy,"Acute prostate brachytherapy-related morbidity is dominated by urinary symptomatology. In this study, we evaluated the effect of severe early brachytherapy-related urinary morbidity on late urinary function. From January 1998 to September 2003, 1029 patients were implanted for clinical stage T1b-T3a (2002 American Joint Committee on Cancer [AJCC] criteria) prostate cancer. Five hundred sixteen (50.1%) received supplemental external beam radiation therapy and 440 (42.8%) received androgen deprivation therapy. Severe acute urinary morbidity (SAUM) was defined as a dysuria frequency score of at least 4 (of 5), a dysuria severity score of at least 8 (of 10), an internation prostate symptom score (IPSS) elevated to at least 30 or 15 above preimplant value for 4 weeks, and/or requirement of a urinary catheter for at least 5 days. Dysuria severity and frequency resolution were defined as a return to within one point of baseline. IPSS resolution was defined as a return to within two points of baseline. Of the 1029 patients, 175 met at least one of the criteria for inclusion. Dysuria frequency resolved in 5.0 vs. 1.3 weeks and dysuria severity in 5.7 vs. 1.4 weeks, for patients with and without SAUM. The mean time for IPSS resolution was 13.8 vs. 6.6 weeks, for patients with and without SAUM. The incidence of transurethral resection (2.3% [4/173] vs. 1.5% [13/841]) and bulbomembranous urethral strictures (2.2% [4/175] vs. 1.8% [15/854]) were comparable among patients with and without SAUM. Patients experiencing brachytherapy-related SAUM have long-term urinary function and complications comparable to patients who did not develop SAUM. ",0
3452,17991880,Astrocyte-derived CO is a diffusible messenger that mediates glutamate-induced cerebral arteriolar dilation by activating smooth muscle Cell KCa channels,"Astrocyte signals can modulate arteriolar tone, contributing to regulation of cerebral blood flow, but specific intercellular communication mechanisms are unclear. Here we used isolated cerebral arteriole myocytes, astrocytes, and brain slices to investigate whether carbon monoxide (CO) generated by the enzyme heme oxygenase (HO) acts as an astrocyte-to-myocyte gasotransmitter in the brain. Glutamate stimulated CO production by astrocytes with intact HO-2, but not those genetically deficient in HO-2. Glutamate activated transient K(Ca) currents and single K(Ca) channels in myocytes that were in contact with astrocytes, but did not affect K(Ca) channel activity in myocytes that were alone. Pretreatment of astrocytes with chromium mesoporphyrin (CrMP), a HO inhibitor, or genetic ablation of HO-2 prevented glutamate-induced activation of myocyte transient K(Ca) currents and K(Ca) channels. Glutamate decreased arteriole myocyte intracellular Ca2+ concentration and dilated brain slice arterioles and this decrease and dilation were blocked by CrMP. Brain slice arteriole dilation to glutamate was also blocked by L-2-alpha aminoadipic acid, a selective astrocyte toxin, and paxilline, a K(Ca) channel blocker. These data indicate that an astrocytic signal, notably HO-2-derived CO, is used by glutamate to stimulate arteriole myocyte K(Ca) channels and dilate cerebral arterioles. Our study explains the astrocyte and HO dependence of glutamatergic functional hyperemia observed in the newborn cerebrovascular circulation in vivo. ",0
3453,17992543,"Iron-sulfur protein folds, iron-sulfur chemistry, and evolution","An inventory of unique local protein folds around Fe-S clusters has been derived from the analysis of protein structure databases. Nearly 50 such folds have been identified, and over 90% of them harbor low-potential [2Fe-2S](2+,+) or [4Fe-4S](2+,+) clusters. In contrast, high-potential Fe-S clusters, notwithstanding their structural diversity, occur in only three different protein folds. These observations suggest that the extant population of Fe-S protein folds has to a large extent been shaped in the reducing iron- and sulfur-rich environment that is believed to have predominated on this planet until approximately two billion years ago. High-potential active sites are then surmised to be rarer because they emerged later, in a more oxidizing biosphere, in conditions where iron and sulfide had become poorly available, Fe-S clusters were less stable, and in addition faced competition from heme iron and copper active sites. Among the low-potential Fe-S active sites, protein folds hosting [4Fe-4S](2+,+) clusters outnumber those with [2Fe-2S](2+,+) ones by a factor of 3 at least. This is in keeping with the higher chemical stability and versatility of the tetranuclear clusters, compared with the binuclear ones. It is therefore suggested that, at least while novel Fe-S sites are evolving within proteins, the intrinsic chemical stability of the inorganic moiety may be more important than the stabilizing effect of the polypeptide chain. The discovery rate of novel Fe-S-containing protein folds underwent a sharp increase around 1995, and has remained stable to this day. The current trend suggests that the mapping of the Fe-S fold space is not near completion, in agreement with predictions made for protein folds in general. Altogether, the data collected and analyzed here suggest that the extant structural landscape of Fe-S proteins has been shaped to a large extent by primeval geochemical conditions on one hand, and iron-sulfur chemistry on the other. ",0
3454,17992679,A Gd3+-based magnetic resonance imaging contrast agent sensitive to beta-galactosidase activity utilizing a receptor-induced magnetization enhancement (RIME) phenomenon,"Magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging of opaque organisms. Gadolinium (Gd(3+)) complexes have become important imaging tools as MRI contrast agents for MRI studies, though most of them are nonspecific and report solely on anatomy. Recently, MRI contrast agents have been reported whose ability to relax water protons is triggered or greatly enhanced by recognition of a particular biomolecule. This new class of MRI contrast agents could open up the possibility of reporting on the physiological state or metabolic activity deep within living specimens. One possible strategy for this purpose is to utilize the increase in the longitudinal water proton r(1) relaxivity that occurs upon slowing the molecular rotation of a small paramagnetic complex, a phenomenon which is known as receptor-induced magnetization enhancement (RIME), by either binding to a macromolecule or polymerization of the agent itself. Here we describe the design and synthesis of a novel beta-galactosidase-activated MRI contrast agent, the Gd(3+) complex [Gd-5], by using the RIME approach. beta-Galactosidase is commonly used as a marker gene to monitor gene expression. This newly synthesized compound exhibited a 57% increase in the r(1) relaxivity in phosphate-buffered saline (PBS) with 4.5% w/v human serum albumin (HSA) in the presence of beta-galactosidase. Detailed investigations revealed that RIME is the dominant factor in this increase of the observed r(1) relaxivity, based on analysis of Gd(3+) complexes [Gd-5] and [Gd-8], which is generated from [Gd-5] by the activity of beta-galactosidase, and spectroscopic analysis of their corresponding Tb(3+) complexes, [Tb-5] and [Tb-8]. ",0
3455,17992743,Mining gene-disease relationships from biomedical literature: weighting protein-protein interactions and connectivity measures,"The promises of the post-genome era disease-related discoveries and advances have yet to be fully realized, with many opportunities for discovery hiding in the millions of biomedical papers published since. Public databases give access to data extracted from the literature by teams of experts, but their coverage is often limited and lags behind recent discoveries. We present a computational method that combines data extracted from the literature with data from curated sources in order to uncover possible gene-disease relationships that are not directly stated or were missed by the initial mining. An initial set of genes and proteins is obtained from gene-disease relationships extracted from PubMed abstracts using natural language processing. Interactions involving the corresponding proteins are similarly extracted and integrated with interactions from curated databases (such as BIND and DIP), assigning a confidence measure to each interaction depending on its source. The augmented list of genes and gene products is then ranked combining two scores: one that reflects the strength of the relationship with the initial set of genes and incorporates user-defined weights and another that reflects the importance of the gene in maintaining the connectivity of the network. We applied the method to atherosclerosis to assess its effectiveness. Top-ranked proteins from the method are related to atherosclerosis with accuracy between 0.85 to 1.00 for the top 20 and 0.64 to 0.80 for the top 90 if duplicates are ignored, with 45% of the top 20 and 75% of the top 90 derived by the method, not extracted from text. Thus, though the initial gene set and interactions were automatically extracted from text (and subject to the impreciseness of automatic extraction), their use for further hypothesis generation is valuable given adequate computational analysis. ",0
3456,17993389,Application of organic acid salts and high-pressure treatments to improve the preservation of blood sausage,"Blood sausages are traditional products in many parts of the world. In most cases, a very short shelf-life limits their consumption to the areas in which they are produced. In this work, different mild preservation methods were applied to Morcilla de Burgos, a Spanish blood sausage, consisting of a range of organic acid salts (OAS) and high-pressure processing (HPP), with the aim of increasing its shelf-life. In the first experiment, three batches of morcillas were produced using three different commercial OAS-PL (3% potassium lactate), PL+SL (3% potassium and sodium lactate) and PL+SD (2.5% potassium lactate and sodium diacetate)-together with a control batch and were stored under chill conditions (4 degrees C) for 35 days. In a further experiment, vacuum-packaged morcillas were treated at three different pressure levels-300, 500 and 600MPa-for 10min, and stored under chill conditions for 28 days. In both batches, a sensory difference test was performed on day 1 after treatment and the morcilla samples were subjected to microbiological and sensory analysis after each week in storage. The results suggest that, in both cases, an addition of PL+SL and the application of 600MPa for 10min increases the shelf-life of the morcillas by 15 days. Once again, it is evident that the initial opportunities for contamination play a very important role in improving the shelf-life of food products. ",0
3457,17993775,Influence of sex hormones on brain excitability and epilepsy,"Epilepsy is one of the most common neurologic problems worldwide. In spite of the many studies carried out, our understanding of generalized epileptogenesis remains far from complete. In recent years many data have clarified the effects of sexual hormones on brain excitability. Female and male sexual hormones may be considered pharmacoactive compounds that alter the seizure threshold, changing the frequency and semeiology of the seizures. In particular, estrogens may increase neuronal excitability while progesterone enhances inhibitions and increases the seizure threshold; on the other hand, androgens can decrease ictal activity in the human brain. This review provides an overview of the current knowledge in this field and highlights some of the prevailing hypotheses about the effects of sexual hormones on neuronal excitability analysing data from both animal and clinical studies. ",0
3458,17993984,Rehabilitation of neuromyelitis optica (Devic syndrome): three case reports,"We describe the inpatient clinical rehabilitation course of three patients with neuromyelitis optica (NMO; Devic syndrome). These patients had varying functional deficits. Each patient improved in several functional independence measures (FIM domains) but had minimal to no progress in other domains after acute rehabilitation stays between 1 and 1.5 mos. NMO is a severe central nervous system demyelinating syndrome distinct from MS, characterized by optic neuritis, myelitis, and at least two of three criteria: longitudinally extensive cord lesion, MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity. Persons with NMO may demonstrate improved function with rehabilitation efforts; though gains may be lost to relapse. Future immunomodulatory intervention may augment the benefits of rehabilitation. ",0
3459,17994618,"Combination of ellipsometry, laser scanning microscopy and Z-scan fluorescence correlation spectroscopy elucidating interaction of cryptdin-4 with supported phospholipid bilayers","The present study has two main objectives. The first is to characterize antimicrobial peptide (AMP) cryptdin-4 (Crp-4) interactions with biological membranes and to compare those interactions with those of magainin 2. The second is to combine the complementary experimental approaches of laser scanning microscopy (LSM), ellipsometry, and Z-scan fluorescence correlation spectroscopy (FCS) to acquire comprehensive information on mechanisms of AMP interactions with supported phospholipid bilayers (SPBs)-a popular model of biological membranes. LSM shows appearance of inhomogeneities in spatial distribution of lipids in the bilayer after treatment with Crp-4. Ellipsometric measurements show that binding of Crp-4 does not significantly change the lipid structure of the bilayer (increase in adsorbed mass without a change in thickness of adsorbed layer). Furthermore, Crp-4 slows the lateral diffusion of lipids within the membrane as shown by Z-scan FCS. All changes of the bilayer induced by Crp-4 can be partially reversed by flushing the sample with excess of buffer. Bilayer interactions of magainin 2 are significantly different, causing large loss of lipids and extensive damage to the bilayer. It seems likely that differences in peptide mode of action, readily distinguished using these combined experimental methods, are related to the distinctive beta-sheet and alpha-helical structures of the respective peptides. ",0
3460,17995580,Quantification of renal pathology by image analysis,"Recent advances in computer image analysis techniques allow more accurate quantification of kidney pathological lesions, which are identified by histological staining or immunohistochemistry. This article provides a detailed description of the basic techniques for quantifying these lesions in digital images of light microscopy using Image J software, which is freely available over the Internet. The methods discussed include calibrating measurements, applying scales to images, assessment of object size and thickness, cell counting and point counting, and analysis of area stained. Our explanations indicate how these methods can be used to evaluate glomerular hypertrophy, tubular and vascular injury, accumulation of inflammatory cells and myofibroblasts, deposition of extracellular matrix, and the development of renal scarring. ",0
3461,17995699,"Egg yolk protein and egg yolk phosvitin inhibit calcium, magnesium, and iron absorptions in rats","Egg yolk decreases the absorption of iron. The effects of egg yolk protein and egg yolk phosvitin on the absorption of calcium, magnesium, and iron were investigated by in vivo studies. Male Wistar rats were fed purified diets containing casein, soy protein, or egg yolk protein for 14 d. The apparent absorptions of calcium, magnesium, and iron in the rats fed the yolk protein-based diet were lower than those in rats fed the casein- and soy protein-based diets. The apparent phosphorus absorption and the apparent protein digestibility in the yolk protein group were lower than those in the casein and soy protein groups. In the feces of the yolk protein group, serine comprised more than 30% of the amino acids. The addition of egg yolk phosvitin to the casein diets at levels of 1% and 2% (w/w) produced effects on calcium and magnesium absorptions similar to those produced by the diet containing yolk protein. The tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) pattern suggested that phosphopeptide fragments having molecular masses of 28, 22, and 15 kDa were evident in the contents of the small intestine of the rats fed phosvitin diets. These results indicate that yolk protein, when compared with casein and soy protein, decreases calcium and magnesium absorption via the resistance of phosvitin to proteolytic action. ",0
3462,17995729,"Contribution of the starch, protein, and lipid fractions to the physical, thermal, and structural properties of amaranth (Amaranthus caudatus) flour films","Amaranth protein-lipid (PL) and protein (P) films were elaborated and compared with amaranth flour films in order to determine the contribution of the interactions between the biopolymer (starch and protein) and the lipids to the film properties. The films were made by the casting method, using the same glycerol concentration (0.9 g glycerol/100 g solution). A separation of the lipid fraction in the PL films and a polymorphic transformation of the corresponding fatty acids were observed by differential scanning calorimetry (DSC) and verified by an analysis of the microstructure by scanning electron microscopy (SEM). The flour films showed no separation of the lipid fraction, evidence that the lipids were strongly associated with the proteins and homogenously distributed throughout the starch network, contributing to the good mechanical properties when compared to the PL films and to the excellent barrier properties when compared to both the PL and P films. The protein-protein interactions also contributed to the mechanical properties of the flour films. The presence of proteins and lipids in the flour films had an important effect on film solubility, and also on the color and opacity of the films. This study showed that the flour film properties depended on the interactions formed by their polymers (starches and proteins) and by the lipid, on the distribution of these interactions within the film matrix and on the concentrations of each component in the film. ",0
3463,17995965,"Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo","The immunomodulatory drugs (IMiDs) lenalidomide and actimid (also known as CC-4047) are thalidomide analogues which are more potent than their parental compound. In combination with rituximab, we have previously demonstrated that IMiDs have synergistic in vivo anti-tumour activity in preclinical studies in a human lymphoma severe combined immunodeficiency mouse model. This report further explored the mechanisms by which IMiDs exert their anti-lymphoma effects. Following exposure of subcutaneous lymphoma tumours in murine models to IMiDs, there was a significant increase in the recruitment of natural killer (NK) cells to tumour sites. This increase in NK cells was mediated via stimulation of dendritic cells and modification of the cytokine microenvironment associated with an increase in monocyte chemotactic protein-1, tumour necrosis factor-alpha and interferon-gamma and probably augmented rituximab-associated antibody-dependent cellular cytotoxicity. IMiDs also had significant anti-angiogenic effects in our B-cell lymphoma models. Thus, by modulation of the immune system mediated via dendritic cells and NK cells, changing the cytokine milieu, as well as by their anti-angiogenic effects, IMiDs in combination with rituximab resulted in augmented in vivo anti-tumour effects against B-cell lymphoma. Our positive preclinical data adds additional support for the evaluation of IMiDs plus rituximab in patients with relapsed/refractory B-cell lymphoma. ",0
3464,17996261,Enantioselective production of 3-hydroxy metabolites of tibolone by yeast reduction,"The enantioselective reduction of tibolone into the corresponding 3alpha-hydroxy or 3beta-hydroxy metabolite can be controlled by choosing suited strains of yeasts and biotransformation conditions. A restricted screening performed among 52 yeasts showed that the 3alpha-epimer was preferentially obtained with high epimeric purity with various strains (i.e. with Kluyveromyces lactis CBS 2359), while only Saccharomyces cerevisiae CBS 3093 gave the 3beta-epimer as major product. The reduction of tibolone with K. lactis CBS 2359 and S. cerevisiae CBS 3093 was optimised. S. cerevisiae CBS 3093 furnished a 96:4 ratio of 3beta/3alpha with complete molar conversion within 72h when the initial concentration of substrate was below 2.5g/L. K. lactis CBS 2359 gave a 99:1 ratio of 3alpha/3beta with complete conversion in 64h. ",0
3465,17996423,Effects of ketogenic diet on epileptiform activity in children with therapy resistant epilepsy,"The purpose was to quantify changes of epileptiform activity during ketogenic diet (KD) treatment in children with therapy resistant epilepsy, and evaluate how these changes are related to activity stage and to clinical effects on seizure frequency, seizure severity, attentional behaviour, quality of life (QOL), and beta-hydroxybutyrate (betaOHb). Eighteen children were investigated with 24h ambulatory EEG monitoring 1 week prior to KD initiation and, after 3 months of KD treatment. Epileptiform activity was evaluated by automated spike detection. This data was compared with data presented in a previous study published in Epilepsia 2006, on sleep structure and different activity stages, clinical data on seizure frequency, seizure severity, QOL and attentional behaviour on the same children [Hallbook, T., Lundgren, J., Rosén, I., 2007. Ketogenic diet improves sleep quality in children with therapy resistant epilepsy. Epilepsia 48, 59-65]. After 3 months of KD treatment the number of interictal epileptiform discharges (IEDs) was significantly reduced (p<0.001). When considering the four activity stages separately, the reduction was significant during non-rapid eye movement sleep stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep (p=0.001, 0.001, 0.002), and not significantly so during awake (p=0.07). Beta-hydroxybutyrate was significantly increased (p<0.001). There was a significant correlation between the reduction in IEDs and clinical seizures (Spearman r=0.6, p=0.005) and between improvement in attentional behaviour and the increase in betaOHb (Spearman r=0.5, p=0.03). There was no significant correlation between changes in attentional behaviour and IEDs or clinical seizures. This study shows that KD reduces the number of IEDs, especially during sleep. It shows a correlation between reduction in epileptiform activity and clinical seizures. There were no correlations between reduction in epileptiform activity and clinical seizures and improvement in QOL or attention. The increase in betaOHb correlated with improvement in attention. ",0
3466,17996776,An assessment of the relationship between congenital transverse deficiency of the forearm and symbrachydactyly,"A relationship between symbrachydactyly and transverse deficiency has been suggested but has not been critically investigated or established by scientific studies. The purpose of this investigation was to evaluate a large group of patients with transverse deficiency of the forearm for clinical and radiologic features typically seen in patients with symbrachydactyly. A retrospective review of the medical records of 291 patients with a diagnosis of upper-extremity transverse deficiency at the level of the forearm was performed. Patient charts, photographs, and radiographs were evaluated for manifestations of symbrachydactyly; specifically, we clinically assessed for the presence of nubbins and skin invaginations and radiologically assessed for hypoplasia of the proximal radius and ulna. Two hundred seven patients had soft tissue nubbins at the end of their amputation stumps including 38 with the additional finding of skin invagination at the distal end. Another 36 extremities had a skin invagination alone. Twenty-nine of the extremities without nubbins or skin invaginations had hypoplasia of the proximal radius and ulna. Thus, 272 of the 291 extremities with transverse deficiency had manifestations of symbrachydactyly. The majority of patients with the diagnosis of transverse deficiency have soft tissue nubbins, skin invaginations, or hypoplasia of the proximal radius and ulna at the end of their amputation stumps. These clinical and radiologic features support the concept that transverse deficiency through the forearm represents a proximal continuum of symbrachydactyly. ",0
3467,17997239,Comparison of distortion product otoacoustic emissions in 28 inbred strains of mice,"Cochlear function was evaluated in a longitudinal study of 28 inbred strains of mice at 3 and 5 mo of age using measures of distortion product otoacoustic emissions (DPOAEs) in response to a federal initiative to develop rapid mouse phenotyping methodologies. DP-grams at f(2) frequencies ranging from 6.3 to 54.2kHz were obtained in about 3min/ear by eliciting 2f(1)-f(2) DPOAEs in 0.1-octave steps of f(2) with primary tones at L(1)=L(2) =55, 65, and 75dB SPL. CBA/CaJ mice exhibited average levels of approximately 26dB SPL and this strain was selected as the normal reference strain against which the others were compared. Based upon the configurations of their DP-grams, the 28 mouse strains could be categorized into four distinct groups. That is, nine of the strains including the CBA were designated as the CBA-like group because these mice displayed robust DPOAE levels across frequency. In contrast, the remaining three groups all exhibited irregular DP-gram patterns. Specifically, eight of the remaining 19 strains showed a progressive high- to low-frequency reduction in DPOAE levels that was typical of age-related hearing loss (AHL) associated with mouse strains homozygous for the ahl allele and were labeled as AHL-like strains. Seven strains demonstrating relatively even patterns of reduced DPOAE levels across the frequency-test range were designated as Flat-loss strains. Finally, the remaining four strains exhibited no measurable DPOAEs at either 3 or 5 mo of age and thus were classified as Absent strains. Extending the f(2) test frequencies up to approximately 54kHz led to the detection of very early-onset reductions in cochlear function in non-CBA-like groups so that all strains could be categorized by 3 mo of age. Predictably, the AHL-like strains showed more pronounced DPOAE losses at 5 mo than at 3 mo. A similar deterioration in DPOAE levels was not apparent for the Flat-loss strains. Both the AHL-like and Flat-loss strains showed considerably more variability in DPOAE levels than did the CBA-like strains. Together, these findings indicate that DP-grams adequately reveal both frequency-specific loss patterns and details of inbred strain variability. ",0
3468,17997467,Receptor use by the Whitewater Arroyo virus glycoprotein,"Whitewater Arroyo virus (WWAV) is a North American New World arenavirus, first isolated from rats in New Mexico in 1993, and tentatively associated with three human fatalities in California in 1999-2000. However, it remains unclear whether WWAV was the cause of these, or any other, human infections. One important characteristic of viruses that influences pathogenic potential is the choice of cellular receptor and the corresponding tropism of the virus. In the arenaviruses, these properties are determined largely by the viral glycoprotein (GP). We have previously noted for the New World clade B arenaviruses, which include four severe human pathogens, that the ability to cause human disease correlates with the ability of the GP to use the human transferrin receptor 1 (hTfR1) to enter cells. In addition, pseudotyped retroviral vectors displaying the GPs from pathogenic clade B viruses transduced a range of cell lines in vitro that were distinct from those that could be transduced by non-pathogenic clade B viruses. WWAV was initially classified as a New World clade A virus, based on sequence analysis of its nucleoprotein gene. However, more extensive analyses have revealed that WWAV and the other North American arenaviruses are probably recombinant clade A/B viruses, and that the WWAV GP is more closely related to the clade B GPs. Based on this finding, we sought to understand more about the possible pathogenic potential of WWAV by determining whether its clade B-like GP exhibited the characteristics of a pathogenic or non-pathogenic clade B virus. Our studies found that WWAV GP did not use hTfR1 for entry, and that its overall in vitro tropism was most similar to the GPs from the non-pathogenic clade B viruses. Although many viral factors in addition to GP receptor use and tropism determine whether a virus is able to cause disease in humans, our analysis of the WWAV GP does not support the idea that WWAV is a human pathogen. ",0
3469,17998127,Treatment of spinal tuberculosis with ultrashort-course chemotherapy in conjunction with partial excision of pathologic vertebrae,"The ultrashort-course chemotherapeutical scheme of less than 6 months has been used for part of patients with pulmonary tuberculosis and satisfactory curative effects have already been achieved. However, few systematic and clinical reports so far about medical treatment of spinal tuberculosis by using ultrashort-course chemotherapeutical schemes have been published in the spine-care literature. To assess the results of ultrashort-course chemotherapy (UCC) in conjunction with partial excision of pathological vertebrae for spinal tuberculosis. This is a retrospective comparative study of case series from a single center. Seventy-six cases of spinal tuberculosis, treated during 1998 and 2003 by senior author, were reviewed. All the cases underwent chemotherapies in conjunction with the uniform partial excision of pathological vertebra and had a minimum follow-up of 2 years. Clinical manifestations, laboratory tests, imaging examination, examination by ultrasonic wave B, drug complications, and clinical effects based on the previously described evaluative measures. Of the 76 cases, 28 had UCC with the scheme of 2SHRZ/2.5H(2)R(2)Z(2), 23 had short-course chemotherapy (SCC) with the scheme of 3SHRZ/5H(2)R(2)Z(2), and 25 had standard chemotherapy (SC) with the scheme of 3SHRZ/9H(2)R(2)Z(2). All the patients had anterior partial excisions of pathological vertebrae, large iliac strut graft, and anterior or posterior fixation. The mean time of follow-up surveys for the ultrashort-course, short-course, and standard chemotherapy cases was 42.3 m, 46.5 m, and 55.4 m, respectively. The observance indices included 1) clinical manifestations: disappearance of tuberculosis symptoms, no CC pains, recovery of normal life or work, no percussion pains on pathologic sites, and recovery of neural functions; 2) laboratory tests: normal or close to normal test results of both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) or one of them; 3) imaging examinations: X-ray films, computed tomography scan, and magnetic resonance imaging examinations show disappearance of abscesses, no new destructive foci, bone union on the bone grafting interface, satisfactory correction of deformities, and less than 5 degrees of the angle loss of deformity corrections; 4) examination by ultrasonic wave B: no opaque dark area of fluid sonolucent areas identified in possible sites of paravertebral abscesses or gravitation abscesses; and 5) drug complications: hepatic and renal functions, nervus vestibularis lesion, and gastrointestinal tract reactions. All the cases met the protetrakis indices and obtained complete clinical cure of spinal tuberculosis in the last follow-up. The significant differences of major drug complications were found among the 3 groups, with 5 cases of UCC (18%), 15 cases of SCC (65%), and 19 cases of SC (76%). The lasting chemotherapeutic lesion of liver, kidney, or the permanent nervus vestibularis lesion were found 3 cases in SCC, 5 cases in SC, and no case in UCC group. No significant differences in clinical cure rate were found among 3 groups. UCC in conjunction with anterior partial excisions of pathological vertebrae, large iliac strut graft, and anterior or posterior internal instrumental fixation achieved excellent clinical results and the lowest complication rate of antituberculosis chemotherapy. ",0
3470,17998153,Duration of chronic toxicity studies for biotechnology-derived pharmaceuticals: is 6 months still appropriate?,"For chronic use biotechnology-derived pharmaceuticals, toxicity studies of 6 months have generally been accepted for regulatory approval. This review assessed the data for 23 approved biotechnology-derived pharmaceuticals to determine whether the studies conducted were predictive of human safety and whether there is new data from approved products indicating that longer than 6 months is necessary. This assessment involved three approaches; whether new toxicities were identified at >6 months, similarity of findings between 6 months and shorter studies and predictivity of clinical adverse events. In two cases there were apparently new findings in studies >6 months. On examination however, one of these cases was a well established risk with foreign protein administration to animals (adalimumab). For insulin aspart, the 12 month study identified tumors not seen in shorter term studies, however, determination of carcinogenic potential is not a goal of chronic toxicity studies and is addressed by separate studies. In most cases the toxicology studies were predictive of common clinical adverse reactions, but were poorly predictive of rare clinical events or some serious adverse reactions. Although specific circumstances may require a longer study, this review indicates no new data is available to refute the utility of 6 month studies to support chronic clinical dosing with biotechnology-derived pharmaceuticals. ",0
3471,17998315,Fetal Down syndrome brains exhibit aberrant levels of neurotransmitters critical for normal brain development,"In the immature developing fetal brain, amino acids (such as gamma-aminobutyric acid, and taurine) and monoamines (serotonin, noradrenaline, and dopamine) act as developmental signals or regulators. In subjects with Down syndrome, dysfunctional brain development is evident from birth as reduction in brain weight, as well as volume reductions in specific brain regions, and an altered number of neurons, dendrites, and dendritic branching is observed. However, mechanisms that underlie the observed dysfunctional brain development in Down syndrome are not clear. Because diverse amino acids and monoamines are critical for normal brain development, we wanted to determine whether dysfunctional brain development observed in subjects with Down syndrome is associated with altered brain amino acid and/or monoamine levels. We quantified tissue concentrations of diverse amino acids, including gamma-aminobutyric acid and taurine, and the monoamines serotonin, noradrenaline, and dopamine in the frontal cortex of fetal Down syndrome tissue at a gestational age of approximately 20 weeks versus age-matched control aborted fetuses. Fetal Down syndrome brains showed reductions in the levels of serotonin, gamma-aminobutyric acid, taurine, and dopamine in the frontal cortex. No alteration in the levels of arginine, aspartate, glutamine, glutamate, glycine, histidine, serine, or noradrenaline was observed. Serotonin, gamma-aminobutyric acid, taurine, and dopamine are critical for the acquisition of brain morphologic features, neuronal and glia proliferation, and synapse formation. The detected reductions in the levels of these neurotransmitters may indicate potential mechanisms for the observed dysfunctional neuronal development in the Down syndrome fetal brain. ",0
3472,17999117,Global stability of equilibria in a two-sex HPV vaccination model,"Human papillomavirus (HPV) is the primary cause of cervical carcinoma and its precursor lesions, and is associated with a variety of other cancers and diseases. A prophylactic quadrivalent vaccine against oncogenic HPV 16/18 and warts-causing genital HPV 6/11 types is currently available in several countries. Licensure of a bivalent vaccine against oncogenic HPV 16/18 is expected in the near future. This paper presents a two-sex, deterministic model for assessing the potential impact of a prophylactic HPV vaccine with several properties. The model is based on the susceptible-infective-removed (SIR) compartmental structure. Important epidemiological thresholds such as the basic and effective reproduction numbers and a measure of vaccine impact are derived. We find that if the effective reproduction number is greater than unity, there is a locally unstable infection-free equilibrium and a unique, globally asymptotically stable endemic equilibrium. If the effective reproduction number is less than unity, the infection-free equilibrium is globally asymptotically stable, and HPV will be eliminated. ",0
3473,17999560,The funny current: cellular basis for the control of heart rate,"The 'funny' (pacemaker, I(f)) current, first described almost 30 years ago in sinoatrial node (SAN) myocytes, is a mixed sodium/potassium inward current, activated on hyperpolarisation in the diastolic range of voltages. 'Funny' (f) channels are activated by intracellular cyclic adenosine monophosphate (cAMP) concentrations according to a mechanism mediating regulation of heart rate by the autonomic nervous system, as well as by voltage hyperpolarisation. Structural subunits of native f-channels are the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels; of the four HCN isoforms known, HCN4 is the most highly expressed in SAN tissue. The I(f) current is a natural target in the search for drugs aimed specifically at affecting heart rate, given its function in pacemaking. Increased heart rate has a negative influence on clinical outcome in patients with cardiovascular disease, and indeed is also an established risk factor for cardiovascular and all-cause mortality in the general population. Clearly, therefore, independent reduction of heart rate, through inhibition of the I(f) current, appears to be a suitable therapeutic option for patients with ischaemic heart disease.beta-Adrenoceptor antagonists (beta-blockers) reduce intracellular cAMP levels, and a substantial part of their negative chronotropic effect is therefore attributable to a reduction of the I(f) current. However, neither beta-blockers nor Ca(2+) channel antagonists, both of which have traditionally been used to reduce myocardial ischaemia, are 'pure' heart rate-lowering drugs. These agents may, in fact, have adverse cardiovascular and noncardiovascular effects.Conversely, the novel heart rate-reducing agent ivabradine is a specific blocker of f-channels, hence a selective inhibitor of the pacemaker I(f) current in the SAN. Ivabradine slows heart rate by reducing the I(f) current-regulated steepness of the diastolic depolarisation in SAN myocytes, thereby increasing diastolic duration, without altering action potential duration or causing negative inotropy. As such, ivabradine is particularly useful in patients with chronic stable angina pectoris. Further clinical studies are ongoing to evaluate the efficacy of ivabradine in patients with coronary heart disease, left ventricular dysfunction and heart failure. This short article reviews the current state of knowledge of the properties of the 'funny' current in relation to exploitation of the I(f) function in pacemaking generation and modulation for the pharmacological control of heart rate. ",0
3474,17999730,Tooth loss and associated factors in long-term institutionalised elderly patients,"To compare partial and total tooth loss in dependent institutionalised elderly patients and identify any associated factors. A poor oral health status, together with a reduction of autonomy can seriously affect the general health and increase the risk of death in elderly people. Those with total tooth loss and in need of assistance are the most at risk. In 2004, a cross-sectional study of 321 elderly patients was conducted in long-term hospital services provided in Montpellier, France. Socio-demographic, behavioural, medical and oral health information was recorded for each patient. Multivariate logistic regression models were performed to test the relationship between those covariates and partial or total tooth loss. Pearson chi-squared tests were used for bivariate analyses. The proportion of edentulousness was 26.9%; among these12.6% had no dentures. The factors significantly associated with edentulism were: an age 'older than 87 years' [odds ratio (OR) = 9.4], the presence of a nephropathy (OR = 6.8), and inadequate oral hygiene (OR = 0.1). The factors most significantly associated with partial tooth loss (at least 21 missing teeth) were 'cancerous disease' (OR = 9.9), the presence of a nephropathy (OR = 5.6) and the presence of a neurological disease (OR = 4.1). The factors significantly related to dentate status (20 or more natural teeth retained) were 'hypertension treatment' (OR = 2.4), and 'cortisone treatment' (OR = 0.2). General health problems as well as a poor oral condition were significant risk indicators for tooth loss among the long-term institutionalised elderly. This suggests that the number of remaining teeth has a strong effect on oral health-related quality of life. ",0
3475,17999818,Blood and body fluid splashes during surgery--the need for eye protection and masks,"While most surgeons make an effort to avoid needlestick injury, some can pay little attention to reduce the potential route of infection occurring when body fluids splash into the eye. It has been shown that transmission of HIV, hepatitis B or C can occur across any mucous membrane. This study aims to quantify how frequently body fluids splash the mask and lens of wrap around protective glasses thus potentially exposing the surgeon to infection. A prospective study was carried out by a single surgeon on all cases performed over a 1-year period. Protective mask and glasses were examined before and after operations. A total of 384 operations were performed with 174 (45%) showing blood or body fluid splash on the lens. A high incidence of splashes was found in vascular surgical procedures (79%). All amputations showed splash on the protective lens. Interestingly, 50% of laparoscopic cases resulted in blood or body fluid splash on the protective lens. This study has shown a high incidence (45%) of blood and body fluid splashes found on protective glasses and masks. There was a very high incidence (79%) during vascular surgical procedures. With the prevalence of HIV and hepatitis increasing, it seems prudent to protect oneself against possible routes of transmission. ",0
3476,17999958,Involvement of p90 ribosomal S6 kinase in termination of cell cycle arrest during development of Artemia-encysted embryos,"Artemia has evolved a unique developmental pattern of encysted embryos to cope with various environmental threats. Cell divisions totally cease during the preemergence developmental stage from gastrula to prenauplius. The molecular mechanism of this, however, remains unknown. Our study focuses on the involvement of p90 ribosomal S6 kinase (RSK), a family of serine/threonine kinase-mediating signal transduction downstream of mitogen-activated protein kinase cascades, in the termination of cell cycle arrest during the post-embryonic development of Artemia-encysted gastrula. With immunochemistry, morphology, and cell cycle analysis, the identified Artemia RSK was established to be specifically activated during the post-embryonic and early larval developmental stages when arrested cells of encysted embryos resumed mitoses. In vivo knockdown of RSK activity by RNA interference, kinase inhibition, and antibody neutralization consistently induced defective larvae with distinct gaps between the exoskeleton and internal tissues. In these abnormal individuals, mitoses were detected to be largely inhibited in the affected regions. These results display the requirement of RSK activity during Artemia development and suggest its role in termination of cell cycle (G(2)/M phase) arrest and promotion of mitogenesis. Our findings may, thus, provide insights into the regulation of cell division during Artemia post-embryonic development and reveal further aspects of RSK functions. ",0
3477,18000456,"Acculturation and expressed emotion in Caucasian, Latino, and black relatives of patients with schizophrenia","High expressed emotion (high EE) in family members (high levels of criticism, emotional overinvolvement, and/or hostility) has been found to be predictive of a poorer course of illness for patients with schizophrenia in many different cultures. Acculturation has also been found to relate to symptom severity and clinical course in a number of disorders (e.g., substance abuse, schizophrenia). There is reason to believe that acculturation may interact with EE, however, this relationship has yet to be examined systematically. The present study evaluated the relationship between acculturation and EE in a sample of 57 Caucasian, Latino, and black caregivers of patients with schizophrenia. Drawing from earlier research, it was hypothesized that more acculturated Caucasian and Latino relatives and less acculturated black relatives would be designated as high EE. Hypotheses were partially supported as results demonstrated that greater acculturation was associated with high EE for Latinos and low EE for blacks. ",0
3478,18000492,A study of the incidence of bipolar spectrum disorders in a private psychiatric practice,"An audit of the diagnosis of 300 consecutive new cases presenting in a private practice over the period of the last four years (from January 2003 to December 2006) is presented. The main observation is the high percentage of patients who fall within the bipolar spectrum who are diagnosed and reported. In particular, there is a large proportion of patients who suffer from Bipolar II illness. The consequences of this in the diagnosis and management of patients is discussed. ",0
3479,18000693,"Temperature, soluble solids and pH effect on Alicyclobacillus acidoterrestris viability in lemon juice concentrate","Alicyclobacillus acidoterrestris is a thermoacidophilic, non-pathogenic, spore-forming bacterium detected in spoiled commercial pasteurized fruit juice. Apple, white grape and tomato are particularly susceptible. A. acidoterrestris spores are resistant to lemon juice pasteurization (2 min at 82 degrees C), and they can germinate and grow causing spoilage. This contamination is characterized by a medicinal or disinfectant smell attributed to guaiacol (o-dihydroxybenzene) production and other taint chemicals. The aim of this work was to study the influence of temperature (82, 86, 92 and 95 degrees C), total soluble solids (SS) (6.20, 9.8, 50 and 68 degrees Brix) and pH (2.28, 2.45, 2.80, 3.25, 3.5) on decimal reduction time (D) of the A. acidoterrestris in clarified and non-clarified concentrated lemon juice. Once D-value was determined, the resistance of A. acidoterrestris at the assayed temperatures was confirmed. SS and pH influence spore viability, because spore resistance increases with higher SS (50 degrees Brix 22 min 82 degrees C-68 degrees Brix 28 min 82 degrees C) and pH values (pH 2.28, 17 min-pH 4.00, 22 min). Bacterial growth was lower in clarified lemon juice, 26 min at 82 degrees C, than in non-clarified lemon juice, 51 min at 82 degrees C. Temperature was the parameter that had the greatest influence on the D value. ",0
3480,18000772,Relationship between the dissected lymph node number and the prognosis in D(2) gastrectomy for gastric cancer],"To examine the relationship between the dissected lymph-node number and the prognosis in D(2) gastrectomy for gastric cancer. From January 1996 to January 2005, 457 patients with primary gastric cancer undergone gastrectomy with different extent of lymphadenectomy in our hospital were followed-up in term of prognostic benefit. In lymph-node metastasis group, the 1-, 3-, 5-year survival rates were 82.4%, 49.0%, 33.4% with dissection of >20 nodes and 71.5%, 49.7%, 40.1% with dissection of 16-20 nodes. In the group without lymph-node metastasis, the 1-, 3-, 5-year survival rates were 98.2%, 92.7%, 84.7% with dissection of >20 nodes and 94.0%, 89.7%, 81.4% with dissection of 16-20 nodes. Whether or not it had lymph-node metastasis, the survival curve failed to show any significant difference with regard to the extent of lymph node dissection. As to lymphadenectomy for gastric cancer, it is enough to excise the lymph node between 16 and 20. The number of excised lymph node should not be overemphasized unless it is metastasized. ",0
3481,18000811,Monitoring of minimal residual disease in acute myeloid leukemia,"Two highly sensitive methods, multiparameter flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR), are increasingly used to monitor minimal residual disease (MRD) and to guide risk-adapted management in acute myeloid leukemia (AML). An independent prognostic impact has been demonstrated for MRD levels obtained by both methods. MFC has been found particularly useful for assessment of early clearance of malignant cells and after consolidation therapy. At the latter checkpoint, MRD levels quantified by RQ-PCR in AML with fusion genes also have the strongest prognostic power. In addition, highly predictive initial expression levels have been identified by RQ-PCR. Both methods are capable of early detection of relapse. Through the use of all available markers including NPM1 mutations and FLT3 mutations in addition to fusion genes, RQ-PCR-based MRD assessment is possible in more than half of patients, whereas MFC is applicable to most AML cases. With a sensitivity of 10(-4) (PML-RARA) to 10(-7) (patient-specific primers, FLT3 and NPM1 mutations), RQ-PCR is more sensitive in most cases. Large clinical trials will determine the exact role and place of immunologic and RQ-PCR-based monitoring of MRD in the therapy of patients with AML. ",0
3482,18000949,"Equity, governance and financing after health care reform: lessons from Mexico","To determine, from the perspective of providers, community leaders and users of health services, equity, governance and health financing outcomes of the Mexican health system reform.Cross-sectional study oriented towards the qualitative analysis of financing, governance and equity indicators for the uninsured population. Taking into account feasibility, as well as political and technical criteria, six Mexican states were selected as study populations and a qualitative research was conducted during 2004-2006. Two hundred and forty in-depth interviews were applied, in all selected states, to 60 decision-makers, including medical and administrative personnel; 60 service providers at health centres; 60 representatives of civil organizations, including municipal representatives and, finally, 60 members of health committees and users of services at second and first levels of care units. The analysis of interviews was performed using ATLAS-Ti software. An outcome mapping of health reform was developed. For political actors, Mexican health system reform has not modified dependence on the central level; ignorance about reform strategies and lack of participation in the search for financial resources to finance health systems were evidenced. Also, in all states under study, community leaders and users of services reported the need to improve an effective accountability system at both municipal and state levels. Health strategies for equity, governance and financing do not have adequate mechanisms to promote participation from all social actors. Improving this situation is a very important goal in the Mexican health democratization process, in the context of health care reform. There are relevant positive and negative effects of the reform on equity, governance and financing in health. Special emphasis is placed on the analysis of lessons learned in Mexico and the usefulness of the main strengths and weaknesses, as relevant evidences for other middle-income countries which are designing, implementing and evaluating reform strategies in order to achieve equity in resource allocation, good levels of governance and a greater financial protection in health. ",0
3483,18001213,Nitrate intake relative to antioxidant vitamin intake affects gastric cancer risk: a case-control study in Korea,"The objective of this study was to determine whether the intake of nitrate relative to antioxidant vitamin rather than absolute intake of nitrate affects the risk of gastric cancer (GC). In a case-control study in Korea using a food frequency questionnaire, trained dietitians interviewed 136 GC cases and an equal number of controls matched by sex and age. As an index of nitrate intake relative to antioxidant vitamins intake, we calculated the nitrate:antioxidant vitamin consumption ratio. The mean daily nitrate intake from foods was very high in our subjects. Higher absolute intake of nitrate was not associated with GC risk [odds ratios (OR) = 1.13; 95% confidence interval (CI) = 0.42-3.06]. However, the GC risk distinctly increased as the nitrate:antioxidant vitamin consumption ratio increased, particularly with higher nitrate:vitamin E (OR = 2.78; 95% CI = 1.01-7.67) and nitrate:folate ratios (OR = 3.37; 95% CI = 1.28-8.87). Therefore, GC risk was influenced by the intake of nitrate relative to antioxidant vitamins. Our results suggest that a decrease in the intake of nitrate relative to antioxidant vitamins is considerably more effective in reducing GC risk than either a lower absolute intake of nitrate or a higher intake of antioxidant vitamins alone. ",0
3484,18001440,4-Methylumbelliferone inhibits hyaluronate synthesis in human uterine cervical fibroblasts,"Hyaluronate plays an important role in the regulation of cervical function during parturition. In our previous study we showed that 4-methylumbelliferone (MU) suppresses hyaluronate synthesis by cultured human skin fibroblasts. The present study investigated the effects of MU on fibroblasts obtained from the human uterine cervix and assessed the possibility of controlling cervical ripening with MU. Human uterine cervical fibroblasts were collected from uterine cervices obtained from the uteri of three patients who had a total hysterectomy for uterine myoma at Hirosaki University Hospital. The fibroblasts were cultured in Dulbecco's modified Eagle's medium until confluence. They were then cultured in medium containing [3H]glucosamine (0.074 MBq/mL) with various MU doses. Hyaluronate synthesis was evaluated by assessing the incorporation of [3H]glucosamine into the soluble fraction of hyaluronate. Three independent studies were carried out on each specimen to clarify whether MU causes compositional changes or promotes hyaluronate degradation, whether the inhibitory effects of MU on hyaluronate synthesis are dose-dependent, and whether the effects of MU are reversible. MU added to the medium of the cultured cells reduced the synthesis of hyaluronate in a dose-dependent manner. After MU was removed from the medium, hyaluronate synthesis recommenced, and the amount of [3H]hyaluronate synthesized was similar to the control level. MU inhibits the synthesis of hyaluronate in human uterine cervical fibroblasts. ",0
3485,18001837,"Vanadate substituted phytase: immobilization, structural characterization and performance for sulfoxidations","A cross-linked enzyme aggregate (CLEA) of 3-phytase (EC 3.1.3.8) was synthesised, which was incubated with vanadate and tested as a biocatalyst in the asymmetric sulfoxidation of thioanisole using hydrogen peroxide as the oxidant. The results show that the 3-phytase-CLEA demonstrates a similar efficiency (ca. 95% conversion) and asymmetric induction (ca. 60%) as the free enzyme. Moreover, the 3-phytase-CLEA can be reused at least three times without significant loss of activity. The activity of the 3-phytase in the presence of organic solvents is however still limited. Studies were undertaken to elucidate the role of vanadate on the active site and on the effect of organic solvents on the conformation of the enzyme. The incorporation of vanadate in the active sites of two different phytases could be followed using (51)V NMR and circular dichroism (CD) spectroscopies. (51)V NMR spectra show the incorporation of vanadate into the active site at pH 5.0 and 7.6, and suggest coordination to oxygen functions at two different binding sites, which probably explains the poor enantioselectivity found in the catalytic studies. After addition of H(2)O(2), only at pH 5.0 and with the 3-phytase a V-phytase-peroxide complex could be observed, which is the active species responsible for the oxidation reactions. CD studies showed that the alpha-helical content of the enzyme decreased upon coordination of vanadate, but in the concentration range used in the catalytic studies (<30 microM) the secondary conformation of the enzyme was unchanged. Acetonitrile decreases the alpha-helical content of both phytases from 59% to 51% and from 42% to 34%, in the 3- and 6-phytases, respectively, this being in agreement with the activity loss in the catalytic experiments. ",0
3486,18001902,A novel point of care diagnostic device: impedimetric detection of a biomarker in whole blood,"There is an unmet medical need for a more reliable and earlier assessment of patients suspected of having a deep vein thrombosis. We describe a novel approach which is developing a highly reliable, accurate, portable and handheld prototype medical diagnostic device to improve radically the speed, accuracy and reliability with which DVT and related blood clotting conditions can be assessed. The device will measure whole blood concentration of D-dimer, a recognized biomarker of increased blood clotting activity, and through innovation in the development of a novel detection, measurement and reporting system, will offer the opportunity to use the test in the point of care setting. The device combines innovation in antibody bio-engineering for high specificity immunoassay-based diagnostics and nano/micro engineered impedimetric analysis electrodes incorporating a biocompatible polymer substrate with development of a disposable microfluidic manifold specifically enabling diagnostics at the point-of-first-contact. ",0
3487,18002115,A technique for the computation of lower leg muscle volume from MRI images in the context of venous return,"A technique to automatically calculate the volume of a patient's calf muscle using MRI scans in the context of venous insufficiency is presented. Rather than giving a quantifiable measurement of volume, the technique provides a pixel count which can be used to compare the calf muscle volume of one leg of a patient against the other in the context of unilateral leg ulcers or to compare one patient's calf muscle volume against another patient. A custom MATLAB program reads the MRI scans (in the form of JPEG images) and determines the number of pixels (right and left limbs separately) that fall within a user defined gray-scale band, designated as being muscle. The output from the MATLAB program was compared with a manual counting method. The pixel counting algorithm was found to have an acceptable accuracy with results indicating a percentage difference from the manual method of between 2 and 9.5%. ",0
3488,18002308,NIR light penetration depth in the rat peripheral nerve and brain cortex,"Near infrared (NIR) light energy has been used in medical applications both for diagnostic and treatment purposes. A priory knowledge of optical tissue properties is necessary in these applications; not only of human but also in animals for testing of devices. However, published data on the optical properties of neural tissue in rodents are rare. The aim of this study was to measure the penetration depth of light into the rat peripheral nerve and brain cortex at NIR wavelengths. Penetration depth was calculated from measurements of transmitted light for various thicknesses of the neural tissue. We found the penetration depth in the rat sciatic nerve to be 0.35 +/- 0.023 mm and in the white matter 0.35 +/- 0.026 mm. The penetration depth of the gray matter was 0.41+/-0.029 mm. Compared to the data reported in literature for the human brain, the rat peripheral and the brain cortex attenuate the NIR light much more strongly. ",0
3489,18046708,Glucocorticoid-induced leucine zipper: A key protein in the sensitization of monocytes to lipopolysaccharide in alcoholic hepatitis,"Glucocorticoid-induced leucine zipper (GILZ), a recently identified protein induced by glucocorticoids (GCs), inhibits the nuclear factor kappaB pathway and the activation of monocytes/macrophages by lipopolysaccharides (LPS). This study aimed to elucidate the contribution of GILZ to the pathogenesis of alcoholic hepatitis (AH): we (1) assessed GILZ expression in the livers of patients with AH and (2) treated patients with severe AH with GCs (prednisolone 40 mg/day) and studied the effect of GILZ modulation on circulating monocyte function. We quantified GILZ expression in the livers of 42 consecutive alcoholic patients (21 with and 21 without AH). GILZ messenger RNA (mRNA) levels were lower in the livers of patients with AH versus those without AH (P < 0.05). We collected circulating monocytes from patients with severe AH before and 48 hours after GC treatment to quantify GILZ expression and cytokine secretion. GC treatment induced significantly higher levels of GILZ mRNA than that observed before treatment and impaired LPS-induced tumor necrosis factor-alpha (TNF-alpha) and regulated upon activation, normal T cell-expressed secretion (RANTES) by these monocytes. We transfected circulating monocytes with GILZ small interfering RNA (siRNA), specifically blocking GILZ expression, to demonstrate the role of GILZ in mediating GC effect. GILZ siRNA abrogated the effect of GC treatment on LPS-induced TNF-alpha and RANTES secretion. CONCLUSION: Low expression of GILZ may contribute to liver inflammation in AH. GCs enhance GILZ expression, abrogating macrophage sensitivity to LPS and proinflammatory cytokine secretion. These findings may explain the beneficial effect of GC treatment in patients with severe AH.",0
3490,18046717,Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders,"In hepatitis C virus (HCV) genotype 1 infection, the duration of interferon-based therapy is a critical determinant in achieving sustained virologic response (SVR). Slow or late responders to peginterferon and ribavirin may benefit from an extended treatment course. We sought to determine if therapy extension could improve response rates in a United States population of slow responders. Slow response was defined by achieving at least a 2-log decrement in HCV RNA from baseline, yet having detectable HCV RNA at 12 weeks and undetectable HCV RNA at 24 weeks (polymerase chain reaction, TaqMan, Roche; detection limit 10 IU/mL). Patients were treatment-na?ve, chronically infected genotype 1-infected slow responders to 1.5 mug/kg/week of peginterferon-alpha2b and 800-1400 mg/day of ribavirin and were randomly assigned 1:1 to complete a total of 48 or 72 weeks of therapy. Dose reductions and treatment discontinuations for adverse events or laboratory abnormalities were similar between the 2 treatment arms. End-of-treatment response rates were similar in the 72-week group compared with those in the 48-week group (48% versus 45%; P value not significant). Overall, the rate of SVR was superior in patients treated for 72 weeks versus 48 weeks (38% versus 18%, respectively; P = 0.026). CONCLUSION: Extending the treatment duration from 48 weeks to 72 weeks in genotype 1-infected patients with slow virologic response to peginterferon-alpha2b and weight-based ribavirin significantly improves SVR rates. Treatment extension does not seem to increase the rate of dose reduction or therapy discontinuation.",0
3491,18046720,Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease,"More than 70% of alcohol is consumed by 10% of the population in the United States. Implicit in this statistic is that tremendous variation in the pattern of drinking (quantity, frequency, and duration) exists among alcohol consumers. Individuals who are binge or chronic drinkers will have different health outcomes than social drinkers. Therefore, knowing the pattern of drinking will shed light on how severely individuals are alcohol-dependent and on the extent of liver damage. Thus, these parameters assume particular relevance for the treatment-providing physician. Genetic factors contribute substantially to differences in alcohol metabolism. Variations in the activities of the alcohol-metabolizing enzymes, cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, in part determine blood alcohol concentration, thereby contributing to the predisposition to becoming alcohol-dependent and to susceptibility to alcohol-induced liver damage. Chronic alcohol consumption induces cytochrome P450 2E1, a microsomal enzyme that metabolizes alcohol at high concentrations and also metabolizes medications such as acetaminophen and protease inhibitors. Alcohol metabolism changes the redox state of the liver, which leads to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The quantity and frequency of alcohol consumption severely impact the liver in the presence of comorbid conditions such as infection with hepatitis B or C and/or human immunodeficiency virus, type 2 diabetes, hemochromatosis, or obesity and thus have implications with respect to the extent of injury and response to medications. CONCLUSION: Knowledge of the relationships between the quantity, frequency, and patterns of drinking and alcoholic liver disease is limited. A better understanding of these relationships will guide hepatologists in managing alcoholic liver disease.",0
3492,18057339,Adolescent overweight and future adult coronary heart disease,"BACKGROUND: The effect of adolescent overweight on future adult coronary heart disease (CHD) is not known. METHODS: We estimated the prevalence of obese 35-year-olds in 2020 on the basis of adolescent overweight in 2000 and historical trends regarding overweight adolescents who become obese adults. We then used the CHD Policy Model, a state-transition computer simulation of U.S. residents who are 35 years of age or older, to project the annual excess incidence and prevalence of CHD, the total number of excess CHD events, and excess deaths from both CHD and other causes attributable to obesity from 2020 to 2035. We also modeled the effect of treating obesity-related increases in blood pressure and dyslipidemia. RESULTS: Adolescent overweight is projected to increase the prevalence of obese 35-year-olds in 2020 to a range of 30 to 37% in men and 34 to 44% in women. As a consequence of this increased obesity, an increase in the incidence of CHD and in the total number of CHD events and deaths is projected to occur in young adulthood. The increase is projected to continue in both absolute and relative terms as the population reaches middle age. By 2035, it is estimated that the prevalence of CHD will increase by a range of 5 to 16%, with more than 100,000 excess cases of CHD attributable to the increased obesity. Aggressive treatment with currently available therapies to reverse modifiable obesity-related risk factors would reduce, but not eliminate, the projected increase in the number of CHD events. CONCLUSIONS: Although projections 25 or more years into the future are subject to innumerable uncertainties, extrapolation from current data suggests that adolescent overweight will increase rates of CHD among future young and middle-aged adults, resulting in substantial morbidity and mortality.",0
3493,18094375,Breast-cancer stromal cells with TP53 mutations and nodal metastases,"BACKGROUND: The importance of cross-talk between a cancer and its microenvironment has been increasingly recognized. We hypothesized that mutational inactivation of the tumor-suppressor gene TP53 and genomic alterations in stromal cells of a tumor's microenvironment contribute to the clinical outcome. METHODS: We performed TP53 mutation analysis and genomewide analysis of loss of heterozygosity and allelic imbalance on DNA from isolated neoplastic epithelial and stromal cells from 43 patients with hereditary breast cancer and 175 patients with sporadic breast cancer. Compartment-specific patterns and TP53 mutations were analyzed. Associations between compartment-specific TP53 status, loss of heterozygosity or allelic imbalance, and clinical and pathological characteristics were computed. RESULTS: TP53 mutations were associated with an increased loss of heterozygosity and allelic imbalance in both hereditary and sporadic breast cancers, but samples from patients with hereditary disease had more frequent mutations than did those from patients with sporadic tumors (74.4% vs. 42.3%, P=0.001). Only 1 microsatellite locus (2p25.1) in stromal cells from hereditary breast cancers was associated with mutated TP53, whereas there were 66 such loci in cells from sporadic breast cancers. Somatic TP53 mutations in stroma, but not epithelium, of sporadic breast cancers were associated with regional nodal metastases (P=0.003). A specific set of five loci linked to an increased loss of heterozygosity and allelic imbalance in the stroma of sporadic tumors was associated with nodal metastases in the absence of TP53 mutations. No associations were found between any of the clinical or pathological features of hereditary breast cancer with somatic TP53 mutations. CONCLUSIONS: Stroma-specific loss of heterozygosity or allelic imbalance is associated with somatic TP53 mutations and regional lymph-node metastases in sporadic breast cancer but not in hereditary breast cancer.",0
3494,18094379,"Outcomes of care by hospitalists, general internists, and family physicians","BACKGROUND: The hospitalist model is rapidly altering the landscape for inpatient care in the United States, yet evidence about the clinical and economic outcomes of care by hospitalists is derived from a small number of single-hospital studies examining the practices of a few physicians. METHODS: We conducted a retrospective cohort study of 76,926 patients 18 years of age or older who were hospitalized between September 2002 and June 2005 for pneumonia, heart failure, chest pain, ischemic stroke, urinary tract infection, acute exacerbation of chronic obstructive pulmonary disease, or acute myocardial infarction at 45 hospitals throughout the United States. We used multivariable models to compare the outcomes of care by 284 hospitalists, 993 general internists, and 971 family physicians. RESULTS: As compared with patients cared for by general internists, patients cared for by hospitalists had a modestly shorter hospital stay (adjusted difference, 0.4 day; P<0.001) and lower costs (adjusted difference, $268; P=0.02) but a similar inpatient rate of death (odds ratio, 0.95; 95% confidence interval [CI], 0.85 to 1.05) and 14-day readmission rate (odds ratio, 0.98; 95% CI, 0.91 to 1.05). As compared with patients cared for by family physicians, patients cared for by hospitalists had a shorter length of stay (adjusted difference, 0.4 day; P<0.001), and the costs (adjusted difference, $125; P=0.33), rate of death (odds ratio, 0.95; 95% CI, 0.83 to 1.07), and 14-day readmission rate (odds ratio, 0.95; 95% CI, 0.87 to 1.04) were similar. CONCLUSIONS: For common inpatient diagnoses, the hospitalist model is associated with a small reduction in the length of stay without an adverse effect on rates of death or readmission. Hospitalist care appears to be modestly less expensive than that provided by general internists, but it offers no significant savings as compared with the care provided by family physicians.",0
3495,18098322,The causes of primary biliary cirrhosis: Convenient and inconvenient truths,"The most difficult issue in autoimmunity remains etiology. Although data exist on effector mechanisms in many autoimmune diseases, the underlying cause or causes are still generically ascribed to genetics and environmental influences. Primary biliary cirrhosis (PBC) is considered a model autoimmune disease because of its signature antimitochondrial autoantibody (AMA), the homogeneity of clinical characteristics, and the specificity of biliary epithelial cell (BEC) pathology. Twenty years ago, we reported the cloning and identification of the E2 component of pyruvate dehydrogenase (PDC-E2) as the immunodominant autoantigen of PBC, allowing for vigorous dissection of T and B lymphocyte responses against PDC-E2 and development of several valid experimental models. There has also been considerable study of the biology of BECs, which has included the unique properties of apoptosis in which there is exposure of PDC-E2 to the effector processes of the immune system. In this review, we present these data in the context of our proposal that the proximal cause of PBC is autoimmunity directed against well-identified mitochondrially located autoantigens in individuals with inherited deficits of immune tolerance. We present these data under the umbrella of convenient truths that support this thesis as well as some inconvenient truths that are not readily accommodated by current theory. CONCLUSION: We emphasize that the potential initiator of PBC includes inter alia particular environmental xenobiotics; pathogenesis is aided and abetted by genetic weaknesses in mechanisms of immune regulation; and subsequent multilineage immunopathology impacts upon uniquely susceptible BECs to culminate clinically in the chronic autoimmune cholangiolitis of PBC.",0
3496,18098326,Susceptibility of chimeric mice with livers repopulated by serially subcultured human hepatocytes to hepatitis B virus,"We previously identified a small population of replicative hepatocytes in long-term cultures of human adult parenchymal hepatocytes (PHs) at a frequency of 0.01%-0.09%. These hepatocytes were able to grow continuously through serial subcultures as colony-forming parenchymal hepatocytes (CFPHs). In the present study, we generated gene expression profiles for cultured CFPHs and found that they expressed cytokeratin 19, CD90 (Thy-1), and CD44, but not mature hepatocyte markers such as tryptophan-2,3-dioxygenase (TO) and glucose-6-phosphatase (G6P), confirming that these cells are hepatic progenitor-like cells. The cultured CFPHs were resistant to infection with human hepatitis B virus (HBV). To examine the growth and differentiation capacity of the cells in vivo, serially subcultured CFPHs were transplanted into the progeny of a cross between albumin promoter/enhancer-driven urokinase plasminogen activator-transgenic mice and severe combined immunodeficient (SCID) mice. The cells were engrafted into the liver and were able to grow for at least 10 weeks, ultimately reaching a maximum occupancy rate of 27%. The CFPHs in the host liver expressed differentiation markers such as TO, G6P, and cytochrome P450 subtypes and could be infected with HBV. CFPH-chimeric mice with a relatively high replacement rate exhibited viremia and had high serum levels of hepatitis B surface antigen. CONCLUSION: Serially subcultured human hepatic progenitor-like cells from postnatal livers successfully repopulated injured livers and exhibited several phenotypes of mature hepatocytes, including susceptibility to HBV. In vitro-expanded CFPHs can be used to characterize the differentiation state of human hepatic progenitor-like cells.",0
3497,18175357,Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C,"This study determined the utility of a panel of serum fibrosis markers along with routine laboratory tests in estimating the likelihood of histological cirrhosis in a cohort of prior nonresponders with chronic hepatitis C. The relationship between serum markers and quantitative hepatic collagen content was also determined. Liver biopsy samples from 513 subjects enrolled in the HALT-C trial were assigned Ishak fibrosis scores. The collagen content of 386 sirius-red stained, nonfragmented biopsy samples was quantified using computerized morphometry. Serum tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), amino-terminal peptide of type III procollagen (PIIINP), hyaluronic acid (HA), and YKL-40 levels were determined using commercially available assays.Sixty-two percent of patients had noncirrhotic fibrosis (Ishak stage 2-4) whereas 38% had cirrhosis (Ishak stage 5,6). Multivariate analysis identified a 3-variable model (HA, TIMP-1, and platelet count) that had an area under the receiver operating curve (AUROC) of 0.81 for estimating the presence of cirrhosis. This model was significantly better than that derived from the cirrhosis discriminant score (AUROC 0.70), the AST-to-platelet ratio (AUROC 0.73), and a prior model developed in HALT-C patients (AUROC 0.79). Multivariate analysis demonstrated that the serum fibrosis markers correlated substantially better with Ishak fibrosis scores than with the log hepatic collagen content (AUROC 0.84 versus 0.72). CONCLUSION: A 3-variable model consisting of serum HA, TIMP-1, and platelet count was better than other published models in identifying cirrhosis in HALT-C Trial subjects. The stronger correlation of the serum markers with Ishak scores suggests that serum fibrosis markers reflect the pattern of fibrosis more closely than the quantity of hepatic collagen.",0
3498,18184961,A gain-of-function mutation in the HIF2A gene in familial erythrocytosis,"Hypoxia-inducible factor (HIF) alpha, which has three isoforms, is central to the continuous balancing of the supply and demand of oxygen throughout the body. HIF-alpha is a transcription factor that modulates a wide range of processes, including erythropoiesis, angiogenesis, and cellular metabolism. We describe a family with erythrocytosis and a mutation in the HIF2A gene, which encodes the HIF-2alpha protein. Our functional studies indicate that this mutation leads to stabilization of the HIF-2alpha protein and suggest that wild-type HIF-2alpha regulates erythropoietin production in adults.",0
3499,18204098,Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX,"BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci. METHODS: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden. RESULTS: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)). CONCLUSIONS: We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.",0
3500,18216353,Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease,"BACKGROUND: Numerous studies have compared the outcomes of two competing interventions for multivessel coronary artery disease: coronary-artery bypass grafting (CABG) and coronary stenting. However, little information has become available since the introduction of drug-eluting stents. METHODS: We identified patients with multivessel disease who received drug-eluting stents or underwent CABG in New York State between October 1, 2003, and December 31, 2004, and we compared adverse outcomes (death, death or myocardial infarction, or repeat revascularization) through December 31, 2005, after adjustment for differences in baseline risk factors among the patients. RESULTS: In comparison with treatment with a drug-eluting stent, CABG was associated with lower 18-month rates of death and of death or myocardial infarction both for patients with three-vessel disease and for patients with two-vessel disease. Among patients with three-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.80 (95% confidence interval [CI], 0.65 to 0.97) and the adjusted survival rate was 94.0% versus 92.7% (P=0.03); the adjusted hazard ratio for death or myocardial infarction was 0.75 (95% CI, 0.63 to 0.89) and the adjusted rate of survival free from myocardial infarction was 92.1% versus 89.7% (P<0.001). Among patients with two-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.71 (95% CI, 0.57 to 0.89) and the adjusted survival rate was 96.0% versus 94.6% (P=0.003); the adjusted hazard ratio for death or myocardial infarction was 0.71 (95% CI, 0.59 to 0.87) and the adjusted rate of survival free from myocardial infarction was 94.5% versus 92.5% (P<0.001). Patients undergoing CABG also had lower rates of repeat revascularization. CONCLUSIONS: For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with lower rates of death or myocardial infarction and repeat revascularization.",0
3501,18220272,Clearance of hepatitis C virus RNA from the peripheral blood mononuclear cells of blood donors who spontaneously or therapeutically control their plasma viremia,"We determined whether hepatitis C virus (HCV) RNA could be detected associated with peripheral blood mononuclear cells (PBMC) of seropositive blood donors who had spontaneously or therapeutically cleared their plasma viremia. Blood donor plasma viremia status was first determined with a highly sensitive transcription-mediated amplification (TMA) test performed in duplicate assays. PBMC from 69 aviremic and 56 viremic blood donors were then analyzed for the presence of HCV RNA with TMA adapted to detect viral RNA in PBMC and with a reverse transcription-nested polymerase chain reaction assay. PBMC-associated HCV RNA was detected in none of the 69 aviremic donors, including all 6 subjects with a sustained viral response following antiviral therapy. PBMC-associated HCV RNA was detected in 43 of the 56 viremic donors. The 13 viremic donors with no detectable PBMC-associated HCV RNA all had very low viral loads (6 positive only in 1 of 2 duplicate plasma TMA assays, 6 with viral loads below 100 HCV RNA copies/mL, and 1 with a viremia of 2700 HCV RNA copies/mL). The absence of detectable PBMC HCV RNA detection in all 69 aviremic donors reported here contrasts with prior studies, possibly as a result of the higher sensitivity of the TMA assay used to test for plasma viremia. CONCLUSION: Our results indicate that PBMC are unlikely to serve as a long-lived reservoir of HCV in aviremic subjects.",0
3502,18222547,Expression of CD95 on mature leukocytes of MRL/lpr mice after transplantation of genetically modified bone marrow stem cells,"Bone marrow transplantation (BMT) is commonly used for the treatment of severe haematological and immunological diseases. For instance, the autoimmune lymphoproliferative syndrome (ALPS) caused by a complete expression defect of CD95 (Fas, APO-1) can be cured by allogeneic BMT. However, since this therapy may not generate satisfactory results when only partially compatible donors are available, we were interested in the development of a potential alternative treatment by using lentiviral gene transfer of a normal copy of CD95 cDNA in hematopoietic stem cells. Here, we show that this approach applied to MRL/lpr mice results in the expression of functional CD95 receptors on the surface of lymphocytes, monocytes, and granulocytes. This suggests that correction of CD95 deficiency can be achieved by gene therapy. ",0
3503,18222566,Plasma adrenomedullin as an independent predictor of future cardiovascular events in high-risk patients: comparison with C-reactive protein and adiponectin,"This study investigated the predictive power of plasma adrenomedullin (AM) for future cardiovascular (CV) events. In 121 patients with multiple CV risk factors and/or disease, plasma concentrations of AM, high sensitive C-reactive protein (hs-CRP), and adiponectin were measured. During follow-up periods (mean, 3.5 years) after the baseline assessment, 28 patients newly experienced CV events such as stroke/transient ischemic attack, acute coronary syndrome, and congestive heart failure. The plasma level of AM, but not hs-CRP or adiponectin, was significantly higher in patients who had CV events than in event-free subjects. When the patients were divided into three groups by tertiles of basal levels of AM (<10.1, 10.1-13.1, and > or =13.1 fmol/mL), cumulative event-free rates by the Kaplan-Meier method were decreased according to the increase in basal AM levels (83.2%, 68.6%, and 52.8% in the lowest, middle, and highest tertiles of AM, respectively; log-rank test, P=0.033). By univariate Cox regression analysis, previous coronary artery disease, creatinine clearance, and plasma AM and hs-CRP levels were significantly associated with CV events during follow-up. Among these possible predictors, high plasma AM (P=0.004) and low creatinine clearance (P=0.043) were independent determinants for morbidity in multivariate analysis. These findings indicate that plasma AM is a powerful independent predictor of future CV events in high-risk patients, suggesting its predictive value is superior to that of hs-CRP or adiponectin. ",0
3504,18222706,Individual and neighborhood differences in diet among low-income foreign and U.S.-born women,"""Research on the """"immigrant"""" or """"Latino health paradox"""" has demonstrated that Latinos exhibit better health than U.S.-born whites, for multiple health outcomes, despite adjusting for socioeconomic status. However, little empirical research has focused on women and even less has focused on how the neighborhood residential environment is associated with these health differences, particularly in the area of diet. We analyzed baseline data from 641 low-income women, nested within 184 census tracts, enrolled in a nutrition intervention trial for postpartum women. Individual-level variables, including race/ethnicity, nativity, duration of time in the United States, language acculturation, emotional and instrumental support, and socioeconomic position, were merged with tract-level variables from U.S. Census data (2000) based on residential address. We assessed daily fruit and vegetable servings through a semiquantitative food frequency questionnaire. Using MLWin 2.0 software, we employed a 2-level linear regression model to ascertain associations of neighborhood immigrant, racial, and socioeconomic composition with individual diet, adjusting for individual-level sociodemographic characteristics. In our fully adjusted model, we observed a statistically significant increase of 1/3 of fruit and vegetable daily servings for each 10-percentage point increase in the tract foreign-born population. Each 10-percentage point increase in the tract Black population was associated with a significant 1/5 serving decrease in individual daily fruit and vegetable intake. Among this population of U.S. and foreign-born women, neighborhood composition was associated with individual diet, above and beyond individual-level characteristics, illuminating neighborhood context, immigrant health, and diet. """,0
3505,18222938,The effect of the UK incentive-based contract on the management of patients with coronary heart disease in primary care,"The new General Medical Services (nGMS) contract was introduced in April 2004 to improve care of chronic diseases such as coronary heart disease (CHD) and reduce differences in treatment between patient subgroups. To determine whether the recording of CHD-related health indicators and prescribing of medicines have increased following the introduction of the nGMS contract and whether differences in the treatment of patients of differing age, gender and deprivation have been affected. A serial cross-sectional study carried out with 310 general practices in Scotland. The subjects were patients with CHD as identified by their GP. Main outcome measures were the recording of CHD-related health indicators and prescribing of medicines at pre- and post-contract time points (covariates: gender, age, co-morbidity, deprivation and practice size). The recording of CHD-related quality indicators and prescribing increased dramatically (mean absolute increase of 17.1%) after the introduction of the nGMS contract. Post-contract, disparities between patient subgroups, continued for certain components of care. Women were less likely to be recorded than men in 9 of 11 components of care, with older patients (7 of 11 components of care) and the most deprived (4 of 11 components of care) also less likely to have a record than the youngest and least deprived, respectively. The introduction of the new contract was associated with a dramatic rise in the recording of CHD-related quality indicators. However, not all the population benefited equally for certain aspects of care. ",0
3506,18223284,Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience,"The role of reduced-intensity conditioning allogeneic stem cell transplantation in relapsed/refractory Hodgkin's lymphoma remains poorly defined. We here present an update of our single-center experience with fludarabine-melphalan as a preparative regimen. Fifty-eight patients with relapsed/refractory Hodgkin's lymphoma underwent RIC and allogeneic stem cell transplantation from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). Forty-eight (83%) had undergone prior autologous stem cell transplantation. Disease status at transplant was refractory relapse (n=28) or sensitive relapse (n=30). Cumulative day 100 and 2-year transplant-related mortality rates were 7% and 15%, respectively (day 100 transplant-related mortality MRD vs. MUD 8% vs. 6%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II-IV) graft-versus-host disease in the first 100 days was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic graft-versus-host disease at any time was 73% (MRD vs. MUD 57% vs. 85%, p=0.006). Projected 2-year overall and progression-free survival rates are 64% (49-76%) and 32% (20-45%), with 2-year disease progression/relapse at 55% (43-70%). There was no statistically significant differences in overall survival progression-free survival, and disease progression/relapse between MRD and MUD transplants. There was a trend for the response status pretransplant to have a favorable impact on progression-free survival (p=0.07) and disease progression/relapse (p=0.049), but not on overall survival (p=0.4) Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in progression-free survival Hodgkin's lymphoma is associated with a significant reduction in transplant-related mortality, with comparable results in MRD and MUD allografts. Optimizing pretransplant response status may improve patients' outcome. ",0
3507,18223307,Measurement of renal tissue oxygen tension: systematic differences between fluorescence optode and microelectrode recordings in anaesthetized rabbits,"The validity of fluorescence optodes for measurement of renal cortical tissue oxygen tension was tested by comparison with Clark electrodes. We varied renal blood flow and inspired O2 content in anaesthetized rabbits while simultaneously measuring cortical tissue oxygen tension. Cortical oxygen tension varied with inspired O2 content. Fluorescence optode measurements were more tightly distributed than those from a Clark electrode. Cumulative frequency distributions for fluorescence optodes were shifted to the left of those for Clark electrodes. The slope of the relationship between oxygen tension in arterial blood and cortical tissue was less for the fluorescence optode than the Clark electrode. Cortical tissue oxygen tension measurements by these two methods were correlated (r(2) = 0.32; p < 0.001), with no fixed bias but considerable proportional bias. Thus, the slope of the relationship between the two measurements was less than unity (0.57 [0.50-0.69]). Cortical oxygen tension values from fluorescence optodes are less variable but proportionally less than those from Clark electrodes. Theoretical considerations suggest that true interstitial oxygen tension lies somewhere between values provided by the two techniques. Nevertheless, the lesser variability of the fluorescence optode technique may aid detection of physiologically significant changes in intrarenal oxygenation. ",0
3508,18223549,Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity,"We recently reported that the upregulation of adrenal G protein-coupled receptor kinase-2 (GRK2) causes enhanced catecholamine (CA) secretion by desensitizing sympatho-inhibitory alpha (2)-adrenergic receptors (alpha (2)ARs) of chromaffin cells, and thereby aggravating heart failure (HF). In this study, we sought to develop an efficient and reproducible in vivo adrenal gene transfer method to determine whether manipulation of adrenal GRK2 levels/activity regulates physiological CA secretion in rats. We specifically investigated two different in vivo gene delivery methods: direct injection into the suprarenal glands, and retrograde delivery through the suprarenal veins. We delivered adenoviral (Ad) vectors containing either GRK2 or an inhibitor of GRK2 activity, the beta ARKct. We found both delivery approaches equally effective at supporting robust (>80% of the whole organ) and adrenal-restricted transgene expression, in the cortical region as well as in the medullar region. Additionally, rats with AdGRK2-infected adrenals exhibit enhanced plasma CA levels when compared with control rats (AdGFP-injected adrenals), whereas plasma CA levels after Ad beta ARKct infection were significantly lower. Finally, in isolated chromaffin cells, alpha (2)ARs of AdGRK2-infected cells failed to inhibit CA secretion whereas Ad beta ARKct-infected cells showed normal alpha (2)AR responsiveness. These results not only indicate that in vivo adrenal gene transfer is an effective way of manipulating adrenal gland signalling, but also identify GRK2 as a critically important molecule involved in CA secretion. ",0
3509,18223587,Evaluation of a head mounted camera for clinical dental teaching,"To evaluate the potential of a novel head mounted camera to both improve the level of detail observed by learners/teachers observing dental procedures being undertaken and to improve the level of feedback given to learners. Questionnaire. Qualified members of the dental team and those in training evaluated the usefulness of the application of a novel head mounted camera in their clinical teaching within Dundee Dental School and Hospital. A total of 210 questionnaires were issued and received for analysis. Although the device generally improved the level of detail observed by learners/teachers and improved the level of feedback given to learners, there was scope for improving upon image quality. The lighting of the environment in which the camera was used was a critical factor in optimising success. The different members of the dental team displayed different expectations of the device. This was attributed in part to their level of previous exposure to clinical work. In applying this technology it is therefore important to understand the needs of the user. The camera system did enhance the learning experience but required further refinement in relation to image quality. ",0
3510,18224370,Emergency department thoracotomy: survival of the least expected,"""Although emergency department thoracotomy (EDT) is often considered a controversial """"last chance"""" method of resuscitation, we hypothesized that EDT performed in a busy urban Level I trauma center has significant salvage rates despite the absence of traditional survival predictors. A retrospective review revealed that 180 patients underwent EDT after traumatic arrest for penetrating injury between 2000 and 2005. All were deemed nonsalvageable by other resuscitation methods. Injury mechanism and location, signs of life (SOLs), initial cardiac rhythm, and presence of vital signs were analyzed. In total, 23 patients survived hospitalization neurologically intact. Compared to nonsurvivors, survivors more often suffered multiple stab wounds (21.7% vs. 1.9%, p = 0.001), presented with field (95.7% vs. 72.6%, p = 0.016) and ED (87.0% vs. 60.5%, p = 0.014) SOLs, had sustainable cardiac rhythms (sinus tachycardia, 43.5% vs. 10.2%, p = 0.001; normal sinus rhythm, 17.4% vs. 4.5%, p = 0.037), and had measurable vital signs (65.2% vs. 25.5%; p = 0.001). However, only 3 of 23 (13.0%) survivors had all survival predictors, and one survivor had none. Frequent predictors in survivors were field SOLs (95.7%), ED SOLs (87.0%), salvageable initial cardiac rhythms (78.3%), and obtainable vital signs (65.2%). Stabbing mechanism (30.4%) and cardiac injury location (30.4%) were least common. Had a strict policy of EDT performance based solely on the presence of survival predictors been followed and EDT withheld, several patients who ultimately survived would have died. Our study suggests that EDT is a technique that should be utilized for patients with critical penetrating injuries even in the absence of many traditional survival predictors. """,0
3511,18224704,"A 3D QSAR model of 17beta-HSD1 inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core applying molecular dynamics simulations and ligand-protein docking","The 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) enzyme plays a crucial role in female hormonal regulation by catalysing the NADPH-dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17beta-HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report the plausible binding modes and a 3D QSAR model of 17beta-HSD1 inhibitors based on a (di)cycloalkenothieno[2,3-d]pyrimidin-4(3H)-one core. Two generated enzyme complexes with potent inhibitors were subjected to molecular dynamics simulation to mimic the dynamic process of inhibitor binding. A set of 17beta-HSD1 inhibitors based on the thieno[2,3-d]pyrimidin-4(3H)-one core were docked into the resulting active site, and a CoMFA model employing the most extensive training set to date was generated. The model was validated with an external test set. Active site residues involved in inhibitor binding and CoMFA fields for steric and electrostatic interactions were identified. The model will be used to guide structural modifications of 17beta-HSD1 inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core in order to improve the biological activity as well as in the design of novel 17beta-HSD1 inhibitors. ",0
3512,18225536,Piroxicam increases colon tumorigenesis and promotes apoptosis in Mlh1 +/- /Apc1638(N/+) mice,"The present study examines the effect of piroxicam, a non-steroidal anti-inflammatory drug, on tumor development in Mlh1+/- /Apc1638(N/+) mice, in a preclinical model of human colon cancer. Mice were fed AIN-76A diet alone or premixed with piroxicam (60 ppm) for 9 weeks. The number, location and volume of tumors, and apoptosis in the flat mucosa were determined in small and large intestine. Piroxicam reduced the number of tumors per mouse by 80% in the small intestine (0.1 vs. 0.5, p < 0.05). In contrast, piroxicam increased tumor incidence (82% vs. 10%, p < 0.01), tumor multiplicity (1.2 vs. 0.1, p < 0.01) and tumor volume (2.1 vs. 0.2 mm3, p < 0.01) in the colon. Apoptosis increased in the epithelium of the small intestine. Consistent with the increased apoptosis, piroxicam reduced tumors in the small intestine. In the cecum, piroxicam increased tumorigenesis but apoptosis was not decreased, suggesting that other mechanisms besides apoptosis are involved in the differential organ-specific effect on tumorigenesis of piroxicam in this colon cancer model. ",0
3513,18226316,Safety of a modification of the triage level for febrile children 6 to 36 months old using the Paediatric Canadian Triage and Acuity Scale,"""The Paediatric Canadian Triage and Acuity Scale (PaedCTAS) stipulates that febrile patients who are 3 to 36 months old should be triaged to the PaedCTAS 3 """"urgent"""" category. To optimize resource use, we implemented a protocol enabling these children to be down-triaged to the PaedCTAS 4 """"less urgent"""" category if there was no sign of toxicity. Our objective was to evaluate the safety of this triage protocol modification. This retrospective cohort study evaluated all patients triaged in an urban tertiary pediatric hospital during a 6-month period between November 22, 2005, and May 22, 2006. Data were retrieved from the emergency department (ED) database and rates of hospitalization and intensive care unit (ICU) admission were compared for 4 groups: all patients triaged as urgent (level 3), all febrile patients from 3 to 36 months old triaged as urgent (level 3), all patients triaged as less urgent (level 4) and all febrile patients aged 3 to 36 months old who were down-triaged to less urgent (level 4). There were 36,285 total ED visits during the study period, including 3477 febrile children who were 3 to 36 months old. Nurses down-triaged 1869 febrile children (54%) to the level-4 (less urgent) category and left 1322 (38%) in the level-3 (urgent) category. Hospitalization rate for down-triaged febrile patients was similar to that seen for all PaedCTAS 4 patients (2.4% v. 2.8%, 95% confidence interval for difference -0.3% to 1.1%). Down-triaged patients had significantly lower admission rates than those remaining in the level-3 (urgent) category (absolute risk reduction 10.7% standard deviation 1.9%, p<0.001). No down-triaged patient died or required ICU admission. Febrile children aged 6 to 36 months who have no signs of toxicity can safely be down-triaged, based on triage nurse clinical judgement, to the less urgent PaedCTAS 4 category. This modification would affect the triage level of approximately 5% of all pediatric ED visits. """,0
3514,18226673,Decreased waiting periods in a public pregnancy termination clinic,"In our public hospital, first-trimester pregnancy termination historically had been performed in an operating room by suction curettage on a separate day following the initial clinic visit. To increase efficiency, we instituted three changes over a 2-year period: (a) pregnancy termination procedures were relocated to the outpatient area; (b) same-day service was initiated; and (c) manual vacuum aspiration was introduced. Our primary objective was to assess the effects of these changes on the waiting period in days from the intake visit to the day of termination procedure. Our secondary objectives included assessing any decrease in gestational age at the time of procedure, increases in the numbers of procedures at <9 weeks, the numbers of procedures per session and the proportion done on the day of intake. This is a retrospective cross-sectional review of the clinical records of patients who requested pregnancy termination. Data were obtained on 625 patients who underwent a surgical termination of pregnancy from February 1, 2004, to January 31, 2006. The waiting period decreased from 20.3 to 3.6 days (p<.01), and mean gestational age at termination decreased from 11 to 9 weeks (p<.01). The proportion at <9 weeks' gestation increased from 1.7% to 40% (p<.01). The number of procedures per session increased by 52.7% (p<.01). The percentage of same-day procedures increased from 7% to 62%. We improved efficiency of care by reducing the waiting period and terminating pregnancies earlier in gestation with manual equipment. ",0
3515,18226974,Retrospective analysis of abdominal pain in postoperative laparoscopic Roux-en-Y gastric bypass patients: is a simple algorithm the answer?,"""Patients who have undergone laparoscopic gastric bypass have a high risk of developing an internal hernia. Most patients present 9-18 months postoperatively with a weight loss of 75-120 lb and pain out of proportion to the physical findings. Given the risks of internal hernias and the difficulty in radiologic diagnosis, we have developed a single algorithm to avoid the triage complication of a """"missed"""" diagnosis. A retrospective review was performed of 1500 bariatric procedures performed from 2001 to 2006, 33% (laparoscopic Roux-en-Y gastric bypass) of which were performed using an antecolic antegastric Roux limb, with all potential defects, including Peterson's, closed. Of these 1500 patients, 75 were evaluated for abdominal pain to rule out an internal hernia. Of the 75 patients, 40 had signs of an internal hernia or abdominal obstruction on computed tomography and underwent laparoscopy. The operative time was 38-45 minutes, and the length of stay was 1.5 days. The remaining 35 patient's computed tomography scans were interpreted as """"no evidence"""" of internal hernia or obstruction. Of the 35 patients, 29 underwent diagnostic laparoscopy and had either an internal hernia or critical adhesions. Thus, 69 patients (92%) underwent diagnostic laparoscopy. In 6 patients, the symptoms resolved completely without any surgical intervention. At our institution, patients who undergo laparoscopic Roux-en-Y gastric bypass with a weight loss of 75-120 lb undergo computed tomography with contrast to rule out other potential nonoperative causes. Also, unless clinically stable or the patient has complete resolution of their pain, they then undergo laparoscopy for evaluation. """,0
3516,18227036,Screening of differentially expressed genes in human renal cell carcinoma using suppression subtractive hybridization],"To suppress COL1A1 and COL3A1 gene expressions in human skin fibroblasts (HSFs) by means of RNA interference (RNAi). SSH was performed in two directions to isolate the differentially expressed genes between human a RCC cell line RLC-310 and a normal renal cell line HK-2 (ATCC). The cDNAs obtained from the final nested PCR were directly inserted into T/A cloning vector to establish a subtractive cDNA library of specifically or highly expressed genes in RCC. Reverse Northern dot blotting was performed to screen the truly differentially expressed genes, and 200 positive genes were randomly selected for sequencing. The two-directional subtractive libraries contained more than 1200 clones, and 213 positive clones were obtained using reverse Northern blotting. Sequence analysis of these clones identified 144 differentially expressed genes, including 67 up-regulated and 77 down-regulated genes, in which 14 novel ESTs and 21 functionally unknown genes were found. Cluster analysis indicated the involvement of the sequenced genes in cell growth, cell adhesion and apoptosis. Reliable subtractive cDNA libraries of human RCC have been constructed successfully with SSH. The identification of the gene expression profile in RCC may help clarify the mechanism of tumorigenesis and development of RCC, and also sheds light on new targets for prevention, diagnosis and therapy of this malignancy. ",0
3517,18227068,Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice,"Tissue ischemia promotes vasculogenesis through chemokine-induced recruitment of bone marrow-derived endothelial progenitor cells (EPCs). Diabetes significantly impairs this process. Because hyperglycemia increases reactive oxygen species in a number of cell types, and because many of the defects responsible for impaired vasculogenesis involve HIF1-regulated genes, we hypothesized that HIF1 function is impaired in diabetes because of reactive oxygen species-induced modification of HIF1alpha by the glyoxalase 1 (GLO1) substrate methylglyoxal. Decreasing superoxide in diabetic mice by either transgenic expression of manganese superoxide dismutase or by administration of an superoxide dismutase mimetic corrected post-ischemic defects in neovascularization, oxygen delivery, and chemokine expression, and normalized tissue survival. In hypoxic fibroblasts cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the EPC mobilizing chemokine stromal cell-derived factor-1 (SDF-1) and of vascular epidermal growth factor, which modulates growth and differentiation of recruited EPCs. In hypoxic EPCs cultured in high glucose, overexpression of GLO1 prevented reduced expression of both the SDF-1 receptor CXCR4, and endothelial nitric-oxide synthase, an enzyme essential for EPC mobilization. HIF1alpha modification by methylglyoxal reduced heterodimer formation and HIF1alpha binding to all relevant promoters. These results provide a basis for the rational design of new therapeutics to normalize impaired ischemia-induced vasculogenesis in patients with diabetes. ",0
3518,18227271,The muscle chloride channel ClC-1 is not directly regulated by intracellular ATP,"ClC-1 belongs to the gene family of CLC Cl(-) channels and Cl(-)/H(+) antiporters. It is the major skeletal muscle chloride channel and is mutated in dominant and recessive myotonia. In addition to the membrane-embedded part, all mammalian CLC proteins possess a large cytoplasmic C-terminal domain that bears two so-called CBS (from cystathionine-beta-synthase) domains. Several studies indicate that these domains might be involved in nucleotide binding and regulation. In particular, Bennetts et al. (J. Biol. Chem. 2005. 280:32452-32458) reported that the voltage dependence of hClC-1 expressed in HEK cells is regulated by intracellular ATP and other nucleotides. Moreover, very recently, Bennetts et al. (J. Biol. Chem. 2007. 282:32780-32791) and Tseng et al. (J. Gen. Physiol. 2007. 130:217-221) reported that the ATP effect was enhanced by intracellular acidification. Here, we show that in striking contrast with these findings, human ClC-1, expressed in Xenopus oocytes and studied with the inside-out configuration of the patch-clamp technique, is completely insensitive to intracellular ATP at concentrations up to 10 mM, at neutral pH (pH 7.3) as well as at slightly acidic pH (pH 6.2). These results have implications for a general understanding of nucleotide regulation of CLC proteins and for the physiological role of ClC-1 in muscle excitation. ",0
3519,18227404,Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability,"Angiotensin II and aldosterone both promote endothelial dysfunction and atherosclerosis. We investigated the effect of a combination of eplerenone, a selective aldosterone antagonist, and enalapril, an angiotensin-converting enzyme inhibitor, on NO bioavailability and spontaneous atherosclerotic changes. Twenty-four myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), eplerenone (50 mg/kg per day), enalapril (3 mg/kg per day), or eplerenone plus enalapril for 8 weeks (n=6 in each group). After treatment, acetylcholine-induced NO production was measured as a surrogate for endothelium-protective function, and vascular peroxynitrite (a product of superoxide and NO) was measured to assess dysfunctional endothelial NO synthase activity. Plaque area was quantified by histology. Intra-aortic infusion of acetylcholine produced an increase in plasma NO concentration that was significantly higher with all of the drug treatments compared with the control. Eplerenone and enalapril, in combination, increased acetylcholine-induced NO by 7.9 nM, which was significantly higher than with either eplerenone or enalapril alone. Vascular peroxynitrite was significantly higher in the control group (1.3 pmol/mg of protein) and significantly lower with combination treatment (0.4 pmol/mg of protein) compared with the enalapril or eplerenone group. The highest tetrahydrobiopterin levels were observed after cotreatment with eplerenone and enalapril. Histology of the thoracic aorta showed a significantly decreased plaque area with combination therapy compared with monotherapy. Combined treatment with a selective aldosterone antagonist and an angiotensin-converting enzyme inhibitor has additive protective effects on endothelial function and on atherosclerotic changes via decreased nitrosative stress. ",0
3520,18227601,Antimicrobial susceptibility profile of Neisseria gonorrhoeae at STI clinic,"A total of 100 consecutive patients who attended a sexually transmitted infections clinic were studied. Thirteen had gonococcal urethritis, of which 10 showed growth of Neisseria gonorrhoeae on culture. All the isolates were tested for antimicrobial susceptibility by Australian Gonococcal Surveillance Programme (AGSP) method and beta lactamase production by chromogenic cephalosporin test. Four patients were co-infected with each of the following: HIV, HBV and Chlamydia trachomatis . Gonococcal urethritis (13%) was found more in male patients. Ten percent gonococcal isolates were penicillinase-producing N. gonorrhoeae , and another 10% were tetracycline-resistant N. gonorrhoeae . ",0
3521,18227788,Primary sexual disorders: recognition and treatment,"Sexual dysfunction is a common complaint in women across different treatment settings and throughout the lifecycle. Defining normality in sexual response is extremely difficult and little data exists to guide the clinician encountering these complaints. The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) provides a useful classification for sexual dysfunction in both women and men. Female sexual dysfunctions defined in DSM-IV-TR are divided into disorders of desire, arousal, orgasm, and pain. This article defines the scope of the problem of female sexual dysfunction, discusses the diagnosis of various disorders of sexual function, and summarizes available psychological and physiologic treatments. ",0
3522,18228556,Performance of the Panleucogating protocol for CD4+ T cell enumeration in an HIV dedicated laboratory facility in Barbados,"To compare the Panleucogating (PLG) protocol with the routinely used four-color protocol for CD4+ T cell count enumeration. One hundred fifty-three blood samples were randomly selected from samples received at the National HIV Laboratory for routine immunological monitoring. Samples were prepared using Coulter CYTO-STAT tetraCHROME monoclonal antibodies and FlowCARE PLG CD4 reagent for four-color and PLG, respectively, and analyzed on the Beckman Coulter EPICS XL flow cytometer. The PLG protocol used a sequential gating strategy where CD4+ T cells were identified using side scatter properties of cells and CD45 staining. The four-color protocol used CD45 and CD3 to identify CD4+ T cells. Absolute CD4+ T cell counts and percentages ranged from 4 to 1,285 cells/microL and 0.9 to 46.7%, respectively. Linear regression analyses revealed good correlation of PLG with the four-color protocol (absolute counts, R2 = 0.95; percentages, R2 = 0.98) over the entire range including the clinically relevant range. Bland Altman statistics revealed no bias for CD4 counts <500 cells/microL and a slight underestimation by PLG for counts >500 cells/microL (Bias = -32.7 cells/microL; 95% agreement limits = -151.3- +86.0). CD4+ T cell percentages were the similar over the entire range (Bias = 0.6%; 95% agreement limits = -1.97 +/- 3.18). PLG is an accurate method for enumerating CD4+ T cells and has resulted in major cost savings to the Government of Barbados. This has implications for the sustainability of the National HIV containment program in Barbados and the other resource limited Caribbean countries. The PLG technique is now being routinely used in Barbados. ",0
3523,18229670,Bleeding Barrett's ulcer as a complication of GERD [corrected] in physically and intellectually disabled children--report of two cases,"Gastroesophageal reflux disease (GERD) is a problem frequently occurring among physically and intellectually disabled individuals. In this group of patients GERD is often overlooked, since the symptoms are usually non-specific. We present two cases of disabled children, who developed complications of GERD in the form of Barrett's esophagus, Barrett's ulceration and bleeding, the life-threatening events which were not preceded by typical GERD complaints. ",0
3524,18230922,"Epidemiology of nervous system tumors in children: a survey of 1,485 cases in Beijing Tiantan Hospital from 2001 to 2005","The purpose of the present retrospective study was to describe the epidemiology of nervous system tumors in children based on the clinical data obtained from a neurosurgical center in Beijing. During a 5-year period, from January 2001 to December 2005, 1,485 primary brain and spinal tumors in children up to 17 years of age were diagnosed histopathologically according to the World Health Organization 2000 nervous system tumor classification. The sex predilection, tumor location, and histological grade in relation to age were investigated, and the epidemiological characteristics of the 5 most common brain tumors are discussed. Of the 1,485 cases evaluated, brain and spinal tumors comprised 92.3% (1,371) and 7.7% (114), respectively, with a predominance of low-grade tumors (65.1 and 78.9% for brain and spinal cord, respectively). For all tumors, the overall sex ratio (male to female) was 1.6:1. 61.9% of the brain tumors were supratentorial, whereas an infratentorial location was slightly more common in the 872 brain tumors of neuroepithelial tissue (53.7%). The 5 most common brain tumors were astrocytic tumors (30.5%), craniopharyngiomas (18.4%), medulloblastomas (14.6%), germ cell tumors (GCTs, 7.9%) and ependymal tumors (5.6%). The highest preponderance of boys was observed in GCTs followed by medulloblastomas. The most common types of spinal tumors were ependymal tumors (19.3%), neurilemmomas (16.7%) and astrocytomas (14.9%). Based on a large hospital series of pediatric patients, the present survey revealed the histopathological diversity of childhood neurological neoplasms, and provides a reliable profile of the epidemiology of nervous system tumors in children in a developing country. ",0
3525,18231126,Sporadic mutations in melanocortin receptor 3 in morbid obese individuals,"Several mutations in the melanocortin receptor 4 gene have been identified in humans and account for 3-6% of morbid obesity. In contrast, strong evidence of a causative role for melanocortin receptor 3 (MC3R) mutations are still lacking. In MC3R knockout mice, high feed efficiency rather than hyperphagia seems to contribute to increased fat mass. On the basis of this evidence, the objective of the present study was to investigate the presence of MC3R mutations in a group of 290 obese subjects (mean BMI 44.2+/-5.9 kg/m2). As a control, a group of 215 normal-weight subjects (mean BMI 22.4+/-2.7 kg/m2) was also screened. Three novel mutations in the MC3R gene (A293T, I335S and X361S) were identified among the obese patients. The mutations segregated with obesity in the members of the families studied. In vitro expression studies of each mutation demonstrated a loss of function of the I335S-mutated receptor. These findings suggest that, in humans, MC3R mutations may be a cause of a dominantly inherited form of obesity. However, this association as well as the specific phenotypic characteristics resulting from these mutations need to be further evaluated in larger series of obese subjects. ",0
3526,18272886,A nationally representative case-control study of smoking and death in India,"BACKGROUND: The nationwide effects of smoking on mortality in India have not been assessed reliably. METHODS: In a nationally representative sample of 1.1 million homes, we compared the prevalence of smoking among 33,000 deceased women and 41,000 deceased men (case subjects) with the prevalence of smoking among 35,000 living women and 43,000 living men (unmatched control subjects). Mortality risk ratios comparing smokers with nonsmokers were adjusted for age, educational level, and use of alcohol. RESULTS: About 5% of female control subjects and 37% of male control subjects between the ages of 30 and 69 years were smokers. In this age group, smoking was associated with an increased risk of death from any medical cause among both women (risk ratio, 2.0; 99% confidence interval [CI], 1.8 to 2.3) and men (risk ratio, 1.7; 99% CI, 1.6 to 1.8). Daily smoking of even a small amount of tobacco was associated with increased mortality. Excess deaths among smokers, as compared with nonsmokers, were chiefly from tuberculosis among both women (risk ratio, 3.0; 99% CI, 2.4 to 3.9) and men (risk ratio, 2.3; 99% CI, 2.1 to 2.6) and from respiratory, vascular, or neoplastic disease. Smoking was associated with a reduction in median survival of 8 years for women (99% CI, 5 to 11) and 6 years for men (99% CI, 5 to 7). If these associations are mainly causal, smoking in persons between the ages of 30 and 69 years is responsible for about 1 in 20 deaths of women and 1 in 5 deaths of men. In 2010, smoking will cause about 930,000 adult deaths in India; of the dead, about 70% (90,000 women and 580,000 men) will be between the ages of 30 and 69 years. Because of population growth, the absolute number of deaths in this age group is rising by about 3% per year. CONCLUSIONS: Smoking causes a large and growing number of premature deaths in India.",0
3527,18302288,Inhibition of mitochondrial fatty acid oxidation in vivo only slightly suppresses gluconeogenesis but enhances clearance of glucose in mice,"Mitochondrial fatty acid oxidation (mFAO) is considered to be essential for driving gluconeogenesis (GNG) during fasting. However, quantitative in vivo data on de novo synthesis of glucose-6-phosphate upon acute inhibition of mFAO are lacking. We assessed hepatic glucose metabolism in vivo after acute inhibition of mFAO by 30 mg kg(-1) 2-tetradecylglycidic acid (TDGA) in hypoketotic hypoglycemic male C57BL/6J mice by the infusion of [U-(13)C]glucose, [2-(13)C]glycerol, [1-(2)H]galactose, and paracetamol for 6 hours, which was followed by mass isotopomer distribution analysis in blood glucose and urinary paracetamol-glucuronide. During TDGA treatment, endogenous glucose production was unaffected (127 +/- 10 versus 118 +/- 7 micromol kg(-1) minute(-1), control versus TDGA, not significant), but the metabolic clearance rate of glucose was significantly enhanced (15.9 +/- 0.9 versus 26.3 +/- 1.1 mL kg(-1) minute(-1), control versus TDGA,P < 0.05). In comparison with control mice, de novo synthesis of glucose-6-phosphate (G6P) was slightly decreased in TDGA-treated mice (108 +/- 19 versus 85 +/- 6 micromol kg(-1) minute(-1), control versus TDGA, P < 0.05). Recycling of glucose was decreased upon TDGA treatment (26 +/- 14 versus 12 +/- 4 micromol kg(-1) minute(-1), control versus TDGA, P < 0.05). Hepatic messenger RNA (mRNA) levels of genes encoding enzymes involved in de novo G6P synthesis were unaltered, whereas glucose-6-phosphate hydrolase mRNA expressions were increased in TDGA-treated mice. Glucokinase and pyruvate kinase mRNA levels were significantly decreased, whereas pyruvate dehydrogenase kinase isozyme 4 expression was increased 30-fold; this suggested decreased glycolytic activity. CONCLUSION: Acute pharmacological inhibition of mFAO using TDGA had no effect on endogenous glucose production and only a marginal effect on de novo G6P synthesis. Hence, fully active mFAO is not essential for maintenance of hepatic GNG in vivo in fasted mice.",0
3528,18317442,Neuroimaging for the pediatric endocrinologist,"Imaging of the sella and surrounding structures has become essential in the evaluation of pituitary dysfunction and its causes. This article begins with a review of the normal anatomy of the sella and the imaging patterns in and about the normal pituitary gland. There exists considerable variability in the size and configuration of the normal gland in all age groups, and absolute determination of a 'large' or 'small' gland can prove difficult and problematic. Absence of the posterior bright-spot may indicate disruption of the normal stalk transport mechanisms. Microadenomas are well-resolved by magnetic resonance imaging as areas with reduced or delayed enhancement relative to the normal gland. Among hormonally active tumors, adrenocorticotropic hormone-releasing adenomas are most common in the first 11 years of life, while prolactinomas become more common into the teenage years. Macroadenomas tend to present clinically because of mass-effect on adjacent structures, such as the bitemporal hemianopsia seen with optic chiasm compression. Cystic lesions such as Rathke's cleft cysts are commonly seen in the gland, even in healthy children, and their presence need not correlate with any functional abnormality; however, such cysts can cause mass effect on the remaining gland, reflect hemorrhage into adenoma, or actually comprise the central portion of a more worrisome tumor such as craniopharyngioma. Solid tumors of the suprasellar region include optic pathway gliomas, hamartomas, and germinomas. Among inflammatory conditions, granulomatous diseases such as sarcoidosis have predilection for involvement of the suprasellar regions and can spread along perivascular spaces deep within the parenchyma. Because of the association of pituitary endocrinopathies with midline anomalies, one should pay careful attention to midline structures included on a sellar survey. ",0
3529,18317451,Protein kinase C epsilon confers resistance of MCF-7 cells to TRAIL by Akt-dependent activation of Hdm2 and downregulation of p53,"Protein kinase C epsilon (PKC epsilon ) acts as an antiapoptotic protein and inhibits tumor necrosis factor-alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in MCF-7 breast cancer cells. Members of the TNF receptor superfamily trigger apoptosis independent of the tumor suppressor protein p53, which primarily affects DNA damage-induced apoptosis. We have previously shown that PKC epsilon acts upstream of Akt to inhibit receptor-initiated cell death. Since Akt can regulate p53, we have examined the involvement of p53 in PKC epsilon-mediated TRAIL resistance. Overexpression of PKC epsilon in MCF-7 cells (MCF-7/PKC epsilon ) caused a decrease in p53 and an increase in human homolog of murine double minute 2 (Hdm2) and phospho-Hdm2. Depletion of p53 by siRNA attenuated, whereas depletion of Hdm2 enhanced TRAIL-mediated apoptosis. Knockdown of Akt decreased Hdm2 phosphorylation, increased p53 level and potentiated TRAIL-induced cell death. Depletion of epsilon from MCF-7 cells caused an increase in p53, whereas knockdown of p53 caused a decrease in Bid mRNA. Depletion of Akt from MCF-7/PKC epsilon cells resulted in an increase in p53 and Bid. These results suggest that PKC epsilon mediates TRAIL resistance by Akt-mediated phosphorylation of Hdm2 resulting in suppression of p53 expression and downregulation of Bid in MCF-7 breast cancer cells. ",0
3530,18317547,Mind/Body psychological treatments for irritable bowel syndrome,"Currently, the goal of treatment for those with irritable bowel syndrome (IBS) is to improve the quality of life through a reduction in symptoms. While the majority of treatment approaches involve the use of traditional medicine, more and more patients seek out a non-drug approach to managing their symptoms. Current forms of non-drug psychologic or mind/body treatment for IBS include hypnotherapy, cognitive behavioral therapy and brief psychodynamic psychotherapy, all of which have been proven efficacious in clinical trials. We propose that incorporating the constructs of mindfulness and acceptance into a mind/body psychologic treatment of IBS may be of added benefit due to the focus on changing awareness and acceptance of one's own state which is a strong component of traditional and Eastern healing philosophies. ",0
3531,18317698,Poly(lactic-co-glycolic acid) nanosphere as a vehicle for gene delivery to human cord blood-derived mesenchymal stem cells: comparison with polyethylenimine,Polyethylenimine (PEI) is one of the most extensively studied non-viral vectors but its cytotoxicity limits its clinical value. PLGA nanospheres are biocompatible and can facilitate sustained release of plasmid DNA. This study compares the cytotoxicity and long-term transgene expression between PLGA nanosphere and PEI. PLGA nanospheres were significantly less cytotoxic than PEI at various concentrations. PLGA nanospheres induced significantly higher transgene expression in vitro for a longer duration (21 days) than PEI. We conclude that PLGA nanospheres have potential as gene delivery vehicles for use in gene therapy for diseases in which a long-term therapeutic gene expression regimen is necessary. ,0
3532,18318439,Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats,"In cirrhosis, splanchnic vasodilation contributes to portal hypertension, subsequent renal sodium retention, and formation of ascites. Urotensin II(U-II) is a constrictor of large conductive vessels. Conversely, it relaxes mesenteric vessels, decreases glomerular filtration, and increases renal sodium retention. In patients with cirrhosis, U-II plasma levels are increased. Thus, we investigated hemodynamic and renal effects of U-II and its receptor antagonist, palosuran, in cirrhotic bile duct-ligated rats (BDL). In BDL and sham-operated rats, we studied acute effects of U-II (3 nmol/kg; intravenously) and palosuran (10 mg/kg; intravenously) and effects of oral administration of palosuran (30 mg/kg/day; 3 days) on hemodynamics and renal function. We localized U-II and U-II-receptor (UTR) in livers and portal veins by immunostaining. We determined U-II-plasma levels by enzyme-linked immunosorbent assay (ELISA), and mesenteric nitrite/nitrate-levels by Griess-reaction. RhoA/Rho-kinase and endothelial nitric oxide synthase (eNOS) pathways were determined by western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) in mesenteric arteries. U-II plasma levels, as well as U-II and UTR-receptor expression in livers and portal veins of cirrhotic rats were significantly increased. U-II administration further augmented the increased portal pressure (PP) and decreased mean arterial pressure (MAP), whereas palosuran decreased PP without affecting MAP. The decrease in PP was associated with an increase in splanchnic vascular resistance. In mesenteric vessels, palosuran treatment up-regulated expression of RhoA and Rho-kinase, increased Rho-kinase-activity, and diminished nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling. Moreover, palosuran increased renal blood flow, sodium, and water excretion in BDL rats. CONCLUSION: In BDL rats, U-II is a mediator of splanchnic vasodilation, portal hypertension and renal sodium retention. The U-II-receptor antagonist palosuran might represent a new therapeutic option in liver cirrhosis with portal hypertension.",0
3533,18318760,Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders,"Ph-negative chronic myeloproliferative disorders (CMPD) are characterized by constitutive Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. SOCS3, SOCS1 and PTPN6 (SHP1) are negative regulators of the JAK-STAT pathway. We investigated epigenetic and genetic inactivation of SOCS3, SOCS1 and PTPN6 in 112 CMPD and 20 acute myeloid leukaemia (AML) post-CMPD. SOCS3 methylation occurred at high frequency in both CMPD (46/112; 41.1%) and AML post-CMPD (10/17; 58.8%) and was associated with transcriptional silencing. In contrast, methylation of SOCS1 and PTPN6 was observed in only a fraction of CMPD (15/112, 13.4% for SOCS1; and 8/112, 7.1% for PTPN6) and AML post-CMPD (3/20, 15% for SOCS1; and 1/20, 5% for PTPN6). No somatic mutations of SOCS1 were found in CMPD. SOCS3, SOCS1 and PTPN6 methylation occurred in both JAK2V617F-positive (35.1% for SOCS3; 14.9% for SOCS1; 8.1% for PTPN6) and JAK2V617F-negative (57.1% for SOCS3; 14.3% for SOCS1; and 9.5% for PTPN6) CMPD. These data indicate that methylation of SOCS3 and, to a lesser extent, SOCS1 and PTPN6 is a frequent event in both JAK2V617F-positive and -negative CMPD and may act as an alternative or complementary mechanism to JAK2 mutations, enhancing cytokine signal transduction. The frequent inactivation of SOCS3 is a novel finding in CMPD with potential implications for the molecular pathology of these disorders. ",0
3534,18318762,Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma,"The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)-alemtuzumab allogeneic HSCT (BEAM-allo) (n = 44) or BEAM-autologous HSCT (BEAM-auto) (n = 82). The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0.001) but received a higher median number of therapies pretransplant (P = 0.015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0.001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0.01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0.99) or disease-free survival (DFS) (P = 0.90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT. ",0
3535,18319572,Histopathological characteristics of hepatic lipogranulomas with portosystemic shunt in dogs,"In the canine liver with portosystemic shunts (PSS), focal lesions consisting of cells with cytoplasmic brown pigments and lipid vacuoles are often observed in the hepatic parenchyma. Termed lipogranulomas, their histopathological characteristics have been little studied. In the present study, we examined liver biopsy samples from 144 dogs (age: 3 months-16 years; 65 PSS and 79 non-PSS cases), and investigated the histopathological characteristics, incidence, and density of lipogranulomas. Lipogranulomas were detected histopathologically in 55.4% of PSS dogs. The lesions were then grouped into 3 types according to the amount of cytoplasmic lipid vacuoles and brown pigments. The pigments were positive for Berlin blue, PAS, and Sudan black B, but negative with the Hall method. The majority of the cells were immunohistochemically positive for macrophage scavenger receptor, class A (MSR-A), while no cells were positive for hepatocyte-antigen and albumin. The cytoplasmic pigments were recognized as electron-dense microgranular materials by electron microscopy. The incidence of lipogranulomas was significantly higher in the PSS group than non-PSS group when dogs less than 1 year old were excluded. The lipogranuloma density in the liver was significantly higher in the PSS group. It is concluded that lipogranulomas are frequently observed in liver biopsies of canine PSS especially in dogs more than 1 year old. The lesions consisted of Kupffer cells and/or macrophages, and the cytoplasmic brown pigments are ceroid and hemosiderin. The pathogenesis of lipogranuloma in PSS needs to be clarified. ",0
3536,18319577,Prevention of biofilm formation with a coating of 2-methacryloyloxyethyl phosphorylcholine polymer,"Device-associated infections are serious complications, and their prevention is an issue of considerable importance. Since biofilms are responsible for these refractory infections, effective methods to inhibit biofilm formation are required. In this investigation, stainless steel plates with and without 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, i.e., poly (MPC-co-n-butyl methacrylate) (PMB) coating, were incubated in a medium containing bacteria. In the course of incubation, half of the specimens received antibiotics. The specimens were stained for nucleic acid and polysaccharides, and then examined with a confocal laser scanning microscope. The numbers of bacteria on the specimen surfaces were evaluated by an ATP assay. On the surfaces of the specimens without PMB coating, the formation of a biofilm enveloping bacteria was confirmed. The addition of antibiotics did not effectively decrease the number of bacteria. On the other hand, on the surfaces of the specimens with PMB coating, no biofilm formation was observed, and the number of bacteria was significantly decreased. The addition of potent antibiotics further decreased the number of bacteria by 1/100 to 1/1000 times. The PMB coating combined with the validated use of antibiotics might provide a method for the simultaneous achievement of biocompatible surfaces of devices and the prevention of device-associated infections. ",0
3537,18319631,Quality of life (QoL) and motivation for treatment: a female issue?,"""The Quality of Life (QoL) of overweight and obese subjects is a widely discussed topic. From numerous studies, it emerges that obese persons suffer significant damage as result of their overweight in terms of QoL with regard to their physical and psychosocial well-being, with greater incidence associated with the degree of obesity. Our study aims at evaluating the usefulness of specific psychometric tests on the """"obese population"""" that may be effective for the overall evaluation of the patient and in identifying specific subgroups on the basis of psychometric characteristics relating to QoL and of motivation for treatment. The study was carried out on a sample of 150 obese subjects who approached the Section of Human Nutrition of the University of Pavia requesting treatment for weight loss. The persons in the selected sample were subjected to a specialized examination during which, as well as collecting all the anamnestic information on each individual patient, they were also asked to fill out the obesity-specific ORWELL 97 (Obesity Related Well- Being) questionnaire and the DBI (Decisional Balance Inventory) questionnaire. An analysis of the results indicates that the female group is strongly characterized by a lower QoL, as well as by a clearly larger number of failed dieting attempts and by a strong motivation to undergo treatment. The evaluation of QoL and motivation for treatment in overweight and obese individuals appears to be an effective tool for better identification of the subjects and for planning the most appropriate diagnostic approach. """,0
3538,18320023,"Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target","Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease. In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%), which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. We suggest that targeting HSP90 will have clinical impact for NSCLC patients. ",0
3539,18320028,Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury,"The blood brain barrier (BBB) and truncated trkB receptor on astrocytes prevent the penetration of brain derived neurotrophic factor (BDNF) applied into the peripheral (PNS) and central nervous system (CNS) thus restrict its application in the treatment of nervous diseases. As BDNF is anterogradely transported by axons, we propose that peripherally derived and/or applied BDNF may act on the regeneration of central axons of ascending sensory neurons. The present study aimed to test the hypothesis by using conditioning lesion of the sciatic nerve as a model to increase the expression of endogenous BDNF in sensory neurons and by injecting exogenous BDNF into the peripheral nerve or tissues. Here we showed that most of regenerating sensory neurons expressed BDNF and p-CREB but not p75NTR. Conditioning-lesion induced regeneration of ascending sensory neuron and the increase in the number of p-Erk positive and GAP-43 positive neurons was blocked by the injection of the BDNF antiserum in the periphery. Enhanced neurite outgrowth of dorsal root ganglia (DRG) neurons in vitro by conditioning lesion was also inhibited by the neutralization with the BDNF antiserum. The delivery of exogenous BDNF into the sciatic nerve or the footpad significantly increased the number of regenerating DRG neurons and regenerating sensory axons in the injured spinal cord. In a contusion injury model, an injection of BDNF into the footpad promoted recovery of motor functions. Our data suggest that endogenous BDNF in DRG and spinal cord is required for the enhanced regeneration of ascending sensory neurons after conditioning lesion of sciatic nerve and peripherally applied BDNF may have therapeutic effects on the spinal cord injury. ",0
3540,18320520,Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial,"To evaluate the additional therapeutic effect of single intravitreal bevacizumab injection on standard laser treatment in the management of proliferative diabetic retinopathy. A prospective, fellow-eye sham controlled clinical trial was conducted on 80 eyes of 40 high-risk characteristic proliferative diabetic retinopathy type II diabetics. All cases received standard laser treatment according to Early Treatment Diabetic Retinopathy Study protocol. Avastin-assigned eyes received 1.25 mg intravitreal bevacizumab (Genentech Inc., San Francisco, CA) on the first session of their laser treatments. Fluorescein angiography was performed at baseline and at weeks 6 and 16, and proliferative diabetic retinopathy regression was evaluated in a masked fashion. The median age was 52 years (range: 39-68) and 30% of the participants were male. All patients were followed for 16 weeks. A total of 87.5% of Avastin-injected eyes and 25% of sham group showed complete regression at week 6 of follow-up (p<0.005). However, at week 16, PDR recurred in a sizable number of the Avastin-treated eyes, and the complete regression rate in the two groups became identical (25%; p=1.000); partial regression rates were 70% vs 65%. In the subgroup of Avastin-treated eyes, multivariate analysis identified hemoglobin A1c as the strongest predictor of proliferative diabetic retinopathy recurrence (p=0.033). Intravitreal bevacizumab remarkably augmented the short-term response to scatter panretinal laser photocoagulation in high-risk characteristic proliferative diabetic retinopathy but the effect was short-lived, as many of the eyes showed rapid recurrence. Alternative dosing (multiple and/or periodic intravitreal Avastin injections) is recommended for further evaluation. ",0
3541,18320532,Optociliary shunt vessels in compressive optic neuropathy by the intracranial internal carotid artery,"To report a clinical case of optic nerve compression by supraclinoidal internal carotid artery associated with optociliary shunt vessels. A 78-year-old woman with the clinical triad of left visual loss, ipsilateral optic disc pallor, and retinochoroidal (optociliary) shunt vessels is reported. She complained of loss of vision in the left eye of 2 years'' duration. A diffuse depression of the visual field was found in the affected eye. Magnetic resonance imaging revealed left optic nerve compression by the supraclinoidal internal carotid artery. The occurrence of optociliary shunt vessels, visual loss, and optic atrophy is a nonspecific sign of chronic optic nerve compression and in some instances may be falsely localized. ",0
3542,18320804,Recent advances of endoscopic treatment for esophageal cancer],"The indications for endoscopic treatment are limited to cases without lymph node metastasis, because it is only a local therapy. The relationship between cancer depth and lymph node metastasis has been clarified based on the pathologic analysis of lymph nodes removed during esophagectomy for early esophageal cancer. Cancer confined to the lamina propria mucosa rarely undergoes lymph node metastasis and complete endoscopic resection (ER) is indicated. ER allows the esophagus to be preserved and is less invasive, enabling specimens to be pathologically examined. Lesions extending over large area can be resected by repeating endoscopic mucosal resection (EMR), but have recently been resected using endoscopic submucosal dissection (ESD), as indicated for gastric cancer. Which of the two procedures, EMR or ESD, to be chosen depends on the difficulty, skill of the surgeon, time to be spared, and economic management. ER is now performed in SM1 without lymph node metastasis, although some patients require additional treatment after pathologic examination of resected lesions. ",0
3543,18320865,"Influence of adiposity on leptin, LH and androgen levels in lean, overweight and obese PCOS patients","Leptin modulates hypothalamic-pituitary-gohadal axis functions. To assess the influence of leptin on LH, and to investigate the potential association of leptin with body mass index (BMI) and androgen concentrations in women with polycystic ovary syndrome (PCOS). Levels of leptin, LH, FSH, E2, testosterone, and androstenedione were measured. 91 patients with PCOS were included in this study. Patients were stratified into three groups according to BMI: normal weight (NW group, N=31), overweight patients (OW group N=30) and obese PCOS patients (Ob group, N=30). Results-Hyperandrogenemia was present in the studied group. A significant correlation was observed between BMI and androgens (both P < 0.01), and between leptin levels and androgens (respectfully for androstenendione P < 0.01 and for testosterone P < 0.05). A positive correlation between the LH and leptin levels in NW (P < 0.05) and OW (P < 0.001) patients was noticed, while negative correlation is seen in the Ob group (P < 0.01). In OW patients the significant positive correlation between leptin levels and androstenendione was found (P < 0.001), after correction for BMI. A linear regression model indicated that leptin concentrations and BMI contributed negatively and significantly (P < 0.001) to LH concentrations. LH secretion in PCOS patients can be viewed as a consequence of the activity of different adipocyte and neuroendocrine factors. The attenuation in basal LH levels in obese PCOS women might be related to a leptin-resistant state. ",0
3544,18321269,"Workforce profile, organisation structure and role responsibility for ventilation and weaning practices in Australia and New Zealand intensive care units","To provide an analysis of the scope of nursing practice and inter-professional role responsibility for ventilatory decision-making in Australian and New Zealand (ANZ) intensive care units (ICU). Currently, little empirical data describe nurses' role in decision-making for ventilation and its weaning. Delineation of roles and responsibilities for ventilatory practices vary according to unit structure, staffing and skill-mix, patient case-mix and unit leadership models. Self-administered questionnaire sent to nurse managers of eligible ICUs within ANZ. Results. Survey responses were available from 54/180 ICUs. The majority (71%) of responding ICUs were located within metropolitan areas and categorised as a tertiary level ICU (50%). The mean number of nurses employed per ICU bed was 4.7 in Australia and 4.2 in NZ, with 69% (IQR: 47-80%) of nurses holding a postgraduate specialty qualification. All units reported a 1:1 nurse-to-patient ratio for ventilated patients with 71% reporting a 1:2 nurse-to-patient ratio for non- ventilated patients. Key ventilator decisions, including assessment of weaning and extubation readiness, were reported as predominantly made by nurses and doctors in collaboration. Overall, nurses described high levels of autonomy and influence in ventilator decision-making. Decisions to change ventilator settings, including FiO(2) (91%, 95% CI: 80-97), ventilator rate (65%, 95% CI: 51-77) and pressure support adjustment (57%, 95% CI: 43-71), were made independently by nurses. The results of this survey suggest, within the ANZ context, nurses participate actively in ventilation and weaning decisions. In addition, the results support an association between the education profile and skill-mix of nurses and the level of collaborative practice in ICU. Relevance to clinical practice. Mechanical ventilation may result in significant complications if not applied appropriately. Collaborative practice that encourages nursing input into decision-making may improve patient outcomes and reduce complications. ",0
3545,18321291,Menopausal symptom perception and severity: results from a screening questionnaire,"Although it is widely acknowledged women experience symptoms during their transition from reproductive to postreproductive stage, there is inconsistency as to the prevalence of symptoms as well as their severity ratings. The purpose of this study was to describe symptom perception and severity in mid-life women volunteering for an intervention study for menopause symptom management. A cross-sectional descriptive design was used to provide data on presenting symptoms in a sample of women negotiating the menopausal transition. A community-based sample of Caucasian women aged 43-55 years was recruited from national nursing media, local media and a variety of local community sources. A screening questionnaire was administered to determine qualification for study entry based upon symptom severity scores from the questionnaire. This report includes results from the screening questionnaire. One hundred and sixty-five women were screened to obtain 110 qualified participants with mean age of 49.3 SD 3.04 years who were 4.7 SD 7 months past their last menstrual period. Sleep difficulties, forgetfulness and irritability were perceived by the highest number of women while sleep difficulties, night sweats, irritability and forgetfulness were rated the most severe. Findings from this study expand understanding of the menopause symptom experience, because few reports include symptom severity reports. All aspects of the symptom experience are necessary to develop appropriate interventions and to evaluate them. Providing education about menopause symptoms is central to nursing practice of mid-life women. Therefore, nurses must keep abreast of current knowledge to prepare women for their transition to postreproductive phase or to reassure women who are surprised to find hot flashes are not the only symptoms encountered. ",0
3546,18321435,Biliary parasites: diagnostic and therapeutic strategies,"Parasitic infections of the biliary tract are a common cause of biliary obstruction in endemic areas. This article focuses on primary biliary parasites: Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Dicrocoelium dendriticum, Fasciola hepatica, and Fasciola gigantica. Tropical and subtropical countries have the highest incidence and prevalence of these infections. Diagnosis is made primarily through direct microscopic examination of eggs in the stool, duodenal, or bile contents. Radiologic imaging may show intrahepatic ductal dilatation, whereas endoscopic retrograde cholangiopancreatography can be used diagnostically and therapeutically. However, oral treatment is inexpensive and effective for most of these parasites and can prevent untoward consequences. Primary and alternative treatments are available and are reviewed in this article. ",0
3547,18321493,The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count,"To assess the value of antimullerian hormone (AMH) as a test to predict poor ovarian response and pregnancy occurrence after IVF and to compare it with the performance of the antral follicle count (AFC). A systematic review of existing literature and a meta-analysis were carried out. After a comprehensive search, studies were included if 2 x 2 tables for outcomes poor response and pregnancy in IVF patients in relation to AMH or AFC could be constructed. Academic referral center for tertiary care. Cases indicated for IVF. None. Poor response and nonpregnancy after IVF. A total of 13 studies were found reporting on AMH and 17 on AFC. Because of heterogeneity among studies, calculation of a summary point estimate for sensitivity and specificity was not possible. However, for both tests summary receiver operating characteristic curves for the outcome measures poor response and nonpregnancy could be estimated and compared. The curves for the prediction of poor response indicated no significant difference between the performances of AMH and AFC. For the prediction of nonpregnancy, poor performance for both AMH and AFC was found. In this meta-analysis it was shown that AMH has at least the same level of accuracy and clinical value for the prediction of poor response and nonpregnancy as AFC. ",0
3548,18321793,Pathogenomics: an updated European Research Agenda,"""The emerging genomic technologies and bioinformatics provide novel opportunities for studying life-threatening human pathogens and to develop new applications for the improvement of human and animal health and the prevention, treatment, and diagnosis of infections. Based on the ecology and population biology of pathogens and related organisms and their connection to epidemiology, more accurate typing technologies and approaches will lead to better means of disease control. The analysis of the genome plasticity and gene pools of pathogenic bacteria including antigenic diversity and antigenic variation results in more effective vaccines and vaccine implementation programs. The study of newly identified and uncultivated microorganisms enables the identification of new threats. The scrutiny of the metabolism of the pathogen in the host allows the identification of new targets for anti-infectives and therapeutic approaches. The development of modulators of host responses and mediators of host damage will be facilitated by the research on interactions of microbes and hosts, including mechanisms of host damage, acute and chronic relationships as well as commensalisms. The study of multiple pathogenic and non-pathogenic microbes interacting in the host will improve the management of multiple infections and will allow probiotic and prebiotic interventions. Needless to iterate, the application of the results of improved prevention and treatment of infections into clinical tests will have a positive impact on the management of human and animal disease. The Pathogenomics Research Agenda draws on discussions with experts of the Network of Excellence """"EuroPathoGenomics"""" at the management board meeting of the project held during 18-21 April 2007, in the Villa Vigoni, Menaggio, Italy. Based on a proposed European Research Agenda in the field of pathogenomics by the ERA-NET PathoGenoMics the meeting's participants updated the established list of topics as the research agenda for the future. """,0
3549,18322172,Morphine withdrawal inhibits IL-12 induction in a macrophage cell line through a mechanism that involves cAMP,"There are very few studies that examine the effects that morphine withdrawal has on immune functioning, and of these even fewer describe the mechanisms by which withdrawal brings about these changes. Our previous work demonstrated that morphine withdrawal contributed to Th cell differentiation by biasing cells toward the Th2 lineage. A major finding from these studies was that IL-12 was decreased following withdrawal, and it was concluded that this decrease may be a mechanism by which morphine withdrawal is mediating Th2 polarization. Therefore, it was the aim of the current studies to develop an in vitro model to examine the process of morphine withdrawal and to understand the signaling mechanisms that withdrawal may use to effect IL-12 production through the use of this model. It was demonstrated and concluded that morphine withdrawal may be effecting IL-12 production by increasing cAMP levels, which activates protein kinase A. Protein kinase A activation then prevents the phosphorylation and subsequent degradation of IkappaB, which in turn prevents translocation of the NF-kappaB p65 subunit to the nucleus to transactivate the IL-12 p40 gene, ultimately resulting in decreased IL-12 production following LPS stimulation. ",0
3550,18322545,A novel renal carbonic anhydrase type III plays a role in proximal tubule dysfunction,"Dysfunction of the proximal tubule (PT) is associated with variable degrees of solute wasting and low-molecular-weight proteinuria. We measured metabolic consequences and adaptation mechanisms in a model of inherited PT disorders using PT cells of ClC-5-deficient (Clcn5Y/-) mice, a well-established model of Dent's disease. Compared to cells taken from control mice, those from the mutant mice had increased expression of markers of proliferation (Ki67, proliferative cell nuclear antigen (PCNA), and cyclin E) and oxidative scavengers (superoxide dismutase I and thioredoxin). Transcriptome and protein analyses showed fourfold induction of type III carbonic anhydrase in a kidney-specific manner in the knockout mice located in scattered PT cells. Kidney-specific carbonic anhydrase type III (CAIII) upregulation was confirmed in other mice lacking the multiligand receptor megalin and in a patient with Dent's disease due to an inactivating CLCN5 mutation. The type III enzyme was specifically detected in the urine of mice lacking ClC-5 or megalin, patients with Dent's disease, and in PT cell lines exposed to oxidative stress. Our study shows that lack of PT ClC-5 in mice and men is associated with CAIII induction, increased cell proliferation, and oxidative stress. ",0
3551,18322690,Axillary nerve palsy after retrograde humeral nailing: clinical confirmation of an anatomical fear,"Locked antegrade or retrograde nailing of humeral shaft and proximal humerus fractures is a well established treatment option. Anatomic-morphological studies revealed a potential high risk of axillary nerve injury within proximal interlocking screw insertion. However, clinical experiences do not seem to confirm this, as there is a lack of interlocking screw insertion associated axillary lesions in literature. We report about a 69-year-old man with a humeral shaft fracture (AO-type 12-A3) stabilized by a retrograde implanted interlocking nail. Proximal interlocking screw insertion was performed in a posterior-to-anterior direction. The fracture healed uneventfully. In a follow-up examination 2 years later, an atrophy and paralysis of the deltoid muscle were visible. Electrophysiological evaluation confirmed an isolated axillary nerve injury. Nevertheless, the patient showed good functional recovery with almost free range of motion. Even for clinical practise proximal interlocking screw insertion is associated with a substantial risk of axillary nerve injury. Particularly for posterior-to-anterior screw insertion anatomic conditions should be considered. In spite of axillary nerve lesion, recovery of almost full shoulder function is possible by compensating the loss of deltoid function by rotator cuff muscles. ",0
3552,18322824,An epidermal growth factor-like repeat of Del1 protein increases the efficiency of gene transfer in vitro,"In this paper, we found that Del1, an extracellular matrix protein secreted by embryonic endothelial cells, increases the efficiency of transfection in vitro. Conditioned medium containing Del1 increased transfection by the LacZ gene using several non-viral gene transfer systems, including lipoplex and polyplex methods. Experiments using deletion mutants and fragments of Del1 revealed that the third epidermal growth factor-like repeat (E3) of Del1 mediates the enhancement of gene transfer and, furthermore, that the motif CXDXXXFXCXC is essential. Incubation of Pro5 cells, a yolk sac-derived cell line, with as low as 16 pM recombinant E3 was sufficient to enhance transfection, and 1 nM recombinant E3 enhanced the transfection 12-fold. Inhibitors of endocytosis suppressed this activity of the recombinant E3. These results suggest that the E3 fragment of Del1 can be used as a general biological enhancer of non-viral gene transfer. ",0
3553,18323126,Cadmium toxicity in a marine diatom as predicted by the cellular metal sensitive fraction,"Prediction of metal bioaccumulation and toxicity in aquatic organisms has been based on the free ion activity (e.g., FIAM) or more recently on the binding with the biological/toxicological sites of action (e.g., biotic ligand model). However, metals are bound to various intracellular ligands that may control metal toxicity. In this study, we examined the bioaccumulation, subcellular distribution, and toxicity of Cd in a marine diatom, Thalassiosira nordenskioeldii, under different irradiance levels. The diatoms accumulated more cellular Cd under higher irradiance at low [Cd2+] concentrations, but the accumulation slowed down when the [Cd2+] concentration further increased, implying that cellular binding saturation had been reached. Among the five operationally defined subcellular fractions (metal-rich granule, cellular debris, organelles, heat-denatured protein [HDP], and heat-stable protein [HSP]), Cd was most bound to HSP, whereas it was least bound to HDP. Cd was redistributed with increasing [Cd2+] concentration from the biologically detoxified pool to the presumed metal-sensitive fractions (MSF, a combination of organelles and HDP), which led to higher cellular Cd accumulation, toxicity, and sensitivity. Although diatom growth inhibition was significantly related to [Cd2+] concentration and Cd cellular bioaccumulation, the calculated inhibition concentrations based on MSF or organelles exhibited the least difference, strongly suggesting that MSF can provide the better predictor of Cd toxicity under different irradiance levels compared with [Cd2+] concentration or cellular accumulation. Our results demonstrated that models predicting metal toxicity need to address the subcellular fates of metals and how they respond to external and internal conditions. ",0
3554,18323166,Quantitative analysis of survivin mRNA expression in bladder transitional cell carcinomas,"We assessed the expression levels of survivin mRNA in bladder transitional cell carcinoma (TCC) to provide additional information regarding its malignant potential. The real-time PCR method was used to detect the survivin mRNA level for 21 bladder tumor specimens, and for urinary exfoliated cells from 12 newly diagnosed bladder tumor patients. All bladder tumor specimens and 7 of 12 voided urine specimens expressed survivin mRNA. In tumor specimens, high grade, high stage tumors had the tendency to express more survivin mRNA. Of 12 superficial bladder tumor patients who had transurethral resection of bladder tumor (TURB), 3 showed high survivin mRNA expression and intravesical recurrence after the surgery. However, for the patients who had total cystectomy due to invasive tumor, no relations were observed between the survivin mRNA expression level and development of local recurrence and/or distant metastasis. Our results suggested that the quantitative analysis of the survivin mRNA may indicate local malignant potential, which contribute to the possibility of an intravesical recurrence. ",0
3555,18323175,Prostate cancer in a relatively young adult: a case report],"We report a case of prostate cancer in a 45-year-old. The patient was found to have an elevated prostate specific antigen (PSA) level at a general health check and was referred to our division. Serum level of PSA was 6.9 ng/ml. Digital rectal examination and magnetic resonance imaging revealed a small nodule on the right lobe. Transperineal needle biopsy of the prostate revealed adenocarcinoma at the bilateral lobe (Gleason score 3+4). Computed tomography and a bone scan showed no evidence of metastasis. The patient was diagnosed as cT2b, NO, MO, and underwent a radical prostatectomy. Patients younger than 45 with prostate cancer are rare, although the incidence of prostate cancer is increasing. Here, 25 cases previously reported in Japan in addition to the present case, are reviewed. ",0
3556,18323402,Pharmacological and clinical aspects of heme oxygenase,"This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system. ",0
3557,18323468,Endotoxin-induced proteolytic reduction in hepatic growth hormone (GH) receptor: a novel mechanism for GH insensitivity,"GH is an important anabolic hormone. We previously demonstrated in cell culture that the cell surface GH receptor (GHR) is susceptible to inducible metalloproteolytic cleavage that yields the shed receptor extracellular domain (called GH binding protein) and renders the cells desensitized to subsequent GH stimulation. Sepsis and inflammatory states are associated with hepatic desensitization to GH, although disparate mechanisms have been postulated in various animal models. Using C3H/HeJ mice, we now demonstrate that administration of lipopolysaccharide (LPS) causes marked hepatic desensitization to GH, assessed by monitoring signal transducer and activator of transcription 5 tyrosine phosphorylation and nuclear accumulation and with a novel noninvasive bioluminescence imaging system to track in vivo hepatic GH signaling serially in individual mice. This endotoxin-induced desensitization was accompanied by marked loss of hepatic GHR, which was not explained by changes in GHR mRNA abundance. Furthermore, we observe that LPS causes GH-binding protein shedding of a hepatically expressed wild-type GHR but not a GHR with a mutation in the metalloprotease cleavage site. These data suggest that in this model system, LPS-induced desensitization to GH is associated with proteolytic GHR cleavage. These data are the first to demonstrate inducible in vivo GHR proteolysis and suggest this is a mechanism to regulate GH sensitivity and its anabolic effects during sepsis or inflammation. ",0
3558,18323716,"Evaluation of a waterless, scrubless chlorhexidine gluconate/ethanol surgical scrub and povidone-iodine for antimicrobial efficacy]","The purpose of this study was to compare 1% chlorhexidine-gluconate/61% ethanol (CHG/Ethanol) emollient and 7.5% povidone-iodine (PVI) scrub for antimicrobial,residual effect, and skin condition. CHG/Ethanol emollient hand hygiene was performed waterless, and brushless by operating doctors and nurses (N=20). PVI hand washing was performed with water and a brush (N=20) for 5 min. The subjects were asked to press their left hand in hand-shaped agar before a surgical scrub, immediately after a surgical scrub and after the operation. The amount of isolated microorganisms were calculated by counting the number of divided areas(1 x 1 cm, 160 cell) which were culture positive in the hand culture plate. The skin condition was evaluated. The antimicrobial count of CHG/Ethanol emollient and PVI immediately post surgical scrub was 0.0 vs. 4.1 (p>.05), and after the operation was 0.1 vs. 37.8 (p>.05)respectively. The Residual effect of CHG/Ethanol emollient immediately post surgical scrub and after the operation were 0.0 vs. 0.1 (p>.05), and PVI were 4.1 vs. 37.8 (p>.05)respectively. The skin condition and satisfaction of CHG/Ethanol emollient was higher than PVI (p<.05). The antimicrobial effect between CHG/Ethanol emollient and PVI were the same. Considering skin condition, satisfaction and allergic reaction CHG/Ethanol emollient for surgical scrub is recommended in Korea. ",0
3559,18323852,Expression-targeted gene therapy for the treatment of transitional cell carcinoma,"Targeted gene delivery for induced apoptosis of transitional cell carcinomas was carried out in vivo in mice via utilization of the murine cyclooxygenase type 2 (Cox-2) promoter (Tis10). MB49 cells, which constitutively overexpress Cox-2 like numerous other carcinomas, selectively expressed delivered genes that utilized this transcriptional control element. The products of the delivered genes were artificially inducible forms of caspases 3 and 9, which remained inactive until a chemical inducer of dimerization was later injected intraperitoneally. The genes were delivered intravesically as plasmids complexed with poly(ethylenimine). Significant improvements, in the form of reduced bladder mass, reduced tumor volume, anti-angiogenesis and inhibition of tumor growth were seen versus untreated or unactivated controls. In some instances, tumors were seen to go into complete remission. There were no apparent bystander effects associated with the treatments. This targeted gene therapy regimen could have wide applicability to numerous cancers due to constitutive overexpression of Cox-2. ",0
3560,18324583,Therapy effects of testosterone on the recovery of bone defects],"Androgens have proliferative effects on osteoblasts and increase fracture healing by systemic and local stimulation of bone formation. The aim of the present study was to evaluate if the systemic stimulation by androgens leads to increased bone-defect healing. 1.5-mm trepanation defects were created in the femoral diaphysis of 30 Sprague-Dawley rats. 10 animals were used as untreated controls and 10 animals per group were treated by intramuscular injection of 1 or 10 mg dihydrotestosterone two days prior to surgery. After 14 days the samples were explanted and examined by macroscopy, histology and histomorphometry. All animals were included into the study and were analysed. Clinical observation showed no complications. Macroscopic examination and histology showed no significant differences. All defects were filled with trabecular bone in direct contact to the surrounding bone. Histomorphometry showed a significantly decreased bone content in the controls in comparison to both therapy groups, while the therapy groups showed no significant differences between each other. The stimulation of healing of bone defects with androgens leads to a significantly higher bone content inside the defects. In clinical application, androgens may be a possibility to increase bone formation, especially in elderly patients. Furthermore, it may be possible to shorten postoperative rehabilitation because of the effects of androgens on muscles. ",0
3561,18324840,Minimizing nonspecific cellular binding of quantum dots with hydroxyl-derivatized surface coatings,"Quantum-dot (QD) nanocrystals are promising fluorescent probes for multiplexed staining assays in biological applications. However, nonspecific QD binding to cellular membranes and proteins remains a limiting factor in detection sensitivity and specificity. Here we report a new class of hydroxyl (-OH)-coated QDs for minimizing nonspecific cellular binding and for overcoming the bulky size problems encountered with previous surface coatings. The hydroxylated QDs are prepared from carboxylated (-COOH) dots via a hydroxylation and cross-linking process. With a compact hydrodynamic size of 13-14 nm (diameter), they are highly fluorescent (>60% quantum yields) and stable under both basic and acidic conditions. By using human cancer cells, we have evaluated their superior nonspecific binding properties against that of carboxylated, protein-coated, and poly(ethylene glycol) (PEG)-coated QDs. Quantitative cellular staining data indicate that the hydroxylated QDs result in a dramatic 140-fold reduction in nonspecific binding relative to that of carboxylated dots and a still significant 10-20-fold reduction relative to that of PEG- and protein-coated dots. ",0
3562,18324916,Significance of GLUT1 expression in adenocarcinoma and adenoma of the ampulla of Vater,"The expression of glucose transporter protein 1 (GLUT1) in malignant tumors is increased due to the higher metabolic needs of the proliferating cell populations. Aberrant GLUT1 expression is exhibited in a wide spectrum of epithelial malignancies and their precursors, which occur with low frequency and intensity; aberrant GLUT1 expression does not occur in normal epithelial cells. The expression of GLUT1 in tumors of the ampulla of Vater was evaluated on immunohistochemistry, and the relationships of GLUT1 expression to histological parameters and p53 expression were analyzed. Twenty-one (58.3%) of 36 adenocarcinomas and three (17.6%) of 17 adenomas had GLUT1 immunoreactivity. None of the regenerating or normal epithelia had any immunoreactivity. No significant relationships were found between GLUT1 expression and histological parameters or p53 expression. It was found that histological subtypes originated from different epithelium were strongly related to different macroscopic types. In the ampulla of Vater, GLUT1 expression was associated with malignant change, and might be a useful marker of malignancy. ",0
3563,18324917,Localized malignant mesenteric mesothelioma causing small bowel obstruction,"Malignant mesothelioma is an uncommon lethal neoplasm in the serous membrane in which peritoneal mesothelioma is a rarer form. Herein is reported a case of malignant mesothelioma presenting as a localized mass inside the mesentery causing focal luminal obstruction of the small intestine. The diagnosis of malignant mesothelioma was obtained on repeat double balloon endoscopic biopsy. Partial resection of the small intestine along with the mesentery was performed, followed by a course of chemotherapy. No relapse of the disease has been found in the 8 months' follow up radiologically. To the best of the authors' knowledge this is the first reported case of localized malignant mesothelioma arising inside the mesentery. Mesothelioma should be considered as the differential diagnosis when small bowel obstruction occurs with unknown primary neoplasm. ",0
3564,18325241,Obesity is more than an eating disorder--the multidimensional perspective of a pandemia],"A summary of the epidemiology, etiology and therapy of obesity is given with special emphasis on psychosomatic aspects. Overweight and obesity are widespread and go hand in hand with an increased health risk. The etiology of obesity is multifactorial based on gene/environment interactions; hyperalimentation and physical inactivity, as an expression of the rapid technical advancements within the past decades, have, however, had a decisive influence on the pandemic spreading of obesity. The prevalence of mental disorders is increased particularly in obese women. Although phylogenetically of relevance, an environment that associates slimness with beauty, health, physical and mental proficiency leads to a stigmatization of the obese. The results are mental symptoms and disorders. On the contrary, mental problems up to and including the full clinical picture of mental disorders may lead to changes in eating and exercise behaviour, the result of which may be a sustained positive energy balance with overweight and obesity. The success of conservative weight reduction measures in obesity is inadequate. Surgical measures are more successful, but they are only indicated for severe obesity. The psychosomatic and psychotherapeutic approach to overweight and obesity is multifactorial and indispensable. Obesity is not an eating disorder; it may, however, be the result of hyperalimentation into which pathogenetic and mental factors have been incorporated. ",0
3565,18325275,"Leptospirosis-associated severe pulmonary hemorrhagic syndrome, Salvador, Brazil","We report the emergence of leptospirosis-associated severe pulmonary hemorrhagic syndrome (SPHS) in slum communities in Salvador, Brazil. Although active surveillance did not identify SPHS before 2003, 47 cases were identified from 2003 through 2005; the case-fatality rate was 74%. By 2005, SPHS caused 55% of the deaths due to leptospirosis. ",0
3566,18325294,Spontaneous intracranial hypotension: the syndrome and its complications,"Spontaneous intracranial hypotension (SIH) is a syndrome that was largely unknown until the advent of MRI. The incidence of SIH is estimated at 5 per 100,000, which is half the incidence of subarachnoid hemorrhage. The major feature is a postural headache of acute or subacute onset. This headache is absent or minimal when the patient is lying down and rapidly worsens to great intensity when the patient sits or stands. Other features may include nausea, vomiting, vertigo, tinnitus, and marked exacerbation by Valsalva maneuver. SIH is due to a leak of cerebrospinal fluid from a tear in the dural membrane, which occurs most often at the exit zones where the cervical spinal roots leave the subarachnoid space. Other leak sites may be the vestibular system, the cribriform plate, or the pituitary fossa. If the leak continues, the brain loses buoyancy within the cranial space and sags toward the foramen magnum. This, in turn, may produce subdural hygroma or hematoma, brainstem compression, focal cranial nerve palsies, or cerebellar tonsillar herniation. The initial therapy is generally strict bed rest. If this fails, an epidural blood patch is usually successful in sealing the leak and restoring brain buoyancy. A significant minority of patients require a repeat epidural blood patch. If the blood patch fails, a surgical approach may be needed. Repair of the leak and restoration of brain buoyancy will stop the postural headache and, in most cases, will reverse the complications. ",0
3567,18325321,Cellular prion protein in mammary gland and milk fractions of domestic ruminants,"The present study shows that PrP(c) is expressed in the mammary gland and milk fractions of domestic ruminants in a species-specific manner. By applying immunohistochemistry, Western blot and ELISA, clear expression differences between bovine, ovine and caprine mammary gland, skimmed milk, acid whey and cream could be demonstrated, the highest relative PrP(c) levels being associated with the cream fraction. In the bovine gland PrP(c) was preferentially detectable at the basolateral surface of mammary gland epithelial cells, whereas in ovine and caprine samples the prion protein was more homogeneously distributed. Moreover, in ovine and caprine bovine mammary gland epithelial cells, apocrine secretory vesicles were strongly stained. Ovine and caprine milk proved to contain PrP(c) in all fractions with an additional truncated form at 12kDa in Western blot. This truncated isoform is the predominate one in caprine acid whey. These results support the hypothesis that the apocrine secretion mode of milk fat globules is a major way of PrP(c) transport into the milk. ",0
3568,18325509,Sildenafil citrate (Viagra) impairs fertilization and early embryo development in mice,"To determine the effects of sildenafil citrate, a cyclic monophosphate-specific type 5 phosphodiesterase inhibitor known to affect sperm function, on fertilization and early embryo cleavage. This acute mammal study included male and female mice assigned randomly, the females sacrificed after mating and their oocytes/embryos evaluated at four time periods after treatment. Academic research environment. Male and female CBAB(6) mice. Female mice were injected intraperitoneally with 5 IU gonadotropin (hCG) to stimulate follicular growth and induce ovulation. They were each caged with a male that had been gavaged with sildenafil citrate (0.06 mg/0.05 mL) and allowed to mate. After 12, 36, 60, and 84 h, females were killed, their oviducts were dissected out, and retrieved embryos were assessed for blastomere number and quality. Fertilization rates and numbers of embryos were evaluated after treatment. Fertilization rates (day 1) were markedly reduced (-33%) in matings where the male had taken sildenafil citrate. Over days 2-4, the numbers of embryos developing in the treated group were significantly fewer than in the control group. There was also a trend for impaired cleavage rates within those embryos, although this did not reach significance. The impairments to fertility caused by sildenafil citrate have important implications for infertility centers and for couples who are using this drug precoitally while attempting to conceive. ",0
3569,18325517,From oocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization,"To assess the real biological efficiency of assisted reproduction technology (ART) cycles by using a new metric called oocyte to baby rate, where live babies born (LBB) are reported in relation to the number of oocytes retrieved and used. Retrospective analysis of clinical and embryological database. University center. Patient's cycles (n = 572) divided by age (<35, 35 to 37, 38 to 40, 41 to 42, >42 years) and by oocyte donors. None. Total number of oocytes collected, the number of embryos transferable (fresh and frozen) and corresponding oocyte to LBB rates. In patients with remaining frozen embryos, the final LBB was estimated according to our reported rates. A total of 572 oocyte retrievals yielded 7213 oocytes. The total number of transferred and frozen embryos was 2252 (a utilization rate of 31.2%). The LBB from fresh embryo transfers was 262 with an additional 64 LBB expected from frozen embryos. The overall oocyte to LBB rate was 4.6% (326 babies born). When analyzed by groups, the oocyte to baby rate was best in donor oocyte cycles (6.8%), and declined to 1% for patients >40. There was no increase in oocyte to LBB if >15 oocytes were obtained. During ART cycles, only approximately 5% of fresh oocytes produce a baby. The time has come to investigate new methods of oocyte viability assessment and consider changing current ART practice to recruit fewer oocytes. ",0
3570,18325591,Usefulness of diffusion-weighted imaging and the apparent diffusion coefficient in the assessment of head and neck tumors,"The aim of this review was to determine the usefulness of diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) in the assessment of head and neck tumors. DWI and the ADC can help in the differential diagnosis of particular disorders (such as carcinomas vs lymphomas, or necrosis vs abscess) of the head and neck. The ADC can also provide further information to help differentiate benign from malignant tumors, as ADC values are usually lower in cases of malignancy. However, the ADC is itself influenced by various complex factors such as the cellularity and matrix of tumors and there is also some overlap between certain benign and malignant tumors of the salivary glands. ",0
3571,18325713,Venous ultrasound testing for suspected thrombosis: incidence of significant non-thrombotic findings,"""Duplex ultrasound (US) is used to """"rule out"""" deep venous thrombosis (DVT), but can also diagnose other causes of leg pain or swelling in Emergency Department (ED) patients. Recent literature suggests that US imaging is unnecessary among patients with low or moderate clinical probability of DVT with a normal D-dimer. We attempted to determine the incidence of clinically important incidental findings detected using venous US imaging in patients with suspected lower extremity DVT. We conducted a retrospective chart review of all ultrasounds performed by the non-invasive vascular laboratory on ED patients > 18 years old. Results were classified: normal, DVT, or incidental finding. The latter were classified as clinically significant major findings if the diagnosis led to immediate and specific treatment to prevent morbidity, or clinically significant minor findings. A total of 484 US studies were reviewed; 179 were excluded (arterial studies, penetrating trauma, upper extremity US). Findings among 305 studies were: 238 (78%) normal, 28 (9%) DVT, and 39 (12%) incidental findings. Among 39 incidental findings, 10 were clinically significant major findings and 29 clinically significant minor findings. Clinically significant major findings included: pseudoaneurysm, arterial occlusive disease, vascular graft complication, compartment syndrome, and tumor. Among 38 abnormal US studies that required immediate treatment, DVT comprised 74% (95% confidence interval 59%-85%) and important major incidental findings 26% (95% confidence interval 14%-41%). Among ED patients who underwent US to evaluate leg pain and swelling, 26% of positive studies showed clinically important findings other than DVT. Further research is needed to determine if D-dimer plus a clinical probability tool will include or exclude the patients with clinically significant major findings. """,0
3572,18325717,Esophageal foreign body sensation: a rare presentation of angioedema,"Angioedema remains a rare but potentially life-threatening complication of angiotensin-converting enzyme (ACE) inhibitor use. Most presentations involve edema of the tongue or oral pharynx. However, in recent years, a visceral form involving the gastrointestinal tract also has been described. We present the case of a rare presentation of esophageal and retropharyngeal edema related to ACE inhibitor use. A review of ACE inhibitor-related angioedema is also presented. ",0
3573,18325719,Perspectives of personal support workers and ventilator-users on training needs,"Ventilator-users living in the community have significant personal care needs that are largely provided by paid personal support workers (PSWs). As part of a larger qualitative study exploring relationships between ventilator-users and PSWs, this project explored training experiences and needs of PSWs from the perspectives of both groups. Individual semi-structured interviews conducted with 10 PSWs and 10 ventilator-users living in Support Service Living Units in Ontario, Canada were tape recorded, transcribed verbatim and analyzed for emerging themes. Training experiences of PSWs varied significantly from on-the-job training, to a formal college diploma in personal care. While none received formal training in the specific care needs of ventilator-users such as tracheal suctioning, ventilator monitoring and tracheotomy care, all recommended improved training in this area. Their perspectives varied on whether training should be delivered in a formalized program or through individualized on-the-job training. Despite differing perspectives on optimal training methods for PSWs, participants identified the need for initial and ongoing training to address specific needs of ventilator-users. We recommend the development of standardized PSW training modules adaptable for use in formal and on-site training programs that can accommodate a variety of learning styles and needs. ",0
3574,18325806,"Changes in Na+/K+-ATPase activity, unsaturated fatty acids and metallothioneins in gills of the shore crab Carcinus aestuarii after dilute seawater acclimation","We have assessed the activity of Na(+)/K(+)-ATPase, cAMP, free fatty acids (FFA) and metallothionein (MT) in the posterior gills of the brackish water shore crab Carcinus aestuarii during acclimation to 10 ppt dilute seawater (DSW). Following 3-18 days acclimation in DSW specific activity of Na(+)/K(+)-ATPase in native gill homogenates and partially purified membrane vesicles was progressively increased, from 1.7- to 3.9-fold. After short-term acclimation of crabs in DSW with added sucrose to make media isosmotic with the haemolymph the specific Na(+)/K(+)-ATPase activity in homogenates was not increased, relative to SW enzyme activity. Moreover, hyposmotic conditions led to depletion of cAMP in gills. In partially purified membrane vesicles isolated from posterior gills, fatty acids with compositions 16:0, 18:0, 18:1, 20:4 and 20:5 dominated in both SW- and DSW-acclimated Carcinus. During a year in which the metabolic activity of crabs was increased, the arachidonic/linoleic acids ratio (ARA/LA) for DSW-acclimated crabs was markedly increased relative to that in SW. Increased Na(+)+K(+)-ATPase activity under hyposmotic stress may be modulated at least partially by the changed proportion of fatty acids in the purified membranes of posterior gills. Long-term acclimation of shore crabs to DSW resulted in a 2.6-fold increase in cytosolic metallothionein (MT) content in posterior gills over those in SW crabs. Assuming an antioxidant role of MT associated with intracellular zinc partitioning, the observed MT induction in posterior gills may be considered an adaptive response of C. aestuarii to hyposmotic stress. ",0
3575,18326131,Prediction of successful defibrillation in human victims of out-of-hospital cardiac arrest: a retrospective electrocardiographic analysis,"In the present study we sought to examine the efficacy of an electrocardiographic parameter, 'amplitude spectrum area' (AMSA), to predict the likelihood that any one electrical shock would restore a perfusing rhythm during cardiopulmonary resuscitation in human victims of out-of-hospital cardiac arrest. AMSA analysis is not invalidated by artefacts produced by chest compression and thus it can be performed during CPR, avoiding detrimental interruptions of chest compression and ventilation. We hypothesised that a threshold value of AMSA could be identified as an indicator of successful defibrillation in human victims of cardiac arrest. Analysis was performed on a database of electrocardiographic records, representing lead 2 equivalent recordings from automated external defibrillators including 210 defibrillation attempts from 90 victims of out-of-hospital cardiac arrest. A 4.1 second interval of ventricular fibrillation or ventricular tachycardia, recorded immediately preceding the delivery of the shock, was analysed using the AMSA algorithm. AMSA represents a numerical value based on the sum of the magnitude of the weighted frequency spectrum between two and 48 Hz. AMSA values were significantly greater in successful defibrillation (restoration of a perfusing rhythm), compared to unsuccessful defibrillation (P < 0.0001). An AMSA value of 12 mV-Hz was able to predict the success of each defibrillation attempt with a sensitivity of 0.91 and a specificity of 0.97. In conclusion, AMSA analysis represents a clinically applicable method, which provides a real-time prediction of the success of defibrillation attempts. AMSA may minimise the delivery of futile and detrimental electrical shocks, reducing thereby post-resuscitation myocardial injury. ",0
3576,18326729,Role of carbonic anhydrase IV in corneal endothelial HCO3- transport,"Carbonic anhydrase activity has a central role in corneal endothelial function. The authors examined the role of carbonic anhydrase IV (CAIV) in facilitating CO(2) flux, HCO(3)(-) permeability, and HCO(3)(-) flux across the apical membrane. Primary cultures of bovine corneal endothelial cells were established on membrane-permeable filters. Apical CAIV was inhibited by benzolamide or siRNA knockdown of CAIV. Apical CO(2) fluxes and HCO(3)(-) permeability were determined by measuring pH(i) changes in response to altering the CO(2) or HCO(3)(-) gradient across the apical membrane. Basolateral to apical (B-to-A) HCO(3)(-) flux was determined by measuring the pH of a weakly buffered apical bath in the presence of basolateral bicarbonate-rich Ringer solution. In addition, the effects of benzolamide and CAIV knockdown on steady state DeltapH (apical-basolateral compartment pH) after 4-hour incubation in DMEM were measured. CAIV expression was confirmed, and CAIV was localized exclusively to the apical membrane by confocal microscopy. Both 10 microM benzolamide and CAIV siRNA reduced apparent apical CO(2) flux by approximately 20%; however, they had no effect on HCO(3)(-) permeability or HCO(3)(-) flux. The steady state apical-basolateral pH gradient at 4 hours was reduced by 0.12 and 0.09 pH units in benzolamide- and siRNA-treated cells, respectively, inconsistent with a net cell-to-apical compartment CO(2) flux. CAIV does not facilitate steady state cell-to-apical CO(2) flux, apical HCO(3)(-) permeability, or B-to-A HCO(3)(-) flux. Steady state pH changes, however, suggest that CAIV may have a role in buffering the apical surface. ",0
3577,18326895,Comparison of pro B-natriuretic peptide in hypertensive patients with and without diastolic dysfunction,"to evaluate whether pro BNP can be used for detection of diastolic dysfunction. thirty nine hypertensive patients with normal systolic function, consecutively referred for echocardiography examination between October and December 2004 were recruited in the study. Diastolic dysfunction was diagnosed when echocardiographic mitral flow pattern demonstrated impaired relaxation, pseudonormalization or restrictive like patterns. NT-pro BNP levels were assessed using electro chemiluminescence Immunoassay (ECLIA) method. Unpaired t test was used to analyze the results. twelve out of thirty nine subjects had normal diastolic function. All base line characteristics, except for uric acid, were equally distributed between normal and abnormal diastolic function group. NT-pro BNP levels were nearly significantly higher in the diastolic dysfunction group (P=0.053). NT-pro BNP levels trends to be higher in hypertensive subjects with diastolic dysfunction. ",0
3578,18326978,Vascular compliance in the cardiometabolic syndrome,"Elevated systolic blood pressure and increased pulse pressure are important predictors of vascular stiffening (compliance), left ventricular hypertrophy, coronary heart disease, heart failure, stroke, vascular dementia, and chronic kidney disease. Advances in noninvasive methods that measure arterial stiffness have led to increased understanding of the mechanisms underlying vascular dysfunction and the development of associated risk factors. The ability to detect and monitor changes in the physical properties of arteries has the potential to allow early interventions that may prevent disease or attenuate its progression. In this paper, the authors briefly review the various methods available to measure vascular compliance and review pathologic processes that lead to insulin resistance, endothelial dysfunction, inflammation, and sympathetic activation, all of which may contribute to increased arterial stiffness in the cardiometabolic syndrome. Strategies to improve vascular compliance are also discussed. ",0
3579,18327298,Treatment of posttraumatic arthrofibrosis of the radioulnar joint with vibration therapy (VMTX Vibromax Therapeutics): a case report and narrative review of literature,"To present the clinical features of post traumatic arthrofibrosis and response to treatment with Vibromax Therapeutics (VMTX) in 28 year old male soccer player. Many studies have reported an increase in muscle performance after whole-body vibration, but to date none have evaluated the possibility of vibration application as a therapy for functional restoration after injury. Vibration training is being utilized in, strength training, performance enhancement and rehabilitation. Despite the lack of research in this area, the literature that is currently available and the results of this case study imply that vibration therapy has the potential to aid in the management of acute soft tissue injury and the sequela of disuse and immobilization. ",0
3580,18327368,Perinatal and neonatal outcomes of growth restricted fetuses with positive end diastolic and absent or reversed umbilical artery doppler waveforms,"To evaluate the outcome of intrauterine growth restriction fetuses with absent or reversed end-diastolic flow in the umbilical artery. This was a retrospective study conducted at the Department of Maternal Fetal Medicine of the Bakirkoy Women and Children's Teaching Hospital, Istanbul, Turkey between 2002 and 2006. Three hundred and ten pregnant women with growth-restricted fetuses confirmed by ultrasound were followed up with Doppler studies of the umbilical artery. The population was subdivided into 2 groups. Group 1, intrauterine growth restriction with positive end diastolic flow velocity waveforms, (n=137) and group 2, intrauterine growth restriction with absent or reversed end diastolic velocities, (n=163). Perinatal and neonatal outcomes of the 2 groups were recorded. Group 1 was associated with a higher perinatal mortality and morbidity rate than group 2 (p=0.02), odds ratio [OR]: 1.09, 95% confidence interval [CI] 1-3.5, (p=0.03, OR: 2, 95% CI 1.2-3.2). In group 1, significantly more neonates were admitted to the neonatal intensive care unit, but no difference was seen in neonatal intensive care unit stay. The frequency of respiratory distress syndrome, septicemia, and necrotizing enterocolitis increased in group 1. There was no significant difference in need for ventilation of respiratory distress syndrome. Our data suggest that pregnancies with absent or reversed end-diastolic flow in the umbilical arteries have high perinatal mortality and morbidity. ",0
3581,18327686,Mechanisms of adaptive angiogenesis to tissue hypoxia,"Angiogenesis is mostly an adaptive response to tissue hypoxia, which occurs under a wide variety of situations ranging from embryonic development to tumor growth. In general, angiogenesis is dependent on the accumulation of hypoxia inducible factors (HIFs), which are heterodimeric transcription factors of alpha and beta subunits. Under normoxia, HIF heterodimers are not abundantly present due to oxygen dependent hydroxylation, polyubiquitination, and proteasomal degradation of alpha subunits. Under hypoxia, however, alpha subunits are stabilized and form heterodimers with HIF-1beta which is not subject to oxygen dependent regulation. The accumulation of HIFs under hypoxia allows them to activate the expression of many angiogenic genes and therefore initiates the angiogenic process. In recent years, however, it has become clear that various other mechanisms also participate in fine tuning angiogenesis. In this review, I discuss the relationship between hypoxia and angiogenesis under five topics: (1) regulation of HIF-alpha abundance and activity by oxygen tension and other conditions including oxygen independent mechanisms; (2) hypoxia-regulated expression of angiogenic molecules by HIFs and other transcription factors; (3) responses of vascular cells to hypoxia; (4) angiogenic phenotypes due to altered HIF signaling in mice; and (5) role of the HIF pathway in pathological angiogenesis. Studies discussed under these topics clearly indicate that while mechanisms of oxygen-regulated HIF-alpha stability provide exciting opportunities for the development of angiogenesis or anti-angiogenesis therapies, it is also highly important to consider various other mechanisms for the optimization of these procedures. ",0
3582,18327709,The potential for translocation of marine species via small-scale disruptions to antifouling surfaces,"Vessel hull fouling is a major vector for the translocation of nonindigenous species (NIS). Antifouling (AF) paints are the primary method for preventing the establishment and translocation of fouling species. However, factors such as paint age, condition and method of application can all reduce the effectiveness of these coatings. Areas of hull that escape AF treatment (through limited application or damage) constitute key areas that may be expected to receive high levels of fouling. The investigation focused on whether small-scale (mm(2) to cm(2)) areas of unprotected surface or experimental 'scrapes' provided sufficient area for the formation of fouling assemblages within otherwise undamaged AF surfaces. Recruitment of fouling taxa such as algae, spirorbids and hydroids was recorded on scrapes as narrow as 0.5 cm wide. The abundance and species richness of fouling assemblages developing on scrapes > or =1 cm often equalled or surpassed levels observed in reference assemblages totally unprotected by AF coatings. Experiments were conducted at three sites within the highly protected and isolated marine park surrounding Lady Elliott Island at the southernmost tip of the Great Barrier Reef, Australia. Several NIS were recorded on scrapes of AF coated surfaces at this location, with 1-cm scrapes showing the greatest species richness and abundance of NIS relative to all other treatments (including controls) at two of the three sites investigated. Slight disruptions to newly antifouled surfaces may be all that is necessary for the establishment of fouling organisms and the translocation of a wide range of invasive taxa to otherwise highly protected marine areas. ",0
3583,18327970,Heart rate effects of intraosseous injections using slow and fast rates of anesthetic solution deposition,"The authors, using a crossover design, randomly administered, in a single-blind manner, 3 primary intraosseous injections to 61 subjects using: the Wand local anesthetic system at a deposition rate of 45 seconds (fast injection); the Wand local anesthetic system at a deposition rate of 4 minutes and 45 seconds (slow injection); a conventional syringe injection at a deposition rate of 4 minutes and 45 seconds (slow injection), in 3 separate appointments spaced at least 3 weeks apart. A pulse oximeter measured heart rate (pulse). The results demonstrated the mean maximum heart rate was statistically higher with the fast intraosseous injection (average 21 to 28 beats/min increase) than either of the 2 slow intraosseous injections (average 10 to 12 beats/min increase). There was no statistically significant difference between the 2 slow injections. We concluded that an intraosseous injection of 1.4 mL of 2% lidocaine with 1 : 100,000 epinephrine with the Wand at a 45-second rate of anesthetic deposition resulted in a significantly higher heart rate when compared with a 4-minute and 45-second anesthetic solution deposition using either the Wand or traditional syringe. ",0
3584,18328028,Telemonitoring and telerehabilitation of patients with Parkinson's disease: health technology assessment of a novel wearable step counter,"Step counting is an important index of motion in telemonitoring. One of the most diffused wearable systems, designed for this purpose, is the pedometer. The accuracy of commercial pedometers has been reported in the literature. Several limits have been found in many commercial systems both in healthy subjects and in people with disabilities. Furthermore, commercial pedometers lack interoperability. This paper introduces a new wearable system for step counting for telemonitoring applications. This system is based on a wearable device with a force-sensing resistor. It is affixed on the gastrocnemius muscle for monitoring muscular expansion correlated with the gait. The data exchange is assured by the XTR-434H (Aurel, FC, Italy) telemetric system. The proposed gastrocnemius expansion measurement unit (GEMU) was tested on 5 subjects with Parkinsons disease at Level 3 of the Tinetti test of unbalance. Ten repetitions of 500 steps with three different speeds (fast, slow, and normal) were performed. The mean error was <0.5%. Results also showed that GEMU performed better than an accelerometer unit (considered in the literature the best solution for this disability). The study showed that GEMU had a high performance in subjects with Parkinsons disease, causing a high degree of unbalance that confounded motion style. The next phase will be the optimization of GEMU for long-term medical applications at the patients home. ",0
3585,18328193,Adenovirus mediated targeted genetherapy of Staphylococcal enterotoxin A and CD80 for hepatoma and its primary immune mechanisms],"To observe the effects of hepatoma-targeting recombinant adenovirus vectors of staphylococcal enterotoxin A (SEA) and/or CD80 gene on hepatoma and to study its immunological mechanisms. Using AdEasy adenovirus system, we constructed recombinant adenovirus vectors of SEA and/or CD80 gene driven by alpha-fetoprotein (AFP) enhancer I and promoter. After intratumoral therapy for the mice bearing subcutaneous xenograft hepatoma with the recombinant adenoviruses, SEA and/or CD80 mRNA and protein were detected by RT-PCR and Western blot. IFN-gamma-producing cell frequency and specific cytotoxicity of T lymphocytes to Hepa1-6 cells were detected by ELISpot and LDH-released assay in the splenocytes. Effects of recombinant adenoviruses on hepatoma were assessed by changes of tumor volumes and survival time in the treated mice. The recombinant adenoviruses constructed by us made SEA and/or CD80 mRNA and protein targetedly express in hepatoma tissues. When compared with the empty vector and PBS groups, the IFN-gamma-producing cell frequency and specific cytotoxicity of T lymphocytes increased, the tumor volumes of mice decreased and the survival time increased in the double-gene and single-gene groups. Double genes elicited better antitumor effects and stronger immune responses. There were no significant differences in the effects between CD80 group and SEA group or between empty vector group and PBS group. The hepatoma-targeting recombinant adenovirus vectors constructed in this study can elicit effective antitumor effects on hepatoma and the effects of double genes are better than that of single gene. ",0
3586,18328264,Analysis of the GAD65-GAD65 autoantibody interaction,"GAD(65)Ab are important markers of risk of development of type 1 DM. With the need to improve the disease specificity of GAD(65)Ab measurement in mind, we have analysed the interaction between recombinant human GAD(65) and GAD(65)Ab from different groups of subjects in terms of association and dissociation rate constants and equilibrium constants. In addition, binding of GAD(65)Ab from various groups of subjects to wild-type GAD(65) versus GAD(65) containing a mutation E517P was studied. Affinity constants for serum GAD(65)Ab in 12 type 1 DM patients ranged from 0.9 x 10(10) L/mol to 11.2 x 10(10) L/mol and from 0.8 x 10(10) L/mol to 14.0 x 10(10) L/mol in sera from 11 individuals without type 1 DM. Serum GAD(65)Ab concentrations assessed by Scatchard analysis ranged from 0.04 to 24.8 microg/mL in type 1 DM patients (n=12) and from 0.04 to 141.8 microg/mL in individuals without type 1 DM (n=11). Overall, our study indicated that GAD(65)Ab in different patients studied showed similar association and dissociation rate constants and similar affinity constants. However, GAD(65)Ab concentrations vary widely between different sera. There was a modest reduction of the median binding of GAD(65)Ab to GAD(65) E517P in the group of patients with type 1 DM compared to patients without type 1 DM. ",0
3587,18328616,Cardiovascular assessment of fetal mice by in utero echocardiography,"To establish a developmental profile of fetal mouse cardiovascular parameters, we analyzed a large body of ultrasound measurements obtained by in utero echocardiography of C57BL/6J fetal mice from embryonic day 12.5 to 19.5 (term). Measurements were obtained using two-dimensional (2D), spectral Doppler and M-mode imaging with standard clinical cardiac ultrasound imaging planes. As these studies were conducted as part of a large scale mouse mutagenesis screen, stringent filtering criteria were used to eliminate potentially abnormal fetuses. Our analysis showed heart rate increased from 190 to 245 beats per minute as the mouse fetus grew from 8 mm at embryonic day 12.5 to 18.7 mm at term. This was accompanied by increases in peak outflow velocity, E-wave, E/A ratio and ventricular dimensions. In contrast, the A-wave, myocardial performance index and isovolemic contraction time decreased gradually. Systolic function remained remarkably stable at 80% ejection fraction. Analysis of intra- and interobserver variabilities showed these parameters were reproducible, with most comparing favorably to clinical ultrasound measurements in human fetuses. A comprehensive database was generated comprising 23 echocardiographic parameters delineating fetal mouse cardiovascular function from embryonic day 12.5 to term. This database can serve as a standard for evaluating cardiovascular pathophysiology in genetically altered and mutant mouse models. ",0
3588,18329182,Psychological coping styles and cortisol over the day in healthy older adults,"Patterns of psychological coping are associated with a variety of health outcomes but the underlying pathways are not yet established. The purpose of this study was to assess the relationship between salivary cortisol output over the course of a day and coping style. Data were available from 350 men and 192 women with an average age of 60.9 years. Participants were drawn from the Whitehall II cohort, and had no history of cardiovascular disease. Individuals who were taking medication that might affect cortisol levels were also excluded. Saliva samples were provided on waking, then 0.5, 2.5, 8 and 12h after waking, and just before the participant went to sleep. Coping style was measured with a standard instrument, the COPE, and data were factor analysed to generate three factors: seeking social support, problem engagement and problem avoidance. The relationships between these factors and the cortisol awakening response (CAR), the slope of cortisol change over the day and total cortisol output over the day (excluding the waking period) were assessed using multiple linear regression. Cortisol output over the day was inversely associated with coping with stress by seeking social support (p=0.034) and by problem engagement (p=0.003), independently of age, gender, body mass index, smoking, depression, self-rated health, time of waking and income. Individuals who coped by problem engagement and seeking support had lower cortisol levels. Additionally, gender, BMI, smoking, self-rated health and time of waking were independently related to cortisol output over the day. There were no significant associations between coping and the CAR or cortisol slope over the day. The results indicate that adaptive coping styles are related to low levels of cortisol over the day, suggesting that neuroendocrine pathways may partly mediate relationships between psychological coping and health. ",0
3589,18329438,"Rear seat safer: seating position, restraint use and injuries in children in traffic crashes in Victoria, Australia","Car crashes are a major cause of death and serious injury to children but most analyses of risk are based on US data. The Australian context is different in at least three ways: (1) the proportion of passenger-side airbags, a potential risk to children in front seats, is much lower; (2) unlike in the US, Australian airbags are designed to work with restrained passengers; (3) restraint use for children 0-12 years is high (>90%). Official data drawn from Victorian crash records (n=30,631) were used to calculate relative risks of death or serious injury for children (0-3 years, 4-7 years; 8-12 years) traveling in passenger cars during 1993-1998 and 1999-2004. Over 90% were reportedly wearing a restraint, and 20% were traveling in the front seat. For children under 4 years traveling in the front seat, the relative risk of death was twice as great as when traveling in the rear, and that of serious injury was 60% greater. The relative risk of death whilst traveling in the front seat was almost four times greater for children aged under 1 year. We suggest that serious consideration should be given to mandating rear seating for children, particularly those aged 4 and under. ",0
3590,18329777,Bioaccessibility of essential and non-essential metals in commercial shellfish from Western Europe and Asia,"Maximum acceptable concentrations of metals in food - based on total concentrations - have been established in many countries. To improve risk assessment, it would be better to take into account bioaccessible concentrations. A total of seven species of molluscs from France, UK and Hong Kong was examined in this study including clams, mussels, oysters, scallops and gastropods. The species which have total metal concentrations higher than the most severe food security limits are mainly oysters (all of the three studied species), the gastropod Buccinum undatum for cadmium and zinc, and scallops for cadmium. The lowest bioaccessibility (in % extractability with gut juices) was observed for silver (median for all of the species: 14%), it was moderate for lead (median: 33%) and higher for cadmium, zinc and copper (medians were respectively 54%, 65%, and 70%). In most cases, bioaccessible concentrations remained higher than the safety limits, except for cadmium in scallops and zinc in B. undatum. The influence of feeding habit (masticated or swallowed, addition of vinegar or lemon) on metal bioaccessibility in oysters is limited. On the contrary, cooking the gastropods decreased the bioaccessibility of metals, except silver. ",0
3591,18329912,Structural effects of sodium hypochlorite solution on RaCe rotary nickel-titanium instruments: an atomic force microscopy study,"The aim of this study was to investigate the effect of sodium hypochlorite immersion on the surface characteristics of RaCe rotary nickel-titanium instruments using atomic force microscopy (AFM). Four new RaCe instruments were used in this study (two 30.06 and two 30.02). One 30.06 and one 30.02 instrument were immersed in sodium hypochlorite solution for 5 min. Surface topography of the instruments was evaluated using the AFM. The instruments were analyzed on 11 points along a 3-mm section. Root mean square (RMS) values were used to compare the topographic deviations. The data were analyzed using Student t test. Mean RMS values for NaOCl measurements were higher than the measurements on new files, and the difference was statistically significant (P < .01). The AFM results show that NaOCl causes deterioration on the surface of RaCe instruments and should be used with care during clinical use because of the risk of unexpected failure. ",0
3592,18330304,Fluorescence and visible spectroscopic studies on interaction of beta-cyclodextrin-thionine inclusion complex with DNA],"The inclusion of beta-cyclodextrin (CD) for thionine (TH) and the interaction of DNA with CD-TH inclusion complex were investigated by fluorescence and visible absorption spectrometry. TH with beta-CD formed a 1 : 1 inclusion complex with the stability constant of 527 L x mol(-1) (visible spectrometry)/444 L x mol(-1) (fluorescence) in the pH 7.2 PBS buffer solutions. The addition of DNA makes the absorbance of the inclusion complex decrease and the absorption spectrum shift toward long wavelengths. The fluorescence experiments indicated that the presence of DNA makes the emission peak of CD-TH shift toward short wavelengths and the fluorescence of inclusion complex quench, and the quenching constant was calculated to be 6.12 x 10(4) L x mol(-1) by Stern-Volmer method. All the data confirmed that CD-TH reacted with DNA in intercalative mode, and the binding numbers and the binding constant were estimated to be 1 and 3.47 X 10(4) L x mol(-1) by spectrophotometry. ",0
3593,18330718,Genetic analysis of hereditary multiple exostoses in Tunisian families: a novel frame-shift mutation in the EXT1 gene,"Hereditary multiple exostoses (HME) is an autosomal dominant orthopaedic disorder most frequently caused by mutations in the EXT1 gene. The aim of the present study is to determine the underlying molecular defect of HME in two multigenerational Tunisian families with 21 affected members and to examine the degree of intrafamilial variability. Linkage analysis was performed using three microsatellite markers encompassing the EXT1 locus and mutation screening was carried out by direct sequencing. In family 1, evidence for linkage to EXT1 was obtained on the basis of a maximum LOD score of 4.26 at theta = 0.00 with D8S1694 marker. Sequencing of the EXT1 revealed a heterozygous G > T transversion (c.1019G>T) in exon 2, leading to a missense mutation at the codon 340 (p.Arg340Leu). In family 2 we identified a novel heterozygous 1 bp deletion in the exon 1 (c.529_531delA) leading to a premature codon stop and truncated EXT1 protein expression (p.Lys177LysfsX15). This mutation was associated with the evidence of an intrafamilial clinical variability and considered to be a novel disease-causing mutation in the EXT1 gene. These findings provide additional support for the involvement of EXT1 gene in the HME disease. ",0
3594,18330753,Homocysteine levels in patients with obstructive sleep apnea syndrome],"The exact mechanism of development of cardiovascular disease in patients with obstructive sleep apnea syndrome (OSAS) remains to be unknown. The role of homocysteine in atherosclerotic disease process has become well established over the past ten years. Our aim was to study to compare homoscysteine levels between OSAS and control levels. Sixty-two subjects with OSAS and twelve similar controls in age, gender, body mass index, smoking and coronary heart disease were included in this prospective study. Serum levels of homocysteine (13.5 +/- 6.0 micromol/L vs. 10.2 +/- 2.9 micromol/L, p= 0.03) in the OSAS group were significantly greater than those in the control group. Logistic regression analyses showed that OSAS (Odds ratio: 9.08 95% CI 2.347-35.120; p= 0.001) was independent risk factors for high levels of serum homocysteine in age, smoking status, diabetes mellitus and coronary heart disease. We conclude that homocysteine may be an important factor for development of cardiovascular disease in patients with OSAS. ",0
3595,18330893,Effect of dihydrotestosterone on hydrogen peroxide-induced apoptosis of mouse embryonic stem cells,"Steroid hormones have been reported to activate various signal transducers that trigger a variety of cellular responses. Among these hormones, testosterone has been identified as an antioxidant that protects against cellular damage. Therefore, using mouse embryonic stem (ES) cells as a model system, this study evaluated the effects of dihydrotestosterone (DHT), a biologically active testosterone metabolite, on H2O2-induced apoptosis. H2O2 increased the release of lactate dehydrogenase (LDH) and DNA fragmentation but reduced the cell viability in a time-dependent manner (> or =8 h). Moreover, H2O2 decreased the level of DNA synthesis and the levels of the cell cycle regulatory proteins [cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 2, and CDK 4]. These effects of H2O2 were inhibited by a pretreatment with DHT. However, a treatment with flutamide (androgen receptor inhibitor, 10(-3) M) abolished the protective effects of DHT. This result was supported by the presence of the androgen receptor in mouse ES cells. The activity of the antioxidant enzyme, catalase, was increased by the DHT treatment but not by a co-treatment with DHT and flutamide. Using CM-H(2)DCFDA (DCF-DA) for the detection of intracellular H2O2, DHT decreased the intracellular H2O2 levels but flutamide blocked this effect. H2O2 also increased the level of p38 MAPK, JNK/SAPK, and NF-kappaB phosphorylation, which were inhibited by the DHT pretreatment. Catalase inhibited the effect of H2O2 on MAPKs and NF-kappaB. However, the flutamide treatment abolished the inhibitory effects of DHT on the H2O2-induced increase in the levels of p38 MAPK, JNK/SAPK, and NF-kappaB phosphorylation. DHT inhibited the H2O2-induced increase in caspase-3 expression and decreased the level of Bcl-2 and the cellular inhibitor of apoptosis protein (cIAP)-2. These effects were abolished by the flutamide treatment. In conclusion, DHT prevents the H2O2-induced apoptotic cell death of mouse ES cells through the activation of catalase and the downregulation of p38 MAPK, JNK/SAPK, and NF-kappaB via the androgen receptor. ",0
3596,18330991,The effect of chitosan on the in vitro biological performance of chitosan-poly(butylene succinate) blends,"Chitosan blends with synthetic biodegradable polymers have been proposed for various biomedical applications due to their versatile mechanical properties and easier processing. However, details regarding the main surface characteristics that may benefit from the blending of these two types of materials are still missing. Hence, this work aims at investigating the surface properties of chitosan-based blends, illustrating the way these properties determine the material-proteins interactions and ultimately the behavior of osteoblast-like cells. The surface characteristics of modified and nonmodified blends were assessed using complimentary techniques such as optical microscopy, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR-ATR), X-ray photoelectron spectroscopy (XPS), contact angle measurements and surface energy calculations. The adsorption of human serum albumin (HSA) and human plasma fibronectin (HFN) onto the different surfaces was quantified by association of an indirect method with a colorimetric assay. It was found that the presence of chitosan on the surface promoted the adsorption of proteins. Moreover, a preferential adsorption of albumin over fibronectin was registered. The in vitro biological performance of the studied materials was further investigated by a direct contact assay with an osteoblastic-like cell line (SaOs-2). A synergistic effect of the two components of the blend was observed. While the synthetic polyester promoted the adhesion of SaOs-2, the presence of chitosan significantly enhanced the osteoblastic activity of these cells. This work further confirmed the interest in designing polymeric blends with natural polymers as a successful strategy to enhance the biological performance of a biomaterial. ",0
3597,18331412,"Use of complementary and alternative medicine in children with type 1 diabetes mellitus - prevalence, patterns of use, and costs","Complementary and alternative medicine (CAM) is increasingly used in adults and children. Studies on CAM in diabetes have mainly focused on the adult population and its use among children with type 1 diabetes has not been well characterized. This study determines prevalence, parental reasons and motivations, perceived effectiveness, costs, and communication of CAM use. Moreover, caregiver-related variables associated with the use of CAM were investigated. A self-completed anonymous questionnaire was administered to parents of children with type 1 diabetes in four pediatric diabetes centers in Germany (Leipzig, Berlin, Stuttgart, and Bonn). Two hundred and twenty eight (65.9%) of 346 families completed the survey. Mean age of the diabetic patients was 11.9 +/- 3.8 yr. Forty two (18.4%) received one or more types of CAM, with the most common types being homeopathy (14.5%), vitamins and minerals (13.7%), modified diet (12.9%), aloe vera (7.3%), and cinnamon (5.6%). Users had a significantly higher family income and parental tertiary education (p < 0.05) and stated a significantly stronger interest in self-care (p < 0.01). Parents' motivations for using CAM were the hope for an improved well-being (92.1%), to try everything (77.8%), and assumption of fewer side effects (55.2%). Costs for the entire treatment varied between less than euro100 and up to euro5000, with mostly no reimbursement. Use of CAM in children with type 1 diabetes is less common than that documented for adults. Parents using CAM do not question the need for insulin. When using CAM, improved well-being and quality of life are important considerations where CAM can have a role. ",0
3598,18331432,Safety and diagnostic yield of laparoscopically assisted full-thickness bowel biospy,"Advances in minimally invasive surgery have made laparoscopy and full-thickness bowel biopsy possible in the investigation of patients with suspected gastrointestinal neuromuscular disorders. The safety and diagnostic yield of this investigation have not been formally reported. A prospective study was undertaken of 124 patients with clinico-physiological diagnoses of chronic intestinal pseudo-obstruction, enteric dysmotility and severe irritable bowel syndrome undergoing LFTB in three European teaching centres with expertise in the management of gastrointestinal neuromuscular disorders. Perioperative data were collected including complications. Diagnostic yield was expressed as proportion with well-established specific neuromuscular abnormalities based on a protocol of routine and immunohistochemical techniques. The majority of patients underwent a laparoscopically assisted procedure with extracorporeal biopsy. Median operating time was 50 min, conversion rate 2% and length of stay 1 day. There was an 8% readmission rate for obstructive symptoms but minimal other morbidity and no mortality. Overall specific diagnostic yield was 81%, being high for jejunal biopsies (89%) but low for a small number of ileal and colonic biopsies. Laparoscopy and full-thickness biopsy of the bowel appears acceptable in terms of safety. It should be performed in a jejunal site to achieve a high diagnostic yield. ",0
3599,18331539,Hematopoietic stem cell transplantation from a donor with Klinefelter syndrome for Wiskott-Aldrich syndrome,"WAS is a rare X-linked recessive disorder characterized by primary progressive T cell immunodeficiency, impaired antipolysaccharide antibody response, thrombocytopenia with small platelet, and eczematoid dermatitis. Untreated patients with typical WAS have poor prognosis with the major causes of death being infection, bleeding, lymphoproliferative disorders, and malignancy. Due to the increased risk of infectious and hemorrhagic episodes the best results with HSCT are achieved in patients less than five yr of age and are recommended as early as possible. Here, we report a three-yr-old boy with WAS who underwent UCB and BMT from his genotypically identical brother with Klinefelter syndrome. ",0
3600,18331727,"Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R","Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels. ",0
3601,18332187,Racial and ethnic variations in caregiver service use,"This article examines whether race and ethnicity contribute to the differential use of caregiver support services, when controlling for caregiver and care recipient characteristics, as represented by predisposing, enabling, and need factors included in the Behavioral Model of Health Services Use. The study includes 1,508 individuals who provide care to an ill or disabled adult aged 50 or older, identified through a random digit dial telephone survey of California households. Logistic regression analysis is utilized to examine factors that predict use of caregiver support services. Race and ethnicity do not contribute significantly to caregiver service utilization, when controlling for relevant covarying factors such as age, education, emotional support, family contribution, care recipient service use, and care recipient impairment. A significant interaction exists between ethnicity and family closeness, with reduced rates of service use among Asian and Pacific Island caregivers whose families are brought closer by the caregiving experience. These findings suggest that racial and ethnic disparities in caregiver service use found at the bivariate level are attributable to covarying predisposing, enabling, and need factors. Further research and theoretical development are suggested to clarify the impact of sociocultural factors on caregiver service use. ",0
3602,18332821,Evaluation of a multidisciplinary pediatric mock trauma code educational initiative: a pilot study,"Our aim was to develop and evaluate a multidisciplinary pediatric mock trauma code orientation program for residents on their pediatric hospital rotation. A before and after evaluation of trauma team residents from various programs was conducted. The 1-hour educational session consisted of a 15-minute mock trauma code, a debriefing and teaching intervention, and then a new, postintervention mock trauma code. Before and after each session, residents completed a self-assessment questionnaire. All codes were videotaped and later evaluated by two blinded observers using a standardized evaluation tool to assess patient management and team functioning. Thirty-seven prequestionnaire (pre) and postquestionnaire (post) pairs were completed. Residents reported a significant improvement in their (1) comfort in managing pediatric trauma (median pre 3, post 5, p < 0.001); (2) understanding of their role on the trauma team (median pre 4.5, post 6, p < 0.001); (3) familiarity with the resuscitation room (median pre 4, post 5, p = 0.001); (4) comfort with procedural skills (median pre 4, post 5, p = 0.001); (5) awareness of pediatric trauma resuscitation management priorities (median pre 5, post 6, p = 0.007). Postintervention, residents reported lower knowledge scores in locating equipment in the resuscitation room (p < 0.001). There was no significant difference in team performance on the videotaped assessments (premean score = 79.8, postmean score = 79.5). The pediatric mock trauma code educational initiative improved residents' self-reported confidence, knowledge, and comfort level in managing pediatric trauma. The experience also raised residents' awareness of knowledge gaps. We were unable to measure a significant change in team functioning post intervention. ",0
3603,18332843,Embolic stroke secondary to cardiac papillary fibroelastoma,"Papillary fibroelastoma is the most common primary cardiac valvular tumor. Historically, papillary fibroelastoma was an incidental autopsy finding, deemed to have no clinical significance. More recently, reports of symptomatic cases of papillary fibroelastoma with complications such as myocardial infarction and stroke suggest it should be considered a potentially dangerous lesion. In this report, we describe the clinical and echocardiographic findings of 3 patients with cardiac papillary fibroelastoma who presented with cerebral vascular events. To describe the clinical and echocardiographic findings of 3 patients with cardiac papillary fibroelastoma (CPF) who presented cerebral vascular events. Describe the findings of 3 patients and review of the literature. We report 3 cases with cerebral ischemic events associated with the presence of CPF that were confirmed by histopathological examination. Cardiogenic embolism is recognized increasingly as an important cause of stroke, accounting of 20% of ischemic strokes. Cardioembolic stroke is largely preventable. The likelihood of recurrence is relatively high for most cardioembolic sources and therefore secondary stroke prevention is fundamental. TEE allowed to characterize well-established sources of embolism, and it was the best diagnostic approach in our patients. Magnetic resonance imaging was used in 1 of these patients, while it confirmed the presumptive diagnosis of cardiac tumor. The first-choice treatment of symptomatic CPF is surgical excision which must be performed as early as possible to reduce the risk of early recurrences of embolic events. The use of TEE in the evaluation of cerebral vascular events is not routinely performed, this method must be considered in patients for whom the cause of cerebrovascular ischemia is unclear, after noninvasive neurovascular studies. ",0
3604,18332891,Measurement of carotid intima-media thickness to assess progression and regression of atherosclerosis,"Imaging modalities have been developed to assess atherosclerosis in vivo in the arterial wall because large clinical end-point studies are time-consuming and costly. Historically, in-hospital angiography and Doppler ultrasonography have been used to assess atherosclerosis development. Investigations of the arterial lumen are, however, increasingly being replaced by modalities that can measure changes in the arterial wall itself-intravascular ultrasonography, MRI and multislice CT. The fact that intravascular ultrasonography is invasive, CT involves substantial radiation exposure and requires contrast agents, and that MRI is time-consuming and technically challenging all limit the widespread use of these techniques. Moreover, all modalities have high associated costs. B-mode ultrasonographic imaging of the carotid arterial walls occupies a unique position in atherosclerosis research. This method enables sensitive, reproducible and noninvasive assessment of intima-media thickness (IMT) as a continuous variable. Epidemiological and clinical trial evidence as well as digitization and standardization have made carotid IMT a validated and accepted marker for generalized atherosclerosis burden and vascular disease risk. Here we describe the application of carotid IMT measurements as a tool in risk evaluation of individuals and in studies of atherosclerosis progression and regression. ",0
3605,18333114,Laparoscopic staging in selected patients with colorectal liver metastases as a prelude to liver resection,"Careful selection of patients with colorectal liver metastases for liver resection should minimize the risk of unnecessary laparotomy due to unresectable disease. The impact of staging laparoscopy with laparoscopic ultrasonography (LapUS) on clinical decision making in selected patients with potentially resectable colorectal liver metastases was evaluated. Staging laparoscopy with or without LapUS was performed in 77 of 415 consecutive patients (19%) with colorectal liver metastases deemed potentially resectable following liver-specific CT and/or MRI scanning. Retrospective analysis of prospectively collected data compared clinical outcomes with those in whom laparoscopy had been deferred in favour of laparotomy. Staging laparoscopy was successful in 76 of 77 patients (99%). Adverse events occurred in three patients (4%): bowel injury n=2; late port site metastasis, n=1. Laparoscopic staging identified factors precluding curative resection in 16 patients (21%), thus averting unnecessary laparotomy. Of the 57 patients (74%) staged laparoscopically who underwent surgical exploration, 7 patients (12%) were unresectable and liver resection was achieved in 50 (88%). Laparoscopic staging remains useful in detecting occult intra- and extra-hepatic tumour in selected patients with potentially operable colorectal liver metastases. ",0
3606,18333812,Critical Steps toward a tissue-engineered cartilage implant using embryonic stem cells,"Embryonic stem (ES) cells are a potential source for cartilage tissue engineering because they provide an unlimited supply of cells that can be differentiated into chondrocytes. So far, chondrogenic differentiation of both mouse and human ES cells has only been demonstrated in two-dimensional cultures, in pellet cultures, in a hydrogel, or on thin biomaterials. The next challenge will be to form cartilage on a load-bearing, clinically relevant-sized scaffold in vitro and in vivo, to regenerate defects in patients suffering from articular cartilage disorders. For a successful implant, cells have to be seeded efficiently and homogenously throughout the scaffold. Parameters investigated were the scaffold architecture, seeding method, and cellular condition. Seeding in a three-dimensional fiber-deposited (3DF) scaffold was more homogenous than in a compression-molded scaffold. The seeding efficiency on bare scaffolds was compromised by the absence of serum in the chondrogenic medium, but could be improved by combining the cells with a gel and subsequent injection into the 3DF scaffolds. However, the viability of the cells was unsatisfactory in the interior of the graft. Cell aggregates, the so-called embryoid bodies (EBs), were seeded with increased survival rate. Mouse ES cells readily underwent chondrogenic differentiation in vitro in pellets, on bare scaffolds, in Matrigel, and in agarose, both as single cells and in EBs. The differentiation protocol requires further improvement to achieve homogenous differentiation and abolish teratoma formation in vivo. We conclude that ES cells can be used as a cell source for cartilage tissue engineering, pending further optimization of the strategy. ",0
3607,18334004,Carbon monoxide-induced stomatal closure in Vicia faba is dependent on nitric oxide synthesis,"Recently, in animals, carbon monoxide (CO), like nitric oxide (NO), was implicated as another important physiological messenger or bioactive molecule. Previous researches indicate that heme oxygenase (HO)-1 (EC 1.14.99.3) catalyzes the oxidative conversion of heme to CO and biliverdin IXa (BV) with the concomitant release of iron. However, little is known about the physiological roles of CO in plant, especially in stomatal movement of guard cells. In the present paper, the regulatory role of CO during stomatal movement in Vicia faba was surveyed. Results indicated that, like sodium nitroprusside (SNP), CO donor hematin induced stomatal closure in dose- and time-dependent manners. These responses were also proved by the addition of gaseous CO aqueous solution with different concentrations, showing for the first time that CO and NO exhibit similar regulation role in the stomatal movement. Moreover, our data showed that 2,4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO)/N(G)-nitro-L-arginine-methyl ester (L-NAME) not only reversed stomatal closure by CO, but also suppressed the NO fluorescence induced by CO, implying that CO-induced stomatal closure probably involves NO/nitric oxide synthase (NOS) signal system. Additionally, the CO/NO scavenger hemoglobin (Hb) and CO-specific synthetic inhibitor zinc protoporphyrin IX (ZnPPIX), NO scavenger cPTIO and NOS inhibitor L-NAME reversed the darkness-induced stomatal closure and NO fluorescence. These results show that, maybe like NO, the levels of CO in guard cells of V. faba is higher in dark than that in light, HO-1 and NOS are the enzyme systems responsible for generating endogenous CO and NO in darkness, respectively, and that CO being from HO-1 mediates darkness-induced NO synthesis in guard cells' stomatal closure of V. faba. ",0
3608,18334023,Quantification of specific bindings of biomolecules by magnetorelaxometry," The binding reaction of the biomolecules streptavidin and anti-biotin antibody, both labelled by magnetic nanoparticles (MNP), to biotin coated on agarose beads, was quantified by magnetorelaxometry (MRX). Highly sensitive SQUID-based MRX revealed the immobilization of the MNP caused by the biotin-streptavidin coupling. We found that about 85% of streptavidin-functionalised MNP bound specifically to biotin-agarose beads. On the other hand only 20% of antibiotin-antibody functionalised MNP were specifically bound. Variation of the suspension medium revealed in comparison to phosphate buffer with 0.1% bovine serum albumin a slight change of the binding behaviour in human serum, probably due to the presence of functioning (non heated) serum proteins. Furthermore, in human serum an additional non-specific binding occurs, being independent from the serum protein functionality.The presented homogeneous bead based assay is applicable in simple, uncoated vials and it enables the assessment of the binding kinetics in a volume without liquid flow. The estimated association rate constant for the MNP-labelled streptavidin is by about two orders of magnitude smaller than the value reported for free streptavidin. This is probably due to the relatively large size of the magnetic markers which reduces the diffusion of streptavidin. Furthermore, long time non-exponential kinetics were observed and interpreted as agglutination of the agarose beads. ",0
3609,18334228,Localization of plasma membrane and secretory calcium pumps in the mammary gland,"Until recently the mechanism for the enrichment of milk with calcium was thought to be almost entirely via the secretory pathway. However, recent studies suggest that a plasma membrane calcium ATPase, PMCA2, is the primary mechanism for calcium transport into milk, highlighting a major role for apical calcium transport. We compared the expression of the recently identified secretory calcium ATPase, SPCA2, and SPCA1, in the mouse mammary gland during development. SPCA2 levels increased over 35-fold during lactation with expression localized to luminal secretory cells, while SPCA1 increased only a modest 2-fold and was expressed throughout the cells of the mammary gland. We also observed major differences in the localization of PMCA2 and PMCA1. Our studies highlight the likely specific roles of PMCA2 and SPCA2 in lactation and indicate that calcium transport into milk is a complex interplay between apical and secretory pathways. ",0
3610,18334264,Fluorotelomer alcohols induce hepatic vitellogenin through activation of the estrogen receptor in male medaka (Oryzias latipes),"Here we report on the in vivo estrogenic effects of two fluorotelomer alcohols, such as 1H,1H,2H,2H-perfluorooctan-1-ol (6:2 FTOH) and 1H,1H,2H,2H-perfluorodecan-1-ol (8:2 FTOH), in male medaka (Oryzias latipes). An in vitro yeast two-hybrid assay indicated a significant, dose-dependent interaction between medaka estrogen receptor alpha (ERalpha) and coactivator TIF2 upon treatment with 6:2 FTOH, 8:2 FTOH or 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluoro-1-decanol (NFDH). The relative ranks of tested chemicals on the estrogenic effects for medaka ERalpha descended in the order of estradiol-17beta (100)>>6:2 FTOH (0.16)>NFDH (0.016)>8:2 FTOH (0.0044). In contrast, no interaction with the ERalpha was observed upon treatment with perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDA) or perfluoroundecanoic acid (PFUnDA). Expression analysis of hepatic vitellogenin (VTG) protein showed estrogenic potentials with, 6:2 FTOH and 8:2 FTOH, indicative of the induction of VTG synthesis in the livers of male medaka. We also investigated mRNA expression levels of two ER subtypes (ERalpha and beta) and two VTGs (VTG I and VTG II) in the livers of male medaka following exposure to FTOHs. Quantitative real-time polymerase chain reaction analyses revealed that hepatic ERalpha, VTG I, and VTG II mRNA responded rapidly to FTOHs such as 6:2 FTOH and 8:2 FTOH after 8-h exposure, whereas no effects of these compounds on ERbeta mRNA transcription were observed. These results from both in vitro and in vivo assays strongly suggest that certain FTOHs, such as 6:2 FTOH and 8:2 FTOH, induce hepatic VTG through activation of ERalpha in male medaka. ",0
3611,18334849,Patient self-perceptions of swallowing difficulties as compared to expert ratings of videofluorographic studies,"Research investigating the relationship between subjective and objective assessment of dysphagia in patients with various diagnoses has yielded conflicting results. The goal of this study is to investigate the reliability of patient self-perceptions of swallowing difficulties compared to expert ratings of videofluorographic studies considering three medical diagnostic categories: neurological disorders, structural deficits and general medical diagnoses. One hundred and three patients who were referred for videofluorographic swallow evaluation were included in the study. Face-to-face interviews with patients were conducted before their videofluorographic studies. The correlation between patient self-perceptions and expert ratings of the videofluorographic studies was established by comparing the results of patients' self-reports with the results of the videofluorographic studies. The correlation between patient self-perceptions of swallowing difficulties and expert ratings of the videofluorographic studies varied greatly depending on the patients' medical diagnoses. The correlation was mild in patients with neurological disorders, moderate in patients with structural deficits and high in patients with general medical diagnoses. The results of this study demonstrated that patient self-perceptions of swallowing difficulties should be used as one of the criteria, but not the only one, in making referrals for further swallowing evaluation, especially in patients with neurological disorders. ",0
3612,18335190,The Crohn's disease susceptibility gene DLG5 as a member of the CARD interaction network,"Discs large homolog 5 (DLG5), a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, has been associated with Crohn's disease (CD), but its role in the pathogenesis of this inflammatory bowel disease is disputed. Here, we used sequence comparisons and phylogenies to analyse the DLG5 gene and its protein product. We identified a 5' exon, which codes for an N-terminal caspase recruitment domain (CARD) and experimentally confirmed its expression in colonic tissue. DLG5 shares this new domain with nucleotide-binding oligomerisation domain containing 2 (NOD2); the first CD susceptibility factor identified in genetic studies. An extensive phylogenetic analysis redefines the family organisation of the MAGUK proteins: DLG5 is closely related to CARD10, CARD11 and CARD14, CARD-containing proteins which initiate pro-inflammatory NFkappaB signalling, but not to DLG1-4, previously considered the closest related proteins. Therefore, we suggest renaming DLG5 to correctly annotate the gene in its phylogenetic and functional context. Our study provides evidence that the scaffolding protein DLG5 belongs to the CARD protein family. Thus, DLG5 likely acts in the regulation of NFkB activation or caspase activation as part of host defence mechanisms. As there is substantial crosstalk between CARD-mediated pathways, both CD susceptibility genes, NOD2 and DLG5, may interact functionally to contribute to CD risk. ",0
3613,18335481,Tissue Doppler imaging for detecting onset of muscle activity,"Tissue Doppler imaging (TDI) is typically used to image and quantify tissue motion. We investigated whether this method would serve as a viable alternative to surface electromyography (EMG) in providing a reliable and valid measure of the onset of muscle activity. Ten healthy subjects performed maximal knee extension exercises at 0 degrees /s (isometric), 60 degrees /s, 120 degrees /s, 180 degrees /s, and 240 degrees /s (5 times each, on each side), using an isokinetic dynamometer. Simultaneous EMG and TDI velocity (superimposed on motion-mode ultrasound cine-loops) recordings were made from vastus lateralis. All tests were repeated 1 week later. There was a good correlation between the onset times determined with TDI velocity and EMG: r = 0.78 (day 1), and r = 0.80 (day 2) (each P < 0.001). The mean difference (and SD) in muscle onset time between the two methods (TDI minus EMG) was -20.3 +/- 31.0 ms (day 1) and -17.4 +/- 27.2 ms (day 2). TDI represents a reliable and valid measure of detecting onset of muscle activity. The mean difference between EMG and TDI onset times (approximately 20 ms) is likely explained by electromechanical delay. TDI represents a viable method for measuring the onset of muscle activity; it may offer a non-invasive alternative to fine-wire EMG for use with small or deep muscles. ",0
3614,18335816,Tissue biomarkers for diagnosis & management of oral squamous cell carcinoma,"Squamous cell carcinoma (SCC) accounts for more than 90% of malignancies of the oral cavity and oropharynx. Globally, SCC is one of the top ten cancers with a predilection for older males. In the U.S., SCC accounts for more deaths annually than cervical cancer, malignant melanoma or Hodgkin's lymphoma and costs about 2 billion dollars in treatment expenses. The 5-year survival rate is less than 50%, a prognosis that is poorer than that of breast cancer or melanoma.2 Significant numbers of patients develop local recurrence, second primary tumors and distant metastases. Patients presenting with late stage disease resulting in poor survival, are common; in part due to inadequate screening protocols and access to care issues. In the following review article, the risk factors, current screening protocols, treatment options and biomarkers for diagnosis and prognosis of SCC, will be discussed. ",0
3615,18336055,Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis,"The mechanistic framework of physiologically based pharmacokinetic (PBPK) models makes them uniquely suited to hypothesis testing and lineshape analysis, which help provide valuable insights into mechanisms that contribute to the observed concentration-time profiles. The aim of this article is to evaluate the utility of PBPK models for simulating oral lineshapes by optimizing clearance and distribution parameters through fitting observed intravenous pharmacokinetic profiles. A generic PBPK model, built in-house using MATLAB software and incorporating absorption, metabolism, distribution, biliary and renal elimination models, was employed for simulation of the concentration-time profiles of nine marketed drugs with diverse physicochemical and pharmacokinetic profiles and absorption rates determined solely by transcellular or paracellular permeability and solubility. The model is based on easily available physicochemical properties of compounds such as the log P, acid dissociation constant and solubility, and in vitro pharmacokinetic data such as Caco-2 permeability, the fraction of the compound unbound in plasma, and microsomal or hepatocyte intrinsic clearance. Clearance and distribution parameters optimized through simulation of intravenous profiles were used to simulate their corresponding oral profiles, which are determined by a multitude of parameters, both compound-dependent and physiological. Comparison of the simulated and observed oral profiles was done using goodness-of-fit parameters such as the reduced chi(2) statistic. Fold errors were calculated for the area under the plasma concentration-time curve (AUC), maximum plasma concentration (C(max)) and time to reach the C(max) (t(max)), to assess the accuracy of predictions. The approach of predicting the oral profiles by optimizing the clearance and distribution parameters using the observed intravenous profile seemed to perform well for the nine compounds chosen for the study. The mean fold error for oral pharmacokinetic parameters, such as the C(max), t(max) and AUC, and for lineshape simulation was within 2-fold. The validation of the generic PBPK model built in-house demonstrated that as long as the absorption profile of a compound is determined solely by solubility and paracellular or transcellular permeability, the PBPK simulations of oral profiles using optimized parameters from intravenous simulations provide reasonably good agreement with the observed profile with respect to both the lineshape fit and prediction of pharmacokinetic parameters. Therefore, any lineshape mismatch between PBPK simulated and observed oral profiles can be interpreted suitably to gain mechanistic insights into the pharmacokinetic processes that have resulted in the observed lineshape. A strategy has been proposed to identify involvement of carrier-mediated transport; clearance saturation; enterohepatic recirculation of the parent compound; extra-hepatic, extra-gut elimination; higher in vivo solubility than predicted in vitro; drug-induced gastric emptying delays; gut loss and regional variation in gut absorption. ",0
3616,18336332,Synthesis and endothelin receptor binding affinity of a novel class of 2-substituted-4-aryl-3-quinolinecarboxylic acid derivatives,"The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, and ET-3. These peptides display a variety of physiological activities including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. They exert their actions via activation of two distinct receptor subtypes, ET(A) and ET(B), belonging to the G protein-coupled receptor (GPCR) superfamily. Ligands of these receptors have received numerous citations in the recent pharmaceutical literature. In particular receptor antagonists, both ET(A)- and ET(B)-selective, as well as non-selective, have been described due to their wide therapeutic potential. As a part of our program toward the development of selective ET(A) ligands we have designed and we now report new molecules based on 2-substituted-4-aryl-3-quinolinecarboxylic acid moiety. Binding profile for some compounds (40, 44, 46, and 47) of this class showed a reasonable affinity and selectivity for ET(A) receptors. ",0
3617,18336363,Linear-polarized IR-spectroscopic and structural elucidation of glycyl-L-phenylalanyl-glycine hydrochloride monohydrate,"As a part of our spectroscopic and structural elucidation of small peptides, their salts and metal complexes, the polarized IR-spectroscopic and structural elucidation of the protonated form of glycyl-(L)-phenylalanyl-glycine as hydrochloride monohydrate (H-Gly-Phe-Gly-OHxHClxH(2)O) is reported. The obtained structure of the protonated tripeptide is supported by quantum chemical ab initio calculations at UHF level of theory and 6-31++G, showing only one stable conformer with two intermolecular NH(3)(+)OH(2) and (C=O)OHOH(2) hydrogen bonds. The N(terminus) amide O=C-N-H amide fragment is flat trans-configured with a dihedral angle value of 179.0(7)degrees, while the corresponding group at C(terminus) is with transoide-configurated and value of the dihedral angle of 151.1(3)degrees, respectively. In addition data of (1)H- and (13)C magnetic resonance spectroscopy (NMR), thermogravimetry (TGA), differential scanning calorimetry (DSC) and high performed liquid chromatography (HPLC) with tandem mass spectrometry (HPLC-MS/MS) as presented. ",0
3618,18336739,Increase of skin-ceramide levels in aged subjects following a short-term topical application of bacterial sphingomyelinase from Streptococcus thermophilus,"Several studies have demonstrated that ceramides play an essential role in both the barrier and water-holding functions of healthy stratum corneum, suggesting that the dysfunction of the stratum corneum associated with ageing as well that observed in patients with several skin diseases could result from a ceramide deficiency. In a previous study our group reported a significant increase in skin ceramide levels in healthy subjects after treatment in vivo with a cream containing a preparation of Streptococcus thermophilus. The presence of high levels of neutral sphingomyelinase activity in this organism was responsible for the observed increase of stratum corneum ceramide levels, thus leading to an improvement in barrier function and maintenance of stratum corneum flexibility. The aim of the present work is to investigate the effects of the topical treatment of a Streptococcus thermophilus-containing cream on ceramide levels of stratum corneum of healthy elderly women. The ceramide levels, transepidermal water loss and capacitance were evaluated on stratum corneum sheets from the forearms of 20 healthy female subjects treated with a base cream or the same cream containing a sonicated preparation of the lactic acid bacterium Streptococcus thermophilus. A 2-week topical application of a sonicated Streptococcus thermophilus preparation led to significant and relevant increase of stratum corneum ceramide levels. Moreover, the hydration values of the treated forearm of each subject was significantly higher than control sites. These results suggest that the experimental cream was able to improve the lipid barrier and to increase a resistance against ageing-associated xerosis. ",0
3619,18337136,"Purification and antibacterial characterization of a novel isoform of the Manila clam lectin (MCL-4) from the plasma of the Manila clam, Ruditapes philippinarum","In many bivalve molluscs, lectins are present in the hemolymph and are thought to be important for internal host defense mechanisms. For this study, we purified a novel isoform of the Manila clam lectin (designated MCL-4) from the plasma of the Manila clam, Ruditapes philippinarum, using affinity chromatography and gel filtration. Native PAGE results showed that the MCL-4 consisted of 70 kDa protein. MCL-4 was found to be composed of 58-kDa and 43-kDa bands when examined using SDS-PAGE under reducing and non-reducing conditions. The native MCL-4 was revealed as a 147 kDa molecular mass protein by gel filtration. The purified MCL-4 agglutinates calcium-dependently in the erythrocytes of sheep and rabbit, but not in cells of the three species of marine bacteria tested. However, the phagocytic ability of the R. philippinarum hemocytes for the MCL-4-opsonized Vibrio tubiashii cells was significantly greater than that for the BSS-treated bacterial cells. Addition of purified MCL-4 markedly suppressed Alteromonas haloplanktis growth. These results suggest that MCL-4, because of its opsonizing and bacteriostatic properties, might contribute to the host defense mechanisms against invading microorganisms in R. philippinarum. ",0
3620,18337212,Use of Folin-Ciocalteu phenol reagent and 3-methyl-2-benzothiazolinone hydrazine hydrochloride in the determination of oxcarbazepine in pharmaceuticals,"Two spectrophotometric methods are proposed for the assay of oxcarbazepine (OXC) in bulk and dosage forms using Folin-Ciocalteu phenol reagent (FCP) and 3-methyl-2-benzothiazolinone hydrazine hydrochloride (MBTH) as reagents. The first method involves addition of FCP reagent to OXC in alkaline medium followed by measurement of absorbance at 760 nm (method A), and the other involves addition of a fixed volume of MBTH after treatment of OXC with ferric chloride and measurement of absorbance at 456 nm (method B). In both methods, the amount of chromogen formed corresponds to the amount of OXC and the measured absorbance was found to increase linearly with the concentration of OXC, which is corroborated by the correlation coefficients of 0.9985 and 0.9984 for method A and B, respectively. The systems obey Beer's law for 5-30 microg mL(-1) and 10-50 microg mL(-1) for methods A and B, respectively. The apparent molar absorptivity was calculated to be 8.06 x 10(3) L mol(-1) cm(-1) and 3.126 x 10(3) L mol(-1) cm(-1) for methods A and B, respectively. The limits of detection (LOD) and limit of quantification (LOQ) were calculated to be 1.6 and 5 microg mL(-1) for method A and 3 and 10 microg mL(-1) for method B. The inter-day and intra-day imprecision of the methods were found to be in the range of 1.1-1.7 and 0.9-1.1% for method A, and 1.1-1.9 and 0.6-0.9% for method B. The accuracy ranged between 98.9-99.7% and 99.3-100.1 for method A and B, respectively. No interference was observed from common pharmaceutical excipients. The methods were successfully applied to the assay of OXC in tablet preparations. ",0
3621,18337343,"Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali","We conducted a randomized single-blinded trial comparing the efficacy and safety of artesunate (AS) + amodiaquine (AQ, 3 days) versus AS (3 days) + sulfadoxine-pyrimethamine (SP, single dose) versus AS monotherapy (5 days) in Southern Mali. Uncomplicated malaria cases were followed for 28 days. Molecular markers of drug resistance were determined. After identification of recrudescences by genotyping, both artemisinin-based combination therapies (ACTs) reached nearly 100% efficacy at Day 14 and Day 28 versus 98.3% and 96.5% for AS, respectively (P > 0.05). AS + SP significantly selected DHFR and DHPS mutations associated with sulfadoxine and pyrimethamine resistance (P < 0.001), and AS + AQ equally selected PfCRT and PfMDR1 point mutations associated with chloroquine and AQ resistance (P < 0.001). No significant adverse event attributable to any of the study drugs was found. The ACTs were efficacious and safe, but the selection of markers for resistance to the partner drugs raises concerns over their lifespan in areas of intense malaria transmission. ",0
3622,18337602,DNA methylation markers and early recurrence in stage I lung cancer,"BACKGROUND: Despite optimal and early surgical treatment of non-small-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor. METHODS: Fifty-one patients with stage I NSCLC who underwent curative resection but who had a recurrence within 40 months after resection (case patients) were matched on the basis of age, NSCLC stage, sex, and date of surgery to 116 patients with stage I NSCLC who underwent curative resection but who did not have a recurrence within 40 months after resection (controls). We investigated whether the methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence. RESULTS: In a multivariate model, promoter methylation of the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of p16 and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an odds ratio of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC. CONCLUSIONS: Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence.",0
3623,18337632,"Effects of housing characteristics and home environmental factors on respiratory symptoms of 10,784 elementary school children from northeast china","Only few studies have assessed the relative impact of housing characteristics and home environmental factors on asthma and asthma-related symptoms in Chinese children, and to our knowledge, few studies have elaborated respiratory symptoms and allergies in this context. It was the aim of this study to assess the effects of housing characteristics, pet keeping, home decorations and other indoor environmental factors on respiratory health of Chinese children. We studied 10,784 children (6-13 years old) from 12 districts in Liaoning province, Northeast China. Information on respiratory health, housing characteristics and environmental pollution was obtained by a standard questionnaire from the American Thoracic Society. Prevalence of asthma-related symptoms was higher for those living along the main stem of traffic, and for those with a house nearby a pollution source. Lower prevalence rates of respiratory morbidity were associated with households with a bigger area of residence and more rooms. Pet keeping was associated with doctor-diagnosed asthma (OR = 1.52; 95% CI 1.25-1.84). Home decorations also increased the risk of doctor-diagnosed asthma (OR = 1.72; 95% CI 1.45-2.04) and current asthma (OR = 1.43; 95% CI 1.06-1.93). Environmental tobacco smoke, pests and visible mold on walls were associated with the occurrence of asthma symptoms. Home environmental factors are particularly important for the development of respiratory morbidity among children. ",0
3624,18338080,Estimating morbidity rates from electronic medical records in general practice. Evaluation of a grouping system,"In this study, we evaluated the internal validity of EPICON, an application for grouping ICPC-coded diagnoses from electronic medical records into episodes of care. These episodes are used to estimate morbidity rates in general practice. Morbidity rates based on EPICON were compared to a gold standard; i.e. the rates from the second Dutch National Survey of General Practice. We calculated the deviation from the gold standard for 677 prevalence and 681 incidence rates, based on the full dataset. Additionally, we examined the effect of case-based reasoning within EPICON using a comparison to a simple, not case-based method (EPI-0). Finally, we used a split sample procedure to evaluate the performance of EPICON. Morbidity rates that are based on EPICON deviate only slightly from the gold standard and show no systematic bias. The effect of case-based reasoning within EPICON is evident. The addition of case-based reasoning to the grouping system reduced both systematic and random error. Although the morbidity rates that are based on the split sample procedure show no systematic bias, they do deviate more from the gold standard than morbidity rates for the full dataset. Results from this study indicate that the internal validity of EPICON is adequate. Assuming that the standard is gold, EPICON provides valid outcomes for this study population. EPICON seems useful for registries in general practice for the purpose of estimating morbidity rates. ",0
3625,18338402,"Hypothesis of active components in volatile oil from a Chinese herb formulation, 'Shao-Fu-Zhu-Yu decoction', using GC-MS and chemometrics","""Traditional Chinese medicine (TCM) with few or no side effects has increasingly attracted attention all over the world. However, the bioactive components and the therapeutic mechanisms are usually not understood because of the complex chemical compositions of these medicines. In this paper, GC-MS coupled with a chemometric method was developed for analysis of active components in volatile oil from a Chinese herb formulation, """"Shao-Fu-Zhu-Yu Decoction"""". The volatile oils, obtained by hydrodistillation from """"Shao-Fu-Zhu-Yu Decoction"""" (SFZYD) and its constituent herbs with abundant volatile oil (Angelica sinensis, Ligusticum chuanxiong, Cinnamomum cassia, Foeniculum vulgare, Zingiber officinale), were chemically analyzed using GC-MS and bioassayed using oxytocin-induced uterine contraction assay in vitro. Then, a mathematic model relating the chemical compositions and their activities in inhibiting mice uterine contraction was established for hypothesis of the bioactive compounds based on chemometrics. As a result, nine compounds which might contribute to the inhibition of oxytocin-induced uterine contraction were selected, and the activities of some of them were further confirmed by our experiments and/or the literature. The data suggest that the developed method is helpful for screening bioactive components from complex mixtures, such as the extracts of TCM. """,0
3626,18338577,Construction of the gene drb0099 deleted mutant and adversity analysis in the extremely radioresistant bacterium Deinococcus radiodurans],"Deinococcus radiodurans R1 has extraordinary resistance to radiation. DRB0099 might play an important role in protecting the bacterium against radiation. To verify the inference, we deleted drb0099 and constructed the mutant. Comparing with the wild type, the mutant grew more slowly in the beginning cultivation stage (0-16 h) under normal conditions. After being cultivated for 16 h, the mutant grew faster than the wild type. The biomass concentration of the wild type was always higher than that of the mutant. The mutant cell's fission during the growing phase might be blocked. When treated with UV, although Deinococcus radiodurans R1 cultures' survival fraction was lower with UV treatment time increased, the survival fraction was much higher than that of drb0099. The wild type could repair DNA double strands breaks better than the mutant. The gene drb0099 might directly relate with the DNA repair system. The mutant was more sensitive to H202 than the wild type. The wild type could better protect protein and DNA against reactive oxygen species (ROS) or in DNA repair. When treated with low concentration of H2O2, although the survival fraction of both R1 and the mutant decreased, the difference was small. However, with the concentration of H2O2 increased, the difference value increased. The mutant without drb0099 was more easily injured than the wild type with ROS increased. Under UV or H2O2 treatment, DRB0099 could protect protein and DNA from oxidation. ",0
3627,18338612,Effect of water stress on growth and accumulation of active components of Isatis indigotica],"To study the effect of water stress on the growth and accumulation of active components of Isatis indigotica. By pot culture experiment,the characteristic indexes of water requirement, chlorophyll content, transpiration rate, photosynthesis, biomass and effective ingredient indirubin were studied under normal and water stress conditions, respectively. With the increase of the extent and duration of water stress, the quantity of water requirement, chlorophyll content, respiration rate, photosynthesis and biomass of I. indigotica were decreased, while water use efficiency increased. It is a critical period of water requirement in July, high water content in soil and extreme water stress are not propitious to the accumulation of indirubin, appropriate water stress can stimulate indirubin accumulatio. The harvest of leaves of I. indigotica is optimal in July, while the harvest of root is appropriate in October. Yield and quantity of I. indigotica are improved when the field capacity is between 45% and 70%. ",0
3628,18338951,The antibacterial chemokine MIG/CXCL9 is constitutively expressed in epithelial cells of the male urogenital tract and is present in seminal plasma,"The integrity of the urogenital tract against potentially invasive pathogens is important for the health of the individual, fertilization, and continuance of species. Antibiotic peptides with broad antimicrobial activity, among them chemokines, are part of the innate immune system. We investigated the presence of the antibacterial interferon (IFN)-dependent CXC chemokines, MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11, in the human male reproductive system. MIG/CXCL9 was detected at 25.0 nM (range 8.1-40.6 nM; n = 14), whereas IP-10/CXCL10 and I-TAC/CXCL11 were detected at lower levels (mean 1.8 nM, range 0.3-5.8 nM and mean 0.6, 0.2-1.6 nM, respectively) in seminal plasma of fertile donors. The levels of MIG/CXCL9 are more than 300-fold higher than those previously reported in blood plasma. In vasectomized donors, significantly lower levels of MIG/CXCL9 (mean 14.7 nM, range 6.6-21.8) were found, suggesting that the testis and epididymis, in addition to the prostate, significantly contribute to the MIG/CXCL9 content of seminal plasma. Strong expression of MIG/CXCL9 was found in the epithelium of testis, epididymis, and prostate, as detected by immunohistochemistry. MIG/CXCL9 at concentrations in the order of those found in seminal plasma possessed antibacterial activity against the urogenital pathogen Neisseria gonorrhoeae. The relatively high levels of MIG/CXCL9 in seminal plasma point to roles for this chemokine in both host defense of the male urogenital tract and during fertilization. ",0
3629,18339020,Rapid non-genomic effects of glucocorticoids on oxidative stress in a guinea pig model of asthma,"Glucocorticoids (GC) may exert therapeutic effects in asthma by a rapid non-genomic mechanism. The lungs of asthmatic patients are exposed to oxidative stress, which is believed to be critical in the pathogenesis of asthma. The aim of this study was to investigate whether GC exert a rapid non-genomic effect on oxidative stress in asthmatic guinea pigs. The guinea pig asthma model was used to assess inhibitory effects of budesonide (BUD) on oxidative stress. BAL fluid (BALF), trolox equivalent antioxidant capacity and lung manganese superoxide dismutase (MnSOD) activity were measured by spectrophotometry. Superoxide anion production was measured by cytochrome c reduction assay. Oxidative stress occurred within minutes following antigen challenge and BUD reduced the severity of oxidative stress in asthmatic guinea pigs within 15 min. BUD significantly decreased BALF trolox equivalent antioxidant capacity and lung MnSOD activity, as compared with those of vehicle-treated asthmatic guinea pigs (P < 0.05). Additionally, BUD rapidly inhibited in vitro superoxide anion production by BALF cells and bronchi harvested from sensitized animals. These rapid effects were not blocked by the GC receptor antagonist RU486 and/or the protein synthesis inhibitor cycloheximide. BUD reduced oxidative stress in a guinea pig model of asthma by a rapid non-genomic mechanism. These data suggest new mechanisms whereby GC treatments may benefit asthma. ",0
3630,18339204,Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multi-ethnic sample,"The rs9939609 T>A single-nucleotide polymorphism (SNP) in the FTO gene has previously been found to be associated with obesity in European Caucasian samples. The objective of this study is to examine whether this association extends to metabolic syndrome (MetS) and applies in non-Caucasian samples. The FTO rs9939609 SNP was genotyped in 2121 subjects from four different non-Caucasian geographical ancestries. Subjects were classified for the presence or absence of MetS according to the International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III definitions. Carriers of > or = 1 copy of the rs9939609 A allele were significantly more likely to have IDF-defined MetS (35.8%) than non-carriers (31.2%), corresponding to a carrier odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.01 to 1.50), with a similar trend for the NCEP ATP III-defined MetS. Subgroup analysis showed that the association was particularly strong in men. The association was related to a higher proportion of rs9939609 A allele carriers meeting the waist circumference criterion; a higher proportion also met the HDL cholesterol criterion compared with wild-type homozygotes. Thus, the FTO rs9939609 SNP was associated with an increased risk for MetS in this multi-ethnic sample, confirming that the association extends to non-Caucasian population samples. ",0
3631,18339423,Altered gene expression in busulfan-resistant human myeloid leukemia,"Busulfan (Bu) resistance is a major obstacle to hematopoietic stem cell transplantation (HSCT) of patients with chronic or acute myelogenous leukemia (CML or AML). We used gene expression analysis to identify cellular factors underlying Bu resistance. Two Bu-resistant leukemia cell lines were established, characterized and analyzed for differentially expressed genes. The CML B5/Bu250(6) cells are 4.5-fold more resistant to Bu than their parental B5 cells. The AML KBM3/Bu250(6) cells are 4.0-fold more Bu-resistant than KBM3 parental cells. Both resistant sublines evade Bu-mediated G2-arrest and apoptosis with altered regulations of CHK2 and CDC2 proteins, constitutively up-regulated anti-apoptotic genes (BCL-X(L), BCL2, BCL2L10, BAG3 and IAP2/BIRC3) and down-regulated pro-apoptotic genes (BIK, BNIP3, and LTBR). Bu-induced apoptosis is partly mediated by activation of caspases; use of the inhibitor Z-VAD-FMK completely abrogated PARP1 cleavage and reduced apoptosis by approximately 50%. Furthermore, Bu resistance in these cells may be attributed in part to up-regulation of HSP90 protein and activation of STAT3. The inhibition of HSP90 with geldanamycin attenuated phosphorylated STAT3 and made B5/Bu250(6) and KBM3/Bu250(6) more Bu-sensitive. The analysis of cells derived from patients classified as either clinically resistant or sensitive to high-dose Bu-based chemotherapy indicated alterations in gene expression that were analogous to those observed in the in vitro model cell lines, confirming the potential clinical relevance of this model for Bu resistance. ",0
3632,18339525,Pentoxifylline to treat radiation proctitis: a small and inconclusive randomised trial,"This prospective randomised controlled study of 40 patients could not show a statistically significant advantage with 6 months of pentoxifylline compared with standard measures for late radiation-induced rectal bleeding. However, a modest benefit cannot be excluded and larger randomised placebo-controlled trials with longer durations of pentoxifylline treatment may be justified. ",0
3633,18339637,Principles of assessing bacterial susceptibility to antibiotics using the agar diffusion method,"The agar diffusion assay is one method for quantifying the ability of antibiotics to inhibit bacterial growth. Interpretation of results from this assay relies on model-dependent analysis, which is based on the assumption that antibiotics diffuse freely in the solid nutrient medium. In many cases, this assumption may be incorrect, which leads to significant deviations of the predicted behaviour from the experiment and to inaccurate assessment of bacterial susceptibility to antibiotics. We sought a theoretical description of the agar diffusion assay that takes into consideration loss of antibiotic during diffusion and provides higher accuracy of the MIC determined from the assay. We propose a new theoretical framework for analysis of agar diffusion assays. MIC was determined by this technique for a number of antibiotics and analysis was carried out using both the existing free diffusion and the new dissipative diffusion models. A theory for analysis of antibiotic diffusion in solid media is described, in which we consider possible interactions of the test antibiotic with the solid medium or partial antibiotic inactivation during diffusion. This is particularly relevant to the analysis of diffusion of hydrophobic or amphipathic compounds. The model is based on a generalized diffusion equation, which includes the existing theory as a special case and contains an additional, dissipative term. Analysis of agar diffusion experiments using the new model allows significantly more accurate interpretation of experimental results and determination of MICs. The model has more general validity and is applicable to analysis of other dissipative processes, for example to antigen diffusion and to calculations of substrate load in affinity purification. ",0
3634,18339848,EphA2 is an essential mediator of UV radiation-induced apoptosis,"One of the physiologic consequences of excessive UV radiation (UVR) exposure is apoptosis. This critical response serves to eliminate genetically injured cells and arises, in part, from activation of DNA damage and p53 signaling. Other contributory pathways, however, likely exist but have not been fully characterized. In a recent global screen of UVR response genes in melanocytes, we identified the receptor tyrosine kinase EPHA2. Using a combination of genetic and pharmacologic approaches, we set out to investigate the upstream regulation of EphA2 by UVR and the functional consequences of this effect. We found that the UVR-associated increase in EphA2 occurs in melanocytes, keratinocytes, and fibroblasts from both human and murine sources. More specifically, UVR effectively up-regulated EphA2 individually in p53-null, p63-null, and p73-null murine embryonic fibroblasts (MEF), suggesting that the p53 family of transcription factors is not essential for the observed effect. However, inhibition of mitogen-activated protein kinase (MAPK) signaling by U0126 and PD98059 significantly reduced the UVR response whereas overexpression of oncogenic NRAS led to an increase in EphA2. These results confirm that UVR induces EphA2 by a p53-independent, but MAPK-dependent, mechanism. In response to UV irradiation, Epha2(-/-) MEFs were highly resistant to UVR-mediated cytotoxicity and apoptosis whereas introduction of EphA2 into both wild-type and p53-null MEFs led to activation of an apoptotic program that can be blocked by caspase-8 inhibition. These functional findings suggest that EphA2 is in fact an essential p53-independent, caspase-8-dependent proapoptotic factor induced by UVR. ",0
3635,18339881,Genome-wide analysis of the homeobox C6 transcriptional network in prostate cancer,"Homeobox transcription factors are developmentally regulated genes that play crucial roles in tissue patterning. Homeobox C6 (HOXC6) is overexpressed in prostate cancers and correlated with cancer progression, but the downstream targets of HOXC6 are largely unknown. We have performed genome-wide localization analysis to identify promoters bound by HOXC6 in prostate cancer cells. This analysis identified 468 reproducibly bound promoters whose associated genes are involved in functions such as cell proliferation and apoptosis. We have complemented these data with expression profiling of prostates from mice with homozygous disruption of the Hoxc6 gene to identify 31 direct regulatory target genes of HOXC6. We show that HOXC6 directly regulates expression of bone morphogenic protein 7, fibroblast growth factor receptor 2, insulin-like growth factor binding protein 3, and platelet-derived growth factor receptor alpha (PDGFRA) in prostate cells and indirectly influences the Notch and Wnt signaling pathways in vivo. We further show that inhibition of PDGFRA reduces proliferation of prostate cancer cells, and that overexpression of HOXC6 can overcome the effects of PDGFRA inhibition. HOXC6 regulates genes with both oncogenic and tumor suppressor activities as well as several genes such as CD44 that are important for prostate branching morphogenesis and metastasis to the bone microenvironment. ",0
3636,18340252,Professionals and managers with severe mental illnesses: findings from a national survey,"This study explores the capacity of individuals with severe mental illness to be employed in managerial or professional jobs and the correlates of their vocational success. Using purposive sampling techniques, we identified a national sample of 347 individuals for a mail survey who had succeeded in obtaining and retaining mid to upper level managerial or professional positions. The majority worked full-time and held their job for more than 2 years. Their vocational success was operationalized based on 4 employment outcomes: employment status (full-time vs. part-time), job tenure, occupational rank, and annual income. Key factors that contributed to respondents' vocational success were lesser severity of the illness as indicated by lack of lifetime receipt of disability benefits, capacity to manage one's own psychiatric condition, and higher education. Study findings point to the role of supported education and self-efficacy in promoting the employment outcomes among individuals with severe mental illnesses. ",0
3637,18340274,EEG markers of future cognitive performance in the elderly,"""This exploratory follow-up study investigated whether EEG parameters can predict future cognitive performance. Forty elderly subjects, ranging from cognitively unimpaired to those with Alzheimer disease underwent EEG registration at baseline and neuropsychological examination at both baseline and follow-up. We assessed relations between EEG measures and future cognitive performance (i.e., global cognition, memory, language, and executive functioning) controlling for age, follow-up time, and baseline cognitive performance. Regression models were constructed to predict performance on the Cambridge Cognitive Examination, a widely used tool within dementia screenings. Baseline EEG measures, i.e., increased theta activity (4-8 Hz) during eyes closed and less alpha reactivity (8-13 Hz) during eyes open and memory activation, indicated lower global cognitive, language (trend significant), and executive performance at follow-up. A regression model combining baseline cognitive and EEG measures provided the best prediction of future Cambridge Cognitive Examination performance (93%). EEG and cognitive measures alone predicted, respectively, 43% and 92% of variance. EEG and cognitive measures combined provided the best prediction of future cognitive performance. Although the """"cognition only"""" model showed similar predictive power, the EEG provided significant additional value. The added value of EEG registration in the diagnostic work-up of dementia should be further assessed in larger samples. """,0
3638,18340542,Hormonal profile of diabetic men and the potential link to prostate cancer,"Previous studies suggest men with diabetes may be at reduced risk for prostate cancer as compared to men without diabetes. To investigate potential biological mechanisms, hormonal profiles of diabetic men and non-diabetic controls were compared. In the Health Professionals Follow-Up Study, plasma levels of C-peptide, testosterone, sex-hormone binding globulin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were determined in 171 diabetic men and 3,001 non-diabetic controls. Multiple linear regression analysis was conducted and least square means were calculated for hormones of interest. Plasma levels of several hormones either < or =1, 1.1-6, 6.1-14.9, or > or =15 years after diagnosis with diabetes were examined. As time since diabetes diagnosis increased, plasma levels of C-peptide and IGFBP-3 significantly decreased (p for trend: C-peptide =.05, IGFBP-3 =.03). While testosterone and SHBG levels both significantly increased with increasing time since diabetes diagnosis (p for trend: testosterone =.02, SHBG =.002), the ratio of testosterone to SHBG decreased, suggesting a reduction in bioavailable testosterone. Plasma IGF-1 levels were lower in diabetics than non-diabetics, but no significant time trend was noted. This study of hormonal profiles of diabetic versus non-diabetic men identified changes in diabetic men that may be consistent with reduced prostate cancer risk. ",0
3639,18340587,A new aspect of tri-modal therapy with superselective intra-arterial chemotherapy in maxillary sinus carcinoma,"This superselective intra-arterial intervention technique enabled us to administer a higher dose of cisplatinum to the local lesion with a lower incidence of adverse issues by use of neutralizer, compared with the conventional methods. A wide variety of modalities, including surgery, radiotherapy, and chemotherapy, alone or in combination, have been reported for the treatment of maxillary sinus cancer. However, there is still much controversy with regard to the optimum treatment to obtain better local control and acceptable preservation of shape and function. Since 2001, we have performed superselective intra-arterial infusion chemotherapy in combination with radiotherapy and surgery aiming at a higher local control rate. This was a review of prospective collected data. The therapeutic design consisted of weekly intra-arterial infusion of high dose CDDP with concomitant radiotherapy and planned surgery performed during chemo-radiation therapy. From June 2001 to January 2004, 14 patients with squamous cell carcinoma of maxillary sinus underwent this treatment procedure at the University of Tokyo Hospital. The local response rate with this combined therapy was 85.7%. Overall survival rates at 1 and 2 years were 78.6% and 56.2%, respectively, with median follow-up of 25.5 months. ",0
3640,18340649,Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha-/- mice,"Inflammatory bowel disease (IBD) is a risk factor for developing colorectal cancer but the mechanisms are poorly characterized. Mice lacking the G-protein alpha subunit Gi2-alpha spontaneously develop colitis and colon cancer with high penetrance. Compared to canonical Wnt/APC signaling-based animal models of colon cancer, the tumors in Gi2-alpha-/- mice more closely recapitulate the features of IBD-associated cancers seen in humans. They are predominantly right-sided, multifocal, mucinous, and arise from areas of flat dysplasia. In evaluating the potential contribution of epithelial Gi2-alpha signaling to this phenotype, we found that Gi2-alpha-/- colonic epithelium is hyperproliferative even before the onset of colitis, and resistant to the induction of apoptosis. We generated colon cancer cell lines overexpressing dominant-negative Gi2-alpha. Like other cells lacking Gi2-alpha, these cells release less arachidonic acid, an important antiinflammatory and epithelial growth regulator. They are also hyperproliferative and resistant to camptothecin-induced apoptosis and caspase-3 activation. The colitis-associated cancers in Gi2-alpha-/- mice appear very similar to those seen in human IBD patients, and Gi2-alpha is a direct negative regulator of colonic epithelial cell growth. ",0
3641,18340652,Practice makes perfect: a volume-outcome study of hospital patients with HIV disease,"There is considerable evidence that patients with HIV fare better in hospitals that treat more HIV-positive patients. Yet, it is possible that much of this benefit is attributable to the care provided by physicians who treat high volumes of HIV-positive patients. This study examines the relation between 2 measures of volume (the number of HIV-positive patients treated in a hospital and the number of HIV-positive patients treated by the attending physician) and the probability of dying in the hospital. This study uses discharge data from 43,325 patients hospitalized with HIV disease in 5 states (Colorado, Maryland, New Jersey, New York, and Washington State) in 2002. These data were obtained from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project State Inpatient Databases. Volume-outcome studies have demonstrated an inverse relation between the number of HIV-positive patients treated at a hospital and the mortality rate for these patients. Yet, the most current of these studies is based on data more than a decade old, and none of these account for the volume of HIV-positive patients treated by the physician. This study uses multivariate logistic regression analyses to estimate the impact of hospital and physician volume on patient mortality. This study found that when measures of physician and hospital volume are included in a regression equation explaining patient mortality, only the variable measuring physician volume remains statistically significant. Moreover, when a variable is defined for each patient based on the quartile rankings of the patient's hospital volume and the patient's physician volume, the quartile ranking of physician volume is a better predictor of survival than the quartile ranking of hospital volume. These findings suggest that the volume of patients treated by the attending physician is the key measure of volume associated with the survival of hospitalized HIV-positive patients. ",0
3642,18341088,Adrenal steroid concentrations in children seven to seventeen years of age,"During puberty, serum steroid concentrations change dramatically. The objective of this study was to determine the adrenal steroid concentrations in children from 7 to 17 years of age. Tanner stage was determined in each child by physical examination. 11-Deoxycortisol, pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone and testosterone were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Androstenedione and dehydroepiandrosterone sulfate were measured by immunoassay. The median and central 95% of the steroid concentrations were determined for age, gender, and Tanner stage. Except for 11-deoxycortisol, all of the steroids exhibited an increase in concentration after age 7-9 years in both boys and girls. 11-Deoxycortisol, which is made exclusively in the adrenal cortex, declined with age and Tanner stage. This suggests that a rise in gonadal function and decreased efficiency of 11beta-hydroxylase with age may contribute to an increase in the remaining steroids. Testosterone concentrations increased more dramatically in boys, but increases were seen with each Tanner stage in girls. ",0
3643,18341220,Pulmonary functions in petrol pump workers: a preliminary study,"Occupational exposures to petrol/diesel vapors have been shown to affect functioning of different systems of the body. The present study was planned to assess the pulmonary functions in petrol pump workers (filling attendants) who are continuously exposed to petrol/diesel vapors during duty hours. Thirty healthy non-smoker males working in petrol pump for more than one year formed the study group, while thirty healthy non-smoker males from hospital staff served as control group. The pulmonary functions were assessed using computerized spirometer. The FVC and FEV1 were decreased in the study group while their ratio did not differ much. Both the inspiratory and expiratory flow rates were also decreased in the study group. These findings point towards adverse effects of petrol/diesel fumes mainly on lower airways with restrictive pattern of disease. ",0
3644,18341350,Synthesis and identification of heterocyclic derivatives of fullerene C60: unexpected reaction of anionic C60 with benzonitrile,"During the reaction of reduced C60 with benzyl bromide in benzonitrile, a novel cis-1 C60 adduct, 1,4-dibenzyl-2,3-cyclic phenylimidate C60 (1), was obtained rather than the expected product of 1,4-dibenzyl C60. The structure of compound 1 was analyzed by X-ray single-crystal diffraction, identifying the presence of a five-membered heterocycle at a [5,6] bond of C60. One of the heteroatoms is assigned as a nitrogen atom; however, the identity of the other heteroatom cannot be determined unambiguously by crystallography due to similarity between the nitrogen and oxygen atoms. A related compound (2) bearing the same heterocycle was obtained from anionic C60 benzonitrile solution when no benzyl bromide was added. The structure of compound 2 was determined by NMR, MALDI FT-ICR MS, and UV-vis. Results from MALDI FT-ICR MS for compound 2 show unambiguously that the second heteroatom is an oxygen atom, which is probably from traces of water in the solvent. Control experiments of the reactivity of the neutral, monoanionic, dianionic, and trianionic C60 have shown that the reactive species for the unexpected reaction is the C60 trianion. ",0
3645,18341559,Cross-contamination in the kitchen: effect of hygiene measures,"To determine the effect of hygiene measures on cross-contamination of Campylobacter jejuni at home and to select a safe tracer organism for C. jejuni. Comparative tests were conducted with nonpathogenic Escherichia coli and Lactobacillus casei and L. casei was chosen as the safe tracer organism. Salads containing chicken breast fillet contaminated with a known number of C. jejuni and L. casei were prepared according to different cross-contamination scenarios and contamination levels of salads were determined. Cross-contamination could be strongly reduced when cleaning cutting board and cutlery with hot water (68 degrees C), but generally was not prevented using consumer-style cleaning methods for hands and cutting board. Dish-washing does not sufficiently prevent cross-contamination, thus different cutting boards for raw meat and other ingredients should be used and meat-hand contact should be avoided or hands should be thoroughly cleaned with soap. Lactobacillus casei can be used as a safe tracer organism for C. jejuni in consumer observational studies. Cross-contamination plays an important role in the transmission of food-borne illness, especially for C. jejuni. This study delivers suitable data to quantitatively assess the risk of campylobacteriosis caused by cross-contamination and it shows the effect of different preventive hygiene measures. ",0
3646,18341782,Cost of starting colorectal cancer screening programs: results from five federally funded demonstration programs,"In 2005, the Centers for Disease Control and Prevention (CDC) started a 3-year colorectal cancer screening demonstration project and funded five programs to explore the feasibility of a colorectal cancer program for the underserved U.S. population. CDC is evaluating the five programs to estimate implementation cost, identify best practices, and determine the most cost-effective approach. The objectives are to calculate start-up costs and estimate funding requirements for widespread implementation of colorectal cancer screening programs. An instrument was developed to collect data on resource use and related costs. Costs were estimated for start-up activities, including program management, database development, creation of partnerships, public education and outreach, quality assurance and professional development, and patient support. Monetary value of in-kind contributions to start-up programs was also estimated. Start-up time ranged from 9 to 11 months for the five programs; costs ranged from $60,602 to $337,715. CDC funding and in-kind contributions were key resources for the program start-up activities. The budget category with the largest expenditure was labor, which on average accounted for 67% of start-up costs. The largest cost categories by activities were management (28%), database development (17%), administrative (17%), and quality assurance (12%). Other significant expenditures included public education and outreach (9%) and patient support (8%). To our knowledge, no previous reports detail the costs to begin a colorectal cancer screening program for the underserved population. Start-up costs were significant, an important consideration in planning and budgeting. In-kind contributions were also critical in overall program funding. Start-up costs varied by the infrastructure available and the unique design of programs. These findings can inform development of organized colorectal cancer programs. ",0
3647,18341823,Electrocardiogram analysis in high risk population of unexplained sudden death in Yunnan province],"The purpose of this study was to analyze the electrocardiographic features of the people living in the area with high incidence of unexplained sudden deaths in Yunnan province. The electrocardiograms of 338 residents from three villages (Dayao, Ninglang, Heqing) with high incidence of unexplained sudden deaths and one control village (Dali) were analyzed [averaged age was (33.4 +/- 11.7) years, 175 men and 163 women]. The incidence of cardiac arrhythmias was similar low in all groups. The left ventricular hypertrophy was observed in 34.6% of residents from Dayao. QTc significantly prolonged in the residents from all 3 high incidence areas compare the control area of Dali [control (386.8 +/- 27.22) ms, Ninglang (428.92 +/- 25.71) ms, Heqing (440.67 +/- 28.03) ms, Dayao (417.7 +/- 24.00) ms, P < 0.05 vs. control]. Incidence of U wave was significantly higher in Heqing village than that in control village (P < 0.05). The QUc of these 3 villages was: (613.67 +/- 37.34) ms, (597.19 +/- 46.47) ms, (608.59 +/- 39.59) ms respectively, and also significantly longer than the control village of Dali (589.33 +/- 41.27) ms (P < 0.05). The typical pattern of U wave presents as enlarged U wave and apparent T-U complex. In the 7 residents who have the family history of unexplained sudden death, 6 residents have U wave, and 4 of them present typical U wave pattern. The significant ECG changes in villages with high incidence of unexplained sudden death in Yunnan province were prolonged QTc, enlarged U wave and apparent T-U complex and these ECG features suggested the repolarization abnormalities of the heart in these subjects. ",0
3648,18342026,Traumatic hip dislocations in children],"Traumatic hip dislocation is a rare event in children. Appropriate management remains a subject of debate. The purpose of this study was to investigate the epidemiological, therapeutic features of this situation and the long-term outcome after treatment. This was a retrospective analysis of 15 traumatic hip dislocations collected over a period of 20 years in pediatric patients with at least two years follow-up. We searched for predisposing factors and factors affecting prognosis. The series included 11 boys and three girls, mean age eight years. Dislocation was posterior in 13 hips and anterior in two. Time to reduction was less than 3h in eight cases, 3-6h in five and greater than 6h in two. After reduction, traction was performed in nine children, for 20 days on average, followed in five cases by immobilization for 40 days on average. Five hips were immobilized directly after reduction. We identified two groups by age: group 1 with dislocations in children aged less than six years (seven children) were characterized by low-energy trauma. Dislocation was not associated with other lesions. Predisposing factors (overt ligament hyperlaxity, insufficient superolateral head cover, coax valga) were noted in six children. Reduction was simple. Later treatment consisted in immobilization with a pelvispedious cast for 30-45 days. Group 2 were dislocations in children aged over six years (seven children) victims of high-energy trauma. Associated injuries were frequent. Predisposing factors were not present. At mean 11 years follow-up, all hips are considered normal clinically. The radiograph was normal for 14 hips. In one case, there was a slight coax magna. In three patients, defective femoral head cover persisted. Coxa valga persisted in two patients. Traumatic dislocation of the hip joint is rare in very young children, but results from a minimally traumatic event. This suggests the presence of predisposing factors in this category of patients, particularly capsuloligamentary hyperlaxity. After reduction, immobilization can be recommended. Traumatic hip dislocations in children are different from the adult variety due to their rarity, the general absence of associated fractures, easy reduction and better prognosis. The epidemiological and therapeutic features in children older than six years are however similar to those in adults. ",0
3649,18342027,Treatment of femoral fracture on previous implants with minimally-invasive surgery and total weight-bearing: benefit of locking plate. Preliminary report],"We report a consecutive prospective series of femoral fractures on previous implants. The purpose was to assess treatment with locking compression plates and total weight-bearing. From June 2002 to December 2005, we treated 21 patients (16 women, five men) for fractures on previous implants: total hip arthroplasty (n=11), total knee arthroplasty (n=1), unicompartmental prosthesis (n=1), gamma nail (n=4), hip screw (n=1). Mean patient age was 75.8 years (range 39-90). Osteosynthesis was performed on an orthopedic table or on a standard table using a minimally-invasive approach for fixation with a locking compression plate (Synthes) LCP) to bridge the implants in place and avoid any zone of weakness. The rehabilitation protocol included immediate total weight bearing. At last follow-up there were three deaths and one failure so that there were 17 patients with a mean follow-up of 15.9 months (range 6-45 months). The following outcomes were noted. Minimally-invasive surgery was used in 18 cases, access to the fracture focus in three. Total weight bearing was possible immediately after surgery in 12 patients and partial weight bearing (20 kg) for two. There were two infections, two general complications and one early displacement. Healing was achieved at 6-10 weeks. Misalignment greater than 10 degrees was noted in three cases. This work illustrates the use of locking plates for minimally-invasive repair of fractures on previous implants with total weight bearing. This technique combines the principles of closed fixation and preservation of the fracture hematoma with material stability. In this form, use developed progressively. It is now common practice to use plate fixation for femoral fractures. The LISS system was then developed progressively for minimally-invasive repair of distal fractures. We widened the concept to include more proximal approaches. The use of the locking screws in the plate corresponds to what could be called an internal external fixator with three pins (two corresponding to the cortical screws plus the plate), which enable a solid fixation. Screw hold seems to be sufficient to allow early weight bearing. Locking plates have been shown to be an effective treatment for femoral fractures on previous implants allowing a stable fixation sufficient for early weight bearing. ",0
3650,18342073,Pseudo-Kaposi's sarcoma secondary to superficial arteriovenous malformation: Stewart-Bluefarb syndrome],"Pseudo-Kaposi's sarcoma or Stewart-Bluefarb subtype acroangiodermatitis is uncommon and is caused by arteriovenous fistula and malformation. We report a new case. A 33-year-old man presented with painful red-violet plaque on the dorsum of the toes with angiomatous nodules on the sole. Histological and immunohistochemical studies for CD34 were consistent with Kaposi's sarcoma. Doppler ultrasonography and femoral angiography showed multiple distal arteriovenous shunts. Free-flow embolisation with fragments of Ethibloc gelatin sponge was performed and arteriography, performed immediately afterwards, showed delayed venous drainage. The outcome was good with complete drainage of the angiomatous lesions. Pseudo-Kaposi's sarcoma Stewart-Bluefarb subtype begins early in life in male subjects, with unilateral skin lesions. It bears clinical and histological resemblance to Kaposi's sarcoma. Doppler ultrasonography and angiography show arteriovenous fistulas that classically develop at shunts, explaining the role of traumatism and high vascular pressure in the genesis of this disease. ",0
3651,18343091,A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice,"Giant axonopathy (gaxp), an autosomal recessive mouse mutation, exhibits ataxia of the hind legs with a slight side-to-side wobble while walking. Within the genomic region of the gaxp locus, a total of 94 transcripts were identified; the annotation of these genes using OMIM and PubMed yielded three potential candidate genes. By cDNA microarray analysis, 54 genes located on or near the gaxp locus were found to exhibit differential expression between gaxp and littermate controls. Based on microarray data and the known function of genes identified, Slc12a6 was selected as the primary candidate gene and analyzed using the Reveal technology of SpectruMedix. A 17-base deletion was detected from within exon 4 of Slc12a6. Reverse transcriptase polymerase chain reaction validated the difference in Slc12a6 expression in different types of mice at the mRNA level, revealing a marked reduction in gaxp mice. Western blot analysis indicated that the protein product of Slc12a6, the K(+)-Cl(-) cotransporter Kcc3, was not detectable in gaxp mice. The causative role of the exon 4 mutation within Slc12a6 in the gaxp phenotype was further confirmed by screening multiple inbred strains and by excluding the mutation of nearby genes within the gaxp locus. ",0
3652,18343158,Assessment of functional recovery in tennis elbow,"(a) To investigate changes in muscular strength, fatigue and activity in recovered tennis elbow (RTE); (b) to assess the appropriateness of EMG and strength measurements in monitoring functional recovery in tennis elbow (TE). Study included three age-matched female groups of Control (C) (n=8, no history of musculoskeletal problems), TE (n=7, local tenderness at the lateral epicondyle and pain with resisted wrist and middle finger extension) and RTE (n=6, asymptomatic for at least 6 months, no lateral epicondyle tenderness). Measurements included metacarpophalangeal (MCP), wrist, shoulder and grip isometric strength and EMG measures of muscle fatigue and activity for five forearm muscles (wrist extensors and flexors). Strength was greater (p<0.05) for all measurements in C compared to RTE and TE except for MCP extension. Only MCP extension was stronger in RTE than TE. EMG revealed increased activity of extensor carpi radialis (ECR) in RTE, decreased in TE. Despite attenuation of pain, global upper limb weakness in RTE indicated incomplete functional recovery. Increased strength of MCP extension may protect weakened wrist extensors from further injury. Monitoring the ECR activity as well as strength measurements may provide a useful assessment of functional recovery in TE. ",0
3653,18343406,"Crystal structure and standardized geometric analysis of InlJ, a listerial virulence factor and leucine-rich repeat protein with a novel cysteine ladder","We report on the crystal structure of the internalin domain of InlJ, a virulence-associated surface protein of Listeria monocytogenes, at 2.7-A resolution. InlJ is a member of the internalin family of listerial cell surface proteins characterized by a common N-terminal domain. InlJ bears 15 leucine-rich repeats (LRRs), the same number as in InlA, the prototypical internalin family member. The LRRs of InlJ differ from those of other internalins by having 21, rather than 22, residues and by replacing 1 LRR-defining hydrophobic residue with a conserved cysteine. These cysteines stack to form an intramolecular ladder and regular hydrophobic interactions in consecutive repeats. Analyzing the curvature, twist, and lateral bending angles of InlJ and comparing these with several other LRR proteins, we provide a systematic geometric comparison of LRR protein structures (http://bragi2.helmholtz-hzi.de/Angulator/). These indicate that both cysteine and asparagine ladders stabilize the LRR fold, whereas substitutions in some repeat positions are more likely than others to induce changes in LRR geometry. ",0
3654,18343454,Central zone carcinoma of the prostate gland: a distinct tumor type with poor prognostic features,"The central zone of the prostate gland is a region rarely associated with carcinoma. To our knowledge central zone tumors have not previously been compared to carcinoma originating in the peripheral or transition zone of the prostate gland. All 2,010 radical prostatectomy cases seen at our institution from October 1998 to December 2006 were reviewed to identify tumor zonal origin. Central zone carcinoma was characterized and compared with tumors of other zones. Zonal origin was determined in a total of 2,494 tumors in 1,703 cases. Of the tumors 63 (2.5%) were of central zone origin with 59 of the 63 representing the index or main tumor. Comparative analysis of a defined subset of 726 cases showed that central zone cancers were significantly more aggressive than peripheral or transition zone cancers with a far greater risk of extracapsular extension, seminal vesicle invasion and positive surgical margins. Escape from the gland was often via the ejaculatory ducts and seminal vesicles. Kaplan-Meier analysis confirmed that the probability of post-prostatectomy biochemical failure was double that of tumors of the other zones with a far more rapid rate of failure. Multivariate Cox regression analysis identified Gleason grade, positive margins, extracapsular extension, tumor volume and preoperative serum prostate specific antigen as the major contributors to this poor prognosis, rather than specific zonal origin. To our knowledge this study provides the first characterization and comparative analysis of central zone carcinoma, identifying these tumors as a rare but highly aggressive form of prostate carcinoma with a distinct route of spread from the gland that contrasts with tumors of other zones. Preoperative identification is currently hampered by the avoidance of biopsy targeting the central zone. However, if recognized preoperatively, aggressive intervention may possibly improve the currently bleak outlook. ",0
3655,18343705,Enhancement of ultraweak photon emission with 3 MHz ultrasonic irradiation on transplanted tumor tissues of mice,"We investigated photon emissions of various bio-samples which were induced by ultrasonic stimulation. It has been reported that ultrasonic stimulations induced the thermal excitation of the bio-tissues. After ultrasonic stimulation, any measurement of photon radiation in the visible spectral range has not been carried out yet. The instruments consisted of electronic devices for an ultrasonic generator of the frequency 3 MHz and a photomultiplier tube (PMT) system counting photons from bio-tissues. The transplanted tumor tissues of mice were prepared for the experiments and their liver and spleen tissues were also used for the controls. It was found that the continuous ultrasonic stimulations with the electrical power 2300 mW induced ultraweak photon emissions from the tumor tissues. The number of induced photon was dependent of the type of the tissues and the stimulation time intervals. The level of photon emission was increased from the mouse tumor exposed to the ultrasonic stimulations, and the changes were discriminated from those of the spleens and livers. ",0
3656,18343729,Critical role of the rostral ventromedial medulla in early spinal events leading to chronic constriction injury neuropathy in rats,"Neuropathic pain is a major clinical problem, and several animal models have been developed to investigate its mechanisms and its treatment. In this report, the role of the rostral ventromedial medulla (RVM) in the early events of the chronic constriction injury (CCI) model was investigated in behavioral and electrophysiological experiments. Placing the 4 CCI ligatures around the sciatic nerve induced large discharges and residual ongoing activity in spinal nociceptive neurons. Two weeks after CCI ligation, the rats showed behavioral hyperalgesia and allodynia as well as increased ongoing activity and responsiveness of spinal nociceptive neurons to innocuous and noxious stimuli. Blockade of excitatory synapses in the RVM by a kynurenate microinjection (2 nmol in 0.5 muL) 5 minutes before placement of the sciatic ligatures had no immediate effect on spinal neuronal activity but largely prevented the activation of spinal neurons. In kynurenate microinjected rats, behavioral hyperalgesia and allodynia developed slowly and incompletely, which corresponded with an incompletely developed hyperexcitability of spinal neurons. To the best of our knowledge, these results show for the first time that the initial response to nerve damage requires facilitation from the RVM. The present and previous findings indicate that descending facilitation from brainstem nuclei critically contributes to the spinal hyperexcitability that underlies neuropathic pain. The present results indicate that this contribution begins at the very moment the nerve is damaged and should be prevented and treated accordingly. ",0
3657,18343849,The block to membrane fusion differs with the site of ligand insertion in modified retroviral envelope proteins,"Efforts to achieve cell type-specific transduction of retroviral vectors for gene therapy have centred on modification of the envelope protein (Env). Typically, addition of a ligand to Env gives binding to the new or target receptor, but little or no infection, and affects the subunit association of the modified Env. We previously discovered two point mutations that increase targeted infection by over 1000-fold when added to an Env modified by N-terminal insertion of the receptor-binding domain from amphotropic murine leukemia virus Env. Here, we asked whether these mutations would similarly increase transduction by Env modified with a clinically relevant ligand, human interleukin-13 (IL-13L). Addition of the point mutations stabilized the weak subunit association observed in some IL-13L-modified Env proteins, but infection via the target IL-13 receptor still did not occur. Fluorescence-based cell-cell fusion assays and studies with a membrane-curving agent revealed that defects in membrane fusion differed with the site of ligand insertion. When IL-13 was inserted into the N terminus of Env, membrane fusion was blocked prior to membrane-lipid mixing, regardless of whether flanking flexible linkers were added. Unexpectedly, insertion of IL-13 in the proline-rich region showed evidence of initiation of fusion and fusion-peptide exposure, but fusion was blocked at a subsequent step prior to fusion-pore formation. Thus, the site of ligand insertion influenced initiation of membrane fusion and its progression. These observations suggest that a novel site for ligand insertion must be identified before clinically useful targeted transduction will be achieved. ",0
3658,18343903,Peptidomimetic 2-cyanopyrrolidines as potent selective cathepsin L inhibitors,"Cathepsins have been found to have important physiological roles. The implication of cathepsin L in various types of cancers is well established. In a search for selective cathepsin L inhibitors as anticancer agents, a series of 2-cyanoprrolidine peptidomimetics, carrying a nitrile group as warhead, were designed. Two series of compounds, one with a benzyl moiety and a second with an isobutyl moiety at P(2) position of the enzyme were synthesized. The synthesized compounds were evaluated for inhibitory activity against human cathepsin L and cathepsin B. Although, none of the compounds showed promising inhibitory activity, (E)N-{(S)1-[(S)2-cyano-1-pyrrolidinecarbonyl]-3-methylbutyl}-2,3-diphenylacrylamide (24) with an isobutyl moiety at P(2) was found to show selectivity as a cathepsin L inhibitor (Ki 5.3 microM for cathepsin L and Ki > 100 microM for cathepsin B). This compound could act as a new lead for the further development of improved inhibitors within this inhibitor type. ",0
3659,18344216,Constrained dansyl derivatives reveal bacterial specificity of highly conserved thymidylate synthases,"The elucidation of the structural/functional specificities of highly conserved enzymes remains a challenging area of investigation, and enzymes involved in cellular replication are important targets for functional studies and drug discovery. Thymidylate synthase (TS, ThyA) governs the synthesis of thymidylate for use in DNA synthesis. The present study focused on Lactobacillus casei TS (LcTS) and Escherichia coli TS (EcTS), which exhibit 50 % sequence identity and strong folding similarity. We have successfully designed and validated a chemical model in which linear, but not constrained, dansyl derivatives specifically complement the LcTS active site. Conversely, chemically constrained dansyl derivatives showed up to 1000-fold improved affinity for EcTS relative to the inhibitory activity of linear derivatives. This study demonstrates that the accurate design of small ligands can uncover functional features of highly conserved enzymes. ",0
3660,18344527,Protein polymorphism between 2 Picea abies populations revealed by 2-dimensional gel electrophoresis and tandem mass spectrometry,"In species with high gene flow and consequent low interpopulation differentiation over wide geographic ranges, differential gene expression along ecological gradients often reveals adaptive significance. We investigated potential differences in protein expression between Picea abies ecotypes adapted to contrasting altitude conditions. Protein expression patterns were compared between needles and roots of 2-month-old P. abies seedlings by means of 2-dimensional electrophoresis. Proteins exhibiting differential expression between the 2 ecotypes were analyzed by tandem mass spectrometry. A total of 19 proteins exhibited qualitative or quantitative polymorphism between the 2 populations. These proteins exhibited organ-specific expression, and the level of interpopulation protein polymorphism was organ dependent. Among differentially expressed proteins, we identified proteins involved in photosynthesis, photorespiration, root tracheary element differentiation, and transmitochondrial membrane transport. Our results show that P. abies seedlings from locally adapted ecotypes exhibit consistent differences in protein expression. The expression polymorphism of some of these proteins has potential adaptive significance. ",0
3661,18344759,A prospective study of early intraocular pressure changes after a single intravitreal triamcinolone injection,"To prospectively monitor intraocular pressure (IOP) and gonioscopy changes within the first month after a single 4-mg intravitreal injection of triamcinolone acetonide (IVK) (Kenalog, Briston-Meyers Squibb, New York). Prospective comparative interventional case series. A consecutive series of 28 eyes of 14 patients with no prior intravitreal injections or history of glaucoma were prospectively enrolled. After baseline evaluation in both eyes, including IOP, gonioscopy, and optic nerve evaluation, a single 4-mg IVK was given in a standard sterile fashion in the eye to be treated. Eyes received IVK for macular edema associated with retinal vein occlusions and in conjunction with photodynamic therapy for choroidal neovascularization secondary to age-related macular degeneration, ocular histoplasmosis, and high myopia. The fellow eye served as the control. After the injection, IOP and gonioscopy were repeated at 1, 2, and 4-week intervals in both eyes. Of the 14 patients, the 5 women and 9 men had a mean age of 67.6 years. Mean baseline IOP of the treated and fellow control eyes were similar at 15.9 versus 16.6 mm Hg, respectively. The control eyes maintained a small IOP range (15.6 to 16.6 mm Hg) during the 1-month follow-up period. In the treated eyes, the mean maximum IOP was 54% above baseline during follow-up, compared with 11% for control eyes. Six of 14 (43%) treated eyes had IOP elevation to 24 mm Hg or higher with mean change of 8.6 mm Hg and a mean maximum IOP of 32.1 mm Hg. There was no correlation between IOP rise and age, sex, diagnosis, or optic nerve appearance. However, during the course of the study, 4 of 6 (67%) of the treated eyes that required topical drops for the IOP elevation had documented abnormal inferior angle changes characterized by pigmented particulate matter in the inferior angle not present at the baseline exam. The most frequent time point for an IOP elevation that required treatment was at 2-week postinjection. No eyes required surgical management of IOP during the course of this 4-week study. We observed a significant IOP rise in eyes after a single intravitreal injection of 4 mg of triamcinolone within 1 month of injection. In this study, the most frequent time point that required IOP treatment was at 2-week postinjection, suggesting that early and frequent monitoring of IOP should be considered. Two-thirds of eyes that required medical control of IOP developed gonioscopy changes, characterized by particulate matter in the inferior angle, not present at baseline. Eyes that developed gonioscopic changes were 5 times more likely to be treated for IOP elevation than those without gonioscopic findings. ",0
3662,18344842,Pulmonary levels of high-mobility group box 1 during mechanical ventilation and ventilator-associated pneumonia,"""High-mobility group box (HMGB) 1 is a recently discovered proinflammatory mediator that contributes to acute lung injury. We determined HMGB-1 levels in bronchoalveolar lavage fluid of patients during mechanical ventilation (MV) and ventilator-associated pneumonia (VAP). Bronchoalveolar lavage fluid was obtained from patients who were ventilated for 5 h because of an elective surgical procedure (""""short-term MV""""; n = 40) or for several days because of respiratory failure without acute lung injury (""""long-term MV""""; n = 10) and from patients who developed unilateral VAP (n = 4). Ten healthy volunteers served as controls. In healthy volunteers, HMGB-1 levels were low (median, 1.6 ngmL(-1); interquartile range [IQR], 0.7-3.7 ng mL(-1)). Although HMGB-1 levels were elevated after short-term MV, differences were not statistically significant compared with healthy volunteers (1.7 ng mL(-1); IQR, 0.8-8.5 ng mL(-1), P = 0.493 vs. healthy volunteers; P = 0.250 vs. start of MV). However, HMGB-1 levels were significantly higher in """"long-term"""" MV patients (11.7 ng mL(-1); IQR, 8.7-37.0 ng mL(-1); P < 0.0001 vs. healthy volunteers). With unilateral VAP, HMGB-1 levels from the infected lung.were 17.4 (IQR, 8.5-23.2) ng mL(-1) (P = 0.014 vs. healthy controls); these levels were not different from those measured in the contralateral noninfected lung (P = 0.625). Summarized, long-term MV is associated with increased HMGB-1 levels in contrast to """"short-term"""" MV. In addition, HMGB-1 levels during VAP are increased compared with healthy volunteers; however, they are not different from those found in patients intubated and mechanically ventilated for a similar period of time. """,0
3663,18345378,The role of MHC haplotypes H2d/H2b in mouse resistance/susceptibility to cyst formation is influenced by the lineage of infective Toxoplasma gondii strain,"Toxoplasma gondii strains displaying the Type I/III genotype are associated with acquired ocular toxoplasmosis in humans. Here, we used a mice model to characterize some immunological mechanisms involved in host resistance to infection with such strains. We have chosen the Type I/III strains D8, G2 and P-Br, which cause a chronic infection in mice that resembles human toxoplamosis. Mice deficient of molecules MyD88, IFN-gamma, and IL-12 were susceptible to all three parasite strains. This finding indicates the importance of innate mechanisms in controlling infection. On the other hand, MHC haplotype did not influenced resistance/susceptibility; since mice lineages displaying a same genetic background but different MHC haplotypes (H2b or H2d) developed similar mortality and cyst numbers after infection with those strains. In contrast, the C57BL/6 genetic background, and not MHC haplotype, was critical for development of intestinal inflammation caused by any of the studied strains. Finally, regarding effector mechanisms, we observed that B and CD8+ T lymphocytes controlled survival,whereas the inducible nitric oxide synthase influenced cyst numbers in brains of mice infected with Type I/III strains. These findings are relevant to further understanding of the immunologic mechanisms involved in host protection and pathogenesis during infection with T. gondii. ",0
3664,18345395,Lipid profile disturbances are highly prevalent in Japanese-Brazilians],"High prevalence of diabetes has been previously reported in Japanese-Brazilians. In an attempt to better estimate the cardiometabolic risk, this study evaluated lipid disorders in 1,330 Japanese-Brazilians (46% men) aged>30 years. Hypercholesterolemia was defined as serum cholesterol>240 mg/dL, hypertriglyceridemia as values>150 mg/dL and low-HDL-C as values<40 mg/dL and <50 mg/dl for men and women respectively. The prevalence of dyslipidemias was compared by the chi-square test between gender and glycemic category. Mean and Standard Deviation of lipids and lipoproteins were compared by the Student t-Test between gender. Hypertriglyceridemia was detected in 66.0% [95% CI: 63.5-68.5] of the population, being more common in men and increasing with deterioration of glucose metabolism. Mean level of triglycerides was 235.7+/-196.3 mg/dL. The prevalence of hypercholesterolemia was 24.4% [95% CI: 22.1-26.7]. Low HDL-C was observed in 17.5% [95% CI: 14.5-20.5] of men and 43.0% [95% CI: 39.4- 46.6] of women but total/HDL-cholesterol ratio was lower in women (4.23+/-0.68 vs. 4.40+/-0.73, p<0.001). In Japanese-Brazilians, hypertriglyceridemia is the commonest dyslipidemia, in agreement with the high prevalence of diabetes. Men showed a worse lipid profile than women; it was suggested that the Western diet and living habits could be deteriorating their health. ",0
3665,18346159,Risk factors for diabetic retinopathy in a South Indian Type 2 diabetic population--the Chennai Urban Rural Epidemiology Study (CURES) Eye Study 4,"To determine risk factors for diabetic retinopathy (DR) in an urban South Indian Type 2 diabetic population. The Chennai Urban Rural Epidemiology Study is a large cross-sectional study conducted in Chennai, South India. A total of 1736 Type 2 diabetic subjects were recruited for this study, which included 1382 known diabetic subjects (90.4% response rate) and 354 randomly selected, newly detected diabetic subjects diagnosed by oral glucose tolerance test. All subjects underwent four-field stereo retinal colour photography, graded by the Early Treatment Diabetic Retinopathy Study protocol. Of the 1736 Type 2 diabetic subjects photographed, photographs could be graded in 1715 subjects. Stepwise ordinal logistic regression analysis revealed that male gender (P = 0.041), duration of diabetes (P < 0.0001), glycated haemoglobin (HbA(1c); P < 0.0001), macroalbuminuria (P = 0.0002) and insulin therapy (P = 0.0001) were significantly associated with severity of DR. The risk for developing DR was 7.7 times (95% confidence interval 4.71-12.48, P < 0.0001) for elevated postprandial plasma glucose levels compared with 4.2 times (95% confidence interval 2.78-6.34, P < 0.0001) for elevated fasting plasma glucose when the fourth quartile values were compared with the first quartile glucose values. In South Indian Type 2 diabetic subjects, duration of diabetes, HbA1c, male gender, macroalbuminuria and insulin therapy were independent risk factors for severity of DR. Postprandial hyperglycaemia indicated a higher risk for DR compared with elevated fasting plasma glucose levels. ",0
3666,18346274,Does productivity influence priority setting? A case study from the field of CVD prevention,"""In this case study, different measures aimed at preventing cardiovascular diseases (CVD) in different target groups have been ranked based on cost per QALY from a health care sector perspective and from a societal perspective, respectively. The innovation in this study is to introduce a budget constraint and thereby show exactly which groups would be included or excluded in treatment or intervention programs based on the two perspectives. Approximately 90% of the groups are included in both perspectives. Mainly elderly women are excluded when the societal perspective is used and mainly middle-aged men are excluded when the health care sector perspective is used. Elderly women have a higher risk of CVD and generally lower income than middle-aged men. Thus the exclusion of older women in the societal perspective is not a trivial consequence since it is in conflict with the general interpretation of the """"treatment according to need"""" rule, as well as societal goals regarding gender equality and fairness. On the other hand, the exclusion of working individuals in the health care perspective undermines a growth of public resources for future health care for the elderly. The extent and consequences of this conflict are unclear and empirical studies of this problem are rare. """,0
3667,18346550,International dermatology: the many faces and challenges of the specialty in the global village,"The technical advances of the last century changed the understanding of the science of cutaneous physiology and pathology and the role of the dermatologist. The major challenges the international dermatologic community faces today are the lack of a common, logical, and accepted language within the specialty; long-accepted but questionable policies to advance academic careers; and the marginalization of dermatology. Methods for communicating and circulating data and ideas also have changed radically. The distribution of knowledge and essential/practical tools in different regions of the world is inequitable, and developing countries must cope with the challenges of high-impact skin diseases. ",0
3668,18346574,Hemodialysis-related steal syndrome: predictive factors and response to treatment with the distal revascularization-interval ligation procedure,"Hand ischemia due to steal causes major disability in affected members of the hemodialysis population. Between February 2000 and March 2007, 24 patients aged 37-77 years were identified who developed hand ischemia distal to a hemodialysis access and required a distal revascularization-interval ligation (DRIL) procedure. Of the 24 patients, 22 (92%) were diabetic, 14 (58%) were women, 7 (29%) had prosthetic grafts, and 17 (71%) had fistulas, all originating from the brachial artery. Duration between the initial dialysis access and the DRIL procedures ranged 12 hours to 10 months. Conduits used were saphenous vein in 13 (54%) cases, cephalic vein in 3 (12%) cases, basilic vein in 5 (21%) cases, and prosthetic grafts in 3 (12%) cases. There were no operative deaths. Improved blood flow and relief of symptoms were observed in 23 (96%) patients. The procedure failed early in one patient who had thrombosis of a prosthetic graft. Two patients required digital amputations. At a median follow-up of 50 months, 14 (58%) patients died using the access requiring the DRIL, 2 (8%) did not require dialysis, 3 (12%) were using a new access, and 5 (21%) were still using the access that had required the DRIL. In late follow-up, only one DRIL bypass required revision and the remainder were patent. One patient developed an ischemic hand 5 years after his DRIL procedure despite a patent bypass. The development of ischemic steal requiring performance of a DRIL procedure is most likely to occur in diabetic patients with dialysis access originating from the brachial artery. The procedure is effective in ameliorating symptoms while preserving the vascular access. The high long-term mortality rate observed in this series underscores the fact that patients requiring a DRIL procedure represent a subset of dialysis patients with advanced diabetic vascular disease and a limited life expectancy. Despite the effectiveness of the DRIL procedure, efforts should be concentrated on prevention of ischemic steal in order to lessen the morbidity and expense of this condition in the dialysis population. ",0
3669,18346652,Local thrombolysis in patients with dural venous thrombosis unresponsive to heparin,"We sought to study the efficacy and complications of local thrombolysis using urokinase in cases of cortical vein thrombosis unresponsive to conventional heparin therapy. Patients with clinical and radiologic diagnosis of cortical vein thrombosis were taken for local thrombolysis using femoral vein approach if they did not respond to heparin therapy after 5 days of administration of the drug. Urokinase was used as the thrombolytic agent and dose was decided depending on the recanalization obtained during the procedure. Of the 3 patients treated, two had complete recanalization and one had partial recanalization. Two had dramatic recovery of the clinical symptoms. One patient in whom thrombolysis was delayed had partial recovery. None had any complications related to the treatment. Local thrombolytic therapy is effective in recanalization of thrombosed sinus. It is worth considering in dire circumstances especially when a patient fails to respond to heparin. However, randomized controlled trials are necessary before any firm recommendations can be made as to whether it can be used as a primary modality of treatment in cases of cortical vein thrombosis. ",0
3670,18346928,Relevance of Arg457 for the nucleotide affinity of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase,"Phosphoenolpyruvate carboxykinases catalyze one of the first steps in the biosynthesis of glucose and depending on the enzyme origin, preferentially use adenine or guanine nucleotides as substrates. The Saccharomyces cerevisiae enzyme has a marked preference for ADP (or ATP) over other nucleotides. Homology models of the enzyme in complex with ADP or ATP show that the guanidinium group of Arg457 is close to the adenine base, suggesting that this group might be involved in the stabilization of the nucleotide substrate. To evaluate this we have performed the mutation Arg457Met, replacing the positively charged guanidinium group by a neutral residue. The mutated enzyme retained the structural characteristics of the wild-type protein. Fluorescence titration experiments showed that mutation causes a loss of 1.7 kcal mol(-1) in the binding affinity of the enzyme for ADPMn. Similarly, kinetic analyses of the mutated enzyme showed 50-fold increase in K(m) for ADPMn, with minor alterations in the other kinetic parameters. These results show that Arg457 is an important factor for nucleotide binding by S. cerevisiae PEP carboxykinase. ",0
3671,18347132,Turning the gene tap off; implications of regulating gene expression for cancer therapeutics,"Cancer poses a tremendous therapeutic challenge worldwide, highlighting the critical need for developing novel therapeutics. A promising cancer treatment modality is gene therapy, which is a form of molecular medicine designed to introduce into target cells genetic material with therapeutic intent. Anticancer gene therapy strategies currently used in preclinical models, and in some cases in the clinic, include proapoptotic genes, oncolytic/replicative vectors, conditional cytotoxic approaches, inhibition of angiogenesis, inhibition of growth factor signaling, inactivation of oncogenes, inhibition of tumor invasion and stimulation of the immune system. The translation of these novel therapeutic modalities from the preclinical setting to the clinic has been driven by encouraging preclinical efficacy data and advances in gene delivery technologies. One area of intense research involves the ability to accurately regulate the levels of therapeutic gene expression to achieve enhanced efficacy and provide the capability to switch gene expression off completely if adverse side effects should arise. This feature could also be implemented to switch gene expression off when a successful therapeutic outcome ensues. Here, we will review recent developments related to the engineering of transcriptional switches within gene delivery systems, which could be implemented in clinical gene therapy applications directed at the treatment of cancer. ",0
3672,18347170,IMP3 predicts aggressive superficial urothelial carcinoma of the bladder,"In this study, we investigated whether an oncofetal protein, IMP3, can serve as a new biomarker to predict progression and metastasis of early-stage urothelial carcinoma of the bladder. The expression of IMP3 in 242 patients with primary superficial bladder urothelial carcinoma and metastatic urothelial carcinoma was evaluated by immunohistochemistry. Patients with primary superficial urothelial carcinoma of the bladder were further investigated by use of survival analysis. Twenty percent (42 of 214) of primary superficial urothelial carcinomas and 93% (26 of 28) of metastatic urothelial carcinomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much lower progression-free survival (P = 0.0002) and disease-free survival rate (P = 0.0067) than did those with IMP3-negative tumors. The 5-year progression-free and disease-free survival rates were 91% and 94% in IMP3-negative patients versus 64% and 76% in IMP3-positive patients, respectively. Sixty percent of IMP3-positive patients with superficial invasive urothelial carcinoma at initial diagnosis went on to develop metastases, whereas no metastasis was found in IMP3-negative patients (P = 0.0017). In the multivariable Cox analysis, patients with IMP3 expression in their superficial urothelial carcinomas subsequently developed invasive tumors or metastasis at a rate that was about five times greater than cases without expression of IMP3 adjusting for other well-known clinical variables (tumor stage and grade, etc.). Our findings indicate that IMP3 is an independent prognostic marker that can identify a group of patients with a high potential to develop progression and who might benefit from early aggressive therapy. ",0
3673,18347407,A long survival case of advanced colon cancer with lung metastasis and cancerous pleuritis responding to CPT-11 and S-1 combination therapy],"A 71-year-old man underwent right hemicolectomy for an ascending colon cancer (stage II, Cur A) in September 2001. Adjuvant chemotherapy with tegafur/uracil was performed, but CT scans and FDG-PET, conducted in May 2003, revealed cancerous pleuritis and lung metastasis. Although 2 courses of the chemotherapy with LV+5-FU (RPMI regimen) were completed, progressive disease was confirmed. Therefore, the chemotherapy with CPT-11 (100 mg/ day; day 1, 15)+S-1 (100 mg/day; day 1-21) was started in May 2004. After completion of 6 courses, CT scan showed a partial response. Only grade 2 vomiting was noted as an adverse reaction to the treatment, however, the patient has been managed on an outpatient basis for the last 3 years with good QOL and the cancer under control. This case suggests that this combination therapy can be expected to be highly effective as a safe approach for continuously maintaining the QOL of patients with advanced or recurrent colorectal cancer. ",0
3674,18348183,New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study,"Correct assessment of gestational age and fetal growth is essential for optimal obstetric management. The objectives of this study were, first, to develop charts for ultrasound dating of pregnancy based on crown-rump length and biparietal diameter and, second, to derive reference curves for normal fetal growth based on biparietal diameter, head circumference, transverse cerebellar diameter, abdominal circumference and femur length from 10 weeks of gestational age onwards. A total of 8313 pregnant women were included for analysis in this population-based prospective cohort study. All women had repeated ultrasound assessments to examine fetal growth. Charts for ultrasound dating of pregnancy, based on crown-rump length and biparietal diameter, were derived. Internal validation with the actual date of delivery showed that ultrasound imaging provided reliable gestational age estimates. Up to 92% of deliveries took place within 37-42 weeks of gestation if gestational age was derived from ultrasound data, compared with 87% based on a reliable last menstrual period. The earlier the ultrasound assessment the more accurate the prediction of date of delivery. After 24 weeks of gestation a reliable last menstrual period provided better estimates of gestational age. Reference curves for normal fetal growth from 10 weeks of gestational age onwards were derived. Charts for ultrasound dating of pregnancy and reference curves for fetal biometry are presented. The results indicate that, up to 24 weeks of pregnancy, dating by ultrasound examination provides a better prediction of the date of delivery than does last menstrual period. The earlier the ultrasound assessment in pregnancy, preferably between 10 and 12 weeks, the better the estimate of gestational age. ",0
3675,18348316,Prediction of diagnosis of immunoglobulin A nephropathy prior to renal biopsy and correlation with urinary sediment findings and prognostic grading,"Several clinical markers correlate well with the diagnosis and prognosis of IgA nephropathy (IgAN). In the present study, we re-evaluated the usefulness of these four clinical markers for prediction of the diagnosis of patients with IgAN through a comparison between many more patients with IgAN and those with other types of renal diseases. 364 patients with IgAN and 289 with other types of renal disease were examined. An analysis was performed prior to renal biopsy, using clinical markers including, serum IgA, serum IgA/C3 ratio, number of red blood cells in urinary sediments, and urinary protein. Patients with IgAN were divided into four groups according to histopathological findings. Presence of microscopic hematuria, persistent proteinuria, high serum IgA levels, and the serum IgA/C3 ratios are useful for prediction of diagnosis of IgAN and distinguishing it from other renal diseases. Blood pressure, urinary protein, serum uric acid, renal function, and urinary sediment findings may be useful for prediction of prognostic grading in patients with IgAN. ",0
3676,18348443,"Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need?","Vtamin D is the sunshine vitamin for good reason. During exposure to sunlight, the utraviolet B photons enter the skin and photolyze 7-dehydrocholesterol to previtamin D3 which in turn is isomerized by the body's temperature to vitamin D3. Most humans have depended on sun for their vitamin D requirement. Skin pigment, sunscreen use, aging, time of day, season and latitude dramatically affect previtamin D3 synthesis. Vitamin D deficiency was thought to have been conquered, but it is now recognized that more than 50% of the world's population is at risk for vitamin D deficiency. This deficiency is in part due to the inadequate fortification of foods with vitamin D and the misconception that a healthy diet contains an adequate amount of vitamin D. Vitamin D deficiency causes growth retardation and rickets in children and will precipitate and exacerbate osteopenia, osteoporosis and increase risk of fracture in adults. The vitamin D deficiency has been associated pandemic with other serious consequences including increased risk of common cancers, autoimmune diseases, infectious diseases and cardiovascular disease. There needs to be a renewed appreciation of the beneficial effect of moderate sunlight for providing all humans with their vitamin D requirement for health. ",0
3677,18367737,Cervical length at mid-pregnancy and the risk of primary cesarean delivery,"BACKGROUND: Physiological and biochemical studies suggest that normal parturition at term is dependent on programmed development of the uterus in early pregnancy. It is recognized that a short cervix in mid-pregnancy is associated with an increased risk of spontaneous preterm birth. We hypothesized that a long cervix in mid-pregnancy would be associated with an increased risk of cesarean delivery during labor at term. METHODS: We studied 27,472 primiparous women who had a cervical length of 16 mm or more at a median of 23 weeks of gestation and who ultimately delivered a live infant in labor at term. RESULTS: The rate of cesarean delivery at term was lowest (16.0%) among women with a mid-pregnancy cervical length in the lowest quartile (16 to 30 mm) and was significantly greater in the second quartile (18.4%, 31 to 35 mm), third quartile (21.7%, 36 to 39 mm), and fourth quartile (25.7%, 40 to 67 mm) (P<0.001 for trend). The odds ratio for cesarean delivery among women in the fourth quartile, as compared with the first quartile, was 1.81 (95% confidence interval [CI], 1.66 to 1.97), and the odds ratio adjusted for maternal age, body-mass index, smoking status, race or ethnic group, gestational age at birth, spontaneous or induced labor, birth-weight percentile, and hospital of delivery was 1.68 (95% CI, 1.53 to 1.84; P<0.001). The increased risk of cesarean delivery was attributable to procedures performed for poor progress in labor. CONCLUSIONS: The cervical length at mid-pregnancy is an independent predictor of the risk of cesarean delivery at term in primiparous women.",0
3678,18393288,Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways,"It has been reported that salicylates (sodium salicylate and aspirin) inhibit the replication of flaviviruses, such as Japanese encephalitis virus and dengue virus. Therefore, we considered it important to test whether acetylsalicylic acid (ASA) had anti-hepatitis C virus (HCV) activity. To this end, we examined the effects of ASA on viral replication and protein expression, using an HCV subgenomic replicon cell culture system. We incubated Huh7 replicon cells with 2-8 mM ASA for different times and measured HCV-RNA and protein levels by northern blot, real-time polymerase chain reaction, and western analysis, respectively. We found that ASA had a suppressive effect on HCV-RNA and protein levels (nearly 58%). ASA-dependent inhibition of HCV expression was not mediated by the 5'-internal ribosome entry site or 3'-untranslated regions, as determined by transfection assays using bicistronic constructs containing these regulatory regions. However, we found that HCV-induced cyclooxygenase 2 (COX-2) messenger RNA and protein levels and activity and these effects were down-regulated by ASA, possibly by a nuclear factor kappa B-independent mechanism. We also observed that the ASA-dependent inhibition of viral replication was due in part to inhibition of COX-2 and activation of p38 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) mitogen-activated protein kinases (MAPKs). Inhibition of these kinases by SB203580 and U0126, respectively, and by short interfering RNA silencing of p38 and MEK1 MAPK prevented the antiviral effect of ASA. Taken together, our findings suggest that the anti-HCV effect of ASA in the Huh7 replicon cells is due to its inhibitory effect on COX-2 expression, which is mediated in part by the activation of MEK1/2/p38 MAPK. CONCLUSION: These findings suggest the possibility that ASA could be an excellent adjuvant in the treatment of chronic HCV infection.",0
3679,18393321,Hepatocyte-specific inhibitor-of-kappaB-kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration,"Nuclear factor kappaB (NF-kappaB) is one of the main transcription factors involved in liver regeneration after partial hepatectomy (PH). It is activated upon IkappaB phosphorylation by the IkappaB kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocyte-specific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2(f/f) (wild-type) and IKK2DeltaLPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2DeltaLPC compared with IKK2(f/f) mice resulted in weaker and delayed NF-kappaB activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-kappaB activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2DeltaLPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G(1)/S progression, IKK2DeltaLPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH. CONCLUSION: We demonstrate that PH in IKK2DeltaLPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation.",0
3680,18393372,S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation,"We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect of exogenous SAMe may be mediated by MTA. The aim of our current work is to examine whether the mechanism of SAMe and MTA's inhibitory effect on proinflammatory mediators might involve modulation of histone methylation. In RAW cells, we found that LPS induced TNFalpha expression by both transcriptional and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the LPS-induced increase in gene transcription. Using the chromatin immunoprecipitation assay, we found that LPS increased the binding of trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). LPS increased the binding of histone methyltransferases Set1 and myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable and cell-permeant. Treatment with SAMe doubled intracellular MTA and S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha and iNOS promoters. CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on proinflammatory mediators is mainly mediated by MTA and SAH at the level of histone methylation.",0
3681,18395842,Lymphoid neogenesis and immune infiltration in aged liver,"Immune dysregulation and inflammation play a major role in the pathology of age-related disorders. In an earlier study, the microarray data from our laboratory indicated an increase in inflammation-related gene expression in the liver with age. We further investigated immune-related changes in the aged liver and found that the levels of inflammatory cytokines, chemokines, and inflammatory genes were higher in aged animals. Immunohistochemical studies showed that immune cells formed clusters or foci in the livers of old mice, preferentially near the perivascular regions. Further analysis revealed an enrichment of macrophages, T cells, B cells, natural killer cells, and neutrophils in old liver. Characterization of the immune clusters showed the presence of shared markers of tertiary lymphoid neogenesis. Levels of lymph node homing cytokines were elevated. Expression of immunoglobulin and recombinase gene transcripts was also higher, indicating the presence of ectopic lymphoid structures in the aged liver. CONCLUSION: Aged liver exhibits a marked inflammatory status accompanied by increased immune cell infiltration. Inflammation and ectopic lymphoid structures have previously been shown to be associated with carcinogenesis, a condition that becomes more prevalent with age. Thus, further study of inflammation-related changes in the microenvironment of the aged liver could provide insights into these disorders.",0
3682,18398918,Mechanisms of hepatocyte growth factor-mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium,"Previous studies from our laboratory have demonstrated that hepatocytes can transdifferentiate into biliary epithelium (BE) both in vivo and in vitro; however, the mechanisms are unclear. The current study was designed to investigate the mechanisms of hepatocyte transdifferentiation in vitro. Rat hepatocytes were cultured in roller bottles to obtain hepatocyte organoid cultures, which were stimulated with various growth factors (GFs) including hepatocyte growth factor (HGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), stem cell factor (SCF), macrophage-stimulating protein (MSP), fibroblast growth factor-a (FGF-a), fibroblast growth factor-b (FGF-b), and fibroblast growth factor-8b (FGF-8b). Only the cultures treated with HGF, EGF, and their combination exhibited formation of hepatocyte-derived biliary epithelium (BE) despite the presence and activation of all the pertinent cognate membrane receptors of the rest of the GFs. Microarray analysis of the organoid cultures identified specific up-regulation of approximately 500 target genes induced by HGF and EGF, including members of the extracellular matrix (ECM) protein family, Wnt/beta-catenin pathway, transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) pathway, and CXC (cysteine-any amino acid-cysteine) chemokines. To investigate the downstream signaling involved in hepatocyte to biliary epithelial cell (BEC) transdifferentiation, we investigated expression and activities of mitogen-activated protein (MAP) kinases [extracellular signal-regulated kinase (ERK)1/2, p38, and c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK)] as well as serine/threonine kinase AKT. The analysis indicated that AKT phosphorylation was particularly increased in cultures treated with HGF, EGF, and their combination. Whereas phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 completely inhibited biliary epithelium formation, AKT inhibitor could only moderately reduce formation of BE in the organoid cultures treated with HGF+EGF. Most of the HGF+EGF target genes were altered by LY294002. CONCLUSION: Taken together, these data indicate that hepatocyte to BE transdifferentiation is regulated by HGF and EGF receptors and that PI3 kinase-mediated signaling independent of AKT is a crucial component of the transdifferentiation process.",0
3683,18403759,"Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function","BACKGROUND: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function. METHODS: We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls. RESULTS: A promoter SNP (-131C-->G) in CHI3L1, the chitinase 3-like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1 x 10(-13)), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case-control populations (combined P=1.2 x 10(-5)) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9 x 10(-3) to 2.5 x 10(-4)). CONCLUSIONS: CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.",0
3684,18450603,MicroRNA expression in cytogenetically normal acute myeloid leukemia,"BACKGROUND: A role of microRNAs in cancer has recently been recognized. However, little is known about the role of microRNAs in acute myeloid leukemia (AML). METHODS: Using microRNA expression profiling, we studied samples of leukemia cells from adults under the age of 60 years who had cytogenetically normal AML and high-risk molecular features--that is, an internal tandem duplication in the fms-related tyrosine kinase 3 gene (FLT3-ITD), a wild-type nucleophosmin (NPM1), or both. A microRNA signature that was associated with event-free survival was derived from a training group of 64 patients and tested in a validation group of 55 patients. For the latter, a microRNA compound covariate predictor (called a microRNA summary value) was computed on the basis of weighted levels of the microRNAs forming the outcome signature. RESULTS: Of 305 microRNA probes, 12 (including 5 representing microRNA-181 family members) were associated with event-free survival in the training group (P<0.005). In the validation group, the microRNA summary value was inversely associated with event-free survival (P=0.03). In multivariable analysis, the microRNA summary value remained associated with event-free survival (P=0.04) after adjustment for the allelic ratio of FLT3-ITD to wild-type FLT3 and for the white-cell count. Using results of gene-expression microarray analysis, we found that expression levels of the microRNA-181 family were inversely correlated with expression levels of predicted target genes encoding proteins involved in pathways of innate immunity mediated by toll-like receptors and interleukin-1beta. CONCLUSIONS: A microRNA signature in molecularly defined, high-risk, cytogenetically normal AML is associated with the clinical outcome and with target genes encoding proteins involved in specific innate-immunity pathways.",0
3685,18452147,Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice,"We recently reported that mice with a T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type II (dnTGFbetaRII) spontaneously develop autoimmune cholangitis that resembles human primary biliary cirrhosis (PBC), including antimitochondrial antibodies (AMAs) and extensive portal CD4(+) and CD8(+) lymphocytic infiltrates. On the basis of these data, we performed a series of experiments to determine whether the pathology was secondary to direct dnTGFbetaRII disruption of the liver and/or alternatively the appearance of autoreactive T cells. First, using dnTGFbetaRIIRag1(-/-) mice, we noted a normal hepatic and biliary structure. Hence, we performed a rigorous series of adoptive transfer studies, transferring Ly5.1(+) unfractionated spleen cell CD4(+) or CD8(+) T cells from dnTGFbetaRII mice into B6/Rag(-/-) (Ly 5.2) recipients. In unmanipulated dnTGFbetaRII mice, there was a marked increase in CD4(+) and CD8(+) T cell biliary infiltrates with AMA. Indeed, B6/Rag(-/-) recipients of dnTGFbetaRII unfractionated cells develop features of liver disease similar to PBC, suggesting that splenic loss of self-tolerance alone is sufficient to cause disease in this model and therefore that there is no specific abnormality in the biliary targets required for appearance of disease. More importantly, adoptive transfer of CD8(+) but not CD4(+) T cells into B6/Rag(-/-) mice led to liver histopathology remarkably similar to PBC, emphasizing a prominent role for CD8 T cell-mediated pathogenesis. In contrast, B6/Rag(-/-) recipients of CD4(+) T cells from dnTGFbetaRII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon gamma and tumor necrosis factor alpha. CONCLUSION: These data suggest that in this model of PBC, autoreactive CD8(+) cells destroy bile ducts.",0
3686,18480202,Class-sparing regimens for initial treatment of HIV-1 infection,"BACKGROUND: The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs. METHODS: In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups. RESULTS: At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups. CONCLUSIONS: Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].).",0
3687,18480203,Use of multiple biomarkers to improve the prediction of death from cardiovascular causes,"BACKGROUND: The incremental usefulness of adding multiple biomarkers from different disease pathways for predicting the risk of death from cardiovascular causes has not, to our knowledge, been evaluated among the elderly. METHODS: We used data from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men, to investigate whether a combination of biomarkers that reflect myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation (troponin I, N-terminal pro-brain natriuretic peptide, cystatin C, and C-reactive protein, respectively) improved the risk stratification of a person beyond an assessment that was based on the established risk factors for cardiovascular disease (age, systolic blood pressure, use or nonuse of antihypertensive treatment, total cholesterol, high-density lipoprotein cholesterol, use or nonuse of lipid-lowering treatment, presence or absence of diabetes, smoking status, and body-mass index). RESULTS: During follow-up (median, 10.0 years), 315 of the 1135 participants in our study (mean age, 71 years at baseline) died; 136 deaths were the result of cardiovascular disease. In Cox proportional-hazards models adjusted for established risk factors, all of the biomarkers significantly predicted the risk of death from cardiovascular causes. The C statistic increased significantly when the four biomarkers were incorporated into a model with established risk factors, both in the whole cohort (C statistic with biomarkers vs. without biomarkers, 0.766 vs. 0.664; P<0.001) and in the group of 661 participants who did not have cardiovascular disease at baseline (0.748 vs. 0.688, P=0.03). The improvement in risk assessment remained strong when it was estimated by other statistical measures of model discrimination, calibration, and global fit. CONCLUSIONS: Our data suggest that in elderly men with or without prevalent cardiovascular disease, the simultaneous addition of several biomarkers of cardiovascular and renal abnormalities substantially improves the risk stratification for death from cardiovascular causes beyond that of a model that is based only on established risk factors.",0
3688,18506850,Adenosine-dependent activation of hypoxia-inducible factor-1 induces late preconditioning in liver cells,"The cellular mechanisms by which ischemic preconditioning increases liver tolerance to ischemia/reperfusion injury are still poorly understood. This study investigated the role of the hypoxia-inducible factor-1 (HIF-1) in the protection associated with the late phase of liver preconditioning. Late preconditioning was induced in primary cultured rat hepatocytes by a transient (10 minute) hypoxic stress or by 15 minutes incubation with the adenosine A(2A) receptors agonist CGS21680 24 hours before exposure to 90 minutes of hypoxia in a serum-free medium. Late preconditioning induced the nuclear translocation of HIF-1 and the expression of carbonic anhydrase IX (CAIX), a HIF-1-regulated transmembrane enzyme that catalyzes bicarbonate production. Such effects were associated with prevention of hepatocyte killing by hypoxia and the amelioration of intracellular acidosis and Na+ accumulation. The inhibition of PKC-mediated and PI3-kinase-mediated signals with, respectively, chelerythrine and wortmannin abolished HIF-1 activation and blocked both CAIX expression and the protective action of late preconditioning. CAIX expression was also prevented by interfering with the transcriptional activity of HIF-1 using a dominant negative HIF-1beta subunit. The inhibition of CAIX with acetazolamide or the block of bicarbonate influx with disodium-4-acetamido-4'-isothiocyanato-stilben-2,2'-disulfonate also reverted the protective effects of late preconditioning on intracellular acidosis and Na+ accumulation. CONCLUSION: The stimulation of adenosine A(2A) receptors induced late preconditioning in liver cells through the activation of HIF-1. HIF-1-induced expression of CAIX increases hepatocyte tolerance to ischemia by maintaining intracellular Na+ homeostasis. These observations along with the importance of HIF-1 in regulating cell survival indicates HIF-1 activation as a possible key event in liver protection by late preconditioning.",0
3689,18506892,Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation,"Store-operated calcium entry (SOCE) is the main Ca(2+) influx pathway involved in controlling proliferation of the human hepatoma cell lines Huh-7 and HepG2. However, the molecular nature of the calcium channels involved in this process remains unknown. Huh-7 and HepG2 cells express transient receptor potential canonical 1 (TRPC1) and TRPC6, as well as STIM1 and Orai1, and these 4 channels are the most likely candidates to account for the SOCE in these cells. We generated stable TRPC6-overexpressing or TRPC6-knockdown Huh-7 clones, in which we investigated correlations between the presence of the protein, the rate of cell proliferation, and SOCE amplitude. TRPC6-overexpressing Huh-7 cells proliferated 80% faster than did untransfected cells and their SOCE amplitude was 160% higher. By contrast, proliferation rate was 50% lower and SOCE amplitude 85% lower in TRPC6-knockdown clones than in untransfected cells. OAG (olyl acetyl glycerol)-induced calcium entry was similar in all cells, and small interfering RNA (siRNA) against TRPC1 had no effect on SOCE amplitude, highlighting the relationship among SOCE, TRPC6 and cell proliferation in Huh-7 cells. SOCE amplitude was reduced by STIM1 and Orai1 knockdowns, suggesting possible cooperation between these proteins and TRPC6 in these cells. Endothelial growth factor and hepatocyte growth factor increased TRPC6 expression and SOCE amplitude in Huh-7 cells, and cyclin D1 expression was decreased by STIM1, Orai1, and TRPC6 knockdowns. CONCLUSION: TRPC6 was very weakly expressed in isolated hepatocytes from healthy patients and expressed more strongly in tumoral samples from the liver of a cancer patient, strongly supporting a role for these calcium channels in liver oncogenesis.",0
3690,18525043,Socioeconomic inequalities in health in 22 European countries,"BACKGROUND: Comparisons among countries can help to identify opportunities for the reduction of inequalities in health. We compared the magnitude of inequalities in mortality and self-assessed health among 22 countries in all parts of Europe. METHODS: We obtained data on mortality according to education level and occupational class from census-based mortality studies. Deaths were classified according to cause, including common causes, such as cardiovascular disease and cancer; causes related to smoking; causes related to alcohol use; and causes amenable to medical intervention, such as tuberculosis and hypertension. Data on self-assessed health, smoking, and obesity according to education and income were obtained from health or multipurpose surveys. For each country, the association between socioeconomic status and health outcomes was measured with the use of regression-based inequality indexes. RESULTS: In almost all countries, the rates of death and poorer self-assessments of health were substantially higher in groups of lower socioeconomic status, but the magnitude of the inequalities between groups of higher and lower socioeconomic status was much larger in some countries than in others. Inequalities in mortality were small in some southern European countries and very large in most countries in the eastern and Baltic regions. These variations among countries appeared to be attributable in part to causes of death related to smoking or alcohol use or amenable to medical intervention. The magnitude of inequalities in self-assessed health also varied substantially among countries, but in a different pattern. CONCLUSIONS: We observed variation across Europe in the magnitude of inequalities in health associated with socioeconomic status. These inequalities might be reduced by improving educational opportunities, income distribution, health-related behavior, or access to health care.",0
3691,18536058,An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha,"Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine that induces context-dependent proliferation, survival, and apoptosis responses in hepatocytes. TNF stimulates and enhances growth factor-mediated hepatocyte proliferation and survival following partial hepatectomy, but also acts in concert with other inflammatory cytokines of the innate immune response during viral infection to induce apoptosis in hepatocytes. In other epithelial cell types, TNF has recently been shown to stimulate autocrine release of transforming growth factor-alpha (TGF-alpha) and interleukin-1 (IL-1) family ligands. Here, we examine the role of these autocrine ligands in modulating TNF-induced proliferation and apoptosis in primary hepatocytes. We show that TNF-induced hepatocyte proliferation is regulated by an inducible, coupled, and self-antagonizing autocrine cascade involving the pro-proliferative TGF-alpha and IL-1 receptor antagonist (IL-1ra) ligands and antiproliferative IL-1alpha/beta ligands. Moreover, cooperative stimulation of hepatocyte proliferation by combined TNF and TGF-alpha treatment is self-limited through antiproliferative autocrine IL-1alpha/beta feedback. We show that TNF potently induces apoptosis of adenovirus-infected hepatocytes in a manner similarly determined through the integrated activity of a coupled TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade. Exogenous TGF-alpha can either enhance or diminish apoptosis in adenoviral vector-treated and TNF-treated hepatocytes, in a biphasic relationship also mediated by autocrine IL-1alpha/beta feedback. CONCLUSION: We demonstrate that TNF-induced hepatocyte proliferation and apoptosis are both governed by a self-antagonizing TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade in vitro, and thus identify multiple molecular targets for control of TNF-regulated hepatocyte phenotypic responses related to liver regeneration and adenoviral gene therapy.",0
3692,18537195,Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells,"Dendritic cell maturation critically modulates antiviral immune responses, and facilitates viral clearance. Hepatitis C virus (HCV) is characterized by its high predisposition to persistent infection. Here, we examined the immune response of human monocyte-derived dendritic cells (MoDCs) to the JFH1 strain of HCV, which can efficiently replicate in cell culture. However, neither HCV RNA replication nor antigen production was detected in MoDCs inoculated with JFH1. None of the indicators of HCV interacting with MoDCs we evaluated were affected, including expression of maturation markers (CD80, 83, 86), cytokines (interleukin-6 and interferon-beta), the mixed lymphocyte reaction, and natural killer (NK) cell cytotoxicity. Strikingly, MoDCs matured by phagocytosing extrinsically-infected vesicles containing HCV-derived double-stranded RNA (dsRNA). When MoDCs were cocultured with HCV-infected apoptotic Huh7.5.1 hepatic cells, there was increased CD86 expression and interleukin-6 and interferon-beta production in MoDCs, which were characterized by the potential to activate NK cells and induce CD4+ T cells into the T helper 1 type. Lipid raft-dependent phagocytosis of HCV-infected apoptotic vesicles containing dsRNA was indispensable to MoDC maturation. Colocalization of dsRNA with Toll-like receptor 3 (TLR3) in phagosomes suggested the importance of TLR3 signaling in the MoDC response against HCV. CONCLUSION: The JFH1 strain does not directly stimulate MoDCs to activate T cells and NK cells, but phagocytosing HCV-infected apoptotic cells and their interaction with the TLR3 pathway in MoDCs plays a critical role in MoDC maturation and reciprocal activation of T and NK cells.",0
3693,18563844,Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease,"There have been important advances in defining effector mechanisms for several human autoimmune diseases. However, for most human autoimmune diseases, the induction stage is less well defined and there are very few clues on etiology. Our laboratory has focused on defining the molecular basis of autoantibody recognition and epitope modification in primary biliary cirrhosis (PBC). Our work has demonstrated that antibodies to mitochondria, the hallmark of disease, are directed against a very conserved site of pyruvate dehydrogenase, the E2 subunit of pyruvate dehydrogenase (PDC-E2). We have also demonstrated that several chemical xenobiotics, chosen based on quantitative structural activity relationship analysis and rigorous epitope analysis, when coupled to the lysine residue that normally binds the lipoic acid cofactor of PDC-E2, reacts as well or better to PBC sera than native autoantigen. In the present studies, we immunized C57BL/6 mice with one such xenobiotic, 2-octynoic acid, coupled to bovine serum albumin and we followed the mice for 24 weeks. Animals were studied for appearance of histologic lesions as well as appearance of antibodies to PDC-E2, serum levels of tumor necrosis factor-alpha and interferon-gamma, and splenic and liver lymphoid phenotyping by flow cytometry. Mice immunized with 2-octynoic acid manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8(+) liver infiltrating cells, particularly CD8(+) T cells that coexpress CD44, and finally an elevation of serum tumor necrosis factor-alpha and interferon-gamma. CONCLUSION: these data provide a persuasive argument in favor of an environmental origin for human PBC.",0
3694,18579814,"Polygenes, risk prediction, and targeted prevention of breast cancer","BACKGROUND: New developments in the search for susceptibility alleles in complex disorders provide support for the possibility of a polygenic approach to the prevention and treatment of common diseases. METHODS: We examined the implications, both for individualized disease prevention and for public health policy, of findings concerning the risk of breast cancer that are based on common genetic variation. RESULTS: Our analysis suggests that the risk profile generated by the known, common, moderate-risk alleles does not provide sufficient discrimination to warrant individualized prevention. However, useful risk stratification may be possible in the context of programs for disease prevention in the general population. CONCLUSIONS: The clinical use of single, common, low-penetrance genes is limited, but a few susceptibility alleles may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening.",0
3695,18614781,Noninvasive ventilation in acute cardiogenic pulmonary edema,"BACKGROUND: Noninvasive ventilation (continuous positive airway pressure [CPAP] or noninvasive intermittent positive-pressure ventilation [NIPPV]) appears to be of benefit in the immediate treatment of patients with acute cardiogenic pulmonary edema and may reduce mortality. We conducted a study to determine whether noninvasive ventilation reduces mortality and whether there are important differences in outcome associated with the method of treatment (CPAP or NIPPV). METHODS: In a multicenter, open, prospective, randomized, controlled trial, patients were assigned to standard oxygen therapy, CPAP (5 to 15 cm of water), or NIPPV (inspiratory pressure, 8 to 20 cm of water; expiratory pressure, 4 to 10 cm of water). The primary end point for the comparison between noninvasive ventilation and standard oxygen therapy was death within 7 days after the initiation of treatment, and the primary end point for the comparison between NIPPV and CPAP was death or intubation within 7 days. RESULTS: A total of 1069 patients (mean [+/-SD] age, 77.7+/-9.7 years; female sex, 56.9%) were assigned to standard oxygen therapy (367 patients), CPAP (346 patients), or NIPPV (356 patients). There was no significant difference in 7-day mortality between patients receiving standard oxygen therapy (9.8%) and those undergoing noninvasive ventilation (9.5%, P=0.87). There was no significant difference in the combined end point of death or intubation within 7 days between the two groups of patients undergoing noninvasive ventilation (11.7% for CPAP and 11.1% for NIPPV, P=0.81). As compared with standard oxygen therapy, noninvasive ventilation was associated with greater mean improvements at 1 hour after the beginning of treatment in patient-reported dyspnea (treatment difference, 0.7 on a visual-analogue scale ranging from 1 to 10; 95% confidence interval [CI], 0.2 to 1.3; P=0.008), heart rate (treatment difference, 4 beats per minute; 95% CI, 1 to 6; P=0.004), acidosis (treatment difference, pH 0.03; 95% CI, 0.02 to 0.04; P<0.001), and hypercapnia (treatment difference, 0.7 kPa [5.2 mm Hg]; 95% CI, 0.4 to 0.9; P<0.001). There were no treatment-related adverse events. CONCLUSIONS: In patients with acute cardiogenic pulmonary edema, noninvasive ventilation induces a more rapid improvement in respiratory distress and metabolic disturbance than does standard oxygen therapy but has no effect on short-term mortality. (Current Controlled Trials number, ISRCTN07448447.)",0
3696,18666240,"Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice","The Notch pathway is an evolutionary conserved, intercellular signaling pathway that plays an important role in cell fate specification and the embryonic development of many organs, including the liver. In humans, mutations in the Notch receptor ligand Jagged1 gene result in defective intrahepatic bile duct (IHBD) development in Alagille syndrome. Developmental abnormalities of IHBD in mice doubly heterozygous for Jagged1 and Notch2 mutations propose that interactions of Jagged1 and its receptor Notch2 are crucial for normal IHBD development. Because different cell types in the liver are involved in IHBD development and morphogenesis, the cell-specific role of Notch signaling is not entirely understood. We investigated the effect of combined or single targeted disruption of Notch1 and Notch2 specifically in hepatoblasts and hepatoblast-derived lineage cells on liver development using AlbCre transgenic mice. Hepatocyte differentiation and homeostasis were not impaired in mice after combined deletion of Notch1 and Notch2 (N1N2(F/F)AlbCre). However, we detected irregular ductal plate structures in N1N2(F/F)AlbCre newborns, and further postnatal development of IHBD was severely impaired characterized by disorganized ductular structures accompanied by portal inflammation, portal fibrosis, and foci of hepatocyte feathery degeneration in adulthood. Further characterization of mutant mice with single deletion of Notch1 (N1(F/F)AlbCre) or Notch2 (N2(F/F)AlbCre) showed that Notch2 but not Notch1 is indispensable for normal perinatal and postnatal IHBD development. Further reduction of Notch2 gene dosage in Notch2 conditional/mutant (N2(F/LacZ)AlbCre) animals further enhanced IHBD abnormalities and concomitant liver pathology. CONCLUSION: Notch2 is required for proper IHBD development and morphogenesis.",0
3697,18666256,A novel role for adiponectin in regulating the immune responses in chronic hepatitis C virus infection,"Adipose tissue releases pro-inflammatory and anti-inflammatory mediators, including adiponectin, which elicit a broad range of metabolic and immunological effects. The study aim was to determine in subjects infected with chronic hepatitis C virus (HCV) the effects of total adiponectin and its high-molecular-weight (HMW) and low-molecular-weight isoforms on HCV-specific immune responses. Serum levels of total adiponectin and its isoforms were determined by immunoassay. The ex vivo effect of adiponectin on the HCV-specific T-cell response was examined by interferon gamma (IFN-gamma) enzyme-linked immunosorbent spot and enzyme-linked immunosorbent assay cytokine assays. The role of the mitogen-activated protein kinase (MAPK) signaling pathway in mediating the adiponectin effect on T cells was also evaluated. We found that serum levels of total and HMW adiponectin were significantly decreased in subjects with chronic HCV and increased body mass index (BMI) compared with HCV-infected lean subjects. The presence of an anti-HCV specific immune response was strongly associated with lower BMI (P = 0.004) and higher serum total (P = 0.01) and HMW (P = 0.02) adiponectin. In ex vivo assays, total adiponectin and the HMW adiponectin isoform enhanced HCV-specific IFN-gamma production (P = 0.02 and 0.03, respectively). Adiponectin-R1 receptors were expressed on T cells and monocytes. In depletion experiments, the IFN-gamma response to adiponectin was entirely dependent on the simultaneous presence of both CD4 and CD8 T cells, and to a lesser extent, natural killer cells. Selective inhibition of p38MAPK activity by SB203580 abrogated the IFN-gamma response to adiponectin, whereas extracellular signal-regulated kinase 1/2 inhibition by PD98059 did not affect the response. CONCLUSION: In chronic HCV, a reciprocal association exists between BMI, adiponectin, and the anti-HCV immune responses, emphasizing the important role played by adiposity in regulating the immune response in HCV infection.",0
3698,18669425,Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission,"BACKGROUND: Women make up more than 50% of adults living with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa. Thus, female-initiated HIV prevention methods are urgently needed. METHODS: We performed a randomized, double-blind, placebo-controlled trial of cellulose sulfate, an HIV-entry inhibitor formulated as a vaginal gel, involving women at high risk for HIV infection at three African and two Indian sites. The primary end point was newly acquired infection with HIV type 1 or 2. The secondary end point was newly acquired gonococcal or chlamydial infection. The primary analysis was based on a log-rank test of no difference in the distribution of time to HIV infection, stratified according to site. RESULTS: A total of 1398 women were enrolled and randomly assigned to receive cellulose sulfate gel (706 participants) or placebo (692 participants) and had follow-up HIV test data. There were 41 newly acquired HIV infections, 25 in the cellulose sulfate group and 16 in the placebo group, with an estimated hazard ratio of infection for the cellulose sulfate group of 1.61 (P=0.13). This result, which is not significant, is in contrast to the interim finding that led to the trial being stopped prematurely (hazard ratio, 2.02 [corrected]; P=0.05 [corrected]) and the suggestive result of a preplanned secondary (adherence-based) analysis (hazard ratio, 2.02; P=0.05). No significant effect of cellulose sulfate as compared with placebo was found on the risk of gonorrheal infection (hazard ratio, 1.10; 95% confidence interval [CI], 0.74 to 1.62) or chlamydial infection (hazard ratio, 0.71; 95% CI, 0.47 to 1.08). CONCLUSIONS: Cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition. (ClinicalTrials.gov number, NCT00153777; and Current Controlled Trials number, ISRCTN95638385.)",0
3699,18687639,Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis,"BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown. METHODS: We examined mortality according to serum phosphate levels in a prospective cohort of 10,044 patients who were beginning hemodialysis treatment and then analyzed FGF-23 levels and mortality in a nested case-control sample of 200 subjects who died and 200 who survived during the first year of hemodialysis treatment. We hypothesized that increased FGF-23 levels at the initiation of hemodialysis would be associated with increased mortality. RESULTS: Serum phosphate levels in the highest quartile (>5.5 mg per deciliter [1.8 mmol per liter]) were associated with a 20% increase in the multivariable adjusted risk of death, as compared with normal levels (3.5 to 4.5 mg per deciliter [1.1 to 1.4 mmol per liter]) (hazard ratio, 1.2; 95% confidence interval [CI], 1.1 to 1.4). Median C-terminal FGF-23 (cFGF-23) levels were significantly higher in case subjects than in controls (2260 vs. 1406 reference units per milliliter, P<0.001). Multivariable adjusted analyses showed that increasing FGF-23 levels were associated with a monotonically increasing risk of death when examined either on a continuous scale (odds ratio per unit increase in log-transformed cFGF-23 values, 1.8; 95% CI, 1.4 to 2.4) or in quartiles, with quartile 1 as the reference category (odds ratio for quartile 2, 1.6 [95% CI, 0.8 to 3.3]; for quartile 3, 4.5 [95% CI, 2.2 to 9.4]; and for quartile 4, 5.7 [95% CI, 2.6 to 12.6]). CONCLUSIONS: Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.",0
3700,18688877,Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response,"Autophagy is important for cellular homeostasis and can serve as innate immunity to remove intracellular pathogens. Here, we demonstrate by a battery of morphological and biochemical assays that hepatitis C virus (HCV) induces the accumulation of autophagosomes in cells without enhancing autophagic protein degradation. This induction of autophagosomes depended on the unfolded protein response (UPR), as the suppression of UPR signaling pathways suppressed HCV-induced lipidation of the microtubule-associated protein light chain 3 (LC3) protein, a necessary step for the formation of autophagosomes. The suppression of UPR or the suppression of expression of LC3 or Atg7, a protein that mediates LC3 lipidation, suppressed HCV replication, indicating a positive role of UPR and the incomplete autophagic response in HCV replication. CONCLUSION: Our studies delineate the molecular pathway by which HCV induces autophagic vacuoles and also demonstrate the perturbation of the autophagic response by HCV. These unexpected effects of HCV on the host cell likely play an important role in HCV pathogenesis.",0
3701,18688880,Rab4 facilitates cyclic adenosine monophosphate-stimulated bile acid uptake and Na+-taurocholate cotransporting polypeptide translocation,"Cyclic adenosine monophosphate (cAMP) stimulates hepatic bile acid uptake by translocating sodium-taurocholate (TC) cotransporting polypeptide (Ntcp) from an endosomal compartment to the plasma membrane. Rab4 is associated with early endosomes and involved in vesicular trafficking. This study was designed to determine the role of Rab4 in cAMP-induced TC uptake and Ntcp translocation. HuH-Ntcp cells transiently transfected with empty vector, guanosine triphosphate (GTP) locked dominant active Rab4 (Rab4(GTP)), or guanosine diphosphate (GDP) locked dominant inactive Rab4 (Rab4(GDP)) were used to study the role of Rab4. Neither Rab4(GTP) nor Rab4(GDP) affected either basal TC uptake or plasma membrane Ntcp level. However, cAMP-induced increases in TC uptake and Ntcp translocation were enhanced by Rab4(GTP) and inhibited by Rab4(GDP). In addition, cAMP increased GTP binding to endogenous Rab4 in a time-dependent, but phosphoinositide-3-kinase-independent manner. CONCLUSION: Taken together, these results suggest that cAMP-mediated phosphoinositide-3-kinase-independent activation of Rab4 facilitates Ntcp translocation in HuH-Ntcp cells.",0
3702,18697212,Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines,"Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4(+) T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4(+) T cells of a T helper 1, T helper 2, or interleukin-10-producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of G(i)-protein-coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration. CONCLUSION: Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation.",0
3703,18712788,Mechanism of T cell tolerance induction by murine hepatic Kupffer cells,"The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KCs could promote immune tolerance by acting as incompetent antigen-presenting cells (APC), as well as actively suppressing T cell activation induced by other potent APCs. The expression of antigen presentation-related molecules by KCs was phenotyped by flow cytometry. The abilities of KCs to act as APCs and to suppress T cell activation induced by splenic dendritic cells (DC) were examined by in vitro proliferation assays using CD4(+) OVA-TCR (ovalbumin T cell receptor) transgenic T cells. We found that, compared with DCs, KCs expressed significantly lower levels of major histocompatibility complex (MHC) II, B7-1, B7-2, and CD40. This result is consistent with our observation that KCs were not as potent as DCs in eliciting OVA-specific T cell proliferation. However, KCs isolated from polyinosinic:polycytidylic acid-treated mice expressed significantly higher levels of MHC II and costimulatory molecules than did na?ve KCs and could stimulate stronger T cell responses. More importantly, we found that KCs could inhibit DC-induced OVA-specific T cell activation. Further investigation of the underlying mechanism revealed that prostaglandins produced by KCs played an important role. The results ruled out the possible involvement of interleukin-10, nitric oxide, 2,3-dioxygenase, and transforming growth factor beta in KC-mediated T cell suppression. CONCLUSION: Our data indicate that KCs are a tolerogenic APC population within the liver. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance. (HEPATOLOGY 2008.).",0
3704,18716297,Preeclampsia and the risk of end-stage renal disease,"BACKGROUND: It is unknown whether preeclampsia is a risk marker for subsequent end-stage renal disease (ESRD). METHODS: We linked data from the Medical Birth Registry of Norway, which contains data on all births in Norway since 1967, with data from the Norwegian Renal Registry, which contains data on all patients receiving a diagnosis of end-stage renal disease (ESRD) since 1980, to assess the association between preeclampsia in one or more pregnancies and the subsequent development of ESRD. The study population consisted of women who had had a first singleton birth between 1967 and 1991; we included data from up to three pregnancies. RESULTS: ESRD developed in 477 of 570,433 women a mean (+/-SD) of 17+/-9 years after the first pregnancy (overall rate, 3.7 per 100,000 women per year). Among women who had been pregnant one or more times, preeclampsia during the first pregnancy was associated with a relative risk of ESRD of 4.7 (95% confidence interval [CI], 3.6 to 6.1). Among women who had been pregnant two or more times, preeclampsia during the first pregnancy was associated with a relative risk of ESRD of 3.2 (95% CI, 2.2 to 4.9), preeclampsia during the second pregnancy with a relative risk of 6.7 (95% CI, 4.3 to 10.6), and preeclampsia during both pregnancies with a relative risk of 6.4 (95% CI, 3.0 to 13.5). Among women who had been pregnant three or more times, preeclampsia during one pregnancy was associated with a relative risk of ESRD of 6.3 (95% CI, 4.1 to 9.9), and preeclampsia during two or three pregnancies was associated with a relative risk of 15.5 (95% CI, 7.8 to 30.8). Having a low-birth-weight or preterm infant increased the relative risk of ESRD. The results were similar after adjustment for possible confounders and after exclusion of women who had kidney disease, rheumatic disease, essential hypertension, or diabetes mellitus before pregnancy. CONCLUSIONS: Although the absolute risk of ESRD in women who have had preeclampsia is low, preeclampsia is a marker for an increased risk of subsequent ESRD.",0
3705,18716299,Health and economic implications of HPV vaccination in the United States,"BACKGROUND: The cost-effectiveness of prophylactic vaccination against human papillomavirus types 16 (HPV-16) and 18 (HPV-18) is an important consideration for guidelines for immunization in the United States. METHODS: We synthesized epidemiologic and demographic data using models of HPV-16 and HPV-18 transmission and cervical carcinogenesis to compare the health and economic outcomes of vaccinating preadolescent girls (at 12 years of age) and vaccinating older girls and women in catch-up programs (to 18, 21, or 26 years of age). We examined the health benefits of averting other HPV-16-related and HPV-18-related cancers, the prevention of HPV-6-related and HPV-11-related genital warts and juvenile-onset recurrent respiratory papillomatosis by means of the quadrivalent vaccine, the duration of immunity, and future screening practices. RESULTS: On the assumption that the vaccine provided lifelong immunity, the cost-effectiveness ratio of vaccination of 12-year-old girls was $43,600 per quality-adjusted life-year (QALY) gained, as compared with the current screening practice. Under baseline assumptions, the cost-effectiveness ratio for extending a temporary catch-up program for girls to 18 years of age was $97,300 per QALY; the cost of extending vaccination of girls and women to the age of 21 years was $120,400 per QALY, and the cost for extension to the age of 26 years was $152,700 per QALY. The results were sensitive to the duration of vaccine-induced immunity; if immunity waned after 10 years, the cost of vaccination of preadolescent girls exceeded $140,000 per QALY, and catch-up strategies were less cost-effective than screening alone. The cost-effectiveness ratios for vaccination strategies were more favorable if the benefits of averting other health conditions were included or if screening was delayed and performed at less frequent intervals and with more sensitive tests; they were less favorable if vaccinated girls were preferentially screened more frequently in adulthood. CONCLUSIONS: The cost-effectiveness of HPV vaccination will depend on the duration of vaccine immunity and will be optimized by achieving high coverage in preadolescent girls, targeting initial catch-up efforts to women up to 18 or 21 years of age, and revising screening policies.",0
3706,18726953,Surface markers for the murine oval cell response,"The biology of progenitor activation in the liver is of considerable medical and scientific interest. The powerful genetic tools available for the mouse make it an ideal model system to study this complex process involving many different cell types. However, reagents for the isolation and study of distinct hepatic subpopulations have been quite limited compared to those available for hematopoietic cells. To produce cell surface reactive reagents more specific for the oval cell response, we generated a new collection of monoclonal antibodies by immunization of Fischer rats with enzymatically dispersed nonparenchymal cells from the livers of adult mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Each of the resulting antibodies recognized a surface antigen present on a liver cell subset and permitted the viable isolation of the associated subpopulation by fluorescence-activated cell sorting. Differential activity was observed on normal liver cells and at different stages of oval cell activation, indicating potential utility for progenitor cell identification. The subdivision of liver cells using these tools should facilitate the study of the biology of ductal and periductal hepatic cell types, including progenitors. CONCLUSION: A new panel of surface reactive monoclonal antibodies to support investigation of the murine oval cell response has been developed.",0
3707,18752323,Hereditary hemochromatosis in the post-HFE era,"""Following the discovery of the HFE gene in 1996 and its linkage to the iron overload disorder hereditary hemochromatosis (HH) there have been profound developments in our understanding of the pathogenesis of the biochemical and clinical manifestations of a number of iron overload disorders. This article provides an update of recent developments and key issues relating to iron homeostasis and inherited disorders of iron overload, with emphasis on HFE-related HH, and is based on the content of the American Association for the Study of Liver Diseases Single-Topic Conference entitled """"Hemochromatosis: What has Happened After HFE?"""" which was held at the Emory Convention Center in Atlanta, September 7-9, 2007.""",0
3708,18765432,Analyses of cancer data from three ezetimibe trials,"BACKGROUND: Five years of statin therapy lowers low-density lipoprotein (LDL) cholesterol substantially and, over a 5-year period, results in reductions in the incidence of cardiovascular events. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677) has raised the hypothesis that adding ezetimibe to statin therapy for larger LDL cholesterol reductions might increase the incidence of cancer. METHODS: We compared the results of a hypothesis-generating analysis of the incidence of cancer in the SEAS trial of ezetimibe plus simvastatin in 1873 patients (mean follow-up after ezetimibe or matching placebo was begun, 4.1 years) with a hypothesis-testing analysis of cancer data from the two large ongoing trials of this regimen: the Study of Heart and Renal Protection (SHARP) (NCT00125593) with 9264 patients (mean follow-up, 2.7 years) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), currently with 11,353 patients (mean follow-up, 1.0 year). RESULTS: In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P=0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up. CONCLUSIONS: The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.",0
3709,18779236,Continuous glucose monitoring and intensive treatment of type 1 diabetes,"BACKGROUND: The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS: In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS: The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS: Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)",0
3710,18798337,Insulin induces calcium signals in the nucleus of rat hepatocytes,"Insulin is an hepatic mitogen that promotes liver regeneration. Actions of insulin are mediated by the insulin receptor, which is a receptor tyrosine kinase. It is currently thought that signaling via the insulin receptor occurs at the plasma membrane, where it binds to insulin. Here we report that insulin induces calcium oscillations in isolated rat hepatocytes, and that these calcium signals depend upon activation of phospholipase C and the inositol 1,4,5-trisphosphate receptor, but not upon extracellular calcium. Furthermore, insulin-induced calcium signals occur in the nucleus, and are temporally associated with selective depletion of nuclear phosphatidylinositol bisphosphate and translocation of the insulin receptor to the nucleus. These findings suggest that the insulin receptor translocates to the nucleus to initiate nuclear, inositol 1,4,5-trisphosphate-mediated calcium signals in rat hepatocytes. This novel signaling mechanism may be responsible for insulin's effects on liver growth and regeneration.",0
3711,18799552,Effectiveness of maternal influenza immunization in mothers and infants,"BACKGROUND: Young infants and pregnant women are at increased risk for serious consequences of influenza infection. Inactivated influenza vaccine is recommended for pregnant women but is not licensed for infants younger than 6 months of age. We assessed the clinical effectiveness of inactivated influenza vaccine administered during pregnancy in Bangladesh. METHODS: In this randomized study, we assigned 340 mothers to receive either inactivated influenza vaccine (influenza-vaccine group) or the 23-valent pneumococcal polysaccharide vaccine (control group). Mothers were interviewed weekly to assess illnesses until 24 weeks after birth. Subjects with febrile respiratory illness were assessed clinically, and ill infants were tested for influenza antigens. We estimated the incidence of illness, incidence rate ratios, and vaccine effectiveness. RESULTS: Mothers and infants were observed from August 2004 through December 2005. Among infants of mothers who received influenza vaccine, there were fewer cases of laboratory-confirmed influenza than among infants in the control group (6 cases and 16 cases, respectively), with a vaccine effectiveness of 63% (95% confidence interval [CI], 5 to 85). Respiratory illness with fever occurred in 110 infants in the influenza-vaccine group and 153 infants in the control group, with a vaccine effectiveness of 29% (95% CI, 7 to 46). Among the mothers, there was a reduction in the rate of respiratory illness with fever of 36% (95% CI, 4 to 57). CONCLUSIONS: Inactivated influenza vaccine reduced proven influenza illness by 63% in infants up to 6 months of age and averted approximately a third of all febrile respiratory illnesses in mothers and young infants. Maternal influenza immunization is a strategy with substantial benefits for both mothers and infants. (ClinicalTrials.gov number, NCT00142389.)",0
3712,18821612,A fresh look at interferon-alpha signaling and treatment outcomes in chronic hepatitis C,"Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFNalpha) and ribavirin. It achieves a sustained viral clearance in only 50-60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFNalpha. In patients with a rapid virological response to treatment, pegIFNalpha induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFNalpha did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.",0
3713,18828153,Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel,"""The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity in vitro led to its classification within the """"viroporin"""" family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity in vitro. Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects in vitro and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput in vitro assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein in vitro; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7 in vitro. Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function. CONCLUSION: These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (HEPATOLOGY 2008;48:1779-1790.).""",0
3714,18832239,Single reading with computer-aided detection for screening mammography,"BACKGROUND: The sensitivity of screening mammography for the detection of small breast cancers is higher when the mammogram is read by two readers rather than by a single reader. We conducted a trial to determine whether the performance of a single reader using a computer-aided detection system would match the performance achieved by two readers. METHODS: The trial was designed as an equivalence trial, with matched-pair comparisons between the cancer-detection rates achieved by single reading with computer-aided detection and those achieved by double reading. We randomly assigned 31,057 women undergoing routine screening by film mammography at three centers in England to double reading, single reading with computer-aided detection, or both double reading and single reading with computer-aided detection, at a ratio of 1:1:28. The primary outcome measures were the proportion of cancers detected according to regimen and the recall rates within the group receiving both reading regimens. RESULTS: The proportion of cancers detected was 199 of 227 (87.7%) for double reading and 198 of 227 (87.2%) for single reading with computer-aided detection (P=0.89). The overall recall rates were 3.4% for double reading and 3.9% for single reading with computer-aided detection; the difference between the rates was small but significant (P<0.001). The estimated sensitivity, specificity, and positive predictive value for single reading with computer-aided detection were 87.2%, 96.9%, and 18.0%, respectively. The corresponding values for double reading were 87.7%, 97.4%, and 21.1%. There were no significant differences between the pathological attributes of tumors detected by single reading with computer-aided detection alone and those of tumors detected by double reading alone. CONCLUSIONS: Single reading with computer-aided detection could be an alternative to double reading and could improve the rate of detection of cancer from screening mammograms read by a single reader. (ClinicalTrials.gov number, NCT00450359.)",0
3715,18832244,Maraviroc for previously treated patients with R5 HIV-1 infection,"BACKGROUND: CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS: We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS: A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS: Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)",0
3716,18844233,High incidence of hepatitis C virus reinfection in a cohort of injecting drug users,"An estimated 170 million people worldwide carry the hepatitis C virus (HCV), and in more developed countries the prevalence and incidence of HCV is particularly high among injecting drug users (IDUs). Spontaneous clearance of HCV infection and reinfection is well recognized but the level of protection against further infection conferred by HCV infection and clearance remains uncertain. We conducted a prospective study of HCV infection in IDUs recruited in Melbourne, Australia, using a much shorter median testing interval than in previous studies. Incidences of naive infection and reinfection were calculated by the person-year method and Cox proportional hazards regression used to adjust for covariates. A significantly higher HCV incidence rate was measured in previously infected IDUs (46.8% per year) compared with HCV-naive IDUs (15.5% per year). The hazard ratio for previously infected IDUs compared to HCV-naive IDUs, after adjustment for time-dependent covariates, was 2.54 (95% confidence interval, 1.11-5.78, P > |z| < 0.05). Viral persistence after reinfection appeared similar to that following naive infection. CONCLUSION: Our data suggest that HCV infection in IDUs is more likely following prior infection and clearance than in HCV-naive individuals, implying no increased immunity against further infection. This result has important implications for the future development of an HCV vaccine.",0
3717,18844235,Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition,"The Rho/ROCK pathway is activated in differentiated hepatic stellate cells (HSCs) and is necessary for assembly of actin stress fibers, contractility, and chemotaxis. Despite the importance of this pathway in HSC biology, physiological inhibitors of the Rho/ROCK pathway in HSCs are not known. We demonstrate that adenosine induces loss of actin stress fibers in the LX-2 cell line and primary HSCs in a manner indistinguishable from Rho/ROCK inhibition. Loss of actin stress fibers occurs via the A2a receptor at adenosine concentrations above 10 muM, which are present during tissue injury. We further demonstrate that loss of actin stress fibers is due to a cyclic adenosine monophosphate, protein kinase A-mediated pathway that results in Rho inhibition. Furthermore, a constitutively active Rho construct can inhibit the ability of adenosine to induce loss of actin stress fibers. Actin stress fibers are required for HSC contraction, and we demonstrate that adenosine inhibits endothelin-1 and lysophosphatidic acid-mediated HSC contraction. We propose that adenosine is a physiological inhibitor of the Rho pathway in HSCs with functional consequences, including loss of HSC contraction.",0
3718,18925642,Alterations in hepatic glucose and energy metabolism as a result of calorie and carbohydrate restriction,"Carbohydrate restriction is a common weight-loss approach that modifies hepatic metabolism by increasing gluconeogenesis (GNG) and ketosis. Because little is known about the effect of carbohydrate restriction on the origin of gluconeogenic precursors (GNG from glycerol [GNG(glycerol)] and GNG from lactate/amino acids [GNG(phosphoenolpyruvate (PEP))]) or its consequence to hepatic energy homeostasis, we studied these parameters in a group of overweight/obese subjects undergoing weight-loss via dietary restriction. We used (2)H and (13)C tracers and nuclear magnetic resonance spectroscopy to measure the sources of hepatic glucose and tricarboxylic acid (TCA) cycle flux in weight-stable subjects (n = 7) and subjects following carbohydrate restriction (n = 7) or calorie restriction (n = 7). The majority of hepatic glucose production in carbohydrate restricted subjects came from GNG(PEP). The contribution of glycerol to GNG was similar in all groups despite evidence of increased fat oxidation in carbohydrate restricted subjects. A strong correlation between TCA cycle flux and GNG(PEP) was found, though the reliance on TCA cycle energy production for GNG was attenuated in subjects undergoing carbohydrate restriction. Together, these data imply that the TCA cycle is the energetic patron of GNG. However, the relationship between these two pathways is modified by carbohydrate restriction, suggesting an increased reliance of the hepatocyte on energy generated outside of the TCA cycle when GNG(PEP) is maximal. CONCLUSION: Carbohydrate restriction modifies hepatic GNG by increasing reliance on substrates like lactate or amino acids but not glycerol. This modification is associated with a reorganization of hepatic energy metabolism suggestive of enhanced hepatic beta-oxidation.",0
3719,18943638,"Impact of Diurnal Periodicity, Temperature, and Light on Sporulation of Bremia lactucae","ABSTRACT We evaluated direct and interactive effects of light quality and intensity, temperature and light, diurnal rhythms, and timing of high relative humidity during long day lengths on sporulation of Bremia lactucae, the causal agent of lettuce downy mildew, using inoculated lettuce seedlings and detached cotyledons. Suppression of sporulation by light was strongly dependent upon temperature and there was little suppression at </=10 degrees C. The most suppressive waveband was in the range from 400 to 450 nm, although a lesser effect of wavebands from 450 to 500 and 500 to 550 nm could be detected. At 15 degrees C, near the lower threshold for suppression of sporulation by light, a clear diurnal pattern of sporulation was observed independent of light and darkness. This diurnal rhythm potentially could interact with light and temperature to confound the results of controlled environment studies, and may be the controlling factor in timing of sporulation at low temperatures. Forecasting models that currently use sunrise and sunset to delimit periods conducive to sporulation can be adapted to short nights and extended twilight conditions by incorporating the effects reported herein. Additionally, models of sporulation could be adapted to better reflect a decrease or absence of the suppressive effect of light at <15 degrees C. ",0
3720,18943671,Characterization of Race-Specific Interactions Among Isolates of Verticillium dahliae Pathogenic on Lettuce,"ABSTRACT Verticillium wilt, caused by Verticillium dahliae, poses a major threat to lettuce (Lactuca sativa) production in California. Incorporation of resistance into commercial lettuce cultivars offers the least expensive technique of sustaining production in infested areas. To test the breadth of the resistance identified in field experiments, a pair of susceptible ('Salinas' and 'Sniper') and resistant ('La Brillante' and 'Little Gem') lettuce cultivars were used as differentials and individually inoculated with 29 isolates of V. dahliae and two isolates of V. albo-atrum from several hosts, including lettuce, in replicated greenhouse experiments. The reactions of the four cultivars were determined based on the disease severity at maturity. None of the V. albo-atrum isolates or V. dahliae isolates from cruciferous hosts caused significant disease on lettuce. Both Salinas and Sniper were susceptible to many isolates of V. dahliae (21 of 23) from noncruciferous hosts, and the isolates varied in their overall virulence. However, of these, only three isolates caused significant disease on the resistant cvs. La Brillante and Little Gem. These three isolates also were distinct from the other V. dahliae isolates based on sequence data from the intergenic spacer (IGS) region of the nuclear ribosomal RNA gene, suggesting that they form a phylogenetically distinct subgroup that differs in virulence toward specific lettuce genotypes. Accordingly, isolates of V. dahliae virulent on all tested cultivars, including the resistant La Brillante and Little Gem, were designated as race 2, whereas those virulent only on the susceptible Salinas and Sniper were designated as race 1. Although a range of virulence among isolates has been described in other hosts, this is the first description of distinct virulence phenotypes in V. dahliae since a similar race structure was described in tomato in the 1960s. ",0
3721,18943673,Selection for Fungicide Resistance Within a Growing Season in Field Populations of Phytophthora infestans at the Center of Origin,"ABSTRACT The central highlands of Mexico should provide an optimal testing ground for evaluating the potential threat of selection for resistance to fungicides in the population of Phytophthora infestans. We evaluated the hypotheses that exposure to the fungicides azoxystrobin, cymoxanil, dimethomorph, fluazinam, mancozeb, metalaxyl, and propamocarb hydrochloride would lead to (i) a shift in the sensitivity distributions (i.e., selection) and (ii) a lower genotypic diversity of the population. We compared populations from unsprayed plots with populations that had been exposed to several applications of each of the fungicides within a single field season. This study provides novel baseline data and shows that the Toluca valley P. infestans population has a wide range of sensitivities to the fungicides fluazinam, cymoxanil, dimethomorph, metalaxyl, and propamocarb. Directional selection toward resistance combined with a reduction in genetic diversity of the P. infestans population was observed only for the fungicide metalaxyl. The results obtained provide direct experimental support for continuing vigilance regarding further introductions of exotic strains of P. infestans into the United States. ",0
3722,18943785,Evaluating predictors of apple scab with receiver operating characteristic curve analysis,"ABSTRACT Apple scab (Venturia inaequalis) is a perennial threat to apple production in temperate climates throughout the world. In the eastern United States, apple scab is managed almost exclusively through the regular application of fungicides. Management of the primary phase of disease is focused on preventing infection by ascospores. Management of secondary cycles of infection is largely dependent on how well primary infections were controlled. In this study, we used receiver operating characteristic curve analysis to evaluate how well mid-season assessments of the incidence of apple scab on cluster leaves, clusters (i.e., the whorl of cluster leaves), or immature fruit can serve as predictors of apple scab on harvested fruit (harvest scab) and whether these mid-season assessments of scab could be used reliably to manage scab under various damage thresholds. Results showed that assessment of scab on immature fruit was superior at predicting harvest scab than were assessments made on clusters or cluster leaves at all damage thresholds evaluated. A management action threshold of 7% scab incidence on immature fruit was identified by Youden's index as the optimal action threshold to prevent harvest scab incidence from exceeding 5%. Action thresholds could be higher or lower than 7% when economic assumptions were factored in to the decision process. The utility of such a predictor is discussed. ",0
3723,18943959,Simultaneous detection of nine grapevine viruses by multiplex reverse transcription-polymerase chain reaction with coamplification of a plant RNA as internal control,"ABSTRACT A multiplex reverse transcription-polymerase chain reaction (mRT-PCR) was developed for simultaneous detection of nine grapevine viruses: Arabis mosaic virus, Grapevine fanleaf virus, Grapevine virus A, Grapevine virus B, Rupestris stem pitting-associated virus, Grapevine fleck virus, Grapevine leafroll-associated virus-1, -2, and -3, in combination with a plant RNA internal control used as an indicator of the effectiveness of RNA extraction and RT-PCR. Primers were designed from conserved regions of each virus and their specificity was confirmed by sequencing PCR products. Two plant total RNA extraction methods (silica capture and modified RNeasy method) and two RT-PCR systems (onestep and two-step) were evaluated to develop a reliable protocol for mRT-PCR. One to nine fragments specific for the viruses were simultaneously amplified from infected samples and identified by their specific molecular sizes in agarose gel electrophoresis. In the two-step mRT-PCR, the detection limits were 10(-3) or 10(-4) extract dilutions, depending on the virus. Leaves, phloem from dormant cuttings, and in vitro plantlets from 103 naturally infected and healthy grapevines were analyzed. The mRT-PCR provided a reliable and rapid method for detecting grapevine viruses from a large number of samples. ",0
3724,18944139,Characterization of Synergy Between Cucumber mosaic virus and Potyviruses in Cucurbit Hosts,"ABSTRACT Mixed infections of cucurbits by Cucumber mosaic virus (CMV) and potyviruses exhibit a synergistic interaction. Zucchini squash and melon plants coinfected by the potyvirus Zucchini yellow mosaic virus (ZYMV) and either Fny-CMV (subgroup IA) or LS-CMV (subgroup II) displayed strong synergistic pathological responses, eventually progressing to vascular wilt and plant death. Accumulation of Fny- or LS-CMV RNAs in a mixed infection with ZYMV in zucchini squash was slightly higher than infection with CMV strains alone. There was an increase in CMV (+) strand RNA levels, but no increase in CMV (-) RNA3 levels during mixed infection with ZYMV. Moreover, only the level of capsid protein from LS-CMV increased in mixed infection. ZYMV accumulated to similar levels in singly and mixed infected zucchini squash and melon plants. Coinfection of squash with the potyvirus Watermelon mosaic virus (WMV) and CMV strains increased both the Fny-CMV RNA levels and the LS-CMV RNA levels. However, CMV (-) strand RNA3 levels were increased little or not at all for CMV on coinfection with WMV. Infection of CMV strains (LS and Fny) containing satellite RNAs (WL47-sat RNA and B5*-sat RNA) reduced the accumulation of the helper virus RNA, except when B5*-sat RNA was mixed with LS- CMV. However, mixed infection containing ZYMV and the CMV strains with satellites reversed the suppression effect of satellite RNAs on helper virus accumulation and increased satellite RNA accumulation. The synergistic interaction between CMV and potyviruses in cucurbits exhibited different features from that documented in tobacco, indicating there are differences in the mechanisms of potyvirus synergistic phenomena. ",0
3725,18944205,"Genetic and Biological Diversity of Trichoderma stromaticum, a Mycoparasite of the Cacao Witches'-Broom Pathogen","ABSTRACT The witches'-broom disease, caused by the basidiomycete Crinipellis perniciosa, is the most limiting factor for cacao cultivation in Brazil. Trichoderma stromaticum is a mycoparasite of the witches'-broom pathogen of cacao that is currently being applied in the field to manage the disease in Bahia State, Brazil. In this work, molecular and traditional methods were used to study the genetic and biological diversity of this mycoparasite. Ninety-one isolates, mostly collected from farms not sprayed with the fungus, were analyzed by amplified fragment length polymorphisms (AFLP), which showed that two genetic groups (I and II) of T. stromaticum occur in Bahia State. This classification of T. stromaticum into two distinct AFLP groups was also in agreement with several other characteristics, including growth on agar media at different temperatures and sporulation on infected stem segments (broom pieces) and rice grains. Group II favors higher temperatures compared with group I. The genetic and biological differences of the isolates, however, were not evident in field experiments, where sporulation was evaluated on the surface of brooms under natural conditions. Our results show that there is considerable genetic and biological diversity within T. stromaticum in Bahia and other cacao-growing regions of South America that are affected by the witches'-broom disease. This diversity could be explored in the development of efficient biological control agents against the disease. Factors that may affect the application and performance of this biocontrol agent in the field, such as sporulation on rice substrate and on the brooms and growth at various temperatures, are discussed. ",0
3726,18944292,A test of taxonomic predictivity: resistance to early blight in wild relatives of cultivated potato,"Host plant resistance offers an attractive method of control for early blight (caused by the foliar fungus Alternaria solani), a widespread disease that appears annually in potato crops worldwide. We tested the assumed ability of taxonomy to predict the presence of early blight resistance genes in wild Solanum species for which resistance was observed in related species. We also tested associations to ploidy, crossing group, breeding system, and geography. As in a prior study of Sclerotinia sclerotiorum (white mold) resistance, tremendous variation for resistance to early blight was found to occur within and among species. There was no discernable relationship between the distribution of resistant phenotypes and taxonomic series (based on an intuitive interpretation of morphological data), clade (based on a cladistic analysis of plastid DNA data), ploidy, breeding system, geographic distance, or climate parameters. Species and individual accessions with high proportions of early blight resistant plants were identified, but high levels of inter- and intra-accession variability were observed. Consequently, the designation of species or accessions as resistant or susceptible must take this variation into account. This study calls into question the assumption that taxonomic or geographic data can be used to predict sources of early blight resistance in wild Solanum species. ",0
3727,18944357,Risk assessment models for wheat fusarium head blight epidemics based on within-season weather data,"ABSTRACT Logistic regression models for wheat Fusarium head blight were developed using information collected at 50 location-years, including four states, representing three different U.S. wheat-production regions. Non-parametric correlation analysis and stepwise logistic regression analysis identified combinations of temperature, relative humidity, and rainfall or durations of specified weather conditions, for 7 days prior to anthesis, and 10 days beginning at crop anthesis, as potential predictor variables. Prediction accuracy of developed logistic regression models ranged from 62 to 85%. Models suitable for application as a disease warning system were identified based on model prediction accuracy, sensitivity, specificity, and availability of weather variables at crop anthesis. Four of the identified models correctly classified 84% of the 50 location-years. A fifth model that used only pre-anthesis weather conditions correctly classified 70% of the location-years. The most useful predictor variables were the duration (h) of precipitation 7 days prior to anthesis, duration (h) that temperature was between 15 and 30 degrees C 7 days prior to anthesis, and the duration (h) that temperature was between 15 and 30 degrees C and relative humidity was greater than or equal to 90%. When model performance was evaluated with an independent validation set (n = 9), prediction accuracy was only 6% lower than the accuracy for the original data sets. These results indicate that narrow time periods around crop anthesis can be used to predict Fusarium head blight epidemics. ",0
3728,18944491,Biological and Molecular Properties of a Begomovirus from Dicliptera sexangularis,"ABSTRACT Sixangle foldwing, Dicliptera sexangularis (Acanthaceae), showing severe yellow mottle and leaf distortion symptoms was collected from the shoreline of Calusa Island (Lee County, FL). The putative virus was transmitted from infected D. sexangularis to healthy seedlings by mechanical, whitefly (Bemisia tabaci biotype B), and graft-inoculations. Different forms of geminivirus-like DNAs were detected in total DNA extracted from infected plants by Southern blot hybridization analyses using DNA-A and -B of Bean golden mosaic virus (BGMV) from Guatemala as probes. Preliminary polymerase chain reaction experiments and sequence comparisons indicated that the virus was a distinct bipartite begomovirus. The virus was designated Dicliptera yellow mottle virus (DiYMV). Replicative dsDNAs of DiYMV were extracted, digested with selected restriction enzymes, and cloned into a plasmid vector. Both DNA-A and -B were sequenced and compared with those of other begomoviruses. Phylogenetic analyses using AV1, AC1, and BV1 nucleotide sequences indicated that DiYMV has a close relationship with the New World begomoviruses, especially those distributed in the nearby geographic areas of the Florida coast and the Caribbean Basin. However, different percent nucleotide sequence identities and phylogenetic relationships were detected when different open reading frames (ORFs) of DiYMV were compared with their counterparts from begomoviruses from the Caribbean Basin. Based on phylogenetic analyses of the AC1 and BV1 ORFs, DiYMV was closely related to BGMV type II isolates, whereas sequence comparisons of the common region and the AC4-derived amino acid sequences indicated its close relationship with Potato yellow mosaic virus from Venezuela. ",0
3729,18944498,Suppression of Phytophthora cinnamomi in Potting Mixes Amended with Uncomposted and Composted Animal Manures,"ABSTRACT We examined the effects of fresh and composted animal manures on the development of root rot, dieback, and plant death caused by Phytophthora cinnamomi. Fresh chicken manure, or chicken manure composted for 5 weeks before incorporation into the potting mix (25%, vol/vol), significantly reduced pathogen survival and the development of symptoms on Lupinus albus seedlings. Chicken manure composted for 2 weeks was less suppressive. Cow, sheep, and horse manure, whether fresh or composted, did not consistently suppress populations of P. cinnamomi or disease symptoms at the rates used (25%, vol/vol). All composts increased organic matter content, total biological activity, and populations of actinomycetes, fluorescent pseudomonads, and fungi. Only chicken manure stimulated endospore-forming bacteria, a factor that was strongly associated with seedling survival. Fallowing the potting mix for an additional 8 weeks after the first harvest increased the survival of lupin seedlings in a second bioassay, with survival rates in chicken manure compost-amended potting mix exceeding 90%. These data suggest that the ability of composted manure to stimulate sustained biological activity, in particular the activity of endospore-forming bacteria, is the key factor in reducing disease symptoms caused by P. cinnamomi. Supporting these results, the survival of rooted cuttings of Thryptomene calycina was significantly higher in sand-peat potting mix following amendment with commercially available chicken manure (15% vol/vol). However, this protection was reduced if the potting mix was steam pasteurized before amendment, indicating that suppression was due to endogenous as well as introduced microbes. Chicken manure compost incorporated at 5% (vol/vol) or more was strongly phytotoxic to young Banksia spinulosa plants and is not suitable as an amendment for phosphorus-sensitive plants. ",0
3730,18944560,Vegetative Compatibility Groups of Verticillium dahliae in Israel: Their Distribution and Association with Pathogenicity,"A collection of 565 isolates of Verticillium dahliae, recovered between 1992 and 1997 from 13 host plant species and soil at 47 sites in Israel, was tested for vegetative compatibility using nitrate-nonutilizing (nit) mutants. Three vegetative compatibility groups (VCGs) were found and identified as VCG2A (28 isolates), VCG2B (158 isolates), and VCG4B (378 isolates) by using international reference strains. One isolate was heterokaryon self-incompatible. Of the VCG2B isolates, 92% were recovered from the northern part of Israel and 90% of VCG4B isolates were recovered from the south, with some overlap in the central region. Isolates of the minor group VCG2A were geographically scattered among the two major VCGs. Isolates of the same VCG resembled one another more than isolates from different VCGs based on colony and microsclerotial morphology, temperature responses, and, partially, pathogenicity. Different pathotypes were defined among 60 isolates tested, using cotton (cv. Acala SJ-2) and eggplant (cv. Black Beauty) as differentials. All isolates in VCG2A and 86% of the isolates in VCG4B, irrespective of their origin, induced weak to moderate symptoms on cotton and moderate to severe symptoms on eggplant and were similar to the previously described cotton nondefoliating patho-type. In contrast, all cotton isolates in VCG2B caused severe foliar symptoms, stunting, and often death, but little or no defoliation of inoculated cotton plants. These were defined as a cotton defoliating-like pathotype and induced only weak to moderate symptoms on eggplant. We concluded that vegetative compatibility grouping of V. dahliae in Israel is closely associated with specific pathogenicity and other phenotypic traits. ",0
3731,18944576,Mathematical models of host plant infection by helper-dependent virus complexes: why are helper viruses always avirulent?,"""ABSTRACT Interactions between viruses in plants are common, and some viruses depend on such interactions for their survival. Frequently, a virus lacks some essential molecular function that another provides. In """"helper-dependent"""" virus complexes, the helper virus is transmitted independently by a vector, whereas the dependent virus depends on molecular agents associated with the helper virus for transmission by a vector. A general mathematical model was developed of the dynamics of host plant infection by a helper-dependent virus complex. Four categories of host plants were considered: healthy, infected with helper virus alone, infected with dependent virus alone, and infected with both viruses. New planting of the host crop was constrained by a maximum abundance due to limitation of the cropping area. The ratio of infection rate to host loss rate due to infection is proposed as an important epidemiological quantity, A, that can be used as a measure of the mutual adaptation of the virus and host. A number of alternative equilibria of host infection could occur and were determined exclusively by parameter values; it was informative to display their distribution in the parameter plane: (1/A)(helper) versus (1/A)(dependent). A simple analysis of the distribution of the final equilibria illustrated that the dependent virus could affect the survival of the helper virus, so facilitation between the two can be reciprocal. The distribution of the final equilibria also indicated that a well-adapted helper virus increases the opportunity for a dependent virus to evolve and survive, and the model, therefore, explains why infection with a helper virus usually causes no or little damage to plants, whereas infection with a dependent virus or mixed infection with both often causes very severe damage. """,0
3732,18944589,Variation and Heritability of Phenology in the Fungus Monilinia vaccinii-corymbosi on Blueberry,"ABSTRACT The germination of field-collected pseudosclerotia and the development of apothecia from eight New Jersey populations of the mummy berry fungus Monilinia vaccinii-corymbosi were evaluated under controlled conditions in the greenhouse. Development data for apothecia were used to describe the timing of apothecium formation and to estimate broad- and narrow-sense heritabilities of fungal phenology. Mean development times for the formation of apothecia ranged from 35.4 to 54.7 days. The mean development times for populations collected from early-season cv. Weymouth ranged from 35.4 to 39.6 days and were significantly shorter than the development times for three of the four populations collected from late-season cv. Jersey (46.9 to 54.7 days) or for the population collected from mixed stands of cultivated blueberries (42.7 days). The development of populations from late cultivars planted in very close proximity to early cv. Weymouth was early (36.5 to 39.0 days) and not significantly different from the development of populations collected from cv. Weymouth. Phenotypic and genetic variances of apothecium development for individual populations ranged from 18.9 to 44.8 and 7.2 to 30.9, respectively. Broad-sense heritabilities of apothecia development for each fungal population, calculated by partitioning phenotypic variation into genetic and environmental components, ranged from 0.31 to 0.78. Narrow-sense heritabilities of apothecia development, based on parent-offspring regression, ranged from 0.58 to 0.78. These results indicate that populations of M. vaccinii-corymbosi differ in phenology and that a significant portion of the phenological variation within populations is genetic. Thus, it is plausible to propose that the phenology of apothecium development is a component of fungal fitness and that host phenology can influence the timing of pathogen development. ",0
3733,18944737,Distribution of Xanthomonas oryzae pv. oryzae Strains Virulent to Xa21 in Korea,"ABSTRACT Strains of Xanthomonas oryzae pv. oryzae that are virulent to rice lines carrying the Xa21 resistance gene were widely distributed in Korea. A total of 105 strains collected during 1987 to 1996 in Korea was characterized by pathogenicity tests and restriction fragment length polymorphism analysis of the XorII methyltransferase (xorIIM) and avrXa10 genes. Although the lesion lengths on rice line IRBB21, which carries Xa21, decreased as plant age increased, resistance and susceptibility of the plants to 31 strains were clearly differentiated at the seedling (14, 21, and 28 days old), maximum tillering, and flag leaf stages. The resistance or susceptibility of seedlings was correlated with bacterial populations within an inoculated leaf. There was a significant change in the population structure of X. oryzae pv. oryzae with regard to virulence to Xa21 over the last 10 years; this change in population was confirmed by genome analysis. Lineage I, which is avirulent to Xa21 and does not have a genomic xorIIM homolog, was the predominant lineage found between 1987 and 1989, while lineage II, which is virulent to Xa21 and contains the xorIIM homolog, was predominant in strains collected between 1994 and 1995. Our results demonstrate that introduction of Xa21 into commercial rice should be based on the regional structure of X. oryzae pv. oryzae populations and suggest that Xa21 will not be useful in Korea. ",0
3734,18944779,Multiphasic analysis of xanthomonads causing bacterial spot disease on tomato and pepper in the Caribbean and central america: evidence for common lineages within and between countries,"ABSTRACT Four hundred thirty-three xanthomonad strains isolated from tomato or pepper plants from 32 different fields in four Caribbean and Central American countries were screened for the ability to hydrolyze starch and sodium polypectate and for resistance to copper and streptomycin. Of these, 95 representative strains were further characterized by various phnetic tests, and 63 of these strains were then analyzed by genomic fingerprinting. Most of the strains (>90%) were tolerant to copper. However, there was much more variability in sensitivity to streptomycin. All strains in Guadeloupe and 93% of the strains in Barbados were sensitive to streptomycin. The majority of strains were typical Xanthomonas campestris pv. vesicatoria group A strains. In Barbados, however, a unique group of strains was identified that was serologically similar to group A strains but was amylolytic. These strains were designated A1. The occurrence of X. campestris pv. vesicatoria group B strains in Central America was found to be limited to two fields in Costa Rica and one in Guatemala. No group B strains were identified in the Caribbean, in contrast to common occurrence in the central United States and in South America. T3 strains were not found in this study, despite the recent increase of such strains in Florida and Mexico. Unique strains from Costa Rica belonging to the X. gardneri group were identified. Little linkage was found among phenotypic and rep-polymerase chain reaction (rep-PCR) genomic fingerprinting profiles of the pathogens except at the species/pathovar level; strains displaying virtually identical fingerprint profiles were found to correspond to distinct races and vice versa. The rep-PCR genomic fingerprinting analyses suggest that certain lineages may have evolved or predominated in specific regions or specific countries. ",0
3735,18944816,Effects of Crop Rotation and Irrigation on Verticillium dahliae Microsclerotia in Soil and Wilt in Cauliflower,"ABSTRACT Experiments were conducted in field plots to evaluate the effects of broccoli residue on population dynamics of Verticillium dahliae in soil and on Verticillium wilt development on cauliflower under furrow and subsurface-drip irrigation and three irrigation regimes in 1994 and 1995. Treatments were a factorial combination of three main plots (broccoli crop grown, harvested, and residue incorporated in V.dahliae-infested plots; no broccoli crop or residue in infested plots; and fumigated control plots), two subplots (furrow and subsurface-drip irrigation), and three sub-subplots (deficit, moderate, and excessive irrigation regimes) arranged in a split-split-plot design with three replications. Soil samples collected at various times were assayed for V. dahliae propagules using the modified Anderson sampler technique. Incidence and severity of Verticillium wilt on cauliflower were assessed at 7- to 10-day intervals beginning a month after cauliflower transplanting and continuing until harvest. Number of propagules in all broccoli plots declined significantly (P < 0.05) after residue incorporation and continued to decline throughout the cauliflower season. The overall reduction in the number of propagules after two broccoli crops was approximately 94%, in contrast to the fivefold increase in the number of propagules in infested main plots without broccoli after two cauliflower crops. Disease incidence and severity were both reduced approximately 50% (P < 0.05) in broccoli treatments compared with no broccoli treatments. Differences between furrow and subsurface-drip irrigation were not significant, but incidence and severity were significantly (P < 0.05) lower in the deficit irrigation regime compared with the other two regimes. Abundance of microsclerotia of V. dahliae on cauliflower roots about 8 weeks after cauliflower harvest was significantly (P < 0.05) lower in treatments with broccoli compared with treatments without broccoli. Rotating broccoli with cauliflower and incorporating broccoli residues into the soils is a novel means of managing Verticillium wilt on cauliflower and perhaps on other susceptible crops. This practice would be successful regardless of the irrigation methods or regimes followed on the susceptible crops. ",0
3736,18944844,The importance of archival and herbarium materials in understanding the role of oospores in late blight epidemics of the past,"ABSTRACT Nineteenth and early twentieth century botanists and mycologists collected healthy and infected plant materials from many regions of the world. Some of these plant collections preserved in herbaria around the world contain samples that are of considerable significance to epidemiologists, population biologists, and botanists. The advent of the polymerase chain reaction (PCR) and the development of molecular marker technology has made DNA amplification from herbarium material a reality. In this mini-review, archival letters and herbarium samples are used to track the historical role of oospores in the biology of the potato late blight pathogen. DNA was successfully amplified by PCR with the Phytophthora infestans-specific PCR primer, PINF, and the universal primer, ITS 5, from oospores observed in a field sample of potato collected by G. P. Clinton in 1902. This experiment demonstrates the potential to utilize molecular methods to amplify DNA from historical samples of the late blight pathogen and represents the earliest definitive record of oospores of the pathogen in field samples in the United States. Studies based upon such materials and techniques, although high risk and laborious, have the potential to open a new window to epidemics of the past. ",0
3737,18944868,Tomato Breeding Lines Resistant and Tolerant to Tomato Yellow Leaf Curl Virus Issued from Lycopersicon hirsutum,"ABSTRACT Two tomato yellow leaf curl virus (TYLCV)-resistant plants from accessions LA1777 and LA386 of the wild tomato species Lycopersicon hirsutum have been crossed. The resulting resistant F1 plants were crossed with the domesticated tomato L. esculentum, and a series of selfing was performed. At each generation, individuals were selected for resistance (no symptoms and undetectable viral DNA) and tolerance (no symptoms but with detectable viral DNA) following controlled massive and repeated inoculations with viruliferous whiteflies. A stable BC1F4 line (denominated 902) that does not segregate for resistance was obtained. This line does not support virus accumulation, even upon extensive whitefly-mediated inoculation of young seedlings, and does not need protection with nets or insecticides. Another stable BC1F4 line (denominated 908) was tolerant to the virus. Both lines have good horticultural characteristics and bear 80- to 120-g red fruits. Analysis of segregation of susceptibility, tolerance, and resistance during the BC1F1 to BC1F4 crosses indicated that tolerance is controlled by a dominant major gene and resistance by two to three additive recessive genes. The resistant and tolerant lines do not need to be protected by insecticides or nets. ",0
3738,18944976,Molecular Evidence That Strain BV-15 of Peanut Stunt Cucumovirus Is a Reassortant Between Subgroup I and II Strains,"ABSTRACT In Northern hybridization assays, RNA1 of peanut stunt virus (PSV) strain BV-15 hybridized strongly with a cloned cDNA probe to RNA1 from strain PSV-W (subgroup II). Cloned probes to PSV-W RNA2 and RNA3, however, did not hybridize with the corresponding RNAs from strain BV-15. The complete nucleotide sequence of PSV-BV-15 RNA2 has been determined, and sequence comparison analysis showed that it is closely related to PSV subgroup I strains; the percent nucleotide sequence identity between PSV-BV-15 RNA2 and RNA2 sequences from PSV subgroup I and II strains were 90.5 and 75%, respectively. The possibility that PSV-BV-15 RNA2 may contain short regions derived from a subgroup II strain (i.e., represent a mosaic structure indicative of recombination) was investigated. Results indicated, however, that the entire PSV-BV-15 RNA2 sequence is derived from a subgroup I strain. PSV-BV-15 RNA3 has previously been shown to belong to subgroup I strains. These results thus establish that PSV strain BV-15 is a natural reassortant between PSV subgroups I and II strains. A reverse transcription-po-lymerase chain reaction assay is proposed for differentiating between this reassortant strain and PSV strains in subgroups I and II. ",0
3739,18945049,Effect of Carotenoids on Aflatoxin B(1) Synthesis by Aspergillus flavus,"ABSTRACT Carotenes and xanthophylls occurring in yellow corn and related terpenoids were tested for their effect on growth and aflatoxin B(1) production by Aspergillus flavus NRRL 3357, using the suspended disc culture method. Aflatoxin synthesis was inhibited at concentrations of beta-carotene, lutein, and zeaxanthin comparable to those found in the horny endosperm of mature corn. Usually growth was not significantly affected. Inhibition of aflatoxin biosynthesis was greater for compounds with an alpha-ionone-type ring (alpha-carotene, lutein, or alpha-ionone) compared with compounds with a beta-ionone ring. The presence of hydroxy groups on the rings tended to decrease inhibition, but did not override the effect of the ring type; lutein was similar to alpha-carotene and zeaxanthin was similar to beta-carotene in inhibition. A mutant accumulating norsolorinic acid (NA), A. parasiticus SRRC 162, incubated with alpha-carotene produced reduced levels of both NA and aflatoxin, indicating that inhibition occurred before NA. Additional A. flavus strains tested against 50 mug/ml of beta-carotene had 89 to 96% inhibition, which was significantly more sensitive than NRRL 3357. A. parasiticus strains were less sensitive and generally had similar or lower inhibition than NRRL 3357. The results indicate that the presence of carotenoids in endosperm may decrease the amount of aflatoxin produced by A. flavus. ",0
3740,18945447,Pooled analysis of patients with thunderclap headache evaluated by CT and LP: is angiography necessary in patients with negative evaluations?,"Severe, abrupt onset headache raises concern for aneurysmal subarachnoid hemorrhage (SAH). The current standard work-up is brain CT scan followed by LP if the CT is non-diagnostic in patients with a normal neurological exam. Some have suggested that angiography is also indicated in this common clinical situation. Is evaluation with brain CT and LP for thunderclap headache to rule out SAH sufficient and is angiography needed? We systematically searched for studies that followed neurologically-intact patients with thunderclap headache and normal CT and LP for at least 1 year. The primary outcome was SAH. We estimated the proportion of patients who developed SAH and the one-sided upper 95% confidence bound. Seven studies including 813 patients were identified. None of the patients developed SAH during follow-up (pooled proportion=0, upper 95% confidence bound=0.004). Although our methods have important limitations, we believe that this analysis will give clinicians better tools to decide whether or not to pursue further work-up with angiography in patients with thunderclap headache and normal neurological exam, CT, and LP. ",0
3741,18945520,The role of colonization pressure in nosocomial transmission of methicillin-resistant Staphylococcus aureus,"Colonized or infected patients are a major reservoir for patient-to-patient transmission of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals. Despite attempted adherence to recommended infection prevention and control procedures, a general medicine unit in our hospital continued to experience ongoing transmission of MRSA. The role that colonization pressure (CP) plays in nosocomial transmission of MRSA on a general medicine unit was assessed, and a threshold CP above which additional IP&C practices should be implemented was proposed. From January 2005 to December 2006, all patients admitted to a 36-bed general medicine unit were screened on admission for MRSA. Monthly MRSA nosocomial incidence (new nosocomial cases x 1000/susceptible patient-days) and CP (number of MRSA patient-days x 100/total patient-days) were calculated. The relative risk (RR) of MRSA transmission above and below the median CP with 95% confidence interval was calculated. Twenty-one cases of nosocomially acquired MRSA were detected during the study period, with transmission occurring in 8 separate months. The median CP during the 2 years was 6.7%. The RR of MRSA acquisition increased as CP increased above the median (RR, 7.6; 95% CI: 1.1-52.6; P = .008). MRSA outbreaks were declared on 2 separate occasions, and, in each, the CP for the preceding month was greater than the median value of 6.7%. CP has a significant effect on the subsequent transmission of MRSA on a general medicine unit. Ongoing monitoring of CP provides the opportunity for early implementation of enhanced infection prevention and control practices and can potentially decrease nosocomial transmission of MRSA and prevent outbreaks. ",0
3742,18945865,"Medication reconciliation in a community, nonteaching hospital","A medication reconciliation program involving physicians, pharmacists, nursing staff, and other personnel at a community hospital is examined. The Joint Commission required hospitals to have a procedure in place for reconciling patient medication across the continuum of care by January 1, 2006. A multidisciplinary team was formed to address reconciliation of medications at DuBois Regional Medical Center. Baseline data on the number of medications unreconciled at admission, transfer, and discharge were collected. A reconciliation process and policy were developed and implemented. The pilot program took place on a nursing unit with a select group of physicians who were known leaders, who had a substantial patient volume, and who showed an interest in the program. Letters were sent to physicians to outline the opportunities of the program. The letters encouraged physicians to participate and cited advantages such as decreased legibility issues, less opportunity for transcription error, improvement in accuracy, convenience, and time saved by using electronically generated lists instead of lists written by hand. Continuous audits, feedback, and education provided an ongoing assessment of the benefit of the program in terms of reduction of unreconciled medications and highlighted opportunities for improvement. In June 2005, baseline statistics of unreconciled medications at admission and discharge were 15% and 18%, respectively. Following implementation of the program, numbers fluctuated but improved. During the second half of 2007, the percentages of unreconciled medications on admission and at discharge were less than 10% and continued the trend downward to less than 5%. A community hospital has instituted a medication reconciliation program that involves physicians, pharmacists, nursing staff, and other personnel. Audits, feedback, and education are key components in the program's operation and improvement. ",0
3743,18945932,Pseudomonas fluorescens WCS374r-induced systemic resistance in rice against Magnaporthe oryzae is based on pseudobactin-mediated priming for a salicylic acid-repressible multifaceted defense response,"Selected strains of nonpathogenic rhizobacteria can reduce disease in foliar tissues through the induction of a defense state known as induced systemic resistance (ISR). Compared with the large body of information on ISR in dicotyledonous plants, little is known about the mechanisms underlying rhizobacteria-induced resistance in cereal crops. Here, we demonstrate the ability of Pseudomonas fluorescens WCS374r to trigger ISR in rice (Oryza sativa) against the leaf blast pathogen Magnaporthe oryzae. Using salicylic acid (SA)-nonaccumulating NahG rice, an ethylene-insensitive OsEIN2 antisense line, and the jasmonate-deficient mutant hebiba, we show that this WCS374r-induced resistance is regulated by an SA-independent but jasmonic acid/ethylene-modulated signal transduction pathway. Bacterial mutant analysis uncovered a pseudobactin-type siderophore as the crucial determinant responsible for ISR elicitation. Root application of WCS374r-derived pseudobactin (Psb374) primed naive leaves for accelerated expression of a pronounced multifaceted defense response, consisting of rapid recruitment of phenolic compounds at sites of pathogen entry, concerted expression of a diverse set of structural defenses, and a timely hyperinduction of hydrogen peroxide formation putatively driving cell wall fortification. Exogenous SA application alleviated this Psb374-modulated defense priming, while Psb374 pretreatment antagonized infection-induced transcription of SA-responsive PR genes, suggesting that the Psb374- and SA-modulated signaling pathways are mutually antagonistic. Interestingly, in sharp contrast to WCS374r-mediated ISR, chemical induction of blast resistance by the SA analog benzothiadiazole was independent of jasmonic acid/ethylene signaling and involved the potentiation of SA-responsive gene expression. Together, these results offer novel insights into the signaling circuitry governing induced resistance against M. oryzae and suggest that rice is endowed with multiple blast-effective resistance pathways. ",0
3744,18946062,Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation,"BACKGROUND: Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants. METHODS: We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors. RESULTS: In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02). CONCLUSIONS: This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.",0
3745,18946175,Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts,"Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. The activated SIK1 then auto-phosphorylates its Ser186 located at the +4 position of Thr182. The phospho-Ser186 is essential for sustained activity of SIK1, which is maintained by sequential phosphorylation at Ser186-Thr182 by glycogen synthase kinase (GSK)-3beta. Meanwhile, SIK1 represses the transcription factor cAMP-response element binding protein (CREB) by phosphorylating its co-activator transducer of regulated CREB activity (TORC). Recently, histone deacetylase (HDAC) 5 was identified as a new substrate of SIK1. Inhibition of SIK1 or AMPK results in the stimulation of glyconeogensis in the liver by enhancing dephosphorylation of TORC2 followed by up-regulation of peroxisome proliferator-activated receptor coactivator (PGC)-1alpha gene expression. However, expression of the PGC-1alpha gene has been found to be repressed in LKB1-defective muscle cells. Our findings show that the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-dependent expression of PGC-1alpha is diminished by inhibitors of GSK-3beta or SIKs in C2C12 myoblasts. Treatment with AICAR or the overexpression of SIK1 induces nuclear export of HDAC5 followed by the activation of myogenic transcription factor (MEF)-2C. The levels of phosphorylation at Thr182 and Ser186 of SIK1 in AICAR-treated C2C12 cells are elevated, and GSK-3beta enzyme purified from AICAR-treated cells shows enhanced phosphorylation activity of SIK1 in vitro. These observations suggest that GSK-3 beta and SIK1 may play important roles in the regulation of PGC-1alpha gene expression by inactivating HDAC5 followed by activation of MEF2C. ",0
3746,18946446,Relationship between blood groups and coronary artery disease,"There are mounting evidences of relationship of different blood groups to disease. For many years, ABO blood group has been associated with predisposition to both arterial and venous disorders, such as venous thromboembolism, peripheral vascular disease and coronary artery disease. To evaluate the relationship of ABO and Rhesus blood groups with coronary artery disease. Total ninety five patients with coronary artery disease admitted in the Cardiac Surgery Department of Zarina Sikhder Women Medical College, Dhaka, and ninety five healthy stuff of same Medical College were studied. Their ABO and Rhesus Blood Groups were determined by standard method in the department of Transfusion Medicine, Zarina Sikhder Women Medical College, Dhaka, Bangladesh with full support from the department of Transfusion Medicine, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. The results obtained in this study show that the prevalence of Coronary Artery Disease (CAD) in blood group O is invariably higher than in all other ABO blood groups (p<0.05). It is striking that despite the fact that the most prevalent blood group among Bangladeshi people is phenotype B, the prevalence of CAD risk is associated with phenotype O (Odd ratio 2.034, 95% confidence interval 1.127 to 3.67). This suggests that a certain CAD risk is associated with phenotype O. Thus we conclude that, in Bangladeshi people, blood group phenotype O is associated with a substantially increased risk for CAD. ",0
3747,18946608,Epidemiology of suspected elderly mistreatment in Singapore,"In our Asian society, respect for our elderly is deeply entrenched and highly valued. However, a previous study had shown that physical mistreatment of the elderly exists in the local population. This present descriptive study aims to evaluate the other types of elderly mistreatment and epidemiology of suspected victims in the local population. Over a period of 12 months, from June 2005 to May 2006, doctors of the Emergency Department (ED) were trained to look for clinical features of mistreatment in patients aged 65 years and above. A specially-developed evaluation form was used to help the staff in assessing suspected cases; these were then referred to medical social workers for further evaluation. 42 cases of suspected mistreatment were detected, with almost three times more female than male patients. The average age of suspected victims was 78.8 years. There were 27 cases of possible physical mistreatment, 25 of possible neglect, six of possible psychological mistreatment, two of possible financial mistreatment, one of possible abandonment and one of possible self-neglect. Most suspected perpetrators were family members, and more than half were the victims' sons. 37 suspected victims had to be warded after ED consultation and eight died within six months of presentation. Mistreatment of the elderly in the local population is more prevalent than expected and victims can suffer adverse outcomes. Understanding of this problem is still incomplete and more research is required. Increased awareness of this problem in the community and the medical fraternity can better identify such patients. ",0
3748,18946669,The cyanide hydratase from Neurospora crassa forms a helix which has a dimeric repeat,The fungal cyanide hydratases form a functionally specialized subset of the nitrilases which catalyze the hydrolysis of cyanide to formamide with high specificity. These hold great promise for the bioremediation of cyanide wastes. The low resolution (3.0 nm) three-dimensional reconstruction of negatively stained recombinant cyanide hydratase fibers from the saprophytic fungus Neurospora crassa by iterative helical real space reconstruction reveals that enzyme fibers display left-handed D(1) S(5.4) symmetry with a helical rise of 1.36 nm. This arrangement differs from previously characterized microbial nitrilases which demonstrate a structure built along similar principles but with a reduced helical twist. The cyanide hydratase assembly is stabilized by two dyadic interactions between dimers across the one-start helical groove. Docking of a homology-derived atomic model into the experimentally determined negative stain envelope suggests the location of charged residues which may form salt bridges and stabilize the helix. ,0
3749,18946992,Purification and properties of membrane-bound methane hydroxylase from Methylococcus capsulatus (strain M)],"Membrane fraction of Methylococcus capsulatus (strain M) were treated with [14C]acetylene, an affinity label binding to the active center of membrane-bound methane monooxygenase (MMO). High-purity particulate form of methane hydroxylase (pMH) was obtained by ion exchange and hydrophobic chromatography. According to SDS-PAGE data, the enzyme contained three polypeptides with molecular weights of 47 (alpha), 27 (beta), and 25 (gamma) kDa in the ratio 1:1:1. The radiolabel was contained in the beta-subunit of pMH. The protein contained 1 or 2 atoms of nonheme iron and 2-4 atoms of copper per a minimum molecular weight of 99 kDa. This protein did not oxidize methane or propylene in the presence of NADH but was able to oxidize low quantities of methane in the presence of duroquinol. It was established that methanol dehydrogenase (MD) and NADH oxidoreductase (NADH-OR) are peripheral membrane proteins. Possible causes of low activity of high-purity methane hydroxylase are discussed. ",0
3750,18947998,"Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues","The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2'-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity. ",0
3751,18948049,Red cell and endothelial Lu/BCAM beyond sickle cell disease,"Recent studies shed new lights on the biological function of blood group antigens, such as the adhesion properties of the Lutheran (Lu) blood group antigens carried by the Lu/BCAM glycoproteins. The Lu/BCAM adhesion glycoproteins were first identified as laminin-10/11 erythroid receptors involved in RBC adhesion to endothelium in sickle cell anemia. Lu/BCAM mediated cell adhesion to laminin is stimulated by epinephrine, a physiological stress mediator, and is dependent of phosphorylation by protein kinase A. More recently, we demonstrated that constitutive phosphorylation of Lu/BCAM is also involved in abnormal RBC adhesion to endothelium in patients with polycythemia vera (PV), a frequent myeloproliferative disorders associated with the V617F mutation of the tyrosine kinase JAK2 leading to continuous stimulation of erythropoiesis. This observation suggests that Lu/BCAM could participate to the high incidence of vascular thrombosis that also characterizes PV disease. In mice, which do not express Lu/BCAM in erytroid tissues, invalidation of the Lu/BCAM gene provided evidence that Lu/BCAM gps, as laminin-alpha5 receptors, are involved in vivo in the maintenance of normal basement membrane organization in different non erythroid tissues since up to 90% of the mutant kidney glomeruli exhibited a reduced number of visible capillary lumens and irregular thickening of the glomerular basement membrane, while intestine exhibited smooth muscle coat thickening and disorganization. All these results further illustrate that minor blood group antigens might have important role under physiological and physiopathological conditions in erythroid and non erythroid tissues as well. ",0
3752,18948126,Isoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms,"GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABA(A) receptor (GABA(A)-R) alpha1 subunit; this mutation abolished sensitivity to the volatile anesthetic isoflurane in recombinant GABA(A)-Rs, and reduced in vivo sensitivity to isoflurane in the loss-of-righting-reflex assay. We examined the effects of the double mutation on GABA(A)-R-mediated synaptic currents and isoflurane sensitivity by recording from thalamic neurons in brain slices. The double mutation accelerated the decay, and decreased the (1/2) width of, evoked inhibitory postsynaptic currents (eIPSCs) in VB neurons and attenuated isoflurane-induced prolongation of the eIPSC. The hypnotic zolpidem, a selective modulator of GABA(A)-Rs containing the alpha1 subunit, prolonged eIPSC duration regardless of genotype, indicating that mutant mice incorporate alpha1 subunit-containing GABA(A)-Rs into synapses. In RTN neurons, which lack the alpha1 subunit, eIPSC duration was longer than in VB, regardless of genotype. Isoflurane reduced the efficacy of GABAergic transmission from RTN to VB, independent of genotype, suggesting a presynaptic action in RTN neurons. Consistent with this observation, isoflurane inhibited both tonic action potential and rebound burst firing in the presence of GABA(A)-R blockade. The suppressed excitability in RTN neurons is likely mediated by isoflurane-enhanced Ba(2+)-sensitive, but 4-aminopyridine-insenstive, potassium conductances. We conclude that isoflurane enhances inhibition of thalamic neurons in VB via GABA(A)-R-dependent, but in RTN via GABA(A)-R-independent, mechanisms. ",0
3753,18948219,ATF-1 transcription factor regulates the expression of ccg-1 and cat-1 genes in response to fludioxonil under OS-2 MAP kinase in Neurospora crassa,"The ATF/CREB family transcriptional factors are regulated by stress-activated MAP kinase in yeast. The disruptants of the atf-1 gene, which encodes an ATF/CREB family transcriptional factor, were isolated and characterized in Neurospora crassa. The characteristic phenotypes in the os-2 MAP kinase strain, such as osmotic sensitivity and fludioxonil resistance, were not observed in the Deltaatf-1 strain; however, like the os-2 strain, up-regulation of the catalase gene cat-1 and the clock-controlled gene ccg-1 by treatment with fludioxonil (1 microg/mL) or 4% NaCl was almost completely abolished in the Deltaatf-1 strain. A gel shift assay indicated that ATF-1 bound to the cat-1 and ccg-1 promoters probably through the CRE motifs. The enzyme activity of large-subunit catalase CAT-1, the major conidial catalase, was not detected in the Deltaatf-1 strain, suggesting that the production of CAT-1 during formation of conidia is largely dependent on ATF-1. Among 11 clock-controlled genes, the expression of ccg-1, ccg-9, ccg-13, and ccg-14 was induced by fludioxonil in an OS-2-dependent manner; however, induction of ccg-13 and ccg-14 was observed in the Deltaatf-1 strain, suggesting the existence of another transcription factor regulated by OS-2. The homozygous cross between the Deltaatf-1 strains produced perithecia and ascospores; however, their ascospores never germinated. These findings suggest that ATF-1 acts as one of the transcriptional factors downstream of the OS-2 MAP kinase and probably regulates some genes involved in conidiation, circadian rhythm, and ascospore maturation in N. crassa. ",0
3754,18948221,Identification of all FK506-binding proteins from Neurospora crassa,"Immunophilins are intracellular receptors of immunosuppressive drugs, carrying peptidyl-prolyl cis-trans isomerase activity, with a general role in protein folding but also involved in specific regulatory mechanisms. Four immunophilins of the FKBP-type (FK506-binding proteins) were identified in the genome of Neurospora crassa. Previously, FKBP22 has been located in the endoplasmic reticulum as part of chaperone/folding complexes and FKBP13 has been found to have a dual location in the cytoplasm and mitochondria. FKBP11 is apparently located exclusively in the cytoplasm. It is not expressed during vegetative development of the fungus although its expression can be induced with calcium and during sexual development. Overexpression of the respective gene appears to confer a growth advantage to the fungus in media containing some divalent ions. FKBP50 is a nuclear protein and its genetic inactivation leads to a temperature-sensitive phenotype. None of these proteins is, alone or in combination, essential for N. crassa, as demonstrated by the isolation of a mutant strain lacking all four FKBPs. ",0
3755,18948310,What next for preimplantation genetic screening? More randomized controlled trials needed?,"The recent debate on preimplantation genetic screening (PGS) has raised questions about its routine use in clinical practice. It has been suggested that the most effective way to resolve the debate about the usefulness of PGS is to perform more well-designed and well-executed randomized controlled trials (RCTs). However, in view of the lack of evidence for the effectiveness of PGS and the accumulating evidence for its harmfulness, it is our opinion that it is unethical to perform additional RCTs for the indication advanced maternal age using cleavage stage biopsy. ",0
3756,18948349,Myocardial heat shock protein 60 expression in insulin-resistant and diabetic rats,"Heat shock protein 60 (HSPD1) plays a critical role in myocardial protection. Its reduced expression may lower myocardial protection against ischemic injury in the diabetic state. This study was conducted to investigate the natural course of fructose-fed insulin-resistant rats, define changes in myocardial HSPD1 expression, and determine the effects of thiazolidinedione or anti-hypertensive treatment. Results showed that insulin resistance with hyperinsulinemia and hypertension developed after 6 weeks of fructose feeding. This time-course study also showed that myocardial HSPD1 expression was mildly increased in week 6 (P=0.05) and significantly increased in week 8. Rosiglitazone-treated rats had restored systolic blood pressure (BP) and normalized plasma insulin level during oral glucose tolerance tests, whereas amlodipine-treated rats restored only systolic BP. Both amlodipine and rosiglitazone treatments normalized the abundance of myocardial HSPD1 expression in fructose-fed rats. When these rats received streptozotocin injection and diabetes developed, myocardial HSPD1 expression decreased despite persistent hypertension. In conclusion, this is the first study to report that myocardial HSPD1 expression is increased in high-fructose-fed rats, which may be due to increased BP. Once the high-fructose-fed rats developed diabetes with insulin deficiency, the myocardial HSPD1 expression decreased in spite of persistent hypertension. ",0
3757,18948652,"Breakfast eating habit and its influence on attention-concentration, immediate memory and school achievement","To study the relationship of breakfast to the attention -concentration, immediate recall memory, nutritional status and academic achievement of school children. Cross-sectional study. Two schools catering to middle class families in Hyderabad city. 379 urban 11 to 13 years old school children studying in 6th, 7th and 8th grades. Data collected in a single way blind procedure using Letter Cancellation test, immediate memory from the PGI Memory Scale, school marks of the previous year and nutritional status. Comparison between groups indicated significant differences in the letter cancellation (LC) total scores with the regular breakfast group achieving the highest mean scores compared to the no breakfast group (P< 0.05). Marks scored by the regular breakfast group in subjects - Science, English and total Percentage were significantly higher compared to those scored by the children in the no breakfast group. Regular breakfast eating habit and weight for age percent were significantly (P< 0.001) associated with immediate recall memory score explaining 4.3 percent variation. Regular habit of eating breakfast as opposed to irregular consumption or skipping breakfast altogether had beneficial influence on attention-concentration, memory and school achievement. ",0
3758,18948697,Mitoxantrone does not restore the impaired suppressive function of natural regulatory T cells in patients suffering from multiple sclerosis. A longitudinal ex vivo and in vitro study,"CD4+CD25+ regulatory T (T(reg)) cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, where T cells are of major importance. T(reg) cell frequency and function are potential therapeutic targets of MS treatment. Mitoxantrone (MX) is a potent immunosuppressant for the treatment of active MS. We investigated the long-term effects of MX on the suppressive function of T(reg) after mitogen and myelin basic protein (MBP) stimulation in 20 MX-treated patients. MX therapy did not restore the reduced suppressive activity of a mixture of CD25(intermediate) or CD25(high) expressing T(reg) (healthy controls, MBP: 37.3%; MS patients, MBP: -1.9 vs. 6.6% suppression after MX treatment for 6 months, p > 0.2). The frequency of T(reg) cells was not affected by MX. A single infusion of MX (10 mg/m(2) body surface) induced a selective and persistent reduction of approximately 30% of absolute and relative counts of B lymphocytes (p < 0.05). MX therapy does not influence T(reg) cell frequency or function. MX seems to exhibit its efficacy in MS mainly by a suppression of humoral immunity. ",0
3759,18948848,Beneficial effects of ethyl pyruvate in a mouse model of spinal cord injury,"The aim of the present study was to evaluate in a mouse model of spinal cord injury (SCI) the effect of the treatment with ethyl pyruvate (EP). Spinal cord injury was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy in mice. Treatment with EP (75, 25, or 8.5 mg/kg) 1 and 6 h after the SCI significantly decreased (a) the degree of spinal cord inflammation and tissue injury (histological score), (b) neutrophil infiltration (myeloperoxidase activity), (c) nitrotyrosine formation and iNOS expression, (d) proinflammatory cytokines expression, (e) nuclear factor kappaB activation, (f) extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase phosphorylation, and (g) apoptosis (TUNEL staining, Fas ligand, Bax, and Bcl-2 expression). Moreover, EP (75, 25, or 8.5 mg/kg) significantly ameliorated in a dose-dependent manner the loss of limb function (evaluated by motor recovery score). Taken together, our results demonstrate that EP treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma. ",0
3760,18949000,Virally mediated inhibition of Bax in leukocytes promotes dissemination of murine cytomegalovirus,"The evolutionary survival of viruses relies on their ability to disseminate infectious progeny to sites of transmission. The capacity to subvert apoptosis is thought to be crucial for ensuring efficient viral replication in permissive cells, but its role in viral dissemination in vivo has not been considered. We show here that the murine cytomegalovirus (MCMV) m38.5 protein specifically counters the action of Bax. As predicted from our biochemical data, the capacity of m38.5 to inhibit apoptosis is only apparent in cells unable to activate Bak. Deletion of m38.5 resulted in an attenuated growth of MCMV in vitro. In vivo replication of the Deltam38.5 virus was not significantly impaired in visceral organs. However, m38.5 played a central role in protecting leukocytes from Bax-mediated apoptosis, thereby promoting viral dissemination to the salivary glands, the principal site of transmission. These results establish that in vivo MCMV replication induces the activation of Bax in leukocytes, but not other permissive cells, and that MCMV interferes with this process to attain maximum dissemination. ",0
3761,18971492,Genetically elevated C-reactive protein and ischemic vascular disease,"BACKGROUND: Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association. METHODS: We studied 10,276 persons from a general population cohort, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. We examined another 31,992 persons from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. Finally, we compared 2238 patients with ischemic heart disease with 4474 control subjects and 612 patients with ischemic cerebrovascular disease with 1224 control subjects. We measured levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms. RESULTS: The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the four CRP polymorphisms were associated with an increase in CRP levels of up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, apolipoprotein E genotypes were associated with both elevated cholesterol levels and an increased risk of ischemic heart disease. CONCLUSIONS: Polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.",0
3762,18972442,Treatment of chronic hepatitis C in hemodialysis patients,"Hepatitis C virus (HCV) infection is especially problematic in patients with end-stage renal disease (ESRD) who are undergoing hemodialysis. Rates of HCV infection are higher among hemodialysis patients than in the general population, and several routes of transmission are thought to stem from the dialysis unit. Management of chronic hepatitis C is also more complicated in hemodialysis patients because of altered pharmacokinetics and a predisposition for drug-related toxicity, particularly ribavirin-induced anemia. Clinical trials of patients with chronic hepatitis C and healthy, functioning kidney grafts are rare because of the inherent dangers of graft rejection. As a result, most studies in patients with ESRD have focused on patients waiting for a kidney transplant. Additionally, because ribavirin is contraindicated in this patient population, many studies have examined monotherapy treatments. According to meta-analyses, conventional interferon alfa treatment yields a sustained virological response (SVR) rate of 37%, whereas studies of pegylated interferon alfa monotherapy have yielded SVR rates between 13% and 75%. Several small studies have also used the monitoring of ribavirin plasma concentrations or hemoglobin levels to facilitate the use of combination therapy. In light of the results from these clinical trials, we herein review treatment guidelines and recommend strategies to help optimize the treatment of patients with ESRD. CONCLUSION: There remains a lack of clarity surrounding the most effective treatment options for patients with chronic hepatitis C and ESRD. Treatment can be effective with many patients attaining SVR; however, unfavorable tolerability with interferon alfa-based therapy remains a concern and thus close supportive care should be aggressively pursued to help maintain adherence.",0
3763,18987363,A functional genetic link between distinct developmental language disorders,"BACKGROUND: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. METHODS: We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment. RESULTS: We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marker of this disorder (peak association, P=5.0x10(-5) at SNP rs17236239). Intriguingly, this region coincides with one associated with language delays in children with autism. CONCLUSIONS: The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language.",0
3764,18987369,Varenicline for tobacco dependence,"A 57-year-old man with a 60-pack-year history visits his primary care provider because he wants to quit smoking. He has a history of stable coronary artery disease, peripheral vascular disease, and hypertension. He also has severe obstructive lung disease (forced expiratory volume in 1 second, 39% of the predicted value) with a progressive increase in dyspnea. He has quit smoking and has had numerous relapses; the longest duration of abstinence from smoking was 7 months. Each relapse involved casual smoking to �test himself.� During previous attempts to quit, he has used a nicotine patch, a nicotine inhaler, and sustained-release bupropion. He feels motivated to quit smoking because he recently heard about a new medication to aid in quitting, and he wants to improve his health. The patient and his physician discuss the therapeutic options and agree that varenicline (Chantix) may be an option.",0
3765,19001507,Mechanical ventilation guided by esophageal pressure in acute lung injury,"BACKGROUND: Survival of patients with acute lung injury or the acute respiratory distress syndrome (ARDS) has been improved by ventilation with small tidal volumes and the use of positive end-expiratory pressure (PEEP); however, the optimal level of PEEP has been difficult to determine. In this pilot study, we estimated transpulmonary pressure with the use of esophageal balloon catheters. We reasoned that the use of pleural-pressure measurements, despite the technical limitations to the accuracy of such measurements, would enable us to find a PEEP value that could maintain oxygenation while preventing lung injury due to repeated alveolar collapse or overdistention. METHODS: We randomly assigned patients with acute lung injury or ARDS to undergo mechanical ventilation with PEEP adjusted according to measurements of esophageal pressure (the esophageal-pressure-guided group) or according to the Acute Respiratory Distress Syndrome Network standard-of-care recommendations (the control group). The primary end point was improvement in oxygenation. The secondary end points included respiratory-system compliance and patient outcomes. RESULTS: The study reached its stopping criterion and was terminated after 61 patients had been enrolled. The ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen at 72 hours was 88 mm Hg higher in the esophageal-pressure-guided group than in the control group (95% confidence interval, 78.1 to 98.3; P=0.002). This effect was persistent over the entire follow-up time (at 24, 48, and 72 hours; P=0.001 by repeated-measures analysis of variance). Respiratory-system compliance was also significantly better at 24, 48, and 72 hours in the esophageal-pressure-guided group (P=0.01 by repeated-measures analysis of variance). CONCLUSIONS: As compared with the current standard of care, a ventilator strategy using esophageal pressures to estimate the transpulmonary pressure significantly improves oxygenation and compliance. Multicenter clinical trials are needed to determine whether this approach should be widely adopted. (ClinicalTrials.gov number, NCT00127491.)",0
3766,19003876,Local accumulation and activation of regulatory Foxp3+ CD4 T(R) cells accompanies the appearance of activated CD8 T cells in the liver,"Only small populations of nonactivated, nonproliferating Foxp3(+) CD4 regulatory T cell (T(R)) cells are found in the nonparenchymal cell compartment of the mouse liver while liver-draining celiac nodes contain expanded, activated T(R) cell populations (similar to other lymph nodes). Liver Foxp3(+) CD4 T(R) cells suppress activation of T cell responses. Polyclonal, systemic T cell activation in vivo (via anti-CD3 antibody injection) is accompanied by intrahepatic accumulation of T blasts and a rapid but transient intrahepatic increase of activated, proliferating Foxp3(+) CD4 T(R) cells. Following vaccination, the appearance of peripherally primed, specific CD8 T blasts in the liver is preceded by a transient rise of Foxp3(+) CD4 T(R) cells in the liver. The adoptive transfer of immune CD8 T cells into congenic hosts that express the relevant antigen only in the liver leads to the accumulation of specific donor CD8 T cells and of host Foxp3(+) CD4 T(R) cells in the liver. CONCLUSION: Although it contains only a small population of quiescent Foxp3(+) CD4 T(R) cells, the liver can rapidly mobilize and/or recruit this T cell control in response to the intrahepatic appearance of peripherally or locally generated CD8 T blasts.",0
3767,19003881,"Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via tumor necrosis factor alpha, reduced glutathione, and transforming growth factor beta-dependent mechanisms","""Because of the contribution of ethanol and polyunsaturated fatty acids (PUFAs) to alcoholic liver disease, we investigated whether chronic ethanol administration and arachidonic acid (AA) could synergistically mediate Kupffer cell (KC) activation and modulate the stellate cell (HSC) fibrogenic response. RESULTS: (1) the effects of ethanol and AA on KC and HSC were as follows: Cell proliferation, lipid peroxidation, H(2)O(2), O(2).(-), nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activity, and tumor necrosis factor alpha (TNF-alpha) were higher in KC(ethanol) than in KC(control), and were enhanced by AA; HSC(ethanol) proliferated faster, increased collagen, and showed higher GSH than HSC(control), with modest effects by AA. (2) AA effects on the control co-culture: We previously reported the ability of KC to induce a pro-fibrogenic response in HSC via reactive oxygen species (ROS)-dependent mechanisms; we now show that AA further increases cell proliferation and collagen in the control co-culture. The latter was prevented by vitamin E (an antioxidant) and by diphenyleneiodonium (a NADPH oxidase inhibitor). (3) Ethanol effects on the co-cultures: Co-culture with KC(control) or KC(ethanol) induced HSC(control) and HSC(ethanol) proliferation; however, the pro-fibrogenic response in HSC(ethanol) was suppressed because of up-regulation of TNF-alpha and GSH, which was prevented by a TNF-alpha neutralizing antibody (Ab) and by L-buthionine-sulfoximine, a GSH-depleting agent. (4) Ethanol plus AA effects on the co-cultures: AA lowered TNF-alpha in the HSC(control) co-cultures, allowing for enhanced collagen deposition; furthermore, AA restored the pro-fibrogenic response in the HSC(ethanol) co-cultures by counteracting the up-regulation of TNF-alpha and GSH with a significant increase in GSSG and in pro-fibrogenic transforming growth factor beta (TGF-beta). CONCLUSION: These results unveil synergism between ethanol and AA to the mechanism whereby KC mediate ECM remodeling and suggest that even if chronic ethanol consumption sensitizes HSC to up-regulate anti-fibrogenic signals, their effects are blunted by a second """"hit"""" such as AA.""",0
3768,19003916,Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls,"Genetic factors are critical in determining susceptibility to primary biliary cirrhosis (PBC), but there has not been a clear association with human leukocyte antigen (HLA) genes. We performed a multicenter case-control study and analyzed HLA class II DRB1 associations using a large cohort of 664 well-defined cases of PBC and 1992 controls of Italian ancestry. Importantly, healthy controls were rigorously matched not only by age and sex, but also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR), 3.3; 95% confidence interval (CI), 2.4-4.5] and DRB1*02 (OR 0.9; 95% CI 0.8-1.2) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4; 95% CI 0.3-0.4) and DRB1*13 (OR 0.7; 95% CI 0.6-0.9) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. Associated DRB1 alleles were found only in a minority of patients, whereas an additive genetic model is supported by the gene dosage effect for DRB1*11 allele and the interaction of DRB1*11,*13, and *08. Lastly, no significant associations were detected between specific DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. In conclusion, we confirm the role for HLA to determine PBC susceptibility and suggest that the effect of HLA is limited to patient subgroups. We suggest that a large whole-genome approach is required to identify further genetic elements contributing to the loss of tolerance in this disease.",0
3769,19026009,Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-na?ve patients,"Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-na?ve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-na?ve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. CONCLUSION: Naturally occurring dominant STAT-C resistance mutations are common in treatment-na?ve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.",0
3770,19038878,Stromal gene signatures in large-B-cell lymphomas,"""BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed """"germinal-center B-cell,"""" """"stromal-1,"""" and """"stromal-2""""--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.""",0
3771,19065670,Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir,"This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-na?ve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-na?ve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated. CONCLUSION: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-na?ve HBeAg-positive patients with CHB.",0
3772,19065671,The cAMP effectors Epac and protein kinase a (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD),"PCK rats, an animal model of autosomal recessive polycystic kidney disease (ARPKD), develop cholangiocyte-derived liver cysts associated with increased intracellular adenosine 3',5'-cyclic adenosine monophosphate (cAMP), the inhibition of which suppresses cyst growth. We hypothesized that elevated cAMP stimulates cholangiocyte proliferation via two downstream effectors, exchange proteins activated by cAMP (Epac1 and Epac2 isoforms) and protein kinase A (PKA), and that intracellular calcium is also involved in this process. Assessment of Epac isoforms and PKA regulatory subunits at the messenger RNA and protein level showed that cultured normal rat cholangiocytes express Epac1, Epac2, and all regulatory PKA subunits. Epac isoforms and the PKA RIbeta subunit were overexpressed in cultured PCK cholangiocytes. Proliferation analysis in response to Epac and PKA activation indicated that both normal and PCK cholangiocytes increase their growth upon Epac-specific stimulation, while PKA-specific stimulation results in differential effects, suppressing proliferation in normal cholangiocytes but accelerating this process in PCK cholangiocytes. On the other hand, both PKA and Epac activation of cystic structures generated by normal and PCK cholangiocytes when cultured under three-dimensional conditions resulted in increased cyst growth, particularly in PCK-cholangiocyte derived cysts. Pharmacological inhibitors and small interfering RNA-mediated gene silencing demonstrated the specificity of each effector activation, as well as the involvement of MEK-ERK1/2 signaling in all the observed effector-associated proliferation changes. Hyperproliferation of PCK cholangiocytes in response to PKA stimulation, but not to Epac stimulation, was found to be associated with decreased intracellular calcium, and restoration of calcium levels blocked the PKA-dependent proliferation via the PI3K/AKT pathway. CONCLUSION: Our data provide strong evidence that both cAMP effectors, Epac and PKA, and the levels of intracellular calcium are involved in the hepatic cystogenesis of ARPKD.",0
3773,19072833,p75 Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis,"Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. We show that human hepatic myofibroblasts co-express p75(NTR) (p75 neurotrophin receptor) and sortilin, thus facilitating differential responses to mature and pro nerve growth factor (proNGF). Although mature NGF is proapoptotic, proNGF protects human hepatic myofibroblasts from apoptosis. Moreover, in recovery from experimental liver fibrosis, the decrease in proNGF parallels loss of hepatic myofibroblasts by apoptosis. Macrophage-derived matrix metalloproteinase 7 (MMP7) cleaves proNGF in a concentration-dependent manner, and its expression in the liver coincides with falling proNGF levels. To define the dominant effect of p75(NTR)-mediated events in experimental liver fibrosis, we have used a mouse lacking the p75(NTR) ligand-binding domain but expressing the intracellular domain. We show that absence of p75(NTR) ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75(NTR) limits hepatocyte and oval cell proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. CONCLUSION: NGF species have a differential effect on hepatic myofibroblast survival. Our data suggest that cleavage of proNGF by MMP7 during the early phase of recovery from liver fibrosis alters the pro/mature NGF balance to facilitate hepatic myofibroblast loss. Whereas fibrosis develops in the absence of p75(NTR) signaling, the dominant effects of loss of p75(NTR) ligand-mediated events are the retardation of liver fibrosis resolution via regulation of hepatic myofibroblast proliferation and apoptosis, and the reduction of hepatocyte and oval cell proliferation.",0
3774,19073975,An obesity-associated FTO gene variant and increased energy intake in children,"BACKGROUND: Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. METHODS: We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. RESULTS: In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). CONCLUSIONS: The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods.",0
3775,19085909,Natural killer cell function is intact after direct exposure to infectious hepatitis C virions,"Although hepatitis C virus (HCV) has been shown to readily escape from virus-specific T and B cell responses, its effects on natural killer (NK) cells are less clear. Based on two previous reports that recombinant, truncated HCV E2 protein inhibits NK cell functions via crosslinking of CD81, it is now widely believed that HCV impairs NK cells as a means to establish persistence. However, the relevance of these findings has not been verified with HCV E2 expressed as part of intact virions. Here we employed a new cell culture system generating infectious HCV particles with genotype 1a and 2a structural proteins, and analyzed direct and indirect effects of HCV on human NK cells. Antibody-mediated crosslinking of CD16 stimulated and antibody-mediated crosslinking of CD81 inhibited NK cell activation and interferon gamma (IFN-gamma) production. However, infectious HCV itself had no effect even at titers that far exceeded HCV RNA and protein concentrations in the blood of infected patients. Consistent with these results, anti-CD81 but not HCV inhibited NK cell cytotoxicity. These results were independent of the presence or absence of HCV-binding antibodies and independent of the presence or absence of other peripheral blood mononuclear cell populations. CONCLUSION: HCV 1a or 2a envelope proteins do not modulate NK cell function when expressed as a part of infectious HCV particles. Without direct inhibition by HCV, NK cells may become activated by cytokines in acute HCV infection and contribute to infection outcome and disease pathogenesis.",0
3776,19085950,Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression,"Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7alpha-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism. CONCLUSION: The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of SHP. In addition to inducing FGF19 in the intestine, bile acids in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis and prevent accumulation of toxic bile acid in human livers.",0
3777,19085953,Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses,"In a recent study, a single nucleotide polymorphism (SNP) of the Toll-like receptor 4 (TLR4) gene (c.1196C>T [rs4986791, p.T399I]) emerged as conferring protection from fibrosis progression compared to a major, wild-type (WT) CC allele (p.T399). The present study examined the functional linkage of this SNP, along with another common, highly cosegregated TLR4 SNP (c.896A>G [rs4986790, p.D299G]), to hepatic stellate cell (HSC) responses. Both HSCs from TLR4(-/-) mice and a human HSC line (LX-2) reconstituted with either TLR4 D299G and/or T399I complementary DNAs were hyporesponsive to lipopolysaccharide (LPS) stimulation compared to those expressing WT TLR4, as assessed by the expression and secretion of LPS-induced inflammatory and chemotactic cytokines (i.e., monocyte chemoattractant protein-1, interleukin-6), down-regulation of bone morphogenic protein and the activin membrane-bound inhibitor expression (an inhibitory transforming growth factor beta pseudoreceptor), and activation of a nuclear factor kappaB (NF-kappaB)-responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-kappaB, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase were greatly increased in HSCs from either TLR4(-/-) or myeloid differentiation factor 88(-/-) (a TLR adaptor protein) mice, as well as in murine HSCs expressing D299G and/or T399I SNPs; increased apoptosis in these lines was accompanied by decreased phospho-ERK and Bcl-2. CONCLUSION: TLR4 D299G and T399I SNPs that are associated with protection from hepatic fibrosis reduce TLR4-mediated inflammatory and fibrogenic signaling and lower the apoptotic threshold of activated HSCs. These findings provide a mechanistic link that explains how specific TLR4 SNPs may regulate the risk of fibrosis progression.",0
3778,19085956,"Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development","The knowledge concerning fetal hepatic stellate cells (HSCs) is scarce, and their cell lineage and functions are largely unknown. The current study isolated fetal liver mesenchymal cells from a mouse expressing beta-galactosidase under the control of Msx2 promoter by fluorescence-activated cell sorting (FACS) and surveyed marker genes by microarray analysis. Based on the location and immunostaining with conventional and newly disclosed markers, we have identified three distinct populations of fetal liver mesenchymal cells expressing both desmin and p75 neurotrophin receptor (p75NTR): HSCs in the liver parenchyma; perivascular mesenchymal cells expressing alpha-smooth muscle actin (alpha-SMA); and submesothelial cells associated with the basal lamina beneath mesothelial cells and expressing activated leukocyte cell adhesion molecule (ALCAM) and platelet-derived growth factor receptor alpha. A transitional cell type from the submesothelial cell phenotype to fetal HSCs was also identified near the liver surface. Mesothelial cells expressed podoplanin and ALCAM. Ki-67 staining showed that proliferative activity of the submesothelial cells is higher than that of mesothelial cells and transitional cells. Using anti-ALCAM antibodies, submesothelial and mesothelial cells were isolated by FACS. The ALCAM(+) cells expressed hepatocyte growth factor and pleiotrophin. In culture, the ALCAM(+) cells rapidly acquired myofibroblastic morphology and alpha-SMA expression. The ALCAM(+) cells formed intracellular lipid droplets when embedded in collagen gel and treated with retinol, suggesting the potential for ALCAM(+) cells to differentiate to HSCs. Finally, we demonstrated that fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are all derived from mesoderm by using MesP1-Cre and ROSA26 reporter mice. CONCLUSION: Fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are mesodermal in origin, and ALCAM(+) submesothelial cells may be a precursor for HSCs in developing liver.",0
3779,19085959,Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and function,"The culture of primary hepatocytes as spheroids creates an efficient three-dimensional tissue construct for hepatic studies in vitro. Spheroids possess structural polarity and functional bile canaliculi with normal differentiated function. Thus, hepatocyte spheroids have been proposed as the cell source in a variety of diagnostic, discovery, and therapeutic applications, such as a bioartificial liver. Using a novel rocking technique to induce spheroid formation, kinetics of spheroid formation, cell-cell adhesion, gene expression, and biochemical activities of rat hepatocyte spheroids were tested over 14 days of culture. Evidence was provided that the formation of spheroids occurred faster and with fewer nonadherent hepatocytes in rocked suspension culture compared to a traditional rotational system. Hepatocyte spheroids in rocked culture showed stable expression of more than 80% of 242 liver-related genes including those of albumin synthesis, urea cycle, phase I and II metabolic enzymes, and clotting factors. Biochemical activity of rocked spheroid hepatocytes was superior to monolayer culture of hepatocytes on tissue culture plastic and collagen. CONCLUSION: Spheroid formation by rocker technique was more rapid and more efficient than by rotational technique. Rocker-formed spheroids appear suitable for application in a bioartificial liver or as an in vitro liver tissue construct.",0
3780,19092153,PHD2 mutation and congenital erythrocytosis with paraganglioma,"Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.",0
3781,19116891,Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential,"Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of alpha-smooth muscle actin and transforming growth factor-beta during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreased HSC proliferation and the expression of phenotypic markers of HSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet-derived growth factor. Moreover, during in vivo liver fibrogenesis caused by CCl(4) administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl(4)-induced inflammation, HSC activation, and collagen deposition. CONCLUSION: These findings support a critical role for cathepsins in HSC activation, suggesting that the antagonism of cathepsins in HSCs may be of relevance for the treatment of liver fibrosis.",0
3782,19120189,Phylogenetic analysis of Mexican Babesia bovis isolates using msa and ssrRNA gene sequences,"Variable merozoite surface antigens of Babesia bovis are exposed glycoproteins having a role in erythrocyte invasion. Members of this gene family include msa-1 and msa-2 (msa-2c, msa-2a(1), msa-2a(2), and msa-2b). Small subunit ribosomal (ssr)RNA gene is subject to evolutive pressure and has been used in phylogenetic studies. To determine the phylogenetic relationship among B. bovis Mexican isolates using different genetic markers, PCR amplicons, corresponding to msa-1, msa-2c, msa-2b, and ssrRNA genes, were cloned and plasmids carrying the corresponding inserts were sequenced. Comparative analysis of nucleotide and deduced amino acid sequences revealed distinct degrees of variability and identity among the coding gene sequences obtained from 12 geographically different B. bovis isolates and a reference strain. Overall sequence identities of 47.7%, 72.3%, 87.7%, and 94% were determined for msa-1, msa-2b, msa-2c, and ssrRNA, respectively. A robust phylogenetic tree was obtained with msa-2b sequences. The phylogenetic analysis suggests that Mexican B. bovis isolates group in clades not concordant with the Mexican geography. However, the Mexican isolates group together in an American clade separated from the Australian clade. Sequence heterogeneity in msa-1, msa-2b, and msa-2c coding regions of Mexican B. bovis isolates present in different geographical regions can be a result of either differential evolutive pressure or cattle movement from commercial trade. ",0
3783,19120211,Study on Theileria lestoquardi antigens as potential vaccine candidates,"Theileria lestoquardi is the causative agent of malignant theileriosis of sheep and goats, causing morbidity and mortality in these animals worldwide. Western blot analysis based on T. lestoquardi schizont antigens was carried out using sera collected from Iranian sheep, which had been immunized with T. lestoquardi schizont-infected cells. The results of Western blot analysis demonstrated that schizont-immunized animals produced antibodies reacting with protein bands at 73, 42, 20, 14, and 12 kDa. Comparison of the results of the current Western blotting test with earlier studies of Theileria spp. revealed two immunogenic schizont proteins with molecular weights of 73 and 42 kDa shared between T. annulata and T. lestoquardi. Two other proteins with molecular weights of 14 and 12 kDa have not been previously found in other Theileria species. Our results suggest that the 73-kDa protein could be a potential vaccine candidate and that the 14- and 12-kDa proteins could be considered as diagnostic antigens. ",0
3784,19120454,Regulators of G-protein signalling are modulated by bacterial lipopeptides and lipopolysaccharide,"Regulators of G-protein signalling accelerate the GTPase activity of G(alpha) subunits, driving G proteins in their inactive GDP-bound form. This property defines them as GTPase activating proteins. Here the effect of different Toll-like receptor agonists on RGS1 and RGS2 expression in murine bone marrow-derived macrophages and J774 cells was analysed. After stimulation with TLR2/1 or TLR2/6 lipopeptide ligands and the TLR4/MD2 ligand lipopolysaccharide, microarray analyses show only modulation of RGS1 and RGS2 among all the regulators of G-protein signalling tested. Real-time PCR confirmed modulation of RGS1 and RGS2. In contrast to RGS2, which was always downregulated, RGS1 mRNA was upregulated during the first 30 min after stimulation, followed by downregulation. Similar results were also found in the murine macrophage cell line J774. The ligand for intracellular TLR9 modulates RGS1 and RGS2 in a similar manner. However, the TLR3 ligand poly(I:C) permanently upregulates RGS1 and RGS2 expression indicating a different modulation by the MyD88- and TRIF-signalling pathway. This was confirmed using MyD88(-/-) and TRIF(-/-) bone marrow-derived macrophages. Modulation of RGS1 and RGS2 by Toll-like receptor ligands plays an important role during inflammatory and immunological reactions after bacterial and viral infection. ",0
3785,19120524,Neuroendocrine differentiation in the progression of prostate cancer,"Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro-hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen-independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA levels can be a predictor for progression and survival after endocrine therapy. It is recommended to measure longitudinal change in serum CGA. The NE pathway can also be a therapeutic target. ",0
3786,19121147,Free distribution of insecticide treated bed nets to pregnant women in Kinshasa: an effective way to achieve 80% use by women and their newborns,"To determine whether long lasting insecticide treated bed nets (LLINs) distributed free of charge to pregnant women at their first antenatal clinic visit in Kinshasa, DRC are used from the time of distribution to delivery and 6 months after delivery. Women were enrolled into a cohort study at their first antenatal care (ANC) visit and provided LLINs free of charge. Reported use of these nets was then measured at the time of delivery (n = 328) and in a random sample of women (n = 100) 6 months post-delivery using an interviewer administered, structured questionnaire. At baseline, only 25% of women reported having slept under a bed net the night before the interview. At the time of delivery, after being provided an LLIN for free, this increased to 79%. Six months post-delivery (n = 100), 80% of women reported sleeping under a net with a child under the age of 5 the night before the interview. Freely distributed bed nets are acceptable, feasible and result in high usage. Free distribution of bed nets during antenatal clinic visits may be a highly effective way to rapidly increase the use of bed nets among both pregnant women and their newborn infants in areas with high levels of ANC attendance. ",0
3787,19121210,Is U.S. health care an appropriate system? A strategic perspective from systems science,"Systems science provides organizational principles supported by biologic findings that can be applied to any organization; any incongruence indicates an incomplete or an already failing system. U.S. health care is commonly referred to as a system that consumes an ever- increasing percentage of the gross domestic product and delivers seemingly diminishing value. To perform a comparative study of U.S. health care with the principles of systems science and, if feasible, propose solutions. General systems theory provides the theoretical foundation for this observational research. A degree of compliance of U.S. health care with systems principles and its space-time functional location within the dynamic systems model. RESULTS OF COMPARATIVE ANALYSIS: U.S. health care is an incomplete system further threatened by the fact that it functions in the zone of chaos within the dynamic systems model. Complying with systems science principles and the congruence of pertinent cycles, U.S. health care would likely dramatically improve its value creation for all of society as well as its resiliency and long-term sustainability.Immediate corrective steps could be taken: Prioritize and incentivize health over care; restore fiscal soundness by combining health and life insurance for the benefit of the insured and the payer; rebalance horizontal/providers and vertical/government hierarchies. ",0
3788,19121211,The impact of obstructive sleep apnea variability measured in-lab versus in-home on sample size calculations,"When conducting a treatment intervention, it is assumed that variability associated with measurement of the disease can be controlled sufficiently to reasonably assess the outcome. In this study we investigate the variability of Apnea-Hypopnea Index obtained by polysomnography and by in-home portable recording in untreated mild to moderate obstructive sleep apnea (OSA) patients at a four- to six-month interval. Thirty-seven adult patients serving as placebo controls underwent a baseline polysomnography and in-home sleep study followed by a second set of studies under the same conditions. The polysomnography studies were acquired and scored at three independent American Academy of Sleep Medicine accredited sleep laboratories. The in-home studies were acquired by the patient and scored using validated auto-scoring algorithms. The initial in-home study was conducted on average two months prior to the first polysomnography, the follow-up polysomnography and in-home studies were conducted approximately five to six months after the initial polysomnography. When comparing the test-retest Apnea-hypopnea Index (AHI) and apnea index (AI), the in-home results were more highly correlated (r = 0.65 and 0.68) than the comparable PSG results (r = 0.56 and 0.58). The in-home results provided approximately 50% less test-retest variability than the comparable polysomnography AHI and AI values. Both the overall polysomnography AHI and AI showed a substantial bias toward increased severity upon retest (8 and 6 events/hr respectively) while the in-home bias was essentially zero. The in-home percentage of time supine showed a better correlation compared to polysomnography (r = 0.72 vs. 0.43). Patients biased toward more time supine during the initial polysomnography; no trends in time supine for in-home studies were noted. Night-to-night variability in sleep-disordered breathing can be a confounding factor in assessing treatment outcomes. The sample size of this study was small given the night-to-night variability in OSA and limited understanding of polysomnography reliability. We found that in-home studies provided a repeated measure of sleep disordered breathing less variable then polysomnography. Investigators using polysomnography to assess treatment outcomes should factor in the increased variability and bias toward increased AHI values upon retest to ensure the study is adequately powered. ",0
3789,19121909,"Simultaneous determination of tetrahydropalmatine, protopine, and palmatine in rat plasma by LC-ESI-MS and its application to a pharmacokinetic study","A sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method has been developed and validated for the simultaneous quantification of tetrahydropalmatine, protopine and palmatine in rat plasma using phenacetin as the internal standard (IS). Two hundred microliters plasma samples were extracted by dichloromethane under a strong basic condition. The analytes were separated by a C18 column and detected with a single quadrupole mass spectrometer. The used mobile phase was acetonitrile-water (40:60, v/v) containing 5mM ammonium acetate and 0.2% glacial acetic acid. Detection was carried out by positive electrospray ionization in selected ion reaction (SIR) mode at m/z 356.6 for tetrahydropalmatine, 354.6 for protopine, 352.6 for palmatine and 180.4 for the IS, respectively. The method was validated over the concentration range of 1.00-500ngmL(-1) and the lower limit of quantification (LLOQ) was 1.00ngmL(-1) for all three analytes. The intra- and inter-day precision values were less than 9% relative standard deviation (R.S.D.), and the relative error ranged from -7.4 to 4.8%. The extraction recoveries were on average 91.42% for tetrahydropalmatine, 84.75% for protopine, 57.26% for palmatine, and 83.18% for IS. The validated method was successfully applied to a pharmacokinetic study of tetrahydropalmatine, protopine and palmatine in rats after oral administration of Rhizoma Corydalis Decumbentis extract. ",0
3790,19121941,Amide derivatives of ethacrynic acid: synthesis and evaluation as antagonists of Wnt/beta-catenin signaling and CLL cell survival,"A series of amides of ethacrynic acid was prepared and evaluated for their ability to inhibit Wnt signaling and decrease the survival of CLL cells. Several of the most potent derivatives were active in the low micromolar range. Reduction of the alpha,beta-unsaturated carbon-carbon double bond of EA abrogated both the inhibition of Wnt signaling as well as the decrease in CLL survival. Preliminary mechanism of action studies suggest that these derivatives covalently modify sulfhydryl groups present on transcription factors important for Wnt/beta-catenin signaling. ",0
3791,19122309,Three new saponins from the fresh rhizomes of Polygonatum kingianum,"Further studies on the fresh rhizomes of Polygonatum kingianum led to the isolation of one new spirostanol saponin (25R)-kingianoside G (1), and two pairs mixture of 25R and 25S stereoisomeric spirostanol saponins (25R, S)-pratioside D1 (2a, 2b) and (25R, S)-kingianoside A (3a, 3b), among them 2b and 3b were new spirostanol saponins, together with another two known compounds, disporopsin (4) and daucosterol (5). The structures of the new saponins were determined by detailed analysis of their 1D and 2D NMR spectra, and chemical evidences. ",0
3792,19122469,Correlation of cell cycle kinetics with p63 expression in human limbal epithelial cells expanded on intact human amniotic membrane,"To analyse the correlation of p63 expression and cell cycle kinetics of human limbal epithelial cells (HLECs) expanded on amniotic membrane (AM) or plastic. Primary HLECs were cultured either on cryopreserved intact AM or plastic dishes for 2 weeks. Cells were labelled with 5 microM 5-bromo-2'-deoxyuridine (BrdU) for 3 days, followed by an interval of either 7 or 14 days in BrdU-free medium. The expression of p63 and BrdU labelling was detected by immunocytochemistry. More cells on AM (56%) than on plastic (24%) retained their BrdU label after the 7-day interval (p < 0.001). The difference was even more pronounced after 14 days (20 and 2%, p < 0.001). All BrdU-labelled cells were also p63 positive. 2.5-fold more cells on AM (54%) than on plastic (21%) were BrdU positive/p63 positive after 7 days (p < 0.001). It increased to a 9-fold difference after 14 days (p < 0.001). The BrdU label was lost more quickly than the p63 expression during the observation period, indicating that p63 expression was not confined to stem cells but existed also in transient amplifying cells. The combination of p63 expression and BrdU label retention is a better criterion to characterize stemness than either marker alone. AM as a culture substrate preserves stemness better than plastic. ",0
3793,19122682,"A clinical investigation of the mechanism of loxoprofen, a non-steroidal anti-inflammatory drug, for patients with nocturia","We previously reported the effectiveness of loxoprofen sodium (loxoprofen), a non-steroidal anti-inflammatory drug, for patients with lower urinary tract symptoms (LUTS) complaining of nocturia. In this study, we explored the mechanism of loxoprofen in the treatment of nocturia. Fifty-six patients complaining of nocturia were enrolled. They took a single 60-mg tablet of loxoprofen at bedtime for 14 days. The effects of this treatment were assessed by bladder diaries. Nocturia improved (nocturia decreased >or=1 void/night) in 40 patients (71.4%). Nocturnal urine volume was reduced in 31 of 40 (77.5%) without nocturnal single-void volume increase. Nocturnal single-void volume increased in 4 of 40 (10.0%) without nocturnal urine volume reduction. Two of 40 (5.0%) demonstrated both nocturnal urine volume reduction and nocturnal single-void volume increase. Three (7.5%) were exceptions to the above. In conclusion, the main mechanism of loxoprofen is the reduction of nocturnal urine volume for the treatment of nocturia and the second mechanism is the increased bladder capacity. ",0
3794,19123050,MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents,"P-glycoprotein (P-gp), encoded by MDR1 (or ABCB1), is important in anticancer drug delivery and resistance. We evaluated alterations in P-gp-mediated transport of anticancer agents due to the MDR1 G1199A polymorphism. Using stable recombinant epithelial cells expressing wild-type (MDR1 (wt)) or G1199A (MDR1 (1199A)), anticancer drug sensitivity and transepithelial permeability were evaluated. The recombinant cells MDR1 (wt) and MDR1 ( 1199A ) displayed comparable doxorubicin resistance. However, MDR1 (1199A) cells displayed greater resistance to vinblastine, vincristine, paclitaxel, and VP-16 (11-, 2.9-, 1.9-, and 2.9-fold, respectively). Alterations in transepithelial permeability paralleled these changes. Efflux of doxorubicin was similar between MDR1 wt - and MDR1 (1199A)-expressing cells, while P-gp-mediated transport was greater for vinblastine and vincristine in MDR1 (1199A) cells (2.9- and 2.0-fold, respectively). The occurrence and magnitude of the MDR1 G1199A effect is drug specific. Overall, the MDR1 G1199A polymorphism may impact anticancer efficacy through modulation of drug distribution and delivery to target tumor cells. ",0
3795,19123081,Pleural effusion as the first sign of multiple myeloma,"Multiple myeloma (MM) is a rare disorder that affects all tissues, except reticuloendothelial tissues, and seldom causes a myelomatous pleural effusion. A 56-year-old male patient attended our clinic complaining of shortness of breath and fatigue for the past month. A posteroanterior chest radiograph revealed a left pleural effusion, which was subsequently assessed as being exudative in nature. Protein electrophoresis demonstrated hypergammaglobulinemia. Serum and pleural fluid immunofixation electrophoresis showed an increase in the IgG and kappa fractions. The Bence-Jones protein level in the 24-hours urine was high. Pleural biopsy showed plasmocyte infiltration. Bone marrow biopsy revealed atypical plasma cell infiltration, some with immature morphology, carrying IgG/Kappa clonality in a diffuse pattern. The patient was diagnosed with IgG/k type MM and underwent chemotherapy with vincristine, doxorubicin, and prednisolone. Complete regression of the pleural effusion was achieved after one round of chemotherapy, and the patient has been followed for 18 months. ",0
3796,19123085,Acute anuric renal failure with streptokinase therapy in a patient with acute venous thromboembolic disease and the review of renal side effects of streptokinase,"The benefits of thrombolytic therapy in acute myocardial infarction are now well established. However many uncertainties, such as adverse effects, are still remain in venous thromboembolic disease. We describe a unique patient who treated with streptokinase for the methylen tetrahydrofolate reductase mutation associated acute deep vein thrombosis and massive pulmonary embolism. After therapy patient developed acute anuric renal failure without an evidence of bleeding or immunologic reaction and we would like to review the renal side effects of streptokinase in patients with venous thromboembolic disease. ",0
3797,19123664,Second-harmonic generation and two-photon-excited autofluorescence microscopy of cardiomyocytes: quantification of cell volume and myosin filaments,"The ability to quantify changes in cardiomyocyte and myosin volume across gestation and in response to intrauterine insults will lead to a better understanding of the link between low birth weight and an increased risk of heart disease in adult life. We present the use of second-harmonic generation (SHG) and two-photon excitation autofluorescence (TPEF) microscopy to image unstained isolated fetal cardiomyocytes. The simultaneous collection of these two images provides a wealth of information on the morphology of cardiomyocytes. The SHG signal provides high-contrast images of myosin filaments and the TPEF signal can be used to clearly visualize cell morphology. A potential issue may arise if SHG microscopy is performed exclusively due to the lack of sensitivity to distinguish between mononucleated and binucleated cardiomyocytes. However, TPEF microscopy has the ability to efficiently separate the two types of cardiomyocytes. In addition, quantitative analysis of the SHG and TPEF images enables quantification of myosin filament level and accurate determination of cell volume. In short, we demonstrate that advanced nonlinear optical microscopy can be used to answer key physiological questions in the early origins of adult health with increased accuracy and speed compared to previously used methods. ",0
3798,19123756,Jewish and non-Jewish World War II child and adolescent survivors at 60 years after war: effects of parental loss and age at exposure on well-being,"The study investigated the effects of World War II (WWII) on psychological and social functioning of Jewish and non-Jewish survivors 60 years after the war. The authors hypothesized that the level of posttraumatic symptoms, depression, and social isolation of survivors who were at least 5 years old (but younger than 18) in the last year of WWII would be predicted by the extent of traumatic loss, (i.e., death of parent[s]) and age at the end of WWII. Data were collected from 211 individuals living in Poland, ages 66-80; 30% were Jewish Holocaust survivors. Current posttraumatic stress disorder was almost 2 times higher for Jewish (55.6%) than for non-Jewish survivors (30.9%), whereas no differences were found for depression and social isolation. Parental loss during the war predicted a global decrement of well-being (across measured outcome indices). For certain subgroups (e.g., Jewish survivors who had not lost their parents during WWII), war trauma may have less profound effects if most of the trauma exposure occurred during an earlier age (i.e., <5 years). ",0
3799,19129520,Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia,"BACKGROUND: Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. METHODS: We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL. RESULTS: More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. CONCLUSIONS: Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.",0
3800,19137587,"Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats","Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. CONCLUSION: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.",0
3801,19140218,Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice,"Natural killer T (NKT) cells and regulatory T cells (Tregs) are both found within the liver and are known to exhibit immune regulatory functions. Hepatic NKT cells are activated early during inflammatory responses and release cytokines, including interferon gamma (IFN-gamma), which we speculated could regulate Treg recruitment to the liver. To examine this, we treated C57BL/6 mice with a specific NKT cell activating ligand alpha galactosyl-C18-ceramide (alphaGal-C18-Cer) and examined the hepatic recruitment of Tregs. We found a time-dependant increase in the hepatic recruitment of Tregs after NKT cell activation, which was absent in NKT cell-deficient mice. Most recruited Tregs expressed interleukin (IL) 10, and to a lesser extent transforming growth factor beta (TGF-beta). Because IFN-gamma induces the production of chemokine (C-X-C motif) ligand 10 (CXCL10), and Tregs can express the cognate receptor for CXCL10 (that is, CXCR3), we considered that CXCL10 might mediate the hepatic recruitment of Tregs after NKT cell activation. Hepatic CXCL10 levels were markedly increased after alphaGal-C18-Cer administration in wild-type but not in NKT cell-deficient mice. Moreover, approximately 50% of Tregs recruited to the liver after alphaGal-C18-Cer administration expressed CXCR3 and CXCR3+ Treg recruitment into the liver was significantly inhibited in IFN-gamma KO mice, and after CXCL10 neutralization. In addition, prevention of CXCR3+ Treg recruitment into the liver enhanced inflammatory effector cell recruitment into the liver after alphaGal-C18-Cer treatment. CONCLUSION: These results show that activated NKT cells can induce the hepatic recruitment of Tregs through a cytokine-to-chemokine pathway, which could be relevant in the development of chemokine blocking or NKT cell activating strategies to treat liver diseases.",0
3802,19177570,In vitro-targeted gene identification in patients with hepatitis C using a genome-wide microarray technology,"Iron in association with reactive oxygen species (ROS) is highly toxic, aggravating oxidative stress reactions. Increased iron not only plays an important role in the progression of hereditary hemochromatosis (HH) but also in common liver diseases such as chronic hepatitis C. The underlying mechanisms of hepatitis C virus (HCV)-mediated iron accumulation, however, are poorly understood. We introduce an in vitro-targeted approach to identify ROS/iron-regulated genes in patients with HCV using a genome-wide DNA microarray. The sensitivity of the 32,231 complementary DNA clone-carrying microarray was approximately 20% as estimated by detecting target genes of the genome-wide transcription factor hypoxia inducible factor 1alpha. Upon in vitro challenge to iron and oxidative stress, 265 iron-related and 1326 ROS-related genes could be identified in HepG2 cells; 233 significantly regulated genes were found in patients with mild (HCV) or severe (HH) iron deposition. Notably, 17 of the in vitro-selected genes corresponded to the genes identified in patients with HCV or HH. Among them, natriuretic peptide precursor B (NPPB) was the only iron-regulated gene identified in vitro that was differentially regulated between HCV and HH. Reverse-transcription polymerase chain reaction confirmed most of the microarray-identified genes in an even larger group of patients (n = 12). In patients with HCV, these included genes that are associated with RNA processing (MED9/NFAT, NSUN2), proliferation, differentiation, hypoxia, or iron metabolism (ISG20, MIG6, HIG2, CA9, NDRG1), whereas none of the nine known iron-related genes showed significant differences between HCV and HH. CONCLUSION: Although high-density microarray technology is less suitable for routine liver diagnosis, its use in combination with prior in vitro selection is a powerful approach to identify candidate genes relevant for liver disease.",0
3803,19205034,Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization,"Peripheral CD8 T-cell tolerance can be generated outside lymphatic tissue in the liver, but the course of events leading to tolerogenic interaction of hepatic cell populations with circulating T-cells remain largely undefined. Here we demonstrate that preferential uptake of systemically circulating antigen by murine liver sinusoidal endothelial cells (LSECs), and not by other antigen-presenting cells in the liver or spleen, leads to cross-presentation on major histocompatibility complex (MHC) I molecules, which causes rapid antigen-specific na?ve CD8 T-cell retention in the liver but not in other organs. Using bone-marrow chimeras and a novel transgenic mouse model (Tie2-H-2K(b) mice) with endothelial cell-specific MHC I expression, we provide evidence that cross-presentation by organ-resident and radiation-resistant LSECs in vivo was both essential and sufficient to cause antigen-specific retention of na?ve CD8 T-cells under noninflammatory conditions. This was followed by sustained CD8 T-cell proliferation and expansion in vivo, but ultimately led to the development of T-cell tolerance. CONCLUSION: Our results show that cross-presentation of circulating antigens by LSECs caused antigen-specific retention of na?ve CD8 T-cells and identify antigen-specific T-cell adhesion as the first step in the induction of T-cell tolerance.",0
3804,19228618,Estimation of the warfarin dose with clinical and pharmacogenetic data,"BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.",0
3805,19228619,IDH1 and IDH2 mutations in gliomas,"BACKGROUND: A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). METHODS: We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. RESULTS: We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. CONCLUSIONS: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.",0
3806,19228620,Quality of life after late invasive therapy for occluded arteries,"BACKGROUND: The open-artery hypothesis postulates that late opening of an infarct-related artery after myocardial infarction will improve clinical outcomes. We evaluated the quality-of-life and economic outcomes associated with the use of this strategy. METHODS: We compared percutaneous coronary intervention (PCI) plus stenting with medical therapy alone in high-risk patients in stable condition who had a totally occluded infarct-related artery 3 to 28 days after myocardial infarction. In 951 patients (44% of those eligible), we assessed quality of life by means of a battery of tests that included two principal outcome measures, the Duke Activity Status Index (DASI) (which measures cardiac physical function on a scale from 0 to 58, with higher scores indicating better function) and the Medical Outcomes Study 36-Item Short-Form Mental Health Inventory 5 (which measures psychological well-being). Structured quality-of-life interviews were performed at baseline and at 4, 12, and 24 months. Costs of treatment were assessed for 458 of 469 patients in the United States (98%), and 2-year cost-effectiveness was estimated. RESULTS: At 4 months, the medical-therapy group, as compared with the PCI group, had a clinically marginal decrease of 3.4 points in the DASI score (P=0.007). At 1 and 2 years, the differences were smaller. No significant differences in psychological well-being were observed. For the 469 patients in the United States, cumulative 2-year costs were approximately $7,000 higher in the PCI group (P<0.001), and the quality-adjusted survival was marginally longer in the medical-therapy group. CONCLUSIONS: PCI was associated with a marginal advantage in cardiac physical function at 4 months but not thereafter. At 2 years, medical therapy remained significantly less expensive than routine PCI and was associated with marginally longer quality-adjusted survival. (ClinicalTrials.gov number, NCT00004562.)",0
3807,19246357,"Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates","BACKGROUND: The possible advantage for weight loss of a diet that emphasizes protein, fat, or carbohydrates has not been established, and there are few studies that extend beyond 1 year. METHODS: We randomly assigned 811 overweight adults to one of four diets; the targeted percentages of energy derived from fat, protein, and carbohydrates in the four diets were 20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%. The diets consisted of similar foods and met guidelines for cardiovascular health. The participants were offered group and individual instructional sessions for 2 years. The primary outcome was the change in body weight after 2 years in two-by-two factorial comparisons of low fat versus high fat and average protein versus high protein and in the comparison of highest and lowest carbohydrate content. RESULTS: At 6 months, participants assigned to each diet had lost an average of 6 kg, which represented 7% of their initial weight; they began to regain weight after 12 months. By 2 years, weight loss remained similar in those who were assigned to a diet with 15% protein and those assigned to a diet with 25% protein (3.0 and 3.6 kg, respectively); in those assigned to a diet with 20% fat and those assigned to a diet with 40% fat (3.3 kg for both groups); and in those assigned to a diet with 65% carbohydrates and those assigned to a diet with 35% carbohydrates (2.9 and 3.4 kg, respectively) (P>0.20 for all comparisons). Among the 80% of participants who completed the trial, the average weight loss was 4 kg; 14 to 15% of the participants had a reduction of at least 10% of their initial body weight. Satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar for all diets; attendance was strongly associated with weight loss (0.2 kg per session attended). The diets improved lipid-related risk factors and fasting insulin levels. CONCLUSIONS: Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize. (ClinicalTrials.gov number, NCT00072995.)",0
3808,19279339,A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy,"BACKGROUND: The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging because the clinical presentation is highly variable and genetic penetrance is often low. METHODS: To determine whether a change in the distribution of desmosomal proteins can be used as a sensitive and specific diagnostic test for ARVC, we performed immunohistochemical analysis of human myocardial samples. RESULTS: We first tested myocardium from 11 subjects with ARVC; of these samples, 8 had desmosomal gene mutations. We also tested myocardium obtained at autopsy from 10 subjects with no clinical or pathological evidence of heart disease as control samples. All ARVC samples but no control samples showed a marked reduction in immunoreactive signal levels for plakoglobin (also known as gamma-catenin), a protein that links adhesion molecules at the intercalated disk to the cytoskeleton. Other desmosomal proteins showed variable changes, but signal levels for the nondesmosomal adhesion molecule N-cadherin were normal in all subjects with ARVC. To determine whether a diminished plakoglobin signal level was specific for ARVC, we analyzed myocardium from 15 subjects with hypertrophic, dilated, or ischemic cardiomyopathies. In every sample, levels of N-cadherin and plakoglobin signals at junctions were indistinguishable from those in control samples. Finally, we performed blinded immunohistochemical analysis of heart-biopsy samples from the Johns Hopkins ARVC registry. We made the correct diagnosis in 10 of 11 subjects with definite ARVC on the basis of clinical criteria and correctly ruled out ARVC in 10 of 11 subjects without ARVC, for a sensitivity of 91%, a specificity of 82%, a positive predictive value of 83%, and a negative predictive value of 90%. The plakoglobin signal level was reduced diffusely in ARVC samples, including those obtained in the left ventricle and the interventricular septum. CONCLUSIONS: Routine immunohistochemical analysis of a conventional endomyocardial-biopsy sample appears to be a highly sensitive and specific diagnostic test for ARVC.",0
3809,19279341,"A nonsimultaneous, extended, altruistic-donor chain","""We report a chain of 10 kidney transplantations, initiated in July 2007 by a single altruistic donor (i.e., a donor without a designated recipient) and coordinated over a period of 8 months by two large paired-donation registries. These transplantations involved six transplantation centers in five states. In the case of five of the transplantations, the donors and their coregistered recipients underwent surgery simultaneously. In the other five cases, """"bridge donors"""" continued the chain as many as 5 months after the coregistered recipients in their own pairs had received transplants. This report of a chain of paired kidney donations, in which the transplantations were not necessarily performed simultaneously, illustrates the potential of this strategy.""",0
3810,19279342,Growth in the care of older patients by hospitalists in the United States,"BACKGROUND: National and population-based information on the increase in patient care by hospitalists in the United States is lacking. METHODS: Using a 5% sample of Medicare beneficiaries in 1995, 1997, 1999, and the period from 2001 through 2006, we identified 120,226 physicians in general internal medicine who were providing care to older patients in 5800 U.S. hospitals. We defined hospitalists as general internists who derived 90% or more of their Medicare claims for evaluation-and-management services from the care of hospitalized patients. We then calculated the percentage of all inpatient Medicare services provided by hospitalists and identified patient and hospital characteristics associated with the receipt of hospitalist services. RESULTS: The percentage of physicians in general internal medicine who were identified as hospitalists increased from 5.9% in 1995 to 19.0% in 2006, and the percentage of all claims for inpatient evaluation-and-management services by general internists that were attributed to hospitalists increased from 9.1% to 37.1% during this same period. Accompanying the increase in care by hospitalists was an increase in the percentage of all hospitalized Medicare patients who were treated by general internists (both hospitalists and traditional, non-hospital-based general internists), from 46.4% in 1995 to 61.0% in 2006. In a multilevel, multivariable analysis controlling for patient and hospital characteristics, the odds of receiving care from a hospitalist increased by 29.2% per year from 1997 through 2006. In 2006, there was marked geographic variation in the rates of care provided by hospitalists, with rates of more than 70% in some hospital-referral regions. CONCLUSIONS: These analyses of data from Medicare claims showed a substantial increase in the care of hospitalized patients by hospitalist physicians from 1995 to 2006.",0
3811,19280315,Giant primary liposarcoma of the chest,"Liposarcomas are the most common soft tissue sarcomas in adults, although liposarcomas of the chest are uncommon. We report two cases of giant liposarcoma in the mediastinum and chest wall, respectively. An 82-year-old man presented with a mass in the right upper mediastinum, as seen by computed tomography (CT). He had a past history of subcutaneous lipoma resection on his back (19 years previously). The patient underwent tumor resection with a right thoracotomy. A 58-year-old woman presented with an enlarging mass of the right lateral chest, involving the diaphragm and ribs, as seen by CT. She had a past history of subcutaneous lipoma resection of the right chest (18 years previously). The patient underwent an en bloc resection that included the tumor and a part of the right diaphragm and ribs. Histological examination of both patients' tumors revealed a well-differentiated liposarcoma, with no pathological relation to the previous lipoma resected in either case. ",0
3812,19280471,Review of advances in the thin layer chromatography of pesticides: 2006-2008,"Applications of thin layer chromatography and high performance thin layer chromatography for the separation, detection, qualitative and quantitative determination, and preparatire isolation of pesticides and their metabolites are reviewed for the period from July 1, 2006 to November 1, 2008. Analyses are described for a variety of sample types and pesticide classes. In addition to references on residue and formulation analysis, studies such as pesticide-structure relationships, identification and characterization of plant pesticides, metabolism, degradation, mobility, and lipophilicity are covered. Future prospects for pesticide thin layer chromatography are also considered. ",0
3813,19280622,Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-na?ve patients is rare through 5 years of therapy,"Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V +/- L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (> or = 300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (> or = 1 log(10) rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside-na?ve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD-refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5-year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved < 300 copies/mL HBV DNA subsequently developed ETVr. CONCLUSION: Long-term monitoring showed low rates of resistance in nucleoside-na?ve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance.",0
3814,19280654,Attitudes to anatomy dissection in an Irish medical school,"Many studies around the world have looked at the stresses placed on medical students by cadaveric dissection. Although these studies have linked the use of cadavers in medical teaching to stress, some investigations have suggested an association with severe psychological stress and even post-traumatic stress disorder. This study assessed the attitudes of medical and biomedical sciences students in an Irish medical school towards cadaveric dissection by recording, through a questionnaire, their perceptions and experience before initial exposure to dissection and subsequently examining their attitudes after the first dissection and after 9 weeks. Student attitudes towards the dissecting room remained consistently positive for the duration of the study with only a minority of respondents reporting negative symptoms. Pre-existing attitudes to the idea of dissection were unaffected by exposure and subsequent continuous experience of dissection. The majority of students in this study did not find the dissecting room experience stressful, and considered time spent in the dissecting room valuable. However, the proportion of students with negative experiences in the dissecting room was higher than has been reported in previous studies. Many respondents felt they could be better prepared for the dissecting room experience, indicating an increasing requirement for effective preparatory programmes. ",0
3815,19280979,Issues associated with evaluating the effectiveness of influenza vaccination by observational studies],"Vaccination against influenza is recommended for subjects at high risk of severe complications if infected with the influenza virus. The effectiveness of influenza vaccination among the elderly has been evaluated in many observational studies but only in a few randomized control trials. However, observational studies have various issues. First, the outcomes should be of high specificity with low nondifferential misclassification, such as laboratory-confirmed influenza or high fever. Differential misclassification between vaccinated and unvaccinated participants may also be a complicating factor due to behavioral differences in the habits of participants with regard to visiting physicians or in the diagnostic processes of physicians. Therefore, preventing differential misclassification by equally precise observation in compared groups seems to be more important than the specificity of outcomes, even if this can be achieved only by techniques with low-specificity outcomes. In observational studies of the elderly, vaccinated elderly individuals may be at low risk of influenza infection or death because they are health conscious. Such confounding may lead to an overestimation of the effectiveness of influenza vaccination. To minimize bias and to adjust for confounders, the effectiveness of influenza vaccination should be compared taking into account the following groups/indicators: influenza season and pre-season, well-matched season and mismatched season between vaccine and circulating viruses, severe season and mild season, high-specificity outcomes and low-specificity outcomes. Low effectiveness is to be expected with the latter of each pair. If no difference in effectiveness is observed between the two conditions in each pair, residual confounding may be present and the true underlying risk factors should be sought. For example, elderly individuals with impaired functional status in addition to chronic diseases may be less able to access vaccination. Hence it is necessary to evaluate the effectiveness of vaccination among such elderly individuals and promote vaccination in those people. ",0
3816,19281265,Why amantadine loses its function in influenza m2 mutants: MD simulations,"Molecular dynamics simulations of the drug-resistant M2 mutants, A30T, S31N, and L26I, were carried out to investigate the inhibition of M2 activity using amantadine (AMT). The closed and open channel conformations were examined via non- and triply protonated H37. For the nonprotonated state, these mutants exhibited zero water density in the conducting region, and AMT was still bound to the channel pore. Thus, water transport is totally suppressed, similar to the wild-type channel. In contrast, the triply protonated states of the mutants exhibited a different water density and AMT position. A30T and L26I both have a greater water density compared to the wild-type M2, while for the A30T system, AMT is no longer inside the pore. Hydrogen bonding between AMT and H37 crucial for the bioactivity is entirely lost in the open conformation. The elimination of this important interaction of these mutations is responsible for the lost of AMT's function in influenza A M2. This is different for the S31N mutant in which AMT was observed to locate at the pore opening region and bond with V27 instead of S31. ",0
3817,19281293,Dissection of the abdominal aorta. Current evidence and implications for treatment strategies: a review and meta-analysis of 92 patients,"To report meta-analyses of published clinical experiences with abdominal aortic dissection (AAD), a rare event that is accountable for up to 4% of all aortic dissections. All English-language articles regarding abdominal aortic dissection were identified using MEDLINE, Cochrane Library Central, and EMBASE databases. All identified articles were critically appraised for relevance and validity before data extraction and the meta-analyses were performed. Original data were identified on 92 AAD patients (62 men; mean age 59+/-16 years). Of all AADs, 73 (79%) were spontaneous, 13 (14%) traumatic, and 6 (7%) iatrogenic; the majority (68, 74%) were acute presentations. The mean dissection length was 59+/-16 mm. A pre-existing abdominal aortic aneurysm was present in 39 (42%). Hypertension was more frequently present in patients with spontaneous dissections compared to other dissection types (p = 0.001). Concurrent aortic aneurysms were more often associated with spontaneous dissections (p = 0.002). Aortic rupture occurred in 9 (10%) AADs. Open surgical repair was performed in 46 (50%), endovascular repair in 19 (21%), and conservative medical treatment in 27 (29%). In-hospital mortality was 4% overall [1 (2%) in the open repair group, 0 endovascular, and 2 (8%) conservative treatment]. Major complications occurred in 9% [6 (13%) in the open repair group, 1 (5%) in the endovascular group, and 1 (4%) in the conservative treatment cohort]. AAD is a rare event that appears to be associated with hypertension and pre-existing aneurysmal degeneration of the abdominal aorta. AAD patients are at considerable risk of in-hospital mortality and complications. Endovascular therapy appears to be associated with a relatively low risk of mortality or major complications compared to open repair and conservative treatment. ",0
3818,19281345,A routine HIV screening program in a South Carolina community health center in an area of low HIV prevalence,"""In 2006, the Centers for Disease Control and Prevention published guidelines for routine HIV screening in healthcare settings. Feasibility studies have demonstrated that screening is effective in high-volume, urban settings, but there are no data for smaller, more rural settings. The main objective of this study was to describe a routine HIV screening program at a community health center in South Carolina serving both urban and rural populations. Margaret J. Weston Community Health Center implemented routine HIV screening using rapid tests at its three locations on December 1, 2006. All individuals utilizing this center over the age of 13 years were screened for HIV unless they opted out. Nurses completed a survey about their experiences with the program. chi(2) tests and logistic regression models were used to analyze the data. In the first 8 months, among 985 eligible visits, 574 (58%) resulted in the patient being screened. The most common reason for refusal was """"doesn't think s/he is at risk."""" Acceptance rates differed significantly by location (p = 0.01), from 62% in the urban site to 47% in the rural site. Other significant predictors of accepting HIV testing were race/ethnicity, age, and method of payment. Three hundred twenty-four (58%) individuals who were tested reported no history of being previously tested for HIV infection. Participation in the screening program was perceived favorably by nurses. This pilot project in a South Carolina community health center demonstrates that implementation of routine HIV screening is acceptable in small healthcare settings and in smaller cities and rural communities in the South. """,0
3819,19281434,"Genetic variation associated with mammalian feeding in Culex pipiens from a West Nile virus epidemic region in Chicago, Illinois","Mosquitoes of the Culex pipiens complex are important vectors of West Nile virus in the United States. We examined the genetic variations of Cx. pipiens mosquitoes from Chicago, Illinois that were determined to be principally ornithophilic but exhibited a relatively higher inclination for mammalian hosts including humans. Microsatellite analysis of 10 polymorphic markers was performed on 346 engorged Cx. pipiens specimens with identified avian or mammalian blood meals. Our results indicated that there were no significant differences in allelic richness, the pattern of conformity to Hardy-Weinberg equilibrium, and linkage disequilibrium, nor was there overall genetic differentiation between specimens with avian- and mammalian-derived blood meals. However, Cx. pipiens form pipiens with mammalian- (including human-) derived blood meals had significantly higher ancestry (p < 0.001) and proportion of hybrids (p < 0.01) from the Cx. pipiens form molestus (population from New York City) than did those with avian-derived blood meals. By contrast, there were no significant differences in the ancestry (p > 0.05) and the proportion of hybrids (p > 0.05) from Cx. quinquefasciatus (population from Harris Country, Texas). No temporal genetic variation was detected in accordance with the observation that there was no shift in blood feeding from birds to mammals. The results of this study in conjunction with regional host-feeding behavior suggest that the probability of genetic ancestry from Cx. pipiens f. molestus may predispose mosquitoes to feed more readily on mammals; however, the genetic mechanisms are unknown. ",0
3820,19281567,In vitro neutralization of tumor necrosis factor-alpha during Chlamydia pneumoniae infection impairs dendritic cells maturation/function and increases chlamydial progeny,"Dendritic cells (DCs) produce tumor necrosis factor (TNF)-alpha upon infection and contribute in various ways to defense against pathogenic agents. Several biological agents have been designed to inhibit TNF-alpha activity. However, the use of these inhibitors has been associated with an increased rate of certain opportunistic infections. To study the effect of TNF-alpha inhibition, human monocyte-derived DCs were infected with Chlamydia pneumoniae. TNF-alpha was neutralized by adalimumab, a human anti-TNF-alpha monoclonal antibody. Chlamydiae induced the maturation of DC as determined by flow cytometry and quantitative real-time PCR. However, DC maturation was impaired in the presence of adalimumab. Moreover, neutralization of TNF-alpha resulted in a significant increase of infectious progeny, 16S rRNA gene copy number and development of larger inclusions consisting of different stages of chlamydial development. Additionally, chlamydial infection induced secretion of cytokines/chemokines, which were downregulated by adalimumab treatment. Our data reveal an indirect effect on maturation of DC by C. pneumoniae and that maturation is crucial for the restriction of chlamydial development. The results also demonstrate an increase in infectious progeny after TNF-alpha inhibition, suggesting a contribution of TNF-alpha produced by DCs to chlamydial growth arrest. These data suggest a possible mechanism by which TNF-alpha inhibition enhances the risk of intracellular infections. ",0
3821,19281586,Survey of surgical skills of RANZCOG trainees,"In Australia, the Integrated Training Program (ITP) of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) offers training in obstetrics and gynaecology. There is anecdotal concern among trainees and Fellows that the surgical component of training is inadequate, with new specialists lacking the confidence and competence to perform many 'standard' surgical procedures. These concerns have not previously been quantified in Australia and New Zealand. To determine trainees' subjective competence and confidence with surgical procedures and trainees' satisfaction with their surgical training. All 430 active RANZCOG trainees and 108 Fellows elevated within the previous two years were invited to complete a self-administered questionnaire (65% response rate), which assessed details of procedures performed and confidence to perform them; satisfaction with the surgical training; and perceived teaching ability of the supervising consultants. Those in ITP year 6 rated their confidence high (>or= 4 of 5) for procedures performed very frequently, but lower for other procedures. No procedure regarding the management of complications reached a confidence score of >or= 4. Teaching abilities were rated best for obstetric procedures, with 54% rating their consultants' teaching ability as 'excellent'; but for laparoscopic procedures and procedures dealing with complications, 21.2% and 23.4% of respondents rated their consultants' teaching ability as 'poor', respectively. Advanced trainees lacked confidence in a range of surgical procedures; and possible weaker areas were identified in the teaching experience of trainers. These limitations must be addressed by medical educators and training program coordinators. ",0
3822,19282107,An investigation on the distribution of eight hazardous heavy metals in the suburban farmland of China,"Understanding spatial variability of hazardous soil heavy metals is an important precondition for suitably monitoring and evaluating eco-environment quality in the primary agricultural production zone. One hundred topsoils were sampled from the urban-rural transition zone in Taihang Piedmont Plain, China. The contents of eight heavy metals Cu, Zn, Cr, Ni, Pb, Cd, Hg and As were tested for each soil sample, and their spatial patterns were analyzed by the semivariogram approach of geostatistics and geographical information system (GIS) technology. Results showed that Cd concentration exceeded its background level. The local pollution from Cd attributed to the anthropogenic influence. The concentrations of eight hazardous heavy metals are relatively lower than the critical values of the national soil quality standard. The correlation distance of soil heavy metals ranged from 3.28 to 11.63 km, with the eight heavy metals having moderate spatial dependence. Cu, Cr, Ni, Pb and As are associated with and controlled by parent material. The results are helpful for improving agricultural and forest ecosystem in the arid and semiarid region. ",0
3823,19282376,Functional role of J domain of cysteine string protein in Ca2+-dependent secretion from acinar cells,"""The heat shock protein 70 family members Hsc70 and Hsp70 are known to play a protective role against the onset of experimental pancreatitis, yet their molecular function in acini is unclear. Cysteine string protein (CSP-alpha) is a zymogen granule (ZG) membrane protein characterized by an NH(2)-terminal """"J domain"""" and a central palmitoylated string of cysteine residues. The J domain functions as a cochaperone by modulating the activity of Hsc70/Hsp70 family members. A role for CSP-alpha in regulating digestive enzyme exocytosis from pancreas was investigated by introducing CSP-alpha truncations into isolated acini following their permeabilization with Perfringolysin O. Incubation of acini with CSP-alpha(1-82), containing the J domain, significantly augmented Ca(2+)-stimulated amylase secretion. Effects of CSP-alpha(1-82) were concentration dependent, with a maximum 80% increase occurring at 200 microg/ml of protein. Although CSP-alpha(1-82) had no effects on basal secretion measured in the presence of < or =10 nM free Ca(2+), it did significantly augment GTP-gammaS-induced secretion under basal Ca(2+) conditions by approximately 25%. Mutation of the J domain to abolish its cochaperone activity failed to augment Ca(2+)-stimulated secretion, implicating the CSP-alpha/Hsc70 cochaperone system as a regulatory component of the secretory pathway. CSP-alpha physically associates with vesicle-associated membrane protein 8 (VAMP 8) on ZGs, and the CSP-alpha-VAMP 8 interaction was dependent on amino acids 83-112 of CSP-alpha. Immunofluorescence analysis of acinar lobules or purified ZGs confirmed the CSP-alpha colocalization with VAMP 8. These data establish a role for CSP-alpha in regulating digestive enzyme secretion and suggest that CSP-alpha and Hsc70 modulate specific soluble N-ethylmaleimide-sensitive attachment receptor interactions necessary for exocytosis. """,0
3824,19282541,Exploring family physician stress: helpful strategies,"To explore the nature of professional stress and the strategies used by family physicians to deal with this stress. Qualitative study. Kitchener-Waterloo, Ont. Ten key-informant family physicians. In-depth interviews were conducted with key informants. A total of 40 key informants were identified, based on selected criteria; 24 provided consent. The potential participants were rank-ordered for interviews to provide maximum variation in age, sex, and years in practice. Interviews were conducted, audiotaped, transcribed verbatim, and analyzed until thematic saturation was reached, as determined through an iterative process. This occurred after 10 in-depth interviews. Immersion and crystallization techniques were used. The participants described professional stresses and strategies at the personal, occupational, and health care system levels. Personal stressors included personality traits and the need to balance family and career, which were countered by biological, psychological, social, and spiritual strategies. Occupational stressors included challenging patients, high workload, time limitations, competency issues, challenges of documentation and practice management, and changing roles within the workplace. Occupational stressors were countered by strategies such as setting limits, participating in continuing medical education, soliciting support from colleagues and staff, making use of teams, improving patient-physician relationships, exploring new forms of remuneration, and scheduling appropriately. Stressors affecting the wider health care system included limited resources, imposed rules and regulations, lack of support from specialists, feeling undervalued, and financial concerns. Family physicians face a multitude of challenges at personal, occupational, and health care system levels. A systems approach provides a new framework in which proactive strategies can augment more than one level of a system and, in contrast, reactive strategies can have negative inputs for different system levels. ",0
3825,19282564,Desmoid tumors: experience of 32 cases and review of the literature,"Desmoids are infiltrative, locally destructive, soft tissue tumors. Although they do not metastasize, the incidence of local recurrence is quite high. Present study aimed at reporting the 10-year experience of 32 desmoid cases and reviewing some facts with symptoms, investigation, and treatment of the disease. Thirty two cases of desmoid tumors were reviewed over a 10-year span. Surgical resection and adjuvant radiotherapy were the treatments of choice whenever histological margins were positive. Multiparous women in reproductive age were the most commonly afflicted. The commonest site of presentation was the abdominal wall. Ninety one percent (20/22) were infraumbilical. The tumors were found in the rectus sheath in 14 patients (64%) and were laterally situated in 8 patients (36%). Local infiltration was found in six patients and the urinary bladder was most commonly involved (3/6). Locally recurrent desmoids were seen in eight patients (25%). In our experience, 25% of the desmoid tumors (8/32) were recurrent and postoperative radiotherapy did not seem to influence the local recurrence rate. The most important predictor for recurrence was tumors of > 5 cm. ",0
3826,19283016,Variability among Populations of Meloidogyne arenaria,"Variability in reproduction and pathogenicity of 12 populations of Meloidogyne arenaria race 1 was evaluated on Florunner peanut, Centennial soybean, Rutgers tomato, G70, K326, and Mc944 tobacco, and Carolina Cayenne, Mississippi Nemaheart, and Santanka pepper. Differences among M. arenaria populations in rates of egg production 45 days after inoculation were observed for all cultivars except Santanka pepper. Differences among populations in dry top weights or fresh root weights were recorded on all cultivars. Numbers of nematode eggs produced on Florunner peanut varied from 3,419 to 11,593/g fresh root weight. On resistant tobacco cultivars (G70 and K326), one nematode population produced high numbers of eggs (12,042 and 6,499/g fresh root weight on G70 and K326, respectively), whereas the other populations produced low numbers of eggs (less than 500 eggs/g fresh root weight on both cultivars). Two variant M. arenaria race 1 populations were identified by factor analysis of reproductive rates on all nine cultivars. Differences m reproduction and pathogenicity observed among populations would affect the design of sustainable management systems for M. arenaria. ",0
3827,19283411,Determinants and implications of cancer patients' psychosocial needs,"""Cancer patients often experience distress. However, the majority of newly diagnosed patients gradually adapt to the crisis. When symptoms of distress and anxiety persist over months, patients require psychosocial support. The aim of the present study was to determine the proportion of cancer patients who indicate the need for psychosocial support and to identify sociodemographic, psychological and illness-related factors predicting the need for psychosocial support in a German sample. The cross-sectional retrospective study was administered to 710 cancer patients who had been inpatients at the University Hospital of Cologne. The response rate was 49.5%. Patients suffering from bronchial, oesophageal, colorectal, breast, prostate and skin cancer participated in the study. The severity of depressive symptoms was assessed using the German version of the Major Depression Inventory. The level of anxiety was assessed with the state subscale of the German version of the State-Trait Anxiety Inventory. To measure the functional aspects of health-related quality of life, the scales """"physical functioning"""", """"role functioning"""", """"emotional functioning"""", """"cognitive functioning"""" and """"role functioning"""" of the European Organisation for Research and Treatment of Cancer QLQ-C30 Questionnaire (EORTC QLQ-C30) were used. Of the cancer patients, 18.9% indicate an unmet need for psychosocial support and 9.5% are actually using psychosocial services. In a multiple logistic regression, significant indicators of the need for psychosocial support are gender [p = 0.014; standardised effect coefficient (sc) = 1.615] and emotional functioning (p < 0.001; sc = 1.533). The estimated model has a specificity of 92.2% and a sensitivity of 54.0%. Almost a third of the cancer patient population indicates an unmet need for psychosocial support or is actually using psychosocial services. Emotional functioning is a central predictor of the requirement for psychosocial support. Women are emotionally more affected than men and need more psychosocial support. The prognostic validity of the severity of depression and anxiety is limited. """,0
3828,19283771,Oxidative demethylenation and subsequent glucuronidation are the major metabolic pathways of berberine in rats,"Present study was designed to explore roles of metabolic clearance in the disposition of berberine (BBR) in rats, with a focus on oxidative metabolism and subsequent glucuronidation. Plasma from rats after intravenous administration of BBR was collected to identify and quantify BBR and its major metabolites. The major circulating metabolites of BBR were oxidative metabolites M1 (via demethylation) and M2 (via demethylenation) and their corresponding glucuronides, with M2-glucuronide approximately 24-fold higher than M1-glucuronide. Incubations with rat liver microsomes were conducted to examine formation kinetics of two oxidative metabolites-M1 and M2, and depletion kinetics of M1 and M2, leading to the formation of glucuronide conjugates. Efforts were also made to examine roles of key CYPs and UGTs isoforms responsible for BBR metabolism using known chemical inhibitors and/or substrates. In vitro, the formation of M1 and M2 were comparable and multiple CYP enzymes were involved. In contrast, the glucuronidation of M2 was much faster than that of M1. Inhibition studies using well-characterized UGT substrates suggested both M1 and M2 could be glucuronidated by UGT1A1 and UGT2B1 while M2 glucuronidation was favored by UGT1A1. In summary, oxidative demethylenation and the subsequent glucuronidation were the major metabolic pathways of BBR in rats. ",0
3829,19283953,HCV in incarcerated populations: an analysis of gender and criminality on risk,"While studies have explored the prevalence and correlates for hepatitis C (HCV) infection in substance-using and incarcerated populations these studies have not examined the attributes of criminal histories for those with HCV infection. This study examines the HCV infection rate as it relates to criminal risk factors using baseline data from a randomized trial of re-entering offenders and examines how these risk factors vary by gender. The HCV-positive population had a longer amount of time in confinement (105 vs. 61 months) than those who tested negative. HCV positive men were more likely to currently be receiving drug treatment than women. Criminal risk was positively associated with HCV infection while controlling for major risk factors (OR 1.25,95% CI: 1.07, 1.46), suggesting that the relationship was not spurious. While criminologists tend to examine risk relative to public safety threats, it appears that the public health needs equally require attention. Policy issues are examined regarding how services can be delivered to treat those with HCV infections within the correctional system and address criminal risk factors. ",0
3830,19284041,Client assessment of animal health care delivery in peri-urban Ghana,"The study used a questionnaire to assess the delivery of veterinary services as perceived by users in four peri-urban areas in Ghana. Eight hundred and eighty nine respondents were interviewed: 10.7% were cattle farmers, 27.4% were small ruminant farmers, 14.2% were pig farmers, 45.1% were poultry farmers and 2.6% reared various animals on a part-time basis. Most of the animal health needs were either met by the owners (50.4%) or by veterinarians (41.6%). Veterinarians were mainly consulted for advice on animal health, disease diagnosis and treatments. Most respondents (65.7%) had no difficulty in getting help from government services. Higher proportions of interviewees perceived effectiveness, efficiency, service quality, staff attitude and technical competence as 'good' or 'very good'. However, equity and accessibility were thought to be 'fair' to 'very poor', and the cost of drugs was considered expensive' or 'very expensive'. The study identified strengths and weaknesses in the delivery of animal health services in peri-urban Ghana and this information could be used as a basis to improve the overall quality of these services in the future. ",0
3831,19284454,Case of cutaneous Scedosporium apiospermum infection successfully treated with voriconazole,"We report a case of cutaneous infection due to Scedosporium apiospermum in a 75-year-old immunocompromised male patient who had received long-term corticosteroid and immunosuppressant therapy for the treatment of nephrotic syndrome. The patient came to our department complaining of erythema with a number of pustules on the dorsal surface of the right hand. S. apiospermum was identified from a culture taken from the pus. After unsuccessful treatment with topical ketoconazole, oral itraconazole and oral terbinafine, the lesion quickly resolved with the daily administration of 400 mg voriconazole. No recurrence was observed despite discontinuation of voriconazole due to drug-induced hepatitis. Voriconazole holds out the promise of an effective treatment for invasive Scedosporium infection. ",0
3832,19284586,Synthesis of rhamnolipid biosurfactant and mode of hexadecane uptake by Pseudomonas species,"""Microorganisms have devised ways by which they increase the bioavailability of many water immiscible substrates whose degradation rates are limited by their low water solubility. Hexadecane is one such water immiscible hydrocarbon substrate which forms an important constituent of oil. One major mechanism employed by hydrocarbon degrading organisms to utilize such substrates is the production of biosurfactants. However, much of the overall mechanism by which such organisms utilize hydrocarbon substrate still remains a mystery. With an aim to gain more insight into hydrocarbon uptake mechanism, an efficient biosurfactant producing and n-hexadecane utilizing Pseudomonas sp was isolated from oil contaminated soil which was found to produce rhamnolipid type of biosurfactant containing a total of 13 congeners. Biosurfactant action brought about the dispersion of hexadecane to droplets smaller than 0.22 mum increasing the availability of the hydrocarbon to the degrading organism. Involvement of biosurfactant was further confirmed by electron microscopic studies. Biosurfactant formed an emulsion with hexadecane thereby facilitating increased contact between hydrocarbon and the degrading bacteria. Interestingly, it was observed that """"internalization"""" of """"biosurfactant layered hydrocarbon droplet"""" was taking place suggesting a mechanism similar in appearance to active pinocytosis, a fact not earlier visually reported in bacterial systems for hydrocarbon uptake. This study throws more light on the uptake mechanism of hydrocarbon by Pseudomonas aeruginosa. We report here a new and exciting line of research for hydrocarbon uptake involving internalization of biosurfactant covered hydrocarbon inside cell for subsequent breakdown. """,0
3833,19284621,Regulation of callose synthase activity in situ in alamethicin-permeabilized Arabidopsis and tobacco suspension cells,"The cell wall component callose is mainly synthesized at certain developmental stages and after wounding or pathogen attack. Callose synthases are membrane-bound enzymes that have been relatively well characterized in vitro using isolated membrane fractions or purified enzyme. However, little is known about their functional properties in situ, under conditions when the cell wall is intact. To allow in situ investigations of the regulation of callose synthesis, cell suspensions of Arabidopsis thaliana (Col-0), and tobacco (BY-2), were permeabilized with the channel-forming peptide alamethicin. Nucleic acid-binding dyes and marker enzymes demonstrated alamethicin permeabilization of plasma membrane, mitochondria and plastids, also allowing callose synthase measurements. In the presence of alamethicin, Ca2+ addition was required for callose synthase activity, and the activity was further stimulated by Mg2+ Cells pretreated with oryzalin to destabilize the microtubules prior to alamethicin permeabilization showed significantly lower callose synthase activity as compared to non-treated cells. As judged by aniline blue staining, the callose formed was deposited both at the cell walls joining adjacent cells and at discrete punctate locations earlier described as half plasmodesmata on the outer walls. This pattern was unaffected by oryzalin pretreatment, showing a quantitative rather than a qualitative effect of polymerized tubulin on callose synthase activity. No callose was deposited unless alamethicin, Ca2+ and UDP-glucose were present. Tubulin and callose synthase were furthermore part of the same plasma membrane protein complex, as judged by two-dimensional blue native SDS-PAGE. Alamethicin permeabilization allowed determination of callose synthase regulation and tubulin interaction in the natural crowded cellular environment and under conditions where contacts between the cell wall, the plasma membrane and cytoskeletal macromolecules remained. The results also suggest that alamethicin permeabilization induces a defense response mimicking the natural physical separation of cells (for example when intercellulars are formed), during which plasmodesmata are transiently left open. ",0
3834,19284749,"Novel 2- and 4-substituted 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor","4-Arylamino and 2- cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A(3) adenosine receptor (AR). In addition to allosteric modulation of the maximum functional efficacy (in [(35)S]GTPgammaS G protein binding assay) of the A(3)AR agonist Cl-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at the 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A(3)AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A(3)AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A(3)AR activity and improved selectivity in comparison to inhibition of orthosteric binding. ",0
3835,19284958,Dose-response patterns of Radix Glycyrrhizae in Shanghan Lun],"In order to explore the dose-response patterns of Gancao (Radix Glycyrrhizae) in Shanghan Lun (Treatise on Febrile Diseases), all prescriptions containing Gancao in Shanghan Lun were analyzed by frequency and hierarchical clustering analysis. The doses of Gancao used in Shanghan Lun ranged from six zhu (Chinese unit, and one zhu is equal to 0.65 g) to four liang (Chinese unit, and one liang is equal to 15.625 g). Doses of one, two, three or four liang were commonly used. One liang Gancao as juvantia was usually matched with Mahuang (Herba Ephedrae), Xingren (Semen Armeniacae) and Guizhi (Ramulus Cinnamomi) for restricting the excessive diaphoresis of Mahuang. Two liang Gancao was often matched with some couple drugs, such as Guizhi and Shaoyao (Radix Paeoniae), Shigao (Gypsum Fibrosum) and Zhimu (Rhizoma Anemarrhenae), Fuzi (Radix Aconiti Lateralis) and Ganjiang (Rhizoma Zingiberis), for warming yang to supplement qi, nourishing yin, detoxifying Fuzi, and preventing qi impairment from heat evil. Three liang Gancao was mainly matched with Banxia (Rhizoma Pinelliae) or Renshen (Radix Ginseng) for treating middle energizer emesis. Four liang Gancao was matched with Ganjiang or tonifying herbs for invigorating vital qi and relieving spasm in deficiency syndromes with contraction, palpitation or diarrhea. Gancao is used for treating many syndromes in Shanghan Lun. It is frequently used to treat excess or heat syndromes with one or two liang in a dose and deficiency or cold syndromes with three or four liang in a dose. ",0
3836,19285097,CYP1A1 and CYP1A2 expression: comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines,"""Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how """"human-like"""" can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1_CYP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+)_severe-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs. """,0
3837,19285609,Plasma parathyroid hormone level and prevalent cardiovascular disease in CKD stages 3 and 4: an analysis from the Kidney Early Evaluation Program (KEEP),"Cardiovascular disease (CVD) is the most common cause of death in patients with chronic kidney disease (CKD). Secondary hyperparathyroidism is common in patients with CKD, and its relationship to CVD is not well defined. This analysis aims to assess whether serum intact parathyroid hormone (PTH) level is an independent risk factor for CVD in patients with CKD stages 3 and 4. In this cross-sectional study, medical history surveys, including CVD events, were collected from 4,472 patients with stages 3 and 4 CKD identified by the National Kidney Foundation Kidney Early Evaluation Program (KEEP), which included blood pressure measurement and laboratory testing. Age, hemoglobin level, estimated glomerular filtration rate, serum phosphorus level, and serum calcium level were evaluated as continuous variables, and plasma PTH levels, by tertile: less than 35, 35 to 70, and greater than 70 pg/mL. Multivariate logistic regression was used to estimate odds ratios (ORs) of CVD predictor variables. Mean age was 68.3 +/- 11.8 years. Of the study population, 68% were women, 69% were white, 6% were current smokers, 45% were obese, 46% had diabetes, and 83% had hypertension. A history of CVD was present for 1,972 (44.1%), and plasma PTH level greater than 70 pg/mL, for 2,239 (50.1%). Multivariate logistic regression showed ORs for CVD events increasing with age (OR, 1.03; P < 0.001), male sex (OR, 1.51; P < 0.001), diabetes (OR, 1.73; P < 0.001), hypertension (OR, 1.43; P < 0.001), and intact PTH level greater than 70 pg/mL (OR, 1.51; P < 0.001; reference, <35 pg/mL). PTH level greater than 70 pg/mL is independently associated with CVD events in patients with CKD stages 3 and 4. No association was observed between serum phosphorus or calcium level and CVD events. These findings provide support for intact PTH testing, along with testing for other indicators of CKD mineral and bone disorders, at earlier CKD stages. ",0
3838,19285617,Quilty effect correlates with biopsy-proven acute cellular rejection but does not predict transplanted heart coronary artery vasculopathy,"The appropriate therapy after orthotopic heart transplantation (OHT) is determined by the results of endomyocardial biopsies (EMBs). The Quilty effect (QE) is a recognized cause of discrepancies in EMB grading, but its clinical implications remain unclear. In this study we assess the correlation of the QE with biopsy-proven acute cellular rejection (AR) and coronary artery vasculopathy (CAV). We reassessed 5,361 EMB samples, obtained from 429 patients, based on QE occurrence and its impact on EMB score. Next, we divided all patients with at least 1 year of follow-up into two groups: a QE(+) group (n = 202, 58.7% of sample, 172 males/30 females, 44.8 +/- 12 years of age) and a QE(-) group (n = 142, 41.3% of sample, 124 males/18 females, 45.4 +/- 12 years of age), and compared AR and CAV occurrences. The QE was observed in 669 EMBs (12.5%), and at least 1 EMB with QE was found among the 231 patients (53.8%). The initial QE occurrence took place during the first 3 months after OHT in 68% of QE(+) patients, and >1 year post-OHT in 13% of patients. The average EMB score was significantly higher in QE(+) biopsies. A comparison of the two groups revealed a significantly higher number of AR episodes and number of patients with at least one episode of AR in QE(+) patients. There was no significant difference in number of CAV occurrences between groups. The QE seems to be a marker of the same increased immune system activity that can lead to AR. A relationship between QE and CAV was not supported by the present results. ",0
3839,19285819,Quantification of synovial and erosive changes in rheumatoid arthritis with ultrasound--revisited,"Synovitis is a predictive factor of irreversible changes in the joints, tendons, and ligaments in patients with rheumatoid arthritis (RA). Therefore, the early demonstration of reversible, pre-erosive inflammatory features to diagnose RA, the monitoring of disease activity, and the response to therapy are of great importance. Technical developments in ultrasound now allow the quantification of synovitis and erosions, and enable the assessment and follow-up of disease activity. However, both the subjective and objective quantification techniques are associated with different problems. This review article highlights the advantages and disadvantages of sonographic quantification, and revisits the somewhat controversial positions apparent in the current literature. Familiarity with the imaging findings and the scoring systems used to characterize erosive changes are prerequisites for considerably improving the detection and monitoring of synovitis and erosions. The role of ultrasound in the diagnostic approach to RA, particularly in the quantification of synovial and erosive changes, will be explored and the current literature will be reviewed. ",0
3840,19285888,Recurrent isolated sixth nerve palsy after consecutive annual influenza vaccinations in a child,Recurrent sixth nerve palsy in children in the absence of structural or other neurological abnormality is a rare occurrence. We report the case of recurrent isolated sixth (abducens) nerve palsy after consecutive annual influenza vaccinations in an otherwise-healthy 2-year-old boy. Investigations including magnetic resonance imaging of the brain and orbits after each episode failed to reveal any abnormality. The temporal relation to the immunizations supports but does not prove that the influenza immunization regimen was responsible. ,0
3841,19285987,Affinity maturation of a humanized rat antibody for anti-RAGE therapy: comprehensive mutagenesis reveals a high level of mutational plasticity both inside and outside the complementarity-determining regions,"Antibodies that neutralize RAGE (receptor for advanced glycation end products)-ligand interactions have potential therapeutic applications in both acute and chronic diseases. We generated XT-M4, a rat anti-RAGE monoclonal antibody that has in vivo efficacy in an acute sepsis model. This antibody was subsequently humanized. To improve the affinity of this antibody for the treatment of chronic indications, we used random and targeted mutagenesis strategies in combination with ribosome and phage-display technologies, respectively, to generate libraries of XT-M4 variants. We identified a panel of single-chain Fv antibody fragments (scFv's) that was improved up to 110-fold in a homogeneous time-resolved fluorescence competition assay against parental XT-M4 immunoglobulin G (IgG). After reformatting to bivalent scFv-Fc fusions and IgGs, we observed similar gains in potency in the same assay. Further analysis of binding kinetics as IgG revealed multiple variants with subnanomolar apparent affinity that was dictated primarily by improvements in the off-rate. All variants also had improved binding to cell surface-expressed human RAGE, and all retained, or had improved, apparent affinity for mouse RAGE. F100bL in V(H) (variable region of the heavy chain) complementarity-determining region 3 (CDR3) was one of a number of key mutations that correlated with affinity improvements and was independently identified by both mutagenesis strategies. Random mutagenesis coupled with ribosome display and high-throughput screening revealed an unexpectedly high level of mutational plasticity across the whole length of the humanized scFv, suggesting greater scope for structural optimization outside of the primary antigen-combining site defined by V(H) CDR3 and V(kappa) CDR3. In summary, our comprehensive mutagenesis approach not only achieved the desired affinity maturation of XT-M4 but also defined multiple mutational hotspots across the antibody sequence, provided an insight into the specificity-determining residues of the antibody paratope, and identified additional sites within the CDR loops where human germ-line amino acids may be introduced without affecting function. ",0
3842,19286379,Synthesis and anti-inflammatory activity of the major metabolites of imrecoxib,"We have developed a novel and moderately selective COX-2 inhibitor, imrecoxib, as a new anti-inflammatory drug. We describe herein the preparation of the major metabolites M2 and M4 of imrecoxib, as well as the in vitro and in vivo activities of the two compounds. The results showed that both M2 and M4 are potential COXs inhibitors with a moderate COX-1/COX-2 selectivity, and their anti-inflammatory activity in vivo was equal to or slightly higher than the clinical celecoxib. ",0
3843,19286516,Metastatic uterine adenocarcinoma and hepatic lipomatosis in a llama (Lama glama),"A 6-year-old, female llama (Lama glama) presented with progressive anorexia and ascites. Postmortem examination revealed an infiltrative uterine adenocarcinoma with widespread metastases. The neoplasm completely replaced and infiltrated the myometrium of the uterine body and cervix and metastasized largely to the serosal surfaces of the peritoneal cavity. Histopathology identified a highly invasive growth of neoplastic cells in solid packets or tubular arrangements and marked fibroplasia. No bovine or llama papillomavirus DNA was detected intralesionally by polymerase chain reaction. ",0
3844,19286791,High rate of N2 fixation by East Siberian cryophilic soil bacteria as determined by measuring acetylene reduction in nitrogen-poor medium solidified with gellan gum,"For evaluating N(2) fixation of diazotrophic bacteria, nitrogen-poor liquid media supplemented with at least 0.5% sugar and 0.2% agar are widely used for acetylene reduction assays. In such a soft gel medium, however, many N(2)-fixing soil bacteria generally show only trace acetylene reduction activity. Here, we report that use of a N(2) fixation medium solidified with gellan gum instead of agar promoted growth of some gellan-preferring soil bacteria. In a soft gel medium solidified with 0.3% gellan gum under appropriate culture conditions, bacterial microbiota from boreal forest bed soils and some free-living N(2)-fixing soil bacteria isolated from the microbiota exhibited 10- to 200-fold-higher acetylene reduction than those cultured in 0.2% agar medium. To determine the N(2) fixation-activating mechanism of gellan gum medium, qualitative differences in the colony-forming bacterial components from tested soil microbiota were investigated in plate cultures solidified with either agar or gellan gum for use with modified Winogradsky's medium. On 1.5% agar plates, apparently cryophilic bacterial microbiota showed strictly distinguishable microbiota according to the depth of soil in samples from an eastern Siberian Taiga forest bed. Some pure cultures of proteobacteria, such as Pseudomonas fluorescens and Burkholderia xenovorans, showed remarkable acetylene reduction. On plates solidified with 1.0% gellan gum, some soil bacteria, including Luteibacter sp., Janthinobacterium sp., Paenibacillus sp., and Arthrobacter sp., uniquely grew that had not grown in the presence of the same inoculants on agar plates. In contrast, Pseudomonas spp. and Burkholderia spp. were apparent only as minor colonies on the gellan gum plates. Moreover, only gellan gum plates allowed some bacteria, particularly those isolated from the shallow organic soil layer, to actively swarm. In consequence, gellan gum is a useful gel matrix to bring out growth potential capabilities of many soil diazotrophs and their consortia in communities of soil bacteria. ",0
3845,19287094,The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells,"Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38-CD19+) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones. ",0
3846,19287732,Effect of Age on Body Wall Cuticle Morphology of Heterodera schachtii Schmidt females,"Fine structure of the body wall cuticle of Heterodera schachtii is compared with respect to age and body region of the female. The cuticle is more complex than previously reported. In newly molted females only layers A, B, and C are present, but 4 weeks after the final molt a thin D layer is present between the midbody and base of the cone. This D layer is absent in the cone of H. schachtii, regardless of age. As females age, an additional layer E is produced and includes zones E and E. Zone El apparently is unique to H. schachtii, whereas E is likely to be homologous with a similar layer in Atalodera. In the cone of old females (ca. 8 weeks after the final molt) of H. schachtii, the two zones become irregular in shape and comprise bullae. The presence of a thin D layer in Heterodera strengthens the previous hypothesis of a single ancestor of cyst nematodes. ",0
3847,19287847,First reported case of infective endocarditis caused by community-acquired methicillin-resistant Staphylococcus aureus not associated with healthcare contact in Brazil,We report here the first case of endocarditis due to CA-MRSA not associated with healthcare contact in Brazil in Brazil. A previously healthy patient presented with history of endocarditis following a traumatic wound infection. Patient had multiple positive blood cultures within 72 h of admission and met modified Duke's criterion for infective endocarditis. The isolate was typed as Staphylococcal cassette chromosome (SCC) mec type IV and was positive for presence of Panton-Valentine leukocidin (PVL). Increased incidence of CA-MRSA endocarditis is a challenge for the internist to choose the best empirical therapy. Several authors have suggested an empirical therapy with both a beta-lactam and an anti-MRSA agent for serious S. aureus infections. Our patient was treated with Vancomycin and made complete recovery in 3 months. ,0
3848,19287902,FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia,"Fanconi anemia is a rare hereditary disease showing genetic heterogeneity due to a variety of mutations in genes involved in DNA repair pathways, which may lead to different clinical manifestations. Phenotypic variability makes diagnosis difficult based only on clinical manifestations, therefore laboratory tests are necessary. New advances in molecular pathogenesis of this disease led researchers to develop a diagnostic test based on Western blot for FANCD2. The objective of the present study was to determine the efficacy of this method for the diagnosis of 84 Brazilian patients with Fanconi anemia, all of whom tested positive for the diepoxybutane test, and 98 healthy controls. The FANCD2 monoubiquitinated isoform (FANCDS+/FANCD2L-) was not detected in 77 patients (91.7%). In 2 patients (2.4%), there was an absence of both the monoubiquitinated and the non-ubiquitinated proteins (FANCD2S-/FANCD2L-) and 5 patients (5.9%) had both isoforms (FANCD2S+/FANCD2L+). This last phenotype suggests downstream subtypes or mosaicism. All controls were diepoxybutane negative and were also negative on the FANCD2 Western blot. The Western blot for FANCD2 presented a sensitivity of 94% (79/84) and specificity of 100% (98/98). This method was confirmed as an efficient approach to screen Brazilian patients with deleterious mutations on FANCD2 (FANCD2S-/FANCD2L-) or other upstream genes of the FA/BRCA pathway (FANCDS+/FANCD2L-), to confirm the chromosome breakage test and to classify patients according to the level of FA/BRCA pathway defects. However, patients showing both FANCD2 isoforms (FANCD2S+/FANCD2L+) require additional studies to confirm mutations on downstream Fanconi anemia genes or the presence of mosaicism. ",0
3849,19287904,Mechanical cardiac remodeling and new-onset atrial fibrillation in long-term follow-up of subjects with chronic Chagas' disease,"Atrial fibrillation (AF) affects subjects with Chagas' disease and is an indicator of poor prognosis. We investigated clinical, echocardiographic and electrocardiographic variables of Chagas' disease in a long-term longitudinal study as predictors of a new-onset AF episode lasting >24 h, nonfatal embolic stroke and cardiac death. Fifty adult outpatients (34 to 74 years old, 62% females) staged according to the Los Andes classification were enrolled. During a follow-up of (mean +/- SD) 84.2 +/- 39.0 months, 9 subjects developed AF (incidence: 3.3 +/- 1.0%/year), 5 had nonfatal stroke (incidence: 1.3 +/- 1.0%/year), and nine died (mortality rate: 2.3 +/- 0.8%/year). The progression rate of left ventricular mass and left ventricular ejection fraction was significantly greater in subjects who experienced AF (16.4 +/- 20.0 g/year and -8.6 +/- 7.6%/year, respectively) than in those who did not (8.2 +/- 8.4 g/year; P = 0.03, and -3.0 +/- 2.5%/year; P = 0.04, respectively). In univariate analysis, left atrial diameter >/=3.2 cm (P = 0.002), pulmonary arterial hypertension (P = 0.035), frequent premature supraventricular and ventricular contraction counts/24 h (P = 0.005 and P = 0.007, respectively), ventricular couplets/24 h (P = 0.002), and ventricular tachycardia (P = 0.004) were long-term predictors of AF. P-wave signal-averaged ECG revealed a limited long-term predictive value for AF. In chronic Chagas' disease, large left atrial diameter, pulmonary arterial hypertension, frequent supraventricular and ventricular premature beats, and ventricular tachycardia are long-term predictors of AF. The rate of left ventricular mass enlargement and systolic function deterioration impact AF incidence in this population. ",0
3850,19288537,Simultaneous measurement of 13C- and 15N-isotopic enrichments of threonine by mass spectrometry,"Under conditions of high isotopic dilution, e.g. in a tracer study, the ability to determine accurately and quantitatively small variations in isotopic enrichments of differently labelled chemical compounds (e.g. (13)C and (15)N in threonine) in a single run by gas chromatography/mass spectrometry (GC/MS) is desirable but remains a technological challenge. Here, we report a new, rapid and simple GC/MS method for simultaneously measuring the isotopic enrichments of doubly labelled threonine ([U(13)C] and (15)N) with isotopic enrichment lower than 1.5 Molar Percent Excess (MPE). The long-term reproducibility measured was around 0.09 MPE for both tracers (throughout a 6 week period). The intra-day repeatability was lower than 0.05 and 0.06 MPE for [U(13)C]-Thr and (15)N-Thr, respectively. To calculate both isotopic enrichments, two modes of calculations were used: one based on work by Rosenblatt et al. in 1992 and the other one using a matrix approach. Both methods gave similar results (ANOVA, P >0.05) with close precision for each mode of calculation. The GC/MS method was then used to investigate the differential utilization of threonine in different organs according to its route of administration in minipigs after administration of both tracers. In plasma samples, the lowest isotopic enrichment measured between two successive time points was at 0.01 and 0.02 MPE for [U(13)C]-Thr and (15)N-Thr, respectively. Moreover, the accuracy of GC/MS (13)C-isotopic enrichment measured was validated by analyzing the same plasma samples by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). Statistical analysis showed that both techniques gave the same results (ANOVA, P >0.05). This new GC/MS method offers the possibility to measure (13)C- and (15)N-isotopic enrichments with higher throughput, and using a lower amount of sample, than using GC/C/IRMS. ",0
3851,19288545,A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency,"Deficiency of X-linked inhibitor of apoptosis (XIAP), caused by BIRC4 gene mutations, is the second known cause of X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency that often presents with life-threatening hemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis of the known genetic causes of HLH, including XIAP deficiency, facilitates the initiation of life-saving treatment and preparation for allogeneic hematopoietic cell transplantation (HCT). Until now, a rapid screening test for XIAP deficiency has not been available. To develop a flow cytometric screening test for XIAP deficiency, we first used lymphoblastic cell lines generated from controls and patients with BIRC4 mutations to identify two commercially available antibodies specific for native intracellular XIAP. Next, we used these antibodies to study control whole blood leukocyte XIAP expression. We then studied XIAP expression in leukocytes from patients with XLP due to BIRC4 mutations, maternal carriers, and patients following HCT. XIAP was expressed by the majority of all whole blood nucleated cells in normal controls. In contrast, XIAP was absent or decreased in all lymphocyte subsets, monocytes and granulocytes from four unrelated patients with XLP due to BIRC4 mutations. Bimodal distribution of XIAP expression was evident in two maternal carriers, with significant skewing toward cells expressing normal XIAP. Bimodal distribution was also observed in a patient following HCT. Flow cytometric analysis of intracellular XIAP provides a rapid screening test for XLP due to XIAP deficiency. It also allows carrier detection and can be used to monitor donor versus recipient reconstitution following HCT. ",0
3852,19288569,Patterns of treatment for early stage breast cancers at the M. D. Anderson Cancer Center from 1997 to 2004,"The objectives of this study were to examine the patterns of use for adjuvant therapy and the changes in surgical practice for patients with early stage breast cancer and to describe how recent large clinical trial results impacted the patterns of care at The University of Texas M. D. Anderson Cancer Center (MDACC). The study included 5486 women who were diagnosed with stage I through IIIA breast cancer between 1997 and 2004 and received their treatment at MDACC. A chi-square trend test and multivariate logistic regression model were used to assess changes in treatment patterns over time. Among lymph node-positive patients, the use of anthracycline plus taxane chemotherapy increased from 17% in 1997 to 81% in 2004 (P < .001). Meanwhile, the use of anthracyclines without taxanes dropped from 76% to 20% (P < .001) between 1997 and 2000. For postmenopausal patients who received endocrine therapy, the use of tamoxifen was replaced increasingly by the use of aromatase inhibitors (from 100% on tamoxifen in 1997 to 14% in 2004; P < .001). The percentage of women who underwent initial sentinel lymph node biopsy increased significantly during the period from 1997 to 2004 (from 1.8% to 69.7%, respectively, among patients who underwent mastectomy; and from 18.1% to 87.1%, respectively, among patients who underwent breast-conserving surgery; P < .001). The results from this study suggested that key findings from adjuvant therapy and surgical procedures from large clinical trials often prompt immediate changes in the patient care practices of research hospitals like MDACC. ",0
3853,19289312,Effects of the Emergency Trauma Training Course on the confidence of final-year medical students dealing with trauma patients,"Trauma is an important issue that has been neglected in the training of medical students. This study evaluated the effects of the Emergency Trauma Training Course (ETTC), after completion of standard medical training, on seventh-year medical students. The ETTC was designed in Taiwan by the Taiwan Society of Emergency Medicine to train physicians and registered nurses who care for trauma patients in the emergency department (ED). We implemented the course for our medical students' internship. One hundred and fifty-one participants were divided into three groups: Group A included 36 medical students before they entered their internship in hospital; Group B included 41 medical students who had received 6 months of internship training in hospital; and Group C included 74 ED nurses. Group C was used to test Cronbach's alpha coefficient of the questionnaire. After the training course, the participants had a final examination and filled out a questionnaire about the training course and their levels of self-confidence. There were no differences in scores between the medical students in Groups A and B (p = 0.064). Using repeated measures analysis of variance, we found that confidence before training was low, with no difference between Groups A and B. Confidence improved after training, but there was still no significant difference between the groups (p = 0.875). However, there were significant differences between confidence levels before and after the training course (p < 0.001). Therefore, although inhospital training for 6 months failed to increase confidence, the confidence of final year medical students after completion of their training was improved by the ETTC. This indicates that the ETTC could increase the confidence of participants. This is the first evaluation of the implementation of the ETTC for final-year medical students in Taiwan. Based on our results, we highly recommend that this training course be taught to final-year medical students before they practice in hospital. ",0
3854,19289922,A review of primary hyperparathyroidism,"Primary hyperparathyroidism is the inappropriate secretion of parathyroid hormone and is the most common cause of hypercalcemia. Most patients with primary hyperparathyroidism are asymptomatic, and the disease is more common in postmenopausal women than in older men. Primary hyperparathyroidism can be treated with medication and long-term monitoring; however, surgical removal of the affected parathyroid gland is the definitive treatment. Rarely occurring, parathyroid crisis must be treated promptly to prevent deleterious effects to the patient. The patient experiencing parathyroid crisis benefits from the infusion nurse's knowledge of drug and fluid therapies and expertise in peripheral access. ",0
3855,19290016,Allogeneic stromal cell implantation in brain tissue leads to robust microglial activation,"Although adult and embryonic stem cell-based therapy for central nervous system (CNS) injury is being developed worldwide, less attention is given to the immunological aspects of allogeneic cell implantation in the CNS. The latter is of major importance because, from a practical point of view, future stem cell-based therapy for CNS injury will likely be performed using well-characterised allogeneic stem cell populations. In this study, we aimed to further describe the immunological mechanism leading to rejection of allogeneic bone marrow-derived stromal cells (BM-SC) after implantation in murine CNS. For this, we first investigated the impact of autologous and allogeneic BM-SC on microglia activation in vitro. Although the results indicate that both autologous and allogeneic BM-SC do not activate microglia themselves in vitro, they also do not inhibit activation of microglia after exogenous stimuli in vitro. Next, we investigated the impact of allogeneic BM-SC on microglia activation in vivo. In contrast to the in vitro observations, microglia become highly activated in vivo after implantation of allogeneic BM-SC in the CNS of immune-competent mice. Moreover, our results suggest that microglia, rather than T-cells, are the major contributors to allograft rejection in the CNS. ",0
3856,19290116,In Vivo Growth of Romanomermis culicivorax: Biochemical Changes During Parasitism,"Biochemical analyses of total protein, lipid, carbohydrate, DNA, amino acid, and length, width, and dry weight measurements are reported for different stages of Romanomermis culicivorax cultured in the mosquito, Culex pipiens. The Bradford technique for assaying total protein was the most sensitive and reliable biochemical technique tested for assaying in vivo growth of R. culicivorax. Increases in total protein, lipid, carbohydrate, and dry weight during growth from preparasite to postparasite were greater than 6,900-fold for females and 2,300-fold for males. DNA increased 650-fold and 233-fold during development to female and male postparasites, respectively. The proportions of amino acids for preparasites were significantly different (P </= 0.01) from female and male postparasites for all amino acids tested, except methionine and tyrosine. Female and male postparasites were similar in protein, lipid, carbohydrate, DNA, and most amino acid proportions, but were significantly different in relative concentrations of serine, glycine, and alanine (P </= 0.01). Preliminary results suggest that the use of amino acid ratios from female postparasites improves the in vitro culture performance of R. culicivorax. ",0
3857,19290531,Erythromycin establishes early oral feeding in neonates operated for congenital intestinal atresias,"The recovery of gastrointestinal function following surgery for congenital intestinal atresias can be prolonged and may increase morbidity and hospital stay. This study was conducted to investigate the prokinetic effect of erythromycin in neonates undergoing surgery for small bowel atresias. A randomized-controlled trial was conducted at the Departments of Paediatrics and Paediatric Surgery, Military Hospital, Rawalpindi, Pakistan, from January to December 2007 to study the prokinetic effect of erythromycin (3 mg/kg per dose 4 times daily). Thirty consecutive neonates undergoing primary anastomosis for congenital small bowel atresias were randomly divided into two groups: group I (erythromycin) and group II (control). The groups were similar in terms of gestational age, sex, mode of delivery, birth weight and types of atresias. Postoperative recovery of intestinal functions was measured as time taken to achieve full enteral feed (150 ml/kg per 24 h), duration of total parenteral nutrition (TPN) and hospital stay. Neonates receiving oral erythromycin achieved full enteral feeding early (13.07 vs. 16.13 days) required TPN for shorter duration (10.53 vs. 13.73 days) and their hospital stay was less (16.2 vs. 18.0 days) as compared to the neonates in the control group who did not receive any erythromycin. The differences were statistically significant. The administration of oral erythromycin following primary anastomosis for small intestinal atresias results in early recovery of intestinal function, fewer days on TPN and a trend for shorter hospital stay. ",0
3858,19290601,Targeted N-linked glycosylation analysis of H5N1 influenza hemagglutinin by selective sample preparation and liquid chromatography/tandem mass spectrometry,"Using liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis of deglycosylated and intact glycopeptides from tryptic digests of whole influenza virus, we determined that the six predicted N-linked glycosylation sites within the N-terminal ectodomain of hemagglutinin (HA) from three selected H5N1 strains are occupied. The use of selective sample preparation strategies, including solid-phase extraction (SPE) of glycopeptides via hydrazide capture chemistry as well as hydrophilic interaction liquid chromatography (HILIC), sufficiently reduced sample complexity to allow determination of occupied glycosylation sites. The specific amino acid sequence of the tryptic glycopeptides for the identified sites varied slightly among strains, but the overall locations of the occupied glycosylation sites were conserved in the protein sequence. We used this knowledge of glycosylation site occupation to examine the glycans attached to these occupied sites on HA for a reassortant H5N1 strain grown in embryonated chicken eggs. By applying mass spectrometry-based methodologies for examining glycosylation to the study of influenza virus proteins, we can better understand the effect that this post-translational modification has upon the virulence and antigenicity of emerging strains. ",0
3859,19290665,Imaging and quantification of isotachophoresis zones using nonfocusing fluorescent tracers,"We present a novel method for visualizing isotachophoresis (ITP) zones. We introduce negligibly small concentrations of a fluorophore that is not focused by isotachophoresis. This nonfocusing tracer (NFT) migrates through multiple isotachophoresis zones. As it enters each zone, the NFT concentration adapts to the local electric field in each zone. ITP zones can then be visualized with a point detector or camera. The method can be used to detect, identify, and quantify unknown analyte zones and can visualize complex and even transient electrophoresis processes. This visualization technique is particularly suited to microfluidic and laboratory-on-a-chip applications, as typical fluorescence microscopes and charge-coupled device (CCD) cameras can provide high-resolution spatiotemporal data. We present a theoretical description, a methodology for identifying analytes, and experimental validation. We also visualize and analyze a complex, transient DNA ITP preconcentration and separation. ",0
3860,19290999,Internet and World Wide Web-based tools for neuropathology practice and education,"The Internet and the World Wide Web (www) serve as a source of information and a communication network. Together they form a so-called web or network that allows for transmission and dissemination of information in unprecedented speed, volume and detail. This article presents an overview of the current status of neuropathology content on the www. As well as considering the Internet as a resource for neuropathology practice, education and research, we also address the issue of quality assurance when evaluating Internet and www content. Four major categories of websites (archival, broker, news and blog) are discussed and resources relevant to neuropathology of each type are highlighted. We believe that our report and similar attempts can provide an opportunity to discuss appropriate and effective use of the Internet by the neuropathology community. ",0
3861,19291086,Should edentulous patients be constrained to removable complete dentures? The use of dental implants to improve the quality of life for edentulous patients,"Nowadays, there is some speculation among dental educators that the need for complete dentures will significantly decrease in the future and that training in their provision should be removed from the dental curriculum. To sensitise the reader to the functional shortcomings of complete denture therapy in the edentulous patient and present restorative options including implants to improve edentulous quality of life in these patients. Information retrieval followed a systematic approach using PubMed. English articles published from 1964 to 2008, in which the masticatory performance of patients with implant-supported dentures was assessed by objective methods and compared with performance with conventional dentures, were included. National epidemiological survey data suggested that the adult population in need of one or two complete dentures will increase from 35.4 million adults in 2000 to 37.9 million adults in 2020. Clinical studies have showed that the ratings of general satisfaction were significantly better in the patients treated with implant overdentures post-delivery compared with the complete denture users. In addition, the implant group gave significantly higher ratings on comfort, stability and ability to chew. Furthermore, patients who received mandibular implant overdentures had significantly fewer oral health-related quality of life problems than did the conventional group. Implant-supported dentures including either complete overdentures or a hybrid prosthesis significantly improve the quality of life for edentulous patients compared with conventional removable complete dentures. Therefore, the contemporary dental practitioner should consider other options as well as conventional removable complete dentures to restore edentulous patients. ",0
3862,19291427,Development of a RT real-time PCR for the detection and quantification of human rhinoviruses,"Human Rhinoviruses (HRV) are the most common viral agents, being responsible for upper as well as lower respiratory tract infections. Evidence demonstrating that HRV disease is not exclusively limited to the upper airways and may cause lower respiratory complications, together with the frequency of HRV infections and the increasing number of immunocompromised patients underline the need for including HRV in virological diagnostics of acute lower respiratory tract illness. This article describes the development and optimization of a reverse transcription (RT) real-time PCR assay for quantification of HRV RNA in clinical samples. Efficiency, sensitivity, specificity, inter- and intra-assay variability, and dynamic range have been determined. Subsequently, the assay has been validated on bronchoalveolar lavage (BAL) specimens obtained from immunocompetent and immunocompromised patients. ",0
3863,19291746,Hypertrophic scarring of the neck following ablative fractional carbon dioxide laser resurfacing,"Ablative fractional carbon dioxide (CO(2)) laser treatments have gained popularity due to their efficacy, shortened downtime, and decreased potential for scarring in comparison to traditional ablative CO(2) resurfacing. To date, scarring with fractional CO(2) lasers has not been reported. Five patients treated with the same fractional CO(2) laser technology for photodamage of the neck were referred to our practices 1-3 months after treatment. Each patient developed scarring. Of the five cases, two are discussed in detail. The first was treated under general anesthesia on the face and anterior neck at a pulse energy of 30 mJ (859 microm depth) with 25% coverage. Eleven days after treatment, three non-healing areas along the horizontal skin folds of the anterior neck were noted. At 2 weeks after CO(2) ablative fractional resurfacing, these areas had become thickened. These raised areas were treated with a non-ablative fractionated 1,550 nm laser to modify the wound healing milieu. One week later, distinct firm pale papules in linear arrays with mild hypopigmentation had developed along involved neck skin folds. Skin biopsy was performed. For the second patient, the neck was treated at a pulse energy of 20 mJ (630 microm depth) with 30% coverage of the exposed skin, with a total treatment energy of 5.0 kJ. Minimal crusting was noted on the neck throughout the initial healing phase of 2 weeks. She then experienced tightness on her neck. Approximately 3 weeks after treatment, she developed multiple vertical and horizontal hypertrophic scars (HS). Histopathology for the first case confirmed the presence of a hypertrophic scar. The papules in this case completely resolved with mild residual hypopigmentation after treatment with topical corticosteroids. HS failed to resolve in the second case to date after 1 month. As with traditional ablative CO(2) laser resurfacing, HS is a potential complication of ablative fractional CO(2) laser resurfacing, particularly on the neck. With early diagnosis and appropriate treatment HS of neck skin may be reversible. We urge caution when treating the neck with this device and close attention to wound care in the post-operative period. ",0
3864,19292302,Tibial tubercle fragmentation: a clue to simultaneous patellar ligament avulsion in pediatric tibial tubercle fractures,"Simultaneous avulsions of the tibial tubercle and patellar ligament have been reported, but are rare. We present an 11-year-old boy who was initially diagnosed with a Type IIIA tibial tubercle avulsion fracture after falling off of his bicycle. Intraoperatively, following exposure and fixation of the tibial tubercle fragment, knee range of motion under live fluoroscopy revealed a stationary patella with no tension in the patellar ligament. The incision was extended and a distal avulsion of the patellar ligament from the tibial tubercle was identified, with a small flap of tibial tubercle periosteum remaining attached. Transosseous suture fixation of the avulsed periosteal flap was achieved with 2 No. 5 ethibond sutures placed through connecting drill holes. Postoperatively, the patient was placed in a long leg cast with the knee in extension for 6 weeks. The injury to healed and the patient returned to full activities, although he required 2 courses of physical therapy and 4.5 months to regain full range of motion. Preoperative diagnosis of simultaneous tibial tubercle fracture and patellar ligament avulsion can be difficult. Palpation of the patellar ligament for gaps may not be possible due to a large knee effusion. Most patients do not tolerate quadriceps testing on examination and do not have patella alta on radiographs. In retrospect, a clue to this diagnosis in our patient was the preoperative radiographic finding of multiple calcified fragments below the patella. The calcified fragments likely represent the avulsed tibial tubercle periosteum attached to the distal patellar ligament. In addition, the large tibial tubercle fragment is separated and rotated superiorly, a finding that was also noted in two other similar case reports. ",0
3865,19292456,Thermodynamics of multivalent carbohydrate-lectin cross-linking interactions: importance of entropy in the bind and jump mechanism,"The high affinity (K(d) = 0.2 nM) of the soybean agglutinin (SBA), a tetrameric GalNAc specific lectin, for a modified form of porcine submaxillary mucin, a linear glycoprotein, with a molecular mass of approximately 10(6) Da and approximately 2300 GalNAcalpha1-O-Ser/Thr residues (Tn-PSM) has been ascribed to an internal diffusion mechanism that involves binding and jumping of the lectin from GalNAc to GalNAc residue of the mucin [Dam, T. K., et al. (2007) J. Biol. Chem. 282, 28256-28263]. Hill plot analysis of the raw ITC data shows increasing negative cooperativity, which correlates with an increasing number of lectin-mucin cross-linking interactions and decreasing favorable binding entropies. However, the affinity of bound SBA for other Tn-PSM molecules during cross-linking is much higher than that of free SBA for GalNAcalpha1-O-Ser, a monovalent analogue. The high affinity of bound SBA for GalNAc residues on other Tn-PSM molecules appears to be due to the favorable entropy of binding associated with the internal diffusion mechanism. Furthermore, the increasing negative cooperativity of SBA binding to Tn-PSM correlates with a decreasing level of internal diffusion of the lectin on the mucin as cross-linking occurs. These findings indicate the importance of the internal diffusion mechanism in generating large, favorable entropies of binding that drive lectin-mucin cross-linking interactions. The results are important for understanding the energetics of lectin-mucin cross-linking interactions that are associated with biological signaling on the surface of cells and the role of the internal diffusion mechanism in ligand-biopolymer interactions in general. ",0
3866,19292475,Inhibitory effects of grape seed procyanidins on foam cell formation in vitro,"Human and animal studies have demonstrated that procyanidin-rich diets reduce the risk of cardiovascular diseases and atherosclerosis. Some beneficial effects have been attributed to the well-known antioxidant activity of procyanidins. This study investigated another potential corrective role of procyanidins in cholesterol flux and inflammation in macrophage-derived foam cells. RAW 264.7 macrophages were cultured with moderately oxidized LDL (oxLDL), minimally oxidized LDL (moxLDL), or LPS (0.5 microg/mL) and oxLDL (LPS + oxLDL) to induce foam cells. Then, cells were treated with procyanidins derived from grape seed (PE, 45 microg/mL) for the last 12 h of incubation with the different lipoproteins (25 microg/mL). After lipid extraction, it was determined that total and esterified cholesterol and triglyceride accumulations in foam cells were increased by lipoprotein treatment but reduced by PE incubation. To asses the effect of PE on gene expression, the relative mRNA levels of CD36, ABCA1, iNOS, COX-2, and IkappaBalpha were determined by RT-PCR. It was shown that PE reduced the oxLDL scavenger receptor expression (CD36) and enhanced ATP-binding cassette A1 (ABCA1) expression, a key regulator of macrophage cholesterol efflux. PE also down-regulated inflammatory-related genes such as inducible nitric oxide synthase (iNOS) and kappa beta inhibitor-alpha (IkappaBalpha) without modifying COX-2 expression. In conclusion, evidence is provided that procyanidins may attenuate the development of foam cell formation by reducing cholesterol accumulation and modulating the expression of key genes in cholesterol flux and inflammation. ",0
3867,19292654,Antioxidative potentiality of a Kampo formulation measured by an ex vivo study,"Antioxidants in herbs or crude herbal formulations are well known. The antioxidative effect of a Kampo formulation, Bofu-tsusho-san (BTS), was studied in healthy human subjects by means of an ex vivo study of the lag time of low-density lipoprotein (LDL) oxidation. Eighteen (18) healthy young males (22 +/- 3 years old), who were screened out from 38 males by strict screening tests of serum lipids, were randomly assigned into 3 groups (active BTS 7.5 g/day, placebo of BTS 7.5 g/day, and vitamin E 500 mg and vitamin C 1000 mg/day). The BTS groups were assigned in a double-blind manner. These 3 groups took each test drug, and the antioxidant effects of their plasma were estimated by assessing the susceptibility of LDL to oxidation induced by 2-2'-azobis (4-methoxy-2,4-dimethyl-valeronitrile) via an ex vivo study. The antioxidative activity was evaluated by measuring the lag time of the production of conjugated dienes. Along with lag time, plasma ephedrine, plasma baicalin, serum lipid peroxide, serum free fatty acids (nonesterified fatty acids), urinary 8(OH)dG/creatinine, blood pressure, and heart rate were monitored for 24 hours. Although lag time of the placebo group revealed no significant changes, the active BTS group showed some tendency of prolonged plasma lag time (p = 0.08). However, urinary 8(OH)dG/creatinine and serum lipid peroxide did not show no significant changes. The physiologic changes were compatible with the pharmacokinetic results of ephedrine and its sympathomimetic effect in the active BTS group. Although the systemic antioxidative effects of BTS have not been ascertained, the antioxidative potentiality on LDL oxidation was suggested by the ex vivo study. ",0
3868,19292787,Oral vs. bath PUVA using 8-methoxypsoralen for chronic palmoplantar eczema,"Both oral and bath PUVA with 8-methoxypsoralen (8-MOP) have been shown to be effective in the treatment of chronic palmoplantar eczema. However, most studies were retrospective and did not include longer follow-up periods. To compare the therapeutic efficacy, tolerability and duration of remission after oral vs. bath PUVA using 8-MOP in patients with chronic palmoplantar eczema. Twenty-nine patients were randomly allocated to treatment with oral or bath PUVA. Treatment was given thrice weekly for a maximum of 20 weeks. The primary outcome measure was the improvement in eczema score at the end of treatment. After clearing patients were followed up until relapse or up to 40 months. Overall, both PUVA modalities appeared comparably effective. However, after stratifying according to eczema type, significant differences in therapeutic outcome in general as well as in response to the two regimes were found. Dyshidrotic eczema responded better to both treatments (P=0.048) and remained longer in remission than hyperkeratotic eczema. Hyperkeratotic eczema cleared significantly better with oral than with bath PUVA (P=0.03). Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema. ",0
3869,19292803,Fiberoptic ductoscopy-guided intraductal biopsy improve the diagnosis of nipple discharge,"Fiberoptic ductoscopy (FDS)-guided intraductal biopsy is a minimally invasive technique developed to obtain pathologic diagnoses for patients with spontaneous nipple discharge. We performed biopsies of 53 intraductal lesions from March 2006 to April 2007 followed by surgical microdochectomy. FDS-guided intraductal biopsy was shown to be a minimally invasive, safe, and convenient technique with a high ability (90.6%) to get adequate samples. Twenty-seven solitary papillomas, 12 multiple intraductal papilloma, five ductal hyperplasia, three ductal carcinoma in situ, and one invasive ductal carcinoma were diagnosed. Compared with conventional microdochectomy, FDS-guided intraductal biopsy can significantly increase the detection rate of solitary papilloma (40.7% versus 92.6%, p < 0.05). It should be a routine procedure after intraductal lesion found by screening FDS. Since it would underestimate all multiple intraductal papilloma and some (50%) cancer, microdochectomy is inevitable if biopsies show atypical ductal hyperplasia. ",0
3870,19292865,Kinetics of inhibition of acetylcholinesterase in the presence of acetonitrile,"The hydrolysis of acetylthiocholine by acetylcholinesterase from Electrophorus electricus was investigated in the presence of the inhibitors tacrine, gallamine and compound 1. The interaction of the enzyme with the substrate and the inhibitors was characterized by the parameters K(I), alpha', b or beta, K(m) and V(max), which were determined directly and simultaneously from nonlinear Michaelis-Menten plots. Tacrine was shown to act as a mixed-type inhibitor with a strong noncompetitive component (alpha' approximately 1) and to completely block deacylation of the acyl-enzyme. In contrast, acetylcholinesterase inhibition by gallamine followed the 'steric blockade hypothesis', i.e. only substrate association to as well as substrate/product dissociation from the active site were reduced in the presence of the inhibitor. The relative efficiency of the acetylcholinesterase-gallamine complex for the catalysis of substrate conversion was determined to be 1.7-25% of that of the free enzyme. Substrate hydrolysis and the inhibition of acetylcholinesterase were also investigated in the presence of 6% acetonitrile, and a competitive pseudo-inhibition was observed for acetonitrile (K(I) = 0.25 m). The interaction of acetylcholinesterase with acetonitrile and tacrine or gallamine resulted in a seven- to 10-fold increase in the K(I) values, whereas the principal mode of inhibition was not affected by the organic solvent. The determination of the inhibitory parameters of compound 1 in the presence of acetonitrile revealed that the substance acts as a hyperbolic mixed-type inhibitor of acetylcholinesterase. The complex formed by the enzyme and the inhibitor still catalysed product formation with 8.7-9.6% relative efficiency. ",0
3871,19293059,Physical activity in prevention and treatment of diabetes],"""Effects and mechanisms of a single bout of physical load and of the regular exercise (training) on the carbohydrate and fat metabolism are reviewed. During exercise and in the following couple of hours sugar utilization improves, """"activity functions like insulin"""". Proper exercise contributes to using up the fat reserves, and slimmer body, fat reduction can be maintained by the combination of exercise and diet-control. Instructions in """"exercise for everybody"""" and particularly for both type diabetics are detailed. In prevention of cardio-metabolic pathologies the most important measure were avoiding the overweight state by rational alimentation and regular physical activity. """,0
3872,19293461,Gene therapy in large animal models of muscular dystrophy,"The muscular dystrophies are a group of genetically and phenotypically heterogeneously inherited diseases characterized by progressive muscle wasting, which can lead to premature death in severe forms such as Duchenne muscular dystrophy (DMD). In many cases they are caused by the absence of proteins that are critical components of the dystrophin-glycoprotein complex, which links the cytoskeleton and the basal lamina. There is no effective treatment for these disorders at present, but several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. We review these strategies, which include the use of stem cells of different tissue origins, gene replacement therapies mediated by various viral vectors, and transcript repair treatments using exon skipping strategies. We comment on their advantages and on limitations that must be overcome before successful application to human patients. Our focus is on studies in a clinically relevant large canine model of DMD. Recent advances in the field suggest that effective therapies for muscular dystrophies are on the horizon. Because of the complex nature of these diseases, it may be necessary to combine multiple approaches to achieve a successful treatment. ",0
3873,19293481,Concurrent chemoradiotherapy in the management of advanced nasopharyngeal carcinoma: current status,"Nasopharyngeal carcinoma (NPC) differs from other head and neck cancers in its epidemiology, natural behavior and, particularly, in the therapeutic considerations. In addition, NPC is responsive to both chemotherapy and radiotherapy (RT). This article reviews the recent advances in concurrent chemoradiotherapy (CCRT) for NPC. To identify the studies mentioned in this article, we searched the MEDLINE database, and abstracts of selected conference proceedings (up to 2008) using the key words 'nasopharyngeal carcinoma,' 'advanced,' 'radiotherapy,' and 'concurrent chemotherapy.' Eight randomized clinical trials of CCRT in NPC have been reported in the English literature. These trials can be classified according to the timing of the chemotherapy, which was given either concurrently with RT (in three trials) or concurrently with radiotherapy and adjuvant after the and of concurrent chemoradiotherapy (in five trials). There have also been four meta-analyses addressing the value and scheduling of chemotherapy in the curative treatment of NPC. This article reviews the recent literature and the pertinent issues concerning the role of CCRT in the treatment of patients with locoregionally advanced NPC. ",0
3874,19293599,Suppression subtractive hybridization analysis of gene expression during late kidney development identifies the developmentally regulated gene rPEA3,"While early kidney development has been studied exhaustively, the later stages of nephrogenesis that occur after birth in the rodent are relatively poorly understood. To gain insight into this process, we detected the alterations in gene expression in rat kidney at two postnatal stages, P0 (0 day after birth), the time at which nephrogensis is still active, and P21 (21 days after birth), when nephrogenesis is complete. Sprague-Dawley rats were mated, and appearance of a vaginal plug was designated as E0. Kidneys were dissected from embryos at E13, E15, E17 and E19, and from postnatal days P0, P7, P14, P21 and adult rats. Suppression subtractive hybridization (SSH) analysis was performed and highly expressed genes were evaluated as molecular markers by real-time reverse transcription-polymerase chain reaction (RT-PCR), in situ hybridization, immunofluorescence, and Western blot. Several differentially expressed genes were identified, including rPEA3, a member of the PEA3 subfamily of Ets domain transcription factors. Real time RT-PCR analysis revealed that rPEA3 exhibited dynamic developmental regulation, with high levels of expression from embryonic day E15 until birth, and declining levels thereafter. By in situ hybridization, rPEA3 mRNA was detected in the ureteric bud (UB) and surrounding metanephric mesenchyme of the kidneys from E15 until birth, but was undetectable in mature kidneys. Double-immunofluorescence staining showed that both rPEA3 and WT1 expressed in the condensed mesenchymal cells at E15 and E17; and later from E19 to P7, both expressed in the epithelial cells of ureteric bud and their branches. These studies provide compelling evidence that SSH is an effective method for identifying genes that are regulated during renal development, and suggest that the newly identified gene rPEA3 may play an important role in kidney development and differentiation. ",0
3875,19293743,Willingness of health care personnel to work in a disaster: an integrative review of the literature,"Effective hospital surge response in disaster depends largely on an adequate number of personnel to provide care. Studies appearing since 1991 indicate health care personnel may not be willing to work in all disaster situations-and if so, this could degrade surge response. A systematic review of the literature was conducted to determine the state of the evidence concerning the willingness of health care personnel to work in disaster. The aims of this review are to collate and assess the literature concerning willingness of health care personnel to work during a disaster, to identify gaps in the literature as areas for future investigation, and to facilitate evidence-based disaster planning. Twenty-seven studies met inclusion criteria (25 quantitative and 2 qualitative studies). The current evidence indicates there may be certain factors related to willingness to work (or lack of willingness) in disaster including the type of disaster, concern for family, and concerns about personal safety. Barriers to willingness to work have been identified including pet care needs and the lack of personal protective equipment. This review describes the state of an emerging area of science. These findings have significant implications for community and organizational emergency planning and policymaking in an environment defined by limited resources. ",0
3876,19293775,HSV-mediated transfer of artemin overcomes myelin inhibition to improve outcome after spinal cord injury,"Artemin is a neurotrophic factor of the glial cell line-derived neurotrophic factor (GDNF) family of ligands that acts through the GDNF family receptor alpha3 (GFRalpha3)/ret receptor found predominantly on sensory and sympathetic neurons. In order to explore the potential utility of artemin to improve functional outcome after spinal cord injury (SCI), we constructed a nonreplicating herpes simplex virus (HSV)-based vector to express artemin (QHArt). We found that QHArt efficiently transfects spinal cord neurons to produce artemin. Transgene-mediated artemin supported the extension of neurites by primary dorsal root ganglion neurons in culture, and allowed those cells to overcome myelin inhibition of neurite extension through activation of protein kinase A (PKA) to phosphorylate cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and increase expression of arginase I. Intraspinal injection of QHArt immediately after thoracic spinal cord dorsal over hemisection produced a statistically significant improvement in motor recovery over the course of four weeks measured by locomotor rating score. ",0
3877,19293944,Multivalent HA DNA vaccination protects against highly pathogenic H5N1 avian influenza infection in chickens and mice,"Sustained outbreaks of highly pathogenic avian influenza (HPAI) H5N1 in avian species increase the risk of reassortment and adaptation to humans. The ability to contain its spread in chickens would reduce this threat and help maintain the capacity for egg-based vaccine production. While vaccines offer the potential to control avian disease, a major concern of current vaccines is their potency and inability to protect against evolving avian influenza viruses. The ability of DNA vaccines encoding hemagglutinin (HA) proteins from different HPAI H5N1 serotypes was evaluated for its ability to elicit neutralizing antibodies and to protect against homologous and heterologous HPAI H5N1 strain challenge in mice and chickens after DNA immunization by needle and syringe or with a pressure injection device. These vaccines elicited antibodies that neutralized multiple strains of HPAI H5N1 when given in combinations containing up to 10 HAs. The response was dose-dependent, and breadth was determined by the choice of the influenza virus HA in the vaccine. Monovalent and trivalent HA vaccines were tested first in mice and conferred protection against lethal H5N1 A/Vietnam/1203/2004 challenge 68 weeks after vaccination. In chickens, protection was observed against heterologous strains of HPAI H5N1 after vaccination with a trivalent H5 serotype DNA vaccine with doses as low as 5 microg DNA given twice either by intramuscular needle injection or with a needle-free device. DNA vaccines offer a generic approach to influenza virus immunization applicable to multiple animal species. In addition, the ability to substitute plasmids encoding different strains enables rapid adaptation of the vaccine to newly evolving field isolates. ",0
3878,19294073,Effect of Inhibitors and Stimulators of Ethylene Production on Gall Development in Meloidogyne javanica-Infected Tomato Roots,"Excised tomato roots infected with Meloidogyne javanica produced ethylene at 3-6 times the rate of noninfected roots. This increase in ethylene production started 5 days after inoculation. Gall growth and ethylene production in infected roots were accelerated by 1-aminocyclopropane-1-carboxylic acid (ACC), indole acetic acid (IAA), and ethrel known as ethylene production stimulators. When inhibitors of ethylene production, like aminoethoxyvinylglycine (AVG) or aminoxyacetic acid (AOA), or inhibitors of ethylene action like silver thiosulfate (STS), were applied, gall growth and ethylene production were inhibited. Enhanced expansion of parenchymatous cells was observed in sections from nematode-induced galls and ethylene-treated roots. Lignification of xylem elements and fibers in the vascular cylinder was markedly inhibited in the gall, compared with noninfected root tissue. Because ethylene is known to induce cell expansion and to inhibit lignification, it is suggested that this plant hormone plays a major role in the development of M. javanica-induced galls. Ethylene affects gall size by enhancing parenchymatous tissue development and allows expansion of giant cells and the nematode body by reducing tissue lignification. ",0
3879,19294093,Leucine Aminopeptidase in Eggs of the Soybean Cyst Nematode Heterodera glycines,"Supernatant from a sonicated macerate of eggs of Heterodera glycines hydrolyzed L-leucine beta-naphthylamide and L-leucine 7-amido-4-methylcoumarin. Rate of substrate hydrolysis was influenced by pH and increased with the duration of incubation. A Michaelis-Menten constant of 0.15 mM was obtained. Rate of substrate hydrolysis was decreased by freezing egg supernatant for 26 days or heating above 60 C for 5 minutes. When egg supernatant was incubated with six different substrates, L-leucine beta-naphthylamide was hydrolyzed most readily and L-valine beta-naphthylamide the least readily. The rate of substrate hydrolysis by egg supernatant was not increased by pretreatment of eggs with 3 mM zinc chloride for up to 14 days. ",0
3880,19294401,"Extensive papillary carcinoma of the thyroid gland treated by external beam radiotherapy, surgery and postoperative radioactive iodine therapy","The treatment of choice for well-differentiated thyroid carcinoma is surgery, radioactive iodine ablation and thyroid stimulating hormone suppression [Richard in Cancer 82:375-388, 1988; James et al. in Endocrinol Metab Clin North Am 37(2):497-509]. We report a case with an extensive papillary carcinoma of thyroid gland treated by external beam radiotherapy as a cytoreductive therapy followed by total thyroidectomy. Postoperatively the patient was given radioactive iodine. The patient is free from tumor a year after the treatment. ",0
3881,19294929,Quantifying a dynamic risk landscape: heterogeneous predator activity and implications for prey persistence,"Spatial heterogeneity in predation risk can ameliorate impacts on prey populations, particularly for prey of generalists. Spatially heterogeneous risk implies the existence of refugia, and the spatial scale of those refugia and their persistence over time affect whether prey can avoid predation by aggregating therein. Our objective was to quantify the magnitude, spatial scale, and temporal persistence of heterogeneity in risk of predation by white-footed mice (Peromyscus leucopus), an abundant generalist predator of gypsy moths (Lymantria dispar) and songbirds. We used track plates to measure white-footed mouse activity at > 170 trees in each of three forest plots in upstate New York during summers of 2003-2005. We quantified the mean and coefficient of variation of track activity among trees by fitting the beta-binomial distribution to data from each plot and study period. We measured temporal persistence by disattenuated autocorrelation, and spatial scale by fitting exponential variograms. Mice were much less abundant in 2005 than the other two years, leading to lower overall track activity but higher coefficient of variation among trees. Mouse track activity at individual trees was positively autocorrelated between monthly study periods in 2003 and 2004, and even between the two years, whereas temporal autocorrelation in 2005 was much weaker. Track activity showed positive spatial autocorrelation over lag distances from approximately 30 to > 1000 m. These findings indicate that mouse activity, and hence risk to their prey, varies substantially in space at spatial and temporal scales that appear responsive to mouse population dynamics. The spatial scale and temporal persistence of that variation imply that prey may benefit from returning to, or failing to disperse from, refugia. ",0
3882,19295062,"Larvicidal activity of an indigenous plant, Centratherum anthelminticum","Crude extracts of fruits and leaves of Centratherum anthelminticum in different solvents were tested for larvicidal activity against Anopheles stephensi, the vector of malaria. The petroleum ether crude extract of both fruits and leaves exhibited significant larvicidal activity against III instar larvae with LC50 values of 162.60 ppm and 522.94 ppm, respectively after 24 hr. The petroleum ether extract of fruit was 11.66, 2.15 and 1.32 times more toxic than that of leaf extract after 24, 48 and 72 hr, respectively at LC90 level. However at LC50 level the corresponding values were 3.22, 1.83 and 1.19, respectively. The petroleum ether extract of C. anthelminticum fruits is a promising source for the control of Anopheles larvae. ",0
3883,19295432,Acute pain in children and adults with sickle cell disease: management in the absence of evidence-based guidelines,"Acute, vaso-occlusive pain is the most characteristic complication of sickle cell disease (SCD). Although there has been rigorous work examining the pathogenesis of vaso-occlusion, fewer studies have focused on approaches to the clinical management of acute pain. In this review, we will examine the epidemiology and management strategies of acute pain events and we will identify limitations in the best available studies. Most acute pain events in adults with SCD are managed at home without physician contact. Prior descriptions of the natural history of pain episodes from the Cooperative Study of Sickle Cell Disease relied on physician contact, limiting the generalizability of these findings to current practice. Patient-controlled analgesia has replaced on-demand therapy to become the standard for management of severe pain events in children and adults with SCD requiring hospital admission. Unfortunately, most clinical practice guidelines for the management of acute pain are not based on randomized clinical trials. As a result, our practice of pain management is primarily limited to expert opinion and inferences from observational studies. Additional clinical trials in management of acute pain in children and adults with SCD are critical for the development of evidence-based guidelines. ",0
3884,19295770,Efficacy of Selected Nonvolatile Nematicides on Control of Ditylenchus destructor in Iris,"Greenhouse and field tests established that fenamiphos at 6.7 and 13.4 kg ai/ha applied in a 30-cm band directly on iris bulbs at planting effectively controlled Ditylenchus destructor. Aldicarb at rates of 5.6 to 11.2 kg ai/ha was less effective. Carbofuran, fensulfothion, and oxamyl at 6.7 to 13.4 kg ai/ha were ineffective. When applied on the bulbs, fenamiphos (granular or liquid) reduced nematode infection from 31 to 0.6% as determined by visual inspection of bulbs at harvest. Populations of D. destructor were reduced from 5.7 nematodes/g of fresh weight of bulb tissue to 0.04, 0.05, and 0.14 with applications of 13.4, 6.7, and 3.3 kg ai/ha fenamiphos, respectively. The most effective treatment was fenamiphos (granular or liquid) applied in a 30-cm band directly on the bulbs at time of planting. ",0
3885,19295997,Severe ocular symptoms as an initial manifestation of superior vena cava syndrome],"Superior vena cava syndrome is obstruction of blood flow through the superior vena cava (SVC). It is most commonly caused by neoplasm, especially lung cancer. An obstructed SVC initiates collateral venous return to the heart from the upper half of the body and the classic symptoms and signs become obvious. Superior vena cava síndrome is a rare cause of ocular manifestations. We report a case of periorbital swelling, conjunctival edema an orbital proptosis in a male patient presenting malignant superior vena cava obstruction. ",0
3886,19296209,The flavonoid quercetin induces changes in mitochondrial permeability by inhibiting adenine nucleotide translocase,"This study shows the effects of the flavonoid quercetin on diverse mitochondrial functions, among them membrane permeability. Our findings indicate that the addition of 50 microM quercetin did not produce reactive oxygen derived species; however, it inhibited the oxidative stress induced after the addition of Fe(2)/H(2)O(2) by about 38%. At this concentration, quercetin also promoted a fast calcium release, inhibited oxidative phosphorylation, stimulated oxygen consumption, and decreased membrane potential. In addition 50 microM quercetin inhibited the adenine nucleotide translocase (ANT) by 46%. These effects induced the opening of the permeability transition pore and release of cytochrome c, by its interaction with a component of the non-specific pore complex, fixed to the carrier in the conformation c, as carboxyatractyloside does. Quercetin-induced permeability transition pore opening was inhibited by 0.5 microM cyclosporin A, but, interestingly, the release of cytochrome c was not inhibited by the immunosuppressor, as quercetin was found to disrupt the outer membrane. ",0
3887,19296952,Low serum bilirubin concentration is associated with coronary artery calcification (CAC),"Bilirubin is a potent antioxidant and previous studies have reported the relationship between low serum bilirubin concentration and atherosclerosis. The purpose of this study was to assess the correlation between serum bilirubin concentration and coronary artery calcification (CAC). This study consisted of 637 participants and we evaluated the relationship between CAC score determined by multislice computed tomography and serum bilirubin concentration. An inverse correlation was found between serum bilirubin concentration and log(CAC+1) (r=-0.361, P<0.0001). Multiple regression analysis also demonstrated that age (beta=0.261, P=0.0125), systolic blood pressure (beta=0.153, P=0.0237), uric acid (beta=0.126, P=0.0441), estimated glomerular filtration rate (beta=-0.139, P=0.0416) and serum bilirubin concentration (beta=-0.281, P<0.0001) were independent determinants of log(CAC+1). An increment of 1 micromol/L in serum bilirubin concentration was associated with 14% decrease in the odds for CAC score > or =400 after adjustment for several risk factors. Both age and SBP were also positively associated with CAC score > or =400, but the odds ratio for CAC score > or =400 was greater for every 1 micromol/L increment in serum bilirubin concentration than for every 1-year increment in age and 1-mmHg increment in SBP. Low serum bilirubin concentration is associated with coronary artery calcification. Serum bilirubin concentration can be measured easily in the clinical laboratory and applied in medical practice, and low serum bilirubin concentration would be useful as a provisional new risk factor of CAC. ",0
3888,19297410,Common genetic control of haemangioblast and cardiac development in zebrafish,"Over the past few years it has become clear that over half of the mammalian heart derives from outside the heart field as originally defined. Such a second heart field, however, has not been described in zebrafish, which could explain its smaller, two-chambered heart. Instead, zebrafish have a population of haemangioblasts, which is absent in mammalian embryos, raising the possibility that these cells represent the evolutionary ancestor of the second heart field. Here, we show for the first time that the genetic programmes of these anterior haemangioblasts and the adjacent heart field are co-regulated, by transcription factors previously associated with heart but not blood or endothelial development. We demonstrate that gata4, gata5 and gata6 are essential for anterior haemangioblast specification, and for subsequent myelopoiesis, acting as early as cloche and upstream of scl. The requirement for gata4, gata5 and gata6 in myeloid, endothelial and cardiac specification is in the mesoderm, but these factors also control, from within the endoderm and the yolk syncytial layer, the migration of the cardiac precursors as they differentiate. This genetic link between the blood/endothelial and cardiac programmes supports the notion that this haemangioblast population in zebrafish is an evolutionary antecedent of the second heart field, and has implications for the differentiation of haemangioblasts and cardiomyocytes from pluripotent cells, and for the origins of stem cells in the adult heart. ",0
3889,19297594,High sensitivity and specificity of acid-fast microscopy for diagnosis of pulmonary tuberculosis in an African population with a high prevalence of human immunodeficiency virus,"Laboratories in low-income countries report that acid-fast microscopy is insensitive and nonspecific. We demonstrate that for a Ugandan population with high prevalences of tuberculosis and human immunodeficiency virus infection, acid-fast microscopy is highly sensitive (93.1%) and specific (100%) when performed by trained technologists in a carefully controlled manner using established techniques. ",0
3890,19298018,A novel blood-saving plan for less-invasive primary total hip replacement,"We conducted a quality improvement program to examine the effect of a blood-saving plan during primary total hip replacement (THR) performed using a nonvascular less invasive approach (LI-THR) and compared the results with historical control subjects. Erythropoietin and tranexamic acid (TA) were administered for selected patients. Analysis of 221 (study group) and 186 (historic group) LI-THRs showed reductions in total blood loss by 20% in a group of 133 patients compared to a control group of 82 patients who did not receive TA. This novel blood plan for LI-THR changed practice, improved quality of care, and allowed all patients to remain blood transfusion free. ",0
3891,19298285,Activation of fibroblast growth factor receptor 3 and oncogene-induced senescence in skin tumours,"The activation of oncogenes is an important step in tumorigenesis, and recently, oncogene-induced senescence (OIS) was proposed as a critical barrier against malignant transformation in normal primary cells. The aim of this study was to examine the activation of fibroblast growth factor receptor 3 (FGFR3) as an oncogene product and OIS in human skin tumours. We investigated the activation of FGFR3 and OIS by mutation and immunohistochemical analysis in skin tumours, including seborrhoeic keratosis, actinic keratosis (AK), Bowen's disease (BD), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Activated point mutations of FGFR3 were identified in four of 22 cases (18%) of seborrhoeic keratosis, but no mutation was detected in the other skin tumours. Twenty-seven of 31 cases (87%) of seborrhoeic keratosis showed moderately to strongly positive expression of the FGFR3 protein, but almost all the other skin tumours were negative. On the other hand, almost all the seborrhoeic keratoses showed negative immunoreactivity for antiphoshohistone H2AX (gamma-H2AX) as a marker of OIS, but 17 of 22 cases (77%) of AK were moderately to strongly positive. Immunoreactivity for gamma-H2AX was significantly greater in AK than in seborrhoeic keratosis, BD, BCC and SCC. The activation of FGFR3 might be a common feature in the tumorigenesis in seborrhoeic keratosis, although the activation does not induce a typical oncogenic signal in keratinocytes. In addition, OIS due to some oncogenic signals rather than activation of FGFR3 might be involved in the early skin carcinogenesis related to chronic ultraviolet radiation exposure. ",0
3892,19298543,Effects of gender and age on paediatric headache,"The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders. ",0
3893,19299150,Evidence of multi-walled carbon nanotube fragmentation induced by sonication during nanotube encapsulation via bulk-suspension polymerization,"The synthesis of multi-walled carbon nanotube/polystyrene composites, with nanotube concentrations of 0.04, 0.08 and 0.16 wt%, was carried out by in situ bulk-suspension polymerization with the assistance of sonication. By using this method both encapsulation and exfoliation of the nanotubes into the polymer host were achieved. Evidence of significant nanotube fragmentation was found by scanning electron microscopy; the cause of such fragmentation was attributed to the induction of strong cavitation due to the application of ultrasound during the synthesis. Infrared spectroscopy showed no evidence of the formation of covalent bonds between the nanotubes and the polystyrene during the process of synthesis. The thermal stability was not improved by the inclusion of the nanotubes, it was attributed to the low nanotube concentrations; however, composites glass transition temperature showed improvements. ",0
3894,19299172,Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in goats,"In a four-period cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to goats intramuscularly (IM) at a dose rate of 2 mg/kg, both alone and in combination with the non-steroidal anti-inflammatory drug tolfenamic acid (TA), also administered IM at a dose rate of 2 mg/kg. Using a tissue cage model of inflammation, based on the irritant actions of carrageenan, the pharmacokinetics (PK) of MB and MB in combination with TA were determined. MB mean values of area under concentration-time curve (AUC) were similar for serum (5.60 microg h/mL), inflamed tissue cage fluid (exudate; 5.32 microg h/mL) and non-inflamed tissue cage fluid (transudate; 4.82 microg h/mL). Values of mean residence time (MRT) of MB in exudate (15.5 h) and transudate (15.8 h) differed significantly from serum MRT (4.23 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB were investigated using a caprine strain of Mannheimia haemolytica. Integration of PK data with ex vivo bacterial time-kill curve data for serum, exudate and transudate provided AUC(24h)/minimum inhibitory concentration (MIC) ratios of 160, 133 and 121 h, respectively, for the strain of organism used. Modelling of the ex vivo time-kill data to the sigmoid E(max) equation provided AUC(24h)/MIC values required for bacteriostatic and bactericidal actions of MB and for virtual eradication of the organism of 27.6, 96.2 and 147.3 h, respectively. Corresponding values for MB+TA were 20.5, 66.5 and 103.0 h. These data were used to predict once daily dosage schedules of MB for subsequent clinical evaluation. ",0
3895,19299410,Smoking cessation behavior in older adults by race and gender: the role of health problems and psychological distress,"Initial research on older smokers suggests that a subgroup of smokers with higher levels of psychological distress and health problems may be more likely to quit smoking than older smokers with fewer such problems. The present study, based on prospective data from a biracial sample of older adults (N = 4,162), examined characteristics of older adult smokers by race and gender. The present study uses both cross-sectional and prospective data to examine the association between smoking behavior, smoking cessation, health functioning, and psychological distress in a biracial sample of community-dwelling older adults. We found baseline psychological distress to be associated with poor health functioning. Consistent with hypotheses, baseline (Time 1) psychological distress predicted smoking cessation 3 years later (Time 2). Moreover, the change in health problems between Time 1 and Time 2 fully mediated the association between Time 1 distress and smoking cessation. Smoking cessation behavior of older adults is best explained by higher levels of distress and health problems regardless of race or gender. These findings may have important treatment implications regarding smoking cessation programs among older adults. Older adult smokers with higher levels of psychological distress and health problems may be more motivated to quit smoking than those with fewer such problems. These difficulties should be targeted within the context of the smoking cessation protocol. Also, we identified a subgroup of older smokers who are reporting fairly good health and lower levels of distress and who are less likely to quit smoking. Motivational methods may need to be developed to engage this group in smoking cessation treatment. ",0
3896,19299443,Mutational analysis of progesterone receptor functional domains in stable cell lines delineates sets of genes regulated by different mechanisms,"Steroid hormone receptors act directly in the nucleus on the chromatin organization and transcriptional activity of several promoters. Furthermore, they have an indirect effect on cytoplasmic signal transduction pathways, including MAPK, impacting ultimately on gene expression. We are interested in distinguishing between the two modes of action of progesterone receptor (PR) on the control of gene expression and cell proliferation. For this, we have stably expressed, in PR-negative breast cancer cells, tagged forms of the PR isoform B mutated at regions involved either in DNA binding (DNA-binding domain) or in its ability to interact with the estrogen receptor and to activate the c-Src/MAPK/Erk/Msk cascade (estrogen receptor-interacting domain). Both mutants impair PR-mediated activation of a well-understood model promoter in response to progestin, as well as hormone-induced cell proliferation. Additional mutants affecting transactivation activity of PR (activation function 2) or a zinc-finger implicated in dimerization (D-box) have also been tested. Microarrays and gene expression experiments on these cell lines define the subsets of hormone-responsive genes regulated by different modes of action of PR isoform B, as well as genes in which the nuclear and nongenomic pathways cooperate. Correlation between CCND1 expression in the different cell lines and their ability to support cell proliferation confirms CCND1 as a key controller gene. ",0
3897,19299721,"B cell proliferation, somatic hypermutation, class switch recombination, and autoantibody production in ectopic lymphoid tissue in murine lupus","""Intraperitoneal exposure of nonautoimmune mice to 2,6,10,14-tetramethylpentadecane (TMPD) causes lupus and the formation of ectopic lymphoid tissue. Although associated with humoral autoimmunity, it is not known whether Ab responses develop within ectopic lymphoid tissue or if B cells only secondarily migrate there. We show that ectopic lymphoid tissue induced by TMPD not only resembles secondary lymphoid tissue morphologically, but it also displays characteristics of germinal center reactions. Proliferating T and B lymphocytes were found within ectopic lymphoid tissue, activation-induced cytidine deaminase was expressed, and class-switched B cells were present. The presence of circular DNA intermediates, a hallmark of active class switch recombination, suggested that class switching occurs within the ectopic lymphoid tissue. Individual collections of ectopic lymphoid tissue (""""lipogranulomas"""") from the same mouse contained different B cell repertoires, consistent with local germinal center-like reactions. Class-switched anti-RNP autoantibody-producing cells were also found in the lipogranulomas. Somatic hypermutation in the lipogranulomas was T cell-dependent, as was the production of isotype-switched anti-Sm/RNP autoantibodies. Thus, ectopic lymphoid tissue induced by TMPD recapitulates many of the functional characteristics of secondary lymphoid tissue and contains autoantibody-secreting cells, which may escape from normal censoring mechanisms in this location. """,0
3898,19299783,"Death from propofol: accident, suicide, or murder?","""A 24-yr-old woman was found dead in her home from apparent propofol """"toxicity."""" Her blood level of propofol was 4.3 microg/mL. She had no history of drug abuse and no evidence of such behavior at autopsy. The medical examiner and police investigators felt that she died from probable homicide. Attention was focused on a male registered nurse acquaintance, who had acquired propofol and other drugs in the course of his regular duties in a surgical intensive care unit. This is the first reported case of murder with propofol. """,0
3899,19300413,In vitro and in vivo anticancer activity of steroid saponins of Paris polyphylla var. yunnanensis,"To confirm the anticancer activity of steroid saponins isolated from the rhizome of Paris polyphylla var. yunnanensis and evaluate the structure-activity relationships of these steroid saponins in vitro and in vivo . Eight known steroid saponins were isolated from the rhizome of Paris polyphylla . The LA795 lung adenocarcinoma cell line from mice was chosen to evaluate cytotoxicity by means of MTT assay, and to study apoptosis by means of AnnexinV-FITC/PI flow cytometry. Diosgenin-3alpha-L-arabinofuranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glycopyranoside (compound 1), the main steroid saponin of Paris polyphylla , and diosgenin (Dio), the aglycone of major steroid saponins, were evaluated for antitumor activity on LA795 lung adenocarcinoma in T739 inbred mice. The steroid saponins showed remarkable cytotoxicity and caused typical apoptosis in a dose-dependent manner. They were evaluated in vivo by their effect on tumor developed in T739 inbred mice. The oral administration to T739 mice bearing LA795 lung adenocarcinoma of compound 1 and diosgenin significantly inhibited tumor growth, by 29.44% and 33.94%, respectively. HE staining showed that lungs and livers of treated mice underwent various levels of histopathological alterations. It was demonstrated by TUNEL assay that apoptosis rate in tumor cells was increased in comparison to cells in control mice. The 3-O-glycoside moiety and spirostanol structure played an important role in the anticancer activity of steroid saponins, and the number and the variety of glycosides of compounds strongly influenced on their anticancer activity. Rhizoma Paridis saponins showed anticancer activity against lung adenocarcinoma cell line, both in vitro and in vivo, and their effect was dependent on compounds' structure in a certain degree. ",0
3900,19300560,An alternative approach to measuring treatment persistence with antipsychotic agents among patients with schizophrenia in the Veterans Health Administration,"Prior studies have demonstrated the importance of treatment persistence with anti-psychotic agents in sustaining control of schizophrenic symptoms. However, the conventional approach in measuring treatment persistence tended to use only the first prescription episode even though some patients received multiple prescriptions (or multiple treatment episodes) of the same medication within one year following the initiation of the index drug. In this study, we used data from the Veterans Health Administration in the United States to assess the extent to which patients received multiple prescriptions. The study found that about a quarter of the patients had two or more treatment episodes and that levels of treatment persistence tended to vary across treatment episodes. Based on these results, we offered an alternative approach in which we calculated treatment persistence with typical and atypical antipsychotic agents separately for patients with one, two, or three treatment episodes. Considering that patients with different number of treatment episodes might differ in disease profiles, this treatment episode-specific approach offered a fair comparison of the levels of treatment persistence across patients with different number of treatment episodes. Future research needs to extend the analyses beyond two antipsychotic classes to individual antipsychotic agents. A more comprehensive assessment using appropriate analytic methods should help physicians make prescription choices that will ultimately improve the care of patients with schizophrenia. ",0
3901,19300777,"Resistance and Resistant Reaction of Gossypium arboreum to the Reniform, Nematode, Rotylenchulus reniformis","Gossypium arboreum 'Nanking CB 1402' possessed a high level of resistance to Rotylenchulus reniformis. Within 16 h, the nematode penetrated roots of resistant and susceptible cottons equally. After 36 h, significantly fewer nematodes were found in resistant roots. Larvae fed in either an endodermal or pericyclic cell and had no specificity for root tissue of a particular age. In roots of resistant G. arboreum '1402,' wall breakdown of pericyclic cells was evident after 3 d, endodermal and cortical cells collapsed, and the hypertrophied pericyclic cells disintegrated within 12 d. Cell walls immediately adjacent to the nematode's head were thickened and more safranin positive in resistant than in susceptible cotton cultivars. Several other cultivars of G. arboreum were also resistant to R. reniformis, based on nematode fecundity and percent egg reduction. ",0
3902,19300970,Cerebral MRI lesions and anti-tumor necrosis factor-alpha therapy,We discuss two cases receiving different anti-tumornecrosis-factor alpha antagonists (anti-TNF-alpha); one for psoriatic arthritis (PA) and the other for ankylosing spondylitis (AS). Due to neurological symptoms cerebral magnetic resonance imaging (MRI) was performed and cerebral lesions were detected. Our interpretations of these cerebral lesions and the resulting diagnostic and therapeutic consequences are presented in regard of data published in the medical literature. ,0
3903,19301280,"Age classes and sex differences in the skull of the Mediterranean monk seal, Monachus monachus (Hermann, 1779). A study based on bone shape and density","This study analyzes morphometrically 17 skulls of the Mediterranean monk seal Monachus monachus housed in different Italian Museums and collections. We considered several morphometric variables (31 linear, 1 volumetric and 1 surface area measurements). In addition, we identified, measured and compared two nonmorphometric variables, namely, the bone densities of selected areas obtained using a dual-energy X-ray absorptiometry (DXA) device. The high correlation coefficient of all variables indicated continuous growth with the onset of age. The ranking of the hierarchical cluster analysis identified the presence of three main groups containing individuals of similar sizes: lactating pups and yearlings; subadult individuals and adult females; and adult males. Smaller groups were identified within these clusters, and their respective allocations into two subgroups were argued on the basis of skull development and other factors. The discriminant analysis of the three main groups indicated a discriminant diagnostic key, based on condilobasilar length (CBlr-L); maximum mandibular branch height (MB-H); and surface area of the bulla tympanica. The proposed diagnostic key is useful to classify monk seal skulls of unidentified age and sex. The data reported here suggest that in this species certain adult skull growth features (enhanced tympanic bullae surface area extension, occipital bone density) are sexually dimorphic and possibly related to specific anatomical functions. These functions may include an enhanced auditory capacity; an increased development of the cranial musculature capable of supporting a large skull and guaranteeing the mandibular strength necessary for mastication; and male to male social interactions. ",0
3904,19301315,Analysis of the indanomycin biosynthetic gene cluster from Streptomyces antibioticus NRRL 8167,"Metabolites that harbor a core indane scaffold are found to have diverse biological properties. Indanomycin and related pyrroloketoindanes are ionophores and have demonstrated antiparasitic, insecticidal, and antibacterial activities. To understand the biochemical mechanisms guiding formation of the central indane ring, the biosynthetic gene cluster for indanomycin was identified from Streptomyces antibioticus NRRL 8167 and sequenced to approximately 80 kb; this revealed five genes encoding subunits of a polyketide synthase (PKS) and 18 other open reading frames. The involvement of this cluster in indanomycin biosynthesis was confirmed by deletion mutagenesis. The indanomycin PKS lacks the expected thioesterase at the carboxy terminus of the final module, and instead appears to house an incomplete module containing an unusual cyclase domain. These findings now enable additional detailed genetic and biochemical studies of the mechanisms guiding the generation of pyrroloketoindanes. ",0
3905,19301972,Assessing the microlesion effect of subthalamic deep brain stimulation surgery with FDG PET,"The authors investigated whether the insertion of deep brain stimulation electrodes into the subthalamic nucleus can alter regional brain metabolism in the absence of stimulation. Six patients with Parkinson disease (PD) underwent preoperative FDG PET scanning, and again after STN electrode implantation with stimulation turned off. Compared with baseline values, glucose utilization was reduced in the postoperative off-stimulation scans in the putamen/globus pallidus and in the ventral thalamus (p < 0.01), and there was increased metabolism in the sensorimotor cortex and cerebellum (p < 0.005). The expression of a specific PD-related spatial covariance pattern measured in the FDG PET data did not change after electrode implantation (p = 0.36), nor was there a significant change in clinical motor ratings (p = 0.44). Differences in PD-related spatial covariance pattern expression among the patients after electrode implantation did, however, correlate with the number of microelectrode recording trajectories placed during surgery (r = -0.82, p < 0.05). These findings suggest that electrode implantation can impart a microlesion effect on regional brain function. Nonetheless, these local changes did not cross the threshold of network modulation needed to achieve clinical benefit. ",0
3906,19301977,Hydrogen peroxide-producing lactobacilli inhibit gonococci in vitro but not during experimental genital tract infection,"Commensal lactobacilli that produce hydrogen peroxide (H(2)O(2)) inhibit Neisseria gonorrhoeae in vitro, and clinical data suggest that they are associated with a reduced risk of gonorrhea. We precolonized mice with Lactobacillus crispatus and then challenged them with N. gonorrhoeae, to measure the effects of H(2)O(2)-producing lactobacilli on gonococcal infection. We found no difference in the duration of infection or the number of gonococci recovered from untreated mice and mice colonized with L. crispatus. A gonococcal catalase mutant and a catalase, cytochrome C peroxidase mutant exhibited greater susceptibility to L. crispatus in vitro than did wild-type bacteria; however, recovery of these mutants from mice was not affected by L. crispatus. We also found no evidence that utilization of lactobacillus-produced lactate by N. gonorrhoeae balances the detrimental effects of H(2)O(2) during infection. We conclude that the association between lactobacilli and gonococci is complex and may be subject to factors that have not been reproduced in vitro. ",0
3907,19302010,Molecular confirmation of Sappinia pedata as a causative agent of amoebic encephalitis,"Pathogenic free-living amoebae, such as Acanthamoeba species, Balamuthia mandrillaris, and Naegleria fowleri, are known to cause infections of the central nervous system in human and other animals. In 2001, a case of human encephalitis was reported that was caused by another amoeba with morphological features suggestive of Sappinia. The amoeba originally identified as Sappinia diploidea was identified, most likely as S. pedata, by use of newly developed real-time polymerase chain reaction assays. This amoeba had previously been found only in environmental sources, such as soil and tree bark. The results illustrate the potential for other free-living amoebae, which are not normally associated with human disease, to cause occasional infections. ",0
3908,19302242,Innate immunity and heat shock response in islet transplantation,"Islet transplantation is an extremely effective therapy for patients with type I diabetes, providing tight control of blood glucose and persistent insulin release. Islet grafts struggle with various stress responses and immunity attacks, which contribute to loss of islet grafts in the long term. In this review we focus upon the innate immunity and heat shock responses, which are closely relevant to the outcome of islet grafts. Potential strategies provided by more comprehensive interventions to control innate immunity and by selective induction of heat shock proteins may ameliorate the outcome of islet transplantation. ",0
3909,19302301,Isolation and partial characterization of novel genes encoding acidic cellulases from metagenomes of buffalo rumens,"To clone and characterize genes encoding novel cellulases from metagenomes of buffalo rumens. A ruminal metagenomic library was constructed and functionally screened for cellulase activities and 61 independent clones expressing cellulase activities were isolated. Subcloning and sequencing of 13 positive clones expressing endoglucanase and MUCase activities identified 14 cellulase genes. Two clones carried two gene clusters that may be involved in the degradation of polysaccharide nutrients. Thirteen recombinant cellulases were partially characterized. They showed diverse optimal pH from 4 to 7. Seven cellulases were most active under acidic conditions with optimal pH of 5.5 or lower. Furthermore, one novel cellulase gene, C67-1, was overexpressed in Escherichia coli, and the purified recombinant enzyme showed optimal activity at pH 4.5 and stability in a broad pH range from pH 3.5 to 10.5. Its enzyme activity was stimulated by dl-dithiothreitol. The cellulases cloned in this work may play important roles in the degradation of celluloses in the variable and low pH environment in buffalo rumen. This study provided evidence for the diversity and function of cellulases in the rumen. The cloned cellulases may at one point of time offer potential industrial applications. ",0
3910,19302988,Pre-analytical workstations: a tool for reducing laboratory errors,"Laboratory testing, a highly complex process commonly called the total testing process (TTP), is usually subdivided into three traditional (pre-, intra-, and post-) analytical phases. The majority of errors in TTP originate in the pre-analytical phase, being due to individual or system design defects. In order to reduce errors in TTP, the pre-analytical phase should therefore be prioritized. In addition to developing procedures, providing training, improving interdepartmental cooperation, information technology and robotics may be a tool to reduce errors in specimen collection and pre-analytical sample handling. It has been estimated that >2000 clinical laboratories worldwide use total or subtotal automation supporting pre-analytic activities, with a high rate of increase compared to 2007; the need to reduce errors seems to be the catalyst for increasing the use of robotics. Automated systems to prevent medical personnel from drawing blood from the wrong patient were introduced commercially in the early 1990s. Correct patient identification and test tube labelling before phlebotomy are of extreme importance for patient safety in TTP, but currently few laboratories are interested in such products. At San Bassiano hospital, the implementation of advanced information technology and robotics in the pre-analytical phase (specimen collection and pre-analytical sample handling) have improved accuracy, and clinical efficiency of the laboratory process and created a TTP that minimizes errors. ",0
3911,19303078,Metal complexes stability constant determination by hyphenation of capillary electrophoresis with inductively coupled plasma mass spectrometry: the case of 1:1 metal-to-ligand stoichiometry,"Nuclear energy development has raised new issues like radionuclides biogeochemistry. The modelling of their biochemical properties involves the accurate determination of thermodynamical data, like stability constants. This can be achieved by using hyphenated capillary electrophoresis (CE)-ICPMS and the method was applied successfully on 1:1 lanthanum-oxalate and uranyl-oxalate complexes. Several significant steps are discussed: choice of analytical conditions, electrophoretic mobility calculation, mathematical treatment of experimental data by using linear regressions, ligand concentration and ionic strength corrections. The following values were obtained with a good precision for lanthanum-oxalate and uranyl-oxalate complexes: log(K degrees (LaOxa(+)))=6.10+/-0.10 and log(K degrees (UO(2)Oxa))=6.40+/-0.30, respectively, at infinite dilution. These values are consistent with the literature data, showing CE-ICPMS potential for metal complexes stability constants determination. ",0
3912,19303697,High-dose chemotherapy plus stem cell transplantation in advanced germ cell cancer: a review,"High-dose chemotherapy (HDCT) with stem cell transplantation (SCT) has been investigated as a treatment strategy for advanced germ cell cancer (GCC) for >2 decades. In an effort to improve on the overall cure rates of 80% achievable with conventional chemotherapy, researchers have investigated this therapeutic option as a first-line therapy for those with poor-prognosis disease and as a salvage therapy for those with relapsed or refractory disease. The primary objective of this review is to define the role of HDCT plus SCT in advanced GCC. Prognostic indicators for this group of patients are also presented. A Medline search of English-language literature was performed to identify studies published in the last 20 yr relating to the use of HDCT plus SCT in advanced GCC. Phase 1, phase 2, and phase 3 trials were included, as were retrospective reviews and meta-analyses. Phase 2 trials investigating HDCT plus SCT as a therapeutic option for advanced germ cell cancer have indicated a survival advantage over conventional chemotherapy. This has not been confirmed in the phase 3 setting. Alternative chemotherapeutic strategies and options following failure of HDCT plus SCT are discussed. Studies to date have not indicated a survival advantage for the use of HDCT plus SCT in advanced germ cell cancer. Many questions, however, remain unanswered, and further research is required to identify whether optimising the strategy of HDCT plus SCT will improve outcome in this predominantly young group of patients. ",0
3913,19303906,Safety evaluation of the double mutant 5-enol pyruvylshikimate-3-phosphate synthase (2mEPSPS) from maize that confers tolerance to glyphosate herbicide in transgenic plants,"Glyphosate tolerance can be conferred by decreasing the herbicide's ability to inhibit the enzyme 5-enol pyruvylshikimate-3-phosphate synthase, which is essential for the biosynthesis of aromatic amino acids in all plants, fungi, and bacteria. Glyphosate tolerance is based upon the expression of the double mutant 5-enol pyruvylshikimate-3-phosphate synthase (2mEPSPS) protein. The 2mEPSPS protein, with a lower binding affinity for glyphosate, is highly resistant to the inhibition by glyphosate and thus allows sufficient enzyme activity for the plants to grow in the presence of herbicides that contain glyphosate. Based on both a review of published literature and experimental studies, the potential safety concerns related to the transgenic 2mEPSPS protein were assessed. The safety evaluation supports that the expressed protein is innocuous. The 2mEPSPS enzyme does not possess any of the properties associated with known toxins or allergens, including a lack of amino acid sequence similarity to known toxins and allergens, a rapid degradation in simulated gastric and intestinal fluids, and no adverse effects in mice after intravenous or oral administration (at 10 or 2000 mg/kg body weight, respectively). In conclusion, there is a reasonable certainty of no harm resulting from the inclusion of the 2mEPSPS protein in human food or in animal feed. ",0
3914,19304406,Mucositis versus tumor control: the therapeutic index of adding chemotherapy to irradiation of head and neck cancer,"""To determine whether the addition of concurrent chemotherapy to radiation for head and neck cancer (HNSCC) improves the therapeutic ratio regarding tumor control vs. mucositis. Data were taken from 14 randomized trials of radiation with or without concurrent chemotherapy for HNSCC. Mucositis-bioequivalent dose (mBED) was computed for each study using mBED = D [1 + d/(alpha/beta)] - 0.693(T - Tk)/Tp. An """"S-value,"""" relating the increase in the rate of Grade 3 (confluent) mucositis to the increase in mBED with radiation alone, was determined using data from trials of radiation alone with altered fractionation. We then determined the difference in the rate of mucositis and used the S-value to estimate the apparent difference in mBED in the chemoradiation and radiation alone arms for each trial. After accounting for differences in the radiation schedules, we estimated the mBED attributable to adding chemotherapy and compared it with previously published estimates of increases in tumor BED. Computed S-values ranged from 0.4 to 1.7. For S = 1, the mean increase in mBED attributable to chemotherapy was 8.3 Gy(10) (SD = 6.4). The average difference between tumor-BED and mBED was 2.8 Gy(10) (SD = 6.0). Increasing the S-value decreases the estimated increase in mBED due to chemotherapy. Concurrent chemotherapy improves the therapeutic index for radiation of HNSCC. Further refinements are needed in quantifying the therapeutic gain attributable to specific radiosensitizing agents in clinical trials, notably better and more consistent reporting of treatment sequelae. """,0
3915,19304453,Ultrasound image texture analysis of the intima and media layers of the common carotid artery and its correlation with age and gender,"The intima-media thickness (IMT) of the common carotid artery (CCA) is widely used as an early indicator of cardiovascular disease (CVD). It was proposed but not thoroughly investigated that the composition and texture of the media layer (ML) can be used as an indicator for the risk of stroke. In this study, we investigate the application of texture analysis of the ML of the CCA and how texture is affected by age and gender. The study was performed on 100 longitudinal-section ultrasound images acquired from asymptomatic subjects at risk of atherosclerosis. The images were separated into three different age groups, namely below 50, 50-60, and above 60 years old. Furthermore, the images were separated according to gender. A total of 61 different texture features were extracted from the intima layer (IL), the ML, and the intima-media complex (IMC). The ML and the IMC were segmented manually by a neurovascular expert and also automatically by a snakes segmentation system. We have found that male patients tended to have larger media layer thickness (MLT) values as compared to the MLT of female patients of the same age. We have found significant differences among texture features extracted from the IL, ML and IMC from different age groups. Furthermore, for some texture features, we found that they follow trends that correlate with a patient's age. For example, the gray-scale median GSM of the ML falls linearly with increasing MLT and with increasing age. Our findings suggest that ultrasound image texture analysis of the media layer has potential as an assessment biomarker for the risk of stroke. ",0
3916,19304531,Expression of ERK5 in multidrug-resistant hepatocellular carcinoma cell line],"To detect the expression of extracellular-signal regulated protein kinase 5 (ERK5) in multidrug-resistant hepatocellular carcinoma cell lines hepG2/ADM and BEL-7402/5-FU and in the parental cell lines (hepG2 and BEL-7402), and study the role of ERK5 in multidrug resistance of hepatocellular carcinoma. MTT assay was used to determine the multidrug resistance (MDR) of hepG2/ADM and BEL-7402/5-FU cells. Real-time PCR and Western blotting were used to detect the expression of ERK5 at mRNA and protein levels in the 4 cell lines. The resistance indices to ADM, 5-FU, and CDDP was 12.34, 5.74, and 3.81 in hepG2/ADM cells, and the resistance indices to 5-FU, VCR, OHP, MTX, and ADM was 15.32, 10.08, 5. 85, 6.74 and 3.26 in BEL-7402 cells, respectively. Compared with those in hepG2 and BEL-7402 cells, the ERK5 gene was up-regulated at both mRNA and protein levels in HepG2/ADM cells, but down-regulated at the mRNA level and up-regulated at the protein level in BEL-7402/5-FU cells. ERK5 is related to multidrug resistance in HepG2/ADM and BEL-7402/5-FU cells, and may provide new clues for reversing multidrug resistance of hepatocellular carcinoma cells. ",0
3917,19305040,The validation of tomotherapy dose calculations in low-density lung media,"The dose-calculation accuracy of the tomotherapy Hi-Art II(R) (Tomotherapy, Inc., Madison, WI) treatment planning system (TPS) in the presence of low-density lung media was investigated. In this evaluation, a custom-designed heterogeneous phantom mimicking the mediastinum geometry was used. Gammex LN300 and balsa wood were selected as two lung-equivalent materials with different densities. Film analysis and ionization chamber measurements were performed. Treatment plans for esophageal cancers were used in the evaluation. The agreement between the dose calculated by the TPS and the dose measured via ionization chambers was, in most cases, within 0.8%. Gamma analysis using 3% and 3 mm criteria for radiochromic film dosimetry showed that 98% and 95% of the measured dose distribution had passing gamma values < or =1 for LN300 and balsa wood, respectively. For a homogeneous water-equivalent phantom, 95% of the points passed the gamma test. It was found that for the interface between the low-density medium and water-equivalent medium, the TPS calculated the dose distribution within acceptable limits. The phantom developed for this work enabled detailed quality-assurance testing under realistic conditions with heterogeneous media. ",0
3918,19305190,Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature,"Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a complex condition characterized by defects of aural, oral, mandibular and vertebral development. The aetiology of this condition is likely to be heterogeneous; most cases are sporadic, however, familial cases suggesting autosomal recessive and autosomal dominant inheritance have been reported. In this study, we describe the clinical aspects of nine familial cases with evidence of autosomal dominant inheritance and compare them with reports in the literature. Interfamilial and intrafamilial clinical variabilities were observed in this study (reinforcing the necessity of careful examination of familial members). We suggest that oculoauriculovertebral spectrum with autosomal dominant inheritance is characterized mainly by bilateral auricular involvement and rarely presents extracranial anomalies. ",0
3919,19305333,Biomechanical analyses of the efficacy of patterns of maternal effort on second-stage progress,"""To develop and use a biomechanical computer model to simulate the effect of varying the timing of voluntary maternal pushes during uterine contraction on second-stage labor duration. Published initial pelvic floor geometry was imported into technical computing software to build a simplified three-dimensional biomechanical model with six representative viscoelastic levator muscle bands interconnected by a hyperelastic iliococcygeal raphe. An incompressible sphere simulated the molded fetal head. Forces from uterine contraction and voluntary expulsive efforts were summed to push the model fetal head along the curve of Carus opposed by the resistance of the pelvic floor structures to stretch. Holding uterine maximal contraction force and push strength constant, pushes were timed before (""""pre""""), at (""""peak""""), and after (""""post"""") maximal uterine contraction force. The effect of different combinations of pushes on second stage duration and the number of pushes required for delivery were evaluated. Calculated second stage durations ranged from 57.5 minutes (triple or pre-peak-post pattern) to 75.8 minutes (prepush and postpush patterns). Delivery with the triple-push pattern required 59 voluntary pushes, while the peak-push pattern required 23 voluntary pushes, a 61% reduction. The corresponding reduction for the pre-and-peak-push pattern was 29%, the peak-and-post push pattern was 30%, the prepush pattern was 54%, and the postpush pattern was 56%. Although the triple-push pattern resulted in a 16% shorter second stage, this came at the energetic expense of a 61% increase in the number of pushes required. III. """,0
3920,19305382,"Survival impact of psammoma body, stromal calcification, and bone formation in papillary thyroid carcinoma","The presence of calcification is the most significant ultrasonographic finding in evaluating thyroid nodules. Calcifications are more frequently detected in papillary thyroid carcinoma than in other thyroid lesions. However, the clinical significance of calcification, including clinical correlations and impact on survival, and the molecular mechanism responsible for calcification in papillary thyroid carcinoma remain uncertain. We performed a retrospective study of patients with primary common-type papillary thyroid carcinoma to determine the clinical correlations of calcification and its impact on survival. Histologically, calcification was classified as either psammoma bodies, stromal calcification, or bone formation. They were identified in 25, 47, and 13% of all 229 cases of papillary thyroid carcinoma, respectively. The presence of psammoma bodies was significantly correlated with gross lymph node metastasis and stage grouping. Both stromal calcification and bone formation were significantly correlated with patient age. In addition, stromal calcification was associated with pT classification and gross lymph node metastasis. Papillary thyroid carcinoma with, compared to that without, psammoma bodies was associated with poorer disease-free survival. We examined the quantitative expression of BMP-1, a metalloproteinase that is reported to be involved in bone and extracellular matrix formations, and found that its expression was significantly higher in tumors with psammoma bodies or with stromal calcification (P=0.0464 and 0.0272, respectively). These results suggest that the presence of psammoma bodies is a useful predictor of outcome for patients suffering from papillary thyroid carcinoma. ",0
3921,19305673,Turning 65 in Ontario: the impact of public drug benefit coverage on hospitalizations for acute and chronic disease,"Ongoing access to medication is required for the management of many chronic diseases. We sought to examine the health impact of entering the provincial drug benefit plan at age 65 years. We constructed cohorts of same-aged individuals with incident heart failure, with diabetes and from the whole population using administrative data. The hazard of hospitalization at a given age compared to one year younger for ages 63 to 67 years was determined. On turning age 65, persons were more rather than less likely to be hospitalized for diabetes and acute infection when compared to the prior year. Among residents of low-income neighbourhoods these effects were no longer significant, but the risk of hospitalization for heart failure was increased. A similar effect was not observed for the paired cohorts at the transition from age 63 to 64 years. A health benefit of obtaining drug insurance was not observed in this study; however, the relationship may have been confounded by the effects of retirement and other changes occurring at age 65. Moreover, a benefit experienced by only a small proportion of the population may not be apparent in this analysis, which included many individuals unaffected by the policy. ",0
3922,19305788,Pharmacodynamics of memantine: an update,"Memantine received marketing authorization from the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of moderately severe to severe Alzheimer s disease (AD) in Europe on 17(th) May 2002 and shortly thereafter was also approved by the FDA for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage-dependency and fast kinetics. Due to this mechanism of action (MOA), there is a wealth of other possible therapeutic indications for memantine and numerous preclinical data in animal models support this assumption. This review is intended to provide an update on preclinical studies on the pharmacodynamics of memantine, with an additional focus on animal models of diseases aside from the approved indication. For most studies prior to 1999, the reader is referred to a previous review [196].In general, since 1999, considerable additional preclinical evidence has accumulated supporting the use of memantine in AD (both symptomatic and neuroprotective). In addition, there has been further confirmation of the MOA of memantine as an uncompetitive NMDA receptor antagonist and essentially no data contradicting our understanding of the benign side effect profile of memantine. ",0
3923,19305854,"The Sterol, Fatty Acid, and Hydrocarbon Composition of Globodera solanacearum","Globodera solanacearum females were found to have less than 0.01% of dry wt as sterols. Seven sterols were detected in the nematode, with stanols (campestanol and stigmastanol) making tip more than 50% of the total sterols present. Lipid amounted to 29.4% of the dry weight of the nematode. Triglyceride, free fatty acid, and phospholipid classes were composed predominantly of 20:4, 20:1, and 18:1 fatty acids. Of the total weight of fatty acids found in G. solanacearum females, the greatest portion occurred in the triglyceride fraction, followed by the free fatty acid fraction then the phospholipid fraction. Several unidentified hydrocarbons were detected in the nematode. Paraffinic hydrocarbons detected ranged in carbon length from C15 to C29. Total concentration of hydrocarbon composed 0.20% of the dry wt. ",0
3924,19306059,Differentiation of benign and malignant breast lesions by mechanical imaging,"Mechanical imaging yields tissue elasticity map and provides quantitative characterization of a detected pathology. The changes in the surface stress patterns as a function of applied load provide information about the elastic composition and geometry of the underlying tissue structures. The objective of this study is the clinical evaluation of breast mechanical imager for breast lesion characterization and differentiation between benign and malignant lesions. The breast mechanical imager includes a probe with pressure sensor array, an electronic unit providing data acquisition from the pressure sensors and communication with a touch-screen laptop computer. We have developed an examination procedure and algorithms to provide assessment of breast lesion features such as hardness related parameters, mobility, and shape. A statistical Bayesian classifier was constructed to distinguish between benign and malignant lesions by utilizing all the listed features as the input. Clinical results for 179 cases, collected at four different clinical sites, have demonstrated that the breast mechanical imager provides a reliable image formation of breast tissue abnormalities and calculation of lesion features. Malignant breast lesions (histologically confirmed) demonstrated increased hardness and strain hardening as well as decreased mobility and longer boundary length in comparison with benign lesions. Statistical analysis of differentiation capability for 147 benign and 32 malignant lesions revealed an average sensitivity of 91.4% and specificity of 86.8% with a standard deviation of +/-6.1%. The area under the receiver operating characteristic curve characterizing benign and malignant lesion discrimination is 86.1% with the confidence interval ranging from 80.3 to 90.9%, with a significance level of P = 0.0001 (area = 50%). The multisite clinical study demonstrated the capability of mechanical imaging for characterization and differentiation of benign and malignant breast lesions. We hypothesize that the breast mechanical imager has the potential to be used as a cost effective device for cancer diagnostics that could reduce the benign biopsy rate, serve as an adjunct to mammography and to be utilized as a screening device for breast cancer detection. ",0
3925,19306250,Relationship between kinematic knee deviations and femoral anteversion in children with cerebral palsy,"The aim of the study was to determine the possible correlation between the degree of femoral anteversion and the quantitative data obtained by 3D Gait Analysis (GA) and then to investigate the relationship between femoral anteversion and the reduced knee flexion during swing phase in children with Cerebral Palsy. Twenty-seven diplegic children with severe rectus femoris spasticity and 20 healthy children (CG) were considered. Clinical evaluation of femoral anteversion, Duncan Ely test and Gait Analysis were performed in all patients. From Gait Analysis data some indices were identified and calculated and statistical analysis performed. Clinical evaluations made the distinction between patients with excessive femoral anteversion (Group 1) and those with normal value (Group 2). Both groups showed a blunt maximum of knee flexion in swing (KMSw), representative of rectus femoris spasticity, but two different gait strategies were found for the timing of KMSw. Group 1 exhibited a reduced KMSw value with its timing close to normal value and an excessive hip internal rotation (Mean Hip Rotation index), correlated to high femoral anteversion; Group 2 presented a limited KMSw and a significant delay of its timing, with Mean Hip Rotation index close to Control Group. No differences were found for other indices. The results demonstrated that the presence of reduced KMSw only can be directly connected to excessive femoral anteversion; the coexistence of reduced KMSw and its delayed timing reveals that the rectus femoris spasticity may be due to rectus spasticity added to an incorrect motor selective control. The results are clinically crucial for treatment strategies (derotative femoral osteotomy vs rectus transfer). ",0
3926,19306688,Expression inhibition of multidrug resistance-associated protein (MRP1) by multi-ribozyme expression system in HEK293 cells,"To study application of multi-ribozyme expression system on expression inhibition of multidrug resistance-associated protein (MRP1) in HEK293 cells, the multi-ribozyme expression system containing 20 cis-acting ribozymes for self-cleavage and 10 trans-acting ribozymes for targeting to MRP1 gene specific site were constructed. HEK293 cells cotransfected multi-ribozyme expression system with MRP1 target gene or full length of MRP1 gene respectively were analyzed by RT-PCR, Western blot analysis and MTT assay. The results showed that multi-ribozyme systems were able to dramatically decrease fluorescent fusion protein expression in HEK293 cells. RT-PCR analysis indicated that the extent of MRP1 target mRNA decrease was correlated with the number of trans-acting ribozyme contained in multi-ribozyme expression system. Similar changes have been observed from Western blot. MTT assay showed that multi-ribozyme systems were able to reverse MDR generated by MRP1 gene in HEK cells. These results suggested that inhibitory effects of multiple copies of ribozymes contained in the system were better than that of single ribozyme contained. Therefore, this strategy could be used in treatment of tumor or other diseases via gene therapy. ",0
3927,19306771,Translation of myocardial metabolic imaging concepts into the clinics,"Flexibility in myocardial substrate metabolism for energy production is fundamental to cardiac health. This loss in plasticity or flexibility leads to overdependence on the metabolism of an individual category of substrates, with the predominance in fatty acid metabolism characteristic of diabetic heart disease and the accelerated glucose use associated with pressure-overload left ventricular hypertrophy being prime examples. There is a strong demand for accurate noninvasive imaging approaches of myocardial substrate metabolism that can facilitate the crosstalk between the bench and the bedside, leading to improved patient management paradigms. In this article potential future applications of metabolic imaging, particularly radionuclide approaches, for assessment of cardiovascular disease are discussed. ",0
3928,19307402,A case of ricin poisoning following ingestion of Korean castor bean,"Ricin is a member of a group of protein toxins whose cytosolic target is the 28S rRNA of the 60S ribosomal subunit. It was recently introduced as a weapon of terrorism in some countries. There is little evidence about the mechanism, diagnosis and treatment of ricin poisoning. The case history is reported of a patient with ricin poisoning who presented with nausea and vomiting following ingestion of Korean castor bean. ",0
3929,19307424,"Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier","""The blood-brain barrier (BBB) does not exclusively refer to brain endothelial cells, which are the site of the barrier proper. In the past few years, it has become increasingly clear that BBB endothelial cells depend considerably on the brain microenvironment to a degree exceeding the environmental influence in other organs. The concept of the BBB has been continuously developed over the decades, culminating now in the recognition that endothelial cell function in the brain is not limited to simply mediating energy and oxygen transfer between blood and neural tissue. Endothelial cells are rather """"Janus-headed beings"""" that are active partners of both luminal molecules and cells, as well as subendothelial cells such as pericytes, astrocytes, and neurons. In this overview, the authors present and discuss both the role of astroglial cells in managing the BBB and aspects of pathological alterations in the brain as far as the BBB is involved. After a brief introduction of the BBB that describes the structure and function of the brain capillary endothelial cells, the authors report on both the water channel protein aquaporin-4 (AQP4) in astrocytes and the extracellular matrix between astrocytes/pericytes and endothelial cells. The AQP4 has an important impact on the homeostasis in the brain parenchyma; however, the mechanistic cascade from the composition of the astrocyte membrane to the maintenance of BBB properties in the endothelial cells, including their tight junction formation, is still completely unknown. """,0
3930,19307441,Endovenous laser treatment for uncomplicated varicose veins,"Endovenous laser ablation (EVLA) of incompetent truncal veins has been proposed as a minimally invasive alternative to conventional surgery for varicose veins. Various strategies have been proposed for successful treatment and this study reviews the evidence for these. A Medline and 'controlled trials online database' search was performed to identify original articles and randomized controlled trials (RCTs) reporting outcomes for EVLA. Information on patient selection, equipment, technique and outcomes were recorded. Ninety-eight original studies, including five RCTs, were identified. RCT data indicate short-term outcomes (abolition of reflux, improvement in quality of life [QOL], patient satisfaction) were equivalent to those for surgery. Long-term follow-up is not available. A further RCT showed superior outcomes for ablation commencing at the lowest point of superficial venous reflux rather than at an arbitrary point (fewer residual varicosities, greater improvement in QOL). Non-randomized series suggest that laser energy of >60 J/cm results in reliable truncal vein occlusion and that longer wavelength lasers may be associated with less post-treatment discomfort. In the short-term EVLA is a safe and effective treatment for patients with varicose veins. Long-term follow-up is still required. ",0
3931,19308428,Primary intracranial leiomyosarcoma: a case report and review of the literature,"Malignant tumours of the central nervous system (CNS) represent the second most common cancer type in the paediatric population of developed countries, and mortality caused by CNS tumours is the highest among paediatric cancers. Tumours of mesenchymal origin occurring either as primary or secondary lesions of the central nervous system are very rare in children. This paper describes the case of a 5-year-old non-immunocompromised male who presented with a right frontal primary intracranial leiomyosarcoma associated with large subdural collections. Following surgical excision and adjuvant chemoradiotherapy, the patient has remained disease-free for 18 months. The literature is reviewed and the possible association of the chronic subdurals to the later development of the leiomyosarcoma explored. ",0
3932,19308525,Reliability of pediobarographs for paediatric foot deformity,"Dynamic pediobarograph measures foot-floor contact pressure during walking and provides a quantitative functional assessment. The goal of this study was to assess the reliability of pediobarograph measurements in normal children and in those with cerebral palsy (CP). During the first investigation, five non-disabled children and four with CP had three pediobarograph measurements taken of each foot, repeated five times. The pediobarographs were analysed by dividing the foot into five segments; the heel, the lateral midfoot, the medial midfoot, the lateral forefoot and the medial forefoot. A measure of valgus/varus foot posture was defined as the relative medial-lateral difference of combined mid- and forefoot impulse, named valgus/varus index. During the second investigation, 50 children (100 feet) with spastic diplegic CP were studied to calculate the standard error of measurements (SEM), to investigate the number of pediobarograph measurements necessary to obtain accurate results. The third investigation was an inter- and intraobserver study performed on one normal subject's repeated measurements. In the first investigation, the group with CP had a significantly increased variability in the medial midfoot (P = 0.013). The variability of the valgus/varus index had a standard deviation of 13%, demonstrating that this measure is relatively stable. The SEM and 95% confidence interval from the second experiment showed that, even if the accuracy increased with the number of measurements, the greatest gain seemed to be contributed by increasing the number of measurements from 3 to 6. The inter- and intraobserver study showed good to mostly excellent agreement. Pediobarograph measurements can be used to monitor and quantitatively assess the progressive changes of foot deformity over time. Pediobarograph is a reliable measurement that shows little variability between measurements at the same occasion and between measurements on different days. Three to six measurements seems practical and adequate to obtain. The technical aspect of measuring shows good repeatability and agreement between observers. ",0
3933,19308691,Microenvironment changes (in pH) affect VEGF alternative splicing,"Vascular endothelial growth factor-A (VEGF-A) has several isoforms, which differ in their capacity to bind extracellular matrix proteins and also in their affinity for VEGF receptors. Although the relative contribution of the VEGF isoforms has been studied in tumor angiogenesis, little is known about the mechanisms that regulate the alternative splicing process. Here, we tested microenvironment cues that might regulate VEGF alternative splicing. To test this, we used endometrial cancer cells that produce all VEGF isoforms as a model, and exposed them to varying pH levels, hormones, glucose and CoCl(2) (to mimic hypoxia). Low pH had the most consistent effects in inducing variations in VEGF splicing pattern (VEGF121 increased significantly, p < 0.001, when compared to VEGF145, 165 or 189). This was accompanied by activation of the p38 stress pathway and SR proteins (splicing factors) expression and phosphorylation. SF2/ASF, SRp20 and SRp40 down-regulation by siRNA impaired the effects of pH stimulation, blocking the shift in VEGF isoforms production. Taken together, we show for the first time that acidosis (low pH) regulates VEGF-A alternative splicing, may be through p38 activation and suggest the possible SR proteins involved in this process. ",0
3934,19309269,A multiplexed ARMS-PCR approach for the detection of common MECP2 mutations,"Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder, is caused mainly by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). Although more than 200 different MECP2 mutations have been identified throughout the gene, 7 of those (p.R133C, p.T158M, p.R168X, p.R255X, p.R270X, p.R294X, and p.R306C) account for up to two-thirds of pathogenic mutations in RTT patients. A rapid and efficient screening strategy for these mutations can be used as a preliminary step for genetic diagnosis of RTT. The current protocols used for this purpose are of high cost and require special equipment. We have designed a simpler multiplex amplification refractory mutation system (ARMS)-PCR strategy that allows identification of these common MECP2 mutant alleles in four PCR reactions. The assay was tested in 14 RTT patients who were previously genotyped using PCR-restriction fragment length polymorphism and DNA sequencing. A complete concordance was observed between the results of the two methods. The multiplex ARMS-PCR does not require any special equipment, and it provides rapid, reproducible, and cost-effective detection of common MECP2 mutations. The assay can be carried out efficiently in a standard molecular genetics laboratory and suitable as a preliminary screen for all patients with RTT diagnosis. ",0
3935,19309438,Enhanced ovicidal activity of an oil formulation of the fungus Metarhizium anisopliae on the mosquito Aedes aegypti,"The effect of humidity on the activity of Metarhizium anisopliae IP 46 (Metsch.) Sorokin (Hypocreales: Clavicipitaceae) formulated in sunflower oil against Aedes aegypti (L.) (Diptera: Culicidae) eggs was examined. After exposure of eggs at 75% relative humidity (RH) for <or= 25 days, ovicidal activity was not increased by oil-in-water formulated conidia, hyphal bodies or pure-oil formulated conidia, compared with conidia or hyphal bodies prepared in water only. At optimal > 98% RH, eclosion was <or= 13.7% after treatment with oil-in-water formulated propagules in <or= 10% oil, and it was completely inhibited when conidia were applied in pure oil. At 86-100% RH, new conidia were found on eggs treated with oil-formulated conidia and incubated down to 91% RH. Ovicidal activity was still detected at 93% RH and was augmented with increasing humidity and time of exposure of eggs. Eclosion of larvae was distinctly reduced by IP 46 pure-oil formulated conidia after a minimal initial exposure of 3 days at > 98% RH, followed by: (a) a 12-day exposure at 75% RH before submersion in water; (b) a minimal 5-day exposure at > 98% RH and direct subsequent transfer of treated eggs to water, or (c) a minimal daily 20-h exposure at > 98% RH alternating with 4 h at 75% RH for 10 days. We demonstrate that oil-based formulations of conidia of M. anisopliae enhance ovicidal activity at high humidities and conclude that these formulations have potential in the integrated control of Ae. aegypti. ",0
3936,19309473,Transfusion of platelet components prepared with photochemical pathogen inactivation treatment during a Chikungunya virus epidemic in Ile de La Réunion,"During the Chikungunya virus (CHIKV) epidemic on Ile de La Réunion, France, more than 30% of 750,000 inhabitants were infected. Local blood donation was suspended to prevent transfusion-transmitted infection (TT-CHIKV). To sustain the availability of platelet (PLT) components, the Etablissement Français du Sang implemented universal pathogen inactivation (INTERCEPT, Cerus Europe BV) of PLT components (CPAs). The study assessed the safety of PLT components treated with pathogen inactivation transfused in routine clinical practice. This was a retrospective observational study using patient medical records and the AFSSAPS hemovigilance database (eFIT) to identify TT-CHIKV and adverse events (AEs) classified as acute transfusion reactions (ATRs) to PLT components prepared with pathogen inactivation. During 1 year, 1950 INTERCEPT-CPAs were transfused to 335 adult, 51 pediatric, and 41 infant patients. Nineteen AEs were observed in 15 patients and 10 were classified as ATRs. Eight ATRs occurred in 6 pediatric hematology-oncology patients. No ATRs were observed in infants. The most frequently reported signs and symptoms were Grade 1 urticaria, itching, chills, fever, and anxiety. No cases of transfusion-related acute lung injury, TT-sepsis, or TT-CHIKV were detected. INTERCEPT-CPAs were well tolerated in a broad range of patients, including infants. ATR incidence was low and when present ATRs were of mild severity. ",0
3937,19309498,Synchronous colorectal adenocarcinoma and gastrointestinal stromal tumor in Meckel's diverticulum; an unusual association,"Coexistence of gastrointestinal stromal tumor with synchronous or metachronous colorectal cancer represents a phenomenon with increasing number of relative reports in the last 5 years. Synchronous occurence of GISTs with other gastrointestinal tumors of different histogenesis presents a special interest. We herein report a case of GIST in Meckel's diverticulum synchronous with colorectal adenocarcinoma. A 69 year old man, presented with abdominal distension and anal bleeding on defecation. Colonoscopy revealed colorectal cancer and a low anterior resection was performed, during which a tumor in Meckel's diverticulum was discovered. Histologic examination revealed GIST in Meckel's diverticulum and a rectosigmoid adenocarcinoma. Whenever GIST is encountered, the surgeon should be alert to recognize a possible coexistent tumor with different histological origin. Correct diagnosis of synchronous tumors of different origin is the cornerstone of treatment. ",0
3938,19309719,Locating the stem cell niche and tracing hepatocyte lineages in human liver,"We have used immunohistochemical and histochemical techniques to identify patches of hepatocytes deficient in the enzyme cytochrome c oxidase, a component of the electron transport chain and encoded by mitochondrial DNA (mtDNA). These patches invariably abutted the portal tracts and expanded laterally as they spread toward the hepatic veins. Here we investigate, using mtDNA mutations as a marker of clonal expansion, the clonality of these patches. Negative hepatocytes were laser-capture microdissected and mutations identified by polymerase chain reaction sequencing of the entire mtDNA genome. Patches of cytochrome c oxidase-deficient hepatocytes were clonal, suggesting an origin from a long-lived cell, presumably a stem cell. Immunohistochemical analysis of function and proliferation suggested that these mutations in cytochrome c oxidase-deficient hepatocytes were nonpathogenic. These data show, for the first time, that clonal proliferative units exist in the human liver, an origin from a periportal niche is most likely, and that the trajectory of the units is compatible with a migration of cells from the periportal regions to the hepatic veins. ",0
3939,19309720,Connective tissue growth factor is a Smad2 regulated amplifier of transforming growth factor beta actions in hepatocytes--but without modulating bone morphogenetic protein 7 signaling,"In vivo knockdown of connective tissue growth factor (CTGF/CCN2) was recently shown to attenuate the formation of experimental liver fibrosis. The secreted, cysteine-rich growth factor is proposed to adversely modulate the binding of profibrogenic transforming growth factor beta (TGF-beta) and its natural antagonist bone morphogenetic protein (BMP) to their cognate receptors in several cellular systems, but the functionality of CTGF in modulation of the TGF-beta/BMP signaling pathways is still unknown. This study aims at characterizing a potentially differential modulating role of CTGF on TGF-beta- and BMP7-dependent transactivation of reporter gene [Ad-(CAGA)(12)-MLP-luc, Ad-hCTGF-luc, and Ad-(BRE)(2)-luc reporter gene] expression in rat hepatocytes. In this context, emphasis is also placed on the differential roles of Smad2 and Smad3 in the TGF-beta-dependent transactivation of the endogenous CTGF gene and the CTGF gene reporter, as investigated following adenoviral infection of wild-type and dominant negative Smad2/3 or treatment with the specific inhibitor of Smad3 or ALK5-specific (SB-431542) inhibitor. In this analysis, we found (1) a selective transcriptional activation of the CTGF promoter by Smad2 (but not Smad3); (2) the failure of BMP7 to inhibit the transcriptional activation of the Smad3-selective (CAGA)(12)-luc reporter by TGF-beta, as well as the failure of TGF-beta to inhibit the transcriptional activation of the Smad5-selective (BRE)(2)-luc reporter by BMP7; and (3) the sensitization of hepatocytes toward TGF-beta type I receptor (ALK5)/Smad2 and Smad3-mediated TGF-beta signaling by CTGF, whereas BMP type I receptor (ALK1)/Smad5-mediated BMP7 signaling is not modulated. CONCLUSION: CTGF acts as a Smad2-dependent sensitizer of TGF-beta actions that does not influence BMP7 signaling in hepatocytes.",0
3940,19309762,"Bioanalytical methods for the determination of itraconazole and hydroxyitraconazole: overview from clinical pharmacology, pharmacokinetic, pharmacodynamic and metabolism perspectives","Itraconazole represents an important therapeutic option for the treatment of fungal infections. Itraconazole undergoes rapid metabolism to form hydroxyitraconazole, which also contributes to the anti-fungal activity exhibited by the parent compound. Since both itraconazole and hydroxyitraconazole are effective inhibitors of cytochrome P450 (CYP) 3A4 and p-glycoprotein (pgp)-mediated efflux transporters, they have the potential to elicit drug-drug interaction with a number of CYP3A4 and/or pgp substrates. This review focuses on providing comprehensive details on the bioanalytical methods available for the quantitation of both itraconazole and hydroxyitraconazole. Additionally, it provides an overview of the clinical pharmacology (several case studies of drug-drug interactions), pharmacokinetics, pharmacodynamics and metabolism related aspects of itraconazole. ",0
3941,19321858,Use of electronic health records in U.S. hospitals,"BACKGROUND: Despite a consensus that the use of health information technology should lead to more efficient, safer, and higher-quality care, there are no reliable estimates of the prevalence of adoption of electronic health records in U.S. hospitals. METHODS: We surveyed all acute care hospitals that are members of the American Hospital Association for the presence of specific electronic-record functionalities. Using a definition of electronic health records based on expert consensus, we determined the proportion of hospitals that had such systems in their clinical areas. We also examined the relationship of adoption of electronic health records to specific hospital characteristics and factors that were reported to be barriers to or facilitators of adoption. RESULTS: On the basis of responses from 63.1% of hospitals surveyed, only 1.5% of U.S. hospitals have a comprehensive electronic-records system (i.e., present in all clinical units), and an additional 7.6% have a basic system (i.e., present in at least one clinical unit). Computerized provider-order entry for medications has been implemented in only 17% of hospitals. Larger hospitals, those located in urban areas, and teaching hospitals were more likely to have electronic-records systems. Respondents cited capital requirements and high maintenance costs as the primary barriers to implementation, although hospitals with electronic-records systems were less likely to cite these barriers than hospitals without such systems. CONCLUSIONS: The very low levels of adoption of electronic health records in U.S. hospitals suggest that policymakers face substantial obstacles to the achievement of health care performance goals that depend on health information technology. A policy strategy focused on financial support, interoperability, and training of technical support staff may be necessary to spur adoption of electronic-records systems in U.S. hospitals.",0
3942,19369666,Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs,"BACKGROUND: Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. METHODS: Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. RESULTS: At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. CONCLUSIONS: In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.",0
3943,19369668,Inhibitors of factor VIII in black patients with hemophilia,"BACKGROUND: Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients. METHODS: We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors. RESULTS: Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P=0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups. CONCLUSIONS: These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies.",0
3944,19399795,Benefits and risks of nucleoside analog therapy for hepatitis B,"Five oral agents have been approved for the treatment of chronic hepatitis B, ranging in virological potency, clinical efficacy, barrier to resistance, and side-effect profile. The degree of histological, biochemical, and serological improvement with therapy generally corresponds to the degree of suppression of serum hepatitis B virus (HBV) DNA achieved with therapy. Conversely, for agents with a low barrier to resistance, the profundity of HBV DNA suppression in individual patients correlates inversely with the likelihood of resistance. The durability of hepatitis B e antigen (HBeAg) responses after a consolidation period of an additional 6-12 months of therapy is approximately 80% in western populations, lower in Asian populations. Loss of hepatitis B surface antigen (HBsAg) during a year of oral-agent therapy is limited, except with the most potent agents, but extending therapy for a second year and beyond can yield frequencies of HBsAg responses close to those reported in trials of interferon-based therapy. The oral agents are approved for 1-2 years of therapy, but treatment is continued indefinitely in the majority of patients (except for the approximately 20% of patients who are HBeAg-reactive who achieve a durable HBeAg response). HBeAg responses and virological/biochemical benefit continue to be maintained and to increase with continued therapy beyond the first year. Data continue to accumulate supporting the link between long-term HBV DNA suppression and reduction in hepatic fibrosis, hepatic decompensation, and liver-related mortality. All the benefits of a single year of injectable peginterferon therapy can be achieved with the newer, low-resistance oral agents continued beyond the first year, without interferon side effects. Future studies are needed to develop drug regimens that are even more effective in achieving clinical endpoints, that are not hampered by resistance, and that are more confined in treatment duration but are more durable.",0
3945,19399912,Vascular disorders of the liver,This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association.,0
3946,19434726,Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation,"Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell-derived factor-1alpha (SDF-1alpha), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1alpha/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1alpha is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1alpha increases expression of alpha-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1alpha/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. CONCLUSION: HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1alpha is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1alpha-induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches.",0
3947,19434737,Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance,"Accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) results in ER stress and lipid overload-induced ER stress has been implicated in the development of insulin resistance. Here, evidence is provided for a molecular link between hepatic apolipoprotein B100 (apoB100), induction of ER stress, and attenuated insulin signaling. First, in vivo upregulation of hepatic apoB100 by a lipogenic diet was found to be closely associated with ER stress and attenuated insulin signaling in the liver. Direct in vivo overexpression of human apoB100 in a mouse transgenic model further supported the link between excessive apoB100 expression and hepatic ER stress. Human apoB100 transgenic mice exhibited hypertriglyceridemia and hyperglycemia. In vitro, accumulation of cellular apoB100 by free fatty acid (oleate) stimulation or constant expression of wild-type or N-glycosylation mutant apoB50 in hepatic cells induced ER stress. This led to perturbed activation of glycogen synthase kinase 3 and glycogen synthase by way of the activation of c-Jun N-terminal kinase and suppression of insulin signaling cascade, suggesting that dysregulation of apoB was sufficient to disturb ER homeostasis and induce hepatic insulin resistance. Small interfering (si)RNA-mediated attenuation of elevated apoB level in the apoB50-expressing cells rescued cells from lipid-induced ER stress and reversed insulin insensitivity. CONCLUSION: These findings implicate apoB100 as a molecular link between lipid-induced ER stress and hepatic insulin resistance.",0
3948,19437487,Human progenitor cells with high aldehyde dehydrogenase activity efficiently engraft into damaged liver in a novel model,"Human cord blood stem cells (hCBSCs) have been reported to generate hepatocyte-like cells and thus hold promise for repairing damaged liver. However, the frequency of hCBSC-derived hepatocytes varies tremendously between different studies, and it is still controversial as to whether hCBSC-derived cells can transdifferentiate into hepatocytes or simply fuse to recipient hepatocytes. We used the beta-glucuronidase-deficient nonobese diabetic/severe combined immunodeficient/mucopolysaccharidosis type VII (NOD/SCID/MPSVII) mouse model for better identification of engrafted cells. We transplanted lineage-depleted human umbilical cord blood-derived cells with high aldehyde dehydrogenase activity (ALDH(hi)Lin(-)) into irradiated NOD/SCID/MPSVII mice followed by carbon tetrachloride administration to induced liver damage. ALDH(hi)Lin(-) cells were efficiently engrafted in the recipient mouse livers and improved recovery of the mice from toxic insult. The percentage of human cells in these livers ranged between 3% and 14.2% using quantitative real-time polymerase chain reaction. Furthermore, human-originated cells expressing liver-specific alpha1-antitrypsin messenger RNA, albumin and hepatocyte nuclear factor 1 protein were detected in the recipient livers. Interestingly, human versus murine centromeric fluorescent in situ hybridization analysis on the liver sections demonstrated that most human cells were not fused to mouse cells. However, the majority of the human originated albumin-expressing cells also carried mouse genetic material, hence were the product of cell fusion. CONCLUSION: hCBSCs or their progeny may home to the injured liver and release trophic factors that hasten tissue repair, whereas fusion of these cells with hepatocytes may occur rarely and contribute to a lesser extent to liver repair.",0
3949,19437494,Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development,"Statins are 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors used for the treatment of hypercholesterolemia. It was recently reported that statins inhibit in vitro hepatitis C virus (HCV) RNA replication. We here report that, of five statins studied, mevastatin and simvastatin exhibit the strongest in vitro anti-HCV activity, lovastatin and fluvastatin have moderate inhibitory effects, and pravastatin is devoid of an antiviral effect. A combination of statins with interferon-alpha (IFN-alpha) or HCV nonstructural (NS)5B polymerase or NS3 protease inhibitors results in an additive antiviral activity in short-term (3 days) antiviral assays. Neither statins, at a concentration of five-fold their median effective concentration (EC(50)) value, nor polymerase, protease inhibitors, or IFN-alpha, at concentrations 10- or 20-fold their EC(50) value, were able to clear cells from their replicon following four or six consecutive passages of antiviral pressure. However, the combination of HCV polymerase or protease inhibitors with mevastatin or simvastatin resulted in an efficient clearance of the cultures from their replicon. In colony formation experiments, mevastatin reduced the frequency or prevented the selection of HCV replicons resistant to the nonnucleoside inhibitor HCV-796. CONCLUSION: A combination of specific HCV inhibitors with statins may result in a more profound antiviral effect and may delay or prevent the development of resistance to such inhibitors.",0
3950,19441101,Toll-like receptor 3 signaling attenuates liver regeneration,"The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor kappaB (NF-kappaB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-beta), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-kappaB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation. In this study, we explored the role of TLR3 in liver regeneration by comparing the response to 70% partial hepatectomy of TLR3(wt) and TLR3(-/-) mice. We found that following partial hepatectomy, TLR3(-/-) mice demonstrated earlier hepatocyte proliferation. Furthermore, within the first hours, we observed a dramatic TLR3-dependent NF-kappaB activation and an increase in Rip3 levels in hepatocytes, accompanied by caspase-8 activation but without an apoptotic outcome. CONCLUSION: TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration.",0
3951,19444872,Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency,"Inappropriate accumulation of the misfolded Z variant of alpha1-antitrypsin in the hepatocyte endoplasmic reticulum (ER) is a risk factor for the development of end-stage liver disease. However, the genetic and environmental factors that contribute to its etiology are poorly understood. ER mannosidase I (ERManI) is a quality control factor that plays a critical role in the sorting and targeting of misfolded glycoproteins for proteasome-mediated degradation. In this study, we tested whether genetic variations in the human ERManI gene influence the age at onset of end-stage liver disease in patients homozygous for the Z allele (ZZ). We sequenced all 13 exons in a group of unrelated Caucasian ZZ transplant recipients with different age at onset of the end-stage liver disease. Homozygosity for the minor A allele at 2484G/A (refSNP ID number rs4567) in the 3'-untranslated region was prevalent in the infant ZZ patients. Functional studies indicated that rs4567(A), but not rs4567(G), suppresses ERManI translation under ER stress conditions. CONCLUSION: These findings suggest that the identified single-nucleotide polymorphism can accelerate the onset of the end-stage liver disease associated with alpha1-antitrypsin deficiency and underscore the contribution of biosynthetic quality control as a modifier of genetic disease.",0
3952,19474426,Mutation in TET2 in myeloid cancers,"BACKGROUND: The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined. METHODS: We conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, and single-nucleotide-polymorphism analyses to identify a candidate tumor-suppressor gene common to patients with myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML). The coding sequence of this gene, TET2, was determined in 320 patients. We analyzed the consequences of deletions or mutations in TET2 with the use of in vitro clonal assays and transplantation of human tumor cells into mice. RESULTS: We initially identified deletions or mutations in TET2 in three patients with myelodysplastic syndromes, in three of five patients with myeloproliferative disorders, in two patients with primary AML, and in one patient with secondary AML. We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene. TET2 defects were observed in 15 of 81 patients with myelodysplastic syndromes (19%), in 24 of 198 patients with myeloproliferative disorders (12%) (with or without the JAK2 V617F mutation), in 5 of 21 patients with secondary AML (24%), and in 2 of 9 patients with chronic myelomonocytic leukemia (22%). TET2 defects were present in hematopoietic stem cells and preceded the JAK2 V617F mutation in the five samples from patients with myeloproliferative disorders that we analyzed. CONCLUSIONS: Somatic mutations in TET2 occur in about 15% of patients with various myeloid cancers.",0
3953,19474427,"Age, neuropathology, and dementia","BACKGROUND: Research in Alzheimer's disease is focused mainly on younger old persons, whereas studies involving very old persons report attenuated relationships between the pathological features of Alzheimer's disease and dementia. METHODS: We assessed 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69 to 103 years of age at death. We used a standard neuropathological protocol that included measures of the pathological features of Alzheimer's disease, cerebral atrophy, and cerebrovascular disease. Neuropathological variables were dichotomized to represent no burden or a mild burden of pathological lesions as compared with a moderate or severe burden. Logistic regression was used to estimate the effect of age on the relationship between neuropathological features and dementia. RESULTS: The difference in the prevalence of moderate and severe Alzheimer's-type pathological changes between persons with and those without dementia decreased with increasing age. The association between neocortical neuritic plaques and dementia was strong at 75 years of age (odds ratio, 8.63; 95% confidence interval [CI], 3.81 to 19.60) and reduced at 95 years of age (odds ratio, 2.48; 95% CI, 0.92 to 4.14), and similar attenuations with advancing age were observed in the association between other pathological changes related to Alzheimer's disease and dementia in all brain areas. In contrast, neocortical cerebral atrophy maintained a relationship with age in persons with dementia at both 75 years of age (odds ratio, 5.11; 95% CI, 1.94 to 13.46) and 95 years of age (odds ratio, 6.10; 95% CI, 2.80 to 13.28) and thus distinguished the cohort with dementia from the cohort without dementia. CONCLUSIONS: The association between the pathological features of Alzheimer's disease and dementia is stronger in younger old persons than in older old persons. Age must be taken into account when assessing the likely effect of interventions against dementia on the population.",0
3954,19474428,Inactivating PAPSS2 mutations in a patient with premature pubarche,"Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS [corrected], thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. We have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels. In vitro coincubation of human SULT2A1 and wild-type or mutant PAPSS2 proteins confirmed the inactivating nature of the mutations. These observations indicate that PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess.",0
3955,19475692,Nonstructural 3/4A protease of hepatitis C virus activates epithelial growth factor-induced signal transduction by cleavage of the T-cell protein tyrosine phosphatase,"The hepatitis C virus (HCV) is a worldwide major cause of chronic liver disease with a high tendency to establish a persistent infection. To permit persistent replication of viral genomes through the cellular translation machinery without affecting host cell viability, viruses must have developed mechanisms to control cellular cascades required for sufficient viral replication, on the one hand, and to adapt viral replication to the cellular requirements on the other hand. The present study aimed to further elucidate mechanisms by which HCV targets growth factor signaling of the host cell and their implications for viral replication. The study describes a novel mechanism by which HCV influences the activation of the epithelial growth factor receptor/Akt pathway through a nonstructural (NS)3/4A-dependent down-regulation of the ubiquitously expressed tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP). NS3/4A is demonstrated to cleave TC-PTP protease-dependently in vitro at two cleavage sites. The in vivo relevance of this finding is supported by the fact that down-regulation of TC-PTP protein expression could also be demonstrated in HCV-infected individuals and in transgenic mice with intrahepatic expression of NS3/4A. CONCLUSION: This down-regulation of TC-PTP results in an enhancement of epithelial growth factor (EGF)-induced signal transduction and increases basal activity of Akt, which is demonstrated to be essential for the maintenance of sufficient viral replication. Hence, therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects, further diminishing viral replication.",0
3956,19489072,PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression,"Human PCSK9 is known to enhance the degradation of membrane-bound receptors such as the hepatocyte low-density lipoprotein receptor (LDLR), ApoER2, and very low-density lipoprotein receptor. Because the LDLR is suspected to be involved in hepatitis C virus (HCV) entry, we also tested whether PCSK9 can affect the levels of CD81, a major HCV receptor. Interestingly, stable expression of PCSK9 or a more active membrane-bound form of the protein (PCSK9-ACE2) resulted in a marked reduction in CD81 and LDLR expression. Therefore, we analyzed the antiviral effect of PCSK9 in vitro using the HCV genotype 2a (JFH1) virus. The results clearly demonstrated that cells expressing PCSK9 or PCSK9-ACE2, but not the ACE2 control protein, were resistant to HCV infection. Furthermore, addition of purified soluble PCSK9 to cell culture supernatant impeded HCV infection in a dose-dependent manner. As expected, HuH7 cells expressing PCSK9-ACE2 were also resistant to infection by HCV pseudoparticles. In addition, we showed that CD81 cell surface expression is modulated by PCSK9 in an LDLR-independent manner. Finally, in the liver of single Pcsk9 and double (Pcsk9 + Ldlr) knockout mice, both LDLR and/or CD81 protein expression levels were significantly reduced, but not those of transferrin and scavenger receptor class B type 1. CONCLUSION: Our results demonstrate an antiviral effect of the circulating liver PCSK9 on HCV in cells and show that PCSK9 down-regulates the level of mouse liver CD81 expression in vivo. Therefore, we propose that the plasma level and/or activity of PCSK9 may modulate HCV infectivity in humans.",0
3957,19492424,Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury,"The nuclear protein high mobility group box 1 (HMGB1) is an important inflammatory mediator involved in the pathogenesis of liver ischemia/reperfusion (I/R) injury. Strategies aimed at preventing its release from stressed or damaged cells may be beneficial in preventing inflammation after I/R. Cisplatin is a member of the platinating chemotherapeutic agents and can induce DNA lesions that are capable of retaining high mobility group proteins inside the nucleus of cells. In vitro studies in primary cultured rat hepatocytes show that nontoxic concentrations of cisplatin can sequester HMGB1 inside the nucleus of hypoxic cells. Similarly, the in vivo administration of nontoxic doses of cisplatin prevents liver damage associated with a well-established murine model of hepatic I/R as measured by lower circulating serum aminotransferase levels, lower hepatic inflammatory cytokine levels including tumor necrosis factor alpha and interleukin-6, lower inducible NO synthase expression, and fewer I/R-associated histopathologic changes. The mechanism of action in vivo appears to involve the capacity of cisplatin to prevent the I/R-induced release of HMGB1 as well as to alter cell survival and stress signaling in the form of autophagy and mitogen-activated protein kinase activation, respectively. CONCLUSION: Low, nontoxic doses of cisplatin can sequester HMGB1 inside the nucleus of redox-stressed hepatocytes in vitro and prevent its release in vivo in a murine model of hepatic I/R. Furthermore, cell survival and stress signaling pathways are altered by low-dose cisplatin. Therefore, platinating agents may provide a novel approach to mitigating the deleterious effects of I/R-mediated disease processes.",0
3958,19492433,Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal-regulated kinase,"Recently, we reported that beta-carotene, vitamin D(2), and linoleic acid inhibited hepatitis C virus (HCV) RNA replication in hepatoma cells. Interestingly, in the course of the study, we found that the antioxidant vitamin E negated the anti-HCV activities of these nutrients. These results suggest that the oxidative stress caused by the three nutrients is involved in their anti-HCV activities. However, the molecular mechanism by which oxidative stress induces anti-HCV status remains unknown. Oxidative stress is also known to activate extracellular signal-regulated kinase (ERK). Therefore, we hypothesized that oxidative stress induces anti-HCV status via the mitogen activated protein kinase (MAPK)/ERK kinase (MEK)-ERK1/2 signaling pathway. In this study, we found that the MEK1/2-specific inhibitor U0126 abolished the anti-HCV activities of the three nutrients in a dose-dependent manner. Moreover, U0126 significantly attenuated the anti-HCV activities of polyunsaturated fatty acids, interferon-gamma, and cyclosporine A, but not statins. We further demonstrated that, with the exception of the statins, all of these anti-HCV nutrients and reagents actually induced activation of the MEK-ERK1/2 signaling pathway, which was inhibited or reduced by treatment not only with U0126 but also with vitamin E. We also demonstrated that phosphorylation of ERK1/2 by cyclosporine A was attenuated with N-acetylcysteine treatment and led to the negation of inhibition of HCV RNA replication. We propose that a cellular process that follows ERK1/2 phosphorylation and is specific to oxidative stimulation might lead to down-regulation of HCV RNA replication. CONCLUSION: Our results demonstrate the involvement of the MEK-ERK1/2 signaling pathway in the anti-HCV status induced by oxidative stress in a broad range of anti-HCV reagents. This intracellular modulation is expected to be a therapeutic target for the suppression of HCV RNA replication.",0
3959,19551908,Human immunodeficiency virus and hepatitis C infections induce distinct immunologic imprints in peripheral mononuclear cells,"Coinfection with hepatitis C virus (HCV) is present in one-third of all human immunodeficiency virus (HIV)-infected individuals in the United States and is associated with rapid progression of liver fibrosis and poor response to pegylated interferon (IFN) and ribavirin. In this study we examined gene expression profiles in peripheral blood mononuclear cells (PBMCs) from different groups of individuals who are monoinfected or coinfected with HIV and HCV. Data showed that HIV and HCV viremia up-regulate genes associated with immune activation and immunoregulatory pathways. HCV viremia is also associated with abnormalities in all peripheral immune cells, suggesting a global effect of HCV on the immune system. Interferon-alpha-induced genes were expressed at a higher level in PBMCs from HIV-infected individuals. HCV and HIV infections leave distinct profiles or gene expression of immune activation in PBMCs. HIV viremia induces an immune activated state; by comparison, HCV infection induces immunoregulatory and proinflammatory pathways that may contribute to progression of liver fibrosis. CONCLUSION: An aberrant type-I IFN response seen exclusively in HIV-infected individuals could be responsible for the poor therapeutic response experienced by HIV/HCV coinfected individuals receiving interferon-alpha-based current standard of care.",0
3960,19571279,M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy,"BACKGROUND: Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown. METHODS: We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody. RESULTS: Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA(2)R. CONCLUSIONS: A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease.",0
3961,19571280,Epidemiologic study of in-hospital cardiopulmonary resuscitation in the elderly,"BACKGROUND: It is unknown whether the rate of survival after in-hospital cardiopulmonary resuscitation (CPR) is improving and which characteristics of patients and hospitals predict survival. METHODS: We examined fee-for-service Medicare data from 1992 through 2005 to identify beneficiaries 65 years of age or older who underwent CPR in U.S. hospitals. We examined temporal trends in the incidence of CPR and the rate of survival after CPR, as well as patient- and hospital-level predictors of survival to discharge. RESULTS: We identified 433,985 patients who underwent in-hospital CPR; 18.3% of these patients (95% confidence interval [CI], 18.2 to 18.5) survived to discharge. The rate of survival did not change substantially during the period from 1992 through 2005. The overall incidence of CPR was 2.73 events per 1000 admissions; the incidence was higher among black and other nonwhite patients. The proportion of patients undergoing in-hospital CPR before death increased over time and was higher for nonwhite patients. The survival rate was lower among patients who were men, were older, had more coexisting illnesses, or were admitted from a skilled-nursing facility. The adjusted odds of survival for black patients were 23.6% lower than those for similar white patients (95% CI, 21.2 to 25.9). The association between race and survival was partially explained by hospital effects: black patients were more likely to undergo CPR in hospitals that have lower rates of post-CPR survival. Among patients surviving in-hospital CPR, the proportion of patients discharged home rather than to a health care facility decreased over time. CONCLUSIONS: Survival after in-hospital CPR did not improve from 1992 through 2005. The proportion of in-hospital deaths preceded by CPR increased, whereas the proportion of survivors discharged home after undergoing CPR decreased. Black race was associated with higher rates of CPR but lower rates of survival after CPR.",0
3962,19571283,The effect of Medicare Part D on drug and medical spending,"BACKGROUND: It is not known what effect the increased use of prescription drugs by enrollees in Medicare Part D has had on spending for other medical care. METHODS: We compared spending for prescription drugs and other medical care 2 years before the implementation of Part D in January 2006 with such expenditures 2 years after the program's implementation in four groups of elderly beneficiaries: Medicare Advantage enrollees with stable, uncapped, employer-based drug coverage throughout the study period (no-cap group), those who had no previous drug coverage, and those who had previous limited benefits (with either a $150 or a $350 quarterly cap) before they were covered by Part D in 2006. RESULTS: Between December 2005 and December 2007, as compared with the increase in the no-cap group, the increase in total monthly drug spending was $41 higher (95% confidence interval [CI], $33 to $50) (74%) among enrollees with no previous drug coverage, $27 higher (95% CI, $20 to $34) (27%) among those with a previous $150 quarterly cap, and $13 higher (95% CI, $8 to $18) (11%) among those with a previous $350 cap. The use of both lipid-lowering and antidiabetic medications rose in the groups with no or minimal previous drug coverage. As compared with expenditures in the no-cap group, monthly medical expenditures (excluding drugs) were $33 lower (95% CI, $29 to $37) in the group with no previous coverage and $46 lower (95% CI, $29 to $63) in the group with a previous $150 quarterly cap, whereas medical spending was $30 higher (95% CI, $25 to $36) in the group with a previous $350 cap. CONCLUSIONS: Enrollment in Medicare Part D was associated with increased spending on prescription drugs. Groups that had no or minimal drug coverage before the implementation of Part D had reductions in other medical spending that approximately offset the increased spending on drugs, but medical spending increased in the group that had more generous previous coverage.",0
3963,19573732,Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve,"""The goal of this study was to assess the predictive value of myocardial perfusion imaging with (13)N-ammonia positron emission tomography (PET) and coronary flow reserve (CFR) on long-term prognosis in patients with suspected myocardial ischemia. No prognostic data exist on the predictive value of CFR and (13)N-ammonia PET. Perfusion and CFR were assessed in 256 patients using (13)N-ammonia PET, and follow-up was obtained in 245 (96%) patients. Sixteen early revascularized patients were excluded and 229 were assigned to normal versus abnormal perfusion or normal versus abnormal CFR (<2.0). Major adverse cardiac events (MACE) (cardiac death, nonfatal myocardial infarction, late revascularization, or hospitalization for cardiac reasons) were assessed using the Kaplan-Meier method. Cox proportional hazard regression was used to identify independent predictors for cardiac events. During follow-up (5.4 +/- 2.2 years), 78 patients had at least 1 cardiac event, including 29 cardiac deaths. Abnormal perfusion (n = 126) was associated with a higher incidence of MACE (p < 0.001) and cardiac death (p < 0.05). In patients with normal perfusion, abnormal CFR was independently associated with a higher annual event rate over 3 years compared with normal CFR for MACE (1.4% vs. 6.3%; p < 0.05) and cardiac death (0.5% vs. 3.1%; p < 0.05). In abnormal perfusion, CFR remained predictive throughout the 10-year follow-up (p < 0.001). Perfusion findings in (13)N-ammonia PET and CFR are strong outcome predictors. CFR allows further risk stratification, suggesting a """"warranty"""" period of 3 years if normal CFR is associated with normal perfusion. Conversely, in patients with abnormal perfusion, an impaired CFR has added value for predicting adverse outcomes. """,0
3964,19573811,Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis,"Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity. ",0
3965,19573961,"Food chain transfer of cadmium and lead to cattle in a lead-zinc smelter in Guizhou, China","Cadmium (Cd) and Lead (Pb) are environmental pollutants. Environmental samples and bovine tissues were collected from the areas around a lead-zinc smelter in Guizhou, China for Cd, Pb, zinc (Zn) and copper (Cu) analysis. Cd in soil (10 mg/kg) and feed (6.6 mg/kg) from the polluted areas was 10 times higher than the Chinese Standards, resulting in higher Cd in bovine kidney (38 mg/kg) and liver (2.5 mg/kg). Pb in feed (132 mg/kg) from the polluted area was much higher than unpolluted areas, causing higher Pb levels in bovine tissues. Environmental Zn was elevated, but bovine tissue Zn was normal. Cu in bovine liver decreased with increased Cd and Pb. Metals in drinking water and in bovine muscle were within the Standard range. Thus, in the areas of this lead-zinc smelter, the environment has been contaminated with Cd and Pb, which has been transferred to cattle through the food chain. ",0
3966,19573963,An intradialysis diagnostic test for restless legs syndrome: a pilot study,"Restless legs syndrome (RLS) is common in dialysis patients, but a simple diagnostic test is not available. Diagnostic test study. 32 patients with RLS and 29 patients without RLS in 2 dialysis centers. The suggested immobilization test (SIT) was performed during dialysis for at least 30 minutes, and periodic limb movements (PLMs) were assessed by means of electromyography of the anterior tibialis muscles using a Holter monitor as an electromyographic monitoring device. We also assessed changes in number of leg movements on the 30-minute SIT (SIT-PLM) after 4 weeks of treatment with the dopamine agonist pergolide. Clinical review by a neurologist, International RLS Rating Scale (IRLSRS) score, and changes in IRLSRS score after pergolide treatment. PLMs on the 30-minute SIT during dialysis were identified in 20 of 32 patients with RLS and 3 of 29 control participants. Sensitivity and specificity of PLMs on the 30-minute SIT during dialysis for RLS diagnosis were 63% and 90%, respectively. SIT-PLM correlated with IRLSRS total score at diagnosis (r = 0.53; P = 0.03), suggesting that SIT-PLM measures the general severity of RLS in uremic patients. Treatment with the dopamine agonist pergolide significantly reduced the IRLSRS total score (from a mean of 24.9 +/- 9.1 [SD] to 9.5 +/- 6.8; P < 0.01) and SIT-PLM (from 41.9 +/- 24.2 to 11.3 +/- 12.3; P < 0.01), but correlation between changes in SIT-PLM and those in IRLSRS score was not significant (r = 0.27; P = 0.3). Poor correlation may be caused by the small sample size. Time available for the SIT was limited because of the patient's condition during dialysis. Time of day during SIT, mental-alerting activities during SIT, or hemodialysis therapy itself may influence the severity of PLMs. A Holter-monitored SIT during dialysis is a valid method for the diagnosis of RLS and to evaluate the effect of treatment with pergolide in uremic patients. ",0
3967,19574025,Intraosseous 'haemangioma' of the zygoma: more appropriately termed a venous malformation,"Vascular anomalies often affect the soft tissues and primary intraosseous lesions are uncommon, with only 33 cases reported in the zygoma. Intraosseous vascular anomalies of the zygoma have traditionally been designated 'haemangiomas' with little attempt to clarify the specific type of the lesion. Recently, specific immunohistochemical markers such as erythrocyte type glucose transporter protein 1 (GLUT-1) have been described to differentiate haemangiomas and vascular malformations. The authors report a case of intraosseous venous malformation of the zygoma and provide supporting evidence to justify the nomenclature. The literature on zygomatic 'haemangiomas' is critically reviewed and the basis for their proper designation as venous malformations highlighted. ",0
3968,19574218,Dissecting activation of the PAK1 kinase at protrusions in living cells,"The p21-activated kinase (PAK) 1 kinase, an effector of the Cdc42 and Rac1 GTPases, regulates cell protrusions and motility by controlling actin and adhesion dynamics. Its deregulation has been linked to human cancer. We show here that activation of PAK1 is necessary for protrusive activity during cell spreading. To investigate PAK1 activation dynamics at live protrusions, we developed a conformational biosensor, based on fluorescence resonance energy transfer. This novel PAK1 biosensor allowed the spatiotemporal visualization of PAK1 activation during spreading of COS-7 cells and during motility of normal rat kidney cells. By using this imaging approach in COS-7 cells, the following new insights on PAK1 regulation were unveiled. First, PAK1 acquires an intermediate semi-open conformational state upon recruitment to the plasma membrane. This semi-open PAK1 species is selectively autophosphorylated on serines in the N-terminal regulatory region but not on the critical threonine 423 in the catalytic site. Second, this intermediate PAK1 state is hypersensitive to stimulation by Cdc42 and Rac1. Third, interaction with PIX proteins contributes to PAK1 stimulation at membrane protrusions, in a GTPase-independent way. Finally, trans-phosphorylation events occur between PAK1 molecules at the membrane possibly playing a relevant role for its activation. This study leads to a model for the complex and accurate regulation of PAK1 kinase in vivo at cell protrusions. ",0
3969,19574839,Molecular alterations associated with aneurysmal remodeling are localized in the high hemodynamic stress region of a created carotid bifurcation,"Although elevated hemodynamics has been speculated to play a key role in intracranial aneurysm (IA) initiation, little is known about the specific hemodynamic microenvironment that triggers aneurysmal vascular degradation. We previously demonstrated maladaptive remodeling characteristic of IA initiation occurring in hemodynamic regions of combined high wall shear stress (WSS) and high WSS gradient near the apex of an experimentally created carotid bifurcation. This study examines whether this remodeling recapitulates the molecular changes found in IAs and whether molecular changes also correspond to specific hemodynamic environments. De novo bifurcations were surgically created using both native common carotid arteries in each of 6 dogs. Bifurcations were imaged 2 weeks or 2 months after surgery by high-resolution 3-dimensional angiography, from which flow fields were obtained by computational fluid dynamics simulations. Subsequently, harvested tissues, demonstrating early aneurysmal changes near the apex, were immunostained for interleukin-1beta, endothelial and inducible nitric oxide synthases, nitrotyrosine, and matrix metalloproteinase-2 and -9. Spatial distributions of these molecules were comapped with computational fluid dynamics results. The aneurysmal wall showed decreased endothelial nitric oxide synthase expression compared with surrounding segments, the feeding artery, and native controls, whereas all other markers increased. Anti-CD68 staining indicated the absence of inflammatory cells in the aneurysmal wall. Comapping molecular marker distributions with flow fields revealed confinement of these molecular changes within the hemodynamic region of high WSS and high, positive WSS gradient. Aneurysm-initiating remodeling induced by combined high WSS and high, positive WSS gradient is associated with molecular changes implicated in IAs. ",0
3970,19575051,Clinical evaluation of polyamide polymer burs for selective carious dentin removal,"The aim of this study was to evaluate the carious dentin removal efficacy of new rotary polyamide burs capable of selectively removing infected dentin without removing sound dentin. This study included 40 subjects with bilateral occlusal carious lesions on mandibular first permanent molars. The lesions were randomly assigned to receive one restoration after carious dentin removal with a polymer bur and the second after removal of carious dentin with a carbon steel round bur. Both procedures were completed by a single operator in one appointment. The efficacy of caries removal, time taken for caries removal, and patients' perception of the treatment were evaluated. The restorations were evaluated immediately and after six months using intraoral periapical radiographs (IOPA). The results revealed statistically significant differences between the polymer burs and carbon steel burs with respect to caries removal efficacy (p<0.001) and the time taken for caries removal (p<0.001). No statistically significant results were obtained regarding patients' perception of the treatment and longevity of the restorations. Carbon steel round burs remove caries lesions more efficiently than polymer burs but they tend to contribute to the over-preparation of the cavity. Polyamide burs were found to be self-limiting and lose their cutting efficiency on reaching affected dentin and do not cut sound dentin. The time required for caries removal using the polymer bur was significantly longer than when using a carbon steel round bur. One of the goals of conservative dentistry is to develop a method for removing caries-infected dentin while preserving caries-unaffected dentin. The use of polymer burs appears to offer a straightforward and efficient means for achieving this goal and conserving healthy tooth structure. ",0
3971,19575147,Information gaps for patients requiring craniotomy for benign brain lesion: a qualitative study,"Doctor-patient communication in the setting of a life-threatening illness poses considerable challenges. This study aimed to determine the information needs of a subset of neurosurgical patients. Qualitative case study methodology was used. Twenty-five semi-structured interviews were conducted with ambulatory adult patients who had undergone surgery for a benign brain tumor, arteriovenous malformation, or unruptured aneurysm. Interviews were digitally audio recorded and transcribed, and the data subjected to thematic analysis. Six overarching themes emerged from the data: (1) the amount of information patients want varies; (2) the type of information needed is not limited to information about treatment options and risks; (3) patients engage in independent information seeking for a variety of reasons; (4) patients consider compassion from their surgeon as important; (5) direct communication with the surgeon post-operatively is very important; and (6) patients' information needs are greatest post-operatively. Many patients felt that the amount and quality of information they received was not sufficient, particularly regarding post-operative recovery and long-term life issues, leading many to do their own research. The findings from this study emphasize the need for improved communication with patients so they can participate meaningfully in choices about their treatment, give a truly informed consent, and effectively participate in their own recovery. ",0
3972,19575210,A simple quality of life questionnaire for patients with faecal incontinence,"A simple quality of life questionnaire was designed to triage patients with faecal incontinence to the most appropriate level of support, investigation and treatment. A questionnaire was developed to include a 'symptom' score, similar in content to St Mark's questionnaire and a 'bothersome' score. A pilot study (34 patients) assessed the clarity of questions. Once content validity was established, it was sent to 360 patients who attended a pelvic floor clinic. Its external validity was assessed against the established standards of the short form 36 (SF-36) and the Manchester Health Questionnaires. Ease of use for these was assessed using a separate form. Of the 360 patients, 86 replied. The questionnaire was shown to be reliable both by measurement of its internal consistency and by test-retest analysis. There was a significant correlation between the scores of the new questionnaire and the Manchester Health Questionnaire as well as the SF-36. Divergence validity, assessed by correlating the number of pads used and the overall symptom score, was established. The new questionnaire was easiest to complete, taking on average 4 min. We have demonstrated that the new questionnaire is reliable and valid. It is easy and quick to complete and assesses both severity and impact of symptoms. ",0
3973,19575274,"Cerebellar brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 expression in male and female rats is differentially affected by hypergravity exposure during discrete developmental periods","We previously reported that the effects of perinatal exposure to hypergravity on cerebellum and motor functions in rat neonates are strongly dependent on the specific developmental period of exposure. In the present study, we explored the hypothesis that neurodevelopmental changes are associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. We compared the effects of hypergravity exposure during four developmental periods: period I extended from gestational day (G) 8 through G15; period II from G15 to birth, period III from birth to postnatal day (P) 6; and period IV extended from G8-P12. For comparison we used stationary control (SC) neonates not exposed to hypergravity. Neurotrophins, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT-3) levels were measured in cerebellar homogenates prepared from postnatal day 12 male and female rat neonates using specific ELISAs. Hypergravity exposure affected individual neurotrophins differently and the effect was further determined by the period of hypergravity exposure. ANOVA showed: (1) a significant effect of the period of exposure to hypergravity on cerebellar BDNF (p = 0.009), with maximal decrease of 28.7% in males and 32.1% in females following exposure during period III; (2) a significant effect on NGF (p < 0.0001), with maximal decrease of 35.6% in male and 48.8% in female neonates following exposure during period III; (3) no statistically significant effect on NT-3 expression with a trend towards decreased expression in female rats following exposure during period IV. Although the molecular mechanisms underlying the differential neurotrophins' response to hypergravity are not clear, an altered pattern of their expression is likely to contribute to neurodevelopmental changes and impaired sensorimotor behavior in exposed neonates. ",0
3974,19575366,Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients,"Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1-infected patients represents one possible strategy. Four hundred thirty-three patients were randomly assigned to receive either 1.5 microg/kg peginterferon alfa-2b weekly plus 800-1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18-48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription-mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. CONCLUSION: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia.",0
3975,19575456,Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver,"The mechanisms of tolerance in the liver that limit susceptibility to food allergy and that mediate the acceptance of liver transplants, even with a complete major histocompatibility complex (MHC) mismatch, remain poorly defined. Here we report that in a model of liver-directed gene transfer, cytotoxic T lymphocyte (CTL) responses to non-self antigens are controlled by hepatic regulatory T cells (Tregs) that secrete the immunosuppressive cytokine interleukin (IL)-10 in response to the antigen. In addition, Kupffer cells (KCs), normally thought to initiate immune responses, are rendered tolerogenic in this context. The depletion of KCs results in a complete abrogation of IL-10 production by hepatic Tregs, indicating an interaction between Tregs and KCs in the induction of tolerance. CONCLUSION: Our study suggests that hepatic Tregs together with KCs create a local suppressive microenvironment that prevents the establishment of the CTL response. These mechanisms provide pivotal insights and may prove instrumental in the tolerization toward non-self therapeutic proteins delivered to the liver.",0
3976,19575557,"Genomics, genetics, and cell biology of magnetosome formation","Magnetosomes are specialized organelles for magnetic navigation that comprise membrane-enveloped, nano-sized crystals of a magnetic iron mineral; they are formed by a diverse group of magnetotactic bacteria (MTB). The synthesis of magnetosomes involves strict genetic control over intracellular differentiation, biomineralization, and their assembly into highly ordered chains. Physicochemical control over biomineralization is achieved by compartmentalization within vesicles of the magnetosome membrane, which is a phospholipid bilayer associated with a specific set of proteins that have known or suspected functions in vesicle formation, iron transport, control of crystallization, and arrangement of magnetite particles. Magnetosome formation is genetically complex, and relevant genes are predominantly located in several operons within a conserved genomic magnetosome island that has been likely transferred horizontally and subsequently adapted between diverse MTB during evolution. This review summarizes the recent progress in our understanding of magnetobacterial cell biology, genomics, and the genetic control of magnetosome formation and magnetotaxis. ",0
3977,19575768,Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf,"Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here, we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress-response conditions. Under nonstressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1-dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses. ",0
3978,19575839,Sudden deafness in a patient with secondary syphilis,"To emphasise the importance of considering a diagnosis of early acquired syphilis in all sexually active adults, and to review the ENT manifestations and treatment of acquired syphilis. A 24-year-old woman presented with sudden hearing loss, and subsequently developed clinical features suggestive of secondary syphilis. She was seen in the departments of ENT, dermatology, rheumatology and infectious diseases before a correct diagnosis was made. Treatment resulted in only partial recovery of hearing. With the exponential rise in syphilis cases in the UK, there has been a re-emergence of presenting manifestations that had previously become rare. Early syphilis should be considered in all sexually active adults who present with deafness, as prompt diagnosis and treatment are crucial for maximum recovery. ",0
3979,19576284,Internodal myelination during development quantitated using X-ray diffraction,"Characterizing the formation, accretion, and stability of myelin during development, maturation, and senescence is important for better understanding critical periods in the function of the nervous system in normal growth and following environmental insult or genetic mutation. Although there are numerous studies on the ultrastructural, biochemical, and genetic aspects of myelin development and maturation, few have used X-ray diffraction (XRD), which can rapidly provide unique metrics about internodal myelin based on measurements from whole, unfixed tissue. Besides periodicity (the classic attribute of internodal myelin measured by XRD), other parameters include: relative amount of myelin, membrane dimensions, and packing disorder. To provide a baseline for future experiments on myelin structural integrity, we used XRD to characterize internodal myelin as a function of age (from 5 to 495 days) in the mouse, a species increasingly used for developing transgenic models of human neurological diseases. As expected, the relative amount of myelin increased with age in both PNS and CNS, with the most rapid accumulation occurring in the youngest age group. Changes in rate of myelin accretion yielded three distinct age brackets during which small but significant changes in structural parameters were detected: in PNS, myelin period increased, packing distortion decreased, width of extracellular apposition (EXT) decreased, and widths of cytoplasmic apposition (CYT) and lipid bilayer (LPG) increased; in CNS, myelin period decreased, packing distortion decreased, EXT and CYT decreased, and LPG increased. We propose that the data obtained here can serve as a basis for rapidly detecting abnormal pathologies during myelination. ",0
3980,19576306,A Jurkat transcriptional reporter cell line for high-throughput analysis of the nuclear factor-kappaB signaling pathway,"The transcription factor, Nuclear Factor-kappaB (NF-kappaB), regulates many genes involved in host immunity and cell survival. Unregulated NF-kappaB activity has been linked to many chronic inflammatory diseases and is an important target for the identification of inhibitors to better manage these disorders. We present a novel screening system to identify NF-kappaB inhibitors that combines sensitive fluorescence detection with medium- to high-throughput flow cytometry (HyperCyt). To validate this approach, we quantified the activation of NF-kappaB by standard flow cytometry and the HyperCyt platform. Results were comparable with regard to EC(50) values for TNFalpha-mediated activation; however, the HyperCyt platform provided more sensitive signal detection and a greater linear range for detection. To demonstrate the usefulness of this screening tool, we identified a novel inhibitor of NF-kappaB activation from a resveratrol-based chemical library. The inhibition of NF-kappaB activation by analog 6q (IC(50) = 19 microm) showed a 3.7-fold improvement over that of resveratrol (IC(50) approximately 70 microm). ",0
3981,19576357,"Value of orthopnea, paroxysmal nocturnal dyspnea, and medications in prospective population studies of incident heart failure","Prospective population studies of incident heart failure (HF) are often limited by difficulties in assembling HF-free cohorts. In this study, public-use copies of the Cardiovascular Health Study (CHS) data sets were used to determine the sensitivity, specificity, and positive and negative predictive values of orthopnea and paroxysmal nocturnal dyspnea (PND), with and without the use of medications used in CHS HF criteria (diuretics plus digoxin or vasodilators), in the diagnosis of prevalent HF and in the assembly of a relatively HF-free population. Of the 5,771 community-dwelling older adults aged > or =65 years, 803 had orthopnea, 660 had PND, 1,075 had either symptom, 388 had both symptoms, 547 were using HF medications, and 4,315 had neither symptom and were not using HF medications. Definite HF was centrally adjudicated in 272 participants. The sensitivity, specificity, and positive and negative predictive values for either orthopnea or PND were 52% (95% confidence interval [CI] 46% to 58%), 83% (95% CI 82% to 84%), 13% (95% CI 11% to 15%), and 97% (95% CI 97% to 98%), respectively, and those for either orthopnea or PND or the use of HF medications were 77% (95% CI 72% to 82%), 77% (95% CI 76% to 79%), 14% (95% CI 13% to 16%), and 99% (95% CI 98% to 99%), respectively. In conclusion, only <20% of those with either orthopnea or PND had definite HF, which limits their usefulness in the diagnosis of prevalent HF in the community. However, nearly 99% (negative predictive value) of those with neither symptom nor using HF medications also did not have HF, which may be useful as a simple and inexpensive tool in assembling relatively HF-free cohorts for prospective population studies of incident HF. ",0
3982,19576380,Determination of HIV drugs in biological matrices: a review,"The present paper reviews the recent advances on the determination of antiretroviral drugs against the human immunodeficiency virus (HIV). Methods have been reviewed with special emphasis on the principal analytical strategies for dealing with clinical samples as well as the determination of the newest drugs. The most critical steps of the analytical procedures including the sample treatment, separation and validation have been discussed. Finally, a brief description of representative applications is given. ",0
3983,19576524,"Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists","In this article, the authors discuss the pharmacology of sedative-analgesic agents like dexmedetomidine, remifentanil, ketamine, and volatile anesthetics. Dexmedetomidine is a highly selective alpha-2 agonist that provides anxiolysis and cooperative sedation without respiratory depression. It has organ protective effects against ischemic and hypoxic injury, including cardioprotection, neuroprotection, and renoprotection. Remifentanil is an ultra-short-acting opioid that acts as a mu-receptor agonist. Ketamine is a nonbarbiturate phencyclidine derivative and provides analgesia and apparent anesthesia with relative hemodynamic stability. Volatile anesthetics such as isoflurane, sevoflurane, and desflurane are in daily use in the operating room in the delivery of general anesthesia. A major advantage of these halogenated ethers is their quick onset, quick offset, and ease of titration in rendering the patient unconscious, immobile, and amnestic. ",0
3984,19576721,Endotension after endovascular treatment of abdominal aortic aneurysm: percutaneous treatment,"Endotension is one of the possible specific late complications of endovascular treatment of abdominal aortic aneurysm (AAA). We describe the treatment of endotension in a small group of 3 patients (all men, aged 58, 70, and 70-years-old) by translumbar puncture of the aneurysm sac and aspiration of its content. It was transudate and its culture was negative. Sac size reduced after aspiration in all patients and no subsequent enlargement was seen. Percutaneous translumbar puncture of the aneurysm sac with aspiration of sac content could be an easy and effective method of treatment in endotension. But a larger group of patients and long-term follow-up are needed. ",0
3985,19576813,Spontaneous rupture of benign ovarian cystic teratoma in a premenarcheal girl,"Spontaneous rupture of benign cystic ovarian teratoma is an unusual occurrence. A 9-year-old girl presented with acute onset of abdominal pain. Under a radiological diagnosis of cystic ovarian teratoma, she underwent laparoscopic cystectomy, preserving as much ovarian tissue as possible. Direct observation of a defect on the tumor surface and the presence of keratinized squamous cells in the ascites were important clues for intraperitoneal rupture. Pathologically, the defect was surrounded by inflamed tissues adjacent to the gastric mucosa, suggesting that autolysis of the wall by proteolytic enzymes induced the spontaneous rupture. We present the youngest and first premenarcheal case of spontaneous rupture of cystic ovarian teratoma. Early diagnosis and minimally invasive surgical procedure are essential to preserve future fertility. ",0
3986,19576968,The essential oils of Chamaecyparis obtusa promote hair growth through the induction of vascular endothelial growth factor gene,"Chamaecyparis obtusa (C. obtusa) is a conifer in the cypress family Cupressaceae, native to northeast Asia. The essential oils of C. obtusa have antibacterial and antifungal effects and several products such as hygienic bands, aromatics, and shampoos contain these oils as a natural source of antimicrobial/antifungal agents. Interestingly, some consumers suffering from baldness and/or other forms of hair loss have reported a hair growth promoting effect of shampoos containing these oils. In the present study, the hair growth promoting effect of C. obtusa oils was elucidated in an animal model. C. obtusa oils promoted the early phase of hair growth in shaved mice. In addition, we examined the molecular effect of C. obtusa oils on the regulation of hair morphogenesis and hair growth using the human keratinocyte cell line HaCaT. In the current study of hair growth regulating genes, the expressions of vascular endothelial growth factor (VEGF), transforming growth factor (TGF beta 1), and keratinocyte growth factor(KGF) have been analyzed by real-time PCR in HaCaT cells. The essential oils of C. obtusa were divided into seven fractions for treatment of HaCaT cells. VEGF transcripts were induced by fractions 6 and 7; however, TGF beta 1 and KGF mRNA levels were unchanged by C. obtusa oils or fractions. Fraction 7 was separated into seven sub-fractions and studied further. Sub-fractions E and D significantly increased VEGF and KGF gene expression without up-regulating the hair growth inhibition factor, TGF beta 1. The components of the two sub-fractions were further analyzed by gas chromatography and mass spectrometry. Cuminol, eucarvone, and calamenene were common to these two sub-fractions, although the effects of these individual components were not determined. Taken together, these results suggest that C. obtusa oils promote hair growth in an animal model and a positive regulator of hair growth, VEGF, was induced by particular components of these oils. ",0
3987,19577665,Medaka dead end encodes a cytoplasmic protein and identifies embryonic and adult germ cells,"dead end (dnd) was identified in zebrafish as a gene encoding an RNA-binding protein essential for primordial germ cell (PGC) development and gametogenesis in vertebrates. The adult dnd RNA expression has been restricted to the ovary in Xenopus or to the testis in mouse. Its protein product is nuclear in chicken germ cells but both cytosolic and nuclear in mouse cell cultures. Here we report the cloning and expression pattern of Odnd, the medakafish (Oryzias latipes) dnd gene. Sequence comparison, gene structure, linkage analysis and expression demonstrate that Odnd encodes the medaka Dnd orthologue. A systematic comparison of Dnd proteins from five fishes and tetrapod representatives led to the identification of five previously unidentified conserved regions besides the RNA recognition motif. The Odnd RNA is maternally supplied and preferentially segregated with PGCs. Its adult expression occurs in both sexes and is restricted to germ cells. In the testis, Odnd is abundant in spermatogonia and meiotic cells but absent in sperm. In the ovary, Odnd RNA persists throughout oogenesis. Furthermore, we developed a dual color fluorescent in situ hybridization procedure allowing for precise comparisons of expression and distribution patterns between two genes in medaka embryos and adult tissues. Importantly, this procedure co-localized Odnd and Ovasa in testicular germ cells and PGCs. Surprisingly, by cell transfection and embryo RNA injection we show that ODnd is cytoplasmic in cell cultures, cleavage embryos and PGCs. Therefore, medaka dnd encodes a cytoplasmic protein and identifies embryonic and adult germ cells of both sexes. ",0
3988,19577753,Neopterin levels and left ventricular dysfunction in patients with chronic stable angina pectoris,"Left ventricular ejection fraction (LVEF) is the strongest predictor of survival in patients with chronic stable angina (CSA). Inflammation plays a key role in the pathogenesis of atherosclerosis and an enhanced inflammatory status has a negative impact on patient outcome. It is not known whether a relationship exists between inflammation and LV function in patients with CSA. We therefore sought to investigate whether C reactive protein (CRP) and neopterin correlate with LV dysfunction in patients with CSA. We assessed 181 patients with CSA who underwent diagnostic coronary angiography in our institution. High-sensitivity CRP and neopterin serum concentrations were measured immediately before angiography. Baseline neopterin levels - but not CRP - showed a significant inverse correlation with LVEF (r=-0.222; p=0.003 and r=-0.097; p=0.194, respectively). After adjustment for relevant confounders which included, among others, the extent and severity of coronary disease, neopterin was found to be independently associated with LVEF (B -2.36, CI 95% -4.560 to -0.176, p=0.034). Moreover, high neopterin levels were an independent predictor of LV dysfunction (LVEF <45%) (OR, 8.52, CI 95% 1.10-65.64; p=0.040). Receiver operating characteristic analysis for neopterin showed an area under the curve of 0.736 (CI 95% 0.59-0.87, p<0.009) for prediction of LV dysfunction. Increased serum neopterin concentrations inversely correlate with LVEF values and high neopterin levels are a predictor of LV dysfunction in patients with CSA, irrespective of the extent and severity of coronary artery disease. Neopterin may thus be clinically useful for patient risk stratification. ",0
3989,19578098,Environmentally induced responses co-opted for reproductive altruism,"Reproductive altruism is an extreme form of altruism best typified by sterile castes in social insects and somatic cells in multicellular organisms. Although reproductive altruism is central to the evolution of multicellularity and eusociality, the mechanistic basis for the evolution of this behaviour is yet to be deciphered. Here, we report that the gene responsible for the permanent suppression of reproduction in the somatic cells of the multicellular green alga, Volvox carteri, evolved from a gene that in its unicellular relative, Chlamydomonas reinhardtii, is part of the general acclimation response to various environmental stress factors, which includes the temporary suppression of reproduction. Furthermore, we propose a model for the evolution of soma, in which by simulating the acclimation signal (i.e. a change in cellular redox status) in a developmental rather than environmental context, responses beneficial to a unicellular individual can be co-opted into an altruistic behaviour at the group level. The co-option of environmentally induced responses for reproductive altruism can contribute to the stability of this behaviour, as the loss of such responses would be costly for the individual. This hypothesis also predicts that temporally varying environments, which will select for more efficient acclimation responses, are likely to be more conducive to the evolution of reproductive altruism. ",0
3990,19578103,Serologic follow-up of children born to mothers with Ro/SSA autoantibodies,"Neonatal lupus erythematosus (NLE) develops in foetuses of mothers with Ro/SSA and La/SSB antibodies and may include foetal atrioventricular block and dermatologic manifestations. In this study, we investigated postnatal Ro and La IgG, IgA and IgM antibody levels up to 1 year of age in 32 children born to Ro/SSA positive mothers. Antibody levels were correlated with NLE manifestations, and the role of breast feeding in transfer of autoantibodies from mother to child was evaluated. Ro52, Ro60 and La IgG antibodies all transferred from the mothers to their foetus in utero and were present in the infant at birth as detected by enzyme-linked immunosorbent assay using recombinant antigens and a synthetic peptide. A significant decrease in Ro52, Ro60 and La IgG autoantibody levels of the infants was observed from birth to 4-5 weeks of age (P < 0.05, P < 0.05 and P < 0.01). Ro- and La-specific IgA and IgM antibodies were detected in the serum from a subset of mothers. However, Ro- and La-specific IgA and IgM antibody levels were low or non-detectable in children raised both with and without breastfeeding. Furthermore, NLE skin lesions developed independently of breastfeeding. Our findings support a role for placental materno-foetal transfer of IgG autoantibodies in the pathogenesis of NLE and indicate that refraining from breastfeeding does not protect from NLE skin involvement. ",0
3991,19578317,A case of solitary fibrous tumor of the pancreas],"A 58-year-old woman without any clinical symptoms had a routine health check-up, during which a mass in the head of the pancreas was detected by US. Abdominal US showed a round, hypoechogenic nodule of the pancreatic head. The tumor measured 3cm in diameter and contained an anechoic area. CT revealed a well-demarcated tumor in the pancreatic head. The tumor was partially enhanced by contrast medium, but the left portion of the tumor, which US had shown to be an anechoic area was not enhanced. Imaging findings suggested an endocrine tumor with cystic changes. A pylorus-preserving pancreatoduodenectomy was performed. The tumor was composed of spindle-shaped cells. There was a typical patternless growth of short fascicles and a short storiform arrangement of cells in the stroma with varying degrees of collagenization. Immunohistochemically, the tumor cells were positive for CD34 and Bcl-2. Based on the light microscopic morphology and immunostaining profile, the tumor was classified as a solitary fibrous tumor (SFT) of the pancreas. ",0
3992,19578409,Posterior tarsal tunnel syndrome: diagnosis and treatment,"Posterior tarsal tunnel syndrome is an uncommon clinical entity which is sometimes misdiagnosed in patients with pain of the retromalleolar region and the plantar aspect of the foot. Surgical intervention is recommended for correctly diagnosed posterior tarsal tunnel syndrome. Selective literature review. Surgical treatment is indicated in the presence of dysesthesias refractory to conservative treatment or of neurological deficits. If a neural tumor or tarsal tunnel ganglion is suspected, diagnostic imaging (MRI, neurosonography) should precede surgery. Division of the flexor retinaculum (ligamentum laciniatum) in the tarsal tunnel must always include distal decompression of the end branches of the tibial nerve posterior to the fascia of the abductor hallucis muscle. Only extensive exposure of the nerve guarantees adequate release. Accurate diagnosis requires the evaluation of relevant clinical, neurological, and neurophysiological findings along with the careful consideration of other possible diagnoses. High success rates of 44% to 91% are reported after operative treatment. The results are better in idiopathic than in posttraumatic cases. If surgery fails, re-operation is indicated only in patients with inadequate release. ",0
3993,19578588,Dissemination of information on visceral leishmaniasis from schoolchildren to their families: a sustainable model for controlling the disease,"A model for the dissemination of information on visceral leishmaniasis from schoolchildren to their families was evaluated in two schools in Caeté, Minas Gerais State, Brazil. Age ranged from 9 to 17 years in the two schools, one receiving the intervention (with 92 students) and the other serving as the control (96 students). All the students attended a class and received a pamphlet on visceral leishmaniasis. The intervention consisted of a homework assignment in which the student discussed the class content and pamphlet with a family member. Knowledge by family members (n = 100) on visceral leishmaniasis was evaluated with a pre and post-intervention questionnaire applied by a health agent, who also completed a form on hygiene around the household as observed during the home visit. A significant improvement was observed in knowledge and hygiene (e.g., sweeping of leaves, fruit, and branches from the yards) among the families that were exposed to the intervention (p < 0.05). The spread of information on visceral leishmaniasis by schoolchildren can contribute to measures for preventing the disease. ",0
3994,19578625,Neurotoxoplasmosis diagnosis for HIV-1 patients by real-time PCR of cerebrospinal fluid,"Encephalitis caused by Toxoplasma gondii is the most common cause of central nervous system damage in patients with acquired immunodeficiency syndrome (AIDS). Toxoplasma may infect any of the brain cells, thus leading to non-specific neurotoxoplasmosis clinical manifestations including focused or non-focused signs and symptoms of central nervous system malfunction. Clinical development ranges from insidious display during weeks to experiencing acute general confusion or ultimately fatal onset. Cerebral toxoplasmosis occurs in advanced stages of immunodeficiency, and the absence of anti-toxoplasmosis antibodies by the immunofluorescence method does not allow us to rule out its diagnosis. As specific therapy begins, diagnosis confirmation is sought through clinical and radiological response. There are few accurate diagnosis methods to confirm such cases. We present a method for T. gondii DNA detection by real time PCR-Multiplex. Fifty-one patients were evaluated; 16 patients had AIDS and a presumptive diagnosis for toxoplasmosis, 23 patients were HIV-positive with further morbidities except neurotoxoplasmosis, and 12 subjects were HIV-negative control patients. Real time PCR-Multiplex was applied to these patients' cephalorachidian liquid with a specific T. gondii genome sequence from the 529bp fragment. This test is usually carried out within four hours. Test sensitivity, specificity, positive predictive value, and negative predictive value were calculated according to applicable tables. Toxoplasma gondii assay by real time Multiplex of cephalorachidian fluid was positive for 11 out of 16 patients with AIDS and a presumptive diagnosis for cerebral toxoplasmosis, while none of the 35 control patients displayed such a result. Therefore, this method allowed us to achieve 68.8% sensitivity, 100% specificity, 100% positive predictive value, and 87.8% negative predictive value. Real time PCR on CSF allowed high specificity and good sensitivity among patients who presumably had cerebral toxoplasmosis. Since this is a low invasive method, it could be included in the diagnosis algorithm of patients with AIDS and central nervous system damage. ",0
3995,19578936,"Dairy intake and 1,25-dihydroxyvitamin D levels in men at high risk for prostate cancer","Dairy food intake has been associated with prostate cancer in previous work, but the mechanism by which this occurs is unknown. Dairy calcium may suppress circulating levels of potentially cancer-protective 1,25-hydroxyvitamin D (1,25(OH)2D). We examined the associations of dairy, milk, calcium, and vitamin D intake with plasma 1,25(OH)2D levels among 296 men (194 black, 102 non-black) enrolled in a high risk program for prostate cancer from 10/96 to 10/07. All participants completed diet and health history questionnaires and provided plasma samples, which were assessed for levels of 25-hydroxyvitamin D and 1,25(OH)2D. We used multivariate linear regression to examine associations with 1,25(OH)2D. After adjustment for age, race, energy intake, BMI, and alcohol intake, we observed no associations for any of our variables of interest with 1,25(OH)2D, or any meaningful differences in estimates by race or vitamin D status. Our findings, in a sample including a large proportion of black participants, do not confirm previous findings showing an inverse association between calcium intake and 1,25(OH)2D levels. As such, they suggest that future work should explore other mechanisms by which dairy foods and calcium might increase prostate cancer risk. ",0
3996,19579053,Multivariate analysis for characteristics of heat tolerance in horses in Brazil,"The environment in which the horse is reared affects its ability to maintain thermal balance which is in turn related to thermal characteristics and regulatory physiological mechanisms. In this study a multivariate analysis of physiological traits in relation to heat tolerance in horses was carried out in the Federal District, Brazil. The aim was to test the ability of these analyses to separate groups of animals and determine which physiological traits are most important in the adaptation to heat stress. Forty adult horses (4 to 13 years) were used, ten from each of four different genetic groups (English thoroughbred, Brazilian showjumper, crossbred and Breton). The traits examined included heart and breathing rate, rectal temperature as well as blood parameters. The data underwent multivariate statistical analysis including cluster, discriminate and canonical using Statistical Analysis System - SAS (R) procedures CLUSTER, STEPDISC, CANCORR and DISCRIM. The tree diagram showed clear distances between groups studied and canonical analysis was able to separate individuals in groups. The discriminate analysis identified the variables which were most important in separating these groups. The multivariate analysis was able to separate the animals into groups with RR, HR and RT being important in this separation. ",0
3997,19579177,"Telcagepant, a calcitonin gene-related peptide antagonist for the treatment of migraine","Telcagepant is an oral calcitonin-gene related peptide (CGRP) receptor antagonist that is being developed by Merck & Co Inc for the treatment of migraine. This compound blocks CGRP receptors and may block the dilation of dural vessels and reduce neurotransmission in the CNS, resulting in pain relief. Telcagepant does not cause vasoconstriction, one of the major limitations in the use of triptans, which are considered to be the standard of care for migraine. Data from phase II and III clinical trials suggest that the use of telcagepant for the acute treatment of migraine was comparable with the use of triptan compounds and was superior to placebo in all primary endpoints, including pain relief and freedom from pain at 2 h. However, recent data reported elevated transaminase levels when telcagepant was dosed daily rather than acutely. It was concluded that, if these hepatic toxicities are not observed in ongoing/future trials of the acute use of telcagepant, then this agent may offer an alternative to triptan therapy for the treatment of migraine. ",0
3998,19579182,Antioxidative phenylpropanoid-substituted epicatechin glycosides from Parabarium huaitingii,"Three new phenylpropanoid-substituted epicatechin glycosides, namely parabarosides A - C ( 1- 3), together with three known compounds, 5-caffeoylquinic acid (4), 5-caffeoylshikimic acid (5), and 3,4-dicaffeoylquinic acid (6), were obtained from the plant Parabarium huaitingii. Their structures were determined and full assignments of (1)H- and (13)C-NMR spectroscopic data were achieved by analyses of 1D- and 2D-NMR, mass, and CD spectra. The oxygen radical absorbance capacity (ORAC) assay was applied to evaluate their antioxidative capacity in vitro, which revealed that 1- 6 showed strong antioxidative properties. ",0
3999,19579691,Mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis isolates from Eastern Poland,"This study investigated mutations in the rpoB gene of rifampin-resistant isolates obtained from patients living in Eastern Poland. A total of 37 phenotypically and/or genotypically confirmed M. tuberculosis rifampin-resistant clinical isolates were included in this study. The strains were selected from symptomatic patients with a diagnosis of pulmonary and extrapulmonary tuberculosis. A line probe assay kit (INNO-LiPA rif Tb) was used for any specific mutational pattern of rpoB gene. Our data support the common notion that rifampin resistance genotypes with mutation at a critical codon, i.e. the one encoding Ser-531, is frequent in M. tuberculosis populations regardless of geographic origin. Our findings also suggest that in a geographic area such as Eastern Poland less common mutations of the rpoB gene occur more frequently. The frequency of substitution at codon 526 (His-Asp) was found to be high in Lublin. This study indicates that mutations associated with nucleotide replacements in codons 526 (His-Asp) and 531 (Ser-Leu) were associated with a high percentage of RMP resistance, whereas mutations in codons 516 (Asp-Val) and 526 (His-Tyr) were observed in a low percentage of RMP-resistance. ",0
4000,19579696,Direct antifungal susceptibility testing of positive Candida blood cultures by sensititre YeastOne,"Invasive candidiasis is associated with high morbidity and mortality. Differences in the virulence and susceptibility of the various Candida spp. to antifungal drugs make the identification and rapid MIC determination very important for clinical management. The aim of this study was to improve the turnaround time (TAT) for antimicrobial test generation by susceptibility testing directly from the bottle of blood culture positive for yeasts, circumventing the isolation process and thereby generating an accurate antifungal MIC determination as quickly as possible. Sensititre YeastOne was used by direct inoculation from positive blood culture bottles in 40 cases of candidaemia. All the results were compared with those obtained using standard laboratory procedures after subculturing from a positive bottle onto solid media. The results obtained from direct inoculation of Sensititre YeastOne compared with tests carried out using standard procedures show that out of a total of 40 strains tested no very major errors or major errors and only 4 minor errors occurred (98% agreement rate out of a total of 240 drug/bug combinations tested), thus generating an accurate antifungal MIC determination and saving an average time of 24 hours compared with the time required for the standard procedures traditionally used. ",0
4001,19579740,Gestational diabetes mellitus--a forerunner of chronic disorders in mother and child,"Gestational Diabetes Mellitus (GDM) can have serious immediate as well as long term consequences, both for the mother as well as the off-spring. It seems that women of south Asian origin are not only more likely to have GDM but also suffer more from the adverse consequences of the disorder. These consequences include the development of type 2 DM in women with a history of GDM and a higher risk of obesity and metabolic syndrome in the off-spring. Pakistani physicians should consider GDM seriously because the WHO states that rise in the prevalence of type 2 DM will mainly occur in developing countries such as ours. Since GDM can lead to development of type 2 DM, efforts should be made to prevent type 2 DM through lifestyle modification strategies in this high risk population. It is important that we develop some clear cut guidelines for prevention and treatment of GDM. ",0
4002,19579782,"Sarcocystis cruzi (Protozoa: Apicomplexa: Sarcocystiidae) infection in european bison (Bison bonasus) from Białowieza Forest, Poland]","Samples of oesophagus, diaphragm and heart muscles were taken from one European bison from Białowieza Forest during seasonal European bison elimination in 2008. Five gram of each muscle was examined by staining small samples in 0.2% aqueous solution of methylene blue. After that they were placed between compressor glasses and examined under a dissecting microscope in order to detect Sarcocystis sp. infection. All sarcocysts observed were counted. The 5-g sample of the heart muscle yielded a total of 756 sarcocysts while that of the diaphragm contained 107 of them and that of the oesophagus--89. All of the sarcocysts were isolated from 1 g of each muscle by using preparation needles (probes). After that the sarcocysts were taken to 0.5% physiological solution and examined under light microscope. The special attention was paid to detection of their cyst wall, which was thin (1 microm up to 1.2 microm) and smooth in all cases. Sometimes villar protrusions were seen on the surface of the cysts. Differences between the size of sarcocysts isolated from different muscle samples were observed. The longest and the slenderest sarcocysts were found in the diaphragm. Slightly smaller in the oesophagus and the smallest ones in the heart muscle tissue. The average size of sarcocysts isolated from diaphragm was 957.6 microm x 112.7 microm. Sarcocysts found in the oesophagus measured 484.1 microm x 194.6 microm and those isolated from the heart muscle attained 305.4 microm x 103.9 microm. All of the sarcocysts isolated from heart, oesophagus and diaphragm muscles were identified Sarcocystis cruzi. ",0
4003,19579789,Animal reservoirs of human virulent microsporidian species],"The main objective of the present study was to determined the occurrence of Encephalitozoon intestinalis, E. hellem, E. cuniculi, and Enterocytozoon bieneusi in Poland in animal faecal using the FISH (Fluorescent In Situ Hybridization) and multiplex FISH techniques. Additional objectives included: (1) identification of animal hosts of microsporidia that are infectious to humans amongst free-ranging, captive, livestock and domestic animals; (2) a molecular analysis of randomly selected parasite isolates and determination of their zoonotic potential; (3) evaluation of the role of animals in the dissemination of microsporidia spores in the environment, and an estimation of the potential risk of infection for other animals and humans. A total of 1340 faecal samples collected from 178 species of animals were examined using conventional staining (chromotrope-2R and calcofluor white M2R staining) and molecular techniques (FISH and multiplex FISH techniques). Microsporidian spores were detected in 33 faecal samples (2.5%) obtained from 17 animal species. Microsporidia were demonstrated more often in birds (6.1%) than in mammals (0.7%); the difference was statistically significant (p < 0.00001). In addition, the prevalence of microsporidian infections in waterfowl was significantly higher than the prevalence of microsporidian infections in other animals (p < 0.03). Animal reservoirs of human infectious microsporidia were disclosed in six of 38 sites where faecal samples were taken from animals. Three species of human virulent microsporidia were identified in animals. Spores of E. hellem were found in 25 faecal samples (1.9%) taken from 12 bird species (6 zoo bird species, 4 free-ranging bird species, 2 livestock bird species). Spores of E. intestinalis were identified in five faecal samples (0.4%) taken from two livestock bird species and two zoo mammal species. In turn, E. bieneusi spores were detected only in three faecal samples (0.2%) taken from three zoo mammal species. It was demonstrated that the new hosts of E. hellem are the following bird species: mallard duck (Anas platyrhynchos), greyleg goose (Anser anser), mute swan (Cygnus olor), black-necked swan (Cygnus melancoryphus), black swan (Cygnus atratus), coscoroba swan (Coscoroba coscoroba), black-crowned crane (Balearica pavonina), nicobar pigeon (Caloenas nicobarica) and carrion crow (Corvus cornix). In addition, E. hellem was found for the first time in birds from the Anseriformes and Gruiformes orders. Whereas E. intestinalis was disclosed for the first time in the domestic goose (Anser anser f. domestica), red ruffed lemur (Varecia variegata rubra) and the ring-tailed lemur (Lemur catta), while the black lemur (Eulemur macaco flavifrons), mongoose lemur (Eulemur mongoz) and the Visayan warty pig (Sus cebifrons negrinus) were first found to carry E. bieneusi. The mammal species that were found to carry E. bieneusi and E. intestinalis are included in The IUCN Red List of Threatened Species. The results of the present study are significant from an epidemiological point of view. The wild, livestock and zoo animals that were found to carry microsporidia live in different conditions, and thus their role as animal reservoirs for these dangerous pathogens varies. Waterfowl birds may be the main source of contamination of surface waters with E. hellem spores and the protection of surface waters is virtually impossible. Moreover, isolates of E. hellem from mute swans have SSU rRNA sequences identical to E. hellem genotype reported 10 years ago in HIV-positive patient in USA (GenBank Accession no. L19070). This result indicate that E. hellem from mute swans can be a potential source of infection for humans. The contamination of the human environment with microsporidian spores infectious to humans is also facilitated by farm and synanthropic birds, because E. hellem and E. intestinalis were found in farms pigeons, domestic goose and the carrion crow. These birds can also be the source of infectious for breeders and ornithologists. The occurrence of microsporidiosis in animals kept in zoological gardens may constitute a deadly hazard not only for the animals themselves, but also for zoo personnel and visitors. The identification of animal reservoirs of E. hellem, E. intestinalis and E. bieneusi in Poland points to the possibility of infection of humans. The results of the present study have shown that the FISH technique, although time-consuming, is very sensitive, not overly costly and--what is of prime importance--it enables identification of microsporidian species, and therefore should be used for diagnosing microsporidiosis in humans and animals. ",0
4004,19580172,Synthetic endovascular prostheses in the treatment of the aortic dissection],"Endovascular technique using endovascular prostheses called stent-grafts offers less invasive new method of the aortic dissection. Assessment of endovascular aortic dissection type B treatment effectiveness, complications and mortality frequency associated with this technique. Among 33 patients (24 men -- 73% and 9 women -- 27%, aged 19-76 years (average [+/- SD]. Underwent endovascular stent-grafts implantation procedures using 3 types of grafts: Zenith (2 prostheses -- 13,3%), Talent (11 prostheses -- 73,3%) and Valiant (2 prostheses --13,3%). The diameter of proximal end of stent-graft ranged from 34 to 42 mm (mean 37,6 +/- 3,44 mm), length -- from 130 to 230 mm (mean 183,6 +/- 37,42 mm). Endovascular technique is promising strategy of aortic dissection type B treatment. Stent-graft application faces up to general aspiration to minimize extension and traumatization of surgical procedures, to reduce peri- and postoperative complications, decrease hospitalization and convalescence period. Endovascular technique is the only available method that interferes in the elementary mechanism of the aortic dissection pathogenesis. Through the initiation of natural repair process (thrombosis of the false lumen), as a result of coverage of the primary entry tear, ensures remodeling and stabilization of the aortic wall. ",0
4005,19580352,Treatment time reduction using tandem shockwaves for lithotripsy: an in vivo study,"Reducing extracorporeal shockwave lithotripsy (SWL) time by increasing the shockwave rate of the lithotripter has been tested in the past; however, basic research and treatment outcomes revealed that this is not convenient. The purpose of this study was to use an animal model to demonstrate that SWL treatment time can be reduced significantly without sacrificing stone fragmentation efficiency using tandem shockwaves. A tandem research lithotripter was used to treat 50 artificial kidney stones implanted into the kidneys of 50 rabbits. Standard single-pulse and tandem shockwaves were compared in two different scenarios: Without a fluid-filled expansion chamber and with a fluid-filled expansion chamber surrounding the stone. The presence of fluid surrounding the stone enhances fragmentation in both the standard and tandem modes. No significant difference in fragmentation efficiency was recorded between the standard and tandem SWL with stones surrounded by fluid; however, the treatment time with tandem shockwaves was reduced by 50%. Significantly shorter SWL treatments may be possible in the future using tandem shockwaves on urinary stones that are surrounded by fluid. ",0
4006,19580507,Comparison of expression profiles of several fibroblast growth factor receptors in the mouse jejunum: suggestive evidence for a differential radioprotective effect among major FGF family members and the potency of FGF1,"Several members of the fibroblast growth factor (FGF) family have the potential to protect the intestine against the side effects of radiation therapy. FGF1 is capable of signaling through all subtypes of FGF receptors (FGFRs), whereas FGF7 and FGF10 activate only the epithelial-specific subtype, FGFR2IIIb (FGFR2b). The present study compared the protective activity of FGF1, FGF7 and FGF10 and examined the profiles of FGFR expression in the jejunum of BALB/c mice given total-body irradiation (TBI) with gamma rays. TBI caused drastic increases in FGFR1-4 transcript levels in the jejunum. However, FGFR2b protein temporarily decreased at 12 and 24 h after irradiation. FGF1 pretreatment minimized the number of apoptotic cells in jejunal crypts at 16 and 24 h after irradiation and increased crypt survival most effectively. In addition, pretreatment with FGF7 or FGF10 decreased FGFR1 transcript levels. The greater effectiveness of FGF1 to enhance crypt survival was also observed even when each FGF was administered 1 h after irradiation. These findings indicate that FGF1 is more potent than FGF7 or FGF10 for protection of the intestine against radiation exposure and suggest that the profiles of FGFR expression in the intestine favor the FGF1 signaling pathway before and during the initial period after irradiation. ",0
4007,19580669,Prediction of localization and interactions of apoptotic proteins,"During apoptosis several mitochondrial proteins are released. Some of them participate in caspase-independent nuclear DNA degradation, especially apoptosis-inducing factor (AIF) and endonuclease G (endoG). Another interesting protein, which was expected to act similarly as AIF due to the high sequence homology with AIF is AIF-homologous mitochondrion-associated inducer of death (AMID). We studied the structure, cellular localization, and interactions of several proteins in silico and also in cells using fluorescent microscopy. We found the AMID protein to be cytoplasmic, most probably incorporated into the cytoplasmic side of the lipid membranes. Bioinformatic predictions were conducted to analyze the interactions of the studied proteins with each other and with other possible partners. We conducted molecular modeling of proteins with unknown 3D structures. These models were then refined by MolProbity server and employed in molecular docking simulations of interactions. Our results show data acquired using a combination of modern in silico methods and image analysis to understand the localization, interactions and functions of proteins AMID, AIF, endonuclease G, and other apoptosis-related proteins. ",0
4008,19580674,The impact of itch symptoms in psoriasis: results from physician interviews and patient focus groups,"""The objective of this qualitative study was to better understand the impact of psoriasis symptoms using a 3-part process: 1) develop a disease model for psoriasis to identify the most important concepts relevant to psoriasis patients; 2) conduct interviews with dermatologists to identify key areas of clinical concern; and 3) explore psoriasis patients' perceptions of the impact of psoriasis. A disease model was developed from a review of the published literature and later revised based on the findings of clinician interviews and patient focus groups. To confirm the clinical relevance of the concepts identified in the disease model, 5 dermatologists were selected and interviewed one-on-one. They were asked to rate major psoriasis symptoms according to importance and bothersomeness level to patients on separate scales of 1 to 10. Results of clinician interviews were used to develop interview guides for patient focus groups. To identify important domains of psoriasis, 39 patients participated in 5 separate concept elicitation focus groups. Four focus groups included patients with severe psoriasis (n = 31) and one included patients with mild psoriasis (n = 8). Patients were asked to describe their current psoriasis symptoms and to rate them on a scale of 1 to 10, according to importance, severity, and troublesomeness. An average mean rating was calculated for each symptom throughout all focus groups. Clinicians most frequently mentioned itch (n = 5), psoriatic arthritis or """"joint pains"""" (n = 4), flaking (n = 4), and pain (n = 3) as primary physical symptoms of psoriasis. Three clinicians gave a rating of 10 for the importance of itch; two clinicians gave ratings of 8 and 7 for importance. The majority of patients rated itch as the most important (31/39), most severe (31/39), and most troublesome (24/39) symptom and noted that itch negatively impacted daily activities (eg, concentration, sleep, ability to attend work or school), as well as emotions (eg, anxiety and embarrassment). These analyses suggest that itch is one of the most important symptoms of psoriasis, contributing to diminished health-related quality of life (HRQoL) in patients with both mild and severe disease. """,0
4009,19580676,"Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults","Position emission tomography (PET) imaging using [18F]-setoperone to quantify cortical 5-HT2A receptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT2A receptor (5HT2AR) binding potential. The purpose of this study was to assess the test-retest variability of [18F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT2AR availability in subjects greater than 60 years old. Six healthy subjects (age range = 65-78 years) completed two [18F]-setoperone PET scans on two separate occasions 5-16 weeks apart. The average difference in the binding potential (BPND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions. We conclude that the test-retest variability of [18F]-setoperone PET in elderly subjects is comparable to that of [18F]-setoperone and other 5HT2AR radiotracers in younger subject samples. ",0
4010,19581000,High incidence of chronic lymphocytic leukemia (CLL) diagnosed by immunophenotyping: a population-based Canadian cohort,"Incidence and outcomes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are not well established at the population level, especially since the widespread use of immunophenotyping. We studied the epidemiology of CLL in Manitoba (Canada) by combining data from a centralized flow cytometry facility and the provincial cancer registry for the period 1998-2003. Of 616 cases identified, 27% of patients identified by flow cytometry were not on the cancer registry. The age-adjusted incidence of 7.99/100,000 is substantially higher than the reported incidence in registry reports. We also noted differences in relative survival based on age and gender. ",0
4011,19581094,The prediction of long-term outcome after subarachnoid hemorrhage as measured by the Short Form-36 Health Survey,"The Glasgow Outcome Scale (GOS) score is widely used to assess outcome after a subarachnoid hemorrhage (SAH). Patients who have recovered fully or with a mild disability (GOS scores 4 and 5) frequently complain about difficulties in conducting their daily activities. The Short Form-36 (SF-36) Health Survey is a questionnaire that assesses outcomes in multiple categories. This study was conducted to compare the quality of outcome assessment between the SF-36 Health Survey and GOS scores. A total of 128 patients with SAH (all data expressed as mean+/-standard deviation) aged 53.1+/-12.1 years, and a mean Hunt and Hess grade on admission of 2+/-1, were retrospectively included in the study. Medical charts were reviewed to assess previous medical history, location of the aneurysm and the presence of vasospasm. The SF-36 and GOS scores were collected in structured interviews approximately 5 years (+/-2 years) after the SAH. The SF-36 data were compared to a historical healthy control cohort of 2,474 individuals. The results showed that 52% of patients experienced a favourable outcome after SAH (GOS scores 4 and 5). Vasospasm was recorded in 25% of patients. However, the average SF-36 results were lower in all tested categories for patients after SAH than the healthy normal controls. None of the SF-36 categories except physical function correlated significantly with the GOS score. Aneurysm location did not have an impact on SF-36 data. Patients after a SAH assessed as GOS score 5 are significantly impaired in social functioning and general health. We conclude that patients continue to suffer neuropsychological deficits years after a SAH. The GOS score is a rough outcome measure that primarily focuses on physical functioning. SF-36 is a useful tool to include in the neuropsychological outcome assessment of patients with SAH. ",0
4012,19581231,Exploring perceptions of cancer care delivery among older Mexican American adults,"To investigate older Mexican Americans' perceptions of cancer care delivery, specifically regarding perceived discrimination. Qualitative. Senior centers and participants' homes. 5 older Mexican American cancer survivors. The sample included five Spanish-speaking Mexican Americans with low incomes who were previously diagnosed with cancer. Ages ranged from 68-86 years (X = 76.4). Participants were recruited through several community-based agencies and resources. Interviews were conducted and recorded on audiotape in participants' homes or at a senior center. A demographic questionnaire and the Mini Mental State Exam were administered in English or Spanish. Perceptions of healthcare delivery. Three themes emerged from the interview data: (a) emotional responses to cancer diagnosis, (b) relationship with healthcare providers, and (c) use of spiritual resources in coping with cancer. Participants denied experiencing any discrimination in health care related to race, ethnicity, income, or language spoken. Perceptions of good and poor-quality health care are described. Participants were satisfied with the cancer care they received, with a few exceptions. The role of age and education level in perceived discrimination needs further exploration. Replication of this study with larger, culturally diverse samples is needed to increase understanding of the role of perceived discrimination in cancer care and to develop culturally responsive, evidence-based healthcare interventions for patients and families coping with cancer. ",0
4013,19581834,Circulatory recovery is as fast with air ventilation as with 100% oxygen after asphyxia-induced cardiac arrest in piglets,"We investigated return of spontaneous circulation and of cerebral oxygenation after asphyxia-induced cardiac arrest, using ventilation with air, throughout, or with 100% oxygen for a shorter or longer period. Arterial pressure, heart rate, regional cerebral oxygen saturation (CrSO2), and brain tissue oxygen tension (PbtO2) were measured in 1-d-old piglets that were hypoventilated with air and left in apnea until cardiac arrest. They were randomly assigned to be resuscitated with air (n = 13), or with oxygen for 3 (n = 12) or 30 min (n = 13) and then with air. Nine, 10, and 10 animals, respectively, needed closed chest cardiac massage. One, none, and one, respectively, died. Median (quartile range) times from start of ventilation until heart rate reached 150 bpm were 67 (60-76), 88 (76-126), and 68 (56-81) s. They were not significantly different, nor were the arterial pressure responses, times until CrSO2 reached 30%, or times until PbtO2 had increased by 0.1 kPa from its nadir. Peak PbtO2 values during resuscitation were 4.2 (3.3-5.4), 12 (6.4-15), and 25 (15-36) kPa. Thus, pure oxygen did not accelerate the recovery of circulation or of cerebral oxygenation, while even a brief exposure caused cerebral hyperoxia. ",0
4014,19582432,Maintaining and engineering neural stem cells for delivery of genetically encoded therapy to brain tumors,"Despite advances for the treatment of cancer, the prognosis for patients suffering from malignant brain tumors remains dismal. High-grade neoplasms, such as gliomas, are highly invasive and spawn widely disseminated microsatellites that have limited the efficacy of surgical and adjunctive therapies. The cancer stem cell hypothesis suggests that conventional chemotherapeutic treatments kill differentiated and differentiating cells which often form the bulk of the tumor. One major concern is that the cells which give rise to the tumor, the cancer stem cells, remain untouched and may be responsible for a relapse of the disease. Therefore, an adjunctive therapy to current cancer treatment is critical for the survivability of patients suffering from brain tumors. We have successfully engineered tumor-tropic neural stem cells to deliver antineoplastic gene products directly to the tumor-producing cells. This potential therapeutic strategy may safely eradicate tumor-producing cells in the brain while minimizing damage to normal, healthy cells. ",0
4015,19582440,Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients,"The aim of this study was to investigate the influence of clinical and genetic factors on warfarin dose requirements in the Japanese population. We enrolled 125 patients on stable warfarin anticoagulant therapy with an international normalized ratio maintained between 1.5 and 3.0. PCR-based methods were performed to analyze genetic polymorphisms in the genes pharmacokinetically and pharmacodynamically related to warfarin reactions, including cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX) and factor VII (FVII). The presence of CYP2C9*3 and VKORC1-1639G>A had a significant impact on the mean maintenance dose of warfarin (CYP2C9*1/*1 2.74 +/- 1.24 mg/day vs. *1/*3 and *3/*3 1.56 +/- 0.85 mg/day, P = 0.009; VKORC1-1639AA 2.42 +/- 0.95 mg/day vs. GA 3.71 +/- 1.43 mg/day vs. GG 7.25 +/- 0.35 mg/day, P < 0.001). In the multiple linear regression model, the combination of age, body surface area, and genotypes of CYP2C9*3 and VKORC1-1639G>A explained 54.8% of the variance in warfarin dose requirements. The influences of CYP2C9*3 and VKORC1-1639G>A on the maintenance dose of warfarin were well-defined in Japanese patients, while polymorphisms of GGCX and FVII did not affect it. The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds. ",0
4016,19582456,The -383A>C TNFRI polymorphism is associated with soluble levels and clinical activity in rheumatoid arthritis,"Tumor necrosis factor-alpha (TNF-alpha) plays a central role in inflammation, and it has been directly implicated in the pathogenesis of rheumatoid arthritis (RA). TNF-alpha activity is mediated through TNFRI and TNFRII cell surface receptors, which act as physiological attenuators of TNF-alpha activity. We recruited 190 RA patients and 190 healthy subjects (HS) in order to associate the -383A>C TNFRI polymorphism with sTNFRI levels and DAS28 score in RA. In results, sTNFRI levels were higher in RA patients than HS (P = 0.04). The -383A>C TNFRI polymorphism did not show significant differences in both studied groups. However, in the RA group the sTNFRI levels were significantly elevated (P = 0.004) in A/A genotype carriers. In addition, the A/A genotype carriers had the higher DAS28 score than A/C genotype (P = 0.02). These data suggest that -383A>C TNFRI polymorphism is not a susceptibility marker in RA, whereas the increased levels of sTNFRI could reflect the clinical activity in RA patients. ",0
4017,19582719,Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistance,"5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5-FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5-FU resistance, we isolated secreted proteins that were up- or downregulated in a 5-FU-resistant cancer cell line, compared with the parent cell line (SNU-C4), using a stable isotope-coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5-FU. In total, 238 proteins with molecular weights ranging from 50 to 75 kDa were identified. Among these, 45 and 35 secreted proteins were up- and downregulated in the 5-FU-resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2 (PK-M2), transketolase, and NADP(+)-dependent malic enzyme 1. In particular, the level of PK-M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5-FU-based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5-FU-based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK-M2 observed with 5-FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5-FU-based chemotherapy suggest the relevance of dysregulated glycolysis and 5-FU-resistant CRC. ",0
4018,19582816,MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads,"Transforming growth factor-beta / bone morphogenetic protein (TGFbeta/BMP) signaling has a gradient of effects on cell fate choice in the fetal mouse liver. The molecular mechanism to understand why adjacent cells develop into bile ducts or grow actively as hepatocytes in the ubiquitous presence of both TGFbeta ligands and receptors has been unknown. We hypothesized that microRNAs (miRNAs) might play a role in cell fate decisions in the liver. miRNA profiling during late fetal development in the mouse identified miR-23b cluster miRNAs comprising miR-23b, miR-27b, and miR-24-1 and miR-10a, miR-26a, and miR-30a as up-regulated. In situ hybridization of fetal liver at embryonic day 17.5 of gestation revealed miR-23b cluster expression only in fetal hepatocytes. A complementary (c)DNA microarray approach was used to identify genes with a reciprocal expression pattern to that of miR-23b cluster miRNAs. This approach identified Smads (mothers against decapentaplegic homolog), the key TGFbeta signaling molecules, as putative miR-23b cluster targets. Bioinformatic analysis identified multiple candidate target sites in the 3' UTRs (untranslated regions) of Smads 3, 4, and 5. Dual luciferase reporter assays confirmed down-regulation of constructs containing Smad 3, 4, or 5, 3' UTRs by a mixture of miR-23b cluster mimics. Knockdown of miR-23b miRNAs during hepatocytic differentiation of a fetal liver stem cell line, HBC-3, promoted expression of bile duct genes, in addition to Smads, in these cells. In contrast, ectopic expression of miR-23b mimics during bile duct differentiation of HBC-3 cells blocked the process. CONCLUSION: Our data provide a model in which miR-23b miRNAs repress bile duct gene expression in fetal hepatocytes while promoting their growth by down-regulating Smads and consequently TGFbeta signaling. Concomitantly, low levels of the miR-23b miRNAs are needed in cholangiocytes to allow TGFbeta signaling and bile duct formation.",0
4019,19582871,Loss of dystrophin and the microtubule-binding protein ELP-1 causes progressive paralysis and death of adult C. elegans,"EMAP-like proteins (ELPs) are conserved microtubule-binding proteins that function during cell division and in the behavior of post-mitotic cells. In Caenorhabditis elegans, ELP-1 is broadly expressed in many cells and tissues including the touch receptor neurons and body wall muscle. Within muscle, ELP-1 is associated with a microtubule network that is closely opposed to the integrin-based adhesion sites called dense bodies. To examine ELP-1 function, we utilized an elp-1 RNA interference assay and screened for synthetic interactions with mutated adhesion site proteins. We reveal a synthetic lethal relationship between ELP-1 and the dystrophin-like protein, DYS-1. Reduction of ELP-1 in a dystrophin [dys-1(cx18)] mutant results in adult animals with motility defects, splayed and hypercontracted muscle with altered cholinergic signaling. Worms fill with vesicles, become flaccid, and die. We conclude that ELP-1 is a genetic modifier of a C. elegans model of muscular dystrophy. ",0
4020,19582887,Negative mood affects brain processing of visceral sensation,"A link between negative emotional state and abnormal visceral sensation has been frequently reported. However, the influence of negative emotion on brain processing of painful visceral sensations has not been investigated. We used functional magnetic resonance imaging (fMRI) and negative emotional stimuli to investigate the effects of negative emotion on brain processing of esophageal sensation. Twelve healthy male volunteers (age range, 21-32 years) participated in the study. Negative emotion was induced using emotionally valent music. fMRI images were acquired during 2 experimental runs; throughout these, volunteers received randomized nonpainful and painful distentions to the esophagus during neutral and negative emotion. Subjective perception of each stimulus was acquired, as were mood ratings. Sadness ratings increased significantly following negative mood induction (P < .01). There was no significant effect of emotion on subjective perception of painful and nonpainful stimulation (P > .05). Following painful stimulation, brain activity increased in the right hemisphere during negative emotion and was localized to the anterior cingulate cortex (ACC; BA24/32), anterior insula, and inferior frontal gyrus. Following nonpainful stimulation during negative emotion, brain activity increased in the right anterior insula and ACC (BA24 and 32). This study provides new information about the influence of negative affect on central processing of visceral pain. Evidence of right hemispheric dominance during negative emotion indicates this hemisphere is predominately associated with sympathetic activity (arousal, negative affect) and that the right insula and right ACC are integral to subjective awareness of emotion through interoception. ",0
4021,19583256,Evaluation of Azadirachta indica leaf fractions for in vitro antioxidant potential and protective effects against H2O2-induced oxidative damage to pBR322 DNA and red blood cells,"We evaluated the protective effects of subfractions of the ethyl acetate fraction (EAF) and the methanolic fraction (MF) from the crude ethanolic extract (CEE) of Azadirachta indica A. Juss (neem) leaves against various free radicals and hydrogen peroxide (H2O2)-induced oxidative damage to red blood cells (RBCs) and pBR322 DNA. Neem leaf fractions reduced DPPH(*), ABTS(*+), superoxide (O(*-)), hydroxyl (OH(*)), and nitric oxide radicals to nonradical forms in a concentration-dependent manner. Treatment with the benzene insoluble fraction from EAF (EBIF), the chloroform insoluble fraction from EAF (ECIF), the chloroform insoluble fraction from MF (MCIF), and the ethyl acetate insoluble fraction from MF (MEIF) significantly mitigated H2O2-induced oxidative damage to RBCs and pBR322 DNA. Although we found low in vitro free radical scavenging activity for the benzene insoluble fraction from EAF (EBSF), the chloroform soluble fraction from EAF (ECSF), the chloroform soluble fraction from MF (MCSF), and the ethyl acetate soluble fraction from MF (MESF), these fractions showed no effect on H2O2-induced lipid peroxidation and pBR322 DNA damage. High-performance liquid chromatography (HPLC) and TLC-Iatroscan analysis revealed that the greater efficacy of EBIF, ECIF, MCIF, and MEIF may be due to the presence of more polar compounds such as nimbolide and quercetin. Our studies suggest that the antioxidant and protective effects of active neem leaf fractions against H2O2-induced lipid peroxidation and pBR322 DNA damage can be attributed to their ability to inhibit various free radicals. ",0
4022,19583691,Drug eruption due to intravesical instillations of both epirubicin and mitomycin C,"We present the first patient to develop drug eruption due to intravesical instillations of both epirubicin and mitomycin C. A 58-year-old-man underwent transurethral resection (TUR) for superficial bladder carcinoma followed by instillations of intravesical chemotherapy. Immediately after TUR, the first instillation of epirubicin was performed. Two days after the first instillation, the patient developed generalized erythema of the face, trunk, upper and lower limbs. Two days after the second instillation, the patient developed severe generalized erythema and was diagnosed as having drug eruption due to intravesical instillations of epirubicin by the dermatologist. Instead of epirubicin, mitomycin C was instilled 2 weeks postoperatively. Two days after the first instillation of mitomycin C, the patient again developed severe generalized erythema and was diagnosed as having drug eruption due to intravesical instillation of mitomycin C. Drug eruption after the first instillation of epirubicin might have been due to drug toxicity of the agent. However, drug eruptions after the second instillation of epirubicin and the first instillation of mitomycin C might have been due to allergic reactions to the drugs. The patient has not received any further intravesical chemotherapy and has not demonstrated any such a drug eruption again. ",0
4023,19584034,Two-dimensional echocardiographic measurements of the left atrium in dogs with cardiac disease,"The aim of the present study was to verify the validity of two-dimensional echocardiographic (2DE) measurement technique in dogs with left atrial enlargement. Thirty-one dogs with clinically and echocardiographically proven cardiac diseases were randomly selected. The left atrial right-to-left diameter (La(r-l)) and the diameter of the left atrium just above the mitral annulus (La(ama)) as well as the ratio of left atrial to aortic diameter ( La/Ao ) were measured by 2DE. The La (r-l) / La(ama) ratio was independent of body weight (R(2) = 0.0006) and age (R(2) = 0.0012), respectively. A significant linear relationship was found between La(ama) and La/Ao (the ratio that expresses the severity of atrial enlargement): La(ama) = 1.2238 La/Ao + 1.1608 (R(2) = 021; P < 0.01). There was also a positive linear relationship between La(r-l) and La/Ao : La(r-l) = 1.6876 La/Ao + 1.2648 (R(2) = 0.27; P < 0.005). In our dogs with cardiac disease, the La(r-l) / La(ama) ratio showed no significant relation to the La/Ao index (R(2) = 0.028). Thus, La(r-l) / La(ama) proved to be independent of the severity of atrial enlargement. Based on the strong relationship stated in the equation between La ama and La r-l [ La(r-l) / La(ama) = 1.31159 (95% confidence interval)], La(ama) can also be used for the assessment of left atrial size even in dogs with cardiac disease. ",0
4024,19584139,Association between global DNA hypomethylation in leukocytes and risk of breast cancer,"Global DNA hypomethylation may result in chromosomal instability and oncogene activation, and as a surrogate of systemic methylation activity, may be associated with breast cancer risk. Samples and data were obtained from women with incident early-stage breast cancer (I-IIIa) and women who were cancer free, frequency matched on age and race. In preliminary analyses, genomic methylation of leukocyte DNA was determined by measuring 5-methyldeoxycytosine (5-mdC), as well as methylation analysis of the LINE-1-repetitive DNA element. Further analyses used only 5-mdC levels. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of breast cancer in relation to amounts of methylation. In a subset of samples tested (n = 37), 5-mdC level was not correlated with LINE-1 methylation. 5-mdC level in leukocyte DNA was significantly lower in breast cancer cases than healthy controls (P = 0.001), but no significant case-control differences were observed with LINE-1 methylation (P = 0.176). In the entire data set, we noted significant differences in 5-mdC levels in leukocytes between cases (n = 176) and controls (n = 173); P value < 0.001. Compared with women in the highest 5-mdC tertile (T3), women in the second (T2; OR = 1.49, 95% CI = 0.84-2.65) and lowest tertile (T1; OR = 2.86, 95% CI = 1.65-4.94) had higher risk of breast cancer (P for trend < or = 0.001). Among controls only and cases and controls combined, only alcohol intake was found to be inversely associated with methylation levels. These findings suggest that leukocyte DNA hypomethylation is independently associated with development of breast cancer. ",0
4025,19584279,Reactivation of androgen receptor-regulated TMPRSS2:ERG gene expression in castration-resistant prostate cancer,"It seems clear that androgen receptor (AR)-regulated expression of the TMPRSS2:ERG fusion gene plays an early role in prostate cancer (PC) development or progression, but the extent to which TMPRSS2:ERG is down-regulated in response to androgen deprivation therapy (ADT) and whether AR reactivates TMPRSS2:ERG expression in castration-resistant PC (CRPC) have not been determined. We show that ERG message levels in TMPRSS2:ERG fusion-positive CRPC are comparable with the levels in fusion gene-positive primary PC, consistent with the conclusion that the TMPRSS2:ERG expression is reactivated by AR in CRPC. To further assess whether TMPRSS2:ERG expression is initially down-regulated in response to ADT, we examined VCaP cells, which express the TMPRSS2:ERG fusion gene, and xenografts. ERG message and protein rapidly declined in response to removal of androgen in vitro and castration in vivo. Moreover, as observed in the clinical samples, ERG expression was fully restored in the VCaP xenografts that relapsed after castration, coincident with AR reactivation. AR reactivation in the relapsed xenografts was also associated with marked increases in mRNA encoding AR and androgen synthetic enzymes. These results show that expression of TMPRSS2:ERG, similarly to other AR-regulated genes, is restored in CRPC and may contribute to tumor progression. ",0
4026,19584539,"Molecular heterogeneity of TIME-EA4, a timer protein in silkworm diapause eggs","TIME-EA4 is an ATPase that measures time intervals as a diapause-duration clock found in diapause eggs of the silkworm, Bombyx mori. In the current studies, we report the molecular heterogeneity of TIME-EA4 protein regarding not only amino acid L62V, but also the numbers and linkage patterns of the sugar chain attached to the Asn(22) residue. These sugar chain structures were determined in a pico-molar amount of the protein by combining the methods of chemical modification (Smith degradation) and nano-HPLC-electrospray ionization-quadrupole-time of fight-mass spectrometry (ESI-Q-TOF-MS) and -MS/MS. The Japanese and bi-voltine Thai silkworm strains were compared to show the heterogeneity represented by four kinds of molecular species. Judicious choice of the combination methods led us to find the first example of a linkage-position difference in the glycosidic bonds even in sugar moieties of the same molecular weight; thus, the Man(1-6)Man(1-4)GlcNAc(1-4)GlcNAc structure in the C108 pure strain and Man(1-3)Man(1-4)GlcNAc(1-4)GlcNAc structure in the Kinshu-Showa hybrid. A total of five kinds of molecular heterogeneity was determined, including the amino acids in TIME-EA4 protein. This paper describes the details for determining the sugar chain linkage in TIME-EA4 from the diapause eggs of various silkworm strains. ",0
4027,19584633,Cor pulmonale due to congenital central hypoventilation syndrome presenting in adolescence,"""To report the first case of congenital central hypoventilation syndrome (CCHS) presenting with severe cor pulmonale in an adolescent. Case report and literature review. Our Institutional Review Board waived the need for consent. Pediatric intensive care unit in a tertiary care children's hospital. A 12-year-old girl who developed profound hypoxia following routine dental extraction under intravenous opiate sedation and became progressively obtunded due to marked hypoventilation without hypoxic arousal, requiring mechanical ventilation. She had evidence of severe right heart failure, but no cardiac, pulmonary, neurologic, or neuromuscular cause was identified. The diagnosis of CCHS was suspected and subsequently confirmed by blood polymerase chain reaction analysis that revealed a heterozygous polyalanine expansion mutation of the PHOX2B gene (five polyalanine repeats). This report describes the unusual presentation of severe cor pulmonale in an adolescent with so-called """"late-onset"""" CCHS. CCHS was previously thought to be a disease affecting only neonates, but the late-onset phenotype has now been well described in adults. It should be considered in any child presenting with unexplained right heart failure without an identifiable cause, particularly if central sleep apnea is present, because early initiation of ventilatory support can prevent cardiac and neurologic sequelae and improve outcome. """,0
4028,19584748,The effects of transcranial stimulation on paretic lower limb motor excitability during walking,"Balanced transcallosal inhibition sustains symmetrical corticomotor excitability and assists the performance of bimanual voluntary movements. After stroke, transcallosal inhibition becomes asymmetric. This finding raised the notion that reducing poststroke asymmetry in transcallosal inhibition might prime the motor system before training and lead to improvements in walking recovery. In this study, we examined three neuromodulatory protocols applied during walking to determine if they could increase ipsilesional and decrease contralesional motor excitability in patients with chronic stroke. Inhibitory repetitive transcranial magnetic stimulation and inhibitory paired associative stimulation were applied to the contralesional motor system, and facilitatory anodal transcranial direct current stimulation was applied to the ipsilesional motor system. We tested the bilateral modulatory effects of each stimulation protocol on the tibialis anterior, medial gastrocnemius, medial hamstrings, and vastus lateralis of nine patients with chronic stroke. All stimulation protocols increased paretic limb and decreased nonparetic limb motor excitability. There was no statistical difference in the extent of modulation between these stimulation protocols. This result suggests these three protocols are promising candidate priming mechanisms for testing the hypothesis in a future study that reducing the poststroke asymmetry of between-hemisphere motor excitability will enhance the effect of gait therapy. ",0
4029,19584950,Predictors of Infant Feeding Frequency by Mexican Immigrant Mothers,"With an increase in the prevalence of overweight being seen as early as infancy, it is essential that the factors which account for early excess weight gain be identified. In this study, maternal and infant characteristics were examined to determine their relation to the frequency of infants being fed. A cohort of 67 low-educated Mexican mothers who formula-fed their infants were recruited at a WIC Center and home-visited when their infants were 6-months-old. Mothers were surveyed with regard to their feeding attitudes and perception of their infant's temperament, and kept a 24-hour diary of their infant's behavior. Nearly 30% of the 6-month-old infants were at or above the 85(th) percentile of weight-for length. A regression analysis revealed only one factor, the number of infant crying episodes, as predictive of infant feeding (Beta = .246, p<.07), with the correlation even stronger (r =.35 (p<.01). As crying appeared to elicit feeding among these mothers, pediatricians, nurses, and WIC educators should consider discussing alternate strategies for quieting infants with the mothers they counsel. ",0
4030,19585578,"Body size, adult BMI gain and endometrial cancer risk: the multiethnic cohort","""The effect of body size and change in BMI on endometrial cancer risk across different racial/ethnic groups has not been studied. We examined the association between body size and endometrial cancer risk and potential effect modification of other risk factors among 50,376 women in the Multiethnic Cohort Study. During 10.3 years of follow-up, 463 endometrial cancer cases were identified. Epidemiologic data were collected from the baseline questionnaire. """"BMI change"""" was defined as the percentage of body mass index change from age 21 to the time of recruitment. Women who were heavier at age 21 or at baseline (weight > or = 53.5 kg or > or = 63.9 kg, respectively) had an increased endometrial cancer risk compared to the lowest quartile of weight during the respective periods. BMI gain > or = 35% had a RR of 4.12 (95% CI: 2.69, 6.30) compared to the reference group (-5% < or = BMI change <+5%). Women who averaged an annual BMI gain > or = 1% had a >3.21-fold (95% CI: 2.37, 4.33) increased risk compared to women who maintained a stable adult BMI (-0.25 to <+0.25%). The highest risk associated with BMI gain was observed among nulliparous women and postmenopausal women who never used hormone therapy. Although African Americans and Whites showed an increase in risk after > or =35% BMI gain, Japanese Americans showed an increase in risk with much smaller gain (> or =5%). In conclusion, adult obesity and increase in adiposity are risk factors for endometrial cancer; and the risk associated with these factors may vary across racial/ethnic groups. """,0
4031,19585612,Porcine liver sinusoidal endothelial cells contribute significantly to intrahepatic ammonia metabolism,"Ammonia metabolism in the liver has been largely credited to hepatocytes (HCs). We have shown that liver nonparenchymal cells that include liver sinusoidal endothelial cells (LSECs) produce ammonia. To address the limited knowledge regarding a role for LSECs in ammonia metabolism, we investigated the ammonia metabolism of isolated LSECs and HCs under three different conditions: (1) bioreactors containing LSECs (LSEC-bioreactors), (2) bioreactors containing HCs (HC-bioreactors), and (3) separate bioreactors containing LSECs and HCs connected in sequence (Seq-bioreactors). Our results showed that LSEC-bioreactors released six-fold more ammonia (22.2 nM/hour/10(6) cells) into the growth media than HC-bioreactors (3.3 nM/hour/10(6) cells) and Seq-bioreactors (3.8 nM/hour/10(6) cells). The glutamate released by LSEC-bioreactors (32.0 nM/hour/10(6) cells) was over four-fold larger than that released by HC-bioreactors and Seq-bioreactors (<7 nM/hour/10(6) cells). LSEC-bioreactors and HC-bioreactors consumed large amounts of glutamine (>25 nM/hour/10(6) cells). Glutaminase is known for catalyzing glutamine into glutamate and ammonia. To determine if this mechanism may be responsible for the large levels of glutamate and ammonia found in LSEC-bioreactors, immunolabeling of glutaminase and messenger RNA expression were tested. Our results demonstrated that glutaminase was present with colocalization of an LSEC-specific functional probe in lysosomes of LSECs. Furthermore, using a nucleotide sequence specific for kidney-type glutaminase, reverse-transcription polymerase chain reaction revealed that this isoform of glutaminase was expressed in porcine LSECs. CONCLUSION: LSECs released large amounts of ammonia, perhaps due to the presence of glutaminase in lysosomes. The ammonia and glutamate released by LSECs in Seq-bioreactors were used by hepatocytes, suggesting an intrahepatic collaboration between these two cell types.",0
4032,19585899,Severe coronary tortuosity and the relationship to significant coronary artery disease,"Severe coronary artery tortuosity on coronary angiogram has not been previously evaluated to determine whether it is associated with coronary artery disease or risk factors for coronary artery disease. A retrospective analysis of all patients who underwent coronary angiography at West Virginia University Hospital during an eight month period was performed. All patients with severe coronary tortuosity (SCT), defined as two consecutive 180 degrees turns by visual estimation in a major epicardial artery, were identified and their medical records reviewed for the presence of coronary artery disease risk factors and presence of significant coronary artery disease. A randomly chosen group of patients who underwent coronary angiography during the same time who did not have SCT was used for a control group. Multivariable analysis using logistic regression was performed to determine predictors of SCT. Severe coronary tortuosity was found in 12.45% of our 1221 patients. Female gender was found to be significantly higher in the tortuosity group of patients compared to the control group (p = 0.039). The presence of severe tortuosity was associated with a statistically significant lower incidence of significant coronary artery disease (p = 0.003). Hypertension, hyperlipidemia, smoking, family history of coronary artery disease, diabetes mellitus, and age > or =65 years were not predictors of SCT. Our study did not find that coronary artery disease risk factors were predictors of coronary tortuosity. Future investigations may provide further insight into the significance or cause of coronary artery tortuosity. ",0
4033,19586195,Relations among parental acceptance and control and children's social adjustment in Chinese American and European American families,"Parental acceptance and control are the 2 dimensions of parenting that have been investigated most; however, little is known about their cross-cultural expressions. This longitudinal study examined acceptance, control, and R. Chao's indigenous Chinese notion of control--chiao shun (training)--in 35 immigrant Chinese American (CA) and 38 European American (EA) families. Data were collected when children were in preschool and kindergarten (T1); first and second grades (T2); and third and fourth grades (T3). Within couples, CA mothers and fathers reported similar levels of acceptance and control, whereas EA mothers and fathers did not. CA fathers' and mothers' and EA mothers' acceptance and control exerted a positive influence on their children's psychological adjustment. CA fathers' training negatively predicted their children's problem behaviors 4 years later. ",0
4034,19586427,Global cultural and socioeconomic factors that influence access to assisted reproductive technologies,"Assisted reproductive technology (ART) is the most successful treatment for the 9% of people at reproductive age who suffer with infertility, but only a small percentage of those needing ART actually access it. Access varies greatly internationally owing to religious, cultural and political factors, probably the most important factor being each society's perspective on the moral status of the embryo. Economic factors, the nature of the healthcare system and public funding affect access both among and within countries. Regulations and guidelines are highly variable, but critical, in determining access and types of services. Cross-border travel for reproductive care is not uncommon. In the future, better public funding of ART, technological improvements, lower cost and slow international harmonization with fewer differences in ART services will probably increase access significantly. ",0
4035,19586757,A double injection ADSA-CSD methodology for lung surfactant inhibition and reversal studies,"This paper presents a continuation of the development of a drop shape method for film studies, ADSA-CSD (Axisymmetric Drop Shape Analysis-Constrained Sessile Drop). ADSA-CSD has certain advantages over conventional methods. The development presented here allows complete exchange of the subphase of a spread or adsorbed film. This feature allows certain studies relevant to lung surfactant research that cannot be readily performed by other means. The key feature of the design is a second capillary into the bulk of the drop to facilitate addition or removal of a secondary liquid. The development will be illustrated through studies concerning lung surfactant inhibition. After forming a sessile drop of a basic lung surfactant preparation, the bulk phase can be removed and exchanged for one containing different inhibitors. Such studies mimic the leakage of plasma and blood proteins into the alveolar spaces altering the surface activity of lung surfactant in a phenomenon called surfactant inhibition. The resistance of the lung surfactant to specific inhibitors can be readily evaluated using the method. The new method is also useful for surfactant reversal studies, i.e. the ability to restore the normal surface activity of an inhibited lung surfactant film by using special additives. Results show a distinctive difference between the inhibition when an inhibitor is mixed with and when it is injected under a preformed surfactant film. None of the inhibitors studied (serum, albumin, fibrinogen, and cholesterol) were able to penetrate a preexisting film formed by the basic preparation (BLES and protasan), while all of them can alter the surface activity of such preparation when mixed with the preparation. Preliminary results show that reversal of serum inhibition can be easily achieved and evaluated using the modified methodology. ",0
4036,19587032,Role for the paramyxovirus genomic promoter in limiting host cell antiviral responses and cell killing,"The parainfluenza virus simian virus 5 (SV5) is a poor inducer of innate immune responses. In contrast, the naturally occurring SV5 variant Wake Forest parainfluenza virus (WF-PIV) activates the synthesis of proinflammatory cytokines and beta interferon (IFN-beta). Comparison of SV5 and WF-PIV genome sequences revealed nine nucleotide differences within the viral genomic promoter, including two substitutions (U5C and A14G) in the most highly conserved 3'-end promoter element. To test the consequences of these promoter variations, a recombinant SV5 mutant [Le-(U5C, A14G)] was engineered to harbor the two WF-PIV genomic promoter substitutions in an otherwise wild-type (WT) SV5 background. Human lung epithelial cells infected with the Le-(U5C, A14G) mutant had higher rates of viral protein synthesis and levels of mRNA than cells infected with WT SV5, but levels of genomic RNA were not changed. Unlike WT SV5, the Le-(U5C, A14G) mutant was a potent inducer of interleukin-6 and IFN-beta synthesis, despite expressing a functional V protein antagonist. Cytokine responses to Le-(U5C, A14G) infection were reduced either by small interfering RNA-mediated knockdown of retinoic acid-inducible gene I (RIG-I) or after infection of cells that were engineered to express the reovirus sigma3 double-stranded RNA-binding protein. Le-(U5C, A14G) induced cytopathic effects not seen with WT SV5, and the extent of cell killing correlated with elevated levels of viral F protein and cell-cell fusion. Our results support a model whereby the SV5 promoter has evolved to function at an attenuated level in order to limit (i) synthesis of aberrant RNAs which induce RIG-I-mediated responses and (ii) overproduction of mRNA for potentially toxic gene products, such as the F protein. Control of genomic promoter activity may be particularly important for viruses such as SV5, that express a V protein targeting mda-5 but do not encode antagonists such as the paramyxovirus C proteins, that specifically target RIG-I. ",0
4037,19587392,Mycoplasma genitalium in asymptomatic patients: implications for screening,"Mycoplasma genitalium is well established as a cause of urethritis and has also been associated with cervicitis, endometritis and pelvic infection. Low rates of infection suggest screening may be inappropriate in the general population, but it remains unclear whether asymptomatic patients attending a sexual-health clinic should be tested routinely. The objective of this study was to measure the positivity rate of M genitalium infection in asymptomatic individuals presenting to a sexual-health clinic to inform the need for screening in this population. Asymptomatic patients were identified using a structured questionnaire and tested for M genitalium from genital swabs or urine using two separate polymerase chain reaction (PCR) assays incorporating different primer sequences. 1304 patients were approached over a 6-month period. 743 (57%) patients were symptomatic, and 168 (13%) refused consent, leaving 394 (30%) patients who entered the study. Residual samples were available for 308 (79%) patients, 168 (54%) men and 140 (46%) women. 14/308 (4.5%, 95% CI 2.2 to 6.9%) asymptomatic patients were infected with M genitalium, and an additional 2 (0.6%, 95% CI 0.2 to 2.3%) patients had discrepant PCR results. No significant associations were found between M genitalium infection and age, gender, ethnicity or isolation site. The positivity rate of M genitalium infection in asymptomatic sexual-health clinic attendees is comparable with that of gonorrhoea or chlamydia, and, if evidence of pathogenicity continues to accumulate, a further assessment of the role of routine screening in this setting would be appropriate. ",0
4038,19587507,The effect of increasing blood flow rate on dialysis adequacy in hemodialysis patients,"Inadequacy of dialysis is one of the determinants of morbidity and mortality in patients undergoing dialysis. The aim of this study was to assess the effect of increasing blood flow rate during hemodialysis (HD) on the adequacy of dialysis. In this study, 42 patients on maintenance HD were assessed. Body weight and blood urea nitrogen (BUN) levels before and after HD sessions were recorded on all the study patients. Volume of ultrafiltration, the duration of dialysis, percentage of filter clearance and flow rate of the dialysate were collected and documented in a checklist. Both Kt/V and urea reduction ratio (URR) were determined at two different blood pump speeds, i.e. 200 and 250 mL/min. During HD, hemodynamic status and vital signs of patients were monitored and controlled. After collecting the necessary data, efficiency of dialysis was calculated using the standard formula. Descriptive and analytical statistics was carried out to analyze the data. Using blood flow rate of 200 mL/min, 16.7% of patients had Kt/V higher than 1.3 and URR higher than 65. On the other hand, with flow rate of 250 mL/min, 26.2% of patients had Kt/V higher than 1.3 and 35.7% of subjects had URR higher than 65. Paired t-test with 95% confidence showed a significant difference in dialysis efficiency between two groups. Our data further confirm that increasing the blood flow rate by 25% is effective in increasing dialysis adequacy in HD patients. ",0
4039,19588436,Single dose oral aceclofenac for postoperative pain in adults,"""Aceclofenac is the prodrug of the non-steroidal anti-inflammatory drug (NSAID) diclofenac, widely used to treat acute and chronic pain. There are no known systematic reviews of its analgesic efficacy in acute postoperative pain. This review sought to evaluate the efficacy and safety of oral aceclofenac in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. To assess the efficacy of single dose oral aceclofenac in acute postoperative pain, and any associated adverse events. We searched The Cochrane Library (Issue 1, 2009), MEDLINE via Ovid (1966 to March 2009); EMBASE via Ovid (1980 to March 2009); the Oxford Pain Relief Database (1950 to 1994); and reference lists of articles. Randomised, double-blind, placebo-controlled clinical trials of oral aceclofenac for relief of acute postoperative pain in adults. Two review authors independently assessed trial quality and extracted data. The area under the """"pain relief versus time"""" curve was used to derive the proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over 4 to 6 hours, using validated equations. The number needed to treat to benefit (NNT) was calculated using 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals was also collected. Searches identified only one study (217 participants total), which used oral aceclofenac 150 mg in patients with established postoperative pain. Aceclofenac 150 mg could not be distinguished from placebo, though ibuprofen 400 mg was distinguished from placebo. In the absence of evidence of efficacy for oral aceclofenac in acute postoperative pain (at least at 150 mg single dose), its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies are lacking, use in other indications should be evaluated carefully. Given the large number of effective drugs available in this and similar classes of analgesics, there is no urgent research agenda required to demonstrate the effective dose of aceclofenac in acute postoperative pain. """,0
4040,19588606,A pilot food store intervention in the Republic of the Marshall Islands,"To improve diet and reduce risk for obesity and chronic disease, we developed, implemented and evaluated a pilot intervention trial with 23 large and small food stores in the Republic of the Marshall Islands (12 intervention, 11 control). The intervention included both mass media (radio announcements, newspaper ads, video) and in-store (cooking demonstrations, taste tests, shelf labeling) components. Consumer exposure to the mass media components was high (65% had heard half or more of the radio announcements, 74% had seen at least one of the newspaper ads). Consumer exposure to the in-store components of the intervention was moderate (61% attended at least one cooking demonstrations, 59% received at least one recipe card). After adjustment for age, sex and education level, increased exposure to the intervention was associated with higher diabetes knowledge (p<0.05) and label reading knowledge (p<0.05), but not with increased self-efficacy for performing promoted healthy behaviors. The intervention was associated with increased purchasing of certain promoted foods (p<0.005), including oatmeal, turkey chili, fish, canned fruit and local vegetables. It was also associated with improvements in healthiness of cooking methods (p<0.05). Food store centered interventions have great potential for changing cognitive and behavioral factors relating to food choice and preparation, and may contribute to lessening the burden of diet-related chronic disease worldwide. ",0
4041,19588756,Repair of high-voltage electric burn in jaw and neck region with insular pectoralis major myocutaneous flap],"To evaluate the effect of insular pectoralis major myocutaneous flap on repair of jaw and neck tissue defect as a result of high-voltage electric burn. Eighteen patients with large area tissue defect in jaw and neck caused by high-voltage electric burn hospitalized from August 2001 to December 2007 were repaired with insular pectoralis major myocutaneous flap. The flaps (from 12 cm x 10 cm to 16 cm x 13 cm) was transplanted in 8 patients after early wound debridement, and in 10 patients on infected wounds. All flaps survived wells except in 4 patients necrotic area (length 2-5 cm, width 1-2 cm) appeared in the distal wound edge, localized dehiscence of wound edge in 2 cases, which were healed after dressing change or secondary suturing. Patients were followed up from 6 months to 3 years, and the appearance and function were satisfactory. Pectoralis major muscle island myocutaneous flap has the advantage of large tissue mass, with thin and flat muscle belly, and rich blood supply, which is suitable for repair of large deep tissue defect in jaw and neck. ",0
4042,19589161,The Brief Fear of Negative Evaluation Scale (BFNE): translation and validation study of the Iranian version,"The Brief Fear of Negative Evaluation Scale (BFNE) is a commonly used instrument to measure social anxiety. This study aimed to translate and to test the reliability and validity of the BFNE in Iran. The English language version of the BFNE was translated into Persian (Iranian language) and was used in this study. The questionnaire was administered to a consecutive sample of 235 students with (n = 33, clinical group) and without social phobia (n = 202, non-clinical group). In addition to the BFNE, two standard instruments were used to measure social phobia severity: the Social Phobia Inventory (SPIN), and the Social Interaction Anxiety Scale (SIAS). All participants completed a brief background information questionnaire, the SPIN, the SIAS and the BFNE scales. Statistical analysis was performed to test the reliability and validity of the BFNE. In all 235 students were studied (111 male and 124 female). The mean age for non-clinical group was 22.2 (SD = 2.1) years and for clinical sample it was 22.4 (SD = 1.8) years. Cronbach's alpha coefficient (to test reliability) was acceptable for both non-clinical and clinical samples (alpha = 0.90 and 0.82 respectively). In addition, 3-week test-retest reliability was performed in non-clinical sample and the intraclass correlation coefficient (ICC) was quite high (ICC = 0.71). Validity as performed using convergent and discriminant validity showed satisfactory results. The questionnaire correlated well with established measures of social phobia such as the SPIN (r = 0.43, p < 0.001) and the SIAS (r = 0.54, p < 0.001). Also the BFNE discriminated well between men and women with and without social phobia in the expected direction. Factor analysis supported a two-factor solution corresponding to positive and reverse-worded items. This validation study of the Iranian version of BFNE proved that it is an acceptable, reliable and valid measure of social phobia. However, since the scale showed a two-factor structure and this does not confirm to the theoretical basis for the BFNE, thus we suggest the use of the BFNE-II when it becomes available in Iran. The validation study of the BFNE-II is in progress. ",0
4043,19589409,Solid organ transection. Open and laparoscopic surgery],"Recent advances in liver surgery have reduced post-hepatectomy mortality to less than 5% in most units specialized in hepato-pancreatic-biliary surgery. Possibly, the single most important factor contributing to these improved results has been the reduction in intraoperative bleeding during liver parenchymal transection. Liver transection is the most risky part of the intervention due to the risk of massive hemorrhage. Some technological advances and refinements to the surgical technique have contributed to making this critical phase of liver surgery safer. Among these advances, the most notable are detailed knowledge of the surgical anatomy of the liver, vascular control techniques and methods of liver parenchymal transection. The present review describes current transection techniques, as well as their advantages and disadvantages. Until there is solid evidence on the best method, the choice of technique and instrument for liver transection depends mainly on the surgeon's personal preference. Nevertheless, some factors can influence the choice of method, such as the surgeon's experience, anesthetic management, type of hepatectomy (central, peripheral), type of approach (open, laparoscopic), quality of the liver (normal, cirrhotic, steatotic) and the availability of the instruments in the center. ",0
4044,19589461,Stroke in sickle cell anemia: alternative etiologies,"Stroke is common in children with sickle cell anemia, but is rarely attributed to the traditional causes of stroke identified in other children. An 11-year-old girl with sickle cell anemia presented with severe headache and was found to have recurrent bilateral multifocal strokes in a cardioembolic pattern. Evaluation revealed the presence of a patent foramen ovale, antiphospholipid antibodies, and elevations in factor VIII and lipoprotein(a). Sickle cell anemia is itself a hypercoagulable state with potential for increased right heart pressures, both of which predispose to paradoxical embolization via right-to-left intracardiac shunting of emboli, thus causing stroke. The present case suggests that the more traditional etiologies for pediatric stroke may also cause stroke in children with sickle cell anemia. ",0
4045,19589467,Early cortical cytotoxic edema in meningococcal meningitis,"Meningococcal disease frequently presents neurologic sequels via vascular, metabolic, or inflammatory processes. Understanding the underlying pathogenic mechanisms may influence both treatment and outcome. We present a 2-year-old child affected by Neisseria meningitidis sepsis, who on the second day from clinical onset manifested recurrent partial motor seizures and focal neurologic signs. An early magnetic resonance angiography of the circle of Willis produced normal results, whereas magnetic resonance imaging of the brain disclosed cortical signal abnormalities consistent with cytotoxic edema, without involvement of the adjacent white matter. Six-month follow-up magnetic resonance imaging of the brain indicated faint cortical atrophy in the same regions, although the neurologic picture had resolved. The literature contains few data on early magnetic resonance parenchymal changes, and their pathogenic mechanism is controversial. Diffusion-weighted images may contribute to an understanding of the mechanisms of such brain damage. ",0
4046,19591124,"Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein","The hepatitis C virus (HCV) core protein is involved in viral pathogenesis such as oxidative stress induction and lipid metabolism disturbance, and is primarily located in the cytoplasm and endoplasmic reticulum in association with lipid droplets as well as in the mitochondria. To clarify the impact of the core protein on mitochondria, we analyzed the expression pattern of mitochondrial proteins in core protein-expressing cells by two-dimensional polyacrylamide gel electrophoresis. Several proteins related to the mitochondrial respiratory chain or protein chaperons were identified by mass spectrometry. Among the identified proteins with consistently different expressions, prohibitin, a mitochondrial protein chaperon, was up-regulated not only in core-expressing cells but also in full-genomic replicon cells and livers of core-gene transgenic mice. The stability of prohibitin was increased through interaction with the core protein. Further analysis demonstrated that interaction of prohibitin with mitochondrial DNA-encoded subunits of cytochrome c oxidase (COX) was disturbed by the core protein, resulting in a significant decrease in COX activity. CONCLUSION: The HCV core protein affects the steady-state levels of a subset of mitochondrial proteins including prohibitin, which may lead to an impaired function of the mitochondrial respiratory chain with the overproduction of oxidative stress.",0
4047,19625717,Effects of pay for performance on the quality of primary care in England,"BACKGROUND: A pay-for-performance scheme based on meeting targets for the quality of clinical care was introduced to family practice in England in 2004. METHODS: We conducted an interrupted time-series analysis of the quality of care in 42 representative family practices, with data collected at two time points before implementation of the scheme (1998 and 2003) and at two time points after implementation (2005 and 2007). At each time point, data on the care of patients with asthma, diabetes, or coronary heart disease were extracted from medical records; data on patients' perceptions of access to care, continuity of care, and interpersonal aspects of care were collected from questionnaires. The analysis included aspects of care that were and those that were not associated with incentives. RESULTS: Between 2003 and 2005, the rate of improvement in the quality of care increased for asthma and diabetes (P<0.001) but not for heart disease. By 2007, the rate of improvement had slowed for all three conditions (P<0.001), and the quality of those aspects of care that were not associated with an incentive had declined for patients with asthma or heart disease. As compared with the period before the pay-for-performance scheme was introduced, the improvement rate after 2005 was unchanged for asthma or diabetes and was reduced for heart disease (P=0.02). No significant changes were seen in patients' reports on access to care or on interpersonal aspects of care. The level of the continuity of care, which had been constant, showed a reduction immediately after the introduction of the pay-for-performance scheme (P<0.001) and then continued at that reduced level. CONCLUSIONS: Against a background of increases in the quality of care before the pay-for-performance scheme was introduced, the scheme accelerated improvements in quality for two of three chronic conditions in the short term. However, once targets were reached, the improvement in the quality of care for patients with these conditions slowed, and the quality of care declined for two conditions that had not been linked to incentives. Continuity of care was reduced after the introduction of the scheme.",0
4048,19637188,Degree of cross-genotype reactivity of hepatitis C virus-specific CD8+ T cells directed against NS3,"The inherent sequence diversity of the hepatitis C virus (HCV) with the existence of multiple genotypes that differ up to 20% at the amino acid level represents one of the major obstacles for immune control. Accordingly, immune control of a heterologous virus challenge, particularly across genotypes, is difficult to achieve; however, the overall role of genotype-specific sequence differences has not yet been defined at the epitope level. The aim of this study was to determine the role of genotype-specific sequence differences for the CD8+ T cell response against HCV. We analyzed a cohort of anti-HCV-positive injection drug users infected with HCV genotype 1 (n = 17) or genotype 3 (n = 22) or undetectable HCV-RNA (n = 14) with overlapping peptides covering consensus sequences of NS3 from both genotypes. Importantly, the majority of HCV-specific CD8 T cells were specific for one genotype only indicating that sequence differences between genotypes are relevant at the epitope level. Interestingly, T cells active against both genotypes were significantly more frequent in HCV-RNA-negative subjects. Of note, we identified five subjects with undetectable viremia and coexistence of two T cell populations-one for each genotype-suggesting immune control of two different genotypes. CONCLUSION: We systematically analyzed the degree of cross-genotype reactivity of HCV-specific T cells and have shown that CD8 responses targeting different HCV genotypes can be primed in the same individual and that such responses potentially characterize a subgroup among injection drug users being protected from chronic HCV infection.",0
4049,19637290,Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice,"Scavenger receptor class B type I (SR-BI) mediates selective uptake of cholesterol from high-density lipoprotein (HDL) particles by the liver and influences biliary cholesterol secretion. However, it is not clear, if this effect is direct or indirect. The aim of this study was to determine the impact of SR-BI on biliary cholesterol secretion, especially in a functional context with ATP-binding cassette transporter g5 (Abcg5)/Abcg8 and Abcb4. SR-BI was overexpressed by means of adenovirus (AdSR-BI) in livers of wild-type, liver X receptor-null (Lxr(-/-)), Abcg5(-/-), and Abcb4(-/-) mice. Consistent with previous reports, AdSR-BI decreased plasma HDL cholesterol levels in all models (P < 0.001). Hepatic cholesterol content increased (at least P < 0.05), whereas expression of sterol regulatory element binding protein 2 target genes was decreased (at least P < 0.05,) and established Lxr target genes were unaltered. Biliary cholesterol secretion was increased by AdSR-BI in wild-type as well as in Lxr(-/-) and Abcg5(-/-) mice, and considerably less in Abcb4(-/-) mice (each P < 0.001), independent of bile acid and phospholipid secretion. Immunogold electron microscopy and western blot showed a substantial increase of SR-BI protein localized to basolateral and canalicular membranes in response to SR-BI overexpression. Subcellular fractionation revealed a significantly higher cholesterol content of canalicular membranes (P < 0.001) upon SR-BI overexpression. Inhibition of microtubule function did not affect SR-BI-mediated biliary cholesterol secretion, indicating that transcytosis pathways are not involved. CONCLUSION: Our data indicate that SR-BI mediates biliary cholesterol secretion independent of Abcg5, yet largely depends on Abcb4-mediated phospholipid secretion and mixed micelles as acceptors in bile. SR-BI-mediated biliary cholesterol secretion has a high capacity, can compensate for the absence of Abcg5, and does not require transcytosis pathways.",0
4050,19641203,Protection against a malaria challenge by sporozoite inoculation,"BACKGROUND: An effective vaccine for malaria is urgently needed. Naturally acquired immunity to malaria develops slowly, and induction of protection in humans can be achieved artificially by the inoculation of radiation-attenuated sporozoites by means of more than 1000 infective mosquito bites. METHODS: We exposed 15 healthy volunteers--with 10 assigned to a vaccine group and 5 assigned to a control group--to bites of mosquitoes once a month for 3 months while they were receiving a prophylactic regimen of chloroquine. The vaccine group was exposed to mosquitoes that were infected with Plasmodium falciparum, and the control group was exposed to mosquitoes that were not infected with the malaria parasite. One month after the discontinuation of chloroquine, protection was assessed by homologous challenge with five mosquitoes infected with P. falciparum. We assessed humoral and cellular responses before vaccination and before the challenge to investigate correlates of protection. RESULTS: All 10 subjects in the vaccine group were protected against a malaria challenge with the infected mosquitoes. In contrast, patent parasitemia (i.e., parasites found in the blood on microscopical examination) developed in all five control subjects. Adverse events were mainly reported by vaccinees after the first immunization and by control subjects after the challenge; no serious adverse events occurred. In this model, we identified the induction of parasite-specific pluripotent effector memory T cells producing interferon-gamma, tumor necrosis factor alpha, and interleukin-2 as a promising immunologic marker of protection. CONCLUSIONS: Protection against a homologous malaria challenge can be induced by the inoculation of intact sporozoites. (ClinicalTrials.gov number, NCT00442377.)",0
4051,19641205,AGC1 deficiency associated with global cerebral hypomyelination,"The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), specific to neurons and muscle, supplies aspartate to the cytosol and, as a component of the malate-aspartate shuttle, enables mitochondrial oxidation of cytosolic NADH, thought to be important in providing energy for neurons in the central nervous system. We describe AGC1 deficiency, a novel syndrome characterized by arrested psychomotor development, hypotonia, and seizures in a child with a homozygous missense mutation in the solute carrier family 25, member 12, gene SLC25A12, which encodes the AGC1 protein. Functional analysis of the mutant AGC1 protein showed abolished activity. The child had global hypomyelination in the cerebral hemispheres, suggesting that impaired efflux of aspartate from neuronal mitochondria prevents normal myelin formation.",0
4052,19657110,Recurring mutations found by sequencing an acute myeloid leukemia genome,"BACKGROUND: The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known. METHODS: We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome. RESULTS: We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis. CONCLUSIONS: By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.",0
4053,19675329,Micrometastases or isolated tumor cells and the outcome of breast cancer,"BACKGROUND: The association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical outcome of breast cancer is unclear. METHODS: We identified all patients in The Netherlands who underwent a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in the regional lymph nodes. Patients with node-negative disease were randomly selected from the years 2000 and 2001. The primary end point was disease-free survival. RESULTS: We identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the node-positive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval [CI], 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort. CONCLUSIONS: Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved.",0
4054,19710483,Exposure to low-dose ionizing radiation from medical imaging procedures,"BACKGROUND: The growing use of imaging procedures in the United States has raised concerns about exposure to low-dose ionizing radiation in the general population. METHODS: We identified 952,420 nonelderly adults (between 18 and 64 years of age) in five health care markets across the United States between January 1, 2005, and December 31, 2007. Utilization data were used to estimate cumulative effective doses of radiation from imaging procedures and to calculate population-based rates of exposure, with annual effective doses defined as low (< or = 3 mSv), moderate (> 3 to 20 mSv), high (> 20 to 50 mSv), or very high (> 50 mSv). RESULTS: During the study period, 655,613 enrollees (68.8%) underwent at least one imaging procedure associated with radiation exposure. The mean (+/-SD) cumulative effective dose from imaging procedures was 2.4+/-6.0 mSv per enrollee per year; however, a wide distribution was noted, with a median effective dose of 0.1 mSv per enrollee per year (interquartile range, 0.0 to 1.7). Overall, moderate effective doses of radiation were incurred in 193.8 enrollees per 1000 per year, whereas high and very high doses were incurred in 18.6 and 1.9 enrollees per 1000 per year, respectively. In general, cumulative effective doses of radiation from imaging procedures increased with advancing age and were higher in women than in men. Computed tomographic and nuclear imaging accounted for 75.4% of the cumulative effective dose, with 81.8% of the total administered in outpatient settings. CONCLUSIONS: Imaging procedures are an important source of exposure to ionizing radiation in the United States and can result in high cumulative effective doses of radiation.",0
4055,19776405,High-dose daunorubicin in older patients with acute myeloid leukemia,"BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)",0
4056,19812403,Accuracy of conflict-of-interest disclosures reported by physicians,"BACKGROUND: The recent public reporting of payments made to physicians by manufacturers of orthopedic devices provides an opportunity to assess the accuracy of physicians' conflict-of-interest disclosures. METHODS: We analyzed the reports of payments made to physicians by five manufacturers of total hip and knee prostheses in 2007. For each payment recipient who was an author of a presentation or served as a committee member or board member at the 2008 annual meeting of the American Academy of Orthopaedic Surgeons, the disclosure statement was reviewed to determine whether the payment had been disclosed. To ascertain the reasons for nondisclosure, a survey was administered to physicians who had received payments that were not disclosed. RESULTS: The overall rate of disclosure was 71.2% (245 of 344 payments). For payments that were directly related to the topic of the presentation at the meeting, the rate was 79.3% (165 of 208); for payments that were indirectly related, the rate was 50.0% (16 of 32); and for payments that were unrelated, the rate was 49.2% (29 of 59) (P=0.008). In the multivariate analysis, payments were also more likely to have been disclosed if they exceeded $10,000 (P<0.001), were directed toward an individual physician rather than a company or organization (P=0.04), or included an in-kind component (P=0.002). Among the 36 physicians who responded to the survey regarding reasons for nondisclosure (response rate, 39.6%), the reasons most commonly given for nondisclosure were that the payment was unrelated to the topic of presentation at the annual meeting (38.9% of respondents) and that the physician had misunderstood the disclosure requirements (13.9%); 11.1% reported that the payment had been disclosed but was mistakenly omitted from the program. CONCLUSIONS: In this study of self-reported conflict-of-interest disclosure by physicians at a large annual meeting, the rate of disclosure was 79.3% for directly related payments and 50.0% for indirectly related payments.",0
4057,19815860,Critical care services and 2009 H1N1 influenza in Australia and New Zealand,"BACKGROUND: Planning for the treatment of infection with the 2009 pandemic influenza A (H1N1) virus through health care systems in developed countries during winter in the Northern Hemisphere is hampered by a lack of information from similar health care systems. METHODS: We conducted an inception-cohort study in all Australian and New Zealand intensive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calculated, per million inhabitants, the numbers of ICU admissions, bed-days, and days of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected data on demographic and clinical characteristics of the patients and on treatments and outcomes. RESULTS: From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% confidence interval [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were pregnant women; of the 601 adults for whom data were available, 172 (28.6%) had a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU for a total of 8815 bed-days (350 per million inhabitants). The median duration of treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 patients (64.6%) with available data underwent mechanical ventilation for a median of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009, a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114 (15.8%) remained in the hospital. CONCLUSIONS: The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand. Our data can assist planning for the treatment of patients during the winter in the Northern Hemisphere.",0
4058,19821484,Mechanistic insights into immunomodulation by hepatic stellate cells in mice: a critical role of interferon-gamma signaling,"The liver is considered to be an immune-privileged organ that favors the induction of tolerance. The underlying mechanisms are not completely understood. Interestingly, liver transplants are spontaneously accepted in several animal models, but hepatocyte transplants are acutely rejected, suggesting that liver nonparenchymal cells may effectively protect the parenchymal cells from immune attack. We have shown the profound T cell inhibitory activity of hepatic stellate cells (HSCs). Thus, cotransplantation with HSCs effectively protects islet allografts from rejection in mice. In this study, using T cell receptor transgenic and gene knockout approaches, we provided definitive evidence that HSCs protected cotransplanted islet allografts by exerting comprehensive inhibitory effects on T cells, including apoptotic death in graft-infiltrating antigen-specific effector T cells and marked expansion of CD4(+) Forkhead box protein (Foxp)3(+) T regulatory (Treg) cells. All these effects required an intact interferon-gamma (IFN-gamma) signaling in HSCs, demonstrated by using HSCs isolated from IFN-gamma receptor 1 knockout mice. B7-H1 expression on HSCs, a product molecule of IFN-gamma signaling, was responsible for induction of T cells apoptosis, but had no effect on expansion of Treg cells, suggesting that undetermined effector molecules produced by IFN-gamma signaling is involved in this process. CONCLUSION: Upon inflammatory stimulation, specific organ stromal cells (such as HSCs in the liver) demonstrate potent immune regulatory activity. Understanding of the mechanisms involved may lead to development of novel strategies for clinical applications in transplantation and autoimmune diseases.",0
4059,19821486,Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein,"Interferons (IFNs) and the interferon-stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We have reported previously that ISGs, including guanylate binding protein 1 (GBP-1), interferon alpha inducible protein (IFI)-6-16, and IFI-27, inhibit HCV subgenomic replication. In this study we investigated the effects of these ISGs against HCV in cell culture and their direct molecular interaction with viral proteins. HCV replication and virus production were suppressed significantly by overexpression of GBP-1, IFI-6-16, or IFI-27. Knockdown of the individual ISGs enhanced HCV RNA replication markedly. A two-hybrid panel of molecular interaction of the ISGs with HCV proteins showed that GBP-1 bound HCV-NS5B directly. A protein truncation assay showed that the guanine binding domain of GBP-1 and the finger domain of NS5B were involved in the interaction. Binding of NS5B with GBP-1 inhibited its guanosine triphosphatase GTPase activity, which is essential for its antiviral effect. Taken together, interferon-induced GBP-1 showed antiviral activity against HCV replication. CONCLUSION: Binding of the HCV-NS5B protein to GBP-1 countered the antiviral effect by inhibition of its GTPase activity. These mechanisms may contribute to resistance to innate, IFN-mediated antiviral defense and to the clinical persistence of HCV infection.",0
4060,19839005,The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production,"The hepatitis C viral (HCV) genome is translated through an internal ribosome entry site (IRES) as a single polyprotein precursor that is subsequently cleaved into individual mature viral proteins. Nonstructural protein 5A (NS5A) is one of these proteins that has been implicated in regulation of viral genome replication, translation from the viral IRES and viral packaging. We sought to identify cellular proteins that interact with NS5A and determine whether these interactions may play a role in viral production. Mass spectrometric analysis of coimmunoprecipitated NS5A complexes from cell extracts identified heat shock proteins (HSPs) 40 and 70. We confirmed an NS5A/HSP interaction by confocal microscopy demonstrating colocalization of NS5A with HSP40 and with HSP70. Western analysis of coimmunoprecipitated NS5A complexes further confirmed interaction of HSP40 and HSP70 with NS5A. A transient transfection, luciferase-based, tissue culture IRES assay demonstrated NS5A augmentation of HCV IRES-mediated translation, and small interfering RNA (siRNA)-mediated knockdown of HSP70 reduced this augmentation. Treatment with an inhibitor of HSP synthesis, Quercetin, markedly reduced baseline IRES activity and its augmentation by NS5A. HSP70 knockdown also modestly reduced viral protein accumulation, whereas HSP40 and HSP70 knockdown both reduced infectious viral particle production in an HCV cell culture system using the J6/JFH virus fused to the Renilla luciferase reporter. Treatment with Quercetin reduced infectious particle production at nontoxic concentrations. The marked inhibition of virus production by Quercetin may partially be related to reduction of HSP40 and HSP70 and their potential involvement in IRES translation, as well as viral morphogenesis or secretion. CONCLUSION: Quercetin may allow for dissection of the viral life cycle and has potential therapeutic use to reduce virus production with low associated toxicity.",0
4061,19839061,Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China,"Liver disease and liver cancer associated with childhood-acquired chronic hepatitis B are leading causes of death among adults in China. Despite expanded newborn hepatitis B vaccination programs, approximately 20% of children under age 5 years and 40% of children aged 5 to 19 years remain unprotected from hepatitis B. Although immunizing them will be beneficial, no studies have examined the cost-effectiveness of hepatitis B catch-up vaccination in an endemic country like China. We examined the cost-effectiveness of a hypothetical nationwide free hepatitis B catch-up vaccination program in China for unvaccinated children and adolescents aged 1 to 19 years. We used a Markov model for disease progression and infections. Cost variables were based on data published by the Chinese Ministry of Health, peer-reviewed Chinese and English publications, and the GAVI Alliance. We measured costs (2008 U.S. dollars and Chinese renminbi), quality-adjusted life years, and incremental cost-effectiveness from a societal perspective. Our results show that hepatitis B catch-up vaccination for children and adolescents in China is cost-saving across a range of parameters, even for adolescents aged 15 to 19 years old. We estimate that if all 150 million susceptible children under 19 were vaccinated, more than 8 million infections and 65,000 deaths due to hepatitis B would be prevented. CONCLUSION: The adoption of a nationwide free catch-up hepatitis B vaccination program for unvaccinated children and adolescents in China, in addition to ongoing efforts to improve birth dose and newborn vaccination coverage, will be cost-saving and can generate significant population-wide health benefits. The success of such a program in China could serve as a model for other endemic countries.",0
4062,19877182,B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice,"The treatment of primary biliary cirrhosis (PBC) with conventional immunosuppressive drugs has been relatively disappointing and there have been few efforts in defining a role for the newer biological agents useful in rheumatoid arthritis and other systemic autoimmune diseases. In this study we took advantage of transforming growth factor-beta (TGF-beta) receptor II dominant negative (dnTGF-betaRII) mice, a mouse model of autoimmune cholangitis, to address the therapeutic efficacy of B-cell depletion using anti-CD20. Mice were treated at either 4-6 weeks of age or beginning at 20-22 weeks of age with intraperitoneal injections of anti-CD20 every 2 weeks. We quantitated B-cell levels in all mice as well as antimitochondrial antibodies (AMA), serum and hepatic levels of proinflammatory cytokines, and histopathology of liver and colon. In mice whose treatment was initiated at 4-6 weeks of age, anti-CD20 therapy demonstrated a significantly lower incidence of liver inflammation associated with reduced numbers of activated hepatic CD8(+) T cells. However, colon inflammation was exacerbated. In contrast, in mice treated at 20-22 weeks of age, anti-CD20 therapy had relatively little effect on either liver or colon disease. As expected, all treated animals had reduced levels of B cells, absence of AMA, and increased levels in sera of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and chemokine (C-C motif) ligand (CCL2) (monocyte chemoattractant protein 1 [MCP-1]). CONCLUSION: These data suggest potential usage of anti-CD20 in early PBC resistant to other modalities, but raise a cautionary note regarding the use of anti-CD20 in inflammatory bowel disease.",0
4063,19890128,Normal spermatogenesis in a man with mutant luteinizing hormone,"Men with mutations in LHB, the gene encoding the beta subunit of luteinizing hormone (LHB), have azoospermia with absent or few fetal Leydig cells. We report a mutation in LHB in a man and his sister. The man presented with absence of virilization, undetectable luteinizing hormone, and a low serum testosterone level. He had complete spermatogenesis with a normal sperm count. The mutant luteinizing hormone had a low level of partial activity in vitro. We concluded that the residual luteinizing hormone activity, resulting in the expression of steroidogenic enzymes in few mature Leydig cells producing small amounts of intratesticular testosterone (20.2 ng per gram), was sufficient for complete and quantitatively normal spermatogenesis.",0
4064,19918975,Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection,"Immune escape driven by selection pressure from virus-specific CD8 T cells has been demonstrated in both chimpanzees and humans infected with the hepatitis C virus (HCV). Although escape mutations have also been characterized in major histocompatibility complex (MHC) class II-restricted HCV epitopes, it is unknown whether selection-driven immune escape by CD4 T cell epitopes is a significant factor in the failure of these responses or contributes to persistent infection. To address this issue, evolution of MHC class I- and class II-restricted HCV epitopes was compared in four chimpanzees persistently infected with the virus for more than 10 years. We identified an amino acid change in a CD4 epitope of the HCV NS3 protein in one of the chimpanzees 3 years after infection. This mutation resulted in diminished activation, cytokine production (interferon-gamma and interleukin-2), and proliferation by an epitope-specific CD4 T cell line. We expanded our analysis to determine if mutations were common in multiple CD4 versus CD8 T cell epitopes in the four chronically infected animals. Whereas we observed mutations in over 75% of CD8 T cell epitopes analyzed in this study, only 18% of CD4 T cell epitopes analyzed showed amino acid changes. The frequency of changes in class II epitopes was not different from flanking regions, so CD4 T cells rarely exert selection pressure against the HCV genome. CONCLUSION: Apparent mutational escape can occur in MHC class II-restricted epitopes, but this is uncommon when compared with class I-restricted epitopes in the same individual. This indicates that other mechanisms for silencing CD4 T cells are dominant in persistent HCV infections.",0
4065,19918980,Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis,"The objective of this study is to determine the efficacy and safety of peginterferon alfa-2a (40 KD)/ribavirin in patients with advanced fibrosis. Data from 341 genotype 1/4 patients (99 with bridging fibrosis/cirrhosis) treated for 48 weeks and 1547 genotype 2/3 patients (380 with bridging fibrosis/cirrhosis) treated for 16 or 24 weeks enrolled in three randomized international studies were analyzed. Sustained virological response (SVR) rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (trend test P = 0.0028); and from 76% to 61% and 57%, respectively, in genotype 2/3 patients treated for 24 weeks (trend test P < 0.0001). Irrespective of genotype, patients without advanced fibrosis were more likely to have an earlier response to treatment that was associated with higher SVR rates and lower relapse rates during untreated follow-up. Among patients with or without a diagnosis of advanced fibrosis, rates of SVR and relapse were similar for patients with similar responses in the first 12 weeks. CONCLUSION: Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis. However, irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR.",0
4066,19920051,Advanced heart failure treated with continuous-flow left ventricular assist device,"BACKGROUND: Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. METHODS: In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuous-flow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity. RESULTS: Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups. CONCLUSIONS: Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)",0
4067,19937651,Clinical presentation and molecular pathophysiology of autosomal dominant hemochromatosis caused by a novel ferroportin mutation,"Mutations in the SLC40A1 gene, which encodes ferroportin, are associated with autosomal dominant hemochromatosis. Ferroportin is inhibited directly by hepcidin, a key iron-regulatory peptide, and functional consequences of SLC40A1 mutations account for observed phenotypic differences in patients with ferroportin disease. We describe a large pedigree with a novel SLC40A1 mutation and, through in vitro analysis, elucidate the associated molecular mechanism of iron overload. The entire coding sequence of the SLC40A1 gene was sequenced in a pedigree, presenting with autosomal dominant hyperferritinemia. The functional effects of a novel SLC40A1 mutation were studied by overexpression of wild-type and mutant ferroportin fusion proteins in human embryonic kidney cells. Iron export was studied in these cells using (59)Fe transport assays; subcellular localization of ferroportin was examined by way of confocal microscopy. A novel SLC40A1 mutation p.R489K segregated with iron overload in a family with clinical and histopathological signs of macrophage-type ferroportin disease. Human embryonic kidney cells overexpressing p.R489K ferroportin showed decreased iron export capacity when compared with wild-type ferroportin overexpressing cells. Subcellular localization studies demonstrated that p.R489K ferroportin was retained abnormally within an intracellular compartment. CONCLUSION: We report a novel pathological SLC40A1 variant associated with abnormal cell surface expression of ferroportin due to intracellular retention of the mutant protein. These findings predict macrophage-type ferroportin disease, the phenotype observed in this kindred. Study of the molecular cell biology of ferroportin and its mutants is key to understanding the pathogenesis of this increasingly recognized form of hemochromatosis, which responds poorly to conventional therapy.",0
4068,19957370,Mechanisms for increased expression of cholesterol 7alpha-hydroxylase (Cyp7a1) in lactating rats,"Cholesterol 7alpha-hydroxylase (Cyp7a1) and the bile acid pool size are increased 2 to 3-fold in lactating postpartum rats. We investigated the interaction of nuclear receptors with the Cyp7a1 proximal promoter and the expression of regulatory signaling pathways in postpartum rats at day 10 (PPd10) versus female controls to identify the mechanisms of increased expression of Cyp7a1, which is maximal at 16 hours. Liver X receptor (LXRalpha) and RNA polymerase II (RNA Pol II) recruitment to Cyp7a1 chromatin were increased 1.5- and 2.5-fold, respectively, at 16 hours on PPd10. Expression of nuclear receptors farnesoid X receptor (FXR), LXRalpha, liver receptor homolog (LRH-1), hepatocyte nuclear factor 4alpha (HNF4alpha), and short heterodimer partner (SHP) messenger RNA (mRNA) and coactivator peroxisome proliferators-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA was unchanged in PPd10 versus controls at 16 hours, whereas chicken ovalbumin upstream transcription factor II (COUP-TFII) was decreased 40% at 16 hours. Investigation of a repressive signaling pathway, the c-Jun-N-terminal kinase (JNK) signaling pathway in PPd10 versus controls, showed decreased mRNA expression of hepatocyte growth factor (HGF; decreased 60% at 16 hours) and tyrosine kinase receptor c-Met (decreased 44%-50% at 16 hours), but these were not accompanied by decreased expression of phosphorylated c-Jun. Importantly, expression of fibroblast growth factor 15 (FGF15) mRNA in the ileum was decreased 70% in PPd10 versus controls, whereas phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2) protein expression in liver was decreased 88% at 16 hours. CONCLUSION: The increased recruitment of LXRalpha, a Cyp7a1 stimulatory pathway, and decreased expression of FGF15 and phosphorylated Erk1/2, a Cyp7a1 repressive pathway, combined to increase Cyp7a1 expression during lactation.",0
4069,19957374,Retinoic acid signaling positively regulates liver specification by inducing wnt2bb gene expression in medaka,"During vertebrate embryogenesis, the liver develops at a precise location along the endodermal primitive gut tube because of signaling delivered by adjacent mesodermal tissues. Although several signaling molecules have been associated with liver formation, the molecular mechanism that regulates liver specification is still unclear. We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. In addition to their liver abnormality, hio mutants lack pectoral fins and die after hatching. Positional cloning indicated that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Mutations of raldh2 in zebrafish preclude the development of pectoral fins. Interestingly, in hio mutants, expression of wnt2bb in the lateral plate mesoderm (LPM) directly adjacent to the liver-forming endoderm was completely lost. CONCLUSION: Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. These results suggest that a common molecular mechanism may underlie liver and pectoral fin specification during piscine embryogenesis.",0
4070,20018959,"MMP12, lung function, and COPD in high-risk populations","BACKGROUND: Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups. METHODS: We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV(1)]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV(1) and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD. RESULTS: The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [-82A-->G]) was positively associated with FEV(1) in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2x10(-6)). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P=0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P=0.005) and among participants in a family-based study of early-onset COPD (P=0.006). CONCLUSIONS: The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.",0
4071,20018961,Genomewide association study of leprosy,"BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.",0
4072,20032318,Variants of DENND1B associated with asthma in children,"BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor ? receptor [corrected]. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.",0
4073,20032323,Genetic variants associated with Lp(a) lipoprotein level and coronary disease,"BACKGROUND: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.",0
4074,20034049,Increased caffeine consumption is associated with reduced hepatic fibrosis,"Although coffee consumption has been associated with reduced frequency of liver disease, it is unclear whether the effect is from coffee or caffeine and whether there is an effect on hepatic fibrosis specifically. This study was undertaken to use a food-frequency instrument for dietary caffeine consumption to evaluate the relationship between caffeine intake and liver fibrosis. Patients undergoing liver biopsy completed a detailed caffeine questionnaire on three occasions over a 6-month period. Caffeine intake was compared between patients with mild and advanced liver fibrosis (bridging fibrosis/cirrhosis). Logistic regression was used to evaluate the association between caffeine consumption and hepatic fibrosis. One hundred seventy-seven patients (99 male, 104 white, 121 with chronic hepatitis C virus [HCV] infection) undergoing liver biopsy completed the caffeine questionnaire on up to three occasions. Results from repeated questionnaires were consistent. Daily caffeine consumption above the 75(th) percentile for the cohort (308 mg = approximately 2.25 cups of coffee equivalents) was associated with reduced liver fibrosis (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14-0.80; P = 0.015) and the protective association persisted after controlling for age, sex, race, liver disease, body mass index, and alcohol intake in all patients (OR, 0.25; 95% CI, 0.09-0.67; P = 0.006), as well as the subset with HCV infection (OR, 0.19; 95% CI, 0.05-0.66; P = 0.009). Despite a modest trend, consumption of caffeine from sources other than coffee or of decaffeinated coffee was not associated with reduced liver fibrosis. A reliable tool for measurement of caffeine consumption demonstrated that caffeine consumption, particularly from regular coffee, above a threshold of approximately 2 coffee-cup equivalents per day, was associated with less severe hepatic fibrosis.",0
4075,20044803,Down-regulation of the LXR transcriptome provides the requisite cholesterol levels to proliferating hepatocytes,"Cholesterol homeostasis is critical for cellular proliferation. Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. Here we employed a mouse model of partial hepatectomy (PH) to dissect the molecular pathways connecting cholesterol homeostasis, cellular proliferation, and LXR. First, we show that hepatic cholesterol content increases after PH, whereas the entire LXR transcriptome is down-regulated. Although LXR messenger RNA (mRNA) levels are unmodified, LXR target genes are significantly down-regulated on day 1 after PH and restored to control levels on day 7, when the liver reaches normal size. The inactivation of LXR following PH is related to the reduced oxysterol availability by way of decreased synthesis, and increased sulfation and secretion. On the contrary, cholesterol synthesis is up-regulated, and extracellular matrix remodeling is enhanced. Second, we show that reactivation of LXR by way of a synthetic ligand determines a negative modulation of hepatocyte proliferation. This effect is sustained by the reactivation of hepatic cholesterol catabolic and secretory pathways, coupled with a significant reduction of cholesterol biosynthesis. Our data unveil a previously unrecognized and apparently paradoxical scenario of LXR modulation. During liver regeneration LXR activity is abated in spite of increasing intracellular cholesterol levels. Turning off LXR-transcriptional pathways is crucial to guaranteeing the requisite intracellular cholesterol levels of regenerating hepatocytes. In line with this hypothesis, pharmacological LXR reactivation during PH significantly reduces liver regeneration capacity.",0
4076,20044805,Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system,"Hepatitis C virus (HCV) infection induces the endogenous interferon (IFN) system in the liver in some but not all patients with chronic hepatitis C (CHC). Patients with a pre-activated IFN system are less likely to respond to the current standard therapy with pegylated IFN-alpha. Mitochondrial antiviral signaling protein (MAVS) is an important adaptor molecule in a signal transduction pathway that senses viral infections and transcriptionally activates IFN-beta. The HCV NS3-4A protease can cleave and thereby inactivate MAVS in vitro, and, therefore, might be crucial in determining the activation status of the IFN system in the liver of infected patients. We analyzed liver biopsies from 129 patients with CHC to investigate whether MAVS is cleaved in vivo and whether cleavage prevents the induction of the endogenous IFN system. Cleavage of MAVS was detected in 62 of the 129 samples (48%) and was more extensive in patients with a high HCV viral load. MAVS was cleaved by all HCV genotypes (GTs), but more efficiently by GTs 2 and 3 than by GTs 1 and 4. The IFN-induced Janus kinase (Jak)-signal transducer and activator of transcription protein (STAT) pathway was less frequently activated in patients with cleaved MAVS, and there was a significant inverse correlation between cleavage of MAVS and the expression level of the IFN-stimulated genes IFI44L, Viperin, IFI27, USP18, and STAT1. We conclude that the pre-activation status of the endogenous IFN system in the liver of patients with CHC is in part regulated by cleavage of MAVS.",0
4077,20052656,Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice,"The origin of fibrogenic cells in liver fibrosis remains controversial. We assessed the emerging concept that hepatocytes contribute to production of extracellular matrix (ECM) in liver fibrosis through epithelial-mesenchymal transition (EMT). We bred triple transgenic mice expressing ROSA26 stop beta-galactosidase (beta-gal), albumin Cre, and collagen alpha1(I) green fluorescent protein (GFP), in which hepatocyte-derived cells are permanently labeled by beta-gal and type I collagen-expressing cells are labeled by GFP. We induced liver fibrosis by repetitive carbon tetrachloride (CCl(4)) injections. Liver sections and isolated cells were evaluated for GFP and beta-gal as well as expression of alpha-smooth muscle actin (alpha-SMA) and fibroblast-specific protein 1 (FSP-1). Upon stimulation with transforming growth factor beta-1, cultured hepatocytes isolated from untreated liver expressed both GFP and beta-gal with a fibroblast-like morphological change but lacked expression of other mesenchymal markers. Cells from CCl(4)-treated livers never showed double-positivity for GFP and beta-gal. All beta-gal-positive cells exhibited abundant cytoplasm, a typical morphology of hepatocytes, and expressed none of the mesenchymal markers including alpha-SMA, FSP-1, desmin, and vimentin. In liver sections of CCl(4)-treated mice, GFP-positive areas were coincident with fibrotic septa and never overlapped X-gal-positive areas. CONCLUSION: Type I collagen-producing cells do not originate from hepatocytes. Hepatocytes in vivo neither acquire mesenchymal marker expression nor exhibit a morphological change clearly distinguishable from normal hepatocytes. Our results strongly challenge the concept that hepatocytes in vivo acquire a mesenchymal phenotype through EMT to produce the ECM in liver fibrosis.",0
4078,20052772,The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells,"Altered expression and activity of immunomodulatory cytokines plays a major role in the pathogenesis of alcoholic liver disease. Chronic ethanol feeding increases the sensitivity of Kupffer cells, the resident hepatic macrophage, to lipopolysaccharide (LPS), leading to increased tumor necrosis factor alpha (TNF-alpha) expression. This sensitization is normalized by treatment of primary cultures of Kupffer cells with adiponectin, an anti-inflammatory adipokine. Here we tested the hypothesis that adiponectin-mediated suppression of LPS signaling in Kupffer cells is mediated via an interleukin-10 (IL-10)/heme oxygenase-1 (HO-1) pathway after chronic ethanol feeding. Knockdown of IL-10 expression in primary cultures of Kupffer cells with small interfering RNA (siRNA) prevented the inhibitory effect of globular adiponectin (gAcrp) on LPS-stimulated TNF-alpha expression. gAcrp increased IL-10 mRNA and protein expression, as well as expression of the IL-10 inducible gene, HO-1; expression was higher in Kupffer cells from ethanol-fed rats compared with pair-fed controls. Although IL-10 receptor surface expression on Kupffer cells was not affected by ethanol feeding, IL-10-mediated phosphorylation of STAT3 and expression of HO-1 was higher in Kupffer cells after ethanol feeding. Inhibition of HO-1 activity, either by treatment with the HO-1 inhibitor zinc protoporphyrin or by siRNA knockdown of HO-1, prevented the inhibitory effect of gAcrp on LPS-stimulated TNF-alpha expression in Kupffer cells. LPS-stimulated TNF-alpha expression in liver was increased in mice after chronic ethanol exposure. When mice were treated with cobalt protoporphyrin to induce HO-1 expression, ethanol-induced sensitivity to LPS was ameliorated. CONCLUSION: gAcrp prevents LPS-stimulated TNF-alpha expression in Kupffer cells through the activation of the IL-10/STAT3/HO-1 pathway. Kupffer cells from ethanol-fed rats are highly sensitive to the anti-inflammatory effects of gAcrp; this sensitivity is associated with both increased expression and sensitivity to IL-10.",0
4079,20071699,Deployment and the use of mental health services among U.S. Army wives,"BACKGROUND: Military operations in Iraq and Afghanistan have involved the frequent and extended deployment of military personnel, many of whom are married. The effect of deployment on mental health in military spouses is largely unstudied. METHODS: We examined electronic medical-record data for outpatient care received between 2003 and 2006 by 250,626 wives of active-duty U.S. Army soldiers. After adjustment for the sociodemographic characteristics and the mental health history of the wives, as well as the number of deployments of the personnel, we compared mental health diagnoses according to the number of months of deployment in Operation Iraqi Freedom in the Iraq-Kuwait region and Operation Enduring Freedom in Afghanistan during the same period. RESULTS: The deployment of spouses and the length of deployment were associated with mental health diagnoses. In adjusted analyses, as compared with wives of personnel who were not deployed, women whose husbands were deployed for 1 to 11 months received more diagnoses of depressive disorders (27.4 excess cases per 1000 women; 95% confidence interval [CI], 22.4 to 32.3), sleep disorders (11.6 excess cases per 1000; 95% CI, 8.3 to 14.8), anxiety (15.7 excess cases per 1000; 95% CI, 11.8 to 19.6), and acute stress reaction and adjustment disorders (12.0 excess cases per 1000; 95% CI, 8.6 to 15.4). Deployment for more than 11 months was associated with 39.3 excess cases of depressive disorders (95% CI, 33.2 to 45.4), 23.5 excess cases of sleep disorders (95% CI, 19.4 to 27.6), 18.7 excess cases of anxiety (95% CI, 13.9 to 23.5), and 16.4 excess cases of acute stress reaction and adjustment disorders (95% CI, 12.2 to 20.6). CONCLUSIONS: Prolonged deployment was associated with more mental health diagnoses among U.S. Army wives, and these findings may have relevance for prevention and treatment efforts.",0
4080,20071703,Tracheal allotransplantation after withdrawal of immunosuppressive therapy,"Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic position. Immunosuppressive therapy was administered before the operation, and the tracheal allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At 4 months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred.",0
4081,20130250,Willful modulation of brain activity in disorders of consciousness,"BACKGROUND: The differential diagnosis of disorders of consciousness is challenging. The rate of misdiagnosis is approximately 40%, and new methods are required to complement bedside testing, particularly if the patient's capacity to show behavioral signs of awareness is diminished. METHODS: At two major referral centers in Cambridge, United Kingdom, and Liege, Belgium, we performed a study involving 54 patients with disorders of consciousness. We used functional magnetic resonance imaging (MRI) to assess each patient's ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks. A technique was then developed to determine whether such tasks could be used to communicate yes-or-no answers to simple questions. RESULTS: Of the 54 patients enrolled in the study, 5 were able to willfully modulate their brain activity. In three of these patients, additional bedside testing revealed some sign of awareness, but in the other two patients, no voluntary behavior could be detected by means of clinical assessment. One patient was able to use our technique to answer yes or no to questions during functional MRI; however, it remained impossible to establish any form of communication at the bedside. CONCLUSIONS: These results show that a small proportion of patients in a vegetative or minimally conscious state have brain activation reflecting some awareness and cognition. Careful clinical examination will result in reclassification of the state of consciousness in some of these patients. This technique may be useful in establishing basic communication with patients who appear to be unresponsive.",0
4082,20146261,Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice,"Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. CONCLUSION: We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.",0
4083,20146263,Caveolin-1 is enriched in the peroxisomal membrane of rat hepatocytes,"Caveolae are a subtype of cholesterol-enriched lipid microdomains/rafts that are routinely detected as vesicles pinching off from the plasma membrane. Caveolin-1 is an essential component of caveolae. Hepatic caveolin-1 plays an important role in liver regeneration and lipid metabolism. Expression of caveolin-1 in hepatocytes is relatively low, and it has been suggested to also reside at other subcellular locations than the plasma membrane. Recently, we found that the peroxisomal membrane contains lipid microdomains. Like caveolin-1, hepatic peroxisomes are involved in lipid metabolism. Here, we analyzed the subcellular location of caveolin-1 in rat hepatocytes. The subcellular location of rat hepatocyte caveolin-1 was analyzed by cell fractionation procedures, immunofluorescence, and immuno-electron microscopy. Green fluorescent protein (GFP)-tagged caveolin-1 was expressed in rat hepatocytes. Lipid rafts were characterized after Triton X-100 or Lubrol WX extraction of purified peroxisomes. Fenofibric acid-dependent regulation of caveolin-1 was analyzed. Peroxisome biogenesis was studied in rat hepatocytes after RNA interference-mediated silencing of caveolin-1 and caveolin-1 knockout mice. Cell fractionation and microscopic analyses reveal that caveolin-1 colocalizes with peroxisomal marker proteins (catalase, the 70 kDa peroxisomal membrane protein PMP70, the adrenoleukodystrophy protein ALDP, Pex14p, and the bile acid-coenzyme A:amino acid N-acyltransferase BAAT) in rat hepatocytes. Artificially expressed GFP-caveolin-1 accumulated in catalase-positive organelles. Peroxisomal caveolin-1 is associated with detergent-resistant microdomains. Caveolin-1 expression is strongly repressed by the peroxisome proliferator-activated receptor-alpha agonist fenofibric acid. Targeting of peroxisomal matrix proteins and peroxisome number and shape were not altered in rat hepatocytes with 70%-80% reduced caveolin-1 levels and in livers of caveolin-1 knockout mice. CONCLUSION: Caveolin-1 is enriched in peroxisomes of hepatocytes. Caveolin-1 is not required for peroxisome biogenesis, but this unique subcellular location may determine its important role in hepatocyte proliferation and lipid metabolism.",0
4084,20162619,Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo,"Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential. However, many handicaps to gene repair therapy remain. Most notable is the low frequency of correction in vivo. To date, this frequency is too low to be of therapeutic value for any disease. To address this, a point-mutation-based mouse model of the metabolic disease hereditary tyrosinemia type I was used to test whether targeted AAV integration by homologous recombination could achieve high-level stable gene repair in vivo. Both neonatal and adult mice were treated with AAV serotypes 2 and 8 carrying a wild-type genomic sequence for repairing the mutated Fah (fumarylacetoacetate hydrolase) gene. Hepatic gene repair was quantified by immunohistochemistry and supported with reverse transcription polymerase chain reaction and serology for functional correction parameters. Successful gene repair was observed with both serotypes but was more efficient with AAV8. Correction frequencies of up to 10(-3) were achieved and highly reproducible within typical dose ranges. In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease. CONCLUSION: AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates.",0
4085,20162732,Vitamin C deficiency attenuates liver fibrosis by way of up-regulated peroxisome proliferator-activated receptor-gamma expression in senescence marker protein 30 knockout mice,"Senescence marker protein 30 (SMP30), an important aging marker molecule that is highly expressed in the liver, has been known to protect hepatocytes from apoptosis by the synthesis of vitamin C. To explore the function of SMP30 in liver fibrosis, the effect of SMP30 deficiency on liver fibrosis was investigated in SMP30 knockout (KO) mice. Moreover, the in vivo results were further confirmed by way of hepatic stellate cell (HSC) isolation. We demonstrated that carbon tetrachloride (CCl(4))-induced liver fibrosis and the nuclear translocation of p-Smad2/3, the immediate downstream of transforming growth factor beta (TGF-beta), were significantly inhibited in the liver of SMP30 KO mice compared with wildtype (WT) mice. We also confirmed that both WT and SMP30 KO HSCs did not express SMP30. Finally, we further confirmed that up-regulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) caused by a lack of vitamin C was the pivotal factor in the mechanisms for attenuated liver fibrosis of SMP30 KO mice, and feeding with vitamin C restored CCl(4)-induced liver fibrosis in SMP30 KO mice. CONCLUSION: Vitamin C deficiency by SMP30 depletion attenuated liver fibrosis by way of up-regulated PPAR-gamma expression in SMP30 KO mice. Our results provide, for the first time, the possible mechanisms underlying inhibition of HSC activation associated with vitamin C and PPAR-gamma up-regulation in liver fibrosis of SMP30 KO mice.",0
4086,20169624,Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia,"Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high-resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multiracial cohort of U.S. women with a high prevalence of HCV and HIV. Our primary analyses evaluated associations between 12 HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV-seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1-2.6), B*5701 (PR=2.0; 95% CI = 1.0-3.1), B*5703 (PR = 1.7; 95% CI = 1.0-2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0-3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), whereas DRB1*0301 (PR = 0.4; 95% CI = 0.2-0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2-11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (N = 838), but no significant relationships were observed. CONCLUSION: HLA genotype influences the host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance because they were a priori hypothesized.",0
4087,20181971,Timing of initiation of antiretroviral drugs during tuberculosis therapy,"BACKGROUND: The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. METHODS: In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim-sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. RESULTS: This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P=0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. CONCLUSIONS: The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services. (ClinicalTrials.gov number, NCT00398996.)",0
4088,20186842,Institute of Medicine recommendations for the prevention and control of hepatitis B and C,"Despite federal, state, and local public health efforts to prevent and control hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, these diseases remain serious health problems in the United States. About 1%-2% of the U.S. population has chronic HBV or HCV infections, and each year about 15,000 people die from liver cancer or liver disease related to these preventable infections. The Institute of Medicine formed an expert committee to determine ways to reduce new HBV and HCV infections and the morbidity and mortality related to chronic viral hepatitis and released its findings in a report. The major factor found to impede current efforts to prevent and control HBV and HCV is lack of knowledge and awareness about these diseases among healthcare and social-service providers, members of the public, and policy makers. Because the extent and seriousness of this public health problem is not appreciated, inadequate resources are being allocated to prevention, control, and surveillance programs. This situation has led to continued transmission of HBV and HCV and inadequate identification of and medical management for chronically infected people. CONCLUSION: To address the situation, the Institute of Medicine report makes recommendations in four areas: improved surveillance for HBV and HCV; improved knowledge and awareness among healthcare and social-service providers and the public, especially at-risk people; improved HBV vaccine coverage; and improved viral hepatitis services and access to those services.",0
4089,20187106,Peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials,"A combination of weekly pegylated interferon (peginterferon) alpha and daily ribavirin represents the standard of care for the treatment of chronic hepatitis C according to current guidelines. It is not established which of the two licensed products (peginterferon alpha-2a or peginterferon alfa-2b) is most effective. We performed a systematic review of head-to-head randomized trials to assess the benefits and harms of the two treatments. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS through July 2009. Using standardized forms, two reviewers independently extracted data from each eligible trial report. We statistically combined data using a random effects meta-analysis according to the intention-to-treat principle. We identified 12 randomized clinical trials, including 5,008 patients, that compared peginterferon alpha-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin. Overall, peginterferon alpha-2a significantly increased the number of patients who achieved a sustained virological response (SVR) versus peginterferon alfa-2b (47% versus 41%; risk ratio 1.11, 95% confidence interval 1.04-1.19; P = 0.004 [eight trials]). Subgroup analyses of risk of bias, viral genotype, and treatment history yielded similar results. The meta-analysis of adverse events leading to treatment discontinuation included 11 trials and revealed no significant differences between the two peginterferons. CONCLUSION: Current evidence suggests that peginterferon alpha-2a is associated with higher SVR than peginterferon alfa-2b. However, the paucity of evidence on adverse events curbs the decision to definitively recommend one peginterferon over the other, because any potential benefit must outweigh the risk of harm.",0
4090,20196118,Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin,"The objective of this analysis was to compare sustained virological response (SVR) and relapse rates in patients with a rapid virological response (RVR, HCV RNA <50 IU/mL at week 4) randomized to 24 or 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 800 mg/day in the multinational ACCELERATE study. The analysis was restricted to patients who received treatment for 80% or more of the planned duration. Of 1309 eligible patients, 863 individuals (65.9%) achieved an RVR and were included in this analysis (458 assigned to 16 weeks and 405 assigned to 24 weeks). The overall SVR rate was significantly higher in patients randomized to 24 weeks of treatment (91% versus 82%; P = 0.0006) and among patients infected with genotype 2 (92% versus 81%; P = 0.0010) but not genotype 3 (90% versus 84%; P = 0.1308). Relapse rates were significantly lower among all patients randomized to 24 weeks of treatment: overall (6% versus 15%, P < 0.0001); in those infected with genotype 2 (5% versus 17%, P = 0.0001), and genotype 3 (7% versus 14%, P = 0.0489). SVR rates in patients with a viral load of 400,000 IU/mL or less randomized to 24 and 16 weeks of treatment were similar, 95% and 91% (P = 0.2012). Significant pretreatment predictors of SVR included assignment to 24 weeks of treatment (P = 0.0006), absence of advanced fibrosis on liver biopsy (P = 0.0032), lower HCV RNA level (P = 0.0017), and lower body weight (P < 0.0001). CONCLUSION: The standard 24-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR. Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR.",0
4091,20220177,Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy,"BACKGROUND: Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot-Marie-Tooth disease. METHODS: We identified a family with a recessive form of Charcot-Marie-Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS: We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot-Marie-Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS: As shown in this study of a family with Charcot-Marie-Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.",0
4092,20220182,Tumor-associated macrophages and survival in classic Hodgkin's lymphoma,"BACKGROUND: Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. METHODS: Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. RESULTS: Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies. CONCLUSIONS: An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.",0
4093,20228403,Effect of valsartan on the incidence of diabetes and cardiovascular events,"BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)",0
4094,20235331,Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection,"Recently, genetic polymorphisms occurring in the interferon (IFN)-lambda gene region were associated with response to IFN-based treatment of hepatitis C infection. Both infection with the hepatitis C virus and IFN therapy are associated with decreased serum cholesterol and high cholesterol has been associated with increased likelihood to respond to IFN. We sought to determine if the IFN-lambda gene variant was also associated with serum lipid levels in chronic hepatitis C patients. We compared genotypes of the rs12979860 polymorphism, located proximal to the IL28 gene, with serum lipid and apolipoprotein levels in 746 subjects with chronic hepatitis C virus infection, not currently undergoing treatment, using multivariable analysis of variance. Levels of total cholesterol (P = 6.0 x 10(-4)), apolipoprotein B (P = 1.3 x 10(-6)) and low-density lipoprotein (LDL) cholesterol (P = 8.9 x 10(-10)) were significantly higher in subjects carrying the rs12979860 CC responder genotype compared with those with the CT or TT genotype. Levels of triglycerides (P = 0.03), apolipoprotein A-I (P = 0.06), and apolipoprotein E (P = 0.01) were slightly lower in the rs12979860 CC genotype group, whereas levels of high-density lipoprotein cholesterol (P = 0.78) and apolipoprotein C-III (P = 0.74) did not vary by rs12979860 genotype. CONCLUSION: Our results suggest that low levels of LDL cholesterol in chronic hepatitis C patients may be a marker of host endogenous IFN response to hepatitis C and that subjects with the rs12979860 CC responder genotype may have a lower endogenous IFN response to the virus.",0
4095,20237345,Nationwide public-access defibrillation in Japan,"BACKGROUND: It is unclear whether dissemination of automated external defibrillators (AEDs) in public places can improve the rate of survival among patients who have had an out-of-hospital cardiac arrest. METHODS: From January 1, 2005, through December 31, 2007, we conducted a prospective, population-based, observational study involving consecutive patients across Japan who had an out-of-hospital cardiac arrest and in whom resuscitation was attempted by emergency responders. We evaluated the effect of nationwide dissemination of public-access AEDs on the rate of survival after an out-of-hospital cardiac arrest. The primary outcome measure was the 1-month rate of survival with minimal neurologic impairment. A multivariate logistic-regression analysis was performed to assess factors associated with a good neurologic outcome. RESULTS: A total of 312,319 adults who had an out-of-hospital cardiac arrest were included in the study; 12,631 of these patients had ventricular fibrillation and had an arrest that was of cardiac origin and that was witnessed by bystanders. In 462 of these patients (3.7%), shocks were administered by laypersons with the use of public-access AEDs, and the proportion increased, from 1.2% to 6.2%, as the number of public-access AEDs increased (P<0.001 for trend). Among all patients who had a bystander-witnessed arrest of cardiac origin and who had ventricular fibrillation, 14.4% were alive at 1 month with minimal neurologic impairment; among patients who received shocks from public-access AEDs, 31.6% were alive at 1 month with minimal neurologic impairment. Early defibrillation, regardless of the type of provider (bystander or emergency-medical-services personnel), was associated with a good neurologic outcome after a cardiac arrest with ventricular fibrillation (adjusted odds ratio per 1-minute increase in the time to administration of shock, 0.91; 95% confidence interval, 0.89 to 0.92; P<0.001). The mean time to shock was reduced from 3.7 to 2.2 minutes, and the annual number of patients per 10 million population who survived with minimal neurologic impairment increased from 2.4 to 8.9 as the number of public-access AEDs increased from fewer than 1 per square kilometer of inhabited area to 4 or more. CONCLUSIONS: Nationwide dissemination of public-access AEDs in Japan resulted in earlier administration of shocks by laypersons and in an increase in the 1-month rate of survival with minimal neurologic impairment after an out-of-hospital cardiac arrest.",0
4096,20237346,Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells,"BACKGROUND: Corticosteroids are commonly used to treat infantile hemangioma, but the mechanism of action of this therapy is unknown. We investigated the effect of corticosteroids in a previously described in vivo model of infantile hemangioma and in cultured hemangioma-derived cells. METHODS: We tested hemangioma-derived stem cells for vasculogenic activity in vivo after implantation into immune-deficient (nude) mice. We studied dexamethasone treatment of both the cells before implantation and the mice after implantation. We also tested hemangioma-derived stem cells for expression of vascular endothelial growth factor A (VEGF-A) in vitro and studied the inhibition of VEGF-A expression, using short hairpin RNA (shRNA) in vivo and in vitro. RESULTS: Systemic treatment with dexamethasone led to dose-dependent inhibition of tumor vasculogenesis in the murine model. Pretreatment of hemangioma-derived stem cells in vitro before implantation also inhibited vasculogenesis. Dexamethasone suppressed VEGF-A production by hemangioma-derived stem cells in vitro but not by hemangioma-derived endothelial cells or human umbilical-vein endothelial cells. Silencing VEGF-A in hemangioma-derived stem cells reduced vasculogenesis in vivo. VEGF-A was detected in hemangioma specimens in the proliferating phase but not in the involuting phase and was shown by immunostaining to reside outside of vessels. Corticosteroid treatment suppressed other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1. CONCLUSIONS: In a murine model, dexamethasone inhibited the vasculogenic potential of stem cells derived from human infantile hemangioma. The corticosteroid also inhibited the expression of VEGF-A by hemangioma-derived stem cells, and silencing of VEGF-A expression in these cells inhibited vasculogenesis in vivo.",0
4097,20237347,Physician cost profiling--reliability and risk of misclassification,"""BACKGROUND: Insurance products with incentives for patients to choose physicians classified as offering lower-cost care on the basis of cost-profiling tools are increasingly common. However, no rigorous evaluation has been undertaken to determine whether these tools can accurately distinguish higher-cost physicians from lower-cost physicians. METHODS: We aggregated claims data for the years 2004 and 2005 from four health plans in Massachusetts. We used commercial software to construct clinically homogeneous episodes of care (e.g., treatment of diabetes, heart attack, or urinary tract infection), assigned each episode to a physician, and created a summary profile of resource use (i.e., cost) for each physician on the basis of all assigned episodes. We estimated the reliability (signal-to-noise ratio) of each physician's cost-profile score on a scale of 0 to 1, with 0 indicating that all differences in physicians' cost profiles are due to a lack of precision in the measure (noise) and 1 indicating that all differences are due to real variation in costs of services (signal). We used the reliability results to estimate the proportion of physicians in each specialty whose cost performance would be classified inaccurately in a two-tiered insurance product in which the physicians with cost profiles in the lowest quartile were labeled as """"lower cost."""" RESULTS: Median reliabilities ranged from 0.05 for vascular surgery to 0.79 for gastroenterology and otolaryngology. Overall, 59% of physicians had cost-profile scores with reliabilities of less than 0.70, a commonly used marker of suboptimal reliability. Using our reliability results, we estimated that 22% of physicians would be misclassified in a two-tiered system. CONCLUSIONS: Current methods for profiling physicians with respect to costs of services may produce misleading results.""",0
4098,20301206,Hepatitis B virus replication in primary macaque hepatocytes: crossing the species barrier toward a new small primate model,"The development of new anti-hepatitis B virus (HBV) therapies, especially immunotherapeutic approaches, has been limited by the lack of a primate model more accessible than chimpanzees. We have previously demonstrated that sylvanus and cynomolgus macaques are susceptible to in vivo HBV infection after intrahepatic HBV DNA inoculation. In this study, we evaluated the susceptibility of primary macaque hepatocytes (PMHs) to HBV infection with a highly efficient HBV genome-mediated transfer system via a recombinant baculovirus (Bac-HBV). Freshly prepared PMHs, isolated from macaque liver tissue by collagenase perfusion, were transduced with Bac-HBV, and intermediates of replication were followed for 9 days post-transduction. Evidence of HBV replication (hepatitis B surface antigen secretion, viral DNA, RNA, and covalently closed circular DNA) was detected from day 1 to day 9 post-transduction. HBV markers were dose-dependent and still detectable at a multiplicity of infection of 10. Importantly, transduced PMHs secreted all typical forms of HBV particles, as evidenced by a cesium chloride gradient as well as transmission electron microscopy. Furthermore, the Toll-like receptor 9 (TLR9) ligand was used to stimulate freshly prepared macaque peripheral blood mononuclear cells to generate TLR9-induced cytokines. We then demonstrated the antiviral effects of both TLR9-induced cytokines and nucleoside analogue (lamivudine) on HBV replication in transduced PMHs. CONCLUSION: Baculovirus-mediated genome transfer initiated a full HBV replication cycle in PMHs; thus highlighted both the baculovirus efficiency in crossing the species barrier and macaque susceptibility to HBV infection. Moreover, our results demonstrate the relevance of thus system for antiviral compound evaluations with either nucleoside analogues or inhibitory cytokines. Cynomolgus macaques are readily available, are immunologically closely related to humans, and may therefore represent a promising model for the development of new immunotherapeutic strategies.",0
4099,20335585,Prevalence of diabetes among men and women in China,"BACKGROUND: Because of the rapid change in lifestyle in China, there is concern that diabetes may become epidemic. We conducted a national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults. METHODS: A nationally representative sample of 46,239 adults, 20 years of age or older, from 14 provinces and municipalities participated in the study. After an overnight fast, participants underwent an oral glucose-tolerance test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance). Previously diagnosed diabetes was determined on the basis of self-report. RESULTS: The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes were 9.7% (10.6% among men and 8.8% among women) and 15.5% (16.1% among men and 14.9% among women), respectively, accounting for 92.4 million adults with diabetes (50.2 million men and 42.2 million women) and 148.2 million adults with prediabetes (76.1 million men and 72.1 million women). The prevalence of diabetes increased with increasing age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and > or = 60 years of age, respectively) and with increasing weight (4.5%, 7.6%, 12.8%, and 18.5% among persons with a body-mass index [the weight in kilograms divided by the square of the height in meters] of < 18.5, 18.5 to 24.9, 25.0 to 29.9, and > or = 30.0, respectively). The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%). The prevalence of isolated impaired glucose tolerance was higher than that of isolated impaired fasting glucose (11.0% vs. 3.2% among men and 10.9% vs. 2.2% among women). CONCLUSIONS: These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed.",0
4100,20357280,Trajectories of disability in the last year of life,"BACKGROUND: Despite the importance of functional status to older persons and their families, little is known about the course of disability at the end of life. METHODS: We evaluated data on 383 decedents from a longitudinal study involving 754 community-dwelling older persons. None of the subjects had disability in essential activities of daily living at the beginning of the study, and the level of disability was ascertained during monthly interviews for more than 10 years. Information on the conditions leading to death was obtained from death certificates and comprehensive assessments that were completed at 18-month intervals after the baseline assessment. RESULTS: In the last year of life, five distinct trajectories were identified, from no disability to the most severe disability: 65 subjects had no disability (17.0%), 76 had catastrophic disability (19.8%), 67 had accelerated disability (17.5%), 91 had progressive disability (23.8%), and 84 had persistently severe disability (21.9%). The most common condition leading to death was frailty (in 107 subjects [27.9%]), followed by organ failure (in 82 subjects [21.4%]), cancer (in 74 subjects [19.3%]), other causes (in 57 subjects [14.9%]), advanced dementia (in 53 subjects [13.8%]), and sudden death (in 10 subjects [2.6%]). When the distribution of the disability trajectories was evaluated according to the conditions leading to death, a predominant trajectory was observed only for subjects who died from advanced dementia (67.9% of these subjects had a trajectory of persistently severe disability) and sudden death (50.0% of these subjects had no disability). For the four other conditions leading to death, no more than 34% of the subjects had any of the disability trajectories. The distribution of disability trajectories was particularly heterogeneous among the subjects with organ failure (from 12.2 to 32.9% of the subjects followed a specific trajectory) and frailty (from 14.0 to 27.1% of the subjects followed a specific trajectory). CONCLUSIONS: In most of the decedents, the course of disability in the last year of life did not follow a predictable pattern based on the condition leading to death.",0
4101,20375405,Vitamins C and E to prevent complications of pregnancy-associated hypertension,"BACKGROUND: Oxidative stress has been proposed as a mechanism linking the poor placental perfusion characteristic of preeclampsia with the clinical manifestations of the disorder. We assessed the effects of antioxidant supplementation with vitamins C and E, initiated early in pregnancy, on the risk of serious adverse maternal, fetal, and neonatal outcomes related to pregnancy-associated hypertension. METHODS: We conducted a multicenter, randomized, double-blind trial involving nulliparous women who were at low risk for preeclampsia. Women were randomly assigned to begin daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the 9th and 16th weeks of pregnancy. The primary outcome was severe pregnancy-associated hypertension alone or severe or mild hypertension with elevated liver-enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or perinatal death. RESULTS: A total of 10,154 women underwent randomization. The two groups were similar with respect to baseline characteristics and adherence to the study drug. Outcome data were available for 9969 women. There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6.1% and 5.7%, respectively; relative risk in the vitamin group, 1.07; 95% confidence interval [CI], 0.91 to 1.25) or in the rates of preeclampsia (7.2% and 6.7%, respectively; relative risk, 1.07; 95% CI, 0.93 to 1.24). Rates of adverse perinatal outcomes did not differ significantly between the groups. CONCLUSIONS: Vitamin C and E supplementation initiated in the 9th to 16th week of pregnancy in an unselected cohort of low-risk, nulliparous women did not reduce the rate of adverse maternal or perinatal outcomes related to pregnancy-associated hypertension (ClinicalTrials.gov number, NCT00135707).",0
4102,20393178,Aggressive lymphomas,"Genomewide molecular profiling has revealed new subtypes of lymphoma that originate from lymphocytes that differ in developmental stage and that use distinct oncogenic programs, yet are indistinguishable under the microscope. In this review, we discuss recent progress in the molecular genetics of aggressive lymphomas and focus on the most common form of this disease, diffuse large-B-cell lymphoma, which accounts for 30 to 40% of newly diagnosed lymphomas.",0
4103,20432258,Generation of endoderm-derived human induced pluripotent stem cells from primary hepatocytes,"Recent advances in induced pluripotent stem (iPS) cell research have significantly changed our perspective on regenerative medicine. Patient-specific iPS cells have been derived not only for disease modeling but also as sources for cell replacement therapy. However, there have been insufficient data to prove that iPS cells are functionally equivalent to human embryonic stem (hES) cells or are safer than hES cells. There are several important issues that need to be addressed, and foremost are the safety and efficacy of human iPS cells of different origins. Human iPS cells have been derived mostly from cells originating from mesoderm and in a few cases from ectoderm. So far, there has been no report of endoderm-derived human iPS cells, and this has prevented comprehensive comparative investigations of the quality of human iPS cells of different origins. Here we show for the first time reprogramming of human endoderm-derived cells (i.e., primary hepatocytes) to pluripotency. Hepatocyte-derived iPS cells appear indistinguishable from hES cells with respect to colony morphology, growth properties, expression of pluripotency-associated transcription factors and surface markers, and differentiation potential in embryoid body formation and teratoma assays. In addition, these cells are able to directly differentiate into definitive endoderm, hepatic progenitors, and mature hepatocytes. CONCLUSION: The technology to develop endoderm-derived human iPS cell lines, together with other established cell lines, will provide a foundation for elucidating the mechanisms of cellular reprogramming and for studying the safety and efficacy of differentially originated human iPS cells for cell therapy. For the study of liver disease pathogenesis, this technology also provides a potentially more amenable system for generating liver disease-specific iPS cells.",0
4104,20445180,Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease,"BACKGROUND: Previous studies have established the superiority of coronary everolimus-eluting stents over paclitaxel-eluting stents with respect to angiographic findings. However, these trials were not powered for superiority in clinical end points. METHODS: We randomly assigned 3687 patients at 66 U.S. sites to receive everolimus-eluting stents or paclitaxel-eluting stents without routine follow-up angiography. The primary end point was the 1-year composite rate of target-lesion failure (defined as cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization). RESULTS: Everolimus-eluting stents were superior to paclitaxel-eluting stents with respect to the primary end point of target-lesion failure (4.2% vs. 6.8%; relative risk, 0.62; 95% confidence interval, 0.46 to 0.82; P=0.001). Everolimus-eluting stents were also superior with respect to the major secondary end point of the 1-year rate of ischemia-driven target-lesion revascularization (P=0.001) and were noninferior with respect to the major secondary end point of the 1-year composite rate of cardiac death or target-vessel myocardial infarction (P<0.001 for noninferiority; P=0.09 for superiority). The 1-year rates of myocardial infarction and stent thrombosis were also lower with everolimus-eluting stents than with paclitaxel-eluting stents (1.9% vs. 3.1%, P=0.02 for myocardial infarction; 0.17% vs. 0.85%, P=0.004 for stent thrombosis). Target-lesion failure was consistently reduced with everolimus-eluting stents as compared with paclitaxel-eluting stents in 12 prespecified subgroups, except in the subgroup of patients with diabetes (6.4% vs. 6.9%, P=0.80). CONCLUSIONS: Everolimus-eluting stents, as compared with paclitaxel-eluting stents, resulted in reduced rates of target-lesion failure at 1 year, results that were consistent in all patients except those with diabetes, in whom the results were nonsignificantly different. (ClinicalTrials.gov number, NCT00307047.)",0
4105,20463333,Clarifying sources of geographic differences in Medicare spending,"BACKGROUND: Although geographic differences in Medicare spending are widely considered to be evidence of program inefficiency, policymakers need to understand how differences in beneficiaries' health and personal characteristics and specific geographic factors affect the amount of Medicare spending per beneficiary before formulating policies to reduce geographic differences in spending. METHODS: We used Medicare Current Beneficiary Surveys from 2000 through 2002 to examine differences across geographic areas (grouped into quintiles on the basis of Medicare spending per beneficiary over the same period). We estimated multivariate-regression models of individual spending that included demographic and baseline health characteristics, changes in health status, other individual determinants of demand, and area-level measures of the supply of health care resources. Each group of variables was entered into the model sequentially to assess the effect on geographic differences in spending. RESULTS: Unadjusted Medicare spending per beneficiary was 52% higher in geographic regions in the highest spending quintile than in regions in the lowest quintile. After adjustment for demographic and baseline health characteristics and changes in health status, the difference in spending between the highest and lowest quintiles was reduced to 33%. Health status accounted for 29% of the unadjusted geographic difference in per-beneficiary spending; additional adjustment for area-level differences in the supply of medical resources did not further reduce the observed differences between the top and bottom quintiles. CONCLUSIONS: Policymakers attempting to control Medicare costs by reducing differences in Medicare spending across geographic areas need better information about the specific source of the differences, as well as better methods for adjusting spending levels to account for underlying differences in beneficiaries' health measures.",0
4106,20472939,Early CPAP versus surfactant in extremely preterm infants,"BACKGROUND: There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS: We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS: A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)",0
4107,20484391,CISH and susceptibility to infectious diseases,"BACKGROUND: The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS: Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS: We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression. CONCLUSIONS: Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.",0
4108,20512985,Multiple effects of silymarin on the hepatitis C virus lifecycle,"Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. CONCLUSION: Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell.",0
4109,20513000,Preapoptotic cell stress response of primary hepatocytes,"Primary hepatocytes are an important in vitro model for studying metabolism in man. Caspase-9 and Bcl-2-associated X protein (Bax) are regulators of the apoptotic pathway. Here we report on the translocation of procaspase-9 and Bax from cytoplasm to nuclei as well as on dispersion of mitochondria; these processes occur after isolation of primary hepatocytes. The observed changes appear similar to those at the beginning of apoptosis; however, the isolated hepatocytes are not apoptotic for the following reasons: (1) cells have a normal morphology and function; (2) the mitochondria are energized; (3) there is no apoptosis unless it is induced by, e.g., staurosporine or nodularin. Staurosporine does not trigger apoptosis through activation of caspase-9, as its activity is detected later than that of caspase-3. We propose that the translocation of procaspase-9 and Bax into the nuclei reduces the ability to trigger apoptosis through the intrinsic apoptotic pathway. The shifts of procaspase-9 and Bax are reversible in the absence of the apoptotic trigger; the spontaneous reversion was confirmed experimentally for procaspase-9, whereas Bax shifted from the nuclei to the cytosol and mitochondria after the initiation of apoptosis. To distinguish this process from apoptosis, we call it preapoptotic cell stress response. It shares some features with apoptosis; however, it is reversible and apoptosis has to be induced in addition to this process. CONCLUSION: Knowledge on preapoptotic cell stress response is important for assessing the quality of the cells used in cell therapies, in regenerative medicine, and of those used for modeling metabolic processes.",0
4110,20513002,Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice,"Mannose receptor (ManR)-mediated liver sinusoidal endothelial cell (LSEC) endocytosis plays a role in antigen presentation and innate immunity, but its role in hepatic metastasis is unknown. We studied ManR-mediated endocytosis during C26 colorectal cancer cell interaction with LSECs and its implications in metastasis. Uptake of labeled ManR ligands (mannan and ovalbumin) and immunohistochemistry were used to study ManR endocytosis and expression. Several interleukin (IL)-1 inhibitors and the cyclooxygenase-2 (COX-2) inhibitor celecoxib were used to analyze the role of IL-1 and COX-2 in ManR regulation. Anti-mouse ManR antibodies and ManR knockout (ManR(-/-)) mice were used to identify ManR-dependent mechanisms during antitumor immune response of liver sinusoidal lymphocytes (LSLs) interacting with tumor-activated LSECs. ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism: (1) Release of COX-2-dependent IL-1-stimulating factors by lymphocyte function-associated antigen-1-expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1. In addition, LSLs that had interacted with tumor-activated LSECs in vivo decreased their antitumor cytotoxicity and interferon (IFN)-gamma secretion while they increased IL-10 release ex vivo. IFN-gamma/IL-10 ratio also decreased in the hepatic blood from tumor-injected mice. Immunosuppressant effects of tumor-activated LSECs on LSLs were abrogated in both LSECs from ManR(-/-) mice and tumor-activated LSECs given anti-mouse ManR antibodies. CONCLUSION: ICAM-1-induced tumor COX-2 decreased antitumor activity during hepatic metastasis through IL-1-induced ManR. ManR constituted a common mediator for prometastatic effects of IL-1, COX-2, and ICAM-1. A rise in hepatic IFN-gamma/IL-10 ratio and antitumor cytotoxicity by way of ManR blockade is consistent with the antimetastatic effects of IL-1, COX-2, and ICAM-1 inhibitors. These data support ManR and ManR-stimulating factors as targets for hepatic colorectal metastasis therapy.",0
4111,20558369,Valproic acid monotherapy in pregnancy and major congenital malformations,"BACKGROUND: The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited. METHODS: We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005. RESULTS: Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs. CONCLUSIONS: The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.",0
4112,20564353,Direct activation of forkhead box O3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice,"The p53 family of proteins regulates the expression of target genes that promote cell cycle arrest and apoptosis, which may be linked to cellular growth control as well as tumor suppression. Within the p53 family, p53 and the transactivating p73 isoform (TA-p73) have hepatic-specific functions in development and tumor suppression. Here, we determined TA-p73 interactions with chromatin in the adult mouse liver and found forkhead box O3 (Foxo3) to be one of 158 gene targets. Global profiling of hepatic gene expression in the regenerating liver versus the quiescent liver revealed specific, functional categories of genes regulated over the time of regeneration. Foxo3 is the most responsive gene among transcription factors with altered expression during regenerative cellular proliferation. p53 and TA-p73 bind a Foxo3 p53 response element (p53RE) and maintain active expression in the quiescent liver. During regeneration of the liver, the binding of p53 and TA-p73, the recruitment of acetyltransferase p300, and the active chromatin structure of Foxo3 are disrupted along with a loss of Foxo3 expression. In agreement with the loss of Foxo3 transcriptional activation, a decrease in histone activation marks (dimethylated histone H3 at lysine 4, acetylated histone H3 at lysine 14, and acetylated H4) at the Foxo3 p53RE was detected after partial hepatectomy in mice. These parameters of Foxo3 regulation are reestablished with the completion of liver growth and regeneration and support a temporary suspension of p53 and TA-p73 regulatory functions in normal cells during tissue regeneration. p53-dependent and TA-p73-dependent activation of Foxo3 was also observed in mouse embryonic fibroblasts and in mouse hepatoma cells overexpressing p53, TA-p73alpha, and TA-p73beta isoforms. CONCLUSION: p53 and p73 directly bind and activate the expression of the Foxo3 gene in the adult mouse liver and murine cell lines. p53, TA-p73, and p300 binding and Foxo3 expression decrease during liver regeneration, and this suggests a critical growth control mechanism mediated by these transcription factors in vivo.",0
4113,20573924,Implications of a circulating vaccine-derived poliovirus in Nigeria,"BACKGROUND: The largest recorded outbreak of a circulating vaccine-derived poliovirus (cVDPV), detected in Nigeria, provides a unique opportunity to analyze the pathogenicity of the virus, the clinical severity of the disease, and the effectiveness of control measures for cVDPVs as compared with wild-type poliovirus (WPV). METHODS: We identified cases of acute flaccid paralysis associated with fecal excretion of type 2 cVDPV, type 1 WPV, or type 3 WPV reported in Nigeria through routine surveillance from January 1, 2005, through June 30, 2009. The clinical characteristics of these cases, the clinical attack rates for each virus, and the effectiveness of oral polio vaccines in preventing paralysis from each virus were compared. RESULTS: No significant differences were found in the clinical severity of paralysis among the 278 cases of type 2 cVDPV, the 2323 cases of type 1 WPV, and the 1059 cases of type 3 WPV. The estimated average annual clinical attack rates of type 1 WPV, type 2 cVDPV, and type 3 WPV per 100,000 susceptible children under 5 years of age were 6.8 (95% confidence interval [CI], 5.9 to 7.7), 2.7 (95% CI, 1.9 to 3.6), and 4.0 (95% CI, 3.4 to 4.7), respectively. The estimated effectiveness of trivalent oral polio vaccine against paralysis from type 2 cVDPV was 38% (95% CI, 15 to 54%) per dose, which was substantially higher than that against paralysis from type 1 WPV (13%; 95% CI, 8 to 18%), or type 3 WPV (20%; 95% CI, 12 to 26%). The more frequent use of serotype 1 and serotype 3 monovalent oral polio vaccines has resulted in improvements in vaccine-induced population immunity against these serotypes and in declines in immunity to type 2 cVDPV. CONCLUSIONS: The attack rate and severity of disease associated with the recent cVDPV identified in Nigeria are similar to those associated with WPV. International planning for the management of the risk of WPV, both before and after eradication, must include scenarios in which equally virulent and pathogenic cVDPVs could emerge.",0
4114,20578126,In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of covalently closed circular DNA in mice,"Chronic hepatitis B virus (HBV) infection is maintained by the presence of covalently closed circular DNA (cccDNA), the template of viral transcription and replication. In quiescent hepatocytes, cccDNA is a stable molecule that can persist throughout the hepatocyte lifespan. However, in chronic HBV infection, immunomediated cell injury and compensatory hepatocyte proliferation may favor cccDNA decline and selection of cccDNA-free cells. To investigate the impact of liver regeneration on cccDNA stability and activity in vivo, we used the urokinase-type plasminogen activator (uPA)/severe combined immunodeficiency (SCID) mouse model. Primary tupaia hepatocytes (PTHs) chronically infected with woolly monkey HBV (WM-HBV) were isolated from one highly viremic uPA/SCID chimeric mouse and transplanted into 20 uPA recipients. Expansion of transplanted PTHs and viral load changes were determined by real-time polymerase chain reaction and immunohistochemistry. Transplantation of WM-HBV infected hepatocytes led to an average of 3.8 PTH doublings within 80 days, 75% reduction of virion productivity (relaxed circular DNA/cccDNA), and lower expression levels of pregenomic RNA and hepatitis B core antigen. Remarkably, a median 2-log decline of cccDNA per cell determined during PTH proliferation was due to both dilution of the cccDNA pool among daughter cells and a 0.5-log loss of intrahepatic cccDNA loads (P = 0.02). Intrahepatic viral DNA sequences persisting at the end of the study were mostly present as replicative intermediates and not as integrated virus. CONCLUSION: Cell division in the setting of liver regeneration and without administration of antiviral drugs induced strong destabilization of the cccDNA reservoir, resulting in cccDNA clearance in the great majority of chronically infected hepatocytes.",0
4115,20578127,Comparison of surrogate and direct measurement of insulin resistance in chronic hepatitis C virus infection: impact of obesity and ethnicity,"Studies using surrogate estimates show high prevalence of insulin resistance in hepatitis C infection. This study prospectively evaluated the correlation between surrogate and directly measured estimates of insulin resistance and the impact of obesity and ethnicity on this relationship. Eighty-six nondiabetic, noncirrhotic patients with hepatitis C virus (age = 48 +/- 7 years, 74% male, 44% white, 22% African American, 26% Latino, 70% genotype 1) were categorized into normal-weight (body mass index [BMI] < 25, n = 30), overweight (BMI = 25-29.9, n = 38), and obese (BMI > or = 30, n = 18). Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during a 240-minute insulin suppression test. Surrogate estimates included: fasting glucose and insulin, glucose/insulin, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), insulin (I-AUC) and glucose (G-AUC) area under the curve during oral glucose tolerance test, and the Belfiore and Stumvoll indexes. All surrogate estimates correlated with SSPG, but the magnitude of correlation varied (r = 0.30-0.64). The correlation coefficients were highest in the obese. I-AUC had the highest correlation among all ethnic and weight groups (r = 0.57-0.77). HOMA-IR accounted for only 15% of variability in SSPG in the normal weight group. The common HOMA-IR cutoff of < or =3 to define insulin resistance had high misclassification rates especially in the overweight group independent of ethnicity. HOMA-IR > 4 had the lowest misclassification rate (75% sensitivity, 88% specificity). Repeat HOMA-IR measurements had higher within-person variation in the obese (standard deviation = 0.77 higher than normal-weight, 95% confidence interval = 0.25-1.30, P = 0.005). CONCLUSION: Because of limitations of surrogate estimates, caution should be used in interpreting data evaluating insulin resistance especially in nonobese, nondiabetic patients with HCV.",0
4116,20578145,Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells,"Hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSCs) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSCs to accumulate in damaged livers: transition of resident, quiescent hepatic stellate cells (Q-HSCs) to MF-HSCs and expansion of MF-HSC numbers through increased proliferation and/or reduced apoptosis. In this study, we identified two novel mediators of MF-HSC accumulation: Ras-related C3 botulinum toxin substrate 1 (Rac1) and Hedgehog (Hh). It is unclear whether Rac1 and Hh interact to regulate the accumulation of MF-HSCs. We evaluated the hypothesis that Rac1 promotes activation of the Hh pathway, thereby stimulating signals that promote transition of Q-HSCs into MF-HSCs and enhance the viability of MF-HSCs. Using both in vitro and in vivo model systems, Rac1 activity was manipulated through adenoviral vector-mediated delivery of constitutively active or dominant-negative rac1. Rac1-transgenic mice with targeted myofibroblast expression of a mutated human rac1 transgene that produces constitutively active Rac1 were also examined. Results in all models demonstrated that activating Rac1 in HSC enhanced Hh signaling, promoted acquisition/maintenance of the MF-HSC phenotype, increased MF-HSC viability, and exacerbated fibrogenesis. Conversely, inhibiting Rac1 with dominant-negative rac1 reversed these effects in all systems examined. Pharmacologic manipulation of Hh signaling demonstrated that profibrogenic actions of Rac1 were mediated by its ability to activate Hh pathway-dependent mechanisms that stimulated myofibroblastic transition of HSCs and enhanced MF-HSC viability. CONCLUSION: These findings demonstrate that interactions between Rac1 and the Hh pathway control the size of MF-HSC populations and have important implications for the pathogenesis of cirrhosis.",0
4117,20578150,Bid agonist regulates murine hepatocyte proliferation by controlling endoplasmic reticulum calcium homeostasis,"BH3-interacting domain death agonist (Bid), a BH3-only B cell lymphoma 2 family molecule, is generally known for its importance in activating the mitochondrial apoptosis pathway after death receptor engagement, particularly in hepatocytes. However, Bid also promotes hepatocyte proliferation during liver regeneration and carcinogenesis. This study was designed to examine the hypothesis that Bid regulates endoplasmic reticulum calcium concentration ([Ca(2+)](ER)) homeostasis to affect hepatocyte proliferation. We found that serum-stimulated hepatocyte proliferation was dependent on calcium, and the depletion of calcium with thapsigargin or ethylene glycol tetraacetic acid (EGTA) inhibited the proliferation. Subcellular fractionation showed that a portion of Bid was inserted into the endoplasmic reticulum (ER)-enriched membranes, and single-cell calcium imaging indicated that Bid was important for maintaining the [Ca(2+)](ER) level. Bid-deficient hepatocytes manifested delayed and reduced serum-stimulated proliferation, which was corrected by ionomycin or reconstitution of Bid, particularly an ER-targeted Bid. Finally, B cell lymphoma 2-associated X protein (Bax) could also be found in the ER-enriched membranes, and Bax deficiency caused the same proliferation defect. However, Bid/Bax double deletion in hepatocytes did not further augment the defect, which suggested that Bid and Bax worked by the same regulatory mechanism in [Ca(2+)](ER) control. CONCLUSION: Bid regulates hepatocyte proliferation by positively affecting [Ca(2+)](ER) homeostasis, and this could be important for liver regeneration and carcinogenesis.",0
4118,20578158,Liver sinusoidal endothelium: a microenvironment-dependent differentiation program in rat including the novel junctional protein liver endothelial differentiation-associated protein-1,"Liver sinusoidal endothelium (LSEC) is a prime example of organ-specific microvascular differentiation and functions. Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular endothelial cells (LMEC) and with LSEC cultured for 42 hours. The LSEC signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (fold change >7 in at least one comparison); quantitative reverse-transcription polymerase chain reaction confirmation of these genes included numerous family members and signaling pathway-associated molecules. The LSEC differentiation program comprised distinct sets of growth (Wnt2, Fzd4, 5, 9, Wls, vascular endothelial growth factors [VEGFR] 1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1, and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26-kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced overexpression in MDCK cells, Leda-1 was sorted basolaterally to E-cadherin-positive adherens junctions, suggesting functional involvement in cell adhesion and polarity. CONCLUSION: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1.",0
4119,20578253,Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice,"The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. CONCLUSION: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication.",0
4120,20578254,Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes,"Genetic host factors may modify the course of the hepatitis C virus (HCV) infection. Very recently, a genome-wide scan that reported association of the IL28B locus with response to treatment in HCV infection was published. The aim of the current study was to investigate the relationship of this locus with outcome of HCV infection in a cohort constituted by a total of 731 Spanish individuals. From these, 284 were subjects with persistent infection, 69 were individuals who naturally cleared the virus, and 378 were noninfected subjects. Genotyping of the rs12979860 (C>T) in the IL28B locus was performed using a TaqMan 5' allelic discrimination assay. The CC genotype was overrepresented among patients infected with viral genotypes non-1 (66.7% versus 39.1% in patients infected with viral genotype-1, P = 8.5 x 10(-5), odds ratio [OR] = 0.32, 95% confidence interval [CI] 0.17-0.60); patients with spontaneous resolution of infection (72.5% versus 45.6% of the individuals with persistent infection, P = 6.2 x 10(-5), OR = 0.32; 95%CI, 0.18-0.57); and lastly, patients with sustained response (60.2% versus 32.1% found in patients with nonsustained response, P = 3.1 x 10(-5), OR = 0.31; 95%CI, 0.17-0.56). CONCLUSION: We have found different rates of viral genotype infection depending on the IL28B variant as well as an association of this locus with natural and treatment-mediated response.",0
4121,20581420,A school-based intervention for diabetes risk reduction,"BACKGROUND: We examined the effects of a multicomponent, school-based program addressing risk factors for diabetes among children whose race or ethnic group and socioeconomic status placed them at high risk for obesity and type 2 diabetes. METHODS: Using a cluster design, we randomly assigned 42 schools to either a multicomponent school-based intervention (21 schools) or assessment only (control, 21 schools). A total of 4603 students participated (mean [+/- SD] age, 11.3 [+/- 0.6 years; 54.2% Hispanic and 18.0% black; 52.7% girls). At the beginning of 6th grade and the end of 8th grade, students underwent measurements of body-mass index (BMI), waist circumference, and fasting glucose and insulin levels. RESULTS: There was a decrease in the primary outcome--the combined prevalence of overweight and obesity--in both the intervention and control schools, with no significant difference between the school groups. The intervention schools had greater reductions in the secondary outcomes of BMI z score, percentage of students with waist circumference at or above the 90th percentile, fasting insulin levels (P=0.04 for all comparisons), and prevalence of obesity (P=0.05). Similar findings were observed among students who were at or above the 85th percentile for BMI at baseline. Less than 3% of the students who were screened had an adverse event; the proportions were nearly equivalent in the intervention and control schools. CONCLUSIONS: Our comprehensive school-based program did not result in greater decreases in the combined prevalence of overweight and obesity than those that occurred in control schools. However, the intervention did result in significantly greater reductions in various indexes of adiposity. These changes may reduce the risk of childhood-onset type 2 diabetes. (Funded by the National Institutes of Health and the American Diabetes Association; ClinicalTrials.gov number, NCT00458029.)",0
4122,20593455,Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells,"Antibodies are thought to exert antiviral activities by blocking viral entry into cells and/or accelerating viral clearance from circulation. In particular, antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) confer protection, by binding circulating virus. Here, we used mathematical modeling to gain information about viral dynamics during and after single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B) antibodies in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, whereas antibody HBV-19 recognizes a linear epitope on the HBsAg. The kinetic profiles of the decline of serum HBV DNA and HBsAg revealed partial blocking of virion release from infected cells as a new antiviral mechanism, in addition to acceleration of HBV clearance from the circulation. We then replicated this approach in vitro, using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics. In vitro, HepeX-B treatment of HBsAg-producing cells showed cellular uptake of antibodies, resulting in intracellular accumulation of viral particles. Blocking of HBsAg secretion also continued after HepeX-B was removed from the cell culture supernatants. CONCLUSION: These results identify a novel antiviral mechanism of antibodies to HBsAg (anti-HBs) involving prolonged blocking of the HBV and HBsAg subviral particles release from infected cells. This may have implications in designing new therapies for patients with chronic HBV infection and may also be relevant in other viral infections.",0
4123,20607688,Expanding access to hepatitis C virus treatment--Extension for Community Healthcare Outcomes (ECHO) project: disruptive innovation in specialty care,"The Extension for Community Healthcare Outcomes (ECHO) Model was developed by the University of New Mexico Health Sciences Center as a platform to deliver complex specialty medical care to underserved populations through an innovative educational model of team-based interdisciplinary development. Using state-of-the-art telehealth technology, best practice protocols, and case-based learning, ECHO trains and supports primary care providers to develop knowledge and self-efficacy on a variety of diseases. As a result, they can deliver best practice care for complex health conditions in communities where specialty care is unavailable. ECHO was first developed for the management of hepatitis C virus (HCV), optimal management of which requires consultation with multidisciplinary experts in medical specialties, mental health, and substance abuse. Few practitioners, particularly in rural and underserved areas, have the knowledge to manage its emerging treatment options, side effects, drug toxicities, and treatment-induced depression. In addition, data were obtained from observation of ECHO weekly clinics and database of ECHO clinic participation and patient presentations by clinical provider. Evaluation of the ECHO program incorporates an annual survey integrated into the ECHO annual meeting and routine surveys of community providers about workplace learning, personal and professional experiences, systems and environmental factors associated with professional practice, self-efficacy, facilitators, and barriers to ECHO. The initial survey data show a significant improvement in provider knowledge, self-efficacy, and professional satisfaction through participation in ECHO HCV clinics. Clinicians reported a moderate to major benefit from participation. We conclude that ECHO expands access to best practice care for underserved populations, builds communities of practice to enhance professional development and satisfaction of primary care clinicians, and expands sustainable capacity for care by building local centers of excellence.",0
4124,20607690,Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy,"Overexpression of epidermal growth factor receptor (ErbB1) and/or ErbB2 has been implicated in the pathogenesis of cholangiocarcinoma, suggesting that combined ErbB1/ErbB2 targeting might serve as a target-based therapeutic strategy for this highly lethal cancer. To test this strategy, we investigated targeting with the ErbB1 inhibitor tryphostin AG1517 and the ErbB2 inhibitor tryphostin AG879, in combination and alone, as well as with the dual ErbB1/ErbB2 inhibitor lapatinib, to assess the effectiveness of simultaneous targeting of ErbB1 and ErbB2 signaling over single inhibitor treatments in suppressing cholangiocarcinoma cell growth in vitro and the therapeutic efficacy of lapatinib in vivo. Our in vitro studies were carried out using rat (BDEneu and C611B) and human (HuCCT1 and TFK1) cholangiocarcinoma cell lines. The efficacy of lapatinib to significantly suppress liver tumor growth was tested in an orthotopic, syngeneic rat model of intrahepatic cholangiocarcinoma progression. Our results demonstrated that simultaneous targeting of ErbB1 and ErbB2 signaling was significantly more effective in suppressing the in vitro growth of both rat and human cholangiocarcinoma cells than individual receptor targeting. Lapatinib was an even more potent inhibitor of cholangiocarcinoma cell growth and inducer of apoptosis than either tryphostin when tested in vitro against these respective cholangiocarcinoma cell lines, regardless of differences in their levels of ErbB1 or ErbB2 protein expression and/or mechanism of activation. Lapatinib treatment also produced a significant suppression of intrahepatic cholangiocarcinoma growth when administered early to rats, but was without effect in inhibiting liver tumor growth in rats with more advanced tumors. CONCLUSION: Our findings suggest that simultaneous targeting of ErbB1 and ErbB2 could be a potentially selective strategy for cholangiocarcinoma therapy, but is likely to be ineffective by itself against advanced cancer.",0
4125,20635398,Is sexual contact a major mode of hepatitis C virus transmission?,"Medical opinion varies considerably regarding the transmission of hepatitis C virus (HCV) through sexual contact. Based on the study design, representativeness of the study population, and the methods used for case ascertainment, we analyzed 80 qualifying reports regarding the evidence for or against sexual transmission. Regarding heterosexual transmission, the weight of evidence is that there is no increased risk of sexual transmission of HCV among heterosexual couples in regular relationships. This risk increases among persons with multiple sexual partners (adjusted odds ratio [aOR] 2.2-2.9), but this association may be confounded by increased likelihood of injection drug use with increased number of partners. There appears to be a real increased risk for women coinfected with human immunodeficiency virus (HIV) or other sexually transmitted infections (aOR 3.3-3.9) and especially for HIV-infected gay men who are having sex with one another compared with HIV-uninfected men (aOR 4.1-5.7). HIV-infected gay men increase their risk of such transmission in association with practices that lead to mucosal trauma (multiple sexual partners, fisting, use of sex toys) and the presence of genital ulcerative disease. CONCLUSION: This review should inform, and not distract from, recommendations to reduce the risk of HCV transmission. Health care providers need to pay special attention to sexual transmission of HCV among HIV-infected individuals.",0
4126,20637696,Changes in the burden of malaria in sub-Saharan Africa,"The burden of malaria in countries in sub-Saharan Africa has declined with scaling up of prevention, diagnosis, and treatment. To assess the contribution of specific malaria interventions and other general factors in bringing about these changes, we reviewed studies that have reported recent changes in the incidence or prevalence of malaria in sub-Saharan Africa. Malaria control in southern Africa (South Africa, Mozambique, and Swaziland) began in the 1980s and has shown substantial, lasting declines linked to scale-up of specific interventions. In The Horn of Africa, Ethiopia and Eritrea have also experienced substantial decreases in the burden of malaria linked to the introduction of malaria control measures. Substantial increases in funding for malaria control and the procurement and distribution of effective means for prevention and treatment are associated with falls in malaria burden. In central Africa, little progress has been documented, possibly because of publication bias. In some countries a decline in malaria incidence began several years before scale-up of malaria control. In other countries, the change from a failing drug (chloroquine) to a more effective drug (sulphadoxine plus pyrimethamine or an artemisinin combination) led to immediate improvements; in others malaria reduction seemed to be associated with the scale-up of insecticide-treated bednets and indoor residual spraying. ",0
4127,20637838,The multikinase inhibitor sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE₂ in murine macrophages,"Classical activating stimuli like LPS drive macrophages to secrete a battery of inflammatory cytokines, including interleukin (IL)-12/23, through Toll-like receptor (TLR) signaling. TLR activation in the presence of some factors, including prostaglandin E₂ (PGE₂), promotes an anti-inflammatory cytokine profile, with production of IL-10 and suppression of IL-12/23 secretion. Extracellular signal-regulated kinase (ERK) is a key regulator of macrophage IL-10 production. Since it inhibits ERK, we investigated the impact of Sorafenib on the cytokine profile of macrophages. In the presence of PGE₂, Sorafenib restored the secretion of IL-12 and suppressed IL-10 production. Moreover, IL-12 secretion was enhanced by Sorafenib under conditions of TLR ligation alone. Furthermore, the impact of tumor culture supernatants, cholera toxin, and cAMP analogs (which suppress IL-12 secretion), was reversed by Sorafenib. Sorafenib inhibited the activation of the MAP kinase p38 and its downstream target mitogen and stress activated protein kinase (MSK), and partially inhibited protein kinase B (AKT) and its subsequent inactivation of the downstream target glycogen synthase kinase 3-β (GSK3-β). Interference with these pathways, which are pivotal in determining the balance of inflammatory versus anti-inflammatory cytokines, provides a potential mechanism by which Sorafenib can modulate the macrophage cytokine phenotype. These data raise the possibility that the use of Sorafenib as cancer therapy could potentially reverse the immunosuppressive cytokine profile of tumor-associated macrophages, rendering the tumor microenvironment more conducive to an anti-tumor immune response. ",0
4128,20648475,Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in mice,"We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1(-/-) Delta-like protein (Dlk)(+) hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf(-/-) Dlk(+) cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk(+) cells. Although Ink4a/Arf(-/-) Dlk(+) cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf(-/-) Dlk(+) cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five down-regulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk(+) cells strongly suppressed colony propagation and tumor growth. CONCLUSION: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells.",0
4129,20648556,A novel role for thyroid-stimulating hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway,"Elevated thyroid-stimulating hormone (TSH) and hypercholesterolemia commonly coexist, as typically seen in hypothyroidism, but there is no known mechanism directly linking the two. Here, we demonstrated that in liver cells, TSH promoted the expression of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis, by acting on the TSH receptor in hepatocyte membranes and stimulating the cyclic adenosine monophosphate / protein kinase A / cyclic adenosine monophosphate-responsive element binding protein (cAMP/PKA/CREB) signaling system. In thyroidectomized rats, the production of endogenous thyroid hormone was eliminated and endogenous TSH was suppressed through pituitary suppression with constant administration of exogenous thyroid hormone, and hepatic HMGCR expression was increased by administration of exogenous TSH. These results suggested that TSH could up-regulate hepatic HMGCR expression, which indicated a potential mechanism for hypercholesterolemia involving direct action of TSH on the liver.",0
4130,20658465,Glucosidase inhibition enhances presentation of de-N-glycosylated hepatitis B virus epitopes by major histocompatibility complex class I in vitro and in woodchucks,"""In this report, the possibility of pharmacologically altering the hepatitis B virus (HBV) epitopes presented by major histocompatibility complex class I on infected cells is demonstrated. The HBV middle envelope glycoprotein (MHBs) maturation appears to require calnexin-mediated folding. This interaction is dependent on glucosidases in the endoplasmic reticulum. Prevention of HBV envelope protein maturation in cultured cells through use of glucosidase inhibitors, such as 6-O-butanoyl castanospermine and N-nonyl deoxynorjirimycin, resulted in MHBs degradation by proteasomes. The de-N-glycosylation associated with polypeptide degradation was predicted to result in conversion of asparagine residues into aspartic acid residues. This prediction was confirmed by showing that peptides corresponding to the N-glycosylation sequons of MHBs, but with aspartic acid replacing asparagine, (1) can prime human cytotoxic T lymphocytes that recognize HBV-producing cells and (2) that the presentation of these envelope motifs by major histocompatibility complex class I is enhanced by incubation with glucosidase inhibitors. Moreover, although peripheral blood mononuclear cells isolated from woodchucks chronically infected with woodchuck hepatitis virus and vaccinated with woodchuck hepatitis virus surface antigen could be induced to recognize the natural MHBs asparagine-containing peptides, only cells isolated from animals treated with glucosidase inhibitor recognized the aspartic acid-containing peptides. CONCLUSION: These data suggest that pharmacological intervention with glucosidase inhibitors can alter the MHBs epitopes presented. This editing of the amino acid sequence of the polypeptide results in a new epitope, or """"editope"""", with possible medical significance.""",0
4131,20660401,A randomized trial of treatment for acute anterior cruciate ligament tears,"BACKGROUND: The optimal management of a torn anterior cruciate ligament (ACL) of the knee is unknown. METHODS: We conducted a randomized, controlled trial involving 121 young, active adults with acute ACL injury in which we compared two strategies: structured rehabilitation plus early ACL reconstruction and structured rehabilitation with the option of later ACL reconstruction if needed. The primary outcome was the change from baseline to 2 years in the average score on four subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS)--pain, symptoms, function in sports and recreation, and knee-related quality of life (KOOS(4); range of scores, 0 [worst] to 100 [best]). Secondary outcomes included results on all five KOOS subscales, the Medical Outcomes Study 36-Item Short-Form Health Survey, and the score on the Tegner Activity Scale. RESULTS: Of 62 subjects assigned to rehabilitation plus early ACL reconstruction, 1 did not undergo surgery. Of 59 assigned to rehabilitation plus optional delayed ACL reconstruction, 23 underwent delayed ACL reconstruction; the other 36 underwent rehabilitation alone. The absolute change in the mean KOOS(4) score from baseline to 2 years was 39.2 points for those assigned to rehabilitation plus early ACL reconstruction and 39.4 for those assigned to rehabilitation plus optional delayed reconstruction (absolute between-group difference, 0.2 points; 95% confidence interval, -6.5 to 6.8; P=0.96 after adjustment for the baseline score). There were no significant differences between the two treatment groups with respect to secondary outcomes. Adverse events were common in both groups. The results were similar when the data were analyzed according to the treatment actually received. CONCLUSIONS: In young, active adults with acute ACL tears, a strategy of rehabilitation plus early ACL reconstruction was not superior to a strategy of rehabilitation plus optional delayed ACL reconstruction. The latter strategy substantially reduced the frequency of surgical reconstructions. (Funded by the Swedish Research Council and the Medical Faculty of Lund University and others; Current Controlled Trials number, ISRCTN84752559.)",0
4132,20660402,Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis,"""BACKGROUND: In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in the glomerular basement membrane (GBM). The specificity and molecular architecture of epitopes of tissue-bound autoantibodies are unknown. Alport's post-transplantation nephritis, which is mediated by alloantibodies against the GBM, occurs after kidney transplantation in some patients with Alport's syndrome. We compared the conformations of the antibody epitopes in Goodpasture's disease and Alport's post-transplantation nephritis with the intention of finding clues to the pathogenesis of anti-GBM glomerulonephritis. METHODS: We used an enzyme-linked immunosorbent assay to determine the specificity of circulating autoantibodies and kidney-bound antibodies to NC1 domains. Circulating antibodies were analyzed in 57 patients with Goodpasture's disease, and kidney-bound antibodies were analyzed in 14 patients with Goodpasture's disease and 2 patients with Alport's post-transplantation nephritis. The molecular architecture of key epitope regions was deduced with the use of chimeric molecules and a three-dimensional model of the alpha345NC1 hexamer. RESULTS: In patients with Goodpasture's disease, both autoantibodies to the alpha3NC1 monomer and antibodies to the alpha5NC1 monomer (and fewer to the alpha4NC1 monomer) were bound in the kidneys and lungs, indicating roles for the alpha3NC1 and alpha5NC1 monomers as autoantigens. High antibody titers at diagnosis of anti-GBM disease were associated with ultimate loss of renal function. The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer. In contrast, in patients with Alport's post-transplantation nephritis, alloantibodies bound to the E(A) region of the alpha5NC1 subunit in the intact hexamer, and binding decreased on dissociation. CONCLUSIONS: The development of Goodpasture's disease may be considered an autoimmune """"conformeropathy"""" that involves perturbation of the quaternary structure of the alpha345NC1 hexamer, inducing a pathogenic conformational change in the alpha3NC1 and alpha5NC1 subunits, which in turn elicits an autoimmune response. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)""",0
4133,20683931,A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis,"Immunotolerance is maintained by regulatory T cells (Tregs), including CD4(+)CD25(hi), CD8(+)CD28(-), gammadelta, and CD3(+)CD56(+) [natural killer T (NKT)] cells. CD4(+)CD25(hi) cells are impaired in children with autoimmune hepatitis (AIH). Little is known about Tregs in adults with AIH. The aim of this study was to investigate the frequency and function of Treg subsets in adult patients with AIH during periods of active disease and remission. Forty-seven AIH patients (16 with active disease and 31 in remission) and 28 healthy controls were studied. Flow cytometry was used to evaluate surface markers and function-related intracellular molecules in gammadelta, CD8(+)CD28(-), NKT, and CD4(+)CD25(hi) cells. CD4(+)CD25(hi) T cell function was determined by the ability to suppress proliferation and interferon gamma (IFN-gamma) production by CD4(+)CD25(-) target cells. Liver forkhead box P3-positive (FOXP3(+)) cells were sought by immunohistochemistry. In AIH patients, particularly during active disease, CD4(+)CD25(hi) T cells were fewer, expressed lower levels of FOXP3, and were less effective at inhibiting target cell proliferation versus healthy controls. Moreover, although the numbers of CD8(+)CD28(-) T cells were similar in AIH patients and healthy controls, NKT cells were numerically reduced, especially during active disease, and produced lower quantities of the immunoregulatory cytokine interleukin-4 versus controls. In contrast, gammadelta T cells in AIH patients were more numerous versus healthy controls and had an inverted Vdelta1/Vdelta2 ratio and higher IFN-gamma and granzyme B production; the latter was correlated to biochemical indices of liver damage. There were few FOXP3(+) cells within the portal tract inflammatory infiltrate. CONCLUSION: Our data show that the defect in immunoregulation in adult AIH is complex, and gammadelta T cells are likely to be effectors of liver damage.",0
4134,20683954,A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells,"Cholangiocarcinoma (CCA) cells paradoxically express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that, failing to kill CCA cells, instead promotes their tumorigenicity and especially the metastatic behaviors of cell migration and invasion. Second mitochondria-derived activator of caspase (smac) mimetics are promising cancer therapeutic agents that enhance proapoptotic death receptor signaling by causing cellular degradation of inhibitor of apoptosis (IAP) proteins. Our aim was to examine the in vitro and in vivo effects of the smac mimetic JP1584 in CCA. Despite JP1584-mediated loss of cellular inhibitor of apoptosis-1 (cIAP-1) and cIAP-2, TRAIL failed to induce apoptosis in KMCH-1, TFK-1, and BDEneu CCA cells; a finding consistent with a downstream block in death signaling. Because cIAP-1 and cIAP-2 also promote nuclear factor kappa B (NF-kappaB) activation by the canonical pathway, the effect of JP1584 on this signaling pathway was examined. Treatment with JP1584 inhibited TRAIL-induced NF-kappaB activation as well as TRAIL-mediated up-regulation of the NF-kappaB target gene, matrix metalloproteinase 7 (MMP7). JP1584 also reduced TRAIL-mediated CCA cell migration and invasion in vitro. Finally, in a syngeneic rat orthotopic CCA model, JP1584 administration reduced MMP7 messenger RNA levels and extrahepatic metastases. CONCLUSION: : Although the smac mimetic JP1584 does not sensitize cells to apoptosis, it reduces TRAIL-induced CCA cell metastatic behavior. These data support the emerging concept that IAPs are prometastatic and represent targets for antimetastatic therapies.",0
4135,20683959,Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis,"Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) develop more rapid fibrosis than those infected with HCV only. In HIV/HCV-coinfected patients, fibrosis progression correlates with HIV RNA levels, suggesting a direct role of HIV in liver fibrogenesis. Chemokine (C-C motif) receptor 5 (CCR5) and cysteine-X-cysteine receptor 4 (CXCR4), the two major coreceptors required for HIV entry into cells, are expressed on activated hepatic stellate cells (HSCs), the principle fibrogenic cell type in the liver. We therefore examined whether HIV can infect HSCs, explored the potential mechanisms of viral entry, and assessed the impact of infection as reflected by the ability of HSCs to transfer virus to T lymphocytes and elicit a proinflammatory and profibrogenic response. We report that the laboratory-adapted viruses HIV-IIIB (CXCR4-tropic or X4) and HIV-BaL (CCR5-tropic or R5) and primary HIV isolates can infect both a human stellate cell line, LX-2, and primary human HSCs. HIV entry and gene expression in HSCs was confirmed using HIV-green fluorescent protein (GFP) expression viral constructs in the presence or absence of the reverse-transcriptase inhibitor azidothymidine. CD4 expression on a subset of primary HSCs was demonstrated using fluorescence-activated cell sorting and immunofluorescence staining. Blocking experiments in the presence of anti-CD4, anti-CXCR4, and anti-CCR5 revealed that HIV entry into HSCs is predominantly CD4/chemokine coreceptor-independent. HIV infection promoted HSC collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein-1. Furthermore, infected LX-2 cells were capable of transferring GFP-expressing virus to T lymphocytes in a coculture system. CONCLUSION: Taken together, our results suggest a potential role of HIV in liver fibrosis/inflammation mediated through effects on HSCs. The role of early highly active antiretroviral therapy initiation in patients with HIV/HCV coinfection warrants further investigation.",0
4136,20683961,Quantifying growth and transformation frequency of oncogene-expressing mouse hepatocytes in vivo,"Gene changes can affect cancer cells in many ways, but changes that increase disease severity--by allowing cells to proliferate when they should be quiescent, by enhancing their rate of growth under growth permissive conditions, or by increasing the risk that they will accumulate additional carcinogenic alterations--must be identified so that strategies to counter their effects can be developed. We describe a novel in vivo assay system based on hepatocyte transplantation that permits us to accomplish this objective for genetically modified hepatocytes. We find that the oncogenes c-myc and transforming growth factor alpha, but not simian virus 40 T-antigen, increase the rate of hepatocyte growth under growth permissive conditions. However, no single oncogene can induce hepatocyte growth in quiescent liver. In contrast, at least one oncogene combination, transforming growth factor alpha/T-antigen, was sufficient to direct cell autonomous growth even in this nonpermissive environment. Furthermore, we could quantify risk for progression to neoplasia associated with oncogene expression; increased transformation frequency was the principal carcinogenic effect of T-antigen. CONCLUSION: This system identifies biological mechanistic role(s) in carcinogenesis for candidate genetic changes implicated in development of human liver cancer. The quantitative and comparative evaluation of gene effects on liver cancer allows us to prioritize targets for therapeutic intervention.",0
4137,20725912,Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism,"Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n = 16) and controls (n = 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment. CONCLUSION: Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved glycemic control in T2DM.",0
4138,20812318,Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro,"CD56(pos) natural killer (NK)/natural T (NT) cells are important innate effectors providing the first line of defense against viral infection. Enhanced NK activity has been shown to protect from human immunodeficiency virus-1 infection. However, the role played by these innate effectors in protection against or development of hepatitis C virus (HCV) infection is unknown. We characterized CD56(pos) populations in 11 injection drug users (IDUs) who remained uninfected despite being repeatedly exposed to HCV. NK profiles in exposed but uninfected (EU) individuals were compared with preinfection samples (median 90 days prior to HCV seroconversion) collected from 14 IDUs who were exposed and subsequently became infected (EI) and unexposed normal control subjects (n = 8). Flow cytometric analysis of CD56(pos) populations demonstrated that EUs had a higher proportion of CD56(low) mature (P = 0.0011) NK cells compared with EI subjects. Bead-isolated NKs ( > 90% purity) from EUs had significantly higher interleukin-2 (IL-2)-induced cytolytic activity against the NK-sensitive cell line K562 at an effector-to-target ratio of 10:1 (P < 0.0001). NKp30, a natural cytotoxicity receptor involved in NK activation, is highest on NK/NT cells in EUs relative to infected subjects. Using the JFH-1 infection system, we demonstrated that NKp30(high) cells in the absence of exogenous stimulation significantly reduce infection of hepatocytes. CONCLUSION: CD56(pos) populations in EUs are enriched for effector NKs displaying enhanced IL-2-induced cytolytic activity and higher levels of the natural cytotoxicity receptor NKp30-activating receptor. In addition, NKp30(high) cells are more effective in preventing infection of Huh-7.5 cells than their NKp30(low/neg) counterparts. These data support the hypothesis that NK cells contribute to anti-HCV defense in vivo in the earliest stages of infection, providing innate protection from HCV acquisition.",0
4139,20815025,Impact of hepatitis B virus surface protein mutations on the diagnosis of occult hepatitis B virus infection,"Genotype D occult hepatitis B virus (HBV) infections (OBIs) have a high frequency of amino acid substitutions in the major hydrophilic region of the small surface protein (S protein). This possibly reflects an escape mutation mechanism to evade detection by the host immune system. Mutations may also impact the detection of hepatitis B surface antigen (HBsAg) by commercial assays. To test these hypotheses, 20 recombinant HBV genotype D surface proteins from OBI carriers with or without antibody to hepatitis B surface antigen (anti-HBs) were expressed in yeast. Recombinant surface protein (rS protein) variants were nonreactive with autologous anti-HBs but reacted weakly with vaccine-induced anti-HBs supporting an immune escape mechanism. rS protein variants tested with a wide range of HBs antibodies, and HBsAg commercial assays showed significantly lower antigenic reactivity in anti-HBs carriers than in donors with antibody to hepatitis B core antigen (anti-HBc) only. Eight out of 10 recombinant variants from anti-HBs carriers reacted weakly or were nonreactive with antibodies to HBs as well as with qualitative and quantitative commercial HBsAg assays, whereas eight out of 10 anti-HBc-only plasmas were fully reactive. rS proteins with substitutions of wild-type cysteine at positions 121, 124, and 137 were nonreactive or showed poor reactivity. However, mutation of cysteine 147 did not alter reactivity compared with controls. Restoration of cysteines 124 and 137 by site-directed mutagenesis improved antigenic reactivity. CONCLUSION: Escape mutation is a mechanism associated with OBI, which also leads to decreased reactivity in HBsAg detection assays. Performance of commercial assays would be improved by the incorporation of OBI mutants in reagent development.",0
4140,20818845,Underinsurance among children in the United States,"BACKGROUND: Recent interest in policy regarding children's health insurance has focused on expanding coverage. Less attention has been devoted to the question of whether insurance sufficiently meets children's needs. METHODS: We estimated underinsurance among U.S. children on the basis of data from the 2007 National Survey of Children's Health (sample size, 91,642 children) regarding parents' or guardians' judgments of whether their children's insurance covered needed services and providers and reasonably covered costs. Data on adequacy were combined with data on continuity of insurance coverage to classify children as never insured during the past year, sometimes insured during the past year, continuously insured but inadequately covered (i.e., underinsured), and continuously insured and adequately covered. We examined the association between this classification and five overall indicators of health care access and quality: delayed or forgone care, difficulty obtaining needed care from a specialist, no preventive care, no developmental screening at a preventive visit, and care not meeting the criteria of a medical home. RESULTS: We estimated that in 2007, 11 million children were without health insurance for all or part of the year, and 22.7% of children with continuous insurance coverage--14.1 million children--were underinsured. Older children, Hispanic children, children in fair or poor health, and children with special health care needs were more likely to be underinsured. As compared with children who were continuously and adequately insured, uninsured and underinsured children were more likely to have problems with health care access and quality. CONCLUSIONS: The number of underinsured children exceeded the number of children without insurance for all or part of the year studied. Access to health care and the quality of health care are suboptimal for uninsured and underinsured children. (Funded by the Health Resources and Services Administration.)",0
4141,20860502,Effect of screening mammography on breast-cancer mortality in Norway,"BACKGROUND: A challenge in quantifying the effect of screening mammography on breast-cancer mortality is to provide valid comparison groups. The use of historical control subjects does not take into account chronologic trends associated with advances in breast-cancer awareness and treatment. METHODS: The Norwegian breast-cancer screening program was started in 1996 and expanded geographically during the subsequent 9 years. Women between the ages of 50 and 69 years were offered screening mammography every 2 years. We compared the incidence-based rates of death from breast cancer in four groups: two groups of women who from 1996 through 2005 were living in counties with screening (screening group) or without screening (nonscreening group); and two historical-comparison groups that from 1986 through 1995 mirrored the current groups. RESULTS: We analyzed data from 40,075 women with breast cancer. The rate of death was reduced by 7.2 deaths per 100,000 person-years in the screening group as compared with the historical screening group (rate ratio, 0.72; 95% confidence interval [CI], 0.63 to 0.81) and by 4.8 deaths per 100,000 person-years in the nonscreening group as compared with the historical nonscreening group (rate ratio, 0.82; 95% CI, 0.71 to 0.93; P<0.001 for both comparisons), for a relative reduction in mortality of 10% in the screening group (P=0.13). Thus, the difference in the reduction in mortality between the current and historical groups that could be attributed to screening alone was 2.4 deaths per 100,000 person-years, or a third of the total reduction of 7.2 deaths. CONCLUSIONS: The availability of screening mammography was associated with a reduction in the rate of death from breast cancer, but the screening itself accounted for only about a third of the total reduction. (Funded by the Cancer Registry of Norway and the Research Council of Norway.)",0
4142,20872776,Tumor necrosis factor ? sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner,"Fas/CD95 is a critical mediator of cell death in many chronic and acute liver diseases and induces apoptosis in primary hepatocytes in vitro. In contrast, the proinflammatory cytokine tumor necrosis factor ? (TNF?) fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Here we report that TNF? sensitizes primary murine hepatocytes cultured on collagen to Fas ligand (FasL)-induced apoptosis. This synergism is time-dependent and is specifically mediated by TNF?. Fas itself is essential for the sensitization, but neither Fas up-regulation nor endogenous FasL is responsible for this effect. Although FasL is shown to induce Bid-independent apoptosis in hepatocytes cultured on collagen, the sensitizing effect of TNF? is clearly dependent on Bid. Moreover, both c-Jun N-terminal kinase activation and Bim, another B cell lymphoma 2 homology domain 3 (BH3)-only protein, are crucial mediators of TNF?-induced apoptosis sensitization. Bim and Bid activate the mitochondrial amplification loop and induce cytochrome c release, a hallmark of type II apoptosis. The mechanism of TNF?-induced sensitization is supported by a mathematical model that correctly reproduces the biological findings. Finally, our results are physiologically relevant because TNF? also induces sensitivity to agonistic anti-Fas-induced liver damage. CONCLUSION: Our data suggest that TNF? can cooperate with FasL to induce hepatocyte apoptosis by activating the BH3-only proteins Bim and Bid.",0
4143,20879027,Putting flesh and polish on autoimmune hepatitis and moving the disease of exclusion to inclusion,"""Autoimmune hepatitis emerged during an era when concepts of neonatal immune tolerance, clonal selection of lymphocytes, and """"forbidden clones"""" of activated immune cells were forming. The diagnosis had to be deduced from circumstantial evidence and by exclusion of other conditions. The goals of this review are to demonstrate how a clinician nonscientist can contribute to the maturation of autoimmune hepatitis and to illustrate the principles of clinical investigation that can be applied broadly to other projects. Autoimmune hepatitis initially had to be distinguished from other diseases, and improvements in the tests for viral and immune markers were instrumental in this regard. Diversification of the clinical phenotype to accommodate acute severe, asymptomatic, elderly, and variant forms enhanced the pertinence of the disease, and the formation of the International Autoimmune Hepatitis Group standardized the diagnosis, interconnected investigators, and promoted global acceptance of the condition. Subsequent studies refined current corticosteroid-based therapies, identified prognostic markers, assessed genetic predispositions, explored new pharmacological agents, and forecast the emergence of cellular and molecular interventions. Good fortune, stimulating mentors, career dedication, practical goal selection, protocol compliance, compulsive record keeping, personal resilience, and strong collaborations were the bases for progress. Autoimmune hepatitis exemplifies an evolutionary process in the science of autoimmunity and the people committed to its study. Lessons derived from this experience can be far-reaching.""",0
4144,20879887,Placebo-controlled trials in osteoporosis--proceeding with caution,"This article presents one viewpoint on the issues surrounding placebo-controlled trials in osteoporosis. The other Sounding Board article in this issue presents an opposing view. At NEJM.org, in a related interactive feature, the authors of each article give their Point of View about the other article. At NEJM.org, readers can participate in forming community opinion by choosing one of the viewpoints and, if they like, providing their reasons.",0
4145,20890893,Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis,"Liver fibrosis is orchestrated by a complex network of signaling pathways regulating the deposition of extracellular matrix proteins during fibrogenesis. MicroRNAs (miRNAs) represent a family of small noncoding RNAs controlling translation and transcription of many genes. Recently, miRNAs have been suggested to crucially modulate cellular processes in the liver such as hepatocarcinogenesis. However, their role in liver fibrosis is not well understood. We systematically analyzed the regulation of miRNAs in a mouse model of carbon tetrachloride-induced hepatic fibrogenesis (CCl(4) ) by gene array analysis, which revealed a panel of miRNA that were specifically regulated in livers of mice undergoing hepatic fibrosis. Within those, all three members of the miR-29-family were significantly down-regulated in livers of CCl(4) -treated mice as well as in mice that underwent bile duct ligation. Specific regulation of miR-29 members in murine fibrosis models correlated with lower expression of miR-29 in livers from patients with advanced liver fibrosis. Moreover, patients with advanced liver cirrhosis showed significantly lower levels of miR-29a in their serum when compared with healthy controls or patients with early fibrosis. On a cellular level, down-regulation of miR-29 in murine hepatic stellate cells (HSCs) was mediated by transforming growth factor beta (TGF-?) as well as inflammatory signals, namely, lipopolysaccharide (LPS) and nuclear factor kappa B (NF-?B). Furthermore, overexpression of miR-29b in murine HSC resulted in down-regulation of collagen expression. CONCLUSION: Our data indicate that miR-29 mediates the regulation of liver fibrosis and is part of a signaling nexus involving TGF-?- and NF-?B-dependent down-regulation of miR-29 family members in HSC with subsequent up-regulation of extracellular matrix genes. Thus they may represent targets for novel therapeutic strategies against hepatic fibrogenesis and also might evolve as biomarkers in the diagnosis of liver fibrosis.",0
4146,20890942,Association of anti-E1E2 antibodies with spontaneous recovery or sustained viral response to therapy in patients infected with hepatitis C virus,"The monoclonal antibody (mAb) D32.10 recognizes a discontinuous epitope encompassing three regions E1 (amino acids 297-306), E2A (amino acids 480-494), and E2B (amino acids 613-621) juxtaposed on the surface of serum-derived hepatitis C virus (HCV) particles (HCVsp). The mAb D32.10 inhibits efficiently and specifically the binding of HCVsp to human hepatocytes. Therefore, we investigated the clinical relevance of anti-E1E2A,B response in the serum of patients infected with HCV. To this end, an enzyme-linked immunosorbent assay (ELISA) using synthetic E1-, E2A-, and E2B-derived peptides was used. The ELISA was validated in terms of sensitivity, specificity, and test efficiency. The detection of the anti-E1E2 D32.10 epitope-binding antibodies during natural HCV infection in more than 300 HCV-positive sera demonstrated significantly (P < 0.001) higher prevalence of these antibodies: (1) in patients who spontaneously cured HCV infection (46 of 52, 88.5%) showing high titers (70% ? 1/1000) compared to never-treated patients with chronic hepatitis C (7 of 50, 14%) who actively replicated the virus, and (2) in complete responders (20 of 52, 38.5%) who cleared virus following treatment and achieved a sustained viral response compared to nonresponders (4 of 40, 10%). Serum anti-E1E2 antibodies were monitored before, during, and after the current standard-of-care therapy (pegylated interferon plus ribavirin) in responder and nonresponder patients. Optimal cutoff values were assessed by receiver operating characteristic curve analysis. One month prior to therapy initiation, the threshold of 1131 (optical density � 1000) gave 100% and 86% positive and negative predictive values, respectively, for achieving or not achieving a sustained viral response. CONCLUSION: The anti-E1E2 D32.10 epitope-binding antibodies are associated with control of HCV infection and may represent a new relevant prognostic marker in serum. This unique D32.10 mAb may also have immunotherapeutic potential.",0
4147,20931554,Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B,"Wilson disease is a copper metabolism disorder caused by mutations in ATP7B, a copper-transporting adenosine triphosphatase. A molecular diagnosis was performed on 135 patients with Wilson disease in Taiwan. We identified 36 different mutations, eight of which were novel: five missense mutations (Ser986Phe, Ile1348Asn, Gly1355Asp, Met1392Lys, and Ala1445Pro), one deletion (2810delT) in the coding region, and two nucleotide substitutions (-133A?C and -215A?T) in the promoter region. These mutations were not observed in 100 control subjects and reduced the activity of the mutated protein by at least 50% when compared with wild-type ATP7B. In addition to exon 8, our data indicate another mutation hotspot in exon 12 where 9.62% of all mutations occurred. An alternative splice variant of ATP7B lacking exon 12 was observed in one patient who had a homozygous 2810delT mutation and very mild clinical symptoms. Clinical examination and functional characterization of alternative splice variants of ATP7B lacking exon 12 showed that they retained 80% of their biological activity. The 2810delT mutation increased the expression of these variants, which may have explained the mild symptoms in the patient with the 2810delT mutation. We also discovered that treating liver cancer cells with a Na(+)/H(+) exchanger inhibitor, 5-(N-ethyl-N-isopropyl)-amiloride, significantly enhanced the expression of the alternative splice variant of ATP7B lacking exon 12. CONCLUSION: This study suggests a novel therapeutic strategy for patients with mutations in exon 12.",0
4148,20942659,"Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia","""We sequenced all protein-coding regions of the genome (the """"exome"""") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).""",0
4149,20949553,Organic anion-transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: Studies in Oatp1b2-null mice,"The organic anion-transporting polypeptide 1b family (Oatp1b2 in rodents and OATP1B1/1B3 in humans) is liver-specific and transports various chemicals into the liver. However, the role of the Oatp1b family in the hepatic uptake of bile acids (BAs) into the liver is unknown. Therefore, in Oatp1b2-null mice, the concentrations of BAs in plasma, liver, and bile were compared with wild-type (WT) mice. It was first determined that livers of the Oatp1b2-null mice were not compensated by altered expression of other hepatic transporters. However, the messenger RNA of Cyp7a1 was 70% lower in the Oatp1b2-null mice. Increased expression of fibroblast growth factor 15 in intestines of Oatp1b2-null mice might be responsible for decreased hepatic expression of Cyp7a1 in Oatp1b2-null mice. The hepatic concentration and biliary excretion of conjugated and unconjugated BAs were essentially the same in Oatp1b2-null and WT mice. The serum concentration of taurine-conjugated BAs was essentially the same in the two genotypes. In contrast, the serum concentrations of unconjugated BAs were 3-45 times higher in Oatp1b2-null than WT mice. After intravenous administration of cholate to Oatp1b2-null mice, its clearance was 50% lower than in WT mice, but the clearance of taurocholate was similar in the two genotypes. CONCLUSION: This study indicates that Oatp1b2 has a major role in the hepatic uptake of unconjugated BAs.",0
4150,20961245,Expression of follicle-stimulating hormone receptor in tumor blood vessels,"BACKGROUND: In adult humans, the follicle-stimulating hormone (FSH) receptor is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. It is minimally expressed by the endothelial cells of gonadal blood vessels. METHODS: We used immunohistochemical and immunoblotting techniques involving four separate FSH-receptor-specific monoclonal antibodies that recognize different FSH receptor epitopes and in situ hybridization to detect FSH receptor in tissue samples from patients with a wide range of tumors. Immunoelectron microscopy was used to detect FSH receptor in mouse tumors. RESULTS: In all 1336 patients examined, FSH receptor was expressed by endothelial cells in tumors of all grades, including early T1 tumors. The tumors were located in the prostate, breast, colon, pancreas, urinary bladder, kidney, lung, liver, stomach, testis, and ovary. In specimens obtained during surgery performed to remove tumors, the FSH receptor was not expressed in the normal tissues located more than 10 mm from the tumors. The tumor lymphatic vessels did not express FSH receptor. The endothelial cells that expressed FSH receptor were located at the periphery of the tumors in a layer that was approximately 10 mm thick; this layer extended both into and outside of the tumor. Immunoelectron microscopy in mice with xenograft tumors, after perfusion with anti�FSH-receptor antibodies coupled to colloidal gold, showed that the FSH receptor is exposed on the luminal endothelial surface and can bind and internalize circulating ligands. CONCLUSIONS: FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of tumors. (Funded by INSERM.).",0
4151,20967755,Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease,"The diagnosis of Wilson disease (WD) is challenging, especially in children. Early detection is desirable in order to avoid dramatic disease progression. The aim of our study was to re-evaluate in WD children with mild liver disease the conventional diagnostic criteria and the WD scoring system proposed by an international consensus in 2001. Forty children with WD (26 boys and 14 girls, age range = 1.1-20.9 years) and 58 age-matched and sex-matched patients with a liver disease other than WD were evaluated. Both groups were symptom-free and had elevated aminotransferases as predominant signs of liver disease. In all WD patients, the diagnosis was supported by molecular analysis, the liver copper content, or both. A receiver operating characteristic (ROC) analysis of ceruloplasmin at the cutoff value of 20 mg/dL showed a sensitivity of 95% [95% confidence interval (CI) = 83%-99.4%] and a specificity of 84.5% (95% CI = 72.6%-92.6%). The optimal basal urinary copper diagnostic cutoff value was found to be 40 ?g/24 hours (sensitivity = 78.9%, 95% CI = 62.7%-90.4%; specificity = 87.9%, 95% CI = 76.7%-95%). Urinary copper values after penicillamine challenge did not significantly differ between WD patients and control subjects, and the ROC analysis showed a sensitivity of only 12%. The WD scoring system was proved to have positive and negative predictive values of 93% and 91.6%, respectively. CONCLUSION: Urinary copper excretion greater than 40 ?g/24 hours is suggestive of WD in asymptomatic children, whereas the penicillamine challenge test does not have a diagnostic role in this subset of patients. The WD scoring system provides good diagnostic accuracy.",0
4152,20979470,Effects of CYP2C19 genotype on outcomes of clopidogrel treatment,"BACKGROUND: It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite. METHODS: We genotyped patients from two large, randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the primary efficacy outcome) among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for three single-nucleotide polymorphisms (*2, *3, *17) that define the major CYP2C19 alleles. RESULTS: Among 5059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype (P=0.12 for heterogeneity). The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo; hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%; hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%; hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P=0.02 for interaction). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status. CONCLUSIONS: Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00249873.).",0
4153,20979473,EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors,"The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).",0
4154,21049473,"Type 2 diabetes in mice induces hepatic overexpression of sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins","Type 2 diabetes mellitus (T2DM) impairs hepatic clearance of atherogenic postprandial remnant lipoproteins. Our work and that of others have identified syndecan-1 heparan sulfate proteoglycans (HSPGs) as remnant lipoprotein receptors. Nevertheless, defects in the T2DM liver have not been molecularly characterized, and neither has the correction that occurs upon caloric restriction. We used microarrays to compare expression of proteoglycan-related genes in livers from control db/m mice; obese, T2DM db/db littermates fed ad libitum (AL); and db/db mice pair-fed to match the intake of db/m mice. Surprisingly, the arrays identified only one gene whose dysregulation by T2DM would disrupt HSPG structure: the heparan sulfate glucosamine-6-O-endosulfatase-2 (Sulf2). SULF2 degrades HSPGs by removing 6-O sulfate groups, but had no previously known role in diabetes or lipoprotein biology. Follow-up quantitative polymerase chain reaction assays revealed a striking 11-fold induction of Sulf2 messenger RNA in the livers of AL T2DM mice compared with controls. Immunoblots demonstrated induction of SULF2 in AL livers, with restoration toward normal in livers from pair-fed db/db mice. Knockdown of SULF2 in cultured hepatocytes doubled HSPG-mediated catabolism of model remnant lipoproteins. Notably, co-immunoprecipitations revealed a persistent physical association of SULF2 with syndecan-1. To identify mechanisms of SULF2 dysregulation in T2DM, we found that advanced glycosylation end products provoked a 10-fold induction in SULF2 expression by cultured hepatocytes and an approximately 50% impairment in their catabolism of remnants and very low-density lipoprotein, an effect that was entirely reversed by SULF2 knockdown. Adiponectin and insulin each suppressed SULF2 protein in cultured liver cells and in murine livers in vivo, consistent with a role in energy flux. Likewise, both hormones enhanced remnant lipoprotein catabolism in vitro. CONCLUSION: SULF2 is an unexpected suppressor of atherogenic lipoprotein clearance by hepatocytes and an attractive target for inhibition.",0
4155,21049545,Unconjugated bile salts shuttle through hepatocyte peroxisomes for taurine conjugation,"Bile acid-CoA:amino acid N-acyltransferase (BAAT) conjugates bile salts to glycine or taurine, which is the final step in bile salt biosynthesis. In addition, BAAT is required for reconjugation of bile salts in the enterohepatic circulation. Recently, we showed that BAAT is a peroxisomal protein, implying shuttling of bile salts through peroxisomes for reconjugation. However, the subcellular location of BAAT remains a topic of debate. The aim of this study was to obtain direct proof for reconjugation of bile salts in peroxisomes. Primary rat hepatocytes were incubated with deuterium-labeled cholic acid (D(4)CA). Over time, media and cells were collected and the levels of D(4)CA, D(4)-tauro-CA (D(4)TCA), and D(4)-glyco-CA (D(4)GCA) were quantified by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Subcellular accumulation of D(4)-labeled bile salts was analyzed by digitonin permeabilization assays and subcellular fractionation experiments. Within 24 hours, cultured rat hepatocytes efficiently (>90%) converted and secreted 100 ?M D(4)CA to D(4)TCA and D(4)GCA. The relative amounts of D(4)TCA and D(4)GCA produced were dependent on the presence of glycine or taurine in the medium. Treatment of D(4)CA-exposed hepatocytes with 30-150 ?g/mL digitonin led to the complete release of D(4)CA, D(4)GCA, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (cytosolic marker). Full release of D(4)TCA, catalase, and BAAT was only observed at 500 ?g/mL digitonin, indicating the presence of D(4)TCA in membrane-enclosed organelles. D(4)TCA was detected in fractions of purified peroxisomes, which did not contain D(4)CA and D(4)GCA. CONCLUSION: We established a novel assay to study conjugation and intra- and transcellular transport of bile salts. Using this assay, we show that cholic acid shuttles through peroxisomes for taurine-conjugation.",0
4156,21064155,B7-H4 mediates inhibition of T cell responses by activated murine hepatic stellate cells,"Liver fibrosis is mediated by the transformation of hepatic stellate cells (HSC) from a quiescent to an activated state. To understand the role of HSC in liver immunity, we investigated the effect of this transition on T cell stimulation in vitro. Unlike quiescent HSC, activated HSC did not induce proliferation of antigen-specific T cells. Phenotypic analysis of quiescent and activated HSC revealed that activated HSC expressed the coinhibitory molecule B7-H4. Silencing B7-H4 by small interfering RNA (siRNA) in activated HSC restored the ability of T cells to proliferate, differentiate, and regain effector recall responses. Furthermore, expression of B7-H4 on HSC inhibits early T cell activation and addition of exogenous interleukin (IL)-2 reversed the T cell anergy induced by activated HSC. CONCLUSION: These studies reveal a novel role for activated HSC in the attenuation of intrahepatic T cell responses by way of expression of the coinhibitory molecule B7-H4, and may provide fundamental insight into intrahepatic immunity during liver fibrogenesis.",0
4157,21067385,Triple-negative breast cancer,"Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review focuses on its origin, molecular and clinical characteristics, and treatment.",0
4158,21080780,Drug-eluting versus bare-metal stents in large coronary arteries,"BACKGROUND: Recent data have suggested that patients with coronary disease in large arteries are at increased risk for late cardiac events after percutaneous intervention with first-generation drug-eluting stents, as compared with bare-metal stents. We sought to confirm this observation and to assess whether this increase in risk was also seen with second-generation drug-eluting stents. METHODS: We randomly assigned 2314 patients needing stents that were 3.0 mm or more in diameter to receive sirolimus-eluting, everolimus-eluting, or bare-metal stents. The primary end point was the composite of death from cardiac causes or nonfatal myocardial infarction at 2 years. Late events (occurring during months 7 to 24) and target-vessel revascularization were the main secondary end points. RESULTS: The rates of the primary end point were 2.6% among patients receiving sirolimus-eluting stents, 3.2% among those receiving everolimus-eluting stents, and 4.8% among those receiving bare-metal stents, with no significant differences between patients receiving either drug-eluting stent and those receiving bare-metal stents. There were also no significant between-group differences in the rate of late events or in the rate of death, myocardial infarction, or stent thrombosis. Rates of target-vessel revascularization for reasons unrelated to myocardial infarction were 3.7% among patients receiving sirolimus-eluting stents, 3.1% among those receiving everolimus-eluting stents, and 8.9% among those receiving bare-metal stents. The rate of target-vessel revascularization was significantly reduced among patients receiving either drug-eluting stent, as compared with a bare-metal stent, with no significant difference between the two types of drug-eluting stents. CONCLUSIONS: In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen. (Funded by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research; Current Controlled Trials number, ISRCTN72444640.).",0
4159,21105791,Reduced mortality after allogeneic hematopoietic-cell transplantation,"BACKGROUND: Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. METHODS: We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. RESULTS: In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. CONCLUSIONS: We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).",0
4160,21105794,Temporal trends in rates of patient harm resulting from medical care,"BACKGROUND: In the 10 years since publication of the Institute of Medicine's report To Err Is Human, extensive efforts have been undertaken to improve patient safety. The success of these efforts remains unclear. METHODS: We conducted a retrospective study of a stratified random sample of 10 hospitals in North Carolina. A total of 100 admissions per quarter from January 2002 through December 2007 were reviewed in random order by teams of nurse reviewers both within the hospitals (internal reviewers) and outside the hospitals (external reviewers) with the use of the Institute for Healthcare Improvement's Global Trigger Tool for Measuring Adverse Events. Suspected harms that were identified on initial review were evaluated by two independent physician reviewers. We evaluated changes in the rates of harm, using a random-effects Poisson regression model with adjustment for hospital-level clustering, demographic characteristics of patients, hospital service, and high-risk conditions. RESULTS: Among 2341 admissions, internal reviewers identified 588 harms (25.1 harms per 100 admissions; 95% confidence interval [CI], 23.1 to 27.2) [corrected]. Multivariate analyses of harms identified by internal reviewers showed no significant changes in the overall rate of harms per 1000 patient-days (reduction factor, 0.99 per year; 95% CI, 0.94 to 1.04; P=0.61) or the rate of preventable harms. There was a reduction in preventable harms identified by external reviewers that did not reach statistical significance (reduction factor, 0.92; 95% CI, 0.85 to 1.00; P=0.06), with no significant change in the overall rate of harms (reduction factor, 0.98; 95% CI, 0.93 to 1.04; P=0.47). CONCLUSIONS: In a study of 10 North Carolina hospitals, we found that harms remain common, with little evidence of widespread improvement. Further efforts are needed to translate effective safety interventions into routine practice and to monitor health care safety over time. (Funded by the Rx Foundation.).",0
4161,21121826,"""Health hazards of """"don't ask, don't tell""""""","""While U.S. courts consider a lawsuit alleging that the military's """"don't ask, don't tell"""" policy violates the rights of gay and lesbian service members, the policy continues to jeopardize the health of those service members, the military, and the country at large.""",0
4162,21140375,Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-?,"The liver, a unique tolerogenic organ, is regarded as the site to trap and destroy aging erythrocytes and activated T cells. However, to date, the mechanisms for why the liver is tolerogenic and whether liver Kupffer cells (KC) are critical phagocytes for apoptotic cells (AC) contributing to the liver immunosuppression remain unclear. Here we report that KC is the main phagocyte for AC in the liver. Contact of AC inhibits proinflammatory cytokine but enhances anti-inflammatory cytokine production of KC in response to lipopolysaccharide (LPS) stimulation. Membrane-bound transforming growth factor (TGF)-? on AC is responsible for the increased production of interleukin (IL)-10 in KC through extracellular signal-regulated kinase (ERK) activation via the Smad3 pathway. Importantly, KC-derived IL-10 is critical for AC infusion-mediated protection of endotoxin-induced fulminant hepatitis through suppression of tumor necrosis factor (TNF)-? and nitric oxide (NO) production from KC and consequently attenuation of KC-mediated cytolysis of hepatocytes. CONCLUSION: AC can be preferentially phagocytosed by KC in the liver, leading to attenuation of fulminant hepatitis through IL-10-mediated suppression of KC-derived inflammatory TNF-? and NO production. These findings demonstrate that priming of KC by AC may contribute to maintain liver immunosuppression, providing a new mechanistic explanation for how immune homeostasis is maintained in the liver.",0
4163,21140472,Antihepatoma activity of chaetocin due to deregulated splicing of hypoxia-inducible factor 1? pre-mRNA in mice and in vitro,"Chaetocin, an antibiotic produced by Chaetomium species fungi, was recently found to have antimyeloma activity. Here we examined whether chaetocin has anticancer activities against solid tumors. Chaetocin inhibited the growth of mouse and human hepatoma grafts in nude mice. Immunohistochemical analyses revealed that chaetocin inhibits hypoxia-inducible factor-1? (HIF-1?) expression and vessel formation in the tumors. Chaetocin also showed antiangiogenic anticancer activities in HIF-1?(+/+) fibrosarcoma grafted in mice, but not in HIF-1?(-/-) fibrosarcoma. Biochemical analyses showed that chaetocin down-regulated HIF-1? and the transcripts of HIF-1 target genes including vascular endothelial growth factor in hepatoma tissues and in various hepatoma cell lines. Based on the reported literature, unsuccessful efforts were made to determine the mechanism underlying the action of chaetocin. Unexpectedly, chaetocin was found to cause the accumulation of HIF-1? premessenger RNA (pre-mRNA) but to reduce mature mRNA levels in hepatoma cells and tissues. Such an effect of chaetocin was not observed in cell lines derived from normal cells, and was cell type-dependent even among cancer cell lines. CONCLUSIONS: Our results suggest that chaetocin could be developed as an anticancer agent to target HIF-1 in some cancers including hepatoma. It is also suggested that the HIF-1? pre-mRNA splicing is a novel therapeutic target for controlling HIF-1-mediated pathological processes.",0
4164,21167894,TNF-α and IL-1β mediate Japanese encephalitis virus-induced RANTES gene expression in astrocytes,"Infection with Japanese encephalitis virus (JEV) causes neuroinfection and neuroinflammation characterized by profound neuronal destruction/dysfunction, concomitant microgliosis/astrogliosis, and production of various molecules that initiate the recruitment of immune cells to the sites of infection. Previously, we reported that glial cells expressed RANTES (regulated upon activation, normal T cell expressed and secreted) with chemotactic activity in response to JEV infection. In this study, we further demonstrated that JEV-infected microglia had an additional activity in regulating RANTES production. Both astrocytes and microglia responded to JEV infection by releasing RANTES through a process likely related to viral replication. Independent of infectious virus, supernatants of JEV-infected microglia, but not JEV-infected astrocytes, caused additional RANTES production from astrocytes. Antibody neutralization studies suggested the potential involvement of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in mediating additional RANTES production. Treatment of astrocyte cultures with TNF-α and IL-1β caused activation of several signaling molecules and transcription factors crucial to RANTES gene expression, including reactive oxygen species, extracellular signal-regulated kinase, NF-κB, and NF-IL6, increased RANTES gene promoter activity, and provoked RANTES production. As with RANTES, neutralization of bioactive TNF-α and IL-1β caused an attenuation of chemotactic activity from supernatants of mixed glia containing astrocytes and microglia during the course of JEV infection. In conclusion, TNF-α and IL-1β produced by JEV-infected microglia might trigger another mechanism which induces a secondary wave of RANTES gene expression by activating astrocytes. The released RANTES from glial cells might play a role in the recruitment of immune cells during JEV infection. ",0
4165,21167960,Tissue specific characterisation of Lim-kinase 1 expression during mouse embryogenesis,"The Lim-kinase (LIMK) proteins are important for the regulation of the actin cytoskeleton, in particular the control of actin nucleation and depolymerisation via regulation of cofilin, and hence may control a large number of processes during development, including cell tensegrity, migration, cell cycling, and axon guidance. LIMK1/LIMK2 knockouts disrupt spinal cord morphogenesis and synapse formation but other tissues and developmental processes that require LIMK are yet to be fully determined. To identify tissues and cell-types that may require LIMK, we characterised the pattern of LIMK1 protein during mouse embryogenesis. We showed that LIMK1 displays an expression pattern that is temporally dynamic and tissue-specific. In several tissues LIMK1 is detected in cell-types that also express Wilms' tumour protein 1 and that undergo transitions between epithelial and mesenchymal states, including the pleura, epicardium, kidney nephrons, and gonads. LIMK1 was also found in a subset of cells in the dorsal retina, and in mesenchymal cells surrounding the peripheral nerves. This detailed study of the spatial and temporal expression of LIMK1 shows that LIMK1 expression is more dynamic than previously reported, in particular at sites of tissue-tissue interactions guiding multiple developmental processes. ",0
4166,21168497,Efficiency of laryngeal motor nerve repair is greater with bulbar than with mucosal olfactory ensheathing cells,"The real ability of OECs provided by olfactory mucosa cultures (OM-OECs) and those from olfactory bulb cultures (OB-OECs) must be better characterized in order to propose their future clinical application. Therefore, we used a lesion of the vagus nerve (VN), which constitutes a severe motor denervation due to long distance of the muscular targets (4.5 cm). We performed a section/anastomosis surgery of the VN, at the third tracheal ring. Then, OM-OECs and OB-OECs were injected in matrigel around the lesion site. Three months after surgery, laryngeal muscle activity, synkinesis phenomena and latency were evaluated by videolaryngoscopy and electromyography recordings. To complete these procedures, axonal morphometric study of the right recurrent nerve was performed to assess axonal regrowth and tracking of green fluorescent protein positive cells was performed. Recurrent nerve is the motor branch innervating the laryngeal muscles, and is located distally to the lesion, near the muscular targets (0.7 cm). These analyses permitted to compare the ability of these two populations to improve functional recovery and axonal regrowth. Our results show that, OM-OECs improved electrical muscular activity and nervous conduction with significant tissue healing but induced aberrant movement and poor functional recovery. In contrast, OB-OECs induced a partial functional recovery associated with an increase in the number of myelinated fibers and nervous conduction. Our study suggests that, as recently reported in a microarray study, OM-OECs and OB-OECs express different properties. In particular, OM-OECs could regulate inflammation processes and extracellular matrix formation but have a poor regeneration potential, whereas, OB-OECs could improve functional recovery by inducing targeted axonal regrowth. ",0
4167,21226580,Iron-chelating therapy for transfusional iron overload,"A 16-year-old boy with sickle cell anemia undergoes routine screening with transcranial Doppler ultrasonography to assess the risk of stroke. This examination shows an abnormally elevated blood-flow velocity in the middle cerebral artery. The hemoglobin level is 7.2 g per deciliter, the reticulocyte count is 12.5%, and the fetal hemoglobin level is 8.0%. Long-term treatment with red-cell transfusion is initiated to prevent stroke. A hematologist recommends prophylactic iron-chelating therapy.",0
4168,21246583,Effect of immune pressure on hepatitis C virus evolution: insights from a single-source outbreak,"The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. CONCLUSION: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts.",0
4169,21274862,Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes,"The role of autophagy in disease pathogenesis following viral infection is beginning to be elucidated. We have previously reported that hepatitis C virus (HCV) infection in hepatocytes induces autophagy. However, the biological significance of HCV-induced autophagy has not been clarified. Autophagy has recently been identified as a novel component of the innate immune system against viral infection. In this study, we found that knockdown of autophagy-related protein beclin 1 (BCN1) or autophagy-related protein 7 (ATG7) in immortalized human hepatocytes (IHHs) inhibited HCV growth. BCN1- or ATG7-knockdown IHHs, when they were infected with HCV, exhibited increased expression of interferon-?, 2',5'-oligoadenylate synthetase 1, interferon-?, and interferon-?-inducible protein 27 messenger RNAs of the interferon signaling pathways in comparison with infected control IHHs. A subsequent study demonstrated that HCV infection in autophagy-impaired IHHs displayed caspase activation, poly(adenosine diphosphate ribose) polymerase cleavage, and apoptotic cell death. CONCLUSION: The disruption of autophagy machinery in HCV-infected hepatocytes activates the interferon signaling pathway and induces apoptosis. Together, these results suggest that HCV-induced autophagy impairs the innate immune response.",0
4170,21274890,Development of molecularly targeted therapies in biliary tract cancers: reassessing the challenges and opportunities,"Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC.",0
4171,21306239,The role of public-sector research in the discovery of drugs and vaccines,"BACKGROUND: Historically, public-sector researchers have performed the upstream, basic research that elucidated the underlying mechanisms of disease and identified promising points of intervention, whereas corporate researchers have performed the downstream, applied research resulting in the discovery of drugs for the treatment of diseases and have carried out development activities to bring them to market. However, the boundaries between the roles of the public and private sectors have shifted substantially since the dawn of the biotechnology era, and the public sector now has a much more direct role in the applied-research phase of drug discovery. METHODS: We identified new drugs and vaccines approved by the Food and Drug Administration (FDA) that were discovered by public-sector research institutions (PSRIs) and classified them according to their therapeutic category and potential therapeutic effect. RESULTS: We found that during the past 40 years, 153 new FDA-approved drugs, vaccines, or new indications for existing drugs were discovered through research carried out in PSRIs. These drugs included 93 small-molecule drugs, 36 biologic agents, 15 vaccines, 8 in vivo diagnostic materials, and 1 over-the-counter drug. More than half of these drugs have been used in the treatment or prevention of cancer or infectious diseases. PSRI-discovered drugs are expected to have a disproportionately large therapeutic effect. CONCLUSIONS: Public-sector research has had a more immediate effect on improving public health than was previously realized.",0
4172,21319199,Insurance status and treatment candidacy of hepatitis C patients: analysis of population-based data from the United States,"Successful treatment with antiviral therapy could potentially reduce morbidity and mortality in patients with hepatitis C virus (HCV) infection. However, at the population level, these benefits may be offset by a limited number of patients who have access to antiviral treatment. Using data from the National Health and Nutrition Examination Survey conducted in 2005-2008, we analyzed the health insurance status and treatment candidacy of HCV-positive (HCV+) individuals. A total of 10,582 subjects were examined; of those, 1.16% had detectable HCV RNA and were defined as HCV+. The HCV+ patients were less likely to be insured than HCV-negative individuals (61.2% versus 81.2%; P = 0.004). Among those with health insurance, HCV+ patients were less likely to have private insurance, whereas the coverage by Medicare/Medicaid and other government-sponsored plans was similar to the rest of the population. In multivariate analysis, HCV infection was an independent predictor of being uninsured even after adjustment for demographic disparity of the HCV+ cohort (odds ratio, 0.43; 95% confidence interval, 0.24-0.78). Of all HCV+ patients, 66.7% were eligible for anti-HCV treatment. However, only 54.3% of HCV+ treatment candidates had any type of insurance coverage. Finally, only 36.3% of HCV+ patients were potentially eligible for treatment and had health insurance. CONCLUSION: A high proportion of HCV+ patients are currently uninsured, and many have publicly funded health insurance. Among those who could be candidates for treatment, the rate of insurance coverage is even lower. These findings can have important implications for health insurance coverage of these patients under the new health care reform legislation in the United States.",0
4173,21360567,Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection,"An excess of coinhibitory signals has been proposed to drive the T-cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA-4 and this correlates with viral load. CTLA-4 is up-regulated on those HBV-specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA-4-mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV-specific CD8 T cells but does not reprogram their CTLA-4(hi) Bim(hi) tolerogenic phenotype. Blocking CTLA-4 is able to increase the expansion of interferon gamma (IFN-?)-producing HBV-specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti-HBV responses by either CTLA-4 or PD-L1 blockade is nonredundant. CONCLUSION: CTLA-4 is expressed by HBV-specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA-4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T-cell exhaustion in this heterogeneous disease.",0
4174,21360721,Hepatic autophagy mediates endoplasmic reticulum stress-induced degradation of misfolded apolipoprotein B,"Induction of endoplasmic reticulum (ER) stress was previously shown to impair hepatic apolipoprotein B100 (apoB) production by enhancing cotranslational and posttranslational degradation of newly synthesized apoB. Here, we report the involvement of autophagy in ER stress-induced degradation of apoB and provide evidence for a significant role of autophagy in regulating apoB biogenesis in primary hepatocyte systems. Induction of ER stress following short-term glucosamine treatment of McA-RH7777 cells resulted in significantly increased colocalization of apoB with green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3), referred to as apoB-GFP-LC3 puncta, in a dose-dependent manner. Colocalization with this autophagic marker correlated positively with the reduction in newly synthesized apoB100. Treatment of McA-RH7777 cells with 4-phenyl butyric acid, a chemical ER stress inhibitor, prevented glucosamine- and tunicamycin-induced increases in GRP78 and phosphorylated eIF2?, rescued newly synthesized [(35) S]-labeled apoB100, and substantially blocked the colocalization of apoB with GFP-LC3. Autophagic apoB degradation was also observed in primary rat and hamster hepatocytes at basal conditions as well as upon the induction of ER stress. In contrast, this pathway was inactive in HepG2 cells under ER stress conditions, unless proteasomal degradation was blocked with N-acetyl-leucinyl-leucinyl-norleucinal and the medium was supplemented with oleate. Transient transfection of McA-RH7777 cells with a wild-type protein kinase R-like ER kinase (PERK) complementary DNA resulted in dramatic induction of apoB autophagy. In contrast, transfection with a kinase inactive mutant PERK gave rise to reduced apoB autophagy, suggesting that apoB autophagy may occur via a PERK signaling-dependent mechanism. CONCLUSION: Taken together, these data suggest that induction of ER stress leads to markedly enhanced apoB autophagy in a PERK-dependent pathway, which can be blocked with the chemical chaperone 4-phenyl butyric acid. ApoB autophagy rather than proteasomal degradation may be a more pertinent physiological mechanism regulating hepatic lipoprotein production in primary hepatocytes.",0
4175,21366472,Diuretic strategies in patients with acute decompensated heart failure,"BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236�1440 and 4373�1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05�0.3 mg per deciliter [4.4�26.5 ?mol per liter] and 0.07�0.3 mg per deciliter [6.2�26.5 ?mol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430�1401 vs. 4171�1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08�0.3 mg per deciliter [7.1�26.5 ?mol per liter] with the high-dose strategy and 0.04�0.3 mg per deciliter [3.5�26.5 ?mol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).",0
4176,21374691,Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus,"Current treatment of chronic hepatitis C virus (HCV) infection is based on the combination of pegylated interferon-? and ribavirin. The recent development of direct-acting antiviral (DAA) molecules that are active on HCV, together with in vitro and in vivo studies showing that these drugs may lead to the selection of resistant viruses if administered alone, has raised concerns that resistance may undermine therapy based on DAAs. A new standard-of-care treatment will soon be available for both treatment-naive and treatment-experienced patients infected with HCV genotype 1, based on a triple combination of pegylated interferon-?, ribavirin, and a protease inhibitor (either telaprevir or boceprevir). With this therapy, most failures to eradicate infection in treatment-adherent patients are due to an inadequate response to pegylated interferon-? and ribavirin, in the context of a low genetic barrier to resistance of first-generation protease inhibitors. This article reviews patterns of resistance to HCV DAA drugs in development, the mechanisms underlying treatment failure when these drugs are combined with pegylated interferon-? and ribavirin, the consequences of treatment failure, and possible means of optimizing future therapies that use DAAs.",0
4177,21381069,High predictive accuracy of an unbiased proteomic profile for sustained virologic response in chronic hepatitis C patients,"""Chronic hepatitis C (CHC) infection is a leading cause of endstage liver disease. Current standard-of-care (SOC) interferon-based therapy results in sustained virological response (SVR) in only one-half of patients, and is associated with significant side effects. Accurate host predictors of virologic response are needed to individualize treatment regimens. We applied a label-free liquid chromatography mass spectrometry (LC-MS)-based proteomics discovery platform to pretreatment sera from a well-characterized and matched training cohort of 55 CHC patients, and an independent validation set of 41 CHC genotype 1 patients with characterized IL28B genotype. Accurate mass and retention time methods aligned samples to generate quantitative peptide data, with predictive modeling using Bayesian sparse latent factor regression. We identified 105 proteins of interest with two or more peptides, and a total of 3,768 peptides. Regression modeling selected three identified metaproteins, vitamin D binding protein, alpha 2 HS glycoprotein, and Complement C5, with a high predictive area under the receiver operator characteristic curve (AUROC) of 0.90 for SVR in the training cohort. A model averaging approach for identified peptides resulted in an AUROC of 0.86 in the validation cohort, and correctly identified virologic response in 71% of patients without the favorable IL28B """"responder"""" genotype. CONCLUSION: Our preliminary data indicate that a serum-based protein signature can accurately predict treatment response to current SOC in most CHC patients.""",0
4178,21384401,Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: implications for treatment duration,"Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase, followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase of decay to treatment effectiveness, whereas the second phase of decay is attributed to the progressive loss of infected cells. Here, we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found the second-phase slope of viral decline to be strongly correlated with treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Because telaprevir is not known to increase the death rate of infected cells, our results suggest that the second-phase slope of viral decline is driven not only by the death of infected cells, but may also involve other mechanisms, such as a treatment-effectiveness-dependent degradation of intracellular viral RNA. As a result of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended.",0
4179,21400553,Regulation of hepatic fat and glucose oxidation in rats with lipid-induced hepatic insulin resistance,"Pyruvate dehydrogenase plays a critical role in the regulation of hepatic glucose and fatty acid oxidation; however, surprisingly little is known about its regulation in vivo. In this study we examined the individual effects of insulin and substrate availability on the regulation of pyruvate dehydrogenase flux (V(PDH) ) to tricarboxylic acid flux (V(TCA) ) in livers of awake rats with lipid-induced hepatic insulin resistance. V(PDH) /V(TCA) flux was estimated from the [4-(13) C]glutamate/[3-(13) C]alanine enrichments in liver extracts and assessed under conditions of fasting and during a hyperinsulinemic-euglycemic clamp, whereas the effects of increased plasma glucose concentration on V(PDH) /V(TCA) flux was assessed during a hyperglycemic clamp in conjunction with infusions of somatostatin and insulin to maintain basal concentrations of insulin. The effects of increases in both glucose and insulin on V(PDH) /V(TCA) were examined during a hyperinsulinemic-hyperglycemic clamp. The effects of chronic lipid-induced hepatic insulin resistance on this flux were also examined by performing these measurements in rats fed a high-fat diet for 3 weeks. Using this approach we found that fasting V(PDH) /V(TCA) was reduced by 95% in rats with hepatic insulin resistance (from 17.2 � 1.5% to 1.3 � 0.7%, P < 0.00001). Surprisingly, neither hyperinsulinemia per se or hyperglycemia per se were sufficient to increase V(PDH) /V(TCA) flux. Only under conditions of combined hyperglycemia and hyperinsulinemia did V(PDH) /V(TCA) flux increase (44.6 � 3.2%, P < 0.0001 versus basal) in low-fat fed animals but not in rats with chronic lipid-induced hepatic insulin resistance. CONCLUSION: These studies demonstrate that the combination of both hyperinsulinemia and hyperglycemia are required to increase V(PDH) /V(TCA) flux in vivo and that this flux is severely diminished in rats with chronic lipid-induced hepatic insulin resistance.",0
4180,21410372,Nurse staffing and inpatient hospital mortality,"BACKGROUND: Cross-sectional studies of hospital-level administrative data have shown an association between lower levels of staffing of registered nurses (RNs) and increased patient mortality. However, such studies have been criticized because they have not shown a direct link between the level of staffing and individual patient experiences and have not included sufficient statistical controls. METHODS: We used data from a large tertiary academic medical center involving 197,961 admissions and 176,696 nursing shifts of 8 hours each in 43 hospital units to examine the association between mortality and patient exposure to nursing shifts during which staffing by RNs was 8 hours or more below the staffing target. We also examined the association between mortality and high patient turnover owing to admissions, transfers, and discharges. We used Cox proportional-hazards models in the analyses with adjustment for characteristics of patients and hospital units. RESULTS: Staffing by RNs was within 8 hours of the target level for 84% of shifts, and patient turnover was within 1 SD of the day-shift mean for 93% of shifts. Overall mortality was 61% of the expected rate for similar patients on the basis of modified diagnosis-related groups. There was a significant association between increased mortality and increased exposure to unit shifts during which staffing by RNs was 8 hours or more below the target level (hazard ratio per shift 8 hours or more below target, 1.02; 95% confidence interval [CI], 1.01 to 1.03; P<0.001). The association between increased mortality and high patient turnover was also significant (hazard ratio per high-turnover shift, 1.04; 95% CI, 1.02 to 1.06; P<0.001). CONCLUSIONS: In this retrospective observational study, staffing of RNs below target levels was associated with increased mortality, which reinforces the need to match staffing with patients' needs for nursing care. (Funded by the Agency for Healthcare Research and Quality.).",0
4181,21413052,Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis,"The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 � 10(-32) and P = 1.8 � 10(-22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. CONCLUSION: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DR? chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented.",0
4182,21480318,Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C,"The widely accepted interleukin-28B (IL-28B) rs12979860 C/T polymorphism and the more recently proposed vitamin D serum concentration are two novel predictors of the response to antiviral treatment in chronic hepatitis C virus (HCV) infection. This study aimed to verify whether the IL-28B rs12979860 C/T polymorphism and pretreatment serum vitamin D levels have independent or complementary roles in predicting the rates of sustained viral response (SVR). The present study included 211 consecutive, treatment-na?ve chronic HCV patients who had their pretreatment serum 25-OH vitamin D level and IL-28B rs12979860 C/T genotype determined. Overall, SVR was achieved by 134/211 (63.5%) patients and by 47/110 (42.7%) patients infected with difficult-to-treat HCV genotypes. On multivariate analysis, SVR was predicted by the HCV genotype, the IL-28B rs12979860 C/T polymorphism, and gamma-glutamyl transpeptidase, HCV RNA, cholesterol, and 25-OH vitamin D serum levels, with an area under the receiver operating characteristic (ROC) curve of 0.827. When difficult-to-treat HCV genotypes were analyzed separately, the SVR was predicted by the IL-28B rs12979860 C/T polymorphism, viral load, and serum vitamin D level, with an area under the ROC curve of 0.836. Moreover, by categorizing these latter patients into four groups-C/C homozygotes with vitamin D levels >20 ng/mL (group A) or ?20 ng/mL (group B) and C/T heterozygotes or T/T homozygotes with vitamin D levels >20 ng/mL (group C) or ?20 ng/mL (group D)-a significant linear trend was observed, with SVR rates in the following descending order: group A, 18/21 (85.7%); group B, 6/11 (54.5%); group C, 14/38 (36.8%); and group D, 9/40 (22.5%) (P < 0.0001). CONCLUSION: Vitamin D serum levels are complementary to the IL-28B rs12979860 C/T polymorphism in enhancing the correct prediction of the SVR in treatment-na?ve chronic hepatitis C.",0
4183,21480319,c-Src is required for complex formation between the hepatitis C virus-encoded proteins NS5A and NS5B: a prerequisite for replication,"Hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide and establishes a persistent infection in more than 60% of infected individuals. This high frequency of persistent infection indicates that HCV has evolved efficient strategies to interfere with the adaptive and innate immune response and to occupy and use host cell infrastructure. The present study provides evidence that c-Src, a member of the Src family kinases that participates in many signal transduction pathways, represents an essential host factor exploited for viral replication. c-Src directly interacts with the viral RNA-dependent RNA polymerase (NS5B) via its SH3 domain and with the nonstructural phosphoprotein NS5A via its SH2 domain. Both interactions are required to maintain the protein-protein interaction of NS5A and NS5B, which has been previously demonstrated to be essential for viral replication. Accordingly, HCV genome replication and production of the viral proteins was strongly reduced upon small interfering RNA-mediated knockdown of c-Src or in the presence of the tyrosine kinase inhibitor herbimycin A. This effect could not be rescued by supplementation of the two other ubiquitously expressed Src family kinases Fyn or Yes. CONCLUSION: Our data suggest that c-Src participates in the formation of an NS5A/NS5B protein complex that is required for efficient replication of HCV.",0
4184,21480341,CD13: Waving the flag for a novel cancer stem cell target,"Cancer stem cells (CSCs) are generally dormant or slowly cycling tumor cells that have the ability to reconstitute tumors. They are thought to be involved in tumor resistance to chemo/radiation therapy and tumor relapse and progression. However, neither their existence nor their identity within many cancers has been well defined. Here, we have demonstrated that CD13 is a marker for semiquiescent CSCs in human liver cancer cell lines and clinical samples and that targeting these cells might provide a way to treat this disease. CD13+ cells predominated in the G0 phase of the cell cycle and typically formed cellular clusters in cancer foci. Following treatment, these cells survived and were enriched along the fibrous capsule where liver cancers usually relapse. Mechanistically, CD13 reduced ROS-induced DNA damage after genotoxic chemo/radiation stress and protected cells from apoptosis. In mouse xenograft models, combination of a CD13 inhibitor and the genotoxic chemotherapeutic fluorouracil (5-FU) drastically reduced tumor volume compared with either agent alone. 5-FU inhibited CD90+ proliferating CSCs, some of which produce CD13+ semiquiescent CSCs, while CD13 inhibition suppressed the self-renewing and tumor-initiating ability of dormant CSCs. Therefore, combining a CD13 inhibitor with a ROS-inducing chemo/radiation therapy may improve the treatment of liver cancer.",0
4185,21488077,Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism,"The liver has a role in T cell tolerance induction, which is mainly achieved through the functions of tolerogenic hepatic antigen-presenting cells (APCs) and regulatory T cells. Hepatic stellate cells (HSCs) are known to have various immune functions, which range from immunogenic antigen presentation to the induction of T cell apoptosis. Here we report a novel role for stellate cells in vetoing the priming of naive CD8 T cells. Murine and human HSCs and stromal cells (but not hepatocytes) prevented the activation of naive T cells by dendritic cells, artificial APCs, and phorbol 12-myristate 13-acetate/ionomycin by a cell contact-dependent mechanism. The veto function for inhibiting T cell activation was directly correlated with the activation state of HSCs and was most pronounced in HSCs from fibrotic livers. Mechanistically, high expression levels of CD54 simultaneously restricted the expression of interleukin-2 (IL-2) receptor and IL-2 in T cells, and this was responsible for the inhibitory effect because exogenous IL-2 overcame the HSC veto function. CONCLUSION: Our results demonstrate a novel function of HSCs in the local skewing of immune responses in the liver through the prevention of local stimulation of naive T cells. These results not only indicate a beneficial role in hepatic fibrosis, for which increased CD54 expression on HSCs could attenuate further T cell activation, but also identify IL-2 as a key cytokine in mediating local T cell immunity to overcome hepatic tolerance.",0
4186,21488082,Racial differences in hepatitis C treatment eligibility,"Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). CONCLUSION: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency.",0
4187,21488083,Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice,"The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. CONCLUSION: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo.",0
4188,21503941,Kr�ppel-like factor 15 activates hepatitis B virus gene expression and replication,"Hepatitis B virus (HBV) is a small DNA virus that requires cellular transcription factors for the expression of its genes. To understand the molecular mechanisms that regulate HBV gene expression, we conducted a yeast one-hybrid screen to identify novel cellular transcription factors that may control HBV gene expression. Here, we demonstrate that Kr�ppel-like factor 15 (KLF15), a liver-enriched transcription factor, can robustly activate HBV surface and core promoters. Mutations in the putative KLF15 binding site in the HBV core promoter abolished the ability of KLF15 to activate the core promoter in luciferase assays. Furthermore, the overexpression of KLF15 stimulated the expression of HBV surface antigen (HBsAg) and the core protein and enhanced viral replication. Conversely, small interfering RNA knockdown of the endogenous KLF15 in Huh7 cells resulted in a reduction in HBV surface- and core-promoter activities. In electrophoretic mobility shift and chromatin immunoprecipitation assays, KLF15 binds to DNA probes derived from the core promoter and the surface promoter. Introduction of an expression vector for KLF15 short hairpin RNA, together with the HBV genome into the mouse liver using hydrodynamic injection, resulted in a significant reduction in viral gene expression and DNA replication. Additionally, mutations in the KLF15 response element in the HBV core promoter significantly reduced viral DNA levels in the mouse serum. CONCLUSION: KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.",0
4189,21503943,Clinical utility of hepatitis B surface antigen quantitation in patients with chronic hepatitis B: a review,"This clinically relevant review focuses on recent findings concerning hepatitis B surface antigen (HBsAg) quantitation in untreated patients and treated patients with chronic hepatitis B. Recent studies and emerging data have shown that both HBsAg and hepatitis B virus (HBV) DNA levels decline during the natural course of a chronic HBV infection; they are lowest in the inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. It has been demonstrated that the combined use of HBsAg and HBV DNA levels might help in the identification of true inactive carriers with high accuracy. Retrospective analyses of HBsAg levels in patients undergoing therapy have suggested a role for HBsAg quantitation in monitoring the response to therapy. In comparison with nucleos(t)ide analogues (NAs), interferon-based therapy results in greater overall declines in serum HBsAg levels. A rapid on-treatment decline in HBsAg levels appears to be predictive of a sustained response. With the aid of HBsAg quantitation, it appears that we can anticipate an individualized approach to tailoring the treatment duration. The proposal of early stopping rules for patients not responding to pegylated interferon (according to a lack of any HBsAg decline) represents a step toward a response-guided approach. The development of stopping rules for patients treated with NAs is desirable for reducing the need for lifelong therapy. However, before stopping rules for antiviral therapy can be applied, we need to learn more about the kinetics of HBsAg declines during the natural history of the infection and as a response to therapy so that we can better define the best timing, the relevant HBsAg cutoff levels, and the best ways to apply these rules in clinical practice.",0
4190,21506742,Ciliopathies,"Diverse developmental and degenerative single-gene disorders such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, the Bardet�Biedl syndrome, the Joubert syndrome, and the Meckel syndrome may be categorized as ciliopathies � a recent concept that describes diseases characterized by dysfunction of a hairlike cellular organelle called the cilium. Most of the proteins that are altered in these single-gene disorders function at the level of the cilium�centrosome complex, which represents nature�s universal system for cellular detection and management of external signals. Cilia are microtubule-based structures found on almost all vertebrate cells. They originate from a basal body, a modified centrosome, which is the organelle that forms the spindle poles during mitosis. The important role that the cilium�centrosome complex plays in the normal function of most tissues appears to account for the involvement of multiple organ systems in ciliopathies. In this review, we consider the role of the cilium in disease.",0
4191,21520166,Modulation of hepatitis B virus replication and hepatocyte differentiation by MicroRNA-1,"MicroRNAs (miRNAs) are highly conserved small noncoding RNAs participating in regulation of various cellular processes. Viruses have been shown to utilize cellular miRNAs to increase their replication in host cells. Until now, the role of miRNAs in hepatitis B virus (HBV) replication has remained largely unknown. In this study, a number of miRNA mimics were transfected into hepatoma cell lines with HBV replication. It was noted that microRNA-1 (miR-1) transfection resulted in a marked increase of HBV replication, accompanied with up-regulated HBV transcription, antigen expression, and progeny secretion. However, bioinformatics and luciferase reporter analysis suggested that miR-1 may not target the HBV genome directly but regulate the expression of host genes to enhance HBV replication. Further studies showed that miR-1 was able to enhance the HBV core promoter transcription activity by augmenting farnesoid X receptor ? expression. In addition, miR-1 arrested the cell cycle at the G(1) phase and inhibited cell proliferation by targeting histone deacetylase 4 and E2F transcription factor 5. Analysis of the cellular gene expression profile indicated that miR-1 transfected hepatoma cells developed a differentiated phenotype of hepatocytes. CONCLUSION: MiR-1 regulates the expression of several host genes to enhance HBV replication and reverse cancer cell phenotype, which is apparently beneficial for HBV replication. Our findings provide a novel perspective on the role of miRNAs in host-virus interactions in HBV infection.",0
4192,21520181,The hepcidin circuits act: balancing iron and inflammation,"Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-? transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.",0
4193,21520195,Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel,"The hepatitis C virus (HCV) p7 ion channel plays a critical role during infectious virus production and represents an important new therapeutic target. Its activity is blocked by structurally distinct classes of small molecules, with sensitivity varying between isolate p7 sequences. Although this is indicative of specific protein-drug interactions, a lack of high-resolution structural information has precluded the identification of inhibitor binding sites, and their modes of action remain undefined. Furthermore, a lack of clinical efficacy for existing p7 inhibitors has cast doubt over their specific antiviral effects. We identified specific resistance mutations that define the mode of action for two classes of p7 inhibitor: adamantanes and alkylated imino sugars (IS). Adamantane resistance was mediated by an L20F mutation, which has been documented in clinical trials. Molecular modeling revealed that L20 resided within a membrane-exposed binding pocket, where drug binding prevented low pH-mediated channel opening. The peripheral binding pocket was further validated by a panel of adamantane derivatives as well as a bespoke molecule designed to bind the region with high affinity. By contrast, an F25A polymorphism found in genotype 3a HCV conferred IS resistance and confirmed that these compounds intercalate between p7 protomers, preventing channel oligomerization. Neither resistance mutation significantly reduced viral fitness in culture, consistent with a low genetic barrier to resistance occurring in vivo. Furthermore, no cross-resistance was observed for the mutant phenotypes, and the two inhibitor classes showed additive effects against wild-type HCV. CONCLUSION: These observations support the notion that p7 inhibitor combinations could be a useful addition to future HCV-specific therapies.",0
4194,21520210,Ubiquitination is associated with lysosomal degradation of cell surface-resident ATP-binding cassette transporter A1 (ABCA1) through the endosomal sorting complex required for transport (ESCRT) pathway,"ATP-binding cassette transporter A1 (ABCA1) plays an essential role in the biogenesis of high-density lipoprotein in liver and in the prevention of foam cell formation in macrophages by mediating the efflux of cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I). Our current study investigated the mechanism of degradation of cell surface-resident ABCA1, focusing on ubiquitination. A coimmunoprecipitation study indicated the presence of ubiquitinated ABCA1 in the plasma membrane of the human hepatoma cell line, HuH-7, of cells from mouse liver, and of macrophages differentiated from the human acute monocytic leukemia cell line, THP-1 (THP-1 macrophages). In HuH-7 cells, degradation of cell surface-resident ABCA1 was inhibited by the overexpression of a dominant-negative form of ubiquitin. Moreover, the disruption of the endosomal sorting complex required for transport (ESCRT) pathway, a dominant mechanism for ubiquitination-mediated lysosomal degradation, by the knockdown of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), significantly delayed the degradation of cell surface-resident ABCA1. This was accompanied by an increase in ABCA1 expression as well as in apoA-I-mediated [3H]-cholesterol efflux function. The effect of HRS knockdown was also observed after calpain inhibitor treatment, which is reported to retard ABCA1 degradation. The induction of ABCA1 by HRS knockdown was confirmed in THP-1 macrophages. CONCLUSION: Together with the fact that lysosomal inhibitor treatments increased ABCA1 expression in HuH-7 and THP-1 macrophages, these results suggest that ubiquitination mediates the lysosomal degradation of cell surface-resident ABCA1 through the ESCRT pathway, and thereby controls the expression and cholesterol efflux function of ABCA1. This mechanism seems to mediate ABCA1 degradation independently of the calpain-involving pathway. The modulation of ABCA1 ubiquitination could thus be a potential new therapeutic target for antiatherogenic drugs.",0
4195,21538438,Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: a vicious circle of clinical significance?,"Insulin resistance (IR) is common in chronic hepatitis C (CHC) and associates with reduced virological response to pegylated-interferon (PEG-IFN)/ribavirin therapy, but the underlying mechanisms are still unclear. We have previously shown that, in CHC patients, insulin plasma levels are inversely related to antiviral effect induced by PEG-IFN. Therefore, we investigated the in vitro effect of insulin on interferon alpha (IFN-?) intracellular signaling as well as that of IFN-? on insulin signaling. HepG2 cells, preincubated with or without insulin, were stimulated with IFN-?2b and messenger RNA (mRNA) and protein expression of IFN-stimulated genes (ISGs) were measured at different timepoints. The role of intracellular suppressors of cytokine signaling 3 (SOCS3) was evaluated with the small interfering RNA (siRNA) strategy. To assess the effect of IFN-? on insulin signaling, HepG2 were preincubated with or without IFN before addition of insulin and cells were then analyzed for IRS-1 and for Akt/PKB Ser473 phosphorylation. Insulin (100 and 1000 nM) significantly reduced in a dose-dependent fashion IFN-induced gene expression of PKR (P=0.017 and P=0.0017, respectively), MxA (P=0.0103 and P=0.00186), and 2'-5' oligoadenylatesynthetase 1 (OAS-1) (P=0.002 and P=0.006). Insulin also reduced IFN-?-induced PKR protein expression. Although insulin was confirmed to increase SOCS3 expression, siRNA SOCS3 did not restore ISG expression after insulin treatment. IFN-? was found to reduce, in a dose-dependent fashion, IRS-1 gene expression as well as Akt/PKB Ser473 phosphorylation induced by insulin. CONCLUSION: These results provide evidence of reciprocal interference between insulin and IFN-? signaling in liver cells. These findings may contribute to understand the role of insulin in CHC: IR might be favored by endogenous cytokines including IFN-?, and the resulting hyperinsulinemia then reduces the antiviral response to exogenous IFN in a vicious circle of clinical significance.",0
4196,21538444,In vivo adaptation of hepatitis C virus in chimpanzees for efficient virus production and evasion of apoptosis,"Hepatitis C virus (HCV) employs various strategies to establish persistent infection that can cause chronic liver disease. Our previous study showed that both the original patient serum from which the HCV JFH-1 strain was isolated and the cell culture-generated JFH-1 virus (JFH-1cc) established infection in chimpanzees, and that infected JFH-1 strains accumulated mutations after passage through chimpanzees. The aim of this study was to compare the in vitro characteristics of JFH-1 strains emerged in each chimpanzee at early and late stages of infection, as it could provide an insight into the phenomenon of viral persistence. We generated full-genome JFH-1 constructs with the mutations detected in patient serum-infected (JFH-1/S1 and S2) and JFH-1cc-infected (JFH-1/C) chimpanzees, and assessed their effect on replication, infectious virus production, and regulation of apoptosis in cell culture. The extracellular HCV core antigen secreted from JFH-1/S1-, S2-, and C-transfected HuH-7 cells was 2.5, 8.9, and 2.1 times higher than that from JFH-1 wild-type (JFH-1/wt) transfected cells, respectively. Single cycle virus production assay with a CD81-negative cell line revealed that the strain JFH-1/S2, isolated from the patient serum-infected chimpanzee at a later time point of infection, showed lower replication and higher capacity to assemble infectious virus particles. This strain also showed productive infection in human hepatocyte-transplanted mice. Furthermore, the cells harboring this strain displayed lower susceptibility to the apoptosis induced by tumor necrosis factor ? or Fas ligand compared with the cells replicating JFH-1/wt. CONCLUSION: The ability of lower replication, higher virus production, and less susceptibility to cytokine-induced apoptosis may be important for prolonged infection in vivo. Such control of viral functions by specific mutations may be a key strategy for establishing persistent infection.",0
4197,21561349,A hemoglobin variant associated with neonatal cyanosis and anemia,"Globin-gene mutations are a rare but important cause of cyanosis. We identified a missense mutation in the fetal G?-globin gene (HBG2) in a father and daughter with transient neonatal cyanosis and anemia. This new mutation modifies the ligand-binding pocket of fetal hemoglobin by means of two mechanisms. First, the relatively large side chain of methionine decreases both the affinity of oxygen for binding to the mutant hemoglobin subunit and the rate at which it does so. Second, the mutant methionine is converted to aspartic acid post-translationally, probably through oxidative mechanisms. The presence of this polar amino acid in the heme pocket is predicted to enhance hemoglobin denaturation, causing anemia.",0
4198,21574170,Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration,"The liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genomewide microRNA (miRNA) microarray studies during liver regeneration in rats after 70% partial hepatectomy (PH) at early and mid time points to more thoroughly understand their role. At 3, 12, and 18 hours post-PH ?40% of the miRNAs tested were up-regulated. Conversely, at 24 hours post-PH, ?70% of miRNAs were down-regulated. Furthermore, we established that the genomewide down-regulation of miRNA expression at 24 hours was also correlated with decreased expression of genes, such as Rnasen, Dgcr8, Dicer, Tarbp2, and Prkra, associated with miRNA biogenesis. To determine whether a potential negative feedback loop between miRNAs and their regulatory genes exists, 11 candidate miRNAs predicted to target the above-mentioned genes were examined and found to be up-regulated at 3 hours post-PH. Using reporter and functional assays, we determined that expression of these miRNA-processing genes could be regulated by a subset of miRNAs and that some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that overexpression of these miRNAs inhibited cell proliferation and modulated cell cycle in both Huh-7 human hepatoma cells and primary rat hepatocytes. From these observations, we postulated that selective up-regulation of miRNAs in the early phase after PH was involved in the priming and commitment to liver regeneration, whereas the subsequent genomewide down-regulation of miRNAs was required for efficient recovery of liver cell mass. CONCLUSION: Our data suggest that miRNA changes are regulated by negative feedback loops between miRNAs and their regulatory genes that may play an important role in the steady-state regulation of liver regeneration.",0
4199,21591946,Acute HIV-1 Infection,"In 2009, the United Nations Estimated that 33.2 Million People worldwide were living with human immunodeficiency virus type 1 (HIV-1) infection and that 2.6 million people had been newly infected. The need for effective HIV-1 prevention has never been greater. In this review, we address recent critical advances in our understanding of HIV-1 transmission and acute HIV-1 infection. Fourth-generation HIV-1 testing, now available worldwide,(,) will allow the diagnosis of infection in many patients and may lead to new treatments and opportunities for prevention.",0
4200,21631324,gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma,"BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).",0
4201,21656538,Hepatocyte cytotoxicity is facilitated by asialoglycoprotein receptor,"It has been recently identified that hepatocytes can act as cytotoxic effectors and can kill contacted cells by way of CD95 ligand-CD95 and perforin-dependent pathways. However, it remained unknown whether hepatocyte-mediated cell killing is indiscriminant or is directed toward targets with particular cell surface characteristics, as well as whether hepatocytes have the capacity to directly eliminate contacted lymphocytes. In this study, we found that desialylation of surface glycoproteins significantly augments cell susceptibility to hepatocyte-mediated killing. Using asialofetuin as a competitive ligand, and by silencing gene transcription with specific small interfering RNA, we found that the asialoglycoprotein receptor (ASGPR) is involved in hepatocyte recognition of cells predestined for killing, including activated autologous T lymphocytes. CONCLUSION: Hepatocytes are constitutively equipped in the molecular machinery capable of eliminating cells brought into contact with their surface in a manner that is reliant, at least in part, upon the recognition of terminally desialylated glycoproteins by hepatocyte ASGPR. The study adds a new dimension to the physiological role of hepatic ASGPR and provides further evidence that hepatocytes can actively contribute to intrahepatic immune regulation and moderation of the local inflammatory response.",0
4202,21675891,Auditing access to specialty care for children with public insurance,"BACKGROUND: Health care reform has expanded eligibility to public insurance without fully addressing concerns about access. We measured children's access to outpatient specialty care to identify disparities in providers' acceptance of Medicaid and the Children's Health Insurance Program (CHIP) versus private insurance. METHODS: Between January and May 2010, research assistants called a stratified, random sample of clinics representing eight specialties in Cook County, Illinois, which has a high proportion of specialists. Callers posed as mothers of pediatric patients with common health conditions requiring outpatient specialty care. Two calls, separated by 1 month, were placed to each clinic by the same person with the use of a standardized clinical script that differed by insurance status. RESULTS: We completed 546 paired calls to 273 specialty clinics and found significant disparities in provider acceptance of Medicaid-CHIP versus private insurance across all tested specialties. Overall, 66% of Medicaid-CHIP callers (179 of 273) were denied an appointment as compared with 11% of privately insured callers (29 of 273) (relative risk, 6.2; 95% confidence interval [CI], 4.3 to 8.8; P<0.001). Among 89 clinics that accepted both insurance types, the average wait time for Medicaid-CHIP enrollees was 22 days longer than that for privately insured children (95% CI, 6.8 to 37.5; P=0.005). CONCLUSIONS: We found a disparity in access to outpatient specialty care between children with public insurance and those with private insurance. Policy interventions that encourage providers to accept patients with public insurance are needed to improve access to care.",0
4203,21675912,Mutations in CYP24A1 and idiopathic infantile hypercalcemia,"BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.",0
4204,21696306,Changes in diet and lifestyle and long-term weight gain in women and men,"""BACKGROUND: Specific dietary and other lifestyle behaviors may affect the success of the straightforward-sounding strategy """"eat less and exercise more"""" for preventing long-term weight gain. METHODS: We performed prospective investigations involving three separate cohorts that included 120,877 U.S. women and men who were free of chronic diseases and not obese at baseline, with follow-up periods from 1986 to 2006, 1991 to 2003, and 1986 to 2006. The relationships between changes in lifestyle factors and weight change were evaluated at 4-year intervals, with multivariable adjustments made for age, baseline body-mass index for each period, and all lifestyle factors simultaneously. Cohort-specific and sex-specific results were similar and were pooled with the use of an inverse-variance-weighted meta-analysis. RESULTS: Within each 4-year period, participants gained an average of 3.35 lb (5th to 95th percentile, -4.1 to 12.4). On the basis of increased daily servings of individual dietary components, 4-year weight change was most strongly associated with the intake of potato chips (1.69 lb), potatoes (1.28 lb), sugar-sweetened beverages (1.00 lb), unprocessed red meats (0.95 lb), and processed meats (0.93 lb) and was inversely associated with the intake of vegetables (-0.22 lb), whole grains (-0.37 lb), fruits (-0.49 lb), nuts (-0.57 lb), and yogurt (-0.82 lb) (P?0.005 for each comparison). Aggregate dietary changes were associated with substantial differences in weight change (3.93 lb across quintiles of dietary change). Other lifestyle factors were also independently associated with weight change (P<0.001), including physical activity (-1.76 lb across quintiles); alcohol use (0.41 lb per drink per day), smoking (new quitters, 5.17 lb; former smokers, 0.14 lb), sleep (more weight gain with <6 or >8 hours of sleep), and television watching (0.31 lb per hour per day). CONCLUSIONS: Specific dietary and lifestyle factors are independently associated with long-term weight gain, with a substantial aggregate effect and implications for strategies to prevent obesity. (Funded by the National Institutes of Health and others.).""",0
4205,21721032,Cross-presentation of antigen by diverse subsets of murine liver cells,"""Antigen cross-presentation is a principal function of specialized antigen-presenting cells of bone marrow origin such as dendritic cells. Although these cells are sometimes known as """"professional"""" antigen-presenting cells, nonbone marrow-derived cells may also act as antigen-presenting cells. Here, using four-way liver cell isolation and parallel comparison of candidate antigen-presenting cells, we show that, depending on the abundance of antigen-donor cells, different subsets of liver cells could cross-present a hepatocyte-associated antigen. This function was observed in both liver sinusoidal endothelial cells and Kupffer cells even at very low antigen concentration, as well as when using soluble protein. Antigen cross-presentation by liver cells induced efficient CD8+ T-cell proliferation in a similar manner to classical dendritic cells from spleen. However, proliferated cells expressed a lower level of T-cell activation markers and intracellular interferon-gamma levels. In contrast to classical spleen dendritic cells, cross-presentation by liver antigen-presenting cells was predominantly dependent on intercellular adhesion molecule-1. CONCLUSION: Hepatic sinusoids are an environment rich in antigen cross-presenting activity. However, the liver's resident antigen-presenting cells cause partial T-cell activation. These results clarify how the liver can act as a primary site of CD8+ T-cell activation, and why immunity against hepatocyte pathogens is sometimes ineffective.""",0
4206,21725993,SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism,"Many aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism, are under precise control by the mammalian circadian clock. However, the molecular mechanism for coordinate integration of the circadian clock and various metabolic pathways is poorly understood. Here we show that BAF60a, a chromatin-remodeling complex subunit, is rhythmically expressed in the liver of mice. Mice with liver-specific knockdown of BAF60a show abnormalities in the rhythmic expression pattern of clock and metabolic genes and in the circulating metabolite profile. Consistently, knockdown of BAF60a impairs the oscillation of clock genes in serum-shocked HepG(2) cells. At the molecular level, BAF60a activates Bmal1 and G6Pase transcription by way of the coactivation of retinoid-related orphan receptor alpha (ROR?). In addition, BAF60a is present near ROR response elements (RORE) on the proximal Bmal1 and G6Pase promoters and turns the chromatin structure into the active state. CONCLUSION: Our data suggest a critical role for BAF60a in the coordinated regulation of hepatic circadian clock and energy metabolism in mammals.",0
4207,21735468,"The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor ? light-chain enhancer of activated B cells (NF-?B) in mice","Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. TGR5 also displays strong attenuation of macrophage reactivity in vitro, but the physiological roles of TGR5 in inflammatory response, and its mechanism, is unknown. Here, we demonstrate that TGR5 is a negative modulator of nuclear factor kappa light-chain enhancer of activated B cells (NF-?B)-mediated inflammation. TGR5 activation suppresses the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (I?B?), the translocation of p65, NF-?B DNA-binding activity, and its transcription activity. Furthermore, TGR5 activation enhances the interaction of I?B? and ?-arrestin2. Suppression of NF-?B transcription activity and its target gene expression by TGR5 agonist are specifically abolished by the expression of anti-?-arrestin2 small interfering RNA. These results show that TGR5 suppresses the NF-?B pathway by mediation of the interaction between I?B? and ?-arrestin2. In a lipopolysaccharide (LPS)-induced inflammation model, TGR5(-/-) mice show more severe liver necroses and inflammation, compared with wild-type (WT) mice. Activation of TGR5 by its agonist ligand inhibits the expression of inflammatory mediators in response to NF-?B activation induced by LPS in WT, but not TGR5(-/-), mouse liver. CONCLUSION: These findings identify TGR5 as a negative mediator of inflammation that may serve as an attractive therapeutic tool for immune and inflammatory liver diseases.",0
4208,21748771,Endothelial nitric oxide synthase is a key mediator of hepatocyte proliferation in response to partial hepatectomy in mice,"Endothelial nitric oxide synthase (eNOS) is a critical modulator of vascular tone and blood flow and plays major roles in liver physiology and pathophysiology. Nitric oxide (NO) is widely recognized as one of the key humoral factors important for the initiation of liver regeneration in response to partial hepatectomy. Liver regeneration in response to partial hepatectomy is dependent on the efficiency of growth factor-mediated cell-cycle progression. Epidermal growth factor receptor (EGFR) is a critical mediator of multiple hepatic mitogens, such as epidermal growth factor (EGF), transforming growth factor alpha, amphiregulin, and heparin-binding EGF in regenerating livers. However, the functional significance of endothelial nitric oxide synthase (eNOS) expressed in hepatocytes, and its potential role in EGFR-mediated hepatocyte proliferation, remains unexplored. We sought to determine whether eNOS is essential for hepatocyte proliferation in response to partial hepatectomy (PH). Our studies with eNOS knockout (eNOS(-/-) ) mice suggest that eNOS activation is essential for the efficient induction of early events and elicitation of a robust hepatocyte proliferative response to PH. Moreover, eNOS expression is essential for the efficient early induction of matrix metalloprotease-9, a known mediator of extracellular matrix remodeling and growth factor activation in regenerating livers. Our in vitro studies suggest that eNOS is a critical mediator of EGF-induced hepatocyte proliferation, potentially via its influence on the induction of early growth response-1 (Egr-1) and phosphorylation of c-Jun--known mediators of cell-cycle progression. EGF-induced eNOS phosphorylation at Ser 1177 is dependent on the phosphorylation and activation of EGFR/PI3 kinase/AKT signaling in hepatocytes. CONCLUSION: Collectively, these results highlight a hitherto unrecognized role for eNOS activation in hepatocyte proliferation with implications for targeted therapies to enhance liver regenerative response in chronic disorders.",0
4209,21751900,Health care spending and quality in year 1 of the alternative quality contract,"BACKGROUND: In 2009, Blue Cross Blue Shield of Massachusetts (BCBS) implemented a global payment system called the Alternative Quality Contract (AQC). Provider groups in the AQC system assume accountability for spending, similar to accountable care organizations that bear financial risk. Moreover, groups are eligible to receive bonuses for quality. METHODS: Seven provider organizations began 5-year contracts as part of the AQC system in 2009. We analyzed 2006-2009 claims for 380,142 enrollees whose primary care physicians (PCPs) were in the AQC system (intervention group) and for 1,351,446 enrollees whose PCPs were not in the system (control group). We used a propensity-weighted difference-in-differences approach, adjusting for age, sex, health status, and secular trends to isolate the treatment effect of the AQC in comparisons of spending and quality between the intervention group and the control group. RESULTS: Average spending increased for enrollees in both the intervention and control groups in 2009, but the increase was smaller for enrollees in the intervention group--$15.51 (1.9%) less per quarter (P=0.007). Savings derived largely from shifts in outpatient care toward facilities with lower fees; from lower expenditures for procedures, imaging, and testing; and from a reduction in spending for enrollees with the highest expected spending. The AQC system was associated with an improvement in performance on measures of the quality of the management of chronic conditions in adults (P<0.001) and of pediatric care (P=0.001), but not of adult preventive care. All AQC groups met 2009 budget targets and earned surpluses. Total BCBS payments to AQC groups, including bonuses for quality, are likely to have exceeded the estimated savings in year 1. CONCLUSIONS: The AQC system was associated with a modest slowing of spending growth and improved quality of care in 2009. Savings were achieved through changes in referral patterns rather than through changes in utilization. The long-term effect of the AQC system on spending growth depends on future budget targets and providers' ability to further improve efficiencies in practice. (Funded by the Commonwealth Fund and others.).",0
4210,21793026,Identification and expansion of a unique stem cell population from adult mouse gallbladder,"The identification of resident stem cells in the mouse gallbladder is, to date, unexplored. In addition, the relationship between adult gallbladder stem cells and intrahepatic bile duct (IHBD) cells is not well understood. The aim of this study was to isolate stem cells from an adult mouse gallbladder and determine whether they were unique, compared to IHBD cells. By limiting dilution analyses and index sorts, we found that an EpCAM(+) CD49f(hi) epithelial cell subpopulation from primary gallbladder is enriched in colony-forming cells, compared to EpCAM(+) CD49f(lo) cells. EpCAM(+) CD49f(hi) cells expressed cluster of differentiation (CD)29, CD133, and stem cell antigen-1, but were negative for lineage markers CD31, CD45, and F4/80. Using a novel feeder cell-culture system, we observed long-term (>passage 20) and clonal expansion of the EpCAM(+) CD49f(hi) cells in vitro. In a matrigel differentiation assay, EpCAM(+) CD49f(+) cells expanding in vitro underwent organotypic morphogenesis forming ductular structures and cysts. These structures are similar to, and recapitulate a transport function of, primary gallbladder. EpCAM(+) CD49f(+) cells also engraft into the subcutaneous space of recipient mice. We compared primary gallbladder and IHBD cells by flow cytometry and found phenotypic differences in the expression of CD49f, CD49e, CD81, CD26, CD54, and CD166. In addition, oligonucleotide microarrays showed that the expanded EpCAM(+) CD49f(+) gallbladder cells and IHBD cells exhibit differences related to lipid and drug metabolism. Notable genes that were different are cytochrome P450, glutathione S-transferase, Indian hedgehog, and solute carrier family genes. CONCLUSION: We have isolated an epithelial cell population from primary mouse gallbladder with stem cell characteristics and found it to be unique, compared to IHBD cells.",0
4211,21793740,Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany,"BACKGROUND: A large outbreak of diarrhea and the hemolytic-uremic syndrome caused by an unusual serotype of Shiga-toxin-producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin-producing E. coli have been reported--3167 without the hemolytic-uremic syndrome (16 deaths) and 908 with the hemolytic-uremic syndrome (34 deaths)--indicating that this strain is notably more virulent than most of the Shiga-toxin-producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS: We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS: The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS: Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin-producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens.",0
4212,21793744,Desensitization in HLA-incompatible kidney recipients and survival,"BACKGROUND: More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. METHODS: We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). RESULTS: In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). CONCLUSIONS: Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).",0
4213,21809361,The Australia antigen and role of the late Philadelphia General Hospital in reducing post-transfusion hepatitis and sequelae,"Baruch Blumberg, who received the Nobel Prize for Physiology or Medicine for his discovery of the Australia antigen, died on April 5, 2011. Arguably, that discovery has been the most important advance in the field of Hepatology. It led to the virtual elimination of transfusion related hepatitis B in most parts of the world and was essential to the identification of hepatitis A, C, D and E viruses. Credit for this is due Dr. Blumberg and teams in Philadelphia and Tokyo. In lieu of an Associate Editor commentary, Drs. Senior, London, and Sutnick, who were members of that remarkable team, tell us their inspiring story.",0
4214,21809362,Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations,"The NS5A replication complex inhibitor, BMS-790052, inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single-ascending dose study and a 14-day multiple-ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a-infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b, and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here, we report on the results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1-infected patients who received BMS-790052 (1, 10, 30, 60, and 100 mg, once-daily or 30 mg twice-daily) in the 14-day MAD study. Sequence analysis was performed on viral complementary DNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (1) established a correlation between resistant variants emerging in vivo with BMS-790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31, and 93 for genotype 1a and residues 31 and 93 for genotype 1b); (2) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) revealed the resistance profile and replicative ability (i.e., fitness) of the variants. CONCLUSION: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination therapy.",0
4215,21837750,"A polymorphism that delays fibrosis in hepatitis C promotes alternative splicing of AZIN1, reducing fibrogenesis","""Among several single-nucleotide polymorphisms (SNPs) that correlate with fibrosis progression in chronic HCV, an SNP in the antizyme inhibitor (AzI) gene is most strongly associated with slow fibrosis progression. Our aim was to identify the mechanism(s) underlying this observation by exploring the impact of the AzI SNP on hepatic stellate cell (HSC) activity. Seven novel AZIN1 splice variants (""""SV2-8"""") were cloned by polymerase chain reaction from the LX2 human HSC line. Expression of a minigene in LX2 containing the AZIN1 slow-fibrosis SNP yielded a 1.67-fold increase in AZIN1 splice variant 2 (AZIN1 SV2) messenger RNA (mRNA) (P = 0.05). In healthy human leukocytes, the SNP variant also correlated with significantly increased SV2 mRNA. Cells (293T) transfected with short hairpin RNA (shRNA) complementary to the exonic splicing chaperone SRp40 expressed 30% less SRp40 (P = 0.044) and 43% more AzI SV2 (P = 0.021) than control shRNA-expressing cells, mimicking the effect of the sequence variant. LX2 cells transfected with AZIN1 full-length complementary DNA expressed 35% less collagen I mRNA (P = 0.09) and 18% less ?-smooth muscle actin mRNA (P = 0.09). Transient transfection of AZIN1 SV2 complementary DNA into LX2 cells reduced collagen I gene expression by 64% (P = 0.001) and ?-smooth muscle actin by 43% (P = 0.005) compared to vector-transfected controls, paralleling changes in protein expression. Both AZIN1 and AZIN-SV2 mRNAs are detectable in normal human liver and reduced in HCV cirrhotic livers. The AZIN1-SV2 acts via a polyamine-independent pathway, as it neither interacts with antizyme nor affects the ability of AZIN1 lacking this variant to neutralize antizyme. CONCLUSION: An SNP variant in the AZIN1 gene leads to enhanced generation of a novel alternative splice form that modifies the fibrogenic potential of HSCs.""",0
4216,21843083,Neem leaf glycoprotein inhibits CD4+CD25+Foxp3+ Tregs to restrict murine tumor growth,"The presence of Tregs in tumors is associated with compromised tumor-specific immune responses and has a clear negative impact on survival of cancer patients. Thus, downregulation of Tregs is considered as a promising cancer immunotherapeutic approach. We have reported previously that neem leaf glycoprotein (NLGP) prophylaxis restricts tumor growth in mice by immune activation. In continuation, here, involvement of NLGP in the modulation of Tregs in association with tumor growth restriction is investigated. NLGP downregulates CD4+CD25+Foxp3+ Tregs within tumors. NLGP-mediated downregulation of CCR4 along with its ligand CCL22 restricts Treg migration at the tumor site. NLGP is not apoptotic to Tregs but significantly downregulates the expression of Foxp3, CTLA4 and GITR. It also reverses the functional impairment of T-effector cells by Tregs, in terms of IFN-γ secretion, cellular proliferation and tumor cell cytotoxicity. NLGP also facilitates reconditioning of tumor microenvironment (hostile) by increasing IFN-γ and IL-12 but decreasing IL-10, TGF-β, VEGF and IDO, creating an antitumor niche. Interaction between Foxp3, p-NFATc3 and p-Smad2/3, needed for successful Treg function, is also inhibited by NLGP. All of these coordinated events might result in inhibition of Treg associated-tumor growth and therefore increased survivability of mice having NLGP treatment before or/and after tumor inoculation. Thus, the possibility of NLGP being an excellent tool as a T-cell anergy breaker by abrogating the suppressor functions of Tregs in cancer needs to be explored further in the clinic. ",0
4217,21843790,Appraisal of anti-inflammatory and free radical scavenging activities of ethanol extract of Ilex ficoidea Hemsl and Ilex centrochinensis S.Y. Hu,"This study was to appraise the anti-inflammatory and free radical scavenging activities of ethanol extracts of Ilex ficoidea Hemsl (EIFH) and Ilex centrochinensis S.Y. Hu (EICC). Anti-inflammatory activities were evaluated using xylene-induced ear edema and the cotton pellet granuloma tests. Some antioxidants produced during chronic inflammation were quantitated and the DPPH, superoxide anion and hydroxyl free radicals scavenging activities in vitro were also investigated. EICC showed a significant anti-inflammatory effect during the acute inflammation and chronic inflammation without any acute oral toxicity. However, EIFH exhibited a negligible anti-acute inflammatory and a moderate anti-chronic inflammatory activity. EICC significantly inhibited the formation of MDA and markedly raised the activities of SOD, CAT and GSH-Px. EIFH could reduce the level of MDA and elevate the activity of SOD only at the high dose. The free radical scavenging activities of EICC are higher than that of EIFH. These results suggest that EICC possesses significant anti-inflammatory and free radical scavenging activities. The anti-inflammatory mechanism is attributed, in part, to enhance the activities of antioxidant enzymes. ",0
4218,21843808,The chemopreventive effects of aged garlic extract against cadmium-induced toxicity,"Garlic has been reported in many previous studies as a potent chemopreventive agent. The protective effect of garlic has been ascribed to the presence of organosulphur compounds (OSC). In this study, the efficacy of aged garlic extract (AGE) compared to diallyl disulfide (DADS) in protecting against toxicity induced by cadmium (Cd) in 1321N1 and HEK293 cells was investigated. The involvement of the transcription factor Nrf2 in this protection was also examined. The results show that AGE significantly prevented loss of cell viability in Cd-treated 1321N1 and HEK293 cells. In comparison DADS had no significant effect in protecting HEK293 cells but did protect 1321N1 cells. AGE significantly reduced Cd-induced TBARS production and LDH leakage in the two cell lines, and AGE and DADS both increased GSH levels in Cd-treated cell lines. Pre-treatment of cells with AGE or DADS increased expression of the protective enzyme NAD(P)H:quinone oxidoreductase (NQO1), and this was associated with the accumulation of the transcription factor Nrf2. These results show that AGE and DADS have beneficial effects against Cd-induced toxicity, and this protection appears to be mediated via induction of cytoprotective enzymes in an Nrf2-dependent manner. This indicates the potential for using AGE as a chemoprevention strategy for Cd toxicity. ",0
4219,21843894,In vitro protection of vascular function from oxidative stress and inflammation by pulsatility in resistance arteries,"Resistance arteries remain subject to pulsatility, a potent regulator of large elastic artery tone and structure, but the effect is incompletely understood. Extracorporeal circulation during cardiac surgery is often associated with absence of pulsatility, which may affect vascular tone. To define the role of the vascular wall in the inflammatory process that may occur with or without pulsatility, we studied resistance arteries functions ex vivo. We measured vascular reactivity, oxidative stress, and inflammation in the arterial wall. Isolated rat mesenteric resistance arteries were mounted in an arteriograph and subjected to pulsatility or not in vitro. Arteries were perfused with a physiologic salt solution without circulating cells. After 180 minutes, flow-mediated dilation was higher and pressure-induced myogenic tone lower in arteries subjected to pulsatility. Without pulsatility, reactive oxygen species and markers of inflammation (monocyte chemotactic protein 1 and tumor necrosis factor α) were higher than baseline. In perfused mesenteric beds under similar conditions, tumor necrosis factor α was higher in perfusate after 180 minutes of nonpulsatility (5.7 ± 1.6 pg/mL vs 1.1 ± 0.4 pg/mL; P < .01). In arteries treated with the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol), flow-mediated dilation and myogenic tone were similar in nonpulsatile and pulsatile arteries; monocyte chemotactic protein 1 and nuclear factor κB expression levels were not increased in tempol-treated nonpulsatile arteries. Absence of pulsatility in resistance arteries increased oxidative stress, which in turn induced inflammation and preferentially altered pressure and flow-dependent tone, which play a key role in control of local blood flow. ",0
4220,21844273,Effects of lipopolysaccharide on the expression of proinflammatory cytokines and chemokines and influx of leukocytes in the hen ovary,"The aim of this study was to determine whether the expression of proinflammatory cytokines and chemokines in ovarian cells was changed to recruit heterophils and T cells in response to lipopolysaccharide (LPS), a gram-negative bacterial component. White Leghorn laying hens were intravenously injected with LPS or saline and their ovarian follicles and stroma were collected. Changes in the mRNA expression of IL-1β, IL-6, and CXCLi2 in the theca and granulosa layers and ovarian stroma were analyzed by quantitative reverse transcriptase PCR, whereas proteins of IL-1β and IL-6 were also identified by Western blot analysis. Localization of heterophil-like cells and CD4(+) and CD8(+) T cells was examined by general histology and immunohistochemistry. The expressions of IL-1β, IL-6, and CXCLi2 were significantly increased in the granulosa layer, theca layer, and stroma tissues by 3 to 6 h after LPS injection. Increase of IL-1β and IL-6 proteins in those tissues was also identified 12 h after LPS injection. The LPS stimulation resulted in the increased influx of heterophil-like cells and CD4(+) T cells, but not CD8(+) cells, in the theca layers of follicles. Saline injection affected neither expression of examined proinflammatory cytokines and chemokines nor frequencies of immunocompetent cells. These results suggest that ovarian follicular cells and stromal cells have the ability to express proinflammatory cytokines and chemokines, and their expression is upregulated by LPS in association with the recruitment of heterophil-like cells and T cells. These responses may play roles in local host defense in ovarian follicles. ",0
4221,21845289,Effect of a participatory educational program on primary school teachers' knowledge of malaria,"To describe a participatory educational program for building up knowledge on malaria among primary school teachers in a highly endemic city. An observational study was conducted. A 40-hour course with a multidisciplinary and problematizing approach was held in 2008, including 46 teachers mainly from rural areas of the city of Barcelos, Northern Brazil. The participatory educational process was comprised of workshops and practical classes. A previously validated questionnaire was applied before and after the course to assess teachers' knowledge and subsequently analyzed using qualitative and quantitative approaches and open-response thematic analysis. Prior to the course, teachers had little information about the transmission mechanisms, means of prevention, and the association between malaria and its vectors, and their health concepts were limited. After the course, teachers' knowledge of malaria increased and they reflected on their role in society. The effect of the educational program on the construction of contextualized knowledge of malaria and health indicates the potential of the strategy developed. Continuing education processes are required for the maintenance of new knowledge and practices directed towards health promotion. ",0
4222,21845314,Strategies for increasing the impact of research on human resources for health policy development,"Despite global recognition of the importance of human resources for health (HRH) in achieving health system goals, very little is known about what works, for whom and under what circumstances, especially for low-income and middle-income countries. Several important events and reports have called for increased funding and capacity for HRH research in recent years and several initiatives have started as a result. Progress has been slow, however. The following strategies can be most valuable in ensuring the relevance of the generated evidence for decision making and its contribution to stronger health systems. The first is to promote national processes to set priorities for HRH research with active participation from decision makers. The second is to make conscious efforts to scale up primary research to address priority questions and to develop sustainable mechanisms to evaluate the impact of current or new HRH strategies to feed into the policy making process. The third is to invest in the development of systematic reviews to synthesize available evidence and in the adaptation of the underlying methods to make them more responsive to the type of questions and the nature of research involving HRH issues. The fourth and most important is to consistently use a systems approach in framing and addressing research questions. While a narrow approach may be more attractive and simple, health systems and the problems facing them are not. Increasing the body of evidence that takes into account the complexity of health systems, and particularly human resources for health, will advance knowledge in this area and will make big strides in the quality and usefulness of the generated evidence. ",0
4223,21845423,Renal masses in pregnancy. Diagnostics and therapeutic management],"Cancer is the second most common cause of death in women of childbearing age. However, renal cell carcinoma (RCC) is a rare tumor in this collective with an incidence far below 5/100,000 cases per year. Therefore, medical experience with respect to diagnostics and therapeutic management of newly diagnosed RCC in pregnant women is scarce and the number of published cases low. However, recent studies indicated that higher estrogen levels and multigravidity could be associated with a higher risk of RCC. The aim of this article is to summarize the clinical experience in treating pregnant women with renal cancer against the background of those cases published in the literature. ",0
4224,21846057,Application of alpha-tocopherol acetate prevents swelling of brain slices during the autoblood clot action],"The swelling of olfactory cortex slices of the hypertensive SHR rats under the long autoblood action have been studied. The influence of a preincubation of slices with vitamins E, C and D on a degree of swelling have been detected by their weighing before and after exposure to autoblood. The water-soluble form of vitamin E have exerted a substantial antiswelling action exceeding the same of vitamin D, whereas vitamin C had no any effect. ",0
4225,21846069,A case of prednisolone therapy for radiation-induced hemorrhagic cystitis],Hemorrhagic cystitis resulting from radiation to pelvic visceral malignant lesions often might be incurable and there have been no established definitive treatment. We experienced a case with severe radiation-induced hemorrhagic cystitis refractory to conventional therapy. The treatment with oral administration of prednisolone was performed and obtained a successful result. Gross hematuria disappeared in 2 weeks in this case. This experience suggested that oral administration of prednisolone could be considered the treatment for patients with radiation-induced hemorrhagic cystitis when usual treatments including transurethral electro-coagulation are unsuccessful. ,0
4226,21846103,Quantitative characterization of temperature-independent and temperature-dependent protein-protein interactions in highly nonideal solutions,"""The interaction among each of three dilute """"tracer"""" proteins (bovine serum albumin, superoxide dismutase, and ovomucoid) at a concentration of 2 mg/mL and each of two """"crowder"""" proteins (ovomucoid and BSA) at concentrations up to 100 mg/mL was characterized by analysis of dependence of the equilibrium gradients of both tracer and crowder upon the concentration of crowder. The equilibrium gradients of both crowder proteins were found to be independent of temperature over the range 5-37 °C. The equilibrium gradients of tracer BSA and ovomucoid in the complementary crowder species were likewise found to be independent of temperature over this range, indicating that interaction among these tracers and crowders is predominantly repulsive and essentially entirely entropic in nature. The equilibrium gradient of tracer SOD in BSA was also found to be independent of temperature over this range, but the gradient of tracer SOD in ovomucoid depended significantly upon temperature in a manner indicating a significant enthalpic (attractive) component of the overall interaction between SOD and ovomucoid. The experimental data are analyzed using model-free expansions of the thermodynamic activity coefficients of tracer and crowder in powers of the concentration of crowder and using approximate statistical thermodynamic models based upon highly simplified descriptions of molecular structure and interactions. Detailed analysis of the results indicates a relatively small contribution of nonspecific attraction to the total protein-protein interaction, which is dominated by steric repulsion. """,0
4227,21846363,Renin angiotensin system and gender differences in dopaminergic degeneration,"There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD). It has been shown that the local renin angiotensin system (RAS) plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1) receptors. In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen). However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen. ",0
4228,21848233,Cytoreductive operations in complex treatment of patients with intrapulmonary metastases of colorectal carcinoma],An analysis of results of treatment of 112 patients with metastases of intrapulmonary colorectal carcinoma (CRC) for the period from 1990 to 2006 has shown that cytoreductive opera tions for excision of the metastases are an effective method of treatment of this category of patients which allows a two times increased survival median as compared with analogous index in the group of patients exposed to palliative chemotherapy. Palliative chemotherapy fails to have statistically significant influence to survival of patients who have ablated intrapulmonary CRC metastases in the volume of complete cytoreduction. ,0
4229,21848659,"A kinetic model linking protein conformational motions, interflavin electron transfer and electron flux through a dual-flavin enzyme-simulating the reductase activity of the endothelial and neuronal nitric oxide synthase flavoprotein domains","NADPH-dependent dual-flavin enzymes provide electrons in many redox reactions, although the mechanism responsible for regulating their electron flux remains unclear. We recently proposed a four-state kinetic model that links the electron flux through a dual-flavin enzyme to its rates of interflavin electron transfer and FMN domain conformational motion [Stuehr DJ et al. (2009) FEBS J276, 3959-3974]. In the present study, we ran computer simulations of the kinetic model to determine whether it could fit the experimentally-determined, pre-steady-state and steady-state traces of electron flux through the neuronal and endothelial NO synthase flavoproteins (reductase domains of neuronal nitric oxide synthase and endothelial nitric oxide synthase, respectively) to cytochrome c. We found that the kinetic model accurately fitted the experimental data. The simulations gave estimates for the ensemble rates of interflavin electron transfer and FMN domain conformational motion in the reductase domains of neuronal nitric oxide synthase and endothelial nitric oxide synthase, provided the minimum rate boundary values, and predicted the concentrations of the four enzyme species that cycle during catalysis. The findings of the present study suggest that the rates of interflavin electron transfer and FMN domain conformational motion are counterbalanced such that both processes may limit electron flux through the enzymes. Such counterbalancing would allow a robust electron flux at the same time as keeping the rates of interflavin electron transfer and FMN domain conformational motion set at relatively slow levels. ",0
4230,21848676,Serum C-reactive protein concentrations in healthy Miniature Schnauzer dogs,"C-reactive protein (CRP) is a sensitive marker for inflammation in people and dogs. In people, an association between CRP concentration and atherosclerosis has been reported. Atherosclerosis is rare in dogs, but the Miniature Schnauzer breed may be at increased risk for developing this vascular disease. It is not known if CRP concentrations in Miniature Schnauzer dogs differ from those in other dog breeds. Our objectives were to validate an automated human CRP assay for measuring CRP in dogs and compare CRP concentrations in healthy Miniature Schnauzer dogs with those in non-Miniature Schnauzer breeds. Sera from 37 non-Miniature Schnauzer dogs with inflammatory disease were pooled and used to validate a human CRP immunoturbidimetric assay for measuring canine CRP. Blood was collected from 20 healthy Miniature Schnauzer dogs and 41 healthy dogs of other breeds. Median serum CRP concentration of healthy Miniature Schnauzer dogs was compared with that of healthy non-Miniature Schnauzer dogs. The human CRP assay measured CRP reliably with linearity between 0 and 20 mg/L. CRP concentration for healthy Miniature Schnauzer dogs (median 4.0 mg/L, minimum-maximum 0-18.2 mg/L) was significantly higher than for the healthy non-Miniature Schnauzer dogs (median 0.1 mg/L, minimum-maximum 0-10.7 mg/L); 17 of the 20 Miniature Schnauzer dogs had values that overlapped with those of the non-Miniature Schnauzer dogs. Median CRP concentration of Miniature Schnauzer dogs was slightly higher than that of other breeds of dogs. A relationship between higher CRP concentration in Miniature Schnauzer dogs and idiopathic hyperlipidemia, pancreatitis, and possible increased risk for atherosclerosis remains to be determined. ",0
4231,21848722,Teaching operating room conflict management to surgeons: clarifying the optimal approach,"Conflict management has been identified as an essential competence for surgeons as they work in operating room (OR) teams; however, the optimal approach is unclear. Social science research offers two alternatives, the first of which recommends that task-related conflict be managed using problem-solving techniques while avoiding relationship conflict. The other approach advocates for the active management of relationship conflict as it almost always accompanies task-related conflict. Clarity about the optimal management strategy can be gained through a better understanding of conflict transformation, or the inter-relationship between conflict types, in this specific setting. The purpose of this study was to evaluate conflict transformation in OR teams in order to clarify the approach most appropriate for an educational conflict management programme for surgeons. A constructivist grounded theory approach was adopted to explore the phenomenon of OR team conflict. Narratives were collected from focus groups of OR nurses and surgeons at five participating centres. A subset of these narratives involved transformation between and within conflict types. This dataset was analysed. The results confirm that misattribution and the use of harsh language cause conflict transformation in OR teams just as they do in stable work teams. Negative emotionality was found to make a substantial contribution to responses to and consequences of conflict, notably in the swiftness with which individuals terminated their working relationships. These findings contribute to a theory of conflict transformation in the OR team. There are a number of behaviours that activate conflict transformation in the OR team and a conflict management education programme should include a description of and alternatives to these behaviours. The types of conflict are tightly interwoven in this setting and thus the most appropriate management strategy is one that assumes that both types of conflict will exist and should be managed actively. ",0
4232,21848856,Faecal chitinase 3-like-1: a novel biomarker of disease activity in paediatric inflammatory bowel disease,"Chitinase 3-like-1 (CHI3L1) is up-regulated in the inflamed mucosa of inflammatory bowel disease (IBD). To evaluate the usefulness of a faecal CHI3L1 assay, as a reliable marker for predicting the severity of paediatric IBD. Faecal samples were obtained from ulcerative colitis (UC, n = 94), Crohn's disease (CD, n = 87), and healthy individuals (n = 56). The faecal CHI3L1 and calprotectin levels were determined by ELISA. For endoscopic evaluation, the sum of the Matts' score for UC and the simple endoscopic score for CD (SES-CD) were used. Ileal lesions were evaluated by ultrasonography. Faecal CHI3L1 levels were significantly elevated in active UC (median 366.6 ng/g, n = 44) and active CD (median 632.7 ng/g, n = 48) patients, as compared with healthy individuals (median 2.2 ng/g, n = 56). In UC patients, the faecal CHI3L1 levels were positively correlated with the sum of the Matts' score (r = 0.73, P < 0.01, n = 42). In CD patients, there was a significant correlation between faecal CHI3L1 levels and endoscopic activity as determined by the SES-CD scoring system (r = 0.61, P < 0.01, n = 25). The faecal CHI3L1 levels of patients with wall thickening of their small intestine were significantly higher than those of healthy controls or patients without wall thickening. The cutoff value of 13.7 ng/g for fecal CHI3L1(the 95th percentile of the control value) predicted active lesions in IBD patients with a sensitivity of 84.7% and a specificity of 88.9%. Faecal CHI3L1 assays may be useful for predicting the severity and activity of mucosal inflammation in IBD. ",0
4233,21849112,Comparisons of epidemiological and clinical characteristics in children with hand-foot-mouth disease caused by Enterovirus 71 and Coxackievirus A16],"To compare the differences of epidemiological and clinical characteristics in children with hand-foot-mouth disease (HFMD) caused by Coxsackievirus A16 (CA16) and Enterovirus 71 (EV71). The samples of vesicle fluid and throat swabs of 108 children with HFMD were collected and detected for enterovirus by RT-PCR. The clinical data of children with EV71 and CA16 infection were retrospectively reviewed and compared. The total positive rate of enterovirus was 97.2% (105/108). Of the 105 cases, 56 cases were positive for EV71 (51.9%), 39 cases were positive for CA16 (36.1%), 2 cases were positive for other enterovirus (1.9%), and 8 cases were co-infected by EV71 and CA16 (7.4%). There were no significant differences in age and sex between EV71 and CV16 infected cases. The univariate analysis showed that the incidences of herpes of mouth, erythra of knees, and nose running in children infected by CA16 were higher than in those infected by EV71. The multivariate logistic regression analysis showed that the HFMD children who had erythra of knees had higher probability of CA16 infection. EV71 should be considered as the pathogen in children with HFMD who have no herpes of mouth, erythra of knees, and nose running. ",0
4234,21849115,Studies of electromyography and genetics in children with Charcot-Marie-Tooth disease type 1],"To study the electromyographic and genetic characteristics in children with Charcot-Marie-Tooth disease type 1 (CMT1). Routine electromyography and nerve conduction were performed in 24 children with CMT1. Polymerase chain reaction (PCR) combined with restriction enzyme digestion was used to detect gene duplication on chromosome 17p11.2-12. Ten healthy children served as the control group. The peripheral nerve conduction velocity slowed or disappeared in all of the 24 patients (100%). The lesions of the sensory nerves were more severe than the motor nerves, and the lesions of the lower limbs were more severe than the upper limbs. Of 72 muscles detected, 40 (56%) showed neurogenic lesions. The older the patients, the more severe the muscle lesions. Specific junction fragments (1760 bp) were identified in 13 (54%) out of 24 patients, but were not identified in the healthy controls. The electromyographic changes are characterized by peripheral nerve conduction velocities slowing and neurogenic lesions of muscles in children with CMT1. The PCR combined with restriction enzyme digestion may be a simple and accurate method for gene diagnosis of CMT1. ",0
4235,21849213,State dependent posterior hippocampal volume increases in patients with major depressive disorder,"The hippocampal formation has been implicated in etiology and therapy response in major depressive disorder (MDD). However, prospective longitudinal studies investigating volumes in hippocampal subregions and their association with clinical findings are still lacking. Global and regional hippocampal volumes and neuropsychological performance were assessed longitudinally in 15 young patients with unipolar early onset MDD who responded to therapy and 13 matched healthy control subjects. Although volumes at baseline did not differ between groups, patients with MDD showed significant posterior hippocampal volume increases during the treatment course (mean observation period 161.4 ± 58.6 days). Posterior hippocampal volume increases were seen in every single patient. The detected posterior hippocampal volume increases were significantly correlated with the number of solved problems in a planning task at baseline. The study is limited by the small sample size. Moreover, future studies should include patients who do not respond to antidepressant treatment. Patients with MDD showed selective increases in posterior hippocampal volumes which were not correlated to the degree of functional restitution. However, posterior hippocampal volume increases might constitute a surrogate parameter of neuroplasticity taking place during antidepressant therapy which might be predicted by executive functioning at baseline. ",0
4236,21849426,Normative database for corneal backscatter analysis by in vivo confocal microscopy,"To ascertain the sex and age relatedness, diurnal variation, and repeatability of backscatter measurement in the normal human cornea. Seven corneal backscatter variants were measured by in vivo confocal microscopy (IVCM) in both normal eyes (n = 314) of 157 healthy subjects. These subjects were assigned to one or more of three groups. The sex and age relatedness of corneal backscatter were assessed in group 1 (n = 300), which comprised 75 men and 75 women evenly distributed over five age categories. To assess diurnal variation, eyes in group 2 (n = 40) were measured four times a day, at 3-hour intervals. The eyes in group 3 (n = 50) were examined four times a year to determine intersession repeatability. Intrasession repeatability was determined by performing all IVCM examinations in duplicate. Linear mixed models were used to assess the effects of sex, age, and time of measurement on corneal backscatter. Mean corneal backscatter was 3.5% higher in men (P = 0.003). From the age of 50 years, backscatter increased significantly in the anterior stroma (P = 0.0003). A small but statistically significant diurnal variation was found in all seven backscatter variants (P < 0.01). The test-retest coefficient of variation of mean corneal backscatter was 5.3%, comprising intra- and intersession repeatability. Sex and time of measurement significantly affect corneal backscatter measured by IVCM, whereas age affects only backscatter in the anterior stroma. All three factors should be taken into account when conducting scientific research. For ophthalmic practice, the authors suggest ignoring these factors and propose a generalized normal range and minimum detectable change for each backscatter variant. ",0
4237,21849467,Newcastle disease virus expressing human immunodeficiency virus type 1 envelope glycoprotein induces strong mucosal and serum antibody responses in Guinea pigs,"Human immunodeficiency virus type 1 (HIV-1) is transmitted mainly through mucosal sites. Optimum strategies to elicit both systemic and mucosal immunity are critical for the development of vaccines against HIV-1. We therefore sought to evaluate the induction of systemic and mucosal immune responses by the use of Newcastle disease virus (NDV) as a vaccine vector. We generated a recombinant NDV, designated rLaSota/gp160, expressing the gp160 envelope (Env) protein of HIV-1 from an added gene. The gp160 protein expressed by rLaSota/gp160 virus was detected on an infected cell surface and was incorporated into the NDV virion. Biochemical studies showed that gp160 present in infected cells and in the virion formed a higher-order oligomer that retained recognition by conformationally sensitive monoclonal antibodies. Expression of gp160 did not increase the virulence of recombinant NDV (rNDV) strain LaSota. Guinea pigs were administered rLaSota/gp160 via the intranasal (i.n.) or intramuscular (i.m.) route in different prime-boost combinations. Systemic and mucosal antibody responses specific to the HIV-1 envelope protein were assessed in serum and vaginal washes, respectively. Two or three immunizations via the i.n. or i.m. route induced a more potent systemic and mucosal immune response than a single immunization by either route. Priming by the i.n. route was more immunogenic than by the i.m. route, and the same was true for the boosts. Furthermore, immunization with rLaSota/gp160 by any route or combination of routes induced a Th1-type response, as reflected by the induction of stronger antigen-specific IgG2a than IgG1 antibody responses. Additionally, i.n. immunization elicited a stronger neutralizing serum antibody response to laboratory-adapted HIV-1 strain MN.3. These data illustrate that it is feasible to use NDV as a vaccine vector to elicit potent humoral and mucosal responses to the HIV-1 envelope protein. ",0
4238,21849559,Small heat shock proteins induce a cerebral inflammatory reaction,"""More than 80% of Alzheimer's disease (AD) patients have some degree of cerebral amyloid angiopathy (CAA). In addition to arteries and veins, capillaries can also be affected. Capillary CAA (capCAA), rather than CAA in larger vessels, is associated with flame-like amyloid-beta (Aβ) deposits that may extend beyond the vessel wall and radiate into the neuropil, a phenomenon also known as """"dyshoric angiopathy."""" Aβ deposits in AD, parenchymal as well as (cap)CAA and dyshoric angiopathy, are associated with a local inflammatory reaction, including activation of microglial cells and astrocytes that, among others, produce cytokines and reactive oxygen species. This neuroinflammatory reaction may account for at least part of the cognitive decline. In previous studies we observed that small heat shock proteins (sHsps) are associated with Aβ deposits in AD. In this study the molecular chaperones Hsp20, HspB8 and HspB2B3 were found to colocalize with CAA and capCAA in AD brains. In addition, Hsp20, HspB8 and HspB2B3 colocalized with intercellular adhesion molecule 1 (ICAM-1) in capCAA-associated dyshoric angiopathy. Furthermore, we demonstrated that Hsp20, HspB8 and HspB2B3 induced production of interleukin 8, soluble ICAM-1 and monocyte chemoattractant protein 1 by human leptomeningeal smooth muscle cells and human brain astrocytes in vitro and that Hsp27 inhibited production of transforming growth factor beta 1 and CD40 ligand. Our results suggest a central role for sHsps in the neuroinflammatory reaction in AD and CAA and thus in contributing to cognitive decline. """,0
4239,21849657,Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis,"Better methods are required to identify patients with asymptomatic carotid stenosis (ACS) at risk of future stroke. Two potential markers of high risk are echolucent plaque morphology on carotid ultrasound and embolic signals (ES) in the ipsilateral middle cerebral artery on transcranial Doppler ultrasound (TCD). We explored the predictive value of a score based on these 2 measures in the prospective, observational, international multicenter Asymptomatic Carotid Emboli Study. A total of 435 recruited subjects with ACS ≥70% had baseline ultrasound images and TCD data available. Subjects were prospectively followed up for 2 years. A total of 164 (37.7%) plaques were graded as echolucent. Plaque echolucency at baseline was associated with an increased risk of ipsilateral stroke alone (hazard ratio [HR] 6.43, 95% confidence interval [CI] 1.36-30.44, p = 0.019). A combined variable of plaque echolucency and ES positivity at baseline was associated with a markedly increased risk of ipsilateral stroke alone (HR 10.61, 95% CI 2.98-37.82, p = 0.0003). This association remained significant after controlling for risk factors, degree of carotid stenosis, and antiplatelet medication. Plaque morphology assessed using a simple, and clinically applicable, visual rating scale predicts ipsilateral stroke risk in ACS. The combination of ES detection and plaque morphology allows a greater prediction than either measure alone and identifies a high-risk group with an annual stroke risk of 8%, and a low-risk group with a risk of <1% per annum. This risk stratification may prove useful in the selection of patients with ACS for endarterectomy. ",0
4240,21849817,Creating drought- and salt-tolerant cotton by overexpressing a vacuolar pyrophosphatase gene,"Increased expression of an Arabidopsis vacuolar pyrophosphatase gene, AVP1, leads to increased drought and salt tolerance in transgenic plants, which has been demonstrated in laboratory and field conditions. The molecular mechanism of AVP1-mediated drought resistance is likely due to increased proton pump activity of the vacuolar pyrophosphatase, which generates a higher proton electrochemical gradient across the vacuolar membrane, leading to lower water potential in the plant vacuole and higher secondary transporter activities that prevent ion accumulation to toxic levels in the cytoplasm. Additionally, overexpression of AVP1 appears to stimulate auxin polar transport, which in turn stimulates root development. The larger root system allows AVP1-overexpressing plants to absorb water more efficiently under drought and saline conditions, resulting in stress tolerance and increased yields. Multi-year field-trial data indicate that overexpression of AVP1 in cotton leads to at least 20% more fiber yield than wild-type control plants in dry-land conditions, which highlights the potential use of AVP1 in improving drought tolerance in crops in arid and semiarid areas of the world.  ",0
4241,21849946,Postoperative pain in open vs. laparoscopic cholecystectomy with and without local application of anaesthetic,"To evaluate the intensity of postoperative pain and benefits of laparoscopic cholecystectomy compared to open cholecystectomy especially after anaesthetic infiltration of surgical incision. This prospective cohort study included three groups of 30 patients each, who had undergone surgical treatment by an open procedure, by laparoscopic technique and by laparoscopic technique with local anaesthetic application. All patients were of similar age, sex and ASA risk (American Society of Anaesthesiologists). Pain intensity was assessed seven times and its evaluation was performed using VAS (Visual Analogue Scale). Postoperative pain intensity was lower in patients operated by laparoscopic technique compared to the open method, measured on the VAS , especially for the first and second measuring. This difference is pronounced throughout the entire postoperative period (p<0,001). The pain intensity was significantly lower in patients treated with local anaesthetic (p<0.05). Laparoscopic cholecystectomy should be preferred over open cholecystectomy with respect to the intensity of postoperative pain, particularly after the application of local anaesthetic. ",0
4242,21850252,Transmission and control of African horse sickness in The Netherlands: a model analysis,"African horse sickness (AHS) is an equine viral disease that is spread by Culicoides spp. Since the closely related disease bluetongue established itself in The Netherlands in 2006, AHS is considered a potential threat for the Dutch horse population. A vector-host model that incorporates the current knowledge of the infection biology is used to explore the effect of different parameters on whether and how the disease will spread, and to assess the effect of control measures. The time of introduction is an important determinant whether and how the disease will spread, depending on temperature and vector season. Given an introduction in the most favourable and constant circumstances, our results identify the vector-to-host ratio as the most important factor, because of its high variability over the country. Furthermore, a higher temperature accelerates the epidemic, while a higher horse density increases the extent of the epidemic. Due to the short infectious period in horses, the obvious clinical signs and the presence of non-susceptible hosts, AHS is expected to invade and spread less easily than bluetongue. Moreover, detection is presumed to be earlier, which allows control measures to be targeted towards elimination of infection sources. We argue that recommended control measures are euthanasia of infected horses with severe clinical signs and vector control in infected herds, protecting horses from midge bites in neighbouring herds, and (prioritized) vaccination of herds farther away, provided that transport regulations are strictly applied. The largest lack of knowledge is the competence and host preference of the different Culicoides species present in temperate regions. ",0
4243,21850538,Urinary tract infections],"Urinary tract infections occur very frequently in the community and in hospitalized patients and are mainly caused by Escherichia (E.) coli. Depending on virulence determinants of uropathogenic microorganisms and host-specific defense mechanisms, urinary tract infections can manifest as cystitis, pyelonephritis (bacterial interstitial nephritis), bacteremia or urosepsis. Uncomplicated urinary tract infections in otherwise healthy women should be treated for 3-7 days depending on the antibiotic therapy chosen, even if spontaneous remission rates of up to 40% have been reported. Antibiotics of the first choice for empirical treatment of uncomplicated urinary tract infection are fluoroquinolones, pivmecillinam and fosfomycin. A huge problem is the increasing antimicrobial resistance of uropathogenic microorganisms. Complicated urinary tract infections associated with anatomical and/or functional abnormalities of the urinary tract and/or comorbidities such as diabetes or immunosuppressive therapy, need longer antibiotic treatment (e.g. 10-14 days) as well as interdisciplinary diagnostic procedures. Treatment of community acquired urosepsis includes cephalosporins of the third generation, piperacillin/tazobactam or ciprofloxacin. For nosocomial urosepsis the combination with an aminoglycoside or a carbapenem is recommended. ",0
4244,21850883,Clinical forensic examination findings and legal outcome in cases of suspected sexual child abuse],"The clinical forensic examinations conducted at the Institute of Legal Medicine of the Hanover Medical School between 1999 and 2008 in cases of suspected sexual abuse of children were evaluated retrospectively and analysed with regard to their legal outcome. In total, the study included 223 children (172 girls, 51 boys) with a median age of 8.6 years. In 34 children (15.2%), forensically relevant diagnostic findings due to anogenital injury and/or detection of semen were recorded. Perpetrators were convicted more often when they were not a member of the victim's family. In cases with victims aged seven years or older, conviction was more common. The study shows that medical findings can best be preserved by an immediate clinical forensic examination. Suspected sexual child abuse can often not be proved by medical examination results, but in some cases diagnostic findings are not mandatory for conviction. ",0
4245,21851021,EEG and bispectral analysis during inhalational anesthesia in children],"Bispectral index (BIS) is a parameter of the depth of anesthesia, but the use of it in children remains discussable. The study was carried out to compare EEG and BIS considering the age of patients during anesthesia with halotane, sevoflurane and consequent combination of sevoflurane and isoflurane. 60 children 3 to 17 years of age, who underwent urological surgeries, were divided into 3 groups (20 patients in each): 1st--halothane group, 2nd--sevoflurane group and 3rd--consequent combination of sevodlurane and isoflurane group. The oxygen: nitrous oxide 1:1 mixture was used in all the mentioned groups. EEG recording (6 channel computerised encephalograph) and BIS monitoring (XP version) was carried out through the whole duration of anesthesia. In the 1st group the gradual reduction of main rhythm was registered on EEG, with slow activity and restoration during awakening. The BIS index values changed from 95-98 to 39-47 with rise to 77-85 during awakening. In the 2nd and 3rd group where sevoflurane was used for anesthesia induction sharpened alpha rhythms, amplitude enlargement and rhythm synchronization were registered on EEG. BIS values changed from 96-99 to 13-38. During the maintenance of anesthesia in the 2nd group BIS values were 30-40 and 72-77 during awakening. In the stage of isoflurane anesthesia in the 3rd group EEG pattern changed towards the rhythm synchronization and slow oscillations in all the leads. The BIS index was 30-39 during maintenance and 70-76 during awakening. The parameters of EEG and BIS in all the investigated groups were proportional to the clinical stage and depth of anesthesia. Based on the clinical data and its comparison to EEG and BIS values it is determined that BIS index can be used for monitoring depth of anesthesia in children. ",0
4246,21851356,"Oral health status, salivary factors and microbial analysis in patients with active gastro-oesophageal reflux disease","To present a complex oral health status including salivary factors, microbial analysis and periodontal and hygiene indices in patients with active gastro-oesophageal reflux disease (GORD). Return of stomach contents is quite common in cases of gastro-oesophageal reflux. Pathological acid movement from the stomach into the oesophagus and oral cavity may lead to a development of dental erosion. Long-lasting untreated GORD may damage hard dental and periodontal tissues and alter the oral microbial environment. The quality and amount of the saliva play an important role in hard and soft oral tissues changes. Fifty patients with diagnosed GORD using 24-hour pH manometry underwent dental examination; 24 patients had active GORD and had been waiting for surgical therapy. In this patient group oral health status and salivary analysis were evaluated. Indicated low salivary flow rates and buffering capacity with a low caries risk but a high risk for dental erosion progression. ",0
4247,21851551,Significance of histological prostatitis in patients with urinary retention and underlying benign prostatic hyperplasia or adenocarcinoma of the prostate,"To compare the clinical features of patients having urinary retention and benign prostatic hyperplasia (BPH) with those having adenocarcinoma of the prostate (ACP) and to evaluate the significance of histological prostatitis. The clinical data and histopathology reports of patients with retention admitted to Tygerberg Hospital between September 1998 and June 2007 were evaluated. Statistical analysis was performed with Student's t-test, Mann-Whitney test and Fisher's exact test where appropriate and P < 0.05 was considered to indicate statistical significance. Prostatic histology was available in 405 patients, 204 with BPH and 201 with ACP. Comparing those with BPH and those with ACP showed statistically significant differences in mean age (69.5 vs 71.9 years), serum prostate-specific antigen (PSA) level (18.6 vs 899.5 ng/mL) and histological prostatitis (48 vs 25%) but not duration of catheterization, prostate volume or urinary tract infection (UTI). Comparing those with BPH only and those with BPH plus prostatitis showed significant differences in mean age (71.9 vs 67.1 year) and PSA level (14.6 vs 22.8 ng/mL) but not prostate volume, UTI or duration of catheterization. Comparing those with ACP only and those with ACP plus prostatitis showed significant differences in stage T4 cancer (68.1 vs 35.4%) and PSA level (1123.4 vs 232.4 ng/mL) but not age, prostate volume, UTI or duration of catheterization. Histological prostatitis was almost twice as common in patients with urinary retention associated with underlying BPH than in patients with ACP, but there was no significant difference in the duration of catheterization, prostatic volume or presence of UTI, suggesting that histological prostatitis more often contributes to the development of retention in patients with underlying BPH than in those with ACP. In patients with BPH, histological prostatitis was associated with urinary retention at a significantly younger age and with higher serum PSA levels. In patients with ACP, histological prostatitis was associated with urinary retention at an earlier stage of cancer. ",0
4248,21851621,Bacterial adaptation during chronic infection revealed by independent component analysis of transcriptomic data,"Bacteria employ a variety of adaptation strategies during the course of chronic infections. Understanding bacterial adaptation can facilitate the identification of novel drug targets for better treatment of infectious diseases. Transcriptome profiling is a comprehensive and high-throughput approach for characterization of bacterial clinical isolates from infections. However, exploitation of the complex, noisy and high-dimensional transcriptomic dataset is difficult and often hindered by low statistical power. In this study, we have applied two kinds of unsupervised analysis methods, principle component analysis (PCA) and independent component analysis (ICA), to extract and characterize the most informative features from transcriptomic dataset generated from cystic fibrosis (CF) Pseudomonas aeruginosa isolates. ICA was shown to be able to efficiently extract biological meaningful features from the transcriptomic dataset and improve clustering patterns of CF isolates. Decomposition of the transcriptomic dataset by ICA also facilitates gene identification and gene ontology enrichment. Our results show that P. aeruginosa employs multiple patient-specific adaption strategies during the early stage infections while certain essential adaptations are evolved in parallel during the chronic infections. ",0
4249,21851881,Diagnostic work-up and risk stratification in X-linked dilated cardiomyopathies caused by dystrophin defects,"We sought to describe the diagnostic work-up, phenotype, and long-term evolution of dilated cardiomyopathy (DCM) associated with Dystrophin (DYS) defects. X-linked DCM associated with DYS defects can be clinically indistinguishable from other types of DCM. The series comprises 436 consecutive male patients diagnosed with DCM. Patients underwent endomyocardial biopsy (EMB). Genetic testing employed multiplex polymerase chain reaction and multiple ligation dependent probe assay for deletions and direct sequencing of the 79 exons and flanking regions of the gene for point mutations or small rearrangements. We identified DYS defects in 34 of 436 patients (7.8%) (onset age 34 ± 11 years, age range 17 to 54 years); 30 had proven X-linked inheritance. The 2 phenotypes included DCM with mild skeletal myopathy and/or increased serum creatine phosphokinase (n = 28) or DCM only (n = 6). The EMB showed defective dystrophin immunostain. The DYS defects consisted of 21 in-frame deletions and 11 out-of-frame deletions as well as 1 stop and 1 splice-site mutation. During a median follow-up of 60 months (interquartile range: 11.25 to 101.34 months) we observed 17 events, all related to heart failure (HF) (median event-free survival: 83.5 months). Eight patients (23%) underwent transplantation, and 9 (26%) died of HF while waiting for transplantation. Eight patients received an implantable cardioverter-defibrillator, although none had device intervention during a median follow-up of 14 months (interquartile range: 5 to 25 months). No patient died suddenly, suffered syncope, or developed life-threatening ventricular arrhythmias. DYS-related DCM should be suspected in male patients with increased serum creatine phosphokinase (82%) and X-linked inheritance. The disease shows a high risk of end-stage HF but a lower risk of life-threatening arrhythmias. ",0
4250,21852015,Socio-demographic patient profiles and hospital efficiency: does patient mix affect a hospital's ability to perform?,"This study investigates whether inclusion of patient profiles impacts on the inferences drawn from measuring performance using patient level data. Performance is in this setting defined by resources used in treating patients in a given diagnose related group where use of resources is approximated by length of stay (LOS). The analysis is based on Danish registry data from 2006. Patient data include registry data on income, employment status and information on whether the patient receives benefits or lives alone. Considerable variation in the socio-demographic characteristics of patients across Danish hospitals was observed, and some patient characteristics were shown to drive the need for longer hospital stays beyond what is captured in DRG scores. Ranking of hospitals based on observed versus expected LOS remained largely unaffected when controlling for patient characteristics, suggesting that variation in LOS across hospitals is mainly driven by other factors than patients' socio-demographic characteristics. Nevertheless, the results of this study indicate that the current Danish remuneration system discriminates hospitals that more often serve older patients and patients with a less developed social network. These hospitals tend to have a reduced turnover of patients and their ability to generate revenue is therefore constrained. ",0
4251,21852194,Eliminating multiple pregnancies: an appropriate target for government intervention?,"The manuscript in this issue of the journal by Bissonette et al. reports on a new government-sponsored intervention into the practice of IVF within the province of Quebec, Canada, which in the authors' opinion highly successfully reduced twinning rates, while maintaining overall acceptable pregnancy rates. Given the opportunity to comment, their manuscript, in my opinion, only reemphasizes why, despite wide professional support, the concept of single embryo transfer (SET) is: (i) damaging to most infertility patients by reducing pregnancy chances; (ii) does so without compensatory benefits; (iii) impinges on patients' rights to self-determination; (iv) has significant negative impact on IVF-generated birth rates; and (v) thus, demonstrating, once more, that governments should not interfere with the patient-physician relationships. ",0
4252,21852246,Additional genomic duplications in AZFc underlie the b2/b3 deletion-associated risk of spermatogenic impairment in Han Chinese population,"The azoospermia factor c (AZFc) region on the Y chromosome is a genetically dynamic locus in the human genome. Numerous genomic rearrangements, including deletion, duplication and inversion, have been identified in AZFc. The complete deletion of AZFc can cause spermatogenic impairment. However, the roles of partial AZFc deletions (e.g. b2/b3 deletion) in spermatogenesis are controversial and variable among human populations. Secondary duplication has been hypothesized to be a compensatory factor for partial AZFc deletions. To further study genomic duplications in AZFc as a potential genetic modifier underlying the phenotypic variations of partial AZFc deletions in spermatogenesis, we conducted comprehensive molecular analyses in 711 idiopathic infertile men and 390 healthy controls. Unexpectedly, we found that additional AZFc duplications accompanying the b2/b3 deletion, instead of the b2/b3 deletion alone, led to the b2/b3 deletion-associated risk of spermatogenic impairment previously reported in Han Chinese population. In addition, partial AZFc duplication also rendered a risk factor in the non-deletion patients. DAZ is a multi-copy AZFc gene (DAZ1-DAZ4) implicated in spermatogenesis. Genetic variations do exist between DAZ copies. Intriguingly, we found that the DAZ1/2 cluster was the main duplicated copies in the partial AZFc duplications associated with spermatogenic impairment, suggesting a potential different role of spermatogenesis between DAZ copies. Our findings demonstrated that additional AZFc duplications did not compensate but convey the susceptibility of the b2/b3 deletion to spermatogenic impairment in the tested population. Notably, genomic duplications and deletions in AZFc deserve comprehensive investigations to uncover spermatogenic roles of the AZFc region. ",0
4253,21852611,The inclusion of stroke in risk stratification for primary prevention of vascular events: the Northern Manhattan Study,"The Framingham coronary heart disease (CHD) risk score estimates 10-year risk of myocardial infarction (MI) and CHD death. Because preventive approaches to CHD and stroke are similar, a composite outcome may be more appropriate. We compared 10-year risk of (1) MI or CHD death; and (2) stroke, MI, or CHD death among individuals free of vascular disease. The Northern Manhattan Study contains a prospective, population-based study of stroke- and CHD-free individuals≥40 years of age followed for a median of 10 years for vascular events. Framingham coronary heart disease risk score was calculated for each individual and for each category of predicted risk, Kaplan-Meier observed 10-year cumulative probabilities were calculated for (1) MI or CHD death; and (2) stroke, MI, or CHD death. The cumulative probability of (1) was subtracted from (2), and 95% CIs for the difference were obtained with 1000 bootstrap samples. Using stratified analyses by race-ethnicity, we compared risk differences among race-ethnic groups. Among 2613 participants (53% Hispanic, 25% non-Hispanic black, and 20% non-Hispanic white), observed 10-year risk of MI or CHD death was 14.20%. With stroke in the outcome, observed risk was 21.98% (absolute risk difference, 7.78%; 95% CI, 5.86% to 9.75%). The absolute risk difference among blacks was significantly larger than among whites (P=0.01). In this multiethnic urban population, adding stroke to the risk stratification outcome cluster resulted in a 55% relative increase in estimated risk and crossing of the absolute risk threshold (>20% over 10 years) considered for preventive treatments such as statins. ",0
4254,21858850,Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus,"Hepatitis C virus (HCV) relies on host lipid metabolic pathways for its replication, assembly, secretion, and entry. HCV induces de novo lipogenesis, inhibits ?-oxidation, and lipoprotein export resulting in a lipid-enriched cellular environment critical for its proliferation. We investigated the effects of a hypolipidemic agent, nordihydroguaiaretic acid (NDGA), on host lipid/fatty acid synthesis and HCV life cycle. NDGA negated the HCV-induced alteration of host lipid homeostasis. NDGA decreased sterol regulatory element binding protein (SREBP) activation and enhanced expression of genes involved in ?-oxidation. NDGA inhibited very low-density lipoprotein (VLDL) secretion by affecting mediators of VLDL biosynthesis. Lipid droplets (LDs), the neutral lipid storage organelles, play a key role in HCV morphogenesis. HCV induces accumulation and perinuclear distribution of LDs, whereas NDGA most notably reduced the overall number and increased the average size of LDs. The antiviral effects of NDGA resulted in reduced HCV replication and secretion. CONCLUSION: NDGA-mediated alterations of host lipid metabolism, LD morphology, and VLDL transport appear to negatively influence HCV proliferation.",0
4255,21879900,Electronic health records and quality of diabetes care,"BACKGROUND: Available studies have shown few quality-related advantages of electronic health records (EHRs) over traditional paper records. We compared achievement of and improvement in quality standards for diabetes at practices using EHRs with those at practices using paper records. All practices, including many safety-net primary care practices, belonged to a regional quality collaborative and publicly reported performance. METHODS: We used generalized estimating equations to calculate the percentage-point difference between EHR-based and paper-based practices with respect to achievement of composite standards for diabetes care (including four component standards) and outcomes (five standards), after adjusting for covariates and accounting for clustering. In addition to insurance type (Medicare, commercial, Medicaid, or uninsured), patient-level covariates included race or ethnic group (white, black, Hispanic, or other), age, sex, estimated household income, and level of education. Analyses were conducted separately for the overall sample and for safety-net practices. RESULTS: From July 2009 through June 2010, data were reported for 27,207 adults with diabetes seen at 46 practices; safety-net practices accounted for 38% of patients. After adjustment for covariates, achievement of composite standards for diabetes care was 35.1 percentage points higher at EHR sites than at paper-based sites (P<0.001), and achievement of composite standards for outcomes was 15.2 percentage points higher (P=0.005). EHR sites were associated with higher achievement on eight of nine component standards. Such sites were also associated with greater improvement in care (a difference of 10.2 percentage points in annual improvement, P<0.001) and outcomes (a difference of 4.1 percentage points in annual improvement, P=0.02). Across all insurance types, EHR sites were associated with significantly higher achievement of care and outcome standards and greater improvement in diabetes care. Results confined to safety-net practices were similar. CONCLUSIONS: These findings support the premise that federal policies encouraging the meaningful use of EHRs may improve the quality of care across insurance types.",0
4256,21898478,Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response,"Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon ? (PEG-IFN?) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFN?-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFN?). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (? 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (? 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. CONCLUSION: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFN?/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.",0
4257,21898481,Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance,"We recently showed that the heparan sulfate proteoglycan syndecan-1 mediates hepatic clearance of triglyceride-rich lipoproteins in mice based on systemic deletion of syndecan-1 and hepatocyte-specific inactivation of sulfotransferases involved in heparan sulfate biosynthesis. Here, we show that syndecan-1 expressed on primary human hepatocytes and Hep3B human hepatoma cells can mediate binding and uptake of very low density lipoprotein (VLDL). Syndecan-1 also undergoes spontaneous shedding from primary human and murine hepatocytes and Hep3B cells. In human cells, phorbol myristic acid induces syndecan-1 shedding, resulting in accumulation of syndecan-1 ectodomains in the medium. Shedding occurs through a protein kinase C-dependent activation of ADAM17 (a disintegrin and metalloproteinase 17). Phorbol myristic acid stimulation significantly decreases DiD (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate)-VLDL binding to cells, and shed syndecan-1 ectodomains bind to VLDL. Although mouse hepatocytes appear resistant to induced shedding in vitro, injection of lipopolysaccharide into mice results in loss of hepatic syndecan-1, accumulation of ectodomains in the plasma, impaired VLDL catabolism, and hypertriglyceridemia. CONCLUSION: These findings suggest that syndecan-1 mediates hepatic VLDL turnover in humans as well as in mice and that shedding might contribute to hypertriglyceridemia in patients with sepsis.",0
4258,21898483,Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients,"Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased interferon gamma (IFN-?) production in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is caused by type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-?-based therapy of HCV. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-?-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (tumor necrosis factor-apoptosis-inducing ligand [TRAIL] expression and degranulation) and decreased IFN-? production. NK cells from patients with a greater than 2 log(10) first-phase HCV RNA decline to IFN-?-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log(10) first-phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (P = 0.024), but retained greater IFN-? responsiveness in vitro (P = 0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-? during the second-phase virological response. CONCLUSION: These data show that IFN-?-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells toward increased cytotoxicity and decreased IFN-? production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-?-based therapy.",0
4259,21898485,Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis,"The cross-talk of cluster of differentiation (CD)40/CD40 ligand (CD40L) plays a key role in CD4(+) T-cell priming, B-cell terminal maturation, and immunoglobulin (Ig) class-switch recombination. Genetic defects in the CD40L lead to a disorder characterized by elevated concentrations of serum IgM and immunodeficiency. Patients with primary biliary cirrhosis (PBC) characteristically show circulating antimitochondrial antibodies (AMAs), liver-infiltrating autoreactive T lymphocytes against mitochondrial antigens, and high levels of IgM. We hypothesized that CD40L may play a key role in the pathogenesis of the elevated serum IgM and analyzed genetic and epigenetic modifications of the gene coding for CD40L in CD4(+) and CD8(+) T cells isolated from circulating mononuclear cells from PBC patients and healthy controls. We herein demonstrate significantly lower levels of DNA methylation of the CD40L promoter in CD4(+) T cells from PBC patients, as compared with controls, and this decreased methylation was inversely correlated with levels of serum IgM in PBC patients. CONCLUSION: The findings of an absence of genetic modifications of the CD40L gene, in concert with decreased DNA methylation of the CD40L promoter in PBC patients, suggests that environmental factors, rather than genetics, must play a major role in the pathogenesis of elevated serum IgM in PBC.",0
4260,21916638,A field trial to assess a blood-stage malaria vaccine,"BACKGROUND: Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. METHODS: In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. RESULTS: The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. CONCLUSIONS: On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00460525.).",0
4261,21932398,Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes,"Bile acids have been shown to be important regulatory molecules for cells in the liver and gastrointestinal tract. They can activate various cell signaling pathways including extracellular regulated kinase (ERK)1/2 and protein kinase B (AKT) as well as the G-protein-coupled receptor (GPCR) membrane-type bile acid receptor (TGR5/M-BAR). Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids has been reported to be sensitive to pertussis toxin (PTX) and dominant-negative G?(i) in primary rodent hepatocytes. However, the GPCRs responsible for activation of these pathways have not been identified. Screening GPCRs in the lipid-activated phylogenetic family (expressed in HEK293 cells) identified sphingosine-1-phosphate receptor 2 (S1P(2) ) as being activated by taurocholate (TCA). TCA, taurodeoxycholic acid (TDCA), tauroursodeoxycholic acid (TUDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and S1P-induced activation of ERK1/2 and AKT were significantly inhibited by JTE-013, a S1P(2) antagonist, in primary rat hepatocytes. JTE-013 significantly inhibited hepatic ERK1/2 and AKT activation as well as short heterodimeric partner (SHP) mRNA induction by TCA in the chronic bile fistula rat. Knockdown of the expression of S1P(2) by a recombinant lentivirus encoding S1P(2) shRNA markedly inhibited the activation of ERK1/2 and AKT by TCA and S1P in rat primary hepatocytes. Primary hepatocytes prepared from S1P(2) knock out (S1P(2) (-/-) ) mice were significantly blunted in the activation of the ERK1/2 and AKT pathways by TCA. Structural modeling of the S1P receptors indicated that only S1P(2) can accommodate TCA binding. In summary, all these data support the hypothesis that conjugated bile acids activate the ERK1/2 and AKT signaling pathways primarily through S1P(2) in primary rodent hepatocytes.",0
4262,21932400,Magnetic resonance imaging of focal liver lesions: approach to imaging diagnosis,"This article is a review of magnetic resonance imaging (MRI) of incidental focal liver lesions. This review provides an overview of liver MRI protocol, diffusion-weighted imaging, and contrast agents. Additionally, the most commonly encountered benign and malignant lesions are discussed with emphasis on imaging appearance and the diagnostic performance of MRI based on a review of the literature.",0
4263,21953056,miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma,"It has been established that microRNA expression and function contribute to phenotypic features of malignant cells, including resistance to apoptosis. Although targets and functional roles for a number of microRNAs have been described in cholangiocarcinoma, many additional microRNAs dysregulated in this tumor have not been assigned functional roles. In this study, we identify elevated miR-25 expression in malignant cholangiocarcinoma cell lines as well as patient samples. In cultured cells, treatment with the Smoothened inhibitor, cyclopamine, reduced miR-25 expression, suggesting Hedgehog signaling stimulates miR-25 production. Functionally, miR-25 was shown to protect cells against TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Correspondingly, antagonism of miR-25 in culture sensitized cells to apoptotic death. Computational analysis identified the TRAIL Death Receptor-4 (DR4) as a potential novel miR-25 target, and this prediction was confirmed by immunoblot, cell staining, and reporter assays. CONCLUSION: These data implicate elevated miR-25 levels in the control of tumor cell apoptosis in cholangiocarcinoma. The identification of the novel miR-25 target DR4 provides a mechanism by which miR-25 contributes to evasion of TRAIL-induced cholangiocarcinoma apoptosis.",0
4264,21953113,The transcription factor c-Jun protects against sustained hepatic endoplasmic reticulum stress thereby promoting hepatocyte survival,"Endoplasmic reticulum (ER) stress due to accumulation of hepatoviral or misfolded proteins is increasingly recognized as an important step in the pathogenesis of inflammatory, toxic, and metabolic liver diseases. ER stress results in the activation of several intracellular signaling pathways including Jun N-terminal kinase (JNK). The AP-1 (activating protein 1) transcription factor c-Jun is a prototypic JNK target and important regulator of hepatocyte survival, proliferation, and liver tumorigenesis. Because the functions of c-Jun during the ER stress response are poorly understood, we addressed this issue in primary hepatocytes and livers of hepatocyte-specific c-Jun knockout mice. ER stress was induced pharmacologically in vitro and in vivo and resulted in a rapid and robust induction of c-Jun protein expression. Interestingly, ER-stressed hepatocytes lacking c-Jun displayed massive cytoplasmic vacuolization due to ER distension. This phenotype correlated with exacerbated and sustained activation of canonical ER stress signaling pathways. Moreover, sustained ER stress in hepatocytes lacking c-Jun resulted in increased cell damage and apoptosis. ER stress is also a strong inducer of macroautophagy, a cell-protective mechanism of self-degradation of cytoplasmic components and organelles. Interestingly, autophagosome numbers in response to ER stress were reduced in hepatocytes lacking c-Jun. To further validate these findings, macroautophagy was inhibited chemically in ER-stressed wildtype hepatocytes, which resulted in cytoplasmic vacuolization and increased cell damage closely resembling the phenotypes observed in c-Jun-deficient cells. CONCLUSION: Our findings indicate that c-Jun protects hepatocytes against excessive activation of the ER stress response and subsequent cell death and provide evidence that c-Jun functionally links ER stress responses and macroautophagy.",0
4265,21953144,Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species,"Impaired T-cell responses in chronic hepatitis C virus (HCV) patients have been reported to be associated with the establishment of HCV persistent infection. However, the mechanism for HCV-mediated T-cell dysfunction is yet to be defined. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in suppressing T-cell responses. In this study we examined the accumulation of MDSCs in human peripheral blood mononuclear cells (PBMCs) following HCV infection. We found that CD33(+) mononuclear cells cocultured with HCV-infected hepatocytes, or with HCV core protein, suppress autologous T-cell responses. HCV core-treated CD33(+) cells exhibit a CD14(+) CD11b(+/low) HLADR(-/low) phenotype with up-regulated expression of p47(phox) , a component of the NOX2 complex critical for reactive oxygen species (ROS) production. In contrast, immunosuppressive factors, arginase-1 and inducible nitric oxide synthase (iNOS), were not up-regulated. Importantly, treatment with an inactivator of ROS reversed the T-cell suppressive function of HCV-induced MDSCs. Lastly, PBMCs of chronic HCV patients mirror CD33(+) cells following treatment with HCV core where CD33(+) cells are CD14(+) CD11b(+) HLADR(-/low) , and up-regulate the expression of p47(phox). CONCLUSION: These results suggest that HCV promotes the accumulation of CD33(+) MDSC, resulting in ROS-mediated suppression of T-cell responsiveness. Thus, the accumulation of MDSCs during HCV infection may facilitate and maintain HCV persistent infection.",0
4266,21991894,End-of-life transitions among nursing home residents with cognitive issues,"BACKGROUND: Health care transitions in the last months of life can be burdensome and potentially of limited clinical benefit for patients with advanced cognitive and functional impairment. METHODS: To examine health care transitions among Medicare decedents with advanced cognitive and functional impairment who were nursing home residents 120 days before death, we linked nationwide data from the Medicare Minimum Data Set and claims files from 2000 through 2007. We defined patterns of transition as burdensome if they occurred in the last 3 days of life, if there was a lack of continuity in nursing homes after hospitalization in the last 90 days of life, or if there were multiple hospitalizations in the last 90 days of life. We also considered various factors explaining variation in these rates of burdensome transition. We examined whether there was an association between regional rates of burdensome transition and the likelihood of feeding-tube insertion, hospitalization in an intensive care unit (ICU) in the last month of life, the presence of a stage IV decubitus ulcer, and hospice enrollment in the last 3 days of life. RESULTS: Among 474,829 nursing home decedents, 19.0% had at least one burdensome transition (range, 2.1% in Alaska to 37.5% in Louisiana). In adjusted analyses, blacks, Hispanics, and those without an advance directive were at increased risk. Nursing home residents in regions in the highest quintile of burdensome transitions (as compared with those in the lowest quintile) were significantly more likely to have a feeding tube (adjusted risk ratio, 3.38), have spent time in an ICU in the last month of life (adjusted risk ratio, 2.10), have a stage IV decubitus ulcer (adjusted risk ratio, 2.28), or have had a late enrollment in hospice (adjusted risk ratio, 1.17). CONCLUSIONS: Burdensome transitions are common, vary according to state, and are associated with markers of poor quality in end-of-life care.",0
4267,21991895,Clinical practice. Treating smokers in the health care setting,"A 45 year-old overweight woman with a history of asthma and depression presents to her primary care physician with her third episode of acute bronchitis in the last 24 months. She began smoking at age 15 and now smokes 10 to 15 cigarettes per day, but every day she starts smoking immediately upon awakening, an indication of severe nicotine dependence. She has made multiple unsuccessful attempts to quit, once briefly using the nicotine patch, but relapsed due to strong urges to smoke and weight gain. She has not used cessation counseling or other medications. She is bothered by the cost of cigarettes, and is worried about smoking�s health effects on her two children and on herself. Importantly, she is reluctant to make a quit attempt now, in part, because she fears she won�t succeed. What would you advise?",0
4268,21991952,Adverse health outcomes in women exposed in utero to diethylstilbestrol,"BACKGROUND: Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS: We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS: In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).",0
4269,21992122,Long interdialytic interval and mortality among patients receiving hemodialysis,"BACKGROUND: Patients with end-stage renal disease requiring dialysis have limited tolerance of metabolic and volume-related deviations from normal ranges; in addition, the prevalence of cardiovascular disease is high among such patients. Given these problems, we hypothesized that a long interdialytic interval is associated with adverse events in patients receiving hemodialysis. METHODS: We studied 32,065 participants in the End-Stage Renal Disease Clinical Performance Measures Project, a nationally representative sample of U.S. patients receiving hemodialysis three times weekly, at the end of calendar years 2004 through 2007. We compared rates of death and cardiovascular-related hospital admissions on the day after the long (2-day) interdialytic interval with rates on other days. RESULTS: The mean age of the cohort was 62.2 years; 24.2% of the patients had been receiving dialysis treatment for 1 year or less. Over a mean follow-up interval of 2.2 years, the following event rates were higher on the day after the long interval than on other days: all-cause mortality (22.1 vs. 18.0 deaths per 100 person-years, P<0.001), mortality from cardiac causes (10.2 vs. 7.5, P<0.001), infection-related mortality (2.5 vs. 2.1, P = 0.007), mortality from cardiac arrest (1.3 vs. 1.0, P = 0.004), mortality from myocardial infarction (6.3 vs. 4.4, P<0.001), and admissions for myocardial infarction (6.3 vs. 3.9, P<0.001), congestive heart failure (29.9 vs. 16.9, P<0.001), stroke (4.7 vs. 3.1, P<0.001), dysrhythmia (20.9 vs. 11.0, P<0.001), and any cardiovascular event (44.2 vs. 19.7, P<0.001). CONCLUSIONS: The long (2-day) interdialytic interval is a time of heightened risk among patients receiving hemodialysis. (Funded by the National Institutes of Health.).",0
4270,21995388,Oil-in-water emulsion adjuvant with influenza vaccine in young children,"BACKGROUND: The efficacy of inactivated influenza vaccines is known to be poor in infants and young children. METHODS: We studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay. RESULTS: Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups. CONCLUSIONS: Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).",0
4271,22006856,Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations,"Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8(+) T-cell epitope, nonstructural protein (NS)5B(2841-2849) (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B(2936-2944) (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a-infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27(+) subjects, rare escape mutations arose at the HLA-B27 anchor residue, R(2937) , which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from <5% to ? 70% of wild-type levels. CONCLUSION: The selection of rare CTL escape mutations in this HLA-B27-restricted epitope dramatically impairs viral replicative fitness, unless properly compensated. These data support a role for the targeting of highly constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens.",0
4272,22010917,"Neighborhoods, obesity, and diabetes--a randomized social experiment","BACKGROUND: The question of whether neighborhood environment contributes directly to the development of obesity and diabetes remains unresolved. The study reported on here uses data from a social experiment to assess the association of randomly assigned variation in neighborhood conditions with obesity and diabetes. METHODS: From 1994 through 1998, the Department of Housing and Urban Development (HUD) randomly assigned 4498 women with children living in public housing in high-poverty urban census tracts (in which ?40% of residents had incomes below the federal poverty threshold) to one of three groups: 1788 were assigned to receive housing vouchers, which were redeemable only if they moved to a low-poverty census tract (where <10% of residents were poor), and counseling on moving; 1312 were assigned to receive unrestricted, traditional vouchers, with no special counseling on moving; and 1398 were assigned to a control group that was offered neither of these opportunities. From 2008 through 2010, as part of a long-term follow-up survey, we measured data indicating health outcomes, including height, weight, and level of glycated hemoglobin (HbA(1c)). RESULTS: As part of our long-term survey, we obtained data on body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) for 84.2% of participants and data on glycated hemoglobin level for 71.3% of participants. Response rates were similar across randomized groups. The prevalences of a BMI of 35 or more, a BMI of 40 or more, and a glycated hemoglobin level of 6.5% or more were lower in the group receiving the low-poverty vouchers than in the control group, with an absolute difference of 4.61 percentage points (95% confidence interval [CI], -8.54 to -0.69), 3.38 percentage points (95% CI, -6.39 to -0.36), and 4.31 percentage points (95% CI, -7.82 to -0.80), respectively. The differences between the group receiving traditional vouchers and the control group were not significant. CONCLUSIONS: The opportunity to move from a neighborhood with a high level of poverty to one with a lower level of poverty was associated with modest but potentially important reductions in the prevalence of extreme obesity and diabetes. The mechanisms underlying these associations remain unclear but warrant further investigation, given their potential to guide the design of community-level interventions intended to improve health. (Funded by HUD and others.).",0
4273,22031499,Human liver cell spheroids in extended perfusion bioreactor culture for repeated-dose drug testing,"Primary cultures of human hepatocyte spheroids are a promising in vitro model for long-term studies of hepatic metabolism and cytotoxicity. The lack of robust methodologies to culture cell spheroids, as well as a poor characterization of human hepatocyte spheroid architecture and liver-specific functionality, have hampered a widespread adoption of this three-dimensional culture format. In this work, an automated perfusion bioreactor was used to obtain and maintain human hepatocyte spheroids. These spheroids were cultured for 3-4 weeks in serum-free conditions, sustaining their phase I enzyme expression and permitting repeated induction during long culture times; rate of albumin and urea synthesis, as well as phase I and II drug-metabolizing enzyme gene expression and activity of spheroid hepatocyte cultures, presented reproducible profiles, despite basal interdonor variability (n = 3 donors). Immunofluorescence microscopy of human hepatocyte spheroids after 3-4 weeks of long-term culture confirmed the presence of the liver-specific markers, hepatocyte nuclear factor 4?, albumin, cytokeratin 18, and cytochrome P450 3A. Moreover, immunostaining of the atypical protein kinase C apical marker, as well as the excretion of a fluorescent dye, evidenced that these spheroids spontaneously assemble a functional bile canaliculi network, extending from the surface to the interior of the spheroids, after 3-4 weeks of culture. CONCLUSION: Perfusion bioreactor cultures of primary human hepatocyte spheroids maintain a liver-specific activity and architecture and are thus suitable for drug testing in a long-term, repeated-dose format.",0
4274,22045672,"Excess liver-related morbidity of chronic hepatitis C patients, who achieve a sustained viral response, and are discharged from care","Our objective was to address two shortfalls in the hepatitis C virus (HCV) literature: (1) Few data exist comparing post-treatment liver-related mortality/morbidity in HCV-sustained virologic response (SVR) patients to non-SVR patients and (2) no data exist examining liver-related morbidity among treatment response subgroups,particularly among noncirrhotic SVR patients, a group who in the main are discharged from care without further follow-up. A retrospective cohort of 1,215 previously na?ve HCV interferon patients (treated 1996-2007)was derived using HCV clinical databases from nine Scottish clinics. Patients were followed up post-treatment for a mean of 5.3 years. (1) By Cox-regression, liver-related hospital episodes (adjusted hazard ratio [AHR]:0.22; 95% confidence interval [CI]: 0.15-0.34) and liver-related mortality [corrected] (AHR: 0.22; 95% CI: 0.09-0.58)were significantly lower in SVR patients, compared to non-SVR patients. (2) Rates of liver-related hospitalization were elevated among all treatment subgroups compared to the general population: Among noncirrhotic SVR patients, adjusted standardized morbidity ratio (SMBR) up to 5.9 (95% CI: 4.5-8.0); among all SVR patients,SMBR up to 10.5 (95% CI: 8.7-12.9); and among non-SVR patients, SMBR up to 53.2 (95% CI: 49.4-57.2).Considerable elevation was also noted among patients who have spontaneously resolved their HCV infection(a control group used to gauge the extent to which lifestyle factors, and not chronic HCV, can contribute toliver-related morbidity), SMBR up to 26.8 (95% CI: 25.3-28.3). CONCLUSIONS: (1) Patients achieving an SVR were more than four times less likely to be hospitalized, or die for a liver-related reason, than non-SVR patients and (2) although discharged, noncirrhotic SVR patients harbor a disproportionate burden of liver-related morbidity; up to six times that of the general population. Further, alarming levels of liver-related morbidity in spontaneous resolvers is an important finding warranting further study..",0
4275,22047561,Results of the Medicare Health Support disease-management pilot program,"BACKGROUND: In the Medicare Modernization Act of 2003, Congress required the Centers for Medicare and Medicaid Services to test the commercial disease-management model in the Medicare fee-for-service program. METHODS: The Medicare Health Support Pilot Program was a large, randomized study of eight commercial programs for disease management that used nurse-based call centers. We randomly assigned patients with heart failure, diabetes, or both to the intervention or to usual care (control) and compared them with the use of a difference-in-differences method to evaluate the effects of the commercial programs on the quality of clinical care, acute care utilization, and Medicare expenditures for Medicare fee-for-service beneficiaries. RESULTS: The study included 242,417 patients (163,107 in the intervention group and 79,310 in the control group). The eight commercial disease-management programs did not reduce hospital admissions or emergency room visits, as compared with usual care. We observed only 14 significant improvements in process-of-care measures out of 40 comparisons. These modest improvements came at substantial cost to the Medicare program in fees paid to the disease-management companies ($400 million), with no demonstrable savings in Medicare expenditures. CONCLUSIONS: In this large study, commercial disease-management programs using nurse-based call centers achieved only modest improvements in quality-of-care measures, with no demonstrable reduction in the utilization of acute care or the costs of care.",0
4276,22085317,Comparative effectiveness of weight-loss interventions in clinical practice,"BACKGROUND: Obesity and its cardiovascular complications are extremely common medical problems, but evidence on how to accomplish weight loss in clinical practice is sparse. METHODS: We conducted a randomized, controlled trial to examine the effects of two behavioral weight-loss interventions in 415 obese patients with at least one cardiovascular risk factor. Participants were recruited from six primary care practices; 63.6% were women, 41.0% were black, and the mean age was 54.0 years. One intervention provided patients with weight-loss support remotely--through the telephone, a study-specific Web site, and e-mail. The other intervention provided in-person support during group and individual sessions, along with the three remote means of support. There was also a control group in which weight loss was self-directed. Outcomes were compared between each intervention group and the control group and between the two intervention groups. For both interventions, primary care providers reinforced participation at routinely scheduled visits. The trial duration was 24 months. RESULTS: At baseline, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) for all participants was 36.6, and the mean weight was 103.8 kg. At 24 months, the mean change in weight from baseline was -0.8 kg in the control group, -4.6 kg in the group receiving remote support only (P<0.001 for the comparison with the control group), and -5.1 kg in the group receiving in-person support (P<0.001 for the comparison with the control group). The percentage of participants who lost 5% or more of their initial weight was 18.8% in the control group, 38.2% in the group receiving remote support only, and 41.4% in the group receiving in-person support. The change in weight from baseline did not differ significantly between the two intervention groups. CONCLUSIONS: In two behavioral interventions, one delivered with in-person support and the other delivered remotely, without face-to-face contact between participants and weight-loss coaches, obese patients achieved and sustained clinically significant weight loss over a period of 24 months. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00783315.).",0
4277,22095670,Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein,"The hepatic expression of Niemann-Pick C1-like 1 (NPC1L1), which is a key molecule in intestinal cholesterol absorption, is high in humans. In addition to NPC1L1, Niemann-Pick C2 (NPC2), a secretory cholesterol-binding protein involved in intracellular cholesterol trafficking and the stimulation of biliary cholesterol secretion, is also expressed in the liver. In this study, we examined the molecular interaction and functional association between NPC1L1 and NPC2. In vitro studies with adenovirus-based or plasmid-mediated gene transfer systems revealed that NPC1L1 negatively regulated the protein expression and secretion of NPC2 without affecting the level of NPC2 messenger RNA. Experiments with small interfering RNA against NPC1L1 confirmed the endogenous association of these proteins. In addition, endocytosed NPC2 could compensate for the reduction of NPC2 in NPC1L1-overexpressing cells, and this demonstrated that the posttranscriptional regulation of NPC2 was dependent on a novel ability of NPC1L1 to inhibit the maturation of NPC2 and accelerate the degradation of NPC2 during its maturation. Furthermore, to confirm the physiological relevance of NPC1L1-mediated regulation, we analyzed human liver specimens and found a negative correlation between the protein levels of hepatic NPC1L1 and hepatic NPC2. CONCLUSION: NPC1L1 down-regulates the expression and secretion of NPC2 by inhibiting its maturation and accelerating its degradation. NPC2 functions as a regulator of intracellular cholesterol trafficking and biliary cholesterol secretion; therefore, in addition to its role in cholesterol re-uptake from the bile by hepatocytes, hepatic NPC1L1 may control cholesterol homeostasis via the down-regulation of NPC2.",0
4278,22095875,Lysine acetylation induced by chronic ethanol consumption impairs dynamin-mediated clathrin-coated vesicle release,"The liver is the major site of ethanol metabolism and thus sustains the most injury from chronic alcohol consumption. Ethanol metabolism by the hepatocyte leads to the generation of reactive metabolites and oxygen radicals that can readily adduct DNA, lipids, and proteins. More recently, it has become apparent that ethanol consumption also leads to increased post-translational modifications of the natural repertoire, including lysine hyperacetylation. Previously, we determined that alcohol consumption selectively impairs clathrin-mediated internalization in polarized hepatocytes. However, neither the step at which the block occurs nor the mechanism responsible for the defect have been identified. To identify the specific step at which clathrin-mediated internalization is impaired, we examined the distributions, levels, and assembly of selected components of the clathrin machinery in control and ethanol-treated cells. To determine whether the impairment is caused by ethanol-induced lysine acetylation, we also examined the same coat components in cells treated with trichostatin A (TSA), a deacetylase inhibitor that leads to protein hyperacetylation in the absence of ethanol. CONCLUSION: We determined that both ethanol and TSA impair internalization at a late stage before vesicle fission. We further determined that this defect is likely the result of decreased dynamin recruitment to the necks of clathrin-coated invaginations resulting in impaired vesicle budding. These results also raise the exciting possibility that agents that promote lysine deacetylation may be effective therapeutics for the treatment of alcoholic liver disease.",0
4279,22105803,(-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry,"Here, we identify (-)-epigallocatechin-3-gallate (EGCG) as a new inhibitor of hepatitis C virus (HCV) entry. EGCG is a flavonoid present in green tea extract belonging to the subclass of catechins, which has many properties. Particularly, EGCG possesses antiviral activity and impairs cellular lipid metabolism. Because of close links between HCV life cycle and lipid metabolism, we postulated that EGCG may interfere with HCV infection. We demonstrate that a concentration of 50 ?M of EGCG inhibits HCV infectivity by more than 90% at an early step of the viral life cycle, most likely the entry step. This inhibition was not observed with other members of the Flaviviridae family tested. The antiviral activity of EGCG on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition, using binding assays at 4�C, we demonstrate that EGCG prevents attachment of the virus to the cell surface, probably by acting directly on the particle. We also show that EGCG has no effect on viral replication and virion secretion. By inhibiting cell-free virus transmission using agarose or neutralizing antibodies, we show that EGCG inhibits HCV cell-to-cell spread. Finally, by successive inoculation of na?ve cells with supernatant of HCV-infected cells in the presence of EGCG, we observed that EGCG leads to undetectable levels of infection after four passages. CONCLUSION: EGCG is a new, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals. Furthermore, it is a novel tool to further dissect the mechanisms of HCV entry into the hepatocyte.",0
4280,22109893,Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid,"Gut-activated T cells migrating into the liver can cause extraintestinal manifestations of inflammatory bowel disease. T cells acquire a gut-homing phenotype dependent on retinoic acid (RA) provided by intestinal dendritic cells (DC). We investigated whether liver antigen-presenting cells can induce gut tropism supporting an enterohepatic lymphocyte circulation. Priming of CD4(+) T cells by liver sinusoidal endothelial cells (LSEC) supported migration into gut and gut-associated lymphoid tissue. As observed for T cells primed by intestinal DCs, this gut tropism depended on ?(4) ?(7) integrin and CC chemokine receptor 9 (CCR9) expression by LSEC-primed CD4(+) T cells. The induction of gut-homing molecules was mediated by RA, a derivate of vitamin A that is stored in large amounts within the liver. LSECs expressed functional retinal dehydrogenases and could convert vitamin A to RA. Conversely, the lack of signaling via the RA receptor prevented the expression of ?(4) ?(7) integrin and CCR9 on LSEC-primed CD4(+) T cells, consequently reducing their in vivo migration to the intestine. Other liver antigen-presenting cells failed to support high expression of ?(4) ?(7) integrin on CD4(+) T cells, thus, the potential to induce gut homing is restricted to LSECs. CONCLUSION: The capacity to promote gut tropism via vitamin A use is not unique for intestinal DCs but is also a feature of LSECs. Our data support the assumption that CD4(+) T cells can migrate from the liver to the gut as one branch of a postulated enterohepatic lymphocyte circulation.",0
4281,22121002,Role of low-density lipoprotein receptor in the hepatitis C virus life cycle,"Hepatitis C virus (HCV) particles are known to be in complex with lipoproteins. As a result of this interaction, the low-density lipoprotein (LDL) receptor (LDLR) has been proposed as a potential entry factor for HCV; however, its implication in virus entry remains unclear. Here, we reinvestigated the role of the LDLR in the HCV life cycle by comparing virus entry to the mechanism of lipoprotein uptake. A small interfering RNA targeting the LDLR in Huh-7 cells reduced HCV infectivity, confirming that this receptor plays a role in the life cycle of HCV generated in cell culture. However, kinetics of internalization were much faster for lipoproteins than for infectious HCV particles. Furthermore, a decrease in HCV RNA replication was observed by blocking the LDLR with a specific antibody, and this was associated with an increase in the ratio of phosphatidylethanolamine to phosphatidylcholine in host cells. Nevertheless, a soluble form of the LDLR inhibited both HCV entry into the hepatocytes and its binding to the LDLR expressed on Chinese hamster ovary cells, suggesting a direct interaction between the HCV particle and the LDLR. Finally, we showed that modification of HCV particles by lipoprotein lipase (LPL) reduces HCV infectivity and increases HCV binding to LDLR. Importantly, LPL treatment also induced an increase in RNA internalization, suggesting that LDLR, at least in some conditions, leads to nonproductive internalization of HCV. CONCLUSION: The LDLR is not essential for infectious HCV particle entry, whereas the physiological function of this receptor is important for optimal replication of the HCV genome.",0
4282,22129253,Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis,"BACKGROUND: Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy. METHODS: We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis. RESULTS: No adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs [E(max) (maximum value)�baseline value�100=420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators. CONCLUSIONS: The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.).",0
4283,22135011,Retraction. I148M PNPLA3 variant and progressive liver disease: A new paradigm in hepatology,"""Retraction: The following editorial from HEPATOLOGY, """"I148M PNPLA3 variant and progressive liver disease: A new paradigm in hepatology"""", by Luca Valenti, Anna Alisi and Valerio Nobili, posted online on 2 December 2011 as an Accepted Article in Wiley Online Library (www.wileyonlinelibrary.com), has been retracted by agreement between the authors, the AASLD, the journal Editor in Chief, Michael H. Nathanson, and Wiley Periodicals, Inc. The retraction has been agreed due to the fact that an incorrect version was posted online. The correct version of the Editorial has been issued under a separate DOI, 10.1002/hep.25617.""",0
4284,22135136,Comparative analysis of portal cell infiltrates in antimitochondrial autoantibody-positive versus antimitochondrial autoantibody-negative primary biliary cirrhosis,"Substantial evidence supports dysregulated B-cell immune responses in patients with primary biliary cirrhosis (PBC), including the presence of serum antimitochondrial antibodies (AMAs). However, recent reports from murine models of PBC suggest that B cells may also provide regulatory function, and indeed the absence of B cells in such models leads to exacerbation of disease. The vast majority of patients with PBC have readily detectable AMAs, but a minority (<5%) are AMA negative (AMA(-)), even with recombinant diagnostic technology. This issue prompted us to examine the nature of B-cell infiltrates surrounding the portal areas in AMA-positive (AMA(+)) and AMA(-) patients, because they display indistinguishable clinical features. Of importance was the finding that the degree of bile duct damage around the portal areas was significantly milder in AMA(+) PBC than those observed in AMA(-) PBC patients. The portal areas from AMA(-) patients had a significant increase of cluster of differentiation (CD)5(+) cells infiltrating the ductal regions, and the levels of B-cell infiltrates were worse in the early phase of bile duct damage. The frequency of positive portal areas and the magnitude of CD5(+) and CD20(+) cellular infiltrates within areas of ductal invasion is associated with the first evidence of damage of biliary duct epithelia, but becomes reduced in the ductopenia stage, with the exception of CD5(+) cells, which remain sustained and predominate over CD20(+) cells. CONCLUSION: Our data suggest a putative role of B-cell autoimmunity in regulating the portal destruction characteristic of PBC.",0
4285,22144107,Expression of paramyxovirus V proteins promotes replication and spread of hepatitis C virus in cultures of primary human fetal liver cells,"Here we demonstrate that primary cultures of human fetal liver cells (HFLC) reliably support infection with laboratory strains of hepatitis C virus (HCV), although levels of virus replication vary significantly between different donor cell preparations and frequently decline in a manner suggestive of active viral clearance. To investigate possible contributions of the interferon (IFN) system to control HCV infection in HFLC, we exploited the well-characterized ability of paramyxovirus (PMV) V proteins to counteract both IFN induction and antiviral signaling. The V proteins of measles virus (MV) and parainfluenza virus 5 (PIV5) were introduced into HFLC using lentiviral vectors encoding a fluorescent reporter for visualization of HCV-infected cells. V protein-transduced HFLC supported enhanced (10 to 100-fold) levels of HCV infection relative to untransduced or control vector-transduced HFLC. Infection was assessed by measurement of virus-driven luciferase, by assays for infectious HCV and viral RNA, and by direct visualization of HCV-infected hepatocytes. Live cell imaging between 48 and 119 hours postinfection demonstrated little or no spread of infection in the absence of PMV V protein expression. In contrast, V protein-transduced HFLC showed numerous HCV infection events. V protein expression efficiently antagonized the HCV-inhibitory effects of added IFNs in HFLC. In addition, induction of the type III IFN, IL29, following acute HCV infection was inhibited in V protein-transduced cultures. CONCLUSION: These studies suggest that the cellular IFN response plays a significant role in limiting the spread of HCV infection in primary hepatocyte cultures. Strategies aimed at dampening this response may be key to further development of robust HCV culture systems, enabling studies of virus pathogenicity and the mechanisms by which HCV spreads in its natural host cell population.",0
4286,22150006,SF3B1 and other novel cancer genes in chronic lymphocytic leukemia,"BACKGROUND: The somatic genetic basis of chronic lymphocytic leukemia, a common and clinically heterogeneous leukemia occurring in adults, remains poorly understood. METHODS: We obtained DNA samples from leukemia cells in 91 patients with chronic lymphocytic leukemia and performed massively parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA, to characterize the spectrum of somatic mutations in this disease. RESULTS: Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with chronic lymphocytic leukemia. We further discovered that tumor samples with mutations in SF3B1 had alterations in pre-messenger RNA (mRNA) splicing. CONCLUSIONS: Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia.",0
4287,22168587,A mutation in the thyroid hormone receptor alpha gene,"Thyroid hormones exert their effects through alpha (TR?1) and beta (TR?1 and TR?2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TR?-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.",0
4288,22183951,A cell-permeable hairpin peptide inhibits hepatitis C viral nonstructural protein 5A-mediated translation and virus production,"NS5A is a key regulator of the hepatitis C virus (HCV) life cycle including RNA replication, assembly, and translation. We and others have shown that NS5A augments HCV internal ribosomal entry site (IRES)-mediated translation. Furthermore, Quercetin treatment and heat shock protein (HSP) 70 knockdown inhibit the NS5A-driven augmentation of IRES-mediated translation and infectious virus production. We have also coimmunoprecipitated HSP70 with NS5A and demonstrated cellular colocalization, leading to the hypothesis that the NS5A/HSP70 complex formation is important for IRES-mediated translation. Here, we have identified the NS5A region responsible for complex formation through in vitro deletion analyses. Deletion of NS5A domains II and III failed to reduce HSP70 binding, whereas domain I deletion eliminated complex formation. NS5A domain I alone also bound HSP70. Deletion mapping of domain I identified the C-terminal 34 amino acids (C34) as the interaction site. Furthermore, addition of C34 to domains II and III restored complex formation. C34 expression significantly reduced intracellular viral protein levels, in contrast to same-size control peptides from other NS5A domains. C34 also competitively inhibited NS5A-augmented IRES-mediated translation, whereas controls did not. Triple-alanine scan mutagenesis determined that an exposed beta-sheet hairpin in C34 was primarily responsible for NS5A-augmented IRES-mediated translation. Moreover, treatment with a 10-amino acid peptide derivative of C34 suppressed NS5A-augmented IRES-mediated translation and significantly inhibited intracellular viral protein synthesis, with no associated cytotoxicity. CONCLUSION: These results support the hypothesis that the NS5A/HSP70 complex augments viral IRES-mediated translation, identify a sequence-specific hairpin element in NS5A responsible for complex formation, and demonstrate the functional significance of C34 hairpin-mediated NS5A/HSP70 interaction. Identification of this element may allow for further interrogation of NS5A-mediated IRES activity, sequence-specific HSP recognition, and rational drug design. (HEPATOLOGY 2012;55:1662-1672).",0
4289,22183976,S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver,"Nutrient homeostasis is tightly regulated by the balance between energy production and utilization. During fasting, production of ketone bodies as an alternative energy source is critical to maintain nutrient homeostasis. An important component in the nutrient-sensitive signaling pathway is S6 kinase 2 (S6K2), a downstream effector of mammalian target of rapamycin. Here, we show that mice lacking S6K2 exhibit elevated levels of ketone bodies and enhanced peroxisome proliferator-activated receptor alpha (PPAR?) activity upon nutrient availability. Consistent with this, knockdown of S6K2 increases the transcriptional activity of PPAR?. S6K2 suppresses PPAR? by associating with its corepressor, nuclear receptor corepressor 1 (NCoR1), and by inducing the recruitment of NCoR1 to the nucleus. Moreover, ob/ob mice, a genetic model of obesity, have markedly elevated S6K2 activity, and S6K2 was strongly associated with NCoR1 in the nucleus of liver cells. CONCLUSION: Our findings suggest that S6K2 regulates hepatic energy homeostasis by repressing PPAR? activity and point to its potential relevance for therapeutic strategies designed to modulate S6K2 activity as a treatment for deregulated ketone body production.",0
4290,22187960,Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers,"BACKGROUND: Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors. METHODS: We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays. RESULTS: DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity. CONCLUSIONS: Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).",0
4291,22204672,Three patients with full facial transplantation,"Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients.",0
4292,22213025,"Awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C: National Health and Nutrition Examination Survey 2001-2008","Many persons infected with hepatitis C virus (HCV) are unknown to the healthcare system because they may be asymptomatic for years, have not been tested for HCV infection, and only seek medical care when they develop liver-related complications. We analyzed data from persons who tested positive for past or current HCV infection during participation in the National Health and Nutrition Examination Survey (NHANES) from 2001 through 2008. A follow-up survey was conducted 6 months after examination to determine (1) how many participants testing positive for HCV infection were aware of their HCV status before being notified by NHANES, (2) what actions participants took after becoming aware of their first positive test, and (3) participants' knowledge about hepatitis C. Of 30,140 participants tested, 393 (1.3%) had evidence of past or current HCV infection and 170 (43%) could be contacted during the follow-up survey and interviewed. Only 49.7% were aware of their positive HCV infection status before being notified by NHANES, and only 3.7% of these respondents reported that they had first been tested for HCV because they or their doctor thought they were at risk for infection. Overall, 85.4% had heard of hepatitis C; correct responses to questions about hepatitis C were higher among persons 40-59 years of age, white non-Hispanics, and respondents who saw a physician after their first positive HCV test. Eighty percent of respondents indicated they had seen a doctor about their first positive HCV test result. CONCLUSION: These data indicate that fewer than half of those infected with HCV may be aware of their infection. The findings suggest that more intensive efforts are needed to identify and test persons at risk for HCV infection.",0
4293,22213147,Mycophenolic acid augments interferon-stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo,"Mycophenolic acid (MPA) is a highly effective immunosuppressant that has broad antiviral activity against different viruses and can act in synergy with interferon-? (IFN-?) on hepatitis C virus (HCV) replication. MPA is a potent inosine monophosphate dehydrogenase (IMPDH) inhibitor but the antiviral mechanisms are less understood. The aim of this study was to investigate the inhibition of HCV infection by MPA and the molecular basis for its synergy with IFN-?. The role of IMPDH and interferon-stimulated genes (ISGs) was investigated in two HCV models using gain- or loss-of-function approaches. The in vivo effect of MPA treatment was studied in NOD/SCID mice engrafted with HCV replicon cells. Potent antiviral effects of MPA at clinically relevant concentrations were observed with both the subgenomic and JFH1-derived infectious HCV models. MPA treatment in mice resulted in a specific and robust inhibition of HCV replication. Ectopic expression of an MPA-resistant IMPDH2 mutant in HCV host cells completely reversed the antiproliferative effect of MPA but only partially affected the antiviral potency. However, similar to ribavirin, MPA induced expression of multiple antiviral ISGs, including interferon regulatory factor 1 (IRF1). Cotreatment of MPA with IFN-? resulted in additive effects on ISG expression and enhanced IFN-induced luciferase reporter activity. Knockdown of IRF1, but not IFITM3, significantly attenuated the inhibition of HCV replication by MPA. CONCLUSION: MPA exerts a potent anti-HCV effect in vitro and in mice and acts in synergy with IFN-?. MPA's antiviral activity partially depends on IMPDH but also involves stimulation of ISGs, providing a molecular basis for its synergy with IFN-?.",0
4294,22216840,Efficacy results of a trial of a herpes simplex vaccine,"BACKGROUND: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. METHODS: We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 ?g of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. RESULTS: The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). CONCLUSIONS: In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.).",0
4295,22234804,Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution,"The aim of this study is to determine whether early viral dynamics and evolution predict outcome of primary acute hepatitis C virus (HCV) infection. HCV- and human immunodeficiency virus-negative injection drug users were enrolled prospectively and followed monthly to identify acute HCV infection using RNA detection. Subjects with more than 1 month between HCV-RNA-negative and -positive visits were excluded to ensure stringent acute infection. Differences in medians of log-transformed viral RNA levels and evolutionary rates in each gene of a 5'-hemigenomic amplicon were assessed using Mann-Whitney's rank-sum test. Correlation coefficient was calculated using Spearman's rank order. Initial viremia level was 50-fold higher in subjects with spontaneous clearance (compared with persistence) of primary acute HCV infection (median, 7.1 versus 5.4 log(10) IU/mL; P = 0.002). Initial viremia level in subjects with interleukin (IL)28B-C allele at rs12979860 and clearance was higher than that in subjects with IL28B-T allele and persistence (P = 0.001). Evolutionary rates in the hypervariable region 1 (HVR1) region of the E2 gene were significantly higher in self-resolvers than those in persistence subjects during early infection, whereas other genes or regions had comparable rates. All major substitutions in HVR1 in persistence subjects were convergent changes, whereas over the same time interval clearance subjects displayed divergent evolution, indicating different immune responses between the two groups. CONCLUSION: Spontaneous clearance of acute HCV infection is predicted by high initial viremia as well as favorable IL28B genotype and is associated with rapid envelope-sequence evolution. This linkage of host genetics, viral dynamics, and evolution provides new directions for mechanistic studies. (HEPATOLOGY 2012;55:1684-1691).",0
4296,22234905,"Impact of a baseline polymorphism on the emergence of resistance to the hepatitis C virus nonstructural protein 5A replication complex inhibitor, BMS-790052","The influence of naturally occurring polymorphisms on the potency of the HCV nonstructural protein 5A (NS5A) replication complex inhibitor, BMS-790052, was investigated by evaluating hybrid replicons in which the entire NS5A coding region of genotype (GT) la and 1b laboratory (lab) strains (H77c and Con1) were replaced with the corresponding regions of specimens collected from 10 GT-1a- and 6 GT-1b-infected subjects. For baseline (BL) specimens, with no previously observed resistance variants identified by population sequencing, the median 50% effective concentration (EC(50) ) values for BMS-790052 were similar for the clinically derived and lab strains. A Q30R variant was observed at viral breakthrough (VBT) in one of the GT-1a-infected subjects. Because the lowest plasma exposure of BMS-790052 observed in this subject was 117 nM and the median 50% effective concentration value for a GT-1a H77c replicon containing a Q30R substitution is ~7 nM, a rigorous investigation was initiated to determine the basis for resistance. Three approaches were used: (1) replacement of the entire H77c NS5A or (2) replacement of the N-terminal region of NS5A, with sequence from BL and day 14, and (3) substitution of specific amino acids. A BL polymorphism (E62D) did not contribute resistance to BMS-790052; however, the linked variant, Q30R-E62D, conferred high-level resistance in vitro and is likely responsible for VBT in vivo. CONCLUSION: Our data show that a BL polymorphism with minimal effect on the anti-HCV effect of BMS-790052 can affect the emergence of resistance and significantly affect clinical outcome. This work establishes a clear, systematic approach to monitor resistance to NS5A inhibitors in the clinic.",0
4297,22256806,Bone-density testing interval and transition to osteoporosis in older women,"BACKGROUND: Although bone mineral density (BMD) testing to screen for osteoporosis (BMD T score, -2.50 or lower) is recommended for women 65 years of age or older, there are few data to guide decisions about the interval between BMD tests. METHODS: We studied 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, -1.00 or higher) or osteopenia (T score, -1.01 to -2.49) and with no history of hip or clinical vertebral fracture or of treatment for osteoporosis, followed prospectively for up to 15 years. The BMD testing interval was defined as the estimated time for 10% of women to make the transition to osteoporosis before having a hip or clinical vertebral fracture, with adjustment for estrogen use and clinical risk factors. Transitions from normal BMD and from three subgroups of osteopenia (mild, moderate, and advanced) were analyzed with the use of parametric cumulative incidence models. Incident hip and clinical vertebral fractures and initiation of treatment with bisphosphonates, calcitonin, or raloxifene were treated as competing risks. RESULTS: The estimated BMD testing interval was 16.8 years (95% confidence interval [CI], 11.5 to 24.6) for women with normal BMD, 17.3 years (95% CI, 13.9 to 21.5) for women with mild osteopenia, 4.7 years (95% CI, 4.2 to 5.2) for women with moderate osteopenia, and 1.1 years (95% CI, 1.0 to 1.3) for women with advanced osteopenia. CONCLUSIONS: Our data indicate that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia. (Funded by the National Institutes of Health.).",0
4298,22271545,Transcriptional regulation of methionine adenosyltransferase 2A by peroxisome proliferator-activated receptors in rat hepatic stellate cells,"Methionine adenosyltransferases (MATs) are critical enzymes that catalyze the formation of the methyl donor S-adenosyl methionine (SAM). The MAT2A gene, which encodes the catalytic subunit ?2, is induced in dedifferentiated liver. We previously demonstrated that MAT2A expression is enhanced in activated hepatic stellate cells (HSCs) and that silencing this gene reduces HSC activation. In this study, we examined the molecular mechanisms responsible for the transcriptional regulation of the MAT2A gene in HSCs. We identified peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) in the rat MAT2A promoter. The PPAR? agonist rosiglitazone (RSG) promoted quiescence in the activated rat HSC cell line (BSC) or culture-activated primary rat HSCs, decreased MAT2A expression and promoter activity, and enhanced PPAR? binding to MAT2A PPREs. In vivo HSC activation in bile duct-ligated rats lowered PPAR? interaction with MAT2A PPREs. Silencing PPAR? increased MAT2A transcription, whereas overexpressing it had the opposite effect, demonstrating that PPAR? negatively controls this gene. Site-directed mutagenesis of PPREs abolished PPAR? recruitment to the MAT2A promoter and its inhibitory effect on MAT2A transcription in quiescent HSCs. PPRE mutations decreased the basal promoter activity of MAT2A in activated HSCs independent of PPAR?, indicating that other factors might be involved in PPRE interaction. We identified PPAR? binding to wild-type but not to mutated PPREs in activated cells. Furthermore, silencing PPAR? inhibited MAT2A expression and promoter activity. Forced expression of MAT2A in RSG-treated HSCs lowered PPAR? and enhanced PPAR? expression, thereby promoting an activated phenotype. CONCLUSION: We identified PPAR? as a negative regulator of MAT2A in quiescent HSCs. A switch from quiescence to activation abolishes this control and allows PPAR? to up-regulate MAT2A transcription.",0
4299,22278637,Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis,"Hepatic stellate cell (HSC) activation is a pivotal event in initiation and progression of hepatic fibrosis and a major contributor to collagen deposition driven by transforming growth factor beta (TGF-?). MicroRNAs (miRs), small noncoding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key regulatory molecules in chronic liver disease. We investigated differentially expressed miRs in quiescent and activated HSCs to identify novel regulators of profibrotic TGF-? signaling. miR microarray analysis was performed on quiescent and activated rat HSCs. Members of the miR-17-92 cluster (19a, 19b, 92a) were significantly down-regulated in activated HSCs. Because miR 19b showed the highest fold-change of the cluster members, activated HSCs were transfected with miR 19b mimic or negative control and TGF-? signaling and HSC activation assessed. miR 19b expression was determined in fibrotic rat and human liver specimens. miR 19b mimic negatively regulated TGF-? signaling components demonstrated by decreased TGF-? receptor II (TGF-?RII) and SMAD3 expression. Computational prediction of miR 19b binding to the 3' untranslated region of TGF-?RII was validated by luciferase reporter assay. Inhibition of TGF-? signaling by miR 19b was confirmed by decreased expression of type I collagen and by blocking TGF-?-induced expression of ?1(I) and ?2(I) procollagen mRNAs. miR 19b blunted the activated HSC phenotype by morphological assessment and decreased smooth muscle ?-actin expression. Additionally, miR 19b expression was markedly diminished in fibrotic rat liver compared with normal liver; similarly, miR 19b expression was markedly down-regulated in fibrotic compared with normal human livers. CONCLUSION: miR 19b is a novel regulator of TGF-? signaling in HSCs, suggesting a potential therapeutic approach for hepatic fibrosis.",0
4300,22287293,Exiting from uncharted territory: hepatitis C virus assembles in mouse cell lines,"BACKGROUND & AIMS: Hepatitis C virus (HCV) has a high propensity to establish persistence; better understanding of this process requires the development of a fully permissive and immunocompetent small animal model. Mouse cells can be engineered to express the human orthologs of the entry molecules CD81 and occludin to allow entry of HCV. However, RNA replication is poor in mouse cells, and it is not clear whether they support assembly and release of infectious HCV particles. We used a trans-complementation-based system to demonstrate HCV assembly competence of mouse liver cell lines. METHODS: A panel of 3 mouse hepatoma cell lines that contain a stable subgenomic HCV replicon was used for ectopic expression of the HCV structural proteins, p7, nonstructural protein 2, and/or apolipoprotein E (ApoE). Assembly and release of infectious HCV particles was determined by measuring viral RNA, proteins, and infectivity of virus released into the culture supernatant. RESULTS: Mouse replicon cells released low amounts of HCV particles, but ectopic expression of apoE increased release of infectious HCV to levels observed in the human hepatoma cell line Huh7.5. ApoE is the limiting factor for assembly of HCV in mouse hepatoma cells but probably not in primary mouse hepatocytes. Products of all 3 human alleles of apoE and mouse apoE support HCV assembly with comparable efficiency. Mouse and human cell-derived HCV particles have similar biophysical properties, dependency on entry factors, and levels of association with ApoE. CONCLUSIONS: Mouse hepatic cells permit HCV assembly and might be developed to create an immunocompetent and fully permissive mouse model of HCV infection.",0
4301,22307831,Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B,"Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN � lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.",0
4302,22331604,Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response,"Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype. CONCLUSION: Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression.",0
4303,22335740,Inactivating KISS1 mutation and hypogonadotropic hypogonadism,"Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [T�B?TAK] and others.).",0
4304,22356322,Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths,"BACKGROUND: In the National Polyp Study (NPS), colorectal cancer was prevented by colonoscopic removal of adenomatous polyps. We evaluated the long-term effect of colonoscopic polypectomy in a study on mortality from colorectal cancer. METHODS: We included in this analysis all patients prospectively referred for initial colonoscopy (between 1980 and 1990) at NPS clinical centers who had polyps (adenomas and nonadenomas). The National Death Index was used to identify deaths and to determine the cause of death; follow-up time was as long as 23 years. Mortality from colorectal cancer among patients with adenomas removed was compared with the expected incidence-based mortality from colorectal cancer in the general population, as estimated from the Surveillance Epidemiology and End Results (SEER) Program, and with the observed mortality from colorectal cancer among patients with nonadenomatous polyps (internal control group). RESULTS: Among 2602 patients who had adenomas removed during participation in the study, after a median of 15.8 years, 1246 patients had died from any cause and 12 had died from colorectal cancer. Given an estimated 25.4 expected deaths from colorectal cancer in the general population, the standardized incidence-based mortality ratio was 0.47 (95% confidence interval [CI], 0.26 to 0.80) with colonoscopic polypectomy, suggesting a 53% reduction in mortality. Mortality from colorectal cancer was similar among patients with adenomas and those with nonadenomatous polyps during the first 10 years after polypectomy (relative risk, 1.2; 95% CI, 0.1 to 10.6). CONCLUSIONS: These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. (Funded by the National Cancer Institute and others.).",0
4305,22367708,Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice,"It is known that plasma phospholipid transfer protein (PLTP) activity influences lipoprotein metabolism. The liver is one of the major sites of lipoprotein production and degradation, as well as of PLTP expression. To address the impact of liver-expressed PLTP on lipoprotein metabolism, we created a mouse model that expresses PLTP in the liver acutely and specifically, with a PLTP-null background. This approach in mouse model preparations can also be used universally for evaluating the function of many other genes in the liver. We found that liver PLTP expression dramatically increases plasma levels of non-high-density lipoprotein (HDL) cholesterol (2.7-fold, P < 0.0001), non-HDL phospholipid (2.5-fold, P < 0.001), and triglyceride (51%, P < 0.01), but has no significant influence on plasma HDL lipids compared with controls. Plasma apolipoprotein (apo)B levels were also significantly increased in PLTP-expressing mice (2.2-fold, P < 0.001), but those of apoA-I were not. To explore the mechanism involved, we examined the lipidation and secretion of nascent very low-density lipoprotein (VLDL), finding that liver PLTP expression significantly increases VLDL lipidation in hepatocyte microsomal lumina, and also VLDL secretion into the plasma. CONCLUSION: It is possible to prepare a mouse model that expresses the gene of interest only in the liver, but not in other tissues. Our results suggest, for the first time, that the major function of liver PLTP is to drive VLDL production and makes a small contribution to plasma PLTP activity.",0
4306,22375972,A randomized trial of nicotine-replacement therapy patches in pregnancy,"BACKGROUND: Nicotine-replacement therapy is effective for smoking cessation outside pregnancy and its use is widely recommended during pregnancy. We investigated the efficacy and safety of nicotine patches during pregnancy. METHODS: We recruited participants from seven hospitals in England who were 16 to 50 years of age with pregnancies of 12 to 24 weeks' gestation and who smoked five or more cigarettes per day. Participants received behavioral cessation support and were randomly assigned to 8 weeks of treatment with active nicotine patches (15 mg per 16 hours) or matched placebo patches. The primary outcome was abstinence from the date of smoking cessation until delivery, as validated by measurement of exhaled carbon monoxide or salivary cotinine. Safety was assessed by monitoring for adverse pregnancy and birth outcomes. RESULTS: Of 1050 participants, 521 were randomly assigned to nicotine-replacement therapy and 529 to placebo. There was no significant difference in the rate of abstinence from the quit date until delivery between the nicotine-replacement and placebo groups (9.4% and 7.6%, respectively; unadjusted odds ratio with nicotine-replacement therapy, 1.26; 95% confidence interval, 0.82 to 1.96), although the rate was higher at 1 month in the nicotine-replacement group than in the placebo group (21.3% vs. 11.7%). Compliance was low; only 7.2% of women assigned to nicotine-replacement therapy and 2.8% assigned to placebo used patches for more than 1 month. Rates of adverse pregnancy and birth outcomes were similar in the two groups. CONCLUSIONS: Adding a nicotine patch (15 mg per 16 hours) to behavioral cessation support for women who smoked during pregnancy did not significantly increase the rate of abstinence from smoking until delivery or the risk of adverse pregnancy or birth outcomes. However, low compliance rates substantially limited the assessment of safety. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Current Controlled Trials number, ISRCTN07249128.).",0
4307,22397651,Donepezil and memantine for moderate-to-severe Alzheimer's disease,"BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).",0
4308,22436048,Familial diarrhea syndrome caused by an activating GUCY2C mutation,"BACKGROUND: Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis. METHODS: We used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells. RESULTS: We identified a heterozygous missense mutation (c.2519G?T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members. CONCLUSIONS: Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.).",0
4309,22454336,Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C,"Randomized controlled trials (RCTs) show that triple therapy (TT) with peginterferon alpha, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ribavirin dual therapy (DT) in the treatment of previously untreated patients with genotype 1 (G(1) ) chronic hepatitis C (CHC). We assessed the cost-effectiveness of TT compared to DT in the treatment of untreated patients with G(1) CHC. We created a Markov Decision Model to evaluate, in untreated Caucasian patients age 50 years, weight 70 kg, with G(1) CHC and Metavir F2 liver fibrosis score, for a time horizon of 20 years, the cost-effectiveness of the following five competing strategies: 1) boceprevir response-guided therapy (BOC-RGT); 2) boceprevir IL28B genotype-guided strategy (BOC-IL28B); 3) boceprevir rapid virologic response (RVR)-guided strategy (BOC-RVR); 4) telaprevir response-guided therapy (TVR-RGT); 5) telaprevir IL28B genotype-guided strategy (TVR-IL28B). Outcomes included life-years gained (LYG), costs (in 2011 euros) and incremental cost-effectiveness ratio (ICER). In the base-case analysis BOC-RVR and TVR-IL28B strategies were the most effective and cost-effective of evaluated strategies. LYG was 4.04 with BOC-RVR and 4.42 with TVR-IL28B. ICER compared with DT was � 8.304 per LYG for BOC-RVR and � 11.455 per LYG for TVR-IL28B. The model was highly sensitive to IL28B CC genotype, likelihood of RVR and sustained virologic response, and BOC/TVR prices. CONCLUSION: In untreated G(1) CHC patients age 50 years, TT with first-generation protease inhibitors is cost-effective compared with DT. Multiple strategies to reduce costs and improve effectiveness include RVR or genotype-guided treatment.",0
4310,22454377,Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice,"Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSCs) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (cyclin E1 [CcnE1] and cyclin E2 [CcnE2]). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homolog, CcnE2, was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wild-type (WT) livers after periodical administration of the profibrotic toxin, CCl(4). To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1(-/-) and CcnE2(-/-) knock-out mice with CCl(4) to induce liver fibrosis. Interestingly, CcnE1(-/-) mice were protected against CCl(4)-mediated liver fibrogenesis, as evidenced by reduced collagen type I ?1 expression and the lack of septum formation. In contrast, CcnE2(-/-) mice showed accelerated fibrogenesis after CCl(4) treatment. We isolated primary HSCs from WT, CcnE1(-/-), and CcnE2(-/-) mice and analyzed their activation, proliferation, and survival in vitro. CcnE1 expression in WT HSCs was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1(-/-) HSCs showed dramatically impaired survival, cell-cycle arrest, and strongly reduced expression of alpha smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSCs expressed an elevated level of CcnE1 and showed enhanced cell-cycle activity and proliferation, compared to WT cells. CONCLUSIONS: CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for the activation, proliferation, and survival of HSCs and thus promotes the synthesis of extracellular matrix and liver fibrogenesis.",0
4311,22455415,Lifestyle change and mobility in obese adults with type 2 diabetes,"BACKGROUND: Adults with type 2 diabetes mellitus often have limitations in mobility that increase with age. An intensive lifestyle intervention that produces weight loss and improves fitness could slow the loss of mobility in such patients. METHODS: We randomly assigned 5145 overweight or obese adults between the ages of 45 and 74 years with type 2 diabetes to either an intensive lifestyle intervention or a diabetes support-and-education program; 5016 participants contributed data. We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline. The primary outcome was self-reported limitation in mobility, with annual assessments for 4 years. RESULTS: At year 4, among 2514 adults in the lifestyle-intervention group, 517 (20.6%) had severe disability and 969 (38.5%) had good mobility; the numbers among 2502 participants in the support group were 656 (26.2%) and 798 (31.9%), respectively. The lifestyle-intervention group had a relative reduction of 48% in the risk of loss of mobility, as compared with the support group (odds ratio, 0.52; 95% confidence interval, 0.44 to 0.63; P<0.001). Both weight loss and improved fitness (as assessed on treadmill testing) were significant mediators of this effect (P<0.001 for both variables). Adverse events that were related to the lifestyle intervention included a slightly higher frequency of musculoskeletal symptoms at year 1. CONCLUSIONS: Weight loss and improved fitness slowed the decline in mobility in overweight adults with type 2 diabetes. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT00017953.).",0
4312,22488653,"The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver","Hepatic stellate cells (HSCs) are liver-specific mesenchymal cells that play vital roles in liver development and injury. Our knowledge of HSC biology is limited by the paucity of in vivo data. HSCs and sinusoidal endothelial cells (SECs) reside in close proximity, and interactions between these two cell types are potentially critical for their development and function. Here, we introduce a transgenic zebrafish line, Tg(hand2:EGFP), that labels HSCs. We find that zebrafish HSCs share many similarities with their mammalian counterparts, including morphology, location, lipid storage, gene-expression profile, and increased proliferation and matrix production, in response to an acute hepatic insult. Using the Tg(hand2:EGFP) line, we conducted time-course analyses during development to reveal that HSCs invade the liver after SECs do. However, HSCs still enter the liver in mutants that lack most endothelial cells, including SECs, indicating that SECs are not required for HSC differentiation or their entry into the liver. In the absence of SECs, HSCs become abnormally associated with hepatic biliary cells, suggesting that SECs influence HSC localization during liver development. We analyzed factors that regulate HSC development and show that inhibition of vascular endothelial growth factor signaling significantly reduces the number of HSCs that enter the liver. We also performed a pilot chemical screen and identified two compounds that affect HSC numbers during development. CONCLUSION: Our work provides the first comprehensive description of HSC development in zebrafish and reveals the requirement of SECs in HSC localization. The Tg(hand2:EGFP) line represents a unique tool for in vivo analysis and molecular dissection of HSC behavior.",0
4313,22505144,Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis C virus immunity,"Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection; however, distinct mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in natural killer (NK) cell populations may explain altered natural history and treatment responses. Our study cohort consisted of 29 African-American (AA; 55% male) and 29 Caucasian-American (CA; 48% male) healthy uninfected control subjects. Multiparameter flow cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine-activated killing (LAK) function. Gene expression was assessed by real-time reverse-transcriptase polymerase chain reaction after 6-hour in vitro stimulation with Toll-like receptor (TLR) ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 coculture system. NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (P = 0.0054). NKp46(high) NKs were more efficient at controlling HCV than their NKp46(low) counterparts (P < 0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 coculture (multiplicity of infection: 0.01) at an effector:target ratio of 5:1 (P < 0.005). After TLR stimulation, genes involved in cytotoxicity, but not cytokine genes, were significantly up-regulated in NKp46(high) NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46(high) NK cells have significantly higher interferon-gamma production than NKp46(low) cells. TLR stimulation significantly induced degranulation as well as tumor necrosis factor alpha (TNF-?)-related apoptosis-inducing ligand, Fas, and TNF-? protein expression in NKp46(high) NKs. NKp46 ligand was induced on HCV-infected hepatocytes. CONCLUSIONS: NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target.",0
4314,22505286,Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents,"Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P?2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P?2-/- mice. CONCLUSION: S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension.",0
4315,22508288,Recruitment mechanisms of primary and malignant B cells to the human liver,"B cells are present within chronically inflamed liver tissue and recent evidence implicates them in the progression of liver disease. In addition, a large proportion of hepatic lymphomas are of B-cell origin. The molecular signals that regulate normal and malignant B-cell recruitment into peripheral tissue from blood are poorly understood, leading us to study human B-cell migration through hepatic sinusoidal endothelial cells in flow-based adhesion assays. In such assays, human blood-derived B cells were captured from shear flow without a previous rolling phase and underwent firm adhesion mediated by vascular cell adhesion molecule-1 (VCAM-1). Unlike T cells, which displayed vigorous crawling behavior on the endothelium, B cells remained static before a proportion underwent transendothelial migration mediated by a combination of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion protein-1, common lymphatic endothelial and vascular endothelial receptor-1/stabilin-1, and the chemokine receptors, CXCR3 and CXCR4. B-cell lymphoma cell lines and primary malignant B cells from patients with chronic lymphocytic leukemia and marginal zone B cell lymphoma also underwent integrin-mediated firm adhesion involving ICAM-1 and/or VCAM-1 and demonstrated ICAM-1-dependent shape-change and crawling behavior. Unlike primary lymphocytes, the malignant cells did not undergo transendothelial migration, which could explain why lymphomas are frequently characterized by the intravascular accumulation of malignant cells in the hepatic sinusoids. CONCLUSION: Our findings demonstrate that distinct combinations of signals promote B-cell recruitment to the liver, suggesting the possibility of novel targets to modulate liver inflammation in disease. Certain features of lymphocyte homing are maintained in lymphoma recruitment to the liver, suggesting that therapeutic targets for lymphocyte recruitment may also prevent hepatic lymphoma dissemination.",0
4316,22512483,"Integrin ?3 mutations with kidney, lung, and skin disease","Integrin ?(3) is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin ?(3) gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis.",0
4317,22532369,Protein arginine methyltransferase 1 regulates hepatic glucose production in a FoxO1-dependent manner,"Postprandial insulin plays a critical role in suppressing hepatic glucose production to maintain euglycemia in mammals. Insulin-dependent activation of protein kinase B (Akt) regulates this process, in part, by inhibiting FoxO1-dependent hepatic gluconeogenesis by direct phosphorylation and subsequent cytoplasmic exclusion. Previously, it was demonstrated that protein arginine methyltransferase 1 (PRMT1)-dependent arginine modification of FoxO1 interferes with Akt-dependent phosphorylation, both in cancer cells and in the Caenorhabditis elegans model, suggesting that this additional modification of FoxO1 might be critical in its transcriptional activity. In this study, we attempted to directly test the effect of arginine methylation of FoxO1 on hepatic glucose metabolism. The ectopic expression of PRMT1 enhanced messenger RNA levels of FoxO1 target genes in gluconeogenesis, resulting in increased glucose production from primary hepatocytes. Phosphorylation of FoxO1 at serine 253 was reduced with PRMT1 expression, without affecting the serine 473 phosphorylation of Akt. Conversely, knockdown of PRMT1 promoted an inhibition of FoxO1 activity and hepatic gluconeogenesis by enhancing the phosphorylation of FoxO1. In addition, genetic haploinsufficiency of Prmt1 reduced hepatic gluconeogenesis and blood-glucose levels in mouse models, underscoring the importance of this factor in hepatic glucose metabolism in vivo. Finally, we were able to observe an amelioration of the hyperglycemic phenotype of db/db mice with PRMT1 knockdown, showing a potential importance of this protein as a therapeutic target for the treatment of diabetes. CONCLUSION: Our data strongly suggest that the PRMT1-dependent regulation of FoxO1 is critical in hepatic glucose metabolism in vivo.",0
4318,22535707,Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice,"Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein ? (SIRP?) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRP? polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-?RAG/?(c) -uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. CONCLUSION: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization.",0
4319,22544759,CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice,"Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and ?-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. CONCLUSION: Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.",0
4320,22544812,Pericentral activity of alpha-fetoprotein enhancer 3 and glutamine synthetase upstream enhancer in the adult liver are regulated by ?-catenin in mice,"We previously showed that mouse alpha-fetoprotein (AFP) enhancer 3 activity is highly restricted to pericentral hepatocytes in the adult liver. Here, using transgenic mice, we show that the upstream enhancer of the rat glutamine synthetase gene is also active, specifically in pericentral regions. Activity of both enhancers is lost in the absence of ?-catenin, a key regulator of zonal gene expression in the adult liver. Both enhancers contain a single, highly conserved T-cell factor/lymphoid enhancer factor binding site that is required for responsiveness to ?-catenin. We also show that endogenous AFP messenger RNA levels in the perinatal liver are lower when ?-catenin is reduced. CONCLUSION: These data identify the first distinct zonally active regulatory regions required for ?-catenin responsiveness in the adult liver, and suggest that postnatal AFP repression and the establishment of zonal regulation are controlled, at least in part, by the same factors.",0
4321,22577043,Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection,"To comprehensively characterize the contribution of virological factors as well as interleukin-28B (IL28B) single-nucleotide polymorphisms (SNPs) in determining treatment responses in pegylated-interferon plus ribavirin (Peg-IFN/RBV) therapy for chronic hepatitis C virus (HCV)-1b infection, we undertook a retrospective cohort analysis for the pretreatment dominant complete HCV open reading frame (ORF) amino-acid (aa) sequence study in 103 consecutive HCV-1b Japanese patients. The dominant HCV sequences classified by the response were subjected to systematic sliding-window comparison analysis to characterize response-specific viral sequences, along with IL28B SNP analyses (rs8099917). In each comparison of the patients between with and without rapid viral response (RVR), nonearly viral response (nEVR), sustained virological response (SVR), or relapse, the following regions were extracted as most significantly associated with the different responses respectively: nonstructural protein 5A (NS5A) aa.2224-2248 (P = 1.2E-07); core aa.70 (P = 4E-04); NS5A aa.2340-2382 (P = 7.0E-08); and NS5A aa.2360-2377 (P = 1.1E-05). Those NS5A regions nearly coincided with the interferon (IFN) sensitivity-determining region (NS5A aa.2209-2248) and the IFN/RBV resistance-determining region (NS5A aa.2339-2379). In a multivariate analysis, the IL28B SNP (odds ratio [OR] = 16.8; P = 0.009) and NS5A aa.2340-2382 (OR = 13.8; P = 0.0003) were extracted as the two most-significant independent variables contributing to the final outcome. CONCLUSION: In Peg-IFN/RBV therapy, polymorphisms in IL28B, NS5A aa.2224-2248, core aa.70, and, most important, NS5A aa.2340-2382 have a tremendous influence on treatment response in association with viral kinetics, resulting in significantly different outcomes in chronic HCV-1b infection.",0
4322,22577054,CD81/CD9 tetraspanins aid plasmacytoid dendritic cells in recognition of hepatitis C virus-infected cells and induction of interferon-alpha,"Recognition of hepatitis C virus (HCV)-infected hepatocyes and interferon (IFN) induction are critical in antiviral immune response. We hypothesized that cell-cell contact between plasmacytoid dendritic cells (pDCs) and HCV-infected cells was required for IFN-? induction through the involvement of cell-surface molecules. Coculture of human peripheral blood mononuclear cells (PBMCs) with genotype 1a full-length (FL) HCV genomic replicon cells or genotype 2a Japanese fulminant hepatitis type 1 (JFH-1) virus-infected hepatoma cells (JFH-1), and not with uninfected hepatoma cells (Huh7.5), induced IFN-? production. Depletion of pDCs from PBMCs attenuated IFN-? release, and purified pDCs produced high levels of IFN-? after coculture with FL replicons or JFH-1-infected cells. IFN-? induction by HCV-containing hepatoma cells required viral replication, direct cell-cell contact with pDCs, and receptor-mediated endocytosis. We determined that the tetraspanin proteins, CD81 and CD9, and not other HCV entry receptors, were required for IFN-? induction in pDCs by HCV-infected hepatoma cells. Disruption of cholesterol-rich membrane microdomains, the localization site of CD81, or inhibition of the CD81 downstream molecule, Rac GTPase, inhibited IFN-? production. IFN-? induction involved HCV RNA and Toll-like receptor (TLR) 7. IFN-? production by HCV-infected hepatoma cells was decreased in pDCs from HCV-infected patients, compared to healthy controls. We found that preexposure of healthy PBMCs to HCV viral particles attenuated IFN-? induction by HCV-infected hepatoma cells or TLR ligands, and this inhibitory effect could be prevented by an anti-HCV envelope glycoprotein 2-blocking antibody. CONCLUSION: Our novel data show that recognition of HCV-infected hepatoma cells by pDCs involves CD81- and CD9-associated membrane microdomains and induces potent IFN-? production.",0
4323,22607134,"Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis","BACKGROUND: A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown. METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period. RESULTS: When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here. CONCLUSIONS: Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.).",0
4324,22607135,Effect of estrogen on pseudomonas mucoidy and exacerbations in cystic fibrosis,"BACKGROUND: Women with cystic fibrosis are at increased risk for mucoid conversion of Pseudomonas aeruginosa, which contributes to a sexual dichotomy in disease severity. METHODS: We evaluated the effects of estradiol and its metabolite estriol on P. aeruginosa in vitro and in vivo and determined the effect of estradiol on disease exacerbations in women with cystic fibrosis. RESULTS: Estradiol and estriol induced alginate production in P. aeruginosa strain 01 and in clinical isolates obtained from patients with and those without cystic fibrosis. After prolonged exposure to estradiol, P. aeruginosa adopted early mucoid morphology, whereas short-term exposure inhibited bacterial catalase activity and increased levels of hydrogen peroxide, which is potentially damaging to DNA. Consequently, a frameshift mutation was identified in mucA, a key regulator of alginate biosynthesis in P. aeruginosa. In vivo levels of estradiol correlated with infective exacerbations in women with cystic fibrosis, with the majority occurring during the follicular phase (P<0.05). A review of the Cystic Fibrosis Registry of Ireland revealed that the use of oral contraceptives was associated with a decreased need for antibiotics. Predominantly nonmucoid P. aeruginosa was isolated from sputum during exacerbations in the luteal phase (low estradiol). Increased proportions of mucoid bacteria were isolated during exacerbations occurring in the follicular phase (high estradiol), with a variable P. aeruginosa phenotype evident in vivo during the course of the menstrual cycle corresponding to fluctuating estradiol levels. CONCLUSIONS: Estradiol and estriol induced mucoid conversion of P. aeruginosa in women with cystic fibrosis through a mutation of mucA in vitro and were associated with selectivity for mucoid isolation, increased exacerbations, and mucoid conversion in vivo. (Funded by the Molecular Medicine Ireland Clinician-Scientist Fellowship Programme.).",0
4325,22610658,Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection,"Hepatitis C virus (HCV) infection increases total healthcare costs but the effect of the severity of liver disease associated with chronic hepatitis C (CHC) on healthcare costs has not been well studied. We analyzed the demographics, healthcare utilization, and healthcare costs of CHC patients in a large U.S. private insurance database (January, 2002 to August, 2010), with at least 1 year of baseline enrollment and 30 days of continuous follow-up. Patients were stratified by liver disease severity: noncirrhotic liver disease (NCD), compensated cirrhosis (CC), and endstage liver disease (ESLD), as defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) codes. Mean all-cause and HCV-related healthcare costs per-patient-per-month (PPPM) during follow-up (mean 634 days) are reported in 2010 U.S.$ from the payer's perspective. A total of 53,796 patients with CHC were included (NCD: 41,858 [78%]; CC: 3,718 [7%]; and ESLD: 8,220 [15%]). Mean all-cause PPPM healthcare costs were 32% and 247% higher for patients with CC and ESLD compared to those with NCD ($1,870 and $4,931 versus $1,420; P < 0.001) and were independent of age or comorbid conditions. Pharmacy, ambulatory, and inpatient care collectively accounted for 90% of NCD costs and 93% of CC and ESLD costs. The largest cost components were inpatient costs for those with ESLD (56%) and ambulatory costs for those with CC and NCD (37% and 36%, respectively). Overall, 56% of costs were HCV-related and this proportion increased with severity (46%, 57%, and 71% for patients with NCD, CC, and ESLD, respectively). CONCLUSION: The direct healthcare costs associated with CHC are high, increase in association with the progression of liver disease, and are highest in those with ESLD.",0
4326,22610885,Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C,"Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after antiviral treatment in hepatitis C virus (HCV) difficult-to-treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of antiviral responses in patients affected by chronic hepatitis C. In all, 206 HCV patients treated with a combination therapy of pegylated (PEG)-interferon plus ribavirin were retrospectively evaluated. GC rs7041 G>T, GC rs4588 C>A, and IL-28B rs12979860 C>T polymorphisms were genotyped. Frequencies of GC rs7041 G>T and rs4588 C>A polymorphisms were: G/G = 64 (31.1%), G/T = 100 (48.5%), T/T = 42 (20.4%) and C/C = 108 (52.4%), C/A = 84 (40.8%), A/A = 14 (6.8%). Patients were divided into those carrying ?3 major alleles (wildtype [WT]+: G-C/G-C, G-C/T-C, G-C/G-A, N = 100) and the remaining (WT-: G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N = 106). Four groups were identified: vitamin D ?20 ng/mL and WT-, vitamin D ?20 and WT+, vitamin D >20 and WT-, vitamin D >20 and WT+. In difficult-to-treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (P = 0.003). At multivariate analysis, having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (odds ratio 4.52, P = 0.015). CONCLUSION: In difficult-to-treat HCV genotypes, simultaneous pretreatment normal serum vitamin D levels and the carriage of GC-globulin WT isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy.",0
4327,22610996,Tracing hepatitis B virus to the 16th century in a Korean mummy,"A rare find of a mummified child from the 16th century AD, in Korea, with relatively preserved organs, enabled a search for ancient hepatitis B virus (aHBV) DNA sequences from laparoscopic-derived liver biopsies. Analysis of the complete aHBV genome (3,215 base pairs) revealed a unique HBV genotype C2 (HBV/C2) sequence commonly spread in Southeast Asia, which probably represents an HBV that infected the Joseon Dynasty population in Korea. Comparison of the aHBV sequences with contemporary HBV/C2 DNA sequences revealed distinctive differences along four open reading frames. Genetic diversity between contemporary and recovered aHBV/C2 DNA may be the result of immunologic, environmental, and/or pharmacologic pressures. The calculated time of most recent common ancestor suggests that the Korean HBV sequence origin dates back at least 3,000 years and possibly as long as 100,000 years. This isolate most likely represents the earliest human HBV sequence that colonized Southeast Asia by human migration. CONCLUSION: This study describes the complete sequence of the oldest HBV isolate and the most ancient full viral genome known so far.",0
4328,22611008,Megakaryocytes promote hepatoepithelial liver cell development in E11.5 mouse embryos by cell-to-cell contact and by vascular endothelial growth factor A signaling,"In the mouse embryo, hematopoietic progenitor cells migrate to the fetal liver (FL) between gestational days (E) 9.5 and 10.5, where they rapidly expand to form the main fetal reservoir of hematopoietic cells. The embryonic megakaryocyte progenitors (MKPs) in the E11.5 FL were identified as CD49f(H) CD41(H) (and c-Kit(D)KDR(+)CD42(+)CD9(++)CD31(+)) cells, expressing several hepato-specific proteins. Unlike adult bone marrow megakaryocytes (MKs), embryonic MKPs were CD45(-) and represent an abundant population in the FL. The CD49f(H)CD41(H) MKPs purified by cytometry differentiated in vitro to produce proplatelets, independent of thrombopoietin stimulation, and they responded to stimulation with adenosine diphosphate, thrombin, and the PAR4 thrombin receptor-activating peptide. Moreover, after removing CD49f(H)CD41(H) MKPs from purified E11.5 FL hepatoepithelial-enriched cell preparations (c-Kit(D)CD45(-)Ter119(-)), the remaining CD49f(D) cells neither differentiated nor survived in vitro. Indeed, direct cell-to-cell contact between the CD49f(H) CD41(H) and CD49f(D) populations was required to promote the hepatocyte differentiation of CD49f(D) cells. The addition of vascular endothelial growth factor A (VEGF-A) and medium conditioned by E11.5 CD49f(H)CD41(H) MKPs produced a partial effect on CD49f(D) cells, inducing the formation of hepatoepithelial layers. This effect was abolished by anti-VEGF-A antibodies. Together, these findings strongly suggest that CD49f(H)CD41(H) MKPs are fundamental to promote FL development, as proposed in adult liver regeneration. CONCLUSION: The cells of the MK lineage present in the developing mouse embryo liver promote the growth of hepatoepithelial cells in vitro through VEGF-A signaling and may play a role in liver development in vivo.",0
4329,22693997,Thrombotic stroke and myocardial infarction with hormonal contraception,"BACKGROUND: Although several studies have assessed the risk of venous thromboembolism with newer hormonal contraception, few have examined thrombotic stroke and myocardial infarction, and results have been conflicting. METHODS: In this 15-year Danish historical cohort study, we followed nonpregnant women, 15 to 49 years old, with no history of cardiovascular disease or cancer. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from four national registries. RESULTS: A total of 1,626,158 women contributed 14,251,063 person-years of observation, during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 ?g was associated with the following relative risks (and 95% confidence intervals) for thrombotic stroke and myocardial infarction, according to progestin type: norethindrone, 2.2 (1.5 to 3.2) and 2.3 (1.3 to 3.9); levonorgestrel, 1.7 (1.4 to 2.0) and 2.0 (1.6 to 2.5); norgestimate, 1.5 (1.2 to 1.9) and 1.3 (0.9 to 1.9); desogestrel, 2.2 (1.8 to 2.7) and 2.1 (1.5 to 2.8); gestodene, 1.8 (1.6 to 2.0) and 1.9 (1.6 to 2.3); and drospirenone, 1.6 (1.2 to 2.2) and 1.7 (1.0 to 2.6), respectively. With ethinyl estradiol at a dose of 20 ?g, the corresponding relative risks according to progestin type were as follows: desogestrel, 1.5 (1.3 to 1.9) and 1.6 (1.1 to 2.1); gestodene, 1.7 (1.4 to 2.1) and 1.2 (0.8 to 1.9); and drospirenone, 0.9 (0.2 to 3.5) and 0.0. For transdermal patches, the corresponding relative risks were 3.2 (0.8 to 12.6) and 0.0, and for a vaginal ring, 2.5 (1.4 to 4.4) and 2.1 (0.7 to 6.5). CONCLUSIONS: Although the absolute risks of thrombotic stroke and myocardial infarction associated with the use of hormonal contraception were low, the risk was increased by a factor of 0.9 to 1.7 with oral contraceptives that included ethinyl estradiol at a dose of 20 ?g and by a factor of 1.3 to 2.3 with those that included ethinyl estradiol at a dose of 30 to 40 ?g, with relatively small differences in risk according to progestin type. (Funded by the Danish Heart Association.).",0
4330,22693998,Rapid whole-genome sequencing for investigation of a neonatal MRSA outbreak,"""BACKGROUND: Isolates of methicillin-resistant Staphylococcus aureus (MRSA) belonging to a single lineage are often indistinguishable by means of current typing techniques. Whole-genome sequencing may provide improved resolution to define transmission pathways and characterize outbreaks. METHODS: We investigated a putative MRSA outbreak in a neonatal intensive care unit. By using rapid high-throughput sequencing technology with a clinically relevant turnaround time, we retrospectively sequenced the DNA from seven isolates associated with the outbreak and another seven MRSA isolates associated with carriage of MRSA or bacteremia in the same hospital. RESULTS: We constructed a phylogenetic tree by comparing single-nucleotide polymorphisms (SNPs) in the core genome to a reference genome (an epidemic MRSA clone, EMRSA-15 [sequence type 22]). This revealed a distinct cluster of outbreak isolates and clear separation between these and the nonoutbreak isolates. A previously missed transmission event was detected between two patients with bacteremia who were not part of the outbreak. We created an artificial """"resistome"""" of antibiotic-resistance genes and demonstrated concordance between it and the results of phenotypic susceptibility testing; we also created a """"toxome"""" consisting of toxin genes. One outbreak isolate had a hypermutator phenotype with a higher number of SNPs than the other outbreak isolates, highlighting the difficulty of imposing a simple threshold for the number of SNPs between isolates to decide whether they are part of a recent transmission chain. CONCLUSIONS: Whole-genome sequencing can provide clinically relevant data within a time frame that can influence patient care. The need for automated data interpretation and the provision of clinically meaningful reports represent hurdles to clinical implementation. (Funded by the U.K. Clinical Research Collaboration Translational Infection Research Initiative and others.).""",0
4331,22706730,High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials,"The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment-naive HCV monoinfected patients (N = 7,163) age ? 18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country-specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow-up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3-50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4-71.7%), 68.4% (95% CI: 65.7-71.0%), and 60.3% (95% CI: 58.5-62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8-86.5%), 76.3% (95% CI: 73.3-79.1%), and 74.2% (95% CI: 71.3-76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1-73.1%), 67.3% (95% CI: 64.2-70.3%), and 63.8% (95% CI: 61.0-66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6-76.3%), 63.3% (95% CI: 54.3-71.6%), and 54.3% (95% CI: 47.5-60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. CONCLUSION: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype.",0
4332,22716977,Thrombosis from a prothrombin mutation conveying antithrombin resistance,"We identified a novel mechanism of hereditary thrombosis associated with antithrombin resistance, with a substitution of arginine for leucine at position 596 (p.Arg596Leu) in the gene encoding prothrombin (called prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild-type prothrombin in clotting assays, but the formation of thrombin-antithrombin complex was substantially impaired. A thrombin-generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of-function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis.",0
4333,22744635,Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates,"Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cancer development. HBV encodes the hepatitis B virus X (HBx) protein that promotes transcription of the viral episomal DNA genome by the host cell RNA polymerase II. Here we provide evidence that HBx accomplishes this task by a conserved and unusual mechanism. Thus, HBx strongly stimulates expression of transiently transfected reporter constructs, regardless of the enhancer and promoter sequences. This activity invariably requires HBx binding to the cellular UV-damaged DDB1 E3 ubiquitin ligase, suggesting a common mechanism. Unexpectedly, none of the reporters tested is stimulated by HBx when integrated into the chromosome, despite remaining responsive to their cognate activators. Likewise, HBx promotes gene expression from the natural HBV episomal template but not from a chromosomally integrated HBV construct. The same was observed with the HBx protein of woodchuck HBV. HBx does not affect nuclear plasmid copy number and functions independently of CpG dinucleotide methylation. CONCLUSION: We propose that HBx supports HBV gene expression by a conserved mechanism that acts specifically on episomal DNA templates independently of the nature of the cis-regulatory sequences. Because of its uncommon property and key role in viral transcription, HBx represents an attractive target for new antiviral therapies.",0
4334,22762315,Estimating glomerular filtration rate from serum creatinine and cystatin C,"BACKGROUND: Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. METHODS: Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. RESULTS: Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). CONCLUSIONS: The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).",0
4335,22784115,Potassium channel KIR4.1 as an immune target in multiple sclerosis,"BACKGROUND: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. METHODS: We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS: Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. CONCLUSIONS: KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.).",0
4336,22806357,Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent,"Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) generates reactive oxygen species (ROS) in hepatic stellate cells (HSCs) during liver fibrosis. In response to fibrogenic agonists, such as angiotensin II (Ang II), the NOX1 components form an active complex, including Ras-related botulinum toxin substrate 1 (Rac1). Superoxide dismutase 1 (SOD1) interacts with the NOX-Rac1 complex to stimulate NOX activity. NOX4 is also induced in activated HSCs/myofibroblast by increased gene expression. Here, we investigate the role of an enhanced activity SOD1 G37R mutation (SODmu) and the effects of GKT137831, a dual NOX1/4 inhibitor, on HSCs and liver fibrosis. To induce liver fibrosis, wild-type (WT) and SOD1mu mice were treated with CCl(4) or bile duct ligation (BDL). Then, to address the role of NOX-SOD1-mediated ROS production in HSC activation and liver fibrosis, mice were treated with a NOX1/4 inhibitor. Fibrosis and ROS generation was assessed by histology and measurement of thiobarbituric acid reactive substances and NOX-related genes. Primary cultured HSCs isolated from WT, SODmu, and NOX1 knockout (KO) mice were assessed for ROS production, Rac1 activity, and NOX gene expression. Liver fibrosis was increased in SOD1mu mice, and ROS production and Rac1 activity were increased in SOD1mu HSCs. The NOX1/4 inhibitor, GKT137831, attenuated liver fibrosis and ROS production in both SOD1mu and WT mice as well as messenger RNA expression of fibrotic and NOX genes. Treatment with GKT137831 suppressed ROS production and NOX and fibrotic gene expression, but not Rac1 activity, in SOD1mut and WT HSCs. Both Ang II and tumor growth factor beta up-regulated NOX4, but Ang II required NOX1. CONCLUSIONS: SOD1mu induces excessive NOX1 activation through Rac1 in HSCs, causing enhanced NOX4 up-regulation, ROS generation, and liver fibrosis. Treatment targeting NOX1/4 may be a new therapy for liver fibrosis.",0
4337,22806577,Simultaneous knockdown of multiple ligands of innate receptor NKG2D prevents natural killer cell-mediated fulminant hepatitis in mice,"NKG2D activation plays an important role in initiating and maintaining liver inflammation, and blockade of NKG2D recognition becomes a promising approach to alleviate liver inflammation. Treatment by silencing NKG2D ligands on hepatocytes, but not NKG2D on circulating immune cells, is more liver-specific, and simultaneous knockdown of multiple NKG2D ligands on hepatocytes will be more efficient in liver disease intervention. Here, we constructed a single vector that could simultaneously express multiple short hairpin RNAs (shRNAs) against all murine NKG2D ligands including Rae1, Mult1, and H60. After hydrodynamic injection of plasmid containing the three shRNA sequences (shRae1-shMult1-shH60), also called pRNAT-shRMH, we found the expression of all three NKG2D ligands on hepatocytes was downregulated both on messenger RNA and protein levels. Moreover, natural killer (NK) cell-mediated NKG2D-dependent fulminant hepatitis of the mice was alleviated, along with inactivation of hepatic NK cells, by pRNAT-shRMH if compared with its counterpart RNA interference vectors against single or double ligands. The therapeutic efficacy of pRNAT-shRMH was equivalent to that of injecting three monoclonal antibodies against Rae1, Mult1, and H60. For better in vivo application, we constructed a recombinant adenovirus containing pRNAT-shRMH (called Ad-RMH) with efficient hepatotropic infection capacity and observed that Ad-RMH intravenous injection exerted a similar therapeutic efficiency as plasmid pRNAT-shRMH hydrodynamic injection. Noticeably, simultaneous knockdown of multiple human NKG2D ligands (MICA/B, ULBP2, and ULBP3) also significantly attenuated NK cell cytolysis against human NKG2D ligand-positive hepatocyte L-02 cells, suggesting a possible translation into human settings. CONCLUSION: Simultaneous knockdown of multiple ligands of NKG2D prevents NK cell-mediated fulminant hepatitis and is a potential therapeutic approach to treat liver diseases.",0
4338,22806830,Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis,"Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGF?, produced by HCV-specific CD8(+) T cells, is a key regulatory cytokine modulating HCV-specific effector T cells. Here we studied TGF? as well as other factors produced by HCV-specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross-sectional study of two well-defined groups of HCV-infected subjects with slow (? 0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV-specific T-cell responses were studied using interferon-gamma (IFN?)-ELISpot �monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme-linked immunosorbent assay (ELISA) and multiparameter fluorescence-activated cell sorting (FACS). The effects of IHL stimulated with HCV-core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV-specific effector (IFN?) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV-specific IFN? responses strongly correlated with HCV-specific TGF?, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV-specific IL-10. HCV-specific TGF? was produced by CD8 and CD4 T cells. HCV-specific TGF?, not interleukin (IL)-10, inversely correlated with liver inflammation (R = -0.63, P = 0.008) and, unexpectedly, fibrosis (R = -0.46, P = 0.05). In addition, supernatants from HCV-stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti-TGF? mAb abrogated such expression. CONCLUSION: Although TGF? is considered a major profibrogenic cytokine, local production of TGF? by HCV-specific T cells appeared to have a protective role in HCV-infected liver, together with other T-cell-derived factors, ameliorating HCV liver disease progression.",0
4339,22807038,PTEN-mediated Akt/?-catenin/Foxo1 signaling regulates innate immune responses in mouse liver ischemia/reperfusion injury,"The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates innate immune responses inversely with phosphoinositide 3-kinase (PI3K) and its direct downstream target gene, Akt. The Forkhead box O (Foxo) transcription factors are essential in the regulation of tissue development, immune homeostasis, and cell survival. This study was designed to investigate the role of PTEN-mediated Akt/?-catenin/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in a mouse model of hepatic inflammatory injury induced by 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion. We found that knockdown of PTEN with small interfering RNA (siRNA) promoted Akt/?-catenin/Foxo1 signaling, leading to resistance against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic function, and downregulation of innate Toll-like receptor 4 (TLR4) expression. A specific PI3K blockade inhibited Akt/?-catenin signaling, increased Foxo1-mediated TLR4-driven local inflammation, and recreated cardinal features of liver IR injury. Moreover, knockdown of PTEN in lipopolysaccharide-stimulated mouse bone marrow-derived macrophages enhanced ?-catenin activity, which in turn provided a negative regulatory feedback to the Foxo1 function, leading to the inhibition of TLR4 and NF-?B, with ultimate depression of proinflammatory cytokine programs in vitro. CONCLUSION: Our novel findings identify the PTEN-mediated Akt/?-catenin/Foxo1 axis as a key regulator of innate inflammatory response in the mouse liver. By identifying molecular mechanisms of PTEN-mediated Akt/?-catenin/Foxo1 signaling in TLR4 innate immune regulation, our study provides a rationale for therapeutic approaches to manage inflammation injury in IR-stressed liver.",0
4340,22807119,"Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid","Protein tyrosine phosphatase 1B (PTP1B) inhibits hepatic insulin signaling by dephosphorylating tyrosine residues in insulin receptor (IR) and insulin receptor substrate (IRS). MicroRNAs may modulate metabolic functions. In view of the lack of understanding of the regulatory mechanism of PTP1B and its chemical inhibitors, this study investigated whether dysregulation of specific microRNA causes PTP1B-mediated hepatic insulin resistance, and if so, what the underlying basis is. In high-fat-diet-fed mice or hepatocyte models with insulin resistance, the expression of microRNA-122 (miR-122), the most abundant microRNA in the liver, was substantially down-regulated among those predicted to interact with the 3'-untranslated region of PTP1B messenger RNA (mRNA). Experiments using miR-122 mimic and its inhibitor indicated that miR-122 repression caused PTP1B induction. Overexpression of c-Jun N-terminal kinase 1 (JNK1) resulted in miR-122 down-regulation with the induction of PTP1B. A dominant-negative mutant of JNK1 had the opposite effect. JNK1 facilitated inactivating phosphorylation of hepatocyte nuclear factor 4? (HNF4?) responsible for miR-122 expression, as verified by the lack of HNF4? binding to the gene promoter. The regulatory role of JNK1 in PTP1B induction by a decrease in miR-122 level was strengthened by cell-based assays using isoliquiritigenin and liquiritigenin (components in Glycyrrhizae radix) as functional JNK inhibitors; JNK inhibition enabled cells to restore IR and IRS1/2 tyrosine phosphorylation and insulin signaling against tumor necrosis factor alpha, and prevented PTP1B induction. Moreover, treatment with each of the agents increased miR-122 levels and abrogated hepatic insulin resistance in mice fed a high-fat diet, causing a glucose-lowering effect. CONCLUSION: Decreased levels of miR-122 as a consequence of HNF4? phosphorylation by JNK1 lead to hepatic insulin resistance through PTP1B induction, which may be overcome by chemical inhibition of JNK.",0
4341,22808957,Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection,"BACKGROUND: Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood. METHODS: We analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution. RESULTS: The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection. CONCLUSIONS: Our results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency-Swedish Agency for Research Cooperation with Developing Countries and others.).",0
4342,22814930,CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-Jun N terminal kinase activation independent from the interferon pathway,"CD40, a member of the tumor necrosis factor receptor family, and its ligand, CD40L (CD154), are important regulators of the antiviral immune response. CD40L is up-regulated on lymphocytes and CD40 on hepatocytes during infection with hepatitis C virus (HCV); we investigated the role of CD40 signaling during HCV replication in hepatocytes. Viral replication was studied in primary human hepatocytes (PHH) and Huh7.5 cells using the infectious HCV Japanese fulminate hepatitis 1 isolate (JFH1) culture system, and in coculture with HCV antigen-specific CD8+ T cells. CD40L rapidly and transiently inhibits expression of the HCV nonstructural proteins NS3 and NS5A as well as HCV structural proteins core and E2 in Huh7.5 cells. Similarly, CD40L prevented replication of HCV in PHH, in synergy with interferon (IFN)-alpha. In Huh7.5 cells with replicating HCV, CD40L prevented production of infectious viral particles. When HCV antigen-specific CD8+ T cells were cocultured with HLA-A2-expressing Huh7 cells that had replicating virus, the T cells became activated, up-regulated CD40L, and inhibited HCV replication. Inhibition of CD40L partially prevented the antiviral activity of the CD8+ T cells. The antiviral effect of CD40L required activation of c-Jun N terminal kinases (JNK)1/2, but not induction of apoptosis or the JAK/STAT pathway that is necessary for the antiviral effects of IFNs. CONCLUSION: CD40 inhibits HCV replication by a novel, innate immune mechanism. This pathway might mediate viral clearance, and disruptions might be involved in the pathogenesis of HCV infection.",0
4343,22894572,Quality-of-life effects of prostate-specific antigen screening,"BACKGROUND: After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. METHODS: On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. RESULTS: Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). CONCLUSIONS: The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.).",0
4344,22894598,Clinical decisions. Screening for prostate cancer,"This interactive feature addresses the diagnosis or management of a clinical case. A case vignette is followed by specific clinical options, neither of which can be considered either correct or incorrect. In short essays, experts in the field then argue for each of the options. Readers can participate in forming community opinion by choosing one of the options and, if they like, providing their reasons.",0
4345,22898823,Differentiated umbilical cord matrix stem cells as a new in vitro model to study early events during hepatitis B virus infection,"The role of cell differentiation state on hepatitis B virus (HBV) replication has been well demonstrated, whereas how it determines cell susceptibility to HBV entry is far less understood. We previously showed that umbilical cord matrix stem cells (UCMSC) can be differentiated towards hepatocyte-like cells in vitro. In this study we infected undifferentiated (UD-) and differentiated (D-) UCMSCs with HBV and studied the infection kinetics, comparing them to primary human hepatocytes (PHHs). UD-UCMSCs, although permissive to viral binding, had a very limited uptake capacity, whereas D-UCMSCs showed binding and uptake capabilities similar to PHHs. Likewise, asialoglycoprotein receptor (ASGPR) was up-regulated in UCMSCs upon differentiation. In D-UCMSCs, a dose-dependent inhibition of HBV binding and uptake was observed when ASGPR was saturated with known specific ligands. Subsequent viral replication was shown in D-UCMSCs but not in UD-UCMSCs. Susceptibility of UCMSCs to viral replication correlated with the degree of differentiation. Replication efficiency was low compared to PHHs, but was confirmed by (1) a dose-dependent inhibition by specific antiviral treatment using tenofovir; (2) the increase of viral RNAs along time; (3) de novo synthesis of viral proteins; and (4) secretion of infectious viral progeny. CONCLUSION: UCMSCs become supportive of the entire HBV life cycle upon in vitro hepatic differentiation. Despite low replication efficiency, D-UCMSCs proved to be fully capable of HBV uptake. Overall, UCMSCs are a unique human, easily available, nontransformed, in vitro model of HBV infection that could prove useful to study early infection events and the role of the cell differentiation state on such events.",0
4346,22911490,Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes,"Sphingolipids are important structural components of cell membranes and act as critical regulators of cell function by modulating intracellular signaling pathways. Specific sphingolipids, such as ceramide, glucosylceramide, and ganglioside GM3, have been implicated in various aspects of insulin resistance, because they have been shown to modify several steps in the insulin signaling pathway, such as phosphorylation of either protein kinase B (Akt) or of the insulin receptor. We now explore the role of the ceramide acyl chain length in insulin signaling by using a ceramide synthase 2 (CerS2) null mouse, which is unable to synthesize very long acyl chain (C22-C24) ceramides. CerS2 null mice exhibited glucose intolerance despite normal insulin secretion from the pancreas. Both insulin receptor and Akt phosphorylation were abrogated in liver, but not in adipose tissue or in skeletal muscle. The lack of insulin receptor phosphorylation in liver correlated with its inability to translocate into detergent-resistant membranes (DRMs). Moreover, DRMs in CerS2 null mice displayed properties significantly different from those in wild-type mice, suggesting that the altered sphingolipid acyl chain length directly affects insulin receptor translocation and subsequent signaling. CONCLUSION: We conclude that the sphingolipid acyl chain composition of liver regulates insulin signaling by modifying insulin receptor translocation into membrane microdomains.",0
4347,22915897,Prolonged nerve blockade in a patient treated with lithium,"We report a case of a patient, chronically treated with oral lithium, who presented with an extremely prolonged (42-hour) duration of sensory and motor paralysis following an uneventful infraclavicular block for hand surgery that was performed under ultrasound guidance using bupivacaine and lidocaine. Due to its direct effect on nerve conduction of action potential, we propose that lithium may have had a role in the unusually prolonged duration of a peripheral nerve block. ",0
4348,22915918,Prefilled certolizumab pegol (Cimzia(®)) syringes for self-use in the treatment of rheumatoid arthritis,"A new anti-tumor necrosis factor alpha (TNF-α) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis (RA). Certolizumab pegol (Cimzia(®)) is a humanized Fab' antibody fragment against TNF-α with a polyethylene glycol tail that prevents complement-dependent and antibody-dependent cell-mediated cytotoxicity or apoptosis. Four randomized clinical trials have been published so far. Reported results are similar to those published in previous studies with other TNF-α inhibitors, with ACR20, ACR50, and ACR70 responses of around 60%, 40%, and 20%, respectively, when combined with methotrexate and slightly lower when used as monotherapy. Safety was shown to be similar to that seen with TNF-α blockers and some cases of tuberculosis were seen in the trials, stressing the importance of a complete screening in these patients. Although we still need effectiveness and safety data in larger numbers of patients and longer follow-up, this new TNF inhibitor is a welcome addition to our current armamentarium for the treatment of RA. ",0
4349,22916030,Transgene induced co-suppression during vegetative growth in Cryptococcus neoformans,"Introduction of DNA sequences into the genome often results in homology-dependent gene silencing in organisms as diverse as plants, fungi, flies, nematodes, and mammals. We previously showed in Cryptococcus neoformans that a repeat transgene array can induce gene silencing at a high frequency during mating (∼50%), but at a much lower frequency during vegetative growth (∼0.2%). Here we report a robust asexual co-suppression phenomenon triggered by the introduction of a cpa1::ADE2 transgene. Multiple copies of the cpa1::ADE2 transgene were ectopically integrated into the genome, leading to silencing of the endogenous CPA1 and CPA2 genes encoding the cyclosporine A target protein cyclophilin A. Given that CPA1-derived antisense siRNAs were detected in the silenced isolates, and that RNAi components (Rdp1, Ago1, and Dcr2) are required for silencing, we hypothesize that an RNAi pathway is involved, in which siRNAs function as trans factors to silence both the CPA1 and the CPA2 genes. The silencing efficiency of the CPA1 and CPA2 genes is correlated with the transgene copy number and reached ∼90% in the presence of >25 copies of the transgene. We term this transgene silencing phenomenon asexual co-suppression to distinguish it from the related sex-induced silencing (SIS) process. We further show that replication protein A (RPA), a single-stranded DNA binding complex, is required for transgene silencing, suggesting that RPA might play a similar role in aberrant RNA production as observed for quelling in Neurospora crassa. Interestingly, we also observed that silencing of the ADE2 gene occurred at a much lower frequency than the CPA1/2 genes even though it is present in the same transgene array, suggesting that factors in addition to copy number influence silencing. Taken together, our results illustrate that a transgene induced co-suppression process operates during C. neoformans vegetative growth that shares mechanistic features with quelling. ",0
4350,22916226,Integrating fasciolosis control in the dry cow management: the effect of closantel treatment on milk production,"The liver fluke Fasciola hepatica is a parasite of ruminants with a worldwide distribution and an apparent increasing incidence in EU member states. Effective control in dairy cattle is hampered by the lack of flukicides with a zero-withdrawal time for milk, leaving the dry period as the only time that preventive treatment can be applied. Here, we present the results of a blinded, randomized and placebo-controlled trial on 11 dairy herds (402 animals) exposed to F. hepatica to 1) assess the effect of closantel treatment at dry-off (or 80-42 days before calving in first-calving heifers) on milk production parameters and 2) evaluate if a number of easy-to-use animal parameters is related to the milk production response after treatment. Closantel treatment resulted in a noticeable decrease of anti-F. hepatica antibody levels from 3-6 months after treatment onwards, a higher peak production (1.06 kg) and a slightly higher persistence (9%) of the lactation, resulting in a 305-day milk production increase of 303 kg. No effects of anthelmintic treatment were found on the average protein and fat content of the milk. Milk production responses after treatment were poor in meagre animals and clinically relevant higher milk production responses were observed in first-lactation animals and in cows with a high (0.3-0.5 optical density ratio (ODR)), but not a very high (≥ 0.5 ODR) F. hepatica ELISA result on a milk sample from the previous lactation. We conclude that in dairy herds exposed to F. hepatica, flukicide treatment at dry-off is a useful strategy to reduce levels of exposure and increase milk production in the subsequent lactation. Moreover, the results suggest that treatment approaches that only target selected animals within a herd can be developed based on easy-to-use parameters. ",0
4351,22916289,A novel role of the PrpR as a transcription factor involved in the regulation of methylcitrate pathway in Mycobacterium tuberculosis,"Mycobacterium tuberculosis, the pathogen that causes tuberculosis, presumably utilizes fatty acids as a major carbon source during infection within the host. Metabolism of even-chain-length fatty acids yields acetyl-CoA, whereas metabolism of odd-chain-length fatty acids additionally yields propionyl-CoA. Utilization of these compounds by tubercle bacilli requires functional glyoxylate and methylcitrate cycles, respectively. Enzymes involved in both pathways are essential for M. tuberculosis viability and persistence during growth on fatty acids. However, little is known about regulatory factors responsible for adjusting the expression of genes encoding these enzymes to particular growth conditions. Here, we characterized the novel role of PrpR as a transcription factor that is directly involved in regulating genes encoding the key enzymes of methylcitrate (methylcitrate dehydratase [PrpD] and methylcitrate synthase [PrpC]) and glyoxylate (isocitrate lyase [Icl1]) cycles. Using cell-free systems and intact cells, we demonstrated an interaction of PrpR protein with prpDC and icl1 promoter regions and identified a consensus sequence recognized by PrpR. Moreover, we showed that an M. tuberculosis prpR-deletion strain exhibits impaired growth in vitro on propionate as the sole carbon source. Real-time quantitative reverse transcription-polymerase chain reaction confirmed that PrpR acts as a transcriptional activator of prpDC and icl1 genes when propionate is the main carbon source. Similar results were also obtained for a non-pathogenic Mycobacterium smegmatis strain. Additionally, we found that ramB, a prpR paralog that controls the glyoxylate cycle, is negatively regulated by PrpR. Our data demonstrate that PrpR is essential for the utilization of odd-chain-length fatty acids by tubercle bacilli. Since PrpR also acts as a ramB repressor, our findings suggest that it plays a key role in regulating expression of enzymes involved in both glyoxylate and methylcitrate pathways. ",0
4352,22916437,Feasibility study on cross-linked biopolymeric concrete encapsulating selenium glass wastes,"Feasibility study was conducted to encapsulate the selenium (Se) contained in glass waste, using the biopolymer-modified concrete. Biopolymer has unique characteristics to provide the chemical sites to metals or toxic compounds through the three-dimensional cross-linked structure. Very minute amount of biopolymer enhanced the characteristics of cementitious material. The resulting biopolymeric composite with selenium glass waste showed 20% higher compressive strength than ordinary concrete and the lower leaching concentration than the equipment detection limit. For a qualitative measurement, X-ray diffraction (XRD; X-ray powder diffractogram) was used to characterize the biopolymeric concrete. The optimum waste content percentage with appropriate biopolymer concrete mixture ratio was identified for its possible commercial use. ",0
4353,22916489,The applied research of a neotype medical drainage bag in clinical care],"To compare and evaluate the effectiveness of two kinds of medical drainage bag. 206 patients were randomly divided into two groups each of which consisted of 103 patients. All the data including four indices, such as the time required to replace the drainage bags, the incidence of the bags detached, draining fluid splashing rates during the replacement of the bags, patient and medical staff satisfaction, were collected and analyzed statistically. The time required to replace the drainage bags, the incidence of the bags detached and draining fluid splashing rates during the replacement of the bags of the experimental group were significantly lower than those of the control group (P < 0.05), while the patient and medical staff satisfaction were significantly higher than those of the control group (P < 0.05). It is convenient, quick and time and effort saving to use the neotype medical drainage bags. Hence, the use of neotype medical drainage bags could help to improve the work efficiency, effectively prevent occupational injuries and protect health care workers. ",0
4354,22916854,Field Epidemiology and Laboratory Training Programs in West Africa as a model for sustainable partnerships in animal and human health,"The concept of animal and human health experts working together toward a healthier world has been endorsed, but challenges remain in identifying concrete actions to move this one health concept from vision to action. In 2008, as a result of avian influenza outbreaks in West Africa, international donor support led to a unique opportunity to invest in Field Epidemiology and Laboratory Training Programs (FELTPs) in the region that engaged the animal and human health sectors to strengthen the capacity for prevention and control of zoonotic diseases. The FELTPs mixed 25% to 35% classroom and 65% to 75% field-based training and service for cohorts of physicians, veterinarians, and laboratory scientists. They typically consisted of a 2-year course leading to a master's degree in field epidemiology and public health laboratory management for midlevel public health leaders and competency-based short courses for frontline public health surveillance workers. Trainees and graduates work in multidisciplinary teams to conduct surveillance, outbreak investigations, and epidemiological studies for disease control locally and across borders. Critical outcomes of these programs include development of a cadre of public health leaders with core skills in integrated disease surveillance, outbreak investigation, vaccination campaigns, laboratory diagnostic testing, and epidemiological studies that address priority public health problems. A key challenge exists in identifying ways to successfully scale up and transform this innovative donor-driven program into a sustainable multisectoral one health workforce capacity development model. ",0
4355,22916859,Liver lobe torsion in six horses,"6 horses were determined to have torsion of a liver lobe at 4 referral institutions over a 21-year period. Clinical findings were nonspecific but often included signs of marked inflammation. Two of the 6 horses were examined because of colic, and 2 were assessed because of peritonitis that failed to respond to treatment; the remaining 2 horses were examined because of nonspecific clinical signs that included inappetence, lethargy, and weight loss. The results of laboratory tests were widely variable, and values for liver enzyme activities were typically within reference limits or only mildly increased. Most affected horses had markedly increased peritoneal nucleated cell counts. Exploratory laparotomy and resection of the affected liver lobe was performed in 5 horses. Three of those patients survived to discharge. Results suggested that diagnosis of liver lobe torsion in horses may be difficult because clinical signs and results of laboratory testing are nonspecific and variable. Most affected horses had markedly abnormal peritoneal fluid. The prognosis for hepatic lobe torsion can be good, and early surgical correction is expected to improve outcome. ",0
4356,22916905,Nonesterified fatty acids modify inflammatory response and eicosanoid biosynthesis in bovine endothelial cells,"Intense lipid mobilization during the transition period in dairy cows is associated with increased disease susceptibility. The potential impact of altered plasma nonesterified fatty acids (NEFA) concentrations and composition on host inflammatory responses that may contribute to disease incidence and severity are not known. The objective of this study was to evaluate if increased NEFA concentrations could modify vascular inflammatory responses in vitro by changing the expression of important inflammatory mediators that are important in the pathogenesis of infectious diseases of transition cows such as mastitis and metritis. Bovine aortic endothelial cells (BAEC) were cultured with different concentrations of a NEFA mixture that reflected the plasma NEFA composition during different stages of lactation. The expression of cytokines, adhesion molecules, and eicosanoids were measured to assess changes in BAEC inflammatory phenotype. Addition of NEFA mixtures altered the fatty acid profile of BAEC by increasing the concentration of stearic acid (C18:0) and decreasing the content of arachidonic acid (C20:4n6c) and other long-chain polyunsaturated fatty acids in the phospholipid fraction. A significant increase also occurred in mRNA expression of cytokine and adhesion molecules that are associated with increased inflammatory responses during the transition period. Expression of cyclooxygenase 2, an important enzyme associated with eicosanoid biosynthesis, was increased in a NEFA concentration-dependent manner. The production of linoleic acid-derived eicosanoids 9- and 13-hydroxyoctadecadienoic acids also was increased significantly after treatment with NEFA mixtures. This research described for the first time specific changes in vascular inflammatory response during in vitro exposure to NEFA mixtures that mimic the composition and concentration found in cows during the transition period. These findings could explain, in part, alterations in inflammatory responses observed during intense lipid mobilization stages such as in the transition period of dairy cows. Future studies should analyze specific mechanisms by which high NEFA concentrations induce a vascular proinflammatory phenotype including the effect of 9 and 13-hydroxyoctadecadienoic acids and other lipid mediators. ",0
4357,22917128,Test-retest reliability of Family L.I.F.E. (Looking Into Family Experiences): an occupation-based assessment,"OBJECTIVE. We examined the test-retest reliability of Family L.I.F.E. (Looking Into Family Experiences) for consistency in identifying occupations desired by families with a child with autism spectrum disorder (ASD), and we compared the perceived efficiency, effectiveness, and satisfaction ratings of those occupations for the families. METHOD. Family L.I.F.E. was administered initially and 1 wk later via interview to 13 families with a child with ASD. RESULTS. Ninety-two percent of the families identified the same occupations as important at test and retest. Wilcoxon signed-rank test indicated no change in the families' perceived efficiency and effectiveness of those occupations, and Spearman's correlations indicated strong relationships. A decrease in satisfaction was noted. CONCLUSION. For families with a child with ASD, desired family occupations and efficiency and effectiveness ratings are likely to remain consistent and are highly linked on retest using Family L.I.F.E. At second interview using this instrument, families with a child with ASD may report decreased satisfaction in desired family occupations. ",0
4358,22917176,Metabolic profiling assisted quality control of phorbolesters in Jatropha curcas seed by high-performance liquid chromatography using a fused-core column,"In this work, fast and sensitive high-performance liquid chromatography (HPLC) coupled with multivariate analysis was utilized to evaluate the metabolic profiling of  Jatropha curcas  seed and screen the marker compounds of phorbolesters (PEs), which significantly contributed to the metabolic profiling for quality control of PEs in J. curcas seed. Thirty-two peaks were separated and detected in J. curcas seed on a fused-core C(18) column between 2 and 25 min. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) of the chromatographic data demonstrated that 12 batches of J. curcas seed could be well-differentiated and categorized into 5 groups. Especially, one sample obtained from Lijiang Yunan was significantly different from the others. Partial least-squares discriminant analysis (PLS-DA) showed that the metabolic profiling differentiation might be explained by 9 components including J.factors C(1)-C(5) of PEs, peak 21 (similar to J.factor C(1)) and 3 peaks (peaks 1, 9, and 10) significantly different in retention time from the PEs. The observation that the content levels of J.factors C(1) and C(2) plus peak 21 (equivalent to J.factor C(1)) were more relevant to the multivariate chromatographic data than the ones of J.factors C(3)-C(5) was confirmed by the PLS prediction models. The results of the present study indicated not only that J.factors C(1) and C(2) were the more rational markers representing the comprehensive quality of PEs in J. curcas seed but also that peak 21 (similar to J.factor C(1)) was a rational marker, too. ",0
4359,22917956,A case of the large retroperitoneal solitary fibrous tumor,"A rare autopsy case of the extremely large retroperitoneal solitary fibrous tumor is reported. A 52-year-old female with a huge abdominal distention was found dead at home. She showed remarkable emaciation. The autopsy revealed a huge retroperitoneal tumor weighing 11.9kg (36×30×20cm in size), which occupied the entire intraperitoneal cavity. Histologically, the tumor consisted of spindle parenchymal cells with fibrous tissues. Immunohistochemically, CD34 was positively stained, whereas S-100, smooth muscle actin, and factor VIII were negative. Her cause of death was diagnosed as emaciation due to the compression of the entire intestine by the tumor. This is a rare case of the extremely large retroperitoneal solitary fibrous tumor, which caused the occasional intestinal obstruction. This disease should be considered in the differential diagnosis of retroperitoneal large tumors that cause accidental deaths in forensic autopsies. ",0
4360,22918645,A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids,"To design and develop a drug-delivery system containing a combination of poly(D,L-lactide-co-glycolide) (PLGA) microparticles and alginate hydrogel for sustained release of retinoids to treat retinal blinding diseases that result from an inadequate supply of retinol and generation of 11-cis-retinal. To study drug release in vivo, either the drug-loaded microparticle-hydrogel combination was injected subcutaneously or drug-loaded microparticles were injected intravitreally into Lrat(-/-) mice. Orally administered 9-cis-retinoids were used for comparison and drug concentrations in plasma were determined by HPLC. Electroretinography (ERG) and both chemical and histologic analyses were used to evaluate drug effects on visual function and morphology. Lrat(-/-) mice demonstrated sustained drug release from the microparticle/hydrogel combination that lasted 4 weeks after subcutaneous injection. Drug concentrations in plasma of the control group treated with the same oral dose rose to higher levels for 6-7 hours but then dropped markedly by 24 hours. Significantly increased ERG responses and a markedly improved retinal pigmented epithelium (RPE)-rod outer segment (ROS) interface were observed after subcutaneous injection of the drug-loaded delivery combination. Intravitreal injection of just 2% of the systemic dose of drug-loaded microparticles provided comparable therapeutic efficacy. Sustained release of therapeutic levels of 9-cis-retinoids was achieved in Lrat(-/-) mice by subcutaneous injection in a microparticle/hydrogel drug-delivery system. Both subcutaneous and intravitreal injections of drug-loaded microparticles into Lrat(-/-) mice improved visual function and retinal structure. ",0
4361,22918719,Metabolism of patupilone in patients with advanced solid tumor malignancies,"A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (Vss: 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2-3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion. ",0
4362,22919063,"The mitochondrial Atp8 mutation induces mitochondrial ROS generation, secretory dysfunction, and β-cell mass adaptation in conplastic B6-mtFVB mice","Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic phenotypes. In this study, we used conplastic mouse strains to characterize the impact of a mtDNA mutation in the Atp8 gene on β-cell function, reactive oxygen species (ROS) generation, β-cell mass, and glucose metabolism in response to high-fat diet (HFD). In comparison with B6-mt(AKR) controls, the B6-mt(FVB) strain carries a point mutation of the mtDNA-coded Atp8 gene (ATP synthase), leading to a fragmentated mitochondrial phenotype. Isolated pancreatic islets from 3-month-old B6-mt(FVB) mice showed increased mitochondrial generation of ROS, reduced cellular ATP levels, reduced glucose-induced insulin secretion, higher susceptibility to palmitate stress, and pathological morphology of mitochondria. ROS generation in β-cells was not affected by changes of the ambient glucose concentrations. Feeding a HFD for 3 months resulted in impaired glucose tolerance in B6-mt(FVB) mice but not in B6-mt(AKR) controls. In B6-mt(FVB) animals, glucose intolerance positively correlated with gain of body weight. Serum insulin levels and β-cell mass significantly increased in B6-mt(FVB) mice after a 3-month HFD. The data indicate that the mutation in the Atp8 gene induces mitochondrial dysfunction in β-cells with concomitant impairment of secretory responsiveness. This mitochondrial dysfunction induced a higher susceptibility to metabolic stressors, although this effect appeared not strictly linked to nutrient-induced ROS generation. The Atp8 gene mutation caused mitochondrial dysfunction, apparently stimulating an adaptive increase of β-cell mass in response to HFD, whereas mitochondrial ROS might have had an supportive role. ",0
4363,22919126,Testosterone replacement and prostate cancer,"This article is intended as a review of the available clinical data outlining the risks and benefits of testosterone (androgen) replacement therapy, specifically addressing the issue of the relationship between exogenous androgen administration and prostate cancer risk. There is controversy over whether androgen replacement is a risk factor for incident prostate cancer. Our review of current clinical information revealed that to date, no study or review has definitively shown that androgen replacement therapy is an independent risk factor for development of prostate cancer. Androgen administration seems to be beneficial in decreasing fatal cardiovascular events, body fat mass, and insulin resistance. Overall, the current clinical data seems to suggest that androgen replacement is an appropriate therapeutic option for men with symptomatic hypogonadism provided that patients continue to receive regular prostate screenings. ",0
4364,22919282,"Constitutive over expression of IL-1β, IL-6, NF-κB, and Stat3 is a potential cause of lung tumorgenesis in urethane (ethyl carbamate) induced Balb/c mice","Lung cancer is a leading cause of cancer death. There has been found a substantial gap in the understanding of lung cancer genesis at the molecular level. We developed urethane (ethyl carbamate) induced lung tumor mice model to understand the mechanism and molecules involved in the cancer genesis. There might be many molecules involved, but we subsequently emphasized here the study of alternation in the expression of NF-κB, Stat3, and inflammatory cytokines interleukin-1β and interleukin-6 to hypothesize that the microenvironment created by these molecules is promoting tumor formation. 7-8 week old Balb/c mice of either sex were given intraperitoneal (i.p.) injection of urethane (1g/kgbw) for eight consecutive weeks. Histopathological analysis was done to detect abnormality or invasions occurred in the lung tissues. Automated cell counter was used to count the number of inflammatory cells. The expression of NF-κB, Stat3, and IL-1β was observed at translational level by western blot, while the expression of IL-1β and IL-6 was observed at transcriptional level by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) method. Secretion of IL-1β and IL-6 in the blood was measured by enzyme-linked immunosorbent assay (ELISA) method at different time intervals. Histopathological analysis showed various lung cancer stages hyperplasia, atypical adenomatous hyperplasia, and adenocarcinoma. Increased population of inflammatory cells, persistant expression of NF-κB, Stat3, pStat3, and IL-1β at translational level, while at transcriptional level constitutive enhanced expression of IL-1β and IL-6 followed by increased secretion of IL-1β and IL-6 in the blood were observed in urethane-injected mice in comparison to phosphate buffer saline (PBS) injected mice at 12, 24, and 36 weeks Overexpression of key molecules such as NF-κB, Stat3, pStat3, IL-1β, and IL-6 might have caused chronic inflammation, leading to the progression of lung cancer. ",0
4365,22919364,"Correlations among PPARγ, DNMT1, and DNMT3B Expression Levels and Pancreatic Cancer","Emerging evidence indicates that peroxisome proliferator-activated receptor γ (PPARγ) and DNA methyltransferases (DNMTs) play a role in carcinogenesis. In this study we aimed to evaluate the expression of PPARγ, DNMT1, and DNMT3B and their correlation with clinical-pathological features in patients with pancreatic cancer (PC), and to define the effect of PPARγ activation on DNMTs expression in PC cell lines. qRT-PCR analysis showed that DNMT3B expression was downregulated in tumors compared to normal tissues (P = 0.03), whereas PPARγ and DNMT1 levels did not show significant alterations in PC patients. Expression levels between PPARγ and DNMT1 and between DNMT1 and DNMT3B were highly correlated (P = 0.008 and P = 0.05 resp.). DNMT3B overexpression in tumor tissue was positively correlated with both lymph nodes spreading (P = 0.046) and resection margin status (P = 0.04), and a borderline association with perineural invasion (P = 0.06) was found. Furthermore, high levels of DNMT3B expression were significantly associated with a lower mortality in the whole population (HR = 0.485; 95%CI = 0.262-0.895, P = 0.02) and in the subgroup of patients without perineural invasion (HR = 0.314; 95%CI = 0.130-0.758; P = 0.01), while such association was not observed in patients with tumor invasion into perineural structures (P = 0.70). In conclusion, in vitro and in vivo PPARγ and DNMTs appear interrelated in PC, and this interaction might influence cell phenotype and disease behavior. ",0
4366,22919418,Phenethyl Isothiocyanate (PEITC) Inhibits the Growth of Human Oral Squamous Carcinoma HSC-3 Cells through G(0)/G(1) Phase Arrest and Mitochondria-Mediated Apoptotic Cell Death,"Phenethyl isothiocyanate (PEITC), an effective anticancer and chemopreventive agent, has been reported to inhibit cancer cell growth through cell-cycle arrest and induction of apoptotic events in various human cancer cells models. However, whether PEITC inhibits human oral squamous cell carcinoma HSC-3 cell growth and its underlying mechanisms is still not well elucidated. In the present study, we evaluated the inhibitory effects of PEITC in HSC-3 cells and examined PEITC-modulated cell-cycle arrest and apoptosis. The contrast-phase and flow cytometric assays were used for examining cell morphological changes and viability, respectively. The changes of cell-cycle and apoptosis-associated protein levels were determined utilizing Western blotting in HSC-3 cells after exposure to PEITC. Our results indicated that PEITC effectively inhibited the HSC-3 cells' growth and caused apoptosis. PEITC induced G(0)/G(1) phase arrest through the effects of associated protein such as p53, p21, p17, CDK2 and cyclin E, and it triggered apoptosis through promotion of Bax and Bid expression and reduction of Bcl-2, leading to decrease the levels of mitochondrial membrane potential (ΔΨ(m)), and followed the releases of cytochrome c, AIF and Endo G then for causing apoptosis in HSC-3 cells. These results suggest that PEITC could be an antitumor compound for oral cancer therapy. ",0
4367,22919498,Concerns of Indian Mothers with Children Having Severe-to-Profound Hearing Impairment at Diagnosis and after 1-3 Years of Therapy,"""Counseling training in graduate programs continues to be underrepresented. If parental queries are not addressed adequately, they keep visiting one doctor after another. Objective. The aim of the study is to identify maternal needs of children with hearing impairment at two stages of habilitation, that is, just after diagnosis (group I) and after receiving 1 to 3 years of language therapy (group II). Methods. Two groups of mothers were asked to speak their queries about aural habilitation of their children. Queries were recorded, summarized, and categorized as per their priorities. Results. Group I mothers wanted to know about how the child would learn to listen and speak (45%), causes of hearing loss (33.7%), understanding the ear and hearing (10.2%), understanding the audiogram (7%), and coping with emotional aspects of hearing loss (5%), while group II parents had priorities concerning speech development (24.5%) followed by child independence and employment (17.3%), schooling (15.6%), problem behaviors (11%), amplification device (9.4%), duration of therapy (8%), future of the child (8%), and questions about how can my child get adjusted to the """"normal"""" world (6%). Conclusions. Culture- and language-specific materials to explain these issues need to be developed. """,0
4368,22919537,Cardiovascular risk in chronic kidney disease: role of the sympathetic nervous system,"Patients with chronic kidney disease are at significantly increased risk for cardiovascular disease and sudden cardiac death. One mechanism underlying increased cardiovascular risk in patients with renal failure includes overactivation of the sympathetic nervous system (SNS). Multiple human and animal studies have shown that central sympathetic outflow is chronically elevated in patients with both end-stage renal disease (ESRD) and chronic kidney disease (CKD). SNS overactivation, in turn, increases the risk of cardiovascular disease and sudden death by increasing arterial blood pressure, arrythmogenicity, left ventricular hypertrophy, and coronary vasoconstriction and contributes to the progression renal disease. This paper will examine the evidence for SNS overactivation in renal failure from both human and experimental studies and discuss mechanisms of SNS overactivity in CKD and therapeutic implications. ",0
4369,22919762,Evaluation of norovirus rapid detection kit],"Evaluating the accuracy and safety as well as the equivalence compared with the control kit of RIDA QUICK Norovirus detection kit(R-Biopharm, Germany). Based on the results of commercially available IDEA Norovirus detection kit (ELISA), the sensitivity and specificity and accuracy of RIDA QUICK Norovirus detection kit (immunochromatographic assay) were evaluated. The sensitivity and specificity of RIDA QUICK Norovirus detection kit were 98.4% and 92.4%, and the accuracy was 97.6% compared with the control kit. RIDA QUICK Norovirus detection kit has good sensitivity and specificity for the detection of norovirus antigens. ",0
4370,22920296,Clinical and radiological profiles and outcomes in pediatric patients with intracranial aneurysms,"Intracranial aneurysms are extremely uncommon in the pediatric population, their characteristics are not well studied, and certain features make them unique. The authors analyzed pediatric patients with aneurysms to try to understand their clinical, radiological, and outcome profile. Sixty-three pediatric patients (≤ 18 years of age) with ages ranging from 4 to 18 years and features (clinical and radiological) suggestive of aneurysm presented to, and were treated at, the authors' center in the past 20 years (1991-2011). Included in the present study were only those patients who underwent surgical intervention, and thus data for 57 patients were analyzed. Seventy-three aneurysms in 57 patients were surgically treated. There was a slight female predominance (M/F 1:1.2), and the mean age among all patients was 12.69 ± 3.75 years. Fifty patients (87.72%) presented with subarachnoid hemorrhage, 4 (7.02%) with mass effect, and 3 (5.26%) with seizure. On presentation the majority of patients (45 [78.95%]) had a good clinical grade. Eleven patients had multiple aneurysms. The internal carotid artery (ICA) bifurcation was the most common aneurysm site (18 cases [24.66%]), followed by the middle cerebral artery (MCA) bifurcation (11 cases [15.07%]). At a mean follow-up of 18.58 ± 10.71 months (range 1.5-44 months), 44 patients (77.19%) had a favorable outcome, and 5 patients had died. Pediatric patients with intracranial aneurysms most commonly presented with subarachnoid hemorrhage, and there was a slight female predominance. The ICA bifurcation followed by the MCA bifurcation was the most common aneurysm site. The incidence of posterior circulation and giant aneurysms is higher in pediatric patients than in the adult population. Children tend to present with better clinical grades and have better overall survival results and good functional outcomes. ",0
4371,22920345,"Effect on examination ordering by physician attitude, common knowledge, and practice behavior regarding CT radiation exposure","We surveyed ordering physician attitudes, knowledge, and behavior with regard to computed tomography (CT)-related radiation exposure at a large medical center. Sixteen questions were sent via electronic survey to 350 physicians. The ability to quickly rule in or rule out conditions effectively strongly influenced the decision to order CT (85%-99%). Fear of litigation influenced CT ordering for those with less experience [odds ratio (OR)=2.3, P<.05]. Residents and primary care physicians were less likely to discuss risks/benefits of CT with patients (P ≤.03) compared to those with >5 years of experience (OR=4.0, P=.04). ",0
4372,22920405,Targeted microbubbles in the experimental and clinical setting,"Microbubbles have improved ultrasonography imaging techniques over the past 2 decades. Their safety, versatility, and easiness of use have rendered them equal or even superior in some instances to other imaging modalities such as computed tomography and magnetic resonance imaging. Herein, we conducted a literature review to present their types, general behavior in tissues, and current and potential use in clinical practice. A literature search was conducted for all preclinical and clinical studies involving microbubbles and ultrasonography. Different types of microbubbles are available. These generally improve the enhancement of tissues during ultrasonography imaging. They also can be attached to ligands for the target of several conditions such as inflammation, angiogenesis, thrombosis, apoptosis, and might have the potential of carrying toxic drugs to diseased sites, thereby limiting the systemic adverse effects. The use of microbubbles is evolving rapidly and can have a significant impact on the management of various conditions. The potential for their use as targeting agents and gene and drug delivery vehicles looks promising. ",0
4373,22920631,Innate immunity in the pathogenesis of cholangiopathy: a recent update,"Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with various biliary diseases. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Recently, regulatory mechanisms by intracellular negative regulators including peroxisome proliferator-activated receptor-γ and micro-RNA have been clarified. In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis, dysregulated biliary innate immunity, namely hyper-responsiveness to PAMPs, is associated with the histopathogenesis of cholangiopathy. Moreover, biliary epithelial cells produce monocyte chemotactic protein-1 (MCP-1/CCL2) as a result of the innate immune response and bile ductules play a role in hepatic fibrosis caused by hepatic stellate cells (HSCs). Also, biliary innate immune responses induce the production of two chemokines, fractalkine and macrophage inflammatory protein-3α (MIP-3α), causing the migration of inflammatory cells and a population of antigen-presenting cell found in epithelium, Langerhans cell, and involve chronic cholangitis associated with biliary epithelium-specific innate and acquired immunity in PBC. ",0
4374,22920659,"""Support needs and preferences of young adolescents with asthma and allergies: """"just no one really seems to understand""""""","The objectives of this study were to identify support needs, support resources, and support barriers for young adolescents with asthma and allergies and to describe preferences for an accessible support intervention. Adolescents (N = 57) completed a survey questionnaire. Eight young adolescents, 10 parents, and 5 older adolescents participated in separate group interviews. Young adolescents' challenges included transition to self-care, balancing restrictions with safety, social isolation, and loneliness. Young teens recommended supportive networks facilitated by older adolescent peers and wanted to meet with other young adolescents living with asthma and allergies online and share information, advice, and encouragement with them. ",0
4375,22920793,Pore-scale investigation of nanoparticle transport in saturated porous media using laser scanning cytometry,"Knowledge of nanoparticle transport and retention mechanisms is essential for both the risk assessment and environmental application of engineered nanomaterials. Laser scanning cytometry, an emerging technology, was used for the first time to investigate the transport of fluorescent nanoparticles in a microfluidic flow cell packed with glass beads. The laser scanning cytometer (LSC) was able to provide the spatial distribution of 64 nm fluorescent nanoparticles attached in a domain of 12 mm long and 5 mm wide. After 40 pV of injection at a lower ionic strength condition (3 mM NaCl, pH 7.0), fewer fluorescent nanoparticles were attached to the center of the flow cell, where the pore-scale velocity is relatively higher. After a longer injection period (300 PV), more were attached to the center of the flow cell, and particles were attached to both the upstream and downstream sides of a glass bead. Nanoparticles attached under a higher ionic strength condition (100 mM NaCl, pH 7.0) were found to be mobilized when flushed with DI water. The mobilized particles were later reattached to some favorable sites. The attachment efficiency factor was found to reduce with an increase in flow velocity. However, torque analysis based on the secondary energy minimum could not explain the observed hydrodynamic effect on the attachment efficiency factor. ",0
4376,22921109,"Synthesis, molecular docking and antiamnesic activity of selected 2- naphthyloxy derivatives","The present paper describes the design and synthesis of a series of some 2-naphthyloxy derivatives with their antiamnesic activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized by spectroscopic techniques and were screened for their efficacy as cognition enhancers by elevated plus maze test and acetylcholinestrase inhibitory assay. Molecular modeling and docking studies of the selected compounds into the crystal structure of acetylcholinestrase complexed with functional ligand succinylcholine using GRAMM software was performed in order to predict the affinity and orientation of the synthesized derivatives at the active site. The binding energy of ligands was calculated using ArgusLab software. The docking score and hydrogen bonds formed with surrounding amino acids show the good agreement with predicted binding affinities obtained by molecular docking studies, as verified by acetylcholinestrase activity. ",0
4377,22921176,"""""""It makes you feel that somebody is out there caring"""": a qualitative study of intervention and control participants' perceptions of the benefits of taking part in an evaluation of dignity therapy for people with advanced cancer""","""Participants in a Phase II randomized controlled trial of Dignity Therapy felt that the intervention had helped them; however, the processes underlying this are not known. To explore intervention and control participants' perceptions of the benefits of taking part in an evaluation of Dignity Therapy within the frame of the underlying model of the intervention. We interviewed 29 patients at one-week follow-up and 20 at four-week follow-up. We also interviewed nine family members of patients in the intervention group. We used the Framework approach to qualitative analysis. This comprised five stages: familiarization, identifying a thematic framework, indexing, charting, and mapping and interpretation. The analysis was both deductive (a priori themes from the model informing the content and therapeutic tone of the intervention) and inductive (from participants' views). There was support for five of the seven themes from the model underlying Dignity Therapy: """"generativity,"""" """"continuity of self,"""" """"maintenance of pride,"""" """"hopefulness,"""" and """"care tenor."""" With the exception of generativity, all were evident in both groups. Prevalent emergent themes for the intervention group were """"reminiscence"""" and """"pseudo life review."""" """"Making a contribution"""" was prevalent in the control group. Patients with advanced cancer and their families found that Dignity Therapy had helped them in many ways; however, patients in the control group sometimes perceived similar benefits from taking part in the study, highlighting elements of Dignity Therapy that are common to dignity conserving care. """,0
4378,22921320,"Influence of cervical spine position, turning time, and cervical segment on cadaver intradiscal pressure during cervical spinal manipulative therapy","""The purpose of this study was to determine influences of cervical spine positions, turning times, and cervical segments on cadaver intradiscal pressure (IDP) during cervical spinal manipulative therapy (SMT). We simulated cervical SMT with stretching and rotation on 7 fresh adult cadaver specimens in the material test system machine. The changes in IDP for cervical intervertebral disks (C3/4, C4/5, and C5/6) during 4 different stages of cervical SMT (physiologic state, end of the traction stage, turning stage, and finish time) were monitored. Five different cervical positions (extension 20°, extension 10°, neutral position, flexion 10°, flexion 20°) and 3 different turning times (0.06, 0.11, 0.16 second) of IDP were monitored, using micropressure sensors. The variable tendency of cervical IDP presents a """"V""""-shaped curve during SMT. The 4 stages of SMT had significantly different IDP (F=5498.956; P<.001). There were also significant differences in IDP between 5 cervical positions ([F=1371.216; P<.001], [flexion 20°>flexion 10°>neutral position>extension 10°>extension 20°]), 3 turning times ([F=419.530; P<.001], [0.06>0.11>0.16 seconds]), and 3 cervical segments ([F=84.282; P<.001], [C3/4<C4/5<C5/6]). Intradiscal pressure was lowest at 20° extension combined with a turning time of 0.16 second. Different cervical positions, turning times, and cervical segments largely influence IDP during the process of SMT. Further research using human subjects should determine if these findings contribute to greater patient comfort, safety, and clinical efficacy with SMT. """,0
4379,22921419,Low phase angle determined by bioelectrical impedance analysis is associated with malnutrition and nutritional risk at hospital admission,"This study determined the association between phase angle (PhA), by bioelectrical impedance analysis (BIA) and nutritional risk by Nutritional Risk Screening (NRS-2002), Subjective Global Assessment (SGA), hospital length of stay (LOS) and 30 day non-survival in patients at hospital admission compared to healthy controls. PhA was determined by BIA in patients (n = 983, 52.7 ± 21.5 yrs, M 520) and compared to healthy age-, sex- and height-matched controls. Low PhA was set at <5.0° (men) and <4.6° (women) as previously determined (Kyle, in press). PhA was lower in patients (men 6.0 ± 1.4°, women 5.0 ± 1.3°) than controls (men 7.1 ± 1.2°, women 6.0 ± 1.2°, un-paired t-test p < 0.001). Patients were more likely to have low PhA than controls: NRS-2002: no risk (relative risk (RR) 1.7, 95th confidence interval (CI) 1.2-2.3), moderate risk (RR 4.5, CI 3.4-5.8) and severe risk (RR 7.5, CI 5.9-9.4); similar results were obtained by SGA; LOS ≥21 days (RR 6.9, CI 5.1-9.1) and LOS 5-20 days (RR 5.2, CI 3.9-6.9) and non-survivors (RR 3.1, CI 2.1-3.4) compared to survivors. There is a significant association between low PhA and nutritional risk, LOS and non-survival. PhA is helpful to identify patients who are at nutritional risk at hospital admission in order to limit the number of in-depth nutritional assessments. ",0
4380,22921468,Electro-clinical features and magnetic resonance imaging correlates in Menkes disease,"Epilepsy is an early and important feature in Menkes disease (MD), an X-linked recessive neurodegenerative disorder of childhood with defect in copper metabolism. There are only few reports on the electro-clinical and magnetic resonance imaging correlates in Menkes disease. The current study describes the electro-clinical features in MD in relation with the structural findings on MRI. Six patients from five families were evaluated between 2005 and 2011. Their diagnosis was based on the characteristic morphological features, microscopic evidence of pili torti and low copper and ceruloplasmin levels. All the patients underwent MRI and EEG as part of the evaluation. All patients had classical form of MD with typical morphological features. All but one patient had refractory seizures. Seizure types included multifocal clonic seizures (n=3), myoclonic jerks (n=4) and tonic spasms (n=1). EEG was markedly abnormal in all except in the patient without clinical seizures. While focal epileptiform discharges predominated before six months of age modified hypsarrhythmia was characteristically noted thereafter. MR Imaging revealed abnormalities in all patients, with cerebral atrophy and delayed myelination being the most common observations. Other features noted were subdural effusion (n=3), leukoencephalopathy (n=3) and basal ganglia signal changes (n=1). Follow up imaging in three patients showed resolution of white matter signal intensity changes. Electro-clinical features in Menkes disease are age dependent and evolve sequentially. White matter changes coincided with acute exacerbation of seizures. There was fair correlation between the electro-clinical features and structural findings on MRI. ",0
4381,22921481,Different levels of lack of improvement at 4 weeks of escitalopram treatment as predictors of poor 8-week outcome in MDD,"Several post-hoc studies have shown that lack of early improvement reduces the chance of later response or remission. This post-hoc analysis evaluates different cut-off points of non-improvement at 4 weeks of escitalopram treatment to predict 8-week non-response and non-remission. This study consisted of MDD patients with an absence of improvement (<30% reduction in baseline score of the HAMD-17) at Week 4 of escitalopram treatment (10mg/day) that continued escitalopram treatment (10-20mg/day) for a further 4-week period (n=251). Predictive, sensitivity and specificity values for the several definitions of non-improvement (≤ 25%, ≤ 20% and ≤ 15% reduction in the HAMD-17 baseline total score) at 4 weeks were calculated. Overall, 70.1% (176/251) of patients did not achieve response at Week 8 and 84.5% (212/251) did not achieve remission. The predictive value for non-response was high (71.4-74.3%) for all cut-off points of non-improvement tested. The respective values for non-remission were placed between 85.0% and 87.2%. This was a post-hoc subgroup analysis. The only drug assessed was escitalopram. Our data indicate that an absence of improvement, <30% reduction in the HAMD-17, after 4 weeks of escitalopram treatment should prompt clinicians to consider a change in treatment strategy. Similar findings were previously reported for other antidepressants. ",0
4382,22921505,Methoxyquinoline labeling--a new strategy for the enantioseparation of all chiral proteinogenic amino acids in 1-dimensional liquid chromatography using fluorescence and tandem mass spectrometric detection,"The determination of trace amounts of d-amino acids (d-AAs) even in tissue samples of higher developed animals, mammals and humans has opened a wide field of biological questions to be investigated. d-Ala, d-Asp and d-Ser have already been identified to exhibit key functions in cellular regulation processes [1-4]. The abundance of trace amounts of these and also of other d-AAs in various biological fluids and in tissue samples is still being investigated. We herein present a facile derivatization method for amino acids using 6-methoxyquinoline-4-carboxylic acid-succinimide ester (MQ-OSu) to yield the corresponding stable N-acyl-amino acids (MQ-AAs). Labeling with the MQ tag supports the enantioseparation of all 19 chiral proteinogenic amino acids on anion exchanger type chiral stationary phases, introduces fluorescence activity and particularly promotes sensitive electrospray tandem mass spectrometric detection. Limit of detection values (LOD) for MQ-l-Ala in water were 1.25 μmol L(-1) with fluorescence detection and 0.015 μmol L(-1) with MS in selected reaction monitoring (SRM) mode. The applicability of this method for the analysis of MQ-d-AAs in biological fluids has been demonstrated. ",0
4383,22921657,Decabromodiphenyl ether in indoor dust from different microenvironments in a university in the Philippines,"This study was conducted to develop a method for the determination of decabromodiphenyl ether (BDE-209) in indoor dust from different microenvironments in a university in the Philippines. BDE-209 was extracted from dust samples by ultrasonication and determined by HPLC-UV. The determination was performed using external calibration and internal standard calibration. Internal standard calibration was shown to be more precise and sensitive than external calibration. The linearity for the concentration range of 0-300 μg L(-1) BDE-209 was good (R(2)=0.993). The % absolute recovery and the % RSD for n=8 spiked dust analysis based on a 0.2 g dust sample was 57% and 19%, respectively. The method detection limit was 285 ng g(-1). All dust samples showed detectable levels of BDE-209 with some at levels below the quantification limits. The concentrations of BDE-209 in the quantified samples are within the range of 1103-4117 ng g(-1) with an average concentration of 2172 ng g(-1). The levels of BDE-209 found in the dust samples are comparable to those reported in house and workplace dusts from other Asian countries. Although not conclusive, it has been shown empirically that BDE-209 concentrations are higher in sampling sites containing more possible BDE-209 sources like electrical and electronic equipment. ",0
4384,22921946,Ammonium metabolism in humans,"Free ammonium ions are produced and consumed during cell metabolism. Glutamine synthetase utilizes free ammonium ions to produce glutamine in the cytosol whereas glutaminase and glutamate dehydrogenase generate free ammonium ions in the mitochondria from glutamine and glutamate, respectively. Ammonia and bicarbonate are condensed in the liver mitochondria to yield carbamoylphosphate initiating the urea cycle, the major mechanism of ammonium removal in humans. Healthy kidney produces ammonium which may be released into the systemic circulation or excreted into the urine depending predominantly on acid-base status, so that metabolic acidosis increases urinary ammonium excretion while metabolic alkalosis induces the opposite effect. Brain and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia in gas phase has been detected in exhaled breath and skin, denoting that these organs may participate in nitrogen elimination. Ammonium homeostasis is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonium clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonium content to the systemic blood stream. Although blood ammonium concentration is usually elevated in liver disease, a substantial role of ammonium causing hepatic encephalopathy has not been demonstrated in human clinical studies. Hyperammonemia is also produced in urea cycle disorders and other situations leading to either defective ammonium removal or overproduction of ammonium that overcomes liver clearance capacity. Most diseases resulting in hyperammonemia and cerebral edema are preceded by hyperventilation and respiratory alkalosis of unclear origin that may be caused by the intracellular acidosis occurring in these conditions. ",0
4385,22922033,"Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome","""The """"vanishing bone"""" syndromes represent a group of rare skeletal disorders characterized by osteolysis and joint destruction, which can mimic severe rheumatoid arthritis. Winchester syndrome was one of the first recognized autosomal-recessive, multicentric forms of the disorder. It was originally described nearly 50 years ago in two sisters with a severe crippling osteolysis. Using cultured fibroblasts from the proband, we have now identified homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14). We demonstrate that the resulting hydrophobic-region signal-peptide substitution (p.Thr17Arg) decreases MT1-MMP membrane localization with consequent impairment of pro-MMP2 activation, and we propose a structure-based mechanism for this effect. """,0
4386,22922348,Free p-cresol sulfate is associated with survival and function of vascular access in chronic hemodialysis patients,"Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (p-CS) have been implicated as an important factor in uremic syndrome. Recent evidence indicates that both IS and p-CS are predictors of cardiovascular as well as all-cause mortality among chronic dialysis patients. We conducted a study to analyze the relationship between IS and p-CS and vascular access (VA) outcome in chronic hemodialysis (HD) patients. A total of 91 chronic stable HD patients were divided into groups according to survival of VA and frequency of VA dysfunction. Demographic and biochemical data were reviewed and recorded. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, and the total and free forms of IS and p-CS were determined. Patients with a history of frequent VA failure and dysfunction had lower albumin and higher levels of ICAM-1, free IS, free and total p-CS. Diabetes was associated with higher IS and p-CS. Logistic regression revealed that diabetes and free p-CS were independent factors associated with poor outcome of VA. Endothelial dysfunction and uremic toxins were associated with survival and function of VA. Diabetes and free p-CS were significantly related to the outcome of VA among chronic HD patients. ",0
4387,22922418,Orphan kidney diseases,"Rare kidney diseases are a unique subset of renal disorders that are often termed 'orphan' as a result of a multitude of reasons: the small number of patients with the consequent lack of well-defined natural history and course of many of these diseases, limited awareness among the medical community, and finally the significant cost of developing novel therapeutics which makes many of these diseases unattractive targets for the pharmaceutical industry. Nevertheless, in the last decade the study and clinical management of rare kidney disease patients has been the focus of many investigative efforts. In recent years we have witnessed an enormous expansion in our knowledge of the genetic nature of a number of rare kidney diseases. Moreover, the investigation of the role of genetic disruption aiming at elucidating the pathogenesis of different and complex renal diseases has helped not only in understanding the disease states, but has also given us fundamental insights into a number of kidney developmental and physiological functions. This article will give an overview of orphan renal diseases with particular emphasis on monogenic kidney diseases. It will also focus on the classification of these diseases while highlighting a prominent example in each category.  ",0
4388,22922474,Long-term outcome of anterior thalamic nucleus stimulation for intractable epilepsy,"Many patients with epilepsy have persistent seizures despite treatment with maximal antiepileptic drug therapy and are not candidates for resective brain surgery. We investigated the effectiveness of seizure reduction after anterior thalamic nucleus (ATN) stimulation in patients with intractable epilepsy undergoing deep brain stimulation (DBS) of the thalamus. Patients included in this study had poorly controlled seizures, despite anticonvulsant medication, and were not candidates for surgical resection of an identifiable seizure focus. Fifteen patients with medically refractory epilepsy underwent the placement of bilateral DBS electrodes in the anterior thalamus. The seizure frequency was monitored and compared with the preimplantation baseline. The treatment demonstrated a statistically significant decrease in the seizure frequency, with a mean reduction of 70.4% (mean follow-up, 27 months). Two of the patients had a remarkable reduction of seizure frequency. It seems to be important that the short-term outcome of ATN DBS reflects the long-term outcome directly. The correlation between the seizure type, characteristics and anticonvulsant effects of ATN DBS did not exhibit significance because of the small number of cases. Therefore, a longer-term follow-up with a larger group of patients is required to fully evaluate the safety and effectiveness of this treatment modality. ",0
4389,22922647,RPN-6 determines C. elegans longevity under proteotoxic stress conditions,"Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders. ",0
4390,22922856,Efficacy of endovascular therapy for direct occlusion of intracranial aneurysms,"Our purpose was to evaluate the effectiveness of endovascular therapy using detachable coils and balloons for the direct occlusion of intracranial aneurysms. We retrospectively reviewed 563 patients undergoing digital subtraction angiography from January 2007 to July 2009. Two hundred and fifty patients with 323 embolized intracranial aneurysms were studied. Among 250 patients, 66 % were female and 34 % male, the age ranging from 19 - 83 years (mean 50.66 ± 12.92). One hundred and seventy-seven had a single aneurysm while 73 showed multiple aneurysms. Seventeen (9.6 %) had giant aneurysms. Three hundred and eleven aneurysms were treated using detachable coils, and 12 giant aneurysms were embolized by detachable balloons for the parent vessel occlusion. Of 323 aneurysms treated via the endovascular approach, total occlusion was seen in 93 % of the aneurysms, near total occlusion in 5.2 % and incomplete embolization in 1.5 %. Among patients presenting with sub-arachnoid hemorrhage, 62 improved to the Glasgow outcome score (GOS) of 5, 93 improved to GOS 4, 14 improved to GOS 3, 10 improved to GOS 2 at the time of discharge and 5 patients died. Angiographic follow-up was scheduled between 6 - 12 months post-embolization. The aneurysm recurred in 1.2 % and were re-embolized using additional coils. Statistically, Hunt and Hess Grade and GOS indicated clinical significance (P < 0.05). The patients, gender, clinical presentation and aneurysmal location did not show statistical significance (P > 0.05). Hunt and Hess VI and V are considered as poor clinical gradings in aneurysmal SAH. However, endovascular treatment has been established as an effective method to obliterate intracranial aneurysms allowing subsequent decrease in mortality and morbidity. ",0
4391,22923196,New steroidal saponins and sterol glycosides from Paris polyphylla var. yunnanensis,"Four new steroidal saponins, pariposides A-D (1-4), and two new sterol glycosides, pariposides E-F (5-6), along with eight known steroidal saponins (7-14), two known sterol glycosides (15-16), and two known ecdysteroids (17-18), were isolated from the roots of Paris polyphylla var. yunnanensis. Among them, compounds 1-4 are the first spirostanol saponins with a peroxy group located between C-5 and C-8 of the aglycone. Their structures were determined by detailed spectroscopic analyses and chemical methods. All the isolated compounds were evaluated for their in vitro cytotoxicities against human nasopharyngeal carcinoma epithelial (CNE) cells, and steroidal saponins 7, 11, 13, and 14 showed a potent antiproliferative effect on CNE cells with IC₅₀ values of 9.2, 4.7, 11.1, and 2.7 µM, respectively. ",0
4392,22931314,HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1,"BACKGROUND: Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. METHODS: We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes. RESULTS: Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01). CONCLUSIONS: Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.).",0
4393,22941940,A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice,"Obesity is highly associated with dyslipidemia and cardiovascular disease. However, the mechanism behind this association is not completely understood. The hormone leptin may be a molecular link between obesity and dysregulation of lipid metabolism. Leptin can affect lipid metabolism independent of its well-known effects on food intake and energy expenditure, but exactly how this occurs is ill-defined. We hypothesized that since leptin receptors are found on the liver and the liver plays an integral role in regulating lipid metabolism, leptin may affect lipid metabolism by acting directly on the liver. To test this hypothesis, we generated mice with a hepatocyte-specific loss of leptin signaling. We previously showed that these mice have increased insulin sensitivity and elevated levels of liver triglycerides compared with controls. Here, we show that mice lacking hepatic leptin signaling have decreased levels of plasma apolipoprotein B yet increased levels of very low density lipoprotein (VLDL) triglycerides, suggesting alterations in triglyceride incorporation into VLDL or abnormal lipoprotein remodeling in the plasma. Indeed, lipoprotein profiles revealed larger apolipoprotein B-containing lipoprotein particles in mice with ablated liver leptin signaling. Loss of leptin signaling in the liver was also associated with a substantial increase in lipoprotein lipase activity in the liver, which may have contributed to increased lipid droplets in the liver. CONCLUSION: Lack of hepatic leptin signaling results in increased lipid accumulation in the liver and larger, more triglyceride-rich VLDL particles. Collectively, these data reveal an interesting role for hepatic leptin signaling in modulating triglyceride metabolism.",0
4394,22970944,PTEN mutations as a cause of constitutive insulin sensitivity and obesity,"BACKGROUND: Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans. METHODS: We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness. RESULTS: Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients' insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution. CONCLUSIONS: PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.).",0
4395,22992075,A randomized study of how physicians interpret research funding disclosures,"BACKGROUND: The effects of clinical-trial funding on the interpretation of trial results are poorly understood. We examined how such support affects physicians' reactions to trials with a high, medium, or low level of methodologic rigor. METHODS: We presented 503 board-certified internists with abstracts that we designed describing clinical trials of three hypothetical drugs. The trials had high, medium, or low methodologic rigor, and each report included one of three support disclosures: funding from a pharmaceutical company, NIH funding, or none. For both factors studied (rigor and funding), one of the three possible variations was randomly selected for inclusion in the abstracts. Follow-up questions assessed the physicians' impressions of the trials' rigor, their confidence in the results, and their willingness to prescribe the drugs. RESULTS: The 269 respondents (53.5% response rate) perceived the level of study rigor accurately. Physicians reported that they would be less willing to prescribe drugs tested in low-rigor trials than those tested in medium-rigor trials (odds ratio, 0.64; 95% confidence interval [CI], 0.46 to 0.89; P=0.008) and would be more willing to prescribe drugs tested in high-rigor trials than those tested in medium-rigor trials (odds ratio, 3.07; 95% CI, 2.18 to 4.32; P<0.001). Disclosure of industry funding, as compared with no disclosure of funding, led physicians to downgrade the rigor of a trial (odds ratio, 0.63; 95% CI, 0.46 to 0.87; P=0.006), their confidence in the results (odds ratio, 0.71; 95% CI, 0.51 to 0.98; P=0.04), and their willingness to prescribe the hypothetical drugs (odds ratio, 0.68; 95% CI, 0.49 to 0.94; P=0.02). Physicians were half as willing to prescribe drugs studied in industry-funded trials as they were to prescribe drugs studied in NIH-funded trials (odds ratio, 0.52; 95% CI, 0.37 to 0.71; P<0.001). These effects were consistent across all levels of methodologic rigor. CONCLUSIONS: Physicians discriminate among trials of varying degrees of rigor, but industry sponsorship negatively influences their perception of methodologic quality and reduces their willingness to believe and act on trial findings, independently of the trial's quality. These effects may influence the translation of clinical research into practice.",0
4396,22996189,Hepatitis B virus polymerase impairs interferon-?-induced STA T activation through inhibition of importin-?5 and protein kinase C-?,"Treatment with exogenous interferon (IFN)-? is not effective in the majority of patients with chronic hepatitis B virus (HBV) infection. Recent evidence suggests that HBV has evolved strategies to block the nuclear translocation of signal transducer and activator of transcription (STAT) 1 to limit IFN-?-induced cellular antiviral responses. However, it remains unclear whether STAT1 translocation is impaired in chronic hepatitis B patients and what mechanisms are involved. Here we report that the expression of HBV polymerase (Pol) in human hepatic cell lines inhibited induction of IFN-stimulated genes and resulted in a weakened antiviral activity of IFN-?. Ectopic expression of Pol suppressed IFN-?-induced STAT1 serine 727 phosphorylation and STAT1/2 nuclear accumulation, whereas STAT1 tyrosine 701 phosphorylation, and STAT1-STAT2 heterodimer formation were not affected. Further studies demonstrated that Pol interacted with the catalytic domain of protein kinase C-? (PKC-?) and perturbed PKC-? phosphorylation and its association with STAT1, which resulted in the suppression of STAT1 Ser727 phosphorylation. Moreover, Pol was found to interfere with nuclear transportation of STAT1/2 by competitively binding to the region of importin-?5 required for STAT1/2 recruitment. Truncation analysis suggested that the terminal protein and RNase H domains of Pol were able to bind to PKC-? and importin-?5, respectively, and were responsible for the inhibition of IFN-? signaling. More importantly, the inhibition of STAT1 and PKC-? phosphorylation were confirmed in a hydrodynamic-based HBV mouse model, and the blockage of IFN-?-induced STAT1/2 nuclear translocation was observed in HBV-infected cells from liver biopsies of chronic HBV patients. CONCLUSIONS: These results demonstrate a role for Pol in HBV-mediated antagonization of IFN-? signaling and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains its persistence.",0
4397,22996292,IFITM1 is a tight junction protein that inhibits hepatitis C virus entry,"Type 1 interferon (IFN) continues to be the foundation for the current standard of care combination therapy for chronic hepatitis C virus (HCV) infection, yet the component interferon-stimulated genes (ISGs) that mediate the antiviral actions of IFN are not fully defined. Interferon-induced transmembrane protein 1 (IFITM1) is an ISG product that suppresses early stage infection by a number of viruses through an unknown mechanism of action. Moreover, the actions of IFITM1 on HCV infection are not fully elucidated. Here we identify IFITM1 as a hepatocyte tight junction protein and a potent anti-HCV effector molecule. IFITM1 expression is induced early during IFN treatment of hepatocytes and accumulates at hepatic tight junctions in HCV-infected human patient liver during IFN therapy. Additionally, we found that IFITM1 interacts with HCV coreceptors, including CD81 and occludin, to disrupt the process of viral entry. Thus, IFITM1 is an anti-HCV ISG whose actions impart control of HCV infection through interruption of viral coreceptor function. CONCLUSION: This study defines IFITM1 as an ISG effector with action against HCV entry. Design of therapy regimens to enhance IFITM1 expression should improve the virologic response among HCV patients undergoing treatment with type I IFN.",0
4398,22996325,Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis,"Collectively, the data in both humans and murine models of human primary biliary cirrhosis (PBC) suggest that activated T cells, particularly CD8 T cells, play a critical role in biliary cell destruction. Under physiological conditions, T-cell activation involves two critical signals that involve the major histocompatibility complex and a set of costimulatory molecules, which include a receptor on T cells termed cytotoxic T lymphocyte antigen 4 (CTLA-4). Germane to the studies reported herein, signaling by CTLA-4 has the potential to modulate costimulation and induce inhibitory signals. In this study, we have taken advantage of our well-defined murine model of PBC, in which mice are immunized with 2-octynoic acid coupled to bovine serum albumin (2OA-BSA), leading to the production of high-titer antimitochondrial autoantibodies (AMAs) and portal cellular infiltrates. To investigate the potential of CTLA-4-Ig (immunoglobulin) as an immunotherapeutic agent, we treated mice both before and after induction of autoimmune cholangitis. First, we demonstrate that CTLA-4-Ig treatment, begun 1 day before 2OA-BSA immunization, completely inhibits the manifestations of cholangitis, including AMA production, intrahepatic T-cell infiltrates, and bile duct damage. However, and more critically, treatment with CTLA-4-Ig, initiated after the development of autoimmune cholangitis in previously immunized mice, also resulted in significant therapeutic benefit, including reduced intrahepatic T-cell infiltrates and biliary cell damage, although AMA levels were not altered. CONCLUSION: These data suggest that an optimized regimen with CTLA-4-Ig has the potential to serve as an investigative therapeutic tool in patients with PBC.",0
4399,22998340,A trial of sugar-free or sugar-sweetened beverages and body weight in children,"BACKGROUND: The consumption of beverages that contain sugar is associated with overweight, possibly because liquid sugars do not lead to a sense of satiety, so the consumption of other foods is not reduced. However, data are lacking to show that the replacement of sugar-containing beverages with noncaloric beverages diminishes weight gain. METHODS: We conducted an 18-month trial involving 641 primarily normal-weight children from 4 years 10 months to 11 years 11 months of age. Participants were randomly assigned to receive 250 ml (8 oz) per day of a sugar-free, artificially sweetened beverage (sugar-free group) or a similar sugar-containing beverage that provided 104 kcal (sugar group). Beverages were distributed through schools. At 18 months, 26% of the children had stopped consuming the beverages; the data from children who did not complete the study were imputed. RESULTS: The z score for the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) increased on average by 0.02 SD units in the sugar-free group and by 0.15 SD units in the sugar group; the 95% confidence interval (CI) of the difference was -0.21 to -0.05. Weight increased by 6.35 kg in the sugar-free group as compared with 7.37 kg in the sugar group (95% CI for the difference, -1.54 to -0.48). The skinfold-thickness measurements, waist-to-height ratio, and fat mass also increased significantly less in the sugar-free group. Adverse events were minor. When we combined measurements at 18 months in 136 children who had discontinued the study with those in 477 children who completed the study, the BMI z score increased by 0.06 SD units in the sugar-free group and by 0.12 SD units in the sugar group (P=0.06). CONCLUSIONS: Masked replacement of sugar-containing beverages with noncaloric beverages reduced weight gain and fat accumulation in normal-weight children. (Funded by the Netherlands Organization for Health Research and Development and others; DRINK ClinicalTrials.gov number, NCT00893529.).",0
4400,23013074,Physicians' warnings for unfit drivers and the risk of trauma from road crashes,"BACKGROUND: Physicians' warnings to patients who are potentially unfit to drive are a medical intervention intended to prevent trauma from motor vehicle crashes. We assessed the association between medical warnings and the risk of subsequent road crashes. METHODS: We identified consecutive patients who received a medical warning in Ontario, Canada, between April 1, 2006, and December 31, 2009, from a physician who judged them to be potentially unfit to drive. We excluded patients who were younger than 18 years of age, who were not residents of Ontario, or who lacked valid health-card numbers under universal health insurance. We analyzed emergency department visits for road crashes during a baseline interval before the warning and a subsequent interval after the warning. RESULTS: A total of 100,075 patients received a medical warning from a total of 6098 physicians. During the 3-year baseline interval, there were 1430 road crashes in which the patient was a driver and presented to the emergency department, as compared with 273 road crashes during the 1-year subsequent interval, representing a reduction of approximately 45% in the annual rate of crashes per 1000 patients after the warning (4.76 vs. 2.73, P<0.001). The lower rate was observed across patients with diverse characteristics. No significant change was observed in subsequent crashes in which patients were pedestrians or passengers. Medical warnings were associated with an increase in subsequent emergency department visits for depression and a decrease in return visits to the responsible physician. CONCLUSIONS: Physicians' warnings to patients who are potentially unfit to drive may contribute to a decrease in subsequent trauma from road crashes, yet they may also exacerbate mood disorders and compromise the doctor-patient relationship. (Funded by the Canada Research Chairs program and others.).",0
4401,23034020,"C-reactive protein, fibrinogen, and cardiovascular disease prediction","""BACKGROUND: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of """"low"""" (<10%), """"intermediate"""" (10% to <20%), and """"high"""" (?20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ?20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. CONCLUSIONS: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).""",0
4402,23050526,Effect of nonpayment for preventable infections in U.S. hospitals,"BACKGROUND: In October 2008, the Centers for Medicare and Medicaid Services (CMS) discontinued additional payments for certain hospital-acquired conditions that were deemed preventable. The effect of this policy on rates of health care-associated infections is unknown. METHODS: Using a quasi-experimental design with interrupted time series with comparison series, we examined changes in trends of two health care-associated infections that were targeted by the CMS policy (central catheter-associated bloodstream infections and catheter-associated urinary tract infections) as compared with an outcome that was not targeted by the policy (ventilator-associated pneumonia). Hospitals participating in the National Healthcare Safety Network and reporting data on at least one health care-associated infection before the onset of the policy were eligible to participate. Data from January 2006 through March 2011 were included. We used regression models to measure the effect of the policy on changes in infection rates, adjusting for baseline trends. RESULTS: A total of 398 hospitals or health systems contributed 14,817 to 28,339 hospital unit-months, depending on the type of infection. We observed decreasing secular trends for both targeted and nontargeted infections long before the policy was implemented. There were no significant changes in quarterly rates of central catheter-associated bloodstream infections (incidence-rate ratio in the postimplementation vs. preimplementation period, 1.00; P=0.97), catheter-associated urinary tract infections (incidence-rate ratio, 1.03; P=0.08), or ventilator-associated pneumonia (incidence-rate ratio, 0.99; P=0.52) after the policy implementation. Our findings did not differ for hospitals in states without mandatory reporting, nor did it differ according to the quartile of percentage of Medicare admissions or hospital size, type of ownership, or teaching status. CONCLUSIONS: We found no evidence that the 2008 CMS policy to reduce payments for central catheter-associated bloodstream infections and catheter-associated urinary tract infections had any measurable effect on infection rates in U.S. hospitals. (Funded by the Agency for Healthcare Research and Quality.).",0
4403,23081697,Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis,"Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1(mid) cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1(mid) recruitment and decreased tumor burden. Depletion of the CD11b/Gr1(mid) subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1(mid) cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. CONCLUSION: Collectively, our findings highlight the importance of myeloid cells--in this case a selective CD11b/Gr1(mid) subset--in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy.",0
4404,23094723,Patients' expectations about effects of chemotherapy for advanced cancer,"BACKGROUND: Chemotherapy for metastatic lung or colorectal cancer can prolong life by weeks or months and may provide palliation, but it is not curative. METHODS: We studied 1193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study (a national, prospective, observational cohort study) who were alive 4 months after diagnosis and received chemotherapy for newly diagnosed metastatic (stage IV) lung or colorectal cancer. We sought to characterize the prevalence of the expectation that chemotherapy might be curative and to identify the clinical, sociodemographic, and health-system factors associated with this expectation. Data were obtained from a patient survey by professional interviewers in addition to a comprehensive review of medical records. RESULTS: Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy was not at all likely to cure their cancer. In multivariable logistic regression, the risk of reporting inaccurate beliefs about chemotherapy was higher among patients with colorectal cancer, as compared with those with lung cancer (odds ratio, 1.75; 95% confidence interval [CI], 1.29 to 2.37); among nonwhite and Hispanic patients, as compared with non-Hispanic white patients (odds ratio for Hispanic patients, 2.82; 95% CI, 1.51 to 5.27; odds ratio for black patients, 2.93; 95% CI, 1.80 to 4.78); and among patients who rated their communication with their physician very favorably, as compared with less favorably (odds ratio for highest third vs. lowest third, 1.90; 95% CI, 1.33 to 2.72). Educational level, functional status, and the patient's role in decision making were not associated with such inaccurate beliefs about chemotherapy. CONCLUSIONS: Many patients receiving chemotherapy for incurable cancers may not understand that chemotherapy is unlikely to be curative, which could compromise their ability to make informed treatment decisions that are consonant with their preferences. Physicians may be able to improve patients' understanding, but this may come at the cost of patients' satisfaction with them. (Funded by the National Cancer Institute and others.).",0
4405,23113483,Comparing local and regional variation in health care spending,"BACKGROUND: Wide geographic variation in health care spending has generated both concern about inefficiency and policy debate about geographic-based payment reform. Evidence regarding variation has focused on hospital referral regions (HRRs), which incorporate numerous local hospital service areas (HSAs). If there is substantial variation across local areas within HRRs, then policies focusing on HRRs may be poorly targeted. METHODS: Using prescription drug and medical claims data from a 5% random sample of Medicare beneficiaries from 2006 through 2009, we compared variation in health care spending and utilization among 306 HRRs and 3436 HSAs. We adjusted for beneficiary-level demographic characteristics, insurance status, and clinical characteristics. RESULTS: There was substantial local variation in health care (drug and nondrug) utilization and spending. Furthermore, many of the low-spending HSAs were located in high-spending HRRs, and many of the high-spending HSAs were in low-spending HRRs. For drug spending, only 50.7% of the HSAs located within the borders of the highest-spending quintile of HRRs were in the highest-spending quintile of HSAs; conversely, only 51.5% of the highest-spending HSAs were located within the borders of the highest-spending HRRs. Similar patterns were observed for nondrug spending. CONCLUSIONS: The effectiveness of payment reforms in reducing overutilization while maintaining access to high-quality care depends on the effectiveness of targeting. Our analysis suggests that HRR-based policies may be too crudely targeted to promote the best use of health care resources. (Funded by the Institute of Medicine and others.).",0
4406,23113832,"""Medicare's enduring struggle to define """"reasonable and necessary"""" care""","""Medicare legislation mandates that the program not pay for items and services that are not """"reasonable and necessary"""" - terms that are open to interpretation and easily politicized. In today's fiscal environment, """"reasonable and necessary"""" warrants a closer look.""",0
4407,23131066,Reduction in inappropriate therapy and mortality through ICD programming,"BACKGROUND: The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects. METHODS: We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ?200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ?250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ?200 beats per minute). RESULTS: During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval [CI], 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups. CONCLUSIONS: Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310.).",0
4408,23134356,Progression of RAS-mutant leukemia during RAF inhibitor treatment,"Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E-mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E-mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors. We report the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib. Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal.",0
4409,23134381,Statin use and reduced cancer-related mortality,"BACKGROUND: A reduction in the availability of cholesterol may limit the cellular proliferation required for cancer growth and metastasis. We tested the hypothesis that statin use begun before a cancer diagnosis is associated with reduced cancer-related mortality. METHODS: We assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. Among patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins. RESULTS: Multivariable-adjusted hazard ratios for statin users, as compared with patients who had never used statins, were 0.85 (95% confidence interval [CI], 0.83 to 0.87) for death from any cause and 0.85 (95% CI, 0.82 to 0.87) for death from cancer. Adjusted hazard ratios for death from any cause according to the defined daily statin dose (the assumed average maintenance dose per day) were 0.82 (95% CI, 0.81 to 0.85) for a dose of 0.01 to 0.75 defined daily dose per day, 0.87 (95% CI, 0.83 to 0.89) for 0.76 to 1.50 defined daily dose per day, and 0.87 (95% CI, 0.81 to 0.91) for higher than 1.50 defined daily dose per day; the corresponding hazard ratios for death from cancer were 0.83 (95% CI, 0.81 to 0.86), 0.87 (95% CI, 0.83 to 0.91), and 0.87 (95% CI, 0.81 to 0.92). The reduced cancer-related mortality among statin users as compared with those who had never used statins was observed for each of 13 cancer types. CONCLUSIONS: Statin use in patients with cancer is associated with reduced cancer-related mortality. This suggests a need for trials of statins in patients with cancer.",0
4410,23134382,Reduced mortality with hospital pay for performance in England,"BACKGROUND: Pay-for-performance programs are being adopted internationally despite little evidence that they improve patient outcomes. In 2008, a program called Advancing Quality, based on the Hospital Quality Incentive Demonstration in the United States, was introduced in all National Health Service (NHS) hospitals in the northwest region of England (population, 6.8 million). METHODS: We analyzed 30-day in-hospital mortality among 134,435 patients admitted for pneumonia, heart failure, or acute myocardial infarction to 24 hospitals covered by the pay-for-performance program. We used difference-in-differences regression analysis to compare mortality 18 months before and 18 months after the introduction of the program with mortality in two comparators: 722,139 patients admitted for the same three conditions to the 132 other hospitals in England and 241,009 patients admitted for six other conditions to both groups of hospitals. RESULTS: Risk-adjusted, absolute mortality for the conditions included in the pay-for-performance program decreased significantly, with an absolute reduction of 1.3 percentage points (95% confidence interval [CI], 0.4 to 2.1; P=0.006) and a relative reduction of 6%, equivalent to 890 fewer deaths (95% CI, 260 to 1500) during the 18-month period. The largest reduction, for pneumonia, was significant (1.9 percentage points; 95% CI, 0.9 to 3.0; P<0.001), with nonsignificant reductions for acute myocardial infarction (0.6 percentage points; 95% CI, -0.4 to 1.7; P=0.23) and heart failure (0.6 percentage points; 95% CI, -0.6 to 1.8; P=0.30). CONCLUSIONS: The introduction of pay for performance in all NHS hospitals in one region of England was associated with a clinically significant reduction in mortality. As compared with a similar U.S. program, the U.K. program had larger bonuses and a greater investment by hospitals in quality-improvement activities. Further research is needed on how implementation of pay-for-performance programs influences their effects. (Funded by the NHS National Institute for Health Research.).",0
4411,23150934,TREM2 variants in Alzheimer's disease,"BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).",0
4412,23161433,A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant,"Two determinants of infectivity have been identified in the hepatitis B virus (HBV) envelope proteins: a pre-S1 receptor-binding site and an uncharacterized determinant in the antigenic loop (AGL), which is structurally related to the antigenic a-determinant. Infection would proceed through virus attachment to cell surface heparan sulfate (HS) proteoglycans (HSPGs) before pre-S1 engages a specific receptor for uptake. Using heparin binding and in vitro infection assays with hepatitis D virus as a surrogate for HBV, we established that HS binding is mediated by the AGL. Electrostatic interaction was shown to depend upon AGL residues R122 and K141, because their substitution with alanine modified the virus net-charge and prevented binding to heparin, attachment to hepatocytes, and infection. In addition to R122 and K141, the HS binding determinant was mapped to cysteines and prolines, which also define the conformational a-determinant. The importance of AGL conformation was further demonstrated by the concomitant loss of a-determinant and heparin binding upon treatment of viral particles with membrane-impermeable reducing agent. Furthermore, envelope proteins extracted from the viral membrane with a nonionic detergent were shown to conserve the a-determinant but to lose heparin affinity/avidity. CONCLUSION: Our findings support a model in which attachment of HBV to HSPGs is mediated by the AGL HS binding site, including only two positively charged residues (R122 and K141) positioned precisely in a three-dimensional AGL structure that is stabilized by disulfide bonds. HBV envelope proteins would individually bind to HS with low affinity, but upon their clustering in the viral membrane, they would reach sufficient avidity for a stable interaction between virus and cell surface HSPGs. Our data provide new insight into the HBV entry pathway, including the opportunity to design antivirals directed to the AGL-HS interaction.",0
4413,23172780,Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence,"In efforts to inform public health decision makers, the Global Burden of Diseases, Injuries, and Risk Factors 2010 (GBD2010) Study aims to estimate the burden of disease using available parameters. This study was conducted to collect and analyze available prevalence data to be used for estimating the hepatitis C virus (HCV) burden of disease. In this systematic review, antibody to HCV (anti-HCV) seroprevalence data from 232 articles were pooled to estimate age-specific seroprevalence curves in 1990 and 2005, and to produce age-standardized prevalence estimates for each of 21 GBD regions using a model-based meta-analysis. This review finds that globally the prevalence and number of people with anti-HCV has increased from 2.3% (95% uncertainty interval [UI]: 2.1%-2.5%) to 2.8% (95% UI: 2.6%-3.1%) and >122 million to >185 million between 1990 and 2005. Central and East Asia and North Africa/Middle East are estimated to have high prevalence (>3.5%); South and Southeast Asia, sub-Saharan Africa, Andean, Central, and Southern Latin America, Caribbean, Oceania, Australasia, and Central, Eastern, and Western Europe have moderate prevalence (1.5%-3.5%); whereas Asia Pacific, Tropical Latin America, and North America have low prevalence (<1.5%). CONCLUSION: The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to secondary and tertiary prevention to reduce the burden of chronic liver disease and to improve survival for those who already have evidence of liver disease.",0
4414,23174804,Chronic intermittent hypoxia aggravates intrahepatic endothelial dysfunction in cirrhotic rats,"Chronic intermittent hypoxia (CIH) occurs with obstructive sleep apnea syndrome (OSAS) and provokes systemic endothelial dysfunction, which is associated with oxidative stress and low nitric oxide (NO) bioavailability. Cirrhotic livers exhibit intrahepatic endothelial dysfunction, which is characterized by an impaired endothelium-dependent response to vasodilators and hyperresponse to vasoconstrictors. We hypothesized that CIH may also contribute to intrahepatic endothelial dysfunction in cirrhosis. Normal and cirrhotic rats were exposed for 14 days to repetitive cycles of CIH mimicking OSAS in humans, or caged with room air (handled controls [HC]). Hepatic endothelial function was assessed in isolated and perfused rat livers by dose-response curves to acetylcholine (ACh) and methoxamine (Mtx). In a group of cirrhotic rats, in vivo systemic and hepatic hemodynamic parameters were evaluated at baseline and after volume expansion. In addition, liver samples were obtained to assess endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), NO bioavailability, and nitrotyrosinated proteins as a marker of oxidative stress. Cirrhotic rats exposed to CIH exhibited an attenuated vasodilatory response to ACh and hyperresponse to Mtx compared with HC rats. During volume expansion, similar portal pressure increases were observed in CIH and HC rats, although the mean arterial pressure increase was lower after CIH. These functional responses were associated with the presence of increased hepatic oxidative stress without changes in p-eNOS after CIH exposure. In normal rats, no hemodynamic changes were found. CONCLUSION: CIH exacerbates intrahepatic endothelial dysfunction in cirrhotic rats, which is associated with increased oxidative stress that may reduce NO bioavailability. Clinical studies are needed to assess whether OSAS contributes to endothelial impairment in human patients with cirrhosis.",0
4415,23212706,Characterization of the inhibition of hepatitis C virus entry by in vitro-generated and patient-derived oxidized low-density lipoprotein,"Oxidized low-density lipoprotein (oxLDL) has been reported as an inhibitor of hepatitis C virus (HCV) cell entry, making it the only known component of human lipid metabolism with an antiviral effect on HCV. However, several questions remain open, including its effect on full-length cell-culture-grown HCV (HCVcc) of different genotypes or on other steps of the viral replication cycle, its mechanism of action, and whether endogenous oxLDL shares the anti-HCV properties of in vitro-generated oxLDL. We combined molecular virology tools with oxLDL serum measurements in different patient cohorts to address these questions. We found that oxLDL inhibits HCVcc at least as potently as HCV pseudoparticles. There was moderate variation between genotypes, with genotype 4 appearing the most oxLDL sensitive. Intracellular RNA replication and assembly and release of new particles were unaffected. HCV particles entering target cells lost oxLDL sensitivity with time kinetics parallel to anti-SR-BI (scavenger receptor class B type I), but significantly earlier than anti-CD81, suggesting that oxLDL acts by perturbing interaction between HCV and SR-BI. Finally, in chronically HCV-infected individuals, endogenous serum oxLDL levels did not correlate with viral load, but in HCV-negative sera, high endogenous oxLDL had a negative effect on HCV infectivity in vitro. CONCLUSION: oxLDL is a potent pangenotype HCV entry inhibitor that maintains its activity in the context of human serum and targets an early step of HCV entry.",0
4416,23213086,Vitamin A deficiency is associated with hepatitis C virus chronic infection and with unresponsiveness to interferon-based antiviral therapy,"Recent data suggest that vitamin A modulates the expression of type I interferon receptor enhancing the antireplication effect of interferon-? on hepatitis C virus (HCV). This study aimed to investigate the prevalence of vitamin A deficiency among patients with chronic HCV infection and to assess whether vitamin A deficiency could be associated with unresponsiveness to interferon-based antiviral therapy. The analysis included 199 consecutive treatment-na?ve chronic HCV patients in whom pretreatment serum vitamin A and 25-OH vitamin D were measured; 119 healthy blood donors were used as controls. Median (interquartile range) serum vitamin A in HCV-positive patients was significantly lower than in controls: 256 ng/mL (128-440) versus 742 (624-942, P<0.0001). Overall sustained viral response was achieved in 122/199 patients, 46/109 infected by difficult to treat HCV genotypes. In these latter, 39/104 (37.5%) were nonresponders. At multivariate analysis, nonresponse to antiviral therapy was predicted by carriage of interleukin (IL)-28B T/* genotypes, baseline serum levels of ?GT>60 IU/mL, of HCV RNA>600,000 IU/mL, of vitamin A?100 ng/mL, and a cumulative dose of ribavirin?80%. Seventeen patients (9.0%) had both serum levels of vitamin A?100 ng/mL and of vitamin D?20 ng/mL; the presence of a combined vitamin A and D deficiency was found to be a strong independent predictor of nonresponse to antiviral therapy. CONCLUSION: A high percentage of patients with chronic HCV infection have serum vitamin A deficiency. This condition is associated with nonresponse to antiviral therapy.",0
4417,23258554,"Hepatic lentiviral gene transfer is associated with clonal selection, but not with tumor formation in serially transplanted rodents","Lentiviral (LV) vectors are promising tools for long-term genetic correction of hereditary diseases. In hematopoietic stem cell gene therapies adverse events in patients due to vector integration-associated genotoxicity have been observed. Only a few studies have explored the potential risks of LV gene therapy targeting the liver. To analyze hepatic genotoxicity in vivo, we transferred the fumarylacetoacetate hydrolase (FAH) gene by LV vectors into FAH((-/-)) mice (n = 97) and performed serial hepatocyte transplantations (four generations). The integration profile (4,349 mapped insertions) of the LV vectors was assessed by ligation-mediated polymerase chain reaction and deep sequencing. We tested whether the polyclonality of vector insertions was maintained in serially transplanted mice, linked the integration sites to global hepatocyte gene expression, and investigated the effects of LV liver gene therapy on the survival of the animals. The lifespan of in vivo gene-corrected mice was increased compared to 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) control animals and unchanged in serially transplanted animals. The integration profile (4,349 mapped insertions) remained polyclonal through all mouse generations with only mild clonal expansion. Genes close to the integration sites of expanding clones may be associated with enhanced hepatocyte proliferation capacity. CONCLUSION: We did not find evidence for vector-induced tumors. LV hepatic gene therapy showed a favorable risk profile for stable and long-term therapeutic gene expression. Polyclonality of hepatocyte regeneration was maintained even in an environment of enforced proliferation.",0
4418,23258666,Comparative effectiveness of two doses versus three doses of hepatitis A vaccine in human immunodeficiency virus-infected and -uninfected men who have sex with men,"The purpose of this prospective cohort study was to compare the serologic response between human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) receiving two and three doses of hepatitis A virus (HAV) vaccine and HIV-uninfected MSM receiving two doses of HAV vaccine. Between June 2009 and December 2010, 582 MSM aged 18 to 40 years who were seronegative for HAV were enrolled in the study. HIV-infected MSM received either two doses of HAV vaccine (1,440 enzyme-linked immunosorbent assay units) (n = 140) with the second dose given at week 24 or three doses (n = 225) with the second and third dose given at weeks 4 and 24, respectively, while HIV-uninfected MSM (n = 217) received two doses. The primary endpoint was seroconversion at week 48. The geometric mean concentration (GMC) of anti-HAV antibody was determined at weeks 48 and 72. At week 48, the seroconversion rate was 75.7%, 77.8%, and 88.5% in intention-to-treat analysis for two-dose HIV-infected, three-dose HIV-infected, and two-dose HIV-uninfected MSM, respectively. The GMC of anti-HAV antibody at week 48 for three-dose HIV-infected MSM (2.29 � 0.73 log10 mIU/mL) was significantly higher than that for two-dose HIV-infected MSM (1.94 � 0.66; P < 0.01), but was lower than HIV-uninfected MSM (2.49 � 0.42; P < 0.01). Multivariate analysis revealed higher CD4 counts (adjusted odds ratio [AOR] for per 50 cells/?L increase, 1.13; 95% confidence interval [CI], 1.05-1.21) and undetectable plasma HIV RNA load (AOR, 1.90; 95% CI, 1.10-3.28) before HAV vaccination were predictive of seroconversion in HIV-infected patients. CONCLUSION: Serologic response rate to three and two doses of HAV vaccine was similar in HIV-infected MSM, which was lower than that in HIV-uninfected MSM receiving two doses. HAV vaccination in HIV-infected patients with a higher CD4 count and suppression of HIV replication increased the seroconversion rate.",0
4419,23292963,Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts,"The human hepatitis B virus (HBV) causes acute and chronic infections in humans and chimpanzees. HBV infects its hosts at minimal inoculation doses and replicates exclusively in hepatocytes. The viral determinants for the pronounced species specificity and the high efficacy to address hepatocytes in vivo are unknown. Previous findings showed that N-terminally myristoylated peptides constituting a receptor binding domain of the HBV large envelope (L)-protein block HBV entry in vitro and in vivo. Here we investigate the ability of such peptidic receptor ligands to target the liver. Injection of radioactively labeled HBVpreS-lipopeptides resulted in rapid accumulation in livers of mice, rats, and dogs but not cynomolgus monkeys. Without lipid moiety the peptide was excreted by renal filtration, indicating its possible retention through the lipid by serum factors. Organ distribution studies of 26 HBVpreS peptide variants revealed a correlation of HBV infection inhibition activity and the ability to target mouse livers. Together with complementary studies using primary hepatocytes of different species, we hypothesize that HBV hepatotropism is mediated through specific binding of the myristoylated N-terminal preS1-domain of the HBV L-protein to a hepatocyte specific receptor. Moreover, the restricted infectivity of HBV to human primates is not generally determined by the absence of this binding receptor in nonsusceptible hosts (e.g., mice) but related to postbinding step(s) (e.g., membrane fusion). CONCLUSION: HBVpreS-lipopeptides target to the liver. This observation has important clinical implications regarding the pharmacokinetic properties of Myrcludex B, the first entry inhibitor for HBV/HDV. In addition, this provides the basis for the application of the peptides as vehicles for hepatocyte-specific drug targeting.",0
4420,23300015,Retinol binding protein 4 stimulates hepatic sterol regulatory element-binding protein 1 and increases lipogenesis through the peroxisome proliferator-activated receptor-? coactivator 1?-dependent pathway,"Recent studies have revealed the essential role of retinol binding protein 4 (RBP4) in insulin resistance. However, the impact of RBP4 on aberrant lipogenesis, the common hepatic manifestation in insulin resistance states, and the underlying mechanism remain elusive. The present study was designed to examine the effect of RBP4 on sterol regulatory element-binding protein (SREBP-1) and hepatic lipogenesis. Treatment with human retinol-bound RBP4 (holo-RBP4) significantly induced intracellular triglyceride (TAG) synthesis in HepG2 cells and this effect is retinol-independent. Furthermore, RBP4 treatment enhanced the levels of mature SREBP-1 and its nuclear translocation, thereby increasing the expression of lipogenic genes, including fatty acid synthase (FAS), acetyl coenzyme A carboxylase-1 (ACC-1), and diacylglycerol O-acyltransferase 2 (DGAT-2). Stimulation of HepG2 cells with RBP4 strongly up-regulated the expression of transcriptional coactivator peroxisome proliferator-activated receptor-? coactivator 1? (PGC-1?) at both the messenger RNA (mRNA) and protein levels. The transcriptional activation of PGC-1? is necessary and sufficient for the transcriptional activation of SREBP-1 in response to RBP4. The cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) was identified as the target transcription factor involved in the RBP4-mediated up-regulation of PGC-1? transcription as a result of phosphorylation on Ser133. Furthermore, in vivo RBP4 infusion induced SREBP-1c activation and consequently accelerated hepatic lipogenesis and plasma TAG in C57BL/6J mice, a phenomenon not observed in Ppargc1b knockout mice. CONCLUSION: These findings reveal a novel mechanism by which RBP4 achieves its effects on hepatic lipid metabolism.",0
4421,23315914,"A global view of hepatitis C: physician knowledge, opinions, and perceived barriers to care","Chronic infection with the hepatitis C virus (HCV) is a leading cause of global morbidity and mortality. Although recent advances in antiviral therapy have led to significant improvements in treatment response rates, only a minority of infected patients are treated. Multiple barriers may impede the delivery of HCV therapy. The aim of this study was to identify perceived barriers to care, knowledge, and opinions among a global sample of HCV treatment providers. An international, multidisciplinary survey of HCV treatment providers was conducted. Each physician responded to a series of 214 questions concerning his or her practice characteristics, opinions regarding the state of HCV care, knowledge regarding HCV treatment, and perception of treatment barriers. A total of 697 physicians from 29 countries completed the survey. Overall, physicians viewed patient-level barriers as most significant, including fear of side effects and concerns regarding treatment duration and cost. There were distinct regional variations, with Central and Eastern European physicians citing government barriers as most important. In Latin America, the Middle East, and Africa, payer-level barriers, including lack of treatment coverage, were prominent. Overall, the perception of barriers was strongly associated with physician knowledge, experience, and region of origin, with the fewest barriers reported by Nordic physicians and the most reported by Middle Eastern and African physicians. Globally, physicians demonstrated deficits in basic treatment principles, including the role of viral kinetics and the management of treatment nonresponders. Two thirds of surveyed physicians believed that patients do not have adequate access to providers in their community. CONCLUSION: Barriers to HCV treatment vary globally, though patient-level factors are viewed as most significant by treating physicians. Efforts to improve awareness, education, and specialist availability are needed.",0
4422,23323897,Short-course antiretroviral therapy in primary HIV infection,"BACKGROUND: Short-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated. METHODS: We randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation. RESULTS: A total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log(10) copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events. CONCLUSIONS: A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.).",0
4423,23323900,Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient,"Ixodes ticks serve as vectors for Borrelia burgdorferi, the agent of Lyme disease. Globally, these ticks often concurrently harbor B. miyamotoi, a spirochete that is classified within the relapsing-fever group of spirochetes. Although humans presumably are exposed to B. miyamotoi, there are limited data suggesting disease attributable to it. We report a case of progressive mental deterioration in an older, immunocompromised patient, and even though Koch's postulates were not met, we posit B. miyamotoi as the cause, owing to its direct detection in cerebrospinal fluid (CSF) with the use of microscopy and a polymerase-chain-reaction (PCR) assay. It is likely that B. miyamotoi is an underrecognized cause of disease, especially in sites where Lyme disease is endemic.",0
4424,23323901,Simulation-based trial of surgical-crisis checklists,"BACKGROUND: Operating-room crises (e.g., cardiac arrest and massive hemorrhage) are common events in large hospitals but can be rare for individual clinicians. Successful management is difficult and complex. We sought to evaluate a tool to improve adherence to evidence-based best practices during such events. METHODS: Operating-room teams from three institutions (one academic medical center and two community hospitals) participated in a series of surgical-crisis scenarios in a simulated operating room. Each team was randomly assigned to manage half the scenarios with a set of crisis checklists and the remaining scenarios from memory alone. The primary outcome measure was failure to adhere to critical processes of care. Participants were also surveyed regarding their perceptions of the usefulness and clinical relevance of the checklists. RESULTS: A total of 17 operating-room teams participated in 106 simulated surgical-crisis scenarios. Failure to adhere to lifesaving processes of care was less common during simulations when checklists were available (6% of steps missed when checklists were available vs. 23% when they were unavailable, P<0.001). The results were similar in a multivariate model that accounted for clustering within teams, with adjustment for institution, scenario, and learning and fatigue effects (adjusted relative risk, 0.28; 95% confidence interval, 0.18 to 0.42; P<0.001). Every team performed better when the crisis checklists were available than when they were not. A total of 97% of the participants reported that if one of these crises occurred while they were undergoing an operation, they would want the checklist used. CONCLUSIONS: In a high-fidelity simulation study, checklist use was associated with significant improvement in the management of operating-room crises. These findings suggest that checklists for use during operating-room crises have the potential to improve surgical care. (Funded by the Agency for Healthcare Research and Quality.).",0
4425,23348596,The antimalarial ferroquine is an inhibitor of hepatitis C virus,"Hepatitis C virus (HCV) is a major cause of chronic liver disease. Despite recent success in improving anti-HCV therapy, additional progress is still needed to develop cheaper and interferon (IFN)-free treatments. Here, we report that ferroquine (FQ), an antimalarial ferrocenic analog of chloroquine, is a novel inhibitor of HCV. FQ potently inhibited HCV infection of hepatoma cell lines by affecting an early step of the viral life cycle. The antiviral activity of FQ on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition to its effect on HCV entry, FQ also inhibited HCV RNA replication, albeit at a higher concentration. We also showed that FQ has no effect on viral assembly and virion secretion. Using a binding assay at 4�C, we showed that FQ does not prevent attachment of the virus to the cell surface. Furthermore, virus internalization was not affected by FQ, whereas the fusion process was impaired in the presence of FQ as shown in a cell-cell fusion assay. Finally, virus with resistance to FQ was selected by sequential passage in the presence of the drug, and resistance was shown to be conferred by a single mutation in E1 glycoprotein (S327A). By inhibiting cell-free virus transmission using a neutralizing antibody, we also showed that FQ inhibits HCV cell-to-cell spread between neighboring cells. Combinations of FQ with IFN, or an inhibitor of HCV NS3/4A protease, also resulted in additive to synergistic activity. CONCLUSION: FQ is a novel, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals.",0
4426,23359250,Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect,"Earlier reports suggest a link between mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a mitochondrial trifunctional protein (MTP) gene defect to determine if a primary defect in mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro using primary hepatocytes isolated from HET and wildtype (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused an ?50% reduction in mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin-stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho-FOXO1 protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3? was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic diacylglycerol content, activated protein kinase C-? (PKC-?), inhibitor ?B kinase ? (IKK-?), c-Jun N-terminal kinase (JNK), or phospho-JNK protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT. CONCLUSION: A primary defect in mitochondrial fatty acid ?-oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered responsible for insulin resistance. (HEPATOLOGY 2013;).",0
4427,23363498,"Myths, presumptions, and facts about obesity","BACKGROUND: Many beliefs about obesity persist in the absence of supporting scientific evidence (presumptions); some persist despite contradicting evidence (myths). The promulgation of unsupported beliefs may yield poorly informed policy decisions, inaccurate clinical and public health recommendations, and an unproductive allocation of research resources and may divert attention away from useful, evidence-based information. METHODS: Using Internet searches of popular media and scientific literature, we identified, reviewed, and classified obesity-related myths and presumptions. We also examined facts that are well supported by evidence, with an emphasis on those that have practical implications for public health, policy, or clinical recommendations. RESULTS: We identified seven obesity-related myths concerning the effects of small sustained increases in energy intake or expenditure, establishment of realistic goals for weight loss, rapid weight loss, weight-loss readiness, physical-education classes, breast-feeding, and energy expended during sexual activity. We also identified six presumptions about the purported effects of regularly eating breakfast, early childhood experiences, eating fruits and vegetables, weight cycling, snacking, and the built (i.e., human-made) environment. Finally, we identified nine evidence-supported facts that are relevant for the formulation of sound public health, policy, or clinical recommendations. CONCLUSIONS: False and scientifically unsupported beliefs about obesity are pervasive in both scientific literature and the popular press. (Funded by the National Institutes of Health.).",0
4428,23386589,Wnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells in mice,"The molecular mechanisms regulating differentiation of fetal hepatic stem/progenitor cells, called hepatoblasts, which play pivotal roles in liver development, remain obscure. Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. Although a ?-catenin-independent noncanonical Wnt pathway is essential for cell adhesion and polarity, the physiological functions of noncanonical Wnt pathways in liver development are unknown. Here we describe a functional role for Wnt5a, a noncanonical Wnt ligand, in the differentiation of mouse hepatoblasts. Wnt5a was expressed in mesenchymal cells and other cells of wild-type (WT) midgestational fetal liver. We analyzed fetal liver phenotypes in Wnt5a-deficient mice using a combination of histological and molecular techniques. Expression levels of Sox9 and the number of hepatocyte nuclear factor (HNF)1?(+) HNF4?(-) biliary precursor cells were significantly higher in Wnt5a-deficient liver relative to WT liver. In Wnt5a-deficient fetal liver, in vivo formation of primitive bile ductal structures was significantly enhanced relative to WT littermates. We also investigated the function of Wnt5a protein and downstream signaling molecules using a three-dimensional culture system that included primary hepatoblasts or a hepatic progenitor cell line. In vitro differentiation assays showed that Wnt5a retarded the formation of bile duct-like structures in hepatoblasts, leading instead to hepatic maturation of such cells. Whereas Wnt5a signaling increased steady-state levels of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in fetal liver, inhibition of CaMKII activity resulted in the formation of significantly more and larger-sized bile duct-like structures in vitro compared with those in vehicle-supplemented controls. CONCLUSION: Wnt5a-mediated signaling in fetal hepatic stem/progenitor cells suppresses biliary differentiation. These findings also suggest that activation of CaMKII by Wnt5a signaling suppresses biliary differentiation. (HEPATOLOGY 2013;).",0
4429,23389926,GABA induces the differentiation of small into large cholangiocytes by activation of Ca(2+) /CaMK I-dependent adenylyl cyclase 8,"Large, but not small, cholangiocytes (1) secrete bicarbonate by interaction with secretin receptors (SRs) through activation of cystic fibrosis transmembrane regulator (CFTR), Cl(-) /HCO3 (-) (apex) anion exchanger 2 (Cl(-) /HCO3 (-) AE2), and adenylyl cyclase (AC)8 (proteins regulating large biliary functions) and (2) proliferate in response to bile duct ligation (BDL) by activation of cyclic adenosine monophosphate (cAMP) signaling. Small, mitotically dormant cholangiocytes are activated during damage of large cholangiocytes by activation of D-myo-inositol 1,4,5-trisphosphate/Ca(2+) /calmodulin-dependent protein kinase (CaMK) I. gamma-Aminobutyric acid (GABA) affects cell functions by modulation of Ca(2+) -dependent signaling and AC. We hypothesized that GABA induces the differentiation of small into large cholangiocytes by the activation of Ca(2+) /CaMK I-dependent AC8. In vivo, BDL mice were treated with GABA in the absence or presence of 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester (BAPTA/AM) or N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) before evaluating apoptosis and intrahepatic bile ductal mass (IBDM) of small and large cholangiocytes. In vitro, control- or CaMK I-silenced small cholangiocytes were treated with GABA for 3 days before evaluating apoptosis, proliferation, ultrastructural features, and the expression of CFTR, Cl(-) /HCO3 (-) AE2, AC8, and secretin-stimulated cAMP levels. In vivo administration of GABA induces the apoptosis of large, but not small, cholangiocytes and decreases large IBDM, but increased de novo small IBDM. GABA stimulation of small IBDM was blocked by BAPTA/AM and W7. Subsequent to GABA in vitro treatment, small cholangiocytes de novo proliferate and acquire ultrastructural and functional phenotypes of large cholangiocytes and respond to secretin. GABA-induced changes were prevented by BAPTA/AM, W7, and stable knockdown of the CaMK I gene. CONCLUSION: GABA damages large, but not small, cholangiocytes that differentiate into large cholangiocytes. The differentiation of small into large cholangiocytes may be important in the replenishment of the biliary epithelium during damage of large, senescent cholangiocytes.",0
4430,23390091,Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin,"The first seven members of the proprotein convertase (PC) family activate protein precursors by cleavage after basic residues. While PC7 has no known specific substrates, it shows redundancy with other PCs. A genome-wide association study suggested that circulating levels of shed human transferrin receptor 1 (hTfR1) are regulated by PC7. We thus examined whether hTfR1 constitutes a specific substrate for PC7. Coexpression of hTfR1 with PCs in several cell lines indicated that PC7 is the only convertase that sheds this receptor into the medium. Site-directed mutagenesis showed that cleavage occurs at the unusual site KTECER100 ?LA, in which the P1 Arg100 and P6 Lys95 are critical. Pharmacological treatments revealed that shedding of hTfR1 by PC7 requires endocytosis into acidic clathrin-coated vesicles. A PC7 chimera, in which the transmembrane domain and the cytosolic tail of PC7 were replaced by that of the convertase furin, lost its ability to cleave the receptor, demonstrating the importance of these domains in the regulation of PC7 function. Analysis of primary hepatocytes from mice lacking furin, PC5, PACE4, or PC7 revealed that hepcidin, which limits iron availability in the circulation, is specifically generated by furin and not by PC7. Finally, depletion of iron in the medium of hepatoma cell lines incubated with the iron chelator desferrioxamine resulted in PC7 down-regulation. CONCLUSION: Among the PC family members, only furin activates hepcidin in hepatocytes, and uniquely the full-length membrane-bound PC7 can directly shed hTfR1 by cleavage at Arg100 ?. Our results support the notion that, when iron is limiting, hTfR1 levels increase at least in part by way of the down-regulation of PC7 expression. (HEPATOLOGY 2013;).",0
4431,23390923,Endovascular therapy after intravenous t-PA versus t-PA alone for stroke,"BACKGROUND: Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS: We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS: The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ?20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). CONCLUSIONS: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).",0
4432,23424168,Alcohol dehydrogenase-specific T-cell responses are associated with alcohol consumption in patients with alcohol-related cirrhosis,"Patients with alcohol-related liver disease (ALD) have antibodies directed to alcohol dehydrogenase (ADH), anti-ADH titers being associated with disease severity and active alcohol consumption. ADH-specific T-cell responses have not been characterized. We aimed to define anti-ADH cellular immune responses and their association with active alcohol consumption and disease severity. Using cultures of peripheral blood mononuclear cells (PBMCs) from 25 patients with alcohol-related cirrhosis (ARC; 12 were actively drinking or abstinent for <6 months, and 13 were abstinent for >6 months) and hepatic mononuclear cells (HMCs) from 14 patients with ARC who were undergoing transplantation, we investigated T-cell reactivity to 25 overlapping peptides representing the full human ADH protein (beta 1 subunit). ADH-specific peripheral T-cell responses were assessed by the quantification of T-cell proliferation and cytokine production and were correlated with the clinical course. In active alcohol consumers, proliferative T-cell responses targeted ADH31-95 and other discontinuous sequences in the ADH peptide, whereas only one sequence was targeted in abstinents. ADH peptides induced the production of interferon-? (IFN-?), interleukin-4 (IL-4), and IL-17. IL-4 production was lower in active drinkers versus abstinents, and IL-17 production was higher. Peptides inducing IFN-? production outnumbered those inducing T-cell proliferation. The intensity of the predominantly T helper 1 (Th 1) responses directly correlated with disease severity. Similar to PBMCs in abstinents, ADH peptides induced weak T-cell proliferation and a similar level of IL-4 production in HMCs but less vigorous Th 1 and T helper 17 responses. CONCLUSION: This suggests that Th 1 responses to ADH in ARC are induced by alcohol consumption. A Th 1/T helper 2 imbalance characterizes T-cell responses in active drinkers with ARC, whereas IL-4 production prevails in abstinents. This identifies new targets for immunoregulatory therapies in ALD patients for halting detrimental effector T-cell responses, which may encourage liver fibrogenesis and progression to end-stage liver disease.",0
4433,23445092,Ondansetron in pregnancy and risk of adverse fetal outcomes,"BACKGROUND: Ondansetron is frequently used to treat nausea and vomiting during pregnancy, but the safety of this drug for the fetus has not been well studied. METHODS: We investigated the risk of adverse fetal outcomes associated with ondansetron administered during pregnancy. From a historical cohort of 608,385 pregnancies in Denmark, women who were exposed to ondansetron and those who were not exposed were included, in a 1:4 ratio, in propensity-score-matched analyses of spontaneous abortion (1849 exposed women vs. 7396 unexposed women), stillbirth (1915 vs. 7660), any major birth defect (1233 vs. 4932), preterm delivery (1792 vs. 7168), and birth of infants at low birth weight and small for gestational age (1784 vs. 7136). In addition, estimates were adjusted for hospitalization for nausea and vomiting during pregnancy (as a proxy for severity) and the use of other antiemetics. RESULTS: Receipt of ondansetron was not associated with a significantly increased risk of spontaneous abortion, which occurred in 1.1% of exposed women and 3.7% of unexposed women during gestational weeks 7 to 12 (hazard ratio, 0.49; 95% confidence interval [CI], 0.27 to 0.91) and in 1.0% and 2.1%, respectively, during weeks 13 to 22 (hazard ratio, 0.60; 95% CI, 0.29 to 1.21). Ondansetron also conferred no significantly increased risk of stillbirth (0.3% for exposed women and 0.4% for unexposed women; hazard ratio, 0.42; 95% CI, 0.10 to 1.73), any major birth defect (2.9% and 2.9%, respectively; prevalence odds ratio, 1.12; 95% CI, 0.69 to 1.82), preterm delivery (6.2% and 5.2%; prevalence odds ratio, 0.90; 95% CI, 0.66 to 1.25), delivery of a low-birth-weight infant (4.1% and 3.7%; prevalence odds ratio, 0.76; 95% CI, 0.51 to 1.13), or delivery of a small-for-gestational-age infant (10.4% and 9.2%; prevalence odds ratio, 1.13; 95% CI, 0.89 to 1.44). CONCLUSIONS: Ondansetron taken during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes. (Funded by the Danish Medical Research Council.).",0
4434,23445093,Nocturnal glucose control with an artificial pancreas at a diabetes camp,"BACKGROUND: Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS: In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS: On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS: Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.).",0
4435,23463364,Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection,"Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-?) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN-? production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T-cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. CONCLUSION: Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity.",0
4436,23484797,Analysis of circulating tumor DNA to monitor metastatic breast cancer,"BACKGROUND: The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer. METHODS: We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points. RESULTS: Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). CONCLUSIONS: This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).",0
4437,23484829,Increased oxidative metabolism in the Li-Fraumeni syndrome,"There is growing evidence that alterations in metabolism may contribute to tumorigenesis. Here, we report on members of families with the Li-Fraumeni syndrome who carry germline mutations in TP53, the gene encoding the tumor-suppressor protein p53. As compared with family members who are not carriers and with healthy volunteers, family members with these mutations have increased oxidative phosphorylation of skeletal muscle. Basic experimental studies of tissue samples from patients with the Li-Fraumeni syndrome and a mouse model of the syndrome support this in vivo finding of increased mitochondrial function. These results suggest that p53 regulates bioenergetic homeostasis in humans. (Funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; ClinicalTrials.gov number, NCT00406445.).",0
4438,23504650,Incidence and prevalence of hepatitis C in prisons and other closed settings: results of a systematic review and meta-analysis,"People detained in prisons and other closed settings are at elevated risk of infection with hepatitis C virus (HCV). We undertook a systematic review and meta-analysis with the aim of determining the rate of incident HCV infection and the prevalence of anti-HCV among detainees in closed settings. We systematically searched databases of peer-reviewed literature and widely distributed a call for unpublished data. We calculated summary estimates of incidence and prevalence among general population detainees and detainees with a history of injection drug use (IDU), and explored heterogeneity through stratification and meta-regression. The summary prevalence estimates were used to estimate the number of anti-HCV positive prisoners globally. HCV incidence among general detainees was 1.4 per 100 person-years (py; 95% confidence interval [CI]: 0.1, 2.7; k?=?4), and 16.4 per 100 py (95% CI: 0.8, 32.1; k?=?3) among detainees with a history of IDU. The summary prevalence estimate of anti-HCV in general detainees was 26% (95% CI: 23%, 29%; k?=?93), and in detainees with a history of IDU, 64% (95% CI: 58%, 70%; k?=?51). The regions of highest prevalence were Central Asia (38%; 95% CI 32%, 43%; k?=?1) and Australasia (35%; 95% CI: 28%, 43%; k?=?9). We estimate that 2.2 million (range: 1.4-2.9 million) detainees globally are anti-HCV positive, with the largest populations in North America (668,500; range: 553,500-784,000) and East and Southeast Asia (638,000; range: 332,000-970,000). CONCLUSION: HCV is a significant concern in detained populations, with one in four detainees anti-HCV-positive. Epidemiological data on the extent of HCV infection in detained populations is lacking in many countries. Greater attention towards prevention, diagnosis, and treatment of HCV infection among detained populations is urgently required.",0
4439,23514287,ERCC1 isoform expression and DNA repair in non-small-cell lung cancer,"BACKGROUND: The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS: We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS: Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).",0
4440,23526496,Proteome-wide analyses of human hepatocytes during differentiation and dedifferentiation,"""Failure to predict hepatotoxic drugs in preclinical testing makes it imperative to develop better liver models with a stable phenotype in culture. Stem cell-derived models offer promise, with differentiated hepatocyte-like cells currently considered to be """"fetal-like"""" in their maturity. However, this judgment is based on limited biomarkers or transcripts and lacks the required proteomic datasets that directly compare fetal and adult hepatocytes. Here, we quantitatively compare the proteomes of human fetal liver, adult hepatocytes, and the HepG2 cell line. In addition, we investigate the proteome changes in human fetal and adult hepatocytes when cultured in a new air-liquid interface format compared to conventional submerged extracellular matrix sandwich culture. From albumin and urea secretion, and luciferase-based cytochrome P450 activity, adult hepatocytes were viable in either culture model over 2 weeks. The function of fetal cells was better maintained in the air-liquid interface system. Strikingly, the proteome was qualitatively similar across all samples but hierarchical clustering showed that each sample type had a distinct quantitative profile. HepG2 cells more closely resembled fetal than adult hepatocytes. Furthermore, clustering showed that primary adult hepatocytes cultured at the air-liquid interface retained a proteome that more closely mimicked their fresh counterparts than conventional culture, which acquired myofibroblast features. Principal component analysis extended these findings and identified a simple set of proteins, including cytochrome P450 2A6, glutathione S transferase P, and alcohol dehydrogenases as specialized indicators of hepatocyte differentiation. CONCLUSION: Our quantitative datasets are the first that directly compare multiple human liver cells, define a model for enhanced maintenance of the hepatocyte proteome in culture, and provide a new protein """"toolkit"""" for determining human hepatocyte maturity in cultured cells.""",0
4441,23532963,Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer,"Yes-associated protein (YAP), the downstream effecter of the Hippo-signaling pathway as well as cyclic adenosine monophosphate response element-binding protein (CREB), has been linked to hepatocarcinogenesis. However, little is known about whether and how YAP and CREB interact with each other. In this study, we found that YAP-CREB interaction is critical for liver cancer cell survival and maintenance of transformative phenotypes, both in vitro and in vivo. Moreover, both CREB and YAP proteins are highly expressed in a subset of human liver cancer samples and are closely correlated. Mechanistically, CREB promotes YAP transcriptional output through binding to -608/-439, a novel region from the YAP promoter. By contrast, YAP promotes protein stabilization of CREB through interaction with mitogen-activated protein kinase 14 (MAPK14/p38) and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC). Gain-of-function and loss-of-function studies demonstrated that phosphorylation of CREB by MAPK14/p38 at ser133 ultimately leads to its degradation. Such effects can be enhanced by BTRC through phosphorylation of MAPK14/p38 at Thr180/Tyr182. However, YAP negatively controls phosphorylation of MAPK14/p38 through inhibition of BTRC expression. CONCLUSION: There is a novel positive autoregulatory feedback loop underlying the interaction between YAP and CREB in liver cancer, suggesting that YAP and CREB form a nexus to integrate the protein kinase A, Hippo/YAP, and MAPK14/p38 pathways in cancer cells and thus may be helpful in the development of effective diagnosis and treatment strategies against liver cancer.",0
4442,23532970,Adenosine kinase is a key determinant for the anti-HCV activity of ribavirin,"Ribavirin (RBV) is often used in conjunction with interferon-based therapy for patients with chronic hepatitis C. There is a drastic difference in the anti-hepatitis C virus (HCV) activity of RBV between the HuH-7-derived assay system, OR6, possessing the RBV-resistant phenotype (50% effective concentration [EC50 ]: >100 �M) and the recently discovered Li23-derived assay system, ORL8, possessing the RBV-sensitive phenotype (EC50 : 8 �M; clinically achievable concentration). This is because the anti-HCV activity of RBV was mediated by the inhibition of inosine monophosphate dehydrogenase in RBV-sensitive ORL8 cells harboring HCV RNA. By means of comparative analyses using RBV-resistant OR6 cells and RBV-sensitive ORL8 cells, we tried to identify host factor(s) determining the anti-HCV activity of RBV. We found that the expression of adenosine kinase (ADK) in ORL8 cells was significantly higher than that in RBV-resistant OR6 cells harboring HCV RNA. Ectopic ADK expression in OR6 cells converted them from an RBV-resistant to an RBV-sensitive phenotype, and inhibition of ADK abolished the activity of RBV. We showed that the differential ADK expression between ORL8 and OR6 cells was not the result of genetic polymorphisms in the ADK gene promoter region and was not mediated by a microRNA control mechanism. We found that the 5' untranslated region (UTR) of ADK messenger RNA in ORL8 cells was longer than that in OR6 cells, and that only a long 5' UTR possessed internal ribosome entry site (IRES) activity. Finally, we demonstrated that the long 5' UTR functioned as an IRES in primary human hepatocytes. CONCLUSION: These results indicate that ADK acts as a determinant for the activity of RBV and provide new insight into the molecular mechanism underlying differential drug sensitivity.",0
4443,23534543,Rhinovirus wheezing illness and genetic risk of childhood-onset asthma,"BACKGROUND: Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. METHODS: We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). RESULTS: The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific. CONCLUSIONS: Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).",0
4444,23550670,Monetary costs of dementia in the United States,"BACKGROUND: Dementia affects a large and growing number of older adults in the United States. The monetary costs attributable to dementia are likely to be similarly large and to continue to increase. METHODS: In a subsample (856 persons) of the population in the Health and Retirement Study (HRS), a nationally representative longitudinal study of older adults, the diagnosis of dementia was determined with the use of a detailed in-home cognitive assessment that was 3 to 4 hours in duration and a review by an expert panel. We then imputed cognitive status to the full HRS sample (10,903 persons, 31,936 person-years) on the basis of measures of cognitive and functional status available for all HRS respondents, thereby identifying persons in the larger sample with a high probability of dementia. The market costs associated with care for persons with dementia were determined on the basis of self-reported out-of-pocket spending and the utilization of nursing home care; Medicare claims data were used to identify costs paid by Medicare. Hours of informal (unpaid) care were valued either as the cost of equivalent formal (paid) care or as the estimated wages forgone by informal caregivers. RESULTS: The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was either $56,290 (95% confidence interval [CI], $42,746 to $69,834) or $41,689 (95% CI, $31,017 to $52,362), depending on the method used to value informal care. These individual costs suggest that the total monetary cost of dementia in 2010 was between $157 billion and $215 billion. Medicare paid approximately $11 billion of this cost. CONCLUSIONS: Dementia represents a substantial financial burden on society, one that is similar to the financial burden of heart disease and cancer. (Funded by the National Institute on Aging.).",0
4445,23553591,Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice,"Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells (DCs) contribute to hepatic stellate cell (HSC) activation and liver fibrosis. We show for the first time that hepatic macrophages enhance myofibroblast survival in a nuclear factor kappa B (NF-?B)-dependent manner and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the NF-?B pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-?B activation in HSCs. Macrophage-induced activation of NF-?B in HSCs in vitro and in vivo was mediated by interleukin (IL)-1 and tumor necrosis factor (TNF). Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSCs in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in coculture experiments and genetic ablation of IL-1 and TNF receptor in vivo. Coculture and in vivo ablation experiments revealed only a minor contribution to NF-?B activation in HSCs by DCs, and no contribution of DCs to liver fibrosis development, respectively. CONCLUSION: Promotion of NF-?B-dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis.",0
4446,23553752,Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels,"On-treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG-IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown limited external validity. We analyzed 803 HBeAg-positive patients treated with PEG-IFN in three global studies with available HBsAg measurements. A stopping-rule based on absence of a decline from baseline was compared to a prediction-rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG-IFN monotherapy (n?=?465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value [NPV]: 97%-100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%-98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). CONCLUSION: HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. HBV genotype-specific stopping-rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype.",0
4447,23594004,Provision of community benefits by tax-exempt U.S. hospitals,"BACKGROUND: The Patient Protection and Affordable Care Act (ACA) requires tax-exempt hospitals to conduct assessments of community needs and address identified needs. Most tax-exempt hospitals will need to meet this requirement by the end of 2013. METHODS: We conducted a national study of the level and pattern of community benefits that tax-exempt hospitals provide. The study comprised more than 1800 tax-exempt hospitals, approximately two thirds of all such institutions. We used reports that hospitals filed with the Internal Revenue Service for fiscal year 2009 that provide expenditures for seven types of community benefits. We combined these reports with other data to examine whether institutional, community, and market characteristics are associated with the provision of community benefits by hospitals. RESULTS: Tax-exempt hospitals spent 7.5% of their operating expenses on community benefits during fiscal year 2009. More than 85% of these expenditures were devoted to charity care and other patient care services. Of the remaining community-benefit expenditures, approximately 5% were devoted to community health improvements that hospitals undertook directly. The rest went to education in health professions, research, and contributions to community groups. The level of benefits provided varied widely among the hospitals (hospitals in the top decile devoted approximately 20% of operating expenses to community benefits; hospitals in the bottom decile devoted approximately 1%). This variation was not accounted for by indicators of community need. CONCLUSIONS: In 2009, tax-exempt hospitals varied markedly in the level of community benefits provided, with most of their benefit-related expenditures allocated to patient care services. Little was spent on community health improvement.",0
4448,23614587,"Achievement of goals in U.S. diabetes care, 1999-2010","BACKGROUND: Tracking national progress in diabetes care may aid in the evaluation of past efforts and identify residual gaps in care. METHODS: We analyzed data for adults with self-reported diabetes from the National Health and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance System to examine risk-factor control, preventive practices, and risk scores for coronary heart disease over the 1999-2010 period. RESULTS: From 1999 through 2010, the weighted proportion of survey participants who met recommended goals for diabetes care increased, by 7.9 percentage points (95% confidence interval [CI], 0.8 to 15.0) for glycemic control (glycated hemoglobin level <7.0%), 9.4 percentage points (95% CI, 3.0 to 15.8) for individualized glycemic targets, 11.7 percentage points (95% CI, 5.7 to 17.7) for blood pressure (target, <130/80 mm Hg), and 20.8 percentage points (95% CI, 11.6 to 30.0) for lipid levels (target level of low-density lipoprotein [LDL] cholesterol, <100 mg per deciliter [2.6 mmol per liter]). Tobacco use did not change significantly, but the 10-year probability of coronary heart disease decreased by 2.8 to 3.7 percentage points. However, 33.4 to 48.7% of persons with diabetes still did not meet the targets for glycemic control, blood pressure, or LDL cholesterol level. Only 14.3% met the targets for all three of these measures and for tobacco use. Adherence to the recommendations for annual eye and dental examinations was unchanged, but annual lipid-level measurement and foot examination increased by 5.5 percentage points (95% CI, 1.6 to 9.4) and 6.8 percentage points (95% CI, 4.8 to 8.8), respectively. Annual vaccination for influenza and receipt of pneumococcal vaccination for participants 65 years of age or older rose by 4.5 percentage points (95% CI, 0.8 to 8.2) and 6.9 percentage points (95% CI, 3.4 to 10.4), respectively, and daily glucose monitoring increased by 12.7 percentage points (95% CI, 10.3 to 15.1). CONCLUSIONS: Although there were improvements in risk-factor control and adherence to preventive practices from 1999 to 2010, tobacco use remained high, and almost half of U.S. adults with diabetes did not meet the recommended goals for diabetes care.",0
4449,23624482,"Spatial distribution and factors shaping the niche segregation of ammonia-oxidizing microorganisms in the Qiantang River, China","Ammonia oxidation is performed by both ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB). However, the current knowledge of the distribution, diversity, and relative abundance of these two microbial groups in freshwater sediments is insufficient. We examined the spatial distribution and analyzed the possible factors leading to the niche segregation of AOA and AOB in the sediments of the Qiantang River, using clone library construction and quantitative PCR for both archaeal and bacterial amoA genes. pH and NH4(+)-N content had a significant effect on AOA abundance and AOA operational taxonomy unit (OTU) numbers. pH and organic carbon content influenced the ratio of AOA/AOB OTU numbers significantly. The influence of these factors showed an obvious spatial trend along the Qiantang River. This result suggested that AOA may contribute more than AOB to the upstream reaches of the Qiantang River, where the pH is lower and the organic carbon and NH4(+)-N contents are higher, but AOB were the principal driver of nitrification downstream, where the opposite environmental conditions were present. ",0
4450,23624506,Histone deacetylase inhibitor AR42 regulates telomerase activity in human glioma cells via an Akt-dependent mechanism,"Epigenetic regulation via abnormal activation of histone deacetylases (HDACs) is a mechanism that leads to cancer initiation and promotion. Activation of HDACs results in transcriptional upregulation of human telomerase reverse transcriptase (hTERT) and increases telomerase activity during cellular immortalization and tumorigenesis. However, the effects of HDAC inhibitors on the transcription of hTERT vary in different cancer cells. Here, we studied the effects of a novel HDAC inhibitor, AR42, on telomerase activity in a PTEN-null U87MG glioma cell line. AR42 increased hTERT mRNA in U87MG glioma cells, but suppressed total telomerase activity in a dose-dependent manner. Further analyses suggested that AR42 decreases the phosphorylation of hTERT via an Akt-dependent mechanism. Suppression of Akt phosphorylation and telomerase activity was also observed with PI3K inhibitor LY294002 further supporting the hypothesis that Akt signaling is involved in suppression of AR42-induced inhibition of telomerase activity. Finally, ectopic expression of a constitutive active form of Akt restored telomerase activity in AR42-treated cells. Taken together, our results demonstrate that the novel HDAC inhibitor AR42 can suppress telomerase activity by inhibiting Akt-mediated hTERT phosphorylation, indicating that the PI3K/Akt pathway plays an important role in the regulation of telomerase activity in response to this HDAC inhibitor. ",0
4451,23624614,Rnh1 promotes differentiation and myelination via RhoA in oligodendrocytes,"Increases in Rattus norvegicus ribonuclease/angiogenin inhibitor 1 (Rnh1) are observed in rat primary neuron injury and/or the regeneration process and in differentiated oligodendrocytes. However, the roles of Rnh1 in the central nervous system are still largely unexplored. RhoA is an important signaling protein that has been implicated in oligodendrocyte differentiation and myelination. We demonstrate enhanced differentiation and myelination of oligodendrocytes mediated by Rnh1 in vitro. We further show that Rnh1 is expressed in oligodendrocyte precursors and oligodendrocytes. Importantly, Rnh1 strongly affects oligodendrocyte differentiation through RhoA-ROCK signaling. Moreover, changes in Rnh1 expression in oligodendrocytes regulates the expression and phosphorylation of Fyn, a regulator of RhoA activity. Finally, Rnh1 promotes myelination in vitro. These results show that Rnh1-mediated RhoA inactivation enhances the differentiation and myelination in oligodendrocytes. Overall, Rnh1 might contribute to oligodendrocyte differentiation and myelination processes in vitro. ",0
4452,23624717,Clinical features of supervoiders who suffer from lower urinary tract symptoms: a propensity score-matching study,"To evaluate the clinical characteristics of patients with maximal urine flow rate (Q max) ≥ 25 ml/s complaining of lower urinary tract symptoms (LUTS), using propensity score-matching analysis to compare with the control group. Medical records from a prospectively maintained database for first visit male patients with LUTS/benign prostatic hyperplasia between 2010 and 2012 were used to select 818 patients. Of these patients, 68 men with Q max ≥ 25 ml/s were defined as the supervoider group, and 68 patients were selected for the control group using propensity scores, which were calculated for each patient using multivariable logistic regression model based on the following covariates: age, prostate volume, voided urine volume, and post-voided residual volume. International Prostate Symptom Score (IPSS), quality of life score, and Overactive Bladder Symptom Score (OABSS) were also analyzed. Mean Q max was 30.82 ± 5.13 in supervoiders and 15.95 ± 4.88 ml/s in controls (p < 0.001). There were statistical differences in IPSS between supervoiders and controls (12.63 ± 5.81 vs. 16.13 ± 6.90; p = 0.002). Although the IPSS voiding symptom sub-score in supervoiders was lower than controls (5.09 ± 3.35 vs. 7.40 ± 4.00; p < 0.001), there were no significant differences in storage symptom and post-micturitional symptom sub-scores. In OABSS and subdomain scores for frequency, nocturia, and urgency, there were no significant differences between the groups. However, the urge incontinence subdomain score was significantly higher in supervoiders versus controls (0.69 ± 1.26 vs. 0.18 ± 0.52; p = 0.003). Supervoiders experience comparable levels of storage and post-micturition symptoms, but display more severe urge incontinence despite milder voiding symptoms and better uroflowmetric measurements than propensity score-matched controls. ",0
4453,23624722,Identification and characterization of an iron ABC transporter operon in Gluconacetobacter diazotrophicus Pal 5,"Gluconacetobacter diazotrophicus is a nitrogen-fixing bacterium and endophyte of sugarcane. We have cloned and sequenced the genes coding for the components of the iron ABC-type acquisition system of G. diazotrophicus. Sequence analysis revealed three ORFs, (feuA, feuB, and feuC) organized as an operon and encoding polypeptides of 346 (38 kDa), 342 (34.2 kDa), and 240 (26 kDa) amino acids, respectively. The deduced translation products of the feu operon showed similarity with a periplasmic solute-binding protein (FeuA), permease (FeuB), and ATPase (FeuC) involved in Fe transport. The role of FeuB in the survival of G. diazotrophicus under iron depletion was evaluated by comparing the ability of wild-type and FeuB-Km(R) -mutant strains in a medium without iron supplementation and in a medium containing 2, 2'-dipyridyl (DP). Growth of the mutant was affected in the medium containing DP. The operon was expressed at higher levels in cells depleted for iron than in those that contained the metal. A decrease in nitrogenase activity was observed with the FeuB-Km(R) -mutant strain that with the wild-type under iron deficiency conditions, suggesting that the Feu operon play role in Fe nutrition of G. diazotrophicus. ",0
4454,23624776,Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex,"Dephosphorylation of extracellular signal-regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) in the dorsomedial prefrontal cortex (dmPFC) at the end of short access (ShA) cocaine self-administration is implicated in cocaine seeking. However, what receptors and phosphatases mediate this effect and whether ERK/CREB and related phospho-proteins in the dmPFC react similarly during early withdrawal from long access (LgA) cocaine self-administration are unknown. The effects of ShA vs. LgA cocaine self-administration on the phosphorylation of protein phosphatase 2A (PP2A) and striatal-enriched protein tyrosine phosphatase (STEP), as well as GluN and GluA receptor subtype expression in the dmPFC during early withdrawal, were compared. Rats self-administered cocaine or received saline during 2- or 6-h daily sessions for 10-11 days. Two hours after the final session, the dmPFC was dissected out and processed for immunoblotting. Similar to previous findings after ShA cocaine, phospho-ERK and phospho-CREB in the dmPFC were decreased after LgA cocaine. Cocaine elevated phospho-PP2A (deactivation) and decreased phospho-STEP (activation) in both ShA and LgA cocaine rats. GluN1, GluN2B, and phospho-GluN2B Tyr1472 in the dmPFC were decreased after ShA and LgA cocaine. Further, a significant reduction of GluA2, GluA1, and phospho-GluA1 Ser845 was found only in LgA rats. Activation of phospho-STEP may underlie ERK and CREB dephosphorylation in the dmPFC as well as internalization and degradation of GluN complexes during early withdrawal from both ShA and LgA cocaine self-administration, whereas differential alteration of AMPA receptor subunits after ShA and LgA cocaine self-administration depends on cocaine intake. ",0
4455,23625018,A prospective study of characteristics and outcomes of bacteremia in patients with solid organ or hematologic malignancies,"To study the epidemiology and outcomes of bacteremia in patients with hematologic or solid organ malignancies cared for at the University Hospital of Heraklion, Greece. This prospective study was conducted during a 4-year period (2007-2011). Patients with bacterial and fungal blood stream infections were followed until discharge. Mortality was the primary outcome, while duration of hospitalization, relapses, time to relapse, and defervescence were the secondary outcomes. Ninety-nine patients with neoplasia (104 episodes) were included. Bacteremia developed mainly in patients with hematologic malignancies (56%). Secondary bacteremias due to respiratory and urinary tract infections were most commonly identified. Gram-negative bacteria were the predominantly isolated pathogens (65%); Pseudomonas spp. was the most common cause (19%), followed closely by E. coli (18%) and Klebsiella pneumoniae (17%). In-hospital mortality was 26.2%. No differences in mortality were seen among patients in different subgroups according to isolated bacteria (according to Gram's stain, species, or number of isolated bacteria in positive cultures), hematologic or solid organ malignancy, neutropenia, and primary or secondary bacteremia. However, patients with bacteremia due to extensively drug resistant bacteria had higher mortality than patients with bacteremia due to multidrug resistant or susceptible pathogens. Patients required a prolonged period of hospitalization (21.8 ± 14.9 days), which was complicated with relapses or reinfections in another body site in 27 % of them. Gram-negative bacteria were the predominantly isolated pathogens from patients with cancer in our population. The overall mortality remains high. ",0
4456,23625194,Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility,"Obesity is frequently present in patients with polycystic ovary syndrome (PCOS) and plays an important role in the pathogenesis of the metabolic, endocrine, and reproductive abnormalities associated with this syndrome. We aimed to summarize the effects of lifestyle changes and anti-obesity pharmacotherapy in patients with PCOS. We reviewed the literature regarding the effects of lifestyle changes and anti-obesity agents on the metabolic and endocrine abnormalities of PCOS. Lifestyle changes, including diet, exercise, and behavioral modification, appear to improve the metabolic and reproductive abnormalities of overweight and obese patients with PCOS. Therefore, lifestyle changes appear to represent the first-line management for all overweight and obese patients with PCOS. However, the optimal composition of diet and the optimal type of exercise in these patients are unknown. Anti-obesity agents that have been studied in PCOS include orlistat, sibutramine, and rimonabant. However, the latter two agents have been withdrawn from the market because of side effects. Long-term studies with orlistat in overweight and obese diabetic patients showed greater weight loss and metabolic and cardiovascular benefits than those achieved with lifestyle changes alone. However, there are limited data on the efficacy of orlistat in women with PCOS. In conclusion, lifestyle changes (diet, exercise and behavioral modification), particularly when combined with anti-obesity agents, exert beneficial effects on the endocrine abnormalities of obese patients with PCOS and improve metabolic parameters.  ",0
4457,23625491,Multispectral imaging and automated laser capture microdissection of human cortical neurons: a quantitative study of CXCR4 expression,"Quantifying protein and RNA expression within specific cell populations in vivo is an essential step in unraveling the complex mechanisms of neurological disease. The challenges associated with studying human brain tissue are commonly compounded by variations in postmortem interval, formalin fixation time, and tissue processing methods among others. The result is a sample population that is inherently heterogeneous, implying the need for reliable protocols that are sensitive to low levels of antigen while minimizing background and nonspecific staining. Here, we describe a single immunohistochemistry protocol on formalin-fixed, paraffin-embedded human cortex which can be adapted to (1) quantify the relative protein expression of the chemokine receptor, CXCR4, using multispectral image or (2) isolate neuronal RNA through automated laser capture microdissection. ",0
4458,23625885,Piper nigrum and piperine: an update,"Black pepper (Piper nigrum L.) is a very widely used spice, known for its pungent constituent piperine. However, in addition to its culinary uses, pepper has important medicinal and preservative properties, and, more recently, piperine has been shown to have fundamental effects on p-glycoprotein and many enzyme systems, leading to biotransformative effects including chemoprevention, detoxification, and enhancement of the absorption and bioavailability of herbal and conventional drugs. Based on modern cell, animal, and human studies, piperine has been found to have immunomodulatory, anti-oxidant, anti-asthmatic, anti-carcinogenic, anti-inflammatory, anti-ulcer, and anti-amoebic properties. In this review, the chemical constituents, biological activities, effects of processing, and future potential of black pepper and piperine have been discussed thoroughly. ",0
4459,23626414,Feasibility of single-incision laparoscopic surgery for appendicitis in abnormal anatomical locations: A single surgeon's initial experience,"Single-incision laparoscopic surgery is considered as a more technically demanding procedure than the standard laparoscopic surgery. Based on an initial and early experience, single-incision laparoscopic appendectomy (LA) was found to be technically advantageous for dealing with appendicitis in unusual anatomical locations. This study aims to highlight the technical advantages of single-incision laparoscopic surgery in dealing with the abnormally located appendixes and furthermore report a case of acute appendicitis occurring in a sub-gastric position, which is probably the first such case to be reported in English literature. A retrospective analysis of the first 10 cases of single-incision LA which were performed by a single surgeon is presented here. There were seven females and three males. The mean age of the patients was 30.6 (range 18-52) years, mean BMI was 22.7 (range 17-28) kg/m(2) and the mean operative time was 85.5 (range 45-150) min. The mean postoperative stay was 3.6 (range 1-7) days. The commonest position of the appendix was retro-caecal (50%) followed by pelvic (30%). In three cases the appendix was found to be in abnormal locations namely sub-hepatic, sub-gastric and deep pelvic or para-vesical or para-rectal. All these cases could be managed with this technique without any conversions. Single-incision laparoscopic surgery appears to be a feasible and safe technique for dealing with appendicitis in rare anatomical locations. Appendectomy may be a suitable procedure for the initial training in single-incision laparoscopic surgery. ",0
4460,23626438,Anti-platelet agents in pediatric cardiac practice,"Pediatric patients with a variety of congenital and acquired cardiac conditions receive antithrombotic therapy. Many of the indications are empirical, and have either not been proven in controlled studies or are extrapolated from adult studies. This article reviews the current available literature regarding the use of anti-platelet drugs in the pediatric cardiac population. ",0
4461,23626651,Hypolipidemia in patients with amyotrophic lateral sclerosis: a possible gender difference?,"We compared the levels of serum lipid, protein, and glucose between patients with amyotrophic lateral sclerosis (ALS) and healthy controls. The serum levels of lipids [including triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)], protein, and glucose of 95 patients with ALS (60 men) were compared with those of 99 age- and sex-matched healthy controls (64 men). Both groups had normal dietary intakes. Total cholesterol (p=0.004), LDL (p=0.040), triglyceride (p=0.025), and protein (p=0.010) levels, and LDL/HDL ratios (p<0.001) in men with ALS were significantly lower than those in their control counterparts. There were no such significant differences in these parameters between female patients with ALS and female controls. The serum levels of lipid and protein were significantly lower in male patients with ALS than in the male controls. Since we controlled for the confounding effects of dietary intake, hypolipidemia in ALS might be associated with the pathophysiology of the disease rather than being the result of the decreased dietary intake in ALS patients. Metabolic demand might increase in ALS, and it may be affected by gender. ",0
4462,23626660,Air pollution and circulating biomarkers of oxidative stress,"Chemical components of air pollutant exposures that induce oxidative stress and subsequent inflammation may be partly responsible for associations of cardiovascular morbidity and mortality with airborne particulate matter and combustion-related pollutant gasses. However, epidemiologic evidence regarding this is limited. An exposure-assessment approach is to measure the oxidative potential of particle mixtures because it is likely that hundreds of correlated chemicals are involved in overall effects of air pollution on health. Oxidative potential likely depends on particle composition and size distribution, especially ultrafine particle concentration, and on transition metals and certain semivolatile and volatile organic chemicals. For health effects, measuring systemic oxidative stress in the blood is one feasible approach, but there is no universal biomarker of oxidative stress and there are many potential target molecules (lipids, proteins, DNA, nitric oxide, etc.), which may be more or less suitable for specific study goals. Concurrent with the measurement of oxidative stress, it is important to measure gene and/or protein expression of endogenous antioxidant enzymes because they can modify relations between oxidative stress biomarkers and air pollutants. Conversely, the expression and activities of these enzymes are modified by oxidative stress. This interplay will likely determine the observed effects of air pollutants on systemic inflammatory and thrombotic mediators and related clinical outcomes. Studies are needed to assess the reliability and validity of oxidative stress biomarkers, evaluate differences in associations between oxidative stress biomarkers and various pollutant measurements (mass, chemical components, and oxidative potential), and evaluate impacts of antioxidant responses on these relations. ",0
4463,23626669,Designed ankyrin repeat proteins: a new approach to mimic complex antigens for diagnostic purposes?,"Inhibitory antibodies directed against coagulation factor VIII (FVIII) can be found in patients with acquired and congenital hemophilia A. Such FVIII-inhibiting antibodies are routinely detected by the functional Bethesda Assay. However, this assay has a low sensitivity and shows a high inter-laboratory variability. Another method to detect antibodies recognizing FVIII is ELISA, but this test does not allow the distinction between inhibitory and non-inhibitory antibodies. Therefore, we aimed at replacing the intricate antigen FVIII by Designed Ankyrin Repeat Proteins (DARPins) mimicking the epitopes of FVIII inhibitors. As a model we used the well-described inhibitory human monoclonal anti-FVIII antibody, Bo2C11, for the selection on DARPin libraries. Two DARPins were selected binding to the antigen-binding site of Bo2C11, which mimic thus a functional epitope on FVIII. These DARPins inhibited the binding of the antibody to its antigen and restored FVIII activity as determined in the Bethesda assay. Furthermore, the specific DARPins were able to recognize the target antibody in human plasma and could therefore be used to test for the presence of Bo2C11-like antibodies in a large set of hemophilia A patients. These data suggest, that our approach might be used to isolate epitopes from different sets of anti-FVIII antibodies in order to develop an ELISA-based screening assay allowing the distinction of inhibitory and non-inhibitory anti-FVIII antibodies according to their antibody signatures. ",0
4464,23627013,Molecular detection assays for 2012 identified novel human coronavirus (HCoV) and probe modification with locked nucleic acid (LNA)],"To develop and optimize the molecular detection assays for recently identified human coronavirus (HCoV) infection. Based on the 208 base pair(bp) sequence of novel HCoV reported by HPA of UK, we designed and obtained several pairs of primer (F-1, R-1; F-2, R-2) and Taqman probes (TZ1,TZ2) for detection of novel HCoV. Two of probes were modified with LNA (LNA-TZ1, LNA-TZ2). Then, RT-PCR and various real time RT-PCR assays were developed and optimized in this study. We also compared our assays with the real time RT-PCR assays reported recently by Europe team based on upE or ORF1b target. The RT-PCR or real time RT-PCR assays for novel HCoV were developed without cross-reactivity with other HCoV and several common respiratory viruses using clinical specimen panel. The analytical sensitivity of assays were less than 50-500 copies per reaction and the detection was improved when Taqman probe modified with LNA-tagged, compared to no LNA-tagged in real time RT-PCR assays. The upE and LNA-TZ1 based assays were better than others. The molecular detection sensitivity and specificity of TaqMan-based real time PCR assay could be improved when probe tagged with LNA. The upE or LNA-TZ1 based real time RT-PCR assay was recommend for detection of novel HCoV. This study laid a foundation for improving the performance of novel HCoV detection. ",0
4465,23627560,Effectiveness of local anaesthetic pain catheters for abdominal donor site analgesia in patients undergoing free lower abdominal flap breast reconstruction: A meta-analysis of comparative studies,"The use of an infusion pain pump with local wound catheters has increased among different surgical specialities. Autologous breast reconstruction with deep inferior epigastric perforator (DIEP) and transverse rectus abdominis myocutaneous (TRAM) flaps may cause severe abdominal donor site morbidity, and infusion devices delivering local anaesthetic are suggested to improve postoperative analgesia. This study performed a meta-analysis comparing pain pump use vs control to evaluate this issue. A systematic literature search was performed. Primary outcome was the amount of opioid use. Secondary outcomes were the amount of antiemetic drugs and the length of hospital stay. Five studies involving 248 patients were retrieved and included in the present analysis. A significantly decreased use of opioids was observed after using pain pump vs control (MD = -15.13, 95% CI = -24.20, -6.06, p = 0.001). Although not statistically significant, the pooled results showed a trend toward reduction of antiemetic medicament use (MD = -0.71, 95% CI = -2.14, 0.72, p = 0.33) and hospital stay time (MD = -0.53, 95% CI = -1.18, 0.11, p = 0.10). The use of local anaesthetic pain catheters for abdominal donor sites in microsurgical breast reconstruction might be associated with a decreased use of narcotics and antiemetic medicaments and shorter hospital stay. Further studies are needed to validate this promising treatment modality. ",0
4466,23627639,Thickness of superficial basal cell carcinoma (sBCC) predicts imiquimod efficacy: a proposal for a thickness-based definition of sBCC,"Basal cell carcinoma (BCC) is the most common malignancy in the white population. It is an important driver of healthcare costs and causes significant morbidity. Topical imiquimod is a good noninvasive treatment alternative for surgical excision in superficial BCC (sBCC). However, there are currently no uniform histological definitions of sBCC. A definition based on tumour thickness might be a good alternative. To determine whether tumour thickness in sBCC is a predictor of treatment failure. We retrospectively examined 127 histological biopsy specimens of sBCC treated primarily with imiquimod five times a week for 6 weeks. Mean follow-up was 34 months (range 3-91). Recurrence was evaluated clinically with histological verification. Among nonrecurrent cases the median tumour thickness was 0·26 mm (range 0·09-0·61), while for recurrent cases the median tumour thickness was 0·57 mm (range 0·41-1·41, P < 0·0001). Among lesions ≤ 0·40 mm in thickness, none recurred, whereas for lesions > 0·40 mm the recurrence rate was 58% (P < 0·0001). We recommend the use of tumour thickness to define the superficial pattern in pathology reports for BCC as this can help to determine treatment response of sBCC to imiquimod. ",0
4467,23627662,"Effects of food processing and fibre content on the digestibility, energy intake and biochemical parameters of Blue-and-gold macaws (Ara ararauna L. - Aves, Psittacidae)","Considering the increased incidence of obesity and metabolic diseases in caged psittacines, the effect of fibre and food processing was evaluated in the Blue-and-gold macaw. Four food formulations (0%, 7%, 14% and 21% of sugarcane fibre) processed by pelleting or extrusion were studied, resulting in eight diets. To study digestibility, 48 macaws housed in pairs in cages was used in a block design. Subsequently, diets containing 0% or 21% sugarcane fibre, pelleted or extrude was fed for 4 months to evaluate energy intake and blood metabolites. A 2 × 2 × 2 (two fibre levels, two food processing methods and two genders) factorial arrangement with subplots (beginning and end) was used. When differences were detected in anova's F test, data were submitted to polynomial contrasts in the first experiment and to orthogonal contrasts in the second experiment (p < 0.05). Fibre addition reduced protein, fat and energy (p < 0.001) digestibility in both food processing. Pelleted foods presented higher dry matter digestibility and food metabolisable energy (ME) than the extruded ones (p < 0.05). Fibre addition or the type of processing did not change ME ingestion (p > 0.05). The macaws gained body weight (p < 0.05) regardless of the diet (p > 0.05), but females fed with the high-fibre diets did not gain weight (p > 0.05), suggesting a low food ME (12.5 kJ/g).The substitution of the original diet (sunflower seeds, fruits and cooked maize) by the experimental foods decreased the basal (12-h fast) concentrations of glucose, cholesterol and triglycerides (p < 0.001). The consumption of pelleted diets reduced serum glucose and cholesterol (p < 0.05). Results suggest that the pelleted diets were more beneficial and can be used to reduce blood metabolites related to metabolic disorders that are commonly observed in macaws. ",0
4468,23627936,Nanoparticles loaded with Nutlin-3 display cytotoxicity towards p53(wild-type) JVM-2 but not towards p53(mutated) BJAB leukemic cells,"The small molecule Nutlin-3 is a potent antagonist of the murine double minute 2 (MDM2)/p53 interaction exhibiting promising therapeutic anti-cancer activity. Nutlin-3 has been proposed as an anti-neoplastic agent for the treatment of onco-hematological diseases characterized by a lower incidence of p53 mutation with respect to solid tumors. Indeed, based on its selective non-genotoxic p53 activation, Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy. To overcome the poor bioavailability of Nutlin-3, we have assessed the potential efficacy of Nutlin-3 loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) against hematological malignancies. To test the specificity of the anti-leukemic activity, we have used leukemic cell lines characterized by different p53 status (JVM-2 and BJAB). NP loaded with Nutlin-3 (NP-Nutlin) were rapidly taken up by the leukemic cells and were as effective as native Nutlin-3 in promoting both induction of apoptosis and cell cycle arrest in p53(wild-type) JVM-2 cells, but not in p53(mutated) BJAB cells. Moreover, injection of NP-Nutlin, but not of free Nutlin-3, in a JVM-2-derived xenograft mouse model, reduced the subcutaneous tumor volume and promoted induction of apoptosis in the tumor mass. Overall, the chemical and structural characteristics of the NP-Nutlin-3, as well as their biological activity in vitro and in vivo, made them promising for further preclinical evaluations as potentially useful anti-leukemic carriers. ",0
4469,23628926,Change in desiccation tolerance of maize embryos during development and germination at different water potential PEG-6000 in relation to oxidative process,"Desiccation tolerance is one of the most important traits determining seed survival during storage and under stress conditions. However, the mechanism of seed desiccation tolerance is still unclear in detail. In the present study, we used a combined model system, desiccation-tolerant and -sensitive maize embryos with identical genetic background, to investigate the changes in desiccation tolerance, malonyldialdehyde (MDA) level, hydrogen peroxide (H₂O₂) content and antioxidant enzyme activity during seed development and germination in 0, -0.6 and -1.2 MPa polyethylene glycol (PEG)-6000 solutions. Our results indicated that maize embryos gradually acquired and lost desiccation tolerance during development and germination, respectively. The acquirement and loss of desiccation tolerance of embryos during development and germination were related to the ability of antioxidant enzymes including superoxide dismutase (SOD, EC 1.15.1.1), ascorbate peroxidase (APX, EC 1.11.1.11), catalase (CAT, EC 1.11.1.6), glutathione reductase (GR, EC 1.6.4.2) and dehydroascorbate reductase (DHAR, EC 1.8.5.1) to scavenge reactive oxygen species (ROS) and to control MDA content. Compared with treatment in water, PEG-6000 treatment could markedly delay the loss of desiccation tolerance of germinating embryos by delaying water uptake and time course of germination, increasing GR activity and decreasing MDA content. Our data showed the combination of antioxidant enzyme activity and MDA content is a good parameter for assessing the desiccation tolerance of maize embryos. In addition, H₂O₂ accumulated in mature embryos and PEG-treated embryos after drying, which was at least partially related to a longer embryo/seedling length in rehydration and the physiological mechanisms of priming. ",0
4470,23629758,Sesquiterpenoids from the herb of Leonurus japonicus,"Two new sesquiterpenoids, (-)-(1S*,2S*,3R*)-3-ethoxycupar-5-ene-1,2-diol (1) and (-)-(1S*,4S*,9S*)-1,9-epoxybisabola-2,10-diene-4-ol (2), along with six known compounds 3-8, were isolated from the EtOH extract of the herb of Leonurus japonicus. Their structures were elucidated by physical and spectroscopic analysis. In the in vitro assays, compounds 7 and 8 showed obvious antibacterial activity against several bacteria strains, while compound 3 significantly inhibited abnormal increase of platelet aggregation induced by ADP. ",0
4471,23629822,Venous thrombosis associated with HMG-CoA reductase inhibitors,"""Among the various hypolipidemic drugs, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (also known as """"statins"""") belong to a heterogeneous class of compounds, sharing an identical hypocholesterolemic effect that develops through direct inhibition of a rate-limiting step in endogenous cholesterol synthesis. Their mechanism of action entails competitive inhibition of HMG-CoA reductase. Several lines of evidence suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, increased susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would provide an effective means of prophylaxis. Plausible biological links can also be found between statin therapy and reduction of thrombotic risk, mainly targeting immune system, blood coagulation, endothelium, lipid metabolism, and inflammation. The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins. The results of the following studies and those of recent meta-analyses have, however, questioned this assumption. Currently, it seems thereby cautious to conclude that the use of statins as part of the approach used for preventing venous thromboembolism appears unwarranted. This is due to the existence of controversial clinical evidence, to the large number of patients who would need to be treated to prevent one case of venous thrombosis, as well as to the tangible risk of side effects. More randomized and the larger studies are needed before definitive conclusions can be drawn. """,0
4472,23630040,Identification of the transcription factor HOXB4 as a novel target of miR-23a,"The transcription factor HOXB4 not only plays a role during nephrogenesis, but displays also oncogenic characteristics in different malignant neoplasms. An in-silico analysis revealed HOXB4 as a new target of microRNA-23a (miR-23a). Nephroblastomas are malignant embryonal renal neoplasms of childhood resembling developing kidney morphologically and genetically. In our study we verified HOXB4 as a target of miR-23a and furthermore examined the expression of HOXB4 and miR-23a in nephroblastomas. We investigated binding of miR-23a to the 3'UTR of HOXB4 by a luciferase assay. Effects on protein levels of HOXB4 were analysed in Western blot experiments. Expression of HOXB4 in nephroblastomas was assessed by quantitative REALtime PCR (qRT PCR) and immunohistochemistry. The luciferase reporter assay showed a statistically significant downregulation of activity by 72,5% demonstrating direct binding of miR-23a to the 3'UTR of HOXB4. In addition, miR-23a reduced the protein expression of HOXB4 statistically significantly by 65.1%. All 21 nephroblastomas investigated had statistically significantly decreased expression levels of miR-23a. A high level of HOXB4 mRNA was found in five out of 33 nephroblastomas including mixed, blastema-type and stroma-type tumors. Protein expression of HOXB4 was stronger in 15 out of 27 nephroblastomas of all subtypes in a semiquantitative comparison to normal kidney parenchyma. Our study demonstrates for the first time the regulation of HOXB4 by miR-23a. In comparison to mature kidney, nephroblastomas had low levels of miR-23a, and in a majority of them a stronger protein expression in comparison to mature kidney was found. ",0
4473,23630060,Does consumption of high-fructose corn syrup beverages cause obesity in children?,"The consumption of high-fructose corn syrup (HFCS) beverages has increased since the 1970s. At the same time, childhood obesity is on the rise, causing children to be at risk of heart disease, diabetes and other diseases. Healthcare providers have attributed childhood obesity to the consumption of HFCS in the form of beverages. This article will look at the available research and determine if there is scientific evidence underlying the idea that sweetened soft drinks, especially those containing HFCS, could cause or contribute to childhood obesity. A thorough literature search was performed using the ISI Web of Sciences, PubMed and Scopus databases within the years 2006-2012. The search generated 19 results. The articles were screened, and six were deemed eligible: four systematic reviews and two meta-analyses. Two systematic reviews found that there is no relationship between consumption of HFCS beverages and obesity in children. The other two systematic reviews found possible links between HFCS and childhood obesity. The meta-analysis articles found that consumption of HFCS beverages can contribute to childhood obesity, and limitation of sweetened beverages may help decrease obesity in children. Available research studies demonstrate inconclusive scientific evidence definitively linking HFCS to obesity in children. ",0
4474,23630160,Zac1 regulates astroglial differentiation of neural stem cells through Socs3,"Cell-fate decisions and differentiation of embryonic and adult neural stem cells (NSC) are tightly controlled by lineage-restricted and temporal factors that interact with cell-intrinsic programs and extracellular signals through multiple regulatory loops. Imprinted genes are important players in neurodevelopment and mental health although their molecular and cellular functions remain poorly understood. Here, we show that the paternally expressed transcriptional regulator Zac1 (zinc finger protein regulating apoptosis and cell cycle arrest) is transiently induced during astroglial and neuronal differentiation of embryonic and adult NSC lines. Thereby, Zac1 transactivates Socs3 (suppressor of cytokine signaling 3), a potent inhibitor of prodifferentiative Jak/Stat3 signaling, in a lineage-specific manner to prevent precocious astroglial differentiation. In vivo, Zac1 and Socs3 colocalize in the neocortical ventricular zone during incipient astrogliogenesis. Zac1 overexpression in primary NSCs delays astroglial differentiation whereas knockdown of Zac1 or Socs3 facilitates formation of astroglial cells. This negative feedback loop is unrelated to Zac1's cell cycle arrest function and specific to the Jak/Stat3 pathway. Hence, reinstating Jak/Stat3 signaling in the presence of increased Zac1 expression allows for timely astroglial differentiation. Overall, we suggest that the imprinted gene Zac1 curtails astroglial differentiation of NSCs in the developing and adult brain. ",0
4475,23630327,Heterozygous alleles restore male fertility to cytoplasmic male-sterile radish (Raphanus sativus L.): a case of overdominance,"The practice of hybridization has greatly contributed to the increase in crop productivity. A major component that exploits heterosis in crops is the cytoplasmic male sterility (CMS)/nucleus-controlled fertility restoration (Rf) system. Through positional cloning, it is shown that heterozygous alleles (RsRf3-1/RsRf3-2) encoding pentatricopeptide repeat (PPR) proteins are responsible for restoring fertility to cytoplasmic male-sterile radish (Raphanus sativus L.). Furthermore, it was found that heterozygous alleles (RsRf3-1/RsRf3-2) show higher expression and RNA polymerase II occupancy in the CMS cytoplasmic background compared with their homozygous alleles (RsRf3-1/RsRf3-1 or RsRf3-2/RsRf3-2). These data provide new insights into the molecular mechanism of fertility restoration to cytoplasmic male-sterile plants and illustrate a case of overdominance. ",0
4476,23630363,Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development,"Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. In this article, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single-chain variable fragment miniAb. Using the tumor-associated Ag her-2/neu extracellular domain, we showed that the coengagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinoma models. Furthermore, four different extracellular domains of her-2/neu could be targeted to B cells to generate Abs against particular domains with different antitumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost, which may be of use not only for cancer therapy but also for infectious agents. ",0
4477,23630577,Effects of microparticle size and Fc density on macrophage phagocytosis,"Controlled induction of phagocytosis in macrophages offers the ability to therapeutically regulate the immune system as well as improve delivery of chemicals or biologicals for immune processing. Maximizing particle uptake by macrophages through Fc receptor-mediated phagocytosis could lead to new delivery mechanisms in drug or vaccine development. Fc ligand density and particle size were examined independently and in combination in order to optimize and tune the phagocytosis of opsonized microparticles. We show the internalization efficiency of small polystyrene particles (0.5 µm to 2 µm) is significantly affected by changes in Fc ligand density, while particles greater than 2 µm show little correlation between internalization and Fc density. We found that while macrophages can efficiently phagocytose a large number of smaller particles, the total volume of phagocytosed particles is maximized through the non-specific uptake of larger microparticles. Therefore, larger microparticles may be more efficient at delivering a greater therapeutic payload to macrophages, but smaller opsonized microparticles can deliver bio-active substances to a greater percentage of the macrophage population. This study is the first to treat as independent variables the physical and biological properties of Fc density and microparticle size that initiate macrophage phagocytosis. Defining the physical and biological parameters that affect phagocytosis efficiency will lead to improved methods of microparticle delivery to macrophages. ",0
4478,23631282,Effects of melatonin on oxygen-dependent processes],"Original and literature data on melatonin effects on various oxygen-dependent processes, in particular, blood oxygen transport and the free-radical reactions, are analyzed. Melatonin influences the oxygen binding properties of hemoglobin by changing hemoglobin oxygen affinity and optimizes the process of tissue oxygenation and prooxidant--antioxidant balance by reducing oxygen participation in free-radical processes. ",0
4479,23631891,Secondary vitellogenesis persists despite disrupted fecundity in amphipods maintained on metal-contaminated sediment: X-ray fluorescence assessment of oocyte metal content,"Melita plumulosa is an epibenthic, detritivorous amphipod found in estuaries along the eastern coast of Australia. It has been utilized as a test organism in rapid ten to thirteen days reproduction toxicity tests for sediment quality assessment. The fecundity of females in the toxicity test has been found to be inhibited by exposure of the amphipods to contaminated sediments enriched with zinc and other metals. This study investigated the proposal that interference in vitellogenesis is the cause of reproductive toxicity of metals in crustaceans. Inspection of the ovaries from amphipods on day 6 of the test either from control or Zn/Pb/Cd/Cu-spiked sediment, that were nearing completion of vitellogenesis, showed that the females in all treatments were producing similar numbers of oocytes undergoing secondary vitellogenesis. The distribution of the Zn, Cu and Pb in the oocytes and ventral caeca of females was examined by X-ray fluorescence microscopy. Elemental mapping revealed a dense accumulation of Zn in primary oocytes and a uniform distribution of Zn and Cu in the secondary oocytes in all treatments. Zn and Cu were also observed to be uniformly distributed in the ventral caeca. Pb was not detected in either of these tissues. The apparent normal morphology and the typical number of oocytes undergoing secondary vitellogenesis suggest that vitellogenesis was not being disrupted by Pb displacing Zn in the metal-binding domain of vitellogenin in amphipods exposed to the contaminated sediment during the test. Alternative mechanisms for the reproductive toxicity of amphipods exposed for six days to metal-contaminated sediment are discussed. ",0
4480,23632152,Management of pancreatic neuroendocrine tumors,"Pancreatic neuroendocrine tumors account for 1% to 2% of pancreatic neoplasms and may occur sporadically or as part of a hereditary syndrome. Patients may present with symptoms related to hormone secretion by functional tumors or to locally advanced or metastatic nonfunctional tumors. Asymptomatic pancreatic neuroendocrine tumors are increasingly detected incidentally during abdominal imaging performed for other reasons. The management of localized pancreatic neuroendocrine tumors is surgical resection. Hepatic metastases are common and their management involves a variety of liver-directed therapies, which should be tailored according to extent of disease, symptoms, presence of extrahepatic metastases, and patient performance status. ",0
4481,23632304,Calcium pathways such as cAMP modulate clothianidin action through activation of α-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptors,"Clothianidin is a neonicotinoid insecticide developed in the early 2000s. We have recently demonstrated that it was a full agonist of α-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptors expressed in the cockroach dorsal unpaired median neurons. Clothianidin was able to act as an agonist of imidacloprid-insensitive nAChR2 receptor and internal regulation of cAMP concentration modulated nAChR2 sensitivity to clothianidin. In the present study, we demonstrated that cAMP modulated the agonist action of clothianidin via α-bungarotoxin-sensitive and insensitive receptors. Clothianidin-induced current-voltage curves were dependent to clothianidin concentrations. At 10 μM clothianidin, increasing cAMP concentration induced a linear current-voltage curve. Clothianidin effects were blocked by 0.5 μM α-bungarotoxin suggesting that cAMP modulation occurred through α-bungarotoxin-sensitive receptors. At 1 mM clothianidin, cAMP effects were associated to α-bungarotoxin-insensitive receptors because clothianidin-induced currents were blocked by 5 μM mecamylamine and 20 μM d-tubocurarine. In addition, we found that application of 1mM clothianidin induced a strong increase of intracellular calcium concentration. These data reinforced the finding that calcium pathways including cAMP modulated clothianidin action on insect nicotinic acetylcholine receptors. We proposed that intracellular calcium pathways such as cAMP could be a target to modulate the mode of action of neonicotinoid insecticides. ",0
4482,23632339,Safety of thromboembolic chemoprophylaxis in spinal trauma patients requiring surgical stabilization,"Retrospective review. To determine the incidence of thromboembolic events, bleeding complications such as epidural hematomas, and wound complications in patients with spinal trauma requiring surgical stabilization. Literature addressing the safety and efficacy of chemoprophylactic agents in postoperative patients with spinal trauma is sparse. As a result, significant variability exists regarding administration of thromboembolic chemoprophylaxis in this population. The risk of bleeding complications is particularly concerning. Patients with spinal trauma who underwent surgical stabilization in 2009 and 2010 at a single level 1 trauma center were retrospectively reviewed. Exclusion criteria included patients who underwent solely decompressive procedures, noninstrumented fusions, kyphoplasty, or had incomplete medical records. Patients who received chemoprophylaxis were compared with patients who did not. Demographical information and injury data were collected. Primary outcome measures were prevalence of thromboembolic events, epidural hematomas, and persistent wound drainage requiring irrigation and debridement. Two hundred twenty-seven of 373 patients were included (56 in the untreated group, 171 in the treated group). Eight patients in the untreated group (14.3%) and 12 patients in the treated group (7%) developed postoperative thromboembolism (P = 0.096). There was 1 pulmonary embolism in the untreated group (1.8%), and 4 pulmonary embolisms in the treated group (2.3%). Surgical irrigation and debridement for wound drainage was required for 1.8% of patients in the untreated group and for 5.3% of patients in the treated group. No epidural hematomas were noted in either group. The treated group had more spinal levels fused (P = 0.46), higher injury severity scores (0.001), and longer hospitalizations (0.018). Patients who developed postoperative thromboembolism had significantly higher body mass indexes (P = 0.01), injury severity scores (0.001), number of spinal levels fused (P = 0.004), incidence of neurological deficits (0.001), and longer hospitalizations (0.16) compared with those who did not. The use of chemoprophylaxis appears to be safe in at-risk patients in the immediate postoperative period after spinal trauma surgery. No epidural hematomas occurred, and the risk of wound drainage is small. Body mass index, injury severity score, presence of neurological deficits, and number of spinal levels fused should be considered when determining which patients should receive chemoprophylaxis after surgical stabilization. ",0
4483,23632633,Lack of myostatin impairs mechanical performance and ATP cost of contraction in exercising mouse gastrocnemius muscle in vivo,"Although it is well established that the lack of myostatin (Mstn) promotes skeletal muscle hypertrophy, the corresponding changes regarding force generation have been studied mainly in vitro and remain conflicting. Furthermore, the metabolic underpinnings of these changes are very poorly documented. To clarify this issue, we have investigated strictly noninvasively in vivo the impact of the lack of Mstn on gastrocnemius muscle function and energetics in Mstn-targeted knockout (Mstn-/-) mice using ¹H-magnetic resonance (MR) imaging and ³¹P-MR spectroscopy during maximal repeated isometric contractions induced by transcutaneous electrostimulation. In Mstn-/- animals, although body weight, gastrocnemius muscle volume, and absolute force were larger (+38, +118, and +34%, respectively) compared with wild-type (Mstn+/+) mice, specific force (calculated from MR imaging measurements) was significantly lower (-36%), and resistance to fatigue was decreased. Besides, Mstn deficiency did not affect phosphorylated compound concentrations and intracellular pH at rest but caused a large increase in ATP cost of contraction (up to +206% compared with Mstn+/+) throughout the stimulation period. Further, Mstn deficiency limits the shift toward oxidative metabolism during muscle activity despite the fact that oxidative ATP synthesis capacity was not altered. Our data demonstrate in vivo that the absence of Mstn impairs both mechanical performance and energy cost of contraction in hypertrophic muscle. These findings must be kept in mind when considering Mstn as a potential therapeutic target for increasing muscle mass in patients suffering from muscle-wasting disorders. ",0
4484,23632740,Early diffusion-weighted magnetic resonance imaging in children after cardiac arrest may provide valuable prognostic information on clinical outcome,"We examined whether early diffusion-weighted magnetic resonance imaging (DW-MRI) abnormalities of the brain and variation of apparent diffusion coefficient (ADC) values can provide prognostic information on clinical outcome in children following cardiac arrest (CA). Retrospective study. A 12-bed paediatric intensive care unit (PICU). Children aged between 1 month and 18 years who had DW-MRI with ADC measurement within the first week following CA. Neurological outcomes were assessed using the Pediatric Cerebral Performance Category Scale (PCPC). Differences between the favourable (PCPC ≤3) and unfavourable (PCPC ≥4) groups were analysed with regard to clinical data, electrophysiological patterns as well as qualitative and quantitative DW-MRI abnormalities. Twenty children with a median age of 20 months (1.5-185) and a male/female sex ratio of 1.5 underwent DW-MRI after CA with a median delay of 3 days (1-7). Aetiologies of CA were (i) asphyxia (n = 10), (ii) haemodynamic (n = 5) or (iii) unknown (n = 5). With regard to DW-MRI findings, the unfavourable outcome group (n = 8) was associated with cerebral cortex (p = 0.02) and basal ganglia (p = 0.005) lesions, with a larger number of injured brain regions (p = 0.001) and a global decrease in measured ADC signal (p = 0.008). Normal DW-MRI (n = 5) was exclusively associated with the favourable outcome group (n = 12). Qualitative, topographic and quantitative analysis of early DW-MRI with ADC measurement in children following CA may provide valuable prognostic information on neurological outcomes. ",0
4485,23632765,Simultaneous recording of single-neuron activities and broad-area intracranial electroencephalography: electrode design and implantation procedure,"There has been growing interest in clinical single-neuron recording to better understand epileptogenicity and brain function. It is crucial to compare this new information, single-neuronal activity, with that obtained from conventional intracranial electroencephalography during simultaneous recording. However, it is difficult to implant microwires and subdural electrodes during a single surgical operation because the stereotactic frame hampers flexible craniotomy. To describe newly designed electrodes and surgical techniques for implanting them with subdural electrodes that enable simultaneous recording from hippocampal neurons and broad areas of the cortical surface. We designed a depth electrode that does not protrude into the dura and pulsates naturally with the brain. The length and tract of the depth electrode were determined preoperatively between the lateral subiculum and the lateral surface of the temporal lobe. A frameless navigation system was used to insert the depth electrode. Surface grids and ventral strips were placed before and after the insertion of the depth electrodes, respectively. Finally, a microwire bundle was inserted into the lumen of the depth electrode. We evaluated the precision of implantation, the recording stability, and the recording rate with microwire electrodes. Depth-microwire electrodes were placed with a precision of 3.6 mm. The mean successful recording rate of single- or multiple-unit activity was 14.8%, which was maintained throughout the entire recording period. We achieved simultaneous implantation of microwires, depth electrodes, and broad-area subdural electrodes. Our method enabled simultaneous and stable recording of hippocampal single-neuron activities and multichannel intracranial electroencephalography. ",0
4486,23633624,Uterine secretome and its modulation in rat (Rattus norvegicus),"The present study identifies uterine fluid (UF) proteins that display differential abundance during the embryo-permissive phase in nonconception and conception cycles in rats. UF samples were collected from nonpregnant rats in the proestrous (n=17) and metestrous (n=18) phases and also from pregnant (n=17) and pseudopregnant (n=17) rats on day 4 post coitus. UF protein profile in the metestrous phase was compared with that in the proestrous phase. Similarly, UF protein profile of the pregnant rats was compared with that of the pseudopregnant rats. Two-dimensional PAGE, followed by densitometric analysis of the paired protein spots, revealed differential abundance of 44 proteins in the metestrous phase, compared with that in the proestrous phase. Of these, 29 proteins were identified by matrix-assisted laser desorption/ionization time-of-flight or liquid chromatography-tandem mass spectrometry. Functional groups such as proteases, protease inhibitors, and oxidoreductases were enriched in differentially abundant proteins. Total protease activity in UF was found to be significantly (P<0.05; t-test) higher in the proestrous phase, compared with that in the metestrous phase. Furthermore, 41 UF proteins were found to be differentially abundant in pregnant rats, compared with pseudopregnant rats. Of these, 11 proteins could be identified. Immunoblotting analysis confirmed significantly higher (P<0.05; t-test) abundance of β-actin, Rho-specific guanine nucleotide dissociation inhibitor alpha (Rho-GDIα), and peroxiredoxin-2 and -6 in the metestrous phase, compared with that in the proestrous phase. Compared with pseudopregnant rats, pregnant rats had significantly higher (P<0.05; t-test) levels of UF β-actin and Rho-GDIα. Furthermore, these proteins could be detected in the culture supernatants of endometrial epithelial cell lines, thereby providing an evidence of their secretion from endometrial epithelial cells. Data obtained from the study expand our knowledge on the uterine milieu that favours embryo implantation. ",0
4487,23633659,Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy,"Increase in reactive oxygen species (ROS) is one of the major retinal metabolic abnormalities associated with the development of diabetic retinopathy. NF-E2-related factor 2 (Nrf2), a redox sensitive factor, provides cellular defenses against the cytotoxic ROS. In stress conditions, Nrf2 dissociates from its cytosolic inhibitor, Kelch like-ECH-associated protein 1 (Keap1), and moves to the nucleus to regulate the transcription of antioxidant genes including the catalytic subunit of glutamylcysteine ligase (GCLC), a rate-limiting reduced glutathione (GSH) biosynthesis enzyme. Our aim is to understand the role of Nrf2-Keap1-GCLC in the development of diabetic retinopathy. Effect of diabetes on Nrf2-Keap1-GCLC pathway, and subcellular localization of Nrf2 and its binding with Keap1 was investigated in the retina of streptozotocin-induced diabetic rats. The binding of Nrf2 at GCLC was quantified by chromatin immunoprecipitation technique. The results were confirmed in isolated retinal endothelial cells, and also in the retina from human donors with diabetic retinopathy. Diabetes increased retinal Nrf2 and its binding with Keap1, but decreased DNA-binding activity of Nrf2 and also its binding at the promoter region of GCLC. Similar impairments in Nrf2-Keap1-GCLC were observed in the endothelial cells exposed to high glucose and in the retina from donors with diabetic retinopathy. In retinal endothelial cells, glucose-induced impairments in Nrf2-GCLC were prevented by Nrf2 inducer tBHQ and also by Keap1-siRNA. Due to increased binding of Nrf2 with Keap1, its translocation to the nucleus is compromised contributing to the decreased GSH levels. Thus, regulation of Nrf2-Keap1 by pharmacological or molecular means could serve as a potential adjunct therapy to combat oxidative stress and inhibit the development of diabetic retinopathy. ",0
4488,23633850,Reversal of dental fluorosis: A clinical study,"This study was conducted to evaluate the clinical reversal of dental fluorosis with various combinations of calcium, vitamin D3, and ascorbic acid, along with changes in levels of certain biochemical parameters concerned with dental fluorosis. The role of fluoride level of drinking water in the etiology of dental fluorosis and the prevalence of dental fluorosis in both dentitions and teeth were also assessed. A total number of 50 patients with clinical features of dental fluorosis without trauma and any adverse habits were selected. Of these, in 30 co-operative patients, estimation of water fluoride level and pretreatment and post-treatment serum and urine fluoride levels were done with ion selective electrode method. The selected 30 patients were divided into three groups, that is, group A, group B, and group C, and were given various combinations of medications like calcium with vitamin D3 supplements, ascorbic acid with vitamin D3 supplements, and chlorhexidine mouthwash (placebo) for three months, respectively. These 30 patients were assessed for any change in the clinical grading of dental fluorosis. No change in clinical grading of dental fluorosis was noted. Considerable reduction in serum and urine fluoride levels was noted in both group A and group B patients. Dental fluorosis was noted in permanent teeth more commonly than deciduous teeth, and permanent maxillary central incisors had the highest prevalence rate. This study comprises only 30 patients with three months of follow-up. So, this sample of patients and duration of follow-up period are conclusive to observe changes in biochemical parameters but not sufficient to observe changes in clinical grading. ",0
4489,23633924,Inauhzin sensitizes p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents,"Toxicity and chemoresistance are two major issues to hamper the success of current standard tumor chemotherapy. Combined therapy of agents with different mechanisms of action is a feasible and effective means to minimize the side effects and avoid the resistance to chemotherapeutic drugs while improving the antitumor effects. As the most essential tumor suppressor, p53 or its pathway has been an attractive target to develop a new type of molecule-targeting anticancer therapy. Recently, we identified a small molecule, Inauhzin (INZ), which can specifically activate p53 by inducing its deacetylation. In this study, we tested if combination with INZ could sensitize tumor cells to the current chemotherapeutic drugs, cisplatin (CIS) and doxorubicin (DOX). We found that compared with any single treatment, combination of lower doses of INZ and CIS or DOX significantly promoted apoptosis and cell growth inhibition in human non-small lung cancer and colon cancer cell lines in a p53-dependent fashion. This cooperative effect between INZ and CIS on tumor suppression was also confirmed in a xenograft tumor model. Therefore, this study suggests that specifically targeting the p53 pathway could enhance the sensitivity of cancer cells to chemotherapeutic agents and markedly reduce the doses of the chemotherapy, possibly decreasing its adverse side effects. ",0
4490,23634146,Gene expression of leptin and long leptin receptor isoform in endometriosis: a case-control study,"In this study, leptin/BMI ratio in serum and peritoneal fluid and gene expression of leptin and long form leptin receptor (OB-RL) were assessed in eutopic and ectopic endometria of women with endometriosis and controls. Increased serum leptin/BMI ratio was found in endometriosis patients. Leptin and OB-RL gene expression was significantly higher in ectopic versus eutopic endometrium of patients and controls. A positive, significant correlation was observed between leptin and OB-RL transcripts in ectopic endometria and also in eutopic endometria in endometriosis and control groups. A negative and significant correlation was found between OB-RL mRNA expression and peritoneal fluid leptin/BMI ratio only in endometriosis. These data suggest that, through a modulatory interaction with its active receptor, leptin might play a role in the development of endometrial implants. ",0
4491,23634297,"Predictors of metabolic syndrome in the Iranian population: waist circumference, body mass index, or waist to hip ratio?","This study aimed to investigate whether body mass index (BMI), waist circumference (WC), or waist to hip ratio (WHR) could be a better predictor of metabolic syndrome and, if so, what would be the cutoff points for these surrogates to appropriately differentiate metabolic syndrome in different age and sex subgroups. Methods. The present cross-sectional study was conducted on a sample of Isfahan Cohort Study (ICS). In total, 468 individuals (194 with and 274 subjects without metabolic syndrome) according to the National Cholesterol Education Program's Adult Treatment Panel III (ATP-III) criteria were selected. Anthropometric indices were measured and plotted using receiver-operating characteristic (ROC) curves. Results. According to ROC curve analysis, WC and WHR parameters were better indicators of metabolic syndrome compared to BMI in women, whereas in men WHR had a lower discriminating value compared to the other two parameters. Among these three anthropometric parameters, BMI had a lower sensitivity and WC and WHR both had a higher sensitivity for predicting metabolic syndrome in women compared with in men. The cut points for WC were nearly equal in men and women, 90.3 versus 90.0, respectively. Women had higher cut points for BMI (28.5 kg/m(2)) compared to men (26.0 kg/m(2)). Our results showed the highest sensitivity and specificity for WC cut points specially in women. To predict metabolic syndrome, we looked into optimal age-specific cut points for BMI, WC, and WHR. The results indicated that WC had the highest discriminating value compared to other indicators in the different age subgroups. The optimal cut points for all three parameters gradually increased with age. Conclusion. Our results demonstrated that regardless of gender and age variables, WC could be a preferred parameter for predicting metabolic syndrome compared to BMI and WHR in Iranian population. ",0
4492,23634710,Expression and cellular trafficking of GP82 and GP90 glycoproteins during Trypanosoma cruzi metacyclogenesis,"The transformation of noninfective epimastigotes into infective metacyclic trypomastigotes (metacyclogenesis) is a fundamental step in the life cycle of Trypanosoma cruzi, comprising several morphological and biochemical changes. GP82 and GP90 are glycoproteins expressed at the surface of metacyclic trypomastigote, with opposite roles in mammalian cell invasion. GP82 is an adhesin that promotes cell invasion, while GP90 acts as a negative regulator of parasite internalization. Our understanding of the synthesis and intracellular trafficking of GP82 and GP90 during metacyclogenesis is still limited. Therefore, we decided to determine whether GP82 and GP90 are expressed only in fully differentiated metacyclic forms or they start to be expressed in intermediate forms undergoing differentiation. Parasite populations enriched in intermediate forms undergoing differentiation were analyzed by quantitative real-time PCR, Western blot, flow cytometry and immunofluorescence to assess GP82 and GP90 expression. We found that GP82 and GP90 mRNAs and proteins are expressed in intermediate forms and reach higher levels in fully differentiated metacyclic forms. Surprisingly, GP82 and GP90 presented distinct cellular localizations in intermediate forms compared to metacyclic trypomastigotes. In intermediate forms, GP82 is localized in organelles at the posterior region and colocalizes with cruzipain, while GP90 is localized at the flagellar pocket region. This study discloses new aspects of protein expression and trafficking during T. cruzi differentiation by showing that the machinery involved in GP82 and GP90 gene expression starts to operate early in the differentiation process and that different secretion pathways are responsible for delivering these glycoproteins toward the cell surface. ",0
4493,23634930,Effects of Ginkgo biloba on chemically-induced mammary tumors in rats receiving tamoxifen,"Ginkgo biloba extract (GbE) is used extensively by breast cancer patients undergoing treatment with Tamoxifen (TAM). Thus, the present study investigated the effects of GbE in female Sprague-Dawley (SD) rats bearing chemically-induced mammary tumors and receiving TAM. Animals bearing mammary tumors (≥1 cm in diameter) were divided into four groups: TAM [10 mg/kg, intragastrically (i.g.)], TAM plus GbE [50 and 100 mg/kg, intraperitoneally (i.p.)] or an untreated control group. After 4 weeks, the therapeutic efficacy of the different treatments was evaluated by measuring the tumor volume (cm(3)) and the proportions of each tumor that were alive, necrotic or degenerative (mm(2)). In addition, labeling indexes (LI%) were calculated for cell proliferation (PCNA LI%) and apoptosis (cleaved caspase-3 LI%), expression of estrogen receptor-alpha (ER-α) and p63 biomarkers. Overall, the tumor volume and the PCNA LI% within live tumor areas were reduced by 83% and 99%, respectively, in all TAM-treated groups when compared to the untreated control group. GbE treatment (100 mg/kg) reduced the proportions of live (24.8%) and necrotic areas (2.9%) (p = 0.046 and p = 0.038, respectively) and significantly increased the proportion of degenerative areas (72.9%) (p = 0.004) in mammary tumors when compared to the group treated only with TAM. The expression of ER-α, p63 and cleaved caspase-3 in live tumor tissues was not modified by GbE treatment. Co-treatment with 100 mg/kg GbE presented a slightly beneficial effect on the therapeutic efficacy of TAM in female SD rats bearing mammary tumors. ",0
4494,23635081,Parental bonding and personality characteristics of first episode intention to suicide or deliberate self-harm without a history of mental disorders,"There is substantial overlap between deliberate self-harm (DSH) and intention to suicide (ITS), although the psychopathologies and motivations behind these behaviors are distinctly different. The purpose of this study was to investigate (i) the pathway relationship among parental bonding, personality characteristics, and alexithymic traits, and (ii) the association of these features with ITS and DSH using structural equation modeling to determine the risks and protective factors for these behaviors. Sixty-nine first-time DSH and 36 first-time ITS patients without medical or psychiatric illnesses, and 66 controls were recruited. The Parental Bonding Inventory (PBI), Eysenck Personality Questionnaire (EPQ), 20-item Toronto Alexithymia Scale (TAS-20), and the Chinese Health Questionnaire (CHQ) were filled out by the participants. Our structural equation models showed that parental bonding had the greatest influence on the development of DSH behavior in patients. On the other hand, participants who were younger, less extraverted, with a greater extent of the alexithymic trait of difficulty identifying feeling (DIF), and a worse mental health condition, were more likely to develop ITS behavior. Males were more likely than females to develop the alexithymic trait of DIF. Although there are many covariates that affect both ITS and DSH behaviors, these covariates may have different functions in the development of these behaviors, thus revealing the psychopathological difference between DSH and ITS. Policymakers should consider these differences and build intervention and prevention programs for gender- and age-specific high-risk groups to target the differences, with a focus on family counseling to treat DSH and a focus on attempting to increase emotional awareness to treat ITS. ",0
4495,23635349,Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation,"""Aggressive chemotherapy/radiotherapy and bone marrow transplantation can cure >90% of girls and young women affected by disorders requiring such treatment. However, the ovaries are very sensitive to cytotoxic drugs, especially to alkylating agents. Several options are currently available to preserve fertility in cancer patients. The present review reports the results of 60 orthotopic reimplantations of cryopreserved ovarian tissue performed by three teams, as well as 24 live births reported in the literature to date. Restoration of ovarian activity occurred in almost all cases in the three series. Among the 60 patients, eleven conceived and six of those had already delivered twelve healthy babies. In the future, we are looking to: 1) improve freezing techniques; and 2) enhance the """"vascular bed"""" before reimplantation to increase pregnancy rates. On the other hand, cryopreservation of ovarian tissue may be combined with removal, via puncture, of small antral follicles, making it possible to freeze both ovarian tissue and isolated immature oocytes. """,0
4496,23635481,Association of functional kallikrein-1 promoter polymorphisms and acute kidney injury: a case-control and longitudinal cohort study,"Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI). We first evaluated the potential role of functional multiallelic KLK1 promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C-rich repeat region of the proximal KLK1 promoter was determined by direct Sanger/capillary resequencing. 16 alleles were identified in a complex, polymorphic G/C-rich region of the KLK1 proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the KLK1 risk-allele (I or G) carrier state was associated with the composite of ≥2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The KLK1 risk-allele carrier state was also marginally associated with the composite of ≥2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06). KLK1 promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings. ",0
4497,23635650,Study of primary IGF-1 deficiency in Egyptian children with idiopathic short stature,"Primary insulin-like growth factor-1 (IGF-1) deficiency (IGFD) is defined by low levels of IGF-1 without growth hormone (GH) deficiency and absence of secondary causes. The aim of this study was to evaluate IGF-1 in Egyptian children with idiopathic short stature (ISS) and describe patients with IGFD. This cross-sectional study included 50 children with ISS following up at the Diabetes Endocrine and Metabolism Pediatric Unit at Cairo University Pediatric Hospital. Children were included based on the following criteria: (1) short stature with current height standard deviation score (SDS) ≤-2.5; (2) age between 2 and 9 years in boys and 2 and 8 years in girls, and (3) prepubertal status. Exclusion criteria were: (1) identified cause of short stature and (2) pubertal children. IGF-1-deficient children were defined as children without GH deficiency and with IGF-1 levels below the 2.5th percentile. Among 50 children with ISS, 14 (28%) patients had low IGF-1 levels, consistent with the diagnosis of primary IGFD. When compared with non-IGFD children, IGFD children had lower birth weight SDS (-1.8 vs. -0.7 SDS, p < 0.0001) and lower height SDS (-4.2 vs. -3.1 SDS, p < 0.05) and more delayed bone age (2.6 vs. 1.6 years, p = 0.001). Primary IGF-1 deficiency is found in 28% of children with ISS. ",0
4498,23635741,Cardiovascular disease risk factors in women with a history of early-onset preeclampsia,"To assess the prevalence of established cardiovascular disease risk factors and to estimate 10-year absolute risk of cardiovascular disease after early-onset preeclampsia. We assessed major cardiovascular disease risk factors in 243 primiparous women with a history of early-onset preeclampsia (delivery at less than 34 weeks of gestation) at least 6 months after delivery; 374 healthy nonpregnant women of similar age served as a reference group. After adjustment for age, we observed significantly higher means for body mass index, blood pressure, total and low-density lipoprotein cholesterol, triglycerides, glucose, and lower mean high-density lipoprotein cholesterol (all P<.01) in women with previous early-onset preeclampsia compared with the reference group. Prevalence of the metabolic syndrome was 15.2% compared with 4.3% (P<.001), two or more major cardiovascular disease risk factors were present in 51.0% compared with 26.5%, and three or more risk factors were present in 18.9% compared with 6.4%, respectively. Mean estimated 10-year cardiovascular disease risks by the Framingham Risk Score were 1.08% (95% confidence interval 1.04-1.12) and 1.01% (95% CI 1.00-1.01; P<.001) for the difference. Women with a history of early-onset preeclampsia have a high prevalence of several major cardiovascular disease risk factors. Although the estimated 10-year cardiovascular disease risk is low (less than 5%) after delivery, cardiovascular disease risk is expected to increase rapidly with increasing age. II. ",0
4499,23635921,Pituitary ischemic apoplexy in a young woman using oral contraceptives: a case report,"Estrogen is suggested to be one of the plausible risk factors for pituitary hemorrhagic apoplexy through pituitary hyperemia. We experienced a 33-year-old woman with pituitary ischemic apoplexy of a nonfunctional macroadenoma under oral contraceptive use. Our case indicates that hypercoagulable state, but not hyperemia, associated with estrogen may promote pituitary ischemic apoplexy.  ",0
4500,23636036,Perennial is more effective than preseasonal subcutaneous immunotherapy in the treatment of seasonal allergic rhinoconjunctivitis,"Two different regimens of subcutaneous immunotherapy (IT), perennial or preseasonal, may be used in the treatment of seasonal allergy. The aim of this study was to compare the efficacy and safety of perennial IT (PIT) and preseasonal IT (PSIT) in patients suffering from seasonal rhinoconjunctivitis. The study was planned as a randomized, double-blind, comparative study on the efficacy and safety of PIT and PSIT. The study group comprised 120 patients allergic to grass and rye pollen. After the observational season they were randomized to receive PIT or PSIT for 3 years. The effect of IT was assessed based on symptom severity and medication use recorded in diaries. Ninety-nine patients completed the study. No difference was seen between the groups regarding combined symptom medication score (SMS) in the first season of IT. During the second season, the difference between PIT and PSIT regarding combined SMS was 27.9% (p = 0.063) and reached 42.7% (p = 0.012) in favor of PIT in the third season. Both treatments had a similar safety profile. PIT was more effective than PSIT in the treatment of rhinoconjunctivitis in patients allergic to grass and rye pollens. ",0
4501,23636590,Adsorptive removal and photocatalytic decomposition of sulfamethazine in secondary effluent using TiO2-zeolite composites,"We investigated the adsorption and decomposition of sulfamethazine (SMT), which is used as a synthetic antibacterial agent and discharged into environmental water, using high-silica Y-type zeolite (HSZ-385), titanium dioxide (TiO2), and TiO2-zeolite composites. By using ultrapure water and secondary effluent as solvents, we prepared SMT solutions (10 μg/L and 10 mg/L) and used them for adsorption and photocatalytic decomposition experiments. When HSZ-385 was used as an adsorbent, rapid adsorption of SMT in the secondary effluent was confirmed, and the adsorption reached equilibrium within 10 min. The photocatalytic decomposition rate using TiO2 in the secondary effluent was lower than that in ultrapure water, and we clarified the inhibitory effect of ions and organic matter contained in the secondary effluent on the reaction. We synthesized TiO2-zeolite composites and applied them to the removal of SMT. During the treatment of 10 μg/L SMT in the secondary effluent using the composites, 76% and more than 99% of the SMT were decomposed within 2 and 4 h by photocatalysis. The SMT was selectively adsorbed onto high-silica Y-type zeolite in the composites. Resultantly, the inhibitory effect of the coexisting materials was reduced, and the composites could remove SMT more effectively compared with TiO2 alone in the secondary effluent. ",0
4502,23636618,Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats,"Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. ",0
4503,23637060,Application of high throughput pretreatment and co-hydrolysis system to thermochemical pretreatment. Part 2: Dilute alkali,"High throughput pretreatment (HTPH) and enzymatic hydrolysis systems are now vital for screening large numbers of biomass samples to investigate biomass recalcitrance over various pretreatment and enzymatic hydrolysis conditions. Although hydrothermal pretreatment is currently being employed in most high throughput applications, thermochemical pretreatment at low and high pH conditions can offer additional insights to better understand the roles of hemicellulose and lignin, respectively, in defining biomass recalcitrance. Thus, after successfully applying the HTPH approach to dilute acid pretreatment [Gao et al. (2012) Biotechnol. Bioeng. 110(3): 754-762], extension to dilute alkali pretreatment was also achieved using a similar single-step neutralization and buffering concept. In the latter approach, poplar and switchgrass were pretreated with 1 wt% sodium hydroxide at 120°C for different reaction times. Following pretreatment, an H₂Cit⁻/HCit²⁻ buffer with a pH of 4.5 was used to condition the pretreatment slurry to a pH range of 4.69-4.89, followed by enzymatic hydrolysis for 72 h of the entire mixture. Sugar yields showed different trends for poplar and switchgrass with increases in pretreatment times, demonstrating the method provided a clearly discernible screening tool at alkali conditions. This method was then applied to selected Populus tremuloides samples to follow ring-by-ring sugar release patterns. Observed variations were compared to results from hydrothermal pretreatments, providing new insights in understanding the influence of biomass structural differences on recalcitrance. ",0
4504,23637086,Nanoparticle transport in epithelial cells: pathway switching through bioconjugation,"The understanding and control of nanoparticle transport into and through cellular compartments is central to biomedical applications of nanotechnology. Here, it is shown that the transport pathway of 50 nm polystyrene nanoparticles decorated with vitamin B12 in epithelial cells is different compared to both soluble B12 ligand and unmodified nanoparticles, and this is not attributable to B12 recognition alone. Importantly, the study indicates that vitamin B12 -conjugated nanoparticles circumnavigate the lysosomal compartment, the destination of soluble vitamin B12 ligand. Whereas cellular trafficking of soluble B12 is confirmed to occur via the clathrin-mediated pathway, transport of B12 -conjugated nanoparticles appears to predominantly take place by a route that is perturbed by caveolae-specific inhibitors. This data suggests that, following its conjugation to nanoparticles, in addition to dramatically increasing the cellular uptake of nanoparticles, the normal cell trafficking of B12 is switched to an alternative pathway, omitting the lysosomal stage: a result with important implications for oral delivery of nanoparticulate diagnostics and therapeutics.  ",0
4505,23637287,The role of the endoplasmic reticulum in peroxisome biogenesis,"Peroxisomes are essential cellular organelles involved in lipid metabolism. Patients affected by severe peroxisome biogenesis disorders rarely survive their first year. Genetic screens in several model organisms have identified more than 30 PEX genes that are required for the formation of functional peroxisomes. Despite significant work on the PEX genes, the biogenic origin of peroxisomes remains controversial. For at least two decades, the prevailing model postulated that peroxisomes propagate by growth and fission of preexisting peroxisomes. In this review, we focus on the recent evidence supporting a new, semiautonomous model of peroxisomal biogenesis. According to this model, peroxisomal membrane proteins (PMPs) traffic from the endoplasmic reticulum (ER) to the peroxisome by a vesicular budding, targeting, and fusion process while peroxisomal matrix proteins are imported into the organelle by an autonomous, posttranslational mechanism. We highlight the contradictory conclusions reached to answer the question of how PMPs are inserted into the ER. We then review what we know and what still remains to be elucidated about the mechanism of PMP exit from the ER and the contribution of preperoxisomal vesicles to mature peroxisomes. Finally, we discuss discrepancies in our understanding of de novo peroxisome biogenesis in wild-type cells. We anticipate that resolving these key issues will lead to a more complete picture of peroxisome biogenesis. ",0
4506,23638127,Harnessing different motivational frames via mobile phones to promote daily physical activity and reduce sedentary behavior in aging adults,"""Mobile devices are a promising channel for delivering just-in-time guidance and support for improving key daily health behaviors. Despite an explosion of mobile phone applications aimed at physical activity and other health behaviors, few have been based on theoretically derived constructs and empirical evidence. Eighty adults ages 45 years and older who were insufficiently physically active, engaged in prolonged daily sitting, and were new to smartphone technology, participated in iterative design development and feasibility testing of three daily activity smartphone applications based on motivational frames drawn from behavioral science theory and evidence. An """"analytically"""" framed custom application focused on personalized goal setting, self-monitoring, and active problem solving around barriers to behavior change. A """"socially"""" framed custom application focused on social comparisons, norms, and support. An """"affectively"""" framed custom application focused on operant conditioning principles of reinforcement scheduling and emotional transference to an avatar, whose movements and behaviors reflected the physical activity and sedentary levels of the user. To explore the applications' initial efficacy in changing regular physical activity and leisure-time sitting, behavioral changes were assessed across eight weeks in 68 participants using the CHAMPS physical activity questionnaire and the Australian sedentary behavior questionnaire. User acceptability of and satisfaction with the applications was explored via a post-intervention user survey. The results indicated that the three applications were sufficiently robust to significantly improve regular moderate-to-vigorous intensity physical activity and decrease leisure-time sitting during the 8-week behavioral adoption period. Acceptability of the applications was confirmed in the post-intervention surveys for this sample of midlife and older adults new to smartphone technology. Preliminary data exploring sustained use of the applications across a longer time period yielded promising results. The results support further systematic investigation of the efficacy of the applications for changing these key health-promoting behaviors. """,0
4507,23638806,Correlation between perceived experience of caries disease and recorded caries activity among adult patients at a Swedish Public Dental Clinic: A longitudinal study,"To compare patients' perceived experiences of caries activity with recorded longitudinal caries prevalence, consequences of caries and length of recall intervals. A questionnaire was mailed to 134 caries active (CA) and 40 caries inactive (CI) adult patients at a Swedish Public Dental Clinic. The overall response rate was 69%. The questionnaire included items regarding perceived caries activity, general health, dietary and oral hygiene habits, level of education and socioeconomic status. Questionnaire responses were studied for their association to clinical data extracted from patient dental records. There was a correlation between patient-perceived and documented caries activity for all respondents (rho = 0.65; p < 0.001). CA patients had significantly more perceived caries activity (p < 0.001), decayed teeth (p < 0.001), root fillings (p = 0.001) and extractions (p < 0.001) than CI patients. The mean recall interval was 1.5 years for CA and 2.1 years for CI (p < 0.001). In multiple logistic regression analysis, CA patients were at increased risk for xerostomia (OR = 22.66, p = 0.003), sleep disturbances (OR = 4.36, p = 0.04) and more frequent use of daily extra fluoride (OR = 3.58, p = 0.03). Patient-perceived experience of caries correlated well with recorded caries activity in this group of middle-aged Swedish adults. Individuals with active caries were aware of their disease and made more frequent attempts to reduce caries activity by use of daily extra fluoride. Individual risk-based recall intervals did not seem to eliminate consequences of disease activity such as root fillings and extractions during the follow-up period. ",0
4508,23639073,Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response,"Rasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy. Quantitative polymerase chain reactions measured the relative expression of 84 genes related to inflammation and autoimmunity in 12 RE specimens and in the reference group of 12 CD surgical specimens. Data were analyzed by consensus clustering using the entire dataset, and by pairwise comparison of gene expression levels between the RE and CD cohorts using the Harrell-Davis distribution-free quantile estimator method. Consensus clustering identified six RE cases that were clearly distinguished from the CD cases and from other RE cases. Pairwise comparison showed that seven mRNAs encoding interferon-γ, CCL5, CCL22, CCL23, CXCL9, CXCL10, and Fas ligand were higher in the RE specimens compared with the CD specimens, whereas the mRNA encoding hypoxanthine-guanine phosphoribosyltransferase was reduced. Interferon-γ, CXCL5, CXCL9 and CXCL10 mRNA levels negatively correlated with time from seizure onset to surgery (P <0.05), whereas CCL23 and Fas ligand transcript levels positively correlated with the degree of tissue destruction and inflammation, respectively (P <0.05), as determined from magnetic resonance imaging (MRI) T2 and FLAIR images. Accumulation of CD4+ lymphocytes in leptomeninges and perivascular spaces was a prominent feature in RE specimens resected within a year of seizure onset. Active disease is characterized by a Th1 immune response that appears to involve both CD8+ and CD4+ T cells. Our findings suggest therapeutic intervention targeting specific chemokine/chemokine receptors may be useful in early stage RE. ",0
4509,23639306,Alveolar nitric oxide and asthma control in mild untreated asthma,"The role of the peripheral airways in asthma is increasingly being recognized as a potential target for the achievement of optimal control of the disease. We postulated that the inflammatory changes of the small airways are implicated in the lack of asthma control in mild asthma. To test this hypothesis, we measured the alveolar fraction of exhaled NO (CalvNO) in patients with mild asthma with different levels of control of symptoms. Seventy-eight patients with asthma (35 men, age, 37 ± 15 years; FEV1 percentage of predicted, 100% ± 9%) were studied. Asthma control was assessed by using the Asthma Control Test (ACT). Measurements of exhaled NO at multiple constant flows were performed. Bronchial NO concentrations were 27.1 ± 20 nL/min, [corrected] and CalvNO levels were 5.7 ± 3.4 ppb. The ACT score was 20 ± 4.2. The level of asthma control was not associated with bronchial NO concentrations (rs = 0.16, P = .15). However, a significant correlation was found between the ACT score and CalvNO (rs = 0.25, P = .03). Moreover, CalvNO was significantly higher in patients with uncontrolled asthma than in patients with controlled/partially controlled asthma (6.7 ± 2.6 ppb vs 4.9 ± 2.6 nL/min, [corrected] respectively, P = .02). In the subgroup of patients with asthma who underwent extrafine inhaled corticosteroid treatment, the magnitude of the inhaled corticosteroid-induced improvement in asthma control positively correlated with baseline CalvNO at 1 month (rs = 0.39, P = .003) and at 3 months (rs = 0.49, P < .0001). The alveolar component of exhaled NO is associated with the lack of asthma control in patients with mild, untreated asthma. This observation supports the notion that abnormalities of the peripheral airways are implicated in the mildest forms of asthma. ",0
4510,23639429,Ischemia-modified albumin and adenosine plasma concentrations are associated with severe systemic inflammatory response syndrome after cardiopulmonary bypass,"Severe systemic inflammatory response syndrome (SIRS) occurring after cardiopulmonary bypass (CPB) is a common cause of mortality during cardiac surgery. These syndromes are characterized by vasoplegia and ischemia-reperfusion phenomenom. Adenosine is a strong endogenous vasodilating agent, which may be involved in blood pressure failure during CPB induced by severe SIRS. Ischemia-modified albumin (IMA) is considered as a sensitive marker of tissue ischemia. We examined whether the IMA or adenosine plasma concentrations (APCs) change during a severe SIRS-induced blood pressure failure during CPB. Plasma concentration and IMA (median [range]) were measured before, during, and after surgery in 86 patients who underwent coronary revascularization under CBP and were correlated to postoperative clinical course. Preoperative APC values (1.45 [0.52-2.11] μmol L(-1) vs 0.36 [0.12-0.66] μmol L(-1)) and IMA (144 [91-198] IU mL(-1) vs 109 [61-183] U mL(-1)) were significantly increased in patients presenting postoperative severe SIRS. Mean durations of mechanical ventilation, stay in the intensive care unit, and requirement of vasoactive drugs were significantly higher in patients with higher APC and IMA, but APC was the best predictive marker a postoperative severe. Adenosine plasma concentration and IMA concentration are associated with postoperative severe SIRS after CPB. ",0
4511,23639484,"Older HIV-infected patients--an underestimated population in northern Greece: epidemiology, risk of disease progression and death","HIV prevalence among older people is on the increase. The aim of this study was to evaluate the epidemiological and clinical features at diagnosis and survival of older patients. This was a retrospective analysis of the data of 558 newly diagnosed antiretroviral-naïve patients between January 1998 and December 2008. Patients were divided into two groups according to their age at diagnosis: ≥50 years (n=103) and 18-49 years (n=455). The most common risk factor for older patients was heterosexual contact (p<0.013). Older patients were more likely to suffer from hypertension (33.0% vs. 5.1%, p<0.0005), cardiovascular disease (20.4% vs. 2.9%, p<0.0005), neurological disorders (11.7% vs. 5.5%, p=0.02), renal dysfunction (12.6% vs. 5.3%, p=0.01), and infections (66.0% vs. 49.7%, p=0.003) than their younger counterparts, and to have more hospital admissions during follow-up (47.5% vs. 19.6%, p<0.0005). Older patients had a shorter survival time (p<0.0005). A statistically significant increase in CD4+ cell number through time was observed in both groups (p<0.0005). Younger patients reached higher magnitudes of absolute numbers of CD4+ cells during follow-up (p<0.0005) after the initiation of antiretroviral therapy. The total number of patients with clinical AIDS from baseline throughout the study period was also higher in the older age group (35.9% vs. 25.0%). HIV-infected people aged ≥50 years differ in epidemiological and clinical features to younger HIV-infected people. The issue of increasing prevalence of HIV infection is a matter of concern due to existing comorbidities, which probably lead to higher mortality rates and faster progression to clinical AIDS. ",0
4512,23639577,"Prevalence, size, number and localization of vascular anastomoses in monochorionic placentas","Most monochorionic (MC) twin pregnancies have an uncomplicated course, but some develop severe complications including selective intrauterine growth restriction (sIUGR), twintwin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). The underlying pathogenesis of these various complications is associated with the ubiquitous presence of vascular anastomoses in MC placentas. The aim of this study was to estimate the prevalence, number, size and localization of the anastomoses in sIUGR, TTTS and TAPS placentas compared to normal MC placentas using color dye injection. We excluded MC twin pregnancies treated with fetoscopic laser surgery or selective feticide. A total of 235 placentas fulfilled the inclusion criteria: 126 normal MC, 47 TTTS, 46 sIUGR and 16 spontaneous TAPS. Median number of anastomoses in normal MC, sIUGR, TTTS and TAPS placentas was 8 (IQR: 4-12), 8 (IQR: 5-14), 7 (IQR: 5-11) and 4 (IQR: 3-5), respectively. The prevalence of arterio-arterial (AA) anastomoses in normal MC, sIUGR, TTTS and TAPS placentas was 96%, 98%, 47% and 19%, respectively. We found AV anastomoses to be evenly distributed along the vascular equator in all MC placentas except in TAPS cases, where anastomoses were mostly localized near the margin. We also found that, in sIUGR and TTTS placentas, AA anastomoses tended to be at the center of the placenta. The present study shows that the prevalence, size, number and localization of the various types of anastomoses differ between normal MC, sIUGR, TTTS and TAPS placentas. ",0
4513,23639643,Screening and treating intermediate lesions to prevent gastric cancer,"Early gastric cancer is defined as adenocarcinoma confined to the mucosa or submucosa irrespective of lymph node involvement. In Japan, mucosal high-grade neoplasia is diagnosed as intramucosal early gastric cancer. Some early gastric cancers progress to advanced gastric cancer after several years of follow-up. Image-enhanced endoscopy (chromoendoscopy), narrow-band imaging, and magnifying endoscopy increase the diagnostic yield in characterizing early gastric cancer. Endoscopic resection of intramucosal early gastric cancer with endoscopic mucosal resection or endoscopic submucosal dissection is currently performed in East Asian countries to prevent the development of advanced gastric cancer and preserve patients' quality of life after treatment. ",0
4514,23639738,Enzyme-responsive surface erosion of poly(ethylene carbonate) for controlled drug release,"Cholesterol esterase (CE) induced surface erosion of poly(ethylene carbonate) (PEC) and drug release from PEC under mild physiological environment was investigated. The degradation process was monitored by changes of mass and molecular weight (MW) and surface morphology of polymer films. During the whole period of degradation, MW of PEC was unchanged. Water uptake of the polymer was only 2.8% and 0.2% for PEC with the MW of 200 kDa (PEC200) and PEC with the MW of 41 kDa (PEC41), respectively. Degradation of less hydrophilic PEC41 with higher density was slower than that of PEC200. By this mechanism, CE-responsive drug in vitro release from PEC in situ forming depots (ISFD) was conducted successfully. As expected, less bovine serum albumin (BSA) was released from PEC41 compared with that of PEC200 in the same time period. In conclusion, this work enabled the in vitro drug release evaluation of existing PEC devices and implied a new candidate for the development of enzyme-responsive systems. ",0
4515,23640434,Uncontrolled hypertension among black Africans in the city of Brussels: a case-control study,"The aim of this study is to identify determinants that are associated with uncontrolled hypertension among black Africans in the city of Brussels. A not-matched case-control study. Seventy-five black Africans were assigned to a case group with uncontrolled hypertension and a control group with controlled hypertension. Demographic characteristics, lifestyle and compliance were recorded as well as their blood pressure. Compliance in patients was evaluated by means of the Morisky Medication Adherence Scale-4 (MMAS-4). The mean age of the case group was 52 years (SD 7.8) and for the control group 49 years (SD 6.2). Almost 60% were women. Uncontrolled hypertension was associated with obesity (p = 0.01) and sedentary lifestyle (p = 0.034). About 50% of women were obese and 70% of these had uncontrolled hypertension. Patients with type 2 diabetes had a 4.5 times higher risk for uncontrolled hypertension and lower compliance to the medication regimen compared to non-diabetics. Patients were often treated with diuretics (29%), renin-angiotensin inhibitors (25%), and calcium-channel inhibitors (23%). According to the MMAS4-score uncontrolled patients had an intermediate compliance and the controlled patients had a high compliance. Black obese women and diabetics had the highest risk for uncontrolled hypertension. Compliance was significantly lower among uncontrolled patients. ",0
4516,23640509,Changes in anterior segment morphology after intravitreal injection of bevacizumab and bevacizumab-triamcinolone acetate combination,"To evaluate the effects of 2 different amounts of commonly used intravitreal agents on anterior segment morphology in conjunction with intraocular pressure (IOP) changes. Two groups of 46 patients who received intravitreal injection of bevacizumab (group 1, 0.05 mL) or bevacizumab-triamcinolone acetate (TA) combination (group 2, 0.1 mL) were included in this prospective study. All patients underwent anterior segment optical coherence tomography (AS-OCT) imaging with Visante OCT and IOP measurement before and at 5 minutes, 1 hour, and 3 hours after injection. Anterior chamber depth (ACD), angle-opening distance (AOD 500-750), trabecular-iris space area (TISA 500-750), and anterior chamber angle (ACA) were measured. Results were compared between groups and measurement time points. The mean change in IOP showed significant difference between baseline and first measurements after the injection in group 1 and group 2 (p = 0.012, p = 0.008, respectively). There was a statistically significant difference from baseline in ACD at the first and second measurements in group 2 (p = 0.005, p = 0.018, respectively). All angle parameters showed insignificant decrease from baseline at all measurement time points in both groups (p>0.05 for each). The difference of angle parameters after injection was not statistically significant between the groups (p>0.05 for each). Intravitreal injection of bevacizumab (0.05 mL) or bevacizumab-TA combination (0.1 mL) caused a change in anterior segment configuration determined by AS-OCT. The changes in anterior chamber parameters returned to baseline values with the normalization of IOP values after the first few minutes of injection. ",0
4517,23640699,Consensus on timing of intervention for common congenital heart diseases: part II - cyanotic heart defects,"The purpose of this review/editorial is to discuss how and when to treat the most common cyanotic congenital heart defects (CHDs); the discussion of acyanotic heart defects was presented in a previous editorial. By and large, the indications and timing of intervention are decided by the severity of the lesion. While some patients with acyanotic CHD may not require surgical or transcatheter intervention because of spontaneous resolution of the defect or mildness of the defect, the majority of cyanotic CHD will require intervention, mostly surgical. Total surgical correction is the treatment of choice for tetralogy of Fallot patients although some patients may need to be palliated initially by performing a modified Blalock-Taussig shunt. For transposition of the great arteries, arterial switch (Jatene) procedure is the treatment of choice, although Rastelli procedure is required for patients who have associated ventricular septal defect (VSD) and pulmonary stenosis (PS). Some of these babies may require Prostaglandin E1 infusion and/or balloon atrial septostomy prior to corrective surgery. In tricuspid atresia patients, most babies require palliation at presentation either with a modified Blalock-Taussig shunt or pulmonary artery banding followed later by staged Fontan (bidirectional Glenn followed later by extracardiac conduit Fontan conversion usually with fenestration). Truncus arteriosus babies are treated by closure of VSD along with right ventricle to pulmonary artery conduit; palliative banding of the pulmonary artery is no longer recommended. Total anomalous pulmonary venous connection babies require anastomosis of the common pulmonary vein with the left atrium at presentation. Other defects should also be addressed by staged correction or complete repair depending upon the anatomy/physiology. Feasibility, safety and effectiveness of treatment of cyanotic CHD with currently available medical, transcatheter and surgical methods are well established and should be performed at an appropriate age in order to prevent damage to cardiovascular structures.  ",0
4518,23640742,Persistent stapedial arteries in human: from phylogeny to surgical consequences,"The stapedial artery is an embryonic artery which disappears during the tenth week in utero, in human species. During its short life, this artery shapes the stapes and transforms the middle meningeal artery from the internal carotid artery to a branch of the external carotid system. Nevertheless, a persistent stapedial artery is seen in 0.2-4.8 per thousand of human adults. This persistence is usually asymptomatic but can sometimes cause pulsatile tinnitus or conductive hearing loss. Despite the risk of facial palsy, hearing loss and even hemiplegia argued by several authors, some surgeons have succeeded in coagulation without side effects. Reviewing the literature, we seek to enlighten the actual knowledge about the persistent stapedial artery to evaluate the risk to coagulate it. Embryologic studies explain the four types of persistent stapedial arteries: the hyoido-stapedial artery, the pharyngo-stapedial artery, the pharyngo-hyo-stapedial artery and aberrant internal carotid with persistent stapedial artery. Phylogenetic studies show that the stapedial artery persists in adulthood in many vertebrates. Its disappearance is therefore either a random effect or an adaptative convergence. This adaptation could be partially linked to the negative allometry of the stapes. Practically, the risk to coagulate a stapedial artery seems limited thanks to anastomoses, for example with the stylomastoid artery. The risk of hemiplegia reported is in fact an extrapolation of variation in rats' embryos. A persistent stapedial artery can therefore reasonably be coagulated, with special attention to the facial nerve, because the facial canal is always dehiscent where the artery penetrates.  ",0
4519,23640827,Disparities in evaluation at certified primary stroke centers: reasons for geographic and racial differences in stroke,"Evaluation at primary stroke centers (PSCs) has the potential to improve outcomes for patients with stroke. We looked for differences in evaluation at Joint Commission certified PSCs by race, education, income, and geography (urban versus nonurban; Southeastern Stroke Belt versus non-Stroke Belt). Community-dwelling, black and white participants from the national Reasons for Geographic And Racial Differences in Stroke (REGARDS) prospective population-based cohort were enrolled between January 2003 and October 2007. Participants were contacted at 6-month intervals for suspected stroke events. For suspected stroke events, it was determined whether the evaluating hospital was a certified PSC. Of 1000 suspected strokes, 204 (20.4%) strokes were evaluated at a PSC. A smaller proportion of women than men (17.8% versus 23.0%; P=0.04), those with a previous stroke (15.1% versus 21.6%; P=0.04), those living in the Stroke Belt (14.7% versus 27.3%; P<0.001), and those in a nonurban area (9.1% versus 23.1%; P<0.001) were evaluated at a PSC. There were no differences by race, education, or income. In multivariable analysis, subjects were less likely to be evaluated at a PSC if they lived in a nonurban area (odds ratio, 0.39; 95% confidence interval, 0.22-0.67) or lived in the Stroke Belt (odds ratio, 0.54; 95% confidence interval, 0.38-0.77) or had a previous stroke (odds ratio, 0.46; 95% confidence interval, 0.27-0.78). Disparities in evaluation by PSCs are predominately related to geographic factors but not to race, education, or low income. Despite an increased burden of cerebrovascular disease in the Stroke Belt, subjects there were less likely to be evaluated at certified hospitals. ",0
4520,23640943,Interactions between an M. tuberculosis strain overexpressing mtrA and mononuclear phagocytes,"It was previously shown that the bacterial two-component regulatory signal transduction (2CR) system MtrAB may be associated with the ability of M. tuberculosis (Mtb) to survive in macrophages. In the present work Mtb mutants: Rv-78 with overexpression of mtrA and Rv-129 with elevated level of phosphorylation-defective MtrA were used for further investigation of the potential influence of the MtrAB system on Mtb interaction with human monocytes. Flow cytometry was used to determine the expression of MHC class II molecules. The expression of genes for inducible nitric oxide synthase (iNOS) and cathepsin G was quantified by RT-PCR. The association of Mtb strains with Rab5 and Rab7 positive vacuoles was investigated applying confocal microscopy. IL-10 and IL-12 secretion by monocytes as well as the Mtb susceptibility to cathepsin G were investigated. Mutation-carried and wild type Mtb strains inhibited MHC class II expression on monocytes to a similar extent. Monocyte stimulation with mycobacteria led to the increased production of IL-10 but no detectable amounts of IL-12 or NO were observed. Expression of the gene for iNOS was not detected while that for cathepsin G was shown, however its intensity was not associated with MtrA mutation. Mtb mutant strains were more effectively enclosed in phagosomes containing the late endosome marker Rab7 as compared to the control. The results may confirm the importance of the MtrAB system in mycobacterial capacity for successful survival in phagocytes, especially in the context of high degree of colocalization of Mtb Rv-78 to mature phagosomes. ",0
4521,23641262,Recent advancement on surgical treatments for lymphedema,"Treatment for limb lymphedema is challenging. The recent development of the super-microsurgical technique has made lymphaticovenular (LV) anastomosis an easier and more accurate surgical method for lymphedema. A summary of our experience as well as recent developments in surgical treatments for lymphedema are described. Ultra-microstructural analysis demonstrated that dysfunction of the lymphatics in lymphedema was caused by the degeneration and incomplete regeneration of smooth muscle cells and valve insufficiency in the lymphatic channel. ICG and infrared ray examinations have been proposed as new means of assessment of lymphatic function. LV anastomosis is suitable for genital edema, arm edema with severe phlegmone with leg edema, and early stage leg edema. Although pre- and postoperative compression therapy is generally required for limb edema, some cases do not require postoperative compression due to remaining or regenerated smooth muscle cells. As new methods of treatment, the vascularized lymphadiposal flap has been effective for progressive cases with LV anastomosis. LV anastomosis is also effective for congenital chyloabdomen. (*English Translation of J Jpn Coll Angiol 2008; 48: 173-178.). ",0
4522,23641265,Surgical treatment or conservative therapy for stanford type a acute aortic dissection with a thrombosed false lumen,"Optimum treatment for acute aortic dissection (AAD) with a thrombosed false lumen (thrombosed AAD) remains controversial. We evaluated the outcome of thrombosed AAD according to treatment strategy. We examined 280 patients with AAD, of which 30 had thrombosed AAD. We compared computed tomography findings, cardiac performance, and clinical course in 28 of these patients. Patients were divided into three groups for the comparison: Group E (emergency surgery), Group C (conservative therapy), and Group S (conservative therapy switched to emergency surgery). In Group E (n = 13), one patient died and 12 survived. In Group C (n = 10), all patients were discharged, of which two died of cancer and two of the remaining eight survivors underwent subsequent elective surgery. In Group S (n = 5), one patient died and four survived following surgery. It was hard to predict re-dissection or rupture following conservative treatment for thrombosed AAD. Basically, we should perform emergency surgery following the diagnosis of thrombosed AAD, particularly in complicated cases such as those with pericardial effusion, tamponade, and large aorta. Conservative therapy has a very limited application in patients with the initial stages of thrombosed AAD. ",0
4523,23641281,Evaluation of the outcome of traumatic thoracic aortic rupture in patients in a trauma and critical care center,"Multiple injuries may lead to traumatic thoracic aortic rupture (TTAR), which can be fatal. We evaluated the relationship between the clinical findings and outcomes of 26 patients with TTAR who were treated at our institution. A total of 26 patients (men, 21; women, 5; average age, 45.8 ± 19.6 years) with a diagnosis of TTAR received from 1999 to 2009 were studied. We categorized patients into groups based on the outcome (survival or death) and investigated the relationship between the outcome and the following factors: injury mechanism, vital signs, other combined injuries, injury severity score (ISS), revised trauma score, and probability of survival (Ps). Of the 26 TTAR patients, 7 underwent emergency operations, 5 underwent delayed operations, 1 received conservative treatment, and 13 suffered cardiopulmonary arrest immediately after consultation and died. Of the 13 patients who died, 11 died within 2 hours after injury because of bleeding. Two of the 7 patients who underwent emergency operations died within 1 day of consultation, whereas all those who underwent delayed operations survived. Patients who underwent TTAR repair had a relatively favorable outcome. Analysis of the relationship between the clinical data and outcome showed that a young age was significantly correlated with survival, and that the Glasgow coma scale (GCS), heart rate, respiratory rate, or occurrence of shock were not significantly related to the outcome. The abbreviated injury scale (AIS) was used to score the severity of multiple injuries, and ISS was calculated from the AIS score. ISS was significantly higher in the death group (P = 0.007). ISS did not significantly differ among body parts (P = 0.077), but ISS of the extremities was higher than those of other parts. Pelvic fractures were frequent in the death group. Our strategy, whereby the patient initially underwent pelvic external fixation followed by TTAR repair was found to be very effective. The P-values calculated by the trauma and injury severity score method were significantly higher in the survival group (both, P = 0.007). To treat TTAR, it is important to accurately evaluate the damage due to multiple injuries and apply an appropriate treatment strategy. Immediate repair of TTAR after bleeding due to combined injury improves the outcome. (English Translation of Jpn J Vasc Surg 2012; 21:5-9). ",0
4524,23641302,Sodium alginate/heparin composites on PVC surfaces inhibit the thrombosis and platelet adhesion: applications in cardiac surgery,"Thrombosis and hemocyte damage are the main problems of applied non-coated biomaterials to cardiac surgery that remain unsolved. The present study is aimed at the chemical modification of polyvinyl chloride (PVC) for applications in cardiac surgery and the biological property assessment of modified PVC. Sodium alginate (SA)/heparin (HEP) composites were covalently immobilized onto the surface of the PVC pipeline. The surface grafting density and protein adsorption were determined by ultraviolet spectrophotometry. The surface contact angles were evaluated by contact-angle measurement, whereas the surface characteristics were evaluated by Fouriertransform infrared spectroscopy. Blood coagulation time and platelet adhesion were measured using an automated blood coagulation analyzer and a hemocytometer, respectively. Surface morphologies of the thrombus and platelets were evaluated by scanning electron microscopy. The immobilization of SA/HEP reduced the contact angles of the coated surface. Protein adsorption was reduced by the immobilization of SA. The activated partial thrombin time and thrombin time of the coated PVC were significantly prolonged as compared with the non-coated PVC. Platelet adhesion and thrombus formation were all reduced by the immobilization of HEP. The results revealed that the SA/HEP coating can improve the antithrombogenicity of the PVC pipeline, as well as improve its biocompatibility and hemocompatibility, which are essential for cardiac pulmonary bypass surgery. ",0
4525,23641308,Primary cervical and uterine corpus lymphoma; a case report and literature review,"Primary lymphoma of the uterine corpus and cervix is rare. We present a case of primary non-Hodgkin follicular lymphoma isolated to uterine corpus and parametria with focal spread to ovaries and fallopian tubes, incidentally found on the background of endometrial malignancy. A summary of the published cases focusing on the presentation and prognosis as well as a review of current management are discussed. The rising incidence of extra-nodal lymphoma and recent changes in classification and therapeutic approach, require clinical vigilance. In the absence of prospective studies assessing the value of the available therapeutic options, data from retrospective series and scattered case reports are presented in this review. ",0
4526,23641402,The importance of family relations for cannabis users: the case of serbian adolescents,"Adolescence is transitional stage of physical and mental human development occuring between childhood and adult life. Social interactions and environmental factors together are important predictors of adolescent cannabis use. This study aimed to examine the relationship between the social determinants and adolescents behavior with cannabis consumption. A cross sectional study as part of the European School Survey Project on Alcohol and other Drugs was conducted among 6.150 adolescents aged 16 years in three regions of Serbia, and three types of schools (gymnasium, vocational - professional, and vocational - handicraft) during May - June 2008. A multivariate logistic regression analysis was carried out to obtain adjusted odds ratios with 95% confidence intervals in which the dependent variable was cannabis consumption non-user and user. Among 6.7% of adolescents who had tried cannabis at least one in their lives, boys were more involved in cannabis use than girls, especially boys from gymnasium school. Well off family, lower education of mother, worse relations with parents were significantly associated with cannabis use (P < 0.05). Behaviors like skipping from schools, frequent evening outs, and playing on slot machines were also related to cannabis use (P < 0.05). The study confirmed the importance of family relationship development. Drug use preventive programmes should include building interpersonal trust in a family lifecycle and school culture. ",0
4527,23641404,"Appraisal the potential of central iran, in the context of health tourism","The aim of the present study was to appraisal the prose and cone of Shiraz City in terms of its potential in the context of health tourism. The statistical sample included medical and health tourism sector in the city of Shiraz in the northwest of Fars Province, south of Iran. The efficient authorities on the topic were identified through the hospitals engaging in medical tourism. The research was based on theoretical sampling through which the experienced people of extensive knowledge on medical tourism were interviewed. Active hospitals on attraction foreign patients averagely admit 15 and 50 foreign patients monthly and annually, respectively. Arab countries in the Persian Gulf were detected as the main marketing for Shiraz medical tourism. Oman encompassed the highest rate with 20% of admitted patients. Eye treatments with 30% and orthopedic with 6% were demonstrated as the highest and lowest rates in terms of foreign patients' needs, respectively. Closeness of cultural and religious beliefs and familial relationships on one hand and trusting to Iranian physicians on the other hand were amongst the most reasons for selecting Iran as a destination for medical tourism by patients. Implementing 4 strategies on monitoring medical tourism would result into significant improvement of attracting more foreigner patients not only into Shiraz but all around Iran. These items have been discussed in the text. ",0
4528,23641567,"Diab'à'table, a patient education program dedicated to eating behaviors]","A long-lasting change in eating behaviour, essential when treating patients suffering from type 2 diabetes, can be difficult to put in practice. In order to achieve this objective, a therapeutic education programme was used with volunteer patients. Its encouraging results show the benefits it can offer for obese patients suffering from type 2 diabetes. ",0
4529,23641730,Legal issues affecting children with preexisting conditions during public health emergencies,"Among the millions of children in the United States exposed to public health emergencies in recent years, those with preexisting health conditions face particular challenges. A public health emergency may, for example, disrupt treatment regimens or cause children to be separated from caregivers. Ongoing shortages of pediatricians and pediatric subspecialists may further exacerbate the risks that children with preexisting conditions face in disaster circumstances. The US Department of Homeland Security recently called for better integration of children's needs into all preparedness activities. To aid in this process, multiple legal concerns relevant to pediatricians and pediatric policymakers must be identified and addressed. Obtaining informed consent from children and parents may be particularly challenging during certain public health emergencies. States may need to invoke legal protections for children who are separated from caregivers during emergencies. Maintaining access to prescription medications may also require pediatricians to use specific legal mechanisms. In addition to practitioners, recommendations are given for policymakers to promote effective pediatric response to public health emergencies. ",0
4530,23641875,"The forgotten smoker: a qualitative study of attitudes towards smoking, quitting, and tobacco control policies among continuing smokers","Although research suggests that the majority of smokers want to quit smoking, the uptake of Stop Smoking Services, designed to assist smokers with quitting, remains low. Little is known about continuing smokers who do not access these services, and opportunities to influence their motivation and encourage quit attempts through the uptake of services. Using PRIME theory, this study explored differences between continuing smokers who had varying levels of motivation to quit, in terms of their plans to quit, evaluative beliefs about smoking, cigarette dependence, and attitudes towards tobacco control policies and services. Twenty-two current smokers, recruited from the community, were classified by motivation level to quit using a self-report questionnaire (two groups: high/low). Four focus groups (n=13) and individual interviews (n=9) were conducted with both groups using an interview guide incorporating aspects of PRIME theory. Discussion areas included motives for smoking, attitudes towards smoking and quitting, perceptions of dependence, motives for quitting, barriers to quitting, and attitudes towards existing and impending tobacco control policies and services. Verbatim transcripts were analysed using thematic framework analysis. All participants expressed low motivation to quit during discussions, despite some initially self-classifying as having high explicit levels of motivation to quit. Both groups reported similar attitudes towards smoking and quitting, including a perceived psychological addiction to smoking, positive evaluations about smoking which inhibited plans to quit, and similar suggested methods to increase motivation (simply wanting to, save money, improve health). Most felt that they 'ought' to quit as opposed to 'wanted' to. Little influence was ascribed towards tobacco control policies such as plain packaging and hidden sales displays, and participants felt that price increases of tobacco products needed to be considerable in order to influence motivation. Highly motivated smokers expressed more willingness to visit Stop Smoking Services, although none had done so. Continuing smokers' attitudes towards smoking and quitting suggests that research and policy need to focus on increasing smokers' implicit motivation to quit smoking, even for those who classified themselves as having high motivation to quit. Targeted information and further education about Stop Smoking Services is required to increase uptake. ",0
4531,23642097,Antilock braking system effectiveness in prevention of road traffic crashes in Iran,"Anti-lock Brake System (ABS) helps the equipped vehicles to stop under heavy braking, in a shorter distance and with a better control of direction. It was expected that this technology will reduce the rate of fatal road traffic crashes (RTC); however, the outcome is controversial in the real world. The aim of this study is to compare the claimed annual incidence rate and financial losses due to RTCs in ABS vs. non-ABS personal vehicles in Iran. A telephone survey among drivers of two similar models of personal vehicles was arranged. The studied vehicles were of the same brand and type; but only one of them was equipped with ABS. The number of RTCs, subsequent financial loss, and drivers' knowledge and perception about ABS were sought. The sample consisted of drivers of 1232 ABS and 3123 non-ABS vehicles. The annual incidence rate of RTC involving another vehicle was 145.1 (134.8-155.9) per 1000 vehicle-years and there was not a statistically significant difference between study groups.The incidence of RTC with another vehicle due to brake failure was 50.3 (42.9-58.5) for 1000 non ABS vehicle-years and 30.0 (21.2-41.2) for 1000 ABS equipped vehicle-years. The difference was statistically significant after adjustment for the driver and vehicle's age and the daily driving time. The attributable risk of RTC for non-ABS vehicles was 20/1000 vehicles and the excess fraction was 39.8%. The mean financial loss due to reported RTCs was $987.9 ± $1547.3 US Dollars and there was not a statistically significant difference between study groups. While 61.1% of ABS vehicle drivers reported situations in which they believed the ABS had prevented a crash, 44.1% of them however, they did not know how to use ABS efficiently. Law enforcement to maintain safe distance and adhere to speed limit while driving, is needed to raise the effectiveness of ABS. This is as necessary as considering mandatory outfitting of ABS. Safety authorities should first consider the global experience and local evidence, before adopting any specific policy in this regard. The drivers need to learn the right way to use ABS for maximum effectiveness. ",0
4532,23642318,Reprint of: B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146(2) 90-103,"Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus.  ",0
4533,23642703,Contribution of endoplasmic reticulum Ca2+ regulatory mechanisms to the inflammation-induced increase in the evoked Ca2+ transient in rat cutaneous dorsal root ganglion neurons,"Persistent inflammation results in an increase in the magnitude and duration of high K(+)-evoked Ca(2+) transients in putative nociceptive cutaneous dorsal root ganglion (DRG) neurons. The purpose of the present study was to determine whether recruitment of Ca(2+)-induced Ca(2+) release (CICR) contributes to these inflammation-induced changes. Acutely dissociated, retrogradely labeled cutaneous DRG neurons from naïve and complete Freund's adjuvant inflamed adult male Sprague-Dawley rats were studied with ratiometric microfluorimetry. Ryanodine only attenuated the duration but not magnitude of the high K(+)-evoked Ca(2+) transient in neurons from inflamed rats. However, there was no significant impact of inflammation on the potency or efficacy of ryanodine-induced block of the caffeine-evoked Ca(2+) transient, or the impact of sarco-endoplasmic reticulum ATPase (SERCA) inhibition on the high K(+)-evoked Ca(2+) transient. Furthermore, while there was no change in the magnitude, an inflammation-induced increase in the duration of the caffeine-evoked Ca(2+) transient was only observed with a prolonged caffeine application. In contrast to the high K(+)-evoked Ca(2+) transient, there was no evidence of direct mitochondrial involvement or that of the Ca(2+) extrusion mechanism, the Na(+)/Ca(2+) exchanger, on the caffeine-evoked Ca(2+) transient, and block of SERCA only increased the duration of this transient. These results indicate the presence of Ca(2+) regulatory domains in cutaneous nociceptive DRG neurons within which cytosolic Ca(2+) increased via influx and release are highly segregated. Furthermore, our results suggest that changes in neither CICR machinery nor the coupling between Ca(2+) influx and CICR are primarily responsible for the inflammation-induced changes in the evoked Ca(2+) transient. ",0
4534,23642781,Emerging therapies for neovascular age-related macular degeneration: drugs in the pipeline,"Discuss the emerging therapies that could improve the treatment of neovascular age-related macular degeneration (AMD). Current antiangiogenic therapies require frequent injections, and not all patients respond to these therapies. Thus, there is a need to identify additional therapies that could improve the treatment of neovascular AMD. Review of medical literature and ongoing clinical trials as well as their results in the area of neovascular AMD treatment. There are numerous areas of investigation into new treatment for AMD, including the newly approved aflibercept eye; sustained-release compounds that may allow for fewer injections, combination therapy with anti-vascular endothelial growth factor (VEGF) therapy and ionizing radiation, and investigational drugs that address different targets along the angiogenic signaling cascade, or other pathways related to the pathophysiology of neovascular AMD altogether. Despite the outstanding advances made in the treatment of neovascular AMD with anti-VEGF therapies, patients still require numerous injections and office visits. Future therapies, however, have the potential not only to reduce patient visits and injections, but also to improve outcomes by targeting additional pathways, increasing target affinity, and lengthening treatment durability. ",0
4535,23642790,"""""""Underwater"""" EMR of sporadic laterally spreading nonampullary duodenal adenomas (with video)""","""EMR for the treatment of duodenal adenomas is challenging due to a thin wall and rich vascularity. To evaluate a novel technique of """"underwater"""" EMR without prior submucosal injection for the removal of large (≥2 cm) laterally spreading nonampullary duodenal adenomas. Prospective, observational study. Tertiary academic referral center. Twelve patients (median age, 60 years) meeting the inclusion criteria. Piecemeal EMR technique after sterile water submersion when using a double-channel endoscope. Technical success, adverse events, completeness of resection on follow-up endoscopy. Median adenoma size was 35 mm (25% greater than one-half circumference, 50% equal to one-third to one-half circumference, and 25% less than one-third circumference). Median procedure time was 65 minutes (range, 32-151). Final histology was tubular adenoma (7), tubulovillous adenoma (1), villous adenoma (3), and high-grade dysplasia (1). Eleven patients (92%) met the primary endpoint (technical success) and all patients met the secondary endpoint (completeness of resection). Median interval until follow-up endoscopy was 16 weeks (range, 11-56). Adverse events were as follows: delayed bleeding (3 patients, of whom 2 required transfusions), water intoxication syndrome manifested by altered mental status and hyponatremia (1), and stricture formation (1) that responded to balloon dilation. No perforation or postresection abdominal pain was found. Single operator, single center, small sample size, limited follow-up. Underwater EMR for large sessile duodenal adenomas has high success rates for complete removal. The risk of delayed bleeding is significant, and precautions are needed when infusing a large volume of fluid into the GI tract. """,0
4536,23643122,Refined liquid smoke: a potential antilisterial additive to cold-smoked sockeye salmon (Oncorhynchus nerka),"Cold-smoked salmon (CSS) is a potentially hazardous ready-to-eat food product due to the high risk of contamination with Listeria monocytogenes and lack of a listericidal step. We investigated the antilisterial property of liquid smokes (LS) against Listeria innocua ATCC 33090 (surrogate to L. monocytogenes) as a potential supplement to vacuum-packaged CSS. A full-strength LS (Code 10-Poly), and three commercially refined fractions (AM-3, AM-10, and 1291) having less color and flavor (lower content of phenols and carbonyl-containing compounds) were tested. In vitro assays showed strong inhibition for all LS except for 1291. The CSS strips were surface coated with AM-3 and AM-10 at 1% LS (vol/wt) with an L-shaped glass rod and then inoculated with L. innocua at 3.5 log CFU/g, vacuum packaged, and stored at 4°C. The LS did not completely eliminate L. innocua but provided a 2-log reduction by day 14, with no growth up to 35 days of refrigerated storage. A simple difference sensory test by 180 untrained panelists showed the application of AM-3 did not significantly influence the overall sensorial quality of CSS. In essence, the application of the refined LS as an antilisterial additive to CSS is recommended. ",0
4537,23643134,Genetic diversity of Cronobacter sakazakii isolates collected from a Swiss infant formula production facility,"In this study, 141 Cronobacter isolates that were collected based on a hygienic monitoring program performed in a powdered infant formula production facility in Switzerland between September 2011 and October 2012 were further characterized. Isolates were identified to the species level by molecular methods, and strains of Cronobacter sakazakii were further subtyped by applying PCR-based O-antigen serotyping, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). C. sakazakii was the most prevalent species identified (93.6%). Among this collection of isolates, representatives of all but one O-antigen serotype (serotype O5) were recognized. MLST analysis of 19 selected isolates revealed that most of the typeable isolates belonged to sequence type (ST) 4. Correlations between ST4 and serotype O2 and between ST83 and serotype O7 were observed. PFGE analysis revealed clusters with multiple isolates, including strains from samples collected at different time points and sampling sources. Generally, the observed heterogeneity among strains collected over the 13 months of the monitoring program was high, suggesting a constant flux among strains rather than a selection for persisting organisms. ",0
4538,23643164,Expressions of reactive oxygen species and fibronectin are regulated by transcriptional co-activator p300 in human mesangial cells exposed to high glucose and methylglyoxal advanced glycation end products],"To study the roles and interrelationship of transcriptional co-activator p300 and protein kinase Cβ2(PKCβ2) in the production of reactive oxygen species (ROS) and the expression of fibronectin in human mesangial cells (HMCs) under the stimulation of high glucose and methylglyoxal-derived advanced glycation end products (AGEs). The HMCs were divided into the following groups: 1 normal glucose group (NG), high glucose group (HG), osmotic control group (LG), normal glucose+bovine serum albumin group (BSA), normal glucose+AGEs group (AGEs); 2 high glucose+empty vector group (HN), high glucose+PKCβ2 group (PO), high glucose+PKCβ2 inhibitor CGP53353 group (PI), AGEs+empty vector group (AN), AGEs+PKCβ2 group (APO), AGEs+PKCβ2 inhibitor CGP53353 group (API); 3 normal glucose+p300 inhibitor garcinol group (NG+Gar), high glucose+garcinol group (HG+Gar), BSA+garcinol group (BSA+Gar), and AGEs+garcinol group (AGEs+Gar). All cells in each group were cultured for 2 d. ROS levels were measured by fluorescence microscope and fluorescence microplate reader. The protein expressions of p300, PKCβ2 and fibronectin were detected by Western blotting. Levels of p300, PKCβ2 and ROS in HG and AGEs groups were elevated by 1.04, 1.26, 0.78 and 1.45, 1.07, 0.71 folds of those in NG group and BSA control group, respectively (P<0.05). However, ROS levels in HG+Gar and AGEs+Gar groups decreased significantly to 0.43 and 0.39 folds of those in HG and AGEs groups, respectively (P<0.05). p300 and PKCβ2 protein expressions in PO and APO groups were up-regulated by 1.19, 1.73 and 1.23, 1.69 folds compared with HG and AGEs groups, respectively (P<0.05). However, in the present of CGP53353, both p300 and PKCβ2 decreased significantly (P<0.05); the two factors stayed stable in HN and AN groups as compared with HG and AGEs groups. Expressions of p300 and FN proteins decreased in HG+Gar and AGEs+Gar groups, being 31%, 43% and 37%, 29% of those in HG and AGEs groups, respectively (P<0.05). High glucose and AGEs can up-regulate the expressions of ROS and fibronectin in human mesangial cells by activating transcriptional co-activator p300. ",0
4539,23643605,Human mesenchymal stem cell culture on heparin-based hydrogels and the modulation of interactions by gel elasticity and heparin amount,"Human adipose-derived stem cells (hADSCs) are a promising cell source for tissue engineering and regenerative medicine with no ethnical issue and easy access of large quantities. Conventional surfaces for hADSC culture, such as tissue culture plates (TCPs), do not provide optimal environmental cues, leading to limited expansion, loss of pluripotency and undesirable differentiation of stem cells. The present study demonstrated that heparin-based hydrogels without additional modification provided an excellent surface for adhesion and proliferation of hADSCs, which were further tunable by both the amount of heparin (in a positive way) and the elasticity of hydrogel (in a negative way). The optimized heparin-based hydrogel could selectively modulate the adhesion of hADSCs and human bone marrow stem cells (but not all kinds of cells), and resulted in a significant increase in cell proliferation compared to TCP. Furthermore, in terms of the maintenance of pluripotency and specific differentiation, heparin-based hydrogel was much superior to TCP. The selective binding and proliferation of human mesenchymal stem cells on heparin-based hydrogel over other hydrogels were largely mediated by integrin β1 and selectin, and these superior characteristics were observed regardless of the presence of serum proteins in the culture medium. Consequently, heparin-based hydrogel could be a powerful platform for cultivation of mesenchymal stem cells in various applications.  ",0
4540,23643662,Topical delivery of anti-TNFα siRNA and capsaicin via novel lipid-polymer hybrid nanoparticles efficiently inhibits skin inflammation in vivo,"The barrier properties of the skin pose a significant but not insurmountable obstacle for development of new effective anti-inflammatory therapies. The objective of this study was to design and evaluate therapeutic efficacy of anti-nociception agent Capsaicin (Cap) and anti-TNFα siRNA (siTNFα) encapsulated cyclic cationic head lipid-polymer hybrid nanocarriers (CyLiPns) against chronic skin inflammatory diseases. Physico-chemical characterizations including hydrodynamic size, surface potential and entrapment efficacies of CyLiPns were found to be 163±9nm, 35.14±8.23mV and 92% for Cap, respectively. In vitro skin distribution studies revealed that CyLiPns could effectively deliver FITC-siRNA up to 360μm skin depth. Further, enhanced (p<0.001) Cap permeation from CyLiPns was observed compared to Capsaicin-Solution and Capzasin-HP. Therapeutic efficacies of CyLiPns were assessed using imiquamod-induced psoriatic plaque like model. CyLiPns carrying both Cap and siTNFα showed significant reduced expression of TNFα, NF-κB, IL-17, IL-23 and Ki-67 genes compared to either drugs alone (p<0.05) and were in close comparison with Topgraf®. Collectively these findings support our notion that novel cationic lipid-polymer hybrid nanoparticles can efficiently carry siTNFα and Cap into deeper dermal milieu and Cap with a combination of siTNFα shows synergism in treating skin inflammation.  ",0
4541,23643697,Differences in self-reported outcomes of open prostatectomy patients and robotic prostatectomy patients in an international web-based survey,"To compare patient reported outcomes between robotic assisted surgery and non-robotic assisted surgery. This was an international web-based survey based on a qualitative research and literature review, an internet-based questionnaire was developed with approximately 70 items. The questionnaire included both closed and open-ended questions. Responses were received from 193 men of whom 86 had received either open (OP) or robotic (RALP) surgery. A statistically significant (p=0.027), ranked analysis of covariance was found demonstrating higher recent distress in the robotic (RALP) surgery group. Although not statistically significant, there was a pattern of men having robotic (RALP) surgery reporting fewer urinary and bowel problems, but having a greater rate of sexual dysfunction. Men who opt for robotic surgery may have higher expectations for robotic (RALP) surgery, when these expectations are not fully met they may be less likely to accept the consequences of this major cancer surgery. Information regarding surgical choice needs to be tailored to ensure that men diagnosed with prostate cancer are fully informed of not only short term surgical and physical outcomes such as erectile dysfunction and incontinence, but also of potential issues with regards to masculinity, lifestyle and sexual health. ",0
4542,23643922,Somatotopic mapping of natural upper- and lower-extremity movements and speech production with high gamma electrocorticography,"Precise delineation of pathological and eloquent cortices is essential in pre-neurosurgical diagnostics of epilepsy. A limitation of existing experimental procedures, however, is that they critically require active cooperation of the patient, which is not always achievable, particularly in infants and in patients with insufficient cognitive abilities. In the present study, we evaluated the potential of electrocorticographic recordings of high gamma activity during natural, non-experimental behavior of epilepsy patients to localize upper- and lower-extremity motor and language functions, and compared the results with those obtained using electrocortical stimulation. The observed effects were highly significant and functionally specific, and agreed well with the somatotopic organization of the motor cortex, both on the lateral convexity and in the supplementary motor area. Our approach showed a similar specificity and sensitivity for extremity movements as previously obtained from experimental data. We were able to quantify, for the first time, sensitivity and specificity of high gamma underlying non-experimental lower-extremity movements in four patients, and observed values in the same range as for upper extremities (analyzed in six patients). Speech-related responses in the three investigated patients, however, exhibited only a very low sensitivity. The present findings indicate that localization of not only upper- but also lower-extremity movements congruent with electrocortical stimulation mapping is possible based on event-related high gamma responses that can be observed during natural behavior. Thus, non-experimental mapping may be usefully applied as adjunct to established clinical procedures for identification of both upper- and lower-extremity motor functions.  ",0
4543,23644049,Effect of high pressure processing on the gel properties of salt-soluble meat protein containing CaCl2 and κ-carrageenan,"The effects of high pressure processing (HPP) on the water-binding capacity and texture profile (TPA) of salt-soluble meat protein (SSMP) containing 0.2% CaCl2 and 0.6% κ-carrageenan (SSMP-CK) gels were investigated. The results showed that 300-400 MPa improved water-binding capacity and decreased TPA parameters of SSMP-CK gels (P<0.05), while 100 MPa could increase hardness and chewiness of the gels. The thermal transition temperature peak for the myosin head (Tpeak1) of SSMP disappeared on addition of CaCl2 and κ-carrageenan. 300 MPa produced a new peak, and caused a shift of the NH-stretching left peak and amide I and the disappearance of NH-stretching right peak. The destruction of network structure and the weakening of molecular interaction within the pressurized gels could result in the decrease of TPA parameters. Thus gelling properties could be modified by HPP, κ-carrageenan and Ca(2+). It is of interest to develop low-fat and sodium-reduced meat products. ",0
4544,23644235,Pre-radiotherapy PSA level as a predictor for biochemical control in prostate cancer patients receiving radiotherapy after radical prostatectomy,"To report the outcome of patients receiving radiotherapy (RT) after radical prostatectomy (RP). Between May 2001 and December 2008, 53 consecutive cases of prostate adenocarcinoma treated with RP and RT were reviewed. A total of 49 patients were eligible for this study. After a median follow-up of 53 months, the 4-year overall survival (OS) and biochemical progression-free survival (bPFS) for all patients were 91.0% and 68.9%, respectively. According to univariate and multivariate analysis, pre-RT prostate-specific antigen (PSA) was the most significant factor for bPFS. Patients with pre-RT PSA levels of < 0.2 ng/ml and ≧ 0.2 ng/ml had a 4-year bPFS of 83.1% and 52.6%, respectively (p = 0.013). The incidence of chronic rectal toxicity was low, with no grade 3 toxicity reported and grade 2 toxicity found in only 6 patients (12.2%). However, long-term urinary toxicity of grade 2 or higher was found in 24 patients (49.0%). For patients with increasing PSA levels following RP, local RT should be administered prior to biochemical failure (PSA ≧ 0.2), to ensure good bPFS. ",0
4545,23644469,Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain,"Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis. ",0
4546,23644480,Modeling the effectiveness of initial management strategies for ductal carcinoma in situ,"The prevalence of ductal carcinoma in situ (DCIS) and the marked variability in patterns of care highlight the need for comparative effectiveness research. We sought to quantify the tradeoffs among alternative management strategies for DCIS with respect to disease outcomes and breast preservation. We developed a disease simulation model integrating data from the published literature to simulate the clinical events after six treatments (lumpectomy alone, lumpectomy with radiation, lumpectomy with radiation and tamoxifen, lumpectomy with tamoxifen, and mastectomy with and without breast reconstruction) for women with newly diagnosed DCIS. Outcomes included disease-free, invasive disease-free, and overall survival and breast preservation. For a cohort of 1 million simulated women aged 45 years at diagnosis, both mastectomy and lumpectomy with radiation and tamoxifen were associated with a 12-month improvement in overall survival relative to lumpectomy alone. Adding radiation therapy to lumpectomy resulted in a 6-month improvement in overall survival but decreased long-term breast-preservation outcomes (likelihood of lifetime breast preservation = 0.781 vs 0.843 for lumpectomy alone). This decrement with radiation therapy was mitigated by the addition of tamoxifen (likelihood of lifetime breast preservation = 0.846). Overall survival benefits of the six management strategies for DCIS are within 1 year, suggesting that treatment decisions can be informed by the patient's preference for breast preservation and disutility for recurrence. Our delineation of personalized outcomes for each strategy can help patients understand the implications of their treatment choice, so their decisions may reflect their own personal values and help improve the quality of care for patients with DCIS. ",0
4547,23644858,Conjoined twins: twenty years' experience at a reference center in Brazil,"This study reports on the experience of one hospital regarding the surgical aspects, anatomic investigation and outcomes of the management of 21 conjoined twin pairs over the past 20 years. All cases of conjoined twins who were treated during this period were reviewed. A careful imaging evaluation was performed to detail the abdominal anatomy (particularly the liver), inferior vena cava, spleen and pancreas, either to identify the number of organs or to evaluate the degree of organ sharing. There were eight sets of ischiopagus twins, seven sets of thoracopagus twins, three sets of omphalopagus twins, two sets of thoraco-omphalo-ischiopagus twins and one set of craniopagus twins. Nine pairs of conjoined twins could not be separated due to the complexity of the organs (mainly the liver and heart) that were shared by both twins; these pairs included one set of ischiopagus twins, six sets of thoracopagus twins and one set of thoraco-omphalo-ischiopagus twins. Twelve sets were separated, including seven sets of ischiopagus twins, three sets of omphalopagus twins, one set of thoracopagus twins and one set of craniopagus conjoined twins. The abdominal wall was closed in the majority of patients with the use of mesh instead of the earlier method of using tissue expanders. The surgical survival rate was 66.7%, and one pair of twins who did not undergo separation is currently alive. A detailed anatomic study of the twins and surgical planning must precede separation. A well-prepared pediatric surgery team is sufficient to surgically manage conjoined twins. ",0
4548,23644859,Fetuin-A levels in hyperthyroidism,"Fetuin-A is a protein secreted from the liver that inhibits arterial calcification deposition and can contribute to insulin resistance. Hyperthyroidism is also associated with insulin resistance. It is not known whether hyperthyroidism has an effect on fetuin-A levels. We measured fetuin-A levels and homeostasis model of assessment-insulin resistance before hyperthyroidism treatment was initiated and after euthyroidism was achieved. A total of 42 patients diagnosed with hyperthyroidism were enrolled in this study. Fetuin-A, insulin, high-sensitivity C-reactive protein, fasting blood glucose, free T3 (fT3), free T4 (fT4), and thyrotropin were measured before and after euthyroidism was established. Basal fasting blood glucose, high-sensitivity C-reactive protein, insulin, c-peptide, homeostasis model of assessment-insulin resistance, fT3, fT4 and fetuin-A levels were significantly decreased after euthyroidism was achieved (Table 1). Basal fasting blood glucose (r:0.407, p:0.008), high-sensitivity C-reactive protein (r:0.523, p<0.0001), insulin (r:0.479, p:0.001), homeostasis model of assessment-insulin resistance (r:0.541, p<0.0001), fT3 (r:0.492, p:0.001) and fT4 (r:0.473, p:0.002) were positively correlated with basal fetuin-A levels. Basal thyrotropin levels were significantly negatively correlated (r:-0.553, p<0.0001) with basal fetuin-A levels. Our findings suggest that hyperthyroidism influences fetuin-A levels. ",0
4549,23645051,Evaluation of bivalirudin hyper- and hypo-ACT responses in the setting of percutaneous coronary intervention,"Bivalirudin has emerged as a suitable alternative anticoagulant to unfractionated heparin and low-molecular-weight heparins during percutaneous coronary intervention (PCI) procedures in the management of coronary artery disease and acute coronary syndromes (ACS). In clinical trials, bivalirudin dosing was standardized, and activated clotting time (ACT) did not influence dosing adjustments. The role of ACT monitoring of bivalirudin in PCI is not defined based on current practice guidelines. The hypothesis of this study is that hyper- and hypo-ACT responses to bivalirudin in PCI may be associated with excessive bleeding or thrombotic complications. The planned protocol screened all patients who received bivalirudin therapy and ACT monitoring during PCI in a single center's cardiac catheterization laboratory from July 2009 to June 2010. The first ACT monitored 5 to 60 minutes after bivalirudin initiation was screened for inclusion. Values above 800 seconds and below 300 seconds were included as hyper- and hypo-ACT responses, respectively. Outcomes assessed include thrombotic and bleeding complications. There were 32 patients identified as hyper-responders and 20 patients identified as hypo-responders. There were no significant thrombotic or bleeding complications in the hyper-responder group. There was 1 case (1/20, 5%) of angiographically confirmed acute stent thrombosis immediately following the placement of 5 adjoining bare-metal stents in the right coronary artery of a hypo-responder. Hyper-ACT responses to bivalirudin therapy in PCI were not associated with additional bleeding risk. Bivalirudin may not adequately protect hypo-ACT responders against thrombotic complications during PCI. ",0
4550,23645387,Role of protein and amino acids in promoting lean mass accretion with resistance exercise and attenuating lean mass loss during energy deficit in humans,"Amino acids are major nutrient regulators of muscle protein turnover. After protein ingestion, hyperaminoacidemia stimulates increased rates of skeletal muscle protein synthesis, suppresses muscle protein breakdown, and promotes net muscle protein accretion for several hours. These acute observations form the basis for strategized protein intake to promote lean mass accretion, or prevent lean mass loss over the long term. However, factors such as protein dose, protein source, and timing of intake are important in mediating the anabolic effects of amino acids on skeletal muscle and must be considered within the context of evaluating the reported efficacy of long-term studies investigating protein supplementation as part of a dietary strategy to promote lean mass accretion and/or prevent lean mass loss. Current research suggests that dietary protein supplementation can augment resistance exercise-mediated gains in skeletal muscle mass and strength and can preserve skeletal muscle mass during periods of diet-induced energy restriction. Perhaps less appreciated, protein supplementation can augment resistance training-mediated gains in skeletal muscle mass even in individuals habitually consuming 'adequate' (i.e., >0.8 g kg⁻¹ day⁻¹) protein. Additionally, overfeeding energy with moderate to high-protein intake (15-25 % protein or 1.8-3.0 g kg⁻¹ day⁻¹) is associated with lean, but not fat mass accretion, when compared to overfeeding energy with low protein intake (5 % protein or ~0.68 g kg⁻¹ day⁻¹). Amino acids represent primary nutrient regulators of skeletal muscle anabolism, capable of enhancing lean mass accretion with resistance exercise and attenuating the loss of lean mass during periods of energy deficit, although factors such as protein dose, protein source, and timing of intake are likely important in mediating these effects. ",0
4551,23645408,Plasma advanced glycation end-products and skin autofluorescence are increased in COPD,"Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These conditions may lead to the formation of advanced glycation end-products (AGEs). In this study we investigated in 88 COPD patients and 55 control subjects (80% ex-smokers) the association of the plasma protein-bound AGEs N(ε)-(carboxymethyl)lysine (CML), pentosidine, N(ε)-(carboxyethyl)lysine (CEL), and AGE accumulation in skin by skin autofluorescence (AFR), with lung function. Mean ± sd plasma CML was decreased (COPD 61.6 ± 15.6 nmol · mmol(-1) lysine, never-smokers 80.7 ± 19.8 nmol · mmol(-1) lysine and ex-smokers 82.9 ± 19.3 nmol · mmol(-1) lysine) and CEL (COPD 39.1 ± 10.9 nmol · mmol(-1) lysine, never-smokers 30.4 ± 5.0 nmol · mmol(-1) lysine and ex-smokers 27.7 ± 6.4 nmol · mmol(-1) lysine) and AFR (COPD 3.33 ± 0.67 arbitrary units (AU), never-smokers 2.24 ± 0.45 AU and ex-smokers 2.31 ± 0.47 AU) were increased in COPD patients compared to controls. Disease state was inversely associated with CML, and linearly associated with CEL and AFR. Performing regression analyses in the total group, CEL and AFR showed a negative association and CML a positive association with lung function, even after correction for potential confounders. In conclusion, CEL and AFR were negatively and CML was positively associated with disease state. In the total group only the AGEs showed an association with forced expiratory volume in 1 s. Our data suggest that AGEs are involved in the pathophysiology of COPD, although their exact role remains to be determined. ",0
4552,23645570,Histological approach to Bacillus subtilis colony-biofilm: evolving internal architecture and sporulation dynamics,"Bacillus subtilis has been used as a classic model to study biofilm formation and sporulation process. Colonies of wild-type strains usually have a complex external morphology, but the details of their internal architecture are still undisclosed. Since bacterial biofilms fulfill the criteria to be considered tissues, the aim of this work was to analyse B. subtilis colony-biofilm internal architecture evolution and sporulation dynamics using histological techniques. Transversal sections of colony-biofilms incubated from 24 hours up to 20 days were stained using histochemical techniques to analyse the internal structure by light and electron microscopy. A morphometric study of the different structural biofilm components was performed by image analysis, and an application to quantify spores was developed. Internal biofilm architecture was characterised by a stratified pattern, which evolved from 3 strata at 24 hours, up to 5 strata at 20 days. At 48 hours, strata at the central area of the biofilm was folded, resulting in elevated structures (vein-like structures) that could reach up to 465 μm in height. Sporulation started at 48 hours, at the top of the vein-like structures, at the interface between the two uppermost strata. At 20 days spores formed a continuous central layer, representing 7.5% of the total biofilm. In summary, our results demonstrate that B. subtilis colony-biofilm has a complex and organized internal architecture, evolving over time, and taking place in different cell subpopulations with different functionalities. Furthermore, in situ spore quantification described in this work could be a good alternative to the classical chamber counting. ",0
4553,23646171,Development and validation of real-time PCR for rapid detection of Mecistocirrus digitatus,"Hematophagous activity of Mecistocirrus digitatus, which causes substantial blood and weight loss in large ruminants, is an emerging challenge due to the economic loss it brings to the livestock industry. Infected animals are treated with anthelmintic drugs, based on the identification of helminth species and the severity of infection; however, traditional methods such as microscopic identification and the counting of eggs for diagnosis and determination of level of infection are laborious, cumbersome and unreliable. To facilitate the detection of this parasite, a SYBR green-based real-time PCR was standardized and validated for the detection of M. digitatus infection in cattle and buffaloes. Oligonucleotides were designed to amplify partial Internal Transcribed Spacer (ITS)-1 sequence of M. digitatus. The specificity of the primers was confirmed by non-amplification of DNA extracted from other commonly occurring gastrointestinal nematodes in ruminants. Plasmids were ligated with partial ITS-1 sequence of M. digitatus, serially diluted (hundred fold) and used as standards in the real-time PCR assay. The quantification cycle (Cq) values were plotted against the standard DNA concentration to produce a standard curve. The assay was sensitive enough to detect one plasmid containing the M. digitatus DNA. Clinical application of this assay was validated by testing the DNA extracted from the faeces of naturally infected cattle (n = 40) and buffaloes (n = 25). The results were compared with our standard curve to calculate the quantity of M. digitatus in each faecal sample. The Cq value of the assay depicted a strong linear relationship with faecal DNA content, with a regression coefficient of 0.984 and efficiency of 99%. This assay has noteworthy advantages over the conventional methods of diagnosis because it is more specific, sensitive and reliable. ",0
4554,23646241,Popliteal sciatic nerve block versus spinal anesthesia in hallux valgus surgery,"We compared clinical properties and patient satisfaction between spinal anesthesia and popliteal sciatic nerve block (PSNB) for hallux valgus surgery. Forty patients undergoing hallux valgus surgery were divided into spinal group (spinal anesthesia with 2.5 ml of 0.5% bupivacaine [n = 20]) and PSNB group (PSNB with 30 ml of 0.75% ropivacaine mixed with 10 ml of normal saline solution using a nerve stimulator [n = 20]). The PSNB group used a patient-controlled-analgesia (PCA) pump for postoperative pain control. The quality and side effects were compared between the two groups. A questionnaire was used to evaluate patient satisfaction with the use of anesthetic techniques and postoperative pain control in the PSNB group. This study was assessed 3 days postoperatively by a blinded observer. Procedure time and time from anesthesia until start of sugery were significantly shorter in the spinal group than those in the PSNB group (P < 0.01). Anesthesia-related complications such as hypotension, bradycardia, shivering, nausea/vomitting, post-dural puncture headache (PDPH) and urinary retension were observed in 15%, 10%, 5%, 5%, 10%, and 20% of patients in the spinal group, respectively. PSNB was not associated with these complications. Patient satisfaction was slightly higher for PSNB than for spinal anesthesia. In the PSNB group, patient satisfaction with postoperative pain-control was 95% above ordinary satisfaction. Despite the long duration of the procedure, PSNB is relatively safe, provides an adequate level of anesthesia, effectively controls postoperative pain and reduces side effects. Therefore, PSNB could be a potential anesthetic technique for hallux valgus surgery. ",0
4555,23646853,Metastatic tumors to the gingiva and the presence of teeth as a contributing factor: a literature analysis,"Gingiva that is prone to inflammation may serve as a pre-metastatic niche for the attraction of circulating malignant cells. The aim of this study is to analyze cases of metastatic lesions to the gingiva compared with cases metastasizing to other oral mucosal sites. The pathogenesis of gingival metastases is discussed, with emphasis on the role of inflammation. The English-language literature between 1916 and 2011 was searched for cases of metastatic lesions to the oral mucosa; only cases metastasizing in the oral mucosa, gingiva, and periodontium were included. Two hundred seven cases were included. The gingiva was the most common site (60.4%), followed by tongue and tonsil. The most common primary sites were lung (24.2%), kidney (13.5%), skin (10.6%), and breast (8.7%). In 27%, the oral lesion was the first sign of a malignant disease. In most cases, the lesion appeared as an exophytic mass (96%) diagnosed clinically as a reactive gingival lesion. The presence of teeth was significantly associated with the development of gingival metastases: in 108 of 125 gingival metastases, the lesion was found adjacent to teeth (P <0.001; odds ratio = 8.2). The average life expectancy after diagnosis of the metastasis was 3.7 months. The gingiva is the most common site for metastases to oral soft tissues, with strong association with the presence of teeth. This finding may be related to the role of inflammation in the attraction of metastatic cells to chronically inflamed gingiva. ",0
4556,23647016,Significant spatial aggregation and fine-scale genetic structure in the homosporous fern Cyrtomium falcatum (Dryopteridaceae),"Spores of homosporous ferns are small, wind-borne and thus have the potential for long-distance dispersal. This common perception has led to a prediction of near-random spatial genetic structure within fern populations. Spore dispersal and spore bank studies, however, indicate that most spores fall close to the maternal plant (< 5 m), supporting a prediction of significant fine-scale genetic structure (FSGS) within populations. To determine which of these two hypotheses is more likely to occur in nature, we measured inbreeding and quantified the spatial distribution of individuals and allozyme-based genotypes using spatial autocorrelation methods within four populations of the fern Cyrtomium falcatum in southern South Korea. Inbreeding levels were low, and all populations exhibited significant aggregation of individuals and strong FSGS. The present results support the second hypothesis, and the substantial FSGS in C. falcatum could reflect the unique features of most homosporous ferns (outcrossing mating systems that lead a majority of spores to occur at short distances and a very limited dispersal distance of male gametes). Although fern spores are physically analogous to orchid seeds, the intensity of FSGS exhibited in C. falcatum is four times stronger than that in 16 terrestrial orchid species. ",0
4557,23647117,Ozone photolysis of paracetamol in aqueous solution,"The degradation of a paracetamol (N-acetil-para-aminofenol) aqueous solution (C (0) P = 5 mmol L(-1)) is studied in a bench-scale setup by means of simple ozonation (O3) and ozonation catalyzed with UV light (O3/UV) in order to quantify the influence of UV light on the degradation process. The results have shown that under the adopted experimental conditions (25°C, applied ozone dose = 9.8 mg L(-1) and gas flow rate of 20 L h(-1)) both oxidative systems are capable of removing the substrate with mineralization degrees up to 51% for ozonation and 53% for O3/UV. HPICE chromatography allowed the detection of nitrate ions and maleic and oxalic acids as ultimate carboxylic acids. The experimental data have been interpreted through 5 indicators: the conversion of paracetamol (XP ), the conversion degree of TOC (XTOC ), the apparent rate constant (kap ), the Hatta number (Ha) and the enhancement factor (E). The main advantage of photo-ozonation compared to simple ozonation was a more advanced conversion (79% vs. 92% after 90 min). The paracetamol decay follows a pseudo-first-order reaction with a superior rate constant (higher by 54%) for the UV catalyzed system in comparison with direct ozonation. Mineralization is slightly accelerated (+4%) in the O3/UV system, due to the additional production of hydroxyl radicals induced by the UV light and a higher Hatta number (+24%). Nevertheless, the process was still in the slow reaction kinetic regime (Ha < 0.3), and the enhancement factor was not significantly increased. The results are useful for the design and scale-up of the gas-liquid processes. ",0
4558,23647661,A simple and novel method for GII norovirus genome clone with generic primers,"This study aims to establish a novel method for cloning GII norovirus genome using generic primers rationally designed based on multiple alignments of 96 GII norovirus genome sequences. Based on conservative analysis of 96 GII norovirus genome sequences available in GenBank, three fragments encompassing the full-length genome were rationally designed. Fragments A, B and C were amplified by primers N1F/N2819R, N2689F/COG2R and COG2F/adaptor, respectively. Meanwhile, the sensitivity of the novel primers was evaluated, which could achieve 10(1) RTPCRU, as determined by the common detection primer pair JV12/JV13. The availability of the novel protocol was verified by sequencing two norovirus strains with different genotypes. Primers for GII norovirus genome clone were rationally designed, and a novel GII genome clone method was established. The three-fragment cloning method can be used as a universal tool to collect information on the genome of norovirus strains for future evolution and antivirus studies. ",0
4559,23647699,Graduated driver license nighttime compliance in U.S. teen drivers involved in fatal motor vehicle crashes,"Examination of teen driver compliance with graduated driver licensing (GDL) laws could be instrumental in identifying factors associated with persistently high motor vehicle mortality rates. Fatality analysis reporting system (FARS) data from the years 2006 to 2009 were used in this nation-wide cross-sectional study of drivers covered by a state nighttime GDL law (n=3492). A new definition of weekend, based on the school night in relation to the teenage social landscape, redefined Friday night as a weekend night and Sunday night as a weekday/school night and compared it to previous weekend definitions. Multiple logistic regression was used to examine independent effects of demographic, behavioral, environmental, contextual, and other factors on compliance with nighttime GDL laws. All analyses were performed in Stata version 11. Given coverage under nighttime GDL laws, drivers aged 15-17 years were non-compliant in 14.9% of the fatal MVCs in which they were involved, and nearly one-fifth (18.8%) of all fatalities aged 15-17 years were associated with non-compliance. Mortality risk was 10% higher using a revised social (school night) versus traditional (Sat-Sun) weekend definitions. In multivariable analysis, drivers non-compliant with nighttime GDL laws were more likely to be drinking (OR=4.97, 3.85-6.40), unbelted (OR=1.58, 1.25-1.99), driving on the weekend (OR=1.82, 1.47-2.24), and killed (OR=1.31, 1.04-1.65). GDL non-compliance contributes to teen motor vehicle mortality. Legislative and enforcement efforts targeting non-school night driving, seatbelt nonuse and alcohol have potential to further reduce teen driving mortality. ",0
4560,23647745,The effect of sacral neuromodulation on anticholinergic use and expenditures in a privately insured population,"Sacral neuromodulation is Food and Drug Administration approved for many types of voiding dysfunction. Goals of treatment often include cessation of anticholinergic therapy. With the goal of understanding the impact of sacral neuromodulation on anticholinergic use, we analyzed patterns of care using a national claims-based dataset. The Ingenix (i3) data base contains insurance claims, including utilization and cost data, for 75 large employers. De-identified patients who underwent sacral neuromodulation between 2002 and 2007 were identified by the unique current procedural terminology-4 procedure code for pulse generator implantation, code 64590. The number and costs of anticholinergic prescriptions were compared before and after treatment. There were 266 percutaneous and 794 two-staged procedures performed from 2002 to 2007 in the i3 dataset. A total of 484 pulse generator implantations were performed, representing 46% of the test procedures. During the year prior to pulse generator placement, each patient purchased an average of 2.1 prescriptions for an anticholinergic agent (SD 3.5). During the year after neuromodulation, each patient purchased an average of 1.0 prescription (SD 2.3, p < 0.0001 by t-test). Prescription charges were $241.31 per patient before and $103.52 after neuromodulation, a statistically significant cost difference (p < 0.0001 by t-test). During the year before the procedure, 50% of patients filled anticholinergic prescriptions. This decreased to 23% after the procedure (p < 0.0001 by chi-square test). Sacral neuromodulation was associated with a significant decrease in the use of anticholinergic medication. Cost-effectiveness analyses that take into account patient quality-adjusted life years are needed to determine the true cost-benefit ratio of sacral neuromodulation. ",0
4561,23647864,An electronic nose discriminates exhaled breath of patients with untreated pulmonary sarcoidosis from controls,"Sarcoidosis is a systemic granulomatous disease of unknown cause that affects the lungs in over 90% of cases. Breath analysis by electronic nose technology provides exhaled molecular profiles that have potential in the diagnosis of several respiratory diseases. We hypothesized that exhaled molecular profiling may distinguish well-characterized patients with sarcoidosis from controls. To that end we performed electronic nose measurements in untreated and treated sarcoidosis patients and in healthy controls. 31 sarcoidosis patients (11 patients with untreated pulmonary sarcoidosis [age: 48.4 ± 9.0], 20 patients with treated pulmonary sarcoidosis [age: 49.7 ± 7.9]) and 25 healthy controls (age: 39.6 ± 14.1) participated in a cross-sectional study. Exhaled breath was collected twice using a Tedlar bag by a standardized method. Both bags were then sampled by an electronic nose (Cyranose C320), resulting in duplicate data. Statistical analysis on sensor responses was performed off-line by principal components (PC) analyses, discriminant analysis and ROC curves. Breathprints from patients with untreated pulmonary sarcoidosis were discriminated from healthy controls (CVA: 83.3%; AUC 0.825). Repeated measurements confirmed those results. Patients with untreated and treated sarcoidosis could be less well discriminated (CVA 74.2%), whereas the treated sarcoidosis group was undistinguishable from controls (CVA 66.7%) Untreated patients with active sarcoidosis can be discriminated from healthy controls. This suggests that exhaled breath analysis has potential for diagnosis and/or monitoring of sarcoidosis. ",0
4562,23648109,"Structure-activity relationships of analogs of 3,4,5-trimethylfuran-2(5H)-one with germination inhibitory activities","Smoke-derived butenolide compounds have, in recent years, been shown to be important germination signaling molecules, which also affect seedling growth. The butenolide 3,4,5-trimethylfuran-2(5H)-one was previously isolated from plant-derived smoke and was found to significantly reduce the effect on germination by the highly active promotor karrikinolide (KAR1, 3-methyl-2H-furo[2,3-c]pyran-2-one), another smoke-derived compound. In this study, 11 analogs of 3,4,5-trimethylfuran-2(5H)-one were synthesized and their effect on the germination of light-sensitive 'Grand Rapids' lettuce seeds (Lactua sativa cv. 'Grand Rapids') were evaluated. A concentration series (1mM-1μM) of the analogs were tested alone, or in combination with 0.01μM KAR1. Only two compounds were found to reduce the germination promotory effect of 0.01μM KAR1 in a similar manner as observed with 3,4,5-trimethylfuran-2(5H)-one, with activity ranging from 1mM to 10μM. Four compounds were found to have inhibitory activity at 1mM and 100μM. The retention of activity by some of the analogs may be useful for designing novel compounds with improved activity. Furthermore, understanding the structure-activity relationships of these compounds may be helpful in synthesizing molecular probes that can be used to further investigate the mechanism of action of these compounds in regulating seed germination.  ",0
4563,23648334,Tissue feature-based intra-fractional motion tracking for stereoscopic x-ray image guided radiotherapy,"Real-time knowledge of tumor position during radiation therapy is essential to overcome the adverse effect of intra-fractional organ motion. The goal of this work is to develop a tumor tracking strategy by effectively utilizing the inherent image features of stereoscopic x-ray images acquired during dose delivery. In stereoscopic x-ray image guided radiation delivery, two orthogonal x-ray images are acquired either simultaneously or sequentially. The essence of markerless tumor tracking is the reliable identification of inherent points with distinct tissue features on each projection image and their association between two images. The identification of the feature points on a planar x-ray image is realized by searching for points with high intensity gradient. The feature points are associated by using the scale invariance features transform descriptor. The performance of the proposed technique is evaluated by using images of a motion phantom and four archived clinical cases acquired using either a CyberKnife equipped with a stereoscopic x-ray imaging system, or a LINAC equipped with an onboard kV imager and an electronic portal imaging device. In the phantom study, the results obtained using the proposed method agree with the measurements to within 2 mm in all three directions. In the clinical study, the mean error is 0.48 ± 0.46 mm for four patient data with 144 sequential images. In this work, a tissue feature-based tracking method for stereoscopic x-ray image guided radiation therapy is developed. The technique avoids the invasive procedure of fiducial implantation and may greatly facilitate the clinical workflow. ",0
4564,23648652,Adherence associated with oral medications in the treatment of spasticity,"To examine adherence to baclofen, tizanidine, and dantrolene (U.S. Food and Drug Administration-approved oral spasticity medications), and identified determinants of adherence. A retrospective administrative claims data analysis that used medical and pharmacy claims data and enrollment information from a large, national U.S. health plan. The subjects were commercial health plan members who initiated treatment on baclofen, tizanidine, or dantrolene from January 1, 2004, through September 30, 2009, and who had stroke, spinal cord injury, traumatic brain injury, cerebral palsy, or multiple sclerosis. Descriptive and logistic regression statistical analyses were performed. Outcomes were adherence, measured as continuous medication possession ratio (MPR) and as a binary indicator (MPR ≥0.80, adherent; MPR <0.80, nonadherent), change in oral spasticity medication, and use of nonoral spasticity therapy. The study population included 2840 subjects. Adherence overall was poor: the range of mean unadjusted MPR values was 0.10-0.50, which indicated that, at best, the subjects were adherent to their index spasticity medications for 50% of their treatment periods. Unadjusted overall MPRs for baclofen and tizanidine were 20.4% and 9.1%, respectively. Fewer than 5% of subjects changed oral spasticity medications. The results of logistic regression to identify determinants of adherence showed that subjects treated with tizanidine versus baclofen had 37.4% lower odds of adherence and that subjects with traumatic brain injury versus stroke had 77.5% lower odds of adherence. The odds of adherence increased with age and with preindex contracture or decubitus ulcer. Adherence to oral spasticity medication was poor irrespective of index spasticity medication or condition. Results from this study indicated that physicians cannot assume that patients are adherent to prescribed oral spasticity medications. A more complete understanding of the reasons behind nonadherence is required. ",0
4565,23648866,Repression of type-1 fimbriae in Shiga toxin-producing Escherichia coli O91:H21 isolated from asymptomatic human carriers in Korea,"Seventy-four Shiga toxin-producing Escherichia coli (STEC) isolates belonging to the serotype O91:H21 were isolated from 1,643 asymptomatic human carriers in a STEC outbreak at Gwangju in Korea. Although the isolates did not cause any symptoms, all of them produced Shiga toxins 1 (Stx1) and 2 (Stx2). In order to determine why these strains cause no symptoms, we explored the differences in virulence potential between the asymptomatic STEC O91:H21 isolates and symptomatic STEC O91:H21 strains (ATCC 51435 and ATCC 51434). The asymptomatic STEC O91:H21 isolates showed strongly reduced cytopathic effects compared with the symptomatic strains when intact bacterial cells were used as an inoculant. Moreover, we found a reduced adherence phenotype when testing asymptomatic strains on HeLa cells. Real-time quantitative PCR results suggest that transcriptional repression of the genes encoding type-1 fimbriae occurs in the asymptomatic isolates but not in the symptomatic strains. ",0
4566,23649113,Clinical profile of myasthenia gravis in the Sultanate of Oman,"Clinical study and follow up of myasthenia gravis patients in Oman. Follow up of 50 consecutive myasthenia gravis patients referred to the Sultan Qaboos University Hospital, Oman for a median period of 3 years from 1997 to 2000. We based the diagnosis on the clinical picture, repetitive nerve stimulation tests and edrophonium test. We performed a computerized tomography scan of the chest and anti-acetylcholine receptor antibodies. We reviewed the results of immuno modulatory treatment including thymectomy and compared these with other studies Of 50 patients, 6 had purely ocular myasthenia. Of the 44 with generalized myasthenia, 28 had bulbar involvement and 12 required ventilatory support. Eight out of 29 thymectomized patients had drug free remission after 2 years. There was worsening of myasthenic symptoms in only one out of 8 pregnancies and deliveries. Bulbar and ventilatory involvement are more common in our series as compared with western data. Pregnancy and delivery were well tolerated. ",0
4567,23649687,Histology of the vaginal wall in women with pelvic organ prolapse: a literature review,"The pathophysiology of pelvic organ prolapse (POP) is incompletely understood. The purpose of this study is to describe the current knowledge about histology of the vaginal wall and its possible involvement in the pathogenesis of pelvic organ prolapse. Eligible studies were selected through a MEDLINE search covering January 1986 to December 2012. The research was limited to English-language publications. Investigations of changes in the vaginal tissue that occur in women with genital prolapse are currently still limited and produced contrary results. The heterogeneity of the patients and the control groups in terms of age, parity and hormonal status, of the localization of biopsies and the histological methods as well as the lack of validation of the quantification procedures do not allow clear and definitive conclusions to be drawn. This review shows that current knowledge of the histological changes observed in women with POP are inconclusive and relatively limited. More studies are needed in this specific field to better understand the mechanisms that lead to POP. ",0
4568,23650023,The impact of positive circumferential margin on survival following oesophagectomy using the new 7th TNM classification,"Previous studies looking at the influence of positive circumferential margin (CRM) on survival after oesophagectomy are conflicting. This may be due to the fact that older versions of the TNM classification were used, which do not predict survival as accurately as the new 7th edition. We examine whether CRM involvement has an impact on survival when the 7th TNM classification is used. Over a 10-year period, 199 patients who had undergone potentially curative resection for oesophageal cancer with postoperative histopathological T3 were identified. A total of 151 (75.9%) were found to have CRM involvement (<1 mm), and these were compared with patients in whom the CRM was free of tumour. Cancers were staged according to the International Union against Cancer TNM 7th edition. First, univariate and then multivariate Cox regression analysis were performed to assess the factors influencing survival. Potentially significant predictors (P < 0.1) from the univariate analysis were inserted in the forward-stepwise Cox regression model and was allowed to remain in the final model if a P-value of <0.05 was achieved. A sub-group analysis was also performed for different N-stages (N0-N3). After all analyses were performed, CRM involvement was found to have no effect on survival following oesophagectomy [hazard ratio 1.28 (95% CI: 0.82-2.01) (P = 0.28)]. This was seen for all N-stages. Stage of disease, age at operation, % predicted forced expiratory volume in 1 second and shortness of breath [(according to New York Heart Association classification)] were all significant predictors of survival. With this study, it became clear that CRM involvement does not affect long-term survival of patients after oesophagectomy. Patients with CRM involvement should not necessarily be considered to have had an incomplete resection. ",0
4569,23650396,Biopolymer-reinforced synthetic granular nanocomposites for affordable point-of-use water purification,"Creation of affordable materials for constant release of silver ions in water is one of the most promising ways to provide microbially safe drinking water for all. Combining the capacity of diverse nanocomposites to scavenge toxic species such as arsenic, lead, and other contaminants along with the above capability can result in affordable, all-inclusive drinking water purifiers that can function without electricity. The critical problem in achieving this is the synthesis of stable materials that can release silver ions continuously in the presence of complex species usually present in drinking water that deposit and cause scaling on nanomaterial surfaces. Here we show that such constant release materials can be synthesized in a simple and effective fashion in water itself without the use of electrical power. The nanocomposite exhibits river sand-like properties, such as higher shear strength in loose and wet forms. These materials have been used to develop an affordable water purifier to deliver clean drinking water at US $2.5/y per family. The ability to prepare nanostructured compositions at near ambient temperature has wide relevance for adsorption-based water purification. ",0
4570,23650801,Effects of weizhong (BL 40) area scraping on blood perfusion level of the skin microcirculation of qihaishu (BL 24) region at the ipsilateral back of the volunteer's body],"To observe the effect of Guasha (scraping) of Weizhong (BL 40) on the cutaneous blood perfusion of Qihaishu (BL 24) region of the Bladder Meridian on the back. Ten healthy volunteer subjects were recuited in the present study. Weizhong (BL 40, at the politeal fossa) area was repeatedly scraped till regional flush using a cornu bubali scraping plate for 5 min after applying scraping oil to the regional skin. Then blood perfusion levels of the skin microcirculation around Weizhong (BL 40) and Qihaishu (BL 24) regions on the ipsilateral back were detected using a Laser Doppler flowmetry (PeriScan PIM II). Following scraping Weizhong (BL 40) region, the cutaneous blood perfusion levels in the stimulated region were increased significantly at the time-points of 0, 15, 60 and 90 min after scraping (P < 0.001, P < 0.01), while those of Qihaishu (BL 24) area at the lumbar part also showed a remarkable increase 15, 60 and 90 min after scraping compared with the basic value (P < 0.05). A positive correlation was found between BL 40 and BL 24 areas in the cutaneous blood perfusion levels after scraping BL 40 (P < 0.05). Scraping stimulation of Weizhong (BL 40) can improve the cutaneous microcirculation of the stimulated BL 40 and Qihaishu (BL 24) regions in healthy volunteers, suggesting a close connection between BL 40 and the back described in Chinese medicine. ",0
4571,23651306,Recent advances in fluorescent probes for monitoring of hydrogen sulfide,"Hydrogen sulfide (H₂S), known for its unpleasant rotten egg smell and its high toxicity, has recently emerged as an important mediator of human physiological and pathological processes, such as the regulation of cell growth, cardiovascular protection, the stimulation of angiogenesis, gastric mucosal injury and Alzheimer's disease. Due to its significant actions in the physiology, H₂S has attracted the abundant concern of numerous researchers in the cutting edge of chemistry, biology and medicine. Recently, several fluorescent probes have been developed for detecting and elucidating the role played by H₂S in biological systems. This review highlights recent advances that have been made on the mechanism and applications of fluorescent probes for the detection of H₂S, demonstrating a new field in which remarkable improvements have been accomplished over the last two years. ",0
4572,23651332,Effects of molybdenum on sperm quality and testis oxidative stress,"In order to investigate the effects of molybdenum (Mo) on sperm parameters and testicular oxidative stress, the ICR strain of adult mice were exposed to different doses of molybdenum for a sub-acute toxicity test. Compared to the control, our results showed that the sperm parameters, including the epididymis index, sperm motility, sperm count, and morphology, increased by a moderate dose of Mo (25 mg/L), but were negatively affected at high doses (≥ 100 mg/L). In addition, the changes of sperm parameters were accompanied with changes of the superoxide dismutase (SOD) activities, the glutathione peroxidase (GPx) activities, and the malondialdehyde (MDA) levels in testes. In conclusion, Mo affects the sperm quality through regulating the testicular oxidative stress in a complex manner. ",0
4573,23651399,Nanotechnology versus other techniques in improving drug dissolution,"Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-down techniques such as wet milling and high pressure homogenisation involve reducing large particles to nano-sizes. Some pharmaceutical products made by these processes have been marketed. Bottom-up methods such as precipitation and controlled droplet evaporation form nanoparticles from molecules in solution. To minimise aggregation upon drying and promote redispersion of the nanoparticles upon reconstitution or administration, hydrophilic matrix formers are added to the formulation. However, the nanoparticles will eventually agglomerate together after dispersing in the liquid and hinders dissolution. Currently there is no pharmacopoeial method specified for nanoparticles. Amongst the current dissolution apparatus available for powders, the flow-through cell has been shown to be the most suitable. Regulatory and pharmacopoeial standards should be established in the future to standardise the dissolution testing of nanoparticles. More nanoparticle formulations of new hydrophobic drugs are expected to be developed in the future with the advancement of nanotechnology. However, the agglomeration problem is inherent and difficult to overcome. Thus the benefit of dissolution enhancement often cannot be fully realised. On the other hand, chemical strategies such as modifying the parent drug molecule to form a more soluble salt form, prodrug, or cyclodextrin complexation are well established and have been shown to be effective in enhancing dissolution. Thus the value of nanoformulations needs to be interpreted in the light of their limitations. Chemical approaches should also be considered in new product development.  ",0
4574,23651712,Ultrasound-guided drainage of subcutaneous abscesses on the trunk is feasible,"Subcutaneous trunk abscesses are frequent, and current treatment options generally involve incision. By contrast, the standard care for breast abscesses is ultrasound-guided drainage. The aim of this study was to evaluate the feasibility of ultrasound-guided drainage combined with antibiotics in the treatment of subcutaneous abscesses on the trunk. In this prospective study, 27 patients were treated with ultrasound-guided needle aspiration and oral antibiotics. Follow-up was performed at a 3-6-day interval, and the procedure was repeated if the abscess was not obliterated. Treatment was initially successful in 25 of the 27 participants (93%); two patients went on to surgery. The median time from first treatment to the final control visit was nine days. The 25 patients with initial successful treatment were contacted after a median of 84 days, and six (24%) of these reported recurrence of an abscess at the puncture site. 88% of the patients reported that they were satisfied or very satisfied with ultrasound-guided drainage. Our results indicate that ultrasound-guided drainage combined with antibiotics is feasible in the treatment of small subcutaneous abscesses on the trunk. Ultrasound-guided drainage was well-tolerated, had a high degree of success and short healing times. Additional randomised studies are needed to verify our findings. not relevant. not relevant. ",0
4575,23651792,Antiplatelet or anticoagulant therapy might not increase the risk of haemoptysis in patients with bronchiectasis,"The aim of this study was to assess whether the use of antiplatelets and anticoagulants increased haemoptysis in patients with bronchiectasis. Cases (n = 242) with a history of haemoptysis were compared with controls (n = 242) without a history of haemoptysis. Of the 242 case patients, 16.5% took antiplatelets compared with 19.8% of controls (P = 0.346). The proportion of warfarin users did not differ between cases and controls (3.3% vs. 2.5%, P = 0.588). The use of these agents might not be associated with increased risk of haemoptysis in patients with bronchiectasis. ",0
4576,23651841,Does skull shape mediate the relationship between objective features and subjective impressions about the face?,"In our previous work, we described facial features associated with a successful recognition of the sex of the face (Marečková et al., 2011). These features were based on landmarks placed on the surface of faces reconstructed from magnetic resonance (MR) images; their position was therefore influenced by both soft tissue (fat and muscle) and bone structure of the skull. Here, we ask whether bone structure has dissociable influences on observers' identification of the sex of the face. To answer this question, we used a novel method of studying skull morphology using MR images and explored the relationship between skull features, facial features, and sex recognition in a large sample of adolescents (n=876; including 475 adolescents from our original report). To determine whether skull features mediate the relationship between facial features and identification accuracy, we performed mediation analysis using bootstrapping. In males, skull features mediated fully the relationship between facial features and sex judgments. In females, the skull mediated this relationship only after adjusting facial features for the amount of body fat (estimated with bioimpedance). While body fat had a very slight positive influence on correct sex judgments about male faces, there was a robust negative influence of body fat on the correct sex judgments about female faces. Overall, these results suggest that craniofacial bone structure is essential for correct sex judgments about a male face. In females, body fat influences negatively the accuracy of sex judgments, and craniofacial bone structure alone cannot explain the relationship between facial features and identification of a face as female. ",0
4577,23651970,Risk factors for hyperuricemia in active and retired employees underwent physical examination],"""To observe serum uric acid (UA) level distribution and explore risk factors of hyperuricemia (HUA) in a large cohort of active and retired employees underwent physical examination. Physical examination was arranged for 21 700 active and retired employees from May 2010 to September 2011, 16 416 employees were examined and complete examination data were obtained in 14 044 subjects. The distribution characteristics of UA level and correlations of UA level and HUA prevalence rate with gender, age, body mass index (BMI), systolic pressure (SBP), diastolic pressure (DBP), fasting blood-glucose (FPG), serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) were analyzed. HUA prevalence rate was 11.2% in this cohort, which was significantly higher in males (15.8%) than in females (4.1%, P < 0.05). The UA level and the HUA prevalence rate presented a """"J"""" curve relationship with aging and positively correlated with BMI, SBP, DBP, TG, LDL-C, TC and FPG while negatively correlated with HDL-C. Multiple linear regression analysis showed that SBP, BMI, FPG, TG, and LDL-C were independent risk factors while HDL-C and female gender were the protective factors of HUA(all P < 0.01). Aging and high DBP were independent risk factors of HUA for females (all P < 0.05) and LDL-C was risk factor of HUA for males (P < 0.05). Serum UA level presents a """"J"""" wave relationship with aging. The risk factors of HUA are increased SBP, BMI, FPG, TG, LDL-C while the protective factors of HUA are female gender and high HDL-C. """,0
4578,23653616,Low Spatial Frequency Bias in Schizophrenia is Not Face Specific: When the Integration of Coarse and Fine Information Fails,"Studies have shown that patients with schizophrenia exhibit visual processing impairments, particularly regarding the processing of spatial frequencies. In a previous work, we found that, compared to healthy volunteers, patients were biased toward low spatial frequencies (LSF) to identify facial expression at a glance. Given the ubiquity of faces in visual perception, it remains an open question whether the LSF bias is face specific or also occurs with other visual objects. Here, 15 patients with schizophrenia and 11 healthy control adults performed a categorization task with hybrid stimuli. These stimuli were single images consisting of two different objects, a fruit and an animal, each in a specific spatial frequency range, either low (LSF) or high (HSF). Observers were asked to report if they saw an animal or a fruit. The reported category demonstrated which spatial scale was preferentially perceived in each trial. In a control experiment, participants performed the same task but with images of only a single object, either a LSF or HSF filtered animal or fruit, to verify that participants could perceive both HSF or LSF when presented in isolation. The results on the categorization task showed that patients chose more frequently LSF with hybrid stimuli compared to healthy controls. However, both populations performed equally well with HSF and LSF filtered pictures in the control experiment, demonstrating that the LSF preference found with hybrid stimuli in patients was not due to an inability to perceive HSF. The LSF preference found in schizophrenia confirms our previous study conducted with faces, and shows that this LSF bias generalizes to other categories of objects. When a broad range of spatial frequencies are present in the image, as in normal conditions of viewing, patients preferentially rely on coarse visual information contained in LSF. This result may be interpreted as a dysfunction of the guidance of HSF processing by LSF processing. ",0
4579,23653736,Implementation of a Service-learning Module in Medical Microbiology and Cell Biology Classes at an Undergraduate Liberal Arts University,"Here we discuss the implementation of a service-learning module in two upper-division biology classes, Medical Microbiology and Cell Biology. This exciting hands-on learning experience provided our students with an opportunity to extend their learning of in-class topics to a real-life scenario. Students were required to volunteer their time (a minimum of 10 hours in a semester) at an under-served clinic in Houston, Texas. As they interacted with the personnel at the clinic, they were asked to identify the most prevalent disease (infectious for Medical Microbiology, and cellular-based for Cell) seen at the clinic and, working in groups, come up with educational material in the form of a display or brochure to be distributed to patients. The material was meant to educate patients about the disease in general terms, as well as how to recognize (symptoms), prevent and treat it. Students were required to keep a reflective journal in the form of a blog throughout the semester, and present their final materials to the class orally. Students were surveyed about their opinion of the experience at the end of the semester. The vast majority of student participants felt that the project was a positive experience and that it helped them develop additional skills beyond what they learn in the classroom and understand how lecture topics relate to every day life. ",0
4580,23653819,Development of higher-level cognitive skills in a learner-centered lab on extensions of mendelian inheritance using Drosophila,"""Students can have difficulty comprehending complex concepts in science. They can memorize the definition but do not understand the underlying biological principles. In the Fundamentals of Genetics course at Arizona State University at the West campus, students grapple with the topic of """"extensions of Mendelism."""" Additionally, in lab, students are challenged by scoring phenotypes that are not binary. Both of these concepts require that students understand not only inheritance but also the principles of protein structure and function. A genetics laboratory exercise was developed that combines study of some extensions of Mendelian inheritance with practice in manipulating Drosophila melanogaster and scoring subtle and variable phenotypes. Students analyze Drosophila with mutations that demonstrate some extensions of Mendelian inheritance: temperature sensitivity, variable expressivity, incomplete penetrance, multiple alleles, dosage compensation, and gene dosage effect. The phenotypes in some of these mutants differ from individual to individual and are difficult to discern; thus, students also gain experience in investigating challenging phenotypes. Pre- and postlab assessments indicate that performing this exercise increased students' mastery of the molecular basis of extensions of Mendelian inheritance and their abilities in scoring and manipulating flies. This is a discovery-based lab exercise in which students examine some extensions of Mendelian inheritance and gain experience in analyzing complex traits in Drosophila. """,0
4581,23653942,Diagnostic difficulties and remission criteria of autoimmune pancreatitis],"The paper describes a clinical case in a 56-year-old female patient who has been suffering from chronic autoimmune pancreatitis, chronic recurrent cholangitis for 3 years. It demonstrates diagnostic difficulties at the early stage of the disease, the specific features of its course, the sequence of treatment in the patient, and problems in choosing a therapy option to achieve a remission. ",0
4582,23653968,Markers of airway inflammation in the exhaled breath condensate of preschool wheezers,"Leukotrienes (LT), isoprostanes, and nitrites/nitrates are biomarkers of airway inflammation and oxidative stress that can be detected in exhaled breath condensate (EBC). The aim of this study was to evaluate LTB4, LTE4, 8-isoprostane, and nitrite/nitrate levels in the EBC of healthy and wheezing preschool children. We included 21 healthy nonatopic children and 25 patients with recurrent wheezing episodes in a cross-sectional study. LTB4, LTE4, and 8-isoprostane concentrations were measured directly in EBC using a specific enzyme immunoassay; nitrite/nitrate concentrations were measured using a colorimetric assay. LTB4 concentrations were higher in children with wheezing episodes than in healthy controls (76 pg/mL vs 20 pg/mL, P < .001). LTE4 was increased in children with wheezing episodes than in healthy controls (68 pg/mL vs 35 pg/mL, P < .001). Nitrite concentrations were higher in children with wheezing episodes than in healthy controls (14 pg/mL vs 9.7 pg/mL, P < .03). We found no differences in 8-isoprostane and nitrate concentrations between the patients and the healthy controls. Our findings suggest that EBC is a suitable noninvasive method for the assessment of airway inflammation and oxidative stress in preschool children. Levels of LTB4, LTE4, and nitrites were higher in children with recurrent wheezing episodes than in healthy controls. ",0
4583,23654009,Simultaneous carotid and coronary surgery without use of extracorporeal circulation--personal experience],"There is still a dilemma about best treatment option for patients with severe carotid and coronary artery disease. Reviving of beating heart revascularization technique and using of carotid stenting makes things even more difficult. Discussion about this subject is getting more and more profound. This is analysis of our initial experience with simultaneous carotid and off pump coronary procedures. This is retrospective analysis of 18 patients operated using this technique in a period from 2001-2003 yrs. Follow up was done by telephone interview. For survivors specially designed questionaire was fulfilled. We operated total number of 18 patients with average age 60,6+/-9.32 years. Carotid recontruction was performed by eversion technique in all patients. Average number of coronary grafts was 2,67+/-0.88. During postoperative period 1 patient (5.55%) had verified perioperative infarction and 1 patient (5.55%) suffered from stroke. Average number of days in hospital was 9.95+/-4.74. During follow up period of 21 months two more patients died from cardiovascular causes. There was no need for repeat coronary angiogram or reintervention on carotid or coronary arteries. Simultaneous carotid and coronary operation performed on beating heart is safe and efficent method of treatment for patients with severe concomitant carotid and coronary artery disease. ",0
4584,23654104,Drinking behaviors of adults at different time of day in four cities of China in summer],"To investigate the drinking behaviors of adults at different time of day in four cities of China in summer. A total of 1483 adults aged 18 - 60 years old from Beijing, Shanghai, Chengdu and Guangzhou were selected using multiple-stage random sampling method. The information of amounts and types of daily drinking water was recorded by subjects for seven consecutive days using a quantitative measurement. The proportion (97% - 99%) and mean (290 - 471 ml) of drinking water of subjects after breakfast, lunch and supper are higher than other time of day (P < 0.01). The distribution of plain water, tea, beverages at different time of day was the same as total drinking water. Among three periods a day, the amount of drinking water in the morning (719 ml/d) was the most, followed by in the afternoon (539 ml/d), and the least in the evening (417 ml/d), the difference was statistically significant (F = 972.55, P < 0.01). The highest consumption of plain water and beverages were in the morning. The consumption of tea in the morning was close to it in the afternoon and higher than that in the evening (t = -52.13, P < 0.01). The average daily drinking water in mealtime was 240 ml, while non-mealtime was 1436 ml, so the difference was statistically significant. Beverages in non-mealtime were higher than mealtime while plain water in non-meal time was higher than meal time (P < 0.05). The highest consumption of drinking was plain water among three periods a day, and beverages were higher in mealtime while plain water higher in non-mealtime. ",0
4585,23656439,Effect of clarithromycin in experimental empyema by multidrug-resistant Pseudomonas aeruginosa,"Evidence from a recent randomized study of our group suggests that intravenous clarithromycin resulted in earlier resolution of ventilator-associated pneumonia. The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug-resistant Pseudomonas aeruginosa in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor-alpha (TNFα). After 7 days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. It also attenuated the pro-inflammatory phenomena induced by the β-lactam. ",0
4586,23656448,Unifying drug safety and clinical databases,"Clinical and drugs safety organisations run their operation independently and use separate databases designed to comply with different data standards. This separation is neither efficient nor effective since investigators need to report serious adverse events both to the clinical and drug safety departments, causing the respective databases to contain partially overlapping data sets containing common elements that need to be reconciled. Electronic data capture provides the opportunity to avoid duplicate storage and obviate reconciliation. It also introduces the risk of non-compliance due to late submission of unexpected serious adverse reactions to competent authorities. This raises the potential for a clinical department to receive a case that the drug safety department is unaware of. However, the most significant inefficiency probably lies in the preparation of aggregate reports and regulatory documents that need to be prepared using data originating from both databases. In a resource-constrained world, unnecessary activities and associated costs are unwelcome, particularly when they are avoidable. The Clinical Data Interchange Consortium (CDISC) has set the standards for clinical trial data, while the International Conference of Harmonization (ICH) dictates drug safety ones. CDISC is expanding its Clinical Data Acquisition Standards Harmonisation (CDASH) model to capture adverse event data associated with ICH E2B. All common data items have two labels that have been mapped. This exercise is showing that there is no scientific justification for data segregation. The differences between these two standards can be attributed to conventions or arise from new technology that renders unnecessary the keying in of certain context information (dates, times and recorder ID). Once this mapping is completed then a common data acquisition process will become feasible. This is the prerequisite to ultimately unifying the two databases and to implementing more efficient processes. The Authors also propose a new workflow to provide safety with the array of benefits that technology and process harmonisation offers and ultimately unifying the clinical drug safety processes. ",0
4587,23656522,Cancer 'survivor-care': II. Disruption of prefrontal brain activation top-down control of working memory capacity as possible mechanism for chemo-fog/brain (chemotherapy-associated cognitive impairment),"Cancer chemotherapy-associated cognitive impairments (termed 'chemo-fog' or 'chemo-brain'), particularly in memory, have been self-reported or identified in cancer survivors previously treated with chemotherapy. Although a variety of deficits have been detected, a consistent theme is a detriment in visuospatial working memory. The parietal cortex, a major site of storage of such memory, is implicated in chemotherapy-induced damage. However, if the findings of two recent publications are combined, the (pre)frontal cortex might be an equally viable target. Two recent studies, one postulating a mechanism for 'top-down control' of working memory capacity and another visualizing chemotherapy-induced alterations in brain activation during working memory processing, are reviewed and integrated. A computational model and the proposal that the prefrontal cortex plays a role in working memory via top-down control of parietal working memory capacity is consistent with a recent demonstration of decreased frontal hyperactivation following chemotherapy. Chemotherapy-associated impairment of visuospatial working memory might include the (pre)frontal cortex in addition to the parietal cortex. This provides new opportunity for basic science and clinical investigation. ",0
4588,23656635,Cytologic appearance of retinal cells included in a fine-needle aspirate of a meningioma around the optic nerve of a dog,"A 6-year-old Wirehair Dachshund had a meningioma around the optic nerve that caused exophthalmos. A benign mesenchymal tumor was suspected based on the cytologic pattern of a fine-needle aspirate, and a meningioma was diagnosed by histopathologic examination. In addition to the meningioma cells, the cytologic smears included groups of cells from apparently 4 layers of normal retina. In particular, uniform rod-shaped structures in the cytologic sample could suggest rod-shaped bacteria, but these structures were identified as cylindrical outer segments of photoreceptor rod cells. Other retinal structures recognized included pigmented epithelial layer cells with their uniquely formed pigment granules, the characteristic bi-lobed, cleaved nuclei from the outer nuclear layer, and nerve tissue likely from the outer plexiform layer of the retina. ",0
4589,23656646,WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta,"This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T?G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C?A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.",0
4590,23656754,Grape juice concentrate protects reproductive parameters of male rats against cadmium-induced damage: a chronic assay,"The aim of the present study was to investigate the effects of long-term grape juice concentrate (GJC) consumption, in two dosages, on the reproductive parameters of cadmium-exposed male rats. The effects of the concentrate on body mass gain, plasma testosterone levels, reproductive organ weights, daily sperm production, sperm morphology, testis histopathological and histomorphometrical parameters, and testicular antioxidant markers were investigated. Wistar rats (n 54) were distributed into six groups: CdCl2; cadmium and grape juice I (1·18 g/kg per d); cadmium and grape juice II (2·36 g/kg per d); grape juice I (1·18 g/kg per d); grape juice II (2·36 g/kg per d); control. A single dose of CdCl2 (1·2 mg/kg body weight (BW)) was injected intraperitoneally and the grape juice was administered orally for 56 d. The results indicated that cadmium changed all reproductive and antioxidant parameters. At dosage I (1·18 g/kg BW), GJC consumption did not show the effects against cadmium-induced damages. In contrast, at dosage II (2·36 g/kg BW), the GJC improved the gonadosomatic index (P= 0·003), serum testosterone levels (P= 0·001), the relative weight of epididymis (P= 0·013) and ventral prostate (P= 0·052), the percentage of normal sperm (P= 0·001), and histopathological and histomorphometrical parameters. In addition, at this dosage, normalisation of the enzymatic activity of superoxide dismutase (P= 0·001) and of testicular levels of glutathione (P= 0·03) were observed. The parameters of the non-exposed rats did not depict significant alterations. In conclusion, the product was able to act as a protector of reproductive function against cadmium-induced damage. Such a property was expressed in a dose-dependent manner as the more effective dose was dosage II. The GJC acted possibly by antioxidant mechanisms.  ",0
4591,23656809,Quality of life survey on patients with peripheral facial paralysis by using Chinese version of the FaCE scale],"To explore the health related quality of life (QOL) status of patients with peripheral facial paralysis. By introducing, translating and adjusting of the FaCE (Facial Clinimetric Evaluation) scale, a Chinese version came into being. The scale was further strictly tested in eighty-one patients with peripheral facial paralysis and thirty healthy volunteers. The feasibility, reliability, validity and responsibility of Chinese version of FaCE scale all passed the test. The split-half reliability, Cronbach's alpha and intraclass correlation coefficient were 0.79, 0.88 and 0.87, respectively. The criteria validity calculated between FaCE and SF-36 was 0.41 (P < 0.05). Factor analysis of the construct validity showed that the 15 items were classified into six domains, which were in accordance with the original version. Every domain was sensitive and effective to discriminate between patient population and healthy population (P < 0.05). Chinese version of FaCE scale showed significant correlation with HBGS and SBGS scores (r = -0.40 and 0.42, P < 0.05). Chinese version of the FaCE scale can effectively assess QOL status of patients with facial paralysis in China. ",0
4592,23656835,Burden of self-reported acute gastrointestinal illness in China: a population-based survey,"Acute gastrointestinal illness (AGI) is an important public-health problem worldwide. Previous national studies of the incidence of AGI in China were performed decades ago, and detailed information was not available. This study therefore sought to determine the magnitude, distribution, and burden of self-reported AGI in China. Twelve-month, retrospective face-to-face surveys were conducted in 20 sentinel sites from six provinces between July 2010 and July 2011. In total, 39686 interviews were completed. The overall adjusted monthly prevalence of AGI was 4.2% (95% confidence interval, 4.0-4.4), corresponding to 0.56 episodes of AGI per person-year. Rates of AGI were highest in children aged < 5 years. Healthcare was sought by 56.1% of those reporting illness. Of the cases who visited a doctor, 32.7% submitted a stool sample. The use of antibiotics was reported by 49.7% of the cases who sought medical care and 54.0% took antidiarrhoeals. In the multivariable model, gender, age, education, household type, residence, season, province and travel were significant risk factors of being a case of AGI. This first population-based study in China indicated that AGI represents a substantial burden of health. Further research into the specific pathogens is needed to better estimate the burden of AGI and foodborne disease in China. ",0
4593,23657402,MicroRNA-21 in scleroderma fibrosis and its function in TGF-β-regulated fibrosis-related genes expression,"Uncontrolled fibrosis in multiple organs is the main cause of death in systemic sclerosis (SSc), and transforming growth factor-β (TGF-β) activation plays a fundamental role in the process. Our previous study demonstrated that miR-21 was significantly up-regulated in SSc fibroblasts. Here, we found that TGF-β regulated the expression of miR-21 and fibrosis-related genes, and decreased Smad7 expression. Over-expression of miR-21 in fibroblasts decreased the levels of Smad7, whereas knockdown of miR-21 increased its expression. Further study using a reporter gene assay demonstrated Smad7 was a direct target of miR-21. Similar to human SSc, the expression of miR-21 increased in the bleomycin induced skin fibrosis. Inhibition of fibrosis by treatment with anti-fibrosis drug bortezomib restored the levels of miR-21 and Smad7. MiR-21 may function in an amplifying circuit to enhance TGF-β signaling events in SSc fibrosis, and suggesting that miR-21 may act as a potential therapeutic target.  ",0
4594,23657645,"Development of gelatin flakes, a new type of anti-adhesive material: a preliminary study of in vivo rat adhesion models","To overcome the problems associated with sheet- or film-type anti-adhesive materials, we developed a new type of anti-adhesive material, gelatin flakes. We made two types of gelatin flakes with or without thermal cross-linking, and preliminarily examined their basic properties and the anti-adhesive efficacy using a rodent adhesion model. Both types of the gelatin flakes rapidly turned into gel and tightly attached the injured surfaces, absorbing the moisture and blood, when applied onto the abraded sites of rats. In addition, these flakes could be sprayed into the desired area by compressed air through a device with a long, thin tube, which could be used in laparoscopic surgery. The anti-adhesive effects of both types of gelatin flakes were similar, and both types were significantly superior compared to the non-treated group. Although further investigations are necessary, the gelatin flakes have unique and useful properties and satisfactory anti-adhesive effects, which indicate that they may be applicable in laparoscopic surgery.  ",0
4595,23657854,Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI,"We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI-/-) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNβ and IFNαs: IFNβ expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNβ. We show by immunohistology and study of isolated cells that IFNβ is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2. ",0
4596,23658029,Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs,"The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. ",0
4597,23658154,"The novel gene tank, a tumor suppressor homolog, regulates ethanol sensitivity in Drosophila","In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex-specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila. ",0
4598,23675659,Current and future therapies for hepatitis C virus infection,"Only 20 years after the discovery of the Hepatitis C Virus (HCV), a cure is now likely for most people affected by this chronic infection, which carries a substantial disease burden, not only in the United States but also worldwide. The recent approval of two direct-acting antiviral agents that specifically inhibit viral replication has dramatically increased the viral clearance rate, from less than 10% with the initial regimen of interferon monotherapy to more than 70% with current therapy. Moreover, many other drugs targeting viral or host factors are in development, and some will almost certainly be approved in the coming years. The questions of who should be treated and with what regimen will be increasingly complex to address and will require careful consideration. As therapy improves, systemwide identification and care of patients who need treatment will be the next challenge. Because most infected persons are unaware of their diagnosis, the Centers for Disease Control and Prevention recently recommended screening for HCV all persons born between 1945 and 1965.(,) It is anticipated that in the course of such a screening process, a large number of persons will be found to be infected with the virus; whether it will be possible to treat all these people is unclear. This article reviews the current therapy for HCV infection and the landscape of drug development.",0
4599,23703590,"The small molecule, genistein, increases hepcidin expression in human hepatocytes","Hepcidin, a peptide hormone that decreases intestinal iron absorption and macrophage iron release, is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. Endogenous stimulants of Hepcidin transcription include bone morphogenic protein 6 (BMP6) and interleukin-6 (IL-6) by effects on mothers against decapentaplegic homolog (Smad)4 or signal transducer and activator of transcription (Stat)3, respectively. We conducted a small-scale chemical screen in zebrafish embryos to identify small molecules that modulate hepcidin expression. We found that treatment with the isoflavone, genistein, from 28-52 hours postfertilization in zebrafish embryos enhanced Hepcidin transcript levels, as assessed by whole-mount in situ hybridization and quantitative real-time reverse-transcriptase polymerase chain reaction. Genistein's stimulatory effect was conserved in human hepatocytes: Genistein treatment of HepG2 cells increased both Hepcidin transcript levels and promoter activity. We found that genistein's effect on Hepcidin expression did not depend on estrogen receptor signaling or increased cellular iron uptake, but was impaired by mutation of either BMP response elements or the Stat3-binding site in the Hepcidin promoter. RNA sequencing of transcripts from genistein-treated hepatocytes indicated that genistein up-regulated 68% of the transcripts that were up-regulated by BMP6; however, genistein raised levels of several transcripts involved in Stat3 signaling that were not up-regulated by BMP6. Chromatin immunoprecipitation and ELISA experiments revealed that genistein enhanced Stat3 binding to the Hepcidin promoter and increased phosphorylation of Stat3 in HepG2 cells. CONCLUSION: Genistein is the first small-molecule experimental drug that stimulates Hepcidin expression in vivo and in vitro. These experiments demonstrate the feasibility of identifying and characterizing small molecules that increase Hepcidin expression. Genistein and other candidate molecules may subsequently be developed into new therapies for iron overload syndromes.",0
4600,23703735,Microbiota-liver axis in hepatic disease,"Accumulating evidence indicates that the gut microbiota, long appreciated to be a key determinant of intestinal inflammation, is also playing a key role in chronic inflammatory disease of the liver. Such studies have yielded a general central hypothesis whereby microbiota products activate the innate immune system to drive proinflammatory gene expression, thus promoting chronic inflammatory disease of the liver. This article reviews the background supporting this hypothesis, outlines how it can potentially explain classic and newly emerging epidemiological chronic inflammatory liver disease, and discusses potential therapeutic means to manipulate the microbiota so as to prevent and/or treat liver disease.",0
4601,23703790,Signal transducer and activator of transcription 3 is a proviral host factor for hepatitis C virus,"Host factors play an important role in all facets of the hepatitis C virus (HCV) life cycle and one such host factor is signal transducer and activator of transcription 3 (STAT3). The HCV core protein has been shown to directly interact with and activate STAT3, while oxidative stress generated during HCV replication in a replicon-based model also induced STAT3 activation. However, despite these findings the precise role of STAT3 in the HCV life cycle remains unknown. We have established that STAT3 is actively phosphorylated in the presence of replicating HCV. Furthermore, expression of a constitutively active form of STAT3 leads to marked increases in HCV replication, whereas, conversely, chemical inhibition and small interfering RNA (siRNA) knockdown of STAT3 leads to significant decreases in HCV RNA levels. This strongly implicates STAT3 as a proviral host factor. As STAT3 is a transcription factor, up-regulation of a distinct set of STAT3-dependent genes may create an environment that is favorable for HCV replication. However, STAT3 has recently been demonstrated to positively regulate microtubule (MT) dynamics, by way of a direct sequestration of the MT depolymerizing protein Stathmin 1 (STMN1), and we provide evidence that STAT3 may exert its effect on the HCV life cycle by way of positive regulation of MT dynamics. CONCLUSION: We have demonstrated that STAT3 plays a role in the life cycle of HCV and have clarified the role of STAT3 as a proviral host factor.",0
4602,23738510,A congenital neutrophil defect syndrome associated with mutations in VPS45,"BACKGROUND: Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity. METHODS: We clinically evaluated seven children from five families who had neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly. To identify the causative gene, we performed homozygosity mapping using single-nucleotide polymorphism arrays, whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, a real-time quantitative polymerase-chain-reaction assay, immunohistochemistry, flow cytometry, fibroblast motility assays, measurements of apoptosis, and zebrafish models. Correction experiments were performed by transfecting mutant fibroblasts with the nonmutated gene. RESULTS: All seven affected children had homozygous mutations (Thr224Asn or Glu238Lys, depending on the child's ethnic origin) in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system. The level of VPS45 protein was reduced, as were the VPS45 binding partners rabenosyn-5 and syntaxin-16. The level of ?1 integrin was reduced on the surface of VPS45-deficient neutrophils and fibroblasts. VPS45-deficient fibroblasts were characterized by impaired motility and increased apoptosis. A zebrafish model of vps45 deficiency showed a marked paucity of myeloperoxidase-positive cells (i.e., neutrophils). Transfection of patient cells with nonmutated VPS45 corrected the migration defect and decreased apoptosis. CONCLUSIONS: Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. (Funded by the National Human Genome Research Institute and others.).",0
4603,23738515,Characterization of uterine leiomyomas by whole-genome sequencing,"BACKGROUND: Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. METHODS: We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women. RESULTS: Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages. CONCLUSIONS: Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.).",0
4604,23744538,Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice,"The liver-derived peptide hepcidin controls the balance between iron demand and iron supply. By inhibiting the iron export activity of ferroportin, hepcidin modulates iron absorption and delivery from the body's stores. The regulation of hepcidin, however, is not completely understood and includes a variety of different signals. We studied iron metabolism and hepcidin expression in mice constitutively overexpressing erythropoietin (Epo) (Tg6 mice), which leads to excessive erythropoiesis. We observed a very strong down-regulation of hepcidin in Tg6 mice that was accompanied by a strong increase in duodenal expression of ferroportin and divalent metal tranporter-1, as well as enhanced duodenal iron absorption. Despite these compensatory mechanisms, Tg6 mice displayed marked circulating iron deficiency and low levels of iron in liver, spleen, and muscle. To elucidate the primary signal affecting hepcidin expression during chronically elevated erythropoiesis, we increased iron availability by either providing iron (thus further increasing the hematocrit) or reducing erythropoiesis-dependent iron consumption by means of splenectomy. Both treatments increased liver iron and up-regulated hepcidin expression and the BMP6/SMAD pathway despite continuously high plasma Epo levels and sustained erythropoiesis. This suggests that hepcidin expression is not controlled by erythropoietic signals directly in this setting. Rather, these results indicate that iron consumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and hepcidin. Analysis of the BMP6/SMAD pathway targets showed that inhibitor of DNA binding 1 (ID1) and SMAD7, but not transmembrane serine protease 6 (TMPRSS6), were up-regulated by increased iron availability and thus may be involved in setting the upper limit of hepcidin. CONCLUSION: We provide evidence that under conditions of excessive and effective erythropoiesis, liver iron regulates hepcidin expression through the BMP6/SMAD pathway.",0
4605,23744636,Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis,"""Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by nonradiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the """"bias,"""" """"precision,"""" and """"accuracy"""" of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG), and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores (differences between mGFR and estimated GFR [eGFR] or between mGFR and CrCl, or between mGFR and CG equation for each subject) (RMSE = 23.56) was significantly better than that of CrCl (37.69, P = 0.001), CG (RMSE = 36.12, P = 0.002), and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P = 0.024), CG (P = 0.0001), 4-variable MDRD (P = 0.027), and CKD-EPI creatinine 2009 (P = 0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%. CONCLUSION: The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.""",0
4606,23775894,"Human serum leads to differentiation of human hepatoma cells, restoration of very-low-density lipoprotein secretion, and a 1000-fold increase in HCV Japanese fulminant hepatitis type 1 titers","In this study, we differentiated the human hepatoma cell line Huh7.5 by supplementing tissue culture media with human serum (HS) and examined the production of hepatitis C virus (HCV) by these cells. We compared the standard tissue culture protocol, using media supplemented with 10% fetal bovine serum (FBS), to media supplemented with 2% HS. Cells cultured in HS undergo rapid growth arrest, have a hepatocyte-like morphology, and increase the expression of hepatocyte differentiation markers. In addition, expression of cell adhesion proteins claudin-1, occludin, and e-cadherin are also increased. The lipid droplet content of these cells is highly increased, as are key lipid metabolism regulators liver X receptor alpha, peroxisome proliferator-activated receptor (PPAR)-?, and PPAR-?. Very-low-density lipoprotein secretion, which is absent in FBS-grown cells, is restored in Huh7.5 cells that are cultured in HS. All these factors have been implicated in the life cycle of HCV. We show that viral production of Japanese fulminant hepatitis type 1 increases 1,000-fold when cells are grown in HS, compared to standard FBS culture conditions. The virus produced under these conditions is associated with apolipoprotein B, has a lower density, higher specific infectivity, and has a longer half-life than virus produced in media supplemented with FBS. CONCLUSION: We describe a convenient, cost-effective method to produce hepatocyte-like cells, which produce large amounts of virus that more closely resemble HCV present in serum of infected patients.",0
4607,23775920,Isolate-dependent use of claudins for cell entry by hepatitis C virus,"Hepatitis C Virus (HCV) entry involves at least four cellular factors, including CD81, the scavenger receptor class B type I (SCARB-1), occludin (OCLN), and claudin-1 (CLDN1). In addition, CLDN6 and CLDN9 have been shown to substitute for CLDN1 as HCV entry factors in human nonliver cells. We examined the role of different CLDN proteins during HCV entry by using cell lines expressing either predominantly CLDN1 (Huh-7.5) or CLDN6 (HuH6). Huh-7.5 cells were susceptible to all tested HCV isolates, whereas HuH6 cells were only permissive to some viral strains. Silencing of CLDN6 in HuH6 cells revealed that these cells are infected in a CLDN6-dependent fashion, and ectopic expression of CLDN1 or CLDN6 in 293T cells lacking endogenous CLDN expression confirmed that only some HCV strains efficiently use CLDN6 for infection. CLDN1-specific neutralizing antibodies (Abs) fully abrogated infection of Huh-7.5 cells by isolates that use CLDN1 only, whereas viruses with broad CLDN tropism were only partially inhibited by these Abs. Importantly, infection by these latter strains in the presence of anti-CLDN1 Ab was further reduced by silencing CLDN6, suggesting that viruses with broad CLDN usage escape CLDN1-specific Abs by utilization of CLDN6. Messenger RNA (mRNA) levels of HCV entry factors in liver biopsies of HCV patients infected with different genotype and with variable degree of liver fibrosis were determined. Uniformly high levels of CD81, SCARB-1, OCLN, and CLDN1 mRNA were detected. In contrast, abundance of CLDN6 mRNA was highly variable between patients. CONCLUSION: These findings highlight differential CLDN usage by HCV isolates, which may evolve based on variable expression of CLDN proteins in human liver cells. Broad CLDN tropism may facilitate viral escape from CLDN1-specific therapeutic strategies.",0
4608,23787765,Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis,"Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T-cell (Treg) impairments. Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. Here, we describe multiple CD39(pos) Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39(pos) Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4(pos) CD25(high) , CD4(pos) CD25(high) CD39(pos) , and CD4(pos) CD25(high) CD39(neg) subsets to suppress both proliferation of effector T cells and interleukin (IL)-17 production was evaluated. In AIH, CD39(pos) Tregs are decreased in frequency, exhibit limited adenosine triphosphate/adenosine diphosphate hydrolysis activity, and fail to suppress IL-17 production by effector CD4 T cells. Moreover, these CD39(pos) Tregs display a more proinflammatory profile in AIH, which is characterized by elevated CD127 positivity, and a greater propensity to produce interferon-gamma or IL-17 upon challenge with proinflammatory stimuli. CONCLUSIONS: In AIH, CD39(pos) Tregs are decreased in number, fail to adequately hydrolyze proinflammatory nucleotides and do not efficiently suppress IL-17 production by effector CD4 T cells. CD39(pos) Tregs show plasticity and are unstable upon proinflammatory challenge, suggesting that defective immunoregulation in AIH might result not only from reduced Treg number and function, but also from increased conversion of Tregs into effector cells.",0
4609,23821142,"Aging, age-related diseases and peroxisomes","Human aging is considered as one of the biggest risk factors for the development of multiple diseases such as cancer, type-2 diabetes, and neurodegeneration. In addition, it is widely accepted that these age-related diseases result from a combination of various genetic, lifestyle, and environmental factors. As biological aging is a complex and multifactorial phenomenon, the molecular mechanisms underlying disease initiation and progression are not yet fully understood. However, a significant amount of evidence supports the theory that oxidative stress may act as a primary etiologic factor. Indeed, many signaling components like kinases, phosphatases, and transcription factors are exquisitely sensitive to the cellular redox status, and a chronic or severe disturbance in redox homeostasis can promote cell proliferation or trigger cell death. Now, almost 50 years after their discovery, there is a wealth of evidence that peroxisomes can function as a subcellular source, sink, or target of reactive oxygen and nitrogen molecules. Yet, the possibility that these organelles may act as a signaling platform for a variety of age-related processes has so far been underestimated and largely neglected. In this review, we will critically discuss the possible role of peroxisomes in the human aging process in light of the available data.  ",0
4610,23821210,"""""""Dedifferentiation"""" and high-grade transformation in salivary gland carcinomas""","""""""Dedifferentiation"""" and/or high-grade transformation (HGT) has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous low-grade adenocarcinoma, myoepithelial carcinoma, low-grade mucoepidermoid carcinoma and hyalinizing clear cell carcinoma, although the phenomenon is a rare event. Recent authors tend to preferably use the term HGT instead of """"dedifferentiation"""" in these cases. HGT-tumors are composed of conventional carcinomas juxtaposed with areas of HG morphology, usually either poorly differentiated adenocarcinoma or """"undifferentiated"""" carcinoma, in which the original line of differentiation is no longer evident. The HG component is generally composed of solid nests, sometimes occurring in cribriform pattern of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli and abundant cytoplasm. Frequent mitoses and extensive necrosis is evident. The Ki-67 labeling index is consistently higher in the HG component. p53 abnormalities have been demonstrated in the transformed component in a few examples, but the frequency varies by the histologic type. HER-2/neu overexpression and/or gene amplification is considerably exceptional. The molecular-genetic mechanisms responsible for the pathway of HGT in salivary gland carcinomas largely still remain to be elucidated. Salivary gland carcinomas with HGT have been shown to be more aggressive than conventional carcinomas with a poorer prognosis, accompanied by higher local recurrence rate and propensity for cervical lymph node metastasis, suggesting the need for wider resection and neck dissection.  """,0
4611,23821366,"Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention","The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations. ",0
4612,23821437,Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium,"Influenza is an acute infection of the respiratory tract, which affects each year millions of people. Influenza virus infection is initiated by the surface glycoprotein hemagglutinin (HA) through receptor binding and fusion of viral and endosomal membranes. HA is synthesized as a precursor protein and requires cleavage by host cell proteases to gain its fusion capacity. Although cleavage of HA is crucial for virus infectivity, little was known about relevant proteases in the human airways for a long time. Recent progress in the identification and characterization of HA-activating host cell proteases has been considerable however and supports the idea of targeting HA cleavage as a novel approach for influenza treatment. Interestingly, certain bacteria have been demonstrated to support HA activation either by secreting proteases that cleave HA or due to activation of cellular proteases and thereby may contribute to virus spread and enhanced pathogenicity. In this review, we give an overview on activation of influenza viruses by proteases from host cells and bacteria with the main focus on recent progress on HA cleavage by proteases HAT and TMPRSS2 in the human airway epithelium. In addition, we outline investigations of HA-activating proteases as potential drug targets for influenza treatment.  ",0
4613,23821578,"Gleason pattern 5 is the strongest pathologic predictor of recurrence, metastasis, and prostate cancer-specific death in patients receiving salvage radiation therapy following radical prostatectomy","The presence of Gleason pattern 5 (GP5) at radical prostatectomy (RP) has been associated with worse clinical outcome; however, this pathologic variable has not been assessed in patients receiving salvage radiation therapy (SRT) after a rising prostate-specific antigen level. A total of 575 patients who underwent primary RP for localized prostate cancer and subsequently received SRT at a tertiary medical institution were reviewed retrospectively. Primary outcomes of interest were biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM), which were assessed via univariate analysis and Fine and Grays competing risks multivariate models. On pathologic evaluation, 563 (98%) patients had a documented Gleason score (GS). The median follow-up post-SRT was 56.7 months. A total of 60 (10.7%) patients had primary, secondary, or tertiary GP5. On univariate analysis, the presence of GP5 was prognostic for BF (hazard ratio [HR] 3.3; P < .0001), DM (HR:11.1, P < .0001), and PCSM (HR:8.8, P < .0001). Restratification of the Gleason score to include GP5 as a distinct entity resulted in improved prognostic capability. Patients with GP5 had clinically worse outcomes than patients with GS8(4+4). On multivariate analysis, the presence of GP5 was the most adverse pathologic predictor of BF (HR 2.9; P < .0001), DM (HR 14.8; P < .0001), and PCSM (HR 5.7; P < .0001). In the setting of SRT for prostate cancer, the presence of GP5 is a critical pathologic predictor of BF, DM, and PCSM. Traditional GS risk stratification fails to fully utilize the prognostic capabilities of individual Gleason patterns among men receiving SRT post-RP. ",0
4614,23822215,The effect of chronic prenatal hypoxia on the development of mature neurons in the cerebellum,"Adverse intrauterine circumstances can result in abnormal brain development, and can contribute to many neurological disorders such as cerebral palsy and cognitive and behavioral deficits. These neurological problems are caused by conditions that cause chronic placental insufficiency (CPI), such as hypoxia and acidemia. Hypoxia has been implicated in structural alterations of the cerebellum during development; however, the changes to the cerebellar external granular layer (EGL) induced by chronic prenatal hypoxia are not well understood. We therefore investigated the effect of chronic prenatal hypoxia on the development of mature neurons in the EGL using the guinea pig CPI model. Unilateral uterine artery ligation was performed at 30 to 32 days of gestation (dg) - with term defined as approximately 67 dg. At 50 dg, 60 dg, and one week after birth, fetuses and newborns were sacrificed and assigned to either the growth-restricted (GR) or control (no ligation) group. After fixation, dissection, and sectioning of cerebellar tissue from these animals, immunohistochemistry was performed with antibodies raised to hypoxia-induced factor 1α (Hif1α), Pax6, NeuroD, and NeuN. The induction of hypoxia was confirmed by the presence of Hif1α immunoreactivity in the EGL of the GR (but not control) fetuses. The only other cellular immunoreactivity found in any of the tissues was to the NeuN antibody, which is a marker of mature neurons. The proportion of NeuN-immunoreactive (NeuN-IR) cells to the total number of cells in the EGL did not differ between the GR and control groups at 50 and 60 dg. The density of NeuN-IR cells was greater in GR fetuses than in controls at 60 dg (P < 0.05) but not at 50 dg. At one week after birth, the EGL was just one cell thick, and only a few NeuN-IR cells could be observed in both groups. TUNEL assays performed to enable the evaluation of apoptosis in the cerebellar EGL revealed that cell death was not affected by hypoxia at 50 dg, 60 dg, and one week after birth. These findings indicate that chronic prenatal hypoxia affects the process of neuronal production late in fetal life, but that this effect does not persist postnatally. ",0
4615,23822419,"BrachyView, a novel inbody imaging system for HDR prostate brachytherapy: design and Monte Carlo feasibility study","High dose rate (HDR) brachytherapy is a form of radiation therapy for treating prostate cancer whereby a high activity radiation source is moved between predefined positions inside applicators inserted within the treatment volume. Accurate positioning of the source is essential in delivering the desired dose to the target area while avoiding radiation injury to the surrounding tissue. In this paper, HDR BrachyView, a novel inbody dosimetric imaging system for real time monitoring and verification of the radioactive seed position in HDR prostate brachytherapy treatment is introduced. The current prototype consists of a 15 × 60 mm(2) silicon pixel detector with a multipinhole tungsten collimator placed 6.5 mm above the detector. Seven identical pinholes allow full imaging coverage of the entire treatment volume. The combined pinhole and pixel sensor arrangement is geometrically designed to be able to resolve the three-dimensional location of the source. The probe may be rotated to keep the whole prostate within the transverse plane. The purpose of this paper is to demonstrate the efficacy of the design through computer simulation, and to estimate the accuracy in resolving the source position (in detector plane and in 3D space) as part of the feasibility study for the BrachyView project. Monte Carlo simulations were performed using the GEANT4 radiation transport model, with a (192)Ir source placed in different locations within a prostate phantom. A geometrically accurate model of the detector and collimator were constructed. Simulations were conducted with a single pinhole to evaluate the pinhole design and the signal to background ratio obtained. Second, a pair of adjacent pinholes were simulated to evaluate the error in calculated source location. Simulation results show that accurate determination of the true source position is easily obtainable within the typical one second source dwell time. The maximum error in the estimated projection position was found to be 0.95 mm in the imaging (detector) plane, resulting in a maximum source positioning estimation error of 1.48 mm. HDR BrachyView is a feasible design for real-time source tracking in HDR prostate brachytherapy. It is capable of resolving the source position within a subsecond dwell time. In combination with anatomical information obtained from transrectal ultrasound imaging, HDR BrachyView adds a significant quality assurance capability to HDR brachytherapy treatment systems. ",0
4616,23822592,Which is false: oxaliplatin or fluoropyrimidine? An analysis of patients with KRAS wild-type metastatic colorectal cancer treated with first-line epidermal growth factor receptor monoclonal antibody,"This meta-analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin-based chemotherapy treatment improves efficacy in KRAS wild-type metastatic colorectal cancer (mCRC), and whether infusional 5-fluorouracil (5-FU) and oxaliplatin is a preferred combination for EGFR mAbs. Oxaliplatin (including treatment), EGFR mAbs, first-line treatment, KRAS wild-type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time-to-event outcomes of overall survival (OS) and progression-free survival (PFS) were analyzed using HRs (hazard ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. A total of 1767 patients who were KRAS wild-type were included in this meta-analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin-based chemotherapy in patients with KRAS wild-type mCRC as first-line treatment resulted in significant improvements in PFS (HR = 0.88; 95% confidence interval (CI), 0.79-0.99; P = 0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14-1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR = 0.96; 95% CI, 0.85-1.08; P = 0.48). However, the differences in OS and PFS were not significant when mAbs were added to bolus 5-FU or capecitabine-based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5-FU and oxaliplatin combination (P = 0.06; PFS, HR = 0.76; 95% CI, 0.65-0.86; P = 0.0002), and even OS was marginally significant, which was consistent with the subgroup analysis of cetuximab and panitumumab. EGFR mAbs combined with oxaliplatin and an infusional 5-FU regimen was associated with significantly improved RR, PFS and OS as first-line treatment in KRAS wild-type mCRC. ",0
4617,23822644,Combined subthreshold dose inhibition of myosin light chain phosphorylation and MMP-2 activity provides cardioprotection from ischaemic/reperfusion injury in isolated rat heart,"Phosphorylation and degradation of myosin light chain 1 (MLC1) during myocardial ischaemia/reperfusion (I/R) injury is a well-established phenomenon. It has been established that MMP-2 is involved in MLC1 degradation and that this degradation is increased when MLC1 is phosphorylated. We hypothesized that simultaneous inhibition of MLC1 phosphorylation and MMP-2 activity will protect hearts from I/R injury. As phosphorylation of MLC1 and MMP-2 activity is important for normal heart function, we used a cocktail consisting combination of low (subthreshold for any protective effect alone) doses of MLC kinase, MMP-2 inhibitors and subthreshold dose of an MLC phosphatase activator. Isolated rat hearts were subjected to 20 min of global, no-flow ischaemia and 30 min reperfusion in the absence and presence of inhibitors of MLC1 phosphorylation and degradation. The recovery of cardiac function was improved in a concentration-dependent manner by the MLC kinase inhibitor, ML-7 (1-5 μM), the MLC phosphatase activator, Y-27632 (0.05-1 μM) or the MMP inhibitor, doxycycline (Doxy, 1-30 μM). Co-administration of subthreshold doses of ML-7 (1 μM) and Y-27632 (0.05 μM) showed a potential synergistic effect in protecting cardiac contractility and MLC1 levels in I/R hearts. Further combination with a subthreshold concentration of Doxy (1 μM) showed additional protection that resulted in full recovery to control levels. The results of this study exemplify a novel low-dose multidrug approach to pharmacological prevention of reperfusion injury that will enable a reduction of unwanted side effects and/or cytotoxicity associated with currently available MMP-2 and kinase inhibiting drugs. ",0
4618,23822756,Gene variants associated with antisocial behaviour: a latent variable approach,"The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation programme in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed. Eight single-nucleotide polymorphisms (SNPs) from eight genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all eight genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid and cholinergic signalling as well as stress response pathways in mediating susceptibility to antisocial behaviour. This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential 'co-action' of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the aetiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a 'shared' variance across genetic risk alleles associated with complex neuropsychiatric dimensional phenotypes using relatively small numbers of well-characterized research participants. ",0
4619,23822800,Virulence factors of Candida albicans isolates from the oral cavities of HIV-1-positive patients,"The present study assessed the phenotypic aspects of oral-cavity Candida albicans isolates from 300 HIV-1- positive patients, relating the most commonly investigated virulence factors (enzyme typing and germ-tube formation) to the most common morphotypes. The samples were seeded into specific media for isolation and subsequent identification using the automated Vitek 2 system. The following assays were performed for phenotypic characterization: morphotyping, germ-tube formation and enzyme typing. Out of 300 collected samples, 144 tested positive for yeasts of the Candida genus, 98 (32.7 %) of which were identified as C. albicans. The latter samples were attributed to seven different morphotypes; the three most common morphotypes were 7208 (49 %), 7308 (14.3 %) and 3208 (13.3 %). All of the C. albicans isolate samples formed germ tubes and produced the enzymes proteinase and phospholipase, with an activity classified as intermediate to high. Due to the identification of virulence factors among the analyzed samples, monitoring of HIV-1-positive patients colonized by different morphotypes must be established because these morphotypes are extremely pathogenic and can trigger severe fungal infections.  ",0
4620,23822827,Primary uveal lymphoma effectively managed with oral chlorambucil: a case report,"Ocular lymphomas account for five to 10 percent of all extra-nodal lymphomas. Primary uveal lymphoma is quite a rare entity and usually unilateral. We present a case of a primary uveal lymphoma with conjunctival and orbital extension, successfully managed with oral chlorambucil. A 71-year-old Caucasian man presented to our facility with visual loss in his only functioning eye (left). On clinical examination, we found a conjunctival lesion with a choroidal infiltration and a secondary retinal detachment. Ultrasound and magnetic resonance imaging studies revealed a choroidal tumour mass and two other lesions around the optic nerve. Results from an incisional biopsy revealed a low-grade B-cell lymphoma (CD20+, CD43+, bcl2+, CD3-). A diagnosis of primary uveal lymphoma was made. Our patient was started on a chemotherapy regime with no effect, and then oral chlorambucil was administered, with a relatively good result. At 10 months after the start of chlorambucil treatment, a best-corrected visual acuity of 0.4 was recorded, the choroidal mass had practically disappeared and the extra-ocular lesions had shrunk. In all, 61 to 80 cases of primary uveal lymphoma have already been described in the literature. Generally, it is an indolent tumor with a good prognosis. However, there are some reports of aggressive tumor behavior a few years after initial diagnosis (about eight percent of cases). Other treatment options are orbital irradiation at low doses (20 to 40 Gy) or steroid administration. This is the first documented report of the efficacy of oral chlorambucil in the treatment of primary uveal lymphoma. ",0
4621,23823021,Involvement of exercise-induced macrophage migration inhibitory factor in the prevention of fatty liver disease,"Physical inactivity can lead to obesity and fat accumulation in various tissues. Critical complications of obesity include type II diabetes and nonalcoholic fatty liver disease (NAFLD). Exercise has been reported to have ameliorating effects on obesity and NAFLD. However, the underlying mechanism is not fully understood. We showed that liver expression of macrophage migration inhibitory factor (MIF) was increased after 4 weeks of treadmill exercise. Phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase in human hepatocyte cell lines was enhanced after MIF treatment. These responses were accompanied by increases in lipid oxidation. Moreover, inhibition of either AMPK or cluster of differentiation 74 resulted in inhibition of MIF-induced lipid oxidation. Furthermore, the administration of MIF to a human hepatocyte cell line and mice liver reduced liver X receptor agonist-induced lipid accumulation. Taken together, these results indicate that MIF is highly expressed in the liver during physical exercise and may prevent hepatic steatosis by activating the AMPK pathway.  ",0
4622,23823043,Time orientation and visual construction subdomains of the MMSE as independent risk factors for hip fractures,"Hip fractures may result in severe morbidity and mortality among elderly patients. Many risk factors for hip fracture have been identified, including cognitive impairment. The authors used the Mini-Mental State Examination (MMSE), a screen test for cognitive impairment, as the study material for their hip fracture survey. The authors hypothesized that certain subdomains would have a strong association with hip fractures. A total of 217 individuals with hip fracture and 215 individuals without hip fractures matched by age and sex were recruited for the study. A standardized questionnaire was used to register their MMSE performance and demographic data. Scores for these subdomains were analyzed using conditional logistic regression with adjustment of 5 clinically important risk factors for hip fractures, including educational level, difficulty with activities of daily living, physical activities, body mass index, and bone mineral density. In univariate analyses, those subdomains with lower scores had significantly higher hip fracture risks. In multivariate analyses, only the subdomains time orientation and visual construction remained significant. Further receiver operating characteristic curve analysis revealed that these 2 subdomains could differentiate hip fractures from nonfractures better than total MMSE. Time orientation and visual construction subdomains are strong predictors for hip fractures and can be used effectively in the hospital to screen patients at high risk of hip fractures. Prospective cohort studies are warranted to further validate this finding.  ",0
4623,23823136,"Genome-Wide Association Study of Genetic Variants in LPS-Stimulated IL-6, IL-8, IL-10, IL-1ra and TNF-α Cytokine Response in a Danish Cohort","Cytokine response plays a vital role in various human lipopolysaccharide (LPS) infectious and inflammatory diseases. This study aimed to find genetic variants that might affect the levels of LPS-induced interleukin (IL)-6, IL-8, IL-10, IL-1ra and tumor necrosis factor (TNF)-α cytokine production. We performed an initial genome-wide association study using Affymetrix Human Mapping 500 K GeneChip® to screen 130 healthy individuals of Danish descent. The levels of IL-6, IL-8, IL-10, IL-1ra and TNF-α in 24-hour LPS-stimulated whole blood samples were compared within different genotypes. The 152 most significant SNPs were replicated using Illumina Golden Gate® GeneChip in an independent cohort of 186 Danish individuals. Next, 9 of the most statistical significant SNPs were replicated using PCR-based genotyping in an independent cohort of 400 Danish individuals. All results were analyzed in a combined study among the 716 Danish individuals. Only one marker of the 500 K Gene Chip in the discovery study showed a significant association with LPS-induced IL-1ra cytokine levels after Bonferroni correction (P<10(-7)). However, this SNP was not associated with the IL-1ra cytokine levels in the replication dataset. No SNPs reached genome-wide significance for the five cytokine levels in the combined analysis of all three stages. The associations between the genetic variants and the LPS-induced IL-6, IL-8, IL-10, IL-1ra and TNF-α cytokine levels were not significant in the meta-analysis. This present study does not support a strong genetic effect of LPS-stimulated cytokine production; however, the potential for type II errors should be considered. ",0
4624,23823346,Effect of pH values of two bleaching gels on enamel microhardness,"This study evaluated the influence of bleaching gel pH and the effect of remineralizing gels after bleaching in different time intervals. Sixty bovine incisors were divided into 2 groups (n = 30). Group 1 was bleached with a 35% hydrogen peroxide (HP) acid gel and Group 2 was bleached with a 35% HP neutral gel. Each group was then divided into 3 subgroups (n = 10) according to the post-bleaching treatment used: storage in artificial saliva, application of a fluoride gel, or application of a gel consisting of fluoride, potassium nitrate, and nanostructured calcium phosphate. Specimens were stored in artificial saliva, and enamel microhardness was evaluated at 24 hours and 15 days postbleaching. Vickers microhardness data were analyzed by means of 2-way ANOVA, with repeated measurements and Bonferroni's post-hoc test. Twenty-four hours after bleaching, no significant differences were found between the bleaching gels. At 15 days postbleaching, Group 2 samples demonstrated a significant reduction in microhardness. No significant differences were found between the remineralizing gels, though all of the postbleaching treatments after the use of 35% neutral gel were able to re-establish baseline microhardness. It was concluded that neutral bleaching gel significantly reduced enamel microhardness 15 days after bleaching and that the use of remineralizing gels did not significantly enhance the microhardness of bleached enamel. However, in clinical situations, the acquired enamel pellicle protects tooth surfaces, and postbleaching, decalcified enamel would undergo recalcification. This study indicates that it is important to consider the bleaching agent's pH and composition when treating patients with reduced salivary secretion.  ",0
4625,23823407,The impact of mobile phone screen size on user comprehension of health information,"Within the field of mobile health, there is little research conducted on the impacts of mobile health technologies and applications on user comprehension of health content. In this study, we examine the difference between small, medium and large screen mobile phone that affect the user comprehension of health content. We designed an experimental study where 33 users read the contents of a health application on different mobile phone screen sizes. Each participant was timed, tracked for correctness, and gave ratings for both readability and satisfaction on each task. In addition, they were asked some questions about the contents. Results show that there was no significant impact of the screen size on user comprehension of the contents. However, it was found that participants with small screen size took longer to read the health contents.  ",0
4626,23823573,Novel surgical classification and treatment strategy for atlantoaxial dislocations,"Retrospective study of 904 patients with a diagnosis of atlantoaxial dislocation (AAD), using a novel surgical classification and treatment strategy. To describe a novel surgical classification and treatment strategy for AADs. AADs can result from a variety of etiologies, yet no comprehensive classification has been accepted that guides treatment. Because of the rarity of the cases, however, the treatment strategy has also been debated. During a period of 12 years, a total of 904 patients with a diagnosis of AAD were recruited from a single academic institution. According to the treatment algorithm that included preoperative evaluation using dynamic radiograph, reconstructive computed tomography, and skeletal traction test, the cases were classified into 4 types: I to IV. Types I and II were fused in the reduced position from a posterior approach. Type III, which were irreducible dislocations, were converted to reducible dislocations using a transoral atlantoaxial release, followed by a posterior fusion. Type IV presented with bony dislocations and required transoral osseous decompressions prior to posterior fusion. Four hundred seventy-two cases were classified as type I, 160 as type II, 268 as type III, and 4 cases as type IV. Follow-up was in the range of 2 to 12 years (average: 60.5 mo). Eight hundred and ninety-nine cases (99.4%) achieved a solid atlantoaxial fusion. Anatomic atlantoaxial reduction was achieved in 892 cases (98.7%), whereas 12 cases had a partial reduction. Neurological improvement was seen in 84.1% (512/609) of the patients with myelopathy. The overall complication rate was 9.1% (82/949). Our surgical classification and treatment strategy for AADs was applied in those 904 cases and associated with excellent clinical results with a minimal risk of complications. 4. ",0
4627,23823707,Identification and Differentiation of Verticillium Species and V. longisporum Lineages by Simplex and Multiplex PCR Assays,"Accurate species identification is essential for effective plant disease management, but is challenging in fungi including Verticillium sensu stricto (Ascomycota, Sordariomycetes, Plectosphaerellaceae), a small genus of ten species that includes important plant pathogens. Here we present fifteen PCR assays for the identification of all recognized Verticillium species and the three lineages of the diploid hybrid V. longisporum. The assays were based on DNA sequence data from the ribosomal internal transcribed spacer region, and coding and non-coding regions of actin, elongation factor 1-alpha, glyceraldehyde-3-phosphate dehydrogenase and tryptophan synthase genes. The eleven single target (simplex) PCR assays resulted in amplicons of diagnostic size for V. alfalfae, V. albo-atrum, V. dahliae including V. longisporum lineage A1/D3, V. isaacii, V. klebahnii, V. nonalfalfae, V. nubilum, V. tricorpus, V. zaregamsianum, and Species A1 and Species D1, the two undescribed ancestors of V. longisporum. The four multiple target (multiplex) PCR assays simultaneously differentiated the species or lineages within the following four groups: Verticillium albo-atrum, V. alfalfae and V. nonalfalfae; Verticillium dahliae and V. longisporum lineages A1/D1, A1/D2 and A1/D3; Verticillium dahliae including V. longisporum lineage A1/D3, V. isaacii, V. klebahnii and V. tricorpus; Verticillium isaacii, V. klebahnii and V. tricorpus. Since V. dahliae is a parent of two of the three lineages of the diploid hybrid V. longisporum, no simplex PCR assay is able to differentiate V. dahliae from all V. longisporum lineages. PCR assays were tested with fungal DNA extracts from pure cultures, and were not evaluated for detection and quantification of Verticillium species from plant or soil samples. The DNA sequence alignments are provided and can be used for the design of additional primers. ",0
4628,23824369,Traditional and new influenza vaccines,"""The challenges in successful vaccination against influenza using conventional approaches lie in their variable efficacy in different age populations, the antigenic variability of the circulating virus, and the production and manufacturing limitations to ensure safe, timely, and adequate supply of vaccine. The conventional influenza vaccine platform is based on stimulating immunity against the major neutralizing antibody target, hemagglutinin (HA), by virus attenuation or inactivation. Improvements to this conventional system have focused primarily on improving production and immunogenicity. Cell culture, reverse genetics, and baculovirus expression technology allow for safe and scalable production, while adjuvants, dose variation, and alternate routes of delivery aim to improve vaccine immunogenicity. Fundamentally different approaches that are currently under development hope to signal new generations of influenza vaccines. Such approaches target nonvariable regions of antigenic proteins, with the idea of stimulating cross-protective antibodies and thus creating a """"universal"""" influenza vaccine. While such approaches have obvious benefits, there are many hurdles yet to clear. Here, we discuss the process and challenges of the current influenza vaccine platform as well as new approaches that are being investigated based on the same antigenic target and newer technologies based on different antigenic targets. """,0
4629,23824440,Identification of acoustically similar and dissimilar vowels in profoundly deaf adults who use hearing aids and/or cochlear implants: some preliminary findings,"In this study, the authors examined the effects of aging and residual hearing on the identification of acoustically similar and dissimilar vowels in adults with postlingual deafness who use hearing aids (HAs) and/or cochlear implants (CIs). The authors used two groups of acoustically similar and dissimilar vowels to assess vowel identification. Also, the Consonant-Nucleus-Consonant Word Recognition Test (Peterson & Lehiste, 1962) and sentences from the Hearing in Noise Test (Nilsson, Soli, & Sullivan, 1994) were administered. Forty CI recipients with postlingual deafness (ages 31-81 years) participated in the study. Acoustically similar vowels were more difficult to identify than acoustically dissimilar vowels. With increasing age, performance deteriorated when identifying acoustically similar vowels. Vowel identification was also affected by the use of a contralateral HA and the degree of residual hearing prior to implantation. Moderate correlations were found between speech perception and vowel identification performance. Identification performance was affected by the acoustic similarity of the vowels. Older adults experienced more difficulty identifying acoustically similar confusable vowels than did younger adults. The findings might lend support to the ease of language understanding model (Ronnberg, Rudner, Foo, & Lunner, 2008), which proposes that the quality and perceptual robustness of acoustic input affects speech perception. ",0
4630,23825109,Loss of c-Jun N-terminal kinase-interacting protein-1 does not affect axonal transport of the amyloid precursor protein or Aβ production,"Disruption to axonal transport is an early pathological feature in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo in Alzheimer's disease since perturbation of its transport increases APP processing and production of amyloid-β peptide (Aβ) that is deposited in the brains of Alzheimer's disease patients. APP is transported anterogradely through axons on kinesin-1 motors. One favoured route for attachment of APP to kinesin-1 involves the scaffolding protein c-Jun N-terminal kinase-interacting protein-1 (JIP1), which has been shown to bind both APP and kinesin-1 light chain (KLC). However, direct experimental evidence to support a role of JIP1 in APP transport is lacking. Notably, the effect of loss of JIP1 on movement of APP through axons of living neurons, and the impact of such loss on APP processing and Aβ production has not been reported. To address these issues, we monitored how siRNA mediated loss of JIP1 influenced transport of enhanced green fluorescent protein (EGFP)-tagged APP through axons and production of endogenous Aβ in living neurons. Surprisingly, we found that knockdown of JIP1 did not affect either APP transport or Aβ production. These results have important implications for our understanding of APP trafficking in Alzheimer's disease.  ",0
4631,23825238,Exploring public discourses about emerging technologies through statistical clustering of open-ended survey questions,"""The primary method by which social scientists describe public opinion about science and technology is to present frequencies from fixed response survey questions and to use multivariate statistical models to predict where different groups stand with regard to perceptions of risk and benefit. Such an approach requires measures of individual preference which can be aligned numerically in an ordinal or, preferably, a continuous manner along an underlying evaluative dimension - generally the standard 5- or 7-point attitude question. The key concern motivating the present paper is that, due to the low salience and """"difficult"""" nature of science for members of the general public, it may not be sensible to require respondents to choose from amongst a small and predefined set of evaluative response categories. Here, we pursue a different methodological approach: the analysis of textual responses to """"open-ended"""" questions, in which respondents are asked to state, in their own words, what they understand by the term """"DNA."""" To this textual data we apply the statistical clustering procedures encoded in the Alceste software package to detect and classify underlying discourse and narrative structures. We then examine the extent to which the classifications, thus derived, can aid our understanding of how the public develop and use """"everyday"""" images of, and talk about, biomedicine to structure their evaluations of emerging technologies.  """,0
4632,23825572,Dynamics and molecular determinants of cytoplasmic lipid droplet clustering and dispersion,"Perilipin-1 (Plin1), a prominent cytoplasmic lipid droplet (CLD) binding phosphoprotein and key physiological regulator of triglyceride storage and lipolysis in adipocytes, is thought to regulate the fragmentation and dispersion of CLD that occurs in response to β-adrenergic activation of adenylate cyclase. Here we investigate the dynamics and molecular determinants of these processes using cell lines stably expressing recombinant forms of Plin1 and/or other members of the perilipin family. Plin1 and a C-terminal CLD-binding fragment of Plin1 (Plin1CT) induced formation of single dense CLD clusters near the microtubule organizing center, whereas neither an N-terminal CLD-binding fragment of Plin1, nor Plin2 or Plin3 induced clustering. Clustered CLD coated by Plin1, or Plin1CT, dispersed in response to isoproterenol, or other agents that activate adenylate cyclase, in a process inhibited by the protein kinase A inhibitor, H89, and blocked by microtubule disruption. Isoproterenol-stimulated phosphorylation of CLD-associated Plin1 on serine 492 preceded their dispersion, and live cell imaging showed that cluster dispersion involved initial fragmentation of tight clusters into multiple smaller clusters, which then fragmented into well-dispersed individual CLD. siRNA knockdown of the cortical actin binding protein, moesin, induced disaggregation of tight clusters into multiple smaller clusters, and inhibited the reaggregation of dispersed CLD into tight clusters. Together these data suggest that the clustering and dispersion processes involve a complex orchestration of phosphorylation-dependent, microtubule-dependent and independent, and microfilament dependent steps.  ",0
4633,23825651,Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry,"Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials. ",0
4634,23825712,Intravitreal diclofenac for refractory uveitic cystoid macular edema,"To evaluate the effect of a single dose of intravitreal diclofenac on best- corrected visual acuity (BCVA) and central macular thickness (CMT) in patients with refractory uveitic cystoid macular edema (CME). In this prospective non-comparative case series, 8 eyes of 8 patients with refractory CME secondary to chronic intermediate uveitis received a single intravitreal injection of diclofenac (500 µg/0.1ml) in addition to other systemic (oral prednisolone and methotraxate) and topical (betamethasone) remission maintaining drugs. Outcome measures were changes in BCVA and CMT after treatment. Mean BCVA remained relatively unchanged at 12, 24 and 36 weeks (0.69, 0.70 and 0.64 LogMAR, respectively) as compared to baseline (0.71 LogMAR). Mean CMT, however, decreased from 488 µm at baseline to 416 and 456 µm at 24 and 36 weeks, respectively. None of the changes were statistically significant. In eyes with refractory uveitic CME, intravitreal injection of diclofenac insignificantly reduced CMT but this was not associated with visual improvement. ",0
4635,23825867,THE EFFECTS OF REDUCED CIGARETTE SMOKING ON DISCOUNTING FUTURE REWARDS: AN INITIAL EVALUATION,"To determine whether reduction of smoking via contingency management in dependent smokers would decrease the discounting of delayed reinforcers compared with smokers who did not reduce their smoking, moderate to heavy cigarette smokers were randomly assigned to one of two conditions: a contingency management condition and a control condition. In three phases (baseline discounting determination for hypothetical money and cigarettes, implementation of a contingency management or control condition, and postintervention discounting determination), the procedure to reinforce reduction in cigarette smoking produced CO decreases in all subjects exposed to that procedure. Discounting decreased significantly for both cigarettes and money among the group for whom smoking reductions were reinforced, whereas the control group showed no significant change for either commodity. Reductions in smoking can lead to reductions in discounting, and increased discounting in current smokers may be a reversible effect of nicotine dependence. ",0
4636,23826093,EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study,"Electronic cigarettes (e-cigarettes) are becoming increasingly popular with smokers worldwide. Users report buying them to help quit smoking, to reduce cigarette consumption, to relieve tobacco withdrawal symptoms, and to continue having a 'smoking' experience, but with reduced health risks. Research on e-cigarettes is urgently needed in order to ensure that the decisions of regulators, healthcare providers and consumers are based on science. Methods ECLAT is a prospective 12-month randomized, controlled trial that evaluates smoking reduction/abstinence in 300 smokers not intending to quit experimenting two different nicotine strengths of a popular e-cigarette model ('Categoria'; Arbi Group Srl, Italy) compared to its non-nicotine choice. GroupA (n = 100) received 7.2 mg nicotine cartridges for 12 weeks; GroupB (n = 100), a 6-week 7.2 mg nicotine cartridges followed by a further 6-week 5.4 mg nicotine cartridges; GroupC (n = 100) received no-nicotine cartridges for 12 weeks. The study consisted of nine visits during which cig/day use and exhaled carbon monoxide (eCO) levels were measured. Smoking reduction and abstinence rates were calculated. Adverse events and product preferences were also reviewed. Declines in cig/day use and eCO levels were observed at each study visits in all three study groups (p<0.001 vs baseline), with no consistent differences among study groups. Smoking reduction was documented in 22.3% and 10.3% at week-12 and week-52 respectively. Complete abstinence from tobacco smoking was documented in 10.7% and 8.7% at week-12 and week-52 respectively. A substantial decrease in adverse events from baseline was observed and withdrawal symptoms were infrequently reported during the study. Participants' perception and acceptance of the product under investigation was satisfactory. In smokers not intending to quit, the use of e-cigarettes, with or without nicotine, decreased cigarette consumption and elicited enduring tobacco abstinence without causing significant side effects. ClinicalTrials.gov NCT01164072 NCT01164072. ",0
4637,23826460,Adalimumab (Humira) induced acute lung injury,"Male, 78. Acute lung injury due to Adalimumab. - Adalimumab. Intubated and put on mechanical ventilation. Pulmonology. Unusual or unexpected effect of treatment. Adalimumab is a recombinant human monoclonal antibody that blocks the effects of tumor necrosis factor-alpha. Adalimumab related acute lung injury is a rare form of acute respiratory distress syndrome of possible immune etiology that develops immediately after an infusion. We describe a 78 year old, male with no previous cardiac comorbidities, who developed acute lung injury (ALI) within one hour of administration of adalimumab. He was successfully treated with mechanical ventilatory support and adjuvant therapy. TNFα antagonists are a part of a new and revolutionary treatment for severe and difficult-to-treat autoimmune and inflammatory diseases. This report emphasizes that this fatal complication may occur with use of this drug. Clinicians need to be aware of this condition as prompt recognition and supportive management can prevent unwanted morbidity and mortality. ",0
4638,23826756,A feasibility study on bedside upper airway ultrasonography compared to waveform capnography for verifying endotracheal tube location after intubation,"In emergency settings, verification of endotracheal tube (ETT) location is important for critically ill patients. Ignorance of oesophageal intubation can be disastrous. Many methods are used for verification of the endotracheal tube location; none are ideal. Quantitative waveform capnography is considered the standard of care for this purpose but is not always available and is expensive. Therefore, this feasibility study is conducted to compare a cheaper alternative, bedside upper airway ultrasonography to waveform capnography, for verification of endotracheal tube location after intubation. This was a prospective, single-centre, observational study, conducted at the HRPB, Ipoh. It included patients who were intubated in the emergency department from 28 March 2012 to 17 August 2012. A waiver of consent had been obtained from the Medical Research Ethics Committee. Bedside upper airway ultrasonography was performed after intubation and compared to waveform capnography. Specificity, sensitivity, positive and negative predictive value and likelihood ratio are calculated. A sample of 107 patients were analysed, and 6 (5.6%) had oesophageal intubations. The overall accuracy of bedside upper airway ultrasonography was 98.1% (95% confidence interval (CI) 93.0% to 100.0%). The kappa value (Κ) was 0.85, indicating a very good agreement between the bedside upper airway ultrasonography and waveform capnography. Thus, bedside upper airway ultrasonography is in concordance with waveform capnography. The sensitivity, specificity, positive predictive value and negative predictive value of bedside upper airway ultrasonography were 98.0% (95% CI 93.0% to 99.8%), 100% (95% CI 54.1% to 100.0%), 100% (95% CI 96.3% to 100.0%) and 75.0% (95% CI 34.9% to 96.8%). The likelihood ratio of a positive test is infinite and the likelihood ratio of a negative test is 0.0198 (95% CI 0.005 to 0.0781). The mean confirmation time by ultrasound is 16.4 s. No adverse effects were recorded. Our study shows that ultrasonography can replace waveform capnography in confirming ETT placement in centres without capnography. This can reduce incidence of unrecognised oesophageal intubation and prevent morbidity and mortality. National Medical Research Register NMRR11100810230. ",0
4639,23827204,A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis,"Severe allergic rhinitis uncontrolled by conventional medication can substantially affect quality of life. Immunotherapy involves administering increasing doses of a specific allergen, with the aim of reducing sensitivity and symptomatic reactions. Recent meta-analyses have concluded that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are more effective than placebo in reducing symptoms. It is uncertain which route of administration is more effective and whether or not treatment is cost-effective. To determine the comparative clinical effectiveness and cost-effectiveness of SCIT and SLIT for seasonal allergic rhinitis in adults and children. Electronic databases {MEDLINE, EMBASE, The Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)], NHS Economic Evaluation Database (NHS EED)} and trial registries (from inception up to April 2011). Standard systematic review methods were used for study selection, data extraction and quality assessment. Double-blind randomised, placebo-controlled trials of SCIT or SLIT, or of SCIT compared with SLIT, and economic evaluations were included. Meta-analysis and indirect comparison meta-analysis and meta-regression were carried out. A new economic model was constructed to estimate cost-utility. Meta-analyses found statistically significant effects for SCIT and SLIT compared with placebo across a number of outcome measures and for the vast majority of subgroup analyses (type and amount of allergen, duration of treatment). There was less evidence for children, but some results in favour of SLIT were statistically significant. Indirect comparisons did not provide conclusive results in favour of either SCIT or SLIT. Economic modelling suggested that, when compared with symptomatic treatment (ST), both SCIT and SLIT may become cost-effective at a threshold of £20,000-30,000 per quality-adjusted life-year (QALY) from around 6 years, or 5 years for SCIT compared with SLIT (NHS and patient perspective). It is uncertain to what extent changes in the outcome measures used in the trials translate into clinically meaningful benefits. Cost-effectiveness estimates are based on a simple model, limited data and a number of assumptions, and should be seen as indicative only. A benefit from both SCIT and SLIT compared with placebo has been consistently demonstrated, but the extent of this effectiveness in terms of clinical benefit is unclear. Both SCIT and SLIT may be cost-effective compared with ST from around 6 years (threshold of £20,000-30,000 per QALY). Further research is needed to establish the comparative effectiveness of SCIT compared with SLIT and to provide more robust cost-effectiveness estimates. The National Institute for Health Research Health Technology Assessment programme. ",0
4640,23827374,Secondary hyperoxaluria and nephrocalcinosis due to ethylene glycol poisoning],"We report the case of a 3-year-old boy admitted to the pediatric emergency department for ethylene glycol poisoning. During hospitalization, he presented dysuria associated with crystalluria. Blood tests showed metabolic acidosis with an elevated anion gap. A renal ultrasound performed a few weeks later revealed bilateral medullary hyperechogenicity. Urine microscopic analysis showed the presence of weddellite crystals. Secondary nephrocalcinosis due to ethylene glycol intoxication was diagnosed. Hyperhydration and crystallization inhibition by magnesium citrate were initiated. Despite this treatment, persistent weddellite crystals and nephrocalcinosis were seen more than 2years after the intoxication. Ethylene glycol is metabolized in the liver by successive oxidations leading to its final metabolite, oxalic acid. Therefore, metabolic acidosis with an elevated anion gap is usually found following ethylene glycol intoxication. Calcium oxalate crystal deposition may occur in several organs, including the kidneys. The precipitation of calcium oxalate in renal tubules can lead to nephrocalcinosis and acute kidney injury. The long-term renal prognosis is related to chronic tubulointerstitial injury caused by nephrocalcinosis. Treatment of ethylene glycol intoxication is based on specific inhibitors of alcohol dehydrogenase and hemodialysis in the most severe forms, and should be started promptly.  ",0
4641,23827391,Functional characterisation of a metagenome derived family VIII esterase with a deacetylation activity on β-lactam antibiotics,"Family VIII esterases represent a poorly characterised esterase family, with high sequence identity to class C β-lactamases, peptidases and penicillin binding proteins. This study reports on the metagenomic library screening and biochemical characterisation of a novel esterase (Est22) derived from an acidic Leachate environment. The enzyme is 423 amino acids in length and contained 22 aa signal peptide. The Est22 primary structure revealed the presence of N-terminus S-x-x-K sequence, which is also highly conserved in class C β-lactamases, peptidases as well as carboxylesterases belonging to family VIII. Phylogenetic analysis using the representative sequences from class C β-lactamases and family VIII esterases indicated that Est22 is a member of family VIII esterases. Substrate specificity profiling using p-nitrophenyl esters (C2-C16) indicated that Est22 preferred shorter chain p-nitrophenyl esters (C2-C5), a characteristic that is typical for true carboxylesterases. In addition of hydrolysing Nitrocefin, Est22 also hydrolysed first generation cephalosporin based derivatives. Detailed selectivity study using different cephalosporin based substrates indicated that Est22 selectively hydrolyse the ester bond of a cephalosporin derivatives leaving the amide bond of the β-lactam ring intact. The selective nature of Est22 makes this enzyme a potential candidate for the use in the synthesis and modification cephalosporin based molecules.  ",0
4642,23827600,Electrocatalytic determination of dopamine in the presence of uric acid using an indenedione derivative and multiwall carbon nanotubes spiked in carbon paste electrode,"In the present study, a modified carbon paste electrode (CPE) containing multi-wall carbon nanotubes and an indenedione derivative(IMWCNT-CPE) was constructed and was successfully used for dopamine(DA) electrocatalytic oxidation and simultaneous determination of DA and uric acid (UA). Cyclic voltammograms of the IMWCNT-CPE show a pair of well-defined and reversible redox. The obtained results indicate that the peak potential of DA oxidation at IMWCNT-CPE shifted by about 65 and 185 mV toward the negative values compared with that at a MWCNT and indenedione modified CPE, respectively. The electron transfer coefficient, α, and the heterogeneous electron transfer rate constant, k', for the oxidation of DA at IMWCNT-CPE were calculated 0.4±0.01 and (1.13±0.03)×10(-3) cm s(-1), respectively. Furthermore, differential pulse voltammetry (DPV) exhibits two linear dynamic ranges of 1.9-79.4 μM, and 79.4-714.3 μM and a detection limit of 0.52 μM for DA determination. Then IMWCNT-CPE was applied to the simultaneous determination of DA and UA with DPV. Finally, the activity of the modified electrode was also investigated for determination of DA and UA in real samples, such as injection solution of DA and urine, with satisfactory results. ",0
4643,23827971,Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome,"The accumulation of amyloid-β-containing neuritic plaques and intracellular tau protein tangles are key histopathological hallmarks of Alzheimer's disease (AD). This type of pathology clearly indicates that the mechanisms of neuronal housekeeping and protein quality control are compromised in AD. There is mounting evidence that the autophagosome-lysosomal degradation is impaired, which could disturb the processing of APP and provoke AD pathology. Beclin 1 is a molecular platform assembling an interactome with stimulating and suppressive components which regulate the initiation of the autophagosome formation. Recent studies have indicated that the expression Beclin 1 is reduced in AD brain. Moreover, the deficiency of Beclin 1 in cultured neurons and transgenic mice provokes the deposition of amyloid-β peptides whereas its overexpression reduces the accumulation of amyloid-β. There are several potential mechanisms, which could inhibit the function of Beclin 1 interactome and thus impair autophagy and promote AD pathology. The mechanisms include (i) reduction of Beclin 1 expression or its increased proteolytic cleavage by caspases, (ii) sequestration of Beclin 1 to non-functional locations, such as tau tangles, (iii) formation of inhibitory complexes between Beclin 1 and antiapoptotic Bcl-2 proteins or inflammasomes, (iv) interaction of Beclin 1 with inhibitory neurovirulent proteins, e.g. herpex simplex ICP34.5, or (v) inhibition of the Beclin 1/Vps34 complex through the activation of CDK1 and CDK5. We will shortly introduce the function of Beclin 1 interactome in autophagy and phagocytosis, review the recent evidence indicating that Beclin 1 regulates autophagy and APP processing in AD, and finally examine the potential mechanisms through which Beclin 1 dysfunction could be involved in the pathogenesis of AD.  ",0
4644,23828630,Multinucleated cells are involved in normal development and apoptosis in mouse testes,"Multinucleated cells are present in impaired spermatogenesis and in the senescent testis. Following accumulating evidence from our previous studies on the identification of multinucleated cells during normal testicle development, the current study further investigated the possible mechanism and role of these multinucleated cells. Healthy male Kunming mice were used in the present study. The association between multinucleated cells and cell apoptosis were analyzed using TUNEL analysis and immunohistochemistry. The results showed that multinucleated cells are widespread in the testicular tissue of seminiferous tubules on postnatal days 23, 27, 30, 33, 36, 40, 47, 50 and 54 suggesting that these cells are involved in the process of normal development of mouse testis. Histochemical analysis revealed a lack of proliferating cell nuclear antigen, cyclin D1 protein expression in multinucleated cells, suggesting that these cells are not involved in the G1 and S phases of the cell cycle and cell proliferation. Increased expression of Bax and caspase 3 was detected, revealing that multinucleated cells may be associated with cell apoptosis during testicular development. To the best of our knowledge, this study demonstrated for the first time that multinucleated cells are present during normal testicular development and may be associated with spermatogonial stem cell apoptosis. Therefore, multinucleated cells may be important in the spermatogenesis process. ",0
4645,23828781,Platelet-rich plasma combined with agarose as a bioactive scaffold to enhance cartilage repair: an in vitro study,"The purpose of this study was to determine whether the platelet-rich plasma-agarose gel scaffold could be a bioactive scaffold capable of growth factors release for cartilage repair. Porcine chondrocytes were seeded in agarose gel and platelet-rich plasma-agarose gel. During the 28-days culture, microstructure of hydrogels and morphologies of chondrocytes seeded in the hydrogels were observed using scanning electron microscope; viability of chondrocytes in gels was examined by live/dead assay; qualitative and quantitative analysis of glycosaminoglycan, collagen and DNA were assessed by histological, immunohistochemical staining and biochemical assay; gene expression was measured by real-time polymerase chain reaction. In vitro cartilage ring models were used to evaluate the integration of the scaffolds, and the integration strength was analyzed by mechanical push-out tests. Scanning electron microscope revealed both scaffolds had highly uniform porous structure. Live/dead scaffolds showed 100% cells alive in both groups. After 28-days culture, glycosaminoglycan, collagen, DNA content and chondrocyte-related genes expression in platelet-rich plasma-agarose gel were significantly higher than pure agarose gel. Integration strength in platelet-rich plasma-agarose gel was also higher compared to pure agarose gel. Platelet-rich plasma showed a positive effect on chondrocytes proliferation, differentiation and integration between native cartilage and engineered tissue when combined with agarose gel. Our findings suggest that platelet-rich plasma-agarose gel scaffold is a promising bioactive scaffold for future cartilage tissue engineering and future clinical works. ",0
4646,23828786,Towards building a disease-phenotype knowledge base: extracting disease-manifestation relationship from literature,"Systems approaches to studying phenotypic relationships among diseases are emerging as an active area of research for both novel disease gene discovery and drug repurposing. Currently, systematic study of disease phenotypic relationships on a phenome-wide scale is limited because large-scale machine-understandable disease-phenotype relationship knowledge bases are often unavailable. Here, we present an automatic approach to extract disease-manifestation (D-M) pairs (one specific type of disease-phenotype relationship) from the wide body of published biomedical literature. Our method leverages external knowledge and limits the amount of human effort required. For the text corpus, we used 119 085 682 MEDLINE sentences (21 354 075 citations). First, we used D-M pairs from existing biomedical ontologies as prior knowledge to automatically discover D-M-specific syntactic patterns. We then extracted additional pairs from MEDLINE using the learned patterns. Finally, we analysed correlations between disease manifestations and disease-associated genes and drugs to demonstrate the potential of this newly created knowledge base in disease gene discovery and drug repurposing. In total, we extracted 121 359 unique D-M pairs with a high precision of 0.924. Among the extracted pairs, 120 419 (99.2%) have not been captured in existing structured knowledge sources. We have shown that disease manifestations correlate positively with both disease-associated genes and drug treatments. The main contribution of our study is the creation of a large-scale and accurate D-M phenotype relationship knowledge base. This unique knowledge base, when combined with existing phenotypic, genetic and proteomic datasets, can have profound implications in our deeper understanding of disease etiology and in rapid drug repurposing. http://nlp.case.edu/public/data/DMPatternUMLS/ ",0
4647,23828958,Shortness: an unknown phenotype of multiple endocrine  neoplasia type 1,"An observation of shortness among the female participants of a regular screening program in multiple endocrine neoplasia type 1 (MEN1) patients has raised the question as to whether shortness represents a phenotype characteristic of the disease. The body height (cm) of genetically confirmed MEN1 patients at the time of diagnosis was compared with the body height of their unaffected relatives (parents, siblings, and children), the midparental body height, and the body height of the age-matched German population. Univariate analysis of the clinical variables was performed using the t-test, Mann–Whitney U test, and ANOVA as appropriate, and multivariate analysis was performed as a logistic regression analysis. P values <0.05 were considered statistically significant. The mean body height of 22 female MEN1 patients (mean age 33.5 years) was 161 +/- 5 cm and thus significantly lesser than the body heights of their unaffected female relatives (mean 165.5 +/- 7.3 cm, P=0.027) and the age-matched German female population (mean 167 cm, P=0.0001) and mid-parental height (177.5 cm, P<0.0001). The mean body height of 24 male MEN1 patients (mean age 34.8 years) was also lesser (177 +/- 6.5 cm) than the average body height of German males in this age group (180 cm, P=0.031) and tended to be lesser than that of their unaffected male relatives (178.5 +/- 5.8 cm, P=0.0915) and the mid-parental body height (177.5 cm, P=0.124). Small body height is a yet unrecognized phenotype characteristic of MEN1 patients, especially in women. The mechanisms behind this phenotypical characteristic warrant further investigation. ",0
4648,23829027,"I trust it, but I don't know why: effects of implicit attitudes toward automation on trust in an automated system","This study is the first to examine the influence of implicit attitudes toward automation on users' trust in automation. Past empirical work has examined explicit (conscious) influences on user level of trust in automation but has not yet measured implicit influences. We examine concurrent effects of explicit propensity to trust machines and implicit attitudes toward automation on trust in an automated system. We examine differential impacts of each under varying automation performance conditions (clearly good, ambiguous, clearly poor). Participants completed both a self-report measure of propensity to trust and an Implicit Association Test measuring implicit attitude toward automation, then performed an X-ray screening task. Automation performance was manipulated within-subjects by varying the number and obviousness of errors. Explicit propensity to trust and implicit attitude toward automation did not significantly correlate. When the automation's performance was ambiguous, implicit attitude significantly affected automation trust, and its relationship with propensity to trust was additive: Increments in either were related to increases in trust. When errors were obvious, a significant interaction between the implicit and explicit measures was found, with those high in both having higher trust. Implicit attitudes have important implications for automation trust. Users may not be able to accurately report why they experience a given level of trust. To understand why users trust or fail to trust automation, measurements of implicit and explicit predictors may be necessary. Furthermore, implicit attitude toward automation might be used as a lever to effectively calibrate trust. ",0
4649,23829179,Geographic disparities in mammography capacity in the South: a longitudinal assessment of supply and demand,"Studies have shown that there is sufficient availability of mammography; however, little is known about geographic variation in capacity. The purpose of this study was to determine the locations and extent of over/undersupply of mammography in 14 southern states from 2002 to 2008. Mammography facility data were collected from the U.S. Food and Drug Administration (FDA). Population estimates, used to estimate the potential demand for mammography, were obtained from GeoLytics Inc. Using the two-step floating catchment area method, we calculated spatial accessibility at the block group level and categorized the resulting index to represent the extent of under/oversupply relative to the potential demand. Results show decreasing availability of mammography over time. The extent of over/undersupply varied significantly across the South. Reductions in capacity occurred primarily in areas with an oversupply of machines, resulting in a 68 percent decrease in the percent of women living in excess capacity areas from 2002 to 2008. The percent of women living in poor capacity areas rose by 10 percent from 2002 to 2008. Our study found decreasing mammography availability and capacity over time, with substantial variation across states. This information can assist providers and policy makers in their business planning and resource allocation decisions. ",0
4650,23829219,Allometric relations of neotropical small rodents (Sigmodontinae) in anthropogenic environments,"The present study aims at assessing allometric relationships in the Sigmodontinae rodents (Calomys tener, Akodon cf. montensis, Necromys lasiurus, Oligoryzomys flavescens, and Oligoryzomys nigripes), and morphological variation among different habitats in human-dominated environments in Southeastern Brazil. We captured rodents using pitfall traps placed in Eucalyptus plantations, abandoned pastures, and remnants of secondary native vegetation, and took the following measurements: body mass, total length, body length, left hind foot length, and left ear length. Males were usually larger than females, except in N. lasiurus. There was no intraspecific difference in body condition among habitats, suggesting that Eucalyptus may not have a deleterious effect upon its residents. However, A. cf montensis from Eucalyptus plantations had longer feet than those from other vegetation associations, suggesting a possible adaptive response to the lower cover in the plantation environment, and its consequent higher predation risk, or alternatively that only individuals with greater dispersal ability are found in Eucalyptus plantations. Future studies should investigate a possible co-evolutionary predator-prey relationship, including rapid evolution by Sigmodontinae rodents in anthropogenic landscapes.  ",0
4651,23830239,"""""""People power"""" or """"pester power""""? YouTube as a forum for the generation of evidence and patient advocacy""","Venoplasty has been proposed, alongside the theory of chronic cerebrospinal venous insufficiency (CCSVI), as a treatment for multiple sclerosis (MS). Despite concerns about its efficacy and safety, thousands of patients have undergone the procedure. This paper analyses YouTube videos where patients have shared their treatment experiences. Content analysis on the 100 most viewed videos from over 4000 identified in a search for 'CCSVI', and qualitative thematic analysis on popular 'channels' demonstrating patients' experiences. Videos adopt an overwhelmingly positive stance towards CCSVI; many were uploaded by patients and present pre- and/or post-treatment experiences. Patients demonstrate rather than merely describe their symptoms, performing tests on themselves before and after treatment to quantify improvement. Videos combine medical terminology and tests with personal experiences of living with MS. Social media technologies provide patients with novel opportunities for advocating for particular treatments; generating alternative forms of 'evidence' built on a hybrid of personal experience and medical knowledge. Healthcare practitioners need to engage with new digital forms of content, including online social media. Instead of disregarding sources not considered 'evidence-based', practitioners should enhance their understanding of what 'experiential-evidence' is deemed significant to patients, particularly in contested areas of healthcare. ",0
4652,23830559,Randomized dose-response analysis of mitomycin-C to prevent haze after photorefractive keratectomy for high myopia,"To evaluate the safety and efficacy of mitomycin-C (MMC) 0.01% (0.1 mg/mL) in preventing haze formation after wavefront-guided photorefractive keratectomy (PRK) for higher myopia at 3 exposures. United States Navy Refractive Surgery Center, San Diego, California, USA. Double-masked randomized prospective trial. Sixty-, 30-, and 15-second exposures of MMC 0.01% were compared in wavefront-guided PRK for higher myopia. One eye received MMC (surgical sponge) and the other a placebo. All eyes received a 4-month tapering postoperative topical steroid regimen. Endothelial cell densities, haze scores, high- and low-contrast acuities, and manifest refraction were measured preoperatively and 1, 3, 6, and 12 months postoperatively. Outcomes were analyzed as repeated measures over time. The mean preoperative manifest refraction spherical equivalent was -5.98 diopters (D) (range -4.4 to -8.0 D). No eye developed more than trace haze. There was a significant difference in haze scores between MMC-treated eyes and untreated eyes at 1 and 3 months (P=.034) but no difference at 6 and 12 months. Endothelial cell densities decreased in the treated eyes and untreated eyes at all 3 exposures at 1 month but returned to baseline by 6 months. There was no difference in acuities or refractions with or without MMC. Mitomycin-C may not be needed to prevent haze after modern PRK with a 4-month steroid taper. There was no clinically significant difference in haze formation between MMC eyes and control eyes at the concentration and exposures used. ",0
4653,23830875,A case of an adoptive girl with precocious puberty: the problem of age estimation,"Age estimation is one of the main tasks of forensic anthropology and odontology, both on the dead and the living. In living subjects, age estimation may be used to establish an individual's status as a minor in cases involving adoption, criminal responsibility, child pornography, and those seeking asylum, especially where adequate identification documents are lacking. The authors report a case about age assessment of a girl born in Mbujimayi (Democratic Republic of Congo) and later adopted in Italy. The birth certificate issued after finding the child in a state of abandonment (in December 2007), bore date of 12.12.2004, but this was in contrast with the year of birth - 2003 - stated on the certification available to the center that had provided accommodation to the girl in Africa. Her adoptive parents reported that the child had been diagnosed with precocious puberty and was thus under treatment. She weighed 32.5 kg and was 132.5 cm tall. Body mass index (BMI) corresponded to the range between 9.5 and 14 years of age. The assessment of maturity indicators (sexual characteristics) placed the child at the lower limits of Stage II of Tanner's classification (sparse growth of long, slightly darkened, downy straight pubic hair; elevation of the breast and nipple as a small mound with increased diameter of the areolae). The skeletal age was determined by taking X-rays of the hand and wrist using Fels, TW2 and Greulich and Pyle methods. Dental growth was assessed through orthopantomogram using Demirjian's technique. The methods applied were adjusted considering the studies on African population found in the literature, and a skeletal and dental age of 10 years was established. Afterwards, the wrist X-rays performed at the Children's Hospital of Bari, 7 months before our investigation, revealed a skeletal age of 7 years. This evidence showed that, despite the treatment the child had promptly initiated, early puberty had influenced the skeletal growth with an acceleration of about 2 years. Therefore, the age we detected (10 years) was the result of precocious puberty. Then, we backdated the girl's birth (by about 2 years, based on current studies), stating that she was about 8 at the time of our investigation. This case is significant both for the racial differences that need to be considered in age assessment, and for the importance of any pathology (growth disorders) that may affect physiological development and make the applied methods poorly reliable. ",0
4654,23831264,Stress-induced enhancement of response inhibition depends on mineralocorticoid receptor activation,"Stress is a well-known modulator of cognitive functions. These effects are, at least in part, mediated by glucocorticoid stress hormones which act via two receptor types in the brain, glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Here, we examined whether stress affects inhibitory control processes and, if so, whether these effects are mediated by the MR. To this end, healthy participants received 300mg of the MR antagonist spironolactone or a placebo and underwent a stressor (socially evaluated cold pressor test) or a non-stressful control task 90min later. Shortly after the stressor, participants performed a stop-signal task that required them to rapidly suppress a well-established response whenever a tone was presented. Results revealed that stress enhanced response inhibition in the stop-signal task and that this enhancement was abolished by spironolactone. Our results show that stress may facilitate inhibitory control and that these effects depend on MR functioning.  ",0
4655,23831338,Emerging treatments for pemphigoid diseases,"Incidence of bullous pemphigoid (BP), the main pemphigoid disease, has increased over the past decades. Despite growing insights into pathogenic mechanisms, treatment is still based on systemic immunosuppression. Furthermore, overall mortality is significantly increased, which can be at least partially attributed to immunosuppressive therapy. Other pemphigoid diseases are also still difficult to treat. Hence, there is a so far unmet need for novel treatment options in patients with pemphigoid disease. Based on recent advances in understanding pathogenesis, several novel potential therapeutic targets have emerged. Interestingly, for some of these targets, lead compounds have been developed. Here, we review emerging therapeutic targets for pemphigoid diseases and discuss which compounds are likely be used in the future.  ",0
4656,23831380,High-level production of calcium malate from glucose by Penicillium sclerotiorum K302,"In this study, after screening of 9 fungal strains for their ability to produce calcium malate, it was found that Penicillium sclerotiorum K302 among them could produce high-level of calcium malate. Under the optimal conditions, the titer of calcium malate in the supernatant was 88.6 g/l at flask level. During 10-l fermentation, the titer of 92.0 g/l, the yield of 0.88 g/g of glucose and the productivity of 1.23 g/l/h were reached within 72 h of the fermentation, demonstrating that the titer, yield and productivity of calcium malate by this strain were very high and the fermentation period was very short. After analysis of the partially purified product with HPLC, it was found that the main product was calcium malate. The results showed that P. sclerotiorum K302 obtained in this study was suitable for developing a novel one-step fermentation process for calcium malate production from glucose on large scale. ",0
4657,23831440,Postprandial serum C-peptide to plasma glucose concentration ratio correlates with oral glucose tolerance test- and glucose clamp-based disposition indexes,"The C-peptide index (CPI), a ratio of serum C-peptide to plasma glucose levels, is a readily measured index of β-cell function. The difference in the physiological features reflected by the index measured under fasting (F-CPI) or postprandial (PP-CPI) conditions has remained unclear, however. We investigated the relationship of the two CPIs to indexes of insulin secretion measured with an oral glucose tolerance test (OGTT) or with hyperglycemic and hyperinsulinemic-euglycemic clamp analyses as well as to disposition indexes (indexes of insulin secretion adjusted for insulin sensitivity) calculated from OGTT- or clamp-based analyses. We also examined the relationship between glucose tolerance and the clamp-based disposition index. The clamp-based disposition index declined progressively from normal glucose tolerance to impaired glucose tolerance to Type 2 diabetes, and it strongly correlated with the 2-h plasma glucose level during an OGTT. For patients with Type 2 diabetes, both F-CPI and PP-CPI correlated with indexes of insulin secretion including HOMA-β, the insulinogenic index, the ratio of the area under the insulin curve to that under the glucose curve during an OGTT, the serum C-peptide level after glucagon challenge, as well as early and total insulin secretion measured with a hyperglycemic clamp. PP-CPI, but not F-CPI, was significantly correlated with clamp-based and OGTT-based disposition indexes. F-CPI was correlated only with unadjusted indexes of insulin secretion, whereas PP-CPI was correlated with such indexes as well as with those adjusted for insulin sensitivity. The better clinical utility of PP-CPI might be attributable to these physiological characteristics. ",0
4658,23831733,Loss of cAMP/CRP regulation confers extreme high hydrostatic pressure resistance in Escherichia coli O157:H7,"Application of high hydrostatic pressure (HHP) constitutes a valuable non-thermal pasteurization process in modern food conservation. Triggered by our interest in the rapid adaptive evolution towards HHP resistance in the food-borne pathogen E. coli O157:H7 (strain ATCC 43888) that was demonstrated earlier, we used genetic screening to identify specific loci in which a loss-of-function mutation would be sufficient to markedly increase HHP survival. As such, individual loss of RssB (anti RpoS-factor), CRP (catabolite response protein) and CyaA (adenylate cyclase) were each found to confer significant HHP resistance in the 300MPa range (i.e. >1,000-fold), and this phenotype invariably coincided with increased resistance against heat as well. In contrast to loss of RssB, however, loss of CRP or CyaA also conferred significantly increased resistance to 600MPa (i.e. >10,000-fold), suggesting cAMP/CRP homeostasis to affect extreme HHP resistance independently of increased RpoS activity. Surprisingly, none of the rapidly emerging HHP-resistant mutants of ATCC 43888 that were isolated previously did incur any mutations in rssB, crp or cyaA, indicating that a number of other loci can guide the rapid emergence of HHP resistance in E. coli O157:H7 as well. The inability of spontaneous rssB, crp or cyaA mutants to emerge during selective enrichment under HHP selection likely stems from their decreased competitive fitness during growth. Overall, this study is the first to shed light on the possible genetic strategies supporting the acquisition of HHP resistance in E. coli O157:H7.  ",0
4659,23831877,Why do potential body donors decide against donating?,"The Department of Anatomy at the University of Otago has been accepting body bequests for anatomical study for about 70 years. Donated bodies are used to teach anatomy to medical and dental students and surgical trainees and a wide range of other undergraduate and postgraduate students rely on body specimens to learn anatomy. Maintaining a robust body bequest programme is essential for these educational programmes. The profile of our body donors is reasonably well understood but little is known about why individuals who are interested in body donation decide not to complete the registration process. To investigate the reason(s) why applicants request bequest information but do not complete the registration process. In March 2012, an anonymous questionnaire was sent to 142 individuals who had contacted the Department between January 2010 and August 2011 requesting bequest information but had not completed the registration process. Eleven questionnaires failed to reach the intended recipient reducing the sample size to 131. Seventy eight respondents (60%) completed the questionnaire. The prime motivation for enquiring about body donation was a desire to aid medicine. The commonest single reason for not completing the registration process was our donor weight restriction of 90 kg, cited by 25% of respondents. Other reasons included objections by a family member and restrictions related to potential prion disease. Fourteen respondents had lost their registration form, and a further 15 hadn't yet made up their mind whether to donate; 18 of these have since completed the registration process. Restrictions on the acceptance of a body at the time of death deter some interested individuals from body donation. About 40% of respondents to this survey had either lost their form or were still considering body donation, many of whom were prompted to complete the registration process by this survey. Bequest programmes should consider sending a follow-up letter to individuals who request information but subsequently fail to register within a few months. ",0
4660,23831889,Tumor and transplantation],"Tumor treatment and transplantation-associated with unavoidable mandatory immunosuppression-appear to be unreconcilable opposites. The clinical reality shows, however, that transplantation in many early stage primary tumors is the most effective treatment. The essential immunosuppression after transplantation can however promote tumor recurrence. Immunosuppression also leads to a significant increased rate of de novo tumors-in all organ transplant recipients. However, not all immunosuppressant drugs have the same effect on tumors. In experimental and clinical settings, the class of mTOR inhibitors has a clear antitumoral effect and is recommended as the immunosuppression treatment of choice in patients with increased tumor risk. The purpose of this review is to provide the reader with the scientific background regarding the clinical problem of tumors and transplantation.  ",0
4661,23832004,Homologous recombination in the archaeon Sulfolobus acidocaldarius: effects of DNA substrates and mechanistic implications,"Although homologous recombination (HR) is known to influence the structure, stability, and evolution of microbial genomes, few of its functional properties have been measured in cells of hyperthermophilic archaea. The present study manipulated various properties of the parental DNAs in high-resolution assays of Sulfolobus acidocaldarius transformation, and measured the impact on the efficiency and pattern of marker transfer to the recipient chromosome. The relative orientation of homologous sequences, the type and position of chromosomal mutation being replaced, and the length of DNA flanking the marked region all affected the efficiency, linkage, tract continuity, and other parameters of marker transfer. Effects predicted specifically by the classical reciprocal-exchange model of HR were not observed. One analysis observed only 90 % linkage between markers defined by adjacent bases; in another series of experiments, sequence divergence up to 4 % had no detectable impact on overall efficiency of HR or on the co-transfer of a distal non-selected marker. The effects of introducing DNA via conjugation, rather than transformation, were more difficult to assess, but appeared to increase co-transfer (i.e. linkage) of relatively distant non-selected markers. The results indicate that HR events between gene-sized duplex DNAs and the S. acidocaldarius chromosome typically involve neither crossing over nor interference from a mismatch-activated anti-recombination system. Instead, the donor DNA may anneal to a transient chromosomal gap, as in the mechanism proposed for oligonucleotide-mediated transformation of Sulfolobus and other micro-organisms.  ",0
4662,23832233,"Biomonitoring of trace metal pollution using the bivalve molluscs, Villorita cyprinoides, from the Cochin backwaters","""Trace metal concentrations in the muscle of the bivalve Villorita cyprinoides from the Cochin backwaters (southwest coast of India) were investigated during the monsoon, post-monsoon and pre-monsoon periods. The seasonal average ranges of metals (μg g(-1), dry weight) in the bivalve were as follows: Fe (18,532.44-28,267.05), Co (23.25-37.58), Ni (10.56-19.28), Cu (3.58-11.35), Zn (48.45-139.15), Cd (1.06-1.50) and Pb (3.05-4.35). The marginally elevated metal concentrations in bivalve muscles are probably related to high influx of metals as a result of pollution from the industries and agricultural fields with consequent increased bioavailability of metals to the bivalve. Evaluation of the risks to human health associated with consumption of the bivalves suggested that there is no health risk for moderate shellfish consumers. A regular and continuous biomonitoring program is recommended to establish V. cyprinoides as a bioindicator for assessing the effects of trace metal pollution and to identify future changes to conserve the """"health"""" of this fragile ecosystem. """,0
4663,23832316,Reemergence of contagious bovine pleuropneumonia in Senegal],"The authors have described an epizootic infection of contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides biotype Small Colony (MmmSC), that has affected Ndama bovine in Lounthy village, a locality based in Bala city in the Eastern part of Senegal, during the post-rainy season in November 2012. After the cessation of vaccination, a hotbed of suspicion of CBPP was identified on November 3rd 2012 in the village of Lounthy: out of the total of 98 cattle, 13 animals were sick and 5 of them died. These studies have been done according to clinical aspects, serological, bacteriological and molecular analysis of the samples. This reemergent disease will give new orientations for CBPP control in Senegal, where it was supposed the disease has been eradicated since 2005.  ",0
4664,23832389,Recreational drugs of abuse,"""The use of recreational drugs of abuse continues to expand without limitations to national boundaries, social status, race, or education. Beyond the prevalence of illicit drug use and dependence, their contribution to the global burden of disease and death are large and troubling. All medical providers should be aware of the evolving drugs of abuse and their medical and social consequences. In addition to heroin and stimulants such as cocaine and methamphetamine, new designer stimulants called """"bath salts"""" and cannabinoids called """"spice,"""" along with the abuse of prescription drugs and volatile substances, are now widely recognized problems in many societies. The wide variety and continuingly expanding clinical manifestations of toxicity of recreational drugs of abuse is not widely appreciated by clinicians. This edition attempts to summarize six major classes of drugs of abuse and their clinical effects with special emphasis on their immunological and respiratory effects.  """,0
4665,23832578,CYP1A1 exon7 polymorphism is associated with lung cancer risk among the female population and among smokers: a meta-analysis,"The genetic polymorphism of the CYP1A1 exon7 (rs1048943) gene is thought to have a significant effect on lung cancer risk, but the results are inconsistent. To assess this relationship more precisely, a meta-analysis was performed. Ultimately, 45 case-control studies, involving 19,689 subjects were included. A significantly increased lung cancer risk was associated with two exon7 genotype variants (for Val/Val vs Ile/Ile: odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.10-1.43; for (Ile/Val + Val/Val) vs Ile/Ile: OR = 1.16, 95% CI = 1.08-1.24) in the overall population. In the stratified analysis by ethnicity, gender, and smoking status, a significant association was found in Asians, Caucasians, and the female population, not the male population. Additionally, a significant association was found in the smoker population, not in the nonsmoker population. This meta-analysis suggests that the exon7 polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility and there is an interaction between CYP1A1 exon7 polymorphisms and smoking, but these associations vary in different genders of the case and control populations. ",0
4666,23832580,Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies,"Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. CONCLUSION: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens.",0
4667,23832665,Distinct FAK activities determine progenitor and mammary stem cell characteristics,"Mammary stem cells (MaSC) and progenitor cells are important for mammary gland development and maintenance and may give rise to mammary cancer stem cells (MaCSC). Yet, there remains limited understanding of how these cells contribute to tumorigenesis. Here, we show that conditional deletion of focal adhesion kinase (FAK) in embryonic mammary epithelial cells (MaEC) decreases luminal progenitors and basal MaSCs, reducing their colony-forming and regenerative potentials in a cell-autonomous manner. Loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas a kinase-independent activity of FAK supported ductal invasion and basal MaSC activity. Deficiency in luminal progenitors suppressed tumorigenesis and MaCSC formation in a mouse model of breast cancer. In contrast with the general inhibitory effect of FAK attenuation, inhibitors of FAK kinase preferentially inhibited proliferation and tumorsphere formation of luminal progenitor-like, but not MaSC-like, human breast cancer cells. Our findings establish distinct kinase-dependent and -independent activities of FAK that differentially regulate luminal progenitors and basal MaSCs. We suggest that targeting these distinct functions may tailor therapeutic strategies to address breast cancer heterogeneity more effectively. ",0
4668,23833416,Etiology and significance of incidentally detected focal colonic uptake on FDG PET/CT,"Incidental colonic uptake of 18F-flurodeoxyglucose (FDG) is not an infrequent finding encountered during whole body positron emission tomography (PET) imaging. Almost all studies on this topic are in Western populations, which have a markedly different epidemiological profile for colorectal premalignant and malignant conditions as compared to that of the Indian subcontinent. The purpose of this study was to assess the etiology of incidentally detected focal FDG uptake in the colon by comparing it with colonoscopy and histopathology. Electronic medical records of patients who underwent FDG PET/computed tomography (CT) at our institution for a 2½-year period from January 2009 to July 2011 were reviewed. There were 32 out of 9000 (0.35%) patients whose PET/CT reports mentioned incidental focal colonic FDG uptake, of which 24 patients subsequently underwent colonoscopy. Lesions which appeared neoplastic on colonoscopy were confirmed with histopathology obtained after biopsy or surgery. Colonoscopy and pathology findings were considered as gold standard. Among the 24 patients who underwent a colonoscopy, 3 patients had normal findings (12.5%). A positive colonoscopy was noted in 21 patients (87.5%) with the lesion coinciding with the location described in the PET/CT report. Adenomatous polyps were detected in 12 patients (37.5%), whereas in 8 patients (25%) malignant lesions were confirmed [adenocarcinoma n = 5, non-Hodgkin's lymphoma (NHL) n = 2, malignant melanoma n = 1]. In one patient, colonic uptake was diagnosed as inflammatory. The mean standardized uptake valuemax (SUVmax) for the 12 premalignant lesions was 16.9 ± 9.6 (range 7.5-37.4) and the mean SUVmax for the 8 malignant lesions was 12.9 ± 5.5 (range 6.7-21.6). The difference in SUVmax between the premalignant adenomatous polyps and the malignant lesions was not statistically significant (P = 0.316). Our study shows that a significant proportion of patients (62.5%, 20/32) showing an incidental focal FDG uptake will harbor premalignant (adenomatous polyps) or malignant lesions, and further evaluation with colonoscopy and biopsy is warranted in such cases. ",0
4669,23833629,"Assessing the effectiveness of interpersonal communication skills training on job satisfaction among nurses in Al-Zahra Hospital of Isfahan, Iran","The worldwide nursing shortage is threatening the quality of healthcare. The two most common causes in maintaining nurses are job satisfaction, a positive working environment, and good relationships among staff. This study aimed to determine the effect of interpersonal communication skills training on job satisfaction among the nurses working in Al-Zahra Hospital affiliated to Isfahan University of Medical Sciences, Isfahan, Iran, in 2011. This study was a quasi-experimental research with two groups and two phases, and was carried out on 70 nurses from Al-Zahra University Hospital. Only nurses who had been employed for more than one year were accepted into the study. There were 35 nurses in the test group and 35 nurses in the control group. The study questionnaire included personal details and job satisfaction scale by Smith and Kendall. Sampling was done randomly and nurses were divided into test and control groups. In the test group, the communication skills training program was done in 6 sessions, twice a week and each session was held for 2 hours. The questionnaire was completed in two stages; before, and two months after the study. Data were analyzed by descriptive and inferential statistics through SPSS Software version 18. Findings showed that pre-intervention mean score of job satisfaction of nurses in both groups had no significant difference (p = 0.92). After the communication skills training program in the experimental group, mean score of job satisfaction increased and it was significant compared to the control group (p < 0.01). The data analysis showed that the interpersonal communication skills training program increased the mean score of job satisfaction in the test group. Therefore, it seems necessary that nursing managers design training programs for them. ",0
4670,23833752,Antibacterial activity of actinomycetes isolated from different soil samples of Sheopur (A city of central India),"The main objective of the present study was isolation, purification, and characterization of actinomycetes from soil samples, having antimicrobial activity against 12 selected pathogenic strains. Soils samples were taken from different niche habitats of Sheopur district, Madhya Pradesh, India. These samples were serially diluted and plated on actinomycete isolation agar media. Potential colonies were screened, purified, and stored in glycerol stock. Isolates were morphologically and biochemically characterized. These isolates were subjected to extraction for production of the antibacterial compound. Antibacterial activity and Minimum Inhibitory Concentration (MIC) of the purified extract of isolates were evaluated. Totally 31 actinomycete isolates were tested for antagonistic activity against 12 pathogenic microorganisms. Isolates AS14, AS27, and AS28 were highly active, while AS1 showed less activity against the pathogenic microorganisms. Isolate AS7 exhibited the highest antagonistic activity against Bacillus cereus (24 mm) and AS16 showed the highest activity against Enterococcus faecalis (21 mm). MIC was also determined for actinomycete isolates against all the tested microorganisms. MIC of actinomycete isolates was found to be 2.5 mg/ml against Shigella dysenteriae, Vancomycin-resistant enterococci, and Klebsiella pneumoniae, and was 1.25 mg/ml for Staphylococcus saprophyticus, Streptococcus pyogenes, Staphylococcus epidermidis, Methicillin-resistant Staphylococcus, Bacillus cereus, Staphylococcus xylosus, Methicillin-resistant Staphylococcus aureus, Enterococcus faecalis, and Staphylococcus aureus. All actinomycetes isolates showed antibacterial activity against S. aureus, while they showed less activity against S. dysenteriae. These isolates had antibacterial activity and could be used in the development of new antibiotics for pharmaceutical or agricultural purposes.  ",0
4671,23834069,Eye tracking communication devices in amyotrophic lateral sclerosis: impact on disability and quality of life,"People with amyotrophic lateral sclerosis (PwALS) show progressive loss of voluntary muscle strength. In advanced disease, motor and phonatory impairments seriously hinder the patient's interpersonal communication. High-tech devices such as eye tracking communication devices (ETCDs) are used to aid communication in the later stages of ALS. We sought to evaluate the effect of ETCDs on patient disability, quality of life (QoL), and user satisfaction, in a group of 35 regular ETCD users in late-stage ALS with tetraplegia and anarthria. The following scales were administered: 1) the Individually Prioritized Problem Assessment (IPPA) scale, in three conditions: without device, with ETCD and, when applicable, with an Eye Transfer (ETRAN) board; 2) the Psychosocial Impact of Assistive Devices Scale (PIADS); and 3) the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0). With ETRAN, IPPA showed an increase in communicative abilities with respect to the condition without device, but ETCD produced a further significant increase. PIADS evidenced a large increase of QoL, and QUEST 2.0 showed high user satisfaction with ETCD use. In conclusion, ETCDs should be considered in late-stage ALS with tetraplegia and anarthria, since in these patients they can reduce communication disability and improve QoL. ",0
4672,23834490,Esophageal intramural pseudodiverticulosis: endoscopic diagnosis and therapy,"Esophageal intramural pseudodiverticulosis is a rare disease that may lead to esophageal stenosis and dysphagia. The aim of the study was to evaluate the endoscopic diagnosis, treatment and clinical course of intramural pseudodiverticulosis. We retrospectively studied endoscopic criteria of intramural pseudodiverticulitis, associated diseases, and the clinical course, particularly in patients with dysphagia because of esophageal stenosis in a period from 2002 to 2012. In 23 patients, the diagnosis was made according to endoscopic criteria. As risk factors, alcohol and tobacco consumption were present in all patients. Concomitant candida infection was present in six (26%) patients. In 12 (52%) patients esophageal stenosis was present, which was localized in the upper half of the esophagus. In 11 patients bougienage has been performed with excellent improvement of the dysphagia score from 3.7 to 1.3 (P = 0.002). However, dysphagia was recurrent in four patients with need for repeated bougienage. About half of the patients with intramural pseudodiverticulosis present with stenosis of the esophagus at the time of diagnosis. In patients with proximal esophageal stenosis and a typical risk constellation, intramural pseudodiverticulosis should be suspected. Treatment of stenosis with bougienage is effective to resolve dysphagia, but repeated bougienage may be necessary.  ",0
4673,23834491,Age-related changes in attentional selection: quality of task set or degradation of task set across time?,"The present study explores the nature of attentional selection in younger and older adults. Following R. De Jong, E. Berendsen, and R. Cools (1999, Acta Psychologica, Vol. 101, pp. 379-394), we manipulated the response to stimulus interval (RSI) in two attentional selection paradigms to examine if there are age-related differences in the quality of task set and/or the maintenance of task set across time. In Experiment 1, we found that the interference effect in a spatial interference task was (a) overall larger in older adults compared with younger adults, and (b) smaller at the short RSI (200 ms) compared with the long RSI (2000 ms), and (c) not associated with an interaction between age and RSI. The second experiment explored the same variables in a Stroop color interference paradigm. Again, older adults produced a disproportionately larger interference effect than younger adults, the interference effect was smaller at the short RSI compared with the long RSI, and there was no evidence of an interaction between age and RSI. In both experiments, the larger interference effect could not be attributed to age-related general slowing and there was evidence from Vincentile analyses of increasing interference and age effects at the slower response latencies. These results indicate that attentional selection deficits in these two experiments were due to a breakdown in the quality of the task set as opposed to age-related differences in the maintenance of the task set across time. ",0
4674,23834609,"The association of screen time, television in the bedroom, and obesity among school-aged youth: 2007 National Survey of Children's Health","Among school-aged youth, we sought to identify characteristics associated with (1) exceeding screen time recommendations (ie, television/videos/video games more than 2 hours/weekday), and (2) exceeding screen time recommendations, the presence of a television in the bedroom, and obesity. Using 2007 National Survey of Children's Health data, we used multivariable logistic regression to identify sociodemographic and behavioral characteristics associated with excessive screen time among 6 to 11- and 12 to 17-year-olds on a typical weekday. For 12 to 17-year-olds only, we used logistic regression to examine the odds of obesity using the same variables as above, with the addition of screen time. Overall, 20.8% of 6 to 11-year-olds and 26.1% of 12 to 17-year-olds had excessive screen time. For both age groups, having a bedroom TV was significantly associated with excessive screen time. For the older age group, the dual scenario of excessive screen time with a bedroom TV had the strongest association with obesity (OR = 2.5, 95% CI 1.9, 3.2). Given the similar risk factors for excess screen time and having a TV in the bedroom, a public health challenge exists to design interventions to reduce screen time among school-aged youth. ",0
4675,23835026,The Basilar Artery International Cooperation Study (BASICS): study protocol for a randomised controlled trial,"Despite recent advances in acute stroke treatment, basilar artery occlusion (BAO) is associated with a death or disability rate of close to 70%. Randomised trials have shown the safety and efficacy of intravenous thrombolysis (IVT) given within 4.5 h and have shown promising results of intra-arterial thrombolysis given within 6 h of symptom onset of acute ischaemic stroke, but these results do not directly apply to patients with an acute BAO because only few, if any, of these patients were included in randomised acute stroke trials.Recently the results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry of patients with acute symptomatic BAO challenged the often-held assumption that intra-arterial treatment (IAT) is superior to IVT. Our observations in the BASICS registry underscore that we continue to lack a proven treatment modality for patients with an acute BAO and that current clinical practice varies widely. BASICS is a randomised controlled, multicentre, open label, phase III intervention trial with blinded outcome assessment, investigating the efficacy and safety of additional IAT after IVT in patients with BAO. The trial targets to include 750 patients, aged 18 to 85 years, with CT angiography or MR angiography confirmed BAO treated with IVT. Patients will be randomised between additional IAT followed by optimal medical care versus optimal medical care alone. IVT has to be initiated within 4.5 h from estimated time of BAO and IAT within 6 h. The primary outcome parameter will be favourable outcome at day 90 defined as a modified Rankin Scale score of 0-3. The BASICS registry was observational and has all the limitations of a non-randomised study. As the IAT approach becomes increasingly available and frequently utilised an adequately powered randomised controlled phase III trial investigating the added value of this therapy in patients with an acute symptomatic BAO is needed (clinicaltrials.gov: NCT01717755). ",0
4676,23835151,"Multidisciplinary teams, and parents, negotiating common ground in shared-care of children with long-term conditions: a mixed methods study","Limited negotiation around care decisions is believed to undermine collaborative working between parents of children with long-term conditions and professionals, but there is little evidence of how they actually negotiate their respective roles. Using chronic kidney disease as an exemplar this paper reports on a multi-method study of social interaction between multidisciplinary teams and parents as they shared clinical care. Phases 1 and 2: a telephone survey mapping multidisciplinary teams' parent-educative activities, and qualitative interviews with 112 professionals (Clinical-psychologists, Dietitians, Doctors, Nurses, Play-specialists, Pharmacists, Therapists and Social-workers) exploring their accounts of parent-teaching in the 12 British children's kidney units. Phase 3: six ethnographic case studies in two units involving observations of professional/parent interactions during shared-care, and individual interviews. We used an analytical framework based on concepts drawn from Communities of Practice and Activity Theory. Professionals spoke of the challenge of explaining to each other how they are aware of parents' understanding of clinical knowledge, and described three patterns of parent-educative activity that were common across MDTs: Engaging parents in shared practice; Knowledge exchange and role negotiation, and Promoting common ground. Over time, professionals had developed a shared repertoire of tools to support their negotiations with parents that helped them accomplish common ground during the practice of shared-care. We observed mutual engagement between professionals and parents where a common understanding of the joint enterprise of clinical caring was negotiated. For professionals, making implicit knowledge explicit is important as it can provide them with a language through which to articulate more clearly to each other what is the basis of their intuition-based hunches about parents' support needs, and may help them to negotiate with parents and accelerate parents' learning about shared caring. Our methodology and results are potentially transferrable to shared management of other conditions. ",0
4677,23835164,Predictive value of primary fluorine-18 fluorodeoxyglucose standard uptake value for a better choice of systematic nodal dissection or sampling in clinical stage ia non--small-cell lung cancer,"To determine whether the standard uptake value (SUV) of the primary lesion can predict mediastinal lymph node metastasis in clinical stage IA non--small-cell lung cancer (NSCLC). At 5 centers, patients with clinical stage IA NSCLC from February 2004 to August 2010 were analyzed retrospectively. Data from Shandong Cancer Hospital and from the Cancer Hospital Affiliated to Harbin Medical University were used as a testing set, and data from the other 3 institutions were used as the validation set. Final diagnosis was established based on the histopathologic examination. Data from 144 patients were collected for the study. The primary results in our study showed that maximal SUV (SUVmax) of primary tumor might be a predictor of lymph node metastasis (χ(2) = 10.424; P = .001) and the best cutoff value was 7.25 (P = .029). For the testing set, lymph node metastasis rates in low-grade group (SUVmax < 7.25) and high-grade group (SUVmax > 7.25) were 5% (2/43) and 36% (9/25) (P = .001) For the total data set, lymph node metastasis rate was 7% (6/93) in low-grade group (SUVmax < 7.25) and 26% (13/51) in high-grade group (SUVmax > 7.25) (χ(2)= 10.424; P = .001). A multivariate analysis revealed that no factors were applied to predict the probability of metastasis. But the analysis showed a weak correlation between SUVmax and nodal status (r = 0.21; P = .011) with bivariate correlation. Analysis of our data suggested that fluorine-18 fluorodeoxyglucose SUVmax of the primary tumor might be a predictor of lymph node involvement in stage IA NSCLC. The rate of mediastinal lymph node metastasis of patients with a lower fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography SUVmax might be relatively low, which provides more evidence for clinical procedures of clinical stage IA NSCLC. ",0
4678,23835183,"T4-like phage Bp7, a potential antimicrobial agent for controlling drug-resistant Escherichia coli in chickens","""Chicken-pathogenic Escherichia coli is severely endangering the poultry industry in China and worldwide, and antibiotic therapy is facing an increasing problem of antibiotic resistance. Bacteriophages can kill bacteria with no known activity in human or animal cells, making them an attractive alternative to antibiotics. In this study, we present the characteristics of a novel virulent bacteriophage, Bp7, specifically infecting pathogenic multidrug-resistant E. coli. Phage Bp7 was isolated from chicken feces. Bp7 belongs to the family Myoviridae, possessing an elongated icosahedral head and contractile sheathed tail. It has a 168-kb double-stranded DNA genome. For larger yields, its optimal multiplicity of infection (MOI) to infect E. coli was about 0.001. The latent period was 10 to 15 min, and the burst size was 90 PFU/infected cell. It was stable both at pH 5.0 to 10.0 and at 40°C or 50°C for at least 1 h. Bp7 could infect 46% of pathogenic clinical E. coli strains. Bp7 harbored 791 open reading frames (ORFs) and 263 possible genes. Among the 263 genes, 199 possessed amino acid sequence identities with ORFs of phage T4, 62 had identities with other T4-like phages, and only one lacked any database match. The genome of Bp7 manifested obvious division and rearrangement compared to phages T4, JS98, and IME08. Bp7 is a new member of the """"T4-like"""" genus, family Myoviridae. Its wide host range, strong cell-killing activity, and high stability to pH make it an alternative to antimicrobials for controlling drug-resistant E. coli in chickens. """,0
4679,23835413,Electrokinetic-enhanced phytoremediation of soils: status and opportunities,"Phytoremediation is a sustainable process in which green plants are used for the removal or elimination of contaminants in soils. Both organic and inorganic contaminants can be removed or degraded by growing plants by several mechanisms, namely phytoaccumulation, phytostabilization, phytodegradation, rhizofiltration and rhizodegradation. Phytoremediation has several advantages: it can be applied in situ over large areas, the cost is low, and the soil does not undergo significant damages. However, the restoration of a contaminated site by phytoremediation requires a long treatment time since the remediation depends on the growth and the biological cycles of the plant. It is only applicable for shallow depths within the reach of the roots, and the remediation efficiency largely depends on the physico-chemical properties of the soil and the bioavailability of the contaminants. The combination of phytoremediation and electrokinetics has been proposed in an attempt to avoid, in part, the limitations of phytoremediation. Basically, the coupled phytoremediation-electrokinetic technology consists of the application of a low intensity electric field to the contaminated soil in the vicinity of growing plants. The electric field may enhance the removal of the contaminants by increasing the bioavailability of the contaminants. Variables that affect the coupled technology are: the use of AC or DC current, voltage level and mode of voltage application (continuous or periodic), soil pH evolution, and the addition of facilitating agents to enhance the mobility and bioavailability of the contaminants. Several technical and practical challenges still remain that must be overcome through future research for successful application of this coupled technology at actual field sites.  ",0
4680,23835954,Essential amino acid leucine and proteasome inhibitor MG132 attenuate cigarette smoke induced catabolism in C2 myotubes,"Exposure to cigarette smoke (CS) and cigarette smoking have been shown to promote catabolism of skeletal muscle. Previous studies and recent findings from our laboratory have demonstrated the involvement of the ubiquitin proteasome system and the muscle-specific E3 ubiquitin ligases MAFbx/atrogin-1 and MuRF1 in CS induced skeletal muscle catabolism. The essential amino acid leucine is a known anticatabolic agent that improves skeletal muscle metabolism in various atrophic conditions. To examine the protective effect of leucine and proteasome inhibition in CS induced muscle catabolism, C2 myotubes, from an in vitro skeletal muscle cell line, were exposed to CS in the presence or absence of leucine and a proteasome inhibitor, MG132. Diameter of myotubes, levels of the main contractile proteins - myosin heavy chain and actin, expression of MAFbx/atrogin-1 and MuRF1 were studied by microscopy, Western blotting, and qPCR. Leucine pretreatment prevented the CS-induced reduction in diameter of myotubes and degradation of myosin heavy chain by suppressing the upregulation of MAFbx/atrogin-1 and MuRF1. MG132 also attenuated the CS-induced decrease in diameter of myotubes and degradation of myosin heavy chain. Our findings demonstrate that supplementation with the essential amino acid leucine and inhibition of the proteasome may protect skeletal muscle from CS induced catabolism.  ",0
4681,23836127,The effect of laparoscopic sleeve gastrectomy on the antireflux mechanism: can it be minimized?,"Laparoscopic sleeve gastrectomy (LSG) is a promising procedure for the treatment of morbid obesity. The stomach is usually transected near the angle of His; hence, the lower esophageal sphincter (LES) may be affected with consequences on postoperative gastroesophageal reflux disease (GERD). The purpose of this study was to examine the effect of LSG on the LES and postoperative GERD. Severely obese asymptomatic patients submitted to LSG underwent esophageal manometry and GERD evaluation preoperatively and at least 6 weeks postoperatively. Data reviewed included patient demographics, manometric measurements, GERD symptoms, and pathology. Statistical analysis was performed by SPSS software. Twelve male and eleven female patients participated in the study. Mean age was 38.5 ± 10.9 years, and initial body mass index was 47.9 ± 5.1 kg/m(2). At follow-up examination, mean excess body mass index loss was 32.3 ± 12.7%. The LES total and abdominal length increased significantly postoperatively, whereas the contraction amplitude in the lower esophagus decreased. There was an increase in reflux symptoms postoperatively (p < 0.009). The operating surgeon who mostly approximated the angle of His resulted in an increased abdominal LES length (p < 0.01). The presence of esophageal tissue in the specimen correlated with increased total GERD score (p < 0.05). LSG weakens the contraction amplitude of the lower esophagus, which may contribute to postoperative reflux deterioration. It also increases the total and the abdominal length of the LES, especially when the angle of His is mostly approximated. However, if this approximation leads to esophageal tissue excision, reflux is again aggravated. Thus, stapling too close to the angle of His should be done cautiously. ",0
4682,23836169,Impact of fluoroquinolone resistance on bactericidal and sterilizing activity of a moxifloxacin-containing regimen in murine tuberculosis,"It has been shown previously that fluoroquinolone resistance (defined by resistance to at least 2 mg/liter ofloxacin) has a different impact on moxifloxacin monotherapy depending on the mutation in the sole fluoroquinolone target in Mycobacterium tuberculosis, i.e., DNA gyrase. Since tuberculosis treatment relies on multidrug therapy, we wished to determine the impact of fluoroquinolone resistance on the bactericidal and sterilizing activity of a second-line antituberculous regimen containing moxifloxacin. A total of 280 mice were inoculated with the wild-type Mycobacterium tuberculosis H37Rv strain or one of 3 isogenic fluoroquinolone-resistant mutant strains with increasing moxifloxacin resistance (the GyrB D500N, GyrA A90V, and GyrA D94G strains) and then treated for 6 months with a second-line regimen containing moxifloxacin, pyrazinamide, and ethionamide supplemented with amikacin during the first 2 months. Mice were sacrificed during treatment for measurement of bactericidal activity and 3 months after treatment completion for measurement of relapse rates (sterilizing activity). The CFU counts decreased faster in mice inoculated with the wild type than in mice inoculated with the mutant strains. The relapse rate after treatment completion was different among mice inoculated with mutant strains in relation to the drug resistance level: wild type, 0%; GyrB D500N strain, 33%; GyrA A90V strain, 50%; and GyrA D94G strain, 86%. The relapse rate observed with the GyrB D500N strain was the only one not statistically different from that observed with the wild-type strain. We demonstrated that the impact on sterilizing activity of the most active second-line drug regimen containing moxifloxacin depends on the MIC of moxifloxacin. We suggest that the precise level of moxifloxacin resistance be determined for all strains resistant to 2 mg/liter ofloxacin.  ",0
4683,23836422,Chromatin remodeling by polyamines and polyamine analogs,"Natural polyamines are involved in many molecular processes, including maintenance of DNA structure and RNA processing and translation. Our aim here is to present an overview of the literature concerning the significance of polyamines in the modulation of chromatin arrangement and the transcriptional regulation of gene expression. The pleiotropic picture emerging from the published data highlights that these polycations take part in apparently diverging effects, possibly depending on the heterogeneous experimental settings described, and on a methodological approach aimed at the evaluation of the global levels of the histone chemical modifications. Since the relevant changes observed appear to be rather local and gene specific, investigating histone modifications at the level of specific gene promoters of interest is thus to be recommended for future studies. Furthermore, decoding the multiple regulatory mechanisms by which polyamines exert their influence on chromatin-modifier enzymes will reasonably require focus on selected individual polyamine-regulated genes. The evaluation of the many known chromatin-remodeling enzymes for their individual susceptibility to polyamines or polyamine derivatives will also be helpful: determining how they discriminate between the different enzyme isoforms is expected to be a fruitful line of research for drug discovery, e.g., in cancer prevention and therapy. Indeed, polyamine derivatives acting as epigenetic modulators appear to be molecules with great potential as antitumor drugs. All these novel polyamine-based pharmacologically active molecules are thus promising tools, both as a stand-alone strategy and in combination with other anticancer compounds.  ",0
4684,23836662,Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy,"The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.  ",0
4685,23836819,LL-37 opsonizes and inhibits biofilm formation of Aggregatibacter actinomycetemcomitans at subbactericidal concentrations,"Host defense peptides are immediate responders of the innate immunity that express antimicrobial, immunoregulatory, and wound-healing activities. Neutrophils are a major source for oral host defense peptides, and phagocytosis by neutrophils is a major mechanism for bacterial clearance in the gingival tissue. Dysfunction of or reduction in the numbers of neutrophils or deficiency in the LL-37 host defense peptide was each previously linked with proliferation of oral Aggregatibacter actinomycetemcomitans which resulted in an aggressive periodontal disease. Surprisingly, A. actinomycetemcomitans shows resistance to high concentrations of LL-37. In this study, we demonstrated that submicrocidal concentrations of LL-37 inhibit biofilm formation by A. actinomycetemcomitans and act as opsonins and agglutinins that greatly enhance its clearance by neutrophils and macrophages. Improved uptake of A. actinomycetemcomitans by neutrophils was mediated by their opsonization with LL-37. Enhanced phagocytosis and killing of A. actinomycetemcomitans by murine macrophage-like RAW 264.7 cells were dependent on their preagglutination by LL-37. Although A. actinomycetemcomitans is resistant to the bactericidal effect of LL-37, our results offer a rationale for the epidemiological association between LL-37 deficiency and the expansion of oral A. actinomycetemcomitans and indicate a possible therapeutic use of cationic peptides for host defense.  ",0
4686,23837042,Clinical study of renal impairment in patients with propylthiouracil-induced small-vessel vasculitis and patients with primary ANCA-associated small-vessel vasculitis,"The aim of this study was to compare renal impairment in patients with propylthiouracil (PTU)-induced small-vessel vasculitis and patients with primary anti-neutrophil cytoplasmic antibody (ANCA)-induced small-vessel vasculitis. The study compared the pathology and clinical conditions of 10 patients with PTU-associated small-vessel vasculitis and 18 patients with primary ANCA-associated small-vessel vasculitis. All patients showed manifestations of renal impairment. Compared with the primary ANCA-induced small-vessel vasculitis, patients with PTU-induced small-vessel vasculitis were mostly female (P<0.05) and deleloped the disease at a younger age (P<0.05). They had a higher positive rate of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA; P<0.05), lower 24 h proteinuria content, lower serum creatinine (P<0.05) and milder histopathological lesions (P<0.05). A number of them had gross hematuria (P<0.05). They rarely used hormone and cytotoxic drugs (P<0.05) during treatment and had a better prognosis (P<0.05). In conclusion, PTU-induced small-vessel vasculitis has a milder pathology and clinical manifestations with a better prognosis. ",0
4687,23837498,Farming practices in Sweden related to feeding milk and colostrum from cows treated with antimicrobials to dairy calves,"Milk produced by cows in receipt of antimicrobial therapy may contain antimicrobial residues. Such antimicrobial-containing waste milk must be withdrawn from human consumption and is therefore sometimes used as calf feed. Unfortunately, this approach might promote selection of antimicrobial resistant bacteria in the calves' intestinal microbiota. The objectives of this study were therefore to obtain an overview of waste milk feeding practices on Swedish dairy farms and to investigate if these practices were associated with certain farm characteristics. A representative group of 457 Swedish dairy farmers participated in a web-based survey with questions about the use of colostrum and milk from cows treated with antimicrobials at dry off or during lactation, respectively, as calf feed. Colostrum (milk from the first milking after calving) and transition milk (milk from the second milking to the fourth day after calving) from cows treated with antimicrobials at dry off was fed to calves on 89% and 85% of the farms in the study, respectively. When antimicrobial therapy was given to cows during lactation, 56% of the farms fed milk that was produced during the course of treatment to calves, whereas milk that was produced during the subsequent withdrawal period was fed to calves on 79% of the farms. Surveyed farmers were less prone to feed such milk if the antimicrobial therapy was due to mastitis than other infections. In Sweden, a majority of antimicrobial treatments during lactation are systemic administration of benzylpenicillin and thus, the bulk of waste milk in Sweden is likely to contain residues of this drug. Feeding waste milk to calves was more common on non-organic farms, and on farms located in Southern Sweden, and was less common on farms with cows housed in cold free stalls barns. Waste milk that may contain antimicrobial residues is, at least occasionally, used as feed for calves on a majority of surveyed Swedish dairy farms. Future work should focus on the effect of waste milk feeding on the occurrence of antimicrobial resistant bacteria in the calves' intestinal microbiota. ",0
4688,23837530,"Time-dependent changes in fresh-frozen bone block grafts: tomographic, histologic, and histomorphometric findings","Bone allografts have shown satisfactory clinical results in alveolar ridge reconstructions. However, the process of incorporation and the resorption rates of these grafts are not yet fully understood. The aim of this study was to use computed tomography (CT), histology, and histomorphometry to assess the time-dependent rates of resorption and incorporation of fresh-frozen bone allografts. Twenty-four patients underwent alveolar ridge reconstruction with bone block allografts and were randomly allocated to three groups with different graft healing periods (4, 6, or 8 months) before implant placement. To assess the resorption rates, CT scans were acquired within 7 days after bone graft surgery and at the end of the period. Graft samples were collected and sent for histological and histomorphometric analyses. The graft resorption mean rates were 50.78% ± 10.43, 32.77% ± 7.84, and 13.02% ± 3.86 for the 4-, 6-, and 8-month groups, respectively, and were significantly different among the three groups. Newly formed bone with osteocytes near the grafted bone was observed in all three groups. The number of osteocytes was significantly lower at 4 months. Grafted bone remains were significantly higher in the shortest period of time. All of the grafts showed large amounts of calcified tissue. All three groups showed new bone formation and different bone resorption rates. Graft healing periods of 4 months showed less graft resorption and seemed to be the most favorable for implant placement. Healing periods of 8 months showed the largest rate of graft resorption, which could render the grafts unfavorable for implant placement. ",0
4689,23837591,Further mulinane diterpenoids from Azorella compacta,"The chemical study of a dichloromethane extract from Azorella compacta was directed to the isolation of characteristic mulinane and azorellane diterpenoids in order to determine their gastroprotective activity. Usual chromatographic techniques on the extract led to the isolation of 12 compounds, which were identified by their spectroscopic properties. The HCl/ethanol-induced gastric lesions model in mice was used to determine the gastroprotective activity. The new diterpenoids, 13β-hydroxymulinane (1), mulin-11,13-dien-20-ol (2), 13α-methoxyazorellanol (3) and mulin-11,13-dien-18-acetoxy-16,20-dioic acid (12) were isolated from A. compacta. The known diterpenoids mulin-11,13-dien-20-oic acid (4), 13α-hydroxyazorellane (5), 13β-hydroxyazorellane (6), mulinic acid (7), mulinolic acid (8) and azorellanol (9), and the aromatic compounds 5,7-dihydroxychromone (10) and isoflavonoid biochanin A (11), were also obtained from the extract. Compounds 6, 9 and 12 at 20 mg/kg reduced gastric lesions by 69%, 71% and 73%, respectively, being statistically similar to lansoprazole at the same dose. The results corroborate the intraspecific chemical variations detected previously in specimens of A. compacta collected at different Chilean latitudes. A high concentration of azorellanol (9) could account in part for some of the therapeutic properties attributed to this species, in particular in ulcer treatment. Most of the mulinane and azorellane diterpenoids isolated in this study showed relevant gastroprotective activity at a low dose in the bioassay. ",0
4690,23837929,Muscle lengthening surgery causes differential acute mechanical effects in both targeted and non-targeted synergistic muscles,"Epimuscular myofascial force transmission (EMFT) is a major determinant of muscle force exerted, as well as length range of force exertion. Therefore, EMFT is of importance in remedial surgery performed, e.g., in spastic paresis. We aimed to test the following hypotheses: (1) muscle lengthening surgery (involving preparatory dissection (PD) and subsequent proximal aponeurotomy (AT)) affects the target muscle force exerted at its distal and proximal tendons differentially, (2) forces of non-operated synergistic muscles are affected as well, (3) PD causes some of these effects. In three conditions (control, post-PD, and post-AT exclusively on m. extensor digitorum longus (EDL)), forces exerted by rat anterior crural muscles were measured simultaneously. Our results confirm hypotheses (1-2), and hypothesis (3) in part: Reduction of EDL maximal force differed by location (i.e. 26.3% when tested distally and 44.5% when tested proximally). EDL length range of active force exertion increased only distally. Force reductions were shown also for non-operated tibialis anterior (by 11.9%), as well as for extensor hallucis longus (by 8.4%) muscles. In tibialis anterior only, part of the force reduction (4.9%) is attributable to PD. Due to EMFT, remedial surgery should be considered to have differential effects for targeted and non-targeted synergistic muscles.  ",0
4691,23837998,Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma,"Phaeochromocytomas and paragangliomas (PPGL) can cause acute catecholamine cardiomyopathy (ACC). We assessed the prevalence of ACC and compared the presentation of cases with and without ACC in a large series of PPGL. Single centre retrospective study. Hypertension Unit, University Hospital, Paris. 140 consecutive patients with PPGL, referred from January 2003 to September 2012. Left ventricular ejection fraction (LVEF), perioperative mortality. Fifteen patients (11%) had suffered an ACC, occurring in 14 cases before the diagnosis of PPGL. Precipitating factors were identified in 11 cases. Twelve patients presented with acute pulmonary oedema, including 10 with cardiogenic shock, requiring life support in eight cases. Seven patients (five with pulmonary oedema) presented with acute chest pain and cardiac dysfunction. Electrocardiographic abnormalities were present in 14 cases: ST segment elevation or pathological Q waves, ST segment depression, and/or diffuse T wave inversion. Six patients displayed classical (apical ballooning) or inverted (basal/mid ventricular stunning) takotsubo-like cardiomyopathy. Coronary arteries were always normal on angiography. In patients with ACC, median LVEF rose from 30% (IQR 23-33%) during ACC to 71% (50-72%) before surgery (n=11, p<0.001). Median LVEF before PPGL surgery was 65% (51-72%) and 65% (60-70%) in patients with and without a history of ACC, respectively (not significant). PPGL may present as ACC in 11% of cases, excluding patients dying from undiagnosed tumours. Left ventricular dysfunction is usually reversible before surgery. PPGL should be suspected in patients with acute heart failure without evidence of valvular or coronary artery disease. ",0
4692,23838160,Cumulative incidence rate of medical consultation for fecundity problems--analysis of a prevalent cohort using competing risks,"What is the incidence of medical consultation for fecundity problems in the French population, taking into account pregnancy occurrence and resumption of contraceptive use?. Considering the occurrence of a pregnancy and resumption of use of contraception as competing risks, the cumulative incidence rate of medical consultation for fecundity problems was 9.0% [95% confidence interval (CI): 6.5%; 11.9%] after 12 months of unprotected intercourse and 12.2% [95% CI: 9.6%; 15.3%] after 24 months. Estimates of the prevalence of medical consultation due to involuntary infertility among couples who have sought a pregnancy for more than 12 months range from 25 to 50%. Most of the studies however are limited by retrospective data collection, without considering the duration of time since the beginning of the period of unprotected intercourse (PUI) and without considering medical consultation for fecundity problems as a competing risk. This study is based on the Observatory of Fecundity in France survey, a population-based probability survey designed to estimate the frequency of involuntary infertility on a nationwide basis and to explore the associations with environmental factors. Women answered two telephone questionnaires, the first at the time of enrolment in 2007, the second at follow-up 1 year later. The current analysis was performed among a subsample of 6577 women recruited before or during a PUI and followed-up for 1 year. The study sample comprised 940 women aged 18-44 years who had a PUI between the time of enrolment and the 1-year follow-up, and who had not consulted a physician for fecundity problems for the current PUI prior to enrolment. Women reported all the medical consultations they had because of difficulties becoming pregnant during the current PUI. The date of each consultation was carefully assessed. In France, women can consult a gynaecologist directly without referral by their general practitioner. The occurrence of a pregnancy and resumption of contraceptive use were considered as informative censoring events, using a competing risk model. Using the competing risk survival model, the cumulative incidence rate of first consultation was 9.0% [95% CI: 6.5%; 11.9%] 12 months after the start of the PUI and 12.2% [95% CI: 9.6%; 15.3%] after 24 months. The Kaplan-Meier method, which does not take competing risks into account, yielded substantially higher estimates: 26.0% [95% CI: 18.8%; 32.5%] at 12 months and 56.8% [95% CI: 44.2%; 66.6%] at 24 months. Among the 219 women who had attempted to become pregnant for at least 12 months, cumulative incidences of first medical consultations were 28.2% [18.7-38.9%] 24 months after the start of the PUI, and 31.2% [21.3- 42.4%] after 36 months. The rates were higher among nulliparous but non-nulligravid women, followed by nulligravid women, as compared with parous women. Age was not strongly related to the occurrence of medical consultation. The main limitation of this study is the number of women lost to follow-up (29.7%). In addition, results regarding the absence of an age effect should be taken with caution as few women in our study were aged over 35 years. Although such an attrition rate is commonly observed in prospective studies in the general population, it could have induced a selection bias that may have led to an underestimation of the rates of medical consultation. Sensitivity analyses, using the inverse probability weighting method suggest that our results are unlikely to be biased. This study reveals frequencies of medical consultation for fertility problems, which, after considering competing events such as pregnancy in a relevant statistical model, are lower than generally reported in the literature. The results also indicate the existence of a difference between the potential need and the actual use of medical care for fecundity problems. This suggests a need for studies to look for factors other than medical recommendations that may play a role in the patterns of medical seeking behaviours for fecundity problems, such as women's reproductive history, socio-economic characteristics or accessibility to infertility services. The study was funded by grants from ANR (French Agency for Research, SEST call on Environmental and Occupational Health), ANSES (French Agency for Food, environmental and Occupational Health Safety, EST call on Environmental and Occupational Health), InVS (French Institute for Public Health Surveillance). The team of Environmental Epidemiology applied to Fecundity and Reproduction has been funded by an AVENIR grant from Inserm (2007). Authors declare no conflict of interest. ",0
4693,23838187,Urinary glycol ether metabolites in women and time to pregnancy: the PELAGIE cohort,"Glycol ethers are present in a wide range of occupational and domestic products. Animal studies have suggested that some of them may affect ovarian function. We examined the relation between women's exposure to glycol ethers and time to pregnancy. We used chromatography coupled to mass spectrometry to measure eight glycol ether metabolites in urine samples from randomly selected women in the PELAGIE mother-child cohort who had samples collected before 19 weeks of gestation. Using time to pregnancy information collected at the beginning of the pregnancy (women were asked how many months it took for them to conceive), we estimated associations between metabolite levels and time to pregnancy in 519 women with complete data using discrete-time Cox proportional hazards models to adjust for potential confounders. We detected glycol ether metabolites in 6% (for ethoxyacetic acid) to 93% (for phenoxyacetic and butoxyacetic acids) of urine samples. Phenoxyacetic acid was the only metabolite with a statistically significant association with longer time to pregnancy [fecundability OR = 0.82; 95% CI: 0.63, 1.06 for the second and third quartile combined; fecundability OR = 0.70; 95% CI: 0.52, 0.95 for a fourth-quartile (≥ 1.38 mg/L) vs. first-quartile concentration (< 0.14 mg/L)]. This association remained stable after multiple sensitivity analyses. Phenoxyacetic acid, which was present in most of the urine samples tested in our study, was associated with increased time to pregnancy. This metabolite and its main parent compound, 2-phenoxyethanol, are plausible causes of decreased fecundability, but they may also be surrogates for potential coexposures to compounds frequently present in cosmetics. ",0
4694,23838317,The mechanism of DAB2IP in chemoresistance of prostate cancer cells,"The docetaxel-based chemotherapy is the standard of care for castration-resistant prostate cancer (CRPC), inevitably, patients develop resistance and decease. Until now, the mechanism and predictive marker for chemoresistance are poorly understood. Immortalized normal prostate and cancer cell lines stably manipulated with different DAB2IP expression levels were used and treated with chemotherapeutic drugs commonly used in prostate cancer therapy. Cell proliferation was measured using MTT assay; Western blot, quantitative PCR, and luciferase reporter assays were used to analyze Clusterin gene regulation by DAB2IP. Immunohistochemical analysis was conducted for evaluating DAB2IP, Clusterin and Egr-1 expression in human prostate cancer tissue. DAB2IP Knockdown (KD) cells exhibited resistance to several chemotherapeutic drugs, whereas increased DAB2IP in C4-2 cells restored the drug sensitivity. Parallel, DAB2IP KD cells exhibited higher expression of Clusterin, an antiapoptotic factor, whereas elevated DAB2IP in C4-2 cells decreased Clusterin expression. Functionally, knocking down Clusterin by short-hairpin RNA or antisense oligonucleotide OGX-011 decreased drug resistance, whereas overexpressing Clusterin in C4-2 D2 enhanced drug resistance. Mechanistically, DAB2IP blocked the cross-talk between Wnt/β-catenin and IGF-I signaling, leading to the suppression of Egr-1 that is responsible for Clusterin expression. A similar result was observed in the prostate of DAB2IP knockout animals. In addition, we observed a significantly inverse correlation between DAB2IP and Egr-1 or Clusterin expression from clinical tissue microarray. This study unveils a new regulation of the Egr-1/Clusterin signaling network by DAB2IP. Loss of DAB2IP expression in CRPC cells signifies their chemoresistance. Clusterin is a key target for developing more effective CRPC therapy. ",0
4695,23838561,Early biochemical and hematological response to intramuscular cyanocobalamin therapy in vitamin B(12)-deficient patients,"Data on early biochemical and hematological responses to cobalamin therapy in vitamin B12-deficient patients are scarce. Therefore, we investigated whether cobalamin injections would include prompt biochemical and hematological responses in vitamin B12-deficient patients. Seven female patients (mean age: 69.4 years, range: 61-78) with a mean serum cobalamin level of 104 ± 38 pmol/l mean ± SD and 7 male patients (mean age: 67.0 years, range: 53-78) with a mean serum cobalamin level of 84 ± 40 (±SD) participated in the study. They were administered 1 mg i.m. cyanocobalamin per week for 3 weeks. Blood samples were collected before and 1, 3, 7, 14 and 21 days after cobalamin injection. The concentrations of plasma aminothiols and serum methylmalonic acid (MMA) were measured with high-performance liquid chromatography and gas chromatography/mass spectrometry, respectively, and hematological parameters were determined with a hematological analyzer. Already 1 day after intramuscular Cobalamin injections, the concentrations of serum vitamin B12 and plasma total cysteine were significantly increased while the concentrations of serum folate, plasma total homocysteine and serum MMA were decreased. Mean cell volume was also significantly decreased first after 14 days of therapy. Intramuscular cobalamin administration causes swift and significant changes in plasma aminothiols, whereas the first change in hematological parameters was detected only after 14 days. ",0
4696,23839252,William Watson Cheyne (1852-1932): a life in medicine and his innovative surgical treatment of congenital hydrocephalus,"William Watson Cheyne lived and trained during a period of great advances in medical knowledge and surgical techniques. Despite his various contributions to the fields of bacteriology and surgery, little is known about his career or his life apart from his affiliations with Joseph Lister. This article aims to identify Cheyne as a pioneer in the treatment of congenital hydrocephalus and sheds light on the man who existed in Lister's shadow for most of his life. Cheyne's technique for surgical intervention of hydrocephalus was a great turning point and contributes to the current treatment strategy utilized today for hydrocephalus.  ",0
4697,23839254,The evaluation of chorionic membrane in guided tissue regeneration for periodontal pocket therapy: a clinical and radiographic study,"Periodontal regenerative therapy is aimed at reconstruction and to restore the architecture and function of lost or injured tissues. Melcher (J Periodontol 47(5):256-260, 1976) introduced the concept of guided tissue regeneration (GTR) for osseous reconstructive surgery. The aim of the present innovative clinical and radiographic study was to evaluate the effect of chorionic membrane (CM) in GTR in periodontal pocket therapy. Ten patients with moderate to severe periodontitis were selected in the single blind randomized controlled clinical trial. Patients were treated with periodontal pocket therapy along with CM in study sites and the control sites were treated with periodontal pocket therapy alone. The clinical parameters were recorded at baseline and 12 months. The radiographic parameters were recorded at baseline, 6 and 12 months. Clinical parameters included gingival index (GI), plaque index (PI), pocket probing depth (PPD) and relative attachment level (RAL). Digital images were analysed for bone gain (BG) and density. Data were evaluated using t test. Statistical significant differences were found in both sites at 12 months for GI, PI, PPD and RAL. Highly significant reduction was seen in GI 0.40 ± 0.08 (p = 0.0001), PI (0.41 ± 0.18), PPD 2.50 ± 0.53 mm (p = 0.0431) and increased BG 0.86 ± 0.18 (p < 0.0001) were observed in study sites. This shows that CM when used with pocket therapy can have influence on clinical parameters. Radiographic findings from this study demonstrated significant BG and density in sites treated with CM as compared to control sites. ",0
4698,23839268,Mechanisms underlying the modulation of L-type Ca2+ channel by hydrogen peroxide in guinea pig ventricular myocytes,"Although Cav1.2 Ca(2+) channels are modulated by reactive oxygen species (ROS), the underlying mechanisms are not fully understood. In this study, we investigated effects of hydrogen peroxide (H2O2) on the Ca(2+) channel using a patch-clamp technique in guinea pig ventricular myocytes. Externally applied H2O2 (1 mM) increased Ca(2+) channel activity in the cell-attached mode. A specific inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) KN-93 (10 μM) partially attenuated the H2O2-mediated facilitation of the channel, suggesting both CaMKII-dependent and -independent pathways. However, in the inside-out mode, 1 mM H2O2 increased channel activity in a KN-93-resistant manner. Since H2O2-pretreated calmodulin did not reproduce the H2O2 effect, the target of H2O2 was presumably assigned to the Ca(2+) channel itself. A thiol-specific oxidizing agent mimicked and occluded the H2O2 effect. These results suggest that H2O2 facilitates the Ca(2+) channel through oxidation of cysteine residue(s) in the channel as well as the CaMKII-dependent pathway.  ",0
4699,23839504,Cerebral ischemia and reperfusion increases the heterogeneity of local oxygen supply/consumption balance,"After cerebral vessel blockage, local blood flow and O2 consumption becomes lower and oxygen extraction increases. With reperfusion, blood flow is partially restored. We examined the effects of ischemia-reperfusion on the heterogeneity of local venous oxygen saturation in rats in order to determine the pattern of microregional O2 supply/consumption balance in reperfusion. The middle cerebral artery was blocked for 1 hour using the internal carotid approach in 1 group (n=9) and was then reperfused for 2 hours in another group (n=9) of isoflurane-anesthetized rats. Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small vessel arterial and venous oxygen saturations were determined microspectrophotometrically. After 1 hour of ischemia, local cerebral blood flow (92±10 versus 50±10 mL/min per 100 g) and O2 consumption (4.5±0.6 versus 2.7±0.5 mL O2/min per 100 g) decreased compared with the contralateral cortex. Oxygen extraction increased (4.7±0.2 versus 5.4±0.3 mL O2/100 mL) and the variation in small vein (20-60 μm) O2 saturation as determined by its coefficient of variation (=100×SD/mean) increased (5.5 versus 10.5). With 2 hours of reperfusion, the blood flow decrement was reduced and O2 consumption returned to the value in the contralateral cortex. Oxygen extraction remained elevated in the ischemic-reperfused area and the coefficient of variation of small vein O2 saturation increased further (17.3). These data indicated continued reduction of O2 supply/consumption balance with reperfusion. They also demonstrated many small regions of low oxygenation within the reperfused cortical region. ",0
4700,23839967,High-throughput assessment of Mammalian cell viability by determination of adenosine triphosphate levels,"There are many assays available for high-throughput assessment of mammalian cell viability or cytotoxicity. Approaches include measurement of metabolic capacity, intracellular adenosine triphosphate (ATP) levels, induction of apoptosis, intracellular esterase and protease activity, and cellular membrane integrity. This unit provides an in-depth protocol for measurement of cellular ATP levels as a readout of mammalian cell viability, using the CellTiter-Glo assay from Promega Corporation. A comparison of the key parameters (sensitivity, speed, and cost) for this and other common high-throughput viability assays is also presented. Curr. Protoc. Chem. Biol. 2:153-161 © 2010 by John Wiley & Sons, Inc.  ",0
4701,23840010,"SlERF36, an EAR-motif-containing ERF gene from tomato, alters stomatal density and modulates photosynthesis and growth","The AP2 domain class of transcription factors is a large family of genes with various roles in plant development and adaptation but with very little functional information in plants other than Arabidopsis. Here, the characterization of an EAR motif-containing transcription factor, SlERF36, from tomato that affects stomatal density, conductance, and photosynthesis is described. Heterologous expression of SlERF36 under the CaMV35S promoter in tobacco leads to a 25-35% reduction in stomatal density but without any effect on stomatal size or sensitivity. Reduction in stomatal density leads to a marked reduction in stomatal conductance (42-56%) as well as transpiration and is associated with reduced CO₂ assimilation rates, reduction in growth, early flowering, and senescence. A prominent adaptive response of SlERF36 overexpressors is development of constitutively high non-photochemical quenching (NPQ) that might function as a protective measure to prevent damage from high excitation pressure. The high NPQ leads to markedly reduced light utilization and low electron transport rates even at low light intensities. Taken together, these data suggest that SlERF36 exerts a negative control over stomatal density and modulates photosynthesis and plant development through its direct or indirect effects. ",0
4702,23840315,Structure and dynamics of the gp120 V3 loop that confers noncompetitive resistance in R5 HIV-1(JR-FL) to maraviroc,"Maraviroc, an (HIV-1) entry inhibitor, binds to CCR5 and efficiently prevents R5 human immunodeficiency virus type 1 (HIV-1) from using CCR5 as a coreceptor for entry into CD4(+) cells. However, HIV-1 can elude maraviroc by using the drug-bound form of CCR5 as a coreceptor. This property is known as noncompetitive resistance. HIV-1(V3-M5) derived from HIV-1(JR-FLan) is a noncompetitive-resistant virus that contains five mutations (I304V/F312W/T314A/E317D/I318V) in the gp120 V3 loop alone. To obtain genetic and structural insights into maraviroc resistance in HIV-1, we performed here mutagenesis and computer-assisted structural study. A series of site-directed mutagenesis experiments demonstrated that combinations of V3 mutations are required for HIV-1(JR-FLan) to replicate in the presence of 1 µM maraviroc, and that a T199K mutation in the C2 region increases viral fitness in combination with V3 mutations. Molecular dynamic (MD) simulations of the gp120 outer domain V3 loop with or without the five mutations showed that the V3 mutations induced (i) changes in V3 configuration on the gp120 outer domain, (ii) reduction of an anti-parallel β-sheet in the V3 stem region, (iii) reduction in fluctuations of the V3 tip and stem regions, and (iv) a shift of the fluctuation site at the V3 base region. These results suggest that the HIV-1 gp120 V3 mutations that confer maraviroc resistance alter structure and dynamics of the V3 loop on the gp120 outer domain, and enable interactions between gp120 and the drug-bound form of CCR5. ",0
4703,23840434,Dietary N-Carbamylglutamate Supplementation Boosts Intestinal Mucosal Immunity in Escherichia coli Challenged Piglets,"N-carbamylglutamate (NCG) has been shown to enhance performance in neonatal piglets. However, few studies have demonstrated the effect of NCG on the intestinal mucosal barrier. This study was conducted to determine the effects of dietary NCG supplementation on intestinal mucosal immunity in neonatal piglets after an Escherichia coli (E. coli) challenge. New-born piglets (4 d old) were assigned randomly to one of four treatments (n = 7), including (I) sham challenge, (II) sham challenge +50 mg/kg NCG, (III) E. coli challenge, and (IV) E. coli challenge +50 mg/kg NCG. On d 8, pigs in the E. coli challenge groups (III and IV) were orally challenged with 5 mL of E. coli K88 (10(8) CFU/mL), whereas pigs in the sham challenge groups (I and II) were orally dosed with an equal volume of water. On d 13, all piglets were sacrificed, and samples were collected and examined. The results show that average daily gain in the E. coli challenged piglets (III and IV) was decreased (PE.coli<0.05). However, it tended to be higher in the NCG treated piglets (II and IV). Ileum secretory IgA, as well as IFN-γ, IL-2, IL-4 and IL-10 in ileal homogenates, were increased in E. coli challenged piglets (III and IV). Similarly, ileum SIgA and IL-10 levels, and CD4(+) percentage in NCG treated piglets (II and IV) were higher than no-NCG treated piglets (PNCG<0.05). However, the IL-2 level was only decreased in the piglets of E. coli challenge + NCG group (IV) compared with E. coli challenge group (III) (P<0.05). No change in the IL-2 level of the sham challenged piglets (III) was observed. In conclusion, dietary NCG supplementation has some beneficial effects on intestinal mucosal immunity in E. coli challenged piglets, which might be associated with stimulated lymphocyte proliferation and cytokine synthesis. Our findings have an important implication that NCG may be used to reduce diarrhea in neonatal piglets. ",0
4704,23840485,Infection with a Virulent Strain of Wolbachia Disrupts Genome Wide-Patterns of Cytosine Methylation in the Mosquito Aedes aegypti,"Cytosine methylation is one of several reversible epigenetic modifications of DNA that allow a greater flexibility in the relationship between genotype and phenotype. Methylation in the simplest models dampens gene expression by modifying regions of DNA critical for transcription factor binding. The capacity to methylate DNA is variable in the insects due to diverse histories of gene loss and duplication of DNA methylases. Mosquitoes like Drosophila melanogaster possess only a single methylase, DNMT2. Here we characterise the methylome of the mosquito Aedes aegypti and examine its relationship to transcription and test the effects of infection with a virulent strain of the endosymbiont Wolbachia on the stability of methylation patterns. We see that methylation in the A. aegypti genome is associated with reduced transcription and is most common in the promoters of genes relating to regulation of transcription and metabolism. Similar gene classes are also methylated in aphids and honeybees, suggesting either conservation or convergence of methylation patterns. In addition to this evidence of evolutionary stability, we also show that infection with the virulent wMelPop Wolbachia strain induces additional methylation and demethylation events in the genome. While most of these changes seem random with respect to gene function and have no detected effect on transcription, there does appear to be enrichment of genes associated with membrane function. Given that Wolbachia lives within a membrane-bound vacuole of host origin and retains a large number of genes for transporting host amino acids, inorganic ions and ATP despite a severely reduced genome, these changes might represent an evolved strategy for manipulating the host environments for its own gain. Testing for a direct link between these methylation changes and expression, however, will require study across a broader range of developmental stages and tissues with methods that detect splice variants. ",0
4705,23840523,A Melanoma Brain Metastasis with a Donor-Patient Hybrid Genome following Bone Marrow Transplantation: First Evidence for Fusion in Human Cancer,"Tumor cell fusion with motile bone marrow-derived cells (BMDCs) has long been posited as a mechanism for cancer metastasis. While there is much support for this from cell culture and animal studies, it has yet to be confirmed in human cancer, as tumor and marrow-derived cells from the same patient cannot be easily distinguished genetically. We carried out genotyping of a metastatic melanoma to the brain that arose following allogeneic bone-marrow transplantation (BMT), using forensic short tandem repeat (STR) length-polymorphisms to distinguish donor and patient genomes. Tumor cells were isolated free of leucocytes by laser microdissection, and tumor and pre-transplant blood lymphocyte DNAs were analyzed for donor and patient alleles at 14 autosomal STR loci and the sex chromosomes. All alleles in the donor and patient pre-BMT lymphocytes were found in tumor cells. The alleles showed disproportionate relative abundances in similar patterns throughout the tumor, indicating the tumor was initiated by a clonal fusion event. Our results strongly support fusion between a BMDC and a tumor cell playing a role in the origin of this metastasis. Depending on the frequency of such events, the findings could have important implications for understanding the generation of metastases, including the origins of tumor initiating cells and the cancer epigenome. ",0
4706,23840873,"Study in vivo intraocular biocompatibility of in situ gelation hydrogels: poly(2-ethyl oxazoline)-block-poly(ε-caprolactone)-block-poly(2-ethyl oxazoline) copolymer, matrigel and pluronic F127","The long term in vivo biocompatibility is an essential feature for the design and development of sustained drug release carriers. In the recent intraocular drug delivery studies, hydrogels were suggested as sustained release carriers. The biocompatibility test for these hydrogels, however, was commonly performed only through in vitro cell culture examination, which is insufficient before the clinical applications. We compared three thermosensitive hydrogels that have been suggested as the carriers for drugs by their gel-solution phase-change properties. A new block terpolymer (PEOz-PCL-PEOz, ECE) and two commercial products (Matrigel® and Pluronic F127) were studied. The results demonstrated that the ocular media remained translucent for ECE and Pluronic F127 in the first 2 weeks, but cataract formation for Matrigel occurred in 2 weeks and for Pluronic F127 in 1 month, while turbid media was observed for both Matrigel and Pluronic F127 in 2 months. The electrophysiology examinations showed significant neuroretinal toxicity of Matrigel and Pluronic F127 but good biocompatibility of ECE. The neuroretinal toxicity of Matrigel and Pluronic F127 and superior biocompatibility of ECE hydrogel suggests ECE as more appropriate biomaterial for use in research and potentially in intraocular application.  ",0
4707,23840923,Non-ideal solution thermodynamics of cytoplasm,"Quantitative description of the non-ideal solution thermodynamics of the cytoplasm of a living mammalian cell is critically necessary in mathematical modeling of cryobiology and desiccation and other fields where the passive osmotic response of a cell plays a role. In the solution thermodynamics osmotic virial equation, the quadratic correction to the linear ideal, dilute solution theory is described by the second osmotic virial coefficient. Herein we report, for the first time, intracellular solution second osmotic virial coefficients for four cell types [TF-1 hematopoietic stem cells, human umbilical vein endothelial cells (HUVEC), porcine hepatocytes, and porcine chondrocytes] and further report second osmotic virial coefficients indistinguishable from zero (for the concentration range studied) for human hepatocytes and mouse oocytes. ",0
4708,23841062,Characterization of bioactive compounds in Tunisian bitter orange (Citrus aurantium L.) peel and juice and determination of their antioxidant activities,"Citrus aurantium peel and juice aroma compounds were investigated by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS), whereas phenolic compounds analysis was performed by reversed-phase high-performance liquid chromatography (RP-HPLC). Limonene was the major volatile compound of bitter orange peel (90.25%) and juice (91.61%). HPLC analysis of bitter orange peel and juice methanolic extracts indicated that phenolic acids constitute their main phenolic class representing 73.80% and 71.25%, respectively, followed by flavonoids (23.02% and 23.13%, resp.). p-Coumaric and ferulic acids were the most abundant phenolic compounds representing 24.68% and 23.79%, respectively, in the peel, while the juice contained 18.02% and 19.04%, respectively. The antioxidant activities of bitter orange peel and juice methanolic extracts have been evaluated using four in vitro assays, and the results were compared with the standard antioxidants (BHT, BHA, and ascorbic acid). Our findings demonstrated that Citrus aurantium peel and juice possess antioxidant activities which were less effective than those of antioxidant standards. Both extracts may be suggested as a new potential source of natural antioxidant.  ",0
4709,23841389,A method for real-time observation of intracellular free Ca2+ concentration in single bovine retinal neurons],"""In order to observe the neurotrophin's influence on intracellular free calcium concentration, the test neuron was labeled by fluorescence indicator Fluo-3, and imaged by self-built real-time fluorescence microscopy system. The authors observed the changes in intracellular free calcium concentration ([Ca2+]i) in the bovine retinal neurons under the influence of four kinds of neurotrophins such as brain derived neurotrophic factor BDNF. On account of the fact that fluorescence indicator's intensity decays over time, it is necessary to apply a """"decay removal correction"""" to the fluorescence intensity in order to show the fluorescence intensity that solely represents [Ca2+]i. The corrected data shows an increase after adding neurotrophins to neurons, which is consistent with similar results published by other groups. Thus, our method of imaging living cells is feasible, and """"decay removal correction"""" is reliable. """,0
4710,23842143,Molecular identification of Mycobacterium avium subspecies paratuberculosis in oral biopsies of Crohn's disease patients,"Oral lesions may be found in patients with Crohn's disease (CD), in a percentage up to 20%. The aim of this study was to investigate a possible relationship between Mycobacterium avium subsp. paratuberculosis (MAP) and oral lesions in CD patients. 23 oral biopsies were examined performing IS900 Nested PCR; 9 of them were positive: 8 from CD patients and 1 from a control. Our purpose is to go on with this study, amplifying the number of subjects examined and testing subjects with oral lesions related to diseases other than CD to verify the specific association between MAP and oral lesions in CD patients.  ",0
4711,23842458,Association of blood antioxidants and vitamins with risk of age-related cataract: a meta-analysis of observational studies,"Observational studies have been inconsistent regarding the association between blood antioxidants or vitamins and risk of age-related cataract. We performed a meta-analysis to determine whether an association exists between blood levels of antioxidants or vitamins and age-related cataract in observational studies. We searched PubMed, EMBASE, and the Web of Science for relevant studies from inception to October 2012. Study-specific risk estimates were combined by using a random-effects model. A total of 13 studies with 18,999 participants were involved in this meta-analysis. A pooled estimate showed vitamin E (OR: 0.75; 95% CI: 0.58, 0.96), α-carotene (OR: 0.72; 95% CI: 0.59, 0.88), lutein (OR: 0.75; 95% CI: 0.65, 0.87), and zeaxanthin (OR: 0.70; 95% CI: 0.60, 0.82) were inversely associated with age-related cataract. Vitamins A (OR: 0.69; 95% CI: 0.58, 0.83) and C (OR: 0.67; 95% CI: 0.57, 0.78) were inversely associated with age-related cataract in Asian populations but not in Western populations. β-Carotene (OR: 0.90; 95% CI: 0.78, 1.05), lycopene (OR: 0.86; 95% CI: 0.65, 1.15), and β-cryptoxanthin (OR: 0.83; 95% CI: 0.68, 1.02) had no significant association with risk of cataract. This meta-analysis provides additional evidence supporting the view that blood levels of certain antioxidants are inversely associated with risk of age-related cataract. However, the role of antioxidant or vitamin supplement intake in preventing cataract should be further investigated in interventional studies. ",0
4712,23842648,Neuronal network plasticity and recovery from depression,"The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.  ",0
4713,23842856,CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial,"The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.  ",0
4714,23843169,A SEM and non-contact surface white light profilometry in vivo study of the effect of a crème containing CPP-ACP and fluoride on young etched enamel,"The aim of this in vivo study was to evaluate the short and a longer term effect on enamel of the application of a crème containing 10% CPP-ACP and 900 ppm fluoride, in orthodontically planned, high caries-risk patients. Epoxy resin replicas of upper lateral incisors were obtained from polyvinyl siloxane (PVS) impressions, before and after etching. The right incisors were left untreated in order to control saliva remineralizing potential. The upper left surfaces were coated with a pea-size amount of the crème. Replicas were obtained at 3 weeks and 6 months and analyzed by SEM and non-contact surface white light profilometry. In the treated sample the profilometric roughness parameters at 3 weeks were statistically significantly lower than the control group values (p < 0.05). At 3 weeks SEM images of the enamel surface showed fewer irregularities. After 6 months, differences between test and control groups were not present on SEM images and profilometric values. CPP-ACP and fluoride crème had positive in vivo effects on enamel surfaces. Significant differences in surface roughness existed after a 3-week period of crème use. ",0
4715,23843805,Effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes,"Osteoporosis and chronic kidney disease are common conditions in older adults, and often occur concurrently. Bone disease is caused by increased bone turnover accompanying secondary hyperparathyroidism, and by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis, even in hemodialysis patients. Raloxifene is commonly used for the treatment of postmenopausal osteoporosis in the general population, and may be a treatment option for osteoporosis in hemodialysis patients. However, the effects of raloxifene in hemodialysis patients with type 2 diabetes have not been examined in detail. This study was performed to investigate the effects of raloxifene on bone turnover markers and bone density in postmenopausal women with type 2 diabetes mellitus who were undergoing hemodialysis in Japan. The subjects were 60 female patients on maintenance hemodialysis (non-diabetic, n=30; diabetic, n=30). Raloxifene hydrochloride (60 mg) was administered to 14 diabetic patients and 14 non-diabetic patients for one year, and these patients were compared with control groups (no raloxifene) of 16 diabetic patients and 16 non-diabetic patients. Serum levels of N-terminal cross-linking telopeptide of type I collagen (NTx), bone alkaline phosphatase, and intact parathyroid hormone (iPTH) were measured, and bone density was determined by quantitative heel ultrasound at the speed of sound (SOS) in the calcaneus during this period. There were no significant differences in the levels of bone turnover markers except for iPTH after treatment of diabetic and non-diabetic patients with raloxifene for one year. SOS increased after treatment with raloxifene, but was significantly decreased in the control groups. Treatment with raloxifene resulted in a significant decrease in NTx and a significant increase in SOS in both diabetic and non-diabetic patients. There were no significant differences between the diabetic and non-diabetic patients who received raloxifene. Treatment with raloxifene can suppress reduction in bone density in postmenopausal women with type 2 diabetes who are undergoing hemodialysis. ",0
4716,23843832,Cardiovascular Risk in Women With PCOS,"Polycystic ovary syndrome (PCOS), or Stein-Leventhal syndrome, is a common endocrine disorder defined by two of the three following features: i) oligoovulation or anovulation, ii) clinical and/or biochemical signs of hyperandrogenism, or iii) polycystic ovaries, once the related endocrinological and gynaecological disorders have been excluded. PCOS does not exclusively involve the reproductive apparatus , it has a complex number of systemic relevancy symptoms. It leads to Metabolic Syndrome, with severe consequences on the cardiovascular apparatus. Many clinical studies have underlined the connection between PCOS and the cardiovascular risk profile of such female patients, due to a lipid/glucose altered metabolism, hypertension, systemic inflammatory condition (assessable by markers such as VES, TNF-alfa, citokines and C-reactive protein (hsPCR) levels), and vascular injuries. Considering the early onset of the disease, PCOS could be considered as a real cardiovascular risk factor which affects the quality of life seriously. The current review aimed to point out the main connections between PCOS and cardiovascular risk factors according to the latest findings coming from literature data analysis, and try to depict the great influences that such a common disease can have on the patients' health integrity.  ",0
4717,23844209,Deficiency of adiponectin protects against ovariectomy-induced osteoporosis in mice,"Adipokine adiponectin (APN) has been recently reported to play a role in regulating bone mineral density (BMD). To explore the mechanism by which APN affects BMD, we investigated BMD and biomechanical strength properties of the femur and vertebra in sham-operated (Sham) and ovariectomized (OVX) APN knockout (KO) mice as compared to their operated wild-type (WT) littermates. The results show that APN deficiency has no effect on BMD but induces increased ALP activity and osteoclast cell number. While OVX indeed leads to significant bone loss in both femora and vertebras of WT mice with comparable osteogenic activity and a significant increase in osteoclast cell number when compared to that of sham control. However, no differences in BMD, ALP activity and osteoclast cell number were found between Sham and OVX mice deficient for APN. Further studies using bone marrow derived mesenchymal stem cells (MSCs) demonstrate an enhanced osteogenic differentiation and extracellular matrix calcification in APN KO mice. The possible mechanism for APN deletion induced acceleration of osteogenesis could involve increased proliferation of MSCs and higher expression of Runx2 and Osterix genes. These findings indicate that APN deficiency can protect against OVX-induced osteoporosis in mice, suggesting a potential role of APN in regulating the balance of bone formation and bone resorption, especially in the development of post-menopausal osteoporosis.  ",0
4718,23844604,Oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction,"Oral L-citrulline supplementation increases serum L-arginine levels more efficiently than L-arginine itself and increases nitric oxide (NO) production. To investigate whether oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction (ED). We divided 8-week-old male Wistar-ST rats into 3 groups: sham-operated rats (control group), arteriogenic ED rats who underwent ligation of both internal iliac arteries (ligation group), and arteriogenic ED rats receiving oral 2% L-citrulline water supplementation (citrulline group). Citrulline water was given to arteriogenic ED rats for 3 weeks from 1 week after surgery. Erectile function was evaluated by maximum intracavernous pressure/mean arterial pressure (ICP/MAP) ratios via cavernous nerve stimulation at 4 weeks after surgery. Then, the penises were resected, stained with Masson's trichrome, and observed microscopically. Serum nitrogen oxides (NOx) levels were measured by high-performance liquid chromatography. Bonferroni's multiple t-test was used for statistical analysis. The main outcome measures were changes in ICP/MAP, smooth muscle (SM)/collagen ratios, and NOx levels following L-citrulline supplementation. The ICP/MAP ratio in the ligation group was significantly lower than that in the control group (P<0.05), denoting ED. The ICP/MAP ratio of the citrulline group was significantly higher than that of the ligation group (P<0.05), indicating ED amelioration. Levels of NOx in the ligation group were significantly lower than in the control group (P<0.05), while those in the citrulline group were significantly higher than in the ligation group (P<0.05). SM/collagen ratios in the ligation group were significantly lower than in the control group (P<0.05), while ratios in the citrulline group were significantly higher than those in the ligation group (P<0.05). Oral L-citrulline supplementation improved ICP/MAP and SM/collagen ratios and increased NOx. Therefore, oral L-citrulline supplementation might be a useful novel therapy for acute arteriogenic ED. ",0
4719,23844688,Serum cytokine profile in Alzheimer's disease patients after ingestion of an antioxidant beverage,"The major neuropathologic hallmarks in Alzheimer's disease (AD) consist of neuronal cell loss in selected brain regions, as well as deposition of extracellular senile plaques and intracellular neurofibrillary tangles. Further to these lesions, neuroinflammation is a feature of AD pathology and is thought to contribute to the neurodegeneration. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, with increased expression of acute phase proteins and pro-inflammatory cytokines. The healthy properties of green tea and apple are linked closely to their content of phenolic compounds. Although the beneficial effects of these compounds are clear, relatively few studies have focused on their anti-inflammatory effects in vivo. The aim of the present study was to test whether daily consumption of a beverage with high antioxidant power combining extracts of green tea and apple over a period of eight months would affect biomarkers of inflammation in AD patients in initial phase, moderate phase and a control group. Administration of the antioxidant beverage (AB) to the three groups did not produce a significant change in serum levels of the antiinflammatory cytokines interleukin-4 and interleukin-10. In contrast, AB decreased serum levels of the pro-inflammatory cytokines interleukin-2 (AD moderate phase vs control group at eight months), interferon-γ (control group vs AD moderate phase and AD initial phase vs placebo beverage at four months) and tumor necrosis factor-α (AD initial phase vs AD moderate phase at four months). AB was more effective against inflammation in the early period of AD, and could be used as a natural complementary therapy to alleviate or improve symptoms of inflammation in early stages of AD.  ",0
4720,23844702,Abnormal activity of default mode network in GERD patients,"Abnormal processing of esophageal sensation at the level of the central nervous system has been proven to be involved in gastroesophageal reflux disease (GERD). However, most studies were focused on the possible functions of perceptual processing related network during task status, little attention has been paid to default mode network, which has been manifested to be important in the pathogenesis of many diseases. In our study, we compared the brain activity characteristic in GERD patients with the healthy subjects (HS) at baseline, looking for whether activities of default mode network were abnormal in GERD patients and attempting to identify their possible roles in GERD. In present study, fractional amplitude of low-frequency fluctuation was adopted to detect the brain activities at baseline. Group-level analyses were conducted by one-sample t test within groups (voxel thresholds were p<0.001 and cluster level>42, corrected P<0.05) and independent-samples t test between groups (p<0.01 and cluster level>90, corrected P<0.05) using SPM5. The predominant activity area in both groups mainly located in default mode network such as medial superior frontal gyrus, precuneus, posterior cingulate gyrus, etc. However, the activities of precuneus and posterior cingulate gyrus were significantly lower in GERD patients than those in the HS. The activities of precuneus and posterior cingulate gyrus of default mode network in GERD patients were significantly lower compared to the HS, suggesting abnormal activities of brain regions in default mode network may be involved in pathophysiology of GERD symptom generation. ",0
4721,23844813,MicroRNA as biomarkers and regulator of cardiovascular development and disease,"MicroRNAs are small noncoding RNAs that have emerged as important regulators of many biological and pathological processes, including those relevant to the development of the heart and cardiovascular disease. Several recent studies using genetic models and profiling of microRNAs have established the important role of these novel molecules in a number of conditions of the heart. These studies have led to a flurry of research focussing on the identification of new therapeutic targets for the treatment of cardiac disease, as well as the identification of potential biomarkers for early diagnosis of heart disease. These early reports have stimulated much interest in microRNAs and indeed other non-coding RNAs in the broader context of cardiovascular disease. This work has been further investigated as a result of ease with which the levels of these molecules can be modulated both in vitro but also in animal disease models. Furthermore, a number of studies have specifically looked at the prognostic potential of these microRNAs as biomarkers of cardiovascular disease. This review is focused on highlighting some of the novel aspects of recent research in the area of the development of new therapeutics and better diagnostics for cardiovascular disease.  ",0
4722,23845006,Primary monophasic synovial sarcoma of the liver in a 13-year-old boy,"Synovial sarcoma originating in the liver is extremely rare, and thus far only 3 cases have been reported in the English literature. Herein, we report a primary hepatic synovial sarcoma in a 13-year-old Chinese boy. This patient present with a 10-day right upper quadrant pain, and a heterogeneous mass was documented in the right hepatic lobe by computed tomography. Subsequently, the patient underwent right hepatectomy. Histologically, the tumor exhibited classic features of monophasic synovial sarcoma. The diagnosis was confirmed by the presence of SS18 gene rearrangement and identification of SS18-SSX1 fusion transcript. Unfortunately, a relapsing mass was detected 11 months after the surgery. To the best of our knowledge, the current case is the 1st published example in the pediatric population. ",0
4723,23845018,Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies,"Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available. This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity. Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46-4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59-3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar. This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings. ",0
4724,23845221,Development of 3D-QSAR CoMSIA models for 5-(biphenyl-2-yl)-1H-tetrazole derivatives as angiotensin II receptor type 1 (AT1) antagonists,"As a development strategy for backups of Fimasartan (1), a comparative molecular similarity indices analysis (CoMSIA) of a set of sixty-five 5-(biphenyl-2-yl)-1H-tetrazole derivatives has been performed to find out the pharmacophore elements for angiotensin II receptor type 1 (AT1) blockade. The most potent compound containing pyrimidin-4(3H)-one ring, Fimasartan (1) was used to align the molecules. As a result, we obtained 3D-QSAR model which provided good predictivity for both the training set (q(2)=0.846, r(2)=0.975) and the external test set (rpred(2)=0.980). This model would guide the design of backups for Fimasartan (1), a launched oral antihypertensive agent.  ",0
4725,23845406,Self-reported wayfinding ability of older drivers,"Some older drivers experience difficulties driving whilst wayfinding in unfamiliar areas. Difficulties in wayfinding have been associated with poorer driving performance and reduced driving mobility. The objective of the current study was to identify cognitive and demographic predictors in older drivers of perceived wayfinding difficulty, avoidance of unfamiliar areas and the use of wayfinding strategies. Five hundred and thirty-four drivers aged 65 years and over (excluding those with dementia or Parkinson's disease) completed a mail-out survey. Drivers commonly reported difficulties with wayfinding, with 59.5% reporting their abilities as poor or fair rather than good. Those significantly more likely to report difficulty were older, reported poorer health and cognition, and had less driving experience. A small proportion of drivers reported regularly avoiding unfamiliar areas (13.8%); these drivers were significantly more likely to be female and to report poorer wayfinding abilities. The most common wayfinding strategies regularly used by older drivers were using a street directory whilst driving (61.9%) and pulling over to check the map (55.1%). Regular passenger guidance (23.9%) or use of a navigation system (9.9%) was less common. The implications of this study are wide and include collecting further information about: (1) the role of cognitive processes in wayfinding ability; (2) the relationship between perceived wayfinding difficulty and restriction of driving in unfamiliar areas; and (3) older drivers' preferences for different wayfinding strategies.  ",0
4726,23845420,Development of an animal frostbite injury model using the Goettingen-Minipig,"A standardized reproducible animal model is desirable to gain a better understanding in the pathophysiology of frostbite injury and to develop novel therapies. Little has been studied about frostbite injury models. The depth and extent were not always being controllable and consistent. Therefore, we developed a frostbite injury model using the Göttingen Minipigs. 42 frostbite injuries were inflicted on the abdomen of seven minipigs using an aluminium bar (300g, circular with a radius of 1cm) frozen with liquid nitrogen to -196°C. The bar was applied for 1, 3, 6, 12, 30 and 60s. Five hours after injury biopsies were performed and evaluated by the presence of denatured collagen, blood vessels, follicular epithelial cells and mesenchymal cells. A large spectrum of frostbite injuries was obtained ranging from superficial, superficial partial, deep partial to full thickness. The depth of injury in the sets of frostbites was highly consistent (Pearson correlation ranged from r=0.89 to 0.94). We described a simple, inexpensive and safe swine frostbite model. The accurate reproducibility of the depth of the frostbite injuries allows researchers to accurately plan frostbite studies. ",0
4727,23845560,A new hypothesis about hematopoietic Pbx-interaction protein (HPIP): can it be a key factor in neurodegeneration in the post-menopausal period?,"Neuronal degeneration in the post-menopausal term leads to cognitive symptoms such as anxiety, difficulty in concentrating, overreacting to minor upsets, quickly becoming irritated and forgetfulness in approximately 70-80% of all women around the world. These symptoms, which result from microtubule damage in the axon extensions of hippocampal neurons in during menopause, greatly reduce individuals' life quality. Thus, an investigation of the estrogen receptor-signaling pathway-microtubule dynamic triangle and the possible links between them is important when it comes to explaining the possible mechanism of neurodegeneration. Hematopoietic Pbx-interaction protein (HPIP), a microtubule-binding protein, is a novel scaffolding protein. The detection of this protein on neurons represents the most important step in our hypothesis. The importance of the hypothesis is that it might provide important clues about the possible role of HPIP and its mechanism through in vivo and in vitro studies of estrogen receptors-microtubules and the HPIP triangle in terms of neuronal degeneration in the post-menopausal period. A preliminary study was performed to test the main part of our hypothesis using real-time PCR. According to the results, the mRNA expression of HPIP was found in hippocampal neurons. After the detection of this novel protein in neurons, it was observed that there were differences in the experimental groups when compared with the control group relating to the mRNA expression of this protein. An important scientific question remains concerning the mechanisms of neurodegeneration appearing in the post-menopausal period and the receptors, proteins, and signaling pathways that play a role in this degeneration. In consideration of the data from in vivo and in vitro studies used to test our hypothesis, we will try to address the relevant questions. As this issue is resolved, new studies and treatment procedures that can help to prevent the possible difficulties in the menopausal period will be illuminated. ",0
4728,23845726,CCL2 increases αvβ3 integrin expression and subsequently promotes prostate cancer migration,"Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family which is associated with the disease status and outcomes of cancers. Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. However, the effect of CCL2 on human prostate cancer cells is largely unknown. The aim of this study was to examine the role of CCL2 in integrin expression and migratory activity in prostate cancers. Prostate cancer migration was examined using Transwell, wound healing, and invasion assay. The PKCδ and c-Src phosphorylations were examined by using western blotting. The qPCR was used to examine the mRNA expression of integrins. A transient transfection protocol was used to examine AP-1 activity. Stimulation of prostate cancer cell lines (PC3, DU145, and LNCaP) induced migration and expression of integrin αvβ3. Treatment of cells with αvβ3 antibody or siRNA abolished CCL2-increased cell migration. CCL2-increased migration and integrin expression were diminished by CCR2 but not by CCR4 inhibitors, suggesting that the CCR2 receptor is involved in CCL2-promoted prostate cancer migration. CCL2 activated a signal transduction pathway that includes PKCδ, c-Src, and AP-1. Reagents that inhibit specific components of this pathway each diminished the ability of CCL2 to effect cell migration and integrin expression. Interaction between CCL2 and CCR2 enhances migration of prostate cancer cells through an increase in αvβ3 integrin production. CCL2 is a critical factor of prostate cancer metastasis. ",0
4729,23845897,Comet assay and air-liquid interface exposure system: a new combination to evaluate genotoxic effects of cigarette whole smoke in human lung cell lines,"Over the past three decades, the genotoxic effects of cigarette smoke have generally been evaluated in non-human cell models after exposure to particulate phase, gas phase, or cigarette smoke condensate, rather than the whole smoke aerosol itself. In vitro setups using human cell lines and whole smoke exposure to mimic actual aerosol exposure should more accurately reflect human cigarette smoke exposure. We investigated the VITROCELL® 24 air-liquid interface exposure system in combination with the comet assay to assess DNA damage in two different human lung epithelial cell lines exposed to whole smoke. Results showed a repeatable and reproducible dose-response relationship between DNA damage and increased whole smoke dose in both cell lines. Thus, the combination of the comet assay with the VITROCELL® 24 represents a valuable new in vitro test system to screen and assess DNA damage in human lung cells exposed to whole smoke.  ",0
4730,23845982,Intensity of daily physical activity is associated with central hemodynamic and leg muscle oxygen availability in COPD,"In chronic obstructive pulmonary disease (COPD), daily physical activity is reported to be adversely associated with the magnitude of exercise-induced dynamic hyperinflation and peripheral muscle weakness. There is limited evidence whether central hemodynamic, oxygen transport, and peripheral muscle oxygenation capacities also contribute to reduced daily physical activity. Nineteen patients with COPD (FEV1, 48 ± 14% predicted) underwent a treadmill walking test at a speed corresponding to the individual patient's mean walking intensity, captured by a triaxial accelerometer during a preceding 7-day period. During the indoor treadmill test, the individual patient mean walking intensity (range, 1.5 to 2.3 m/s2) was significantly correlated with changes from baseline in cardiac output recorded by impedance cardiography (range, 1.2 to 4.2 L/min; r = 0.73), systemic vascular conductance (range, 7.9 to 33.7 ml·min(-1)·mmHg(-1); r = 0.77), systemic oxygen delivery estimated from cardiac output and arterial pulse-oxymetry saturation (range, 0.15 to 0.99 L/min; r = 0.70), arterio-venous oxygen content difference calculated from oxygen uptake and cardiac output (range, 3.7 to 11.8 mlO2/100 ml; r = -0.73), and quadriceps muscle fractional oxygen saturation assessed by near-infrared spectrometry (range, -6 to 23%; r = 0.77). In addition, mean walking intensity significantly correlated with the quadriceps muscle force adjusted for body weight (range, 0.28 to 0.60; r = 0.74) and the ratio of minute ventilation over maximal voluntary ventilation (range, 38 to 89%, r = -0.58). In COPD, in addition to ventilatory limitations and peripheral muscle weakness, intensity of daily physical activity is associated with both central hemodynamic and peripheral muscle oxygenation capacities regulating the adequacy of matching peripheral muscle oxygen availability by systemic oxygen transport. ",0
4731,23846011,Neurological recovery after out-of-hospital cardiac arrest: hospital admission predictors and one-year survival in an urban cardiac network experience,"""The aim of the study was to detect early predictors of neurological recovery and evaluate one year survival related to neurological status at discharge in patients (pts) admitted after out of hospital cardiac arrest (OHCA). Sixty-three consecutive pts with OHCA from any cardiac cause, admitted to our cardiac intensive care unit, were classified according to survival and cerebral performance category (CPC) scale from 1 to 4 at hospital discharge. Pre-hospital and emergency room (ER) variables were analyzed to identify early predictors of neurological recovery as defined CPC=1-2. Overall in-hospital survival was 60%. Sixty-eight and 32% of survivors were classified as CPC 1-2 and CPC 3-4 respectively. During one year follow-up 96% of patients classified as CPC 1-2 survived and 100% of CPC 3-4 died. Emergency crew witnessing, performance of cardio pulmonary resuscitation (CPR) by witnesses, the call for chest pain, no history of heart disease and a Glasgow coma scale (GCS) of ≥9 on arrival to the ER, were more frequent in patients classified as CPC 1-2 and times from """"OHCA to return of spontaneous circulation (ROSC)"""", from """"emergency medical system (EMS) arrival to ROSC"""" and """"first DC shock to ROSC"""" were also significantly shorter in these patients. The time of first DC shock to ROSC in pts who presented with rhythm in ventricular fibrillation and the time from OHCA to ROSC in pts with witnessed OHCA were an independent predictors of neurological recovery. Forty-one percent of pts admitted to our tertiary centre after OHCA were discharged with CPC 1-2 and at one year follow-up 96% of these were alive, while all pts classified as CPC 3-4 died. Easily documented information such as the time from OHCA to ROSC and the time of first shock to ROSC are early independent predictors of neurological recovery. """,0
4732,23846148,Preparation and application of a molecularly imprinted polymer for determination of glibenclamide residues,"The performance of a molecularly imprinted polymer (MIP) as selective packing material for solid-phase extraction (SPE) of residual glibenclamide in an industrial process was investigated. MIP was prepared using 4-vinylpyridine as monomer, ethylenedimethacrylate as cross linker, 2,2'-azobis-2-methylpropionitrile as initiator and dimethyl formamide as porogen. Use of acetonitrile as a rebinding solvent allows good recognition of the glibenclamide template. It was found that this polymer can be used for determination of trace levels of glibenclamide with a recovery percentage that could reach 87.1 %. Furthermore, the synthesized MIP showed higher selectivity towards glibenclamide than other compounds such as glimepiride and metformin. The synthesized MIP enabled direct determination of the target contaminant after an enrichment step that allowed quantification of glibenclamide at a concentration as low as 0.016 mg L-1. Combination of high performance liquid chromatography with MIP-SPE could be successfully used for quality control of pharmaceuticals during the cleaning process in the production of dry drug forms. ",0
4733,23846797,"Which behavioral and psychological symptoms of dementia are the most problematic? Variability by prevalence, intensity, distress ratings, and associations with caregiver depressive symptoms","""Behavioral and psychological symptoms of dementia (BPSD) impact well-being for persons with dementia (PWD) and caregivers. Identifying the most problematic symptoms is vital in targeting interventions and allocating resources. The current study highlights inconsistencies in the """"most problematic"""" symptoms when identified via prevalence, intensity, caregiver distress, or associations with caregiver depressive symptoms. Caregivers (N = 177) were mostly female (77%) and spouses of PWD (73%), with average age of 66.7 years (SD = 16.1). They reported BPSD frequency and distress via the Revised Memory and Behavior Problem Checklist (RMBPC) and Neuropsychiatric Inventory (NPI), and their own depressive symptoms via the Geriatric Depression Scale (GDS). BPSD were ranked by prevalence, average frequency, and average distress ratings. RMBPC subscales were correlated with GDS, and discriminant function analyses used NPI symptoms to discriminate between caregivers' normal (range 0-9) or elevated (10+) GDS. Most prevalent NPI symptoms were Apathy, Depression, and Agitation. Most intense (frequency × severity) were Appetite, Motor behaviors, and Apathy, and most distressing were Delusions, Agitation, and Irritability. For RMBPC, Memory was most frequent but least distressing, whereas Disruptive was least frequent but most distressing. RMBPC frequency and distress subscales were significantly associated with caregiver GDS. Discriminant function analyses were statistically significant (Lambda = 0.822; χ(2) (12) = 30.62; p = 0.002. Canonical correlation = 0.442); NPI symptoms correctly classified caregivers GDS status 72% of the time. Symptoms revealed as """"most problematic"""" varied by measurement criterion. Common or frequent symptoms are not necessarily the most distressing or most predictive of caregiver depression. """,0
4734,23847008,The role of signalling in cellular cholesterol homeostasis,"Cholesterol is a vital lipid and performs diverse functions on a whole body and cellular level. However, excess cellular cholesterol is toxic, and thus, elegant mechanisms have evolved to tightly regulate this important lipid. The regulation of cholesterol homeostasis is an area of intense research, and the role that signalling plays is gradually becoming more widely recognised. Cholesterol homeostasis is achieved through intricate mechanisms involving synthesis, uptake, and efflux. Although there is a large body of work elucidating these cholesterol-related pathways, less is known about the role of signalling in these processes. Here, we discuss the variety of ways that signalling impacts on these modes and levels of cholesterol homeostasis, including transcriptional regulation. Most work thus far has investigated the role of kinases in cholesterol efflux (especially on ATP-binding cassette transporter A1, ABCA1), and therefore constitutes a major focus of this review. We also indicate further avenues to explore in the area of signalling in cellular cholesterol homeostasis. ",0
4735,23847711,Incidental diagnosis of unilateral renal and adnexal agenesis in a 46-year-old multiparous woman,"Female, 46 FINAL DIAGNOSIS: Unilateral adneksial and renal agenesis Symptoms: Menometrorrhagia Medication: - Clinical Procedure: Total abdominal hysterectomy and unilateral salphingoopherectomy Specialty: Obstetrics and gynecology. Rare disease. Unilateral renal and adnexal agenesis is quite rare. Absence of any uterine abnormality accompanying current urogenital abnormalities is even rarer. We report on the case of a 46-year-old multiparous woman, incidentally diagnosed to have unilateral renal, ovarian, and tubal agenesis just before hysterectomy due to menometrorrhagia and myoma uteri. Any diagnosis of a urogenital abnormality necessitates investigation of comorbid renal or genital abnormalities. ",0
4736,23847736,Direct identification of breast cancer pathologies using blind separation of label-free localized reflectance measurements,"Breast tumors are blindly identified using Principal (PCA) and Independent Component Analysis (ICA) of localized reflectance measurements. No assumption of a particular theoretical model for the reflectance needs to be made, while the resulting features are proven to have discriminative power of breast pathologies. Normal, benign and malignant breast tissue types in lumpectomy specimens were imaged ex vivo and a surgeon-guided calibration of the system is proposed to overcome the limitations of the blind analysis. A simple, fast and linear classifier has been proposed where no training information is required for the diagnosis. A set of 29 breast tissue specimens have been diagnosed with a sensitivity of 96% and specificity of 95% when discriminating benign from malignant pathologies. The proposed hybrid combination PCA-ICA enhanced diagnostic discrimination, providing tumor probability maps, and intermediate PCA parameters reflected tissue optical properties.  ",0
4737,23847936,Expression analysis and subcellular localization of an ERF transcription factor from Salvia miltiorrhiza],"A SmERF1 gene was isolated from Salvia miltiorrhiza, and expression patterns to different stress condition were analysed in the root tissues of S. miltiorrhiza. The cDNA of SmERF1 gene from S. miltiorrhiza was isolated by RTPCR, and the phylogenetic tree using the neighbour-joining tree method in Mega 5 was obtained. To confirm the protein is likely to localize in the nucleus, the SmERF1 coding region was fused to the N-terminus of the GFP gene under the control of the CaMV 35S promoter and transferred into onion epidermal cells using the particle bombardment method. Semi-quantitative RT-PCR analysis revealed different expression pattern of SmERF1 gene in response to exogenous ABA, MeJA and SA. The phylogenetic tree analysis revealed that SmERF1 is most similar to AP2/ERF VII subgroup members. The transient expression of the SmERF1::GFP fusion protein indicated that the SmERF1 was exclusively localized to the nucleus. The transcript of SmERF1 highly accumulated when the plants were treated with MeJA, while accumulated slightly in response to exogenous ABA, salicylic acid. These results suggest hormone such as ABA, MeJA and SA signaling pathways can be involved in the activation and inhibition of the SmERF1. ",0
4738,23848159,Efficacy of quetiapine off-label uses: data synthesis,"Quetiapine (Seroquel(®)) is a potent U.S. Food and Drug Administration (FDA)-approved antipsychotic agent that has been used extensively for off-label indications. The current study was performed to ascertain the efficacy of some of the most prevalent off-label uses of this agent. An extensive search of electronic databases was completed using the search terms quetiapine or Seroquel, off-label and anxiety, substance abuse, dementia, delirium, personality disorder, insomnia, and sleep. Data were predictably mixed according to the indication being examined. The strongest evidence exists for anxiety and delirium. Moderate evidence exists for quetiapine as a pharmacological intervention for insomnia, dementia, and specific personality disorders. Evidence for quetiapine as a treatment for substance abuse is limited. More data are needed to establish specific dosing regimens for off-label uses and to examine the dose relationship to metabolic side effects and extrapyramidal side effects to determine whether various off-label uses justify the risk incurred with using this powerful drug. ",0
4739,23848193,Co-transplantation of endothelial progenitor cells and mesenchymal stem cells promote neovascularization and bone regeneration,"Bone formation relies on sufficient blood supply and osteoprogenitor cells. The study aims to evaluate the influence of endothelial progenitor cells (EPCs) in combination with mesenchymal stem cells (MSCs) on early vascularization and intramembranous bone regeneration. Vertical bone regeneration was tested in rat calvarium guided bone regeneration model. Gold domes were filled with a mixture of 5 × 10(5) osteogenic transformed MSC and 5 × 10(5) EPC (EPC/MSC) that were mixed with β-tricalcium phosphate (βTCP) scaffold. Domes filled with βTCP alone served as control. Rats were sacrificed after 4 or 12 weeks. Histomorphometry was used to determine blood vessel (Bv) density, vertical bone height, and bone area in the regenerated tissue. At both time points, new augmented hard tissue filled the space under the dome, and Bv density was higher in the EPC/MSC transplanted group vs control. However, bone height and bone area were similar among the groups 4 weeks posttransplantation, but were doubled in the EPC/MSC transplanted group 12 weeks posttransplantation. EPC/MSC transplantation increases Bv formation in the early stages of healing that precedes enhancement of extracortical bone regeneration in later stages. ",0
4740,23848209,Vascular endothelial growth factor A (VEGFA) polymorphisms in Chinese patients with rheumatoid arthritis,"Vascular endothelial growth factor A (VEGFA) is the most potent proangiogenic molecule promoting the angiogenic phenotype of rheumatoid arthritis (RA). We hypothesized that VEGFA polymorphisms may contribute to RA susceptibility. We studied VEGFA rs699947 C/A, rs2010963 G/C, and rs3025039 C/T gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). VEGFA rs699947 C/A, rs2010963 G/C, and rs3025039 C/T polymorphisms were not associated with the risk of RA. However, in the dominant genetic model, a significantly decreased risk for RA associated with the VEGFA rs699947 CA/AA genotypes was evident among older patients and anti-cyclic citrullinated peptide antibody (ACPA)-negative patients compared with the VEGFA rs699947 CC genotype. A significantly decreased risk for RA associated with the VEGFA rs699947 CA genotype was evident among older patients. These findings suggest that the functional single nucleotide polymorphism (SNP) VEGFA rs699947 C/A allele may decrease the risk of RA in older patients and ACPA-negative patients. However, our results were obtained from a moderate-sized sample and therefore this is a preliminary conclusion. Validation by a larger study from a more diverse ethnic population is needed to confirm these findings. ",0
4741,23848344,The interacting effect of the BDNF Val66Met polymorphism and stressful life events on adolescent depression is not an artifact of gene-environment correlation: evidence from a longitudinal twin study,"Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the rGE by two means: separating pure environmental factors (independent SLEs) from the environmental factors under partial genetic control (dependent SLEs) and adopting a prospective longitudinal design. A total of 780 pairs of Chinese twins, aged 11-17 years (mean = 13.6, SD = 1.8) at intake, were followed up twice. Self-reported depression symptoms at Time 1 and Time 2 were assessed by the Children's Depression Inventory (CDI). SLEs occurring between Time 1 and Time 2 were assessed by a self-reported checklist. SLEs were differentiated into independent and dependent ones and were validated by heritability analyses using twin design. The interacting effects between the BDNF Val66Met polymorphism and numbers of SLEs (total SLEs and independent SLEs) on intraindividual change of depression symptoms were examined. After controlling for sex, age, age square, and Time 1 depression, both total SLEs × BDNF Val66Met genotype and independent SLEs × BDNF Val66Met genotype significantly predicted Time 2 depression. Val allele carriers (Val/Val and Val/Met) were more susceptible to the detrimental effects of stress. There is a true G × E effect underlying the observed interaction between BDNF Val66Met polymorphism and environmental stress on depression. ",0
4742,23848355,"Preparation, evaluation and need of spherical crystallization in case of high speed direct tabletting","In direct compression (DC), the significance of usual flow properties of powder from the hopper to the dies of the tablet machine cannot be overstressed. Ensuring the free flow of powder presents a number of challenges to the pharmaceutical formulator in case of high speed tabletting. This research work was conceived to obtain directly compressible agglomerates by spherical crystallization technique and were comparatively evaluated for physicochemical properties as well as tableting properties of agglomerates and unprocessed aceclofenac. Agglomerates of aceclofenac were developed via spherical crystallization method by a solvent arrangement containing dichloromethane (DCM) as a good solvent, water as a bad solvent and acetone as a bridging liquid. Hydroxypropyl cellulose (HPC) in variable quantity was implemented as hydrophilic polymer. The agglomerates were evaluated for yield, solubility, drug content, FTIR spectroscopy, porosity, particle size, micromeritic properties, differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy (SEM), and dissolution studies. The agglomerates expressed improved micromeritic and dissolution properties, in equivalence to pure drug. Formulation F3 (optimized agglomerates) exposed estimable rotundity, better drug release, and easily compression into tablets by high speed DC Technique. The tablets showed acceptable physicochemical properties and complied with the pharmacopoeial specifications. The dissolution rate of prepared tablets from agglomerates was better than the tablets of pure drug. The F3 agglomerates show splendid physicochemical and micromeritic properties. Agglomerated compression mix also showed good tableting properties as needed for high speed compression and enough stability under accelerated conditions at least for 1 month.  ",0
4743,23848426,Atorvastatin is beneficial for muscle reinnervation after complete sciatic nerve section in rats,"Nerve regeneration and functional recovery are often incomplete after peripheral neurotmetic lesion. Atorvastatin has been shown to be neuroprotective after transient ischaemia or traumatic injury. The aim of this study was to establish if systemic administration of Atorvastatin could improve functional muscle reinnervation after complete sciatic nerve section. Sixteen female Sprague-Dawley rats were used in this study. After a complete right sciatic nerve section, end-to-end microsuture repair was performed and fibrin glue was added. Three groups were studied: (1) sutures (S) + fibrin glue (F) only + saline administration for 14 days; (2) S+F+Atorvastatin administration for 14 days; and (3) uninjured nerve. Five months later, the sciatic nerve and the gastrocnemius muscle were isolated to perform in vivo electrophysiological measurements. Better kinematics was observed in atorvastatin-treated rats 5 months after its administration. Indeed, a larger excursion of the hip-ankle-toe angle during walking was observed. This effect was associated with the preservation of electromyographic activity (2.91 mV vs 0.77 mV) and maximal muscle force (85.1 g vs 28.6 g) on stimulation of the proximal nerve section. Five months after a neurotmetic lesion, the recovery is incomplete when using suture and fibrin glue only. Furthermore, the systemic administration of Atorvastatin for 14 days after lesion was beneficial in improving locomotion capability associated with the re-establishment of muscle strength and EMG activity. ",0
4744,23849101,Multi-modality imaging findings of methotrexate-related Epstein-Barr virus-associated hepatic tumor,"Methotrexate (MTX)-associated lymphoproliferative disorders (MTX-LPDs) that occur in rheumatoid arthritis patients who were administered MTX for long periods are well known. However, studies on their pathology in forming hepatic tumors are rare. An approach using diagnostic imaging modalities, mainly computed tomography (CT), is considered a very useful tool for the differential diagnosis of various hepatic tumors. In the present study, detailed findings of dynamic CT, magnetic resonance (MR) imaging, and contrast-enhanced ultrasonography of a hepatic tumor that was confirmed as infected by Epstein-Barr virus, in a rheumatoid arthritis patient administered MTX are presented.  ",0
4745,23849185,"ELIXYS - a fully automated, three-reactor high-pressure radiosynthesizer for development and routine production of diverse PET tracers","Automated radiosynthesizers are vital for routine production of positron-emission tomography tracers to minimize radiation exposure to operators and to ensure reproducible synthesis yields. The recent trend in the synthesizer industry towards the use of disposable kits aims to simplify setup and operation for the user, but often introduces several limitations related to temperature and chemical compatibility, thus requiring reoptimization of protocols developed on non-cassette-based systems. Radiochemists would benefit from a single hybrid system that provides tremendous flexibility for development and optimization of reaction conditions while also providing a pathway to simple, cassette-based production of diverse tracers. We have designed, built, and tested an automated three-reactor radiosynthesizer (ELIXYS) to provide a flexible radiosynthesis platform suitable for both tracer development and routine production. The synthesizer is capable of performing high-pressure and high-temperature reactions by eliminating permanent tubing and valve connections to the reaction vessel. Each of the three movable reactors can seal against different locations on disposable cassettes to carry out different functions such as sealed reactions, evaporations, and reagent addition. A reagent and gas handling robot moves sealed reagent vials from storage locations in the cassette to addition positions and also dynamically provides vacuum and inert gas to ports on the cassette. The software integrates these automated features into chemistry unit operations (e.g., React, Evaporate, Add) to intuitively create synthesis protocols. 2-Deoxy-2-[18F]fluoro-5-methyl-β-l-arabinofuranosyluracil (l-[18F]FMAU) and 2-deoxy-2-[18F]fluoro-β-d-arabinofuranosylcytosine (d-[18F]FAC) were synthesized to validate the system. l-[18F]FMAU and d-[18F]FAC were successfully synthesized in 165 and 170 min, respectively, with decay-corrected radiochemical yields of 46% ± 1% (n = 6) and 31% ± 5% (n = 6), respectively. The yield, repeatability, and synthesis time are comparable to, or better than, other reports. d-[18F]FAC produced by ELIXYS and another manually operated apparatus exhibited similar biodistribution in wild-type mice. The ELIXYS automated radiosynthesizer is capable of performing radiosyntheses requiring demanding conditions: up to three reaction vessels, high temperatures, high pressures, and sensitive reagents. Such flexibility facilitates tracer development and the ability to synthesize multiple tracers on the same system without customization or replumbing. The disposable cassette approach simplifies the transition from development to production. ",0
4746,23849454,Benefits of polyphenols on gut microbiota and implications in human health,"""The biological properties of dietary polyphenols are greatly dependent on their bioavailability that, in turn, is largely influenced by their degree of polymerization. The gut microbiota play a key role in modulating the production, bioavailability and, thus, the biological activities of phenolic metabolites, particularly after the intake of food containing high-molecular-weight polyphenols. In addition, evidence is emerging on the activity of dietary polyphenols on the modulation of the colonic microbial population composition or activity. However, although the great range of health-promoting activities of dietary polyphenols has been widely investigated, their effect on the modulation of the gut ecology and the two-way relationship """"polyphenols ↔ microbiota"""" are still poorly understood. Only a few studies have examined the impact of dietary polyphenols on the human gut microbiota, and most were focused on single polyphenol molecules and selected bacterial populations. This review focuses on the reciprocal interactions between the gut microbiota and polyphenols, the mechanisms of action and the consequences of these interactions on human health.  """,0
4747,23849562,Acquired reactive digital fibroma: a clinicopathologic report of 5 cases of a new entity,"Fibroblastic proliferations in the dermis comprise a heterogeneous group of disorders that can pose diagnostic challenges. We sought to study the clinicopathologic features of this tumor. We reviewed the clinicopathologic features of 5 unusual mesenchymal tumors of the digits that, to our knowledge, correspond to an entity not previously described. The patients were 5 men. All cases were located in the digits and were associated with history of trauma. Histopathologically, the neoplasms were located mainly in the reticular dermis. The tumors consisted of solitary nodules composed of fascicles of benign-appearing spindle cells devoid of cytologic atypia. The spindle cells formed short fascicles arranged in a haphazard manner. On immunohistochemistry, the tumor cells expressed vimentin and in 2 cases, CD34. The tumor cells were negative for smooth muscle actin (SMA), desmin, h-caldesmon, epithelial membrane antigen (EMA), S100, CD68, CD99, and beta-catenin. Only 5 cases were studied. Awareness of this entity is of importance to avoid misdiagnosis with other conditions. Based on the immunohistochemical pattern, we believe that these tumors are fibroblastic in origin. The peculiar gross appearance and location of the lesions is clinically quite distinctive and may lead to confusion with other neoplastic and reactive processes. ",0
4748,23849787,"Lung cancer epidemiology in North Sardinia, Italy","The aim of this study was to analyze and describe the epidemiological characteristics and trends of lung cancer in North Sardinia, Italy, in the period 1992-2010. Data were obtained from the tumor registry of Sassari province which is a part of a wider registry web, coordinated today by the Italian Association for Tumor Registries. The overall number of lung cancer cases registered was 4,325. The male-to-female ratio was 4.6:1 and the mean age 68.1 years for males and 67 years for females. The standardized incidence rates were 73.1/100,000 and 13.5/100,000 and the standardized mortality rates 55.7/100,000 and 9.9/100,000 for males and females, respectively. An increasing trend in incidence of lung cancer in women was evidenced. Conversely, incidence was found to decrease in males. Relative survival at 5 years from diagnosis was low (8.8% for males and 14.9% for females). Furthermore, an increase in mortality rates was observed in both sexes in the period under investigation. Our data show an increasing trend of lung cancer incidence in women in North Sardinia in the last decades. Conversely, a reduction of incidence rates was observed in males. Furthermore, a slightly increasing trend in mortality rates was observed in both sexes, suggesting the need to enhance smoking control strategies, consider adoption of effective surveillance policies, and improve diagnosis and treatment methods. ",0
4749,23849931,Application of the steepest slope model reveals different perfusion territories within the mouse placenta,"The steepest slope model is a numerically robust and fast method for perfusion quantification. The purpose of this study was to evaluate if the steepest slope model can be used for quantifying placental perfusion in mice based on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) datasets. T1-weighted DCE MRI was performed in 5 pregnant BALB/c mice on gestation day (gd) 14.5 and in 5 mice on gd 16.5 using a 7T small animal MRI scanner. The placentas were manually delineated in the DCE datasets and the arterial input function (AIF) was selected from the kidney hilus. Placental perfusion was determined on a voxel-by-voxel basis using the steepest slope model. Perfusion was averaged over the entire placenta as well as separately calculated for the high-flow compartment within the central labyrinth zone and for the remaining low-flow placenta tissue. The AIF selection was independently performed by two observers for assessment of inter-observer differences. Mean perfusion on gd 14.5 was 135 ml/min/100 ml (standard deviation SD: 29 ml/min/100 ml placenta) and 112 ml/min/100 ml on gd 16.5 for the whole placenta (SD: 32 ml/min/100 ml). Perfusion in the high flow compartment in the central labyrinth was significantly higher (p ≤ 0.002) than in the low-flow compartment including the remaining placenta tissue: 184 ml/min/100 ml (SD: 39 ml/min/100 ml) vs. 119 ml/min/100 ml (SD 28 ml/min/100 ml) on gd 14.5 and 158 ml/min/100 ml (SD: 58 ml/min/100 ml) vs. 114 ml/min/100 ml (SD: 52 ml/min/100 ml of placenta) on gd 16.5. The mean relative inter-rater observer difference was 6%. The steepest slope model is a computationally simple method, which allows perfusion quantification in the mouse placenta. Furthermore, the results of this work indicate that the different placental compartments should be analyzed separately to prevent biased results due to averaging. ",0
4750,23850050,Feeding disorders in infants and toddlers: advantages of a joint consultation with pediatrician and psychologist],"Feeding disorders and food refusal can be found in 25% of infants, a minority of these disorders has an organic explanation. Failure to thrive and/or severe malnutrition is found in 3-5% of infants in the general population. The authors describe the various phases of the interdisciplinary therapeutic intervention by underlining the advantages and the objectives to integrate therapeutic approaches across professional boundaries. Caregiver-infant relationship disturbances are certainly the most important factor, but the induced psychosomatic conditions also have a multifactorial etiology. This article points out the specificities of the disorders of infant feeding behaviors and explains the advantages of a joint pediatrician-psychologist consultation compared to separate consultations in pediatrics and child psychiatry.  ",0
4751,23850568,"The effect of novel [3-fluoro-(2-phosphonoethoxy)propyl]purines on the inhibition of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases","Protozoan parasites from the Plasmodiidae family are the causative agents of malaria. Inhibition of hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) has been suggested as a target for development of new anti-malarial therapeutics. Acyclic nucleoside phosphonates (ANPs) are potent and selective inhibitors of plasmodial HG(X)PRTs. A new series of ANPs, based on the chemical structure and inhibitory activity of three ANPs, 2-(phosphonoethoxy)ethyl with either guanine or hypoxanthine as the base (PEEG and PEEHx) and 3-hydroxy-2-(phosphonomethoxy)propyl with guanine as the base (HPMPG), were prepared. These compounds are stereoisomers of 3-fluoro-(2-phosphonoethoxy)propyl (FPEPs) and 3-fluoro-(2-phosphonomethoxy)propyl (FPMPs) analogues. Both the (R)- and (S)-isomers of these fluorinated derivatives have higher Ki values (by 10- to 1000-fold) for human HGPRT and Plasmodium falciparum HGXPRT than the non-fluorinated ANPs. Possible explanations for these changes in affinity are proposed based on docking studies using the known crystal structures of human HGPRT in complex with PEEG.  ",0
4752,23850581,Rats classified as low or high cocaine locomotor responders: a unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors,"Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine's discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors.  ",0
4753,23850719,Effects of exposure to pile driving sounds on fish inner ear tissues,"Impulsive pile driving sound can cause injury to fishes, but no studies to date have examined whether such injuries include damage to sensory hair cells in the ear. Possible effects on hair cells were tested using a specially designed wave tube to expose two species, hybrid striped bass (white bass Morone chrysops × striped bass Morone saxatilis) and Mozambique tilapia (Oreochromis mossambicus), to pile driving sounds. Fish were exposed to 960 pile driving strikes at one of three treatment levels: 216, 213, or 210dB re 1 μPa(2)·s cumulative Sound Exposure Level. Both hybrid striped bass and tilapia exhibited barotraumas such as swim bladder ruptures, herniations, and hematomas to several organs. Hybrid striped bass exposed to the highest sound level had significant numbers of damaged hair cells, while no damage was found when fish were exposed at lower sound levels. Considerable hair cell damage was found in only one out of 11 tilapia specimens exposed at the highest sound level. Results suggest that impulsive sounds such as from pile driving may have a more significant effect on the swim bladders and surrounding organs than on the inner ears of fishes, at least at the sound exposure levels used in this study.  ",0
4754,23851054,Waterborne exposure of zebrafish embryos to micromole concentrations of ioxynil and diethylstilbestrol disrupts thyrocyte development,"The herbicide ioxynil (IOX) and synthetic estrogen diethylstilbestrol (DES) are common aquatic contaminants with an endocrine disrupting action. In juvenile teleost fish IOX and DES disrupt the hypothalamic-pituitary-thyroid (HPT) axis. To assess how IOX and DES influence the developing HPT axis prior to establishment of central regulation of thyroid hormones, zebrafish embryos were exposed to low concentrations of the chemicals in water. IOX and DES (1 and 0.1 μM) exposure failed to modify hypothalamic development but had a negative effect on thyrocyte development. Specifically, IOX and DES caused a significant (p<0.05) reduction in the size of the thyroid anlagen by decreasing the mRNA expression field of both nk2.1a and thyroglobulin (Tg) genes. Inhibition of thyroid gland development by IOX and DES (0.1 μM) was strongly associated with altered heart morphology. To test if the effect of IOX and DES on the thyroid was a consequence of altered cardiac development a morpholino (MO) against zebrafish cardiac troponin I (zcTnI) was microinjected. The zcTnI morphants had modified heart function, a small thyroid anlagen and a reduction in the mRNA expression of nk2.1a and Tg genes similar to that of zebrafish exposed to IOX (1 and 0.1 μM) and DES (0.1 μM). Collectively the data indicate that IOX and DES alter thyroid development in zebrafish and chemicals that alter heart development and function can have an indirect endocrine disrupting action on the thyroid in teleosts. ",0
4755,23851116,"Synthesis and biological evaluation of pyrazolo[4,3-d]pyrimidine analogues","A series of pyrazolo[3,4-d]pyrimidine analogues 3, 4, 5a-f, 6a-f with various amines and ester groups at C-4 and N-1 were synthesized and evaluated for antitumour activity. They were also evaluated for xanthine oxidase inhibitory activity, with most compounds having no significant impact. Compound 5e had the strongest activity against human hepatoma carcinoma cells 7402 and 7221, with half-maximal inhibitory concentration values of 4.55 and 6.28, respectively. Structure-activity relationship studies indicate that chlorine atoms in the structure of 4-((4-(substituted amides)phenyl)amino pyrazolo[4,3-d]pyrimidine analogues is crucial for antitumour activity.  ",0
4756,23851148,Time series analysis of maternal mortality in Africa from 1990 to 2005,"Most global maternal deaths occur in Africa and Asia. In response, the Millennium Development Goal (MDG-5) calls for a 75% reduction in maternal mortality from 1990 to 2015. To assess the potential for progress in MDG-5 in Africa, we examined the cross-sectional and longitudinal associations of socioeconomic, demographic and population-health factors with maternal mortality rates in Africa. We used data from global agencies and the published literature to identify socioeconomic, demographic and population-health explanatory factors that could be correlated with maternal mortality in 49 countries of Africa for the years 1990, 1995, 2000 and 2005. We used correlation, negative binomial and mixed Poisson regression models to investigate whether there exist associations between potential explanatory factors and maternal mortality. Some African countries have made substantial progress towards achieving MDG-5 while others have fallen behind. Lower gross domestic product (GDP) and female enrolment in primary schools, but higher HIV prevalence, neonatal mortality rate and total fertility rate, were associated with higher maternal mortality. Maternal mortality rates in African countries appear to be declining. The mean maternal mortality ratios in Africa decreased from 695.82 in 1990 to 562.18 in 2005. Yet some countries are more likely than others to achieve MDG-5. Better socioeconomic, demographic and population health development appear to be conducive to better maternal health in Africa. Sustained efforts on all these fronts will be needed to close the gap in maternal survival and achieve MDG-5 in Africa. ",0
4757,23851242,"From research to medical advice: prescription of physical activity to 1,005 subjects with type 2 diabetes mellitus by 48 family doctors. Results]","to involve a group of general practitioners (GPs) in a programme for prescribing physical activity (PhA) for patients with type 2 diabetes; to document, for each patient, the amount of physical activity carried out and the modifications in biomedical variables and in the medical expenses possibly occurring after the PhA programme. 48 GPs joined the project. The beneficial effects of regular PhA on diabetes were presented to each patient enrolled. Walking daily for at least 15 minutes was suggested. A booklet with specific instructions and a step meter were given to each patient. Diet programmes were not modified. average daily PhA; values of Body Mass Index (BMI), waist circumference, systolic and diastolic blood pressure, blood glucose and HbA1c, blood cholesterol (total, LDL, HDL) and triglycerides determined before and at the end of the programme; pharmaceutical expenses attributed to the enrolled patients in 2008 (the year preceding the PhA programme) and in 2010 (the year of end of the PhA programme). of the 1,005 patients enrolled, 766 indicated their daily PhA. In all patients, and especially in those who presented values outside the norm in the variables considered at the start of the programme, improvements up to normalization were observed. A reduction in pharmaceutical expenses proportional to the PhA carried out was documented in the more active group of patients, who walked 1 km or more daily. the domiciliary PhA recommended by 48 GPs for 1,005 patients with type 2 diabetes enrolled in the programme was carried out by 766 subjects. The biomedical improvements and the reduction in pharmaceutical expenses, proportional to the PhA carried out, are in keeping with other reports in the literature. The major finding of this project is that GPs can effectively prescribe PhA to their patients who suffer form sport-sensitive diseases, such as type 2 diabetes. ",0
4758,23851247,Population-based registries of Acute Myocardial Infarction in Italy],"The purpose of this study is to discuss some issues related to changes in the diagnostic detection of acute myocardial infarction (AMI) and to present international and national experiences of registration of the major coronary events (MONICA project, EUROCISS project, National Register of the major coronary events, experiences based on the use of current health databases). This paper does not take into account activities aimed to assess quality of care given to patients with AMI and/or acute coronary syndromes (ACS), developed in clinical settings or using current data. In Italy there have been few experiences in registration of AMI and/or ACS, some of them are still in progress. Despite the importance of ACS in terms of public health and health care resources utilisation, these initiatives have not led to a registration network with consistent and comparable recording criteria. This problem is very relevant in relation to the significant changes that have occurred in the past, and which continue to occur, in diagnostic and therapeutic criteria. Currently, the geographic and temporal trends of coronary heart disease are only provided by the current data of hospitalization and mortality, with the limits that these databases involve. The presence of ACS registries could provide standardized diagnostic criteria and comparability of results between different areas of the Country, contributing to a better understanding of the epidemiological dynamics of AMI in Italy.  ",0
4759,23851760,Association of Chiari I malformation and cerebellar ectopia with sensorineural hearing loss,"We aimed to examine the prevalence of cerebellar tonsil ectopia and Chiari 1 malformation in sensorineural hearing loss (SHL) that has, to the best of our knowledge, not been studied previously. Magnetic resonance imaging records of 166 subjects with SHL and 50 controls without known otologic disturbances were included in the study. A tonsils descent more than 2 mm was assumed as cerebellar ectopia, and a descent equal to or more than 5 mm was assumed as Chiari 1 malformation. A tonsil descent group was also formed by summation of both groups. Transverse diameters of bilateral intracranial vertebral arteries and transverse sinuses were also measured, and all parameters were analyzed using appropriate statistics. A significant difference of frequencies of Chiari 1, ectopia, and tonsil descent was detected between patients and controls. In comparison of cerebellar ectopia and Chiari 1 groups, SHL did not show any significant difference. The left lateral sinus diameter showed positive correlation with tonsil descent. There was no significant correlation for the diameters of other vessels. A powerful correlation was detected between SHL and age. In addition, right and vertebral artery diameters showed positive correlations with age. Chiari 1 malformation and cerebellar ectopia showed an association with SHL. These patients should also be evaluated for otologic disturbances. Further high-resolution magnetic resonance imaging studies to explain the exact cause of this currently unknown association seems required.  ",0
4760,23853552,The effect of intermittent antenatal iron supplementation on maternal and infant outcomes in rural Viet Nam: a cluster randomised trial,"Anemia affects over 500 million women, and in pregnancy is associated with impaired maternal and infant outcomes. Intermittent antenatal iron supplementation is an attractive alternative to daily dosing; however, the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Viet Nam. This cluster randomised trial was conducted in Ha Nam province, Viet Nam. 1,258 pregnant women (< 16 wk gestation) in 104 communes were assigned to daily iron-folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Mean birth weight was 3,148 g (standard deviation 416). There was no difference in the birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI -22 to 78), or twice weekly MMN compared to daily IFA (MD -36.8 g; 95% CI -82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly IFA compared to daily IFA (geometric mean ratio 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (geometric mean ratio 0.62; 95% CI 0.57 to 0.68), but there was no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56). Twice weekly antenatal IFA or MMN did not produce a clinically important difference in birth weight, when compared to daily IFA supplementation. The significant improvement in infant cognitive outcomes at 6 mo of age following twice weekly antenatal IFA requires further exploration, and provides additional support for the use of intermittent, rather than daily, antenatal IFA in populations with low rates of iron deficiency. Australia New Zealand Clinical Trials Registry 12610000944033. ",0
4761,23853595,"Reprogramming of murine macrophages through TLR2 confers viral resistance via TRAF3-mediated, enhanced interferon production","""The cell surface/endosomal Toll-like Receptors (TLRs) are instrumental in initiating immune responses to both bacteria and viruses. With the exception of TLR2, all TLRs and cytosolic RIG-I-like receptors (RLRs) with known virus-derived ligands induce type I interferons (IFNs) in macrophages or dendritic cells. Herein, we report that prior ligation of TLR2, an event previously shown to induce """"homo"""" or """"hetero"""" tolerance, strongly """"primes"""" macrophages for increased Type I IFN production in response to subsequent TLR/RLR signaling. This occurs by increasing activation of the transcription factor, IFN Regulatory Factor-3 (IRF-3) that, in turn, leads to enhanced induction of IFN-β, while expression of other pro-inflammatory genes are suppressed (tolerized). In vitro or in vivo """"priming"""" of murine macrophages with TLR2 ligands increase virus-mediated IFN induction and resistance to infection. This priming effect of TLR2 is mediated by the selective upregulation of the K63 ubiquitin ligase, TRAF3. Thus, we provide a mechanistic explanation for the observed antiviral actions of MyD88-dependent TLR2 and further define the role of TRAF3 in viral innate immunity.  """,0
4762,23855326,The club concept: targeting behavioral issues in a residential setting for cognitively impaired adults,"Behavior and psychological symptoms of dementia are common in residential care facilities. These symptoms not only detract from the quality of life of the resident with dementia, but they can be disruptive to the unit and result in harm to staff and other residents. With the trend away from pharmacological management, other creative psychosocial-environmental strategies are being explored. One innovative approach involves the use of the club concept, where selected agitated residents spend a portion of the day in a separate structured environment. This program combines trained staff and tailored activities that optimize mental stimulation, functional independence, and self-esteem. Benefits include reduced incidents of aggressive behaviors and use of psychoactive medications, as well as enhanced quality of life. Not only do the participants benefit from time spent in this specialized setting, but the therapeutic milieu of the facility is also enhanced. Further evaluation of such strategies is needed to quantify the benefits of targeted behavioral interventions for those with cognitive impairment. ",0
4763,23855545,Adjunctive therapy with intravenous lipid emulsion and methocarbamol for permethrin toxicity in 2 cats,"To describe the use of an intravenous lipid emulsion (ILE) as an adjunctive therapy in 2 cats with permethrin toxicity. Two cats that presented with severe permethrin toxicity were treated with ILE as part of their treatment regimens. Both cats improved dramatically following therapy with decontamination, ILE, methocarbamol, and supportive care. This is the first reported use of ILE as an adjunctive treatment for cats with permethrin toxicity. Outcome was favorable in both cats and no adverse effects were noted from the ILE. ",0
4764,23856005,"11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer?","Adrenal C19 steroids, dehydroepiandrostenedione (DHEA(S)) and androstenedione (A4), play a critical role in castration resistant prostate cancer (CRPC) as they are metabolised to dihydrotestosterone (DHT), via testosterone (T), or via the alternate 5α-dione pathway, bypassing T. Adrenal 11OHA4 metabolism in CRPC is, however, unknown. We present a novel pathway for 11OHA4 metabolism in CRPC leading to the production of 11ketoT (11KT) and novel 5α-reduced C19 steroids - 11OH-5α-androstanedione, 11keto-5α-androstanedione, 11OHDHT and 11ketoDHT (11KDHT). The pathway was validated in the androgen-dependent prostate cancer cell line, LNCaP. Androgen receptor (AR) transactivation studies showed that while 11KT and 11OHDHT act as a partial AR agonists, 11KDHT is a full AR agonist exhibiting similar activity to DHT at 1nM. Our data demonstrates that, while 11OHA4 has negligible androgenic activity, its metabolism to 11KT and 11KDHT yields androgenic compounds which may be implicated, together with A4 and DHEA(S), in driving CRPC in the absence of testicular T. ",0
4765,23856070,MD simulations suggest important surface differences between reconstituted and circulating spherical HDL,"Since spheroidal HDL particles (sHDL) are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models. Here we use MD to simulate sHDL with stoichiometries of reconstituted and circulating particles. The hydrophobic effect during simulations rapidly remodels discoidal HDL containing mixed lipids to sHDL containing a cholesteryl ester/triglyceride (CE/TG) core. We compare the results of simulations of previously characterized reconstituted sHDL particles containing two or three apoA-I created in the absence of phospholipid transfer protein (PLTP) with simulations of circulating human HDL containing two or three apoA-I without apoA-II. We find that circulating sHDL compared with reconstituted sHDL with the same number of apoA-I per particle contain approximately equal volumes of core lipid but significantly less surface lipid monolayers. We conclude that in vitro reconstituted sHDL particles contain kinetically trapped excess phospholipid and are less than ideal models for circulating sHDL particles. In the circulation, phospholipid transfer via PLTP decreases the ratio of phospholipid to apolipoprotein for all sHDL particles. Further, sHDL containing two or three apoA-I adapt to changes in surface area by condensation of common conformational motifs. These results represent an important step toward resolving the complicated issue of the protein and lipid stoichiometry of circulating HDL.  ",0
4766,23856303,"A systematic review of studies comparing body image concerns among female college athletes and non-athletes, 1997-2012","Research prior to 2001 indicated that athletes experienced better body image than non-athletes, with no differences among sport types. Since then, female athletes have become increasingly sexually objectified in the media, and the sociocultural beauty ideal has shifted to emphasize appearing both athletic and thin. Part I of this paper explores the literature describing these changes. Part II presents a systematic and comprehensive literature review of 10 recent studies comparing body image concerns (BIC) among collegiate female athletes and non-athletes to identify the current status of BIC in female athletes. Findings indicate that involvement in collegiate athletics provides some protection from BIC; however, this protection appears attenuated for athletes in more feminine sports (e.g., gymnastics), and higher level athletes (Division I). Researchers should examine how sociocultural pressures unrelated to competition predict female athletes' BIC using measures that focus on objectification, positive body image, body functionality, and thin- and athletic-ideal internalization.  ",0
4767,23863050,Alpha emitter radium-223 and survival in metastatic prostate cancer,"BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).",0
4768,23863051,Targeting of low-dose CT screening according to the risk of lung-cancer death,"BACKGROUND: In the National Lung Screening Trial (NLST), screening with low-dose computed tomography (CT) resulted in a 20% reduction in lung-cancer mortality among participants between the ages of 55 and 74 years with a minimum of 30 pack-years of smoking and no more than 15 years since quitting. It is not known whether the benefits and potential harms of such screening vary according to lung-cancer risk. METHODS: We assessed the variation in efficacy, the number of false positive results, and the number of lung-cancer deaths prevented among 26,604 participants in the NLST who underwent low-dose CT screening, as compared with the 26,554 participants who underwent chest radiography, according to the quintile of 5-year risk of lung-cancer death (ranging from 0.15 to 0.55% in the lowest-risk group [quintile 1] to more than 2.00% in the highest-risk group [quintile 5]). RESULTS: The number of lung-cancer deaths per 10,000 person-years that were prevented in the CT-screening group, as compared with the radiography group, increased according to risk quintile (0.2 in quintile 1, 3.5 in quintile 2, 5.1 in quintile 3, 11.0 in quintile 4, and 12.0 in quintile 5; P=0.01 for trend). Across risk quintiles, there were significant decreasing trends in the number of participants with false positive results per screening-prevented lung-cancer death (1648 in quintile 1, 181 in quintile 2, 147 in quintile 3, 64 in quintile 4, and 65 in quintile 5). The 60% of participants at highest risk for lung-cancer death (quintiles 3 through 5) accounted for 88% of the screening-prevented lung-cancer deaths and for 64% of participants with false positive results. The 20% of participants at lowest risk (quintile 1) accounted for only 1% of prevented lung-cancer deaths. CONCLUSIONS: Screening with low-dose CT prevented the greatest number of deaths from lung cancer among participants who were at highest risk and prevented very few deaths among those at lowest risk. These findings provide empirical support for risk-based targeting of smokers for such screening. (Funded by the National Cancer Institute.).",0
4769,23873628,"Cell entry, efficient RNA replication, and production of infectious hepatitis C virus progeny in mouse liver-derived cells","Only humans and chimpanzees are susceptible to chronic infection by hepatitis C virus (HCV). The restricted species tropism of HCV is determined by distinct host factor requirements at different steps of the viral life cycle. In addition, effective innate immune targeting precludes efficient propagation of HCV in nonhuman cells. Species-specificity of HCV host factor usage for cell entry and virus release has been explored. However, the reason for inefficient HCV RNA replication efficiency in mouse liver cells remains elusive. To address this, we generated novel mouse liver-derived cell lines with specific lesions in mitochondrial antiviral signaling protein (MAVS), interferon regulatory factor 3 (IRF3), or Interferon-?/? receptor (IFNAR) by in vivo immortalization. Blunted innate immune responses in these cells modestly increased HCV RNA replication. However, ectopic expression of liver-specific human microRNA 122 (miR-122) further boosted RNA replication in all knockout cell lines. Remarkably, MAVS(-/-) miR-122 cells sustained vigorous HCV RNA replication, attaining levels comparable to the highly permissive human hepatoma cell line Huh-7.5. RNA replication was dependent on mouse cyclophilin and phosphatidylinositol-4 kinase III alpha (PI4KIII?) and was also observed after transfection of full-length viral RNA. Additionally, ectopic expression of either human or mouse apolipoprotein E (ApoE) was sufficient to permit release of infectious particles. Finally, expression of human entry cofactors rendered these cells permissive to HCV infection, thus confirming that all steps of the HCV replication cycle can be reconstituted in mouse liver-derived cells. CONCLUSION: Blunted innate immunity, abundant miR-122, and HCV entry factor expression permits propagation of HCV in mouse liver-derived cell lines.",0
4770,23883380,A novel channelopathy in pulmonary arterial hypertension,"BACKGROUND: Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes. METHODS: We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis. RESULTS: We identified a novel heterozygous missense variant c.608 G?A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082. CONCLUSIONS: Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (Funded by the National Institutes of Health.)",0
4771,23907803,Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection,"Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-? by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-? production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-? production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. CONCLUSION: Endogenous HBV-CpG ODNs from the HBV genome induce IFN-? production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection.",0
4772,23913866,Kinetic differences in the induction of interferon stimulated genes by interferon-? and interleukin 28B are altered by infection with hepatitis C virus,"Several genome-wide association studies (GWAS) have identified a genetic polymorphism associated with the gene locus for interleukin 28B (IL28B), a type III interferon (IFN), as a major predictor of clinical outcome in hepatitis C. Antiviral effects of the type III IFN family have previously been shown against several viruses, including hepatitis C virus (HCV), and resemble the function of type I IFN including utilization of the intracellular Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. Effects unique to IL28B that would distinguish it from IFN-? are not well defined. By analyzing the transcriptomes of primary human hepatocytes (PHH) treated with IFN-? or IL28B, we sought to identify functional differences between IFN-? and IL28B to better understand the roles of these cytokines in the innate immune response. Although our data did not reveal distinct gene signatures, we detected striking kinetic differences between IFN-? and IL28B stimulation for interferon stimulated genes (ISGs). While gene induction was rapid and peaked at 8 hours of stimulation with IFN-? in PHH, IL28B produced a slower, but more sustained increase in gene expression. We confirmed these findings in the human hepatoma cell line Huh7.5.1. Interestingly, in HCV-infected cells the rapid response after stimulation with IFN-? was blunted, and the induction pattern resembled that caused by IL28B. CONCLUSION: The kinetics of gene induction are fundamentally different for stimulations with either IFN-? or IL28B in hepatocytes, suggesting distinct roles of these cytokines within the immune response. Furthermore, the observed differences are substantially altered by infection with HCV.",0
4773,23924002,Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome,"BACKGROUND: Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin. METHODS: We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls. RESULTS: DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease. CONCLUSIONS: We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen. (Funded by the National Cancer Institute and others.)",0
4774,23929627,Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression,"Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize virus replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, clustering and promoter analyses of microarray-based gene expression profiling were combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-??>?IFN-??>?IFN-?3?>?IFN-?1?>?IFN-?2). Notably, although the hierarchy identified varying numbers of differentially expressed genes when quantified using common statistical thresholds, further analysis of gene expression over multiple timepoints indicated that the individual IFNs do not in fact regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-?. While stimulation with either IFN-? or IFN-?s resulted in a similar long-lasting ISG induction, IFN-? signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-? reveal potential specific roles for individual IFNs in the immune response, and elucidate the mechanism behind previously observed differences in IFN antiviral activity. While current clinical trials are focused on IFN-?1 as a potential antiviral therapy, the finding that IFN-?3 invariably possesses the highest activity among type III IFNs suggests that this cytokine may have superior clinical activity.",0
4775,23929719,Quantitative proteomics identifies the membrane-associated peroxidase GPx8 as a cellular substrate of the hepatitis C virus NS3-4A protease,"The hepatitis C virus (HCV) NS3-4A protease is not only an essential component of the viral replication complex and a prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. It cleaves and thereby inactivates two crucial adaptor proteins in viral RNA sensing and innate immunity, mitochondrial antiviral signaling protein (MAVS) and TRIF, a phosphatase involved in growth factor signaling, T-cell protein tyrosine phosphatase (TC-PTP), and the E3 ubiquitin ligase component UV-damaged DNA-binding protein 1 (DDB1). Here we explored quantitative proteomics to identify novel cellular substrates of the NS3-4A protease. Cell lines inducibly expressing the NS3-4A protease were analyzed by stable isotopic labeling using amino acids in cell culture (SILAC) coupled with protein separation and mass spectrometry. This approach identified the membrane-associated peroxidase GPx8 as a bona fide cellular substrate of the HCV NS3-4A protease. Cleavage by NS3-4A occurs at Cys 11, removing the cytosolic tip of GPx8, and was observed in different experimental systems as well as in liver biopsies from patients with chronic HCV. Overexpression and RNA silencing studies revealed that GPx8 is involved in viral particle production but not in HCV entry or RNA replication. CONCLUSION: We provide proof-of-concept for the use of quantitative proteomics to identify cellular substrates of a viral protease and describe GPx8 as a novel proviral host factor targeted by the HCV NS3-4A protease.",0
4776,24002901,Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway,"The molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We performed a genome-wide analysis for aberrant promoter methylation in human CCs. We profiled 10 intrahepatic and 8 extrahepatic CCs in comparison to non-neoplastic biliary tissue specimens, using methyl-CpG immunoprecipitation (MCIp) combined with whole-genome CpG island arrays. DNA methylation was confirmed by quantitative mass spectrometric analysis and functional relevance of promoter hypermethylation was shown in demethylation experiments of two CC cell lines using 5-aza-2'deoxycytidine (DAC) treatment. Immunohistochemical staining of tissue microarrays (TMAs) from 223 biliary tract cancers (BTCs) was used to analyze candidate gene expression at the protein level. Differentially methylated, promoter-associated regions were nonrandomly distributed and enriched for genes involved in cancer-related pathways including Wnt, transforming growth factor beta (TGF-?), and PI3K signaling pathways. In CC cell lines, silencing of genes involved in Wnt signaling, such as SOX17, WNT3A, DKK2, SFRP1, SFRP2, and SFRP4 was reversed after DAC administration. Candidate protein SFRP2 was substantially down-regulated in neoplastic tissues of all BTC subtypes as compared to normal tissues. A significant inverse correlation of SFRP2 protein expression and pT status was found in BTC patients. CONCLUSION: We provide a comprehensive analysis to define the genome-wide methylation landscape of human CC. Several candidate genes of cancer-relevant signaling pathways were identified, and closer analysis of selected Wnt pathway genes confirmed the relevance of this pathway in CC. The presented global methylation data are the basis for future studies on epigenetic changes in cholangiocarcinogenesis.",0
4777,24004119,Results of the two incidence screenings in the National Lung Screening Trial,"BACKGROUND: The National Lung Screening Trial was conducted to determine whether three annual screenings (rounds T0, T1, and T2) with low-dose helical computed tomography (CT), as compared with chest radiography, could reduce mortality from lung cancer. We present detailed findings from the first two incidence screenings (rounds T1 and T2). METHODS: We evaluated the rate of adherence of the participants to the screening protocol, the results of screening and downstream diagnostic tests, features of the lung-cancer cases, and first-line treatments, and we estimated the performance characteristics of both screening methods. RESULTS: At the T1 and T2 rounds, positive screening results were observed in 27.9% and 16.8% of participants in the low-dose CT group and in 6.2% and 5.0% of participants in the radiography group, respectively. In the low-dose CT group, the sensitivity was 94.4%, the specificity was 72.6%, the positive predictive value was 2.4%, and the negative predictive value was 99.9% at T1; at T2, the positive predictive value increased to 5.2%. In the radiography group, the sensitivity was 59.6%, the specificity was 94.1%, the positive predictive value was 4.4%, and the negative predictive value was 99.8% at T1; both the sensitivity and the positive predictive value increased at T2. Among lung cancers of known stage, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group at T1; in the radiography group, 31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV at T1. These differences in stage distribution between groups persisted at T2. CONCLUSIONS: Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiography. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).",0
4778,24038151,Critical interaction between E1 and E2 glycoproteins determines binding and fusion properties of hepatitis C virus during cell entry,"Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are important mediators for productive cell entry. However, knowledge about their structure, intra- or intermolecular dialogs, and conformational changes is scarce, limiting the design of therapeutic strategies targeting E1E2. Here we sought to investigate how certain domains of E1 and E2 have coevolved to optimize their interactions to promote efficient HCV entry. For this purpose we generated chimeric E1E2 heterodimers derived from two HCV 1a strains to identify and characterize crosstalk between their domains. We found an E1E2 combination that drastically impaired the infectivity of cell culture-derived HCV particles, whereas the reciprocal E1E2 combination led to increased infectivity. Using HCV pseudoparticle assays, we confirmed the opposing entry phenotypes of these heterodimers. By mutagenesis analysis, we identified a particular crosstalk between three amino acids of E1 and the domain III of E2. Its modulation leads to either a full restoration of the functionality of the suboptimal heterodimer or a destabilization of the functional heterodimer. Interestingly, we found that this crosstalk modulates E1E2 binding to HCV entry receptors SR-BI and CD81. In addition, we found for the first time that E1E2 complexes can interact with the first extracellular loop of Claudin-1, whereas soluble E2 did not. These results highlight the critical role of E1 in the modulation of HCV binding to receptors. Finally, we demonstrated that this crosstalk is involved in membrane fusion. CONCLUSIONS: These results reveal a multifunctional and crucial interaction between E1 and E2 for HCV entry into cells. Our study highlights the role of E1 as a modulator of HCV binding to receptors and membrane fusion, underlining its potential as an antiviral target.",0
4779,24047455,Effects of bracing in adolescents with idiopathic scoliosis,"BACKGROUND: The role of bracing in patients with adolescent idiopathic scoliosis who are at risk for curve progression and eventual surgery is controversial. METHODS: We conducted a multicenter study that included patients with typical indications for bracing due to their age, skeletal immaturity, and degree of scoliosis. Both a randomized cohort and a preference cohort were enrolled. Of 242 patients included in the analysis, 116 were randomly assigned to bracing or observation, and 126 chose between bracing and observation. Patients in the bracing group were instructed to wear the brace at least 18 hours per day. The primary outcomes were curve progression to 50 degrees or more (treatment failure) and skeletal maturity without this degree of curve progression (treatment success). RESULTS: The trial was stopped early owing to the efficacy of bracing. In an analysis that included both the randomized and preference cohorts, the rate of treatment success was 72% after bracing, as compared with 48% after observation (propensity-score-adjusted odds ratio for treatment success, 1.93; 95% confidence interval [CI], 1.08 to 3.46). In the intention-to-treat analysis, the rate of treatment success was 75% among patients randomly assigned to bracing, as compared with 42% among those randomly assigned to observation (odds ratio, 4.11; 95% CI, 1.85 to 9.16). There was a significant positive association between hours of brace wear and rate of treatment success (P<0.001). CONCLUSIONS: Bracing significantly decreased the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis. The benefit increased with longer hours of brace wear. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and others; BRAIST ClinicalTrials.gov number, NCT00448448.).",0
4780,24064413,Sexuality and couple intimacy in dementia,"The review assesses recent research and its impact on understanding of intimacy and sexuality in older adults with dementia. There is no universally accepted definition of inappropriate sexual behaviors (ISBs), but they have been divided into overt acts associated with increased libido and uninhibited sexual behaviors directed at oneself or other people. Couples affected by dementia frequently maintain physical intimacy. Nonintercourse intimate activities may be preferred over intercourse. Early therapeutic interventions may assist partners in modifying activities, behaviors, and expectations about the future of the relationship. Inappropriate sexual behaviors are commonly due to the disruption of interconnected brain structures. Trauma to the temporal lobes may lead to hypersexuality and ISB. Trauma to the limbic system can produce changes in sexual preference. Both temporal and frontotemporal dementias, or either of them, often present with socially and sexually inappropriate behaviors. Huntington's disease can exhibit hypersexuality, pedophilia, promiscuity, and marital infidelity. The involvement of the medial striatum of the basal ganglia in this disease explains the prevalence of ISB. There is no consensus regarding first-line pharmacotherapy for ISB. Little information is known about the adverse effects. Clinicians and society need to consider how dementia might affect physical intimacy. ",0
4781,24064674,Nano-volume drop patterning for rapid on-chip neuronal connect-ability assays,"""The ability of neurons to extend projections and to form physical connections among them (i.e., """"connect-ability"""") is altered in several neuropathologies. The quantification of these alterations is an important read-out to investigate pathogenic mechanisms and for research and development of neuropharmacological therapies, however current morphological analysis methods are very time-intensive. Here, we present and characterize a novel on-chip approach that we propose as a rapid assay. Our approach is based on the definition on a neuronal cell culture substrate of discrete patterns of adhesion protein spots (poly-d-lysine, 23 ± 5 μm in diameter) characterized by controlled inter-spot separations of increasing distance (from 40 μm to 100 μm), locally adsorbed in an adhesion-repulsive agarose layer. Under these conditions, the connect-ability of wild type primary neurons from rodents is shown to be strictly dependent on the inter-spot distance, and can be rapidly documented by simple optical read-outs. Moreover, we applied our approach to identify connect-ability defects in neurons from a mouse model of 22q11.2 deletion syndrome/DiGeorge syndrome, by comparative trials with wild type preparations. The presented results demonstrate the sensitivity and reliability of this novel on-chip-based connect-ability approach and validate the use of this method for the rapid assessment of neuronal connect-ability defects in neuropathologies.  """,0
4782,24065351,Loss of control eating and weight outcomes after bariatric surgery: a study with a Portuguese sample,"The present study aim is to investigate the frequency of loss of control eating (LOC) episodes in three groups with different assessment times: one before, one at short and one at long-term after bariatric surgery; as well as to explore the association of postoperative problematic eating behaviors and weight outcomes and psychological characteristics. This cross-sectional study compared a group of preoperative bariatric surgery patients (n = 176) and two postoperative groups, one at short-term with <2 years follow-up (n = 110), and one at long-term >2 years follow-up (n = 53). Assessments included the EDE diagnostic interview and a set of self-report measures assessing eating disordered symptomatology, depression, and body image. We found the presence of LOC in 26.7 and 16.9 % of the pre-operative and long-term patients, respectively, and in about 11.8% of the short-term patients. One patient (0.9%) reported objective binge eating episodes at short-time, but subjective binge eating episodes were present in about 10% of the patients in all groups. LOC eating was related with the highest BMIs, the least weight loss, most weight regain, and most psychological impairment in the long-term assessments, but not at short-term. Despite the lower frequencies of disordered eating behavior in the short-term group, patients reporting LOC seem to represent a subgroup of individuals with poorest outcomes after surgery and most psychological distress. ",0
4783,24065955,Relaxin-3/RXFP3 Signaling and Neuroendocrine Function - A Perspective on Extrinsic Hypothalamic Control,"""Complex neural circuits within the hypothalamus that govern essential autonomic processes and associated behaviors signal using amino acid and monoamine transmitters and a variety of neuropeptide (hormone) modulators, often via G-protein coupled receptors (GPCRs) and associated cellular pathways. Relaxin-3 is a recently identified neuropeptide that is highly conserved throughout evolution. Neurons expressing relaxin-3 are located in the brainstem, but broadly innervate the entire limbic system including the hypothalamus. Extensive anatomical data in rodents and non-human primate, and recent regulatory and functional data, suggest relaxin-3 signaling via its cognate GPCR, RXFP3, has a broad range of effects on neuroendocrine function associated with stress responses, feeding and metabolism, motivation and reward, and possibly sexual behavior and reproduction. Therefore, this article aims to highlight the growing appreciation of the relaxin-3/RXFP3 system as an important """"extrinsic"""" regulator of the neuroendocrine axis by reviewing its neuroanatomy and its putative roles in arousal-, stress-, and feeding-related behaviors and links to associated neural substrates and signaling networks. Current evidence identifies RXFP3 as a potential therapeutic target for treatment of neuroendocrine disorders and related behavioral dysfunction.  """,0
4784,24066099,Task-sharing of HIV care and ART initiation: evaluation of a mixed-care non-physician provider model for ART delivery in rural Malawi,"Expanding access to antiretroviral therapy (ART) in sub-Saharan Africa requires implementation of alternative care delivery models to traditional physician-centered approaches. This longitudinal analysis compares outcomes of patients initiated on antiretroviral therapy (ART) by non-physician and physician providers. Adults (≥15 years) initiating ART between September 2007 and March 2010, and with >1 follow-up visit were included and classified according to the proportion of clinical visits performed by nurses or by clinical officers (≥ 80% of visits). Multivariable Poisson models were used to compare 2-year program attrition (mortality and lost to follow-up) and mortality by type of provider. In sensitivity analyses only patients with less severe disease were included. A total of 10,112 patients contributed 14,012 person-years to the analysis: 3386 (33.5%) in the clinical officer group, 1901 (18.8%) in the nurse care group and 4825 (47.7%) in the mixed care group. Overall 2-year program retention was 81.8%. Attrition was lower in the mixed care and higher in the clinical officer group, compared to the nurse group (adjusted incidence rate ratio [aIRR]=0.54, 95%CI 0.45-0.65; and aIRR=3.03, 95%CI 2.56-3.59, respectively). While patients initiated on ART by clinical officers in the mixed care group had lower attrition (aIRR=0.36, 95%CI 0.29-0.44) than those in the overall nurse care group; no differences in attrition were found between patients initiated on ART by nurses in the mixed care group and those included in the nurse group (aIRR=1.18, 95%CI 0.95-1.47). Two-year mortality estimates were aIRR=0.72, 95%CI 0.49-1.09 and aIRR=5.04, 95%CI 3.56-7.15, respectively. Slightly higher estimates were observed when analyses were restricted to patients with less severe disease. The findings of this study support the use of a mixed care model with well trained and regularly supervised nurses and medical assistants to provide HIV care in countries with high HIV prevalence. ",0
4785,24066160,Colorectal cancers from distinct ancestral populations show variations in BRAF mutation frequency,"It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer.  ",0
4786,24066178,Impact of personalised feedback about physical activity on change in objectively measured physical activity (the FAB study): a randomised controlled trial,"Low levels of physical activity are a major public health concern, and interventions to promote physical activity have had limited success. Whether or not personalised feedback about physical activity following objective measurement motivates behaviour change has yet to be rigorously examined. And Findings: In a parallel group, open randomised controlled trial, 466 healthy adults aged 32 to 54 years were recruited from the ongoing population-based Fenland Study (Cambridgeshire, UK). Participants were randomised to receive either no feedback until the end of the trial (control group, n=120) or one of three different types of feedback: simple, visual, or contextualised (intervention groups, n=346). The primary outcome was physical activity (physical activity energy expenditure (PAEE) in kJ/kg/day and average body acceleration (ACC) in m/s(2)) measured objectively using a combined heart rate monitor and accelerometer (Actiheart(®)). The main secondary outcomes included self-reported physical activity, intention to increase physical activity, and awareness of physical activity (the agreement between self-rated and objectively measured physical activity). At 8 weeks, 391 (83.9%) participants had complete physical activity data. The intervention had no effect on objectively measured physical activity (PAEE: β=-0.92, 95% CI=-3.50 to 1.66, p=0.48 and ACC: β=0.01, 95% CI=-0.00 to 0.02, p=0.21), self-reported physical activity (β=-0.39, 95% CI=-1.59 to 0.81), or intention to increase physical activity (β=-0.05, 95% CI=-0.22 to 0.11). However, it was associated with an increase in awareness of physical activity (OR=1.74, 95% CI=1.05 to 2.89). Results did not differ according to the type of feedback. Personalised feedback about physical activity following objective measurement increased awareness but did not result in changes in physical activity in the short term. Measurement and feedback may have a role in promoting behaviour change but are ineffective on their own. Current Controlled Trials ISRCTN92551397 http://www.controlled-trials.com/ISRCTN92551397. ",0
4787,24066287,Initial dose of three monthly intravitreal injections versus PRN intravitreal injections of bevacizumab for macular edema secondary to branch retinal vein occlusion,"To compare visual and anatomic outcomes of intravitreal bevacizumab injections administered as needed (PRN group) and initial treatment with 3 monthly injections followed by as-needed injections (3 monthly initial dose group) in patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO). This retrospective study included 69 and 26 patients in the PRN and 3 monthly initial dose groups, respectively. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were compared between the 2 groups 6 months after initial injection. At month 6, BCVA change from baseline was -0.27 ± 0.28 (mean ± standard deviation) logMAR in the PRN group and -0.28 ± 0.20 logMAR in the 3 monthly initial dose group. Mean CRT changes were -204 ± 168 in the PRN group and -161 ± 149  μ m in the 3 monthly initial dose group at month 6. There were no statistically significant differences in BCVA or CRT changes between groups at any time point. The number of intravitreal injections over 6 months was significantly lower in the PRN group (1.8 ± 0.8 injections) than in the 3 monthly initial dose group (3.4 ± 0.5 injections; P < 0.001). Our results suggest that as-needed intravitreal bevacizumab injections are more tolerable for patients with ME secondary to BRVO. ",0
4788,24066536,"Effects of relative abundance of Quercus mongolica acorns on five tree species seed dispersal in Xiaoxing' an Mountains, Northeast China]","An investigation was conducted in a forest farm in the Xiaoxing' an Mountains in autumn, 2009 and 2010 to study the effects of Quercus mongolica acorn quantity and rodent density on the seed dispersal of five tree species (Juglans mandshurica, Pinus koraiensis, Corylus mandshurica, Corylus heterophylla, and Q. mongolica). In the farm, there was an annual change in rodent density. The total capture rate of small rodents in 2009 (31.0%) was significantly higher than that in 2010 (16.7%). The acorn quantity and relative seed abundance (per capita rodent) of Quercus mongolica in 2009 (6.2 +/- 2.1 acorns x m(-2) and 20.0, respectively) were significantly lower than those in 2010 (26.7 +/- 10.2 acorns x m(-2) and 160.0, respectively). In 2009, all the seeds of the five tree species except J. mandshurica were dispersed or eaten in situ, among which, the acorns of Q. mongolica were scatter-hoarded most, and their average dispersal distance was the furthest. In 2010, the seeds of J. mandshurica were scatter-hoarded most, and their average dispersal distance was the furthest. The relative seed abundance of Q. mongolica could be the key factor determining the seed dispersal of the other tree species in the study area. ",0
4789,24066744,Robotic leg control with EMG decoding in an amputee with nerve transfers,"The clinical application of robotic technology to powered prosthetic knees and ankles is limited by the lack of a robust control strategy. We found that the use of electromyographic (EMG) signals from natively innervated and surgically reinnervated residual thigh muscles in a patient who had undergone knee amputation improved control of a robotic leg prosthesis. EMG signals were decoded with a pattern-recognition algorithm and combined with data from sensors on the prosthesis to interpret the patient's intended movements. This provided robust and intuitive control of ambulation--with seamless transitions between walking on level ground, stairs, and ramps--and of the ability to reposition the leg while the patient was seated.",0
4790,24066915,Evaluation of mRNA expression levels and electrophysiological function of neuron-like cells derived from canine bone marrow stromal cells,"To investigate the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into functional, mature neurons. Bone marrow from 6 adult dogs. BMSCs were isolated from bone marrow and chemically induced to develop into neurons. The morphology of the BMSCs during neuronal induction was monitored, and immunocytochemical analyses for neuron markers were performed after the induction. Real-time PCR methods were used to evaluate the mRNA expression levels of markers for neural stem or progenitor cells, neurons, and ion channels, and western blotting was used to assess the expression of neuronal proteins before and after neuronal induction. The electrophysiological properties of the neuron-like cells induced from canine BMSCs were evaluated with fluorescent dye to monitor Ca(2)+ influx. Canine BMSCs developed a neuron-like morphology after neuronal induction. Immunocytochemical analysis revealed that these neuron-like cells were positive for neuron markers. After induction, the cells' mRNA expression levels of almost all neuron and ion channel markers increased, and the protein expression levels of nestin and neurofilament-L increased significantly. However, the neuron-like cells derived from canine BMSCs did not have the Ca(2)+ influx characteristic of spiking neurons. Although canine BMSCs had neuron-like morphological and biochemical properties after induction, they did not develop the electrophysiological characteristics of neurons. Thus, these results have suggested that canine BMSCs could have the capacity to differentiate into a neuronal lineage, but the differentiation protocol used may have been insufficient to induce development into functional neurons. ",0
4791,24067949,Idiopathic sudden sensorineural hearing loss: vascular or viral?,"To demonstrate that sudden sensorineural hearing loss is possibly of viral origin rather than vascular. The histopathologic morphology in 7 temporal bones with known vascular impairment due to surgical interventions was compared with that of 11 bones with a history of idiopathic sudden sensorineural hearing loss (ISSNHL). Attention was paid to the spiral ligament, stria vascularis, organ of Corti hair cells, tectorial membrane, ganglion cell population, and degree of perilymph fibrosis and the auditory nerve. A temporal bone laboratory that has been in operation for more than 50 years and includes a database consisting of clinical and histopathological information that facilitates quantitative and qualitative analysis. Eight hundred forty-nine individuals who pledged their temporal bones for scientific study, of which 18 were selected for this study by means of the database criteria of sudden sensorineural hearing loss and postmiddle fossa and retro sigmoid sinus tumor removal or vestibular nerve section. Sudden sensorineural hearing loss bones exhibited no perilymph fibrosis compared with 6 of 7 vascular cases with fibrosis (P ≤ .001), exhibited less loss of ganglion cells (P ≤ .026), exhibited greater survival of spiral ligament (P ≤ .029), and averaged twice the survival of hair cells and more widespread tectorial membrane abnormalities. Analysis of human temporal bones from patients with a sudden sensorineural hearing loss does not support a vascular insufficiency but is more suggestive of a viral etiology. ",0
4792,24067960,Apoptosis induction influences reovirus replication and virulence in newborn mice,"Apoptosis is a type of controlled cell death that is essential for development and tissue homeostasis. It also serves as a robust host response against infection by many viruses. The capacity of neurotropic viruses to induce apoptosis strongly correlates with virulence. However, the precise function of apoptosis in viral infection is not well understood. Reovirus is a neurotropic virus that induces apoptosis in a variety of cell types, including central nervous system neurons, leading to fatal encephalitis in newborn mice. To determine the effect of apoptosis on reovirus replication in the host, we generated two otherwise isogenic viruses that differ in a single amino acid in viral capsid protein μ1 that segregates with apoptotic capacity. Apoptosis-proficient and apoptosis-deficient viruses were compared for replication, dissemination, tropism, and tissue injury in newborn mice and for the capacity to spread to uninfected littermates. Our results indicate that apoptotic capacity enhances reovirus replication in the brain and consequent neurovirulence but reduces transmission efficiency. The replication advantage of the apoptosis-proficient strain is limited to the brain and correlates with enhanced infectivity of neurons. These studies reveal a new cell type-specific determinant of reovirus virulence.  ",0
4793,24067971,"Parvovirus B19 uptake is a highly selective process controlled by VP1u, a novel determinant of viral tropism","The VP1 unique region (VP1u) of human parvovirus B19 (B19V) is the immunodominant part of the viral capsid. Originally inaccessible, the VP1u becomes exposed upon primary attachment to the globoside receptor. To study the function of the exposed VP1u in B19V uptake, we expressed this region as a recombinant protein. Here, we report that purified recombinant VP1u binds and is internalized in UT7/Epo cells. By means of truncations and specific antibodies, we identified the most N-terminal amino acid residues of VP1u as the essential region for binding and internalization. Furthermore, the recombinant VP1u was able to block B19V uptake, suggesting that the protein and the virus undertake the same internalization pathway. Assays with different erythroid and nonerythroid cell lines showed that the N-terminal VP1u binding was restricted to a few cell lines of the erythroid lineage, which were also the only cells that allowed B19V internalization and infection. These results together indicate that the N-terminal region of VP1u is responsible for the internalization of the virus and that the interacting receptor is restricted to B19V-susceptible cells. The highly selective uptake mechanism represents a novel determinant of the tropism and pathogenesis of B19V.  ",0
4794,24068491,"Oral health care in children with haemophilia in Helsinki, Finland","The bleeding tendency and fear of bleeds may have a negative effect on preventive dental care of patients with haemophilia both at home and at dental appointments. To describe the clinical practice of dental care in children with haemophilia in Helsinki, Finland. This study evaluated retrospectively the medical records of 28 paediatric patients with haemophilia (aged 5.3-17.4 years) from dental visits during 2009-2010. Decayed, missing and filled teeth in the primary (dmft) and permanent dentition (DMFT), Community Periodontal Index (CPI), signs of developmental dental defects in enamel and the number of preventive and restorative procedures were gathered. Dmft + DMFT scores were compared with those of 17,079 non-haemophiliac boys. The Mann-Whitney U-test was used to compare the data between the groups of different severity of haemophilia. The median number of dental visits per patient was three (range 1-11). Twenty-two patients (79 %) had dmft + DMFT-scores within the 95 % reference range for age. None of the children had a CPI >2. Twelve (43 %) patients had developmental enamel defects. Half had received restorative dental care and three out of four preventive procedures. Dental care during hospital visits in children with haemophilia may enhance confidence in the preventive dental care and help minimise bleeding during dental procedures. ",0
4795,24068529,Current management of choroid plexus carcinomas,"Choroid plexus carcinoma (CPC) is a World Health Organization (WHO) grade III brain tumor with a poor prognosis that occurs mainly in children. Gross total resection of CPC is highly recommended and is associated with improved overall survival, although it is often associated with increased morbidity. The use of adjuvant therapies has yet to be standardized, although evidence suggests that for patients with incompletely resected CPCs, a combination of chemotherapy and radiation therapy may be beneficial. The use of radiation therapy for younger children (<3 years old) with CPC, however, is not recommended, due to the potential negative neurological sequelae associated with radiation to the developing brain. Given that the majority of CPC patients are young children, questions regarding optimal radiation dose, chemotherapy agents, and how to combine these two adjuvant treatment modalities to achieve the best outcomes remain unanswered. In this paper we summarize the current management of CPC in the literature. Further studies are needed to standardize the treatment paradigm for this malignant brain tumor. ",0
4796,24069211,The ral exchange factor rgl2 promotes cardiomyocyte survival and inhibits cardiac fibrosis,"Cardiomyocytes compensate to acute cardiac stress by increasing in size and contractile function. However, prolonged stress leads to a decompensated response characterized by cardiomyocyte death, tissue fibrosis and loss of cardiac function. Identifying approaches to inhibit this transition to a decompensated response may reveal important targets for treating heart failure. The Ral guanine nucleotide disassociation (RalGDS) proteins are Ras-interacting proteins that are upregulated by hypertrophic stimuli. The Ral guanine nucleotide dissociation stimulator-like 2 (Rgl2) is a member of the RalGDS family that modulates expression of hypertrophic genes in cardiomyocytes. However, the pathophysiologic consequence of increased Rgl2 expression in cardiomyoctyes remains unclear. To evaluate the effect of increasing Rgl2 activity in the heart, transgenic mice with cardiac-targeted over-expression of Rgl2 were generated. Although Ral activation was increased, there were no apparent morphologic or histological differences between the hearts of Rgl2 transgenic and nontransgenic mice indicating that increased Rgl2 expression had no effect on basal cardiac phenotype. To determine if Rgl2 modulates the cardiac response to stress, mice were infused with the ß-adrenergic receptor agonist, isoproterenol. Isoproterenol infusion increased heart mass in both Rgl2 transgenic and nontransgenic mice. However, unlike nontransgenic mice, Rgl2 transgenic mice showed no morphologic evidence of cardiomyocyte damage or increased cardiac fibrosis following isoproterenol infusion. Increased Rgl2 expression in cultured cardiomyocytes stimulated Ral activation and inhibited staurosporine-induced apoptosis via increased activation of PI3-kinase. Activation of the PI3-kinase signaling pathway was confirmed in hearts isolated from Rgl2 transgenic mice. Increased expression and function of Rgl2 in cardiomyocytes promotes activation of the PI3-kinase signaling cascade and protects from carciomyocyte death and pathologic cardiac fibrosis. Taken further, these results suggest that Rgl2 upregulation in hypertrophic hearts may be a protetive mechanism, and that Rgl2 may be a novel therapeutic target in treating heart disease.  ",0
4797,24069399,ALG-2 attenuates COPII budding in vitro and stabilizes the Sec23/Sec31A complex,"Coated vesicles mediate the traffic of secretory and membrane cargo proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. The coat protein complex (COPII) involved in vesicle budding is constituted by a GTPase, Sar1, the inner coat components of Sec23/Sec24 and the components of the outer coat Sec13/Sec31A. The Ca(2+)-binding protein ALG-2 was recently identified as a Sec31A binding partner and a possible link to Ca(2+) regulation of COPII vesicle budding. Here we show that ALG-2/Ca(2+) is capable of attenuating vesicle budding in vitro through interaction with an ALG-2 binding domain in the proline rich region of Sec31A. Binding of ALG-2 to Sec31A and inhibition of COPII vesicle budding is furthermore dependent on an intact Ca(2+)-binding site at EF-hand 1 of ALG-2. ALG-2 increased recruitment of COPII proteins Sec23/24 and Sec13/31A to artificial liposomes and was capable of mediating binding of Sec13/31A to Sec23. These results introduce a regulatory role for ALG-2/Ca(2+) in COPII tethering and vesicle budding.  ",0
4798,24069553,Sphingosine-1-phosphate: Driver of NFκB and STAT3 persistent activation in chronic intestinal inflammation and colitis-associated cancer,"Inflammatory bowel disease is associated with an increased risk of colorectal cancer. Colitis-associated cancer is a classical inflammation-driven cancer in which constitutive NFκB and STAT3 activation drive tumorigenesis. Recent findings published by Liang et al. in Cancer Cell demonstrate that sphingosine kinase 1 (SphK1)-mediated upregulation of sphingosine-1-phosphate (S1P) drives a persistent NFκB/IL-6/STAT3/sphingosine-1-phosphate receptor 1 (S1PR1) amplification loop that is critical to the development of chronic colitis and colitis-associated cancer. FTY720, an antagonist of S1PR1, abolished persistent NFκB/IL-6/STAT3 signaling and reduced the development and progression of colitis-associated cancer. Targeting SphK1/S1P/S1PR1 may provide a therapeutic option to prevent the progression of colitis to cancer.  ",0
4799,24069863,Tourist activity of young people as a factor contributing to their health and proper development,"The aim of this paper is to assess the level of tourist activity of pupils and students from schools in Warsaw, as well as factors influencing this level of activity. A two-part questionnaire was used that included questions related to participation in tourist trips (day, long, short, and trips abroad) and the International Physical Activity Questionnaire (IPAQ). Among the analyzed factors (gender, level of school, level of physical activity), only the level of school turned out to be the factor which significantly (p=0.000) influenced the physical activity of the respondents. It was observed that tourist activity among pupils and students decreased with age. There is an urgent need for a systematic approach towards promoting and supporting the participation of children and young people in tourism. as well as setting examples of how to travel and rest. Carrying out intervention programmes demands the further identification of factors determining them (e.g. influence of parents' leisure time behaviour), as well as the application of standardized research tools. ",0
4800,24070603,Glial cell line-derived neurotrophic factor induces cell migration in human oral squamous cell carcinoma,"Perineural invasion is a prominent clinical feature of various cancers, which causes difficulty in curative resection. Glial cell-derived neurotrophic factor (GDNF), a potent neurotrophic factor, plays an important role in the invasive and metastatic behavior of various cancers. The aim of this study was to examine the role of GDNF on oral squamous cell carcinoma. GDNF expression in tissue samples was analyzed by immunohistochemistry. Transwell assay, zymography, Western blot, reverse transcription-PCR, and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of GDNF on oral cancer cells. Human oral cancer tissues showed higher GDNF expression than that in normal tissues. We also found that application of human GDNF enhanced the cell migration ability of human oral cancers. Moreover, treatment with GDNF increased matrix metalloproteinase (MMP)-9 and MMP-13 expression in oral cancer. Inhibition of MMP-9 and MMP-13 in oral cancer cells by pharmacological inhibitors or neutralizing antibodies reduced GDNF-enhanced cell migration. Moreover, transfection with siRNA against MMP-13 inhibited GDNF-enhanced cell migration. Treatment with GDNF also increased ERK, p38 and JNK phosphorylation, and AP-1 DNA binding activity in human oral cancer cells. Inhibition of MAP kinase or AP-1 also reduced GDNF-induced oral cancer cell migration. In migration-prone sublines, oral cancer cells showed a higher migration ability than that of the original oral cancer cells. Surprisingly, the enhancement of cell migratory activity in migration-prone sublines was reduced by a GDNF-neutralizing antibody. Importantly, migration-prone sublines of oral cancer revealed higher GDNF expression. These results indicate a regulatory effect on cell migration by GDNF in oral squamous cancer. ",0
4801,24070614,A functional magnetic resonance imaging study of working memory in youth after sports-related concussion: is it still working?,"Abstract In children, the importance of detecting deficits after mild traumatic brain injury (mTBI) or concussion has grown with the increasing popularity of leisure physical activities and contact sports. Whereas most postconcussive symptoms (PCS) are similar for children and adults, the breadth of consequences to children remains largely unknown. To investigate the effect of mTBI on brain function, we compared working memory performance and related brain activity using blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in 15 concussed youths and 15 healthy age-matched control subjects. Neuropsychological tests, self-perceived PCS, and levels of anxiety and depression were also assessed. Our results showed that, behaviorally, concussed youths had significantly worse performances on the working memory tasks, as well as on the Rey figure delayed recall and verbal fluency. fMRI results revealed that, compared to healthy children, concussed youths had significantly reduced task-related activity in bilateral dorsolateral prefrontal cortex, left premotor cortex, supplementary motor area, and left superior parietal lobule during performance of verbal and nonverbal working memory tasks. Additionally, concussed youths also showed less activation than healthy controls in the dorsal anterior cingulate cortex, left thalamus, and left caudate nucleus during the nonverbal task. Regression analysis indicated that BOLD signal changes in bilateral dorsolateral prefrontal cortex were significantly correlated with performance such that greater activities in these regions, relative to the control condition, were associated with greater accuracy. Our findings confirmed functional alterations in brain activity after concussion in youths, a result similar to that observed in adults. However, significant differences were noted. In particular, the observation of reduced working memory accuracy suggests that youths may be unable to engage compensatory strategies to maintain cognitive performance after mTBI. This has significant implications for safe return to daily activities, including competitive sport.  ",0
4802,24071493,Interventional oncology in the elderly: complications and early response in liver and kidney malignancies,"The complication rate, loco-regional responses and length of hospital stay were analyzed in patients with liver and kidney cancer older than 70years treated with interventional oncology procedures. The findings from the older population were compared with the younger patients (<70years) to detect any difference not related to chance. Prospectively collected data on patients who underwent hepatic artery embolization (with or without radiofrequency ablation) and kidney radiofrequency ablation were retrospectively analyzed. Complication rates, loco-regional responses and length of hospital stay for patients older and younger than 70 were compared. 163 patients were treated, 66 (40.5%) older and 97 (59.5%) younger than 70years. The complication rate in patients older than 70 was 4.5% (3/66 pts) versus 3.1% (3/97 pts) (p=0.69) in the younger age-group. The complication rates for the liver embolization group, liver embolization plus radiofrequency and kidney radiofrequency group were 2/90 pts (2.2%), 2/42 pts (4.8%) and 2/31 pts (6.5%), respectively (p=0.46). Median hospital stay was three nights in both older and younger patients. Response rates were not significantly influenced by age. Liver embolization with or without radiofrequency and renal radiofrequency are safe and effective in older patients. Age alone should not be considered a contraindication to treatment in carefully selected patients. ",0
4803,24071704,Expression and significance of thrombonspondin-1 in oxygen-induced retinopathy in mice],"To examine the expression and function of thrombonspondin-1 (TSP-1) in oxygeninduced retinopathy in new-born mice, and to investigate its role in retinal neovascularization. A total of 40 C57BL / 6J newborn mice were divided equally into a model group (n=20) and a normal control group (n=20). Mice in the model group were exposed to 75% oxygen to establish the oxygen-induced retinopathy (OIR) model. On the 7th, 9th, and 11th day after the birth of mice, 5 mice were randomly selected each time from the 2 groups to examine the expression of TSP-1 mRNA with reverse transcription polymerase chain reaction (RT-PCR). After that, 5 mice were selected on the 11th day to observe the retinal neovascularization by fluorescein angiography retinal flatmount. On the 11th day, fluorescein angiography retinal flatmount showed that the retinal blood vessels presented mean network distribution in the normal control group, while in the model group, a lot of dilatated areas in the retinal main vessels surrounded the optic disc. Meanwhile lots of new blood vessels were found surrounding the optic disc with irregular distribution but well distributed peripheral retinal small vessels, which was typical of early stage OIR. There was no significant difference in the retinal TSP-1 mRNA level between the model group and the normal control group in the postnatal 7-day mice (P>0.05). Compared with the normal control group, the expression of TSP-1 mRNA in the model group was significantly lower in postnatal 9-day and 11-day mice (P<0.05, P<0.01) , and the expression of TSP-1 mRNA in postnatal 9-day mice was lower than that in the postnatal 11-day mice(P<0.05). In the early stage of OIR model (retinal vascular growth and development stage), the expression of TSP-1 mRNA in the retinal tissue is gradually decreased, implying that TSP-1 (as a negative regulatory factor) may be involved in the formation of retinal neovascularization in the early stage. ",0
4804,24071734,Differential interaction of neuroleptics with apomorphine-induced behavior in rats as a function of changing levels of dopamine receptor stimulation,"Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose-dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal grooming that typically occurs immediately after the agitation phase has been terminated. Progressively higher doses were required to antagonize higher levels of apomorphine at earlier time intervals after the intravenous injection. The compounds also decreased palpebral opening, and most of them suppressed grooming behavior at higher doses. Compounds differed considerably in dose increments required for: 1) suppression of grooming, from 0.33 for clozapine to >600 for remoxipride, raclopride, and droperidol; 2) blockade of agitation at 5 minutes after apomorphine, from 2.6 for pimozide to 165 for chlorprothixene and 254 for remoxipride; 3) mild decrease of palpebral opening, from 0.21 for sertindole to 191 for remoxipride; and 4) pronounced decrease of palpebral opening, from 10 for melperone to >820 for raclopride. Only four compounds were able to advance grooming to 15 minutes postapomorphine, but again dose increments varied considerably: droperidol (3.4), pimozide (9.1), raclopride (42), and remoxipride (383). Based on these results obtained in a single animal model, compounds were differentiated in terms of behavioral specificity, incisiveness (the power to counteract the effects of progressively higher apomorphine concentrations), and sedative side-effect liability. Possible explanations for the observed differences and clinical relevance are discussed.  ",0
4805,24071782,Coffee and tea: perks for health and longevity?,"Tea and coffee, after water, are the most commonly consumed beverages in the world and are the top sources of caffeine and antioxidant polyphenols in the American diet. The purpose of this review is to assess the health effects of chronic tea and/or coffee consumption. Tea consumption, especially green tea, is associated with significantly reduced risks for stroke, diabetes and depression, and improved levels of glucose, cholesterol, abdominal obesity and blood pressure. Habitual coffee consumption in large epidemiological studies is associated with reduced mortality, both for all-cause and cardiovascular deaths. In addition, coffee intake is associated with risks of heart failure, stroke, diabetes mellitus and some cancers in an inverse dose-dependent fashion. Surprisingly, coffee is associated with neutral to reduced risks for both atrial and ventricular arrhythmias. However, caffeine at high doses can increase anxiety, insomnia, calcium loss and possibly the risk of fractures. Coffee and tea can generally be recommended as health-promoting additions to an adult diet. Adequate dietary calcium intake may be particularly important for tea and coffee drinkers. ",0
4806,24071878,Adenocarcinoma arising from vaginal stump: unusual vaginal carcinogenesis 7 years after hysterectomy due to cervical intraepithelial neoplasia,"Primary vaginal adenocarcinomas are one of the rarest malignant neoplasms, which develop in the female genital tract. Because of the extremely low incidence, their clinical and pathologic characteristics are still obscure. Recently, we experienced a case of vaginal adenocarcinoma that appeared 7 yr after hysterectomy because of cervical intraepithelial neoplasia. The patient, a 65-yr-old obese woman, was diagnosed as having adenocarcinoma in the vaginal stump and was treated by simple tumor excision and radiation. Immunohistochemical and molecular biologic examinations indicated a potential association with human papilloma virus infection in the development of the vaginal adenocarcinoma. There has been no evidence of recurrence for 3 yr after the operation.  ",0
4807,24072093,Multiple pituitary hormone deficiency due to gunshot injury in a 6-year-old girl,"Gunshot injuries (GSI) of the cranial area have an extremely high mortality rate. Herein, we present a girl who has been living with a bullet in the posterior sellar region. A 6-year-old girl was admitted with complaints of headache, polyuria and polydypsia, which started after a GSI. At the time of admission the patient's anthropometric, physical and neurological examinations were normal. Urine output was 5.5 L/m2/24h. A water deprivation test suggested central diabetes insipidus, which responded to treatment. Evaluation of other pituitary hormones revealed central hypothyroidism and growth hormone deficiency. Pituitary hormone deficiency must be kept in mind in patients injured by a gunshot to the sellar/parasellar region.  ",0
4808,24072364,Prevalence of flatfoot and anthropometric comparison between flat and normal feet in the Hausa ethnic group of Nigeria,"Flat arches in children usually become proper arches and high arches as the child progresses through adolescence and into adulthood. Only if the deformity persists or presents in adolescence or adulthood is it considered abnormal. We sought to determine the incidence of flatfoot in schoolchildren and to make an anthropometric comparison between flat and normal feet with respect to age and sex in the Hausa ethnic group of Nigeria. Two hundred 9- to 14-year-old students (100 boys and 100 girls) were studied. Navicular height, medial malleolar height, lateral malleolar height, foot length, and transverse arch length were measured with a ruler, marker, and measuring tape. Statistical analysis was conducted using analysis of variance and independent-samples t tests (P < .05). The overall prevalence of flatfoot was 10% (n = 20) (7% in boys [n = 7] and 13% in girls [n = 13]). Statistically significant differences were found in all of the measured parameters except foot length. This study showed that flatfoot has a higher incidence in girls than in boys in the Hausa ethnic group, with the incidence decreasing with age. Girls had a higher incidence of flatfoot than boys, and it was also influenced by age. ",0
4809,24072731,Internal quality control: best practice,"There is a wide variation in laboratory practice with regard to implementation and review of internal quality control (IQC). A poor approach can lead to a spectrum of scenarios from validation of incorrect patient results to over investigation of falsely rejected analytical runs. This article will provide a practical approach for the routine clinical biochemistry laboratory to introduce an efficient quality control system that will optimise error detection and reduce the rate of false rejection. Each stage of the IQC system is considered, from selection of IQC material to selection of IQC rules, and finally the appropriate action to follow when a rejection signal has been obtained. The main objective of IQC is to ensure day-to-day consistency of an analytical process and thus help to determine whether patient results are reliable enough to be released. The required quality and assay performance varies between analytes as does the definition of a clinically significant error. Unfortunately many laboratories currently decide what is clinically significant at the troubleshooting stage. Assay-specific IQC systems will reduce the number of inappropriate sample-run rejections compared with the blanket use of one IQC rule. In practice, only three or four different IQC rules are required for the whole of the routine biochemistry repertoire as assays are assigned into groups based on performance. The tools to categorise performance and assign IQC rules based on that performance are presented. Although significant investment of time and education is required prior to implementation, laboratories have shown that such systems achieve considerable reductions in cost and labour.  ",0
4810,24072837,Paradoxical air embolism following central venous catheter removal,Central venous catheters are commonly used in the management of critically ill patients. This case report described a rare but potentially fatal complication of central venous catheter use. A 52-year-old man underwent mechanical aortic valve replacement for infective endocarditis. On day 8 postoperatively he accidentally removed his catheter and collapsed with symptoms and signs suggestive of a cerebral air embolism. A transthoracic echocardiogram showed air bubbles in both the right and left ventricles of the heart confirming the presence of a paradoxical air embolism.  ,0
4811,24072838,Spinal epidural abscess in brucellosis,"Involvement of the skeletal system is a common complication of brucellosis. However, muscle involvement or paraspinal abscess formation are rare complications. Paraspinal abscess usually develops secondary to spondylitis. A case is reported here of a 33-year-old woman with symptoms of night sweats, fever and low back pain. Rose-Bengal test for brucellosis was positive and Brucella standard tube agglutination test was positive at a titre of 1/160. The diagnosis was made on MRI. The patient was treated with doxycycline and rifampin daily for 16 weeks. On day 14 of treatment, decline was observed in the patient's symptoms. In the presence of inflammatory lower back pain and fever, brucellosis should be considered particularly in the endemic areas. Furthermore, tuberculosis should be remembered in the differential diagnosis when a spinal epidural abscess is determined.  ",0
4812,24073135,"Behavioral health in the Department of Defense Patient-Centered Medical Home: history, finance, policy, work force development, and evaluation","""Integrating behavioral health services into the patient-centered medical home (PCMH) is an important component for meeting the goals of easy access, whole person, coordinated, and integrated care. Unlike most PCMH initiatives, the Department of Defense's (DoD) Military Health System (MHS) launched its PCMH initiative with integrated behavioral health services. This integration facilitates the MHS's goal to meet its strategic imperatives under the """"Quadruple Aim"""" of (1) maximizing readiness, (2) improving the health of the population, (3) enhancing the patient experience of care (including quality, access, and reliability), and (4) responsibly managing per capita cost of care. The MHS experience serves as a guide to other organizations. We discuss the historical underpinnings, funding, policy, and work force development strategies that contributed to integrated behavioral healthcare being a mandated component of the MHS's PCMH.  """,0
4813,24073973,Internet use in patients with cardiovascular diseases: Bad Berka Cross-Sectional Study (BABSY),"Internet has become a significant resource for dissemination of medical information. We sought to investigate prevalence and usage patterns of Internet access among consecutive patients with cardiovascular diseases. A cross-sectional study was performed using a questionnaire as study tool. Among patients with Internet access, the type of health information sought and the impact of these on daily life were assessed. Of 1063 patients invited to the study, 1000 patients [68% male gender, mean age 66 ± 11 years (range 27-83 years)] agreed to complete the questionnaire. 216/1000 (21.6%) used Internet to obtain information related to their disease. The patient education was graded as: low (15%), medium (66%) and high (19%). Reasons for Internet use were as follows: 24-h availability 142/216 (65.7%); free of charge 58/216 (26.9%); and anonymity 50/216 (23.2%). Younger (≤ 66 years) age (35.2% vs. 15.3%; p = 0.0001), male gender (24.6% vs. 15.4%; p = 0.001) and higher education level (49.4% vs. 16.1%; p = 0.001) were significantly associated with Internet use. 30.6% (66/216) of Internet users changed their individual health behaviour attributable to information found on the Internet. However, this was not related to age, gender or level of education (p = 0.5, p = 0.6 and p = 0.4, respectively). Patients without Internet use obtain health information mainly from the pharmacist (62%) or from their treating physician (58%). A relevant number of patients with cardiovascular disease access the Internet for health information. The impact of such information on health-related behaviour in daily life was low. ",0
4814,24074157,Resident and family perceptions of the nurse practitioner role in long term care settings: a qualitative descriptive study,"Research evidence supports the positive impact on resident outcomes of nurse practitioners (NPs) working in long term care (LTC) homes. There are few studies that report the perceptions of residents and family members about the role of the NP in these settings. The purpose of this study was to explore the perceptions of residents and family members regarding the role of the NP in LTC homes. The study applied a qualitative descriptive approach. In-depth individual and focus group interviews were conducted with 35 residents and family members from four LTC settings that employed a NP. Conventional content analysis was used to identify themes and sub-themes. Two major themes were identified: NPs were seen as providing resident and family-centred care and as providing enhanced quality of care. NPs established caring relationships with residents and families, providing both informational and emotional support, as well as facilitating their participation in decision making. Residents and families perceived the NP as improving availability and timeliness of care and helping to prevent unnecessary hospitalization. The perceptions of residents and family members of the NP role in LTC are consistent with the concepts of person-centred and relationship-centred care. The relationships NPs develop with residents and families are a central means through which enhanced quality of care occurs. Given the limited use of NPs in LTC settings, there is an opportunity for health care policy and decision makers to address service inadequacies through strategic deployment of NPs in LTC settings. NPs can use their expert knowledge and skill to assist residents and families to make informed choices regarding their health care and maintain a positive care experience. ",0
4815,24074481,Bereavement-related depression in the older adult population: a distinct disorder?,"Bereavement is a phenomenon that shares many symptoms with depression, and that a great number of older adults experience following the loss of a close relative. The objectives of the present study were to (1) determine whether the symptoms of depression reported by bereaved individuals differ from those with non-bereavement minor/major depression (NBRD), (2) assess whether BRD is as persistent during a one year follow-up as compared to NBRD, and (3) identify factors and consequences associated with BRD. The data used for this study came from the Longitudinal Study ESA (Study Health of Elders), conducted between 2005 and 2008, using a representative sample (n=2811) of community-dwelling older adults, aged 65 and over. To test our hypothesis, an exploratory latent class analysis and multivariate logistic regression were used. BRD prevalence among older adults suffering from depression was 39%. BRD individuals report all symptoms of depression, but in lower probabilities, and BRD is as persistent as MDD over 12 months, suggesting that it does not differ from NBRD. The principal factors associated with BRD were widowhood and lower level of education. Individuals with BRD are less likely to consult medical services and be dispensed an antidepressant, compared to NBRD. We have to be cautious when generalizing our findings to individuals with major depression alone, since our results included both minor and major depressions in the same group. No evidence was found that BRD differed from non BRD in terms of depressive symptoms and persistence. The bereavement exclusion criterion in the DSM-IV should be reconsidered. ",0
4816,24074598,Divergent gyroviruses in the feces of Tunisian children,"The Gyrovirus genus consists of the immunosuppressive Chicken Anemia Virus (CAV) prototype and since 2011 three other viral species found in sera/tissues of chickens, human feces, and on human skin. Here the genomes of two other gyrovirus species were characterized in diarrhea samples from Tunisian children whose main ORFs shared amino acid identity of 46-59% with those of the previously characterized gyroviruses and were provisionally named GyV5 and GyV6. All currently known gyroviruses grouped into two clades with distinct genomic features including replacement of the VP2 overlapping Apoptin gene with a distinct ORF of unknown function. Previous reports of gyrovirus DNA in human blood and on human skins warrant studies of possible human tropisms for these newly characterized gyroviruses.  ",0
4817,24074637,"Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial","N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. ",0
4818,24074773,Hypofractionation in the era of modulated radiotherapy (RT),"The use of radiation therapy (RT) as a component of breast-conserving therapy (BCT) has been shown to reduce the risk of local-regional recurrence and improve overall survival. As has been the common practice in the United States and Continental Europe, the majority of studies that demonstrated these benefits utilized daily radiation doses ranging from 1.8 to 2.0 Gray (Gy) per day given for approximately 5 weeks. However, due to geographic limitations, patient preferences, and financial considerations, there have been continued attempts to evaluate the efficacy and safety of abbreviated or hypofractionated courses of whole-breast radiation. Two key factors in these attempts have been: 1) advances in radiobiology allowing for a more precise estimation of equivalent dosing, and 2) advances in the delivery of RT ('modulation') that have resulted in substantially improved dose homogeneity in the target volume. Hypofractionated schedules have been compared to conventional radiation courses in several randomized controlled trials, as well as many prospective and retrospective experiences. These studies, now with about 10 years of follow-up, have demonstrated equivalent rates of local-regional recurrence, disease-free survival, and overall survival. The rates of toxicity have generally not been increased with hypofractionated regimens; however, certain toxicities may take decades to manifest. The generalizability of these results is unclear, as the majority of patients in the trials were elderly with early-stage hormone-receptor positive disease. Nevertheless, there is now sufficient evidence to recommend hypofractionated whole breast RT for a substantial percentage of patients. ",0
4819,24075206,Less invasive surfactant administration (LISA) - ways to deliver surfactant in spontaneously breathing infants,"""The idea to deliver surfactant to spontaneously breathing premature infants is not new. The spectrum of methods reported reaches from aerosol administration over pharyngeal deposition, the use of laryngeal masks, short term intubation, surfactant administration and rapid extubation (INSURE) to an approach of keeping premature neonates on spontaneous breathing with continuous positive airway pressure support and administering surfactant by laryngoscopy via a small diameter tube. This way of Less Invasive Surfactant Administration (LISA) is in increasing use in the last decade in Germany. More than 1000 babies have been included in clinical studies on LISA by now. A first prospective randomized controlled trial (AMV-trial) demonstrated a significant reduction in the use of mechanical ventilation in LISA patients compared to standard treatment with intratracheal bolus administration of surfactant. Another recent study (Take Care study) indicates, that LISA may even be superior to INSURE. The search for even more """"gentle"""" methods (e.g. nebulization) to deliver surfactant continues.  """,0
4820,24075340,"Bioefficacy of crude extract of Cyperus aromaticus (Family: Cyperaceae) cultured cells, against Aedes aegypti and Aedes albopictus mosquitoes","To evaluate the growth inhibition activity of the crude extract of Cyperus aromaticus (C. aromaticus) cultured cells against the 3rd instar larvae of Aedes aegypti (Linn.) and Aedes albopictus Skuse (Ae. albopictus) under laboratory conditions, and determine the sublethal effects (EI50) of the crude extract of C. aromaticus cultured cells on some biological and morphological parameters of both Aedes mosquito species during two generations as well. The cell suspension cultures of C. aromaticus were activated from five callus lines (P4, Pa, Z1, Z6 and Ml) derived from the root explants of in vitro plantlets. The cultured cells were extracted in chloroform and used as plant material for the present study. For detection of juvenile hormone III, the crude extracts were analyzed by HPLC. Then the crude extracts of the three C. aromaticus cultured cell lines which contained varied amounts of juvenile hormone III [high level (P4 cell line), medium level (Z1 cell line) and low level (Ml cell line)] were tested against Aedes mosquito species. Laboratory evaluation was performed against late third instar larvae of the Vector Control Research Unit strains of Ae. aegypti and Ae. albopictus using the standard WHO method. The effects of EI50 of the C. aromaticus cultured P4 cells on fecundity, fertility, growth period, sex ratio, adult size and longevity of Aedes mosquitoes were assessed. Bioassay tests presented the remarkable growth inhibition activity of the crude extracts of C. aromaticus cultured cells against the two Aedes mosquitoes. Between the two mosquito species, Ae. albopictus was more susceptible to the crude extracts with lower EI50 values. EI50 of the crude extract of C. aromaticus cultured cells (P4) increased the sterility indices in the parental generation females in both Aedes mosquito species. A significant delay in the pupal formation and adult emergence were observed in the parental generation of the both mosquito species. The sex ratio of the adult population either parental or F1 generation of the Aedes mosquito species was not significantly affected by the EI50 dosage of the crude extract of C. aromaticus cultured P4 cells. A significant decrease in the wing length of the treated adult (female and male) of Aedes aegypti as well as the treated female of Ae. albopictus were observed. Longevity of the adult female of the parental generation of both Aedes mosquitoes as well as females of F1 generation of Ae. albopictus were significantly decreased. The present study revealed the potential of the crude extract of C. aromaticus cultured cells in controlling vector mosquito populations in the effort to reduce the transmission of vector borne diseases. ",0
4821,24075364,Complication from hearing aid mold material: a case report and review of legal matters,"Ear mold impression middle ear foreign bodies are a rare complication of hearing aid fitting. Only a small number of cases have been reported; however, the actual incidence is unknown and likely much higher than expected. We present the case of a 77-year-old man with a history of preexisting tympanic membrane perforations who presented with an ear mold impression middle ear foreign body that required surgical removal. We explore the state and federal laws that guide the interaction between patients, hearing aid sellers and otolaryngologists. We highlight steps that can be taken to reduce the incidence of this complication.  ",0
4822,24075427,The effect of enoxaparin-containing irrigation fluid used during cataract surgery on postoperative inflammation in patients with diabetes,"To investigate effects of enoxaparin on postoperative inflammation in patients with moderate nonproliferative diabetic retinopathy (NPDR) and nuclear cataract. Prospective masked controlled trial. setting: Institutional practice. study population: The study included 51 eyes of 51 diabetes mellitus (DM) patients with moderate NPDR and grade 2-3 nuclear cataracts. Group 1 included randomly selected patients who received enoxaparin in balanced salt solution (BSS) during cataract surgery, while standard BSS was used in Group 2. observation procedure: Patients were followed up 1 day, 1 week, and 1 and 2 months after the surgery. main outcome measures: Anterior chamber cell and flare. Postoperatively, 20 patients from Group 1 and 4 patients in Group 2 had less than a mean of 10 cells at day 1 (P = .012). At the first week, 20 patients from Group 1 and 10 patients from Group 2 had less than a mean of 10 cells (P = .004). When compared for flare, 20 patients from Group 1 and 8 patients from Group 2 had a flare between 0 and +1 at postoperative day 1 (P < .001). By the end of postoperative first week, 24 patients from Group 1and 18 patients from Group 2 had a flare between 0 and +1 (P = .012). There was no difference between groups in terms of postoperative inflammation at the first and second months after the surgery. The results of the study suggest that enoxaparin added into the infusion fluid may reduce postoperative inflammation in patients with DM, and this result supports the anti-inflammatory effect of enoxaparin. ",0
4823,24088043,PLS3 mutations in X-linked osteoporosis with fractures,"Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.",0
4824,24106936,Surgical skill and complication rates after bariatric surgery,"BACKGROUND: Clinical outcomes after many complex surgical procedures vary widely across hospitals and surgeons. Although it has been assumed that the proficiency of the operating surgeon is an important factor underlying such variation, empirical data are lacking on the relationships between technical skill and postoperative outcomes. METHODS: We conducted a study involving 20 bariatric surgeons in Michigan who participated in a statewide collaborative improvement program. Each surgeon submitted a single representative videotape of himself or herself performing a laparoscopic gastric bypass. Each videotape was rated in various domains of technical skill on a scale of 1 to 5 (with higher scores indicating more advanced skill) by at least 10 peer surgeons who were unaware of the identity of the operating surgeon. We then assessed relationships between these skill ratings and risk-adjusted complication rates, using data from a prospective, externally audited, clinical-outcomes registry involving 10,343 patients. RESULTS: Mean summary ratings of technical skill ranged from 2.6 to 4.8 across the 20 surgeons. The bottom quartile of surgical skill, as compared with the top quartile, was associated with higher complication rates (14.5% vs. 5.2%, P<0.001) and higher mortality (0.26% vs. 0.05%, P=0.01). The lowest quartile of skill was also associated with longer operations (137 minutes vs. 98 minutes, P<0.001) and higher rates of reoperation (3.4% vs. 1.6%, P=0.01) and readmission (6.3% vs. 2.7%) (P<0.001). CONCLUSIONS: The technical skill of practicing bariatric surgeons varied widely, and greater skill was associated with fewer postoperative complications and lower rates of reoperation, readmission, and visits to the emergency department. Although these findings are preliminary, they suggest that peer rating of operative skill may be an effective strategy for assessing a surgeon's proficiency.",0
4825,24114775,Endothelin-1 receptor A blocker darusentan decreases hepatic changes and improves liver repopulation after cell transplantation in rats,"Cell transplantation-induced hepatic ischemia and recruitment of vasoconstrictors (e.g., endothelin-1; Edn1) leads to clearance of transplanted cells and poses problems for liver repopulation. Therefore, we determined whether darusentan (DAR), which potently blocks Edn1 receptor type A, could benefit cell engraftment. We transplanted primary F344 rat hepatocytes with or without DAR in dipeptidyl peptidase IV-deficient rats. Analysis of microcirculatory events included hepatic ischemia, endothelial injury, including with gene expression arrays, and activations of Kupffer cells (KCs), neutrophils, or hepatic stellate cells (HSCs). The retrorsine-partial hepatectomy model was used for liver repopulation studies. Whether DAR was directly cytoprotective was examined in cultured rat hepatocytes or CFSC-8B rat HSCs. We found that DAR induced hepatic sinusoidal vasodilation, caused more transplanted cells to be deposited in liver parenchyma, and decreased hepatic ischemia and endothelial injury. This lessened perturbations in expression of endothelial biology genes, including regulators of vessel tone, inflammation, cell adhesion, or cell damage, versus drug-untreated controls. Moreover, in DAR-treated animals, cell transplantation-induced activation of KCs, albeit not of neutrophils, decreased, and fewer HSCs expressed desmin. In DAR-treated rats, improvements in cell engraftment led to greater extent of liver repopulation, compared to drug-untreated controls. In cell-culture assays, DAR did not stimulate release of cytoprotective factors, such as vascular endothelial growth factor, from HSCs. Moreover, DAR did not protect hepatocytes from tumor necrosis factor alpha- or oxidative stress-induced toxicity. Endothelin receptor A blockade in vitro did not improve engraftment of subsequently transplanted hepatocytes. CONCLUSION: Systemic administration of DAR decreases hepatic ischemia-related events and thus indirectly improves cell engraftment and liver repopulation. This vascular mechanism may permit the development of combinatorial drug-based regimens to help optimize cell therapy.",0
4826,24122846,Novel Death Defying Domain in Met entraps the active site of caspase-3 and blocks apoptosis in hepatocytes,"Met, the transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF), is known to function as a potent antiapoptotic mediator in normal and neoplastic cells. Herein we report that the intracellular cytoplasmic tail of Met has evolved to harbor a tandem pair of caspase-3 cleavage sites, which bait, trap, and disable the active site of caspase-3, thereby blocking the execution of apoptosis. We call this caspase-3 cleavage motif the Death Defying Domain (DDD). This site consists of the following sequence: DNAD-DEVD-T (where the hyphens denote caspase cleavage sites). Through functional and mechanistic studies, we show that upon DDD cleavage by caspase-3 the resulting DEVD-T peptide acts as a competitive inhibitor and entraps the active site of caspase-3 akin to DEVD-CHO, which is a potent, synthetic inhibitor of caspase-3 activity. By gain- and loss-of-function studies using restoration of DDD expression in DDD-deficient hepatocytic cells, we found that both caspase-3 sites in DDD are necessary for inhibition of caspase-3 and promotion of cell survival. Employing mutagenesis studies, we show that DDD could operate independently of Met's enzymatic activity as determined by using kinase-dead human Met mutant constructs. Studies of both human liver cancer tissues and cell lines uncovered that DDD cleavage and entrapment of caspase-3 by DDD occur in vivo, further proving that this site has physiological and pathophysiological relevance. CONCLUSION: Met can directly inhibit caspase-3 by way of a novel mechanism and promote hepatocyte survival. The results presented here will further our understanding of the mechanisms that control not only normal tissue homeostasis but also abnormal tissue growth such as cancer and degenerative diseases in which apoptotic caspases are at play.",0
4827,24123265,Small proline rich protein 2a in benign and malignant liver disease,"STAT3-driven expression of small proline rich protein 2a (SPRR2a), which acts as an src homology 3 (SH3) domain ligand, induces biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT), which, in turn, promotes wound healing. SPRR2a also quenches free radicals and protects against oxidative stress and DNA damage in nonneoplastic BEC. Sprr2a-induced EMT also increases local invasiveness of cholangiocarcinomas (CC), but prevents metastases. Understanding SPRR2a regulation of EMT has potential for therapeutic targeting in both benign and malignant liver disease. Molecular mechanisms responsible for SPRR2a-induced EMT were characterized, in vitro, and then evidence for utilization of these pathways was sought in human intrahepatic CC, in vivo, using multiplex labeling and software-assisted morphometric analysis. SPRR2a complexes with ZEB1 and CtBP on the microRNA (miR)-200c/141 promoter resulting in synergic suppression of miR-200c/141 transcription, which is required for maintenance of the BEC epithelial phenotype. SPRR2a induction promotes dephosphorylation and nuclear translocation of the SH3-domain containing protein GRB2 and an SH3-domain ligand in ZEB1 is required for SPRR2a-induced synergic suppression of miR-200c/141. Multiplex protein labeling of CC and morphometric analyses showed: 1) up-regulation of ZEB-1, and 2) down-regulation of CK19 in intrahepatic CC compared to nonneoplastic BEC, consistent with previous CC proteomic studies showing EMT during cholangiocarcinogenesis. CONCLUSION: SPRR2a modulates ZEB-1 signaling by way of miR-200c/141-associated EMT through SH3-domain networks and contributes to benign and malignant BEC wound-healing responses.",0
4828,24131139,"Public reporting, consumerism, and patient empowerment","Public reporting of health care outcomes is largely ignored by consumers, perhaps because it doesn't include concise, comprehensible information on factors such as out-of-pocket costs, the effectiveness of a procedure or treatment, and applicability to their situation.",0
4829,24152233,Absence of detectable HIV-1 viremia after treatment cessation in an infant,"An infant born to a woman with human immunodeficiency virus type 1 (HIV-1) infection began receiving antiretroviral therapy (ART) 30 hours after birth owing to high-risk exposure. ART was continued when detection of HIV-1 DNA and RNA on repeat testing met the standard diagnostic criteria for infection. After therapy was discontinued (when the child was 18 months of age), levels of plasma HIV-1 RNA, proviral DNA in peripheral-blood mononuclear cells, and HIV-1 antibodies, as assessed by means of clinical assays, remained undetectable in the child through 30 months of age. This case suggests that very early ART in infants may alter the establishment and long-term persistence of HIV-1 infection.",0
4830,24171517,Cost-effectiveness of HIV treatment as prevention in serodiscordant couples,"BACKGROUND: The cost-effectiveness of early antiretroviral therapy (ART) in persons infected with human immunodeficiency virus (HIV) in serodiscordant couples is not known. Using a computer simulation of the progression of HIV infection and data from the HIV Prevention Trials Network 052 study, we projected the cost-effectiveness of early ART for such persons. METHODS: For HIV-infected partners in serodiscordant couples in South Africa and India, we compared the early initiation of ART with delayed ART. Five-year and lifetime outcomes included cumulative HIV transmissions, life-years, costs, and cost-effectiveness. We classified early ART as very cost-effective if its incremental cost-effectiveness ratio was less than the annual per capita gross domestic product (GDP; $8,100 in South Africa and $1,500 in India), as cost-effective if the ratio was less than three times the GDP, and as cost-saving if it resulted in a decrease in total costs and an increase in life-years, as compared with delayed ART. RESULTS: In South Africa, early ART prevented opportunistic diseases and was cost-saving over a 5-year period; over a lifetime, it was very cost-effective ($590 per life-year saved). In India, early ART was cost-effective ($1,800 per life-year saved) over a 5-year period and very cost-effective ($530 per life-year saved) over a lifetime. In both countries, early ART prevented HIV transmission over short periods, but longer survival attenuated this effect; the main driver of life-years saved was a clinical benefit for treated patients. Early ART remained very cost-effective over a lifetime under most modeled assumptions in the two countries. CONCLUSIONS: In South Africa, early ART was cost-saving over a 5-year period. In both South Africa and India, early ART was projected to be very cost-effective over a lifetime. With individual, public health, and economic benefits, there is a compelling case for early ART for serodiscordant couples in resource-limited settings. (Funded by the National Institute of Allergy and Infectious Diseases and others.).",0
4831,24214142,Inhibition of Niemann-Pick-type C1-like1 by ezetimibe activates autophagy in human hepatocytes and reduces mutant ?1-antitrypsin Z deposition,"Autophagy can degrade aggregate-prone proteins, but excessive autophagy can have adverse effects. It would be beneficial if autophagy could be enhanced in a cell type-specific manner, but this has been difficult because the basic mechanism of autophagy is common. In the present study we found that inhibition of Niemann-Pick-type C1-like 1 (NPC1L1) by ezetimibe activates autophagy only in hepatocytes and small intestinal epithelia, but not in other cells. Ezetimibe induced accumulation of free cholesterol in the late endosome/lysosome and increased partitioning of a Ragulator component, LAMTOR1, in rafts. The latter change led to down-regulation of mammalian target of rapamycin (mTOR)C1 activity by decreasing mTOR recruitment to the late endosome/lysosome and activated autophagy. A primary effect of ezetimibe was found to be a decrease of free cholesterol in the plasma membrane, because all the results caused by ezetimibe were suppressed by supplementation of cholesterol as a methyl-?-cyclodextrin complex. By enhancing autophagy in human primary hepatocytes with ezetimibe, insoluble mutant ?1-antitrypsin Z was reduced significantly. CONCLUSION: Inhibition of NPC1L1 by ezetimibe activates autophagy in human hepatocytes by modulating cholesterol homeostasis. Ezetimibe may be used to ameliorate liver degeneration in ?1-antitrypsin deficiency.",0
4832,24224620,The National Children's Study--a proposed plan,"With its coordinated longitudinal biologic, environmental-exposure, and phenotypic data and samples, the National Children's Study is aiming to provide an important resource for understanding children's growth, development, and health.",0
4833,24224621,"""Expediting drug development--the FDA's new """"breakthrough therapy"""" designation""","""The FDA's new """"breakthrough therapy"""" designation for investigational drugs adds to the agency's portfolio of expedited programs for serious conditions. The designation requires preliminary clinical evidence demonstrating substantial improvement over existing therapies.""",0
4834,24224625,"Publication of trials funded by the National Heart, Lung, and Blood Institute","BACKGROUND: Rapid publication of clinical trials is essential in order for the findings to yield maximal benefits for public health and scientific progress. Factors affecting the speed of publication of the main results of government-funded trials have not been well characterized. METHODS: We analyzed 244 extramural randomized clinical trials of cardiovascular interventions that were supported by the National Heart, Lung, and Blood Institute (NHLBI). We selected trials for which data collection had been completed between January 1, 2000, and December 31, 2011. Our primary outcome measure was the time between completion of the trial and publication of the main results in a peer-reviewed journal. RESULTS: As of March 31, 2012, the main results of 156 trials (64%) had been published (Kaplan-Meier median time to publication, 25 months, with 57% published within 30 months). Trials that focused on clinical events were published more rapidly than those that focused on surrogate measures (median, 9 months vs. 31 months; P<0.001). The only independent predictors of more rapid publication were a focus on clinical events rather than surrogate end points (adjusted publication rate ratio, 2.11; 95% confidence interval, 1.26 to 3.53; P=0.004) and higher costs of conducting the trial, up to a threshold of approximately $5 million (P<0.001). The 37 trials that focused on clinical events and cost at least $5 million accounted for 67% of the funds spent on clinical trials but received 82% of the citations. After adjustment of the analysis for a focus on clinical events and for cost, trial results that were classified as positive were published more quickly than those classified as negative. CONCLUSIONS: Results of less than two thirds of NHLBI-funded randomized clinical trials of cardiovascular interventions were published within 30 months after completion of the trial. Trials that focused on clinical events were published more quickly than those that focused on surrogate end points. (Funded by the National Heart, Lung, and Blood Institute.).",0
4835,24224626,Clinical practice: Adult attention deficit-hyperactivity disorder,"Short-term trials involving adults with ADHD have shown significant improvements in symptoms with stimulants and atomoxetine; however, data on long-term benefits and risks of these medications, particularly among older persons, have been insufficient.",0
4836,24305748,Medical management of early pregnancy failure (EPF): a retrospective analysis of a combined protocol of mifepristone and misoprostol used in clinical practice,"To evaluate the efficacy of a combined protocol of mifepristone and misoprostol in the management of early pregnancy failure (EPF) and the average time to expulsion of tissue and rate of side effects. Retrospective chart review of all consecutive women treated with primary medical management for EPF at our institution from 2006 to 2012. 168 patients were included in the present study. The overall success rate, defined as the absence of the need for surgical intervention, was 61 % and did not differ by calendar year. There was no difference in success rate grouped by diagnosis [intrauterine embryonic/fetal demise (IUED/IUFD) vs. anembryonic gestation; p = 0.30] or gestational age (<9 or ≥9 weeks; p = 0.48). The success rate varied significantly according to the required dose of misoprostol, ≤800 or >800 μg (68 vs. 50 %, p = 0.029). Of the possible predictive factors of success, only the dose of misoprostol required was a significant independent negative predictor. Mean and median time to tissue expulsion after the first dose of misoprostol were 8.4 and 5.5 h, respectively. The incidence of side effects was low with no blood transfusions required. The success rate in this study is markedly below published data. This can possibly be attributed to retrospective study design, allowing for physician subjectivity and patients' wishes in the absence of strict study requirements. The protocol was well tolerated with a paucity of side effects. We make suggestions for enhancing success rates in the clinical setting by optimizing medication protocols, establishing precise treatment guidelines and training physicians in the accurate interpretation of treatment outcomes. ",0
4837,24305984,Pancreas transplants venous graft thrombosis: endovascular thrombolysis for graft rescue,"To retrospectively assess the efficacy and safety of percutaneous endovascular treatment in patients with pancreas venous graft thrombosis (PVGT). Between 2001 and 2009, 206 pancreas transplants were performed at our institution. A retrospective review of pancreas graft recipients who underwent endovascular therapy for PVGT was performed. The study group included 17 patients (10 men, 7 women; mean age 38 years) with PVGT (<60 % [9 patients]; 30-60 % [8 patients]) 6.6 ± 5.7 days after grafting. The angiographic studies, type of endovascular procedure, endovascular procedural and postprocedural effectiveness, and patient and graft outcomes were assessed. In 16 of 17 cases (94 %), significant (87.5 %) or partial (12.5 %) lysis of thrombi was achieved. One patient had external compression of the portal vein due to a hematoma, which hindered mechanical removal of the thrombi. This patient required graft pancreatectomy for extensive areas of parenchymal necrosis 2 days after the endovascular procedure. No complications related to endovascular treatment were observed. Postprocedural bleeding episodes related to anticoagulation were observed in five patients. Patient and pancreas graft survival rates at 12 months were 94 and 76 %, respectively. Catheter-directed thrombectomy is an effective treatment for patients with PVGT. Percutaneous thrombectomy, followed by anticoagulation, appears to be an effective therapy to remove the thrombus and is associated with a low complication rate. ",0
4838,24306208,"Genome-wide transcriptional analysis of differentially expressed genes in diabetic, healing corneal epithelial cells: hyperglycemia-suppressed TGFβ3 expression contributes to the delay of epithelial wound healing in diabetic corneas","Patients with diabetes mellitus (DM) may develop corneal complications and delayed wound healing. The aims of this study are to characterize the molecular signatures and biological pathways leading to delayed epithelial wound healing and to delineate the involvement of TGFβ3 therein. Genome-wide cDNA microarray analysis revealed 1,888 differentially expressed genes in the healing epithelia of normal (NL) versus type 1 DM rat corneas. Gene ontology and enrichment analyses indicated TGFβ signaling as a major altered pathway. Among three TGFβ isoforms, TGF-β1 and β3 were upregulated in response to wounding in NL corneal epithelial cells (CECs), whereas the latter was greatly suppressed by hyperglycemia in rat type 1 and 2 and mouse type 1 DM models. Functional analysis indicated that TGF-β3 contributed to wound healing in NL corneas. Moreover, exogenously added TGF-β3 accelerated epithelial wound closure in type 2 rat and type 1 mouse DM corneas via Smad and PI3K-AKT signaling pathways, autoregulation, and/or upregulation of Serpine1, a well-known TGFβ target gene. Taken together, our study for the first time provides a comprehensive list of genes differentially expressed in the healing CECs of NL versus diabetic corneas and suggests the therapeutic potential of TGF-β3 for treating corneal and skin wounds in diabetic patients.  ",0
4839,24306282,"Stress, illness, and the social environment: depressive symptoms among first generation mandarin speaking Chinese in greater Los Angeles","This study documents the indirect effects of social and environmental variables as mediated by immigrant stress and physical health. Using data from a large dual frame sample of first generation mandarin speaking Chinese immigrants in metropolitan Los Angeles counties with the largest groups of Chinese immigrants, this study uses a path analytic approach to trace how predictors are related to depressive symptoms and to measure direct and indirect influences of variables. Although bivariate analyses suggested that many predictors were associated with depressive symptoms, multivariate path analysis revealed a more complex structure of mediated associations. In the multivariate path analysis only reports of physical health and immigrant stress were directly related to depressive symptoms (P < 0.05), while acculturation, time in the US, income, US citizenship, and distance of persons on whom one could rely were related to stress (but not to physical health status) and only to depressive symptoms as mediated by stress. Age and educational attainment were related to health status (and to stress as mediated by physical health) and to depressive symptoms as mediated by both health and stress. These variables were also unrelated directly to health status and to depressive symptoms. Associations were evaluated using statistical significance, P < 0.05. This study demonstrates the significance of stress and health as mediators of variables in the larger context of the physical environment and suggests that the mechanisms linking ecological characteristics of immigrants to depressive symptoms may be stress and physical health among immigrants.  ",0
4840,24306419,Comparative analysis of Papaver somniferum genotypes having contrasting latex and alkaloid profiles,"Papaver somniferum produces therapeutically useful benzylisoquinoline alkaloids (BIAs) like papaverine, thebaine, codeine, and morphine that accumulate in its capsular latex. Morphine is a potent analgesic but is also abused as a narcotic, which has increased the demand for non-narcotic thebaine that can be converted into various analgesics. To curtail the narcotic menace, many distinct genotypes of the plant have been developed that are deficient in morphine and/or latex. Sujata is one such latex-less low alkaloid-producing variety developed from the alkaloid-rich gum harvest variety Sampada. Its utility for gene prospecting and studying differential gene regulation responsible for its low alkaloid, nutritive seed oil, and latex-less phenotype has been exploited in this study. BIA profiling of Sujata and Sampada capsules at the early and late stages indicated that except for thebaine, Sujata had a depressed alkaloid phenotype as compared to Sampada. Comparative transcript-based analysis of the two genotypes was carried out in the early stage capsule (higher thebaine) using subtractive hybridization and microarray. Interrogation of a P. somniferum array yielded many differentially expressing transcripts. Their homology-based annotation classified them into categories--latex related, oil/lipid related, alkaloid related, cell wall related, and others. These leads will be useful to characterize the highly sought after Sujata phenotype. ",0
4841,24306626,Use of drugs among Senegalese school going adolescents,"""Though it may appear more severe and dramatic in most industrialized nations, drug addiction has also become a matter for concern in some developing nations. The problem is even more complex when, prior to the advent of colonialism and the adoption of Western values by those countries, there already existed traditional forms of drug addiction. This paper examines the attitudes of Senegalese school-going adolescents to the problem of drug addiction. It describes the nature, development, and perception of drug addiction in the country from an historical and sociological point of view. It shows the tolerance of Senegalese society toward drugs - some were used in traditional medicine - and its rejection of """"hard"""" and intermediate drugs, as they are viewed negatively by the society. The authors finally analyze the motivations of the drug addicts which also indicate, in Africa as in the West, a crisis of identity reflecting a global crisis of civilization.  """,0
4842,24306680,Biochemical analysis of the articular disc of the temporomandibular joint with magnetic resonance T2 mapping: a feasibility study,"Symptoms of temporomandibular joint (TMJ) dysfunction can seriously compromise patients' quality of life. The aim of our study was to use magnetic resonance imaging (MRI) T2 mapping of the articular disc to determine whether T2 mapping of the TMJ disc is feasible in routine clinical imaging and to assess the normal T2 relaxation time distribution within the TMJ. Included were ten asymptomatic volunteers without pain, any mouth-opening limitations, or any clicking phenomena. MR imaging was performed on a 3-T MR scanner using a flexible, dedicated, eight-channel multielement coil. T2 mapping was performed in the oblique sagittal plane. The regions of interest (ROIs) for the T2 relaxation time maps of the disc were selected manually. The mean values for ROIs ranged between 22.4 and 28.8 ms, and the mean for all ROIs was 26.0 ± 5.0 ms. Intraclass correlation (ICC) for interobserver variability was 0.698, and ICC for intraobserver variability was 0.861. There was no statistically significant difference between raters (p = 0.091) or sides (p = 0.810). The T2 mapping technique enables ultrastructural analysis of the composition of TMJ disc. This biochemical technique is feasible in vivo, as shown in our study, when a high-field (3 T) MR and a dedicated TMJ coil are used. T2 mapping as a biochemical technique, together with morphological MRI, may help to gain more insights into the physiology and into the pathophysiology of the articular disc in the TMJ noninvasively and in vivo. ",0
4843,24307030,Assessing modulation of stromal and thylakoid light-harvesting complex-II phosphatase activities with phosphopeptide substrates,"The study of the light-harvesting complex II (LHC-II) phosphatase activity has been difficult due to the membrane association of its substrate. Thylakoid membranes labeled with [γ-(32)P]ATP were incubated with chymotrypsin, releasing phosphopeptides which served as labeled substrates for LHC-II phosphatase. Utilizing these phosphopeptides as substrates, protein phosphatase activities have been identified in both the thylakoid membrane and the stromal fraction. The thylakoid-bound phosphatase was liberated from the membrane with a sub-solubilizing concentration of Brij 35. The membrane and the stromal protein phosphatases were inhibited by NaF and EDTA, but not inhibited by microcystin-LR. The stromal phosphatase differed from the membrane phosphatase in pH optimum, in its lack of inhibition by molybdate ions, and by its response to magnesium and manganese ions. Using the soluble chymotryptic peptide substrate, the effect of light on pea thylakoid-bound LHC-II phosphatase activity was also assessed. Incubation of the thylakoid membranes in the light caused a 35% inhibition of LHC-II phosphatase activity. The inhibition was diminished by the addition of DCMU. Addition of 10 mM dithiothreitol stimulated the activity in darkness and obviated the inhibition when exposed to light. These studies suggest that positive or negative regulation of the LHC-II phosphatase activity is possible in vivo.  ",0
4844,24307183,An association between external hydrocephalus in infants and reversible collapse of the venous sinuses,"The etiology of external hydrocephalus is usually ascribed to either a delay in maturation or obstruction of the arachnoid granulations, but the arachnoid granulations are absent in neonates. Venous outflow stenoses, similar to those seen in idiopathic intracranial hypertension (IIH), have been described in external hydrocephalus. A reversible collapse of the sinuses is known to operate in IIH, but collapsible sinuses have not been previously described in infants with external hydrocephalus. Three infants with external hydrocephalus had magnetic resonance venography at differing time points during their illness. The venous sinuses varied in size depending on the cerebrospinal fluid pressure similar to IIH in adults. External hydrocephalus may be analogous to IIH in adults.  ",0
4845,24307251,Transcriptional regulatory network and protein-protein interaction to reveal the mechanism of pancreatic cancer,"The development of pancreatic cancer (PC) may involve the over-expression of oncogenes, inactivation tumor suppressor genes or the deregulation of various signaling proteins. Thus identification and analysis of transcriptional regulatory relationship as well as protein-protein interaction (PPI) in PC to provide deep insights into the pathogenetic mechanism of pancreatic cancer. In this study, we downloaded the gene expression profile of PC from Gene Expression Omnibus and identified differentially expressed genes (DEGs) in PC patients compared with controls. To further understand how these DEGs act together to account for the initiation of pancreatic cancer, a transcriptional regulatory network was constructed to find the notes for GO function and KEGG pathways annotation, aiming to explore the clusters and pathways in PC. A total of 1,821 transcriptional regulatory relationships were identified. Then, a PPI network was constructed and noted by GO and KEGG, and some special modules, clusters and pathways were identified to involved in PC. Finally, we constructed the transcriptional regulatory network and PPI network of pancreatic cancer. Comparing the pathways involved in Transcriptional regulatory network and PPI network, pathway in cancer, PC, p53 signaling pathway, Hematopoietic cell lineage and graft-versus-host disease co-existed in these two network, so we predict these pathways may play key factors in development of cancer.  ",0
4846,24307330,Multi-state models for colon cancer recurrence and death with a cured fraction,"In cancer clinical trials, patients often experience a recurrence of disease prior to the outcome of interest, overall survival. Additionally, for many cancers, there is a cured fraction of the population who will never experience a recurrence. There is often interest in how different covariates affect the probability of being cured of disease and the time to recurrence, time to death, and time to death after recurrence. We propose a multi-state Markov model with an incorporated cured fraction to jointly model recurrence and death in colon cancer. A Bayesian estimation strategy is used to obtain parameter estimates. The model can be used to assess how individual covariates affect the probability of being cured and each of the transition rates. Checks for the adequacy of the model fit and for the functional forms of covariates are explored. The methods are applied to data from 12 randomized trials in colon cancer, where we show common effects of specific covariates across the trials. ",0
4847,24307399,Focus on international research strategy and teaching: the FIRST programme,"Research, education and patient care are important missions of academic health centres and their respective teaching programmes. Yet, teaching hospitals struggle with ways to effectively support quality research initiatives. These issues are even more pronounced in countries with developing medical education systems where inconsistencies in training programme structure and quality, along with the lack of uniformity in the backgrounds and experience of the faculty, can hinder meaningful research activities. Hospital leaders recognized the need to inculcate both the desire and the ability to conduct quality research into every postgraduate training programme. Given the lack of global benchmarks, the institution developed and implemented the FIRST Programme (Focus on International Research Strategy and Teaching), a hospital-wide approach to research strategy training and support in 2010-2012. Over a 3-year period, the number of resident and faculty research activities has more than doubled. The types of research studies have also changed over the past few years, with an increase in basic science and randomized clinical trials. Our experience with implementing an institution-wide research initiative has been quite encouraging. Through leadership commitment, the institution has witnessed substantial increases in both trainee and faculty scholarship over a 3-year period.  ",0
4848,24308909,Physician and patient characteristics affecting repeat use of abdominal ultrasound: A nationwide population-based study,"Ultrasound is a useful and popular imaging modality. Our aim was to assess the association between the use and repeat use of abdominal ultrasound and diagnosis, physicians, and hospital characteristics according to a Taiwanese national database. The Taiwan National Health Insurance database contains data for approximately 22,134,270 insured individuals during 2004-2005 (>98% of the population in Taiwan). Patients who were scanned with abdominal ultrasound once or more during that period were identified. Associations between physicians, hospital characteristics, diagnoses, and repeat use of abdominal ultrasound were analyzed. Logistic regression with generalized estimating equations was used. A total of 2,319,164 abdominal ultrasound scans were performed (approximately 6.42% of the population in Taiwan). Among these, 38.34% received repeat examinations. Multiple logistic regression analysis showed that gastroenterologists [odds ratio (OR) = 1.07], male physicians, physicians younger than 40 years of age, and physicians in medical centers were more likely to use repeat abdominal ultrasound. The analysis also showed that male patients, older patients, patients with liver and biliary disease (OR = 1.17), and patients with other abdominal disease (OR = 1.37) were more likely to receive repeat abdominal ultrasound. Our study shows that the use and repeat use of abdominal ultrasound is very high and is related to diagnosis and physician and hospital characteristics. ",0
4849,24308921,"Establishing the value of Indigenous eye health programs: health needs, economic priority and performance assessment approaches","The aim of this paper was to compare three different approaches that are used in support of additional funding of health programs, using Indigenous eye health programs (IEHPs) as an example. These approaches are Heath and Health Care Needs, Economic Priority (Value for Money) and Conformity with Health Services Performance Standards. A review of relevant literature was conducted to identify relevant benchmarks and assess IEHPs. In terms of health needs, vision loss is the fourth highest contributor to the Indigenous health gap. Additional funding for Indigenous eye treatment services to remove the gap is estimated at A$28.1million per annum. As an economic priority, IEHPs (specifically for refractive error, cataract, diabetic retinopathy and trachoma) demonstrate excellent value for money and compare favourably with other better-researched health programs. Evaluation of health performance measures indicated that IEHPs also perform well, as judged by Australian performance standards for health services generally and Indigenous health services more specifically, the later involving local delivery, including care coordination through Aboriginal-controlled community health services. The value of IEHPs was demonstrated using all three approaches. Different approaches are likely to be more or less persuasive with different audiences. The application of these approaches is relevant to other health programs. WHAT IS KNOWN ABOUT THIS TOPIC? Supporters of additional funding for health programs frequently use the impact of this additional funding on the health and health care needs of the affected populations and individuals. Indigenous Eye Health programs are considered for illustrative purposes. This argument is not necessarily persuasive to funders of health programs. WHAT DOES THIS PAPER ADD? This paper demonstrates that two further approaches, namely Economic Priority and Conformity with Health Performance Measure Standards, both demonstrate good arguments in support of additional funding and that these outcomes may be more persuasive to funders of health programs. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Practitioners are able to harness additional approaches with a higher likelihood of success of submissions for additional funding for the program they are promoting. ",0
4850,24309402,Detection of genes encoding for virulence and adherence factors in Escherichia coli isolated in slaughtered Sarda breed sheep,"""In order to investigate the pathogenic profile of Escherichia coli hosted in """"Sarda"""" sheep, autochthonous race present in Sardinia, thirty-seven E. coli strains collected from different sources (fleeces, carcass swabs and gut mucosa) of pre-chill slaughtered sheep (ewes and lambs) were serotyped using pheno- and genotypic methods. Furthermore, the presence of genes encoding for virulence factors and mediating for localized mucosal adherence factors was investigated, and pulsed-field gel electrophoresis (PFGE) characterization was performed. Twenty-one (56.8%) of the isolates belonged to O91 serogroup and sixteen (43.2%) belonged to nine different serotypes (O5:H11, O8:H14, O26:H2, O38:H26, O116:H9, O116:H11, O132:H34, O149:H?, O161:H-). Of these non-O91 strains, five (13.5%) were able to produce verocytotoxin (VT) and were ascribed to VTEC pathogroup, eleven (29.7%) were attributed to the Enteropathogenic E. coli (EPEC) pathogroup; the other strains (n.21) cannot be ascribed to a pathogenic group. However, various associated virulence genes were observed in all isolated strains. Macrorestriction analysis highlighted a large heterogeneity of the E. coli strains. The results confirm the role of sheep as reservoir of pathogenic E. coli serotypes potentially able to colonize and to damage the intestinal mucosa. """,0
4851,24309922,Cervical disc arthroplasty: a critical review and appraisal of the latest available evidence,"Anterior cervical discectomy and fusion (ACDF) has been a very successful procedure in the management of cervical radiculopathy and myelopathy. Concerns with adjacent segment disease and the desire to preserve physiological motion have led to technological and clinical efforts for cervical disc arthroplasty. The suggested move to cervical disc replacement has led to this latter procedure being one of the most scrutinised surgical treatments in the twenty-first century. Short- and medium-term prospective randomised clinical trials and systematic reviews show cervical disc replacement to be at least as good as ACDF as regards the clinical outcomes in the management of degenerative cervical spondylosis. This is logical since the neural decompression procedure is essentially the same. However, the rationale for arthroplasty over arthrodesis has been built on two main proposed roles: the preservation of segmental motion and the prevention of adjacent segment disease. Whilst results thus far show that this first role seems to be achieved, its clinical significance is as yet unproven; the second is so far not proven. In addition, the long-term fate of the implants is also unknown. Long-term safety and efficacy, therefore, still await further clinical studies.  ",0
4852,24310509,Demand uncertainty and hospital costs: an application to Portuguese public hospitals,"In this paper, we evaluate the effect of demand uncertainty on hospital costs. Since hospital managers want to minimize the probability of not having enough capacity to satisfy demand, and since demand is uncertain, hospitals have to build excess capacity and incur the associated costs. Using panel data comprising information for 43 Portuguese public hospitals for the period 2007-2009, we estimate a translog cost function that relates total variable costs to the usual variables (outputs, the price of inputs, some of the hospitals' organizational characteristics) and an additional term measuring the excess capacity related to the uncertainty of demand. Demand uncertainty is measured as the difference between actual and projected demand for emergency services. Our results indicate that the cost function term associated with the uncertainty of demand is significant, which means that cost functions that do not include this type of term may be misspecified. For most of our sample, hospitals that face higher demand uncertainty have higher excess capacity and higher costs. Furthermore, we identify economies of scale in hospital costs, at least for smaller hospitals, suggesting that a policy of merging smaller hospitals would contribute to reducing hospital costs.  ",0
4853,24310688,The translation and cultural adaptation of the Management of Aggression and Violence Attitude Scale - MAVAS - for nurses in Brazil],"This study translated and culturally adapted the Management of Aggression and Violence Attitude Scale - MAVAS - for use in Brazil (BR). The methodology followed the international guidelines for the cultural adaptation of psychometric scales: conceptual equivalence, semantic equivalence, items equivalence, and operational equivalence. A group of judges performed a content validity analysis that resulted in a 23-item scale divided into four factors with satisfactory content validity coefficients (CVCs) for the following parameters: clarity of language (CL; 0.88), practical relevance (PR; 0.91), and theoretical relevance (TR; 0.92). The data were collected in Londrina, state of Paraná, BR in 2011. The MAVAS was translated and culturally adapted for use in BR, and the MAVAS-BR exhibited satisfactory content validity. Future studies concerning the MAVAS-BR are suggested, including the evaluation of psychometric qualities, such as its construct validity and reliability.  ",0
4854,24310695,Evaluation of an educational website on First Aid],"The aim of this study was to evaluate the structure, quality of information and usability of a website on First Aid. The evaluation was performed by information technology (IT) and health care professionals and by students, using specific and validated instruments. The kappa method was used to evaluate the agreement of the answers, and Cronbach's α coefficient was used to assess the reliability of the instrument. There was no agreement (0.047) among the answers obtained from the IT professionals, indicating that the structure of the website must be reviewed. There was also no agreement in the evaluation by the health care professionals (-0.062); however, the overall positive scores suggest that the quality of the information of the website is adequate. The assessment of reliability of the instrument to evaluate the navigability rendered a value of α=0.974. Although improvement of the website structure is recommended, the quality of the information is good, and its use has contributed to the apprenticeship of students.  ",0
4855,24311039,"Kinetic characteristics of photoassimilate translocation in Alaria esculenta (Laminariales, Phaeophyceae)","The kinetics of translocation of (14)C-labeled photoassimilate were studied in the kelp, Alaria esculenta (L.) Grev., using a Geiger-Müller detector-probe to measure radioactivity in the source and sink regions of dumbbell-shaped explants cut from blades. Rapid tracer efflux from the source occurred for 4 days following a pulse of [(14)C]bicarbonate, with 40-60% of the initial activity remaining in the source after 10-14 days. Portions of source and sink tissue were analysed for distribution of radioactivity in mannitol, amino-acid, organic-acid and insoluble fractions. About 75% of the radioactivity in both source and sink at the end of the experiments was in soluble organic matter. The translocation velocity of the moving solute front (1.0-1.6 cm·h(-1)) was derived from time-course profiles of tracer arriving in Alaria sinks. Relative rates of translocation, calculated from these profiles, yielded skewed curves, with maximum rates of import by the sink occurring 72-96 h after the source was pulsed.  ",0
4856,24311269,"A rapid method for isolation of purified, physiologically active chloroplasts, used to study the intracellular distribution of amino acids in pea leaves","A procedure is described for the rapid (<5 min) isolation of purified, physiologically active chloroplasts from Pisum sativum L. Mitochondrial and microbody contamination is substantially reduced and broken chloroplasts are excluded by washing through a layer containing a treated silica sol. On average the preparations contain 93% intact chloroplasts and show high rates of (14)CO2 fixation and CO2-dependent O2 evolution (over 100 μmol/mg chlorophyll(chl)/h); they are also able to carry out light-driven incorporation of leucine into protein (4 nmol/mg chl/h). The amino-acid contents of chloroplasts prepared from leaves and from leaf protoplasts have been determined. Asparagine is the most abundant amino acid in the pea chloroplast (>240 nmol/mg chl), even thought it is proportionately lower in the chloroplast relative to the rest of the cell. The chloroplasts contain about 20% of many of the amino acids of the cell, but for individual amino acids the percentage in the chloroplast ranges from 8 to 40% of the cell total. Glutamic acid, glutamine and aspartic acid are enriched in the chloroplasts, while asparagine, homoserine and β-(isoxazolin-5-one-2-yl)-alanine are relatively lower. Leakage of amino acids from the chloroplast during preparation or repeated washing was ca. 20%. Some differences exist between the amino-acid composition of chloroplasts isolated from intact leaves and from protoplasts. In particular, γ-aminobutyric acid accumulates to high levels, while homoserine and glutamic acid decrease, during protoplast formation and breakage.  ",0
4857,24311400,Hypercalcemia due to giant cell myocarditis: a case report,"Granulomatous diseases are a rare cause of hypercalcemia. The pathogenesis is presumed to be from endogenous production of 1,25-dihydroxyvitamin D by activated macrophages in granulomatous lesions, which harbor the 1α-hydroxylase enzyme. Herein the first case of hypercalcemia associated with giant cell myocarditis, an unusual type of granulomatous process, is reported. In this case, a patient with giant cell myocarditis had development of progressive heart failure and cardiorenal syndrome that required biventricular support. One year later, hypercalcemia associated with a relatively high 1,25-vitamin D level and a concomitantly suppressed parathyroid hormone level developed in the presence of stage 4 chronic kidney disease. Her other workup of hypercalcemia was unrevealing for vitamin D intoxication and multiple myeloma. Computed tomography of her chest showed no signs of hilar lymphadenopathy. Her calcium levels returned to normal with low-dose steroid therapy and have remained normal following a successful heart transplant. This case illustrates an unusual cause of hypercalcemia thought to be due to extrarenal calcitriol production associated with giant cell myocarditis.  ",0
4858,24311525,Hypoglycemia in Kabuki syndrome,"Kabuki syndrome (KS) is a congenital malformation disorder with a spectrum of clinical manifestations involving different organs. Until the identification of MLL2 gene mutation in 2010, the diagnosis was made only clinically by the characteristic facial features with other common and uncommon features. Hypoglycemia, although an uncommon feature in KS, is very important to be recognized, as early diagnosis and appropriate management will reduce further long-term neurologic morbidity in these patients. We report on four patients with KS presenting with persistent hypoglycemia. Hyperinsulinemic hypoglycemia was the cause of hypoglycemia in two out of four patients and one patient had growth hormone deficiency. The mechanism of the hypoglycemia in one patient is still unclear. Three out of these four patients were found to have mutation in the MLL2 gene. Our observations suggest that patients with KS may have hypoglycemia due to different mechanisms and that MLL2 gene may have a role in glucose physiology. ",0
4859,24311635,The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells,"The mammalian target of rapamycin (mTOR) has been suggested as a target for radiosensitization. Given that radiotherapy is a primary treatment modality for glioblastoma (GBM) and that mTOR is often dysregulated in GBM, the goal of this study was to determine the effects of AZD2014, a dual mTORC1/2 inhibitor, on the radiosensitivity of GBM stem-like cells (GSCs). mTORC1 and mTORC2 activities were defined by immunoblot analysis. The effects of this mTOR inhibitor on the in vitro radiosensitivity of GSCs were determined using a clonogenic assay. DNA double strand breaks were evaluated according to γH2AX foci. Orthotopic xenografts initiated from GSCs were used to define the in vivo response to AZD2014 and radiation. Exposure of GSCs to AZD2014 resulted in the inhibition of mTORC1 and 2 activities. Based on clonogenic survival analysis, addition of AZD2014 to culture media 1 hour before irradiation enhanced the radiosensitivity of CD133+ and CD15+ GSC cell lines. Whereas AZD2014 treatment had no effect on the initial level of γH2AX foci, the dispersal of radiation-induced γH2AX foci was significantly delayed. Finally, the combination of AZD2014 and radiation delivered to mice bearing GSC-initiated orthotopic xenografts significantly prolonged survival as compared with the individual treatments. These data indicate that AZD2014 enhances the radiosensitivity of GSCs both in vitro and under orthotopic in vivo conditions and suggest that this effect involves an inhibition of DNA repair. Moreover, these results suggest that this dual mTORC1/2 inhibitor may be a radiosensitizer applicable to GBM therapy. ",0
4860,24311702,The risk of radiation-induced breast cancers due to biennial mammographic screening in women aged 50-69 years is minimal,"The main aim of mammographic screening is to reduce the mortality from breast cancer. However, use of ionizing radiation is considered a potential harm due to the possible risk of inducing cancer in healthy women. To estimate the potential number of radiation-induced breast cancers, radiation-induced breast cancer deaths, and lives saved due to implementation of organized mammographic screening as performed in Norway. We used a previously published excess absolute risk model which assumes a linear no-threshold dose-response. The estimates were calculated for 100,000 women aged 50-69 years, a screening interval of 2 years, and with an assumed follow-up until the age of 85 or 105 years. Radiation doses of 0.7, 2.5, and 5.7 mGy per screening examination, a latency time of 5 or 10 years, and a dose and dose-rate effectiveness factor (DDREF) of 1 or 2 were applied. The total lifetime risk of radiation-induced breast cancers per 100,000 women was 10 (95% CI: 4-25) if the women were followed from the ages of 50 to 85 years, for a dose of 2.5 mGy, a latency time of 10 years, and a DDREF of 1. For the same parameter values the number of radiation-induced breast cancer death was 1 (95% CI: 0-2). The assumed number of lives saved is approximately 350. The risk of radiation-induced breast cancer and breast cancer death due to mammographic screening is minimal. Women should not be discouraged from attending screening due to fear of radiation-induced breast cancer death. ",0
4861,24311712,A comorbidity index for mortality prediction in Chinese patients with ESRD receiving hemodialysis,"Chinese patients with ESRD have different comorbidity patterns than white patients with ESRD and require a validated comorbidity index. The objective of this study was to develop a new index for mortality prediction in 2006-2009 Taiwanese incident hemodialysis patients. Data were retrieved from 2005 to 2010 Taiwan National Health Insurance claim records, and follow-up was available until December 31, 2010. The same comorbid conditions as the US Renal Data System (USRDS) index that occurred during a 12-month period from 9 months before to 3 months after dialysis initiation were used to construct the index. Integer weight of the comorbid conditions was derived from coefficient estimates of Cox regression for all-cause mortality, and the index was internally validated. The performance of the index was assessed by discrimination, calibration, and reclassification. A total of 30,303 hemodialysis patients were included in this study. The weight for individual comorbid conditions of this index differed from that of the USRDS index. The performance of this index was similar to that of USRDS and Charlson indices in terms of model fit statistics, overall predictive ability, discrimination, and calibration. Hosmer-Lemeshow test showed that all three indices demonstrated significant differences between predicted and observed mortality rates. When patients were categorized by the predicted 2.5-year survival probabilities, the index achieved a net reclassification improvement of 4.71% (P<0.001), referenced to USRDS index. Compared with USRDS index, this new index demonstrated better reclassification ability, but future studies should address the clinical significance. ",0
4862,24311920,Primary localized amylodoisis of bladder: Is there a need for cystoscopic surveillance?,"Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of amorphous proteinaceous material in various tissues. Amyloidosis of bladder is of significant clinical interest to the urologist because of its presentation as urothelial cancer. Transurethral resection and histology examination is essential to exclude malignancy and to establish the benign nature of amyloidosis. Apart from managing the localized bladder amyloidosis, it is important to exclude systemic amyloidosis. Here in we describe two cases of localized, primary amyloidosis and discuss briefly their management and follow-up.  ",0
4863,24311923,Prevalence and risk factors for thyroid eye disease among Korean dysthyroid patients,"To determine the prevalence of thyroid eye disease among dysthyroid Korean patients and to analyze the relationship between demographic data, lifestyle risk factors, and status of thyroid disease and thyroid eye disease. All dysthyroid patients who visited endocrinology clinics in 24 general hospitals in Korea during a chosen one-week period were enrolled in this cross-sectional study. Data were collected during an interviewer-administered questionnaire and chart review. Demographic data, lifestyle risk factors, and status of thyroid disease variables were analyzed as risk factors using multivariable regression models to identify independent associations with thyroid eye disease. A total of 1,632 dysthyroid patients were included (1,301 females [79.7%] and 331 males [20.3%]). Two hundred eighty-three of these patients (17.3%) had thyroid eye disease. Multiple logistic regression analyses revealed that female gender, young age, Graves' disease, dermopathy, anti-thyroid medication treatment, and radioiodine treatment were independent risk factors for thyroid eye disease. The lower prevalence of thyroid eye disease in dysthyroid Korean patients and the influence of gender on risk factors in this study are novel findings compared to studies performed involving Europeans. Although the risk factors for thyroid eye disease are understood in part, a more in-depth comparative study of gender and ethnic groups is needed to fully understand the biological significance of the demographic factors. ",0
4864,24312219,Dynamic impacts of the inhibition of the molecular chaperone Hsp90 on the T-cell proteome have implications for anti-cancer therapy,"The molecular chaperone Hsp90-dependent proteome represents a complex protein network of critical biological and medical relevance. Known to associate with proteins with a broad variety of functions termed clients, Hsp90 maintains key essential and oncogenic signalling pathways. Consequently, Hsp90 inhibitors are being tested as anti-cancer drugs. Using an integrated systematic approach to analyse the effects of Hsp90 inhibition in T-cells, we quantified differential changes in the Hsp90-dependent proteome, Hsp90 interactome, and a selection of the transcriptome. Kinetic behaviours in the Hsp90-dependent proteome were assessed using a novel pulse-chase strategy (Fierro-Monti et al., accompanying article), detecting effects on both protein stability and synthesis. Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects. As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients. Most likely, consequences of the role of Hsp90 in gene expression determined a global reduction in net de novo protein synthesis. This decrease appeared to be greater in magnitude than a concomitantly observed global increase in protein decay rates. Several novel putative Hsp90 clients were validated, and interestingly, protein families with critical functions, particularly the Hsp90 family and cofactors themselves as well as protein kinases, displayed strongly increased decay rates due to Hsp90 inhibitor treatment. Remarkably, an upsurge in survival pathways, involving molecular chaperones and several oncoproteins, and decreased levels of some tumour suppressors, have implications for anti-cancer therapy with Hsp90 inhibitors. The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions. Data are available via ProteomeXchange with identifier PXD000537.  ",0
4865,24312256,Molecular markers for granulovacuolar degeneration are present in rimmed vacuoles,"Rimmed vacuoles (RVs) are round-oval cytoplasmic inclusions, detected in muscle cells of patients with myopathies, such as inclusion body myositis (IBM) and distal myopathy with RVs (DMRV). Granulovacuolar degeneration (GVD) bodies are spherical vacuoles containing argentophilic and hematoxyphilic granules, and are one of the pathological hallmarks commonly found in hippocampal pyramidal neurons of patients with aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These diseases are common in the elderly and share some pathological features. Therefore, we hypothesized that mechanisms of vacuolar formation in RVs and GVD bodies are common despite their role in two differing pathologies. We explored the components of RVs by immunohistochemistry, using antibodies for GVD markers. Subjects included one AD case, eight cases of sporadic IBM, and three cases of DMRV. We compared immunoreactivity and staining patterns for GVD markers. These markers included: (1) tau-modifying proteins (caspase 3, cyclin-dependent kinase 5 [CDK5], casein kinase 1δ [CK1δ], and c-jun N-terminal kinase [JNK]), (2) lipid raft-associated materials (annexin 2, leucine-rich repeat kinase 2 [LRRK2], and flotillin-1), and (3) other markers (charged multi-vesicular body protein 2B [CHMP2B] and phosphorylated transactive response DNA binding protein-43 [pTDP43]) in both GVD bodies and RVs. Furthermore, we performed double staining of each GVD marker with pTDP43 to verify the co-localization. GVD markers, including lipid raft-associated proteins and tau kinases, were detected in RVs. CHMP2B, pTDP43, caspase 3, LRRK2, annexin 2 and flotillin-1 were detected on the rim and were diffusely distributed in the cytoplasm of RV-positive fibers. CDK5, CK1δ and JNK were detected only on the rim. In double staining experiments, all GVD markers colocalized with pTDP43 in RVs. These results suggest that RVs of muscle cells and GVD bodies of neurons share a number of molecules, such as raft-related proteins and tau-modifying proteins. ",0
4866,24312299,Serological response of patients with influenza A (H1N1) pdm09-associated pneumonia: an observational study,"Little is known about the dynamics or magnitude of antibody response in patients with influenza A (H1N1) pdm09-associated pneumonia. We described and compared the antibody response to influenza A (H1N1) pdm09 in patients with and without pneumonia. We collected serum samples and determined antibody titers by the hemagglutination inhibition (HI) and microneutralization (mNT) assays from patients with RT-PCR confirmed influenza A (H1N1) pdm09 virus at baseline, 1, 2 and 6 months after onset of illness. Fifty-nine patients were enrolled, 45 (76.3%) were between 15 and 60 years of age, 49 (83.1%) were hospitalized and 25 (42.4%) had complications with pneumonia. Ninety-four percent of patients had HI titers ≥ 1: 40 and 90% had mNT titers ≥ 1: 160 at 2 months after illness. Geometric mean titers (GMT) of HI and mNT increased significantly (p<0.001) between baseline and months 1 or 2, then declined significantly (p<0.001) at month 6 by the HI assay, but dropped to an insignificant level (p=0.24) by the mNT assay. The mNT-GMT was at least twice as high as corresponding HI antibodies over a 6 month period. The GMT of HI and mNT in those with pneumonia (1 mo) peaked earlier than that of those without pneumonia (2 mo). When adjusted by age and gender, those with pneumonia had a higher HI-GMT than those without pneumonia at 1 month (264 vs. 117, p=0.007), 2 months (212 vs. 159, p=0.013), and 6 months (160 vs. 82, p=0.018). The patients recovered from influenza A (H1N1) pdm09-associated pneumonia, clearly developed an earlier and more robust antibody response until 6 months after onset of illness. The results in our study are useful to determine an appropriate donor and timing to obtain convalescent plasma for adjunctive treatment of seriously ill patients with pandemic H1N1 influenza. ",0
4867,24312440,Elevated frequencies of circulating Th22 cell in addition to Th17 cell and Th17/Th1 cell in patients with acute coronary syndrome,"Atherosclerosis is a chronic inflammatory disease mediated by immune cells. Th22 cells are CD4(+) T cells that secret IL-22 but not IL-17 or IFN-γ and are implicated in the pathogenesis of inflammatory disease. The roles of Th22 cells in the pathophysiologic procedures of acute coronary syndrome (ACS) remain unclear. The purpose of this study is to investigate the profile of Th22, Th17 and Th17/Th1 cells in ACS patients, including unstable angina (UA) and acute myocardial infarction (AMI) patients. In this study, 26 AMI patients, 16 UA patients, 16 stable angina (SA) patients and 16 healthy controls were included. The frequencies of Th22, Th17 and Th17/Th1 cells in AMI, UA, SA patients and healthy controls were examined by flow cytometry. Plasma levels of IL-22, IL-17 and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). Th22, Th17 and Th17/Th1 cells were significantly increased in AMI and UA patients compared with SA patients and healthy controls. Moreover, plasma IL-22 level was significantly elevated in AMI and UA patients. In addition, Th22 cells correlated positively with IL-22 as well as Th17 cells in AMI and UA patients. Our findings showed increased frequencies of both Th22 and Th17 cells in ACS patients, which suggest that Th22 and Th17 cells may play a potential role in plaque destabilization and the development of ACS. ",0
4868,24312465,Low body weight in females is a risk factor for increased tenofovir exposure and drug-related adverse events,"Treatment with tenofovir sometimes leads to non-reversible kidney and/or bone diseases. Factors associated with these drug-related adverse events are poorly characterized. Our objective was to investigate such factors in patients treated long term with daily tenofovir. One-hundred Caucasian HIV-positive patients with basal creatinine clearance >80 mL/min treated with tenofovir for at least 6 months and with at least one assessment of tenofovir plasma trough concentrations were considered. Tenofovir-associated adverse events were defined as the appearance of pathological proteinuria, worsening of renal function or bone demineralization. By multivariate regression analysis, we found that serum creatinine (p = 0.003) and body weight (p = 0.002) were the factors independently associated with plasma tenofovir concentrations. In particular, women with body weight<50 kg had significantly higher plasma tenofovir concentrations than those weighting >50 Kg (160±93 vs.71±52 ng/mL, p<0.001). High tenofovir plasma trough concentrations and the age of the patients were independently associated with the development of drug-related kidney and bone toxicity. In this retrospective study we have shown that HIV-infected women with low body weight are at risk to be exposed to high tenofovir plasma trough concentrations, ultimately resulting in a significant hazard to develop long-term tenofovir complications.  ",0
4869,24312486,"Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: Δ(12)-prostaglandin J3","Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ(12)-PGJ3. The stability of Δ(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.  ",0
4870,24312764,Modulating effect of Allium cepa on kidney apoptosis caused by Toxoplasma gondii,"Toxoplasma gondii is a widespread protozoan parasite that infects a broad range of warm blooded animals as well as humans. The present study was investigated to evaluate the effects of allium cepa on renal failur in male rats which experimentally infected by Toxoplasma gondii, RH strain. Wistar male rat (n=40) were allocated into four groups, group one that received tachyzoites of T. gondii (ip) (n=10), group two that received tachyzoites of T. gondii (ip), plus fresh onion juice by gavages method (n=10), group three received just fresh onion juice by gavages method (n=10) and control group (n=10) that received nothing. Animals were kept in standard condition. In 30 day after inducing Toxoplasma infection, 5cc blood was collected for serum protein and TAC levels. Kidney tissues of Rat in whole groups were removed and prepared for apopetosis analysis. Serum protein and kidneys weights were significantly decreased in groups that were infected with T. gondii, in comparison to control and onions groups. Kidneys Apopetosis in toxoplasma group significantly increased in comparison to control group (P<0.05).level of TAC was significantly increased in groups that received onio juice (P<0.05). This study showed that T. gondii have significantly effect on serum protein and TAC, apopetosis and fresh onion juice returned and treated this harmful effect, so it is suggested that eating of onion is useful in toxoplasma infection. ",0
4871,24312803,Phytochemical Screening and Antimicrobial Properties of a Common Brand of Black Tea (Camellia sinensis) Marketed in Nigerian Environment,"This study is aimed at determining chemical constituents and antimicrobial activities of a common brand of black tea (Lipton®) in Nigeria. Standard methods were employed for testing carbohydrates, tannins, saponins, flavonoids, alkaloids, steroids and terpenes in the tea. Antimicrobial activities of methanolic and aqueous extracts of the tea on four standard strains of organisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis were also determined by standard methods. RESULTs showed that the tea contains tannin and reducing sugar. Concentrations of 1%, 2%, 4%, 6%, 8% and 10% aqueous and methanolic extract of black tea were prepared and their zones of inhibition determined against the four test organisms using the cup plate method. This was compared with zones for standard disc Gentamicin (10 µg) and Erythromycin (15 µg). Pseudomonas aeruginosa was sensitive to 2% to 10% aqueous extracts and intermediate to 6%, 8% and 10% methanolic extracts. E. coli was intermediately sensitive to 6%, 8% and 10% aqueous extract and 2% to 10% methanolic extracts. B. subtilis was intermediately sensitive to 4%, 6% and 8% aqueous extract and 4% to 10% methanolic extract but sensitive to 10% aqueous extract. Staph.aureus was intermediately sensitive to 4% to 10% aqueous extracts and 2% to 10% methanolic extracts. B. subtilis had the lowest MIC values of both aqueous and methanolic extracts. In conclusion, this study has shown that Lipton® has antimicrobial properties on E.coli, Staph.aureus, B.subtilis and Ps.aeruginosa and contains tannin and reducing sugar. ",0
4872,24312845,Gene expression in Mammalian cells and its applications,"The production of proteins in appropriate quantity and quality is an essential requirement of the present time. There appears to be a progressive increase in the application of mammalian cells for proteins production. Expression systems utilizing mammalian cells for recombinant proteins are able to introduce proper protein folding, post-translational modifications, and product assembly, which are important for complete biological activity. This review article is totally based on literature survey. In this article much emphasis has been done on the mammalian expression system. The author focused on different mammalian cell lines that express the gene. The different vector systems that transfer the gene into mammalian cells like plasmid based expression vectors, adenovirus vectors, vaccinia vectors, retroviral vector and baculovirus as vectors were explored. The processes for the transfer of gene into mammalian cells were also reviewed. Application and limitations of mammalian expression system were also focused. The purpose of research in writing this article is to create awareness in researchers, starting their career in gene expression related to mammalian cells. The principal result and major conclusion of this article is to make available the molecular technologies, expression system and applications of gene expression in mammalian cell lines.  ",0
4873,24313098,Perceptions of educational experience and inpatient workload among pediatric residents,"""Education of residents in academic medical centers occurs as part of clinical care, but little is known about the relationship between clinical workload and educational experiences among pediatric residents. The goal of this study was to assess residents' perceptions of learning on inpatient services at a children's hospital in relation to perceived workload and actual patient census. This was a prospective cohort study of pediatric residents at 1 urban academic children's hospital. Surveys on educational experience were administered weekly to residents on 12 inpatient units from October 2010 to June 2011. Daily peak medical inpatient census data were collected, and Pearson correlations were performed. Mean weekly response rate was 25%. Perceived workload was correlated with weekly peak of patient census for interns (r = 0.66; P= .00) and senior residents (r = 0.73; P = .00). Many aspects of perceived learning were negatively correlated with perceived workload among interns and residents in """"acute care"""" units. Activities beyond direct patient care (eg, attending conferences, independent reading) revealed more negative correlation than educational experience during rounds. Among seniors, scores of aspects of perceived learning did not correlate with workload. The study found mostly negative associations between high perceived workload and perceived learning, especially for interns. Results suggest varied impact of workload on perceived learning by training year. Although patient care is essential for resident education, higher workload may adversely affect learning opportunities for pediatric trainees. More research is needed to identify if generalizable thresholds of patient census and/or clinical workload cause declines in perceived or real education. """,0
4874,24313557,"Thriving in long-term care facilities: instrument development, correspondence between proxy and residents' self-ratings and internal consistency in the Norwegian version","To develop an instrument for measuring thriving among residents in long-term care facilities, to assess the correspondence between proxy ratings and self-report and the internal consistency of the Norwegian version. The instrument was developed from the life-world concept of thriving and thereby has a different theoretical basis than existing 'dementia related' quality-of-life instruments. Thriving relates the experience of older persons to the place where they live. Proxy instruments need to be developed for residents in long-term care facilities who are not able to report their subjective experiences. Instrument development using cross-sectional survey design. The instrument was developed in three versions (resident, family and staff) from a theory on thriving. Forty-eight triads consisting of a resident, family member and primary nurse from 12 Norwegian nursing homes participated. Data collection took place between March-December 2011. Inter-rater agreement between the groups was assessed by Cohen's kappa coefficient (weighted). Internal consistency was evaluated by Cronbach's alpha. Homogeneity was explored through item-total correlations. Agreement between residents, family members and staff was poor or fair (<0.41) in six of 38 items. These items were excluded. The 32-items instrument had satisfactory Cronbach's alpha values in each of the three samples and satisfactory homogeneity as item-total correlations was substantial without being excessive and thus indicated that items were measuring the same construct. The instrument appears to have internal consistency and enable reliable proxy measures of the thriving construct. Further psychometric assessment including checking for possible item redundancy is needed. ",0
4875,24313681,Current status of robotic liver resection: a systematic review,"Robotic surgery is an emerging technique for the management of patients with liver disease, and only a limited number of reports are available. A systematic search of electronic databases (PubMed, Embase and Cochrane), including only case series with more than five patients, identified nine series (with one from our institution), which totaled to 232 patients. Overall, the peri-operative outcomes of the reported patients are similar to those utilizing the laparoscopic and open approaches. Robotic surgery appears to be a valid option for selected hepatic resections in experienced hands. It could represent a bridge toward minimally invasive approaches for confirmed liver surgeons. By contrast, the long-term oncological outcomes remain uncertain and need further studies.  ",0
4876,24314631,Role of the cytosolic tails of Rift Valley fever virus envelope glycoproteins in viral morphogenesis,"The correct folding, heterodimerization and trafficking of Gn/Gc envelope glycoproteins of Rift Valley fever virus, RVFV (Bunyaviridae and Phlebovirus genus) are essential for Golgi assembly and budding of viral particles. The Gn and Gc carboxy-terminus contain a Golgi targeting and an ER-retrieval signal, respectively. We generated RVFV-like particles with mutations in the cytosolic tails of Gn or Gc and identified regions important for release of infectious particles. The role of specific amino-acids in these regions was further investigated by creating recombinant mutant viruses by reverse-genetics. Residues outside the suspected Golgi targeting motif, i.e. the di-lysine K29-K30 motif and the N43, R44 and I46 residues of the Gn cytosolic domain, appeared important for Golgi localization and RNP packaging. Concerning the Gc tail, replacement of K2 or K3 in the di-lysine motif, had a drastic impact on Gn trafficking and induced an important organelle redistribution and cell remodeling, greatly affecting particle formation and release. ",0
4877,24314739,CYP17A1 inhibitors in prostate cancer: mechanisms of action independent of the androgenic pathway],"The objective of this article is to review the mechanisms of action of abiraterone acetate, independently of the androgenic pathway. A systematic review of the literature was carried out on Medline and Embase databases. Inhibition of CYP17A1 with abiraterone acetate induces changes in steroid metabolism, whose main component is the reduction of DHEA and androstenedione synthesis. This results in inhibition of androgen pathway in prostatic cancerous epithelial cell. Regardless of androgen activation pathway, abiraterone acetate could also act via an alternative mechanism of action not fully elucidated. Stromal cells, like tumor cells, could undergo the effects of CYP17A1 inhibition, resulting in blocking the production of secondary mediators that contribute to tumor progression. Similarly, it has been suggested that abiraterone acetate efficacy may be related to its ability to alter intratumoral concentrations of estrogen and progesterone. The validation of these mechanisms could contribute to improved therapeutic strategies based on the use of abiraterone acetate alone or in combination. ",0
4878,24314775,Stasis dermatitis as a complication of recurrent levofloxacin-associated bilateral leg edema,"Several drugs have been associated with the development of peripheral edema. Leg edema can result in dermatitis of the lower extremities. We describe levofloxacin-induced peripheral leg edema, which progressed to stasis dermatitis. A 76-year-old man with a history of esophageal adenocarcinoma was administered intravenous vancomycin and a combination of piperacillin and tazobactam by injection for treatment of aspiration pneumonia. Prior to discharge, the patient's antibiotic therapy was switched to oral levofloxacin. The patient developed drug-associated bilateral peripheral leg edema and stasis dermatitis. Both the dermatitis and leg edema resolved after withdrawal of levofloxacin and administration of topical corticosteroid therapy. The patient had a similar reaction to levofloxacin one year prior, which had subsided with discontinuation of the drug. Several medications have been documented to cause leg edema and secondary stasis dermatitis. The timing, recurrence, and resolution of edema and stasis dermatitis with respect to the administration and termination of levofloxacin suggest that the leg edema and stasis dermatitis occurred secondary to levofloxacin administration. Levofloxacin can be added to the list of drugs associated with the development of peripheral leg edema. Stasis dermatitis proceeded by lower extremity edema can be added to the list of adverse events associated with levofloxacin. ",0
4879,24314782,An atypical case of cutaneous leishmaniasis caused by Leishmania infantum in Portugal,"Leishmaniasis is a parasitic disease caused by an intracellular protozoan that belongs to the genus Leishmania and is transmitted by a phlebotomine sandfly. In Southwest Europe, including Portugal, cutaneous leishmaniasis is considered a rare disease of unknown or underestimated prevalence. Leishmania infantum is the only species identified as responsible for the autochthonous cases.We report the case of a 66-year-old man with an erythematous, painless plaque on the mid face region, accompanied by nasal obstruction with 9 months of evolution. The initial diagnoses were: lymphoma, subcutaneous mycosis, Wegener's granulomatosis, and lupus vulgaris. The diagnosis of leishmaniasis was based on histopathology findings and identification of L. infantum by DNA based methods. Blood cultures, abdominal ultrasound and myelogram ruled out systemic involvement. The patient was treated with intravenous meglumine antimoniate (20 mg per kg/day) for four weeks, without major side effects.We emphasize the importance of this case because human cutaneous leishmaniasis has rarely been diagnosed in Portugal and some cases are atypical, such as the situation herein described.  ",0
4880,24314938,Reliability of bioelectrical impedance analysis in the evaluation of the nutritional status of hemodialysis patients - a comparison with Mini Nutritional Assessment,"Protein-energy wasting (PEW) is a strong predictive factor for morbidity and mortality in patients who have end-stage renal disease (ESRD). Mini Nutritional Assessment (MNA) is an important and confirmed tool to evaluate PEW that has been recommended by many guidelines. Bioelectrical impedance analysis (BIA) is a noninvasive technique for assessing body composition. The aim of the present study was to analyze the reliability of BIA in malnutrition diagnosis by comparing it with standard MNA in a group of 100 ESRD patients. One hundred ESRD patients who were medically stable and under dialysis treatment for at least 6 months were enrolled to the study. Monthly assessed serum creatinine, albumin, C-reactive protein (CRP), and lipid profiles from the last 6 months prior to the study were retrospectively collected. A standard Full-MNA and body composition analyses were applied to all patients. Body compositions were analyzed with the BIA technique using the Body Composition Analyzer (Tanita BC-420 MA; Tanita, Tokyo, Japan). Patients were classified into three groups according to MNA scores as PEW (n = 15, score <17), moderate PEW or risk group (n = 49, score 17-23.5), and well-nourished (n = 36, score ≥ 24) patients. Mean duration of maintenance hemodialysis treatment was significantly shorter in the PEW group compared to both of the other groups described (P = .015). Well-nourished and risk groups had lower CRP and higher albumin levels compared to PEW patients; however, these values were statistically similar in these two groups (P = .018, .01, respectively). According to BIA findings, well-nourished patients had the highest fat ratio, fat mass, muscle mass, visceral fat mass, and fat-free mass compared to both moderate the PEW/risk and the PEW groups (P < .05). Risk group patients also had higher muscle mass, visceral fat mass, and fat-free mass values compared to the PEW group (P < .05). A correlation analysis revealed that MNA scores were positively correlated with albumin (P = .005), creatinine (P = .049), fat mass (P = .045), muscle mass (P = .001), visceral fat ratio (P = .007), and BMI (P = .047) and in negative correlation with CRP (r = -0.357, P = .0001) levels. We recommend BIA as a complementary diagnostic tool to evaluate nutritional status of ESRD along with MNA, anthropometric measures, and classical biochemical markers. ",0
4881,24314943,Value of early diethylentriamine penta-acetic acid renograms in predicting late allograft outcomes,"Tc-99m-diethylentriamine penta-acetic acid (DTPA) renal scintigraphy is useful, noninvasive diagnostic tool for the management and follow-up of the transplanted kidney. There have not been any studies of the predictive value of DTPA renal scintigraphy for short- and long-term allograft functions. Our aim was to reveal the significance of different perfusion-uptake patterns observed on Tc-99m-DTPA renal scintigraphy for long-term graft outcomes. We retrospectively analyzed 59 renal transplanted children (30 male and 29 female). All patients were underwent DTPA on posttransplant day 7. Perfusion- and function-related parameters of DTPA (the ratio of peak perfusion counts to plateau counts [P:PL], the ratio of counts at peak perfusion to counts at peak uptake [P:U], and glomerular filtration rate [GFR] calculated using commercially available software) were studied. The mean P:PL and P:U calculated using the half-moon-shaped background region of interest. A renal time activity curve was generated for evaluate perfusion- and function-related parameters. The patterns were classified and the value of these early DTPA parameters in predicting long-term graft function was analyzed. The mean age of patients was 16.69 ± 4.77 years. The mean posttransplant follow-up time was 3.5 ± 0.4 years. Thirty-nine patients received living-related donor allografts and the remaining 20 were from deceased donors. Thirteen children suffered ≥ 1 acute rejection episode. Eight patients lost their grafts during follow-up. Mean GFR value at year 3 was 80.61 ± 39.03 mL/1.73 m(2) BSA/min. There was a significant difference for mean creatinine values at year 3 between recipients with normal perfusion and function and normal P:PL with decreased P:U patterns in early DTPA (P < .05). The normal P:PL with decreased P:U pattern is associated with lowest GFR value at posttransplant year 3. There was also a significant difference for mean GFR values at year 3 between recipients with normal perfusion and function and acute tubular necrosis (P < .05). Acute rejection episodes and graft loss were mostly seen in recipient with a decreased P:PL with or without decreased P:U pattern in early DTPA. The decreased P:PL with or without decreased P:U pattern may be associated with high risk of acute rejection episodes and graft loss. Posttransplant early perfusion uptake patterns observed on Tc-99m-DTPA renal scintigraphy can be used as a long-term prognostic marker of poor renal outcomes. This would permit an opportunity for early intervention. ",0
4882,24314968,Incidence of post-transplantation lymphoproliferative disease in Andalusia (1990-2009),"Post-transplantation lymphoproliferative disease (PTLD) is a severe complication of renal transplantation (RT) but information about its incidence and predisposing factors is diverse, varying according to geographic area and study period. We analyzed the incidence of PTLD after all RT performed at adult transplantation centers in Andalusia from January 1, 1990 to December 31, 2009, recorded in the Andalusian Transplant Co-ordination Information System (SICATA) regional computerized database (n = 5577). We calculated the risk of PTLD using the Kaplan-Meier curve, censoring for organ failure and incidence rate per patient-year of exposure. Log-rank comparisons were made by center (n = 5), decade (1990-1999 vs 2000-2009), age group, recipient gender, hepatitis C virus (HCV) serology, transplantation number, and duration of pre-RT replacement therapy (per quartiles). We identified 60 cases of PTLD. The pre-RT treatment time was 48.2 ± 60 months; 11.7% were retransplantations, and 10.4% had a positive HCV serology. The median post-RT time before diagnosis of PTLD was 5.98 years. At the time of the database analysis, only 11 patients (18%) were alive with a functioning transplant; 10% had returned to dialysis and 72% had died. The actuarial incidence of PTLD at 1, 5, 10, and 20 years post-RT was 0.2%, 0.5%, 1.6%, and 2.9%, respectively; the exposure rate was 14.71 PTLD/10,000 patient-years (95% confidence interval [CI], 12.3-17.1). Although the incidence tended to be higher in 1990-1999 than 2000-2009 (16.8 vs 12.1 cases/10,000 patient-years), in the actuarial study the difference was far from significant (at 7.5 years, 1.2 vs 0.8%; P = .4). Nor were there significant differences in the curves of incidence per RT center (1%-1.2% of patients) or recipient characteristics. The cumulative incidence of PTLD in Andalusia in patients with a functioning kidney transplant during 1990-2009 was 2.9% at 20 years. There was no significant variation between the RT centers or over time. No associated factors were identified among the basic recipient variables studied. ",0
4883,24315029,Extraction of polyphenols from black tea--conventional and ultrasound assisted extraction,"Products from plant raw materials gain increasing importance in food-, cosmetics and pharmaceutical industry. By way of contrast, due to lack of detailed physico-chemical fundamentals, existing production processes are economically not optimal designed. This leads to a need for deeper understanding of the processes and furthermore a systematic process and equipment design for the potentially applicable extraction techniques. Using the example of polyphenol extraction from black tea (Kenya), the conventional and ultrasound assisted extractions are investigated. Here, the state of the art as well as a comparison between the two techniques is in focus. Especially, resulting quasi-equilibria and mass transport kinetics serves as a criteria. The physico-chemical background is discussed taking particle size distributions and scanning electron microscope (SEM) measurements into account. Conclusively, process alternatives are projected and discussed. Hence, the present study makes influences of ultrasound technique on physico-chemical characteristics during extraction a subject of discussion.  ",0
4884,24315216,Gradenigo's syndrome: is fusobacterium different? Two cases and review of the literature,"Gradenigo's syndrome is a rare but life threatening complication of acute otitis media (AOM), which includes a classic triad of otitis media, deep facial pain and ipsilateral abducens nerve paralysis. The incidence of Fusobacterium necrophorum infections has increased in recent years. We describe two cases of Gradenigo's syndrome caused by F. necrophorum. Additional four cases were identified in a review of the literature. Gradenigo's syndrome as well as other neurologic complications should be considered in cases of complicated acute otitis media. F. necrophorum should be empirically treated while awaiting culture results. ",0
4885,24315508,Maternal body-mass index and cord blood circulating endothelial colony-forming cells,"Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that are particularly abundant in umbilical cord blood. We sought to determine whether ECFC abundance in cord blood is associated with maternal body-mass index (BMI) in nonpathologic pregnancies. We measured the level of ECFCs in the cord blood of neonates (n = 27) born from non-obese healthy mothers with nonpathologic pregnancies and examined whether ECFC abundance correlated with maternal BMI. We also examined the effect of maternal BMI on ECFC phenotype and function using angiogenic and vasculogenic assays. We observed variation in ECFC abundance among subjects and found a positive correlation between prepregnancy maternal BMI and ECFC content (r = 0.51, P = .007), which was independent of other obstetric factors. Despite this variation, ECFC phenotype and functionality were deemed normal and highly similar between subjects with maternal BMI <25 kg/m(2) and BMI between 25-30 kg/m(2), including the ability to form vascular networks in vivo. This study underlines the need to consider maternal BMI as a potential confounding factor for cord blood levels of ECFCs in future comparative studies between healthy and pathologic pregnancies. ",0
4886,24316062,Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas,"Using a cancer profiling array, our laboratory has shown that apelin gene is up-regulated in half of colon adenocarcinomas. We have therefore postulated that apelin signalling might play a prominent role in the growth of colon tumours. We first confirmed by immunohistochemistry that apelin peptide is overexpressed in human colon adenomas and adenocarcinomas. We also observed a significant overexpression of apelin receptor (APJ) in adjacent sections. We then demonstrated that several colorectal cancer cell lines also expressed apelin and its receptor, the highest gene and peptide expression being detected in LoVo cells. In this cell line, the expression and functionality of apelin receptor were revealed by apelin-induced adenylyl cyclase inhibition and Akt phosphorylation. In addition, apelin clearly protected LoVo cells from apoptosis by inactivating a caspase-dependent pathway and decreasing the degradation of poly ADP ribose polymerase protein (PARP). Finally, treatment of these tumour cells by the (F13A)apelin13 receptor antagonist significantly reduced their proliferation rate. Altogether, these data suggest the existence of an autocrine loop by which constitutive activation of apelin signalling should participate in the growth of colon adenocarcinomas. Accordingly, apelin signalling is a promising pharmacological target for the treatment of human colon adenomas and adenocarcinomas.  ",0
4887,24316063,Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: a phase I-II study from the Italian Sarcoma Group,"To study feasibility, safety and activity of the combination of high-dose long-infusion ifosfamide (HLI) and radiotherapy (RT) as preoperative treatment for resectable localised retroperitoneal sarcoma (RPS). Patients received three cycles of HLI (14 g/m2). RT was started in combination with second cycle and administered up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. Primary end-point was 3-year relapse free survival (RFS). The trial is registered with ITASARC_∗II_2004_003. Between December 2003 and 2010, 83 patients were recruited. Main histological subtypes were well differentiated liposarcoma (19/83, 23%), dedifferentiated liposarcoma (26/83, 31%), leiomyosarcoma (14/83, 17%). Median tumour size was 120 mm (interquartile (IQ) range=82-160). The overall preoperative treatment was completed in 60 patients. Chemotherapy (CT) was completed in 65, while RT in 73. Four patients progressed before surgery and were not operated. 79 patients underwent surgery. At a median follow-up of 4.8 years (IQ range = 3-6.1), 23 and 15 patients developed local recurrence (LR) and distant metastases (DM); 30 patients died of disease. 3 and 5-year RFS and overall survival were 0.56 (90% confidence interval (CI): 0.45, 0.65) and 0.44 (90% CI: 0.27, 0.48), and 0.74 (90% CI: 0.62, 0.81) and 0.59 (90% CI: 0.33, 0.58). Crude cumulative incidence of LR and DM at 5 years were 0.37 (standard error (SE): 0.06) and 0.26 (SE: 0.06). The combination of preoperative HLI and RT was feasible in two thirds of patients, while preoperative RT could be completed in most (73/83). Although a systemic coverage can be added to RT when this is felt to be appropriate, the ongoing international phase III trial is exploring the role of RT alone. This is a pure academic trial. No funding sources contributed to it. ",0
4888,24316283,Benefits and risks of splenectomy,"Splenectomy is a powerful therapeutic procedure in a wide variety of medical disorders provided that it is not undertaken lightly and the risks are weighed against the potential benefits in each individual case. Most of this risk seems to be due to the underlying splenectomy indication and not to splenectomy alone. There has been an increased tendency in recent years towards splenic preservation to prevent not only the risk of subsequent overwhelming post-splenectomy infection (OPSI) but the long term risk of cardiovascular complications. As there is no condition that can be cured by splenectomy, this paper reviewed the rationale behind the indications for, and the associated risks. Electronic searches of the medline (PubMed) database, Cochrane library, and science citation index were performed to identify original published studies on splenectomy. Relevant articles were searched from relevant chapters in specialized texts and all included. ",0
4889,24316364,DNA-polymer conjugates for immune stimulation through Toll-like receptor 9 mediated pathways,"Oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotide motifs are agonists of Toll-like receptor 9 and are currently being investigated for use as vaccine adjuvants through the promotion of type I immunity. Several classes of ODN have been developed which differ in their propensity to aggregate, which in turn alters cytokine profiles and cellular subsets activated. Although aggregation state is correlated with the change in cytokine response, it is unknown if this results from a change in the number of ODNs available for binding and/or the possible engagement of multiple TLR9 molecules. Here, we examined the role of ligand valency on the activation of TLR9 through the synthesis of ODN-poly(acrylic acid) (PAA) conjugates. The compositions and size of the conjugates were characterized by UV-vis spectroscopy, proton nuclear magnetic resonance, gel permeation chromatography and dynamic light scattering. Enzyme-linked immunosorbent assays of cytokine secretion by murine-like macrophages indicate that these ODN-PAA polymer conjugates show enhanced immunostimulation at 100-fold lower concentrations than those required for ODN alone, for both TNF-α and IL-6 release, and are more potent than any other previously reported multivalent ODN constructs. Increasing valency was shown to significantly enhance cytokine expression, particularly for IL-6. Knockdown by siRNA demonstrates that these polymer conjugates are specific to TLR9. Our results define valency as a critical design parameter and polymer conjugation as an advantageous strategy for producing ODN immunomodulatory agents.  ",0
4890,24316448,The expression of vesicular glutamate transporter 3 and vesicular monoamine transporter 2 induced by brain-derived neurotrophic factor in dorsal root ganglion neurons in vitro,"The vesicular glutamate transporter 3 (VGLUT3) and the vesicular monoamine transporter 2 (VMAT2) are expressed in dorsal root ganglion (DRG) neurons and play an important role in packing the neurotransmitter into synaptic vesicles. Brain-derived neurotrophic factor (BDNF) is one of the most profound known regulators of survival in the developing peripheral nervous system (PNS). Whether BDNF regulates the expression of VGLUT3 and VMAT2 in DRG neurons is still unclear. In the present study, primary cultured rat DRG neurons were used to evaluate the effects of BDNF on VGLUT3 and VMAT2 expression. The signaling pathways of the extracellular signal-regulated protein kinase 1/2 (ERK1/2), the phosphatidylinositol 3-kinase (PI3K)/Akt, and the phospholipase C-gamma (PLC-γ) involved in these effects were also determined. DRG neurons at 48h post-culture were incubated with BDNF and/or ERK1/2 inhibitor PD98059, PI3K inhibitor LY294002, and PLC-γ inhibitor U73122 for an additional 24h. After that, the neurite growth and growth-associated protein 43 (GAP-43) expressions after different doses of BDNF treatment were determined by immunofluorescent labeling. The expression of mRNA and protein of VGLUT3 and VMAT2 in different experimental conditions was assessed by real-time PCR, immunoblotting, and immunofluorescent labeling, respectively. The results showed that BDNF exposure promoted neurite growth and GAP-43 expression in DRG neurons in a dose-dependent manner. BDNF induced VGLUT3 upregulation through activation of PLC-γ signaling pathway. Although BDNF administration did not elevate the levels of VMAT2, the block of the PI3K/Akt or PLC-γ signaling pathways could inhibit VMAT2 expression in DRG neurons in the presence of BDNF. The knockdown of VGLUT3 or VMAT2 gene by siRNA did not affect the BDNF's effects on GAP-43 upregulation and neurite growth. The upregulation of VGLUT3 induced by BDNF might be that BDNF improved neuronal outgrowth status by promoting GAP-43 expression to stimulate neurite elongation. The contribution of distinct VGLUT3 and VMAT2 transporter expression induced by BDNF might be one of the mechanisms that BDNF regulates neuropathic pain. These data imply that BDNF signaling system might be a potential target on modifying distinct transporter-mediated biological effects of primary sensory neurons.  ",0
4891,24316714,"HS-1793, a resveratrol analogue, induces cell cycle arrest and apoptotic cell death in human breast cancer cells","Resveratrol, a polyphenolic compound, is a naturally occurring phytochemical and is found in a variety of plants, including food such as grapes, berries and peanuts. It has gained much attention for its potential anticancer activity against various types of human cancer. However, the usefulness of resveratrol as a chemotherapeutic agent is limited by its photosensitivity and metabolic instability. In this study the effects of a synthetic analogue of resveratrol, HS-1793, on the proliferation and apoptotic cell death were investigated using MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) human breast cancer cells. HS-1793 inhibited cell growth and induced apoptotic cell death in a concentration-dependent manner. The induction of apoptosis was determined by morphological changes, cleavage of poly(ADP-ribose) poly-merase, alteration of Bax/Bcl-2 expression ratio and caspase activities. Flow cytometric analysis revealed that HS-1793 induced G2/M arrest in the cell cycle progression in both types of cells. Of note, HS-1793 induced p53/p21WAF1/CIP1-dependent apoptosis in MCF-7 cells, whereas it exhibited p53-independent apoptosis in MDA-MB-231 cells. Furthermore, HS-1793 showed more potent anticancer effects in several aspects compared to resveratrol in MCF-7 and MDA-MB-231 cells. Thus, these findings suggest that HS-1793 has potential as a candidate chemotherapeutic agent against human breast cancer. ",0
4892,24316894,Radiographic changes of cervical spine in rheumatoid arthritis,"The involvement of the cervical spine is a common feature of rheumatoid arthritis (RA). To study the prevalence of radiographic changes of the cervical spine in patients with RA and their association with clinical and serological profiles of the disease. We analysed lateral (neutral position, hyperextension, hyperflexion) and transoral views of cervical spine radiographs from 80 individuals with RA to investigate the presence of atlanto-axial subluxation (AAS), basilar invagination (BI), and subaxial instability (SAI). Demographic, clinical (nodules, interstitial pneumonitis, secondary Sjögren's syndrome, medications etc.), and serologic (rheumatoid factor--RF, cyclic citrullinated peptide antibody--anti-CCP, and antinuclear factor--ANF) data were obtained from the clinical records. Cervical spine misalignments were identified in 26/80 (32.5%) participants; AAS occurred in 12/80 (15%) participants, BI in 6/80 (7.5%), and SAI in 13/80 (32.5%). Odontoid erosions were identified in 16/80 (20.0%) participants. Cervical spine misalignment exhibited associations with age at onset and disease duration (P = 0.03 and 0.02, respectively). No associations were identified between the cervical spine changes and the participants' ethnicity or gender, presence of nodules, interstitial pneumonitis, secondary Sjögren's syndrome, RF, ANF, or anti-CCP. The participants with cervical spine misalignment exhibited higher frequencies of odontoid erosion (P = 0.03). Cervical spine misalignment was a common radiographic finding and occurred more frequently in participants with earlier onset and longer length of RA. ",0
4893,24316954,Does sedation type affect colonoscopy perforation rates?,"Sedation with propofol is gaining popularity. It is unclear whether sedation with propofol is associated with colonoscopic perforation. The purpose of this study was to compare perforation rates during colonoscopy using sedation with or without propofol. This was a retrospective case series study. Data from a tertiary center were analyzed. Demographics, method of sedation, and type of endoscopic procedure performed were collected. Patients who underwent a colonoscopy from January 2003 to October 2012 were analyzed. Perforation rate expressed per 10,000 colonoscopies was measured. A total of 118,004 colonoscopies were performed during the study period, with 48 perforations (0.041% or 4.1 per 10,000). Overall, the use of propofol was associated with a 2.5 times increased rate of perforation (6.9 vs 2.7 per 10,000; p = 0.0015). Similarly, in patients undergoing therapeutic colonoscopies, there was a 3.4-times increased risk of perforation associated with the use of propofol (8.7 vs 2.6 per 10,000; p = 0.0016). However, in patients undergoing diagnostic colonoscopies, there was no significantly increased risk of perforation with the use of propofol (4.2 vs 2.9 per 10,000; p = 0.64). In univariate and multivariate analyses, there were no differential perforation risks on the basis of sex, but each decade increase in age was associated with an increased risk of perforation. In those patients having a therapeutic colonoscopy, age (per decade) and propofol use were independently and significantly associated with an increased perforation risk, with adjusted ORs of 1.32 (p = 0.04) and 3.38 (p = 0.001). This was a retrospective study with the potential for selection bias. This study shows that propofol administration is associated with an increased risk of colonoscopic perforation among patients undergoing a therapeutic colonoscopy; however, this association was not evident in patients undergoing a diagnostic colonoscopy. Further studies, such as a prospective, randomized clinical trial, should be done to further evaluate this association. ",0
4894,24316964,Evaluation of the economic burden of diseases associated with poor nutrition status,"Geriatric acutely ill patients may frequently have insufficient nutrition intake, leading to malnutrition and increased susceptibility to additional morbidity. This compromised health status can increase costs by extending length of stay in the hospital, promoting the development of comorbidities, and requiring more intensive care. Understanding the value of measures improving the health of these patients depends in part on estimating the costs of prevented adverse outcomes. Because clinical trials often do not record these costs, it is difficult to assess the value of nutrition interventions. This article comprehensively reviews 15 years of clinical trials of nutrition interventions to identify salient diseases and complications measured by previous clinical trials and then estimates costs corresponding with these conditions associated with poor nutrition status. The most costly complication associated with poor nutrition status is acute respiratory infections ($13,350-$19,530 per hospitalization), while institutional long-term care is the greatest chronic cost contributor across many diseases ($77,000 per year of care). This review can facilitate imputation of nutrition intervention benefits for acutely ill patients by characterizing the costs of clinical outcomes often reported in trials. ",0
4895,24316968,Carnosol inhibits cell adhesion molecules and chemokine expression by tumor necrosis factor-α in human umbilical vein endothelial cells through the nuclear factor-κB and mitogen-activated protein kinase pathways,"Inflammatory bowel diseases (IBD) are gastrointestinal disorders associated with chronic inflammatory processes. Carnosol has been demonstrated to possess anti-inflammatory properties. This study examined the suppressive effect of carnosol on the expression of cell adhesion molecules (CAMs) and chemokines in human umbilical vein endothelial cells (HUVECs) and the possible underlying mechanism. The effect of carnosol on CAM and chemokine expression in HUVECs was identified by western blotting and ELISA, respectively. nuclear factor (NF)-κB activation of HUVECs was analyzed using the TransAM NF-κB Family kit. The effect of carnosol on the tumor necrosis factor (TNF)-α-induced activation of the NF-κB and mitogen-activated protein kinase (MAPK) pathways, and was subsequently analyzed using western blotting. Carnosol not only inhibited TNF-α-induced protein expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and E-selectin in HUVECs, but also suppressed interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 expression. In addition, carnosol inhibited the TNF-α-induced phosphorylation of p-65 and IκB-α, as well as the activation of NF-κB. The same result was observed in TNF-α-stimulated phosphorylation of ERK1/2 and p-38. It was demonstrated that carnosol inhibited TNF-α-induced CAM and chemokine expression in HUVECs. The underlying mechanism may be associated with the blocking of the NF-κB and MAPK pathways. These results indicate that carnosol may be a novel therapeutic agent for targeting endothelial cells in IBDs. ",0
4896,24317345,The role of cholecystokinin in the induction of aggressive behavior: a focus on the available experimental data (review),"Cholecystokinin (CCK) is a neuropeptide that is (among others) reportedly involved in the pathophysiology of psychiatric disorders. The excitatory role of CCK in negative affective emotions as well as in aversive reactions, antisocial behaviors and memories, has been indicated by numerous electrophysiological, neurochemical and behavioral methodologies on both animal models for anxiety and human studies. The current review article summarizes the existing experimental evidence with regards to the role of CCK in the induction of aggressive behavior, and: (a) synopsizes the anatomical circuits through which it could potentially mediate all types of aggressive behavior, as well as (b) highlights the potential use of these experimental evidence in the current research quest for the clinical treatment of mood and anxiety disorders.  ",0
4897,24317526,Effects of Aronia melanocarpa constituents on biofilm formation of Escherichia coli and Bacillus cereus,"Many bacteria growing on surfaces form biofilms. Adaptive and genetic changes of the microorganisms in this structure make them resistant to antimicrobial agents. Biofilm-forming organisms on medical devices can pose serious threats to human health. Thus, there is a need for novel prevention and treatment strategies. This study aimed to evaluate the ability of Aronia melanocarpa extracts, subfractions and compounds to prevent biofilm formation and to inhibit bacterial growth of Escherichia coli and Bacillus cereus in vitro. It was found that several aronia substances possessed anti-biofilm activity, however, they were not toxic to the species screened. This non-toxic inhibition may confer a lower potential for resistance development compared to conventional antimicrobials.  ",0
4898,24317750,Ivory: a recessive white-eyed tryptophan metabolism mutant with intermediate F2 - and R 1 - progenies in the flesh fly Sarcophaga barbata,The recessive autosomal gene ivory (i) causes white eyes in the flesh fly Sarcophaga barbata. The mutation completely blocks the synthesis of formylkynurenine. Ivory larvae and ivory imagoes are able to synthesize xanthommatin if formylkynurenine and kynurenine respectively are provided with the food. The eye colour of the F2- and the R1-mutants respectively is intermediate because these animals have taken up xanthommatin precursors that were excreted by the wild-type larvae. The white eye colour is not influenced by temperature. The viability of the ivory stock is somewhat lower than that of the wild-type stock. The mutation ivory is homologous to the mutation vermilion of Drosophila melanogaster and to the mutation green of Musca domestica respectively.  ,0
4899,24318543,Fetal vibroacoustic stimulation for facilitation of tests of fetal wellbeing,"Acoustic stimulation of the fetus has been suggested to improve the efficiency of antepartum fetal heart rate testing. To assess the advantages and disadvantages of the use of fetal vibroacoustic stimulation in conjunction with tests of fetal wellbeing. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013). All published and unpublished randomised controlled trials assessing the merits of the use of fetal vibroacoustic stimulation in conjunction with tests of fetal wellbeing. All review authors independently extracted data and assessed trial quality. Authors of published and unpublished trials were contacted for further information. Altogether 12 trials with a total of 6822 participants were included. Fetal vibroacoustic stimulation reduced the incidence of non-reactive antenatal cardiotocography test (nine trials; average risk ratio (RR) 0.62, 95% confidence interval (CI) 0.48 to 0.81). Vibroacoustic stimulation compared with mock stimulation evoked significantly more fetal movements when used in conjunction with fetal heart rate testing (one trial, RR 0.23, 95% CI 0.18 to 0.29). Vibroacoustic stimulation offers benefits by decreasing the incidence of non-reactive cardiotocography and reducing the testing time. Further randomised trials should be encouraged to determine not only the optimum intensity, frequency, duration and position of the vibroacoustic stimulation, but also to evaluate the efficacy, predictive reliability, safety and perinatal outcome of these stimuli with cardiotocography and other tests of fetal wellbeing. ",0
4900,24318625,Long-term results of debridement and primary repair of peroneal tendon tears,"Peroneal tendon tears are relatively common; however, there are few reports on the long-term success of operative treatment. The purpose of this study was to review the long-term clinical and patient-reported outcomes of a cohort of patients with peroneal tendon tears treated with debridement and primary repair. Patients who underwent debridement and primary repair of tears of the peroneus longus and brevis from 1994 to 2008 were included in the study. A chart review was performed to determine patient demographics, postoperative complications, and return to sport. Clinical outcomes scores used to assess patients preoperatively and at most recent follow-up included a visual analog scale (VAS) for pain, the SF-12 Health Survey, and the Lower Extremity Functional Scale (LEFS) questionnaire. We identified 34 patients with a tear of one or both peroneal tendons treated operatively by a single surgeon. Eighteen patients participated in the follow-up survey with an average follow-up time of 6.5 years (range, 2-14 years). There was significant improvement in mean VAS pain scores at the time of final follow-up (P < .001) from a mean of 39 (range, 0-80) preoperatively to a mean of 10 (range, 0-52) postoperatively. In addition, there was a significant increase in the LEFS score from a mean of 45 (range, 23-70) preoperatively to a mean of 71 (range, 24-80) postoperatively (P < .001). Of the 18 patients who responded, 17 returned to full sporting activity without limitation. There were no reoperations or operative failures during this time interval. Our study found excellent long-term functional outcomes for patients with tears of the peroneal tendons treated with debridement and primary operative repair. Moreover, we observed that the majority of patients returned to their previous level of activity without the need for reoperation or revision of the repair. Level IV, case series. ",0
4901,24318956,Is digoxin use for cardiovascular disease associated with risk of prostate cancer?,"Digoxin is a commonly used medication for heart failure and cardiac arrhythmias that has recently been suggested as a novel chemotherapeutic agent. Preclinical studies of prostate cancer (PCa) have shown anti-tumor activity with digoxin. We explore the relationship between use of digoxin and PCa risk. Data from a population-based case-control study of incident cases aged 35-74 years at PCa diagnosis in 2002-2005 in King County, Washington were available. Controls were identified by random digit dialing and frequency matched by age. Use of digoxin was determined from in-person questionnaires regarding medical and prescription history. The relationship of digoxin use with PCa risk was evaluated with logistic regression. One thousand one cases of PCa and 942 controls were analyzed. The prevalence of digoxin use in controls was 2.7%, and use was positively correlated with age. In multivariate analysis adjusting for age, race, PSA screening, and family history of PCa, digoxin use was associated with a reduction in the odds ratio of PCa (OR 0.58, 95% CI: 0.30-1.10). Among those with ≥3 PSA tests over the preceding 5 years (546 cases, 380 controls), digoxin use was associated with a stronger reduction of PCa risk (OR 0.44, 95% CI: 0.20-0.98). These data indicate digoxin use may be associated with a reduction in risk of PCa. Given the potential mechanisms by which digoxin may exert an anti-neoplastic effect and other recent studies showing a negative association between digoxin use and PCa, further research is warranted. ",0
4902,24319132,Complementary and alternative medicine in predoctoral dental curricula: an exploratory survey of U.S. dental schools,"The purpose of this study was to identify the prevalence of complementary and alternative medicine (CAM) education in U.S. dental schools. A survey was administered via e-mail to each U.S. dental school's academic dean, and data were collected from respondents in a fillable PDF form submitted electronically to the study investigators. The survey asked respondents whether CAM was taught at the institution; if the response was yes, information was requested regarding the CAM therapies included, credentials of the instructor, number of hours taught, reason for teaching CAM, and format in which CAM was taught. Of the sixty dental schools contacted, twenty-two responded to the survey (37 percent response rate). Of these respondents, ten (45.5 percent) reported offering instruction in CAM as part of their predoctoral curricula. Herb/drug interactions were found to be taught with more frequency than any other CAM topic (in six out of the ten institutions). Limitations of the study are discussed, and suggestions for future studies are made.  ",0
4903,24319272,Rounding of birth weights in a neonatal intensive care unit over 20 years: an analysis of a large cohort study,"To determine the frequency of birth weight digit preference for infants admitted to a large neonatal intensive care unit (NICU), the scale of rounding and its dependence on birth weight, and time and the impact on prescribing accuracy. A consecutive cohort of birth weights extracted retrospectively from a single clinical database. Birth weights from 9170 inborn infants recorded on an electronic prescribing database admitted to NICU over 20 years. Data are presented for the frequency of each of the possible pairs of final digits. A statistical model of digit preference assuming rounding is used to quantify the proportions rounding to specific accuracy levels. These proportions are compared between those <1000 g and those above and over the 20-year time period. From a population of 9170 infants admitted over 20 years, there was a highly statistically significant digit bias with an increased prevalence of multiples of 100 (p<0.0001), 50 (p=0.007), 20 (p<0.0001), 10 (p<0.0001), 5 (p<0.0001) and 2 (p=0.0005). There was clear evidence of a reduced 100 g digit bias for infants 500 and 1000 g (0%) compared with those between 1000 and 4500 g (3.7%). The maximum birth weight error due to digit bias for all infants was 5%. There was clear evidence of an improvement in accuracy over 20 years. Digit bias in birth weights over 20 years in a tertiary NICU is highly significant at the 100, 50, 20, 10, 5 and 2-digit levels. There has been a substantial improvement in the accuracy of birth weight measurements over 20 years. The likely maximum error due to birth weight digit bias is 5% and is within an acceptable tolerance for drug dosing even at very low birth weights. ",0
4904,24320096,Distribution and chemical speciation of arsenic in ancient human hair using synchrotron radiation,"Pre-Columbian populations that inhabited the Tarapacá mid river valley in the Atacama Desert in Chile during the Middle Horizon and Late Intermediate Period (AD 500-1450) show patterns of chronic poisoning due to exposure to geogenic arsenic. Exposure of these people to arsenic was assessed using synchrotron-based elemental X-ray fluorescence mapping, X-ray absorption spectroscopy, X-ray diffraction and Fourier transform infrared spectromicroscopy measurements on ancient human hair. These combined techniques of high sensitivity and specificity enabled the discrimination between endogenous and exogenous processes that has been an analytical challenge for archeological studies and criminal investigations in which hair is used as a proxy of premortem metabolism. The high concentration of arsenic mainly in the form of inorganic As(III) and As(V) detected in the hair suggests chronic arsenicism through ingestion of As-polluted water rather than external contamination by the deposition of heavy metals due to metallophilic soil microbes or diffusion of arsenic from the soil. A decrease in arsenic concentration from the proximal to the distal end of the hair shaft analyzed may indicate a change in the diet due to mobility, though chemical or microbiologically induced processes during burial cannot be entirely ruled out.  ",0
4905,24320512,Texture analysis improves level set segmentation of the anterior abdominal wall,"The treatment of ventral hernias (VH) has been a challenging problem for medical care. Repair of these hernias is fraught with failure; recurrence rates ranging from 24% to 43% have been reported, even with the use of biocompatible mesh. Currently, computed tomography (CT) is used to guide intervention through expert, but qualitative, clinical judgments, notably, quantitative metrics based on image-processing are not used. The authors propose that image segmentation methods to capture the three-dimensional structure of the abdominal wall and its abnormalities will provide a foundation on which to measure geometric properties of hernias and surrounding tissues and, therefore, to optimize intervention. In this study with 20 clinically acquired CT scans on postoperative patients, the authors demonstrated a novel approach to geometric classification of the abdominal. The authors' approach uses a texture analysis based on Gabor filters to extract feature vectors and follows a fuzzy c-means clustering method to estimate voxelwise probability memberships for eight clusters. The memberships estimated from the texture analysis are helpful to identify anatomical structures with inhomogeneous intensities. The membership was used to guide the level set evolution, as well as to derive an initial start close to the abdominal wall. Segmentation results on abdominal walls were both quantitatively and qualitatively validated with surface errors based on manually labeled ground truth. Using texture, mean surface errors for the outer surface of the abdominal wall were less than 2 mm, with 91% of the outer surface less than 5 mm away from the manual tracings; errors were significantly greater (2-5 mm) for methods that did not use the texture. The authors' approach establishes a baseline for characterizing the abdominal wall for improving VH care. Inherent texture patterns in CT scans are helpful to the tissue classification, and texture analysis can improve the level set segmentation around the abdominal region. ",0
4906,24320618,Lung and serum teicoplanin concentration after aerosol and intravenous administration in a rat model,"Ventilator-associated pneumonia (VAP) caused by methicillin-resistant Staphylococcus aureus is a major cause of mortality in mechanically ventilated patients. Nebulization of teicoplanin is an alternative way of administration that may provide higher lung tissue concentrations than intravenous (IV) delivery. The aim of this study was to compare the administration of teicoplanin via aerosol with the IV route by measuring the lung and the serum teicoplanin concentrations in a rat model. Eighty healthy male Sprague-Dawley rats were anesthetized and received a single dose of teicoplanin by the IV or aerosol route. After sacrifice, lung and blood samples were collected and teicoplanin concentrations were measured with fluorescence polarization. A noncompartmental approach was used. The area under the concentration curve/minimal inhibition concentration ratio (AUC/MIC), AUC, absorbed fraction, mean residence time (MRT), and mean absorption time (MAT) of teicoplanin were calculated. Mean±SD lung tissue concentrations of teicoplanin in the aerosol group were significantly higher than those in the IV group (p<0.0001). The mean lung tissue concentration achieved at 15 min was 1.94±1.33 mg/g in the aerosol group and 0.04±0.01 mg/g in the IV group. The mean AUClung was 67.4 mg hr(-1)g(-1) after aerosol and 0.8 mg hr(-1)g(-1) after the IV route. In the aerosol group, AUCserum/MIC ratio was 605/2, and in the IV route, AUCserum/MIC ratio was 682/2. MAT was longer after aerosol than after the IV route (0.91 hr versus 0.06 hr), and MRT was longer after aerosol than after IV bolus administration (6.52 hr versus 5.61 hr). Teicoplanin concentrations in the lung tissue of the rat model were significantly higher by the aerosol route than by the IV route. The AUClung after nebulization was 84 times higher than delivery by the IV route, and the AUClung/MIC ratio after nebulization met the recommended target to eradicate Staphylococcus aureus. Administration of teicoplanin by the aerosol route could represent one of the new therapeutic weapons of the treatment of the VAP. ",0
4907,24320626,Novel presentation of lepromatous leprosy in an erythema gyratum repens-like pattern,"Leprosy can have diverse cutaneous and occasionally perplexing presentations. We report an unusual case of lepromatous leprosy (LL) with annular lesions resembling erythema gyratum repens. A 55-year-old man presented with a symmetrical, hypopigmented, and erythematous rash of bizarre appearance over the lateral aspect of the upper arm, and anterior and posterior aspects of the trunk of two months' duration. He gave a history of self-resolving episodes of bilateral pedal edema, and numbness and pricking sensations in both the hands and feet, which had occurred intermittently over the previous six years. An ulcer measuring 2 cm in size was present over the adjacent surface of the right first and second toes. The bilateral ulnar and radial cutaneous nerves were symmetrically thickened. Slit-skin smears revealed numerous acid-fast bacilli. Skin biopsy from the trunk showed collections of histiocytes, lymphocytes, and plasma cells in the dermis and around the blood vessels. The patient was diagnosed with LL and started on multibacillary multi-drug therapy. Lepromatous leprosy can have varied clinical manifestations and is often a great imitator. However, the skin smear positivity, even in normal skin, symmetrical cutaneous and peripheral nerve involvement, and histopathology in the present patient were indicative of LL. This report highlights a rare presentation of leprosy. Clinicians should be aware of these rare manifestations as lepromatous cases still occur in certain regions. ",0
4908,24320698,Clinical considerations on Buruli ulcer employing two molecular tests for the detection of Mycobacterium ulcerans in 100 skin biopsies,"Buruli ulcer (BU) is an infected cutaneous lesion, the etiological agent of which is Mycobacterium ulcerans. Diagnosis is confirmed by the identification of acid-fast bacilli and culture. In clinically suspicious forms with negative bacteriological or Ziehl-Neelsen (ZN) findings, molecular tests are used. This study compared the concordance of nested polymerase chain reaction (PCR) (targeting IS2404) and PCR (targeting IS2606) in different clinical situations. A total of 57 samples were sourced from 39 BU patients. Control samples (n = 43) were obtained from non-BU ulcers in 38 patients. Samples were divided into two pieces and submitted to, respectively, histological examination and ZN staining, and PCR. Subsamples submitted to PCR were divided and submitted to nested PCR IS2404 and PCR IS2606, respectively. Of the 57 BU biopsies, positive results were obtained by nested PCR in 18 (31.6%) and by IS2606 PCR in 37 (64.9%) cases. Sequencing of the positive samples confirmed the specificity of amplicons in all nested PCR samples and in 26 of 37 (70.2%) samples positive to IS2606. Hence, nested PCR was more specific (100% vs. 93%) and less sensitive (32% vs. 46%) than IS2606 PCR. In the BU samples, nested PCR was negative in 15 instances, and IS2606 PCR was negative in 11 instances in which ZN histology had been positive (false negatives). Both PCRs were positive in six ZN-negative smears. We considered 57 samples from 39 BU patients in various clinical stages and at different times after the beginning of therapy. These provided positive results in 18 cases with IS2404 nested PCR and in 37 cases with PCR IS2606; only 26 of the latter remained positive subsequent to sequencing. Hence, even if IS2404 PCR is considered more specific, in subjects who appear to fail to respond to therapy, it is advisable to also carry out IS2606 PCR. A possible interpretation of the discordance between the two techniques due to unavoidable technical errors as well as to different sensitivity of the two tests at M. ulcerans DNA low concentration (i.e. in recent infection and in well-treated cases) is discussed. ",0
4909,24321291,Neurochemical study of amino acids in rodent brain structures using an improved gas chromatography-mass spectrometry method,"The analysis of amino acid levels is crucial for neuroscience studies because of the roles of these molecules as neurotransmitters and their influence on behavior. The present study describes the distribution and levels of 16 amino acids (alanine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, valine, and threonine) in brain tissues (prefrontal cortex, striatum, hippocampus and cerebellum) and the serum. Neurochemical analysis was performed on Wistar rats and C57BL/6 mice using an efficient method for extraction, a fast microwave-assisted derivatization and gas chromatography-mass spectrometry analysis. The amino acid concentration varied across brain regions for 14 of the 16 analyzed molecules, with detection limits ranging from 0.02±0.005μmolL(-1) to 7.07±0.05μmolL(-1). In rats, the concentrations of alanine, glycine, methionine, serine and threonine were higher in prefrontal cortex than in other areas, whereas in mice, the concentrations of glutamic acid, leucine and proline were highest in the hippocampus. In conclusion, this study provides a cerebral profile of amino acids in brain regions and the serum of rats and mice.  ",0
4910,24321736,Attention-deficit hyperactivity disorder (ADHD) as a pyridoxine-dependent condition: urinary diagnostic biomarkers,"The data obtained in children with different forms of epilepsy allowed us to consider epilepsy as an inborn error of pyridoxine (vitamin B6) metabolism (Dolina et al., 2012). Mutual interconnections between ADHD and epilepsy indicate that such an approach is reasonable for ADHD. To check such an assumption we analyzed in ADHD patients the same parameters of pyridoxal phosphate (PLP)-dependent tryptophan (TRP) degradation, which were analyzed in epileptic children. The level of TRP and concentrations of compounds formed or metabolized by TRP degradation, the ratios between some of them, and the level of 4-pyridoxic acid were HPLC detected in ADHD children and healthy controls. The data obtained, including low values of 4PA/TRP, IND/TRP and IND/KYN ratios, have evidenced dramatically impaired activity of pyridoxine-dependent enzymes in ADHD patients. Ritalin treatment did not change the general pattern of TRP degradation, but still created a kind of balance between some of detected metabolites. However, the 4PA/TRP, IND/TRP and IND/KYN ratios remained as low as in untreated patients, keeping the importance of diagnostic markers. Almost identical parameters of TRP degradation in untreated ADHD and epileptic patients allow to assume that inborn disorders of vitamin B6 metabolism are the common biochemical background of both diseases. The disturbed activity of PLP dependent enzymes apparently forms those profound disturbances of neurotransmitter systems, which are inherent in ADHD: low concentrations of monoamines and disordered amino acid metabolism. If vitamin B6 disorders are the core biochemical disturbances inherent in ADHD, then the long-term pyridoxine treatment is pathogenetically based replacement therapy of the disease. According to our data, multi-year pyridoxine treatment normalizes completely the pattern of ADHD behavior, without causing any serious side effects.  ",0
4911,24322214,Estimating the global incidence of traumatic spinal cord injury,"Population modelling--forecasting. To estimate the global incidence of traumatic spinal cord injury (TSCI). An initiative of the International Spinal Cord Society (ISCoS) Prevention Committee. Regression techniques were used to derive regional and global estimates of TSCI incidence. Using the findings of 31 published studies, a regression model was fitted using a known number of TSCI cases as the dependent variable and the population at risk as the single independent variable. In the process of deriving TSCI incidence, an alternative TSCI model was specified in an attempt to arrive at an optimal way of estimating the global incidence of TSCI. The global incidence of TSCI was estimated to be 23 cases per 1,000,000 persons in 2007 (179,312 cases per annum). World Health Organization's regional results are provided. Understanding the incidence of TSCI is important for health service planning and for the determination of injury prevention priorities. In the absence of high-quality epidemiological studies of TSCI in each country, the estimation of TSCI obtained through population modelling can be used to overcome known deficits in global spinal cord injury (SCI) data. The incidence of TSCI is context specific, and an alternative regression model demonstrated how TSCI incidence estimates could be improved with additional data. The results highlight the need for data standardisation and comprehensive reporting of national level TSCI data. A step-wise approach from the collation of conventional epidemiological data through to population modelling is suggested. ",0
4912,24322607,Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium,"Following coronary artery occlusion growth of collateral vessels can provide an effective blood supply to the dependent myocardium. The ischemia, which results in growth of collateral vessels, recruits an inflammatory response with expression of cytokines and growth factors, upregulation of endothelial nitric oxide (NO) synthase (eNOS) in vascular endothelial cells, and expression of inducible nitric oxide synthase (iNOS) in both vessels and cardiac myocytes. Because NO is a potent collateral vessel dilator, this study examined whether NO derived from iNOS or constitutive NOS regulates myocardial blood flow (MBF) in the collateral region. Nonselective NOS inhibition with N(G)-nitro-l-arginine (LNA) caused vasoconstriction with a significant decrease in MBF to the collateral region during exercise. In contrast, the highly selective iNOS inhibitor 1400W caused a 21 ± 5% increase of MBF in the collateral region. This increase in MBF following selective iNOS blockade was proportionate to an increase in myocardial O2 consumption (MVo2). The results suggest that NO produced by iNOS inhibits MVo2 in the collateralized region, so that the increase in MBF following iNOS blockade was the result of metabolic vasodilation secondary to an increase in MVo2. Thus the coordinated expression of iNOS to restrain MVo2 and eNOS to maintain collateral vasodilation act to optimize the O2 supply-demand relationship and protect the collateralized myocardium from ischemia.  ",0
4913,24323277,Bench to cribside: the path for developing a neuroprotectant,"The consequences of perinatal brain injury include immeasurable anguish for families and substantial ongoing costs for care and support of effected children. Factors associated with perinatal brain injury in the preterm infant include inflammation and infection, and with increasing gestational age, a higher proportion is related to hypoxic-ischemic events, such as stroke and placental abruption. Over the past decade, we have acquired new insights in the mechanisms underpinning injury and many new tools to monitor outcome in perinatal brain injury in our experimental models. By embracing these new technologies, we can expedite the screening of novel therapies. This is critical as despite enormous efforts of the research community, hypothermia is the only viable neurotherapeutic, and this procedure is limited to term birth and postcardiac arrest hypoxic-ischemic events. Importantly, experimental and preliminary data in humans also indicate a considerable therapeutic potential for melatonin against perinatal brain injury. However, even if this suggested potential is proven, the complexity of the human condition means we are likely to need additional neuroprotective and regenerative strategies. Thus, within this review, we will outline what we consider the key stages of preclinical testing and development for a neuroprotectant or regenerative neurotherapy for perinatal brain injury. We will also highlight examples of novel small animal physiological and behavioral testing that gives small animal preclinical models greater clinical relevance. We hope these new tools and an integrated bench to cribside strategic plan will facilitate the fulfillment of our overarching goal, improving the long-term brain health and quality of life for infants suffering perinatal brain injury.  ",0
4914,24323526,Premature termination of treatment for anorexia nervosa: differences between patient-initiated and staff-initiated discharge,"To investigate treatment drop-out by comparing clinical indicators of patients whose discharge was initiated by staff with those who initiated discharge themselves. Ninety participants with anorexia completed questionnaires at admission and four weeks into hospitalized treatment. Weight data was collected over this same period. At discharge, participants were categorized into completer (n = 38) or patient-initiated (n = 36) /staff-initiated (n = 16) premature termination groups. Significant differences between staff-initiated and patient-initiated discharge groups were found at admission. Staff initiated groups were on average older (p = .035), and more likely to have had prior compelled treatment (p = .039). At 4 weeks those in the patient-initiated group had put on weight at a faster rate (p = .032) and reported a decrease in alliance (p = .017). At discharge, staff initiated discharge demonstrated greater time in treatment (p = .001), greater weight gain (p = .027), and a higher discharge BMI (p = .013). At discharge, staff-initiated drop-outs had comparable end-of-treatment outcomes to those who completed treatment as planned. There are key differences between those who prematurely discharge themselves from treatment, compared to those who are prematurely discharged by clinical staff. Future research into drop-out needs to take into account and recognize these differences. ",0
4915,24323767,Differential impact of types of social support in the mental health of formerly incarcerated Latino men,"The role of social support in the mental health of formerly incarcerated Latino men (FILM) is an issue overlooked in public health prevention efforts. The objectives of this analysis were to (a) describe the levels of social support perceived and received by FILM; (b) identify the associations, if any, between levels of social support and mental health indicators such as depression and anxiety; and (c) explore the impact of familism and hypermasculinity on the receptivity of social support and the potential role of these factors in mediating associations between social support and mental health indicators. To accomplish the objectives, we conducted a cross-sectional survey with FILM (n = 259), ages 18 to 59, in New York City, and one nominated member of their social network (n = 130 dyads). In this analysis, we examined four dimensions of social support (instrumental, informational, appraisal, and emotional) from two perspectives: provided (as reported by members of the social networks) and perceived (as reported by FILM). The major outcome variables for this analysis were the presence/absence of major anxiety and depressive symptoms. Our logistic regression analyses suggest that perceived emotional support was inversely associated with both anxiety and depression. Our findings suggest that familism mediated the association between perceived emotional support and anxiety/depression. Therefore, we must consider designing network enhancement interventions that focus on both FILM and their social support systems. ",0
4916,24323774,Perfusion/Diffusion mismatch is valid and should be used for selecting delayed interventions,"The mismatch between a larger perfusion lesion and smaller diffusion lesion on magnetic resonance imaging is a validated signal of the ischemic penumbra, namely the region at risk in acute ischemic stroke that is critically hypoperfused and the target of reperfusion therapies. Clinical trials have shown strong correlations between reperfusion in mismatch patients and improved clinical outcomes. Attenuation of infarct growth is associated with reperfusion and corresponding clinical gains. Using computed tomography perfusion, the mismatch between relative cerebral blood flow or cerebral blood volume and perfusion delay is a comparable penumbral marker. Automated techniques allow rapid quantitative assessment of mismatch with thresholding to exclude benign oligemia. The penumbra is often present beyond the current 4.5-h time window, defined for the use of intravenous tPA. Treatment beyond this time point remains investigational. Although the efficacy of thrombolysis in mismatch patients requires further validation in randomized trials, there is now sufficient evidence to recommend that advanced neuroimaging of mismatch should be used for selection of delayed therapies in phase 3 trials.  ",0
4917,24323911,Role of sphingolipids in oestrogen signalling in breast cancer cells: an update,"The signaling pathways activated by the steroid hormone oestrogen include a variety of cytoplasmic second messengers linked to a multitude of tissue-specific effects. In the last decade, sphingolipids and their membrane receptors were added to the list of oestrogen-activated mediators. Oestrogen triggers the sphingolipid signalling cascade in various tissues including breast cancer. Extensive research has shown that sphingolipids are the key regulatory molecules in growth factor networks. Sphingolipids can control the rate of cell proliferation and the differentiation outcome during malignant transformation. In this study, we summarise novel experimental evidences linking sphingolipids to oestrogen-activated effects, highlight the role of sphingolipids in cancer cells and discuss new avenues for future research at the intersection between oestrogen and sphingolipid signalling.  ",0
4918,24324054,Genomic aberrations associated with erlotinib resistance in non-small cell lung cancer cells,"Mechanisms of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are not fully-understood. In this study we aimed to elucidate remaining unknown mechanisms using erlotinib-resistant NSCLC cells. We performed array comparative genomic hybridization (aCGH) to identify genomic aberrations associated with EGFR-TKI resistance in erlotinib-resistant PC-9ER cells. Real-time polymerase chain reaction (PCR) and immunoblot analyses were performed to confirm the results of aCGH. Among the five regions with copy number gain detected in PC-9ER cells, we focused on 22q11.2-q12.1 including v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL), the overexpression of which seemed to be associated with EGFR-TKI resistance. Blockade of downstream phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) signaling using NVP-BEZ235 suppressed the proliferation of PC-9ER cells, implying the involvement of acquired CRKL amplification in EGFR-TKI resistance. Acquired CRKL amplification was identified as contributing to EGFR-TKI resistance; this cell line model can be utilized to study this resistance mechanism. ",0
4919,24324223,Evolution and genetic diversity of the Spain23F-ST81 clone causing adult invasive pneumococcal disease in Barcelona (1990-2012),"We aimed to analyse the clinical epidemiology and genetic diversity of invasive pneumococcal disease (IPD) episodes attributed to the Spain(23F)-ST81 (PMEN1) clone. Fifty-eight (2.7%) of 2117 invasive pneumococci isolated from adult patients during the 1990-2012 period shared a PFGE pattern related to the PMEN1 clone. The genotype was confirmed by multilocus sequence typing. The pbp2x, pbp1a, pbp2b and pspA genes were PCR-amplified and sequenced. Polymorphisms in the pspC gene were identified by PCR restriction fragment length polymorphism. The presence of transposons with erythromycin and tetracycline resistance determinants was detected by PCR. The prevalence of the PMEN1 clone increased from 0.8% in 1991 to 6.2% in 2001, and decreased to 0% in 2010-12, concomitant with the introduction of the seven-valent pneumococcal conjugate vaccine for children. A total of 93.1% of patients had pneumonia, meningitis or peritonitis; 87.9% of patients had associated underlying diseases, mainly cancer, chronic obstructive pulmonary disease and diabetes. Two closely related sequence types (STs) (ST81, n = 52; ST85, n = 6) were detected, with different serotypes: 23F (n = 42), 19A (n = 9) and 19F (n = 6). All the isolates were resistant to penicillin, co-trimoxazole and chloramphenicol. All the isolates also shared the same pbp1a allele, whereas multiple alleles of pbp2b, pbp2x, pspA and pspC were detected. Of the isolates, 89.7% were tetracycline resistant and 60.3% (n = 35) were macrolide resistant, and resistance was associated with different Tn916-like transposons. Adult IPD caused by this clone was mainly detected in patients with underlying conditions, and genetic variability was observed among PMEN1 isolates collected in our area over the past 20 years. ",0
4920,24324290,Predictive value of admission N-terminal pro-B-type natriuretic peptide and renal function in older people hospitalized for dyspnoea,"We investigated the relationship between NT-pro-BNP, glomerular filtration rate (GFR), and all-cause mortality rates in a cohort of older people discharged from an internal medicine unit after admission for dyspnoea. NT-pro-BNP was evaluated in serum samples of 134 patients aged 80 ± 6 years who presented to a single academic centre with worsening dyspnoea. History data and anthropometric, clinical, and biochemical parameters including GFR were collected at the time of admission. 119 out of 134 were discharged alive from hospital and were included in the follow-up of 779 ± 370 days. 35 out of 119 subjects died after a follow-up of 266 ± 251 days. Cox proportional hazards model showed that GFR and Ln (NT-pro-BNP) were predictors for all-cause mortality with estimated hazard ratios of 0.969 (95% confidence interval: 0.950-0.988; P = 0.001) and 2.360 (95% confidence interval: 1.208-4.610; P = 0.012), respectively. Patients characterized by high NT-pro-BNP levels and GFR ≥ 60 mL/min/1.73 m(2) showed a dramatic reduction in survival duration compared with the groups with different combinations of the two variables (P = 0.008). In the elderly, NT-pro-BNP and GFR are predictors of all-cause mortality after admission because of dyspnoea. Since the fact that subjects with high NT-pro-BNP and GFR ≥ 60 mL/min/1.73 m(2) exhibited a reduced survival, high admission NT-pro-BNP suggests future negative outcome. ",0
4921,24324345,"""Epidemiology of """"fragile skin"""": results from a survey of different skin types""","""Epidemiologic information regarding the prevalence of """"fragile skin"""" in different adult populations is currently limited. The objective of the current survey was to assess the occurrence of perceived """"fragile skin"""" across different skin types in the general adult population. Individuals aged 15-65 years from five representative geographic regions (France, Spain, Sweden, Japan, and the US) were interviewed and grouped into the following skin types: Caucasian North skin (n=1,218), Caucasian South skin (n=1,695), Asian skin (n=1,500), and Black skin (n=500). The main survey question was """"In your opinion, do you have fragile skin?"""" Concepts relating to the nature and appearance of an individual's skin were also evaluated. A total of 4,913 individuals were interviewed. Subjects in the Caucasian North, Caucasian South, Asian, and Black skin type groups responded positively to the question """"In your opinion, do you have fragile skin?"""" in the following proportions: 24.44%, 29.71%, 52.67%, and 42.20%, respectively. With the exception of individuals in the Black skin group, """"fragile skin"""" was prevalent in significantly more women than men (P<0.0001). Compared with other age categories, the prevalence of """"fragile skin"""" was significantly higher in individuals aged 15-34 years (P<0.0001), regardless of skin type. In general, individuals reporting """"fragile skin"""" were 2-3-fold more likely to respond positively to a series of questions relating to the nature and appearance of their skin. The prevalence of """"fragile skin"""" was also higher in individuals who experienced dermatosis (skin lesions of any type) in the previous 12 months. Whilst these findings need to be confirmed through objective evaluation, the current survey demonstrated that """"fragile skin"""" is perceived to occur in a substantial proportion of individuals from any given country, particularly in the age range of 15-34 years, regardless of skin type. """,0
4922,24324900,E. coli Meningitis Presenting in a Patient with Disseminated Strongyloides stercoralis,"Introduction. Spontaneous Escherichia coli meningitis is an infrequent condition in adults and is associated with some predisposing factors, including severe Strongyloides stercoralis (SS) infections. Case Presentation. A 43-year-old Hispanic man, with history of travelling to the jungle regions of Peru and Brazil two decades ago, and who received prednisone due to Bell's palsy for three weeks before admission, presented to the Emergency Department with diarrhea, fever, and hematochezia. A week after admission he developed drowsiness, meningeal signs, abdominal distension, and constipation. A cerebrospinal fluid culture showed extended spectrum β -lactamase producing E. coli. A colonoscopy was performed and showed pancolitis. Three days after the procedure the patient became unstable and developed peritoneal signs. He underwent a laparotomy, which ended up in a total colectomy and partial proctectomy due to toxic megacolon. Three days later the patient died in the intensive care unit due to septic shock. Autopsy was performed and microscopic examination revealed the presence of multiple Strongyloides larvae throughout the body. Conclusion. Strongyloides stercoralis infection should be excluded in adults with spontaneous E. coli meningitis, especially, if gastrointestinal symptoms and history of travelling to an endemic area are present. Even with a proper diagnosis and management, disseminated strongyloidiasis has a poor prognosis.  ",0
4923,24324916,"In Vitro Antioxidative Evaluation of α- and β-Carotene, Isolated from Crude Palm Oil","The present work describes the isolation of α - and β -carotene from crude palm oil and their antioxidant potential in an in vitro model. Pure product was isolated by the method adopted. Antioxidant activities of the isolated α - and β -carotene were analyzed in five different concentrations of 0.001, 0.005, 0.01, 0.05, and 0.1% (w/v). From the several assays conducted, an observation was made that the antioxidant activity of the product shifted between antioxidant and prooxidant effects depending on the concentration and the system analyzed. The metal chelation, DPPH radical scavenging, and superoxide scavenging activities showed almost similar results in terms of high activity at lowest concentrations. ABTS-scavenging activity was displayed only by a particular antioxidant concentration of 0.1%. Lipid peroxidation assay pronounced the activity of 0.1% antioxidant in inhibiting oxidation of sensitive bioactive lipids. In vitro antidenaturation test again specified the efficacy of low concentrations in preventing protein denaturation. Through this study a definite dosage formulation for consumption of carotenoids is being proposed which will enhance health promotion and prevent chronic diseases when taken as fortified foods or dietary supplements.  ",0
4924,24325265,Biotransformation of the high-molecular weight polycyclic aromatic hydrocarbon (PAH) benzo[k]fluoranthene by Sphingobium sp. strain KK22 and identification of new products of non-alternant PAH biodegradation by liquid chromatography electrospray ionization tandem mass spectrometry,"A pathway for the biotransformation of the environmental pollutant and high-molecular weight polycyclic aromatic hydrocarbon (PAH) benzo[k]fluoranthene by a soil bacterium was constructed through analyses of results from liquid chromatography negative electrospray ionization tandem mass spectrometry (LC/ESI(-)-MS/MS). Exposure of Sphingobium sp. strain KK22 to benzo[k]fluoranthene resulted in transformation to four-, three- and two-aromatic ring products. The structurally similar four- and three-ring non-alternant PAHs fluoranthene and acenaphthylene were also biotransformed by strain KK22, and LC/ESI(-)-MS/MS analyses of these products confirmed the lower biotransformation pathway proposed for benzo[k]fluoranthene. In all, seven products from benzo[k]fluoranthene and seven products from fluoranthene were revealed and included previously unreported products from both PAHs. Benzo[k]fluoranthene biotransformation proceeded through ortho-cleavage of 8,9-dihydroxy-benzo[k]fluoranthene to 8-carboxyfluoranthenyl-9-propenic acid and 9-hydroxy-fluoranthene-8-carboxylic acid, and was followed by meta-cleavage to produce 3-(2-formylacenaphthylen-1-yl)-2-hydroxy-prop-2-enoic acid. The fluoranthene pathway converged with the benzo[k]fluoranthene pathway through detection of the three-ring product, 2-formylacenaphthylene-1-carboxylic acid. Production of key downstream metabolites, 1,8-naphthalic anhydride and 1-naphthoic acid from benzo[k]fluoranthene, fluoranthene and acenaphthylene biotransformations provided evidence for a common pathway by strain KK22 for all three PAHs through acenaphthoquinone. Quantitative analysis of benzo[k]fluoranthene biotransformation by strain KK22 confirmed biodegradation. This is the first pathway proposed for the biotransformation of benzo[k]fluoranthene by a bacterium. ",0
4925,24325356,Somatic mutations of calreticulin in myeloproliferative neoplasms,"BACKGROUND: Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. METHODS: We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. RESULTS: Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. CONCLUSIONS: Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).",0
4926,24325418,Quality of reporting clinical trials published in five leading Sri Lankan medical journals,"To assess the quality of reporting of clinical trials published in five leading Sri Lankan medical journals. Six medical journals were hand searched for clinical trials published from 1982 to 2011. Eligible criteria were all randomized and non-randomized clinical trials conducted in humans. A checklist was developed based on CONSORT and TREND recommendations. Each study was independently evaluated by two reviewers. Outcome measures were presence of checklist items in published reports. Fifteen randomized and 24 non-randomized parallel group trials from 724 studies in five journals met the inclusion criteria. Out of 39 trials, 39 (97%) clearly described the objectives, 16 (41%) defined the periods of recruitment, 7 (18%) reported how sample size was determined, 10 (25.6%) reported the methods to enhance the quality of measurements, 20 (51%) reported baseline demographic and clinical characteristics of each group, 4 (10%) showed flow diagrams, 23 (69%) reported statistical methods used to compare groups for primary outcomes, 21 (54%) reported effect size, 4 (10%) reported its precision, and 20 (51%) interpreted the results in the context of current evidence, and 5 (13%) described the generalizability of the findings. Of the 15 randomized trials, only one (7%) reported sequence generation, 5 (33%) allocation concealment, 9 (60%) reported blinding status of participants or investigators, and 2 (13%) reported intention to treat analysis. Reporting of several essential recommendations remained suboptimal. Education and training of trial methods and awareness of the CONSORT and TREND statements and more attention to the quality of reporting may improve matters. ",0
4927,24325809,The role of actigraphy in the assessment of primary insomnia: a retrospective study,"The aim of our study was to evaluate quantitative actigraphic criteria obtained using the Actiwatch device (AW64; Cambridge Neurotechnology Ltd., Cambridge, UK) to differentiate participants with insomnia from normal sleepers. In our retrospective study, we recovered 493 actigraphic records from two sleep measure databases of patients with insomnia (n=151) and one of normal sleepers (n=342). We considered the following actigraphic sleep parameters: time in bed (TIB), sleep-onset latency (SOL), total sleep time (TST), wake after sleep onset (WASO), sleep efficiency (SE), number of awakenings (NWAK), terminal wakefulness (TWAK), fragmentation index (FI), and mean motor activity (MA). We also considered two actigraphic circadian indexes: interdaily stability and intradaily variability. Using the Youden index, we calculated the quantitative actigraphic criteria that performed best for each actigraphic sleep parameter. Finally, we created receiver operating characteristic curves to test the accuracy of each criterion identified. All sleep parameters except TST and TWAK differentiated the two groups of participants, allowing calculation of quantitative actigraphic criteria. There were no differences in the circadian indices. The quantitative actigraphic criteria obtained in our study were not the same as those obtained previously with a different device, suggesting the need to adopt shared technical solutions for actigraphy. ",0
4928,24326154,Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation,"Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention.  ",0
4929,24326357,Oncological imaging for therapy response assessment],"This review illustrates different radiological methods for therapy response assessment in the field of oncological imaging. Unidimensional measurement of tumor size according to the response evaluation criteria in solid tumors (RECIST) is of utmost importance. The established RECIST definitions of changes in size are decisive for subdivision into the categories complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), which are generally accepted as the concise characterization for therapy response. Problems with size-dependent response assessment occur particularly in targeted therapy and by phenomena, such as pseudoprogression. Several variants of functional imaging and their role in cancer imaging regarding practical requests are introduced.  ",0
4930,24326390,Hydrocephalus after intraventricular hemorrhage: the role of thrombin,"Previous studies demonstrated that thrombin is an important factor in brain injury after intracerebral hemorrhage. This study investigated the effect of thrombin on hydrocephalus development in a rat intraventricular hemorrhage (IVH) model. There were three parts in this study. First, male Sprague-Dawley rats had an injection of 200 μL saline, autologous blood or heparinized blood, into the right lateral ventricle. Second, rats had an injection of 50 μL saline or 3U thrombin into the right lateral ventricle. Third, rats had an injection of thrombin (3U) with a protease-activated receptor-1 (PAR-1) antagonist, SCH79797 (0.15 nmol), or vehicle into the right lateral ventricle. Lateral ventricle volumes were measured by magnetic resonance imaging and the brains were used for immunohistochemistry and western blot analyses. Intraventricular injection of autologous blood induced hydrocephalus from day 1 to 28. Heparinized blood injection resulted in less hydrocephalus at all time points compared with blood injection alone (P<0.05). Intraventricular injection of thrombin caused significant hydrocephalus, ventricular wall damage, and periventricular blood-brain barrier disruption. Thrombin-induced hydrocephalus was reduced by co-injection of the PAR-1 antagonist SCH79797 (P<0.05). In conclusion, thrombin contributes to hydrocephalus development after IVH and thrombin-induced hydrocephalus is through PAR-1.  ",0
4931,24326601,Optimizing the use of surveillance data for monitoring the care status of persons recently diagnosed with HIV in NYC,"""Comprehensive laboratory reporting of CD4 and viral load (VL) tests to surveillance has been used to assess HIV care-related outcomes at the population level, but their validity for this purpose has not been comprehensively evaluated. Assess performance characteristics and validity of surveillance-based measures of linkage to and establishment of HIV primary care among HIV-infected persons in the first 12 months after diagnosis using medical record (MR) data on outpatient HIV primary care visits as the gold standard. All patients diagnosed with HIV in 2009 at 24 New York City high-volume, HIV diagnostic and treatment facilities who linked to care within 12 months at the same site as defined by the presence of ≥1 CD4/VL report received by surveillance were selected for MR review to confirm linkage to outpatient HIV primary care within the first year. All HIV care visit dates were abstracted and considered associated with a surveillance laboratory report, if within 14 days of a care visit. The proportion linking to care according to the MR was compared with the proportion linking per CD4/VL tests reported to surveillance. Four measures of the establishment of outpatient HIV primary care in the first year were assessed: (1) sustained care (first visit within 3 months; second visit, 3-9 months later), (2) continuous care (2 visits at least 90 days apart), (3) trimester visits (visit in each 4-month period), and (4) visit constancy (visit in each 3-month period). The validity of surveillance data for measuring this outcome was assessed by comparing results for each of the 4 measures calculated using surveillance data to those calculated using MR data. Of the 782 patients selected, 20% (N = 157) of patients did not link to outpatient HIV primary care at the co-located care facility within 12 months of diagnosis. Half (48.5%) of patients' care visits after linkage did not have an associated CD4/VL reported to surveillance. Of the 4 establishment measures, sustained and continuous care had the highest agreement with MR (86.6% and 88.8%, respectively) as compared with the trimester visits and visit constancy (77.8% and 72.8%, respectively). Surveillance data overestimated linkage rates but underestimated the frequency of HIV care in the first year after HIV diagnosis. Of the 4 measures of establishment of HIV care evaluated, """"sustained care"""" is best suited for measurement using surveillance data because of its high level of agreement with MR data and close alignment with national standards for timely linkage and flexible follow-up. """,0
4932,24326618,The differential diagnosis of hypoglycorrhachia in adult patients,"Hypoglycorrhachia, a low glucose level in the cerebrospinal fluid (CSF), can suggest bacterial, fungal or tuberculous meningitis. When tests for these common infectious etiologies are negative, many clinicians are unsure of which diagnoses to consider, resulting in delayed treatment. The authors analyzed the diagnoses associated with hypoglycorrhachia to determine their relative frequencies at our institution and summarized all the diagnoses associated with hypoglycorrhachia in the literature. Retrospective analysis of adults with hypoglycorrhachia at a tertiary care teaching hospital over a 5-year period. Inclusion criteria included CSF glucose <40 mg/dL and age 18 years or older. Exclusion criteria included CSF/serum glucose ≥0.6. Eighty-nine unique hypoglycorrhachia episodes were identified. The most common etiologies among all episodes of hypoglycorrhachia were bacterial meningitis (24%), fungal meningitis (15%), stroke/bleed (13%), malignancy (11%), viral meningitis (6%), neurosarcoidosis (4%), neurosyphilis (4%) and cerebral toxoplasmosis (3%). The most common etiology was fungal meningitis (38%) among HIV-infected patients and bacterial meningitis (62%) among neurosurgery patients. However, in patients without HIV or neurosurgical history, noninfectious etiologies (stroke/bleed, 24%; malignancy, 22%) were most common. Many diagnoses, both infectious and noninfectious, lead to hypoglycorrhachia and must be considered in the differential diagnosis. ",0
4933,24326672,Milder multiple sclerosis course in patients with concomitant inflammatory bowel disease,"An association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) has been suggested. The purpose of this study was to compare the disease course of patients with both MS and IBD with that of patients with isolated MS or isolated IBD. Sixty-six MS-IBD patients were identified and were matched with 251 isolated MS and 257 isolated IBD controls. Main outcomes were scores using the Expanded Disability Status Scale (EDSS) in MS and extent of disease extension in IBD at last clinical evaluation. After a median 12 years of disease duration, the median EDSS and the percentages of patients reaching an EDSS of 3.0 and 4.0 were significantly lower in MS-IBD patients than in controls. MS had no impact on IBD. MS course appears to be milder in patients with concomitant IBD. ",0
4934,24326837,Palliative two-dimensional radiotherapy of pancreatic carcinoma: a feasibility study,"The aim of the study was to analyze the dose to be administered with two-dimensional involved-field palliative radiotherapy in advanced pancreatic carcinoma with respect to current dose-volume constraints (QUANTEC). The following standard regimens were evaluated: 30 Gy at 3 Gy/fraction (regimen A), 36 Gy at 2.4 Gy/fraction (regimen B), 45 Gy at 1.8 Gy/fraction (regimen C), and 50 Gy at 2 Gy /fraction (regimen D). The following constraints were considered: spinal cord Dmax <50 Gy, duodenum Dmax <55 Gy, liver Dmean <30 Gy, kidneys Dmean <15 Gy. For dose/fraction different from 1.8-2 Gy, the correction of constraints using a value of alpha/beta = 3 for late effects was considered. The calculation of dose/volume constraints was repeated for three different radiation beams: cobalt unit, 6 MV photons, and 15 MV photons. Standard field sizes were used and adapted according to the different beam types, using the parameters of our previous study. Respect of dose-volume constraints was assessed for each type of beam and treatment (dose per fractionation) in all patients. Treatments were considered acceptable in case of: 1) respect of the constraints for spinal cord and duodenum in all patients; 2) respect in >10/15 patients of constraints for kidneys and liver. Therefore, minor violations (<10%) of the constraints for these organs were accepted (in less than 5/15 patients), in consideration of the palliative aim of treatment. In regimen A (30 Gy, 3 Gy/fraction), evaluated constraints were respected in all patients, regardless of the type of energy. In regimen B (36 Gy, 2.4 Gy/fraction), constraints were met in all patients undergoing irradiation with 6 and 15 MV photons. However, using the cobalt unit, kidney constraint was respected only in 5 of 15 patients. In regimens C and D (45 Gy, 1.8 Gy/fraction and 50 Gy, 2 Gy/fraction, respectively), the constraint for the kidney was respected only in 2-5 patients, depending on the energy used. Furthermore, using 50 Gy, the spinal cord constraint was not respected in 2-3 patients, depending on the beam used. Therefore, only the following treatments were considered acceptable: 1) 30 Gy, 3 Gy/fraction, regardless of the energy used; 2) 36 Gy, 2.4 Gy/fraction, only for treatments performed with linear accelerator (6-15 MV). The clinical benefits of radiotherapy in pancreatic tumors should not be withheld from patients treated in centers only with two-dimensional technology. Prospective trials, particularly in developing countries, would be useful to evaluate the efficacy in this setting of involved-field two-dimensional treatments using the dose and fractionation defined in this analysis. ",0
4935,24326921,Sitting and cardiometabolic risk factors in U.S. adolescents,"To examine sitting time and cardiometabolic disease risk in US adolescents. Data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) were utilized. Self-reported daily sitting was ascertained by total time in seated activities. Cardiometabolic disease risk was defined by using age- and sex-specific metabolic syndrome (MetS), continuous metabolic risk score, and individual risk factors. There were 394 adolescents (12-20 yrs) meeting the inclusion criteria. Mean age (± SE) was 16.1 ± 0.1 yrs and 51% were male. Mean daily sitting time (± SE) was 407 ± 11 min/day(6.8 hrs/day) and prevalence of MetS was 8.3%. Adolescents in the highest tertile for sitting time were more likely to be overweight/obese (42%) than adolescents in the other tertiles (22-28%). Multivariate regression analyses revealed that daily sitting time was not associated with MetS (odds ratio 0.94, 95%CI 0.80-1.11) or the continuous risk score (b=0.02, SE=0.03, p=0.44). However, daily sitting time was positively correlated with insulin resistance (HOMA-IR) (b=0.03, SE=0.04, p=0.04); this association was attenuated after accounting for adiposity (sum of skinfolds), diet, and physical activity (b=0.04, SE=0.03, p=0.21). In adolescents, daily sitting time was not associated with MetS but was positively associated with fasting insulin resistance, although this relationship appears to be secondary to the influence of adiposity. ",0
4936,24327736,Weissella confusa septicemia in a foal,"Weissella confusa is a Gram-positive bacterium that has been identified in environmental and food samples from around the world. Rare cases of bacteremia in immunocompromised people have been reported. A 2-day-old foal was presented for weakness and suspected sepsis. Blood culture yielded pure growth of a Gram-positive coccobacillus, which was identified as W. confusa through sequencing of the 16S ribosomal DNA. Although the foal initially responded to antimicrobial therapy with ceftiofur and metronidazole, it later developed septic complications of the right tarsocrural joint and right digital flexor tendon sheath and was euthanized. Postmortem examination and histology revealed subcutaneous icterus, severe diffuse interstitial pneumonia, septic synovitis, necrotizing vasculitis with marked thrombosis and hemorrhage in the medial digital vessels of the right hind limb, and ischemic necrosis of the right hind hoof laminae. Gram-positive, coccobacilli were observed in the vascular lesion.  ",0
4937,24328097,SILAC peptide ratio calculator: a tool for SILAC quantitation of peptides and post-translational modifications,This paper describes an algorithm to assist in relative quantitation of peptide post-translational modifications using stable isotope labeling by amino acids in cell culture (SILAC). The described algorithm first determines the normalization factor and then calculates SILAC ratios for a list of target peptide masses using precursor ion abundances. Four yeast histone mutants were used to demonstrate the effectiveness of this approach for quantitation of peptide post-translational modifications changes. The details of the algorithm's approach for normalization and peptide ratio calculation are described. The examples demonstrate the robustness of the approach as well as its utility to rapidly determine changes in peptide post-translational modifications within a protein.  ,0
4938,24328326,Simple nanoparticle-based luminometric method for molecular weight determination of polymeric compounds,A nanoparticle-based method utilizing time-resolved luminescence resonance energy transfer (TR-LRET) was developed for molecular weight determination. This mix-and-measure nanoparticle method is based on the competitive adsorption between the analyte and the acceptor-labeled protein to donor Eu(III) nanoparticles. The size-dependent adsorption of molecules enables the molecular weight determination of differently sized polymeric compounds down to a concentration level of micrograms per liter. The molecular weight determination from 1 to 10 kDa for polyamino acids and from 0.3 to 70 kDa for polyethylene imines is demonstrated. The simple and cost-effective nanoparticle method as microtiter plate assay format shows great potential for the detection of the changes in molecular weight or for quantification of differently sized molecules in biochemical laboratories and in industrial polymeric processes.  ,0
4939,24328571,Radical acylation of L-lysine derivatives and L-lysine-containing peptides by peroxynitrite-treated diacetyl and methylglyoxal,"Highly electrophilic α-dicarbonyls such as diacetyl, methylglyoxal, 3-deoxyglucosone, and4,5-dioxovaleric acid have been characterized as secondary catabolites that can aggregate proteins and form DNA nucleobase adducts in several human maladies, including Alzheimer's disease, rheumatoid arthritis, diabetes, sepsis, renal failure, and respiratory distress syndrome. In vitro, diacetyl and methylglyoxal have also been shown to rapidly add up the peroxynitrite anion (k2 ~ 10(4)-10(5) M(-1) s(-1)), a potent biological nucleophile, oxidant and nitrosating agent, followed by carbon chain cleavage to carboxylic acids via acetyl radical intermediate that can modify amino acids. In this study, we used the amino acid derivatives Ac-Lys-OMe and Z-Lys-OMe and synthesized the tetrapeptides H-KALA-OH, Ac-KALA-OH, and H-K(Boc)ALA-OH to reveal the preferential Lys amino group targeted by acyl radical generated by the α-dicarbonyl/peroxynitrite system. The pH profiles of the reactions are bell-shaped, peaking at approximately 7.5; hence, they are close to the pKa values of ONOOH and of the catalytic H2PO4(-) anion. RP-HPLC and ESI-MS analyses of reaction products confirmed (α)N- and (ϵ)N-acetylation of Lys by diacetyl as well as acetylation and formylation by methylglyoxal, with preference for the α-amino group. These data suggest the possibility of radical acylation of proteins in epigenetic processes, where enzymatic acetylation of these biomolecules is a well-documented event, recently reported to be as critical to the cell cycle as phosphorylation. Also noteworthy is the observed formylation of L-Lys containing peptides by methylglyoxal never reported to occur in amino acid residues of peptides and proteins. ",0
4940,24329704,Effect of an inhibitor of neuronal nitric oxide synthase 7-nitroindazole on cerebral hemodynamic response and brain excitability in urethane-anesthetized rats,"The role of neuronal nitric oxide synthase (nNOS) in the pathophysiology of epilepsy and seizures remains disputable. One of the reasons why results from the acute in vivo studies display controversies might be the effect on the regulation of cerebral blood flow (CBF) during pharmacologically induced alterations of NO system. We examined neurovascular coupling in the rat sensorimotor cortex in response to transcallosal stimulation under nNOS inhibition by 7-nitroindazole (7-NI). Adult Wistar rats were anesthetized with urethane and epidural silver EEG electrodes were implanted over sensorimotor cortices. Regional CBF was measured by Laser Doppler Flowmetry (LDF). We catheterized a common carotid artery to measure arterial blood pressure (BP). 7-NI did not significantly affect blood pressure and heart rate. Electrophysiological recordings of evoked potentials (EPs) revealed no effect on their amplitude, rhythmic potentiation or depression of EPs. Transcallosal stimulation of the contralateral cortex induced a frequency dependent rise in CBF. Although 7-NI did not significantly affect basal CBF and cortical excitability, hemodynamic responses to the transcallosal stimulation were diminished implicating a role of nNOS in neurovascular coupling. Urethane anesthesia is suitable for future epileptological experiments. Our findings demonstrate that NO contributes to the hemodynamic response during brain activation.  ",0
4941,24329912,"An efficient and economical method for extraction of DNA amenable to biotechnological manipulations, from diverse soils and sediments","An attempt was made to optimize a new protocol for isolation of pure metagenomic DNA from soil samples. Various chemicals (FeCl3 , MgCl2 , CaCl2 and activated charcoal) were tested for their efficacy in isolation of metagenomic DNA from different soil and compost samples. Among these trials, charcoal and MgCl2 when used in combination yielded highly pure DNA free from humic acids and other contaminants. The DNA extracted with the optimized protocol was readily digested, amplified and cloned. Moreover, compared with a well-established commercial DNA isolation kit (UltraClean™ Soil DNA Isolation Kit), our method for DNA isolation was found to be economical. This demonstrated that the method developed can be applied to a wide variety of soil samples and allows handling of multiple samples at a given time. The optimized protocol developed has successfully yielded pure metagenomic DNA amenable to biotechnological manipulations. A user-friendly and economical protocol for isolation of DNA from soil and compost samples has been developed. ",0
4942,24330029,Inefficacy of a highly selective T-type calcium channel blocker in preventing atrial fibrillation related remodeling,"The T-type Ca(2+) channel (I(CaT)) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to I(CaT) inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca(2+) channels, Na(+) channels and cytochromes. Thus, the relationship between I(CaT) inhibition and remodeling protection in AF is still unknown. To assess the effects of a novel highly selective Cav3 (I(CaT)) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs. Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8). One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration. I(CaT) blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to I(CaT) blockade. These results indicate that I(CaT) inhibition is not likely to be a useful approach for AF therapy. ",0
4943,24330075,Signalling properties and pharmacology of a 5-HT7 -type serotonin receptor from Tribolium castaneum,"In the last decade, genome sequence data and gene structure information on invertebrate receptors has been greatly expanded by large sequencing projects and cloning studies. This information is of great value for the identification of receptors; however, functional and pharmacological data are necessary for an accurate receptor classification and for practical applications. In insects, an important group of neurotransmitter and neurohormone receptors, for which ample sequence information is available but pharmacological information is missing, are the biogenic amine G protein-coupled receptors (GPCRs). In the present study, we investigated the sequence information, pharmacology and signalling properties of a 5-HT7 -type serotonin receptor from the red flour beetle, Tribolium castaneum (Trica5-HT7 ). The receptor encoding cDNA shows considerable sequence similarity with cognate 5-HT7 receptors and phylogenetic analysis also clusters the receptor within this 5-HT receptor group. Real-time reverse transcription PCR demonstrated high expression levels in the brain, indicating the possible importance of this receptor in neural processes. Trica5-HT7 was dose-dependently activated by 5-HT, which induced elevated intracellular cyclic AMP levels but had no effect on calcium signalling. The synthetic agonists, α-methyl 5-HT, 5-methoxytryptamine, 5-carboxamidotryptamine and 8-hydroxy-2-(dipropylamino)tetralin hydrobromide, showed a response, although with a much lower potency and efficacy than 5-HT. Ketanserin and methiothepin were the most potent antagonists. Both showed characteristics of competitive inhibition on Trica5-HT7 . The signalling pathway and pharmacological profile offer important information that will facilitate functional and comparative studies of 5-HT receptors in insects and other invertebrates. The pharmacology of invertebrate 5-HT receptors differs considerably from that of vertebrates. The present study may therefore contribute to establishing a more reliable classification of invertebrate 5-HT receptors.  ",0
4944,24330348,The first recombinant FVIII produced in human cells--an update on its clinical development programme,"The development of inhibitors and the need for frequent venous access for FVIII injection are major challenges in current haemophilia treatment. Presently available recombinant FVIII (rFVIII) products produced in hamster cell lines are associated with inhibitor formation in up to 32% of previously untreated patients. The new human cell line-derived recombinant human FVIII (Human-cl rhFVIII) protein is the first native, unmodified truly human rFVIII product produced in a human cell line without additive animal proteins. The aim of using a human cell line for the production of rFVIII is the avoidance of non-human epitopes on rFVIII, thereby potentially reducing the rate of inhibitor development, avoiding allergic reactions and allowing personalized prophylaxis with the chance of fewer infusions. Studies to date show that prophylaxis with Human-cl rhFVIII prevents 96% of bleeding events in adults with severe haemophilia A when compared to on-demand treatment. Available pharmacokinetic data with a mean half-life of 17.1 h allow personalized prophylaxis with the chance of fewer infusions. Studies in previously treated children and adults indicate that Human-cl rhFVIII is efficacious and safe in the prevention and treatment of bleeding episodes and that none of the treated patients developed inhibitors or allergic reactions thus far. ",0
4945,24330447,Antifungal and antibacterial activity and chemical composition of polar and non-polar extracts of Athrixia phylicoides determined using bioautography and HPLC,"Athrixia phylicoides DC. (Asteraceae) is used medicinally in South Africa to treat a plethora of ailments, including heart problems, diabetes, diarrhoea, sores and infected wounds. It is also prepared in the form of a tea (hot decoction) taken as a refreshing, pleasant-tasting beverage with commercialization potential. Extracts of the dried ground aerial parts were prepared using organic solvents (diethyl ether, dichloromethane/methanol, ethyl acetate and ethanol) and water. These extracts were subjected to HPLC, TLC and bioautography analysis with the aim of linking a range of peaks visualized in HPLC chromatography profiles to antibacterial and antifungal activity of the same extracts. HPLC revealed a group of compounds extracted by more than one solvent. Compounds identified include inositol, caffeic acid, quercetin, kaempferol, apigenin, hymenoxin and oleanolic acid. The organic extracts displayed similar TLC profiles, and bioautography indicated approximately five antibacterial compounds, but only two antifungal compounds in these extracts. Bioautography indicated that cold water extracted the least antimicrobial compounds. Several previously unknown compounds were identified in Athrixia phylicoides extracts, and bioautography indicated a number of antibacterial and antifungal compounds. There were notable differences in chemical composition and bioactivity between the organic and aqueous extracts. Further research is necessary to fully characterize the active components of the extracts. ",0
4946,24330462,A system to simultaneously detect tick-borne pathogens based on the variability of the 16S ribosomal genes,"DNA microarrays can be used to quickly and sensitively identify several different pathogens in one step. Our previously developed DNA microarray, based on the detection of variable regions in the 16S rDNA gene (rrs), which are specific for each selected bacterial genus, allowed the concurrent detection of Borrelia spp., Anaplasma spp., Francisella spp., Rickettsia spp. and Coxiella spp. In this study, we developed a comprehensive detection system consisting of a second generation DNA microarray and quantitative PCRs. New oligonucleotide capture probes specific for Borrelia burgdorferi s.l. genospecies and Candidatus Neoehrlichia mikurensis were included. This new DNA microarray system required substantial changes in solution composition, hybridization conditions and post-hybridization washes. This second generation chip displayed high specificity and sensitivity. The specificity of the capture probes was tested by hybridizing the DNA microarrays with Cy5-labeled, PCR-generated amplicons encoding the rrs genes of both target and non-target bacteria. The detection limit was determined to be 10(3) genome copies, which corresponds to 1-2 pg of DNA. A given sample was evaluated as positive if its mean fluorescence was at least 10% of the mean fluorescence of a positive control. Those samples with fluorescence close to the threshold were further analyzed using quantitative PCRs, developed to identify Francisella spp., Rickettsia spp. and Coxiella spp. Like the DNA microarray, the qPCRs were based on the genus specific variable regions of the rrs gene. No unspecific cross-reactions were detected. The detection limit for Francisella spp. was determined to be only 1 genome copy, for Coxiella spp. 10 copies, and for Rickettsia spp., 100 copies. Our detection system offers a rapid method for the comprehensive identification of tick-borne bacteria, which is applicable to clinical samples. It can also be used to identify both pathogenic and endosymbiontic bacteria in ticks for eco-epidemiological studies, tick laboratory colony testing, and many other applications. ",0
4947,24330551,Matrix forming characteristics of inner and outer human meniscus cells on 3D collagen scaffolds under normal and low oxygen tensions,"Limited intrinsic healing potential of the meniscus and a strong correlation between meniscal injury and osteoarthritis have prompted investigation of surgical repair options, including the implantation of functional bioengineered constructs. Cell-based constructs appear promising, however the generation of meniscal constructs is complicated by the presence of diverse cell populations within this heterogeneous tissue and gaps in the information concerning their response to manipulation of oxygen tension during cell culture. Four human lateral menisci were harvested from patients undergoing total knee replacement. Inner and outer meniscal fibrochondrocytes (MFCs) were expanded to passage 3 in growth medium supplemented with basic fibroblast growth factor (FGF-2), then embedded in porous collagen type I scaffolds and chondrogenically stimulated with transforming growth factor β3 (TGF-β3) under 21% (normal or normoxic) or 3% (hypoxic) oxygen tension for 21 days. Following scaffold culture, constructs were analyzed biochemically for glycosaminoglycan production, histologically for deposition of extracellular matrix (ECM), as well as at the molecular level for expression of characteristic mRNA transcripts. Constructs cultured under normal oxygen tension expressed higher levels of collagen type II (p = 0.05), aggrecan (p < 0.05) and cartilage oligomeric matrix protein, (COMP) (p < 0.05) compared to hypoxic expanded and cultured constructs. Accumulation of ECM rich in collagen type II and sulfated proteoglycan was evident in normoxic cultured scaffolds compared to those under low oxygen tension. There was no significant difference in expression of these genes between scaffolds seeded with MFCs isolated from inner or outer regions of the tissue following 21 days chondrogenic stimulation (p > 0.05). Cells isolated from inner and outer regions of the human meniscus demonstrated equivalent differentiation potential toward chondrogenic phenotype and ECM production. Oxygen tension played a key role in modulating the redifferentiation of meniscal fibrochondrocytes on a 3D collagen scaffold in vitro. ",0
4948,24330608,"Detoxification and stress response genes expressed in a western North American bumble bee, Bombus huntii (Hymenoptera: Apidae)","The Hunt bumble bee (Bombus huntii Greene, Hymenoptera: Apidae) is a holometabolous, social insect important as a pollinator in natural and agricultural ecosystems in western North America. Bumble bees spend a significant amount of time foraging on a wide variety of flowering plants, and this activity exposes them to both plant toxins and pesticides, posing a threat to individual and colony survival. Little is known about what detoxification pathways are active in bumble bees, how the expression of detoxification genes changes across life stages, or how the number of detoxification genes expressed in B. huntii compares to other insects. We found B. huntii expressed at least 584 genes associated with detoxification and stress responses. The expression levels of some of these genes, such as those encoding the cytochrome P450s, glutathione S-transferases (GSTs) and glycosidases, vary among different life stages to a greater extent than do other genes. We also found that the number of P450s, GSTs and esterase genes expressed by B. huntii is similar to the number of these genes found in the genomes of other bees, namely Bombus terrestris, Bombus impatiens, Apis mellifera and Megachile rotundata, but many fewer than are found in the fly Drosophila melanogaster. Bombus huntii has transcripts for a large number of detoxification and stress related proteins, including oxidation and reduction enzymes, conjugation enzymes, hydrolytic enzymes, ABC transporters, cadherins, and heat shock proteins. The diversity of genes expressed within some detoxification pathways varies among the life stages and castes, and we typically identified more genes in the adult females than in larvae, pupae, or adult males, for most pathways. Meanwhile, we found the numbers of detoxification and stress genes expressed by B. huntii to be more similar to other bees than to the fruit fly. The low number of detoxification genes, first noted in the honey bee, appears to be a common phenomenon among bees, and perhaps results from their symbiotic relationship with plants. Many flowering plants benefit from pollinators, and thus offer these insects rewards (such as nectar) rather than defensive plant toxins. ",0
4949,24330651,Vernalization treatment induces site-specific DNA hypermethylation at the VERNALIZATION-A1 (VRN-A1) locus in hexaploid winter wheat,"Certain temperate species require prolonged exposure to low temperature to initiate transition from vegetative growth to flowering, a process known as vernalization. In wheat, winter cultivars require vernalization to initiate flowering, making vernalization requirement a trait of key importance in wheat agronomy. The genetic bases of vernalization response have been largely studied in wheat, leading to the characterization of a regulation pathway that involves the key gene VERNALIZATION1 (VRN1). While previous studies in wheat and barley have revealed the functional role of histone modification in setting VRN1 expression, other mechanisms might also be involved. Here, we were interested in determining whether the cold-induced expression of the wheat VRN-A1 gene is associated with a change in DNA methylation. We provide the first DNA methylation analysis of the VRN-A1 gene, and describe the existence of methylation at CG but also at non CG sites. While CG sites show a bell-shape profile typical of gene-body methylation, non CG methylation is restricted to the large (8.5 kb) intron 1, in a region harboring fragments of transposable elements (TEs). Interestingly, cold induces a site-specific hypermethylation at these non CG sites. This increase in DNA methylation is transmitted through mitosis, and is reset to its original level after sexual reproduction. These results demonstrate that VRN-A1 has a particular DNA methylation pattern, exhibiting rapid shift within the life cycle of a winter wheat plant following exposure to particular environmental conditions. The finding that this shift occurs at non CG sites in a TE-rich region opens interesting questions onto the possible consequences of this type of methylation in gene expression. ",0
4950,24330963,The efficacy analysis of selective decompression of lumbar root canal of elderly lumbar spinal stenosis],"To evaluate the effect of the treatments of lumbar spinal stenosis by selective decompression of lumbar root canal and laminectomy. From March 2007 to March 2011, 144 lumbar spinal stenosis patients were treated by selective decompression of lumbosacral root canal and laminectomy. All of these patients included 64 male and 80 female patients, age range 60-87 years, average (66 ± 5) years. Duration 6-72 months, average (12 ± 16) months. The patients were divided into 2 groups according to surgical procedure underwent: group A including 70 patients who were treated with selective decompression of lumbar root canal, group B including 74 patients who were treated with traditional laminectomy. Five time points were selected to assess clinical effect using Oswestry disability index (ODI) and Japanese Orthopaedic Association (JOA), which were pre-operation and 1 month, 6 months, 12 months and last follow-up. The data were analyzed through Wilcoxon matched-pairs signed-ranks test. All operations were completed well without severe complications. The duration of follow-up was 12-55 months, average (31 ± 6) months. All patients' symptoms got improved or partial remission. The average pre- and post-operative scores of JOA in group A and B were from 14.0 ± 1.6 to 20.3 ± 1.7, from 13.6 ± 1.7 to 20.2 ± 2.0, respectively, there were significant statistical differences (Z = 2.41 and 2.23, P < 0.05). The average pre- and post-operative scores of ODI in group A and B were from 62% ± 4% to 28% ± 4%, from 63% ± 4% to 27% ± 3%, respectively, there were significant statistical differences (Z = 2.93 and 2.64, P < 0.05). Personalized treatment programs should be established for elderly lumbar spinal stenosis according to stenosis location. Laminectomy is carried out with the stenosis in the central spinal canal; selective decompression of lumbosacral root canal is accepted with the stenosis in the nerve root canal without central stenosis. ",0
4951,24331268,Material decomposition images generated from spectral CT: detectability of urinary calculi and influencing factors,"To evaluate the detectability of urinary calculi on material decomposition (MD) images generated from spectral computed tomography (CT) and identify the influencing factors. Forty-six patients were examined with true nonenhanced (TNE) CT and spectral CT urography in the excretory phase. The contrast medium was removed from excretory phase images using water-based (WB) and calcium-based (CaB) MD analysis. The sensitivity for detection on WB and CaB images was evaluated using TNE results as the reference standard. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) on MD images were evaluated. Using logistic regression, the influences of image noise, attenuation, stone size, and patient's body mass index (BMI) were assessed. Threshold values with maximal sensitivity and specificity were calculated by means of receiver operating characteristic analyses. One hundred thirty-six calculi were detected on TNE images; 98 calculi were identified on WB images (sensitivity, 72.06%) and 101 calculi on CaB images (sensitivity, 74.26%). Sensitivities were 76.92% for the 3-5-mm stones and 84.51% for the 5-mm or larger stones on both WB and CaB images but reduced to 46.15% on WB images and 53.85% on CaB images for small calculi (<3 mm). Compared to WB images, CaB images showed lower image noise, higher SNR but similar CNR. Larger stone sizes (both >2.71 mm on WB and CaB) and greater CT attenuation (>280 Hounsfield units [HU] on WB, >215 HU on CaB) of the urinary stones were significantly associated with higher stone visibility rates on WB and CaB images (P ≤ .003). Image noise and BMI showed no impact on the stone detection. MD images generated from spectral CT showed good reliability for the detection of large (>2.71 mm) and hyperattenuating (>280 HU on WB, >215 HU on CaB) urinary calculi. ",0
4952,24332010,Flow cytometric evaluation of sperm apoptosis in semen of silver foxes in the breeding period,"The objective of the study was to evaluate cytometrically the percentage of apoptotic and necrotic spermatozoa in fresh semen of silver foxes in the breeding season. In males F3 and F4 with high percentages of early apoptotic (A+Pi-), late apoptotic (A+Pi+) and necrotic (A-Pi+) spermatozoa as well as 56-65% of living spermatozoa (A-Pi-) with progressive motility, the semen was characterised by reduced fertility. In males F1 and F2 with spermatozoa showing the motility and viability of 89-90% and high percentages of living cells that do not bind Annexin V and propidium iodide, the semen was assessed as valuable and useful for artificial insemination. Amongst 16 females of group I and II inseminated with semen from F1 and F2 males, 15 (93.75%) had multi-cub litters - on average 6.1 and 4.8, respectively. In contrast, amongst 16 females of group III and IV inseminated with semen from F3 and F4 males, only 10 (62.5%) had litters with few cubs (on average 2.6 in group III and 2.1 in group IV). Our findings explicitly indicate that semen of farm male foxes should be evaluated before the breeding season, as one of the causes of reproduction failures is likely to be a high percentage of apoptotic and necrotic spermatozoa. Thanks to flow cytometry, fresh ejaculates can be speedily evaluated and their usefulness for artificial insemination determined.  ",0
4953,24332478,"Role of disulfide bond isomerase DsbC, calcium ions, and hemin in cell-free protein synthesis of active manganese peroxidase isolated from Phanerochaete chrysosporium","A cell-free protein synthesis system can produce various types of proteins directly from DNA templates such as PCR products, and therefore attracts great attention as an alternative protein synthesis system especially for high-throughput functional screening of proteins. Here, we report successful expression of active Phanerochaete chrysosporium manganese peroxidase (MnP) in an Escherichia coli cell-free protein synthesis system, wherein reaction conditions such as the concentrations of hemin, calcium ions, and disulfide bond isomerase were optimized to increase the solubility and activity of the synthesized enzyme. Moreover, cell-free synthesized MnP purified using the hemagglutinin tag showed higher specific activity than the commercial wild-type enzyme, suggesting that the cell-free system can be used as a preparative method for efficient synthesis of disulfide bond-containing metalloenzymes such as MnP. We believe that our system is a solid foundation for the development of a high-throughput screening method for the directed evolution of these enzymes.  ",0
4954,24332557,The role of apparent diffusion coefficient values in differentiation between adrenal masses,"The aim of this study was to evaluate the utility of apparent diffusion coefficient (ADC) values in differentiation between solid adrenal masses. The ADC values of 73 adrenal lesions (54 benign, 19 malignant) in 69 patients were measured at b 100, 600 and 1000 gradients on diffusion-weighted magnetic resonance imaging (DW-MRI). No statistically significant difference was found between ADC values of benign and malignant adrenal masses, nonadenomatous benign adrenal masses and malignant adrenal masses, adrenal adenomas and nonadenomatous lesions, adenomas and metastases, adenomas and pheochromocytomas, metastases and pheochromocytomas. ADC values are not helpful in the differentiation between solid adrenal masses.  ",0
4955,24332567,"Incidence, hospital stay and risk factors associated with the occurrence of pharyngo-cutaneous fistula after total laryngectomy]","Pharyngo-cutaneous fistula (PCF) is one of the main problems for patients undergoing total laryngectomy. There are many risk factors described and associated with the appearance of PCF; however, some of these are currently under discussion. The aim of this work is to analyse the incidence of PCF, hospital stay and associated risk factors in patients undergoing total laryngectomy in a secondary hospital. This was an observational study in a retrospective cohort. We included all patients who underwent total laryngectomy between 2006 and 2011. We considered sociodemographic and clinical items, and most of the risk factors studied in the literature by other authors (tracheostomy, tumour stage, chemotherapy or radiotherapy before surgery, etc.). Statistical analyses were performed using SPSS(®) 15.0 and Epidat(®) 3.1. We analysed 70 total laryngectomies. The incidence of PCF in the time period studied was 48.6%. There were significant differences between the mean hospital stay of patients with and without PCF. Affected locoregional lymph nodes were found to be the only risk factor for the occurrence of PCF [RR=1.60 (1.006-2.54)]. The incidence of PCF is associated with the presence of affected locoregional lymph nodes. It is not associated with tracheostomy, administration of radio/chemotherapy before surgery or tumour location. ",0
4956,24332721,An arthroscopic check valve release improves knee intrameniscal cyst symptoms in adolescent: a case report,"Intrameniscal cysts begin with the flow of synovial fluid from a meniscal tear in one direction, enlarging probably as a result of an on-and-off valve mechanism of the tear flap. The current available literature focuses primarily on the necessity for surgery, however a large meniscus resection to remove cysts may place an additional burden on menisci, leading ultimately to knee joint degenerative changes. In this article, we present a rare case of intrameniscal cysts with an isolated horizontal meniscal tear in an adolescent, and describe a new arthroscopic procedure for treating this type of intrameniscal cyst. We performed arthroscopic partial release of the meniscal tear check-valve mechanism, preventing further intrameniscal cyst expansion. The patient's clinical symptoms improved, and this procedure may also be useful in treating intrameniscal cysts with an isolated horizontal meniscal tear and can be considered as an option to preserve meniscal function and minimize degenerative arthritis in young athletes.  ",0
4957,24332795,Preservation and compensation: the functional neuroanatomy of insight and working memory in schizophrenia,"Poor insight in schizophrenia has been theorised to reflect a cognitive deficit that is secondary to brain abnormalities, localized in the brain regions that are implicated in higher order cognitive functions, including working memory (WM). This study investigated WM-related neural substrates of preserved and poor insight in schizophrenia. Forty stable schizophrenia outpatients, 20 with preserved and 20 with poor insight (usable data obtained from 18 preserved and 14 poor insight patients), and 20 healthy participants underwent functional magnetic resonance imaging (fMRI) during a parametric 'n-back' task. The three groups were preselected to match on age, education and predicted IQ, and the two patient groups to have distinct insight levels. Performance and fMRI data were analysed to determine how groups of patients with preserved and poor insight differed from each other, and from healthy participants. Poor insight patients showed lower performance accuracy, relative to healthy participants (p=0.01) and preserved insight patients (p=0.08); the two patient groups were comparable on symptoms and medication. Preserved insight patients, relative to poor insight patients, showed greater activity most consistently in the precuneus and cerebellum (both bilateral) during WM; they also showed greater activity than healthy participants in the inferior-superior frontal gyrus and cerebellum (bilateral). Group differences in brain activity did not co-vary significantly with performance accuracy. The precuneus and cerebellum function contribute to preserved insight in schizophrenia. Preserved insight as well as normal-range WM capacity in schizophrenia sub-groups may be achieved via compensatory neural activity in the frontal cortex and cerebellum. ",0
4958,24332906,Stay and play eFAST or scoop and run eFAST? That is the question!,"The concept that ultrasonography could be interesting in the prehospital setting and during the transfer of traumatized patients is not new. Paradoxically, there is a lack of description of routine use of ultrasonography in emergency ambulances. The aim of this study was to compare the feasibility and efficiency of an extended focused assessment sonography for trauma (eFAST) examination performed on-site, during the patient's transfer, or both. From February 2010 to June 2012, 30 prehospital emergency physicians were divided randomly into 3 groups. Group 1 performed an ultrasound examination on-site; group 2, during patient transfer; and group 3, in both settings. The eFAST examination was systematically performed in all severe traumas. Ninety-eight patients were included. Forty-four eFAST examinations were performed on-site only; 33, only during transport; and 21, in both settings. The feasibility was 95.4%, 93.9%, and 95.2%, respectively, and efficiency, 95%, 97%, and 100%, respectively. There was no significant difference in performance or duration whether the examination was performed on-site, during the transfer, or both (w = 0.68). Last but not least, in 2 cases in group 3, the second examination carried out during transfer showed new results with the occurrence of intraperitoneal effusion in one case and a pleural effusion in the other. The eFAST examination can provide reliable and important information in the initial evaluation of traumatized patients. It can be completed either on-site or during patient transfer. Its feasibility and efficiency are similar to that done in intensive units, especially if the examination is repeated. ",0
4959,24333115,Transfusion dependence development and disease evolution in patients with MDS and del(5q) and without transfusion needs at diagnosis,"Patients with isolated del(5q) and MDS are considered to have good prognosis as compared to other MDS subtypes. Most patients suffered of anemia and 50% of them required transfusions at diagnosis. It is known that for patients with MDS and del(5q) in transfusion dependence(TD), Lenalidomide is the first choice treatment. However, there are no data regarding natural evolution of anemia in patients diagnosed in MDS and del(5q) without TD, factors that may impact on the development of TD or disease outcome. In the present study we have performed a retrospective multicenter analysis on 83 patients with low-int 1 MDS and del(5q) without TD. During the study 61 patients became TD at a median of 1.7 years and only the Hb level 9 g/dL was associated with poorer TFS (p = 0.007) in the multivariate analysis. Among these 61 TD patients, 49 received treatment (19 Lenalidomide). Median follow up was 48 months, estimated OS at 2 and 5 year was 92% and 50% respectively. In the multivariate analysis for OS, platelets <100,000 mm(-3) and Lenalidomide treatment retained the statistical significant impact. LFS at 2 and 5 years was 86% and 73% respectively, and median time to sAML was 8.16 years (CI 95%: 6.05-10.27). In the multivariate analysis only thrombocytopenia retained statistical significance. In summary, this retrospective study show that level of Hb is an important parameter in order to determine the time until TD, it should be also stressed the importance of an early treatment in order to prevent TD development and shorter survival. ",0
4960,24333155,Changes in sugar content and proteome of potato in response to cold and dehydration stress and their implications for cryopreservation,"The key to successful cryopreservation lies in the induction of tolerance towards dehydration/desiccation and freezing. The accumulation of osmo-active compounds, which can be induced by drought and cold stress, is therefore important. In the present study, three-week old shoots from in vitro plantlets of the cultivated potato Solanum tuberosum and its frost-resistant relative Solanum commersonii were submitted to osmotic stress (by using sucrose) and chilling (6°C). After 14days of exposure, shoot tips were sampled in order to gain an insight into changes of the proteome and soluble sugars. Also, the effect of these treatments on growth performance behaviour and on the success of cryopreservation was evaluated. Identified proteins that changed in abundance due to stress were associated with stress response. Additionally, carbohydrate analyses in both species, after exposure to chilling, also indicated species-related differences; this observation could point towards a better-adapted physiological state of the donor plants of S. commersonii prior to the cryoprocedure and therefore a better recovery of the meristems. To our knowledge, this is the first study in which cryopreservation experiments are combined with the observation of the responses to abiotic stress exposure involving the potato species S. commersonii and S. tuberosum. These two species are known to have a different cold-acclimation behaviour, which seems to be closely related to their tolerance towards cryopreservation. Furthermore, common and differential responses to abiotic stresses were observed in the two species indicating that some pathways could be crucial not only in the plant's response to stress but also in tolerance towards cryopreservation. ",0
4961,24333377,Sleep deprivation impairs performance in the 5-choice continuous performance test: similarities between humans and mice,"Several groups undergo extended periods without sleep due to working conditions or mental illness. Such sleep deprivation (SD) can deleteriously affect attentional processes and disrupt work and family functioning. Understanding the biological underpinnings of SD effects may assist in developing sleep therapies and cognitive enhancers. Utilizing cross-species tests of attentional processing in humans and rodents would aid in mechanistic studies examining SD-induced inattention. We assessed the effects of 36h of: (1) Total SD (TSD) in healthy male and female humans (n=50); and (2) REM SD (RSD) in male C57BL/6 mice (n=26) on performance in the cross-species 5-choice continuous performance test (5C-CPT). The 5C-CPT includes target trials on which subjects were required to respond and non-target trials on which subjects were required to inhibit from responding. TSD-induced effects on human psychomotor vigilance test (PVT) were also examined. Effects of SD were also examined on mice split into good and poor performance groups based on pre-deprivation scores. In the human 5C-CPT, TSD decreased hit rate and vigilance with trend-level effects on accuracy. In the PVT, TSD slowed response times and increased lapses. In the mouse 5C-CPT, RSD reduced accuracy and hit rate with trend-level effects on vigilance, primarily in good performers. In conclusion, SD induced impaired 5C-CPT performance in both humans and mice and validates the 5C-CPT as a cross-species translational task. The 5C-CPT can be used to examine mechanisms underlying SD-induced deficits in vigilance and assist in testing putative cognitive enhancers.  ",0
4962,24333535,Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction,"Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-β and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.  ",0
4963,24333611,"Synthesis, characterization and antibacterial activity of polyaniline/Pt-Pd nanocomposite","Pt colloid and Pt-Pd colloid, pristine polyaniline, polyaniline/Pt nanocomposite and polyaniline/Pt-Pd nanocomposite were synthesized by simple chemical method. They were characterized by UV-Vis, FT-IR, XRD, TGA, SEM, HR-SEM and HR-TEM with EDAX techniques. The results proved that there is a strong interaction between metal nanoparticles (Pt-Pd) and polyaniline chains. This interaction creates changes in the backbone chain of polyaniline/Pt-Pd nanocomposite when compared to pristine polyaniline. The synthesized materials were evaluated for antibacterial activity, minimal inhibitory concentration and minimal bactericidal concentration. The results indicated that the nanocomposites exhibited improved antibacterial activity when compared to pristine polyaniline and individual metal colloids. This is the first report on the chemical synthesis of polyaniline/Pt-Pd nanocomposite, which exhibits antibacterial activity at micro molar concentration levels.  ",0
4964,24333704,Development and validation of an indirect pulsed electrochemical detection method for monitoring the inhibition of Abl1 tyrosine kinase,"A new method for monitoring the enzyme inhibition of Abl1 tyrosine kinase by liquid chromatography-indirect pulsed electrochemical detection (LC-InPED) was developed. In this method, adsorption of a peptide analyte at the noble metal electrode suppresses the oxidation of polyols under alkaline condition to elicit an indirect response resulting in a negative peak of the target peptide. Among the reagents tested, D-gluconic acid sodium salt gave the best overall signal to noise (S/N) values for the indirect detection of p-Abltide, the product of Abl1 enzymatic reaction. 50 μM D-gluconic acid sodium salt dissolved in a mixture of 78% water-22% acetonitrile-0.03% trifluoroacetic acid (TFA) was used as the mobile phase. Chromatographic separation was achieved on an Alltima C18 (I.D. 5 μm; 250 mm × 4.6 mm) column with the mobile phase flow rate of 0.5 ml/min. 0.5M sodium hydroxide was added post-column to maintain alkaline conditions in the PED cell. The limit of quantification (LOQ) was 0.2 μM for p-Abltide, which was about 50-fold lower than direct PED analysis. The residual plot of the linear calibration curve indicated a good fit with a linear model within the investigated concentration range of p-Abltide. Intra- and inter-day precision was not more than 6.5% and accuracy was from -5.75% to +1.54%. The validated LC-InPED method was successfully applied for monitoring of p-Abltide in Abl1 enzyme reaction and the inhibition study of Abl1. The determined IC50 values of model inhibitors, imatinib, nilotinib and dasatinib, were 601.4 nM (R(2)=0.99), 32.3 nM (R(2)=0.99) and 1.3 nM (R(2)=0.98), respectively. These results were consistent with literature data. To the best of our knowledge this is the first time a LC-InPED method has been used to monitor an enzyme reaction. ",0
4965,24333908,Formation and dissolution of chitosan/pyrophosphate nanoparticles: is the ionic crosslinking of chitosan reversible?,"Ionically crosslinked chitosan particles with submicron dimensions attract widespread interest as materials for controlled release. To this end, we have examined the formation and dissolution of nanoparticles prepared by crosslinking chitosan with pyrophosphate (PPi). The formation of these particles required a critical PPi concentration (which increased with the chitosan concentration), and their z-average hydrodynamic diameters could be predictably tuned from roughly 60 to 220 nm by varying the concentration of the parent chitosan solutions. Unlike the nanoparticles crosslinked with the commonly used tripolyphosphate (TPP), which coagulated and precipitated when TPP was in excess, the chitosan/PPi nanoparticles remained colloidally stable even at high PPi concentrations. Moreover, the analysis of their dissolution revealed hysteresis in the particle formation/dissolution cycle, where portions of the crosslinked chitosan/PPi complexes remained stably intact at PPi concentrations below those required for their formation. This irreversible behavior was surmised to reflect the cooperativity of chitosan/PPi binding and was qualitatively modeled using the Bragg-Williams theory. ",0
4966,24333939,"Hot spots in mortality from drug poisoning in the United States, 2007-2009","Over the past several years, the death rate associated with drug poisoning has increased by over 300% in the U.S. Drug poisoning mortality varies widely by state, but geographic variation at the substate level has largely not been explored. National mortality data (2007-2009) and small area estimation methods were used to predict age-adjusted death rates due to drug poisoning at the county level, which were then mapped in order to explore: whether drug poisoning mortality clusters by county, and where hot and cold spots occur (i.e., groups of counties that evidence extremely high or low age-adjusted death rates due to drug poisoning). Results highlight several regions of the U.S. where the burden of drug poisoning mortality is especially high. Findings may help inform efforts to address the growing problem of drug poisoning mortality by indicating where the epidemic is concentrated geographically.  ",0
4967,24334043,Use of smart photochromic indicator for dynamic monitoring of the shelf life of chilled chicken based products,"This study evaluated the applicability of a photochromic time temperature indicator (TTI) to monitor the time-temperature history and shelf life of chilled boneless chicken breast. The results showed that the smart indicator showed good reproducibility during the discoloring process in all the conditions investigated. The response was not only visibly interpretable but also well adaptable to measurement using appropriate equipment. For an activation configuration of 4 s of ultraviolet light (UV) per label, the TTI's rate of discoloration was similar to the quality loss of the meat samples analyzed. Thus, the photochromic label (4 s UV/label) attached to the samples set out to be a dynamic shelf-life label, assuring consumers the final point of quality of chilled boneless chicken breast in an easy and precise form, providing a reliable tool to monitor the supply chain of this product. ",0
4968,24334336,Bronchial thermoplasty: interventional therapy in asthma,"Bronchial thermoplasty is a new treatment option for patients with severe bronchial asthma who remain symptomatic despite maximal medical therapy. The aim of this interventional therapy option is the reduction of smooth muscle in the central and peripheral airways in order to reduce symptomatic bronchoconstriction via the application of heat. A full treatment with bronchial thermoplasty is divided into three bronchoscopies. Randomized, controlled clinical trials have shown an increase in quality of life, a reduction in severe exacerbations, and decreases in emergency department visits as well as days lost from school or work. The trials did not show a reduction in hyperresponsiveness or improvement in forced expiratory volume in 1 s. Short-term adverse effects include an increase in exacerbation rate, an increase in respiratory infections and an increase in hospitalizations. In the 5-year follow up of the studies available there was evidence of clinical and functional stability of the treated patients. Further studies are necessary to identify an asthma phenotype that responds well to this treatment.  ",0
4969,24334409,Carbodiimide inactivation of MMPs and effect on dentin bonding,"The use of protein cross-linking agents during bonding procedures has been recently proposed to improve bond durability. This study aimed to use zymography and in situ zymography techniques to evaluate the ability of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) cross-linker to inhibit matrix metalloproteinase (MMP) activity. The hypotheses tested were that: (1) bonding procedures increase dentin gelatinolytic activity and (2) EDC pre-treatment prevents this enzymatic activity. The zymographic assay was performed on protein extracts obtained from dentin powder treated with Optibond FL or Scotchbond 1XT with or without 0.3M EDC pre-treatment. For in situ zymography, adhesive/dentin interfaces were created with the same adhesives applied to acid-etched dentin slabs pre-treated or not with EDC conditioner. Zymograms revealed increased expression of dentin endogenous MMP-2 and -9 after adhesive application, while the use of EDC as a primer inactivated dentin gelatinases. Results of in situ zymograpy showed that hybrid layers of tested adhesives exhibited intense collagenolytic activity, while almost no fluorescence signal was detected when specimens were pre-treated with EDC. The correlative analysis used in this study demonstrated that EDC could contribute to inactivate endogenous dentin MMPs within the hybrid layer created by etch-and-rinse adhesives.  ",0
4970,24334537,An efficient method for differentiation of human induced pluripotent stem cells into hepatocyte-like cells retaining drug metabolizing activity,"The use of human induced pluripotent stem (iPS) cells would be of great value for a variety of applications involving drug development studies. Several reports have been published on the differentiation of human iPS cells into hepatocyte-like cells; however, the cells were insufficient for application in drug metabolism studies. In this study, we aimed to establish effective methods for differentiation of human iPS cells into hepatocytes. Two human iPS cell lines were differentiated by addition of activin A, dimethyl sulfoxide, hepatocyte growth factor, oncostatin M, and dexamethasone. The differentiated cells expressed hepatocyte markers and drug-metabolizing enzymes, revealing that the human iPS cells were differentiated into hepatocyte-like cells. Expression of CYP3A4 and UGT1A1 mRNAs increased with treatment with typical inducers of the enzymes, and the response of the cells against the inducers was similar to that of human hepatocytes. Furthermore, the drug-metabolizing activity of CYP3A4, as monitored by testosterone 6β-hydroxylase activity, was elevated by these inducers. In conclusion, we established methods for differentiation of hepatocyte-like cells expressing drug metabolizing activity from human iPS cells. The hepatocyte-like cells derived from human iPS cells will be useful for drug metabolism studies.  ",0
4971,24334697,Occupational physicians' system in the United kingdom and fit note to promote access to occupational health services],"The Statement of Fitness for Work (Fit Note) policy was started in the UK in 2010 in order to promote return to work after sickness absence. Fit Note is issued by General Practitioners (GP). We conducted an interview survey of 2 occupational physicians working in the UK to ascertain the impact of the introduction of Fit Note on occupational health in the UK. They regard the low coverage of occupational health services in the UK, especially among small companies and self-employed workers, as a serious issue. Fit Note was regarded as a tool to induce GPs to participate in occupational health services, and it is expected that they will be new partners in occupational health. The English occupational physicians evaluated the Fit Note system highly, and believe that the increasing participation of GPs in occupational health services will be a steady advancement in occupational health in the UK.  ",0
4972,24334704,The corepressor Atrophin specifies odorant receptor expression in Drosophila,"In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes. ",0
4973,24334816,Clinical utility of computed tomographic lung volumes in patients with chronic obstructive pulmonary disease,"Published data concerning the utility of computed tomography (CT)-based lung volumes are limited to correlation with lung function. The aim of this study was to evaluate the clinical utility of the CT expiratory-to-inspiratory lung volume ratio (CT Vratio) by assessing the relationship with clinically relevant outcomes. A total of 75 stable chronic obstructive pulmonary disease (COPD) patients having pulmonary function testing and volumetric CT at full inspiration and expiration were retrospectively evaluated. Inspiratory and expiratory CT lung volumes were measured using in-house software. Correlation of the CT Vratio with patient-centered outcomes, including the modified Medical Research Council (MMRC) dyspnea score, the 6-min walk distance (6MWD), the St. George's Respiratory Questionnaire (SGRQ) score, and multidimensional COPD severity indices, such as the BMI, airflow obstruction, dyspnea, and exercise capacity index (BODE) and age, dyspnea, and airflow obstruction (ADO), were analyzed. The CT Vratio correlated significantly with BMI (r = -0.528, p < 0.001). The CT Vratio was also significantly associated with MMRC dyspnea (r = 0.387, p = 0.001), 6MWD (r = -0.459, p < 0.001), and SGRQ (r = 0.369, p = 0.001) scores. Finally, the CT Vratio had significant correlations with the BODE and ADO multidimensional COPD severity indices (r = 0.605, p < 0.001; r = 0.411, p < 0.001). The CT Vratio had significant correlations with patient-centered outcomes and multidimensional COPD severity indices. ",0
4974,24335016,Nonexcisional tissue tightening: creating skin surface area reduction during abdominal liposuction by adding radiofrequency heating,"Recent publications show that heat-mediated tissue tightening is a promising treatment for the lax abdomen and may provide better long-term outcomes than traditional suction-assisted liposuction (SAL). The author evaluates the degree and duration of skin surface area contraction, as well as the influence of anatomic location of the treatment region on the degree of tissue tightening, in a study comparing SAL alone vs SAL plus radiofrequency-assisted liposuction (RFAL). In this prospective, randomized, split abdominal study, 12 consecutive patients were treated with SAL alone on 1 side and with SAL plus RFAL on the other side. Each patient had 4 (3 × 3-cm) squares-2 per treatment type-tattooed in the lower abdominal region (2 on the right and 2 on the left). The surface area of these squares was measured with the Vectra computerized measurement system (Canfield, Inc, Fairfield, New Jersey) at pretreatment, at 6 weeks posttreatment, and at 1 year posttreatment. All measurements were subjected to statistical analysis using predictive analytic software and were evaluated for statistical significance. In regions treated with SAL alone, there was a 10.4% mean skin surface area contraction at 6 weeks and 8.3% at 1 year posttreatment. The mean skin surface area reduction was 25.8% in regions treated with radiofrequency plus SAL at 6 weeks and at 1 year. The anatomic location of each square (medial vs lateral) did not statistically correlate with more or less tissue tightening. Radiofrequency-assisted tissue tightening, when applied in conjunction with SAL, is effective in achieving greater skin surface area reduction. ",0
4975,24335152,Acceptable but limited efficacy of capecitabine-based doublets in the first-line treatment of metastatic triple-negative breast cancer: a pilot study,"This open-label, nonrandomized phase II clinical trial investigated the efficacy of capecitabine-based doublets in the first-line treatment of metastatic triple-negative breast cancer (mTNBC). Eligible mTNBC women with measurable diseases were recruited to receive either TX regimen (docetaxel 75 mg/m(2) i.v. on day 1 plus capecitabine 1,000 mg/m(2) b.i.d. on days 1-14 every 3 weeks) or NX regimen (vinorelbine 25 mg/m(2) i.v. on days 1 and 8 plus capecitabine 1,000 mg/m(2) b.i.d. on days 1-14 every 3 weeks) for up to 6 cycles until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR). Forty-five mTNBC patients, 27 in TX and 18 in NX were recruited. The total ORR was 20.0% and CBR was 40%. After a median follow-up of 28 months, PFS was 5.2 months (95% CI, 4.1-6.3 months) and OS was 18.2 months (95% CI, 8.7-27.7 months). The response rate was numerically but not statistically lower in the TX group than in the NX group (27.8 vs. 14.8%, p = 0.449). No difference was found in either PFS (4.9 vs. 5.2 months, p = 0.483) or OS (21.5 vs. 18.3 months, p = 0.964) between the two regimens. Although the OS seems to be reasonable, the efficacy of capecitabine-containing TX or NX regimen was limited in terms of response and PFS in mTNBC patients, suggesting capecitabine-based doublet may be acceptable but has limited potency in this subtype. ",0
4976,24335503,Applicability of chronic kidney disease epidemiology collaboration equations in a Chinese population,"Accurate estimated glomerular filtration rates (eGFR) is an important step in the diagnosis of chronic kidney disease (CKD). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, based on creatinine alone (eGFRcr), was developed to improve on the Modification of Diet in Renal Disease equation, in particular by addressing the systematic underestimation of high GFR. Whether the CKD-EPI equation, based on cystatin C alone (eGFRcys), or the combined creatinine-cystatin C CKD-EPI equation (eGFRcr-cys C), actually perform better than the CKD-EPI equation based on creatinine (eGFRcr) remains unknown, especially in Asians including Chinese populations, where eGFR equations may overestimate true GFR. A standard dual plasma sampling method (DPSM) of estimating (99m)Tc-diethylene triamine penta-acetic acid clearance was used to determine the reference or measured GFR (mGFR). Linear regression analysis, Bland-Altman analysis, bias, absolute bias and accuracy (P30) were used to compare the performance of the combined creatinine-cystatin C equation (eGFRcr-cys) and equations based on each marker alone (eGFRcr and eGFRcys) in Chinese subjects, including both patients with CKD and healthy individuals. We enrolled 617 Chinese participants (49.11% female, 47.11 ± 17.25 years old), with a mean mGFR of 73.80 ± 37.55 mL/min/1.73 m(2). The predictive abilities (r), the accuracy (P15, P30, P50), bias and absolute bias of the eGFRcr-cys equation were superior to eGFRcr equation and the eGFRcys equation in overall samples. Bland-Altman analysis also demonstrated a consistent result. When compared in subgroups, the accuracy (P30) of all three equations exceeded 90% at mGFR ≥90 mL/min/1.73m(2); the eGFRcr-cys equation had the highest accuracy (P30: 95.56%). At mGFR 60-89 mL/min/1.73 m(2), the accuracies (P30) of the eGFRcr-cys and eGFRcr equations exceeded the acceptable level (≥70%), and there was no significant difference between them (P = 0.58). At mGFR <60 mL/min/1.73 m(2), the accuracy (P30) of all three equations was below 70%, but the eGFRcr-cys equation had the greatest precision. The performances of the eGFRcr-cys and eGFRcr equations were similar to superior to that of the eGFRcys equation at higher GFR levels in an Asian population, especially in normal and mild to moderate kidney disease. Further improvement is needed for these equations at GFR <60 mL/min per 1.73 m(2). ",0
4977,24335647,Enrichment and purging of human embryonic stem cells by detection of cell surface antigens using the monoclonal antibodies TG30 and GCTM-2,"Human embryonic stem cells (hESC) can self-renew indefinitely in vitro, and with the appropriate cues can be induced to differentiate into potentially all somatic cell lineages. Differentiated hESC derivatives can potentially be used in transplantation therapies to treat a variety of cell-degenerative diseases. However, hESC differentiation protocols usually yield a mixture of differentiated target and off-target cell types as well as residual undifferentiated cells. For the translation of differentiated hESC-derivatives from the laboratory to the clinic, it is important to be able to discriminate between undifferentiated (pluripotent) and differentiated cells, and generate methods to separate these populations. Safe application of hESC-derived somatic cell types can only be accomplished with pluripotent stem cell-free populations, as residual hESCs could induce tumors known as teratomas following transplantation. Towards this end, here we describe a methodology to detect pluripotency associated cell surface antigens with the monoclonal antibodies TG30 (CD9) and GCTM-2 via fluorescence activated cell sorting (FACS) for the identification of pluripotent TG30(Hi)-GCTM-2(Hi) hESCs using positive selection. Using negative selection with our TG30/GCTM-2 FACS methodology, we were able to detect and purge undifferentiated hESCs in populations undergoing very early-stage differentiation (TG30(Neg)-GCTM-2(Neg)). In a further study, pluripotent stem cell-free samples of differentiated TG30(Neg)-GCTM-2(Neg) cells selected using our TG30/GCTM-2 FACS protocol did not form teratomas once transplanted into immune-compromised mice, supporting the robustness of our protocol. On the other hand, TG30/GCTM-2 FACS-mediated consecutive passaging of enriched pluripotent TG30(Hi)-GCTM-2(Hi) hESCs did not affect their ability to self-renew in vitro or their intrinsic pluripotency. Therefore, the characteristics of our TG30/GCTM-2 FACS methodology provide a sensitive assay to obtain highly enriched populations of hPSC as inputs for differentiation assays and to rid potentially tumorigenic (or residual) hESC from derivative cell populations.  ",0
4978,24335737,"Screening, brief intervention, and referral to treatment and the role of nursing","The first article is a good starting place for building an SBIRT program. It provides a good overview of the evidence and explains SBIRT as defined by SAMHSA. It should only serve as a starting point since it leaves questions unanswered. It does not clearly explain how to actually do each part of SBIRT. Other resources, such as National Institute on Alcohol Abuse and Alcoholism’s guide to clinicians or the American College of Surgeon’s guide, are recommended reading prior to implementing SBIRT. The major issue appears to be the lack of clear evidence that referral to treatment actually results in positive long-term outcomes for those with a substance use disorder. In addition, the development of an SBIRT program in an institution should utilize an interdisciplinary approach with a nurse lead program as a promising alternative to a hierarchical program that requires physician oversight. ",0
4979,24336133,"Progress in immunization information systems - United States, 2012","Immunization information systems (IIS) are confidential, computerized, population-based systems that collect and consolidate vaccination data from vaccination providers that can be used in designing and sustaining effective immunization strategies. To monitor progress toward achieving IIS program goals, CDC annually surveys immunization program grantees using the IIS Annual Report (IISAR). Results from the 2012 IISAR, completed by 54 of 56 grantees, indicate that 86% (19.5 million) of U.S. children aged <6 years, and 25% (57.8 million) of U.S. adults participated in IIS. Eight of 12 minimum functional standards for IIS published by the National Vaccine Advisory Committee (NVAC) have been met by ≥90% of grantees. During 2011-2012, progress was also made in meeting three additional functional standards, including the presence of core data element fields, timeliness of vaccine records, and Health Level 7 (HL7) messaging, and will be monitored in new functional standards for IIS published in 2013. Several new and ongoing initiatives, including interoperability between IIS and electronic health records (i.e., ensuring systems can work together and exchange information), the use of IIS to support vaccine ordering and inventory management, the use of two-dimensional barcodes to record vaccination information, and collaboration with pharmacies, federal agencies, and other adult vaccination providers, will support further progress in meeting functional standards and enhance reporting of adult vaccinations to IIS.  ",0
4980,24336344,Unbiased estimation of chloroplast number in mesophyll cells: advantage of a genuine three-dimensional approach,"Chloroplast number per cell is a frequently examined quantitative anatomical parameter, often estimated by counting chloroplast profiles in two-dimensional (2D) sections of mesophyll cells. However, a mesophyll cell is a three-dimensional (3D) structure and this has to be taken into account when quantifying its internal structure. We compared 2D and 3D approaches to chloroplast counting from different points of view: (i) in practical measurements of mesophyll cells of Norway spruce needles, (ii) in a 3D model of a mesophyll cell with chloroplasts, and (iii) using a theoretical analysis. We applied, for the first time, the stereological method of an optical disector based on counting chloroplasts in stacks of spruce needle optical cross-sections acquired by confocal laser-scanning microscopy. This estimate was compared with counting chloroplast profiles in 2D sections from the same stacks of sections. Comparing practical measurements of mesophyll cells, calculations performed in a 3D model of a cell with chloroplasts as well as a theoretical analysis showed that the 2D approach yielded biased results, while the underestimation could be up to 10-fold. We proved that the frequently used method for counting chloroplasts in a mesophyll cell by counting their profiles in 2D sections did not give correct results. We concluded that the present disector method can be efficiently used for unbiased estimation of chloroplast number per mesophyll cell. This should be the method of choice, especially in coniferous needles and leaves with mesophyll cells with lignified cell walls where maceration methods are difficult or impossible to use.  ",0
4981,24336425,Use of formal advance care planning documents: a national survey of UK Paediatric Intensive Care Units,"Advance Care Planning (ACP) is nationally a core element of adult and paediatric palliative care strategies. It is defined as a process of discussion between an individual, their care providers and those close to them, about future care. Formal procedures and processes can help with some of the most difficult elements of communication related to ACP. The majority of children who die do so in a Paediatric Intensive Care Unit (PICU). This survey aimed to identify and compare paediatric ACP documents that are in use within UK hospitals with a PICU. Email survey of lead clinicians from UK PICUs (n=28). 24 (86%) questionnaires were returned. 14 (58%) responded that formal ACP documents were currently in use within their hospital trust. Of the remainder, 2 (8%) detailed plans to launch local ACP documents in the near future, 1 (4%) had a 'Children and Young Persons Deterioration Management (CAYPDM) Document' and 3 (12%) listed rapid discharge and extubation pathways. 6 (25%) provided details of the document in use. They varied widely in terms of their presentation, content and intended use with some having been developed locally and others having been adopted across regions. There is variation around the UK in the existence of formal ACP documents for paediatric patients with palliative care needs, as well as variation in the type of document that is used. Consideration of a national policy should be informed by further review and evaluation of these documents, as well as current practice in ACP. ",0
4982,24350901,Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis,"BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (�SD) level of CXCL4 in patients with systemic sclerosis was 25,624�2652 pg per milliliter, which was significantly higher than the level in controls (92.5�77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346�1011 pg per milliliter), ankylosing spondylitis (1368�1162 pg per milliliter), or liver fibrosis (1668�1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).",0
4983,24382002,Romosozumab in postmenopausal women with low bone mineral density,"BACKGROUND: Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS: In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 ?g daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS: All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).",0
4984,24382065,Distracted driving and risk of road crashes among novice and experienced drivers,"BACKGROUND: Distracted driving attributable to the performance of secondary tasks is a major cause of motor vehicle crashes both among teenagers who are novice drivers and among adults who are experienced drivers. METHODS: We conducted two studies on the relationship between the performance of secondary tasks, including cell-phone use, and the risk of crashes and near-crashes. To facilitate objective assessment, accelerometers, cameras, global positioning systems, and other sensors were installed in the vehicles of 42 newly licensed drivers (16.3 to 17.0 years of age) and 109 adults with more driving experience. RESULTS: During the study periods, 167 crashes and near-crashes among novice drivers and 518 crashes and near-crashes among experienced drivers were identified. The risk of a crash or near-crash among novice drivers increased significantly if they were dialing a cell phone (odds ratio, 8.32; 95% confidence interval [CI], 2.83 to 24.42), reaching for a cell phone (odds ratio, 7.05; 95% CI, 2.64 to 18.83), sending or receiving text messages (odds ratio, 3.87; 95% CI, 1.62 to 9.25), reaching for an object other than a cell phone (odds ratio, 8.00; 95% CI, 3.67 to 17.50), looking at a roadside object (odds ratio, 3.90; 95% CI, 1.72 to 8.81), or eating (odds ratio, 2.99; 95% CI, 1.30 to 6.91). Among experienced drivers, dialing a cell phone was associated with a significantly increased risk of a crash or near-crash (odds ratio, 2.49; 95% CI, 1.38 to 4.54); the risk associated with texting or accessing the Internet was not assessed in this population. The prevalence of high-risk attention to secondary tasks increased over time among novice drivers but not among experienced drivers. CONCLUSIONS: The risk of a crash or near-crash among novice drivers increased with the performance of many secondary tasks, including texting and dialing cell phones. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Highway Traffic Safety Administration.).",0
4985,24425205,Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation,"Sterol regulatory element binding protein1c (SREBP1c) is a key transcription factor for de novo lipogenesis during the postprandial state. During nutritional deprivation, hepatic SREBP1c is rapidly suppressed by fasting signals to prevent lipogenic pathways. However, the molecular mechanisms that control SREBP1c turnover in response to fasting status are not thoroughly understood. To elucidate which factors are involved in the inactivation of SREBP1c, we attempted to identify SREBP1c-interacting proteins by mass spectrometry analysis. Since we observed that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of SREBP1c-interacting proteins, we hypothesized that fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this work, we demonstrate that RNF20 physically interacts with SREBP1c, leading to degradation of SREBP1c via ubiquitination. In accordance with these findings, RNF20 represses the transcriptional activity of SREBP1c and turns off the expression of lipogenic genes that are targets of SREBP1c. In contrast, knockdown of RNF20 stimulates the expression of SREBP1c and lipogenic genes and induces lipogenic activity in primary hepatocytes. Furthermore, activation of protein kinase A (PKA) with glucagon or forskolin enhances the expression of RNF20 and potentiates the ubiquitination of SREBP1c via RNF20. In wild-type and db/db mice, adenoviral overexpression of RNF20 markedly suppresses FASN promoter activity and reduces the level of hepatic triglycerides, accompanied by a decrease in the hepatic lipogenic program. Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation. CONCLUSION: RNF20 acts as a negative regulator of hepatic fatty acid metabolism through degradation of SREBP1c upon PKA activation. Knowledge regarding this process enhances our understanding of how SREBP1c is able to turn off hepatic lipid metabolism during nutritional deprivation.",0
4986,24432154,Synthesis and character investigation of new collagen Hydrolysate/polyvinyl alcohol/hydroxyapatite Polymer-Nano-Porous Membranes: I. Experimental design optimization in thermal and structural properties,"Development of bioorganic-inorganic composites has drawn eyes to extensive attention in biomedical fields and tissue engineering. So many attempts to prepare hydroxyapatite (HA), in conjunction with various binders including polyvinyl alcohol (PVA), and collagen has performed for late 20 years. We applied a method based on the phase separation for making of polymer porous membranes. This procedure is induced through the addition of a small quantity of water (polymer-rich phase) to a solution with HA precursors (polymer-poor phase). Thermal and structural composite properties of collagen Hydrolysate (CH)-PVA/HA Polymer-Nano-Porous Membranes were analyzed by Design of experiment that was undertaken using D-optimal approach, to select the optimal combination of nano composites precursor. The resulted composite characters were investigated by Fourier transform infrared, scanning electron microscopy (SEM) and thermal gravimetric analysis. Based on the SEM images, this new method could be clearly concluded to porous CH-PVA/HA hybrid materials. Finally the hemocompatibility of nanocomposite membranes were evaluated by the hemolysis study. ",0
4987,24432212,Management of Scedosporium apiospermum in a pre- and post-lung transplant patient with cystic fibrosis,"Although the predominant type of infection seen in the cystic fibrosis lung remains bacterial, fungal organisms are being isolated more frequently and are associated with a high mortality rate in lung transplant recipients. We present a case of a patient with CF with sputum cultures positive for Scedosporium apiospermum prior to a successful lung transplant. She remains without evidence of infection 18 months later following treatment with a combination of triazoles and terbinafine.  ",0
4988,24432491,Better colon cancer care for extremely poor Canadian women compared with American women,"Extremely poor Canadian women were recently observed to be largely advantaged on most aspects of breast cancer care as compared with similarly poor, but much less adequately insured, women in the United States. This historical study systematically replicated the protective effects of single- versus multipayer health care by comparing colon cancer care among cohorts of extremely poor women in California and Ontario between 1996 and 2011. The Canadian women were again observed to have been largely advantaged. They were more likely to have received indicated surgery and chemotherapy, and their wait times for care were significantly shorter. Consequently, the Canadian women were much more likely to experience longer survival times. Regression analyses indicated that health insurance nearly completely explained the Canadian advantages. Implications for contemporary and future reforms of U.S. health care are discussed. ",0
4989,24432676,Anti-depressive effect of acupuncture on selective serotonin reuptake inhibitors],"To evaluate anti-depressive effects of acupuncture on selective serotonin reuptake inhibitors (SSRIs). Totally 60 patients with depression were randomly assigned to the control group (30 cases) and the treatment group (30 cases). All patients took one kind of SSRIs. Those in the treatment group were additionally treated by acupuncture. All were treated for 6 weeks. Patients' efficacies were evaluated with Hamilton Depression Scale (HAMD), Self-rating Depression Scale (SDS), and Eisenberg antidepressant side effects scale (Asberg). Compared with the control group after 6 weeks of treatment, the cured-markedly effective rate was improved by 33.4% in the treatment group (P < 0.05). The HAMD was lower in the treatment group. The tendency of interaction of sleep disorder factor and anxiety/somatization factor was different between at the end of 1-week treatment and at the end of 6-week treatment in the treatment group (P < 0.05). The SDS score decreased at the end of 6-week treatment in the treatment group. The reduction rate was elevated by 19.23% (P < 0.05). By the end of 6-week treatment, the average score of Asberg decreased by 3.77 score in average in the treatment group, while it decreased by 0.07 score in average in the control group (P < 0.05). Acupuncture could effectively improve anti-depressive effects of SSRIs and reduce their adverse reactions. ",0
4990,24432997,WITHDRAWN: Low-density lipoprotein cholesterol is associated with fracture risk in diabetes patients - a nested case-control study,"Diabetes Mellitus is associated with an increased risk of fractures, which is not explained fully by bone mineral density and common risk factors. The aim of this study is to investigate the association of medication and biochemical markers on the risk of fracture in a diabetes population. Nested case-control study based on Danish diabetes patients from The Danish National Hospital Discharge Registry. The cases of the study were diabetes patients with a fracture (n= 24,349) and controls were diabetes patients with no fracture (n=132,349). A total of 2,816 diabetes patients were available for an analysis of patient characteristics, co-morbidities, biochemical parameters and drug usage. Patient age at the time of diabetes diagnosis, a diagnosis of previous fracture, an alcohol related diagnosis, total cholesterol level, and the usage of antidepressants, antiepileptics and insulin all increased the odds of fracture. Low-density lipoprotein cholesterol (LDL) levels decreased the odds of fracture, where the level of 3.04-5.96 mmol/l was optimal with regard to fracture risk. LDL may add to the understanding of fractures in diabetes patients and it may be added to current fracture risk models in diabetes patients. ",0
4991,24433880,Cytotoxicity and apoptotic effects of tea polyphenol-loaded chitosan nanoparticles on human hepatoma HepG2 cells,"Tea polyphenols have strong antioxidant and antitumor activities. However, these health benefits are limited due to their poor in vivo stability and low bioavailability. Chitosan nanoparticles as delivery systems may provide an alternative approach for enhancing bioavailability of poorly absorbed drugs. In this study, tea polyphenol-loaded chitosan nanoparticles have been prepared using two different chitosan biomaterials, and their antitumor effects were evaluated in HepG2 cells, including cell cytotoxicity comparison, cell morphology analysis, cell apoptosis and cell cycle detection. The results indicated that the tea polyphenol-loaded chitosan nanoparticles showed a branch shape and heterogeneous distribution in prepared suspension. MTT assay suggested that tea polyphenol-loaded chitosan nanoparticles could inhibit the proliferation of HepG2 cells, and the cytotoxicity rates were increased gradually and appeared an obvious dose-dependent relationship. Transmission electron microscope images showed that the HepG2 cells treated with tea polyphenol-loaded chitosan nanoparticles exhibited some typical apoptotic features, such as microvilli disappearance, margination of nuclear chromatin, intracytoplasmic vacuoles and the mitochondrial swelling. In addition, the tea polyphenol-loaded chitosan nanoparticles had relatively weak inhibitory effects on HepG2 cancer cells compared with tea polyphenols. Tea polyphenols not only induced cancer cell apoptosis, but also promoted their necrosis. However, tea polyphenol-loaded chitosan nanoparticles exhibited their antitumor effects mainly through inducing cell apoptosis. Our results revealed that the inhibition effects of tea polyphenol-loaded chitosan nanoparticles on tumor cells probably depended on their controlled drug release and effective cell delivery. The chitosan nanoparticles themselves as the delivery carrier showed limited antitumor effects compared with their encapsulated drugs.  ",0
4992,24433968,Distribution and morphology of calcitonin gene-related peptide and substance P immunoreactive axons in the whole-mount atria of mice,"The murine model has been used to investigate the role of cardiac sensory axons in various disease states. However, the distribution and morphological structures of cardiac nociceptive axons in normal murine tissues have not yet been well characterized. In this study, whole-mount atria from FVB mice were processed with calcitonin gene-related peptide (CGRP) and substance P (SP) primary antibodies followed by secondary antibodies, and then examined using confocal microscopy. We found: 1) Large CGRP-IR axon bundles entered the atria with the major veins, and these large bundles bifurcated into small bundles and single axons that formed terminal end-nets and free endings in the epicardium. Varicose CGRP-IR axons had close contacts with muscle fibers, and some CGRP-IR axons formed varicosities around principle neurons (PNs) within intrinsic cardiac ganglia (ICGs). 2) SP-IR axons also were found in the same regions of the atria, attached to veins, and within cardiac ganglia. Similar to CGRP-IR axons, these SP-IR axons formed terminal end-nets and free endings in the atrial epicardium and myocardium. Within ICGs, SP-IR axons formed varicose endings around PNs. However, SP-IR nerve fibers were less abundant than CGRP-IR fibers in the atria. 3) None of the PNs were CGRP-IR or SP-IR. 4) CGRP-IR and SP-IR often colocalized in terminal varicosities around PNs. Collectively, our data document the distribution pattern and morphology of CGRP-IR and SP-IR axons and terminals in different regions of the atria. This knowledge provides useful information for CGRP-IR and SP-IR axons that can be referred to in future studies of pathological remodeling.  ",0
4993,24434315,"T cell ageing: effects of age on development, survival & function","Age associated decline of the immune system continues to be a major health concern. All components of innate and adaptive immunity are adversely affected to lesser or greater extent by ageing resulting in an overall decline of immunocompetence. As a result in the aged population, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity. There is an increasing focus on the role of T cells during ageing because of their impact on the overall immune responses. A steady decline in the production of fresh naïve T cells, more restricted T cell receptor (TCR) repertoire and weak activation of T cells are some of the effects of ageing. In this review we summarize our present understanding of the effects of ageing on naïve CD4 T cells and potential approaches for therapeutic interventions to restore protective immunity in the aged population.  ",0
4994,24434559,GRK3 is essential for metastatic cells and promotes prostate tumor progression,"The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.  ",0
4995,24434570,The effects on health behavior and health outcomes of Internet-based asynchronous communication between health providers and patients with a chronic condition: a systematic review,"In support of professional practice, asynchronous communication between the patient and the provider is implemented separately or in combination with Internet-based self-management interventions. This interaction occurs primarily through electronic messaging or discussion boards. There is little evidence as to whether it is a useful tool for chronically ill patients to support their self-management and increase the effectiveness of interventions. The aim of our study was to review the use and usability of patient-provider asynchronous communication for chronically ill patients and the effects of such communication on health behavior, health outcomes, and patient satisfaction. A literature search was performed using PubMed and Embase. The quality of the articles was appraised according to the National Institute for Health and Clinical Excellence (NICE) criteria. The use and usability of the asynchronous communication was analyzed by examining the frequency of use and the number of users of the interventions with asynchronous communication, as well as of separate electronic messaging. The effectiveness of asynchronous communication was analyzed by examining effects on health behavior, health outcomes, and patient satisfaction. Patients' knowledge concerning their chronic condition increased and they seemed to appreciate being able to communicate asynchronously with their providers. They not only had specific questions but also wanted to communicate about feeling ill. A decrease in visits to the physician was shown in two studies (P=.07, P=.07). Increases in self-management/self-efficacy for patients with back pain, dyspnea, and heart failure were found. Positive health outcomes were shown in 12 studies, where the clinical outcomes for diabetic patients (HbA1c level) and for asthmatic patients (forced expiratory volume [FEV]) improved. Physical symptoms improved in five studies. Five studies generated a variety of positive psychosocial outcomes. The effect of asynchronous communication is not shown unequivocally in these studies. Patients seem to be interested in using email. Patients are willing to participate and are taking the initiative to discuss health issues with their providers. Additional testing of the effects of asynchronous communication on self-management in chronically ill patients is needed. ",0
4996,24434575,Complication rate of endosonography (endobronchial and endoscopic ultrasound): a systematic review,"Endosonography [endoscopic ultrasound (EUS)-guided fine needle aspiration and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration] is increasingly used for lung cancer staging and the assessment of sarcoidosis. Serious adverse events (SAE) have been reported in case reports, but the true incidence of complications is yet unknown. To assess the rate of SAE related to endosonography and to investigate associated risk factors. PubMed, EMBASE and Cochrane libraries were searched for eligible references up to April 2012 and these included studies reporting on linear EUS or EBUS for the analysis of mediastinal/hilar nodal or central intrapulmonary lesions. Case series describing complications were excluded. Reported complications were classified into SAE or minor adverse events (AE). 190 studies met the inclusion criteria. Information on follow-up was missing in half of the studies. In 16,181 patients, 23 SAE (0.14%) and 35 AE (0.22%) were reported. No mortality was observed. SAE were more frequent in patients investigated with EUS (0.30%) than in those investigated with EBUS (0.05%). Infectious SAE were most prevalent (0.07%) and predominantly occurred in patients with cystic lesions and sarcoidosis. In lung cancer patients, complications were rare. Endosonography for intrathoracic nodal assessment seems safe for lung cancer patients and mortality has not been reported. For cystic lesions and sarcoidosis, there may be a small, but nonnegligible risk of infectious complications. The true incidence of SAE might be higher as accurate documentation of complications is missing in most studies. ",0
4997,24434746,Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy,"Metastatic melanoma often relapses despite cytotoxic treatment, and hence the understanding of melanoma tumor repopulation is crucial for improving our current therapies. In this study, we aim to define the role of caspase 3 in melanoma tumor growth after cytotoxic therapy. We examined a paradigm-changing hypothesis that dying melanoma cells undergoing apoptosis during cytotoxic treatment activate paracrine signaling events that promote the growth of surviving tumor cells. We propose that caspase 3 has a key role in the initiation of the release of signals from dying cells to stimulate melanoma tumor growth. We created a model for tumor cell repopulation in which a small number of luciferase-labeled, untreated melanoma cells are seeded onto a layer of a larger number of unlabeled, lethally treated melanoma cells. We found that dying melanoma cells significantly stimulate the growth of living melanoma cells in vitro and in vivo. Furthermore, we observed that caspase 3 gene knockdown attenuated the growth-stimulating effect of irradiated, dying cells on living melanoma cell growth. Finally, we showed that caspase 3-mediated dying melanoma cell stimulation of living cell growth involves secreted prostaglandin E2 (PGE2). Our study therefore suggests a counterintuitive strategy to inhibit caspase 3 for therapeutic gain in melanoma treatment.  ",0
4998,24434873,A non-intrusive method for monitoring the degradation of MOSFETs,"Highly reliable embedded systems have been widely applied in the fields of aerospace, nuclear power, high-speed rail, etc., which are related to security and economic development. The reliability of the power supply directly influences the security of the embedded system, and has been the research focus of numerous electronic information and energy studies. The degradation of power modules occupies a dominant position among the key factors affecting the power supply reliability. How to dynamically determine the degradation state and forecast the remaining useful life of working power modules is critical. Therefore, an online non-intrusive method of obtaining the degradation state of MOSFETs based on the Volterra series is proposed. It uses the self-driving signal of MOSFETs as a non-intrusive incentive, and extracts the degradation characteristics of MOSFETs by the frequency-domain kernel of the Volterra series. Experimental results show that the identification achieved by the method agrees well with the theoretical analysis.  ",0
4999,24434888,Feedback system based on plantar pressure for monitoring toe-walking strides in children with cerebral palsy,"The aim of this study was to develop a feedback system to assist gait rehabilitation of cerebral palsy (CP) toe walkers with dynamic equinus. Plantar pressure of the forefoot and the heel was collected by sensorized insoles embedded in custom-built shoes and transmitted to a smartphone via Bluetooth. Dynamic foot pressure index of each stride was calculated by purpose-designed software running in the smartphone to distinguish toe-walking strides from normal strides in real time. An auditory signal would be produced to alert the patient each time a toe-walking stride was detected. For CP toe walkers, the one-way analysis of variance indicated a significant difference (F1,14 = 19.492, P = 0.001) in dynamic foot pressure index between the affected side (31.4 ± 12.0) and the unaffected side (58.6 ± 2.5). In addition, the validation test showed that this system can distinguish toe-walking strides from normal strides of children with CP with an accuracy of 95.3%. This system was able to monitor the toe-walking strides of children with CP in real time and had the potential to enhance rehabilitation training efficiency and correct toe-walking gait in children with CP with dynamic equinus. ",0
5000,24435419,Genetic studies on the resistance of barley to yellow rust (Puccinia striiformis West.)],"Five spring barley varieties resistant to race 24 of Puccinia striiformis were crossed with each other and with three susceptible varieties (Table 1) in almost all possible combinations. The F 2 generations and in two cases also the F 3, were inoculated in the greenhouse with race 24. F 2 generations of some of the crosses were, in addition, tested with race 24 in the field. Dependable classification of resistance and, consequently, unambiguous interpretation of results was possible only for the experiments carried out in the greenhouse. Although the field tests confirmed these results, they would not have been conclusive by themselves.The resistance of all of the five varieties studied is due to single recessive genes (Table 2). Three of the varieties have alleles at the same locus, the other two varieties have other resistance genes (Tables 3 and 4): 'Bigo' - yr, 'Ab. 14' - yr, 'BBA 2890' - yr; 'Abed Binder 12' - yr2; 'I 5' - yr3. The results suggest that the three genes are inherited independently, close linkage can be excluded.  ",0
5001,24436157,"Uncovering nativity disparities in cancer patterns: Multiple imputation strategy to handle missing nativity data in the Surveillance, Epidemiology, and End Results data file","Although birthplace data are routinely collected in the participating Surveillance, Epidemiology, and End Results (SEER) registries, such data are missing in a nonrandom manner for a large percentage of cases. This hinders analysis of nativity-related cancer disparities. In the current study, the authors evaluated multiple imputation of nativity status among Hispanic patients diagnosed with cervical, prostate, and colorectal cancer and demonstrated the effect of multiple imputation on apparent nativity disparities in survival. Multiple imputation by logistic regression was used to generate nativity values (US-born vs foreign-born) using a priori-defined variables. The accuracy of the method was evaluated among a subset of cases. Kaplan-Meier curves were used to illustrate the effect of imputation by comparing survival among US-born and foreign-born Hispanics, with and without imputation of nativity. Birthplace was missing for 31%, 49%, and 39%, respectively, of cases of cervical, prostate, and colorectal cancer. The sensitivity of the imputation strategy for detecting foreign-born status was ≥90% and the specificity was ≥86%. The agreement between the true and imputed values was ≥0.80 and the misclassification error was ≤10%. Kaplan-Meier survival curves indicated different associations between nativity and survival when nativity was imputed versus when cases with missing birthplace were omitted from the analysis. Multiple imputation using variables available in the SEER data file can be used to accurately detect foreign-born status. This simple strategy may help researchers to disaggregate analyses by nativity and uncover important nativity disparities in regard to cancer diagnosis, treatment, and survival. ",0
5002,24436243,"Catalytic scope of the thiamine-dependent multifunctional enzyme cyclohexane-1,2-dione hydrolase","The thiamine diphosphate (ThDP)-dependent enzyme cyclohexane-1,2-dione hydrolase (CDH) was expressed in Escherichia coli and purified by affinity chromatography (Ni-NTA). Recombinant CDH showed the same C-C bond-cleavage and C-C bond-formation activities as the native enzyme. Furthermore, we have shown that CDH catalyzes the asymmetric cross-benzoin reaction of aromatic aldehydes and (decarboxylated) pyruvate (up to quantitative conversion, 92-99 % ee). CDH accepts also hydroxybenzaldehydes and nitrobenzaldehydes; these previously have not (or only in rare cases) been known as substrates of other ThDP-dependent enzymes. On a semipreparative scale, sterically demanding 4-(tert-butyl)benzaldehyde and 2-naphthaldehyde were transformed into the corresponding 2-hydroxy ketone products in high yields. Additionally, certain benzaldehydes with electron withdrawing substituents were identified as potential inhibitors of the ligase activity of CDH. ",0
5003,24436664,Perioperative protocols in colorectal surgery,"The reduction in health-care expenditures and more efficient use of medical resources are now overriding health policy priorities with the two-pronged goal of improving patient outcomes while decreasing overall cost. Current reports show colorectal surgery accounting for 25% of all operative complications and an average length of stay of 8 to 12 days for a standard elective colon resection. To combat this, Kehlet and colleagues introduced a concept of enhanced recovery after surgery (ERAS) or fast-track pathways, with the goal of using current evidence and multimodal therapies to decrease surgical stress, enhance postoperative recovery, and reduce length of stay. The benefits, safety, and cost-effectiveness of fast-track protocols are validated in multiple randomized controlled trials. In this review, the authors focus on the evidence regarding fast-track pathways, use of minimally invasive surgery and its role in fast-track pathways, newer perioperative interventions, and future directions.  ",0
5004,24436827,Malignant giant cell tumor in the carpal tunnel: a case report and review of literature,"Background Malignant tenosynovial giant cell tumors (GCTs) are extremely rare, and their etiology is unknown. However, this type of malignancy is associated with high metastasis and mortality rates. Therefore, the treatment of choice is wide excision. Case Description A 66-year-old man complained of tingling and loss of sensation in the left hand, caused by a tumor that compressed the median nerve. The tumor was excised. Histopathologic examination revealed a ganglion cyst. Two years later, the patient visited our clinic with recurrent and similar complaints of the left hand. This time, however, the lesion turned out to be a malignant tenosynovial GCT and was treated by amputation of the forearm. Literature Review Since 1979, only 37 malignant tenosynovial GCTs have been reported in literature. Follow-up of these patients showed that 11 patients died of the disease, 4 patients were still living with the disease, and 14 patients had no evidence of disease after treatment. The other seven patients were lost to follow-up, and one patient died of other causes. In these 37 patients, a high incidence of lymph node metastasis (41%) and a high mortality rate (30%) were seen. Clinical Relevance Although this malignant tenosynovial GCT is very rare, high mortality rates have been observed because of the high incidence of lymph node metastases. Therefore, more awareness has to be created, to recognize and treat this tumor timely.  ",0
5005,24436941,Endoscopic endonasal transplanum approach to the paraclinoid internal carotid artery,"Objective To investigate the relevance of an endoscopic transnasal approach to the surgical treatment of paraophthalmic aneurysms. Setting Binasal endoscopic transplanum surgery was performed. Participants Seven cadaver heads were studied. Main Outcome Measures (1) Dimensions of the endonasal corridor, including the operative field depth, lateral limits, and the transplanum craniotomy. (2) The degree of vascular exposure. (3) Surgical maneuverability and access for clip placements. Results The mean operative depth was 90 ± 4 mm. The lateral corridors were limited proximally by the alar rim openings (29 ± 4 mm) and distally by the distance between the opticocarotid recesses (19 ± 2 mm). The mean posteroanterior distance and width of the transplanum craniotomy were 19 ± 2 mm and 17 ± 3 mm, respectively. Vascular exposure was achieved in 100% of cases for the clinoidal internal carotid artery (ICA), ophthalmic artery, superior hypophyseal artery, and the proximal ophthalmic ICA. Surgical access and clip placement was achieved in 97.6% of cases for vessels located anterior to the pituitary stalk (odds ratio [OR] 73.8; 95% confidence interval [CI] 7.66 to 710.8; p = 0.00). Conclusion The endoscopic transnasal approach provides excellent visualization of the paraclinoid region vasculature and offers potential surgical alternative for paraclinoid aneurysms.  ",0
5006,24437207,The effectiveness of the spa and health resort treatment for the pre-gravid preparation of the women at high risk of obstetric and perinatal pathology],"Chronic recurrent inflammatory diseases of the small pelvis are known to be responsible for the development of the adhesive process and infertility. Therefore, they require surgical treatment and increase the risk of obstetric and perinatal pathology. The present study was focused on the assessment of therapeutic and prophylactic effectiveness of the application of natural and preformed physical factors for the pre-gravid preparation of the patients presenting with gynecological problems and pregnant women at high risk of obstetric and perinatal pathology based at the spa and health resort facilities of the Krasnodar Krai (region). The treatment included aero-, helio-, and thalassotherapy, transcranial electroneural stimulation, UHF therapy, hydrogen sulfide or iodine-bromine therapy. A total of 267 women were included in the study. Pregnancy was documented in 52% of the 144 patients who comprised the main group and underwent a course of rehabilitative treatment; it developed within 3-5 months after therapeutic and prophylactic laparoscopic procedures. The frequency of obstetric and perinatal pathology in this group significantly decreased in comparison with that among the control patients which allowed to greatly reduce material and financial expenditures. ",0
5007,24438369,Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use,"The thiopurine medications are standard inflammatory bowel disease treatments. Therapeutic failure is observed, however, often because of variable drug metabolism. Allopurinol can enhance the potency of thiopurine treatment. Our objective is to review the relevant literature, and our own experience, to determine if allopurinol enhancement of thiopurine treatment is a reasonable therapeutic strategy. Published reports of, and our own experience using, allopurinol-thiopurine combination therapy indicate that the addition of allopurinol will enhance thiopurine treatment in up to 60% of patients. There are risks to this approach, but with appropriate monitoring, these risks should approximate those observed with thiopurine therapy alone. Combination therapy with allopurinol and a thiopurine is a reasonable alternative for inflammatory bowel disease patients not responding to thiopurine monotherapy. Physicians experienced in thiopurine treatment, who have familiarity with thiopurine metabolism, and are willing to engage in appropriate therapeutic monitoring, should consider this strategy. ",0
5008,24438811,Cervical spondylodiscitis--a clinical analysis of surgically treated patients and review of the literature,"The aim of this study was to analyze our clinical and neurological results of surgically treated patients suffering from cervical spondylodiscitis with focusing particularly on the surgical methods used and to review the literature. We present a series of 21 patients operated with cervical spondylodiscitis between 1998 and 2011. Basic demographic data, comorbidities, the radiological segments involved, the surgical strategy with special consideration of the material used and the clinical outcome were evaluated retrospectively. The mean age of 6 female and 12 male patients was 65 years (range 28-89 years). The mean follow-up was 3.7 years ranging between 4 weeks and 9 years. The leading symptom was neurological deficits rather than pain. The segments C 5/6 (n=8) and C 6/7 (n=7) were most frequently involved. Different surgical methods depending on the location, anatomical and pathological condition and extension of the lesion were performed. In conclusion, cervical spondylodiscitis could effectively be treated in the presented patient cohort by surgical decompression, debridement and PMMA or bone graft implants followed by long term antibiotic therapy. The presented surgical reconstruction technique with PMMA might be a feasible alternative to the use of bone graft or cages. The promising clinical results warrant future prospective studies to further investigate this technique. ",0
5009,24438915,Extrahepatic visualization in the distribution of falciform artery in posttreatment Bremsstrahlung images after radioembolization with (90)Y microspheres,"We report the case of a 39-year-old female with metastatic colorectal cancer. Pretreatment SPECT/CT imaging revealed extrahepatic tracer accumulation along the falciform artery distribution. Prior to the administration of (90)Y microspheres, hepatic arterial anatomy was evaluated angiographically. It was not possible to identify the hepatic falciform artery so that no coil-embolization was performed. The patient tolerated the treatment well with only mild pain around the umbilicus during the procedure that spontaneously abated. As far as we know, this is the first report of Bremsstrahlung SPECT/CT images that has clearly shown that the microspheres accumulation in the anterior abdominal wall corresponds to hepatic falciform artery distribution on CT. ",0
5010,24439270,Reliability and validity of the Calgary Depression Scale for Schizophrenia (CDSS) in youth at clinical high risk for psychosis,"""Assessment of depression in individuals who are considered to be at clinical high risk (CHR) for psychosis is important as high rates of depression have been reported in CHR individuals. The Calgary Depression Scale (CDSS) is the most widely used scale for assessing depression in schizophrenia. It has excellent psychometric properties, internal consistency, inter-rater reliability, sensitivity, specificity, and discriminant and convergent validity. The aim of this study was to test the reliability and validity of the CDSS in a sample of youth at CHR for psychosis. Participants were assessed for depression, presence of axis 1 mood disorders, and prodromal symptoms using the CDSS, the Structured Clinical Interview for DSM-IV Disorders (SCID-1), and the Scale of Prodromal Symptoms (SOPS). The CDSS total score as well as all individual items, except """"guilty ideas of reference,"""" were significantly associated with the presence of a major depressive disorder. Significant correlations were observed between CDSS total score and the dysphoric mood item on the SOPS. There was some evidence of overlap between the CDSS and both attenuated positive symptoms and negative symptoms as assessed by the SOPS. It is concluded that CDSS is a reliable scale suitable for assessing depression in individuals considered to be at CHR for psychosis.  """,0
5011,24439294,Expression profiles of fetal membrane nicotinamide adenine dinucleotide phosphate oxidases (NOX) 2 and 3 differentiates spontaneous preterm birth and pPROM pathophysiologies,"Nicotinamide adenine dinucleotide phosphate oxidases (NOX 1-5) are enzymes that generate cellular reactive oxygen species (ROS) besides mitochondria and might be important ROS sources associated with pregnancy complications, particularly preterm premature rupture of membranes (pPROM), that has been related to ROS. To characterize NOX enzymes expression in human fetal membranes. Differential expression and localization of NOX isoforms in human fetal membranes collected from women with uncomplicated pregnancies at term, preterm birth (PTB) or pPROM and in vitro in normal term membranes maintained in an organ explant system stimulated with water-soluble cigarette smoke extract (wsCSE) were documented by real time PCR and immunohistochemistry. Fetal membranes from term deliveries, PTB and pPROM expressed NOX 2, 3 and 4 mRNAs whereas NOX 1 and 5 were not detected. NOX 2 expression was 2.3-fold higher in PTB than pPROM (p = 0.005) whereas NOX 3 was 2.2-fold higher in pPROM compared to PTB (p = 0.04). NOX 2 and 3 expressions at term mimicked pPROM and PTB, respectively. No difference in NOX 4 expression was observed among the studied groups. NOX 2, 3 and 4 were localized to both amniotic and chorionic cells. Expression of NOX 2, 3 and 4 were not significant in wsCSE-stimulated membranes compared to untreated controls. NOX enzymes are present in the fetal membranes and are differentially expressed in PTB and pPROM. Absence of any changes in NOXs expression after wsCSE stimulation suggests ROS generation in the membranes does not always correlate with NOX expression. ",0
5012,24439348,"Vaccinations given during pregnancy, 2002-2009: a descriptive study","""A number of studies have described influenza vaccination coverage during pregnancy but few publications have described rates of other vaccinations. To describe vaccination rates during pregnancy in the Vaccine Safety Datalink (VSD), with particular focus on vaccinations contraindicated during pregnancy. Pregnancies ending in 2002 through 2009 and vaccinations administered during these pregnancies were identified in the VSD. Vaccination rates per 1000 pregnancies during the study period were calculated by vaccine type, recommendation category, pregnancy year, maternal age, and trimester. Analyses were conducted in 2012-2013. In the VSD, 669,695 pregnancies and 141,389 vaccinations were identified. Trivalent inactivated influenza (TIV) was the most commonly administered vaccination (174.1 doses per 1000 pregnancies) and was most often administered during the 2nd and 3rd trimesters. The most common vaccines in the """"consider if indicated"""" category were tetanus-diphtheria (6.1 per 1000) and hepatitis B (3.7 per 1000). Contraindicated vaccination was infrequent, and the majority of these were measles-mumps-rubella (MMR) (1.2 per 1000); varicella (1.0 per 1000); and live-attenuated influenza vaccine (LAIV) (0.3 per 1000). Both """"consider if indicated"""" and contraindicated vaccines were more frequently administered during early pregnancy. TIV was the most commonly administered vaccine. With the exception of TIV, other vaccines were most frequently administered during early pregnancy and among younger women, suggesting that vaccination may occur when the woman and/or provider are unaware of the pregnancy. Contraindicated vaccines were infrequently administered during pregnancy; however, given that some women received contraindicated vaccines later in pregnancy, clearer recommendations and improved provider education may be needed. """,0
5013,24439355,Active living research: creating and using evidence to support childhood obesity prevention,"The second phase of Active Living Research (ALR-2, 2007-2012) focused on advancing the Robert Wood Johnson Foundation (RWJF)'s goal of reversing the childhood obesity epidemic. The mission was to stimulate and support research to identify environmental factors and policies that influence physical activity for children and families to inform effective childhood obesity prevention strategies, with an emphasis on the lower-income and racial/ethnic communities with highest childhood obesity prevalence. The present report describes ALR activities undertaken to accomplish three goals. The first goal-to build an evidence base-was furthered by funding 230 competitive grants to identify and evaluate promising environment and policy changes. More than 300 publications have been produced so far. The second goal-to build an interdisciplinary and diverse field of investigators-was supported through annual conferences and linked journal supplements, academic outreach to multiple disciplines, and grants targeting young investigators and those representing groups historically disadvantaged or underrepresented in RWJF-funded research. The third goal-to use research to inform policy and practice-was advanced through research briefs; webinars; research-translation grants supporting ALR grantees to design communications tailored to decision-maker audiences; active engagement of policymakers and other stakeholders in ALR program meetings and annual conferences; ALR presentations at policy-related meetings; and broad outreach through a widely used website, e-mailed newsletters, and social media. ALR-2 findings and products have contributed to a rapid increase in the evidence base and field of active living research, as documented by an independent program evaluation.  ",0
5014,24439580,Chest tube placement in children during extracorporeal membrane oxygenation (ECMO),"Pleural collections of air and fluid are frequent in infants and children treated with extracorporeal membrane oxygenation (ECMO). In this anticoagulated population, chest tube placement is potentially hazardous, and catastrophic hemorrhage has been reported. We sought to define the risks associated with chest tube placement in a large population of children managed with ECMO. The records of 189 consecutive children managed with ECMO at two children's hospitals were reviewed. Demographics, indications for ECMO, and ECMO courses were reviewed. In particular, the occurrence of pleural collections and the frequency and technique of chest tube placement were evaluated. The incidence of complications and mortality were determined. The median age of the subjects was 2days. The overall mortality was 26.5%. A pneumothorax was found in 19 (10.1%), a pleural effusion in 26 (13.8%), and a hemothorax in 2 (1.0%). A chest tube was placed in 27 (19 by a needle-guide wire technique and 8 by cut-down). Major bleeding complications occurred in 6 subjects (22%). There was a significant incidence of major bleeding complications and death in subjects in whom chest tubes were placed. The placement of a chest tube during ECMO should be done only if it is likely to improve pump flow or promote weaning of support. ",0
5015,24439604,"""""""Trap-door"""" and """"clamshell"""" surgical approaches for the management of pediatric tumors of the cervicothoracic junction and mediastinum""","""For pediatric tumors of the cervicothoracic junction, an isolated cervical or thoracic surgical approach provides insufficient exposure for achieving complete resection. We retrospectively examined """"trap-door"""" and """"clamshell"""" pediatric thoracotomies as a surgical approach to these tumors. We searched our database for pediatric patients with cervicothoracic tumors who underwent clamshell or trap-door thoracotomy between 1991 and 2013, reviewing tumor characteristics, surgical technique, completeness of resection, morbidity, and outcome. Trap-door (n=13) and clamshell (n=4) thoracotomies were performed for neuroblastoma (n=9), non-rhabdomyosarcoma soft tissue sarcoma (n=4), germ cell tumor (n=2), rhabdomyosarcoma (n=1), and neuroendocrine small cell carcinoma (n=1). Fourteen of these cervicothoracic tumors were primary, and three were metastatic. Gross total resection was achieved in 15 patients (94%). Operative complications included vocal cord paralysis (n=2), mild upper-extremity neuropraxia (n=2), and hemidiaphragm paralysis (n=1), All but one involved encased nerves. Overall survival was 61% for the series and 80% for patients with primary tumors. Eleven (73%) of 15 patients who underwent gross total resection had no evidence of recurrence. Three patients with metastatic disease died of distant progression within 1.3years. Gross total resection of primary cervicothoracic tumors can be accomplished with specialized exposure in pediatric patients with minimal morbidity. """,0
5016,24439890,The operating surgeon is an independent predictor of chest tube drainage following cardiac surgery,"Bleeding into the chest is a major cause of blood transfusion and adverse outcomes following cardiac surgery. The authors investigated predictors of bleeding following cardiac surgery to identify potentially correctable factors. Data were retrieved from the medical records of patients undergoing cardiac surgery over the period of 2002 to 2008. Multivariate analysis was used to identify the independent predictors of chest tube drainage. Tertiary hospital. Two thousand five hundred seventy-five patients. Cardiac surgery. The individual operating surgeon was independently associated with the extent of chest tube drainage. Other independent factors included internal mammary artery grafting, cardiopulmonary bypass time, urgency of surgery, tricuspid valve surgery, redo surgery, left ventricular impairment, male gender, lower body mass index and higher preoperative hemoglobin levels. Both a history of diabetes and administration of aprotinin were associated with reduced levels of chest tube drainage. The individual operating surgeon was an independent predictor of the extent of chest tube drainage. Attention to surgeon-specific factors offers the possibility of reduced bleeding, fewer transfusions, and improved patient outcomes. ",0
5017,24439952,Selected preconception health indicators and birth weight disparities in a national study,"This analysis explored the effect of timing, sequencing, and change in preconception health across adolescence and young adulthood on racial/ethnic disparities in birth weight in a diverse national cohort of young adult women. Data came from Waves I (1994-1995), III (2001-2002), and IV (2007-2008) of the National Longitudinal Study of Adolescent Health. Eligibility was restricted to all singleton live births to female non-Hispanic White, non-Hispanic Black, Mexican-origin Latina, or Asian/Pacific Islander participants (n = 3,014) occurring between the Wave III (ages 18-26 years) and IV (ages 24-32 years) interviews. Birth weight was categorized into low (<2,500 g), normal (2,500-4,000 g), and macrosomic (>4,000 g). Preconception health indicators were cigarette smoking, heavy alcohol consumption, overweight or obesity, and inadequate physical activity, measured in adolescence (Wave I, ages 11-19 years) and early adulthood (Wave III) and combined into four-category variables to capture the timing and sequencing of exposure. Measures of preconception health did not explain the Black-White disparity in low birth weight, which increased after adjustment for confounders (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.33-3.53) and effect modification by overweight/obesity (OR, 3.58; 95% CI, 1.65-7.78). A positive association between adult-onset overweight/obesity and macrosomia was modified by race (OR, 3.83; 95% CI, 1.02-14.36 for Black women). This longitudinal analysis provides new evidence on preconception health and racial/ethnic disparities in birth weight. Specifically, it indicates that interventions focused on prevention of overweight/obesity and maintenance of healthy weight during the transition to adulthood, especially among Black females, may be warranted. ",0
5018,24439973,Amsterdam Investigator-initiateD Absorb strategy all-comers trial (AIDA trial): a clinical evaluation comparing the efficacy and performance of ABSORB everolimus-eluting bioresorbable vascular scaffold strategy vs the XIENCE family (XIENCE PRIME or XIENCE Xpedition) everolimus-eluting coronary stent strategy in the treatment of coronary lesions in consecutive all-comers: rationale and study design,"""The Absorb everolimus-eluting bioresorbable vascular scaffold (AbsorbBVS) is a completely resorbable device engineered to overcome the limitations of permanent metallic stents, providing temporary scaffolding and antiproliferative drug delivery for the treatment of obstructive coronary artery disease. The objective of the AIDA trial is to evaluate the efficacy and performance in an contemporary all-comer population of the AbsorbBVS strategy vs the XIENCE family everolimus-eluting metallic coronary stent system in the treatment of coronary lesions. The AIDA trial is a prospective, randomized (1:1), active-control, single-blinded, all-comer, noninferiority trial. A total of 2,690 subjects will be enrolled with broad inclusion and limited exclusion criteria according to the """"Instructions for Use"""" of the AbsorbBVS strategy. The study population includes both simple and complex lesions, in patients with stable and acute coronary syndrome. The follow-up continues for 5years. The primary end point of the trial is target vessel failure, defined as the composite of cardiac death, myocardial infarction, and target vessel revascularization, at 2years. This study is registered on ClinicalTrials.gov with number NCT01858077. The AIDA trial will provide the first randomized direct comparison between the everolimus-eluting bioresorbable vascular scaffold and the everolimus-eluting metallic stent in contemporary percutaneous coronary intervention practice. """,0
5019,24440369,Psychostimulants and brain dysfunction: a review of the relevant neurotoxic effects,"Psychostimulants abuse is a major public concern because is associated with serious health complications, including devastating consequences on the central nervous system (CNS). The neurotoxic effects of these drugs have been extensively studied. Nevertheless, numerous questions and uncertainties remain in our understanding of these toxic events. Thus, the purpose of the present manuscript is to review cellular and molecular mechanisms that might be responsible for brain dysfunction induced by psychostimulants. Topics reviewed include some classical aspects of neurotoxicity, such as monoaminergic system and mitochondrial dysfunction, oxidative stress, excitotoxicity and hyperthermia. Moreover, recent literature has suggested new phenomena regarding the toxic effects of psychostimulants. Thus, we also reviewed the impact of these drugs on neuroinflammatory response, blood-brain barrier (BBB) function and neurogenesis. Assessing the relative importance of these mechanisms on psychostimulants-induced brain dysfunction presents an exciting challenge for future research efforts. This article is part of the Special Issue entitled 'CNS Stimulants'.  ",0
5020,24440573,Clinical trial design in contemporary device studies in heart failure: is there a gold standard?,"The assessment of the efficacy and safety of implantable cardiac devices used for the management of heart failure is complicated by procedural challenges. We present an overview of the advantages and disadvantages of different clinical trial designs, and discuss investigator and patient blinding. We conclude that blinding is optimal, but methodologically difficult. Until rules for and assessment of blinding are developed or surrogate measures are considered to be acceptable from a regulatory standpoint, an open-label design with objective end points is an unavoidable default standard.  ",0
5021,24441300,The value of early placement in a supported employment program for individuals with traumatic brain injury,"Predicting return to work in persons with traumatic brain injury has been a challenge for doctors, rehabilitation therapists and vocational counselors. Although traditional vocational rehabilitation may be beneficial to many clients, there are others who are unable to return to work through customary means. Supported employment is a method of vocational rehabilitation in which a professional staff person (a job coach) provides structured job placement services and highly individualized training at the job site in addition to ongoing services throughout the entire length of employment. This approach has been used as a last resort to treatment, but has very high success rates (50-78% success rates for those deemed unemployable by other means). Work hardening was used in the 1980s as a last resort to therapy for the industrial injured worker. However, it was found that when clients entered the program sooner, they had a greater chance of return to work than if they entered the program after a prolonged period of time, thus saving money. If the individual with a traumatic brain injury is placed in supported employment programs sooner, he may have a greater chance of return to work than if supported employment is used only as a last resort.  ",0
5022,24441521,ADHD symptoms as risk factors for dysfunctional eating habits in adolescents: results from a longitudinal study],"The aim of this study is to analyze the relationship between attention deficit hyperactivity disorder (ADHD) symptoms in childhood and early-adolescence and the development of dysfunctional eating habits later in life. The sample under investigation is composed of 217 adolescents (males: 30.9%; mean age: 17.1 ± 0.88 ys; range: 16-19 ys) voluntarily recruited in the city of Parma (Northern Italy) in the context of a longitudinal research project focused on developmental factors of antisocial behaviour. All subjects were assessed at T1 (mean age: 12 ys) and at T2 (mean age: 14 ys) using a structured clinical interview to collect information on ADHD symptoms on a lifetime basis and, at T3 (mean age: 17 ys), they were administered an interview to assess pathological eating habits. Correlation and regression analyses were carried out between scores of the three symptom domains of ADHD and eating habits as assessed at T3. Results suggest that the association between ADHD symptoms and eating habits show differences according to gender, in that in females ADHD symptoms assessed at T2 are associated with compensatory behaviours, while in males they are predictive of overweight as assessed at T3. ADHD symptoms, although under threshold, may lead to chaotic and unorganized eating habits which might put female at risk for compensatory behaviours and males for overweight. ",0
5023,24441653,"Synthesis, crystal structure and anti-fatigue effects of some benzamide derivatives","A series of benzamide derivatives such as 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine (1-BCP) were synthesized by the reaction of substituted benzoic acids with piperidine, morpholine or pyrrolidine using a novel method. The crystals of these benzamide derivatives were obtained by recrystallization. Structures of target and intermediate compounds were determined via FT-IR, 1H-NMR and elemental analysis and X-ray crystallography of select examples. The crystal structures of these compounds have potential applications to identify the binding site for allosteric modulators of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. The anti-fatigue effects of the benzamide derivatives in weight-loaded forced swimming mice were investigated in a swimming endurance capacity test used as an indicator of fatigue. The swimming times to exhaustion were longer in the b3, d3, and e3 groups than in the caffeine group (p<0.05). In conclusion, b3, d3 and e3 enhanced the forced swimming capacity of mice. The mechanism of the anti-fatigue effects will be studied in the future. ",0
5024,24441663,Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry,"""Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder in which germline mutations of fumarate hydratase (FH) gene confer an increased risk of cutaneous and uterine leiomyomas and renal cancer. HLRCC-associated renal cancer is highly aggressive and frequently presents as a solitary mass. We reviewed the clinicopathologic features of 9 patients with renal tumors presenting as sporadic cases but who were later proven to have FH germline mutations. Histologically, all tumors showed mixed architectural patterns, with papillary as the dominant pattern in only 3 cases. Besides papillary, tubular, tubulopapillary, solid, and cystic elements, 6 of 9 tumors contained collecting duct carcinoma-like areas with infiltrating tubules, nests, or individual cells surrounded by desmoplastic stroma. Prominent tubulocystic carcinoma-like component and sarcomatoid differentiation were identified. Although all tumors exhibited the proposed hallmark of HLRCC (large eosinophilic nucleolus surrounded by a clear halo), this feature was often not uniformly present throughout the tumor. Prior studies have shown that a high level of fumarate accumulated in HLRCC tumor cells causes aberrant succination of cellular proteins by forming a stable chemical modification, S-(2-succino)-cysteine (2SC), which can be detected by immunohistochemistry. We thus explored the utility of detecting 2SC by immunohistochemistry in the differential diagnosis of HLRCC tumors and other high-grade renal tumors and investigated the correlation between 2SC staining and FH molecular alterations. All confirmed HLRCC tumors demonstrated diffuse and strong nuclear and cytoplasmic 2SC staining, whereas all clear cell (184/184, 100%), most high-grade unclassified (93/97, 96%), and the large majority of """"type 2"""" papillary (35/45, 78%) renal cell carcinoma cases showed no 2SC immunoreactivity. A subset of papillary (22%) and rare unclassified (4%) tumors showed patchy or diffuse cytoplasmic staining without nuclear labeling, unlike the pattern seen with confirmed HLRCC tumors. Sequencing revealed no germline or somatic FH alterations in 14 tumors that either exhibited only cytoplasmic 2SC staining (n=5) or were negative for 2SC (n=9), despite their HLRCC-like morphologic features. Our results emphasize the pivotal role of pathologic examination in the diagnosis of HLRCC patients and indicate immunohistochemical detection of 2SC as a useful ancillary tool in the differentiation of HLRCC renal tumors from other high-grade renal cell carcinomas.  """,0
5025,24442505,Nitrite reductase genes as functional markers to investigate diversity of denitrifying bacteria during agricultural waste composting,"The purpose of this study was to investigate the diversity of denitrifier community during agricultural waste composting. The diversity and dynamics of the denitrifying genes (nirK and nirS) were determined using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE). Relationships between physico-chemical parameters and denitrifying genes structures were simultaneously evaluated by redundancy analysis (RDA). Phylogenetic analysis indicated that nirK clones grouped into six clusters and nirS clones into two major clusters, respectively. The results showed a very high diversity of nir gene sequences within composting samples. RDA showed that the nirK and nirS gene structures were significantly related to pH and pile temperature (P < 0.05). Significant amounts of the variation (49.2 and 38.3 % for nirK and nirS genes, respectively) were explained by pH and pile temperature, suggesting that those two parameters were the most likely ones to influence, or be influenced by the denitrifiers harboring nirK and nirS genes.  ",0
5026,24442592,The Cultural Relevance of Mindfulness Meditation as a Health Intervention for African Americans: Implications for Reducing Stress-Related Health Disparities,"""African Americans experience a disproportionate rate of stress-related health conditions compared to European Americans. Mindfulness meditation has been shown to be effective for managing stress and various stress-related health conditions. This study explored the cultural relevance of mindfulness meditation training for African Americans adults. Fifteen African American adults with past or current experience with mindfulness meditation training were interviewed. Participants felt that mindfulness meditation helped them with enhanced stress management, direct health improvement, and enhanced self-awareness and purposefulness. They felt that they would recommend it and that other African Americans would be open to the practice but suggested that its presentation may need to be adapted. They suggested emphasizing the health benefits, connecting it to familiar spiritual ideology and cultural practices, supplementing the reading material with African American writers, increasing communication (education, instructor availability, """"buddy system,"""" etc.), and including African Americans as instructors and participants. By implementing minor adaptations that enhance cultural relevance, mindfulness meditation can be a beneficial therapeutic intervention for this population.  """,0
5027,24442596,Arterial and fat tissue inflammation are highly correlated: a prospective 18F-FDG PET/CT study,"There is evidence that the link between obesity and cardiovascular disease might relate to inflammation in both fat tissue and the arterial wall. (18)F-FDG uptake on PET is a surrogate marker of vessel wall inflammation. The aim of the study was to measure FDG uptake in both regions using PET and identify links between adipose and arterial inflammation. Included in the study were 173 cardiovascular patients who were prospectively imaged with FDG PET/CT. Arterial FDG uptake was measured in the carotid arteries and ascending aorta. The same was done in fat tissue in the neck, the presternal region (both subcutaneous) and the pericardium. FDG uptake was quantified as average maximal target-to-background ratio (mean TBR max). Multivariate regression analyses were performed to identify significant associations between arterial and adipose tissue FDG uptake and clinical variables as given by the standardized correlation coefficient (β). FDG uptake values in all fat tissue regions were highly predictive of vascular FDG uptake in both the carotids (β 0.262, p < 0.0001, in the neck subcutaneous region) and aorta (β 0.22, p = 0.008, in the chest pericardial region; β 0.193, p = 0.019, in the chest subcutaneous region). Obesity was significantly associated with elevated FDG uptake in adipose tissue (β 0.470, p < 0.0001, in the neck subcutaneous region; β 0.619, p = 0.028, in the chest subcutaneous region; β 0.978, p = 0.035, in the chest pericardial region). FDG uptake in diverse fat tissue regions was significantly associated with arterial FDG uptake, a reasonable surrogate of inflammation. Increasing body weight significantly predicted the level of fatty inflammation. FDG PET therefore provides imaging evidence of an inflammatory link between fat tissue and the vasculature in patients with cardiovascular disease. ",0
5028,24442891,pH signaling in human fungal pathogens: a new target for antifungal strategies,"Fungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signaling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signaling in C. albicans, A. fumigatus, and C. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signaling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition, and (v) to slow the emergence of resistant mutants.  ",0
5029,24443047,"Sorption-desorption and transport of trimethoprim and sulfonamide antibiotics in agricultural soil: effect of soil type, dissolved organic matter, and pH","Use of animal manure is a main source of veterinary pharmaceuticals (VPs) in soil and groundwater through a series of migration processes. The sorption-desorption and transport of four commonly used VPs including trimethoprim (TMP), sulfapyridine, sulfameter, and sulfadimethoxine were investigated in three soil layers taken from an agricultural field in Chongming Island China and two types of aqueous solution (0.01 M CaCl2 solution and wastewater treatment plant effluent). Results from sorption-desorption experiments showed that the sorption behavior of selected VPs conformed to the Freundlich isotherm equation. TMP exhibited higher distribution coefficients (K d = 6.73-9.21) than other sulfonamides (K d = 0.03-0.47), indicating a much stronger adsorption capacity of TMP. The percentage of desorption for TMP in a range of 8-12 % is not so high to be considered significant. Low pH (<pK a of tested VPs) and rich soil organic matter (e.g., 0-20 cm soil sample) had a positive impact on sorption of VPs. Slightly lower distribution coefficients were obtained for VPs in wastewater treatment plant (WWTP) effluent, which suggested that dissolved organic matter might affect their sorption behavior. Column studies indicated that the transport of VPs in the soil column was mainly influenced by sorption capacity. The weakly adsorbed sulfonamides had a high recovery rate (63.6-98.0 %) in the leachate, while the recovery rate of TMP was only 4.2-10.4 %. The sulfonamides and TMP exhibited stronger retaining capacity in 20-80 cm and 0-20 cm soil samples, respectively. The transport of VPs was slightly higher in the columns leached by WWTP effluent than by CaCl2 solution (0.01 M) due to their sorption interactions.  ",0
5030,24443711,Occupational Lung Diseases among Soldiers Deployed to Iraq and Afghanistan,"""Military personnel deployed to Iraq and Afghanistan, from 2004 to the present, has served in a setting of unique environmental conditions. Among these are exposures to burning trash in open air """"burn pits"""" lit on fire with jet fuel JP-8. Depending on trash burned--water bottles, styrofoam trays, medical waste, unexploded munitions, and computers--toxins may be released such as dioxins and n-hexane and benzene. Particulate matter air pollution culminates from these fires and fumes. Additional environmental exposures entail sandstorms (Haboob, Shamal, and Sharqi) which differ in direction and relationship to rain. These wars saw the first use of improvised explosive devices (roadside phosphate bombs),as well as vehicle improvised explosive devices (car bombs), which not only potentially aerosolize metals, but also create shock waves to induce lung injury via blast overpressure. Conventional mortar rounds are also used by Al Qaeda in both Iraq and Afghanistan. Outdoor aeroallergens from date palm trees are prevalent in southern Iraq by the Tigris and Euphrates rivers, while indoor aeroallergen aspergillus predominates during the rainy season. High altitude lung disease may also compound the problem, particularly in Kandahar, Afghanistan. Clinically, soldiers may present with new-onset asthma or fixed airway obstruction. Some have constrictive bronchiolitis and vascular remodeling on open lung biopsy - despite having normal spirometry and chest xrays and CT scans of the chest. Others have been found to have titanium and other metals in the lung (rare in nature). Still others have fulminant biopsy-proven sarcoidiosis. We found DNA probe-positive Mycobacterium Avium Complex in lung from a soldier who had pneumonia, while serving near stagnant water and camels and goats outside Abu Gharib. This review highlights potential exposures, clinical syndromes, and the Denver Working Group recommendations on post-deployment health. """,0
5031,24443842,A huge malignant solitary fibrous tumor of kidney: case report and review of the literature,"Solitary fibrous tumor (SFT) is a spindle cell neoplasm that rarely occurs in the kidney. Malignant SFT of the kidney is particularly rare. Here, we report a 66-year old woman with a right flank mass that has been proved clinically and radiographically. Grossly, the largest diameter of the mass were measured up to 23 cm, was poorly circumscribed. Approximately 80% of the neoplasm consisted of hyperchromatic and pleomorphic spindled cells surrounding staghornlike blood vessels. Tumor cells frequently had mitoses and necrosis. However, the remainder of the mass was composed of haphazard, storiform or short fascicular arrangements of spindle cells in a loose myxoid to fibrous stroma. Immunohistochemically, we observed diffusely strong CD34 staining and an 85% Ki-67 proliferative index. The tumor partly showed negative CD34 and a 20% proliferative index. To our knowledge, this is the largest malignant renal SFT in the reported literatures and shows an obviously high proliferative index. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1603694556107408. ",0
5032,24444362,MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function,"MiR126 was found to be frequently lost in many types of cancer, including malignant mesothelioma (MM), which represents one of the most challenging neoplastic diseases. In this study, we investigated the potential tumor suppressor function of MiR126 in MM cells. The effect of MiR126 was examined in response to oxidative stress, aberrant mitochondrial function induced by inhibition of complex I, mitochondrial DNA (mtDNA) depletion, and hypoxia. MiR126 was up-regulated by oxidative stress in nonmalignant mesothelial (Met5A) and MM (H28) cell lines. In Met5A cells, rotenone inhibited MiR126 expression, but mtDNA depletion and hypoxia up-regulated MiR126. However, these various stimuli suppressed the levels of MiR126 in H28 cells. MiR126 affected mitochondrial energy metabolism, reduced mitochondrial respiration, and promoted glycolysis in H28 cells. This metabolic shift, associated with insulin receptor substrate-1 (IRS1)-modulated ATP-citrate lyase deregulation, resulted in higher ATP and citrate production. These changes were linked to the down-regulation of IRS1 by ectopic MiR126, reducing Akt signaling and inhibiting cytosolic sequestration of Forkhead box O1 (FoxO1), which promoted the expression of genes involved in gluconeogenesis and oxidative stress defense. These metabolic changes induced hypoxia-inducible factor-1α (HIF1α) stabilization. Consequently, MiR126 suppressed the malignancy of MM cells in vitro, a notion corroborated by the failure of H28(MiR126) cells to form tumors in nude mice. MiR126 affects mitochondrial energy metabolism, resulting in MM tumor suppression. Since MM is a fatal neoplastic disease with a few therapeutic options, this finding is of potential translational importance. ",0
5033,24444504,Evaluation and management of the acutely injured worker,"Approximately 3 million work-related injuries were reported by private industries in 2011, and primary care physicians provided care for approximately one out of four injured workers. To appropriately individualize the treatment of an injured worker and expedite the return to work process, primary care physicians need to be familiar with the workers' compensation system and treatment guidelines. Caring for an injured worker begins with a medical history documenting preexisting medical conditions, use of potentially impairing medications and substances, baseline functional status, and psychosocial factors. An understanding of past and current work tasks is critical and can be obtained through patient-completed forms, job analyses, and the patient's employer. Return to work in some capacity is an important part of the recovery process. It should not be unnecessarily delayed and should be an expected outcome communicated to the patient during the initial visit. Certain medications, such as opioids, may delay the return to work process, and their use should be carefully considered. Accurate and legible documentation is critical and should always include the location, date, time, and mechanism of injury.  ",0
5034,24444530,Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment,"Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. Thirty-three patients were treated with re-irradiation defined by the prior 30 Gy isodose line. Kaplan-Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. Median follow-up was 17 months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50 Gy and 10 fractions (fx), with a median of 18 months (6-61) between treatments. Median OS was 21 months and 2 year LC 67%, yet LC for >1 fraction was 88% (p=0.006 for single vs. multiple). 10 patients suffered chronic grade 2-3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54 Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200 Gy. Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity. ",0
5035,24444815,Behaviour of cytoplasmic organelles and cytoskeleton during oocyte maturation,"Assisted reproduction technology (ART) has become an attractive option for infertility treatment and holds tremendous promise. However, at present, there is still room for improvement in its success rates. Oocyte maturation is a process by which the oocyte becomes competent for fertilization and subsequent embryo development. To better understand the mechanism underlying oocyte maturation and for the future improvement of assisted reproduction technology, this review focuses on the complex processes of cytoplasmic organelles and the dynamic alterations of the cytoskeleton that occur during oocyte maturation. Ovarian stimulation and in-vitro maturation are the major techniques used in assisted reproduction technology and their influence on the organelles of oocytes is also discussed. Since the first birth by assisted reproduction treatment was achieved in 1978, numerous techniques involved in assisted reproduction have been developed and have become attractive options for infertility treatment. However, the unsatisfactory success rate remains as a main challenge. Oocyte maturation is a process by which the oocyte becomes competent for fertilization and subsequent embryo development. Oocyte maturation includes both nuclear and cytoplasmic maturation. Nuclear maturation primarily involves chromosomal segregation, which has been well studied, whereas cytoplasmic maturation involves a series of complicated processes, and there are still many parts of this process that remain controversial. Ovarian stimulation and in-vitro maturation (IVM) are the major techniques of assisted reproduction. The effect of ovarian stimulation or IVM on the behaviour of cell organelles of the oocyte has been postulated as the reason for the reduced developmental potential of in-vitro-produced embryos. To further understanding of the mechanism of oocyte maturation and future improvement of assisted reproduction treatment, the complex events of cytoplasmic organelles and the cytoskeleton that occur during oocyte maturation and the influence of ovarian stimulation and IVM on these organelles are described in this review.  ",0
5036,24449428,Systems biology for hepatologists,"Medicine is expected to benefit from combining usual cellular and molecular studies with high-throughput methods (genomics, transcriptomics, proteomics, and metabolomics). These methods, collectively known as omics, permit the determination of thousands of molecules (variations within genes, RNAs, proteins, metabolites) within a tissue, cell, or biological fluid. The use of these methods is very demanding in terms of the design of the study, acquisition, storage, analysis, and interpretation of the data. When carried out properly, these studies can reveal new etiological pathways, help to identify patients at risk for disease, and predict the response to specific treatments. Here we review these omics methods and mention several applications in hepatology research.",0
5037,24450892,"National trends in patient safety for four common conditions, 2005-2011","BACKGROUND: Changes in adverse-event rates among Medicare patients with common medical conditions and conditions requiring surgery remain largely unknown. METHODS: We used Medicare Patient Safety Monitoring System data abstracted from medical records on 21 adverse events in patients hospitalized in the United States between 2005 and 2011 for acute myocardial infarction, congestive heart failure, pneumonia, or conditions requiring surgery. We estimated trends in the rate of occurrence of adverse events for which patients were at risk, the proportion of patients with one or more adverse events, and the number of adverse events per 1000 hospitalizations. RESULTS: The study included 61,523 patients hospitalized for acute myocardial infarction (19%), congestive heart failure (25%), pneumonia (30%), and conditions requiring surgery (27%). From 2005 through 2011, among patients with acute myocardial infarction, the rate of occurrence of adverse events declined from 5.0% to 3.7% (difference, 1.3 percentage points; 95% confidence interval [CI], 0.7 to 1.9), the proportion of patients with one or more adverse events declined from 26.0% to 19.4% (difference, 6.6 percentage points; 95% CI, 3.3 to 10.2), and the number of adverse events per 1000 hospitalizations declined from 401.9 to 262.2 (difference, 139.7; 95% CI, 90.6 to 189.0). Among patients with congestive heart failure, the rate of occurrence of adverse events declined from 3.7% to 2.7% (difference, 1.0 percentage points; 95% CI, 0.5 to 1.4), the proportion of patients with one or more adverse events declined from 17.5% to 14.2% (difference, 3.3 percentage points; 95% CI, 1.0 to 5.5), and the number of adverse events per 1000 hospitalizations declined from 235.2 to 166.9 (difference, 68.3; 95% CI, 39.9 to 96.7). Patients with pneumonia and those with conditions requiring surgery had no significant declines in adverse-event rates. CONCLUSIONS: From 2005 through 2011, adverse-event rates declined substantially among patients hospitalized for acute myocardial infarction or congestive heart failure but not among those hospitalized for pneumonia or conditions requiring surgery. (Funded by the Agency for Healthcare Research and Quality and others.).",0
5038,24476431,Incidence of childhood obesity in the United States,"""BACKGROUND: Although the increased prevalence of childhood obesity in the United States has been documented, little is known about its incidence. We report here on the national incidence of obesity among elementary-school children. METHODS: We evaluated data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999, a representative prospective cohort of 7738 participants who were in kindergarten in 1998 in the United States. Weight and height were measured seven times between 1998 and 2007. Of the 7738 participants, 6807 were not obese at baseline; these participants were followed for 50,396 person-years. We used standard thresholds from the Centers for Disease Control and Prevention to define """"overweight"""" and """"obese"""" categories. We estimated the annual incidence of obesity, the cumulative incidence over 9 years, and the incidence density (cases per person-years) overall and according to sex, socioeconomic status, race or ethnic group, birth weight, and kindergarten weight. RESULTS: When the children entered kindergarten (mean age, 5.6 years), 12.4% were obese and another 14.9% were overweight; in eighth grade (mean age, 14.1 years), 20.8% were obese and 17.0% were overweight. The annual incidence of obesity decreased from 5.4% during kindergarten to 1.7% between fifth and eighth grade. Overweight 5-year-olds were four times as likely as normal-weight children to become obese (9-year cumulative incidence, 31.8% vs. 7.9%), with rates of 91.5 versus 17.2 per 1000 person-years. Among children who became obese between the ages of 5 and 14 years, nearly half had been overweight and 75% had been above the 70th percentile for body-mass index at baseline. CONCLUSIONS: Incident obesity between the ages of 5 and 14 years was more likely to have occurred at younger ages, primarily among children who had entered kindergarten overweight. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).""",0
5039,24500966,The ABCs of viral hepatitis that define biomarker signatures of acute viral hepatitis,"Viral hepatitis is the leading cause of liver disease worldwide and can be caused by several agents, including hepatitis A (HAV), B (HBV), and C (HCV) virus. We employed multiplexed protein immune assays to identify biomarker signatures of viral hepatitis in order to define unique and common responses for three different acute viral infections of the liver. We performed multianalyte profiling, measuring the concentrations of 182 serum proteins obtained from acute HAV- (18), HBV- (18), and HCV-infected (28) individuals, recruited as part of a hospital-based surveillance program in Cairo, Egypt. Virus-specific biomarker signatures were identified and validation was performed using a unique patient population. A core signature of 46 plasma proteins was commonly modulated in all three infections, as compared to healthy controls. Principle component analysis (PCA) revealed a host response based upon 34 proteins, which could distinguish HCV patients from HAV- and HBV-infected individuals or healthy controls. When HAV and HBV groups were compared directly, 34 differentially expressed serum proteins allowed the separation of these two patient groups. A validation study was performed on an additional 111 patients, confirming the relevance of our initial findings, and defining the 17 analytes that reproducibly segregated the patient populations. CONCLUSIONS: This combined discovery and biomarker validation approach revealed a previously unrecognized virus-specific induction of host proteins. The identification of hepatitis virus specific signatures provides a foundation for functional studies and the identification of potential correlates of viral clearance.",0
5040,24521104,"PCORI at 3 years--progress, lessons, and plans","The Patient-Centered Outcomes Research Institute (PCORI) has established distinctive pathways for funding and conducting practical research and has awarded over $318 million for studies covering a wide range of conditions, locations, and socioeconomic characteristics.",0
5041,24521105,"Misfearing--culture, identity, and our perceptions of health risks","Despite knowing that heart disease kills more women each year than all cancers combined, most women fear breast cancer far more - and their health-related behavior reflects this difference. If our sense of risk is less about fact than about feeling, how do we adjust it?",0
5042,24521110,Occupational asthma,"Occupational asthma has been defined as asthma due to conditions attributable to work exposures, not to causes outside the workplace. This review focuses on current data on pathogenesis, evaluation, and management.",0
5043,24585515,Treatment of phenylketonuria using minicircle-based naked-DNA gene transfer to murine liver,"Host immune response to viral vectors, persistence of nonintegrating vectors, and sustained transgene expression are among the major challenges in gene therapy. To overcome these hurdles, we successfully used minicircle (MC) naked-DNA vectors devoid of any viral or bacterial sequences for the long-term treatment of murine phenylketonuria, a model for a genetic liver defect. MC-DNA vectors expressed the murine phenylalanine hydroxylase (Pah) complementary DNA (cDNA) from a liver-specific promoter coupled to a de novo designed hepatocyte-specific regulatory element, designated P3, which is a cluster of evolutionary conserved transcription factor binding sites. MC-DNA vectors were subsequently delivered to the liver by a single hydrodynamic tail vein (HTV) injection. The MC-DNA vector normalized blood phenylalanine concomitant with reversion of hypopigmentation in a dose-dependent manner for more than 1 year, whereas the corresponding parental plasmid did not result in any phenylalanine clearance. MC vectors persisted in an episomal state in the liver consistent with sustained transgene expression and hepatic PAH enzyme activity without any apparent adverse effects. Moreover, 14-20% of all hepatocytes expressed transgenic PAH, and the expression was observed exclusively in the liver and predominately around pericentral areas of the hepatic lobule, while there was no transgene expression in periportal areas. CONCLUSION: This study demonstrates that MC technology offers an improved safety profile and has the potential for the genetic treatment of liver diseases.",0
5044,24616020,Identification of microRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression,"The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR-214 was validated to be significantly down-regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR-214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR-214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR-214. Restoring miR-214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR-214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR-214 on CRC cells. Moreover, miR-214 expression levels were inversely correlated with FGFR1 in CRC patients. CONCLUSION: Down-regulation of miR-214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR-214 may serve as a potential marker to predict survival, and the miR-214-FGFR1 axis may be a therapeutic target in CRC patients.",0
5045,24668739,Suppression of autophagy during liver regeneration impairs energy charge and hepatocyte senescence in mice,"Autophagy is a homeostatic mechanism that regulates protein and organelle turnover and uses the amino acids from degraded proteins to produce adenosine 5'-triphosphate (ATP). We investigated the activity of autophagy-associated pathways in liver regeneration after partial hepatectomy (PHx) in liver-specific autophagy-related gene 5 (Atg5) knockout (KO) mice. Liver regeneration was severely impaired by 70% PHx, with a reduction in postoperative mitosis, but a compensating increase in hepatocyte size. PHx induced intracellular adenosine triphosphate and ?-oxidation reduction as well as injured cellular mitochondria. Furthermore, PHx in Atg5 KO mice enhanced hepatic accumulation of p62 and ubiquitinated proteins. These results indicated that reorganization of intracellular proteins and organelles during autophagy was impaired in the regenerating liver of these mice. Up-regulation of p21 was associated with hepatocyte senescence, senescence-associated ?-galactosidase expression, irreversible growth arrest, and secretion of senescence-associated molecules, including interleukin (IL)-6 and IL-8. CONCLUSION: These findings indicate that autophagy plays a critical role in liver regeneration and in the preservation of cellular quality, preventing hepatocytes from becoming fully senescent and hypertrophic.",0
5046,24668880,Engineering liver,"""Interest in """"engineering liver"""" arises from multiple communities: therapeutic replacement; mechanistic models of human processes; and drug safety and efficacy studies. An explosion of micro- and nanofabrication, biomaterials, microfluidic, and other technologies potentially affords unprecedented opportunity to create microphysiological models of the human liver, but engineering design principles for how to deploy these tools effectively toward specific applications, including how to define the essential constraints of any given application (available sources of cells, acceptable cost, and user-friendliness), are still emerging. Arguably less appreciated is the parallel growth in computational systems biology approaches toward these same problems-particularly in parsing complex disease processes from clinical material, building models of response networks, and in how to interpret the growing compendium of data on drug efficacy and toxicology in patient populations. Here, we provide insight into how the complementary paths of engineering liver-experimental and computational-are beginning to interplay toward greater illumination of human disease states and technologies for drug development.""",0
5047,24670167,Patches of disorganization in the neocortex of children with autism,"BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development. METHODS: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type-specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years. RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches. CONCLUSIONS: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.).",0
5048,24670168,Mutant ZP1 in familial infertility,"The human zona pellucida is composed of four glycoproteins (ZP1, ZP2, ZP3, and ZP4) and has an important role in reproduction. Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members. In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte.",0
5049,24670178,Abatacept in B7-1-positive proteinuric kidney disease,"Abatacept (cytotoxic T-lymphocyte�associated antigen 4�immunoglobulin fusion protein [CTLA-4�Ig]) is a costimulatory inhibitor that targets B7-1 (CD80). The present report describes five patients who had focal segmental glomerulosclerosis (FSGS) (four with recurrent FSGS after transplantation and one with primary FSGS) and proteinuria with B7-1 immunostaining of podocytes in kidney-biopsy specimens. Abatacept induced partial or complete remissions of proteinuria in these patients, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies. Our data indicate that abatacept may stabilize ?1-integrin activation in podocytes and reduce proteinuria in patients with B7-1�positive glomerular disease.",0
5050,24677194,Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice,"The liver is a tolerogenic environment exploited by persistent infections, such as hepatitis B (HBV) and C (HCV) viruses. In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8(+) T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8(+) T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8(+) T cells also appear to have a T-regulatory (Treg) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (Teff ) cells in vitro and in vivo via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8(+) Treg cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8(+) Treg cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1). CONCLUSION: Virus-specific Tim-3(+) CD8(+) T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections.",0
5051,24691835,Cost-effectiveness of sofosbuvir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C,"We assessed the cost-effectiveness of sofosbuvir (SOF)-based triple therapy (TT) compared with boceprevir (BOC)- and telaprevir (TVR)-based TT in untreated genotype 1 (G1) chronic hepatitis C (CHC) patients discriminated according to IL28B genotype, severity of liver fibrosis, and G1 subtype. The available published literature provided the data source. The target population was made up of untreated Caucasian patients, aged 50 years, with G1CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euros at 2013 value), life-years gained (LYG), quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). Cost of SOF was assumed to be � 3,500 per week, i.e., the price generating a willingness-to-pay threshold of � 25,000 per LYG compared with TVR in the entire population of untreated G1 patients. The robustness of the results was evaluated by one-way deterministic and multivariate probabilistic sensitivity analyses. SOF was cost-effective compared with BOC in all strategies with the exception of cirrhosis and IL28B CC patients. In comparison with TVR-based strategies, SOF was cost-effective in IL28B CT/TT (ICER per LYG � 22,229) and G1a (� 19,359) patients, not cost-effective in IL28B CC (�45,330), fibrosis F0-F3 (� 26,444), and in cirrhosis (� 34,906) patients, and dominated in G1b patients. The models were sensitive to SOF prices and to likelihood of sustained virological response. CONCLUSION: In untreated G1 CHC patients, SOF-based TT may be a cost-effective alternative to first-generation protease inhibitors depending on pricing. The cost-effectiveness of SOF improved in IL28B CT/TT and G1a patients. SOF was dominated by TVR in G1b patients even if, in clinical practice, this issue could be counterbalanced by the good tolerability profile of SOF and by the shorter treatment duration.",0
5052,24693892,Thyroid hormone inactivation in gastrointestinal stromal tumors,"Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.",0
5053,24700342,Ribavirin improves the IFN-? response of natural killer cells to IFN-based therapy of hepatitis C virus infection,"Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-?/? receptor signaling, as NK cell cytotoxicity and IFN-? production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-? production decreases in response to endogenous, virus-induced IFN-? and during IFN-?-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-? response of NK cells in the presence of IFN-?, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-? decreased (P?=?0.049 and P?=?0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P?<?0.01) but not pSTAT1 response of NK cells to subsequent stimulation with IFN-?. This was associated with an increase in IFN-? production but not cytotoxicity of NK cells during subsequent IFN-?-based therapy. The frequency of IFN-?-producing NK cells was greater in fast second-phase virological responders than in slow responders. CONCLUSION: RBV enhances the pSTAT4 and IFN-? response of NK cells to IFN-?-stimulation.",0
5054,24700390,"Integrins, myofibroblasts, and organ fibrosis","Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding ?(V) integrin subunit because various ?(V)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride�induced hepatic fibrosis, whereas global loss of ?3, ?5 or ?6 integrin or conditional loss of ?8 integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the ?V integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of ?(V)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all ?(V) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.",0
5055,24700614,Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice,"Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological responses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1(-) (/) (-) mice, and through neutralizing antibodies, respectively. Models of interleukin-10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet-derived serotonin. Downstream of serotonin, systemic protection was spread through up-regulation of circulating Vegf. Both RIPC and serotonin-Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up-regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults. CONCLUSIONS: We have identified a platelet-serotonin-Vegf-Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet-dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm.",0
5056,24710669,Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir-containing regimens,"Whether the presence of cirrhosis influences patient-reported outcomes (PROs), including health-related quality of life, during treatment with newly available anti-HCV (hepatitis C virus) regimens is unclear. Our aim was to assess the association of cirrhosis with PROs in patients treated with sofosbuvir (SOF)-containing regimens. Four PRO questionnaires (Short Form-36 [SF-36], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI-SHP]) were administered to subjects receiving SOF and ribavirin (RBV; FUSION trial, N=201, 34% cirrhosis; VALENCE trial: N=333, 21% cirrhosis) and SOF, RBV, and pegylated interferon (Peg-IFN; NEUTRINO trial: N=327, 17% cirrhosis). HCV patients with cirrhosis showed significant impairment of PROs before initiation of treatment. During treatment, patients with cirrhosis treated with the IFN-free regimen experienced moderate decline in their PRO scores (0.6%-5.2% on a normalized scale of the summary scores; all P>0.02). In contrast, patients with cirrhosis treated with IFN-containing regimen showed decline in PRO scores that ranged from 3.4% to 16.0% (all P<0.005). Nevertheless, by follow-up week 12, no PRO decrement from baseline was observed in patients with cirrhosis regardless of the treatment regimen. Furthermore, in patients with cirrhosis with HCV who achieved sustained virological response at 12 weeks (SVR-12), some improvement in PROs from baseline was observed. During treatment, changes in PRO scores were similar between patients with and without cirrhosis for both treatment regimens (all P>0.05). Independent predictors of lower PROs in patients with cirrhosis included baseline depression, anxiety, fatigue, high HCV viral load, female gender, and receiving IFN-containing treatment. CONCLUSIONS: Treatment with SOF+RBV with or without Peg-IFN is tolerated by HCV patients with and without cirrhosis in terms of their PRO scores. After achieving SVR-12 with the IFN-free regimen, patients with cirrhosis showed improvement in some aspects of their PROs.",0
5057,24711282,Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism,"Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. Moreover, the Na+-taurocholate cotransporting polypeptide (NTCP), responsible for bile acid (BA) uptake into hepatocytes, was identified as the functional cellular receptor mediating HBV entry. The aim of the study was to determine whether HBV alters the liver metabolic profile by employing HBV-infected and uninfected human liver chimeric mice. Humanized urokinase plasminogen activator/severe combined immunodeficiency mice were used to establish chronic HBV infection. Gene expression profiles were determined by real-time polymerase chain reaction using primers specifically recognizing transcripts of either human or murine origin. Liver biopsy samples obtained from HBV-chronic individuals were used to validate changes determined in mice. Besides modest changes in lipid metabolism, HBV-infected mice displayed a significant enhancement of human cholesterol 7?-hydroxylase (human [h]CYP7A1; median 12-fold induction; P<0.0001), the rate-limiting enzyme promoting the conversion of cholesterol to BAs, and of genes involved in transcriptional regulation, biosynthesis, and uptake of cholesterol (human sterol-regulatory element-binding protein 2, human 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and human low-density lipoprotein receptor), compared to uninfected controls. Significant hCYP7A1 induction and reduction of human small heterodimer partner, the corepressor of hCYP7A1 transcription, was also confirmed in liver biopsies from HBV-infected patients. Notably, administration of Myrcludex-B, an entry inhibitor derived from the pre-S1 domain of the HBV envelope, provoked a comparable murine CYP7A1 induction in uninfected mice, thus designating the pre-S1 domain as the viral component triggering such metabolic alterations. CONCLUSION: Binding of HBV to NTCP limits its function, thus promoting compensatory BA synthesis and cholesterol provision. The intimate link determined between HBV and liver metabolism underlines the importance to exploit further metabolic pathways, as well as possible NTCP-related viral-drug interactions.",0
5058,24716661,"Glycosylation, hypogammaglobulinemia, and resistance to viral infections","Genetic defects in MOGS, the gene encoding mannosyl-oligosaccharide glucosidase (the first enzyme in the processing pathway of N-linked oligosaccharide), cause the rare congenital disorder of glycosylation type IIb (CDG-IIb), also known as MOGS-CDG. MOGS is expressed in the endoplasmic reticulum and is involved in the trimming of N-glycans. We evaluated two siblings with CDG-IIb who presented with multiple neurologic complications and a paradoxical immunologic phenotype characterized by severe hypogammaglobulinemia but limited clinical evidence of an infectious diathesis. A shortened immunoglobulin half-life was determined to be the mechanism underlying the hypogammaglobulinemia. Impaired viral replication and cellular entry may explain a decreased susceptibility to infections.",0
5059,24756990,Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue,"""Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bethigh IFN-?- """"T-helper (Th)1-suppressing"""" phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-?; T-bet+IFN-?+), thus becoming """"Th1-like"""" cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-?, ultimately leading to complete,?full Th1-like Treg differentiation. CONCLUSION: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ.""",0
5060,24771613,Incorporation of primary patient-derived glycoproteins into authentic infectious hepatitis C virus particles,"The Japanese fulminant hepatitis-1 (JFH1)-based hepatitis C virus (HCV) infection system has permitted analysis of the complete viral replication cycle in vitro. However, lack of robust infection systems for primary, patient-derived isolates limits systematic functional studies of viral intrahost variation and vaccine development. Therefore, we aimed at developing cell culture models for incorporation of primary patient-derived glycoproteins into infectious HCV particles for in-depth mechanistic studies of envelope gene function. To this end, we first constructed a packaging cell line expressing core, p7, and NS2 based on the highly infectious Jc1 genotype (GT) 2a chimeric genome. We show that this packaging cell line can be transfected with HCV replicons encoding cognate Jc1-derived glycoprotein genes for production of single-round infectious particles by way of trans-complementation. Testing replicons expressing representative envelope protein genes from all major HCV genotypes, we observed that virus production occurred in a genotype- and isolate-dependent fashion. Importantly, primary GT 2 patient-derived glycoproteins were efficiently incorporated into infectious particles. Moreover, replacement of J6 (GT 2a) core, p7, and NS2 with GT 1a-derived H77 proteins allowed production of infectious HCV particles with GT 1 patient-derived glycoproteins. Notably, adaptive mutations known to enhance virus production from GT 1a-2a chimeric genomes further increased virus release. Finally, virus particles with primary patient-derived E1-E2 proteins possessed biophysical properties comparable to Jc1 HCVcc particles, used CD81 for cell entry, were associated with ApoE and could be neutralized by immune sera. CONCLUSION: This work describes cell culture systems for production of infectious HCV particles with primary envelope protein genes from GT 1 and GT 2-infected patients, thus opening up new opportunities to dissect envelope gene function in an individualized fashion.",0
5061,24844924,Etanercept blocks inflammatory responses orchestrated by TNF-? to promote transplanted cell engraftment and proliferation in rat liver,"Engraftment of transplanted cells is critical for liver-directed cell therapy, but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells (KCs). To define whether tumor necrosis factor alpha (TNF-?) served roles in cell-transplantation-induced hepatic inflammation, we used the TNF-? antagonist, etanercept (ETN), for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas ETN before cell transplantation essentially normalized these responses. Moreover, ETN down-regulated cell-transplantation-induced intrahepatic release of secretory cytokines, such as high-mobility group box 1. These effects of ETN decreased cell-transplantation-induced activation of neutrophils, but not of KCs. Transplanted cell engraftment improved by several-fold in ETN-treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with ETN before multiple cell transplantation sessions. Transplanted cell numbers did not change over time, indicating absence of cell proliferation after ETN alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after ETN pretreatment significantly accelerated liver repopulation, compared to control rats. CONCLUSION: TNF-? plays a major role in orchestrating cell-transplantation-induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. Because TNF-? antagonism by ETN decreased transplanted cell clearance, improved cell engraftment, and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy.",0
5062,24896817,Evidence for camel-to-human transmission of MERS coronavirus,"We describe the isolation and sequencing of Middle East respiratory syndrome coronavirus (MERS-CoV) obtained from a dromedary camel and from a patient who died of laboratory-confirmed MERS-CoV infection after close contact with camels that had rhinorrhea. Nasal swabs collected from the patient and from one of his nine camels were positive for MERS-CoV RNA. In addition, MERS-CoV was isolated from the patient and the camel. The full genome sequences of the two isolates were identical. Serologic data indicated that MERS-CoV was circulating in the camels but not in the patient before the human infection occurred. These data suggest that this fatal case of human MERS-CoV infection was transmitted through close contact with an infected camel.",0
5063,24912841,TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk,"Overactivation of innate immunity, particularly natural killer (NK) cells, is harmful to liver regeneration; however, the molecular mechanisms that limit NK cell overactivation during liver regeneration are still elusive. Here we show that a coinhibitory receptor, T cell Ig and ITIM domain (TIGIT), was selectively up-regulated on NK cells, along with high expression of its ligand, poliovirus receptor (PVR/CD155), on hepatocytes during liver regeneration. The absence of TIGIT impaired liver regeneration in vivo, along with overactivation of NK cells and higher NK-derived interferon-gamma (IFN-?) production. We also show that both depletion of NK cells and deficiency of IFN-?, but not deficiency of RAG1, rescued impaired liver regeneration caused by the absence of TIGIT. Adoptive transfer of Tigit(-/-) NK cells into NK-deficient Nfil3(-/-) mice sufficiently led to impairment of liver regeneration. On the other hand, silencing PVR in hepatocytes rescued impaired liver regeneration caused by TIGIT deficiency in vivo, while blockade of TIGIT in NK-hepatocyte coculture increased IFN-? production by NK cells in vitro. CONCLUSION: TIGIT is a safeguard molecule to improve liver regeneration through negatively regulating NK-hepatocyte crosstalk. This finding suggests a novel mechanism of NK cell self-tolerance towards regenerative hyperplasia of the host.",0
5064,24917558,Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors,"Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-?) stimulation, hepatic stellate cells (HSCs), which are liver-specific pericytes, transdifferentiate into tumor-associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated the TGF-?-mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up-regulation of VASP and alpha-smooth muscle actin (?-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-?-mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF-? receptor II (T?RII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of T?RII to the plasma membrane, thereby desensitizing HSCs to TGF-?1 stimulation. CONCLUSIONS: Our study demonstrates a requirement of VASP for TGF-?-mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of T?RII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver.",0
5065,24918394,Videos in clinical medicine. Insertion of an intraosseous needle in adults,"Intraosseous needle insertion is used as a temporary measure when intravascular access cannot be achieved through peripheral or central venous routes. The intraosseous needle may remain in situ for 72 to 96 hours, but it is best removed within 6 to 12 hours, as soon as an alternative site of intravascular access has been established. The intraosseous route provides fast and reliable vascular access in emergency medical situations. The use of the appropriate technique will ensure that the procedure is performed as safely and effectively as possible.",0
5066,24931572,Outpatient glycemic control with a bionic pancreas in type 1 diabetes,"""BACKGROUND: The safety and effectiveness of automated glycemic management have not been tested in multiday studies under unrestricted outpatient conditions. METHODS: In two random-order, crossover studies with similar but distinct designs, we compared glycemic control with a wearable, bihormonal, automated, """"bionic"""" pancreas (bionic-pancreas period) with glycemic control with an insulin pump (control period) for 5 days in 20 adults and 32 adolescents with type 1 diabetes mellitus. The automatically adaptive algorithm of the bionic pancreas received data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. RESULTS: Among the adults, the mean plasma glucose level over the 5-day bionic-pancreas period was 138 mg per deciliter (7.7 mmol per liter), and the mean percentage of time with a low glucose level (<70 mg per deciliter [3.9 mmol per liter]) was 4.8%. After 1 day of automatic adaptation by the bionic pancreas, the mean (�SD) glucose level on continuous monitoring was lower than the mean level during the control period (133�13 vs. 159�30 mg per deciliter [7.4�0.7 vs. 8.8�1.7 mmol per liter], P<0.001) and the percentage of time with a low glucose reading was lower (4.1% vs. 7.3%, P=0.01). Among the adolescents, the mean plasma glucose level was also lower during the bionic-pancreas period than during the control period (138�18 vs. 157�27 mg per deciliter [7.7�1.0 vs. 8.7�1.5 mmol per liter], P=0.004), but the percentage of time with a low plasma glucose reading was similar during the two periods (6.1% and 7.6%, respectively; P=0.23). The mean frequency of interventions for hypoglycemia among the adolescents was lower during the bionic-pancreas period than during the control period (one per 1.6 days vs. one per 0.8 days, P<0.001). CONCLUSIONS: As compared with an insulin pump, a wearable, automated, bihormonal, bionic pancreas improved mean glycemic levels, with less frequent hypoglycemic episodes, among both adults and adolescents with type 1 diabetes mellitus. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01762059 and NCT01833988.).""",0
5067,24979722,Reductive nitrosylation of the cardiolipin-ferric cytochrome c complex,"Native horse heart cytochrome c (cytc) displays a very low reactivity toward ligands and does not exhibit catalytic properties. However, upon bovine cardiolipin (CL) binding, cytc achieves myoglobin-like properties. Here, NO binding to CL-cytc(III) between pH 7.2 and 9.5, at 20 °C, is reported. At pH 7.2, CL-cytc(III) undergoes reversible nitrosylation, whereas between pH 7.9 and 9.5 CL-cytc(III) undergoes irreversible reductive nitrosylation leading to the formation of CL-cytc(II)-NO. Over the whole pH range explored, first-order kinetics of NO binding to CL-cytc(III) (k = 9.3 s(-1) ) indicates that ligand binding is limited by the cleavage of the weak heme-Fe distal bond. Between pH 7.9 and 9.5, nitrosylated CL-cytc(III) converts to the ligand-free ferrous derivative (CL-cytc(II)), this process being pH-dependent (hOH-  = 3.0 × 10(3) M(-1) s(-1) ). Then, CL-cytc(II) converts to nitrosylated CL-cytc(II), in the presence of NO excess. The value of the second-order rate constant for CL-cytc(II) nitrosylation is essentially pH-independent, the average value of lon being 1.4 × 10(7) M(-1) s(-1) . These results agree with the view that CL-cytc nitrosylation may play a role in apoptosis regulation. ",0
5068,24979879,Clinical cytology: why and how?],"Clinical cytology is a morphological diagnostic profession, which has not been properly utilized in current medicine, primarily due to inadequate awareness among physicians of its diagnostic possibilities and advantages. The purpose of this historical review of clinical cytology and its diagnostic role is to contribute to higher awareness of the current possibilities offered by cytologic diagnosis and its future development in the era of technological progress and medical striking into profitability, with its negative connotations. The main features of cytologic diagnosis, i.e. non-aggressiveness, simplicity, promptness and accuracy, should be maintained while following new technological possibilities. Standard cytomorphology provides a basis for deciding on using additional technologies (cytochemistry, immunocytochemistry, flow cytometry, molecular analysis and cytogenetics) after thorough microscopic analysis, on cytologic samples or/and cytologic smears. The conditio sine qua non for that purpose is appropriate education of cytologists and cytotechnologists as well as appropriate organization of cytology in the healthcare system. As in the historical development of clinical cytology, enthusiasts are necessary to maintain and even improve all its possibilities to the benefit of our patients. ",0
5069,24979947,Identification of mycobacteria by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry--using reference strains and clinical isolates of Mycobacterium],"Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) method is being played an important role for the inspection of clinical microorganism as a rapid and the price reduction. Mass spectra obtained by measuring become points of identification whether the peak pattern match any species mass spectral pattern. We currently use MALDI-TOF MS for rapid and accurate diagnosis of inactivated reference and clinical isolates of Mycobacterium because of the improved pretreatment techniques compared with former inspection methods that pose a higher risk of infection to the operator. The identification matching rate of score value (SV) peak pattern spectra was compared with that of conventional methods such as strain diffusion/amplification. Also, cultures were examined after a fixed number of days. Compared with the initial inspection technique, the pretreatment stage of current MALDI-TOF MS inspection techniques can improve the analysis of inactivated acid-fast bacteria that are often used as inspection criteria strains of clinical isolates. Next, we compared the concordance rate for identification between MALDI-TOF MS and conventional methods such as diffusion/amplification by comparison of peak pattern spectra and evaluated SV spectra to identify differences in the culture media after the retention period. In examination of 158 strains of clinical isolated Mycobacterium tuberculosis complex (MTC), the identification coincidence rate in the genus level in a matching pattern was 99.4%, when the species level was included 94.9%. About 37 strains of nontuberculous mycobacteria (NTM), the identification coincidence rate in the genus level was 94.6%. M. bovis BCG (Tokyo strain) in the reference strain was judged by the matching pattern to be MTC, and it suggested that they are M. tuberculosis and affinity species with high DNA homology. Nontuberculous mycobacterial M. gordonae strain JATA 33-01 shared peak pattern spectra, excluding the isolates, with each clinically isolated strain. However, the mass spectra of six M. gordonae clinical isolates suggested polymorphisms with similar mass-to-charge ratios compared with those of the reference strains. The peak pattern spectra of the clinical isolates and reference strains, excluding the NTM M. gordonae strain JATA33-01, were consistent with the peak pattern characteristics of each isolate. However, a comparison between the peak patterns of the reference strains and those of the six clinically isolated M. gordonae strains revealed a similar mass-to-charge ratio, which may indicate few polymorphisms. The SV spectrum of the improved inspection technique showed no fidelity, but it was acceptable after days of culture as indicated by the decrease in SV (0.3 degree). Also, the reproducibility of this method was good, but no difference was observed from the SV of the improved inspection technique, which decreased by approximately 0.3 because of the number of days of culture storage. In addition, expansion of the database and dissemination of regional specificity by genotype analysis of clinical isolates was relevant to the accumulated data, as expected. In future studies, the relevance and regional specificity of clinical isolates by genotype analysis can be determined by stacking the solid media and database penetration. ",0
5070,24980221,"Optimization of paclitaxel-loaded poly (d,l-lactide-co-glycolide-N-p-maleimido benzoic hydrazide) nanoparticles size using artificial neural networks","The aim of this study was to find a model using artificial neural networks (ANNs) to predict PLGA-PMBH nanoparticles (NPs) size in preparation by modified nanoprecipitation. The input variables were polymer content, drug content, power of sonication and ratio of organic/aqueous phase (i.e. acetone/water), while the NPs size of PLGA-PMBH was assumed as the output variable. Forty samples of PLGA-PMBH NPs containing anticancer drug (i.e. paclitaxel) were synthesized by changing the variable factors in the experiments. The data modeling were performed using ANNs. The effects of input variables (namely, polymer content, drug content, power of sonication and ratio of acetone/water) on the output variables were evaluated using the 3D graphs obtained after modeling. Contrasting the 3D graphs from the generated model revealed that the amount of polymer (PLGA-PMBH) and drug content (PTX) have direct relation with the size of polymeric NPs in the process. In addition, it was illustrated that the ratio of acetone/water was the most important factor affecting the particle size of PLGA-PMBH NPs provided by solvent evaporation technique. Also, it was found that increasing the sonication power (up to a certain amount) indirectly affects the polymeric NPs size however it was directly affected in higher values. ",0
5071,24980778,Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor α and CD86,"Limiting the severity of inflammation and promoting its eventual resolution are vital for protecting host tissues both in autoimmunity and chronic infection. The aim of this study was to determine the suitability of repurposing anti-CD3 monoclonal antibody (mAb) therapy for rheumatoid arthritis (RA) by analyzing its ability to induce CD8+FoxP3+ Treg cells from peripheral blood mononuclear cells (PBMCs). Anti-CD3 mAb was cultured with RA PBMCs to induce CD8+FoxP3+ Treg cells, which were analyzed by flow cytometry to determine their phenotype. Treg cell induction was investigated via neutralization or blocking antibodies, cellular depletion, or ImageStream technology. Blotting was used to determine the signaling pathways involved in CD8+FoxP3+ Treg cell induction. Suppression of CD4+ T cell effector responses was assessed by Treg cell suppression assays and Mosaic enzyme-linked immunosorbent assay. Potent CD8+FoxP3+ Treg cells were induced from RA PBMCs by anti-CD3 mAb. Unlike their CD4+ counterparts, CD8+FoxP3+ Treg cells inhibited Th17 responses in a contact-dependent manner, thereby functioning to limit a wider range of inflammatory pathways. CD8+FoxP3+ Treg cell induction was supported both by p38 phosphorylation intrinsic to naive CD8+ T cells and by monocytes via CD86 and membrane tumor necrosis factor α (TNFα). Artificially increasing monocyte membrane TNFα or inhibiting CD8+ T cell p38 phosphorylation drove FoxP3 expression in a subset of initially unresponsive CD8+ T cells. These data define an unknown mechanism of CD8+FoxP3+ Treg cell induction by anti-CD3 mAb, which could be combined with a p38 inhibitor to improve therapeutic efficacy in RA patients and resolve chronic inflammation via the restoration of tolerance. ",0
5072,24981482,Systematic review of minimally invasive ablation treatment for locally advanced pancreatic cancer,"Unresectable locally advanced pancreatic cancer with or without metastatic disease is associated with a very poor prognosis. Ablation techniques are based on direct application of chemical, thermal, or electrical energy to a tumor, which leads to cellular necrosis. Initial studies about ablation therapies of the pancreas were associated with significant morbidity and mortality, which limited widespread adoption. Modifications to the various applications, in particular combining the techniques with high-quality imaging and intra-operative approach has enabled real-time treatment monitoring and significant improvements in safety. Inoperable cases of pancreatic cancer have been treated by various ablation techniques in the last few years with promising results. The purpose of this review is to present the current status of local ablative therapies in the treatment of pancreatic advanced tumor.  ",0
5073,24981930,Relationships between PON1 Q192R polymorphism and clinical outcome of antiplatelet treatment after percutaneous coronary intervention: a meta-analysis,"This meta-analysis was performed to assess the relationships between the PON1 Q192R (rs662 T>C) polymorphism and the clinical outcome of antiplatelet treatment after percutaneous coronary intervention (PCI). A range of electronic databases were searched: Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013) and the Chinese Biomedical Database (CBM) (1982-2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Six clinical cohort studies with a total number of 5,189 patients undergoing PCI for coronary heart disease were included. Our meta-analysis revealed that the PON1 Q192R polymorphism was correlated with an increased risk of major adverse cardiovascular events (MACE) in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.22, 95 % CI 1.04-1.43, P = 0.014; CT+CC vs. TT: OR = 1.38, 95 % CI 1.03-1.86, P = 0.029; CC vs. TT: OR = 1.45, 95 % CI 1.05-1.99, P = 0.024; respectively), especially among Asians. Furthermore, we found significantly positive correlations between the PON1 Q192R polymorphism and the incidence of stent thrombosis in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.42, 95 % CI 1.08-1.87, P = 0.011; CT+CC vs. TT: OR = 1.93, 95 % CI 1.01-3.67, P = 0.046; CC vs. TT: OR = 2.18, 95 % CI 1.09-4.35, P = 0.027; respectively). Our meta-analysis of clinical cohort studies provides evidence that the PON1 Q192R polymorphism may increase the risk of MACE and stent thrombosis in patients receiving antiplatelet treatment after PCI. ",0
5074,24982116,Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy,"The relevance of the dissociation of circulating pentameric C-reactive protein (pCRP) to its monomeric subunits (mCRP) is poorly understood. We investigated the role of conformational C-reactive protein changes in vivo. We identified mCRP in inflamed human striated muscle, human atherosclerotic plaque, and infarcted myocardium (rat and human) and its colocalization with inflammatory cells, which suggests a general causal role of mCRP in inflammation. This was confirmed in rat intravital microscopy of lipopolysaccharide-induced cremasteric muscle inflammation. Intravenous pCRP administration significantly enhanced leukocyte rolling, adhesion, and transmigration via localized dissociation to mCRP in inflamed but not noninflamed cremaster muscle. This was confirmed in a rat model of myocardial infarction. Mechanistically, this process was dependent on exposure of lysophosphatidylcholine on activated cell membranes, which is generated after phospholipase A2 activation. These membrane changes could be visualized intravitally on endothelial cells, as could the colocalized mCRP generation. Blocking of phospholipase A2 abrogated C-reactive protein dissociation and thereby blunted the proinflammatory effects of C-reactive protein. Identifying the dissociation process as a therapeutic target, we stabilized pCRP using 1,6-bis(phosphocholine)-hexane, which prevented dissociation in vitro and in vivo and consequently inhibited the generation and proinflammatory activity of mCRP; notably, it also inhibited mCRP deposition and inflammation in rat myocardial infarction. These results provide in vivo evidence for a novel mechanism that localizes and aggravates inflammation via phospholipase A2-dependent dissociation of circulating pCRP to mCRP. mCRP is proposed as a pathogenic factor in atherosclerosis and myocardial infarction. Most importantly, the inhibition of pCRP dissociation represents a promising, novel anti-inflammatory therapeutic strategy. ",0
5075,24982148,Structures of benzylsuccinate synthase elucidate roles of accessory subunits in glycyl radical enzyme activation and activity,"Anaerobic degradation of the environmental pollutant toluene is initiated by the glycyl radical enzyme benzylsuccinate synthase (BSS), which catalyzes the radical addition of toluene to fumarate, forming benzylsuccinate. We have determined crystal structures of the catalytic α-subunit of BSS with its accessory subunits β and γ, which both bind a [4Fe-4S] cluster and are essential for BSS activity in vivo. We find that BSSα has the common glycyl radical enzyme fold, a 10-stranded β/α-barrel that surrounds the glycyl radical cofactor and active site. Both accessory subunits β and γ display folds related to high potential iron-sulfur proteins but differ substantially from each other in how they interact with the α-subunit. BSSγ binds distally to the active site, burying a hydrophobic region of BSSα, whereas BSSβ binds to a hydrophilic surface of BSSα that is proximal to the active site. To further investigate the function of BSSβ, we determined the structure of a BSSαγ complex. Remarkably, we find that the barrel partially opens, allowing the C-terminal region of BSSα that houses the glycyl radical to shift within the barrel toward an exit pathway. The structural changes that we observe in the BSSαγ complex center around the crucial glycyl radical domain, thus suggesting a role for BSSβ in modulating the conformational dynamics required for enzyme activity. Accompanying proteolysis experiments support these structural observations.  ",0
5076,24982578,Myeloid sarcoma as the presenting symptom of chronic myelogenous leukemia blast crisis,"Myeloid sarcoma is an extramedullary tumor composed of immature myeloid cells that efface the underlying tissue architecture. It is usually associated with acute myelogenous leukemia, but can be associated with myeloproliferative neoplasms, myelodysplastic disorders, or myeloproliferative/ myelodysplastic syndromes. If it is unrecognized, appropriate chemotherapy may be delayed and survival jeopardized. We present a case of a myeloid sarcoma presenting in an otherwise asymptomatic patient who ultimately was found to have chronic myelogenous leukemia, presenting in blast crisis. We also review the distinct clinical and pathologic features of myeloid sarcoma, as well as treatment of the disease.  ",0
5077,24982780,Effectiveness of combined high-dosed trospium and solifenacin depending on severity of OAB symptoms in elderly men and women under cyclic therapy,"313 patients, 196 women and 117 men over 65 (average age 68.6) were included in this study. All patients underwent urodynamic examination before enrollment and after the study was completed. For clinical evaluation of LUT state ICIQ-SF questionnaires and bladder diaries were used. Patients with moderate (А, n = 155) and severe (В, n = 158) symptoms of OAB. Each group was divided into subgroups in which patients received Trospium 60 mg/day and Solifenacin 20 mg/day during two cycles - 1.5 and 1 month with one month interval (А1 and В1); subgroups in which second cycle was substituted with placebo (А2, В2), and control groups (А3, В3). In groups with moderate symptoms of OAB ratio of patients demonstrated decrease of frequency of EI ≥1.5 a day remained at the level of 45-60% during all observation period. In subgroups with severe symptoms of OAB percentage of such patients was 55.3% for the subgroup which received two cycle therapy, and decreased to 26% in the subgroup which underwent 1 cycle therapy. Urodynamic indices for state of LUT correlated with clinical indicators (r =0.57-0.71 at p≤ 0.05). Short single cycle of high-dosed Solifenacin and Trospium in elderly patients with moderate symptoms of OAB enables to maintain long therapeutic effect with acceptable level of side effects. This treatment algorithm applied in two cycle course is an effective and safe method for management of severe symptoms of OAB in elderly patients without increased risk of side effects. ",0
5078,24982837,Evaluation of a real-time PCR assay for simultaneous detection of Kingella kingae and Staphylococcus aureus from synovial fluid in suspected septic arthritis,"Direct plating of synovial fluid (SF) on agar-based media often fails to identify pathogens in septic arthritis (SA). We developed a PCR assay for the simultaneous detection of Kingella kingae and Staphylococcus aureus from SF to evaluate molecular detection in SF and to estimate the incidence of K. kingae in SA in North America. The assay was based on detection of the cpn60 gene of K. kingae and the spa gene of S. aureus in multiplex real-time PCR. K. kingae was identified in 50% of patients between 0 and 5 yr of age (n=6) but not in any patients >18 yr old (n=105). Direct plating of SF on agar-based media failed to detect K. kingae in all samples. The PCR assay was inferior to the culture-based method for S. aureus, detecting only 50% of culture-positive cases. Our findings suggest that K. kingae is a common pathogen in pediatric SA in North America, in agreement with previous reports from Europe. PCR-based assays for the detection of K. kingae may be considered in children with SA, especially in those with a high degree of clinical suspicion.  ",0
5079,24983145,Pharmacologically and Edinger-Westphal stimulated accommodation in rhesus monkeys does not rely on changes in anterior chamber pressure,"This study was undertaken to understand the role of anterior chamber pressure (ACP) during pharmacological and Edinger-Westphal (EW) stimulated accommodation in anesthetized monkeys. Experiments were performed on one iridectomized eye each of 7 anesthetized adolescent rhesus monkeys. Accommodation was induced by EW stimulation (n = 2) and intravenous administration of 0.25-4.0 mg/kg pilocarpine (n = 6). Accommodative refractive and biometric changes were measured with continuous 60 Hz infrared photorefraction (n = 6) and 100 Hz A-scan ultrasound biometry (n = 1). An ocular perfusion system was used to measure and manipulate ACP. Pressure was recorded via a 27-gauge needle in the anterior chamber connected to a pressure transducer (n = 7). The needle was also connected to a fluid reservoir to allow ACP to be manipulated and clamped (n = 4) by raising or lowering the fluid reservoir. In all six pharmacologically stimulated monkeys ACP increased during accommodation, from 0.70 to 2.38 mmHg, four of which showed pressure decreases preceding the pressure increases. Two eyes also showed increases in ACP during EW-stimulated accommodation of 2.8 and 7.2 mmHg. ACP increased with increasing EW stimulus amplitudes (n = 2). Clamping or externally manipulating ACP had no effect on resting refraction or on EW and pharmacologically stimulated accommodation in four eyes. The results show that EW stimulated and pharmacologically stimulated accommodation do not rely on ACP in rhesus monkeys.  ",0
5080,24983416,Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor,"On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki=5 μM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity. ",0
5081,24983693,"Nanofiltration, bipolar electrodialysis and reactive extraction hybrid system for separation of fumaric acid from fermentation broth","A novel approach based on a hybrid system allowing nanofiltration, bipolar electrodialysis and reactive extraction, was proposed to remove fumaric acid from fermentation broth left after bioconversion of glycerol. The fumaric salts can be concentrated in the nanofiltration process to a high yield (80-95% depending on pressure), fumaric acid can be selectively separated from other fermentation components, as well as sodium fumarate can be conversed into the acid form in bipolar electrodialysis process (stack consists of bipolar and anion-exchange membranes). Reactive extraction with quaternary ammonium chloride (Aliquat 336) or alkylphosphine oxides (Cyanex 923) solutions (yield between 60% and 98%) was applied as the final step for fumaric acid recovery from aqueous streams after the membrane techniques. The hybrid system permitting nanofiltration, bipolar electrodialysis and reactive extraction was found effective for recovery of fumaric acid from the fermentation broth.  ",0
5082,24983810,Molecular and in vitro Toxicology at the FHNW,"In the recently established Molecular Toxicology laboratory at the Institute for Chemistry and Bioanalytics of the School of Life Sciences in the FHNW, we aim to develop and apply in vitro models for the investigation of toxic effects, with a primary focus on liver and kidney. In collaboration with other institutions, we are developing multicellular type 2D and 3D cell culture assays to be able to closely mimic relevant in vivo situations. In parallel we are broadening the choice of available endpoint analyses.  ",0
5083,24983839,Electrocardiographic differences between COPD patients evaluated for lung transplantation with and without pulmonary hypertension,"Pulmonary hypertension (PH) is an indicator of poor prognosis in COPD patients; particularly in those with mean pulmonary artery pressure ≥ 40 mm Hg. Electrocardiography (ECG) might be useful for screening of this condition. Retrospective study of COPD patients evaluated for lung transplantation in whom we analyzed the 12-lead ECG performed closest to the time of right heart catheterization. We included 142 patients. PH was present in 90 patients (63%) and 16 (11%) had a mean PAP ≥ 40 mmHg. The PR interval was longer in PH patients (151 (29) versus 139 (22) ms, p = 0.01) and T wave axis had a left shift (56.9 (32) versus 68.7 (19) degrees, p = 0.006). PR interval was longer (178.5 (35) versus 142.2 (23) ms, p = 0.001), T wave axis had a leftward deflection (63.6 (24) versus 42.8 (46) degrees, p = 0.005) and S wave in lead I was larger (0.19 (0.13) versus 0.12 (0.12) mV, p = 0.03) in patients with mean PAP ≥ 40 mmHg. A PR interval > 137 ms and S wave in DI > 0.02 mV had a sensitivity of 100% and a specificity of 59.5% to identify COPD patients with a mean PAP ≥ 40 mmHg. There are significant ECG differences between advanced COPD patients with and without PH; however the ECG is an inadequate tool to differentiate between the groups. A prolonged PR interval suggests the presence of severe PH. ",0
5084,24984612,Reproducibility of area at risk assessment in acute myocardial infarction by T1- and T2-mapping sequences in cardiac magnetic resonance imaging in comparison to Tc99m-sestamibi SPECT,"""Area at risk (AAR) is an important parameter for the assessment of the salvage area after revascularization in acute myocardial infarction (AMI). By combining AAR assessment by T2-weighted imaging and scar quantification by late gadolinium enhancement imaging cardiovascular magnetic resonance (CMR) offers a promising alternative to the """"classical"""" modality of Tc99m-sestamibi single photon emission tomography (SPECT). Current T2 weighted sequences for edema imaging in CMR are limited by low contrast to noise ratios and motion artifacts. During the last years novel CMR imaging techniques for quantification of acute myocardial injury, particularly the T1-mapping and T2-mapping, have attracted rising attention. But no direct comparison between the different sequences in the setting of AMI or a validation against SPECT has been reported so far. We analyzed 14 patients undergoing primary coronary revascularization in AMI in whom both a pre-intervention Tc99m-sestamibi-SPECT and CMR imaging at a median of 3.4 (interquartile range 3.3-3.6) days after the acute event were performed. Size of AAR was measured by three different non-contrast CMR techniques on corresponding short axis slices: T2-weighted, fat-suppressed turbospin echo sequence (TSE), T2-mapping from T2-prepared balanced steady state free precession sequences (T2-MAP) and T1-mapping from modified look locker inversion recovery (MOLLI) sequences. For each CMR sequence, the AAR was quantified by appropriate methods (absolute values for mapping sequences, comparison with remote myocardium for other sequences) and correlated with Tc99m-sestamibi-SPECT. All measurements were performed on a 1.5 Tesla scanner. The size of the AAR assessed by CMR was 28.7 ± 20.9 % of left ventricular myocardial volume (%LV) for TSE, 45.8 ± 16.6 %LV for T2-MAP, and 40.1 ± 14.4 %LV for MOLLI. AAR assessed by SPECT measured 41.6 ± 20.7 %LV. Correlation analysis revealed best correlation with SPECT for T2-MAP at a T2-threshold of 60 ms (ms) (slope = 0.99, Pearson's r = 0.94), and for MOLLI at T1-threshold of 1,075 ms (slope 0.86, r = 0.91, Pearson's r = 0.45). For the assessment of AAR in AMI, the novel T2-mapping technique correlates best with SPECT size, T1-mapping with MOLLI and standard T2-weighted imaging showed similar good correlations. """,0
5085,24984621,"Multiple, multifocal odontogenic keratocysts in non-syndrome patient: a case-report","Occurrence of multiple odontogenic keratocyst involving the jaws is rare. When multiple, it is usually associated with a syndrome. Occurrence of multiple odontogenic keratocyst without syndromic association is extremely rare. Gorlin-Goltz syndrome which is also known as Nevoid Basal Cell Carcinoma Syndrome is a rare autosomal dominant disorder. Multiple Odontogenic Keratocysts (OKCs) are principle features of nevoid basal cell carcinoma syndrome (NBCCS; Gorlin-Goltz syndrome). However, a case of multiple odontogenic keratocysts unassociated with any syndrome is reported here so as to add to the growing number of such cases in the literature. The possibility of this case being a partial expression of the Gorlin-Goltz syndrome is discussed.  ",0
5086,24984657,A study on mast cell number and lipid profile in oral submucous fibrosis,"Prevention of oral precancer is most desirable and should take precedence over its diagnosis and therapy. As both, mast cell counts in connective tissue and serum lipids are altered in Oral Submucous Fibrosis (OSF), so study of both the factors is vitally important in OSF. A total of 50 persons were included in the study of which 40 were OSF patients and 10 controls. Tissue sections and blood samples were collected for mast cell count and lipid profile estimation for both OSF patients and controls. Mean mast cells in all grades of OSF were higher as compared to apparently normal appearing oral mucosa but as severity of OSF increases (from Grade II to Grade IV), count of Mast cell decreases. Further, the mean mast cells in OSF Grade II, III and IV groups were found 95.5%, 93.8% and 92.2% higher respectively as compared to normal (highly significant for all the groups p<0.001). The mean serum lipid profile of OSF groups was comparatively lower than age and sex matched healthy controls but was highly significant for all the groups (p<0.001). Thus, it can be said that in the present study serum lipid profile decreases in OSF patients and mast cell count is increased when compared with apparently normal appearing mucosa but with the advancement of the grades mast cell number decreases in tissue sections of OSF. It can be suggested that biochemical and histological assessment of OSF patients may help in earlier diagnosis and/or prognosis of this disease. ",0
5087,24985472,MicroRNA-146 inhibits thrombin-induced NF-κB activation and subsequent inflammatory responses in human retinal endothelial cells,"Nuclear factor-κB (NF-κB), a key regulator of immune and inflammatory responses, plays important roles in diabetes-induced microvascular complications including diabetic retinopathy (DR). Thrombin activates NF-κB through protease-activated receptor (PAR)-1, a member of the G-protein-coupled receptor (GPCR) superfamily, and contributes to DR. The current study is to uncover the roles of microRNA (miRNA) in thrombin-induced NF-κB activation and retinal endothelial functions. Target prediction was performed using the TargetScan algorithm. Predicted target was experimentally validated by luciferase reporter assays. Human retinal endothelial cells (HRECs) were transfected with miRNA mimics or antimiRs and treated with thrombin. Expression levels of miR-146 and related protein-coding genes were analyzed by quantitative (q)RT-PCR. Functional changes of HRECs were analyzed by leukocyte adhesion assays. We identified that caspase-recruitment domain (CARD)-containing protein 10 (CARD10), an essential scaffold/adaptor protein of GPCR-mediated NF-κB activation pathway, is a direct target of miR-146. Thrombin treatment resulted in NF-κB-dependent upregulation of miR-146 in HRECs; while transfection of miR-146 mimics resulted in significant downregulation of CARD10 and prevented thrombin-induced NF-κB activation, suggest that a negative feedback regulation of miR-146 on thrombin-induced NF-κB through targeting CARD10. Furthermore, overexpression of miR-146 prevented thrombin-induced increased leukocyte adhesion to HRECs. We uncovered a novel negative feedback regulatory mechanism on thrombin-induced GPCR-mediated NF-κB activation by miR-146. In combination with the negative feedback regulation of miR-146 on the IL-1R/toll-like receptor (TLR)-mediated NF-κB activation in RECs that we reported previously, our results underscore a pivotal, negative regulatory role of miR-146 on multiple NF-κB activation pathways and related inflammatory processes in DR. ",0
5088,24985696,Training maternal and child health epidemiologists: leaders for the twenty first century,"This paper reports on the structure, implementation and outcomes of the Maternal and Child Health (MCH) Epidemiology (MCHEPI) program at the University of Illinois School of Public Health (UIC-SPH) and discusses the successes and challenges in developing MCH Epidemiology leaders for the local, state, and national public health workforce. The MCHEPI program at UIC-SPH offers both the MPH and PhD degree and is based on six key components: integration across school divisions, competency-based training, tailored curricula, practica/dissertations with public health agencies, personal leadership training and development, and socialization. Based on data from the 1998-2012 cohorts, all former and current MCHEPI MPH students (n = 28) have participated in practica with local or state public health agencies and former and current MCHEPI doctoral students at the dissertation stage (12 out of 15) have partnered with local, state or national public health agencies in conducting their dissertations. The alumni of the MCHEPI MPH program (n = 25) appear to serve in higher level positions in their second compared to their first placements post-graduation. All MCHEPI doctoral alumni (n = 8) serve at the emerging senior level or senior scientist level upon graduation, in local, state and federal agencies, or in academe. Explicit linkage of MCHEPI students to practice through tailored curricula, practica, and dissertations with public health agencies, and the development of an identity as a member of the MCHEPI field appear to be important to the generation of epidemiology leaders for the MCH workforce. Leadership development is a lifelong process and as such, snapshots of current students and alumni at any one point in time do not provide the entire picture of the impact of MCH epidemiology training programs. Examining the trajectories of emerging leaders over time is essential for evaluating the true success of Maternal and Child Health Bureau workforce and training investments. ",0
5089,24985752,Hippocampal abnormalities in magnetic resonance imaging (MRI) of 15q duplication syndromes,"Patients with 15q duplication syndromes, including isodicentric chromosome 15 and interstitial duplications, usually present with autism spectrum disorder, intellectual disability, and frequently epilepsy. Neuroimaging studies in these patients are typically reported as normal, but nonspecific findings such as thinning of the corpus callosum and increased pericerebral spaces have been reported. A review of brain magnetic resonance imaging (MRI) studies of 11 individuals seen at the Massachusetts General Hospital Dup15q Center was performed. Hippocampus morphology was specifically reviewed, as a recent neuropathologic study has found frequent hippocampal heterotopias and dysplasias in these disorders. Two subjects had unilateral hippocampal sclerosis and 6 had bilateral hippocampal malformations. Hypoplasia of the corpus callosum was present in 2 subjects.  ",0
5090,24985996,Preclinical cardiovascular diseases and aortic stiffness],"To compare aortic stiffness (represented by aortic pulse wave velocity - PWVao) as a marker of cardiovascular risk with cardiovascular risk estimated by standard scoring systems in treated hypertensive patients. In a group of 41 hypertensive patients without clinical manifestation of cardiovascular disease (18 men/23 women, mean age 59 years) we investigated the presence of risk factors and preclinical cardiovascular diseases. To estimate cardiovascular risk we have used SCORE-HDL model and categorical risk stratification recommended by ESC/ESH. Linear regression was used for evaluation of relation between risk estimation scores and PWVao values. We have found out statistically significant relationship between PWVao and cardiovascular risk assessment systems in our group of patients. The correlation between PWVao and ESC/ESH risk stratification (r = 0.414, P < 0.01) was the most relevant, the correlation between PWVao and SCORE-HDL values was also significant (r = 0.315; P < 0.05). Increased aortic stiffness as one of the preclinical cardiovascular diseases can be an integrative marker of cardiovascular risk in patients with arterial hypertension. ",0
5091,24986165,"""""""We have become doctors for ourselves"""": motives for malaria self-care among adults in southeastern Tanzania""","Prompt and appropriate treatment of malaria with effective medicines remains necessary if malaria control goals are to be achieved. The theoretical concepts from self-care and the health belief model were used to examine the motivations for malaria self-care among the adult population. A qualitative study was conducted through eight focus group discussions with adult community members to explore their general opinions, views and perceptions of malaria and of its treatments. These groups were followed by 15 in-depth interviews of participants with a recent malaria experience to allow for an in-depth exploration of their self-care practices. The analysis followed principles of grounded theory and was conducted using Nvivo 9 qualitative data management software. The self-treatment of malaria at home was found to be a common practice among the study participants. The majority of the participants practiced self-medication with a painkiller as an initial response. The persistence and the worsening of the disease symptoms prompted participants to consider other self-care options. Perceptions that many malaria symptoms are suggestive of other conditions motivated participants to self-refer for malaria test. The accessibility of private laboratory facilities and drug shops motivated their use for malaria tests and for obtaining anti-malarial medicines, respectively. Self-treatment with anti-malarial monotherapy was common, motivated by their perceived effectiveness and availability. The perceived barriers to using the recommended combination treatment, artemether-lumefantrine, were related to the possible side-effects and to uncertainty about their effectiveness, and these doubts motivated some participants to consider self-medication with local herbs. Several factors were mentioned as motivating people for self-care practices. These included poor patient provider relationship, unavailability of medicine and the costs associated with accessing treatments from the health facilities. Malaria self-care and self-treatment with anti-malarial monotherapy are common among adults, and are motivated by both individual characteristics and the limitations of the existing health care facilities. There is a need for public health interventions to take into account community perceptions and cultural schemas on malaria self-care practices. ",0
5092,24986285,Physical activity as a clinical tool in the assessment of malnutrition,"To measure physical activity in children with wasting and to look for association between poor physical activity and wasting. Physical activity was measured in 56 children with wasting, using Childrens Activity Rating Scale, and compared with age- and sex-matched controls. A significant association was found between poor physical activity and malnutrition as determined by weight-for-height Z Score <-2 (P=0.001) and mid-upper-arm circumference (P=0.002). Physical activity can be used as clinical parameter to assess malnutrition. ",0
5093,24986342,DSM-5 and neurocognitive disorders,"The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduces several changes in the diagnostic criteria for dementia and other cognitive disorders. Some of these changes may prove helpful for clinical and forensic practitioners, particularly when evaluating less severe cognitive impairments. The most substantial change is that the cognitive disorder-not otherwise specified category found in prior editions has been eliminated. Those disorders that do not cause sufficient impairment to qualify for a diagnosis of dementia are now defined as neurocognitive disorders and placed on a spectrum with the more severe conditions. The concept of social cognition is also introduced as one of the core functional domains that can be affected by a neurocognitive disorder. This concept may be particularly significant in the evaluation of patients with non-Alzheimer's dementias, such as frontotemporal dementia. With the aging of the population and the increasing recognition of the possibility of long-lasting cognitive deficits after traumatic brain injury, the need for assessment of cognitive disorders in medicolegal contexts is certain to increase. Forensic psychiatrists who perform these evaluations should understand the conceptualization of Neurocognitive Disorders as presented in DSM-5 and how it differs from prior diagnostic systems.  ",0
5094,24986866,Umbilical cord mesenchymal stem cells suppress host rejection: the role of the glycocalyx,"Umbilical cord mesenchymal stem cells (UMSCs) have unique immunosuppressive properties enabling them to evade host rejection and making them valuable tools for cell therapy. We previously showed that human UMSCs survive xenograft transplantation and successfully correct the corneal clouding defects associated with the mouse model for the congenital metabolic disorder mucopolysaccharidosis VII. However, the precise mechanism by which UMSCs suppress the immune system remains elusive. This study aimed to determine the key components involved in the ability of the UMSCs to modulate the inflammatory system and to identify the inflammatory cells that are regulated by the UMSCs. Our results show that human UMSCs transplanted into the mouse stroma 24 h after an alkali burn suppress the severe inflammatory response and enable the recovery of corneal transparency within 2 weeks. Furthermore, we demonstrated in vitro that UMSCs inhibit the adhesion and invasion of inflammatory cells and also the polarization of M1 macrophages. UMSCs also induced the maturation of T-regulatory cells and led to inflammatory cell death. Moreover, UMSCs exposed to inflammatory cells synthesize a rich extracellular glycocalyx composed of the chondroitin sulfate-proteoglycan versican bound to a heavy chain (HC)-modified hyaluronan (HA) matrix (HC-HA). This matrix also contains TNFα-stimulated gene 6 (TSG6), the enzyme that transfers HCs to HA, and pentraxin-3, which further stabilizes the matrix. Our results, both in vivo and in vitro, show that this glycocalyx confers the ability for UMSCs to survive the host immune system and to regulate the inflammatory cells.  ",0
5095,24986988,A quality improvement study to improve inpatient problem list use,"The problem list is a meaningful use incentivized criterion, and >80% of patients should have 1 problem entered as structured data. The aim of the present study was to use a series of interventions to increase the use of the problem list for inpatients to >80% as measured by at least 1 hospital problem at discharge. This study was a quasi-experimental time series quality improvement trial. The primary outcome was 80% of medical and psychiatric inpatients with a problem added to the problem list before discharge. Control charts of percentage (p charts) of medical and psychiatric patients with an inpatient problem list at discharge were constructed with three-σ control limits. Control limits were revised after evidence of improvement. The charts were annotated with interventions, including increasing awareness, focused education, and timely feedback in the form of performance graphs e-mailed to providers. For medical inpatients, use rose from 31% to 97% at its peak in April 2011 and continues to maintain above the goal of 80%. In psychiatry, problem list use rose from 2% initially to an average of 72% after the interventions. Significant gains were made with inpatient problem list usage by the medical and psychiatric teams. Our goal ascribed by meaningful use for >80% of inpatients to have a problem at discharge was met after initiation of our series of interventions. ",0
5096,24987120,Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis,"""Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated """"parthanatos"""" in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD(+) and energetic collapse, which have been thought to be caused by the consumption of cellular NAD(+) by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD(+) depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD(+) depletion in N-methyl-N-nitroso-N-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1-mediated mitochondrial dysfunction. Depleting neurons of NAD(+) with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.  """,0
5097,24987169,Assessment methods for angiogenesis and current approaches for its quantification,"Angiogenesis is a physiological process which describes the development of new blood vessels from the existing vessels. It is a common and the most important process in the formation and development of blood vessels, so it is supportive in the healing of wounds and granulation of tissues. The different assays for the evaluation of angiogenesis have been described with distinct advantages and some limitations. In order to develop angiogenic and antiangiogenic techniques, continuous efforts have been resulted to give animal models for more quantitative analysis of angiogenesis. Most of the studies on angiogenic inducers and inhibitors rely on various models, both in vitro, in vivo and in ova, as indicators of efficacy. The angiogenesis assays are very much helpful to test efficacy of both pro- and anti- angiogenic agents. The development of non-invasive procedures for quantification of angiogenesis will facilitate this process significantly. The main objective of this review article is to focus on the novel and existing methods of angiogenesis and their quantification techniques. These findings will be helpful to establish the most convenient methods for the detection, quantification of angiogenesis and to develop a novel, well tolerated and cost effective anti-angiogenic treatment in the near future.  ",0
5098,24987529,Local Intracoronary Eptifibatide versus Mechanical Aspiration in Patients with Acute ST-Elevation Myocardial Infarction,"Objectives. We compared local delivery of intracoronary eptifibatide via perfusion catheter to thrombus aspiration in primary PCI. Background. Perfusion catheter increases local concentration of the drugs at the culprit site and prolongs their residency time. Methods. 75 patients with acute STEMI were randomized to three groups: 25 received local intracoronary eptifibatide and verapamil via perfusion catheter; 25 patients were managed by Diver CE thrombectomy device and 25 patients by primary PCI without thrombus aspiration. Primary end point was assessment of postprocedural TIMI flow, MPG, and corrected TIMI frame count (cTFC) in the culprit vessel. Results. Perfusion catheter was superior to thrombus aspiration and conventional PCI as regards MBG (68% versus 36% in Diver CE and 20% in the control arm; P value = 0.002), with shorter cTFC rates than thrombectomy and control groups (20.76 ± 4.44 versus 26.68 ± 8.40 and 28.16 ± 5.96, resp.; P = 0.001). TIMI flow was not different between the 3 groups. Eptifibatide led to less time to peak CK (13.12 hours versus 16.5 and 19.5 hours, respectively, P value = 0.001). Conclusion. Local intracoronary eptifibatide by perfusion catheter reduces thrombus burden with better results in microvascular perfusion assessed by cTFC and MBG compared to aspiration device or conventional PCI.  ",0
5099,24987609,"Epithelial-myoepithelial carcinoma of the parotid gland: Clinicopathological aspect, diagnosis and surgical consideration","The present paper describes the clinical and pathological features of epithelial-myoepithelial carcinoma (EMC) of the parotid gland. This rare tumor represents <1% of all salivary gland tumors and arises most commonly in the parotid gland, but it has also been described in the submandibular gland, minor salivary glands and palate. EMC is considered to be a low-grade malignant tumor that may commonly recur locally after resection in 23-50% of cases. The complex and varied morphological expression of this neoplasm has attracted numerous investigators, who have presented valuable but often contradictory data. After an in-depth analysis of the clinicopathological aspects of EMC, we speculate that adequate resection with negative soft-tissue margins is the minimum recommended and necessary therapy.  ",0
5100,24987849,"Prevalence and genetic diversity analysis of human coronavirus OC43 among adult patients with acute respiratory infections in Beijing, 2012","To determine the prevalence, epidemiology and genetic diversity of human coronavirus OC43 (HCoV-OC43) among adult patients with acute respiratory infections (ARI) in Beijing,five hundred and fifty-nine nasopharyngeal swab samples were collected from adult patients with ARI in Beijing. The prevalence of HCoV-OC43 infection among these patients was assessed using two different OneStep reverse transcription polymerase chain reaction (RT-PCR) assays. The epidemiological profiles of the patients with HCoV-OC43 infection were described. Partial S and N genes of HCoV-OC43 circulating strains were sequenced followed by phylogenetic analysis and amino acid alignment. Our results showed that the prevalence of HCoV-OC43 infection was 12.52% (95% CI: 9.78-15.26%), and the epidemic peak occurred in autumn. Fifty partial S and 40 partial N fragments were obtained from these patients. Phylogenetic analysis based on neighbour-joining method showed that at least three distinct clusters (A, B, C/D) of HCoV-OC43 strains were circulating among adult patients with ARI in Beijing. In addition, some novel unique clusters (UNT) of HCoV-OC43 were found in the S- and N-based phylogenetic trees. Furthermore, consensus amino acids substitutes for each cluster were also found after alignment of partial S or N sequence coding region in this study. In conclusion, we herein describe the prevalence of HCoV-OC43 among adult patients and provide substantial evidence for the genetic diversity of HCoV-OC43 circulating in Beijing.  ",0
5101,24988057,Management of Liver Cancer Argon-helium Knife Therapy with Functional Computer Tomography Perfusion Imaging,"The objective of this study was to observe the change in blood perfusion of liver cancer following argon-helium knife treatment with functional computer tomography perfusion imaging. Twenty-seven patients with primary liver cancer treated with argon-helium knife and were included in this study. Plain computer tomography (CT) and computer tomography perfusion (CTP) imaging were conducted in all patients before and after treatment. Perfusion parameters including blood flows, blood volume, hepatic artery perfusion fraction, hepatic artery perfusion, and hepatic portal venous perfusion were used for evaluating therapeutic effect. All parameters in liver cancer were significantly decreased after argon-helium knife treatment (p < 0.05 to all). Significant decrease in hepatic artery perfusion was also observed in pericancerous liver tissue, but other parameters kept constant. CT perfusion imaging is able to detect decrease in blood perfusion of liver cancer post-argon-helium knife therapy. Therefore, CTP imaging would play an important role for liver cancer management followed argon-helium knife therapy.  ",0
5102,24988072,Trait mindfulness as a limiting factor for residual depressive symptoms: an explorative study using quantile regression,"Mindfulness has been suggested to be an important protective factor for emotional health. However, this effect might vary with regard to context. This study applied a novel statistical approach, quantile regression, in order to investigate the relation between trait mindfulness and residual depressive symptoms in individuals with a history of recurrent depression, while taking into account symptom severity and number of episodes as contextual factors. Rather than fitting to a single indicator of central tendency, quantile regression allows exploration of relations across the entire range of the response variable. Analysis of self-report data from 274 participants with a history of three or more previous episodes of depression showed that relatively higher levels of mindfulness were associated with relatively lower levels of residual depressive symptoms. This relationship was most pronounced near the upper end of the response distribution and moderated by the number of previous episodes of depression at the higher quantiles. The findings suggest that with lower levels of mindfulness, residual symptoms are less constrained and more likely to be influenced by other factors. Further, the limiting effect of mindfulness on residual symptoms is most salient in those with higher numbers of episodes.  ",0
5103,24988093,Contrasting effects of water salinity and ozone concentration on two cultivars of durum wheat (Triticum durum Desf.) in Mediterranean conditions,"This paper reports the results of an Open-Top Chambers experiment on the responses of two durum wheat cultivars (Neodur and Virgilio) exposed to two different levels of ozone (charcoal-filtered air and ozone-enriched air) and irrigation water salinity (tap water as control and a 75 mM NaCl solution once a week). The stomatal conductance of the flag leaves was measured on four dates during May. Flag leaf samples were collected to detect ozone visible leaf injuries. At the end of the growing season, the yield/biomass and grain quality parameters were assessed. Saline irrigation caused significant reductions in gs, yield and grain quality in Neodur, while Virgilio was more tolerant. The yield response to ozone was almost negligible, with Virgilio, despite the higher susceptibility to visible leaf injuries, being more productive than Neodur. The responses to the combined stress were not consistent, with the main tendencies undoubtedly driven by the saline irrigation factor.  ",0
5104,24988299,Is it time for a tobacco-free military?,Achieving a tobacco-free military requires rethinking current perceptions of service members' tobacco use and unmasking the forces perpetuating those perceptions. Prohibiting tobacco use would be entirely consistent with other military requirements regarding health.,0
5105,24988306,Bird to human transmission biases and vaccine escape mutants in H5N1 infections,"The avian influenza A H5N1 virus occasionally infects humans, with high mortality rates. Although all current human infections are from avian-to-human transmission, it has been shown that H5N1 can be evolved to transmit between mammals, and is therefore a pandemic threat. For H5N1 surveillance, it is of interest to identify the avian isolates most likely to infect humans. In this study, we develop a method to identify mutations significantly associated with avian to human transmission. Using protein sequences for the surface glycoprotein hemagglutinin from avian and human H5N1 isolates in China, Egypt, and Indonesia from the years 1996-2011, we used Principle Component Analysis and a Maximum Likelihood Multinomial method to identify mutations associated with avian to human transmission. In each geographic region, transmission bias residues were identified using two signatures: a) significantly different amino-acid frequencies in human isolates compared to avian isolates from the same year, and b) significantly low probability of neutral evolution of the human isolates from the avian viral pool of the previous year. In each geographic region, we find specific transmission bias mutations associated with human infections. These mutations are located in antigenic regions and receptor binding, glycosylation and polybasic cleavage sites of HA. We show that human isolates derive from a limited, subset of the avian pool characterized by geography specific mutations. In Egypt, two of three PCA clusters have very few human isolates but are highly enriched in mutations associated with a vaccine escape mutant H5N1 avian sub-clade that is known to be resistant to the Mexican H5N2 vaccine Furthermore, at these transmission bias associated residues, the mutations characteristic of these two clusters are distinct from those associated with the cluster enriched in human isolates, suggesting that vaccine resistant avian strains are unable to infect humans. Our results are relevant for surveillance and vaccination strategies for human H5N1 infections. ",0
5106,24988354,Sulfate anion delays the self-assembly of human insulin by modifying the aggregation pathway,"The understanding of the molecular mechanisms underlying protein self-assembly and of their dependence on solvent composition has implications in a large number of biological and biotechnological systems. In this work, we characterize the aggregation process of human insulin at acidic pH in the presence of sulfate ions using a combination of Thioflavin T fluorescence, dynamic light scattering, size exclusion chromatography, Fourier transform infrared spectroscopy, and transmission electron microscopy. It is found that the increase of sulfate concentration inhibits the conversion of insulin molecules into aggregates by modifying the aggregation pathway. At low sulfate concentrations (0-5 mM) insulin forms amyloid fibrils following the nucleated polymerization mechanism commonly observed under acidic conditions in the presence of monovalent anions. When the sulfate concentration is increased above 5 mM, the sulfate anion induces the salting-out of ∼18-20% of insulin molecules into reversible amorphous aggregates, which retain a large content of α-helix structures. During time these aggregates undergo structure rearrangements into β-sheet structures, which are able to recruit monomers and bind to the Thioflavin T dye. The alternative aggregation mechanism observed at large sulfate concentrations is characterized by a larger activation energy and leads to more polymorphic structures with respect to the self-assembly in the presence of chloride ions. The system shown in this work represents a case where amorphous aggregates on pathway to the formation of structures with amyloid features could be detected and analyzed.  ",0
5107,24988468,CXC chemokine ligand 12 protects pancreatic β-cells from necrosis through Akt kinase-mediated modulation of poly(ADP-ribose) polymerase-1 activity,"The diabetes prevention paradigm envisages the application of strategies that support the maintenance of appropriate β-cell numbers. Herein we show that overexpression of CXC chemokine ligand12 (CXCL12) considerably improves the viability of isolated rat Langerhans islet cells and Rin-5F pancreatic β-cells after hydrogen peroxide treatment. In rat islets and wt cells hydrogen peroxide treatment induced necrotic cell death that was mediated by the rapid and extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1). In contrast, CXCL12-overexpressing cells were protected from necrotic cell death as a result of significantly reduced PARP-1 activity. CXCL12 downstream signalling through Akt kinase was responsible for the reduction of PARP-1 activity which switched cell death from necrosis to apoptosis, providing increased protection to cells from oxidative stress. Our results offer a novel aspect of the CXCL12-mediated improvement of β-cell viability which is based on its antinecrotic action through modulation of PARP-1 activity.  ",0
5108,24988613,The role of hepcidin in iron metabolism in inflammatory bowel diseases],"Hepcidin is a 25-amino-acid peptide synthesized predominantly in hepatocytes, which plays an essential role in the regulation of systemic iron homeostasis. As a result of inflammation, hepcidin binds to ferroportin resulting in its internalization and degradation in enterocytes and macrophages. Thus iron is trapped in both enterocytes and macrophages, leading to functional hypoferremia. In iron deficiency or enhanced erythropoiesis, hepcidin expression is reduced. That fact results in increase of iron absorption and releasing iron storage from macrophages. The discovery of the biological properties of hepcidin clarified the relationship between iron homeostasis, immune response, and anaemia of chronic disease. Anaemia is the most common extra intestinal manifestation of inflammatory bowel disease. Anaemia significantly reduces the quality-of-life among patients and can lead to a number of serious complications, even life-threatening. The main types of anaemia in inflammatory bowel diseases are iron deficiency anaemia and anaemia of chronic disease. These two types of anaemia coexist commonly. The key issue is differentiation these types of anaemia to implement a proper management. Commonly used parameters as iron concentration, ferritin and transferrin, are rather unreliable indices for the evaluation of anaemia in inflammatory bowel diseases. In recent studies the important role of hepcidin as a potential alternative marker of anemia and iron status has been shown. Moreover, there are data that antihepcidin treatment may be an effective treatment of anaemia of chronic disease in inflammatory bowel disease. This paper presents hepcidin structure, mechanism of action and regulation, and highlights hepcidin function in anaemia in inflammatory bowel disease. ",0
5109,24989010,Chalcone derivatives inhibit human platelet aggregation and inhibit growth in human bladder cancer cells,"In an effort to develop potent cyclooxygenase-1 (COX-1) inhibitors used as anticancer agent, a series of 2',5'-dimethoxychalcones was screened to evaluate their antiplatelet effect on human washed platelets suspension. Compound 2 exhibited potent inhibition of human washed platelet aggregation induced by collagen, significantly inhibited collagen- and arachidonic acid-induced thromboxane B2 release, and revealed inhibitory effect on COX-1 activity. Molecular docking studies showed that 1, 2, and 4 were bound in the active site of COX-1. These indicated that the antiplatelet effect of these compounds were mainly mediated through the suppression of COX-1 activity and reduced the thromboxane formation. To investigate the mechanistic action of COX-1 inhibitor enhanced the cytotoxic effect against human bladder cancer cells, NTUB1, we assessed the cytotoxic effect of 2 against NTUB1. Treatment of NTUB1 cells with various concentrations of 2 led to a concentration-dependent increase of cell death and decrease of reactive oxygen species levels. The flow-cytometric analysis showed that 2 induced a G1 phase cell cycle arrest but did not accompany an appreciable sub-G1 phase in NTUB1 cells. In addition, compound 2 increased p21 and p27 expressions and did not inhibit the expression of COX-1 in NTUB1 cells. Our results suggested that 2 enhanced cell growth inhibition or antiproliferative activity in NTUB1 cells through G1 arrest by COX-1 independent mechanism.  ",0
5110,24989020,Roles of the pharmacist in the use of safe and highly effective long-acting reversible contraception: an opinion of the women's health practice and research network of the American College of Clinical Pharmacy,"The U.S. population continues to experience an alarmingly high rate of unintended pregnancies that have an impact on individual families and society alike. Lack of effective contraception accounts for most unintended pregnancies, along with incorrect use of contraceptives. The most common reversible contraceptive method used in the United States is the oral contraceptive pill, which has significant failure and discontinuation rates. Use of long-acting reversible contraceptive (LARC) methods has been increasing in recent years after efforts to educate providers and patients. Women are more likely to use LARC methods when barriers such as access and cost are removed. An uptake in the use of LARC methods would allow for markedly reduced contraception failure rates and higher user satisfaction and thus higher continuation rates than those seen with current contraception use. Promoting the use of LARC methods is an important strategy in improving both individual and public health outcomes by reducing unintended pregnancies. The pharmacist's role in family planning is expanding and can contribute to these efforts. Although knowledge regarding LARC has not been studied among pharmacists, a knowledge deficit exists among health care professionals in general. Thus pharmacist education and training should include LARC methods along with other contraceptives. The American College of Clinical Pharmacy Women's Health Practice and Research Network advocates for the pharmacist's role in the use of safe and highly effective LARC methods. These roles include educating patients, informing providers, facilitating access by providing referrals, and modifying institutional procedures to encourage provision of LARC methods.  ",0
5111,24989065,From isolation and dependence to autonomy - expectations before and experiences after cochlear implantation in adult cochlear implant users and their significant others,"The aim of the study was to examine pre-operative expectations and the post-operative experiences related to cochlear implants (CI) in CI-users and their significant others. A questionnaire was used and the responses were analysed by means of The Qualitative Content Analysis. All adults implanted between 1992 and 2010, who had had their implants for a minimum of 12 months (n = 120) were contacted. Response rate was high (90.8%), and all-inclusive answers were received from 101 CI-users (84.2%). The overall sense of increased well-being and life satisfaction was described as having lived in two different worlds, one with the auditory stimulation and one without. In the overall sense of increased well-being and satisfaction three interwoven subcategories, alienation - normality, fear - autonomy, and living a social life emerged. When CI-users and their significant others recalled the time prior to receiving the CI, a sense of fear was present with origins in the concern for the respondents' (CI-users) ability to cope and care independently in society. Conversely, after the implantation both parties emphasized the notion of a distinct transformation within the CI-user towards autonomy. Communication was highlighted as a large part of living social life. The CI increases well-being and satisfaction for both CI-users and their significant others, which is especially evident regarding enhanced autonomy, normality and living social life. Before implantation it is important to discuss the fact that phone calls and listening to music are improvement expectations that might not be met by the CI. The perceived life changes affect the lives of both the CI-users and the significant others, a finding important to take into consideration before implantation and during rehabilitation after the implantation. Before implantation it is important to inform both CI-recipients and significant others about the length of time required to be able to hear selectively after the implantation and about past experiences of CI-users. ",0
5112,24989252,Expression profiles of histone lysine demethylases during cardiomyocyte differentiation of mouse embryonic stem cells,"Histone lysine demethylases (KDMs) control the lineage commitments of stem cells. However, the KDMs involved in the determination of the cardiomyogenic lineage are not fully defined. The aim of this study was to investigate the expression profiles of KDMs during the cardiac differentiation of mouse embryonic stem cells (mESCs). An in vitro cardiac differentiation system of mESCs with Brachyury (a mesodermal specific marker) and Flk-1(+)/Cxcr4(+) (dual cell surface biomarkers) selection was used. The expression profiles of KDMs during differentiation were analyzed using Q-PCR. To understand the contributions of KDMs to cardiomyogenesis, the mESCs on differentiation d 3.5 were sorted by FACS into Brachyury(+) cells and Brachyury(-) cells, and mESCs on d 5.5 were sorted into Flk-1(+)/Cxcr4(+) and Flk-1(-)/Cxcr4(-) cells. mESCs were differentiated into spontaneously beating cardiomyocytes that were visible in embryoid bodies (EBs) on d 7. On d 12-14, all EBs developed spontaneously beating cardiomyocytes. Among the 16 KDMs examined, the expression levels of Phf8, Jarid1a, Jhdm1d, Utx, and Jmjd3 were increased by nearly 2-6-fold on d 14 compared with those on d 0. Brachyury(+) cells showed higher expression levels of Jmjd3, Jmjd2a and Jhdm1d than Brachyury(-) cells. A higher level of Jmjd3 was detected in Flk-1(+)/Cxcr4(+) cells, whereas the level of Jmjd2c was lower in both Brachyury(+) cells and Flk-1(+)/Cxcr4(+) cells. KDMs may play important roles during cardiomyogenesis of mESCs. Our results provide a clue for further exploring the roles of KDMs in the cardiac lineage commitment of mESCs and the potential interference of cardiomyogenesis. ",0
5113,24989906,Does the association between musculoskeletal pain and sickness absence due to musculoskeletal diagnoses depend on biomechanical working conditions?,"To investigate single-site and multi-site musculoskeletal pain as predictors of future sickness absence due to musculoskeletal disorders (MSD) among blue-collar employees in food industry, and to study to what extent this relationship depends on physical loading at work. Survey responses of 901 employees on working conditions and musculoskeletal pain during the past week were linked to their future sickness absence records obtained from the personnel register of a food industry company. Negative binomial regression models were computed to determine associations of pain in one and in multi-site with the number of sickness absence days due to MSD during a four-year follow-up. Analyses were made in the whole cohort and stratified by the occurrence of repetitive movements and awkward postures (low/high). Multi-site pain occurred among 59 % in the total cohort and predicted sickness absence with a rate ratio of 1.48 [95 % confidence interval (CI) 1.21-1.80], adjusted for age, gender, biomechanical and psychosocial working conditions, body mass index and physical exercise. Similar associations were seen in the sub-cohorts with a low occurrence of repetitive movements (RR 2.18, CI 1.69-2.80) and awkward postures (RR 1.78, CI 1.39-2.28), but not in the sub-cohorts with a high occurrence of these exposure. Single-site pain was not predictive of sickness absence. A very high level of sickness absence in biomechanically strenuous work was found. Multi-site pain predicted sickness absence due to MSD among the employees with low exposure, but not among those with high exposure. ",0
5114,24989971,Effects of the topographical extent of coronary artery ectasia on coronary blood flow in patients with aortic aneurysms,"Aortic aneurysms are associated with coronary artery ectasia (CAE). However, the relation between the extent of CAE and coronary blood flow in patients with aortic aneurysms is not fully understood. This study was undertaken to assess the angiographic characteristics and effects of the topographical extent of CAE on coronary blood flow in patients with aortic aneurysms. This study consisted of 93 consecutive patients with aortic aneurysms (AA group) and 79 patients without aortic aneurysms who had angiographically normal coronary arteries as the control group (Control group). Coronary flow velocity was determined using the thrombolysis in myocardial infarction frame count (TFC) and the topographical extent of CAE was assessed. In the AA group, 43 patients (46.2 %) had significant coronary artery stenosis and 37 patients (40.2 %) had diffuse CAE. TFC was significantly higher in the AA group than in the control group in all 3 coronary arteries. Furthermore, mean corrected TFC (CTFC) was significantly higher in the AA group than in the control group (40.1 ± 10.7 vs. 25.8 ± 6.5, p < 0.001). In the AA group, mean CTFC in patients with diffuse CAE was significantly higher than that in patients with segmental CAE (50.2 ± 8.7 vs. 33.6 ± 5.2, p < 0.001). The mean CTFC correlated positively with the topographical extent of CAE. Many patients with aortic aneurysms were accompanied with angiographic coronary artery stenosis and CAE. Furthermore, patients with aortic aneurysms had higher CTFC than those without aortic aneurysms and it was primarily driven by more frequent prevalence of diffuse CAE. ",0
5115,24990217,Prognostic significance of hMLH1/hMSH2 gene mutations and hMLH1 promoter methylation in sporadic colorectal cancer,"No study in China has focused on the relationships between germline and somatic hMLH1/hMSH2 gene mutations, hMLH1 promoter methylation, and the prognosis of colorectal cancer (CRC), especially in sporadic CRC. Therefore, we carried out this study with 433 primary sporadic CRC patients to investigate the associations between germline and somatic hMLH1/hMSH2 gene mutations, hMLH1 promoter methylation, and the overall survival (OS) of CRC; to evaluate the effect of interaction between gene mutation and methylation on the risk of CRC prognosis. As a result, the 3-, 5-, and 7-year survival of the sporadic CRC patients was 67, 57, and 50.0 %, respectively. There were no significant associations observed between germline and somatic hMLH1/hMSH2 gene mutations after adjusted (HR = 1.37, 95 % CI 0.70-2.67, p = 0.35; HR = 1.31, 95 % CI 0.69-2.47, p = 0.42, respectively). When the analyses were stratified based on tumor stage, tumor location, and chemotherapy, no significant survival advantage of hMLH1/hMSH2 gene mutation was illustrated. In addition, no significant association between germline and somatic hMLH1 promoter methylation and OS of CRC was observed (HR = 1.46, 95 % CI 0.57-3.74, p = 0.43; HR = 0.70, 95 % CI 0.32-1.53, p = 0.37, respectively). In conclusion, the research did not find the significant association between germline and somatic hMLH1/hMSH2 gene mutations, hMLH1 promoter methylation, and sporadic CRC prognosis. ",0
5116,24990412,Effects of schema group therapy in older outpatients: a proof of concept study,"Short-term group schema cognitive behavior therapy (SCBT-g) showed improvements in overall symptomatology, early maladaptive schemas (EMS) and schema modes, both in adults and adolescents with personality disorder (PD) features and long-standing mood disorders. However, no research has yet been carried out on the effect in older adults. Therefore, in a proof of concept study, we explored the effect of SCBT-g in older outpatients with PD features and longstanding mood disorders. Thirty-one older outpatients, aged 60-78 years with PD features and/or longstanding mood disorders were included in a proof of concept study with pre-mid-post design. Primary outcome was psychological distress (Brief Symptom Inventory) and intermediate outcomes were EMS (Young Schema Questionnaire) and schema modes (Schema Mode Inventory), assessed at baseline, mid-treatment and end-of-treatment. Paired samples t-tests were conducted, and Cohen's d effect sizes reported for pre mid- and post-treatment. As proof of concept analysis, hierarchical regression analyses with residual change scores were used to analyse whether early process changes in EMS (intermediate outcomes) predicted later outcome changes in symptoms. SCBT-g led to significant improvement in all three measures of psychological symptoms, EMS and modes with medium effect sizes. Pre-treatment to mid-treatment changes in schema severity predicted symptom improvement from mid- to end-of-treatment. This proof of concept study shows that SCBT-g has potential to change EMS and to show significant effect at symptom level in older outpatients with PD features. A control condition in a randomized controlled trial is a necessary step for further research. ",0
5117,24990465,Quantification of prenatal liver and spleen iron in a sheep model and assessment of iron stores in a human neonate with neonatal hemochromatosis using R2* mapping,"We evaluated the feasibility of prenatal quantification of liver and spleen iron by magnetic resonance imaging (MRI) gradient recalled echo (GRE) measurements of transverse relaxation time (R2*) (MRI-GRE-R2*) in a fetal sheep model and applied the method to a human neonate with suspected neonatal hemochromatosis. We subjected 13 fetal sheep to MRI at 1.5 Tesla using a breath-triggered (ewe) multi-echo sequence to determine the transverse relaxation rate (R2*) of the liver and spleen. In the human neonate, we measured the R2* of the liver, spleen, and pancreas on the 30th postgestational day. The median R2* of the fetal sheep liver was 25.6 s(-1) (range 20 to 114 s(-1)) and of the spleen, 40.2 s(-1) (range 20 to 70 s(-1)), and the corresponding median iron concentration in the liver was 0.85 mg/g dry weight (d.w.) and in the spleen, 1.22 mg/gd.w.. R2* rates in the human neonate liver were elevated between 67 s(-1) (average), which corresponded with an iron concentration of 1.9 mg Fe/gd.w., and 126 s(-1) (regional maximum), which corresponded with 3.4 mg Fe/gd.w.. The average pancreatic R2* (72.4 s(-1)) was significantly above normal values, which indicated iron overload. We demonstrated the feasibility of prenatal quantification of tissue iron by fetal MRI in this sheep model and successfully quantified iron, including that in the pancreas, in a human neonate to confirm the diagnosis of neonatal hemochromatosis. Transferring the successful approach of quantifying iron in intrauterine tissue in fetal sheep to human pregnancies with suspected fetal siderosis could aid early diagnosis. ",0
5118,24991087,Niacin inhibits vascular inflammation via downregulating nuclear transcription factor-κB signaling pathway,"The study aimed to investigate the effect of niacin on vascular inflammatory lesions in vivo and in vitro as well as its lipid-regulating mechanism. In vivo study revealed that niacin downregulated the levels of inflammatory factors (IL-6 and TNF-α) in plasma, suppressed protein expression of CD68 and NF-κB p65 in arterial wall, and attenuated oxidative stress in guinea pigs that have been fed high fat diet. In vitro study further confirmed that niacin decreased the secretion of IL-6 and TNF-α and inhibited NF-κB p65 and notch1 protein expression in oxLDL-stimulated HUVECs and THP-1 macrophages. Moreover, niacin attenuated oxLDL-induced apoptosis of HUVECs as well. In addition, niacin significantly lessened lipid deposition in arterial wall, increased HDL-C and apoA levels and decreased TG and non-HDL-C levels in plasma, and upregulated the mRNA amount of cholesterol 7 α-hydroxylase A1 in liver of guinea pigs. These data suggest for the first time that niacin inhibits vascular inflammation in vivo and in vitro via downregulating NF-κB signaling pathway. Furthermore, niacin also modulates plasma lipid by upregulating the expression of factors involved in the process of reverse cholesterol transport. ",0
5119,24991690,Evolutionarily distinct versions of the multidomain enzyme α-isopropylmalate synthase share discrete mechanisms of V-type allosteric regulation,"Understanding the evolution of allostery in multidomain enzymes remains an important step in improving our ability to identify and exploit structure-function relationships in allosteric mechanisms. A recent protein similarity network for the DRE-TIM metallolyase superfamily indicated there are two evolutionarily distinct forms of the enzyme α-isopropylmalate synthase (IPMS) sharing approximately 20% sequence identity. IPMS from Mycobacterium tuberculosis has been extensively characterized with respect to catalysis and the mechanism of feedback regulation by l-leucine. Here, IPMS from Methanococcus jannaschii (MjIPMS) is used as a representative of the second form of the enzyme, and its catalytic and regulatory mechanism is compared with that of MtIPMS to identify any functional differences between the two forms. MjIPMS exhibits kinetic parameters similar to those of other reported IPMS enzymes and is partially inhibited by l-leucine in a V-type manner. Identical values of (D2O)kcat (3.1) were determined in the presence and absence of l-leucine, indicating the hydrolytic step is rate-determining in the absence of l-leucine and remains so in the inhibited form of the enzyme. This mechanism is identical to the mechanism identified for MtIPMS ((D2O)kcat = 3.3 ± 0.3 in the presence of l-leucine) despite product release being rate-determining in the uninhibited MtIPMS enzyme. The identification of identical regulatory mechanisms in enzymes with low sequence identity raises important evolutionary questions concerning the acquisition and divergence of multidomain allosteric enzymes and highlights the need for caution when comparing regulatory mechanisms for homologous enzymes.  ",0
5120,24991784,Cross-talk between RORγt+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease,"Interleukin (IL)-22-producing RORγt innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORγt ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD. CD45 lineage marker ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14 macrophages, and IL-22 production was evaluated. CD127CD56 and CD127CD56 ILC, but not CD127CD56 or CD127CD56 ILC, subsets expressed RORγt and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1α and Claudin-1 in human intestinal epithelial organoids. RORγt ILCs might enhance mucosal barrier function through the upregulation of Reg1α through production of IL-22. Although CD14 macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by RORγt ILCs. ",0
5121,24991811,"Sero-survey of polio antibodies during wild poliovirus outbreak in southern Xinjiang Uygur Autonomous Region, China","After being polio free for more than 10 years, an outbreak following importation of wild poliovirus (WPV) was confirmed in Xinjiang Uygur Autonomous Region, China, in 2011. A cross-sectional study was conducted prior to supplementary immunization activities (SIAs), immediately after the confirmation of the WPV outbreak. In selected prefectures, participants aged ≤ 60 years old who visited hospitals at county-level or above to have their blood drawn for reasons not related to the study, were invited to participate in our study. Antibody titers ≥ 8 were considered positive. Among the 2,611 participants enrolled, 2,253 (86.3%), 2,283 (87.4%), and 1,989 (76.2%) were seropositive to P1, P2 and P3 respectively, and 1744 (66.8%) participants were seropositive to all the three serotypes. Lower antibody seropositivities and geometric mean titers were observed in children <1 year of age and in adults aged 15-39 years. Serosurveys to estimate population immunity in districts at high risk of polio importation might be useful to gauge underlying population immunity gaps to polio and possibly to guide preparedness and response planning. Consideration should be given to older children and adults during polio risk assessment planning and outbreak response. ",0
5122,24992057,Wake-up test in total hip arthroplasty with high-riding developmental dysplasia,"Total hip arthroplasty (THA) for patients with Crowe type IV developmental dysplasia of the hip is technically challenging. This group of patients has a higher incidence of nerve injury during THA. Although neurophysiologic intraoperative monitoring has been developed to provide nerve monitoring, it is not always available. The wake-up test has been used for intraoperative spinal cord monitoring during major spinal surgery, but no study has reported the use of the wake-up test for neurologic monitoring during THA in patients with severe developmental dysplasia of the hip. The authors retrospectively reviewed 22 THA procedures in 20 patients with Crowe type IV developmental dysplasia of the hip who underwent the wakeup test during THA. In the current study, 1 patient could not dorsiflex her foot during the wake-up test. Therefore, the authors immediately reduced the length of limb lengthening by 1 cm. Postoperative drop foot and numbness occurred but resolved completely 2 months later. None of the patients who showed no deficits in motion of the feet during the intraoperative wake-up test had signs of postoperative nerve injury. In the current study, there was no false-positive or false-negative finding. The authors concluded that the wake-up test, which is simple, safe, and reliable, is a useful technique and a possible alternative to neurophysiologic intraoperative monitoring in checking nerve function during THA in patients with severe developmental dysplasia of the hip.  ",0
5123,24992353,Early pelvic fixation failure in neuromuscular scoliosis,"To report on early failures of pelvic fixation in posterior spinal fusions for neuromuscular scoliosis. A retrospective review of posterior-only spinal instrumentation and fusion to the pelvis with iliac screws was performed. Forty-one patients with a mean age of 14 years and mean 16 levels fused met the inclusion criteria. Diagnoses include cerebral palsy (22), Duchenne muscular dystrophy (7), other neuromuscular (10), and spina bifida (2). Cox proportional hazards regression modeling was used to compare rates of failure. The mean preoperative primary Cobb angle was 82 degrees (range, 21 to 144 degrees). The pelvic obliquity correction was 76%. The fixation in the pelvis failed in 12/41 patients (29%). Failures include: screw head disengaged from screw shaft (5), iliac screw disengaged from rod (2), iliac connector disengaged from rod (2), iliac connector disengaged from iliac screw (4), and iliac screw loosened from bone (3). No failures occurred if there were at least 6 screws in L5, S1, and pelvis (0/7 patients). The failure rate with <6 screws in L5, S1, and pelvis was higher at 35% (12/34 patients) (P=0.16). When using traditional iliac screws with connectors to rods, all constructs had <6 screws in L5, S1, and pelvis. Only 1 failure occurred when S2-iliac screws were used, but was without clinical consequence. The mean time from surgery to failure was 18 months (range, 1 to 49 mo). Not placing bilateral pedicle screws at L5 and S1, in addition to 2 iliac screws, was associated with a 35% early failure rate of pelvic fixation. Level IV. ",0
5124,24992569,The role of the calcium-sensing receptor in disorders of abnormal calcium handling and cardiovascular disease,"The calcium-sensing receptor (CaSR) has a central role in parathyroid gland function. Genetic alterations in CaSR are well known to cause inherited forms of abnormal calcium homeostasis. This review focuses on studies investigating the role of CaSR in common disorders of abnormal calcium handling and in cardiovascular calcification. Genetic population studies tested the association of common allelic CASR variants with serum and urine calcium levels, kidney stone disease, primary hyperparathyroidism and bone mineral density. The results of these association studies suggested either minor or no effects of CASR variants in these phenotypes. Decreased expression of CaSR was associated with the etiology of cardiovascular calcification in individuals with advanced chronic kidney disease. Ionized calcium plays a central role in the physiology of many organ systems and disease states, but the roles of CaSR other than as illustrated by Mendelian forms of CaSR dysfunction remain unclear. The contributions of CaSR to bone mineral homeostasis, vascular calcification and other forms of cardiovascular disease need further investigation. ",0
5125,24992761,Role and mechanism of radiological protection cream in treating radiation dermatitis in rats,"To explore the role and mechanism of a radiation protection cream (Rp) in the treatment of radiation dermatitis, and to accumulate necessary technical information for a new drug report on Rp. High-performance liquid chromatography was used to establish the method of measuring the main effective ingredients of sovereign and adjuvant herbs of Rp drugs, and to formulate the draft quality standards of Rp. A total of 48 Sprague-Dawley male rats were randomly divided into the Model, Trolamine cream (Tc), Rp and Blank groups according to a random number table method. The skin of each rat's buttocks was irradiated using an electron linear accelerator to establish an acute radiation dermatitis model. The histological changes were observed under light microscopy and electron microscopy during wound healing and the effect of Rp on rat fibroblast Ku70/80 gene expression was detected at the transcriptional level. Pathological examination revealed that Rp protected the cellular and subcellular structures of skin after irradiation, promoting the proliferation and restoration of collagen fibers. Ku70/80 mRNA expression levels in the Rp and Tc groups were higher than that in the model group (P < 0.05). Moreover, The majority of grade radiation dermatitis relative to the Model, Rp and Tc groups for reducing grade III and IV dermatitis efficiency were 85.7% and 69.2% (P < 0.05), respectively. The efficacy of Rp group in treating radiation dermatitis was better than the Trolamine cream group by 16.5% (P < 0.05). Compared with Tc, Rp had certain advantages in the efficacy and performance to price ratio. Thus, Rp is considered an effective alternative formulation for the prevention and treatment of radiation dermatitis. ",0
5126,24993300,Tumor necrosis factor-α-stimulated brain pericytes possess a unique cytokine and chemokine release profile and enhance microglial activation,"Brain pericytes are involved in neurovascular dysfunction, neurodegeneration and/or neuroinflammation. In the present study, we focused on the proinflammatory properties of brain pericytes to understand their participation in the induction of inflammation at the neurovascular unit (NVU). The NVU comprises different cell types, namely, brain microvascular endothelial cells, pericytes, astrocytes and microglia. Among these, we found pericytes to be the most sensitive to tumor necrosis factor (TNF)-α, possessing a unique cytokine and chemokine release profile. This was characterized by marked release of interleukin (IL)-6 and macrophage inflammatory protein-1α. Furthermore, TNF-α-stimulated pericytes induced expression of inducible nitric oxide synthase and IL-1β mRNAs, as an index of BV-2 microglial cell activation state, to the highest levels. Based on these findings, the possibility that brain pericytes act specifically as TNF-α-sensitive cells and as effectors of TNF-α through the release of proinflammatory factors, and that, as such, they have a role in inducing brain inflammation, should be considered.  ",0
5127,24993352,Implementation and adherence issues in a workplace treadmill desk intervention,"We report experiences, observations, and general lessons learned, specifically with regards to participant recruitment and adherence, while implementing a 6-month randomized controlled treadmill desk intervention (the WorkStation Pilot Study) in a real-world office-based health insurance workplace. Despite support from the company's upper administration, relatively few employees responded to the company-generated e-mail to participate in the study. Ultimately only 41 overweight/obese participants were deemed eligible and enrolled from a recruitment pool of 728 workers. Participants allocated to the Treadmill Desk Group found the treadmill desk difficult to use for 45 min twice a day as scheduled. Overall attendance averaged 45%-50% of all possible scheduled sessions. The most frequently reported reasons for missing sessions included work conflict (35%), out of office (30%), and illness/injury/drop-out (20%). Although focus groups indicated consistently positive comments about treadmill desks, an apparent challenge was fitting a rigid schedule of shared use to an equally rigid and demanding work schedule punctuated with numerous tasks and obligations that could not easily be interrupted. Regardless, we documented that sedentary office workers average ∼43 min of light-intensity (∼2 METs) treadmill walking daily in response to a scheduled, facilitated, and shared access workplace intervention. Workstation alternatives that combine computer-based work with light-intensity physical activity are a potential solution to health problems associated with excessive sedentary behavior; however, there are numerous administrative, capital, and human resource challenges confronting employers considering providing treadmill desks to workers in a cost-effective and equitable manner.  ",0
5128,24993357,Up-regulation of MDP and tuftsin gene expression in Th1 and Th17 cells as an adjuvant for an oral Lactobacillus casei vaccine against anti-transmissible gastroenteritis virus,"The role of muramyl dipeptide (MDP) and tuftsin in oral immune adjustment remains unclear, particularly in a Lactobacillus casei (L. casei) vaccine. To address this, we investigated the effects of different repetitive peptides expressed by L. casei, specifically the MDP and tuftsin fusion protein (MT) repeated 20 and 40 times (20MT and 40MT), in mice also expressing the D antigenic site of the spike (S) protein of transmissible gastroenteritis virus (TGEV) on intestinal and systemic immune responses and confirmed the immunoregulation of these peptides. Treatment of mice with a different vaccine consisting of L. casei expressing MDP and tuftsin stimulated humoral and cellular immune responses. Both 20MT and 40MT induced an increase in IgG and IgA levels against TGEV, as determined using enzyme-linked immunosorbent assay. Increased IgG and IgA resulted in the activation of TGEV-neutralising antibody activity in vitro. In addition, 20MT and 40MT stimulated the differentiation of innate immune cells, including T helper cell subclasses and regulatory T (Treg) cells, which induced robust T helper type 1 and T helper type 17 (Th17) responses and reduced Treg T cell immune responses in the 20MT and 40MT groups, respectively. Notably, treatment of mice with L. casei expressing 20MT and 40MT enhanced the anti-TGEV antibody immune responses of both the humoral and mucosal immune systems. These findings suggest that L. casei expressing MDP and tuftsin possesses substantial immunopotentiating properties, as it can induce humoral and T cell-mediated immune responses upon oral administration, and it may be useful in oral vaccines against TGEV challenge.  ",0
5129,24993425,Identification and functional characterization of the human ether-a-go-go-related gene Q738X mutant associated with hereditary long QT syndrome type 2,"QT interval prolongation, a risk factor for arrhythmias, may be associated with genetic variants in genes governing cardiac repolarization. Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go‑go-related gene (hERG). This gene encodes a voltage-gated potassium channel comprised of 4 subunits, and the formation of functional channels requires the proper assembly of these 4 subunits. In the present study, we investigated the role of the LQT2 mutation, Q738X, which causes truncation of the C-terminus of hERG channels, in the assembly and function of hERG channels. When expressed in HEK293 cells, Q738X did not generate an hERG current. The co-expression of Q738X with wild-type (WT)-hERG did not cause the dominant-negative suppression of the WT-hERG current. Western blot analysis and confocal microscopy revealed that the Q738X mutation caused defective trafficking of hERG channel proteins. Co-immunoprecipitation demonstrated that Q738X did not exhibit dominant-negative effects due to the failure of the mutant and WT subunits to co-assemble. In conclusion, the functional loss caused by the Q738X mutation in hERG K+ channels may be attributed to the disruption of tetrameric assembly.  ",0
5130,24993483,Geographical heterogeneity and influenza infection within households,"Although it has been suggested that schoolchildren vaccination reduces influenza morbidity and mortality in the community, it is unknown whether geographical heterogeneity would affect vaccine effectiveness. A 3-year prospective, non-randomized sero-epidemiological study was conducted during 2008-2011 by recruiting schoolchildren from both urban and rural areas. Respective totals of 124, 206, and 176 households were recruited and their household contacts were followed. Serum samples were collected pre-vaccination, one-month post-vaccination and post-season from children and household contacts for hemagglutination inhibition (HI) assay. A multivariate logistic model implemented with generalized estimation equations (GEE) was fitted with morbidity or a four-fold increase in HI titer of the household contacts for two consecutive sera as the dependent variable; with geographical location, vaccination status of each household and previous vaccination history as predictor variables. Although our results show no significant reduction in the proportion of infection or clinical morbidity among household contacts, a higher risk of infection, indicated by odds ratio>1, was consistently observed among household children contacts from the un-vaccinated households after adjusting for confounding variables. Interestingly, a statistically significant lower risk of infection was observed among household adult contacts from rural area when compared to those from urban area (OR=0.89; 95% CI: 0.82-0.97 for Year 2 and OR=0.85; 95% CI: 0.75-0.96 for Year 3). A significant difference in the risk of influenza infection among household adults due to geographical heterogeneity, independent of schoolchildren vaccination status, was revealed in this study. Its impact on vaccine effectiveness requires further study. ",0
5131,24993768,Association of early childhood abdominal circumference and weight gain with blood pressure at 36 months of age: secondary analysis of data from a prospective cohort study,"To assess whether changes in measures of fat distribution and body size during early life are associated with blood pressure at 36 months of age. Analysis of data collected from a prospective cohort study. Community-based investigation in Southampton, UK. 761 children with valid blood pressure measurements, born to women participating in the Southampton Women's Survey. Anthropometric measurements were collected at 0, 6, 12, 24 and 36 months and conditional changes between the time points calculated. Blood pressure was measured at 36 months. Factors possibly influencing the blood pressure were assessed using linear regression. All independent variables of interest and confounding variables were included in stepwise multiple regression to identify the model that best predicted blood pressure at 36 months. Greater conditional gains in abdominal circumference (AC) between 0-6 and 24-36 months were associated with higher systolic and diastolic blood pressures at 36 months (p<0.001). Subscapular skinfold and height gains were weakly associated with higher blood pressures, while greater weight gains between 0-6, 12-24 and 24-36 months were more strongly associated, but the dominant influences were AC gains, particularly from 0-6 to 24-36 months. Thus one SD score increases in AC between 0-6 and 24-36 months were associated with 1.59 mm Hg (95% CI 0.97 to 2.21) and 1.84 mm Hg (1.24 to 2.46) higher systolic blood pressures, respectively, and 1.04 mm Hg (0.57 to 1.51) and 1.02 mm Hg (0.56, 1.48) higher diastolic pressures, respectively. Conditional gains in abdominal circumference, particularly within 6 months of birth and in the year preceding measurement, were more positively associated with blood pressure at 36 months than gains in other anthropometric measures. Above-average AC gains in early childhood may contribute to adult hypertension and increased cardiovascular disease risk. ",0
5132,24993853,Mode of action studies on the formation of enamel minerals from a novel toothpaste containing calcium silicate and sodium phosphate salts,"To investigate in vitro and in situ the deposition and formation of hydroxyapatite (HAP) on enamel surfaces following brushing with a novel toothpaste containing calcium silicate (CaSi), sodium phosphate salts and fluoride. Polished enamel blocks were brushed in vitro with a slurry of the CaSi toothpaste. After one brush and four weeks simulated brushing the enamel surfaces were analysed. In an in situ protocol, enamel blocks were attached to first or second molar teeth of healthy subjects, exposed to 4 weeks twice per day brushing with the CaSi toothpaste and then analysed. The surface deposits were analysed using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM) and selected area electron diffraction (SAED). In addition, the CaSi toothpaste was slurried in simulated oral fluid (SOF) over a 3 hour period and the solids were isolated and analysed by Fourier transform infrared spectroscopy (FTIR). The FTIR study demonstrated that calcium phosphate phases had formed and these became increasingly crystalline over 3 hours. CaSi was deposited onto enamel surfaces following one brushing with the toothpaste in vitro.The deposited particles showed evidence of HAP crystalline phases associated with the CaSi. Following 4 weeks brushing in vitro, the deposition increased and analyses showed that the deposited material was HAP. These results were confirmed by the in situ study. Calcium silicate can be deposited onto enamel surfaces from a novel toothpaste formulation where it can form the enamel mineral HAP. A novel toothpaste formulation containing CaSi can form HAP on enamel surfaces. The potential of this technology is for a novel approach to the repair of demineralised enamel and the protection of enamel during acid exposure. ",0
5133,24994049,Practical approach to hip pain,"Hip pain is a common complaint among patients presenting to outpatient clinics. Stratifying patients based on age, acuity, and location of pain (extra-articular vs intra-articular) can help to aid in appropriate imaging and timely referral to an orthopedic surgeon. A thorough history and an organized physical examination combined with radiographs are usually sufficient to diagnose most hip complaints. If the diagnosis remains uncertain, magnetic resonance imaging, usually with intra-articular gadolinium, is the imaging modality of choice in diagnosing both intra-articular and extra-articular pathologies.  ",0
5134,24994830,Whole-brain diffusion tensor imaging in correlation to visual-evoked potentials in multiple sclerosis: a tract-based spatial statistics analysis,"Functional correlates of microstructural damage of the brain affected by MS are incompletely understood. The purpose of this study was to evaluate correlations of visual-evoked potentials with microstructural brain changes as determined by DTI in patients with demyelinating central nervous disease. Sixty-one patients with clinically isolated syndrome or MS were prospectively recruited. The mean P100 visual-evoked potential latencies of the right and left eyes of each patient were calculated and used for the analysis. For DTI acquisition, a single-shot echo-planar imaging pulse sequence with 80 diffusion directions was performed at 3T. Fractional anisotropy, radial diffusivity, and axial diffusivity were calculated and correlated with mean P100 visual-evoked potentials by tract-based spatial statistics. Significant negative correlations between mean P100 visual-evoked potentials and fractional anisotropy and significant positive correlations between mean P100 visual-evoked potentials and radial diffusivity were found widespread over the whole brain. The highest significance was found in the optic radiation, frontoparietal white matter, and corpus callosum. Significant positive correlations between mean P100 visual-evoked potentials and axial diffusivity were less widespread, notably sparing the optic radiation. Microstructural changes of the whole brain correlated significantly with mean P100 visual-evoked potentials. The distribution of the correlations showed clear differences among axial diffusivity, fractional anisotropy, and radial diffusivity, notably in the optic radiation. This finding suggests a stronger correlation of mean P100 visual-evoked potentials to demyelination than to axonal damage. ",0
5135,24995175,Comparison of In-vitro Activities of Linezolid and Vancomycin against Staphylococcus aureus Isolated from A Tertiary Care Hospital,"Methicillin resistant Staphylococcus aureus (MRSA) has emerged as one of the commonest cause of hospital acquired infections worldwide. Vancomycin is the antibiotic of choice for treatment of MRSA, but due to slow increase in vancomycin minimum inhibitory concentration (MIC) (vancomycin creep),Vancomycin has become a suboptimal therapeutic option in critically ill patients. Linezolid has emerged as an alternative drug in the treatment of such cases. To compare in vitro activities of linezolid and vancomycin against Staphylococcus aureus, in order to help in formulating a better treatment. 200 strains of Staphylococcus aureus were isolated from different clinical specimens between April 2010 to March 2011. Antibiotic sensitivity testing was performed by Kirby Bauer disc diffusion method and MICs of vancomycin and linezolid were determined for all 200 strains by agar dilution method by following CLSI guidelines. Among 200 strains, MIC for linezolid was 4 μg/ml for 3 strains, MIC was 2 μg/ml for 71 strains, and MIC was 1 μg/ml for 126 strains, while for the same 200 strains of Staphylococcus aureus, MIC of vancomycin was 4 μg/ml for 8 strains, it was 2 μg/ml for 103 strains and it was 1 μg/ml for 89 strains. Linezolid and vancomycin had similar in-vitro efficacies for Staphylococcus aureus in disc diffusion method, but the number of strains with higher ranges of MICs of vancomycin (1-4 μg/ml) were more as compared to those which had higher ranges of MICs for linezolid. So, we suggest that linezolid can be a good alternative for the treatment of multidrug resistant Staphylococcus aureus as compared to vancomycin. ",0
5136,24995203,Indian tick typhus - an uncommon cause of hepatitis: a case report,"Although viruses remain the most common cause of hepatitis, other causes like rickettsial hepatitis are also well known. However, this aetiology has not been well recognized and it has been rarely reported in the Indian literature. Here, we are discussing a case of acute hepatitis, its clinical presentation, diagnosis and treatment, which was later found to be caused by Indian tick typhus (a spotted fever group rickettsia), which was diagnosed on the basis of serology and its clinical response to doxycycline. Further literature review has been done, to discuss various clinical presentations and prevalence of rickettsial infection in this part of the world.  ",0
5137,24995293,Nanotechnology-applied curcumin for different diseases therapy,"Curcumin is a lipophilic molecule with an active ingredient in the herbal remedy and dietary spice turmeric. It is used by different folks for treatment of many diseases. Recent studies have discussed poor bioavailability of curcumin because of poor absorption, rapid metabolism, and rapid systemic elimination. Nanotechnology is an emerging field that is potentially changing the way we can treat diseases through drug delivery with curcumin. The recent investigations established several approaches to improve the bioavailability, to increase the plasma concentration, and to enhance the cellular permeability processes of curcumin. Several types of nanoparticles have been found to be suitable for the encapsulation or loading of curcumin to improve its therapeutic effects in different diseases. Nanoparticles such as liposomes, polymeric nanoparticles, micelles, nanogels, niosomes, cyclodextrins, dendrimers, silvers, and solid lipids are emerging as one of the useful alternatives that have been shown to deliver therapeutic concentrations of curcumin. This review shows that curcumin's therapeutic effects may increase to some extent in the presence of nanotechnology. The presented board of evidence focuses on the valuable special effects of curcumin on different diseases and candidates it for future clinical studies in the realm of these diseases.  ",0
5138,24995319,Correlates of cessation success among Romanian adults,"Tobacco smoking and its consequences are a serious public health problem in Romania. Evidence-based data on factors associated with successful smoking cessation are crucial to optimize tobacco control. The aim of the study was to determine the sociodemographic and other factors associated with smoking cessation success among adults. Data was from a sample of 4,517 individuals derived from the Global Adult Tobacco Survey (GATS). GATS is a cross-sectional, nationally representative household survey implemented in Romania in 2011. Data was analyzed with logistic regression. Among females, the quit rate was 26.3% compared with 33.1% in males (P < 0.02). We found disparities in cessation success among the analyzed groups of respondents. Being economically active, being aged 40 and above, and having an awareness of smoking health consequences were associated with long-term quitting smoking among men, while initiating smoking at a later age increased the odds of quitting smoking among women. However, cohabitation with nonsmokers was the strongest predictor of successful cessation among both genders. Programs increasing quit rates and encourage cessation among groups less likely to quit, adopting voluntary smoke-free homes, and increasing the awareness of smoking and tobacco pollution risks are needed. ",0
5139,24995683,Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS,"Reliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow-up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03-3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority. ",0
5140,24995704,Involvement of two distinct signalling pathways in IGF-1-mediated central control of hypotensive effects in normotensive and hypertensive rats,"Insulin-like growth factor-1 (IGF-1) is abundantly expressed in the nucleus tractus solitarii (NTS). In a previous study, we revealed that the induction of nitric oxide (NO) production in the NTS reduces blood pressure (BP). It is well known that both acute administration and chronic administration of IGF-I reduce BP. The aim of this study was to evaluate the short-term hypotensive effect of IGF-1 in the NTS and to delineate the underlying molecular mechanisms of IGF-1 in the NTS of normotensive WKY rats and spontaneously hypertensive rats (SHRs). Microinjections of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the MAP kinase-ERK kinase (MEK) inhibitor PD98059 into the NTS in WKY rats and SHRs were used to study the involvement of IGF-1-induced depressor effects. An IGF-1 (7.7 pmol) injection into the NTS resulted in a significant decrease in BP and HR in WKY rats and SHRs. Immunoblotting and immunohistochemical analysis showed that the microinjection of LY294002 (0.6 pmol) or PD98059 (3.0 pmol) into the NTS attenuated the IGF-1-induced depressor effects and Akt or ERK phosphorylation in WKY rats. An attenuation effect of LY294002, but not PD98059, was found in the SHRs. However, the mRNA and protein expression levels of the IGF-1R showed no significant differences in the NTS of the WKY rats and the SHRs. These results suggest that distinct Akt and ERK signalling pathways mediated the IGF-1 control of the central depressor effects in WKY rats and SHRs. ERK signalling defects may be associated with the development of hypertension. ",0
5141,24996293,Cannabis-associated myocardial infarction in a young man with normal coronary arteries,"The use of cannabis is not usually regarded as a risk factor for acute coronary syndrome. However, several cases of myocardial infarction (MI) associated with cannabis use have been reported in the scientific literature. The etiology of this phenomenon is not known. To present a case of cannabis-associated MI in which atherosclerotic coronary disease was excluded as a potential etiology by intravascular ultrasound examination, and briefly review the other possible mechanisms by which this effect may be mediated. We present the case of a previously healthy 21-year-old man who regularly smoked cannabis and presented to the Emergency Department with ST-elevation myocardial infarction after participating in a sport. He was also a cigarette smoker, but had no other conventional cardiovascular risk factors. At coronary angiography, a large amount of thrombus was found in the left anterior descending coronary artery. He recovered with medical treatment, and subsequent intravascular ultrasound examination showed no evidence of atherosclerosis at the site of the thrombus. Cannabis-associated MI is increasingly recognized. The etiology is unclear, but we believe this is the first report of the phenomenon where atherosclerotic plaque rupture has been excluded as the cause with a high degree of confidence. ",0
5142,24996399,The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function,"""The use of specific activators and inhibitors that penetrate the central nervous system has suggested an essential functional role of L-type calcium channels (LTCC) in several important physiological processes of the brain, including the modulation of the mesoaccumbal dopamine signalling pathway, synaptic transmission of auditory stimuli and synaptic plasticity of neutral and aversive learning and memory processes. However, the lack of selectivity of available pharmacological agents towards the most prominent LTCC isoforms in the brain, namely Cav1.2 and Cav1.3, has hampered the elucidation of the precise contribution made by each specific channel isoform within these specific physiological processes. Modern genetic approaches, both in rodents and in human, have recently enhanced our understanding of the selective functional roles of Cav1.2 and Cav1.3 channels. In rodents, the characterisation of global and conditional isoform-specific knockouts suggests a contribution of Cav1.2 channels in spatial memory formation, whereas Cav1.3 channels seem to be involved in the consolidation of fear memories and in neurodegenerative mechanisms associated with the development of Parkinson's disease. With regard to the molecular mechanisms underlying drug addiction, Cav1.3 channels are necessary for the development and Cav1.2 channels for the expression of cocaine and amphetamine behavioural sensitisation. In humans, both the identification of naturally occurring LTCC variants (""""channelopathies"""") and unbiased genome-wide association studies have linked LTCCs to working memory performance in healthy individuals and schizophrenic patients. Individually, CACNA1C polymorphisms and CACNA1D variants have been linked to a variety of psychiatric diseases and to congenital deafness, respectively. However, the contribution of individual LTCCs and their polymorphisms to human brain function and diseases remains unclear, necessitating the use of isoform-specific pharmacological agents.  """,0
5143,24996532,The relationship between TSH and systemic inflammation in extremely preterm newborns,"Elevated thyrotropin (TSH) levels in critically ill extremely premature infants have been attributed to transient hypothyroidism of prematurity or non-thyroidal illness syndrome. We evaluated the hypothesis that relatively high TSH levels in the first 2 postnatal weeks follow recovery from systemic inflammation, similar to non-thyroidal illness syndrome. The study was conducted in 14 Neonatal Intensive Care Units and approved by each individual Institutional Review Board. We measured the concentrations of TSH and 25 inflammation-related proteins in blood spots obtained on postnatal days 1, 7, and 14. We then evaluated the temporal relationships between hyperthyrotropinemia (HTT), defined as a TSH concentration in the highest quartile for gestational age and postnatal day, and elevated levels of inflammation-related proteins. 880 newborns less than 28 weeks of gestation were included. Elevated concentrations of inflammation-related proteins during the first or second week did not precede day-14 HTT. Systemic inflammation on day 7 was associated with day-14 HTT only if inflammation persisted through the end of the 2 week period. HTT frequently accompanied elevated concentrations of inflammation-related proteins on the same day. The hypothesis that HTT follows recovery from severe illness, defined as preceding systemic inflammation, is weakly supported by our study. Our findings more prominently support the hypothesis that TSH conveys information about concomitant inflammation in the extremely premature newborn. ",0
5144,24996656,"Sensitive determination of taurine, γ-aminobutyric acid and ornithine in wolfberry fruit and cortex lycii by HPLC with fluorescence detection and online mass spectrometry identification","A new, simple and highly sensitive method for the determination of taurine, γ-aminobutyric acid and ornithine using high-performance liquid chromatography (HPLC) with fluorescence detection is described. Three non-protein amino acids were derivatized by a novel precolumn derivatization reagent 2-[2-(dibenzocarbazol)-ethoxy]ethyl chloroformate before injected. Optimum derivatization was obtained at 40°C for 5 min in the presence of sodium borate buffer (pH 9.0). Derivatives were sufficiently stable to be efficiently analyzed by HPLC without pretreatment. On a reversed-phase Hypersil BDS C8 column, the amino acids were separated in conjunction with a gradient elution with a good baseline resolution. The identification of derivatives was carried out by online postcolumn mass spectrometry with an electrospray ionization source in positive ion mode. Excellent linear responses were observed with the correlation coefficients of >0.9996, and instrument detection limits (at a signal to noise of 3 : 1) were in the range of 0.30-0.33 nmol/L. The proposed method is sensitive and reproducible for the precise determination of the amino acids from wolfberry fruit and cortex lycii samples.  ",0
5145,24996772,The tyrosine kinase inhibitor nilotinib has antineoplastic activity in prostate cancer cells but up-regulates the ERK survival signal-Implications for targeted therapies,"Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail. The National Cancer Institute-Approved Oncology Drug Set II was used in a phenotypic drug screen to identify novel compounds with antineoplastic activity in prostate cancer cells. Validation experiments were carried out in vitro and in vivo. We identified the TKI nilotinib as a novel compound with antineoplastic activity in hormone-refractory prostate cancer cells. However, further analyses revealed that treatment with nilotinib was associated with a significant up-regulation of the phospho-extracellular-signal-regulated kinases (ERK) survival signal. ERK blockade alone led to a significant antitumoral effect and enhanced the cytotoxicity of nilotinib when used in combination. Our findings underscore that TKIs, such as nilotinib, have antitumoral activity in prostate cancer cells but that survival signals, such as ERK up-regulation, may mitigate their effectiveness. ERK blockade alone or in combination with TKIs may represent a promising therapeutic strategy in advanced prostate cancer. ",0
5146,24996864,Lack of evidence to support present medial release methods in total knee arthroplasty,"The aim of this review was to identify a reliable sequential medial release protocol for restoration of soft tissue balance in total knee arthroplasty of the varus osteoarthritic knee and to allow for improved intraoperative decision-making. Current medial release sequences and applicability based upon pre-operative deformity have been reviewed. Furthermore, risks associated with over release, and the necessity of medial release, are discussed. The different medial release sequences are discussed in relation to pre-operative deformity, along with potential complications associated with medial release. It was found that release sequences may include the deep and superficial components of the medial collateral ligament, the posteromedial capsule, the posterior oblique ligament, the pes anserinus (pes A), and tendons of the semimembranosus and medial gastrocnemius muscle. The sequences described were found to vary substantially between studies, and very few studies had systematically quantified the effect of each release on balance. While medial release is the standard intraoperative mode of balancing, there is a lack of evidence to support current methods. The correct method for defining intraoperatively the sequence, extent and magnitude of releases required remains ill-defined. It could be argued that the classic extensive medial release may be unnecessary and may be associated with iatrogenic injury to the pes A and saphenous nerve, instability and abnormal knee kinematics. Minimal medial release may allow for improved soft tissue balancing leading ultimately to improved functional outcome. V (expert opinion). ",0
5147,24997415,"Inferior vena cava filter usage, complications, and retrieval rate in cancer patients","Venous thromboembolism contributes significantly to morbidity and mortality in cancer patients. Because cancer patients frequently have contraindications to anticoagulation, inferior vena cava filters are commonly placed. The use, safety, and retrieval of retrievable inferior vena cava filters in cancer patients have not been well studied. A retrospective review of retrievable inferior vena cava filter use at a tertiary referral hospital was conducted between January 1, 2009 and December 31, 2011. Indications for inferior vena cava filter placement, anticoagulation practices, complications, filter retrieval, and patient outcomes were analyzed for patients with and without active cancer and for cancer subtypes, including localized and metastatic cases. Of 666 patients receiving retrievable inferior vena cava filters during this time period, 247 (37.1%) had active cancer. Of these, 151 (22.7%) had carcinoma, 92 (13.8%) had sarcoma, and 115 (17.3%) had metastatic disease. Overall, follow-up was available for a median of 401.0 (interquartile range: 107.5-786.5) days. Indwelling filter-related complications occurred in 19.8% of patients without cancer and 17.7% with an active cancer (P = .50). Patients with cancer were less likely to have the filter retrieved (28.0% vs 42.0%, P < .001). In multivariable analysis, cancer was not associated with filter-related complications but was associated with a lower rate of filter retrieval. In a modern cohort of patients undergoing retrievable inferior vena cava filter placement, active diagnosis of cancer is not associated with a significant increase in filter-related complications, but is associated with a reduced rate of filter retrieval. ",0
5148,24997974,Design of a macroalgae amperometric biosensor; application to the rapid monitoring of organophosphate insecticides in an agroecosystem,"The immobilization of enzymes onto transducer support is a mature technology and has been successfully implemented to improve biocatalytic processes for diverse applications. However, there exists still need to design more sophisticated and specialized strategies to enhance the functional properties of the biosensors. In this work, a biosensor platform based on innovative fabrication strategy was designed, and employed for the detection of organophosphate (OP) in natural waters. The biosensor was prepared by incorporating acetylcholinesterase enzyme (AChE) to the graphite paste modified with tetracyanoquinodimethane (TCNQ) mediator, along with the use of a macroalgae (Cladaphropsis membranous) as a functional immobilization support. The novel immobilization design resulted in a synergic effect, and led to enhanced stability and sensitivity of the biosensor. The designed biosensor was used to analyze methyl parathion OP insecticide in water samples collected from a demonstrably contaminated lake of São Luis Island, Maranhão, Northeast of Brazil. Water analysis revealed that the aquatic ecosystem was polluted by sub-ppm concentrations of the OP insecticide, and a good correlation was found between values obtained through biosensor and GC-MS techniques. Our results demonstrated that macroalgae-biosensor could be used as a low-cost and sensitive screening method to detect target analyte.  ",0
5149,24998134,Behavioral cardiology: current advances and future directions,"""Growing epidemiological evidence identifies key domains relevant to behavioral cardiology, including health behaviors, emotions, mental mindsets, stress management, social connectedness, and a sense of purpose. Each of these domains exists along a continuum, ranging from positive factors that promote health, to negative factors, which are pathophysiological. To date, there has been relatively little translation of this growing knowledge base into cardiology practice. Four initiatives are proposed to meet this challenge: 1) promulgating greater awareness of the potency of psychosocial risks factors; 2) overcoming a current """"artificial divide"""" between conventional and psychosocial risk factors; 3) developing novel cost-effective interventions using Internet and mobile health applications, group-based counseling, and development of tiered-care behavioral management; and 4) in recognition that """"one size does not fit all"""" with respect to behavioral interventions, developing specialists who can counsel patients in multidisciplinary fashion and use evidence-based approaches for promoting patient motivation and execution of health goals. """,0
5150,24998434,"Quantitative analysis of UV-A shock and short term stress using iTRAQ, pseudo selective reaction monitoring (pSRM) and GC-MS based metabolite analysis of the cyanobacterium Nostoc punctiforme ATCC 29133","A quantitative proteomics and metabolomics analysis was performed using iTRAQ, HPLC and GC-MS in the filamentous cyanobacterium Nostoc punctiforme ATCC 29133 to understand the effect of short and long term UV-A exposure. Changes in the proteome were measured for short-term stress (4-24h) using iTRAQ. Changes in the photosynthetic pigments and intracellular metabolites were observed at exposures of up to 7days (pigments) and up to 11days (intracellular metabolites). To assess iTRAQ measurement quality, pseudo selected reaction monitoring (pSRM) was used, with this confirming underestimation of protein abundance levels by iTRAQ. Our results suggest that short term UV-A radiation lowers the abundance of PS-I and PS-II proteins. We also observed an increase in abundance of intracellular redox homeostasis proteins and plastocyanin. Additionally, we observed statistically significant changes in scytonemin, Chlorophyll A, astaxanthin, zeaxanthin, and β-carotene. Assessment of intracellular metabolites showed significant changes in several, suggesting their potential role in the Nostoc's stress mitigation strategy. Cyanobacteria under UV-A radiation have reduced growth due to intensive damage to essential functions, but the organism shows a defense response by remodeling bioenergetics pathway, induction of the UV protection compound scytonemin and increased levels of proline and tyrosine as a mitigation response. The effect of UV-A radiation on the proteome and intracellular metabolites of N. punctiforme ATCC 29133 including photosynthetic pigments has been described. We also verify the expression of 13 iTRAQ quantified protein using LC-pSRM. Overall we observed that UV-A radiation has a drastic effect on the photosynthetic machinery, photosynthetic pigments and intracellular amino acids. As a mitigation strategy against UV-A radiation, proline, glycine, and tyrosine were accumulated. ",0
5151,24998517,Three-dimensional principal strain analysis for characterizing subclinical changes in left ventricular function,"Subendocardial strain analysis is currently feasible in two-dimensional and three-dimensional (3D) echocardiography; however, there is a lack of clarity regarding the most useful strain component for subclinical disease detection. The aim of this study was to test the hypothesis that strain analysis along the direction of strongest and weakest systolic compression (referred to as principal and secondary strain, respectively) circumvents the need for multidirectional strains and provides a more simplified assessment of left ventricular subendocardial function. Strain analyses were performed by using two-dimensional and 3D echocardiography in 41 consecutive subjects with normal results on electron-beam computed tomography, including 15 controls and 26 patients with systemic hypertension. The direction of principal strain referenced the myofiber geometry obtained from diffusion tensor magnetic resonance imaging of a normal autopsied human heart. The incremental value of principal strain over multidirectional two-dimensional and 3D strain was analyzed. In healthy subjects, 50 ± 3% of the subendocardial shortening occurred in the cross-fiber direction (left-handed helical); this balance was significantly altered in patients with hypertension (P = .01). The magnitude of longitudinal and circumferential strain was similar in patients with hypertension and controls. However, the alteration of the directional contraction pattern resulted in reduced secondary strain magnitude in patients with hypertension (P = .01), and the differences were further exaggerated when the secondary strain was normalized by the principal strain magnitude (P = .004). Two-component principal and secondary strain analysis can be related to left ventricular myofiber geometry and may simplify the assessment of 3D left ventricular deformation by circumventing the need to assess multiple shortening and shear strain components. ",0
5152,24998745,Preliminary results on a new method for producing yttrium phosphorous microspheres,"This paper reports on a new method to embed phosphorus particles into the matrix of yttrium aluminum silicate microspheres. Yttrium phosphorus glass microspheres about 20µm in size were obtained when an aqueous solution of YCl3 and AlCl3 were added to tetraethyl orthosilicate (TEOS) (phosphoric acid was used to catalyze the hydrolysis and condensation of TEOS) and was pumped into silicone oil under constant stirring. The shapes of the particles produced by this method are regular and nearly spheric in shape. Paper chromatography was used to determine the radiochemical impurity of radioactive microspheres. Radionuclide purity was determined using a gamma spectrometry system and an ultra-low level liquid scintillation spectrometer. The P(+) ions implantation stage was eliminated by embedding phosphorus particles in the matrix of the glass microspheres. This paper shows that a high temperature is not required to produce yttrium phosphorus aluminum silicate microspheres. The result shows that the silicone oil spheroidization method is a very suitable way to produce yttrium phosphorus glass microspheres. The topographical analysis of microspheres shows that the Y, P, Si, and Al elements are distributed in the microspheres and the distribution of elements in the samples is homogenous.  ",0
5153,24999265,Implementation of a national automated external defibrillator program in Portugal],"To describe the stages of development and implementation of an automated external defibrillator (AED) program within the Emergency Medical Service System and in public places in Portugal. Description of the implementation process in terms of logistics, training and supervision of activity. By the end of 2012 there were 442 emergency ambulances equipped with AEDs included in the AED program of the National Institute for Medical Emergencies (INEM). Between 2010 and 2012, 2130 emergency medical technicians were trained and considered qualified to use AEDs. With regard to AED programs in public places, by the end of 2012 there were 207 licensed programs, covering 302 public places, 66 patient transport ambulances, 463 AEDs and 6133 AED operators. Between 2010 and 2012, 19 organizations were licensed to provide training in basic life support and AEDs. In INEM's AED program in 2012, AEDs were used 3250 times, with shockable rhythms in 12.5% of cases (407). Of these, a pulse was restored in 38.6% (157) after a shock, with recovery of spontaneous circulation in 45.9% of these (72). Survival to hospital discharge was 26% (19 cases). Implementation of the program followed recommended scientific criteria, and the results obtained, following significant growth in early access to AEDs, are satisfactory and in line with those in other countries. Strengthening the chain of survival requires the involvement of the community in general and in particular the widespread learning of basic life support measures, which must be the next step for all partners in the Emergency Medical Service System. ",0
5154,24999521,Family culture in mental health help-seeking and utilization in a nationally representative sample of Latinos in the United States: The NLAAS,"Considering the central role of familismo in Latino culture, it is important to assess the extent to which familismo affects mental health help-seeking. This study examined the role of behavioral familismo, the level of perceived family support, in the use of mental health services of Latinos in the United States. Data come from the National Latino and Asian American Study (NLAAS), a representative household survey examining the prevalence of mental disorders and services utilization among Latinos and Asian Americans. Analyses were limited to Latino adults with a clinical need for mental health services, indexed by meeting DSM-IV diagnostic criteria for any mood, anxiety, or substance use disorder during the past 12 months (N = 527). One-third of Latinos with a clinical need used any type of service in the past year, including specialty mental health, general medical, and informal or religious services. High behavioral familismo was significantly associated with increased odds of using informal or religious services, but not specialty or medical services. Self-perceived need and social perceptions of need for care within close networks (i.e., told by family/friends to seek professional help) also were significant predictors of service use. These results carry important implications toward expansions of the mental health workforce in the informal and religious services settings. ",0
5155,24999868,Predictive validity of delay discounting behavior in adolescence: a longitudinal twin study,"A standard assumption in the delay discounting literature is that individuals who exhibit steeper discounting of hypothetical rewards also experience greater difficulty deferring gratification to real-world rewards. There is ample cross-sectional evidence that delay discounting paradigms reflect a variety of maladaptive psychosocial outcomes, including substance use pathology. We sought to determine whether a computerized assessment of hypothetical delay discounting (HDD) taps into behavioral impulsivity in a community sample of adolescent twins (N = 675). Using a longitudinal design, we hypothesized that greater HDD at age 14-15 predicts real-world impulsive choices and risk for substance use disorders in late adolescence. We also examined the genetic and environmental structure of HDD performance. Individual differences in HDD behavior showed moderate heritability, and were prospectively associated with real-world temporal discounting at age 17-18. Contrary to expectations, HDD was not consistently related to substance use or trait impulsivity. Although a significant association between HDD behavior and past substance use emerged in males, this effect was mediated by cognitive ability. In both sexes, HDD failed to predict a comprehensive index of substance use problems and behavioral disinhibition in late adolescence. In sum, we present some of the first evidence that HDD performance is heritable and predictive of real-world temporal discounting of rewards. Nevertheless, HDD might not serve as a valid marker of substance use disorder risk in younger adolescents, particularly females. ",0
5156,24999898,Experiencing racism in health care: the mental health impacts for Victorian Aboriginal communities,"To examine experiences of racism in health settings and their impact on mental health among Aboriginal Australians. A cross-sectional survey of experiences of racism and mental health was conducted in two metropolitan and two rural Victorian local government areas (LGAs) between 1 December 2010 and 31 October 2011. Participants included 755 Aboriginal Australians aged over 18 years who had resided in the relevant LGA for at least a year. The response rate across all LGAs was 99%. Being above or below the threshold for high or very high psychological distress on the Kessler Psychological Distress Scale. 221 participants reported experiences of racism in health settings in the past 12 months. The results suggested that people experiencing racism in health settings (OR, 4.49; 95% CI, 2.28-8.86) and non-health settings (OR, 2.66; 95% CI, 1.39-5.08) were more likely than people who did not experience racism to be above the threshold for high or very high psychological distress. Experiencing interpersonal racism in health settings is associated with increased psychological distress over and above what would be expected in other settings. This finding supports the rationale for improving cultural competency and reducing racism as a means of closing the health gap between Aboriginal and other Australians. Capitalising on this investment will require explicitly evaluating the impact of these initiatives on reducing patient experiences of racism. ",0
5157,25000404,"Characterization of estrogen and androgen activity of food contact materials by different in vitro bioassays (YES, YAS, ERα and AR CALUX) and chromatographic analysis (GC-MS, HPLC-MS)","Endocrine active substances (EAS) show structural similarities to natural hormones and are suspected to affect the human endocrine system by inducing hormone dependent effects. Recent studies with in vitro tests suggest that EAS can leach from packaging into food and may therefore pose a risk to human health. Sample migrates from food contact materials were tested for estrogen and androgen agonists and antagonists with different commonly used in vitro tests. Additionally, chemical trace analysis by GC-MS and HPLC-MS was used to identify potential hormone active substances in sample migrates. A GC-MS method to screen migrates for 29 known or potential endocrine active substances was established and validated. Samples were migrated according to EC 10/2011, concentrated by solid phase extraction and tested with estrogen and androgen responsive reporter gene assays based on yeast cells (YES and YAS) or human osteoblast cells (ERα and AR CALUX). A high level of agreement between the different bioassays could be observed by screening for estrogen agonists. Four out of 18 samples tested showed an estrogen activity in a similar range in both, YES and ERα CALUX. Two more samples tested positive in ERα CALUX due to the lower limits of detection in this assay. Androgen agonists could not be detected in any of the tested samples, neither with YAS nor with AR CALUX. When testing for antagonists, significant differences between yeast and human cell-based bioassays were noticed. Using YES and YAS many samples showed a strong antagonistic activity which was not observed using human cell-based CALUX assays. By GC-MS, some known or supposed EAS were identified in sample migrates that showed a biological activity in the in vitro tests. However, no firm conclusions about the sources of the observed hormone activity could be obtained from the chemical results.  ",0
5158,25000626,Breast cancer update],"Breast Cancer, with a life-time prevalence of about 10-12%, is the most common cancer in women. In 2013, the actress Angelina Jolie, by announcing she had a double mastectomy, increased the awareness of a family history of breast and ovarian cancer and the treatment available to reduce the inherited risks. In Germany, each year about 25 out of 100,000 women (age-standardized according to European Standard) die of the disease. The number of newly diagnosed cases is about 72,000 per year. In comparison, many other countries record higher levels. Investing in the development of new therapies has therefore been key for many years. Prevention programs, such as the mammography screening are publicly touted, in both cases with the aim to reduce breast cancer mortality. To accurately assess the risk in underwriting, it is important to know about the risk factors for the development of breast cancer, as well as the latest advances in prevention, therapy and their prognostic classification. The following article provides an overview. ",0
5159,25000674,Frequency and outcomes of hyponatremic patients with heart failure hospitalized in the Clinical Emergency Hospital of Bucharest,"The purpose of the study was to analyze the frequency of hyponatremia and outcomes in patients with chronic heart failure consecutively admitted in the Internal Medicine Clinic of the Clinical Emergency Hospital of Bucharest, during a period of 8 months. A total of 434 hospitalized patients with heart failure were included in the study. Serum sodium concentration was recorded at the day of admission in hospital, several times during hospitalization and at discharge. Patients were categorized with normonatremia (serum sodium concentration > 134 mEq/L on admission day), persistent hyponatremia (serum sodium level < 134 mEq/L on admission and throughout the hospitalization) and corrected hyponatremia (initial seric sodium < 134 mEq/L that increased to > 134 mEq/L during hospitalization). Hyponatremia was present in 127 patients (29.26%) on admission day and persisted during hospitalization in 91 out of 127 patients (71.65%). From the remaining 307 patients, 269 were normonatremic and 38 (12.37%) were missing serum sodium concentration data on admission day and were excluded from this analysis. Compared with normonatremic patients, those with persistent hyponatremia had lower systolic blood pressure and received higher doses of diuretics during hospitalization. Hyponatremia was associated with higher in-hospital mortality (19.78% of persistent hyponatremic patients) compared with normonatremic patients (1.48%). Persistent hyponatremia can be a predictor of mortality in hospitalized heart failure patients. In most patients, it is not corrected during hospitalization. Those with persistent hyponatremia usually received higher doses of diuretic. The duration of hospitalization is greater in patients with hyponatremia. ",0
5160,25000900,"Characterization of a genetic and antigenic variant of avian paramyxovirus 6 isolated from a migratory wild bird, the red-necked stint (Calidris ruficollis)","A hemagglutinating virus (8KS0813) was isolated from a red-necked stint. Hemagglutination inhibition and neutralization tests indicated that 8KS0813 was antigenically related to a prototype strain, APMV-6/duck/Hong Kong/18/199/77, but with an 8- and 16-fold difference, respectively, in their titers. The full genome sequence of 8KS0813 showed 98.6 % nucleotide sequence identity to that of APMV-6/duck/Italy/4524-2/07, which has been reported to belong to an APMV-6 subgroup, and showed less similarity to that of the prototype strain (70.6 % similarity). The growth of 8KS0813 and the prototype strain in four different cell cultures was greatly enhanced by adding trypsin. Interestingly, this virus induced syncytia only in Vero cells. 8KS0813 was identified as APMV-6/red-necked stint/Japan/8KS0813/08, but it is antigenically and genetically distinguishable from the prototype strain, suggesting that variant APMV-6 is circulating in migratory birds. ",0
5161,25000937,Primary pulmonary artery sarcoma: a new surgical technique for pulmonary artery reconstruction using a self-made stapled bovine pericardial graft conduit,"Primary pulmonary artery sarcoma is an uncommon neoplasm with a grim prognosis. Complete resection is the only treatment that can improve the patient's survival. The role of multimodality treatment is still controversial, although adjuvant chemotherapy possibly could improve outcomes of these patients. Several pulmonary artery reconstructive techniques have been reported in the scientific literature, such as patch reconstruction, end-to-end anastomosis, synthetic prosthesis or biological grafts. In this article, we propose a new surgical option for pulmonary artery reconstruction after radical tumour resection using a self-made stapled bovine pericardial graft conduit in a patient with a mass in the pulmonary trunk and right pulmonary artery. We believe that the use of this technique adds safety and effectiveness, and reduces the surgical time.  ",0
5162,25000974,Special role of Foxp3 for the specifically altered microRNAs in Regulatory T cells of HCC patients,"Regulatory T cells (Tregs) exhibit functional abnormalities in the context of hepatocellular carcinoma (HCC). The microRNAs (miRNAs) are identified as the key modulators in Tregs. This study was to explore whether the expression profiles of miRNAs of Tregs were different in HCC-activated Tregs and whether Foxp3 had special effects on them. We isolated HCC-activated Tregs from mice bearing HCC and compared the expression profiles of miRNAs between HCC-activated Tregs and control Tregs by microarray. RNA interference against Foxp3 was also performed through transfection of synthetic siRNAs to Tregs for analyzing the effect of Foxp3 on the expression of miRNAs. Tregs isolated from HCC patients (n = 12) and healthy controls (n = 7) were used for validation of the differentially expressed miRNAs. Finally, bioinformatic analysis was applied to infer their possible roles. We found nine specifically altered miRNAs in HCC-activated Tregs from the murine model. After transfection with siRNAs against Foxp3, control Tregs showed obvious reduction of Foxp3 and five miRNAs were significantly changed; HCC-activated Tregs exhibited a slight reduction of Foxp3 with three miRNAs significantly changed. Tregs from HCC patients and healthy controls finally confirmed the up-regulation of four miRNAs (hsa-miR-182-5p, hsa-miR-214-3p, hsa-miR-129-5p and hsa-miR-30b-5p). Following bioinformatic analysis suggested these altered miRNAs would target eight important signaling pathways that could affect the functions of Tregs. Our studies provided the first evidence that Tregs in HCC had the specifically altered expression of miRNAs, which was affected by Foxp3. These results are useful both in finding new biomarkers and in further exploring the functions of Tregs in HCC patients. ",0
5163,25001003,Differential mtDNA damage patterns in a transgenic mouse model of Machado-Joseph disease (MJD/SCA3),"Mitochondrial dysfunction has been associated with late onset neurodegenerative disorders, among which is Machado-Joseph disease (MJD/SCA3). In a previous study, using a transgenic mouse model of MJD, we reported a decrease in mitochondrial DNA (mtDNA) copy number and an accumulation of the 3876-bp deletion with age and with phenotype development. We extended this study by analyzing the pattern of mtDNA depletion and the accumulation of the 3876-bp deletion in 12 older transgenic (TG) and 4 wild-type (wt) animals, and by investigating the accumulation of somatic mutations in the D-loop region in 76 mice (42 TG and 34 wt). mtDNA damage was studied in TG and wt mice at different ages and tissues (blood, pontine nuclei, and hippocampus). Results for older mice demonstrate an accumulation of the mtDNA 3867-bp deletion with age, which was more pronounced in TG animals. Furthermore, the tendency for mtDNA copy number decrease with age, in all analyzed tissues of TG and wt animals, was also confirmed. No point mutations were detected in the D-loop, neither in TG nor wt animals, in any of the tissues analyzed. Due to the absence of mtDNA somatic mutations, we can suggest that mtDNA point mutation accumulation cannot be used to monitor the development and progression of the phenotype in this mouse model and likely in any MJD mice model. The present results further confirm not only the association between mtDNA alterations (copy number and deletions) and age, but also between such alterations and the expression of the mutant ataxin-3 in TG mice.  ",0
5164,25001097,Multi-institutional assessment of sphincter preservation for rectal cancer,"Sphincter-preserving surgery (SPS) has been proposed as a quality measure for rectal cancer surgery. However, previous studies on SPS rates lack critical clinical characteristics, rendering it unclear if variation in SPS rates is due to unmeasured case-mix differences or surgeons' selection criteria. In this context, we investigate the variation in SPS rates at various practice settings. Ten hospitals in the Michigan Surgical Quality Collaborative collected rectal cancer-specific data, including tumor location and reasons for non-SPS, of patients who underwent rectal cancer surgery from 2007 to 2012. Hospitals were divided into terciles of SPS rates (frequent, average, and infrequent). Patients were categorized as 'definitely SPS eligible' a priori if they did not have any of the following: sphincter involvement, tumor <6 cm from the anal verge, fecal incontinence, stoma preference, or metastatic disease. Fixed-effects logistic regression was used to evaluate for factors associated with SPS. In total, 329 patients underwent rectal cancer surgery at 10 hospitals (5/10 higher volume, and 6/10 major teaching). Overall, 72 % had SPS (range by hospital 47-91 %). Patient and tumor characteristics were similar between hospital terciles. On multivariable analysis, only hospital ID, younger age, and tumor location were associated with SPS, but not sex, race, body mass index, American Joint Committee on Cancer (AJCC) stage, preoperative radiation, or American Society of Anesthesiologists (ASA) class. Analysis of the 181 (55 %) 'definitely-eligible' patients revealed an SPS rate of 90 % (65-100 %). SPS rates vary by hospital, even after accounting for clinical characteristics using detailed chart review. These data suggest missed opportunities for SPS, and refute the general hypothesis that hospital variation in previous studies is due to unmeasured case-mix differences. ",0
5165,25001119,Role of empirical and targeted therapy in hospitalized patients with bloodstream infections caused by ESBL-producing Enterobacteriaceae,"Bloodstream infection (BSI) due to extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae are a major cause of in-hospital mortality. The effect on survival of empirical and targeted antibiotic therapy in these patients remains controversial. A prospective cohort study was conducted analyzing data from 94 patients (age 59 ± 21 years) with BSI due to ESBL producing strains (Sixty-one E. coli, 26 K. pneumoniae, 4 Proteus spp and 3 Enterobacter spp). Risk factors associated with 21-day mortality at univariate analysis were: recent administration of antibiotic therapy (p=0.049), higher SOFA score (p=0.05), ICU stay (p <0.01), hypotension at presentation (p =0.001) or septic shock (p <0.001) and bacteremia from source other than urinary tract (p=0.03). Regardless of antibiotic class used, no differences in survival were noted between patients receiving or not adequate initial antimicrobial treatment (37.1% vs 23.7% p=0.23); on the other hand, compared with the administration of other in vitro active antibiotics, the use of carbapenem as definitive therapy was associated with a significantly lower 21-day mortality (54.3% vs 28.5% p=0.02). These findings suggest that the administration of an adequate initial therapy is not associated with mortality in hospitalized patients with BSI due to Enterobacteriaceae. The severity of clinical conditions at presentation and the administration of carbapenems as definitive therapy seems to be really important in affecting the outcome of patients with BSI due to ESBL producing strains. ",0
5166,25001153,Usefulness of intravascular ultrasound guidance in percutaneous coronary intervention with second-generation drug-eluting stents for chronic total occlusions (from the Multicenter Korean-Chronic Total Occlusion Registry),"Despite the usefulness of intravascular ultrasound (IVUS) in percutaneous coronary intervention (PCI), the impact of IVUS guidance on clinical outcomes, particularly for chronic total occlusion (CTO) intervention, has rarely been studied. We sought to investigate the clinical usefulness of IVUS-guided CTO intervention with second-generation drug-eluting stent implantation. From 2007 to 2009, a total of 2,568 patients were enrolled in the Korean-CTO registry and 534 patients with successful implantation of second-generation drug-eluting stents were analyzed. IVUS-guided PCI was performed on 206 patients (39%). Clinical outcomes at 2 years were compared between the IVUS-guidance group and the angiography-guidance group in 201 propensity score-matched pairs. The primary end point was the occurrence of definite or probable stent thrombosis. Clinical characteristics were similar between both groups after matching. At 2 years, the IVUS-guidance group showed significantly less stent thrombosis than the angiography-guidance group (0% vs 3.0%, p = 0.014) and a lesser trend toward myocardial infarction (1.0% vs 4.0%, p = 0.058). Target lesion revascularization (TLR) and major adverse cardiovascular event rates were similar. However, a significant interaction was observed between the use of IVUS and lesion length for predicting the TLR (p = 0.037), suggesting usefulness of IVUS in long-lesion (≥3 cm) relative to short-lesion CTO. In conclusion, although IVUS-guided CTO PCI was not associated with a reduction in overall major adverse cardiovascular events, IVUS guidance appears to be associated with a reduction of stent thrombosis and myocardial infarction compared with angiography-guided CTO PCI. Additionally, TLR occurred less frequently in the IVUS-guidance group, especially for long lesions.  ",0
5167,25002116,Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching,"The tumor necrosis factor (TNF) receptor family member CD40 plays an essential role in the activation of antigen-presenting cells, B cell maturation, and immunoglobulin (Ig) class switching critical for adaptive immunity. Although the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinase that produces it, sphingosine kinase 1 (SphK1), have long been implicated in the actions of TNF mediated by engagement of TNFR1, nothing is yet known of their role in CD40-mediated events. We have now found that ligation of CD40 activates and translocates SphK1 to the plasma membrane, leading to generation of S1P. SphK1 inhibition in human tonsil B cells, as well as inhibition or deletion of SphK1 in mouse splenic B cells, significantly reduced CD40-mediated Ig class switching and plasma cell differentiation ex vivo. Optimal activation of downstream CD40 signaling pathways, including NF-κB, p38, and JNK, also required SphK1. In mice treated with a SphK1 inhibitor or in SphK1(-/-) mice, isotype switching to antigen-specific IgE was decreased in vivo by 70 and 55%, respectively. Our results indicate that SphK1 is important for CD40-mediated B cell activation and regulation of humoral responses and suggest that targeting SphK1 might be a useful therapeutic approach to control antigen-specific IgE production. ",0
5168,25002347,An effective method of isolating endothelial cells from intact rat aorta,"Rat aorta has been widely utilized in studies on cardiovascular diseases. Due to its small size, the endothelial cells are difficult to isolate. Here, we developed a modified method to obtain the endothelial cells from the rat aorta. The thoracic aorta of Wistar rat was harvested with its inside was turned out to expose the tunica intima. With its both ends ligated and cultured in ECM in T25 flask, a small amount of cells grew out from the aorta on day 4 and manifested the characteristic cobble stone-like monolayer on day 9-10. The cells were identified to be endothelial cells using reverse transcription (RT)-polymerase chain reaction (PCR), immunocytochemical staining for Von Willebrand Factor (vWF), Dil-Ac-LDL uptake assay, and capillary tube formation assay. This method serves as an easy way to get a large amount of endothelial cells from small-sized vessels, which, therefore, will greatly benefit the researches of vascular disease.  ",0
5169,25002848,Evaluation of carcinogenic modes of action for pesticides in fruit on the Swedish market using a text-mining tool,"Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals' modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in apples and oranges was evaluated. The literature was classified according to a taxonomy that specifies the main type of scientific evidence used for determining carcinogenic properties of chemicals. The publication profiles of many pesticides were similar, containing evidence for both genotoxic and non-genotoxic modes of action, including effects such as oxidative stress, chromosomal changes and cell proliferation. We also found that 18 of the 26 pesticides studied here had previously caused tumors in at least one animal species, findings which support the mode of action data. This study shows how a text-mining tool could be used to identify carcinogenic modes of action for a group of chemicals in large quantities of text. This strategy could support the risk assessment process of chemical mixtures.  ",0
5170,25003306,Transient muscarinic and glutamatergic stimulation of neural stem cells triggers acute and persistent changes in differentiation,"While aberrant cell proliferation and differentiation may contribute to epileptogenesis, the mechanisms linking an initial epileptic insult to subsequent changes in cell fate remain elusive. Using both mouse and human iPSC-derived neural progenitor/stem cells (NPSCs), we found that a combined transient muscarinic and mGluR1 stimulation inhibited overall neurogenesis but enhanced NPSC differentiation into immature GABAergic cells. If treated NPSCs were further passaged, they retained a nearly identical phenotype upon differentiation. A similar profusion of immature GABAergic cells was seen in rats with pilocarpine-induced chronic epilepsy. Furthermore, live cell imaging revealed abnormal de-synchrony of Ca(++) transients and altered gap junction intercellular communication following combined muscarinic/glutamatergic stimulation, which was associated with either acute site-specific dephosphorylation of connexin 43 or a long-term enhancement of its degradation. Therefore, epileptogenic stimuli can trigger acute and persistent changes in cell fate by altering distinct mechanisms that function to maintain appropriate intercellular communication between coupled NPSCs.  ",0
5171,25003314,Immunotherapy and radiation therapy: considerations for successfully combining radiation into the paradigm of immuno-oncology drug development,"As the immunotherapy of cancer comes of age, adding immunotherapeutic agents to radiation therapy has the potential to improve the outcomes for patients with a wide variety of malignancies. Despite the enormous potential of such combination therapy, laboratory data has been lacking and there is little guidance for pursuing novel treatment strategies. Animal models have significant limitation in combining radiation therapy with immunotherapy and some of the limitations of preclinical models are discussed in this article. In addition to the preclinical challenges, radiation therapy and immunotherapy combinations may have overlapping toxicities, and for both types of therapy, early and late manifestations of toxicity are possible. Given these risks, special attention should be given to the design of the specific Phase I clinical trial that is chosen. In this article, we describe several Phase I design possibilities that may be employed, including the 3 + 3 design (also known as the cohort of 3 design), the continual reassessment method (CRM), and the time-to-event continual reassessment method (TITE-CRM). Efficacy end points for further development of combination therapy must be based on multiple factors, including disease type, stage of disease, the setting of therapy and the goal of therapy. While the designs for future clinical trials will vary, it is clear that these two successful modalities of therapy can and should be combined for the benefit of cancer patients.  ",0
5172,25003397,Mental health of children and adolescents with epilepsy: analysis of clinical and neuropsichological aspects,"Epilepsy compromises the development of cognitive and social skills and represents a risk of psychiatric comorbidity. To compare psychopathological symptoms in children with epilepsy and in a healthy group, and to correlate the results with neuropsychological and clinical variables. Forty five children with idiopathic epilepsy and sixty five healthy controls underwent neuropsychological evaluation and their caregivers replied to a psychopathology questionnaire (Child Behavior Checklist - CBCL). There were significant differences in CBCL, with poorer results showed mainly by patients with epilepsy. There was no significant association between any psychopathological symptom and disease duration or amount of antiepileptic drugs used. There was positive correlation between intelligence quocient and CBCL on items such as sluggish cognitive tempo, aggressive behavior, attention problems and activities and a negative relation between academic achievement, conduct and rule-breaking behavior. Children with epilepsy had the worse results in the psychopathology evaluation. Certain psychopathological variables are related to the cognitive profile, with no relation to clinical variables. ",0
5173,25003552,"The impact of multiple concussions on emotional distress, post-concussive symptoms, and neurocognitive functioning in active duty United States marines independent of combat exposure or emotional distress","Controversy exists as to whether the lingering effects of concussion on emotional, physical, and cognitive symptoms is because of the effects of brain trauma or purely to emotional factors such as post-traumatic stress disorder or depression. This study examines the independent effects of concussion on persistent symptoms. The Defense Automated Neurobehavioral Assessment, a clinical decision support tool, was used to assess neurobehavioral functioning in 646 United States Marines, all of whom were fit for duty. Marines were assessed for concussion history, post-concussive symptoms, emotional distress, neurocognitive functioning, and deployment history. Results showed that a recent concussion or ever having experienced a concussion was associated with an increase in emotional distress, but not with persistent post-concussive symptoms (PPCS) or neurocognitive functioning. Having had multiple lifetime concussions, however, was associated with greater emotional distress, PPCS, and reduced neurocognitive functioning that needs attention and rapid discrimination, but not for memory-based tasks. These results are independent of deployment history, combat exposure, and symptoms of post-traumatic stress disorder and depression. Results supported earlier findings that a previous concussion is not generally associated with post-concussive symptoms independent of covariates. In contrast with other studies that failed to find a unique contribution for concussion to PPCS, however, evidence of recent and multiple concussion was seen across a range of emotional distress, post-concussive symptoms, and neurocognitive functioning in this study population. Results are discussed in terms of implications for assessing concussion on return from combat. ",0
5174,25003582,Identification of the augmin complex in the filamentous fungus Aspergillus nidulans,"Augmin is a protein complex that binds to spindle microtubules (MTs), recruits the potent MT nucleator, γ-tubulin, and thereby promotes the centrosome-independent MT generation within mitotic and meiotic spindles. Augmin is essential for acentrosomal spindle assembly, which is commonly observed during mitosis in plants and meiosis in female animals. In many animal somatic cells that possess centrosomes, the centrosome- and augmin-dependent mechanisms work cooperatively for efficient spindle assembly and cytokinesis. Yeasts have lost the augmin genes during evolution. It is hypothesized that their robust MT nucleation from the spindle pole body (SPB), the centrosome-equivalent structure in fungi, compensates for the lack of augmin. Intriguingly, however, a gene homologous to an augmin subunit (Aug6/AUGF) has been found in the genome of filamentous fungi, which has the SPB as a robust MT nucleation centre. Here, we aimed to clarify if the augmin complex is present in filamentous fungi and to identify its role in mitosis. By analysing the Aug6-like gene in the filamentous fungus Aspergillus nidulans, we found that it forms a large complex with several other proteins that share weak but significant homology to known augmin subunits. In A. nidulans, augmin was enriched at the SPB and also associated with spindle MTs during mitosis. However, the augmin gene disruptants did not exhibit growth defects under normal, checkpoint-deficient, or MT-destabilised conditions. Moreover, we obtained no evidence that A. nidulans augmin plays a role in γ-tubulin recruitment or in mitotic cell division. Our study uncovered the conservation of the augmin complex in the fungal species, and further suggests that augmin has several functions, besides mitotic spindle MT nucleation, that are yet to be identified.  ",0
5175,25003640,Polymorphisms of leptin-b gene associated with growth traits in orange-spotted grouper (Epinephelus coioides),"In mammals, leptin has been demonstrated to perform important roles in many physiological activities and to influence development, growth, metabolism and reproduction. However, in fish, its function is still unclear. Duplicate leptin genes, leptin-a and leptin-b, have been identified in the orange-spotted grouper. In the present study, the polymorphisms in the leptin-b gene of the orange-spotted grouper were detected, and the relation between these polymorphisms and 12 growth traits were analyzed. Six polymorphisms (including 3 single nucleotide polymorphisms (c.14G>A, c.93A>G, c.149G>A) in exon 1, 2 SNPs (c.181A>G, c.193G>A) in intron 1, and 1 SNP (c.360C>T) in exon 2) were identified and genotyped from 200 different individuals. The results revealed that the SNP c.149G>A was significantly associated with growth traits, that the heterozygous mutation genotype GA having negative effects on growth traits. However, the other five SNPs (c.14G>A, c.93A>G, c.181A>G, c.193G>A, c.360C>T) did not show significant associations with all the growth traits. Compared with our findings in leptin-a gene, the results suggested that the leptin-a hormone has more important physiological effects in fish bodies than the leptin-b type. Moreover, leptin genes were supposed to be one class of major candidate genes of regulating growth traits in the orange-spotted grouper.  ",0
5176,25003665,Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours,"We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine. Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted. Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment. Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing. ",0
5177,25003830,Modeling strategies for pharmaceutical blend monitoring and end-point determination by near-infrared spectroscopy,"The implementation of a blend monitoring and control method based on a process analytical technology such as near infrared spectroscopy requires the selection and optimization of numerous criteria that will affect the monitoring outputs and expected blend end-point. Using a five component formulation, the present article contrasts the modeling strategies and end-point determination of a traditional quantitative method based on the prediction of the blend parameters employing partial least-squares regression with a qualitative strategy based on principal component analysis and Hotelling's T(2) and residual distance to the model, called Prototype. The possibility to monitor and control blend homogeneity with multivariate curve resolution was also assessed. The implementation of the above methods in the presence of designed experiments (with variation of the amount of active ingredient and excipients) and with normal operating condition samples (nominal concentrations of the active ingredient and excipients) was tested. The impact of criteria used to stop the blends (related to precision and/or accuracy) was assessed. Results demonstrated that while all methods showed similarities in their outputs, some approaches were preferred for decision making. The selectivity of regression based methods was also contrasted with the capacity of qualitative methods to determine the homogeneity of the entire formulation.  ",0
5178,25003867,O-chlorobenzylidene malononitrile (CS riot control agent) associated acute respiratory illnesses in a U.S. Army Basic Combat Training cohort,"Acute respiratory illnesses (ARIs) are among the leading causes for hospital visits in U.S. military training populations and historically peak during U.S. Army Basic Combat Training (BCT) following mandatory exposure to the riot control agent o-chlorobenzylidene malononitrile (CS). This observational prospective cohort studied the association between CS exposures and ARI-related health outcomes in 6,723 U.S. Army recruits attending BCT at Fort Jackson, South Carolina from August 1 to September 25, 2012 by capturing and linking the incidence of ARI before and after the mask confidence chamber to CS exposure data. Recruits had a significantly higher risk (risk ratio = 2.44; 95% confidence interval = 1.74, 3.43) of being diagnosed with ARI following exposure to CS compared to the period of training preceding exposure, and incidence of ARI after CS exposure was dependent on the CS exposure concentration (p = 0.03). There was a significant pre-/postexposure ARI difference across all CS concentration levels (p < 0.01), however, no significant differences were detected among these rate ratios (p = 0.72). As CS exposure is positively associated with ARI health outcomes in this population, interventions designed to reduce respiratory exposures could result in decreased hospital burden and lost training time in the U.S. Army BCT population.  ",0
5179,25004202,Targeting breast tumors with pH (low) insertion peptides,"Extracellular acidity is associated with tumor progression. Elevated glycolysis and acidosis promote the appearance of aggressive malignant cells with enhanced multidrug resistance. Thus, targeting of tumor acidity can open new avenues in diagnosis and treatment of aggressive tumors and targeting metastatic cancers cells within a tumor. pH (low) insertion peptides (pHLIPs) belong to the class of pH-sensitive agents capable of delivering imaging and/or therapeutic agents to cancer cells within tumors. Here, we investigated targeting of highly metastatic 4T1 mammary tumors and spontaneous breast tumors in FVB/N-Tg (MMTV-PyMT)634Mul transgenic mice with three fluorescently labeled pHLIP variants including well-characterized WT-pHLIP and, recently introduced, Var3- and Var7-pHLIPs. The Var3- and Var7-pHLIPs constructs have faster blood clearance than the parent WT-pHLIP. All pHLIPs demonstrated excellent targeting of the above breast tumor models with tumor accumulation increasing over 4 h postinjection. Staining of nonmalignant stromal tissues in transgenic mice was minimal. The pHLIPs distribution in tumors showed colocalization with 2-deoxyglucose and the hypoxia marker, Pimonidazole. The highest degree of colocalization of fluorescent pHLIPs was shown to be with lactate dehydrogenase A, which is related to lactate production and acidification of tumors. In sum, the pHLIP-based targeting of breast cancer presents an opportunity to monitor metabolic changes, and to selectively deliver imaging and therapeutic agents to tumors.  ",0
5180,25004292,Simplified technique for reconstruction of the digestive tract after total and subtotal gastrectomy for gastric cancer,"Laparoscopic surgery has been increasingly applied to gastric cancer surgery. Gastrointestinal tract reconstruction totally done by laparoscopy also has been a challenge for those who developed this procedure. To describe simplified reconstruction after total or subtotal gastrectomy for gastric cancer by laparoscopy and the results of its application in a series of cases. In the last four years, 75 patients were operated with gastric cancer and two with GIST. Thirty-four were women and 43 men. The age ranged from 38 to 77 years with an average of 55 years. In two patients with GIST a total and a subtotal gastrectomy were performed. In the other 75 patients were done 21 total gastrectomies and 54 subtotal. In all cancers, gastrectomy with D2 lymphadenectomy was completed with at least 37 lymph nodes removed. Was used in these operations a modified laparoscopic technique proposed by the authors consisting in a latero lateral esophagojejunal anastomosis with linear stapler in TG as well in STG, and reconstruction of the digestive continuity also in the upper abdomen. The intraoperative and immediate postoperative course were uneventful, except for one case of bleeding due to an opening clip, necessitating re-intervention. The operative time was 300 minutes, with no difference between total or subtotal gastrectomy. The number of lymph nodes removed varied from 28 to 69, averaging 37. Postoperative staging showed one case in T4 N2 M0; 13 in T2 N0 MO; 27 in T2 N1 M0; 24 in T3 N1 M0 and 10 in T3 N2 M0. Complication in only one case was observed on the 10th postoperative day with a small anastomotic leakage in esophagojejunal anastomose with spontaneous closure. The patient's evolution with no complications, no mortality and just one small anastomotic leakage with no systemic repercussions is a strong indication of the liability and feasibility of this innovative technical method. ",0
5181,25004327,Cogan syndrome in pregnancy,"Cogan syndrome is a rare, multisystem, autoimmune disorder of unknown etiology. Little is known about whether it affects pregnancy or whether pregnancy affects the disease. A 24-year-old primigravid woman with Cogan syndrome diagnosed 3 years before her pregnancy presented to our clinic for prenatal care. During pregnancy she experienced no worsening of symptoms of her disease but reported subjective improvement in vision and hearing. Cesarean delivery was performed at term because of nonreassuring fetal status. There were no obstetric or postpartum complications. Cogan syndrome requires close monitoring. If it worsens, then the disease process can be similar to both physiologic and pathologic changes of pregnancy. However, unlike the former, worsening Cogan syndrome can have irreversible maternal consequences. ",0
5182,25004585,Survivors of brain injury: the narrative experiences of being a college or university student,"The deficits associated with a brain injury may pose many challenges to young adult students. The purpose of this study was to conduct an in-depth exploration of the experiences and processes individuals who self-identify as having a brain injury go through during college or university to overcome obstacles. This study used a basic interpretative qualitative design. Data were collected through semi-structured interviews and analyzed with the constant comparative method. Three themes emerged: balancing act, reality versus injury, and square peg in a round hole. Participants discussed personal strategies that they used to help them be successful. Despite these strategies, the participants continued to feel out of place and felt that seeking disability services would further set them apart from their non-injured peers. Individuals post-brain injury may benefit from occupational therapy services to reduce the challenges associated with functioning in the student role in college and university environments. ",0
5183,25004888,Gastrodia elata shows neuroprotective effects via activation of PI3K signaling against oxidative glutamate toxicity in HT22 cells,"Dried roots of Gastrodia elata have traditionally been used in Korean medicine for the treatment of neurological disorders such as scotodinia, paralysis, and epilepsy. In our study, we attempted to investigate the neuroprotective effects of methanol extract from G. elata (MEGE) against glutamate-mediated oxidative stress and to explore underlying neuroprotective mechanisms. Analyses for cell viability, lactate dehydrogenase (LDH), flow cytometry, Western blot, and reactive oxygen species (ROS) were performed in HT22 hippocampal cells. Pretreatment with MEGE resulted in a potent neuroprotective effect against oxidative glutamate toxicity and these effects were exerted mainly by the abrogation of glutamate-induced apoptotic death. Treatment with glutamate resulted in a significant expression of both phosphorylated p38 and dephosphorylated phosphatidylinositol-3-kinase (PI3K). However, pretreatment with MEGE resulted in the inhibition of these expressions. In the inhibitor studies, treatment with PI3K inhibitor LY294002 resulted in the abrogation of the neuroprotective effect of MEGE. In addition, pretreatment with MEGE also resulted in the suppression of the glutamate-induced production of ROS. Treatment with MEGE and anti-oxidant N-acetyl-L-cysteine (NAC) resulted in the enhanced phosphorylation of both PI3K and cAMP responsive element binding protein (CREB), and, in particular, treatment with MEGE resulted in significantly enhanced expression of mature brain-derived neurotrophic factor (BDNF). These results suggest that the extract from G. elata mainly exerted neuroprotective effects through the up-regulation of the PI3K signaling pathway in association with BDNF and may be a useful therapeutic agent for treatment of oxidative neuronal death. ",0
5184,25004911,The miR-29 family in hematological malignancies,"MicroRNAs are short non-coding regulators of gene expression. The human miR-29 family consists of three members: miR-29a, miR-29b and miR-29c. Members of this family were found to be aberrantly expressed in various types of tumors, including hematological malignancies. This family was described to have both oncogenic and tumor suppressor features influencing various pathological processes, such as tumor growth and apoptosis. This review summarizes current knowledge about the miR-29 family in selected hematological malignancies. Recent research of miR-29 family in hematological malignancies has proven its oncogenic as well as tumor suppressive potential. Nevertheless, the level of current evidence is not sufficient, and data remain inconclusive. ",0
5185,25005431,Prevalence of bovine tuberculosis in a dairy cattle farm and a research farm in Ghana,"The aim of the study was to estimate the prevalence of bovine tuberculosis (BTB) and to identify the mycobacterial species causing BTB in a dairy farm and research farm. Six hundred and eighty-five cattle were screened for BTB by using the Comparative intradermal tuberculin test (CTT). Positive reactors were slaughtered and carcasses were taken for isolation of mycobacterial species. This was followed by speciation of isolates using both standard conventional and molecular assays. Seventeen of the cattle were positive by CTT, giving a crude BTB prevalence of 2.48% among cattle from the two farms. Six of the 17 samples (35.30%) yielded positive acid-fast bacilli cultures and three of the isolates were identified as Mycobacterium tuberculosis complex (MTBC), which were sub-divided into two Mycobacterium tuberculosis sensu scrito (Mtb) and one Mycobacterium africanum; the remaining three were Mycobacterium other than tuberculoisis (MOTT). Spoligotyping further characterised the two Mtb isolates as Ghana (spoligotype Data Base 4 number 53) and Latin American Mediterranean (LAM), whilst spoligotyping and Single Nucleotide Polymorphism (SNP) analysis typed the M. africanum as West African 1. Microseq 500 analysis identified two of the MOTT as Mycobacterium flavescens and Mycobacterium Moriokaense respectively, whilst the remaining one could not be identified. This study observed the prevalence of bovine TB among cattle from two farms in Ghana as 2.48% and confirms the public health importance of M. africanum as a pathogen in Ghana. ",0
5186,25005444,Desmopressin improves platelet activity in acute intracerebral hemorrhage,"Minimizing hematoma growth in high-risk patients is an attractive strategy to improve outcomes after intracerebral hemorrhage. We tested the hypothesis that desmopressin (DDAVP), which improves hemostasis through the release of von Willebrand factor, improves platelet activity after intracerebral hemorrhage. Patients with reduced platelet activity on point-of-care testing alone (5), known aspirin use alone (1), or both (8) received desmopressin 0.4 μg/kg IV. We measured Platelet Function Analyzer-epinephrine (Siemens AG, Germany) and von Willebrand factor antigen from baseline to 1 hour after infusion start and hematoma volume from the diagnostic to a follow-up computed tomographic scan. We enrolled 14 patients with of mean age 66.8±14.6 years, 11 (85%) of whom were white and 8 (57%) were men. Mean Platelet Function Analyzer-epinephrine results shortened from 192±18 seconds pretreatment to 124±15 seconds (P=0.01) 1 hour later, indicating improved plate activity. von Willebrand factor antigen increased from 242±96% to 289±103% activity (P=0.004), indicating the expected increase in von Willebrand factor. Of 7 (50%) patients who received desmopressin within 12 hours of intracerebral hemorrhage symptom onset, changes in hematoma volume were modest, -0.5 (-1.4 to 8.4) mL and only 2 had hematoma growth. One patient had low blood pressure and another had a new fever within 6 hours of desmopressin administration. Intravenous desmopressin was well tolerated and improved platelet activity after acute intracerebral hemorrhage. Larger studies are needed to determine its potential effects on reducing hematoma growth versus platelet transfusion or placebo. http://www.clinicaltrials.gov. Unique identifier: NCT00961532. ",0
5187,25005497,AKAP150 mobilizes cPKC-dependent cardiac glucotoxicity,"Activation of conventional PKCs (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cardiac cPKC signaling. This study was designed to investigate the role of AKAP150 in cPKC-mediated cardiac glucotoxicity. In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose-treated neonatal rat cardiomyocytes, both mRNA and protein levels of AKAP150 increased significantly, and marked elevations were observed in cPKC activity and both expression and phosphorylation levels of p65 NF-κB and p47(phox). AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150-targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction as manifested by decreased left ventricular end-diastolic diameter and early/late mitral diastolic wave ratio. AKAP150 inhibition also abrogated high-glucose-induced cardiomyocyte apoptosis (TUNEL staining and annexin V/propidium iodide flow cytometry) and oxidative stress (ROS production, NADPH oxidase activity, and lipid peroxidation). More importantly, reduced AKAP150 expression significantly inhibited high-glucose-induced membrane translocation and activation of cPKC and suppressed the increases in the phosphorylation of p65 NF-κB and p47(phox). Immunofluorescent coexpression and immunoprecipitation indicated enhanced anchoring of AKAP150 with cPKC within the plasma membrane under hyperglycemia, and AKAP150 preferentially colocalized and functionally bound with PKCα and -β isoforms. These results suggest that cardiac AKAP150 positively responds to hyperglycemia and enhances the efficiency of glucotoxicity signaling through a cPKC/p47(phox)/ROS pathway that induces myocardial dysfunction, cardiomyocyte apoptosis, and oxidative stress.  ",0
5188,25005511,Association between dysfunctional elimination syndrome and sensory processing disorder,"OBJECTIVE. We explored whether sensory processing disorder (SPD) is related to dysfunctional elimination syndrome (DES). METHOD. We used the Vancouver Nonneurogenic Lower Urinary Tract Dysfunction/Dysfunctional Elimination Syndrome Questionnaire and the Short Sensory Profile with participants who sought treatment of DES (n = 19) and healthy control participants (n = 55). RESULTS. Significantly more children with DES (53%) had SPD than was reported for the general population (p < .001; Ahn, Miller, Milberger, & McIntosh, 2004). Control participants did not have a greater rate of SPD (p = .333). We found a significant association between the occurrence of DES and SPD, χ²(1) = 20.869, p < .001, and a significant correlation between test scores (Spearman's ρ = -.493, Rs² = .243, p < .001). CONCLUSION. Many children with DES may also have SPD, suggesting that a child's sensory processing pattern would be an important aspect that could influence the plan of care.  ",0
5189,25005553,Readiness to quit as a predictor for outcomes of smoking-reduction programme with transdermal nicotine patch or bupropion in a sample of 308 patients with schizophrenia,"Readiness to quit has been found to predict smoking-cessation outcomes in a general population. However, little is known about the relationship between the readiness to quit and smoking-reduction outcomes in patients with schizophrenia treated with pharmacological adjuvants. The aim of this study was to examine the association between readiness to quit and smoking-reduction outcomes in patients with schizophrenia. A total of 308 subjects using nicotine replacement therapy (NRT) (N = 242) or bupropion (N = 66) participated in an 8-week smoking-reduction programme. Participants were categorised into precontemplators (N = 127), contemplators (N = 76) and preparators (N = 105) to quit smoking based on the transtheoretical model. There was a significant difference in change in number of cigarettes (NOC) (p = 0.007) and Fagerstrom test for nicotine dependence (FTND) score (nicotine dependence level) (p = 0.029) across the stages of change. A linear regression model revealed trend of increasing reduction in NOC and FTND scores in different stages of change (NOC: B = -1.22, t = -2.81, p = 0.005; FTND: B = -0.43, t = -2.57, p = 0.011). However, the 7-day point prevalence of abstinence was 5.5% (18/308), but there was no significant association between stage of change and smoking cessation (p = 0.26), possibly due to a very small sample size of successful quitters. In summary, among a cohort of institutionalised chronic schizophrenia patients receiving 8-week NRT or bupropion, stage of change can predict smoking reduction and may serve as a useful indicator for patients' preparedness before a trial of smoking reduction. ",0
5190,25005732,An unexpected finding: younger fathers have a higher risk for offspring with chromosomal aneuploidies,"The past decades have seen a remarkable shift in the demographics of childbearing in Western countries. The risk for offspring with chromosomal aneuploidies with advancing maternal age is well known, but most studies failed to demonstrate a paternal age effect. Retrospectively, we analyzed two case data sets containing parental ages from pre- and postnatal cases with trisomies 21, 13 and 18. The reference data set contains the parental ages of the general Swiss population. We dichotomized all couples into two distinct groups. In the first group, the mothers' integral age was as least as the father's age or older. We compared the frequency of cases in nine 5-year intervals of maternal age. In addition, we computed logistic regression models for the binary endpoint aneuploidy yes/no where paternal ages were incorporated as linear or quadratic, as well as smooth functions within a generalized additive model framework. We demonstrated that the proportion of younger fathers is uniformly different between cases and controls of live-born trisomy 21 as well, although not reaching significance, for fetuses over all mother's ages. Logistic regression models with different strategies to incorporate paternal ages confirmed our findings. The negative paternal age effect was also found in pre- and postnatal cases taken together with trisomies 13 and 18. The couples with younger fathers face almost twofold odds for a child with Down syndrome (DS). We estimated odds curves for parental ages. If confirmation of these findings can be achieved, the management of couples at risk needs a major correction of the risk stratification.  ",0
5191,25005866,Retrospective review of the drop in observer detection performance over time in lesion-enriched experimental studies,"The vigilance decrement describes a decrease in sensitivity or increase in specificity with time on task. It has been observed in a variety of repetitive visual tasks, but little is known about these patterns in radiologists. We investigated whether there is systematic variation in performance over the course of a radiology reading session. We re-analyzed data from six previous lesion-enriched radiology studies. Studies featured 8-22 participants assessing 27-100 cases (including mammograms, chest CT, chest x-ray, and bone x-ray) in a reading session. Changes in performance and speed as the reading session progressed were analyzed using mixed effects models. Time taken per case decreased 9-23% as the reading session progressed (p < 0.005 for every study). There was a sensitivity decrease or specificity increase over the course of reading 100 chest x-rays (p = 0.005), 60 bone fracture x-rays (p = 0.03), and 100 chest CT scans (p < 0.0001). This effect was not found in the shorter mammography sessions with 27 or 50 cases. We found evidence supporting the hypothesis that behavior and performance may change over the course of reading an enriched test set. Further research is required to ascertain whether this effect is present in radiological practice. ",0
5192,25006039,Sleep in trigeminal autonomic cephalagias: a review,"Sleep and cluster headache (CH) are believed to be interconnected but the precise relation to the other trigeminal autonomic cephalalgias (TACs) is uncertain and complex. A better understanding of these relations may eventually lead to a clarification of the underlying mechanisms and eventually to more effective therapeutic regimens. This review aims to evaluate the existing literature on the subject of TACs and sleep. An association between episodic CH and distinct macrostructural sleep phases, especially the relation to rapid eye movement (REM) sleep, has been described in some older studies but could not be confirmed in other, more recent studies. Investigations into the microstructure of sleep in these patients are lacking. Only a few case reports exist on the relation between sleep and other TACs. Recent studies do not find an association between CH and REM sleep. One older study suggests chronic paroxysmal hemicranias may be locked to REM sleep but otherwise the relation is unknown. Reports indicate that CH and obstructive sleep apnoea are associated in some individuals but results are diverging. Single cases show improvement of CH upon treatment of sleep apnoea, but the causal relationship remains in question. Other TACs are probably not connected to sleep and strictly nocturnal attacks should prompt investigations for secondary causes. The relation between CH and sleep is, however, fascinating and detailed sleep studies in carefully diagnosed patients are warranted. ",0
5193,25006082,"Atmospheric pressure: Russian drug policy as a driver for violations of the UN Convention against Torture and the International Covenant on Economic, Social and Cultural Rights","""Responding to problematic drug use in Russia, the government promotes a policy of """"zero tolerance"""" for drug use and """"social pressure"""" against people who use drugs (PWUD), rejecting effective drug treatment and harm reduction measures. In order to assess Russian drug policy against the UN Convention Against Torture and the International Covenant on Economic, Social, and Cultural Rights, we reviewed published data from government and non-governmental organizations, scientific publications, media reports, and interviews with PWUD. Drug-dependent people (DDP) are the most vulnerable group of PWUD. The state strictly controls all aspects of drug dependence. Against this background, the state promotes hatred towards PWUD via state-controlled media, corroding public perception of PWUD and of their entitlement to human rights. This vilification of PWUD is accompanied by their widespread ill-treatment in health care facilities, police detention, and prisons. In practice, zero tolerance for drug use translates to zero tolerance for PWUD. Through drug policy, the government deliberately amplifies harms associated with drug use by causing PWUD (especially DDP) additional pain and suffering. It exploits the particular vulnerability of DDP, subjecting them to unscientific and ideologically driven methods of drug prevention and treatment and denying access to essential medicines and services. State policy is to legitimize and encourage societal ill-treatment of PWUD. The government intentionally subjects approximately 1.7 million people to pain, suffering, and humiliation. Aimed at punishing people for using drugs and coercing people into abstinence, the official drug policy disregards the chronic nature of drug dependence. It also ignores the ineffectiveness of punitive measures in achieving the purposes for which they are officially used, that is, public safety and public health. Simultaneously, the government impedes measures that would eliminate the pain and suffering of DDP, prevent infectious diseases, and lower mortality, which amount to systematic violations of Russia's human rights obligations. """,0
5194,25006241,Invasive aspergillosis caused by Aspergillus terreus: an emerging opportunistic infection with poor outcome independent of azole therapy,"Invasive aspergillosis (IA) caused by Aspergillus terreus is a significant cause of morbidity and mortality in patients with haematological malignancy (HM). Very few data are available in this patient population to differentiate IA patients with A. terreus from those with non-terreus species of Aspergillus to compare outcomes. We retrospectively investigated 513 HM patients who were treated for either definite or probable IA between June 1993 and August 2012 in a cancer centre. We compared baseline characteristics, antifungal therapies and outcomes between patients infected with A. terreus (n = 96, 18.7%) and those infected with non-terreus Aspergillus species (n = 335, 65.3%). Eighty-one patients with mixed or unspecified Aspergillus infections were excluded. Breakthrough infections occurred more frequently in the A. terreus group (91% versus 77%, P = 0.009). A. terreus infection was associated with a lower rate of final response to antifungal therapy (21% versus 38%, P = 0.0015) and a higher rate of IA-associated mortality (51% versus 30%, P < 0.001). Multivariate analyses showed that these associations were independent of patients' clinical characteristics and the antifungal regimens they received. Factors independently associated with final response included treatment with azoles (OR 3.1, 95% CI 1.9-5.0, P < 0.0001) and Aspergillus species (A. terreus versus non-terreus Aspergillus species) (OR 0.5, 95% CI 0.3-0.98, P = 0.043). Additionally, Aspergillus species and treatment with azoles were independently associated with IA-associated mortality. A. terreus IA in HM patients was associated with worse outcome than IA caused by non-terreus Aspergillus species. Poor prognosis in patients with invasive A. terreus infections is independent of anti-Aspergillus azole-based treatment. ",0
5195,25006290,Posterior reversible encephalopathy syndrome in pediatric acute leukemia: Case series and literature review,"Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state coupled with a unique radio imaging appearance. We describe this rare, mostly reversible condition in five cases undergoing similar treatment under preset protocol (MCP-841) for acute lymphoblastic leukemia (ALL) at our centre. Hypertension is a well-known adverse effect of high-dose corticosteroid therapy primarily mediated by its effects on the mineralocorticoid receptor especially in pediatric population and we hypothesize that this may be the etiology of PRES in two of these patients.  ",0
5196,25006361,Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis,"Several studies have reported an association between chronic periodontitis (CP) and cardiovascular diseases. Detection of periodontopathogens, including red complex bacteria (RCB), in vascular lesions has suggested these bacteria to be involved in the pathogenesis of atherosclerosis and abdominal aortic aneurysms. In this study, we investigate bacteria and their DNA in vascular biopsies from patients with vascular diseases (VD; i.e. abdominal aortic aneurysms, atherosclerotic carotid, and common femoral arteries), with and without CP. DNA was extracted from vascular biopsies selected from 40 VD patients: 30 with CP and 10 without CP. The V3-V5 region of the 16S rDNA (V3-V5) was polymerase chain reaction (PCR)-amplified, and the amplicons were cloned into Escherichia coli, sequenced, and classified (GenBank and the Human Oral Microbiome database). Species-specific primers were used for the detection of Porphyromonas gingivalis. In addition, 10 randomly selected vascular biopsies from the CP group were subjected to scanning electron microscopy (SEM) for visualization of bacteria. Checkerboard DNA-DNA hybridization was performed to assess the presence of RCB in 10 randomly selected subgingival plaque samples from CP patients. A higher load and mean diversity of bacteria were detected in vascular biopsies from VD patients with CP compared to those without CP. Enterobacteriaceae were frequently detected in vascular biopsies together with cultivable, commensal oral, and not-yet-cultured bacterial species. While 70% of the subgingival plaque samples from CP patients showed presence of RCB, only P. gingivalis was detected in one vascular biopsy. Bacterial cells were seen in all 10 vascular biopsies examined by SEM. A higher bacterial load and more diverse colonization were detected in VD lesions of CP patients as compared to patients without CP. This indicated that a multitude of bacterial species both from the gut and the oral cavity, rather than exclusively periodontopathogens, may be involved as additional risk factors in the pathogenesis of VD. ",0
5197,25006567,Genome-wide Association Studies for Osteoporosis: A 2013 Update,"In the past few years, the bone field has witnessed great advances in genome-wide association studies (GWASs) of osteoporosis, with a number of promising genes identified. In particular, meta-analysis of GWASs, aimed at increasing the power of studies by combining the results from different study populations, have led to the identification of novel associations that would not otherwise have been identified in individual GWASs. Recently, the first whole genome sequencing study for osteoporosis and fractures was published, reporting a novel rare nonsense mutation. This review summarizes the important and representative findings published by December 2013. Comments are made on the notable findings and representative studies for their potential influence and implications on our present understanding of the genetics of osteoporosis. Potential limitations of GWASs and their meta-analyses are evaluated, with an emphasis on understanding the reasons for inconsistent results between different studies and clarification of misinterpretation of GWAS meta-analysis results. Implications and challenges of GWAS are also discussed, including the need for multi- and inter-disciplinary studies.  ",0
5198,25006899,Forensic age estimation by spheno-occipital synchondrosis fusion degree: computed tomography analysis,"The analysis of ossification points plays a considerable role in forensic age estimation. Although traditional methods are still in use, researchers are working on different age estimation procedures especially within the development of radiologic methods. One of these methods is to define spheno-occipital synchondrosis fusion degree. Spheno-occipital synchondrosis, an important growth point on cranial base, provides noteworthy information about age estimation through its late stage ossification nature. This study aimed to investigate spheno-occipital synchondrosis fusion degree for age estimation in the Turkish population. In our study, 1-mm-sectioned computed tomography images of 638 (399 men and 139 women) subjects within the age of 10 to 25 years were retrospectively examined. It is stated in our study that spheno-occipital syncondrosis fusion begins superiorly and progresses inferiorly until it is completed. Spheno-occipital syncondrosis is known to be totally open at the mean (SD) age of 11.5 (1.5) years in men and 10.7 (0.8) years in women. In addition, fusion degree is known to be increased with age. Fusion starts approximately 2 years earlier in women than in men, and the process of fusion completes at the age of 17 years in both sexes. An analysis of fusion degree between sex groups showed significance at the age of 11 to 15 years, and Spearman rank correlations indicate a significant positive relationship between age and degree of spheno-occipital fusion (P < 0.001; men, ρ = 0.714; women, ρ = 0.698). Consequently, 5-staged analysis of spheno-occipital synchondrosis fusion degree in use with 1-mm computed tomography images will be helpful for age estimation between 11 and 17 years.  ",0
5199,25006926,Papillary meningioma with vital abnormal vessels,"Papillary meningioma is an uncommon meningioma subtype of World Health Organization grade III. It could show some radiologic profiles pointing to malignant behavior, such as a cystic change, a heterogeneous enhancement, and an ill- defined border. However, to date, the radiologic profile described in this article has not been reported in previous literatures, and it is just the characteristic being considered as the major cause for patients' death. A 16-year-old adolescent boy with a 6-month history of headache was admitted to our department on June 28, 2012. Magnetic resonance imaging showed a giant well-defined mass in the left temporal region, with a severe flow void on T2-weighted image and an abundant stripelike enhancement on T1-weighted contrast-enhanced scan. In view of its middle cranial fossa location (one predilection site for meningioma), meningioma was suspected preoperatively. A regular left frontotemporal craniotomy was performed. Unexpectedly, extreme hemorrhage happened intraoperatively, and it was difficult to stop the bleeding. After identification of no hemorrhage in the operative cavity through intraoperative magnetic resonance imaging, the operation was finished, with an overall blood loss of 15,000 mL. The patient died of brain stem dysfunction the second day after the operation.  ",0
5200,25006937,Primary diffuse large B-cell non-Hodgkin lymphoma of the paranasal sinuses presenting as cavernous sinus syndrome,"Primary paranasal sinus lymphoma is an uncommon malignancy that accounts for only 0.17% of all lymphomas and is often difficult to diagnose. Initially, tumors in this area cause very few symptoms and are at an advanced stage at the time of diagnosis. Ophthalmologic signs and symptoms occur early in the disease process because of close proximity of the orbit to the paranasal sinuses. We report on a case of primary malignant lymphoma of the sphenoid and ethmoid sinuses with involvement of the cavernous sinus, initially presenting with ophthalmologic signs and symptoms in association with cavernous sinus syndrome.  ",0
5201,25007016,Liver regeneration--the best kept secret. A model of tissue injury response,"Liver regeneration (LR) is one of the most amazing tissue injury response. Given its therapeutic significance has been deeply studied in the last decades.LR is an extraordinary complex process, strictly regulated, which accomplishes the characteristics of the most evolutionary biologic systems (robustness) and explains the difficulties of reshaping it with therapeutic goals.TH reproduces the physiological tissue damage response pattern, with a first phase of priming of the hepatocytes-cell-cycle transition G0-G1–, and a second phase of proliferation –cell-cycleS/M phases– which ends with the liver mass recovering. This process has been related with the tissue injury response regulators as: complement system, platelets, inflammatory cytokines(TNF-a, IL-1b, IL-6), growth factors (HGF, EGF, VGF) and anti-inflammatory factors (IL-10, TGF-b).Given its complexity and strict regulation, illustrates the unique alternative to liver failure is liver transplantation.The recent induced pluripotential cells (iPS) description and the mesenchymal stem cell (CD133+) plastic capability have aroused new prospects in the cellular therapy field. Those works have assured the cooperation between mesenchymal and epithelial cells. Herein, we review the physiologic mechanisms of liver regeneration. ",0
5202,25007031,International confederation for cleft lip and palate and related craniofacial anomalies task force report: palatoplasty in the speaking individual with unrepaired cleft palate,"Introduction : The benefits or otherwise of late palate repair in older children or adults are uncertain. The outcomes, particularly without appropriate speech therapy, are often disappointing. The issue is of special importance in the poorer countries where these patients are most commonly seen and where limited capacity and facilities may have to be rationed. Method : A task force was set up to report back to the International Congress in Orlando in May 2013. The chairman and some members were nominated by the organizers and further members were added during the discussion process. Some of the members had considerable experience of late palate repair. The task force compiled a report after 9 months of e-mail correspondence. The report includes reports of some previously unpublished studies. A summary of the report was presented at Cleft 2013 in Orlando. Conclusions : There was a general consensus that late palate repair is of benefit for many patients and that, even if normal speech is not attained, outcomes are positive. Outcomes depend on the age of the patient (the younger the better), on the skill of the surgeon and, ideally, on the availability of appropriate speech therapy. A protocol for a prospective international multi-center study is proposed.  ",0
5203,25007068,Cordycepin inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production via activating amp-activated protein kinase (AMPK) signaling,"Tumor necrosis factor (TNF)-α is elevated during the acute phase of Kawasaki disease (KD), which damages vascular endothelial cells to cause systemic vasculitis. In the current study, we investigated the potential role of cordycepin on TNFα expression in both lipopolysaccharide (LPS)-stimulated macrophages and ex vivo cultured peripheral blood mononuclear cells (PBMCs) of KD patients. We found that cordycepin significantly suppressed LPS-induced TNFα expression and production in mouse macrophages (RAW 264.7 cells and bone marrow-derived macrophages (BMDMs)). Meanwhile, cordycepin alleviated TNFα production in KD patients' PBMCs. PBMCs from healthy controls had a much lower level of basal TNF-α content than that of KD patients. LPS-induced TNF-α production in healthy controls' PBMCs was also inhibited by cordycepin. For the mechanism study, we discovered that cordycepin activated AMP-activated protein kinase (AMPK) signaling in both KD patients' PBMCs and LPS-stimulated macrophages, which mediated cordycepin-induced inhibition against TNFα production. AMPK inhibition by its inhibitor (compound C) or by siRNA depletion alleviated cordycepin's effect on TNFα production. Further, we found that cordycepin inhibited reactive oxygen species (ROS) production and nuclear factor kappa B (NF-κB) activation in LPS-stimulate RAW 264.7 cells or healthy controls' PBMCs. PBMCs of KD patients showed higher basal level of ROS and NF-κB activation, which was also inhibited by cordycepin co-treatment. In conclusion, our data showed that cordycepin inhibited TNFα production, which was associated with AMPK activation as well as ROS and NF-κB inhibition. The results of this study should have significant translational relevance in managing this devastating disease.  ",0
5204,25007130,"Metabolic disposition of AZD8931, an oral equipotent inhibitor of EGFR, HER2 and HER3 signalling, in rat, dog and man","1. This series of studies in rats, dogs and humans (Clinicaltrials.gov identifier: NCT01284595) investigated the pharmacokinetics, tissue distribution, metabolism and excretion of the EGFR, HER2 and HER3 signalling inhibitor AZD8931. 2. Single oral or intravenous doses of 2-(4-[4-(3-chloro-2-fluoro[U-(14)C]-phenylamino)-7-methoxy-quinazolin-6-yloxy]-piperidin-1-yl)-N-methyl-acetamide difumarate ([(14)C]-AZD8931) were administered. 3. AZD8931 absorption was rapid in all species. Following [(14)C]-AZD8931 administration to rats, radioactivity was widely and rapidly distributed, with the highest levels in organs of metabolism and excretion (gastrointestinal tract, liver). Following oral and intravenous [(14)C]-AZD8931 administration, excretion of radioactivity by all species occurred predominantly via the bile into faeces, with <5% of the dose being eliminated in urine. In all species, AZD8931 was principally cleared by metabolism. The major route of metabolism was hydroxylation and O-demethylation in rat, and aryl ring oxidation in dog. Metabolism of AZD8931 in humans was attributed to three pathways; oxidation and amine or ether cleavage around the piperidine ring with subsequent glucuronide or sulphate conjugation. 4. AZD8931 is largely cleared by metabolism in the rat, dog and human. Excretory profiles indicate that there are no unique human metabolites. ",0
5205,25007240,Induction of ulcerative colitis in mice influences the course of infection with the nematode Trichuris muris,"The aim of this study was to assess the effect of infection with the nematode whipworm Trichuris muris on the course of chemically induced acute ulcerative colitis in CBA/J mice, a strain proven to be highly resistant to infection with T. muris. Each mouse was infected with 50 embryonated eggs of T. muris by oral gavage. Acute colitis was triggered by administering 4% dextran sulphate sodium (DSS) in the drinking water for nine consecutive days at different times after infection. Concurrent infection and DSS administration exacerbate the severity of the colitis while favouring the permanence of parasites in the intestine. The induction of ulcerative colitis from days 54 to 62 post-infection (p.i.), when all worms had been expelled, ameliorated the course of the inflammatory disease. When ulcerative colitis was triggered earlier on, from days 27 to 35 p.i., the beneficial effects on inflammatory events were clearly shown with signs of mucosal epithelization and regeneration as early as day 1 after DSS administration. Previous infections by T. muris therefore accelerate recovery from subsequently induced inflammatory bowel disease and such an effect assists the nematode to persist in the intestinal niche.  ",0
5206,25007281,"Validation of the French version of the yale food addiction scale: an examination of its factor structure, reliability, and construct validity in a nonclinical sample","The concept of food addiction has recently been proposed by applying the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for substance dependence to eating behaviour. Food addiction has received increased attention given that it may play a role in binge eating, eating disorders, and the recent increase in obesity prevalence. Currently, there is no psychometrically sound tool for assessing food addiction in French. Our study aimed to test the psychometric properties of a French version of the Yale Food Addiction Scale (YFAS) by establishing its factor structure and construct validity in a nonclinical population. A total of 553 participants were assessed for food addiction (French version of the YFAS) and binge eating behaviour (Bulimic Investigatory Test Edinburgh and Binge Eating Scale). We tested the scale's factor structure (factor analysis for dichotomous data based on tetrachoric correlation coefficients), internal consistency, and construct validity with measures of binge eating. Our results supported a 1-factor structure, which accounted for 54.1% of the variance. This tool had adequate reliability and high construct validity with measures of binge eating in this population, both in its diagnosis and symptom count version. A 2-factor structure explained an additional 9.1% of the variance, and could differentiate between patients with high, compared with low, levels of insight regarding addiction symptoms. In our study, we validated a psychometrically sound French version of the YFAS, both in its symptom count and diagnostic version. Future studies should validate this tool in clinical samples. ",0
5207,25008174,Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis,"Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation. ",0
5208,25008478,The intra-individual variability of faecal calprotectin: a prospective study in patients with active ulcerative colitis,"Leukocyte-derived proteins in faeces, especially calprotectin, are increasingly used to assess disease activity in ulcerative colitis. The objectives of the present study were to assess the importance of factors related to the stool sampling procedure. For 2 days, patients with active ulcerative colitis collected two stool samples at each bowel movement. The time of defecation, consistency and presence of blood were self-recorded in a diary. The variability in the concentrations of calprotectin during the day and between two consecutive days was assessed, as was the stability of calprotectin concentrations in samples stored at room temperature. Altogether, 18 patients collected 287 stool samples. The intraclass correlation coefficient in pairs of samples from 132 bowel movements was 0.79 (95% CI 0.48-0.90). The median individual coefficient of variation in samples collected during the same day was 52% (4-178). There was a correlation between the level of calprotectin and the time between bowel movements (r = 0.5; p = 0.013). After 3 days at room temperature the calprotectin concentrations in stool samples were unchanged, but after 7 days a significant (p < 0.01) decrease was found (mean 28%; 95% CI 0.10-0.47). The present data reveal a great variability in the concentrations of calprotectin in stool samples collected during a single day. Since the levels of calprotectin increased with longer time between the bowel movements, it seems most appropriate to analyse stool from the first bowel movement in the morning. Moreover, storage of stool samples at room temperature for more than 3 days is not advisable. ",0
5209,25008482,Helios expression in T-regulatory cells in patients with di George Syndrome,"Syndrome diGeorge is associated amongst other clinical signs with various degrees of thymic dysplasia, related immunodeficiency and autoimmune disorders. Helios, a transcription factor from Ikaros family, has been proposed as a marker for thymus derived Tregs. We therefore examined Helios + Tregs in a cohort of patients with genetically proven diGeorge syndrome with typical T cell lymphopenia due to the thymic pathology. T cells, FoxP3+ Tregs and Helios + FoxP3+ Tregs were examined in 52 samples from 37 patients. One patient with diGeorge/CHARGE syndrome with total thymic aplasia was also included. Statistical analysis was performed using a linear regression comparison. Total absolute Tregs were significantly lower in diGeorge patients as compared to controls in all age groups (0-20 years) (p = 0.0016). The difference was more expressed in the first four years of age. Relative Treg numbers expressed as the percentage of Tregs in CD4+ T-cells, however, were not different in patients and controls in all age groups (p = 0.661), neither could we find any significant difference in the percentage of Helios + Tregs between patients and controls (p = 0.238). Helios + Tregs were still present in a patient with diGeorge/CHARGE syndrome with complete athymia 7 years after partially matched unrelated repeated T lymphocytes infusions. Our findings show that while there was a significant decrease in absolute numbers of Tregs in patients with diGeorge syndrome, the relative percentage of this population did not differ between patients and controls. Low absolute Tregs thus reflected typical T cells lymphopenia in patients. Helios expression was not affected in diGeorge syndrome. ",0
5210,25008769,An outbreak of adult measles by nosocomial transmission in a high vaccination coverage community,"The aims of this study were to determine the mechanism of an outbreak of measles in adults and to provide scientific measures for putting forward a measles elimination program. We performed a cross-sectional investigation during the measles outbreak to identify a possible communication link. From November 1, 2011 to January 26, 2012, the town reported 11 cases of measles in total. The case study identified an obvious propagation chain, which showed ordered and intimate exposure between cases. Hospital exposure 1-2 weeks before infection with measles was the main cause of the measles outbreak. We must be fully aware of the possibility of nosocomial infection in an outbreak of measles; controlling nosocomial infections is a vital step in the prevention and control of the propagation of measles. ",0
5211,25009066,Global variation in thermal tolerances and vulnerability of endotherms to climate change,"The relationships among species' physiological capacities and the geographical variation of ambient climate are of key importance to understanding the distribution of life on the Earth. Furthermore, predictions of how species will respond to climate change will profit from the explicit consideration of their physiological tolerances. The climatic variability hypothesis, which predicts that climatic tolerances are broader in more variable climates, provides an analytical framework for studying these relationships between physiology and biogeography. However, direct empirical support for the hypothesis is mostly lacking for endotherms, and few studies have tried to integrate physiological data into assessments of species' climatic vulnerability at the global scale. Here, we test the climatic variability hypothesis for endotherms, with a comprehensive dataset on thermal tolerances derived from physiological experiments, and use these data to assess the vulnerability of species to projected climate change. We find the expected relationship between thermal tolerance and ambient climatic variability in birds, but not in mammals-a contrast possibly resulting from different adaptation strategies to ambient climate via behaviour, morphology or physiology. We show that currently most of the species are experiencing ambient temperatures well within their tolerance limits and that in the future many species may be able to tolerate projected temperature increases across significant proportions of their distributions. However, our findings also underline the high vulnerability of tropical regions to changes in temperature and other threats of anthropogenic global changes. Our study demonstrates that a better understanding of the interplay among species' physiology and the geography of climate change will advance assessments of species' vulnerability to climate change.  ",0
5212,25009290,PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle,"Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle. To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle. Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease. PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise. ",0
5213,25009452,Solitary Candida albicans Infection Causing Fournier Gangrene and Review of Fungal Etiologies,"Polymicrobial bacterial infections are commonly found in cases of Fournier gangrene (FG), although fungal growth may occur occasionally. Solitary fungal organisms causing FG have rarely been reported. The authors describe a case of an elderly man with a history of diabetes who presented with a necrotizing scrotal and perineal soft tissue infection. He underwent emergent surgical debridement with findings of diffuse urethral stricture disease and urinary extravasation requiring suprapubic tube placement. Candida albicans was found to be the single causative organism on culture, and the patient recovered well following antifungal treatment. Fungal infections should be considered as rare causes of necrotizing fasciitis and antifungal treatment considered in at-risk immunodeficient individuals.  ",0
5214,25009470,Revisiting enigmatic cortical calretinin-expressing interneurons,"Cortical calretinin (CR)-expressing interneurons represent a heterogeneous subpopulation of about 10-30% of GABAergic interneurons, which altogether total ca. 12-20% of all cortical neurons. In the rodent neocortex, CR cells display different somatodendritic morphologies ranging from bipolar to multipolar but the bipolar cells and their variations dominate. They are also diverse at the molecular level as they were shown to express numerous neuropeptides in different combinations including vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), neurokinin B (NKB) corticotrophin releasing factor (CRF), enkephalin (Enk) but also neuropeptide Y (NPY) and somatostatin (SOM) to a lesser extent. CR-expressing interneurons exhibit different firing behaviors such as adapting, bursting or irregular. They mainly originate from the caudal ganglionic eminence (CGE) but a subpopulation also derives from the dorsal part of the medial ganglionic eminence (MGE). Cortical GABAergic CR-expressing interneurons can be divided in two main populations: VIP-bipolar interneurons deriving from the CGE and SOM-Martinotti-like interneurons originating in the dorsal MGE. Although bipolar cells account for the majority of CR-expressing interneurons, the roles they play in cortical neuronal circuits and in the more general metabolic physiology of the brain remained elusive and enigmatic. The aim of this review is, firstly, to provide a comprehensive view of the morphological, molecular and electrophysiological features defining this cell type. We will, secondly, also summarize what is known about their place in the cortical circuit, their modulation by subcortical afferents and the functional roles they might play in neuronal processing and energy metabolism.  ",0
5215,25009540,Role of Gag and lipids during HIV-1 assembly in CD4(+) T cells and macrophages,"HIV-1 is an RNA enveloped virus that preferentially infects CD4(+) T lymphocytes and also macrophages. In CD4(+) T cells, HIV-1 mainly buds from the host cell plasma membrane. The viral Gag polyprotein targets the plasma membrane and is the orchestrator of the HIV assembly as its expression is sufficient to promote the formation of virus-like particles carrying a lipidic envelope derived from the host cell membrane. Certain lipids are enriched in the viral membrane and are thought to play a key role in the assembly process and the envelop composition. A large body of work performed on infected CD4(+) T cells has provided important knowledge about the assembly process and the membrane virus lipid composition. While HIV assembly and budding in macrophages is thought to follow the same general Gag-driven mechanism as in T-lymphocytes, the HIV cycle in macrophage exhibits specific features. In these cells, new virions bud from the limiting membrane of seemingly intracellular compartments, where they accumulate while remaining infectious. These structures are now often referred to as Virus Containing Compartments (VCCs). Recent studies suggest that VCCs represent intracellularly sequestered regions of the plasma membrane, but their precise nature remains elusive. The proteomic and lipidomic characterization of virions produced by T cells or macrophages has highlighted the similarity between their composition and that of the plasma membrane of producer cells, as well as their enrichment in acidic lipids, some components of raft lipids and in tetraspanin-enriched microdomains. It is likely that Gag promotes the coalescence of these components into an assembly platform from which viral budding takes place. How Gag exactly interacts with membrane lipids and what are the mechanisms involved in the interaction between the different membrane nanodomains within the assembly platform remains unclear. Here we review recent literature regarding the role of Gag and lipids on HIV-1 assembly in CD4(+) T cells and macrophages.  ",0
5216,25009627,Red cell distribution width predicts short- and long-term outcomes of acute congestive heart failure more effectively than hemoglobin,"The present study compared short- and long-term prognostic values of red blood cell distribution width (RDW) with those of hemoglobin (Hgb) among patients with acute congestive heart failure (CHF) in a cardiac care unit. The cross-sectional study examined data from 521 patients with acute CHF who were admitted to a cardiac care unit and followed up for 24 months (median). Mean Hgb levels in patients who succumbed (DIH) or remained alive (AIH) were 11.0±1.8 and 11.8±2.6 g/l (P>0.05), respectively. Median values of RDW were 16.2% and 14.4%, respectively (P<0.0001). During the 24-month follow-up, mean levels of Hgb in groups with and without endpoints were 11.4±2.5 and 12.5±2.4 g/dl (P<0.0001), respectively. Median RDW values were 14.9 and 13.8%, respectively (P<0.0001). Logistic regression analysis showed that in-hospital mortality was significantly associated with RDW (P=0.044), New York Heart Association (NYHA) functional class IV (P=0.0037), estimated glomerular filtration rate (eGFR) (P=0.042) and C-reactive protein (P=0.0044), but not with Hgb (P=0.10). The multivariate Cox proportional hazard model selected RDW [hazard ratio (HR), 2.19; P<0.0001], left ventricular ejection fraction (HR 0.81, P=0.0016), age (10-year increase; HR 1.19, P=0.0017) and NYHA functional classes III/IV (HR 1.52, P=0.0029) as independent predictors of long-term outcomes after adjustment, but not Hgb (HR 1.01, P=0.86). Higher RDW values in acute CHF patients at admission were associated with worse short- and long-term outcomes and RDW values were more prognostically relevant than Hgb levels. ",0
5217,25009645,Protein O-glucosyltransferase 1 overexpression downregulates p16 in BT474 human breast cancer cells,"Protein O-glucosyltransferase 1 (POGLUT1) is a novel gene that was initially isolated and identified from the bone marrow cells of patients with myelodysplastic syndrome/acute myeloid leukemia. Previous findings have suggested that POGLUT1 promotes the proliferation of U937 human tissue lymphoma cells. Furthermore, POGLUT1 has been identified in other tissues, including the mammary glands, lymph nodes, intestine, liver and spleen. In the present study, in order to investigate the function and target of POGLUT1 in BT474 breast cancer cells, the effect of POGLUT1 on cell proliferation, differentiation, apoptosis and key proteins in the transforming growth factor (TGF)-β1 signaling pathway was investigated in BT474 cells. The overexpression of POGLUT1 in the presence of TGF-β1 was found to significantly enhance cell viability. Flow cytometric and quantitative polymerase chain reaction analyses revealed that POGLUT1 had an effect on the cell cycle and inhibited the TGF-β1-induced transcriptional upregulation of p16, a major cyclin-dependent kinase inhibitor (CDKI). Furthermore, phosphorylated (p)-Smad3, which has a key role in mediating the TGF-β antiproliferative response, was greatly inhibited by exogenous POGLUT1, suggesting a role for POGLUT1 in the TGF-β1-mediated signaling pathway in the BT474 cell cycle. However, no significant changes were observed in the expression of other CDKIs or in cell apoptosis. The findings of the present study show that the increase in BT474 cell viabilty induced by POGLUT1 is associated with POGLUT1-induced inhibition of the transcriptional upregulation of p16 by TGF-β1, which may be a result of the inhibition of p-Smad3. ",0
5218,25010406,Fitness testing in the fibromyalgia diagnosis: the al-Ándalus project,"This study aimed to determine the ability of a set of physical fitness tests to discriminate presence or absence of fibromyalgia in women. The sample comprised 487 women with fibromyalgia (52.1 ± 8 yr) and 250 control women (49.3 ± 9 yr). We assessed physical fitness using the arm curl, 30-s chair stand, handgrip strength, 8-ft up and go, 6-min walk, chair sit and reach, and the back scratch tests. The revised fibromyalgia impact questionnaire was used to assess fibromyalgia severity and symptomatology. Patients with fibromyalgia performed worse than control women in all the fitness tests studied (all, P < 0.001). The receiver operating characteristic analysis showed that all the fitness tests were able to discriminate between presence and absence of fibromyalgia (all, P < 0.001). The area under the curve ranged from 0.708 to 0.910 (all, P < 0.001). Among the fitness tests studied, the arm curl test, followed by the 30-s chair-stand and handgrip strength tests, showed the highest capacity discriminating between the presence and absence of fibromyalgia. An arm curl test score of <20 repetitions was associated with increased odds of having fibromyalgia (odds ratio (OR), 35.6; 95% confidence interval, 12.6-101) in women age 35-44 yr. An arm curl test score of <16 repetitions was associated with increased odds of having fibromyalgia (OR, 23.7; 95% confidence interval, 10.3-54.0) in women age 35-44 yr. In the group of women age 55-65 yr, the highest OR was observed for the handgrip strength test and the odds of having fibromyalgia was 17 times greater than that in patients who performed less than 19 kg. The arm curl, 30-s chair stand, and handgrip strength tests powerfully discriminated women with fibromyalgia from healthy women. Identification of women who fail to meet the suggested standards can help to easily, quickly, and cheaply rule out the presence of the disease, especially in primary care settings. ",0
5219,25010731,A higher anti-Müllerian hormone level is associated with an increased chance of pregnancy in patients undergoing controlled ovarian stimulation and intrauterine insemination,"Anti-Müllerian hormone (AMH) level has been found to be a useful marker of ovarian reserve, and a predictor of poor and hyper-responses in patients undergoing controlled ovarian stimulation (COS). The study aimed to determine the association of serum AMH level with achieving pregnancy in patients undergoing COS with intrauterine insemination. The cross-sectional study investigated 204 patients who underwent COS with intrauterine insemination at the Obstetrics and Gynecology Department of Taipei Medical University Hospital, from January 2011 to March 2012. The medical records of these patients were reviewed, and serum AMH levels were evaluated for association with successful clinical pregnancy. The AMH level in the patients who achieved clinical pregnancy was significantly higher than in patients who did not (median 2.7 vs 2.0 ng/ml, p = 0.005). Controlling for factors affecting infertility, AMH level had a significant independent influence on outcome; a higher AMH level was associated with a decreased risk of a non-pregnant outcome (odds ratio, OR = 0.895, p = 0.026). In patients undergoing COS and intrauterine insemination, a low AMH level is associated with a decreased chance of a clinical pregnancy, and this association remains irrespective of the presence or absence of endometriosis. ",0
5220,25042122,CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis,"There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5(+) CD4(+) Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. CONCLUSION: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches.",0
5221,25042607,"Phylogenetic clustering of hepatitis C virus among people who inject drugs in Vancouver, Canada","Little is known about factors associated with hepatitis C virus (HCV) transmission among people who inject drugs (PWID). Phylogenetic clustering and associated factors were evaluated among PWID in Vancouver, Canada. Data were derived from the Vancouver Injection Drug Users Study. Participants who were HCV antibody-positive at enrolment and those with HCV antibody seroconversion during follow-up (1996 to 2012) were tested for HCV RNA and sequenced (Core-E2 region). Phylogenetic trees were inferred using maximum likelihood analysis and clusters were identified using ClusterPicker (90% bootstrap threshold, 0.05 genetic distance threshold). Factors associated with clustering were assessed using logistic regression. Among 655 eligible participants, HCV genotype prevalence was: G1a: 48% (n=313), G1b: 6% (n=41), G2a: 3% (n=20), G2b: 7% (n=46), G3a: 33% (n=213), G4a: <1% (n=4), G6a: 1% (n=8), G6e: <1% (n=1), and unclassifiable: 1% (n=9). The mean age was 36 years, 162 (25%) were female, and 164 (25%) were HIV+. Among 501 participants with HCV G1a and G3a, 31% (n=156) were in a pair/cluster. Factors independently associated with phylogenetic clustering included: age <40 (versus age?40, adjusted odds ratio [AOR]=1.64; 95% confidence interval [CI] 1.03, 2.63), human immunodeficiency virus (HIV) infection (AOR=1.82; 95% CI 1.18, 2.81), HCV seroconversion (AOR=3.05; 95% CI 1.40, 6.66), and recent syringe borrowing (AOR 1.59; 95% CI 1.07, 2.36). CONCLUSION: In this sample of PWID, one-third demonstrated phylogenetic clustering. Factors independently associated with phylogenetic clustering included younger age, recent HCV seroconversion, prevalent HIV infection, and recent syringe borrowing. Strategies to enhance the delivery of prevention and/or treatment strategies to those with HIV and recent HCV seroconversion should be explored, given an increased likelihood of HCV transmission in these subpopulations.",0
5222,25043065,Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis,"The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of immunoglobulin M (IgM) and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also crossreactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We used flow cytometry and enzyme-linked immunospot assay (ELISPOT) to examine B-cell subsets in 59 subjects, including 28 with PBC, 13 with primary sclerosing cholangitis (PSC), and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B-cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+ CCR10low plasmablast population. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct noncirculating tissue source of xenobiotic crossreacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+ CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28. CONCLUSION: Our findings suggest a sustained rigorous B-cell response in PBC, likely activated and perpetuated by cognate autoantigen.",0
5223,25048716,Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections,"Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-?)-based therapy. Second, IFN-?, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-?-based and IFN-?-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens.",0
5224,25066844,Type I interferon rapidly restricts infectious hepatitis C virus particle genesis,"Interferon-alpha (IFN?) has been used to treat chronic hepatitis C virus (HCV) infection for over 20 years with varying efficacy, depending on the infecting viral genotype. The mechanism of action of IFN? is not fully understood, but is thought to target multiple stages of the HCV lifecycle, inhibiting viral transcription and translation leading to a degradation of viral RNA and protein expression in the infected cell. IFN? induces the expression of an array of interferon-stimulated genes within minutes of receptor engagement; however, the impact of these early responses on the viral lifecycle are unknown. We demonstrate that IFN? inhibits the genesis of infectious extracellular HCV particles within 2 hours of treating infected cells, with minimal effect on the intracellular viral burden. Importantly, this short duration of IFN? treatment of infected cells significantly reduced cell-free and cell-to-cell dissemination. The secreted viral particles showed no apparent change in protein content or density, demonstrating that IFN? inhibits particle infectivity but not secretion rates. To investigate whether particles released from IFN?-treated cells have a reduced capacity to establish infection we used HCV lentiviral pseudotypes (HCVpp) and demonstrated a defect in cell entry. Using a panel of monoclonal antibodies targeting the E2 glycoprotein, we demonstrate that IFN? alters glycoprotein conformation and receptor utilization. CONCLUSION: These observations show a previously unreported and rapid effect of IFN? on HCV particle infectivity that inhibits de novo infection events. Evasion of this response may be a contributing factor in whether a patient achieves early or rapid virological response, a key indicator of progression to sustained virological response or clearance of viral infection.",0
5225,25075834,Spread of artemisinin resistance in Plasmodium falciparum malaria,"""BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the """"propeller"""" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).""",0
5226,25092403,Molecular pathophysiology of portal hypertension,"Over the past two decades the advances in molecular cell biology have led to significant discoveries about the pathophysiology of portal hypertension (PHT). In particular, great progress has been made in the study of the molecular and cellular mechanisms that regulate the increased intrahepatic vascular resistance (IHVR) in cirrhosis. We now know that the increased IHVR is not irreversible, but that both the structural component caused by fibrosis and the active component caused by hepatic sinusoidal constriction can be, at least partially, reversed. Indeed, it is now apparent that the activation of perisinusoidal hepatic stellate cells, which is a key event mediating the augmented IHVR, is regulated by multiple signal transduction pathways that could be potential therapeutic targets for PHT treatment. Furthermore, the complexity of the molecular physiology of PHT can also be appreciated when one considers the complex signals capable of inducing vasodilatation and hyporesponsiveness to vasoconstrictors in the splanchnic vascular bed, with several vasoactive molecules, controlled at multiple levels, working together to mediate these circulatory abnormalities. Added to the complexity is the occurrence of pathological angiogenesis during the course of disease progression, with recent emphasis given to understanding its molecular machinery and regulation. Although much remains to be learned, with the current availability of reagents and new technologies and the exchange of concepts and data among investigators, our knowledge of the molecular basis of PHT will doubtless continue to grow, accelerating the transfer of knowledge generated by basic research to clinical practice. This will hopefully permit a better future for patients with PHT.",0
5227,25099578,Long-term effect of hospital pay for performance on mortality in England,"BACKGROUND: A pay-for-performance program based on the Hospital Quality Incentive Demonstration was introduced in all hospitals in the northwest region of England in 2008 and was associated with a short-term (18-month) reduction in mortality. We analyzed the long-term effects of this program, called Advancing Quality. METHODS: We analyzed 30-day in-hospital mortality among 1,825,518 hospital admissions for eight conditions, three of which were covered by the financial-incentive program. The hospitals studied included the 24 hospitals in the northwest region that were participating in the program and 137 elsewhere in England that were not participating. We used difference-in-differences regression analysis to compare risk-adjusted mortality for an 18-month period before the program was introduced with subsequent mortality in the short term (the first 18 months of the program) and the longer term (the next 24 months). RESULTS: Throughout the short-term and the long-term periods, the performance of hospitals in the incentive program continued to improve and mortality for the three conditions covered by the program continued to fall. However, the reduction in mortality among patients with these conditions was greater in the control hospitals (those not participating in the program) than in the hospitals that were participating in the program (by 0.7 percentage points; 95% confidence interval [CI], 0.3 to 1.2). By the end of the 42-month follow-up period, the reduced mortality in the participating hospitals was no longer significant (-0.1 percentage points; 95% CI, -0.6 to 0.3). From the short term to the longer term, the mortality for conditions not covered by the program fell more in the participating hospitals than in the control hospitals (by 1.2 percentage points; 95% CI, 0.4 to 2.0), raising the possibility of a positive spillover effect on care for conditions not covered by the program. CONCLUSIONS: Short-term relative reductions in mortality for conditions linked to financial incentives in hospitals participating in a pay-for-performance program in England were not maintained.",0
5228,25119605,Genotype-phenotype correlation--promiscuity in the era of next-generation sequencing,"""Newly cost-effective next-generation sequencing has led to an explosion of discoveries of novel genetic mutations that reveal the rampant """"promiscuity"""" of genotype-phenotype relationships. Such discoveries should ultimately revolutionize clinical care.""",0
5229,25119611,Syndromes of thrombotic microangiopathy,This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs.,0
5230,25123381,Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir,"Sofosbuvir (Sovaldi, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication. High sustained virological response rates are achieved when SOF is used in combination with ribavirin with or without pegylated interferon in subjects with chronic HCV infection. Potential mechanisms of HCV resistance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood. SOF was the first U.S. Food and Drug Administration (FDA)-approved antiviral drug for which genotypic resistance analyses were based almost entirely on next-generation sequencing (NGS), an emerging technology that lacks a standard data analysis pipeline. The FDA Division of Antiviral Products developed an NGS analysis pipeline and performed independent analyses of NGS data from five SOF clinical trials. Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low-frequency, treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virological failure were also noted and further evaluated. The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2%-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modeled in NS5B crystal structures indicated that all four substitutions could feasibly affect SOF anti-HCV activity. CONCLUSION: SOF has a high barrier to resistance; however, low-frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection.",0
5231,25131509,Liver sinusoidal endothelial cells in hepatic fibrosis,"Capillarization, lack of liver sinusoidal endothelial cell (LSEC) fenestration, and formation of an organized basement membrane not only precedes fibrosis, but is also permissive for hepatic stellate cell activation and fibrosis. Thus, dysregulation of the LSEC phenotype is a critical step in the fibrotic process. Both a vascular endothelial growth factor (VEGF)-stimulated, nitric oxide (NO)-independent pathway and a VEGF-stimulated NO-dependent pathway are necessary to maintain the differentiated LSEC phenotype. The NO-dependent pathway is impaired in capillarization and activation of this pathway downstream from NO restores LSEC differentiation in vivo. Restoration of LSEC differentiation in vivo promotes HSC quiescence, enhances regression of fibrosis, and prevents progression of cirrhosis.",0
5232,25145286,Myeloid-specific disruption of recombination signal binding protein J? ameliorates hepatic fibrosis by attenuating inflammation through cylindromatosis in mice,"Macrophages play multidimensional roles in hepatic fibrosis, but their control has not been fully understood. The Notch pathway mediated by recombination signal binding protein J? (RBP-J), the transcription factor transactivated by signals from four mammalian Notch receptors, is implicated in macrophage activation and plasticity. In this study, by using mouse hepatic fibrosis models, we show that myeloid-specific disruption of RBP-J resulted in attenuated fibrosis. The activation of hepatic stellate cells and production of profibrotic factors including platelet-derived growth factor (PDGF)-B and transforming growth factor beta1 (TGF-?1) reduced significantly in myeloid-specific RBP-J deficient mice. The infiltration of inflammatory cells and production of proinflammatory factors were reduced in liver of myeloid-specific RBP-J-deficient mice during fibrosis. In RBP-J-deficient macrophages, the nuclear factor kappa B (NF-?B) activation was remarkably attenuated as compared with the control. This could be attributed to the up-regulation of cylindromatosis (CYLD), a negative regulator of NF-?B, in Notch signal-compromised macrophages, because the knockdown of CYLD in RBP-J-deficient macrophages or overexpression of p65 in RBP-J knockdown cells both restored NF-?B activation and the production of proinflammatory and/or profibrotic factors by macrophages. In human hepatic fibrosis biopsies, stronger Notch activation is correlated with more severe fibrosis, which is accompanied by a lower level of CYLD but irrespective of etiological reasons. CONCLUSION: RBP-J-mediated Notch signaling is required for macrophages to promote hepatic fibrosis by up-regulation of NF-?B activation through CYLD.",0
5233,25163856,The impact of injecting networks on hepatitis C transmission and treatment in people who inject drugs,"""With the development of new highly efficacious direct-acting antiviral (DAA) treatments for hepatitis C virus (HCV), the concept of treatment as prevention is gaining credence. To date, the majority of mathematical models assume perfect mixing, with injectors having equal contact with all other injectors. This article explores how using a networks-based approach to treat people who inject drugs (PWID) with DAAs affects HCV prevalence. Using observational data, we parameterized an exponential random graph model containing 524 nodes. We simulated transmission of HCV through this network using a discrete time, stochastic transmission model. The effect of five treatment strategies on the prevalence of HCV was investigated; two of these strategies were (1) treat randomly selected nodes and (2) """"treat your friends,"""" where an individual is chosen at random for treatment and all their infected neighbors are treated. As treatment coverage increases, HCV prevalence at 10 years reduces for both the high- and low-efficacy treatment. Within each set of parameters, the treat your friends strategy performed better than the random strategy being most marked for higher-efficacy treatment. For example, over 10 years of treating 25 per 1,000 PWID, the prevalence drops from 50% to 40% for the random strategy and to 33% for the treat your friends strategy (6.5% difference; 95% confidence interval: 5.1-8.1). CONCLUSION: Treat your friends is a feasible means of utilizing network strategies to improve treatment efficiency. In an era of highly efficacious and highly tolerable treatment, such an approach will benefit not just the individual, but also the community more broadly by reducing the prevalence of HCV among PWID.""",0
5234,25207766,Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia,"BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).",0
5235,25238930,Morphological and phylogenetic analysis of Fusarium solani species complex in Malaysia,"Members of Fusarium solani species complex (FSSC) have been known as plant, animal, and human pathogens. Nevertheless, the taxonomic status of such an important group of fungi is still very confusing and many new species as well as lineages have been elucidated recently. Unfortunately, most of the new taxa came from temperate and subtropical regions. Therefore, the objectives of the present study were to identify strains of FSSC recovered from different sources in Malaysia. In the present study, 55 strains belonging to the FSSC were examined and phylogenetically analyzed on the basis of internal transcribed spacer (ITS) regions and partial translation elongation factor-1 (TEF-1α) sequences. Based on morphological features, a total of 55 strains were selected for molecular studies. Based on morphological features, the strains were classified into four described Fusarium species, namely Fusarium keratoplasticum, Fusarium falciforme, FSSC 5, and Fusarium cf. ensiforme, and one unknown phylogenetic species was introduced. Although the data obtained from morphological and molecular studies sufficiently supported each other, the phylogenetic trees based on ITS and TEF-1α dataset clearly distinguished closely related species and distinctly separated all morphological taxa. All members of FSSC in this research were reported for the first time for Malaysian mycoflora.  ",0
5236,25239152,Reproducibility of telomere length assessment: an international collaborative study,"Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories. ",0
5237,25239802,Alternative splicing impairs soluble guanylyl cyclase function in aortic aneurysm,"Nitric oxide (NO) receptor soluble guanylyl cyclase (sGC) is a key regulator of several important vascular functions and is important for maintaining cardiovascular homeostasis and vascular plasticity. Diminished sGC expression and function contributes to pathogenesis of several cardiovascular diseases. However, the processes that control sGC expression in vascular tissue remain poorly understood. Previous work in animal and cell models revealed the complexity of alternative splicing of sGC genes and demonstrated its importance in modulation of sGC function. The aim of this study was to examine the role of alternative splicing of α1 and β1 sGC in healthy and diseased human vascular tissue. Our study found a variety of α1 and β1 sGC splice forms expressed in human aorta. Their composition and abundance were different between samples of aortic tissue removed during surgical repair of aortic aneurysm and samples of aortas without aneurysm. Aortas with aneurysm demonstrated decreased sGC activity, which correlated with increased expression of dysfunctional sGC splice variants. In addition, the expression of 55-kDa oxidation-resistant α1 isoform B sGC (α1-IsoB) was significantly lower in aortic samples with aneurysm. The α1-IsoB splice variant was demonstrated to support sGC activity in aortic lysates. Together, our results suggest that alternative splicing contributes to diminished sGC function in vascular dysfunction. Precise understanding of sGC splicing regulation could help to design new therapeutic interventions and to personalize sGC-targeting therapies in treatments of vascular disease.  ",0
5238,25239987,Streptococcus pneumoniae bacteraemia leading to the diagnosis of multiple myeloma,"Multiple myeloma (MM) is a malignant plasma cell disorder characterised by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Anaemia, bone pain from lytic lesions, hypercalcaemia and renal failure are the most common presentations at diagnosis; however, the presence of infection at the time of diagnosis is rarely reported. The author reports an elderly male presenting with isolated fever and initial blood cultures positive for Streptococcus pneumoniae. Investigating the patient's underlying immunodeficient state predisposing him to this infection, serum and urine immunofixation electrophoresis identified monoclonal IgG λ and bone marrow biopsy revealed diffuse plasma cell infiltration that comprised 35% of the cellular elements, which were all consistent with MM. This case report highlights the importance of considering MM in asymptomatic elderly patients who present with acute pneumococcal infection without an apparent predisposing factor.  ",0
5239,25240117,Beating the blues: is there any music in fighting cyanobacteria with ultrasound?,"""The hypothesis that cyanobacteria can be controlled by commercially available ultrasound transducers was tested in laboratory experiments with cultures of the cyanobacteria Anabaena sp., Cylindrospermopsis raciborskii and Microcystis aeruginosa and the green alga Scenedesmus obliquus that were grown in the absence or presence of ultrasound (mix of 20, 28 and 44 kHz). The Scenedesmus experiment also included a treatment with the zooplankton grazer Daphnia magna. Chlorophyll-a and biovolume-based growth of Anabaena was significantly lower in ultrasound exposed cultures than in controls. Particle based growth rates were higher in ultrasound treatments. Filaments were significantly shorter in ultrasound exposed cultures reflecting filament breakage. Photosystem II efficiency was not affected by ultrasound. In Cylindrospermopsis chlorophyll-a based growth rates and photosystem II efficiencies were similar in controls and ultrasound treatments, but biovolume-based growth was significantly lower in ultrasound exposed cultures compared to controls. Despite biovolume growth rates of the filamentous cyanobacteria were reduced in ultrasound treatments compared to controls, growth remained positive implying still a population increase. In Microcystis and Scenedesmus growth rates were similar in controls and ultrasound treatments. Hence, no effect of ultrasound on these phytoplankton species was found. Ultrasound should not be viewed """"environmental friendly"""" as it killed all Daphnia within 15 min, releasing Scenedesmus from grazing control in the cultures. Based on our experiments and critical literature review, we conclude that there is no music in controlling cyanobacteria in situ with the commercially available ultrasound transducers we have tested.  """,0
5240,25240128,A ratiometric fluorescent probe based on a coumarin-hemicyanine scaffold for sensitive and selective detection of endogenous peroxynitrite,"In the study described herein, the red emitting probe CHCN, which possesses a linked coumarin-hemicyanine scaffold, was developed for detection of peroxynitrite (ONOO(-)) under physiological conditions. The studies show that CHCN displays a dual ratiometric and colorimetric response to ONOO(-) that is caused by an oxidation process. A possible mechanism of this oxidation process was proposed and confirmed by ESI-MS spectra for the first time. CHCN shown highly selective and sensitive towards ONOO(-) with a low limit of detection LOD (49.7 nM). Moreover, CHCN has appreciable cell permeability and, as a result, it is applicable to ratiometric detection of exogenous and endogenous ONOO(-) in living cells during phagocytic immune response. We anticipate that, owing to their ideal properties, probes of this type will find great use in explorations of the role played by ONOO(-) in biology. ",0
5241,25240273,OpenVirtualToxLab--a platform for generating and exchanging in silico toxicity data,"The VirtualToxLab is an in silico technology for estimating the toxic potential--endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity--of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of currently 16 proteins, known or suspected to trigger adverse effects: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The toxic potential of a compound--its ability to trigger adverse effects--is derived from its computed binding affinities toward these very proteins: the computationally demanding simulations are executed in client-server model on a Linux cluster of the University of Basel. The graphical-user interface supports all computer platforms, allows building and uploading molecular structures, inspecting and downloading the results and, most important, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. Access to the VirtualToxLab is available free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. ",0
5242,25241066,Serotonin in the ventral hippocampus modulates anxiety-like behavior during amphetamine withdrawal,"Withdrawal from amphetamine is associated with increased anxiety and sensitivity to stressors which are thought to contribute to relapse. Rats undergoing amphetamine withdrawal fail to exhibit stress-induced increases in serotonin (5-HT) release in the ventral hippocampus and show heightened anxiety-like behaviors. Therefore, we tested the hypothesis that reducing 5-HT levels in the ventral hippocampus is a causal mechanism in increasing anxiety-like behaviors during amphetamine withdrawal. First, we tested whether reducing 5-HT levels in the ventral hippocampus directly increases anxiety behavior. Male rats were bilaterally infused with 5,7-dihydroxytryptamine (5,7-DHT) into the ventral hippocampus, which produced a 83% decrease in ventral hippocampus 5-HT content, and were tested on the elevated plus maze (EPM) for anxiety-like behavior. Reducing ventral hippocampus 5-HT levels decreased the time spent in the open arms of the maze, suggesting that diminished ventral hippocampus 5-HT levels increases anxiety-like behavior. Next, we tested whether increasing 5-HT levels in the ventral hippocampus reverses anxiety behavior exhibited by rats undergoing amphetamine withdrawal. Rats were treated daily with either amphetamine (2.5-mg/kg, i.p.) or saline for 2weeks, and at 2weeks withdrawal, were infused with the selective serotonin reuptake inhibitor paroxetine (0.5μM) bilaterally into the ventral hippocampus and tested for anxiety-like behavior on the EPM. Rats pre-treated with amphetamine exhibited increased anxiety-like behavior on the EPM. This effect was reversed by ventral hippocampus infusion of paroxetine. Our results suggest that 5-HT levels in the ventral hippocampus are critical for regulating anxiety behavior. Increasing 5-HT levels during withdrawal may be an effective strategy for reducing anxiety-induced drug relapse.  ",0
5243,25241110,Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis,"Infantile myofibromatosis (IM) is a rare disorder characterized by the development of benign tumors in the skin, muscle, bone, and viscera. The incidence is 1/150,000 live births and the disease is the most common cause of fibrous tumors in infancy. Cases which lack visceral involvement generally have a more benign course, usually with spontaneous regression of the tumors. On the other hand, the prognosis tends to be unfavorable when there is involvement of vital organs, which can lead to significant mortality. The identification of rare variants in genes that may cause IM is the first step towards the possibility of targeted treatments; however, the molecular pathogenesis of IM is poorly understood. In the present study, we report the results of exome sequence analysis of two brothers diagnosed with visceral multicentric infantile myofibromatosis, and their healthy consanguineous parents. In the two brothers we identified novel homozygous variants in NDRG4 gene (N-myc downregulated gene family member 4) and in RLTPR gene (RGD motif, leucine rich repeats, tropomodulin domain and proline-rich containing). The healthy parents were heterozygous for both variants. Consistent with the phenotype of IM, NDRG4 is a tumor-related gene; its expression has been shown to be decreased in numerous tumor types, suggesting that it might be a tumor suppressor gene. Additionally, studies have demonstrated that NDRG4 may have a role in cell survival and tumor invasion. We thus propose that this homozygous variant in NDRG4 may be the causative variant of the autosomal recessive form of IM in the studied family and that it should be investigated in other cases of autosomal recessive infantile myofibromatosis.  ",0
5244,25241125,Effects of Ilex paraguariensis (yerba mate) treatment on leptin resistance and inflammatory parameters in obese rats primed by early weaning,"We evaluated the effects of yerba mate treatment over 30 days on body weight, food intake, hypothalamic leptin action and inflammatory profile in adult rats that were weaned early. To induce early weaning, the teats of lactating rats were blocked with a bandage to interrupt milk access for the last 3 days of lactation (EW group). Control offspring had free access to milk throughout lactation. On postnatal day (PN) 150, EW offspring were subdivided into: EW and M groups were treated with water and mate aqueous solution (1g/kg BW/day, gavage), respectively, for 30 days. Control offspring received water by gavage. On PN180, offspring were killed. EW group presented hyperphagia; higher adiposity; higher NPY and TNF-α expression in the ARC nucleus; higher TNF-α and IL-1β levels in the adipose tissue; and lower IL-10 levels in the adipose tissue. These characteristics were normal in M group. As expected, the leptin injection in control offspring caused lower food intake. However, EW group exhibited no change in food intake after the leptin injection, indicating leptin resistance. In contrast, M group had a normal response to the leptin injection. Thirty days of mate treatment prevented the development of hyperphagia, overweight, visceral obesity and central leptin resistance. This beneficial effect on the satiety of M offspring most likely occurred after the improvement of inflammatory markers in the hypothalamus and adipocytes, which suggests that Ilex paraguariensis plays an important role in the management of obesity by acting on the inflammatory profile. ",0
5245,25241223,Remote monitoring of patients with implantable cardioverter-defibrillators: can results from large clinical trials be transposed to clinical practice?,"Remote monitoring (RM) is increasingly used to follow up patients with implantable cardioverter-defibrillators (ICDs). Randomized control trials provide evidence for the benefit of this intervention, but data for RM in daily clinical practice with multiple-brands and unselected patients is lacking. To assess the effect of RM on patient management and clinical outcome for recipients of ICDs in daily practice. We reviewed ICD recipients followed up at our institution in 2009 with RM or with traditional hospital only (HO) follow-up. We looked at the effect of RM on the number of scheduled ambulatory follow-ups and urgent unscheduled consultations, the time between onset of asymptomatic events to clinical intervention and the clinical effectiveness of all consultations. We also evaluated the proportion of RM notifications representing clinically relevant situations. We included 355 patients retrospectively (RM: n=144, HO: n=211, 76.9% male, 60.3±15.2 years old, 50.1% with ICDs for primary prevention and mean left ventricular ejection fraction 35.5±14.5%). Average follow-up was 13.5 months. The RM group required less scheduled ambulatory follow-up consultations (1.8 vs. 2.1/patient/year; P<0.0001) and a far lower median time between the onset of asymptomatic events and clinical intervention (7 vs. 76 days; P=0.016). Of the 784 scheduled ambulatory follow-up consultations carried out, only 152 (19.4%) resulted in therapeutic intervention or ICD reprogramming. We also found that the vast majority of RM notifications (61.9%) were of no clinical relevance. RM allows early management of asymptomatic events and a reduction in scheduled ambulatory follow-up consultations in daily clinical practice, without compromising safety, endorsing RM as the new standard of care for ICD recipients. ",0
5246,25241332,Sulforaphane inhibits advanced glycation end product-induced pericyte damage by reducing expression of receptor for advanced glycation end products,"Advanced glycation end products (AGEs) not only inhibit DNA synthesis but also play a role in diabetic retinopathy by evoking apoptosis and inflammation in retinal pericytes via interaction with a receptor for AGE (RAGE). Similarly, sulforaphane, which is a naturally occurring isothiocyanate that is found in widely consumed cruciferous vegetables, protects against oxidative stress-induced tissue damage. Therefore, we hypothesized that sulforaphane could inhibit AGE-induced pericytes injury through its antioxidative properties. Advanced glycation end product stimulated superoxide generation as well as RAGE gene and protein expression in bovine-cultured retinal pericytes, and these effects were prevented by the treatment with sulforaphane. Antibodies directed against RAGE also blocked AGE-evoked reactive oxygen species generation in pericytes. Sulforaphane and antibodies directed against RAGE significantly inhibited the AGE-induced decrease in DNA synthesis, apoptotic cell death, and up-regulation of monocyte chemoattractant protein 1 messenger RNA levels in pericytes. For the first time, the present study demonstrates that sulforaphane could inhibit DNA synthesis, apoptotic cell death, and inflammatory reactions in AGE-exposed pericytes, partly by suppressing RAGE expression via its antioxidative properties. Blockade of the AGE-RAGE axis in pericytes by sulforaphane might be a novel therapeutic target for the treatment of diabetic retinopathy.  ",0
5247,25241609,Intraoperative parathyroid hormone monitoring corroborates the success of parathyroidectomy in children,"""To assess the efficacy of intraoperative parathyroid hormone (PTH) monitoring in evaluating the outcome of parathyroidectomy in pediatric patients. Intraoperative PTH monitoring during parathyroidectomy was performed in five children (3M, 2F); three had parathyroid adenomas (single gland disease) and two had primary hyperplasia. One patient had undergone two previous surgical interventions to remove the parathyroid glands, but the PTH levels had remained high with persistence of symptoms. Immunoradiometric analysis was used for PTH measurements. Preoperative PTH values were obtained to monitor the baseline levels. Serum samples were collected 20 minutes after removal of the adenoma/parathyroid gland(s) and PTH levels were compared with preoperative values. Specimens were also confirmed by frozen sectional examination. Mean age of the patients was 11 years (range: 3 months-16 years). Mean preoperative PTH values were 633.3±579 pg/mL (range: 143-1300 pg/mL). Intraoperative values decreased to 18.7±5.5 pg/mL (range: 8-27 pg/mL) following removal of the gland(s). Normal calcium levels were achieved with adequate management following surgery. One patient (with multiple surgeries and found to have an ectopic parathyroid gland) had hungry bone syndrome after the operation and was treated successfully. There were no major complications. All patients maintained normal calcium/phosphorus levels in the follow-up period, ranging from 2 to 5 years. An ectopic parathyroid gland or another undetected adenoma can be overlooked during surgery. Owing to the short life of the hormone, intraoperative PTH monitoring to determine PTH clearance proved to be a feasible marker for adequacy and safety of surgery and """"cure"""". """,0
5248,25241772,"""""""Are you available for the next 18 months?"""" - methods and aims of a longitudinal birth cohort study investigating a universal developmental surveillance program: the 'Watch Me Grow' study""","Universal developmental surveillance programs aimed at early identification and targeted early intervention significantly improve short- and long-term outcomes in children at risk of developmental disorders. However, a significant challenge remains in providing sufficiently rigorous research and robust evidence to inform policy and service delivery. This paper describes the methods of the 'Watch Me Grow' study that aims to maximise accurate early detection of children with developmental disorders through a partnership formed between policy makers, service providers and researchers. A mixed methods study design was developed consisting of: (1) a qualitative study of parents and health service providers to investigate barriers and enablers of developmental surveillance; (2) recruitment of a birth cohort and their longitudinal follow-up to 18 months of age to: a) assess risk factors for not accessing existing developmental surveillance programs and b) estimate the prevalence of children identified with developmental risk; (3) comparison of surveillance outcomes with a reference standard at 18 months of age to assess the diagnostic test accuracy of existing and alternative developmental surveillance tools; and (4) comparison of developmental surveillance models to inform policy recommendations. Data linkage will be used to determine the uptake and representativeness of the study participant group versus non-participants. The Watch Me Grow study is expected to provide a collaborative opportunity to enhance universal developmental surveillance for early accurate identification of developmental risk. This will also provide quality evidence about identification of developmental risk and access to services to be embedded in existing practice with linkages to policy development. ",0
5249,25242052,An epidemiologic investigation of physical activity and breast cancer risk in Africa,"Physical activity (PA) is modifiable and linked to decreased breast cancer risk but its impact has not been investigated among indigenous African populations. From 2011 to 2013, 558 cases and 1,014 controls were recruited into the African Breast Cancer Study in Nigeria, Cameroon, and Uganda, and completed a culturally tailored PA questionnaire that assesses habitual PA the year before diagnosis/interview. PA sub-scores (housework, occupational, and leisure PA) and a total PA score were calculated (metabolic equivalent of task, MET-hours/day). Multiple logistic regressions were performed, adjusting for age, body mass index (BMI), study sites, and menopausal status. The models were then stratified by BMI and study site, respectively. The overall PA score among controls (17.8 MET-hours/day on average) was mainly composed by housework PA and occupational PA with little leisure PA (7.0, 10.3, and 0.5 MET-hours/day, respectively). Multivariable analyses showed that PA was significantly associated with reduced breast cancer risk in both pre- and postmenopausal women (up to 60% risk reduction), with a dose-responsive relationship (Ptrend < 0.001). The inverse association was strong among lean women, less strong but still significant among overweight women, but not existing among obese women. The inverse association held for all intensity-level and domains of PA. PA of African women mainly consists of housework and work-related activities. The preliminary data show that PA may be significantly associated with reduced breast cancer risk. An inverse association between PA and breast cancer risk was observed among indigenous African women, a unique and understudied population. ",0
5250,25242084,"Role of inositol-1,4,5-trisphosphate receptor in the regulation of calcium transients in neonatal rat ventricular myocytes","This study determined the regulatory effect of inositol 1,4,5-trisphosphate receptors (IP3Rs) on the basal Ca(2+) transients in cardiomyocytes. In cultured neonatal rat ventricular myocytes (NRVMs) at different densities, we used confocal microscopy to assess the effect of IP3Rs on the endogenous spontaneous Ca(2+) oscillations through specific activation of IP3Rs with myo-IP3 hexakis (butyryloxymethyl) ester (IP3BM), a membrane permeable IP3, and interference of IP3R expression with shRNA. We found that NRVMs at the monolayer state displayed coordinated Ca(2+) transients with less rate, shorter duration, and higher amplitude compared to single NRVMs. In addition, monolayer NRVMs exhibited 4 or 10 times more increased Ca(2+) transients in response to phenylephrine, an α-adrenergic receptor agonist, or IP3BM than single NRVMs did, while the transient pattern remained unaltered, suggesting that the sensitivity of intracellular Ca(2+) response to IP3R activation is different between single and monolayer NRVMs. However, interference of IP3R expression with shRNA reduced the frequency and amplitude of the spontaneous Ca(2+) fluctuates similarly in both densities of NRVMs, resembling the effects of ryanodine receptor inhibition by ryanodine or tetracaine. Our findings suggest that IP3Rs are involved, in part, in the regulation of native Ca(2+) transients, in profiles of their initiation and Ca(2+) release extent, in developing cardiomyocytes. In addition, caution should be paid in evaluating the behavior of Ca(2+) signaling in primary cultured cardiomyocytes at different densities.  ",0
5251,25242307,Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase,"Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1(+/-)), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1(+/-) mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1(+/-) mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.  ",0
5252,25242332,PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt(high) metastatic colon cancer cells,"The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1(+) cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1(+) cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.  ",0
5253,25242359,Cognitive insight in schizophrenia patients and their biological parents: a pilot study,"Clinical insight in schizophrenia patients is partly associated with familial environment but has been poorly studied to date. We aimed to explore (1) the relationship between parents' cognitive insight and their offspring's; (2) the relationship between parents' cognitive insight and their clinical insight into the disease of their offspring; and (3) the clinical and cognitive determinants of cognitive insight in parents. Cognitive insight was assessed in 37 patient-biological parent pairs/dyads with the Beck Cognitive Insight Scale (BCIS). Other measures included the Scale to assess Unawareness of Mental Disorder and cognitive assessments. We found no significant association between parents' cognitive insight and their offspring's. Conversely, a positive association between parents' cognitive insight and parents' insight into their offspring's symptoms was found. Better awareness of their offspring's specific symptoms was associated with lower levels of overconfidence in one's beliefs and with BCIS total score. BCIS Self-Certainty and BCIS total score were associated with better executive functioning and verbal comprehension. Better insight into their offspring's symptoms is associated with cognitive insight in biological parents of schizophrenia patients. Our results support the integration of cognitive intervention targeting parents' cognitive flexibility in family psychoeducational programs and provide an important first step towards developing a more refined understanding of the factors involved in insight into symptoms of illness in parents of schizophrenia patients. ",0
5254,25242752,A new proposal of surgical suture in case of spontaneous renal allograft rupture,"Spontaneous kidney allograft rupture (KAR) is a rare but potentially life-threatening complication after kidney transplantation. It is associated with a high risk of graft loss and patient death. We report a new technique of surgical repair in case of KAR. A 53-year-old man transplanted due to diabetic nephropathy-related end-stage renal disease experienced a spontaneous KAR 10 days after KT. Immediate laparotomy revealed the presence of a 4-cm linear kidney fracture. Dexon 2-0 wires were used for the suture, stopping each wire with Hem-o-Loks on a cylinder of oxidized cellulose gauze, with the intent of avoiding the risk of tissue fracture caused by the suture itself. Bleeding was thus controlled. The patient experienced an uneventful course and was discharged on postoperative day 26. According to the recent literature, graft nephrectomy for KAR is no longer considered the standard surgical treatment. A new approach to rupture repair has been proposed, providing good rates of graft and patient survival. ",0
5255,25242802,Delayed recovery from Cheyne-Stokes respiration in heart failure after successful cardiac transplantation: a case report,"Sleep-disordered breathing (SDB), especially central sleep apnea with Cheyne-Stokes respiration (CSA-CSR), is highly prevalent in patients with severe heart failure (HF). SDB, and predominantly CSR, may improve after recovery of cardiac function, but available data are limited and inconclusive, particularly in patients who have undergone heart transplantation (HTX). The case of a 59-year-old man with dilated cardiomyopathy and advanced chronic HF, plus CSA-CSR, is reported. The patient showed normalization of cardiac function after successful HTX, with delayed but gradual stepwise improvements in CSA-CSR over time. Although there is a close relationship between cardiac function and manifestations of SDB and CSA-CSR, stabilization of nocturnal respiration after improvement in cardiac function may be delayed rather than immediate. ",0
5256,25242997,Effect of lithium chloride on the luteal steroidogenesis in gonadotropin-stimulated rat,"Main function of corpus luteum is progesterone synthesis that is significantly accompanied with an increase in levels of mRNA encoding of steroidogenic enzymes known as luteal markers. This study was designed to evaluate effects of lithium chloride on the release of steroid hormones and steroidogenic enzymes in gonadotropin-stimulated rats. Immature 23 days old Wistar rats were divided into 10 groups; each group comprised of 8 rats, and induced with single injection of pregnant mare's serum gonadotrophin (PMSG) and followed by single injection of human chorionic gonadotropin (hCG). Then, rats were given lithium chloride (LiCl) or saline at 12 hours post-hCG injection. Ovaries were collected in 4-hour interval from 8-24 hour post-hCG injection. Expression pattern of steroidogenic acute regulatory protein (StAR), side-chain cleavage cytochrome P450 (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD) genes were determined by semi-quantitative RT-PCR. In addition, serum levels of progesterone and 17β-estradiol were measured by ELISA. Our results showed that hCG stimulation of progesterone was markedly diminished and transcript levels of key steroidogenic enzymes were altered in the hormone-stimulated rats following LiCl treatment. These results suggest that critical steps in the function of corpus luteum are disrupted by lithium. It is concluded that LiCl is an effective factor for suppressing of steroid genes expression. ",0
5257,25243426,Cardiac myocyte dysfunction induced by streptolysin O is membrane pore and calcium dependent,"Septic cardiomyopathy is a severe complication among some patients who develop group A streptococcal toxic shock syndrome. Despite the importance of cardiac dysfunction in determining prognosis, very little is known about mechanisms that reduce cardiac output in association with streptococcal infection. Here, we investigated the effects of streptococcal extracellular toxins on mechanical contractility of electrically paced primary murine cardiomyocytes. Our data demonstrate that streptolysin O (SLO) is the major streptococcal toxin responsible for cardiomyocyte contractile dysfunction. Streptolysin O dose-dependently affected cardiac myocyte function in discrete stages. Exposure to SLO caused a failure of cardiac cells to respond to electrical pacing, followed by spontaneous dysregulated contractions and augmented strength of contraction. Central to these SLO-mediated effects is a marked influx of calcium into the cytosol through SLO-mediated pores in the cytoplasmic membrane. Such calcium mobilization in response to SLO correlated temporally with hypercontractility and unpaced contractions. During continued exposure to SLO, cardiomyocytes exhibited periods of reversion to normal electrical pacing suggestive of membrane lesion repair and restoration of calcium handling. Together, these observations are consistent with the clinical observation that septic cardiomyopathy is a reversible condition in patients who survive streptococcal toxic shock syndrome. These data provide strong evidence that streptococcal exotoxins, specifically SLO, can directly impact cardiac mechanical function.  ",0
5258,25243470,"Multivariate analyses of Ki-67, cytokeratin 13 and cytokeratin 17 in diagnosis and prognosis of oral precancerous lesions","Ki-67, cytokeratin 13, and/or cytokeratin 17 detection by immunohistochemistry has been reported to be useful for the diagnosis of oral precancerous lesions. However, the use of these markers remains controversial because of the lack of appropriately designed statistical studies. We assessed the hypothesis that Ki-67, cytokeratin 13, or cytokeratin 17 immunohistochemistry could facilitate the diagnosis of oral precancerous lesions and/or predict prognosis. Epithelial dysplasia was classified as low grade (none or mild dysplasia) or high grade (moderate dysplasia, severe dysplasia, or carcinoma in situ). This study included 58 low-grade and 36 high-grade dysplasia cases. We used logistic regression to assess the diagnostic values of Ki-67, cytokeratin 13, and cytokeratin 17 for high-grade dysplasia. Correlations between these markers and the prognosis of oral atypical epithelium were assessed using the Cox proportional hazards model. Ki-67 overexpression and cytokeratin 13 loss were independent diagnostic markers for high-grade dysplasia (odds ratios, 1.92 and 2.53; 95% confidence intervals, 1.03-3.58, and 1.19-5.38, respectively). The area under the curve of Ki-67 was 0.73 and that of cytokeratin 13 was 0.72. However, the combination of Ki-67 and cytokeratin 13 yielded the area under the curve of 0.78. Ki-67 overexpression was significantly associated with recurrence and/or malignant transformation of oral atypical epithelium (hazard ratio, 7.25; 95% confidence interval, 1.07-48.92). Ki-67 overexpression and cytokeratin 13 loss may be useful for distinguishing oral precancerous lesions from reactive atypical epithelium. Moreover, Ki-67 overexpression may be a risk factor for recurrence and/or malignant transformation of oral atypical epithelium. ",0
5259,25243650,Plumbagin Protects Against Spinal Cord Injury-induced Oxidative Stress and Inflammation in Wistar Rats through Nrf-2 Upregulation,"Spinal cord injury causes post-traumatic degeneration through series of biochemical events. This study aims to evaluate the possible protective mechanism of Plumbagin against Spinal cord injury induced oxidative stress and inflammation. Plumbagin is a potent antioxidant and shows anti-carcinogenic, anti-inflammatory and analgesic activities. However, its exact molecular mechanism of action has yet to be explored. We tested the effects of Plumbagin on spinal cord injury induced ROS generation and lipid peroxidation content in wistar rats. Additionally, the expression of 2 important transcription factors NF-κB and Nrf-2 was investigated. Plumbagin treatment significantly ameliorated oxidative stress through inhibition of ROS and lipid peroxidation with a concomitant increase in antioxidant status. Western blot analysis revealed enhanced nuclear levels of Nrf-2, while NF-κB expression was suppressed during Plumbagin administration. Enzyme linked immunosorbent assay for pro-inflammatory cytokines (TNF-α, IL-1β) showed a significant downregulation followed by Plumbagin treatment in spinal cord injury rats. Taken together, the data suggests potential and novel role of Plumbagin in cytoprotection by modulating NF-κB and Nrf-2 levels against spinal cord injury. ",0
5260,25243822,Clathrin-mediated endocytosis of gold nanoparticles in vitro,"Gold nanoparticles (AuNPs) have potential biomedical and scientific applications. In this study, we evaluated the uptake and internalization of FBS-coated 20 nm AuNPs into lung fibroblasts and liver cells by different microscopy techniques. AuNP aggregates were observed inside MRC5 lung fibroblasts and Chang liver cells under light microscopy, especially after enhancement with automegallography. Clusters of AuNPs were observed to be adsorbed on the cell surface by scanning electron microscopy. Ultrathin sections showed that AuNPs were mainly enclosed within cytoplasmic vesicles when viewed under transmission electron microscopy. We also investigated the mechanism of uptake for AuNPs, using endocytosis inhibitors and quantification of Au with inductively coupled plasma mass spectrometry. Cells treated with concanavalin A and chlorpromazine showed significant decrease of Au uptake in MRC5 lung fibroblasts and Chang liver cells, respectively, implying that the uptake of AuNPs was facilitated by clathrin-mediated endocytosis. It would therefore appear that uptake of 20 nm AuNPs in both cell types with different tissues of origin, was dependent upon clathrin-mediated endocytosis. ",0
5261,25243977,High-dose chemotherapy for germ cell tumors: do we have a model?,"Since the late nineties, the intensification of chemotherapy doses with hematopoietic stem cell rescue held promise for patients with advanced and poor prognosis germ cell tumors (GCTs). High-dose chemotherapy (HDCT) has, nowadays, a recognized indication in the salvage setting of advanced GCTs and is steadily utilized worldwide. We evaluated the available data with the use of HDCT in these patients. In addition, we provided an original perspective on several issues as experts on behalf of the European Society for Blood and Marrow Transplantation and IGG, including peripheral blood stem cells mobilization and the use of HDCT in special subpopulations of GCT, with the aim to help clarify critical issues in the absence of available clear-cut information. Despite HDCT being currently considered a therapeutic option in the salvage setting, critical questions regarding patient selection are still unanswered. Eligibility of patients with a chemoresistant disease, the use of available prognostic factors as well as tumor marker decline in clinical practice are pending issues. Moving forward, these are critical arguments in favor of further clinical research in the field of advanced GCTs. ",0
5262,25244346,Improving photoprotection attitudes in the tropics: sunburn vs vitamin D,"The ultraviolet radiation of type B (the UVB) stimulates both the production of vitamin D (VD) and the incorporation of erythema dose (ED). The UVA also contributes to ED. The turning point between the benefit of producing VD and the harm of incorporating ED cannot be determined easily. However, the casual behavior regarding the exposure to the Sun can be changed in order to improve the protoprotection attitudes and create a trend towards benefit. In the case, people living in the low latitudes should exposure themselves to the Sun for a determined time interval within the noon time and avoid the Sun in other periods. This would produce an adequate amount of VD through the VD dose (207-214 J m(-2)) against minimum ED (≈105 J m(-2)) for skin type II. For it, unprotected forearms and hands must be exposed to the noon Sun (cloudless) for 11 min (winter) and 5 min (summer). The exposure at other times different from noon can represent increases of up to 24% in ED and up to 12 times in the time interval to be in the Sun in relation to the minimum amounts of both ED and time interval at noon. ",0
5263,25244637,Altered circadian patterns of salivary cortisol in low-functioning children and adolescents with autism,"Reports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism. The study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day 1, 1600 h, 0800 h-Day 2 for 46 individuals with autism and 27 controls, and 0800 h-Day 1, 1100 h, 1600 h, 2400 h, 0800 h-Day 2 for 13 individuals with autism and 20 controls). Overnight (2000 h-0800 h) urinary cortisol excretion was also measured. The autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day 2 compared to Day 1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups. Anticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day 2 versus 0800 h-Day 1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety. ",0
5264,25244686,Quantifying diet-borne metal uptake in Gammarus pulex using stable isotope tracers,"Gammarids are aquatic amphipods widely used for water quality monitoring. To investigate the copper and cadmium diet-borne metal uptake in Gammarus pulex, we adapted the pulse-chase stable isotopes-based approach to determine the food ingestion rate (IR), the gut retention time (GRT) and the metal assimilation efficiencies (AE). G. pulex were fed with (65)Cu-, (106)Cd-, and (53)Cr-labeled alder leaves for 7.5h and then with unlabeled leaves for 5d. The metal stable isotope contents in the gammarids, leaves, filtered water and periodically collected feces were determined. Chromium was poorly assimilated by the gammarids; thus, Cr was used as an unassimilated tracer. The first tracer defecation occurred before the first feces harvest, indicating a gut passage time of less than 9h. A 24-h GRT and a 0.69gg(-1)d(-1) IR were estimated. The Cd AE value was estimated as 5-47%, depending on the assimilation determination method applied. The Cu AE value could not be evaluated regardless of the determination method used, most likely because of the rapid Cu regulation in gammarids in addition to analytical uncertainties when determining the Cu content in leaves. Application of the Cd AE value in the framework of the biodynamic bioaccumulation model shows that the diet-borne uptake of Cd significantly contributes (66-95%) to the metal bioaccumulation in G. pulex fed with alder leaves.  ",0
5265,25244763,HPLC determination of two phenylpropanoid amides in solani melongenae radix from different cultivation regions],"A quantitative HPLC-DAD method was developed for simultaneous determination of N-trans-p-coumaroyloctopamine and N-trans-p-coumaroyltyramine in Solani Melongenae Radix from different cultivation regions in China The separation was performed on an Agilent Eclipse XDB C18 column (4.6 mm x 250 mm, 5 microm) at 30 degrees C with a gradient elution of methanol and 0.1% formic acid in water as mobile phase. The flow rate was set at 1.0 mL x min(-1) and the detection wavelength was 300 nm. The calibration curves of N-trans-p-coumaroyloctopamine and N-trans-p-coumaroyltyramine were linear over the ranges of 2.84-68.16, 3.10-74.40 mg x L(-1), and the average recoveries (n = 9) were 99.30% and 102.8%, respectively. The developed method was successfully applied for the analysis of sixteen samples from different cultivation regions in China, which indicated that the method is simple, rapid, accurate, and reliable for quality evaluation of Solani Melongenae Radix. ",0
5266,25244856,"Distribution characteristics and risk assessment of organochlorine pesticides in soil from Jiufeng Mountain Range in Fujian, China]","Totally 81 surface soil samples were collected from Jiufeng Mountain Range, and 8 compounds of organochlorine pesticides (OCPs) were determined by a Ni electron capture detector (GC-ECD) to investigate the distribution, composition, source and potential health risks of these compounds in the study region. The detection ratio of HCHs and DDTs' isomers ranged from 77.78% to 100.00%. Concentrations of HCHs and DDTs in surface soils ranged from 0.97 ng x g(-1) to 247.40 ng x g(-1) (mean 10.17 ng x g(-1)) and 0.01 ng x g(-1) to 384.75 ng x g(-1) (mean 18.91 ng x g(-1)), respectively. Compared with other regions, the pollution of OCPs in Jiufeng Mountain Range stayed at a low level. The residue level in different types of lands was in the order as: paddy field > vegetable land > tea land > woodland. Source analysis indicated that Lindane and dicofol might be used recently in this area. The incremental lifetime, cancer risks (ILCRs) of different age groups (children, youths, and adults) were all within the acceptable risk range of 10(-6) to 10(-4) recommended by USEPA for carcinogenic chemicals. The residue level of OCPs in soil may not cause cancer risk for local residents basically. ",0
5267,25245105,"Men and women who attend Al-Anon: gender differences in reasons for attendance, health status and personal functioning, and drinker characteristics","Although Al-Anon Family Groups (Al-Anon) is the most common source of help for people concerned about someone else's drinking, only 16% of members are men. To identify gender differences, we compared demographics, reasons for attendance, health status, and personal functioning, and drinker characteristics of 174 men and women attending Al-Anon. Men and women were similar in most areas; however, some key differences emerged. Men reported better overall mental health than women, and described some differing concerns and drinker characteristics. With this information, healthcare providers may facilitate men's participation in Al-Anon by addressing their unique concerns and possible barriers to attendance.  ",0
5268,25245399,MIP-1α enhances Jurkat cell transendothelial migration by up-regulating endothelial adhesion molecules VCAM-1 and ICAM-1,"The aim of this study is to evaluate the expression of macrophage inflammatory protein-1α (MIP-1α) in Jurkat cells and its effect on transendothelial migration. In the present study, human acute lymphoblastic leukemia Jurkat cells (Jurkat cells) were used as a model of T cells in human T-cell acute lymphoblastic leukemia (T-ALL), which demonstrated significantly higher MIP-1α expression compared with that in normal T-cell controls. The ability of Jurkat cells to cross a human brain microvascular endothelial cell (HBMEC) monolayer was almost completely abrogated by MIP-1α siRNA. In addition, the overexpression of MIP-1α resulted in the up-regulated expression of endothelial adhesion molecules, which enhanced the migration of Jurkat cells through a monolayer of HBMEC. MIP-1α levels in Jurkat cells appeared to be an important factor for its transendothelial migration, which may provide the theoretical basis to understand the mechanisms of brain metastases of T-ALL at cellular and molecular levels.  ",0
5269,25245425,Practice patterns in the delivery of radiation therapy after mastectomy among the University of California Athena Breast Health Network,"Practice patterns vary with the planning and delivery of PMRT. In our investigation we examined practice patterns in the use of chest wall bolus and a boost among the Athena Breast Health Network (Athena). Athena is a collaboration among the 5 University of California Medical Centers that aims to integrate clinical care and research. From February 2011 to June 2011, all physicians specializing in the multidisciplinary treatment of breast cancer were invited to take a Web-based practice patterns survey. Sixty-two of the 239 questions focused on radiation therapy practice environment, decision-making processes, and treatment management, including the use of a bolus or boost in PMRT. Ninety-two percent of the radiation oncologists specializing in breast cancer completed the survey. All of the responders use a material to increase the surface dose to the chest wall during PMRT. Materials used included brass mesh, commercial bolus, and custom-designed wax bolus. Fifty percent used tissue equivalent superflab bolus. Fifty-five percent of the respondents routinely use a boost to the chest wall in PMRT. Eighteen percent give a boost depending on the margin status, and 3 of 11 (27%) do not use a boost. Our investigation documents practice pattern variation for the use of a PMRT boost and the use of chest wall bolus among the University of California breast cancer radiation oncologists. Further understanding of the practice pattern variation will help guide clinicians in our cancer centers to a more uniform approach in the delivery of PMRT. ",0
5270,25245808,Toll-like receptor-triggered calcium mobilization protects mice against bacterial infection through extracellular ATP release,"""Extracellular ATP (eATP), released as a """"danger signal"""" by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in both Escherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only by N-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG). In addition, the secretion of interleukin-1β (IL-1β) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation. Furthermore, extracellular ATP reduced the number of invading bacteria and protected mice from peritonitis by activating purinergic receptors. Mechanistically, phosphorylation of AKT and ERK was overtly increased by ATP in antibacterial immune responses. Accordingly, if we blocked the P2X- and P2Y-associated signaling pathway by using suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid), tetrasodium salt (PPADS), the ATP-enhanced immune response was restrained significantly. Taken together, our findings reveal an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of calcium mobilization-mediated ATP release in infectious diseases.  """,0
5271,25245858,"Impact of nasogastric tubes on swallowing physiology in older, healthy subjects: A randomized controlled crossover trial","The presence of a nasogastric tube (NGT) affects swallowing physiology but not function in healthy young adults. The swallowing mechanism changes with increasing age, therefore the impact of a NGT on swallowing in elderly individuals is likely to be different but is not yet known. The aims of this study were to determine the effects of NGTs of different diameter on (1) airway penetration-aspiration, (2) pharyngeal residue, and (3) pharyngeal transit, in older healthy subjects. Randomized controlled crossover design. Healthy elderly volunteers underwent 3 modified barium swallow studies in which multiple diet and fluid consistencies were swallowed under the following conditions: (A) no NGT (control), (B) fine bore NGT, and (C) wide bore NGT. The control condition was assessed first to establish baseline swallowing function, then NGT order was randomly allocated. Of the 15 volunteers (median age 65 years, range 60-81) complete data sets were obtained for 9 (4 with allocation order ABC; 5 with ACB). Wide bore NGT data could not be obtained for 6 volunteers mainly due to tube intolerance. The presence of a NGT was associated with: (i) an increase in airway penetration-aspiration (fine bore NGT with serial liquid swallows and puree) (p < 0.01); (ii) increased pharyngeal residue (p < 0.05) in the pyriform sinus (fine bore NGT with puree); and in the valleculae (both fine and wide bore NGT with soft solids); and (iii) an increase in pharyngeal transit duration regardless of consistency (p < 0.01), with longest swallowing durations with the widest tube. NGT presence increases airway penetration-aspiration, pharyngeal residue and prolongs transit through the pharynx in older healthy individuals. Consideration of NGT impact on swallowing during concurrent oral and enteral feeding is recommended, with further systematic investigation required in elderly patients recovering from critical illness. Clinical trial registry Australia & New Zealand Clinical Trials Registry (ACTRN12613000577718). ",0
5272,25246283,In vitro effect of moxifloxacin and rifampicin on biofilm formation by clinical MRSA isolates,"In this study, it was aimed to investigate in vitro activity of moxifloxacin and rifampicin on biofilm formation by clinical MRSA isolates. Methicillin resistant Staphylococcus aureus (MRSA) strains could be the causative agent in chronical and medical device associated infections by biofilm formation. Moxifloxacin and rifampicin MIC values of 98 MRSA clinical isolates were determined by microdilution method. Biofilm formation of all isolates was determined in 96-well microplates by using spectrophotometric method. Effects of MIC and sub-inhibitory concentrations (1/2 and 1/4 MIC) of antibiotics on biofilm formation were examined in 46 strong biofilm producer strains. Biofilm production decreased in 37 and 44 isolates at all studied concentrations of moxifloxacin and rifampicin, respectively. Biofilm production increased in six isolates with moxifloxacin and in two isolates with rifampicin. Biofilm inhibitory effect of rifampicin was found to be stronger than moxifloxacin in the examined strains. The studied antimicrobials also induced biofilm formation in some strains. Results of this study may help to evaluate the effects of these antibiotics on biofilm formation of clinical MRSA strains and to control the antibiotic resistance in clinical settings (Tab. 2, Ref. 25). ",0
5273,25246341,Preliminary study of Huai Qi Huang granules delay the development of primary glomerular diseases in human,"To evaluate the effects of Huai Qi Huang (HQH) granules on primary glomerulonephritis patients, and to discuss its possible mechanisms. Sixteen patients diagnosed with primary glomerular disease between December 2011 and December 2012 were enrolled. Their blood and urine samples were collected at day 0 (the baseline levels), 30, and 90 of receiving HQH granules orally. Levels of creatinine and cystatin C (Cys-C) in serum and urine, and total protein and albumin in urine were measured by automatic biochemical analyzer. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine was tested by ELISA; serum malondialdehyde (MDA) was measured by thiobarbituric acid method, the erythrocyte count in urine was calculated under light microscope. Serum levels of creatinine, MDA, Cys-C and NGAL at day 30 and 90 were significantly lower than the baseline levels. Urinary levels of Cys-C, NGAL, total protein, albumin and erythrocyte counts were also decreased; level of estimated glomerular filtration (eGFR) was increased. HQH granules have certain effect on delaying the development of primary glomerular disease with mild proteinuria and hematuresis in patients. This study may supply a new treatment for primary glomerular diseases. ",0
5274,25246514,Oestrogens are Not Related to Emotional Processing: a Study of Regional Brain Activity in Female-to-Male Transsexuals Under Gonadal Suppression,"Although the prevailing opinion is that emotional processes are influenced by sex hormones, the literature is still inconclusive. The aim of the current study was to examine the effects of gonadal suppression on brain activity during affective picture processing. Twenty-one female-to-male (FtM) transsexuals and 19 control women were recruited and underwent functional magnetic resonance imaging scanning while rating emotional pictures adapted from the International Affective Picture System. The gonadal hormone production of the FtMs was suppressed for 8 weeks, the control group did not receive any treatment before scanning. Under gonadal suppression, FtMs showed less brain activation in the superior temporal lobe compared with female controls during perception of positive affective pictures. Regression analysis showed that during processing of positive affective images, brain activity within the right superior temporal lobe was not correlated with levels of estradiol, luteinizing hormone, and follicle-stimulating hormone. In the absence of associations with hormonal levels, the difference in activation in the superior temporal lobe during positive emotional stimuli between FtMs and control women may be attributed to a priori differences between the 2 groups. Future studies should clarify if these differences are a result of atypical sexual differentiation of the brain in FtMs.  ",0
5275,25246959,"Photo, thermal and chemical degradation of riboflavin","Riboflavin (RF), also known as vitamin B2, belongs to the class of water-soluble vitamins and is widely present in a variety of food products. It is sensitive to light and high temperature, and therefore, needs a consideration of these factors for its stability in food products and pharmaceutical preparations. A number of other factors have also been identified that affect the stability of RF. These factors include radiation source, its intensity and wavelength, pH, presence of oxygen, buffer concentration and ionic strength, solvent polarity and viscosity, and use of stabilizers and complexing agents. A detailed review of the literature in this field has been made and all those factors that affect the photo, thermal and chemical degradation of RF have been discussed. RF undergoes degradation through several mechanisms and an understanding of the mode of photo- and thermal degradation of RF may help in the stabilization of the vitamin. A general scheme for the photodegradation of RF is presented.  ",0
5276,25247087,Cystolithiasis in women as a distant complication after minimal invasive treatment of stress urinary incontinence,"Stress urinary incontinence (SUI) is a condition of social dimension which generally pertains to women of various age. The only effective treatments of SUI are surgical procedures. The use of tension-free vaginal tape (TVT) ensures low invasiveness but also carries the risk of complications. One of the complications may be migration of the tape into the urinary bladder creating conditions for urinary stones. There is a number of treatment methods for cystolithiasis, among them the optical lithotripter, ultrasound and pneumatic probes, and recently, the holmium laser. From January 2009 to February 2010, six women suffering from bladder stones were treated at our department. All patients had previously undergone SUI procedures and over time, thread or tape had penetrated into the urinary bladder. The stone diameters were in the range of 1.6 cm-3.5 cm. Lithotripsy was performed with the use of an 80 W holmium YAG laser as an endoscopic procedure: beam frequency length of 2100 nm and applied energy was in the range of 0.2-3.5 J. The urinary bladder stones were disintegrated and suctioned out. During the same procedure, the threads or tape from the SUI procedure were excised from the bladder. All patients were discharged from the hospital in good general condition after two days. The holmium laser is an effective treatment for patients with bladder stone complications after SUI procedures when threads or tape have migrated and penetrated the bladder wall. The procedure is straightforward and safe for patients. ",0
5277,25247579,Brain metastases in gastrointestinal cancers: is there a role for surgery?,"About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and impact of surgical resection of brain metastases originating from gastrointestinal cancers such as esophageal, gastric, pancreatic and colorectal cancer. The incidence of brain metastases is <1% in pancreatic and gastric cancer and <4% in esophageal and colorectal cancer. Overall, prognosis of these patients is very poor with a median survival in the range of only months. Interestingly, a substantial number of patients who had received surgical resection of brain metastases showed prolonged survival. However, it should be taken into account that all these studies were not randomized and it is likely that patients selected for surgical treatment presented with other important prognostic factors such as solitary brain metastases and exclusion of extra-cranial disease. Nevertheless, other reports have demonstrated long-term survival of patients upon resection of brain metastases originating from gastrointestinal cancers. Thus, it appears to be justified to consider aggressive surgical approaches for these patients.  ",0
5278,25247591,Leptin deficiency in maltreated children,"Consistent with findings from experimental research in nonhuman primates exposed to early-life stress, children exposed to maltreatment are at high risk of detrimental physical health conditions, such as obesity and systemic inflammation. Because leptin is a key molecule involved in the regulation of both energy balance and immunity, we investigated abnormalities in leptin physiology among maltreated children. We measured leptin, body mass index and C-reactive protein in 170 12-year-old children members of the Environmental-Risk Longitudinal Twin Study, for whom we had prospectively-collected information on maltreatment exposure. We found that maltreated children exhibited blunted elevation in leptin levels in relation to increasing levels of physiological stimuli, adiposity and inflammation, compared with a group of non-maltreated children matched for gender, zygosity and socioeconomic status. These findings were also independent of key potential artifacts and confounders, such as time of day at sample collection, history of food insecurity, pubertal maturation and depressive symptoms. Furthermore, using birth weight as a proxy measure for leptin, we found that physiological abnormalities were presumably not present at birth in children who went on to be maltreated but only emerged over the course of childhood, after maltreatment exposure. Leptin deficiency may contribute to onset, persistence and progression of physical health problems in maltreated children.  ",0
5279,25247619,Drug-induced immune neutropenia/agranulocytosis,"Neutrophils are the most abundant white blood cell in blood and play a critical role in preventing infections as part of the innate immune system. Reduction in neutrophils below an absolute count of 500 cells/pL is termed severe neutropenia or agranulocytosis. Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction. Affected patients have fever, chills, and infections; severe infections left untreated can result in death. Treatment with granulocyte colony-stimulating factor can hasten neutrophil recovery. Cumulative data show that severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs ranges from approximately 1.6 to 15.4 cases per million population per year. Drugs most often associated with neutropenia or agranulocytosis include dipyrone, diclofenac, ticlopidine, calcium dobesilate, spironolactone, antithyroid drugs (e.g., propylthiouracil), carbamazepine, sulfamethoxazole- trimethoprim, [3-lactam antibiotics, clozapine, levamisole, and vancomycin. Assays used for detection of neutrophil drug-dependent antibodies (DDAbs) include flow cytometry, monoclonal antibody immobilization of granulocyte antigens, enzyme-linked immunosorbent assay, immunoblotting, granulocyte agglutination, and granulocytotoxicity. However, testing for neutrophil DDAbs is rarely performed owing to its complexity and lack of availability. Mechanisms proposed for DIIN have not been rigorously studied, but those that have been studied include drug- or hapten-induced antibody formation and autoantibody production against drug metabolite or protein adducts covalently attached to neutrophil membrane proteins. This review will address acute, severe neutropenia caused by neutrophil-reactive antibodies induced by nonchemotherapy drugs-DIIN ",0
5280,25247729,Psychometric properties of the portuguese version of the adaptive behavior scale,"The adaptive behavior construct has gained prominent attention in human services over the last several years in Portugal, and its measurement has become an integral part of the assessment of populations with intellectual disability. In Portugal, diagnosis remains exclusively based on IQ measures, although some attention recently has been given to the adaptive behavior concept. In this article, we explain the adaptation and validation process of the Portuguese version of the Adaptive Behavior Scale (PABS) on a sample of 1,875 people with and without intellectual disability. Results of the study are discussed in terms of the reliability and validity of PABS on the sample. The PABS appears to be a valid and reliable assessment of adaptive behavior in individuals in Portugal with intellectual disability. ",0
5281,25247952,Tumor load in patients with multiple myeloma: β2-microglobulin levels versus whole-body MRI,"Beta-2-microglobulin is a serum maker of tumor burden in hematologic malignancies. We aimed to correlate serum β2-microglobulin levels in patients with multiple myeloma (MM) to tumor mass determined by whole-body MRI. We retrospectively included patients with newly diagnosed, untreated MM who underwent whole-body MRI at our institution between 2003 and 2011. Patients with a glomerular filtration rate of less than 60 mL/min were excluded from analysis because β2-microglobulin levels are increased in renal failure. Thirty patients could be included. Whole-body MRI examinations (T1-weighted turbo spin-echo and STIR sequences) were assessed by two musculoskeletal radiologists in consensus for focal lesions and the presence of diffuse myeloma infiltration. The presence of diffuse infiltration was confirmed by histology as the reference standard. MM was staged according to the Durie and Salmon PLUS staging system. According to whole-body MRI findings, MM was classified as Durie and Salmon PLUS stage I (low grade) in 13 patients, stage II (intermediate grade) in six patients, and stage III (high grade) in 11 patients. As we expected, most patients with stage I disease (12/13) had normal β2-microglobulin levels (≤ 3 mg/L). Higher β2-microglobulin values were associated with a higher stage of disease (p < 0.05). However, five of six patients with stage II MM and five of 11 patients with stage III MM showed normal β2-microglobulin levels. Thus, 10 of 17 patients (58.8%) with substantial infiltration in the bone marrow showed false-negative β2-microglobulin levels. Serum β2-microglobulin levels correlate with tumor stage in MM. However, it may be misleading as a marker of tumor load in a subset of patients with substantial myeloma infiltration in the bone marrow. Whole-body MRI may display the full tumor load and correctly show the extension of myeloma infiltrates. ",0
5282,25247990,Family physicians' ability to perform population management is associated with adoption of other aspects of the patient-centered medical home,"The patient-centered medical home (PCMH) model is considered a promising approach to improving population health, but how elements of these advanced practice models relate to population health capability is unknown. To measure associations between family physicians' performance of population management with PCMH components, a cross-sectional survey was conducted with physicians accessing the American Board of Family Medicine Web site in 2011. Bivariate analysis and logistic regression tested associations between physician and practice demographics and specific PCMH features. The primary outcome was performance of population management. The final sample included 3855 physicians, 37.3% of whom reported performing population management. Demographic characteristics significantly associated with greater use of population management were female sex and graduation from an international medical school. PCMH components that remained associated with population management after adjustment were access to clinical case managers (odds ratio [OR]=2.01, 95% confidence interval [95% CI]: 1.69, 2.39), behavioral health collaboration (OR=1.49, 95% CI: 1.26, 1.77), having an electronic health record that supports meaningful use (OR=1.47, 95% CI: 1.25, 1.74), recent participation in a quality improvement project (OR=2.47, 95% CI: 2.12, 2.89), and routine measurement of patient difficulty securing an appointment (OR=2.87, 95% CI: 2.45, 3.37). Performance of population management was associated with several PCMH elements and resources not present in traditional primary care offices. Attention to these elements likely will enhance delivery of population management services in primary care. ",0
5283,25248395,Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness,"Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.  ",0
5284,25248407,Detection of RHDV strains in the Iberian hare (Lepus granatensis): earliest evidence of rabbit lagovirus cross-species infection,"Rabbit hemorrhagic disease virus (RHDV) is a highly lethal Lagovirus, family Caliciviridae, that threatens European rabbits (Oryctolagus cuniculus). Although a related virus severely affects hares, cross-species infection was only recently described for new variant RHDV in Cape hares (Lepus capensis mediterraneus). We sequenced two strains from dead Iberian hares (Lepus granatensis) collected in the 1990s in Portugal. Clinical signs were compatible with a Lagovirus infection. Phylogenetic analysis of the complete capsid gene positioned them in the RHDV genogroup that circulated on the Iberian Peninsula at that time. This is the earliest evidence of RHDV affecting a species other than European rabbits.  ",0
5285,25248426,Flavonoids enhance melanogenesis in human melanoma cells,"Flavonoids are pigmentary compounds existing widely in plants. We have reported that quercetin (3, 3', 4', 5, 7-pentahydroxylflavone), one of the typical flavonoids, strongly promotes melanogenesis by melanocytes. Meanwhile, there are 8000 or more flavonoids having a chemical structure different from each other in the natural world. Their distinctive chemical properties suggest that they may be different in melanogenic actions. In the present study, the melanogenic actions of 14 flavonoids were analyzed to correlate their chemical structures with melanogenic actions. To evaluate the effects of flavonoids on melanogenesis, the HMV II cell line derived from human malignant melanoma was used. Flavonols including quercetin, kaempferol, rhamnetin and fisetin, flavones including apigenin, luteolin and chrysin, and isoflavones including genestein showed melanogenesis-promoting actions but rutin, robinetin, myricetin, ipriflavone, epigalocatechin gallate (EGCg) and naringin did not. From analyses of the relationships between the chemical structures of flavonoids and their melanogenesis-promoting actions, it was inferred that a hydroxyl group bound to the phenyl group plays an important role in stimulating melanogenesis. From the above results, 8 flavonoids were identified as melanogenesis promoters. Also, correlations were established between the melanogenesis-promoting actions of flavonoids and their chemical structures.  ",0
5286,25248445,Hope: A further dimension for engaging family members of people with ABI,"Family member engagement is increasingly recognised as an influential factor in the rehabilitation continuum following Acquired Brain Injury, including the inpatient setting and longer-term community integration phases. To explore the experiences of patients and family members about their involvement in brain injury rehabilitation. This study comprised individual and group interviews with 14 ex-patients and family members. Interviews explored effects of inpatient rehabilitation on family relationships. Interview audio recordings were analysed using an interpretive approach by two independent researchers. Findings clearly confirmed the significance of engaging family members in inpatient rehabilitation, and specifically reinforced the importance of informational, emotional, practical and peer support. However, the key finding of the study was the importance of hope, and the need for rehabilitation professionals to foster hope. Despite not having included any questions on this topic, all interviewees noted the importance of hope, some saw it as fundamental to positive outcomes, and many were unconvinced of rehabilitation professionals' concern to avoid false hope. Various dimensions of hope are explored. The study notes that hope has been identified as highly important in many areas beyond brain injury rehabilitation. Based on this small preliminary study, the issue of hope is seen as a key focus for future research. ",0
5287,25248586,Imaging of pituitary pathology,"Modern imaging techniques play a vital role in the diagnosis, surveillance, and treatment monitoring of patients with pituitary disease. For its high soft tissue contrast, magnetic resonance (MR) imaging provides detailed information about the localization and extent of a lesion. It is thus, to date, the most important imaging technique for documenting or ruling out structural lesions. It is usually the first and only imaging procedure to be employed in pituitary pathology. While large pituitary adenomas are reliably depicted in standard T1-weighted sequences, small microadenomas, such as in Cushing's disease, may only become visible if repeat studies, sophisticated techniques and high-field scanners are employed. For monitoring treatment effects after surgical procedures, drug applications, or irradiation, follow-up studies with identical parameters should be employed, preferably at the same investigation site. Some space is devoted to intraoperative imaging, which not only allows assessment of how radical tumor resection needs to be during pituitary tumor surgery, but also provides extremely accurate structural data for neuronavigation. Less frequent lesions, such as craniopharyngiomas, meningiomas, germ cell tumors, gliomas, skull base tumors, hypothalamic hamartomas, vascular malformations, inflammatory and developmental lesions and other, even less frequent pathologies should be considered in the differential diagnosis. The particular strength of computed tomography (CT) is the direct depiction of calcification, a weakness of MRI, and the high resolution of bone structures at the skull base. This chapter presents the characteristics of both frequent and less commonly encountered tumoral lesions, with an emphasis on computed tomography and magnetic resonance imaging.  ",0
5288,25248593,"Alternative causes of hypopituitarism: traumatic brain injury, cranial irradiation, and infections","Hypopituitarism often remains unrecognized due to subtle clinical manifestations. Anterior pituitary hormone deficiencies may present as isolated or multiple and may be transient or permanent. Traumatic brain injury (TBI) is recognized as a risk factor for hypopituitarism, most frequently presenting with isolated growth hormone deficiency (GHD). Data analysis shows that about 15% of patients with TBI have some degree of hypopituitarism which if not recognized may be mistakenly ascribed to persistent neurologic injury and cognitive impairment. Identification of predictors for hypopituitarism after TBI is important, one of them being the severity of TBI. The mechanisms involve lesions in the hypothalamic-pituitary axis and inflammatory changes in the central nervous system (CNS). With time, hypopituitarism after TBI may progress or reverse. Cranial irradiation is another important risk factor for hypopituitarism. Deficiencies in anterior pituitary hormone secretion (partial or complete) occur following radiation damage to the hypothalamic-pituitary region, the severity and frequency of which correlate with the total radiation dose delivered to the region and the length of follow-up. These radiation-induced hormone deficiencies are irreversible and progressive. Despite numerous case reports, the incidence of hypothalamic-pituitary dysfunction following infectious diseases of the CNS has been underestimated. Hypopituitarism usually relates to the severity of the disease, type of causative agent (bacterial, TBC, fungal, or viral) and primary localization of the infection. Unrecognized hypopituitarism may be misdiagnosed as postencephalitic syndrome, while the presence of a sellar mass with suprasellar extension may be misdiagnosed as pituitary macroadenoma in a patient with pituitary abscess which is potentially a life-threatening disease.  ",0
5289,25248735,"Lipotourism, not without risks: a complication of cosmetic surgery abroad]","Postoperative infections with non-tuberculous mycobacteria (NTM) are rare. Early diagnosis is important so tailored antibiotic therapy can be started. This can prevent unnecessary radiological and surgical interventions. A 40-year old woman underwent abdominoplasty and liposuction in Colombia. One and a half months postoperatively, she presented with a wound dehiscence followed by recurrent subcutaneous abscesses. She received multiple antibiotic courses and drainage procedures. Standard bacterial cultures remained negative. One and a half years later another abscess was drained and cultures grew Mycobacterium abscessus. Tailored antibiotic therapy was initiated and so far no large abscesses have re-occurred. Infections with NTM should be part of the differential diagnosis in patients with postoperative wound infections, especially after cosmetic surgery performed in Latin America and the Caribbean. Unsuccessful wound healing, infection recurrence, sterile standard bacterial cultures and the lack of response to conventional antibiotic regimens should raise the suspicion of an NTM infection. ",0
5290,25248934,Comment on and reinterpretation of Gabriel et Al. (2014) 'fish mercury and surface water sulfate relationships in the everglades protection area',"Mercury (Hg) methylation and bioaccumulation is a major environmental issue in the Everglades Protection Area (EvPA). Therefore, it is critical to improve our predictive understanding of Hg dynamics. This commentary critically reviews a recently published manuscript concerning the possible relationship between Hg in fish tissue and surface water sulfate within EvPA marshes. The commentary addresses fundamental issues with the authors' data analysis, results and interpretation as well as highlights inconsistencies with published literature and the lack of support for their suggested ecosystem management actions. A number of chemical, biological, and physical factors influence Hg methylation and bioaccumulation, and water sulfate is sometimes viewed as a keystone factor, Gabriel et al. (2014) conclude that Hg bioaccumulation is favored at elevated sulfate concentrations, and suggest mitigation strategies to reduce sulfate inputs to the EvPA. A careful review of their data and conclusions reveals major flaws and in fact, a more straightforward and defensible interpretation of their data would be that no predictable relationship exists between fish tissue Hg and surface water sulfate concentrations in south Florida. Given the complexity of Hg cycling and the influence of trophic and habitat characteristics on aquatic consumer Hg accumulation, expecting one parameter to predict Hg accumulation dynamics within fish species within a dynamic marsh environment is unrealistic. Furthermore, proposing any management guidance from this relationship with little to no quantitative statistical analysis is inappropriate and misleading.  ",0
5291,25249011,Sarcopenia and frailty in elderly trauma patients,"Sarcopenia describes a loss of muscle mass and resultant decrease in strength, mobility, and function that can be quantified by CT. We hypothesized that sarcopenia and related frailty characteristics are related to discharge disposition after blunt traumatic injury in the elderly. We reviewed charts of 252 elderly blunt trauma patients who underwent abdominal CT prior to hospital admission. Data for thirteen frailty characteristics were abstracted. Sarcopenia was measured by obtaining skeletal muscle cross-sectional area (CSA) from each patient's psoas major muscle using Slice-O-Matic(®) software. Dispositions were grouped as dependent and independent based on discharge location. χ (2), Fisher's exact, and logistic regression were used to determine factors associated with discharge dependence. Mean age 76 years, 49 % male, median ISS 9.0 (IQR = 8.0-17.0). Discharge destination was independent in 61.5 %, dependent in 29 %, and 9.5 % of patients died. Each 1 cm(2) increase in psoas muscle CSA was associated with a 20 % decrease in dependent living (p < 0.0001). Gender, weakness, hospital complication, and cognitive impairment were also associated with disposition; ISS was not (p = 0.4754). Lower psoas major muscle CSA is related to discharge destination in elderly trauma patients and can be obtained from the admission CT. Lower psoas muscle CSA is related to loss of independence upon discharge in the elderly. The early availability of this variable during the hospitalization of elderly trauma patients may aid in discharge planning and the transition to dependent living. ",0
5292,25249167,Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells,"Despite the high prevalence of chronic gastritis caused by Helicobacter pylori, the gastric mucosa has received little investigative attention as a unique immune environment. Here, we analyzed whether retinoic acid (RA), an important homeostatic factor in the small intestinal mucosa, also contributes to gastric immune regulation. We report that human gastric tissue contains high levels of the RA precursor molecule retinol (ROL), and that gastric epithelial cells express both RA biosynthesis genes and RA response genes, indicative of active RA biosynthesis. Moreover, primary gastric epithelial cells cultured in the presence of ROL synthesized RA in vitro and induced RA biosynthesis in co-cultured monocytes through an RA-dependent mechanism, suggesting that gastric epithelial cells may also confer the ability to generate RA on gastric dendritic cells (DCs). Indeed, DCs purified from gastric mucosa had similar levels of aldehyde dehydrogenase activity and RA biosynthesis gene expression as small intestinal DCs, although gastric DCs lacked CD103. In H. pylori-infected gastric mucosa, gastric RA biosynthesis gene expression was severely disrupted, which may lead to reduced RA signaling and thus contribute to disease progression. Collectively, our results support a critical role for RA in human gastric immune regulation.  ",0
5293,25249417,Peripheral sea-fan retinal neovascularization as a manifestation of chronic rhegmatogenous retinal detachment and surgical management,"To report the rare occurrence of peripheral retinal sea-fan neovascularization in a patient with chronic rhegmatogenous retinal detachment and describe the surgical management. A 29-year-old female patient was referred to our department by her ophthalmologist for investigation and treatment of peripheral retinal neovascularization in her right eye(RE). Visual acuity(VA) at presentation was 20/200 RE and 20/20 LE. Fundoscopy of the RE revealed a chronic inferotemporal retinal detachment and peripheral neovascularization with a sea fan configuration. Fundoscopy of the LE was without any findings. Fluorescein angiography confirmed the sea fan neovascularization in the RE with leakage of the newly formed vessels and peripheral ischemia while the LE did not demonstrate any neovascularization angiographically. Family history was negative for retinitis pigmentosa and haemoglobinopathies. Patient underwent full blood count and haemoglobin electrophoresis to exclude thrombocytosis and sickle cell anaemia, and serum angiotensin-converting enzyme (SACE) measurement to exclude sarcoidosis. Examination with scleral indentation of the RE revealed 2 peripheral small retinal holes close to the ora serrata . The patient underwent a scleral buckling procedure with a small segmental buckle limited to the area of the holes and cryotherapy. Ccryotherapy was not applied to the area with neovascularization and no subretinal fluid drainage was performed. The detached retina was successfully re-attached surgically and the subretinal fluid was gradually absorbed within three months from the time of surgery. Complete regression of neovascularization was evident 2 months postoperatively and VA improved to 20/30. Three years later the clinical and functional findings remain unchanged. Our case illustrates the rare but possible association of chronic retinal detachment with peripheral retinal sea-fan neovascularization; although the incidence is rare it may pose diagnostic and treatment dilemmas. In such cases and in the presence of retinal breaks, cryotherapy and a segmental buckle limited to the retinal holes and not on the neovascularization seems to suffice for the regression of the new vessels. ",0
5294,25249579,β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure,"Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I tetramer staining to quantify and characterize β-cell-specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarkably, we found that β-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy control subjects, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the β-cell-specific CD8 T cell compartment. Molecular analysis of selected β-cell-specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor repertoires comprising exclusively private clonotypes. Collectively, these data identify novel and distinctive features of disease-relevant CD8 T cells that inform the immunopathogenesis of type 1 diabetes.  ",0
5295,25250117,Attitude toward death in healthy people and patients with diabetes and cancer,"A person's beliefs can influence the progression of his/her disease;and battling an illness can trigger severe anxiety about death. This study aims to compare the attitude toward death between healthy people and those suffering from diabetes and cancer. In a cross-sectional study, 300 individuals were selected by convenient sampling method. Three groups were matched by gender, age, education, and monthly income. Information was collected through a Death Attitude Profile-Revised (DAPR) questionnaire and Analyzed Via Covariance (ANCOVA). The results indicated no difference in death attitude among the three groups (f=2.705, p<0.05). All the three groups displayed a higher mean in neutral and approach acceptance. In this study, it was found that disease did not seem to change death attitudes; rather the patients' current attitude had been shaped by previous stages of their sickness. ",0
5296,25250167,"""In Silico Design and Analysis of TGFαL3-SEB Fusion Protein as """"a New Antitumor Agent"""" Candidate by Ligand-Targeted Superantigens Technique""","Bacterial superantigen Staphylococcal Enterotoxins (SEs), has stimulated polyclonal T cells irrespective of their antigen specificity, resulted a massive release of cytokines, and suggested that they could be assigned as a candidate of new antitumor agents. Recent attempts have done to specifically target superantigens towards tumors, subsequently Monoclonal antibodies and tumor-related ligands have employed as targeting molecules of superantigen for the preclinical treatment of different tumors. Here, we have evaluated TGFαL3-SEB fusion protein as a new antitumor candidate by genetically fusing the third loop of transforming growth factor alpha (TGFαL3) to Staphylococcal Enterotoxin type B. An in silico techniques have launched to characterize the properties and structure of the protein, before initiating the experimental study, we have predicted physicochemical properties, structures, stability, MHC binding properties and ligand-receptor interaction of this chimeric protein by means of computational bioinformatics tools and servers. Our results have indicated codon adaptation index of tgfαl3-seb fusion gene has increased from 0.5 in the wild type sequences to 0.85 in the chimeric optimized gene. The mfold data has shown the tgfαl3-seb mRNA was stable enough for efficient translation in the new host. Based on Ramachandran plot TGFαL3-SEB has classified as a stable fusion protein. Our result has shown fusing of TGFaL3 in N-terminal of the TGFαL3-SEB construct, had no effects on MHC binding and subsequently superantigenic activity of SEB. Finally based on ligand-receptor docking the binding ability of TGFaL3 was strong enough to its receptor, so TGFαL3-SEB could be assigned as a new antitumor candidate in cancer immunotherapy. Our results have proposed that TGFαL3-SEB was a stable fusion protein with proper affinity to its receptor that overexpressed in various human carcinomas, so it could generate potent immune response towards tumors. ",0
5297,25250506,Undervalued criteria in the evaluation of multimodal trials for upper GI cancers,"Global economies and their health systems face a huge challenge from cancer: 1 in 3 women and 1 in 2 men will develop cancer in their lifetime. In the less developed countries, the volume of cancer patients will overwhelm the existing healthcare systems. Even in developed regions, patients with upper gastrointestinal (GI) cancer usually present with locally advanced tumors that their prognosis is poor. A detailed knowledge of anatomy, embryology, epidemiology, tumor classifications and tumor growth is key understanding and evaluating the relevant research. We review undervalued criteria necessary to evaluate the response to multimodal therapy for upper GI cancers.  ",0
5298,25250739,The use of electronic devices for communication with colleagues and other healthcare professionals - nursing professionals' perspectives,"The aim of the study is to describe nursing professionals' experiences of the use of electronic devices for communication with colleagues and other healthcare professionals. Information and communication technology applications in health care are rapidly expanding, thanks to the fast-growing penetration of the Internet and mobile technology. Communication between professionals in health care is essential for patient safety and quality of care. Implementing new methods for communication among healthcare professionals is important. A cross-sectional survey was used in the study. The data were collected in spring 2012 using an electronic questionnaire with structured and open-ended questions. The target group comprised the nursing professionals (N = 567, n = 123) in one healthcare district who worked in outpatient clinics in publically funded health care in Finland. Nursing professionals use different electronic devices for communication with each other. The most often used method was email, while the least used methods were question-answer programmes and synchronous communication channels on the Internet. Communication using electronic devices was used for practical nursing, improving personnel competences, organizing daily operations and administrative tasks. Electronic devices may speed up the management of patient data, improve staff cooperation and competence and make more effective use of working time. The obstacles were concern about information security, lack of technical skills, unworkable technology and decreasing social interaction. According to our findings, despite the obstacles related to use of information technology, the use of electronic devices to support communication among healthcare professionals appears to be useful. ",0
5299,25250776,The parasitic eyeworm Oxyspirura petrowi as a possible cause of decline in the threatened lesser prairie-chicken (Tympanuchus pallidicinctus),"Lesser prairie-chickens (Tympanuchus pallidicinctus) have been declining range wide since the early 1900's despite efforts to establish conservation and improve their habitat. In early 2014, the lesser prairie-chicken was listed as a threatened species under the U.S Endangered Species Act and the need to find out why they are declining is more important than ever. Nine hunter shot lesser prairie-chickens were donated and sampled for the presence or absence of the eyeworm Oxyspirura petrowi, a known parasite that can cause damage to the eye of its host, and common environmental contaminants. Eyeworm infection was found in 7 of 9 birds (78% infection rate) with an infection range between 0-16 O. petrowi per bird. Breast, liver, and fat tissue samples from the lesser prairie-chickens were analyzed for the frequency of 20 organochlorine pesticides. Femurs and livers were also tested on these birds for metal contaminants. Pesticides were found in several samples above the detection limits but were still in the low ng/g range. Notable was the ubiquitous presence of endrin aldehyde across all tissues. One femur showed 5.66 µg/g of lead (Pb) but this is still relatively low. No liver samples had elevated mercury (Hg) above detection limits. The presence of these organochlorines is consistent with the historic use of pesticides in this region. With pesticide and metals found in such low levels and parasitic nematode infections at rather high levels, it is recommended that these parasites be further evaluated as a contributing factor to the decline of the lesser prairie-chicken. ",0
5300,25250777,The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components,"Epidemiological studies have reported that cigarette smoking increases the risk of developing multiple sclerosis (MS) and accelerates its progression. However, the molecular mechanisms underlying these effects remain unsettled. We have investigated here the effects of the nicotine and the non-nicotine components in cigarette smoke on MS using the experimental autoimmune encephalomyelitis (EAE) model, and have explored their underlying mechanism of action. Our results show that nicotine ameliorates the severity of EAE, as shown by reduced demyelination, increased body weight, and attenuated microglial activation. Nicotine administration after the development of EAE symptoms prevented further disease exacerbation, suggesting that it might be useful as an EAE/MS therapeutic. In contrast, the remaining components of cigarette smoke, delivered as cigarette smoke condensate (CSC), accelerated and increased adverse clinical symptoms during the early stages of EAE, and we identify a particular cigarette smoke compound, acrolein, as one of the potential mediators. We also show that the mechanisms underlying the opposing effects of nicotine and CSC on EAE are likely due to distinct effects on microglial viability, activation, and function.  ",0
5301,25251157,Lkb1 deletion promotes ectopic lipid accumulation in muscle progenitor cells and mature muscles,"Excessive intramyocellular triglycerides (muscle lipids) are associated with reduced contractile function, insulin resistance, and Type 2 diabetes, but what governs lipid accumulation in muscle is unclear. Here we report a role of Lkb1 in regulating lipid metabolism in muscle stem cells and their descendent mature muscles. We used Myod(Cre) and Lkb1(flox/flox) mice to specifically delete Lkb1 in myogenic cells including stem and differentiated cells, and examined the lipid accumulation and gene expression of myoblasts cultured from muscle stem cells (satellite cells). Genetic deletion of Lkb1 in myogenic progenitors led to elevated expression of lipogenic genes and ectopic lipid accumulation in proliferating myoblasts. Interestingly, the Lkb1-deficient myoblasts differentiated into adipocyte-like cells upon adipogenic induction. However, these adipocyte-like cells maintained myogenic gene expression with reduced ability to form myotubes efficiently. Activation of AMPK by AICAR prevented ectopic lipid formation in the Lkb1-null myoblasts. Notably, Lkb1-deficient muscles accumulated excessive lipids in vivo in response to high-fat diet feeding. These results demonstrate that Lkb1 acts through AMPK to limit lipid deposition in muscle stem cells and their derivative mature muscles, and point to the possibility of controlling muscle lipid content using AMPK activating drugs. ",0
5302,25251616,A randomized trial comparing treatments for varicose veins,"BACKGROUND: Ultrasound-guided foam sclerotherapy and endovenous laser ablation are widely used alternatives to surgery for the treatment of varicose veins, but their comparative effectiveness and safety remain uncertain. METHODS: In a randomized trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of foam, laser, and surgical treatments. Primary outcomes at 6 months were disease-specific quality of life and generic quality of life, as measured on several scales. Secondary outcomes included complications and measures of clinical success. RESULTS: After adjustment for baseline scores and other covariates, the mean disease-specific quality of life was slightly worse after treatment with foam than after surgery (P=0.006) but was similar in the laser and surgery groups. There were no significant differences between the surgery group and the foam or the laser group in measures of generic quality of life. The frequency of procedural complications was similar in the foam group (6%) and the surgery group (7%) but was lower in the laser group (1%) than in the surgery group (P<0.001); the frequency of serious adverse events (approximately 3%) was similar among the groups. Measures of clinical success were similar among the groups, but successful ablation of the main trunks of the saphenous vein was less common in the foam group than in the surgery group (P<0.001). CONCLUSIONS: Quality-of-life measures were generally similar among the study groups, with the exception of a slightly worse disease-specific quality of life in the foam group than in the surgery group. All treatments had similar clinical efficacy, but complications were less frequent after laser treatment and ablation rates were lower after foam treatment. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN51995477.).",0
5303,25251834,Kinetics of Competitive Adsorption between Lysozyme and Lactoferrin on Silicone Hydrogel Contact Lenses and the Effect on Lysozyme Activity,"To determine the effect of competitive adsorption between lysozyme and lactoferrin on silicone hydrogel contact lenses and the effect on lysozyme activity. Three commercially available silicone hydrogel contact lens materials (senofilcon A, lotrafilcon B and balafilcon A) were examined, for time points ranging from 10 s to 2 h. Total protein deposition was determined by I(125) radiolabeling of lysozyme and lactoferrin, while the activity of lysozyme was determined by a micrococcal activity assay. Senofilcon A and balafilcon A did not show any relevant competitive adsorption between lysozyme and lactoferrin. Lotrafilcon B showed reduced protein deposition due to competitive adsorption for lactoferrin at all time points and lysozyme after 7.5 min. Co-adsorption of lactoferrin and lysozyme decreased the activity of lysozyme in solution for senofilcon A and lotrafilcon B, but co-adsorption had no effect on the surface activity of lysozyme for all lens types investigated. Competition between lysozyme and lactoferrin is material specific. Co-adsorption of lysozyme and lactoferrin does not affect the activity of surface-bound lysozyme but can reduce the activity of subsequently desorbed lysozyme. ",0
5304,25251864,Complications of immunosuppressive agents therapy in transplant patients,"Solid organ transplantation remains the gold standard for the treatment of end-stage organ dysfunction and saves thousands of lives. Besides the progress of surgery, advances in understanding transplant physiology, immunology and the development of immunosuppressive drugs lead to improved short- and long-term survival. Transplantation is offered to an increasing number of patients with higher age and comorbidities. Approximately one third of organ recipients require hospital readmission after transplantation because of a multitude of clinical problems related to immunosuppressive therapy. We review the current knowledge on typical complications associated with immunosuppressants with emphasis on the intensivist's perspective.  ",0
5305,25252071,Measurement of cytokine levels in cerebrospinal fluid over time in neonatal Enterococcal meningitis,"Enterococcus faecalis is rarely involved in neonatal meningitis. Several studies have indicated that the cytokines related to bacterial infection may induce nerve cell damage; therefore, the cytokine levels in cerebrospinal fluid (CSF) could represent a valuable hallmark for rapid recognition of the disease and evaluation of the degree of neurological involvement. We analyzed cytokine levels in the CSF of a neonate with E. faecalis meningitis over time. Tumor necrosis factor-α (TNF-α) tended to be elevated during the acute phase of infection, and then decreased during the convalescent stage after treatment. CSF inflammatory cytokine measurement may provide important clues for predicting the development of complications in the host because some of these cytokines, such as TNF-α, can injure neurons. ",0
5306,25252080,Fatalism moderates the relationship between family history of cardiovascular disease and engagement in health-promoting behaviors among at-risk rural Kentuckians,"In rural communities that experience high rates of cardiovascular disease (CVD) morbidity and mortality, family history education may enhance risk awareness and support engagement in healthy behaviors but could also engender fatalism. This study was conducted to assess if the relationship between family history and adherence to healthy lifestyle behaviors is moderated by fatalism. Baseline data were obtained from 1,027 adult participants in the HeartHealth in Rural Kentucky study. Multiple linear regression was used to determine whether fatalism moderated the relationship between high-risk family history of CVD and adherence to healthy lifestyle behaviors, controlling for sociodemographic variables and CVD risk factors. The relationship between family history and healthy behaviors was assessed for subgroups of participants divided according to the upper and lower quartiles of fatalism score. The relationship between high-risk family history of CVD and adherence to healthy behaviors was moderated by fatalism. Among those with the highest quartile of fatalism scores, high-risk family history predicted greater adherence to healthy behaviors, while among those in the lowest quartile, and among those with the middle 50% of fatalism scores, there was no association between family history and healthy behavior scores. Family history education can provide people at increased risk for CVD important information to guide health practices. This may be particularly relevant for those with a high degree of fatalistic thinking. In rural communities with limited health resources, family history education, combined with assessment of fatalism, may support better targeted interventions to enhance engagement in healthy behaviors. ",0
5307,25252123,A five generation family with a novel mutation in FOXC2 and lymphedema worsening to hydrops in the youngest generation,"We describe a five generation family with dominantly inherited lymphedema, but no distichiasis, in which 3/3 affected offspring in the fifth generation have died of fetal hydrops and related birth defects. Mutational analysis disclosed a novel mutation in FOXC2 (R121C) in affected members. We searched for possible genetic influences on the greater severity of lymphedema (hydrops) in the fifth generation. Karyotypes disclosed an extra band in Xp in one affected fetus, but this was also found in the mother. Copy number variation (CNV) studies on four members of the pedigree (mother of the three severely affected fetuses/infants; one severely affected; a full, and a half, unaffected sibs) did not detect the source of the Xp band or a possible influence on the severe phenotype. However, use of SNP arrays did allow identification of the portion of the maternal proximal Xp shared by a hydrops-affected daughter and son which was not shared by an unaffected daughter from the same sibship. ",0
5308,25252816,Molecular and cellular control of cell death and defense signaling in pepper,"Pepper (Capsicum annuum L.) provides a good experimental system for studying the molecular and functional genomics underlying the ability of plants to defend themselves against microbial pathogens. Cell death is a genetically programmed response that requires specific host cellular factors. Hypersensitive response (HR) is defined as rapid cell death in response to a pathogen attack. Pepper plants respond to pathogen attacks by activating genetically controlled HR- or disease-associated cell death. HR cell death, specifically in incompatible interactions between pepper and Xanthomonas campestris pv. vesicatoria, is mediated by the molecular genetics and biochemical machinery that underlie pathogen-induced cell death in plants. Gene expression profiles during the HR-like cell death response, virus-induced gene silencing and transient and transgenic overexpression approaches are used to isolate and identify HR- or disease-associated cell death genes in pepper plants. Reactive oxygen species, nitric oxide, cytosolic calcium ion and defense-related hormones such as salicylic acid, jasmonic acid, ethylene and abscisic acid are involved in the execution of pathogen-induced cell death in plants. In this review, we summarize recent molecular and cellular studies of the pepper cell death-mediated defense response, highlighting the signaling events of cell death in disease-resistant pepper plants. Comprehensive knowledge and understanding of the cellular functions of pepper cell death response genes will aid the development of novel practical approaches to enhance disease resistance in pepper, thereby helping to secure the future supply of safe and nutritious pepper plants worldwide. ",0
5309,25252910,Development of pod borer-resistant transgenic chickpea using a pod-specific and a constitutive promoter-driven fused cry1Ab/Ac gene,"We studied pod-specific msg promoter from soybean and developed different transgenic lines of chickpea expressing fused cry1Ab/Ac constitutively and pod specifically for resistance against the destructive pest Helicoverpa armigera. Crystal (Cry) proteins derived from the soil bacterium Bacillus thuringiensis (Bt) play an important role in controlling infestation of Helicoverpa armigera, which has been considered a serious problem in chickpea productivity. This study was undertaken to overcome the problem by introducing fused cry1Ab/Ac insecticidal gene under the control of pod-specific soybean msg promoter as well as rice actin1 promoter into chickpea var. DCP 92-3 by Agrobacterium-mediated transformation. Transgenic chickpea lines were characterized by real-time PCR, ELISA and insect bioassay. Expression of fused cry gene under constitutive and pod-specific promoter results in increase of 77- and 110-fold, respectively, compared to non-transgenic control plants. Levels of Cry toxins produced under the control of actin1 and soybean msg promoter were also estimated by ELISA in the leaves and pods, respectively. The higher expression of fused cry gene caused a lethal effect in larvae. The results of insect bioassay study revealed significant reduction in the survival rate of H. armigera reared on transgenic chickpea twigs as well as on pods. Pod-specific promoter-driven fused cry gene provides better and significant management strategy of pest control of chickpea without phenotypic cost. ",0
5310,25253258,In vitro modeling of gallbladder-associated Salmonella spp. colonization,"The host-pathogen interactions occurring in the gallbladder during Salmonella Typhi colonization contribute to typhoid fever pathogenesis during the acute and chronic stages of disease. The gallbladder is the primary reservoir during chronic typhoid carriage. In this organ, Salmonella encounters host-barriers including bile, immunoglobulins, and mucus. However, the bacterium possesses mechanisms to resist and persist in this environment, in part by its ability to attach to and invade into the gallbladder epithelium. Such persistence in the gallbladder epithelium contributes to chronic carriage. In addition, patients harboring gallstones in their gallbladders have increased risk of becoming carriers because these abnormalities serve as a substrate for Salmonella biofilm formation. Our laboratory has studied the Salmonella interactions in this specific environment by developing in vitro methods that closely mimic the gallbladder and gallstones niches. These methods are reproducible and provide a platform for future studies of acute and chronic bacterial infections in the gallbladder.  ",0
5311,25253690,"Interactions between metal-binding domains modulate intracellular targeting of Cu(I)-ATPase ATP7B, as revealed by nanobody binding","The biologically and clinically important membrane transporters are challenging proteins to study because of their low level of expression, multidomain structure, and complex molecular dynamics that underlies their activity. ATP7B is a copper transporter that traffics between the intracellular compartments in response to copper elevation. The N-terminal domain of ATP7B (N-ATP7B) is involved in binding copper, but the role of this domain in trafficking is controversial. To clarify the role of N-ATP7B, we generated nanobodies that interact with ATP7B in vitro and in cells. In solution NMR studies, nanobodies revealed the spatial organization of N-ATP7B by detecting transient functionally relevant interactions between metal-binding domains 1-3. Modulation of these interactions by nanobodies in cells enhanced relocalization of the endogenous ATP7B toward the plasma membrane linking molecular and cellular dynamics of the transporter. Stimulation of ATP7B trafficking by nanobodies in the absence of elevated copper provides direct evidence for the important role of N-ATP7B structural dynamics in regulation of ATP7B localization in a cell.  ",0
5312,25253765,Reproducibility of retinal oxygen saturation in normal and treated glaucomatous eyes,"To measure the reproducibility of retinal oxygen saturation (SaO2) levels among treated glaucomatous eyes and normal controls in a prospective non-randomised study. Patients with perimetric glaucoma (PG) and normal controls were included. Exclusion criteria for both groups included visual acuity <20/30, unreliable visual fields, thyroidopathies, hemoglobinopathies, cardiovascular and pulmonary diseases. Retinal oximetry was performed twice consecutively on one randomly selected eye of PG and normal controls using spectrophotometric retinal oximeter (SRO; Oxymap ehf., Iceland). Four main retinal vessel pairs were analysed separately. Coefficients of variability (CoV), coefficients of repeatability (CoR) and intraclass correlation coefficients (ICCs) in arteries (a.SaO2) and veins (v.SaO2) were calculated. 23 PG (mean age 68.3±10.8 years) and 22 normal subjects (mean age 61.5±18.2 years; p=0.14) were included. The intraocular pressure and mean ocular perfusion pressure in glaucoma (14.4±4.2 mm Hg; 45.8±5.8 mm Hg) and controls (14.3±3.3 mm Hg; 45.8±6.1 mm Hg) were similar (p >0.05). In the PG group, the a.SaO2 had a CoV of 1.6%, a CoR of 4.7 and an ICC of 0.97; the v.SaO2 had a CoV of 5.9%, a CoR of 8.7 and an ICC of 0.96. In normals, the a.SaO2 had a CoV of 0.98%, a CoR of 3.3 and an ICC of 0.97; the v.SaO2 had a CoV of 4.8%, a CoR of 7.7 and an ICC of 0.93. Retinal oximetry measurements using SRO are highly reproducible in both treated glaucomatous and normal eyes. ",0
5313,25254009,The adherence and illness perception of patients diagnosed with asthma or chronic obstructive pulmonary disease treated with polytherapy using new generation Cyclohaler,"The factors influencing adherence of patients diagnosed with asthma and chronic obstructive pulmonary disease (COPD) include the complexity of the therapy, fear of side effects of drugs, method of taking the drug, dosage regimen, polypharmacy, adverse events, knowledge about the essence of the disease and its complications, illness perception and priorities in life, training on the use of the inhaler, the duration of treatment, social support, and drug availability. To assess the adherence of patients diagnosed with asthma and COPD treated with polytherapy with fluticasone propionate and formoterol fumarate using the Fantasmino inhaler in relation to primary diagnosis and illness perception as well as patients' and doctors' opinion about this form of therapy. A questionnaire survey covering adherence, illness perception and opinion about polytherapy using new generation Cyclohaler performed by pulmonologists, allergologists and general practitioners in 3,618 patients with asthma and 2,602 with COPD. On visit 1, a lower adherence rate was observed in COPD than in the asthma group (72.0% vs. 61.5%; p < 0.01). During the observation, the adherence rate increased significantly in the COPD group, only (61.5% vs. 73.0%; p < 0.01). A negative correlation between total MMAS-8 and BIPQ scores was observed in both study groups (R = -0.15; p < 0.001 and R = -0.24; p < 0.001, respectively). During the observation, a percentage of patients who believed that the administration of the two drugs in a single inhaler considerably facilitates their use increased significantly in both study groups. In addition, an increased percentage of doctors believed that this therapeutic option facilitated education of patients and decreased the number of errors made by the patients. The illness perception, younger age, disease duration and severity are predictors of adherence to treatment with fluticasone propionate and formoterol fumarate using the Fantasmino inhaler among patients with asthma and COPD. The positive opinion of patients and doctors about administration of fluticasone propionate and formoterol fumarate using the Fantasmino inhaler increased during observation. ",0
5314,25254107,Case Report: Expanding the tumour spectrum associated with the Birt-Hogg-Dubé cancer susceptibility syndrome,"Patients with the Birt-Hogg-Dubé cancer susceptibility syndrome are at high risk of developing renal cell carcinoma, pulmonary cysts and pneumothorax, and skin lesions called fibrofolliculomas. Here we report the case of a Birt-Hogg-Dubé patient with a primary clear cell carcinoma of the thyroid (a very rare type of thyroid cancer), and FLCN loss of heterozygosity within the tumour, providing molecular evidence for this association. Our findings expand the tumour spectrum associated with this syndrome. It is paramount to identify individuals with Birt-Hogg-Dubé so that they, and subsequently their affected relatives, can benefit from tailored cancer screening and prevention.  ",0
5315,25254161,Burden of respiratory syncytial virus infection in young children,"Respiratory syncytial virus (RSV) is the most frequent and important cause of lower respiratory tract infection in infants and children. It is a seasonal virus, with peak rates of infection occurring annually in the cold season in temperate climates, and in the rainy season, as temperatures fall, in tropical climates. High risk groups for severe RSV disease include infants below six mo of age, premature infants with or without chronic lung disease, infants with hemodynamically significant congenital heart disease, infants with immunodeficiency or cystic fibrosis, and infants with neuromuscular diseases. Mortality rates associated with RSV infection are generally low in previous healthy infants (below 1%), but increase significantly in children with underlying chronic conditions and comorbidities. Following early RSV lower respiratory tract infection, some patients experience recurrent episodes of wheezing mimicking early childhood asthma with persistence of lung function abnormalities until adolescence. There is currently no RSV vaccine available, but promising candidate vaccines are in development. Palivizumab, a monoclonal RSV antibody that is the only tool for immunoprophylaxis in high-risk infants, lowers the burden of RSV infection in certain carefully selected patient groups.  ",0
5316,25254305,Implementation of a rotational ultrasound biomicroscopy system equipped with a high-frequency angled needle transducer--ex vivo ultrasound imaging of porcine ocular posterior tissues,"The mechanical scanning of a single element transducer has been mostly utilized for high-frequency ultrasound imaging. However, it requires space for the mechanical motion of the transducer. In this paper, a rotational scanning ultrasound biomicroscopy (UBM) system equipped with a high-frequency angled needle transducer is designed and implemented in order to minimize the space required. It was applied to ex vivo ultrasound imaging of porcine posterior ocular tissues through a minimal incision hole of 1 mm in diameter. The retina and sclera for the one eye were visualized in the relative rotating angle range of 270°~330° and at a distance range of 6~7 mm, whereas the tissues of the other eye were observed in relative angle range of 160°~220° and at a distance range of 7.5~9 mm. The layer between retina and sclera seemed to be bent because the distance between the transducer tip and the layer was varied while the transducer was rotated. Certin features of the rotation system such as the optimal scanning angle, step angle and data length need to be improved for ensure higher accuracy and precision. Moreover, the focal length should be considered for the image quality. This implementation represents the first report of a rotational scanning UBM system. ",0
5317,25254426,Secular changes in relative leg length confound height-based spirometric reference values,"Most but not all data from different ethnic groups fit the Global Lung Function Initiative (GLI) spirometric reference model. This study investigates to what extent discrepancies are caused by secular changes in body proportions. FEV1 and FVC from 20,336 healthy Japanese subjects (13,492 women) aged 17 to 95 years were compared with GLI-2012 reference values for Europeans. Data on the sitting height/standing height ratio (Cormic index) in 17-year-old students, collected from 1949 to 2012 in successive birth cohorts, were used to assess secular changes in body frame. The cohort-specific Cormic index was used to assess how variation in body frame affected pulmonary function. FEV1 and FVC were lower than GLI-2012 reference values, with values progressively falling until age 35 to 40 years and then rising to European levels in the elderly. The Cormic index rose until 1942, then fell, with a nadir in the 1970s, before rising again until 1995. Nearly one-half of the spirometric variability from predicted values could be explained by differences in the Cormic index between birth cohorts. In low-income countries, improving health conditions are likely to drive increases in height and changes in relative leg length similar to those observed in Japan and, thus, to a change in body frame. This implies that height-based prediction equations for such populations will need to be periodically updated. ",0
5318,25255140,"Correlation between tear film osmolarity, dry eye disease, and rheumatoid arthritis","The aim of this study was to evaluate the reliability of tear film osmolarity as a diagnostic tool for detecting dry eye disease (DED) in patients with rheumatoid arthritis (RA). The second aim was to determine whether there is a relationship between tear film osmolarity, a commonly used RA score, and diagnostic blood tests for RA. A group of 74 patients with RA but without any previously established diagnosis of DED at University Hospital Wurzburg was examined. A Modified Dry Eye Severity Score was calculated based on tear film osmolarity, Schirmer test, tear film break-up time, ocular surface disease index questionnaire, corneal fluorescein staining, conjunctival lissamine green staining, and meibomian gland grading score. RA assessment included disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) scoring and serum levels of C-reactive protein (CRP) and rheumatoid factor (RF). Tear film osmolarity showed a high coefficient of determination and correlation when regressed to Modified Dry Eye Severity Score (R = 0.727, P < 0.001). Using a cutoff point of 316 mOsmol/L, there was significant correlation between DAS28-ESR values and tear film osmolarity (P = 0.016). Spearman correlation coefficients between osmolarity and CRP or RF were not significant (CRP: r = -0.104, P = 0.353; RF: r = 0.138, P = 0.226). Tear film osmolarity highly correlates with a modified dry eye severity scale in patients with RA with previously unknown DED. Tear film hyperosmolarity >316 mOsmol/L is correlated significantly with a commonly used DAS of RA (DAS28-ESR) but not with serum markers such as CRP and RF. Patients with RA with a high DAS28-ESR score show higher prevalence of tear film hyperosmolarity. ",0
5319,25255756,"Effects of heat acclimation on photosynthesis, antioxidant enzyme activities, and gene expression in orchardgrass under heat stress","The present study was designed to examine the effects of heat acclimation on enzymatic activity, transcription levels, the photosynthesis processes associated with thermostability in orchardgrass (Dactylis glomerata L.).The stomatal conductance (Gs), net photosynthetic rate (Pn), and transpiration rates (Tr) of both heat-acclimated (HA) and non-acclimated (NA) plants were drastically reduced during heat treatment [using a 5-day heat stress treatment (38/30 °C ‒ day/night) followed by a 3-day recovery under control conditions (25/20 °C ‒ day/night), in order to consolidate the second cycle was permitted]. Water use efficiency increased more steeply in the HA (4.9 times) versus the NA (1.8 times) plants, and the intercellular CO2 concentration decreased gently in NA (10.9%) and HA (25.3%) plants after 20 d of treatments compared to 0 days'. Furthermore, heat-acclimated plants were able to maintain significant activity levels of superoxide disumutase (SOD), catalase (CAT), guaiacol peroxidase (POD), and transcription levels of genes encoding these enzymes; in addition, HA plants displayed lower malondialdehyde content and lower electrolyte leakage than NA plants. These results suggest that maintenance of activity and transcription levels of antioxidant enzymes as well as photosynthesis are associated with variable thermostability in HA and NA plants. This likely occurs through cellular membrane stabilization and improvements in water use efficiency in the photosynthetic process during heat stress. The association between antioxidant enzyme activity and gene expression, both of which may vary with genetic variation in heat tolerance, is important to further understand the molecular mechanisms that contribute to heat tolerance.  ",0
5320,25255913,Addressing equity in interventions to reduce air pollution in urban areas: a systematic review,"We did a systematic review to assess quantitative studies investigating the association between interventions aiming to reduce air pollution, health benefits and equity effects. Three databases were searched for studies investigating the association between evaluated interventions aiming to reduce air pollution and heath-related benefits. We designed a two-stage selection process to judge how equity was assessed and we systematically determined if there was a heterogeneous effect of the intervention between subgroups or subareas. Of 145 identified articles, 54 were reviewed in-depth with eight satisfying the inclusion criteria. This systematic review showed that interventions aiming to reduce air pollution in urban areas have a positive impact on air quality and on mortality rates, but the documented effect on equity is less straightforward. Integration of equity in evidence-based public health is a great challenge nowadays. In this review we draw attention to the importance of considering equity in air pollution interventions. We also propose further methodological and theoretical challenges when assessing equity in interventions to reduce air pollution and we present opportunities to develop this research area. ",0
5321,25256158,"Effect of post-thaw addition of seminal plasma on motility, viability and chromatin integrity of cryopreserved donkey jack (Equus asinus) spermatozoa","Pregnancy rates in donkeys after artificial insemination with cryopreserved semen are still low, compared to the horse species. Addition of autologous seminal plasma to frozen-thawed semen appeared to improve pregnancy rates. The aims of this study were to evaluate (1) sperm motility and plasma membrane integrity after thawing (T0) and after one and 2 h (T1 and T2) of post-thaw incubation in either 0% (SP0) or 70% (SP70) autologous seminal plasma and (2) sperm motility, plasma membrane integrity and DNA quality (%COMP-αt) after thawing (T0) and after 2 and 4 h (T2 and T4) of post-thaw incubation in either 0% (SP0), 5% (SP5) or 20% (SP20) homologous seminal plasma. In experiment 1, seminal plasma decreased total and progressive sperm motility and plasma membrane intact spermatozoa immediately after dilution and at all following time points (p < 0.05). In experiment 2, total and progressive motility did not differ between treatments immediately after dilution and between SP0 and SP5 at T2, while they were lower in both SP5 and SP20 than in SP0 at T4. Plasma membrane intact sperm cells did not differ between SP0 and SP5 and were lower in SP20 at all time points. DNA quality was not affected by treatment immediately after dilution and was significantly worse for SP20 after 4 h of incubation (p < 0.05). The post-thaw addition of seminal plasma at the tested concentrations did not improve donkey frozen semen characteristics in vitro over time. ",0
5322,25256165,Group determination of 14-membered macrolide antibiotics and azithromycin using antibodies against common epitopes,"Erythromycin (ERY), clarithromycin (CLA), roxithromycin (ROX), and azithromycin (AZI) are macrolide antibiotics widely used in livestock and human medicine. Therefore, they are frequently found as pollutants in environmental water. A method based on indirect competitive enzyme-linked immunosorbent assay (ELISA) for group determination of these macrolides in foodstuffs, human biofluids, and water was developed. Carboxymethyloxime of clarithromycin (CMO-CLA) was synthesized and conjugated to bovine serum albumin (BSA) and gelatin to prepare immunogen and coating antigen with advantageous presentation of target epitopes, l-cladinose and d-desosamine, common for these analytes. Antibodies generated in rabbits were capable of recognizing ERY, CLA, and ROX as a group (100-150%), and AZI (12%) and did not cross-react with ERY degradants, which lack antibiotic activity. Assay displayed sensitivity of determination of 14-membered macrolides (IC50=0.13-0.2ng/ml) and low limit of detection (LOD) that was achieved at 0.02 to 0.03ng/ml. It allowed performing analysis of milk, muscle, eggs, bovine serum, water, human serum and urine, and avoiding matrix effect without special pretreatment using simple dilution with assay buffer. For 15-membered macrolide AZI, the corresponding characteristics were IC50=1.6ng/ml and LOD=0.14ng/ml. The recoveries of veterinary and human medicine macrolides from corresponding matrices were validated and found to be satisfactory. ",0
5323,25257232,Assessment of faculty productivity in academic departments of medicine in the United States: a national survey,"Faculty productivity is essential for academic medical centers striving to achieve excellence and national recognition. The objective of this study was to evaluate whether and how academic Departments of Medicine in the United States measure faculty productivity for the purpose of salary compensation. We surveyed the Chairs of academic Departments of Medicine in the United States in 2012. We sent a paper-based questionnaire along with a personalized invitation letter by postal mail. For non-responders, we sent reminder letters, then called them and faxed them the questionnaire. The questionnaire included 8 questions with 23 tabulated close-ended items about the types of productivity measured (clinical, research, teaching, administrative) and the measurement strategies used. We conducted descriptive analyses. Chairs of 78 of 152 eligible departments responded to the survey (51% response rate). Overall, 82% of respondents reported measuring at least one type of faculty productivity for the purpose of salary compensation. Amongst those measuring faculty productivity, types measured were: clinical (98%), research (61%), teaching (62%), and administrative (64%). Percentages of respondents who reported the use of standardized measurements units (e.g., Relative Value Units (RVUs)) varied from 17% for administrative productivity to 95% for research productivity. Departments reported a wide variation of what exact activities are measured and how they are monetarily compensated. Most compensation plans take into account academic rank (77%). The majority of compensation plans are in the form of a bonus on top of a fixed salary (66%) and/or an adjustment of salary based on previous period productivity (55%). Our survey suggests that most academic Departments of Medicine in the United States measure faculty productivity and convert it into standardized units for the purpose of salary compensation. The exact activities that are measured and how they are monetarily compensated varied substantially across departments. ",0
5324,25257393,Could acupuncture have a role in the treatment of autism spectrum disorder via modulation of BDNF expression and activation?,"Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions characterised by early-onset difficulties in social communication and unusually restricted repetitive behaviour and interests. Multiple lines of evidence directly or indirectly suggest an involvement in autism of the brain-derived neurotrophic factor (BDNF), which plays a pivotal role in the development and plasticity of the brain. Recent studies have demonstrated the neuroprotective effect of acupuncture-induced activation of BDNF in many neurological disorders. In view of these findings, we hypothesise the potential therapeutic effect of acupuncture-induced activation of BDNF in the treatment of ASD.  ",0
5325,25257516,"Uterine tumors resembling ovarian sex cord tumors, a clinicopathologic study of six cases","Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) cause difficulties, both with respect to diagnosis as well as to the nomenclature. They belong to the group of low-grade malignant neoplasms, and their clinical course likely depends on the percentage of the sex cord-like component. Morphologically, they can be divided into type I and type II with less or more than 50% of sex cord-like areas, respectively. Six patients with an age range of 24 to 63 years underwent the treatment for primary UTROSCT at the Cancer Center and Institute of Oncology in Warsaw, Poland, between 2000 and 2011. In addition to the surgery, 4 patients were treated with gestagens. Biopsies or excisions from the tumors were examined microscopically and immunohistochemically. Two cases were classified as type I, and 4 cases, as type II tumors. The tumor size ranged from 3 to 24 cm. The sex cord component varied from 25% to 70%. By immunohistochemical examination, the sex cord-like component was calretinin positive, whereas the stromal component was positive for CD10 and negative for h-caldesmon in all the cases studied. In addition, progesterone receptor positivity was found in all the cases, and 4 tumors were positive for smooth muscle actin, cytokeratin AE1/3, and inhibin. No recurrences were noted in any of the 6 patients over 3 to 14.5 years of follow-up period. A correct subclassification of sarcomas of UTROSCT type is of crucial importance because most patients with this rare neoplasm respond well to gestagen therapy and have a good prognosis, compared with other uterine stromal sarcomas.  ",0
5326,25257552,The crystal structure of archaeal serine hydroxymethyltransferase reveals idiosyncratic features likely required to withstand high temperatures,"Serine hydroxymethyltransferases (SHMTs) play an essential role in one-carbon unit metabolism and are used in biomimetic reactions. We determined the crystal structure of free (apo) and pyridoxal-5'-phosphate-bound (holo) SHMT from Methanocaldococcus jannaschii, the first from a hyperthermophile, from the archaea domain of life and that uses H₄MPT as a cofactor, at 2.83 and 3.0 Å resolution, respectively. Idiosyncratic features were observed that are likely to contribute to structure stabilization. At the dimer interface, the C-terminal region folds in a unique fashion with respect to SHMTs from eubacteria and eukarya. At the active site, the conserved tyrosine does not make a cation-π interaction with an arginine like that observed in all other SHMT structures, but establishes an amide-aromatic interaction with Asn257, at a different sequence position. This asparagine residue is conserved and occurs almost exclusively in (hyper)thermophile SHMTs. This led us to formulate the hypothesis that removal of frustrated interactions (such as the Arg-Tyr cation-π interaction occurring in mesophile SHMTs) is an additional strategy of adaptation to high temperature. Both peculiar features may be tested by designing enzyme variants potentially endowed with improved stability for applications in biomimetic processes. ",0
5327,25257613,Severe demyelination but no astrocytopathy in clinically definite neuromyelitis optica with anti-myelin-oligodendrocyte glycoprotein antibody,"We report a patient with neuromyelitis optica (NMO) presenting anti-myelin-oligodendrocyte glycoprotein (MOG)-seropositive, in whom biomarkers of demyelination and astrocyte damage were measured during an acute attack. A 31-year-old man developed right optic neuritis followed by longitudinally extensive transverse myelitis, fulfilling the criteria for definite NMO. He was anti-MOG-seropositive and anti-aquaporin-4 seronegative. The myelin basic protein level was markedly elevated whereas glial fibrillary acidic protein was not detectable in cerebrospinal fluid during an acute attack. His symptoms quickly improved after high-dose methylprednisolone therapy. This case suggests that NMO patients with anti-MOG may have severe demyelination in the absence of astrocyte injury.  ",0
5328,25257811,Surface and boney landmarks for sacral neuromodulation: a cadaveric study,"Standard external landmarks have been suggested as a guide for in-office percutaneous nerve evaluation (PNE), but validity of these landmarks has not been assessed. Our objective was to determine whether the standard 9 cm from the tip of the coccyx indicates the position of the S3 sacral foramen and whether other boney landmarks and measurements improved positioning. Measurements and distances between external boney landmarks were obtained in 22 embalmed cadavers. Spinal needles were placed 9 cm superior to the coccyx and 2 cm lateral to midline bilaterally. After dissection, internal measurements relating to sacral length, position of S3, and location of the needle in relation to S3 were recorded. Correlations among measured variables were assessed using descriptive statistics. Mean distance from the tip of coccyx to S3 was 9.26 cm (±0.84), from S3 to midline 2.30 cm (±0.2); from needle to S3 1.25 cm, and needle placement was as likely to be placed above or below S3; and S2-S3 and S3-S4 interforamenal distance 1.48 cm (±0.30) and 1.48 cm (±0.24), respectively. Mean distance from S3 to sacroiliac joint (SIJ) was shorter than S2 to SIJ. All associations between external measurements and length from tip of coccyx to S3 were not significant. A distance 9 cm from the tip of the coccyx is a reasonable starting landmark for in-office blind PNE. However, given the variability in coccyx length, caution should be taken; also, sensory-motor response is necessary to confirm proper placement. ",0
5329,25257912,Drug shortages in European countries: a trade-off between market attractiveness and cost containment?,"Drug shortages are a global problem. While extensively studied in the United States, numbers about drug shortages in European countries are scarce. This study aims to collect and present data about drug shortages in European countries. A reporting template for the collection of data about drug shortages was designed based on a literature search. Countries offering a reporting system for drug shortages such as Belgium, the Netherlands, England, Italy, France, Germany and Spain were included in this study. Data about the characteristics of the drugs in shortage and the causes of the shortage were collected from publicly available online reporting systems. Descriptive analyses were performed. Drug shortages included in the considered reporting systems can be characterized as branded, oral drugs that affect different disease domains. When considering essential medicines and oncology drugs, generic injectables are more involved. Causes for drug shortages are largely underreported. In case the cause is known, production problems take the lead. Reporting of drug shortages in Europe needs to be standardized and more transparency about the reasons for drug shortage is required to investigate the problem. A link between production problems and market attractiveness and market capacity is recognized to be at the root of drug shortages in U.S. Such insights are highly lacking in Europe. Monitoring of the effect of national and European health policies on the sustainability of the drug market is required to present fundamental solutions and to tackle the problem of drug shortages in Europe. ",0
5330,25257975,Mendelian randomization of serum urate and parkinson disease progression,"Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach. The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment. Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels. ",0
5331,25258008,Cerebral Hypoperfusion in Posterior Reversible Encephalopathy Syndrome is Different from Transient Ischemic Attack on CT Perfusion,"PRES is a reversible neurotoxic state presenting with headache, altered mental status, visual loss, and seizures. Delayed diagnosis can be avoided if radiological patterns could distinguish PRES from cerebral ischemia. Clinical and radiological data were collected on all hospitalized patients who had (1) discharge diagnosis of PRES and (2) acute CTP/CTA. Data were compared with 10 TIA patients with proven cytotoxic edema on MRI. Of the four PRES patients found, three were correlated with acute blood pressure and one with chemotherapy. At the radiological level, quantitative analyses of the CTP parameters showed that 2 out of 4 patients had bilaterally reduced CBF-values (23.2-47.1 ml/100g/min) in occipital regions, as seen in the pathological regions of TIA patients (27.3 ± 13.5 ml/100g/min). When compared with TIA patients, the pathological ROI's demonstrated decreased CBV-values (3.4-5.6 ml/100g). Vasogenic edema on MRI FLAIR imaging was seen in only one PRES patient, and cytotoxic edema on DWI-imaging was never found. CT angiography showed in one PRES patient a vasospasm-like unilateral posterior cerebral artery. If confirmed by other groups, CTP and CTA imaging in patients with acute visual loss and confusion may help to distinguish PRES from bi-occipital ischemia. These radiological parameters may identify PRES patients at risk for additional tissue infarction. ",0
5332,25258010,RNA-sequencing reveals oligodendrocyte and neuronal transcripts in microglia relevant to central nervous system disease,"Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures [fluorescence-activated cell sorting (FACS)] or from postnatal glial cultures by mechanic isolation. Given the highly dynamic and state-dependent functions of these cells, the use of FACS or short-term culture methods may not accurately capture the biology of brain microglia. In the current study, we performed RNA-sequencing using Cx3cr1(+/GFP) labeled microglia isolated from the brainstem of 6-week-old mice to compare the transcriptomes of FACS-sorted versus laser capture microdissection (LCM). While both isolation techniques resulted in a large number of shared (common) transcripts, we identified transcripts unique to FACS-isolated and LCM-captured microglia. In particular, ∼50% of these LCM-isolated microglial transcripts represented genes typically associated with neurons and glia. While these transcripts clearly localized to microglia using complementary methods, they were not translated into protein. Following the induction of murine experimental autoimmune encephalomyelitis, increased oligodendrocyte and neuronal transcripts were detected in microglia, while only the myelin basic protein oligodendrocyte transcript was increased in microglia after traumatic brain injury. Collectively, these findings have implications for the design and interpretation of microglia transcriptome-based investigations. ",0
5333,25258131,Assessing the impact of a medical librarian on identification of valid and actionable practice gaps for a continuing medical education committee,"Identifying educational needs related to professional practice gaps can be a complex process for continuing medical education (CME) committees and for physicians who submit activity applications. Medical librarians possess unique skills that may be useful for identifying practice gaps relevant to CME committees. We assessed this assumption by assessing a medical librarian's contributions to practice gap identification for the Marshfield Clinic's CME Committee. We reviewed all locally relevant, locally actionable practice gaps identified annually by various stakeholders and presented to our CME Committee from 2010 to 2013. Total numbers of practice gaps identified, total categorized as actionable, and numbers of subsequent activities resulting from these gaps were calculated for each year. Medical librarian totals were compared to those of other CME committee stakeholders to determine the relative contribution. The medical librarian identified unique, actionable published practice gaps that directly contributed to CME activity planning. For each study year, contributions by the medical librarian grew, from 0 of 27 actionable gaps validated by CME Committee in 2010 to 49 of 108 (45.4%) in 2013. With the librarian's assistance, the number of valid practice gaps submitted between 2010 and 2013 by stakeholders climbed from 23 for 155 activities (14.8%) to 133 for 157 activities (84.7%). Medical librarians can provide a valuable service to CME committees by identifying valid professional practice gaps that inform decisions about educational activities aimed at improving clinical practice. Medical librarians bring into deliberations unique information, including national health policy priorities, practice gaps found in the literature, and point-of-care search engine statistics. ",0
5334,25258622,"Influence of zinc supplementation on histopathological changes in the stomach, liver, kidney, brain, pancreas and spleen during subchronic exposure of Wistar rats to glyphosate","A subchronic toxicity study was carried out to determine the glyphosate-induced histopathological changes in the stomach, liver, kidney, brain, pancreas and spleen of rats and the attendant ameliorative effect when pretreated with zinc at the dose rate of 50 mg/kg body weight. The rats were exposed to two doses of the glyphosate (375 and 14.4 mg/kg body weight) for the period of 8 weeks which was the duration of the study, and some groups were exposed to the glyphosate after pretreatment with zinc. The histopathological changes recorded during the study were only in the rats exposed to the glyphosate at the dose rate of 375 mg/kg body weight except the vacuolation encountered in the brains and haemosiderosis in the spleens of rats exposed to zinc alone. Degenerated mucosal epithelial cells which involved the muscularis mucosa and the glands in the stomachs of rats were seen microscopically. Hepatic cells degeneration especially at the portal areas of the livers of rats was observed. The histopathological examination of the kidneys showed glomerular degeneration, mononuclear cells infiltration into the interstices of the tubules and tubular necrosis. The conspicuous changes seen in the brains were neuronal degeneration. Pancreatic acinar cells were degenerated while the spleen of the rats showed depopulated splenic cells in both the red and the white pulps. It was concluded that zinc supplementation in rats prior to glyphosate exposure ameliorated the histopathological changes observed in the stomach, liver, kidney, brain, pancreas and spleen with no observable alteration in the histoarchitecture in the organs of the zinc-supplemented rats. ",0
5335,25259623,External control of the Drosophila melanogaster egg to imago development period by specific combinations of 3D low-frequency electric and magnetic fields,"We report that the duration of the egg-to-imago development period of the Drosophila melanogaster, and the imago longevity, are both controllable by combinations of external 3-dimensional (3D) low-frequency electric and magnetic fields (LFEMFs). Both these periods may be reduced or increased by applying an appropriate configuration of external 3D LFEMFs. We report that the longevity of D. melanogaster imagoes correlates with the duration of the egg-to-imago development period of the respective eggs. We infer that metabolic processes in both eggs and imago are either accelerated (resulting in reduced time periods) or slowed down (resulting in increased time periods). We propose that external 3D LFEMFs induce electric currents in live systems as well as mechanical vibrations on sub-cell, whole-cell and cell-group levels. These external fields induce media polarization due to ionic motion and orientation of electric dipoles that could moderate the observed effects. We found that the longevity of D. melanogaster imagoes is affected by action of 3D LFEMFs on the respective eggs in the embryonic development period (EDP). We interpret this effect as resulting from changes in the regulation mechanism of metabolic processes in D. melanogaster eggs, inherited by the resulting imagoes. We also tested separate effects of either 3D electric or 3D magnetic fields, which were significantly weaker.  ",0
5336,25260142,A case of solitary angiokeratoma successfully treated with a 1064-nm long-pulsed Nd:YAG laser,"Angiokeratomas are vascular malformations that are clinically or histologically verrucous, with superficial vessels just beneath the epidermis. Solitary angiokeratomas occur most commonly as a small, warty, black papule on the lower extremities. Various therapeutic methods, including laser, electrocoagulation, excision, and cryotherapy, may be used for their treatment. A 13-year-old girl presented to the laser clinic for the treatment of her lesions that were present for two months. A 1064-nm long-pulsed Nd:YAG (yttrium aluminium garnet) laser was used to treat the patient's lesions. We performed two laser treatment sessions at a 4-week interval. We saw the patient 1 month after the last treatment session and obtained successful cosmetically acceptable results. No recurrence was observed over a follow-up period of 3 months. Long-pulsed Nd:YAG laser is more effective for the treatment of hyperkeratotic angiokeratomas due to deeper skin penetration of laser. Long-pulsed Nd:YAG laser is an effective and safe therapeutic option for the treatment of solitary angiokeratomas.  ",0
5337,25260245,Repeated apnea-induced contraction of the spleen in cyclists does not enhance performance in a subsequent time-trial,"Splenic contraction induced by repeated apneas has been shown to increase oxygen availability. Our aim was to determine whether repeated maximal voluntary apnea enhances the performance of cyclists in a subsequent 4-km time trial. Seven male cyclists [age: 27.1 ± 2.1 years; height: 182 ± 8 cm; body mass: 74.8 ± 9.2 kg; peak oxygen uptake: 56.9 ± 6.6 mL min(-1) kg(-1) (mean ± SD)] performed a 4-km time trial on an ergometer with and without four prior maximal bouts of apnea interspersed with 2 min of recovery. The average power output during the time trial was similar with (293 ± 48 W) and without (305 ± 42 W) prior apnea (P = 0.11, d = 0.27). The spleen was reduced in size after the fourth bout of apnea (-12.4 ± 9.0 %), as well as one (-36.6 ± 10.3 %) and 10 min (-19.5 ± 17.9 %) after the time trial, while with normal breathing the spleen was smaller one (-35.0 ± 11.3 %) and 10 min (-23.4 ± 19.7 %) after the time trial. Heart rate; oxygen uptake and carbon dioxide production; tissue oxygen saturation; and the lactate concentration, pH, oxygen saturation, level of hemoglobin and hematocrit of the blood were similar under both conditions. Our present findings reveal that four apneas by cyclists prior to a 4-km time trial led to splenic contraction, but no change in mean power output, the level of hemoglobin, hematocrit, oxygen saturation of the m. vastus lateralis or oxygen uptake. ",0
5338,25260330,Alteration of sFAS and sFAS ligand expression during canine visceral leishmaniosis,"Visceral leishmaniosis (VL) is caused by intracellular parasites of the genus Leishmania that affect humans and several animal species. Dogs are one of the main urban reservoirs of Leishmania infantum and play a central role in the transmission cycle to humans via sandflies. CD3+ cells apoptosis is involved in the immune response in VL. Dysregulation of apoptosis has been implicated in various disease states. An important regulator of apoptosis is the FAS-FAS-associated death domain protein (cluster of differentiation 95 - CD95) and FASL-FAS ligand protein (cluster of differentiation 178 - CD178) system involved in the down-regulation of immune reactions and in T cell-mediated cytotoxicity. FAS is a member of the tumor necrosis factor (TNF) receptor super family, which can be expressed in transmembrane or soluble forms. The soluble levels of FAS (sFAS), FASL (sFASL) and active Caspase-3, this last related to apoptotic cascade, were investigated in the spleen of 19 symptomatic dogs presenting moderate VL and 6 healthy dogs, determined by ELISA assay. The splenic parasite load was determined by real-time PCR monitoring of amplification of the intergenic internal transcribed spacer (ITS1) gene of parasite rRNA. sFAS levels were lower (p<0.05). sFASL and active Caspase-3 levels were higher (p<0.05) in dogs with VL compared with controls. Negative correlation was observed between parasite burden and sFASL levels. The increase in sFASL could be related to the mechanism involved in the elimination of the parasite.  ",0
5339,25260355,The buffering effect of tangible social support on financial stress: influence on psychological well-being and psychosomatic symptoms in a large sample of the adult general population,"Financial stress is an important source of distress and is related to poor mental and physical health outcomes. The present study investigated whether tangible social support could buffer the effect of financial stress on psychological and psychosomatic health. Two separate postal surveys were sent to random samples in five counties in Sweden in 2004 and 2008, with a total of 84 263 respondents. The questionnaires included questions about financial stress, tangible social support, psychosomatic symptoms, and psychological well-being (General Health Questionnaire-12). Individuals with high financial stress and low tangible social support had six to seven times increased odds ratios for low psychological well-being and many psychosomatic symptoms. By contrast, individuals with high financial stress and high tangible social support had only two to three times increased odds ratios for low psychological well-being and three to four times increased odds ratios for many psychosomatic symptoms, suggesting a buffering effect of tangible social support. Consistent with the buffering hypothesis, there were significant interactions between financial stress and social support, particularly in relation to low psychological well-being. Social support had its strongest effect at high levels of financial stress. The question whether the altering of our social networks may improve physical health is important for the prevention of ill health in people experiencing financial stress. Strengthening social networks may have the potential to influence health-care costs and improve quality of life. ",0
5340,25260445,A nonrandomized prospective comparison of robotic-assisted partial nephrectomy in the elderly to a younger cohort: an analysis of 339 patients with intermediate-term follow-up,"To assess the role of robotic-assisted partial nephrectomy (RAPN) in elderly patients focusing on perioperative, functional, and oncologic outcomes in comparison with a younger cohort. From a prospectively maintained institutional review board-approved database, 339 patients were divided into 2 groups defined by age ≥ 70 (n = 71) or <70 years (n = 268) at the time of RAPN. They were compared for perioperative outcomes and complications, including risk of chronic kidney disease (CKD) stage progression. The standard t test and chi square test were used for continuous and categorical variables, respectively. Logistic regression identified risk factors for progression of renal dysfunction. Kaplan-Meier estimates modeled tumor recurrence at 368 and 462 days in the elderly and young, respectively. Elderly patients were more likely to have hypertension (86% vs 60%; P < .001) or coronary artery disease (27% vs 9%; P < .001), and rates of chronic obstructive pulmonary disorder and diabetes were also higher. Preoperative estimated glomerular filtration rate was significantly lower in the elderly (70 vs 82 mL/min/1.73 m2; P < .001). Twenty-four percent of elderly patients progressed in CKD stage as compared to 14% in the younger cohort (P = .08). Elderly age was not a statistically significant risk factor for CKD progression (relative risk, 2.34; 95% confidence interval, 0.81-6.05; P = .11). Surgical and medical complication rates were similar between the cohorts (P = .75 and .80, respectively) as were Kaplan-Meier estimates of risk of tumor recurrence (P = .47). Limitations include nonrandomized, single-center study, and intermediate-term follow-up for oncologic outcomes. Elderly patients undergoing RAPN had no increased risk of perioperative complications. CKD progression and risk of oncologic recurrence were similar to younger patients at intermediate-term follow-up. ",0
5341,25260485,Kinesin KIF4A transports integrin β1 in developing axons of cortical neurons,"CNS axons have poor regenerative ability compared to PNS axons, and mature axons regenerate less well than immature embryonic axons. The loss of regenerative ability with maturity is accompanied by the setting up of a selective transport filter in axons, restricting the types of molecule that are present. We confirm that integrins (represented by subunits β1 and α5) are present in early cortical axons in vitro but are excluded from mature axons. Ribosomal protein and L1 show selective axonal transport through association with kinesin kif4A; we have therefore examined the hypothesis that integrin transport might also be in association with kif4A. Kif4A is present in all processes of immature cortical neurons cultured at E18, then downregulated by 14days in vitro, coinciding with the exclusion of integrin from axons. Kif4a co-localises with β1 integrin in vesicles in neurons and non-neuronal cells, and the two molecules co-immunoprecipitate. Knockdown of KIF4A expression with shRNA reduced the level of integrin β1 in axons of developing neurons and reduced neurite elongation on laminin, an integrin-dependent substrate. Overexpression of kif4A triggered apoptosis in neuronal and non-neuronal cells. In mature neurons expression of kif4A-GFP at a modest level did not kill the cells, and the kif4A was detectable in their axons. However this was not accompanied by an increase in integrin β1 axonal transport, suggesting that kif4A is not the only integrin transporter, and that integrin exclusion from axons is controlled by factors other than the kif4A level.  ",0
5342,25260607,Involvement of NLRP3 inflammasome in CVB3-induced viral myocarditis,"Viral myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Inflammasome plays an essential role in the regulation of diverse inflammatory responses by serving as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of IL-1β. Although inflammasome has been reported to be crucial for the development of many inflammatory diseases, its role in the pathogenesis of viral myocarditis is still elusive. The present study aims to investigate whether CVB3 infection activates inflammasome and whether the activation of inflammasome contributes to CVB3-induced myocarditis. Our results showed that CVB3 infection induced inflammasome activation both in vitro and in vivo. With the inhibition of inflammasome activation, the severity of CVB3-induced myocarditis was significantly alleviated as evidenced by less weight loss, decreased serological indexes of creatine kinase and creatinekinase-MB activities, as well as less severe myocardial injury. Of importance, echocardiography results showed that inhibition of inflammasome activation also efficiently improved cardiac function as revealed by enhanced left ventricular ejection fraction and left ventricular fractional shortening. Despite that CVB3 infection significantly increased the expression of both retinoic acid-inducible gene 1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3) in cardiac myocytes, CVB3-induced inflammasome activation was NLRP3-, but not retinoic acid-inducible gene 1, dependent. Further study showed that reactive oxygen species production and K(+) efflux were critical for the activation of NLRP3 inflammasome upon CVB3 infection. Collectively, our study demonstrated a crucial role of the NLRP3 inflammasome in the pathogenesis of CVB3-induced myocarditis, and modulation of inflammasome activation might represent a promising therapeutic strategy for viral myocarditis.  ",0
5343,25260756,Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice,"The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. ",0
5344,25261044,Impaired processing speed and attention in first-episode drug naive schizophrenia with deficit syndrome,"Although first-episode drug naive patients with schizophrenia are known to show cognitive impairment, the cognitive performances of these patients, who suffer deficit syndrome, compared with those who suffer non-deficit syndrome is undetermined. The aim of this study was to compare cognitive performances in first-episode drug-naive schizophrenia with deficit syndrome or non-deficit syndrome. First-episode drug naive patients (n=49) and medicated patients (n=108) with schizophrenia, and age, sex, and education matched healthy controls (n=57 for the first-episode group, and n=128 for the medicated group) were enrolled. Patients were divided into deficit or non-deficit syndrome groups, using the Schedule for Deficit Syndrome. Cognitive performance was assessed using the CogState computerized cognitive battery. All cognitive domains in first-episode drug naive and medicated patients showed significant impairment compared with their respective control groups. Furthermore, cognitive performance in first-episode drug naive patients was significantly worse than in medicated patients. Interestingly, the cognitive performance markers of processing speed and attention, in first-episode drug naive patients with deficit syndrome, were both significantly worse than in equivalent patients without deficit syndrome. In contrast, no differences in cognitive performance were found between the two groups of medicated patients. In conclusion, this study found that first-episode drug naive schizophrenia with deficit syndrome showed significantly impaired processing speed and attention, compared with patients with non-deficit syndrome. These findings highlight processing speed and attention as potential targets for pharmacological and psychosocial interventions in first-episode schizophrenia with deficit syndrome, since these domains are associated with social outcomes.  ",0
5345,25261107,Kefir: a multifaceted fermented dairy product,"""Kefir is a fermented dairy beverage produced by the actions of the microflora encased in the """"kefir grain"""" on the carbohydrates in the milk. Containing many bacterial species already known for their probiotic properties, it has long been popular in Eastern Europe for its purported health benefits, where it is routinely administered to patients in hospitals and recommended for infants and the infirm. It is beginning to gain a foothold in the USA as a healthy probiotic beverage, mostly as an artisanal beverage, home fermented from shared grains, but also recently as a commercial product commanding shelf space in retail establishments. This is similar to the status of yogurts in the 1970s when yogurt was the new healthy product. Scientific studies into these reported benefits are being conducted into these health benefits, many with promising results, though not all of the studies have been conclusive. Our review provides an overview of kefir's structure, microbial profile, production, and probiotic properties. Our review also discusses alternative uses of kefir, kefir grains, and kefiran (the soluble polysaccharide produced by the organisms in kefir grains). Their utility in wound therapy, food additives, leavening agents, and other non-beverage uses is being studied with promising results.  """,0
5346,25261154,SIRRACT: An International Randomized Clinical Trial of Activity Feedback During Inpatient Stroke Rehabilitation Enabled by Wireless Sensing,"Walking-related disability is the most frequent reason for inpatient stroke rehabilitation. Task-related practice is a critical component for improving patient outcomes. To test the feasibility of providing quantitative feedback about daily walking performance and motivating greater skills practice via remote sensing. In this phase III randomized, single blind clinical trial, patients participated in conventional therapies while wearing wireless sensors (triaxial accelerometers) at both ankles. Activity-recognition algorithms calculated the speed, distance, and duration of walking bouts. Three times a week, therapists provided either feedback about performance on a 10-meter walk (speed only) or walking speed feedback plus a review of walking activity recorded by the sensors (augmented). Primary outcomes at discharge included total daily walking time, derived from the sensors, and a timed 15-meter walk. Sixteen rehabilitation centers in 11 countries enrolled 135 participants over 15 months. Sensors recorded more than 1800 days of therapy, 37 000 individual walking bouts, and 2.5 million steps. No significant differences were found between the 2 feedback groups in daily walking time (15.1 ± 13.1 vs 16.6 ± 14.3 minutes, P = .54) or 15-meter walking speed (0.93 ± 0.47 vs 0.91 ± 0.53 m/s, P = .96). Remarkably, 30% of participants decreased their total daily walking time over their rehabilitation stay. In this first trial of remote monitoring of inpatient stroke rehabilitation, augmented feedback beyond speed alone did not increase the time spent practicing or improve walking outcomes. Remarkably modest time was spent walking. Wireless sensing, however, allowed clinicians to audit skills practice and provided ground truth regarding changes in clinically important, mobility-related activities. ",0
5347,25261168,Contribution of cardiac MRI in the initial evaluation and follow-up of myocarditis mimicking acute coronary syndrome: a series of 43 patients],"The diagnosis of acute myocarditis is complex, especially when the clinical presentation mimics an acute coronary syndrome. This condition may promote the progression to dilated cardiomyopathy and the occurrence of severe arrhythmias. A reassessment integrating a cardiac MRI at three months after the acute episode could help identify patients with a poor prognosis. This prospective series of 43 consecutive patients hospitalised for acute myocarditis included 36 men and seven women, with a mean age of 32 years, with no indication of heart failure. All patients presented elevated levels of troponin I. Echocardiography showed moderate left ventricular dysfunction in six cases and segmental wall motion abnormalities in 22 cases. After gadolinium injection, a subepicardial late enhancement was observed in 39 cases. Three months after the acute episode, all patients were asymptomatic. The echocardiography and laboratory tests were normal. In 23 cases, the MRI showed persistence of the late enhancement without segmental wall motion abnormality. After a mean follow-up of three years, one patient was lost to follow-up and only one suffered a heart failure revealing a dilated cardiomyopathy complicated by ventricular arrhythmias. On admission, the subepicardial localisation of late enhancement in the cardiac MRI is reliable criteria for the diagnosis of acute myocarditis, enabling to rule out an acute coronary syndrome. During follow-up, the persistence of late enhancement has no impact on prognosis. In this series, after a mean follow-up of three years, it was not associated with clinical or paraclinical abnormalities, except in one patient. ",0
5348,25261264,Effects of physiological and/or disease status on the response of postpartum dairy cows to synchronization of estrus using an intravaginal progesterone device,"Progesterone treatments are used to increase submission rates in postpartum dairy cows; however, in many cases the protocol is used as a blanket therapy for all cows without regard for physiological or disease state. The objective of this study was to identify the physiological or disease classes of cows that respond well (or not) to synchronization of estrus via progesterone. Dairy cows (n = 402) were monitored peri and postpartum to establish their physiological or disease status. Animals were classified as having negative energy balance, clinical lameness, uterine infection (UI), anovulatory anestrus, high somatic cell counts, and healthy (H). Blood samples were collected at five different time points and analyzed for metabolites. All animals received an 8-day controlled internal drug release protocol, which included GnRH at insertion and PGF2α the day before removal. Response to the protocol was determined by visual observation of estrus synchronization. Conception rate was determined by ultrasonography between Days 32 and 35 after artificial insemination. Animals without UI were 1.9 times more likely to respond and two times more likely to be confirmed pregnant than those with UI. There was no relationship between negative energy balance and clinical lameness in the visual estrous response, but both conditions were associated with reduced conception rates. Dairy cows in anovulatory anestrus responded successfully to the protocol in both estrous response and conception rates. High glutathione peroxidase concentrations had a positive effect on conception rates, whereas high non-esterified fatty acids and beta-hydroxybutyrate had a negative effect on the estrous response. In conclusion, disease and physiological states of dairy cows determined the response to progesterone-based synchronization. The more disease or physiological problems the cows had, the lower the estrous response and conception rates; cows with these problems were not ideal candidates for synchronization. Both anestrus and healthy dairy cows were good responders to progesterone-based synchronization. ",0
5349,25261435,Albumin reverses the echinocytic shape transformation of stored erythrocytes,"The storage of red blood cells (RBCs) leads to storage lesions, which have a negative impact on the clinical outcome after transfusion. A hallmark of storage lesions is echinocytosis. Albumin may reverse this shape transformation, which was the topic of this study. Echinocytosis was generated by incubation of blood for 48 h at room temperature or in RBC units stored 48 days at 5°C. Human serum albumin was diluted in phosphate-buffered saline. RBCs were fixed in 1% glutaraldehyde and examined by light and scanning electron microscopy. The degree of echinocytosis was quantified by calculating the morphological index. Incubation and storage of RBCs led to an echinocytic shape transformation, which was reversible upon incubation in albumin solutions. This process was time-, concentration- and hematocrit-dependent. Treating RBC units at the end of their shelf-life by adding 20% albumin or washing them in 0.2% albumin reversed all degrees of echinocytosis towards discocytosis. In conclusion, albumin has the capacity to reverse echinocytosis generated by RBC storage. This observation may improve the quality of RBC units stored for longer periods of time. ",0
5350,25261675,Role of SPECT-CT in radiotherapy,"The role of fusion imaging methods SPECT-CT and PET-CT is currently being investigated in radiotherapy (RT) treatment planning. SPECT and PET provide extra information for gross tumor volume (GTV) delineation. The purpose of this study was to evaluate the role of SPECT-CT in RT. SPECT-CT studies were performed in 55 patients with (99m)Tc-MIBI/Tetrofosmin (TF), with 99mTc-Nanoco, with 99mTc-MDP and with 185 MBq (131)I scan. All studies were performed with SPECT-CT camera, using low dose CT (130KeV, 30 mA, 3-5 mm step). Corresponding slices on SPECT-CT were compared to the diagnostic CT projections from the simulator. Diagnostic CT scans were performed using 3-5 mm slices both to aid volume definition and to create high quality digitally reconstructed radiographs (DRRs) to aid verification. The volumetric CT data were sent to the treatment planning system. Application of SPECT-CT with (99m)Tc-MIBI/TF allowed to diagnose residual malignant mass or a recurrent tumor after combined (surgery and chemotherapy/ hormonotherapy/ therapy in studied patients with breast cancer, thymomas and lung cancer. SPECT-CT (99m)Tc-MIBI/ TF contributed to the definition of clinical target volume (CTV). SPECT-CT imaging of sentinel lymph nodes (SLNs) in medially located breast cancer was important for correct topography of intercostal space in cases with parasternal drainage. Irradiation of this subgroup of patients in conjunction with the chest wall and the supraclavicular region should be considered electively for each patient. The combined application of baseline whole body bone scintigraphy, followed by SPECT-CT fusion gave the possibility for correct radiotherapy planning of the GTV in tumor-induced bone disease. SPECT-CT is useful for diagnosis of recently discovered non-responsive to (131)I treatment patients with differentiated thyroid cancer. SPECT-CT data are important to avoid prescribed (131)I therapy and to define CTV for external beam RT (EBRT). SPECT-CT images could be applicable in RT planning to precisely delinate tumor volume. ",0
5351,25261940,Hormones in the immune system and their possible role. A critical review,"Immune cells synthesize, store and secrete hormones, which are identical with the hormones of the endocrine glands. These are: the POMC hormones (ACTH, endorphin), the thyroid system hormones (TRH, TSH, T3), growth hormone (GH), prolactin, melatonin, histamine, serotonin, catecholamines, GnRH, LHRH, hCG, renin, VIP, ANG II. This means that the immune cells contain all of the hormones, which were searched at all and they also have receptors for these hormones. From this point of view the immune cells are similar to the unicells (Tetrahymena), so it can be supposed that these cells retained the properties characteristic at a low level of phylogeny while other cells during the evolution accumulated to form endocrine glands. In contrast to the glandular endocrine cells, immune cells are polyproducers and polyreceivers. As they are mobile cells, they are able to transport the stored hormone to different places (packed transport) or attracted by local factors, accumulate in the neighborhood of the target, synthesizing and secreting hormones locally. This is taking place, e.g. in the case of endorphin, where the accumulating immune cells calms pain caused by the inflammation. The targeted packed transport is more economical than the hormone-pouring to the blood circulation of glandular endocrines and the targeting also cares the other receptor-bearing cells timely not needed the effect. Mostly the immune-effects of immune-cell derived hormones were studied (except endorphin), however, it is not exactly cleared, while the system could have scarcely studied important roles in other cases. The evolutionary aspects and the known as well, as possible roles of immune-endocrine system and their hormones are listed and discussed.  ",0
5352,25262222,Multiphase computed tomography for localization of parathyroid disease in patients with primary hyperparathyroidism: How many phases do we really need?,"Multiphase computed tomography (CT) involves multiple cervical CT acquisitions to accurately identify hyperfunctional parathyroid glands, thus increasing radiation exposure to the patient. We hypothesized that only 2 cervical acquisitions, instead of the conventional 4, would provide equivalent localization information and halve the radiation exposure. We identified 53 consecutive patients with primary hyperparathyroidism who underwent multiphase CT before parathyroidectomy. All scans were reinterpreted first using 2 phases then using all 4 phases. The accuracies of interpretations were determined with surgical findings serving as the standard of reference. Sixty-four hyperfunctional parathyroid glands were resected with a mean weight of 394.3 mg. Two-phase CT lateralized the hyperfunctional glands in 38 patients with a sensitivity, positive predictive value (PPV), and accuracy of 100%, 71.7%, and 71.7%, respectively. Four-phase CT lateralized the hyperfunctional glands in 39 patients with a sensitivity, PPV, and accuracy of 95.1%, 76.5%, and 73.6%, respectively. For quadrant localization, the accuracy of 2-phase and 4-phase CT was 50.9% and 52.8%, respectively. Our results suggest that 2-phase and 4-phase CT provide an equivalent diagnostic accuracy in localizing hyperfunctional parathyroid glands. The reduced radiation exposure to the patient may make 2-phase acquisitions a more acceptable alternative for preoperative localization. ",0
5353,25262633,In vitro air removal characteristics of two neonatal cardiopulmonary bypass systems: filtration may lead to fractionation of bubbles,"Introduction of gaseous microemboli (GME) into the arterial line of a pediatric cardiopulmonary bypass (CPB) circuit may lead to cognitive decline and adverse outcomes of the pediatric patient.Arterial filters are incorporated into CPB circuits as a safeguard for gross air and to reduce GME. Recently, arterial filters were integrated in two neonatal oxygenators to reduce volume and foreign surface area. In this study a clinical CPB scenario was simulated. The oxygenators, the corresponding venous reservoirs and the complete CPB circuits were compared regarding air removal and bubble size distribution after the introduction of an air bolus or GME. During a GME challenge, the Capiox FX05 oxygenator removed a significantly higher volume of GME than the QUADROX-i Neonatal oxygenator (97% vs. 86%). Detailed air removal characteristics showed that more GME in the range of 20-50 µm were leaving the devices than were entering. This phenomenon seems to be more present in the Capiox FX05. The circuits were also challenged with an air bolus. Each individual component tested removed 99.9%, which resulted in an air volume reduction of 99.99% by either complete CBP circuit. Overall, we conclude that both CPB systems were very adequate in removing GME and gross air. The air removal properties of both systems are considered safe and reliable. Detailed GME distribution data show that the Capiox FX05 showed more small GME (<50 µm) due to fractionation of larger GME when compared to the QUADROX-i Neonatal. We may conclude that filtration may lead to fractionation. ",0
5354,25262639,"Social anxiety disorder in the Chinese military: prevalence, comorbidities, impairment, and treatment-seeking","The objective of this work is To investigate the prevalence, comorbidities, impairment, and treatment-seeking of social anxiety disorder in the Chinese military personnel. Military personnel (n=11,527) were surveyed from May to August 2007 using a multistage whole cohort probability sampling method. A Chinese version of the World Health Organization Composite International Diagnostic Interview (CIDI) was used for assessment, and a military-related socio-demographic questionnaire was used to describe the prevalence distribution. A unified survey was performed to investigate 11 different social situations. The short-form health survey was used to assess role impairment. The 12-month and lifetime prevalence rates of social anxiety disorder were 3.34% (95% CI: 3.25-3.42%) and 6.22% (95% CI: 6.11-6.32%), respectively. Social anxiety disorder was associated with increased odds of depression, substance abuse, panic attacks/disorder, and generalized anxiety disorder. Childhood foster, female, stressful life events, younger age, and being divorced/widowed increase the incidence of social anxiety disorder. Treatment-seeking was relatively rare. Social anxiety disorder is a common disorder in military personnel in China, and it is a risk factor for subsequent depressive illness, substance abuse and other mental disorder. Early detection and treatment of social anxiety disorder are important because of the low rate of treatment-seeking.  ",0
5355,25262649,Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants,"Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness. ",0
5356,25271604,"Provision of no-cost, long-acting contraception and teenage pregnancy","BACKGROUND: The rate of teenage pregnancy in the United States is higher than in other developed nations. Teenage births result in substantial costs, including public assistance, health care costs, and income losses due to lower educational attainment and reduced earning potential. METHODS: The Contraceptive CHOICE Project was a large prospective cohort study designed to promote the use of long-acting, reversible contraceptive (LARC) methods to reduce unintended pregnancy in the St. Louis region. Participants were educated about reversible contraception, with an emphasis on the benefits of LARC methods, were provided with their choice of reversible contraception at no cost, and were followed for 2 to 3 years. We analyzed pregnancy, birth, and induced-abortion rates among teenage girls and women 15 to 19 years of age in this cohort and compared them with those observed nationally among U.S. teens in the same age group. RESULTS: Of the 1404 teenage girls and women enrolled in CHOICE, 72% chose an intrauterine device or implant (LARC methods); the remaining 28% chose another method. During the 2008-2013 period, the mean annual rates of pregnancy, birth, and abortion among CHOICE participants were 34.0, 19.4, and 9.7 per 1000 teens, respectively. In comparison, rates of pregnancy, birth, and abortion among sexually experienced U.S. teens in 2008 were 158.5, 94.0, and 41.5 per 1000, respectively. CONCLUSIONS: Teenage girls and women who were provided contraception at no cost and educated about reversible contraception and the benefits of LARC methods had rates of pregnancy, birth, and abortion that were much lower than the national rates for sexually experienced teens. (Funded by the Susan Thompson Buffett Foundation and others.).",0
5357,25284723,Lineage-dependent effects of aryl hydrocarbon receptor agonists contribute to liver tumorigenesis,"Rodent cancer bioassays indicate that the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD), causes increases in both hepatocytic and cholangiocytic tumors. Effects of AHR activation have been evaluated on rodent hepatic stem cells (rHpSCs) versus their descendants, hepatoblasts (rHBs), two lineage stages of multipotent, hepatic precursors with overlapping but also distinct phenotypic traits. This was made possible by defining the first successful culture conditions for ex vivo maintenance of rHpScs consisting of a substratum of hyaluronans and Kubota's medium (KM), a serum-free medium designed for endodermal stem/progenitor cells. Supplementation of KM with leukemia inhibitory factor elicited lineage restriction to rHBs. Cultures were treated with various AHR agonists including TCDD, 6-formylindolo-[3,2-b]carbazole (FICZ), and 3-3'-diindolylmethane (DIM) and then analyzed with a combination of immunocytochemistry, gene expression, and high-content image analysis. The AHR agonists increased proliferation of rHpSCs at concentrations producing a persistent AHR activation as indicated by induction of Cyp1a1. By contrast, treatment with TCDD resulted in a rapid loss of viability of rHBs, even though the culture conditions, in the absence of the agonists, were permissive for survival and expansion of rHBs. The effects were not observed with FICZ and at lower concentrations of DIM. CONCLUSION: Our findings are consistent with a lineage-dependent mode of action for AHR agonists in rodent liver tumorigenesis through selective expansion of rHpSCs in combination with a toxicity-induced loss of viability of rHBs. These lineage-dependent effects correlate with increased frequency of liver tumors.",0
5358,25337749,High-dose rifapentine with moxifloxacin for pulmonary tuberculosis,"BACKGROUND: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. METHODS: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. RESULTS: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). CONCLUSIONS: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).",0
5359,25346535,Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice,"The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) and its closest homolog, MLL4 (aka KMT2D), belong to two homologous transcriptional coactivator complexes, named MLL3 and MLL4 complexes, respectively. MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation are unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice. We also performed comparative genome-wide transcriptome analyses in livers of MLL3, MLL4, and MLL3;MLL4 mutant mice. These analyses revealed that MLL3 and MLL4 complexes are key epigenetic regulators of common metabolic processes and the hepatic circadian clock. Subsequent mechanistic analyses uncovered that MLL3/4 complexes function as pivotal coactivators of the circadian transcription factors (TFs), retinoid-related orphan receptor (ROR)-? and -?, in the hepatic circadian clock. Consistent with disturbed hepatic clock gene expression in MLL4 mutant mice, we found that rhythmic fluctuation of hepatic and serum bile acid (BA) levels over the circadian cycle is abolished in MLL4 mutant mice. Our analyses also demonstrate that MLL4 primarily impinges on hepatic BA production among several regulatory pathways to control BA homeostasis. Together, our results provide strong in vivo support for important roles of both MLL3 and MLL4 in similar metabolic pathways. CONCLUSION: Both MLL3 and MLL4 complexes act as major epigenetic regulators of diverse metabolic processes (including circadian control of bile acid homeostasis) and as critical transcriptional coactivators of the circadian TFs, RORs.",0
5360,25353968,Voters and the Affordable Care Act in the 2014 election,"In this analysis of data from 27 public opinion polls, the authors examine the role of the Affordable Care Act in the 2014 congressional elections. The outcome of the elections is likely to influence implementation of the ACA and future U.S. health care policy.",0
5361,25372087,Cost-effectiveness of CT screening in the National Lung Screening Trial,"BACKGROUND: The National Lung Screening Trial (NLST) showed that screening with low-dose computed tomography (CT) as compared with chest radiography reduced lung-cancer mortality. We examined the cost-effectiveness of screening with low-dose CT in the NLST. METHODS: We estimated mean life-years, quality-adjusted life-years (QALYs), costs per person, and incremental cost-effectiveness ratios (ICERs) for three alternative strategies: screening with low-dose CT, screening with radiography, and no screening. Estimations of life-years were based on the number of observed deaths that occurred during the trial and the projected survival of persons who were alive at the end of the trial. Quality adjustments were derived from a subgroup of participants who were selected to complete quality-of-life surveys. Costs were based on utilization rates and Medicare reimbursements. We also performed analyses of subgroups defined according to age, sex, smoking history, and risk of lung cancer and performed sensitivity analyses based on several assumptions. RESULTS: As compared with no screening, screening with low-dose CT cost an additional $1,631 per person (95% confidence interval [CI], 1,557 to 1,709) and provided an additional 0.0316 life-years per person (95% CI, 0.0154 to 0.0478) and 0.0201 QALYs per person (95% CI, 0.0088 to 0.0314). The corresponding ICERs were $52,000 per life-year gained (95% CI, 34,000 to 106,000) and $81,000 per QALY gained (95% CI, 52,000 to 186,000). However, the ICERs varied widely in subgroup and sensitivity analyses. CONCLUSIONS: We estimated that screening for lung cancer with low-dose CT would cost $81,000 per QALY gained, but we also determined that modest changes in our assumptions would greatly alter this figure. The determination of whether screening outside the trial will be cost-effective will depend on how screening is implemented. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).",0
5362,25390739,High-cost generic drugs--implications for patients and policymakers,"Some older generic drugs have become very expensive, owing to factors including drug shortages, supply disruptions, and consolidations in the generic-drug industry. But generics manufacturers that legally obtain a market monopoly can also unilaterally raise prices.",0
5363,25390747,Expectation management,"As physicians transform observed frequencies from studies into predicted probabilities for a given patient, we generally fail to consider that the predictions we utter about a given therapeutic intervention are themselves part of the intervention.",0
5364,25399660,Genomic comparison of virulent and non-virulent Streptococcus agalactiae in fish,"Streptococcus agalactiae infections in fish are predominantly caused by beta-haemolytic strains of clonal complex (CC) 7, notably its namesake sequence type (ST) 7, or by non-haemolytic strains of CC552, including the globally distributed ST260. In contrast, CC23, including its namesake ST23, has been associated with a wide homeothermic and poikilothermic host range, but never with fish. The aim of this study was to determine whether ST23 is virulent in fish and to identify genomic markers of fish adaptation of S. agalactiae. Intraperitoneal challenge of Nile tilapia, Oreochromis niloticus (Linnaeus), showed that ST260 is lethal at doses down to 10(2) cfu per fish, whereas ST23 does not cause disease at 10(7) cfu per fish. Comparison of the genome sequence of ST260 and ST23 with those of strains derived from fish, cattle and humans revealed the presence of genomic elements that are unique to subpopulations of S. agalactiae that have the ability to infect fish (CC7 and CC552). These loci occurred in clusters exhibiting typical signatures of mobile genetic elements. PCR-based screening of a collection of isolates from multiple host species confirmed the association of selected genes with fish-derived strains. Several fish-associated genes encode proteins that potentially provide fitness in the aquatic environment. ",0
5365,25399780,Temporal evolution and variability of dissolved inorganic nitrogen in beach pore water revealed using radon residence times,"We coupled measurements of beach pore water residence time, determined using the radioisotopic tracer (222)Rn, with dissolved carbon and nitrogen chemistry to identify the temporal evolution and variability of dissolved inorganic nitrogen (DIN) concentrations in beach pore water along the Santa Barbara, California coastline. Pore water dissolved organic carbon (DOC) and total dissolved nitrogen (TDN) ratios (DOC:TDN) were negative exponentially correlated with residence time. Mean pore water residence times were positively correlated with tidal amplitudes, and ranged from 4.4 to 6.4 days. We used this range in mean residence times to model radon residence time distributions (RTDs), and integrated them with modeled DIN vs residence time relationships (DIN-temporal evolution, or DIN-te curves) to derive volume-weighted mean (VWM) DIN concentrations. We observed 1.2-fold and 5.2-fold differences (20% and 420% increases) in VWM DIN concentrations over the range in modeled RTDs and DIN-te curves, respectively, and a maximum 6.4-fold difference (540% increase) in VWM DIN concentrations for an interactive shift in the RTD and the DIN-te curve. Our study suggests that accounting for temporal variability in the RTD and DIN concentration of pore water is necessary to obtain more accurate estimates of DIN delivery to coastal oceans.  ",0
5366,25400010,Emergence of Lineage IV Peste des Petits Ruminants Virus in Ethiopia: Complete Genome Sequence of an Ethiopian Isolate 2010,"Isolates of peste des petits ruminants virus (PPRV) can be segregated genetically into four lineages. For decades, lineages I-III have been reported across Africa whilst lineage IV has predominantly circulated across Asia. However, the lineage distribution is currently changing in Africa. Importantly, full genome sequence data for African field isolates have been lacking. Here, we announce the first complete genome sequence of a field isolate of peste des petits ruminants virus (PPRV) from East Africa. This isolate was derived from the intestine of a goat suffering from severe clinical disease during the 2010 outbreak in Ethiopia. The full genome sequence of this isolate, PPRV Ethiopia/2010, clusters genetically with other lineage IV isolates of PPRV, sharing high levels of sequence identity across the genome. Further, we have carried out a phylogenetic analysis of all of the available African partial N gene and F gene PPRV sequences to investigate the epidemiology of PPRV with a focus on the emergence of different lineages of PPRV in Africa.  ",0
5367,25400021,Defining contralateral adrenal suppression in primary aldosteronism: implications for diagnosis and outcome,"Unilateral primary aldosteronism (PA) should have a contralaterally normal and therefore suppressed adrenal zona glomerulosa. However, there is no validated definition of adrenal suppression. We created two biochemical hypotheses of adrenal suppression based upon measurements taken during adrenal vein sampling (AVS) to determine whether either proved useful for interpretation of AVS or prediction of hypertension outcome in operated cases. Retrospective database analysis. Ninety-nine cases of PA from a tertiary hypertension unit. Hypothesis 1 was the proportional suppression of the uninvolved/lowest adrenal(aldo/cortisol) to IVC(aldo/cortisol) ratio pre- and post cosyntropin. Hypothesis 2 was the absolute decrease in the uninvolved adrenal(aldo/cortisol) ratio after cortrosyn injection. ROC analysis performed using lateralization and hypertension resolution as the outcomes of interest. Hypothesis 1 proved highly predictive of lateralization with a ROC AUC of 0.958, P < 0.0001, giving adrenal(aldo/cortisol):IVC(aldo/cortisol) <1.4 as the optimized criterion (sensitivity 90%, specificity 94%). For blood pressure outcomes in the surgical subgroup (n = 52), hypertension resolution was most commonly seen among subjects with adrenal suppression by both definitions although there was significant overlap with subjects requiring ongoing medication. Post cosyntropin suppression of the uninvolved adrenal-to-IVC ratio is a highly useful definition of adrenal suppression that accurately predicts unilateral PA. This may be particularly useful in a case where AVS fails to catheterize one of the adrenal veins but suppression is seen on the other side. Adrenal suppression may also predict blood pressure outcome, however, a much larger PA database is likely necessary to determine the relative contribution of this predictor. ",0
5368,25400359,Brain perfusion single photon emission computed tomography in major psychiatric disorders: From basics to clinical practice,"Brain single photon emission computed tomography (SPECT) is a well-established and reliable method to assess brain function through measurement of regional cerebral blood flow (rCBF). It can be used to define a patient's pathophysiological status when neurological or psychiatric symptoms cannot be explained by anatomical neuroimaging findings. Though there is ample evidence validating brain SPECT as a technique to track human behavior and correlating psychiatric disorders with dysfunction of specific brain regions, only few psychiatrists have adopted brain SPECT in routine clinical practice. It can be utilized to evaluate the involvement of brain regions in a particular patient, to individualize treatment on basis of SPECT findings, to monitor the treatment response and modify treatment, if necessary. In this article, we have reviewed the available studies in this regard from existing literature and tried to present the evidence for establishing the clinical role of brain SPECT in major psychiatric illnesses.  ",0
5369,25400369,18 Fluoride-fluorodeoxyglucose positron emission tomography in initial staging and response assessment of primary non-Hodgkin lymphoma of the tibia,Primary lymphoma of the bone is a rare clinical presentation constituting to <1% of all lymphomas. The long bones are usually involved. Combined treatment with chemotherapy and radiation offers long-term survival. The authors present the role of 18 fluoride-fluorodeoxyglucose positron emission tomography-computerized tomography in initial staging and response assessment in a case of primary diffuse large B cell lymphoma of the tibia.  ,0
5370,25400403,Mini review on tricyclic compounds as an inhibitor of trypanothione reductase,Trypanosomiasis and leishmaniasis are two most ruinous parasitic infectious diseases caused by Trypanosoma and Leishmania species. The disease affects millions of people all over the world and associated with high morbidity and mortality rates. The review discuss briefly on current treatment of these parasitic diseases and trypanothione reductase (TryR) as potential targets for rational drug design. The enzyme trypanothione reductase (TryR) has been identified as unique among these parasites and has been proposed to be an effective target against for developing new drugs. The researchers have selected this enzyme as target is due to its substrate specificity in contrast to human analogous glutathione reductase and its absence from the host cell which makes this enzyme an ideal target for drug discovery. In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed.  ,0
5371,25400443,Single port laparoscopy in gastroenterology and hepatology: a fine step forward,"Single incision laparoscopy (SIL) has become an emerging technology aiming at a further reduction of abdominal wall trauma in minimally invasive surgery. Available data is encouraging for the safe application of standardized SIL in a wide range of procedures in gastroenterology and hepatology. Compared to technically simple SIL procedures, the merit of SIL in advanced surgeries, such as liver or colorectal interventions, compared to conventional laparsocopy is self-evident without any doubt. SIL has already passed the learning curve and is routinely utilized in expert centers. This minimized approach has allowed to enter a new era of surgical management that can not be acceded without a fruitful combination of prudent training, consistent day-to-day work and enthusiastic motivation for technical innovations. Both, basic and novel technical specifics as well as particular procedures are described herein. The focus is on the most important surgical interventions in gastroenterology and aims at reviewing the current literature and shares our experience in a high volume center.  ",0
5372,25400619,Conceptualizing lennox-gastaut syndrome as a secondary network epilepsy,"""Lennox-Gastaut Syndrome (LGS) is a category of severe, disabling epilepsy, characterized by frequent, treatment-resistant seizures, and cognitive impairment. Electroencephalography (EEG) shows characteristic generalized epileptic activity that is similar in those with lesional, genetic, or unknown causes, suggesting a common underlying mechanism. The condition typically begins in young children, leaving many severely disabled with recurring seizures throughout their adult life. Scalp EEG of the tonic seizures of LGS is characterized by a diffuse high-voltage slow transient evolving into generalized low-voltage fast activity, likely reflecting sustained fast neuronal firing over a wide cortical area. The typical interictal discharges (runs of slow spike-and-wave and bursts of generalized paroxysmal fast activity) also have a """"generalized"""" electrical field, suggesting widespread cortical involvement. Recent brain mapping studies have begun to reveal which cortical and subcortical regions are active during these """"generalized"""" discharges. In this critical review, we examine findings from neuroimaging studies of LGS and place these in the context of the electrical and clinical features of the syndrome. We suggest that LGS can be conceptualized as """"secondary network epilepsy,"""" where the epileptic activity is expressed through large-scale brain networks, particularly the attention and default-mode networks. Cortical lesions, when present, appear to chronically interact with these networks to produce network instability rather than triggering each individual epileptic discharge. LGS can be considered as """"secondary"""" network epilepsy because the epileptic manifestations of the disorder reflect the networks being driven, rather than the specific initiating process. In this review, we begin with a summation of the clinical manifestations of LGS and what this has revealed about the underlying etiology of the condition. We then undertake a systematic review of the functional neuroimaging literature in LGS, which leads us to conclude that LGS can best be conceptualized as """"secondary network epilepsy.""""  """,0
5373,25400643,A purification strategy for analysis of the DNA/RNA-associated sub-proteome from chloroplasts of mustard cotyledons,"Plant cotyledons are a tissue that is particularly active in plastid gene expression in order to develop functional chloroplasts from pro-plastids, the plastid precursor stage in plant embryos. Cotyledons, therefore, represent a material being ideal for the study of composition, function and regulation of protein complexes involved in plastid gene expression. Here, we present a pilot study that uses heparin-Sepharose and phospho-cellulose chromatography in combination with isoelectric focussing and denaturing SDS gel electrophoresis (two-dimensional gel electrophoresis) for investigating the nucleic acids binding sub-proteome of mustard chloroplasts purified from cotyledons. We describe the technical requirements for a highly resolved biochemical purification of several hundreds of protein spots obtained from such samples. Subsequent mass spectrometry of peptides isolated out of cut spots that had been treated with trypsin identified 58 different proteins within 180 distinct spots. Our analyses indicate a high enrichment of proteins involved in transcription and translation and, in addition, the presence of massive post-translational modification of this plastid protein sub-fraction. The study provides an extended catalog of plastid proteins from mustard being involved in gene expression and its regulation and describes a suitable purification strategy for further analysis of low abundant gene expression related proteins.  ",0
5374,25400704,Is initial preservation of deep tendon reflexes in West Nile Virus paralysis a good prognostic sign?,"Typical West Nile virus paralysis is characterized by muscle weakness, decreased tone, and loss of deep tendon reflexes attributed to destruction of anterior horn cells. Two cases in which deep tendon reflexes were initially preserved in the presence of profound and persistent muscle weakness are presented here. In both cases, deep tendon reflexes were later severely attenuated or lost, while weakness of the involved muscles remained profound and unchanged. Both patients showed good motor recovery at 6 months. Initial preservation of deep tendon reflexes in the presence of persistent muscle weakness indicates that in the early stages of disease, the muscle weakness in these two cases was not caused by destruction of anterior horn cells. Pathology involving anterior horns preceding AHC destruction could potentially disrupt upper motor neuron pathways to anterior horn cells, causing weakness with initial preserved deep tendon reflexes. ",0
5375,25401292,Multi-Spectroscopic Analysis of Seed Quality and 13C-Stable-Iotopologue Monitoring in Initial Growth Metabolism of Jatropha curcas L,"In the present study, we applied nuclear magnetic resonance (NMR), as well as near-infrared (NIR) spectroscopy, to Jatropha curcas to fulfill two objectives: (1) to qualitatively examine the seeds stored at different conditions, and (2) to monitor the metabolism of J. curcas during its initial growth stage under stable-isotope-labeling condition (until 15 days after seeding). NIR spectra could non-invasively distinguish differences in storage conditions. NMR metabolic analysis of water-soluble metabolites identified sucrose and raffinose family oligosaccharides as positive markers and gluconic acid as a negative marker of seed germination. Isotopic labeling patteren of metabolites in germinated seedlings cultured in agar-plate containg 13C-glucose and 15N-nitrate was analyzed by zero-quantum-filtered-total correlation spectroscopy (ZQF-TOCSY) and 13C-detected 1H-13C heteronuclear correlation spectroscopy (HETCOR). 13C-detected HETOCR with 13C-optimized cryogenic probe provided high-resolution 13C-NMR spectra of each metabolite in molecular crowd. The 13C-13C/12C bondmer estimated from 1H-13C HETCOR spectra indicated that glutamine and arginine were the major organic compounds for nitrogen and carbon transfer from roots to leaves.  ",0
5376,25401673,POLVSM (Polarized Volume Scattering Meter) instrument: an innovative device to measure the directional and polarized scattering properties of hydrosols,"An innovative instrument dedicated to the multispectral measurements of the directional and polarized scattering properties of the hydrosols, so-called POLVSM, is described. The instrument could be used onboard a ship, as a benchtop instrument, or at laboratory. The originality of the POLVSM concept relies on the use of a double periscopic optical system whose role is (i) to separate the plane containing the light source from the scattering plane containing the sample and the receiver and (ii) to prevent from any specularly reflected light within the sample chamber. As a result, a wide range of scattering angle, namely from 1° to 179°, is covered by the detector. Another originality of the instrument is to measure the Mueller scattering matrix elements, including the degree of polarization. A relevant calibration procedure, which could be of great interest as well for other instruments, is proposed to convert the raw data into physical units. The relative uncertainty in POLVSM data was determined at ± 4.3%. The analysis of measurements of the volume scattering function and degree of polarization performed under controlled conditions for samples dominated either by inorganic hydrosols or phytoplankton monospecific species showed a good consistency with literature, thus confirming the good performance of the POLVSM device. Comparisons of POLVSM data with theoretical calculations showed that Mie theory could reproduce efficiently the measurements of the VSF and degree of polarization for the case of inorganic hydrosols sample, despite the likely non sphericity of these particles as revealed by one of the element of the Mueller matrix. Our results suggested as well that a sophisticated modeling of the heterogeneous internal structure of living cells, or at least, the use of layered sphere models, is needed to correctly predict the directional and polarized effects of phytoplankton on the oceanic radiation. The relevance of performing angularly resolved measurements of the Mueller scattering elements to gain understanding on the mechanisms processes involved in the scattering of light by marine particles, which has important implications for ocean color remote sensing studies, is demonstrated.  ",0
5377,25401961,Allogeneic umbilical cord blood red cell concentrates: an innovative blood product for transfusion therapy of preterm infants,"Preterm infants often receive blood transfusions early in life. In this setting, umbilical cord blood (UCB) might be safer than adult blood (A) with respect to infectious and immunologic threats. To evaluate, as a first objective, the feasibility of fulfilling transfusion needs of preterm infants with allogeneic UCB red blood cell (RBC) concentrates and, as a secondary objective, to assess the safety of allogeneic cord blood transfusions. At the Neonatal Intensive Care Unit and the UNICATT Cord Blood Bank of 'A. Gemelli' Hospital in Rome, a prospective study was carried out over a 1-year period, enrolling newborns with gestational age ≤30 weeks and/or birth weight ≤1,500 g requiring RBC transfusions within the first 28 days of life. At first transfusion, patients were assigned to receive UCB-RBCs or A-RBCs depending on the availability of ABO-Rh(D)-matched UCB-RBC units. The same regimen (UCB-RBC or A-RBC units) was thereafter maintained, unless ABO-Rh(D)-matched UCB-RBC units were not available. Overall, 23 UCB-RBC units were transfused to 9 patients; the requests for UCB-RBC units were met in 45% of patients at the first transfusion and in 78% at the subsequent transfusions. At a median follow-up of 57 days (range 6-219), no acute or delayed transfusion-related adverse events occurred. Hematocrit gain after transfusion and time intervals between transfusions were similar in the UCB-RBC and A-RBC group, as well. Transfusing allogeneic UCB-RBC units in preterm infants appears a feasible and safe approach, although the transfusion needs of our study population were not completely covered. More data are necessary to validate this novel transfusion practice. ",0
5378,25402351,Permanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction,"Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood. IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts. The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere. ",0
5379,25402445,Absorption kinetics of low-dose chewable aspirin--implications for acute coronary syndromes,"This study describes the implications of the pharmacokinetics of low-dose chewable aspirin for acute coronary syndromes. Current guidelines recommend the administration of 162-325 mg aspirin chewing tablets for the treatment of acute myocardial infarction. Although aspirin is widely used and a cornerstone in myocardial infarction, there is no information available on the pharmacokinetics of low doses of chewable aspirin. This prospective trial assessed the pharmacokinetics of acetylsalicylic acid and its metabolite salicylic acid after intake of 162 mg chewable low-dose aspirin in 35 healthy volunteers. Plasma drug and metabolite levels were analysed using high-performance liquid chromatography, and corresponding pharmacodynamics were determined by impedance aggregometry. Acetylsalicylic acid was rapidly absorbed with a mean Tmax of 27 ± 8 min. Tmax of salicylic acid was 69 ± 21 min. Mean Cmax was 1·8 ± 0·6 mg/L and 7·6 ± 1·4 for acetylsalicylic acid and salicylic acid, respectively. Arachidonic acid-induced aggregation showed maximum platelet inhibition 30 min after drug ingestion. The characterization of the plasma-time profile fills the gap between the lack of data on pharmacokinetics and the pharmacodynamics and the recommendation for using low-dose chewable aspirin for acute coronary syndromes. We describe for the first time that a 162-mg dose of chewable aspirin is rapidly absorbed and achieves plasma concentrations of the active metabolite salicylic acid required to maximally inhibit platelet aggregation. However, a 162-mg dose is truly a minimum, and doubling this dose might be better for patients with myocardial infarction. ",0
5380,25402547,Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta,"Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay. ",0
5381,25402556,Radiation-induced alterations in synaptic neurotransmission of dentate granule cells depend on the dose and species of charged particles,"The evaluation of potential health risks associated with neuronal exposure to space radiation is critical for future long duration space travel. The purpose of this study was to evaluate and compare the effects of low-dose proton and high-energy charged particle (HZE) radiation on electrophysiological parameters of the granule cells in the dentate gyrus (DG) of the hippocampus and its associated functional consequences. We examined excitatory and inhibitory neurotransmission in DG granule cells (DGCs) in dorsal hippocampal slices from male C57BL/6 mice at 3 months after whole body irradiation with accelerated proton, silicon or iron particles. Multielectrode arrays were used to investigate evoked field synaptic potentials, an extracellular measurement of synaptic excitability in the perforant path to DG synaptic pathway. Whole-cell patch clamp recordings were used to measure miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in DGCs. Exposure to proton radiation increased synaptic excitability and produced dose-dependent decreases in amplitude and charge transfer of mIPSCs, without affecting the expression of γ-aminobutyric acid type A receptor α2, β3 and γ2 subunits determined by Western blotting. Exposure to silicon radiation had no significant effects on synaptic excitability, mEPSCs or mIPSCs of DGCs. Exposure to iron radiation had no effect on synaptic excitability and mIPSCs, but significantly increased mEPSC frequency at 1 Gy, without changes in mEPSC kinetics, suggesting a presynaptic mechanism. Overall, the data suggest that proton and HZE exposure results in radiation dose- and species-dependent long-lasting alterations in synaptic neurotransmission, which could cause radiation-induced impairment of hippocampal-dependent cognitive functions.  ",0
5382,25402658,"Isolation and characterization of a novel angiotensin-converting enzyme-inhibitory tripeptide from enzymatic hydrolysis of soft-shelled turtle (Pelodiscus sinensis) egg white: in vitro, in vivo, and in silico study","In this study, a novel angiotensin-converting enzyme (ACE)-inhibitory tripeptide (IVR) was isolated and identified from unfertilized soft-shelled turtle egg white (SSTEW). The IC50 value of IVR was measured in vitro as low as 0.81 ± 0.03 μM, and its inhibition type was suggested as competitive according to the Lineweaver-Burk plot. This peptide can be generated from either thermolysin followed by trypsin digestion (two stages) or only trypsin digestion (one stage). Quantitative LC-MS/MS analysis indicated that two-stage digestion gave 3.14 ± 0.17 mg of IVR from 1 g of SSTEW, better than that from one-stage digestion (1.31 ± 0.12 mg). In vivo antihypertensive activity of the tripeptide IVR after single oral administration (0.1 and 1 mg/kg of body weight) led to a significant reduction in systolic blood pressure 2-4 h after administration in spontaneously hypertensive rats. In addition, the binding mechanism of IVR has been rationalized through docking simulations using the testicular ACE (tACE)-lisinopril complex at 2 Å resolution (PDB 108A ). The best docking pose was located at the tACE catalytic site resembling the mode of inhibition exerted by lisinopril, an effective hypertensive synthetic drug. The degree of inhibition of this peptide correlated with the H-bond interaction between the C-terminal of IVR and Lys511 and Tyr520 residues of tACE, a significant inhibitor registration for lisinopril. This study illustrated that IVR behaves as a transition-state analogue inhibitor and is useful in therapeutic intervention for blood pressure control. To the best of our knowledge, this is the first report of an efficient ACE-inhibitory tripeptide generated from the unfertilized egg of soft-shelled turtle.  ",0
5383,25402811,The course and the anatomo-functional relationships of the optic radiation: a combined study with 'post mortem' dissections and 'in vivo' direct electrical mapping,"Even if different dissection, tractographic and connectivity studies provided pure anatomical evidences about the optic radiations (ORs), descriptions of both the anatomical structure and the anatomo-functional relationships of the ORs with the adjacent bundles were not reported. We propose a detailed anatomical and functional study with 'post mortem' dissections and 'in vivo' direct electrical stimulation (DES) of the OR, demonstrating also the relationships with the adjacent eloquent bundles in a neurosurgical 'connectomic' perspective. Six human hemispheres (three left, three right) were dissected after a modified Klingler's preparation. The anatomy of the white matter was analysed according to systematic and topographical surgical perspectives. The anatomical results were correlated to the functional responses collected during three resections of tumours guided by cortico-subcortical DES during awake procedures. We identified two groups of fibres forming the OR. The superior component runs along the lateral wall of the occipital horn, the trigone and the supero-medial wall of the temporal horn. The inferior component covers inferiorly the occipital horn and the trigone, the lateral wall of the temporal horn and arches antero-medially to form the Meyer's Loop. The inferior fronto-occipital fascicle (IFOF) covers completely the superior OR along its entire course, as confirmed by the subcortical DES. The inferior longitudinal fascicle runs in a postero-anterior and inferior direction, covering the superior OR posteriorly and the inferior OR anteriorly. The IFOF identification allows the preservation of the superior OR in the anterior temporal resection, avoiding post-operative complete hemianopia. The identification of the superior OR during the posterior temporal, inferior parietal and occipital resections leads to the preservation of the IFOF and of the eloquent functions it subserves. The accurate knowledge of the OR course and the relationships with the adjacent bundles is crucial to optimize quality of resection and functional outcome.  ",0
5384,25403145,Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors,"Hepatitis C virus (HCV) replication is dependent on a liver-specific microRNA (miRNA), miR-122. A recent clinical trial reported that transient inhibition of miR-122 reduced viral titres in HCV-infected patients. Here we set out to better understand how miR-122 inhibition influences HCV replication over time. Unexpectedly, we observed the emergence of an HCV variant that is resistant to miR-122 knockdown. Next-generation sequencing revealed that this was due to a single nucleotide change at position 28 (G28A) of the HCV genome, which falls between the two miR-122 seed-binding sites. Naturally occurring HCV isolates encoding G28A are similarly resistant to miR-122 inhibition, indicating that subtle differences in viral sequence, even outside the seed-binding site, greatly influence HCV's miR-122 concentration requirement. In addition, we found that HCV itself reduces miR-122's activity in the cell, possibly through binding and sequestering miR-122. Our study provides insight into the interaction between miR-122 and HCV, including viral adaptation to reduced miR-122 bioavailability, and has implications for the development of anti-miR-122-based HCV drugs.  ",0
5385,25403316,An unexpected ferromagnetic foreign body detected during emergency magnetic resonance imaging: a case report,"Sedation or anesthesia is often necessary in pediatrics when magnetic resonance imaging is performed. This anesthesia outside of the operation room combines specific requirements and risks. Ferromagnetic foreign bodies are a clear contraindication for magnetic resonance imaging due to the high magnetic field within the scanner. However, insertion of various small objects in mouth, nose or external auditory is not uncommon in small children and often remains unnoticed until specific symptoms develop. Early warning sings like movement of the object or heat development are then concealed by sedation or anesthesia preventing a timely termination of the possibly hazardous procedure. We present a case of a three year old Caucasian with an acute sinusitis due to unknown ferromagnetic foreign body in his nasal cavity. As soon as the suspicion was raised the procedure was aborted and the object that revealed to be a small button battery was successfully removed. The potential of unwelcome side effects and effective safety strategies of magnetic resonance imaging are discussed as well as the complications arising from ingested batteries. ",0
5386,25403445,Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells,"Leptin is a circulating hormone that plays a critical role in regulating energy expenditure and food intake. Evidence to suggest the involvement of endoplasmic reticulum (ER) stress in the development of obesity is increasing. To adapt against ER stress, cells trigger the unfolded protein response (UPR). The 78 kDa glucose-regulated protein (GRP78) is an ER chaperone that protects cells against ER stress by inducing protein folding. In the present study, we hypothesized that leptin may activate UPR and protect against ER stress associated with obesity. SH-SY5Y, a human neuroblastoma cell line stably transfected with the Ob-Rb leptin receptor (SH-SY5Y-ObRb), was treated with leptin. We demonstrated that leptin induced GRP78 expression. We then validated the mechanism responsible for the leptin-induced expression of GRP78. Interestingly, leptin-induced GRP78 expression was not dependent on IRE1-XBP1 pathway. On the other hand, the PI3K inhibitor, LY294002, and mTOR inhibitor, rapamycin, inhibited the leptin-induced expression of GRP78. These results suggested that the leptin-induced expression of GRP78 may be dependent on the PI3K-mTOR pathway. Leptin specifically induced GRP78 because the induction of the ER-apoptotic marker, CHOP, was not detected in leptin-treated cells. Therefore, leptin may upregulate the expression of GRP78, thereby protecting against ER stress associated with obesity. ",0
5387,25403813,Mindfulness-based cognitive therapy in obsessive-compulsive disorder: protocol of a randomized controlled trial,"Obsessive-compulsive disorder (OCD) is a very disabling condition with a chronic course, if left untreated. Though cognitive behavioral treatment (CBT) with or without selective serotonin reuptake inhibitors (SSRI) is the method of choice, up to one third of individuals with obsessive-compulsive disorder (OCD) do not respond to treatment in terms of at least 35% improvement of symptoms. Mindfulness based cognitive therapy (MBCT) is an 8-week group program that could help OCD patients with no or only partial response to CBT to reduce OC symptoms and develop a helpful attitude towards obsessions and compulsive urges. This study is a prospective, bicentric, assessor-blinded, randomized, actively-controlled clinical trial. 128 patients with primary diagnosis of OCD according to DSM-IV and no or only partial response to CBT will be recruited from in- and outpatient services as well as online forums and the media. Patients will be randomized to either an MBCT intervention group or to a psycho-educative coaching group (OCD-EP) as an active control condition. All participants will undergo eight weekly sessions with a length of 120 minutes each of a structured group program. We hypothesize that MBCT will be superior to OCD-EP in reducing obsessive-compulsive symptoms as measured by the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) following the intervention and at 6- and 12-months-follow-up. Secondary outcome measures include depressive symptoms, quality of life, metacognitive beliefs, self-compassion, mindful awareness and approach-avoidance tendencies as measured by an approach avoidance task. The results of this study will elucidate the benefits of MBCT for OCD patients who did not sufficiently benefit from CBT. To our knowledge, this is the first randomized controlled study assessing the effects of MBCT on symptom severity and associated parameters in OCD. German Clinical Trials Register DRKS00004525 . Registered 19 March 2013. ",0
5388,25403981,Meta-analysis of association between ALDH2 rs671 polymorphism and essential hypertension in Asian populations,"Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is an enzyme that oxidizes acetaldehyde into acetic acid during alcohol metabolism. Many studies indicate that the rs671 GG genotype in the ALDH2 gene may play a critical role in increasing the risk of essential hypertension (EH) associated with alcohol consumption, which predominantly occurs in men. However, the literature is inconclusive in this regard. This meta-analysis aims to derive a more precise estimation of the relationship between the rs671 polymorphism and EH for both male and female drinkers and nondrinkers. Ten cohort and case-control studies were included in the analysis with a total of 12,161 subjects; 7,062 patients and 5,099 healthy controls. Our results show that the rs671 GG genotype was associated with an increased risk of EH compared with the AG+AA genotype (OR = 1.27, 95 % CI = 1.17-1.37, p < 0.00001). When comparing male and female subjects, only among male individuals was a higher risk of EH found in the GG genotype compared with the AG+ AA genotype (OR = 1.59, 95 % CI = 1.40-1.80, p < 0.00001). By contrast, among female subjects, the risk of EH in the rs671 GG genotype did not differ from that detected in the AA + GG genotype. The proportion of patients with EH was significantly higher for the GG genotype carriers than for the AG+AA genotype carriers, both in the subset of drinkers (OR = 1.51, 95 % CI = 1.23-1.86, p < 0.0001) and in that of nondrinkers (OR = 1.22, 95 % CI = 1.01-1.47, p = 0.03). In addition, among carriers of the GG genotype, the risk of EH among the drinkers was similar to that found in the nondrinkers' subset (OR = 1.12, 95 %CI = 0.89-1.41, p = 0.34). Our meta-analysis demonstrates that the rs671 GG genotype increases the risks of EH, especially in men, and is independent of alcohol consumption. ",0
5389,25404042,Targeted gene disruption by use of transcription activator-like effector nuclease (TALEN) in the water flea Daphnia pulex,"The cosmopolitan microcrustacean Daphnia pulex provides a model system for both human health research and monitoring ecosystem integrity. It is the first crustacean to have its complete genome sequenced, an unprecedented ca. 36% of which has no known homologs with any other species. Moreover, D. pulex is ideally suited for experimental manipulation because of its short reproductive cycle, large numbers of offspring, synchronization of oocyte maturation, and other life history characteristics. However, existing gene manipulation techniques are insufficient to accurately define gene functions. Although our previous investigations developed an RNA interference (RNAi) system in D. pulex, the possible time period of functional analysis was limited because the effectiveness of RNAi is transient. Thus, in this study, we developed a genome editing system for D. pulex by first microinjecting transcription activator-like effector nuclease (TALEN) mRNAs into early embryos and then evaluating TALEN activity and mutation phenotypes. We assembled a TALEN construct specific to the Distal-less gene (Dll), which is a homeobox transcription factor essential for distal limb development in invertebrates and vertebrates, and evaluated its activity in vitro by single-strand annealing assay. Then, we injected TALEN mRNAs into eggs within 1 hour post-ovulation. Injected embryos presented with defects in the second antenna and altered appendage development, and indel mutations were detected in Dll loci, indicating that this technique successfully knocked out the target gene. We succeeded, for the first time in D. pulex, in targeted mutagenesis by use of Platinum TALENs. This genome editing technique makes it possible to conduct reverse genetic analysis in D. pulex, making this species an even more appropriate model organism for environmental, evolutionary, and developmental genomics. ",0
5390,25404211,"Cloning, overexpression, and characterization of a novel alkali-thermostable xylanase from Geobacillus sp. WBI","""An endo-β-1,4-xylanase gene xynA of a thermophilic Geobacillus sp. WBI from """"hot"""" compost was isolated by PCR amplification. The gene encoding 407 residues were overexpressed in E. coli and purified by Ni-NTA chromatography. The purified enzyme (47 kDa) had a broad pH optimum of 6.0 to 9.0, and was active between 50 and 90 °C. The enzyme retained 100% of its activity when incubated at 65 °C for 1 h under alkaline condition (pH 10.0) and retained 75% activity at pH 11.0. The K(m) and V(max) of the enzyme were 0.9 mg ml(-1) and 0.8 µmol ml(-1) min(-1), respectively. In molecular dynamics simulation at 338 K (65 °C), the enzyme was found to be stable. At an elevated temperature (450 K) specific α-helix and β-turns of the proteins were most denatured. The denaturation was less in WBI compared with its highest homolog G. stearothermophilus T-6 xylanase with difference of six residues. The results predict that these regions are responsible for the improved thermostability observed over related enzymes. The present work encourages further experimental demonstration to understand how these regions contribute thermostability to WBI xylanase. The study noted that WBI produces a xylanase with unique characteristics, specifically alkali-thermostability. """,0
5391,25404627,Functional results after osteosynthesis of distal humeral fractures with pre-contoured LCP system,"Evaluate the functional results and determine the complications after treating distal humerus fractures with an anatomically pre-contoured double plate system. Twenty-five patients with distal humeral fractures were treated with a pre-contoured double plate system. There were 18 males (72%), 7 females (28%), with an average age of 39.68 years (22-70years). As per the AO classification, there were 4 type A fractures (16%) and 21 type C fractures (84%). In addition to clinical examination, functional results were evaluated using the Mayo elbow performance score (MEPS). Using the Mayo elbow performance score, the results obtained were graded as excellent or good results in 22 patients (88%), fair in 2 (8%) and poor in 1 (4%) of cases. Average time interval between admission and surgery was 3.8 days (average 1-9 days). All the fractures as well as the olecranon osteotomies united by 10-16 weeks (12.56 weeks). No patient had deep infection, implant failure, non-union of fracture site or olecranon osteotomy site. Superficial wound infection, which occurred in 4 (16%) patients, resolved with oral antibiotics. Transient ulnar nerve palsy developed in 1(4%) case. However, the patient recovered with conservative treatment. 1. An anatomically pre-shaped distal humerus locking plate system is useful in providing stable fixation of distal humerus fractures, thereby facilitating early postoperative rehabilitation. 2. In contrast to conventional plating, we did not observe any case of secondary fracture displacement, non-union or implant failure even in elderly patients with potentially reduced bone mass. 3. The multiple angular stable point fixation seems to be effective in the application of this system. ",0
5392,25404849,Safer conception needs for HIV prevention among female sex workers in Burkina Faso and Togo,"Reproductive health programming for female sex workers (FSW) may include contraceptive services but rarely addresses safer pregnancy planning. Adult FSW were enrolled into a cross-sectional study across four sites in Burkina Faso and Togo using respondent-driven sampling. Sociobehavioral questionnaires and HIV counseling and testing were administered. Sample statistics and engagement in HIV treatment were described and compared using Chi-squared statistics. 1,349 reproductive-aged FSW were enrolled from January to July 2013. Overall, 267 FSW (19.8%) were currently trying to conceive. FSW trying to conceive were more likely to test positive for HIV at enrollment as compared to women not trying to become pregnant (24.5% versus 17.7%, P < 0.01); however awareness of HIV status was similar across groups. Among FSW trying to conceive, 79.0% (211/267) had previously received HIV testing, yet only 33.8% (23/68) of HIV-infected FSW reported a previous HIV diagnosis. Overall 25.0% (17/68) of HIV-infected FSW trying to conceive were on antiretroviral therapy. FSW frequently desire children. However engagement in the HIV prevention and treatment cascade among FSW trying to conceive is poor potentiating periconception transmission risks to partners and infants. Programs to facilitate earlier HIV diagnosis for FSW and safer conception counseling are needed as components of effective combination HIV prevention services. ",0
5393,25405095,Metallic debris from metal-on-metal total hip arthroplasty regulates periprosthetic tissues,"The era of metal-on-metal (MoM) total hip arthroplasty has left the orthopaedic community with valuable insights and lessons on periprosthetic tissue reactions to metallic debris. Various terms have been used to describe the tissue reactions. Sometimes the nomenclature can be confusing. We present a review of the concepts introduced by Willert and Semlitsch in 1977, along with further developments made in the understanding of periprosthetic tissue reactions to metallic debris. We propose that periprosthetic tissue reactions be thought of as (1) gross (metallosis, necrosis, cyst formation and pseudotumour); (2) histological (macrophage-dominated, lymphocyte-dominated or mixed); and (3) molecular (expression of inflammatory mediators and cytokines such as interleukin-6 and tumor necrosis factor-alpha). Taper corrosion and modularity are discussed, along with future research directions to elucidate the antigen-presenting pathways and material-specific biomarkers which may allow early detection and intervention in a patient with adverse periprosthetic tissue reactions to metal wear debris.  ",0
5394,25405618,Tailoring subunit vaccine immunity with adjuvant combinations and delivery routes using the Middle East respiratory coronavirus (MERS-CoV) receptor-binding domain as an antigen,"The development of an effective vaccine is critical for prevention of a Middle East respiratory syndrome coronavirus (MERS-CoV) pandemic. Some studies have indicated the receptor-binding domain (RBD) protein of MERS-CoV spike (S) is a good candidate antigen for a MERS-CoV subunit vaccine. However, highly purified proteins are typically not inherently immunogenic. We hypothesised that humoral and cell-mediated immunity would be improved with a modification of the vaccination regimen. Therefore, the immunogenicity of a novel MERS-CoV RBD-based subunit vaccine was tested in mice using different adjuvant formulations and delivery routes. Different vaccination regimens were compared in BALB/c mice immunized 3 times intramuscularly (i.m.) with a vaccine containing 10 µg of recombinant MERS-CoV RBD in combination with either aluminium hydroxide (alum) alone, alum and polyriboinosinic acid (poly I:C) or alum and cysteine-phosphate-guanine (CpG) oligodeoxynucleotides (ODN). The immune responses of mice vaccinated with RBD, incomplete Freund's adjuvant (IFA) and CpG ODN by a subcutaneous (s.c.) route were also investigated. We evaluated the induction of RBD-specific humoral immunity (total IgG and neutralizing antibodies) and cellular immunity (ELISpot assay for IFN-γ spot-forming cells and splenocyte cytokine production). Our findings indicated that the combination of alum and CpG ODN optimized the development of RBD-specific humoral and cellular immunity following subunit vaccination. Interestingly, robust RBD-specific antibody and T-cell responses were induced in mice immunized with the rRBD protein in combination with IFA and CpG ODN, but low level of neutralizing antibodies were elicited. Our data suggest that murine immunity following subunit vaccination can be tailored using adjuvant combinations and delivery routes. The vaccination regimen used in this study is promising and could improve the protection offered by the MERS-CoV subunit vaccine by eliciting effective humoral and cellular immune responses.  ",0
5395,25405658,Rab25 is responsible for phosphoinositide 3-kinase/AKT‑mediated cisplatin resistance in human epithelial ovarian cancer cells,"Rab25, a member of the Rab family of small guanosine triphosphatase, was reported to have an essential role in the development of human epithelial ovarian cancer. The present study demonstrated that Rab25 mediated the sensitivity of ovarian cancer to cisplatin, a first‑line chemotherapeutic agent for the treatment of ovarian cancer in the clinic. Overexpression of Rab25 and increased phosphoinositide 3‑kinase (PI3K)/AKT signaling were detected in cisplatin‑resistant SKOV‑3 cells compared with those in cisplatin‑sensitive ES‑2 cells. The results of the present study indicated that cisplatin resistance was primarily due to reduced G1 cell cycle arrest following cisplatin treatment in SKOV‑3 cells. By contrast, the corresponding phenomenon was not observed following treatment with a Rab25‑specific small interfering RNA or treatment with the PI3K/AKT inhibitor LY294002. Of note, inhibition of the PI3K/AKT pathway reduced Rab25 gene expression and sensitized SKOV‑3 cells to cisplatin. Furthermore, knockdown of Rab25 showed an effect comparable with blocking the PI3K/AKT pathway. In conclusion, the results of the present study demonstrated that PI3K/AKT and Rab25 significantly contributed to cisplatin resistance in human epithelial ovarian cancer; in addition, silencing Rab25 or inhibiting the PI3K/AKT pathway markedly increased the sensitivity of these cells to cisplatin. ",0
5396,25405720,"Comparing HbA1c, fasting and 2-h plasma glucose for screening for abnormal glucose regulation in patients undergoing coronary angiography","We aimed to investigate the prevalence of undiagnosed abnormal glucose regulation (AGR, including diabetes and prediabetes) in patients undergoing coronary angiography (CAG) by using both glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) to screen, and to compare the performance of fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), and HbA1c for screening for AGR. Eligible patients were adults without known diabetes who were admitted for CAG. Patients' glucose regulation status was defined by conducting HbA1c and OGTT 2-4 weeks after hospital discharge. The performance of FPG, 2hPG, and HbA1c for detecting AGR was evaluated using receiver operating characteristic (ROC) analysis. A total of 689 subjects were included. According to OGTT, the prevalence rates of diabetes and prediabetes were 19.9% and 41.7%, respectively. The corresponding values were 28.0% and 60.4%, respectively, when HbA1c was adopted as a diagnostic criterion in addition to OGTT. For detecting diabetes, the area under the ROC curve (AUC) was higher for HbA1c than for FPG (0.87 vs. 0.80, p=0.005), but was not significantly different from that for 2hPG (0.87 vs. 0.88, p=0.58). For detecting AGR, the AUC was higher for HbA1c than for either FPG (0.94 vs. 0.74, p<0.001) or 2hPG (0.94 vs. 0.83, p<0.001). Using HbA1c and OGTT to screen, we reported an extremely high prevalence of previously undiagnosed AGR (28.0% diabetes and 60.4% prediabetes) in patients admitted for CAG. HbA1c may be adopted as an alternative to OGTT for screening for AGR in patients undergoing CAG. ",0
5397,25405753,MicroRNA let-7a suppresses the growth and invasion of cholesteatoma keratinocytes,"Cholesteatomas are benign epidermally‑derived lesions of the temporal bone that are caused by migration of hyperproliferative keratinocytes into the middle ear and mastoid cavity. The molecular mechanisms that regulate the pathogenesis of cholesteatomas are currently not fully understood. The present study demonstrated the antigrowth and anti‑invasive effects of let‑7a microRNA (miRNA) on cholesteatoma keratinocytes. Let‑7a inhibited the growth of cholesteatoma keratinocytes through two different mechanisms: Restriction of the proliferation of keratinocytes by promoting cell cycle arrest in the G0/G1 phase, and the induction of apoptosis of the cells. In addition to its role in the inhibition of cell growth, let‑7a suppressed the migration and invasion of cholesteatoma keratinocytes. A mechanistic study showed that let‑7a downregulated the expression of miR‑21. Considering the function of miR‑21 in the regulation of proliferation and apoptosis, let‑7a may control cell proliferation and apoptosis by regulating miR‑21, and its targets, in cholesteatoma keratinocytes. In conclusion, the present study showed that let‑7a downregulates the expression of miR‑21, resulting in the suppression of proliferation and induction of apoptosis. The results of the present study reveal the crucial role of let‑7a miRNA in the inhibition of growth and invasion of cholesteatoma keratinocytes. ",0
5398,25405980,A multi-criteria index for ecological evaluation of tropical agriculture in southeastern Mexico,"The aim of this study was to generate an easy to use index to evaluate the ecological state of agricultural land from a sustainability perspective. We selected environmental indicators, such as the use of organic soil amendments (green manure) versus chemical fertilizers, plant biodiversity (including crop associations), variables which characterize soil conservation of conventional agricultural systems, pesticide use, method and frequency of tillage. We monitored the ecological state of 52 agricultural plots to test the performance of the index. The variables were hierarchically aggregated with simple mathematical algorithms, if-then rules, and rule-based fuzzy models, yielding the final multi-criteria index with values from 0 (worst) to 1 (best conditions). We validated the model through independent evaluation by experts, and we obtained a linear regression with an r2 = 0.61 (p = 2.4e-06, d.f. = 49) between index output and the experts' evaluation.  ",0
5399,25406093,Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate,"Human d-3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthetic pathway, is genomically amplified in tumors including breast cancer and melanoma. In PHGDH-amplified cancer cells, knockdown of PHGDH is not fully rescued by exogenous serine, suggesting possible additional growth-promoting roles for the enzyme. Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of α-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). Knockdown of PHGDH decreased cellular 2HG by approximately 50% in the PHGDH-amplified breast cancer cell lines MDA-MB-468 (normal concentration 93 μM) and BT-20 (normal concentration 35 μM) and overexpression of PHGDH increased cellular 2HG by over 2-fold in non-PHGDH-amplified MDA-MB-231 breast cancer cells, which normally display very low PHGDH expression. The reduced 2HG level in PHGDH knockdown cell lines can be rescued by PHGDH re-expression, but not by a catalytically inactive PHGDH mutant. The initial connection between cancer and d-2HG involved production of high levels of d-2HG by mutant isocitrate dehydrogenase. More recently, however, elevated d-2HG has been observed in breast cancer tumors without isocitrate dehydrogenase mutation. Our results suggest that PHGDH is one source of this d-2HG.  ",0
5400,25406173,Related strains of African swine fever virus with different virulence: genome comparison and analysis,"Two strains of African swine fever virus (ASFV), the high-virulence Lisboa60 (L60) and the low-virulence NH/P68 (NHV), which have previously been used in effective immunization/protection studies, were sequenced. Both were isolated in Portugal during the 11-year period after the introduction of ASFV to the European Continent in 1957. The predicted proteins coded by both strains were compared, and where differences were found these were also compared to other strains of known virulence. This highlighted several genes with significant alterations in low-virulence strains of ASFV that may constitute virulence factors, several of which are still uncharacterized regarding their function. Phylogenetic analysis grouped L60 and NHV closest to other P72 genotype I ASFV strains from Europe and West Africa, consistent with the assumed West African origin of all European strains. Interestingly, a relatively lower genomic identity exists between L60 and NHV, both isolated in a similar geographical location 8 years apart, than with other European and west African strains isolated subsequently and in more distant locations. This may reflect the intensive passage in tissue culture, during the early 1960s, of a Portuguese isolate to obtain an attenuated vaccine, which may have led to NHV. This study contributes to a better understanding of the evolution of ASFV, and defines additional potential virulence genes for future studies of pathogenesis towards the development of effective vaccines.  ",0
5401,25406956,Evaluation of morphological changes in the adult skull with age and sex,"The morphology of the brain and skull are important in the evaluation of the aging human; however, little is known about how the skull may change with age. The objective of this study was to evaluate the morphological changes of the adult skull using three-dimensional geometric morphometric analysis of thousands of landmarks with the focus on anatomic regions that may be correlated with brain atrophy and head injury. Computed tomography data were collected between ages 20 and 100. Each scan was segmented using thresholding techniques. An atlas image of a 50th percentile skull was registered to each subject scan by computing a series of rigid, affine, and non-linear transformations between atlas space and subject space. Landmarks on the atlas skull were transformed to each subject and partitioned into the inner and outer cranial vault and the cranial fossae. A generalized Procrustes analysis was completed for the landmark sets. The coordinate locations describing the shape of each region were regressed with age to generate a model predicting the landmark location with age. Permutation testing was performed to assess significant changes with age. For the males, all anatomic regions reveal significant changes in shape with age except for the posterior cranial fossa. For the females, only the middle cranial fossa and anterior cranial fossa were found to change significantly in shape. Results of this study are important for understanding the adult skull and how shape changes may pertain to brain atrophy, aging, and injury. ",0
5402,25406989,Does powder and granular activated carbon perform equally in immobilizing chlorobenzenes in soil?,"The objective of this study is to compare the efficacies of powder activated carbon (PAC) and granular activated carbon (GAC) as amendments for the immobilization of volatile compounds in soil. Soil artificially-spiked with chlorobenzenes (CBs) was amended with either PAC or GAC to obtain an application rate of 1%. The results showed that the dissipation and volatilization of CBs from the amended soil significantly decreased compared to the unamended soil. The bioavailabilities of CBs, which is expressed as butanol extraction and earthworm accumulation, were significantly reduced in PAC and GAC amended soils. The lower chlorinated and hence more volatile CBs experienced higher reductions in both dissipation and bioavailability in the amended soils. The GAC and PAC equally immobilized more volatile CBs in soil. Therefore, it could be concluded that along with environmental implication, applying GAC was the more promising approach for the effective immobilization of volatile compounds in soil.  ",0
5403,25407290,Physiological and biochemical characteristics of the ethyl tiglate production pathway in the yeast Saprochaete suaveolens,"A yeast identified as Saprochaete suaveolens was investigated for its capacity to produce a large panel of flavouring molecules. With a production of 32 compounds including 28 esters, S. suaveolens seems to be a good producer of fruity flavours and fragrances and especially of unsaturated esters, such as ethyl tiglate. Physiological and biochemical analyses were performed in this study in an attempt to comprehend the metabolic route to the formation of this compound. We show that the accumulation of ethyl tiglate by S. suaveolens is specifically induced by isoleucine. However, and contrary to S. cerevisiae, which harbours a classical Ehrlich pathway leading to the production of 2-methylbutanol from isoleucine, our results provide phenotypic and enzymological evidence of ethyl tiglate biosynthesis in S. suaveolens through the catabolism of this amino acid by the β-oxidation pathway, which generates tiglyl-CoA as a probable intermediate. A kinetic analysis of this flavour molecule during growth of S. suaveolens on glucose and isoleucine showed a phase of production of ethyl tiglate that culminated concurrently with isoleucine exhaustion, followed by a disappearance of this compound, likely due to reassimilation by the yeast. ",0
5404,25407297,"""""""More than skin deep"""": stress neurobiology and mental health consequences of racial discrimination""","Ethnic minority groups across the world face a complex set of adverse social and psychological challenges linked to their minority status, often involving racial discrimination. Racial discrimination is increasingly recognized as an important contributing factor to health disparities among non-dominant ethnic minorities. A growing body of literature has recognized these health disparities and has investigated the relationship between racial discrimination and poor health outcomes. Chronically elevated cortisol levels and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis appear to mediate effects of racial discrimination on allostatic load and disease. Racial discrimination seems to converge on the anterior cingulate cortex (ACC) and may impair the function of the prefrontal cortex (PFC), hence showing substantial similarities to chronic social stress. This review provides a summary of recent literature on hormonal and neural effects of racial discrimination and a synthesis of potential neurobiological pathways by which discrimination affects mental health. ",0
5405,25408528,Molecular aspects of anti-atherosclerotic effects of short peptides,"We studied molecular mechanisms of the vasoprotective effects of tripeptide T-38 and dipeptide RR-1. Short peptides T-38 and the RR-1 activate the processes of cell renewal in organotypic and dissociated cultures of vascular cells during aging by increasing the expression of Ki-67 and reducing the synthesis of p53 protein. T-38 and RR-1 reduce the synthesis of E-selectin, adhesion molecule involved in the formation of atherosclerotic plaques.  ",0
5406,25408889,Production of transgenic pigs over-expressing the antiviral gene Mx1,"The myxovirus resistance gene (Mx1) has a broad spectrum of antiviral activities. It is therefore an interesting candidate gene to improve disease resistance in farm animals. In this study, we report the use of somatic cell nuclear transfer (SCNT) to produce transgenic pigs over-expressing the Mx1 gene. These transgenic pigs express approximately 15-25 times more Mx1 mRNA than non-transgenic pigs, and the protein level of Mx1 was also markedly enhanced. We challenged fibroblast cells isolated from the ear skin of transgenic and control pigs with influenza A virus and classical swine fever virus (CFSV). Indirect immunofluorescence assay (IFA) revealed a profound decrease of influenza A proliferation in Mx1 transgenic cells. Growth kinetics showed an approximately 10-fold reduction of viral copies in the transgenic cells compared to non-transgenic controls. Additionally, we found that the Mx1 transgenic cells were more resistant to CSFV infection in comparison to non-transgenic cells. These results demonstrate that the Mx1 transgene can protect against viral infection in cells of transgenic pigs and indicate that the Mx1 transgene can be harnessed to develop disease-resistant pigs.  ",0
5407,25408994,In situ characterization of mycobacterial growth inhibition by lytic enzymes expressed in vectorized E. coli,"The emergence of extremely drug resistant Mycobacterium tuberculosis necessitates new strategies to combat the pathogen. Engineered bacteria may serve as vectors to deliver proteins to human cells, including mycobacteria-infected macrophages. In this work, we target Mycobacterium smegmatis, a nonpathogenic tuberculosis model, with E. coli modified to express trehalose dimycolate hydrolase (TDMH), a membrane-lysing serine esterase. We show that TDMH-expressing E. coli are capable of lysing mycobacteria in vitro and at low pH. Vectorized E. coli producing TDMH were found suppress the proliferation of mycobacteria in infected macrophages.  ",0
5408,25409128,Age-dependent changes in DNA repair in radiation-exposed mice,"Ionizing radiation (IR) is a well-known human carcinogen. Young and adult individuals are known to respond to radiation in a different manner. In this study, we analyzed changes in the spleen of juvenile (two-week-old), adult (two-month-old) and old (18-month-old) C57BL/6 male mice subjected to a whole-body exposure to 1 Gy of X rays. We measured the number of γ-H2AX foci and ATM protein levels as a reflection of the level of DNA double-strand breaks (DSBs), and found that old animals had a high frequency of occurrence of noninduced DSBs. Exposure to X rays resulted in a rapid increase in the number of DSBs in juvenile and adult animals at 6 h postirradiation followed by a return to preirradiated DSB values at 96 h postirradiation. No changes were observed in old animals. The analysis of the levels of proteins involved in DNA damage base excision and mismatch repair pathways, including KU70, RAD51, POL β, POL δ, POL ε, APE1 and MSH2 showed substantial age-dependent radiation-induced differences. Finally, we demonstrated that old animals had a higher background level of cell apoptosis compared to younger animals, but in contrast to younger animals, old animals were not able to commit spleen cells to apoptosis after being irradiated. Thus, spleen cells of old mice have a high level of spontaneous DNA damage, but they are not able to deal with additional radiation-induced damage as efficiently as younger animals, substantiating age-depending differences in radiation-induced DNA damage and repair response and its outcomes.  ",0
5409,25409153,Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide,"Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2'-deoxyguanosine, which is found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate Escherichia coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerases discriminate between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine and 8-oxo-dGTP(syn) uses its Hoogsteen edge to base pair with adenine. Here we use time-lapse crystallography to follow 8-oxo-dGTP insertion opposite adenine or cytosine with human pol β, to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen-bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxo-dGTP uses charge modulation during insertion that can lead to a blocked DNA repair intermediate.  ",0
5410,25409260,Genetic basis for clinical response to CTLA-4 blockade in melanoma,"BACKGROUND: Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. METHODS: We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. RESULTS: Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. CONCLUSIONS: These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).",0
5411,25409901,Longitudinal increase in total IgE levels in patients with adult asthma: an association with poor asthma control,"Immunoglobulin (Ig) E is well-known to play a critical role in allergic diseases. We investigated the association between longitudinal change in total IgE level and the asthma control in patients with adult asthma. For this retrospective study, 154 patients with asthma aged 21-82 years were recruited from the allergy and pulmonary units of the Showa University Hospital. Data on longitudinal changes in IgE over the preceding 10 years were collected and logarithmically transformed. Associations between longitudinal change in IgE and clinical characteristics including asthma control test (ACT) score, asthma control, pulmonary function test, and antigen specific IgE, were assessed. Patients with increased IgE tended to have significantly higher mean age, more episodes of acute exacerbation within a year, lower ACT scores, and used oral corticosteroids more frequently than those with decreased or unchanged IgE. The prevalence of uncontrolled asthma was higher in patients with increased IgE than in those with decreased or unchanged IgE. Mean %FEV1 and FEV1% were lower in patients with increased IgE than in those with decreased or unchanged IgE. Moreover, the prevalence of Aspergillus-specific IgE was higher in patients with increased IgE than in those with decreased or unchanged IgE. These data suggest that a longitudinal increase in total IgE is associated with both poor asthma control and Aspergillus-specific IgE in patients with adult asthma. ",0
5412,25410057,Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I,"Progressive skeletal and connective tissue disease represents a significant clinical burden in all of the mucopolysaccharidoses. Despite the introduction of enzyme replacement strategies for many of the mucopolysaccharidoses, symptomatology related to bone and joint disease appears to be recalcitrant to current therapies. In order to address these unmet medical needs a clearer understanding of skeletal and connective tissue disease pathogenesis is required. Historically the pathogenesis of the mucopolysaccharidoses has been assumed to directly relate to progressive storage of glycosaminoglycans. It is now apparent for many lysosomal storage disorders that more complex pathogenic mechanisms underlie patients' clinical symptoms. We have used proteomic and genome wide expression studies in the murine mucopolysaccharidosis I model to identify early pathogenic events occurring in micro-dissected growth plate tissue. Studies were conducted using 3 and 5-week-old mice thus representing a time at which no obvious morphological changes of bone or joints have taken place. An unbiased iTRAQ differential proteomic approach was used to identify candidates followed by validation with multiple reaction monitoring mass spectrometry and immunohistochemistry. These studies reveal significant decreases in six key structural and signaling extracellular matrix proteins; biglycan, fibromodulin, PRELP, type I collagen, lactotransferrin, and SERPINF1. Genome-wide expression studies in embryonic day 13.5 limb cartilage and 5 week growth plate cartilage followed by specific gene candidate qPCR studies in the 5week growth plate identified fourteen significantly deregulated mRNAs (Adamts12, Aspn, Chad, Col2a1, Col9a1, Hapln4, Lum, Matn1, Mmp3, Ogn, Omd, P4ha2, Prelp, and Rab32). The involvement of biglycan, PRELP and fibromodulin; all members of the small leucine repeat proteoglycan family is intriguing, as this protein family is implicated in the pathogenesis of late onset osteoarthritis. Taken as a whole, our data indicates that alteration of the extracellular matrix represents a very early event in the pathogenesis of the mucopolysaccharidoses and implies that biomechanical failure of chondro-osseous tissue may underlie progressive bone and joint disease symptoms. These findings have important therapeutic implications. ",0
5413,25410293,Two- and live/real time three-dimensional transthoracic echocardiographic assessment of infective endocarditis of a valved pulmonary conduit,"We describe the use of a nonstandard left infraclavicular approach in making the diagnosis of an infected valved conduit with two-dimensional transthoracic echocardiography. The patient was an adult with tetralogy of Fallot and pulmonary atresia who had undergone multiple surgical repair procedures. The initial diagnosis of infective endocarditis was made by transesophageal echocardiography. Both techniques demonstrated a single, large vegetation in the conduit. Live/real time three-dimensional transthoracic echocardiography, on the other hand, provided further information by demonstrating several additional vegetations in the conduit and more comprehensively assessed their size by enabling measurement of their azimuthal dimensions and volumes. The patient was treated with antibiotics with complete resolution of the vegetations.  ",0
5414,25410455,"Antiepileptic drugs patterns in elderly inpatients in a Brazilian tertiary center, Salvador, Brazil","Epilepsy is very prevalent among elderly inpatients and treatment is far from ideal. To analyze prescribing patterns of antiepileptic drugs (AEDs) for hospitalized elderly with epilepsy, their relations with comorbidities and comedications. We assessed prescription regimen of elderly patients that were under AED use for treatment of epileptic seizures, during hospitalization. One hundred and nine patients were enrolled. AED regimen was categorized into two groups: Group 1 defined as appropriate (carbamazepine, oxcarbazepine, valproic acid, gabapentin, clobazan and lamotrigine) and Group 2 as inappropriate (phenytoin and phenobarbital). We found 73.4% of patients used inappropriate AEDs (p<0.001). Monotherapy was prescribed for 71.6% of patients. The most common comorbidity was hypertension. Potentially proconvulsant drugs as comedications were used for nearly half of patients. Inappropriate AED therapy was commonly prescribed regimen for elderly inpatients. Some recommendations are discussed for a better care of elderly inpatients with epilepsy. ",0
5415,25410567,A severe case of Lemierre Syndrome with Streptococcus constellatus Infection,"A 76-year-old Japanese male presenting with high fever, headache, and disturbance of consciousness was hospitalized. Contrast computed tomography revealed thrombophlebitis in the internal jugular vein and abscesses in the posterior neck region, pharynx, and pterygoid muscle. Streptococcus constellatus infection was confirmed by culture of blood samples, and the patient was diagnosed with Lemierre syndrome. In addition to the administration of antibiotics and anticoagulants, abscess drainage was performed. S. constellatus should be considered as a causative bacterium in elderly patients with Lemierre syndrome.  ",0
5416,25410786,Runx/Cbfb signaling regulates postnatal development of granular convoluted tubule in the mouse submandibular gland,"The rodent salivary gland is not fully developed at birth and the cellular definitive differentiation takes place postnatally. However, little is known about its molecular mechanism. Here we provide the loss-of-function genetic evidence that Runx signaling affects postnatal development of the submandibular gland (SMG). Core binding factor β (Cbfb) is a cotranscription factor which forms a heterodimer with Runx proteins. Cbfb was specifically expressed in the duct epithelium, specifically in the SMG. Epithelial Cbfb deficiency resulted in decrease in the size of the SMG and in the saliva secretion on postnatal day 35. The Cbfb mutant SMG specifically exhibited involution of the granular convoluted tubules (GCT), with a down-regulated expression of its marker genes, such as Klk1, Ngf, and Egf. The induction of GCT is under the control of androgens, and the Cbfb mutant SMG demonstrated down-regulated expression of Crisp3, an androgen-dependent transcript. Because the circulating testosterone or tissue dihydrotestosterone levels were not affected in the Cbfb mutants, it appears that Runx/Cbfb signaling regulate androgen receptor pathway, but does not affect the circulating testosterone levels or the enzymatic conversion to DHT. Runx signaling is important in the postnatal development of androgen-dependent GCT in the SMG. ",0
5417,25411007,Complete genome sequence of a clinical Bordetella pertussis isolate from Brazil,"There has been a resurgence in the number of pertussis cases in Brazil and around the world. Here, the genome of a clinical Bordetella pertussis strain (Bz181) that was recently isolated in Brazil is reported. Analysis of the virulence-associated genes defining the pre- and post-vaccination lineages revealed the presence of the prn2-ptxS1A-fim3B-ptxP3 allelic profile in Bz181, which is characteristic of the current pandemic lineage. A putative metallo-β-lactamase gene presenting all of the conserved zinc-binding motifs that characterise the catalytic site was identified, in addition to a multidrug efflux pump of the RND family that could confer resistance to erythromycin, which is the antibiotic of choice for treating pertussis disease.  ",0
5418,25411121,Chronic elevation of systemic glucagon-like peptide-1 following surgical weight loss: association with nausea and vomiting and effects on adipokines,"We determined whether persistent nausea and vomiting (N/V) symptoms following Roux-en-Y gastric bypass surgery is due to elevated systemic glucagon-like peptide-1 (GLP-1) and leptin in female non-diabetic subjects. Subjects with N/V post-Roux-en-Y gastric bypass (RYGB) surgery had significantly elevated fasting GLP-1 levels compared to that with post-operative asymptomatic subjects and to morbidly obese, obese and lean subjects not undergoing surgery. Weight loss, glycaemia, insulin and post-prandial GLP-1 levels were similar in all post-operative subjects. Despite comparable BMI, leptin was significantly lower in symptomatic subjects. Furthermore, leptin secretion from subcutaneous adipose tissue was inhibited by GLP-1 (0.1-1.0 nM; n = 6). Persistent N/V following RYGB surgery is associated with elevated fasting GLP-1, but lower leptin levels. The latter may be a consequence of the direct GLP-1 inhibition of leptin secretion from adipose tissue. ",0
5419,25411188,Quantitative analysis of the cellular composition in seminiferous tubules in normal and genetically modified infertile mice,"The aim of this study was to establish a quantitative standard for the cellular composition in seminiferous tubules at each stage of spermatogenesis in the mouse testis, and thereby evaluate abnormalities in the infertile mouse testis. We applied a combination of lectin histochemistry for acrosomes and immunohistochemistry for various specific cell markers, both of which were visualized with fluorescence, on paraffin sections of the testis. We first examined seminiferous tubules from normal mice and counted the number of each cell type at each stage of spermatogenesis. We then examined seminiferous tubules from genetically modified mice deficient (-/-) for one of the cell adhesion molecules, nectin-2 or nectin-3, and compared the number of each cell type at each stage of spermatogenesis with the corresponding value in normal mice. In both nectin-2-/- and nectin-3-/- mice, which are infertile despite the apparently normal morphology of the seminiferous epithelia, we measured a progressive loss in the later-step spermatids, with significantly lower numbers of step 11-16 spermatids in nectin-3-/- mice and step 15-16 spermatids in nectin-2-/- mice as compared with that in normal control mice. The present study demonstrated that a quantitative analysis of cellular compositions at different stages in seminiferous tubules was useful for evaluating abnormalities in spermatogenesis. ",0
5420,25411511,"A Structural Approach to Establishing a Platform Chemistry for the Tunable, Bulk Electron Beam Cross-Linking of Shape Memory Polymer Systems","The synthetic design and thermomechanical characterization of shape memory polymers (SMPs) built from a new polyurethane chemistry that enables facile, bulk and tunable cross-linking of low-molecular weight thermoplastics by electron beam irradiation is reported in this study. SMPs exhibit stimuli-induced geometry changes and are being proposed for applications in numerous fields. We have previously reported a polyurethane SMP system that exhibits the complex processing capabilities of thermoplastic polymers and the mechanical robustness and tunability of thermomechanical properties that are often characteristic of thermoset materials. These previously reported polyurethanes suffer practically because the thermoplastic molecular weights needed to achieve target cross-link densities severely limit high-throughput thermoplastic processing and because thermally unstable radiation-sensitizing additives must be used to achieve high enough cross-link densities to enable desired tunable shape memory behavior. In this study, we demonstrate the ability to manipulate cross-link density in low-molecular weight aliphatic thermoplastic polyurethane SMPs ( ",0
5421,25412027,"Prevalence and reasons for initiating use of electronic cigarettes among adults in Montana, 2013","""We used data from the 2013 Montana Adult Tobacco Survey to estimate the prevalence of electronic cigarette (e-cigarette) use and reasons for initiation among Montana adults. More than 1 in 10 (11.2%, 95% confidence interval [CI], 9.1%-13.2%) adults reported ever using e-cigarettes, and 1.3% (95% CI, 0.7%-1.9%) reported current use. Most respondents reported """"trying something new"""" (64%) or """"trying to quit or reduce cigarette use"""" (56%) as a reason for initiating use. Ongoing surveillance of these addictive products is needed.  """,0
5422,25412219,Rapid immunoenzyme assay of aflatoxin B1 using magnetic nanoparticles,"The main limitations of microplate-based enzyme immunoassays are the prolonged incubations necessary to facilitate heterogeneous interactions, the complex matrix and poorly soluble antigens, and the significant sample dilutions often required because of the presence of organic extractants. This study presents the use of antibody immobilization on the surface of magnetic particles to overcome these limitations in the detection of the mycotoxin, aflatoxin B1. Features of the proposed system are a high degree of nanoparticle dispersion and methodologically simple immobilization of the antibodies by adsorption. Reactions between the immobilized antibodies with native and labeled antigens are conducted in solution, thereby reducing the interaction period to 5 min without impairing the analytical outcome. Adsorption of immunoglobulins on the surface of magnetic nanoparticles increases their stability in aqueous-organic media, thus minimizing the degree of sample dilution required. Testing barley and maize extracts demonstrated a limit of aflatoxin B1 detection equal to 20 pg/mL and total assay duration of 20 min. Using this method, only the 3-fold dilution of the initial methanol/water (60/40) extraction mixture in the microplate wells is necessary. The proposed pseudo-homogeneous approach could be applied toward immunodetection of a wide range of compounds.  ",0
5423,25412260,Endothelium trans differentiated from Wharton's jelly mesenchymal cells promote tissue regeneration: potential role of soluble pro-angiogenic factors,"Mesenchymal stem cells have a high capacity for trans-differentiation toward many adult cell types, including endothelial cells. Feto-placental tissue, such as Wharton's jelly is a potential source of mesenchymal stem cells with low immunogenic capacity; make them an excellent source of progenitor cells with a potential use for tissue repair. We evaluated whether administration of endothelial cells derived from mesenchymal stem cells isolated from Wharton's jelly (hWMSCs) can accelerate tissue repair in vivo. Mesenchymal stem cells were isolated from human Wharton's jelly by digestion with collagenase type I. Endothelial trans-differentiation was induced for 14 (hWMSC-End14d) and 30 (hWMSC-End30d) days. Cell phenotyping was performed using mesenchymal (CD90, CD73, CD105) and endothelial (Tie-2, KDR, eNOS, ICAM-1) markers. Endothelial trans-differentiation was demonstrated by the expression of endothelial markers and their ability to synthesize nitric oxide (NO). hWMSCs can be differentiated into adipocytes, osteocytes, chondrocytes and endothelial cells. Moreover, these cells show high expression of CD73, CD90 and CD105 but low expression of endothelial markers prior to differentiation. hWMSCs-End express high levels of endothelial markers at 14 and 30 days of culture, and also they can synthesize NO. Injection of hWMSC-End30d in a mouse model of skin injury significantly accelerated wound healing compared with animals injected with undifferentiated hWMSC or injected with vehicle alone. These effects were also observed in animals that received conditioned media from hWMSC-End30d cultures. These results demonstrate that mesenchymal stem cells isolated from Wharton's jelly can be cultured in vitro and trans-differentiated into endothelial cells. Differentiated hWMSC-End may promote neovascularization and tissue repair in vivo through the secretion of soluble pro-angiogenic factors. ",0
5424,25412614,Effects of depression co-morbidity and treatment on quality of life in patients with acute coronary syndrome: the Korean depression in ACS (K-DEPACS) and the escitalopram for depression in ACS (EsDEPACS) study,"Depression is common after acute coronary syndrome (ACS) with adverse effects on prognosis. There is little evidence on whether depression treatment improves quality of life (QoL) in ACS patients. The aim of this study was to investigate the effects of co-morbid depression and its treatment on QoL in ACS. In total, 1152 patients were recruited at baseline, 2-14 weeks after a confirmed ACS episode, and 828 were followed 1 year thereafter. Of 446 baseline participants with co-morbid depressive disorders, 300 were randomized to a 24-week double blind trial of escitalopram or placebo, while the remaining 146 received medical treatment only (MTO). QoL was measured by the World Health Organization Quality of Life -Abbreviated form (WHOQOL-BREF). At baseline, QoL was significantly lower in patients with co-morbid depressive disorder than those without. QoL improvement was significantly greater in those receiving escitalopram than those receiving placebo over the 24-week treatment period. In the 1-year follow-up, the better outcomes associated with escitalopram remained evident against both placebo and MTO. Depression was significantly associated with worse QoL even in patients with recently developed ACS. Depression treatment was associated with QoL improvement in ACS patients in the 24-week treatment period, the effects of which extended to 1 year. ",0
5425,25412625,"A multifunctional peptide based on the neutrophil immune defense molecule, CAP37, has antibacterial and wound-healing properties","CAP37, a protein constitutively expressed in human neutrophils and induced in response to infection in corneal epithelial cells, plays a significant role in host defense against infection. Initially identified through its potent bactericidal activity for Gram-negative bacteria, it is now known that CAP37 regulates numerous host cell functions, including corneal epithelial cell chemotaxis. Our long-term goal is to delineate the domains of CAP37 that define these functions and synthesize bioactive peptides for therapeutic use. We report the novel finding of a multifunctional domain between aa 120 and 146. Peptide analogs 120-146 QR, 120-146 QH, 120-146 WR, and 120-146 WH were synthesized and screened for induction of corneal epithelial cell migration by use of the modified Boyden chamber assay, antibacterial activity, and LPS-binding activity. In vivo activity was demonstrated by use of mouse models of sterile and infected corneal wounds. The identity of the amino acid at position 132 (H vs. R) was important for cell migration and in vivo corneal wound healing. All analogs demonstrated antimicrobial activity. However, analogs containing a W at position 131 showed significantly greater antibacterial activity against the Gram-negative pathogen Pseudomonas aeruginosa. All analogs bound P. aeruginosa LPS. Topical administration of analog 120-146 WH, in addition to accelerating corneal wound healing, effectively cleared a corneal infection as a result of P. aeruginosa. In conclusion, we have identified a multifunctional bioactive peptide, based on CAP37, that induces cell migration, possesses antibacterial and LPS-binding activity, and is effective at healing infected and noninfected corneal wounds in vivo.  ",0
5426,25412696,p62 Deficiency Enhances α-Synuclein Pathology in Mice,"In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regard to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbor of the brca1 gene (NBr1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 affect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.  ",0
5427,25412786,Current and future oral systemic therapies for psoriasis,"For patients with moderate to severe psoriasis, there is a large range of variably effective and safe oral, systemic medications. With appropriate monitoring, these therapies may be used as either monotherapy or in combination with other therapies. Newer drugs in the research pipeline hold significant promise.  ",0
5428,25412828,Cre-ativity in the liver: transgenic approaches to targeting hepatic nonparenchymal cells,"Rapid evolution in transgenic (Tg) mouse technology now permits cell-specific and temporal control of fluorescent cell-labeling and gene inactivation. Here, we discuss the principal strategies that have been utilized to target, label, and manipulate hepatic nonparenchymal cells, with emphasis on the utility of constitutive and inducible Cre-lox systems. We summarize key findings of studies employing Tg technology to target hepatic stellate cells, myofibroblasts, liver sinusoidal endothelial cells, and macrophages to illustrate the power of these approaches in identifying cell-specific molecular mechanisms critical to the pathophysiology of liver disease. Increasing adoption of Tg techniques will help to answer fundamental questions regarding the pathogenesis of hepatic diseases and provide the mechanistic rationale to allow identification of novel drug targets, ultimately translating into effective therapies for patients with liver disease.",0
5429,25413056,Preliminary screening of downstream proteins of Sox2 and role of Sox2 in colonic cancer cell migration and invasion],"To screen the down-stream proteins of transcription factor Sox2 and explore the role of Sox2 in the proliferation and migration of colonic cancer cells in vitro. The cellular proteins were separated by SDS-PAGE electrophoresis and stained with Coomassie blue and amine plated silver. The differentially expressed proteins was identified by mass spectrometry and verified by QPCR and Western blotting. A cell counting kit-8 (CCK8) assay was performed to evaluate the cell proliferation, and the cell migration was assessed using Transwell assay. S3a was identified by proteomics technology as a Sox2-downregulated protein while ENO1 and gama-actin the up-regulated proteins. QPCR and Western blotting analyses showed that overexpression of Sox2 significantly decreased the expression of S3a (P<0.005) and increased the expression of ENO1(P<0.05), but had no significant effect on gama-actin expression. Sox2 overexpression obviously promoted cell proliferation and migration (P<0.05), while inhibition of Sox2 produced contrary effects (P<0.05). Sox2 negatively regulates S3a expression and positively regulates ENO1 expression to promot the proliferation and migration of colonic cancer cells. ",0
5430,25413488,Organ procurement in forensic deaths: French developments,"Organ procurement and transplantation have grown steadily, and the need for organs will only rise in the future. Increasing the number of potential donors is therefore paramount. However, transplant coordination teams face refusals that can be linked to the contexts of the deaths, especially when they involve legal issues. In France, deaths involving legal proceedings are not uncommon (7-10%). In these cases, the prosecutor is immediately contacted, and makes the decision of whether to remove the involved organs. Refusals of this type represent 4% (approximately 30 cases per year) of obstacles to organ removals, and are governed by specific legislation. Thus, the prosecutor must arrange contact with a forensic pathologist and with the organ transplant teams to assemble all of the necessary elements for him to take the decision. To assist prosecutors in their decision making and to ensure them scientific rigour, the French Society of Forensic Medicine sought to develop a national recommendation to harmonise practices; it emerged in early 2013. The guideline makes practical recommendations, including among others: nominating local referents; writing regional protocols between judicial authorities, forensic pathologists and transplant teams; establishing terms for the forensic pathologist's intervention on the donor's body before and after a procurement. This recommendation by the French Society of Forensic Medicine aimed to combine two interests: addressing the shortage of organs, and fulfilling the requisites of a criminal investigation by standardising practices and encouraging communication.  ",0
5431,25413505,Title Maximizing sales of atypical antipsychotic drugs,"""A pharmaceutical firm that has an antidepressant is a happy one for 1/5 of the population is likely to consume it. A pharmaceutical firm that has an antipsychotic is less happy since the prevalence of schizophrenic and other psychotic disorders is stable, and averages around only 1-2%. However, between 1997 and 2007, the daily consumption of neuroleptic drugs has increased by 14% in Belgium! Whatcommunication strategies have been implemented to promote their sales? Four messages have been identified and examined: 1) These disorders are serious and require the systematic prescription of neuroleptics; 2) These are chronic disorders for which we must consider lifelong treatment, preferably as """"deposit""""; 3) schizophrenia, in particular, has a peak prevalence at 18: Young people should be monitored; 4) There are means of early detection of at-risk youth that must be addressed at this stage with neuroleptics. 1) YES these disorders are serious and require the prescription of neuroleptics, HOWEVER 2) At least 40% of patients do NOT display a chronic evolution and the """"deposit"""" forms should be reserved for certain situations; 3) YES, schizophrenia has a peak prevalence at 18, and young people must be monitored, However 4) Our ability to achieve pre-diagnosis is limited. If prescribing neuroleptic drugs to all at-risk youth might prevent the onset of the disorders, it would also result in prescribing them to some persons who do not need them two out of five times. From these four arguments, only one is valid whereas the remaining three are only partially valid; nevertheless, since the advent of second generation antipsychotic drugs, their consumption has increased by 14% in 10 years. """,0
5432,25413532,"""The Help-line """"Invito alla Vita"""": a new project for suicide prevention in Trentino region""","""""""Invito alla Vita"""" is a community-based suicide prevention project that officially started in Trentino in late 2008. The project was promoted by the local Health Services, trying from the beginning to involve other community subjects, and has been working over five years and a half in different directions, particularly promoting a phone help-line. The aims of the Invito alla Vita (IaV) Help Line have been clear from the beginning: decrease the sense of loneliness, offer encouragement and support, promote engagement with health services, reduce stigma and prejudice. Contrary to popular misconceptions, talking with people about suicide will not increase suicide risk, neither will it induce patients to commit suicide.The volunteers involved in the IaV help-line offer people empathic listening without judgment and easy tips, to reduce loneliness, sadness and supply reassurance that other people care. In this study we tried to deepen our knowledges about the volunteers' motivations and necessities to use them for creating a better system of support: we realized indeed that continuous training and supervision, along with official awards given by community institutions, are basic factors to sustain the volunteers' motives to cooperate with the help line.  """,0
5433,25413636,Depression in HIV infected patients: a review,"Depression is the most common neuropsychiatric complication in HIV-infected patients and may occur in all phases of the infection. Accurately, diagnosing major depressive disorder in the context of HIV is an ongoing challenge to clinicians and researchers, being complicated by the complex biological, psychological, and social factors associated with the HIV illness. Evidences exist to support the importance of improving the identification of depressive symptoms and their adequate treatment. Depression has long been recognized as a predictor of negative clinical outcomes in HIV-infected patients, such as reducing medication adherence, quality of life, and treatment outcome, and possibly worsening the progression of the illness and increasing mortality. By analyzing the most relevant studies (MEDLINE, EMBASE, PsycLit, Cochrane Library), the review discusses the epidemiology and the main clinical features of depression in HIV-infected patients, the causal pathways linking depression and HIV infection, the validity of screening tools, and the efficacy of different treatment approaches, including psychosocial interventions, psychopharmacology as well as HIV-specific health psychology health service models.  ",0
5434,25414109,Technical note: Evaluation of a real-time wireless pH measurement system relative to intraruminal differences of digesta in dairy cattle,"The aim of this study was to evaluate the accuracy and precision of indwelled wireless sensors relative to intrareticuloruminal differences in dairy cows transitioned from a forage to a high-concentrate diet. A feeding trial was performed with 8 rumen-cannulated Holstein cows. The cows were stepwise switched from 0 to 60% concentrate in the diet and fed 5 wk. Samples from the free ruminal liquid (FRL) from the ventral rumen and from the particle-associated ruminal liquid (PARL) in the rumen mat were manually taken at 0, 4, and 8 h after the morning feeding on d 0, 7, 14, and 34 of the experiment through the ruminal cannula to measure pH in FRL and PARL using a pH electrode. Additionally indwelling reticular wireless pH sensors were used to measure reticular pH every 10 min throughout the experiment. Precision and accuracy properties as a measure of reproducibility of the methods were statistically evaluated. Data showed significant differences among pH readings of indwelling sensors and pH measurements taken by means of a conventional electrode in both FRL and PARL (P<0.05). These differences became more evident when 60% concentrate diet was fed. Across all experimental days, the pH of the FRL was greatest and the pH reported by indwelling sensors intermediate, whereas the pH of PARL was lowest. The concordance correlation coefficient (CCC) analysis revealed a high agreement between indwelling sensors and FRL (CCC=0.709) but a low agreement with the pH of PARL (CCC=0.495). In conclusion, the study indicated that wireless sensors can satisfactorily reflect the pH of FRL but poorly reflect that of PARL. ",0
5435,25414377,Alabama Physicians and Accountable Care Organizations: Will What We Don't Know Hurt Us?,"Accountable care organizations (ACOs) were designed to improve the quality of care delivered to Medicare beneficiaries while also halting the growth in Medicare spending. Many existing health systems in the Northeast, Midwest, and West have formed ACOs, whereas implementation in Southern states has been slower. The study team conducted a survey of all physician members of the Medical Association of the State of Alabama to determine the likelihood of their participation in an ACO and their attitudes toward some of the characteristics, such as quality measures, regulations, and risks versus rewards. The team found that many physicians reported a lack of knowledge about these areas. Physicians who reported that they were either likely or not likely to participate overwhelmingly held unfavorable attitudes about ACOs. It would be advantageous for Alabama physicians to become more knowledgeable about ACOs in the case that they become a more predominant form of care delivery in the future.  ",0
5436,25414651,Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens,"Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions.  ",0
5437,25415068,Extracorporeal irradiation of tumorous calvaria: a case series,"OBJECT When intracranial tumors invade the overlying skull, gross resection typically includes removal of the involved bone. Methods used to repair the resulting structural defect in the cranium include artificial prostheses, allogeneic bone grafts, and autoclaving the autologous graft. The authors have previously reported a case involving high-dose extracorporeal ionizing radiation to treat the tumorous calvaria intraoperatively, followed by reimplantation of the treated bone flap. In this paper the authors report the long-term follow-up of that case, as well as results of using extracorporeal irradiation of tumorous calvaria (EITC) for an additional 20 patients treated similarly. METHODS The decision to undergo EITC was typically anticipated preoperatively, but determined intraoperatively, if upon inspection the bone flap was invaded by tumor. The bone flap was then delivered to the radiation oncology department, where a total dose of 120 Gy was delivered, using a clinical linear accelerator, over a period of approximately 15 minutes. After the intracranial tumor resection was completed, the irradiated craniotomy bone flap was reimplanted and the wound was closed in a standard fashion. A retrospective review of patients who had undergone EITC was performed for evidence of calvarial tumor recurrence or other complications. RESULTS Since the originally reported case, 20 additional patients have received EITC during craniotomy for invasive tumors. Eighteen (86%) of 21 patients were diagnosed with meningioma: 12 (67%) with WHO Grade I, 5 (28%) with WHO Grade II, and 1 with WHO Grade III (6%). The remaining 3 patients presented with dural-based B-cell lymphoma with extensive adjacent bone invasion (n = 2) and metastatic adenocarcinoma of the lung (n = 1). Follow-up of the 21 patients ranged from 1 to 132 months, with a mean of 41 months and a median of 23 months. No patients have experienced tumor recurrence, infection associated with the treated calvaria, or evidence of bone flap resorption. CONCLUSIONS Calvaria reconstructions represent an important component in structural and cosmetic outcome following craniectomy for tumorous bone. The authors' long-term experience with EITC has been excellent with no local tumor recurrence or complications. Therefore, EITC represents an excellent and efficient option for cranial reconstruction in such patients.  ",0
5438,25415094,Cleft care in international adoption,"Standards of cleft care abroad differ from those in the United States, particularly in less developed countries, where international adoption rates are high. Children adopted from these countries present to plastic surgeons in the United States at various ages and states of repair. The operative and perioperative needs of these children are poorly understood. This study attempts to characterize the preadoption history, the postadoption course, and surgical outcomes of children adopted with cleft deformities. The authors performed a retrospective review of all adopted cleft lip-cleft palate patients presenting to an academic craniofacial referral center and compared outcomes among adopted children who were repaired abroad, adopted children who underwent repair performed by the two senior authors (C.R.D. and S.B.B.), and children born in the United States who underwent repair performed by one of the senior authors (S.B.B.) : Between May of 1993 and August of 2010, 83 adopted children with cleft deformities were evaluated in the authors' craniofacial center. Average age at adoption was 30.5 months (range, 5.0 to 95.0 months). Comparing outcomes among adopted children repaired abroad, adopted children repaired by the senior authors, and children born in the United States who underwent repair in the United States, the authors found no statistically significant differences in lip revision rates, fistula rates, or velopharyngeal insufficiency. Adopted cleft patients constitute a complex and variable population with high rates of revision and delayed presentation. Internationally adopted children with orofacial clefts fared no better or worse after undergoing primary cleft repair abroad or in the United States. ",0
5439,25415521,Acute cervical segmental denervation in neuromyelitis optica spectrum disorder,"Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of central nervous system. We report a case of NMO spectrum disorder that developed acute cervical segmental denervation during an episode of transverse myelitis. Case report and a literature review. A 69-year-old woman presented with right leg weakness, which improved in 2 weeks of intravenous methylprednisolone. Six weeks later, she returned with recurrent transverse myelitis followed by left hand weakness and atrophy. Electromyography showed active denervation on left C8/T1-innervated muscles. Magnetic resonance imaging of thoracic spine showed patchy T2-signal enhancement from T10 to lower cervical spine. NMO antibody was positive. Review of literature revealed 5 cases of cervical transverse myelitis that developed denervation on electromyography. Segmental denervation may occur in NMO and variants resulting from severe myelitis extending to involve gray and white matter leads to anterior horn cell loss. ",0
5440,25415616,JAK inhibition and progressive kidney disease,"To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases. The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases. Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases. ",0
5441,25416171,A systematic review of the prevalence of nutrition labels and completeness of nutrient declarations on pre-packaged foods in China,"The Chinese government launched a voluntary nutrition labelling code in 2007 and made it mandatory since 1 January 2013. This article aims to quantify the prevalence of nutrition labels and the completeness of nutrient declarations on pre-packaged foods in China and to explore the impact of the 2007 code. A systematic search of the published and grey literature was done, and a random-effects meta-analysis was used to obtain summary estimates. There were 15 surveys identified from 13 reports. For 44% (95% confidence interval: 37-51%) of the 22 636 food items, the product label provided information on one or more nutrients. There was significant heterogeneity between the surveys (I(2) = 99%, P < 0.001) raising some uncertainty about the reliability of the estimate. The heterogeneity was in part explained by differences in labelling between food categories (P < 0.001) but not by changes in the prevalence of nutrition labels over time (P = 0.36). Most pre-packaged foods in this survey had a nutrition label non-compliant with current Chinese nutrition labelling standards. The voluntary code launched in 2007 had limited impact on nutrition labelling. There is significant scope for the recently introduced mandatory labelling requirements to improve nutrition labelling in China. ",0
5442,25416425,The degree of N-glycosylation affects the trafficking and cell surface expression levels of Kv1.4 potassium channels,"Kv1.4 potassium channels are heavily glycosylated proteins involved in shaping action potentials and in neuronal excitability and plasticity. Kv1.4 N354Q, without an N-glycan, exhibited decreased protein stability and trafficking to the cell surface (Watanabe et al. in J Biol Chem 279:8879-8885, 2004). Here we investigated whether the composition of the N-glycan affected Kv1.4 cell surface expression. Kv1.4 proteins carrying N-glycans with different compositions were generated by adding glycosidase inhibitors or using N-glycosylation-deficient mutant cell lines. We found that oligomannose-type, hybrid-type, or incomplete complex-type N-glycans had a negative effect on surface protein expression of Kv1.4 compared with complex-type N-glycans. The decrease in surface protein level of Kv1.4 was mainly due to a reduction in total protein level, induced by altered N-glycan composition. Kv1.4 in CSTP-treated cells carried a unique oligomannose-type N-glycan that contains three glucose residues. This N-glycan had the most negative effect on cell surface expression of Kv1.4. It decreased Kv1.4 surface protein level by a combined mechanism of reducing total protein level and increasing ER-retention. Our data suggest that composition of the N-glycan plays an important role in protein stability and trafficking, and a sialylated complex-type N-glycan promoted high cell surface expression of Kv1.4.  ",0
5443,25416470,Sudden death in a case of megalencephaly capillary malformation associated with a de novo mutation in AKT3,"Megalencephaly capillary malformation (MCAP) is a syndrome involving brain overgrowth, characterized by megalencephaly, capillary malformations, asymmetric growth, polymicrogyria, polydactyly, and syndactyly. Cerebellar tonsillar herniation (CTH) and ventriculomegaly are also observed in over half the patients with this syndrome. Early sudden death has been reported in MCAP, but its causes and the surgical strategies for its prevention remain unclear. Here, we report on a patient with MCAP who died suddenly at 5 months of age. He presented with progressive macrocephaly and hypotonia. MRI performed at 4 months of age showed tight posterior fossa, bilateral perisylvian polymicrogyria, enlargement of the straight sinus, and a thickened corpus callosum. However, since the patient did not exhibit capillary malformation, polydactyly, or syndactyly, a definitive diagnosis of MCAP could not be made. He died suddenly while asleep at home 1 month later. The sudden death of MCAP patients was previously attributed to CTH, convulsion, or arrhythmia. In this case, progressive cerebellar enlargement appeared to be the underlying cause. After the patient's death, using his preserved DNA, a missense mutation in the AKT3 gene was identified. Vakt murine thymoma viral oncogene homologue (AKT) is a serine-threonine kinase that functions in the mammalian target of rapamycin (mTOR) pathway and plays an important role in cell proliferation. Accurate early diagnosis, including imaging and genetic analyses, and the recognition and treatment of critical conditions are required to prevent the sudden death of patients with MCAP. ",0
5444,25416530,Trace element inhibition of phytase activity,"Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p < 0.001 was verified. The proteinate sources of OTMs were consistently and significantly less inhibitory than the majority of the other sources, p < 0.05. This was verified for Escherichia coli and Peniophora lycii phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.  ",0
5445,25416577,Is workplace health promotion research in the Nordic countries really on the right track?,"""The aims of this scoping review of research on workplace health promotion interventions in the Nordic countries were to investigate: how the studies defined health; whether the studies intended to change the workplace itself (the settings approach); and whether the research focus regarding their definitions of health and use of settings approaches has changed in the past five-year period versus previous times. Using scientific literature databases, we searched for intervention studies labelled as """"health promotion"""" in an occupational setting in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) published from 1986 to 2014. We identified 63 publications and qualitatively analysed their content regarding health outcomes and their use of settings approaches. The reviewed studies focused primarily on preventing disease rather than promoting positive measures of health. In addition, most studies did not try to change the workplace but rather used the workplace as a convenient setting for reaching people to change their behaviour related to lifestyles and disease prevention. Participatory and non-participatory settings approaches to promote well-being and other positive health measures have been used to a minor degree. The recent studies' definitions of health and use of settings approaches did not differ much from the studies published earlier. workplace health promotion in the nordic countries should more often include positive health measures and settings approaches in intervention research it is important to anchor workplace health promotion among important stakeholders such as unions and employers by arguing that sustainable production is dependent on workers' health. """,0
5446,25416654,The temporal crescent syndrome,"Retro-chiasmal lesions almost always give rise to homonymous field defects with only one exception. The nasal visual field extends to 60% of the horizon, whereas the temporal field extends to a further 30°-40° beyond that; this part of the visual field is represented on the contralateral anterior parieto-occipital sulcus. A lesion in this area will give rise to monocular visual field defect affecting the contralateral eye. This is called the temporal crescent or the half moon syndrome. In this case report, a woman presented with seizures secondary to haemorrhagic infarction of the anterior part of the parieto-occipital sulcus. She later presented with right-sided visual disturbance; her examination confirmed temporal crescent syndrome. I explain the pathophysiology of this rare neurological syndrome in this report.  ",0
5447,25416967,Differential pro-inflammatory responses of TNF-α receptors (TNFR1 and TNFR2) on LOX-1 signalling,"TNF-α potently induces LOX-1 expression in THP-1 macrophages at concentrations between 1.25-50 ng/mL. The interplay between the two TNF receptors (TNFR1 and TNFR2) was apparent in the expression pattern of LOX-1 in response to TNF-α. Interestingly, R1 signal abrogation depleted both TNFR2 as well as LOX-1 transcript expression, suggesting that TNFR1 holds priority in the relative signaling mechanism between TNFR1 and TNFR2. TNF-α was also found to abrogate the oxidized-LDL (ox-LDL) mediated increase in intracellular pool of NO, a known downstream intermediate of LOX-1 pro-inflammatory signaling cascade. At the level of ox-LDL clearance, TNF-α inhibited the uptake (scavenging) of ox-LDL via LOX-1. Our study demonstrates the ability of TNF-α to enhance the signaling propensity of LOX-1 by increasing its expression and inhibiting its scavenging property. ",0
5448,25417605,Validation of a chicken wing training model for endoscopic microsurgical dissection,"To determine if training with a chicken wing model improves performance of endoscopic endonasal surgery (EES) with microvascular dissection. Randomized experimental study. A single-blinded randomized clinical trial of trainees with various levels of endoscopic experience was conducted to determine if prior training on a nonhuman model augments endoscopic skill and efficiency in a surrogate model for live surgery. Medical students, residents, and fellows were randomized to two groups: a control group that performed an endoscopic transantral internal maxillary artery dissection on a silicone-injected anatomical specimen, and an interventional group that underwent microvascular dissection training on a chicken wing model prior to performing the anatomic dissection on the cadaver specimen. Time to completion and quality of dissection were measured. A Mann-Whitney test demonstrated a significant improvement in time and quality outcomes respectively across all interventional groups, with the greatest improvements seen in participants with less endoscopic experience: medical students (P = .032, P = .008), residents and fellows (P = .016, P = .032). Prior training on the chicken wing model improves surgical performance in a surrogate model for live EES. ",0
5449,25417615,"""The validity and reliability of """"The liver disease symptom index 2.0"""" for Turkish society""","Chronic liver diseases have been shown to adversely affect the quality of life. Standardized tools for patient assessment are of great importance for treatment and follow-up of these patients. In this study, we aimed to determine the validity and reliability of the Liver Symptom Index 2.0 (LDSI 2.0) for Turkish society, for use in other studies and in daily clinical practice. A total of 308 patients with chronic liver disease attending to the outpatient liver clinic of the Department of Gastroenterology, Faculty of Medicine, Dokuz Eylül University between September 2011 and May 2012 were included in this study. A sociodemographic data questionnaire, the LDSI 2.0 comprising 24 items, and the Short Form-36 (SF-36) were completed by the participating patients. After 6 weeks, these tools were re-administered to a total of 115 patients. After obtaining the required permissions, LDSI 2.0 was translated into Turkish using the translation/re-translation method. Of the 308 participants, 160 (51.9%) were male and 184 (43.1%) were female, with an average age of 48.67±13.31 years. Of all cases, 70.5% had viral hepatitis. The average Child-Pugh score was 5.9±1.2, and the average Model For End-Stage Liver Disease (MELD) score was 10.2±3.2. The assessment tool comprised the following sub-items: itching, joint pain, abdominal pain, sleepiness, worry, appetite, depression, fear, jaundice, memory, personality, financial status, use of time, sexual desire, and sexual activity. For more than 50% of the patients, worry (68.8%), depression (65.3%), joint pain (62.3%), itch (56.5%), sleepiness (54.2%), memory problems (53.6), and sexual problems (50%) were present. The internal coefficient of consistency (Cronbach alpha coefficient) was 0.908, which indicates a very high level of consistency. The correlation coefficient for the intraobserver test/re-test reliability was 0.746 (p<0.000), which denotes a significant and good level of reliability. The construct validity between each sub-item of the tool and sub-items of SF-36 was assessed using Spearman's correlation test, which showed a weak to moderate correlation (<0.04 and 0.4-0.7) in the reverse direction. Our study findings provide supportive evidence of the reliability of the assessment tool. Its validity is similar to the original construct validity and was confirmed in our sample. Therefore, it was concluded that LDSI 2.0 was an appropriate tool for daily clinical use and research purposes. Simultaneous use of this life-quality assessment tool and SF-36 will enable a comprehensive but practical assessment of our patients. ",0
5450,25418113,Systematic prediction of drug combinations based on clinical side-effects,"Drug co-prescription (or drug combination) is a therapeutic strategy widely used as it may improve efficacy and reduce side-effect (SE). Since it is impractical to screen all possible drug combinations for every indication, computational methods have been developed to predict new combinations. In this study, we describe a novel approach that utilizes clinical SEs from post-marketing surveillance and the drug label to predict 1,508 novel drug-drug combinations. It outperforms other prediction methods, achieving an AUC of 0.92 compared to an AUC of 0.69 in a previous method, on a much larger drug combination set (245 drug combinations in our dataset compared to 75 in previous work.). We further found from the feature selection that three FDA black-box warned serious SEs, namely pneumonia, haemorrhage rectum, and retinal bleeding, contributed mostly to the predictions and a model only using these three SEs can achieve an average area under curve (AUC) at 0.80 and accuracy at 0.91, potentially with its simplicity being recognized as a practical rule-of-three in drug co-prescription or making fixed-dose drug combination. We also demonstrate this performance is less likely to be influenced by confounding factors such as biased disease indications or chemical structures.  ",0
5451,25418293,Molecular determinants of mechanical properties of V. cholerae biofilms at the air-liquid interface,"Biofilm formation increases both the survival and infectivity of Vibrio cholerae, the causative agent of cholera. V. cholerae is capable of forming biofilms on solid surfaces and at the air-liquid interface, termed pellicles. Known components of the extracellular matrix include the matrix proteins Bap1, RbmA, and RbmC, an exopolysaccharide termed Vibrio polysaccharide, and DNA. In this work, we examined a rugose strain of V. cholerae and its mutants unable to produce matrix proteins by interfacial rheology to compare the evolution of pellicle elasticity in real time to understand the molecular basis of matrix protein contributions to pellicle integrity and elasticity. Together with electron micrographs, visual inspection, and contact angle measurements of the pellicles, we defined distinct contributions of the matrix proteins to pellicle morphology, microscale architecture, and mechanical properties. Furthermore, we discovered that Bap1 is uniquely required for the maintenance of the mechanical strength of the pellicle over time and contributes to the hydrophobicity of the pellicle. Thus, Bap1 presents an important matrix component to target in the prevention and dispersal of V. cholerae biofilms.  ",0
5452,25418352,Impacts of anastomotic complications on the health-related quality of life after esophagectomy,"Health-related quality of life (HRQL) is of great importance in cancer management. The aim was to identify factors that influence postoperative HRQL in esophageal carcinoma patients. A prospective cohort study was conducted to enroll 196 patients with esophageal carcinoma from November 2012 to June 2013. Sociademographic and clinicopathological parameters were recorded in detail. EORTC-QLQ C30 and ES18 were used to assess HRQL before surgery, at discharge, 1 and 6 months after discharge. Logistic regression models were used to identify factors independently influencing quality of life at 6 months after discharge. HRQL dramatically decreased after esophagectomy, but restored within 6 months in the most scales. Multivariate logistic regression analysis showed that gender (P = 0.002) and anastomotic stricture (P = 0.001) were the independent predictors of poor global quality-of-life 6 months after discharge. Anastomotic stricture occurred in 22 patients (11.2%), and their performance in social function (P = 0.04), problems with eating (P = 0.006), choking when swallowing (P < 0.001) were significantly poorer at 6 months after discharge. There were not significant differences in global quality-of-life between patients with and without anastomotic leakage at three postoperative assessments. Postoperative HRQL is restored within 6 months after discharge. Occurrence of anastomotic stricture significantly decreases HRQL after esophagectomy. ",0
5453,25418484,"Body mass index, waist-to-hip ratio, waist circumference and waist-to-height ratio cannot predict male semen quality: a report of 1231 subfertile Chinese men","There were controversial results between obesity-associated markers and semen quality. In this study, we investigated the correlations between age, obesity-associated markers including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and waist circumference (WC), the combination of age and obesity-associated markers, semen parameters and serum reproductive hormone levels in 1231 subfertile men. The results showed that BMI, WC, WHR and WHtR were positively related to age, and there were also positive relations between BMI, WHR, WC and WHtR and between sperm concentration (SC), total sperm count (TSC), progressive motility (PR), sperm motility and per cent of normal sperm morphology (NSM). However, age, each of obesity-associated markers and the combination of obesity-associated markers and age were unrelated to any of semen parameters including total normal-progressively motile sperm count (TNPMS). Age, BMI, WHR, WC and WHtR were negatively related to serum testosterone and SHBG levels. However, only serum LH and FSH levels were negatively related to sperm concentration, NSM and sperm motility. In a conclusion, although age and obesity have significant impacts on reproductive hormones such as testosterone, SHBG and oestradiol, semen parameters related to FSH and LH could not be influenced, indicating that obesity-associated markers could not predict male semen quality. ",0
5454,25418592,Having a child and PND/PGD access in women with a BRCA1/2 mutation? Different approach whether ill or healthy],"Genetic tests in families with a mutation related to breast and ovarian cancers (BRCA1/2) are now offered to the persons before completion of their reproductive project. The aim of this qualitative study was to descriptively explore how the issues of reproduction are faced in women belonging to these families, and how the possible use of prenatal diagnostic (PND) and preimplantation genetic diagnosis (PGD) would be faced in a theoretical context. We conducted in-depth interviews, face to face, according to the so-called Grounded Theory approach. Twenty women with a BRCA genetic mutation participated in the study (age range: 31-57 years); 12 have had a breast and/or ovarian cancer. The knowledge of having the mutation did not modify the parental project; however prophylactic anexectomy was likely to alter it in some women. If the majority of women were in favor of PGD (n = 14), medical termination of pregnancy was a constraint towards the position in relation to PND. Besides ethical and moral arguments, the women's attitudes were constructed differently according to their own personal or familial experience of the disease. The women's perceptions of the cancer severity, risk and cure were organized according to this experience. ",0
5455,25418762,Discrepancies in quantitative assessment of normal and regenerated peripheral nerve fibers between light and electron microscopy,"Quantitative estimation of myelinated nerve fiber number, together with fiber size parameters, is one of the most important tools for nerve regeneration research. In this study we used a design-based stereological method to evaluate the regenerative process in two experimental paradigms: crush injury and autograft repair. Samples were embedded in resin and morphometric counting and measurements were performed using both light and electron microscopes. Results show a significant difference in myelinated fiber number estimation between light and electron microscopes, especially after autograft repair; light microscope significantly underestimates the number of fibers because of the large number of very small axons that can be detected only in electron microscope. The analysis of the size parameters also shows a higher number of small fibers in electron microscopic analysis, especially in regenerated nerves. This comparative study shows that the integration of data obtained in light microscope with those obtained in electron microscope is necessary in revealing very small myelinated fibers that cannot be detected otherwise. Moreover, the difference in the estimation of total number of myelinated fibers between light and electron microscopes must be considered in data analysis to ensure accurate interpretation of the results.  ",0
5456,25419252,Stroke: bowel dysfunction in patients admitted for rehabilitation,"to assess the prevalence of diminished frequency of bowel movements, lumpy or hard stools, intestinal constipation, straining, incomplete evacuation, incontinence (bowel dysfunctions) in patients with brain injury resulting from cerebrovascular accident, either self-reported or reported by their caregivers; to describe the type and frequency of such dysfunctions; and the prevalence of laxative use both before and after stroke. cross-sectional study with 98 hospitalized patients admitted for rehabilitation between December 2009 and May 2010. the prevalence of bowel dysfunctions before stroke was 23.96% whereas after the lesion it was 55.21% (p<0.0001). As reported by patients/caregivers, the chances of developing bowel dysfunctions increase sevenfold after stroke, 95% CI (2.44-24.26). The most frequent dysfunctions before stroke were intestinal constipation (73.91%) and diminished frequency of bowel movements (17.39%). After stroke, constipation remains to be the most frequent dysfunction reported (50%), followed by diminished frequency of bowel movements (26.79%), incomplete evacuation (12.50%), and lack of privacy (5.36%). The use of laxatives was 19,15% after the lesion, but not statisticaly significant (p=0.0736). Bowel dysfunctions increases significantly after stroke. Therefore, further studies are needed to better understand and characterize such dysfunctions, which are scarcely described in the literature. ",0
5457,25419380,Does early use of bilevel positive airway pressure (bipap) in cardiothoracic intensive care unit prevent reintubation?,"Non-invasive ventilation (NIV) is a preferred treatment in acute respiratory failure after operations. Our aim is to investigate the success of early use of bilevel positive airway pressure (BIPAP) after cardiac or thoracic surgeries to prevent reintubation. In a prospective randomized study, 254 patients were divided into two groups depending on the time period between extubation and the application of BIPAP. In Group 1 BIPAP was applied after extubation within 48 hours after surgery following fulfilling of acute respiratory failure criterias whereas, in Group 2, BIPAP was applied one hour after extubation for two episodes of 20 minute duration and 3 hours apart. Arterial blood gas values (pH, PaO2, PaCO2) at first and fourth hour after BIPAP were collected. In comparison between groups, no significant differences were observed for arterial blood gas values of pH and PaCO2 at baseline, one and four hours after BIPAP (p > 0.05) however, the PaO2 values at one and four hours after BIPAP were significantly better in Group 1 in comparison to Group 2 (p < 0.001, p < 0.001; respectively). Reintubation rate was 14 patients (11%) in Group 1 and 7 patients (5.5%) in Group 2 (p = 0.103). The early and prophylactic use of BIPAP after cardiac or thoracic operations did not provide diminished rates in the postoperative complications such as reintubation. ",0
5458,25419457,Bioinspired amphiphilic phosphate block copolymers as non-fluoride materials to prevent dental erosion,"Inspired by the fact that certain natural proteins, e.g. casein phosphopeptide or amelogenin, are able to prevent tooth erosion (mineral loss) and to enhance tooth remineralization, a synthetic amphiphilic diblock copolymer, containing a hydrophilic methacryloyloxyethyl phosphate block (MOEP) and a hydrophobic methyl methacrylate block (MMA), was designed as a novel non-fluoride agent to prevent tooth erosion under acidic conditions. The structure of the polymer, synthesized by reversible addition-fragment transfer (RAFT) polymerization, was confirmed by gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). While the hydrophilic PMOEP block within the amphiphilic block copolymer strongly binds to the enamel surface, the PMMA block forms a hydrophobic shell to prevent acid attack on tooth enamel, thus preventing/reducing acid erosion. The polymer treatment not only effectively decreased the mineral loss of hydroxyapatite (HAP) by 36-46% compared to the untreated control, but also protected the surface morphology of the enamel specimen following exposure to acid. Additionally, experimental results confirmed that low pH values and high polymer concentrations facilitate polymer binding. Thus, the preliminary data suggests that this new amphiphilic diblock copolymer has the potential to be used as a non-fluoride ingredient for mouth-rinse or toothpaste to prevent/reduce tooth erosion. ",0
5459,25419507,Ischemia/reperfusion Injury and its Consequences on Immunity and Inflammation,"Ischemia/reperfusion injury (IRI), an inherent component of transplantation, affects organ quality and transplant outcomes. Although the complexity of the pathophysiology is recognized, detailed mechanisms remain unclear, and strategies preventing the consequences of IRI have been challenging. Of critical significance appears the link between IRI, the initiation of innate immune responses, and the (potential) augmentation of adaptive immunity. An improved understanding of those complex mechanisms and interactions may pave the way for more effective treatment strategies. ",0
5460,25419509,Proximity Does Not Equal Access: Racial Disparities in Access to High Quality Dialysis Facilities,"For patients receiving hemodialysis, distance to their dialysis facility may be particularly important due to the need for thrice weekly dialysis. We sought to determine whether African-Americans and Whites differ in proximity and access to high quality dialysis facilities. We analyzed urban, Whites and African-Americans aged 18-65 receiving in-center hemodialysis linked to data on neighborhood and dialysis facility quality measures. In multivariable analyses, we examined the association between individual and neighborhood characteristics, and our outcomes: distance from home zip code to nearest dialysis facility, their current facility and the nearest high quality facility, as well as likelihood of receiving dialysis in a high quality facility. African-Americans lived a half mile closer to a dialysis facility (B=-0.52) but traveled the same distance to their own dialysis facility compared to Whites. In initial analysis, African-Americans are 14% less likely than their White counterparts to attend a high quality dialysis facility (OR 0.86); and those disparities persist, though are reduced, even after adjusting for region, neighborhood poverty and percent African-American. In predominately African-American neighborhoods, individuals lived closer to high quality facilities (B=--5.92), but were 53% less likely to receive dialysis there (OR 0.47, highest group versus lowest, p<0.05). Living in a predominately African-American neighborhood explains 24% of racial disparity in attending a high quality facility. African-Americans' proximity to high quality facilities does not lead to receiving care there. Institutional and social barriers may also play an important role in where people receive dialysis. ",0
5461,25419726,The promise of science-based training and application in psychological clinical science,"Baker, McFall, and Shoham (2008) analyzed and critiqued the state of training in clinical psychology, asserting that much of this training is not sufficiently influenced by science. They asserted that the emergent demands of health care, with its attendant costs and resource constraints, require that mental and behavioral health care become increasingly efficient, effective, and cost-effective. Baker et al. (2008) then offered examples of how science-based evidence and methods could influence training in clinical psychology to achieve those goals. Laska, Gurman, and Wampold (2014, pp. 467-481) critiqued aspects of the Baker et al. (2008) paper. In the current paper, we argue that Laska et al. (2014) misconstrued points made in the early Baker paper. We also assert that evidence of common factors in psychological interventions is in no way antithetical or problematic to a science-based approach to clinical training and application. Further, we argue for a multidimensional approach to evaluating intervention performance, one that involves an evaluation of efficacy, effectiveness, cost-effectiveness, translation potential, and so on. Finally, we discuss how researchers can most efficiently develop intervention methods and delivery systems that are superior to the induction of common factors per se. ",0
5462,25420711,"Trends and educational differences in non-communicable disease risk factors in Pitkäranta, Russia, from 1992 to 2007","Mortality and morbidity from non-communicable diseases (NCDs) is a major public health problem in Russia. The aim of the study was to examine trends and educational differences from 1992 to 2007 in NCD risk factors in Pitkäranta in the Republic of Karelia, Russia. Four cross-sectional population health surveys were carried out in the Pitkäranta region, Republic of Karelia, Russia, in 1992, 1997, 2002, and 2007. An independent random sample of 1000 persons from the general population aged 25-64 years was studied in each survey round. The total number of respondents in the four surveys was 2672. The surveys included a questionnaire, physical measurements, and blood sampling, and they were carried out following standard protocols. The NCD risk factor trends generally increased in Pitkäranta during the study period with the exception of systolic blood pressure and smoking among men. Especially significant increases were observed in alcohol consumption among both sexes and in smoking among women. Educational differences and differences in trends were relatively small with the exception of a significant increase in smoking in the lowest female educational category. Trends showing an increase in some major NCD risk factors and signs of emerging socio-economic differences call for stronger attention to effective health promotion and preventive policies in Russia. ",0
5463,25420790,The Leaflex™ Catheter System - a viable treatment option alongside valve replacement? Preclinical feasibility of a novel device designed for fracturing aortic valve,"""To demonstrate the feasibility of the Leaflex™ Catheter System, a novel percutaneous device for fracturing valve calcification using mechanical impact in order to regain leaflet mobility. Radiographic analysis of calcium patterns in 90 ex vivo human aortic valve leaflets demonstrated that 82% of leaflets had a typical """"bridge"""" or """"half-bridge"""" pattern, which formed the basis for the catheter design. The therapeutic effect was quantified in 13 leaflets showing a reduction of 49±16% in leaflet resistance to folding after treatment. A pulsatile flow simulator was then used with 11 ex vivo valves demonstrating an increase in aortic valve area of 35±12%. Using gross pathology and histology on fresh calcified leaflets, we then verified that mechanical impacts do not entail excessive risk of embolisation. In vivo safety and usability were then confirmed in the ovine model. We demonstrated preclinically that it is feasible to improve valve function using the Leaflex™ technology. Once demonstrated clinically, such an approach may have an important role as preparation for or bridging to TAVI, as destination treatment for patients where TAVI is clinically or economically questionable and, in the future, maybe even as a means to slow disease progression in asymptomatic patients. """,0
5464,25421114,X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis,"X-linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β-thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild-moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis. ",0
5465,25421146,Calcareous sponge genomes reveal complex evolution of α-carbonic anhydrases and two key biomineralization enzymes,"Calcium carbonate biominerals form often complex and beautiful skeletal elements, including coral exoskeletons and mollusc shells. Although the ability to generate these carbonate structures was apparently gained independently during animal evolution, it sometimes involves the same gene families. One of the best-studied of these gene families comprises the α- carbonic anhydrases (CAs), which catalyse the reversible transformation of CO2 to HCO3 - and fulfill many physiological functions. Among Porifera -the oldest animal phylum with the ability to produce skeletal elements- only the class of calcareous sponges can build calcitic spicules, which are the extracellular products of specialized cells, the sclerocytes. Little is known about the molecular mechanisms of their synthesis, but inhibition studies suggest an essential role of CAs. In order to gain insight into the evolution and function of CAs in biomineralization of a basal metazoan species, we determined the diversity and expression of CAs in the calcareous sponges Sycon ciliatum and Leucosolenia complicata by means of genomic screening, RNA-Seq and RNA in situ hybridization expression analysis. Active biomineralization was located with calcein-staining. We found that the CA repertoires of two calcareous sponge species are strikingly more complex than those of other sponges. By characterizing their expression patterns, we could link two CAs (one intracellular and one extracellular) to the process of calcite spicule formation in both studied species. The extracellular biomineralizing CAs seem to be of paralogous origin, a finding that advises caution against assuming functional conservation of biomineralizing genes based upon orthology assessment alone. Additionally, calcareous sponges possess acatalytic CAs related to human CAs X and XI, suggesting an ancient origin of these proteins. Phylogenetic analyses including CAs from genomes of all non-bilaterian phyla suggest multiple gene losses and duplications and presence of several CAs in the last common ancestor of metazoans. We identified two key biomineralization enzymes from the CA-family in calcareous sponges and propose their possible interaction in spicule formation. The complex evolutionary history of the CA family is driven by frequent gene diversification and losses. These evolutionary patterns likely facilitated the numerous events of independent recruitment of CAs into biomineralization within Metazoa. ",0
5466,25421375,Study of the enantioseparation capability of chiral dual system based on chondroitin sulfate C in CE,"It has been reported that chiral dual system is able to improve the enantioseparation of enantiomers in many cases. Currently, the dual systems involved in CE chiral separation are mostly dual CDs systems, and the polysaccharides-based chiral dual system was reported in only one paper. To the best of our knowledge, the use of chondroitin sulfate C (CSC)-based dual system for enantiomeric separation has not been reported previously. Herein, four CSC-based chiral dual systems, namely CSC/glycogen, CSC/chondroitin sulfate A (CSA), CSC/hydroxypropyl-β-CD (HP-β-CD), as well as CSC/β-CD (β-CD), were evaluated for the first time for their enantioseparation capability by CE in this paper. During the course of the work, the influences of chiral selector concentration and buffer pH values on enantioseparation in dual systems were systematically investigated. Under the optimized conditions, the dual system consisting of CSC and glycogen exhibited better separations toward nefopam, duloxetine, sulconazole, atenolol, laudanosine, and cetirizine enantiomers compared to the single CSC or glycogen system. The combination of CSC and HP-β-CD improved the separation of amlodipine and chlorphenamine enantiomers. However, no synergistic effect was observed in the CSC/CSA and CSC/β-CD systems.  ",0
5467,25421438,A new chromene from the fruiting bodies of Chroogomphus rutilus,"A new chromene, acetic acid 2R-(4,8-dimethylnona-3,7-dienyl)-8-hydroxy-2-methyl-2H-chromen-6-yl ester (1), was isolated from the fruiting bodies of Chroogomphus rutilus, together with six known compounds (2-7). The structures of these compounds were identified based on 1D and 2D NMR, including (1)H-(1)H COSY, HMQC and HMBC spectroscopic methods. Of these seven compounds, 2 and 3 showed cytotoxicity against HSC-T6, SK-Hep1 and A549 cell lines.  ",0
5468,25421567,The process of engaging members from two underserved populations in the development of interventions to promote the uptake of the HPV vaccine,"We describe a community-engaged research process used to develop multilevel interventions (caregivers, providers, system) to improve the uptake of human papillomavirus vaccine among adolescents by partnering with members from two underserved populations in Ohio. We began by conducting focus groups to better understand the knowledge and attitudes of caregivers and providers about the human papillomavirus vaccine and to develop teams of community members to assist with development of the interventions. The process continued with conducting writing sessions to determine the content and format of the interventions, and initial feedback was obtained during review sessions to refine the interventions prior to implementation. Using this approach, we were able to consider contextual factors that made the interventions more acceptable and relevant to members of the priority populations. Challenges included development and maintenance of a team of community members to participate in the entire intervention development process, rejection of ideas presented by academic researchers, the need to balance community members' suggestions with what was known from evidence-based research, and the time, cost, and effort associated with partnering with community members. The benefits, however, outweigh the challenges associated with using a community-engaged research process to develop interventions aimed at reducing cancer disparities among underserved populations.  ",0
5469,25421629,Effect of ethanol and methanol on growth of ruminal bacteria Selenomonas ruminantium and Butyrivibrio fibrisolvens,"The effect of ethanol and methanol on growth of several ruminal bacterial strains was examined. Ethanol concentrations as low as 0.2% had a significant, but moderate, inhibitory effect on lag time or growth over time and 3.3% ethanol significantly inhibited maximum optical density obtained by both Selenomonas ruminantium and Butyrivibrio fibrisolvens. Little growth of either strain occurred at 10% ethanol concentrations. Methanol concentrations below 0.5% had little effect on either growth or maximum optical density of Selenomonas ruminantium whereas methanol concentrations below 3.3% had little effect on growth or maximum optical density of Butyrivibrio fibrisolvens. Higher methanol concentrations increasingly inhibited growth of both strains and no growth occurred at a 10% methanol concentration. Concentrations of ethanol or methanol used to add hydrophobic compounds to culture media should be kept below 1%.  ",0
5470,25421678,Detection of circulatory microRNAs in prostate cancer,"Prostate cancer (PCa) is one of the most common cancer worldwide and accounts for 14.4 % of all new cancer cases. The clinical outcome and management of PCa can be significantly improved by use of biomarker assays for early detection, prognosis and also for prediction and monitoring of treatment response. MiRNAs are short, endogenous, single-stranded RNA molecules that play important role in regulation of gene expression and can modulate a number of cellular processes. Discovery of miRNAs in circulation has not only facilitated understanding their role in various diseases but also paved new avenues for biomarker discovery due to their ease of access and stability. The fact that a minimally invasive test based on miRNAs profiles can distinguish the presence or absence of disease illustrates immense potential of these molecules as predictive biomarkers.In this chapter, we have summarized the presumed mechanisms of miRNA release into the circulation and systematically summarized the studies of circulatory miRNAs in PCa. Also, we have mainly focused on the methodology of identification of circulatory miRNAs from biofluids.  ",0
5471,25421683,Promoter hypermethylation as a biomarker in prostate adenocarcinoma,"There is increasing evidence that DNA methylation is a critical source of gene regulation. In addition, interindividual differences in DNA methylation status in cancer related genes are associated with risk and progression of prostate cancer. Therefore, DNA methylation in cancer related genes can be potential biomarkers and therapeutic targets for prostate cancer.In this chapter, current information on frequently hypermethylated genes associated with the carcinogenesis and progression of prostate cancer was updated. The potential biological role of hypermethylated genes in prostate cancer is discussed. These findings may provide new information of the pathogenesis, the exciting potential to be predictive and to provide strategies for personalized treatment of prostate cancer.  ",0
5472,25421715,Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin,"Cells cope with replication-blocking lesions via translesion DNA synthesis (TLS). TLS is carried out by low-fidelity DNA polymerases that replicate across lesions, thereby preventing genome instability at the cost of increased point mutations. Here we perform a two-stage siRNA-based functional screen for mammalian TLS genes and identify 17 validated TLS genes. One of the genes, NPM1, is frequently mutated in acute myeloid leukaemia (AML). We show that NPM1 (nucleophosmin) regulates TLS via interaction with the catalytic core of DNA polymerase-η (polη), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of polη. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in ~30% of AML patients results in excessive degradation of polη. These results establish the role of NPM1 as a key TLS regulator, and suggest a mechanism for the better prognosis of AML patients carrying mutations in NPM1.  ",0
5473,25421731,On the use of tert-butanol/water cosolvent systems in production and freeze-drying of poly-ε-caprolactone nanoparticles,"This work deals with the use of a water/tert-butyl alcohol (TBA) system in the manufacturing process of poly-ε-caprolactone (PCL) nanoparticles, namely in the synthesis stage, using the solvent displacement method in a confined impinging jet mixer (CIJM), and in the following freeze-drying stage. The experimental investigation evidenced that the nanoparticles size is significantly reduced with respect to the case where acetone is the solvent. Besides, the solvent evaporation step is not required before freeze-drying as TBA is fully compatible with the freeze-drying process. The effect of initial polymer concentration, flow rate, water to TBA flow rate ratio, and quench volumetric ratio on the mean nanoparticles size was investigated, and a simple equation was proposed to relate the mean nanoparticles size to these operating parameters. Then, freeze-drying of the nanoparticles suspensions was studied. Lyoprotectants (sucrose and mannitol) and steric stabilizers (Cremophor EL and Poloxamer 388) have to be used to avoid nanoparticles aggregation, thus preserving particle size distribution and mean nanoparticles size. Their effect, as well as that of the heating shelf temperature, has been investigated by means of statistical techniques, with the goal to identify which of these factors, or combination of factors, plays the key role in the nanoparticles size preservation at the end of the freeze-drying process. ",0
5474,25421836,Identification of Chlamydiae and Mycoplasma species in ruminants with ocular infections,"Infectious keratoconjunctivitis (IKC) is a highly contagious ocular inflammatory condition, which is often reported in domestic small and large ruminants. Multiple infectious aetiologies are reported to be involved, but information about the role of certain fastidious bacterial pathogens such as chlamydiae and mycoplasmas is limited in India. Hence, this study was performed to determine the role of these pathogens and their identification by molecular approach. A total of 53 samples from 31 ovine, 14 caprine and eight bovine having clinical symptoms were collected and tested using species-specific PCR tests for chlamydiae and mycoplasmas followed by nucleotide sequence analysis. The results showed 77.41, 14.29 and 25% samples were chlamydiae positive in ovine, caprine and bovine, respectively, whereas 41.93, 14.29 and 37.5% prevalence of mycoplasma infection was detected in ovine, caprine and bovines, respectively. Chlamydophila abortus, Chlamydophila psittaci, Mycoplasma arginini and Mycoplasma hyorhinis were detected from tested samples. To the best of our knowledge, this is the first time these species are identified in IKC cases from India. Coinfection of both chlamydial and mycoplasmal species was detected in eight IKC cases of ovine which suggest synergistic roles played by both chlamydiae and mycoplasma in IKC samples. ",0
5475,25422190,Analysis of the biological function of ELDF15 using an antisense recombinant expression vector,"ELDF15, homologous with AT2 receptor-interaction protein 1 (ATIP1), may play an important role in cell differentiation, proliferation, and carcinogenesis. We aimed to understand the biological function of ELDF15 via construction and transfection of a recombinant expression vector containing antisense ELDF15. Recombinant expression vectors were successfully constructed and transfected into K562 cells. A stable transfectant, known as pXJ41-asELDF15, stably produced antisense ELDF15. Compared with K562 and K562-zeo cells, K562- pXJ41-asELDF15 cells showed inhibition of cell proliferation. RT-PCR analysis showed that the expression and protein level of ELDF15 decreased significantly in K562 cells transfected with pXJ41-asELDF15. Expression of hemoglobin increased in K562 cells transfected with pXJ41-asELDF15 by benzidine staining. increases NBT reduction activity in K562 cells transfected with pXJ41-asELDF15.Colony forming efficiency in two-layer soft agar was clearly inhibited as assessed by electron microscopy. These results suggest that ELDF15 plays a potential role in cell differentiation, proliferation and carcinogenesis.  ",0
5476,25422302,Bordetella parapertussis PagP mediates the addition of two palmitates to the lipopolysaccharide lipid A,"Bordetella bronchiseptica PagP (PagPBB) is a lipid A palmitoyl transferase that is required for resistance to antibody-dependent complement-mediated killing in a murine model of infection. B. parapertussis contains a putative pagP homolog (encoding B. parapertussis PagP [PagPBPa]), but its role in the biosynthesis of lipid A, the membrane anchor of lipopolysaccharide (LPS), has not been investigated. Mass spectrometry analysis revealed that wild-type B. parapertussis lipid A consists of a heterogeneous mixture of lipid A structures, with penta- and hexa-acylated structures containing one and two palmitates, respectively. Through mutational analysis, we demonstrate that PagPBPa is required for the modification of lipid A with palmitate. While PagPBB transfers a single palmitate to the lipid A C-3' position, PagPBPa transfers palmitates to the lipid A C-2 and C-3' positions. The addition of two palmitate acyl chains is unique to B. parapertussis. Mutation of pagPBPa resulted in a mutant strain with increased sensitivity to antimicrobial peptide killing and decreased endotoxicity, as evidenced by reduced proinflammatory responses via Toll-like receptor 4 (TLR4) to the hypoacylated LPS. Therefore, PagP-mediated modification of lipid A regulates outer membrane function and may be a means to modify interactions between the bacterium and its human host during infection. ",0
5477,25422415,Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis,"""The role of cell-free extracellular matrix (ECM) in triggering tissue and organ regeneration has gained increased recognition, yet current approaches are predominantly based on the use of ECM from fully developed native tissues at nonhomologous sites. We describe a strategy to generate customized ECM, designed to activate endogenous regenerative programs by recapitulating tissue-specific developmental processes. The paradigm was exemplified in the context of the skeletal system by testing the osteoinductive capacity of engineered and devitalized hypertrophic cartilage, which is the primordial template for the development of most bones. ECM was engineered by inducing chondrogenesis of human mesenchymal stromal cells and devitalized by the implementation of a death-inducible genetic device, leading to cell apoptosis on activation and matrix protein preservation. The resulting hypertrophic cartilage ECM, tested in a stringent ectopic implantation model, efficiently remodeled to form de novo bone tissue of host origin, including mature vasculature and a hematopoietic compartment. Importantly, cartilage ECM could not generate frank bone tissue if devitalized by standard """"freeze & thaw"""" (F&T) cycles, associated with a significant loss of glycosaminoglycans, mineral content, and ECM-bound cytokines critically involved in inflammatory, vascularization, and remodeling processes. These results support the utility of engineered ECM-based devices as off-the-shelf regenerative niches capable of recruiting and instructing resident cells toward the formation of a specific tissue.  """,0
5478,25422474,Substrate recognition by the cell surface palmitoyl transferase DHHC5,"The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, but requires a ∼ 120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme-substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump. ",0
5479,25422561,Management of diabetes in the elderly with canagliflozin: A newer hypoglycemic drug on the horizon,"Canagliflozin is the first available oral inhibitor of sodium/glucose cotransporter 2 (SGLT2) in the market. At the outset it sounds excellent for the use in the elderly diabetic population, because of its minimal tendency to cause hypoglycemia. However, the clinician needs to exercise caution as it needs to be dosed renally. The clinician needs to be circumspect about potential drug interactions, especially when there is an underlying chronic kidney disease (CKD) and congestive heart failure (CHF). Also its use is best avoided in people who are predisposed to genital mycotic and urinary tract infections (UTI).  ",0
5480,25422604,Spinal anesthesia for laparoscopic cholecystectomy: Thoracic vs. Lumbar Technique,"In our group, after a study showing that spinal anesthesia is safe when compared with general anesthesia, spinal anesthesia has been the technique of choice for this procedure. This is a prospective study with all patients undergoing LC under spinal anesthesia in our department since 2007. Prospective observational. From 2007 to 2011, 369 patients with symptoms of colelithiasis, laparoscopic cholecystectomy were operated under spinal anesthesia with pneumoperitoneum and low pressure CO2. We compared 15 mg of hyperbaric bupivacaine and lumbar puncture with 10 or 7.5 mg of hyperbaric bupivacaine thoracic puncture, all with 25 μg fentanyl until the sensory level reached T3. Intraoperative parameters, post-operative pain, complications, recovery, patient satisfaction, and cost were compared between both groups. Means were compared by ANOVA or Kruskal-Wallis test, the percentages of the Chi-square test or Fisher's exact test when appropriate. Time of motor and sensory block in spinal anesthesia group was compared by paired t test or Mann-Whitney test. Differences were considered significant when P ≤ 0.05, and for comparisons of mean pain visual scale, we employed the Bonferroni correction applied to be considered significant only with P ≤ 0.0125. All procedures were completed under spinal anesthesia. The use of lidocaine 1% was successful in the prevention of shoulder pain in 329 (89%) patients. There were significant differences in time to reach T3, obtaining 15 mg > 10 mg = 7.5 mg. There is a positive correlation between the dose and the incidence of hypotension. The lowest doses gave a decrease of 52.2% in the incidence of hypotension. There was a positive correlation between the dose and duration of sensory and motor block. Sensory block was almost twice the motor block at all doses. With low doses, 60% of patients went from table to stretcher. Satisfaction occurred in 99% of patients. Laparoscopic cholecystectomy can be performed successfully under spinal anesthesia with low-pressure pneumoperitoneum of CO2. The use of thoracic puncture and low doses of hyperbaric bupivacaine provided better hemodynamic stability, less hypotension, and shorter duration of sensory and motor blockade than lumbar spinal anesthesia with conventional doses. ",0
5481,25423189,Structure of putrescine aminotransferase from Escherichia coli provides insights into the substrate specificity among class III aminotransferases,"YgjG is a putrescine aminotransferase enzyme that transfers amino groups from compounds with terminal primary amines to compounds with an aldehyde group using pyridoxal-5'-phosphate (PLP) as a cofactor. Previous biochemical data show that the enzyme prefers primary diamines, such as putrescine, over ornithine as a substrate. To better understand the enzyme's substrate specificity, crystal structures of YgjG from Escherichia coli were determined at 2.3 and 2.1 Å resolutions for the free and putrescine-bound enzymes, respectively. Sequence and structural analyses revealed that YgjG forms a dimer that adopts a class III PLP-dependent aminotransferase fold. A structural comparison between YgjG and other class III aminotransferases revealed that their structures are similar. However, YgjG has an additional N-terminal helical structure that partially contributes to a dimeric interaction with the other subunit via a helix-helix interaction. Interestingly, the YgjG substrate-binding site entrance size and charge distribution are smaller and more hydrophobic than other class III aminotransferases, which suggest that YgjG has a unique substrate binding site that could accommodate primary aliphatic diamine substrates, including putrescine. The YgjG crystal structures provide structural clues to putrescine aminotransferase substrate specificity and binding.  ",0
5482,25423581,Influence of the ionic liquid cation on the solvent extraction of trivalent rare-earth ions by mixtures of Cyanex 923 and ionic liquids,"Trivalent rare-earth ions were extracted from nitric acid medium by the neutral phosphine oxide extractant Cyanex 923 into ionic liquid phases containing the bis(trifluoromethylsulfonyl)imide anion. Five different cations were considered: 1-butyl-3-methylimidazolium, 1-decyl-3-methylimidazolium, methyltributylammonium, methyltrioctylammonium and trihexyl(tetradecyl)phosphonium. The extraction behavior of neodymium(iii) was investigated as a function of various parameters: pH, extractant concentration, concentration of the neodymium(iii) ion in the aqueous feed and concentration of the salting-out agent. The loading capacity of the ionic liquid phase was studied. The extraction efficiency increased with increasing pH of the aqueous feed solution. The extraction occurred for all ionic liquids via an ion-exchange mechanism and the extraction efficiency could be related to the solubility of the ionic liquid cation in the aqueous phase: high distribution ratios for hydrophilic cations and low ones for hydrophobic cations. Addition of nitrate ions to the aqueous phase resulted in an increase in extraction efficiency for ionic liquids with hydrophobic cations due to extraction of neutral complexes. Neodymium(iii) could be stripped from the ionic liquid phase by 0.5-1.0 M nitric acid solutions and the extracting phase could be reused. The extractability of other rare earths present in the mixture was compared for the five ionic liquids.  ",0
5483,25423908,Early management of patients with acute heart failure: state of the art and future directions--a consensus document from the SAEM/HFSA acute heart failure working group,"Heart failure (HF) afflicts nearly 6 million Americans, resulting in 1 million emergency department (ED) visits and over 1 million annual hospital discharges. The majority of inpatient admissions originate in the ED; thus, it is crucial that emergency physicians and other providers involved in early management understand the latest developments in diagnostic testing, therapeutics, and alternatives to hospitalization. This article discusses contemporary ED management as well as the necessary next steps for ED-based acute HF research. ",0
5484,25424134,End-of-Life Medical Costs of Medicaid Cancer Patients,"To quantify end-of-life (EOL) medical costs for adult Medicaid beneficiaries diagnosed with cancer. We linked Medicaid administrative data with 2000-2003 cancer registry data to identify 3,512 adult Medicaid beneficiaries who died after a cancer diagnosis and matched them to a cohort of beneficiaries without cancer who died during the same period. We used multivariable regression analysis to estimate incremental per-person EOL cost after controlling for beneficiaries' age, race/ethnicity, sex, cancer site, and state of residence. End-of-life costs during the final 4 months of life were about $10,000 higher for Medicaid cancer patients than for those without cancer. Medicaid cancer patients are more intensive users of inpatient and ambulatory services than are Medicaid patients without cancer. Medicaid cancer patients who die soon after diagnosis have higher costs of care and use inpatient services more intensely than do Medicaid patients without cancer. Medicaid cancer patients incur substantially higher EOL costs than noncancer patients. This increased cost may reflect the cost of palliative care. Future studies should assess the types and timing of services provided to Medicaid cancer patients at the EOL. ",0
5485,25424438,Associations with dental caries experience among a convenience sample of Aboriginal Australian adults,"Few studies have examined dental caries experience in Aboriginal adults. The objectives of this study were to describe the dental caries experience of some Aboriginal Australian adults residing in the Northern Territory, and to determine associations with dental caries experience. A convenience sample of Aboriginal adults from Australia's Northern Territory was dentally examined. Self-reported oral health information was collected through a questionnaire. Data were available for 312 participants. The per cent of untreated decayed teeth (per cent DT >0) was 77.9 (95% CI 73.0 to 82.1), the mean DT was 3.0 (95% CI 2.6 to 3.4), the prevalence of any caries experience (the per cent DMFT >0) was 95.5 (95% CI 92.6 to 97.3) and the mean DMFT was 9.7 (95% CI 8.9 to 10.5). In multivariable analyses, unemployment and not brushing teeth the previous day were associated with the per cent DT >0. Problem-based dental attendance was associated with both the mean DT and the per cent DMFT >0. Older age, residing in the capital city, being non-incarcerated, last visiting a dentist <1 year ago and problem-based dental attendance were associated with the mean DMFT. Dental caries experience among this convenience sample of Aboriginal Australian adults was very high. Most factors associated with dental caries were social determinants or dental service access-related. ",0
5486,25424677,Early detection of cervical cancer in Chile: time for change],"Mortality rates for cervical cancer (CC) in Chile are higher than those of developed countries and it has an unequal socioeconomic distribution. The recognition of human papilloma virus (HPV) as the causal agent of cervical cancer in the early 80's changed the prevention paradigms. Current goals are to prevent HPV infection by vaccination before the onset of sexual activity and to detect HPV infection in women older than 30 years. This article reviews CC prevention and early detection methods, discusses relevant evidence to support a change in Chile and presents an innovation proposal. A strategy of primary screening based on HPV detection followed by triage of HPV-positive women by colposcopy in primary care or by cytological or molecular reflex testing is proposed. Due to the existence in Chile of a well-organized nationwide CC prevention program, the replacement of a low-sensitivity screening test such as the Papanicolau test with a highly sensitive one such as HPV detection, could quickly improve the effectiveness of the program. The program also has a network of personnel qualified to conduct naked-eye inspections of the cervix, who could easily be trained to perform triage colposcopy. The incorporation of new prevention strategies could reduce the deaths of Chilean women and correct inequities.  ",0
5487,25424714,Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations,"Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.  ",0
5488,25425026,Manual urine microscopy versus automated urine analyzer microscopy in patients with acute kidney injury,"To examine whether a significant difference exists between the reported ranges of granular and muddy brown casts in urine specimens using manual microscopy compared with an automated urine analyzer in a cohort of patients with acute kidney injury (AKI). Freshly voided urine specimens from 25 consecutive patients who were under evaluation by the Department of Nephrology for AKI were simultaneously examined using the iQ200 automated microscopy system and manual microscopy performed by a trained observer. We coded the results according to the number of pathological casts identified and performed a 3 × 2 Freeman-Halton extension of the Fisher exact probability test. Overall, the number of casts identified via manual microscopy differed significantly (P <.001) from the number identified via the automated microscopy system. This study provides evidence of the importance of performing a manual microscopic examination of urine sediment in patients with AKI. Further studies are needed to assess whether manual microscopy provides prognostic implications regarding renal recovery, hemodialysis dependency, and mortality. ",0
5489,25425321,Prolonged P wave duration predicts stroke mortality among type 2 diabetic patients with prevalent non-major macrovascular disease,"Prolonged P wave duration is a marker of delayed inter-atrial conduction which may predict cardiovascular disease (CVD). Type 2 diabetes is a risk factor for all atherosclerotic manifestations including stroke. We evaluated the prognostic significance of prolonged P wave duration among middle-aged Finnish type 2 diabetes patients with and without prevalent non-major macrovascular disease (PNMMVD) with respect to total and stroke mortality. We followed up for 18 years 739 type 2 diabetic patients without previous major CVD event at baseline. Participants were stratified according to P wave duration (<114 or ≥ 114 ms) and PNMMVD (i.e. coronary heart disease defined as ischaemic ECG changes and typical symptoms of angina pectoris, or claudication; yes or no). The Cox proportional hazards model was used to estimate the joint association between P wave duration, PNMMVD and the mortality risk. During the follow-up, 509 patients died, and 59 of them died from stroke. Those who had prolonged P wave duration had 2.45 (95% confidence interval: 1.11-5.37) increased stroke mortality among PNMMVD patients. In patients without PNMMVD, there was no relationship between P wave duration and stroke mortality. As an easily measurable factor P wave duration merits further studies with higher number of patients to evaluate its importance in the estimation of stroke risk in type 2 diabetic patients with PNMMVD. ",0
5490,25425440,Prospective study of the Transurethral Suprapubic endo-Cystostomy (T-SPEC(®)): an 'inside-out' approach to suprapubic catheter insertion,"To prospectively evaluate the new medical device Transurethral Suprapubic endo-Cystostomy (T-SPeC(®)), used for suprapubic catheter (SPC) placement via the transurethral (inside-to-out) approach, and examine the 30-day outcomes in the first US series. IRB approval was obtained for this prospective study. We evaluated the first 114 consecutive cases of SPC placement using the T-SPeC(®) device by a single surgeon at in a 20-month period. We excluded patients who underwent alternative approaches to suprapubic catheter placement including open abdominal approach (12) and percutaneous approach (5). Preoperative patient demographics, operative detail, success rate and 30-day complication rate were recorded. We successfully placed an 18 Fr suprapubic catheter using the T-SPeC(®) device in 98.2 % of patients. During the procedure, the capture housing was missed twice. The mean patient age was 56.6, BMI 29.4 kg/m(2), skin to bladder distance 6.7 cm and operative time 3.6 min. There were 12 postoperative complications within 30 days of the procedure including urinary tract infections (6), SPC exit site infection (2), SPC blockage (2) and catheter expulsion (2). There were no Clavien-Dindo grade III-IV complications such as re-operation, small bowel injury, hemorrhage or death. The T-SPeC(®) device is a novel, simple, accurate and minimally invasive device for SPC insertion from an inside-to-out approach. Our prospective study demonstrates that the T-SPeC(®) device can be placed safely and efficiently in a variety of patients with a need for urinary drainage. ",0
5491,25425651,"PaCO2 in surfactant, positive pressure, and oxygenation randomised trial (SUPPORT)","To determine the association of arterial partial pressure of carbon dioxide PaCO2 with severe intraventricular haemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18-22 months in premature infants. Secondary exploratory data analysis of Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT). Multiple referral neonatal intensive care units. 1316 infants 24 0/7 to 27 6/7 weeks gestation randomised to different oxygenation (SpO2 target 85-89% vs 91-95%) and ventilation strategies. Blood gases from postnatal day 0 to day14 were analysed. Five PaCO2 variables were defined: minimum (Min), maximum (Max), SD, average (time-weighted), and a four level categorical variable (hypercapnic (highest quartile of Max PaCO2), hypocapnic (lowest quartile of Min PaCO2), fluctuators (hypercapnia and hypocapnia), and normocapnic (middle two quartiles of Max and Min PaCO2)). PaCO2 variables were compared for infants with and without sIVH, BPD and NDI (±death). Multivariable logistic regression models were developed for adjusted results. sIVH, BPD and NDI (±death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (per 10 mm Hg increase: sIVH/death: OR 1.27 (1.13 to 1.41); BPD/death: OR 1.27 (1.12 to 1.44); NDI/death: OR 1.23 (1.10 to 1.38), death: OR 1.27 (1.12 to 1.44), all p<0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) and ventilator days (rs0.61, p<0.0001). Higher PaCO2 was an independent predictor of sIVH/death, BPD/death and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high-risk infants. ",0
5492,25425699,Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: multicenter cohort studies in the United States and Finland,"We investigated whether children with a higher respiratory syncytial virus (RSV) genomic load are at a higher risk of more-severe bronchiolitis. Two multicenter prospective cohort studies in the United States and Finland used the same protocol to enroll children aged <2 years hospitalized for bronchiolitis and collect nasopharyngeal aspirates. By using real-time polymerase chain reaction analysis, patients were classified into 3 genomic load status groups: low, intermediate, and high. Outcome measures were a length of hospital stay (LOS) of ≥3 days and intensive care use, defined as admission to the intensive care unit or use of mechanical ventilation. Of 2615 enrolled children, 1764 (67%) had RSV bronchiolitis. Children with a low genomic load had a higher unadjusted risk of having a length of stay of ≥3 days (52%), compared with children with intermediate and those with high genomic loads (42% and 51%, respectively). In a multivariable model, the risk of having a length of stay of ≥3 days remained significantly higher in the groups with intermediate (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.20-1.69) and high (OR, 1.58; 95% CI, 1.29-1.94) genomic loads. Similarly, children with a high genomic load had a higher risk of intensive care use (20%, compared with 15% and 16% in the groups with low and intermediate genomic loads, respectively). In a multivariable model, the risk remained significantly higher in the group with a high genomic load (OR, 1.43; 95% CI, 1.03-1.99). Children with a higher RSV genomic load had a higher risk for more-severe bronchiolitis. ",0
5493,25425739,"Motivations, Satisfaction, and Fears of Death and Dying in Residential Hospice Volunteers: A Prospective Longitudinal Study","Studies conducted on hospice volunteers' characteristics and experiences have been cross-sectional. We conducted a prospective study to examine changes in the volunteer experience over time in a cohort of volunteers during the first year of a new residential hospice. Eighty-two active volunteers completed an online baseline survey, and of these, 39 completed a follow-up survey at 6 months. The survey included measures of motivations to volunteer, satisfaction with role and with the organization, and fear of death and dying. Repeated measures analyses indicated that motivations to volunteer remained stable over time while volunteer satisfaction increased with time. Baseline level of fears of death and dying varied by age, volunteer role, and motivations to volunteer and decreased at 6 months. Volunteering in a residential hospice tends to be a satisfying experience that helps to allay fears about death and dying. ",0
5494,25425829,Sodium valproate induced gingival enlargement in 22 months old child,"Gingival enlargement is a common clinical feature seen in patients suffering from gingival and periodontal diseases and is a common side-effect of drugs such as anti-convulsants, calcium channel blockers and immunosuppresants. This is a case report of 22 months old child suffering from gingival enlargement following intake of sodium valproate. Among the anti-convulsants phenytoin is commonly associated with gingival enlargement; however, there are not many cases reported on sodium valproate induced gingival enlargement.  ",0
5495,25426292,Uncontrollable behavior or mental illness? Exploring constructions of bulimia using Q methodology,"""In medical and psychological literature bulimia is commonly described as a mental illness. However, from a social constructionist perspective the meaning of bulimia will always be socially and historically situated and multiple. Thus, there is always the possibility for other understandings or constructions of bulimia to circulate in our culture, with each having distinct real-world implications for those engaging in bulimic behaviors; for instance, they might potentially influence likelihood of help-seeking and the success of treatment. This study used Q methodology to explore culturally-available constructions of bulimia nervosa. Seventy-seven adults with varying experience of eating disorders took part in this Q methodological study. Online, they were asked to rank-order 42 statements about bulimia, and then answer a series of questions about the task and their knowledge of bulimia. A by-person factor analysis was then conducted, with factors extracted using the centroid technique and a varimax rotation. Six factors satisfied selection criteria and were subsequently interpreted. Factor A, """"bulimia as uncontrolled behavior"""", positions bulimia as a behavioral rather than psychological issue. Factor B, entitled """"bulimia is a distressing mental illness"""", reflects an understanding of bulimic behaviors as a dysfunctional coping mechanism, which is often found in psychological literature. Other perspectives position bulimia as about """"self-medicating with food"""" (Factor C), """"the pathological pursuit of thinness"""" (Factor D), """"being the best at being thin"""" (Factor E), or as """"extreme behavior vs. mentally ill"""" (Factor F). These constructions have distinct implications for the subjective experience and behavior of those engaged in bulimic behaviors, with some constructions possibly being more useful in terms of help-seeking (Factor B), while others position these individuals in ways that may be distressing, for instance as shallow (Factor D) or to blame (Factor E). This study has identified a range of distinct constructions of bulimia. These constructions are considered to have implications for the behaviors and experiences of those engaging in bulimic behaviors. As such, further research into constructions of bulimia may illuminate factors that influence help-seeking and the self-perceptions of such individuals. """,0
5496,25426390,Topological Analysis for Arteriovenous Malformations via Computed Tomography Angiography: Part 2: Practical Application,"In a previous study, the authors outlined a technique for calculating the number of abnormal vascular loop structures described in 3-dimensional computed tomography angiography. To be developed into a quantitative evaluation method for soft-tissue arteriovenous malformations (AVMs), the concept needs assessment of validity. Computed tomography angiography results of 19 soft-tissue AVMs and 18 control abdominal vessels are utilized. Enhanced vascular lumen regions over 120 HU were extracted by a region growing method and skeletonized into wire frame graph models. The number of vascular loop structures in graphs is calculated as 1 - [Number of nodes] + [Number of edges], and results are compared between AVM/control groups, pre-/postprogression, and pre-/posttreatment. Average vascular lumen capacity of AVMs was 57.5 ml/lesion, and average number of vascular loops was 548 loops/lesion. Loop density of AVMs (weighted average, 9.5 loops/ml) exhibited statistically significant (P < 0.001) greater value than normal abdominal blood vessels (weighted average, 1.3 loops/ml). In all 4 cases without treatment, number of loops and loop density both increased. Particularly, number of loops increased greatly by 2 times or more in 3 cases. In all 7 cases with treatment, number of loops and vascular lumen capacity significantly (P = 0.0156) decreased. Particularly, number of loops showed clearer decrease in cases with entire lesion treatment than partial treatment. Total number of described vascular loop structures and their density or volume well reflected the existence, progression, and remission of soft-tissue AVMs. Topological analysis can be expected to be developed into a quantitative evaluation for AVMs. ",0
5497,25426465,Effects of communal exercise with visual and auditory feedback provided by a smart application on gait ability and fear of falling in Parkinson's disease patients,"Parkinson's disease is a chronically developing neurodegenerative disease showing typical motor symptoms of the following triad: resting tremor, freezing of gait, and bradykinesia-hypokinesia. In the present study, we investigated the effects of a communal exercise program, using the visual and auditory feedback provided by a smart application, to assess gait ability, fear of falling, and fall efficacy in Parkinson's disease patients. Subjects consisted of 29 Parkinson's disease patients who were non-demented individuals. The subjects were randomly divided into three groups: the control group (n= 9, CG), the communal exercise group using the smart application (n= 10, CCEG), and the individual exercise group using the smart application (n= 10, ICEG). The communal exercise program consisted of a warm up (10 min) followed by communal exercise using the smart application (40 min), and a cool down (10 min) for 3 days per week over 10 weeks. The results presented here show that velocity and cadence were significantly increased among groups. Step and stride length were significantly increased among times. Fear of falling and fall efficacy were significantly different among groups and times. In particular, fear of falling was lower and fall efficacy was higher in the CCEG than in the ICEG and CG. These findings indicate that 10 weeks of the communal exercise program using the smart application can be effective in improving gait ability, fear of falling, and fall efficacy in Parkinson's disease patients.  ",0
5498,25426566,Elevated hypertension risk for African-origin populations in biracial societies: modeling the Epidemiologic Transition Study,"Blood pressures in persons of African descent exceed those of other racial/ethnic groups in the United States. Whether this trait is attributable to the genetic factors in African-origin populations, or a result of inadequately measured environmental exposures, such as racial discrimination, is not known. To study this question, we conducted a multisite comparative study of communities in the African diaspora, drawn from metropolitan Chicago, Kingston, Jamaica, rural Ghana, Cape Town, South Africa, and the Seychelles. At each site, 500 participants between the age of 25 and 49 years, with approximately equal sex balance, were enrolled for a longitudinal study of energy expenditure and weight gain. In this study, we describe the patterns of blood pressure and hypertension observed at baseline among the sites. Mean SBP and DBP were very similar in the United States and South Africa in both men and women, although among women, the prevalence of hypertension was higher in the United States (24 vs. 17%, respectively). After adjustment for multiple covariates, relative to participants in the United States, SBP was significantly higher among the South Africans by 9.7 mmHg (P < 0.05) and significantly lower for each of the other sites: for example, Jamaica: -7.9 mmHg (P = 0.06), Ghana: -12.8 mmHg (P < 0.01) and Seychelles: -11.1 mmHg (P = 0.01). These data are consistent with prior findings of a blood pressure gradient in societies of the African diaspora and confirm that African-origin populations with lower social status in multiracial societies, such as the United States and South Africa, experience more hypertension than anticipated based on anthropometric and measurable socioeconomic risk factors. ",0
5499,25426606,Changes in the oral cavity might reflect psychological disorders in some patients,"The treatment of oral dysesthesias, such as burning mouth syndrome, can be challenging. Patient acceptance of the role of psychological etiological factors might be improved if there are clinical signs that patients could confirm themselves, which could be used as reinforcement of clinical discussions. Published associations between psychological disorder and various oral signs and symptoms are not suited to this purpose, as they are ambiguous in origin and implication. Others, used clinically in this situation, are not supported by published literature. Therefore, the purpose of this study was to determine if a demonstrable relationship could be established between psychological profile and the appearance and function of the oral cavity. Seventy-nine participants underwent an oral examination and completed a Depression Anxiety Stress Scale-21 questionnaire. Correlations were calculated between clinical variables and the raw Depression Anxiety Stress Scale scores. Univariate analyses determined variables with significant differences between a high-risk and normal group, and multiple logistic regression models were calculated for these. Various oral signs and symptoms were found to correlate with depression, anxiety, and/or stress, with some predictive of psychological disturbance. These signs and symptoms might be used to reinforce the psychological aspects of an oral dysesthesia. ",0
5500,25426675,Resistance to targeted cancer drugs through hepatocyte growth factor signaling,"Cancer therapeutics that target a signaling pathway to which the cancer cells are addicted can deliver dramatic initial responses, but resistance is nearly always inevitable. A variety of mechanisms that cancer cells employ to escape from targeted cancer drugs have been described. We review here the role of Hepatocyte Growth Factor (HGF) and its receptor MET in drug resistance. We present data demonstrating that HGF can confer resistance to a number of kinase inhibitors in a variety of cancer cell lines and discuss our results in relation to the findings of others. Together, these data point at a major role for HGF/MET signaling in resistance to a variety of targeted cancer drugs.  ",0
5501,25426774,Ankyrin is the major oxidised protein in erythrocyte membranes from end-stage renal disease patients on chronic haemodialysis and oxidation is decreased by dialysis and vitamin C supplementation,"Chronically haemodialysed end-stage renal disease patients are at high risk of morbidity arising from complications of dialysis, the underlying pathology that has led to renal disease and the complex pathology of chronic kidney disease. Anaemia is commonplace and its origins are multifactorial, involving reduced renal erythropoietin production, accumulation of uremic toxins and an increase in erythrocyte fragility. Oxidative damage is a common risk factor in renal disease and its co-morbidities and is known to cause erythrocyte fragility. Therefore, we have investigated the hypothesis that specific erythrocyte membrane proteins are more oxidised in end-stage renal disease patients and that vitamin C supplementation can ameliorate membrane protein oxidation. Eleven patients and 15 control subjects were recruited to the study. Patients were supplemented with 2 × 500 mg vitamin C per day for 4 weeks. Erythrocyte membrane proteins were prepared pre- and post-vitamin C supplementation for determination of protein oxidation. Total protein carbonyls were reduced by vitamin C supplementation but not by dialysis when investigated by enzyme linked immunosorbent assay. Using a western blot to detect oxidised proteins, one protein band, later identified as containing ankyrin, was found to be oxidised in patients but not controls and was reduced significantly by 60% in all patients after dialysis and by 20% after vitamin C treatment pre-dialysis. Ankyrin oxidation analysis may be useful in a stratified medicines approach as a possible marker to identify requirements for intervention in dialysis patients. ",0
5502,25426797,Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues,"The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.  ",0
5503,25426910,Results from Canada's 2014 Report Card on Physical Activity for Children and Youth,"The Active Healthy Kids Canada (AHKC) Report Card consolidates and translates research and assesses how Canada is being responsible in providing physical activity opportunities for children (3- to 11-years-old) and youth (12- to 17-years-old). The primary aim of this article is to summarize the results of the 2014 AHKC 10th Anniversary Report Card. Ten physical activity indicators were graded using the AHKC Report Card development process, which includes a synthesis of the best available research, surveillance, policy and practice findings, and expert consensus. Grades assigned were for: 'Behaviors that Contribute to Overall Physical Activity Levels' (Overall Physical Activity Levels, D-; Organized Sport Participation, C+; Active Play, INCOMPLETE; Active Transportation, D; Sedentary Behaviors, F), 'Settings and Sources of Influence' (Family and Peers, C; School, C+; and Community and the Built Environment, B+), and 'Strategies and Investments' (Government Strategies and Investments, C; and Non-Government Strategies and Investments, A-). Despite good availability of policies, programs, and infrastructure, the overall physical activity levels of Canadian children and youth remain low while sedentary behavior levels remain high. As with many nations, there is room for improvement in most physical activity behaviors and some sources of influence. ",0
5504,25426920,Results from New Zealand's 2014 Report Card on Physical Activity for Children and Youth,"This brief report provides grades for the 2014 New Zealand Report Card on Physical Activity for Children and Youth. The Report Card presents a review of current evidence across 9 key indicators, including physical activity (PA), organized sport and free play, sedentary behavior, and community and government initiatives across New Zealand. Nationally representative survey data were collated by researchers at the University of Auckland, New Zealand, between June and December 2013. The grade for each indicator is based on the percentage of children and youth meeting a defined benchmark: A is 81%-100%; B is 61%-80%; C is 41%-60%, D is 21%-40%; F is 0%-20%; INC is incomplete data. Overall PA received a score of B, as did Organized Sport Participation and Active Play. PA participation in School Environment scored slightly less with a score of B-. Sedentary Behaviors, Family and Peers, and Community and Built Environment scored a grade of C. Active transportation received a score of C-. An inconclusive grade was given for the Government indicator due to a lack of established international criteria for assessment. PA participation in New Zealand is satisfactory, but could improve. However, sedentary behavior is high. Of particular concern is the age-related decline in PA participation, particularly among adolescent females, and the increase in sedentary behavior. ",0
5505,25426940,The combination of pill count and self-reported adherence is a strong predictor of first-line ART failure for adults in South Africa,"Suboptimal adherence to antiretroviral therapy (ART) is a strong predictor of virologic failure (VF) among people with HIV. Various methods such as patient self-report, pill counts and pharmacy refills have been utilized to monitor adherence. However, there are limited data on the accuracy of combining methods to better predict VF in routine clinical settings. We examined various methods to assess adherence including pill count, medication possession ratio (MPR), and self-reported adherence in order to determine which was most highly associated with VF after > 6 months on ART. We conducted a secondary analysis of data from a case-control study. At enrollment, pharmacy refill data were collected retrospectively from the medical chart, pill counts were completed to derive a pill count adherence ratio (PCAR) and a self-report questionnaire was administered to all participants. Parametric smooth splines and receiver operator characteristic (ROC) analyses were carried out to assess the accuracy of the adherence methods. 458 patients were enrolled from October 2010 to June 2012. Of these, 158 (34.50%) experienced VF (cases) and 300 (65.50%) were controls. The median (IQR) PCAR was 1.10 (0.99-1.14) for cases and 1.13 (1.08-1.18) for controls (p < 0.0001). The median MPR was 1.00 (0.97-1.07) for cases and 1.03 (0.96-1.07) for controls (p = 0.83). Combination of PCAR and self-reported questions was highly associated with VF. In this setting, a combination of pill count adherence and self-report adherence questions had the highest diagnostic accuracy for VF. Further validation of this simple, low-cost combination is warranted in large prospective studies. ",0
5506,25426943,Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis among Han Chinese population,"Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese with a large sample size. We studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system. Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r = 0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR = 1.275, 95% CI 1.082-1.502, p = 0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2: OR = 1.192, 95% CI 0.889-1.598, p = 0.241; tertile 3: OR = 2.003, 95% CI 1.383-2.903, p <0.001) and high GS (fibrinogen tertile 2: OR = 1.079, 95% CI 0.833-1.397, p = 0.565; tertile 3: OR = 1.524, 95% CI 1.155-2.011, p = 0.003) in a dose-dependent manner. Receiver-operating characteristic curve analysis showed that the best fibrinogen cut-off value for predicting the severity of coronary stenosis was 3.21 g/L. Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis in Han Chinese population. ",0
5507,25427062,Reduction of pressor response to stress by centrally acting apelin in spontaneously hypertensive rats,"Numerous studies suggest that apelin plays a significant role in cardiovascular regulation and in the pathogenesis of hypertension. The purpose of the present study was to determine whether apelin-13 (AP-13) is involved in the regulation of cardiovascular responses to acute stress in spontaneous hypertension. The effects of intracerebroventricular (ICV) administration of AP-13 on changes in mean arterial blood pressure (MABP) and heart rate evoked by an alarming stress (air jet stress) were compared in awake normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The rats were divided into four groups: Groups 1 (WKY) and 3 (SHR) received ICV infusion of 0.9% sodium chloride (vehicle), whereas Groups 2 (WKY) and 4 (SHR) were ICV infused with AP-13. All animals were exposed to the alarming stress. During the ICV administration of the vehicle, the pressor response to stress was significantly greater in SHR than in WKY. The ICV infusion of AP-13 reduced the pressor response evoked by the application of the stressor in SHR but not in WKY. It also abolished the difference in stress-induced MABP increases between WKY and SHR. The results show that centrally acting apelin may play an essential role in the regulation of blood pressure responses to an alarming stress in SHR rats. ",0
5508,25427448,Involvement of metformin and AMPK in the radioresponse and prognosis of luminal versus basal-like breast cancer treated with radiotherapy,"Metformin is under evaluation as a potential anticancer agent. Expression of total and phospho(Thr172)-adenosine monophosphate-activated kinase-α (AMPKα and pAMPKα(Thr172) respectively), a main metformin target, was examined in radiotherapy treated breast cancers and metformin's ability to modulate Trx system expression and breast cancer radiosensitivity evaluated in vitro. AMPKα and pAMPKα(Thr172) expression was assessed using a discovery (n=166) and validation cohort (n=609). Metformin's role in regulating radioresponse, and Trx family expression, was examined via clonogenic assays and Western blots. Intracellular reactive oxygen species (ROS) levels, cell cycle progression and apoptosis were assessed by flow cytometry. High AMPKα expression associated with improved local recurrence-free (P=0.019), relapse-free (P=0.016) and breast cancer-specific survival (P=0.000065) and was, from multivariate analysis, an independent prognostic factor from the discovery cohort. From the validation cases AMPKα expression associated with relapse-free and breast cancer-specific survival in luminal breast cancers. Metformin substantially increased radiosensitivity, intracellular ROS levels and reduced Trx expression, in luminal breast cancer cells, but had little effect on basal phenotype cells. In conclusion, high AMPKα expression associates with improved prognosis, especially in luminal breast cancer. Metformin preferentially radiosensitises luminal breast cancer cells, potentially due to alterations to intracellular ROS levels via modulation of Trx family protein expression.  ",0
5509,25427467,Modified gold surfaces by 6-(ferrocenyl)hexanethiol/dendrimer/gold nanoparticles as a platform for the mediated biosensing applications,"An electrochemical biosensor mediated by using 6-(Ferrocenyl) hexanethiol (FcSH) was fabricated by construction of gold nanoparticles (AuNPs) on the surface of polyamidoamine dendrimer (PAMAM) modified gold electrode. Glucose oxidase (GOx) was used as a model enzyme and was immobilized onto the gold surface forming a self assembled monolayer via FcSH and cysteamine. Cyclic voltammetry and amperometry were used for the characterization of electrochemical response towards glucose substrate. Following the optimization of medium pH, enzyme loading, AuNP and FcSH amount, the linear range for the glucose was studied and found as 1.0 to 5.0mM with the detection limit (LOD) of 0.6mM according to S/N=3. Finally, the proposed Au/AuNP/(FcSH+Cyst)/PAMAM/GOx biosensor was successfully applied for the glucose analysis in beverages, and the results were compared with those obtained by HPLC.  ",0
5510,25427490,Poly (hydroxyethyl methacrylate-glycidyl methacrylate) films modified with different functional groups: In vitro interactions with platelets and rat stem cells,"Copolymerization of 2-hydroxyethylmethacrylate (HEMA) with glycidylmethacrylate (GMA) in the presence of α-α'-azoisobisbutyronitrile (AIBN) resulted in the formation of hydrogel films carrying reactive epoxy groups. Thirteen kinds of different molecules with pendant NH2 group were used for modifications of the p(HEMA-GMA) films. The NH2 group served as anchor binding site for immobilization of functional groups on the hydrogel film via direct epoxy ring opening reaction. The modified hydrogel films were characterized by FTIR, and contact angle studies. In addition, mechanical properties of the hydrogel films were studied, and modified hydrogel films showed improved mechanical properties compared with the non-modified film, but they are less elastic than the non-modified film. The biological activities of these films such as platelet adhesion, red blood cells hemolysis, and swelling behavior were studied. The effect of modified hydrogel films, including NH2, (using different aliphatic CH2 chain lengths) CH3, SO3H, aromatic groups with substituted OH and COOH groups, and amino acids were also investigated on the adhesion, morphology and survival of rat mesenchymal stem cells (MSCs). The MTT colorimetric assay reveals that the p(HEMA-GMA)-GA-AB, p(HEMA-GMA)-GA-Phe, p(HEMA-GMA)-GA-Trp, p(HEMA-GMA)-GA-Glu formulations have an excellent biocompatibility to promote the cell adhesion and growth. We anticipate that the fabricated p(HEMA-GMA) based hydrogel films with controllable surface chemistry and good stable swelling ratio may find extensive applications in future development of tissue engineering scaffold materials, and in various biotechnological areas.  ",0
5511,25427896,Ten key research issues for integrated and sustainable wastewater reuse in the Middle East,"Wastewater management is not limited to the technology used to collect and treat wastewater. It begins with the early planning phase of building a society and includes considerations of how that society will grow. Therefore, history, culture, religion, and socioeconomy are important components to include in any relevant and integrated studies of wastewater management and reuse. Engineering, health, chemistry, biology, food production, cultural heritage, and the needs of people of all ages should be considered together when making management decisions regarding issues so intimately tied with humanity as water and sanitation. Other escalating challenges such as poverty, food, and water scarcity, migration and instability, flooding and catastrophes, diseases and mortality, etc. should also be considered as part of wastewater management and reuse planning. Emerging contaminants could be associated with the urbanization, modernization, and industrialization of several countries. Several arid countries have developed water security strategies where wastewater reuse is a major component. The existing wastewater treatment technologies in these countries are, in most cases, unable to remove such contaminants which may affect irrigation waters, industrial products, groundwater, etc. People would have to accept that the food on their tables could be irrigated with treated wastewater that they generated a few months ago, even if very advanced technologies were used to treat it. The purpose of this review is to highlight multidisciplinary areas of research on wastewater and to propose applicable and affordable mechanisms by which we may consider wastewater as a legitimate resource.  ",0
5512,25428252,Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer,"The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations, are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.  ",0
5513,25428282,"Prevalence of HIV, sexually transmitted infections, and risk behaviours among female sex workers in Nairobi, Kenya: results of a respondent driven sampling study","We conducted a respondent driven sampling survey to estimate HIV prevalence and risk behavior among female sex workers (FSWs) in Nairobi, Kenya. Women aged 18 years and older who reported selling sex to a man at least once in the past 3 months were eligible to participate. Consenting FSWs completed a behavioral questionnaire and were tested for HIV and sexually transmitted infections (STIs). Adjusted population-based prevalence and 95 % confidence intervals (CI) were estimated using RDS analysis tool. Factors significantly associated with HIV infection were assessed using log-binomial regression analysis. A total of 596 eligible participants were included in the analysis. Overall HIV prevalence was 29.5 % (95 % CI 24.7-34.9). Median age was 30 years (IQR 25-38 years); median duration of sex work was 12 years (IQR 8-17 years). The most frequent client-seeking venues were bars (76.6 %) and roadsides (29.3 %). The median number of clients per week was seven (IQR 4-18 clients). HIV testing was high with 86.6 % reported ever been tested for HIV and, of these, 63.1 % testing within the past 12 months. Of all women, 59.7 % perceived themselves at 'great risk' for HIV infection. Of HIV-positive women, 51.0 % were aware of their infection. In multivariable analysis, increasing age, inconsistent condom use with paying clients, and use of a male condom as a method of contraception were independently associated with unrecognized HIV infection. Prevalence among STIs was low, ranging from 0.9 % for syphilis, 1.1 % for gonorrhea, and 3.1 % for Chlamydia. The data suggest high prevalence of HIV among FSWs in Nairobi. Targeted and routine HIV and STI combination prevention strategies need to be scaled up or established to meet the needs of this population. ",0
5514,25428283,Childhood Sexual Abuse and Syringe Sharing Among People Who Inject Drugs,"Childhood sexual abuse is associated with adverse health outcomes. However, the impact of sexual abuse on HIV risk behaviors among people who inject drugs (IDU) has not been thoroughly characterized. We therefore sought to identify whether childhood sexual abuse was associated with syringe sharing among a sample of IDU in Vancouver, Canada. We assessed sexual abuse among two cohorts of IDUs via the Childhood Trauma Questionnaire. Multivariate logistic regression was used to estimate the relationship between childhood sexual abuse and syringe sharing. In total, 1380 IDU were included in the study, and 426 (30.9 %) IDU reported childhood sexual abuse. Syringe sharing (Adjusted Odds Ratio = 1.83, 95 % Confidence Interval 1.28-2.60) remained independently associated with childhood sexual abuse after adjustment for potential confounders. Given that a history of childhood sexual abuse appears to be elevated among IDU who engage in HIV risk behaviors (i.e., syringe sharing), HIV prevention efforts should include efforts to address historical trauma in this population.  ",0
5515,25428711,Ferric carboxymaltose: a review of its use in iron deficiency,"Ferric carboxymaltose (Ferinject(®), Injectafer(®)) is an intravenous iron preparation approved in numerous countries for the treatment of iron deficiency. A single high dose of ferric carboxymaltose (up to 750 mg of iron in the US and 1,000 mg of iron in the EU) can be infused in a short time frame (15 min). Consequently, fewer doses of ferric carboxymaltose may be needed to replenish iron stores compared with some other intravenous iron preparations (e.g. iron sucrose). Ferric carboxymaltose improved self-reported patient global assessment, New York Heart Association functional class and exercise capacity in patients with chronic heart failure and iron deficiency in two randomized, placebo-controlled trials (FAIR-HF and CONFIRM-HF). In other randomized controlled trials, ferric carboxymaltose replenished iron stores and corrected anaemia in various populations with iron-deficiency anaemia, including patients with chronic kidney disease, inflammatory bowel disease or heavy uterine bleeding, postpartum iron-deficiency anaemia and perioperative anaemia. Intravenous ferric carboxymaltose was generally well tolerated, with a low risk of hypersensitivity reactions. It was generally better tolerated than oral ferrous sulfate, mainly reflecting a lower incidence of gastrointestinal adverse effects. The most common laboratory abnormality seen in ferric carboxymaltose recipients was transient, asymptomatic hypophosphataemia. The higher acquisition cost of ferric carboxymaltose appeared to be offset by lower costs for other items, with the potential for cost savings. In conclusion, ferric carboxymaltose is an important option for the treatment of iron deficiency.  ",0
5516,25428869,Influenza A virus uses intercellular connections to spread to neighboring cells,"In the extracellular environment, cell-free virions seek out naive host cells over long distances and between organisms. This is the primary mechanism of spread for most viruses. Here we provide evidence for an alternative pathway previously undescribed for orthomyxoviruses, whereby the spread of influenza A virus (IAV) infectious cores to neighboring cells can occur within intercellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection. Connected cells have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. A live-cell movie of green fluorescent protein (GFP)-tagged NS1 of IAV shows viral protein moving from one cell to another through an intercellular connection. The movement of tagged protein was saltatory but overall traveled only in one direction. Infectious virus cores can move from one cell to another without budding and release of cell-free virions, as evidenced by the finding that whereas a neuraminidase inhibitor alone did not inhibit the development of IAV microplaques, the presence of a neuraminidase inhibitor together with drugs inhibiting actin dynamics or the microtubule stabilizer paclitaxel (originally named taxol) precluded microplaque formation. Similar results were also observed with parainfluenza virus 5 (PIV5), a paramyxovirus, when neutralizing antibody was used to block spread by cell-free virions. Intercellular spread of infectious core particles was unaffected or enhanced in the presence of nocodazole for IAV but inhibited for PIV5. The intercellular connections have a core of filamentous actin, which hints toward transport of virus particles through the use of a myosin motor. Here we describe a new method by which influenza A virus (IAV) spreads from cell to cell: IAV uses intracellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection and the absence of microtubules. Connected cells appeared to have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. Infectious virus cores can move from one cell to another without budding and release of cell-free virions. Similar results were also observed with parainfluenza virus 5 (PIV5). ",0
5517,25428884,"The primary cilium as sensor of fluid flow: new building blocks to the model. A review in the theme: cell signaling: proteins, pathways and mechanisms","The primary cilium is an extraordinary organelle. For many years, it had the full attention of only a few dedicated scientists fascinated by its uniqueness. Unexpectedly, after decades of obscurity, it has moved very quickly into the limelight with the increasing evidence of its central role in the many genetic variations that lead to what are now known as ciliopathies. These studies implicated unique biological functions of the primary cilium, which are not completely straightforward. In parallel, and initially completely unrelated to the ciliopathies, the primary cilium was characterized functionally as an organelle that makes cells more susceptible to changes in fluid flow. Thus the primary cilium was suggested to function as a flow-sensing device. This characterization has been substantiated for many epithelial cell types over the years. Nevertheless, part of the central mechanism of signal transduction has not been explained, largely because of the substantial technical challenges of working with this delicate organelle. The current review considers the recent advances that allow us to fill some of the holes in the model of signal transduction in cilium-mediated responses to fluid flow and to pursue the physiological implications of this peculiar organelle.  ",0
5518,25428914,Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner,"The long non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) was recently implicated in breast cancer metastasis and is predictive of poor prognosis in colorectal and pancreatic cancers. We recently discovered that HOTAIR is a cell cycle-related lncRNA in human glioma, and its expression is closely associated with glioma staging and poor prognosis. Although lysine specific demethylase 1 (LSD1) and polycomb repressive complex 2 (PRC2) have been demonstrated to be functional targets of HOTAIR, how HOTAIR regulates glioma cell cycle progression remains largely unknown. In this study, we found that EZH2 (predominant PRC2 complex component) inhibition blocked cell cycle progression in glioma cells, consistent with the effects elicited by HOTAIR siRNA. However, the inhibition of LSD1 did not affect cell cycle progression in glioma cells. These results suggest that HOTAIR might regulate cell cycle progression through EZH2. Our intracranial mice model also revealed delayed tumor growth in HOTAIR siRNA- and EZH2 inhibitor-treated groups. Moreover, in HOTAIR knock-down cell lines, the expression of the PRC2-binding domain of HOTAIR (5' domain) but not of the LSD1-binding domain of HOTAIR (3' domain) resulted in accelerated cell cycle progression. In conclusion, HOTAIR promotes cell cycle progression in glioma as a result of the binding of its 5' domain to the PRC2 complex.  ",0
5519,25429454,Development of a spectrophotometric method for on-site analysis of peroxygens during in-situ chemical oxidation applications,"Activated peroxygens are frequently used as active agents in in-situ chemical oxidation (ISCO) contaminated site remediation applications, and fast and simple quantitative analysis of these species on site is necessary. In this work, the use of a spectrophotometric method based on classic iodometric titration is studied for quantitative analysis of S2O8(2-) and H2O2. Instead of a back-titration step, the absorbance of the yellow iodide colour was measured at 352 nm in the presence of a bicarbonate buffer. A linear calibration curve was obtained from 0 to 0.1 mM for both S2O8(2-) and H2O2. By dilution, the method can be used for all concentrations typically applied in the field. Concerning pH dependence, neutral pH levels caused no significant error whereas pH levels above 8 caused a 9% and 6% deviation from the theoretical peroxygen concentrations. Furthermore, the method showed little dependence on other matrix components, and absorbance was stable (<2% change) for more than a week. Overall, the method proved to be fast and simple, which are important features for a field method.  ",0
5520,25429662,"A mini review on biological activities of pyridazinone derivatives as antiulcer, antisecretory, antihistamine and particularly against histamine H3R","Pyridazinone derivatives and their related analoges were introduced for gastric antiulcer and antisecretory activities. Selected compounds were applied to ulcer models and showed their antiulcer and anti secretary activities. Some pyridazinone compounds are recently reported as H3R antagonists. Some amine analogs of pyridazinones, pyridazinone- phenethylamines and 4,5-fused pyridazinones showed histamine H3R antagonist activity with significant affinity for rat and human H3R. These pyridazinone analogs also showed excellent selectivity and metabolic stability, with adequate pharmacokinetics.  ",0
5521,25429790,"Raspberry ketone, a naturally occurring phenolic compound, inhibits adipogenic and lipogenic gene expression in 3T3-L1 adipocytes","Raspberry ketone (RK) is a natural phenolic compound of red raspberry. The dietary intake of RK has been reported to exert anti-obese actions and alter the lipid metabolism in vivo and human studies. To elucidate a possible mechanism for anti-obese actions of RK, the effects of RK on the adipogenic and lipogenic gene expression in 3T3-L1 adipocytes were investigated. 3T3-L1 maturing pre-adipocytes were treated from day 2 to day 8 of differentiation and mature adipocytes for 24 h on day 12 with 1, 10, 20, and 50 μM of RK. Triacylglycerols were assessed by spectrophotometry and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). Treatment of adipocytes with RK suppressed adipocyte differentiation and fat accumulation in a concentration-dependent manner. RK suppressed the expression of major genes involved in the adipogenesis pathway including peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT enhancer binding protein-α (C/EBPα), which led to further down-regulation of adipocyte fatty acid-binding protein-2 (aP2). In addition, treatment with 10 μM of RK also reduced mRNA levels of lipogenic genes such as acetyl-CoA carboxylase-1 (ACC1), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1). In mature adipocytes, RK increased the transcriptional activities of genes involved in lipolysis and the oxidative pathways including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), and carnitine palmitoyl transferase-1B (CPT1B). These findings suggest that RK holds great promise for an herbal medicine with the biological activities altering the lipid metabolism in 3T3-L1 adipocytes. ",0
5522,25429815,Expression of microRNA-203 and P63 in human epidermal stem cells and keratinocytes],"To observe the changes in expression of microRNA-203 and P63 in human epidermal stem cells and KCs, and to investigate their effects and significance in the epidermal proliferation and differentiation. (1) Five normal foreskin tissue specimens were collected from 5 patients by circumcision in Department of Urinary Surgery of the First Affiliated Hospital of Nanchang University from March to June in 2013. Then single cell suspension was obtained by separating epidermis with trypsin digestion method. The cells were divided into quick adherent cells and non-quick adherent cells by type IV collagen differential adherent method. The biological characteristics of cells were observed by inverted phase contrast microscope immediately after isolation and on post culture day (PCD) 3. The expression of CD29, keratin 19, keratin 1, and keratin 10 was identified by immunocytochemical staining. The expression of microRNA-203 and mRNA of P63 was determined by real-time fluorescent quantitative RT-PCR. The protein expression of P63 was determined by Western blotting. Data were processed with t test and Pearson correlation analysis. (1) Immediately after isolation, quick adherent cells were small, round, and dispersed uniformly. On PCD 3, the cells adhered firmly, and they grew in clones. Immediately after isolation, non-quick adherent cells appeared in different shapes and sizes, and dispersed unevenly. On PCD 3, the cells adhered precariously and did not show clonal growth. Quick adherent cells showed positive expression of CD29 and keratin 19, while non-quick adherent cells showed positive expression of keratin 1 and keratin 10. Quick adherent cells were identified as epidermal stem cells, and non-quick adherent cells were identified as KCs. (2)The expression level of microRNA-203 in epidermal stem cells (0.74 ± 0.20) was lower than that in KCs (3.66 ± 0.34, t =16.582, P <0.001). The mRNA expression level of P63 in epidermal stem cells (4. 16 ± 0.28) was higher than that in KCs (2.90 ± 0.39, t =5. 850, P =0.001). The protein expression level of P63 in epidermal stem cells (1.42 ± 0.05) was higher than that in KCs (0.73 ± 0.03, t =26.460, P <0. 001). (3) The expression level of microRNA-203 was in significantly negative correlation with the expression levels of mRNA and protein of P63 (with r values respectively - 0. 94 and -0.98 , P values below 0.05). The expression levels of microRNA-203 and P63 in human epidermal stem cells and KCs were significantly different, which might be related to the different characteristics of proliferation and differentiation of the cells. ",0
5523,25429989,RP-HPLC-DAD method for the identification of two potential antioxidant agents namely verminoside and 1-O-(E)-caffeoyl-β-gentiobiose from Spathodea campanulata leaves,"A simple and reliable high-performance liquid chromatographic method was successfully developed for the study of fingerprint chromatograms of extract and fractions from the leaves of Spathodea campanulata (SC) using verminoside (1) and 1-O-(E)-caffeoyl-β-gentiobiose (2) as marker compounds. Antioxidant activity of SC was determined by using free radical of 2,2-diphenyl-1-picryl-hydrazyl-hydrate as an experimental model. The docking study of selected target, tyrosinase and ligands (ascorbic acid, compounds 1 and 2) was performed through Autodock Vina v0.8. Fingerprints of methanol, chloroform, ethylacetate, n-butanol and water extracts could resolve 13, 11, 22, 16 and 5 peaks, respectively. Extract, fractions and compounds 1 and 2 previously isolated from SC displayed remarkable antioxidant activity with radical-scavenging activity ranging from 2.5 to 6.7 μg/mL. In silico study identified compounds 1 and 2 as potential inhibitors of tyrosinase correlating with the observed antioxidant activity in vitro. ",0
5524,25430525,Follow-up design of unexpected enhancing lesions on preoperative MRI of breast cancer patients,"We aimed to analyze the characteristics and long-term follow-up results of unexpected enhancing lesions on preoperative magnetic resonance imaging (MRI) of breast cancer patients. From August 2007 through February 2010, second-look ultrasound (SLUS) was recommended for 84 of 312 breast cancer patients having unexpected enhancing lesions on MRI. SLUS was performed for 85 unexpected enhancing lesions in 72 patients. We performed a retrospective review to determine the size, lesion type, enhancement kinetic curve, and location in relation to the index cancer. We obtained the pathologic outcome of the detected lesions and in case of a negative finding on SLUS, we performed follow-up examinations for at least two years. Of 85 unexpected lesions, 72 (85%) were detected on SLUS. In total, 41 lesions (56.9%) were confirmed as malignant and 31 lesions (43.6%) as benign. Cancer rate was statistically higher in lesions having type III enhancement pattern, located at the same quadrant as the index cancer. However, no significant association was observed between the cancer rate and the lesion size and type. None of the 13 negative cases on SLUS developed cancer on follow-up. In case of unexpected enhancing lesions on preoperative MRI of breast cancer patients, SLUS can be useful to find out the matched lesion. Lesions with type III enhancement pattern or those located at the same quadrant as the index cancer should be considered as a separate cancer. In the absence of any suspicious findings on SLUS, patient may be followed up with confidence. ",0
5525,25430528,CT-guided transthoracic biopsy: histopathologic results and complication rates,"We aimed to investigate the effectiveness and complications of transthoracic CT-guided biopsy techniques. A total of 94 CT-guided percutaneous transthoracic biopsy procedures performed in 85 patients were retrospectively evaluated. Core biopsy technique was used in 87 procedures and transthoracic fine-needle aspiration biopsy was used in seven procedures. Diagnostic results were achieved in 79 of 94 biopsy procedures. Pathology results were malignant in 54 patients, suspicious for malignancy in three patients, benign in five patients, and benign nonspecific in 17 patients. Specific diagnoses were obtained in 59 patients (62.8%) using core biopsy, but no specific diagnosis could be reached with transthoracic fine-needle aspiration biopsy. Complications included pneumothorax in 27 patients (28.7%) and parenchymal hemorrhage during and after the procedure in eight patients (8.5%). CT-guided percutaneous transthoracic needle biopsy is a highly accurate procedure for histopathological diagnosis of thoracic masses. In addition, percutaneous transthoracic biopsy has an acceptably low complication rate and it reduces the need for more invasive surgical procedures. ",0
5526,25430632,Evaluation of the implementation of the Montreal At Home/Chez Soi project,"Homelessness and mental disorders constitute a major problem in Canada. The purpose of the At Home/Chez Soi pilot project was to house and provide supports to marginalised groups. Policymakers are in a better position to nurture new, complex interventions if they know which key factors hinder or enable their implementation. This paper evaluates the implementation process for the Montreal site of this project. We collected data from 62 individuals, through individual interviews, focus groups, questionnaires, observations and documentation. The implementation process was analysed using a conceptual framework with five constructs: Intervention Characteristics (IC), Context of Implementation (CI), Implementation Process (IP), Organizational Characteristics (OC) and Strategies of Implementation (SI). The most serious obstacle to the project came from the CI construct, i.e., lack of support from provincial authorities and key local resources in the homelessness field. The second was within the OC construct. The chief hindrances were numerous structures, divergent values among stakeholders, frequent turnover of personnel and team leaders; lacking staff supervision and miscommunication. The third is related to IC: the complex, unyielding nature of the project undermined its chances of success. The greatest challenges from IP were the pressure to perform, along with stress caused by planning, deadlines and tension between teams. Conversely, SI construct conditions (e.g., effective governing structures, comprehensive training initiatives and toolkits) were generally very positive even with problems in power sharing and local leadership. For the four other constructs, the following proved useful: evidence of the project's scope and quality, great needs of services consolidation, generous financing and status as a research pilot project, enthusiasm and commitment toward the project, substantially improved services, and overall user satisfaction. This study demonstrated the difficulty of implementing a complex project in the healthcare system. While the project faced many barriers, minimal conditions were also achieved. At the end of the study period, major tensions between organizations and teams were significantly reduced, supporting its full implementation. However, in late 2013, the project was unsustainable, calling into question the relevance of achieving a significant number of positive conditions in each area of the framework. ",0
5527,25477247,Hepatitis C virus-induced reduction in miR-181a impairs CD4(+) T-cell responses through overexpression of DUSP6,"T cells play a crucial role in viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. MicroRNA (miR) has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4(+) T-cell responses through overexpression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with overexpression of DUSP6 was observed in CD4(+) T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 overexpression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4(+) T cells led to improved T-cell responses including enhanced CD25 and CD69 expression, increased interleukin-2 expression, and improved proliferation of CD4(+) T cells derived from chronically HCV-infected individuals. CONCLUSION: Since a decline of miR-181a concomitant with DUSP6 overexpression is the signature marker for age-associated T-cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T-cell aging through miR-181a-regulated DUSP6 signaling and reveal new targets for therapeutic rejuvenation of impaired T-cell responses during chronic viral infection.",0
5528,25482139,Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus,"Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-na?ve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. CONCLUSIONS: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established.",0
5529,25494269,Quality and equity of care in U.S. hospitals,"BACKGROUND: Nearly every U.S. hospital publicly reports its performance on quality measures for patients who are hospitalized for acute myocardial infarction, heart failure, or pneumonia. Because performance rates are not reported according to race or ethnic group, it is unclear whether improvements in equity of care have accompanied aggregate improvements in health care quality over time. METHODS: We assessed performance rates for quality measures covering three conditions (six measures for acute myocardial infarction, four for heart failure, and seven for pneumonia). These rates, adjusted for patient- and hospital-level covariates, were compared among non-Hispanic white, non-Hispanic black, and Hispanic patients who received care between 2005 and 2010 in acute care hospitals throughout the United States. RESULTS: Adjusted performance rates for the 17 quality measures improved by 3.4 to 57.6 percentage points between 2005 and 2010 for white, black, and Hispanic adults (P<0.001 for all comparisons). In 2005, as compared with adjusted performance rates for white patients, adjusted performance rates were more than 5 percentage points lower for black patients on 3 measures (range of differences, 12.3 to 14.2) and for Hispanic patients on 6 measures (5.6 to 14.5). Gaps decreased significantly on all 9 of these measures between 2005 and 2010, with adjusted changes for differences between white patients and black patients ranging from -8.5 to -11.8 percentage points and from -6.2 to -15.1 percentage points for differences between white patients and Hispanic patients. Decreasing differences according to race or ethnic group were attributable to more equitable care for white patients and minority patients treated in the same hospital, as well as to greater performance improvements among hospitals that disproportionately serve minority patients. CONCLUSIONS: Improved performance on quality measures for white, black, and Hispanic adults hospitalized for acute myocardial infarction, heart failure, or pneumonia was accompanied by increased racial and ethnic equity in performance rates both within and among U.S. hospitals. (Funded by the Centers for Medicare and Medicaid Services and the Veterans Affairs Health Services Research and Development Career Development Program.).",0
5530,25503476,Determining the fate of hepatic cells by lineage tracing: facts and pitfalls,"Slow renewal of the epithelial cells by proliferation ensures homeostasis of the liver, but extensive proliferation may occur upon injury. When proliferation is impaired, transdifferentiation of mature cells or differentiation of stem cells allows production of new hepatocytes and cholangiocytes. While lineage tracings using cyclization recombinase (Cre) recombinase-mediated cell labeling represent the gold standard for defining cell fate, there are more variables than was initially realized. This led to controversies about the capacity of liver cells to switch their fate. Here, I review how cells are traced in the liver and highlight the experimental pitfalls that may cause misinterpretations and controversies.",0
5531,25517348,A randomized trial of intraarterial treatment for acute ischemic stroke,"BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).",0
5532,25551524,The amyloidogenic V122I transthyretin variant in elderly black Americans,"BACKGROUND: Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS: We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS: After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS: We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.).",0
5533,25559313,Abdominal oxygen saturation for monitoring return of spontaneous circulation in out-of-hospital cardiac arrest using near infrared spectrophometry,We used near-infrared spectrophotometry to assess the initial and final abdominal and cerebral saturations during cardiopulmonary resuscitation (CPR) of patients with out-of-hospital cardiac arrest to determine if there is a correlation between increase in these saturation values and return of spontaneous circulation. We evaluated 34 patients with out-of-hospital cardiac arrest without witnesses brought to our emergency department. Abdominal and cerebral saturations were measured using near-infrared spectrophotometry from the start of CPR. Cardiopulmonary resuscitation was performed for a maximum of 30 minutes. The effect of abdominal saturations in patients with or without spontaneous circulation restored through CPR was then assessed. Thirty-four patients (17 males + females) with a mean age of 63.06 ± 11.66 years were included in the study. A significant correlation was determined between increase in abdominal saturations measured at the start and end of CPR and the return of spontaneous circulation (P < .001). A good positive correlation was also identified between abdominal saturation and return of spontaneous circulation. Patients with increased abdominal and cerebral saturation values have a higher survival rate after appropriate CPR. This noninvasive measurement system and monitoring of patients during CPR may be a good method of predicting return of spontaneous circulation and assessing abdominal perfusion. ,0
5534,25559451,Mass accuracy improvement of reversed-phase liquid chromatography/electrospray ionization mass spectrometry based urinary metabolomic analysis by post-run calibration using sodium formate cluster ions,"Typically, a batch metabolomics analysis using liquid chromatography/electrospray ionization time-of-flight mass spectrometry (LC/ESI-TOF MS) takes 2 to 3 days. However, the mass accuracy - which has an important influence on metabolite identification - can drift by as much as about 17 ppm in such a time period. In an untargeted urinary metabolomics analysis by reversed-phase liquid chromatography (RPLC)/ESI-MS, the signals of sodium formate cluster ions were detected at the column-washing step. The cluster ions were used to calibrate the mass spectrometer for more accurate detection. The spectra were calibrated post-run by the sodium formate cluster ions, which were used as the internal standard, in order to improve the mass accuracy. In the analysis of urine samples, we calibrated the spectra acquired by the micrOTOF with the sodium cluster ions. In positive mode ESI, the average errors of these cluster ions were improved to ±0.48 ppm and in negative mode ESI, to ±0.94 ppm after calibration. The mass accuracy remained within ±0.01 ppm over the duration of 6.25 days. An error window of 4 ppm appears to be suitable for metabolite identification when using post-calibration. The results showed that sodium formate cluster ions could be utilized for the calibration of LC/ESI-TOF MS and the average instrumental errors could be maintained at low levels for long-term analyses. This method could be applied not only to urine sample, but also to low sodium samples, such as saliva, by dissolving the sample in 1 μM sodium formate solution. This method provides a good solution for accurate mass detection of metabolomic analysis. ",0
5535,25559509,Retina evaluation with nonmydriatic ultrawide-field color imaging after cataract extraction surgeries in asymptomatic patients,"To evaluate the role of nonmydriatic ultrawide-field (UWF) color retinal imaging as a screening tool in the follow-up of asymptomatic patients after cataract extraction surgeries. A retrospective, observational case series. A review of electronic medical records identified patients after cataract extraction followed with UWF retinal imaging (Optos 200Tx; Optos, Dunfermline, Scotland). Images were graded and reviewed by a retina specialist. Outcome measures included image quality, the detection of peripheral lesions, and association with perioperative risk factors. Seventy-six eyes of 58 consecutive patients were enrolled. A good visualization of the peripheral retina was accomplished in more than 90% of patients. Peripheral lesions were identified in 40 eyes (52.6%) with no surgery-related retinal breaks and/or detachments. Additional pathologies were found in 35 eyes (46.1%). Nonmydriatic UWF color retinal imaging was found to be a useful screening tool in the follow-up of asymptomatic patients after cataract extraction in this series. ",0
5536,25559693,Platform switch and dental implants: A meta-analysis,"To test the null hypothesis of no difference in the implant failure rates, marginal bone loss (MBL) and postoperative infection in patients who received platform-switched implants or platform-matched implants, against the alternative hypothesis of a difference. Main search terms used in combination: dental implant, oral implant, platform switch, switched platform, platform mismatch, and dental implant-abutment design. An electronic search without time or language restrictions was undertaken in December/2014 in PubMed/Medline, Web of Science, Cochrane Oral Health Group Trials Register plus hand-searching. Eligibility criteria included clinical human studies, either randomized or not. Twenty-eight publications were included, with a total of 1216 platform-switched implants (16 failures; 1.32%) and 1157 platform-matched implants (13 failures; 1.12%). There was less MBL loss at implants with platform-switching than at implants with platform-matching (mean difference -0.29, 95% CI -0.38 to -0.19; P<0.00001). An increase of the mean difference of MBL between the procedures was observed with the increase in the follow-up time (P=0.001) and with the increase of the mismatch between the implant platform and the abutment (P=0.001). Due to lack of satisfactory information, meta-analyses for the outcomes 'implant failure' and 'postoperative infection' were not performed. The results of the present review should be interpreted with caution due to the presence of uncontrolled confounding factors in the included studies, most of them with short follow-up periods. The question whether platform-matched implants are more at risk for failure and loose more marginal bone than platform-switched implants has received increasing attention in the last years. As the philosophies of treatment alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures, forming a basis for optimum treatment. ",0
5537,25559837,An evaluation of direct PCR amplification,"To generate complete DNA profiles from blood and saliva samples deposited on FTA® and non-FTA® paper substrates following a direct amplification protocol. Saliva samples from living donors and blood samples from deceased individuals were deposited on ten different FTA® and non-FTA® substrates. These ten paper substrates containing body fluids were kept at room temperature for varying lengths of time ranging from one day to approximately one year. For all assays in this research, 1.2 mm punches were collected from each substrate containing one type of body fluid and amplified with reagents provided in the nine commercial polymerase chain reaction (PCR) amplification kits. The substrates were not subjected to purification reagent or extraction buffer prior to amplification. Success rates were calculated for all nine amplification kits and all ten substrates based on their ability to yield complete DNA profiles following a direct amplification protocol. Six out of the nine amplification kits, and four out of the ten paper substrates had the highest success rates overall. The data show that it is possible to generate complete DNA profiles following a direct amplification protocol using both standard (non-direct) and direct PCR amplification kits. The generation of complete DNA profiles appears to depend more on the success of the amplification kit rather than the than the FTA®- or non-FTA®-based substrates. ",0
5538,25559859,Blockade of lipid accumulation by silibinin in adipocytes and zebrafish,"Silibinin is a compound present mainly in milk thistle. In this study, we investigated the mechanism by which silibinin suppresses adipogenesis of 3T3-L1 cells, and evaluated the anti-adipogenic effect of silibinin in zebrafish. Silibinin reduced lipid accumulation by downregulating adipogenic factors, such as, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer binding protein α (C/EBPα), and fatty acid-binding protein 4 (FABP4). The reduction of these adipogenic protein levels was associated with the regulation of early adipogenic factors, such as, C/EBPβ and Krüppel-like factor 2 (KLF2), and was reflected in downregulation of lipid synthetic enzymes. Silibinin arrested cells in the G0/G1 phase of the cell cycle, accompanied by downregulation of cyclins and upregulation of p27, a cell cycle inhibitor. These results correlated with the finding of deactivation of extracellular signal-regulated kinase (ERK) and AKT, a serine/threonine-specific kinase. In addition, silibinin activated AMP-activated protein kinase α (AMPKα) to inhibit fatty acid synthesis. As observed in 3T3-L1 cells, silibinin inhibited lipid accumulation in zebrafish with the reduction of adipogenic factors and triglyceride levels. Our data revealed that silibinin inhibited lipid accumulation in 3T3-L1 cells and zebrafish, and this inhibitory effect was associated with abrogation of early adipogenesis via regulation of cell cycle and AMPKα signaling.  ",0
5539,25560091,Correlations between homocysteine and grey matter volume in patients with Alzheimer's disease,"Previous studies have reported that elevated total homocysteine levels are associated with cognitive dysfunction. However, few studies have examined the radiological markers of associated neuropathology in Alzheimer's disease (AD). We hypothesized that elevated levels of homocysteine are associated with cerebral grey matter volume loss. We compared the grey matter in a high homocysteine group and a normal homocysteine group using an optimized voxel-based morphometry. The study included 79 patients with AD who were divided into two groups: a high homocysteine group and a normal homocysteine group. The participants underwent brain magnetic resonance imaging using a standardized protocol and neurocognitive evaluation. Homocysteine tests and other routine laboratory examinations for dementia assessment were carried out in all patients. There was no significant difference in grey matter volume between the patients with high homocysteine levels and those with normal homocysteine levels. A multiple regression analysis also revealed that the levels of homocysteine were not associated with the grey matter volume in patients with AD. Homocysteine levels were not correlated significantly with Mini-Mental State Examination, Global Deterioration Scale, or Clinical Dementia Rating. Our results showed that elevated homocysteine levels are not associated with reduced cerebral grey matter volume in AD. Larger samples will be needed to assess potential correlations between homocysteine and neuroanatomical pathology in the future. ",0
5540,25560328,Nature of job and psychiatric problems: the experiences of industrial workers,"The present study aimed to examine the effect of nature of job (High risk/low risk) on psychiatric problems of 200 workers of Tata Motors Ltd. in Jamshedpur. The workers/participants were divided on the basis of the nature of their job (high/low risk) and their salary (high/low paid) resulting in four sub-groups with 50 participants respectively s. The Middlesex Hospital Questionnaire (M.H.Q) constructed by Crown and Crisp (1966) and adapted in Hindi by Srivastava and Bhat in 1974 was administered on the participants. Results clearly indicated that nature of job (high and low risk) played a significant role in creating psychiatric problems in workers. Workers doing high risk jobs showed a greater amount of psychiatric problems compared to workers doing low risk jobs in both high paid and low paid categories. Psychiatric problems included free-floating anxiety, obsessional traits and symptoms, phobic anxiety, somatic concomitants of anxiety, neurotic depression, and hysterical personality traits were seen more in high risk job workers. High risk job workers had significantly higher psychiatric problems compared to low risk job workers. ",0
5541,25560368,Inhibition of recombinase polymerase amplification by background DNA: a lateral flow-based method for enriching target DNA,"Recombinase polymerase amplification (RPA) may be used to detect a variety of pathogens, often after minimal sample preparation. However, previous work has shown that whole blood inhibits RPA. In this paper, we show that the concentrations of background DNA found in whole blood prevent the amplification of target DNA by RPA. First, using an HIV-1 RPA assay with known concentrations of nonspecific background DNA, we show that RPA tolerates more background DNA when higher HIV-1 target concentrations are present. Then, using three additional assays, we demonstrate that the maximum amount of background DNA that may be tolerated in RPA reactions depends on the DNA sequences used in the assay. We also show that changing the RPA reaction conditions, such as incubation time and primer concentration, has little effect on the ability of RPA to function when high concentrations of background DNA are present. Finally, we develop and characterize a lateral flow-based method for enriching the target DNA concentration relative to the background DNA concentration. This sample processing method enables RPA of 10(4) copies of HIV-1 DNA in a background of 0-14 μg of background DNA. Without lateral flow sample enrichment, the maximum amount of background DNA tolerated is 2 μg when 10(6) copies of HIV-1 DNA are present. This method requires no heating or other external equipment, may be integrated with upstream DNA extraction and purification processes, is compatible with the components of lysed blood, and has the potential to detect HIV-1 DNA in infant whole blood with high proviral loads.  ",0
5542,25560394,Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations,"Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations. ",0
5543,25560868,"A 44-year-old woman with metabolic acidosis, high anion gap, and delayed neurologic deterioration","A 44-year-old woman was brought to the ED from John F. Kennedy International Airport. The patient was returning with her son from a 3-month visit to Bangladesh. Her journey started with a 4-h flight from Dhaka, Bangladesh to Dubai, United Arab Emirates. She consumed 240 mL of whiskey during the flight. This was followed by a 14-h flight from Dubai to New York. According to the patient's son, she did not consume any alcohol during the second flight. The patient was in her usual state of health with normal mentation throughout her journey. Upon landing, she started complaining of shortness of breath. After disembarking, she was witnessed to have seizure-like activity with involuntary passage of urine, following which she collapsed. The patient was intubated by emergency medical services in the field. ",0
5544,25561149,An exclusively based parenteral fish-oil emulsion reverses cholestasis,"Prolonged parenteral nutrition (PN) leads to liver damage. Recent interest has focused on the lipid component of PN. A lipid emulsion based on w-3 fatty acids decrease conjugated bilirubin. A mixed lipid emulsion derived from soybean, coconut, olive, and fish oils reverses jaundice. Here we report the reversal of cholestasis and the improvement of enteral feeding tolerance in 1 infant with intestinal failure-associated liver disease. Treatment involved the substitution of a mixed lipid emulsion with one containing primarily omega-3 fatty acids during 37 days. Growth and biochemical tests of liver function improved significantly. This suggests that fat emulsions made from fish oils may be more effective means of treating this condition compared with an intravenous lipid emulsion containing soybean oil, medium -chain triglycerides, olive oil, and fish oil.  La nutrición parenteral prolongada produce daño hepático. Recientemente se ha comunicado el efecto de las emulsiones lipídicas intravenosas basadas exclusivamente en ácidos grasos omega-3 en la resolución de la colestasis. Lo mismo se ha observado con el uso de emulsiones lipídicas mixta derivadas del aceite de soja, coco, oliva y pescado. Comunicamos la desaparición de colestasis y mejoría de la tolerancia enteral en un niño con enfermedad hepática asociada a nutrición parenteral. El tratamiento consistió en sustituir una emulsión lipídica mixta por otra que contenía de forma exclusiva aceite de pescado durante 37 días. El crecimiento y los datos bioquímicos de función hepática mejoraron de forma significativa. Este caso sugiere que emulsiones lipídicas intravenosas a partir de aceite de pescado pueden ser mas eficaces para tratar la colestasis si se comparan con emulsiones mixtas. ",0
5545,25561169,"Structural insights into stereospecific reduction of α, β-unsaturated carbonyl substrates by old yellow enzyme from Gluconobacter oxydans","We report the crystal structure of old yellow enzyme (OYE) family protein Gox0502 (a.a 1-315) in free form at 3.3 Å. Detailed structural analysis revealed the key residues involved in stereospecific determination of Gox0502, such as Trp66 and Trp100. Structure-based computational analysis suggested the bulky side chains of these tryptophan residues may play important roles in product stereoselectivity. The introduction of Ile or Phe or Tyr mutation significantly reduced the product diastereoselectivity. We hypothesized that less bulky side chains at these critical residues could create additional free space to accommodate intermediates with different conformations. Notably, the introduction of Phe mutation at residue Trp100 increased catalytic activity compared to wild-type Gox0502 toward a set of substrates tested, which suggests that a less bulky Phe side chain at residue W100F may facilitate product release. Therefore, Gox0502 structure could provide useful information to generate desirable OYEs suitable for biotechnological applications in industry.  ",0
5546,25561195,Surgical Care and Health Systems,"""While surgical care impacts a wide variety of diseases and conditions with non-operative and operative services, both preventive and curative, there has been little discussion concerning how surgery might be integrated within the health system of a low and middle-income country (LMIC), nor how strengthening surgical services may improve health systems and population health. We reviewed reports from several meetings of the working group on health systems strengthening of the Global Initiative for Emergency and Essential Surgical Care, and also performed a review of the literature including the search terms """"surgery,"""" """"health system,"""" """"developing country,"""" """"health systems strengthening,"""" """"health information system,"""" """"financing,"""" """"governance,"""" and """"integration."""" The literature search revealed no reports which focused on the integration of surgical services within a health system or as a component of health system strengthening. A conceptual model of how surgical care might be integrated within a health system is proposed, based on the discussions of our working group, combined with sources from the medical literature, and utilizing the World Health Organization's conceptual model of a health system. Strengthening the delivery of surgical services in LMICs will require inputs at multiple levels within a health system, and this effort will require the coalescence of committed individuals and organizations, supported by civil society. """,0
5547,25561307,Considering care-seeking behaviors reveals important differences among HIV-positive women not engaged in care: implications for intervention,"""We sought to examine characteristics of HIV-positive women with varying levels of engagement in care and care-seeking behaviors. From 2010 to 2013, in a multi-site US-based study of engagement in care among HIV-positive women, we conducted baseline interviews, which included socio-demographic, clinical, and risk behavior characteristics, and barriers to care. We used multinomial logistic regression to compare differences among three distinct categories of 748 women: engaged in care; not engaged in care, but seeking care (""""seekers""""); and not engaged in care and not seeking care (""""non-seekers""""). Compared with women in care, seekers were more likely to be uninsured and to report fair or poor health status. In contrast, non-seekers were not only more likely to be uninsured, but, also, to report current high-risk drug use and sexual behaviors, and less likely to report transportation as a barrier to care. Examining care-seeking behaviors among HIV-positive women not engaged in care revealed important differences in high-risk behaviors. Because non-seekers represent a particularly vulnerable population of women who are not engaged in care, interventions targeting this population likely need to address drug use and be community-based given their limited interaction with the health care system. """,0
5548,25561470,Regulation of the transcription factor EB-PGC1α axis by beclin-1 controls mitochondrial quality and cardiomyocyte death under stress,"In cardiac ischemia-reperfusion injury, reactive oxygen species (ROS) generation and upregulation of the hypoxia-inducible protein BNIP3 result in mitochondrial permeabilization, but impairment in autophagic removal of damaged mitochondria provokes programmed cardiomyocyte death. BNIP3 expression and ROS generation result in upregulation of beclin-1, a protein associated with transcriptional suppression of autophagy-lysosome proteins and reduced activation of transcription factor EB (TFEB), a master regulator of the autophagy-lysosome machinery. Partial beclin-1 knockdown transcriptionally stimulates lysosome biogenesis and autophagy via mTOR inhibition and activation of TFEB, enhancing removal of depolarized mitochondria. TFEB activation concomitantly stimulates mitochondrial biogenesis via PGC1α induction to restore normally polarized mitochondria and attenuate BNIP3- and hypoxia-reoxygenation-induced cell death. Conversely, overexpression of beclin-1 activates mTOR to inhibit TFEB, resulting in declines in lysosome numbers and suppression of PGC1α transcription. Importantly, knockdown of endogenous TFEB or PGC1α results in a complete or partial loss, respectively, of the cytoprotective effects of partial beclin-1 knockdown, indicating a critical role for both mitochondrial autophagy and biogenesis in ensuring cellular viability. These studies uncover a transcriptional feedback loop for beclin-1-mediated regulation of TFEB activation and implicate a central role for TFEB in coordinating mitochondrial autophagy with biogenesis to restore normally polarized mitochondria and prevent ischemia-reperfusion-induced cardiomyocyte death.  ",0
5549,25561514,Meox2/Tcf15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake,"Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking. Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport-related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility. Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage. ",0
5550,25561743,"A novel post-translational modification of nucleolin, SUMOylation at Lys-294, mediates arsenite-induced cell death by regulating gadd45α mRNA stability","Nucleolin is a ubiquitously expressed protein and participates in many important biological processes, such as cell cycle regulation and ribosomal biogenesis. The activity of nucleolin is regulated by intracellular localization and post-translational modifications, including phosphorylation, methylation, and ADP-ribosylation. Small ubiquitin-like modifier (SUMO) is a category of recently verified forms of post-translational modifications and exerts various effects on the target proteins. In the studies reported here, we discovered SUMOylational modification of human nucleolin protein at Lys-294, which facilitated the mRNA binding property of nucleolin by maintaining its nuclear localization. In response to arsenic exposure, nucleolin-SUMO was induced and promoted its binding with gadd45α mRNA, which increased gadd45α mRNA stability and protein expression, subsequently causing GADD45α-mediated cell death. On the other hand, ectopic expression of Mn-SOD attenuated the arsenite-generated superoxide radical level, abrogated nucleolin-SUMO, and in turn inhibited arsenite-induced apoptosis by reducing GADD45α expression. Collectively, our results for the first time demonstrate that nucleolin-SUMO at K294R plays a critical role in its nucleus sequestration and gadd45α mRNA binding activity. This novel biological function of nucleolin is distinct from its conventional role as a proto-oncogene. Therefore, our findings here not only reveal a new modification of nucleolin protein and its novel functional paradigm in mRNA metabolism but also expand our understanding of the dichotomous roles of nucleolin in terms of cancer development, which are dependent on multiple intracellular conditions and consequently the appropriate regulations of its modifications, including SUMOylation.  ",0
5551,25561789,Motility patterns of ex vivo intestine segments depend on perfusion mode,"To evaluate and characterize motility patterns from small intestinal gut segments depending on different perfusion media and pressures. Experiments were carried out in a custom designed perfusion chamber system to validate and standardise the perfusion technique used. The perfusion chamber was built with a transparent front wall allowing for optical motility recordings and a custom made fastener to hold the intestinal segments. Experiments with different perfusion and storage media combined with different luminal pressures were carried out to evaluate the effects on rat small intestine motility. Software tools which enable the visualization and characterization of intestinal motility in response to different stimuli were used to evaluate the videotaped experiments. The data collected was presented in so called heatmaps thus providing a concise overview of form and strength of contractility patterns. Furthermore, the effect of different storage media on tissue quality was evaluated. Haematoxylin-Eosin stainings were used to compare tissue quality depending on storage and perfusion mode. Intestinal motility is characterized by different repetitive motility patterns, depending on the actual situation of the gut. Different motility patterns could be recorded and characterized depending on the perfusion pressure and media used. We were able to describe at least three different repetitive patterns of intestinal motility in vitro. Patterns with an oral, anal and oro-anal propagation direction could be recorded. Each type of pattern finalized its movement with or without a subsequent distension of the wavefront. Motility patterns could clearly be distinguished in heatmap diagrams. Furthermore undirected motility could be observed. The quantity of the different patterns varies and is highly dependent on the perfusion medium used. Tissue preservation varies depending on the perfusion medium utilized, therefore media with a simple composition as Tyrode solution can only be recommended for short time experiments. The more complex media, MEM-HEPES medium and especially AQIX(®) RS-I tissue preservation reagent preserved the tissue much better during perfusion. Perfusion media have to be carefully chosen considering type and duration of the experiments. If excellent tissue quality is required, complex media are favorable. Perfusion pressure is also of great importance due to the fact that a minimum amount of luminal pressure seems to be necessary to trigger intestinal contractions. ",0
5552,25561820,Modified simultaneous integrated boost radiotherapy for an unresectable huge refractory pelvic tumor diagnosed as a rectal adenocarcinoma,"A clinical trial of radiotherapy with modified simultaneous integrated boost (SIB) technique against huge tumors was conducted. A 58-year-old male patient who had a huge pelvic tumor diagnosed as a rectal adenocarcinoma due to familial adenomatous polyposis was enrolled in this trial. The total dose of 77 Gy (equivalent dose in 2 Gy/fraction) and 64.5 Gy was delivered to the center of the tumor and the surrounding area respectively, and approximately 20% dose escalation was achieved with the modified SIB technique. The tumor with an initial maximum size of 15 cm disappeared 120 d after the start of the radiotherapy. Performance status of the patient improved from 4 to 0. Radiotherapy with modified SIB may be effective for patients with a huge tumor in terms of tumor shrinkage/disappearance, improvement of QOL, and prolongation of survival.  ",0
5553,25562056,Tuberculous meningitis in child born in the US to immigrants from a tuberculosis-endemic country,This is a case of a child born in the US to immigrant parents from a tuberculosis (TB)-endemic area of Liberia who was diagnosed with TB meningitis after a greater than 1-month history of unremitting fever. This report aims to highlight the importance of early identification of TB in the pediatric population with risk factors for TB and considering TB as a diagnosis among US born children to immigrants from TB-endemic countries. ,0
5554,25562369,Performance of microbial phytases for gastric inositol phosphate degradation,"Microbial phytases catalyze dephosphorylation of phytic acid, thereby potentially releasing chelated iron and improving human iron absorption from cereal-based diets. For this catalysis to take place in vivo, the phytase must be robust to low pH and proteolysis in the gastric ventricle. This study compares the robustness of five different microbial phytases, evaluating thermal stability, activity retention, and extent of dephosphorylation of phytic acid in a simulated low-pH/pepsin gastric environment and examines secondary protein structural changes at low pH via circular dichroism. The Peniophora lycii phytase was found to be the most thermostable, but the least robust enzyme in gastric conditions, whereas the Aspergillus niger and Escherichia coli phytases proved to be most resistant to gastric conditions. The phytase from Citrobacter braakii showed intermediate robustness. The extent of loss of secondary structure at low pH correlated positively with the extent of activity loss at low pH.  ",0
5555,25562428,PDZK1/NHERF3 differentially regulates corticotropin-releasing factor receptor 1 and serotonin 2A receptor signaling and endocytosis,"The corticotropin-releasing factor receptor 1 (CRFR1) and serotonin 2A receptor (5-HT2AR) are linked to cellular mechanisms underlying stress anxiety and depression. Both receptors are members of the G protein-coupled receptor (GPCR) superfamily and encode class I PSD-95/DiscsLarge/Zona Occludens 1 (PDZ) binding motifs (-S/T-x-V/I/L) at the end of their carboxyl-terminal tails. We have identified PDZK1, also referred to as Na(+)/H(+) exchange regulatory cofactor 3 (NHERF3) as both a CRFR1- and 5-HT2AR-interacting protein. We have examined whether PDZK1 plays a role in regulating both CRFR1 and 5-HT2AR activity. We find that while PDZK1 interactions with CRFR1 are PDZ binding motif-dependent, PDZK1 associates with 5-HT2AR in a PDZ binding motif-independent manner and CRFR1 expression, but not 5-HT2AR expression, redistributes PDZK1 to the plasma membrane in PDZ binding motif-dependent manner. PDZK1, negatively regulates 5-HT2AR endocytosis and has no effect upon 5-HT2AR-mediated ERK1/2 phosphorylation. In contrast, PDZK1 overexpression does not affect CRFR1 endocytosis, but selectively increases CRFR1-stimulated ERK1/2 phosphorylation. Similar to what has been previously reported for PSD-95 and SAP97, PDZK1 positively influences 5-HT2AR-stimulated inositol phosphate formation, but does not contribute to the regulation of CRFR1-mediated cAMP signaling. Taken together, these results indicate that PDZK1 differentially regulates the signaling and trafficking of CRFR1 and 5-HT2AR via PDZ-dependent and -independent mechanisms, respectively. ",0
5556,25562447,Code status discussions in psychiatric and medical inpatients,"""The Patient Self-Determination Act along with regulatory standards and institutional standards of care highlight the need for collaboration between care providers and patients with respect to goals of care and, in emergency situations, code status and measures to be taken in keeping with patients' wishes. Addressing code status may be lacking in patients who require psychiatric hospitalization due to the nature of psychiatric illness, relative medical stability, and a general expectation of survival. We sought to compare code status documentation and discussion between psychiatric and medical inpatients, as this knowledge will help shape future interventions for process improvement. We conducted a retrospective chart review of hospitalized patients in psychiatric and medical units during a 12-month period in 2008. For those with multiple admissions, we reviewed only the index (or first) hospitalization. Data collected included demographic information, clinical information regarding cancer as a primary diagnosis or a diagnosis that met National Hospice and Palliative Care Organization (NHPCO) guidelines, code status order and discussion documentation, the presence of an advance directive, length of stay, and 1-year mortality. Data were summarized using mean values, percentages, and frequencies. The 2 groups (psychiatric and medical groups) were compared. The charts of 276 psychiatric patients and 317 general medical patients were reviewed. More psychiatric patients had dementia (P < .001). Medical inpatients had a higher rate of code status order documented on admission (96% vs 65%, P < .001) and """"full-code, discussed"""" order (67% vs 33%, P < .001). Psychiatric inpatients had more """"do not resuscitate/do not intubate"""" orders (20% vs 13%, P = .037), more frequent changes in code status order (18% vs 7%, P < .001), and a higher percentage of advance directives (46% vs 25%, P < .001). A code status discussion with hospitalized patients needs to occur at admission regardless of reason for admission. Strategies are needed to improve this process for psychiatric inpatients. """,0
5557,25562877,Dysfluency in a service member with comorbid diagnoses: a case study,"Because of the noted increase in dysfluency among service members returning from Iraq and Afghanistan, this article describes differentiation between the various types of fluency as well as an evaluation and treatment course of a service member returning from war with the comorbid diagnoses of post-traumatic stress disorder, mild traumatic brain injury, and resulting stuttering. The subject of this case study signed a consent on his admission to National Intrepid Center of Excellence (NICoE) for use of any clinical information for research purposes. The patient-centered method of his evaluation and treatment is one standard for NICoE's 4-week treatment program. Fluency data were collected from the patient using observational and standardized assessment (Stuttering Severity Instrument-4). The patient underwent a course of treatment using fluency strategy education and practice to lead to generalization of skills across all communication environments. This service member responded favorably following a short course of fluency treatment because of the psychogenic nature of his stuttering, which was a symptom of his psychological health diagnoses. The NICoE patient-centered care model achieved the desired results of fluency and improved overall function in this service member. ",0
5558,25562960,Host factor Moloney leukemia virus 10 (MOV10) protein inhibits replication of the xenotropic murine leukemia virus-related virus (XMRV)],"We investigated inhibition of Moloney leukemia virus 10 (MOV10) upon xenotropic murine leukemia virus-related virus (XMRV) and made a preliminary study of the mechanism of action. Using transfection, infection, western blotting and real-time polymerase chain reaction, we found that MOV10 inhibited XMRV replication. Using MOV10 overexpressed in viral producer cells, MOV10 was shown to reduce the infectivity of XMRV. MOV10 could be incorporated into XMRV, suggesting that MOV10 could undergo encapsidation by XMRV during viral assembly. MOV10 could also restrict the DNA production of XMRV in target cells. We found that the putative RNA-helicase domain of MOV10 maintained most of its XMRV inhibition. These results suggest that MOV10 could be required during the retroviral lifecycle. Perturbation of MOV10 disrupts the generation of infectious viral particles, suggesting that MOV10 has broad antiretroviral activity. Hence, MOV10 could be actively involved in host defense against retroviral infection. ",0
5559,25563297,'I don't get this climate stuff!' Making sense of climate change among the corporate middle class in Lagos,"Public engagement continues to be central to wider efforts to address climate change. This study contributes to public engagement debates by investigating engagement with climate change among an often overlooked group, the corporate middle class in Africa's second largest megacity, Lagos. Combining survey and interviews, I focus analysis on three aspects: awareness, knowledge and concern; role of scientific and social frames in shaping general attitude; and spatial attribution of causes and consequences. The study reveals a universal awareness and high concern about climate change among the respondents, although understanding and perceptions of climate change are significantly socially framed. Social situatedness, more than scientific facts, is the most important definer of overall engagement with climate change. This study thus underscores a nuanced constructionist stance, showing how corporate professionals' 'ways of knowing' climate change is underpinned by a certain co-production between scientific and socio-experiential frames. I highlight implications for research and public engagement with climate change.  ",0
5560,25563429,Phase I dose escalation study of lestaurtinib in patients with myelofibrosis,"We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. Dose-limiting toxicities were observed in three patients overall, at the 100 mg (n = 1) and 160 mg (n = 2) twice-daily dose levels. The maximum tolerated dose was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event. Sixteen patients were evaluable for response at 12 weeks. Seven patients had clinical improvement by International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria. Meaningful reductions in JAK2V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of signal transducer and activator of transcription 5 (STAT5): doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed (ClinicalTrials.gov identifier: NCT00668421).  ",0
5561,25563471,In-hospital outcomes and mortality in octogenarians after percutaneous coronary intervention,"There is systematic growth in the number of number of elderly patients treated with percutaneous coronary intervention (PCI); however, little is known about PCI results in the very elderly (long-lived) patients aged 85 years and above. To assess the demographic, clinical, and angiographic findings in patients aged > 85 years (GER), undergoing PCI, compared with younger patients treated in the year 2012. This was a single centre retrospective study based on a consecutive group of 920 patients with coronary disease (stable and acute coronary syndrome [ACS]). Patients were divided into two groups: GER aged 85 years and over (n = 82) and controls (CG) below 85 years (n = 838). The mean age in the GER group was 88.6 vs. 66.7 years in the CG. There were more females in the GER group (57% vs. 29%) than in the CG (p < 0.001). The indication for PCI was mainly ACS in GER (65%) vs. CG (50%) including ST segment elevation myocardial infarction (STEMI) 30% vs. 29% (p = NS), ACS non-STEMI 35% vs. 20% (p = 0.01). GER patients had more comorbidities and more advanced multivessel coronary artery disease. The ratio of procedural success was lower in GER compared to CG. The incidence of in-hospital death was higher in GER (4.8%) compared to CG (0.83%); the most common complication in GER group was contrast-induced nephropathy (18.2% vs. 6.2%). Major adverse cardiovascular events were significantly more frequent in GER patients with ACS compared to CG patients with the same diagnosis. Patients > 85 years old, especially with ACS undergoing PCI, are at greater risk of in-hospital complications, especially contrast-induced nephropathy and procedural complications, compared to younger patients. ",0
5562,25563487,"Circadian clocks in rat skin and dermal fibroblasts: differential effects of aging, temperature and melatonin","As a peripheral tissue localized at the interface between internal and external environments, skin performs functions which are critical for the preservation of body homeostasis, in coordination with environmental changes. Some of these functions undergo daily variations, such as temperature or water loss, suggesting the presence of time-keeping mechanisms. Rhythmic functions are controlled by a network of circadian oscillators present virtually in every cell and coordinated by the central clock located in the suprachiasmatic nuclei. At the molecular level, circadian rhythms are generated by conserved transcriptional-translational feedback loops involving several clock genes, among which Per1 and Per2 play a central role. Here we characterize clock activity in skin of the transgenic Per1-luciferase rat during postnatal development and adulthood, by real-time recording of bioluminescence in explants and primary dermal fibroblasts, and report marked transformation in circadian properties, from early life to aging. Using primary dermal fibroblast cultures we provide evidence that melatonin treatment phase dependently increases the amplitude of circadian oscillations and that ambient temperature impacts on their period, with slight overcompensation. Together, these findings demonstrate that skin contains a self-sustained circadian clock undergoing age-dependent changes. Dermal fibroblasts, one of the major skin cell types, also exhibit robust, yet specific, circadian rhythmicity which can be fine-tuned by both internal (melatonin) and external (temperature) factors.  ",0
5563,25563703,Correlation of clinical stage and performance status with quality of life in patients seen in a pancreas multidisciplinary clinic,"The objectives of this study were to evaluate quality of life (QoL) in patients presenting to the Johns Hopkins Pancreas Multidisciplinary Clinic (PMDC), and to examine associations between disease status, performance status, and QoL in order to identify patient subgroups that are most at risk for reduced QoL. Data from 77 patients were evaluated. At initial presentation, disease and performance status were assessed, as well as QoL, which was obtained with the European Organisation for Research and Treatment of Cancer QLQ-PAN26 questionnaire. Statistical analyses examined associations between QoL, disease status, and performance status. Digestive symptoms (P < .003) significantly differed by pancreatic disease status (resectable, resected, locally advanced, and metastatic). Patients with a worse performance status, defined as Eastern Cooperative Oncology Group ≥ 1, were more likely to report symptomatic pancreatic pain (P = .001), digestive symptoms (P = .017), cachexia (P = .004), and ascites (P < .001) compared with patients with a performance status of 0. The majority (92%) of patients reported a significant fear of future health problems, regardless of disease status or performance status. Although several measures of QoL have been observed in all patients, certain measures appear to correlate specifically with worse disease status. Therefore, routine assessment of QoL is suggested in order to guide treatment decisions. Further investigation on optimizing the use of QoL measures and patient-reported outcomes to better tailor management is warranted. ",0
5564,25563714,A randomised double-blind placebo-controlled 12- week feasibility trial of methotrexate added to treatment as usual in early schizophrenia: study protocol for a randomised controlled trial,"Methotrexate is a commonly used anti-inflammatory and immunosuppressive drug. There is growing evidence that inflammatory processes are involved in the pathogenesis of schizophrenia. In our recent randomised double-blind placebo-controlled clinical trial in Pakistan and Brazil, the addition of minocycline (antibiotic and anti-inflammatory drug) for 1 year to treatment as usual reduced negative symptoms and improved some cognitive measures. A meta-analysis of cytokine changes in the peripheral blood has identified IL-2, IFN-gamma, TNF-alpha and soluble IL-2 receptor as trait markers of schizophrenia because their levels were elevated during acute exacerbations and reduced in remission. This suggests immune activation and an inflammatory syndrome in schizophrenia. Based on the evidence of the strong anti-inflammatory properties of methotrexate, we propose that low-dose methotrexate may be an effective therapy in early schizophrenia. This is a double-blind placebo-controlled study of methotrexate added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be with 72 patients, 36 in each arm over 3 months. There will be screening, randomisation and follow-up visits. Full clinical assessments will be carried out at baseline, 2, 4, 8 and 12 weeks. Social and cognitive assessments will be carried out at baseline and 12 weeks. Methotrexate will be given at a dose of 10 mgs orally once a week for a 3-month period. Evidence suggests inflammatory processes are involved in the pathogenesis of schizophrenia and anti-inflammatory treatments have shown to have some beneficial effects. Methotrexate is a known immunosuppressant and anti-inflammatory drug. The aim of this study is to establish the degree of improvement in positive and negative symptoms, as well as cognitive functioning with the addition of methotrexate to treatment as usual.ClinicalTrials.gov identifier: NCT02074319 (24 February 2014). ",0
5565,25563760,Two pairs of brothers with juvenile idiopathic arthritis (JIA): case reports],"This is a case report of juvenile idiopathic arthritis (JIA) in two pairs of brothers followed in the department of pediatric rheumatology, Universidade Federal da Bahia. Genetic involvement in JIA pathogenesis is clear and the risk of recurrence among siblings supports this contribution. An important landmark of this discovery involves the acknowledgment of major histocompatibility complex (MHC) polymorphism contribution to JIA development susceptibility. Despite many advances, the numerous available studies cannot explain several implicit mechanisms in JIA pathogenesis yet.  ",0
5566,25563866,Matched Case-Control Analysis Comparing Laparoscopic and Open Pylorus-preserving Pancreaticoduodenectomy in Patients With Periampullary Tumors,"To evaluate the safety, feasibility, and oncologic outcomes of laparoscopic pylorus-preserving pancreaticoduodenectomy (L-PPPD) to treat periampullary tumors. The clinical outcomes of L-PPPD were compared with open pylorus-preserving pancreaticoduodenectomy (O-PPPD). Despite recent advances in laparoscopic pancreatic surgery, few studies have compared L-PPPD with O-PPPD. The safety, short-term clinical benefits, and oncologic outcomes of L-PPPD remain controversial. Between January 2007 and December 2012, a total of 2192 patients diagnosed with periampullary tumors were treated with curative resection at our institution. Of these patients, 137 underwent a laparoscopic approach and 2055 an open technique. A retrospective study was performed to evaluate the safety, feasibility, and oncologic outcomes of L-PPPD compared with O-PPPD. The mean operation time for the L-PPPD group was longer than for the O-PPPD group (P < 0.001). Estimated blood loss was similar, as was the incidence of complications, such as pancreatic fistula and delayed gastric empting (P > 0.05). The mean number of analgesic injections administered was lower in the L-PPPD group than in the O-PPPD group (P < 0.001), and the mean duration of the postoperative hospital stays was shorter (P < 0.001). The surgical resection margins and the number of lymph nodes in the resected specimens did not differ between the 2 groups, and there was no significant difference in overall survival curves. L-PPPD had the typical advantages of minimally invasive abdominal procedures, such as less pain, shorter hospital stay, and quicker recovery. It is technically safe and feasible, and has favorable oncologic outcomes in comparison with O-PPPD in patients with periampullary tumors. ",0
5567,25563986,Innate immunity for better or worse govern the allograft response,"To update knowledge concerning the cause and consequences of the detrimental forms of innate immunity that inevitably occurs in peritransplant period tissue and cellular transplants. In addition, we review the information that a newly discovered, engraftment-promoting, and tolerance-inducing macrophage population is identified and characterized. The allograft response mounted by adaptive immune cells is shaped by innate immunity. The early allograft response is uniquely intense as a result of activation of the innate immune response created by ischemia reperfusion injury in organ transplants, delayed revascularization of cell transplants, and hypoxia. Inflammation is created by both cellular 'debris' and cytokines. However, a newly discovered prominent, albeit fragile, tissue-resident, noninvasive, and immunoregulatory macrophage promotes engraftment and tolerance. The role of intracellular 'debris' as well as inflammation in evoking detrimental rejection-provoking peritransplant inflammation is emphasized as well as characterization of a prominent and highly immunoregulatory albeit fragile macrophage population that is tissue-resident and does not circulate is characterized. Opportunity lies in the ability to rein in detrimental peri-transplant inflammation and in the ability to promote the longevity of a subpopulation of highly potent tissue-resident immunoregulatory macrophages. ",0
5568,25563992,Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance,"The present review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, and to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications. ",0
5569,25564662,Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice,"Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.  ",0
5570,25565063,Trends in imaging after diagnosis of thyroid cancer,"The largest growth noted among differentiated thyroid cancer (DTC) diagnosis is in low-risk cancers. Trends in imaging after the diagnosis of DTC are understudied. Hypothesizing a reduction in imaging use due to rising low-risk disease, the authors evaluated postdiagnosis imaging patterns over time and patient characteristics that are associated with the likelihood of imaging. Using the Surveillance, Epidemiology, and End Results-Medicare database, the authors identified patients diagnosed with localized, regional, or distant DTC between 1991 and 2009. Medicare claims were reviewed for use of neck ultrasound, iodine-131 (I-131) scan, or positron emission tomography (PET) scan within 3 years after diagnosis. Trends in imaging use were evaluated using regression analyses. Multivariable logistic regression was used to estimate the likelihood of imaging based on patient characteristics. A total of 23,669 patients were included. Compared with patients diagnosed between 1991 and 2000, those diagnosed between 2001 and 2009 were more likely to have localized disease (P<.001) and tumors measuring <1 cm (P<.001). Use of neck ultrasound and I-131 scans increased in patients with localized disease (P ≤.001 and P = .003, respectively), regional disease (P<.001 and P<.001, respectively), and distant metastasis (P = .001 and P = .015, respectively). Patients diagnosed after 2000 were more likely to undergo neck ultrasound (odds ratio, 2.15; 95% confidence interval, 2.02-2.28) and I-131 scan (odds ratio, 1.44; 95% confidence interval, 1.35-1.54). Compared with 1996 through 2004, PET scan use from 2005 to 2009 increased 32.4-fold (P≤.001) in patients with localized disease, 13.1-fold (P<.001) in patients with regional disease, and 33.4-fold (P<.001) in patients with distant DTC. Despite an increase in the diagnosis of low-risk disease, the use of postdiagnosis imaging increased among patients with all stages of disease. The largest growth observed was in the use of PET after 2004. ",0
5571,25565309,Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis,"Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.  ",0
5572,25565401,Forkhead box G1 gene haploinsufficiency: an emerging cause of dyskinetic encephalopathy of infancy,"14q12 deletions, including the Forkhead Box G1 (FOXG1) gene and point mutations of this gene, are associated with a complex encephalopathy described as a congenital variant of Rett syndrome. A mixture of jerks, athetosis, chorea, and dystonia is observed early in life in many patients. The aim of this article is to report on the spectrum of movement disorders associated with FOXG1 haploinsufficiency, as described in the literature. We provide a review of the cases reported in the literature, adding two new patients. We searched for a comprehensive set of clinical features, including age at onset and semiology of the movement disorder, occurrence and type of stereotypies, and neurological outcome. A total of 51 cases were included in our study. Nonepileptic abnormal movements occurred in 33 cases, often variably combined and presenting during the first year of life. The neurological phenotype of FOXG1 haploinsufficiency shows the features of a dyskinetic encephalopathy of infancy. ",0
5573,25565640,"Individual-Specific, Beat-to-beat Trending of Significant Human Blood Loss: The Compensatory Reserve","Current monitoring technologies are unable to detect early, compensatory changes that are associated with significant blood loss. We previously introduced a novel algorithm to calculate the Compensatory Reserve Index (CRI) based on the analysis of arterial waveform features obtained from photoplethysmogram recordings. In the present study, we hypothesized that the CRI would provide greater sensitivity and specificity to detect blood loss compared with traditional vital signs and other hemodynamic measures. Continuous noninvasive vital sign waveform data, including CRI, photoplethysmogram, heart rate, blood pressures, SpO2, cardiac output, and stroke volume, were analyzed from 20 subjects before, during, and after an average controlled voluntary hemorrhage of ∼1.2 L of blood. Compensatory Reserve Index decreased by 33% in a linear fashion across progressive blood volume loss, with no clinically significant alterations in vital signs. The receiver operating characteristic area under the curve for the CRI was 0.90, with a sensitivity of 0.80 and specificity of 0.76. In comparison, blood pressures, heart rate, SpO2, cardiac output, and stroke volume had significantly lower receiver operating characteristic area under the curve values and specificities for detecting the same volume of blood loss. Consistent with our hypothesis, CRI detected blood loss and restoration with significantly greater specificity than did other traditional physiologic measures. Single measurement of CRI may enable more accurate triage, whereas CRI monitoring may allow for earlier detection of casualty deterioration.  ",0
5574,25565844,"Biokinetics of zinc oxide nanoparticles: toxicokinetics, biological fates, and protein interaction","Biokinetic studies of zinc oxide (ZnO) nanoparticles involve systematic and quantitative analyses of absorption, distribution, metabolism, and excretion in plasma and tissues of whole animals after exposure. A full understanding of the biokinetics provides basic information about nanoparticle entry into systemic circulation, target organs of accumulation and toxicity, and elimination time, which is important for predicting the long-term toxic potential of nanoparticles. Biokinetic behaviors can be dependent on physicochemical properties, dissolution property in biological fluids, and nanoparticle-protein interaction. Moreover, the determination of biological fates of ZnO nanoparticles in the systemic circulation and tissues is critical in interpreting biokinetic behaviors and predicting toxicity potential as well as mechanism. This review focuses on physicochemical factors affecting the biokinetics of ZnO nanoparticles, in concert with understanding bioavailable fates and their interaction with proteins.  ",0
5575,25565925,Common somatic alterations identified in maffucci syndrome by molecular karyotyping,"Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS.  ",0
5576,25565940,"Functional genomic analysis and neuroanatomical localization of miR-2954, a song-responsive sex-linked microRNA in the zebra finch","Natural experience can cause complex changes in gene expression in brain centers for cognition and perception, but the mechanisms that link perceptual experience and neurogenomic regulation are not understood. MicroRNAs (miRNAs or miRs) have the potential to regulate large gene expression networks, and a previous study showed that a natural perceptual stimulus (hearing the sound of birdsong in zebra finches) triggers rapid changes in expression of several miRs in the auditory forebrain. Here we evaluate the functional potential of one of these, miR-2954, which has been found so far only in birds and is encoded on the Z sex chromosome. Using fluorescence in situ hybridization and immunohistochemistry, we show that miR-2954 is present in subsets of cells in the sexually dimorphic brain regions involved in song production and perception, with notable enrichment in cell nuclei. We then probe its regulatory function by inhibiting its expression in a zebra finch cell line (G266) and measuring effects on endogenous gene expression using Illumina RNA sequencing (RNA-seq). Approximately 1000 different mRNAs change in expression by 1.5-fold or more (adjusted p < 0.01), with increases in some but not all of the targets that had been predicted by Targetscan. The population of RNAs that increase after miR-2954 inhibition is notably enriched for ones involved in the MAP Kinase (MAPK) pathway, whereas the decreasing population is dominated by genes involved in ribosomes and mitochondrial function. Since song stimulation itself triggers a decrease in miR-2954 expression followed by a delayed decrease in genes encoding ribosomal and mitochondrial functions, we suggest that miR-2954 may mediate some of the neurogenomic effects of song habituation.  ",0
5577,25566134,Frequency of provision of knowledge of performance on skill acquisition in older persons,"The provision of feedback is a crucial factor for the evolution of the learner's performance. It is known that the knowledge of performance has the function of guiding the learner's attention to critical aspects of the movement pattern. The objective of this study was to examine the effect of frequency of knowledge of performance (KP) during the acquisition of the basketball free throw in older persons. Sixty active individuals (men and women) aged 60-69 years of age, divided into three experimental groups received KP in 100, 66, and 33% of their attempts during three practice sessions totaling 90 trials. The task was the basketball free throw. Volunteers were asked to conduct tests of immediate retention, 24 h retention, and 24 h transfer test, after the last practice session. During the acquisition phase, the volunteers received KP on the movement pattern on the previous attempt, which was obtained from a qualitative hierarchical checklist of the free throw (14 items). Sessions were recorded in order to confirm whether volunteers were able to score throughout sessions. ANOVA indicated that all individuals showed an improved performance in the retention and transfer tests. But the KP frequency of 66% was superior in both qualitative (movement pattern) and quantitative (score) measurements throughout the trials (p ≤ 0.05). In conclusion older persons seem to need an optimal KP frequency supply during the learning process.  ",0
5578,25566165,Hearing and music in unilateral spatial neglect neuro-rehabilitation,"Unilateral spatial neglect (USN) is an attention deficit in the contralesional side of space which occurs after a cerebral stroke, mainly located in the right hemisphere. USN patients are disabled in all daily activities. USN is an important negative prognostic factor of functional recovery and of socio-professional reinsertion. Thus, patient rehabilitation is a major challenge. As this deficit has been described in many sensory modalities (including hearing), many sensory and poly-sensory rehabilitation methods have been proposed to USN patients. They are mainly based on visual, tactile modalities and on motor abilities. However, these methods appear to be quite task-specific and difficult to transfer to functional activities. Very few studies have focused on the hearing modality and even fewer studies have been conducted in music as a way of improving spatial attention. Therefore, more research on such retraining needs is neccessary in order to make reliable conclusions on its efficiency in long-term rehabilitation. Nevertheless, some evidence suggests that music could be a promising tool to enhance spatial attention and to rehabilitate USN patients. In fact, music is a material closely linked to space, involving common anatomical and functional networks. The present paper aims firstly at briefly reviewing the different procedures of sensory retraining proposed in USN, including auditory retraining, and their limits. Secondly, it aims to present the recent scientific evidence that makes music a good candidate for USN patients' neuro-rehabilitation.  ",0
5579,25566250,Persistent Immune Activation in CVID and the Role of IVIg in Its Suppression,"Common variable immunodeficiency (CVID) is one of the most common and clinically important primary immune deficiencies. CVID patients have poor humoral immunity, resulting in recurrent infections of the gastrointestinal and upper respiratory tracts, as well as increased incidence of some forms of cancers and autoimmune diseases. The treatment for CVID is IgG replacement, often given as intravenous immunoglobulins (IVIg). IVIg consists of monomeric IgG purified from pooled plasma from healthy donors and is used to treat an increasing number of conditions including autoimmune diseases. In the case of CVID, IVIg has mainly been seen as reconstitution therapy, providing patients with pathogen-specific antibodies. Recent evidence shows that IVIg has diverse effects on the immune system of CVID patients, and one important component is that IVIg alleviates the state of chronic immune activation. In this review, we will discuss causes and consequences of persistent immune activation in CVID, possible underlying mechanisms for how IVIg treatment reduces immune activation, and implications for our understanding of primary as well as acquired immune deficiencies.  ",0
5580,25566520,Scaling up a Mobile Telemedicine Solution in Botswana: Keys to Sustainability,"""Effective health care delivery is significantly compromised in an environment where resources, both human and technical, are limited. Botswana's health care system is one of the many in the African continent with few specialized medical doctors, thereby posing a barrier to patients' access to health care services. In addition, the traditional landline and non-robust Information Technology (IT) network infrastructure characterized by slow bandwidth still dominates the health care system in Botswana. Upgrading of the landline IT infrastructure to meet today's health care demands is a tedious, long, and expensive process. Despite these challenges, there still lies hope in health care delivery utilizing wireless telecommunication services. Botswana has recently experienced tremendous growth in the mobile telecommunication industry coupled with an increase in the number of individually owned mobile devices. This growth inspired the Botswana-UPenn Partnership (BUP) to collaborate with local partners to explore using mobile devices as tools to improve access to specialized health care delivery. Pilot studies were conducted across four medical specialties, including radiology, oral medicine, dermatology, and cervical cancer screening. Findings from the studies became vital evidence in support of the first scale-up project of a mobile telemedicine solution in Botswana, also known as """"Kgonafalo."""" Some technical and social challenges were encountered during the initial studies, such as malfunctioning of mobile devices, accidental damage of devices, and cultural misalignment between IT and healthcare providers. These challenges brought about lessons learnt, including a strong need for unwavering senior management support, establishment of solid local public-private partnerships, and efficient project sustainability plans. Sustainability milestones included the development and signing of a Memorandum of Understanding (MOU) between the Botswana government and a private telecommunications partner, the publication and awarding of the government tender to a local IT company, and the development and signing of a Memorandum of Agreement between the Ministry of Health Clinical Services department and the local tender winner. The initial system scale-up is scheduled to occur in 2014 and to ensure the project's sustainability, the system is aligned with the national eHealth strategy and local ownership of the project remains at the forefront (1).  """,0
5581,25567140,"'If you are circumcised, you are the best': understandings and perceptions of voluntary medical male circumcision among men from KwaZulu-Natal, South Africa","While the uptake of voluntary medical male circumcision (VMMC) is increasing, South Africa has only attained 20% of its target to circumcise 80% of adult men by 2015. Understanding the factors influencing uptake is essential to meeting these targets. This qualitative study reports on findings from focus-group discussions with men in rural KwaZulu-Natal, South Africa, about what factors influence their perceptions of VMMC. The study found that VMMC is linked to perceptions of masculinity and male gender identity including sexual health, sexual performance and pleasure, possible risk compensation and self-identity. Findings highlight the need to understand how these perceptions of sexual health and performance affect men's decisions to undergo circumcision and the implications for uptake of VMMC. The study also highlights the need for individualised and contextualised information and counselling that can identify, understand and address the perceptions men have of VMMC, and the impacts they believe it will have on them.  ",0
5582,25567226,Avian schistosomes and outbreaks of cercarial dermatitis,"Cercarial dermatitis (swimmer's itch) is a condition caused by infective larvae (cercariae) of a species-rich group of mammalian and avian schistosomes. Over the last decade, it has been reported in areas that previously had few or no cases of dermatitis and is thus considered an emerging disease. It is obvious that avian schistosomes are responsible for the majority of reported dermatitis outbreaks around the world, and thus they are the primary focus of this review. Although they infect humans, they do not mature and usually die in the skin. Experimental infections of avian schistosomes in mice show that in previously exposed hosts, there is a strong skin immune reaction that kills the schistosome. However, penetration of larvae into naive mice can result in temporary migration from the skin. This is of particular interest because the worms are able to migrate to different organs, for example, the lungs in the case of visceral schistosomes and the central nervous system in the case of nasal schistosomes. The risk of such migration and accompanying disorders needs to be clarified for humans and animals of interest (e.g., dogs). Herein we compiled the most comprehensive review of the diversity, immunology, and epidemiology of avian schistosomes causing cercarial dermatitis. ",0
5583,25567366,Addressing the challenges of low clearance in drug research,"As a result of high-throughput ADME screening, early metabolite identification, and exploration of novel chemical entities, low-intrinsic-clearance compounds continue to increase in drug discovery portfolios. Currently available in vitro tools have limited resolution below a certain intrinsic clearance value, which can lead to overestimation of clearance and dose and underestimation of half-life. Significant advances have been made in recent years and novel approaches have been developed to address the challenges of low clearance in drug discovery, such as the hepatocyte relay method, use of qNMR-based standards of biosynthesized drug metabolites to permit monitoring metabolite formation, coculture hepatocyte systems, and the time depending modeling approach. Future development in the field will enable faster, more precise, and lower cost profiling of the properties of low-clearance compounds for intrinsic clearance, metabolite identification, and reaction phenotyping.  ",0
5584,25567746,Characterization of the amino acid residues mediating the unique amino-sugar-1-phosphate acetyltransferase activity of the archaeal ST0452 protein,"The ST0452 protein from the thermophilic archaean Sulfolobus tokodaii has been identified as an enzyme with multiple sugar-1-phosphate nucleotidylyltransferase and amino-sugar-1-phosphate acetyltransferase (amino-sugar-1-P AcTase) activities. Analysis of the protein showed that in addition to glucosamine-1-phosphate (GlcN-1-P) AcTase activity, it possesses unique galactosamine-1-phosphate (GalN-1-P) AcTase activity not detected in any other proteins. Comparison of the crystal structures of the ST0452 protein and GlmU from Escherichia coli (EcGlmU), which possesses only GlcN-1-P AcTase activity, showed that the overall sequence identity between these two proteins is less than 25 %, but the amino acid residues predicted to comprise the catalytic center of EcGlmU are conserved in the ST0452 protein. To understand the molecular mechanism by which the ST0452 amino-sugar-1-P AcTase activity recognizes two independent substrates, several ST0452 substitution and truncation mutant proteins were constructed and analyzed. We found that His308 is essential for both GalN-1-P and GlcN-1-P AcTase activities, whereas Tyr311 and Asn331 are important only for the GalN-1-P AcTase activity. In addition, deletion of the C-terminal 5 or 11 residues showed that the 11-residue C-terminal region exerts a modest stimulatory effect on GalN-1-P AcTase activity but dramatically suppresses GlcN-1-P AcTase activity. This region also appears to make an important contribution to the thermostability of the entire ST0452 protein. Systematic deletions from the C-terminus also demonstrated that the C-terminal region with the β-helix structure has an important role mediating the trimerization of the ST0452 protein. This is the first report of an analysis of a thermostable archaeal enzyme exhibiting multiple amino-sugar-1-P AcTase activities. ",0
5585,25567971,How evolutionary principles improve the understanding of human health and disease,"An appreciation of the fundamental principles of evolutionary biology provides new insights into major diseases and enables an integrated understanding of human biology and medicine. However, there is a lack of awareness of their importance amongst physicians, medical researchers, and educators, all of whom tend to focus on the mechanistic (proximate) basis for disease, excluding consideration of evolutionary (ultimate) reasons. The key principles of evolutionary medicine are that selection acts on fitness, not health or longevity; that our evolutionary history does not cause disease, but rather impacts on our risk of disease in particular environments; and that we are now living in novel environments compared to those in which we evolved. We consider these evolutionary principles in conjunction with population genetics and describe several pathways by which evolutionary processes can affect disease risk. These perspectives provide a more cohesive framework for gaining insights into the determinants of health and disease. Coupled with complementary insights offered by advances in genomic, epigenetic, and developmental biology research, evolutionary perspectives offer an important addition to understanding disease. Further, there are a number of aspects of evolutionary medicine that can add considerably to studies in other domains of contemporary evolutionary studies.  ",0
5586,25568045,Evolutionary and ecological feedbacks of the survival cost of reproduction,"Arguably the most fundamental of trade-offs in life-history evolution is the increase in natural mortality resulting from sexual maturity and reproduction. Despite its central importance, this increase in mortality, a survival cost, garners surprisingly little attention in fish and fisheries modeling studies. We undertook an exploratory analysis to evaluate the consequences of this omission for life-history projections. To this end, we developed a simulation approach that integrates quantitative genetics into the ecological dynamics of a fish population and parameterized the model for Atlantic cod (Gadus morhua, L.). When compared to simulations in which the mortality of immature and mature individuals is equal, the inclusion of a survival cost results in larger asymptotic body size, older age at maturity, and larger size at maturity. We also find that measures of population productivity (spawning stock biomass, recruits-per-spawner) are overestimated if the survival cost is excluded. This sensitivity of key metrics of population growth rate and reproductive capacity to the magnitude of the survival cost of reproduction underscores the need to explicitly account for this trade-off in projections of fish population responses to natural and anthropogenic environmental change, including fisheries.  ",0
5587,25568278,Air Duster abuse causing rapid airway compromise,"Inhalant abuse is potentially life-threatening and has resulted in many complications such as central nervous system depression, cardiac dysrhythmia and hypoxia. Inhalant abuse causing angioedema is rarely reported in the medical literature. In this report we present a case of rapidly progressive airway compromise following recreational huffing. Our patient required intubation and intensive care unit admission with complete recovery after 5 days. The aetiology of airway compromise is postulated to be due to commonly reported frost bite injury and rarely reported angioedema. To the best of our knowledge this the second case reporting angioedema secondary to huffing Air Duster.  ",0
5588,25568292,Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy,"""To identify the cause of sensorimotor neuropathy in a cohort of patients with genetically unsolved neuropathies (57 families with a total of 74 members) in whom hitherto known disease genes had been excluded. We used autozygosity mapping or haplotype analysis to delineate potential disease loci in informative families. For mutation detection, we used either whole-exome sequencing or Sanger sequencing of positional candidates. Subsequently, a larger cohort was specifically screened for IGHMBP2 mutations. The pathogenicity of a splice-site mutation was verified in cultured patient skin fibroblasts on the messenger RNA level and by Western blot. We report on 5 patients with neuropathy from 3 families who carried truncating mutations in IGHMBP2. Contrary to the """"classic"""" phenotype, they did not manifest with respiratory distress, but with progressive sensorimotor neuropathy. Only one patient required nocturnal mask ventilation, while 4 others maintained normal respiratory function by the age of 14, 18, 22, and 37 years. Three patients were still able to walk independently. All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms. Two patients had signs of autonomic neuropathy. Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms. """,0
5589,25568350,AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice,"Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 10(12) vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB.  ",0
5590,25568661,"Transcriptional profiling of reproductive development, lipid storage and molting throughout the last juvenile stage of the marine copepod Calanus finmarchicus","Calanus finmarchicus, a highly abundant copepod that is an important primary consumer in North Atlantic ecosystems, has a flexible life history in which copepods in the last juvenile developmental stage (fifth copepodid, C5) may either delay maturation and enter diapause or molt directly into adults. The factors that regulate this developmental plasticity are poorly understood, and few tools have been developed to assess the physiological condition of individual copepods. We sampled a cultured population of C. finmarchicus copepods daily throughout the C5 stage and assessed molt stage progression, gonad development and lipid storage. We used high-throughput sequencing to identify genes that were differentially expressed during progression through the molt stage and then used qPCR to profile daily expression of individual genes. Based on expression profiles of twelve genes, samples were statistically clustered into three groups: (1) an early period occurring prior to separation of the cuticle from the epidermis (apolysis) when expression of genes associated with lipid synthesis and transport (FABP and ELOV) and two nuclear receptors (ERR and HR78) was highest, (2) a middle period of rapid change in both gene expression and physiological condition, including local minima and maxima in several nuclear receptors (FTZ-F1, HR38b, and EcR), and (3) a late period when gonads were differentiated and expression of genes associated with molting (Torso-like, HR38a) peaked. The ratio of Torso-like to HR38b strongly differentiated the early and late groups. This study provides the first dynamic profiles of gene expression anchored with morphological markers of lipid accumulation, development and gonad maturation throughout a copepod molt cycle. Transcriptomic profiling revealed significant changes over the molt cycle in genes with presumed roles in lipid synthesis, molt regulation and gonad development, suggestive of a coupling of these processes in Calanus finmarchicus. Finally, we identified gene expression profiles that strongly differentiate between early and late development within the C5 copepodid stage. We anticipate that these findings and continued development of robust gene expression biomarkers that distinguish between diapause preparation and continuous development will ultimately enable novel studies of the intrinsic and extrinsic factors that govern diapause initiation in Calanus finmarchicus. ",0
5591,25568794,Antibiotic management of complicated intra-abdominal infections in adults: The Asian perspective,"Regional epidemiological data and resistance profiles are essential for selecting appropriate antibiotic therapy for intra-abdominal infections (IAIs). However, such information may not be readily available in many areas of Asia and current international guidelines on antibiotic therapy for IAIs are for Western countries, with the most recent guidance for the Asian region dating from 2007. Therefore, the Asian Consensus Taskforce on Complicated Intra-Abdominal Infections (ACT-cIAI) was convened to develop updated recommendations for antibiotic management of complicated IAIs (cIAIs) in Asia. This review article is based on a thorough literature review of Asian and international publications related to clinical management, epidemiology, microbiology, and bacterial resistance patterns in cIAIs, combined with the expert consensus of the Taskforce members. The microbiological profiles of IAIs in the Asian region are outlined and compared with Western data, and the latest available data on antimicrobial resistance in key pathogens causing IAIs in Asia is presented. From this information, antimicrobial therapies suitable for treating cIAIs in patients in Asian settings are proposed in the hope that guidance relevant to Asian practices will prove beneficial to local physicians managing IAIs.  ",0
5592,25569204,Prescription Drug Misuse and Sexual Behavior Among Young Adults,"Though research indicates a complex link between substance use and sexual risk behavior, there is limited research on the association between sexual risk behavior and prescription drug misuse. In light of alarming increases in prescription drug misuse and the role of demographic characteristics in sexual risk behavior and outcomes, the current study examined demographic differences (gender, sexual identity, age, relationship status, parental class background, and race/ethnicity) in sexual risk behavior, sexual behavior under the influence of prescription drugs, and sexual risk behavior under the influence of prescription drugs in a sample of 402 young adults (ages 18 to 29) who misused prescription drugs. Nearly half of the sexually active young adult prescription drug misusers in this sample reported recent sex under the influence of prescription drugs; more than three-quarters reported recent sex without a condom; and more than one-third reported recent sex without a condom after using prescription drugs. Zero-inflated Poisson regression models indicated that White race, younger age, higher parental class, and being a heterosexual man were all associated with sexual risk behavior, sex under the influence of prescription drugs, and sexual risk under the influence of prescription drugs. Findings have implications for the targeting of prevention and intervention efforts.  ",0
5593,25569340,Reduction of assaultive behavior following anger treatment of forensic hospital patients with intellectual disabilities,"Anger is related to violence prior to hospitalization, during hospitalization, and after discharge. Meta-analyses have established treatment efficacy in reducing anger, but few studies have addressed whether reduced anger leads to lowered aggressive behavior. This study concerns individually-delivered anger treatment, specialized for offenders with intellectual disabilities, delivered twice weekly for 18 sessions to 50 forensic hospital patients. Assessments involved patient self-report of anger, staff ratings of anger and aggression, and case records of assaultive incidents. Physical assault data were obtained from records 12 months pre-treatment and 12 months post-treatment. Significant reductions in assaults following treatment were found by GEE analyses, controlling for age, gender, length of stay, IQ, and pre-hospital violence. Following treatment, physical attacks reduced by more than half, dropping from approximately 3.5 attacks per patient 6 months prior to treatment, versus approximately 1 attack per patient in the 6-12 month interval post-treatment. In hierarchical regressions, controlling for IQ, reduction in physical assaults was associated with pre-to post-treatment change in anger level. These findings buttress the efficacy of anger treatment for patients having histories of violence and have significance for patient mental health, hospital staff well-being, therapeutic milieu, hospital management, and service delivery costs.  ",0
5594,25569457,Three-dimensional visualization of the Autographa californica multiple nucleopolyhedrovirus occlusion-derived virion envelopment process gives new clues as to its mechanism,"Baculoviruses produce two virion phenotypes, occlusion-derived virion (ODV) and budded virion (BV). ODV envelopment occurs in the nucleus. Morphogenesis of the ODV has been studied extensively; however, the mechanisms underlying microvesicle formation and ODV envelopment in nuclei remain unclear. In this study, we used electron tomography (ET) together with the conventional electron microscopy to study the envelopment of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ODV. Our results demonstrate that not only the inner but also the outer nuclear membrane can invaginate and vesiculate into microvesicles and that intranuclear microvesicles are the direct source of the ODV membrane. Five main events in the ODV envelopment process are summarized, from which we propose a model to explain this process.  ",0
5595,25569481,Long-term effects of 3-month telemetric blood pressure intervention in patients with inadequately treated arterial hypertension,"We have shown that better blood pressure (BP) control can be achieved by using 3-month telemetric BP measurement (TBPM) in comparison with a standard-care control group (C-G). The present analysis should clarify if this will also lead to a better middle- and long-term BP control. Fifty-seven patients finished the main study. After the 3 months no TBPM was performed. For 40 patients, 18 from the TBPM group (TBPM-G) and 22 from the C-G, we obtained ambulant BP measurements (ABPMs) with a mean follow-up of 20 months. Seventeen patients were lost to follow-up. BP target values were defined as ABPM ≤130/80 or ≤125/75 mm Hg with diabetes or renal failure. At the end of the follow-up, the systolic BP was 121.2±11.2 mm Hg in TBPM-G and 130.7±10.4 mm Hg in C-G, and the diastolic BP was 72.8±10.9 versus 77.0±7.1 mm Hg, respectively. Fifty-six percent in TBPM-G versus 40% in C-G (p=0.024) had a controlled BP as defined by ABPM criteria. TBPM helps achieve BP target values in patients with previously inadequately treated arterial hypertension, and the benefit is sustained. Beyond its immediate application, in comparison with standard treatment, TBPM allows for a better BP adjustment in the long term as well. ",0
5596,25569691,High throughput absorbance spectra of cancerous cells: a microscopic investigation of spectral artifacts,"""FTIR spectroscopy was recently demonstrated to be a useful tool to obtain a unique fingerprint of the effects of several anticancer drugs on cells in culture. While FTIR spectroscopy appears to have a definite potential to sort anticancer drugs on the basis of the metabolic modifications they induced, the present challenge is to evaluate the drug-induced spectral changes in cancer cells on a larger scale. The coupling of FTIR spectroscopy with a high throughput screening extension could become a useful method to generate drug classifications based on their """"modes of action"""". Practically, the robustness of this approach is jeopardized by the variability that can appear from one cell smear to the next. When a few cells are scattered on the support, strong scattering effects are observed and locally dense cell aggregates could result in non-linearity of the signal. A microscopic study using infrared imaging demonstrates that the mean HTS (96-well High Throughput Spectroscopy) spectra recorded on 96 well ZnSe plates are the averages of contributions characterized by a wide absorbance distribution and by Mie scattering effects which significantly vary from point to point. Spectrum quality is at its best at the highest cell concentrations, i.e. from 300 000 to 400 000 cells per well, which present the best S/N and a relatively smaller Mie scattering effect. When the breast cancer cell line MDA-MB-231 was treated with four different polyphenols, spectra showed quite similar variations with respect to control spectra, with more intense variations for the quercetin and EGCG compared to resveratrol and capsaicin. Correction of the spectra with the RMieS algorithm improved their clustering according to the polyphenolic treatment.  """,0
5597,25569733,Risk for colorectal neoplasia in patients with inflammatory bowel disease and mucosa indefinite for dysplasia,"The management of colonic epithelial changes indefinite for dysplasia (IND) in patients with inflammatory bowel disease (IBD) remains controversial because of a paucity of published outcome data. We analyzed data from 93 patients with IBD who were IND and 52 IBD patients without dysplasia (controls) from the Department of Anatomic Pathology database at the Cleveland Clinic from 1989 to 2004. Pathology reports, histologic slides, clinical features, and outcomes were reviewed. Twenty-two patients (23.7%) had surgical resections within 6 months of the IND assignment; of these, 6 had dysplasia (27.3%; 1 low-grade dysplasia and 5 high-grade dysplasia [HGD]). The remaining 71 patients received regular colonoscopy examinations for a mean period of 98.6 months; 18 patients developed dysplasia or carcinoma (25.2%; 10 low-grade dysplasia, 5 HGD, and 3 colorectal cancer). There was a mean interval of 53.9 months between an IND assignment and identification of dysplasia or carcinoma. Histology review of 59 cases revealed 3.2 cases per 100 person-years for neoplasia (low-grade dysplasia, HGD, or colorectal cancer) and 1.5 cases per 100 person-years for advanced neoplasia (HGD or colorectal cancer); these values were higher than those for controls (1.9 cases per 100 person-years for neoplasia and 0.7 cases per 100 person-years for advance neoplasia; P = 0.1 and P = 0.2, respectively, for IND versus controls). Patients aged more than 44 years when they were found to be IND were more likely than younger patients to develop neoplasia (hazard ratio, 6.7; P = 0.01). Patients with IBD and IND are at significant risk for colorectal dysplasia and cancer. These patients should be closely followed. ",0
5598,25570707,Two-dimensional sample entropy analysis of rat sural nerve aging,"Entropy analysis of images are usually performed using Shannon entropy, which calculates the probability of occurrency of each gray level on the image. However, not only the pixel gray level but also the spatial distribution of pixels might be important for image analysis. On the other hand, sample entropy (SampEn) is an important tool for estimation of irregularity in time series, which calculates the probability of pattern occurrence within the series. Therefore, we propose here an extension of SampEn to a two-dimensional case, namely SampEn2D, as an entropy method for extracting features from images that accounts for the spatial distribution of pixels. SampEn2D was applied to histological segments of sural nerve obtained from young (30 days) and elderly (720 days) rats. Morphometric indexes, such as the total number of myelinated fibers and the average myelinated fibers area and perimeter were also calculated. Results show that SampEn2D can extract useful information from histological nerve images, classifying elderly rat image as more regular than young rat. As SampEn2D is related to irregularity/unpredictability, we can conclude that the proposed method is complementary to morphometric indexes. Further studies are being built to validate SampEn2D.  ",0
5599,25571005,"Adaptation of five indirect insulin sensitivity evaluation methods to three populations: metabolic syndrome, athletic and normal subjects","Insulin sensitivity is determined using direct or indirect methods. Indirect methods are less invasive than direct methods, but have lower accuracy. The accuracy is set through the Spearman's rank correlation coefficient between the indirect method and a direct method. Since the set of parameters of each indirect method has been set empirically, different values of insulin sensitivity have been reported when they are applied on different populations. In this paper, five indirect methods (Avignon, HOMA-IR, QUICKI, Raynaud, and Matsuda) used to determine insulin sensitivity were adapted to three different populations: athletics, metabolic syndrome and normal subjects. The parameters of each method were varied in a range of values until the optimal value that gives the best correlation coefficient with a gold standard was obtained. Results show that the adaptation procedure led to an improved correlation coefficient. Additionally, the method of Matsuda was the most accurate, followed by the method of Avignon. We have confirmed that each indirect method needs a different set of parameters when it is applied to a specific population in order to obtain an accurate value of insulin sensitivity.  ",0
5600,25571086,An in silico approach for pre-surgical evaluation of an epileptic cortex,"Clinical evidence indicates that a third of patients with epilepsy are refractory to anti-epileptic drug treatment. For some of these patients better seizure control can be achieved by surgical treatment in which the seizure focus is localised and resected while avoiding injury to crucial cortical tissues. In this paper, non-seizure (interictal) epoch of electrographic recording was used to calculate the functional synchrony between different cortical regions. This synchrony measure was then used as the connectivity parameter in a computational model of transitions to a seizure like state. The seizure focus was localised using this model and the surgical intervention procedure was simulated. It was shown that the in silico removal of a subset of seizure focus can decrease the likelihood of a seizure in the model. The in silico results were also compared with the clinical outcomes and a convincing agreement was shown for five out of six patients; sixth being a counter-example. These methods may aid in the identification of the seizure onset zone using the interictal electrographic data. Moreover, it may facilitate neurosurgeons to investigate alternative cortical tissues to operate on if the seizure focus cannot be operated.  ",0
5601,25571667,Progress on osteochondritis dissecans],"""Along with the popularity of youth movement, the incidence of osteochondritis dissecans (OCD) showed a trend of increase, but its pathogenesis is not yet clear. Previous studies suggested that trauma is the main potential cause, but with the emergence of vast family cases, hereditary factor is also gradually taken seriously. Arthroscopy is the """"gold standard"""" for diagnosing OCD, but for the patient with early incomplete joint surface lesions, the diagnositic value of MRI is better than the arthroscopy. For the patients with stable form OCD, nonoperative management should be used such as adjusting activity, fixator and drugs; for the patient with unstable form OCD or failing after conservative treatment, surgery should be generally used such as joint clearing, drilling, microfracture method, fixation and transplantation. With the progress of research, stem cell technology and platelet-rich plasma gradually applied in cartilage repair, which will improve the curative effect of OCD, but still further clinical and experimental research, and also a long-term effective follow-up are needed. """,0
5602,25571717,The distribution of caspase-3 positive apoptotic cells in 18 months old SD rat's brainstem compared with that in 3 months rat],"To study whether there is apoptosis in brainstem neurons while aging by oberving the distribution of Caspase-3 positive apoptotic cells in in brainstem of young and old SD rats. Healthy male SD rats were divided into 2 groups (3 and 18 month-old respectively), 3 rats each group. Brainstem specimens were treated followed the brainstem's common paraffin embedding, sectioning and HE staining procedures (sections were 6 μm in thickness). The sections were also determined by Caspase-3 immunostaining and TUNEL. The Caspase-3 positive cells on the rat stereotaxic atlas were drew, then composed the sections into a 3D model. Compared to 3 month-old rats, there were more Caspase-3 positive neurons in the brainstem and the positive neurons were distributed more extensively in 18 month-old rats spectially in nucleus of solitary tract and pontine reticular nuclei. More neurons suffer apoptotic changes in the brainstem while aging. ",0
5603,25571917,"Ubenimex inhibits cell proliferation, migration and invasion in renal cell carcinoma: the effect is autophagy-associated","Ubenimex is a low-molecular-weight dipeptide with the ability to inhibit aminopeptidase N (APN) activity, enhance the function of immunocompetent cells and confer antitumor effects. We sought to characterize the effects of ubenimex on renal cell carcinoma (RCC). The 786-O and OS-RC-2 human RCC cell lines were positive for APN expression and ubenimex decreased APN activity without affecting the expression. Ubenimex suppressed the proliferation of both cell lines in a concentration‑dependent manner, as assessed by curve growth analysis and WST-8 proliferation assay. Wound healing and Matrigel invasion assays demonstrated that the migration and invasion of the RCC cells were also markedly suppressed by ubenimex. Furthermore, ubenimex increased the mortality of both RCC cell lines as determined by the LDH cytotoxicity assay. This affect was accompanied by increased levels of LC3B with no apparent effect on Caspase3; and we observed that autophagy increased significantly after ubenimex treatment in both RCC cell lines by electron microscopy. Moreover, rapamycin enhanced the cytotoxic effect of ubenimex, while 3-methyladenine reversed the effect, indicating that ubenimex cytotoxicity occured through an autophagy-related mechanism. To further assess the potential applicability of ubenimex in the treatment of RCC, we performed immunohistochemistry using tissue microarrays representing 76 RCC patients that underwent radical nephrectomy. The results showed that APN was expressed in most, but not all of the RCC tissues and that the expression was reduced in RCC as compared to the normal kidney tissues, suggesting a potential role for APN in RCC development. Collectively, these results indicated that ubenimex inhibits proliferation, migration and invasion of RCC cells. Ubenimex may induce autophagy, which may be associated with its effect on the growth arrest and the cell death of RCC cells. ",0
5604,25572144,The acute psychobiological impact of the intensive care experience on relatives,"There is a growing awareness amongst critical care practitioners that the impact of intensive care medicine extends beyond the patient to include the psychological impact on close family members. Several studies have addressed the needs of relatives within the intensive care context but the psychobiological impact of the experience has largely been ignored. Such impact is important in respect to health and well-being of the relative, with potential to influence patient recovery. The current feasibility study aimed to examine the acute psychobiological impact of the intensive care experience on relatives. Using a mixed methods approach, quantitative and qualitative data were collected simultaneously. Six relatives of patients admitted to the intensive care unit (ICU) of a District General Hospital, were assessed within 48 h of admission. Qualitative data were provided from semi-structured interviews analysed using interpretative phenomenological analysis. Quantitative data were collected using a range of standardised self-report questionnaires measuring coping responses, emotion, trauma symptoms and social support, and through sampling of diurnal salivary cortisol as a biomarker of stress. Four themes were identified from interview: the ICU environment, emotional responses, family relationships and support. Questionnaires identified high levels of anxiety, depression and trauma symptoms; the most commonly utilised coping techniques were acceptance, seeking support through advice and information, and substance use. Social support emerged as a key factor with focused inner circle support relating to family and ICU staff. Depressed mood and avoidance were linked to greater mean cortisol levels across the day. Greater social network and coping via self-distraction were related to lower evening cortisol, indicating them as protective factors in the ICU context. The experience of ICU has a psychological and physiological impact on relatives, suggesting the importance of identifying cost-effective interventions with evaluations of health benefits to both relatives and patients.  ",0
5605,25572159,Substantia nigra hyperechogenicity in hypokinetic Huntington's disease patients,"Substantia nigra (SN) hyperechogenicity can be detected by transcranial sonography (TCS) to assist the early diagnosis of idiopathic Parkinson's disease (IPD). This study prospectively investigated whether SN hyperechogenicity is also present in Huntington's disease (HD) patients with symptoms of hypokinesia and/or rigidity. All patients recruited to the study (n = 15) were characterised by hypokinesia and/or rigidity while nine of these patients also displayed chorea and/or dystonia. The control group included 15 individuals. Clinical examination was documented using the Unified Huntington's Disease Rating Scale (UHDRS). TCS examination revealed SN hyperechogenicity in 14/15 (93.3 %) patients (9/14 unilateral, 5/14 bilateral). Hyperechogenicity of the caudate and lentiform nuclei (CN, LN) was less frequent (CN: 80 % total, LN: 53.3 % total). This is the first study to assess SN hyperechogenicity in hypokinetic HD patients. Assuming that the primary sites of pathology in IPD and HD are the SN and the striatum, respectively, our observations suggest a functional impairment of the nigrostriatal system in HD, an effect that is potentially independent of the primarily-affected basal ganglia nucleus. ",0
5606,25572211,Chemical defense against fouling in the solitary ascidian Phallusia nigra,"The solitary ascidian Phallusia nigra is rarely fouled by epibionts. Here, we tested the antifouling activity of its crude extracts in laboratory and field assays. P. nigra extracts inhibited the growth of all eight tested environmental bacteria and two of four laboratory bacteria. Extracts of the sympatric, but fouled solitary ascidian Herdmania momus inhibited only one test bacterium. Scanning electron microscopy confirmed that the tunic surface of P. nigra is largely bacteria-free. Both ascidian extracts significantly inhibited the larval metamorphosis of the bryozoan Bugula neritina at the tested concentration range of 0.05-2 mg ml(-1). Both crude extracts were toxic to larvae of the brine shrimp Artemia salina at natural volumetric whole-tissue concentrations, but only P. nigra showed activity at 2 mg ml(-1) and below (LC50 = 1.11 mg ml(-1)). P. nigra crude extracts also significantly reduced the settlement of barnacles, polychaetes, and algae in Mediterranean field assays and barnacle settlement in Red Sea trials. Comparisons between control experiments and pH values monitored in all experiments indicate that the observed effects were not due to acidity of the organic extracts. Our results show that P. nigra secondary metabolites have antifouling activities, which may act in synergy with previously proposed physiological antifouling mechanisms.  ",0
5607,25572252,Molecular and genetic basis of depression,"Joyousness or sadness is normal reaction to state of life. If any of these lead to certain semi-permanent changes in daily life, then it is termed as mental disorder. Depression is one of the mental disorders with a state of low mood and aversion to activities that exerts a negative effect on a person's thoughts and behaviour. Adolescent group is probably the world's largest active group of people, who are getting prone to this state of mind leading to their diminished mental and physical abilities. Depression is closely linked to stress and thus a chronic stressful life can increase the risk of depression. Depression is a complex disease having both genetic and environmental components as contributing factors. In this study an attempt has been made to put forward the understanding of the known genes and their functional relationships with depression and stress with special reference to BDNF and 5-HTTLPR. Analysis of common genetic variants associated with depression, especially in the members of a family who had a previous history, might help in identifying the individuals at risk prior to the onset of depression.  ",0
5608,25572481,Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period,"Previous works have shown that differentiated human HepaRG cells can exhibit drug metabolism activities close to those of primary human hepatocytes for several weeks at confluence. The present study was designed to evaluate their long-term functional stability and their response to repeated daily drug treatments over a 14-day period, using a transcriptomic approach. Our data show that less than 1% of the expressed genes were markedly deregulated over this two weeks period and mainly included down-regulation of genes related to the cell cycle and from 3 days, overexpression of genes involved in xenobiotic and lipid metabolism. After daily treatment with the three PPAR agonists, fenofibrate, troglitazone and rosiglitazone qualitative and/or quantitative changes in gene profiling were observed depending on the compound and duration of treatment. The highest increase in the number of deregulated genes as a function of drug treatment was seen with rosiglitazone. The most up-regulated genes common across the three compounds were mainly related to lipid and xenobiotic metabolisms. All the data support the conclusion that human HepaRG cells have an exceptional functional stability at confluence and that they are suitable for investigations on chronic effects of drugs and other chemicals. ",0
5609,25572529,Icotinib hydrochloride enhances the effect of radiotherapy by affecting DNA repair in colorectal cancer cells,"The aim of the present study was to explore the efficacy and mechanism of the radiosensitisation of icotinib hydrochloride (IH), a novel oral epidermal growth factor receptor-tyrosine kinase activity inhibitor, by evaluating the changes in tumour cell double-strand breaks (DSBs) repair, cell cycle and apoptosis following a combination of IH and radiotherapy (RT) in human colorectal adenocarcinoma cell lines. The HT29 and HCT116 human CRC cell lines were treated with IH and/or radiation. Effects on cell viability and cell cycle progression were measured by MTT, a clonogenic survival assay, and flow cytometry. Immunofluorescent staining and western blot analysis were applied to detect the expression of γ-H2AX and 53BP1 in the different treatment groups. Finally, the in vivo effect on the growth of CRC xenografts was assessed in athymic nude mice. IH inhibited the proliferation and enhanced the radiosensitivity in HT29 and HCT116 CRC cells lines. IH combined with radiation increased cell cycle arrest in the G2/M phase compared to the other treatments in the HT29 cell line (P<0.05). Similarly, cell cycle arrest occurred in the HCT116 cell line, although this increase did not result in significant differences in the RT group (P>0.05). IH combined with radiation significantly inhibited the expression of γ-H2AX and 53BP1 based on results of immunofluorescent staining and western blot analysis. In vivo, IH plus radiation significantly inhibited the tumour growth compared to either agent independently. In conclusion, IH significantly increased the radiosensitivity of HT29 and HCT116 cells in vitro and in vivo. Radiation combined with EGFR blockade inhibited tumour proliferation, increased apoptosis, prolonged G2/M arrest and significantly enhanced DNA injury in colorectal cancer. These data support the clinical trials of biologically targeted and conventional therapies in the treatment of cancer. ",0
5610,25572871,Hydrophilic polymer monolithic capillary microextraction online coupled to ICPMS for the determination of carboxyl group-containing gold nanoparticles in environmental waters,"In this study, the hydrophilic polymer monolithic capillary (poly(acrylamide-vinylpyridine-methylene bis(acrylamide)), poly(AA-VP-Bis)) was prepared for the separation and enrichment of carboxyl group-containing gold nanoparticles (Au NPs) from environmental waters followed by online ICPMS determination. The extraction mechanism of the prepared poly(AA-VP-Bis) monolithic capillary for Au NPs is based on the static electrical and hydrogen bond interactions between the carboxyl group on the surface of Au NPs and pyridine/amide groups on the surface of the monolith. Under the optimal conditions, a detection limit of 24.2 fmol L(-1) and a sample throughput of 6 h(-1) were achieved for 3 nm citrate stabilized Au NPs, and the original morphology of the Au NPs could be maintained during the extraction process. The developed method was successfully applied for the analysis of carboxyl group-containing Au NPs in environmental water samples, such as tap water, the Yangtze River water, and the East Lake water, with recoveries in the range of 77-103%. Compared with the reported approaches for analysis of Au NPs, this method is an online strategy for carboxyl group-containing Au NPs determination and has the merits of low detection limit, small sample consumption, fast extraction/desorption kinetics, wide linear range, high selectivity, and high throughput.  ",0
5611,25572931,The biopsychology of salt hunger and sodium deficiency,"""Sodium is a necessary dietary macromineral that tended to be sparsely distributed in mankind's environment in the past. Evolutionary selection pressure shaped physiological mechanisms including hormonal systems and neural circuits that serve to promote sodium ingestion. Sodium deficiency triggers the activation of these hormonal systems and neural circuits to engage motivational processes that elicit a craving for salty substances and a state of reward when salty foods are consumed. Sodium deficiency also appears to be associated with aversive psychological states including anhedonia, impaired cognition, and fatigue. Under certain circumstances the psychological processes that promote salt intake can become powerful enough to cause """"salt gluttony,"""" or salt intake far in excess of physiological need. The present review discusses three aspects of the biopsychology of salt hunger and sodium deficiency: (1) the psychological processes that promote salt intake during sodium deficiency, (2) the effects of sodium deficiency on mood and cognition, and (3) the sensitization of sodium appetite as a possible cause of salt gluttony.  """,0
5612,25573117,Immunohistochemical Characterization of Sympathetic Chain Ganglia (SChG) Neurons Supplying the Porcine mammary Gland,"The aim of this study was to investigate the chemical coding of mammary gland-projecting SChG neurons using double-labelling immunohistochemistry. Earlier observation showed that after injection of the retrograde tracer fast blue (FB) into the second, right thoracic mamma, FB+ mammary gland-projecting neurons were found in Th1-3, Th9-14 and L1-4 right SChG. The greatest number of FB+ nerve cell bodies was observed in Th10 (approx. 843) and Th11 (approx. 567). Neurons projecting to the last right abdominal mamma were found in L1-4 SChG. The greatest number of FB+ neurons was observed in L2 (approx. 1200). Immunohistochemistry revealed that the vast majority of FB+ mammary-projecting neurons contained immunoreactivities to TH (96.97%) and/or DßH (95.92%). Many TH/DßH-positive neurons stained for SOM (41.5%) or NPY (33.2%), and less numerous nerve cells expressed VIP (16.9%). This observation strongly corresponds to the results of previous studies concerning the immunohistochemical characterization of nerve fibres supplying the porcine mammary gland.  ",0
5613,25573134,A new classification of cochleovestibular malformations and implications for predicting speech perception ability after cochlear implantation,"The aims of this study were to introduce a new classification of cochleovestibular malformation (CVM) and to investigate how well this classification can predict speech perception ability after cochlear implantation in children with CVM. Fifty-nine children with CVM who had used a cochlear implant for more than 3 years were included. CVM was classified into 4 subtypes based on the morphology of the cochlea and the modiolus on temporal bone computed tomography (TBCT): normal cochlea and normal modiolus (type A, n = 16), malformed cochlea and partial modiolus (type B, n = 31), malformed cochlea and no modiolus (type C, n = 6), and no cochlea and no modiolus (type D, n = 6). Speech perception test scores were compared between the subtypes of CVM using analysis of covariance with post hoc Bonferroni test. Univariate and multivariate regression analyses were used to identify the significant predictors of the speech perception test scores. The speech perception test scores after implantation were significantly better in children with CVM type A or type B than in children with CVM type C or type D. The test scores did not differ significantly between the implanted children with CVM type A or type B and those without CVM. In univariate regression analysis, the type of CVM was a significant predictor of the speech perception test scores in implanted children with CVM. Multivariate regression analysis revealed that the age at cochlear implantation, cochlear nerve size and preimplantation speech perception test scores were significant predictors of the postimplantation speech perception test scores. The chance of cochlear nerve deficiency increased progressively from CVM type A to type D. The new classification of CVM based on the morphology of the cochlea and the modiolus is simple and easy to use, and correlated well with postimplantation speech perception ability and cochlear nerve status. This simple classification of CVM using TBCT with cochlear nerve assessment by magnetic resonance imaging is helpful in the preoperative evaluation of children with CVM. ",0
5614,25573181,Cardiac and inflammatory biomarkers do not correlate with volume of heart or lung receiving radiation,"Thoracic and cardiac irradiation increases the risk of pulmonary and cardiovascular disease. In addition, radiation, often in combination with chemotherapy, can cause treatment-related pneumonitis. Previously, we showed that the common marker for cardiac damage, troponin T, was not elevated by chemoradiation [Lung Cancer 62:351-355, 2008]. In this study, we explore whether dose-volume metrics and biomarkers for cardiac damage, inflammation or angiogenesis could identify patients receiving thoracic radiation who would later have cardiac or pulmonary complications. To this end, we quantified cardiac biomarkers including c-reactive protein (cRP) as well as a panel of angiogenic and inflammatory molecules in thirty patients who received radiation therapy to the thorax with or without concurrent chemotherapy between May 2006 and May 2007. Serum was collected at baseline, 2 weeks into radiation treatment and at the completion of radiation therapy. Heart and lung dosimetric parameters and clinical risk factors were also examined, along with the monitoring of adverse pulmonary and cardiac events during follow-up. Contrary to our hypothesis, there was no correlation between serum biomarker levels and cardiac radiation dose. Similarly there was little association between lung dose-volume metrics and inflammatory or angiogenic biomarkers. Furthermore, there was no correlation with serum biomarkers and adverse pulmonary or cardiovascular events. Based on these data, acute elevations in serum biomarkers of cardiac damage, inflammation or angiogenesis should not be attributed to thoracic (chemo)radiation and elevations in such biomarkers of tissue damage should be further evaluated. ",0
5615,25573529,"CD44v6 promotes β-catenin and TGF-β expression, inducing aggression in ovarian cancer cells","A high expression of CD44v6 has been reported in numerous malignant cancers, including stomach, prostate, lung and colon. However, the pathological role and the regulatory mechanisms of CD44v6 have yet to be elucidated. In the present study, the expression levels of CD44v6 were shown to be significantly higher in ovarian cancer tissues, as compared with adjacent normal tissues. Furthermore, the upregulated expression levels of CD44v6 were correlated with disease recurrence and poor survival in patients. The expression of CD44v6 was knocked down in the CAOV3 ovarian cell line, by transfection of a specific small hairpin RNA. The present study showed a correlation between the aggression, viability, invasion and migration of the ovarian cancer cells, with the expression of CD44v6. In addition, the expression of CD44v6 was positively correlated with the expression levels of β‑catenin and tumor growth factor‑β, which indicates that the effects of CD44v6 on ovarian cancer cell aggression may be mediated by these two signaling pathways. In conclusion, the present study provides a novel insight into the association between CD44v6 expression and ovarian cancer. CD44v6 may provide a novel target for the prognosis and treatment of ovarian cancer. ",0
5616,25573542,Obesity and its association with comorbidities and hospital charges among patients hospitalized for dental conditions,"The aim of the present study was to examine the impact of obesity on hospitalization charges and comorbid burden following hospitalization due to dental conditions. The Nationwide Inpatient Sample for 2004-2010 was used. All hospitalizations due to dental conditions were selected. The prevalence of obesity was estimated among these hospitalizations. Multivariable linear regression models were used to examine the impact of obesity on outcomes. A total of 11 965 hospitalizations were attributed to dental conditions; 5.6% were related to obesity. The proportion of those who were obese increased over the study period (ranging from 3.7% in 2004 to 7.3% in 2010). The mean age of those who were obese was 45 years (compared to 38.7 years for those who were not obese). Close to 41% of those who were obese were males (compared to 51% who were not obese). Whites comprised 62.4% of those who were obese (compared to 59.2% of those who were not obese). Those who were obese had a higher comorbid burden compared to those who were not obese (83.5% of those who were obese had at least one comorbid condition, whereas 56.4% of those who were not obese had at least one comorbid condition). Those who were obese had higher hospitalization charges ($US2225 more, P = 0.0001). Obesity is associated with high comorbid burden and hospital charges among patients hospitalized due to dental conditions. ",0
5617,25573587,Simultaneous detection and quantification of indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA) produced by rhizobacteria from l-tryptophan (Trp) using HPTLC,"A simple, quick and reliable method is proposed for the detection and quantitation of indole-3-acetate (IAA) and indole-3-butyrate (IBA), an auxin phytohormone produced by rhizobacteria from l-tryptophan (Trp) metabolism using high performance thin-layer chromatography (HPTLC). Microbial auxin biosynthesis routes involve Trp as a precursor where other than IAA and IBA, products such as indole-3-pyruvate (IPA), indole-3-acetamide (IAM), tryptamine, indole-3-acetonitrile (IAN), indole-3-lactic acid (ILA) and indole-3-acetaldehyde (IAAld) are also produced. In traditional spectrophotometric method, Salkowski reagent develops color by reacting with indolic compounds. The color development is non-specific contributed by several Trp derivatives produced by rhizobacteria rather than IAA only. To overcome this limitation, HPTLC based protocol is developed to precisely detect and quantify IAA and IBA in the range of 100 to 1000ng per spot. This protocol is applicable to detect and quantify IAA and IBA from microbial samples ignoring other Trp derivatives. For microbial samples, the spectrophotometric method gives larger values as compared to HPTLC derived values which may be attributed by total indolic compounds reacting with Salkowski reagent rather than only IAA and/or IBA.  ",0
5618,25573589,Frameshift mutations of MUC15 gene in gastric and its regional heterogeneity in gastric and colorectal cancers,"Mucins are important in tumorigenesis and expressional alterations of mucins are common in human cancers. A membrane-bound mucin MUC15 and secreted mucins MUC4 and MUC7 are known to involve in tumorigenesis, but their mutation status in cancers remains unknown. Aim of this study was to explore whether MUC4, MUC7 and MUC15 genes are mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC). In a public database, we found that MUC15 and MUC7 genes had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with microsatellite instability (MSI). We analyzed the mutations in 90 GC and 141 CRC (high MSI (MSI-H) or stable MSI/low MSI (MSS/MSI-L)) by single-strand conformation polymorphism analysis and DNA sequencing. In the present study, we found MUC15 frameshift mutations (14.7% of GC and 15.2% of CRC with MSI-H), MUC 7 frameshift mutations (2.9% of GC with MSI-H) and MUC4 frameshift mutations (8.8% of GC and 3.8% of CRC with MSI-H). These mutations were not found in in MSS/MSI-L (0/118). Additionally, we analyzed intratumoral heterogeneity (ITH) of MUC15 mutation in 16 CRC and found that seven CRC (43.8%) harbored regional ITH of MUC15. We also analyzed MUC15 expression in GC and CRC by immunohistochemistry. Negative MUC15 expression was identified in 15-41% of the GC and CRC irrespective of MSI status. Of note, the negative expression was more common in those with MUC15 mutations. We identified alterations of MUC genes at various levels (frameshift mutations, genetic ITH and expression loss), which together might play a role in tumorigenesis of GC and CRC with MSI-H. Our data suggest that mutation analysis in multiple regions is needed for a better evaluation of mutation status in CRC with MSI-H. ",0
5619,25573726,Chemopreventive potential of alpha lipoic acid in the treatment of colon and cervix cancer cell lines,"The nuclear factor κB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer. The aim of this study was to examine the influence of the alpha lipoic acid in the chemoprevention of colon and cervix carcinoma in vitro. In recent years, special attention has been paid to the potential chemopreventive properties of antioxidants. There are no published data on the impact of alpha lipoc acid of chemoprevention of cervix and colon cancer. We examined the effect of alpha lipoic acid alone or in combination with cisplatin and 5-fluorouracil on proliferation of the two cell lines, HeLa (human cervical carcinoma cells) and Caco-2 (human colon cancer cells) by MTT test. The measurement of the level of transcription factor NF-κB was also performed in the cells of both cell lines. At least one of the mechanisms of the antiproliferative and/or cytotoxic effect of alpha lipoic acid on Caco-2 and HeLa cells at high concentrations, the transcription factor NF-κB, may be involved, as well as the products of transcription of genes that are under its control. The alpha lipoic acid has proven to be a promising candidate in the combat arena against cancer (Tab. 4, Ref. 31). ",0
5620,25573983,"Anticoagulation during pregnancy in women with prosthetic valves: evidence, guidelines and unanswered questions","The management of women with mechanical heart valves during pregnancy remains difficult and controversial. There is no ideal anticoagulation regimen for this unique population, as there are inherent risks and benefits of each approach for both mother and fetus. There has been limited data available to guide the clinician in the optimal treatment strategy for an individual patient. The AHA/ACC Guidelines for the Management of Patients with Valvular Heart Disease created class recommendations for this population based upon current evidence, which is summarized in this review.  ",0
5621,25575044,The association between daytime napping and cognitive functioning in chronic fatigue syndrome,"The precise relationship between sleep and physical and mental functioning in chronic fatigue syndrome (CFS) has not been examined directly, nor has the impact of daytime napping. This study aimed to examine self-reported sleep in patients with CFS and explore whether sleep quality and daytime napping, specific patient characteristics (gender, illness length) and levels of anxiety and depression, predicted daytime fatigue severity, levels of daytime sleepiness and cognitive functioning, all key dimensions of the illness experience. 118 adults meeting the 1994 CDC case criteria for CFS completed a standardised sleep diary over 14 days. Momentary functional assessments of fatigue, sleepiness, cognition and mood were completed by patients as part of usual care. Levels of daytime functioning and disability were quantified using symptom assessment tools, measuring fatigue (Chalder Fatigue Scale), sleepiness (Epworth Sleepiness Scale), cognitive functioning (Trail Making Test, Cognitive Failures Questionnaire), and mood (Hospital Anxiety and Depression Scale). Hierarchical Regressions demonstrated that a shorter time since diagnosis, higher depression and longer wake time after sleep onset predicted 23.4% of the variance in fatigue severity (p <.001). Being male, higher depression and more afternoon naps predicted 25.6% of the variance in objective cognitive dysfunction (p <.001). Higher anxiety and depression and morning napping predicted 32.2% of the variance in subjective cognitive dysfunction (p <.001). When patients were classified into groups of mild and moderate sleepiness, those with longer daytime naps, those who mainly napped in the afternoon, and those with higher levels of anxiety, were more likely to be in the moderately sleepy group. Napping, particularly in the afternoon is associated with poorer cognitive functioning and more daytime sleepiness in CFS. These findings have clinical implications for symptom management strategies. ",0
5622,25575299,Bifunctional fatty acid chemical reporter for analyzing S-palmitoylated membrane protein-protein interactions in mammalian cells,"Studying the functions of S-palmitoylated proteins in cells can be challenging due to the membrane targeting property and dynamic nature of protein S-palmitoylation. New strategies are therefore needed to specifically capture S-palmitoylated protein complexes in cellular membranes for dissecting their functions in vivo. Here we present a bifunctional fatty acid chemical reporter, x-alk-16, which contains an alkyne and a diazirine, for metabolic labeling of S-palmitoylated proteins and photo-cross-linking of their involved protein complexes in mammalian cells. We demonstrate that x-alk-16 can be metabolically incorporated into known S-palmitoylated proteins such as H-Ras and IFITM3, a potent antiviral protein, and induce covalent cross-linking of IFITM3 oligomerization as well as its specific interactions with other membrane proteins upon in-cell photoactivation. Moreover, integration of x-alk-16-induced photo-cross-linking with label-free quantitative proteomics allows identification of new IFITM3 interacting proteins.  ",0
5623,25575313,"Syntheses, characterization, interaction with DNA, cytotoxic and apoptosis of two novel complexes of Zn(II) and Mn(II) with 2-methyl-1H-4,5-imidazoledicarboxylic acid","Two new complexes, Zn(L)2(H2O)2 (1) and Mn(L)2(H2O)2 (2) [L = 2-Methyl-1H-4,5-imidazoledicarboxylic acid] were synthesized and characterized by elemental analysis, infrared spectroscopy, and single crystal X-ray diffraction. Intramolecular weak interactions, such as hydrogen-bond and intermolecular interactions were presented in the complexes. The activities of the complexes binding with DNA, and cytotoxic activities were studied. The binding of complexes with fish sperm DNA (FS-DNA) was investigated by fluorescence spectra. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pBR322 plasmid DNA. The cytotoxic activities of the complexes were tested against the KB cell line. Cytotoxic activity studies showed the two complexes exhibited significant cancer cell inhibitory rate. The most active compound was complex 1 with IC50 and CC50value of 36.5, 429, with the selectivity index (SI = 11.75) among the tested compounds.  ",0
5624,25575473,Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane,"In this study, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane (Eudragit(®) RS) via osmotic pressure (with NaCl as the osmogent) was developed and characterized for omeprazole, omeprazole sodium, and propranolol HCl which have different water solubilities. Multiparticulates in pellet form for incorporation with or without the osmogent were manufactured by three methods and then used to coat a polymeric membrane. Results demonstrated that drug/osmogent-containing pellets manufactured by the extrusion/spheronization method with incorporation of the osmogent were optimal. The lag time (tL) to initiate pulsatile release is regulated by tL=l(2)/(6×D), which is dependent on the coating levels (l(2)) and plasticizer content (D). The pulsatile release pattern was found to be dependent on the osmotic pressure (osmogent), drug solubility, and mechanical properties of the polymeric membrane (elasticity and toughness). Omeprazole with lower water solubility could not generate sufficient osmotic pressure to create a crack in the membrane to activate pulsatile release, whereas the two other model drugs with higher solubilities could. But adsorption of omeprazole sodium on Eudragit(®) RS via charge-charge interactions led the its incomplete release. Finally, with 4% osmogent of NaCl added, a lag time in a range from 0 to 12h proportionally regulated by varying both the membrane thickness and plasticizer level initiated the complete pulsatile release of propranolol HCl. In conclusion, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane via osmotic pressure was successfully developed, and clinical applications of chronotherapy with drugs like propranolol HCl are expected.  ",0
5625,25575527,Putative immunogenicity expression profiling using human pluripotent stem cells and derivatives,"""Autologous human induced pluripotent stem cells (hiPSCs) should allow cellular therapeutics without an associated immune response. This concept has been controversial since the original report that syngeneic mouse iPSCs elicited an immune response after transplantation. However, an investigative analysis of any potential acute immune responses in hiPSCs and their derivatives has yet to be conducted. In the present study, we used correlative gene expression analysis of two putative mouse """"immunogenicity"""" genes, ZG16 and HORMAD1, to assay their human homologous expression levels in human pluripotent stem cells and their derivatives. We found that ZG16 expression is heterogeneous across multiple human embryonic stem cell and hiPSC-derived cell types. Additionally, ectopic expression of ZG16 in antigen-presenting cells is insufficient to trigger a detectable response in a peripheral blood mononuclear cell coculture assay. Neither of the previous immunogenicity-associated genes in the mouse currently appears to be relevant in a human context.  """,0
5626,25575538,Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results,"The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) can be safely administered to patients with end-stage relapsed/refractory multiple myeloma (RRMM). However, we observed a shorter median progression-free survival (PFS) and overall survival (OS) in these patients when characterized with adverse cytogenetics (deletion 17p and translocation [4;14]) in the Intergroupe Francophone Myélome (IFM) 2009-02 trial. We then sought to determine whether MM with adverse cytogenetics would benefit more from Pom-Dex if exposed earlier in the multicenter IFM 2010-02 trial. The intention-to-treat population included 50 patients, with a median age of 63 years (38% were ≥65 years). Interestingly, there was a striking difference in time to progression (TTP), duration of response, and overall response rate (ORR) according to the presence of del(17p) compared with t(4;14) (TTP, 7.3 vs 2.8 months; duration of response, 8.3 vs 2.4 months; and ORR, 32% vs 15%). OS was prolonged after Pom-Dex, particularly in t(4;14), given the short TTP, suggesting that patients were rescued at relapse with further lines of therapy. Pom-Dex, a doublet immunomodulatory drug-based regimen, is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p), who are characterized by a high and rapid development of a refractoriness state and known for their poor prognosis. Future studies will determine the underlying mechanisms of Pom-Dex activity in del(17p). This trial is registered at www.clinicaltrials.gov as #NCT01745640.  ",0
5627,25575589,"One-step purification and porin transport activity of the major outer membrane proteins P2 from Haemophilus influenzae, FomA from Fusobacterium nucleatum and PorB from Neisseria meningitidis","Bacterial porins are major outer membrane proteins that function as essential solute transporters between the bacteria and the extracellular environment. Structural features of porins are also recognized by eukaryotic cell receptors involved in innate and adaptive immunity. To better investigate the function of porins, proper refolding is necessary following purification from inclusion bodies [1, 2]. Using a single-step size exclusion chromatographic method, we have purified three major porins from pathogenic bacteria, the OmpP2 (P2) from Haemophilus influenzae, FomA from Fusobacterium nucleatum and PorB from Neisseria meningitidis, at high yield and report their unique solute transport activity with size exclusion limit. Furthermore, we have optimized their purification method and achieved improvement of their thermostability for facilitating functional and structural analyses.  ",0
5628,25575621,Host effects contributing to cancer therapy resistance,"There are several approaches for the management of malignant disease. However, tumor resistance to therapy is still a major challenge in the clinic. Efflux transporters, genetic responses and enzyme activity in tumor cells are examples of the main modalities that account for resistance to therapy. In addition, emerging evidence suggests that the host also plays a significant role in promoting therapy resistance. Recruitment of different host cell types to the treated tumor site occurs in response to a range of therapies, including chemotherapy, radiation and even targeted drugs. This host response may have a protective effect on the tumor cells, not only negating anti-tumor activity, but also promoting a resistant tumor. In this review, we focus on host-tumor interactions leading to therapy resistance with special emphasis on different host cells and secreted factors within the tumor microenvironment. The development of novel inhibitors that block the host response to therapy could be used as a treatment strategy to enhance therapy outcomes and survival.  ",0
5629,25576014,Targeted prevention of childhood anxiety: engaging parents in an underserved community,"Selective prevention programs hold the promise of alleviating child anxiety symptoms, decreasing the risk for emotional problems across the lifespan. Such programs have particular public health import for young children of poor, underserved communities. Identifying factors related to parent engagement, and methods to improve engagement, are paramount in the effort to develop anxiety-focused, community prevention programs. This feasibility study investigated the effect of an enhanced recruitment strategy to maximize parent engagement, as well as factors related to attendance in a single session focused on anxiety prevention. Participants were poor, ethnic minority parents of children aged 11-71 months (n = 256) who completed a survey that assessed anxiety risk according to trauma exposure, child anxiety, or parent anxiety, as well as preferences for preventive services (phase 1). Those meeting risk criteria (n = 101) were invited to a preventive group session (phase 2). Half of parents received enhanced recruitment (ER), which included personalized outreach, matching parent preferences, and community endorsement. Other parents were invited by mail. Chi square analyses indicated that ER was associated with planning to attend (49 vs. 6% of control). Parents receiving ER were 3.5 times more likely to attend. Higher sociodemographic risk was correlated with higher child anxiety symptoms but not attendance. Results highlight the need for improved strategies for engaging parents in preventive, community-based interventions. ",0
5630,25576055,Enhancement of hypothalamic STAT3 acetylation by nuclear receptor Nur77 dictates leptin sensitivity,"Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin's reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aging-induced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus. ",0
5631,25576161,Combined methylation of p16 and hMLH1 (CMETH2) discriminates a subpopulation with better prognosis in colorectal cancer patients with microsatellite instability tumors,"The aim of this study was to determine the frequency of p16 and hMLH1 genes simultaneous methylation in colorectal cancer patients with Microsatellite Instability (MSI) tumors. We also wanted to analyze the relationship with other clinical features, with BRAF gene V600E mutation and with prognosis. Samples from fifty one patients with MSI positive sporadic colorectal cancer were included. DNA was extracted from tumor samples. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. BRAF gene was amplified using specific primers and mutations were detected by real time PCR. Simultaneous methylation was transformed in a new variable called CMETH2. Frequency of CMETH2 was analyzed and compared with other clinicopathological variables. 33.3 % of patients were positive for CMETH2 and 25 % had BRAF V600E mutation. CMETH2 was related with proximal location, with poorly differentiated tumors and with BRAF V600E mutation. CMETH2 only showed influence in the overall survival (OS) in patients with distal tumors. However, with regard to the disease free survival (DFS) measure, CMETH2 was independent prognostic factor. We were able to discriminate tumors with high methylation features using a transformation analysis of variables into a new computed one (CMETH2). CMETH2 has demonstrated to be a useful prognostic factor in MSI tumors. The prognostic value of CMETH2 in DFS was independent of other clinicopathological variables. The use of CMETH2 could help in the election of the best therapeutic alternative for CCR patients with MSI tumors. ",0
5632,25576363,Cold tolerance of the Antarctic nematodes Plectus murrayi and Scottnema lindsayae,"The cold tolerance of the Antarctic nematodes Scottnema lindsayae and Plectus murrayi was determined using material freshly isolated from the field. Both species could survive low temperatures but the survival of S. lindsayae was greater than that of P. murrayi. Field soil temperatures in late spring-early summer indicated a minimum temperature of -19.5 °C and a maximum cooling rate of 0.71 °C min(-1). In P. murrayi grown in culture, there was no significant effect of acclimation, nor of the two culture media used, on survival after freezing but survival was greater if freezing was seeded at -1 °C than at lower temperatures. The freezing survival ability of P. murrayi is much less than that of Panagrolaimus davidi CB1, another Antarctic nematode. Cryomicroscopy indicates that P. murrayi can survive low temperatures by either cryoprotective dehydration or freezing tolerance, but that freezing tolerance is the dominant strategy. Measurable thermal hysteresis was detected only in highly concentrated extracts of the nematodes, indicating the presence of an antifreeze protein, but at the concentrations likely to be found in vivo, the major function of the ice active protein involved is probably recrystallization inhibition.  ",0
5633,25576448,Altered breathing syndrome in heart failure: newer insights and treatment options,"""In patients with heart failure (HF), altered breathing patterns, including periodic breathing, Cheyne-Stokes breathing, and oscillatory ventilation, are seen in several situations. Since all forms of altered breathing cause similar detrimental effects on clinical outcomes, they may be considered collectively as an """"altered breathing syndrome."""" Altered breathing syndrome should be recognized as a comorbid condition of HF and as a potential therapeutic target. In this review, we discuss mechanisms and therapeutic options of altered breathing while sleeping, while awake at rest, and during exercise.  """,0
5634,25576499,Adolescent diet and time use clusters and associations with overweight and obesity and socioeconomic position,"Risk factors for adolescent overweight and obesity include low levels of physical activity, high levels of sedentary behavior, low fruit and vegetable intake, and low socioeconomic position (SEP). To date, the vast majority of research investigating associations between lifestyle behaviors and weight status analyze dietary and time use factors separately. Our research aimed to describe Australian youth time use and diet clusters and explore relationships with weight status and SEP (parental education and income). Cluster analysis of the National Children's Nutrition and Physical Activity Survey data from Australians aged 9 to 16 years (random sample n = 1,853) was conducted. Time use data (17 age-adjusted time use variables) and dietary data (7 age-adjusted diet variables) were collected via 24-hour recalls. Two clusters were associated with a reduced frequency of overweight and obesity (the boys' Active Sitter and girls' Healthy Academic clusters) and one with an increased frequency of overweight and obesity (the boys' Unhealthy cluster). Of these three clusters, two demonstrated associations with parental income and/or parental education level. The boys' Unhealthy cluster was associated with low SEP status (parental income and education), and the girls' Healthy Academic cluster was associated with high parental income. Not all unhealthy adolescent clusters were associated with overweight and obesity. The findings suggest sex-specific diet and activity clusters can be used to identify at-risk subgroups and inform multifaceted interventions to address overweight and obesity.  ",0
5635,25576529,"New plasmid-mediated aminoglycoside 6'-N-acetyltransferase, AAC(6')-Ian, and ESBL, TLA-3, from a Serratia marcescens clinical isolate","Enterobacteriaceae clinical isolates showing amikacin resistance (MIC 64 to >256 mg/L) in the absence of 16S rRNA methyltransferase (MTase) genes were found. The aim of this study was to clarify the molecular mechanisms underlying amikacin resistance in Enterobacteriaceae clinical isolates that do not produce 16S rRNA MTases. PCR was performed to detect already-known amikacin resistance determinants. Cloning experiments and sequence analyses were performed to characterize unknown amikacin resistance determinants. Transfer of amikacin resistance determinants was performed by conjugation and transformation. The complete nucleotide sequence of the plasmids was determined by next-generation sequencing technology. Amikacin resistance enzymes were purified with a column chromatography system. The enzymatic function of the purified protein was investigated by thin-layer chromatography (TLC) and HPLC. Among the 14 isolates, 9 were found to carry already-known amikacin resistance determinants such as aac(6')-Ia and aac(6')-Ib. Genetic analyses revealed the presence of a new amikacin acetyltransferase gene, named aac(6')-Ian, located on a 169 829 bp transferable plasmid (p11663) of the Serratia marcescens strain NUBL-11663, one of the five strains negative for known aac(6') genes by PCR. Plasmid p11663 also carried a novel ESBL gene, named blaTLA-3. HPLC and TLC analyses demonstrated that AAC(6')-Ian catalysed the transfer of an acetyl group from acetyl coenzyme A onto an amine at the 6'-position of various aminoglycosides. We identified aac(6')-Ian as a novel amikacin resistance determinant together with a new ESBL gene, blaTLA-3, on a transferable plasmid of a S. marcescens clinical isolate. ",0
5636,25576576,The FRK1 mitogen-activated protein kinase kinase kinase (MAPKKK) from Solanum chacoense is involved in embryo sac and pollen development,"The fertilization-related kinase 1 (ScFRK1), a nuclear-localized mitogen-activated protein kinase kinase kinase (MAPKKK) from the wild potato species Solanum chacoense, belongs to a small group of pMEKKs that do not possess an extended N- or C-terminal regulatory domain. Initially selected based on its highly specific expression profile following fertilization, in situ expression analyses revealed that the ScFRK1 gene is also expressed early on during female gametophyte development in the integument and megaspore mother cell and, later, in the synergid and egg cells of the embryo sac. ScFRK1 mRNAs are also detected in pollen mother cells. Transgenic plants with lower or barely detectable levels of ScFRK1 mRNAs lead to the production of small fruits with severely reduced seed set, resulting from a concomitant decline in the number of normal embryo sacs produced. Megagametogenesis and microgametogenesis were affected, as megaspores did not progress beyond the functional megaspore (FG1) stage and the microspore collapsed around the first pollen mitosis. As for other mutants that affect embryo sac development, pollen tube guidance was severely affected in the ScFRK1 transgenic lines. Gametophyte to sporophyte communication was also affected, as observed from a marked change in the transcriptomic profiles of the sporophytic tissues of the ovule. The ScFRK1 MAPKKK is thus involved in a signalling cascade that regulates both male and female gamete development.  ",0
5637,25576780,Automated external defibrillator rescues among children with diagnosed and treated long QT syndrome,"Long QT syndrome (LQTS) is a potentially lethal yet highly treatable cardiac channelopathy. A comprehensive LQTS-directed treatment program often includes an automated external defibrillator (AED). The purpose of this study was to determine the incidence of AED rescues among children evaluated, risk-stratified, and treated in an LQTS specialty center. We performed a retrospective review of the electronic medical records to identify 1665 patients evaluated in our Genetic Heart Rhythm Clinic (1999-2013). Subset analysis was performed on 291 children managed without an implantable cardioverter-defibrillator (ICD). The average age at diagnosis was 8.3 ± 5.7 years with an average. QTc of 463 ± 40 ms (17% ≥500 ms). The represented LQTS genotypes included type 1 (LQT1) in 52%, type 2 (LQT2) in 35%, and type 3 (LQT3) in 7%. During follow-up, 3 of 291 children (1%) had a cardiac arrest with an appropriate AED rescue (2/51 symptomatic, 1/240 asymptomatic). The first AED rescue occurred during exercise in a symptomatic 3-year-old boy with compound LQT1 treated with beta-blocker and videoscopic left cardiac sympathetic denervation (LCSD). The second AED rescue occurred in a remotely symptomatic 14-year-old boy with high-risk LQT2 (QTc >550 ms) on a beta-blocker who previously declined a prophylactic ICD. The third AED rescue involved an asymptomatic 17-year-old girl with LQT3 on mexiletine who collapsed in school. An AED should seldom be necessary in an appropriately treated child with LQTS. Nevertheless, despite only 3 AED rescues in more than 1700 patient-years, an AED can be a lifesaving and cost-effective part of an LQTS patient's comprehensive sudden death prevention program. ",0
5638,25577524,DCE-MRI of the breast in a stand-alone setting outside a complementary strategy - results of the TK-study,"To evaluate the accuracy of MRI of the breast (DCE-MRI) in a stand-alone setting with extended indications. According to the inclusion criteria, breast specialists were invited to refer patients to our institution for DCE-MRI. Depending on the MR findings, patients received either a follow-up or biopsy. Between 04/2006 and 12/2011 a consecutive total of 1,488 women were prospectively examined. Of 1,488 included patients, 393 patients were lost to follow-up, 1,095 patients were evaluated. 124 patients were diagnosed with malignancy by DCE-MRI (76 TP, 48 FP, 971 TN, 0 FN cases). Positive cases were confirmed by histology, negative cases by MR follow-ups or patient questionnaires over the next 5 years in 1,737 cases (sensitivity 100 %; specificity 95.2 %; PPV 61.3 %; NPV 100 %; accuracy 95.5 %). For invasive cancers only (DCIS excluded), the results were 63 TP; 27 FP; 971 TP and 0 FN (sensitivity 100 %; specificity 97.2 %; PPV 70 %; NPV 100 %; accuracy 97.5 %). The DCE-MRI indications tested imply that negative results in DCE-MRI reliably exclude cancer. The results were achieved in a stand-alone setting (single modality diagnosis). However, these results are strongly dependent on reader experience and adequate technical standards as prerequisites for optimal diagnoses. • DCE-MRI of the breast has a high accuracy in finding breast cancer. • The set of indications for DCE-MRI of the breast is still very limited. • DCE-MRI can achieve a high accuracy in a 'screening-like' setting. • Accuracy of breast DCE-MRI is strongly dependent on technique and reader experience. • A negative DCE-MRI effectively excludes cancer. ",0
5639,25577556,Which approach is best for subungual glomus tumors? Transungual with microsurgical dissection of the nail bed or periungual?,"Glomus tumors are rare, accounting for 1% to 5% of all hand tumors. The treatment of subungual glomus tumors consists of complete surgical excision, either by the periungual or transungual approach. Tumor recurrence and nail dystrophy are the main complications. The purpose of this study was to evaluate the outcome as a function of the surgical approach used - transungual or periungual. Fifty-three patients presenting with a subungual glomus tumor underwent surgical excision through the periungual approach if the tumor was peripheral, or the transungual approach if the tumor was centrally located. These patients were followed for an average of 2years. Pain relief was always obtained the day following surgery. Wound healing was achieved on average after 2weeks with the periungual approach and 5weeks with the transungual approach. Other than some longitudinal striations in 10 patients (18.9%) who had been operated through the transungual approach, there were no complications or tumor recurrence. We recommend a periungual approach for a peripheral tumor and a transungual approach for a central tumor. The latter approach, which carries some risks of nail-related sequelae--always minor in our experience--allows for better exposure if the tumor is centrally located. ",0
5640,25577591,Treatment of lip hemangioma using forced dehydration with induced photocoagulation via diode laser: report of three cases,"Several vascular lesions are related to the lip area. There is no universally accepted protocol for the treatment of hemangiomas and vascular malformations. In the oral cavity, high-power lasers represent an excellent therapeutic option for this type of lesion. Their coagulative properties allow for the performance of procedures without the risk of bleeding, which promotes a better healing pattern and a differentiated postoperative appearance. This study describes three cases of lip hemangioma treated with forced dehydration with induced photocoagulation (FDIP) via diode laser. All the reported cases were followed up until complete healing of the operated area had total remission of lesions, with no complications or adverse effects. The findings of the present study suggest that FDIP is effective and useful in the treatment of hemangiomas in the oral cavity. Laser treatment of these lesions prevents their recurrence and is well tolerated by patients.  ",0
5641,25578000,"Validity evidence of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in Chile]","This study aims to psychometrically validate the Chilean version of the Alcohol, Smoking and Substance Involvement Screening Test ASSIST. Specifically, this study is interested in evaluating the reliability, consistency and concurrent and discriminant validity of this instrument. The sample was composed for a total of 400 people from four different settings: treatment centers (residential and ambulatories), primary health care, police stations and companies. The reliability of the ASSIST was high (&#945; = .86 for Alcohol, &#945; = .84 for marijuana and &#945; = .90 for cocaine). The intra class correlation coefficient (ICC) with test-retest comparison was statistically significant for Alcohol (ICC = .66), marijuana (ICC = .74) and cocaine (ICC = .80). There were statistically significant correlations between the ASSIST and the AUDIT score (Pearson’s r = .85), the ASSIST and the ASI-Lite score (r between .66 and .83 for tobacco, alcohol, marijuana and cocaine), and the ASSIST and the SDS score (r = .65). The original cutoff point for high risk detection was 27 points, however, in order to have a better balance between sensitivity and specificity the cut was changed to 21 points. The ASSIST presents good psychometric properties and therefore is a reliable and valid instrument to be used as a mechanism to detect risk levels of substance use in the Chilean population.  ",0
5642,25579057,Are caveolae a cellular entry route for non-viral therapeutic delivery systems?,"The development of novel therapies increasingly relies on sophisticated delivery systems that allow the drug or gene expression-modifying agent of interest entry into cells. These systems can promote cellular targeting and/or entry, and they vary in size, charge, and functional group chemistry. Their optimization requires an in depth knowledge of the cellular routes of entry in normal and pathological states. Caveolae are plasma membrane invaginations that have the potential to undergo endocytosis. We critically review the literature exploring whether drug or nucleic acid delivery systems exploit and/or promote cellular entry via caveolae. A vast majority of studies employ pharmacological tools, co-localization experiments and very few make use of molecular tools. We provide clarification on how results of such studies should be interpreted and make suggestions for future studies.  ",0
5643,25579537,"Depression, anxiety and quality of life through the use of complementary and alternative medicine among breast cancer patients in Turkey","Breast cancer is the most common type of cancer amongst women today. The aim of this study was to examine the association between complementary and alternative medicine (CAM) and the quality of life (QoL), anxiety and depression and demographic characteristics of women with breast cancer. QoL was measured by the European Organization for Treatment and Research of Cancer quality of life core questionnaire (QLQ-C30, version 3.0) and anxiety and depression was measured by the hospital anxiety and depression scale. In total, 122 patients with breast cancer were enrolled in the study and 50% (n=61) of them reported that they were using CAM. The most commonly used CAM methods were stinging nettle (57%) and prayer and spiritual healing (49%). No relationship was found between the use of CAM and the patient's age, time to diagnosis, cancer stage, chemotherapy use, smoking and residence. However, the analyses showed a positive association between CAM and role functioning (P=0.014) and financial difficulties (P=0.011); and a negative association between CAM and emotional functioning (P=0.033). Based on the previous studies, 20-83.3% of breast cancer patients among different countries and cultures used CAM. Our results suggested that the use of CAM among women is quite popular, but they showed no correlation between CAM usage and anxiety and depression. In addition, CAM usage was more common in breast cancer patients with a poor emotional and financial status. ",0
5644,25579563,Clear cell sarcoma of the kidney: a case report,"Clear cell sarcoma of the kidney is a rare malignant neoplasm of childhood, known for its aggressiveness, its tendency for recurrence, and to metastasize to bone. We report the observation of 8-month-old child presenting with a large abdominal mass. Clinically, it was diagnosed as Wilm's tumor, and left nephrectomy was done. Grossly, 10 cm×8 cm×3.5 cm globular, white, encapsulated, smooth mass uniformly involving the whole kidney was noted. Histologically, the tumor was diagnosed as clear cell sarcoma with renal vein showing presence of tumor embolus in lumen. The tumor was given stage-II (NWTS-5 protocol). Immunohistochemistry showed vimentin positive and cytokeratin negative tumor cells. The child is currently undergoing chemotherapy and has not yet shown any sign of bony metastasis. ",0
5645,25579743,Spectrum of intradialytic complications during hemodialysis and its management: a single-center experience,"Hemodialysis (HD) is one of the important modalities of renal replacement therapy in acute renal failure (ARF) as well as chronic renal failure (CRF). This study was performed to evaluate the various intradialytic complications that occur during HD and their management. This is a retrospective study performed in patients who underwent conventional HD during the period of 1 January 2000 to 31 December 2011 at our center. Clinical details, various complications faced and their management were retrieved from dialysis case sheets. A total of 2325 patients of renal failure (790 ARF and 1535 CRF patients) were assessed for the intradialytic complications of HD. During the study period, there were 12,785 bicarbonate dialyses performed on these patients. In the ARF patients, the common intradialytic complications were: Hypotension, seen in 1296 sessions (30.4%), nausea and vomiting seen in 1125 sessions (26.4%), fever and chills seen in 818 sessions (19.2%), headache seen in 665 sessions (15.6%), cramps seen in 85 sessions (2.0%), chest pain and back pain seen in 82 sessions (1.92%), hypoglycemia seen in 77 sessions (1.8%), first-use syndrome seen in 72 sessions (1.7%) and femoral hematoma seen in 31 sessions (0.73%). In the CRF group, common complications were hypotension in 2230 sessions (26.1%), nausea and vomiting in 1211 sessions (14.2%), fever and chills in 1228 sessions (14.4%), chest pain and back pain in 1108 cases (13.0%), hypertension in 886 sessions (10.4%), headache in 886 sessions (10.4%), cramps in 256 sessions (3.0%), hematoma in 55 sessions (0.64%), intracerebral hemorrhage in three sessions (0.03%) and catheter tip migration in three sessions (0.03%). There is a need for special attention for the diagnosis and management of intradialytic complications of HD because such complications could be managed successfully without the need for termination of the dialysis procedure.  ",0
5646,25580054,"Think globally, act globally: An epidemiologist's perspective on instrumental variable estimation","""We appreciated Imbens' summary and reflections on the state of instrumental variable (IV) methods from an econometrician's perspective. His review was much needed as it clarified several issues that have been historically a source of confusion when individuals from different disciplines discussed IV methods. Among the many topics covered by Imbens, we would like to focus on the common choice of the local average treatment effect (LATE) over the """"global"""" average treatment effect (ATE) in IV analyses of epidemiologic data. As Imbens acknowledges, this choice of the LATE as an estimand has been contentious (Angrist, Imbens and Rubin, 1996; Robins and Greenland, 1996; Deaton, 2010; Imbens, 2010; Pearl, 2011). Several authors have questioned the usefulness of the LATE for informing clinical practice and policy decisions, because it only pertains to an unknown subset of the population of interest: the so-called """"compliers"""". To make things worse, many studies do not even report the expected proportion of compliers in the study population (Swanson and Hernán, 2013). Other authors have wondered whether the LATE is advocated for simply because of the relatively weaker assumptions required for its identification, analogous to the drunk who stays close to the lamp post and declares whatever he finds under its light is what he was looking for all along (Deaton, 2010). Here we explore the limitations of the LATE in the context of epidemiologic and public health research. First we discuss the relevance of LATE as an effect measure and conclude that it is not our primary choice. Second, we discuss the tenability of the monotonicity condition and conclude that this assumption is not a plausible one in many common settings. Finally, we propose further alternatives to the LATE, beyond those discussed by Imbens, that refocus on the global ATE in the population of interest. """,0
5647,25580087,Tissue oxygenation as a target for goal-directed therapy in high-risk surgery: a pilot study,"Tissue hypoperfusion occurs frequently during surgery and may contribute to postoperative organ dysfunction. There is a need for perioperative treatment protocols aiming at improving tissue oxygenation (StO2). We hypothesised that intra-operative optimisation of StO2 improves tissue perfusion and thus reduces postoperative complications. Furthermore, we evaluated the feasibility of the optimisation algorithm used. We randomized 50 high-risk patients, all >65 years with ASA physical status III, who underwent major abdominal surgery under standardized balanced general anesthesia combined with epidural analgesia. Throughout surgery StO2 was monitored at the thenar eminence using near-infrared spectroscopy. All patients were treated according to a standard care algorithm. In addition, patients in the intervention group were treated with dobutamine if necessary to keep or raise StO2 ≥ 80%. Data were recorded continuously and complications were recorded during hospital stay with a maximum of 28 days. The number of complications was not significantly different between groups (11 vs 20; p = 0.23). Eleven patients in the intervention group had no complication, versus 7 in the control group. There was no significant difference between groups in length of stay in ICU or in hospital. Only ten patients in the intervention group received dobutamine. Administration of dobutamine resulted in a moderate 6 [-3 to 10] % increase of StO2. The overall protocol adherence was 94%. No statistically significant difference in outcome was realized through intraoperative optimization of StO2 values in this pilot study. The protocol used may be considered feasible for clinical practice. Further research is obligatory to define both the optimal StO2 threshold and intervention to treat tissue hypoperfusion. ClinicalTrials.gov identifier: NCT01342900. Registered 21 April 2011. ",0
5648,25580118,A framework for prediction of response to HCV therapy using different data mining techniques,"Hepatitis C which is a widely spread disease all over the world is a fatal liver disease caused by Hepatitis C Virus (HCV). The only approved therapy is interferon plus ribavirin. The number of responders to this treatment is low, while its cost is high and side effects are undesirable. Treatment response prediction will help in reducing the patients who suffer from the side effects and high costs without achieving recovery. The aim of this research is to develop a framework which can select the best model to predict HCV patients' response to the treatment of HCV from clinical information. The framework contains three phases which are preprocessing phase to prepare the data for applying Data Mining (DM) techniques, DM phase to apply different DM techniques, and evaluation phase to evaluate and compare the performance of the built models and select the best model as the recommended one. Different DM techniques had been applied which are associative classification, artificial neural network, and decision tree to evaluate the framework. The experimental results showed the effectiveness of the framework in selecting the best model which is the model built by associative classification using histology activity index, fibrosis stage, and alanine amino transferase.  ",0
5649,25580226,The ACCE method: an approach for obtaining quantitative or qualitative estimates of residual confounding,"""  Nonrandomized studies typically cannot account for confounding from unmeasured factors.    A method is presented that exploits the recently-identified phenomenon of  """"confounding amplification"""" to produce, in principle, a quantitative estimate of total residual confounding resulting from both measured and unmeasured factors.  Two nested propensity score models are constructed that differ only in the deliberate introduction of an additional variable(s) that substantially predicts treatment exposure.  Residual confounding is then estimated by dividing the change in treatment effect estimate between models by the degree of confounding amplification estimated to occur, adjusting for any association between the additional variable(s) and outcome.   A hypothetical example is provided to illustrate how the method produces a quantitative estimate of residual confounding if the method's requirements and assumptions are met.  Previously published data is used to illustrate that, whether or not the method routinely provides precise quantitative estimates of residual confounding, the method appears to produce a valuable qualitative estimate of the likely direction and general size of residual confounding.   Uncertainties exist, including identifying the best approaches for: 1) predicting the amount of confounding amplification, 2) minimizing changes between the nested models unrelated to confounding amplification, 3) assessing the association of the introduced variable(s) with outcome, and 4) deriving confidence intervals for the method's estimates (although bootstrapping is one plausible approach).   To this author's knowledge, it has not been previously suggested that the phenomenon of confounding amplification, if such amplification is as predictable as suggested by a recent simulation, provides a logical basis for estimating total residual confounding. The method's basic approach is straightforward.  The method's routine usefulness, however, has not yet been established, nor has the method been fully validated. Rapid further investigation of this novel method is clearly indicated, given the potential value of its quantitative or qualitative output. """,0
5650,25580686,The role of selected flavonols in tumor necrosis factor-related apoptosis-inducing ligand receptor-1 (TRAIL-R1) expression on activated RAW 264.7 macrophages,"Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptors (TRAIL-R) are an important factor of apoptosis in cancer cells. There are no data about the effect of flavonols on the receptor expression on a surface of macrophage like cells. In this study, the expression level of TRAIL-R1 on murine RAW264.7 macrophages in the presence of selected flavonols: galangin, kaempferol, kaempferide and quercetin, which differ from their phenyl ring substituents, were studied. The expression of TRAIL-R1 death receptors on non-stimulated and lipopolysaccharide (LPS)-stimulated macrophages was determined using flow cytometry. The results suggested that compounds being tested can modulate TRAIL-R1 expression and can enhance TRAIL-mediated apoptosis.  ",0
5651,25580784,NAVS naphthalan for the treatment of oral mucosal diseases--a pilot study,"""""""Non-Aromatic Very rich in Steranes"""" (NAVS) naphthalan is a purified natural oil derivative, abundant in steranes (geogenic """"steroids""""). The purpose of this study was to evaluate the effectiveness of NAVS in the treatment of oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS). We used NAVS oil in adhesive paste in 11 patients with clinically and histologically proven OLP (open label), and in 7 patients with RAS (double blind randomized; topical betamethasone in adhesive paste used as control). The severity of the OLP lesions was objectively scored. The number and diameter of RAS lesions were assessed on days 0, 3, and 5. The intensity of pain and discomfort was determined using visual analogue scale (VAS) and """"Oral health impact profile"""" (OHIP-14) before and after therapy. OLP cumulative activity scores on days 0 and 28 were 101.5 and 48.5, respectively (t=5.99; P=0.0001). Using NAVS for 28 days resulted in 52.2% overall clinical improvement. Cumulative OHIP-14 scores on days 0 and 28 were 210 and 142, respectively (t=5.65; P=0.0002). Out of a total of 7 patients with RAS, 4 of them were treated with NAVS and 3 with topical corticosteroids. There were no statistically significant differences in improvement rate between the two groups (lesion number (day 3 P=0.29; day 5 P=0.32); lesion diameter (day 3 P=0.64; day 5 P=0.74)). NAVS successfully reduced the clinical signs and symptoms of OLP, and reduced the number, diameter, and symptoms in patients with RAS, statistically comparable with corticosteroids.  """,0
5652,25581025,"Hodgkin transformation of chronic lymphocytic leukemia: Incidence, outcomes, and comparison to de novo Hodgkin lymphoma","Although transformation to Hodgkin lymphoma (HL) is a recognized complication in patients with chronic lymphocytic leukemia (CLL), its incidence, clinical characteristics and outcomes are not well defined. We used the Mayo Clinic CLL and Lymphoma Databases to identify CLL patients who developed biopsy-proven HL (CLL/HL) on follow-up, as well as cases of de novo HL (i.e., without prior CLL). Among 3887 CLL patients seen at Mayo Clinic from January 1995 through August 2011, 26 (0.7%) developed HL. In a nested cohort of 2,465 newly diagnosed CLL patients followed prospectively, the incidence of HL was 0.05%/year (10 year risk = 0.5%). The median overall survival (OS) from date of HL diagnosis in patients with CLL/HL was 3.9 years compared to not reached for de novo HL patients (n = 709) seen during the same time interval (P < 0.001). The shorter OS of CLL/HL patients persisted after adjusting for differences in age and Ann Arbor stage of disease. The International Prognostic score (IPS) developed for de novo HL stratified prognosis among CLL/HL patients with median survival of not reached, 6.2, 2.4, and 0.3 years (P = 0.006) for those with IPS scores of ≤2, 3, 4, and ≥5, respectively. In summary, approximately 1 of every 200 CLL patients will develop HL within 10 years. Survival after HL diagnosis in patients with CLL is shorter than de novo HL patients. The IPS for de novo HL may be useful for stratifying survival in CLL/HL patients. ",0
5653,25581654,Social cognition deficits and associations with drinking history in alcoholic men and women,"Previous studies have demonstrated the presence of a social cognition factor as an element of general cognition in healthy control and clinical populations. Recently developed measures of social cognition include the social perception and faces subtests of the Wechsler Advanced Clinical Solutions (ACS) Social Cognition module. While these measures have been validated on various clinical samples, they have not been studied in alcoholics. Alcoholism has been associated with emotional abnormalities and diminished social cognitive functioning as well as neuropathology of brain areas underlying social processing abilities. We used the ACS Social Perception and Faces subtests to assess alcoholism-related impairments in social cognition. Social cognitive functioning was assessed in 77 abstinent alcoholic individuals (37 women) and 59 nonalcoholic control participants (29 women), using measures of the ACS Social Cognition module and subtests of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) that contain a social cognition component (Picture Completion and Comprehension). Group and gender differences in ACS and WAIS-IV performance were assessed, as well as relationships between measures of alcoholism severity and social cognitive functioning. Alcoholics performed significantly worse than nonalcoholics on the ACS measures of Affect Naming and Faces Content. Alcoholic men were impaired relative to alcoholic women on Prosody Face Matching and Faces Content scores. Among alcoholics, longer durations of heavy drinking were associated with poorer performance on Affect Naming, and a greater number of daily drinks were associated with lower Prosody Face Matching performance. For alcoholic women, a longer duration of abstinence was associated with better performance on Affect Naming. Alcoholic men and women showed different patterns of associations between alcoholism indices and clinically validated social cognition assessments. These findings extend into the social cognition domain, previous literature demonstrating the presence of cognitive deficits in alcoholism, their association with alcoholism severity, and variability by gender. Moreover, because impairments in social cognition can persist despite extended abstinence, they have important implications for relapse prevention. ",0
5654,25581790,Recognition determinants of broadly neutralizing human antibodies against dengue viruses,"Dengue disease is caused by four different flavivirus serotypes, which infect 390 million people yearly with 25% symptomatic cases and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3, 4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies. We recently isolated human antibodies potently neutralizing all four dengue virus serotypes. Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell, explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus.  ",0
5655,25581903,Indolo-phakellins as β5-specific noncovalent proteasome inhibitors,"The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers.  ",0
5656,25581958,Celiac disease: 10-year experience in a Romanian tertiary center,"To evaluate the experience of a single coeliac center over a 10-year-observational period. Between January 2003 and December 2013 a total of 195 consecutive patients admitted with celiac disease were tested by multiple duodenal biopsies, anti-tissue transglutaminase and anti-gliadin antibodies, and baseline demographic, clinical, biological and immunological parameters. Patients were divided into two major groups according to the clinical features and number of signs and symptoms present upon admission: gastrointestinal (131, 67.17%) and non-gastrointestinal (64, 32.8%). Anti-tissue transglutaminase and anti-gliadin antibodies showed seropositivity in 109/158. Histological samples were available in 152 cases, according to Marsh-Oberhuber classification 11.18% being type 0, 17.76%, type I-II, and 71.05% type III. Correlations between anti-tissue transglutaminase antibody titers and Marsh-Oberhuber classification were found to be statistically significant. Body mass index was available in 96 cases. We found that severe atrophy was predominant in patients with a BMI<18 kg/m2. Celiac disease has an increasing prevalence and can be diagnosed at any age. Histology samples were indicative of different stages of villous atrophy. The disease prevalence is significantly higher among women. There was no statistically significant correlation between Marsh classification and BMI values. ",0
5657,25582051,The use of novel phenotyping methods for validation of equine conformation scoring results,"In this experiment, which is based on a cohort of 44 Lipizzan mares from the Austrian state stud farm of Piber, we present new statistical techniques for the analysis of shape and equine conformation using image data. In addition, we examined which strategies and procedures of image processing techniques led to a successful interpretation of the traits implemented in horse breeding programs. A total of 246 two-dimensional anatomical and somatometric landmarks were digitized from standardized photographs, and the variation of shape has been analyzed by the use of generalized orthogonal least-squares Procrustes (generalized Procrustes analysis (GPA)) procedures. The resulting shape variables have been regressed on the results from linear type trait classifications. In addition, the rating scores of six conformation classifiers were tested for agreement, yielding an inter-rater correlation (inter-class correlation) ranging from 0.41 to 0.68, respectively, a κ coefficient ranging from 0.16 to 0.53. From the 12 linear type traits assessed on a valuating scale, only the type-related traits (type, breed-type and harmony) revealed significant (P<0.05) results in the regression analysis of shape variables on linear type traits. The other nine traits were characterized by a lower agreement between classifiers and did not result in a significant 'shape regression'. Finally, the 'horse shape space' defined by shape variables resulting from GPA procedures offered the possibility to assist in trait definition and in the evaluation of ratings, and it is an adequate biological and objective scale to human perception of conformation, which is expressed in numerical data only.  ",0
5658,25582063,Impact on the improvement of paediatric emergency services using a standardised model for the declaration and analysis of incidents],"The aim of this study is to analyse changes in the incidents reported after the implementation of a new model, and study its results on patient safety. In 2012 an observational study with prospective collection of incidents reported between 2007 and 2011 was conducted. In May 2012 a model change was made in order to increase the number of reports, analyse their causes, and improve the feedback to the service. Professional safety representatives were assigned to every department, information and diffusion sessions were held, and a new incident reporting system was implemented. With the new model, a new observational study with prospective collection of the reports during one year was initiated, and the results compared between models. In 2011, only 19 incidents were reported in the Emergency Department, and between June 1, 2012 to June 1, 2013, 106 incidents (5.6 times more). The incidents reported were medication incidents (57%), identification (26%), and procedures (7%). The most frequent causes were human (70.7%), lack of training (22.6%), and working conditions (15.1%). Some measures were implemented as a result of these incidents: a surgical checklist, unit doses of salbutamol, tables of weight-standardised doses of drugs for cardiopulmonary resuscitation. The new model of reporting incidents has enhanced the reports and has allowed improvements and the implementation of preventive measures, increasing the patient safety in the Emergency Department. ",0
5659,25582332,Targeting Pim kinases for cancer treatment: opportunities and challenges,"Pim oncogenes are highly expressed in many types of hematological and solid cancers. Pim kinases regulate the network of signaling pathways that are critical for tumorigenesis and development, making Pim kinases the attractive drug targets. Currently, two approaches have been employed in designing Pim kinase inhibitors: ATP-mimetics and non-ATP mimetics; but all target the ATP-binding pocket and are ATP-competitive. In this review, we summarize the current progress in understanding the Pim-related structure and biology, and provide insights into the binding modes of some prototypical Pim-1 inhibitors. The challenges as well as opportunities are highlighted for development of Pim kinase inhibitors as potential anticancer agents.  ",0
5660,25582431,Infection with Helicobacter bilis but not Helicobacter hepaticus was Associated with Extrahepatic Cholangiocarcinoma,"The biliary tract cancer or cholangiocarcinoma (CCA) represents the sixth leading cause of gastrointestinal tumors in the Western world, and mortality varies across the world, with regions such as Chile, Thailand, Japan, and northeastern India presenting the highest rates. CCA may develop in the bile duct, gallbladder, or ampulla of Vater; and risk factors include obesity, parity, genetic background, geographical and environmental factors. Inflammation induced by bacterial infections might play a role in the pathogenesis of CCA. In this work, we investigated whether there is an association between extrahepatic cholangiocarcinoma (ECCA) and infection with S. typhi, H. hepaticus, or H. bilis in a Mexican population. A total of 194 patients were included and divided into 91 patients with benign biliary pathology (controls) and 103 with ECCA (cases). Tumor samples were taken during endoscopic retrograde cholangiopancreatography by biliary brushing, followed by DNA extraction and PCR testing for infections. We found that 44/103 cases were positive for H. bilis, compared with 19/91 controls (p = 0.002; OR 2.83, 95% CI 1.49-5.32), and when analyzed by sub-site, H. bilis infection was significantly more associated with cancer in the common bile duct (p = 0.0005; OR 3.56, 95% CI 1.77-7.17). In contrast, H. hepaticus infection was not different between cases (17/103) and controls (13/91) (p = 0.82; OR 1.19, 95% CI 0.54-2.60). None of the samples were positive for S. typhi infection. In conclusion, infection with H. bilis but neither H. Hepaticus nor S. typhi was significantly associated with ECCA, particularly with tumors located in the common bile duct. ",0
5661,25582909,Processing barley grain with lactic acid and tannic acid ameliorates rumen microbial fermentation and degradation of dietary fibre in vitro,"Cereal grains are important ingredients of ruminant diets, but their rapid degradation seriously impairs rumen fermentation and the host's health. The goal of this study was to evaluate whether processing of barley grain with 1 or 5% lactic acid (LA) and 1 or 5% tannic acid (TA), without or with an additional heat treatment (1% LAH or 1% TAH), may affect microbial ruminal abundance, fermentation profile, and nutrient degradation in vitro. Processing with LA lowered (P < 0.05) the concentration of short-chain fatty acids (SCFAs), proportions of branched-chain SCFA, and the acetate-to-propionate ratio. Treatment with 1% TAH and 1% LAH lowered (P < 0.05) gene copy numbers of total protozoa, rumen lipopolysaccharide, and degradation of crude protein, and tended (P = 0.08) to lower the proportion of the genus Prevotella. Treatment of barley grain with 1% LA or 1% LAH stimulated Clostridium cluster XIV. Degradation of fibre was enhanced (P < 0.05) by all LA and TA treatments. Chemical and heat treatment of barley grain modulated the ruminal fermentation profile and enhanced fibre degradation; however, processing of grain with LA seems to be superior because this effect was not associated with a concomitant depression in ruminal degradation of organic matter. ",0
5662,25583006,Effect of pre-storage on Lilium martagon L. seed longevity following cryopreservation,"The aim of the study was to compare different strategies for the cryopreservation of Lilium martagon L. seeds. The starting material was seeds of the martagon lily (without or with a special pretreatment involving sucrose pre-culture dehydratation and desiccation) subjected to cryopreservation after preliminary storage under conventional conditions (-5 degree C, 5 degree C, or 15 degree C). The effects of storage, pretreatment and cryopreservation on the seeds were assessed in terms of seed germination and phenotypic changes in the seedlings derived from those seeds. Subjecting the seeds to cold hardening or pretreatment did not affect significantly their germination capacity or the average germination time after cryopreservation. Combination of these strategies, however, significantly affected the capacity of the seeds to germinate. The highest germinability (100%) after cryopreservation was observed in the seeds stored at 15 degree C and subjected to sucrose pre-culture dehydration and air flow desiccation (seed moisture content [MC] 13.1%), and in those seeds stored at the same temperature but subjected subsequently to 5 h desiccation, not pretreated, with MC of 7.6 degree. Cryopreservation did not affect the germination capacity of the seeds but shortened the average germination time from 40.7 to 34.4 days. The obtained results demonstrate that a simple cryopreservation method without any special pretreatment of seeds can be used successfully for preserving L. martagon seeds. Neither the low temperature nor the sucrose concentration used affected the germination capacity or the average germination time of L. martagon seeds following cryopreservation. ",0
5663,25583386,"Adults with congenital limb deficiency in Norway: demographic and clinical features, pain and the use of health care and welfare services. A cross-sectional study","To describe an adult population with congenital limb deficiency (CLD) recruited through the National Resource Centre for Rare Disorders (TRS) in Norway: (1) demographic factors, (2) clinical features, (3) pain and (4) use of health care and welfare services. Cross-sectional study. In 2012, a postal questionnaire was sent to 186 eligible persons with CLD, age 20 years and older. Ninety-seven respondents, median-age 39 years (range: 20-82); 71% were women. The population was divided into two subgroups: (1) unilateral upper-limb deficiency (UULD) n = 77, (2) multiple and/or lower-limb deficiency (MLD/LLD). About 40% worked full-time, 18% received disability pensions and 64% reported chronic pain, mostly bilateral pain. Grip-improving devices were used more often than prostheses; 23% were previous prosthesis users. Use of health care and welfare services are described. No significant differences were found between the subgroups regarding pain or employment status. Persons with CLD reported increased prevalence of chronic pain, mostly bilateral, and increased prevalence of early retirement. A greater focus on the benefits of the use of assistive devices, the consequences of overuse and vocational guidance may moderate pain and prevent early retirement. Further studies of more representative samples should be conducted to confirm our findings. Most adults with congenital limb deficiency (CLD) live ordinary lives and experience normal life events. However, several report chronic pain and retire before normal retirement age. In spite of free and accessible prosthetic services, a large fraction chooses not to use prosthesis, more use grip-improving devices for specific activities. These preferences should be acknowledged by rehabilitation specialists. Focus on individually adapted environments, more information about the consequences of overuse, and vocational guidance may moderate pain and prevent early retirement. ",0
5664,25583618,Comparison of frequency and time domain electromyography parameters in women with patellofemoral pain,"Despite its high incidence, patellofemoral pain etiology remains unclear. No prior study has compared surface electromyography frequency domain parameters and surface electromyography time domain variables, which have been used as a classic analysis of patellofemoral pain. Thirty one women with patellofemoral pain and twenty eight pain-free women were recruited. Each participant was asked to descend a seven step staircase and data from five successful trials were collected. During the task, the vastus medialis and vastus lateralis muscle activities were monitored by surface electromyography. The data were processed and analyzed in four variables of the frequency domain (median frequency, low, medium and high frequency bands) and three time domain variables (Automatic, Cross-correlation and Visual Onset between the vastus medialis and vastus lateralis muscles). Reliability, Receiver Operating Characteristic curves and regression models were performed. The medium frequency band was the most reliable variable and different between the groups for both muscles, also demonstrated the best values of sensitivity and sensibility, 72% and 69% for the vastus medialis and 68% and 62% for the vastus lateralis, respectively. The frequency variables predicted the pain of individuals with patellofemoral pain, 26% for the vastus medialis and 20% for the vastus lateralis, being better than the time variables, which achieved only 7%. The frequency domain parameters presented greater reliability, diagnostic accuracy and capacity to predict pain than the time domain variables during stair descent and might be a useful tool to diagnose individuals with patellofemoral pain. ",0
5665,25583638,Individual risk factors for deep infection and compromised fracture healing after intramedullary nailing of tibial shaft fractures: a single centre experience of 480 patients,"Despite modern advances in the treatment of tibial shaft fractures, complications including nonunion, malunion, and infection remain relatively frequent. A better understanding of these injuries and its complications could lead to prevention rather than treatment strategies. A retrospective study was performed to identify risk factors for deep infection and compromised fracture healing after intramedullary nailing (IMN) of tibial shaft fractures. Between January 2000 and January 2012, 480 consecutive patients with 486 tibial shaft fractures were enrolled in the study. Statistical analysis was performed to determine predictors of deep infection and compromised fracture healing. Compromised fracture healing was subdivided in delayed union and nonunion. The following independent variables were selected for analysis: age, sex, smoking, obesity, diabetes, American Society of Anaesthesiologists (ASA) classification, polytrauma, fracture type, open fractures, Gustilo type, primary external fixation (EF), time to nailing (TTN) and reaming. As primary statistical evaluation we performed a univariate analysis, followed by a multiple logistic regression model. Univariate regression analysis revealed similar risk factors for delayed union and nonunion, including fracture type, open fractures and Gustilo type. Factors affecting the occurrence of deep infection in this model were primary EF, a prolonged TTN, open fractures and Gustilo type. Multiple logistic regression analysis revealed polytrauma as the single risk factor for nonunion. With respect to delayed union, no risk factors could be identified. In the same statistical model, deep infection was correlated with primary EF. The purpose of this study was to evaluate risk factors of poor outcome after IMN of tibial shaft fractures. The univariate regression analysis showed that the nature of complications after tibial shaft nailing could be multifactorial. This was not confirmed in a multiple logistic regression model, which only revealed polytrauma and primary EF as risk factors for nonunion and deep infection, respectively. Future strategies should focus on prevention in high-risk populations such as polytrauma patients treated with EF. ",0
5666,25583918,Variation in rotavirus vaccine coverage by provider location and subsequent disease burden,"Rotavirus vaccines were introduced in the United States in 2006. Full-series coverage is lower than for other vaccines, and disease continues to occur. We examined variation in vaccine coverage among provider locations and correlated coverage with the detection of rotavirus in children who sought treatment of severe acute gastroenteritis (AGE). Vaccine records of children enrolled in an AGE surveillance program were obtained and children were grouped by the location that administered each child's 2-month vaccines. Cases were children with laboratory-confirmed rotavirus AGE; controls were children with rotavirus-negative AGE or acute respiratory infection. Location-level coverage was calculated using ≥ 1 dose rotavirus vaccine coverage among controls and classified as low (<40%), medium (≥ 40% to <80%), or high (≥ 80%). Rotavirus detection rates among patients with AGE were calculated by vaccine coverage category. Of controls, 80.4% (n = 1123 of 1396) received ≥ 1 dose of rotavirus vaccine from 68 locations. Four (5.9%) locations, including a NICU, were low coverage, 22 (32.3%) were medium coverage, and 42 (61.8%) were high coverage. In low-coverage locations, 31.4% of patients with AGE were rotavirus-positive compared with 13.1% and 9.6% in medium- and high-coverage locations, respectively. Patients with AGE from low-coverage locations had 3.3 (95% confidence interval 2.4-4.4) times the detection rate of rotavirus than patients with AGE from high vaccine coverage locations. We observed the highest detection of rotavirus disease among locations with low rotavirus vaccine coverage, suggesting that ongoing disease transmission is related to failure to vaccinate. Educational efforts focusing on timely rotavirus vaccine administration to age-eligible infants are needed. ",0
5667,25584438,Utilizing relative potency factors (RPF) and threshold of toxicological concern (TTC) concepts to assess hazard and human risk assessment profiles of environmental metabolites: a case study,"There is currently no standard paradigm for hazard and human risk assessment of environmental metabolites for agrochemicals. Using an actual case study, solutions to challenges faced are described and used to propose a generic concept to address risk posed by metabolites to human safety. A novel approach - built on the foundation of predicted human exposures to metabolites in various compartments (such as food and water), the threshold of toxicological concern (TTC) and the concept of comparative toxicity - was developed for environmental metabolites of a new chemical, sulfoxaflor (X11422208). The ultimate aim was to address the human safety of the metabolites with the minimum number of in vivo studies, while at the same time, ensuring that human safety would be considered addressed on a global regulatory scale. The third component, comparative toxicity, was primarily designed to determine whether the metabolites had the same or similar toxicity profiles to their parent molecule, and also to one another. The ultimate goal was to establish whether the metabolites had the potential to cause key effects - such as cancer and developmental toxicity, based on mode-of-action (MoA) studies - and to develop a relative potency factor (RPF) compared to the parent molecule. Collectively, the work presented here describes the toxicology programme developed for sulfoxaflor and its metabolites, and how it might be used to address similar future challenges aimed at determining the relevance of the metabolites from a human hazard and risk perspective. Sulfoxaflor produced eight environmental metabolites at varying concentrations in various compartments - soil, water, crops and livestock. The MoA for the primary effects of the parent molecule were elucidated in detail and a series of in silico, in vitro, and/or in vivo experiments were conducted on the environmental metabolites to assess relative potency of their toxicity profiles when compared to the parent. The primary metabolite, X11719474 found in soil, crops and, potentially, at low concentrations, in groundwater, was the most extensively studied, with genetic, acute, short-term rat and dog, rodent reproductive and developmental toxicity studies, and MoA studies conducted. These data supported that the toxicity profile for X11719474 was limited to liver effects via the same MoA as the parent and, overall, X11719474 was significantly less toxic than parent. Subsequently, the comparative toxicology programme was extended to cover all metabolites of sulfoxaflor. Based on structure (i.e., similarity of metabolite structures to one another), toxic effects in comparison with parent (i.e., consistency of the toxicity profiles and confidence in terms of ability to read across), residue compartment (e.g., crop, soil, water) and predicted level of exposure, fewer studies were required for establishing safety of these metabolites compared to X11719474. For example, for some metabolites with very low predicted environmental concentrations only genotoxicity testing was required. For some metabolites with low predicted concentrations, for example only present in liver, a TTC approach was utilized. This strategy of comparative assessment utilizing MoA data, relative potency, hazard characterization, read-across, predicted exposure and TTC provided a robust database, which minimized animal use, comprehensively assessed the hazard and human risk presented by these metabolites.  ",0
5668,25584599,"Alcohol, drugs and tobacco smoking causes much of the burden of disease--Trends in Sweden 1990-2010 mapped based DALY method]","Various attempts have been made to measure the burden of alcohol, drugs and tobacco smoking on population health, and mortality is an often used measure. As part of the governmental strategy to prevent use of alcohol, drugs, doping and tobacco (ANDT) in Sweden, we assessed disease burden measured by DALY (Disability Adjusted Life Years), attributed to alcohol, drugs and tobacco over time, as an overall indicator of problem level. DALY was developed within the Global Burden of Disease study (GBD), and combines life lost to premature death (YLL) and years lived with disability (YLD) in one measure. In 2010 tobacco contributed to 7.7% of the total disease burden in Sweden, followed by alcohol (3.4%) and drugs (1.3%). The disease burden caused by tobacco has decreased substantially since 1990, while small changes are observed for alcohol and drugs. Much of the disease burden specially related to drugs and alcohol was related to YLD, which can be captured with the DALY measure.  ",0
5669,25586253,The effect of raloxifene on symptoms and cognitive functioning in a postmenopausal schizophrenia patient: a case report,"We report on a 61-year-old postmenopausal female with schizophrenia included in a raloxifene vs. placebo clinical trial and monitored during a 12-month period including a 3-month withdrawal period (6-9 months) without treatment. The patient was treated with raloxifene 60 mg/day adjuvant to antipsychotic medication for 6 months, medication was then withdrawn for 3 months and was reintroduced due to a worsening of symptoms. We assessed the patient with PANSS and other neuropsychological tests. The patient improved in psychopathology and cognitive level in some aspects related to executive functions. During 3 months without the drug, the patient's condition deteriorated. When the drug was reintroduced, improvements were again observed. Raloxifene may be useful as an adjuvant treatment for psychopathological symptoms and some cognitive aspects in women with chronic schizophrenia.  ",0
5670,25586708,Real-time pretreatment review limits unacceptable deviations on a cooperative group radiation therapy technique trial: quality assurance results of RTOG 0933,"""RTOG 0933 was a phase II trial of hippocampal avoidance during whole brain radiation therapy for patients with brain metastases. The results demonstrated improvement in short-term memory decline, as compared with historical control individuals, and preservation of quality of life. Integral to the conduct of this trial were quality assurance processes inclusive of pre-enrollment credentialing and pretreatment centralized review of enrolled patients. Before enrolling patients, all treating physicians and sites were required to successfully complete a """"dry-run"""" credentialing test. The treating physicians were credentialed based on accuracy of magnetic resonance imaging-computed tomography image fusion and hippocampal and normal tissue contouring, and the sites were credentialed based on protocol-specified dosimetric criteria. Using the same criteria, pretreatment centralized review of enrolled patients was conducted. Physicians enrolling 3 consecutive patients without unacceptable deviations were permitted to enroll further patients without pretreatment review, although their cases were reviewed after treatment. In all, 113 physicians and 84 sites were credentialed. Eight physicians (6.8%) failed hippocampal contouring on the first attempt; 3 were approved on the second attempt. Eight sites (9.5%) failed intensity modulated radiation therapy planning on the first attempt; all were approved on the second attempt. One hundred thirteen patients were enrolled in RTOG 0933; 100 were analyzable. Eighty-seven cases were reviewed before treatment; 5 (5.7%) violated the eligibility criteria, and 21 (24%) had unacceptable deviations. With feedback, 18 cases were approved on the second attempt and 2 cases on the third attempt. One patient was treated off protocol. Twenty-two cases were reviewed after treatment; 1 (4.5%) violated the eligibility criteria, and 5 (23%) had unacceptable deviations. Although >95% of the cases passed the pre-enrollment credentialing, the pretreatment centralized review disqualified 5.7% of reviewed cases, prevented unacceptable deviations in 24% of reviewed cases, and limited the final unacceptable deviation rate to 5%. Thus, pretreatment review is deemed necessary in future hippocampal avoidance trials and is potentially useful in other similarly challenging radiation therapy technique trials. """,0
5671,25587040,Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia,"Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.  ",0
5672,25587449,A pilot study of an exercise-based patient education program in people with multiple sclerosis,"There is increasing evidence that physical exercise leads to numerous positive effects in PwMS. However, long-term effects of exercise may only be achievable if training is implemented in daily routine. Enabling patients to exercise regularly, we developed a patient education program focused on evidence-based information of training. PwMS were educated in neurophysiological effects of physical exercise, exercise-induced benefits for PwMS, and risk factors (e.g., weather). Fifteen PwMS were analyzed before (T 0) and after (T 1) a 12-week patient education. Afterwards, participants performed their exercises autonomously for 32 weeks and were tested in sustainability tests (T 2). Guided interviews were carried out, additionally. Significant improvements from T 0 to T 1 were found in 6MWT, gait velocity, TUG, fatigue, and quality of life. Significant results of TUG and gait velocity from T 1 to T 2 demonstrated that participants kept few effects after the 32-week training phase. Qualitative analyses showed improved self-confidence and identified training strategies and barriers. This pilot study provides evidence that PwMS are able to acquire good knowledge about physical exercise and apply this knowledge successfully in training management. One might conclude that this exercise-based patient education seems to be a feasible option to maintain or improve patients' integral constitution concerning physical and mental health.  ",0
5673,25587454,"Differences in the malariometric indices of asymptomatic carriers in three communities in ibadan, Nigeria","This study was conducted to determine the malariometric indices of children in three different settings in Ibadan, Nigeria. Children were recruited from an urban slum (Oloomi) and a periurban (Sasa) and a rural community (Igbanda) in Ibadan. Children aged between 2 and 10 years were randomly selected from primary schools in the urban and periurban areas. In the rural community, children were recruited from the centre of the village. A total of 670 (55.0%) out of 1218 children recruited were positive for malaria parasitaemia. The urban population had the highest proportion of children with malaria parasitaemia. Splenomegaly was present in 31.5%, hepatomegaly in 41.5%, hepatosplenomegaly in 27.5%, and anaemia in 25.2% of the children. The parasite density was not significantly different among children in the three communities. Children in the rural community had the highest mean PCV of 34.2% and the lowest rates of splenomegaly (6.1%), hepatomegaly (7.6%), and hepatosplenomegaly (4.6%). The spleen rates, liver rates, and presence of hepatosplenomegaly and anaemia were similar in the urban and periurban communities. The malariometric indices among the asymptomatic carriers were high, especially in the urban slum. This stresses the need for intensified efforts at controlling the disease in the study area.  ",0
5674,25587700,The crystal structure of the versatile cytochrome P450 enzyme CYP109B1 from Bacillus subtilis,"The crystal structure of the versatile CYP109B1 enzyme from Bacillus subtilis has been solved at 1.8 Å resolution. This is the first structure of an enzyme from this CYP family, whose members are prevalent across diverse species of bacteria. In the crystal structure the enzyme has an open conformation with an access channel leading from the heme to the surface. The substrate-free structure reveals the location of the key residues in the active site that are responsible for binding the substrate in the correct orientation for regioselective oxidation. Importantly, there are significant differences among these residues in members of the CYP109 and closely related CYP106 families and these likely account for the variations in substrate binding and oxidation profiles observed with these enzymes. A whole-cell oxidation biosystem was developed, which contains CYP109B1 and a phthalate family oxygenase reductase (PFOR), from Pseudomonas putida KT24440, as the electron transfer partner. This electron transfer system is able to support CYP109B1 activity resulting in the regioselective hydroxylation of both α- and β-ionone in vivo and in vitro. The PFOR is therefore a versatile electron transfer partner that is able to support the activity of CYP enzymes from other bacterium. The crystal structure of CYP109B1 has a positively charged proximal face and this explains why it can interact with PFOR and adrenodoxin which are predominantly negatively charged around their [2Fe-2S] clusters.  ",0
5675,25588312,Ionic interaction of positive amino acid residues of fungal hydrophobin RolA with acidic amino acid residues of cutinase CutL1,"Hydrophobins are amphipathic proteins secreted by filamentous fungi. When the industrial fungus Aspergillus oryzae is grown in a liquid medium containing the polyester polybutylene succinate co-adipate (PBSA), it produces RolA, a hydrophobin, and CutL1, a PBSA-degrading cutinase. Secreted RolA attaches to the surface of the PBSA particles and recruits CutL1, which then condenses on the particles and stimulates the hydrolysis of PBSA. Here, we identified amino acid residues that are required for the RolA-CutL1 interaction by using site-directed mutagenesis. We quantitatively analyzed kinetic profiles of the interactions between RolA variants and CutL1 variants by using a quartz crystal microbalance (QCM). The QCM analyses revealed that Asp142, Asp171 and Glu31, located on the hydrophilic molecular surface of CutL1, and His32 and Lys34, located in the N-terminus of RolA, play crucial roles in the RolA-CutL1 interaction via ionic interactions. RolA immobilized on a QCM electrode strongly interacted with CutL1 (K(D)  = 6.5 nM); however, RolA with CutL1 variants, or RolA variants with CutL1, showed markedly larger KD values, particularly in the interaction between the double variant RolA-H32S/K34S and the triple variant CutL1-E31S/D142S/D171S (K(D)  = 78.0 nM). We discuss a molecular prototype model of hydrophobin-based enzyme recruitment at the solid-water interface. ",0
5676,25588556,"Gene Cloning, High-Level Expression, and Characterization of an Alkaline and Thermostable Lipase from Trichosporon coremiiforme V3","The present study describes the gene cloning and high-level expression of an alkaline and thermostable lipase gene from Trichosporon coremiiforme V3. Nucleotide analysis revealed that this lipase gene has an open reading frame of 1,692 bp without any introns, encoding a protein of 563 amino acid residues. The lipase gene without its signal sequence was cloned into plasmid pPICZαA and overexpressed in Pichia pastoris X33. The maximum lipase activity of recombinant lipase was 5,000 U/ml, which was obtained in fed-batch cultivation after 168 h induction with methanol in a 50 L bioreactor. The purified lipase showed high temperature tolerance, and being stable at 60 °C and kept 45% enzyme activity after 1 h incubation at 70 °C. The stability, effects of metal ions and other reagents were also determined. The chain length specificity of the recombinant lipase showed high activity toward triolein (C18:1) and tripalmitin (C16:0). ",0
5677,25588602,Zoonotic origin of hepatitis E,"The concept of zoonotic viral hepatitis E has emerged a few years ago following the discovery of animal strains of hepatitis E virus (HEV), closely related to human HEV, in countries where sporadic cases of hepatitis E were autochthonous. Recent advances in the identification of animal reservoirs of HEV have confirmed that strains circulating in domestic and wild pigs are genetically related to strains identified in indigenous human cases. The demonstration of HEV contamination in the food chain or pork products has indicated that HEV is frequently a foodborne zoonotic pathogen. Direct contacts with infected animals, consumption of contaminated animal meat or meat products are all potential means of zoonotic HEV transmission. The recent identification of numerous other genetically diverse HEV strains from various animal species poses additional potential concerns for HEV zoonotic infection.  ",0
5678,25588965,"Matrix metalloproteinases (MMP-1, MMP-2, MMP-3 and MMP-9, and TIMP-1, TIMP-2 and TIMP-3) and markers for vascularization in functioning and non-functioning bleb capsules of glaucoma drainage implants","To investigate and compare functioning versus non-functioning glaucoma drainage implant (GDI) capsules for selective markers of extracellular matrix degradation and vascularity. In three samples of both functioning and non-functioning blebs, immunohistochemistry was used to determine the expression of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, TIMP-3 and CD31. A non-functioning bleb was defined as IOP >21 mmHg or <20% reduction in IOP from baseline with maximal tolerated medication. The samples were classified into five grades based on immunostaining: no staining, no significant staining, mild, moderate or marked staining. Expression of MMP-1, MMP-2 and MMP-3 was mostly low in both functioning and non-functioning blebs. However, immunostaining of MMP-9 was marked in samples taken from functioning GDIs and correlated with the presence of vascular profiles in the luminal bleb. CD31 immunoreactivity was more intense in the outer layers of the bleb than in the inner layers. In non-functioning blebs, immunoreactivity for TIMP-3 was significant through the whole bleb wall, but only mild in the inner zone of functioning blebs. TIMP-1 and TIMP-2 were barely detectable. Staining of TIMP-3 was seen to be lower in the vicinity of the small blood vessels. In avascular bleb wall, increased expression of TIMP-3 suggests its potential role in the inhibition of angiogenesis as reported previously in vivo. The abundance of MMP-9 in bleb capsule wall of relatively old patients might lead to weakened bleb capsule wall architecture and increasing filtration of aqueous humour through the capsule, which are reflected in a lower IOP. ",0
5679,25589154,Surgery under general anaesthesia in severe hidradenitis suppurativa: a study of 363 primary operations in 113 patients,"Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially as there is no consensus on what surgical technique is preferred. At our centre severe HS (Hurley II/III) is operated under general anaesthesia, mostly with the STEEP procedure. To investigate characteristics, surgical outcomes and patient satisfaction of HS patients who underwent deroofing or STEEP under general anaesthesia. A clinical records-based retrospective analysis was conducted of all patients who had surgery under general anaesthesia between 1999 and 2013. Patient satisfaction was retrospectively investigated with questionnaires. A total of 482 operations (363 primary operations and 119 re-operations) were performed during the study period. The proportion of women in the included population was 68%. The median diagnostic delay (patient's and doctor's delay) was 6.5 years. Relapses occurred after 29.2% of primary operations. Women had higher relapse rates than men [odds ratio 2.85 (1.07;7.61)]. Hypergranulation of the wound was the most common complication and occurred in 7% of all operations. The median score patients attributed to the medical effect of surgery was eight of 10 (zero corresponding to very dissatisfied and 10 to very satisfied). The diagnostic delay in HS is long due to a lack of knowledge in both patients and health care professionals, indicating that there is a need for education. Deroofing and the STEEP are effective surgical procedures in severe cases of HS and lead to a relatively high patient satisfaction. The postoperative relapse risk is higher in women. Prospective studies are required for the development of clear guidelines on the appropriate choice of surgery. ",0
5680,25589238,An expanded taxonomy of hepatitis C virus genotype 6: Characterization of 22 new full-length viral genomes,"We characterized the full-length genomes of 22 hepatitis C virus genotype 6 (HCV-6) isolates: 10 from Vietnam (classified into subtypes 6e, 6h, 6p, 6r, 6s, and 6u), one from China (confirmed as a new subtype 6xd), and 11 from the Lao PDR (representing a new subtype 6xe plus eight novel variants). With these 22 new genomes, HCV-6 now has a diverse and extended taxonomic structure, comprised of 28 assigned subtypes (denoted 6a-6xe) and 27 unassigned lineages, all of which have been represented by full-length genomes. Our phylogenetic analyses also included many partially-sequenced novel variants of HCV-6 from Lao PDR. This revealed that Lao HCV isolates are genetically very diverse and are phylogenetically distributed in multiple lineages within genotype 6. Our results suggest that HCV-6 has been maintained in Laos, a landlocked country, since the common ancestor of genotype 6 and indicates historical dispersal of HCV-6 across Southeast Asia.  ",0
5681,25589729,Partial Loss of the Glutamate Transporter GLT-1 Alters Brain Akt and Insulin Signaling in a Mouse Model of Alzheimer's Disease,"The glutamate transporter GLT-1 (also called EAAT2 in humans) plays a critical role in regulating extracellular glutamate levels in the central nervous system (CNS). In Alzheimer's disease (AD), EAAT2 loss is associated with neuropathology and cognitive impairment. In keeping with this, we have reported that partial GLT-1 loss (GLT-1+/-) causes early-occurring cognitive deficits in mice harboring familial AD AβPPswe/PS1ΔE9 mutations. GLT-1 plays important roles in several molecular pathways that regulate brain metabolism, including Akt and insulin signaling in astrocytes. Significantly, AD pathogenesis also involves chronic Akt activation and reduced insulin signaling in the CNS. In this report we tested the hypothesis that GLT-1 heterozygosity (which reduces GLT-1 to levels that are comparable to losses in AD patients) in AβPPswe/PS1ΔE9 mice would induce sustained activation of Akt and disturb components of the CNS insulin signaling cascade. We found that partial GLT-1 loss chronically increased Akt activation (reflected by increased phosphorylation at serine 473), impaired insulin signaling (reflected by decreased IRβ phosphorylation of tyrosines 1150/1151 and increased IRS-1 phosphorylation at serines 632/635 - denoted as 636/639 in humans), and reduced insulin degrading enzyme (IDE) activity in brains of mice expressing familial AβPPswe/PS1ΔE9 AD mutations. GLT-1 loss also caused an apparent compensatory increase in IDE activity in the liver, an organ that has been shown to regulate peripheral amyloid-β levels and expresses GLT-1. Taken together, these findings demonstrate that partial GLT-1 loss can cause insulin/Akt signaling abnormalities that are in keeping with those observed in AD.  ",0
5682,25590287,Metastatic atypical fibroxanthoma: a series of 11 cases including with minimal and no subcutaneous involvement,"""Atypical fibroxanthoma (AFX) is a dermal mesenchymal neoplasm arising in sun-damaged skin, primarily of the head and neck region of older men. Conservative excision cures most. However, varying degrees of subcutaneous involvement can lead to a more aggressive course and rare metastases. Thus, AFX involving the subcutis are termed pleomorphic dermal sarcomas or other monikers by some to recognize the more threatening natural history. We reviewed cases of """"metastatic AFX"""" from our institution and from the files of a consultative dermatopathology practice. Nine of 152 patients with AFX were identified at a single institution (2000-2011). Two additional patients were identified from the files of a consultative practice. Clinical, radiological, and pathological features were reviewed and cases with histologically verified metastases identified. Median age was 67 (range, 45-91) years, all male, and involving the head and neck region. Two cases had no documented involvement of the subcutis, and 2 cases had only superficial subcutis involvement. Median time to metastases was 13 (range, 8-49) months. Three patients developed solitary regional lymph node metastases while 8 had widespread metastases. Five patients developed local recurrence within 8 months, and all 5 developed widespread metastasis. With median follow-up of 26 (range, 10-145) months, 6 died of disease (median, 19 months; range, 10-35 months), 4 were alive and well, and 1 was alive with disease. AFX has very rare metastatic potential, even those without or with minimal subcutis involvement, and can lead to mortality. Most metastasis and local recurrence occurred within 1 year of presentation. Solitary regional metastases were associated with better outcomes than those with multiple distant metastases. Patients with repeated local recurrences portended more aggressive disease including development of distant metastases.  """,0
5683,25590742,Effect of storage in overcoming seed dormancy of Annona coriacea Mart. seeds,"The aim of this study was to evaluate the effect of pre-treatments on overcoming dormancy of A. coriacea seeds. Seeds were processed and stored in polyethylene bags at temperatures of at -18°C (42% RH), 5°C (34% RH), 15°C (60% RH) and 25°C (34% RH), during 0, 30, 60, 90, 120 and 150 days. After storage, seeds were immersed in 350 mg.L-1 gibberellic acid for 144 hours. Sowing was carried out in plastic bags containing Red Latosol + Bioplant®. Moisture content, emergence percentage, emergence speed index, length and dry mass of seedlings, were evaluated. The experimental design was completely randomized in a factorial with four replications of 50 seeds each. The seed storage at 5°C and subsequent immersion in gibberellic acid was efficient to reach high percentage, emergence speed and plant growth. A. coriacea seeds showed non-deep simple morphophysiological dormancy wherein the physiological component can be overcome after the seeds are storage at 5°C for a maximum period of 53 days and subsequent immersed in exogenous GA (350 mg.L-1 for 144 hours). ",0
5684,25626988,"Strategies and endpoints of antifibrotic drug trials: Summary and recommendations from the AASLD Emerging Trends Conference, Chicago, June 2014","There is an urgent need to develop antifibrotic therapies for chronic liver disease, and clarify which endpoints in antifibrotic trials will be acceptable to regulatory agencies. The American Association for the Study of Liver Diseases sponsored an endpoints conference to help accelerate the efficient testing of antifibrotic agents and develop recommendations on clinical trial design for liver fibrosis. In this review, we summarize the salient and novel elements of this conference and provide directions for future clinical trial design. The article follows the structure of the conference and is organized into five areas: (1) antifibrotic trial design; (2) preclinical proof-of-concept studies; (3) pharmacological targets, including rationale and lessons to learn; (4) rational drug design and development; and (5) consensus and recommendations on design of clinical trials in liver fibrosis. Expert overviews and collaborative discussions helped to summarize the key unmet needs and directions for the future, including: (1) greater clarification of at-risk populations and study groups; (2) standardization of all elements of drug discovery and testing; (3) standardization of clinical trial approaches; (4) accelerated development of improved noninvasive markers; and (5) need for exploration of potential off-target toxicities of future antifibrotic drugs.",0
5685,25627620,Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis,"The serological hallmark of primary biliary cirrhosis (PBC) is the presence of high titer and specific antimitochondrial antibodies (AMAs). Although there is no global immune defect in patients with PBC, there is widespread dysregulated B-cell function, including increased sera levels of immunoglobulin M and enhanced B-cell responses to cytosine-phosphate-guanine stimulation. The mechanisms involved in this B-cell dysfunction have remained unknown. To address this issue, we focused on identifying the frequencies of B-cell subsets in patients with PBC and the mechanisms that lead to B-cell dysregulation, including the relationships with chemokine (C-X-C motif) receptor 5 (CXCR5)(+) CD4(+) T cells. Herein, we report that elevations of both serum and intrahepatic interleukin-21 (IL-21) were found in patients with PBC and, in particular, promoted B-cell proliferation, signal transducer and activator of transcription 3 phosphorylation and AMA production in vitro. More important, upon stimulation with recombinant E2 subunit of pyruvate dehydrogenase complex, CXCR5(+) CD4(+) T cells in PBC produced higher levels of IL-21 than healthy controls. Additionally, sorted CXCR5(+) CD4(+) T cells increased production of AMAs by autologous CD19(+) B cells. Indeed, elevated expression of intrahepatic chemokine (C-X-C motif) ligand 13 (CXCL13), a key chemokine of CXCR5(+) cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4(+) , CXCR5(+) , CD19(+) , and CD38(+) cells. CONCLUSION: CXCL13 promotes aggregation of CD19(+) B cells and CXCR5(+) CD4(+) T cells, which directs the aberrant AMA response by IL-21. These data have implications for potential immunotherapy and also reflect the unique lymphoid biology in liver of PBC.",0
5686,25629662,Mitochondrial donation--how many women could benefit?,"Mitochondrial disease is maternally inherited and refractory to treatment, but assisted reproduction methods can result in unaffected pregnancies. The authors provide estimates of the number of affected pregnancies per year in the United Kingdom and the United States.",0
5687,25629663,A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA,"BACKGROUND: The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. METHODS: In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels--1�10(10) viral particles, 2.5�10(10) viral particles, and 5�10(10) viral particles--with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. RESULTS: No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). CONCLUSIONS: The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.).",0
5688,25629742,Cost-effectiveness of hypertension therapy according to 2014 guidelines,"BACKGROUND: On the basis of the 2014 guidelines for hypertension therapy in the United States, many eligible adults remain untreated. We projected the cost-effectiveness of treating hypertension in U.S. adults according to the 2014 guidelines. METHODS: We used the Cardiovascular Disease Policy Model to simulate drug-treatment and monitoring costs, costs averted for the treatment of cardiovascular disease, and quality-adjusted life-years (QALYs) gained by treating previously untreated adults between the ages of 35 and 74 years from 2014 through 2024. We assessed cost-effectiveness according to age, hypertension level, and the presence or absence of chronic kidney disease or diabetes. RESULTS: The full implementation of the new hypertension guidelines would result in approximately 56,000 fewer cardiovascular events and 13,000 fewer deaths from cardiovascular causes annually, which would result in overall cost savings. The projections showed that the treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs for men between the ages of 35 and 74 years and for women between the ages of 45 and 74 years. The treatment of men or women with existing cardiovascular disease or men with stage 2 hypertension but without cardiovascular disease would remain cost-saving even if strategies to increase medication adherence doubled treatment costs. The treatment of stage 1 hypertension was cost-effective (defined as <$50,000 per QALY) for all men and for women between the ages of 45 and 74 years, whereas treating women between the ages of 35 and 44 years with stage 1 hypertension but without cardiovascular disease had intermediate or low cost-effectiveness. CONCLUSIONS: The implementation of the 2014 hypertension guidelines for U.S. adults between the ages of 35 and 74 years could potentially prevent about 56,000 cardiovascular events and 13,000 deaths annually, while saving costs. Controlling hypertension in all patients with cardiovascular disease or stage 2 hypertension could be effective and cost-saving. (Funded by the National Heart, Lung, and Blood Institute and others.).",0
5689,25644509,Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma,"Early detection of the highly aggressive malignancy cholangiocarcinoma (CCA) remains a challenge but has the potential to render the tumor curable by surgical removal. This study evaluates a biomarker panel for the diagnosis of CCA by DNA methylation analyses of biliary brush samples. The methylation status of 13 candidate genes (CDO1, CNRIP1, DCLK1, FBN1, INA, MAL, SEPT9, SFRP1, SNCA, SPG20, TMEFF2, VIM, and ZSCAN18) was investigated in 93 tissue samples (39 CCAs and 54 nonmalignant controls) using quantitative methylation-specific polymerase chain reaction. The 13 genes were further analyzed in a test series of biliary brush samples (15 CCAs and 20 nonmalignant primary sclerosing cholangitis controls), and the methylation status of the four best performing markers was validated (34 CCAs and 34 primary sclerosing cholangitis controls). Receiver operating characteristic curve analyses were used to evaluate the performance of individual biomarkers and the combination of biomarkers. The 13 candidate genes displayed a methylation frequency of 26%-82% in tissue samples. The four best-performing genes (CDO1, CNRIP1, SEPT9, and VIM) displayed individual methylation frequencies of 45%-77% in biliary brushes from CCA patients. Across the test and validation biliary brush series, this four-gene biomarker panel achieved a sensitivity of 85% and a specificity of 98%, with an area under the receiver operating characteristic curve of 0.944. CONCLUSION: We report a straightforward biomarker assay with high sensitivity and specificity for CCA, outperforming standard brush cytology, and suggest that the biomarker panel, potentially in combination with cytological evaluation, may improve CCA detection, particularly among primary sclerosing cholangitis patients.",0
5690,25645518,Tenofovir-associated Fanconi syndrome and nephrotic syndrome in a patient with chronic hepatitis B monoinfection,"Tenofovir disoproxil fumarate (TDF) is widely used as an effective first-line therapy for chronic hepatitis B (CHB) infection. While TDF demonstrates successful viral suppression, it has been linked to the development of renal proximal tubular (PT) dysfunction, leading to Fanconi syndrome. However, Fanconi syndrome has been rarely reported in CHB-monoinfected patients, and there were no reports of TDF-associated nephrotic syndrome. Here, we report a case of combined Fanconi and nephrotic syndrome in CHB patients after TDF exposure.",0
5691,25645961,Differentiation of acute from chronic hepatitis C virus infection by nonstructural 5B deep sequencing: a population-level tool for incidence estimation,"The ability to classify acute versus chronic hepatitis C virus (HCV) infections at the time of diagnosis is desirable to improve the quality of surveillance information. The aim of this study was to differentiate acute from chronic HCV infections utilizing deep sequencing. HCV nonstructural 5B (NS5B) amplicons (n?=?94) were generated from 77 individuals (13 acute and 64 chronic HCV infections) in British Columbia, Canada, with documented seroconversion time frames. Amplicons were deep sequenced and HCV genomic diversity was measured by Shannon entropy (SE) and a single nucleotide variant (SNV) analysis. The relationship between each diversity measure and the estimated days since infection was assessed using linear mixed models, and the ability of each diversity measure to differentiate acute from chronic infections was assessed using generalized estimating equations. Both SE and the SNV diversity measures were significantly different for acute versus chronic infections (P?<?0.009). NS5B nucleotide diversity continued to increase for at least 3 years postinfection. Among individuals with the least uncertainty with regard to duration of infection (n?=?39), the area under the receiver operating characteristic curve (AUROC) was high (0.96 for SE; 0.98 for SNV). Although the AUROCs were lower (0.86 for SE; 0.80 for SNV) when data for all individuals were included, they remain sufficiently high for epidemiological purposes. Synonymous mutations were the primary discriminatory variable accounting for over 78% of the measured genetic diversity. CONCLUSIONS: NS5B sequence diversity assessed by deep sequencing can differentiate acute from chronic HCV infections and, with further validation, could become a powerful population-level surveillance tool for incidence estimation.",0
5692,25651247,Prehospital use of magnesium sulfate as neuroprotection in acute stroke,"BACKGROUND: Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents. METHODS: We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability). RESULTS: Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (�SD) age was 69�13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7�1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events. CONCLUSIONS: Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.).",0
5693,25677072,Cost-effectiveness of hepatitis C treatment for patients in early stages of liver disease,"New treatments for hepatitis C virus (HCV) may be highly effective but are associated with substantial costs that may compel clinicians and patients to consider delaying treatment. This study investigated the cost-effectiveness of these treatments with a focus on patients in early stages of liver disease. We developed a state-transition (or Markov) model to calculate costs incurred and quality-adjusted life-years (QALYs) gained following HCV treatment, and we computed incremental cost-effectiveness ratios (cost per QALY gained, in 2012 US dollars) for treatment at different stages of liver disease versus delaying treatment until the subsequent liver disease stage. Our analysis did not include the potential treatment benefits associated with reduced non-liver-related mortality or preventing HCV transmission. All parameter values, particularly treatment cost, were varied in sensitivity analyses. The base case scenario represented a 55-year-old patient with genotype 1 HCV infection with a treatment cost of $100,000 and treatment effectiveness of 90%. In this scenario, for a 55-year-old patient with moderate liver fibrosis (Metavir stage F2), the cost-effectiveness of immediately initiating treatment at F2 (versus delaying treatment until F3) was $37,300/QALY. For patients immediately treated at F0 (versus delaying treatment until F1), the threshold of treatment costs that yielded $50,000/QALY and $100,000/QALY cost-effectiveness ratios were $22,200 and $42,400, respectively. CONCLUSION: Immediate treatment of HCV-infected patients with moderate and advanced fibrosis appears to be cost-effective, and immediate treatment of patients with minimal or no fibrosis can be cost-effective as well, particularly when lower treatment costs are assumed.",0
5694,25685040,Use of an entacapone-containing drug combination and risk of death: Analysis of the FDA AERS (FAERS) database,"To assess the signal of death associated with the use of an entacapone-containing drug combination in the FDA Adverse Event Reporting System (FAERS) database. Reports of death events submitted between January 2004 and December 2010 were retrieved and analysed by the reporting odds ratio (ROR). The ROR of case/non-case reports of death associated with an entacapone-containing drug combination was compared with the levodopa/carbidopa combination using the FDA AERS database. Eighty-seven reports linked the entacapone-containing drug combination to death, compared to 27 reports of death linking the levodopa/carbidopa combination. The ROR was statistically significant for the association between deaths with the use of an entacapone-containing drug combination (1.86 [95% CI 1.50-2.31]). In contrast, the ROR of death associated with the combination of levodopa and carbidopa was not statistically significant (0.89 [95% CI 0.61-1.30)]. Based on analysing reports in the FAERS database, there is a risk of death with the use of an entacapone-containing drug combination. These results generated a signal of death with the use of this drug. However, epidemiological studies are required to confirm this association.  ",0
5695,25685205,"Neural oscillation, network, eloquent cortex and epileptogenic zone revealed by magnetoencephalography and awake craniotomy","Magnetoencephalography (MEG) is a method of functional neuroimaging. The concomitant use of MEG and electrocorticography has been found to be useful in elucidating neural oscillation and network, and to localize epileptogenic zone and functional cortex. We describe our early experience using MEG in neurosurgical patients, emphasizing on its impact on patient management as well as the enrichment of our knowledge in neurosciences. A total of 10 subjects were included; five patients had intraaxial tumors, one with an extraaxial tumor and brain compression, two with arteriovenous malformations, one with cerebral peduncle hemorrhage and one with sensorimotor cortical dysplasia. All patients underwent evoked and spontaneous MEG recordings. MEG data was processed at band-pass filtering frequency of between 0.1 and 300 Hz with a sampling rate of 1 kHz. MEG source localization was performed using either overdetermined equivalent current dipoles or underdetermined inversed solution. Neuromag collection of events software was used to study brain network and epileptogenic zone. The studied data were analyzed for neural oscillation in three patients; brain network and clinical manifestation in five patients; and for the location of epileptogenic zone and eloquent cortex in two patients. We elucidated neural oscillation in three patients. One demonstrated oscillatory phenomenon on stimulation of the motor-cortex during awake surgery, and two had improvement in neural oscillatory parameters after surgery. Brain networks corresponding to clinico-anatomical relationships were depicted in five patients, and two networks were illustrated here. Finally, we demonstrated epilepsy cases in which MEG data was found to be useful in localizing the epileptogenic zones and functional cortices. The application of MEG while enhancing our knowledge in neurosciences also has a useful role in epilepsy and awake surgery. ",0
5696,25685293,Modelling of photo-thermal control of biological cellular oscillators,"We study the transient dynamics of biological oscillators subjected to brief heat pulses. A prospective well-defined experimental system for thermal control of oscillators is the peripheral electroreceptors in paddlefish. Epithelial cells in these receptors show spontaneous voltage oscillations which are known to be temperature sensitive. We use a computational model to predict the effect of brief thermal pulses in this system. In our model thermal stimulation is realized through the light excitation of gold nanoparticles delivered in close proximity to epithelial cells and generating heat due to plasmon resonance. We use an ensemble of modified Morris-Lecar systems to model oscillatory epithelial cells. First, we validate that the model quantitatively reproduces the dynamics of epithelial oscillations in paddlefish electroreceptors, including responses to static and slow temperature changes. Second, we use the model to predict transient responses to short heat pulses generated by the light actuated gold nanoparticles. The model predicts that the epithelial oscillators can be partially synchronized by brief 5 - 15 ms light stimuli resulting in a large-amplitude oscillations of the mean field potential. ",0
5697,25685488,In vitro study of nano-hydroxyapatite/chitosan-gelatin composites for bio-applications,"The present work aims to study the in vitro properties of nano-hydroxyapatite/chitosan-gelatin composite materials. In vitro behavior was performed in simulated body fluid (SBF) to verify the formation of apatite layer onto the composite surfaces. The in vitro data proved the deposition of calcium and phosphorus ions onto hydroxyapatite /polymeric composite surfaces especially those containing high concentrations of polymer content. The degradation of the composites decreased with increase in the polymeric matrix content and highly decreased in the presence of citric acid (CA), especially these composites which contain 30% polymeric content. The water absorption of the composites increased with increase in the polymeric content and highly increased with CA addition. The Fourier transformed infrared reflectance (FT-IR) and scanning electron microscope (SEM) for the composites confirmed the formation of bone-like apatite layer on the composite surfaces, especially those containing high content of polymers (30%) with 0.2 M of CA. These promising composites have suitable properties for bio-applications such as bone grafting and bone tissue engineering applications in the future.  ",0
5698,25685556,Prognostic Value of Serum Uric Acid in Patients on the Waiting List before and after Renal Transplantation,"Background. High serum uric acid (UA) is associated with increased cardiovascular (CV) risk in the general population. The impact of UA on CV events and mortality in CKD is unclear. Objective. To assess the relationship between UA and prognosis in hemodialysis (HD) patients before and after renal transplantation (TX). Methods. 1020 HD patients assessed for CV risk and followed from the time of inception until CV event, death, or TX (HD) or date of TX, CV event, death, or return to dialysis (TX). Results. 821 patients remained on HD while 199 underwent TX. High UA (≥428 mmol/L) was not associated with either composite CV events or mortality in HD patients. In TX patients high UA predicted an increased risk of events (P = 0.03, HR 1.6, and 95% CI 1.03-2.54) but not with death. In the Cox proportional model UA was no longer significantly associated with CV events. Instead, a reduced GFR (<50 mL/min) emerged as the independent risk factor for events (P = 0.02, HR 1.79, and % CI 1.07-3.21). Conclusion. In recipients of TX an increased posttransplant UA is related to higher probability of major CV events but this association probably caused concurrent reduction in GFR.  ",0
5699,25685590,A case of primary renal carcinoid tumor,"Primary renal carcinoid tumors are extremely rare kidney lesions, with fewer than 100 reported cases previously. We describe a 75-year-old man with an incidentally detected cystic renal mass. Computed tomography showed a 3 cm tumor with a cystic component enhanced with contrast. No evidence of metastasis was detected. We treated the patient with radical nephrectomy. Pathological examinations revealed a cellular arrangement specific to carcinoid tumor and positive for chromogranin A, neural cell adhesion molecule, and somatostatin receptor type 2. The tumor cells had a mitotic count of 4 mitoses/10 high-power fields, and the level of the proliferation marker Ki-67 was 5%. The pathological diagnosis was renal neuroendocrine tumor grade 2. No local recurrence and no systemic metastasis were detected during the 18-month follow-up period. To our knowledge, this is the 6th case of renal neuroendocrine grade 2 tumor reported thus far.  ",0
5700,25685803,Intracranial biodegradable silica-based nimodipine drug release implant for treating vasospasm in subarachnoid hemorrhage in an experimental healthy pig and dog model,"Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.  ",0
5701,25686104,Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers,"The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.  ",0
5702,25686157,"The role of the South African Veterinary Council, with special reference to the period 1982-2011","The current South African Veterinary Council (SAVC) has a long and laborious history associated with the legislation responsible for its establishment. The forerunner of the SAVC, the South African Veterinary Board, was established in terms of the Veterinary Act 1933 (Act No. 16 of 1933), which was launched through Parliament as a private motion by Dr Hjalmar Reitz M.P. After several amendments, the Act was replaced with the Veterinary and Para-veterinary Professions Act 1982 (Act No. 19 of 1982), superseding the existing Board with the SAVC. One of the reasons for replacing this Act was to comply with Government policy for professional statutory bodies to become self-funding, with fees paid by registered professionals, and to constitute councils that were more representative of the profession. Apart from providing some background information, this article was virtually entirely confined to some historic aspects of the SAVC, using, as its basis, the main developments that occurred during the terms of office of its various presidents, serving from 1982 to 2011. The presidents concerned are: Prof. B.C. Jansen (28 March 1983 - 28 March 1986), Dr G.E. Frost (14 April 1986 - 31 March 1992), Prof. R.I. Coubrough (07 April 1992 - 21 March 1994), Dr P.C. Ardington (21 March 1994 - 31 March 1998), Prof H.M. Terblanche (31 March 1998 - 31 March 2004), Prof. S.S. van den Berg (01 April 2004 - 30 July 2007) and Dr R. Moerane (06 August 2007 - 31 July 2013).  ",0
5703,25686162,Environmental and nursing-staff factors contributing to aggressive and violent behaviour of patients in mental health facilities,"Aggressive and violent behaviour of inpatients in mental health facilities disrupts the therapeutic alliance and hampers treatment. The aim of the study was to describe patients' perceptions of the possible environmental and staff factors that might contribute to their aggressive and violent behaviour after admission to a mental health facility; and to propose strategies to prevent and manage such behaviour. A qualitative, phenomenological study was utilised, in which purposefully sampled inpatients were interviewed over a six-month period. Inpatients were invited to participate if they had been admitted for at least seven days and were in touch with reality. Forty inpatients in two mental health facilities in Cape Town participated in face-to-face, semi-structured interviews over a period of six months. Tesch's descriptive method of open coding formed the framework for the data analysis and presentation of the results. Trustworthiness was ensured in accordance with the principles of credibility, confirmability, transferability and dependability. Analysis of the data indicates two central categories in the factors contributing to patients' aggressive and violent behaviour, namely, environmental factors and the attitude and behaviour of staff. From the perspective of the inpatients included in this study, aggressive and violent episodes are common and require intervention. Specific strategies for preventing such behaviour are proposed and it is recommended that these strategies be incorporated into the in-service training programmes of the staff of mental health facilities. These strategies could prevent, or reduce, aggressive and violent behaviour in in-patient facilities. ",0
5704,25686200,Biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo,"RNA-based delivery system for cancer therapy remains a challenge. In this study, a stearyl-peptide (SHR) was synthesized using arginine, histidine, cysteine, and stearyl moieties. Further, the stearyl-peptides were cross-linked by disulfide bonds to obtain cross-linked polypeptides (SHRss) with different molecular weight (SHRss1, SHRss2, SHRss3, SHRss4). The SHRss could effectively condense small interfering RNA (siRNA) into polyplexes with a hydrodynamic size of 100-300 nm and zeta potential of 20-40 mV. Flow cytometry and confocal laser scanning microscope studies revealed high cellular uptake and rapid dissociation behavior of SHRss2/siRNA complexes. Long-lasting high concentration of siRNA in cytoplasm was observed even at 24 h after SHRss2/Cy3-siRNA transfection. Compared with SHR, the SHRss showed much improved siRNA interference efficiency targeting luciferase on Luc-Hela cells. Moreover, SHRss2 exhibited higher interference efficiency and slower decay rate on Luc-Hela cells than Lipofectamine 2000 and SHR. In addition, much weaker expression of red fluorescence protein was also observed on SHRss2/simCh-treated mCherry-HEK293 cells than Lipofectamine 2000 and SHR. The SHRss did not induce cytotoxicity at siRNA concentrations of 25-200 nM under transfection. The in vivo studies demonstrated the gene interference efficiency of SHRss2/siRNA complexes. Our studies indicated that the SHRss are promising and efficient nonviral vectors for siRNA delivery.  ",0
5705,25686220,Haemangiosarcoma of the os penis in a dog: The most common neoplasm of the canine penis,"A castrated 9-year-old intact male boerboel cross-breed dog was presented with a month-long history of stranguria. On physical examination, a mass was noted at the caudal extremity of the os penis. Haematology, serum chemistry and urinalysis were all unremarkable. Abdominal and urethral ultrasound demonstrated an enlarged bladder and a dilated urethra, which was followed to the caudal extremity of the os penis. A hyperechoic, roughly spherical,vascularised mass was noted at the caudal os penis, which resulted in obstruction of the penile urethra. Radiographs demonstrated a soft tissue mass with osteolysis of the os penis. Cytology suggested an osteosarcoma. Treatment included amputation of the penis and adjuvant doxorubicin with carboplatin. Histopathology of the penis confirmed a haemangiosarcoma. The patient survived for 20 months. This is only the second published case report describing a penile haemangiosarcoma, and the first published report demonstrating the treatment and outcome of a case of haemangiosarcoma of the os penis. Based on published and unpublished reports, haemangiosarcoma appears to be the most common neoplasm of the canine penis. ",0
5706,25686336,Validation of subjective and objective evaluation methods for orthodontic treatment outcome],"""To assess the correlations between objective measurements of 108 finished orthodontic cases and subjective assessments made by 69 orthodontic specialists, to explore the statistically significant measuring categories of cast and cephalogram and to validate the regression model. A stratified random sample of 108 cases was drawn from the large sample of 2 383 patients who finished orthodontic treatment between July 2006 and August 2008 in six orthodontic treatment centers around China. For each patient, the post-treatment information sources evaluated in this study included standardized plaster study casts and a lateral cephalometric X-ray image. These information sources were evaluated both singly and in combination by a panel of 69 orthodontic specialists. The average subjective grading scores of 69 orthodontists were regarded as the gold standard. Six examiners used the peer assessment rating (PAR) index and American board of orthodontics-objective grading system (ABO-OGS) to measure all the study casts respectively and three other examiners measured all the lateral cephalometric X-ray images by using customized software. The objective measuring data were correlated with the gold standard. The correlations between the objective measurement and the subjective evaluation were assessed, the statistically significant measuring categories of cast and cephalogram were explored and the regression model was validated. The ABO-OGS scores of """"occlusal relationship"""" correlated most strongly with the subjective scores of cast (r=0.655, P<0.01), and the secondarily correlated category with those were the PAR scores of """"overjet"""" (r=0.525, P<0.01). The proclination of the lower incisors correlated most strongly with the subjective scores of cephalogram (r=0.446, P<0.01), and the secondarily correlated category with those was the protrusion of the lower lips (r=0.436, P<0.01). Nine components were predictive for the post-treatment model and lateral ephalometric film (Post-M+C) outcome: alignment (ABO-OGS), occlusal relationship (ABO-OGS), interproximal contact(ABO-OGS), L1/NB°, overjet (PAR), SNB°, occlusal contacts (ABO-OGS), U1/SN2° and centerline (PAR). These 9 components accounted for 72% of the variability in the average subjective grading scores. The objective regression model could replace the averaged opinion of Chinese orthodontic experts effectively, making objective assessment of orthodontic treatment outcome for Chinese patients. """,0
5707,25686482,Stereotactic body radiation therapy for lung metastases from soft tissue sarcoma,"To appraise the role of stereotactic body radiation therapy (SBRT) in patients with lung metastasis from primary soft tissue sarcoma. Twenty-eight patients (51 lesions) were analysed. All patients were in good performance status (1-2 eastern cooperative oncology group (ECOG)), unsuitable for surgical resection, with controlled primary tumour and the number of lung metastases was ⩽4. In a risk adaptive scheme, the dose prescription was: 30Gy/1fr, 60Gy/3fr, 60Gy/8fr and 48Gy/4fr. Treatments were performed with Volumetric Modulated Arc Therapy. Clinical outcome was evaluated by thoracic and abdominal computed tomography (CT) scan before SBRT and than every 3months. Toxicity was evaluated with Common Terminology Criteria for Adverse Events (CTCAE) scale version 4.0. Leiomyosarcoma (36%) and synovial sarcoma (25%) were the most common histologies. Five patients (18%) initially presented with pulmonary metastasis, whereas 23 (82%) developed them at a median time of 51months (range 11-311months) from the initial diagnosis. The median follow-up time from initial diagnosis was 65months (5-139months) and from SBRT was 21months (2-80months). No severe toxicity (grades III-IV) was recorded and no patients required hospitalisation. The actuarial 5-years local control rate (from SBRT treatment) was 96%. Overall survival at 2 and 5years was 96.2% and 60.5%, respectively. At last follow-up 15 patients (54%) were alive. All other died because of distant progression. SBRT provides excellent local control of pulmonary metastasis from soft tissue sarcoma (STS) and may improve survival in selected patients. SBRT should be considered for all patients with pulmonary metastasis (PM) and evaluated in a multidisciplinary team. ",0
5708,25686854,"Analysis of essential oils from Voacanga africana seeds at different hydrodistillation extraction stages: chemical composition, antioxidant activity and antimicrobial activity","In this study, essential oils from Voacanga africana seeds at different extraction stages were investigated. In the chemical composition analysis, 27 compounds representing 86.69-95.03% of the total essential oils were identified and quantified. The main constituents in essential oils were terpenoids, alcohols and fatty acids accounting for 15.03-24.36%, 21.57-34.43% and 33.06-57.37%, respectively. Moreover, the analysis also revealed that essential oils from different extraction stages possessed different chemical compositions. In the antioxidant evaluation, all analysed oils showed similar antioxidant behaviours, and the concentrations of essential oils providing 50% inhibition of DPPH-scavenging activity (IC50) were about 25 mg/mL. In the antimicrobial experiments, essential oils from different extraction stages exhibited different antimicrobial activities. The antimicrobial activity of oils was affected by extraction stages. By controlling extraction stages, it is promising to obtain essential oils with desired antimicrobial activities. ",0
5709,25687050,Mechanisms of sorafenib induced NB4 cell apoptosis],"To investigate the effects of sorafenib on human acute promyelocytic leukemia cell NB4 and its mechanism. The human acute promyelocytic leukemia cell NB4 was treated with different concentrations (0, 1.5, 3, 6 and 12 µmol/L) of sorafenib, the proliferation inhibitory rate of NB4 cells was assayed by MTT, the apoptosis of NB4 was determined with flow-cytomatry after treatment; after extraction of total protein, the Western blot was performed to determine the expressions of apoptosis-relatived molecules Caspase-3, Caspase-8 and MCL-1. The mRNA expressions of Caspase-3, Caspase-8 and MCL-1 were determined by RT-PCR. As compared with the control group, the proliferation of NB4 significantly decreased after treatment with different concentrations of sorafenib. The sorafenib significantly induced the apopotosis of NB4 cells in time- and dose-dependent manners. Furthermore, sorafenib treatment resulted in the obvious increase of the Caspase-3 and Caspase-8 protein and mRNA expressions, and down-regulated the MCL-1 protein and mRNA expressions in NB4 cells. Sorafenib can inhibit proliferation and induce apopotosis of human acute promyelocytic leukemia cell NB4 through the expression of Caspase-3 and Caspase-8, and down-regulation of the expression of MCL-1. ",0
5710,25687077,"""Influence of """"dosage effect"""" on unexpected antibody identification]""","""This study was to investigate the influence of """"dosage effect"""" on unexpected antibody identification and explore its condition, scope and regularity. A total of 40 blood recipient samples containing definite unexpected antibodies were selected by column agglutination technology, then AB fresh plasma was used to dilute the samples to obtain different concentrate liquid. After selecting panel cells which show positive with corresponding unexpected antibody in the serum, """"single dosage"""" antigens were distinguished from """"double dosage"""" ones, and then the antigen-antibody reactions were observed between """"single dosage"""" panel cells and respective diluted recipient samples (by column agglutination technology). It's believable that the highest concentration which retains a negative result was choose to evaluate the agglutination strength between """"double dosage"""" panel cells and diluted unexpected antibody, and to observe the difference happened at different """"dosage"""" antigens with unexpressed antibody. Among 40 diluted recipient samples detected by column agglutination technology, the """"dosage effect"""" appeared in 31 diluted samples. There were 30 samples in which the unexpected antibody agglutinated """"double dosage"""" antigens ≤ 2+, while """"single dosage"""" antigens negative. It appeared in another 1 diluted sample, in which the unexpected antibody agglutinated """"double dosage"""" antigens 3+. There were 9 diluted samples in which the unexpected antibody agglutinated panel cells showing negative results (strength was between 1+-3+ before dilution). When the unexpected antibodies in Rh, MNS, Kidd, Duffy agglutinated """"double dosage"""" antigens ≤ 2+ (by column agglutination technology) , """"single dosage"""" antibody reaction maybe weaken, even be negative, and it may cause the """"dosage effect"""" to interfere the unexpected antibody identification. The """"dosage effect"""" appears in Rh, MNS, Kidd, Duffy blood system usually. """,0
5711,25687114,In vivo localization studies in the stramenopile alga Nannochloropsis oceanica,"The tiny eustigmatophyte Nannochloropsis sp. recently emerged as a promising model organism for biotechnology as it possesses a considerably high cellular oil content interesting for biodiesel production. Furthermore, the alga was shown to be genetically well accessible providing powerful tools for biotechnological engineering as well as basic research. Nannochloropsis sp. can be transformed very efficiently taking advantage of homologous recombination, however, so far it remained unclear whether these organisms are also suitable model systems for in vivo protein localization studies due to their small cell size. Here we present, to our knowledge, the first protein localization studies based on the expression of chimeric fluorescent fusion proteins in the genus Nannochloropsis using N. oceanica CCMP1779 as a model organism. Besides expressing a cytosolic green fluorescent protein (GFP), the reporter could be directed into subcellular structures such as the mitochondria, the endoplasmic reticulum and secretory pathway as well as the complex plastid including the periplastidal compartment and the stroma via fusion of specific N-terminal targeting sequences. These results expand the potential of N. oceanica as a model system in biotechnology as well as cellular biology for which now an almost complete molecular tool set exists.  ",0
5712,25687215,Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family,"To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling. ",0
5713,25687332,In-depth analysis of drivers' merging behavior and rear-end crash risks in work zone merging areas,"This study investigates the drivers' merging behavior and the rear-end crash risk in work zone merging areas during the entire merging implementation period from the time of starting a merging maneuver to that of completing the maneuver. With the merging traffic data from a work zone site in Singapore, a mixed probit model is developed to describe the merging behavior, and two surrogate safety measures including the time to collision (TTC) and deceleration rate to avoid the crash (DRAC) are adopted to compute the rear-end crash risk between the merging vehicle and its neighboring vehicles. Results show that the merging vehicle has a bigger probability of completing a merging maneuver quickly under one of the following situations: (i) the merging vehicle moves relatively fast; (ii) the merging lead vehicle is a heavy vehicle; and (iii) there is a sizable gap in the adjacent through lane. Results indicate that the rear-end crash risk does not monotonically increase as the merging vehicle speed increases. The merging vehicle's rear-end crash risk is also affected by the vehicle type. There is a biggest increment of rear-end crash risk if the merging lead vehicle belongs to a heavy vehicle. Although the reduced remaining distance to work zone could urge the merging vehicle to complete a merging maneuver quickly, it might lead to an increased rear-end crash risk. Interestingly, it is found that the rear-end crash risk could be generally increased over the elapsed time after the merging maneuver being triggered.  ",0
5714,25687723,Epigenetic dimension of oxygen radical injury in spermatogonial epithelial cells,"The present work reports a direct role of mitochondrial oxidative stress induced aberrant chromatin regulation, as a central phenomenon, to perturbed genomic integrity in the testicular milieu. Oxygen-radical injury following N-succinimidyl N-methylcarbamate treatment in mouse spermatogonial epithelial (GC-1 spg) cells induced functional derailment of mitochondrial machinery. Mitophagy resulted in marked inhibition of mitochondrial respiration and reduced mtDNA copy number. Impaired cell cycle progression along with altered H3K9me1, H4K20me3, H3, AcH3 and uH2A histone modifications were observed in the treated cells. Dense heterochromatin foci and aberrant expression of HP1α in nuclei of treated cells implied onset of senescence associated secretory phenotype mediated through nuclear accumulation of NF-κB. Neoplastic nature of daughter clones, emerged from senescent mother phenotypes was confirmed by cytogenetic instability, aberrant let-7a and let-7b miRNA expression and anchorage independent growth. Together, our results provide the first insights of redox-dependent epigenomic imbalance in spermatogonia, a previously unknown molecular paradigm.  ",0
5715,25687769,Effects of strain artefacts arising from a pre-defined callus domain in models of bone healing mechanobiology,"Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models' initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated.  ",0
5716,25687973,Interaction of a peptide derived from C-terminus of human TRPA1 channel with model membranes mimicking the inner leaflet of the plasma membrane,"The transient receptor potential ankyrin 1 channel (TRPA1) belongs to the TRP cation channel superfamily that responds to a panoply of stimuli such as changes in temperature, calcium levels, reactive oxygen and nitrogen species and lipid mediators among others. The TRP superfamily has been implicated in diverse pathological states including neurodegenerative disorders, kidney diseases, inflammation, pain and cancer. The intracellular C-terminus is an important regulator of TRP channel activity. Studies with this and other TRP superfamily members have shown that the C-terminus association with lipid bilayer alters channel sensitivity and activation, especially interactions occurring through basic residues. Nevertheless, it is not yet clear how this process takes place and which regions in the C-terminus would be responsible for such membrane recognition. With that in mind, herein the first putative membrane interacting region of the C-terminus of human TRPA1, (corresponding to a 29 residue peptide, IAEVQKHASLKRIAMQVELHTSLEKKLPL) named H1 due to its potential helical character was chosen for studies of membrane interaction. The affinity of H1 to lipid membranes, H1 structural changes occurring upon this interaction as well as effects of this interaction in lipid organization and integrity were investigated using a biophysical approach. Lipid models systems composed of zwitterionic and anionic lipids, namely those present in the lipid membrane inner leaflet, where H1 is prone to interact, where used. The study reveals a strong interaction and affinity of H1 as well as peptide structuration especially with membranes containing anionic lipids. Moreover, the interactions and peptide structure adoption are headgroup specific.  ",0
5717,25688004,Evidence for dose-additive effects of a type II pyrethroid mixture. In vitro assessment,"Despite the widespread use of pyrethroid insecticides that led to common exposure in the population, few studies have been conducted to quantitatively assess dose-additive effects of pyrethroids using a funcional measure involved in the common toxic mode of action. The aim of this study was to evaluate the potency and efficacy of 6 Type II pyretroids (α-cypermethrin, cyfluthrin, λ-cyhalothrin, deltamethrin, cyphenothrin and esfenvalerate) to evoke induction of both nitric oxide and lipid peroxides levels measured as malondialdehyde in three in vitro models (SH-SY5Y, HepG2 and Caco-2 human cells) as well as to test the hypothesis of dose additivity for mixtures of these same 6 pyrethroids. Concentration-responses for 6 pyrethroids were determined as well as the response to mixtures of all 6 pyrethroids. Additivity was tested assuming a dose-additive model. The human neuroblastoma SH-SY5Y cell line was the most sensitive in vitro model. The rank order of potency for cell SH-SY5Y viability MTT assay was deltamethrin>cyphenothrin>λ-cyhalothrin>cyfluthrin>esfenvalerate>α-cypermethrin. When 6 pyrethroids were present in the mixture at an equitoxic mixing ratio, the action on nitric oxide (NO) and lipid peroxides measured as malondialdehyde (MDA) production was consistent with a dose-additive model. The results of the present study are consistent with previous reports of additivity of pyrethroids in vivo e in vitro.  ",0
5718,25688062,Patient radiation doses in various fluoroscopically guided orthopaedic procedures,"All orthopaedic fluoroscopic procedures performed using C-arm guidance were monitored for 1 y. The type of procedure, fluoroscopy time (T), kerma-area product (KAP) values and number of radiographs (F) were recorded. The two most often performed techniques were as follows: intramedullary nailing (IMN) of intertrochanteric/peritrochanteric (IP) fractures (101 cases, 49.3 %) and antergrade IMN of femur or tibia shaft (TS) fractures (28 cases, 13.7 %). For the remaining procedures, none accounted for >5 %, categorised as 'various' (76 cases, 37 %). Large variations in T, KAP and F were observed. For IMN of IP fractures, antergrade IMN of femur and TS fractures and for various procedures, respectively, median values were T--2.1, 2.2 and 0.6 min, KAP--6.3, 6.3 and 0.6 Gy cm(-2) and F--21, 2.2 and 6.7. The patient doses during fluoroscopically guided procedures are relatively low compared with other interventional procedures. ",0
5719,25688222,Mindfulness meditation and explicit and implicit indicators of personality and self-concept changes,"The scientific interest on mindfulness meditation (MM) has significantly increased in the last two decades probably because of the positive health effects that this practice exerts in a great variety of clinical and non-clinical conditions. Despite attention regulation, emotional regulation, and body awareness have been argued to be critical mechanisms through which MM improves well-being, much less is known on the effects of this practice on personality. Here we review the current state of knowledge about the role of MM in promoting changes in practitioners' personality profiles and self-concepts. We first focus on studies that investigated the relations between mindfulness and personality using well-known self-report inventories such as the Five-Factor model of personality traits and the Temperament and Character Inventory. Second, based on the intrinsic limitations of these explicit personality measures, we review a key set of results showing effects of MM on implicit, as well as explicit, self-representations. Although the research on MM and personality is still in its infancy, it appears that this form of meditative practice may notably shape individuals' personality and self-concept toward more healthy profiles.  ",0
5720,25688329,Sleep and Women's Health,"Sex differences in sleep begin at a very early age and women report poorer sleep quality and have higher risk for insomnia than do men. Sleep may be affected by variation in reproductive hormones, stress, depression, aging, life/role transitions, and other factors. The menstrual cycle is associated with changes in circadian rhythms and sleep architecture. Menstruating women (even without significant menstrual-related complaints) often report poorer sleep quality and greater sleep disturbance during the premenstrual week compared to other times of her menstrual cycle. In addition to these sleep disturbances, women with severe premenstrual syndrome often report more disturbing dreams, sleepiness, fatigue, decreased alertness and concentration during the premenstrual phase. Sleep disturbances are also commonly reported during pregnancy and increase in frequency and duration as the pregnancy progresses. The precipitous decline in hormones and unpredictable sleep patterns of the newborn contribute to and/or exacerbate poor sleep and daytime sleepiness during the early postpartum period. Insomnia is also among the most common health complaints that are reported by perimenopausal women. Women are particularly vulnerable to developing insomnia disorder during these times of reproductive hormonal change. In this review, we present a discussion on the most relevant and recent publications on sleep across the woman's lifespan, including changes in sleep related to menstruation, pregnancy, postpartum, and the menopausal transition. Treatment for sleep disturbances and insomnia disorder and special considerations for treating women will also be discussed. ",0
5721,25688374,Determining predictors of early response to exenatide in patients with type 2 diabetes mellitus,"Exenatide is a GLP-1 analogue used in the management of T2DM yet within a subset of patients fails due to adverse side effects or from failure to attain the end goal. This retrospective observational study aimed to determine whether we could predict response to exenatide in patients with T2DM. 112 patients on exenatide were included with patient age, gender, duration of T2DM, medications alongside exenatide and weight, BMI, and HbA1c at baseline and 3 and 6 months of exenatide use being recorded. 63 responded with 11 mmol/mol reduction from baseline HbA1c after six months and 49 did not respond to exenatide. HbA1c solely differed significantly between cohorts at baseline, 3 months, and 6 months (P < 0.05). Regression analyses identified a negative linear relationship with higher baseline HbA1c correlating to greater reductions in HbA1c by 6 months (P < 0.0001). HbA1c was the sole predictor of exenatide response with higher baseline HbA1c increasing the odds of response by 5% (P = 0.004). Patients with HbA1c reductions ≥15-20% by 3 months were more likely to be responders by 6 months (P = 0.033). Our study identified that baseline HbA1c acted as the sole predictor of exenatide response and that response may be determined after 3 months of exenatide administration.  ",0
5722,25689177,Simulating the dynamic effect of land use and transport policies on the health of populations,"We identified the features of a land use-transportation system that optimizes the health and well-being of the population. We developed a quantitative system dynamics model to represent relationships among land use, transport, economic development, and population health. Simulation experiments were conducted over a 10-year simulation period to compare the effect of different baseline conditions and land use-transport policies on the number of motor vehicle crash deaths and disability-adjusted life years lost. Optimal reduction in the public health burden attributable to land transport was demonstrated when transport safety risk reduction policies were combined with land use and transport polices that minimized reliance on individual motorized transport and maximized use of active transport modes. The model's results were particularly sensitive to the level of development that characterized each city at the start of the simulation period. Local, national, and international decision-makers are encouraged to address transport, land use, and health as an integrated whole to achieve the desired societal benefits of traffic safety, population health, and social equity. ",0
5723,25689639,Urine and serum metabolite profiling of rats fed a high-fat diet and the anti-obesity effects of caffeine consumption,"In this study, we investigated the clinical changes induced by a high fat diet (HFD) and caffeine consumption in a rat model. The mean body weight of the HFD with caffeine (HFDC)-fed rat was decreased compared to that of the HFD-fed rat without caffeine. The levels of cholesterol, triglycerides (TGs), and free fatty acid, as well as the size of adipose tissue altered by HFD, were improved by caffeine consumption. To investigate the metabolites that affected the change of the clinical factors, the urine and serum of rats fed a normal diet (ND), HFD, and HFDC were analyzed using ultra performance liquid chromatography quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS), gas chromatography (GC-TOF-MS), and linear trap quadruple mass spectrometry (LTQ-XL-MS) combined with multivariate analysis. A total of 68 and 52 metabolites were found to be different in urine and serum, respectively. After being fed caffeine, some glucuronide-conjugated compounds, lysoPCs, CEs, DGs, TGs, taurine, and hippuric acid were altered compared to the HFD group. In this study, caffeine might potentially inhibit HFD-induced obesity and we suggest possible biomarker candidates using MS-based metabolite profiling.  ",0
5724,25689689,Association between recent internal travel and malaria in Ugandan highland and highland fringe areas,"To examine the association between travel (recency of travel, transmission intensity at destination compared to origin and duration of travel) and confirmed malaria in Uganda. Health facility-based case-control study in highland (~2200 m), and highland fringe (~1500 m) areas with adjustment for other covariates. In the highland site, patients who had travelled to areas of higher transmission intensity than their home (origin) areas recently were nearly seven times more likely to have confirmed malaria than those who had not (OR 6.9; P = 0.01, 95% CI: 1.4-33.1). In the highland fringe site, there was also a statistically significant association between travel and malaria (OR 2.1; P = 0.04, 95% CI: 1.1-3.9). For highland areas, or areas of low malaria transmission, health authorities need to consider internal migrants when designing malaria control programs. Control interventions should include information campaigns reminding residents in these areas of the risk of malaria infection through travel and to provide additional mosquito nets for migrants to use during travel. Health authorities may wish to improve diagnosis in health facilities in highland areas by adding travel history to malaria case definitions. Where routine monitoring data are used to evaluate the impact of interventions on the malaria burden in highland areas, health authorities and donors need ensure that only cases from the local area and not 'imported cases' are counted. ",0
5725,25689738,Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of irinotecan and its main metabolites in human plasma and its application in a clinical pharmacokinetic study,"Irinotecan is currently used in several cancer regimens mainly in colorectal cancer (CRC). This drug has a narrow therapeutic range and treatment can lead to side effects, mainly neutropenia and diarrhea, frequently requiring discontinuing or lowering the drug dose. A wide inter-individual variability in irinotecan pharmacokinetic parameters and pharmacodynamics has been reported and associated to patients' genetic background. In particular, a polymorphism in the UGT1A1 gene (UGT1A1*28) has been linked to an impaired detoxification of SN-38 (irinotecan active metabolite) to SN-38 glucuronide (SN-38G) leading to increased toxicities. Therefore, therapeutic drug monitoring of irinotecan, SN-38 and SN-38G is recommended to personalize therapy. In order to quantify simultaneously irinotecan and its main metabolites in patients' plasma, we developed and validated a new, sensitive and specific HPLC-MS/MS method applicable to all irinotecan dosages used in clinic. This method required a small plasma volume, addition of camptothecin as internal standard and simple protein precipitation. Chromatographic separation was done on a Gemini C18 column (3 μM, 100 mm x 2.0 mm) using 0.1% acetic acid/bidistilled water and 0.1% acetic acid/acetonitrile as mobile phases. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring. The standard curves were linear (R2 ≥0.9962) over the concentration ranges (10-10000 ng/mL for irinotecan, 1-500 ng/mL for SN-38 and SN-38G and 1-5000 ng/mL for APC) and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy, determined on three quality control levels for all the analytes, were always <12.3% and between 89.4% and 113.0%, respectively. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method was successfully applied to a pharmacokinetic study in metastatic CRC patients enrolled in a genotype-guided phase Ib study of irinotecan administered in combination with 5-fluorouracil/leucovorin and bevacizumab.  ",0
5726,25689936,Can serum albumin level affect the pharmacological action of tolvaptan in patients with liver cirrhosis? A post hoc analysis of previous clinical trials in Japan,"Patients with hypoalbuminemia often fail to respond to increased doses of loop diuretics. We therefore performed a post hoc analysis to investigate the pharmacological action of tolvaptan and whether it is dependent on the serum albumin level. This analysis was based on four previous clinical trials of tolvaptan in patients with liver cirrhosis who exhibited insufficient response to conventional diuretics. We analyzed the correlation between the change in the initial 24-h cumulative urine volume from baseline and the serum albumin level at baseline, and assessed potential predictive factors of response to tolvaptan. The correlation coefficient was 0.029 in the placebo group and -0.112 in the 7.5 mg tolvaptan group of patients with liver cirrhosis. Administration of tolvaptan provoked a stable response regardless of the serum albumin level. Tolvaptan use was identified as a significant predictor of pharmacological action, and was shown to change the initial urine volume by 885 mL (P < 0.0001) in liver cirrhosis patients. In this post hoc analysis, tolvaptan increased the initial urine volume from baseline regardless of serum albumin levels. Use of tolvaptan as an add-on therapy to loop diuretics can be considered an optimal therapeutic option in patients with insufficient response to loop diuretics. ",0
5727,25690076,Periprocedural management of rivaroxaban-treated patients,"The increasing and widespread use of direct oral anticoagulants (DOACs) demands guidelines and experts' consensus for their rational and safe use, especially in certain situations for which there is no evidence-based consensus, such as the periprocedural setting. Rivaroxaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF) and for treatment and prevention of venous thromboembolism (VTE) in major orthopedic surgery. This article is addressed to all the clinicians involved in the periprocedural approach of patients treated with rivaroxaban, with the aim to give practical recommendations to improve patients' management during and after surgery. This article is based on a consensus of specialists involved in anticoagulant treatment and in periprocedural setting, including experts in thrombosis, cardiologists, internists, clinical pathologists and anesthesiologists. The authors performed a review of the literature and expressed statements based on the results of the review as well as on personal experience. Rivaroxaban is a safe and effective drug that simplifies management of anticoagulation also in patients undergoing invasive procedures. However, periprocedural management could be challenging and physicians must carefully balance the risk of bleeding and the risk of thrombosis. ",0
5728,25690695,DXD motif-dependent and -independent effects of the chlamydia trachomatis cytotoxin CT166,"The Gram-negative, intracellular bacterium Chlamydia trachomatis causes acute and chronic urogenital tract infection, potentially leading to infertility and ectopic pregnancy. The only partially characterized cytotoxin CT166 of serovar D exhibits a DXD motif, which is important for the enzymatic activity of many bacterial and mammalian type A glycosyltransferases, leading to the hypothesis that CT166 possess glycosyltransferase activity. CT166-expressing HeLa cells exhibit actin reorganization, including cell rounding, which has been attributed to the inhibition of the Rho-GTPases Rac/Cdc42. Exploiting the glycosylation-sensitive Ras(27H5) antibody, we here show that CT166 induces an epitope change in Ras, resulting in inhibited ERK and PI3K signaling and delayed cell cycle progression. Consistent with the hypothesis that these effects strictly depend on the DXD motif, CT166 with the mutated DXD motif causes neither Ras-ERK inhibition nor delayed cell cycle progression. In contrast, CT166 with the mutated DXD motif is still capable of inhibiting cell migration, suggesting that CT166 with the mutated DXD motif cannot be regarded as inactive in any case. Taken together, CT166 affects various fundamental cellular processes, strongly suggesting its importance for the intracellular survival of chlamydia.  ",0
5729,25691074,"'Peripheric' pancreatic cysts: performance of CT scan, MRI and endoscopy according to final pathological examination","To assess the accuracy of pre-operative staging in patients with peripheral pancreatic cystic neoplasms (pPCNs). From 2005 to 2011, 148 patients underwent a pancreatectomy for pPCNs. The pre-operative examination methods of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) were compared for their ability to predict the suggested diagnosis accurately, and the definitive diagnosis was affirmed by pathological examination. A mural nodule was detected in 34 patients (23%): only 1 patient (3%) had an invasive pPCN at the final histological examination. A biopsy was performed in 79 patients (53%) during EUS: in 55 patients (70%), the biopsy could not conclude a diagnosis; the biopsy provided the correct and wrong diagnosis in 19 patients (24%) and 5 patients (6%), respectively. A correct diagnosis was affirmed by CT, EUS and pancreatic MRI in 60 (41%), 103 (74%) and 80 (86%) patients (when comparing EUS and MRI; P = 0.03), respectively. The positive predictive values (PPVs) of CT, EUS and MRI were 70%, 75% and 87%, respectively. Pancreatic MRI appears to be the most appropriate examination to diagnose pPCNs accurately. EUS alone had a poor PPV. Mural nodules in a PCN should not be considered an indisputable sign of pPCN invasiveness. ",0
5730,25691093,Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes,"Glycogen synthase kinase-3 β (GSK3β) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3β is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3β becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3β (phospho-GSK3β) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3β has never been studied in humans. In 27 patients with bipolar depression, total GSK3β and phospho-GSK3β were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group. No differences in phospho-GSK3β or total GSK3β were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3β and total GSK3β levels. From baseline to endpoint, lithium treatment inactivated GSK3β by significantly increasing phospho-GSK3β levels (p = 0.010). Clinical improvement (baseline HAM-D - endpoint HAM-D) negatively correlated with the increase in phospho-GSK3β (p = 0.03). The present results show that lithium inactivates platelet GSK3β in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3β as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3β in other neuropsychiatric disorders and as a new therapeutic target per se. ",0
5731,25691148,The social ties that bind: social anxiety and academic achievement across the university years,"Given that engagement and integration in university/college are considered key to successful academic achievement, the identifying features of social anxiety, including fear of negative evaluation and distress and avoidance of new or all social situations, may be particularly disadvantageous in the social and evaluative contexts that are integral to university/college life. Thus, the purpose of this study was to examine the direct effects of social anxiety on academic achievement, as well as investigate an indirect mechanism through which social anxiety might impact on academic achievement, namely, the formation of new social ties in university. The participants were 942 (71.7 % female; M = 19 years at Time 1) students enrolled in a mid-sized university in Southern Ontario, Canada. Students completed annual assessments of social anxiety, social ties, and academic achievement for three consecutive years. The results from an autoregressive cross-lag path analysis indicated that social anxiety had a significant and negative direct relationship with academic achievement. Moreover, the negative indirect effect of social anxiety on academic achievement through social ties was significant, as was the opposing direction of effects (i.e., the indirect effect of academic achievement on social anxiety through social ties). These findings highlight the critical role that social ties appear to play in successful academic outcomes and in alleviating the effects of social anxiety during university/college.  ",0
5732,25691238,Association Between Receipt of Brief Alcohol Intervention and Quality of Care among Veteran Outpatients with Unhealthy Alcohol Use,"Brief alcohol intervention, including advice to reduce or abstain from drinking, is widely recommended for general medical outpatients with unhealthy alcohol use, but it is challenging to implement. Among other implementation challenges, providers report reluctance to deliver such interventions, citing concerns about negatively affecting their patient relationships. The purpose of this study was to determine whether patient-reported receipt of brief intervention was associated with patient-reported indicators of high-quality care among veteran outpatients with unhealthy alcohol use. Cross-sectional secondary data analysis was performed using the Veterans Health Administration (VA) Survey of Healthcare Experiences of Patients (SHEP). The study included veteran outpatients who (1) responded to the outpatient long-form SHEP (2009-2011), (2) screened positive for unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire score ≥ 3 for women, ≥ 4 for men), and (3) responded to questions assessing receipt of brief intervention and quality of care. We used logistic regression models to estimate the adjusted predicted prevalence of reporting two indicators of high-quality care--patient ratings of their VA provider and of overall VA healthcare (range 0-10, dichotomized as ≥ 9 indicating high quality)--for both patients who did and did not report receipt of brief intervention (receiving alcohol-related advice from a provider) within the previous year. Among 10,612 eligible veterans, 43.8% reported having received brief intervention, and 84.2% and 79.1% rated their quality of care as high from their provider and the VA healthcare system, respectively. In adjusted analyses, compared to veterans who reported receiving no brief intervention, a higher proportion of veterans reporting receipt of brief intervention rated the quality of healthcare from their provider (86.9% vs. 82.0%, p < 0.01) and the VA overall (82.7% vs. 75.9%, p < 0.01) as high. In this cross-sectional analysis of veterans with unhealthy alcohol use, a higher proportion of those who reported receipt of brief intervention reported receiving high-quality care compared to those who reported having received no such intervention. These findings do not support provider concerns that delivering brief intervention adversely affects patients' perceptions of care. ",0
5733,25691510,Impact of a pharmacoinvasive strategy when delays to primary PCI are prolonged,"Primary percutaneous coronary intervention (P-PCI) is the preferred reperfusion option in ST-elevation myocardial infarction, but its benefits become attenuated as time to its potential delivery becomes prolonged. Based on the STrategic Reperfusion Early After Myocardial Infarction trial, we assessed the impact of increasing time delay on outcomes in patients randomised to a pharmacoinvasive strategy (PI) or P-PCI. Thirty-day clinical outcomes were examined according to PCI-related delay (P-RD). Data from hospitals that enrolled >10 randomised patients were used and P-RD categorised as ≤55 min, >55-97 min and >97 min. Composite of death/congestive heart failure/cardiogenic shock/myocardial infarction in PI and P-PCI arms occurred in 10.6% versus 10.3% (≤55 min, p=0.910); 13.9% versus 17.9% (>55-97 min, p=0.148) and 13.5% versus 16.2% (>97 min, p=0.470), respectively. While there was no worsening of outcomes for PI across the P-RD spectrum, this occurred in the P-PCI arm (p(trend)=0.038). For P-RD ≤55 min, fewer events tended to occur with P-PCI than PI. Conversely, as P-RD increased to >55 min, PI-assigned patients had better outcomes than P-PCI, suggesting an event-free advantage with PI as P-RD increased (p(interaction)=0.094). Analysing P-RD continuously showed that for every 10-min increment there was an increasing trend towards benefit among PI-assigned patients (p(interaction)=0.073). As P-RD increased, PI outcomes became superior to P-PCI when P-RD is prolonged and exceeds guideline-mandated times. In such circumstances, a PI strategy may provide an alternative reperfusion option. Adverse time delays for delivery of P-PCI should be considered when evaluating reperfusion strategies. NCT00623623. ",0
5734,25691652,"A novel tricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor, GRL-0739, effectively inhibits the replication of multidrug-resistant HIV-1 variants and has a desirable central nervous system penetration property in vitro","We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 μM). GRL-0739 blocked the infectivity and replication of HIV-1NL4-3 variants selected by concentrations of up to 5 μM ritonavir or atazanavir (EC50, 0.035 to 0.058 μM). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2ROD variant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous system (CNS) penetration property, as assessed using a novel in vitro blood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS penetration profiles.  ",0
5735,25691848,Perianal Abscess and Proctitis by Klebsiella pneumoniae,"Klebsiella pneumoniae (K. pneumoniae) can at times cause invasive infections, especially in patients with diabetes mellitus and a history of alcohol abuse. A 61-year-old man with diabetes mellitus and a history of alcohol abuse presented with abdominal and anal pain for two weeks. After admission, he underwent sigmoidoscopy, which revealed multiple ulcerations with yellowish exudate in the rectum and sigmoid colon. The patient was treated with ciprofloxacin and metronidazole. After one week, follow up sigmoidoscopy was performed owing to sustained fever and diarrhea. The lesions were aggravated and seemed webbed in appearance because of damage to the rectal mucosa. Abdominal computed tomography and rectal magnetic resonance imaging were performed, and showed a perianal and perirectal abscess. The patient underwent laparoscopic sigmoid colostomy and perirectal abscess incision and drainage. Extended-spectrum beta-lactamase-producing K. pneumoniae was identified in pus culture. The antibiotics were switched to ertapenem. He improved after surgery and was discharged. K. pneumoniae can cause rapid invasive infection in patients with diabetes and a history of alcohol abuse. We report the first rare case of proctitis and perianal abscess caused by invasive K. pneumoniae infection.  ",0
5736,25691916,Assessing the experiences of intra-uterine device users in a long-term conflict setting: a qualitative study on the Thailand-Burma border,"In Burma, severe human rights violations, civil conflict, and the persecution of ethnic and linguistic minority populations has resulted in the displacement of millions of people, many of whom now reside as internally displaced populations (IDPs) in Eastern Burma or in Thailand as refugees or undocumented migrants. Use of the intra-uterine device (IUD), a non-user dependent and highly reliable method of long acting reversible contraception, has the potential to make a significant impact on reproductive health in this protracted conflict setting. This qualitative study aimed to understand Burmese women's experiences with and perceptions of the IUD and identify avenues for improving contraceptive service delivery along the Thailand-Burma border. In the summer of 2013, we conducted in-person in-depth open-ended interviews with 31 women who obtained IUDs from a clinic along the border. We conducted a content and thematic analysis of these data using both a priori (pre-determined) and emergent codes and inductive techniques. Women's experiences with the IUD are overwhelmingly positive and the experiences of friends and family impact use of the device. Financial considerations and access to reproductive health facilities also shape the use of the IUD in this region. The IUD is rare along the Thailand-Burma border and misinformation about this method of contraception is pervasive. Our findings suggest that this modality of contraception is culturally acceptable and may be able to address structural barriers to reproductive health services along the Thailand-Burma border. Ensuring that information provided by health care providers and among peer groups is evidence-based, a full range of contraceptive methods is available, and adoption of an IUD is affordable are priorities for expanding access to reproductive health services in this setting. ",0
5737,25691950,Association of ADAM33 gene polymorphisms with allergic asthma,"Asthma results from the interaction between genetic and environmental factors. ADAM33 gene on chromosome 20p13 is associated with asthma and airway hyperresponsiveness. This is a case-control study, where four SNPs S1 (rs3918396), T1 (rs2280091), T2 (rs2280090), V4 (rs2787094) of ADAM33 gene have been assessed in patients with allergic asthma and normal controls (95 patients and 86 normal). Blood samples of these participants have been genotyped by PCR and the RFLP method. There was no association between asthmatic patients and polymorphisms of alleles, genotypes and haplotypes of the ADAM33 gene. When categorizing the asthmatic patients in severe, moderate and mild groups, associations in the subcategories of asthmatic patients were found. There were associations between polymorphisms of C allele of T1 SNP with severe asthmatic patients and G allele of V4 SNP with moderate asthmatics respectively (P=0.006, P=0.01). There was a significant association between sensitivity to mite and polymorphism of C allele of T1 SNP (P=0.02). Besides, there was a significant association between sensitivity to weeds and genotype GG of V4 SNP (P=0.05). Polymorphisms of ADAM33 gene might be associated with severe asthma and sensitivity to aeroallergens in northeast of Iran, but further studies are needed to determine the polymorphisms in this area and other regions of our country. ",0
5738,25692723,Observational studies and the natural history of screen-detected prostate cancer,"To review the recent observational studies and clinical trials that guide our understanding of the natural history of screen-detected prostate cancer. Data from observational studies and clinical trials have been updated during the past year. The most important include the Scandinavian Prostate Cancer Group 4 study and the European Randomized Study of Prostate Cancer Screening. Both retrospective population-based analyses and prospective randomized trials show that men who harbor low-volume low-grade prostate cancers have less than 6% risk of disease progression within a decade of diagnosis. For the men who pursue active surveillance prostate cancer mortality remains under 1% after a median follow-up of 6.8 years. Up to one-third of men abandon active surveillance protocols because of either prostate-specific antigen or biopsy progression. Around 10% abandon active surveillance because of anxiety. Researchers are actively exploring new imaging modalities and genetic markers to identify men whose prostate cancers are likely to progress. For now, patients with newly diagnosed prostate cancer must carefully weigh the threat posed by their disease against the possible benefits and harms associated with intervention. For some, active surveillance will be an appropriate choice. ",0
5739,25692777,Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-κB signaling pathway,"Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKα, IKKβ, IKKγ, IKBα, NF-κB p50 and NF-κB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-α in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-κB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection.  ",0
5740,25692800,High prevalence of rectal gonorrhea and Chlamydia infection in women attending a sexually transmitted disease clinic,"Testing women for urogenital Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) is common in sexually transmitted disease (STD) clinics. However, women may not be routinely tested for rectal GC/CT. This may lead to missed infections in women reporting anal intercourse (AI). This was a retrospective review of all women who underwent rectal GC/CT testing from August 2012 to June 2013 at an STD clinic in Columbus, Ohio. All women who reported AI in the last year had a rectal swab collected for GC/CT nucleic acid amplification testing (n=331). Using log-binomial regression models, we computed unadjusted and adjusted associations for demographic and behavioral factors associated with rectal GC/CT infection. Participants (n=331) were 47% African-American, with median age of 29 years. Prevalence of rectal GC was 6%, rectal CT was 13%, and either rectal infection was 19%. Prevalence of urogenital GC and CT was 7% and 13% respectively. Among women with rectal GC, 14% tested negative for urogenital GC. Similarly, 14% of women with rectal CT tested negative for urogenital CT. In unadjusted analyses, there was increased rectal GC prevalence among women reporting sex in the last year with an injection drug user, with a person exchanging sex for drugs or money, with anonymous partners, and while intoxicated/high on alcohol or illicit drugs. After multivariable adjustment, no significant associations persisted, but a trend of increased rectal GC prevalence was observed for women <26 years of age (p=0.06) and those reporting sex while intoxicated/high on alcohol or drugs (p=0.05). For rectal CT, only age <26 years was associated with prevalent infection in unadjusted models; this association strengthened after multivariable adjustment (prevalence ratio: 6.03; 95% confidence interval: 2.29-15.90). Nearly one in five women who reported AI in the last year had rectal GC or CT infection. Urogenital testing alone would have missed 14% of rectal infections. Standardized guidelines would increase rectal GC/CT testing in women and help detect missed infections. ",0
5741,25692915,"Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema","BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61�10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).",0
5742,25692924,Apolipoprotein C-III: a potent modulator of hypertriglyceridemia and cardiovascular disease,"The purpose of this article is to summarize the recent epidemiological, basic science, and pharmaceutical research linking apolipoprotein C-III (apoC-III) with the development and treatment of cardiovascular disease (CVD). ApoC-III is an important emerging target linking hypertriglyceridemia with CVD. ApoC-III is a potent modulator of many established CVD risk factors, and is found on chylomicrons, very-low density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles. Recent studies show that in humans, apoC-III levels are an independent risk factor for CVD, and its presence on lipoproteins may promote their atherogenicity. This year, two large-scale epidemiological studies have linked mutations in apoC-III with increased incidence of CVD and hypertriglyceridemia. ApoC-III raises plasma triglycerides through inhibition of lipoprotein lipase, stimulation of very-low density lipoprotein secretion, and is a novel factor in modulating intestinal triglyceride trafficking. ApoC-III also stimulates inflammatory processes in the vasculature and the pancreas. The combination of raising plasma triglycerides and independently stimulating inflammatory processes makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled. Clinical trials on apoC-III antisense oligonucleotides are in progress. ApoC-III is a potent direct modulator of established CVD risk factors: plasma triglycerides and inflammation. Recent findings show that changes in apoC-III levels are directly associated with changes in cardiovascular risk and the atherogenicity of the lipoproteins on which apoC-III resides. Emerging roles of apoC-III include a role in directing the atherogenicity of high-density lipoprotein, intestinal dietary triglyceride trafficking, and modulating pancreatic β-cell survival. The combination of these roles makes apoC-III an important therapeutic target for the management and prevention of CVD. ",0
5743,25693931,Endo-laparoscopic rendezvous approach for pericardia with gastric posterior wall of gastrointestinal stromal tumor: analysis of 52 consecutive cases,"Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract and most frequently developed in the stomach, and surgical therapy is limited on removal of the tumor lesion. The aim of this study was to investigate the clinical values of endo-laparoscopic rendezvous approach for pericardial GISTs within gastric posterior wall. Surgical outcome and clinical data of 52 patients with pericardial GISTs within gastric posterior wall treated at Tianjin Peoples' Hospital from January 2004 to October 2013 were analyzed. Endo-laparoscopic rendezvous approach was used as an operative procedure for tumor resection ranged from 10 to 50 mm. Endoscopic ultrasound, computed tomography and microscopic findings all certified the gastric spindle type GIST locating in the submucosa to muscle proper. Endo-laparoscopic rendezvous approach was attempted in 52 patients (male/female: 31/21) with median age of 51 years (25-71 years). The median operating time was 80 min (range: 40-120 min) and median intra-operative blood loss was 26 ml (range: 10-50 ml). The median hospital stay was 5 days (range: 4-6 days), while the median tumor size was 25 mm (range: 7-50 mm). All operative margins were clear. There were no recurrences or metastases of all patients in a median follow-up of 24 months (range: 6-36 months). Endo-laparoscopic rendezvous approach is considered to represent the next revolution in surgery. The new technique is reliable and effective in clinical application, due to the advantages of accurate and quick localization for pericardial GIST within gastric posterior wall. ",0
5744,25694190,"Neonatal hypertension: an underdiagnosed condition, a review article","Advances in neonatology and intensive monitoring has increased our ability to identify and measure blood pressure in sick premature and term infants and this has contributed to an increased awareness of hypertension in the NICU. A few recent studies done by Zubrow and others have offered many new information on blood pressure values over the first month after birth and on other many intrinsic and extrinsic factors that can cause effects on the blood pressure in the neonatal period. There are no definite cut off for labelling hypertension in newborn period and also doubts are there on the pharmacological treatment. This is a field in neonatology which is least studied hence requires further inquiry. This review article will cover several aspects of neonatal hypertension like definition, normotensive data, etiology, clinical characteristics, diagnostic modalities, treatment choices and long term effect of these newborns. ",0
5745,25694425,Structure of Escherichia coli dGTP triphosphohydrolase: a hexameric enzyme with DNA effector molecules,"The Escherichia coli dgt gene encodes a dGTP triphosphohydrolase whose detailed role still remains to be determined. Deletion of dgt creates a mutator phenotype, indicating that the dGTPase has a fidelity role, possibly by affecting the cellular dNTP pool. In the present study, we have investigated the structure of the Dgt protein at 3.1-Å resolution. One of the obtained structures revealed a protein hexamer that contained two molecules of single-stranded DNA. The presence of DNA caused significant conformational changes in the enzyme, including in the catalytic site of the enzyme. Dgt preparations lacking DNA were able to bind single-stranded DNA with high affinity (Kd ∼ 50 nM). DNA binding positively affected the activity of the enzyme: dGTPase activity displayed sigmoidal (cooperative) behavior without DNA but hyperbolic (Michaelis-Menten) kinetics in its presence, consistent with a specific lowering of the apparent Km for dGTP. A mutant Dgt enzyme was also created containing residue changes in the DNA binding cleft. This mutant enzyme, whereas still active, was incapable of DNA binding and could no longer be stimulated by addition of DNA. We also created an E. coli strain containing the mutant dgt gene on the chromosome replacing the wild-type gene. The mutant also displayed a mutator phenotype. Our results provide insight into the allosteric regulation of the enzyme and support a physiologically important role of DNA binding. ",0
5746,25694495,Alcohol's harm to others' well-being and health: a comparison between Chile and Australia,"To assess the degree to which relationships with heavy drinkers affect health and well-being of the Chilean population, and how this compares with previously published analyses of an Australian sample in order to establish intercultural differences in the effects of others' heavy drinking. Data are from a face-to-face survey of 1500 Chileans. Respondents were asked to identify people in their lives who were heavy drinkers. Information on respondents' well-being and health was collected using the Personal Well-Being Index and the EuroQol Group 5-Dimension Self-Report Questionnaire score (EQ-5D) index. Sociodemographic information was also gathered. Bivariate and multivariate analyses were performed to determine whether heavy drinkers in the respondents' lives (both living in or out of their household) were related to health and well-being. Results were contrasted with those for Australia reported by Livingston et al. [in (2010) Impact of heavy drinkers on others' health and well-being. J Stud Alcohol Drugs 71: , 778-785]. Heavy drinkers inside the household negatively affect the health and well-being of Chileans. Heavy drinkers outside the household have a negative but smaller effect on their health and well-being. This contrasts with Australia where most of the harm seems to arise from heavy drinkers identified outside the household. In both countries, health and well-being are affected by others' heavy drinking. The particular structure of harm may vary across cultures: in Chile, heavy drinkers identified inside the household are the most harmful, whereas in Australia those identified outside the household are the most harmful. This should have an impact on the policy design. ",0
5747,25694553,Myelin abnormalities in the optic and sciatic nerves in mice with GM1-gangliosidosis,"GM1-gangliosidosis is a glycosphingolipid lysosomal storage disease involving accumulation of GM1 and its asialo form (GA1) primarily in the brain. Thin-layer chromatography and X-ray diffraction were used to analyze the lipid content/composition and the myelin structure of the optic and sciatic nerves from 7- and 10-month old β-galactosidase (β-gal) +/? and β-gal -/- mice, a model of GM1gangliosidosis. Optic nerve weight was lower in the β-gal -/- mice than in unaffected β-gal +/? mice, but no difference was seen in sciatic nerve weight. The levels of GM1 and GA1 were significantly increased in both the optic nerve and sciatic nerve of the β-gal -/- mice. The content of myelin-enriched cerebrosides, sulfatides, and plasmalogen ethanolamines was significantly lower in optic nerve of β-gal -/- mice than in β-gal +/? mice; however, cholesteryl esters were enriched in the β-gal -/- mice. No major abnormalities in these lipids were detected in the sciatic nerve of the β-gal -/- mice. The abnormalities in GM1 and myelin lipids in optic nerve of β-gal -/- mice correlated with a reduction in the relative amount of myelin and periodicity in fresh nerve. By contrast, the relative amount of myelin and periodicity in the sciatic nerves from control and β-gal -/- mice were indistinguishable, suggesting minimal pathological involvement in sciatic nerve. Our results indicate that the greater neurochemical pathology observed in the optic nerve than in the sciatic nerve of β-gal -/- mice is likely due to the greater glycolipid storage in optic nerve.  ",0
5748,25694731,Studies on the nutraceuticals composition of wheat derived oils wheat bran oil and wheat germ oil,"Fat-soluble nutraceuticals of cereals are known for number of disease preventive activities. Hence wheat bran oil (WBO) and wheat germ oil (WGO) were extracted from wheat bran and germ which yielded 3.35 % and 7.35 % of oil, containing polyunsaturated fatty acids (PUFA) (64 %, 61.2 %) respectively. Both oils contained tocopherols and carotenoids, which were higher in wheat germ oil (273 mg/100 g, 12.23 mg/100 g) than wheat bran oil (190 mg/100 g, 2.21 mg/100 g). Steryl ferulates were also present in both the oils, but their content was eight-fold higher in WBO than in WGO. Three major steryl ferulates identified by HPLC were campesteryl ferulate and sitostenyl ferulate, campestanyl ferulate and β-sitosteryl ferulate as in γ-oryzanol and another ferulate, viz., sitostanyl ferulate. A strong IC50 value of 7.5 mg/mL and 21.6 mg/mL DPPH free radicals scavenging for wheat germ oil for wheat bran oil was observed. NMR ((13)C and (1)H) profile explored the evidence of distribution of antioxidant molecules in the unsaponifiable matter of wheat derived oil. Since oils rich in PUFA and minor components are required for the normal physiological activities, blending such oils with other edible oils of the diet in wheat growing countries like India may be useful to provide health benefits.  ",0
5749,25694761,Computer-assisted evaluation of Mandibular Cortical Width (MCW) index as an indicator of osteoporosis,"To assess the diagnostic accuracy of mandibular cortical width (MCW) as an indicator of the presence of osteoporosis. The study included 343 women between 45-75 years of age. After informed consent, all subjects underwent dual energy X-ray absorptiometry (DXA) of the hip and the lumbar spine (L1 to L4) in order to establish a gold standard diagnosis of osteoporosis and an orthopantomogram (OPG). From the initial subjects, 28 (8.2%) did not meet the inclusion criteria. In the final sample 315 patients were included, of whom 293 were postmenopausal (93.3%) and 22 perimenopausal (6.7%). Based on the DXA examination the sample was divided into three groups: a)normal controls (n=106), b)osteopenics (n=103) and c)osteoporotics (n=106). The MCW index was calculated by three different observers using the Emago image processing software. Inter - rater agreement was considered important since MCW was being tested as a possible screening tool for osteoporosis. Comparisons of MCW values between normal controls, osteopenic and osteoporotic women in our sample showed that these values clearly differentiate between the three groups, especially between normal and osteoporotic subjects. Furthermore, the receiver operator characteristic curve (ROC) analysis showed this to hold true in real diagnostic terms, giving a threshold value of 3.24 for differentiating between normal and osteoporotic women. With ROC values ranging between 0.80 and 0.87 we can reasonably assume that the MCW index is a reliable indication of the presence of osteoporosis in a patient. Hippokratia 2014; 18 (3): 251-257. ",0
5750,25694817,Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children's Health Study,"Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Children's Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect children's health while control measures are being implemented.  ",0
5751,25694953,The application of backscattered ultrasound and photoacoustic signals for assessment of bone collagen and mineral contents,"This study examines the backscattered ultrasound (US) and back-propagating photoacoustic (PA) signals from trabecular bones, and their variations with reduction in bone minerals and collagen content. While the collagen status is directly related to the strength of the bone, diagnosis of its condition using US remains a challenge. For both PA and US methods, coded-excitation signals and matched filtering were utilized to provide high sensitivity of the detected signal. The optical source was a 805-nm CW laser and signals were detected employing a 2.2-MHz ultrasonic transducer. Bone decalcification and decollagenization were induced with mild ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite solutions, respectively. The PA and US signals were measured on cattle bones, and apparent integrated backscatter/back-propagating (AIB) parameters were compared before and after demineralization and decollagenization. The results show that both PA and US are sensitive to mineral changes. In addition, PA is also sensitive to changes in the collagen content of the bone, but US is not significantly sensitive to these changes. ",0
5752,25695024,The accuracy of transrectal ultrasound-guided biopsy for decision making in prostate cancer,"The most important surgical complications of renal transplantation are stenosis and obstruction of anastomosis of the ureter to the bladder. Hence, routine use of ureteral stents to prevent such complications seems logical; however, the optimal time to remove the ureteral stent is still controversial. The purpose of this study was to compare the benefits and complications of the early or delayed ureteral stent removal post-transplantation. All patients who underwent kidney transplantation in Modarres Hospital from May 2011 through March 2012 were recruited. The patients were allocated to three groups. Ureteral stent removed 10, 20, and 30 days after transplantation in groups one, two, and three, respectively. A total of 91 patients had undergone renal transplantation in our center. Ureteral stent was removed at 10, 20, and 30 days after surgery. Urologic complications among the three groups included hydronephrosis, urinoma, and collection around the graft; there was no statistically significant difference among study groups with regard to frequency of complications. We can remove the ureteral stent at shorter interval after renal transplantation with no increased risk of urologic complications. ",0
5753,25695135,Epilepsy and malformations of cortical development: new developments,"Malformations of cortical development (MCD) are increasingly recognized as causes of epilepsy and neurodevelopmental disorders. This review summarizes recent developments in the classification, specifically focusing on how genetic and cellular pathway advances are changing our understanding of MCD and how this applies to clinical care. Recent studies have shown that mutations can have variable impact on not only the pattern of MCD but also the location of cortical involvement. Regulatory G protein GPR56 mutations can selectively cause polymicrogyria in the Sylvian fissure bilaterally. In addition, recent data suggest that somatic mutations can be detected in about 30% of patients with diffuse and focal MCD but the majority are not detectable with common sequencing. Similarly, MRI at higher field is able to detect abnormalities not seen on clinical scanners. The classification scheme and pathogenesis of MCD converge by common genes affecting similar pathways, which, in turn, modify the classification of these disorders. These advances are impacting treatment and genetic management. The classification of MCD in epilepsy has progressed from simple correlations with syndromes and imaging data to molecular pathways underscoring the significance of common mechanism in brain maldevelopment and epilepsy. ",0
5754,25695259,"Trends in major risk factors for cardiovascular disease among adults in the Mississippi Delta region, Mississippi Behavioral Risk Factor Surveillance System, 2001-2010","The prevalences of major modifiable risk factors for cardiovascular disease (CVD) are disproportionately high in the 18-county Mississippi Delta region, and many of these risk factors disproportionately affect blacks. Temporal trends in the prevalence of CVD risk factors in the Mississippi Delta have not been determined. We examined trends in CVD risk factors from 2001 to 2010 in the region. Longitudinal trends in prevalence of high blood pressure, high cholesterol, diabetes, obesity, physical inactivity, and current smoking were investigated using self-reported data from the Behavioral Risk Factor Surveillance System. Joinpoint regression models were used to examine annual percentage change (APC) in the prevalence of these risk factors. Overall, from 2001 to 2010, we observed significant increases in the prevalence of high cholesterol (APC, 4.22%), obesity (APC, 3.65%), and diabetes (APC, 3.54%). Among blacks, we found significant increases in the prevalence of high cholesterol (APC, 3.41%), obesity (APC, 3.48%), and diabetes (APC, 4.96%). Among whites, we found significant increases in high blood pressure (APC, 2.18%), high cholesterol (APC, 4.78%), obesity (APC, 4.18%), and physical inactivity (APC, 3.06%). We also observed a significant decrease in smoking among whites (APC, -1.99%). From 2001 to 2010, we found a significant increase in the prevalence of high cholesterol, diabetes, and obesity in the Mississippi Delta. We also observed racial differences in those prevalences. ",0
5755,25695670,"Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design","The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.  ",0
5756,25695775,Role of pentraxin 3 in shaping arthritogenic alphaviral disease: from enhanced viral replication to immunomodulation,"The rising prevalence of arthritogenic alphavirus infections, including chikungunya virus (CHIKV) and Ross River virus (RRV), and the lack of antiviral treatments highlight the potential threat of a global alphavirus pandemic. The immune responses underlying alphavirus virulence remain enigmatic. We found that pentraxin 3 (PTX3) was highly expressed in CHIKV and RRV patients during acute disease. Overt expression of PTX3 in CHIKV patients was associated with increased viral load and disease severity. PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication. Furthermore, binding of the N-terminal domain of PTX3 to RRV facilitated viral entry and replication. Thus, our study demonstrates the pivotal role of PTX3 in shaping alphavirus-triggered immunity and disease and provides new insights into alphavirus pathogenesis. ",0
5757,25696173,Aortic coarctation: the need for lifelong surveillance,"Survival of patients with aortic coarctation improved dramatically after surgical repair became available and the number of patients who undergo surgery and reach adulthood is steadily increasing. However, life expectancy is still not as normal as in unaffected peers. Cardiovascular complications are frequent and require indefinite follow-up. Concern falls chiefly into five categories: recoarctation, endocarditis, stenotic and/or incompetent coexisting bicuspid aortic valve, aortic aneurysm formation and systemic hypertension. In this review, these complications, with particular reference to late hypertension, are discussed and strategies for the clinical management of postcoarctectomy patients are described. ",0
5758,25697107,Predictive role of circulating endothelial-derived microparticles in cardiovascular diseases,"Endothelial-derived microparticles (EMPs) are a novel biological marker of endothelium injury and vasomotion disorders that are involved in pathogenesis of cardiovascular, metabolic, and inflammatory diseases. Circulating levels of EMPs are thought to reflect a balance between cell stimulation, proliferation, apoptosis, and cell death. Increased EMPs may be defined in several cardiovascular diseases, such as stable and unstable coronary artery disease, acute and chronic heart failure, hypertension, arrhythmias, thromboembolism, asymptomatic atherosclerosis as well as renal failure, metabolic disorders (including type two diabetes mellitus, abdominal obesity, metabolic syndrome, insulin resistance) and dyslipidemia. This review highlights the controversial opinions regarding impact of circulating EMPs in major cardiovascular and metabolic diseases and summarizes the perspective implementation of the EMPs in risk stratification models.  ",0
5759,25697211,"Clinical, genetic and molecular characterization of the X-linked chronic granulomatous disease. A case report of a new splicing mutation]","Chronic granulomatous disease (CGD) is caused by mutations in the genes that encode five of the subunits of the human NADPH oxidase. The most common form is caused by mutations in CYBB, the human gene encoding gp 91 phox. To identify the molecular defects causing CGD. A male patient with a history of acute diarrhea and recurrent perianal abscess since two months old. At 6 months, the patient presented a chronic inflammatory disease of the colon and bacterial colitis. After three years, he developed infections in the lower and perianal respiratory tract. The cDNA analysis identified abnormal mRNA expression, which was confirmed by sequencing. Specifically the exclusion of exon 2 was observed. Additionally, gDNA sequencing identified an alteration in the acceptor splice site of intron 1, including a deletion followed by insertion of three nucleotides (c.46-14_-11delTTCT insGAA). The first molecular study of a patient with CGD due to splicing pattern change, reported in Colombia, is presented. The definition of the mutation and its correlation with the phenotype is essential to provide appropriate genetic counseling to patients and their families. ",0
5760,25697611,Catching up on celiac disease],"Knowledge about celiac disease continues to grow and amaze those who investigate, seek and treat this condition. Gone are the days when it was considered just a rare child's digestive disease. It is now recognized as a highly prevalent autoimmune condition that affects children and adults with digestive and extra-digestive symptoms of diverse intensity, disorder that may be either mono, oligo or asymptomatic from a digestive point of view. Today, it is an underdiagnosed condition, not actively considered, and often mistakes are made regarding its diagnosis, treatment and gluten-free diet monitoring. This article reviews the current definition of the disease, clinical presentations, potential patients, how to search for the disease, how the diagnosis is made and characteristics of the treatment and monitoring of celiac patients, all based on internationally agreed standards, and emphasizing those aspects that have proven to be useful in other countries regarding the management of the disease.  ",0
5761,25697669,Does safety climate predict safety performance in Italy and the USA? Cross-cultural validation of a theoretical model of safety climate,"Previous studies have acknowledged the relevance of assessing the measurement equivalence of safety related measures across different groups, and demonstrating whether the existence of disparities in safety perceptions might impair direct group comparisons. The Griffin and Neal (2000) model of safety climate, and the accompanying measure (Neal et al. [NGH], 2000), are both widely cited and utilized. Yet neither the model in its entirety nor the measure have been previously validated across different national contexts. The current study is the first to examine the NGH measurement equivalence by testing whether their model of safety climate predicting safety performance is tenable in both English speaking and non-English speaking countries. The study involved 616 employees from 21 organizations in the US, and 738 employees from 20 organizations in Italy. A multi-group confirmatory factor analytic approach was used to assess the equivalence of the measures across the two countries. Similarly, the structural model of relations among the NGH variables was examined in order to demonstrate its cross-country invariance. Results substantially support strict invariance across groups for the NGH safety scales. Moreover, the invariance across countries is also demonstrated for the effects of safety climate on safety knowledge and motivation, which in turn positively relate to both compliance and participation. Our findings have relevant theoretical implications by establishing measurement and relational equivalence of the NGH model. Practical implications are discussed for managers and practitioners dealing with multi-national organizational contexts. Future research should continue to investigate potential differences in safety related perceptions across additional non-English speaking countries.  ",0
5762,25697899,Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo,"Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor perifosine and the MEK\ERK inhibitor MEK-162 synergistically induced lung cancer cell (A549 and H460 lines) growth inhibition and apoptosis. The combined efficiency was significantly higher than either agent alone. For the molecular study, perifosine and MEK-162 worked together to concurrently block AKT, mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and MEK-ERK signalings in lung cancer cells, while either agent alone only affected one or two signalings with lower efficiency. In vivo, MEK-162 and perifosine co-administration dramatically inhibited A549 lung cancer xenograft growth, without inducing apparent toxicities. The synergistic activity in vivo was again superior than either agent alone. Thus, perifosine and MEK-162 combination is biologically plausible by acting through effects on different proliferation and survival-related signaling pathways. Our in vitro and in vivo results support the feasibility of investigating the synergism regimen in clinical tests.  ",0
5763,25698615,"Senkyunolide I protects rat brain against focal cerebral ischemia-reperfusion injury by up-regulating p-Erk1/2, Nrf2/HO-1 and inhibiting caspase 3","Oxidative damage and apoptosis are critical factors contributing to neuronal death during a stroke. The aim of the present study was to evaluate the neuroprotective effects of senkyunolide I (SEI) on focal cerebral ischemia-reperfusion (I/R) injury in rats, and investigate the underlying mechanisms. Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) for 2h, followed by 24h reperfusion, and then randomly assigned into four groups: Sham (sham-operated), Vehicle (tMCAO +normal saline), SEI-L (tMCAO +SEI 36 mg/kg) and SEI-H (tMCAO +SEI 72 mg/kg) groups. SEI was administered intravenously, 15 min after occlusion. Neurological deficit, brain edema and infarct volume were detected after 24h of reperfusion. Histological structures of cortices and hippocampus were observed by hematoxylin and eosin staining. Biochemical indexes in the cortex were assayed by colorimetry. The impact of SEI on the Nrf2-ARE-interaction was assayed using a luciferase reporter gene. Western blotting was performed to analysis the expressions of proteins related to anti-oxidation and apoptosis. SEI administration significantly ameliorated the neurological deficit, reduced the infarct volume and brain edema, reversed the cerebral morphologic damage, decreased the levels of MDA and increased the activities of superoxide dismutase. Furthermore, the high dose SEI could significantly activate the Nrf2/ARE pathway by up-regulating the phosphorylation of Erk1/2 and inducing Nrf2 nuclear translocation with enhanced HO-1 and NQO1 expressions. Additionally, treatment with SEI remarkably promoted the ratio of Bcl-2/Bax and inhibited the expressions of cleaved caspase 3 and caspase 9. These results suggest that the neuroprotective mechanisms of SEI are associated with its anti-oxidation and anti-apoptosis properties. ",0
5764,25698658,Risk factors and clinical outcomes of candidaemia in patients treated for Clostridium difficile infection,The alterations occurring in the intestinal flora during Clostridium difficile infection (CDI) may promote the translocation of Candida to the blood and the development of candidaemia. The aim of our study was to analyse clinical findings of these patients to determine the risk factors associated with the development of candidaemia subsequent to CDI. We compared 35 patients with candidaemia subsequent to CDI with 105 patients with CDI. Patients with candidaemia showed more severe infections and higher mortality. The ribotype 027 strain and vancomycin treatment at ≥ 1000 mg/day were prevalent in patients developing candidaemia. CDI may predispose to the translocation of Candida. ,0
5765,25699030,Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens,"Biological disease models can be difficult and costly to develop and use on a routine basis. Particularly, in vivo lung infection models performed to study lung pathologies use to be laborious, demand a great time and commonly are associated with ethical issues. When infections in experimental animals are used, they need to be refined, defined, and validated for their intended purpose. Therefore, alternative and easy to handle models of experimental infections are still needed to test the virulence of bacterial lung pathogens. Because non-mammalian models have less ethical and cost constraints as a subjects for experimentation, in some cases would be appropriated to include these models as valuable tools to explore host-pathogen interactions. Numerous scientific data have been argued to the more extensive use of several kinds of alternative models, such as, the vertebrate zebrafish (Danio rerio), and non-vertebrate insects and nematodes (e.g., Caenorhabditis elegans) in the study of diverse infectious agents that affect humans. Here, we review the use of these vertebrate and non-vertebrate models in the study of bacterial agents, which are considered the principal causes of lung injury. Curiously none of these animals have a respiratory system as in air-breathing vertebrates, where respiration takes place in lungs. Despite this fact, with the present review we sought to provide elements in favor of the use of these alternative animal models of infection to reveal the molecular signatures of host-pathogen interactions.  ",0
5766,25699474,Nicotinic acetylcholine receptors (nAChR) are increased in the pre-eclamptic placenta,"The role of the nicotinic acetylcholine receptors (nAChR) in pre-eclampsia is unknown. Given that ACh levels are affected in pre-eclampsia, it has been suggested that compensatory changes in nAChR expression may ensue. This study aimed to determine the effects of pre-eclampsia on the mRNA and protein expression of 12 mammalian nAChR subunits. Placentas were collected from healthy term pregnancies (n = 8) and pregnancies complicated by pre-eclampsia (n = 7), both being non-cigarette smoke exposed to rule out any role of nicotine. Using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR), 12 subunits (α2, α3, α4, α5, α6, α7, α9, β1, β2, β4, δ, and γ) were able to be studied at the mRNA level, while at the protein level using Western blotting, nine subunits (α2, α3, α4, α5, α7, α9, β1, β2, and γ) were studied. At the mRNA level, pre-eclamptic placentas showed an increase in α2 (p = 0.003), α9 (p < 0.001), β1 (p = 0.03) and β2 (p = 0.02) subunit expression, while at the protein level, α7 (p = 0.004), α9 (p = 0.02), and δ (p = 0.003) subunits were increased compared to controls. Certain nAChR subunits are increased in the pre-eclamptic placenta. Given the absence of cigarette smoking, the changes in expression are hypothesised to be due to the hypoxic environment resulting from the pathophysiology of pre-eclampsia, which subsequently affects endogenous ACh levels, yielding compensatory increases in α2, α7, α9, β1, β2, and δ nAChR subunits. ",0
5767,25699645,Investigation of the photochemical changes of chlorogenic acids induced by ultraviolet light in model systems and in agricultural practice with Stevia rebaudiana cultivation as an example,"Mono- and diacyl chlorogenic acids undergo photochemical trans-cis isomerization under ultraviolet (UV) irradiation. The photochemical equilibrium composition was established for eight selected derivatives. In contrast to all other dicaffeoylquinic acid derivatives, cynarin (1,3-dicaffeoylquinic acid) undergoes a [2 + 2] photochemical cycloaddition reaction, constituting a first example of Schmidt's law in a natural product family. The relevance of photochemical isomerization in agricultural practice was investigated using 120 samples of Stevia rebaudiana leave samples grown under defined cultivation conditions. Ratios of cis to trans chlorogenic acids were determined in leaf samples and correlated with climatic and harvesting conditions. The data indicate a clear correlation between the formation of cis-caffeoyl derivatives and sunshine hours prior to harvesting and illustrate the relevance of UV exposure to plant material affecting its phytochemical composition.  ",0
5768,25700640,Low rate of Propionibacterium acnes in arthritic shoulders undergoing primary total shoulder replacement surgery using a strict specimen collection technique,"Propionibacterium acnes is a recognized pathogen in postoperative shoulder infections. A recent study reported growth of P acnes in 42% of glenohumeral joints in primary shoulder arthroplasty, concluding that P acnes may cause shoulder osteoarthritis. Whether these results reflect true bacterial infection or specimen contamination is unclear. Our prospective study aimed to determine the rate of P acnes infection in arthritic shoulders using a strict specimen collection technique. We used modified Oxford protocol to collect tissue specimens from the glenohumeral joint of 32 consecutive patients undergoing primary shoulder arthroplasty. Specimens were cultured specifically for P acnes. Diagnosis of P acnes infection required 2 or more positive cultures and histopathology compatible with infection. Three of 32 patients had a positive culture for P acnes. Overall, 3.125% of specimens grew P acnes without histologic evidence of infection. There were no patients with P acnes infection. The difference in culture rates between patients with idiopathic osteoarthritis and those with a predisposing cause for osteoarthritis was not significant. We found a low rate of positive cultures for P acnes, but no P acnes infection and no difference between types of osteoarthritis. These results do not support a cause-and-effect relationship between P acnes and osteoarthritis. The differing results from previous studies are likely explained by our strict specimen collection technique, reflecting different rates of contamination rather than infection. That P acnes contamination occurs in primary shoulder arthroplasty is concerning. Further studies are needed to assess the rates of contamination in shoulder surgery, its clinical effect, and to determine optimal antibiotic prophylaxis. ",0
5769,25700658,Barbed suture in minimally invasive hysterectomy: a systematic review and meta-analysis,"Total laparoscopic or robotic hysterectomy represents one of the most performed gynecological procedures nowadays. Minimally invasive procedures seem to increase the risk of vaginal cuff dehiscence (VCD). Barbed suture is a new class of suture introduced to aid surgeons during laparoscopic suturing, with the aim to reduce operative time, blood loss, and vaginal dehiscence. We identified all articles that report a series of laparoscopic or robotic-assisted hysterectomy using barbed suture compared to conventional suture for vaginal cuff closure. The main outcome measures were vaginal cuff suturing time, vaginal bleeding, and vaginal dehiscence with or without small bowel evisceration. Suturing time was meta-analyzed as the standardized mean difference, which is the difference in means of two arms divided by pooled standard deviation with 95 % confidence intervals. For vaginal bleeding and dehiscence risk difference were calculated for each study and then meta-analyzed. Fixed models were considered if heterogeneity was low (I (2) < 50 %), otherwise random models were preferred. We show that minor bleeding (RD = 0, 95 % CI 0.03-0.03; p value = 0.907) and VCD (RD = -0.01, 95 % CI 0.02-0.00; p value = 0.119) are comparable in minimally invasive hysterectomy with or without the use of barbed suture. The major bleeding (RD = -0.03; 95 % CI 0.05-0.00; p value = 0.047) appears borderline significant, but the difference between the two types of sutures is not high and the upper limit of 95 % IC is equal to 0 so they were considered comparable. Instead, meta-analysis on vaginal cuff suturing time demonstrates that suturing time is reduced with the use of barbed suture (SMD = -0.96, 95 % CI 1.26-0.70; p value <0.001). Barbed suture is safe and well tolerated as traditional sutures and is associated with reduced operative time of laparoscopic vaginal vault closure. ",0
5770,25700885,Large-scale crystallization of proteins for purification and formulation,"Since about 170 years, salts were used to create supersaturated solutions and crystallize proteins. The dehydrating effect of salts as well as their kosmotropic or chaotropic character was revealed. Even the suitability of organic solvents for crystallization was already recognized. Interestingly, what was performed during the early times is still practiced today. A lot of effort was put into understanding the underlying physico-chemical interaction mechanisms leading to protein crystallization. However, it was understood that already the solvation of proteins is a highly complex process not to mention the intricate interrelation of electrostatic and hydrophobic interactions taking place. Although many basic questions are still unanswered, preparative protein crystallization was attempted as illustrated in the presented case studies. Due to the highly variable nature of crystallization, individual design of the crystallization process is needed in every single case. It was shown that preparative crystallization from impure protein solutions as a capture step is possible after applying adequate pre-treatment procedures like precipitation or extraction. Protein crystallization can replace one or more chromatography steps. It was further shown that crystallization can serve as an attractive alternative means for formulation of therapeutic proteins. Crystalline proteins can offer enhanced purity and enable highly concentrated doses of the active ingredient. Easy scalability of the proposed protein crystallization processes was shown using the maximum local energy dissipation as a suitable scale-up criterion. Molecular modeling and target-oriented protein engineering may allow protein crystallization to become part of a platform purification process in the near future.  ",0
5771,25701178,Pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes,"Clostridium difficile infection remains a major healthcare burden. Until the recent introduction of fidaxomicin, antimicrobial treatments were limited to metronidazole and vancomycin. The emergence of epidemic C. difficile PCR ribotype 027 and its potential link to decreased antibiotic susceptibility highlight the lack of large-scale antimicrobial susceptibility and epidemiological data available. We report results of epidemiological and antimicrobial susceptibility investigations of C. difficile isolates collected prior to fidaxomicin introduction, establishing important baseline data. Thirty-nine sites in 22 countries submitted a total of 953 C. difficile isolates for PCR ribotyping, toxin testing, and susceptibility testing to metronidazole, vancomycin, fidaxomicin, rifampicin, moxifloxacin, clindamycin, imipenem, chloramphenicol, and tigecycline. Ninety-nine known ribotypes were identified. Ribotypes 027, 014, 001/072, and 078 were most frequently isolated in line with previous European studies. There was no evidence of resistance to fidaxomicin, and reduced susceptibility to metronidazole and vancomycin was also scarce. Rifampicin, moxifloxacin, and clindamycin resistance (13%, 40%, and 50% of total isolates, respectively) were evident in multiple ribotypes. There was a significant correlation between lack of ribotype diversity and greater antimicrobial resistance (measured by cumulative resistance score). Well-known epidemic ribotypes 027 and 001/072 were associated with multiple antimicrobial resistance, but high levels of resistance were also observed, particularly in 018 and closely related emergent ribotype 356 in Italy. This raises the possibility of antimicrobial exposure as the underlying reason for their appearance, and highlights the need for ongoing epidemiological and antimicrobial resistance surveillance. ",0
5772,25701201,The Primary Obesity Surgery Endolumenal (POSE) procedure: one-year patient weight loss and safety outcomes,"Obesity is at epidemic proportions and increasing. Bariatric surgical procedures have demonstrated better durable weight loss than diet and exercise; however, risk may limit adoption of these procedures. Endoscopic procedures may offer less risk, lower cost, and satisfactory results, but limited safety and outcome data is available. The present report describes the Primary Obesity Surgery Endolumenal (POSE(™)) procedure, perioperative care, and 1-year safety and weight loss outcomes for a single center. One hundred forty-seven patients undergoing the POSE procedure between July 2011 and January 2013 were followed for 1 year. Overall patient status and weight data were collected at baseline and at 3, 6, and 12 months. Outcomes included change in total weight loss (TWL), percentage of TWL (%TWL), percentage of excess weight loss (%EWL), and adverse events. Patients tolerated the procedure well with no serious short-term or long-term adverse events. All but 1 patient were discharged within 24 hours of the procedure. Baseline body mass index (BMI) was 38.0 ± 4.8 kg/m(2). Initial weight (106.8 ± 18.2 kg) was significantly reduced at 3, 6, and 12 months. At 1 year, 116 patients (79% of total) who were available for follow-up had a mean TWL of 16.6 ± 9.7 kg, %TWL of 15.1 ± 7.8, and %EWL of 44.9 ± 24.4. After 1-year follow-up, POSE was considered an effective, safe and well tolerated procedure for the treatment of patients with obesity. ",0
5773,25701255,Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis,"The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo. ",0
5774,25701344,Energy restriction does not prevent insulin resistance but does prevent liver steatosis in aging rats on a Western-style diet,"The aim of this study was to evaluate the effects of long-term energy restriction (ER) on plasma, liver, and skeletal muscle metabolite profiles in aging rats fed a Western-style diet. Three groups of male Sprague-Dawley rats were studied. Group 1 consisted of 2 mo old rats fed ad libitum; group 2 were 19 mo old rats also fed ad libitum; and group 3 were 19 mo old rats subjected to 40% ER for the last 11.5 mo. To imitate a Western-style diet, all rats were given a high-sucrose, very low ω-3 polyunsaturated fatty acid (PUFA) diet. High-resolution magic angle spinning-(1)H nuclear magnetic resonance spectroscopy was used for hepatic and skeletal muscle metabolite determination, and fatty acid profiles were measured by capillary gas chromatography on plasma, liver, and skeletal muscle. ER coupled with a Western-style diet did not prevent age-induced insulin resistance or the increase in triacylglycerol content in plasma and skeletal muscle associated with aging. However, in the liver, ER did prevent steatosis and increased the percent of saturated and monounsaturated fatty acids relative to ω-6 and ω-3 PUFA. Although steatosis was reduced, the beneficial effects of ER on systemic insulin resistance and plasma and skeletal muscle metabolites observed elsewhere with a balanced diet seem to be compromised by high-sucrose and low ω-3 PUFA intake. ",0
5775,25701454,"Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma","In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor. ",0
5776,25701632,Large-scale manufacturing of GMP-compliant anti-EGFR targeted nanocarriers: production of doxorubicin-loaded anti-EGFR-immunoliposomes for a first-in-man clinical trial,"We describe the large-scale, GMP-compliant production process of doxorubicin-loaded and anti-EGFR-coated immunoliposomes (anti-EGFR-ILs-dox) used in a first-in-man, dose escalation clinical trial. 10 batches of this nanoparticle have been produced in clean room facilities. Stability data from the pre-GMP and the GMP batch indicate that the anti-EGFR-ILs-dox nanoparticle was stable for at least 18 months after release. Release criteria included visual inspection, sterility testing, as well as measurements of pH (pH 5.0-7.0), doxorubicin HCl concentration (0.45-0.55 mg/ml), endotoxin concentration (<1.21 IU/ml), leakage (<10%), particle size (Z-average of Caelyx ± 20 nm), and particle uptake (uptake absolute: >0.50 ng doxorubicin/μg protein; uptake relatively to PLD: >5 fold). All batches fulfilled the defined release criteria, indicating a high reproducibility as well as batch-to-batch uniformity of the main physico-chemical features of the nanoparticles in the setting of the large-scale GMP process. In the clinical trial, 29 patients were treated with this nanoparticle between 2007 and 2010. Pharmacokinetic data of anti-EGFR-ILs-dox collected during the clinical study revealed stability of the nanocarrier in vivo. Thus, reliable and GMP-compliant production of anti-EGFR-targeted nanoparticles for clinical application is feasible. ",0
5777,25701725,Erythroid differentiation ability of butyric acid analogues: identification of basal chemical structures of new inducers of foetal haemoglobin,"Several investigations have demonstrated a mild clinical status in patients with β-globin disorders and congenital high persistence of foetal haemoglobin. This can be mimicked by a pharmacological increase of foetal γ-globin genes expression and foetal haemoglobin production. Our goal was to apply a multistep assay including few screening methods (benzidine staining, RT-PCR and HPLC analyses) and erythroid cellular model systems (the K562 cell line and erythroid precursors collected from peripheral blood) to select erythroid differentiation agents with foetal haemoglobin inducing potential. With this methodology, we have identified a butyric acid derivative, namely the 4174 cyclopropanecarboxylic acid compound, able to induce erythroid differentiation without antiproliferative effect in K562 cells and increase of γ-globin gene expression in erythroid precursor cells. The results are relevant for pharmacological treatments of haemoglobinopathies, including β-thalassaemia and sickle cell anaemia.  ",0
5778,25701764,"Preclinical studies on the pharmacokinetics, safety, and toxicology of oxfendazole: toward first in human studies","A 2-week study in rats identified target organs of oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.  ",0
5779,25702190,Reduction in posterior semicircular canal gain by age in video head impulse testing. Observational study,"and objectives: In-depth assessment of the vestibulo-ocular reflex with the new video systems available provides information on various previously-unidentified characteristics in patients with peripheral vestibular disorder. The aim of this work is to quantify how often pathological gain (uni- or bilateral) in the posterior semicircular canal (PSC) gain appears in video head-impulse testing (vHIT) with preservation of the gain in the rest of the semicircular canals, and to analyse the relation of this frequency with patient age and/or diagnosis. This was a prospective observational study on adults referred to our unit between June 2012 and February 2014. Age, sex, pathological antecedents, prior history of vestibular pathology, diagnosis and time of evolution of the clinical picture and its characteristics were recorded. Each patient underwent a complete otoneurological examination, including vHIT (Otometrics®). Depending on suspected diagnosis, patients also received cervical vestibular evoked myogenic potential (VEMP) testing, tonal audiometry and speech test, as well as assessment by Neurology and/or nuclear magnetic resonance or computed axial tomography scan imaging study. In all, 363 patients were assessed; 57 (16%) patients (33 males and 24 females; mean age, 57 ± 15 years) showed pathological PSC gains, 46 (81%) unilateral and 11 (19%) bilateral. Ménière's Disease was the most frequent diagnosis, followed by benign paroxysmal positional vertigo (27%). Patients with unilateral involvement were younger than those with bilateral (55 vs. 68 years; p=0.03). In the patients with bilateral involvement, PSC gain and age were related (-0.7; 0.04) and the gain value was symmetrical in both ears (0.7; p=0.05). The gain in the anterior and horizontal canals tended to decrease with age, but without statistical significance in our sample. Of the patients referred for an otoneurological consultation, 16% showed pathological PSC gain (unilateral in 81% and bilateral in 19% of the cases). This gain involvement was attributable to age when the gain was bilateral and symmetrical. ",0
5780,25702364,Neurocognitive functioning in overweight and obese patients with bipolar disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM),"Obesity is frequent in people with bipolar I disorder (BD I) and has a major impact on the course of the illness. Although obesity negatively influences cognitive function in patients with BD, its impact in the early phase of the disorder is unknown. We investigated the impact of overweight and obesity on cognitive functioning in clinically stable patients with BD recently recovered from their first manic episode. Sixty-five patients with BD (25 overweight or obese and 40 normal weight) recently remitted from a first episode of mania and 37 age- and sex-matched healthy control. subjects (9 overweight or obese and 28 normal weight) were included in this analysis from the Systematic Treatment Optimization Program for Early Mania (commonly referred to as STOP-EM). All subjects had their cognitive function assessed using a standard neurocognitive battery. We compared cognitive function between normal weight patients, overweight-obese patients, and normal weight healthy control subjects. There was a negative affect of BD diagnosis on the domains of attention, verbal memory, nonverbal memory, working memory, and executive function, but we were unable to find an additional effect of weight on cognitive functioning in patients. There was a trend for a negative correlation between body mass index and nonverbal memory in the patient group. These data suggest that overweight-obesity does not negatively influence cognitive function early in the course of BD. Given that there is evidence for a negative impact of obesity later in the course of illness, there may be an opportunity to address obesity early in the course of BD. ",0
5781,25702379,Bone deformities and skeletal malformations in the Roman Imperial Age,"""This paper describes some cases of individuals affected by skeletal deformities resulting in """"freak"""" appearance. The skeletal remains were found during large archaeological excavations in the Roman territory, carried out by the Special Superintendence to the Archeological Heritage of Rome in the last years, dated back to the Imperial Age. The first cases reported are referred to two growth disorders with opposite effects: a case of dwarfism and another of gigantism. The former concerns a young man from the Collatina necropolis with very short and malformed limbs, which allowed a diagnosis of acondroplasic dwarfism, a rare congenital disorder that limits height below 130 cm. The latter case comes from the necropolis of Torre Serpentana in Fidenae, and is instead referred to a young person of very high stature, about 204 cm, suffering from Gigantism, a rare condition which in this case seems to have been linked to a hormonal dysfunction due to a pituitary adenoma. A third case regards a joint disease affecting the vertebral column and causing severe deformities. The skeleton was found in the Collatina necropolis and belongs to an old woman, suffering from ankylosing spondylitis. Finally, the last and very peculiar case is related to an individual recovered in the necropolis of Castel Malnome. The skeletal remains belong to an adult man with a complete fusion of the temporo-mandibular joint, which compromised mastication and caused severe deformation of the maxillofacial complex. These cases are described in detail together with the possible implications that these deformities could have on in the social context. """,0
5782,25702521,A small multifunctional pentatricopeptide repeat protein in the chloroplast of Chlamydomonas reinhardtii,"Organellar biogenesis is mainly regulated by nucleus-encoded factors, which act on various steps of gene expression including RNA editing, processing, splicing, stabilization, and translation initiation. Among these regulatory factors, pentatricopeptide repeat (PPR) proteins form the largest family of RNA binding proteins, with hundreds of members in flowering plants. In striking contrast, the genome of the unicellular green alga Chlamydomonas reinhardtii encodes only 14 such proteins. In this study, we analyzed PPR7, the smallest and most highly expressed PPR protein in C. reinhardtii. Green fluorescent protein-based localization and gel-filtration analysis revealed that PPR7 forms a part of a high-molecular-weight ribonucleoprotein complex in the chloroplast stroma. RIP-chip analysis of PPR7-bound RNAs demonstrated that the protein associates with a diverse set of chloroplast transcripts in vivo, i.e. rrnS, psbH, rpoC2, rbcL, atpA, cemA-atpH, tscA, and atpI-psaJ. Furthermore, the investigation of PPR7 RNAi strains revealed that depletion of PPR7 results in a light-sensitive phenotype, accompanied by altered levels of its target RNAs that are compatible with the defects in their maturation or stabilization. PPR7 is thus an unusual type of small multifunctional PPR protein, which interacts, probably in conjunction with other RNA binding proteins, with numerous target RNAs to promote a variety of post-transcriptional events.  ",0
5783,25702584,A new method of surgical margin assuring for abdominal radical trachelectomy in frozen section,"The aim of this study was to introduce a new method of assuring surgical margins for abdominal radical trachelectomy (ART) and report our experience using the method. We combined transverse and perpendicular sections to assess surgical margins of specimens from RT. All surgeries from 1st August 2012 to 1st October 2013 were performed by one surgeon. The frozen section (FS) was consistently performed by a group of gynaecologic pathologists according to the detailed protocol described in this article. All cases were prepared by the same pathologist, and the slides were reviewed by two pathologists. There were 53 patients treated using the new method in our institution. The patient ages ranged from 20 to 41 years old (median 32). The surgeries were performed for clinical stage IA (n = 11) with LVSI and IB (n = 42) tumours (40 squamous cell carcinoma, 11 adenocarcinoma, two adenosquamous and two others). In 20 (37.74%) cases, no residual tumour of the ART specimen on frozen section was observed in the specimens as it was cleared by the preceding loop electrical excision procedure (LEEP) or conization. The margins were initially reported as negative in 45 cases and positive in nine cases. In those nine cases, a second slice of cervix was removed and negative in six cases and positive again in two cases, the other one with positive nodes. The results of frozen sections were concordant with the final paraffin-embedded sections. There were no false negative intraoperative assessments. There were no recurrences after a median follow-up of 15.4 months (range, 6-21 months). Combining transverse and perpendicular sections to assess surgical margins of specimens from RT makes the protocol simple, reliable and produces accurate results. ",0
5784,25702985,Determination of hexanal and heptanal in human urine using magnetic solid phase extraction coupled with in-situ derivatization by high performance liquid chromatography,"In this study, magnetic solid phase extraction coupled with in-situ derivatization (MSPE-ISD) was established for the determination of hexanal and heptanal in human urine. 2,4-Dinitrophenylhydrazine (DNPH) was used as the derivatization reagent that was adsorbed onto the surface of magnetite/silica/poly(methacrylic acid-co-ethylene glycol dimethacrylate) (Fe3O4/SiO2/P(MAA-co-EGDMA)). And then simultaneous extraction and derivatization of the aldehydes were performed on the DNPH-adsorbed Fe3O4/SiO2/P(MAA-co-EGDMA). The simple, rapid and sensitive determination of hexanal and heptanal can be accomplished within 9min. Under optimized conditions, the limits of detection (LODs) were 1.7 and 2.5nmol/L for hexanal and heptanal, respectively. The relative recoveries ranged from 72.8% to 91.4% with the intra- and inter-day relative standard deviations (RSDs) being less than 9.6%. Furthermore, the proposed method was successfully applied to determine endogenous hexanal and heptanal in human urine from healthy persons and lung cancer patients. The results showed the higher concentrations of hexanal and heptanal were observed in lung cancer patients compared to healthy controls. Thus, the developed MSPE-ISD method is suitable for the determination of aldehydes in urines.  ",0
5785,25703282,A survey of interprofessional activity of acute and long-term care employed nurse practitioners,"To describe activities of interprofessional (IP) care, a key aspect of high-quality care, performed by nurse practitioners (NPs) employed in acute and long-term care institutions. We developed and tested a new theory-driven process tool to quantify NP everyday activities of IP care. We then invited NPs in acute and long-term care to complete the IP self-assessment tool (IPSAT). The IPSAT is a validated tool shown to be reliable for use with NPs. Testing with other healthcare professionals is suggested. More than 50% of NPs engage in all activities of IP care. Many engage in shared decision making, professional relationship, communication, and partnership or collaboration activities on most work days. Less-common activities were interdependence and collective problem solving including efforts to create role clarity. It is important to evaluate the everyday use of activities that enhance high-quality care. Awareness and enhanced knowledge of IP care activities such as promoting interdependence, collective problem solving, and ensuring role clarity will improve care quality. The tool results are valuable for practicing NPs and their educators to reflect on practice and advance knowledge to influence purposeful engagement in interprofessional care. ",0
5786,25703360,A diagnostic study on folium and orchil dyes with non-invasive and micro-destructive methods,"Folium and orchil are dyes of vegetal origin. Folium is obtained from Chrozophora tinctoria (L.) A. Juss., whereas orchil is obtained from Roccella and other genera of lichens. These dyes were used in the past to impart purple hue to paintings and textiles as substitutes for the more prised Tyrian purple dye, obtained from shellfish. Despite several citations in ancient technical treatises dating back at least to the Greek-Roman age, the identification of these dyes in artworks is rare. In the case of folium, an additional drawback is that its composition is presently unknown. In this work different non-invasive (FT-IR, FT-Raman, fibre optic reflectance spectrophotometry, spectrofluorimetry, X-ray fluorescence spectrometry) and micro-invasive (surface enhanced Raman spectroscopy, matrix assisted laser desorption ionisation-time of flight-mass spectrometry, inductively coupled plasma-mass spectrometry) techniques were used in order to increase the diagnostic information available on these dyes. Measurements were carried out on the dyes extracted from raw materials and on painted or dyed parchments. The possibility to distinguish between folium and orchil by chemical analysis is discussed.  ",0
5787,25703536,Mannitol induces selective astroglial death in the CA1 region of the rat hippocampus following status epilepticus,"In the present study, we addressed the question of whether treatment with mannitol, an osmotic diuretic, affects astrogliovascular responses to status epilepticus (SE). In saline-treated animals, astrocytes exhibited reactive astrogliosis in the CA1-3 regions 2-4 days after SE. In the mannitol-treated animals, a large astroglial empty zone was observed in the CA1 region 2 days after SE. This astroglial loss was unrelated to vasogenic edema formation. There was no difference in SE-induced neuronal loss between saline- and mannitol-treated animals. Furthermore, mannitol treatment did not affect astroglial loss and vasogenic edema formation in the dentate gyrus and the piriform cortex. These findings suggest that mannitol treatment induces selective astroglial loss in the CA1 region independent of vasogenic edema formation following SE. These findings support the hypothesis that the susceptibility of astrocytes to SE is most likely due to the distinctive heterogeneity of astrocytes independent of hemodynamics. ",0
5788,25703620,The relationship between neuropsychological functioning and FDG-PET hypometabolism in intractable mesial temporal lobe epilepsy,"We examined the relationship between baseline neuropsychological functioning and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in intractable mesial temporal lobe epilepsy (MTLE). We hypothesized relationships between dominant temporal lobe hypometabolism and verbal memory and between nondominant temporal lobe hypometabolism and nonverbal memory in line with the lateralized material-specific model of memory deficits in MTLE. We also hypothesized an association between performance on frontal lobe neuropsychological tests and prefrontal hypometabolism. Thirty-two patients who had undergone temporal lobectomy for treatment of MTLE and who completed both presurgical FDG-PET and comprehensive neuropsychological investigations with widely used standardized measures were included. Age-adjusted composite measures were calculated for verbal memory, nonverbal memory, relative material-specific memory, IQ, executive function, attention/working memory, and psychomotor speed. Fluorodeoxyglucose positron emission tomography was analyzed with statistical parametric mapping (SPM) to identify hypometabolism relative to healthy controls. Pearson's correlation was used to determine the relationship between regions of hypometabolism and neuropsychological functioning. Dominant temporal lobe hypometabolism was associated with relatively inferior verbal memory, while nondominant temporal lobe hypometabolism was associated with inferior nonverbal memory. No relationship was found between performance on any frontal lobe measures and prefrontal hypometabolism. Statistical parametric mapping-quantified lateralized temporal lobe hypometabolism correlates with material-specific episodic memory impairment in MTLE. In contrast, prefrontal hypometabolism is not associated with performance on frontal lobe measures. We suggest that this is because frontal lobe neuropsychology tests may not be good measures of isolated frontal lobe functioning.  ",0
5789,25703669,The impact of recent chemotherapy innovation on the longevity of myeloma patients: US and international evidence,"The longevity of multiple myeloma patients increased sharply since the late 1990s. This increase coincided with the introduction of several important innovations in chemotherapy for myeloma. In this study, we aim to quantify the impact of recent chemotherapy innovation on the longevity of myeloma patients using both time-series US data and longitudinal data on 38 countries. We estimate that almost two-thirds (0.99 years) of the 1997-2005 increase in the life expectancy of American myeloma patients was due to an increase in the number of chemotherapy regimens now preferred by specialists. Based on a back-of-the-envelope calculation, this means that the cost per US life-year gained from post-1997 chemotherapy innovation is unlikely to have exceeded $46,000. We also investigate the impact of chemotherapy innovation on the myeloma mortality rate using longitudinal country-level data on 38 countries during the period 2002-2012. Countries that had larger increases in the number of chemotherapy regimens now preferred by specialists had larger subsequent declines in myeloma mortality rates, controlling for myeloma incidence. The (marginal) effect on the mortality rate of one additional preferred chemotherapy regimen is similar in other countries to its effect in the US. Non-US prices of two of the three new drugs were lower than US prices, so recent myeloma chemotherapy innovation may have been more cost-effective in other countries than it was in the US. Recent chemotherapy innovation has had a significant positive impact on the longevity of myeloma patients in the countries in which the drugs have been available.  ",0
5790,25703812,Stem cells from foetal adnexa and fluid in domestic animals: an update on their features and clinical application,"Over the past decade, stem cell research has emerged as an area of major interest for its potential in regenerative medicine applications. This is in constant need of new cell sources to conceive regenerative medicine approaches for diseases that are still without therapy. Scientists drew the attention towards alternative sources such as foetal adnexa and fluid, as these sources possess many advantages: first of all, cells can be extracted from discarded foetal material and it is non-invasive and inexpensive for the patient; secondly, abundant stem cells can be obtained; and finally, these stem cell sources are free from ethical considerations. Cells derived from foetal adnexa and fluid preserve some of the characteristics of the primitive embryonic layers from which they originate. Many studies have demonstrated the differentiation potential in vitro and in vivo towards mesenchymal and non-mesenchymal cell types; in addition, the immune-modulatory properties make these cells a good candidate for allo- and xenotransplantation. Naturally occurring diseases in domestic animals can be more ideal as disease model of human genetic and acquired diseases and could help to define the potential therapeutic use efficiency and safety of stem cells therapies. This review offers an update on the state of the art of characterization of domestic animals' MSCs derived from foetal adnexa and fluid and on the latest findings in pre-clinical or clinical setting of the stem cell populations isolated from these sources.  ",0
5791,25704405,Gas induction for pyloromyotomy,"Infants with pyloric stenosis are considered to be at high risk of aspiration on induction of anesthesia. Traditionally, texts have recommended classic rapid sequence induction (RSI) or awake intubation (AI). AI has generally fallen out of favor, while the components of RSI have become increasingly controversial. Infants are at high risk of hypoxemia if ventilation is not maintained while waiting for neuromuscular blockade to establish. The efficacy of cricoid pressure (CP) to prevent aspiration has not been proven. It can impair visualization of the glottis and make intubation difficult. It is debatable whether any RSI technique is needed for pyloromyotomy. A recent review of 235 infants reported no aspiration events. These children were anesthetized with a variety of techniques, including RSI, gas induction, and AI. In our institution, we teach a gaseous induction. The nasogastric tube is used to empty the stomach and anesthesia is induced with sevoflurane. A nondepolarizing muscle relaxant is administered and ventilation maintained until neuromuscular blockade is established and intubating conditions are optimal. We report our experience of this technique. A retrospective medical notes review of all patients undergoing pyloromyotomy between 2005 and 2012. There were 269 patients (84.4% male, mean weight 3.74 kg ± 0.74). Two hundred and fifty-two (93.7%) received gas inductions and 17 (6.3%) intravenous (IV) inductions. Two children received an RSI. No patient-specific factors were identified to explain operator choice in those receiving IV inductions. There were no recorded aspiration events. Gas induction can be considered for children undergoing pyloromyotomy. ",0
5792,25704433,Enhanced removal of Zn(2+) or Cd(2+) by the flocculating Chlorella vulgaris JSC-7,"Microalgae are attracting attention due to their potentials in mitigating CO2 emissions and removing environmental pollutants. However, harvesting microalgal biomass from diluted cultures is one of the bottlenecks for developing economically viable processes for this purpose. Microalgal cells can be harvested by cost-effective sedimentation when flocculating strains are used. In this study, the removal of Zn(2+) and Cd(2+) by the flocculating Chlorella vulgaris JSC-7 was studied. The experimental results indicated that more than 80% Zn(2+) and 60% Cd(2+) were removed by the microalgal culture within 3 days in the presence up to 20.0mg/L Zn(2+) and 4.0mg/L Cd(2+), respectively, which were much higher than that observed with the culture of the non-flocculating C. vulgaris CNW11. Furthermore, the mechanism underlying this phenomenon was explored by investigating the effect of Zn(2+) and Cd(2+) on the growth and metabolic activities of the microalgal strains. It was found that the flocculation of the microalga improved its growth, synthesis of photosynthetic pigments and antioxidation activity under the stressful conditions, indicating a better tolerance to the heavy metal ions for a potential in removing them more efficiently from contaminated wastewaters, together with a bioremediation of other nutritional components contributed to the eutrophication of aquatic ecosystems.  ",0
5793,25704569,Antimicrobial susceptibility of uropathogens isolated from Cambodian children,"Bacterial resistance to commonly used antimicrobials is an increasing problem in Asia but information concerning the antimicrobial susceptibility of bacteria causing urinary tract infections (UTIs) in children is limited. This was a 5-year retrospective study of children with suspected UTI attending a paediatric hospital in north-west Cambodia. Urines with a positive culture containing a single organism with a count of >10(5) colony-forming units (CFU)/ml were considered diagnostic of infection. The organism was identified and the resistance pattern (using CLSI guidelines) and presence of an extended-spectrum β-lactamase (ESBL) phenotype was determined. In total, there were 217 episodes of infection, 210 (97%) with Gram-negative bacteria. Escherichia coli was the most common infecting isolate with high levels of resistance to most oral antibiotics, except nitrofurantoin. Nearly half of the E. coli (44%) were extended-spectrum cephalosporin (ESC)-resistant with the proportion increasing significantly over the 5-year period. ESC-resistant E. coli were more likely to be multi-drug-resistant and 91% demonstrated an ESBL phenotype. The data highlight the importance of microbiological surveillance of UTIs in children, particularly in areas where there are known to be multiply resistant organisms. ",0
5794,25704829,Gene transcription patterns and energy reserves in Daphnia magna show no nanoparticle specific toxicity when exposed to ZnO and CuO nanoparticles,"There is still a lot of contradiction on whether metal ions are solely responsible for the observed toxicity of ZnO and CuO nanoparticles to aquatic species. While most experiments have studied nanoparticle effects at organismal levels (e.g. mortality, reproduction), effects at lower levels of biological organization may clarify the role of metal ions, nanoparticles and nanoparticle aggregates. In this study, the effect of ZnO and CuO nanoparticles was tested at two lower levels: energy reserves and gene transcription and compared with zinc and copper salts. Daphnia magna was exposed during 96h to 10% immobilization concentrations of all chemicals, after which daphnids were sampled for determination of glycogen, lipid and protein concentration and for a differential gene transcription analysis using microarray. The dissolved, nanoparticle and aggregated fraction in the medium was characterized. The results showed that ZnO nanoparticles had largely dissolved directly after addition to the test medium. The CuO nanoparticles mostly formed aggregates, while only a small fraction dissolved. The exposure to zinc (both nano and metal salt) had no effect on the available energy reserves. However, in the copper exposure, the glycogen, lipid and protein concentration in the exposed daphnids was lower than in the unexposed ones. When comparing the nanoparticle (ZnO or CuO) exposed daphnids to the metal salt (zinc or copper salt) exposed daphnids, the microarray results showed no significantly differentially transcribed gene fragments. The results indicate that under the current exposure conditions the toxicity of ZnO and CuO nanoparticles to D. magna is solely caused by toxic metal ions.  ",0
5795,25705242,Repeated stressors in adulthood increase the rate of biological ageing,"Individuals of the same age can differ substantially in the degree to which they have accumulated tissue damage, akin to bodily wear and tear, from past experiences. This accumulated tissue damage reflects the individual's biological age and may better predict physiological and behavioural performance than the individual's chronological age. However, at present it remains unclear how to reliably assess biological age in individual wild vertebrates. We exposed hand-raised adult Eurasian blackbirds (Turdus merula) to a combination of repeated immune and disturbance stressors for over one year to determine the effects of chronic stress on potential biomarkers of biological ageing including telomere shortening, oxidative stress load, and glucocorticoid hormones. We also assessed general measures of individual condition including body mass and locomotor activity. By the end of the experiment, stress-exposed birds showed greater decreases in telomere lengths. Stress-exposed birds also maintained higher circulating levels of oxidative damage compared with control birds. Other potential biomarkers such as concentrations of antioxidants and glucocorticoid hormone traits showed greater resilience and did not differ significantly between treatment groups. The current data demonstrate that repeated exposure to experimental stressors affects the rate of biological ageing in adult Eurasian blackbirds. Both telomeres and oxidative damage were affected by repeated stress exposure and thus can serve as blood-derived biomarkers of biological ageing. ",0
5796,25705303,Intellectual disability and epilepsy in down syndrome,"Down Syndrome (DS) is the most common genetic cause of mental retardation, with a reported frequency of epilepsy between 1.4-17% (1). There is a paucity of data in the literature regarding epilepsy in Down syndrome and its relation to intellectual disability. The purpose of this article is to analyze the association of epilepsy in children with DS - frequency and type of seizures, treatment, outcome and to compare cognitive impairment of children with DS and epilepsy and DS without epilepsy from our cohort. A four years systematic retrospective analysis of the database of the Pediatric Neurology Clinic (January 2010 - December 2013) identified a cohort of 39 pediatric cases with DS and neurological symptoms, 9 of them (23%) associating epileptic seizures. Following data were analysed: clinical and neurological examination, type/s of seizures, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), psychological examination, psychiatric evaluation in selected cases, electrocardiography (ECG), cardiac ultrasonography, ophthalmologic examination. 23% (9 patients) of the children with DS of our cohort presented epilepsy. Five patients had epileptic spasms (56%), one of these further developed astatic seizures. Focal seizures were observed in three patients (33%) and absence with eyelid myoclonias in one patient (11%). Two of the nine patients with DS and epilepsy had generalized seizures, both with very good response to levetiracetam (LEV). EEG was abnormal at seizure onset, and was improved after treatment. Of the nine children with DS and epilepsy, two (22%) presented mild mental retardation and seven (78%) had moderate to severe cognitive delay. Of the 30 children with DS and without epilepsy, 21 (70%) had mild mental retardation and 9 (30%) had moderate to severe cognitive impairment. The most frequent epileptic syndrome associated with DS is West syndrome, with good response to specific antiepileptics. All children with DS from our cohort have intelectual disability, more severe in those with epilepsy. Slight improvement of intelectual and language capabilities were seen after seizures control. ",0
5797,25705404,"Limitations of global end-diastolic volume index as a parameter of cardiac preload in the early phase of severe sepsis: a subgroup analysis of a multicenter, prospective observational study","In patients with severe sepsis, depression of cardiac performance is common and is often associated with left ventricular (LV) dilatation to maintain stroke volume. Although it is essential to optimize cardiac preload to maintain tissue perfusion in patients with severe sepsis, the optimal preload remains unknown. This study aimed to evaluate the reliability of global end-diastolic volume index (GEDI) as a parameter of cardiac preload in the early phase of severe sepsis. Ninety-three mechanically ventilated patients with acute lung injury/acute respiratory distress syndrome secondary to sepsis were enrolled for subgroup analysis in a multicenter, prospective, observational study. Patients were divided into two groups-with sepsis-induced myocardial dysfunction (SIMD) and without SIMD (non-SIMD)-according to a threshold LV ejection fraction (LVEF) of 50% on the day of enrollment. Both groups were further subdivided according to a threshold stroke volume variation (SVV) of 13% as a parameter of fluid responsiveness. On the day of enrollment, there was a positive correlation (r = 0.421, p = 0.045) between GEDI and SVV in the SIMD group, whereas this paradoxical correlation was not found in the non-SIMD group and both groups on day 2. To evaluate the relationship between attainment of cardiac preload optimization and GEDI value, GEDI with SVV ≤13% and SVV >13% was compared in both the SIMD and non-SIMD groups. SVV ≤13% implies the attainment of cardiac preload optimization. Among patients with SIMD, GEDI was higher in patients with SVV >13% than in patients with SVV ≤13% on the day of enrollment (872 [785-996] mL/m(2) vs. 640 [597-696] mL/m(2); p < 0.001); this finding differed from the generally recognized relationship between GEDI and SVV. However, GEDI was not significantly different between patients with SVV ≤13% and SVV >13% in the non-SIMD group on the day of enrollment and both groups on day 2. In the early phase of severe sepsis in mechanically ventilated patients, there was no constant relationship between GEDI and fluid reserve responsiveness, irrespective of the presence of SIMD. GEDI should be used as a cardiac preload parameter with awareness of its limitations. ",0
5798,25705815,"Follow-up telephone calls to patients discharged after undergoing orthopaedic surgery: double-blind, randomised controlled trial of efficacy","To evaluate the effectiveness of a follow-up telephone call to reduce the number of issues after hospital discharge. The postdischarge period is often a time of uncertainty and risk. The decreasing length of hospital stays has increased the need for specific instructions about the postdischarge period. A telephone follow-up could be a valuable tool to fill this information gap. Double-blind, randomised controlled trial. The participants included medium or low-intensity orthopaedic patients. We implemented a structured telephone follow-up call conducted by a senior orthopaedic nurse to provide educational support to the intervention group (n = 110), while the control group (n = 109) received routine care after being discharged. Data were collected between September 2011-January 2012. Statistical differences between the two groups were tested using chi-square test or Wilcoxon rank sum test, as appropriate. A linear regression model was performed to investigate factors involved into postdischarge outcomes. The intervention group had a statistically significant reduction in all postdischarge problems except for pain and mobilisation; the group also had a lower chance of experiencing frequent or severe problems. The educational intervention and prior poor health had a strong correlation with problems after discharge. Patients who received a telephone follow-up call believed the information provided was valuable. This nurse-led follow-up intervention significantly contributed to solving or reducing postdischarge health problems and contributed to reduce unnecessary burden on the community health system. A nurse-led telephone follow-up is a simple, feasible and low-cost tool to improve patients' outcomes after discharge. ",0
5799,25706168,Squamous cell carcinoma of the oropharynx: single-institution outcome analysis of patients treated with concurrent chemoradiotherapy,"The object of this study was to analyse our experience with the effects of concurrent chemoradiotherapy for oropharyngeal squamous cell carcinoma, the treatment results of this therapeutic strategy and a salvage treatment for recurrent oropharyngeal squamous cell carcinoma. Seventy-five patients with oropharyngeal squamous cell carcinoma were treated with chemoradiotherapy. The study included twenty-five of these patients who had recurrent oropharyngeal squamous cell carcinoma after chemoradiotherapy Results: The three-year actuarial survival rates for 75 patients by disease stage were as follows: stage II, 100 per cent; stage III, 71.1 per cent; stage IV, 51.7 per cent and overall, 58.2 per cent. The mean time of detection of recurrence was 6.2 months. The total salvage rates of recurrence were 21 per cent. The one and three-year tumour-free actuarial survival rates of those patients who received salvage treatment were 83 and 33 per cent. Surgical salvage was only feasible for early recurrent tumour. Close follow-up surveillance of early recurrence is essential after primary treatment of patients with chemoradiotherapy. ",0
5800,25706977,Altered molecular expression of the TLR4/NF-κB signaling pathway in mammary tissue of Chinese Holstein cattle with mastitis,"Toll-like receptor 4 (TLR4) mediated activation of the nuclear transcription factor κB (NF-κB) signaling pathway by mastitis initiates expression of genes associated with inflammation and the innate immune response. In this study, the profile of mastitis-induced differential gene expression in the mammary tissue of Chinese Holstein cattle was investigated by Gene-Chip microarray and bioinformatics. The microarray results revealed that 79 genes associated with the TLR4/NF-κB signaling pathway were differentially expressed. Of these genes, 19 were up-regulated and 29 were down-regulated in mastitis tissue compared to normal, healthy tissue. Statistical analysis of transcript and protein level expression changes indicated that 10 genes, namely TLR4, MyD88, IL-6, and IL-10, were up-regulated, while, CD14, TNF-α, MD-2, IL-β, NF-κB, and IL-12 were significantly down-regulated in mastitis tissue in comparison with normal tissue. Analyses using bioinformatics database resources, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the Gene Ontology Consortium (GO) for term enrichment analysis, suggested that these differently expressed genes implicate different regulatory pathways for immune function in the mammary gland. In conclusion, our study provides new evidence for better understanding the differential expression and mechanisms of the TLR4 /NF-κB signaling pathway in Chinese Holstein cattle with mastitis.  ",0
5801,25707015,Synthesis and antimicrobial activity of novel structural hybrids of benzofuroxan and benzothiazole derivatives,"New compounds containing both benzofuroxan and benzothiazole scaffolds were synthesized through electrophile/nucleophile combination of nitrobenzofuroxan derivatives and 2-mercapto- or 2-aminobenzothiazole derivatives and their biological effect on the natural strain Vibrio genus and different bacterial lux-biosensors was studied. Among all the compounds synthesized, that obtained from 2-mercaptobenzothiazole and 7-chloro-4,6-dinitrobenzofuroxan was toxic for bacterial cells, and also able to activated the 1st type Quorum Sensing system. The reaction between 7-chloro-4,6-dinitrobenzofuroxan and 2-aminobenzothiazole derivatives gave two products, one bearing the benzofuroxan moiety linked to the exocyclic amino nitrogen, and the second derived from the attack of two molecules of electrophile to both the nitrogen atoms of the benzothiazole reagent. Their relative ratio is modifiable by tuning the reagents ratio and the reaction time.  ",0
5802,25707023,Thiamine responsive megaloblastic anemia syndrome: a novel homozygous SLC19A2 gene mutation identified,"Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease - megaloblastic anemia, early onset deafness, and non-type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania - a 3-year-old boy born to a non-consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis - novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition. ",0
5803,25707869,Evidence-Based Protocols to Guide Pulse Oximetry and Oxygen Weaning in Inpatient Children with Asthma and Bronchiolitis: A Pilot Project,"Nurses', respiratory therapists' (RTs), and physicians' concerns about oxygen weaning practices and pulse oximetry use in healthy children during inpatient admissions prompted this multidisciplinary evidence-based project. A nurse-led inter-professional team found lack of consistent oxygen weaning practices and lack of guidelines for nurses or RTs regarding pulse oximetry use with children admitted for acute respiratory illness. The team created and piloted evidence-based oxygen weaning and pulse oximetry protocols. After a 6 month pilot, children in the pilot had shorter length of stay, time on oxygen, and time on continuous pulse oximetry. Protocols improved patient outcomes and decreased associated charges. ",0
5804,25708149,Transcriptional upregulation of myelin components in spontaneous myelin basic protein-deficient mice,"Myelin is essential for efficient signal transduction in the nervous system comprising of multiple proteins. The intricacies of the regulation of the formation of myelin, and its components, are not fully understood. Here, we describe the characterization of a novel myelin basic protein (Mbp) mutant mouse, mbp(jive), which spontaneously occurred in our mouse colony. These mice displayed the onset of a shaking gait before 3 weeks of age and seizure onset before 2 months of age. Due to a progressive increase of seizure intensity, mbp(jive) mice experienced premature lethality at around 3 months of age. Mbp mRNA transcript or protein was undetectable and, accordingly, genetic analysis demonstrated a homozygous loss of exons 3 to 6 of Mbp. Peripheral nerve conductance was mostly unimpaired. Additionally, we observed grave structural changes in white matter predominant structures were detected by T1, T2 and diffusion weighted magnetic resonance imaging. We additionally observed that Mbp-deficiency results in an upregulation of Qkl, Mag and Cnp, suggestive of a regulatory feedback mechanism whereby compensatory increases in Qkl have downstream effects on Mag and Cnp. Further research will clarify the role and specifications of this myelin feedback loop, as well as determine its potential role in therapeutic strategies for demyelinating disorders.  ",0
5805,25708257,Effects of Intrauterine Growth Restriction During Late Pregnancy on the Development of the Ovine Fetal Thymus and the T-Lymphocyte Subpopulation,"The retarded development of fetal thymus in intrauterine growth restriction (IUGR) from maternal undernutrition during late pregnancy destroys the tridimensional structure and modifies the development of fetal T lymphocytes. The mechanisms, however, remain unclear. The objective of this study was to investigate the effect of IUGR during late pregnancy on the development of the ovine fetal thymus and the T-lymphocyte subpopulation. Eighteen time-mated ewes with singleton fetuses were allocated to three groups at day 90 of pregnancy: restricted group 1 (RG1, 0.18 MJ ME/BW(0.75) /day, n = 6), restricted group 2 (RG2, 0.33 MJ ME/BW(0.75) /day, n = 6) and a control group (CG, ad libitum, 0.67 MJ ME/BW(0.75) /day, n = 6). Fetuses were recovered at slaughter on day 140. Fetuses in RG1 exhibited decreased (P < 0.05) thymic weight, cortical thickness, cortical:medullary, DNA content, total antioxidant capacity, and superoxide dismutase; intermediate changes were found in RG2 fetuses, including decreased thymic weight, cortical thickness, and DNA content (P < 0.05). The reductions (P < 0.05) of CD4(+) CD8(+) T cells, relative mRNA expression of keratin 8, recombination activating gene 1 (RAG1), and B-cell lymphoma 2 (Bcl-2) were found in both restricted groups. In addition, there was reduced mRNA expression (P < 0.05) of T-cell receptor, apoptosis antigen 1 ligand, and RAG2 in the RG1 group. In contrast, increases in glutathione peroxidase, malondialdehyde, caspase-3, Cytochrome c, and CD4(+) T cells were observed (P < 0.05), and higher mRNA expressions (P < 0.05) of protein 53, Bcl-2 associated X protein (Bax), and apoptosis antigen 1 (Fas) were found in RG1 fetuses; and thymuses of RG2 fetuses had increased caspase-3, and expression of Fas and Bax (P < 0.05), relative to control fetuses. These results indicate that reduced cell proliferation, oxidative stress, and increased cell apoptosis were the potential mechanisms for impaired development and microenvironment of IUGR fetal thymus, and for modifying the maturation of CD4(+) CD8(+) thymocytes underlying their reduced numbers . ",0
5806,25708344,Oesophagectomy is a safe option for early adenocarcinoma arising from Barrett's oesophagus,"Over the last decade, there has been a shift towards endoscopic treatment of high-grade dysplasia (HGD) and T1 stage adenocarcinoma arising in Barrett's oesophagus. Although short-term outcomes are promising, longer-term outcomes remain uncertain and the role of these therapies versus surgery is debated, with surgical mortality rates assumed. However, few studies have specifically determined the outcome for oesophagectomy in the subgroup with HGD or T1 adenocarcinoma. To determine this, we evaluated experience with oesophagectomy for HGD and T1 adenocarcinoma in Barrett's oesophagus. Data were analysed from a prospective audit database for oesophagectomy performed at two public and four associated private hospitals in Adelaide, South Australia. Patients with HGD, T1a and T1b adenocarcinoma who underwent oesophagectomy from 20 February 1998 to 17 February 2012 were identified, and their perioperative, post-operative and survival outcomes were determined. From 452 oesophagectomy procedures, 63 (13.9%) individuals who underwent surgery for HGD or T1 adenocarcinoma were identified; HGD - 19 (30.1%), T1a - 18 (28.5 %), T1b - 26 (41.3%). Major complications occurred in eight (12.7%) patients including one (1.6%) death following surgery. Five-year survival for HGD and T1a cancers using Kaplan-Meier analysis was not significantly different from a matched general population without cancer. Oesophagectomy for HGD and T1 stage adenocarcinoma in Barrett's oesophagus is associated with favourable outcomes. Outcomes following endoscopic treatments should be benchmarked against these outcomes, not those following oesophagectomy for advanced cancer. ",0
5807,25708562,Marginal artery stump pressure in left colic artery-preserving rectal cancer surgery: a clinical trial,"The aim of this clinical trial is to evaluate the influence of high and low ligation of the inferior mesenteric artery with apical lymph node dissection on the anastomotic blood supply, lymph node retrieval rate, operative time and anastomotic leakage rate in rectal cancer surgery. A total of 57 Chinese patients were randomly distributed into group A and group B and underwent radical resection of rectal cancer. Patients in group A underwent high ligation of the inferior mesenteric artery, and patients in group B underwent apical lymph node resection around the root of the inferior mesenteric artery with preservation of the left colic artery. The marginal artery stump pressure was measured after colon and artery reconstruction. Systemic pressure, distal colon length, operative time and lymph node retrieval rate were measured and recorded. The results were analysed and related to patient characteristics and post-operative complications. The anastomotic blood supply negatively and linearly correlated with age and distal colon length and showed a positive linear correlation with systemic pressure. Patients who received low ligation with apical lymph node dissection had a better anastomotic blood supply than those who received high ligation. No differences were found in lymph node retrieval rate, operative time and anastomotic leakage rate. Anastomotic leakage was associated with a worse anastomotic blood supply. Low ligation with apical lymph node dissection in rectal cancer treatment provides better anastomotic blood supply but is not associated with differences in node retrieval rate or operation time. ",0
5808,25708597,Usefulness of an in vitro cellular expression model for haemophilia A carrier diagnosis: illustration with five novel mutations in the F8 gene in women with isolated factor VIII:C deficiency,"This study aims to determine the way to predict the haemophilia A (HA) carrier status and the potential severity in six females with low C levels (<0.50 IU mL(-1) ), F8 gene variations and without family history of HA. Except p.Ser577Tyr, F8 gene variations that we reported have never been described (p.Leu107His, p.Pro521Leu, p.Val682Leu, p.Leu2032Pro, p.Ala315dup). Prediction of their potential causal impact was studied by two strategies: bioinformatics approaches and site-directed mutagenesis followed by FVIII cellular expression into COS-1 cell. FVIII clotting assay ( C) and antigen ( Ag) were assayed in vitro. In silico analysis showed the probably damaging effect of all substitutions and the full conservation of the residues across mammalian species, except for p.Leu2032Pro. The in vitro variant expression model showed abnormal intra and/or extracellular C and Ag levels for five mutations, which suggest their causality in HA and provide informations about the involved mechanism. We suspect a defect in synthesis and secretion for p.Leu107His, p.Ala315dup and p.Pro521Leu. The mutation p.Val682Leu only affects the FVIII function while p.Ser577Tyr alters function and synthesis. The variant p.Leu2032Pro is probably a polymorphism because no alteration of the FVIII protein expression was observed in vitro. In vitro results suggest that mutations p.Ser577Tyr and p.Ala315dup could led to a severe HA in men. This study demonstrates the ability of this in vitro cellular expression model to contribute to the diagnosis strategy for female suspected of being HA carrier, without HA family history and with a novel F8 gene variation and to provide new criteria for the genetic counselling. ",0
5809,25708601,Measuring the reactivity of commercially available zero-valent iron nanoparticles used for environmental remediation with iopromide,"The high specific surface area and high reactivity of nanoscale zero-valent iron (nZVI) particles have led to much research on their application to environmental remediation. The reactivity of nZVI is affected by both the water chemistry and the properties of the particular type of nZVI particle used. We have investigated the reactivity of three types of commercially available Nanofer particles (from Nanoiron, s.r.o., Czech Republic) that are currently either used in, or proposed for use in full scale environmental remediation projects. The performance of one of these, the air-stable and thus easy-to-handle Nanofer Star particle, has not previously been reported. Experiments were carried out first in batch shaking reactors in order to derive maximum reactivity rates and provide a rapid estimate of the Nanofer particle's reactivity. The experiments were performed under near-natural environmental conditions with respect to the pH value of water and solute concentrations, and results were compared with those obtained using synthetic water. Thereafter, the polyelectrolyte-coated Nanofer 25S particles (having the highest potential for transport within porous media) were chosen for the experiments in column reactors, in order to elucidate nanoparticle reactivity under a more field-site realistic setting. Iopromide was rapidly dehalogenated by the investigated nZVI particles, following pseudo-first-order reaction kinetics that was independent of the experimental conditions. The specific surface area normalized reaction rate constant (kSA) value in the batch reactors ranged between 0.12 and 0.53Lm(-2)h(-1); it was highest for the uncoated Nanofer 25 particles, followed by the polyacrylic acid-coated Nanofer 25S and air-stable Nanofer Star particles. In the batch reactors all particles were less reactive in natural water than in synthetic water. The kSA values derived from the column reactor experiments were about 1000 times lower than those from the batch reactors, ranging between 2.6×10(-4) and 5.7×10(-4)Lm(-2)h(-1). Our results revealed that the easy-to-handle and air-stable Nanofer Star particles are the least reactive of all the Nanofer products tested. The reaction kinetics predicted by column experiments were more realistic than those predicted by batch experiments and these should therefore be used when designing a full-scale field application of nanomaterials for environmental remediation.  ",0
5810,25708640,Time of flight secondary ion mass spectrometry surface and in-depth study of degradation of nanosheet poly(L-lactic acid) films,"With the advent of novel fabrication technologies, free-standing poly(l-lactic acid) (PLLA) nanosheets have been shown to have enhanced performance over their micro- or macroscale equivalents as tissue engineering and drug delivery constructs. In the present research, the authors investigated the surface degradation behavior of PLLA films as a function of confinement to a quasi-two-dimensional structure, and the degradation behavior of nanoscale PLLA films as a function of the initial molecular weight and depth, using time-of-flight secondary ion mass spectrometry. The authors found that nanofilms exhibit less segregation of shorter chains to the surface than microfilms, due to the constrained geometries of these morphologies. It was also concluded that the degradation rate at the surface of nanofilms related to the inverse of the initial molecular weight, as is the case in bulk-scale systems.  ",0
5811,25708652,"ERK1/2: Function, signaling and implication in pain and pain-related anxio-depressive disorders","Despite the increasing knowledge regarding pain modulation, the understanding of the mechanisms behind a complex and pathologic chronic pain condition is still insufficient. These knowledge gaps might result in ineffective therapeutic approaches to relieve painful sensations. As a result, severe untreated chronic pain frequently triggers the onset of new disorders such as depression and/or anxiety, and therefore, both the diagnosis and treatment of patients suffering from chronic pain become seriously compromised, prompting a self-perpetuating cycle of symptomatology. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are molecules strongly implicated in the somatic component of pain at the spinal cord level and have been emerging as mediators of the emotional-affective component as well. Although these molecules might represent good biomarkers, their use as pharmacological targets is still open to discussion as paradoxical information has been obtained. Here we review the current scientific literature regarding ERK1/2 signaling in the modulation of pain, depression and anxiety, including the emotional-affective spheres of the pain experience.  ",0
5812,25711908,Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity,"""Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Here, we postulated that the immune regulatory properties of HSCs might promote the profibrogenic activity of B cells. Fibrosis is completely attenuated in carbon tetrachloride-treated, B cell-deficient �MT mice, showing that B cells are required. The retinoic acid produced by HSCs augmented B-cell survival, plasma cell marker CD138 expression, and immunoglobulin G production. These activities were reversed following addition of the retinoic acid inhibitor LE540. Transcriptional profiling of fibrotic liver B cells revealed increased expression of genes related to activation of nuclear factor ? light chain enhancer of activated B cells, proinflammatory cytokine production, and CD40 signaling, suggesting that these B cells are activated and may be acting as inflammatory cells. Biological validation experiments also revealed increased activation (CD44 and CD86 expression), constitutive immunoglobulin G production, and secretion of the proinflammatory cytokines tumor necrosis factor-?, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1?. Likewise, targeted deletion of B-cell-intrinsic myeloid differentiation primary response gene 88 signaling, an innate adaptor with involvement in retinoic acid signaling, resulted in reduced infiltration of migratory CD11c(+) dendritic cells and Ly6C(++) monocytes and, hence, reduced liver pathology. CONCLUSION: Liver fibrosis occurs through a mechanism of HSC-mediated augmentation of innate B-cell activity. These findings highlight B cells as important """"first responders"""" of the intrahepatic immune environment.""",0
5813,25714157,Anesthetic neurotoxicity--clinical implications of animal models,Some anesthetics and sedatives have been shown to cause neurotoxic effects in laboratory animals. The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age.,0
5814,25714163,Enduring and emerging challenges of informed consent,The author summarizes emerging standards for informed consent as the underpinning of ethical research in humans.,0
5815,25720337,Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure,"Activation of hepatitis B virus (HBV)-specific CD8 T cells by therapeutic vaccination may promote sustained control of viral replication by clearance of covalently closed circular DNA from infected hepatocytes. However, little is known about the exact targets of the CD8 T-cell response and whether HBV reproducibly evades CD8 T-cell immune pressure by mutation. The aim of this study was to address if HBV reproducibly selects substitutions in CD8 T-cell epitopes that functionally act as immune escape mutations. The HBV core gene was amplified and sequenced from 148 patients with chronic HBV infection, and the human leukocyte antigen (HLA) class I genotype (A and B loci) was determined. Residues under selection pressure in the presence of particular HLA class I alleles were identified by a statistical approach utilizing the novel analysis package SeqFeatR. With this approach we identified nine residues in HBV core under selection pressure in the presence of 10 different HLA class I alleles. Additional immunological experiments confirmed that seven of the residues were located inside epitopes targeted by patients with chronic HBV infection carrying the relevant HLA class I allele. Consistent with viral escape, the selected substitutions reproducibly impaired recognition by HBV-specific CD8 T cells. CONCLUSION: Viral sequence analysis allows identification of HLA class I-restricted epitopes under reproducible selection pressure in HBV core; the possibility of viral escape from CD8 T-cell immune pressure needs attention in the context of therapeutic vaccination against HBV.",0
5816,25738663,A precious jewel--the role of general practice in the English NHS,"General practice, long considered the jewel in the crown of the English National Health Service, is being criticized for its small scale, isolation, and lack of accountability. There is growing concern that many general practices cannot respond to new expectations.",0
5817,25738671,Clinical management of potential bioterrorism-related conditions,"The agents most likely to be used in bioterrorism attacks are reviewed, along with the clinical syndromes they produce and their treatment.",0
5818,25830323,Copy-number variation and false positive prenatal aneuploidy screening results,"Investigations of noninvasive prenatal screening for aneuploidy by analysis of circulating cell-free DNA (cfDNA) have shown high sensitivity and specificity in both high-risk and low-risk cohorts. However, the overall low incidence of aneuploidy limits the positive predictive value of these tests. Currently, the causes of false positive results are poorly understood. We investigated four pregnancies with discordant prenatal test results and found in two cases that maternal duplications on chromosome 18 were the likely cause of the discordant results. Modeling based on population-level copy-number variation supports the possibility that some false positive results of noninvasive prenatal screening may be attributable to large maternal copy-number variants. (Funded by the National Institutes of Health and others.).",0
5819,25830423,Demographic and epidemiologic drivers of global cardiovascular mortality,"BACKGROUND: Global deaths from cardiovascular disease are increasing as a result of population growth, the aging of populations, and epidemiologic changes in disease. Disentangling the effects of these three drivers on trends in mortality is important for planning the future of the health care system and benchmarking progress toward the reduction of cardiovascular disease. METHODS: We used mortality data from the Global Burden of Disease Study 2013, which includes data on 188 countries grouped into 21 world regions. We developed three counterfactual scenarios to represent the principal drivers of change in cardiovascular deaths (population growth alone, population growth and aging, and epidemiologic changes in disease) from 1990 to 2013. Secular trends and correlations with changes in national income were examined. RESULTS: Global deaths from cardiovascular disease increased by 41% between 1990 and 2013 despite a 39% decrease in age-specific death rates; this increase was driven by a 55% increase in mortality due to the aging of populations and a 25% increase due to population growth. The relative contributions of these drivers varied by region; only in Central Europe and Western Europe did the annual number of deaths from cardiovascular disease actually decline. Change in gross domestic product per capita was correlated with change in age-specific death rates only among upper-middle income countries, and this correlation was weak; there was no significant correlation elsewhere. CONCLUSIONS: The aging and growth of the population resulted in an increase in global cardiovascular deaths between 1990 and 2013, despite a decrease in age-specific death rates in most regions. Only Central and Western Europe had gains in cardiovascular health that were sufficient to offset these demographic forces. (Funded by the Bill and Melinda Gates Foundation and others.).",0
5820,25853659,Genetically determined height and coronary artery disease,"BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).",0
5821,25855031,The biliary epithelium presents antigens to and activates natural killer T cells,"Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as well as human primary cholangiocytes expressed CD1d as determined by flow cytometry and western blotting. Murine cholangiocyte cell lines were able to present both exogenous and endogenous lipid antigens to invariant and noninvariant NKT cell hybridomas and primary NKT cells in a CD1d-dependent manner. A human cholangiocyte cell line, cholangiocarcinoma cell lines, and human primary cholangiocytes also presented exogenous CD1d-restricted antigens to invariant NKT cell clones. CD1d expression was down-regulated in the biliary epithelium of patients with late primary sclerosing cholangitis, primary biliary cirrhosis, and alcoholic cirrhosis compared to healthy controls. CONCLUSIONS: Cholangiocytes express CD1d and present antigens to NKT cells and CD1d expression is down-regulated in diseased biliary epithelium, findings which show that the biliary epithelium can activate an important lymphocyte subset of the liver. This is a potentially important immune pathway in the biliary system, which may be capable of regulating inflammation in the context of biliary disease.",0
5822,25866017,Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication,"Hepatitis A virus (HAV) and hepatitis C virus (HCV) are two positive-strand RNA viruses sharing a similar biology, but causing opposing infection outcomes, with HAV always being cleared and HCV establishing persistence in the majority of infections. To gain deeper insight into determinants of replication, persistence, and treatment, we established a homogenous cell-culture model allowing a thorough comparison of RNA replication of both viruses. By screening different human liver-derived cell lines with subgenomic reporter replicons of HAV as well as of different HCV genotypes, we found that Huh7-Lunet cells supported HAV- and HCV-RNA replication with similar efficiency and limited interference between both replicases. HAV and HCV replicons were similarly sensitive to interferon (IFN), but differed in their ability to establish persistent replication in cell culture. In contrast to HCV, HAV replicated independently from microRNA-122 and phosphatidylinositol 4-kinase III? and ? (PI4KIII). Both viruses were efficiently inhibited by cyclosporin A and NIM811, a nonimmunosuppressive analog thereof, suggesting an overlapping dependency on cyclophilins for replication. However, analysis of a broader set of inhibitors revealed that, in contrast to HCV, HAV does not depend on cyclophilin A, but rather on adenosine-triphosphate-binding cassette transporters and FK506-binding proteins. Finally, silibinin, but not its modified intravenous formulation, efficiently inhibited HAV genome replication in vitro, suggesting oral silibinin as a potential therapeutic option for HAV infections. CONCLUSION: We established a cell-culture model enabling comparative studies on RNA replication of HAV and HCV in a homogenous cellular background with comparable replication efficiency. We thereby identified new host cell targets and potential treatment options for HAV and set the ground for future studies to unravel determinants of clearance and persistence.",0
5823,25875257,"A randomized, controlled trial of an aerosolized vaccine against measles","BACKGROUND: Aerosolized vaccine can be used as a needle-free method of immunization against measles, a disease that remains a major cause of illness and death. Data on the immunogenicity of aerosolized vaccine against measles in children are inconsistent. METHODS: We conducted an open-label noninferiority trial involving children 9.0 to 11.9 months of age in India who were eligible to receive a first dose of measles vaccine. Children were randomly assigned to receive a single dose of vaccine by means of either aerosol inhalation or a subcutaneous injection. The primary end points were seropositivity for antibodies against measles and adverse events 91 days after vaccination. The noninferiority margin was 5 percentage points. RESULTS: A total of 1001 children were assigned to receive aerosolized vaccine, and 1003 children were assigned to receive subcutaneous vaccine; 1956 of all the children (97.6%) were followed to day 91, but outcome data were missing for 331 children because of thawed specimens. In the per-protocol population, data on 1560 of 2004 children (77.8%) could be evaluated. At day 91, a total of 662 of 775 children (85.4%; 95% confidence interval [CI], 82.5 to 88.0) in the aerosol group, as compared with 743 of 785 children (94.6%; 95% CI, 92.7 to 96.1) in the subcutaneous group, were seropositive, a difference of -9.2 percentage points (95% CI, -12.2 to -6.3). Findings were similar in the full-analysis set (673 of 788 children in the aerosol group [85.4%] and 754 of 796 children in the subcutaneous group [94.7%] were seropositive at day 91, a difference of -9.3 percentage points [95% CI, -12.3 to -6.4]) and after multiple imputation of missing results. No serious adverse events were attributable to measles vaccination. Adverse-event profiles were similar in the two groups. CONCLUSIONS: Aerosolized vaccine against measles was immunogenic, but, at the prespecified margin, the aerosolized vaccine was inferior to the subcutaneous vaccine with respect to the rate of seropositivity. (Funded by the Bill and Melinda Gates Foundation; Measles Aerosol Vaccine Project Clinical Trials Registry-India number, CTRI/2009/091/000673.).",0
5824,25913111,Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs,"BACKGROUND: The incidence of the neonatal abstinence syndrome, a drug-withdrawal syndrome that most commonly occurs after in utero exposure to opioids, is known to have increased during the past decade. However, recent trends in the incidence of the syndrome and changes in demographic characteristics and hospital treatment of these infants have not been well characterized. METHODS: Using multiple cross-sectional analyses and a deidentified data set, we analyzed data from infants with the neonatal abstinence syndrome from 2004 through 2013 in 299 neonatal intensive care units (NICUs) across the United States. We evaluated trends in incidence and health care utilization and changes in infant and maternal clinical characteristics. RESULTS: Among 674,845 infants admitted to NICUs, we identified 10,327 with the neonatal abstinence syndrome. From 2004 through 2013, the rate of NICU admissions for the neonatal abstinence syndrome increased from 7 cases per 1000 admissions to 27 cases per 1000 admissions; the median length of stay increased from 13 days to 19 days (P<0.001 for both trends). The total percentage of NICU days nationwide that were attributed to the neonatal abstinence syndrome increased from 0.6% to 4.0% (P<0.001 for trend), with eight centers reporting that more than 20% of all NICU days were attributed to the care of these infants in 2013. Infants increasingly received pharmacotherapy (74% in 2004-2005 vs. 87% in 2012-2013, P<0.001 for trend), with morphine the most commonly used drug (49% in 2004 vs. 72% in 2013, P<0.001 for trend). CONCLUSIONS: From 2004 through 2013, the neonatal abstinence syndrome was responsible for a substantial and growing portion of resources dedicated to critically ill neonates in NICUs nationwide.",0
5825,25923551,A cluster-randomized trial to reduce cesarean delivery rates in Quebec,"BACKGROUND: In Canada, cesarean delivery rates have increased substantially over the past decade. Effective, safe strategies are needed to reduce these rates. METHODS: We conducted a cluster-randomized, controlled trial of a multifaceted 1.5-year intervention at 32 hospitals in Quebec. The intervention involved audits of indications for cesarean delivery, provision of feedback to health professionals, and implementation of best practices. The primary outcome was the cesarean delivery rate in the 1-year postintervention period. RESULTS: Among the 184,952 participants, 53,086 women delivered in the year before the intervention and 52,265 women delivered in the year following the intervention. There was a significant but small reduction in the rate of cesarean delivery from the preintervention period to the postintervention period in the intervention group as compared with the control group (change, 22.5% to 21.8% in the intervention group and 23.2% to 23.5% in the control group; odds ratio for incremental change over time, adjusted for hospital and patient characteristics, 0.90; 95% confidence interval [CI], 0.80 to 0.99; P=0.04; adjusted risk difference, -1.8%; 95% CI, -3.8 to -0.2). The cesarean delivery rate was significantly reduced among women with low-risk pregnancies (adjusted risk difference, -1.7%; 95% CI, -3.0 to -0.3; P=0.03) but not among those with high-risk pregnancies (P=0.35; P = 0.03 for interaction). The intervention group also had a reduction in major neonatal morbidity as compared with the control group (adjusted risk difference, -0.7%; 95% CI, -1.3 to -0.1; P=0.03) and a smaller increase in minor neonatal morbidity (adjusted risk difference, -1.7%; 95% CI, -2.6 to -0.9; P<0.001). Changes in minor and major maternal morbidity did not differ significantly between the groups. CONCLUSIONS: Audits of indications for cesarean delivery, feedback for health professionals, and implementation of best practices, as compared with usual care, resulted in a significant but small reduction in the rate of cesarean delivery, without adverse effects on maternal or neonatal outcomes. The benefit was driven by the effect of the intervention in low-risk pregnancies. (Funded by the Canadian Institutes of Health Research; QUARISMA Current Controlled Trials number, ISRCTN95086407.).",0
5826,25923552,Intensive diabetes therapy and ocular surgery in type 1 diabetes,"BACKGROUND: The Diabetes Control and Complications Trial (DCCT) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes. METHODS: Between 1983 and 1989, a total of 1441 patients with type 1 diabetes in the DCCT were randomly assigned to receive either intensive diabetes therapy or conventional therapy aimed at preventing hyperglycemic symptoms. They were treated and followed until 1993. Subsequently, 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. The self-reported history of ocular surgical procedures was obtained annually. We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies. RESULTS: Over a median follow-up of 23 years, 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy (8.9%) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy (13.4%) (P<0.001). After adjustment for DCCT baseline factors, intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P<0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P=0.01). Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction (adjusted risk reduction with intensive therapy, 48%; 95% CI, 23 to 65; P=0.002); 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy, retinal-detachment surgery, or both (adjusted risk reduction, 45%; 95% CI, 12 to 66; P=0.01). The costs of surgery were 32% lower in the intensive-therapy group. The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up. CONCLUSIONS: Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.).",0
5827,25970009,Randomized trial of four financial-incentive programs for smoking cessation,"BACKGROUND: Financial incentives promote many health behaviors, but effective ways to deliver health incentives remain uncertain. METHODS: We randomly assigned CVS Caremark employees and their relatives and friends to one of four incentive programs or to usual care for smoking cessation. Two of the incentive programs targeted individuals, and two targeted groups of six participants. One of the individual-oriented programs and one of the group-oriented programs entailed rewards of approximately $800 for smoking cessation; the others entailed refundable deposits of $150 plus $650 in reward payments for successful participants. Usual care included informational resources and free smoking-cessation aids. RESULTS: Overall, 2538 participants were enrolled. Of those assigned to reward-based programs, 90.0% accepted the assignment, as compared with 13.7% of those assigned to deposit-based programs (P<0.001). In intention-to-treat analyses, rates of sustained abstinence from smoking through 6 months were higher with each of the four incentive programs (range, 9.4 to 16.0%) than with usual care (6.0%) (P<0.05 for all comparisons); the superiority of reward-based programs was sustained through 12 months. Group-oriented and individual-oriented programs were associated with similar 6-month abstinence rates (13.7% and 12.1%, respectively; P=0.29). Reward-based programs were associated with higher abstinence rates than deposit-based programs (15.7% vs. 10.2%, P<0.001). However, in instrumental-variable analyses that accounted for differential acceptance, the rate of abstinence at 6 months was 13.2 percentage points (95% confidence interval, 3.1 to 22.8) higher in the deposit-based programs than in the reward-based programs among the estimated 13.7% of the participants who would accept participation in either type of program. CONCLUSIONS: Reward-based programs were much more commonly accepted than deposit-based programs, leading to higher rates of sustained abstinence from smoking. Group-oriented incentive programs were no more effective than individual-oriented programs. (Funded by the National Institutes of Health and CVS Caremark; ClinicalTrials.gov number, NCT01526265.).",0
5828,25970010,"X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men","BACKGROUND: The genetic basis of nonobstructive azoospermia is unknown in the majority of infertile men. METHODS: We performed array comparative genomic hybridization testing in blood samples obtained from 15 patients with azoospermia, and we performed mutation screening by means of direct Sanger sequencing of the testis-expressed 11 gene (TEX11) open reading frame in blood and semen samples obtained from 289 patients with azoospermia and 384 controls. RESULTS: We identified a 99-kb hemizygous loss on chromosome Xq13.2 that involved three TEX11 exons. This loss, which was identical in 2 patients with azoospermia, predicts a deletion of 79 amino acids within the meiosis-specific sporulation domain SPO22. Our subsequent mutation screening showed five novel TEX11 mutations: three splicing mutations and two missense mutations. These mutations, which occurred in 7 of 289 men with azoospermia (2.4%), were absent in 384 controls with normal sperm concentrations (P=0.003). Notably, five of those TEX11 mutations were detected in 33 patients (15%) with azoospermia who received a diagnosis of azoospermia with meiotic arrest. Meiotic arrest in these patients resembled the phenotype of Tex11-deficient male mice. Immunohistochemical analysis showed specific cytoplasmic TEX11 expression in late spermatocytes, as well as in round and elongated spermatids, in normal human testes. In contrast, testes of patients who had azoospermia with TEX11 mutations had meiotic arrest and lacked TEX11 expression. CONCLUSIONS: In our study, hemizygous TEX11 mutations were a common cause of meiotic arrest and azoospermia in infertile men. (Funded by the National Institutes of Health and others.).",0
5829,25981908,High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure,"BACKGROUND: Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia. METHODS: We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28. RESULTS: A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24�8 days, vs. 22�10 in the standard-oxygen group and 19�12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006). CONCLUSIONS: In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interr�gional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.).",0
5830,25992747,Trends in mental health care among children and adolescents,"BACKGROUND: Increasing mental health treatment of young people and broadening conceptualizations of psychopathology have triggered concerns about a disproportionate increase in the treatment of youths with low levels of mental health impairment. METHODS: We analyzed the 1996-1998, 2003-2005, and 2010-2012 Medical Expenditure Panel Surveys, which were nationally representative surveys of U.S. households, for trends in outpatient use of mental health services by persons 6 to 17 years of age; 53,622 persons were included in the analysis. Mental health impairment was measured with the use of the Columbia Impairment Scale (range, 0 to 52, with higher scores indicating more severe impairment); we classified youths with scores of 16 or higher as having more severe impairment and those with scores of less than 16 as having less severe impairment. RESULTS: The percentage of youths receiving any outpatient mental health service increased from 9.2% in 1996-1998 to 13.3% in 2010-2012 (odds ratio, 1.52; 95% confidence interval, 1.35 to 1.72). The proportionate increase in the use of mental health services among youths with more severe impairment (from 26.2% to 43.9%) was larger than that among youths with less severe or no impairment (from 6.7% to 9.6%). However, the absolute increase in annual service use was larger among youths with less severe or no impairment (from 2.74 million to 4.19 million) than among those with more severe impairment (from 1.56 million to 2.28 million). Significant overall increases occurred in the use of psychotherapy (from 4.2% to 6.0%) and psychotropic medications (from 5.5% to 8.9%), including stimulants and related medications (from 4.0% to 6.6%), antidepressants (from 1.5% to 2.6%), and antipsychotic drugs (from 0.2% to 1.2%). CONCLUSIONS: Outpatient mental health treatment and psychotropic-medication use in children and adolescents increased in the United States between 1996-1998 and 2010-2012. Although youths with less severe or no impairment accounted for most of the absolute increase in service use, youths with more severe impairment had the greatest relative increase in use, yet fewer than half accessed services in 2010-2012. (Funded by the Agency for Healthcare Research and Quality and the New York State Psychiatric Institute.).",0
5831,25998209,Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice,"Nuclear receptor corepressor 1 (NCoR1) is a transcriptional coregulator that has wide-ranging effects on gene expression patterns. In the liver, NCoR1 represses lipid synthesis in the fasting state, whereas it inhibits activation of peroxisome proliferator-activated receptor alpha (PPAR?) upon feeding, thereby blunting ketogenesis. Here, we show that insulin by activation of protein kinase B induces phosphorylation of NCoR1 on serine 1460, which selectively favors its interaction with PPAR? and estrogen-related receptor alpha (ERR?) over liver X receptor alpha (LXR?). Phosphorylation of NCoR1 on S1460 selectively derepresses LXR? target genes, resulting in increased lipogenesis, whereas, at the same time, it inhibits PPAR? and ERR? targets, thereby attenuating oxidative metabolism in the liver. Phosphorylation-gated differential recruitment of NCoR1 to different nuclear receptors explains the apparent paradox that liver-specific deletion of NCoR1 concurrently induces both lipogenesis and oxidative metabolism owing to a global derepression of LXR?, PPAR?, and ERR? activity. CONCLUSION: Phosphorylation-mediated recruitment switch of NCoR1 between nuclear receptor subsets provides a mechanism by which corepressors can selectively modulate liver energy metabolism during the fasting-feeding transition.",0
5832,26033675,A clinician's guide to drug-drug interactions with direct-acting antiviral agents for the treatment of hepatitis C viral infection,"The US Food and Drug Administration has recently approved a number of new direct-acting antiviral agents for the treatment of chronic hepatitis C virus that have significantly increased the likelihood of a virological cure. These agents are highly effective but present a substantial risk for a host of clinically relevant drug-drug interactions. These interactions must be considered both when starting and stopping any medication, including over-the-counter medications and herbal supplements. These drug-drug interactions can increase the risk of toxicity or decrease the likelihood of treatment response. Knowledge of these interactions is paramount in optimizing the success of antiviral therapy. CONCLUSION: In this review we summarize the available data regarding drug-drug interactions for direct-acting antiviral agents, the interactions being the most clinically relevant that are currently known; this review is intended to serve as a clinician's guide to understanding and managing these complex interactions. (Hepatology 2016;63:634-643).",0
5833,26061837,Efficacy of a sexual assault resistance program for university women,"BACKGROUND: Young women attending university are at substantial risk for being sexually assaulted, primarily by male acquaintances, but effective strategies to reduce this risk remain elusive. METHODS: We randomly assigned first-year female students at three universities in Canada to the Enhanced Assess, Acknowledge, Act Sexual Assault Resistance program (resistance group) or to a session providing access to brochures on sexual assault, as was common university practice (control group). The resistance program consists of four 3-hour units in which information is provided and skills are taught and practiced, with the goal of being able to assess risk from acquaintances, overcome emotional barriers in acknowledging danger, and engage in effective verbal and physical self-defense. The primary outcome was completed rape, as measured by the Sexual Experiences Survey-Short Form Victimization, during 1 year of follow-up. RESULTS: A total of 451 women were assigned to the resistance group and 442 women to the control group. Of the women assigned to the resistance group, 91% attended at least three of the four units. The 1-year risk of completed rape was significantly lower in the resistance group than in the control group (5.2% vs. 9.8%; relative risk reduction, 46.3% [95% confidence interval, 6.8 to 69.1]; P=0.02). The 1-year risk of attempted rape was also significantly lower in the resistance group (3.4% vs. 9.3%, P<0.001). CONCLUSIONS: A rigorously designed and executed sexual assault resistance program was successful in decreasing the occurrence of rape, attempted rape, and other forms of victimization among first-year university women. (Funded by the Canadian Institutes of Health Research and the University of Windsor; SARE ClinicalTrials.gov number, NCT01338428.).",0
5834,26077809,Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis,"Although necrosis in the acetaminophen (APAP) model is known to be regulated by c-Jun NH2-terminal kinase (JNK) through interaction with mitochondria, the role of necroptosis through receptor-interacting proteins 1 and 3 (RIPK1 and RIPK3) has also been suggested. Our aim was to determine the relationship between these two mechanisms of cell death. To verify the participation of RIPK1, we used antisense knockdown and confirmed protection comparable to the RIPK1 inhibitor, necrostatin, in vivo and in vitro. However, we found no evidence that RIPK3 is expressed in primary mouse hepatocytes under basal conditions or after APAP and RIPK3(-/-) mice were not protected. RIPK3 was exclusively expressed in nonparenchymal cells. RIPK1 knockdown protected RIPK3(-/-) mice to the same extent as wild-type mice, underscoring the independent role of RIPK1. We confirmed that necroptosis is not involved in APAP toxicity by using mixed lineage kinase domain-like protein (MLKL) knockout mice, which were not protected from APAP. Next, we addressed whether there is interplay between RIPK1 and JNK. RIPK1 knockdown decreased the level of JNK activation and translocation to mitochondria and abrogated subsequent translocation of dynamin-related protein 1 (Drp1). Interestingly, APAP induced translocation of RIPK1 to mitochondria, which was unaffected by knockdown of the mitochondrial JNK docking protein, Sh3 homology 3 binding protein 5 (Sab). CONCLUSION: RIPK1 participates in APAP-induced necrosis upstream of JNK activation whereas RIPK3 and MLKL are dispensable, indicating that necroptosis does not contribute to APAP-induced necrosis and RIPK1 has a unique, independent role.",0
5835,26096332,Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 in patients with cirrhosis,"Interferon (IFN)-free regimens are needed to treat hepatitis C virus (HCV) infection. Combined simeprevir (SMV) and sofosbuvir (SOF) with or without ribavirin (RBV) results in high sustained virological response (SVR) rates along with minimal adverse events (AEs) in patients with hepatitis C genotype 1 (HCV GT1). The aim of this study was to report on the virological response, safety, and tolerability of SOF and SMV with or without RBV in compensated and decompensated patients with cirrhosis with HCV GT1 infection. Patients treated with standardized clinical protocol utilizing SMV+SOF with or without RBV at three transplant centers were retrospectively reviewed. A total of 119 patients (61% male, 87% white, 69% subtype 1a, 30% Child-Pugh-Turcott [CPT]-B liver cirrhosis [LC], and 82% were treatment experienced) received treatment and were followed for a median of 38 weeks (range, 12-58). Sustained virological response (SVR) at week 12 (SVR12) was achieved in 78% (92 of 118) of patients (95% confidence interval: 69-85). Lower pretreatment Model for End Stage Liver Disease (MELD) score was a predictor of SVR12 (P?=?0.018). Baseline viral load, previous treatment status, RBV use, or GT1 subtype did not impact SVR 12. The majority of patients with SVR12 showed stability or improvement in MELD score. Treatment was very well tolerated with mild degrees of AEs. CONCLUSIONS: The regimen of SMV+SOF with or without RBV for 12 weeks was very well tolerated and resulted in high SVR12 rates (78%) in HCV GT1 patients with LC. SVR12 was inversely related to pretreatment MELD. SVR12 had favorable short-term impact on MELD score. Long-term impact on disease stability is yet to be determined. Longer treatment duration or the use of different regimen may still be needed in this population.",0
5836,26126491,PKC412 normalizes mutation-related keratin filament disruption and hepatic injury in mice by promoting keratin-myosin binding,"Keratins, among other cytoskeletal intermediate filament proteins, are mutated at a highly conserved arginine with consequent severe disease phenotypes due to disruption of keratin filament organization. We screened a kinase inhibitor library, using A549 cells that are transduced with a lentivirus keratin 18 (K18) construct, to identify compounds that normalize filament disruption due to K18 Arg90Cys mutation at the conserved arginine. High-throughput screening showed that PKC412, a multikinase inhibitor, ameliorated K18 Arg90Cys-mediated keratin filament disruption in cells and in the livers of previously described transgenic mice that overexpress K18 Arg90Cys. Furthermore, PKC412 protected cultured A549 cells that express mutant or wild-type K18 and mouse livers of the K18 Arg90Cys-overexpressing transgenic mice from Fas-induced apoptosis. Proteomic analysis of proteins that associated with keratins after exposure of K18-expressing A549 cells to PKC412 showed that nonmuscle myosin heavy chain-IIA (NMHC-IIA) partitions with the keratin fraction. The nonmuscle myosin-IIA (NM-IIA) association with keratins was confirmed by immune staining and by coimmunoprecipitation. The keratin-myosin association is myosin dephosphorylation-dependent; occurs with K8, the obligate K18 partner; is enhanced by PKC412 in cells and mouse liver; and is blocked by hyperphosphorylation conditions in cultured cells and mouse liver. Furthermore, NMHC-IIA knockdown inhibits PKC412-mediated normalization of K18 R90C filaments. CONCLUSION: The inhibitor PKC412 normalizes K18 Arg90Cys mutation-induced filament disruption and disorganization by enhancing keratin association with NM-IIA in a myosin dephosphorylation-regulated manner. Targeting of intermediate filament disorganization by compounds that alter keratin interaction with their associated proteins offers a potential novel therapeutic approach for keratin and possibly other intermediate filament protein-associated diseases.",0
5837,26173068,Identification of a mitochondrial defect gene signature reveals NUPR1 as a key regulator of liver cancer progression,"Many cancer cells require more glycolytic adenosine triphosphate production due to a mitochondrial respiratory defect. However, the roles of mitochondrial defects in cancer development and progression remain unclear. To address the role of transcriptomic regulation by mitochondrial defects in liver cancer cells, we performed gene expression profiling for three different cell models of mitochondrial defects: cells with chemical respiratory inhibition (rotenone, thenoyltrifluoroacetone, antimycin A, and oligomycin), cells with mitochondrial DNA depletion (Rho0), and liver cancer cells harboring mitochondrial defects (SNU354 and SNU423). By comparing gene expression in the three models, we identified 10 common mitochondrial defect-related genes that may be responsible for retrograde signaling from cancer cell mitochondria to the intracellular transcriptome. The concomitant expression of the 10 common mitochondrial defect genes is significantly associated with poor prognostic outcomes in liver cancers, suggesting their functional and clinical relevance. Among the common mitochondrial defect genes, we found that nuclear protein 1 (NUPR1) is one of the key transcription regulators. Knockdown of NUPR1 suppressed liver cancer cell invasion, which was mediated in a Ca(2+) signaling-dependent manner. In addition, by performing an NUPR1-centric network analysis and promoter binding assay, granulin was identified as a key downstream effector of NUPR1. We also report association of the NUPR1-granulin pathway with mitochondrial defect-derived glycolytic activation in human liver cancer. CONCLUSION: Mitochondrial respiratory defects and subsequent retrograde signaling, particularly the NUPR1-granulin pathway, play pivotal roles in liver cancer progression.",0
5838,26173433,"YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors","The Yes-associated protein (YAP)/Hippo pathway has been implicated in tissue development, regeneration, and tumorigenesis. However, its role in cholangiocarcinoma (CC) is not established. We show that YAP activation is a common feature in CC patient biopsies and human CC cell lines. Using microarray expression profiling of CC cells with overexpressed or down-regulated YAP, we show that YAP regulates genes involved in proliferation, apoptosis, and angiogenesis. YAP activity promotes CC growth in vitro and in vivo by functionally interacting with TEAD transcription factors (TEADs). YAP activity together with TEADs prevents apoptosis induced by cytotoxic drugs, whereas YAP knockdown sensitizes CC cells to drug-induced apoptosis. We further show that the proangiogenic microfibrillar-associated protein 5 (MFAP5) is a direct transcriptional target of YAP/TEAD in CC cells and that secreted MFAP5 promotes tube formation of human microvascular endothelial cells. High YAP activity in human CC xenografts and clinical samples correlates with increased MFAP5 expression and CD31(+) vasculature. CONCLUSIONS: These findings establish YAP as a key regulator of proliferation and antiapoptotic mechanisms in CC and provide first evidence that YAP promotes angiogenesis by regulating the expression of secreted proangiogenic proteins.",0
5839,26174697,Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells,"The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille-Calemette-Gu�rin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid-lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration. CONCLUSIONS: Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans.",0
5840,26174965,NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer,"Stem cell populations are maintained through self-renewing divisions in which one daughter cell commits to a particular fate whereas the other retains the multipotent characteristics of its parent. The NUMB, a tumor suppressor, in conjunction with another tumor-suppressor protein, p53, preserves this property and acts as a barrier against deregulated expansion of tumor-associated stem cells. In this context, NUMB-p53 interaction plays a crucial role to maintain the proper homeostasis of both stem cells, as well as differentiated cells. Because the molecular mechanism governing the assembly and stability of the NUMB-p53 interaction/complex are poorly understood, we tried to identify the molecule(s) that govern this process. Using cancer cell lines, tumor-initiating cells (TICs) of liver, the mouse model, and clinical samples, we identified that phosphorylations of NUMB destabilize p53 and promote self-renewal of TICs in a pluripotency-associated transcription factor NANOG-dependent manner. NANOG phosphorylates NUMB by atypical protein kinase C zeta (aPKC?), through the direct induction of Aurora A kinase (AURKA) and the repression of an aPKC? inhibitor, lethal (2) giant larvae. By radioactivity-based kinase activity assays, we showed that NANOG enhances kinase activities of both AURKA and aPKC?, an important upstream process for NUMB phosphorylation. Phosphorylation of NUMB by aPKC? destabilizes the NUMB-p53 interaction and p53 proteolysis and deregulates self-renewal in TICs. CONCLUSION: Post-translational modification of NUMB by the NANOG-AURKA-aPKC? pathway is an important event in TIC self-renewal and tumorigenesis. Hence, the NANOG-NUMB-p53 signaling axis is an important regulatory pathway for TIC events in TIC self-renewal and liver tumorigenesis, suggesting a therapeutic strategy by targeting NUMB phosphorylation. Further in-depth in vivo and clinical studies are warranted to verify this suggestion.",0
5841,26200980,AVI-7288 for Marburg Virus in Nonhuman Primates and Humans,"BACKGROUND: AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined. METHODS: We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3:1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans. RESULTS: Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P<0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates. CONCLUSIONS: This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans. (Funded by the Department of Defense; ClinicalTrials.gov number, NCT01566877.).",0
5842,26207521,B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice,"Increasing evidence in recent years has suggested that B cells act as a crucial regulator in autoimmune diseases. However, little is known about their role in autoimmune hepatitis (AIH) and the underlying regulatory mechanisms. In this study, we show that B cells ameliorated experimental AIH (EAH) by suppressing CD4+ T-cell responses and that CD11b expression on B cells was required for the regulatory function of B cells. In vitro studies reveal that the suppressive function of CD11b was mediated by the impairment of T-cell antigen receptor (TCR) signaling transduction and the promotion of TCR down-regulation. Moreover, we show that the increased CD11b expression on B cells was interleukin (IL)-10 dependent and that additional IL-10 stimulation promoted CD11b expression on B cells, thereby enhancing B-cell regulatory effects. CONCLUSION: These findings reveal a previously unrecognized role for CD11b in B-cell regulatory function and its protective effect on EAH.",0
5843,26222560,Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer,"Familial nonmedullary thyroid cancer accounts for 3 to 9% of all cases of thyroid cancer, but the susceptibility genes are not known. Here, we report a germline variant of HABP2 in seven affected members of a kindred with familial nonmedullary thyroid cancer and in 4.7% of 423 patients with thyroid cancer. This variant was associated with increased HABP2 protein expression in tumor samples from affected family members, as compared with normal adjacent thyroid tissue and samples from sporadic cancers. Functional studies showed that HABP2 has a tumor-suppressive effect, whereas the G534E variant results in loss of function.",0
5844,26248546,Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1,"To explore mechanisms of hepatitis C viral (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. CONCLUSION: These observations reveal novel details about HCV membrane fusion; moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as a cost-effective component of HCV combination therapies.",0
5845,26250868,A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance,"Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ?15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction. CONCLUSION: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity.",0
5846,26251214,Antibodies to an interfering epitope in hepatitis C virus E2 can mask vaccine-induced neutralizing activity,"Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here, we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred twelve blinded serum samples from a phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in enzyme-linked immunosorbent assay for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using cell-culture HCV 1a(H77)/2a chimera, HCV pseudotype particles (HCVpp) H77, and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples, we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only, and 70 double negative. Depleting EP-II antibodies from double-positive serum samples increased 50% inhibitory dose (ID50) neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (P ? 0.0005), contrasting with ID50 neutralization titer increases in 2 of 70 double-negative samples (2.9%; P > 0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (P < 0.0003). CONCLUSION: These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins, and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins.",0
5847,26256354,Review on biomedical and bioengineering applications of cellulose sulfate,"Polysaccharide sulfates are naturally existing chemicals that show important biological activities in living organisms. Cellulose sulfate is a semi-synthesized polysaccharide sulfate with a relatively simple chain structure and unique biological properties and its biological applications have been explored in research and clinical trials. With the advance of cellulose derivatization and characterization, cellulose sulfate molecules with tailored structures have been developed to fulfill individual requirements. This review aims to provide a summary of recent development of cellulose sulfate in biomedical applications. Its synthesis pathways were discussed with structure-property relationship elucidated. The application of cellulose sulfate in drug delivery and microbe/cell immobilization were summarized with emphasis given on its polyelectrolyte complex formation processes.  ",0
5848,26256376,Physicochemical and functional properties of dietary fiber from maca (Lepidium meyenii Walp.) liquor residue,"Using maca (Lepidium meyenii) liquor residue as the raw material, dietary fiber (DF) was prepared by chemical (MCDF) and enzymatic (MEDF) methods, respectively, of which the physicochemical and functional properties were comparatively studied. High contents of DF were found in MCDF (55.63%) and MEDF (81.10%). Both fibers showed good functional properties, including swelling capacity, water holding capacity, oil holding capacity, glucose adsorption capacity and glucose retardation index. MEDF showed better functional properties, which could be attributed to its higher content of DF, more irregular surface and more abundant monosaccharide composition. The results herein suggest that maca DF prepared by enzymatic method from liquor residue is a good functional ingredient in food products.  ",0
5849,26256408,17β-Estradiol in the systemic circulation derives mainly from the parietal cells in cholestatic female rats,"Estrogenic symptoms of liver disease patients including biliary tract disorder with high frequency is observed in clinical cases. However, the origin of 17β-estradiol which is abundant enough to cause symptoms remains uncertain. In male rats, it has been reported that the parietal cells which have an abundance of aromatase-synthesized 17β-estradiol, and a part of 17β-estradiol secreted into the portal vein, may flow into the systemic circulation under a pathophysiological condition of the liver including bile duct ligation (BDL). The aim of this study is to reveal the origin of 17β-estradiol increment in female rats and to investigate the effect of BDL on the ovary during the estrus cycle. Wistar female rats were used, and the common bile duct was ligated twice and transected completely at 7 days before termination. Serum portal venous and arterial 17β-estradiol levels, Cyp19a1 expressions, aromatase protein levels, and estrogen receptor (ER) α levels in the liver were measured during the estrus cycle. Both arterial and portal venous 17β-estradiol levels increased 2.9 times at proestrus and maintained constant levels during the cycle. The expression of Cyp19a1 and aromatase protein in the stomach maintained constant levels, and significantly decreased during the estrus cycle in the ovary. Hepatic ERα protein and Esr1 expressions decrease by BDL in all stages. These results suggest that the increment of serum 17β-estradiol levels in obstructive cholestasis induced by BDL is derived from 17β-estradiol secreted from the parietal cells in females as well as males. ",0
5850,26256428,Rosacea is associated with chronic systemic diseases in a skin severity-dependent manner: results of a case-control study,"Rosacea is a common chronic inflammatory dermatosis of unclear origin. It has been associated with systemic comorbidities, but methodical studies addressing this association are lacking. We evaluated: (1) the association between rosacea and systemic comorbidities; and (2) if the severity of rosacea is impacted by comorbidities. This was a case-control study: patients with rosacea were matched (1:1) to rosacea-free control subjects by age, sex, and race. Relative risk estimates were calculated using logistic regression as odds ratios with 95% confidence intervals. Among 130 participants (65 patients/65 control subjects), we observed a significant association between rosacea and allergies (airborne, food), respiratory diseases, gastroesophageal reflux disease, other gastrointestinal diseases, hypertension, metabolic and urogenital diseases, and female hormone imbalance. Compared with mild rosacea, moderate to severe rosacea was significantly associated with hyperlipidemia, hypertension, metabolic diseases, cardiovascular diseases, and gastroesophageal reflux disease. This was a case-control study with moderate sample size. Associated medical conditions were self-reported and could not always be confirmed by medication use and medical records. Rosacea is associated with numerous systemic comorbid diseases in a skin severity-dependent manner. Physicians should be aware of these associations to provide comprehensive care to patients with rosacea, especially to those with more severe disease. ",0
5851,26256487,Cocaine - Effects on Human Performance and Behavior,"A brief history of cocaine is provided followed by an overview of the pharmacology of cocaine. In addition to the mechanism of action, the effects of cocaine withdrawal and its effects in combination with ethanol are discussed. Special emphasis is placed on the metabolism of cocaine and the interpretation of the concentration of cocaine and metabolites detected in various matrices. Consideration is given to stability of the drug, pathology, postmortem observations, passive and unknowing ingestion, and dermal exposure. A brief overview of analytical methodology is also presented. Finally, the effects of cocaine on driving are examined.  ",0
5852,26256549,Population Landscape of Familial Cancer,"Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers.  ",0
5853,26256667,Predictors of Long-Term Survival Following Transvenous Extraction of Defibrillator Leads,"Little data exist on long-term outcomes following extraction of implantable cardioverter defibrillator (ICD) leads, particularly for noninfectious indications. We sought to identify predictors of long-term survival after ICD lead extraction. We retrospectively reviewed ICD lead extractions at our institution (n = 508). Procedural outcomes and long-term survival were ascertained by medical records review. Indication for lead extraction was infection in 32.5% and lead failure in 61.8%. Mean dwell time of the oldest extracted lead was 5.1 ± 5.9 years. Complete procedural success was achieved in 96.5% of cases. Major procedure-related complications occurred in 1.6% with six periprocedural deaths. During a mean follow-up of 866 ± 798 days, survival was significantly worse among patients with infection as the indication for extraction. At 1 year after extraction, survival among those with infection was 88.2%, compared to 95.0% in the lead failure cohort (P < 0.001). Procedural failure was a significant predictor of long-term mortality, even after excluding periprocedural deaths. In multivariate models, the presence of chronic kidney disease, increased number of leads requiring extraction, lower ejection fraction, and procedural failure were predictors of mortality. Despite high rates of procedural success, infectious indication for ICD lead extraction is associated with increased long-term mortality. In contrast, among patients undergoing extraction for lead failure, long-term survival was excellent. The presence of procedural failure was a significant predictor of long-term mortality. Further studies will be necessary to better understand the mechanisms by which procedural failure may adversely impact long-term outcomes. ",0
5854,26256697,"Molecular cloning, expression and bioactivity of B cell activating factor (BAFF) in African ostrich","B cell activating factor (BAFF), which belongs to the tumor necrosis factor (TNF) family, is testified to play a critical role in B cell survival, proliferation, maturation and immunoglobulin secretion. In the present study, the cDNA of open reading frame (ORF) in African ostrich (Struthio camelus) BAFF (designated OsBAFF) was cloned by reverse transcription-PCR (RT-PCR). The OsBAFF gene encodes a 288-amino acid protein containing a predicted transmembrane domain and a putative furin protease cleavage site like BAFFs from chicken (cBAFF), quail (qBAFF), duck (dBAFF), goose (gBAFF) and dove (doBAFF). RT-PCR analysis showed that the OsBAFF gene is strongly expressed in the bursa of Fabricius, thymus, spleen, and bone marrow. The soluble OsBAFF had been cloned into pET28a. SDS-PAGE and Western blotting analysis confirmed that the soluble fusion protein His-OsBAFF was efficiently expressed in Escherichia coli Rosset (DE3). In vitro, purified OsBAFF was not only able to promote the survival of African ostrich bursal lymphocytes, but also able to co-stimulate proliferation of mouse splenic B cells. The expression of OsBAFF in lymphocyte cells was higher than the control after LPS stimulation. These findings indicated that OsBAFF plays an important role in survival and proliferation of African ostrich bursal lymphocytes, which may provide valuable information for research into the immune system of African ostrich and OsBAFF may serve as a potential immunologic factor for enhancing immunological efficacy in African ostrich and any other birds.  ",0
5855,26256717,Exopolysaccharides from co-cultures of Weissella confusa 11GU-1 and Propionibacterium freudenreichii JS15 act synergistically on wheat dough and bread texture,"The storage of bread is limited by both physical (staling) and microbial (mainly fungal) spoilage. Exopolysaccharides (EPS) produced by lactic acid bacteria (LAB) and organic acids from propionibacteria (PAB) have been used to enhance texture and extend shelf-life of bakery products. In this study the functionality of EPS of Weissella confusa A3/2-1 (dextran), W. confusa F3/2-2 (dextran and levan), W. confusa 11GU-1 (dextran and ropy capsular polysaccharide) was evaluated in wheat bread. Two strains of Propionibacterium freudenreichii (Pf), shown to produce a heteropolysaccharide (Pf JS15) or a β-glucan (Pf DF30), were tested in single and mixed cultures with W. confusa (Wc). The EPS fermentates were prepared by batch fermentation of cereal- or malt-based medium using sucrose (Wc) or lactic acid (Pf) as carbon source. Incorporation of EPS from single culture fermentates and 1:1 Weissella-Propionibacterium fermentate mixtures revealed strong positive effects of dextran and ropy capsular polysaccharide produced by Wc 11GU-1 on bread staling retardation, with synergistic effects of EPS mixture from Wc 11GU-1 and Pf JS15. A co-fermentation of Wc 11GU-1 and Pf JS15 was developed to produce EPS together with antifungal organic acid mixture (acetate and propionate) in a single step process. The addition of 15% (w/w flour base) co-culture, yielding EPS, acetate and propionate concentrations of 1.5, 0.5 and 1g/kg dough, respectively, resulted in improved bread texture, increased loaf volume and decreased crumb firming during storage for 3days compared with control breads and breads supplemented with equivalent levels of chemical organic acids. Our data showed that EPS could compensate for the negative effects of chemical acetate and propionate in a concentration range exerting antifungal effects. The natural bioingredient produced by Wc 11GU-1 and Pf JS15 has potential for applications as antifungal, texture-building and anti-staling agent in breads, consistent with consumer demands for clean label products.  ",0
5856,26257359,Effects of chronic and subtoxic chlorobenzenes on adrenocorticotrophic hormone release,"Many environmental chemicals and pesticides have been found to alter neuroendocrine communication in exposed biological objects. The environmental loads have primary and secondary effects that can alter the homeostatic regulation potential. Since it is difficult to avoid human exposition, a potentially important area of research to develop in vivo and in vitro experimental models. In this context, the primary aim of this study was to demonstrate the effects of chlorobenzenes on adrenocorticotrophic hormone (ACTH) release. In our experimental study, male Wistar rats were exposed to 0.1, 1.0 and 10 μg/b.w. (body weight)kg of 1,2,4- trichlorobenzene and hexachlorobenzene (ClB) mix via gastric tube for 30, 60 or 90 days. At the endpoints of the experiment blood samples were taken and animals were decapitated. Primary, monolayer adenohypophysis cell cultures were prepared by enzymatic and mechanical digestion. The ACTH hormone content in serum and supernatant media was measured by immuno-chemiluminescence assay. The Mg(2+)-dependent ATPase activity was determined by modified method of Martin and Dotty. Significant differences were detected in the hormone release between the control and treated groups. The hormone release was enhanced characteristically in exposed groups depending upon the dose and duration of exposure. The Mg(2+)-ATPase activity enhanced after chronic and subtoxic ClB exposition. Light microscopy revealed that the adenohypophysis seemed to be more abundant. Results indicate that Wistar rats exposed to subtoxic ClB have direct and indirect effects on hypothalamus-hypophysis-adrenal axis. ",0
5857,26257816,Strong Manual Acupuncture Manipulation Could Better Inhibit Spike Frequency of the Dorsal Horn Neurons in Rats with Acute Visceral Nociception,"Afferent impulses from visceral nociception can be regulated by acupuncture at spinal cord level; however, the effects of different manual acupuncture (MA) manipulations on the afferent impulses are still unknown. Here, we analyzed the spike frequency of excitatory gastric-related wide dynamic range (WDR) neurons in spinal dorsal horn (SDH) following acute gastric distension (GD) in rats and compared their responses to MA manipulations with four different frequencies (0.5, 1, 2, and 3 Hz) at Zusanli (ST36). Results indicated that the spike frequency was increased by acute GD stimulation. Under acute GD circumstances, the spike frequency was further activated by weak MA stimulation (0.5 and 1 Hz), while being significantly inhibited by strong MA stimulation (2 and 3 Hz). After 10 minutes of the strong MA stimulation, same intensity of acute GD caused less spike frequency. Our previous researches had demonstrated that different MA manipulations could increase spike frequency in an intensity-dependent manner in normal rats; these findings suggest that acupuncture may have different modulatory effects depending on the state of the stomach. Since neuronal spike frequency was related to the level of nociception, the results suggest that strong MA manipulation may have better effect on acute visceral nociception.  ",0
5858,26257960,Neural Stem Cell Transplant-Induced Effect on Neurogenesis and Cognition in Alzheimer Tg2576 Mice Is Inhibited by Concomitant Treatment with Amyloid-Lowering or Cholinergic α7 Nicotinic Receptor Drugs,"Stimulating regeneration in the brain has the potential to rescue neuronal networks and counteract progressive pathological changes in Alzheimer's disease (AD). This study investigated whether drugs with different mechanisms of action could enhance neurogenesis and improve cognition in mice receiving human neural stem cell (hNSC) transplants. Six- to nine-month-old AD Tg2576 mice were treated for five weeks with the amyloid-modulatory and neurotrophic drug (+)-phenserine or with the partial α7 nicotinic receptor (nAChR) agonist JN403, combined with bilateral intrahippocampal hNSC transplantation. We observed improved spatial memory in hNSC-transplanted non-drug-treated Tg2576 mice but not in those receiving drugs, and this was accompanied by an increased number of Doublecortin- (DCX-) positive cells in the dentate gyrus, a surrogate marker for newly generated neurons. Treatment with (+)-phenserine did however improve graft survival in the hippocampus. An accumulation of α7 nAChR-expressing astrocytes was observed around the injection site, suggesting their involvement in repair and scarring processes. Interestingly, JN403 treatment decreased the number of α7 nAChR-expressing astrocytes, correlating with a reduction in the number of DCX-positive cells in the dentate gyrus. We conclude that transplanting hNSCs enhances endogenous neurogenesis and prevents further cognitive deterioration in Tg2576 mice, while simultaneous treatments with (+)-phenserine or JN403 result in countertherapeutic effects.  ",0
5859,26258087,Hormones in Dairy Foods and Their Impact on Public Health - A Narrative Review Article,"The presence of hormones in milk and dairy foods was discussed decades ago but rather more concerns attended to that with respect to finding hormones as biomarkers in milk for diseases and pregnancy diagnosis. Moreover, considerable amount of studies demonstrated that existing of hormones in humans and animals milk are essential for infants growing and immunity. During the last couple of years, increasing body of evidence are indicating another property of hormones in dairy products as possible impact on human health including the role of some estrogens and insulin-like growth factor-1 in initiation and provoking of breast, prostate and endometrial tumours. Data was gathered from the published articles in database such as MEDLINE, science direct, Google scholar and web of science. We put no limitation on date of published date. Moreover, our own published and conducted methods and results also are presented. In this review we concentrated on several aspects of presence of hormones in dairy foods with especial emphasize on cow's milk as a major source of consuming milk for humans especially for children. The collected data from other researchers and our own data are indicating that the presence of steroid hormones in dairy products could be counted as an important risk factor for various cancers in humans. Our gathered data in this review paper may suggest more sophisticate analytical detection methods for oestrogens determination and also could be considered as a remarkable concern for consumers, producers and public health authorities. ",0
5860,26258649,Formation of Novel Aqueous Two-Phase Systems with Piperazinium-Based Ionic Liquids and Anionic Surfactants: Phase Behavior and Microstructure,"Two novel aqueous two-phase systems (ATPSs) involving protic piperazinium-based ionic liquids (ILs) and anionic surfactants were found in the 1-ethylpiperazinium tetrafluoroborate ([C2pi][BF4]) + sodium dodecyl sulfate (SDS) + H2O system and the 1-phenylpiperazinium tetrafluoroborate ([Phpi][BF4]) + sodium dodecyl benzenesulfonate (SDBS) + H2O system. The ATPS regions in the ternary phase diagrams were determined, and the compositions and the microstructures of the conjugated phases were analyzed by UV-vis, (1)H NMR, DLS, and cryogenic TEM measurements. The results demonstrate size-enhanced micelles for both ATPSs. The strong electrostatic interactions between the cationic moiety of IL and the anionic surfactant play a very important role in the assembly of the large aggregates, and the cation-π interactions are involved in the [Phpi][BF4] + SDBS + H2O ATPS. In addition, the small cationic moiety of [C2pi][BF4] can be packed in the micelles, while the larger hydrophilic cationic moiety of [Phpi][BF4] makes it difficult to get into the micelles, leading to the different size enhancement effects. The driving force of phase separation is the formation and distribution of the large aggregates in the aqueous solutions. This work presents a novel nonaromatic ATPS formed by a piperazinium-based IL and an anionic surfactant, in which considerable size enhancement of aggregates takes place without the assistance of aromaticity in contrast to the other aromatic ATPSs.  ",0
5861,26258855,Acute Strength Training Increases Responses to Stimulation of Corticospinal Axons,"Acute strength training of forearm muscles increases resting twitch forces from motor cortex stimulation. It is unclear if such effects are spinal in origin and if they also occur with training of larger muscles. With the use of subcortical stimulation of corticospinal axons, the current study examined if one session of strength training of the elbow flexor muscles leads to spinal cord changes and if the type of training is important. In experiment 1, 10 subjects completed ballistic isometric training, ballistic concentric training, and no training (control) on separate days. In experiment 2, 13 subjects completed ballistic isometric training and slow-ramp isometric training. Before and after training, transcranial magnetic stimulation over the contralateral motor cortex elicited motor-evoked potentials (MEPs) in the resting biceps brachii, and electrical stimulation of corticospinal tract axons at the cervicomedullary junction elicited cervicomedullary motor-evoked potentials (CMEPs). Motor-evoked potential and CMEP twitch forces were also measured. In experiment 1, CMEPs and CMEP twitch forces were significantly facilitated after ballistic isometric training compared to control. In experiment 2, MEPs, MEP twitch forces, CMEPs, and CMEP twitch forces increased for 15 to 25 min after ballistic and slow-ramp isometric training. Via processes within the spinal cord, one session of strength training of the elbow flexors increases net output from motoneurons projecting to the trained muscles. Likely mechanisms include increased efficacy of corticospinal-motoneuronal synapses or increased motoneuron excitability. However, the rate of force generation during training is not important for inducing these changes. A concomitant increase in motor cortical excitability is likely. These short-term changes may represent initial neural adaptations to strength training. ",0
5862,26258891,SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression,"Colorectal cancer (CRC) is the third most common cancer in the world, and second leading cause of cancer deaths in the US. Although, anti-EGFR therapy is commonly prescribed for CRC, patients harboring mutations in KRAS or BRAF show poor treatment response, indicating an ardent demand for new therapeutic targets discovery. SPINK1 (serine peptidase inhibitor, Kazal type 1) overexpression has been identified in many cancers including the colon, lung, breast and prostate. Our study demonstrates the functional significance of SPINK1 in CRC progression and metastases. Stable knockdown of SPINK1 significantly decreases cell proliferation, invasion and soft agar colony formation in the colon adenocarcinoma WiDr cells. Conversely, an increase in these oncogenic phenotypes was observed on stimulation with SPINK1-enriched conditioned media (CM) in multiple benign models such as murine colonic epithelial cell lines, MSIE and YAMC (SPINK3-negative). Mechanistically, SPINK1 promotes tumorigenic phenotype by activating phosphatidylinositol 3-kinase (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways, and the SPINK1-positive WiDr cells are sensitive to AKT and MEK inhibitors. Importantly, SPINK1 silencing mediated upregulation of various Metallothionein isoforms, considered as tumor suppressors in CRC, confer sensitivity to doxorubicin, which strengthens the rationale for using the combinatorial treatment approach for the SPINK1-positive CRC patients. Furthermore, in vivo studies using chicken chorioallantoic membrane assay, murine xenograft studies and metastasis models further suggest a pivotal role of SPINK1 in CRC progression and metastasis. Taken together, our study demonstrates an important role for the overexpressed SPINK1 in CRC disease progression, a phenomenon that needs careful evaluation towards effective therapeutic target development.  ",0
5863,26258946,"Influence of Temperature, Relative Humidity, and Soil Properties on the Soil-Air Partitioning of Semivolatile Pesticides: Laboratory Measurements and Predictive Models","Soil-air partition coefficient (Ksoil-air) values are often employed to investigate the fate of organic contaminants in soils; however, these values have not been measured for many compounds of interest, including semivolatile current-use pesticides. Moreover, predictive equations for estimating Ksoil-air values for pesticides (other than the organochlorine pesticides) have not been robustly developed, due to a lack of measured data. In this work, a solid-phase fugacity meter was used to measure the Ksoil-air values of 22 semivolatile current- and historic-use pesticides and their degradation products. Ksoil-air values were determined for two soils (semiarid and volcanic) under a range of environmentally relevant temperature (10-30 °C) and relative humidity (30-100%) conditions, such that 943 Ksoil-air measurements were made. Measured values were used to derive a predictive equation for pesticide Ksoil-air values based on temperature, relative humidity, soil organic carbon content, and pesticide-specific octanol-air partition coefficients. Pesticide volatilization losses from soil, calculated with the newly derived Ksoil-air predictive equation and a previously described pesticide volatilization model, were compared to previous results and showed that the choice of Ksoil-air predictive equation mainly affected the more-volatile pesticides and that the way in which relative humidity was accounted for was the most critical difference.  ",0
5864,26259026,TM6SF2 rs58542926 is not associated with steatosis and fibrosis in large cohort of patients with genotype 1 chronic hepatitis C,"We tested the putative association of the rs58542926 variant of TM6SF2, a recently described genetic determinant of nonalcoholic fatty liver disease, with steatosis and fibrosis in genotype 1(G1) chronic hepatitis C(CHC) patients. A total of 694 consecutively biopsied Caucasian G1 CHC patients were genotyped for TM6SF2 rs58542926, IL28B rs12979860 and PNPLA3 rs738409. Steatosis was classified as absent (<5%), mild-moderate(5-29%) and severe(≥30%), Fibrosis was considered severe if=F3-F4. Carriers of TM6SF2 rs58542926 (6.3% of patients) exhibited lower serum levels of cholesterol (P = 0.04) and triglycerides (P = 0.01), but a similar distribution of steatosis severity (P = 0.63), compared to noncarriers. Prevalence and severity of steatosis were reduced in IL28B C allele carriers (P = 0.005) and elevated in PNPLA3 G allele carriers (P < 0.001). After adjustment for age, gender, body mass index and homoeostasis model assessment score, steatosis severity was independently associated with IL28B rs12979860 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.55-0.86, P = 0.001) and PNPLA3 rs738409 (OR 1.84, 95% CI 1.46-2.83, P < 0.001), but not TM6SF2 rs58542926 (OR 1.48, 95% CI 0.82-2.69, P = 0.19). Variants of TM6SF2 (30.9% vs. 25%, P = 0.40), IL28B and PNPLA3 were not directly associated with fibrosis severity, although variants of IL28B and PNPLA3 promoted steatosis (OR 1.36, 95% CI 1.06-1.75, P = 0.01) that in turn is associated with severe fibrosis. In G1 CHC patients, TM6SF2 rs58542926 does not affect the histological severity of liver damage. However, IL28B rs12979860 and PNPLA3 rs738409 modify steatosis. ",0
5865,26259093,Neuroplasticity in Human Alcoholism: Studies of Extended Abstinence with Potential Treatment Implications,"Alcoholism is characterized by a lack of control over excessive alcohol consumption despite significant negative consequences. This impulsive and compulsive behavior may be related to functional abnormalities within networks of brain regions responsible for how we make decisions. The abnormalities may result in strengthened networks related to appetitive drive-or the need to fulfill desires-and simultaneously weakened networks that exercise control over behaviors. Studies using functional magnetic resonance imaging (fMRI) in abstinent alcoholics suggest that abstinence is associated with changes in the tone of such networks, decreasing resting tone in appetitive drive networks, and increasing resting tone in inhibitory control networks to support continued abstinence. Identifying electroencephalographic (EEG) measures of resting tone in these networks initially identified using fMRI, and establishing in longitudinal studies that these abstinence-related changes in network tone are progressive would motivate treatment initiatives to facilitate these changes in network tone, thereby supporting successful ongoing abstinence.  ",0
5866,26259287,"Obesity and the prognosis of heart failure: the obesity paradox, myth or reality?]","""Obesity has now reached epidemic proportions worldwide. Obesity is associated with numerous comorbidities, including hypertension, lipid disorders and type II diabetes, and is also a major cause of cardiovascular disease, coronary disease, heart failure, atrial fibrillation, and sudden death. Obesity is the main cause of heart failure in respectively 11% and 14% of cases in men and women. The Framingham study showed that, after correction for other risk factors, each point increase in the body mass index raises the risk of heart failure by 5% in men and 7% in women. Obesity increases the heart workload, causes left ventricular hypertrophy, and impairs both diastolic and systolic function. The most common form of heart failure is diastolic dysfunction, and heart failure in obese individuals is associated with preserved systolic function. Despite these comorbidities and the severity of heart failure, numerous studies have revealed an """"obesity paradox"""" in which overweight and obese individuals with heart failure appear to have a better prognosis than non overweight subjects. This review summarizes the adverse cardiac effects of this nutritional disease, the results of some studies supporting the obesity paradox, the better survival rate of obese patients with heart failure. Potential explanations for these surprising data include the possibility that a number of obese patients may simply not have heart failure, as well as methodological bias, and protective effects of adipose tissue. Further studies of large populations are needed to determine how obesity may improve the prognosis of heart failure. """,0
5867,26259388,Strategies used in the clinical trials of gene therapy for cancer,"Advances in understanding and manipulating genes have set the stage for scientists to alter a person's genetic material to prevent or treat diseases. Over the past decade, somatic gene therapy has been increasingly applied in clinical trials where the genetic material (DNA and RNA) introduced into a person's cell. Mutation and inactivation of the tumor suppressor genes are the unified concept of the development of tumor in humans. Therefore, researchers have discovered potential of gene therapies in the treatment of cancer. Among the clinical trials of gene therapy conducted so far, approximately 66% were for the treatment of cancer which includes cancer of prostate, head and neck, kidneys, lungs, breast and skin. Introducing a wild type p53 gene, enhancing the immune system to protect against the cancer cells, enhancing the apoptosis of cancer cells and inhibiting the process of angiogenesis in the tumor are some of the clinical trials that are achieved through the gene therapy. Broad spectrum of delivery constructs, including viral vectors, liposomes, cationic polymers and dendrimers, cell-penetrating peptides, semiconductor quantum dots, and gold and magnetic nanoparticles have been investigated. A well designed vector is the most forward approach to increase the safety of gene therapy. Though, Gendicine and Oncorine have been marketed, gene therapy is still in its infancy stages in cancer research. More experimental and clinical trials using well-designed and effective doses of vectors are needed to ensure the therapeutic efficacy of gene therapy for its clinical use against a wide variety of cancers. This review article discuses about the various strategies used in clinical trials of gene therapy for cancer. ",0
5868,26259553,Chemical chaperone treatment for galactosialidosis: Effect of NOEV on β-galactosidase activities in fibroblasts,"Galactosialidosis is a rare lysosomal storage disease caused by a combined deficiency of GM1 β-galactosidase (β-gal) and neuraminidase secondary to a defect of a lysosomal enzyme protective protein/cathepsin A (PPCA) and mutation in CTSA gene. Three subtypes are recognized: early infantile, late infantile, and juvenile/adult. There is no specific therapy for patients with galactosialidosis at this time. The aim of this study was to determine the chaperone effect of N-octyl-4-epi-β-valienamine (NOEV) on β-gal proteins in skin fibroblasts of PPCA-deficit patients. β-Gal and neuraminidase activities were measured for the diagnosis of the patients with galactosialidosis. Western blotting for PPCA protein and direct sequencing for CTSA gene were performed. Cultured skin fibroblast were treated with NOEV. We report four novel patients with galactosialidosis: one had the early infantile form and the other three had the juvenile/adult form. We found that NOEV stabilized β-gal activity in lysate from cultured skin fibroblasts from these patients. Treatment with NOEV significantly enhanced β-gal activity in cultured skin fibroblasts in the absence of PPCA. Our results indicate the possibility that NOEV chaperone therapy might have a beneficial effect, at least in part, for patients with galactosialidosis. ",0
5869,26260984,"Sex-Specific Association between Longitudinal Changes in Adiposity, FTO rs9939609 Polymorphism, and Leukocyte Telomere Length","A longitudinal study was conducted to examine sex-specific associations between changes in adiposity over a 10-year period, the FTO rs9939609 polymorphism, and leukocyte telomere length (LTL). A population-based cohort including 2128 middle-aged and older Korean men (n = 1087) and women (n = 1041) participated in a prospective study. Anthropometric measurements of weight, height, and waist and hip circumference were taken at baseline (from 2001 to 2003) and at the 10-year follow-up period (from 2011 to 2012). The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline and LTL was assessed at the 10-year follow-up period. Multiple linear regression analysis was used with adjustments for age, baseline body mass index, and other potential confounders. Presence of the FTO rs9939609 polymorphism risk allele was inversely associated with LTL (p < 0.01) in all participants, with a significant association seen only in women when the genders were modeled separately. Conversely, a significant inverse association between changes in waist circumference and LTL was found in men (p < 0.001) but not in women. No significant interaction between adiposity measures and the FTO polymorphism in association with LTL was identified for either sex. These data suggest that biological aging in men may be accelerated by increasing waist circumference, whereas in women, aging may be affected by genetic variations in FTO regardless of adiposity changes over time. ",0
5870,26261103,ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients,"Mutations in the estrogen receptor (ER)α gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Because of limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from patients with metastatic breast cancer. We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild-type ESR1 identified by next-generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital PCR (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS, and ptDNA ESR1 mutations were analyzed by ddPCR. In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in 6 of 12 patients (50%). We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion. ",0
5871,26267621,High HLA-DP Expression and Graft-versus-Host Disease,"BACKGROUND: Transplantation of hematopoietic cells from unrelated donors can cure blood disorders but carries a significant risk of acute graft-versus-host disease (GVHD). The risk is higher when the recipient and donor are HLA-DPB1-mismatched, but the mechanisms leading to GVHD are unknown. The HLA-DPB1 regulatory region variant rs9277534 is associated with HLA-DPB1 expression. We tested the hypothesis that the GVHD risk correlates with the rs9277534 allele linked to the mismatched HLA-DPB1 in the recipient. METHODS: We genotyped rs9277534 in 3505 persons to define rs9277534-DPB1 haplotypes. Among 1441 recipients of transplants from HLA-A,B,C,DRB1,DQB1-matched unrelated donors with only one HLA-DPB1 mismatch, linkage of the rs9277534 A and G alleles to the mismatched HLA-DPB1 was determined. HLA-DPB1 expression was assessed by means of a quantitative polymerase-chain-reaction assay. The risk of acute GVHD among recipients whose mismatched HLA-DPB1 allele was linked to rs9277534G (high expression) was compared with the risk among recipients whose mismatched HLA-DPB1 allele was linked to rs9277534A (low expression). RESULTS: The mean HLA-DPB1 expression was lower with rs9277534A than with rs9277534G. Among recipients of transplants from donors with rs9277534A-linked HLA-DPB1, the risk of acute GVHD was higher for recipients with rs9277534G-linked HLA-DPB1 mismatches than for recipients with rs9277534A-linked HLA-DPB1 mismatches (hazard ratio, 1.54; 95% confidence interval [CI], 1.25 to 1.89; P<0.001), as was the risk of death due to causes other than disease recurrence (hazard ratio, 1.25; 95% CI, 1.00 to 1.57; P=0.05). CONCLUSIONS: The risk of GVHD associated with HLA-DPB1 mismatching was influenced by the HLA-DPB1 rs9277534 expression marker. Among recipients of HLA-DPB1-mismatched transplants from donors with the low-expression allele, recipients with the high-expression allele had a high risk of GVHD. (Funded by the National Institutes of Health and others.).",0
5872,26287746,FTO Obesity Variant Circuitry and Adipocyte Browning in Humans,"BACKGROUND: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. METHODS: We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. RESULTS: Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. CONCLUSIONS: Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.).",0
5873,26287850,Palliative Care for the Seriously Ill,"Palliative care is the interdisciplinary specialty focused on improving quality of life for persons with serious illness and their families. Over the past decade, the field has undergone substantial growth and change, including an expanded evidence base, new care-delivery models, innovative payment mechanisms, and increasing public and professional awareness.",0
5874,26323938,Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure,"BACKGROUND: Central sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea. METHODS: We randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure. RESULTS: In the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval [CI], 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006). CONCLUSIONS: Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).",0
5875,26324049,Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes,"BACKGROUND: Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome. METHODS: We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion. Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events. RESULTS: The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P=0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34). CONCLUSIONS: In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.).",0
5876,26376044,Politics and Universal Health Coverage--The Post-2015 Global Health Agenda,"What political, social, and economic factors allow a movement toward universal health coverage to take hold in some low- and middle-income countries? Can we use that knowledge to help other such countries achieve health care for all?",0
5877,26398068,Physician Payment after the SGR--The New Meritocracy,"With the Merit-Based Incentive Payment System, Medicare shifts from payment based on macroeconomic indicators to relying on physician- or group-level indicators of cost and quality--and could create a large fee differential between high- and low-performing physicians.",0
5878,26398069,Deception by Research Participants,"Study participants who fabricate, falsify, or fail to disclose important information can undermine the integrity of clinical trials, with negative consequences for both future patients and the participants themselves. What can investigators do to address the problem?",0
5879,26403564,Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats,"Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1 a -AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30-minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice-daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose-dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a -AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a -AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta. CONCLUSION: FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a -AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis.",0
5880,26406355,Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin,"Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and ?2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. CONCLUSION: These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice.",0
5881,26406534,Interferon lambda 4 genotypes and resistance-associated variants in patients infected with hepatitis C virus genotypes 1 and 3,"Single-nucleotide polymorphisms (SNPs) in the interferon lambda 4 (IFNL4) gene are predictors for treatment success in patients with hepatitis C virus (HCV) infection. For direct-acting antiviral combinations only weak association with IFNL4 SNPs was observed. Little is known about potential selections of resistance-associated variants (RAVs) by the IFNL4 genotype. This study analyzed the prevalence of RAVs to currently approved direct-acting antivirals in a large European population in correlation to SNPs in IFNL4. Samples of 633 patients chronically infected with HCV genotypes 1a (n = 259), 1b (n = 323), and 3 (n = 51) were genotyped for rs12979860 (formerly known as IL28B) and rs368234815. RAVs in NS3, NS5A, and NS5B were detected by population-based sequencing. In addition, IFNL4 SNPs and NS5A RAVs were analyzed including deep sequencing (n = 109) in an independent replication cohort of HCV genotype 1-infected patients (n = 201). No significant correlation was found between IFNL4 SNPs and rare and common RAVs within NS3 and NS5B. In contrast, the NS5A RAV Y93H was detected frequently in HCV genotype 1b (14%) and significantly associated with the beneficial IFNL4 SNPs (P < 0.001 and P = 0.002, respectively). Moreover, the presence of Y93H in HCV genotype 1b patients was significantly associated with the second site variant T83M (P < 0.001). Independent factors significantly associated with the presence of Y93H were IFNL4 genotype and high baseline viral load. CONCLUSION: The NS5A RAV Y93H is significantly associated with the presence of beneficial IFNL4 SNPs and a high baseline viral load in HCV genotype 1-infected patients, which may explain a lack of correlation or even an inverse correlation of treatment response with IFNL4 genotype in some NS5A inhibitor containing IFN-free regimens.",0
5882,26415085,Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy,"BACKGROUND: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).",0
5883,26422721,Cardiometabolic Risks and Severity of Obesity in Children and Young Adults,"BACKGROUND: The prevalence of severe obesity among children and young adults has increased over the past decade. Although the prevalence of cardiometabolic risk factors is relatively low among children and young adults who are overweight or obese, those with more severe forms of obesity may be at greater risk. METHODS: We performed a cross-sectional analysis of data from overweight or obese children and young adults 3 to 19 years of age who were included in the National Health and Nutrition Examination Survey from 1999 through 2012 to assess the prevalence of multiple cardiometabolic risk factors according to the severity of obesity. Weight status was classified on the basis of measured height and weight. We used standard definitions of abnormal values for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, glycated hemoglobin, and fasting glucose and report the prevalence of abnormal values in children and young adults according to weight status. RESULTS: Among 8579 children and young adults with a body-mass index at the 85th percentile or higher (according to the Centers for Disease Control and Prevention growth charts), 46.9% were overweight, 36.4% had class I obesity, 11.9% had class II obesity, and 4.8% had class III obesity. Mean values for some, but not all, cardiometabolic variables were higher with greater severity of obesity in both male and female participants, and the values were higher in male participants than in female participants; for HDL cholesterol, the mean values were lower with greater severity of obesity. Multivariable models that controlled for age, race or ethnic group, and sex showed that the greater the severity of obesity, the higher the risks of a low HDL cholesterol level, high systolic and diastolic blood pressures, and high triglyceride and glycated hemoglobin levels. CONCLUSIONS: Severe obesity in children and young adults was associated with an increased prevalence of cardiometabolic risk factors, particularly among boys and young men.",0
5884,26444221,Hypothermia for Intracranial Hypertension after Traumatic Brain Injury,"BACKGROUND: In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. METHODS: We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35�C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). RESULTS: We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). CONCLUSIONS: In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).",0
5885,26448099,"Integrin ?v?6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis","Integrin ?v?6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGF?1). In human liver cirrhosis, ?v?6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that ?v?6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin ?v?6-dependent TGF?1 activation. Freshly isolated ?v?6(+) liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by ?v?6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-?v?6 antibody is recapitulated by TGF?1 neutralization and rescued by addition of bioactive TGF?1. Genetic disruption or selective targeting of ?v?6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. CONCLUSION: These results suggest that ?v?6 is a promising target for chronic fibrotic liver diseases and associated cancers.",0
5886,26465263,Docs and Nukes--Still a Live Issue,Physicians have played a key role in warning governments and the public about the danger of nuclear war and the need to abolish nuclear weapons. That role is still needed: existing nuclear warheads pose an existential threat to humanity.,0
5887,26488692,"Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy","BACKGROUND: Prevention of reinfection and resurgence is an integral component of the goal to eradicate malaria. However, the adverse effects of malaria resurgences are not known. METHODS: We assessed the prevalence of Plasmodium falciparum infection among 1819 Mozambican women who delivered infants between 2003 and 2012. We used microscopic and histologic examination and a quantitative polymerase-chain-reaction (qPCR) assay, as well as flow-cytometric analysis of IgG antibody responses against two parasite lines. RESULTS: Positive qPCR tests for P. falciparum decreased from 33% in 2003 to 2% in 2010 and increased to 6% in 2012, with antimalarial IgG antibody responses mirroring these trends. Parasite densities in peripheral blood on qPCR assay were higher in 2010-2012 (geometric mean [�SD], 409�1569 genomes per microliter) than in 2003-2005 (44�169 genomes per microliter, P=0.02), as were parasite densities in placental blood on histologic assessment (50�39% of infected erythrocytes vs. 4�6%, P<0.001). The malaria-associated reduction in maternal hemoglobin levels was larger in 2010-2012 (10.1�1.8 g per deciliter in infected women vs. 10.9�1.7 g per deciliter in uninfected women; mean difference, -0.82 g per deciliter; 95% confidence interval [CI], -1.39 to -0.25) than in 2003-2005 (10.5�1.1 g per deciliter vs. 10.6�1.5 g per deciliter; difference, -0.12 g per deciliter; 95% CI, -0.67 to 0.43), as was the reduction in birth weight (2863�440 g in women with past or chronic infections vs. 3070�482 g in uninfected women in 2010-2012; mean difference, -164.5 g; 95% CI, -289.7 to -39.4; and 2994�487 g vs. 3117�455 g in 2003-2005; difference, -44.8 g; 95% CI, -139.1 to 49.5). CONCLUSIONS: Antimalarial antibodies were reduced and the adverse consequences of P. falciparum infections were increased in pregnant women after 5 years of a decline in the prevalence of malaria. (Funded by Malaria Eradication Scientific Alliance and others.).",0
5888,26513111,Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct-acting antiviral,"Exhaustion of antiviral CD8(+) T cells contributes to persistence of hepatitis C viral (HCV) infection. This immune response has proved difficult to restore by therapeutic vaccination, even when HCV replication is suppressed using antiviral regimens containing type I interferon. Because immunomodulatory effects of type I interferon may be a factor in poor T-cell priming, we undertook therapeutic vaccination in two chronically infected chimpanzees during treatment with a direct-acting antiviral (DAA) targeting the HCV NS5b polymerase protein. Immunization with genetic vaccines encoding the HCV NS3-NS5b nonstructural proteins during DAA treatment resulted in a multifunctional CD8(+) T-cell response. However, these antiviral CD8(+) T cells did not prevent persistent replication of DAA-resistant HCV variants that emerged during treatment. Most vaccine-induced CD8(+) T cells targeted class I epitopes that were not conserved in the circulating virus. Exhausted intrahepatic CD8(+) T-cell targeting-conserved epitopes did not expand after vaccination, with a notable exception. A sustained, multifunctional CD8(+) T-cell response against at least one intact class I epitope was detected in blood after vaccination. Persistence of HCV was not due to mutational escape of this epitope. Instead, failure to control HCV replication was likely caused by localized exhaustion in the liver, where CD8(+) T-cell expression of the inhibitory receptor programmed cell death 1 increased 25-fold compared with those in circulation. CONCLUSION: Treatment with a DAA during therapeutic vaccination provided transient control of HCV replication and a multifunctional T-cell response, primarily against nonconserved class I epitopes; exhaustion of liver-infiltrating CD8(+) T cells that target conserved epitopes may not be averted when DAA therapy fails prematurely due to emergence of resistant HCV variants.",0
5889,26535513,Malignant Transformation of Hymenolepis nana in a Human Host,"Neoplasms occur naturally in invertebrates but are not known to develop in tapeworms. We observed nests of monomorphic, undifferentiated cells in samples from lymph-node and lung biopsies in a man infected with the human immunodeficiency virus (HIV). The morphologic features and invasive behavior of the cells were characteristic of cancer, but their small size suggested a nonhuman origin. A polymerase-chain-reaction (PCR) assay targeting eukaryotes identified Hymenolepis nana DNA. Although the cells were unrecognizable as tapeworm tissue, immunohistochemical staining and probe hybridization labeled the cells in situ. Comparative deep sequencing identified H. nana structural genomic variants that are compatible with mutations described in cancer. Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer.",0
5890,26536169,Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma,"BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). CONCLUSIONS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).",0
5891,26559576,Targeting Stem Cells in Chronic Myeloid Leukemia with a PPAR-? Agonist,Combining a tyrosine kinase inhibitor (imatinib) and a thiazolidinedione (pioglitazone) is proposed for the treatment of chronic myeloid leukemia.,0
5892,26559594,Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis,"Treatment of multidrug-resistant Mycobacterium tuberculosis is a challenge. This letter describes the emergence of resistance to new therapies, bedaquiline and delamanid.",0
5893,26637987,Persistence of seropositivity among persons vaccinated for hepatitis A during infancy by maternal antibody status: 15-year follow-up,"The effect of passively transferred maternal antibody to hepatitis A virus (anti-HAV) on the duration of seropositivity after hepatitis A vaccination during infancy and early childhood is unclear. We obtained levels of anti-HAV at intervals through age 15-16 years among three groups of Alaskan Native children who initiated a two-dose inactivated hepatitis A vaccination series at ages 6 months (group 1), 12 months (group 2), and 15 months (group 3), each group randomized according to maternal anti-HAV status. Seropositivity (anti-HAV ?20 mIU/mL) 30 years after the second vaccine dose among the three groups was predicted using a random effects model. One hundred eighty-three children participated in the study; follow-up did not differ significantly by vaccine group or maternal anti-HAV status. Although the frequency of seropositivity among all participants through age 10 years was high (100% among groups 2 and 3 and >90% among group 1), there was a decrease thereafter through age 15-16 years among group 1 children, who initiated vaccination at age 6 months (50%-75%), and among maternal anti-HAV-positive children in groups 2 and 3 (67%-87%), who initiated vaccination at ages 12 months and 15 months, respectively. Nonetheless, the model indicated that anti-HAV seropositivity should persist for ?30 years after vaccination in 64% of all participants; among those seropositive at age 15-16 years, 84% were predicted to remain so for ?30 years. CONCLUSION: Most children vaccinated during early childhood available for sampling maintained seropositivity through age 15-16 years; however, seropositivity was less frequent among those starting vaccination at age 6 months and among maternal antibody-positive participants who started vaccination at age 12 months or 15 months; overall, our findings support current vaccine recommendations and continued follow-up of this cohort.",0
5894,26735990,Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia,"BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS: We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS: In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS: An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).",0
5895,26789727,Assessment of Minimal Residual Disease in Standard-Risk AML,"BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.).",0
5896,26789866,Regulating Homeopathic Products - A Century of Dilute Interest,"In 2015, U.S. government agencies began considering greater regulation of both homeopathic drugs and the advertising of such products. These actions came after more than a century of missed opportunities to regulate homeopathic medicines.",0
5897,26789871,Mutations in TUBB8 and Human Oocyte Meiotic Arrest,"Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other ?-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one ?-tubulin polypeptide and one ?-tubulin polypeptide (?/?-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed ?-tubulin. The mutations affect chaperone-dependent folding and assembly of the ?/?-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).",0
5898,26789879,Kindling the Kidney,"Investigators have generated kidney-like organoids - complete with nephrons, collecting ducts, stroma, and vasculature - from induced pluripotent stem cells.",0
5899,26836220,National Cluster-Randomized Trial of Duty-Hour Flexibility in Surgical Training,"BACKGROUND: Concerns persist regarding the effect of current surgical resident duty-hour policies on patient outcomes, resident education, and resident well-being. METHODS: We conducted a national, cluster-randomized, pragmatic, noninferiority trial involving 117 general surgery residency programs in the United States (2014-2015 academic year). Programs were randomly assigned to current Accreditation Council for Graduate Medical Education (ACGME) duty-hour policies (standard-policy group) or more flexible policies that waived rules on maximum shift lengths and time off between shifts (flexible-policy group). Outcomes included the 30-day rate of postoperative death or serious complications (primary outcome), other postoperative complications, and resident perceptions and satisfaction regarding their well-being, education, and patient care. RESULTS: In an analysis of data from 138,691 patients, flexible, less-restrictive duty-hour policies were not associated with an increased rate of death or serious complications (9.1% in the flexible-policy group and 9.0% in the standard-policy group, P=0.92; unadjusted odds ratio for the flexible-policy group, 0.96; 92% confidence interval, 0.87 to 1.06; P=0.44; noninferiority criteria satisfied) or of any secondary postoperative outcomes studied. Among 4330 residents, those in programs assigned to flexible policies did not report significantly greater dissatisfaction with overall education quality (11.0% in the flexible-policy group and 10.7% in the standard-policy group, P=0.86) or well-being (14.9% and 12.0%, respectively; P=0.10). Residents under flexible policies were less likely than those under standard policies to perceive negative effects of duty-hour policies on multiple aspects of patient safety, continuity of care, professionalism, and resident education but were more likely to perceive negative effects on personal activities. There were no significant differences between study groups in resident-reported perception of the effect of fatigue on personal or patient safety. Residents in the flexible-policy group were less likely than those in the standard-policy group to report leaving during an operation (7.0% vs. 13.2%, P<0.001) or handing off active patient issues (32.0% vs. 46.3%, P<0.001). CONCLUSIONS: As compared with standard duty-hour policies, flexible, less-restrictive duty-hour policies for surgical residents were associated with noninferior patient outcomes and no significant difference in residents' satisfaction with overall well-being and education quality. (FIRST ClinicalTrials.gov number, NCT02050789.).",0
5900,26841242,Vibratory Urticaria Associated with a Missense Variant in ADGRE2,"Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).",0
5901,26849406,Cancer Stem cells and their cellular origins in primary liver and biliary tract cancers,"""Liver and biliary tract cancers are highly aggressive, are heterogeneous in their phenotypic traits, and result in clinical outcomes that are difficult to manage. Cancers have subpopulations of cells termed """"cancer stem cells"""" (CSCs) that share common intrinsic signaling pathways for self-renewal and differentiation with normal stem cells. These CSCs likely have the potential to evolve over time and to give rise to new genetically and functionally diverse subclones by accumulating genetic mutations. Extrinsic signaling from the tumor microenvironment, including the CSC niche, has been implicated in tumor initiation/progression and heterogeneity through dynamic crosstalk. CSCs have become recognized as pivotal sources of tumor initiation/progression, relapse/metastasis, and chemoresistance. CONCLUSION: The origins of CSCs are hypothesized to derive from the transformation of normal stem/progenitors and/or from the reprogramming of adult cells that converts them to stem/progenitor traits; however, the precise mechanisms have not yet been fully elucidated. (Hepatology 2016;64:645-651).""",0
5902,26863265,Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants,"BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).",0
5903,26910198,"Readmissions, Observation, and the Hospital Readmissions Reduction Program","BACKGROUND: The Hospital Readmissions Reduction Program, which is included in the Affordable Care Act (ACA), applies financial penalties to hospitals that have higher-than-expected readmission rates for targeted conditions. Some policy analysts worry that reductions in readmissions are being achieved by keeping returning patients in observation units instead of formally readmitting them to the hospital. We examined the changes in readmission rates and stays in observation units over time for targeted and nontargeted conditions and assessed whether hospitals that had greater increases in observation-service use had greater reductions in readmissions. METHODS: We compared monthly, hospital-level rates of readmission and observation-service use within 30 days after hospital discharge among Medicare elderly beneficiaries from October 2007 through May 2015. We used an interrupted time-series model to determine when trends changed and whether changes differed between targeted and nontargeted conditions. We assessed the correlation between changes in readmission rates and use of observation services after adoption of the ACA in March 2010. RESULTS: We analyzed data from 3387 hospitals. From 2007 to 2015, readmission rates for targeted conditions declined from 21.5% to 17.8%, and rates for nontargeted conditions declined from 15.3% to 13.1%. Shortly after passage of the ACA, the readmission rate declined quickly, especially for targeted conditions, and then continued to fall at a slower rate after October 2012 for both targeted and nontargeted conditions. Stays in observation units for targeted conditions increased from 2.6% in 2007 to 4.7% in 2015, and rates for nontargeted conditions increased from 2.5% to 4.2%. Within hospitals, there was no significant association between changes in observation-unit stays and readmissions after implementation of the ACA. CONCLUSIONS: Readmission trends are consistent with hospitals' responding to incentives to reduce readmissions, including the financial penalties for readmissions under the ACA. We did not find evidence that changes in observation-unit stays accounted for the decrease in readmissions.",0
5904,26928938,"Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis","Regulatory T cells (Treg ) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of Treg in the liver, suggesting that the local hepatic microenvironment might affect Treg stability, survival, and function. We hypothesized that interactions between Treg and endothelial cells during recruitment and then with epithelial cells within the liver affect Treg stability, survival, and function. To model this, we explored the function of Treg after migration through human hepatic sinusoidal-endothelium (postendothelial migrated Treg [PEM Treg ]) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of Treg . Our findings suggest that the intrahepatic microenvironment is highly enriched with proinflammatory cytokines but deficient in the Treg survival cytokine interleukin (IL)-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect Treg stability; however, functional capacity was reduced. Furthermore, the addition of exogenous IL-2 enhanced PEM Treg phosphorylated STAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL-2 in the inflamed liver. Liver-infiltrating Treg reside close to bile ducts and coculture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared with CD8 effector cells. Treg from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL-2 or blockade of CD95. CONCLUSION: Recruitment through endothelium does not impair Treg stability, but a proinflammatory microenvironment deficient in IL-2 leads to impaired function and increased susceptibility of Treg to epithelial cell-induced Fas-mediated apoptosis. These results provide a mechanism to explain Treg dysfunction in inflamed tissues and suggest that IL-2 supplementation, particularly if used in conjunction with Treg therapy, could restore immune homeostasis in inflammatory and autoimmune liver disease. (Hepatology 2016;64:138-150).",0
5905,26943128,Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants,"BACKGROUND: The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy. METHODS: We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age. RESULTS: In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe. CONCLUSIONS: The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.).",0
5906,26962729,Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors,"BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).",0
5907,26970079,Hedgehog regulates yes-associated protein 1 in regenerating mouse liver,"Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1- and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. CONCLUSIONS: Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post-PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. (Hepatology 2016;64:232-244).",0
5908,26970415,Development and Validation of a Disease-Specific Questionnaire to Assess Patient-Reported Symptoms in Polycystic Liver Disease,"Treatment of polycystic liver disease (PLD) focuses on symptom improvement. Generic questionnaires lack sensitivity to capture PLD-related symptoms, a prerequisite to determine effectiveness of therapy. We developed and validated a disease-specific questionnaire that assesses symptoms in PLD (PLD-Q). We identified 16 PLD-related symptoms (total score 0-100 points) by literature review and interviews with patients and clinicians. The developed PLD-Q was validated in Dutch (n = 200) and United States (US; n = 203) PLD patients. We assessed the correlation of PLD-Q total score with European Organization for Research and Treatment of Cancer (EORTC) symptom scale, global health visual analogue scale (VAS) of EQ-5D, and liver volume. To test discriminative validity, we compared PLD-Q total scores of patients with different PLD severity stages (Gigot classification) and PLD-Q total scores of PLD patients with general controls and polycystic kidney disease patients without PLD. Reproducibility was tested by comparing original test scores with 2-week retest scores. In total, 167 Dutch and 124 US patients returned the questionnaire. Correlation between PLD-Q total score and EORTC symptom scale (The Netherlands [NL], r = 0.788; US, r = 0.811) and global health VAS (NL, r = -0.517; US, r = -0.593) was good. There was no correlation of PLD-Q total score with liver volume (NL, r = 0.138; P = 0.236; US, r = 0.254; P = 0.052). Gigot type III individuals scored numerically higher than type II patients (NL, 46 vs. 40; P = 0.089; US, 48 vs. 36; P = 0.055). PLD patients scored higher on the PLD-Q total score than general controls (NL, 42 vs. 17; US, 40 vs. 13 points) and polycystic kidney disease patients without PLD (22 points). Reproducibility of PLD-Q was excellent (NL, r = 0.94; US, 0.96). CONCLUSION: PLD-Q is a valid, reproducible, and sensitive disease-specific questionnaire that can be used to assess PLD-related symptoms in clinical care and future research. (Hepatology 2016;64:151-160).",0
5909,27050205,Fresh Fruit Consumption and Major Cardiovascular Disease in China,"""BACKGROUND: In Western populations, a higher level of fruit consumption has been associated with a lower risk of cardiovascular disease, but little is known about such associations in China, where the consumption level is low and rates of stroke are high. METHODS: Between 2004 and 2008, we recruited 512,891 adults, 30 to 79 years of age, from 10 diverse localities in China. During 3.2 million person-years of follow-up, 5173 deaths from cardiovascular disease, 2551 incident major coronary events (fatal or nonfatal), 14,579 ischemic strokes, and 3523 intracerebral hemorrhages were recorded among the 451,665 participants who did not have a history of cardiovascular disease or antihypertensive treatments at baseline. Cox regression yielded adjusted hazard ratios relating fresh fruit consumption to disease rates. RESULTS: Overall, 18.0% of participants reported consuming fresh fruit daily. As compared with participants who never or rarely consumed fresh fruit (the """"nonconsumption"""" category), those who ate fresh fruit daily had lower systolic blood pressure (by 4.0 mm Hg) and blood glucose levels (by 0.5 mmol per liter [9.0 mg per deciliter]) (P<0.001 for trend for both comparisons). The adjusted hazard ratios for daily consumption versus nonconsumption were 0.60 (95% confidence interval [CI], 0.54 to 0.67) for cardiovascular death, and 0.66 (95% CI, 0.58 to 0.75), 0.75 (95% CI, 0.72 to 0.79), and 0.64 (95% CI, 0.56 to 0.74), respectively, for incident major coronary events, ischemic stroke, and hemorrhagic stroke. There was a strong log-linear dose-response relationship between the incidence of each outcome and the amount of fresh fruit consumed. These associations were similar across the 10 study regions and in subgroups of participants defined by baseline characteristics. CONCLUSIONS: Among Chinese adults, a higher level of fruit consumption was associated with lower blood pressure and blood glucose levels and, largely independent of these and other dietary and nondietary factors, with significantly lower risks of major cardiovascular diseases. (Funded by the Wellcome Trust and others.).""",0
5910,27074035,Two-Year Costs and Quality in the Comprehensive Primary Care Initiative,"BACKGROUND: The 4-year, multipayer Comprehensive Primary Care Initiative was started in October 2012 to determine whether several forms of support would produce changes in care delivery that would improve the quality and reduce the costs of care at 497 primary care practices in seven regions across the United States. Support included the provision of care-management fees, the opportunity to earn shared savings, and the provision of data feedback and learning support. METHODS: We tracked changes in the delivery of care by practices participating in the initiative and used difference-in-differences regressions to compare changes over the first 2 years of the initiative in Medicare expenditures, health care utilization, claims-based measures of quality, and patient experience for Medicare fee-for-service beneficiaries attributed to initiative practices and a group of matched comparison practices. RESULTS: During the first 2 years, initiative practices received a median of $115,000 per clinician in care-management fees. The practices reported improvements in approaches to the delivery of primary care in areas such as management of the care of high-risk patients and enhanced access to care. Changes in average monthly Medicare expenditures per beneficiary did not differ significantly between initiative and comparison practices when care-management fees were not taken into account (-$11; 95% confidence interval [CI], -$23 to $1; P=0.07; negative values indicate less growth in spending at initiative practices) or when these fees were taken into account ($7; 95% CI, -$5 to $19; P=0.27). The only significant differences in other measures were a 3% reduction in primary care visits for initiative practices relative to comparison practices (P<0.001) and changes in two of the six domains of patient experience--discussion of decisions regarding medication with patients and the provision of support for patients taking care of their own health--both of which showed a small improvement in initiative practices relative to comparison practices (P=0.006 and P<0.001, respectively). CONCLUSIONS: Midway through this 4-year intervention, practices participating in the initiative have reported progress in transforming the delivery of primary care. However, at this point these practices have not yet shown savings in expenditures for Medicare Parts A and B after accounting for care-management fees, nor have they shown an appreciable improvement in the quality of care or patient experience. (Funded by the Department of Health and Human Services, Centers for Medicare and Medicaid Services; ClinicalTrials.gov number, NCT02320591.).",0
5911,27074389,Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood,"BACKGROUND: In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood. METHODS: We grouped data on BMI, as measured from 1967 through 2010 in 2.3 million Israeli adolescents (mean age, 17.3�0.4 years), according to age- and sex-specific percentiles from the U.S. Centers for Disease Control and Prevention. Primary outcomes were the number of deaths attributed to coronary heart disease, stroke, sudden death from an unknown cause, or a combination of all three categories (total cardiovascular causes) by mid-2011. Cox proportional-hazards models were used. RESULTS: During 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from cardiovascular causes, including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death. On multivariable analysis, there was a graded increase in the risk of death from cardiovascular causes and all causes that started among participants in the group that was in the 50th to 74th percentiles of BMI (i.e., within the accepted normal range). Hazard ratios in the obese group (?95th percentile for BMI), as compared with the reference group in the 5th to 24th percentiles, were 4.9 (95% confidence interval [CI], 3.9 to 6.1) for death from coronary heart disease, 2.6 (95% CI, 1.7 to 4.1) for death from stroke, 2.1 (95% CI, 1.5 to 2.9) for sudden death, and 3.5 (95% CI, 2.9 to 4.1) for death from total cardiovascular causes, after adjustment for sex, age, birth year, sociodemographic characteristics, and height. Hazard ratios for death from cardiovascular causes in the same percentile groups increased from 2.0 (95% CI, 1.1 to 3.9) during follow-up for 0 to 10 years to 4.1 (95% CI, 3.1 to 5.4) during follow-up for 30 to 40 years; during both periods, hazard ratios were consistently high for death from coronary heart disease. Findings persisted in extensive sensitivity analyses. CONCLUSIONS: A BMI in the 50th to 74th percentiles, within the accepted normal range, during adolescence was associated with increased cardiovascular and all-cause mortality during 40 years of follow-up. Overweight and obesity were strongly associated with increased cardiovascular mortality in adulthood. (Funded by the Environment and Health Fund.).",0
5912,27075832,Early Performance of Accountable Care Organizations in Medicare,"BACKGROUND: In the Medicare Shared Savings Program (MSSP), accountable care organizations (ACOs) have financial incentives to lower spending and improve quality. We used quasi-experimental methods to assess the early performance of MSSP ACOs. METHODS: Using Medicare claims from 2009 through 2013 and a difference-in-differences design, we compared changes in spending and in performance on quality measures from before the start of ACO contracts to after the start of the contracts between beneficiaries served by the 220 ACOs entering the MSSP in mid-2012 (2012 ACO cohort) or January 2013 (2013 ACO cohort) and those served by non-ACO providers (control group), with adjustment for geographic area and beneficiary characteristics. We analyzed the 2012 and 2013 ACO cohorts separately because entry time could reflect the capacity of an ACO to achieve savings. We compared ACO savings according to organizational structure, baseline spending, and concurrent ACO contracting with commercial insurers. RESULTS: Adjusted Medicare spending and spending trends were similar in the ACO cohorts and the control group during the precontract period. In 2013, the differential change (i.e., the between-group difference in the change from the precontract period) in total adjusted annual spending was -$144 per beneficiary in the 2012 ACO cohort as compared with the control group (P=0.02), consistent with a 1.4% savings, but only -$3 per beneficiary in the 2013 ACO cohort as compared with the control group (P=0.96). Estimated savings were consistently greater in independent primary care groups than in hospital-integrated groups among 2012 and 2013 MSSP entrants (P=0.005 for interaction). MSSP contracts were associated with improved performance on some quality measures and unchanged performance on others. CONCLUSIONS: The first full year of MSSP contracts was associated with early reductions in Medicare spending among 2012 entrants but not among 2013 entrants. Savings were greater in independent primary care groups than in hospital-integrated groups.",0
5913,27168434,Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma,"BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [�SD] age, 26.0�1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).",0
5914,27273268,A highly specific and sensitive hepatitis C virus antigen enzyme immunoassay for One-step diagnosis of viremic hepatitis C virus infection,"The current standard in diagnosing hepatitis C virus (HCV) infection requires two sequential steps: anti-HCV test to screen, followed by HCV RNA reverse-transcription polymerase chain reaction to confirm viremic HCV (V-HCV) infection. HCV core antigen tests provided potential for possible one-step diagnosis. However, low sensitivity and specificity limit their clinical utility. The present study developed a novel HCV antigens enzyme immunoassay (HCV-Ags EIA) and assessed its sensitivity, specificity, and utility for one-step diagnosis of V-HCV infection using 365 serum specimens, including 176 without and 189 with V-HCV infection. First, we confirmed the presence of HCV nonstructural proteins 3, 4b, and 5a besides HCV core antigen during HCV infection and developed a novel HCV-Ags EIA through simultaneous detection of all four HCV proteins. For the first time, the present study demonstrated that serum sample denaturation decreases the test specificity due to release of HCV-Ags sequestered in HCV immune complexes and should not be used in any HCV-Ags, including all the current HCV core antigen assays. On the other hand, using sample nondenaturation, the HCV-Ags EIA results showed 98.9% specificity and 100% sensitivity compared to serum anti-HCV and HCV RNA reverse-transcription polymerase chain reaction results. Using serum sample dilution, and nondenaturation, the lowest limits of detection of the HCV-Ags EIA were equivalent to serum HCV RNA levels of approximate 150-250 IU/mL. CONCLUSIONS: The highly specific and sensitive HCV-Ags EIA developed in the present study has the lowest limit of detection equivalent to serum HCV RNA levels of 150-250 IU/mL; using nondenaturation of serum samples, our HCV-Ags EIA reliably differentiated V-HCV infection from resolved HCV infection, accomplishing screening and diagnosis of V-HCV infection in one step. (Hepatology 2016;64:415-424).",0
5915,27276561,Genomic Classification and Prognosis in Acute Myeloid Leukemia,"BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. RESULTS: We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. CONCLUSIONS: The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.).",0
5916,27299809,Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis,"BACKGROUND: Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS: We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS: In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS: In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).",0
5917,27332904,A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms,"BACKGROUND: Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale. METHODS: We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci. RESULTS: We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas--one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China--with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay. CONCLUSIONS: No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.).",0
5918,27355532,"Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children","BACKGROUND: The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules. METHODS: We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ?37.5�C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group. RESULTS: Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]). CONCLUSIONS: A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).",0
5919,27355534,Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease,"BACKGROUND: Cortical-bone fragility is a common feature in osteoporosis that is linked to nonvertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS: We evaluated four patients with Pyle's disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger sequencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS: In all affected patients, we found biallelic truncating mutations in SFRP4, the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4, like persons with Pyle's disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treatment of Sfrp4-deficient mice with a soluble Bmp2 receptor (RAP-661) or with antibodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS: Our study showed that Pyle's disease was caused by a deficiency of sFRP4, that cortical-bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss National Foundation and the National Institutes of Health.).",0
5920,27410922,Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting,"BACKGROUND: We examined the efficacy of olanzapine for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy. METHODS: In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3-receptor antagonist, in patients with no previous chemotherapy who were receiving cisplatin (?70 mg per square meter of body-surface area) or cyclophosphamide-doxorubicin. The doses of the three concomitant drugs administered before and after chemotherapy were similar in the two groups. The two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. Nausea prevention was the primary end point; a complete response (no emesis and no use of rescue medication) was a secondary end point. RESULTS: In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P=0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P=0.002), and the overall 120-hour period (37% vs. 22%, P=0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2. CONCLUSIONS: Olanzapine, as compared with placebo, significantly improved nausea prevention, as well as the complete-response rate, among previously untreated patients who were receiving highly emetogenic chemotherapy. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02116530.).",0
5921,27468058,Immunogenicity of a Meningococcal B Vaccine during a University Outbreak,"BACKROUND: In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak. METHODS: We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher. RESULTS: Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson's correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearson's correlation,-0.06; P=0.43). CONCLUSIONS: Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.).",0
5922,27468060,Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist,"Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).",0
5923,27482645,Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling,"Liver is one of the most common sites of cancer metastasis. Once disseminated, the prognosis is poor as these tumors often display generalized chemoresistance, particularly for carcinomas that derive not from the aerodigestive tract. When these cancers seed the liver, the aggressive cells usually undergo a mesenchymal to epithelial reverting transition that both aids colonization and renders the tumor cells chemoresistant. In vitro studies demonstrate that hepatocytes drive this phenotypic shift. However, the in vivo evidence and the molecular signals that protect these cells from induced death are yet to be defined. Herein, we report that membrane surface E-cadherin-expressing prostate cancer cells were resistant to cell death by chemotherapeutic drugs but E-cadherin null cells or those expressing E-cadherin only in the cytoplasm were sensitive to death signals and chemotherapies both in vitro and in vivo. While cell-cell E-cadherin ligandation reduced mitogenesis, this chemoprotection was proliferation-independent as killing of both 5-ethynyl-2'-deoxyuridine-positive (or Ki67(+) ) and 5-ethynyl-2'-deoxyuridine-negative (Ki67(-) ) cells was inversely related to membrane-bound E-cadherin. Inhibiting the canonical survival kinases extracellular signal-regulated protein kinases, protein kinase B, and Janus kinase, which are activated by chemotherapeutics in epithelial cell-transitioned prostate cancer, abrogated the chemoresistance both in cell culture and in animal models of metastatic cancer. For disseminated tumors, protein kinase B disruption in itself had no effect on tumor survival but was synergistic with chemotherapy, leading to increased killing. CONCLUSION: Liver microenvironment-driven phenotypic switching of carcinoma cells and subsequent survival signaling results in activation of canonical survival pathways that protect the disseminated prostate cancer liver micrometastases in a proliferation-independent manner, and these pathways can be targeted as an adjuvant treatment to improve the efficacy of traditional chemotherapeutics (Hepatology 2016;64:1725-1742).",0
5924,27518662,"Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers","BACKGROUND: Studies have suggested that sickle cell trait elevates the risks of exertional rhabdomyolysis and death. We conducted a study of sickle cell trait in relation to these outcomes, controlling for known risk factors for exertional rhabdomyolysis, in a large population of active persons who had undergone laboratory tests for hemoglobin AS (HbAS) and who were subject to exertional-injury precautions. METHODS: We used Cox proportional-hazards models to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status among 47,944 black soldiers who had undergone testing for HbAS and who were on active duty in the U.S. Army between January 2011 and December 2014. We used the Stanford Military Data Repository, which contains comprehensive medical and administrative data on all active-duty soldiers. RESULTS: There was no significant difference in the risk of death among soldiers with sickle cell trait, as compared with those without the trait (hazard ratio, 0.99; 95% confidence interval [CI], 0.46 to 2.13; P=0.97), but the trait was associated with a significantly higher adjusted risk of exertional rhabdomyolysis (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P=0.008). This effect was similar in magnitude to that associated with tobacco use, as compared with no use (hazard ratio, 1.54; 95% CI, 1.23 to 1.94; P<0.001), and to that associated with having a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30.0 or more, as compared with a BMI of less than 25.0 (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P=0.03). The effect was less than that associated with recent use of a statin, as compared with no use (hazard ratio, 2.89; 95% CI, 1.51 to 5.55; P=0.001), or an antipsychotic agent (hazard ratio, 3.02; 95% CI, 1.34 to 6.82; P=0.008). CONCLUSIONS: Sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis. (Funded by the National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences.).",0
5925,27530084,First international external quality assessment for hepatitis delta virus RNA quantification in plasma,"Infection by the hepatitis delta virus (HDV), a satellite of the hepatitis B virus (HBV), increases viral liver disease severity. Its diagnosis is thus vital for HBV-infected patients. HDV-RNA load (HDVL) should be assessed and monitored in plasma using real-time reverse-transcriptase polymerase chain reaction assays. Taking advantage of the recently-developed World Health Organization (WHO) HDV international standard (WHO-HDV-IS), the first international external quality control for HDVL quantification was performed. Two panels of samples were sent to 28 laboratories in 17 countries worldwide. Panel A comprised 20 clinical samples of various genotypes (1, 2, and 5-8) and viral loads, including two negative controls. Panel B, composed of dilutions of the WHO-HDV-IS, allowed the conversion of results from copies/mL into IU/mL for HDVL standardization and interlaboratory comparisons. Comprehensive analysis revealed a very high heterogeneity of assay characteristics, including their technical steps and technologies. Thirteen labs (46.3%) properly quantified all 18 positive samples; 16 (57.1%) failed to detect one to up to 10 samples, and several others underestimated (>3 log IU/mL) HDVL of African genotype strains (1 and 5-8). Discrepancies were mainly attributed to either primers or probe mismatches related to the high genetic variability of HDV and, possibly, to the complex secondary structure of the target genomic RNA. The labs were grouped in four clusters by the statistical analysis of their performances. The best clusters comprised the 17 labs that obtained the expected HDVL values, including five that otherwise failed to quantify one or two samples. CONCLUSION: The results of this international quality-control study underline the urgent need to improve methods used to monitor HDV viremia and will be instrumental in achieving that goal. (Hepatology 2016;64:1483-1494).",0
5926,27531557,Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ,"In the adult liver, the Hippo pathway mammalian STE20-like protein kinases 1 and 2 and large tumor suppressor homologs 1 and 2 (LATS1/2) control activation of the transcriptional coactivators Yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ) in hepatocytes and biliary epithelial cells, thereby regulating liver cell proliferation, differentiation, and malignant transformation. Less is known about the contribution of Hippo signaling to liver development. We used conditional mutagenesis to show that the Hippo signaling pathway kinases LATS1 and LATS2 are redundantly required during mouse liver development to repress YAP and TAZ in both the biliary epithelial and hepatocyte lineages. In the absence of LATS1/2, biliary epithelial cells exhibit excess proliferation while hepatoblasts fail to mature into hepatocytes, defects that result in perinatal lethality. Using an in vitro hepatocyte differentiation assay, we demonstrate that YAP activity decreases and Hippo pathway kinase activities increase upon differentiation. In addition, we show that YAP activation in vitro, resulting from either depletion of its negative regulators LATS1/2 or expression of a mutant form of YAP that is less efficiently phosphorylated by LATS1/2, results in transcriptional suppression of genes that normally accompany hepatocyte maturation. Moreover, we provide evidence that YAP activity is repressed by Hippo pathway activation upon hepatocytic maturation in vitro. Finally, we examine the localization of YAP during fetal liver development and show that higher levels of YAP are found in biliary epithelial cells, while in hepatocytes YAP levels decrease with hepatocyte maturation. CONCLUSION: Hippo signaling, mediated by the LATS1 and LATS2 kinases, is required to restrict YAP and TAZ activation during both biliary and hepatocyte differentiation. These findings suggest that dynamic regulation of the Hippo signaling pathway plays an important role in differentiation and functional maturation of the liver. (Hepatology 2016;64:1757-1772).",0
5927,27532830,Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes,"BACKGROUND: In patients with type 1 diabetes who are not pregnant, closed-loop (automated) insulin delivery can provide better glycemic control than sensor-augmented pump therapy, but data are lacking on the efficacy, safety, and feasibility of closed-loop therapy during pregnancy. METHODS: We performed an open-label, randomized, crossover study comparing overnight closed-loop therapy with sensor-augmented pump therapy, followed by a continuation phase in which the closed-loop system was used day and night. Sixteen pregnant women with type 1 diabetes completed 4 weeks of closed-loop pump therapy (intervention) and sensor-augmented pump therapy (control) in random order. During the continuation phase, 14 of the participants used the closed-loop system day and night until delivery. The primary outcome was the percentage of time that overnight glucose levels were within the target range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]). RESULTS: The percentage of time that overnight glucose levels were in the target range was higher during closed-loop therapy than during control therapy (74.7% vs. 59.5%; absolute difference, 15.2 percentage points; 95% confidence interval, 6.1 to 24.2; P=0.002). The overnight mean glucose level was lower during closed-loop therapy than during control therapy (119 vs. 133 mg per deciliter [6.6 vs. 7.4 mmol per liter], P=0.009). There were no significant differences between closed-loop and control therapy in the percentage of time in which glucose levels were below the target range (1.3% and 1.9%, respectively; P=0.28), in insulin doses, or in adverse-event rates. During the continuation phase (up to 14.6 additional weeks, including antenatal hospitalizations, labor, and delivery), glucose levels were in the target range 68.7% of the time; the mean glucose level was 126 mg per deciliter (7.0 mmol per liter). No episodes of severe hypoglycemia requiring third-party assistance occurred during either phase. CONCLUSIONS: Overnight closed-loop therapy resulted in better glucose control than sensor-augmented pump therapy in pregnant women with type 1 diabetes. Women receiving day-and-night closed-loop therapy maintained glycemic control during a high proportion of the time in a period that encompassed antenatal hospital admission, labor, and delivery. (Funded by the National Institute for Health Research and others; Current Controlled Trials number, ISRCTN71510001.).",0
5928,27533020,N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway,"Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. CONCLUSION: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).",0
5929,27559197,Lung Transplantation and Survival in Children with Cystic Fibrosis,"BACKGROUND: The effects of lung transplantation on the survival and quality of life in children with cystic fibrosis are uncertain. METHODS: We used data from the U.S. Cystic Fibrosis Foundation Patient Registry and from the Organ Procurement and Transplantation Network to identify children with cystic fibrosis who were on the waiting list for lung transplantation during the period from 1992 through 2002. We performed proportional-hazards survival modeling, using multiple clinically relevant covariates that were available before the children were on the waiting list and the interactions of these covariates with lung transplantation as a time-dependent covariate. The data were insufficient in quality and quantity for a retrospective quality-of-life analysis. RESULTS: A total of 248 of the 514 children on the waiting list underwent lung transplantation in the United States during the period from 1992 through 2002. Proportional-hazards modeling identified four variables besides transplantation that were associated with changes in survival. Burkholderia cepacia infection was associated with a trend toward decreased survival, regardless of whether the patient underwent transplantation. A diagnosis of diabetes before the patient was placed on the waiting list decreased survival while the patient was on the waiting list but did not decrease survival after transplantation, whereas older age did not affect waiting-list survival but decreased post-transplantation survival. Staphylococcus aureus infection increased waiting-list survival but decreased post-transplantation survival. Using age, diabetes status, and S. aureus infection status as covariates, we estimated the effect of transplantation on survival for each patient group, expressed as a hazard factor of less than 1 for a benefit and more than 1 for a risk of harm. Five patients had a significant estimated benefit, 283 patients had a significant risk of harm, 102 patients had an insignificant benefit, and 124 patients had an insignificant risk of harm associated with lung transplantation. CONCLUSIONS: Our analyses estimated clearly improved survival for only 5 of 514 patients on the waiting list for lung transplantation. Prolongation of life by means of lung transplantation should not be expected in children with cystic fibrosis. A prospective, randomized trial is needed to clarify whether and when patients derive a survival and quality-of-life benefit from lung transplantation.",0
5930,27602507,Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension,"""BACKGROUND: The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. METHODS: From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to """"upper good recovery"""" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. RESULTS: The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03). CONCLUSIONS: At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).""",0
5931,27642141,Hepatitis C virus double-stranded RNA is the predominant form in human liver and in interferon-treated cells,"Hepatitis C virus (HCV) is unique among RNA viruses in its ability to establish chronic infection in the majority of exposed adults. HCV persists in the liver despite interferon (IFN)-stimulated gene (ISG) induction; robust induction actually predicts treatment failure and viral persistence. It is unclear which forms of HCV RNA are associated with ISG induction and IFN resistance during natural infections. To thoroughly delineate HCV RNA populations, we developed conditions that fully separate the strands of long double-stranded RNA (dsRNA) and allow the released RNAs to be quantified in reverse transcription/polymerase chain reaction assays. These methods revealed that dsRNA, a pathogen-associated molecular pattern (PAMP), comprised 52% (standard deviation, 28%) of the HCV RNA in the livers of patients with chronic infection. HCV dsRNA was proportionally higher in patients with the unfavorable IL28B TT (rs12979860) genotype. Higher ratios of HCV double-stranded to single-stranded RNA (ssRNA) correlated positively with ISG induction. In Huh-7.5 cells, IFN treatment increased the total amount of HCV dsRNA through a process that required de novo viral RNA synthesis and shifted the ratio of viral dsRNA/ssRNA in favor of dsRNA. This shift was blocked by ribavirin (RBV), an antiviral drug that reduces relapse in HCV patients. Northern blotting established that HCV dsRNA contained genome-length minus strands. CONCLUSION: HCV dsRNA is the predominant form in the HCV-infected liver and has features of both a PAMP and a genomic reservoir. Interferon treatment increased rather than decreased HCV dsRNA. This unexpected finding suggests that HCV produces dsRNA in response to IFN, potentially to antagonize antiviral defenses. (Hepatology 2017;66:357-370).",0
5932,27689813,"Conformational Change in the Mechanism of Inclusion of Ketoprofen in β-Cyclodextrin: NMR Spectroscopy, Ab Initio Calculations, Molecular Dynamics Simulations, and Photoreactivity","Inclusion of drugs in cyclodextrins (CDs) is a recognized tool for modifying several properties such as solubility, stability, bioavailability, and so on. The photoreactive behavior of the β-CD/ketoprofen (KP) complex upon UV exposure showed a significant increase in photodecarboxylation, whereas the secondary degradation products by hydroxylation of the benzophenone moiety were inhibited. The results may account for an improvement of KP photophysical properties upon inclusion, thus better fostering its topical use. To correlate the structural details of the inclusion with these results, an NMR spectroscopic study of KP upon inclusion in β-CD was performed. Effects of the magnetically anisotropic centers of KP, changing their orientations upon inclusion and giving chemical shift variations, were specifically correlated with the results of the molecular dynamic simulations and ab initio calculations. In the large variety of papers focusing on the structural analysis of β-CD complexes, this work represents one of the few examples in which a detailed analysis of these simultaneous upfield-downfield NMR shifts of the same aromatic molecule upon inclusion is reported. Interestingly, the results demonstrate that the observed upfield and downfield shifts upon inclusion are not related to any direct magnetic role of β-CD. The conformational change of KP upon the inclusion process consists of a slight reduction in the angle between the two phenyl rings and in a remarkable reduction in the mobility of the carboxyl group, the latter being one of the main contributions to the NMR resonance shifts. These structural details help in understanding the features of the inclusion complex and, eventually, the driving force for its formation. ",0
5933,27689932,Professional Variability in Decision Making in Modern Dentistry: A Pilot Study,"Dental treatment planning is usually expected to take account of the individual patient's clinical risks and benefits. Ideally, the therapeutic choice for each and every patient should be based on adequate clinical diagnostics and risk assessment that facilitates stabilization of the patient's clinical condition as well as prevents further oral impairment. However, identification of the most suitable approach tends to become more and more challenging as the number of therapeutic alternatives continues to increase due to medical innovation. In this study, the challenge of decision making in modern dentistry is illustrated using the example of bounded edentulous spaces. Many therapeutic alternatives exist for such clinical scenarios, including a noninvasive monitoring approach, minimally invasive tooth recontouring, orthodontic and prosthodontic treatment, and implant placement. The findings of this pilot study highlight the utmost relevance of incorporating individual patients' needs and risks into clinical treatment planning and providing appropriate guidelines. ",0
5934,27723434,Mapping Plasmodium falciparum Mortality in Africa between 1990 and 2015,"BACKGROUND: Malaria control has not been routinely informed by the assessment of subnational variation in malaria deaths. We combined data from the Malaria Atlas Project and the Global Burden of Disease Study to estimate malaria mortality across sub-Saharan Africa on a grid of 5 km(2) from 1990 through 2015. METHODS: We estimated malaria mortality using a spatiotemporal modeling framework of geolocated data (i.e., with known latitude and longitude) on the clinical incidence of malaria, coverage of antimalarial drug treatment, case fatality rate, and population distribution according to age. RESULTS: Across sub-Saharan Africa during the past 15 years, we estimated that there was an overall decrease of 57% (95% uncertainty interval, 46 to 65) in the rate of malaria deaths, from 12.5 (95% uncertainty interval, 8.3 to 17.0) per 10,000 population in 2000 to 5.4 (95% uncertainty interval, 3.4 to 7.9) in 2015. This led to an overall decrease of 37% (95% uncertainty interval, 36 to 39) in the number of malaria deaths annually, from 1,007,000 (95% uncertainty interval, 666,000 to 1,376,000) to 631,000 (95% uncertainty interval, 394,000 to 914,000). The share of malaria deaths among children younger than 5 years of age ranged from more than 80% at a rate of death of more than 25 per 10,000 to less than 40% at rates below 1 per 10,000. Areas with high malaria mortality (>10 per 10,000) and low coverage (<50%) of insecticide-treated bed nets and antimalarial drugs included much of Nigeria, Angola, and Cameroon and parts of the Central African Republic, Congo, Guinea, and Equatorial Guinea. CONCLUSIONS: We estimated that there was an overall decrease of 57% in the rate of death from malaria across sub-Saharan Africa over the past 15 years and identified several countries in which high rates of death were associated with low coverage of antimalarial treatment and prevention programs. (Funded by the Bill and Melinda Gates Foundation and others.).",0
5935,27771985,Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting,"BACKGROUND: We previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report the results at 5 years (the end of the trial). METHODS: A total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. RESULTS: There were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-pump CABG, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72) or in the rates of the components of the outcome, including repeat coronary revascularization, which was performed in 2.8% of the patients in the off-pump group and in 2.3% of the patients in the on-pump group (hazard ratio, 1.21; 95% CI, 0.85 to 1.73; P=0.29). The secondary outcome for the overall period of the trial - the mean cost in U.S. dollars per patient - also did not differ significantly between the off-pump group and the on-pump group ($15,107 and $14,992, respectively; between-group difference, $115; 95% CI, -$697 to $927). There were no significant between-group differences in quality-of-life measures. CONCLUSIONS: In our trial, the rate of the composite outcome of death, stroke, myocardial infarction, renal failure, or repeat revascularization at 5 years of follow-up was similar among patients who underwent off-pump CABG and those who underwent on-pump CABG. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .).",0
5936,27774647,Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart,"Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-? coactivator 1?, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-? coactivator 1? overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice. CONCLUSIONS: Decreased proliferator-activated receptor-? coactivator 1? expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201).",0
5937,27863453,"A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins","Introduction of direct-acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral-targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell-based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP-mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan-genotypic anti-HBV activity and was also effective against a clinically relevant nucleoside analog-resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more-potent anti-HBV activity over PAC. CONCLUSION: PAC and its analogs represent a new class of anti-HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well-tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2017;65:1104-1116).",0
5938,27959697,Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation,"BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77�10(-7)). CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).",0
5939,27973993,Zombie Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York,"""BACKGROUND: New psychoactive substances constitute a growing and dynamic class of abused drugs in the United States. On July 12, 2016, a synthetic cannabinoid caused mass intoxication of 33 persons in one New York City neighborhood, in an event described in the popular press as a """"zombie"""" outbreak because of the appearance of the intoxicated persons. METHODS: We obtained and tested serum, whole blood, and urine samples from 8 patients among the 18 who were transported to local hospitals; we also tested a sample of the herbal """"incense"""" product """"AK-47 24 Karat Gold,"""" which was implicated in the outbreak. Samples were analyzed by means of liquid chromatography-quadrupole time-of-flight mass spectrometry. RESULTS: The synthetic cannabinoid methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB) was identified in AK-47 24 Karat Gold at a mean (�SD) concentration of 16.0�3.9 mg per gram. The de-esterified acid metabolite was found in the serum or whole blood of all eight patients, with concentrations ranging from 77 to 636 ng per milliliter. CONCLUSIONS: The potency of the synthetic cannabinoid identified in these analyses is consistent with strong depressant effects that account for the """"zombielike"""" behavior reported in this mass intoxication. AMB-FUBINACA is an example of the emerging class of """"ultrapotent"""" synthetic cannabinoids and poses a public health concern. Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action.""",0
5940,27997681,The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs,"A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type-specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor-binding domain (?123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2-CD81 receptor interactions, suggesting improved bNAb epitope exposure. In this study, the immunogenicity of ?123 was examined. We show that high-molecular-weight forms of ?123 elicit distinct antibody specificities with potent and broad neutralizing activity against all seven HCV genotypes. Antibody competition studies revealed that immune sera raised to high-molecular-weight ?123 was poly specific, given that it inhibited the binding of human bNAbs directed to three major neutralization epitopes on E2. By contrast, the immune sera raised to monomeric ?123 predominantly blocked the binding of a non-neutralizing antibody to ?123, while having reduced ability to block bNAb binding to E2, and neutralization was largely toward the homologous genotype. This increased ability of oligomeric ?123 to generate bNAbs correlates with occlusion of the non-neutralizing face of E2 in this glycoprotein form. CONCLUSION: The results from this study reveal new information on the antigenic and immunogenic potential of E2-based immunogens and provide a pathway for the development of a simple, recombinant protein-based prophylactic vaccine for HCV with potential for universal protection. (Hepatology 2017;65:1117-1131).",0
5941,27997980,New therapeutic concepts in bile acid transport and signaling for management of cholestasis,"The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA-induced gut hormones, fibroblast growth factor 19 and glucagon-like peptide 1, and the BA transport systems, apical sodium-dependent bile acid transporter and Na(+) -taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393-1404).",0
5942,28029926,Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring,"BACKGROUND: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS: We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood(2010) (COPSAC(2010)) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS: A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS: Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).",0
5943,28029927,Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy,"A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13R?2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13R?2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).",0
5944,28074885,"First objective evaluation of taste sensitivity to 6-n-propylthiouracil (PROP), a paradigm gustatory stimulus in humans","Practical and reliable methods for the objective measure of taste function are critically important for studying eating behavior and taste function impairment. Here, we present direct measures of human gustatory response to a prototypical bitter compound, 6-n-propyltiouracil (PROP), obtained by electrophysiological recordings from the tongue of subjects who were classified for taster status and genotyped for the specific receptor gene (TAS2R38), and in which taste papilla density was determined. PROP stimulation evoked negative slow potentials that represent the summated depolarization of taste cells. Depolarization amplitude and rate were correlated with papilla density and perceived bitterness, and associated with taster status and TAS2R38. Our study provides a robust and generalizable research tool for the quantitative measure of peripheral taste function, which can greatly help to resolve controversial outcomes on the PROP phenotype role in taste perception and food preferences, and be potentially useful for evaluating nutritional status and health. ",0
5945,28075369,Validation of a Dish-Based Semiquantitative Food Questionnaire in Rural Bangladesh,"A locally validated tool was needed to evaluate long-term dietary intake in rural Bangladesh. We assessed the validity of a 42-item dish-based semi-quantitative food frequency questionnaire (FFQ) using two 3-day food diaries (FDs). We selected a random subset of 47 families (190 participants) from a longitudinal arsenic biomonitoring study in Bangladesh to administer the FFQ. Two 3-day FDs were completed by the female head of the households and we used an adult male equivalent method to estimate the FD for the other participants. Food and nutrient intakes measured by FFQ and FD were compared using Pearson's and Spearman's correlation, paired  ",0
5946,28075446,NF‑κB inhibition is associated with OPN/MMP‑9 downregulation in cutaneous melanoma,"The development of cutaneous melanoma is influenced by genetic factors, including BRAF mutations and environmental factors, such as ultraviolet exposure. Its progression has been also associated with the involvement of several tumour microenvironmental molecules. Among these, nuclear factor‑κB (NF‑κB) has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase‑9 (MMP‑9) activation. However, whether NF‑κB plays a role in the development and progression of melanoma in association with the OPN/MMP‑9 axis according to the BRAFV600E mutation status has not been investigated in detail to date. Thus, in the present study, in order to shed light on this matter, 148 patients with melanoma and 53 healthy donors were recruited for the analysis of OPN, MMP‑9 and NF‑κB. Significantly higher circulating levels of OPN and MMP‑9 were observed in the patients with melanoma when compared to the healthy donors. Similar data were obtained for NF‑κB p65 activity. The OPN levels did not differ significantly between melanomas with or without BRAFV600E mutation. However, as regards NF‑κB and MMP‑9, significant differences were observed between the melanomas with or without BRAFV600E mutation. To determine whether NF‑κB inhibition is associated with a decrease in the levels of OPN and MMP‑9, peripheral blood mononuclear cells from 29 patients with melanoma were treated with the NF‑κB inhibitor, dehydroxymethylepoxyquinomycin (DHMEQ), with or without OPN. As expected, the inhibition of NF‑κB induced a marked decrease in both the OPN and MMP‑9 levels. Furthermore, the decrease in MMP‑9 levels was higher among melanomas harbouring the BRAFV600E mutation. Overall, our data suggest that the activation of MMP‑9 is associated with the BRAFV600E mutation status. Furthermore, such an activation is mediated by NF‑κB, suggesting its role as therapeutic target in patients with melanoma. ",0
5947,28076626,Development of a Multifunctional Needle for Percutaneous Heart Biopsy and Cell Therapy. A Technical Note,"Validation of transendocardial injection as a method for delivering therapeutic agents to the diseased heart is increasing. Puncture heart biopsies should re-emerge as a possible alternative method to allow access to the myocardium and implantable biomaterial for cell therapy. Therefore, this work aims to present a percutaneous puncture device for biopsy and intramyocardial biomaterial injection, standardize the technique and attest to the safety of the method. The adaptation consists of creating myocardial microlesions that allow for better fixation of stem cells. The objective of this technical note covers only the development of the needle and the histological quality of the biopsies. It has not been used in humans yet. ",0
5948,28077026,A case-control study of risk factors of chronic venous ulceration in patients with varicose veins,"Background/objectives Venous ulcers carry psychological and high financial burden for patients, causing depression, pain, and limitation of mobility. The study aimed to identify factors associated with an increased risk of venous ulceration in patients with varicose veins in Armenia. Methods A case-control study design was utilized enrolling 80 patients in each group, who underwent varicose treatment surgery in two specialized surgical centers in Armenia during 2013-2014 years. Cases were patients with varicose veins and venous leg ulcers. Controls included patients with varicose veins but without venous leg ulcers. Data were collected using interviewer-administered telephone interviews and medical record abstraction. Multiple logistic regression analysis was used to identify the risk factors of venous ulceration. Results There were more females than males in both groups (72.5% of cases and 85.0 % of controls). Cases were on average older than controls (53.9 vs. 39.2 years old, p ≤ 0.001). After adjusting for potential confounders, the estimated odds of developing venous ulcer was higher in patients with history of post thrombotic syndrome (odds ratio = 14.90; 95% confidence interval: 3.95-56.19; p = 0.001), with higher average sitting time (odds ratio = 1.32 per hour of sitting time; 95% confidence interval: 1.08-1.61; p = 0.006), those with reflux in deep veins (odds ratio = 3.58; 95% confidence interval: 1.23-10.31; p = 0.019) and history of leg injury (odds ratio = 3.12; 95% confidence interval: 1.18-8.23; p = 0.022). Regular exercise in form of walking (≥5 days per week) was found to be a protective factor from venous ulceration (odds ratio = 0.26; 95% confidence interval: 0.08-0.90; p = 0.034). Conclusion We found that reflux in deep veins, history of leg injury, history of post thrombotic syndrome, and physical inactivity were significant risk factors for venous ulceration in patients with varicose veins, while regular physical exercise mitigated that risk. Future studies should investigate the relationships between the duration and type of regular exercise and the risk of venous ulceration to make more specific recommendations on preventing ulcer development. ",0
5949,28077068,Structure and evolution of the filaggrin gene repeated region in primates,"The evolutionary dynamics of repeat sequences is quite complex, with some duplicates never having differentiated from each other. Two models can explain the complex evolutionary process for repeated genes-concerted and birth-and-death, of which the latter is driven by duplications maintained by selection. Copy number variations caused by random duplications and losses in repeat regions may modulate molecular pathways and therefore affect phenotypic characteristics in a population, resulting in individuals that are able to adapt to new environments. In this study, we investigated the filaggrin gene (FLG), which codes for filaggrin-an important component of the outer layers of mammalian skin-and contains tandem repeats that exhibit copy number variation between and within species. To examine which model best fits the evolutionary pathway for the complete tandem repeats within a single exon of FLG, we determined the repeat sequences in crab-eating macaque (Macaca fascicularis), orangutan (Pongo abelii), gorilla (Gorilla gorilla), and chimpanzee (Pan troglodytes) and compared these with the sequence in human (Homo sapiens). In this study we compared concerted and birth-and-death evolution models, commonly used for gene copies. We found that there is high nucleotide diversity between filaggrin repeat regions, which fits the birth-and-death model. Phylogenetic analyses also suggested that independent duplication events created the repeat sequences in crab-eating macaques and orangutans, while different duplication and loss events created the repeats in gorillas, chimpanzees, and humans. Comparison of the repeat sequences detected purifying selection within species and lineage-specific duplications across species. We also found variation in the length of the repeated region within species such as chimpanzee and crab-eating macaque. We conclude that the copy number variation in the repeat sequences of FLG between primates may be a consequence of species-specific divergence and expansion. ",0
5950,28077754,Double-blinded randomised placebo-controlled clinical trial of individualised homeopathic treatment of hyperthyroid cats,"Feline hyperthyroidism is a common endocrine disorder in older cats for which homeopathic treatment has been advocated. A double-blinded, placebo-controlled randomised trial was performed to look for evidence of efficacy for the use of individualised homeopathy in the treatment of this disease. Using a case definition of a concentration of the thyroid hormone T4 >66 nmol/l, cats were randomised into two treatment arms. Either a placebo or a homeopathic treatment was given to each cat blindly. After 21 days, the T4 levels, weight (Wt) and heart rate (HR) were compared with pretreatment values. There were no statistically significant differences in the changes seen between the two treatment arms following placebo or homeopathic treatment (T4 P=0.96, Wt P=0.16, HR P=0.36) or between the means of each parameter for either treatment arm before and after placebo or homeopathic treatment (all P values >0.13). In a second phase of the study, patients in both treatment arms were given methimazole treatment for 21 days and T4, Wt and HR determined again. Again there were no statistically significant differences between the groups, but there were statistically significant reductions in T4 (P<0.0001) and HR (P=0.02), and a statistically significant increase in Wt (P=0.004) in both groups compared with their pre-methimazole treatment levels. The results of this study failed to provide any evidence of the efficacy of homeopathic treatment of feline hyperthyroidism. ",0
5951,28078445,Energy-dependent expansion of .177 caliber hollow-point air gun projectiles,"Amongst hundreds of different projectiles for air guns available on the market, hollow-point air gun pellets are of special interest. These pellets are characterized by a tip or a hollowed-out shape in their tip which, when fired, makes the projectiles expand to an increased diameter upon entering the target medium. This results in an increase in release of energy which, in turn, has the potential to cause more serious injuries than non-hollow-point projectiles. To the best of the authors' knowledge, reliable data on the terminal ballistic features of hollow-point air gun projectiles compared to standard diabolo pellets have not yet been published in the forensic literature. The terminal ballistic performance (energy-dependent expansion and penetration) of four different types of .177 caliber hollow-point pellets discharged at kinetic energy levels from approximately 3 J up to 30 J into water, ordnance gelatin, and ordnance gelatin covered with natural chamois as a skin simulant was the subject of this investigation. Energy-dependent expansion of the tested hollow-point pellets was observed after being shot into all investigated target media. While some hollow-point pellets require a minimum kinetic energy of approximately 10 J for sufficient expansion, there are also hollow-point pellets which expand at kinetic energy levels of less than 5 J. The ratio of expansion (RE, calculated by the cross-sectional area (A) after impact divided by the cross-sectional area (A  ",0
5952,28078675,Overexpression of a diacylglycerol acyltransferase gene in Phaeodactylum tricornutum directs carbon towards lipid biosynthesis,"Under nutrient deplete conditions, diatoms accumulate between 15% to 25% of their dry weight as lipids, primarily as triacylglycerols (TAGs). As in most eukaryotes, these organisms produce TAGs via the acyl-CoA dependent Kennedy pathway. The last step in this pathway is catalyzed by diacylglycerol acyltransferase (DGAT) that acylates diacylglycerol (DAG) to produce TAG. To test our hypothesis that DGAT plays a major role in controlling the flux of carbon towards lipids, we overexpressed a specific type II DGAT gene, DGAT2D, in the model diatom Phaeodactylum tricornutum. The transformants had 50- to 100-fold higher DGAT2D mRNA levels and the abundance of the enzyme increased 30- to 50-fold. More important, these cells had a 2-fold higher total lipid content and incorporated carbon into lipids more efficiently than the wild type (WT) while growing only 15% slower at light saturation. Based on a flux analysis using  ",0
5953,28078868,Minoxidil dose response study in female pattern hair loss patients determined to be non-responders to 5% topical minoxidil,"Topical minoxidil is the only US FDA approved drug for the treatment of female pattern hair loss (FPHL). 5% minoxidil foam is only effective at re-growing hair in a minority of women (approximately 40%). Thus, the majority of FPHL patients remain untreated. Previously, we demonstrated that nonresponders to 5% minoxidil have low metabolism of minoxidil in hair follicles. As such, we hypothesized that increasing the dosage of topical minoxidil to low metabolizers would increase the number of responders without increasing the incidence of adverse events. In this study, we recruited FPHL subjects that were identified as non-responders to 5% topical minoxidil utilizing the previously validated assay for minoxidil response. Subjects were treated for 12 weeks with a novel 15% topical minoxidil solution. At 12 weeks, 60% of subjects achieved a clinically significant response based on target area hair counts (>13.7% from baseline), as well as significant improvement in global photographic assessment. None of the subjects experienced significant hemodynamic changes or any other adverse events. To the best of our knowledge, this is the first study to demonstrate the potentially beneficial effect of a higher dosage of minoxidil in FPHL subjects who fail to respond to 5% minoxidil. ",0
5954,28078985,Designing Isoform-selective Inhibitors Against Classical HDACs for Effective Anticancer Therapy: Insight and Perspectives from In Silico,"Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting. Furthermore, the article discusses extensively the role of in silico strategies such as Molecular Docking, Molecular Dynamics Simulation and Energetically-optimized structure based pharmacophore approach in designing on-target inhibitors against classical HDACs. ",0
5955,28079156,A mucin-like peptide from Fasciola hepatica instructs dendritic cells with parasite specific Th1-polarizing activity,"Fasciolosis is a trematode zoonosis of interest in public health and cattle production. We report here the immunostimulatory effect of a 66 mer mucin-like peptide from Fasciola hepatica (Fhmuc), which synergizes with lipopolysaccharide (LPS) to promote dendritic cell (DC) maturation, endowing these cells with Th1-polarizing capacity. Exposure of DCs to Fhmuc in presence of LPS induced enhanced secretion of pro-inflammatory cytokines and expression of co-stimulatory molecules by DCs, promoting their T cell stimulatory capacity and selectively augmenting IFN-γ secretion by allogeneic T cells. Furthermore, exposure of DCs to Fhmuc augmented LPS-induced Toll-like receptor (TLR) 4 expression on the cell surface. Finally, Fhmuc-conditioned DCs induced parasite specific-adaptive immunity with increased levels of IFN-γ secreted by splenocytes from vaccinated animals, and higher parasite-specific IgG antibodies. However, Fhmuc-treated DC conferred modest protection against F. hepatica infection highlighting the potent immuno-regulatory capacity of the parasite. In summary, this work highlights the capacity of a mucin-derived peptide from F. hepatica to enhance LPS-maturation of DCs and induce parasite-specific immune responses with potential implications in vaccination and therapeutic strategies. ",0
5956,28079251,Maturation-associated gene expression profiles along normal human bone marrow monopoiesis,"Human monopoiesis is a tightly coordinated process which starts in the bone marrow (BM) haematopoietic stem cell (HSC) compartment and leads to the production of circulating blood mature monocytes. Although mature monocytes/macrophages have been extensively studied in both normal or inflammatory conditions, monopoiesis has only been assessed in vitro and in vivo animal models, due to low frequency of the monocytic precursors in the normal human BM. Here we investigated the transcriptional profile along normal human BM monopoiesis. Five distinct maturation-associated stages of monocytic precursors were identified and isolated from (fresh) normal human BM through fluorescence-activated cell sorting, and the gene expression profile (GEP) of each monocytic precursor subset was analysed by DNA-oligonucleotide microarrays. Overall, >6000 genes (18% of the genes investigated) were expressed in ≥1 stage of BM monopoiesis at stable or variable amounts, showing early decrease in cell proliferation with increased levels of expression of genes linked with cell differentiation. The here-defined GEP of normal human BM monopoiesis might contribute to better understand monocytic differentiation and the identification of novel monocytic candidate markers, while also providing a frame of reference for the study of monocytic maturation in both neoplastic and non-neoplastic disease conditions involving monocytic precursor cells. ",0
5957,28079501,Clinical efficacy of oral alendronate in ankylosing spondylitis: a randomised placebo-controlled trial,"A prospective, double blind, randomised, placebo controlled trial over 2 years was performed to test the efficacy of alendronate, an oral aminobisphosphonate, in improving symptoms and arrest disease progression in patients with mild to severe ankylosing spondylitis (AS). 180 patients with AS were randomised to receive weekly alendronate 70 mg or placebo (1:1 randomisation). BAS-G was the primary outcome measure with Bath indices as secondary outcomes. Vertebral x-rays were performed at 0 and 24 months. Biomarkers (including CRP, IL-1beta, IL6, VEGF, MMP-1, and MMP-3) were collected during the first 12 months. There was no significant difference between the placebo and treatment groups in any of the recorded outcomes over the 2 years including clinical indices, biomarkers, and radiology. The change in BAS-G, the primary outcome measure, was -0.21 for the treatment group and -0.42 for the placebo group p=0.57. Change in all other clinical outcome measures were also non-significant; BASDAI p=0.86, BASFI p=0.37, BASMI p=0.021. Sub-group analysis of those subjects with a baseline BASDAI >4 were also non-significant. This prospective study demonstrates that alendronate 70mg weekly for 2 years was no more efficacious than placebo in improving clinical or laboratory measures of disease activity or measures of physical impact in subjects with mild to severe active AS. ID SRCTN12308164, registered on 15.12.2015. ",0
5958,28079775,Association of Hospital Volume With Racial and Ethnic Disparities in Locally Advanced Cervical Cancer Treatment,"To evaluate racial-ethnic disparities in guideline-based care in locally advanced cervical cancer and their relationship to hospital case volume. Using the National Cancer Database, we performed a retrospective cohort study of women diagnosed between 2004 and 2012 with locally advanced squamous or adenocarcinoma of the cervix undergoing definitive primary radiation therapy. The primary outcome was the race-ethnicity-based rates of adherence to the National Comprehensive Cancer Network guideline-based care. The secondary outcome was the effect of guideline-based care on overall survival. Multivariable models and propensity matching were used to compare the hospital risk-adjusted rates of guideline-based adherence and overall survival based on hospital case volume. The final cohort consisted of 16,195 patients. The rate of guideline-based care was 58.4% (95% confidence interval [CI] 57.4-59.4%) for non-Hispanic white, 53% (95% CI 51.4-54.9%) for non-Hispanic black, and 51.5% (95% CI 49.4-53.7%) for Hispanic women (P<.001). From 2004 to 2012, the rate of guideline-based care increased from 49.5% (95% CI 47.1-51.9%) to 59.1% (95% CI 56.9-61.2%) (Ptrend<.001). Based on a propensity score-matched analysis, patients receiving guideline-based care had a lower risk of mortality (adjusted hazard ratio 0.65, 95% CI 0.62-0.68). Compared with low-volume hospitals, the increase in adherence to guideline-based care in high-volume hospitals was 48-63% for non-Hispanic white, 47-53% for non-Hispanic black, and 41-54% for Hispanic women. Racial and ethnic disparities in the delivery of guideline-based care are the highest in high-volume hospitals. Guideline-based care in locally advanced cervical cancer is associated with improved survival. ",0
5959,28080057,Identification of Binding Modes for Amino Naphthalene 2-Cyanoacrylate (ANCA) Probes to Amyloid Fibrils from Molecular Dynamics Simulations,"The amino naphthalene 2-cyanoacrylate (ANCA) probe is a kind of fluorescent amyloid binding probe that can report different fluorescence emissions when bound to various amyloid deposits in tissue, while their interactions with amyloid fibrils remain unclear due to the insoluble nature of amyloid fibrils. Here, all-atom molecular dynamics simulations were used to investigate the interaction between ANCA probes with three different amyloid fibrils. Two common binding modes of ANCA probes on Aβ40 amyloid fibrils were identified by cluster analysis of multiple simulations. The van der Waals and electrostatic interactions were found to be major driving forces for the binding. Atomic contacts analysis and binding free energy decomposition results suggested that the hydrophobic part of ANCA mainly interacts with aromatic side chains on the fibril surface and the hydrophilic part mainly interacts with positive charged residues in the β-sheet region. By comparing the binding modes with different fibrils, we can find that ANCA adopts different conformations while interacting with residues of different hydrophobicity, aromaticity, and electrochemical properties in the β-sheet region, which accounts for its selective mechanism toward different amyloid fibrils. ",0
5960,28080906,ORAL SQUAMOUS CELL CARCINOMA IN AN AGED CAPTIVE WHITE RHINOCEROS (CERATOTHERIUM SIMUM),"A 48-yr-old captive white rhinoceros ( Ceratotherium simum ) was euthanized due to old age, pododermatitis, and progressive laminitis of the middle toe of the left fore- and hindlimbs. Severe chronic necrotizing periodontitis and dental loss was diagnosed, although food intake prior to death had not decreased. In addition, extensive ulceration of the tongue was noted. Histologically, squamous cell carcinoma of the tongue was diagnosed with chronic severe ulcerative glossitis. Metastatic lesions were not detected. Clinicians should monitor the oral health of aging rhinoceros due to the occult nature of these lesions. ",0
5961,28081482,Following Lives Undergoing Change (Flux) study: Implementation and baseline prevalence of drug use in an online cohort study of gay and bisexual men in Australia,"Drug use among gay and bisexual men (GBM) is higher than most populations. The use of crystal methamphetamine, erectile dysfunction medication (EDM), and amyl nitrite have been associated with sexual risk behaviour and HIV infection among gay and bisexual men (GBM). This paper describes an online prospective observational study of licit and illicit drug use among GBM and explores baseline prevalence of drug use in this sample. Capturing these data poses challenges as participants are required to disclose potentially illegal behaviours in a geographically dispersed country. To address this issue, an entirely online and study specific methodology was chosen. Men living in Australia, aged 16.5 years of age or older, who identified as homosexual or bisexual or had sex with at least one man in the preceding 12 months were eligible to enrol. Between September 2014 and July 2015, a total of 2250 participants completed the baseline questionnaire, of whom, 1710 (76.0%) consented to six-monthly follow-up. The majority (65.7%) were recruited through Facebook targeted advertising. At baseline, over half (50.5%) the men reported the use of any illicit drug in the previous six months, and 28.0% had used party drugs. In the six months prior to enrolment, 12.0% had used crystal methamphetamine, 21.8% had used EDM, and 32.1% had used amyl nitrite. Among the 1710 men enrolled into the cohort, 790 men had used none of these drugs. Ease of entry and minimal research burden on participants helped ensure successful recruitment into this online cohort study. Study outcomes will include the initiation and cessation of drug use, associated risk behaviours, and health consequences, over time. Results will provide insights into the role gay community plays in patterns of drug use among GBM. ",0
5962,28082074,Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV,"Adeno-associated virus (AAV) is a safe and effective vector for gene therapy for retinal disorders. Gene therapy for hearing disorders is not as advanced, in part because gene delivery to sensory hair cells of the inner ear is inefficient. Although AAV transduces the inner hair cells of the mouse cochlea, outer hair cells remain refractory to transduction. Here, we demonstrate that a vector, exosome-associated AAV (exo-AAV), is a potent carrier of transgenes to all inner ear hair cells. Exo-AAV1-GFP is more efficient than conventional AAV1-GFP, both in mouse cochlear explants in vitro and with direct cochlear injection in vivo. Exo-AAV shows no toxicity in vivo, as assayed by tests of auditory and vestibular function. Finally, exo-AAV1 gene therapy partially rescues hearing in a mouse model of hereditary deafness (lipoma HMGIC fusion partner-like 5/tetraspan membrane protein of hair cell stereocilia [Lhfpl5/Tmhs ",0
5963,28082214,"Are perioperative bundles associated with reduced postoperative morbidity in women undergoing benign hysterectomy? Retrospective cohort analysis of 16,286 cases in Michigan","""Healthcare teams that frequently follow a bundle of evidence-based processes provide care with lower rates of morbidity. Few process bundles to improve surgical outcomes in hysterectomy have been identified. The purpose of this study was to investigate whether a bundle of 4 perioperative care processes is associated with fewer postoperative complications and readmissions for hysterectomies in the Michigan Surgical Quality Collaborative. A bundle of perioperative care process goals was developed retrospectively with 30-day peri- and postoperative outcome data from the Hysterectomy Initiative in Michigan Surgical Quality Collaborative. All benign hysterectomies that had been performed between January 2013 and January 2015 were included. Based on evidence of lower complication rates after benign hysterectomy, the following processes were considered to be the """"bundle"""": use of guideline-appropriate preoperative antibiotics, a minimally invasive surgical approach, operative duration <120 minutes, and avoidance of intraoperative hemostatic agent use. Each process was considered present or absent, and the number of processes was summed for a bundle score that ranged from 0-4. Cases with a score of zero were excluded. Outcomes measured were rates of complications (any and major) and hospital readmissions, all within 30 days of surgery. Postoperative events that were considered a """"major complication"""" included acute renal failure, cardiac arrest that required cardiopulmonary resuscitation, central line infection, cerebral vascular accident, death, deep vein thrombosis, intestinal obstruction, myocardial infarction, pelvic abscess, pulmonary embolism, rectovaginal fistula, sepsis, surgical site infection (deep and organ-space), unplanned intubation, ureteral obstruction, and ureterovaginal and vesicovaginal fistula. The outcome """"any complication"""" included all those events already described in addition to blood transfusion within 72 hours of surgery, urinary tract infection, and superficial surgical site infection. Outcomes were adjusted for patient demographics, surgical factors, and hospital-level clustering effects. There were 16,286 benign hysterectomies available for analysis. Among all hysterectomies that were reviewed, 33.6% met criteria for all bundle processes; however, there was wide variation in the rate among the 56 hospitals in the study sample with 9.1% of cases at the lowest quartile and 60.4% at the highest quartile of hospitals that met criteria for all bundle processes. Overall, the rate of any complication was 6.8% and of any major complication was 2.3%. The rate of hospital readmissions was 3.6%. After adjustment for confounders, in cases in which all bundle criterion were met compared with cases in which all bundle criterion were not met, the rate of any complications increased from 4.3-7.8% (P<.001); major complications increased from 1.7-2.6% (P<.001), and readmissions increased from 2.6-4.1% (P<.001). After adjustment for confounders, hospitals with greater rates of meeting all 4 criteria were associated significantly with lower hospital-level rates of postoperative complications (P<.001) and readmissions (P<.001). This multiinstitutional evaluation reveals that reduced morbidity and readmission are associated with rates of bundle compliance. The proposed bundle is a surgical goal, which is not possible in every case, and there is significant variation in the proportion of cases meeting all 4 bundle processes in Michigan hospitals. Implementation of evidence-based process bundles at a healthcare system level are worthy of prospective study to determine whether improvements in patient outcomes are possible. """,0
5964,28082811,"Risk stratification for malignant progression in Barrett's esophagus: Gender, age, duration and year of surveillance","To clarify risk based upon segment length, diagnostic histological findings, patient age and year of surveillance, duration of surveillance and gender. Patients registered with the United Kingdom Barrett's Oesophagus Registry from 9 United Kingdom centers were included. The outcome measures were (1) development of all grades of dysplasia; (2) development of high-grade of dysplasia or adenocarcinoma; and (3) development of adenocarcinoma. Prevalent cases and subjects with < 1 year of follow-up were excluded. The covariates examined were segment length, previous biopsy findings, age at surveillance, duration of surveillance, year of surveillance and gender. One thousand and one hundred thirty six patients were included (total 6474 patient-years). Fifty-four patients developed adenocarcinoma (0.83% per annum), 70 developed high-grade dysplasia/adenocarcinoma (1.1% per annum) and 190 developed any grade of dysplasia (3.5% per annum). High grade dysplasia and adenocarcinoma increased with age and duration of surveillance. The risk of low-grade dysplasia development was not dependent on age at surveillance. Segment length and previous biopsy findings were also significant factors for development of dysplasia and adenocarcinoma. The risk of development of low-grade dysplasia is independent of age at surveillance, but high-grade dysplasia and adenocarcinoma were more commonly found at older age. Segment length and previous biopsy findings are also markers of risk. This study did not demonstrate stabilisation of the metaplastic segment with prolonged surveillance. ",0
5965,28082923,Therapeutic Perspective on Tardive Syndrome with Special Reference to Deep Brain Stimulation,"Tardive syndrome (TDS) is a potentially permanent and irreversible hyperkinetic movement disorder caused by exposure to dopamine receptor blocking agents. Guidelines published by the American Academy of Neurology recommend pharmacological first-line treatment for TDS with clonazepam (level B), ginkgo biloba (level B), amantadine (level C), and tetrabenazine (level C). Recently, a class II study provided level C evidence for use of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with TDS. Although the precise pathogenesis of TDS remains to be elucidated, the beneficial effects of GPi-DBS in patients with TDS suggest that the disease may be a basal ganglia disorder. In addition to recent advances in understanding the pathophysiology of TDS, this article introduces the current use of DBS in the treatment of medically intractable TDS. ",0
5966,28082989,Neuroimmune Interface in the Comorbidity between Alcohol Use Disorder and Major Depression,"Bidirectional communication links operate between the brain and the body. Afferent immune-to-brain signals are capable of inducing changes in mood and behavior. Chronic heavy alcohol drinking, typical of alcohol use disorder (AUD), is one such factor that provokes an immune response in the periphery that, by means of circulatory cytokines and other neuroimmune mediators, ultimately causes alterations in the brain function. Alcohol can also directly impact the immune functions of microglia, the resident immune cells of the central nervous system (CNS). Several lines of research have established the contribution of specific inflammatory mediators in the development and progression of depressive illness. Much of the available evidence in this field stems from cross-sectional data on the immune interactions between isolated AUD and major depression (MD). Given their heterogeneity as disease entities with overlapping symptoms and shared neuroimmune correlates, it is no surprise that systemic and CNS inflammation could be a critical determinant of the frequent comorbidity between AUD and MD. This review presents a summary and analysis of the extant literature on neuroimmune interface in the AUD-MD comorbidity. ",0
5967,28083027,Relationship of coping ways and anxiety with Pregnancy Specific-stress,"To explore whether coping strategies and general anxiety are associated with pregnancy-specific stress (PSS) and how much of variance of PSS is explained with these variables. A cross sectional study was conducted at two teaching hospitals between November 2013 and December 2015. Total 190 pregnant women (60 women at 6-13-weeks of gestation, 60 at 13-26 weeks, and 70 at 27-40 weeks of gestation) completed the study. The participants completed three questionnaires including; Pregnancy experience scale (PES-41), Ways of Coping Questionnaire (WCQ), and State-Trait anxiety inventory (SATI). Pearson coefficients and analysis of regression was done to assess the correlations between variables. Pregnant women who experienced higher mean level of pregnancy specific-stress had significantly higher mean level of occult anxiety, overt anxiety, and total anxiety than women who did not experience PSS. Although there was a positive and significant relationship between intensity of hassles and uplifts and ways of coping, the correlation between PSS and ways of coping was not significant. The results of analysis regression showed that general anxiety during pregnancy predicted 25% of the variance of PSS (F=4.480, β=0.159). Also, ways of coping predicted 38% of the variance in pregnancy Hassles (F=7.033, β=0.194). The ways of coping predicted the variance of pregnancy hassles, but does not evaluate pregnancy specific-stress. To think about PSS in terms of general anxiety may help to clarify past findings and to guide future research and interventions. ",0
5968,28083035,Chemotherapy alone or combined chemotherapy and involved field radiotherapy in favorable risk early-stage classical Hodgkin lymphoma-a 10 years experience,"To determine the outcome of patients with early-stage (stage I-II) favorable risk classical Hodgkin lymphoma treated with chemotherapy alone or combined modality treatment (CMT) utilizing chemotherapy and involved field radiotherapy. This retrospective study was done at Department of Medical oncology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan from January 2004 to December 2013. There were 101 patients, with male predominance (71.3%). Mean age was 34 years. Sixty three (62.4%) patients received CMT and 38 (37.6%) patients had chemotherapy alone. Ninety eight percent patients had ABVD chemotherapy. Dose of radiotherapy ranged from 20 to 36 gray. Difference between baseline characteristics and major toxicities among the two groups was insignificant. Patients treated with CMT had better overall survival compared to chemotherapy alone: 100% versus 91% at five years and 96% versus 81% at 10 years, respectively (p=0.03). Progression free survival was also better with CMT against chemotherapy alone at five years (98% versus 81%) and 10 years (82% versus 71%) (p=0.01). Favorable risk classical Hodgkin lymphoma patients had better overall survival and progression free survival when treated with CMT against chemotherapy alone. ",0
5969,28084045,Tapentadol for Cancer Pain Management: A Narrative Review,"""Pain is one of the most common symptoms in patients with cancer. The aim of this review is to summarize the most recent literature regarding tapentadol use in oncology patients and moderate or severe pain. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar for all manuscripts published between 2008 and 2016, using the key words """"tapentadol,"""" """"cancer,"""" """"pain,"""" """"tumor,"""" and """"malignant."""" Nine studies met the inclusion criteria (four randomized clinical trials and five prospective cohort studies). The scope of the literature was diverse, with 15 instruments used to measure different aspects of pain (intensity, health status, quality of life, psychometric and well-being, perception of change, and neuropathic pain). All these studies concluded that tapentadol is seemingly a well-tolerated and efficacious agent for moderate-severe cancer pain, with few typically mild adverse reactions. However, the most significant detected weaknesses of research were that (1) existing studies do not clearly show a superiority of tapentadol with respect to previous generation opioids, (2) low-to-moderate sample sizes prevent obtaining robust conclusions about effectiveness, (3) there was an absence of noninferiority trials comparing tapentadol vs. fentanyl or oxycodone-naloxone, and (4) there was scarce generalizability of prospective observational studies. Tapentadol is seemingly an effective, well-tolerated alternative for moderate or severe cancer pain. Most prospective cohort studies have relatively small samples, are restricted to few research centers, and lack detailed subgroup information. More experience is required to draw valid generalizable conclusions. """,0
5970,28084321,Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of 'soluble CD163' in plasma,"CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammation-inducible TACE/ADAM17 enzyme. Accordingly, plasma 'soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting 'soluble CD163' in plasma may therefore add to the diagnostic and prognostic value. ",0
5971,28084859,Radiotherapy-induced vaginal fibrosis in cervical cancer survivors,"Cervical cancer survivors treated with radiotherapy report vaginal inelasticity and decreased lubrication that may affect their sexual health, but it is unknown which normal tissue reactions mediate these symptoms. The aim of this study was to investigate the morphology of the connective tissue of the vaginal wall in cervical cancer survivors treated with radiotherapy. We recruited 34 cervical cancer survivors treated with radiotherapy and 37 age-matched controls. Via clinical examination the degree of vaginal atrophy and pelvic fibrosis were estimated. We collected vaginal biopsies, which underwent morphometric analysis focused on elastin and collagen. Additionally, radiation dose at biopsy site were calculated and correlated to the clinical and morphological findings. The survivors had marked morphological vaginal changes, most prominent in the survivors that had received the highest radiation dose at the biopsy site. Mucosal atrophy was observed in 91% and pelvic fibrosis in 97%. A shorter vagina was measured; 7.0 cm versus 10.3 cm in controls (p < 0.001). The area fraction of elastin was greater in survivors; 10.0% (range 5.8-12.9), compared with controls; 3.4% (range 1.8-5.8), p < 0.001. The survivors had signs of elastosis with thick aggregated elastin fibers irregularly scattered throughout the connective tissue, while the controls had elastin fibers in a thin sub-epithelial layer. The area fraction of high density collagen in the connective tissue was larger among the survivors (p < 0.001). The collagen with the highest density (fibrosis) was more common in the group of cancer survivors that had received external radiation. We found drastic differences in the vaginal wall between the irradiated cervical cancer survivors and the controls, indicating that radiotherapy-induced vaginal symptoms are mediated by connective tissue fibrosis and elastosis. Our results also support that patients treated with external radiation have the highest risk of developing vaginal fibrosis with impairment of their sexual health. ",0
5972,28085245,Stereoselective Polymer-Supported Synthesis of Morpholine- and Thiomorpholine-3-carboxylic Acid Derivatives,"Herein we report the polymer-supported synthesis of 3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid derivatives using immobilized Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH as the starting materials. After the solid-phase-synthesis of N-alkyl-N-sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys(Trt)-OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3-carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable N-acylmorpholine rotamers. ",0
5973,28085524,Evaluation of genome-wide susceptibility loci for high myopia in a Han Chinese population,"High myopia (HM) is a common cause of visual impairment worldwide. Previous genome-wide association studies have reported that seven single nucleotide polymorphisms (SNPs), including rs1254319, rs3138144, rs12205363, rs17648524, rs7829127, rs1656404, and rs7084402, are associated with HM in Caucasians. The aim of this study was to investigate the association of these SNPs in Han Chinese. SNPs were genotyped by SNaPshot method in a Chinese cohort composed of 830 HM patients and 1140 controls. Rs17648524 (C/G) and rs7084402 (A/G) were significantly associated with HM (p = 3.0 × 10 Our findings suggested rs17648524 (intronic RBFOX1 gene) and rs7084402 (7.5kb 5' of the BICC1 gene) showed gender-specific associations with high myopia in the Han Chinese. ",0
5974,28085565,Resting-State Functional Connectivity Alterations Associated with Six-Month Outcomes in Mild Traumatic Brain Injury,"Brain lesions are subtle or absent in most patients with mild traumatic brain injury (mTBI) and the standard clinical criteria are not reliable for predicting long-term outcome. This study investigates resting-state functional MRI (rsfMRI) to assess semiacute alterations in brain connectivity and its relationship with outcome measures assessed 6 months after injury. Seventy-five mTBI patients were recruited as part of the prospective multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) pilot study and compared with matched 47 healthy subjects. Patients were classified following radiological criteria: CT/MRI positive, evidence of lesions; CT/MRI negative, without evidence of brain lesions. rsfMRI data were acquired and then processed using probabilistic independent component analysis. We compared the functional connectivity of the resting-state networks (RSNs) between patients and controls, as well as group differences in the interactions between RSNs, and related both to cognitive and behavioral performance at 6 months post-injury. Alterations were found in the spatial maps of the RSNs between mTBI patients and healthy controls in networks involved in behavioral and cognition processes. These alterations were predictive of mTBI patients' outcomes at 6 months post-injury. Moreover, different patterns of reduced network interactions were found between the CT/MRI positive and CT/MRI negative patients and the control group. These rsfMRI results demonstrate that even mTBI patients not showing brain lesions on conventional CT/MRI scans can have alterations of functional connectivity at the semiacute stage that help explain their outcomes. These results suggest rsfMRI as a sensitive biomarker both for early diagnosis and for prediction of the cognitive and behavioral performance of these patients. ",0
5975,28085725,Effectiveness of robotic assisted rehabilitation for mobility and functional ability in adult stroke patients: a systematic review protocol,The objective of this review is to synthesize the best available evidence on the effectiveness of robotic assistive devices in the rehabilitation of adult stroke patients for recovery of impairments in the upper and lower limbs. The secondary objective is to investigate the sustainability of treatment effects associated with use of robotic devices.The specific review question to be addressed is: can robotic assistive devices help adult stroke patients regain motor movement of their upper and lower limbs? ,0
5976,28086802,Brain metabolic pattern analysis using a magnetic resonance spectra classification software in experimental stroke,"Magnetic resonance spectroscopy (MRS) provides non-invasive information about the metabolic pattern of the brain parenchyma in vivo. The SpectraClassifier software performs MRS pattern-recognition by determining the spectral features (metabolites) which can be used objectively to classify spectra. Our aim was to develop an Infarct Evolution Classifier and a Brain Regions Classifier in a rat model of focal ischemic stroke using SpectraClassifier. A total of 164 single-voxel proton spectra obtained with a 7 Tesla magnet at an echo time of 12 ms from non-infarcted parenchyma, subventricular zones and infarcted parenchyma were analyzed with SpectraClassifier ( http://gabrmn.uab.es/?q=sc ). The spectra corresponded to Sprague-Dawley rats (healthy rats, n = 7) and stroke rats at day 1 post-stroke (acute phase, n = 6 rats) and at days 7 ± 1 post-stroke (subacute phase, n = 14). In the Infarct Evolution Classifier, spectral features contributed by lactate + mobile lipids (1.33 ppm), total creatine (3.05 ppm) and mobile lipids (0.85 ppm) distinguished among non-infarcted parenchyma (100% sensitivity and 100% specificity), acute phase of infarct (100% sensitivity and 95% specificity) and subacute phase of infarct (78% sensitivity and 100% specificity). In the Brain Regions Classifier, spectral features contributed by myoinositol (3.62 ppm) and total creatine (3.04/3.05 ppm) distinguished among infarcted parenchyma (100% sensitivity and 98% specificity), non-infarcted parenchyma (84% sensitivity and 84% specificity) and subventricular zones (76% sensitivity and 93% specificity). SpectraClassifier identified candidate biomarkers for infarct evolution (mobile lipids accumulation) and different brain regions (myoinositol content). ",0
5977,28086929,Early virological failure and HIV drug resistance in Ugandan adults co-infected with tuberculosis,"This cross-sectional study took place in the integrated tuberculosis (TB) clinic of a large outpatient clinic for HIV-infected patients in Kampala, Uganda. The purpose of this study was to describe the proportion of TB/HIV co-infected adults with virological failure, type and frequency of HIV drug resistance-associated mutations, and the proportion of patients with suboptimal efavirenz levels. HIV-1 plasma viral loads, CD4 cell count measurements, and efavirenz serum concentrations were done in TB/HIV co-infected adults. Genotypic resistance testing was performed in case of confirmed virological failure. After a median time on ART of 6 months, virological failure was found in 22/152 patients (14.5%). Of 147 participants with available efavirenz serum concentration, 26 (17.6%) had at least one value below the reference range, including 20/21 (95.2%) patients with confirmed virological failure. Genotypic resistance testing was available for 16/22 (72.7%) patients, of which 15 (93.8%) had at least one major mutation, most commonly M184V (81.2%) and K103NS (68.8%). We found a high proportion of TB/HIV co-infected patients with virological failure, the majority of which had developed relevant resistance-mutations after a median time on anti-retroviral treatment (ART) of 6 months. Virological monitoring should be prioritized in TB/HIV co-infected patients in resource-limited settings. ",0
5978,28086957,Regulatory T cells and IL10 suppress pulmonary host defense during early-life exposure to radical containing combustion derived ultrafine particulate matter,"Exposure to elevated levels of particulate matter (PM) is associated with increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Recent identification of environmentally persistent free radicals (EPFRs) in the PM from a variety of combustion sources suggests its role in the enhancement of disease severity of lower respiratory tract infections (LRTI). Our previous studies demonstrated that acute exposure to EPFRs induces pulmonary immunosuppression allowing for enhanced influenza disease severity. Here, we determine the mechanism of EPFR-induced immunosuppression and its impact on the immune response towards influenza infection. Neonatal mice (3 days old) were acutely exposed to DCB (combustion derived PM with chemisorbed EPFR) for seven consecutive days. Four days post-exposure (dpe), mice were infected with influenza virus. Pulmonary T cell phenotypes including regulatory T cells (Tregs) were analyzed by flow cytometry. The role of IL10 in EPFR-induced exacerbation of influenza disease severity was determined by administering recombinant IL10 (rIL10) to wild type mice or by using IL10 deficient (IL10 Neonatal mice exposed to EPFRs had a significant increase in pulmonary Tregs and the immunosuppressive cytokine IL10 following influenza infection, which coincided with decreased protective T cell responses to influenza infection at 6 dpi. Depletion of Tregs in EPFR-exposed neonatal mice resulted in increased protective, adaptive T cell responses, whereas adoptive transfer of Tregs from EPFR-exposed neonates to air-exposed neonatal mice suppressed adaptive T cell responses towards influenza infection. Further, treatment with rIL10 could recapitulate EPFR-induced exacerbation of morbidity and pulmonary viral load compared to air exposed and influenza infected mice, whereas, EPFR-exposed IL10 Neonatal exposure to EPFRs induced Tregs and IL10 resulting in suppressed adaptive T cell responses and enhanced influenza disease severity in neonatal mice. Depletion of Tregs increased adaptive T cell responses and deficiency of IL10 reduced morbidity and conferred enhanced protection against influenza virus. ",0
5979,28087047,Rational design of low immunogenic anti CD25 recombinant immunotoxin for T cell malignancies by elimination of T cell epitopes in PE38,"LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes. The novel RIT, LMB-142 contains a 38kDa toxin and nine point mutations that diminished T cell response to the corresponding peptides by an average of 75%. LMB-142 has good cytotoxic activity and has lower nonspecific toxicity in mice. LMB-142 should be more efficient in cancer therapy because more treatment cycles can be given. ",0
5980,28087128,Intranasal Oxytocin to Prevent Posttraumatic Stress Disorder Symptoms: A Randomized Controlled Trial in Emergency Department Patients,"There are currently few preventive interventions available for posttraumatic stress disorder (PTSD). Intranasal oxytocin administration early after trauma may prevent PTSD, because oxytocin administration was previously found to beneficially impact PTSD vulnerability factors, including neural fear responsiveness, peripheral stress reactivity, and socioemotional functioning. Therefore, we investigated the effects of intranasal oxytocin administration early after trauma on subsequent clinician-rated PTSD symptoms. We then assessed whether baseline characteristics moderated the intervention's effects. We performed a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult emergency department patients with moderate to severe acute distress (n = 120; 85% accident victims) were randomized to intranasal oxytocin (8 days/40 IU twice daily) or placebo (8 days/10 puffs twice daily), initiated within 12 days posttrauma. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline (within 10 days posttrauma) and at 1.5, 3, and 6 months posttrauma. The intention-to-treat sample included 107 participants (oxytocin: n = 53; placebo: n = 54). We did not observe a significant group difference in CAPS total score at 1.5 months posttrauma (primary outcome) or across follow-up (secondary outcome). Secondary analyses showed that participants with high baseline CAPS scores receiving oxytocin had significantly lower CAPS scores across follow-up than participants with high baseline CAPS scores receiving placebo. Oxytocin administration early after trauma did not attenuate clinician-rated PTSD symptoms in all trauma-exposed participants with acute distress. However, participants with high acute clinician-rated PTSD symptom severity did show beneficial effects of oxytocin. Although replication is warranted, these findings suggest that oxytocin administration is a promising preventive intervention for PTSD for individuals with high acute PTSD symptoms. ",0
5981,28087283,Benefits of using the ultrasonic BoneScalpel™ in temporomandibular joint reconstruction,"The main objective of this retrospective study is to analyze and report on our operative experiences and outcomes using the ultrasonic BoneScalpel™ (BoneScalpel) versus a conventional reciprocating saw (RecipSaw) for the purpose of completing the osteotomies in total temporomandibular joint reconstruction (TJR) surgery. 23 consecutive patients presented with a diagnosis of either degenerative joint disease (n = 23), a failing autogenous TJR (n = 1), heterotrophic bone formation (n = 1) or a subcondylar fracture (n = 1) for a total of 26 joints that received a TJR. 13 unique TJR surgeries employed the use of the BoneScalpel to perform the osteotomies and 13 used the RecipSaw. There was a 49% reduction in the average volume of blood loss in the BoneScalpel group compared to the RecipSaw group (130cc vs. 268cc, p ≤ 0.004), unpaired t-test). For the other variables it was observed that there were more favorable clinical results using the BoneScalpel but without statistically significant differences given the small sample size relative to the prevalence of the outcome that was being measured. Use of the BoneScalpel in TMJ reconstruction is overall safer and results in less blood loss compared to surgeries employing the use of the conventional RecipSaw for completing osteotomies. ",0
5982,28087319,Biliary fistula after pancreaticoduodenectomy: data from 1618 consecutive pancreaticoduodenectomies,"Biliary fistula (BF) occurs in 3-8% of patients following pancreaticoduodenectomy (PD). It usually pursues a benign course, but rarely may represent a life-threatening event. Data from 1618 PDs were collected prospectively. BF was defined as the presence of bile stained fluid from drains by post-operative day 3 and confirmed by sinogram in the majority of cases. Three classifications were validated. BF occurred in 58 (3.6%) patients. In 22 cases was associated with pancreatic fistula (POPF). POPF, PPH, operative time and a smaller common bile duct (CBD) were significantly associated with BF. Only CBD diameter (HR 0.55, CI 95% 0.44-0.7, p < 0.01) was an independent predictor of BF. Patients with smaller CBDs developing concomitant BF and POPF carried the highest mortality rate (34.8%, n = 8/22). All the existing classifications resulted in discrete categories of BFs when considering hospital stay and total cost as dependent variables. Biliary fistula is rare, but it can be life threatening when associated with POPF. As the sole independent risk factor is the CBD diameter, surgical technique is crucial. Regardless of the existing classification systems, further studies must assess the additive burden of BF when a concomitant POPF is present. ",0
5983,28087475,Immunohistochemical approach for the diagnosis of a liver mass on small biopsy specimens,"Well-differentiated hepatocellular carcinoma (HCC) shares overlapping histological features with benign hepatocellular lesions, including hepatocellular adenoma and focal nodular hyperplasia in non-cirrhotic liver, and with high-grade dysplastic nodule in cirrhotic liver. Several metastatic tumors, such as neuroendocrine tumor, renal cell carcinoma, adrenocortical carcinoma, melanoma, and epithelioid angiomyolipoma, can be indistinguishable from HCC on histologic grounds. Since this distinction has important therapeutic implications, judicious use of immunohistochemical markers plays an important role in establishing an accurate diagnosis, especially when limited material of tumor is available on cell block or a small core biopsy. This review describes commonly used immunohistochemical markers used in the diagnosis of HCC, highlighting advantages and disadvantages of each marker, and suggests appropriate immunohistochemical panels for specific clinicopathologic situations. ",0
5984,28087620,E152A substitution drastically affects NDM-5 activity,"New Delhi Metallo beta-lactamase (NDM) is of significant public health concern due to its enormous potential to hydrolyse all major beta-lactams including carbapenems. Amino acid substitutions outside the active site reportedly affect NDM beta-lactamase activities. Here, the effect of amino acid substitutions in the possible omega-like loop region of NDM-5 has been elucidated. Overall, three substitution mutations near active site of NDM-5 were done, namely, E152A, S191A and D223A and subsequently, the change in antimicrobial resistance was monitored upon expressing each mutant in a suitable host. Among the three mutants, E152A substitution on a loop near the active site resulted in significant reduction in beta-lactam antibiotic resistance as compared to NDM-5 that compelled us to conduct further studies on the E152A-substituted NDM-5. The purified NDM-5 was able to hydrolyse all the beta-lactams tested whereas the E152A mutation suppressed its activities. NDM-5 showed maximum kcat/Km ratio against penicillins and carbapenems and had lower Km as compared to NDM-5_E152A. Though, the amino acid substitution did not affect the overall folding pattern of NDM-5, significant differences in thermal stability between the wild-type and mutated protein were observed. Therefore, we infer that the E152 residue is important in regulating the beta-lactam hydrolysing properties of NDM-5. ",0
5985,28087651,"Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation","Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3. However, using primary murine macrophages, we found that particle-induced cell death occurs independent of NLRP3/caspase-1 and depends instead on multiple, redundant cathepsins. In contrast, nigericin, a soluble activator of NLRP3 inflammasomes, induced cell death that was dependent on the NLRP3. Interestingly, nigericin-induced cell death depended partly on a single cathepsin, cathepsin X. By inhibiting or silencing multiple cathepsins in macrophages, several key proinflammatory events induced by sterile particles are blocked, including cell death, pro-IL-1β production, and IL-1β secretion. These data suggest that cathepsins might be potential therapeutic targets in particulate-mediated inflammatory disease. In support of this concept, we find that a broad-spectrum cathepsin inhibitor can suppress particle-induced IL-1-dependent peritonitis. ",0
5986,28087660,The morphophysiological dormancy in Amborella trichopoda seeds is a pleisiomorphic trait in angiosperms,"Recent parsimony-based reconstructions suggest that seeds of early angiosperms had either morphophysiological or physiological dormancy, with the former considered as more probable. The aim of this study was to determine the class of seed dormancy present in Amborella trichopoda , the sole living representative of the most basal angiosperm lineage Amborellales, with a view to resolving fully the class of dormancy present at the base of the angiosperm clade. Drupes of A. trichopoda without fleshy parts were germinated and dissected to observe their structure and embryo growth. Pre-treatments including acid scarification, gibberellin treatment and seed excision were tested to determine their influence on dormancy breakage and germination. Character-state mapping by maximum parsimony, incorporating data from the present work and published sources, was then used to determine the likely class of dormancy present in early angiosperms. Germination in A. trichopoda requires a warm stratification period of at least approx. 90 d, which is followed by endosperm swelling, causing the water-permeable pericarp-mesocarp envelope to split open. The embryo then grows rapidly within the seed, to radicle emergence some 17 d later and cotyledon emergence after an additional 24 d. Gibberellin treatment, acid scarification and excision of seeds from the surrounding drupe tissues all promoted germination by shortening the initial phase of dormancy, prior to embryo growth. Seeds of A. trichopoda have non-deep simple morphophysiological dormancy, in which mechanical resistance of the pericarp-mesocarp envelope plays a key role in the initial physiological phase. Maximum parsimony analyses, including data obtained in the present work, indicate that morphophysiological dormancy is likely to be a pleisiomorphic trait in flowering plants. The significance of this conclusion for studies of early angiosperm evolution is discussed. ",0
5987,28087667,PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis,"In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4 ",0
5988,28087897,FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split-Hand/Foot Malformation: Implications for the Promoter Region,"Heterozygous loss-of-function mutations of FGFR1 (fibroblast growth factor receptor 1) cause various disorders including hypogonadotropic hypogonadism with split-hand/foot malformation (HH-SHFM). We examined FGFR1 in four Japanese patients with HH-SHFM (cases 1-4) and the mother of case 4 with HH only. Cases 1 and 2 had heterozygous loss-of-function mutations with no dominant negative effect (c.289G>A, p.[G97S]; and c.2231G>C, p.[R744T]), and case 3 had a splice donor site mutation (c.1663+1G>T). Notably, case 4 had a maternally inherited 8,312 bp microdeletion that involved noncoding exon 1U and impaired FGFR1 expression. Furthermore, consistent with the presence of transcription-related histone marks (e.g., H3K4Me3, H3K4Me1, and H3K27Ac) and multiple transcription factor-binding sites around exon 1U, functional studies demonstrated a marked transactivation function of a 414-bp segment harboring the transcription start site. These results support the relevance of FGFR1 mutations to HH-SHFM, and argue for the presence of the FGFR1 core-promoter elements around exon 1U. ",0
5989,28088167,"Randomized, double-blind, placebo-controlled clinical trial to assess the safety and effectiveness of a novel dual-action oral topical formulation against upper respiratory infections","Current prevention options for upper respiratory infections (URIs) are not optimal. We conducted a randomized, double-blinded, placebo-controlled pilot clinical trial to evaluate the safety and efficacy of ARMS-I™ (currently marketed as Halo™) in the prevention of URIs. ARMS-I is patented novel formulation for the prevention and treatment of influenza, comprising a broad-spectrum antimicrobial agent (cetylpyridinium chloride, CPC) and components (glycerin and xanthan gum) that form a barrier on the host mucosa, thus preventing viral contact and invasion. Healthy adults (18-45 years of age) were randomized into ARMS-I or placebo group (50 subjects each). The drug was sprayed intra-orally (3× daily) for 75 days. The primary objectives were to establish whether ARMS-I decreased the frequency, severity or duration of URIs. Secondary objectives were to evaluate safety, tolerability, rate of virus detection, acceptability and adherence; effect on URI-associated absenteeism and medical visits; and effect of prior influenza vaccination on study outcomes. Of the 94 individuals who completed the study (placebo: n = 44, ARMS-I: n = 50), six presented with confirmed URI (placebo: 4, ARMS-I: 2), representing a 55% relative reduction, albeit this was statistically not significant). Influenza, coronavirus or rhinovirus were detected in three participants; all in the placebo group. Moreover, frequency of post-treatment exit visits was reduced by 55% in ARMS-I compared to the placebo group (N = 4 and 2, respectively). Fever was reported only in the placebo group. ARMS-I significantly reduced the frequency and severity of cough and sore throat, and duration of cough (P ≤ .019 for all comparisons). ARMS-I was safe, well tolerated, had high acceptability and high adherence to medication use. Medical visits occurred only in the placebo group while absenteeism did not differ between the two arms. Prior influenza vaccination had no effect on study outcome. This randomized proof-of-concept clinical trial demonstrated that ARMS-I tended to provide protection against URIs in the enrolled study participants, while reducing severity and duration of cough and sore throat. A clinical trial with a larger number of study participants is warranted. ClinicalTrials.gov NCT02644135 (retrospectively registered). ",0
5990,28088245,The value of dynamic contrast-enhanced MRI in characterizing complex ovarian tumors,"The study aimed to investigate the utility of dynamic contrast enhanced MRI (DCE-MRI) in the differentiation of malignant, borderline, and benign complex ovarian tumors. DCE-MRI data of 102 consecutive complex ovarian tumors (benign 15, borderline 16, and malignant 71), confirmed by surgery and histopathology, were analyzed retrospectively. The patterns (I, II, and III) of time-signal intensity curve (TIC) and three semi-quantitative parameters, including enhancement amplitude (EA), maximal slope (MS), and time of half rising (THR), were evaluated and compared among benign, borderline, and malignant ovarian tumors. The types of TIC were compared by Pearson Chi-square χ  Fifty-nine of 71 (83%) malignant tumors showed a type-III TIC; 9 of 16 (56%) borderline tumors showed a type-II TIC, and 10 of 15 (67%) benign tumors showed a type-II TIC, with a statistically significant difference between malignant and benign tumors (P < 0.001) and between malignant and borderline tumors (P < 0.001). MS was significantly higher in malignant tumors than in benign tumors and in borderline than in benign tumors (P < 0.001, P = 0.013, respectively). THR was significantly lower in malignant tumors than in benign tumors and in borderline than in benign tumors (P < 0.001, P = 0.007, respectively). There was no statistically significant difference between malignant and borderline tumors in MS and THR (P = 0.19, 0.153) or among malignant, borderline, and benign tumors in EA (all P > 0.05). DCE-MRI is helpful for characterizing complex ovarian tumors; however, semi-quantitative parameters perform poorly when distinguishing malignant from borderline tumors. ",0
5991,28088395,Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure,"To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate ≥ 2.5 mmol/L or L:P  ≥ 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days. Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days. A serum lactate ≥ 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. ClinicalTrials.gov: NCT00986648. ",0
5992,28088750,Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays,"The present work describes an attractive skin-worn microneedle sensing device for the minimally invasive electrochemical monitoring of subcutaneous alcohol. The device consists of an assembly of pyramidal microneedle structures integrated with Pt and Ag wires, each with a microcavity opening. The microneedle aperture was modified by electropolymerizing o-phenylene diamine onto the Pt wire microtransducer, followed by the immobilization of alcohol oxidase (AOx) in an intermediate chitosan layer, along with an outer Nafion layer. The resulting microneedle-based enzyme electrode displays an interference-free ethanol detection in artificial interstitial fluid without compromising its sensitivity, stability and response time. The skin penetration ability and the efficaciousness of the biosensor performance towards subcutaneous alcohol monitoring was substantiated by the ex vivo mice skin model analysis. Our results reveal that the new microneedle sensor holds considerable promise for continuous non-invasive alcohol monitoring in real-life situations. ",0
5993,28088886,Tongue necrosis as an uncommon manifestation of temporal arteritis],"Authors present a rare manifestation of the temporal arteritis, wich caused initial diagnostic difficulties, but it responded well for corticosteroid treatment. The features of the disease, pathogenesis, possible therapy are briefly summarized beside the description of clinical course. Orv. Hetil., 2017, 158(2), 77-80. ",0
5994,28088926,Proxy rated quality of life of care home residents with dementia: a systematic review,"Quality of life (QoL) is an important outcome for people with dementia living in care homes but usually needs to be rated by a proxy. We do not know if relative or paid carer proxy reports differ. We conducted the first systematic review and meta-analysis of data investigating whether and how these proxy reports of QoL differ. We searched four databases: Medline, Embase, PsychInfo, and CINAHL in October 2015 with the terms: dementia, QoL, proxy, and care home. Included studies either compared proxy QoL ratings or investigated the factors associated with them. We meta-analyzed data comparing staff and family proxy rated QoL. We included 17/105 papers identified. We found no difference between global proxy ratings of QoL (n = 1,290; pooled effect size 0.06 (95% CI = -0.08 to 0.19)). Studies investigating factors associated with ratings (n = 3,537) found family and staff ratings correlated with the resident's physical and mental health. Staff who were more distressed rated resident QoL lower. Relatives rated it lower when the resident had lived in the care home for longer, when they observed more restraint, or contributed more to fees. Relatives and staff proxy QoL ratings share a clear relationship to resident health and overall ratings were similar. Rater-specific factors were, however, also associated with scores. Understanding why different raters consider the QoL of the same person differently is an important consideration when evaluating the meaning of proxy rated QoL. Proxy raters' backgrounds may affect their rating of QoL. ",0
5995,28089043,Contrasting microsatellite diversity in the evolutionary lineages of Phytophthora lateralis,"Following recent discovery of Phytophthora lateralis on native Chamaecyparis obtusa in Taiwan, four phenotypically distinct lineages were discriminated: the Taiwan J (TWJ) and Taiwan K (TWK) in Taiwan, the Pacific Northwest (PNW) in North America and Europe and the UK in west Scotland. Across the four lineages, we analysed 88 isolates from multiple sites for microsatellite diversity. Twenty-one multilocus genotypes (MLGs) were resolved with high levels of diversity of the TWK and PNW lineages. No alleles were shared between the PNW and the Taiwanese lineages. TWK was heterozygous at three loci, whereas TWJ isolates were homozygous apart from one isolate, which exhibited a unique allele also present in the TWK lineage. PNW lineage was heterozygous at three loci. The evidence suggests its origin may be a yet unknown Asian source. North American and European PNW isolates shared all their alleles and also a dominant MLG, consistent with a previous proposal that this lineage is a recent introduction into Europe from North America. The UK lineage was monomorphic and homozygous at all loci. It shared its alleles with the PNW and the TWJ and TWK lineages, hence a possible origin in a recent hybridisation event between a Taiwan lineage and PNW cannot be ruled out. ",0
5996,28089088,Synovial chondromatosis of the temporomandibular joint: Immunohistochemical examinations regarding the role of insulin-like growth factors and their binding proteins in the etiology of this disease,"Synovial chondromatosis (SC) is a benign disease of the joints without a known cause. It sometimes affects the temporomandibular joint (TMJ) and is accompanied by pain, swelling, malocclusion, and crepitation. It has been divided into three stages by Milgram and is supposed to originate from the synovia and cartilage of a joint (Milgram, 1977b). The aim of this study was to examine an involvement of the insulin-like growth factors (IGF-I/-II) and their binding proteins (IGFBP-1 to -6) in the etiology of this disease. Therefore 23 specimen of SC from 16 patients were immunohistochemically stained and microscopically examined. Staining was assessed semiquantitatively: negative (-), weakly positive ((+)), moderately positive (+), strongly positive (++) and very strongly positive (+++). It could be seen that especially the chondro- and fibrocytes and the synovia showed positive staining for almost all IGFs and IGFBPs. The underlying tissue, consisting of connective tissue or chondroid matrix, was stained as well but more weakly so. We conclude that the IGF/IGFBP system seems to contribute to the pathogenesis of SC, especially IGF-I and -II, and their effects enhancing binding protein 5. ",0
5997,28089404,The SCHHS hip fracture clinical network experience-Improving care and outcomes through an interprofessional approach,"Hip fractures are a major global health care issue, with the 1.26 million estimated cases in 1990 predicted to increase to 4.5 million by 2050. Varying models of care have been developed to improve outcomes following fragility hip fractures. Most of these care models embrace an interprofessional approach to care. Specialist orthopedic nurses play an important role in the management of fragility hip fracture patients and their contribution to the interprofessional health care team is an important predictor of patient outcomes. The Sunshine Coast Hospital and Health Service (SCHHS) is compromised of four hospitals in South East Queensland, Australia however only one large regional hospital provides specialist hip fracture services. Approximately, 350 older hip fracture patients present to the Sunshine Coast Hospital & Health Service (SCHHS) each year. We used Hospital Health round table (HHRT) data to identify and assess key performance care and management of hip fracture patient and outcomes at SCHHS. The HHRT is a nonprofit membership organisation of health services across Australia and New Zealand that aims to provide opportunity for Health Services to achieve best practice, collect analyse and publish information, identify ways to improve and promote collaboration and networking. Exemplars of best practice are also identified in the data so that organizations can adopt similar models of care. HHRT data identified underperformance in management of hip fracture patients in a number of quality indicators at the study site, including length of stay (LOS), time to surgery and relative stay index (RSI). Following review of HHRT data key stakeholders undertook a quality improvement project and formed the Hip Fracture Clinical Network Group (HFCNG). This was established in 2013 with the aim of improving outcomes and achieving key performance indicators for all elderly patients who sustain a hip fracture through active collaboration and regular communication between a broad group of key clinical stakeholders. Following the implementation of the initiative the Relative Stay Index reduced from 88% in 2012/13 to 78% in 2014/15, and the average LOS reduced from 10.4 days to 8.6 days. The percentage of patients receiving surgery within 2 days rose from 85% to 96%; demonstrating consistent outperformance of the time to surgery key performance indicator of 80%. The percentage of patients discharged to their place of usual residence increased from 45% to 54%. The rate of complications reduced slightly from 69% to 66%. Rates of hospital acquired anaemia reduced from 20.7% to 15%. Detection of delirium rose over the reporting period from 22% to 34%, enabling rapid management. We noted during this period that there was no corresponding increase in readmission rates for this group of patients. These data reflect improvement to clinical documentation and the appropriate identification of cognitive changes. In this quality improvement report, we describe how key stakeholders were engaged to improve communication and collaboration, and how the use of a national benchmarking dataset enabled health care providers to identify care gaps and inconsistencies in clinical practice. This quality improvement project markedly improved collaboration, clinical practice and patient outcomes. ",0
5998,28089559,Microglia-derived neuregulin expression in psychiatric disorders,"Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD. ",0
5999,28089768,Sleep Problems in Children With Agenesis of the Corpus Callosum,"Very little is known about sleep habits in children with agenesis of the corpus callosum (ACC). The purpose of this investigation was to evaluate sleep problems in children with ACC and examine the association with quality of life. We performed a cross-sectional, anonymous, internet-based survey offered to parents of children with ACC, aged five to 18 years. The Children's Sleep Habits Questionnaire (CSHQ) and pediatric quality of life (PedsQL) were used to assess sleep habits and quality of life, respectively. Associations between the total and all subdomains of CSHQ and PedsQL were tested. The final sample included 66 parents of children with ACC. Overall, 78% of the children had clinically significant sleep problems, using a cutoff score of 41 on the CSHQ. Compared with a prior national sample of typically developing children, children with ACC scored significantly higher overall and in all subdomains of the CSHQ. The overall CSHQ and PedsQL were moderately correlated (r = -0.485, P < 0.001), indicating that children with more sleep problems had worse quality of life. In addition, the total CSHQ correlated with all subdomains of the pediatric quality of life, including emotional (r = -0.515, P < 0.01), social (r = -0.394, P < 0.01), physical (r = -0.263, P < 0.01), and school (r = -0.362, P < 0.01). These associations remained statistically significant in multivariable regression models controlling for age and gender. Sleep problems are common and associated with lower quality of life in children with ACC. ",0
6000,28090365,Nurse Communication About Goals of Care,"""Conversations about goals of care with the patient and family are a critical component of advanced practice in oncology. However, there are often inadequate team structures, training, or resources available to assist advanced practitioners in initiating these conversations. We conducted a study to assess nurses' perceived role and communication tasks in such conversations about goals of care. In a cross-sectional survey of 109 nurses attending a comprehensive 2-day end-of-life nursing education course, nurses were asked to describe how they would participate in a """"goals of care"""" meeting in three different scenarios. They were also asked what changes they desired in their clinical settings. Nurses overwhelmingly described that their primary task and communication role was to assess patient/family understanding. Nurses referenced their team members and team support with the least frequency across scenarios. Team roles, structure, and process were reported as areas in greatest need of change in patient/family goals of care meetings. These findings demonstrate that lack of preparation to function as a team is a barrier for nurses in communicating about goals of care, and there is a demand to move such conversations upstream in oncology care. """,0
6001,28090674,Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication,"Hepatitis C virus (HCV) infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here, we show that the HCV protein, nonstructural protein (NS) 5B, directly binds to the tumor suppressor, NORE1A (RASSF5), and promotes its proteosomal degradation. In addition, we show that NORE1A colocalizes to sites of HCV viral replication and suppresses the replication process. Thus, NORE1A has antiviral activity, which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV-induced liver cancer by shifting Ras signaling away from prosenescent/proapoptotic signaling pathways. CONCLUSION: HCV uses NS5B to specifically suppress NORE1A, facilitating viral replication and elevated Ras signaling. (Hepatology 2017;65:1462-1477).",0
6002,28090815,Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments,"Assisted reproductive technologies are associated with altered methylation in term placenta. However, it is unclear whether methylation patterns are the result of fertility treatments or intrauterine environment. Thus, we set out to determine whether there are differences in the first-trimester placenta that may be altered by the underlying fertility treatments. Genome-wide DNA methylation analyses from chorionic villus sampling (CVS) from matched singleton pregnancies conceived using in vitro fertilization (IVF), non-IVF fertility treatment (NIFT), or those conceived spontaneously were performed using Illumina Infinium HumanMethylation450 BeadChip from 15 matched CVS samples. Nanofluidic quantitative polymerase chain reaction (qPCR) of differently methylated genes was performed in a confirmatory cohort of 23 IVF conceptions and 24 NIFT conceptions. Global methylation was similar among the IVF, NIFT, and spontaneous conceptions. However, differential methylation from IVF and NIFT pregnancies was present at 34 CpG sites, which was significantly different. Of those, 14 corresponded to known genes, with methylation changes detected at multiple loci in 3 genes, anaphase-promoting complex subunit 2 ( ANAPC2), C-X-C motif chemokine ligand 14 ( CXCL14), and regulating synaptic membrane exocytosis 1 ( RIMS1). Nanofluidic qPCR of differentially methylated genes identified pre T-cell antigen receptor alpha ( PTCRA) to be significantly downregulated in IVF versus NIFT conceptions. Although global methylation patterns are similar, there are differences in methylation of specific genes in IVF compared to NIFT conceptions, leading to altered gene expression. PTCRA was differentially methylated and downregulated in IVF conceptions, warranting further investigation. It remains to be determined whether these changes affect placentation and whether it is due to the more profound underlying infertility requiring IVF, yet these data provide unique insight into the first-trimester placental epigenome. ",0
6003,28091727,Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning,"This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 μM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPC ",0
6004,28091955,"Genome-wide exploration of silicon (Si) transporter genes, Lsi1 and Lsi2 in plants; insights into Si-accumulation status/capacity of plants","Silicon (Si) is a nonessential, beneficial micronutrient for plants. It increases the plant stress tolerance in relation to its accumulation capacity. In this work, root Si transporter genes were characterized in 17 different plants and inferred for their Si-accumulation status. A total of 62 Si transporter genes (31 Lsi1 and 31 Lsi2) were identified in studied plants. Lsi1s were 261-324 residues protein with a MIP family domain whereas Lsi2s were 472-547 residues with a citrate transporter family domain. Lsi1s possessed characteristic sequence features that can be employed as benchmark in prediction of Si-accumulation status/capacity of the plants. Silicic acid selectivity in Lsi1s was associated with two highly conserved NPA (Asn-Pro-Ala) motifs and a Gly-Ser-Gly-Arg (GSGR) ar/R filter. Two NPA regions were present in all Lsi1 members but some Ala substituted with Ser or Val. GSGR filter was only available in the proposed high and moderate Si accumulators. In phylogeny, Lsi1s formed three clusters as low, moderate and high Si accumulators based on tree topology and availability of GSGR filter. Low-accumulators contained filters WIGR, AIGR, FAAR, WVAR and AVAR, high-accumulators only with GSGR filter, and moderate-accumulators mostly with GSGR but some with A/CSGR filters. A positive correlation was also available between sequence homology and Si-accumulation status of the tested plants. Thus, availability of GSGR selectivity filter and sequence homology degree could be used as signatures in prediction of Si-accumulation status in experimentally uncharacterized plants. Moreover, interaction partner and expression profile analyses implicated the involvement of Si transporters in plant stress tolerance. ",0
6005,28092094,Comparison and evaluation of stresses generated by rapid maxillary expansion and the implant-supported rapid maxillary expansion on the craniofacial structures using finite element method of stress analysis,"The study aimed to evaluate and compare the stress distribution and 3-dimensional displacements along the craniofacial sutures in between the Rapid maxillary Expansion (RME) and Implant supported RME (I-RME). METHODS: Finite element model of the skull and the implants were created using ANSYS software. The finite element model thus built composed of 537692 elements and 115694 nodes in RME model & 543078 elements and 117948 nodes with implants model. The forces were applied on the palatal surface of the posterior teeth to cause 5mm of transverse displacement on either side of the palatal halves, making it a total of 10mm. The stresses and the displacement values were obtained and interpreted. Varying pattern of stress and the displacements with both positive and negative values were seen. The maximum displacement was seen in the case of plain RME model and that too at Pterygomaxillary suture and Mid-palatal suture in descending order. In the case of I-RME maximum displacement was seen at Zygomaticomaxillary suture followed by Pterygomaxillary suture. The displacements produced in all the three planes of space for the plain RME model were greater in comparison to the Implant Supported RME model. And the stresses remained high for all the sutures in case of an I-RME. There is a definite difference in the stress and the displacement pattern produced by RME and I-RME model and each can be used according to the need of the patient. The stresses generated in case of conventional RME were considerably less than that of the I-RME for all the sutures. ",0
6006,28092143,Human leucocyte antigen-adverse drug reaction associations: from a perspective of ethnicity,"Whilst immune-mediated adverse drug reactions (ADRs) are rare, they are potentially life-threatening and present a major problem for clinicians. The underlying mechanisms that cause ADRs are not fully understood although genomewide association studies (GWAS) and case-control investigations have associated human leucocyte antigen (HLA) alleles as risk factors. There is evidence that a patient's ethnic background can have an impact on their risk of developing an ADR. This review summarizes the evidence related to HLA alleles and ADRs with particular focus on patient ethnicity. Our analysis indicated that many of the alleles which have been associated with ADRs are found at higher frequencies in Asian populations. The data also showed that many of the alleles that are reported to be statistically significantly associated with ADRs are in linkage disequilibrium with each other and that they form haplotypes specific to certain ethnicities indicating at least some of the allele associations may not be causal. ",0
6007,28092230,Octamethylcyclotetrasiloxane (D4),"Octamethylcyclotetrasiloxane (D4; CAS No. 556-67-2) is used as a monomer in the manufacture of polymeric materials, which are widely used in various industrial and/or medical applications, such as breast implants. D4 has a relatively low order of toxicity following acute administration via the oral, dermal, and inhalation routes of exposure and is not considered to be a dermal or eye irritant or to be a dermal sensitizer. There is no appreciable dermal absorption of D4 based on results from in vivo and in vitro studies. D4 has not been shown to be genotoxic/mutagenic when tested in a number of short-term in vitro and in vivo assays. Overall, studies have demonstrated adverse effects on specific female reproductive endpoints at higher exposure concentrations; however, no D4 exposure-specific effects were noted with respect to developmental endpoints. Inhalation exposure of rats to 700 ppm D4 for up to 24 months produced effects in the liver, kidney, and uterus (weight changes, hepatocellular hypertrophy, endometrial hyperplasia, and nephropathy). Changes in the nasal epithelium (eosinophilic globules) were also noted at 150 and 700 ppm. Despite 24 months of exposure, only mild to minimal inflammatory responses were found at 150 ppm, and overall, the basic integrity of the respiratory tract was unchanged at this dose. At 700 ppm, there was an increased incidence of endometrial adenomas in female rats. Based on the adverse changes in the respiratory tract, kidney, and female reproductive tract in the chronic inhalation study, 150 ppm was determined to be the no-observed-adverse-effect level (NOAEL) and was selected as the point of departure for the derivation of the workplace environmental exposure level (WEEL®) value. The inhalation NOAEL was adjusted to account for interindividual variability and residual uncertainty regarding upper respiratory tract changes still occurring at 150 ppm. An 8-h time-weighted average WEEL value of 10 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to airborne D4. ",0
6008,28092269,Analysis of microtubule growth dynamics arising from altered actin network structure and contractility in breast tumor cells,"The periphery of epithelial cells is shaped by opposing cytoskeletal physical forces generated predominately by two dynamic force generating systems-growing microtubule ends push against the boundary from the cell center, and the actin cortex contracts the attached plasma membrane. Here we investigate how changes to the structure and dynamics of the actin cortex alter the dynamics of microtubules. Current drugs target actin polymerization and contraction to reduce cell division and invasiveness; however, the impacts on microtubule dynamics remain incompletely understood. Using human MCF-7 breast tumor cells expressing GFP-tagged microtubule end-binding-protein-1 (EB1) and coexpression of cytoplasmic fluorescent protein mCherry, we map the trajectories of growing microtubule ends and cytoplasmic boundary respectively. Based on EB1 tracks and cytoplasmic boundary outlines, we calculate the speed, distance from cytoplasmic boundary, and straightness of microtubule growth. Actin depolymerization with Latrunculin-A reduces EB1 growth speed as well as allows the trajectories to extend beyond the cytoplasmic boundary. Blebbistatin, a direct myosin-II inhibitor, reduced EB1 speed and yielded less straight EB1 trajectories. Inhibiting signaling upstream of myosin-II contractility via the Rho-kinase inhibitor, Y-27632, altered EB1 dynamics differently from Blebbistatin. These results indicate that reduced actin cortex integrity can induce distinct alterations in microtubule dynamics. Given recent findings that tumor stem cell characteristics are increased by drugs which reduce actin contractility or stabilize microtubules, it remains important to clearly define how cytoskeletal drugs alter the interactions between these two filament systems in tumor cells. ",0
6009,28092336,Construction of Expanded Prefabricated Adipose Tissue Using an External Volume Expansion Device,"Multiple studies have demonstrated that mechanical forces promote the growth of adipose tissue. However, the mechanism of adipose tissue regeneration induced by mechanical forces remains unclear. In an experiment using rats, prefabricated adipose tissue with a vessel pedicle was expanded using an external volume expansion device. The volume of fat flaps was tested at different time points. Cell proliferation and angiogenesis were analyzed using immunofluorescence. The expression of adipogenic genes and inflammatory cytokines was evaluated using real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay, respectively. There were more CD31 cells and Ki67/CD34 cells in the experimental group than in the control group. The number of Ki67/CD34 cells peaked at 1 to 4 weeks. However, the expression levels of peroxisome proliferator-activated receptor-γ and CCAAT/enhancer-binding protein-β were highest from 4 to 12 weeks in the experimental group. Compared with the control group, the experimental group showed more proinflammatory cytokines: interleukin-1β, interleukin-6, tumor necrosis factor-α, and macrophage migration inhibitory factor. The construction of expanded prefabricated adipose tissue by mechanical forces is a dynamic and complex process. Mechanical forces promoted cell proliferation and angiogenesis in the early stage of adipose tissue regeneration (before 4 weeks) and induced adipogenic differentiation at a later stage (after 4 weeks) through up-regulation of macrophage migration inhibitory factor, which provided an adipogenic inductive microenvironment. ",0
6010,28092576,Multiple-Instance Learning for Medical Image and Video Analysis,"Multiple-instance learning (MIL) is a recent machine-learning paradigm that is particularly well suited to medical image and video analysis (MIVA) tasks. Based solely on class labels assigned globally to images or videos, MIL algorithms learn to detect relevant patterns locally in images or videos. These patterns are then used for classification at a global level. Because supervision relies on global labels, manual segmentations are not needed to train MIL algorithms, unlike traditional single-instance learning (SIL) algorithms. Consequently, these solutions are attracting increasing interest from the MIVA community: since the term was coined by Dietterich et al. in 1997, 73 research papers about MIL have been published in the MIVA literature. This paper reviews the existing strategies for modeling MIVA tasks as MIL problems, recommends general-purpose MIL algorithms for each type of MIVA tasks, and discusses MIVA-specific MIL algorithms. Various experiments performed in medical image and video datasets are compiled in order to back up these discussions. This meta-analysis shows that, besides being more convenient than SIL solutions, MIL algorithms are also more accurate in many cases. In other words, MIL is the ideal solution for many MIVA tasks. Recent trends are discussed, and future directions are proposed for this emerging paradigm. ",0
6011,28093038,Metabonomic Strategy for the Evaluation of Chinese Medicine Salvia miltiorrhiza and Dalbergia odorifera Interfering with Myocardial Ischemia/Reperfusion Injury in Rats,"Extract of Salvia miltiorrhiza and Dalbergia Odorifera (SM-DOO) has been traditionally used for the prevention and treatment of cardiovascular diseases. However, information regarding the pharmacodyamic material basis and potential mechanism remain unknown. Male Sprague-Dawley rats were divided into four groups: Sham, Model, Diltiazem, and SM-DOO group, n = 6. Rats were pretreated with homologous drugs for 7 days, and then subjected to 30 minutes of ischemia followed by 180 minutes of reperfusion. Cardioprotection effects of SM-DOO on myocardial ischemia/reperfusion (MI/R) injury rats were examined by hemodynamics, infarct area, histopathology, biochemical indicators, and Western blot analysis. Metabonomics technology was further performed to evaluate the endogenous metabolites profiling systematically. According to the results of pattern recognition analysis, a clear separation of MI/R injury in the Model group and Sham group was achieved and SM-DOO pretreatment group was located much closer to the Sham group than the Model group, which was consistent with results of biochemistry and histopathological assay. Moreover, potential biomarkers were identified to elucidate the drug mechanism of SM-DOO, which may be related with pathways of energy metabolism, especially tricarboxylic acid (TCA) cycle (citric acid) and β-oxidation of fatty acids (3-hydroxybutyric, palmitoleic acid, heptadecanoic acid, and arachidonic acid). In addition, the protein expressions of p-AMPK and p-ACC in the SM-DOO group were significantly elevated, while the levels of carnitine palmitoyl-CoA transferase-1 (CPT-1), p-PDK, and p-PDC were dramatically reduced by SM-DOO. In conclusion, SM-DOO pretreatment could ameliorate MI/R injury by intervening with energy metabolism, especially TCA cycle and β-oxidation of fatty acids. This work showed that the metabonomics method combinate with conventional pharmacological methods is a promising tool in the efficacy and mechanism research of traditional Chinese medicines. ",0
6012,28093289,R- and S-Warfarin Were Transported by Breast Cancer Resistance Protein: From In Vitro to Pharmacokinetic-Pharmacodynamic Studies,"Warfarin, a racemate of R- and S-warfarin, is an important oral anticoagulant with narrow therapeutic window. Being an acidic drug, warfarin (pKa = 4.94) exists mainly as anion under physiological pH. We hypothesized that the transport of warfarin anion across cell membrane was mediated by breast cancer resistance protein (BCRP), an efflux transporter having a variety of acidic substrates. This study aimed at verifying that warfarin was a substrate of BCRP. Cell lines and mice were used for transport assay and pharmacokinetic-pharmacodynamic studies, respectively. The concentrations of R- and S-warfarin were simultaneously determined by liquid chromatography-mass spectrometry method. Transport assay showed that the intracellular concentrations of R- and S-warfarin in MDCKII-BCRP were significantly lower than those in MDCKII. In addition, Ko143, a potent BCRP inhibitor, significantly inhibited the efflux transport of R- and S-warfarin in MDCKII-BCRP, but not in MDCKII. Pharmacokinetic study showed that the plasma concentrations of R- and S-warfarin in Bcrp ",0
6013,28093299,Freeze concentration-induced PLGA and polystyrene nanoparticle aggregation: Imaging and rational design of lyoprotection,"Long-term storage of stable nanoparticulate systems is critical to the utilization of nanotechnology in biomedical applications. Freeze-drying or lyophilization is the most commonly used approach to preparing stable injectable nano formulations. A detailed understanding of the freezing stress on nanoparticles is essential to the successful preservation of original particle attributes and to the development of reliable lyophilization processes. However, visualization of the freezing process and the underlying mechanisms that result in particle aggregation remains challenging. Here, we show a clear causal relationship between the freeze-concentration event and particle aggregation by employing correlative imaging techniques, encompassing both real-time dynamic visualization and super-resolution imaging for frozen systems. Direct evidence was obtained to corroborate the particle isolation hypothesis. Moreover, ice-ice, ice-air and ice-container interfaces were identified as hotspots for generating freezing stress on susceptible nanoparticles. In light of these observations, sphere close packing models were explored. Based on the relationship between jammed particles and void fraction within a confined interfacial space, we are able to define the boundary condition of the minimal 'cryoprotectant to particle ratio' required for effective design space of particle isolation and cryoprotection. These findings clearly demonstrated the utility of visualization techniques and modeling in elucidating the mechanism of freezing stress and protection, providing guiding tools to the rational design of cryoprotectant containing nano formulations and processes. ",0
6014,28093368,"Surface modification of PdlLGA microspheres with gelatine methacrylate: Evaluation of adsorption, entrapment, and oxygen plasma treatment approaches","Injectable poly (dl-lactic-co-glycolic acid) (PdlLGA) microspheres are promising candidates as biodegradable controlled release carriers for drug and cell delivery applications; however, they have limited functional groups on the surface to enable dense grafting of tissue specific biocompatible molecules. In this study we have evaluated surface adsorption, entrapment and oxygen plasma treatment as three approaches to modify the surfaces of PdlLGA microspheres with gelatine methacrylate (gel-MA) as a biocompatible and photo cross-linkable macromolecule. Time of flight secondary ion mass spectroscopy (TOF SIMS) and X-ray photoelectron spectroscopy (XPS) were used to detect and quantify gel-MA on the surfaces. Fluorescent and scanning electron microscopies (SEM) were used to image the topographical changes. Human mesenchymal stem cells (hMSCs) of immortalised cell line were cultured on the surface of gel-MA modified PdlLGA microspheres and Presto-Blue assay was used to study the effect of different surface modifications on cell proliferation. Data analysis showed that the oxygen plasma treatment approach resulted in the highest density of gel-MA deposition. This study supports oxygen plasma treatment as a facile approach to modify the surface of injectable PdlLGA microspheres with macromolecules such as gel-MA to enhance proliferation rate of injected cells and potentially enable further grafting of tissue specific molecules. Poly (dl lactic-co-glycolic) acid (PdlLGA) microspheres offer limited functional groups on their surface to enable proper grafting of tissue specific bioactive molecules. To overcome this limitation, previous approaches have suggested using alkaline solutions to introduce active groups to the surface; however, they may compromise surface topography and lose any potential surface patterns. Plasma polymerisation of bioactive monomers has been suggested to enhance surface biocompatibility; however, it is not applicable on low vapour pressure macromolecules such as most extracellular matrix (ECM) proteins and growth factors. This study aims to evaluate three different approaches to modify the surface of PdlLGA microspheres with gelatine-methacrylate (gel-MA) to enable further grafting of cross-linkable biomolecules without compromising the surface topography or the biocompatibility of the system. ",0
6015,28093383,"Effect of minimal acupuncture for infantile colic: a multicentre, three-armed, single-blind, randomised controlled trial (ACU-COL)","Evidence for treating infantile colic with acupuncture is contradictory. To evaluate and compare the effect of two types of acupuncture versus no acupuncture in infants with colic in public child health centres (CHCs). A multicentre, randomised controlled, single-blind, three-armed trial (ACU-COL) comparing two styles of acupuncture with no acupuncture, as an adjunct to standard care, was conducted. Among 426 infants whose parents sought help for colic and registered their child's fussing/crying in a diary, 157 fulfilled the criteria for colic and 147 started the intervention. All infants received usual care plus four extra visits to CHCs with advice/support (twice a week for 2 weeks), comprising gold standard care. The infants were randomly allocated to three groups: (A) standardised minimal acupuncture at LI4; (B) semi-standardised individual acupuncture inspired by Traditional Chinese Medicine; and (C) no acupuncture. The CHC nurses and parents were blinded. Acupuncture was given by nurses with extensive experience of acupuncture. The effect of the two types of acupuncture was similar and both were superior to gold standard care alone. Relative to baseline, there was a greater relative reduction in time spent crying and colicky crying by the second intervention week (p=0.050) and follow-up period (p=0.031), respectively, in infants receiving either type of acupuncture. More infants receiving acupuncture cried <3 hours/day, and thereby no longer fulfilled criteria for colic, in the first (p=0.040) and second (p=0.006) intervention weeks. No serious adverse events were reported. Acupuncture appears to reduce crying in infants with colic safely. NCT01761331; Results. ",0
6016,28093691,Middle age enhances expression of innate immunity genes in a female mouse model of pulmonary fibrosis,"""The lungs are highly sensitive to tissue fibrosis, with a clear age-related component. Among the possible triggers of pulmonary fibrosis are repeated inhalations of fine organic particles. How age affects this response, is still far from being fully understood. We examined the impact of middle-age on gene expression in pulmonary fibrosis, using the novel """"inhalation challenge set"""" mouse model. Our results demonstrate that the response of female mice to exposure of Pantoea agglomerans extract primarily involves various immune-related pathways and cell-cell/cell-extracellular matrix interactions. We found that middle-age had a strong effect on the response to the P. agglomerans-induced lung fibrosis, featured by a more rapid response and increased magnitude of expression changes. Genes belonging to innate immunity pathways (such as the TLR signaling and the NK-cell mediated cytotoxicity) were particularly up-regulated in middle-aged animals, suggesting that they may be potential targets for the treatment of pulmonary fibrosis caused by inhalations of organic particles. Our analysis also highlights the relevance of the """"inhalation challenge set"""" mouse model to lung aging and related pathology. """,0
6017,28093714,Neuroplasticity-Based Technologies and Interventions for Restoring Motor Functions in Multiple Sclerosis,"Motor impairments are very common in multiple sclerosis (MS), leading to a reduced Quality of Life and active participation. In the past decades, new insights into the functional reorganization processes that occur after a brain injury have been introduced. Specifically, the motor practice seems to be determinant to induce neuroplastic changes and motor recovery. More recently, these findings have been extended to multiple sclerosis, in particular, it has been hypothesized that disease progression, functional reorganization and disability are mutually related. For this reason, neuroplasticity-based technologies and interventions have been rapidly introduced in MS rehabilitation. Constraint-induced movement therapy (CIMT), robotics and virtual reality training are new rehabilitative interventions that deliver an intensive e task-specific practice, which are two critical factors associated with functional improvements and cortical reorganization. Another promising strategy for enhancing neuroplastic changes is non-invasive brain stimulation that can be used with a priming effect on motor training. The aims of this chapter are to review the evidence of neuroplastic changes in multiple sclerosis and to present technologies and interventions that have been tested in clinical trials. ",0
6018,28094065,Risk factors for antimicrobial-resistant Neisseria gonorrhoeae and characteristics of patients infected with gonorrhea,"There are very few data available regarding risk factors associated with antibiotic resistant-Neisseria gonorrhoeae. A study was conducted on 110 samples from 101 patients with gonococcal infection, in order to describe their characteristics and compare them with the antimicrobial susceptibility profile of their samples. An association was observed between resistant infections and heterosexual men, older age, concurrent sexually transmitted infection, and unsafe sexual behaviors. There is a need for improved data on the risk factors associated with antibiotic resistant gonococcal infection in order to identify risk groups, and to propose public health strategies to control this infection. ",0
6019,28094229,"Perceived Stress in Patients with Common Gastrointestinal Disorders: Associations with Quality of Life, Symptoms and Disease Management","Research supports relationships between stress and gastrointestinal (GI) symptoms and disorders. This pilot study assesses relationships between perceived stress, quality of life (QOL), and self-reported pain ratings as an indicator of symptom management in patients who self-reported gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). In the full sample (n = 402) perceived stress positively correlated with depression (r = 0.76, P < .0001), fatigue (r = 0.38, P < .0001), sleep disturbance (r = 0.40, P < .0001), average pain (r = 0.26, P < .0001), and worst pain (r = 0.25, P < .0001). Higher perceived stress also correlated with lower mental health-related QOL. Similar correlations were found for the participants with GERD (n = 188), IBS (n = 132), and IBD (n = 82). Finally, there were significant correlations in the GERD cohort between perceived stress, and average pain (r = 0.34, P < .0001) and worst pain (r = 0.29, P < .0001), and in the IBD cohort between perceived stress, and average pain (r = 0.32, P < .0001), and worst pain (r = 0.35, P < .01). Perceived stress broadly correlated with QOL characteristics in patients with GERD, IBS, and IBD, and their overall QOL was significantly lower than the general population. Perceived stress also appeared to be an indicator of symptom management (self-reported pain ratings) in GERD and IBD, but not IBS. While future research using objective measures of stress and symptom/disease management is needed to confirm these associations, as well as to evaluate the ability of stress reduction interventions to improve perceived stress, QOL and disease management in these GI disorders, integrative medicine treatment programs would be most beneficial to study. ",0
6020,28094275,Sulfated Cyclocarya paliurus polysaccharides markedly attenuates inflammation and oxidative damage in lipopolysaccharide-treated macrophage cells and mice,"Natural polysaccharides and their modified derivatives are crucial supplements to the prevention of inflammation. This study aimed to evaluate the effect of sulfated modification on the anti-inflammatory and anti-oxidative activities of Cyclocarya paliurus polysaccharides (CP). A sulfated CP, S-CP ",0
6021,28094370,Probing sub-nano level molecular packing and correlated positron annihilation characteristics of ionic cross-linked chitosan membranes using positron annihilation spectroscopy,"Chitosan, CS, cross-linked with bivalent palladium has shown enhanced mechanical and thermal properties depending on the transformation of the structure at a microscopic scale. In the present study, CS directly cross-linked by palladium cation membranes (CS-cr-PM) was prepared through a solution-casting method. Mobility of chitosan chains were greatly reduced after crosslinking, making a great reduction in the swelling ratio studied by a water-swelling degree measurement, which led to an improvement in molecular chain rigidity. In order to investigate the chain packing at the molecular level in the ionic cross-linked CS system, the structure of chemically-crosslinked CS is investigated by means of the combined use of wide angle X-ray diffraction (WAXD) and infrared measurements, and a combination of positron annihilation lifetime spectroscopy (PALS) and simultaneous coincidence Doppler broadening (CDB) spectroscopy offers coherent information on both the free-volume related sub-nano level molecular packing and the chemical surrounding of free volume nanoholes in CS-cr-PM as a function of palladium salt loading. The variations in the free volume size and size distribution have been determined through the ortho-positronium (o-Ps) lifetime and its lifetime distribution. The studies showed that a strong interaction between CS molecules and palladium cations results in the change in crystallinity in formed CS-cr-PM leading to variational chain packing density. Meanwhile, significant inhibition effects on positronium formation due to doping are observed, which could be interpreted in terms of the existence of chloride ions. Applications of positron annihilation spectroscopy to study the microstructure and correlated positron annihilation characteristics of an ionic cross-linked CS system are systematically discussed. ",0
6022,28094457,Granzyme A potentiates chemokine production in IL-17-stimulated keratinocytes,"Plaque psoriasis presents with focal skin inflammation, partially maintained by IL-17-mediated interactions between infiltrating epidermal T cells and activated keratinocytes. Here we show that the majority of lesional epidermal CD8 T cells express granzyme A, alone or in combination with IL-17. To assess proinflammatory properties of granzyme A in psoriasis, primary human keratinocytes were stimulated with granzyme A in the presence or absence of IL-17. Out of 33 analysed keratinocyte-derived inflammatory mediators, granzyme A potentiated IL-17-induced secretion of CXCL 1, CXCL 12 and CCL 4. Intriguingly, all three chemokines are implicated in psoriasis pathogenesis and are involved in recruitment of T cells, neutrophils and pDCs into inflamed tissues. Our results indicate that granzyme A produced by lesional CD8 T cells specifically increase the chemokine production from inflamed keratinocytes, thereby amplifying a chemotactic inflammatory loop that sustains psoriasis lesions. ",0
6023,28094532,Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties,"Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor α (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with  ",0
6024,28094736,Characterization of Patient Expectations and Satisfaction after Total Hip Arthroplasty,"""We conducted a prospective multicenter study in which outcome-related expectations of 236 primary total hip arthroplasty patients were determined. Clinical surveys and radiographs were used to determine the relationship between postoperative level of patient satisfaction and patient-reported and radiographic outcomes. At 1 year, 82.6% of expectations were achieved, most of the time with high satisfaction (89.3%). Younger, lower body-mass index, male patients were more likely to expect the surgery to benefit """"return to work"""" and """"sexual function"""", whereas older, heavier patients, selected """"elimination of assistive devices"""" and """"independence in daily activities"""". The ability of the patient to meet their expectations fully did not correlate directly with level of satisfaction or clinical outcomes, suggesting limitations in current clinical surveys. The characterization of patient expectations is essential in providing patient-centered care. """,0
6025,28094864,Quantifying the structural integrity of nanorod arrays,"Arrays of aligned nanorods oriented perpendicular to a support, which are accessible by top-down lithography or by means of shape-defining hard templates, have received increasing interest as sensor components, components for nanophotonics and nanoelectronics, substrates for tissue engineering, surfaces having specific adhesive or antiadhesive properties and as surfaces with customized wettability. Agglomeration of the nanorods deteriorates the performance of components based on nanorod arrays. A comprehensive body of literature deals with mechanical failure mechanisms of nanorods and design criteria for mechanically stable nanorod arrays. However, the structural integrity of nanorod arrays is commonly evaluated only visually and qualitatively. We use real-space analysis of microscopic images to quantify the fraction of condensed nanorods in nanorod arrays. We suggest the number of array elements apparent in the micrographs divided by the number of array elements a defect-free array would contain in the same area, referred to as integrity fraction, as a measure of structural array integrity. Reproducible procedures to determine the imaged number of array elements are introduced. Thus, quantitative comparisons of different nanorod arrays, or of one nanorod array at different stages of its use, are possible. Structural integrities of identical nanorod arrays differing only in the length of the nanorods are exemplarily analysed. ",0
6026,28095048,AN APPROACH TO USING DATA MINING TO SUPPORT EARLY IDENTIFICATION OF ACROMEGALY,"Data mining using insurance claims presents an opportunity to incorporate new analytic techniques in identifying rare conditions. This study aims to identify dyads of clinical conditions associated with acromegaly that may, with further validation and testing, be used to initially identify and diagnose this rare disease more accurately and efficiently. This case-control study used two claims databases to identify acromegaly patients (cases) (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 253.0) from 2008-2013. Each case was assigned two nonacromegaly controls (same age, gender, and region). Matched patients were randomly split into development and validation datasets. With expert clinician input, we isolated common associated conditions using ICD-9-CM codes. We identified all 2-way combinations of these conditions (dyads) and calculated the rate and risk relative (RR) to controls. Dyads meeting certain criteria (case rate ≥5% [or ≥1% if RR ≥5] or observed RR > expected) were replicated in the validation dataset to confirm results. We identified 3,731 cases and 7,462 controls: mean age 41.8 (SD, 16.1) years, 51.8% female. A total of 32 and 38 dyads, reduced from 630, met study criteria. Among replicated dyads, case rates varied -15.9% (hypertension and metabolic disorder) to 0.6% (arthritis and menstrual abnormalities). The highest RRs (e.g., valvular insufficiency and colon polyps [RR, 13.5; rate, 0.7%]) also exceeded expected values. Replication showed similar RR direction and size. This novel analytic approach revealed several dyads that were significantly associated with an acromegaly diagnosis. Presence of high-risk condition pairs, if verified by a detailed data source (e.g., medical charts), may be incorporated into screening tools or serve as potential markers for physicians to consider an acromegaly diagnosis. ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification ID = identification RR = relative risk. ",0
6027,28095284,Family Carers' Perspectives on Integrated Community Care in the Czech Republic,"""The problem of family care for people dependent on another person has only recently become a focus of research. As demand for health and social services has not been adequately met by public service providers, growing attention has been given to informal care and the integration of families within systems of health and social care at the community level. This paper presents the results of a survey on informal carers' views and opinions under the current conditions of social support in the Czech Republic. The survey was based on theoretical concepts of caring societies, deinstitutionalization, refamilization, and integrated community care, and aimed to shed light on caring families' experiences and needs in the Czech Republic. Family lay carers completed an original self-administered questionnaire. A convenient sample of 200 family carers was selected. The survey collected information about the most influential factors in determining whether the families continue to provide care for their relatives in the household. More than 50% of the caregivers provide care from moral and emotional reasons. Financial problems, risk of losing their jobs, and further deterioration of health of the person they care for emerged as key risk factors, but overall, determination among carers to continue providing care """"at any cost"""" was high (53%). Involving local communities and services, e.g. general practitioners (GPs) to a greater extent in the coordination of various social and health services, and in support mechanisms at the juncture between informal and formal care would make it easier for family carers to continue providing long-term care. """,0
6028,28095439,Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways,"We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV-infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T-cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain. ",0
6029,28095515,Effects of Ultraviolet Photofunctionalization on Bone Augmentation and Integration Capabilities of Titanium Mesh and Implants,"Ultraviolet (UV)-mediated photofunctionalization has earned considerable attention for the enhancement of the biologic capabilities of titanium. The effects of photofunctionalization on bone augmentation and gap closure were examined using titanium implants and mesh in a rat femur model. An acid-etched titanium implant (4-mm length, 1-mm diameter) was placed in the gluteal tuberosity that resembles a knife-edge-like edentulous ridge. The lower half of the implant was located in a 2-mm-diameter defect created in the bone without cortical bone support; the upper half was exposed and covered with a titanium mesh to provide augmentation space. After 12 and 24 days of healing, specimens were subjected to microcomputed tomography (micro-CT)- and histology-based bone morphometry in three zones of analysis: augmentation, cortical bone-implant gap, and bone marrow. A biomechanical push-in test was performed to examine the strength of bone-implant integration. Photofunctionalization was performed by treating titanium implants and mesh with UV light for 12 minutes. Photofunctionalized titanium mesh and implants were hydrophilic, whereas untreated controls were hydrophobic. Bone volume was significantly greater in photofunctionalized implants and mesh than in untreated implants in all zones on days 12 and 24. Bone-to-implant contact of photofunctionalized implants was greater than that of untreated implants, not just in the bone marrow but also in the gap and augmented zones. The strength of osseointegration was three times greater for photofunctionalized implants than for untreated implants. Use of photofunctionalized titanium mesh and implants effectively enhanced vertical bone augmentation, cortical bone-implant gap closure, and osseointegration without innate bone support. ",0
6030,28095610,Uveal schwannoma in a brown-eyed dog,"An eleven-year-old, female spayed Boxer dog was diagnosed with a uveal schwannoma (formerly known as the spindle cell tumor of the blue-eyed dog or SCTBED) despite having a uniformly brown iris. The patient presented to emergency for ocular discomfort, and the right globe was subsequently enucleated due to glaucoma and submitted for histopathology. Upon histopathologic evaluation, a uveal schwannoma was diagnosed and confirmed with immunohistochemical staining. Complete metastatic evaluation 1 and 6 months after initial presentation did not reveal evidence of metastasis, and the dog remains systemically healthy. This case represents a unique variant of uveal schwannoma and is relevant because although the vast majority of these tumors occur in blue-eyed dogs, clinicians should not completely rule out this tumor as a differential based on the iris color. ",0
6031,28095742,Lithium response in bipolar disorders and core clock genes expression,"We examine whether the lithium response is associated with changes in the expression of core clock genes. The effect of a therapeutic concentration of lithium (1 mM) on the expression levels of 17 circadian genes was examined in lymphoblastoid cell lines (LCLs) derived from two well-characterized groups of bipolar disorder patients, defined as lithium non-responders (NR, n = 20) or excellent responders (ER, n = 16). Quantitative real-time PCR (qRT-PCR) was conducted at 2, 4 and 8 days (d2, d4 and d8) with and without lithium exposure. At d2, in ER only, BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40 and CSNK1D were upregulated, whereas NR1D1 was downregulated. At d4, in ER only, CRY1 was downregulated. At d8, in NR only, GSK3β was upregulated and DBP, TIMELESS and CRY1 were downregulated. Significant Group × Lithium interactions existed for NR1D1 at d2 (P = 0.02), and CRY1 at d4 (P = 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time × Group interaction) for PER3, NR1D1, DBP, RORA, CSNK1D and TIMELESS; and a significant Time × Lithium interaction for NR1D1. Coexpression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium. In LCLs, lithium influences expression of circadian genes with differences in amplitude and kinetics according to the patient's lithium response status. ",0
6032,28095905,Imputing HIV treatment start dates from routine laboratory data in South Africa: a validation study,"""Poor clinical record keeping hinders health systems monitoring and patient care in many low resource settings. We develop and validate a novel method to impute dates of antiretroviral treatment (ART) initiation from routine laboratory data in South Africa's public sector HIV program. This method will enable monitoring of the national ART program using real-time laboratory data, avoiding the error potential of chart review. We developed an algorithm to impute ART start dates based on the date of a patient's """"ART workup"""", i.e. the laboratory tests used to determine treatment readiness in national guidelines, and the time from ART workup to initiation based on clinical protocols (21 days). To validate the algorithm, we analyzed data from two large clinical HIV cohorts: Hlabisa HIV Treatment and Care Programme in rural KwaZulu-Natal; and Right to Care Cohort in urban Gauteng. Both cohorts contain known ART initiation dates and laboratory results imported directly from the National Health Laboratory Service. We assessed median time from ART workup to ART initiation and calculated sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of our imputed start date vs. the true start date within a 6 month window. Heterogeneity was assessed across individual clinics and over time. We analyzed data from over 80,000 HIV-positive adults. Among patients who had a workup and initiated ART, median time to initiation was 16 days (IQR 7,31) in Hlabisa and 21 (IQR 8,43) in RTC cohort. Among patients with known ART start dates, SE of the imputed start date was 83% in Hlabisa and 88% in RTC, indicating this method accurately predicts ART start dates for about 85% of all ART initiators. In Hlabisa, PPV was 95%, indicating that for patients with a lab workup, true start dates were predicted with high accuracy. SP (100%) and NPV (92%) were also very high. Routine laboratory data can be used to infer ART initiation dates in South Africa's public sector. Where care is provided based on protocols, laboratory data can be used to monitor health systems performance and improve accuracy and completeness of clinical records. """,0
6033,28096311,The Comparison of Health Status Between Male and Female Medical Radiation Workers in China,"To assess the health statue of chronically exposed Chinese medical radiation workers. A cross-sectional study of 530 medical radiation workers in a city of China was conducted to document the health status and the monitored annually absorbed doses. Long-term and low-dose radiation exposure can affect a number of health indicators in the individuals, which covered the cardiovascular system, hematologic system, ophthalmology, liver and kidney's functions, chromosome aberration and micronucleus. The differences in the health status between male and female individuals were associated with job types and exposed years of service. The monitored doses of individuals were lower than the limit value of the national standard. The health status in chronically exposed individuals demonstrated some gender difference associated with length of exposure and work type. This study provides some evidence to understand the health status of medical radiation workers in China and have the potentially to inform screening and clinical diagnosis. ",0
6034,28096639,Association between serum 25-hydroxyvitamin D levels and bone mineral density in normal postmenopausal women,"This study was conducted with the objective of assessing serum 25-hydroxyvitamin D (25(OH)D) in postmenopausal women (PMW), to detect osteopenia or osteoporosis in PMW and to establish a correlation between serum 25(OH)D levels and bone mineral density (BMD). A total of 100 healthy PMW were selected, and a prospective observational study was conducted to correlate the BMD with serum 25(OH)D levels. Their laboratory investigations along with serum 25(OH)D levels were done. Their BMD was assessed with dual-energy X-ray absorptiometry at lumbar spine and neck of femur; T-scores were derived. Correlation analysis was done to investigate the relationship between serum 25(OH)D levels and BMD. The proportion of osteoporosis at the hip was 31.9% in deficient group, 16.1% in insufficient, and 18.2% in sufficient group and at lumbar spine, it was 27.7%, 16.1%, and 22.7%, respectively. Forty-seven percent of PMW had deficient (<20 ng/ml) serum 25(OH)D levels and 31% had insufficiency. T-score at hip in deficient group was -2.05 ± 0.25, and in an insufficient group, it was -1.79 ± 0.13; T-score at lumbar spine was -1.92 ± 0.12 and -1.79 ± 0.12, respectively, but both were not statistically significant. Osteoporosis was seen in 24%, osteopenia in 55% at hip level and 23% and 59% respectively at lumbar spine. There was no association between serum 25(OH)D levels and BMD neither at hip nor at lumbar spine ( In this study, among our cohort of patients there was no correlation between serum 25(OH)D levels and BMD. However, Vitamin D deficiency coexists with low BMD. Vitamin D insufficiency is a common risk factor for osteoporosis associated with increased bone remodeling and low bone mass. ",0
6035,28096670,"Lung-targeting drug delivery system of baicalin-loaded nanoliposomes: development, biodistribution in rabbits, and pharmacodynamics in nude mice bearing orthotopic human lung cancer","The present study aims to develop a kind of novel nanoliposomes for the lung-targeting delivery system of baicalin as a Chinese medicine monomer. Baicalin-loaded nanoliposomes were prepared by the effervescent dispersion and lyophilized techniques. Baicalin-loaded nanoliposomes had an average particle size of 131.7±11.7 nm with 0.19±0.02 polydispersity index, 82.8%±1.24% entrapment efficiency and 90.47%±0.93% of yield and sustaining drug release effect over 24 h and were stable for 12 months at least. In vitro no hemolytic activity was observed for the experimental drug concentration. After intravenous administration of baicalin-loaded nanoliposomes to rabbits, drug concentration in the lungs was the highest among the tested organs at all time points and was significantly higher than that of its solution. For the targeting parameters, the relative intake rate and the ratio of peak concentration of lung were 4.837 and 2.789, respectively. Compared with plasma, liver, spleen, and kidney, the ratios of targeting efficacy (T ",0
6036,28096695,Hysterosalpingo-foam sonography: patient selection and perspectives,"We present an overview of the common types of tubal patency tests, with a focus on hysterosalpingo-foam sonography (HyFoSy). Current evidence suggests that HyFoSy is an accurate alternative to X-ray hysterosalpingography (HSG) for outpatient tubal evaluation in women who are at low risk for tubal disease. It may be superior to saline hysterosalpingo-contrast sonography (HyCoSy) in excluding tubal occlusion. A hyperechogenic medium may enhance contrast visualization and enable clearer delineation of tubal anatomy. This may enhance confidence in the diagnosis of tubal patency, reduce false occlusion results, and improve the diagnostic yield of the test. It would be reasonable to deduce that HyFoSy would have similar performance characteristics as HyCoSy with other positive contrast agents. The available evidence supports the accuracy of HyFoSy compared to other forms of tubal investigation. We suggest a decision-making pathway based on the most current professional recommendations and available evidence. However, in this article, we do not provide a definitive exposition of the methods used for investigating tubal patency. Rather, we explore the contexts in which the various investigations are most and least suitable, and identify their strengths and limitations. Finally, we also discuss challenges encountered when performing tubal contrast sonography in clinical practice, including the problem of false occlusion results. ",0
6037,28096959,The effect of aminoguanidine on sperm motility and mitochondrial membrane potential in varicocelized rats,"Increased levels of nitric oxide (NO) in the testicular veins of people suffering from varicocele have already been reported. However, the role of NO-synthase (NOS) isozymes and their inhibitors have not been extensively studied. We aimed to evaluate the inhibitory effects of aminoguanidine (AG), on sperm motility, vitality, and mitochondrial membrane potential (MMP) in varicocelized rats. Twenty fore male Wister rats were divided into control, sham, varicocele, and treatment groups. Varicocele and treatment groups underwent partial ligation of left renal vein. Rats in the sham group underwent the same procedures as the varicocele group with the exception of vein ligation. 10 weeks after varicocele induction, sperm parameters were evaluated in all groups. The treatment group received 50 mg/kg AG injection daily for 10 weeks after which they were sacrificed prior to assessment of the parameters. Sperm viability and MMP were assessed by flow cytometry using propidium iodide (PI) and rhodamine 123 (Rh123), respectively. The results of this study show a decrease in sperm viability, motility and MMP in the varicocele group compared with the other groups. After AG injection, we observed that all the parameters were significantly enhanced in the treatment group compared with the other groups. Rh123 staining revealed a positive relation between MMP and sperm motility, whereas PI staining showed a positive relation between sperm motility and viability. The findings of our study show that AG improves sperm motility and MMP, and thus, might be useful in the management of varicocele-related infertility. ",0
6038,28097287,Using Active Learning to Identify Health Information Technology Related Patient Safety Events,"The widespread adoption of health information technology (HIT) has led to new patient safety hazards that are often difficult to identify. Patient safety event reports, which are self-reported descriptions of safety hazards, provide one view of potential HIT-related safety events. However, identifying HIT-related reports can be challenging as they are often categorized under other more predominate clinical categories. This challenge of identifying HIT-related reports is exacerbated by the increasing number and complexity of reports which pose challenges to human annotators that must manually review reports. In this paper, we apply active learning techniques to support classification of patient safety event reports as HIT-related. We evaluated different strategies and demonstrated a 30% increase in average precision of a confirmatory sampling strategy over a baseline no active learning approach after 10 learning iterations. ",0
6039,28097704,Prophylactic RhCE and Kell antigen matching: impact on alloimmunization in transfusion-dependent patients with myelodysplastic syndromes,"Thirty to 80 per cent of patients with myelodysplastic syndromes (MDS) become transfusion-dependent and are at risk for red blood cell (RBC) alloimmunization. This study compared alloimmunization rates in transfusion-dependent patients with MDS at an institution with a policy of prophylactic antigen matching for RhCE and K (PAM) with those transfused at institutions without such a policy (non-PAM). Transfusion records were retrospectively reviewed to determine total number of RBC transfusions received, whether RBC phenotyping was performed, the type and date of first alloantibody development and receipt of prophylactic antigen matching for RhCE and K. In 176 transfusion-dependent patients with MDS, the overall rate of new alloimmunization was 17%; the majority of patients (87%) developed at least one alloantibody to Rh or Kell antigens. The alloimmunization rate at the institution with a PAM policy was 11% compared with 23% at non-PAM institutions (P = 0·06). The rate of Rh/K alloimmunization was 7 vs. 22%, respectively (P = 0·008). No patient who received PAM developed a Rh/K alloantibody. The rate of alloimmunization was 11% at an institution with a PAM policy which was non-significantly lower than 23% at institutions without a PAM policy. However, rates of Rh/K alloimmunization were significantly lower. Such a policy should be considered in transfusion-dependent patients with MDS, although further studies on cost-effectiveness and careful consideration of resource availability in the local context are required. ",0
6040,28097837,"Food and beverage advertising on children's TV channels in Argentina: Frequency, duration, and nutritional quality","Food and beverage marketing has been identified as one of the determinants of unhealthy food and beverage consumption in the child population. To determine the frequency and duration of food and beverage advertising in children's programming and the nutritional quality of advertised food and beverages. Descriptive, cross-sectional study. Children's cable and broadcast channel programming was recorded in two periods: over the week and on the weekend. The type, quantity, and duration of commercials were recorded. The nutritional quality of advertised food and beverages was analyzed. A total of 402.3 hours of children's programming were recorded. In total, 3711 commercials were identified. Among these, 20.9% corresponded to food and beverages, i.e., an average of 1.9 ± 1.0 commercials per hour or equivalent to 0.68 ± 0.36 min/hour. Dairy products, candies, and fast-food meals were the most advertised food products. Only a third of advertised food and beverages (35.8%) were categorized as healthy as per the nutrient profiling system. Based on the traffic light labeling system, 50% of advertised food and beverages were high in sugar, 25% were high in saturated fat, and approximately 15% were high in sodium or fat. Food and beverage advertising accounted for 20% of television advertising time. The most advertised products were dairy products, followed by candies and sweet snacks, fast-food meals, and beverages. Two-thirds of advertised food and beverages were considered unhealthy. ",0
6041,28098412,A hierarchical modeling approach to estimate regional acute health effects of particulate matter sources,"Exposure to particulate matter (PM) air pollution has been associated with a range of adverse health outcomes, including cardiovascular disease hospitalizations and other clinical parameters. Determining which sources of PM, such as traffic or industry, are most associated with adverse health outcomes could help guide future recommendations aimed at reducing harmful pollution exposure for susceptible individuals. Information obtained from multisite studies, which is generally more precise than information from a single location, is critical to understanding how PM impacts health and to informing local strategies for reducing individual-level PM exposure. However, few methods exist to perform multisite studies of PM sources, which are not generally directly observed, and adverse health outcomes. We developed SHared Across a REgion (SHARE), a hierarchical modeling approach that facilitates reproducible, multisite epidemiologic studies of PM sources. SHARE is a two-stage approach that first summarizes information about PM sources across multiple sites. Then, this information is used to determine how community-level (i.e., county-level or city-level) health effects of PM sources should be pooled to estimate regional-level health effects. SHARE is a type of population value decomposition that aims to separate out regional-level features from site-level data. Unlike previous approaches for multisite epidemiologic studies of PM sources, the SHARE approach allows the specific PM sources identified to vary by site. Using data from 2000 to 2010 for 63 northeastern US counties, we estimated regional-level health effects associated with short-term exposure to major types of PM sources. We found that PM from secondary sulfate, traffic, and metals sources was most associated with cardiovascular disease hospitalizations. Copyright © 2017 John Wiley & Sons, Ltd. ",0
6042,28098864,VICTOR: Vinflunine in advanced metastatic transitional cell carcinoma of the urothelium: A retrospective analysis of the use of vinflunine in multi-centre real life setting as second line chemotherapy through Free of Charge Programme for patients in the UK and Ireland,"There is no standard of care in the UK or Ireland for second-line chemotherapy for patients with advanced transitional cell carcinoma (TCCU). Vinflunine is approved for TCCU patients who have failed a platinum-based regimen, and is standard of care in Europe but is not routinely available in the UK. Data were collected retrospectively on patients who received vinfluine as a second-line treatment. The aims were to document the toxicity and efficacy in a real life setting. Data were collected on 49 patients from 9 sites across the UK and Ireland [median age, 64 (IQR, 57-70) years, 33 males]. All patients had advanced metastatic TCCU. Thirteen patients had bone or liver metastases, 4 patients had PS 2 and 11 patients had HB <10. Median vinflunine administration was 3.5 cycles (range 1-18). Most common grade 3-4 toxicities were constipation (4 patients) and fatigue (3 patients). Partial response rate was 29% (14 PR, 11 SD, 19 PD, 4 NE, 1 not available). Median OS was 9.1 (6.0, 12.7) months. Results are consistent with real life data from Europe. Toxicity is further reduced with prophylactic laxative and oral antibiotics. Vinflunine is an efficient and tolerable second line treatment in advanced TCCU. ",0
6043,28098927,The role of HE4 and CA125 in differentiation between malignant and non-malignant endometrial pathologies,"The aim of the study was to assess the role of HE4 and CA125 in differentiation between malignant and non-malignant endometrial pathologies. A retrospective study of 87 patients with endometrial pathologies was conducted. Tumor markers were assessed two weeks before surgical intervention in each subject. The final diagnosis was established on the basis of the histopathological examination of the endometrium. Serum HE4 levels were significantly higher in patients with endometrial cancer (EC) as compared to non-malignant endometrial pathologies (p < 0.001), patients with stage I EC as compared to non-malignant endometrial pathologies (p < 0.001), and patients with stage Ia EC as compared to non-malignant endometrial pathologies (p = 0.003). Serum CA125 levels were not significantly different as far as these groups of patients were concerned. Both tumor markers were significantly higher in patients with stage II-III as compared to stage I EC and non-malignant endometrial pathologies (p < 0.001 for both markers). Sensitivity and specificity of HE4 at the cut-off level of 70 pmol/L for detecting endometrial malignancies were 73.08% and 85.71%, respectively. Sensitivity and specificity of CA125 at the cut-off level of 35 U/mL were 29.41% and 94.29%, respectively. The area under the curve (AUC) for HE4 was 0.875, suggesting that this marker reliably differentiates malignant from non-malignant endometrial pathologies (p < 0.001). AUC for CA125 was 0.552, suggesting that this marker does not reliably differentiate between malignant and non-malignant endometrial pathologies (p = 0.414). HE4, in contrast to CA125, might be a useful tool for detecting malignant endometrial pathologies. ",0
6044,28099077,DISEASE COMPLEXITY IN A DECLINING ALASKAN MUSKOX (OVIBOS MOSCHATUS) POPULATION,"The muskox ( Ovibos moschatus ) population inhabiting the eastern North Slope (ENS) of Alaska, US declined dramatically during 1999-2006, whereas populations in western Alaska (WA) were stable or increasing. To understand morbidity and mortality factors contributing to the decline, Alaska Department of Fish and Game conducted pathologic investigations of carcasses from 2005 until 2008. Additionally, archived sera from both ENS and WA muskoxen collected during 1984-92, before the documented beginning of the ENS decline; sera collected during 2000, near the beginning of the decline; and contemporary sera (from live capture-release, adult females) collected during 2006, 2007, and 2008 were analyzed to determine whether prevalence of antibody to potential pathogens differed in the two areas or changed over time. The pathogens investigated were those that were believed could cause lameness or poor reproduction or adversely affect general health. Furthermore, trace mineral levels, hemograms, and gastrointestinal parasites were evaluated in live adult females captured 2006-08. Pathologic investigations identified several comorbid conditions, including predation, polyarthritis caused by or consistent with Chlamydophila spp. infection, hoof lesions, copper deficiency, contagious ecthyma, verminous pneumonia, hepatic lipidosis suggestive of negative energy balance, and bacterial bronchopneumonia due to Trueperella pyogenes and Bibersteinia trehalosi . Pathogens suspected to be newly introduced in the ENS muskox population on the basis of serologic detection include bovine viral diarrhea, respiratory syncytial virus, Chlamydophila spp., Brucella spp., Coxiella burnetii , and Leptospira spp., whereas parainfluenza virus-3 antibody prevalence has increased in the WA population. Although multiple disease syndromes were identified that contributed to mortality and, in combination, likely limited the ENS muskox population, further holistic investigations of disease agents, trace mineral status, and nutritional factors in conjunction with intensive demographic and environmental analyses would provide a better understanding of factors that influence Alaskan muskox populations. ",0
6045,28099264,Post-treatment 18F-FDG-PET/CT versus contrast-enhanced CT in patients with oropharyngeal squamous cell carcinoma: comparative effectiveness study,"To compare the accuracy of same-day therapy-assessment PET/computed tomography (PET/CT) and conventional contrast-enhanced computed tomography (CECT) in patients with oropharyngeal squamous cell carcinoma (OPSCC). A total of 110 (95 men and 15 women; mean age 59 years) patients with biopsy-proven OPSCC were evaluated with same-day PET/CT and CECT pair scans as part of follow-up therapy assessment. Scans were performed within 6 months after the completion of primary treatment (median time: 3.1 months; range: 0.5-6 months). PET/CT and CECT scans were reviewed retrospectively for residual primary site disease, and right and left cervical lymph node involvement. Histopathology or 6 month clinical/imaging follow-up were used as the gold standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the primary site and cervical nodal disease. Of 110 OPSCC patients, 90.9% were human papilloma virus positive, 80.8% were stage 4, and 76.4% received chemoradiation as the primary treatment. The sensitivity, specificity, PPV, NPV, and accuracy of PET/CT and CECT were similar in the evaluation of the primary cancer site (PET/CT: 75.0, 91.5, 25.0, 99.0, and 90.9, respectively, versus CECT: 75.0, 90.6, 23.1, 99.0, and 90.0, respectively). In evaluating cervical lymph node involvement, PET/CT appeared to have higher accuracy (96.8 vs. 81.7%), specificity (97.7 vs. 81.7%), and PPV (45.8 vs. 16.5%), comparable NPV (99.4% for both), and lower sensitivity (65 vs. 75%) compared with same-day CECT. Same-day PET/CT and CECT scans had comparable accuracy in the evaluation of primary tumor sites after completion of therapy in patients with OPSCC. PET/CT showed higher accuracy in the evaluation of cervical lymph node involvement. ",0
6046,28099546,Multiple keratoacanthomas occurring in surgical margins and de novo treated with intralesional methotrexate,"Keratoacanthomas (KAs) are common skin lesions known for their rapid growth and spontaneous regression. Keratoacanthomas also can occur in sites of prior trauma, such as surgical scars. We report a case of multiple KAs occurring in the site of trauma from a prior surgery and de novo as well as the response to treatment with intralesional methotrexate (MTX). ",0
6047,28099873,Antimicrobial photodynamic therapy as an adjunct for treatment of deep carious lesions-A systematic review,"""For deep carious lesions, a more conservative treatment modality (""""selective caries removal"""") has been proposed, where only the heavily contaminated dentine is removed. In this regard, effective adjuncts for cavity disinfection such as the antimicrobial photodynamic therapy (aPDT) can be valuable clinically prior to definitive restoration. Therefore, the aim of this study was to systematically assess clinical studies on the effectiveness of aPDT as a supplementary tool in the treatment of deep caries lesions. Searches were performed in four databases (PubMed, EMBASE, ISI Web of Science, ClinicalTrials.gov) from 1st January, 2011 until 21st June, 2016 for search terms relevant to the observed parameters, pathological condition, intervention and anatomic entity. The pooled information was evaluated according to PRISMA guidelines. At first, 1651 articles were recovered, of which 1249 full-text articles were evaluated, 270 articles thereof were reviewed for eligibility and finally 6 articles met all inclusion criteria. The aPDT protocols involved Methylene Blue, Toluidine Blue and aluminium-chloride-phthalocyanine as photosensitizers and diode lasers, light-emitting diodes and halogen light-sources. The data from five reports, utilizing both culture-dependent and -independent methods, disclosed significant reduction of cariogenic bacterial load after mechanical caries removal with adjunct aPDT. As these studies exhibit some methodological limitations, e.g. lack of positive controls, this systematic review can support the application of aPDT to a limited extent only in terms of reducing the microbial load in deep carious lesions before restorative treatment. """,0
6048,28099951,Complex X-Chromosomal Rearrangements in Two Women with Ovarian Dysfunction: Implications of Chromothripsis/Chromoanasynthesis-Dependent and -Independent Origins of Complex Genomic Alterations,"Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46,X,der(X)(pter→ p22.1::p11.23→q24::q21.3→q24::p11.4→pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46,X,der(X)(pter→ p22.31::q22.1→q10::q10→q22.1::p22.31→pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X-chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haploinsufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and -independent processes. ",0
6049,28100173,Whole genome-wide transcript profiling to identify differentially expressed genes associated with seed field emergence in two soybean low phytate mutants,"Seed germination is important to soybean (Glycine max) growth and development, ultimately affecting soybean yield. A lower seed field emergence has been the main hindrance for breeding soybeans low in phytate. Although this reduction could be overcome by additional breeding and selection, the mechanisms of seed germination in different low phytate mutants remain unknown. In this study, we performed a comparative transcript analysis of two low phytate soybean mutants (TW-1 and TW-1-M), which have the same mutation, a 2 bp deletion in GmMIPS1, but show a significant difference in seed field emergence, TW-1-M was higher than that of TW-1 . Numerous genes analyzed by RNA-Seq showed markedly different expression levels between TW-1-M and TW-1 mutants. Approximately 30,000-35,000 read-mapped genes and ~21000-25000 expressed genes were identified for each library. There were ~3900-9200 differentially expressed genes (DEGs) in each contrast library, the number of up-regulated genes was similar with down-regulated genes in the mutant TW-1and TW-1-M. Gene ontology functional categories of DEGs indicated that the ethylene-mediated signaling pathway, the abscisic acid-mediated signaling pathway, response to hormone, ethylene biosynthetic process, ethylene metabolic process, regulation of hormone levels, and oxidation-reduction process, regulation of flavonoid biosynthetic process and regulation of abscisic acid-activated signaling pathway had high correlations with seed germination. In total, 2457 DEGs involved in the above functional categories were identified. Twenty-two genes with 20 biological functions were the most highly up/down- regulated (absolute value Log2FC >5) in the high field emergence mutant TW-1-M and were related to metabolic or signaling pathways. Fifty-seven genes with 36 biological functions had the greatest expression abundance (FRPM >100) in germination-related pathways. Seed germination in the soybean low phytate mutants is a very complex process, which involves a series of physiological, morphological and transcriptional changes. Compared with TW-1, TW-1-M had a very different gene expression profile, which included genes related to plant hormones, antioxidation, anti-stress and energy metabolism processes. Our research provides a molecular basis for understanding germination mechanisms, and is also an important resource for the genetic analysis of germination in low phytate crops. Plant hormone- and antioxidation-related genes might strongly contribute to the high germination rate in the TW-1-M mutant. ",0
6050,28100252,A cognitive electrophysiological signature differentiates amnestic mild cognitive impairment from normal aging,"Noninvasive and effective biomarkers for early detection of amnestic mild cognitive impairment (aMCI) before measurable changes in behavioral performance remain scarce. Cognitive event-related potentials (ERPs) measure synchronized synaptic neural activity associated with a cognitive event. Loss of synapses is a hallmark of the neuropathology of early Alzheimer's disease (AD). In the present study, we tested the hypothesis that ERP responses during working memory retrieval discriminate aMCI from cognitively normal controls (NC) matched in age and education. Eighteen NC, 17 subjects with aMCI, and 13 subjects with AD performed a delayed match-to-sample task specially designed not only to be easy enough for impaired participants to complete but also to generate comparable performance between subjects with NC and those with aMCI. Scalp electroencephalography, memory accuracy, and reaction times were measured. Whereas memory performance separated the AD group from the others, the performance of NC and subjects with aMCI was similar. In contrast, left frontal cognitive ERP patterns differentiated subjects with aMCI from NC. Enhanced P3 responses at left frontal sites were associated with nonmatching relative to matching stimuli during working memory tasks in patients with aMCI and AD, but not in NC. The accuracy of discriminating aMCI from NC was 85% by using left frontal match/nonmatch effect combined with nonmatch reaction time. The left frontal cognitive ERP indicator holds promise as a sensitive, simple, affordable, and noninvasive biomarker for detection of early cognitive impairment. ",0
6051,28100268,Upper lip metastasis of sarcomatoid carcinoma of the lung - an unusual site of disease: a case report,"Lip metastases are rare clinical events that are frequently mistaken for other diagnoses. For sarcomatoid lung carcinoma, a rare histologic variant of non-small cell lung cancer, the incidence and pattern of cutaneous spread is poorly understood. We present a case of a 79-year-old African American man with a rapidly progressive upper lip cutaneous lesion that provided the first evidence of distant metastatic spread of sarcomatoid lung carcinoma. This is the first reported case of lip metastasis in sarcomatoid lung carcinoma. It highlights the importance of maintaining a high level of suspicion for metastatic disease in the presence of new cutaneous findings as they may be the first evidence of advanced disease. ",0
6052,28100525,Transoesophageal echocardiographic evaluation of central venous catheter positioning using Peres' formula or a radiological landmark-based approach: a prospective randomized single-centre study,"The lower superior vena cava (SVC), near its junction with the right atrium (RA), is considered the ideal location for the central venous catheter tip to ensure proper function and prevent injuries. We determined catheter insertion depth with a new formula using the sternoclavicular joint and the carina as radiological landmarks, with a 1.5 cm safety margin. The accuracy of tip positioning with the radiological landmark-based technique (R) and Peres' formula (P) was compared using transoesophageal echocardiography. Real-time ultrasound-guided central venous catheter insertion was done through the right internal jugular or subclavian vein. Patients were randomly assigned to either the P group (n=93) or the R group (n=95). Optimal catheter tip position was considered to be within 2 cm above and 1 cm below the RA-SVC junction. Catheter tip position, abutment, angle to the vascular wall, and flow stream were evaluated on a bicaval view. The distance from the skin insertion point to the RA-SVC junction and determined depth of catheter insertion were more strongly correlated in the R group [17.4 (1.2) and 16.7 (1.5) cm; r=0.821, P<0.001] than in the P group [17.3 (1.2) and 16.4 (1.1) cm; r=0.517, P<0.001], with z=3.96 (P<0.001). More tips were correctly positioned in the R group than in the P group (74 vs 93%, P=0.001). Abutment, tip angle to the lateral wall >40°, and disrupted flow stream were comparable. Catheter tip position was more accurate with a radiological landmark-based technique than with Peres' formula. Clinical Trial Registry of Korea: https://cris.nih.go.kr/cris/index.jsp KCT0001937. ",0
6053,28100564,Ageing and mental health: changes in self-reported health due to physical illness and mental health status with consecutive cross-sectional analyses,"It is known that self-reported health (SRH) declines with increasing age and that comorbidity increases with age. We wished to examine how age transfers its effect to SRH through comorbid disease and mental illness and whether these processes remained stable from 1994 until 2008. The hypothesis is that ageing and/or the increased age-related burden of pathology explains the declining SRH. The Tromsø Study (TS) is a cohort study using a survey approach with repeated physical examinations. It was conducted in the municipality of Tromsø, Norway, from 1974 to 2008. A total of 21 199 women and 19 229 men participated. SRH is the outcome of interest. We calculated and compared the effect sizes of age, comorbidity and mental health symptoms using multimediator analysis based on OLS regression. Ageing had a negative impact on SRH, but the total effect of age decreased from 1994 to 2007. We assessed the direct effect of age and then the proportion of indirect age-related effects through physical illness and mental health symptoms on the total effect. The direct effect of age represented 79.3% of the total effect in 1994 and decreased to 58.8% in 2007. Physical illness emerged as an increasingly important factor and increased its influence from 15.7% to 41.2% of the total effect. Age alone had a protective effect on mental health symptoms and this increased (2.5% to 17.3%), but we found a stronger association between mental health symptoms and physical disease in the later waves of the study (increasing from 3.7% to 14.8%). The results suggest that the effect on SRH of mental health symptoms caused by physical illness is an increasing public health problem. Treatment and care for specific medical conditions must therefore focus more strongly on how these conditions affect the patient's mental health and address these concerns accordingly. ",0
6054,28100771,Janus Kinase 2 (JAK2) Dissociates Hepatosteatosis from Hepatocellular Carcinoma in Mice,"Hepatocellular carcinoma is an end-stage complication of non-alcoholic fatty liver disease (NAFLD). Inflammation plays a critical role in the progression of non-alcoholic fatty liver disease and the development of hepatocellular carcinoma. However, whether steatosis  ",0
6055,28100945,Study of 433 Operated Cases of Thoracic Trauma,"Patients with thoracic trauma constitute one third of all the trauma cases. Of traumatic patients, 20-25 % die because of thoracic trauma. Our aim was to compare our clinical experience and the results with the related literature. Four hundred thirty-three patients, who underwent surgical interventions due to thoracic trauma, were evaluated. The latest form of treatment applied were taken as the criteria for the quantitative detection of patients. Continuous variables were expressed as mean ± standard deviation, while categorical variables were explained as number and percentage. The significance of the analysis results was evaluated using Fisher's exact test.  ",0
6056,28101252,Identification of proteins from wild cardoon flowers (,"Proteomic approach was applied to identify total proteins, particularly the enzymatic content, from wild cardoon flowers. As the selection of an appropriate sample preparation method is the key for getting reliable results, two different extraction/precipitation methods (trichloroacetic acid and phenol/ammonium acetate) were tested on fresh and lyophilized flowers. After two-dimensional electrophoresis (2D-E) separations, a better protein pattern was obtained after phenol extraction from lyophilized flowers. Only 46 % of the total analyzed spots resulted in a protein identification by mass spectrometry MALDI-TOF. Four proteases (cardosins A, E, G, and H), which have become a subject of great interest in dairy technology, were identified. They presented molecular weights and isoelectric points very close and high levels of homology between matched peptides sequences. The absence of the other cardosins (B, C, D, and F) could be an advantage, as it reduces the excessive proteolytic activity that causes bitter flavors and texture defects, during cheese making. ",0
6057,28101347,Clinical presentation and management of uveal melanoma,"Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The majority of the patients are Caucasian (97.8%) and aged 50-80 years. Choroidal melanoma is the predominant type (86.3%). The clinical presentation may range from no symptoms over various types of visual disturbances to visual loss. Examination includes slit-lamp biomicroscopy, indirect ophthalmoscopy and diagnostic testing, such as B-scan ultrasonography. A number of patients with posterior UM are treated with plaque radiation therapy or enucleation. At present, targeted therapy includes inhibitors of the mitogen-activated protein kinase/mitogen-activated protein kinase kinase signaling pathway. UM disseminates hematogenously, with a high propensity for metastasis to the liver, which the most common site (93% of the cases). While UM is uncommon, a significant proportion of affected patients succumb to this disease and new treatment options to improve patient survival are required. ",0
6058,28101386,A Rare Manifestation of Tuberculosis Presenting in the United States,"A 64-year-old Bangladeshi female presented to her primary care physician with a tender right breast lump that had been present for 4-5 days along with subjective fevers and malaise. Initial biopsy revealed granulomas, but Ziehl-Neelsen and Gram stain were negative for TB so antibiotics were prescribed for abscess until culture came positive for tuberculosis. She was started on triple therapy for extrapulmonary tuberculosis, an exceedingly rare presentation that requires high clinical suspicion in the Western world. ",0
6059,28101563,World Health Organisation Global Disability Action Plan 2014-2021: Challenges and perspectives for physical medicine and rehabilitation in Pakistan,"To provide an update on disability and outline potential barriers and facilitators for implementation of the World Health Organization Global Disability Action Plan (GDAP) in Pakistan. A 6-day workshop at the Armed Forces Institute of Rehabilitation Medicine, Islamabad facilitated by rehabilitation staff from Royal Melbourne Hospital, Australia. Local healthcare professionals (n = 33) from medical rehabilitation facilities identified challenges in service provision, education and attitudes/approaches to people with disabilities, using consensus agreement for objectives listed in the GDAP. Respondents agreed on the following challenges in implementing the GDAP: shortage of skilled work-force, fragmented healthcare system, poor coordination between acute and subacute healthcare sectors, limited health services infrastructure and funding, lack of disability data, poor legislation, lack of guidelines and accreditation standards, limited awareness/knowledge of disability, socio-cultural perceptions and geo-topographical issues. The main facilitators included: need for governing/leadership bodies, engagement of healthcare professionals and institutions using a multi-sectoral approach, new partnerships and strategic collaboration, provision of financial and technical assistance, future policy direction, research and development. The barriers to implementing the GDAP identified here highlight the emerging priorities and challenges in the development of rehabilitation medicine and GDAP implementation in a developing country. The GDAP summary actions were useful planning tools to improve access and strengthen rehabilitation services. ",0
6060,28101752,The impact of hydrocortisone treatment on neutrophil gelatinase-associated lipocalin release in porcine endotoxemic shock,"A key feature of sepsis is systemic inflammatory activation that could be counteracted by steroids. In this experimental model of systemic inflammation, we sought to investigate whether septic neutrophil activation, evaluated by the plasma levels of neutrophil gelatinase-associated protein (NGAL), is modulated by the timing of hydrocortisone treatment. Sixteen anesthetized pigs were allocated to one of four equally sized groups. Three of these groups received endotoxin at 2 μg × kg Hydrocortisone treatment prior to endotoxemia attenuated some inflammatory, hematological, circulatory, and metabolic manifestations of shock (i.e., higher white blood cell count, higher mean arterial pressure, lower heart rate and mean pulmonary arterial pressure, higher left ventricular stroke work index, higher base excess). Endotoxemic shock increased plasma NGAL (p < 0.001). In pigs given hydrocortisone before the endotoxin infusion, plasma NGAL was lower as compared to those given hydrocortisone at endotoxemic shock (p < 0.05). Plasma NGAL levels correlated inversely to neutrophil granulocyte counts (rho = -0.65) but not to urine output (rho = -0.10) at the end of the experiment. The increase in plasma NGAL is counteracted by hydrocortisone administration prior to endotoxemia; concomitantly, this treatment was associated with less expressed circulatory derangement. Urine NGAL did not differ between the groups, suggesting that the NGAL response was not primarily related to kidney injury. ",0
6061,28101788,"Embling Production in Althaea officinalis L., Through Somatic Embryogenesis and Their Appraisal via Histological and Scanning Electron Microscopical Studies","In vitro propagation of a medicinally important plant, Althaea officinalis, has been achieved through somatic embryogenesis. Somatic embryos (globular to torpedo-shaped embryos) were induced on Murashige and Skoog's (MS) medium augmented with various concentrations of 2,4-dichlorophenoxyacetic acid (2,4-D, 5.0, 10.0, 15.0, 20.0, and 25.0) alone or combined with N6-benzylaminopurine (BA, 0.1, 0.5, 1.0, 1.5, and 2.0 μM). These were directly formed from the cut ends and subsequently spread on the whole surface of internodal explants. For embryo maturation, torpedo embryos were transferred on a medium containing different levels of BA (0.1, 0.5, or 1.0 μM) and abscisic acid (ABA) (0.5, 1.0, or 1.5 μM) or α-naphthalene acetic acid (NAA) (0.1, 0.5 or 1.0 μM). Among the different concentrations tested, 0.5 μM BA along with 1.0 μM ABA was found most effective, on which a highest yield (58.0%) with an optimum number (35.0) of mature embryos (cotyledonary stage) was observed after 2 weeks of transfer. Germination of cotyledonary embryos into plantlets with 68% were observed on ½ MS medium. Histological and scanning electron microscopical (SEM) studies proved that the regenerated structures were somatic embryos and not shoot primordia. Plants grew vigorously when transferred to a greenhouse. ",0
6062,28102151,Pleiotropic genetic effects influencing sleep and neurological disorders,"Research evidence increasingly points to the large impact of sleep disturbances on public health. Many aspects of sleep are heritable and genes influencing traits such as timing, EEG characteristics, sleep duration, and response to sleep loss have been identified. Notably, large-scale genome-wide analyses have implicated numerous genes with small effects on sleep timing. Additionally, there has been considerable progress in the identification of genes influencing risk for some neurological sleep disorders. For restless legs syndrome, implicated variants are typically in genes associated with neuronal development. By contrast, genes conferring risk for narcolepsy function in the immune system. Many genetic variants associated with sleep disorders are also implicated in neurological disorders in which sleep abnormalities are common; for example, variation in genes involved in synaptic homoeostasis are implicated in autism spectrum disorder and sleep-wake control. Further investigation into pleiotropic roles of genes influencing both sleep and neurological disorders could lead to new treatment strategies for a variety of sleep disturbances. ",0
6063,28102315,Methyl-Cytosine-Driven Structural Changes Enhance Adduction Kinetics of an Exon 7 fragment of the p53 Gene,"Methylation of cytosine (C) at C-phosphate-guanine (CpG) sites enhances reactivity of DNA towards electrophiles. Mutations at CpG sites on the p53 tumor suppressor gene that can result from these adductions are in turn correlated with specific cancers. Here we describe the first restriction-enzyme-assisted LC-MS/MS sequencing study of the influence of methyl cytosines (MeC) on kinetics of p53 gene adduction by model metabolite benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), using methodology applicable to correlate gene damage sites for drug and pollutant metabolites with mutation sites. This method allows direct kinetic measurements by LC-MS/MS sequencing for oligonucleotides longer than 20 base pairs (bp). We used MeC and non-MeC (C) versions of a 32 bp exon 7 fragment of the p53 gene. Methylation of 19 cytosines increased the rate constant 3-fold for adduction on G at the major reactive CpG in codon 248 vs. the non-MeC fragment. Rate constants for non-CpG codons 244 and 243 were not influenced significantly by MeC. Conformational and hydrophobicity changes in the MeC-p53 exon 7 fragment revealed by CD spectra and molecular modeling increase the BPDE binding constant to G in codon 248 consistent with a pathway in which preceding reactant binding greatly facilitates the rate of covalent S ",0
6064,28102640,Activated macrophages as key mediators of capsule formation on adipose constructs in tissue engineering chamber models,"In plastic and reconstructive field, it would be much beneficial to fabricate an engineered adipose tissue substitute allowing reliable and complete fat tissue regeneration. Tissue engineering chamber (TEC) holds the promise to optimize an adipogenic configuration that is efficacious as well as reproducible. A frequently occurring complication involves the adipose tissue flap encapsulation and, effectively, its shielding, by a thick fibrous membrane, which hinders development into the proliferative stage. The reason for the deposition of the collagen capsule remains unclear. Numerous studies have highlighted that macrophages play a key role in adipogenesis in a TEC model using a silicone chamber enclosing the fat flap with a superficial epigastric pedicle. As a verification of the role of macrophages in capsule formation, we propose the inhibition of transforming growth factor β1 (TGF-β1) synthesis by macrophage populations in the local microenvironment by administrating tranilast into the TEC. We hypothesize that upon reduction of TGF-β1 levels, capsule formation and inhibition of new adipose tissue development will decrease. Furthermore, we propose that a tissue engineering chamber model in which macrophages are closely related to both neo-adipogenesis and capsule formation. ",0
6065,28103412,What Determines Posttraumatic Stress and Growth Following Various Traumatic Events? A Study in a Turkish Community Sample,"This study aimed to examine the roles of personality traits, traumatic event types, coping, rumination, and social support in explaining posttraumatic stress symptoms (PTS) and posttraumatic growth (PTG) in a representative community sample of 498 Turkish adults. The results of 2 multiple regression analyses showed that PTS was associated with neuroticism, experiencing events involving intentional/assaultive violence, intrusive and deliberate rumination, and fatalistic coping. In contrast, PTG was related to conscientiousness, openness to experience, injury/shocking and sudden-death type of events, deliberate rumination, problem-solving coping, and perceived social support. When all variables were entered into the equation, almost two thirds of the variability (R ",0
6066,28103504,l-arginine alters the effect of 5-fluorouracil on breast cancer cells in favor of apoptosis,"Chemoresistance in breast cancer is a major obstacle, especially in p53 mutation types. The aim of this study was to evaluate if a combination therapy of l-arginine with 5-fluorouracil (5-FU) can alter the effect of this chemotherapy drug on breast cancer cells. The study was performed on BT-20 and MCF-7 cell lines. The effects of l-arginine alone and in combination with 5-FU were investigated on cell viability, apoptosis and nitric oxide (NO) production. Drugs effects on the cellular energetic metabolism were investigated through the lactate production and glucose-6-phosphate dehydrogenase (G6PD) activity assay. Migration and invasion of treated cells were assessed. Real- time PCR was used for analyzing the changes in the expression level of CXCL12 and CXCR4 as two important genes involved in migration and metastasis of breast cancer cells. l-arginine increased 5-FU effect on BT-20 and MCF-7 cell lines by reducing cell viability and increasing apoptosis and NO production. Lactate production and G6PD activity assays showed that cellular energetic metabolism of both cells was altered in favor of cell death. Moreover, l-arginine decreased the metastatic activity of both cells which was confirmed through migration, invasion and gene expression results performed for both cell lines. However, drugs effect on MCF-7 (p53 wild-type) was greater than that of BT-20 (p53 mutation) in all sets of experiments. Our findings indicated that l-arginine increased the anticancer effect of 5-FU in BT-20 and MCF-7 cell lines. So, combination therapy with l-arginine and 5-FU could be considered as an effective strategy in breast cancer therapy. ",0
6067,28103655,Temporomandibular Joint Disorders as a Cause of Aural Fullness,"Temporomandibular joint disorders (TMD) are often associated with aural manifestations. However, it is not clear whether aural fullness could be induced by TMD. The purpose was to investigate the TMD and effectiveness of TMD treatments in patients with mainly or exclusively aural fullness complaint. One hundred and twelve patients, who had aural fullness as the main or sole complaint, presented to the Otolaryngology Department, PLA Army General Hospital, Beijing, China, between January 2010 and January 2015. Patients' medical history indicated that they had previously been diagnosed and treated for otitis media or sensorineural hearing loss but without positive results. Patients were subjected to pure tone audiometry and acoustic immittance screening using GSI-61 clinical audiometer and GSI TympStar middle ear analyzer respectively. Patients were examined by questionnaire, X-ray and/or computed tomography scan of temporomandibular joint. TMD was categorized according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Patients were then treated for TMD. All the patients showed normal eardrum and type A tympanogram. The patients of 60.7% (68/112) were classified as group I TMD disorders (muscle disorders), 34.8% (39/112) were group II (disc displacements), and 4.5% (5/112) were group III (arthralgia, osteoarthritis, and osteoarthrosis). Aural fullness was completely resolved or significantly improved in 67 and 34 patients respectively following treatments aimed at improving TMD, with a combined effectiveness of 90.2% (101/112). TMD treatments are especially effective (94.1%) in group I TMD. TMD as a potential cause of aural fullness should be considered in otolaryngology practice. ",0
6068,28103880,"The use of genome-scale metabolic network reconstruction to predict fluxes and equilibrium composition of N-fixing versus C-fixing cells in a diazotrophic cyanobacterium, Trichodesmium erythraeum","Computational, genome based predictions of organism phenotypes has enhanced the ability to investigate the biological phenomena that help organisms survive and respond to their environments. In this study, we have created the first genome-scale metabolic network reconstruction of the nitrogen fixing cyanobacterium T. erythraeum and used genome-scale modeling approaches to investigate carbon and nitrogen fluxes as well as growth and equilibrium population composition. We created a genome-scale reconstruction of T. erythraeum with 971 reactions, 986 metabolites, and 647 unique genes. We then used data from previous studies as well as our own laboratory data to establish a biomass equation and two distinct submodels that correspond to the two cell types formed by T. erythraeum. We then use flux balance analysis and flux variability analysis to generate predictions for how metabolism is distributed to account for the unique productivity of T. erythraeum. Finally, we used in situ data to constrain the model, infer time dependent population compositions and metabolite production using dynamic Flux Balance Analysis. We find that our model predicts equilibrium compositions similar to laboratory measurements, approximately 15.5% diazotrophs for our model versus 10-20% diazotrophs reported in literature. We also found that equilibrium was the most efficient mode of growth and that equilibrium was stoichiometrically mediated. Moreover, the model predicts that nitrogen leakage is an essential condition of optimality for T. erythraeum; cells leak approximately 29.4% total fixed nitrogen when growing at the optimal growth rate, which agrees with values observed in situ. The genome-metabolic network reconstruction allows us to use constraints based modeling approaches to predict growth and optimal cellular composition in T. erythraeum colonies. Our predictions match both in situ and laboratory data, indicating that stoichiometry of metabolic reactions plays a large role in the differentiation and composition of different cell types. In order to realize the full potential of the model, advance modeling techniques which account for interactions between colonies, the environment and surrounding species need to be developed. ",0
6069,28104155,Immunosuppression Modification by Everolimus With Minimization of Calcineurin Inhibitors Recovers Kidney Graft Function Even in Patients With Very Late Conversion and Also With Poor Graft Function,"""Although kidney graft survival within 5 years after transplantation is now achieved in >95% of recipients, chronic graft deterioration remains a factor limiting long-term survival. Chronic nephrotoxicity induced by calcineurin inhibitors (CNIs) is one of the major causes of chronic graft injury; thus, minimization of CNIs by administration of everolimus (EVR) is expected to relieve their toxic effects. Fifty-six kidney transplant recipients receiving CNI-based immunosuppression (tacrolimus, n = 34; cyclosporine, n = 22) were analyzed. The average posttransplant period at conversion was 7.4 years and no less than 3 years. Conversion of immunosuppression was accomplished by reducing CNI by 40% in dose and beginning EVR at 1 or 1.5 mg. Changes in graft function were examined, and adverse effects were evaluated. Significant improvement in graft function was observed quickly after EVR administration, and it had persisted for 1 year after conversion as a 7% increase in estimated glomerular filtration rate. No obvious acute rejection was observed. Further analyses concerning """"timing of EVR conversion"""" and """"graft function at conversion"""" were performed. Graft function was significantly improved even in patients with late conversion at 2 to 10 years. The estimated glomerular filtration rate was significantly improved even in patients with poor function. We concluded that this modification to the immunosuppressive regimen, as expected, reduced CNI nephrotoxicity. Our results showed that even patients with very late conversion or poor graft function also benefited from EVR conversion with CNI minimization. """,0
6070,28104545,"Trial of labour and vaginal birth after previous caesarean section: A population based study of Eastern African immigrants in Victoria, Australia","Variations in caesarean section (CS) between some immigrant groups and receiving country populations have been widely reported. Often, African immigrant women are at higher risk of CS than the receiving population in developed countries. However, evidence about subsequent mode of birth following CS for African women post-migration is lacking. The objective of this study was to examine differences in attempted and successful vaginal birth after previous caesarean (VBAC) for Eastern African immigrants (Eritrea, Ethiopia, Somalia and Sudan) compared with Australian-born women. A population-based observational study was conducted using the Victorian Perinatal Data Collection. Pearson's chi-square test and logistic regression analysis were performed to generate adjusted odds ratios for attempted and successful VBAC. Victoria, Australia. 554 Eastern African immigrants and 24,587 Australian-born eligible women with previous CS having singleton births in public care. 41.5% of Eastern African immigrant women and 26.1% Australian-born women attempted a VBAC with 50.9% of Eastern African immigrants and 60.5% of Australian-born women being successful. After adjusting for maternal demographic characteristics and available clinical confounding factors, Eastern African immigrants were more likely to attempt (OR There are disparities in attempted and successful VBAC between Eastern African origin and Australian-born women. Unsuccessful VBAC attempt is more common among Eastern African immigrants, suggesting the need for improved strategies to select and support potential candidates for vaginal birth among these immigrants to enhance success and reduce potential complications associated with failed VBAC attempt. ",0
6071,28104551,A framework for analysis of linear ultrasound videos to detect fetal presentation and heartbeat,"Confirmation of pregnancy viability (presence of fetal cardiac activity) and diagnosis of fetal presentation (head or buttock in the maternal pelvis) are the first essential components of ultrasound assessment in obstetrics. The former is useful in assessing the presence of an on-going pregnancy and the latter is essential for labour management. We propose an automated framework for detection of fetal presentation and heartbeat from a predefined free-hand ultrasound sweep of the maternal abdomen. Our method exploits the presence of key anatomical sonographic image patterns in carefully designed scanning protocols to develop, for the first time, an automated framework allowing novice sonographers to detect fetal breech presentation and heartbeat from an ultrasound sweep. The framework consists of a classification regime for a frame by frame categorization of each 2D slice of the video. The classification scores are then regularized through a conditional random field model, taking into account the temporal relationship between the video frames. Subsequently, if consecutive frames of the fetal heart are detected, a kernelized linear dynamical model is used to identify whether a heartbeat can be detected in the sequence. In a dataset of 323 predefined free-hand videos, covering the mother's abdomen in a straight sweep, the fetal skull, abdomen, and heart were detected with a mean classification accuracy of 83.4%. Furthermore, for the detection of the heartbeat an overall classification accuracy of 93.1% was achieved. ",0
6072,28104575,Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases,"Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy. ",0
6073,28104635,Transverse Sinus Stenosis Is the Most Sensitive MR Imaging Correlate of Idiopathic Intracranial Hypertension,"Patients with idiopathic intracranial hypertension have transverse sinus stenosis on gadolinium-bolused MRV, but other MR imaging signs are less consistently seen. Our aim was to demonstrate that transverse sinus stenosis could be identified on conventional MR imaging, and this identification would allow improved diagnostic sensitivity to this condition. MR imaging and MRV images from 63 patients with idiopathic intracranial hypertension and 96 controls were reviewed by using 3 independent procedures. MRV images were graded for the presence and degree of stenosis of the transverse sinus. Postgadolinium coronal T1-weighted sequences were evaluated independent of MRV. The dimensions of the proximal and distal transverse sinus were measured from the MRV examinations, and the cross-sectional area of the transverse sinus was calculated. Correlation among the 3 modes of evaluation of the transverse sinus was conducted by using Wilcoxon/Kruskal-Wallis, Pearson, and Spearman ρ nonparametric statistical techniques. Transverse sinus stenosis was identified bilaterally on MRV in 94% of patients with idiopathic intracranial hypertension and in 3% of controls. On coronal T1 postgadolinium MR images, transverse sinus stenosis was identified in 83% of patients with idiopathic intracranial hypertension and 7% of controls. Previously described MR imaging signs of intracranial hypertension were identified in 8%-61% of patients with idiopathic intracranial hypertension. Correlation among the 3 modes of evaluation was highly significant ( Even without the assistance of an MRV sequence, neuroradiologists can validly identify bilateral transverse sinus stenosis in patients with intracranial hypertension more reliably than other previously described MR imaging findings in this condition. We conclude that transverse sinus stenosis is the most useful and sensitive imaging indicator of this disease state. ",0
6074,28104972,Utilization Study of Antihypertensives in a South Indian Tertiary Care Teaching Hospital and Adherence to Standard Treatment Guidelines,"Hypertension represents a major health problem primarily because of its role in contributing to the initiation and progression of major cardiovascular diseases. Concerns pertaining to hypertension and its sequelae can be substantially addressed and consequent burden of disease reduced by early detection and appropriate therapy of elevated blood pressure. This cross-sectional observational study aims at analyzing the utilization pattern of antihypertensives used for the treatment of hypertension at a tertiary care hospital in perspective of standard treatment guidelines. Prescriptions were screened for antihypertensives at the medicine outpatient department of a tertiary care teaching hospital. Medical records of the patients were scrutinized after which 286 prescriptions of patients suffering from hypertension were included. The collected data were sorted and analyzed on the basis of demographic characteristics and comorbidities. The calcium channel blockers were the most frequently used antihypertensive class of drugs (72.3%). Amlodipine (55.6%) was the single most frequently prescribed antihypertensive agent. The utilization of thiazide diuretics was 9%. Adherence to the National List of Essential Medicines (NLEMs) was 65%. The combination therapy was used more frequently (51.5%) than monotherapy (48.8%). The use of angiotensin-converting enzyme inhibitors/angiotensin 2 receptor blockers (ACE-I/ARB) was 41.4% in diabetes. The treatment pattern, in general, conformed to standard treatment guidelines. Few areas, however, need to be addressed such as the underutilization of thiazide diuretics, need for more awareness of drugs from the NLEMs and enhanced use of ACE-I/ARB in diabetic hypertensives. ",0
6075,28105101,Urinary neutrophil gelatinase-associated lipocalin is an early predictor of acute kidney injury in premature infants,"Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is produced in response to tubular epithelial injury and is a biomarker of tubulointerstitial injury. The aim of the present study was to examine whether acute kidney injury (AKI) could be predicted by measuring uNGAL in very low-birth weight (VLBW) infants. Forty VLBW infants with birthweight below 1,500 g were enrolled in the present study. uNGAL and serum creatinine (sCre) were measured daily from postnatal days 0 to 8. Infants with sCre ≥1.2 mg/dl were diagnosed with AKI. The relationship of uNGAL with sCre was measured on the day after uNGAL measurement (next-day sCre) was examined. The results showed that 16 infants had sCre ≥1.2 mg/dl in this period. Logistic regression analysis revealed that uNGAL on postnatal days 2, 3, 4, 5 and 6 was correlated with next-day sCre (P<0.05). uNGAL corrected by urinary Cre (uCre) (uNGAL/uCre) was only correlated with an increase in next-day sCre on postnatal days 5 and 6 (P<0.05). For the logistic analysis, subjects with high and low uNGAL levels based on the median value for each day, uNGAL on postnatal days 2, 3 and 6 in the high uNGAL group was correlated with an increase in next-day sCre. Thus, AKI may be predicted by measuring uNGAL in VLBW infants. This measurement was non-invasive, and is potentially useful for the evaluation of renal function in VLBW infants. ",0
6076,28105473,"Recent applications of the combination of mesoporous silica nanoparticles with nucleic acids: development of bioresponsive devices, carriers and sensors","The discovery and control of the biological roles mediated by nucleic acids have turned them into a powerful tool for the development of advanced biotechnological materials. Such is the importance of these gene-keeping biomacromolecules that even nanomaterials have succumbed to the claimed benefits of DNA and RNA. Currently, there could be found in the literature a practically intractable number of examples reporting the use of combination of nanoparticles with nucleic acids, so boundaries are demanded. Following this premise, this review will only cover the most recent and powerful strategies developed to exploit the possibilities of nucleic acids as biotechnological materials when in combination with mesoporous silica nanoparticles. The extensive research done on nucleic acids has significantly incremented the technological possibilities for those biomacromolecules, which could be employed in many different applications, where substrate or sequence recognition or modulation of biological pathways due to its coding role in living cells are the most promising. In the present review, the chosen counterpart, mesoporous silica nanoparticles, also with unique properties, became a reference material for drug delivery and biomedical applications due to their high biocompatibility and porous structure suitable for hosting and delivering small molecules. Although most of the reviews dealt with significant advances in the use of nucleic acid and mesoporous silica nanoparticles in biotechnological applications, a rational classification of these new generation hybrid materials is still uncovered. In this review, there will be covered promising strategies for the development of living cell and biological sensors, DNA-based molecular gates with targeting, transfection or silencing properties, which could provide a significant advance in current nanomedicine. ",0
6077,28105511,Bone Density in the Obese Child: Clinical Considerations and Diagnostic Challenges,"The prevalence of obesity in children has reached epidemic proportions. Concern about bone health in obese children, in part, derives from the potentially increased fracture risk associated with obesity. Additional risk factors that affect bone mineral accretion, may also contribute to obesity, such as low physical activity and nutritional factors. Consequences of obesity, such as inflammation, insulin resistance, and non-alcoholic fatty liver disease, may also affect bone mineral acquisition, especially during the adolescent years when rapid increases in bone contribute to attaining peak bone mass. Further, numerous pediatric health conditions are associated with excess adiposity, altered body composition, or endocrine disturbances that can affect bone accretion. Thus, there is a multitude of reasons for considering clinical assessment of bone health in an obese child. Multiple diagnostic challenges affect the measurement of bone density and its interpretation. These include greater precision error, difficulty in positioning, and the effects of increased lean and fat tissue on bone health outcomes. Future research is required to address these issues to improve bone health assessment in obese children. ",0
6078,28105567,Effects of oleuropein on pentylenetetrazol-induced seizures in mice: involvement of opioidergic and nitrergic systems,"Oleuropein, a well-known olive polyphenol, has been shown to mediate neuroprotection in Alzheimer's disease and cerebral ischemia. We investigated the effects of oleuropein on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice, with diazepam as the standard drug. We also examined the possible involvement of opioidergic/nitrergic pathways in the probable effects of oleuropein. Intraperitoneal (i.p.) administration of different doses of oleuropein (10, 20 and 30 mg/kg) significantly increased the seizure threshold 60 min prior to induction of seizure, in a dose-dependent manner. Administration of naltrexone (10 mg/kg, i.p.), an opioid receptor antagonist, completely reversed the anticonvulsant effects of oleuropein (10 mg/kg). On the other hand, the anticonvulsant effect of oleuropein (10 mg/kg) was blocked by a non-effective dose of nonspecific inhibitor of nitric oxide synthase (NOS), L-NAME (1 and 10 mg/kg, i.p) and a selective inhibitor of neuronal NOS, 7-nitroindazole (30 mg/kg, i.p.). However, the nitric oxide precursor, L-arginine (30 and 60 mg/kg, i.p.) potentiated the anticonvulsant activity of oleuropein (10 mg/kg). A selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) did not change the anticonvulsant activity of oleuropein. It seems that the opioidergic system and constitutive neuronal NOS may be involved in the anticonvulsant properties of oleuropein. ",0
6079,28194813,MicroRNA-191 acts as a tumor promoter by modulating the TET1-p53 pathway in intrahepatic cholangiocarcinoma,"Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).",0
6080,28195337,Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and meta-analysis,"There is an increased awareness of hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients coinfected with HBV treated with pan-oral direct-acting antiviral agents (DAAs). We performed a systematic review and meta-analysis to compare the rate of HBV reactivation in CHC patients coinfected with overt HBV (hepatitis B surface antigen [HBsAg] positive) and occult HBV (HBsAg negative with positive HBV DNA) infection separately, treated with interferon (IFN)-based therapy to those with pan-oral DAAs. The primary outcome was HBV reactivation, and the secondary outcomes included hepatitis due to HBV reactivation, sustained virologic response (SVR) for CHC, loss of HBV DNA and HBsAg seroclearance. Although the pooled incidence rate of HBV reactivation, among CHC patients with overt HBV (n = 779), was similar among those treated with IFN-based therapy (14.5%, P < 0.001) and DAAs (12.2%, P = 0.03; P = 0.91 for heterogeneity between subgroups), it was reported to occur much earlier in those treated with DAAs (4-12 weeks during treatment) than in those treated with IFN-based therapies (most at the end of treatment and some during follow-up). Also, studies with DAA-based therapies were more likely to report incidence of hepatitis due to HBV reactivation (12.2% in DAAs vs. 0% in IFN; P = 0.009 for heterogeneity between subgroups). HBV reactivation and hepatitis due to HBV reactivation also occurred, though less frequently in CHC patients with occult HBV infection. CHC SVR was not affected by HBV reactivation (P = 0.27). CONCLUSION: HBV reactivation occurs earlier and is clinically more significant in CHC patients coinfected with overt and occult HBV who are treated with pan-oral DAAs compared with IFN-based therapy. It is therefore important to have all patients screened for evidence of overt or occult HBV infection and managed during pan-oral DAAs therapy. (Hepatology 2017;66:13-26).",0
6081,28195359,Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes,"Infections with the human hepatitis B virus (HBV) and hepatitis D virus (HDV) depend on species-specific host factors like the receptor human sodium taurocholate cotransporting polypeptide (hNTCP). Complementation of mouse hepatocytes with hNTCP confers susceptibility to HDV but not HBV, indicating the requirement of additional HBV-specific factors. As an essential premise toward the establishment of an HBV-susceptible animal model, we investigated the role of hNTCP as a limiting factor of hepatocytes in commonly used laboratory animals. Primary hepatocytes from mice, rats, dogs, pigs, rhesus macaques, and cynomolgus macaques were transduced with adeno-associated viral vectors encoding hNTCP and subsequently infected with HBV. Cells were analyzed for Myrcludex B binding, taurocholate uptake, HBV covalently closed circular DNA formation, and expression of all HBV markers. Sodium taurocholate cotransporting polypeptide (Ntcp) from the respective species was cloned and analyzed for HBV and HDV receptor activity in a permissive hepatoma cell line. Expression of hNTCP in mouse, rat, and dog hepatocytes permits HDV infection but does not allow establishment of HBV infection. Contrarily, hepatocytes from cynomolgus macaques, rhesus macaques, and pigs became fully susceptible to HBV upon hNTCP expression with efficiencies comparable to human hepatocytes. Analysis of cloned Ntcp from all species revealed a pronounced role of the human homologue to support HBV and HDV infection. CONCLUSION: Ntcp is the key host factor limiting HBV infection in cynomolgus and rhesus macaques and in pigs. In rodents (mouse, rat) and dogs, transfer of hNTCP supports viral entry but additional host factors are required for the establishment of HBV infection. This finding paves the way for the development of macaques and pigs as immunocompetent animal models to study HBV infection in vivo, immunological responses against the virus and viral pathogenesis. (Hepatology 2017;66:703-716).",0
6082,28195391,RIG-I is a key antiviral interferon-stimulated gene against hepatitis E virus regardless of interferon production,"Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of an individual ISG. The mechanism of action of the key anti-HEV ISG was further studied. We identified retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5, and IFN regulatory factor 1 (IRF1) as the key anti-HEV ISGs. We found that basal expression of RIG-I restricts HEV infection. Pharmacological activation of the RIG-I pathway by its natural ligand 5'-triphosphate RNA potently inhibits HEV replication. Overexpression of RIG-I activates the transcription of a wide range of ISGs. RIG-I also mediates but does not overlap with IFN-?-initiated ISG transcription. Although it is classically recognized that RIG-I exerts antiviral activity through the induction of IFN production by IRF3 and IRF7, we reveal an IFN-independent antiviral mechanism of RIG-I in combating HEV infection. We found that activation of RIG-I stimulates an antiviral response independent of IRF3 and IRF7 and regardless of IFN production. However, it is partially through activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) cascade of IFN signaling. RIG-I activated two distinct categories of ISGs, one JAK-STAT-dependent and the other JAK-STAT-independent, which coordinately contribute to the anti-HEV activity. CONCLUSION: We identified RIG-I as an important anti-HEV ISG that can be pharmacologically activated; activation of RIG-I stimulates the cellular innate immunity against HEV regardless of IFN production but partially through the JAK-STAT cascade of IFN signaling. (Hepatology 2017;65:1823-1839).",0
6083,28195756,Persistence of Zika Virus in Body Fluids - Final Report,"BACKGROUND: To estimate the frequency and duration of detectable Zika virus (ZIKV) RNA in human body fluids, we prospectively assessed a cohort of newly infected participants in Puerto Rico. METHODS: We evaluated samples obtained from 150 participants (including 55 men) in whom ZIKV RNA was detected on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay in urine or blood in an enhanced arboviral clinical surveillance site. We collected serum, urine, saliva, semen, and vaginal secretions weekly for the first month and then at 2, 4, and 6 months. All specimens were tested by means of RT-PCR, and serum was tested with the use of anti-ZIKV IgM enzyme-linked immunosorbent assay. Among the participants with ZIKV RNA in any specimen at week 4, biweekly collection continued until all specimens tested negative. We used parametric Weibull regression models to estimate the time until the loss of ZIKV RNA detection in each body fluid and reported the findings in medians and 95th percentiles. RESULTS: The medians and 95th percentiles for the time until the loss of ZIKV RNA detection were 14 days (95% confidence interval [CI], 11 to 17) and 54 days (95% CI, 43 to 64), respectively, in serum; 8 days (95% CI, 6 to 10) and 39 days (95% CI, 31 to 47) in urine; and 34 days (95% CI, 28 to 41) and 81 days (95% CI, 64 to 98) in semen. Few participants had detectable ZIKV RNA in saliva or vaginal secretions. CONCLUSIONS: The prolonged time until ZIKV RNA clearance in serum in this study may have implications for the diagnosis and prevention of ZIKV infection. Current sexual-prevention guidelines recommend that men use condoms or abstain from sex for 6 months after ZIKV exposure; in 95% of the men in this study, ZIKV RNA was cleared from semen after about 3 months. (Funded by the Centers for Disease Control and Prevention.).",0
6084,28236308,PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation,"Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The covalently closed circular DNA (cccDNA) minichromosome, which serves as the template for the transcription of viral RNAs, plays a key role in viral persistence. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation of cccDNA-bound histone 3 (H3) and H4, the potential contributions of histone methylation and related host factors remain obscure. Here, by screening a series of methyltransferases and demethylases, we identified protein arginine methyltransferase 5 (PRMT5) as an effective restrictor of HBV transcription and replication. In cell culture-based models for HBV infection and in liver tissues of patients with chronic HBV infection, we found that symmetric dimethylation of arginine 3 on H4 on cccDNA was a repressive marker of cccDNA transcription and was regulated by PRMT5 depending on its methyltransferase domain. Moreover, PRMT5-triggered symmetric dimethylation of arginine 3 on H4 on the cccDNA minichromosome involved an interaction with the HBV core protein and the Brg1-based human SWI/SNF chromatin remodeler, which resulted in down-regulation of the binding of RNA polymerase II to cccDNA. In addition to the inhibitory effect on cccDNA transcription, PRMT5 inhibited HBV core particle DNA production independently of its methyltransferase activity. Further study revealed that PRMT5 interfered with pregenomic RNA encapsidation by preventing its interaction with viral polymerase protein through binding to the reverse transcriptase-ribonuclease H region of polymerase, which is crucial for the polymerase-pregenomic RNA interaction. CONCLUSION: PRMT5 restricts HBV replication through a two-part mechanism including epigenetic suppression of cccDNA transcription and interference with pregenomic RNA encapsidation; these findings improve the understanding of epigenetic regulation of HBV transcription and host-HBV interaction, thus providing new insights into targeted therapeutic intervention. (Hepatology 2017;66:398-415).",0
6085,28249145,Gene Therapy in a Patient with Sickle Cell Disease,"Sickle cell disease results from a homozygous missense mutation in the ?-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector-mediated addition of an antisickling ?-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling ?-globin remained high (approximately 50% of ?-like-globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 ClinicalTrials.gov number, NCT02151526 .).",0
6086,28273020,Realizing the Potential of Cancer Prevention - The Role of Implementation Science,"In the past two decades, we and others have estimated that more than half of cancers could have been prevented by applying knowledge that we already have. Tobacco use, inactivity, and obesity are modifiable causes of cancer,(�) and evidence now suggests that vaccination against the human papillomavirus, the use of aspirin and selective estrogen-receptor modulators, and participation in screening programs further reduce the risk of specific cancers.(,) The effect of these strategies on cancer-related outcomes in the general population is significant. A 62% reduction in lung-cancer mortality is associated with smoking cessation at age 50, and environmental and policy strategies are effective at increasing cessation.(�) A 95% reduction in mortality is associated with screening for cervical cancer, a 100% reduction in mortality is associated with vaccination against the human papillomavirus, (�) and a 90% reduction in mortality related to chronic liver disease and liver cancer is associated with vaccination against hepatitis B virus. There is also benefit for those at high risk for cancer. Lung-cancer screening is associated with a 20% reduction in mortality among smokers at high risk, salpingo-oophorectomy reduces the risk of breast and ovarian cancer among women with a BRCA1/2 mutation,(,) and treatment with selective estrogen receptor modulators reduces the incidence of breast cancer by 50% among women at high risk.(,) Screening, diagnosis, and treatment of hepatitis C virus infection reduces the risk of all-cause mortality by 50% among those with infection. Our ability to prevent cancer has improved significantly.",0
6087,28296613,Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration,"We assessed the feasibility of transplanting a sheet of retinal pigment epithelial (RPE) cells differentiated from induced pluripotent stem cells (iPSCs) in a patient with neovascular age-related macular degeneration. The iPSCs were generated from skin fibroblasts obtained from two patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. The RPE cells and the iPSCs from which they were derived were subject to extensive testing. A surgery that included the removal of the neovascular membrane and transplantation of the autologous iPSC-derived RPE cell sheet under the retina was performed in one of the patients. At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present. (Funded by Highway Program for Realization of Regenerative Medicine and others; University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000011929 .).",0
6088,28379800,Body-Weight Fluctuations and Outcomes in Coronary Disease,"BACKGROUND: Body-weight fluctuation is a risk factor for death and coronary events in patients without cardiovascular disease. It is not known whether variability in body weight affects outcomes in patients with coronary artery disease. METHODS: We determined intraindividual fluctuations in body weight from baseline weight and follow-up visits and performed a post hoc analysis of the Treating to New Targets trial, which involved assessment of the efficacy and safety of lowering low-density lipoprotein cholesterol levels with atorvastatin. The primary outcome was any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina). Secondary outcomes were any cardiovascular event (a composite of any coronary event, a cerebrovascular event, peripheral vascular disease, or heart failure), death, myocardial infarction, or stroke. RESULTS: Among 9509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body-weight variability (measured according to average successive variability and used as a time-dependent covariate) was associated with an increase in the risk of any coronary event (2091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P=0.01), any cardiovascular event (2727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P<0.001), and death (487 events; hazard ratio,1.09; 95% CI, 1.07 to 1.12; P<0.001). Among patients in the quintile with the highest variation in body weight, the risk of a coronary event was 64% higher, the risk of a cardiovascular event 85% higher, death 124% higher, myocardial infarction 117% higher, and stroke 136% higher than it was among those in the quintile with the lowest variation in body weight in adjusted models. CONCLUSIONS: Among participants with coronary artery disease, fluctuation in body weight was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00327691 .).",0
6089,28395113,A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2,"Cholesterol synthesis is regulated by the transcription factor sterol regulatory element binding protein 2 (SREBP-2) and its target gene 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), which is the rate-limiting enzyme in cholesterol synthesis. Cyclic adenosine monophosphate-responsive element (CRE) binding protein-regulated transcription coactivator (CRTC) 2 is the master regulator of glucose metabolism. However, the effect of CRTC2 on cholesterol and its potential molecular mechanism remain unclear. Here, we demonstrated that CRTC2 expression and liver cholesterol content were increased in patients with high serum cholesterol levels who underwent resection of liver hemangiomas, as well as in mice fed a 4% cholesterol diet. Mice with adenovirus-mediated CRTC2 overexpression also showed elevated lipid levels in both serum and liver tissues. Intriguingly, hepatic de novo cholesterol synthesis was markedly increased under these conditions. In contrast, CRTC2 ablation in mice fed a 4% cholesterol diet (18 weeks) showed decreased lipid levels in serum and liver tissues compared with those in littermate wild-type mice. The expression of lipogenic genes (SREBP-2 and HMGCR) was consistent with hepatic CRTC2 levels. In vivo imaging showed enhanced adenovirus-mediated HMGCR-luciferase activity in adenovirus-mediated CRTC2 mouse livers; however, the activity was attenuated after mutation of CRE or sterol regulatory element sequences in the HMGCR reporter construct. The effect of CRTC2 on HMGCR in mouse livers was alleviated upon SREBP-2 knockdown. CRTC2 modulated SREBP-2 transcription by CRE binding protein, which recognizes the half-site CRE sequence in the SREBP-2 promoter. CRTC2 reduced the nuclear protein expression of forkhead box O1 and subsequently increased SREBP-2 transcription by binding insulin response element 1, rather than insulin response element 2, in the SREBP-2 promoter. CONCLUSION: CRTC2 regulates the transcription of SREBP-2 by interfering with the recognition of insulin response element 1 in the SREBP-2 promoter by forkhead box O1, thus inducing SREBP-2/HMGCR signaling and subsequently facilitating hepatic cholesterol synthesis. (Hepatology 2017;66:481-497).",0
6090,28402770,Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes,"BACKGROUND: Long-term trends in excess risk of death and cardiovascular outcomes have not been extensively studied in persons with type 1 diabetes or type 2 diabetes. METHODS: We included patients registered in the Swedish National Diabetes Register from 1998 through 2012 and followed them through 2014. Trends in deaths and cardiovascular events were estimated with Cox regression and standardized incidence rates. For each patient, controls who were matched for age, sex, and county were randomly selected from the general population. RESULTS: Among patients with type 1 diabetes, absolute changes during the study period in the incidence rates of sentinel outcomes per 10,000 person-years were as follows: death from any cause, -31.4 (95% confidence interval [CI], -56.1 to -6.7); death from cardiovascular disease, -26.0 (95% CI, -42.6 to -9.4); death from coronary heart disease, -21.7 (95% CI, -37.1 to -6.4); and hospitalization for cardiovascular disease, -45.7 (95% CI, -71.4 to -20.1). Absolute changes per 10,000 person-years among patients with type 2 diabetes were as follows: death from any cause, -69.6 (95% CI, -95.9 to -43.2); death from cardiovascular disease, -110.0 (95% CI, -128.9 to -91.1); death from coronary heart disease, -91.9 (95% CI, -108.9 to -75.0); and hospitalization for cardiovascular disease, -203.6 (95% CI, -230.9 to -176.3). Patients with type 1 diabetes had roughly 40% greater reduction in cardiovascular outcomes than controls, and patients with type 2 diabetes had roughly 20% greater reduction than controls. Reductions in fatal outcomes were similar in patients with type 1 diabetes and controls, whereas patients with type 2 diabetes had smaller reductions in fatal outcomes than controls. CONCLUSIONS: In Sweden from 1998 through 2014, mortality and the incidence of cardiovascular outcomes declined substantially among persons with diabetes, although fatal outcomes declined less among those with type 2 diabetes than among controls. (Funded by the Swedish Association of Local Authorities and Regions and others.).",0
6091,28402772,Delays in Emergency Care and Mortality during Major U.S. Marathons,"BACKGROUND: Large marathons frequently involve widespread road closures and infrastructure disruptions, which may create delays in emergency care for nonparticipants with acute medical conditions who live in proximity to marathon routes. METHODS: We analyzed Medicare data on hospitalizations for acute myocardial infarction or cardiac arrest among Medicare beneficiaries (?65 years of age) in 11 U.S. cities that were hosting major marathons during the period from 2002 through 2012 and compared 30-day mortality among the beneficiaries who were hospitalized on the date of a marathon, those who were hospitalized on the same day of the week as the day of the marathon in the 5 weeks before or the 5 weeks after the marathon, and those who were hospitalized on the same day as the marathon but in surrounding ZIP Code areas unaffected by the marathon. We also analyzed data from a national registry of ambulance transports and investigated whether ambulance transports occurring before noon in marathon-affected areas (when road closures are likely) had longer scene-to-hospital transport times than on nonmarathon dates. We also compared transport times on marathon dates with those on nonmarathon dates in these same areas during evenings (when roads were reopened) and in areas unaffected by the marathon. RESULTS: The daily frequency of hospitalizations was similar on marathon and nonmarathon dates (mean number of hospitalizations per city, 10.6 and 10.5, respectively; P=0.71); the characteristics of the beneficiaries hospitalized on marathon and nonmarathon dates were also similar. Unadjusted 30-day mortality in marathon-affected areas on marathon dates was 28.2% (323 deaths in 1145 hospitalizations) as compared with 24.9% (2757 deaths in 11,074 hospitalizations) on nonmarathon dates (absolute risk difference, 3.3 percentage points; 95% confidence interval, 0.7 to 6.0; P=0.01; relative risk difference, 13.3%). This pattern persisted after adjustment for covariates and in an analysis that included beneficiaries who had five or more chronic medical conditions (a group that is unlikely to be hospitalized because of marathon participation). No significant differences were found with respect to where patients were hospitalized or the treatments they received in the hospital. Ambulance scene-to-hospital transport times for pickups before noon were 4.4 minutes longer on marathon dates than on nonmarathon dates (relative difference, 32.1%; P=0.005). No delays were found in evenings or in marathon-unaffected areas. CONCLUSIONS: Medicare beneficiaries who were admitted to marathon-affected hospitals with acute myocardial infarction or cardiac arrest on marathon dates had longer ambulance transport times before noon (4.4 minutes longer) and higher 30-day mortality than beneficiaries who were hospitalized on nonmarathon dates. (Funded by the National Institutes of Health.).",0
6092,28402773,"Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012","BACKGROUND: Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden. The prevalence of these diseases increased in the 2001-2009 period, but data on recent incidence trends are lacking. METHODS: We ascertained cases of type 1 and type 2 diabetes mellitus at five study centers in the United States. Denominators (4.9 million youths annually) were obtained from the U.S. Census or health-plan member counts. After the calculation of annual incidence rates for the 2002-2012 period, we analyzed trends using generalized autoregressive moving-average models with 2-year moving averages. RESULTS: A total of 11,245 youths with type 1 diabetes (0 to 19 years of age) and 2846 with type 2 diabetes (10 to 19 years of age) were identified. Overall unadjusted estimated incidence rates of type 1 diabetes increased by 1.4% annually (from 19.5 cases per 100,000 youths per year in 2002-2003 to 21.7 cases per 100,000 youths per year in 2011-2012, P=0.03). In adjusted pairwise comparisons, the annual rate of increase was greater among Hispanics than among non-Hispanic whites (4.2% vs. 1.2%, P<0.001). Overall unadjusted incidence rates of type 2 diabetes increased by 7.1% annually (from 9.0 cases per 100,000 youths per year in 2002-2003 to 12.5 cases per 100,000 youths per year in 2011-2012, P<0.001 for trend across race or ethnic group, sex, and age subgroups). Adjusted pairwise comparisons showed that the relative annual increase in the incidence of type 2 diabetes among non-Hispanic whites (0.6%) was lower than that among non-Hispanic blacks, Asians or Pacific Islanders, and Native Americans (P<0.05 for all comparisons) and that the annual rate of increase among Hispanics differed significantly from that among Native Americans (3.1% vs. 8.9%, P=0.01). After adjustment for age, sex, and race or ethnic group, the relative annual increase in the incidence of type 1 diabetes was 1.8% (P<0.001) and that of type 2 diabetes was 4.8% (P<0.001). CONCLUSIONS: The incidences of both type 1 and type 2 diabetes among youths increased significantly in the 2002-2012 period, particularly among youths of minority racial and ethnic groups. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention.).",0
6093,28407288,Efficient replication of blood-borne hepatitis C virus in human fetal liver stem cells,"The development of pathogenic mechanisms, specific antiviral treatments and preventive vaccines for hepatitis C virus (HCV) infection has been limited due to lack of cell culture models that can naturally imitate the entire HCV life cycle. Here, we established an HCV cell culture model based on human fetal liver stem cells (hFLSCs) that supports the entire blood-borne hepatitis C virus (bbHCV) life cycle. More than 90% of cells remained infected by various genotypes. bbHCV was efficiently propagated, and progeny virus were infectious to hFLSCs. The virus could be passed efficiently between cells. The viral infectivity was partially blocked by specific antibodies or small interfering RNA against HCV entry factors, whereas HCV replication was inhibited by antiviral drugs. We observed viral particles of approximately 55 nm in diameter in both cell culture media and infected cells after bbHCV infection. CONCLUSION: Our data show that the entire bbHCV life cycle could be naturally imitated in hFLSCs. This model is expected to provide a powerful tool for exploring the process and the mechanism of bbHCV infection at the cellular level and for evaluating the treatment and preventive strategies of bbHCV infection. (Hepatology 2017;66:1045-1057).",0
6094,28445677,Overexpression of the Cytokine BAFF and Autoimmunity Risk,"BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT?A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).",0
6095,28445927,Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice,"Strong tolerance to hepatitis B virus (HBV) surface antigens limits the therapeutic effect of the conventional hepatitis B surface antigen (HBsAg) vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of the preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1-polypeptide rather than HBsAg vaccination induced robust immune responses in HBV carrier mice. The anti-preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1-polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1-polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg/hepatitis B surface antibody serological conversion and clear chronic HBV infection in carrier mice. CONCLUSION: These results suggest that preS1 can function as a therapeutic vaccine for the control of CHB. (Hepatology 2017;66:1067-1082).",0
6096,28467879,Bystander Efforts and 1-Year Outcomes in Out-of-Hospital Cardiac Arrest,"BACKGROUND: The effect of bystander interventions on long-term functional outcomes among survivors of out-of-hospital cardiac arrest has not been extensively studied. METHODS: We linked nationwide data on out-of-hospital cardiac arrests in Denmark to functional outcome data and reported the 1-year risks of anoxic brain damage or nursing home admission and of death from any cause among patients who survived to day 30 after an out-of-hospital cardiac arrest. We analyzed risks according to whether bystander cardiopulmonary resuscitation (CPR) or defibrillation was performed and evaluated temporal changes in bystander interventions and outcomes. RESULTS: Among the 2855 patients who were 30-day survivors of an out-of-hospital cardiac arrest during the period from 2001 through 2012, a total of 10.5% had brain damage or were admitted to a nursing home and 9.7% died during the 1-year follow-up period. During the study period, among the 2084 patients who had cardiac arrests that were not witnessed by emergency medical services (EMS) personnel, the rate of bystander CPR increased from 66.7% to 80.6% (P<0.001), the rate of bystander defibrillation increased from 2.1% to 16.8% (P<0.001), the rate of brain damage or nursing home admission decreased from 10.0% to 7.6% (P<0.001), and all-cause mortality decreased from 18.0% to 7.9% (P=0.002). In adjusted analyses, bystander CPR was associated with a risk of brain damage or nursing home admission that was significantly lower than that associated with no bystander resuscitation (hazard ratio, 0.62; 95% confidence interval [CI], 0.47 to 0.82), as well as a lower risk of death from any cause (hazard ratio, 0.70; 95% CI, 0.50 to 0.99) and a lower risk of the composite end point of brain damage, nursing home admission, or death (hazard ratio, 0.67; 95% CI, 0.53 to 0.84). The risks of these outcomes were even lower among patients who received bystander defibrillation as compared with no bystander resuscitation. CONCLUSIONS: In our study, we found that bystander CPR and defibrillation were associated with risks of brain damage or nursing home admission and of death from any cause that were significantly lower than those associated with no bystander resuscitation. (Funded by TrygFonden and the Danish Heart Foundation.).",0
6097,28498614,Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice,"The Na(+) -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7?-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. CONCLUSION: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).",0
6098,28520105,Large-scale computational models of liver metabolism: How far from the clinics?,"Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases. This knowledge can be obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modeling can reveal hidden principles of the system by classification of individual components, analyzing their interactions and simulating the effects that are difficult to investigate experimentally. Herein, we review the state-of-the-art computational models that describe liver dynamics from metabolic, gene regulatory, and signal transduction perspectives. We focus especially on large-scale liver models described either by genome scale metabolic networks or an object-oriented approach. We also discuss the benefits and limitations of each modeling approach and their value for clinical applications in diagnosis, therapy, and prevention of liver diseases as well as precision medicine in hepatology. (Hepatology 2017;66:1323-1334).",0
6099,28528569,Time to Treatment and Mortality during Mandated Emergency Care for Sepsis,"BACKGROUND: In 2013, New York began requiring hospitals to follow protocols for the early identification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients. METHODS: We studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Patients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care for patients with sepsis (i.e., blood cultures, broad-spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3-hour bundle and risk-adjusted mortality. We also examined the times to the administration of antibiotics and to the completion of an initial bolus of intravenous fluid. RESULTS: Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P=0.21). CONCLUSIONS: More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. (Funded by the National Institutes of Health and others.).",0
6100,28543567,TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/G?s signaling,"Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and G? proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5(-/-) ;Pkhd1(del2/del2) mice. Compared to control, expression of TGR5 and G?(s) (but not G?(i) and G?(q) ) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ?40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5(-/-) ;Pkhd1(del2/del2) mice. TGR5 expression and its colocalization with G?(s) were increased ?2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ?30% in cystic cholangiocytes after treatment with SBI-115 alone and by ?50% when SBI-115 was combined with pasireotide. CONCLUSION: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).",0
6101,28597951,Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis,"Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4(+) CD127(+) CD25(high) cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood-derived CD4(+) CD127(+) CD25(high) cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4(+) CD127(+) CD25(high) cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4(+) CD127(+) CD25(high) cells obtained from CD4(+) cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4(+) CD127(+) CD25(high) cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. CONCLUSION: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570-1584).",0
6102,28608964,Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis,"Chronic hepatitis B virus (HBV) infection is a leading cause in the occurrence of hepatitis B, liver cirrhosis, and liver cancer, in which nuclear HBV covalently closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence, plays crucial roles. In the present study, we explored the hypothesis that HBV X protein (HBx)-elevated male-specific lethal 2 (MSL2) activated HBV replication by modulating cccDNA in hepatoma cells, leading to hepatocarcinogenesis. Immunohistochemical analysis revealed that the expression of MSL2 was positively associated with that of HBV and was increased in the liver tissues of HBV-transgenic mice and clinical HCC patients. Interestingly, microarray profiling identified that MSL2 was associated with those genes responding to the virus. Mechanistically, MSL2 could maintain HBV cccDNA stability through degradation of APOBEC3B by ubiquitylation in hepatoma cells. Above all, HBx accounted for the up-regulation of MSL2 in stably HBx-transfected hepatoma cell lines and liver tissues of HBx-transgenic mice. Luciferase reporter gene assays revealed that the promoter region of MSL2 regulated by HBx was located at nucleotide -1317/-1167 containing FoxA1 binding element. Chromatin immunoprecipitation assay validated that HBx could enhance the binding property of FoxA1 to MSL2 promoter region. HBx up-regulated MSL2 by activating YAP/FoxA1 signaling. Functionally, silencing MSL2 was able to block the growth of hepatoma cells in vitro and in vivo. CONCLUSION: HBx-elevated MSL2 modulates HBV cccDNA in hepatoma cells to promote hepatocarcinogenesis, forming a positive feedback loop of HBx/MSL2/cccDNA/HBV. Our finding uncovers insights into the mechanism by which MSL2 as a promotion factor in host cells selectively activates extrachromosomal DNA. (Hepatology 2017;66:1413-1429).",0
6103,28636834,Implementation of Medical Homes in Federally Qualified Health Centers,"BACKGROUND: From 2011 through 2014, the Federally Qualified Health Center Advanced Primary Care Practice Demonstration provided care management fees and technical assistance to a nationwide sample of 503 federally qualified health centers to help them achieve the highest (level 3) medical-home recognition by the National Committee for Quality Assurance, a designation that requires the implementation of processes to improve access, continuity, and coordination. METHODS: We examined the achievement of medical-home recognition and used Medicare claims and beneficiary surveys to measure utilization of services, quality of care, patients' experiences, and Medicare expenditures in demonstration sites versus comparison sites. Using difference-in-differences analyses, we compared changes in outcomes in the two groups of sites during a 3-year period. RESULTS: Level 3 medical-home recognition was awarded to 70% of demonstration sites and to 11% of comparison sites. Although the number of visits to federally qualified health centers decreased in the two groups, smaller reductions among demonstration sites than among comparison sites led to a relative increase of 83 visits per 1000 beneficiaries per year at demonstration sites (P<0.001). Similar trends explained the higher performance of demonstration sites with respect to annual eye examinations and nephropathy tests (P<0.001 for both comparisons); there were no significant differences with respect to three other process measures. Demonstration sites had larger increases than comparison sites in emergency department visits (30.3 more per 1000 beneficiaries per year, P<0.001), inpatient admissions (5.7 more per 1000 beneficiaries per year, P=0.02), and Medicare Part B expenditures ($37 more per beneficiary per year, P=0.02). Demonstration-site participation was not associated with relative improvements in most measures of patients' experiences. CONCLUSIONS: Demonstration sites had higher rates of medical-home recognition and smaller decreases in the number of patients' visits to federally qualified health centers than did comparison sites, findings that may reflect better access to primary care relative to comparison sites. Demonstration sites had larger increases in emergency department visits, inpatient admissions, and Medicare Part B expenditures. (Funded by the Centers for Medicare and Medicaid Services.).",0
6104,28671339,Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology,"The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (Hepatology 2018;67:762-773).",0
6105,28714143,Efficacy and safety of new direct antiviral agents in hepatitis C virus-infected patients with diffuse large B-cell non-Hodgkin's lymphoma,"The association of hepatitis C virus (HCV) with non-Hodgkin's lymphoma (NHL) has been demonstrated throughout the world. The new interferon-free direct antiviral agents (DAAs) showed high efficacy and safety, and preliminary data seem to confirm their activity on low-grade NHL. The question arises as whether or not-and how-to treat the HCV-positive patients suffering from diffuse large B-cell lymphomas (DLBCLs). The aim of this observational study was to evaluate whether DAA antiviral treatment of DLBCL/HCV-infected patients in concomitance with chemotherapy is a safe and effective option. Twenty (13 males and 7 females) HCV genotype 1b-positive subjects, undergoing chemotherapy for DLBCL, were enrolled between June 2015 and December 2015. After informed consent, all patients underwent antiviral therapy (AVT) with sofosbuvir/ledipasvir and chemotherapy (14 rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and 6 cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL. Complete hematological (Revised European-American Lymphoma classification, Ann Arbor, and International Prognostic Index [IPI] scores) and hepatological (viral markers, liver stiffness, and biochemical parameters) evaluations were made. A historical retrospective cohort of 101 DLBCL/HCV-positive patients not undergoing AVT was enrolled for comparison. DAA-treated and untreated patients were similar for sex distribution, IPI score, and NHL stage, and differed for age (older in treated), chemotherapy and use of AVT. Overall survival (OS) and disease-free survival (DFS) were evaluated among a 52-week of follow-up. No statistical difference was found in OS after 52 weeks (P = 0.122), whereas a statistically significant higher DFS was achieved in treated patients (P = 0.036). At the multivariate analysis, only IPI score and AVT were independently correlated with a better DFS. No differences in adverse events were reported. CONCLUSION: DAA treatment in concomitance with chemotherapy was shown to be safe and effective in influencing remission of aggressive lymphomas in HCV patients. (Hepatology 2018;67:48-55).",0
6106,28727166,Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia,"It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc(-/-) mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc(-/-) mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc(-/-) mice. It also showed increased glycogen phosphorylase flux in L-G6pc(-/-) mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic ?-glucosidases, were unaltered in L-G6pc(-/-) mice, pharmacological inhibition of ?-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. CONCLUSION: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that ?-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054).",0
6107,28745986,Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years,"BACKGROUND: Assisted ventilation for extremely preterm infants (<28 weeks of gestation) has become less invasive, but it is unclear whether such developments in care are associated with improvements in short-term or long-term lung function. We compared changes over time in the use of assisted ventilation and oxygen therapy during the newborn period and in lung function at 8 years of age in children whose birth was extremely premature. METHODS: We conducted longitudinal follow-up of all survivors of extremely preterm birth who were born in Victoria, Australia, in three periods - the years 1991 and 1992 (225 infants), 1997 (151 infants), and 2005 (170 infants). Perinatal data were collected prospectively, including data on the duration and type of assisted ventilation provided, the duration of oxygen therapy, and oxygen requirements at 36 weeks of age. Expiratory airflow was measured at 8 years of age, and values were converted to z scores for age, height, ethnic group, and sex. RESULTS: The duration of assisted ventilation rose substantially over time, with a large increase in the duration of nasal continuous positive airway pressure. Despite the increase in the use of less invasive ventilation over time, the duration of oxygen therapy and the rate of oxygen dependence at 36 weeks rose, and airflows at 8 years of age were worse in 2005 than in earlier periods. For instance, for 2005 versus 1991-1992, the mean difference in the z scores for the ratio of forced expiratory volume in 1 second to forced vital capacity was -0.75 (95% confidence interval [CI], -1.07 to -0.44; P<0.001), and for 2005 versus 1997 the mean difference was -0.53 (95% CI, -0.86 to -0.19; P=0.002). CONCLUSIONS: Despite substantial increases in the use of less invasive ventilation after birth, there was no significant decline in oxygen dependence at 36 weeks and no significant improvement in lung function in childhood over time. (Funded by the National Health and Medical Research Council of Australia and the Victorian Government's Operational Infrastructure Support Program.).",0
6108,28792867,Influenza Vaccine Effectiveness in the United States during the 2015-2016 Season,"BACKGROUND: The A(H1N1)pdm09 virus strain used in the live attenuated influenza vaccine was changed for the 2015-2016 influenza season because of its lack of effectiveness in young children in 2013-2014. The Influenza Vaccine Effectiveness Network evaluated the effect of this change as part of its estimates of influenza vaccine effectiveness in 2015-2016. METHODS: We enrolled patients 6 months of age or older who presented with acute respiratory illness at ambulatory care clinics in geographically diverse U.S. sites. Using a test-negative design, we estimated vaccine effectiveness as (1-OR)�100, in which OR is the odds ratio for testing positive for influenza virus among vaccinated versus unvaccinated participants. Separate estimates were calculated for the inactivated vaccines and the live attenuated vaccine. RESULTS: Among 6879 eligible participants, 1309 (19%) tested positive for influenza virus, predominantly for A(H1N1)pdm09 (11%) and influenza B (7%). The effectiveness of the influenza vaccine against any influenza illness was 48% (95% confidence interval [CI], 41 to 55; P<0.001). Among children 2 to 17 years of age, the inactivated influenza vaccine was 60% effective (95% CI, 47 to 70; P<0.001), and the live attenuated vaccine was not observed to be effective (vaccine effectiveness, 5%; 95% CI, -47 to 39; P=0.80). Vaccine effectiveness against A(H1N1)pdm09 among children was 63% (95% CI, 45 to 75; P<0.001) for the inactivated vaccine, as compared with -19% (95% CI, -113 to 33; P=0.55) for the live attenuated vaccine. CONCLUSIONS: Influenza vaccines reduced the risk of influenza illness in 2015-2016. However, the live attenuated vaccine was found to be ineffective among children in a year with substantial inactivated vaccine effectiveness. Because the 2016-2017 A(H1N1)pdm09 strain used in the live attenuated vaccine was unchanged from 2015-2016, the Advisory Committee on Immunization Practices made an interim recommendation not to use the live attenuated influenza vaccine for the 2016-2017 influenza season. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health.).",0
6109,28834483,Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes,"BACKGROUND: The previously published results of the Systolic Blood Pressure Intervention Trial showed that among participants with hypertension and an increased cardiovascular risk, but without diabetes, the rates of cardiovascular events were lower among those who were assigned to a target systolic blood pressure of less than 120 mm Hg (intensive treatment) than among those who were assigned to a target of less than 140 mm Hg (standard treatment). Whether such intensive treatment affected patient-reported outcomes was uncertain; those results from the trial are reported here. METHODS: We randomly assigned 9361 participants with hypertension to a systolic blood-pressure target of less than 120 mm Hg or a target of less than 140 mm Hg. Patient-reported outcome measures included the scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12-Item Health Survey, the Patient Health Questionnaire 9-item depression scale (PHQ-9), patient-reported satisfaction with their blood-pressure care and blood-pressure medications, and adherence to blood-pressure medications. We compared the scores in the intensive-treatment group with those in the standard-treatment group among all participants and among participants stratified according to physical and cognitive function. RESULTS: Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3 to 15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ-9 scores were relatively stable over a median of 3 years of follow-up, with no significant differences between the two treatment groups. No significant differences between the treatment groups were noted when participants were stratified according to baseline measures of physical or cognitive function. Satisfaction with blood-pressure care was high in both treatment groups, and we found no significant difference in adherence to blood-pressure medications. CONCLUSIONS: Patient-reported outcomes among participants who received intensive treatment, which targeted a systolic blood pressure of less than 120 mm Hg, were similar to those among participants who received standard treatment, including among participants with decreased physical or cognitive function. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062 .).",0
6110,28857232,Hepatic peroxisome proliferator-activated receptor ? coactivator 1? drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice,"The peroxisome proliferator-activated receptor ? (PPAR?) coactivator-1? (PGC-1 ?) is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically, in the liver, PGC-1? also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC-1? as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic-specific PGC-1?-overexpressing (LivPGC-1?) and PGC-1? knockout (LivPGC-1?KO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC-1? in driving liver tumor development. Indeed, whereas mice overexpressing PGC-1? show greater tumor susceptibility, PGC-1? knockout mice are protected from carcinogenesis. High levels of PGC-1? are able to boost reactive oxygen species (ROS) scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC-1? promotes the accumulation of ROS-driven macromolecule damage, finally limiting tumor growth. CONCLUSION: The present data elect hepatic PGC-1? as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. (Hepatology 2018;67:884-898).",0
6111,28877031,Genetic Associations with Gestational Duration and Spontaneous Preterm Birth,"BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0�10(-8)) or an association with suggestive significance (P<1.0�10(-6)) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).",0
6112,28902596,Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis,"BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid. METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M. tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions. RESULTS: Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 ?g per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 ?g per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 ?g per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater. CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327 .).",0
6113,28921638,Graft-infiltrating PD-L1(hi) cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance,"Although a key role of cross-dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. We investigated the role of intragraft dendritic cells (DCs) and cross-dressing in mouse major histocompatibility complex (MHC)-mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. Although donor interstitial DCs diminished rapidly after transplantation, they were replaced in the liver by host DCs that peaked on postoperative day (POD) 7 and persisted indefinitely. Approximately 60% of these recipient DCs displayed donor MHC class I, indicating cross-dressing. By contrast, only a very minor fraction (0%-2%) of cross-dressed DCs (CD-DCs) was evident in the spleen. CD-DCs sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD-L1) and high levels of interleukin-10 compared with non-CD-DCs (nCD-DCs) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD-1)(hi) T cell immunoglobulin and mucin domain containing 3 (TIM-3)(+) exhausted graft-infiltrating CD8(+) T cells were observed. Unlike nCD-DCs, the CD-DCs failed to stimulate proliferation of allogeneic T cells but markedly suppressed antidonor host T cell proliferation. CD-DCs were much less evident in allografts from DNAX-activating protein of 12 kDa (DAP12)(-/-) donors that were rejected acutely. CONCLUSION: These findings suggest that graft-infiltrating PD-L1(hi) CD-DCs may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. (Hepatology 2018;67:1499-1515).",0
6114,28927227,Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection,"The effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial. The single-centre cohort included 26 patients receiving surotomycin [125 or 250 mg twice daily (n = 9 each)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days. Faecal samples were collected at days 0-42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR. Surotomycin 250 mg twice daily or vancomycin 125 mg four times daily reduced faecal C. difficile counts from ∼105-107 log10 cfu/g at baseline to ≤ 102 cfu/g by days 4-10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125 mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log10 or remained unchanged with surotomycin 125 and 250 mg twice daily, respectively, whereas vancomycin reduced counts by 2.5-3.2 log10 (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5-2.8 log10; surotomycin moderately suppressed these microbes in a dose-dependent manner. In this Phase 2 trial substudy, compared with vancomycin 125 mg four times daily, surotomycin 250 mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results. ",0
6115,28927488,Investigation of the Antifatigue Effects of Korean Ginseng on Professional Athletes by Gas Chromatography-Time-of-Flight-Mass Spectrometry-Based Metabolomics,"Ginseng is usually used for alleviating fatigue. The purpose of this paper was to evaluate the regulatory effect of Korean ginseng on the metabolic pattern in professional athletes, and, further, to explore the underlying mechanism of the antifatigue effect of Korean ginseng. GC-time-of-flight-MS was used to profile serum samples from professional athletes before training and after 15 and 30 day training, and professional athletes administered with Korean ginseng in the meanwhile. Biochemical parameters of all athletes were also analyzed. For the athlete control group, strength-endurance training resulted in an elevation of creatine kinase (CK) and blood urea nitrogen (BUN), and a reduction in blood hemoglobin, and a dynamic trajectory of the metabolomic profile which were related to fatigue. Korean ginseng treatment not only lead to a marked reduction in CK and blood urea nitrogen (BUN) in serum, but also showed regulatory effects on the serum metabolic profile and restored scores plots close to normal, suggesting that the change in metabolic profiling could reflect the antifatigue effect of Korean ginseng. Furthermore, perturbed levels of 11 endogenous metabolites were regulated by Korean ginseng significantly, which might be primarily involved in lipid metabolism, energy balance, and chemical signaling. These findings suggest that metabolomics is a potential tool for the evaluation of the antifatigue effect of Korean ginseng and for the elucidation of its pharmacological mechanism. ",0
6116,28927551,Impaired contextual fear-conditioning in MAM rodent model of schizophrenia,"The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning. ",0
6117,28927742,The effect of sex and menstrual phase on memory formation during a nap,"Memory formation can be influenced by sleep and sex hormones in both men and women, and by the menstrual cycle in women. Though many studies have shown that sleep benefits the consolidation of memories, it is not clear whether this effect differs between men and women in general or according to menstrual phase in women. The present study investigated the effect of sex and menstrual cycle on memory consolidation of face-name associations (FNA) following a daytime nap. Recognition memory was tested using a face-name paired associates task with a polysomnographic nap between morning and evening testing. Seventeen healthy women (age: 20.75 (1.98) years) were studied at two time points of their menstrual cycles, defined from self-report and separated by 2weeks (perimenses: -5days to +6days from the start of menses, and non-perimenses: outside of the perimenses phase), and compared with eighteen healthy men (age: 22.01 (2.91) years). Regardless of menstrual phase, women had better pre-nap performance than men. Further, menstrual phase affected post-nap memory consolidation, with women showing greater forgetting in their perimenses phase compared with their non-perimenses phase and men. Interestingly, post-nap performance correlated with electrophysiological events during sleep (slow oscillations, spindles, and temporal coupling between the two), however, these correlations differed according to menstrual phase and sex. Men's performance improvement was associated with the temporal coupling of spindles and slow oscillations (i.e., spindle/SO coincidence) as well as spindles. Women, however, showed an association with slow oscillations during non-perimenses, whereas when they were in their perimenses phase of their cycle, women appeared to show an association only with sleep spindle events for consolidation. These findings add to the growing literature demonstrating sex and menstrual phase effects on memory formation during sleep. ",0
6118,28927894,Freezing-related perception deficits of asymmetrical walking in Parkinson's disease,"Patients with Parkinson's disease (PD), and especially those with freezing of gait (FOG), are known to experience impairments in gait rhythmicity, symmetry, and bilateral coordination between both legs. In the current study, we investigated whether deficits in perception of gait speed between limbs were more pronounced in freezers than in non-freezers and could explain some of these gait impairments. We also assessed cognitive ability and proprioception. Twenty-five PD patients (13 freezers, 12 non-freezers) and 12 healthy controls walked on a split-belt treadmill, while the speed of one of the belts was gradually increased. Participants had to indicate the moment at which they perceived belt speeds to be different. The main outcome variables were the number of correct responses (perception accuracy) and the difference in belt speeds at the moment the participants perceived belt speeds to be different (perception threshold). In addition, gait characteristics during both split- and tied-belt walking were determined. Results showed significantly lower perception accuracy in freezers, whereas the perception threshold did not differ between groups. During tied-belt walking, freezers exhibited more asymmetrical step lengths and limb excursions than non-freezers and healthy controls. Greater step length and limb excursions were associated with better perception, whereas more variable gait was associated with more impaired perception. The results confirm the hypothesis that freezers have impaired perception of locomotor asymmetry. While proprioceptive and cognitive ability did not explain these findings, the possible causal link with the occurrence of FOG needs further corroboration. ",0
6119,28928023,U.S. Army physical demands study: Prevalence and frequency of performing physically demanding tasks in deployed and non-deployed settings,"To compare percentages of on-duty time spent performing physically demanding soldier tasks in non-deployed and deployed settings, and secondarily examine the number of physically demanding tasks performed among five Army combat arms occupational specialties. Job task analysis. Soldiers (n=1295; over 99% serving on active duty) across five Army jobs completed one of three questionnaires developed using reviews of job and task related documents, input from subject matter experts, observation of task performance, and conduct of focus groups. Soldiers reported estimates of the total on-duty time spent performing physically demanding tasks in both deployed and non-deployed settings. One-way analyses of variance and Duncan post-hoc tests were used to compare percentage time differences by job. Two-tailed t-tests were used to evaluate differences by setting. Frequency analyses were used to present supplementary findings. Soldiers reported performing physically demanding job-specific tasks 17.7% of the time while non-deployed and 19.6% of the time while deployed. There were significant differences in time spent on job-specific tasks across settings (p<0.05) for three of five occupational specialties. When categories of physically demanding tasks were grouped, all soldiers reported spending more time on physically demanding tasks when deployed (p<0.001). Twenty-five percent reported performing less than half the physically demanding tasks represented on the questionnaire in the last two years. Soldiers spent more time performing physically demanding tasks while deployed compared to non-deployed but spent similar amounts of time performing job-specific tasks. ",0
6120,28928677,Virtual Reality Objectifies the Diagnosis of Psychiatric Disorders: A Literature Review,"To date, a diagnosis in psychiatry is largely based on a clinical interview and questionnaires. The retrospective and subjective nature of these methods leads to recall and interviewer biases. Therefore, there is a clear need for more objective and standardized assessment methods to support the diagnostic process. The introduction of virtual reality (VR) creates the possibility to simultaneously provoke and measure psychiatric symptoms. Therefore, VR could contribute to the objectivity and reliability in the assessment of psychiatric disorders. In this literature review, we will evaluate the assessment of psychiatric disorders by means of VR environments. First, we investigate if these VR environments are capable of simultaneously provoking and measuring psychiatric symptoms. Next, we compare these measures with traditional diagnostic measures. We performed a systematic search using PubMed, Embase, and Psycinfo; references of selected articles were checked for eligibility. We identified studies from 1990 to 2016 on VR used in the assessment of psychiatric disorders. Studies were excluded if VR was used for therapeutic purposes, if a different technique was used, or in case of limitation to a non-clinical sample. A total of 39 studies were included for further analysis. The disorders most frequently studied included schizophrenia ( In general, nearly all VR environments studied were able to simultaneously provoke and measure psychiatric symptoms. Furthermore, in 14 studies, significant correlations were found between VR measures and traditional diagnostic measures. Relatively small clinical sample sizes were used, impeding definite conclusions. Based on this review, the innovative technique of VR shows potential to contribute to objectivity and reliability in the psychiatric diagnostic process. ",0
6121,28928738,Age-Stratified T Cell Responses in Children Infected with ,"Tuberculosis (TB) in young children differs from adult TB in that the risk of rapid progression to active TB (aTB) is higher in children than in adults. The reasons for this increased risk are not fully understood. Early differentiation remains difficult between children at risk to develop aTB from those who will remain healthy and develop a latent TB infection (LTBI). Biomarkers to differentiate aTB from LTBI in children, especially in very young children, are urgently needed. To identify  ",0
6122,28928910,Phase I/II randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke,To examine the safety and efficacy of mesenchymal stem cell (MSC) therapy for intracerebral haemorrhage with neurological dysfunctions for a year. MSC were  A mean of 4.57 × 10 Intravenous administration of autologous bone marrow-derived MSC is safe and has the potential of improving neurological functions in chronic stroke patients with severe disability. ,0
6123,28929904,Sexual behaviours in the context of the Ebola virus disease (EVD) in Ghana,"Evidence suggests that Ebola virus disease can be transmitted through unprotected sexual intercourse, in particular through contact with the semen of an infected person. Yet few studies examine sexual behaviours in the context of Ebola. Using data collected from 460 women and 340 men within 40 selected communities in the Greater Accra Region of Ghana, this study employed hierarchical linear modelling to examine individual and community-level factors that influence willingness to engage in behaviours that protect against the sexual transmission of Ebola. Results indicate that both individual and community-level factors are significant predictors of respondents' willingness to engage in preventive behaviours. Compared with those with no risks, female respondents with low and medium risk perceptions were significantly more likely to indicate they would use condoms to prevent the sexual transmission of Ebola (AOR = 2.23; p < 0.01). Compared with men who were very concerned, those who were not very concerned (AOR = 0.356; p < 0.01) and not at all concerned (AOR = 0.356; p < 0.05) about Ebola were significantly less likely to protect against the sexual transmission of Ebola. Female respondents in communities with high knowledge about Ebola were significantly more likely to engage in behaviours preventing the sexual transmission of Ebola virus disease (AOR = 1.93; p < 0.05). ",0
6124,28929913,Development of acute promyelocytic leukemia in a patient with tetraplegia while in inpatient rehabilitation: A case report,"a single case report. To report a case of a patient with tetraplegia who developed acute promyelocytic leukemia (APL) while in inpatient rehabilitation after 10.5 months. A VA Medical Center Spinal Cord Injury Service and Disorders Unit Case Report: A 47 year-old male with a stage IV sacral pressure ulcer and C4 AIS A complete tetraplegia secondary to a motor vehicle collision, developed fever, thrombocytopenia, and anemia 20 months after his injury while in inpatient rehabilitation and was found to have APL, confirmed following bone marrow biopsy. There is a wide differential for fever after a spinal cord injury. In this case report, the source of fever was APL. It is important as healthcare providers to not overlook fevers when otherwise common causes do not fit the clinical picture. Additionally, there has been no association found between traumatic spinal cord injury and the development of acute leukemia, however this is the first case report. Therefore, it is important to continue investigating to determine if an association exists. ",0
6125,28929914,The conundrum of opioid tapering in long-term opioid therapy for chronic pain: A commentary,"In response to the opioid epidemic and new guidelines, many patients on high-dose long term opioid therapy (LTOT) for chronic pain are getting tapered off opioids. As a result, a unique clinical challenge is emerging: while many on LTOT have poor pain control, functional decline, psychiatric instability, aberrancies and misuse, these issues may often worsen with opioid tapering. Currently, a clear explanation and practical guidance on how to manage this perplexing clinical scenario is lacking. We offer a commentary with our perspective on possible mechanisms involved in this clinical phenomena and offer practical management guidance, supported by available evidence. It is not well recognized that allostatic opponent process involved in development of opioid dependence can cause worsening pain, functional status, sleep and psychiatric symptoms over time, and significant fluctuation of pain and other affective symptoms due to their bidirectional dynamic interaction with opioid dependence ('affective dynamism'). These elements of complex persistent dependence (CPD), the grey area between simple dependence and addiction, can lead to escalating and labile opioid need, often generating aberrant behaviors. Opioid tapering, a seemingly logical intervention in this situation, may lead to worsening of pain, function and psychiatric symptoms due to development of protracted abstinence syndrome. We offer practicing clinicians management principles and practical guidance focused on management of CPD in addition to chronic pain in these difficult clinical scenarios. Awareness of the science of the neuroplasticity effects of repeated use of opioids is necessary to better manage these patients with complex challenges. ",0
6126,28929963,Comparison of phenotypic methods and polymerase chain reaction for the detection of carbapenemase production in clinical Klebsiella pneumoniae isolates],"""Being a member of the Enterobacteriaceae family, Klebsiella pneumoniae is an opportunistic pathogen that inhabits normal human microbiota and causes predominantly hospital-acquired infections. The emergence of K.pneumoniae isolates which are resistant particularly to the carbapenem group of antibiotics has led to an increase in hospitalization period, mortality and morbidity. Although different rates of resistance are observed between countries, regions and even healthcare facilities, there has been a rapid increase in the prevalence of carbapenem-resistant strains in the last 10 years. Fast and correct identification of carbapenem-resistant strains is important for the successful treatment of infections caused by these resistant bacteria. The objective of this study was to investigate the presence and the types of carbapenemases in carbapenem-resistant K.pneumoniae strains using """"MASTDISCS™ ID carbapenemase detection disc set"""", a commercial product that can be used for this purpose, and """"Carbapenem Inactivation Method (CIM)"""", a relatively new method, and compare the results of these methods by polymerase chain reaction (PCR). For this purpose, we used 54 K.pneumoniae strains isolated in 2015-2016, that were resistant to any of the ertapenem, meropenem or imipenem antibiotics. The identification of the strains was performed using VITEK MS and their antibiotic susceptibility tests were carried out using the VITEK 2 Compact® automated system. For the strains that were found resistant to carbapenems in the automated system, the minimum inhibitor concentration (MIC) values were determined by the gradient testing method according to the recommendations of """"The European Committee on Antimicrobial Susceptibility Testing (EUCAST)"""". The blaOXA-48, blaIMP, blaNDM, blaVIM, and blaSIM genes were investigated with PCR among these isolates. Phenotypic enzyme typing was performed in the carbapenem-resistant strains using the """"MASTDISCS™ ID carbapenemase detection disc set"""" and """"Carbapenem Inactivation Method (CIM)"""". REP-PCR was used to reveal clonal relationship of the isolates. The 54 K.pneumoniae isolates were found as resistant to carbapenem and the MIC50 and MIC90 values of imipenem, meropenem and ertapenem were 32 µg/ml. Only 33 of the strains had blaOXA-48 and two of them had only blaNDM, the remaining 19 strains had both of these two genes. The blaIMP, blaVIM and blaSIM genes were not encountered in any of the isolates. When the isolates were assessed by the REP-PCR method, six main clones were detected. The """"MASTDISCS™ ID carbapenemase detection disc set"""" was able to detect all the carbapenemase producing strains and it remained incapable of distinguishing OXA-48 in the strains which had both OXA-48 and metallo beta lactamase (MBL) enzymes. The CIM method showed a low rate of positivity (46.15%) in the strains containing blaOXA-48, but was found much more successful in the strains containing blaNDM with a detection rate of 85.71%. In this study, it was concluded that the Mastdiscs-ID method could be successfully used to detect the presence of blaOXA-48 which has a high prevalence in our country. """,0
6127,28929979,Pharmacists as Care Providers for Stroke Patients: A Systematic Review,"Pharmacists have become an integral member of the multidisciplinary team providing clinical patient care in various healthcare settings. Although evidence supporting their role in the care of patients with other disease states is well-established, minimal literature has been published evaluating pharmacist interventions in stroke patients. The purpose of this systematic review is to summarize the evidence evaluating the impact of pharmacist interventions on stroke patient outcomes. Study abstracts and full-text articles evaluating the impact of a pharmacist intervention on outcomes in patients with an acute stroke/transient ischemic attack (TIA) or a history of an acute stroke/TIA were identified and a qualitative analysis performed. A total of 20 abstracts and full-text studies were included. The included studies provided evidence supporting pharmacist interventions in multiple settings, including emergency departments, inpatient, outpatient, and community pharmacy settings. In a significant proportion of the studies, pharmacist care was collaborative with other healthcare professionals. Some of the pharmacist interventions included participation in a stroke response team, assessment for thrombolytic use, medication reconciliation, participation in patient rounds, identification and resolution of drug therapy problems, risk-factor reduction, and patient education. Pharmacist involvement was associated with increased use of evidence-based therapies, medication adherence, risk-factor target achievement, and maintenance of health-related quality of life. Available evidence suggests that a variety of pharmacist interventions can have a positive impact on stroke patient outcomes. Pharmacists should be considered an integral member of the stroke patient care team. ",0
6128,28930579,Using comparative genomics to decode the genetics of acaricide resistance,"The availability of genome assemblies and other genomic resources is facilitating investigations of complex genetic traits for several species of ticks. Understanding the genetics of acaricide resistance is a priority for tick and tick-borne disease control. The synaptic enzyme acetylcholinesterase (ACE) is recognized as the target of organophosphates (OPs) and carbamates, and mutations in ACE have been tied to resistance. Multiple studies support three ACE (ace) loci in  ",0
6129,28930591,Lipoprotein(a) and cardiovascular disease: current state and future directions for an enigmatic lipoprotein,"""Lipoprotein (a) (Lp (a)) is a complex polymorphic lipoprotein. Although structurally similar to low-density lipoprotein, Lp(a) has a glycoprotein, apolipoprotein(a) (apo(a)), attached to the apolipoprotein B-100 component. Several unique properties of Lp(a) can be attributed to the presence of apo(a). Several decades of research has improved our understanding of the structure, biochemistry, and pathophysiology of Lp(a) associated diseases. Genetic, epidemiological, and translational data indicate that elevated Lp(a) levels are likely in the causal pathway for atherosclerotic cardiovascular diseases as well as calcification of the aortic valves. The """"Lp(a) hypothesis,"""" unlike the """"LDL hypothesis,"""" has not been tested in clinical trials yet. Currently, the management of elevated Lp(a) is directed at lowering low-density lipoprotein cholesterol levels. Developing therapies include antisense oligonucleotides which inhibit the synthesis of apo(a). This review discusses the current state of literature on pathophysiological and clinical aspects of Lp(a), including its role in coronary heart disease, stroke, aortic valve stenosis, and other vascular diseases. Current and emerging therapies aimed at treatment for elevated Lp(a) levels are also discussed. """,0
6130,28930656,More Is Less: IL-9 in the Resolution of Inflammation,"In a recent study in Nature Medicine, Rauber et al. (2017) identify interleukin-9 (IL-9) derived from group 2 innate lymphoid cells as crucial regulators inducing resolution of chronic inflammation in rheumatoid arthritis. Their findings provide insight into the varied functions of IL-9 and open the door to novel therapeutic interventions. ",0
6131,28930830,Effect of dexmedetomidine as an adjuvant to ropivacaine for wound infiltration in patients undergoing open gastrectomy: A prospective randomized controlled trial,"The primary objective of this study was to investigate whether dexmedetomidine could potentiate the analgesic efficacy of ropivacaine, when added to ropivacaine for wound infiltration in patients undergoing open gastrectomy. Fifty patients scheduled for open gastrectomy were divided into 2 equal groups that were received wound infiltration using 20 mL 0.3% ropivacaine plus 2 mL normal saline (group R) or 20 mL 0.3% ropivacaine plus 2 mL 1.0 μg/kg dexmedetomidine (group DR). Visual analogue scale (VAS) pain score, patient-controlled analgesia (PCA) pump press number, sufentanil consumption, postoperative nausea and vomiting (PONV), and wound healing score were recorded. The VAS pain score were comparable between the 2 groups at the observation time points (P > .05), PCA pump press number and sufentanil consumption were higher in group R than that in group DR at 0 to 2, 2 to 4, 4 to 6 time intervals (P < .05) except for 6 to 8, 8 to 10, 10 to 12 time intervals (P > .05), meanwhile, the 24 hours total sufentanil consumption was also higher in group R than that in group DR (90.4 ± 20.5 vs 79.2 ± 9.4) (P < .05), there were no significant differences in PONV and wound healing score between the 2 groups (P > .05). Dexmedetomidine as an adjuvant to ropivacaine for wound infiltration promoted the analgesic efficacy of ropivacaine, reduced sufentanil consumption, and had no effect on wound healing; it could be as an ideal adjuvant which could potentiate the analgesic efficacy of local anesthetics. ",0
6132,28930951,Routine computed tomography after recent operative exploration for penetrating trauma: What injuries do we miss?,"Patients with penetrating trauma who cannot be stabilized undergo operative intervention without preoperative imaging. In such cases, postoperative imaging may reveal additional injuries not identified during the initial operative exploration. The purpose of this study is to explore the utility of postoperative CT imaging in the setting of penetrating trauma. This was a retrospective analysis of patients with penetrating trauma treated at an urban Level 1 trauma center between 2010 and 2015. Patients were included if they underwent an emergent laparotomy without preoperative imaging. Patients were excluded if they had prior imaging or concomitant blunt injury. For the purposes of this study, occult injury was defined as a CT scan finding not mentioned in the first operative report. Descriptive statistics were used to compare patient characteristics who had received imaging immediately postoperatively with those who had not. During the 5-year study period, 328 patients who had a laparotomy for penetrating trauma over the study period, 225 patients met the inclusion criteria. Seventy-three (32%) patients underwent CT scanning immediately postoperatively with occult injuries identified in 38 (52%) patients. The most frequent occult injuries were orthopedic (20 of 43) and genitourinary (9 of 43). Importantly, 10 (26%) of the 38 patients required an intervention for these occult injuries. Those selected for immediate postoperative imaging were more likely to have sustained gunshot wounds and were significantly more severely injured (higher Injury Severity Score and longer length of hospital stay) when compared to patients who did not receive immediate imaging. We recommend the use of immediate postoperative CT after emergent laparotomy especially when there is a high index of suspicion for spine or genitourinary injuries and in patients who have sustained ballistic penetrating injuries. Therapeutic/care management, level IV; diagnostic tests or criteria, level IV. ",0
6133,28930954,Acute procedural interventions after pediatric blunt abdominal trauma: A prospective multicenter evaluation,"Pediatric intra-abdominal injuries (IAI) from blunt abdominal trauma (BAT) rarely require emergent intervention. For those children undergoing procedural intervention, our aim was to understand the timing and indications for operation and angiographic embolization. We prospectively enrolled children younger than 16 years after BAT at 14 Level I Pediatric Trauma Centers over a 1-year period. Patients with IAI who received an intervention (IAI-I) were compared with those who did not receive an intervention using descriptive statistics and univariate analysis; p less than 0.05 was considered significant. Two hundred sixty-one (11.9%) of 2,188 patients had IAI. Forty-five (17.2%) IAI patients received an acute procedural intervention (38 operations, seven angiographic embolization). The mean age for patients requiring intervention was 7.1 ± 4.1 years and not different from the population. Most patients (88.9%) with IAI-I were normotensive. IAI-I patients were significantly more likely to have a mechanism of motor vehicle collision (66.7% vs. 38.9%), more likely to present as a Level I activation (44.4% vs. 26.9%), more likely to have a Glascow Coma Scale less than 14 (31.1% vs. 15.5%), and more likely to have an abnormal abdominal physical examination (93.3% vs. 65.7%) than patients that did not require acute intervention. All patients underwent computed tomography scan before intervention. Operations consisted of laparotomy (n = 21), laparoscopy converted to open (n = 11), and laparoscopy alone (n = 6). The most common surgical indications were hollow viscus injury (HVI) (11 small bowel, 10 colon, 6 small bowel/colon, 2 duodenum). All interventions for solid organ injury, including seven angioembolic procedures, occurred within 8 hours of arrival; many had hypotension and received a transfusion. Procedural interventions were more common for HVI than for solid organ injury (59.2% vs. 7.6%). Postoperative mortality from IAI was 2.6%. Acute procedural interventions for children with IAI from BAT are rare, predominantly for HVI, are performed early in the hospital course and have excellent clinical outcomes. Prognostic/epidemiologic study, level III; therapeutic study, level IV. ",0
6134,28931025,"The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015","Enteric fever remains a major public health problem in low resource settings and antibiotic resistance is increasing. In Asia, an increasing proportion of infections is caused by Salmonella enterica serovar Paratyphi A, which for a long time was assumed to cause a milder clinical syndrome compared to Salmonella enterica serovar Typhi. A retrospective chart review study was conducted of 254 unique cases of blood culture confirmed enteric fever who presented at a referral adult hospital in Phnom Penh, Cambodia between 2008 and 2015. Demographic, clinical and laboratory data were collected from clinical charts and antibiotic susceptibility testing was performed. Whole genome sequence analysis was performed on a subset of 121 isolates. One-hundred-and-ninety unique patients were diagnosed with Salmonella Paratyphi A and 64 with Salmonella Typhi. In the period 2008-2012, Salmonella Paratyphi A comprised 25.5% of 47 enteric fever cases compared to 86.0% of 207 cases during 2013-2015. Presenting symptoms were identical for both serovars but higher median leukocyte counts (6.8 x 109/L vs. 6.3 x 109/L; p = 0.035) and C-reactive protein (CRP) values (47.0 mg/L vs. 36 mg/L; p = 0.034) were observed for Salmonella Typhi infections. All but one of the Salmonella Typhi isolates belonged to haplotype H58 associated with multidrug resistance (MDR) (i.e. resistance to ampicillin, chloramphenicol and co-trimoxazole).;42.9% actually displayed MDR compared to none of the Salmonella Paratyphi A isolates. Decreased ciprofloxacin susceptibility (DCS) was observed in 96.9% (62/64) of Salmonella Typhi isolates versus 11.5% (21/183) of Salmonella Paratyphi A isolates (all but one from 2015). All isolates were susceptible to azithromycin and ceftriaxone. In Phnom Penh, Cambodia, Salmonella Paratyphi A now causes the majority of enteric fever cases and decreased susceptibility against ciprofloxacin is increasing. Overall, Salmonella Typhi was significantly more associated with MDR and DCS compared to Salmonella Paratyphi A. ",0
6135,28931092,The genome-wide associated candidate gene ZNF804A and psychosis-proneness: Evidence of sex-modulated association,"The Zinc finger protein 804A (ZNF804A) is a promising candidate gene for schizophrenia and the broader psychosis phenotype that emerged from genome-wide association studies. It is related to neurodevelopment and associated to severe symptoms of schizophrenia and alterations in brain structure, as well as positive schizotypal personality traits in non-clinical samples. Moreover, a female-specific association has been observed between ZNF804A and schizophrenia. The present study examined the association of two ZNF804A polymorphisms (rs1344706 and rs7597593) with the positive dimension of schizotypy and psychotic-like experiences in a sample of 808 non-clinical subjects. Additionally, we wanted to explore whether the sexual differences reported in schizophrenia are also present in psychosis-proneness. Our results showed an association between rs7597593 and both schizotypy and psychotic-like experiences. These associations were driven by females, such those carrying the C allele had higher scores in the positive dimension of both variables compared to TT allele homozygotes. The findings of the present study support the inclusion of ZNF804 variability in studies of the vulnerability for the development of psychopathology in non-clinical samples and consideration of sex as a moderator of this association. ",0
6136,28931100,"Venous thromboembolism (VTE) - current diagnosis and therapy, with special attention towards oncologic patients]","Deep vein thrombosis (DVT), pulmonary embolism (PE), or with the common name venous thromboembolism (VTE) are frequent manifestations of pathologic hemostasis in malignancies, thereby contributing to the large number of patients despite recent developments in thrombosis prevention. In the present paper up-to-date practice of diagnosis and therapy will be discussed partly based on the author's previous publications on epidemiology and prophylaxis of VTE in oncological patients. A malignus betegségeket gyakran kíséri a hemosztázis zavara, amely többnyire mélyvénás trombózisban (MVT), pulmonális embóliában (PE), együttes megnevezéssel vénás tromboembóliában (VTE) nyilvánul meg, nem kis mértékben hozzájárulva a hatékonyabb megelõzés ellenére sem csökkenõ betegszámhoz. A szerzõ a jelen munkában a VTE korszerû diagnózisának és kezelésének fontosabb általános és onkológiai szempontjait tekinti át, támaszkodva saját korábbi, az epidemiológiai adatokat és a profilaxis kérdését tárgyaló közleményeire. ",0
6137,28931166,A clustered randomized controlled trial to determine impacts of the Harvest of the Month program,"The study purpose was to examine the impact of the Harvest of the Month (HOTM) program on fruit and vegetable (FV) consumption, FV preferences, other eating behaviors, physical activity and other variables related to healthy eating. A clustered randomized controlled trial was employed in 28 elementary schools. After parental consent was obtained, students in grades 4-6 were randomly assigned to treatment and control conditions (Intervention= 127, Control= 148). Students in the intervention group participated in HOTM, a widely used school-based nutrition promotion and obesity prevention program. Control group schools continued their usual practice. Participants completed baseline and follow-up surveys measuring fruit and vegetable (FV) consumption, FV preferences, other eating behaviors, physical activity, FV knowledge and self-efficacy to eat, prepare and ask for FV. No impacts of HOTM were found for FV consumption or other nutritional behaviors, physical activity, FV knowledge, or self-efficacy. A positive impact of the program was only found for FV preferences. This study suggests that the HOTM program did not affect eating behaviors or physical activity behaviors. The evidence base regarding school-based nutrition education programs including HOTM could be strengthened by the use of more rigorous impact evaluations to examine their effectiveness prior to wide-spread use. ",0
6138,28931677,Structurally Guided Removal of DeISGylase Biochemical Activity from Papain-Like Protease Originating from Middle East Respiratory Syndrome Coronavirus,"Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV poses a significant ongoing threat to global human health. As part of its viral genome, MERS-CoV encodes a papain-like protease (PLpro) that has been observed to act as a deubiquitinase and deISGylase to antagonize type I interferon (IFN-I) immune pathways. This activity is in addition to its viral polypeptide cleavage function. Although the overall impact of MERS-CoV PLpro function is observed to be essential, difficulty has been encountered in delineating the importance of its separate functions, particularly its deISGylase activity. As a result, the interface of MERS-CoV and human interferon-stimulated gene product 15 (hISG15) was probed with isothermal calorimetry, which suggests that the C-terminal domain of hISG15 is principally responsible for interactions. Subsequently, the structure of MERS-CoV PLpro was solved to 2.4 Å in complex with the C-terminal domain of hISG15. Utilizing this structural information, mutants were generated that lacked appreciable deISGylase activity but retained wild-type deubiquitinase and peptide cleavage activities. Hence, this provides a new platform for understanding viral deISGylase activity within MERS-CoV and other CoVs. ",0
6139,28931876,Evidence that CA3 is Underling the Comorbidity Between Pain and Depression and the Co-curation by Wu-Tou decoction in Neuropathic Pain,"In neuropathic pain (NP), the atrophy of hippocampus contributes to the comorbidity between pain, depression and the cognitive deficits. However, the exact mechanism underling the comorbidity, the effective control of the degenerations in hippocampus and the remission of the accompanied depressive symptoms are still lacking. Wu-Tou decoction (WTD) has been prescribed for inflammatory pain for thousands of years. In this study, we manifested the effects of WTD on the pain, depression and anxiety co-curative symptoms of NP. Moreover, we reported that WTD rescued the mal-regulated BDNF and TNF-α in hippocampal CA3 alone, which is proven contributing to the pain and induced psychiatric symptoms. Finally, analysis of biochemistry, morphology and electrophysiology exhibited the potential mechanism of WTD in CA3. We found that, in the late stage of SNL condition, WTD mediated the rescue of the down-regulated glutamate as well as its pre-synaptic vesicular glutamate transporters (VGLuT1) and the post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in CA3. In sum, the targeted mediation of glutamatergic system in CA3 suggest that WTD may be responsible for the remission of the hypo-functioned CA3 glutamatergic neurons and further contribute to the co-curative effects of WTD. ",0
6140,28932047,A relationship between salivary flow rates and Candida counts in patients with xerostomia,"Most of the adult population is colonized by Candida in their oral cavity. The process of colonization depends on several factors, including the interaction between Candida and salivary proteins. Therefore, salivary gland hypofunction may alter the oral microbiota and increase the risk for opportunistic infections, such as candidiasis. Hence, it is necessary to evaluate the relationship between salivary flow rates (SFRs) and Candida colony counts in the saliva of patients with xerostomia. This study aims to determine and evaluate the relationship between SFRs and Candida colony forming units (CFUs) in patients with xerostomia. This study was a descriptive study. The study participants were taken from the patients attending outpatient department in a private dental college. Fifty patients, who reported xerostomia in a questionnaire of the symptoms of xerostomia, were selected. Chewing stimulated whole saliva samples were collected from them and their SFRs were assessed. Saliva samples were inoculated in the Sabouraud dextrose agar culture media for 24-48 h, and Candida CFUs were counted. Chi-squared test was used to analyze the data. There was a significant inverse relationship between salivary flow and candida CFUs count when patients with high colony counts were analyzed (cutoff point of 400 or greater CFU/mL). Females had less SFR than males. Most of the patients who had hyposalivation were taking medication for the underlying systemic diseases.  There was a significantly negative correlation between SFRs and Candida CFUs in the patients with xerostomia. ",0
6141,28932981,"The spatial distribution and accumulation characteristics of heavy metals in steppe soils around three mining areas in Xilinhot in Inner Mongolia, China","Metal deposition has become a major environmental problem in China due to its adverse effects on human and ecosystem health, particularly in Inner Mongolia, where frequent dust storms (due to steppe degradation and desertification) and soil pollution (associated with the increasing mining activities) have occurred in recent decades. To assess spatial distribution of heavy metals and the influences of mining activities on geochemical behavior of heavy metals in soils, soil samples with depth of 0-10, 10-20, and 20-30 cm at each site were collected from different directions in the vicinity of three mines (coal mine, gold mine, and fluorite mine) in a typical steppe zone of Inner Mongolia, China. Six elements (Cd, Pb, Zn, Cr, Cu, and Ni) in the soils were analyzed using inductively coupled plasma emission spectrometer (ICP-OES). The results indicated that the average concentrations of Cd, Pb, Zn, Cr, Cu, and Ni in the soil of the study area around three mines were lower than the second class level of the National Soil Environment Safety Standard, but mostly were higher than the background value of soil in the Inner Mongolia. Northwest, southwest, and northeast wind directions have a great influence on the distribution of metals in coal, gold, and fluorite mine area, respectively. The concentration of heavy metals in coal, gold, and fluorite increased with the distance from the center of the mine, then reached a peak, then decreased gradually. The vertical mobility of metals in soil profiles was slightly significant for Cd > Cr > Zn > Ni in coal mine area and was not significant in gold and fluorite mines. Multivariate statistical methods such as principal component analysis and cluster analysis, coupled with correlation coefficient analysis, showed that Cd, Cu, Cr, and Ni in the mining area came from the same source, while Zn and Pb came from the other source. That the sources of heavy metals in the mining area were discussed would not only enhance our knowledge regarding the soil pollution status in the study area but would also provide us information to manage the sources of these elements in the study area. ",0
6142,28933274,An Overview on Cardiovascular Protective Effects of Catechins,"The impact of diet strategies to manage cardiovascular disease has been focused in recent years. The food ingredients, such as flavonoids, are known as cardioprotective agents; however, it is not fully understood how these compounds are effective against cardiovascular problems. Catechins are polyphenolic compounds exhibiting several biological activities in the human body, potentially in the treatment of cardiovascular disease. The present study indicates that catechins may be effective against cardiovascular problems through modulating blood lipid metabolism, protecting vascular endothelial, and decreasing blood pressure. The current review has evaluated various studies on the role of catechins in the prevention and treatment of cardiovascular disorders by focusing on oxidative stress and inflammatory responses. ",0
6143,28933366,"The Role of the MAPK Signaling, Topoisomerase and Dietary Bioactives in Controlling Cancer Incidence","Reactive oxygen species (ROS) are common products of mitochondrial oxidative phosphorylation, xenobiotics metabolism and are generated in response to several environmental stress conditions. Some of them play important biochemical roles in cellular signal transduction and gene transcription. On the other hand, ROS are known to be involved in a wide range of human diseases, including cancer. The excessive production of such ROS together with disruption of homeostasis detoxifying mechanisms can mediate a series of cellular oxidative stresses. The oxidative stress of redundant free radicals production can lead to oxidative denaturation of cellular macromolecules including proteins, lipids and DNA. Moreover, oxidative damage is one of the major causes of DNA mutations, replication errors and genomic abnormalities which result in either inhibition or induction of transcription, and end with the disturbance of signal transduction pathways. Among affected signaling pathways are redox-sensitive kinases. The stimulation of these kinases induces several transcription factors through the phosphorylation of their module proteins. The activation of such pathways induces proliferation and cellular transformation. A diet rich in antioxidant compounds has potential health benefits, and there is a growing interest in the role of natural antioxidants in nutrition for prevention and cure of cancer diseases. A controversy has risen regarding the relation between antioxidants and the significant decrease in the risk of cancer incidence. In this review, we will focus on redox-sensitive kinases signaling pathways, highlighting the effects of dietary antioxidant on the prevention, incidence, prognosis or even treatment of human cancers. In addition, we will place emphasis on the chemical classes of pterocarpans as natural anti-oxidants/cancers as well as their underlying mechanisms of action, including their effects on MAPKs and topoisomerase activities. ",0
6144,28933934,Emergency Medical Service Personnel's Risk From Violence While Serving the Community,"""To determine the risks of violence-related injury among emergency medical services (EMS) personnel in the United States. We analyzed 1630 violence-related occupational injury cases reported to the US Bureau of Labor Statistics for the years 2012 to 2015 and conducted secondary searches within the Bureau of Labor Statistics Web site. The number of cases per year varied between 250 and 560. Perpetrators included patients (77%) and coworkers (8%). Female EMS personnel had a disproportionately greater risk of violence-related injuries. The most common (35%) injury type was """"sprains-strains-tears""""; about 4% of the assault cases resulted in fractures, 13% resulted in surface wounds, and 190 were head injuries. About a third of the cases were classified as intentional. The findings indicate a clear need for reliable interventions. The differences in risk for women indicate that some interventions may need to be demographic-specific. Because of the limitations of national data, future researchers will need access to agency-level data that include hours worked and call volume by demographic factors such as gender. """,0
6145,28934127,Removal of Phenolic Compounds from Water Using Sewage Sludge-Based Activated Carbon Adsorption: A Review,"Due to their industrial relevance, phenolic compounds (PC) are amongst the most common organic pollutants found in many industrial wastewater effluents. The potential detrimental health and environmental impacts of PC necessitate their removal from wastewater to meet regulatory discharge standards to ensure meeting sustainable development goals. In recent decades, one of the promising, cost-effective and environmentally benign techniques for removal of PC from water streams has been adsorption onto sewage sludge (SS)-based activated carbon (SBAC). This is attributed to the excellent adsorptive characteristics of SBAC and also because the approach serves as a strategy for sustainable management of huge quantities of different types of SS that are in continual production globally. This paper reviews conversion of SS into activated carbons and their utilization for the removal of PC from water streams. Wide ranges of topics which include SBAC production processes, physicochemical characteristics of SBAC, factors affecting PC adsorption onto SBAC and their uptake mechanisms as well as the regeneration potential of spent SBAC are covered. Although chemical activation techniques produce better SBAC, yet more research work is needed to harness advances in material science to improve the functional groups and textural properties of SBAC as well as the low performance of physical activation methods. Studies focusing on PC adsorptive performance on SBAC using continuous mode (that are more relevant for industrial applications) in both single and multi-pollutant aqueous systems to cover wide range of PC are needed. Also, the potentials of different techniques for regeneration of spent SBAC used for adsorption of PC need to be assessed in relation to overall economic evaluation within realm of environmental sustainability using life cycle assessment. ",0
6146,28934397,A modifier of Huntington's disease onset at the MLH1 locus,"Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets. ",0
6147,28934555,Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk,"The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction. Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed. Thirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue. ",0
6148,28934906,Autonomic symptoms in patients with moderate and severe chronic obstructive pulmonary disease,"A synoptic description of the autonomic symptoms profile (ASP) of patients with COPD is not available. Therefore, we aimed to provide an overview of autonomic symptoms and its associates in COPD. We evaluated 89 subjects with COPD (65 ± 7.3 years; 66 males; GOLD II-IV) with an equal number of age- and sex-matched control subjects by means of the composite autonomic symptom score (COMPASS 31) questionnaire, which assesses autonomic symptoms across six domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, urinary and pupillomotor). Lung function, medication use and health status variables (quality of life: physical/mental component summary [PCS/MCS], fatigue, anxiety, depression and dyspnea levels) were also assessed. Compared to controls, all subjects with COPD reported significantly higher orthostatic intolerance, secretomotor and total autonomic symptom scores (p < .05). Additionally, subjects with moderate COPD also reported significantly higher scores for vasomotor, gastrointestinal, urinary and pupillomotor symptoms compared to controls (p < .05). Nevertheless, these symptoms were comparable between the moderate and severe COPD subgroups (p > .05). The COPD subjects had poorer health status compared to controls as exhibited by significantly higher scores for depression, anxiety, fatigue and dyspnea, and lower scores values for PCS and MCS scores (p < .05). These health status variables were mildly associated with autonomic symptoms (0.214 ≤ r ≥ 0.421; p < .05), but not with demographic and lung function (p > .05). The MCS was the only significant predictor of total autonomic symptoms score in COPD (p = 0.001; β = -0.430). Autonomic symptoms are present in all domains of the COMPASS-31 in COPD, irrespective of disease severity and demographic variables. Autonomic symptoms in COPD were mainly influenced by poor mental health. ",0
6149,28935268,Repeated cortisol administration does not reduce intrusive memories - A double blind placebo controlled experimental study,"""PTSD is a severe mental disorder, which may develop after exposure to traumatic events and is characterized by intrusive memories. Intrusions are sudden brief sensory memories of the traumatic event, that cause immense distress and impairment in every day functioning. Thus, the reduction of intrusive memories is one of the main aims of PTSD therapy. Recently, the glucocorticoid cortisol has been proposed as a pharmacological option to reduce intrusive memories, because cortisol is known to have memory retrieval inhibiting effects. However, the research on the effects of cortisol administration on intrusive memories is not conclusive. The aim of the present study was to examine if repeated cortisol administration inhibits intrusions and recognition memory in an experimental study using the trauma film paradigm. In a randomized double-blind placebo controlled design participants were exposed to a traumatic film (known to induce intrusions in healthy participants) and received either a low dose of cortisol (20mg) or placebo on the three days following """"trauma exposure"""". Intrusive memories were assessed with an Electronic Diary and an Intrusion Triggering Task. Furthermore, we assessed explicit memory for the traumatic film clip with a recognition test. Contrary to our predictions, the cortisol group did not report fewer intrusions than the placebo group nor did it show diminished performance on the recognition test. Our results show that sole cortisol administration after a traumatic experience cannot reduce intrusive re-experiencing. """,0
6150,28935710,Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation,"Paxillin and Hic-5 are homologous focal adhesion adaptor proteins that coordinate cytoskeletal rearrangements in response to integrin signaling, but their role(s) in cortical development are unknown. Here, we find that Hic-5-deficient mice are postnatal viable with normal cortical layering. Mice with a neural-specific deletion of paxillin are also postnatal viable, but show evidence of a cortical neuron migration delay that is evident pre- and perinatally, but is not detected at postnatal day 35 (P35). This phenotype is not modified by Hic-5 deficiency (double knockout). Specific deletion of paxillin in postmitotic neurons using Nex-Cre-mediated recombination as well as  ",0
6151,28935979,Intergrative metabolomic and transcriptomic analyses unveil nutrient remobilization events in leaf senescence of tobacco,"Leaf senescence in plants is a coordinated process that involves remobilization of nutrients from senescing leaves to sink tissues. The molecular events associated with nutrient remobilization are however not well understood. In this study the tobacco system with a source-sink relationship between different leaf positions was used in analyzing the spatiotemporal changes of 76 metabolites from leaves at 3 different stalk positions and 8 developmental stages. The metabolomic data was then compared with RNA-seq data from the same samples to analyze the activities of the metabolic pathways that are important for nutrient remobilization. Integrative analyses on metabolites accumulation and expression changes of enzyme-encoding genes in corresponding metabolic pathways indicated a significant up-regulation of the tricarboxylic acid cycle and related metabolism of sugars, amino acids and fatty acids, suggesting the importance of energy metabolism during leaf senescence. Other changes of the metabolism during tobacco leaf senescence include increased activities of the GS/GOGAT cycle which is responsible for nitrogen recycling, and increased accumulation of nicotine. The results also suggested that a number of compounds seemed to be transported from senescing leaves at lower positions to sink leaves at upper positions. Some of these metabolites could play a role in nutrient remobilization. ",0
6152,28936074,Syndromes of Rapidly Progressive Cognitive Decline-Our Experience,"Dementias are fairly slowly progressive degenerative diseases of brain for which treatment options are very less and carry a lot of burden on family and society. A small percentage of them are rapidly progressive and mostly carry a different course outcome. However, there are no definite criteria other than the time line for these patients. The aim of this was to identify and categorize the causes and course of rapidly progressive dementias seen in our center. Patients who presented with rapid deterioration of cognitive functions within weeks to 1 year between 2011 and December 2016 were evaluated. All patients underwent all mandatory tests for dementia including brain imaging. Complete vasculitis workup, autoimmune encephalitis profile including Voltage Gated Potassium Channel, N-methyl-D-aspartic acid receptor, glutamic acid-decarboxylase, thyroid-peroxidase antibody, cerebrospinal fluid, and other special tests such as duodenal biopsy and paraneoplastic workup were done based on clinical indications. Out of 144 patients 42 had immune-mediated encephalopathy, 18 had Creutzfeldt-Jakob disease, 3 had Vitamin B12 deficiency, 63 had infection with neurocysticercosis, 7 had tuberculosis, 2 had HIV, 1 had herpes simplex encephalitis, 1 had neurosyphilis, 1 Whipples disease, 1 had Subacute Sclerosing Panencephalitis, 1 had Mass lesion, 3 had Frontotemporal dementia, and 3 had small vessel disease. Good majority of these patients have infective and immune-mediated causes and less number belong to degenerative group. Therefore, caution is needed to look for treatable cause as it carries a different treatment options and outcome. ",0
6153,28936139,Does active ageing contribute to life satisfaction for older people? Testing a new model of active ageing,"Several debates have emerged across the literature about the conceptualisation of active ageing. The aim of this study is to develop a model of the construct that is focused on the individual, including different elements of people's lives that have the potential to be modified by intervention programs. Moreover, the paper examines the contributions of active ageing to life satisfaction, as well as the possible predictive role of coping styles on active ageing. For this purpose, a representative sample of 404 Galician (Spain) community-dwelling older adults (aged ≥60 years) were interviewed using a structured survey. The results demonstrate that the proposed model composed of two broad categories is valid. The model comprises status variables (related to physical, psychological, and social health) as well as different types of activities, called processual variables. This model is tested using partial least squares (PLS) regression. The findings show that active ageing is a fourth-order, formative construct. In addition, PLS analyses indicate that active ageing has a moderate and positive path on life satisfaction and that coping styles may predict active ageing. The discussion highlights the potential of active ageing as a relevant concept for people's lives, drawing out policy implications and suggestions for further research. ",0
6154,28936152,"Prevalence and severity of dental caries among public school students aged 16-l8 in Hai'l, Kingdom of Saudi Arabia","The objective of the study was to determine the prevalence and severity of dental caries among school students aged 16-18 in Ha'il urban city, Kingdom of Saudi Arabia (KSA). This cross-sectional study randomly selected 480 students from eight secondary schools in Ha'il urban city from September to October 2015. Three calibrated examiners used the decayed, missing and filled teeth index (DMFT), based on the World Health Organization criteria, to examine the students. Data analyses were subsequently performed. The overall prevalence of dental caries in secondary school students in Ha'il city was 78.9% ( The results of this study provide evidence of a high prevalence of caries in students aged 16-18 years in Ha'il city, KSA. Thus, the oral health of adolescents should receive more consideration in Saudi Arabia. ",0
6155,28936374,Helical Tomotherapy for Postmastectomy Radiotherapy after Immediate Left Breast Reconstruction: A Case Study,"A 43-year-old premenopausal female presented with a multicentric infiltrating lobular carcinoma of the left breast with axillary nodes metastasis. She underwent modified radical mastectomy with axillary lymph node dissection (level I and II) followed by a mixed autologous latissimus dorsi flap reconstruction with the addition of prosthesis. The final pathological analysis revealed a 6 cm invasive lobular carcinoma pT3N2aM0, grade III/III, estrogen and progesterone positive, human epidermal growth factor receptor 2 (HER2) negative, with 5/16 positive lymph nodes. She received neoadjuvant chemotherapy with doxorubicin and cyclophosphamide followed by paclitaxel. Post-mastectomy radiotherapy with axillary, supraclavicular and internal mammary lymph nodes (IMLN) irradiation was delivered to a dose of 50 Gy/25 fx. In this case with multiple risk factors for radiation-induced cardiac toxicity (left-sided lesion, internal mammary lymph nodes (IMLN) irradiation), we discuss the role of helical tomotherapy as a treatment alternative to conventional tangential radiotherapy. ",0
6156,28936694,Evaluating the effectiveness of physician counseling to promote physical activity in Mexico: an effectiveness-implementation hybrid study,"Integrating physical activity (PA) counseling in routine clinical practice remains a challenge. The purpose of this study was to evaluate the implementation and effectiveness of a pragmatic strategy aimed to improve physician PA counseling and patient PA. An effectiveness-implementation type-2 hybrid design was used to evaluate a 3-h training (i.e., implementation strategy-IS) to increase physician use of the 5-As (assess, advise, agree, assist, arrange) for PA counseling (i.e., clinical intervention-CI) and to determine if the CI improved patient PA. Patients of trained and untrained physicians reported on PA and quality of life pre-post intervention. Medical charts (N = 1700) were examined to assess the proportion of trained physicians that used the 5-As. The RE-AIM framework informed our evaluation. 305/322 of eligible physicians participated in the IS (M age = 40 years, 52% women) and 683/730 of eligible patients in the CI (M age = 49 years, 77% women). The IS was adopted by all state regions and cost ~ $20 Mexican pesos (US$1) per provider trained. Physician adoption of any of the 5-As improved from pre- to post-training (43 vs. 52%, p < .01), with significant increases in the use of assessment (43 vs. 52%), advising (25 vs. 39%), and assisting with barrier resolution (7 vs. 15%), but not in collaborative goal setting (13 vs. 17%) or arranging for follow-up (1 vs. 1%). Patient PA and quality of life did not improve. The IS intervention was delivered with high fidelity at a low cost, but appears to be insufficient to lead to broad adoption of the CI. ",0
6157,28936737,Peripartum Cardiomyopathy: Do Exosomes Play a Role?,"Peripartum cardiomyopathy (PPCM) refers to irreversible cardiomyocyte damage that occurs during the last month of pregnancy, or within 5 months after giving birth. It is characterized by systolic heart failure. This life-threatening condition is relatively uncommon, but the incidence has been climbing up. Because of its high mortality, it is crucial for physicians to have high suspicious for the disease. Studies have been done to search into specific lab test and treatment for PPCM. Therapies like anti-viral, anti-inflammatory and immunosuppression regimen have been explored. New regimen like exosomes has also been explored and revealed promising effects. ",0
6158,28936819,"The Scope, Quality and Safety Requirements of Drug Abuse Testing]","The aim of this review is to inform about the scopes and requirements of drug abuse testing. Drug abuse testing is one of the tools for determination of drug use. It must fulfill the quality and safety requirements in judgmental legal and administrative decisions. Drug abuse testing must fulfill some requirements like selection of the appropriate test matrix, appropriate screening test panel, sampling in detection window, patient consent, identification of the donor, appropriate collection site, sample collection with observation, identification and control of the sample, specimen custody chain in preanalytical phase; analysis in authorized laboratories, specimen validity tests, reliable testing METHODS, strict quality control, two-step analysis in analytical phase; storage of the split specimen, confirmation of the split specimen in the objection, result custody chain, appropriate cut-off concentration, the appropriate interpretation of the result in postanalytical phase. The workflow and analytical processes of drug abuse testing are explained in last regulation of the Department of Medical Laboratory Services, Ministry of Health in Turkey. The clinical physicians have to know and apply the quality and safety requirements in drug abuse testing according to last regulations in Turkey. ",0
6159,28936827,Core elements of safety monitoring report of medicines(Chinese patent medicines)],"Studies on post-marketing drug surveillance have become increasingly important in recent years. In particular, many researchers for traditional Chinese medicine have paid more attention to the safety of post-marketing Chinese patent medicines. Observational studies, like cohort study, registry study, and intensive hospital monitoring, were conducted to collect data on safety information. How to accurately report and assess these studies and let readers to completely understand relevant published reports and obtain transparent information about its methodology and findings remain unsolved. According to the reporting guidelines made by EQUATOR, our research team drafted a framework based on a four-year study by reference to relevant rules, guidelines and standards all over the world in the field of drug safety evaluation. Besides, we consulted relevant experts in this field and formed a framework on how to report post-marketing safety studies of Chinese patent medicines. There were seven core components, namely drug, population, setting, design, quality, adverse reaction and statistics, which could be abbreviated to DPSDQAS. We introduced the framework here to provide reference for future researchers. ",0
6160,28936923,"EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features","Colorectal cancer is a multistep process affecting several signaling pathways including EGFR (epidermal growth factor receptor), a therapeutic target for metastatic disease. Our aim was to characterize the mutational and expression profiles of the EGFR pathway in colorectal tumors and to integrate these results according to five previously defined groups. We screened seven genes for mutations ( KRAS-BRAF-PIK3CA-PIK3R1-AKT1-MAP2K1-PTEN) and six proteins (EGFR-p110α-p85α-PTEN-phosphoAKT-phosphoMEK1) by immunohistochemistry, PTEN deletion, and MSI. At least one mutated gene was observed in 68% of tumors ( KRAS 45%, PIK3CA 21%, BRAF 14%, and PTEN 7%). PTEN deletion was observed in 10.7% of tumors and 19.6% were MSI-High. In all, 54% of tumors showed a high EGFR expression, 48% p110α, 4.4% phosphoAKT, and 22% phosphoMEK1; and 43% showed low PTEN expression and 22% p85α. In total, five groups of tumors were defined based on MSI, BRAF, and KRAS mutations. Three groups gather mainly early-stage tumors, whereas a fourth group is mostly conformed by advanced tumors. We described here that 71.4% of tumors from one group have a mutated PI3K/PTEN pathway, in comparison to other groups having 32%, 27%, and 25%. In addition, the five groups are differentiated by molecular features such as EGFR, p85α, p110α, and PTEN, showing variable expression among tumor groups. In conclusion, alterations on the EGFR pathway were found in a high percentage of colorectal cancer patients. Using the integration of diverse molecular markers, we ratified previous classification in an ethnic group having relevant genetic differences and living in a different environmental background, adding complementary molecular targets related to therapy. ",0
6161,28937528,LONG-TERM FOLLOW-UP OF PATIENTS WITH CHOROIDEREMIA WITH SCLERAL PITS AND TUNNELS AS A NOVEL OBSERVATION,"To evaluate the long-term clinical course and visual outcome of patients with choroideremia. Clinical examination, a social questionnaire, and medical records review of 21 patients with choroideremia from 14 families. The mean follow-up time was 25.2 years (SD: 13.3; range 2-57 years). The mean age at symptom onset was 15.1 years (SD: 10.1; range 5-40 years). Best-corrected visual acuity was stable until the age of 35 (P = 0.96), but declined significantly faster after the age of 35 (11%/year, P = 0.001), with a high variability between individual patients. The mean age at which patients discontinued working was 48.1 years (SD: 11.7, range 25-65 years). The reason for work discontinuation was vision related in 60% of cases. Most patients (70%) reported visual field constriction as the most debilitating symptom. The authors report scleral pits and tunnels as a novel finding visible on spectral domain optical coherence tomography and ophthalmoscopy. Choroideremia is a severely debilitating disease showing a rapid decline of visual acuity generally after the age of 35, but a more gradual decline for other abnormalities. ",0
6162,28937620,Dysbindin-1 Involvement in the Etiology of Schizophrenia,"Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world's population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia.  ",0
6163,28937780,Isolated infectious endocarditis of the pulmonary valve: a case report],"Isolated infectious endocarditis of the pulmonary valve is a rare condition and represents 1,5-2% of all cases of infectious endocarditis. We present a case of a 37year-old woman without any relevant medical history. The woman was hospitalized with hallmarks of severe sepsis and bilateral pneumonia; she died several hours after admission with progressive multiorgan failure and disseminated intravascular coagulopathy. Microbiologic examination approved Staphylococcus aureus as the etiological agent. The autopsy showed isolated endocarditis of the pulmonary valve, without any known predisposing factor. Literary data refer single cases or small groups of patients with isolated pulmonary infectious endocarditis. The clinical suspicion of this rare disease in differential diagnosis of febrile conditions is an essential factor in prognosis of afflicted persons. The crucial diagnostic methods for infectious endocarditis are echocardiography and CT examination. ",0
6164,28937801,Clinical Implications of Hand Position and Lower Limb Length Measurement Method on Y-Balance Test Scores and Interpretations,"  The Lower Quarter Y-Balance Test (LQ-YBT) was developed to provide an effective and efficient screen for injury risk in sports. Earlier protocol recommendations for the LQ-YBT involved the athlete placing the hands on the hips and the clinician normalizing scores to lower limb length measured from the anterior-superior iliac spine to the lateral malleolus. The updated LQ-YBT protocol recommends the athlete's hands be free moving and the clinician measure lower limb length to the medial malleolus.   To investigate the effect of hand position and lower limb length measurement method on LQ-YBT scores and their interpretation.   Cross-sectional study.   National Sports Institute of Malaysia.   A total of 46 volunteers, consisting of 23 men (age = 25.7 ± 4.6 years, height = 1.70 ± 0.05 m, mass = 69.3 ± 9.2 kg) and 23 women (age = 23.5 ± 2.5 years, height = 1.59 ± 0.07 m, mass = 55.7 ± 10.6 kg).   Participants performed the LQ-YBT with hands on hips and hands free to move on both lower limbs.   In a single-legged stance, participants reached with the contralateral limb in each of the anterior, posteromedial, and posterolateral directions 3 times. Maximal reach distances in each direction were normalized to lower limb length measured from the anterior-superior iliac spine to the lateral and medial malleoli. Composite scores (average of the 3 normalized reach distances) and anterior-reach differences (in raw units) were extracted and used to identify participants at risk for injury (ie, anterior-reach difference ≥4 cm or composite score ≤94%). Data were analyzed using paired t tests, Fisher exact tests, and magnitude-based inferences (effect size [ES], ±90% confidence limits [CLs]).   Differences between hand positions in normalized anterior-reach distances were trivial (t   Hand position exerted nontrivial effects on LQ-YBT outcomes and interpretation, whereas the lower limb length measurement method had trivial effects. ",0
6165,28937985,Interference with plastome gene expression and Clp protease activity in Arabidopsis triggers a chloroplast unfolded protein response to restore protein homeostasis,"Disruption of protein homeostasis in chloroplasts impairs the correct functioning of essential metabolic pathways, including the methylerythritol 4-phosphate (MEP) pathway for the production of plastidial isoprenoids involved in photosynthesis and growth. We previously found that misfolded and aggregated forms of the first enzyme of the MEP pathway are degraded by the Clp protease with the involvement of Hsp70 and Hsp100/ClpC1 chaperones in Arabidopsis thaliana. By contrast, the combined unfolding and disaggregating actions of Hsp70 and Hsp100/ClpB3 chaperones allow solubilization and hence reactivation of the enzyme. The repair pathway is promoted when the levels of ClpB3 proteins increase upon reduction of Clp protease activity in mutants or wild-type plants treated with the chloroplast protein synthesis inhibitor lincomycin (LIN). Here we show that LIN treatment rapidly increases the levels of aggregated proteins in the chloroplast, unleashing a specific retrograde signaling pathway that up-regulates expression of ClpB3 and other nuclear genes encoding plastidial chaperones. As a consequence, folding capacity is increased to restore protein homeostasis. This sort of chloroplast unfolded protein response (cpUPR) mechanism appears to be mediated by the heat shock transcription factor HsfA2. Expression of HsfA2 and cpUPR-related target genes is independent of GUN1, a central integrator of retrograde signaling pathways. However, double mutants defective in both GUN1 and plastome gene expression (or Clp protease activity) are seedling lethal, confirming that the GUN1 protein is essential for protein homeostasis in chloroplasts. ",0
6166,28937999,Structures of foot and mouth disease virus pentamers: Insight into capsid dissociation and unexpected pentamer reassociation,"Foot-and-mouth disease virus (FMDV) belongs to the Aphthovirus genus of the Picornaviridae, a family of small, icosahedral, non-enveloped, single-stranded RNA viruses. It is a highly infectious pathogen and is one of the biggest hindrances to the international trade of animals and animal products. FMDV capsids (which are unstable below pH6.5) release their genome into the host cell from an acidic compartment, such as that of an endosome, and in the process dissociate into pentamers. Whilst other members of the family (enteroviruses) have been visualized to form an expanded intermediate capsid with holes from which inner capsid proteins (VP4), N-termini (VP1) and RNA can be released, there has been no visualization of any such state for an aphthovirus, instead the capsid appears to simply dissociate into pentamers. Here we present the 8-Å resolution structure of isolated dissociated pentamers of FMDV, lacking VP4. We also found these pentamers to re-associate into a rigid, icosahedrally symmetric assembly, which enabled their structure to be solved at higher resolution (5.2 Å). In this assembly, the pentamers unexpectedly associate 'inside out', but still with their exposed hydrophobic edges buried. Stabilizing interactions occur between the HI loop of VP2 and its symmetry related partners at the icosahedral 3-fold axes, and between the BC and EF loops of VP3 with the VP2 βB-strand and the CD loop at the 2-fold axes. A relatively extensive but subtle structural rearrangement towards the periphery of the dissociated pentamer compared to that in the mature virus provides insight into the mechanism of dissociation of FMDV and the marked difference in antigenicity. ",0
6167,28938011,A novel hazard assessment method for biomass gasification stations based on extended set pair analysis,"Biomass gasification stations are facing many hazard factors, therefore, it is necessary to make hazard assessment for them. In this study, a novel hazard assessment method called extended set pair analysis (ESPA) is proposed based on set pair analysis (SPA). However, the calculation of the connection degree (CD) requires the classification of hazard grades and their corresponding thresholds using SPA for the hazard assessment. In regard to the hazard assessment using ESPA, a novel calculation algorithm of the CD is worked out when hazard grades and their corresponding thresholds are unknown. Then the CD can be converted into Euclidean distance (ED) by a simple and concise calculation, and the hazard of each sample will be ranked based on the value of ED. In this paper, six biomass gasification stations are introduced to make hazard assessment using ESPA and general set pair analysis (GSPA), respectively. By the comparison of hazard assessment results obtained from ESPA and GSPA, the availability and validity of ESPA can be proved in the hazard assessment for biomass gasification stations. Meanwhile, the reasonability of ESPA is also justified by the sensitivity analysis of hazard assessment results obtained by ESPA and GSPA. ",0
6168,28938074,Native Electron Capture Dissociation Maps to Iron-Binding Channels in Horse Spleen Ferritin,"Native electron capture dissociation (NECD) is a process during which proteins undergo fragmentation similar to that from radical dissociation methods, but without the addition of exogenous electrons. However, after three initial reports of NECD from the cytochrome c dimer complex, no further evidence of the effect has been published. Here, we report NECD behavior from horse spleen ferritin, a ∼490 kDa protein complex ∼20-fold larger than the previously studied cytochrome c dimer. Application of front-end infrared excitation (FIRE) in conjunction with low- and high-m/z quadrupole isolation and collisionally activated dissociation (CAD) provides new insights into the NECD mechanism. Additionally, activation of the intact complex in either the electrospray droplet or the gas phase produced c-type fragment ions. Similar to the previously reported results on cytochrome c, these fragment ions form near residues known to interact with iron atoms in solution. By mapping the location of backbone cleavages associated with c-type ions onto the crystal structure, we are able to characterize two distinct iron binding channels that facilitate iron ion transport into the core of the complex. The resulting pathways are in good agreement with previously reported results for iron binding sites in mammalian ferritin. ",0
6169,28938127,Stomach perforation post cardiopulmonary resuscitation-A case report,Stomach perforation after cardiopulmonary resuscitation is a rare finding. This is mainly caused by incorrect management of the airway during CPR performed by non-medical personnel. We report a case of 72year old female who sustained a stomach perforation during prolonged CPR in an out of hospital arrest situation. This was diagnosed on a computed tomography scan of the abdomen requiring midline laparotomy and a primary repair of the stomach. The training of medical and non-medical persons in cardiopulmonary resuscitation is to be encouraged. However it should be emphasized that any technique which breaches the normal integrity of the body can itself lead to life-threatening complications. A high degree of vigilance is required in patients presenting after a cardiac arrest and CPR. ,0
6170,28938238,Impact of diabetes mellitus on 5-year clinical outcomes in patients with chronic total occlusion lesions,"Diabetes mellitus (DM) is a major predictor of cardiovascular morbidity and mortality. However, there are limited data on the impact of DM in patients who have chronic total occlusion (CTO) lesion on long-term outcomes. A total of 822 CTO patients who underwent coronary angiography, treated by either percutaneous coronary intervention or optimal medical therapy, were enrolled and divided into two groups: (i) diabetic group (n=363) and (ii) nondiabetic group (n=459). Individual and composite major clinical outcomes were compared up to 5 years. Propensity score matching analysis was carried out generating two groups (298 pairs, n=596, C-statistic=0.655) with balanced baseline characteristics. Up to 5 years, the DM group showed a higher trend toward revascularization (19.5 vs. 13.5%, P=0.051) and major adverse cardiovascular events (MACE) (24.7 vs. 19.1%, P=0.097) compared with the nondiabetic group. However, there was no difference in the incidence of death and myocardial infarction between the two groups. Subgroup analysis showed that the chronic kidney disease (CKD) subgroup was associated with a higher incidence of all-cause death, cardiac death, myocardial infarction, revascularization, and MACE in comparison with diabetic patients without CKD and nondiabetic patients, respectively (total MACE: 39 vs. 20.5 vs. 19.2% , P=0.001). Insulin-dependent diabetic patients had a significantly higher incidence of MACE (hazard ratio=1.58; 95% confidence interval: 1.04-2.40; P=0.03) compared with the nondiabetic patients. Diabetic patients with CTO were associated with a trend toward a higher incidence of revascularization and total MACE up to 5 years. Insulin-dependent and diabetic patients with CKD subgroups had a significantly higher incidence of total MACE. ",0
6171,28938300,Enhancing the quality and safety of the perioperative patient,"Many possible hazards bedevil the perioperative patient. This review focuses on a number of aspects of perioperative management where the patient's quality and safety can be enhanced. Our understanding of the relationship between preoperative preparation and postoperative outcomes has improved. There have also been recent developments in our understanding of how to construct useful cognitive aids and make the best use of checklists by understanding the cultural environment supporting their use. Postoperatively, the concept of 'failure to rescue' in the surgical patients has been explored. A clear vision of what postoperative recovery should mean for practitioner and patients; careful risk stratification and prophylactic measures to avoid postoperative complications; the judicious use of checklists and other cognitive aids to complement clinical expertise in promoting safety within each local context; and the prompt recognition and rescue of postoperative problems when they occur are all important aspects of a safe perioperative care. ",0
6172,28938551,Overexpression of ubiquitin specific proteases 44 promotes the malignancy of glioma by stabilizing tumor-promoter securin,"Ubiquitin specific peptidase 44 (USP44) has been identified as an important component of spindle assemble checkpoint (SAC) to prevent the formation of aneuploidy. However, recent study raised a controversy about the effect of USP44 in tumor. Here, we first confirmed the intranuclear localization of USP44 by testing several specific antibodies to recognize endogenous USP44. Then, data from IHC and qRT-PCR assay indicated that the high expression of USP44 existed in high-grade glioma tissues and signified a poor prognosis. Knockdown of USP44 inhibited proliferation, migration and invasion, induced apoptosis, and arrested cell cycle in G2/M phase in the established glioma cell lines. Down-regulation of oncoprotein securin was detected in USP44 deficient cells, and the interaction of endogenous USP44 and securin was confirmed by immunoprecipitation in U251MG cells, which indicated that securin was a substrate of USP44, and might be stabilized by USP44.  ",0
6173,28938619,Anti-cancer efficacy of biotinylated chitosan nanoparticles in liver cancer,The present study investigated the synthesis of biotinylated chitosan (Bio-CS) from chitosan using a nanomaterial skeleton with biotin and the successful targeting of the formulation in liver cancer cells. Bio-CS was validated by fourier transformed infrared spectroscopy and hydrogen ,0
6174,28938652,Correlation between apparent diffusion coefficient (ADC) and cellularity is different in several tumors: a meta-analysis,"The purpose of this meta-analysis was to provide clinical evidence regarding relationship between ADC and cellularity in different tumors based on large patient data. Medline library was screened for associations between ADC and cell count in different tumors up to September 2016. Only publications in English were extracted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) was used for the research. Overall, 39 publications with 1530 patients were included into the analysis. The following data were extracted from the literature: authors, year of publication, number of patients, tumor type, and correlation coefficients. The pooled correlation coefficient for all studies was ρ = -0.56 (95 % CI = [-0.62; -0.50]),. Correlation coefficients ranged from  ",0
6175,28938773,Characteristics of global organic matrix in normal and pimpled chicken eggshells,"The organic matrix from normal and pimpled calcified chicken eggshells were dissociated into acid-insoluble, water-insoluble, and facultative-soluble (both acid- and water-soluble) components, to understand the influence of shell matrix on eggshell qualities. A linear correlation was shown among these 3 matrix components in normal eggshells but was not observed in pimpled eggshells. In pimpled eggshells, the percentage contents of all 4 groups of matrix (the total matrix, acid-insoluble matrix, water-insoluble matrix, and facultative-soluble matrix) were significantly higher than that in normal eggshells. The amounts of both total matrix and acid-insoluble matrix in individual pimpled calcified shells were high, even though their weight was much lower than a normal eggshell. In both normal and pimpled eggshells, the calcified eggshell weight and shell thickness significantly and positively correlated with the amounts of all 4 groups of matrix in an individual calcified shell. In normal eggshells, the calcified shell thickness and shell breaking strength showed no significant correlations with the percentage contents of all 4 groups of matrix. In normal eggshells, only the shell membrane weight significantly correlated with the constituent ratios of both acid-insoluble matrix and facultative-soluble matrix in the whole matrix. In pimpled eggshells, 3 variables (calcified shell weight, shell thickness, and breaking strength) were significantly correlated with the constituent proportions of both acid-insoluble matrix and facultative-matrix. This study suggests that mechanical properties of normal eggshells may not linearly depend on the organic matrix content in the calcified eggshells and that pimpled eggshells might result by the disequilibrium enrichment of some proteins with negative effects. ",0
6176,28938843,Comparison of specific IgE detection by immunoblotting and fluorescence enzyme assay with in vivo skin prick test,"Diagnostic tools to identify allergens that cause allergic symptom is important part in the care of allergic patients. Detection of causative allergen can be performed by in vivo skin prick test (SPT) or in vitro tests for detection serum specific immunoglobulin E (sIgE). The common methods used are fluorescent enzyme assay and immunoblotting assay. We aim to evaluate performance of the two sIgE determination systems, immunoblotting assay (Euroline) and fluorescent enzyme assay (ImmunoCAP) in comparison with SPT. Two hundred and two participants with allergic diseases were enrolled. Sensitization to common allergens was identified using skin prick test and serum specific IgE assays with Euroline and ImmunoCAP. Both systems provide the result in the same unit and the same cut-off value (0.35 kUA/L). The specific IgE levels of 4 aeroallergens, 6 food allergens and 3 food allergen components were analyzed to evaluate the performance of both sIgE assays with SPT. When compared with the result of SPT, ImmunoCAP has 63.9-93.2% agreement and Euroline has 68.4-86.2% agreement for allergen detection. Both sIgE assays have significant correlation in measuring sIgE of almost all allergens (r=0.626-0.901, p< 0.001) except for dog. For food allergen components, both sIgE tests have outstanding correlation and agreement (r=0.816-0.952, p< 0.001; agreement =87.0-92.9%, respectively). The receiver-operating characteristic curve analysis indicated slight discrepancy of both sIgE assays. Both sIgE determination systems demonstrate fair to good performance when compared to SPT depending on type of allergens. The two sIgE determination systems had favorable correlation and agreement. ",0
6177,28938865,"Binding of ibuprofen to human hemoglobin: elucidation of their molecular recognition by spectroscopy, calorimetry, and molecular modeling techniques","Ibuprofen, used for the treatment of acute and chronic pain, osteoarthritis, rheumatoid arthritis, and related conditions has ample affinity to globular proteins. Here we have explored this fundamental study pertaining to the interaction of ibuprofen with human hemoglobin (HHb), using multispectroscopic, calorimetric, and molecular modeling techniques to gain insights into molecular aspects of binding mechanism. Ibuprofen-induced graded decrease in absorption spectra indicates protein disruption along with sedimentation of HHb particle. Red shifting of absorption peak at 195 nm indicates alteration in the secondary structure of HHb upon interaction with ibuprofen. Flouremetric and isothermal titration calorimetric (ITC) studies suggested one binding site in HHb for ibuprofen at 298.15 K. However, with increase in temperature, ITC revealed increasing number of binding sites. The negative values of Gibbs energy change (ΔG ",0
6178,28939063,Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma,"To evaluate long-term results of a phase II study of induction and adjuvant gemcitabine and cisplatin (GP) chemotherapy with intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). One hundred and twelve patients (Stage III: 65, IVA-B: 47) with locoregionally advanced NPC were enrolled in this study. All patients received induction chemotherapy consisting of 1000 mg/m2 gemcitabine on day 1 and 8, and cisplatin 25 mg/m2 on day 1–3, every 3 weeks for 2 cycles. Adjuvant chemotherapy for 2 cycles of the same regime was given 28 days after the end of IMRT. The IMRT technique was utilized for all patients. In total, 97.3% patients completed 2 cycles of induction chemotherapy. The overall response rate (RR) of cervical lymph nodes was 89.0%. Acute toxicities were mainly grade 1–2 myleosuppression and vomiting. And 83.9% patients completed 2 cycles of adjuvant chemotherapy. All patients finished IMRT with RR at the end of IMRT for nasopharynx, lymph nodes of neck and retropharyngeal area being 99.1%, 97.9% and 97.7%, respectively. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 93.2%, 92.3%, 89.0% and 82.1%, respectively. The 5-year overall survival of stage III and IVA-B were 87.0%, and 75.5%, respectively. The incidence of grade 3–4 acute radiotherapy-related mucositis was 28.6%. Severe late toxicities were uncommon. IMRT combined with GP for locoregionally advanced NPC is well tolerated, effective, and convenient, and warrants further studies. ",0
6179,28939180,What is the optimal number of library plans in ART for locally advanced cervical cancer?,"Library-of-plans ART is used to manage daily anatomy changes in locally advanced cervical cancer. In our institute, the library contains 2 VMAT plans for patients with large cervix-uterus motion. Increasing this number could be beneficial for tissue sparing, but is burdensome while the dosimetric gain is yet unclear. This study's aim is to determine the optimal number of plans at an individual patient level. Data of 14 treated patients were analyzed. Plan libraries were created containing 1-4 VMAT plans. Pre-treatment extent of uterus motion was defined by the 99th percentile of the Hausdorff distance (HD99). For dosimetric evaluations, OARs were contoured in daily CBCT scans, plan selection was simulated, and the V Moderate to strong correlations were found between HD99 and the volume of spared OARs. All patients benefitted from adding a 2nd plan, as is the clinical practice. For patients with a HD99 between 30 and 50mm, a 3-plan library reduced the composite V Patients with large uterus motion (HD99>30mm) would benefit from an extension of the plan library to 3. HD99 is an easy-to-implement criteria to select those patients pre-treatment. ",0
6180,28939735,The Elusive Standard of Care,"In medical negligence cases, the forensic expert must explain to a trier of fact what a defendant physician should have done, or not done, in a specific set of circumstances and whether the physician's conduct constitutes a breach of duty. The parameters of the duty are delineated by the standard of care. Many facets of the standard of care have been well explored in the literature, but gaps remain in a complete understanding of this concept. We examine the standard of care, its origins, and who determines the prevailing standard, beginning with an overview of the historical roots of the standard of care and, using case law, tracing its evolution from the 19th century through the early 21st century. We then analyze the locality rule and consider local, state, and national standards of care. The locality rule requires a defendant physician to provide the same degree of skill and care that is required of a physician practicing in the same or similar community. This rule remains alive in some jurisdictions in the United States. Last, we address the relationship between the standard of care and clinical practice guidelines. ",0
6181,28940000,Fabrication of novel surface-imprinted magnetic graphene oxide-grafted cellulose nanocrystals for selective extraction and fast adsorption of fluoroquinolones from water,"A novel adsorbent based on the surface of magnetic graphene oxide-grafted cellulose nanocrystal molecularly imprinted polymers (Mag@GO-g-CNCs@MIPs) was developed for the selective extraction and fast adsorption of fluoroquinolones (FQs) from river water samples. Cellulose nanocrystals (CNCs) were grafted onto activated graphene oxide (GO), and the surfaces of the obtained magnetic GO-g-CNC particles were molecularly imprinted with polymers using ofloxacin (OFX) as a template molecule and methacrylic acid (MAA) as a functional monomer. The resulting Mag@GO-g-CNCs@MIP material was characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, vibrating sample magnetometry, and X-ray photoelectron spectroscopy. Under optimum adsorption conditions, the Mag@GO-g-CNCs@MIPs with large specific surface area were easily collected and separated using an external magnetic field. Mag@GO-g-CNCs@MIPs exhibited an ultra-fast adsorption profile for FQs (5 min to achieve the maximum adsorption capacity of 74 mg/g), with imprinting factor values ranging from 1.5 to 3.1. High recognition selectivity towards nine FQs from real river water samples was established through coupling with high-performance liquid chromatography (HPLC), and the recovery of samples spiked with nine FQs was found to be in the range of 79.2-96.1%, with a detection limit ranging from 6.5 to 51 ng/g. Moreover, the data obtained adhered to the Freundlich isotherm model, and the adsorption kinetics followed a pseudo-second-order model. Finally, the Mag@GO-g-CNCs@MIPs could be regenerated and reused for seven consecutive cycles with only a 13% drop in adsorption capacity, indicating its effective application as a new, reusable, and selective adsorbent for the enrichment and separation of FQs from aqueous solutions. ",0
6182,28940260,Authentication of M14 melanoma cell line proves misidentification of MDA-MB-435 breast cancer cell line,"A variety of analytical approaches have indicated that melanoma cell line UCLA-SO-M14 (M14) and breast carcinoma cell line MDA-MB-435 originate from a common donor. This indicates that at some point in the past, one of these cell lines became misidentified, meaning that it ceased to correspond to the reported donor and instead became falsely identified (through cross-contamination or other means) as a cell line from a different donor. Initial studies concluded that MDA-MB-435 was the misidentified cell line and M14 was the authentic cell line, although contradictory evidence has been published, resulting in further confusion. To address this question, we obtained early samples of the melanoma cell line (M14), a lymphoblastoid cell line from the same donor (ML14), and donor serum preserved at the originator's institution. M14 samples were cryopreserved in December 1975, before MDA-MB-435 cells were established in culture. Through a series of molecular characterizations, including short tandem repeat (STR) profiling and cytogenetic analysis, we demonstrated that later samples of M14 and MDA-MB-435 correspond to samples of M14 frozen in 1975, to the lymphoblastoid cell line ML14, and to the melanoma donor's STR profile, sex and blood type. This work demonstrates conclusively that M14 is the authentic cell line and MDA-MB-435 is misidentified. With clear provenance information and authentication testing of early samples, it is possible to resolve debates regarding the origins of problematic cell lines that are widely used in cancer research. ",0
6183,28940377,G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35,"It is widely appreciated that G protein-coupled receptors have been the most successfully exploited class of targets for the development of small molecule medicines. Despite this, to date, less than 15% of the non-olfactory G protein-coupled receptors in the human genome are the targets of a clinically used medicine. In many cases, this is likely to reflect a lack of understanding of the basic underpinning biology of many G protein-coupled receptors that are not currently in the spotlight, as well as a paucity of pharmacological tool compounds and appropriate animal models to test in vivo function of such G protein-coupled receptors in both normal physiology and in the context of disease. 'Open Innovation' arrangements, in which pharmaceutical companies and public-private partnerships provide wider access to tool compounds identified from ligand screening programmes, alongside enhanced medicinal chemistry support to convert such screening 'hits' into useful 'tool' compounds will provide important routes to improved understanding. However, in parallel, novel approaches to define and fully appreciate the selectivity and mode of action of such tool compounds, as well as better understanding of potential species orthologue variability in the pharmacology and/or signalling profile of a wide range of currently poorly understood and understudied G protein-coupled receptors, will be vital to fully exploit the therapeutic potential of this large target class. I consider these themes using as exemplars two G protein-coupled receptors, free fatty acid receptor 2 and GPR35. ",0
6184,28940423,The Patient Protection and Affordable Care Act dependent coverage expansion: Disparities in impact among young adult oncology patients,"Private health insurance is associated with improved outcomes in patients with cancer. However, to the authors' knowledge, little is known regarding the impact of the Patient Protection and Affordable Care Act Dependent Coverage Expansion (ACA-DCE), which extended private insurance to young adults (to age 26 years) beginning in 2010, on the insurance status of young adults with cancer. The current study was a retrospective, population-based analysis of hospitalized young adult oncology patients (aged 22-30 years) in California during 2006 through 2014 (11,062 patients). Multivariable regression analyses examined factors associated with having private insurance. Results were presented as adjusted odds ratios and 95% confidence intervals. A difference-in-difference analysis examined the influence of the ACA-DCE on insurance coverage by race/ethnicity and federal poverty level. Multivariable regression demonstrated that patients of black and Hispanic race/ethnicity were less likely to have private insurance before and after the ACA-DCE, compared with white patients. Younger age (22-25 years) was associated with having private insurance after implementation of the ACA-DCE (odds ratio, 1.20; 95% confidence interval, 1.06-1.35). In the difference-in-difference analysis, private insurance increased among white patients aged 22 to 25 years who were living in medium-income (2006-2009: 64.6% vs 2011-2014: 69.1%; P = .003) and high-income (80.4% vs 82%; P = .043) zip codes and among Asians aged 22 to 25 years living in high-income zip codes (73.2 vs 85.7%; P = .022). Private insurance decreased for all Hispanic patients aged 22 to 25 years between the 2 time periods. The ACA-DCE provision increased insurance coverage, but not among all patients. Private insurance increased for white and Asian patients in higher income neighborhoods, potentially widening social disparities in private insurance coverage among young adults with cancer. Cancer 2018;124:110-7. © 2017 American Cancer Society. ",0
6185,28940525,Estimation of initial phenobarbital dosing in term neonates with moderate-to-severe hypoxic ischaemic encephalopathy following perinatal asphyxia,"Phenobarbital is the first-line treatment of seizures in asphyxiated neonates; however, due to the high pharmacokinetic variability in this population, there is no consensus on the optimal dosage regimen. This study was conducted to identify variables that affect phenobarbital fate during routine clinical care and then to evaluate the dosage schedule that could be applied in term asphyxiated neonates with respect to achieving the target therapeutic range. Phenobarbital pharmacokinetics was calculated based on serum concentrations measurements using one-compartmental model. Body weight, body surface area, gestational age, creatinine clearance, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, Apgar scores, umbilical cord arterial pH and base excess were explored as covariates in linear regression models. Based on this analysis, phenobarbital loading and maintenance dose regimen were projected. In the whole study population (N = 36), phenobarbital volume of distribution, clearance and half-life median (interquartile range) values were 0.49 (0.38-0.59) L/kg, 0.0045 (0.0034-0.0055) L/h/kg and 75.1 (60.2-103.3) hours, respectively. The drug volume of distribution was associated with body weight, length and body surface area, whereas clearance was not in relationship with any explored features. Weight-normalized loading dose of 15 mg/kg and weight-normalized daily maintenance dose of 3 mg/kg proved to be optimal in our study population to reach phenobarbital therapeutic range. This study presents basis for phenobarbital initial dosing in term asphyxiated neonates during first week of life. Phenobarbital weight-normalized loading dose of 15 mg/kg lead to simulated target peak concentrations in 72% of neonates, weight-normalized maintenance dose of 3 mg/kg lead to steady state within therapeutic window in the same proportion of patients. ",0
6186,28940531,Tear film evaluation and management in soft contact lens wear: a systematic approach,"The human tear film is a highly ordered structure consisting of a thin layer of lipid on the surface and a thicker aqueous-mucin phase, which increases in mucin concentration toward the corneal epithelial cell layer. The health of the tear film and ocular surface influences the likelihood of being able to achieve successful contact lens wear. Contact lens discomfort and dryness are the most frequent reasons why contact lens wearers experience reduced wearing times, which can eventually lead to contact lens discontinuation. Comprehensive clinical assessment of tear film integrity and ocular surface health is therefore essential prior to commencing contact lens wear, to enable the ocular surface environment to be optimised to support lens wear. These parameters should also be evaluated over the course of contact lens wear, in order to identify any aspects requiring clinical management and ensure maintenance of optimal lens-wearing conditions. This review summarises current knowledge relating to the effects of soft contact lens wear on the tear film and ocular surface. It also provides a systematic approach to evaluating tear film and ocular surface integrity, in order to guide the clinical management of tear film anomalies with respect to contact lens wear. ",0
6187,28940682,Rural-urban disparity in oral health-related quality of life,"The objective of this population-based cross-sectional study was to estimate rural-urban disparity in the oral health-related quality of life (OHRQoL) of the Quebec adult population. A 2-stage sampling design was used to collect data from the 1788 parents/caregivers of schoolchildren living in the 8 regions of the province of Quebec in Canada. Andersen's behavioural model for health services utilization was used as a conceptual framework. Place of residency was defined according to the Statistics Canada Census Metropolitan Area and Census Agglomeration Influenced Zone classification. The outcome of interest was OHRQoL measured using the Oral Health Impact Profile (OHIP)-14 validated questionnaire. Data weighting was applied, and the prevalence, extent and severity of negative oral health impacts were calculated. Statistical analyses included descriptive statistics, bivariate analyses and binary logistic regression. The prevalence of poor oral health-related quality life (OHRQoL) was statistically higher in rural areas than in urban zones (P = .02). Rural residents reported a significantly higher prevalence of negative daily-life impacts in pain, psychological discomfort and social disability OHIP domains (P < .05). Additionally, the rural population showed a greater number of negative oral health impacts (P = .03). There was no significant rural-urban difference in the severity of poor oral health. Logistic regression indicated that the prevalence of poor OHRQoL was significantly related to place of residency (OR = 1.6; 95% CI = 1.1-2.5; P = .022), perceived oral health (OR = 9.4; 95% CI = 5.7-15.5; P < .001), dental treatment needs factors (perceived need for dental treatment, pain, dental care seeking) (OR = 8.7; 95% CI = 4.8-15.6; P < .001) and education (OR = 2.7; 95% CI = 1.8-3.9; P < .001). The results of this study suggest a potential difference in OHRQoL of Quebec rural and urban populations, and a need to develop strategies to promote oral health outcomes, specifically for rural residents. Further studies are needed to confirm these results. ",0
6188,28940761,The Cognitive-Evolutionary Model of Surprise: A Review of the Evidence,"Research on surprise relevant to the cognitive-evolutionary model of surprise proposed by Meyer, Reisenzein, and Schützwohl (1997) is reviewed. The majority of the assumptions of the model are found empirically supported. Surprise is evoked by unexpected (schema-discrepant) events and its intensity is determined by the degree if schema-discrepancy, whereas the novelty and the valence of the eliciting events probably do not have an independent effect. Unexpected events cause an automatic interruption of ongoing mental processes that is followed by an attentional shift and attentional binding to the events, which is often followed by causal and other event analysis processes and by schema revision. The facial expression of surprise postulated by evolutionary emotion psychologists has been found to occur rarely in surprise, for as yet unknown reasons. A physiological orienting response marked by skin conductance increase, heart rate deceleration, and pupil dilation has been observed to occur regularly in the standard version of the repetition-change paradigm of surprise induction, but the specificity of these reactions as indicators of surprise is controversial. There is indirect evidence for the assumption that the feeling of surprise consists of the direct awareness of the schema-discrepancy signal, but this feeling, or at least the self-report of surprise, is also influenced by experienced interference. In contrast, facial feedback probably does contribute substantially to the feeling of surprise and the evidence for the hypothesis that surprise is affected by the difficulty of explaining an unexpected event is, in our view, inconclusive. Regardless of how the surprise feeling is constituted, there is evidence that it has both motivational and informational effects. Finally, the prediction failure implied by unexpected events sometimes causes a negative feeling, but there is no convincing evidence that this is always the case, and we argue that even if it were so, this would not be a sufficient reason for regarding this feeling as a component, rather than as an effect of surprise. ",0
6189,28940936,Screening and support for emotional burdens of youth with type 1 diabetes: Strategies for diabetes care providers,"Multiple sources of burden for youth with type 1 diabetes (T1D) impact key outcomes including quality of life, self-management, and glycemic control. Professional diabetes organizations recommend diabetes care providers screen for psychosocial and behavioral challenges and implement strategies to support youth with T1D. The purpose of this article is to review the literature and recommend practical strategies medical providers can use for screening and behavioral support for youth with diabetes and their families. As part of their routine medical care, diabetes care providers are well-positioned to identify and intervene to address emotional distress related to the burdens of living with diabetes. In collaboration with multidisciplinary team members, including psychologists and mental health professionals, medical providers may be able to successfully implement brief behavioral strategies for screening and providing emotional support. ",0
6190,28941083,From model to crop: functional characterization of SPL8 in M. truncatula led to genetic improvement of biomass yield and abiotic stress tolerance in alfalfa,"Biomass yield, salt tolerance and drought tolerance are important targets for alfalfa (Medicago sativa L.) improvement. Medicago truncatula has been developed into a model plant for alfalfa and other legumes. By screening a Tnt1 retrotransposon-tagged M. truncatula mutant population, we identified three mutants with enhanced branching. Branch development determines shoot architecture which affects important plant functions such as light acquisition, resource use and ultimately impacts biomass production. Molecular analyses revealed that the mutations were caused by Tnt1 insertions in the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 8 (SPL8) gene. The M. truncatula spl8 mutants had increased biomass yield, while overexpression of SPL8 in M. truncatula suppressed branching and reduced biomass yield. Scanning electron microscopy (SEM) analysis showed that SPL8 inhibited branching by directly suppressing axillary bud formation. Based on the M. truncatula SPL8 sequence, alfalfa SPL8 (MsSPL8) was cloned and transgenic alfalfa plants were produced. MsSPL8 down-regulated or up-regulated alfalfa plants exhibited similar phenotypes to the M. truncatula mutants or overexpression lines, respectively. Specifically, the MsSPL8 down-regulated alfalfa plants showed up to 43% increase in biomass yield in the first harvest. The impact was even more prominent in the second harvest, with up to 86% increase in biomass production compared to the control. Furthermore, down-regulation of MsSPL8 led to enhanced salt and drought tolerance in transgenic alfalfa. Results from this research offer a valuable approach to simultaneously improve biomass production and abiotic stress tolerance in legumes. ",0
6191,28941329,Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis,"The initial management of patients with suspected acute biliary infection starts with the measurement of vital signs to assess whether or not the situation is urgent. If the case is judged to be urgent, initial medical treatment should be started immediately including respiratory/circulatory management if required, without waiting for a definitive diagnosis. The patient's medical history is then taken; an abdominal examination is performed; blood tests, urinalysis, and diagnostic imaging are carried out; and a diagnosis is made using the diagnostic criteria for cholangitis/cholecystitis. Once the diagnosis has been confirmed, initial medical treatment should be started immediately, severity should be assessed according to the severity grading criteria for acute cholangitis/cholecystitis, and the patient's general status should be evaluated. For mild acute cholangitis, in most cases initial treatment including antibiotics is sufficient, and most patients do not require biliary drainage. However, biliary drainage should be considered if a patient does not respond to initial treatment. For moderate acute cholangitis, early endoscopic or percutaneous transhepatic biliary drainage is indicated. If the underlying etiology requires treatment, this should be provided after the patient's general condition has improved; endoscopic sphincterotomy and subsequent choledocholithotomy may be performed together with biliary drainage. For severe acute cholangitis, appropriate respiratory/circulatory management is required. Biliary drainage should be performed as soon as possible after the patient's general condition has been improved by initial treatment and respiratory/circulatory management. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included. ",0
6192,28941468,Prospective evaluation of uterine receptivity in mice,"In current infertility treatments it is necessary to evaluate uterine receptivity in each menstrual cycle. During the implantation period, the uterus goes through many complex orchestrated changes, including changes to the glycocalyx. The changes to the glycocalyx are due to sialylation, sulfation and fucosylation. Can the measurement of in-vivo uterine pH and/or oxidation-reduction potential (ORP) determine the alterations of uterine endometrium for implantation and evaluate prospective uterine receptivity? In the present study we assessed in vivo uterine pH and ORP during the early stages of pregnancy in naïve mice, as well as in a murine model of implantation failure created by local and transient suppression of signal transducer and activator of transcription 3. There was no change in the in vivo uterine pH between post-coitus Days 2 and 6. In vivo uterine ORP was significantly higher compared to the day before. One day before implantation began, uterine ORP was significantly decreased in the implantation failure group compared with the naïve and control groups. Receiver operator characteristic (ROC) curve analysis of uterine ORP as a predictor of non-conception showed an area under the ROC curve of 0.96 (95% confidence interval 0.92-1.00). Thus, in vivo uterine ORP could be a parameter to prospectively evaluate uterine receptivity. ",0
6193,28941769,"A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression","A large body of evidence indicates that major affective disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum depression. This review provides a critical appraisal of available evidence linking IO&NS pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites, lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression. ",0
6194,28942278,"Effects of endosulfan, thiamethoxam, and indoxacarb in combination with atrazine on multi-biomarkers in Gammarus kischineffensis","Studies addressing the toxicity of pesticides towards non-target organisms focus on the median lethal concentration and biochemical response of individual pesticides. However, when determining environmental risks, it is important to test the combined effects of pesticides, such as insecticides and herbicides, which are frequently used together in agricultural areas. Here we aimed to investigate the toxic effects of the combined use of the herbicide atrazine and the insecticides, endosulfan, indoxacarb, and thiamethoxam on Gammarus kischineffensis. To do this, we tested the activities of oxidative stress, detoxification, and neurotoxicity biomarkers. Compared to atrazine alone, we detected higher glutathione-S-transferase, catalase and superoxide dismutase activities (oxidative stress biomarkers) when atrazine was combined with either endosulfan or indoxacarb. However, higher IBR values were determined in organisms where pesticide mixtures were used according to individual use. Based on these results, mixtures of atrazine and other pesticides may cause synergistic effects and may be evidence of increased toxicity and oxidative stress. ",0
6195,28942364,Toll-Like Receptor-Mediated Upregulation of CXCL16 in Psoriasis Orchestrates Neutrophil Activation,"Innate immune processes are central in the development of the chronic inflammatory skin disease psoriasis. Studying stimulation of keratinocytes, monocytes, and dendritic cells by type I interferons or ligation of Toll-like receptors 1/2, 2/6, or 7, but not 7/8, resulted in enhanced surface expression and secretion of CXC chemokine ligand (CXCL) 16. The corresponding CXC chemokine receptor 6 was expressed on neutrophils whose recruitment into skin is important, especially in early psoriatic disease. Using the recently developed technique real-time deformability cytometry demonstrated that CXCL16 and IL-8 decreased the stiffness and enhanced deformation of neutrophils facilitating transmigration through vessel wall. In addition, CXCL16 potently induced migration of neutrophils and enhanced the chemotactic effect of IL-8. The positive feedback loop was supported by IL-8 enhancing CXCL16 production of neutrophils. Blocking of CXCL16 expression by effective treatment of psoriasis patients with tumor necrosis factor-α blockers further supported the pathogenic role of this chemokine. In summary, the data link innate immune stimulation to CXCL16 upregulation and neutrophil infiltration into skin. CXCL16 could therefore represent a potent future target for treatment of psoriasis. ",0
6196,28942398,Disseminated herpes zoster causing acute respiratory distress syndrome in an immunocompetent patient,"Disseminated cutaneous varicella herpes zoster with visceral involvement is rare and seen almost exclusively in immunocompromised patients. We describe an unusual case of fulminant herpes zoster (HZ) in a healthy, immunocompetent 37-year-old woman. She initially presented to an urgent care centre with a classic HZ rash localised to her neck, and upper respiratory symptoms and was treated with prednisone and cephalexin. Within 1 week, the rash became diffuse and her clinical status rapidly deteriorated with development of severe acute respiratory distress syndrome. Varicella zoster infection was confirmed via skin biopsy, bronchial viral PCR and serology for varicella antibodies. She was successfully treated with intravenous acyclovir and aggressive supportive care. Though physicians readily recognise typical zoster infection, this case reminds clinicians that HZ infection can be fulminant and potentially life-threatening in younger, immunocompetent individuals. Early recognition and antiviral therapy is important to reduce morbidity and mortality. ",0
6197,28942404,Successful treatment using rituximab in a patient with refractory polymyositis complicated by scleroderma renal crisis,"Corticosteroids are the first-line treatment for patients with inflammatory myopathies. Myositis can be a clinical feature of scleroderma (polymyositis-scleroderma overlap syndrome), and treatment of this syndrome is a challenge for clinicians because moderate to high doses of corticosteroids are considered a risk factor for development of acute kidney injury in affected patients. We report here the case of a 56-year-old woman with scleroderma who developed polymyositis and was successfully treated with rituximab. Initial treatment of the polymyositis with prednisolone 40 mg/day was rapidly tapered to 2.5 mg/day due to development of scleroderma renal crisis, for which four weekly infusions of rituximab (500 mg; off-label) were given. She responded well to rituximab in addition to prednisolone 2.5 mg/day. Rituximab may improve inflammatory myopathies, even in cases where high-dose corticosteroids should be avoided due to complications. Rituximab should be considered as a treatment option in cases of refractory polymyositis. ",0
6198,28942496,Neovascularization during leafy gall formation on Arabidopsis thaliana upon Rhodococcus fascians infection,"""Extensive de novo vascularization of leafy galls emerging upon Rhodococcus fascians infection is achieved by fascicular/interfascicular cambium activity and transdifferentiation of parenchyma cells correlated with increased auxin signaling. A leafy gall consisting of fully developed yet growth-inhibited shoots, induced by the actinomycete Rhodococcus fascians, differs in structure compared to the callus-like galls induced by other bacteria. To get insight into the vascular development accompanying the emergence of the leafy gall, the anatomy of infected axillary regions of the inflorescence stem of wild-type Arabidopsis thaliana accession Col-0 plants and the auxin response in pDR5:GUS-tagged plants were followed in time. Based on our observations, three phases can be discerned during vascularization of the symptomatic tissue. First, existing fascicular cambium becomes activated and interfascicular cambium is formed giving rise to secondary vascular elements in a basipetal direction below the infection site in the main stem and in an acropetal direction in the entire side branch. Then, parenchyma cells in the region between both stems transdifferentiate acropetally towards the surface of the developing symptomatic tissue leading to the formation of xylem and vascularize the hyperplasia as they expand. Finally, parenchyma cells in the developing gall also transdifferentiate to vascular elements without any specific direction resulting in excessive vasculature disorderly distributed in the leafy gall. Prior to any apparent anatomical changes, a strong auxin response is mounted, implying that auxin is the signal that controls the vascular differentiation induced by the infection. To conclude, we propose the """"sidetracking gall hypothesis"""" as we discuss the mechanisms driving the formation of superfluous vasculature of the emerging leafy gall. """,0
6199,28942583,Maleimido-proxyl as an EPR spin label for the evaluation of conformational changes of albumin,"Albumin is the most abundant plasma protein and as such has been the subject of many studies using a variety of techniques. One of them, capable of monitoring the conformational changes and the binding capacity of proteins, is electron paramagnetic resonance spectroscopy (EPR) spin labeling. To date, albumin has been investigated using a number of different spin labels, mostly spin-labeled fatty acids (SLFAs). However, albumin can bind up to seven equivalents of fatty acids, making it difficult to determine which parts of the molecule undergo conformational changes. To obtain information from a specific site on a protein, spin labels that bind to free cysteine residues may be used. In this work, the applicability of such a label, 3-maleimido proxyl (5-MSL), was evaluated for monitoring conformational changes of bovine serum albumin (BSA) at different temperatures and pH values. Also, the effect of ethanol, reactive oxygen species (hydrogen peroxide and superoxide radical), and the binding of ligands specific for albumin, namely fatty acids, and several drugs were evaluated. The results indicate that the labeling of albumin at its free cysteine residue (Cys-34) using 5-MSL may successfully be used for the detection of conformational changes, even in the case of the subtle alterations induced by ligand binding. ",0
6200,28942612,Interactions of homocysteine and conventional predisposing factors on hypertension in Chinese adults,"This study aimed to investigate whether conventional predisposing factors modify the associations of homocysteine with blood pressure levels and hypertension. A total of 2615 adults were recruited from Liaoning province. An elevated homocysteine level was significantly associated with increased hypertension risk and blood pressure (all P<.05). Interaction analyses showed that homocysteine acted synergistically with age, overweight/obesity, dyslipidemia, and family history of hypertension to affect hypertension risk, and the relative excess risk due to interaction was 1.21 (95% confidence interval, 0.07-2.35), 0.72 (95% confidence interval, 0.07-1.36), 0.45 (95% confidence interval, 0.06-0.85), and 1.87 (95% confidence interval, 0.77-2.97), respectively. Increases in blood pressure were higher in patients who were overweight/obese or had a family history of hypertension than in their counterparts (all P ",0
6201,28942960,Periostin in Skin Tissue Skin-Related Diseases,"Extracellular matrix (ECM) is not only involved in the maintenance of normal physiological tissue but also in interactions with other ECM components, tissue remodeling, and modulating immune responses. The skin provides a distinctive environment characterized by rich fibroblasts producing various ECM proteins, epithelial-mesenchymal interactions, and immune responses induced by external stimuli. Recently, periostin-a matricellular protein-has been highlighted for its pivotal functions in the skin. Analysis of periostin null mice has revealed that periostin contributes to collagen fibrillogenesis, collagen cross-linking, and the formation of ECM meshwork via interactions with other ECM components. Periostin expression is enhanced by mechanical stress or skin injury; this is indicative of the physiologically protective functions of periostin, which promotes wound repair by acting on keratinocytes and fibroblasts. Along with its physiological functions, periostin plays pathogenic roles in skin fibrosis and chronic allergic inflammation. In systemic sclerosis (SSc) patients, periostin levels reflect the severity of skin fibrosis. Periostin null mice have shown reduced skin fibrosis in a bleomycin-induced SSc mouse model, indicating a key role of periostin in fibrosis. Moreover, in atopic dermatitis (AD), attenuated AD phenotype has been observed in periostin null mice in a house dust mite extract-induced AD mouse model. Th2 cytokine-induced periostin acts on keratinocytes to produce inflammatory cytokines that further enhance the Th2 response, thereby sustaining and amplifying chronic allergic inflammation. Thus, periostin is deeply involved in the pathogenesis of AD and other inflammation-related disorders affecting the skin. Understanding the dynamic actions of periostin would be key to dissecting pathogenesis of skin-related diseases and to developing novel therapeutic strategies. ",0
6202,28943626,Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma,Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to  ,0
6203,28943879,Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies,"Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase) may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I-V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13) kinetics for up to ~90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA. We observed a rapid but transient increase in exhausted tissue-like memory, activated memory, and plasmablast B cells accompanied by decline in resting memory cells in untreated, but not treated women. B cell subset frequencies in untreated women positively correlated with viral loads but did not predict emergence of cross-neutralizing antibodies measured 12 months post detection of plasma viremia. Plasma BAFF and CXCL13 levels increased only in untreated women, but their levels did not correlate with viral loads. Importantly, early CXCL13 but not BAFF levels predicted the later emergence of detectable cross-neutralizing antibodies at 12 months post detection of plasma viremia. Thus, hyperacute HIV-1 infection is associated with B cell subset changes, which do not predict emergence of cross-neutralizing antibodies. However, plasma CXCL13 levels during hyperacute infection predicted the subsequent emergence of cross-neutralizing antibodies, providing a potential biomarker for the evaluation of vaccines designed to elicit cross-neutralizing activity or for natural infection studies to explore mechanisms underlying development of neutralizing antibodies. ",0
6204,28943982,Awareness of physicians and pharmacists of aldosterone antagonists in heart failure and myocardial infarction in Jordan,"to evaluate physicians and clinical pharmacists' awareness and practices regarding use of aldosterone antagonists in heart failure (HF) and post-myocardial infarction (MI). First, we reviewed the prescription of aldosterone antagonists among 408 patients presenting to the cardiology clinic at a major hospital in Jordan. Second, physicians and pharmacists working in cardiovascular departments completed a questionnaire related to use of aldosterone antagonists in HF and post-MI. Thirty patients (7.59%) were eligible for aldosterone antagonist; only 4 received them at discharge (13.3%). The survey was completed by 153 professionals (response rate 76.12%). About 72.1% of participants were aware of studies regarding use of aldosterone antagonists post-MI and in HF. Moreover, 10.45%/53.6% of participants strongly agreed/agreed that these agents are useful in normotensive post-MI and HF patients. Spironolactone was the most prescribed drug by 92.1% of participants. About 41.8% of participants reported use of spironolactone in post-MI and HF. With respect to guidelines, only 39.2% of participants agreed that adding spironolactone to standard therapy in HF is recommended, and 48.3% agreed on adding it directly post-MI. Clinical pharmacists and cardiologists were generally more aware of guidelines than pharmacists, cardiac surgeons and residents/fellows. there is an under-use of aldosterone antagonists in HF and post-MI patients, and a lack of detailed awareness of current guidelines among health care providers. Dissemination of evidence-based guidelines and usage protocols may improve management of post-MI and HF. ",0
6205,28944113,Psychiatric Symptoms as the First Clinical Presentation of Multiple Sclerosis: A Case Report,"Multiple sclerosis (MS) is an autoimmune condition which affects the axon myelination in the brain. There can be multiple ways it can present initially, but physical signs and symptoms are the most common ones. We are reporting a case of MS from Pakistan which presented with neuropsychiatric features and was offered psychiatric care, but the patient declined treatment because of stigma related to psychiatric care. Four months later when her condition worsened, further investigation showed it to be a case of MS. The purpose of this case report is that psychiatric features should be considered for differentials of MS. ",0
6206,28944141,Nationwide trends of hospitalizations for cystic fibrosis in the United States from 2003 to 2013,"Cystic fibrosis (CF) is a multisystem autosomal recessive genetic disorder with significant advances in early diagnosis and treatment in the last decade. It is important to provide updated information regarding these changing demographics as they also reflect a considerable improvement in survival. We analyzed the National Inpatient Sample Database (NIS) in the United States for all patients in which CF was the primary discharge diagnosis (ICD-9: 277.0-277.09) from 2003 to 2013 to evaluate the rate of hospitalizations and determine the cost and mortality associated with CF along with other epidemiological findings. The statistical significance of the difference in the number of hospital discharges, lengths of stays and associated hospital costs over the study period was calculated. In 2003, there were 8,328 hospital discharges with the principal discharge diagnosis of CF in the United States, which increased to 12,590 discharges in 2013 ( ",0
6207,28944522,Sensitivity for Cues Predicting Reward and Punishment in Young Women with Eating Disorders,"Increasing evidence shows that sensitivity to reward (SR) and punishment (SP) may be involved in eating disorders (EDs). Most studies used self-reported positive/negative effect in rewarding/punishing situations, whereas the implied proneness to detect signals of reward/punishment is largely ignored. This pilot study used a spatial orientation task to examine transdiagnostic and interdiagnostic differences in SR/SP. Participants (14-29 years) were patients with anorexia nervosa of restricting type (AN-R, n = 20), binge/purge ED group [AN of binge/purge type and bulimia nervosa (n = 16)] and non-symptomatic individuals (n = 23). Results revealed stronger difficulties to redirect attention away from signals of rewards in AN-R compared with binge/purge EDs, and binge/purge EDs showed stronger difficulties to direct attention away from signals of punishment compared with AN-R. Findings demonstrate interdiagnostic differences and show that the spatial orientation task is sensitive for individual differences in SP/SR within the context of EDs, thereby sustaining its usefulness as behavioural measure of reinforcement sensitivity. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. ",0
6208,28944837,Role of PIM2 in allergic asthma,"T cell‑associated inflammation, particularly type 2 inflammation, has an important role in asthma pathogenesis, which is suppressed by regulatory T cells (Tregs). Proviral integration site for Moloney murine leukemia virus 2 (PIM2), a member off the serine/threonine kinase family, promotes the growth and survival of T cells and influences the function of Treg cells. However, whether PIM2 affects asthma pathogenesis remains unclear. Peripheral blood mononuclear cells and Treg cells from asthmatic and healthy subjects were obtained, and the expression level of PIM2 was measured by reverse transcription‑quantitative polymerase chain reaction and immunocytochemistry. In addition, BALB/c female mice sensitized and challenged by ovalbumin were used as an asthma model, and PIM2 inhibitor was injected during the challenge period to observe the effect of PIM2 on asthma. The asthma symptoms were recorded, and airway hyper‑responsiveness (AHR), expression levels of cytokines in the serum or bronchoalveolar lavage fluid (BALF), and the number of BALF leukocytes were evaluated. In addition, hematoxylin and eosin staining and immunohistochemistry of lung tissues was performed. The results demonstrated that PIM2 was overexpressed in patients with asthma in natural Treg cells. Inhibition of PIM2 attenuated asthma symptoms, and improved AHR and airway inflammation compared with asthmatic mice without inhibition of PIM2. In addition, expression levels of interleukin (IL)‑10 and forkhead box protein 3 (FOXP3) in BALF were increased following PIM2 inhibition (IL‑10, 470.3±21.78 vs. 533.7±25.55 pg/ml, P<0.05; FOXP3, 259±4.68 vs. 279.3±3.68 pg/ml; asthma and PIM2 inhibition groups, respectively; P<0.05). In conclusion, PIM2 may exhibit an important role in asthma pathogenesis and exacerbate AHR, airway inflammation and asthma symptoms. These effects of PIM2 may be dependent on Treg cells and the secretion of IL‑10 by Tregs. The results of the present study suggest that PIM2 may be a potential target molecule for asthma treatment. ",0
6209,28944951,Successful Application of the Ventriculo-Gallbladder Shunt: A Salvage Procedure,"Ventriculo gallblader shunt is very rarely used in the treatment of hydrocephalus. A 44 year old male with ventriculoatrial shunt dysfunction was evaluated. His ventriculoatrial shunt was not working. His medical history revealed that his hydrocephalus was treated five times by venrtriculoperitoneal shunt, four times by ventriculoatrial shunt. Another trial for ventriculoperitoneal or ventriculoatrial shunting was not considered feasible. Ventriculo-gallbladder shunt as potential salvage procedure was placed to the patient. Remarkably, the patient benefitted from the ventriculo-gallbladder shunt and was discharged from the hospital. We think that ventriculo-gallbladder shunting is a safe and effective treatment for hydrocephalus as last resort in complicated cases of shunt dysfunction. ",0
6210,28944962,"Human papillomavirus E6 protein enriches the CD55(+) population in cervical cancer cells, promoting radioresistance and cancer aggressiveness","Accumulating evidence indicates that the human papillomavirus (HPV) E6 protein plays a crucial role in the development of cervical cancer. Subpopulations of cells that reside within tumours are responsible for tumour resistance to cancer therapy and recurrence. However, the identity of such cells residing in cervical cancer and their relationship with the HPV-E6 protein have not been identified. Here, we isolated sphere-forming cells, which showed self-renewal ability, from primary cervical tumours. Gene expression profiling revealed that cluster of differentiation (CD) 55 was upregulated in primary cervical cancer sphere cells. Flow-cytometric analysis detected abundant CD55(+) populations among a panel of HPV-positive cervical cancer cell lines, whereas few CD55(+) cells were found in HPV-negative cervical cancer and normal cervical epithelial cell lines. The CD55(+) subpopulation isolated from the C33A cell line showed significant sphere-forming ability and enhanced tumourigenicity, cell migration, and radioresistance. In contrast, the suppression of CD55 in HPV-positive CaSki cells inhibited tumourigenicity both in vitro and in vivo, and sensitized cells to radiation treatment. In addition, ectopic expression of the HPV-E6 protein in HPV-negative cervical cancer cells dramatically enriched the CD55(+) subpopulation. CRISPR/Cas9 knockout of CD55 in an HPV-E6-overexpressing stable clone abolished the tumourigenic effects of the HPV-E6 protein. Taken together, our data suggest that HPV-E6 protein expression enriches the CD55(+) population, which contributes to tumourigenicity and radioresistance in cervical cancer cells. Targeting CD55 via CRISPR/Cas9 may represent a novel avenue for developing new strategies and effective therapies for the treatment of cervical cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ",0
6211,28945018,Expert consensus on the design and implementation of clinical safety centralized monitoring study of Chinese medical injection],"Along with the increase of clinical application, the safety of traditional Chinese medicine gained more and more attentions. In particular, the safety evaluation of Chinese medical injections has become a mandatory task should be completed by pharmaceutical companies under the supervision of China Food and Drug Administration(CFDA). Due to the weak foundation of previous studies, the safety issues of Chinese medical injections have not been fully understood, and lack of scientific and rational risk management programs. Clinical safety centralized monitoring(CSCM) is an important method for post-market safety evaluation of Chinese medicine. Due to the lack of appropriate norms and procedures, the quality of similar research is uneven, and the results vary. Combined with practical experience with experts' suggestions, we developed this expert consensus on the design and implementation of CSCM from three stages (design, implementation and report) with 20 technical points, which will provide technical support for future CSCM studies. ",0
6212,28945380,Unraveling Binding Interactions between Human RANKL and Its Decoy Receptor Osteoprotegerin,"Recent studies have revealed the importance and the active contribution of the RANKL/OPG/RANK pathway in many bone diseases including different forms of common osteoporosis. In this study, we present an extensive atomistic molecular dynamic study of the OPG/RANKL system. Within the molecular models, we varied the number of OPG molecules bound to the RANKL trimer and carried out a study to determine how the binding affinity of the OPG/RANKL system changes as a function of OPG concentration. The molecular mechanics Poisson-Boltzmann surface area method was used to analyze binding free energies. It is shown that the binding affinity decreases with increasing numbers of OPG molecules. Additionally, conformational changes of RANKL, interactions between the N-terminus outlier module of OPG with RANKL, and residues that play an important role in the binding of OPG to RANKL trimer were investigated. A probable cause for unfavorable binding for a third OPG molecule was found. Along with the currently available experimental studies, this computational study will be valuable for the comprehensive understanding of OPG/RANKL at the atomistic level. ",0
6213,28945714,Autologous Stem Cell Transplantation: The Predictive Value of the Morse Fall Scale in Hospitalized Patients ,"Falls are common in hospitalized patients undergoing autologous stem cell transplantation (ASCT). Research demonstrates that preventing patient falls requires knowledge of the risk factors and the circumstances preceding the patient's fall.. To identify risk factors related to falls in recipients of ASCT and assess the predictive value of the Morse Fall Scale (MFS).. Of the 288 patients who underwent transplantation during the study period, 14 were fallers. Twenty controls were randomly selected. The study used descriptive case-control analysis and simple logistic regression to analyze the data. . Eight fallers and four non-fallers had high MFS scores. The logistic regression model indicated that patients with high MFS scores were 5.3 times more likely to fall and that for each day patients experienced diarrhea, their risk of fall increased 1.2 times. ",0
6214,28945835,Alcohol and cigarette consumption predict mortality in patients with head and neck cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium,"This study evaluated whether demographics, pre-diagnosis lifestyle habits and clinical data are associated with the overall survival (OS) and head and neck cancer (HNC)-specific survival in patients with HNC. We conducted a pooled analysis, including 4759 HNC patients from five studies within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Cox proportional hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated including terms reported significantly associated with the survival in the univariate analysis. Five-year OS was 51.4% for all HNC sites combined: 50.3% for oral cavity, 41.1% for oropharynx, 35.0% for hypopharynx and 63.9% for larynx. When we considered HNC-specific survival, 5-year survival rates were 57.4% for all HNC combined: 54.6% for oral cavity, 45.4% for oropharynx, 37.1% for hypopharynx and 72.3% for larynx. Older ages at diagnosis and advanced tumour staging were unfavourable predictors of OS and HNC-specific survival. In laryngeal cancer, low educational level was an unfavourable prognostic factor for OS (HR = 2.54, 95% CI 1.01-6.38, for high school or lower versus college graduate), and status and intensity of alcohol drinking were prognostic factors both of the OS (current drinkers HR = 1.73, 95% CI 1.16-2.58) and HNC-specific survival (current drinkers HR = 2.11, 95% CI 1.22-3.66). In oropharyngeal cancer, smoking status was an independent prognostic factors for OS. Smoking intensity (>20 cigarettes/day HR = 1.41, 95% CI 1.03-1.92) was also an independent prognostic factor for OS in patients with cancer of the oral cavity. OS and HNC-specific survival differ among HNC sites. Pre-diagnosis cigarette smoking is a prognostic factor of the OS for patients with cancer of the oral cavity and oropharynx, whereas pre-diagnosis alcohol drinking is a prognostic factor of OS and HNC-specific survival for patients with cancer of the larynx. Low educational level is an unfavourable prognostic factor for OS in laryngeal cancer patients. ",0
6215,28946061,Liposomally formulated phospholipid-conjugated novel near-infrared fluorescence probe for particle size effect on cellular uptake and biodistribution in vivo,"Lipid based nanoparticles (LBNs) with excellent biocompatibility and versatility have received much attention from the drug delivery community recently. A detailed understanding of in vitro and vivo fate of LBNs is important for developing different types of LBNs with improved selectivity and low cytotoxicity. We developed a novel near-infrared (NIR) probe with high fluorescence, designated as DSPE-ir623 (iDSPE). Then, we prepared iDSPE-embeded liposomes (iLPs) with two different hydrodynamic sizes (∼100nm and ∼400nm) to evaluate the effect of particle size on cellular uptake and biodistribution of nanoliposomes in vivo. These iLPs were proved to exhibit good monodispersity, excellent fluorescence and stability. In vitro cell uptake tests demonstrated that iLPs-1 (∼100nm) were taken up more by HT-29 cells than iLPs-2 (∼400nm). Notably, the fluorescence of iLPs can be employed for real-time monitoring of the subcellular locating and its metabolic distribution in vivo. Near-infrared imaging in vivo illustrated that iLPs-1 was mainly accumulated in the tumor tissues, while iLPs-2 was accumulated in liver and spleen. The results indicated that the size of iLPs play an important role in the regulation of intracellular trafficking and biodistribution of liposomes, which also provide a new insight into the development of more effective LBNs. Hence, iDSPE might be a promising tool for the reliable tracing of different types of LBNs. ",0
6216,28946128,Systematic characterization of the metabolites of paeonol in rats using ultra performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry with an integrative strategy,"Paeonol, an active constituent in the root bark of Paeonia suffruticosa Andrews, is used to treat inflammation, headache and other diseases in clinic. Though the data on pharmacological researches of paeonol abounds, its metabolic profile is not so clear. It is essential to systematically characterize the in vivo metabolites in order to better understand its mechanism of action. In this study, ultra performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q/TOF-MS) with an integrative strategy was developed for analysis of paeonol metabolites. As a result, based on seven reference substances isolated or synthesized, twenty-five metabolites were detected and identified in urine, feces, bile and plasma of rats after oral administration of paeonol. To the best of our knowledge, 14 of these metabolites have not been reported previously. In addition, the dominating metabolic fates were oxidation, demethylation, hydrogenation, glucuronic acid and sulfate conjugations, and hydrogenation of paeonol was reported for the first time. This research provides scientific and reliable support for full understanding of the metabolic profiling of paeonol. ",0
6217,28946273,Understanding the release and metabolism of aroma compounds using micro-volume saliva samples by ex vivo approaches,"This study investigated the behaviour of key aroma compounds in the presence of human saliva (200μL) from different individuals (n=3) submitted or not to centrifugation (whole vs clarified saliva). HS-GC results showed that human saliva strongly decreased the release of carbonyl compounds (aldehydes and ketones). This effect was dependent on i) the structure of the aroma compounds and ii) the saliva composition. Whole saliva exerted a higher effect than clarified saliva on aroma compounds. Moreover, this effect was individual-dependent and related to the total protein content and the total antioxidant capacity of saliva. HS-SPME and LLE-GC/MS analyses revealed that metabolism of the compounds by salivary enzymes was involved. This observation indicates that some aroma compounds could be metabolized in the oral cavity in an individual manner, which could have implications for aroma perception (e.g., formation of new metabolites with different odor thresholds and qualities) and/or organisms' health status (e.g., compound detoxification). ",0
6218,28946370,Physicochemical characteristics and functionality of tree peony (Paeonia suffruticosa Andr.) seed protein,"The physicochemical and functional properties of tree peony seed protein were investigated. Tree peony seed protein with a favourable amino acid profile was composed of a 60kDa protein with two subunits of 38 and 23kDa. The isoelectric points of the two subunits were 3.6 and 9.0. Moreover, acid-Schiff staining indicated both of them were glycoproteins. Diagonal and 2-D electrophoresis data indicated the 38kDa subunit included three types, which two types had inter-disulphide bonds and one type had no-disulphide bonds. So did the 23kDa subunit. Circular dichroism spectra indicated the tree peony seed protein had predominantly a β-sheet structure. Differential scanning calorimetry analysis indicated the denaturation temperatures of the tree peony seed protein at pH 5.0, 7.0 and 9.0 were 92.0, 97.1 and 95.2°C, respectively. Tree peony seed protein could be a food ingredient in the food industry due to its desirable physicochemical and functional properties. ",0
6219,28946621,Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle,"Autophagy is a lysosomal-dependent degradative process essential for maintaining cellular homeostasis, and is a key player in innate and adaptive immune responses to intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). In HIV-1 target cells, autophagy mechanisms can (i) selectively direct viral proteins and viruses for degradation; (ii) participate in the processing and presentation of viral-derived antigens through major histocompatibility complexes; and (iii) contribute to interferon production in response to HIV-1 infection. As a consequence, HIV-1 has evolved different strategies to finely regulate the autophagy pathway to favor its replication and dissemination. HIV-1 notably encodes accessory genes encoding Tat, Nef and Vpu proteins, which are able to perturb and hijack canonical and non-canonical autophagy mechanisms. This review outlines the current knowledge on the complex interplay between autophagy and HIV-1 replication cycle, providing an overview of the autophagy-mediated molecular processes deployed both by infected cells to combat the virus and by HIV-1 to evade antiviral response. ",0
6220,28946860,Severe hydronephrosis secondary to uterine artery pseudoaneurysm in the early second trimester of pregnancy: A case report,"Uterine artery pseudoaneurysm (UAP) normally presents genital bleeding in the puerperal period, and severe hydronephrosis rarely presents during pregnancy. We report a rare case of severe ureteral obstruction accompanied by uterine artery pseudoaneurysm in the early second trimester of pregnancy, which was successfully treated by surgical intervention. A 42-year-old nulligravid woman who had undergone myomectomy 3 years earlier was referred to our hospital for acute left abdominal pain at the 17th week of gestation. Ultrasonography showed severe left hydronephrosis and a 6-cm mass in the parauterine space. Color Doppler ultrasonography revealed a spinning turbulent flow pattern inside the mass lesion. Contrast-enhanced computed tomography revealed the left uterine artery feeding blood flow to the mass and left ureteral obstruction by the mass. These results indicated left hydronephrosis secondary to left uterine artery pseudoaneurysm. To resolve the problem, laparotomy was performed. As uterine artery isolation was impossible, ligation of the left internal iliac artery and releasing of the ureteral obstruction were carried out. The hydronephrosis and abdominal pain promptly resolved after the surgery. Thereafter, fetal development proceeded normally in the remaining months of the pregnancy. A healthy baby was delivered through cesarean section at 36 weeks gestational age. At the cesarean section, the left lower uterine segment where the UAP had been present was not visible because of the firm adhesion in around it. Uterine artery pseudoaneurysm can cause hydronephrosis in the early second trimester of pregnancy. Ligation of the unilateral internal iliac artery is a safe and effective intervention to block the blood flow to the uterine artery pseudoaneurysm during pregnancy, when uterine artery ligation seems not possible. In the pregnancy after previous surgical procedures to the uterus, uterine artery pseudoaneurysm should be considered in the differential diagnosis of symptomatic hydronephrosis. ",0
6221,28946873,Myanmar mortality registration: an assessment for system improvement,"The vital registration system in Myanmar has a long history and geographical coverage is currently high. However, a recent assessment of vital registration systems of 148 countries showed poor performance of the death registration system in Myanmar, suggesting the need for improvement. This study assessed the quality of mortality data generated from the vital registration system with regard to mortality levels and patterns, quality of cause of death data, and completeness of death registration in order to identify areas for improvement. The study used registered deaths in 2013 from the vital registration system, data from the 2014 Myanmar Population and Housing Census, and mortality indicators and COD information for the country estimated by international organizations. The study applied the guidelines recommended by AbouZahr et al. 2010 to assess mortality levels and patterns and quality of cause of death data. The completeness of death registration was assessed by a simple calculation based on the estimated number of deaths. Findings suggested that the completeness of death registration was critically low (less than 60%). The under-registration was more severe in rural areas, in states and regions with difficult transportation and poor accessibility to health centers and for infant and child deaths. The quality of cause of death information was poor, with possible over-reporting of non-communicable disease codes and a high proportion of ill-defined causes of death (22.3% of total deaths). The results indicated that the vital registration system in Myanmar does not produce reliable mortality statistics. In response to monitoring mortalities as mandated by the Sustainable Development Goals, a significant and sustained government commitment and investment in strengthening the vital registration system in Myanmar is recommended. ",0
6222,28946929,Dietary zinc addition influenced zinc and lipid deposition in the fore- and mid-intestine of juvenile yellow catfish Pelteobagrus fulvidraco,"The present study explored the mechanisms of dietary Zn influencing Zn and lipid deposition in the fore- and mid- intestine in yellow catfish Pelteobagrus fulvidraco, and investigated whether the mechanism was intestinal-region dependent. For this purpose, yellow catfish were fed three diets containing Zn levels of 8·83, 19·20 and 146·65 mg Zn/kg, respectively. Growth performance, intestinal TAG and Zn contents as well as activities and mRNA expression of enzymes and genes involved in Zn transport and lipid metabolism in the fore- and mid-intestine were analysed. Dietary Zn increased Zn accumulation as well as activities of Cu-, Zn-superoxide dismutase and ATPase in the fore- and mid-intestine. In the fore-intestine, dietary Zn up-regulated mRNA levels of ZnT1, ZnT5, ZnT7, metallothionein (MT) and metal response element-binding transcription factor-1 (MTF-1), but down-regulated mRNA levels of ZIP4 and ZIP5. In the mid-intestine, dietary Zn up-regulated mRNA levels of ZnT1, ZnT5, ZnT7, MT and MTF-1, but down-regulated mRNA levels of ZIP4 and ZIP5. Dietary Zn reduced TAG content, down-regulated activities of 6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and fatty acid synthase (FAS) activities, and reduced mRNA levels of 6PGD, G6PD, FAS, PPARγ and sterol-regulator element-binding protein (SREBP-1), but up-regulated mRNA levels of carnitine palmitoyltransferase IA, hormone-sensitive lipase (HSLa), adipose TAG lipase (ATGL) and PPARα in the fore-intestine. In the mid-intestine, dietary Zn reduced TAG content, activities of G6PD, ME, isocitrate dehydrogenase and FAS, down-regulated mRNA levels of 6PGD, G6PD, FAS, acetyl-CoA carboxylase a, PPARγ and SREBP-1, but up-regulated mRNA expression of HSLa, ATGL and PPARγ. The reduction in TAG content following Zn addition was attributable to reduced lipogenesis and increased lipolysis, and similar regulatory mechanisms were observed between the fore- and mid-intestine. ",0
6223,28947103,Interrogation of side chain biases for oligomannose recognition by antibody 2G12 via structure-guided phage display libraries,"""Monoclonal antibodies (mAbs) are essential reagents for deciphering gene or protein function and have been a fruitful source of therapeutic and diagnostic agents. However, developing anticarbohydrate antibodies to target glycans for those purposes has been less successful because the molecular basis for glycan-mAb interactions is poorly understood relative to protein- or peptide-binding mAbs. Here, we report our investigation on glycan-mAb interactions by using the unique architectural scaffold of 2G12, an antibody that targets oligomannoses on the HIV-1 glycoprotein gp120, as the template for engineering highly specific mAbs to target glycans. We first analyzed 24 different X-ray structures of antiglycan mAbs from the Protein Data Bank to determine side chain amino acid distributions in of glycan-mAb interactions. We identified Tyr, Arg, Asn, Ser, Asp, and His as the six most prevalent residues in the glycan-mAb contacts. We then utilized this information to construct two phage display libraries (""""Lib1"""" and """"Lib2"""") in which positions on the heavy chain variable domains of 2G12 were allowed to vary in restricted manner among Tyr, Asp, Ser, His, Asn, Thr, Ala and Pro to interrogate the minimal physicochemical requirements for oligomannose recognition. We analyzed the sequences of 39 variants from Lib1 and 14 variants from Lib2 following selection against gp120, the results showed that there is a high degree of malleability within the 2G12 for glycan recognitions. We further characterized five unique phage clones from both libraries that exhibited a gp120-specific binding profile. Expression of two of these variants as soluble mAbs indicated that, while specificity of gp120-binding was retained, the affinity of these mutants was significantly reduced relative to WT 2G12. Nonetheless, the results indicate these is some malleability in the identity of contact residues and provide a novel insight into the nature of glycan-antibody interactions and how they may differ from protein-antibody binding interactions. """,0
6224,28947314,Evaluation of the water quality of the upper reaches of the main Southern Brazil river (Iguaçu river) through in situ exposure of the native siluriform Rhamdia quelen in cages,"""Increase in industrial growth, urban and agricultural pollution, with consequent impacts on aquatic ecosystems are a major focus of research worldwide. Still, not many studies assess the impacts of contamination through in situ studies, using native species, also considering the influence of seasonality on their responses. This study aimed to evaluate the water quality of the basin of the Upper Iguaçu River, the main source of water supply to Curitiba, a major capital of Southern Brazil, and its Metropolitan area. Several biomarkers were evaluated after in situ exposure of the native catfish Rhamdia quelen inside cages for 7 days. Ten study sites were chosen along the basin, based on a diffuse gradient of contamination, corresponding to regions upstream, downstream, and within """"great Curitiba"""". In each site, fish were exposed in Summer and Winter. The complex mixture of contaminants of this hydrographic basin generated mortality, and ion-, osmoregulatory and respiratory disturbances in the catfish as, for example, reduction of plasma osmolality and ionic concentrations, increased hematocrit levels and gill water content, altered branchial and renal activities of the enzyme carbonic anhydrase, as well as raised levels of plasma cortisol and glucose. Biomarkers were mostly altered in fish exposed in Great Curitiba and immediately downstream. There was a notable influence of season on the responses of the jundiá. A multivariate redundancy analysis revealed that the best environmental variables explained 30% of the variation in biomarkers after controlling for spatial autocorrelation. Thus, this approach and the chosen parameters can be satisfactorily used to evaluate contamination environments with complex mixtures of contaminants, in other urban basins as well. """,0
6225,28947375,The role of neuroimaging in elucidating the pathophysiology of cerebral ischemia,"Neuroimaging provides detailed information regarding the hemodynamic, metabolic and cellular parameters of cerebral ischemia (CI). Although providing just a snapshot in time, it assists in delineating the boundaries and extent of this continually evolving process, from the irreversibly damaged infarct core to the penumbral tissue, where salvage via reperfusion has been the focus of acute stroke therapies. Beyond the extent of the ischemic lesion, neuroimaging elucidates the topography and underlying mechanism of CI. Finally, based on the pathophysiological information, neuroimaging assists in the selection of optimal therapeutic strategies, from hyperacute to chronic phases of CI. Here we review different neuroimaging techniques by which the pathophysiology of cerebral ischemia can be delineated. This article is part of the Special Issue entitled 'Cerebral Ischemia'. ",0
6226,28947438,"Medical leadership, a systematic narrative review: do hospitals and healthcare organisations perform better when led by doctors?","Despite common assumptions that doctors are well placed to lead hospitals and healthcare organisations, the peer-reviewed literature contains little evidence on the performance of doctors in leadership roles in comparison with that of non-medical managers. To determine whether there is an association between the leader's medical background and management performance in terms of organisational performance or patient outcomes. We searched for peer-reviewed, English language studies using Medline, Embase and Emerald Management between 2005 and 2017. We included quantitative, qualitative and mixed method empirical studies on the performance of senior healthcare managers where participants were described as doctors or leaders and where comparative performance data were provided on non-medical leaders. Studies without full text available, or no organisational, leadership behaviour or patient measures, were excluded. The search, conducted in Medline (n=3395), Embase (n=1913) and Emerald Management (n=454) databases, yielded 3926 entries. After the application of inclusion and exclusion criteria, 16 studies remained. Twelve studies found that there were positive differences between medical and non-medical leaders, and eight studies correlated those findings with hospital performance or patient outcomes. Six studies examined the composition of boards of directors; otherwise, there were few common areas of investigation. Five inter-related themes emerged from a narrative analysis: the impact of medical leadership on outcomes; doctors on boards; contribution of qualifications and experience; the medical leader as an individual or part of a team and doctors transitioning into the medical leadership role. A modest body of evidence supports the importance of including doctors on organisational governing boards. Despite many published articles on the topic of whether hospitals and healthcare organisations perform better when led by doctors, there were few empirical studies that directly compared the performance of medical and non-medical managers. This is an under-researched area that requires further funding and focus. ",0
6227,28947709,"The first report of diablo in Megalobrama amblycephala: characterization, phylogenetic analysis, functional annotation and expression","Smac/DIABLO gene is essential for the apoptosis mechanism in mammals. This study is the first report of the Megalobrama amblycephala (ma) diablo gene, and the first report of the tertiary structure of a Diablo polypeptide in fish. Madiablo is 1540-bp long with an open reading frame of 792 bp, encoding a putative protein of 263 amino acids with a molecular weight of 29.2 kDa. Phylogenetic analysis indicates that it is closely related to the zebrafish Diablo-a homologue. It also indicates the existence of two diablo copies (a and b) in teleosts; apart fromthe Percomorpha group,where diablo-b has been lost, but diablo-a had undergone an independent duplication. Madiablo protein contains a long Smac_DIABLO super family domain (Leu32-Asp263) and alpha helices were prevalent in the secondary structure. Homology model of madiablo protein was constructed using the comparative modelling method. Expression of madiablo mRNA transcript was investigated using qPCR: (i) in five tissues from a healthy blunt snout bream, indicating the highest constitutive expression level in liver. (ii) During the embryo and juvenile development, indicating a spike in expression during hatching and in later phases of the juvenile development. (iii) In response to Aeromonas hydrophila infection, indicating the downregulation in liver, spleen and kidney during the first 12 h postinfection and upregulation in spleen and kidney after 24 h postinfection (hpi). The results imply that madiablo is homologous to Diablo orthologues in other species, both structurally and functionally, and that, it probably plays a role in the immune system of M. amblycephala. ",0
6228,28947735,A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival,"Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival. Tau is recruited, along with upstream-binding factor, to ribosomal DNA loci. Tau downregulation decreases upstream binding factor recruitment, ribosomal RNA synthesis, ribonucleotide levels, and affects ribosomal DNA stability, leading to the formation of a new subclass of human ribosomal ultrafine anaphase bridges. We describe here Tau functions in maintaining survival of cytidine deaminase-deficient cells, and ribosomal DNA transcription and stability. Moreover, our findings for cancer tissues presenting concomitant cytidine deaminase underexpression and Tau upregulation open up new possibilities for anti-cancer treatment.Cytidine deaminase (CDA) deficiency leads to genome instability. Here the authors find a synthetic lethal interaction between CDA and the microtubule-associated protein Tau deficiencies, and report that Tau depletion affects rRNA synthesis, ribonucleotide pool balance, and rDNA stability. ",0
6229,28947783,Clinical importance of TERT overexpression in hepatocellular carcinoma treated with curative surgical resection in HBV endemic area,"This study was designed to investigate the associations between TERT overexpression and the clinicopathologic factors of hepatocellular carcinoma (HCC). A total of 291 patients with HCC were enrolled. The site of first recurrence (anywhere in the liver) was classified as intrahepatic recurrence (IHR). Recurrence was then sub classified as either early or late IHR according to whether it was discovered within 2 years of resection, or after, respectively. TERT overexpression was not significantly correlated with previously recognized prognostic factors. During follow-up, early IHR occurred in 126 (63.6%) patients, while late IHR was detected in 59 patients among 145 patients who remained free of HCC recurrence for ≥ 2 years after surgery. Multivariate analysis showed late IHR was significantly correlated with TERT overexpression (P < 0.001, hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.51-4.72). Intrahepatic metastasis (P < 0.001, HR 4.48, 95% CI 2.62-7.65) and TERT overexpression (P < 0.001, HR 1.77, 95% CI 1.28-2.45) were significant prognostic factors for IHR-free survival in both univariate and multivariate analyses. TERT overexpression was the only significant prognostic factor for late IHR in HCC treated with curative resection. And, the statistical significance of TERT overexpression on late IHR was limited to HBsAg-positive patients. ",0
6230,28948396,"Breast cancer recurrence, bone metastases, and visceral metastases in women with stage II and III breast cancer in Denmark","We developed and validated algorithms to identify metastases and breast cancer recurrence in Danish medical registries. We computed the incidence rate (IR) and hazard ratios (HRs) to evaluate predictors of these outcomes in stage II/III breast cancer patients. We included all women in Denmark diagnosed during 1999-2011 with regional or stage II/III breast cancer. Demographic, tumor, and treatment data were ascertained from population-based health registries. To facilitate diagnostic work-up of the primary cancer, follow-up began 180 days after diagnosis and continued until recurrence/metastases, death, or 31 December 2012, whichever occurred first. We computed the positive predictive values (PPVs) of recurrence, bone metastases, and visceral metastases using medical records as a gold standard. We calculated the cumulative incidence, IR per 10,000 person years, and used Cox regression to compute the HRs and associated 95% confidence intervals (95% CI) for each outcome. Among 23,478 patients, 7073 had regional stage and 16,405 had stage II/III breast cancer. The PPV for recurrence was 72.6% (95% CI 59.3, 83.3%). The PPVs for bone and visceral metastases were 92.3% (95% CI 69.3-99.2%) and 70.8% (95% CI 51.1, 85.9%), but had low sensitivity. Five-year cumulative incidence of recurrence, bone metastases, and visceral metastases were 18.4, 2.2, and 5.2%, with corresponding 5-year IRs of 540 (95% CI 524, 557), 60 (95% CI 55, 65), and 144 (95% CI 136, 152), respectively. Predictors of recurrence and metastases included age, stage, hormone receptor status, and cancer treatment. Our algorithms show moderate to high PPVs for recurrence and metastases. The IRs of metastases were lower compared with other registry-based cohort studies, so may be underestimated in Danish registries. ",0
6231,28949080,Everyday task knowledge and everyday function in dementia,"Tests of everyday action semantics were developed and piloted in a group of healthy adults (n = 53) and then administered to individuals with Alzheimer's disease (AD; n = 17) or Parkinson's disease dementia (PDD; n = 20). Relations between everyday action knowledge and everyday function were explored. Three action semantic tests were developed: Probe Test - 45 forced-choice questions regarding task sequences, objects, and steps; Picture Sequencing Test - sequential ordering of 4-5 cards depicting task steps; Script Test - open-ended verbal description of the steps required to complete everyday tasks. Cognitive tests, informant reports of functioning, and the Naturalistic Action Test (NAT), a performance-based test of function, also were administered to AD and PDD participants. NAT performance was scored for omission (failure to complete steps) and commission (inaccurate performance of step) errors. The AD and PDD groups performed worse than healthy participants on all action semantic tasks. AD and PDD groups significantly differed on only the Script Test - AD participants generated fewer correct steps. Performance on each of the action semantic tests significantly correlated with NAT omission errors. Only the Sequencing Test significantly predicted omissions, commissions, and informant report of everyday functioning. In sum, task knowledge is associated with omissions in everyday tasks and is impaired in both AD and PDD. The ability to accurately sequence task steps is associated with multiple aspects of everyday function and may be easily assessed with picture arrangement. ",0
6232,28949356,"Essential arterial hypertension patients present higher cell adhesion forces, contributing to fibrinogen-dependent cardiovascular risk","The increase of erythrocyte aggregation by high fibrinogen levels may be an indicator of cardiovascular risk. γ' fibrinogen variant has been considered as a possible player in enhancing aggregation. Here, we assessed, at the single-cell level, the influence of fibrinogen on erythrocyte aggregation in essential arterial hypertension. We also aimed at understanding how γ' fibrinogen is altered in this disease. Using atomic force microscopy (AFM), we show that the work and force necessary for erythrocyte-erythrocyte detachment is higher for patients than for healthy donors, with these parameters further increasing in both groups when higher fibrinogen concentrations are present. This can be associated with changes in blood flow, due to transient bridging of two erythrocytes by fibrinogen, representing an important cardiovascular risk factor. γ' fibrinogen can influence the increased risk in essential arterial hypertension, as we demonstrate that its levels are significantly increased in these patients' blood. Nevertheless, this cannot be the only cause for the changes observed in the AFM data. ",0
6233,28949445,Impact of selective anti-BMP9 treatment on tumor cells and tumor angiogenesis,"The role of bone morphogenic protein 9 (BMP9) signaling in angiogenesis has been controversial, with a number of studies showing that it acts either as a pro-angiogenic or, conversely, as an anti-angiogenic factor in a context-dependent manner. Notably, BMP9 was also reported to function in both pro- or anti-tumorigenic roles during tumor progression. It has therefore remained unclear, whether selective BMP9 inhibition is a useful target for antibody therapy of cancer. To shed light on these questions, we characterized BMP9 expression in plasma of patients with different cancer indications and found elevated levels of pro-domains and precursor BMP9 with a strong response in renal cell carcinoma (RCC). These studies prompted us to evaluate the potential of selective anti-BMP9 cancer therapy in RCC. We generated a novel monoclonal therapeutic antibody candidate, mAb BMP9-0093, that selectively targets all different BMP9 variants but does not bind to the closest homolog BMP10. In vitro, mAb BMP9-0093 treatment inhibited signaling, endothelin-1 (ET-1) production and spreading of endothelial cells and restored BMP9-induced decrease in pericyte migration and attachment. Furthermore, BMP9-mediated epithelial-mesenchymal transition of renal cell carcinoma cells was reversed by mAb BMP9-0093 treatment in vitro. In vivo, mAb BMP9-0093 showed significant anti-tumor activity that was associated with an increase in apoptosis as well as a decrease in tumor cell proliferation and ET-1 release. Furthermore, mAb BMP9-0093 induced mural cell coverage of endothelial cells, which was corroborated by a reduction in vascular permeability, demonstrated by a diminished penetration of omalizumab-Alexa 647 into tumor tissue. Our findings provide new evidence for a better understanding of BMP9 contribution in tumor progression and angiogenesis that may result in the development of effective targeted therapeutic interventions. ",0
6234,28949804,Can Dexmedetomidine Influence Recovery Profiles from General Anesthesia in Nasal Surgery?,"Objectives Dexmedetomidine has sympatholytic, sedative, anesthetic, and analgesic effects, as well as vasoconstrictive effects, which may help prevent hypotension under general anesthesia. This meta-analysis aimed to perform a systematic review of the literature and investigate the effect of dexmedetomidine on perioperative morbidity following nasal surgery and its adverse effects. Data Sources MEDLINE, SCOPUS, and the Cochrane database. Review Methods Two authors independently searched the databases from their inception to March 2017. Studies were selected that compared perioperative dexmedetomidine administration (dexmedetomidine groups) with a placebo or remifentanil (control groups) with regard to intraoperative morbidity, including surgical time, bleeding amount, hypotension, and bradycardia during operation, and postoperative morbidity, such as emergence agitation, nausea and vomiting, and sedation after operation. Results Surgical time, intraoperative blood loss, dose of inhaled anesthetic gas, dose of fentanyl, postoperative pain, and incidence of emergence agitation were significantly lower in the dexmedetomidine group versus the placebo group. In contrast, there were no significant differences in intraoperative hemodynamic stability and postoperative residual sedation and nausea and vomiting between groups. Additionally, compared with remifentanil (a currently widely used agent), dexmedetomidine was superior in view of postoperative pain and intraoperative blood pressure control. Conclusion This meta-analysis shows that the systemic administration of dexmedetomidine can decrease surgical time, intraoperative blood loss, and doses of intraoperative inhaled anesthetic gas and fentanyl as compared with placebo. It can also decrease postoperative pain and incidence of the emergence agitation. Due to the small number of studies, further clinical trials are needed to confirm these results. ",0
6235,28950003,The endothelial αENaC contributes to vascular endothelial function in vivo,"The Epithelial Sodium Channel (ENaC) is a key player in renal sodium homeostasis. The expression of α β γ ENaC subunits has also been described in the endothelium and vascular smooth muscle, suggesting a role in vascular function. We recently demonstrated that endothelial ENaC is involved in aldosterone-modulated endothelial stiffness. Here we explore the functional role of the endothelial αENaC subunit in vascular function in vivo. Compared to littermates, mice with conditional αENaC subunit gene inactivation in the endothelium only (endo-αENaC Knock Out mice) had no difference in their physiological parameters such as systolic blood pressure or heart rate. Acute and long-term renal Na+ handlings were not affected, indicating that endothelial αENaC subunit is not involved in renal sodium balance. Pharmacological inhibition of ENaC with benzamil blunted acetylcholine-induced nitric oxide production in mesenteric arteries from wild type mice but not in endo-αENaC KO mice, suggesting a critical role of endothelial ENaC in agonist-induced nitric oxide production. In endo-αENaC KO mice, compensatory mechanisms occurred and steady state vascular function was not altered except for flow-mediated dilation. Our data suggest that endothelial αENaC contributes to vascular endothelial function in vivo. ",0
6236,28950073,Consider the chemokines: a review of the interplay between chemokines and T cell subset function,"Subsets of T cells can be classified by the functions executed or by the anatomic location at which they operate. In vitro analysis of T cell subsets and even commercial kits for subset separation often incorporate chemokine receptors into the panel of markers to distinguish among them, but what is the functional significance of these receptors? In this review, we discuss chemokine receptors that are expressed exclusively on different T cell subsets as well as those that are commonly expressed across subsets with the goal of linking receptor expression to cellular localization and intended cellular function. By understanding the chemokine network, we can better predict T cell migration and the immune reactivity of a given tissue environment. This is of particular importance for the chemokine expression patterns of solid tumor microenvironments as it relates to T cell infiltration. A successful immunotherapeutic strategy needs to incorporate not only the activation state of cytotoxic T cells but also the likelihood that these cells come into contact with tumor cells. We highlight what is currently known about chemokine expression by tumors of various origins and how this relates to immune suppression or activation. Chemokine signaling represents a promising area of potential anti-tumor intervention and the current state of agonists or antagonists is discussed. Overall, this review relates chemokine signaling to T cell function and emphasizes the importance of chemokines and chemokine receptors in tumor infiltration by T cells. ",0
6237,28950315,Quantitative global plaque characteristics from coronary computed tomography angiography for the prediction of future cardiac mortality during long-term follow-up,"Adverse plaque characteristics determined by coronary computed tomography angiography (CTA) have been associated with future cardiac events. Our aim was to investigate whether quantitative global per-patient plaque characteristics from coronary CTA can predict subsequent cardiac death during long-term follow-up. Out of 2748 patients without prior history of coronary artery disease undergoing CTA with dual-source CT, 32 patients suffered cardiac death (mean follow-up of 5 ± 2 years). These patients were matched to 32 controls by age, gender, risk factors, and symptoms (total 64 patients, 59% male, age 69 ± 10 years). Coronary CTA data sets were analysed by semi-automated software to quantify plaque characteristics over the entire coronary tree, including total plaque volume, volumes of non-calcified plaque (NCP), low-density non-calcified plaque (LD-NCP, attenuation <30 Hounsfield units), calcified plaque (CP), and corresponding burden (plaque volume × 100%/vessel volume), as well as stenosis and contrast density difference (CDD, maximum percent difference in luminal attenuation/cross-sectional area compared to proximal cross-section). In patients who died from cardiac cause, NCP, LD-NCP, CP and total plaque volumes, quantitative stenosis, and CDD were significantly increased compared to controls (P < 0.025 for all). NCP > 146 mm³ [hazards ratio (HR) 2.24; 1.09-4.58; P = 0.027], LD-NCP > 10.6 mm³ (HR 2.26; 1.11-4.63; P = 0.025), total plaque volume > 179 mm³ (HR 2.30; 1.12-4.71; P = 0.022), and CDD > 35% in any vessel (HR 2.85;1.4-5.9; P = 0.005) were associated with increased risk of future cardiac death, when adjusted for segment involvement score. Among quantitative global plaque characteristics, total, non-calcified, and low-density plaque volumes as well as CDD predict cardiac death in long-term follow-up. ",0
6238,28950412,Knowledge of and attitudes toward climate change and its effects on health among nursing students: A multi-Arab country study,"Climate change and its impact on health continues to receive inadequate attention in the nursing literature, especially in the Arab region. This study explored the knowledge of and attitudes toward climate change and its effect on health among nursing students from four Arab countries. A cross-sectional study was conducted among a convenience sample of 1,059 baccalaureate nursing students from four Arab countries using the New Ecological Paradigm scale and an adapted questionnaire. The findings indicate an average range of attitude toward the environment, with country of residence, type of community, academic-year level, and climate change related variables as significant factors influencing students' attitudes. A moderate level of knowledge about the potential health related impacts of climate change was revealed. Students from Saudi Arabia and Palestinian Territory reported a significantly higher level of knowledge than Egyptian and Iraqi students. Most of the respondents reported that all identified health related effects of climate change have already increased, while more than two-thirds reported that each of the health-related impacts would increase within the next 20 years. The findings underscore the need for more coverage of topics related to climate change and its health-related impacts in nursing education curricula in Arab countries. ",0
6239,28950807,Durable complete remission following anti-EGFR antibodies in recurrent metastatic colorectal cancer,"In this case report, we describe a patient who remains in complete remission two years after the discontinuation of anti-EGFR monotherapy as a third-line treatment, accompanied by persistent severe hypomagnesemia. A 45-year-old Caucasian woman with mCRC started chemotherapy with weekly cetuximab. After ten months of treatment, the therapy was stopped because the patient had persistent grade III hypomagnesemia despite amiloride, oral, and intravenous magnesium. A month later, the patient was switched to panitumumab 6 mg/kg every two weeks for four additional months to avoid weekly visits to the clinic. Following discontinuation of panitumumab, PET scans remain negative to this day, two years after anti-EGFR therapy discontinuation. No factor has been identified to explain the complete and sustained response experienced by this patient. Hypomagnesemia is a common adverse effect of anti-EGFR therapy that can lead to treatment interruption and discontinuation if severe. This case highlights the importance of pursuing anti-EGFR therapy when a response is observed in spite of severe hypomagnesemia. It also provides preliminary information that anti-EGFR therapy could be stopped after a complete response is obtained. ",0
6240,28951509,From disability to ability: comprehensive rehabilitation providing a holistic functional improvement in a child with neglected neural tube defect,"Neural Tube defects are one of the most common congenital disorders, presenting in a paediatric rehabilitation set-up. With its wide spectrum of clinical presentation and possible complications, the condition can significantly impact an individual's functional capacity and quality of life. The condition also affects the family of the child leaving them with a lifelong impairment to cope up with. Through this 16-year-old child, we shed light on the effects of providing rehabilitation, even at a later stage and its benefits. We also get a glimpse of difficulties in availing rehabilitation services in developing countries and the need to reach out many more neglected children like him with good functional abilities. ",0
6241,28951777,Hepatitis B in renal transplant patients,"Hepatitis B virus (HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccination. Patients with chronic renal disease should ideally be vaccinated prior to dialysis, otherwise, reinforced vaccination practices and close antibody titer monitoring should be applied while on dialysis. HBV infected dialysis patients who are renal transplant candidates must be thoroughly examined by HBV-DNA, and liver enzyme testing and by liver biopsy. When needed, one must consider treating patients with tenofovir or entecavir rather than lamivudine. Depending on the cirrhosis stage, dialysis patients are eligible transplant recipients for either a combined kidney-liver procedure in the case of decompensated cirrhosis or a lone kidney transplantation since even compensated cirrhosis after sustained viral responders is no longer considered an absolute contraindication. Nucleoside analogues have led to improved transplantation outcomes with both long-term patient and graft survival rates nearing those of HBsAg(-) recipients. Moreover, in the cases of immunized HBsAg(-) potential recipients with concurrent prophylaxis, we are enabled today to safely use renal grafts from both HBsAg(+) and HBsAg(-)/anti-HBc(+) donors. In so doing, we avoid unnecessary organ discarding. Universal prophylaxis with entecavir is recommended in HBV kidney recipients and should start perioperatively. One of the most important issues in HBV(+) kidney transplantation is the duration of antiviral prophylaxis. In the absence of robust data, it seems that prophylactic treatment may be discontinued in selected stable, low-risk recipients during maintenance immunosuppression and should be reintroduced when the immune status is altered. All immunosuppressive agents in kidney transplantation can be used in HBV(+) recipients. Immunosuppression is intimately associated with increased viral replication; thus it is important to minimize the total immunosuppression burden long term. ",0
6242,28951810,Development of the KOSHA Proficiency Testing Scheme on Asbestos Analysis in Korea,"This commentary presents the regulatory backgrounds and development of the national proficiency testing (PT) scheme on asbestos analysis in the Republic of Korea. Since 2009, under the amended Occupational Safety and Health Act, the survey of asbestos in buildings and clearance test of asbestos removal works have been mandated to be carried out by the laboratories designated by the Ministry of Employment and Labor (MOEL) in the Republic of Korea. To assess the performance of asbestos laboratories, a PT scheme on asbestos analysis was launched by the Korea Occupational Safety and Health Agency (KOSHA) on behalf of the MOEL in 2007. Participating laboratories are evaluated once a year for fiber counting and bulk asbestos analysis by phase contrast microscopy and polarized light microscopy, respectively. Currently, the number of laboratory enrollments is > 200, and the percentage of passed laboratories is > 90. The current status and several significant changes in operation, sample preparations, and statistics of assigning the reference values of the KOSHA PT scheme on asbestos analysis are presented. Critical retrospect based on the experiences of operating the KOSHA PT scheme suggests considerations for developing a new national PT scheme for asbestos analysis. ",0
6243,28951813,"""Spontaneous reoccurrence of """"scooping"""", a wild tool-use behaviour, in naïve chimpanzees""","""Modern human technological culture depends on social learning. A widespread assumption for chimpanzee tool-use cultures is that they, too, are dependent on social learning. However, we provide evidence to suggest that individual learning, rather than social learning, is the driver behind determining the form of these behaviours within and across individuals. Low-fidelity social learning instead merely facilitates the reinnovation of these behaviours, and thus helps homogenise the behaviour across chimpanzees, creating the population-wide patterns observed in the wild (what here we call """"socially mediated serial reinnovations""""). This is the main prediction of the Zone of Latent Solutions (ZLS) hypothesis. This study directly tested the ZLS hypothesis on algae scooping, a wild chimpanzee tool-use behaviour. We provided naïve chimpanzees ( """,0
6244,28951863,A Case of Granular Cell Tumor of the Clitoris in a Postmenopausal Woman,"Granular cell tumor (GCT) is a rare soft tissue tumor that derived from Schwann cells. Most are benign, less than 2% are malignant and, in the malignant cases, the prognosis of survival is poor. Most of these tumors are less than 3 cm in size, and they are more common in black women. The disease usually occurs in the 40s to the 60s and occurs after menopause, but there are few cases reported in adolescence. A 45-year-old woman visited the outpatient clinic with a solid mass that developed 2 years ago and present to date on the left side of the clitoris. After complete resection, pathologic examination proved to be a granular cell. The patient has been living without recurrence for one year. We report the first case of the GCT of the clitoris in postmenopausal woman in Korea with a brief review of the literature. ",0
6245,28951937,Personal light-at-night exposures and components of variability in two common shift work industries: uses and implications for future research,"Objectives Shift workers' increased risk of various adverse health outcomes has been linked to light-at-night (LAN) exposure, but few studies have measured LAN exposure in workplaces. To inform future research methods, this study aimed to (i) measure shift workers' exposures to LAN across industries, occupations, and work environments and (ii) assess components of variance across different exposure groupings and metrics. Methods Between October 2015 and March 2016, 152 personal full-shift measurements were collected from 102 night shift workers in emergency health services (paramedics, dispatchers) and healthcare industries (nurses, care aides, security guards, unit clerks, and laboratory, pharmacy, and respiratory therapy staff) in the province of British Columbia, Canada. Descriptive and variance component analyses were conducted for the 23:00-05:00 period to characterize exposures using multiple metrics of potential biological relevance (median lux, 90  ",0
6246,28951939,Biological and Pro-Angiogenic Properties of Genetically Modified Human Primary Myoblasts Overexpressing Placental Growth Factor in In Vitro and In Vivo Studies,"Cardiovascular diseases are a growing problem in developing countries; therefore, there is an ongoing intensive search for new approaches to treat these disorders. Currently, cellular therapies are focused on healing the damaged heart by implanting stem cells modified with pro-angiogenic factors. This approach ensures that the introduced cells are capable of fulfilling the complex requirements of the environment, including the replacement of the post-infarction scar with cells that are able to contract and promote the formation of new blood vessels that can supply the ischaemic region with nutrients and oxygen. This study focused on the genetic modification of human skeletal muscle cells (SkMCs). We chose myoblast cells due to their close biological resemblance to cardiomyocytes and the placental growth factor (PlGF) gene due to its pro-angiogenic potential. In our in vitro studies, we transfected SkMCs with the PlGF gene using electroporation, which has previously been proven to be efficient and generate robust overexpression of the PlGF gene and elevate PlGF protein secretion. Moreover, the functionality of the secreted pro-angiogenic proteins was confirmed using an in vitro capillary development assay. We have also examined the influence of PlGF overexpression on VEGF-A and VEGF-B, which are well-known factors described in the literature as the most potent activators of blood vessel formation. We were able to confirm the overexpression of VEGF-A in myoblasts transfected with the PlGF gene. The results obtained in this study were further verified in an animal model. These data were able to confirm the potential therapeutic effects of the applied treatments. ",0
6247,28952425,Reduction of acrylamide in whole-wheat bread by combining lactobacilli and yeast fermentation,"This study mainly focuses on a strategy for reducing acrylamide content in whole-wheat bread by combining lactobacilli and yeast in sourdough breadmaking. Combinations of sourdough (fermented dough using different Lactobacillus strains including Lactobacillus plantarum PTCC 1896 [probiotic], L. sakei DSM 20,017, L. rhamnosus DSM 20,021, and L. delbrueckii DSM 20,081) and yeast, in comparison with yeast alone, were used for breadmaking. The results showed that acrylamide levels in breads fermented using sourdough+yeast were in all cases much lower (6.9-20 μg/kg on a dry weight basis [d.b.]) than those in the yeast-only fermented bread (47.6 μg/kg d.b.). Significant (p < 0.05) correlations were also found between pH, total titratable acids (TTA) and lactic acid, and acrylamide content. Furthermore, the obtained results showed that the moisture content of dough directly influenced the formation of acrylamide in bread (r = 0.925, p < 0.0001). In addition, no significant correlations were observed between acrylamide content in breads and either the reducing sugar or free amino acid contents in dough samples. According to the different effects of Lactobacillus strains, it could be concluded that the acrylamide reducing potential of lactobacilli was strain-specific, with L. rhamnosus being the most effective. This suggests that sourdough fermentation with appropriate Lactobacillus strains can be used as an advantageous technology to reduce the acrylamide content of whole-wheat breads. ",0
6248,28952879,Exploring the Link between Radiation Exposure and Multifocal Basal Cell Carcinomas in a Former Chernobyl Clean-up Worker by Combining Different Molecular Biological Techniques,"Thirty years after the Chernobyl nuclear power plant accident we report on a patient who was a clean-up worker, who subsequently developed multiple cutaneous basal cell carcinomas (BCCs). We used several methods to assess the biological long-term effects related to low-dose external and internal radiation exposure. Specifically, because BCC risk may be increased with ionizing radiation exposure, we endeavored to determine whether the multifocal BCCs were related to the patient's past clean-up work. We assessed cytogenetic changes using peripheral blood, and internal incorporation was measured with a whole-body counter. Gene expression alterations were determined and array-based comparative genomic hybridization was performed for copy number aberration analysis of available BCC samples. In 1,053 metaphase cells, the dicentric yield of 0.005 dicentrics, with acentrics/cell, was significantly increased compared to the established calibration curve (P < 0.001). A 2.5-fold increase in total translocations was observed compared to the expected translocation rate. No internal contamination was detected with the whole-body counter. At the RNA level, two of seven genes (HNRNPA1, AGAP4/6/8) indicated internal plutonium exposure associated with the lowest dose category found in Mayak workers (>0-0.055 Gy). Relevant DNA copy number changes were only detected within the most aggressive BCC focus. Our results suggest that the examined worker had low and more recent radiation exposure with presumably internalized radionuclides that were below the detection level of a whole-body counter. The multifocal BCC could not be related to past occupational radiation exposure. The findings from our study suggest that integrating different methodologies potentially provides an improved overall assessment of individual health risks associated with or excluding occupational radiation exposure. ",0
6249,28952905,The Use of Orthotic Insoles to Prevent Lower Limb Overuse Injuries: A Critically Appraised Topic,"Overuse injuries are common in physically active populations. Lower limb overuse injuries can occur anywhere in the lower-extremity and include injuries such as medial tibial stress syndrome, plantar fasciitis, and anterior knee pain. One reason that overuse injuries have received attention is because they have both short- and long-term consequences on health and burden the lives of physically active people. Over the years, a variety of approaches have been proposed for prevention of lower limb overuse injury that addresses various intrinsic or extrinsic risk factors. One extrinsic risk factor is footwear and the use of orthotic insoles to prevent injury. To date, there is no consensus as to whether these supports prevented lower limb overuse injuries. A critical appraisal of recent studies examining the injury prevention capabilities of orthotic insoles was completed. The long-term objective of this research is to help identify effective strategies for preventing injuries in physically active people. ",0
6250,28953079,Associations Between Type and Route of Hormone Use on Urinary Incontinence and Pelvic Organ Prolapse in Premenopausal and Postmenopausal Women,"""The aim of this study was to evaluate the associations between type and route of hormone use and urinary incontinence (UI) and pelvic organ prolapse (POP) in premenopausal and postmenopausal women. The authors used the National Health and Nutritional Examination Survey database for data from 2005-2006, 2007-2008, 2009-2010, and 2011-2012. Seven thousand sixty-six of the women included were premenopausal, and 5387 were postmenopausal. Premenopausal women were younger than 51 years and reported menstrual periods in the last 12 months. Postmenopausal women reported being in natural or surgical menopause. Urinary incontinence was defined as experiencing urinary leakage """"less than once a month"""" or more. Pelvic organ prolapse was defined as an affirmative response to """"experience bulging in the vaginal area."""" Hormone route and use were stratified in years. Pearson χ and Pearson correlations were used, with P < 0.05 considered significant. In premenopausal women, birth control pills, estrogen/progestin pills, and estrogen-only patch use are associated with UI (P < 0.05). Birth control pills are associated with both UI and POP in premenopausal women (P < 0.05 for UI and POP). In postmenopausal women, estrogen-only pills, and estrogen/progestin pill use are associated with UI (P < 0.05). Birth control pill use is associated with POP in postmenopausal women (P = 0.029). Neither estrogen patch nor estrogen/progestin patch is associated with UI or POP in postmenopausal women. Type and route of hormone use have varied associations with UI and POP in premenopausal and postmenopausal women. Prospective studies are needed to further evaluate the effect of hormone type and route on UI and POP in premenopausal and postmenopausal women. """,0
6251,28953427,Comparison of Strategies of Treatment with Ranibizumab in Newly-Diagnosed Cases of Neovascular Age-Related Macular Degeneration,"In several case-studies improved outcomes have been reported after switching from a pro-re-nata (PRN)- to a treat-and-extend (T&E)-based therapeutic approach in cases of neovascular age-related macular degeneration (nAMD). We therefore wished to compare the effects of instigating 2 different protocols in newly-diagnosed nAMD undergoing treatment with Ranibizumab. The outcomes of a PRN- and a T&E-based regime were retrospectively compared in treatment-naïve eyes under therapy with Ranibizumab for minimally 12 months in a routine clinical setting. The primary outcome measures included the proportion of the eyes with intraretinal fluid in OCT and visual stability after the initial drug-loading phase. The comparative case-series included 107 eyes (PRN: 68; T&E: 39). During the 2-year follow-up period, a similar number of clinical examinations were performed in the 2 groups (PRN: 14.0 ± 6.2; T&E 13.4 ± 4.4; P = 0.97), whereas the number of injections that were administered differed for the first (PRN: 5.5 ± 2.0 vs. T&E 6.8 ± 2.4; P = 0.008) and the second year (PRN: 1.9 ± 2.0 vs. T&E 3.8 ± 2.3; P = 0.002). The proportion of eyes with intraretinal fluid after the initial drug-loading phase remained stable (PRN: from 33.8% to 36.4%; T&E: from 25.6% to 29.0%); so, too, did the central retinal thickness and the visual acuity. Despite a limited sample size, this retrospective analysis revealed the anatomical and the functional improvements during the 2-year follow-up period to be not roughly different for the 2 strategies. However, when the PRN-approach is instigated, the risk of under-treatment due to lapses in visits or to over-extensions in the intervals between treatments may be underestimated. ",0
6252,28953556,Uncontrolled bleeding of the gastrointestinal tract,"Acute gastrointestinal bleeding is a frequent emergency situation, whose incidence will likely rise as a result of the increasing use of direct anticoagulants and of the medical progresses resulting in longer life expectancy with underlying comorbidities. Updated guidelines and improvements in the diagnostic and therapeutic tools are now available and will likely improve the management of massive gastrointestinal bleeding in the near future. The assessment of severity has been improved by validated scores useable upon admission. Massive blood transfusion protocols and specific care in case of bleeding of patients treated with direct anticoagulants, including concentrates of coagulation factors and monoclonal antibodies are now available. The endoscopic management has been facilitated by the use of hemostatic powders and by the use of self-expanding metal stents in case of variceal hemorrhage. New diagnostic tools include emergency video-capsule endoscopy, multiphasic computed tomography angiography and enterography. The implementation of multidisciplinary diagnostic and therapeutic algorithms for the management of massive bleeding requires a close collaboration between emergency physicians, intensivists, endoscopists, radiologists and surgeons. A sequential strategy involving each of these specialists is desirable for a successful management of acute and massive gastrointestinal bleeding. ",0
6253,28953679,Neuroleptic malignant syndrome with thyroid disorder: An unusual case report,"Neuroleptic malignant syndrome (NMS) is a life threatening neurologic emergency associated with neuroleptic or antipsychotic agent use. NMS is rarely related to thyroid disease. We report a case of NMS in a 66-year-old male with past medical history of paranoid schizophrenia on chlorpromazine, diabetes, hypertension and asthma, who presented with a humeral fracture after a fall. Patient developed hyperpyrexia, altered consciousness, autonomic instability, elevated serum creatine kinase (CK) without rigidity. CT head and workup for infection were negative. Electroencephalogram (EEG) showed generalized slow wave activity. Ultrasound revealed a large goiter with nodules. Chlorpromazine was stopped due to concern of NMS. Patient was treated with cooling, fluid and electrolyte maintenance. Patient slowly improved and CK level normalized. Thyroid-stimulating hormone (TSH) level trended down from 10.2 mIU/L to 0.02 mIU/L. Patient was discharged with aripiprazole. Hypothyroidism predisposes patients to NMS by altering central dopaminergic systems. The typical symptoms may be masked by hypothyroidism. Thyroid dysfunction should be excluded in all patients with NMS. Discontinuing antipsychotic agents decreases TSH levels which maybe due to the negative feedback of dopaminergic activity. This is the first case report describing dramatic changes in TSH after discontinuing chlorpromazine in NMS. ",0
6254,28953782,Harnessing the Power of Film to Combat Mental Health Stigma. A University College London Psychiatry Society Event,"""To conduct a pilot study on a motion picture based, anti-stigma programme entitled, """"The Wounded Healer film"""" to measure if it is associated with any changes in stigma variables in healthcare students and if it encouraged care seeking in this group. The 2008 Stigma Shout Survey of almost 4000 people using mental health services and carers revealed that healthcare professionals are a common source of stigma reported by people with mental illness. Psychological problems are common in medical students and doctors, however, thelevel of care seeking in this group is low. Fear of exposure to stigmatization is a crucial barrier to accessing and using mental health services. Recent research has revealed that film-based interventions can be used to challenge mental health stigma and encourage care seeking. We conducted a single-arm, pre-post comparison study on students who attended the Wounded Healer film at a University College London Psychiatry Society event (n=11). Before and after exposure to the film, students were asked to complete validated stigma scales that measured mental health-related knowledge, attitudes and behaviours. Responses were on a Likert scale and participants also provided free free-text comments which were subjected to thematic analyses. There was a statistically significant difference in the mental health-related knowledge pre-intervention score compared to the post-intervention score (p=0.0322). All participants either strongly agreed or agreed with the post-evaluation statement, """"I feel inspired to raise awareness of the importance of mental health and to take action to challenge stigma."""" This pilot study provides provisional support that The Wounded Healer film may be associated with reductions in stigma variables in healthcare students and encourage them to seek care for their own psychological problems. More robust research in this area is needed before we can scale up such an initiative. """,0
6255,28953803,Overcoming the Social Stigma on Mood Disorders with Dancing,"""In our society, the social stigma against people who suffer from mood disorders is a very powerful factor that negatively affects the healing of patient. He is often isolated from the others for the fear of being judged """"fool, crazy or dangerous"""" or discriminated and emarginated for his mental health problem. For this reason, a cornerstone of mood disorder rehabilitation is the bringing out of the patient from his isolation, the reintegration of the user in the social context with the increase and the improvement in the quality of interpersonal relationships in the family and in the external context. The method used in our project is the dance-therapy one. In particular dancing the """"Bachata"""" becomes a rehabilitation tool to express emotions through the body and to open to the world, on the territory, overcoming the fear of being judged by others, and of the prejudice and the social stigma about mental illness. The strength and cohesion of the rehabilitation group has given to the patients the opportunity to believe in their own abilities, to accept themselves with their difficulties and to improve the relationship with their body in relation to each other. """,0
6256,28953829,Analysis of Urinary Incontinence and Depression among Young Women,"Urinary incontinence has a negative impact on a health related quality of life, and it contributes to depression. Depression is a serious illness affecting health, family and professional activity of many people in all sectors of society. Both conditions concern young women. Following study presents depression among young women suffering urinary incontinence. There are various aspects of the young women's comorbid depression and urinary incontinence, mentioned in the present literature: coexistence of depression and urinary incontinence, area of postpartum period, associated sexual dysfunction, and impact on the professional sphere. To conclude, it should be highlighted that the problem of urinary incontinence and depression affects not only elderly, as it would be suspected, but on a large scale also young women and there is a strong need of the further prevention and investigation these coexisting diseases. ",0
6257,28953846,Does Risperidone Long Acting Injectable Depot (RLAI) Reduce number of Admissions to Hospital,"Adherence to treatment is a major issue in relapse prevention in schizophrenia. Injectable depot has been claimed to improve non-adherence. A study in the North of England has shown that risperidone long acting injectable form has reduced number of admissions and number of days stayed in hospital. Our study aimed to replicate the previous study in the South of England. A retrospective study was conducted in the South Essex Foundation University NHS trust. We selected every fifth patient on the Hospital Pharmacy list for risperidone long acting injectable (RLAI). We collected information on. Age, sex, diagnosis and medication ,regular follow up, investigation of each patient which included weight, FBS, S. lipid and hormones at the start of treatment, at three months and six months intervals. We recorded reasons for starting RLAI. Number of antipsychotics prescribed before RLAI, illness duration, number of admissions and days stayed in hospital in each episode before and after RLAI. Patients were included if they stayed for one year or on RLAI. We reviewed 65 case notes. The most common reason for starting RLAI was non compliance. 80% of our sample had the illness for more than five years. Half of them had physical morbidity. After RLAI was commenced there was a significant association with number and length of admissions. We have found an association between prescription of RLAI and reduction in number and length of admission. This needs to be confirmed in a randomised controlled trial. ",0
6258,28954094,Wound natural healing in treatment of tumor-like hypertrophic scar,"Surgical sutures, wound tension, additional skin incisions and other factors may result in recurrence of tumor-like scar. To investigate the role of wound natural healing therapy in tumor-like hypertrophic scar. In this study, tumor-like hypertrophic scars of 47 cases were excised completely and the residual wounds were treated with natural healing. The short-term and long-term effects of treatment were evaluated. All cases were successfully cured by natural healing therapy. The healing time of the maximum wound (80mm × 20mm) and the minimal wound (5mm× 5mm) was 25 days and 7 days respectively. The size of new skin scars ranged from 3mm to 11 mm. Clinical followed-up was performed in 34 cases for 36 months. Among them, no recurrence happened in 31 cases and new scar size ranged from 2mm to 8mm, while local recurrence happened in 3 cases whose scar size were less than 5 mm. The cure rate of the therapy was 91.2%. The wound natural healing therapy is effective in treating tumor-like hypertrophic scar, which can prevent recurrence and has good cosmetic results. ",0
6259,28954240,"Depression, functional disability and quality of life among Nigerian older adults: Prevalences and relationships","Ageing is associated with increased morbidity, depression and decline in function. These may consequently impair the quality of life (QoL) of older adults. This study was used to investigate the prevalence of functional disability, depression, and level of quality of life of older adults residing in Uyo metropolis and its environs, Nigeria. This cross sectional survey involved 206 (116 females and 90 males) older adults with mean age of 69.8±6.7. The World Health Organization Quality of Life-OLD, Functional status Questionnaire (FSQ) and Geriatric Depression Scale (GDS) were used to measure quality of life, functional disability and depression respectively. Data was analysed using frequency counts and percentages and Spearman rank-order correlation coefficient, at 0.05 alpha level. 45.5% of participants had depression, and at least 30% had functional disability in at least one domain, but their quality of life was fairly good (>60.0%) across all domains. Significant correlation existed between depression scores and individual quality of life and functional disability domains and between overall QoL and each functional disability domain (p<0.001). Depression and functional disability were quite prevalent among sampled older adults but their QOL was not too severely affected. Since the constructs were interrelated, it seems interventions targeted at depression and functional status may invariably enhance the quality of life of the older adults. ",0
6260,28954241,Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy,"Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in γH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved γH2AX response. β1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype. ",0
6261,28954272,CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2,"Pancreatic cancer cells (PCC) is one of the most risky cancers and gemcitabine (GEM) is the standard first-line drug for treating PCC. The PCC will develop drug resistance to GEM after a period of treatment. However, the detailed molecular mechanism of pathogenesis and drug resistance remains unresolved. we employed qRT-PCR and western blot to examine the expression level of CXCR4, let-7a and HMGA2. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The expression level of epithelial marker E-cadherin and mesenthymal marker N-cadherin was detected by western blot. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. we first proved that CXCR4 negatively regulated let-7a in PCC. Next, let-7a was confirmed to play crucial role in tumorigenesis, metastasis and drug resistance of pancreatic cancer cells Bxpc-3 and Panc-1 in vitro and in vivo. Finally, we identified HMGA2 as important downsteam target of let-7a in PCC and overexpression of HMGA2 restores cell proliferation, metastasis and chemosensitivity of GEM inhibited by let-7a. Conlusion: Taken together, we show an important signaling pathway involved in pathogenesis and drug resistance of PCC, thereby providing deeper insight into molecular mechanism by which CXCR4/let-7a regulates tumorigenesis and drug resistance of PCC. These findings will help us develop new strategies for diagnosis and treatment of PCC. ",0
6262,28954633,Clusterin modulates transdifferentiation of non-small-cell lung cancer,"Secreted clusterin (sCLU), a 75-80 kDa disulfide-linked heterodimeric protein, plays crucial roles in various pathophysiological processes, including lipid transport, tissue remodeling, cell apoptosis and reproduction. Our previous studies demonstrated that sCLU could influence cell apoptosis, proliferation, and invasion of non-small cell lung cancer (NSCLC) cells. In this study, clusterin's function in regulating transdifferentiation of NSCLC cells was investigated. In addition, we examined the correlation between clusterin and clinicopathological features of lung cancer. We found that clusterin was increased in lung adenocarcinoma tissues and decreased in lung squamous cell carcinoma tissues through immunohistochemical technique. In cultured lung adenocarcinoma cell lines, clusterin addition could increase SP-C protein expression in 2.75-fold, and decrease p63 protein expression in 0.65-fold (1.54 to 1). And also clusterin addition could increase SP-C mRNA expression in 4.05-fold, decreased p63 mRNA expression in 0.51-fold. Our study demonstrated that clusterin could promote EMT and influence transdifferentiation from lung squamous cell carcinoma to lung adenocarcinoma. However, we found that clusterin expression have no correlation with malignance associate clinicopathological data. Our study may help to further elucidate the development and progression of NSCLC, also it may contribute to the research of therapies targeting sCLU. ",0
6263,28955031,Printing of small molecular medicines from the vapor phase,"There is growing need to develop efficient methods for early-stage drug discovery, continuous manufacturing of drug delivery vehicles, and ultra-precise dosing of high potency drugs. Here we demonstrate the use of solvent-free organic vapor jet printing to deposit nanostructured films of small molecular pharmaceutical ingredients, including caffeine, paracetamol, ibuprofen, tamoxifen, BAY 11-7082 and fluorescein, with accuracy on the scale of micrograms per square centimeter, onto glass, Tegaderm, Listerine tabs, and stainless steel microneedles. The printed films exhibit similar crystallographic order and chemistry as the original powders; controlled, order-of-magnitude enhancements of dissolution rate are observed relative to powder-form particles. In vitro treatment of breast and ovarian cancer cell cultures in aqueous media by tamoxifen and BAY 11-7082 films shows similar behavior to drugs pre-dissolved in dimethyl sulfoxide. The demonstrated precise printing of medicines as films, without the use of solvents, can accelerate drug screening and enable continuous manufacturing, while enhancing dosage accuracy.Traditional approaches used in the pharmaceutical industry are not precise or versatile enough for customized medicine formulation and manufacture. Here the authors produce a method to form coatings, with accurate dosages, as well as a means of closely controlling dissolution kinetics. ",0
6264,28955073,Comparison of embryo morphokinetics following intracytoplasmic sperm injection in smoker and non-smoker couples: Are the results different?,"To assess early embryo development via time-lapse in smokers and non-smokers. The retrospective study was conducted at Novafertil IVF centers in Konya, Turkey and comprised oocytes of both smoker and non-smoker couples subjected to in vitro fertilisation / introcytoplasmic sperm injection from 2012 to 2015. Age, basal follicle-stimulating hormone, number of stimulation days, amount of gonadotropin used, number of metaphase II oocytes, number of embryos transferred and pregnancy, abortus and clinical pregnancy rates were noted. The embryos were observed for 72 hours in the time-lapse monitoring system. SPSS 22 was used for data analysis. Of the 257 couples, 132(51.4%) were non-smokers and 125(48.6%) were smokers. A total of 1,414 oocytes were collected from non-smokers and 1,280 oocytes from smokers. There was no significant difference in the age of patients and number of stimulation days between the smoker and non-smoker groups (p>0.05). The number of oocytes, fertilised oocytes, transferred embryos and metaphase II oocytes was significantly less in the smoker group (p<0.05). The rate of pregnancy and ongoing pregnancy was also lower in the smoker group (p<0.05). A difference was observed in time of pronuclei appearance, t8, t9+ cleavage times in time-lapse in the smoker and non-smoker groups (p<0.05). A prolongation was observed in time to pronuclear fading and t2 cleavage times in time-lapse in the non-smoker group (p<0.05). Some chromosomal number and structural defects were identified in pre-implantation genetic in some embryos with prolongation in time-lapse cleavage time in the smoker and non-smoker groups. The negative impacts of smoking were not observed at each cleavage phase of embryo development in time-lapse. ",0
6265,28955088,Effects of virtual reality training on mobility and physical function in stroke,"Stroke is a common disabling condition which declines the functional and mobility level. The purpose of the case series was to determine the effect of virtual reality training on sensorimotor function and mobility level in stroke patients. Ten male (40-60 year) patients of stroke (08 Infarction, 02 Haemorrhagic) were selected from Physiotherapy department of Pakistan Railway Hospital, Rawalpindi. The additional virtual reality training (15-20 minutes) was provided 03 days per week for 06weeks along with task oriented training. All patients were assessed through Fugl-Meyer Assessment-Lower Extremity (FMA-LE) and Timed Get Up and Go Test (TUG) at baseline and after 06 weeks of training. The results showed that there was significant improvement in mobility level of stroke patients. It is concluded that combination of task oriented and virtual reality training considerably improves the physical performance and mobility level in stroke patients. ",0
6266,28955232,The Beneficial Effect of Praeruptorin C on Osteoporotic Bone in Ovariectomized Mice via Suppression of Osteoclast Formation and Bone Resorption,"Being a highly prevalent disease, osteoporosis causes metabolism defects. Low bone density, compromised bone strength, and an increased danger of fragility fracture are its main characteristics. Natural compounds have been considered as potential alternative therapeutic agents for treating osteoporosis. In this study, we demonstrated that a natural compound, praeruptorin C (Pra-C), derived from the dried roots of  ",0
6267,28955265,Facilitating Development Research: Suggestions for Recruiting and Re-Recruiting Children and Families,"Recruiting children and families for research studies can be challenging, and re-recruiting former participants for longitudinal research can be even more difficult, especially when a study was not prospectively designed to encompass continuous data collection. In this article, we explain how researchers can set up initial studies to potentially facilitate later waves of data collection; locate former study participants using newer, often digital, tools; schedule families using recruitment phone/email/mail scripts that highlight the many benefits to continued study participation; and confirm appointments with other digital tools. We draw from prior methodological and longitudinal pieces to provide suggestions to others wishing to re-recruit families for longitudinal studies. In addition, we draw upon our own experience conducting a non-prospective longitudinal study 6 years after an educational intervention, in which we successfully re-located 122 (90%) and interviewed 101 of 136 (83% of the located sample and 74% of the full original sample) parents and their early adolescent children. Although the majority of participants were recruited via original contact information (especially phone numbers), using a range of strategies to recruit (e.g., search engines focused on contact information, social media) and motivate participation (e.g., multifaceted phone/email/mail scheduling scripts, flexibility in location and means of participation) yielded a more desirable sample size at relatively low costs. ",0
6268,28955396,Systematic Review of Treatment for Trapped Thrombus in Patent Foramen Ovale,"Trapped thrombus in patent foramen ovale (PFO) is a rare complication of pulmonary embolism that may lead to tragic clinical events. The aim of this study was to identify the optimal treatment for different clinical situations in patients with trapped thrombus in a PFO by conducting a literature review. A PubMed database search was conducted from 1991 through 2015, and 194 patients (185 articles) with trapped thrombus in a PFO were identified. Patient characteristics, paradoxical embolic events, and factors affecting 60-day mortality were analyzed retrospectively. Among all patients, 112 (57.7%) were treated with surgery, 28 with thrombolysis, and 54 with anticoagulation alone. Dyspnea (79.4%), chest pain (33.0%), and syncope (17.5%) were the most common presenting symptoms. Pretreatment embolism was found in 37.6% of cases, and stroke (24.7%) was the most common event. Surgery was associated with fewer post-treatment embolic events than were other treatment options (p=0.044). In the multivariate analysis, initial shock or arrest, and thrombolysis were independent predictors of 60-day mortality. Thrombolysis was related with higher 60-day mortality compared with surgery in patients who had no initial shock or arrest. This systematic review showed that surgery was associated with a lower overall incidence of post-treatment embolic events and a lower 60-day mortality in patients with trapped thrombus in a PFO. In patients without initial shock or arrest, thrombolysis was related with a higher 60-day mortality compared with surgery. ",0
6269,28955432,Reframing noncommunicable diseases and injuries for the poorest Malawians: the Malawi National NCDI Poverty Commission,"""Noncommunicable diseases and injuries (NCDIs) account for nearly 70% of deaths worldwide, with an estimated 75% of these deaths occurring in low- and middle-income countries. Globally, the burden of disease from noncommunicable diseases (NCDs) is most often caused by the """"big 4,"""" namely: diabetes, cardiovascular diseases, cancer, and chronic lung diseases. However, in Malawi, these 4 conditions account for only 29% of the NCDI disease burden. The Malawi National NCDI Poverty Commission was launched in November 2016 and will describe and evaluate the current NCDI situation in Malawi, with a focus on the poorest populations. The National Commission will investigate which NCDIs cause the biggest burden, which are more present in the young, and which interventions are available to avert death and disability from NCDIs in Malawi, particularly among the poorest segments of the population. The evidence gained through the work of this Commission will help inform research, policy, and programme interventions, all through an advocacy lens, as we strive to address the impact of NCDIs among all populations in Malawi. """,0
6270,28955781,An evolutionary perspective on the role of mesencephalic astrocyte-derived neurotrophic factor (MANF): At the crossroads of poriferan innate immune and apoptotic pathways,"The mesencephalic astrocyte-derived neurotrophic factor (MANF) belongs to a recently discovered family of neurotrophic factors. MANF can be secreted but is generally resident within the endoplasmic reticulum (ER) in neuronal and non-neuronal cells, where it is involved in the ER stress response with pro-survival effects. Here we report the discovery of the MANF homolog SDMANF in the sponge  ",0
6271,28956272,First Detection of Hepatitis E Virus in Shellfish and in Seawater from Production Areas in Southern Italy,"Shellfish samples (n = 384) from production areas, water samples from the same areas (n = 39) and from nearby sewage discharge points (n = 29) were analyzed for hepatitis E virus (HEV) by real-time and nested RT-PCR. Ten shellfish samples (2.6%) and five seawater samples (12.8%) tested positive for HEV; all characterized strains were G3 and showed high degree of sequence identity. An integrated surveillance in seafood and waters is relevant to reduce the risk of shellfish-associated illnesses. ",0
6272,28956420,Targeted ultrasound molecular imaging in mouse atherosclerotic plaque model,"This study aims to assess the early diagnosis of mouse atherosclerotic plaque through targeted ultrasound molecular imaging. Forty Apolipoprotein E-deficient (ApoE-/-) mice and 40 C57BL/6 wild type mice were randomly divided into 4 groups, 20 mice per group. Mice included in the study group were fed with high cholesterol diet for 20 weeks, after which the targeted ultrasound microbubbles were prepared. The mice with atherosclerotic plaque were studied with targeted ultrasound molecular imaging in comparison with red oil O staining. The results of targeted ultrasound molecular imaging of atherosclerotic plaque indicate that the GP Ib and GP IIb/IIIa are viable biomarkers for early diagnosis of vulnerable atherosclerotic plaque. The targeted ultrasound molecular imaging is worth studying in order to identify the atherosclerotic progress as a noninvasive effective identification method which could be used widely. ",0
6273,28956617,The Use of User-Centered Participatory Design in Serious Games for Anxiety and Depression,"There is increasing interest in using serious games to deliver or complement healthcare interventions for mental health, particularly for the most common mental health conditions such as anxiety and depression. Initial results seem promising, yet variations exist in the effectiveness of serious games, highlighting the importance of understanding optimal design features. It has been suggested that the involvement of end-users in the design and decision-making process could influence game effectiveness. In user-centered design (UCD) or participatory design (PD), users are involved in stages of the process, including planning, designing, implementing, and testing the serious game. To the authors' knowledge, no literature review to date has assessed the use of UCD/PD in games that are designed for mental health, specifically for anxiety or depression. The aim of this review is, therefore, to document the extent to which published studies of serious games that are designed to prevent or treat anxiety and depression have adopted a PD framework. A search of keywords in PubMed and PsychINFO databases through to December 2016 was conducted. We identified 20 serious games developed to prevent, treat or complement existing therapies for anxiety and/or depression. Half (N = 10; 50%) of these games were developed with input from the intended end-users, in either informant (N = 7; 70%) or full participatory co-design roles (N = 3; 30%). Less than half of games (45%) included users only in the testing phase. ",0
6274,28956655,Evaluation of the Protective Role of Glycine max Seed Extract (Soybean Oil) in Drug-Induced Nephrotoxicity in Experimental Rats,"This study was conducted to evaluate the nephroprotective effect of Glycine max seed extract (soybean oil) against gentamicin- and rifampicin-induced nephrotoxicity in Sprague-Dawley rats and to compare its effects with those of vitamin E, which has well-established antioxidant and nephroprotective effects. Sixty male Sprague-Dawley rats (body weight 150-210 g) were divided into 10 groups. The first five groups were treated for 14 consecutive days with normal saline (5 ml/kg, by mouth [p.o.]); gentamicin (80 mg/kg intraperitoneally [i.p.]); gentamicin (80 mg/kg, i.p.) + vitamin E (250 mg/kg p.o.); gentamicin (80 mg/kg i.p.) + soybean oil (2.5 ml/kg p.o.); and gentamicin (80 mg/kg, i.p.) + soybean oil (5 ml/kg p.o.), respectively. For the next five groups, the same group allocation was done, but gentamicin was replaced with rifampicin (1 g/kg i.p.). Various biomarkers for nephrotoxicity in serum and urine were evaluated along with histopathological examination of kidneys. Analysis of variance (ANOVA) was done following Tukey's multiple comparison test; p < .05 was considered significant. Soybean oil in both doses significantly (p < .005) decreased serum blood urea nitrogen, creatinine, urea, uric acid and urine volume, kidney weight, urinary sodium, urinary potassium, and total protein and significantly (p < .005) increased serum total protein and urine creatinine in gentamicin- and rifampicin-treated animals, exhibiting nephroprotective effects. Soybean oil also showed strong antioxidant effects, causing significant (p < .005) increase in kidney homogenate catalases, glutathione peroxidase, and superoxide dismutase and significant (p < .005) decrease in lipid peroxidase in gentamicin- and rifampicin-treated animals. Soybean oil demonstrated good nephroprotective activity due to antioxidant effects. ",0
6275,28957315,"The diversity of the Chagas parasite, Trypanosoma cruzi, infecting the main Central American vector, Triatoma dimidiata, from Mexico to Colombia","Little is known about the strains of Trypanosoma cruzi circulating in Central America and specifically in the most important vector in this region, Triatoma dimidiata. Approximately six million people are infected with T. cruzi, the causative agent of Chagas disease, which has the greatest negative economic impact and is responsible for ~12,000 deaths annually in Latin America. By international consensus, strains of T. cruzi are divided into six monophyletic clades called discrete typing units (DTUs TcI-VI) and a seventh DTU first identified in bats called TcBat. TcI shows the greatest geographic range and diversity. Identifying strains present and diversity within these strains is important as different strains and their genotypes may cause different pathologies and may circulate in different localities and transmission cycles, thus impacting control efforts, treatment and vaccine development. To determine parasite strains present in T. dimidiata across its geographic range from Mexico to Colombia, we isolated abdominal DNA from T. dimidiata and determined which specimens were infected with T. cruzi by PCR. Strains from infected insects were determined by comparing the sequence of the 18S rDNA and the spliced-leader intergenic region to typed strains in GenBank. Two DTUs were found: 94% of infected T. dimidiata contained TcI and 6% contained TcIV. TcI exhibited high genetic diversity. Geographic structure of TcI haplotypes was evident by Principal Component and Median-Joining Network analyses as well as a significant result in the Mantel test, indicating isolation by distance. There was little evidence of association with TcI haplotypes and host/vector or ecotope. This study provides new information about the strains circulating in the most important Chagas vector in Central America and reveals considerable variability within TcI as well as geographic structuring at this large geographic scale. The lack of association with particular vectors/hosts or ecotopes suggests the parasites are moving among vectors/hosts and ecotopes therefore a comprehensive approach, such as the Ecohealth approach that makes houses refractory to the vectors will be needed to successfully halt transmission of Chagas disease. ",0
6276,28957486,Admissions to inpatient care facilities in the last year of life of community-dwelling older people in Europe,"In the last year of life, many older people rather avoid admissions to inpatient care facilities. We describe and compare such admissions in the last year of life of 5092 community-dwelling older people in 15 European countries (+Israel). Proxy-respondents of the older people, who participated in the longitudinal SHARE study, reported on admissions to inpatient care facilities (hospital, nursing home or hospice) during the last year of their life. Multivariable regression analyses assessed associations between hospitalizations and personal/contextual characteristics. The proportion of people who had been admitted at least once to an inpatient care facility in the last year of life ranged from 54% (France) to 76% (Austria, Israel, Slovenia). Admissions mostly concerned hospitalizations. Multivariable analyses showed that especially Austrians, Israelis and Poles had higher chances of being hospitalized. Further, hospitalizations were more likely for those being ill for 6 months or more (OR:1.67, CI:1.39-2.01), and less likely for persons aged 80+ (OR:0.54, CI:0.39-0.74; compared with 48-65 years), females (OR:0.74, CI:0.63-0.89) and those dying of cardiovascular diseases (OR:0.66, CI:0.51-0.86; compared with those dying of cancer). Although healthcare policies increasingly stress the importance that people reside at home as long as possible, admissions to inpatient care facilities in the last year of life are relatively common across all countries. Furthermore, we found a striking variation concerning the proportion of admissions across countries which cannot only be explained by patient needs. It suggests that such admissions are at least partly driven by system-level or cultural factors. ",0
6277,28960380,Distinct role of nuclear receptor corepressor 1 regulated de novo fatty acids synthesis in liver regeneration and hepatocarcinogenesis in mice,"It is urgent that the means to improve liver regeneration (LR) be found, while mitigating the concurrent risk of hepatocarcinogenesis (HCG). Nuclear receptor corepressor 1 (NCoR1) is a co-repressor of nuclear receptors, which regulates the expression level of metabolic genes; however, little is known about its potential contribution for LR and HCG. Here, we found that liver-specific NCoR1 knockout in mice (NCoR1(?hep) ) dramatically enhances LR after partial hepatectomy and, surprisingly, blocks the process of diethylnitrosamine (DEN)-induced HCG. Both RNA-sequencing and metabolic assay results revealed improved expression of Fasn and Acc2 in NCoR1(?hep) mice, suggesting the critical role of de novo fatty acid synthesis (FAS) in LR. Continual enhanced de novo FAS in NCoR1(?hep) mice resulted in overwhelmed adenosine triphosphate ATP and nicotinamide adenine dinucleotide phosphate (NADPH) consumption and increased mitochondrial reactive oxygen species production, which subsequently attenuated HCG through inducing apoptosis of hepatocytes at an early stage after DEN administration. CONCLUSION: NCoR1 functions as a negative modulator for hepatic de novo FAS and mitochondria energy adaptation, playing distinct roles in regeneration or carcinogenesis. (Hepatology 2018;67:1071-1087).",0
6278,29083504,The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis,"Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. CONCLUSION: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions. (Hepatology 2018;67:1284-1302).",0
6279,29091568,ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes,"BACKGROUND: Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting-enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. METHODS: We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima-media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine). RESULTS: The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima-media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. CONCLUSIONS: The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .).",0
6280,29130810,Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine,"BACKGROUND: Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy. METHODS: Using a 2-by-2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention-to-treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast-associated acute kidney injury was a secondary end point. RESULTS: The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between-group differences in the rates of contrast-associated acute kidney injury. CONCLUSIONS: Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast-associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466 .).",0
6281,29171639,Nutritional supplements in depressive disorders,"There is increasing evidence about the role of nutrients in mental health. An adequate intake of nutrients contributes to better overall health and mental health in particular. Major depression is a severe mental illness with a high prevalence for which effective treatments exist but not in all cases the patient&#8217;s remission is achieved. Therefore, it is increasingly aimed at optimizing the supply of nutrients necessary for adequate brain functioning as adjunctive therapy to antidepressant treatment in depressive disorders. In this article we review those nutrients that have been related to depression: Omega-3 fatty acids, B vitamins, s-adenosylmethionine, tryptophan, magnesium, zinc and probiotics. ",0
6282,29171889,The Shifting Landscape of Prenatal Testing: Between Reproductive Autonomy and Public Health,"Since the 1970s, prenatal testing has been integrated into many health care systems on the basis of two competing and largely irreconcilable rationales. The reproductive autonomy rationale focuses on nondirective counseling and consent as ways to ensure that women's decisions about testing and subsequent care are informed and free of undue pressures. It also represents an easily understandable and ethically convincing basis for widespread access to prenatal testing, since the value of autonomy is well established in Western bioethics and widely recognized by funders of health care. In contrast, the public health rationale approaches prenatal testing as designed to reduce the incidence of certain conditions in the population to reduce the burden of disease. This rationale emphasizes the societal consequences of reproduction and the aggregate impact of women's individual reproductive decisions on the overall health of future populations. In this essay, I argue that, despite what could be seen as a persistent failure to meet the ideals of reproductive autonomy, resisting the public health rationale as a basis for prenatal screening is ethically and pragmatically crucial. I recommend policy mechanisms that can enhance reproductive autonomy at a societal level to support choice at the individual level. ",0
6283,29172122,Brain substrates of early (4h) cigarette abstinence: Identification of treatment targets,"Research indicates that overnight nicotine abstinence disrupts neural activity in the mesocorticolimbic reward network; however, less is known about the time course of abstinence-induced brain changes. To examine the potential neural effects of early abstinence, we used arterial spin labeling perfusion fMRI, to measure regional cerebral blood flow (rCBF) changes in the resting brain induced by 4h of nicotine abstinence. In a repeated measures design, 5min of resting perfusion fMRI data were acquired in awake nicotine-dependent individuals (eyes open) during 'smoking as usual' (SMK) and following 4h of monitored nicotine abstinence (ABS) conditions (N=20). Conditions were compared using a paired t test in SPM8. Craving was assessed prior to each condition. Compared to SMK, ABS significantly increased craving and reduced rCBF in select regions, including the hippocampus and ventral striatum (cluster corr, α=0.01, 943 contiguous voxels). The magnitude of the abstinence-induced change in rCBF correlated with the magnitude of the change in craving across conditions in select regions, including the medial and lateral orbitofrontal cortices and the anterior ventral insula (r values ranging from 0.59-0.74). Results show that as few as 4h of abstinence can reduce resting rCBF in multiple nodes of the brain's mesocorticolimbic network, disrupting neural processing. Identifying early withdrawal treatment targets has far-reaching implications, which include thwarting relapse proclivities. Results parallel those of the extant human literature and are in agreement with an extensive preclinical literature showing compromised mesolimbic dopaminergic function and impairments in reward function during nicotine withdrawal. ",0
6284,29172364,An Update on Current Resuscitation Council (UK) Guidelines,"On 15 October 2015, The Resuscitation Council (UK) published new resuscitation guidelines following the review of resuscitation science by the International Liaison Committee on Resuscitation (ILCOR). The 2015 guidelines emphasize the importance of interactions between the emergency medical dispatcher, the bystander who provides cardiopulmonary resuscitation (CPR) and the prompt deployment of an automated external defibrillator (AED); the co-ordination of these three elements is crucial to improving out-of-hospital cardiac arrest survival. Medical emergencies in dental practices are thought to occur on average once every 3−4 years per dentist in primary care. The GDC consider medical emergencies as a highly recommended topic for Continuing Professional Development (CPD) and recommend at least 10 hours in every CPD cycle. Clinical relevance: The publication of the updated guidelines serves as a reminder to the clinical team of the importance of being up to date with recognition and treatment of cardiac arrest and choking and how seamless interaction between members of both the dental and medical teams improves long-term outcomes for patients. ",0
6285,29172395,The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma,"""We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines. A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of """"stemness""""-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)-related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers. Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p<.05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p<.05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394). The gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of """"stemness""""- and EMT-related markers, and decreased survival. """,0
6286,29172906,"Telenursing and Nurse-Patient Communication Within Fertility, Inc","The purpose of this study is to examine patient perceptions of practitioner-patient communication in reproductive endocrinology and infertility (REI) practices. During this study, we uncovered the importance of telenursing for nurse-patient communication during REI treatment. Telenursing, which is defined as the use of wireless technology for out-of-office communication, is the basis for out-of-office communication. We examined participants' conceptualization of supportive and unsupportive communication, through the lens of biomedicalization theory. After conducting 23 interviews, we conclude that telenursing is integral to providing holistic nursing care during treatment at REI practices. We discuss efficient and effective uses of telenursing and patients' positive perceptions telenursing and assess telenursing as both an embrace of and form of resistance to biomedicalization within Fertility, Inc. Theoretical and practical implications are offered, including suggestions for increasing patient access to telenursing while protecting REI nurses from burnout. ",0
6287,29174322,Comparison of Patient Survival Between Hemodialysis and Peritoneal Dialysis Among Patients Eligible for Both Modalities,"Although peritoneal dialysis (PD) costs less to the health care system compared to in-center hemodialysis (HD), it is an underused therapy. Neither modality has been consistently shown to confer a clear benefit to patient survival. A key limitation of prior research is that study patients were not restricted to those eligible for both therapies. Retrospective cohort study. All adult patients developing end-stage renal disease from January 2004 to December 2013 at any of 7 regional dialysis centers in Ontario, Canada, who had received at least 1 outpatient dialysis treatment and had completed a multidisciplinary modality assessment. HD or PD. Mortality from any cause. Among all incident patients with end-stage renal disease (1,579 HD and 453 PD), PD was associated with lower risk for death among patients younger than 65 years. However, after excluding approximately one-third of all incident patients deemed to be ineligible for PD, the modalities were associated with similar survival regardless of age. This finding was also observed in analyses that were restricted to patients initiating dialysis therapy electively as outpatients. The impact of modality on survival did not vary over time. The determination of PD eligibility was based on the judgment of the multidisciplinary team at each dialysis center. HD and PD are associated with similar mortality among incident dialysis patients who are eligible for both modalities. The effect of modality on survival does not appear to change over time. Future comparisons of dialysis modality should be restricted to individuals who are deemed eligible for both modalities to reflect the outcomes of patients who have the opportunity to choose between HD and PD in clinical practice. ",0
6288,29174486,Accumulation of steroid hormones in the eggshells of Japanese quail (Coturnix coturnix japonica),"Oviparous mother transfer significant amounts of steroid to egg yolk during oviposition and the amounts may vary throughout the embryonic development. Eggshell may contain steroid hormones and the amounts could be different during embryonic development inside the egg. This study was designed to quantify the steroid concentrations in the eggshells of Japanese quail. We hypothesized that the steroids would be accumulated in the eggshells in a sex-dependent manner. Eggshells were obtained from three different stages (after laying, 15 days of incubation, and after hatching). The internal contents of the shells were carefully removed, completely dried and pulverized. The steroid contents of the eggshells were then measured by RIA. Physiologic variations in steroids were analyzed according to the amounts accumulated in the eggshells with the different embryonic stages. Results indicate that eggshell testosterone concentrations were high after laying. However, the concentrations were decreased during embryonic development and hatching and no difference was found in eggshell testosterone levels between male and female. However, eggshell estradiol concentrations were undetectable at laying time and the amounts were significantly increased at 15 days of incubation and slightly after hatching. Eggshell estradiol levels were significantly high in female eggshells than male during embryonic development. In contrast, eggshell corticosterone levels were significantly higher in males than in females after hatching. These results clearly demonstrated that eggshells accumulated steroid hormones, and the amounts varied during embryonic development concomitant with changes the internal contents of the eggs. ",0
6289,29174577,Caffeic acid and licochalcone A interfere with the glyoxylate cycle of Trichophyton rubrum,"Trichophyton rubrum is the most common causative agent of dermatomycoses worldwide. Despite the increasing incidence of fungal infections, the number of commercially available antifungal drugs is limited, mainly because of the biochemical similarities between fungal and mammalian cells. Biomolecules of different origins might lead to the discovery of new pharmacological targets that are more specific to the fungal cell. In this respect, caffeic acid (CA) and licochalcone A (LicoA) exhibit activity against some human pathogenic fungi by acting on important fungal molecular targets. The glyoxylate cycle is involved in the adaptation of fungal cells inside the human cell and is well established for some fungi of clinical interest. Activation of this cycle is related to the survival of fungi in nutrient-limited environments. However, little is known about the involvement of the glyoxylate cycle in this process in dermatophytes. The objective of this study was to evaluate the antifungal activity of CA and LicoA against T. rubrum, investigating specifically the effect of these compounds on important antifungal targets such as ergosterol synthesis, cell wall and glyoxylate cycle. The minimum inhibitory concentration was 86.59 μM for CA and 11.52 μM for LicoA. Plasma membrane damage and a reduction in ergosterol levels were observed after the exposure of T. rubrum to CA, but not to LicoA. Evaluation of gene expression in T. rubrum co-cultured with human keratinocytes (HaCat) in the absence of the antifungal compounds showed induction of genes related to the ergosterol biosynthesis pathway and genes encoding enzymes involved in cell wall synthesis and in the glyoxylate cycle. The same genes were significantly repressed after exposure of the co-culture to subinhibitory concentrations of CA and LicoA. The enzymatic activity of isocitrate lyase was reduced in the presence of LicoA and a moderate reduction was observed in the presence of CA. These results indicate that CA and LicoA act on targets that play important roles in pathogen-host interactions, in antifungal activity and, especially, in the glyoxylate cycle. ",0
6290,29174719,Contaminant source identification using semi-supervised machine learning,"Identification of the original groundwater types present in geochemical mixtures observed in an aquifer is a challenging but very important task. Frequently, some of the groundwater types are related to different infiltration and/or contamination sources associated with various geochemical signatures and origins. The characterization of groundwater mixing processes typically requires solving complex inverse models representing groundwater flow and geochemical transport in the aquifer, where the inverse analysis accounts for available site data. Usually, the model is calibrated against the available data characterizing the spatial and temporal distribution of the observed geochemical types. Numerous different geochemical constituents and processes may need to be simulated in these models which further complicates the analyses. In this paper, we propose a new contaminant source identification approach that performs decomposition of the observation mixtures based on Non-negative Matrix Factorization (NMF) method for Blind Source Separation (BSS), coupled with a custom semi-supervised clustering algorithm. Our methodology, called NMFk, is capable of identifying (a) the unknown number of groundwater types and (b) the original geochemical concentration of the contaminant sources from measured geochemical mixtures with unknown mixing ratios without any additional site information. NMFk is tested on synthetic and real-world site data. The NMFk algorithm works with geochemical data represented in the form of concentrations, ratios (of two constituents; for example, isotope ratios), and delta notations (standard normalized stable isotope ratios). ",0
6291,29174769,Variation in training and use of the focused assessment with sonography in trauma (FAST),"Training in ultrasound is variable among residents and practicing traumatologists. Focused Assessment with Sonography in Trauma (FAST) may be underused in non-urbanized areas, possibly due to lack of training. State trauma registry data from January 2014-June 2016 were reviewed for FAST results. Trauma practitioners were surveyed querying training, confidence, and obstacles to performing FAST. 12,855 records revealed highest FAST use at the urban Level II center (39%, p < 0.0001). Despite similar injury patterns, non-urban/Level III centers' frequency of FAST was only 1-28%. 39 practitioners were surveyed, those with training (54%) were more likely to use FAST (p < 0.05). 61% of practitioners outside the Level II center cited lack of confidence in their ability to perform FAST as the primary reason for omitting the exam. FAST is relatively underused in non-urbanized areas of the state. Lack of confidence in ability to perform FAST was cited as the primary barrier. ",0
6292,29174810,"Design, synthesis, and biological evaluation of new 1,2,3-triazolo-2'-deoxy-2'-fluoro- 4'-azido nucleoside derivatives as potent anti-HBV agents","Novel drugs are urgently needed to combat hepatitis B virus (HBV) infection due to drug-resistant virus. In this paper, a series of novel 4-monosubstituted 2'-deoxy-2'-β-fluoro-4'-azido-β-d-arabinofuranosyl 1,2,3-triazole nucleoside analogues (1a-g) were designed, synthesized and screened for in vitro anti-HBV activity. At 5.0 μM in the cellular model, all the synthetic compounds display activities comparable to that of the positive control, lamivudine at 20 μM. Of the compounds tested, the amide-substituted analogue (1a) shows the most promising anti-HBV activity and low cytotoxicity in the cell model. In particular, it retains excellent activity against lamivudine-resistant HBV mutants. In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (67.4% and 53.3%, respectively) were reduced markedly by the treatment with 1a. Analysis of the structure of HBV polymer/1a-triphosphate (1a-TP) complex shows that 1a-TP is stabilized by specific van der Waals interactions with the enzyme residues arising from 4-amino-1,2,3-triazole and the 4'-azido group. ",0
6293,29175280,"Surfing as a risk factor for sensitization to poly(γ-glutamic acid) in fermented soybeans, natto, allergy","Poly(γ-glutamic acid) (PGA) is an allergen in natto, fermented soybeans, which causes late-onset anaphylaxis. We hypothesized that jellyfish stings sensitize adults to PGA because a surfer had allergies to both natto and jellyfish, whose sting contains PGA. The aim of the study was to identify behavioral factors, such as marine sports, associated with PGA sensitization. Outpatients diagnosed with food allergies based on relevant clinical history, positive skin test and/or food challenge test answered a questionnaire during a regular visit in 2016. Questionnaire data from 140 outpatients were analyzed. These patients were divided into two groups: natto allergy group (13 patients, M:F = 10:3, mean age 40.6 years) and non-natto allergy group (127 patients, M:F = 46:81, mean age 44.5 years). All patients with natto allergy had positive results in skin prick test and basophil activation test with PGA. Of these, 92.3% had a marine sport hobby, especially surfing (84.6%). PGA sensitization was independently associated with marine sports (odds ratio, 278.0, 95 percent confidence interval, 36.9-6315.9, p < 0.001) adjusted for male sex and sea bathing, but not with male sex or sea bathing. In addition, although there was no significant difference in the experience of marine sports between natto and non-natto allergy groups, the natto allergy group participated significantly more frequently in marine sports than the non-natto allergy group (p < 0.001). There was no significant difference between natto consumption amount and PGA sensitization. Surfing is a risk factor for PGA sensitization in those with allergy to natto. ",0
6294,29175390,Human adipose-derived stem cells and simvastatin-functionalized biomimetic calcium phosphate to construct a novel tissue-engineered bone,"To repair bone defects, we evaluate the in-vitro and in-vivo osteogenic activities of a novel tissue-engineered bone (TEB) by elaborately combining biomimetic calcium phosphate (BioCaP) granules with internally-incorporated simvastatin (SIM) and human adipose-derived stem cells (hASCs). First, we constructed BioCaP with SIM internally incorporated (SIM-BioCaP). Then we characterized the morphology and chemical composition of SIM-BioCaP. The release kinetics of SIM was monitored in vitro spectroscopically. Thereafter, we explored the in-vitro cellular responses of hASCs to SIM-BioCaP by performing scanning electron microscopy observation, proliferation assay, alkaline phosphatase (ALP) activity assay, alizarin red staining and real-time PCR. Finally, we investigated the in-vivo osteogenic activities of the novel TEB in a subcutaneous bone induction model in nude mice. We found that SIM was successfully incorporated internally in BioCaP and showed a slow release manner without significantly affecting the attachment and proliferation of hASCs. The released SIM from BioCaP could significantly enhance the proliferation, ALP activities, mineralized nodules formation and osteogenic genes of hASCs. The in-vivo tests showed this TEB could induce new bone formation while the other groups could not. Taken together, the present data show that this novel TEB represented a very promising construct to treat critical-volume bone defects. ",0
6295,29175522,Characterization of cellulosic paper coated with chitosan-zinc oxide nanocomposite containing nisin and its application in packaging of UF cheese,"A new antimicrobial bilayer film was developed using chitosan, cellulose, and nisin. Chitosan solution containing nisin (500 and 1000μg/mL) was prepared by sol-gel method and then the solution was coated on cellulose paper by dip coating method. A chitosan-cellulose film without antimicrobial had no inhibitory effect on Listeria monocytogenes, whereas, the incorporation of nisin made a significant increase (P<0.05) in antimicrobial characteristics of the films. Moreover, no significant differences were shown on antimicrobial activity of developed films during the storage at 4°C for one month. However, the addition of nisin showed a significant increase in the swelling index and solubility of bilayer film. Scanning electron microscope images revealed a uniform coating of chitosan solution on cellulose paper. The FTIR analysis also confırmed successful introducing and binding of the nisin in double layer film. Films with 1000μg/mL of nisin completely inactivated the initial (∼5log ",0
6296,29175628,Neuronal death/apoptosis induced by intracellular zinc deficiency associated with changes in amino-acid neurotransmitters and glutamate receptor subtypes,"In the present study, a model of zinc deficiency was developed by exposing primary neurons to an N,N,N',N'-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN)-containing medium. The cell survival rate, apoptosis rate, intracellular and extracellular concentrations of 4 amino acids, and the expression of 2 glutamate receptor subtypes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (GluR2)and N-methyl-d-aspartate receptor subtype 2B (NR2B) were evaluated in zinc-deficient cells. The results revealed that zinc deficiency led to a decrease in cell viability and an increase in the apoptosis rate. Additionally, in cultured neurons, zinc deficiency led to an increase in the concentration of aspartic acid (Asp) and a decrease in the concentrations of glutamate (Glu), glycine (Gly), and gamma-aminobutyric acid (GABA). These changes were reversed by concurrent zinc supplementation. Furthermore, zinc deficiency led to an increase in the secreted amounts of Glu, Gly, and Asp but a decrease in secreted amounts of GABA, as measured using the concentrations of these amino acids in the cell-culture medium. These changes were partially reversed by zinc supplementation. Finally, zinc deficiency led to a significant decrease in GluR2 expression and an increase in NR2B expression in cultured neurons, whereas simultaneous treatment with zinc sulfate (ZnSO ",0
6297,29175989,"3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)- benzoic acid: a new cause of sensitiser induced occupational asthma, rhinitis and urticaria","3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) has not previously been identified as a respiratory sensitiser. We detected two cases who presented respiratory and urticaria symptoms related to BCMBA and had positive skin prick tests to the agent. Subsequently, we conducted outbreak investigations at the BCMBA-producing factory and performed clinical examinations to confirm occupational diseases. The outbreak investigations included observations of work processes, assessment of exposure, a medical survey with a questionnaire and skin prick tests with 0.5% BCMBA water solution on 85 exposed workers and 9 unexposed workers. We used specific inhalation or nasal challenge and open skin application test to investigate BCMBA-related occupational asthma, rhinitis and contact urticaria. We identified nine workers with respiratory and/or skin symptoms and positive skin prick tests to BCMBA in a chemical factory. A survey among chemical factory workers indicated a BCMBA-related sensitisation rate of 8% among all exposed workers; the rate was highest (25%) among production workers in the production hall. Sensitisation was detected only in workers with the estimated highest exposure levels. Six cases of occupational asthma, rhinitis and/or contact urticaria caused by BCMBA were confirmed with challenge tests. Asthma-provoking doses in specific inhalation challenges were very low (0.03% or 0.3% BCMBA in lactose). We identified a new low molecular weight agent causing occupational asthma, rhinitis and contact urticaria. A typical clinical picture of allergic diseases and positive skin prick tests suggest underlying IgE-mediated disease mechanisms. Stringent exposure control measures are needed in order to prevent BCMBA-related diseases. ",0
6298,29176322,Differential Expression Profiles of the Transcriptome in Breast Cancer Cell Lines Revealed by Next Generation Sequencing,"As MCF-7 and MDA-MB-231 cells are the typical cell lines of two clinical breast tumour subtypes, the aim of the present study was to elucidate the transcriptome differences between MCF-7 and MDA-MB-231 breast cancer cell lines. The mRNA, miRNA (MicroRNA) and lncRNA (Long non-coding RNA) expression profiles were examined using NGS (next generation sequencing) instrument Illumina HiSeq-2500. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to identify the biological functions of differentially expressed coding RNAs. Subsequently, we constructed an mRNA-ncRNA (non-coding RNA) targeting regulatory network. Finally, we performed RT-qPCR (real-time quantitative PCR) to confirm the NGS results. There are sharp distinctions of the coding and non-coding RNA profiles between MCF-7 and MDA-MB-231 cell lines. Among the mRNAs and ncRNAs with the most differential expression, SLPI, SOD2, miR-7, miR-143 and miR-145 were highly expressed in MCF-7 cells, while CD55, KRT17, miR-21, miR-10b, miR-9, NEAT1 and PICSAR were over-expressed in MDA-MB-231 cells. Differentially expressed mRNAs are primarily involved in biological processes of locomotion, biological adhesion, ECM-receptor interaction pathway and focal adhesion. In the targeting regulatory network of differentially expressed RNAs, mRNAs and miRNAs are primarily associated with tumour metastasis, but the functions of lncRNAs remain uncharacterized. These results provide a basis for future studies of breast cancer metastasis and drug resistance. ",0
6299,29176631,Lack of Adipocyte-Fndc5/Irisin Expression and Secretion Reduces Thermogenesis and Enhances Adipogenesis,"Irisin is a browning-stimulating molecule secreted from the fibronectin type III domain containing 5 precursor (FNDC5) by muscle tissue upon exercise stimulation. Despite its beneficial role, there is an unmet and clamorous need to discern many essential aspects of this protein and its mechanism of action not only as a myokine but also as an adipokine. Here we contribute to address this topic by revealing the nature and role of FNDC5/irisin in adipose tissue. First, we show that FNDC5/irisin expression and secretion are induced by adipocyte differentiation and confirm its over-secretion by human obese visceral (VAT) and subcutaneous (SAT) adipose tissues. Second, we show how secreted factors from human obese VAT and SAT decrease PGC1α, FNDC5 and UCP1 gene expression on differentiating adipocytes; this effect over UCP1 is blunted by blocking irisin in obese secretomes. Finally, by stable gene silencing FNDC5 we reveal that FNDC5-KO adipocytes show reduced UCP1 expression and enhanced adipogenesis. ",0
6300,29176649,No evidence for social immunity in co-founding queen associations,"Ant queens often associate to found new colonies, yet the benefits of this behaviour remain unclear. A major hypothesis is that queens founding in groups are protected by social immunity and can better resist disease than solitary queens, due to mutual grooming, sharing of antimicrobials, or higher genetic diversity among their workers. We tested this hypothesis by manipulating the number of queens in incipient colonies of Lasius niger and measuring their resistance to the fungal entomopathogen Metarhizium brunneum. We found no evidence for social immunity in associations of founding queens. First, co-founding queens engaged in self-grooming, but performed very little allo-grooming or trophallaxis. Second, co-founding queens did not exhibit higher pathogen resistance than solitary queens, and their respective workers did not differ in disease resistance. Finally, queens founding in groups increased their investment in a component of individual immunity, as expected if they do not benefit from social immunity but respond to a higher risk of disease. Overall, our results provide no evidence that joint colony founding by L. niger queens increases their ability to resist fungal pathogens. ",0
6301,29177171,Grafting with Cryopreserved Amniotic Membrane versus Conservative Wound Care in Treatment of Pressure Ulcers: A Randomized Clinical Trial,"To compare the healing process of pressure ulcers treated with cryopreserved human amniotic membrane allograft and routine pressure ulcer care in our hospital. From January 2012 to December 2013, in a prospective randomized clinical trial (IRCT201612041335N2), 24 patients with second and third stage of pressure ulcers were enrolled in this study. All patients needed split-thickness skin grafts for pressure ulcer-wound coverage. Selected patients had symmetric ulcers on both upper and lower extremities. The patients were randomly divided into two groups: amnion and control. In the amnion group, the ulcer was covered with cryopreserved amniotic membrane and in the control group it was treated with local Dilantin powder application. The duration and success rate of complete healing was compared between the two groups. The study group was composed of 24 pressure ulcers in 24 patients (19 males and 5 females) with a mean age of 44±12.70 years. The demographic characteristics, ulcer area, and underlying diseases were similar in both groups. The early sign of response, such as decrease in wound discharge, was detected 12-14 days after biological dressing. Complete pressure ulcer healing occurred only in the amnion group ( Cryopreserved amniotic membrane is an effective biologic dressing that promotes re-epithelialization in pressure ulcers. ",0
6302,29177503,Mice with either diminished or elevated levels of anti-Müllerian hormone have decreased litter sizes,"Anti-Müllerian hormone (AMH) is both a gonadal hormone and a putative paracrine regulator of neurons, the uterus, and the placenta. A mouse line with neuronal expression of AMH (Thy1.2-AMH) was generated to examine the role of paracrine AMH in the brain. The mice had normal behavior, but unexpectantly AMH was present in the circulation of the transgenic mice. Thy1.2-AMHTg/0 studs sired pups with a normal frequency, when mated with wild-type dams. In stark contrast, Thy1.2-AMHTg/0 dams rarely gave birth, with evidence of spontaneous midgestational abortion. This leads to the hypothesis that AMH influences the capacity of dams to carry concepti to term. This hypothesis was tested by mating AMH-deficient (Amh-/-), Thy1.2-AMHTg/0, and wild-type dams when 49-, 80-, and 111 days old, using proven wild-type studs. The litter sizes from the first two matings and the number of fetuses present on the 10th day of gestation of the third mating were recorded. Thy1.2-AMHTg/0 dams carried near normal numbers of midterm fetuses, but typically produced no pups, indicating that extensive late resorption of fetuses was occurring. Amh-/- dams exhibited a lesser reduction in litter size than the Thy1.2-AMHTg/0 dams, with no evidence of enhanced loss of fetuses. In conclusion, this study provides the first evidence that high AMH levels can cause a miscarriage phenotype and that the absence of AMH affects reproductive output. ",0
6303,29177679,Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition,"There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4-91.4, 98.83% white) individuals from the Alzheimer's Disease Neuroimaging Initiative 1, GO, and 2. We further investigated the association of PHS with post-mortem amyloid load and neurofibrillary tangles in the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 485, age at death range = 71.3-108.3). In CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%; for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. High PHS individuals with amyloid and tau pathology showed the steepest longitudinal cognitive and clinical decline, even among APOE ε4 noncarriers. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression. In the ROSMAP cohort, higher PHS was associated with higher post-mortem amyloid load and neurofibrillary tangles, even in APOE ε4 noncarriers. Together, our results show that even after accounting for APOE ε4 effects, PHS may be useful in MCI and preclinical AD therapeutic trials to enrich for biomarker-positive individuals at highest risk for short-term clinical progression. ",0
6304,29177682,Density functional theory study of structural and electronic properties of trans and cis structures of thiothixene as a nano-drug,"The geometrical structure, electronic and optical properties, electronic absorption spectra, vibrational frequencies, natural charge distribution, MEP analysis and thermodynamic properties of the trans and cis structures of the drug thiothixene were investigated using density functional theory (DFT) and time-dependent DFT (TDDFT) methods with the B3LYP hybrid functional and 6-311 + G(d,p) basis set. The results of the calculations demonstrate that the cis structure of thiothixene has appropriate quantum properties that can act as an active medicine. The relative energies of trans and cis structures of thiothixene shows that the cis structure is more stable than the trans structure, with a small energy difference. TDDFT calculations show that the cis structure of thiothixene has the best absorption properties. The calculated NLO properties show that the NLO properties of the cis structure of thiothixene are higher than the trans structure, and the fact that the chemical hardness of the cis structure is lower than that of the trans structure that indicates that the reactivity and charge transfer of the cis isomer of thiothixene is higher than that of trans thiothixene. The molecular electrostatic potential (MEP) maps of both structures of thiothixene demonstrate that the oxygen atoms of the molecule are appropriate areas for electrophilic reactions. The vibrational frequencies of the two conformations of thiothixene demonstrate that both structures of thiothixene have almost similar modes of vibrations. The calculated thermodynamic parameters show that these quantities increase with enhancing temperature due to the enhancement of molecular vibrational intensities with temperature. Graphical abstract Trans/Cis isomerization of thiothixene drug. ",0
6305,29178011,"Pyridoxine-dependent epilepsies: an observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort","""The aim of our study was to describe the clinical, electroencephalogram, molecular findings and the diagnostic and therapeutic flow-chart of children with pyridoxine-dependent epilepsies (PDEs). We performed a retrospective observational study on children with PDEs, diagnosed and followed-up in Italian Pediatric Departments. In each centre, the authors collected data from a cohort of children admitted for intractable seizures, responsive to pyridoxine administration and resistant to other anticonvulsant therapies. Data were retrospectively analysed from January 2016 to January 2017. Sixteen patients (13 males, and 3 females) were included. We found that 93.75% of patients underwent conventional anticonvulsant therapy before starting pyridoxine administration and 62.5% had ex-juvantibus diagnosis, as specific serum diagnostic tests had been performed in only 37.5% of patients by alpha-AASA and pipecolic acid blood and urine dosage. The most common type of seizure was generalized tonic-clonic in 7 patients and the most common EEG pattern was characterized by a """"burst suppression"""" pattern. Before pyridoxine administration, other anticonvulsant drugs were used in 93.75% of patients, with consequent onset of drug-resistance. Phenobarbital was the most frequently used drug as first-line treatment. The importance of our study relies on the need of a deeper knowledge of PDEs in terms of early diagnosis, avoiding incorrect treatment and related adverse events, clinical and EEG pathognomonic features, and genetic aspects of the disease. """,0
6306,29178077,Regulatory Roles of Mitochondrial Ribosome in Lung Diseases and Single Cell Biology,"The mitochondria have the most vital processes in eukaryotic cells to produce ATP composed of polypeptides that are produced via ribosomes, as oxidative phosphorylation. Initially, studies regarding human mitochondrial ribosomes were performed in the model system, bovine mitochondrial ribosome, to investigate how ribosomes are biosynthesized and evolved as well as what their structure and function are. Advances in X-ray crystallography have led to dramatic progresses in structural studies of the ribosome. In recent years, there has been a growing interest in the properties of the mitochondrial ribosome. Although one of its main functions is the production of ATP, it was also linked to multiple diseases. A key area that remains unexplored and requires investigation and exploration is how mitochondrial ribosomal RNA (mt-rRNA) variations can affect the mitochondrial ribosomes in developing disease. This review summarizes the structure, elements, functions, and regulatory roles in associated diseases. With the continuous development of technology, studies on the mechanism of mitochondrial ribosome related diseases are crucial, in order to identify methods of prevention and treatment of these disorders. ",0
6307,29178212,Evolution of diastolic function algorithms: Implications for clinical practice,"We undertook this study of echocardiographic classification of diastolic function by three different algorithms to determine: (1) how frequently each algorithm classified patients and (2) how well the results agreed with one another. Several algorithms exist to grade diastolic function (DF), the Mayo Clinic scheme of Redfield et al (Mayo 2003) and the 2 ASE guideline documents of 2009 and 2016 (ASE 2009 and ASE 2016). A total of 200 consecutive echocardiograms were retrospectively analyzed; mean age of patients 60.3 ± 3.5 years, 45% male. Echocardiograms were performed using Intersocietal Accreditation Commission guidelines. Diastolic function was assessed by Mayo 2003 and ASE 2009 and 2016. Coexisting conditions affecting DF analysis, such as mitral annular calcification (MAC), were tabulated. Data were compared using a paired t-test. Concordance between algorithms was assessed using the Kappa statistic. A total of 117 of 200 studies (58.5%) were excluded for the presence of coexisting conditions (51.5%), poor image quality (2.5%), or incomplete data (4.5%). Thirty-three of the remaining 83 studies (40%) received the same grade of DF based on assessments made using the Mayo 2003 and ASE 2016 algorithms; the Kappa statistic was 0.20. 36 of the 83 studies (43%) received the same grade of DF based on assessments made using the ASE 2009 and ASE 2016 algorithms; the Kappa statistic was 0.25. Assessment of diastolic function via echocardiography cannot be reliably accomplished in approximately 50% of patients using current guidelines. Further, when studies are suitable for assessment, widely used guidelines yield discordant results. ",0
6308,29178461,The guardian of the genome p53 regulates exercise-induced mitochondrial plasticity beyond organelle biogenesis,"The Guardian of the Genome p53 has been established as a potent tumour suppressor. However, culminating from seminal findings in rodents more than a decade ago, several studies have demonstrated that p53 is required to maintain basal mitochondrial function [ie, respiration and reactive oxygen species (ROS) homeostasis]. Specifically, via its role(s) as a tumour suppressor, p53 intimately surveys cellular DNA damage, in particular mitochondrial DNA (mtDNA), to ensure that the mitochondrial network is carefully monitored and cell viability is upheld, because aberrant mtDNA damage leads to apoptosis and widespread cellular perturbations. Indeed, data from rodents and humans have demonstrated that p53 forms an integral component of the exercise-induced signal transduction network regulating skeletal muscle mitochondrial remodelling. In response to exercise-induced disruptions to cellular homeostasis that have the potential to harm mtDNA (eg, contraction-stimulated ROS emissions), appropriate p53-regulated, mitochondrial turnover responses prevail to protect the genome and ultimately facilitate a shift from aerobic glycolysis to oxidative phosphorylation, adaptations critical for endurance-based exercise that are commensurate with p53's role as a tumour suppressor. Despite these observations, several discrepancies exist between rodent and human studies pinpointing p53 subcellular trafficking from nuclear-to-mitochondrial compartments following acute exercise. Such interspecies differences in p53 activity and the plausible p53-mediated adaptations to chronic exercise training will be discussed herein. ",0
6309,29178537,Chemical Composition and In vitro Anthelmintic Activity of Extracts of Tagetes patula Against a Multidrug-Resistant Isolate of Haemonchus contortus,"Sheep breeding has suffered economic losses due to parasitism by gastrointestinal nematodes, particularly Haemonchus contortus. The use of natural products, specifically Tagetes patula, has been suggested as an alternative method of combatting this issue. Chemical analyses of the extracts of this species described in the literature report the presence of important classes of secondary metabolites such as thiophenes, flavonoids, alkaloids, and benzofurans, some of which were identified and isolated in this study. The aim of this work was to test the effect of the essential oil (EO) and the ethanolic extract of the aerial parts (Tp ",0
6310,29178583,Bariatric Surgery and the Incidence of Psoriasis and Psoriatic Arthritis in the Swedish Obese Subjects Study,"The aim of this study was to assess the effect of bariatric surgery (vertical gastroplasty, gastric banding, or gastric bypass) compared with usual care on the incidence of psoriasis and psoriatic arthritis (PsA) in the Swedish Obese Subjects study. This report includes 1,991 subjects who underwent bariatric surgery and 2,018 controls with obesity from the SOS study; none of them had psoriasis or PsA at baseline. Information about psoriasis and PsA diagnosis was retrieved through the Swedish National Patient Register and questionnaires. During follow-up for up to 26 years, bariatric surgery was associated with a lower incidence of psoriasis compared with usual care (number of events = 174; hazard ratio 0.65; 95% CI: 0.47-0.89; P = 0.008). Both smoking and a longer duration of obesity were independently associated with a higher risk for psoriasis. No significant difference was detected among the three surgical procedures in terms of lowering the risk of developing psoriasis. The association between bariatric surgery and psoriasis incidence was not influenced by baseline confounders. No significant difference in the risk of developing PsA (number of events = 46) was detected when comparing the surgery and the control groups. This study shows that bariatric surgery is associated with a lower risk of developing psoriasis compared with usual care. ",0
6311,29178846,An optimized protocol for the preparation of oxygen-evolving thylakoid membranes from Cyclotella meneghiniana provides a tool for the investigation of diatom plastidic electron transport,"The preparation of functional thylakoid membranes from diatoms with a silica cell wall is still a largely unsolved challenge. Therefore, an optimized protocol for the isolation of oxygen evolving thylakoid membranes of the centric diatom Cyclotella meneghiniana has been developed. The buffer used for the disruption of the cells was supplemented with polyethylene glycol based on its stabilizing effect on plastidic membranes. Disruption of the silica cell walls was performed in a French Pressure cell and subsequent linear sorbitol density gradient centrifugation was used to isolate the thylakoid membrane fraction. Spectroscopic characterization of the thylakoids by absorption and 77 K fluorescence spectroscopy showed that the photosynthetic pigment protein complexes in the isolated thylakoid membranes were intact. This was supported by oxygen evolution measurements which demonstrated high electron transport rates in the presence of the artificial electron acceptor DCQB. High photosynthetic activity of photosystem II was corroborated by the results of fast fluorescence induction measurements. In addition to PSII and linear electron transport, indications for a chlororespiratory electron transport were observed in the isolated thylakoid membranes. Photosynthetic electron transport also resulted in the establishment of a proton gradient as evidenced by the quenching of 9-amino-acridine fluorescence. Because of their ability to build-up a light-driven proton gradient, de-epoxidation of diadinoxanthin to diatoxanthin and diatoxanthin-dependent non-photochemical quenching of chlorophyll fluorescence could be observed for the first time in isolated thylakoid membranes of diatoms. However, the ∆pH, diadinoxanthin de-epoxidation and diatoxanthin-dependent NPQ were weak compared to intact diatom cells or isolated thylakoids of higher plants. The present protocol resulted in thylakoids with a high electron transport capacity. These thylakoids can thus be used for experiments addressing various aspects of the photosynthetic electron transport by, e.g., employing artificial electron donors and acceptors which do not penetrate the diatom cell wall. In addition, the present isolation protocol yields diatom thylakoids with the potential for xanthophyll cycle and non-photochemical quenching measurements. However, the preparation has to be further refined before these important topics can be addressed systematically. ",0
6312,29178881,Atrial ERK1/2 activation in the embryo leads to incomplete Septal closure: a novel mouse model of atrial Septal defect,"MEK1 mutation and activated MAPK signaling has been found in patients with RASopathies and abnormal cardiac development. Previous studies have suggested that regulation of fetal MAPK signaling is essential for normal cardiac development. We investigated the effect of active MEK1 overexpression on fetal atrial septal development. An inducible double transgenic (DTg) mouse model was developed in which cardiac-specific fetal expression of a constitutively active form of human MEK1 (aMEK1) was induced primarily in the atrium via the withdrawal of doxycycline from the drinking water of pregnant mice. Atrial septal defect (ASD) was found in 51% (23/45) of DTg mice. Fifty-two percent (12/23) of ASD mice died before weaning, and surviving ASD mice exhibited hypertrophic hearts with enlarged right atria and decreased fractional shorting (40 ± 2% vs. 48 ± 0%, p < 0.05). The model mimicked human ASD in several key clinical features: severe ASD was associated with growth impairment; ASD-specific mortality was highest within the early postnatal period; despite an even distribution of ASD among the sexes, early mortality was significantly higher in males. The expression of aMEK1 and increased phosphorylation of ERK1/2 was documented via Western blot in DTg fetal hearts, with the largest increases seen in atrial tissue. In an alternative transgenic aMEK1 model with elevated atrial MKP3 expression and corresponding suppression of increases in ERK1/2 phosphorylation, animals did not develop ASD. This new model of ASD suggests that enhanced atrial MEK1-ERK1/2 signaling during fetal development disrupts normal atrial septation, possibly regulated by the balance of ERK1/2 phosphorylation. ",0
6313,29178990,Variants in chondroitin sulfate metabolism genes in thrombotic storm,"Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (<5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors. ",0
6314,29179049,"Histological estimation of age at death in amputated lower limbs: Issues of disuse, advanced age, and disease in the analysis of pathological bone","Histological studies of healed bone tissue following amputation are relatively rare in the literature. This study describes the histomorphological features of femoral thin sections from six uni- and bi-lateral amputees of documented age and sex. Thin sections were cut from the midshaft of both the right and left femora from each amputee and analyzed following standard forensic methods for histological estimation of age at death from the human femur. The histological age at death estimations for the thin sections from amputated bone were consistently lower than the actual chronological age of each individual, suggesting that the effects of amputation prohibit the effective use of age at death estimation methods. The nature of each amputation is unknown, which suggests that alternative factors could be responsible for the slowed bone turnover seen in the thin sections from the amputated bone. First, it is reasonable to assume that the amputations in this sample could have resulted from complications of diabetes mellitus rather than trauma so the possible effects on bone remodeling due to disease are explored. Second, the mobility of the decedents following their amputations is unknown so the histomorphological results could be due to disuse osteoporosis. ",0
6315,29179590,Induction of apoptosis by metformin and progesterone in estrogen-induced endometrial hyperplasia in rats: involvement of the bcl-2 family proteins,"This study compared the antiproliferative effects of metformin and progesterone, via examination of the Bcl-2/Bax-caspase apoptotic pathway in estrogen-induced endometrial hyperplasia (EH) in 40 rats. Two rats died after bilateral oophorectomy, and 1 week after surgery, the remaining 38 were randomly divided into three groups: the first (control, n = 12) received 4 mg/kg 17β estradiol hemihydrate (E); the second (n = 13) received 4 mg/kg 17β estradiol hemihydrate and 50 mg/kg metformin (E + M); and the third (n = 13) received 4 mg/kg 17β estradiol hemihydrate and 1 mg/day medroxiprogesterone acetate (E + MPA). Histological markers and Bcl-2, Bax and caspase 9 expression were analyzed. Luminal epithelial thickness, density of gland and epithelial height was significantly higher in group E than in groups E + M and E + MPA. Histopathologic parameters were similar between the E + M and E + MPA groups. Bcl-2/Bax ratio was significantly decreased in the E + M and E + MPA groups and caspase 9 expression levels were significantly increased in the E + M and E + MPA groups, compared with the control group. In addition, Bcl-2/Bax ratio and caspase 9 expression were similar between the E + M and E + MPA groups. The data indicate that metformin reduces estrogen-induced EH in rats, via activation of the caspase-dependent mitochondrial apoptotic pathway, to the same degree as progesterone. ",0
6316,29179687,Faecal microbiota transplantation: a regulatory hurdle?,"During faecal microbiota transplantation, stool from a healthy donor is transplanted to treat a variety of dysbiosis-associated gut diseases. Competent authorities are faced with the challenge to provide adequate regulation. Currently, regulatory harmonization is completely lacking and authorities apply non-existing to most stringent requirements. A regulatory approach for faecal microbiota transplantation could be inserting faecal microbiota transplantation in the gene-, cell- and tissue regulations, including the hospital exemption system in the European Advanced Therapy Medicinal Products regulation, providing a pragmatic and efficacy-risk balanced approach and granting all patients as a matter of principle access to this therapy. ",0
6317,29180030,The efficacy of recombinant turkey herpesvirus vaccines targeting the H5 of highly pathogenic avian influenza virus from the 2014-2015 North American outbreak,"The outbreak of highly pathogenic avian influenza virus in North American poultry during 2014 and 2015 demonstrated the devastating effects of the disease and highlighted the need for effective emergency vaccine prevention and control strategies targeted at currently circulating strains. This study evaluated the efficacy of experimental recombinant turkey herpesvirus vector vaccines with three different inserts targeting the hemagglutinin gene of an isolate from the recent North American influenza outbreak. White leghorn chickens were vaccinated at one day of age and challenged with A/Turkey/Minnesota/12582/2015 H5N2 at 4 weeks of age. Birds were analyzed for survival, viral shedding at two and four days after infection, and specific antibody prior to challenge and from surviving birds. The three experimental vaccines demonstrated 100%, 45% and 15% survival with the most effective vaccine significantly reducing oral and cloacal viral shedding compared to all other groups and generated specific antibody prior to challenge with highly pathogenic avian influenza virus. More studies are needed using diverse H5Nx highly pathogenic virus isolates to fully determine the breadth of coverage against possible exposure strains, as well as possible impact of maternally derived antibody on protection and vaccine efficacy. ",0
6318,29180126,Belimumab in the treatment of systemic lupus erythematous: An evidence based review of its place in therapy,"Systemic lupus erythematous is an autoimmune disease with diverse clinical features and has its development associated with a complexity of genetic, hormonal and environmental factors and the development of autoantibodies. Identification of new treatments is currently an area of intense investigation. Belimumab is the first biologic approved for the treatment of the disease inhibiting the excessive B cell activity observed in these patients and consequently reduction of autoantibodies. To review the current transition of the evidence available of its use in real life patients with persistent active disease while on conventional therapies. The results observed on the large series of patients (over 50 patients) followed for at least six months confirm the observations from phase 3 trials. In clinical practice close to two third of the patients remained on belimumab and one third discontinued mostly due to evaluation by the doctor or the patient or both of no detectable positive response. The presence of adverse events was considerably low and the subgroups with skin and joint manifestations appear to benefit the most. Daily steroid use is usually reduced to a significantly low when compared with the intake before introduction of the biologic Although not seen on trials in real life the addition of belimumab to the conventional therapy in lupus nephritis is being reported in several patients. Cost of the medication is still an issue that hampers its use. Further evidence of its use in certain specific groups is under investigation and its results should shed light on additional indications. Considering what is currently published on the evidence here reviewed in the use of belimumab in clinical practice it is our understanding that belimumab it will be gradually incorporated in the armamentarium of treatment not necessarily on refractory patients. We believe that with the upcoming of the subcutaneous route in the near future should also help in widen the use of the belimumab to be considered in first line combination set ups. ",0
6319,29180197,TSG-6 is highly expressed in human abdominal aortic aneurysms,"The formation of abdominal aortic aneurysms (AAA) is characterized by a dominance of proinflammatory forces that result in smooth muscle cell apoptosis, extracellular matrix degradation, and progressive diameter expansion. Additional defects in the antiinflammatory response may also play a role but have yet to be fully characterized. TSG-6 (TNF-stimulated gene-6) is a potent antiinflammatory protein involved in extracellular matrix stabilization and cell migration active in many pathological conditions. Here, we describe its role in AAA formation. Blood and/or aortic tissue samples were collected from organ donors, subjects undergoing elective AAA screening, and open surgical AAA repair. Aortic specimens collected were preserved for IHC or immediately assayed after tissue homogenization. Protein concentrations in tissue and plasma were assayed by ELISA. All immune cell populations were assayed using FACS. In vitro, macrophage polarization from monocytes was performed with young, healthy donor PBMCs. TSG-6 was found to be abnormally elevated in both the plasma and aortic wall of patients with AAA compared with healthy and risk-factor matched non-AAA donors. We observed the highest tissue concentration of TSG-6 in the less-diseased proximal and distal shoulders compared with the central aspect of the aneurysm. IHC localized most TSG-6 to the tunica media with minor expression in the tunica adventitia of the aortic wall. Higher concentrations of both M1 and M2 macrophages where also observed, however M1/M2 ratios were unchanged from healthy controls. We observed no difference in M1/M2 ratios in the peripheral blood of risk-factor matched non-AAA and AAA patients. Interesting, TSG-6 inhibited the polarization of the antiinflammatory M2 phenotype in vitro. AAA formation results from an imbalance of inflammatory forces causing aortic wall infiltration of mononuclear cells leading to the vessel breakdown. In the AAA condition, we report an elevation of TSG-6 expression in both the aortic wall and the peripheral circulation. ",0
6320,29180208,MZB1 in borderline resectable pancreatic cancer resected after neoadjuvant chemoradiotherapy,A high accumulation of CD8 We studied 72 resected borderline resectable PDAC patients treated with NACRT between April 2009 and March 2014. Three matched pairs of high CD8 Marginal zone B- and B1-cell-specific protein (MZB1) was detected in the tumor stroma. MZB1 expression was positively correlated with a high accumulation of CD8 MZB1 is a potential marker of a high accumulation of CD8 ,0
6321,29181633,Amphiregulin regulates proliferation and migration of HER2-positive breast cancer cells,"Tumor initiation and progression rely on cellular proliferation and migration. Many factors are involved in these processes, including growth factors. Amphiregulin (AREG) is involved in normal mammary development and the development of estrogen receptor (ER)-positive breast cancer. The aim of this project was to determine if AREG is involved in the proliferation and progression of HER2-positive breast cancer. Mouse cell lines MMTV-neu, HC-11 and COMMA-D, as well as human cell lines MCF10A, SKBR3, HCC1954 and BT474 were used. Real-time PCR was used to quantify AREG expression and neutralizing antibodies were used to reduce the autocrine/paracrine effects of AREG. Transfections using siRNA and shRNA were used to knockdown AREG expression in the cancer cell lines. Free-floating sphere formation, colony forming, scratch wound and Transwell assays were used to assess the proliferation, tumor forming and migratory capacities of transfected cancer cells. We found AREG expression in both normal epithelial cell lines and tumor-derived cell lines. Knockdown of AREG protein expression resulted in reduced sphere sizes and reduced sphere numbers in both mouse and human cancer cells that overexpress erbB2/HER2. AREG was found to be involved in cancer cell migration and invasion. In addition, we found that AREG expression knockdown resulted in different migration capacities in normal and erbB2/HER2 overexpressing cancer cells. Based on our results we conclude that AREG is involved in regulating the proliferation and migration of erbB2/HER2-positive breast cancer cells. ",0
6322,29181769,"Cognitive functioning, subjective memory complaints and risky behaviour predict minor home injuries in elderly","Home accidents are one of the major causes of death, particularly in older people, young children and women. The first aim of this study was to explore the role of subjective memory complaints, cognitive functioning and risky behaviour as predictors of home injuries occurred in a year in a sample of healthy Italian older adults. The second aim was to investigate the role of risky behaviour as a mediator in the relationship between subjective and objective cognitive functioning and home injuries. One hundred thirty-three community-dwelling older people from southern Italy were administered a battery of tests to evaluate cognitive functioning, subjective memory complaints, and risky behaviour during home activities. Risky behaviour was evaluated using the Domestic Behaviour Questionnaire, created specifically for this purpose. The number of home injuries was recorded for a year throughout monthly telephone interviews. A path analysis was performed to test the following model: cognitive functioning and subjective memory complaints directly influence risky behaviour and number of accidents over a year; risky behaviour mediates the impact of cognitive functioning and subjective memory on number of accidents over a year. Path analysis confirmed the model tested except the role of risky behaviour as a mediator between cognitive functioning and home accidents. Risky behaviour could represent a further risk factor in cognitively intact older adults with subjective memory complaints. The assessment of both cognition and behaviour in elderly can make a valuable contribution in preventing home accidents in elderly. ",0
6323,29181803,Functional Characterization of Probiotic Potential of Novel Pigmented Bacterial Strains for Aquaculture Applications,"The bioprospecting proficient of novel pigmented probiotic strains with respect to aquaculture industry was unexplored hitherto. In this study, we investigated the probiotic potential of novel pigmented bacterial strains isolated from the indigenous soil sediments in their vicinal habitats, which were screened for their antimicrobial activity against aquatic pathogens using agar well diffusion assay. The strains namely Exiguobacterium acetylicum (S01), Aeromonas veronii (V03), and Chryseobacterium joostei (V04) were phenotypically identified and confirmed by 16S rRNA gene sequence analysis. Further characterization revealed that strains S01 and V03 survive relatively in lower pH and higher bile salt concentrations and possess good adherence ability and broad-spectrum antibiotic susceptibility. The isolate S01 exhibited the higher adhesion ability to hydrocarbons (82%) and mannose-specific adhesion (msa) gene expression. Additionally, the probiotic effects were evaluated in Artemia nauplii fed with algae supplemented with S01, V03, and V04 strains (2.7 × 10 ",0
6324,29181853,Toward the elimination of hepatitis C in the United States,"The emergence of effective direct-acting antiviral (DAA) agents has reignited discussion over the potential for hepatitis C elimination in the United States. Eliminating hepatitis C will require a critical examination of technical feasibility, economic considerations, and social/political attention. Tremendous advancement has been made with the availability of sensitive diagnostic tests and highly effective DAAs capable of achieving sustained viral response (SVR) in more than 95% of patients. Eliminating hepatitis C also requires escalating existing surveillance networks to monitor for new epidemics. All preventive interventions such as clean syringe and needle exchange programs, safe injection sites, opioid substitution therapies, and mental health services need to be expanded. Although costs of DAAs have raised budget concerns for hepatitis C elimination, studies have shown that eliminating hepatitis C will produce a savings of up to 6.5 billion USD annually along with other intangible benefits such as increased work productivity and quality of life. Economic models and meta-analyses strongly suggest universal hepatitis C screening for all adults rather than just for birth cohort and high-risk populations. Social and political factors are at least as important as technical feasibility and economic considerations. Due to lack of promotion and public awareness, HCV elimination efforts continue to receive inadequate funding. Social stigma continues to impede meaningful policy changes. Eliminating hepatitis C is an attainable public health goal that will require intense collaboration and sustained public support. (Hepatology 2018;67:2449-2459).",0
6325,29182023,"PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer","Vascular-targeted photodynamic therapy (PDT) is an important strategy for cancer therapy. Conventional vascular-targeted PDT has been achieved by passive photosensitizer (PS) delivery, which involves a high risk of adverse effects. Active PS delivery is urgently required for vascular-targeted PDT. Although endothelial cells and pericytes are major cellular components of tumor blood vessels, little attention has been paid to pericyte-targeted PDT for cancer therapy. PDGFRβ is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z ",0
6326,29182633,Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study,"Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures-including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue-the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case. allo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs. ",0
6327,29182944,Learning to feel tired: A learning trajectory towards chronic fatigue,"Chronic fatigue complaints are frequently reported in the general population and fatigue ranks among the most commonly reported symptoms in chronic disease. In contrast to its high prevalence and impact on quality of life, relatively little is understood about the etiology of chronic fatigue. We present a cognitive-behavioral framework, the 'ALT+F' model, that conceptualizes fatigue from an associative learning perspective, and we will evaluate the current evidence for this position. Central to this framework is the notion that interoceptive and exteroceptive stimuli can become associated with the fatigue experience. Consequently, these stimuli may acquire the capacity to elicit fatigue as well as anticipatory fear-related avoidance behavior. We will argue that associative learning processes may contribute to the development of chronic fatigue, fear of fatigue, avoidance of fatigue and activity, and eventually, functional disability. The extent to which associative learning processes give rise to chronic fatigue and fear-related avoidance behavior may depend on a number of risk factors, including perceptual-cognitive biases, sensitization, fatigue catastrophizing, and excessive generalization. The presented framework offers a new window on treatment and intervention options for chronic fatigue. ",0
6328,29183075,Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet,"Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels. Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association-approved analytical procedures. Analytical findings were compared against the label information. Products marketed and sold as selective androgen receptor modulators. Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators. Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%). In this limited investigation involving chemical analyses of 44 products marketed as selective androgen receptor modulators and sold via the internet, most products contained unapproved drugs and substances. Only 52% contained selective androgen receptor modulators and many were inaccurately labeled. ",0
6329,29183097,Predictors of PDA Treatment in Preterm Neonates Who Had Received Prophylactic Indomethacin," To identify clinical factors those predict the need for patent ductus arteriosus (PDA) treatment in preterm neonates who had received prophylactic indomethacin.  Preterm neonates with <28 weeks' gestational age admitted to level III neonatal intensive care units (NICUs) in Canada between 2010 and 2015 and who had received prophylactic indomethacin were included. Primary outcome was surgical ligation of PDA, while secondary outcomes were any PDA treatment and common neonatal morbidities.  Of the 7,024 eligible neonates, 843 (12%) neonates had received prophylactic indomethacin. Of them, 84 neonates (10%) required surgical ligation while 367 neonates (44%) received medical or surgical treatment for PDA. Logistic regression analyses identified gestational age (odds ratio [OR]: 0.71, 95% confidence interval [CI]: 0.58-0.87) and outborn status (OR: 2.07, 95% CI: 1.09-3.93) as predictors for surgical ligation. Maternal hypertension (OR: 0.57, 95% CI: 0.37-0.89), rupture of membranes (ROM) ≥24 hours (OR: 0.68, 95% CI: 0.48-0.96), and surfactant treatment (OR: 1.70, 95% CI: 1.09-2.66) were predictors for medical or surgical treatment of PDA.  In extremely preterm neonates who had received prophylactic indomethacin, gestational age and outborn status were predictors for surgical ligation of PDA, while maternal hypertension, ROM ≥24 hours, and surfactant treatment were associated with the medical or surgical treatment of PDA. ",0
6330,29183282,Bilateral muscle fiber and nerve influences by TNF-alpha in response to unilateral muscle overuse - studies on TNF receptor expressions,"TNF-alpha is suggested to be involved in muscle damage and muscle inflammation (myositis). In order to evaluate whether TNF-alpha is involved in the myositis that occurs in response to muscle overuse, the aim was to examine the expression patterns of TNF receptors in this condition. A rabbit muscle overuse model leading to myositis in the soleus muscle was used. The expression patterns of the two TNF receptors Tumor Necrosis Factor Receptor type 1 (TNFR1) and Tumor Necrosis Factor Receptor type 2 (TNFR2) were investigated. In situ hybridization and immunofluorescence were utilized. Immunostainings for desmin, NK-1R and CD31 were made in parallel. Immunoreactions (IR) for TNF receptors were clearly observed in white blood cells, fibroblasts and vessel walls, and most interestingly also in muscle fibers and nerve fascicles in the myositis muscles. There were very restricted reactions for these in the muscles of controls. The upregulation of TNF receptors was for all types of structures seen for both the experimental side and the contralateral nonexperimental side. TNF receptor expressing muscle fibers were present in myositis muscles. They can be related to attempts for reparation/regeneration, as evidenced from results of parallel stainings. Necrotic muscle fibers displayed TNFR1 mRNA and TNFR2 immunoreaction (IR) in the invading white blood cells. In myositis muscles, TNFR1 IR was observed in both axons and Schwann cells while TNFR2 IR was observed in Schwann cells. Such observations were very rarely made for control animals. The findings suggest that there is a pronounced involvement of TNF-alpha in the developing myositis process. Attempts for reparation of the muscle tissue seem to occur via both TNFR1 and TNFR2. As the myositis process also occurs in the nonexperimental side and as TNF receptors are confined to nerve fascicles bilaterally it can be asked whether TNF-alpha is involved in the spreading of the myositis process to the contralateral side via the nervous system. Taken together, the study shows that TNF-alpha is not only associated with the inflammation process but that both the muscular and nervous systems are affected and that this occurs both on experimental and nonexperimental sides. ",0
6331,29183344,Oral verruciform xanthoma and erythroplakia associated with chronic graft-versus-host disease: a rare case report and review of the literature,"""Oral verruciform xanthoma is an uncommon benign lesion. Although oral verruciform xanthoma occurs in healthy individuals, it has been also reported in association with some inflammatory conditions. The aim of this study is to report a case of oral verruciform xanthoma associated with chronic graft-versus-host disease and to review the literature on this topic. A 47-year-old Caucasian male presented to the Sector of Oral Medicine """"V. Margiotta"""", University Policlinic """"P. Giaccone"""" of Palermo complaining of a mass on the gingiva. He first noticed the painless mass 1 year ago. He reported to have undergone allogenic hematopoietic stem cell transplantation 15 years ago for acute lymphoblastic leukaemia. Intraoral examination revealed a well-circumscribed, sessile yellowish and verrucous nodule upon canine, multiple yellowish and verrucous nodules on the hard palate, yellowish and verrucous nodules on left buccal mucosa. In addiction an area of white striae in a reticular pattern with erythema and ulceration was present on the dorsum of the tongue. This lesion was consistent with a known history of oral chronic graft versus host disease. Moreover, we observed a suspected area of oral erythroplakia yet on the dorsum of the tongue. In biopsy specimen of hard palate histopathological examination revealed a diagnosis of verrucous xanthoma of the oral cavity; in addiction in biopsy specimen of the dorsum of the tongue revealed the presence of erythroplakia with high grade dysplasia. Verruciform xanthoma of the oral cavity associated with chronic graft-versus-host disease is a rare condition with a usually benign clinical course but malignant transformation has been described in association with oral potential malignant disorder (e.g. chronic graft versus host disease, erythroplakia). Very rare cases showed association with oral chronic graft versus-host-disease. To date, only eight cases were published in the world literature. Therefore it could be important follow up patients also for oral verruciform xanthoma onset. """,0
6332,29183391,Oxidative stress and cellular pathologies in Parkinson's disease,"Parkinson's disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for the death of these neurons is unclear; however, studies have demonstrated the potential involvement of mitochondria, endoplasmic reticulum, α-synuclein or dopamine levels in contributing to cellular oxidative stress as well as PD symptoms. Even though those papers had separately described the individual roles of each element leading to neurodegeneration, recent publications suggest that neurodegeneration is the product of various cellular interactions. This review discusses the role of oxidative stress in mediating separate pathological events that together, ultimately result in cell death in PD. Understanding the multi-faceted relationships between these events, with oxidative stress as a common denominator underlying these processes, is needed for developing better therapeutic strategies. ",0
6333,29183952,Cerebellar Hematoma Location: Implications for the Underlying Microangiopathy,"Spontaneous cerebellar intracerebral hemorrhage (ICH) has been reported to be mainly associated with vascular changes secondary to hypertension. However, a subgroup of cerebellar ICH seems related to vascular amyloid deposition (cerebral amyloid angiopathy). We sought to determine whether location of hematoma in the cerebellum (deep and superficial regions) was suggestive of a particular hemorrhage-prone small-vessel disease pathology (cerebral amyloid angiopathy or hypertensive vasculopathy). Consecutive patients with cerebellar ICH from a single tertiary care medical center were recruited. Based on data from pathological reports, patients were divided according to the location of the primary cerebellar hematoma (deep versus superficial). Location of cerebral microbleeds (CMBs; strictly lobar, strictly deep, and mixed CMB) was evaluated on magnetic resonance imaging. One-hundred and eight patients (84%) had a deep cerebellar hematoma, and 20 (16%) a superficial cerebellar hematoma. Hypertension was more prevalent in deep than in patients with superficial cerebellar ICH (89% versus 65%, respectively;  Our study showed that superficial cerebellar ICH is related to the presence of strictly lobar CMB-a pathologically proven marker of cerebral amyloid angiopathy. Cerebellar hematoma location may thus help to identify those patients likely to have cerebral amyloid angiopathy pathology. ",0
6334,29184268,Impacts of Bone Marrow Stem Cells on Caspase-3 Levels after Spinal Cord Injury in Mice,"Spinal cord injury (SCI) is a drastic disability that leads to spinal cord impairment. This study sought to determine the effects of bone marrow stem cells (BMSCs) on caspase-3 levels after acute SCI in mice. Forty-two mice were randomly divided into 3 groups: control (2 subcategories), subjected to no intervention; sham (3 subcategories), subjected to acute SCI; and experimental (2 subcategories), subjected to SCI and cell transplantation. In the experimental group, 2×10 ",0
6335,29184274,The relationship between physical capacity and fear avoidance beliefs in patients with chronic low back pain,"[Purpose] The aim of this study was to investigate the relationship between physical capacity and fear avoidance beliefs in patients with chronic low back pain. [Subjects and Methods] This cross sectional study included 131 male university students with chronic low back pain. All the patients completed a fear avoidance beliefs questionnaire. Each participant performed a physical capacity test, which included hand grip force, leg strength, abdominal muscle endurance, flexibility, and cardiopulmonary endurance testing. [Results] Negative correlation was observed between physical capacity (leg strength, abdominal muscle endurance) and fear avoidance beliefs regarding work. Physical capacity (hand grip force, leg strength, cardiopulmonary endurance) showed a negative correlation with fear avoidance beliefs about physical activity. Abdominal muscle endurance and cardiopulmonary endurance were predictors of fear avoidance beliefs. [Conclusion] Physical capacity showed a negative correlation with fear avoidance beliefs in patients with chronic low back pain. The results of this study suggest that physical capacity is an important factor for predicting fear avoidance beliefs in patients with chronic low back pain. ",0
6336,29184403,Confocal laser scanning microscopy to estimate nanoparticles' human skin penetration in vitro,"""With rapid development of nanotechnology, there is increasing interest in nanoparticle (NP) application and its safety and efficacy on human skin. In this study, we utilized confocal laser scanning microscopy to estimate NP skin penetration. Three different-sized polystyrene NPs marked with red fluorescence were applied to human skin, and Calcium Green 5N was used as a counterstain. Dimethyl sulfoxide (DMSO) and ethanol were used as alternative vehicles for NPs. Tape stripping was utilized as a barrier-damaged skin model. Skin biopsies dosed with NPs were incubated at 4°C or 37°C for 24 hours and imaged using confocal laser scanning microscopy. NPs were localized in the stratum corneum (SC) and hair follicles without penetrating the epidermis/dermis. Barrier alteration with tape stripping and change in incubation temperature did not induce deeper penetration. DMSO enhanced NP SC penetration but ethanol did not. Except with DMSO vehicle, these hydrolyzed polystyrene NPs did not penetrate intact or barrier-damaged human """"viable"""" epidermis. For further clinical relevance, in vivo human skin studies and more sensitive analytic chemical methodology are suggested. """,0
6337,29184416,Variations in patient safety climate and perceived quality of collaboration between professions in out-of-hours care,"To get an overview of health care workers perceptions of patient safety climates and the quality of collaboration in Slovenian out-of-hours health care (OOHC) between professional groups. This was a cross-sectional study carried out in all (60) Slovenian OOHC clinics; 37 (61.7%) agreed to participate with 438 employees. The questionnaire consisted of the Slovenian version of the Safety Attitudes Questionnaire - Ambulatory Version (SAQ-AV). The study sample consisted of 175 (70.0%) physicians, nurse practitioners, and practice nurses. Practice nurses reported the highest patient safety climate scores in all dimensions. Total mean (standard deviation) SAQ-AV score was 60.9±15.2. Scores for quality of collaboration between different professional groups were high. The highest mean scores were reported by nurse practitioners on collaboration with practice nurses (4.4±0.6). The lowest mean scores were reported by practice nurses on collaboration with nurse practitioners (3.8±0.9). Due to large variations in Slovenian OOHC clinics with regard to how health care workers from different professional backgrounds perceive safety culture, more attention should be devoted to improving the team collaboration in OOHC. A clearer description of professional team roles should be provided. ",0
6338,29184676,Exosomes as diagnostic and predictive biomarkers in lung cancer,"The concept of exosomes has evolved from be considered garbage bags to the demonstration that exosomes could play very interesting roles and functions, from biomarkers detection to the potential of work as drug delivery systems. It has been widely proved that exosomes can contain key molecules important for the tumour development. The current review summarizes the latest investigations developed in the field of predictive exosomal biomarkers. The microRNAs (miRNAs) are the more known molecules due to their amount inside the exosomes and the sensitivity of the techniques available for their study. However, exosomal proteins, RNA and DNA are becoming an interesting and more feasible field of study due to the improvement in the techniques available for their analysis. In the future years, it is hoped that exosomes will become an established member of the liquid biopsies in the clinical practice due to their diagnostic and prognostic properties. ",0
6339,29184821,Approach to hypoglycemia in infants and children,"Hypoglycemia is a heterogeneous disorder with many different possible etiologies, including hyperinsulinism, glycogen storage disorders, fatty acid disorders, hormonal deficiencies, and metabolic defects, among others. This condition affects newborns to adolescents, with various approaches to diagnosis and management. This paper will review current literature on the history of hypoglycemia, current discussion on the definition of hypoglycemia, as well as etiologies, diagnosis, and management. ",0
6340,29185441,Intracellular localization of nanoparticle dimers by chirality reversal,"The intra- and extracellular positioning of plasmonic nanoparticles (NPs) can dramatically alter their curative/diagnostic abilities and medical outcomes. However, the inability of common spectroscopic identifiers to register the events of transmembrane transport denies their intracellular vs. extracellular localization even for cell cultures. Here we show that the chiroptical activity of DNA-bridged NP dimers allows one to follow the process of internalization of the particles by the mammalian cells and to distinguish their extra- vs intra-cellular localizations by real-time spectroscopy in ensemble. Circular dichroism peaks in the visible range change from negative to positive during transmembrane transport. The chirality reversal is associated with a spontaneous twisting motion around the DNA bridge caused by the large change in electrostatic repulsion between NPs when the dimers move from interstitial fluid to cytosol. This finding opens the door for spectroscopic targeting of plasmonic nanodrugs and quantitative assessment of nanoscale interactions. The efficacy of dichroic targeting of chiral nanostructures for biomedical applications is exemplified here as photodynamic therapy of malignancies. The efficacy of cervical cancer cell elimination was drastically increased when circular polarization of incident photons matched to the preferential absorption of dimers localized inside the cancer cells, which is associated with the increased generation of reactive oxygen species and their preferential intracellular localization. ",0
6341,29185762,"Impacts of Future European Emission Reductions on Aerosol Particle Number Concentrations Accounting for Effects of Ammonia, Amines, and Organic Species","Although they are currently unregulated, atmospheric ultrafine particles (<100 nm) pose health risks because of, e.g., their capability to penetrate deep into the respiratory system. Ultrafine particles, often minor contributors to atmospheric particulate mass, typically dominate aerosol particle number concentrations. We simulated the response of particle number concentrations over Europe to recent estimates of future emission reductions of aerosol particles and their precursors. We used the chemical transport model PMCAMx-UF, with novel updates including state-of-the-art descriptions of ammonia and dimethylamine new particle formation (NPF) pathways and the condensation of organic compounds onto particles. These processes had notable impacts on atmospheric particle number concentrations. All three emission scenarios (current legislation, optimized emissions, and maximum technically feasible reductions) resulted in substantial (10-50%) decreases in median particle number concentrations over Europe. Consistent reductions were predicted in Central Europe, while Northern Europe exhibited smaller reductions or even increased concentrations. Motivated by the improved NPF descriptions for ammonia and methylamines, we placed special focus on the potential to improve air quality by reducing agricultural emissions, which are a major source of these species. Agricultural emission controls showed promise in reducing ultrafine particle number concentrations, although the change is nonlinear with particle size. ",0
6342,29186043,Trend in H₂S Biology and Medicine Research-A Bibliometric Analysis,"The biological and medical importance of hydrogen sulfide (H₂S) has been recognized for decades. The aim of this bibliometric study is to analyze the quantity and quality of publications in H₂S biology and medicine (H₂SBM) based on the databases of Web of Science and Google Scholar. A total of 5881 publications published between 1990 and 2016 were analyzed. The number of H₂SBM papers published before 2004 was below 100 annually, but thereafter this number rapidly increased and peaked in 2015 with more than 7-fold increase. All publications related to H₂SBM research achieved a total  ",0
6343,29186180,"Clonogenic, myogenic progenitors expressing MCAM/CD146 are incorporated as adventitial reticular cells in the microvascular compartment of human post-natal skeletal muscle","""Recent observation identifies subendothelial (mural) cells expressing MCAM, a specific system of clonogenic, self-renewing, osteoprogenitors (a.k.a, """"mesenchymal stem cells"""") in the microvascular compartment of post-natal human bone marrow (BM). In this study, we used MCAM/CD146, as a marker to localize, isolate and assay subendothelial clonogenic cells from the microvasculature of postnatal human skeletal muscle. We show here that these cells share with their BM counterpart, anatomic position (subendothelial/adventitial) and ex vivo clonogenicity (CFU-Fs). When assayed under the stringent conditions, these cells display a high spontaneous myogenic potential (independent of co-culture with myoblasts or of in vivo fusion with local myoblasts), which is otherwise only attained in cultures of satellite cells. These muscle-derived mural cells activated a myogenic program in culture. Cultured CD146+ cells expressed the myogenic factors (Pax7, Pax3 and Myf5), NCAM/CD56, desmin as well as proteins characteristic of more advanced myogenic differentiation, such as myosin heavy chain. In vivo, these cells spontaneously generate myotubes and myofibrils. These data identify the anatomy and phenotype of a novel class of committed myogenic progenitor in human post-natal skeletal muscle of subendothelial cells associated with the abluminal surface of microvascular compartment distinct from satellite cells. """,0
6344,29186215,Revisiting monosaccharide analysis - quantitation of a comprehensive set of monosaccharides using dynamic multiple reaction monitoring,"A rapid method for the quantitation of sixteen neutral and acidic monosaccharides, from both animal and plant sources was developed using ultra-high performance liquid chromatography triple quadrupole mass spectrometry (UHPLC/QqQ-MS) in dynamic multiple reaction monitoring (dMRM) mode. Monosaccharides including three pentoses (ribose, xylose, arabinose), two deoxyhexoses (rhamnose, fucose), five hexoses (fructose, mannose, allose, glucose, galactose), two hexuronic acids (glucuronic acid, galacturonic acid), and two N-acetyl-hexosamines (GlcNAc, GalNAc), were derivatized with 1-phenyl-3-methyl-5-pyrazolone (PMP), while underivatized sialic acids, Neu5Ac and Neu5Gc, were simultaneously analyzed with a 10-minute run. With the optimized UHPLC conditions, baseline separations of the isomers were achieved. The sensitivity and calibration ranges of this method were determined. The limits of detection were between femtomoles and attomoles with linear ranges spanning four to six orders of magnitude and coefficients of variation (CVs) ≤7.2%. Spiking experiments performed on a pooled fecal sample demonstrated the high accuracy of this method even when applied to samples with complicated matrices. The validated method was applied to fecal samples from an infant transitioning from breast milk to weaning foods. Major milk monosaccharides including galactose, fucose, glucose, GlcNAc, and Neu5Ac were found to be the most abundant components in the feces of milk-fed infants. PMP-derivatives of nine other monosaccharides including apiose, lyxose, altrose, talose, gulose, glucosamine, galactosamine, mannosamine, and N-acetylmannosamine (ManNAc) were also tested and could be added to the quantitation method depending on the need. The speed and sensitivity of the method makes it readily adaptable to rapid throughput analysis of monosaccharides in biological samples. ",0
6345,29186402,In vitro and in vivo activity of single and dual antimicrobial agents against KPC-producing Klebsiella pneumoniae,"Options for treatment of infections due to KPC-producing Klebsiella pneumoniae are limited and combination therapy is often recommended. In this report, the in vitro and in vivo activity of potential therapeutic agents and combinations was assessed against four KPC-producing K. pneumoniae isolates. Using clinically relevant concentrations, time-kill experiments and the Galleria mellonella model of infection were used to examine the activity of polymyxin B, ceftazidime/avibactam, meropenem, rifampicin and amikacin alone and in combination. Two K. pneumoniae isolates were resistant to polymyxin B and had ceftazidime/avibactam MICs of 8/4 mg/L. When ceftazidime/avibactam was combined with either amikacin or meropenem, synergy was observed in vitro, and these combinations were associated with improved survival in the in vivo model. Improved survival was also observed using higher doses of ceftazidime/avibactam. The other two K. pneumoniae isolates were susceptible to polymyxin B and had lower (1/4 mg/L) MICs of ceftazidime/avibactam. For these two isolates, bactericidal activity was observed in vitro at ceftazidime/avibactam concentrations four times the MIC. At one-quarter of the MIC, synergy was observed when ceftazidime/avibactam was combined with meropenem. In the in vivo model with the two susceptible isolates, improved survival rates were observed following therapy with ceftazidime/avibactam monotherapy. For all four isolates, polymyxin B with or without rifampicin or meropenem performed poorly in the in vivo model. Pending clinical studies, combining ceftazidime/avibactam with another agent (e.g. a carbapenem) should be considered when treating serious infections due to these pathogens, particularly for isolates with ceftazidime/avibactam MICs near the susceptibility breakpoint. ",0
6346,29186571,Oxygen gradients can determine epigenetic asymmetry and cellular differentiation via differential regulation of Tet activity in embryonic stem cells,"Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis. ",0
6347,29186597,Factors for a Good Surgical Outcome in Posterior Decompression and Dekyphotic Corrective Fusion with Instrumentation for Thoracic Ossification of the Posterior Longitudinal Ligament: Prospective Single-Center Study,"Surgery for thoracic ossification of the posterior longitudinal ligament (T-OPLL) is still challenging, and factors for good surgical outcomes are unknown. To identify factors for good surgical outcomes with prospective and comparative study. Seventy-one consecutive patients who underwent posterior decompression and instrumented fusion were divided into good or poor outcome groups based on ≥50% and <50% recovery rates for the Japanese Orthopaedic Association score. Preoperative, intraoperative, and postoperative findings were compared in the 2 groups, and significant factors for a good outcome were analyzed. Patients with a good outcome (76%) had significantly lower nonambulatory rate and positive prone and supine position tests preoperatively; lower rates of T-OPLL, ossification of the ligamentum flavum, high-intensity area at the same level, thoracic spinal cord alignment difference, and spinal canal stenosis on preoperative magnetic resonance imaging; lower estimated blood loss; higher rates of intraoperative spinal cord floating and absence of deterioration of intraoperative neurophysiological monitoring; and lower rates of postoperative complications (P < .0005). In multivariate logistic regression analysis, negative prone and supine position test (odds ratio [OR]: 17.00), preoperative ambulatory status (OR: 6.05), absence of T-OPLL, ossification of the ligamentum flavum, high-intensity area at the same level (OR: 5.84), intraoperative spinal cord floating (OR: 4.98), and lower estimated blood loss (OR: 1.01) were significant factors for a good surgical outcome. This study demonstrated that early surgery is recommended during these positive factors. Appropriate surgical planning based on preoperative thoracic spinal cord alignment difference, as well as sufficient spinal cord decompression and reduction of complications using intraoperative ultrasonography and intraoperative neurophysiological monitoring, may improve surgical outcomes. ",0
6348,29186678,Hyperglycemia Impairs Neutrophil Mobilization Leading to Enhanced Metastatic Seeding,"Preexisting diabetes is a risk factor for the development of multiple types of cancer. Additionally, diabetic patients face a poorer prognosis when diagnosed with cancer. To gain insight into the effects of hyperglycemia, a hallmark of diabetes, on tumor growth and metastatic progression, we combined mouse models of cancer and hyperglycemia. We show that while hyperglycemia attenuates primary tumor growth, it concomitantly increases metastatic seeding in a distant organ. We further show that the increase in metastatic seeding is due to impaired secretion of granulocyte colony-stimulating factor (G-CSF) and impaired neutrophil mobilization. Normalizing blood glucose levels using insulin rescues neutrophil recruitment and tumor growth and concomitantly reduces metastatic seeding. These results provide links among hyperglycemia-induced changes in neutrophil mobilization, primary tumor growth, and metastatic progression. Furthermore, our observations highlight the importance of normalizing blood glucose levels in hyperglycemic cancer patients. ",0
6349,29186827,Eukaryotic Elongation Factor 2 Kinase (eEF2K) in Cancer,"Eukaryotic elongation factor 2 kinase (eEF2K) is a highly unusual protein kinase that negatively regulates the elongation step of protein synthesis. This step uses the vast majority of the large amount of energy and amino acids required for protein synthesis. eEF2K activity is controlled by an array of regulatory inputs, including inhibition by signalling through mammalian target of rapamycin complex 1 (mTORC1). eEF2K is activated under conditions of stress, such as energy depletion or nutrient deprivation, which can arise in poorly-vascularised tumours. In many such stress conditions, eEF2K exerts cytoprotective effects. A growing body of data indicates eEF2K aids the growth of solid tumours in vivo. Since eEF2K is not essential (in mice) under 'normal' conditions, eEF2K may be a useful target in the treatment of solid tumours. However, some reports suggest that eEF2K may actually impair tumorigenesis in some situations. Such a dual role of eEF2K in cancer would be analogous to the situation for other pathways involved in cell metabolism, such as autophagy and mTORC1. Further studies are needed to define the role of eEF2K in different tumour types and at differing stages in tumorigenesis, and to assess its utility as a therapeutic target in oncology. ",0
6350,29186854,Evaluation of the Effects of Crushed and Expanded Waste Glass Aggregates on the Material Properties of Lightweight Concrete Using Image-Based Approaches,"Recently, the recycling of waste glass has become a worldwide issue in the reduction of waste and energy consumption. Waste glass can be utilized in construction materials, and understanding its effects on material properties is crucial in developing advanced materials. In this study, recycled crushed and expanded glasses are used as lightweight aggregates for concrete, and their relation to the material characteristics and properties is investigated using several approaches. Lightweight concrete specimens containing only crushed and expanded waste glass as fine aggregates are produced, and their pore and structural characteristics are examined using image-based methods, such as scanning electron microscopy (SEM), X-ray computed tomography (CT), and automated image analysis (RapidAir). The thermal properties of the materials are measured using both Hot Disk and ISOMET devices to enhance measurement accuracy. Mechanical properties are also evaluated, and the correlation between material characteristics and properties is evaluated. As a control group, a concrete specimen with natural fine sand is prepared, and its characteristics are compared with those of the specimens containing crushed and expanded waste glass aggregates. The obtained results support the usability of crushed and expanded waste glass aggregates as alternative lightweight aggregates. ",0
6351,29186886,Protein Kinase Targets in Breast Cancer,"With 1.67 million new cases and 522,000 deaths in the year 2012, breast cancer is the most common type of diagnosed malignancy and the second leading cause of cancer death in women around the world. Despite the success of screening programs and the development of adjuvant therapies, a significant percentage of breast cancer patients will suffer a metastatic disease that, to this day, remains incurable and justifies the research of new therapies to improve their life expectancy. Among the new therapies that have been developed in recent years, the emergence of targeted therapies has been a milestone in the fight against cancer. Over the past decade, many studies have shown a causal role of protein kinase dysregulations or mutations in different human diseases, including cancer. Along these lines, cancer research has demonstrated a key role of many protein kinases during human tumorigenesis and cancer progression, turning these molecules into valid candidates for new targeted therapies. The subsequent discovery and introduction in 2001 of the kinase inhibitor imatinib, as a targeted treatment for chronic myelogenous leukemia, revolutionized cancer genetic pathways research, and lead to the development of multiple small-molecule kinase inhibitors against various malignancies, including breast cancer. In this review, we analyze studies published to date about novel small-molecule kinase inhibitors and evaluate if they would be useful to develop new treatment strategies for breast cancer patients. ",0
6352,29186913,Colorectal Cancer and Colitis Diagnosis Using Fourier Transform Infrared Spectroscopy and an Improved K-Nearest-Neighbour Classifier,"Combining Fourier transform infrared spectroscopy (FTIR) with endoscopy, it is expected that noninvasive, rapid detection of colorectal cancer can be performed in vivo in the future. In this study, Fourier transform infrared spectra were collected from 88 endoscopic biopsy colorectal tissue samples (41 colitis and 47 cancers). A new method, viz., entropy weight local-hyperplane k-nearest-neighbor (EWHK), which is an improved version of K-local hyperplane distance nearest-neighbor (HKNN), is proposed for tissue classification. In order to avoid limiting high dimensions and small values of the nearest neighbor, the new EWHK method calculates feature weights based on information entropy. The average results of the random classification showed that the EWHK classifier for differentiating cancer from colitis samples produced a sensitivity of 81.38% and a specificity of 92.69%. ",0
6353,29186930,"Protective Effects of Liquiritigenin against Citrinin-Triggered, Oxidative-Stress-Mediated Apoptosis and Disruption of Embryonic Development in Mouse Blastocysts","The mycotoxin citrinin (CTN), a natural contaminant in foodstuffs and animal feeds, exerts cytotoxic and genotoxic effects on various mammalian cells and embryos. A previous investigation by our group revealed potentially hazardous effects of CTN on mouse oocyte maturation and pre- and post-implantation embryo development via the induction of apoptosis. The present study showed that CTN induces apoptosis and inhibits cell proliferation in the inner cell mass of mouse blastocysts. Notably, we observed for the first time that both these effects are suppressed by liquiritigenin (LQ). LQ is a type of flavonoid isolated from  ",0
6354,29187190,"Ethical considerations in forensic genetics research on tissue samples collected post-mortem in Cape Town, South Africa","The use of tissue collected at a forensic post-mortem for forensic genetics research purposes remains of ethical concern as the process involves obtaining informed consent from grieving family members. Two forensic genetics research studies using tissue collected from a forensic post-mortem were recently initiated at our institution and were the first of their kind to be conducted in Cape Town, South Africa. This article discusses some of the ethical challenges that were encountered in these research projects. Among these challenges was the adaptation of research workflows to fit in with an exceptionally busy service delivery that is operating with limited resources. Whilst seeking guidance from the literature regarding research on deceased populations, it was noted that next of kin of decedents are not formally recognised as a vulnerable group in the existing ethical and legal frameworks in South Africa. The authors recommend that research in the forensic mortuary setting is approached using guidance for vulnerable groups, and the benefit to risk standard needs to be strongly justified. Lastly, when planning forensic genetics research, consideration must be given to the potential of uncovering incidental findings, funding to validate these findings and the feedback of results to family members; the latter of which is recommended to occur through a genetic counsellor. It is hoped that these experiences will contribute towards a formal framework for conducting forensic genetic research in medico-legal mortuaries in South Africa. ",0
6355,29187371,"""Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a """"U-shaped"""" relationship""","""The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a """"U-shaped"""" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery. """,0
6356,29187378,Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria,"Platelet collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type lectin-like receptor 2 (CLEC2) are receptors implicated in platelet activation that both signal via an immunoreceptor tyrosine-based activation motif. Platelets are necessary for host defense and prevention of hemorrhage during sepsis, but the role of platelet GPVI and CLEC2 herein is unknown. To investigate this, we infected mice depleted of platelet GPVI or CLEC2 by antibody treatment or GPVI ",0
6357,29187478,The Relationship Between Peripheral Neuropathy Induced by Docetaxel and Systemic Inflammation-based Parameters in Patients with Breast Cancer,"Docetaxel often induces peripheral neuropathy (PN). The aim of this study was to elucidate the relationship between PN and systemic inflammation parameters, namely the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). We retrospectively evaluated 67 patients with breast cancer who were treated with docetaxel. Thirty patients (44.8%) had received previous chemotherapy including anthracycline. Overall, 51 patients (76.1%) experienced PN. All the parameters increased with the number of administered courses of docetaxel. In an analysis of patients without previous chemotherapy, those suffering from PN had a significantly higher NLR at the first and third cycles than those not suffering from PN (2.9 vs. 2.0, and 3.1 vs. 2.6, respectively, both p<0.05), and the MLR at the first cycle was also significantly higher in those with PN than in those without (0.18 vs. 0.15, p<0.05). Systemic inflammation appears to contribute to the occurrence of PN induced by docetaxel. ",0
6358,29187525,Humanin is an endogenous activator of chaperone-mediated autophagy,"Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects. ",0
6359,29187929,"Role of GeneXpert MTB/RIF test in the screening for pulmonary tuberculosis at the General Referral Provincial Hospital of Bukavu, in the East of the Democratic Republic of the Congo: balance after 10 months of use]","In sub-Saharan Africa, diagnostic methods for tuberculosis are inadequate and are essentially based on microscopy. They constitute a real obstacle to the control of tuberculosis. This study aimed to evaluate the performance of GeneXpert MTB/RIF test compared to classical Ziehl-Neelsen staining at the the general referral provincial hospital of Bukavu, in the east of the Democratic Republic of the Congo after 10 months of use. The results of Ziehl-Neelsen staining and GeneXpert MTB/RIF molecular biology test performed in 452 patients with suspected tuberculosis were collected. This study compares the validity of these different diagnostic tests in the detection of tuberculosis. In the entire group, the frequency of the pulmonary tuberculosis was 16.3%. The positivity rate was significantly higher in GeneXpert MTB/RIF test than in Ziehl-Neelsen staining in the entire group (15.9% vs 9.3%, p = 0.03) and in HIV seropositive patients (52.0% vs 24.0%; p = 0.007). However, the sensitivity of GeneXpert MTB/RIF test compared to that in Ziehl-Neelsen staining wasn't maximum (95.2%). Finally, GeneXpert MTB/RIF test detected rifampicin resistance in 20.8%. This study confirms the superiority of GeneXpert MTB/RIF test compared to Ziehl-Neelsen staining in the detection of tuberculosis and in the prediction of multi-resistance. Its systematic use coupled with Ziehl-Neelsen staining would better control tuberculosis in sub-Saharan Africa. ",0
6360,29187998,Quantifying resilience of multiple ecosystem services and biodiversity in a temperate forest landscape,"Resilience is increasingly being considered as a new paradigm of forest management among scientists, practitioners, and policymakers. However, metrics of resilience to environmental change are lacking. Faced with novel disturbances, forests may be able to sustain existing ecosystem services and biodiversity by exhibiting resilience, or alternatively these attributes may undergo either a linear or nonlinear decline. Here we provide a novel quantitative approach for assessing forest resilience that focuses on three components of resilience, namely resistance, recovery, and net change, using a spatially explicit model of forest dynamics. Under the pulse set scenarios, we explored the resilience of nine ecosystem services and four biodiversity measures following a one-off disturbance applied to an increasing percentage of forest area. Under the pulse + press set scenarios, the six disturbance intensities explored during the pulse set were followed by a continuous disturbance. We detected thresholds in net change under pulse + press scenarios for the majority of the ecosystem services and biodiversity measures, which started to decline sharply when disturbance affected >40% of the landscape. Thresholds in net change were not observed under the pulse scenarios, with the exception of timber volume and ground flora species richness. Thresholds were most pronounced for aboveground biomass, timber volume with respect to the ecosystem services, and ectomycorrhizal fungi and ground flora species richness with respect to the biodiversity measures.  ",0
6361,29188494,Menin Modulates Mammary Epithelial Cell Numbers in Bovine Mammary Glands Through Cyclin D1,"Menin, the protein encoded by the MEN1 gene, is abundantly expressed in the epithelial cells of mammary glands. Here, we found MEN1/menin expression slowly decreased with advancing lactation but increased by the end of lactation. It happened that the number of bovine mammary epithelial cells decreases since lactation, suggesting a role of menin in the control of mammary epithelial cell growth. Indeed, reduction of menin expression through MEN1-specific siRNA transfection in the bovine mammary epithelial cells caused cell growth arrest in G1/S phase. Decreased mRNA and protein expression of Cyclin D1 was observed upon MEN1 knockdown. Furthermore, menin was confirmed to physically bind to the promoter region of Cyclin D1 through a ChIP assay, indicating that menin plays a regulatory role in mammary epithelial cell cycle progression. Moreover, lower expression of MEN1/menin induced increased epithelial cell apoptosis and caused extracellular matrix remodeling by down-regulating its associated genes, such as DSG2 and KRT5, suggesting that menin's role may also be involved in the control of cell-cell adhesion in normal mammary glands. Taken together, our data revealed an unknown molecular function of menin in epithelial cell proliferation, which may be important in the regulation of lactation behavior of mammary glands. ",0
6362,29188633,Advance in molecular genetic research on X-linked syndromic hearing impairment],"In addition to hearing impairment, syndromic hearing impairment is often accompanied by disorders of urinary, skeletal, muscular, nervous, and ocular systems. Genetic factors have shown to play an important role in the pathogenesis of deafness. Mutations of X-linked genes may cause syndromic hearing impairment. Gene mapping, linkage analysis and next-generation sequencing may facilitate delineation of the pathogenesis of X-linked syndromic hearing impairment. This article reviews recent progress in molecular genetic research on X-linked syndromic hearing impairment, which may shed light for the diagnosis and treatment of these diseases. ",0
6363,29188768,Radiolabeling of benzylpenicillin with lutetium-177: Quality control and biodistribution study to develop theranostic infection imaging agent,"Benzylpenicillin acts through binding with beta-lactamase enzyme and inhibiting the bacterial cell wall biosynthesis. Therefore, the radiolabeling of benzylpenicillin with lutetium-177 is expected to serve as a theranostic agent for deep-seated bacterial infections. The radiolabeling of benzylpenicillin resulted ~93% radiochemical yield at optimized reaction conditions. Radiochemical purity analysis was tested with the help of Whatman No. 2 paper and instant thin layer chromatography. Biodistribution study with healthy New Zeeland white rabbit revealed moderate accumulation in different organs. Kidneys are the major organs, showed not more than 4.57±0.89% injected dose per gram organ (ID/gm organ) at 1 h time point and 3.48±1.11% ID/gm organ at 6 h time point. The accumulation of tracer agent in liver was found in the range of 7.42±2.42% to 9.09±2.76 ID/gm organ. The glomerular filtration rate studies revealed rapid clearance - omitting the chance of nephrotoxicity. The radiolabeling yield, biodistribution and glomerular filtration rate results revealed <sup>177</sup>Lu-benzylpencillin could be a potential candidate to diagnose the deep-seated bacterial infection. ",0
6364,29188887,The Influence of Age the BMI and All-Cause Mortality Association: A Meta-Analysis,"To assess BMI range with the lowest mortality for those aged <65 years and those ≥65 years, utilising cohort studies that spanned the entire adult age range. A two-stage random effects meta-analysis of studies that reported mortality in cohorts both ≥65 years and <65 years. Setting / Participants: Community living adults aged ≥65 and <65 years. Eight studies were included with a total of 370 416 subjects (306 340 aged <65 years; 64 076 ≥65 years). In the older age group, mortality risk increased at BMIs lower than 22 (BMI range 21.0-21.9: hazard ratio (HR) (95% confidence interval (CI)): 1.05 (1.03, 1.07)), which was not seen in younger adults. In the younger group, mortality increased from BMI range 28.0-28.9 (HR (95% CI): 1.13 (1.00, 1.29)), but mortality did not tend to increase significantly in the older group at BMIs above 23. The recommended healthy weight range is appropriate for younger and middle aged adults but a higher BMI range should be recommended for older adults based on mortality. ",0
6365,29188897,Better Body Composition and Lipid Profile Can Be Associated with Vitamin D Status in Spanish Elderly? The PHYSMED Study,"Studies have shown that vitamin D deficiency increases the risk for lipid metabolism disorders, but this relationship has provided inconsistent results in elderly. Thus the aim was to assess the association between body composition and blood lipid profile levels on serum 25-hydrovitamin D [25(OH)D] concentration in Spanish elderly. A cross-sectional multicentre study was carried out in 383 participants (58.2% females) aged of 55-88 years. Fasting blood samples analyzed serum concentrations of 25(OH)D, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG) and total cholesterol (TC). Body composition parameters (fat mass, fat free mass) were obtained by bioimpedance, waist circumference (WC), physical activity and vitamin D intake were also evaluated. BMI, fat mass and total fat mass were lower in vitamin D sufficient subjects than vitamin D insufficient and deficient subjects, but this difference was not significant (p>0,05). Those with vitamin D adequate levels also showed lower TC/HDL ratio than those who had inadequate (insufficient or deficient) vitamin D levels (p=0.04). Significant association between 25(OH)D and BMI, waist circumference, total muscle mass, TC/HDL-c ratio, HDL and TG (for all p≤ 0.05) was found after controlling for some confounders. Subjects with inadequate HDL levels (<40mg/dL) showed 1.7 times higher odds than vitamin D deficiency than those with adequate HDL levels (>60mg/dL) (95% CI= 1.10 to 2.85 p= 0.017) and WC was negatively associated with vitamin D status odds ratio of 0.98 (0.96 to 1.00; p= 0.04). Vitamin D concentration was positively correlated with HDL-c and total muscle mass, as well as negatively correlated with WC, LDL-c/HDL-c and TC/HDL-c independently of age, gender and some confounders. ",0
6366,29189176,The Emerging Role of Complement C3 as A Biomarker of Insulin Resistance and Cardiometabolic Diseases: Preclinical and Clinical Evidence,"An intricate network of reciprocal interactions between adipose tissue and immune system have been largely demonstrated, leading to the well-accepted concept of insulin resistance as a low grade inflammatory state and, conversely, chronic high-grade inflammation as a dysmetabolic condition. Immune homeostasis is regulated by several players including the complement system, a complex protein network at the crossroad between the innate and adaptive arms of the human defences against pathogens. Complement C3 represents the nodal point of the complement cascade independently of the pathway recruited. Aim of this review is to collect the evidence supporting the role of complement C3 as a candidate biomarker of insulin resistance and other metabolic disorders. We reviewed the available evidence pointing to a role of complement system, and in particular complement C3, in insulin resistance and other cardiometabolic diseases including diabetes (T2D), hypertension, non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Compelling preclinical evidence demonstrated a role of adipose-tissue C3 and its cleavage products C3a and acylation stimulating protein (ASP) in adipose tissue inflammation and insulin resistance. To further support this hypothesis, several clinical studies, both cross-sectional and longitudinal, confirmed this association in independent cohorts. Moreover, preliminary evidence support a role of complement C3 in other cardiometabolic diseases such as hypertension, NAFLD and atherosclerosis. Future studies are needed to fully confirm the usefulness of C3 as a clinical biomarker and to establish accurate cut-off values. Moreover, the therapeutic potential of C3 modulation in either cardiometabolic and inflammatory diseases need to be investigated. ",0
6367,29189208,Extraneuraxial Hemangioblastoma: Clinicopathologic Features and Review of the Literature,"Extraneuraxial hemangioblastoma occurs in nervous paraneuraxial structures, somatic tissues, and visceral organs, as part of von Hippel-Lindau disease (VHLD) or in sporadic cases. The VHL gene plausibly plays a key role in the initiation and tumorigenesis of both central nervous system and extraneuraxial hemangioblastoma, therefore, the underlying molecular and genetic mechanisms of the tumor growth are initially reviewed. The clinical criteria for the diagnosis of VHLD are summarized, with emphasis on the distinction of sporadic hemangioblastoma from the form fruste of VHLD (eg, hemangioblastoma-only VHLD). The world literature on the topic of extraneuraxial hemangioblastomas has been comprehensively reviewed with ∼200 cases reported to date: up to 140 paraneuraxial, mostly of proximal spinal nerve roots, and 65 peripheral, 15 of soft tissue, 6 peripheral nerve, 5 bone, and 39 of internal viscera, including 26 renal and 13 nonrenal. A handful of possible yet uncertain cases from older literature are not included in this review. The clinicopathologic features of extraneuraxial hemangioblastoma are selectively presented by anatomic site of origin, and the differential diagnosis is emphasized in these subsets. Reference is made also to 10 of the authors' personal cases of extraneuraxial hemangioblastomas, which include 4 paraneuraxial and 6 peripheral (2 soft tissue hemangioblastoma and 4 renal). ",0
6368,29189334,Considerations in the Care of Athletes With Attention Deficit Hyperactivity Disorder,"Uncover literature pertaining to: (1) attention deficit hyperactivity disorder (ADHD) and how it impacts athletes; (2) ADHD medication effects; (3) regulations regarding ADHD medications; (4) approaches to conditions similar to, and occurring with, ADHD; and (5) use of stimulants. MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, Ovid interface. ADHD can have many effects on athletes and sports participation. Exercise has positive benefits on ADHD behaviors and players' attitudes. Athletes with ADHD can have worsened ADHD symptoms after concussions. Attention deficit hyperactivity disorder is a modifier of return to play; baseline ADHD symptoms should be used to guide management. Management should include medications, behavioral/psychosocial therapy, and academic accommodations. Behavioral therapy combined with medication is superior to behavioral treatment alone. Sustained exercise as ADHD treatment should be considered mainstay in management. Sports can increase thermogenic effects of stimulants, heat injury, and cardiac arrhythmias. Increased aggressiveness, improved pain tolerance, and decreased sense of fatigue are some attributes of stimulants that are presumed to impart some advantage to athletes, but evidence is uncertain. Attention deficit hyperactivity disorder medications may lead to myocardial infarctions, cerebrovascular accidents, paranoid psychoses, seizures, insomnia, tremors, anxiety, hypertension, and death. Athletes' performance and quality of life can be negatively affected by ADHD. Risks exist for those who take ADHD medications. More research is needed on the implications ADHD may have in specific sports, and on possible advantages of medication use. Potential deleterious effects of these medications should be addressed. ",0
6369,29189342,The Diagnostic Accuracy of Ultrasound in Detecting Distal Radius Fractures in a Pediatric Population,"Sports ultrasound (US) is becoming popular in diagnosing musculoskeletal injuries. This study, also called the Pediatric Distal Radius Ultrasound Study (PeDRUS), compared the diagnostic accuracy of sports US with plain radiographs in possible distal radius buckle fractures in pediatric population. In this prospective observational study, patients (2-15 years) presenting to an outpatient orthopedic injury clinic with distal forearm injuries without deformity were recruited. Bedside ultrasonography was performed and interpreted by the investigators as positive or negative for fracture. Plain radiographs were then performed and interpreted by the same investigator. The radiographs were considered the definitive imaging study for this investigation. Fifty-one patients were included with a mean age of 9.9 years. Fractures were diagnosed on both US and plain radiographs in 34 patients. Fractures were ruled out on both US and plain radiographs in 16 patients. There was only one case in which the US was interpreted differently than radiograph. For fractures of the distal radius in this population, the sensitivity was 97.1% [95% confidence interval (CI) = 89.2-97.1] and the specificity was 100% (95% CI = 82.5-100). The positive predictive value was 100% (95% CI = 91.8-100), whereas the negative predictive value was 94.1% (95% CI = 77.7-94.1). The positive likelihood ratio was infinite, suggesting utility in confirming a fracture. The negative likelihood ratio was 0.03 (95% CI = 0.03-0.13), suggesting that US has value in ruling out a fracture. Our study suggests that diagnostic sports US is sensitive and specific for detecting distal radius fractures in pediatric patients with nondeformed forearm injuries, demonstrating that US is an acceptable alternative to plain radiographs for evaluating fractures in a pediatric population. ",0
6370,29189932,Contrast-enhanced US for characterization of focal liver lesions: a comprehensive meta-analysis,"This meta-analysis was performed to evaluate the accuracy of contrast-enhanced ultrasound (CEUS) in differentiating malignant from benign focal liver lesions (FLLs). Cochrane Library, PubMed and Web of Science databases were systematically searched and checked for studies using CEUS in characterization of FLLs. Data necessary to construct 2×2 contingency tables were extracted from included studies. The QUADAS tool was utilized to assess the methodologic quality of the studies. Meta-analysis included data pooling, subgroup analyses, meta-regression and investigation of publication bias was comprehensively performed. Fifty-seven studies were included in this meta-analysis and the overall diagnostic accuracy in characterization of FLLs was as follows: pooled sensitivity, 0.92 (95%CI: 0.91-0.93); pooled specificity, 0.87 (95%CI: 0.86-0.88); diagnostic odds ratio, 104.20 (95%CI: 70.42-154.16). Subgroup analysis indicated higher diagnostic accuracy of the second-generation contrast agents (CAs) than the first-generation CA (Levovist; DOR: 118.27 vs. 62.78). Furthermore, Sonazoid demonstrated the highest diagnostic accuracy among three major CAs (SonoVue, Levovist and Sonazoid; DOR: 118.82 vs. 62.78 vs. 227.39). No potential publication bias was observed of the included studies. CEUS is an accurate tool to stratify the risk of malignancy in FLLs. The second-generation CAs, especially Sonazoid may greatly improve diagnostic performance. • CEUS shows excellent diagnostic accuracy in differentiating malignant from benign FLLs. • The second-generation CAs have higher diagnostic accuracy than first-generation CAs. • Sonazoid demonstrates the highest diagnostic accuracy among three major CAs. ",0
6371,29189950,Cost assessment of a new oral care program in the intensive care unit to prevent ventilator-associated pneumonia,"Ventilator-associated pneumonia (VAP) is the most frequent hospital-acquired infections in intensive care units (ICU). In the bundle of care to prevent the VAP, the oral care is very important strategies, to decrease the oropharyngeal bacterial colonization and presence of causative bacteria of VAP. In view of the paucity of medical economics studies, our objective was to determine the cost of implementing this oral care program for preventing VAP. In five ICUs, during period 1, caregivers used a foam stick for oral care and, during period 2, a stick and tooth brushing with aspiration. Budgetary effect of the new program from the hospital's point of view was analyzed for both periods. The costs avoided were calculated from the incidence density of VAP (cases per 1000 days of intubation). The cost study included device cost, benefit lost, and ICU cost (medication, employer and employee contributions, blood sample analysis…). A total of 2030 intubated patients admitted to the ICUs benefited from oral care. The cost of implementing the study protocol was estimated to be €11,500 per year. VAP rates decreased significantly between the two periods (p1 = 12.8% and p2 = 8.5%, p = 0.002). The VAP revenue was ranged from €28,000 to €45,000 and the average cost from €39,906 to €42,332. The total cost assessment calculated was thus around €1.9 million in favor of the new oral care program. Our study showed that the implementation of a simple strategy improved the quality of patient care is economically viable. NCT02400294. ",0
6372,29190513,"""The role of algal organic matter in the separation of algae and cyanobacteria using the novel """"Posi"""" - Dissolved air flotation process""","Algae and cyanobacteria frequently require separation from liquid media in both water treatment and algae culturing for biotechnology applications. The effectiveness of cell separation using a novel dissolved air flotation process that incorporates positively charged bubbles (PosiDAF) has recently been of interest but has been shown to be dependent on the algae or cyanobacteria species tested. Previously, it was hypothesised that algal organic matter (AOM) could be impacting the separation efficiency. Hence, this study investigates the influence of AOM on cell separation using PosiDAF, in which bubbles are modified using a commercially available cationic polyelectrolyte poly(N, N-diallyl-N,N-dimethylammonium chloride) (PDADMAC). The separation of Chlorella vulgaris CS-42/7, Mychonastes homosphaera CS-556/01 and two strains of Microcystis aeruginosa (CS-564/01 and CS-555/1), all of which have similar cell morphology but different AOM character, was investigated. By testing the cell separation in the presence and absence of AOM, it was determined that AOM enhanced cell separation for all the strains but to different extents depending on the quantity and composition of carbohydrates and proteins in the AOM. By extracting AOM from the strain for which optimal separation was observed and adding it to the others, cell separation improved from <55% to >90%. This was attributed to elevated levels of acidic carbohydrates as well as glycoprotein-carbohydrate conjugations, which in turn were related to the nature and quantity of proteins and carbohydrates present in the AOM. Therefore, it was concluded that process optimisation requires an in-depth understanding of the AOM and its components. If culturing algae for biotechnology applications, this indicates that strain selection is not only important with respect to high value product content, but also for cell separation. ",0
6373,29190536,"State-level climate, anti-discrimination law, and sexual minority health status: An ecological study","How social and legal climate influence LGB health is an under-studied topic. In response, this study examines whether the lesbian/gay/bisexual (LGB) climate index and presence of anti-discrimination law show population health significance for U.S. sexual minorities. The LGB climate index uses survey data collected between 2012 and 2013 to gauge states' support of lesbian, gay, and bisexual individuals, whereas anti-discrimination law captures any state-level law that makes it illegal to discriminate because of sexual orientation in employment, housing, and public accommodations. We merge these two contextual measures with 2011-2015 Behavioral Risk Factor Surveillance System (BRFSS) aggregated, individual-level survey data, from which we generate three measures of state-level rates: excellent self-rated health, routine health care utilization, and health insurance among self-identified lesbian/gay and bisexual adults. We find that the LGB climate index associates positively with rates of excellent self-rated health, routine health care utilization, and health insurance-but only for states with anti-discrimination laws, and only among lesbian/gay adults. Analyses confirm salubrious synergism between a sexually-minority-friendly climate and anti-discrimination law-together these two contextual measures interact to protect lesbian/gay population health. ",0
6374,29190547,Low-folate stress reprograms cancer stem cell-like potentials and bioenergetics metabolism through activation of mTOR signaling pathway to promote in vitro invasion and in vivo tumorigenicity of lung cancers,"Low-folate (LF) nutritional status is associated with increased risks of lung cancer. It has unexplored effects on lung cancer malignancy, a cancer stem cell (CSC) disease. We hypothesized that LF may reprogram CSC-like potential and bioenergetics metabolism to increase metastasis potential of lung cancers. Cultivation of human non-small-cell lung cancer cells (H23) in an LF medium enhanced CSC-like properties signified by increased expressions of the CSC surface marker CD44 and pluripotency markers Sox2, Oct4 and ALDH1A1, and promoted self-renewal ability of anchorage-independent oncospheroid formation. The CSC-like phenotype of LF-treated H23 cells coupled with the metabolic reprogramming to aerobic glycolysis evident by elevated lactate release and medium acidification suppressed expressions of pyruvate dehydrogenase E1-α, and elevated redox status of the NADH/NAD+ and NADPH/NADP+ ratios. The LF-induced metabostemness phenotype of H23 cells was modified by DNA methylation inhibitor 5-AdC and histone acetylation inhibitor EX. Treatment of H23 cells with mTOR siRNA or the mTOR inhibitor rapamycin abrogated LF-activated Akt-mTOR-Hif1-Foxo signaling and stemness-associated sonic hedgehog pathway, reversed Warburg metabolic switch and diminished invasion of H23 cells. Intrapleural injection of LF-induced lung oncospheres into the LF recipient mice, but not the control recipient mice, caused metastasis xenograft lung tumors. The in vitro and in vivo data corroboratively demonstrate that LF stress reprograms metabostemness signatures through activated mTOR signaling pathway to promote metastasis tumorigenicity of lung cancers. ",0
6375,29190568,Polydopamine-assisted immobilization of hierarchical zinc oxide nanostructures on electrospun nanofibrous membrane for photocatalysis and antimicrobial activity,"Depositing of hierarchical ZnO nanostructures on electrospun nanofibers and their proper attachment has gained significant interest for myriad applications. However, the weak attachment of such nanostructures to the nanofiber surface limits their practical applications. In this study, a simple and efficient method has been developed for preparing hierarchical ZnO nanorod deposited polyurethane (PU) nanofiber by combining electrospinning, surface functionalization and hydrothermal treatment. Electrospun PU nanofibers were coated with polydopamine (Pdopa) via dip coating method. The resulting Pdopa coated PU nanofibrous mat was soaked in aqueous ZnO nanoparticles (ZnONPs) solution in order to seed the metal-oxide particles on its surface. Later, ZnO nanorods (ZNRs) were grown on the ZnO-seeded electrospun PU nanofiber via a hydrothermal process. X-ray photoelectron spectroscopy (XPS), Field-Emission Scanning electron microscopy (FE-SEM), X-ray diffraction pattern (XRD) and infra-red (IR) spectra indicated that ZnO nanorods firmly adhered to the functionalized PU nanofiber surface and had high photocatalytic/antimicrobial activity at the low-intensity UV-LED device with good reusability. The catechol group of Pdopa not only causes adhesion of ZnO nanostructures, but also act as an electron trap, preventing the recombination of e-h pairs and thereby improving the photocatalytic efficiency. We believe that the fabricated composite membrane with antifouling effect and photocatalytic activity is a potential candidate for organic pollutant degdration and wastewater purification. ",0
6376,29190919,Molecular characterization of pro-metastatic functions of β4-integrin in colorectal cancer,"The β4-integrin subunit has been implicated in development and progression of several epithelial tumor types. However, its role in metastases of colorectal cancer (CRC) remains elusive. To study CRC metastasis, we generated a highly invasive, metastatic cell line MC38-LM10 (LM10) by passaging mouse CRC MC38 cells ten times, using a splenic injection model of liver metastasis. Affymetrix microarray analyses of LM10 and MC38 cell lines and their corresponding liver metastases generated a gene signature for CRC metastasis. This signature shows strong upregulation of β4-integrin in LM10 cells and corresponding metastases. Upregulation of β4-integrin in highly aggressive LM10 cells is associated with increased migration, invasion, and liver metastases. Furthermore, stable knockdown of β4-integrin in human CRC SW620 cells reduces Bcl-2 expression, increases apoptosis, and decreases invasion, tumorigenicity, and liver metastasis, thus resulting in significantly increased survival of mice (hazard ratio = 0.32, 95% confidence interval = 0.15-0.66, P<0.01). Patients with CRC tumors display higher β4-integrin levels in stages 1-4 and significantly lower survival rate. Collectively, β4-integrin plays a critical role in CRC progression, invasion, and metastasis, suggesting that it could be a potential therapeutic target for CRC patients. ",0
6377,29191128,Suppressive effect of nobiletin and epicatechin gallate on fructose uptake in human intestinal epithelial Caco-2 cells,"Inhibition of excessive fructose intake in the small intestine could alleviate fructose-induced diseases such as hypertension and non-alcoholic fatty liver disease. We examined the effect of phytochemicals on fructose uptake using human intestinal epithelial-like Caco-2 cells which express the fructose transporter, GLUT5. Among 35 phytochemicals tested, five, including nobiletin and epicatechin gallate (ECg), markedly inhibited fructose uptake. Nobiletin and ECg also inhibited the uptake of glucose but not of L-leucine or Gly-Sar, suggesting an inhibitory effect specific to monosaccharide transporters. Kinetic analysis further suggested that this reduction in fructose uptake was associated with a decrease in the apparent number of cell-surface GLUT5 molecules, and not with a change in the affinity of GLUT5 for fructose. Lastly, nobiletin and ECg suppressed the permeation of fructose across Caco-2 cell monolayers. These findings suggest that nobiletin and ECg are good candidates for preventing diseases caused by excessive fructose intake. ",0
6378,29191349,Clinical trials: Kids are not just little people,"Clinical trials are the backbone of modern evidence-based medicine. They are the vital bridge between research-based discovery and cutting edge patient care. Randomized, controlled clinical trials are the gold standard of medical research, providing a method for evaluation and discovery of novel therapies that improve and even save lives. Despite an increase in the number of pediatric and adult clinical trials over recent decades, this growth has not been equal among these populations. The volume of clinical trials involving children lags substantially behind their adult counterparts. Children are not simply little adults. As a result, extrapolating results from adult clinical trials to the treatment of children may be inappropriate and, possibly, harmful. In this review, we discuss the intricacies of performing clinical trials in all patients and stress the unique distinguishing characteristics of pediatric clinical trials. ",0
6379,29191555,Discovery of benzotriazole-azo-phenol/aniline derivatives as antifungal agents,"A series of benzotriazole-azo-phenol/aniline derivatives were prepared and evaluated for their antifungal activities against six phytopathogenic fungi such as Fusarium graminearum, Fusarium solani, Alternaria alternate, Valsa mali, Botrytis cinerea, and Curvularia lunata. Among them, compounds IIf, IIn, and IIr showed a broad-spectrum of potent antifungal activities. Especially some compounds displayed 3.5-10.8 folds more potent activities than carbendazim against A. alternata and C. lunata. Notably, compounds IIc, IIm, and IIr exhibited good protective and therapeutic effects against B. cinerea at 200 μg/mL. Their structure-activity relationships were also discussed. ",0
6380,29191667,"Complete genome sequence of Streptomyces formicae KY5, the formicamycin producer","Here we report the complete genome of the new species Streptomyces formicae KY5 isolated from Tetraponera fungus growing ants. S. formicae was sequenced using the PacBio and 454 platforms to generate a single linear chromosome with terminal inverted repeats. Illumina MiSeq sequencing was used to correct base changes resulting from the high error rate associated with PacBio. The genome is 9.6 Mbps, has a GC content of 71.38% and contains 8162 protein coding sequences. Predictive analysis shows this strain encodes at least 45 gene clusters for the biosynthesis of secondary metabolites, including a type 2 polyketide synthase encoding cluster for the antibacterial formicamycins. Streptomyces formicae KY5 is a new, taxonomically distinct Streptomyces species and this complete genome sequence provides an important marker in the genus of Streptomyces. ",0
6381,29191714,Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial,"Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients' death. Therefore, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were randomly enrolled: 24 of them were assigned to receive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-treated patients showed a significantly lower number of severe infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients. By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the use of antibiotics. ",0
6382,29191778,Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database,"Thymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs. The International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis. A total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p = 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio = 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor. Previously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs. ",0
6383,29192201,Mechanism in External Field-mediated Trapping of Bacteria Sensitive to Nanoscale Surface Chemical Structure,"Molecular imprinting technique enables the selective binding of nanoscale target molecules to a polymer film, within which their chemical structure is transcribed. Here, we report the successful production of mixed bacterial imprinted film (BIF) from several food poisoning bacteria by the simultaneous imprinting of their nanoscale surface chemical structures (SCS), and provide highly selective trapping of original micron-scale bacteria used in the production process of mixed BIF even for multiple kinds of bacteria in real samples. Particularly, we reveal the rapid specific identification of E. coli group serotypes (O157:H7 and O26:H11) using an alternating electric field and a quartz crystal microbalance. Furthermore, we have performed the detailed physicochemical analysis of the specific binding of SCS and molecular recognition sites (MRS) based on the dynamic Monte Carlo method under taking into account the electromagnetic interaction. The dielectrophoretic selective trapping greatly depends on change in SCS of bacteria damaged by thermal treatment, ultraviolet irradiation, or antibiotic drugs, which can be well explained by the simulation results. Our results open the avenue for an innovative means of specific and rapid detection of unknown bacteria for food safety and medicine from a nanoscale viewpoint. ",0
6384,29192203,Habitat-dependent changes in vigilance behaviour of Red-crowned Crane influenced by wildlife tourism,"The Endangered Red-crowned Crane (Grus japonensis) is one of the most culturally iconic and sought-after species by wildlife tourists. Here we investigate how the presence of tourists influence the vigilance behaviour of cranes foraging in Suaeda salsa salt marshes and S. salsa/Phragmites australis mosaic habitat in the Yellow River Delta, China. We found that both the frequency and duration of crane vigilance significantly increased in the presence of wildlife tourists. Increased frequency in crane vigilance only occurred in the much taller S. salsa/P. australis mosaic vegetation whereas the duration of vigilance showed no significant difference between the two habitats. Crane vigilance declined with increasing distance from wildlife tourists in the two habitats, with a minimum distance of disturbance triggering a high degree of vigilance by cranes identified at 300 m. The presence of wildlife tourists may represent a form of disturbance to foraging cranes but is habitat dependent. Taller P. australis vegetation serves primarily as a visual obstruction for cranes, causing them to increase the frequency of vigilance behaviour. Our findings have important implications for the conservation of the migratory red-crowned crane population that winters in the Yellow River Delta and can help inform visitor management. ",0
6385,29192260,Antisense oligonucleotides: the next frontier for treatment of neurological disorders,"Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future. ",0
6386,29192408,Prolonged delivery of BMP-2 by a non-polymer hydrogel for bone defect regeneration,"Bone morphogenetic protein 2 (BMP-2) is a potent inducer of bone formation that is currently used in a limited number of clinical indications to treat extensive bone loss. Extending the field of applications of this molecule requires design of the delivery system to protect the protein from early degradation and allow a slow long-term release. This study describes the use of a non-polymer hydrogel, based on the self-assembly of small amphiphilic glycosyl-nucleolipids into micellar structures, as a new type of delivery system for BMP-2. BMP-2 was readily encapsulated in glycosyl-nucleosyl-fluorinated (GNF)-based gels and slowly released in vitro, while maintaining its osteogenic activity. When hydrogel pieces containing fluorophore-tagged BMP-2 were deposited onto a calvaria defect in mouse, the signal detected in living mice gradually decreased and was still detectable at 3 weeks. Gel-embedded protein promoted significant calvarial bone defect regeneration at 8 weeks after surgery. In contrast, when a solution of BMP-2 without hydrogel was injected into the defects, the fluorescence signal decreased rapidly and no significant bone formation was observed. The unique property of the GNF-based hydrogel as an injectable delivery system for low doses of BMP-2 was revealed in a subcutaneous model of ectopic bone formation. Injected BMP-2-laden GNF hydrogel blocks elicited the formation of cancellous bone, showing all the typical features of remodeling bone that contains bone marrow. These results show that this GNF-based hydrogel is an easy-to-use, efficient delivery system for BMP-2 and osteogenic material to support bone regeneration. ",0
6387,29192634,"The Pattern of significant lesions found in computerized tomography scan of recurrent seizure patients at a center in Enugu, Nigeria","Seizures are common reasons for neurologic consultations and investigations. In the absence of magnetic resonance imaging, computerized tomography scanning of the brain is a reliable and cheaper alternative. Little is known about the pattern of brain lesions in patients with recurrent seizures in Nigeria. To determine the pattern of significant intracerebral lesions in patients presenting with recurrent seizures in a tertiary hospital in Enugu. All the medical and computer tomography records of patients with a clinical diagnosis of recurrent seizures were reviewed. The study duration was 11 years (January 2003 to December 2013). Relevant data were obtained and statistical analysis was done using SPSS version 19 and GraphPad Prism 6. The diagnostic yield of CT was 55.1%. Twenty (9.3%) individuals had two lesions each. The significant findings were tumors (20.4%), encephalomalacia (18.9%) and strokes (7.7% (ischemic stroke, 4.1%, intracerebral hemorrhage, 3.1%, subarachnoid hemorrhage/intraventricular hemorrhage, 0.5%). Hydrocephalus (HCP) was found in 18 (9.2%) cases, and 30% of them occurred together with other lesions. The diagnostic yield increased with age reaching 84.4% from the age of 60 years. Only patients with encephalomalacia were statistically older than those with normal imaging. Computed tomography scan has a high diagnostic yield, especially in elderly patients with recurrent generalized seizures. Brain tumors, encephalomalacia, and HCP are most common causes of recurrent seizures in the adults. ",0
6388,29192652,ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity,"High-grade endometrial stromal sarcoma likely encompasses underrecognized tumors harboring genetic abnormalities besides YWHAE-NUTM2 fusion. Triggered by three initial endometrial stromal sarcomas with ZC3H7B-BCOR fusion characterized by high-grade morphology and aggressive clinical behavior, we herein investigate the clinicopathologic features of this genetic subset by expanding the analysis to 17 such tumors. All of them occurred in adult women with a median age of 54 (range, 28-71) years. They were predominantly based in the endomyometrium and demonstrated tongue-like and/or pushing myometrial invasion. Most were uniformly cellular and displayed haphazard fascicles of spindle cells with mild to moderate nuclear atypia. Myxoid matrix was seen in 14 of 17 (82%) tumors, and collagen plaques were seen in 8 (47%). The mitotic index was ≥10 mitotic figures/10 high-power fields (HPFs) in 14 of 17 (82%) tumors with a median of 14.5 mitotic figures/10 HPFs. No foci of conventional or variant low-grade endometrial stromal sarcoma were seen. All tumors expressed CD10 with only limited or absent desmin, SMA and/or h-caldesmon staining. ER and PR expression in >5% of cells was seen in 4 of 12 (33%) tumors. Diffuse cyclin D1 and BCOR immunoreactivity was present in 7 of 8 (88%) and 7 of 14 (50%) tumors, respectively. Fluorescence in situ hybridization or targeted RNA sequencing confirmed ZC3H7B-BCOR fusion in all tumors, including four and two previously diagnosed as myxoid leiomyosarcoma and undifferentiated uterine sarcoma, respectively. Limited clinical data suggest that patients present at higher stage and have worse prognosis compared with published outcomes in low-grade endometrial stromal sarcoma. Tumors with ZC3H7B-BCOR fusion constitute a distinct group of endometrial stromal sarcomas with high-grade morphology that should be distinguished from other uterine mesenchymal neoplasms that may demonstrate myxoid morphology. ",0
6389,29192745,Impact of coexistent adenomyosis on outcomes of patients with endometrioid endometrial cancer: a propensity score-matched analysis,"Despite the common occurrence of adenomyosis in endometrial cancer (EC), there is a paucity and conflict in the literature regarding its impact on outcomes of patients. We sought to compare outcomes of patients with endometrioid type EC with or without adenomyosis. A total of 314 patients were included in the analysis. Patients were divided into 2 groups according to the presence or absence of adenomyosis. Adenomyosis was identified in 79 patients (25.1%). A propensity score-matched comparison (1:1) was carried out to minimize selection biases. The propensity score was developed through multivariable logistic regression model including age, stage, and tumor grade as covariates. After performing propensity score matching, 70 patients from each group were successfully matched. Primary outcome of the study was disease-free survival (DFS), and the secondary outcomes were overall survival (OS) and disease-specific survival (DSS). Median follow-up time was 61 months for the adenomyosis positive group and 76 months for the adenomyosis negative group. There were no statistically significant differences in 3- and 5-year DFS, OS, and DSS rates between the 2 groups. Five-year DFS was 92% vs 88% (hazard ratio [HR] 1.54 [0.56-4.27]; p = 0.404), 5-year OS was 94% vs 92% (HR 1.60 [0.49-5.26]; p = 0.441), and 5-year DSS was 94% vs 96% (HR 2.51 [0.46-13.71]; p = 0.290) for patients with and without adenomyosis, respectively. Coexistent adenomyosis in EC is not a prognostic factor and does not impact survival outcomes. ",0
6390,29194043,The role of corticosteroid-binding globulin in the evaluation of adrenal insufficiency,"Cortisol is a hydrophobic molecule that is largely bound to corticosteroid-binding globulin (CBG) in the circulation. In the assessment of adrenal insufficiency, many clinicians measure a total serum cortisol level, which assumes that CBG is present in normal concentrations and with a normal binding affinity for cortisol. CBG concentration and affinity are affected by a number of common factors including oral contraceptive pills (OCPs), fever and infection, as well as rare mutations in the serine protease inhibitor A6 (SERPINA6) gene, and as such, total cortisol levels might not be the ideal way to assess adrenal function in all clinical circumstances. This paper reviews the limitations of immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the measurement of total cortisol, the challenges of measuring free serum cortisol directly as well as the difficulties in calculating an estimated free cortisol from total cortisol, CBG and albumin concentrations. Newer approaches to the evaluation of adrenal insufficiency, including the measurement of cortisol and cortisone in the saliva, are discussed and a possible future role for these tests is proposed. ",0
6391,29194181,Feasibility of a Skills-Based Group Reintegration Workshop for OEF/OIF Veterans: STEP-Home,"To evaluate the feasibility of a newly developed reintegration workshop for Operation Iraqi Freedom/Operation Enduring Freedom (OEF/OIF) Veterans that is based on an evidence-based rehabilitation program shown to be effective in treating mild traumatic brain injury-related symptoms in civilians. Underutilization and resistance to mental health treatment remain a significant problem for OEF/OIF Veterans. Innovative, integrative, transdiagnostic, and acceptable interventions are needed, particularly for this heterogeneous group. Eighty-four OEF/OIF/Operation New Dawn Veterans (74 male and 10 female)-mean age = 35; standard deviation = 7.4. VA Healthcare System. A 12-week, 2-hour/wk, group skills-based workshop with individual skill building to assist all OEF/OIF Veterans (with and without psychiatric and/or traumatic brain injury) in reintegration after military service. Primary outcomes were feasibility measures including treatment fidelity, acceptability, tolerability/adherence, and treatment-related skill acquisition. Secondary outcomes were interest and engagement in future treatment and reintegration status. Veterans' enrollment, adherence, and attrition data indicated that Short-Term Executive Plus adapted for Veteran civilian reintegration (STEP-Home) was acceptable and tolerable. Pre-/postintervention differences in attention, problem-solving, and emotional regulation skills demonstrated treatment-related skills acquisition. Secondary outcome data demonstrated Veterans who were hesitant to participate in mental health treatments before enrollment were more open to treatment engagement after STEP-Home, and reintegration status improved. This study demonstrated that the STEP-Home workshop is feasible in OEF/OIF Veterans and changes in treatment-related skill acquisition and reintegration status were observed. STEP-Home has potential to facilitate readjustment and serves as a gateway to additional, critically needed Veterans Administration services. ",0
6392,29194288,Area at risk can be assessed by iodine-123-meta-iodobenzylguanidine single-photon emission computed tomography after myocardial infarction: a prospective study,"Myocardial salvage is an important surrogate endpoint to estimate the impact of treatments in patients with ST-segment elevation myocardial infarction (STEMI). The aim of this study was to evaluate the correlation between cardiac sympathetic denervation area assessed by single-photon emission computed tomography (SPECT) using iodine-123-meta-iodobenzylguanidine (I-MIBG) and myocardial area at risk (AAR) assessed by cardiac magnetic resonance (CMR) (gold standard). A total of 35 postprimary reperfusion STEMI patients were enrolled prospectively to undergo SPECT using I-MIBG (evaluates cardiac sympathetic denervation) and thallium-201 (evaluates myocardial necrosis), and to undergo CMR imaging using T2-weighted spin-echo turbo inversion recovery for AAR and postgadolinium T1-weighted phase sensitive inversion recovery for scar assessment. I-MIBG imaging showed a wider denervated area (51.1±16.0% of left ventricular area) in comparison with the necrosis area on thallium-201 imaging (16.1±14.4% of left ventricular area, P<0.0001). CMR and SPECT provided similar evaluation of the transmural necrosis (P=0.10) with a good correlation (R=0.86, P<0.0001). AAR on CMR was not different compared with the denervated area (P=0.23) and was adequately correlated (R=0.56, P=0.0002). Myocardial salvage evaluated by SPECT imaging (mismatch denervated but viable myocardium) was significantly higher than by CMR (P=0.02). In patients with STEMI, I-MIBG SPECT, assessing cardiac sympathetic denervation may precisely evaluate the AAR, providing an alternative to CMR for AAR assessment. ",0
6393,29194682,Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: Regulatory analyses and perspectives,"Several highly effective, interferon-free, direct-acting antiviral (DAA)-based regimens are available for the treatment of chronic hepatitis C virus (HCV) infection. Despite impressive efficacy overall, a small proportion of patients in registrational trials experienced treatment failure, which in some cases was associated with the detection of HCV resistance-associated substitutions (RASs) at baseline. In this article, we describe methods and key findings from independent regulatory analyses investigating the impact of baseline nonstructural (NS) 3 Q80K and NS5A RASs on the efficacy of current United States Food and Drug Administration (FDA)-approved regimens for patients with HCV genotype (GT) 1 or GT3 infection. These analyses focused on clinical trials that included patients who were previously na?ve to the DAA class(es) in their investigational regimen and characterized the impact of baseline RASs that were enriched in the viral population as natural or transmitted polymorphisms (i.e., not drug-selected RASs). We used a consistent approach to optimize comparability of results across different DAA regimens and patient populations, including the use of a 15% sensitivity cutoff for next-generation sequencing results and standardized lists of NS5A RASs. These analyses confirmed that detection of NS3 Q80K or NS5A baseline RASs was associated with reduced treatment efficacy for multiple DAA regimens, but their impact was often minimized with the use of an intensified treatment regimen, such as a longer treatment duration and/or addition of ribavirin. We discuss the drug resistance-related considerations that contributed to pretreatment resistance testing and treatment recommendations in drug labeling for FDA-approved DAA regimens. CONCLUSION: Independent regulatory analyses confirmed that baseline HCV RASs can reduce the efficacy of certain DAA-based regimens in selected patient groups. However, highly effective treatment options are available for patients with or without baseline RASs. (Hepatology 2018;67:2430-2448).",0
6394,29194722,The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response,"The outcomes of hepatitis E virus (HEV) infection are diverse, ranging from asymptomatic carrier, self-limiting acute infection, and fulminant hepatitis to persistent infection. This is closely associated with the immunological status of the host. This study aimed to understand the innate cellular immunity as the first-line defense mechanism in response to HEV infection. Phosphorylation of signal transducer and activator of transcription 1, a hallmark of the activation of antiviral interferon (IFN) response, was observed in the liver tissues of the majority of HEV-infected patients but not in the liver of uninfected individuals. In cultured cell lines and primary liver organoids, we found that HEV RNA genome potently induced IFN production and antiviral response. This mechanism is conserved among different HEV strains, including genotypes 1, 3, and 7 as tested. Interestingly, single-stranded HEV RNA is sufficient to trigger the antiviral response, without the requirement of viral RNA synthesis and the generation of an RNA replicative form or replicative intermediate. Surprisingly, the m(7) G cap and poly A tail are not required, although both are key features of the HEV genome. Mechanistically, this antiviral response occurs in a retinoic acid-inducible gene-I-independent, melanoma differentiation-associated protein 5-independent, mitochondrial antiviral signaling protein-independent, and ?-catenin-independent but IRF3-dependent and IRF7-dependent manner. Furthermore, the integrity of the Janus kinase-signal transducer and activator of transcription pathway is essentially required. CONCLUSION: HEV infection elicits an active IFN-related antiviral response in vitro and in patients, triggered by the viral RNA and mediated by IFN regulatory factors 3 and 7 and the Janus kinase-signal transducer and activator of transcription cascade; these findings have revealed new insights into HEV-host interactions and provided the basis for understanding the pathogenesis and outcome of HEV infection. (Hepatology 2018;67:2096-2112).",0
6395,29195591,"Variability in motivational interviewing adherence across sessions, providers, sites, and research contexts","Providers' adherence in the delivery of behavioral interventions for substance use disorders is not fixed, but instead can vary across sessions, providers, and intervention sites. This variability can substantially impact the quality of intervention that clients receive. However, there has been limited work to systematically evaluate the extent to which substance use intervention adherence varies from session-to-session, provider-to-provider, and site-to-site. The present study quantifies the extent to which adherence to Motivational Interviewing (MI) for alcohol and drug use varies across sessions, providers, and intervention sites and compares the extent of this variability across three common MI research contexts that evaluate MI efficacy, MI effectiveness, and MI training. Independent raters coded intervention adherence to MI from 1275 sessions delivered by 216 providers at 15 intervention sites. Multilevel models indicated that 57%-94% of the variance in MI adherence was attributable to variability between sessions (i.e., within providers), while smaller proportions of variance were attributable to variability between providers (3%-26%) and between intervention sites (0.1%-28%). MI adherence was typically lowest and most variable within contexts evaluating MI training (i.e., where MI was not protocol-guided and delivered by community treatment providers) and, conversely, adherence was typically highest and least variable in contexts evaluating MI efficacy and effectiveness (i.e., where MI was highly protocolized and delivered by trained therapists). These results suggest that MI adherence in efficacy and effectiveness trials may be substantially different from that obtained in community treatment settings, where adherence is likely to be far more heterogeneous. ",0
6396,29195717,The efficacy of two different dosages of hepatitis B immunoglobulin combined with hepatitis B vaccine in preventing mother-to-child transmission of hepatitis B virus: A prospective cohort study,"A birth dose of hepatitis B immunoglobulin (HBIG), in combination with hepatitis B vaccine (HepB), is recommended for infants born to hepatitis B surface antigen (HBsAg)-positive mothers. However, the optimal dosage of HBIG remains to be resolved. This prospective cohort study aimed to compare the efficacy of two dosages of HBIG combined with HepB to prevent mother-to-child transmission (MTCT) of HBV. From 2009 to 2011, we prospectively enrolled mother-infant pairs with positive maternal HBsAg in China. Infants were assigned to receive one dose of 100 IU or 200 IU HBIG within 12 h of birth according to maternal numbering, followed by completion of the 3-dose 10 μg HepB series. At 7 months, post-vaccination serologic testing (PVST) was performed in 545 and 632 infants in 100 IU and 200 IU HBIG groups, respectively, among whom, 451 and 529 were followed up to 12 months. Maternal and birth characteristics were comparable between infants in 100 IU and 200 IU HBIG groups. At 7 months, the rates of perinatal infection were 1.5% (8/545) and 1.9% (12/632) in 100 IU and 200 IU HBIG groups, respectively (p = .568). One non-responder infant in 200 IU HBIG group became newly infected at 12 months. The antibody to hepatitis B surface antigen (anti-HBs) positive rates were 98.5% (529/537) and 98.2% (609/620) in 100 IU and 200 IU HBIG groups at 7 months, respectively (p = .704), and the corresponding figures were 98.2% (431/439) and 97.1% (496/511) at 12 months (p = .266). The anti-HBs geometric mean concentrations were comparable between two groups at 7 months (707.95 mIU/mL vs. 602.56 mIU/mL, p = .062) and 12 months (245.47 mIU/mL vs. 229.09 mIU/mL, p = .407). One birth dose of 100 IU HBIG, combined with the HepB series, might be enough for preventing MTCT of HBV in infants born to HBsAg-positive mothers. ",0
6397,29195723,A non-language-specific speech test to evaluate the speech of cleft patients from different language and cultural backgrounds - A pilot study,"Cleft speech tests are not universally available. We developed a tool to fill this gap, especially in the context of a cleft mission setting. We performed a pilot study to evaluate the test's ability to differentiate between the speech of cleft patients and healthy individuals from three different language backgrounds. We used 78 made-up, nonsensical syllables to evaluate hypernasality, nasal emissions, and consonant errors. Cleft (n = 41) and non-cleft (n = 39) individuals from three countries were included in this study. Two speech and language pathologists, blinded to the examination, rated the audio recording independently. Patients from Germany (n = 12; mean age 15.2), Iran (n = 14; mean age 7), and India (n = 15; mean age 14.7 years) were evaluated. We observed a significant difference in each category (p < 0.05) between patients and control subjects of the same language and cultural background. Hypernasality was affected the most. The test proved to possess the correct phonetic characteristics to reveal and provoke relevant cleft speech pathologies independent of cultural and language backgrounds. The test sounds posed no articulatory difficulties to non-cleft individuals, with some exceptions regarding non-specific consonant errors. A comparison with other existing tests will further illuminate its value as a speech test. ",0
6398,29195754,Determination of Acoustic Cavitation Probabilities and Thresholds Using a Single Focusing Transducer to Induce and Detect Acoustic Cavitation Events: I. Method and Terminology,"A method to determine acoustic cavitation probabilities in tissue-mimicking materials (TMMs) is described that uses a high-intensity focused ultrasound (HIFU) transducer for both inducing and detecting the acoustic cavitation events. The method was evaluated by studying acoustic cavitation probabilities in agar-based TMMs with and without scatterers and for different sonication modes like continuous wave, single pulses (microseconds to milliseconds) and repeated burst signals. Acoustic cavitation thresholds (defined here as the peak rarefactional in situ pressure at which the acoustic cavitation probability reaches 50%) at a frequency of 1.06 MHz were observed between 1.1 MPa (for 1 s of continuous wave sonication) and 4.6 MPa (for 1 s of a repeated burst signal with 25-cycle burst length and 10-ms burst period) in a 3% (by weight) agar phantom without scatterers. The method and its evaluation are described, and general terminology useful for standardizing the description of insonation conditions and comparing results is provided. In the accompanying second part, the presented method is used to systematically study the acoustic cavitation thresholds in the same material for a range of sonication modes. ",0
6399,29196463,Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer,"""""""Liquid biopsy"""" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in  """,0
6400,29196616,17β-Estradiol sensitizes ovarian surface epithelium to transformation by suppressing Disabled-2 expression,"Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates the initiation of ovarian cancer is by up-regulation of microRNA-378 via the ESR1 pathway to result in the down-regulation of a tumour suppressor called Disabled-2 (Dab2). Estrogen suppression of Dab2 was reproducible in vivo and across many cell types including mouse oviductal epithelium and primary cultures of human ovarian cancer cells. Suppression of Dab2 resulted in increased proliferation, loss of contact inhibition, morphological dysplasia, and resistance to oncogene-induced senescence - all factors that can sensitize OSE to transformation. Given that DAB2 is highly expressed in healthy human OSE and is absent in the majority of ovarian tumours, this study has taken the first steps to provide a mechanistic explanation for how estrogen therapy may play a role in the initiation of ovarian cancer. ",0
6401,29196770,Effect of Gravity Acceleration on Choroidal and Retinal Nerve Fiber Layer Thickness: A Swept-Source Optical Coherence Tomography Study,"The purpose of this study was to evaluate the effect of gravity acceleration on choroidal and retinal nerve fiber layer (RNFL) thickness using swept-source optical coherence tomography (SS-OCT). Thirteen healthy volunteers who planned to participate in human centrifuge training as part of the flight surgeon selection process enrolled this study. During centrifuge training, gravity was gradually increased up to six times that of sea level. All subjects underwent complete ophthalmologic examination and three-dimensional wide-scanning SS-OCT imaging (DRI OCT-1 Atlantis; Topcon, Tokyo, Japan). Imaging was performed before (baseline), immediately after, and 15, 30, and 60 minutes after centrifuge training. Changes in choroidal thickness, choroidal volume, retinal thickness, and RNFL thickness after centrifuge training were analyzed. Mean choroidal thickness significantly and transiently decreased immediately (258.19 ± 73.54 μm, P < 0.001), 15 minutes (258.54 ± 75.12 μm, P = 0.001), and 30 minutes (254.31 ± 66.92, P = 0.001) after human centrifuge training, relative to baseline (273.35 ± 80.80 μm). However, the decreased choroidal thickness returned to baseline levels 1 hour after centrifuge training (270.12 ± 71.69 μm, P = 0.437). Mean retinal thickness and RNFL thickness were not significantly affected by human centrifuge training. In participants who suffered from gravity-force induced loss of consciousness (G-LOC) during training, the amount of the choroidal thickness decrease was larger than in participants who did not experience G-LOC. However, because of the small sample size, the difference, although large, was not statistically significant. Choroidal thickness and volume significantly and transiently decreased after human centrifuge training, which might reflect that choroidal perfusion was transiently decreased during human centrifuge training. Considering choroidal thickness decreased after human centrifuge training, long-term exposure to a high gravity environment may lead to ischemic injury to ocular structures. ",0
6402,29196854,Fourteen years of progress testing in radiology residency training: experiences from The Netherlands,"To describe the development of the Dutch Radiology Progress Test (DRPT) for knowledge testing in radiology residency training in The Netherlands from its start in 2003 up to 2016. We reviewed all DRPTs conducted since 2003. We assessed key changes and events in the test throughout the years, as well as resident participation and dispensation for the DRPT, test reliability and discriminative power of test items. The DRPT has been conducted semi-annually since 2003, except for 2015 when one digital DRPT failed. Key changes in these years were improvements in test analysis and feedback, test digitalization (2013) and inclusion of test items on nuclear medicine (2016). From 2003 to 2016, resident dispensation rates increased (Pearson's correlation coefficient 0.74, P-value <0.01) to maximally 16 %. Cronbach´s alpha for test reliability varied between 0.83 and 0.93. The percentage of DRPT test items with negative item-rest-correlations, indicating relatively poor discriminative power, varied between 4 % and 11 %. Progress testing has proven feasible and sustainable in Dutch radiology residency training, keeping up with innovations in the radiological profession. Test reliability and discriminative power of test items have remained fair over the years, while resident dispensation rates have increased. • Progress testing allows for monitoring knowledge development from novice to senior trainee. • In postgraduate medical training, progress testing is used infrequently. • Progress testing is feasible and sustainable in radiology residency training. ",0
6403,29196963,Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study,"A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET. ",0
6404,29197335,"Trends in prevalence, mortality, health care utilization and health care costs of Swiss IBD patients: a claims data based study of the years 2010, 2012 and 2014","Real-life data on inflammatory bowel disease (IBD) prevalence and costs are scarce. The aims of this study were to provide an overview of the prevalence, mortality, health care utilization and costs of IBD patients in Switzerland in the years 2010, 2012, and 2014. Based on claims data of the Helsana-Group, prevalence of IBD was assessed for 2010, 2012 and 2014. Mortality rates, costs (inpatient, outpatient, medication costs) and utilization (visits, hospitalizations) were compared between patients with and without IBD, and between IBD patients treated with and without biologics. Results were extrapolated to the Swiss general population using national census data. Multivariate linear regression was used to identify socio-demographic and regional factors influencing total costs. The overall extrapolated prevalence rates of IBD were 0.32% in 2010, 0.38% in 2012, and 0.41% in 2014. Mortality rate didn't differ between the IBD and non-IBD population. Costs increased annually by 6% in IBD versus 2.4% in non-IBD subjects, which was solely due to increased outpatient costs. Almost one-fourth of IBD patients were hospitalized at least once a year. Costs were higher in IBD patients treated with biologics (OR = 3.98, CI: 3.72-4.27, p < 0.001) when compared to IBD patients without biologic therapies. Over 70% of the total costs in IBD patients treated with biologics were due to drug costs, compared with 28% in patients without use of biologic therapies, whereas inpatient costs didn't differ. The prevalence of IBD seems to be increasing in Switzerland. Outpatient costs increased substantially, while no decrease in inpatient costs was found. Treatment of IBD is more and more based on biologic therapies. ",0
6405,29197730,Platanic acid: A new scaffold for the synthesis of cytotoxic agents,"Thirty-seven different derivatives (2-38) have been prepared from platanic acid, a natural occurring triterpenoid. Main emphasis was the introduction of several N-containing functional groups such as amines, amides and oximes and their screening for cytotoxic activity employing several human tumor cell lines using SRB assays. In these SRB assays, nearly all compounds showed good cytotoxicity for these human tumor cell lines. Two compounds (17 and 38), however, were submitted to extended biological testing and investigated with respect to their mode of action using fluorescence microscopy and FACS analysis. Compound 17, a methyl (3β, 20R) 3-acetyloxy-20-amino-30-norlupan-28-oate, induced apoptosis in A2780 ovarian carcinoma cells. ",0
6406,29197838,Leg length discrepancy: the importance of a complete history and examination,"A 26-year-old woman with a 1-year history of right knee pain had failed to respond to analgesia and activity modification in the community. Her general practitioner referred her to the orthopaedic department for specialist review. A thorough history revealed that she had multiple orthopaedic interventions as a child. The patient had significant postoperative infection of the left knee following knee surgery at 7 years of age. Examination demonstrated the presence of a limp, scoliosis and suspected leg length discrepancy. Plain film radiography confirmed the presence of leg length discrepancy, with the right limb measuring 30 mm longer than the left. The leg length discrepancy was likely secondary to a growth arrest of the left knee following the postoperative infection in childhood. The patient was managed with physiotherapy and heel raises and received regular orthopaedic follow-up. ",0
6407,29197916,An investigation into the variability between different shear wave elastography systems in muscle,"The reliability and agreement between shear wave elastography (SWE) systems using different acquisition methods in muscles is not yet established. The objectives were to determine the reliability of a new SWE system on normal resting muscles using different acquisition methods and to compare its performance to an established state-of-the-art system. Small, medium and large ROI sizes in addition to longitudinal, oblique and transverse orientations over five different locations within the rectus femoris muscle were tested using the new system. Results were compared to the established system to test for inter-system reproducibility. Lowest within-subject coefficient of variance (4.3%) andshear wave velocity (1.83 m/s) were associated with the medium ROI and longitudinal orientation from the lateral location. This combination resulted in a strong internal agreement of intra-class correlation of 0.76 (0.57-0.89) for the new system and an almost perfect agreement of 0.92 (0.82-0.97) for the established. Inter-system reproducibility for the best combination was 0.71 (0.48-1) with a mean velocity difference ±95% limits of agreement of 0.07±0.49 m/s. Altering SWE acquisition methods can produce variable results. The new system produced reliable results that are comparable with but not as reliable as the established. ",0
6408,29198062,An evaluation of four modes of low-dose anticoagulation during intermittent haemodialysis,"Intensive care participants that need dialysis frequently suffer from increased risk of bleeding. Standard intermittent haemodialysis (SHD) includes anticoagulation to avoid clotting of the dialysis system. The aim of this study was to clarify which of four different low-dose anticoagulant modes was preferable in reducing the exposure to i.v. unfractionated heparin (heparin) and maintaining patency of the dialysis circuit. Twenty-three patients on SHD were included to perform haemodialysis with four modes of low-dose anticoagulation. For comparative analyses, patients served as their own control. Haemodialysis with a single bolus of tinzaparin at the start was compared to haemodialysis initiated without i.v. heparin but priming with (1) heparin in saline (H), (2) heparin and albumin in saline (HA), (3) heparin and albumin in combination with a citrate-containing dialysate (HAC), (4) saline and usinga heparin-coated filters (Evodial®). The priming fluid was discarded before dialysis started. Blood samples were collected at 0, 30 and 180 min during haemodialysis. Smaller bolus doses of heparin (500 Units/dose) were allowed during the modes to avoid interruption by clotting. The mean activated partial thromboplastin (APTT) time as well as the doses of anticoagulation administered was highest with SHD and least with HAC and Evodial®. Mode H versus SHD had the highest rate of prematurely interrupted dialyses (33%, p = 0.008). The urea reduction rate was less with Evodial® vs. SHD (p < 0.01). One hypersensitivity reaction occurred with Evodial®. Changes in blood cell concentrations and triglycerides differed between the modes. If intermittent haemodialysis is necessary in patients at risk of bleeding, anticoagulation using HAC and Evodial® appeared most preferable with least administration of heparin, lowest APTT increase and lowest risk for prematurely clotted dialyzers in contrast to the least plausible H mode. ",0
6409,29198334,Mind and body practices for fatigue reduction in patients with cancer and hematopoietic stem cell transplant recipients: A systematic review and meta-analysis,"To determine whether non-physical activity mind and body practices reduce the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients compared to control interventions. We included randomized trials which compared non-physical activity mind and body practices compared with control interventions for the management of fatigue in cancer and HSCT patients. Among 55 trials (4975 patients), interventions were acupuncture or acupressure (n=12), mindfulness (n=11), relaxation techniques (n=10), massage (n=6), energy therapy (n=5), energizing yogic breathing (n=3) and others (n=8). When combined, all interventions significantly reduced fatigue severity compared to all controls (standardized mean difference -0.51, 95% confidence interval -0.73 to -0.29). More specifically, mindfulness and relaxation significantly reduced fatigue severity. Mindfulness and relaxation were effective at reducing fatigue severity in patients with cancer and HSCT recipients. Future studies should evaluate how to translate these findings into clinical practice across different patient groups. ",0
6410,29198667,Donation After Circulatory Arrest in Pancreas Transplantation: A Report of 10 Cases,"Transplantation of pancreas allografts procured from donation after circulatory death (DCD) remains uncommon. This study reviews a series of pancreas transplants at a single center to assess the donor and recipient characteristics for DCD pancreas transplant and to compare clinical outcomes. DCD procurement was performed with a 5-minute wait time from pronouncement of death to first incision. In 2 patients, tissue plasminogen activator was infused as a thrombolytic during the donor flush. All kidney grafts were placed on pulsatile perfusion. There were 606 deceased donor pancreas transplants, 596 standard donors and 10 DCD donors. Of the 10 DCD transplants, 6 were simultaneous pancreas-kidney and 4 were pancreas transplant alone. The average time from incision to aortic cannulation was less than 3 minutes. The median total ischemia time for the DCD grafts was 5.4 hours, compared with 8.0 hours for standard donors (P = .15). Median length of hospital stay was 7 days for both groups, and there were no episode of acute cellular rejection in the first year post-transplant for the DCD group (4.2 % for standard group, P = .65). There was no difference in early or late graft survival, with 100% graft survival in the DCD group up to 1 year post-transplant. Ten-year Kaplan-Meier analysis shows similar graft survival for the 2 groups (P = .92). These results support the routine use of carefully selected DCD pancreas donors. There were no differences in graft function, postoperative complications, and early and late graft survival. ",0
6411,29198875,Gancao-Gansui combination impacts gut microbiota diversity and related metabolic functions,"""The theory of """"eighteen incompatible medicaments"""" (EIM) in traditional Chinese medicine (TCM) is the most representative case of herbal-herbal interactions. Gancao and Gansui are one of the incompatible herbal pairs in EIM. Gancao, also known as """"licorice"""", is the most frequently used Chinese herb or food additive. Gansui, the root of Euphorbia kansui T.P. Wang, is another famous Chinese herb usually used to treat edema, ascites and asthma but could induce gastrointestinal (GI) tract irritation. Although Gancao and Gansui are incompatible herbal pairs, they are still used in combination in the famous """"Gansui-Banxia"""" decoction. This study was conducted to investigate if Gancao-Gansui combination could exacerbate Gansui induced GI tract injury. Moreover, the impact of Gancao-Gansui combination to gut microbiota and related metabolism pathways were evaluated. Normal mice were divided into different groups and treated with Gancao extracts, Gansui extracts, and Gancao-Gansui combination extracts for 7 days. Serum biomarkers (diamine oxidase activity, lipopolysaccharide, motilin, IL-1β, IL-6, TNF-α) were determined to reflect GI tract damage. Gut microbiota diversity was studied by 16S rDNA sequencing and metagenomes analysis were also conducted to reflect functional genes expression alteration. Fecal hydrogen sulfide concentrations were measured by spectrophotometry to confirm the alteration of Desulfovibrio genus. Fecal lipid metabolomics study was conducted by GC-MS analysis to confirm the change of metagenomes and Mycoplasma abundance. Gancao-Gansui combination did not exacerbate GI tract tissue or functional damage but caused gut microbiota dysbiosis and increased some rare genus's abundance including Desulfovibrio and Mycoplasma. Desulfovibrio genus proliferation was confirmed by the disturbance of fecal hydrogen sulfide homeostasis. Gancao-Gansui combination also dys-regulated the metabolic genes in metagenomes. Mycoplasma genus proliferation and the metagenomes changes were both confirmed by metabolic profile analysis of fecal lipids, especially cholesterol. Gancao-Gansui combination can impact the gut microbiota diversity and related metabolic functions. Further studies should be carried out when the combination of Gancao-Gansui is used in herbal formulations as this may alter the diversity of the microbiota. """,0
6412,29198938,Outcomes of arthroscopic revision rotator cuff repair with acellular human dermal matrix allograft augmentation,"The purpose was to assess the minimum 2-year patient-reported outcomes and failure rate of patients who underwent revision arthroscopic rotator cuff repair augmented with acellular human dermal matrix (AHDM) allograft for repairable retears. From 2008-2014, patients who underwent revision rotator cuff repair augmented with AHDM with greater than 2 years' follow-up by a single surgeon were retrospectively reviewed. Data regarding surgical history, demographic characteristics, and medical comorbidities were collected. Outcome data included American Shoulder and Elbow Surgeons (ASES) and Single Assessment Numeric Evaluation (SANE) scores, as well as rotator cuff healing on magnetic resonance imaging or ultrasound. Retears and subsequent surgical procedures were characterized. A total of 28 patients met our inclusion criteria, and 23 (82%) were available for follow-up at 2 years. The mean age was 60.1 ± 9.3 years (range, 43-79 years), with a mean follow-up period of 48 ± 23 months. All patients had at least 1 prior rotator cuff repair. Of the 23 patients, 13 (56%) underwent postoperative imaging, and 4 of these 13 (31%) had a retear. A reoperation was performed in 3 of 23 patients (13%). Among the 6 patients with both preoperative and postoperative outcome scores, we saw improvement in the ASES score from 56 to 85 (P = .03) and in the SANE score from 42 to 76 (P = .03). The full cohort's mean postoperative ASES and SANE scores were 77 and 69, respectively. AHDM allograft augmentation is a safe and effective treatment method for patients with full-thickness rotator cuff retears. Further research is needed with larger studies to confirm these findings from our small cohort of patients. ",0
6413,29199348,Unhealthy lifestyle and sleep problems as risk factors for increased direct employers' cost of short-term sickness absence,"Objectives Unhealthy lifestyle (eg, smoking) as well as sleep problems are associated with increased risk of sickness absence, but the financial impact of these associations beyond risk ratios is not well known. We aimed to estimate the additive contribution of lifestyle and sleep problems (risk factors) to direct costs of short-term (<15 days) sickness absence. Methods The Helsinki Health Study is a longitudinal cohort of employees of the City of Helsinki, Finland (N=8960, response rate 67%). During 2000-2002 the participants were mailed a survey questionnaire that gathered information on their lifestyle and sleep. A sum of the risk factors was calculated: participants received one point for being a smoker; high alcohol user (>7 servings/week for women and >14 servings/week for men); physically inactive [<14 metabolic equivalents (MET) hours/week]; having low fruit and vegetable consumption (<1 times/day); or suffering from frequent insomnia symptoms. Sickness absence, salary, and time of employment were followed through the employer's register between 2002-2016. Individual salary data were used to calculate the direct costs of short-term sickness absence. Data were analyzed using a two-part model. Results Direct costs of short-term sickness absences were on average €9057 (standard deviation €11 858) per employee over the follow-up. Those with ≥3 risk factors had €3266 [95% confidence interval (95% CI) €2114-4417] higher direct costs for the employer over the follow-up compared to those without any risk factors. Conclusions Unhealthy lifestyle and sleep problems may increase the costs of short-term sickness absence to the employer by 10-30%. Consequently, programs addressing lifestyle and sleep may yield to significant savings. ",0
6414,29199442,Assessing the cost-effectiveness of a routine versus an extensive laboratory work-up in the diagnosis of anaemia in Dutch general practice,"Background Establishing the underlying cause of anaemia in general practice is a diagnostic challenge. Currently, general practitioners individually determine which laboratory tests to request (routine work-up) in order to diagnose the underlying cause. However, an extensive work-up (consisting of 14 tests) increases the proportion of patients correctly diagnosed. This study investigates the cost-effectiveness of this extensive work-up. Methods A decision-analytic model was developed, incorporating all societal costs from the moment a patient presents to a general practitioner with symptoms suggestive of anaemia (aged ≥ 50 years), until the patient was (correctly) diagnosed and treated in primary care, or referred to (and diagnosed in) secondary care. Model inputs were derived from an online survey among general practitioners, expert estimates and published data. The primary outcome measure was expressed as incremental cost per additional patient diagnosed with the correct underlying cause of anaemia in either work-up. Results The probability of general practitioners diagnosing the correct underlying cause increased from 49.6% (95% CI: 44.8% to 54.5%) in the routine work-up to 56.0% (95% CI: 51.2% to 60.8%) in the extensive work-up (i.e. +6.4% [95% CI: -0.6% to 13.1%]). Costs are expected to increase slightly from €842/patient (95% CI: €704 to €994) to €845/patient (95% CI: €711 to €994), i.e. +€3/patient (95% CI: €-35 to €40) in the extensive work-up, indicating incremental costs of €43 per additional patient correctly diagnosed. Conclusions The extensive laboratory work-up is more effective for diagnosing the underlying cause of anaemia by general practitioners, at a minimal increase in costs. As accompanying benefits in terms of quality of life and reduced productivity losses could not be captured in this analysis, the extensive work-up is likely cost-effective. ",0
6415,29199502,ADHD Among Offenders: Prevalence and Relationship With Psychopathic Traits,"Longitudinal studies have shown a strong association between ADHD and criminal behavior. The aims of this study were to examine the prevalence of adult ADHD in a high-security facility and to investigate the relationship between ADHD symptoms and psychopathic traits in criminal offenders. Participants were recruited between October 2015 and January 2016 among the inmates from a high-security all-male correctional facility in Portugal. Self-report scales were used to measure ADHD symptoms, current psychopathology, and psychopathic traits. An interview was conducted to collect sociodemographic data, along with information about adverse childhood experiences, substance use, and criminal record. The statistical analysis was conducted using STATA 13 with the significance level set at .05. From the final sample of 101 male prisoners, 17 participants (16.8%) screened positive for ADHD. Participants positive for ADHD had higher levels of general psychopathology and psychopathic traits. Psychopathic traits remained significantly higher in ADHD offenders after controlling for age, substance abuse, and early childhood adversities (OR = 1.07, p = .002) and this was explained by differences in the Meanness subscale (OR = 1.11, p = .013). The present study shows that ADHD symptoms are highly prevalent among offenders and might have a modulating effect on the course of delinquent behavior. The cross-sectional association between ADHD symptoms and psychopathic traits reinforces the previously documented correlation between these disorders and can lead to a better understanding of the prevalent criminal behavior in ADHD patients. ",0
6416,29199601,A Review of Sensing Systems and Their Need for Environmental Water Monitoring,"Water is a valuable natural resource and is needed to sustain human life. Water pollution significantly jeopardizes clean drinking water supplies, it is hazardous to human health, and it inhibits economic development. Well-designed sensors that can continuously monitor water quality during transport and identify contaminants in the watershed help effectively control pollution and thereby manage water resources. However, the commercially available sensors are expensive and require frequent maintenance. These limitations often make these sensors inadequate for continuous water monitoring applications. This review evaluates many sensors based on colorimetric, electrochemical, and optical sensors. Sensors suitable for estimating the amount of dissolved oxygen, nitrates, chlorine, and phosphates are presented. A review of recently developed high quality sensors for measuring the previously mentioned components of water is also presented. Future directions in this area of developing high quality sensors for water monitoring are discussed. ",0
6417,29200087,Rapid Explantation of Rapid-Deployment Sutureless Valve in Case of Acute Endocarditis: How to Remove Safely Sutureless Perceval S Prostheses,"""We report a case of infective endocarditis on a Perceval S aortic valve bioprosthesis, and we describe a feasible and useful technique that can help remove the infected valve. These maneuvers consist of an """"x-movement"""" reached with the aid of anatomical forceps. The risk of infective endocarditis in patients with prosthetic valves is a well-known phenomena in cardiac surgery, and it can represent a life-threatening event in many cases. According to guidelines, an emergency surgical intervention is required in case of high risk of embolization, vegetation superior than 1 cm or acute cardiac failure secondary to the acute valve dysfunction. In the reported case, the patient was submitted to emergency surgery because of vegetation with diameter superior to 1 cm on the aortic bioprosthesis. The described """"x-movement"""" technique allowed an easily """"en block"""" excision of the damaged bioprostheses together with vegetation, minimizing the risk of vegetation fragmentation. """,0
6418,29200689,Acute Lymphoblastic Leukemia as Secondary Malignancy in a Case of Ewing's Sarcoma on Treatment,"The survival of Ewing's sarcoma (ES) has improved due to advances in both local and systemic therapy. This has given rise to an increased detection of second malignant neoplasms which can be in the form of solid tumors and hematological malignancies. The most common hematological malignancies are acute myeloid leukemia/myelodysplastic syndrome. Acute lymphoblastic leukemia (ALL) is relatively uncommon in occurrence in this setting. Furthermore, the average refractory period for hematological malignancies varies from 3 to 5 years. We report a case of a young female who developed ALL while on adjuvant therapy for ES. ",0
6419,29201120,Long-term Video-EEG Monitoring Findings in Children and Adolescents with Intractable Epilepsy,"Long Term Video-EEG Monitoring (LTM) may give us important information in the preoperative assessment of these patients. We performed this study for the first time in pediatric age group in Iran. In this cross-sectional study, 43 children between 4 to 18 yr, with intractable epilepsy referred to Shefa Neuroscience Research Center, Tehran, Iranfrom2007-2012, were enrolled to study in order to evaluate their long-term video EEG findings. The patients mean age was10.07 yr, from which 24(65.9%) were boys.Seven patients with definite epileptogenic zone were advised to perform lesionectomy surgery.In two patients, there was not any seizure onset focus but corpus callosotomy was advised to control their frequent falling.Eight cases were recommended to perform electrocorticography or invasive EEG monitoring and26 cases to adjust medical treatment. In three cases, there was not any electrical seizure activity during clinical attacks, so discontinuing anti-epileptic drugs were recommended fordiagnosis of conditions that mimic epilepsy. It is necessary to perform LTM in patients with refractory epilepsy in order to determine their treatment strategy. If there is any doubt about pseudoseizureLTM can help to differentiate epilepsy from conditions that mimic epilepsy. ",0
6420,29201217,Curcumin inhibits the development of non-small cell lung cancer by inhibiting autophagy and apoptosis,"Among patients with primary lung cancer, 75-80% present with non-small cell lung cancer (NSCLC). However, there is a lack of studies into the potential preventive effects of curcumin against the activation of autophagy in NSCLC. Therefore, the present study primarily focused on the protective role of curcumin in NSCLC. It was demonstrated that curcumin decreased the viability of the human lung cancer cells lines, A549 and H1299, in a time-and dose-dependent manner (P<0.05). Treatment with curcumin also suppressed the colony formation capacities of A549 and H1299 cells. Following incubation with 10 µM curcumin for 48 h, cell apoptosis was significantly increased by 2.35- and 3.02-fold in A549 and H1299 cells, respectively, when compared with controls (P<0.01). Furthermore, curcumin treatment markedly increased the number and volume of autophagosomes in A549 and H1299 cells when compared with controls. Treatment with 10 µM curcumin for 48 h also significantly reduced the phosphorylation levels of mechanistic target of rapamycin (mTOR), ribosomal protein S6, phosphoinositide 3-kinase and AKT (protein kinase B) in A549 and H1299 cells (P<0.05). These data indicated that curcumin enhanced autophagy and apoptosis in NSCLC cells by acting as an mTOR complex1/2 inhibitor. ",0
6421,29201228,Insect tea attenuates hydrochloric acid and ethanol-induced mice acute gastric injury,"The aim of the present study was to investigate the protective effect of insect tea on HCl/ethanol-induced gastric ulcers in ICR mice. The serum levels of vasoactive intestinal peptide, substance P, somatostatin, motilin and endothelin-1 in mice were assessed using commercial kits and gastric tissues of superoxide dismutase (SOD, nitric oxide (NO) and malondialdehyde (MDA) were determined using western blot analysis Insect tea significantly reduced HCl/ethanol-induced gastric juice secretion and increased the pH of gastric juice (P<0.05). Insect tea treatment signfiicantly increased vasoactive intestinal peptide and somatostatin, and significantly decreased motilin, substance P and endothelin levels in the serum (P<0.05). Treatment with insect tea was demonstrated to significantly increase levels of gastric SOD and NO and to reduce levels of MDA in the gastric ulcer mouse model (P<0.05). The gastric expression of inhibitor of nuclear factor-κB (NF-κB), epidermal growth factor (EGF), EGF receptor, neuronal nitric oxide synthase (nNOS), endothelial NOS, Mn-SOD, Cu/Zn-SOD and catalase was significantly increased in mice treated with inset tea compared with untreated model mice (P<0.05). Levels of NF-κB, and inducible NOS were demonstrated to be decreased in mice treated with insect tea compared with untreated model mice (P<0.05). The results of the present study suggest that insect tea has a protective effect against HCl/ethanol-induced gastric ulcers in ICR mice. This effect may be achieved via modulating serum neuropeptide levels, reducing gastric juice secretion, and modulating the inflammation- and antioxidant-associated protein expressions in gastric tissue. ",0
6422,29201302,Antibiotic Spacers in Shoulder Arthroplasty: Comparison of Stemmed and Stemless Implants,"Antibiotic spacers in shoulder periprosthetic joint infection deliver antibiotics locally and provide temporary stability. The purpose of this study was to evaluate differences between stemmed and stemless spacers. All spacers placed from 2011 to 2013 were identified. Stemless spacers were made by creating a spherical ball of cement placed in the joint space. Stemmed spacers had some portion in the humeral canal. Operative time, complications, reimplantation, reinfection, and range of motion were analyzed. There were 37 spacers placed: 22 were stemless and 15 were stemmed. The stemless spacer population was older (70.9 ± 7.8 years vs. 62.8 ± 8.4 years,  Stemmed and stemless spacers had similar clinical outcomes. When analyzing all antibiotic spacers, over 70% were converted to revision arthroplasties. The results of this study do not suggest superiority of either stemmed or stemless antibiotic spacers. ",0
6423,29201318,Antibiotic resistance status and its costs in hematological patients: A two-year analysis,"Most frequently, empirical antibiotic therapy is immediately administered for patients with febrile neutropenia (FN). In this study, its aim was to assess the antibiotic resistance status and the cost of antibacterial agents in FN patients associated with hematological malignancies. The cost of antibacterial agents used in FN episodes in patients with hematologic neoplasms followed-up at the Department of Hematology from November 2010 to November 2012 were analyzed retrospectively. In the study period, 15 of 141 patients who were admitted to the hematology ward and ineligible for the study criteria were excluded. In total, 282 febrile episodes of 126 consecutive patients with neutropenia were retrospectively investigated. Imipenem was found to be the most commonly used among the antibacterial drugs as 1.16 patient daily dose (PDD)/100 patient-days, 117.16 is the mean defined daily dose (DDD) per month and US $73264.66 total cost per year, followed by meropenem, cefoperazone-sulbactam, and linezolid. Choosing noncarbapenem-based antibacterial therapy for empirical treatment of FN until the growth of microorganisms and switching to carbapenem therapy subsequent to new radiological, or microbiological, or/ and clinical findings, the appropriate vancomycin use may decrease the cost of antibacterial agents in the treatment of FN episodes in patients with hematologic malignancies contributing to antimicrobial stewardship. ",0
6424,29201391,The effect of obesity on intraoperative complication rates with hysteroscopic compared to laparoscopic sterilization: a retrospective cohort study,"Surgical sterilization is a common method of contraception. There have been few studies evaluating the effect of obesity on procedural complications with either laparoscopic or hysteroscopic methods of sterilization. The purpose of this study was to compare the incidence of intraoperative complications of hysteroscopic tubal occlusion with laparoscopic tubal ligation among obese and nonobese women. This retrospective cohort study compared women undergoing interval laparoscopic or hysteroscopic sterilization in the operating room between September 2009 and December 2011 at a single hospital. Serious complications included: unintended surgery, uterine perforation, anaphylaxis, blood transfusion, infection requiring antibiotics, hospital admission, fluid overload, myocardial infarction, and venous thromboembolism. Post-operative events included: nausea/vomiting, doctor evaluation or additional pain medication required in the recovery room, and emergency department visit within 2 weeks of surgery. The association between sterilization type and incidence of complications was examined overall, separately by BMI group, and also among patients who received general anesthesia. A total of 433 laparoscopic and 277 hysteroscopic procedures were reviewed. The BMI distribution of the sample was 35 % normal weight, 31 % overweight, and 34 % obese which is comparable to the general US female population. No life-threatening events were identified. Serious complications were similar with 20 (4.6 %) in the laparoscopic group and 11 (4.0 %) in the hysteroscopic group ( Both laparoscopic and hysteroscopic tubal sterilization are safe with few serious complications based on these data. No cases of laparotomy, blood transfusion, or life-threatening events were identified. There was no difference in serious complication rate by sterilization method. Overweight and obese women were no more likely to experience a serious complication with either method than women with a BMI <25. There were fewer postoperative events ( ",0
6425,29201413,High-risk sexual behaviors while on depot medroxyprogesterone acetate as compared to oral contraception,"Depot medroxyprogesterone acetate (DMPA) contraceptive use is associated with an increased risk for  In this cross-sectional study of 630 reproductive-aged women seeking routine gynecologic care (449 OCP and 181 DMPA users) sexual risk-taking was evaluated by use of the Safe Sex Behavior Questionnaire, a validated measure of sexual behaviors and attitudes. All women were screened for  Oral contraceptive pill users differed from DMPA users in age, race, marital status, education level, and pregnancy history ( Oral contraceptive pill and DMPA users differed with respect to both demographic factors and frequency of condom use. Odds of current  ",0
6426,29201525,Complete penile skin necrosis,"Superficial penile skin infections may be presented in different clinical situations that vary from simple infection to organ loss and serious morbidity and mortality. Antibiotic treatment and, if necessary, urgent debridement is required. A 46-year-old male patient with the complaints of urethral discharge and pain admitted to our outpatient clinic. He declared that there were midpenil tenderness and erythema 14 days ago which occurred after sexual intercourse. Complete penile skin necrosis with purulent discharge was detected in physical examination. After wound debridement and 14-days of intravenous antibiotic treatment, wound site culture was negative and then full-thickness skin grafting was performed. Urgent antibiotic treatment should be given, especially for the skin infections of the genital area. Despite the rapid spread of antibiotic treatment, clinical presentation may worsen within hours. It should be noted that especially in diabetics and elderly patients with poor hygiene, the infection may spread to anogenital region and may lead to fulminant necrotizing fasciitis which can present with severe morbidity and mortality. Reconstructive surgery is planned after the control of infection and according to the amount of tissue loss. ",0
6427,29201588,Reminders make people adhere better to a self-help sleep intervention,"The experiment presented in this paper investigated the effects of different kinds of reminders on adherence to automated parts of a cognitive behavioural therapy for insomnia (CBT-I) delivered via a mobile device. Previous studies report that computerized health interventions can be effective. However, treatment adherence is still an issue. Reminders are a simple technique that could improve adherence. A minimal intervention prototype in the realm of sleep treatment was developed to test the effects of reminders on adherence. Two prominent ways to determine the reminder-time are: a) ask users when they want to be reminded, and b) let an algorithm decide when to remind users. The prototype consisted of a sleep diary, a relaxation exercise and reminders. A within subject design was used in which the effect of reminders and two underlying principles were tested by 45 participants that all received the following three different conditions (in random order): a) event-based reminders b) time-based reminders c) no reminders. Both types of reminders improved adherence compared to no reminders. No differences were found between the two types of reminders. Opportunity and self-empowerment could partly mediate adherence to filling out the sleep diary, but not to the number of relaxation exercises conducted. Although the study focussed on CBT-I, we expect that designers of other computerized health interventions benefit from the tested opportunity and self-empowerment principles for reminders to improve adherence, as well. ",0
6428,29201716,The Evaluation of Serum Ascites Albumin Gradient and Portal Hypertensive changes in Cirrhotic Patients with Ascites,"Ascites is a common complication of chronic liver diseases and is related to the extent of portal hypertension. This study evaluated whether the serum ascites albumin gradient (SAAG) (the difference between the albumin level of serum and of ascitic fluid) is endowed with clinical implications. This is a prospective study involving 50 patients with cirrhosis of liver with ascites. The SAAG was measured in all patients and its relation with portal hypertensive changes was analyzed. Based on SAAG values, the patients were divided into three groups: Group 1 - SAAG value 1.1 to 1.49 gm/dL (n = 15); group 2 - SAAG value 1.5 to 1.99 gm/dL (n = 9); and group 3 - SAAG value 2.0 gm/dL (n = 26). In group 1, 14 patients had esophageal varices (93.3%) and 13 had gastropathy (86.6%). In group 2, all 9 patients had esophageal varices (100%), 7 (77.7%) had gastropathy, and 1 (11.1%) had gastric varices. In group 3, all 26 patients had esophageal varices (100%), 24 patients (92.3%) had gastropathy, and 1 patients (3.8%) had gastric varices. Serum ascites albumin gradient value is weakly related to the extent of portal hypertension in patients with liver cirrhosis and its implication seems to be limited in clinics. Shahed FHM, Al-Mahtab M, Rahman S. The Evaluation of Serum Ascites Albumin Gradient and Portal Hypertensive changes in Cirrhotic Patients with Ascites. Euroasian J Hepato-Gastroenterol 2016;6(1):8-9. ",0
6429,29251788,Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks,"Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)-infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti-DHBsAg antibodies were monitored by enzyme-linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow-up by immunohistochemistry. On-treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (>3 log) and cccDNA (>2 log), which were tightly correlated with the clearance of DHBsAg in the liver. CONCLUSION: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (Hepatology 2018;67:2127-2140).",0
6430,29278425,Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma,"""Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, """"undetermined""""). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations (""""undetermined"""") harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings. CONCLUSION: Stratification of intrahepatic cholangiocarcinoma patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (Hepatology 2018).""",0
6431,29331071,Hepatic PPAR? function is controlled by polyubiquitination and proteasome-mediated degradation through the coordinated actions of PAQR3 and HUWE1,"Peroxisome proliferator-activated receptor ? (PPAR?) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPAR? is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPAR? ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPAR? functions both in vitro and in vivo. Adenovirus-mediated Paqr3 knockdown and liver-specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting-induced expression of PPAR? target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism-modulating effects of PPAR?. PAQR3 directly interacted with PPAR? and increased the polyubiquitination and proteasome-mediated degradation of PPAR?. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPAR? polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPAR?. CONCLUSION: Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPAR? in response to starvation. (Hepatology 2018;68:289-303).",0
6432,29342379,Elimination of Cost Sharing for Screening Mammography in Medicare Advantage Plans,"BACKGROUND: The Affordable Care Act (ACA) required most insurers and the Medicare program to eliminate cost sharing for screening mammography. METHODS: We conducted a difference-in-differences study of biennial screening mammography among 15,085 women 65 to 74 years of age in 24 Medicare Advantage plans that eliminated cost sharing to provide full coverage for screening mammography, as compared with 52,035 women in 48 matched control plans that had and maintained full coverage. RESULTS: In plans that eliminated cost sharing, adjusted rates of biennial screening mammography increased from 59.9% (95% confidence interval [CI], 54.9 to 65.0) in the 2-year period before cost-sharing elimination to 65.4% (95% CI, 61.8 to 69.0) in the 2-year period thereafter. In control plans, the rates of biennial mammography were 73.1% (95% CI, 69.2 to 77.0) and 72.8% (95% CI, 69.7 to 76.0) during the same periods, yielding a difference in differences of 5.7 percentage points (95% CI, 3.0 to 8.4). The difference in differences was 9.8 percentage points (95% CI, 4.5 to 15.2) among women living in the areas with the highest quartile of educational attainment versus 4.3 percentage points (95% CI, 0.2 to 8.4) among women in the lowest quartile. As indicated by the difference-in-differences estimates, after the elimination of cost sharing, the rate of biennial mammography increased by 6.5 percentage points (95% CI, 3.7 to 9.4) for white women and 8.4 percentage points (95% CI, 2.5 to 14.4) for black women but was almost unchanged for Hispanic women (0.4 percentage points; 95% CI, -7.3 to 8.1). CONCLUSIONS: The elimination of cost sharing for screening mammography under the ACA was associated with an increase in rates of use of this service among older women for whom screening is recommended. The effect was attenuated among women living in areas with lower educational attainment and was negligible among Hispanic women. (Funded by the National Institute on Aging.).",0
6433,29364767,Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging,"BACKGROUND: Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. METHODS: We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. RESULTS: The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). CONCLUSIONS: Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).",0
6434,29385364,History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease,"BACKGROUND: The long-term risk associated with childhood kidney disease that had not progressed to chronic kidney disease in childhood is unclear. We aimed to estimate the risk of future end-stage renal disease (ESRD) among adolescents who had normal renal function and a history of childhood kidney disease. METHODS: We conducted a nationwide, population-based, historical cohort study of 1,521,501 Israeli adolescents who were examined before compulsory military service in 1967 through 1997; data were linked to the Israeli ESRD registry. Kidney diseases in childhood included congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease; all participants included in the primary analysis had normal renal function and no hypertension in adolescence. Cox proportional-hazards models were used to estimate the hazard ratio for ESRD associated with a history of childhood kidney disease. RESULTS: During 30 years of follow-up, ESRD developed in 2490 persons. A history of any childhood kidney disease was associated with a hazard ratio for ESRD of 4.19 (95% confidence interval [CI], 3.52 to 4.99). The associations between each diagnosis of kidney disease in childhood (congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease) and the risk of ESRD in adulthood were similar in magnitude (multivariable-adjusted hazard ratios of 5.19 [95% CI, 3.41 to 7.90], 4.03 [95% CI, 3.16 to 5.14], and 3.85 [95% CI, 2.77 to 5.36], respectively). A history of kidney disease in childhood was associated with younger age at the onset of ESRD (hazard ratio for ESRD among adults <40 years of age, 10.40 [95% CI, 7.96 to 13.59]). CONCLUSIONS: A history of clinically evident kidney disease in childhood, even if renal function was apparently normal in adolescence, was associated with a significantly increased risk of ESRD, which suggests that kidney injury or structural abnormality in childhood has long-term consequences.",0
6435,29443378,Hepatitis C Virus E2 Envelope Glycoprotein Induces an Immunoregulatory Phenotype in Macrophages,"A comprehensive strategy to control hepatitis C virus (HCV) infection needs a vaccine. Our phase I study with recombinant HCV E1/E2 envelope glycoprotein (EnvGPs) as a candidate vaccine did not induce a strong immune response in volunteers. We analyzed the interactions of HCV EnvGPs with human monocyte-derived macrophages as antigen-presenting cells. HCV E2 induced immune regulatory cytokine interleukin (IL)-10 and soluble CD163 (sCD163) protein expression in macrophages from 7 of 9 blood donors tested. Furthermore, HCV E2 enhanced Stat3 and suppressed Stat1 activation, reflecting macrophage polarization toward M2 phenotype. E2-associated macrophage polarization appeared to be dependent of its interaction with CD81 leading endothelial growth factor receptor (EGFR) activation. Additionally, E2 suppressed the expression of C3 complement, similar to HCV-exposed dendritic cells (DCs), implying potential impairment of immune cell priming. Conclusion: Our results suggest that E2 EnvGP may not be an ideal candidate for HCV vaccine development, and discrete domains within E2 may prove to be more capable of elliciting a protective immune response. (Hepatology 2018).",0
6436,29486523,Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism,"Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the FEX-induced metabolic phenotypes and inhibited taurolithocholic acid synthesis, adipose tissue browning, and liver bile acid synthesis gene expression but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP-1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice. CONCLUSION: This study uncovered a mechanism in which activation of intestinal FXR shaped the gut microbiota to activate TGR5/GLP-1 signaling to improve hepatic glucose and insulin sensitivity and increase adipose tissue browning; the gut microbiota plays a critical role in bile acid metabolism and signaling to regulate metabolic homeostasis in health and disease. (Hepatology 2018).",0
6437,29514032,A Gain-of-Function Mutation in EPO in Familial Erythrocytosis,"Familial erythrocytosis with elevated erythropoietin levels is frequently caused by mutations in genes that regulate oxygen-dependent transcription of the gene encoding erythropoietin ( EPO). We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis. This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1. (Funded by the Gebert R�f Foundation and others.).",0
6438,29526139,Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure,"BACKGROUND: In an early analysis of this trial, use of a magnetically levitated centrifugal continuous-flow circulatory pump was found to improve clinical outcomes, as compared with a mechanical-bearing axial continuous-flow pump, at 6 months in patients with advanced heart failure. METHODS: In a randomized noninferiority and superiority trial, we compared the centrifugal-flow pump with the axial-flow pump in patients with advanced heart failure, irrespective of the intended goal of support (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke (with disabling stroke indicated by a modified Rankin score of >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove a malfunctioning device. The noninferiority margin for the risk difference (centrifugal-flow pump group minus axial-flow pump group) was -10 percentage points. RESULTS: Of 366 patients, 190 were assigned to the centrifugal-flow pump group and 176 to the axial-flow pump group. In the intention-to-treat population, the primary end point occurred in 151 patients (79.5%) in the centrifugal-flow pump group, as compared with 106 (60.2%) in the axial-flow pump group (absolute difference, 19.2 percentage points; 95% lower confidence boundary, 9.8 percentage points [P<0.001 for noninferiority]; hazard ratio, 0.46; 95% confidence interval [CI], 0.31 to 0.69 [P<0.001 for superiority]). Reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (3 patients [1.6%] vs. 30 patients [17.0%]; hazard ratio, 0.08; 95% CI, 0.03 to 0.27; P<0.001). The rates of death and disabling stroke were similar in the two groups, but the overall rate of stroke was lower in the centrifugal-flow pump group than in the axial-flow pump group (10.1% vs. 19.2%; hazard ratio, 0.47; 95% CI, 0.27 to 0.84, P=0.02). CONCLUSIONS: In patients with advanced heart failure, a fully magnetically levitated centrifugal-flow pump was superior to a mechanical-bearing axial-flow pump with regard to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755 .).",0
6439,29539283,HIV-Associated Cancers and Related Diseases,"Clusters of cases of pneumocystis pneumonia and Kaposi�s sarcoma in New York and California in men who had sex with men were early harbingers of the acquired immunodeficiency syndrome (AIDS) epidemic. The syndrome was also soon noted to be associated with a high incidence of aggressive B-cell lymphomas. As the AIDS definition crystallized, Kaposi�s sarcoma, aggressive B-cell lymphomas, and invasive cervical cancer were considered to be AIDS-defining cancers when they developed in patients with human immunodeficiency virus (HIV) infection. Additional cancers are now known to be associated with HIV (Table 1). The term HIV-associated cancer is used here to describe this larger group of cancers (both AIDS-defining and non�AIDS-defining cancers) that have an increased incidence among patients with HIV infection. In addition, incidental cancers also may develop in patients with HIV infection.",0
6440,29539291,Injection of Cultured Cells with a ROCK Inhibitor for Bullous Keratopathy,"BACKGROUND: Corneal endothelial cell (CEC) disorders, such as Fuchs's endothelial corneal dystrophy, induce abnormal corneal hydration and result in corneal haziness and vision loss known as bullous keratopathy. We investigated whether injection of cultured human CECs supplemented with a rho-associated protein kinase (ROCK) inhibitor into the anterior chamber could increase CEC density. METHODS: We performed an uncontrolled, single-group study involving 11 persons who had received a diagnosis of bullous keratopathy and had no detectable CECs. Human CECs were cultured from a donor cornea; a total of 1�10(6) passaged cells were supplemented with a ROCK inhibitor (final volume, 300 ?l) and injected into the anterior chamber of the eye that was selected for treatment. After the procedure, patients were placed in a prone position for 3 hours. The primary outcome was restoration of corneal transparency, with a CEC density of more than 500 cells per square millimeter at the central cornea at 24 weeks after cell injection. Secondary outcomes were a corneal thickness of less than 630 ?m and an improvement in best corrected visual acuity equivalent to two lines or more on a Landolt C eye chart at 24 weeks after cell injection. RESULTS: At 24 weeks after cell injection, we recorded a CEC density of more than 500 cells per square millimeter (range, 947 to 2833) in 11 of the 11 treated eyes (100%; 95% confidence interval [CI], 72 to 100), of which 10 had a CEC density exceeding 1000 cells per square millimeter. A corneal thickness of less than 630 ?m (range, 489 to 640) was attained in 10 of the 11 treated eyes (91%; 95% CI, 59 to 100), and an improvement in best corrected visual acuity of two lines or more was recorded in 9 of the 11 treated eyes (82%; 95% CI, 48 to 98). CONCLUSIONS: Injection of human CECs supplemented with a ROCK inhibitor was followed by an increase in CEC density after 24 weeks in 11 persons with bullous keratopathy. (Funded by the Japan Agency for Medical Research and Development and others; UMIN number, UMIN000012534 .).",0
6441,29603325,Loss of PDK4 switches the hepatic NF-?B/TNF pathway from pro-survival to pro-apoptosis,"It has been established that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological inhibition of NF-?B is required for tumor necrosis factor (TNF)-induced hepatocyte apoptosis. In this study, we demonstrate that this pro-survival pathway is switched to pro-apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)-deficient conditions. PDK4-deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c-Jun N-terminal Kinase (JNK) activation, and reduction of glutathione (GSH). Interestingly, PDK4 retained p65 in cytoplasm via a direct protein-protein interaction. Disruption of PDK4-p65 association promoted p65 nuclear translocation. This, in turn, facilitated p65 binding to the TNF promoter to activate TNF-TNFR1 apoptotic pathway. Pdk4(-/-) livers were sensitized to Jo2 and D-(+)-Galactosamine /Lipopolysaccharide (GalN/LPS)-mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro-survival activity of TNF was shifted, which was switched to a pro-apoptotic activity in Pdk4(-/-) hepatocytes as a result of impaired activation of pro-survival NF-?B targets. Conclusion: PDK4 is indispensable to dictate the fate of TNF/NF-?B-mediated hepatocyte apoptosis. (Hepatology 2018).",0
6442,29617589,Change in Overweight from Childhood to Early Adulthood and Risk of Type 2 Diabetes,"BACKGROUND: Childhood overweight is associated with an increased risk of type 2 diabetes in adulthood. We investigated whether remission of overweight before early adulthood reduces this risk. METHODS: We conducted a study involving 62,565 Danish men whose weights and heights had been measured at 7 and 13 years of age and in early adulthood (17 to 26 years of age). Overweight was defined in accordance with Centers for Disease Control and Prevention criteria. Data on type 2 diabetes status (at age ?30 years, 6710 persons) were obtained from a national health registry. RESULTS: Overweight at 7 years of age (3373 of 62,565 men; 5.4%), 13 years of age (3418 of 62,565; 5.5%), or early adulthood (5108 of 62,565; 8.2%) was positively associated with the risk of type 2 diabetes; associations were stronger at older ages at overweight and at younger ages at diagnosis of type 2 diabetes. Men who had had remission of overweight before the age of 13 years had a risk of having type 2 diabetes diagnosed at 30 to 60 years of age that was similar to that among men who had never been overweight (hazard ratio, 0.96; 95% confidence interval [CI], 0.75 to 1.21). As compared with men who had never been overweight, men who had been overweight at 7 and 13 years of age but not during early adulthood had a higher risk of type 2 diabetes (hazard ratio, 1.47; 95% CI, 1.10 to 1.98), but their risk was lower than that among men with persistent overweight (hazard ratio [persistently overweight vs. never overweight], 4.14; 95% CI, 3.57 to 4.79). An increase in body-mass index between 7 years of age and early adulthood was associated with an increased risk of type 2 diabetes, even among men whose weight had been normal at 7 years of age. CONCLUSIONS: Childhood overweight at 7 years of age was associated with increased risks of adult type 2 diabetes only if it continued until puberty or later ages. (Funded by the European Union.).",0
6443,29641966,Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma,"""BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88(L265P) and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on """"chronic active"""" B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).""",0
6444,29669224,Evaluation of Intussusception after Monovalent Rotavirus Vaccination in Africa,"BACKGROUND: Postlicensure evaluations have identified an association between rotavirus vaccination and intussusception in several high- and middle-income countries. We assessed the association between monovalent human rotavirus vaccine and intussusception in lower-income sub-Saharan African countries. METHODS: Using active surveillance, we enrolled patients from seven countries (Ethiopia, Ghana, Kenya, Malawi, Tanzania, Zambia, and Zimbabwe) who had intussusception that met international (Brighton Collaboration level 1) criteria. Rotavirus vaccination status was confirmed by review of the vaccine card or clinic records. The risk of intussusception within 1 to 7 days and 8 to 21 days after vaccination among infants 28 to 245 days of age was assessed by means of the self-controlled case-series method. RESULTS: Data on 717 infants who had intussusception and confirmed vaccination status were analyzed. One case occurred in the 1 to 7 days after dose 1, and 6 cases occurred in the 8 to 21 days after dose 1. Five cases and 16 cases occurred in the 1 to 7 days and 8 to 21 days, respectively, after dose 2. The risk of intussusception in the 1 to 7 days after dose 1 was not higher than the background risk of intussusception (relative incidence [i.e., the incidence during the risk window vs. all other times], 0.25; 95% confidence interval [CI], <0.001 to 1.16); findings were similar for the 1 to 7 days after dose 2 (relative incidence, 0.76; 95% CI, 0.16 to 1.87). In addition, the risk of intussusception in the 8 to 21 days or 1 to 21 days after either dose was not found to be higher than the background risk. CONCLUSIONS: The risk of intussusception after administration of monovalent human rotavirus vaccine was not higher than the background risk of intussusception in seven lower-income sub-Saharan African countries. (Funded by the GAVI Alliance through the CDC Foundation.).",0
6445,29669226,Gene Therapy in Patients with Transfusion-Dependent ?-Thalassemia,"BACKGROUND: Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent ?-thalassemia. After previously establishing that lentiviral transfer of a marked ?-globin (?(A-T87Q)) gene could substitute for long-term red-cell transfusions in a patient with ?-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent ?-thalassemia. METHODS: In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent ?-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA(T87Q)). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA(T87Q), transfusion requirements, and average vector copy number. RESULTS: At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-?(0)/?(0) genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a ?(0)/?(0) genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS: Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe ?-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).",0
6446,29672888,Fibroblast Growth Factor 15-Dependent and Bile Acid-Independent Promotion of Liver Regeneration in Mice,"The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy (PHx) are not entirely known, but bile acids (BAs) and fibroblast growth factor 15 (Fgf15) that is highly expressed in the mouse ileum could promote hepatocyte proliferation. Fgf15 strongly suppresses the synthesis of BAs, and emerging evidence indicates that Fgf15 is important for liver regeneration. The mechanisms by which Fgf15 promotes liver regeneration are unclear, but Fgf15 may do so indirectly by reducing BA levels and/or directly by promoting cell proliferation. However, it remains undetermined whether these two mechanisms are independent or integrated. In this study, we aimed to clarify these relationships by generating Fgf15 Tet-Off, transgenic mice (Fgf15 Tg) that had very low BA levels as a result from overexpressed Fgf15-mediated suppression of BA synthesis. Compared with wild-type mice, the Fgf15 Tg mice showed increased hepatocyte proliferation even without surgery, and a further induction of the genes in cell-cycle progression after PHx. Moreover, overexpression of Fgf15 by adeno-associated virus (AAV)-Fgf15 transduction or treatment with the recombinant Fgf15 protein led to increased cell proliferation in vivo. Furthermore, Fgf15 Tg mice exhibited an earlier and greater activation of mitogen-activated protein kinase, signal transducer and activator of transcription 3, and NF-?B signaling pathways in the priming stage, and a disruption of the hippo signaling pathway in the termination stage of liver regeneration. Conclusion: Direct in vivo evidence demonstrates that Fgf15 is critical in stimulating the phases of priming and termination of liver regeneration that are critical for cell survival and liver-size determination, independent of BA levels. (Hepatology 2018; 00:000-000).",0
6447,29679386,Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Sensing in Human Hepatocytes,"Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was identified as a DNA sensor. In this study, we investigated the functional role of cGAS in sensing HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss-of-function and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes, and HBV-infected human liver chimeric mice. Here, we show that cGAS is expressed in the human liver, primary human hepatocytes, and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral covalently closed circular DNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. Conclusion: HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways.",0
6448,29694819,Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia,"Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).",0
6449,29699857,Prevalence and significance of notched T-waves in elite professional cyclists,"To identify the frequency and significance of notched T-waves (NTW) in elite endurance athletes. Professional cyclists were followed for 4 years with a clinical, electrocardiographic and echocardiographic assessment. Electrocardiograms were classified according to the presence or absence of NTWs; clinical and echocardiographic correlates were assessed. 42 Caucasian male cyclists were included. NTW were detected in 8 (19%) cyclists who showed significantly longer QT (461 ± 15 vs 422 ± 33 ms, p < 0.01) and QTc intervals (434 ± 19 vs 383 ± 21 ms, p < 0.01), a larger left ventricular end-diastolic volume (163 ± 27 vs 137 ± 23 mL, p = 0.014), end-diastolic volume index (84 ± 13 vs 73 ± 11 mL, p = 0.037) and end-diastolic apex-to-base length (9.9 ± 0.7 vs 9.3 ± 0.5 mm. p = 0.035). There were no detected arrhythmic events, and echocardiography did not reveal any abnormalities. This is to our knowledge the first study reporting a high prevalence of NTW in athletes. In our small cohort of cyclists NTW were associated with QT interval prolongation and left ventricular changes. This may be indicative of underlying inhomogeneity of repolarisation. Expanding on this research could reveal a role for NTW in identifying ventricular morphological changes. ",0
6450,29699922,"Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors","Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent. ",0
6451,29701049,Analysing the defect of control design of acupuncture: taking RCTs of treating simple obesity with acupuncture for example],"By analysing the defect of control design in randomized controlled trials (RCTs) of simple obesity treated with acupuncture and using acupuncture as the contrast, presenting the essential factors which should be taken into account as designing the control of clinical trial to further improve the clinical research. Setting RCTs of acupuncture treating simple obesity as a example, we searched RCTs of acupuncture treating simple obesity with acupuncture control. According to the characteristics of acupuncture therapy, this research sorted and analysed the control approach of intervention from aspects of acupoint selection, the penetration of needle, the depth of insertion, etc, then calculated the amount of difference factor between the two groups and analyzed the rationality. In 15 RCTs meeting the inclusion criterias, 7 published in English, 8 in Chinese, the amount of difference factors between two groups greater than 1 was 6 (40%), 4 published in English abroad, 2 in Chinese, while only 1 was 9 (60%), 3 published in English, 6 in Chinese. Control design of acupuncture in some clinical RCTs is unreasonable for not considering the amount of difference factors between the two groups. ",0
6452,29701074,Thymidine phosphorylase: the unforeseen driver in colorectal cancer treatment?,"5-Fluorouracil- and leucovorin-based chemotherapy regimens are the backbone of colorectal cancer treatment. The addition of oxaliplatin, irinotecan and monoclonal antibodies to this backbone has largely improved clinical outcomes, but has also led to new questions, with conflicting data frequently reported in studies. Thymidine phosphorylase (TP) is a nucleoside-metabolizing enzyme involved in 5-fluorouracil pharmacokinetics, as well as inflammatory responses, neoangiogenesis and apoptosis. TP expression is regulated by hypoxia, inflammatory cytokines and antitumoral agents. We hypothesize that TP could be the unforeseen driver in the conflicting data observed with different regimens commonly used in colorectal cancer treatment. Greater comprehension of the role of this enzyme in tumor progression and pyrimidine metabolism may lead to more accurate, patient-tailored therapy. ",0
6453,29701149,Nigella sativa L. and Its Bioactive Constituents as Hepatoprotectant: A Review,"The pharmacological properties of Nigella sativa L. are well attributed to the presence of bioactive compounds, mainly, thymoquinone (TQ), thymol (THY) and α hederin and their antioxidant effects. TQ, THY and alpha-hederin (α-hederin) provide protection to liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and (GSH) level, radical scavenging, increasing the activity of quinone reductase, catalase, superoxide dismutase (SOD) and glutathione transferase (GST), inhibition of NF-κB activity and inhibition of both (COX) and (LOX) protects liver from injuries. Review and Conclusion: The main aim of this literature review is to reflect the relevant role of ROS in inducing hepatic diseases and also the preventive role of N. sativa L. in hepatic diseases. The present article is directed towards highlighting the beneficial contribution of researchers to explore the pharmacological actions with therapeutic potential of this precious natural herb and its bioactive compounds pertaining to the hepatoprotective effects. We systematically searched for research literature through well-framed review question and presented the data in the tabular forms for the convenience of the readers. Two hundred and forty-one papers were embodied in this review, oxidative effect and the reactive oxygen species (ROS) are known to be the major causes of many diseases such as hepatic cancer. Many drugs and chemicals have shown to incite oxidative damage by generation of ROS in the body. Therefore, this review intends to focus the role of ROS in liver diseases and the mechanisms through which N. sativa prevents hepatic diseases. The mechanisms by which N. sativa impede progression in chronic liver diseases should be used as a preventive medicine in patients with hepatic disorders. ",0
6454,29742375,Investigational Testing for Zika Virus among U.S. Blood Donors,"BACKGROUND: Because of the potential severe clinical consequences of Zika virus (ZIKV) infection, the large numbers of asymptomatic travelers returning from ZIKV-active areas, the detection of ZIKV nucleic acid in blood, and reports of transmission of ZIKV through transfusion, in 2016 the Food and Drug Administration released recommendations for individual-unit nucleic acid testing to minimize the risk of transmission of ZIKV through blood transfusions. METHODS: The American Red Cross implemented investigational screening of donated blood for ZIKV RNA by means of transcription-mediated amplification (TMA). Confirmatory testing of reactive donations involved repeat TMA, TMA testing in exploratory minipools, real-time reverse-transcriptase polymerase chain reaction, IgM serologic testing, and red-cell TMA. Viral loads in plasma and red cells were estimated by means of end-point TMA. The costs of interdicting a donation that was confirmed to be positive were calculated for the 15-month period between June 2016 and September 2017. RESULTS: Of the 4,325,889 donations that were screened, 393,713 (9%) were initially tested in 24,611 minipools, and no reactive donations were found. Of the 3,932,176 donations that were subsequently tested individually, 160 were initially reactive and 9 were confirmed positive (a 1:480,654 confirmed-positive rate overall; positive predictive value, 5.6%; specificity, 99.997%). Six (67%) of the confirmed-positive donations were reactive on repeat TMA, of which 4 were IgM-negative; of these 4, all 3 that could be tested were reactive on minipool TMA. Two confirmed-positive donors had infections that had been transmitted locally (in Florida), 6 had traveled to ZIKV-active areas, and 1 had received an experimental ZIKV vaccine. ZIKV RNA levels in red cells ranged from 40 to 800,000 copies per milliliter and were detected up to 154 days after donation, as compared with 80 days of detection in plasma at levels of 12 to 20,000 copies per milliliter. On the basis of industry-reported costs of testing and the yield of the tests in our study, the cost of identifying 8 mosquito-borne ZIKV infections through individual-unit nucleic acid testing was $5.3 million per ZIKV RNA-positive donation. CONCLUSIONS: Screening of U.S. blood donations for ZIKV by individual-donation TMA was costly and had a low yield. Among the 9 confirmed ZIKV-positive donations, only 4 were IgM-negative; of these donations, all 3 that were tested were reactive on minipool TMA. (Funded by the American Red Cross and Grifols Diagnostic Solutions.).",0
6455,29742809,B Cell-Mediated Maintenance of Cluster of Differentiation 169-Positive Cells Is Critical for Liver Regeneration,"The liver has an extraordinary capacity to regenerate through activation of key molecular pathways. However, central regulators controlling liver regeneration remain insufficiently studied. Here, we show that B cell-deficient animals failed to induce sufficient liver regeneration after partial hepatectomy (PHx). Consistently, adoptive transfer of B cells could rescue defective liver regeneration. B cell-mediated lymphotoxin beta production promoted recovery from PHx. Absence of B cells coincided with loss of splenic cluster of differentiation 169-positive (CD169(+) ) macrophages. Moreover, depletion of CD169(+) cells resulted in defective liver regeneration and decreased survival, which was associated with reduced hepatocyte proliferation. Mechanistically, CD169(+) cells contributed to liver regeneration by inducing hepatic interleukin-6 (IL-6) production and signal transducer and activator of transcription 3 activation. Accordingly, treatment of CD169(+) cell-depleted animals with IL-6/IL-6 receptor rescued liver regeneration and severe pathology following PHx. Conclusion: We identified CD169(+) cells to be a central trigger for liver regeneration, by inducing key signaling pathways important for liver regeneration.",0
6456,29768139,Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes,"BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).",0
6457,29776647,"Effect of green alga Ulva lactuca polysaccharides supplementation on blood pressure and on atherogenic risk factors, in rats fed a high fat diet]","To highlight the benefits of green alga Ulva lactuca polysaccharides supplementation on blood pressure and atherogenic risk factors in rats fed a high fat diet. Wistar male rats were fed a high fat diet (30% sheep fat) for 3 months. At an average body weight (BW) of 360g, the rats (n=18) were divided into 3 groups and consumed, for 28 days, either a high fat diet (HFD) or a high fat diet enriched with 1% of whole green algae (WGA) powder or with 1% of its polysaccharides (PLS). In HFD, WGA and PLS supplementation reduced BW and food intake. WGA and PLS compared to HFD reduced systolic (PAS) (-17% and -19%) and diastolic (PAD) blood pressure (-38% and -39%), serum glucose (-37% and -30%, respectively), insulinemia (-55% and -74%, respectively), serum and hepatic total lipids, triglycerides, total cholesterol levels, as well as the total cholesterol concentration of low and very low density lipoproteins. The same, atherogenicity ratios and membrane fluidity decreased in the WGA and PLS vs HFD while lecithin: cholesterol acyltransferase (LCAT) activity increased (51 and 41% respectively). Ulva lactuca and its polysaccharides, one of the bioactive compounds of this macroalga, seem to have hypotensive, hypoglycemic, hypolipaemic and antiatherogenic properties that can correct or prevent certain cardiovascular complications linked to a high fat diet. ",0
6458,29776825,A review of research efforts to address the 2008 ACEP guideline for mild traumatic brain injury,"The objective of this study was to evaluate the temporal relationship between clinical practice guideline development and subsequent research performed, with the goal of providing more data on areas of sparse evidence that serve to underlie guideline recommendations. We aimed to assess the quality of current research efforts to address the American College of Emergency Physicians guideline and to provide suggestions for future research of mild traumatic brain injury. We identified clinical practice guideline recommendations with low levels of underlying evidence and searched ClinicalTrials.gov and the World Health Organization's International Clinical Trial Registry Portal to determine whether subsequent research has reflected an effort to address guideline recommendations. Few currently registered clinical trials attempt to focus on clinical practice guideline recommendations where the basis of evidence is weak, and even fewer might benefit future iterations of the guideline due to multiple problems in study design and reporting. The amount of research dedicated to investigation of mild traumatic brain injury continues to be sparse and of poor quality. Study results should always be posted, even if the null hypothesis is confirmed. Efforts to improve the evidence base of a guideline should be realized by designing studies that directly assess and speak to the questions posed by guideline authors. ",0
6459,29776950,Clinical effects and safety of electroacupuncture for the treatment of post-stroke depression: a systematic review and meta-analysis of randomised controlled trials,"The aim of this systematic review was to assess the efficacy/effectiveness and safety of electroacupuncture (EA) in the treatment of post-stroke depression (PSD). A comprehensive literature search in the Pubmed, Embase, CENTRAL, ISI Web of Science, CNKI and Wanfang databases was conducted, and all relevant randomised controlled trials (RCTs) were screened for eligibility by two independent reviewers. The Cochrane Collaboration's tool and Jadad score were used to assess the risk of bias of included studies, and only RCTs scoring ≥3 were included in a meta-analysis. 18 RCTs involving a total of 813 participants (mean age 61.6 years) in the EA groups and 723 participants (mean age 61.9 years) in the control groups were included. The included studies had an average 3 point Jadad score. PSD was diagnosed according to the Chinese Classification of Cerebrovascular Disease (CCCD) and the Chinese Classification of Mental Disease (CCMD) criteria. There was no significant difference between EA and antidepressants (fluoxetine 10-40 mg/day, citalopram 20 mg/day, sertraline 50 mg/day) in terms of the Hamilton Depression Rating Scale (HAMD) scores at week 4 after treatment (standardised mean difference (SMD) -0.11, 95% CI -0.31 to 0.10), at week 6 after treatment (SMD 0.04, 95% CI -0.43 to 0.51) or at week 8 after treatment (SMD -0.01, 95% CI -0.23 to 0.22). However, the combined incidence of adverse events in the EA groups was significantly lower than in the antidepressant groups (RR 0.21, 95% CI 0.14 to 0.33). There was no significant difference between EA and antidepressants in the severity of depression, however EA caused fewer adverse events than antidepressants. Additional larger scale RCTs with rigorous study design are required. ",0
6460,29777278,Low platelet count as risk factor for infections in patients with primary immune thrombocytopenia: a retrospective evaluation,"Infectious complications are common and sometimes life threatening in patients with immune thrombocytopenia (ITP), mainly due to the immune-suppressive therapy. Recent evidence suggests a potential role of platelets in the inflammation process. In this clinical study, we further investigated the role of thrombocytopenia on infections in patients with primary ITP. We retrospectively evaluated data from the recently published large randomized clinical trial of a cohort of 195 patients with primary ITP, who were randomized for prednisone or high-dose dexamethasone. From 158 patients (81%), data on platelet count and infections within the first month of treatment were collected. In this period, 24% of the ITP patients had an infection. Patients with infection had significant lower platelet counts during the first month of treatment leading to a significant lower therapy response at 1 month and a significant longer hospital stay (14.0 versus 9.8 days). Additionally, Cox regression analysis showed that an increase in platelet count of 20 × 10 ",0
6461,29777535,The Relationship between Costs and Quality in Veterans Health Administration Community Living Centers: An Analysis Using Longitudinal Data,"To examine the relationship between cost and quality in Veterans Health Administration (VA) nursing homes (called Community Living Centers, CLCs) using longitudinal data. One hundred and thirty CLCs over 13 quarters (from FY2009 to FY2012) were studied. Costs, resident days, and resident severity (RUGs score) were obtained from the VA Managerial Cost Accounting System. Clinical quality measures were obtained from the Minimum Data Set, and resident-centered care (RCC) was measured using the Artifacts of Culture Change Tool. We used a generalized estimating equation model with facilities included as fixed effects to examine the relationship between total cost and quality after controlling for resident days and severity. The model included linear and squared terms for all independent variables and interactions with resident days. With the exception of RCC, all other variables had a statistically significant relationship with total costs. For most poorer performing smaller facilities (lower size quartile), improvements in quality were associated with higher costs. For most larger facilities, improvements in quality were associated with lower costs. The relationship between cost and quality depends on facility size and current level of performance. ",0
6462,29777566,Care provider allocation on admissions to acute mental health wards: The development and validation of the Admission Team Score List,"Currently, support tools are lacking to prioritize steps in the care coordination process to enable safe practice and effective clinical pathways in the first phase of acute psychiatric admissions. This study describes the development, validity, and reliability of an acute care coordination support tool, the Admission Team Score List (ATSL). The ATSL assists in care provider allocation during admissions. Face validity and feasibility of the ATSL were tested in 77 acute admissions. Endscores of filled out ATSL's were translated to recommended team compositions. These ATSL team (ATSL-T) compositions were compared to the actually present team (AP-T) and the most preferred team (MP-T) composition in hindsight. Consistency between the ATSL-T and the MP-T was substantial; K ",0
6463,29778005,Impact on the physical and sensory properties of salt-and fat-reduced traditional Irish breakfast sausages on various age cohorts acceptance,"The properties of varying salt and fat levels in traditional breakfast sausages were investigated. Sausages were produced with fat levels of: 30%, 20% and 15%. Fat was replaced with pea extract. Salt levels employed were: 2.5%, 1.1% and 0.0%. A reduced sodium salt which contains 45% less sodium than standard salt was used. Sensory analysis was conducted on consumers (n = 228): 18-40 yrs., 41-64 yrs. and 65-85 yrs. The 18-40 yr. olds preferred sausages containing 20% fat, 41-64 yr. olds preferred sausages with 15% fat, 65+ age group preferred sausages containing 30% fat. The 18-40 yr. olds preferred high salt samples, 41-64 yr. olds displayed no salt preference, while the 65+ age group preferred high salt sausages. Sausage formulation choice was found to be driven by texture for the younger age cohort, flavour for the middle age cohort and visual aspects from the oldest age cohort. There is a need to understand how meat products might be reformulated different age palates. ",0
6464,29778348,Preoperative Antibiotics in Wrist Arthroscopy,"This study seeks to evaluate the need for preoperative antibiotics for wrist arthroscopy. A retrospective review of 576 consecutive wrist arthroscopies was performed over a 10-year period at a single ambulatory surgery center. The chart of each included patient was reviewed for postoperative infections following the National Nosocomial Infections Surveillance criteria for diagnosis. Of the 576 wrist arthroscopies reviewed, 324 met the inclusion criteria. Preoperative antibiotics were administered in 209 cases (65%) and not administered in 115 cases (35%). There were 116 cases (36%) with concomitant open soft tissue procedures. We identified 2 infections (0.6% overall infection rate), both of which were in patients who had received preoperative antibiotics. Both of these patients underwent concomitant percutaneous pinning of carpal bones with Kirschner wires, which were buried beneath the skin. Administering preoperative antibiotics for routine wrist arthroscopy does not appear to lower the surgical site infection rate. The rate of surgical site infection is so low in both cohorts that a meaningful difference cannot be determined between the 2 groups. This study adds to the current body of literature suggesting that it is acceptable practice to withhold preoperative antibiotics for surgeries that have a very low rate of infection. Therapeutic IV. ",0
6465,29778611,Traumatic Aorto-Cisterna Chlyi Fistula with Treatment of Aortic Pseudoaneurysm with CT-Guided Thrombin Injection,"Only 3 cases of aorto-cisterna chyli fistula have been described in the literature but none with a resulting pseudoaneurysm (PSA). A 68-year-old man presented following a motor vehicle collision. Imaging revealed a retroperitoneal hematoma with enhancement of the cisterna chyli, representing an aortic to cisterna chyli fistula. Three days later, computed tomography angiography showed resolution of the fistula, but revealed a PSA. The patient underwent arteriography that confirmed the PSA, and then a computed tomography-guided thrombin injection was performed. Follow-up imaging showed resolution of the PSA. Only 3 cases of aorto-cisterna chyli fistula have been described. We hypothesize that this fistula was caused from his L2 vertebral body fracture, which avulsed the lumbar artery and injured the cisterna chyli. The cisterna chyli provided an outflow tract for the aortic injury. We believe this type of fistula follows a benign clinical course. Aorto-cisterna chyli fistula is rare, and reports point to spontaneous resolution. Our case is unique in that the patient progressed from a fistula to a PSA. Options for treatment of this PSA include covered stent graft, open repair, coil embolization, or thrombin injection. This case report describes an extremely rare diagnosis and the natural history of this aorto-cisterna chyli fistula. Furthermore, the resulting aortic PSA was successfully treated with computed tomography-guided thrombin injection, which in the appropriate setting, should be considered an acceptable option. ",0
6466,29778630,BCG vaccination protects against infection with Mycobacterium tuberculosis ascertained by tuberculin skin testing,"There is conflicting evidence as to whether Bacillus Calmette-Guérin (BCG) vaccination offers protection against Mycobacterium tuberculosis infection ascertained by a positive tuberculin skin test (TST). We investigated the association between BCG vaccination status and TST results in a set of surveys at increasing TST cut-off values to take cross-reactions to BCG vaccination into account. Secondary analysis of data from three consecutive tuberculin surveys done among schoolchildren in Tanzania between 1990 and 2002. BCG vaccination status was ascertained by the presence of a typical scar. We analyzed data of 277,588 children of whom 77.7% were BCG vaccinated and 8.5% had TST indurations ≥ 15 mm, 5.1% ≥ 17 mm and 2.8% ≥ 19 mm. In the combined analysis, odds ratios for a positive TST were > 1 for children with BCG up to TST cut-off values of 16 mm. For cut-off values > 17 mm crude and adjusted odds ratios were significantly < 1, and decreased with further increasing cut-off values. Using a methodology that makes use of the differences in TST reaction sizes between specific and non-specific responses, we showed that BCG vaccination was associated with reduced prevalence of M. tuberculosis infection as measured by the tuberculin skin test, suggesting a protective effect. ",0
6467,29778691,Alterations in apparent diffusion coefficient values of the kidney during the cardiac cycle: Evaluation with ECG-triggered diffusion-weighted MR imaging,"To evaluate dynamic changes in apparent diffusion coefficient (ADC) values of the kidney at different time points during the cardiac cycle using electrocardiographic (ECG)-triggered diffusion-weighted MR imaging in normal subjects, and to elucidate the differences in ADC values between the right and left kidneys during a cardiac cycle. The study was approved by our institutional review board and informed consent was obtained from subjects. Twenty healthy volunteers who underwent ECG-triggered diffusion-weighted MR imaging of the kidney were included. The differences in ADC values of each kidney during different cardiac phases were compared. Additionally, the differences in maximum and minimum ADC values between the right and left kidney were also evaluated. ADC values in the right and left kidney changed significantly during the cardiac cycle (P < 0.00001). Maximum and minimum ADC values during the cardiac cycle of the left kidney were significantly higher (P = 0.026 and 0.017, respectively) than those of the right kidney. Maximum ADC value in the left kidney had a significantly strong positive correlation with the left renal vein ratio (r = 0.83, P < 0.00001). In the right kidney, maximum ADC showed a weakly positive correlation with the diameter of the right renal vein (r = 0.45, P = 0.048). ADC values of the kidney obtained using ECG-triggered diffusion-weighted MR imaging change significantly during the cardiac cycle. Maximum (systolic) ADC during the cardiac cycle of the left kidney was significantly higher than that of the right kidney, probably due to the anatomical difference in the renal vein. ",0
6468,29778700,Paediatric cystolitholapaxy through the Mitrofanoff/Monti channel,"Bladder calculi are a known complication of bladder augmentation. Open cystolithotomy remains the preferred option for treating large or multiple stones. Increasingly, however, minimal access techniques have been used. Reports of Mitrofanoff cystolitholapaxy are rare and have been limited to adults. This study presented a two centre series of children treated by cystolitholapaxy via the Mitrofanoff/Monti channel. With institutional approval the current study retrospectively reviewed and identified 14 patients, on a prospective database, who underwent Mitrofanoff cystolitholapaxy to treat bladder calculi at two independent institutions in the UK and Chile between 2004 and 2016. It looked at patient demographics, surgical technique, stone clearance and recurrence, as well as leak or catheterisation difficulties of the Mitrofanoff/Monti channel post-procedure. Fourteen patients underwent Mitrofanoff cystolitholapaxy during the period 2004-2016. One patient was excluded due to lack of follow-up. The remaining 13 patients were aged 5-22 (median 14) years at the time of the procedure. Their underlying diagnoses were four neuropathic bladders, four bladder exstrophy, four cloacal exstrophy and one posterior urethral valve. Patients underwent augmentation cystoplasty at a median age of 5 (range 1-15) years, using ileum in 10 and sigmoid colon in three. The channel for clean intermittent catheterisation was an appendix Mitrofanoff in nine and a Monti channel in four. An Amplatz sheath was placed through the Mitrofanoff to allow safe access to the bladder for treating the stones (see Summary Table). Recurrent stones were treated using the same technique. Stone and channel outcomes were analysed for each procedure. There were 22 procedures in 13 patients; five (38%) patients had recurrent stones. Median time to recurrence was 6 months. There were no immediate complications. Stone clearance was confirmed by ultrasound and abdominal x-ray at 3-6 months after the procedure. Median follow-up was 15 (range 3-53) months. There were no leaks or difficulties catheterising the channel on follow-up. This was the first series of Mitrofanoff/Monti cystolitholapaxy for the treatment of calculi in augmented bladders of paediatric patients. Previous concerns about damaging the continence mechanism of the conduit appeared to be unwarranted. The use of an Amplatz sheath protected the continence system from repeated instrumentation, and permitted free backflow of irrigation and rapid clearance of stone fragments. Recurrence of stones occurred in 38%, which was in keeping with rates reported in the wider literature. Mitrofanoff cystolitholapaxy was safe, and with appropriate care did not result in leakage or difficulty catheterising. ",0
6469,29779169,"""""""Keeping in mind the gender stereotype"""": the role of need for closure in the retrieval-induced forgetting of female managers' qualities""","The present research addressed the question of whether need for closure (NFC; Kruglanski in The psychology of closed mindedness, Psychology Press, New York, 2004) biases individuals' memory of female leaders. Merging research on role congruity theory of leadership (Koenig et al. in Psychol Bull 4:616-642, 2011. https://doi.org/10.1037/a0023557 ) and research on retrieval-induced forgetting (RIF, Anderson et al. in J Exp Psychol Learn Mem Cognit 20:1063-1087, 1994. https://doi.org/10.1037/0022-3514.65.5.861 ), we hypothesized and found that high-NFC participants show (1) a higher RIF of dimensions commonly associated with the leadership prototype (agentic/masculine) ascribed to female manager targets, when selectively retrieved dimensions commonly associated with the female prototype (communal/feminine) were ascribed to the same target; and (2) a lessened RIF of female stereotypical dimensions ascribed to female manager targets, when selectively retrieved prototypical leadership dimensions were ascribed to the same target. Overall, the present findings suggest that when faced with women leaders, high NfC enhances the accessibility of gender stereotype-congruent memories and reduces the accessibility of prototypical leadership ones, thus reducing the RIF of communal/feminine memories. ",0
6470,29779542,Improving Data for Behavioral Health Workforce Planning: Development of a Minimum Data Set,"The behavioral health workforce, which encompasses a broad range of professions providing prevention, treatment, and rehabilitation services for mental health conditions and substance use disorders, is in the midst of what is considered by many to be a workforce crisis. The workforce shortage can be attributed to both insufficient numbers and maldistribution of workers, leaving some communities with no behavioral health providers. In addition, demand for behavioral health services has increased more rapidly as a result of federal legislation over the past decade supporting mental health and substance use parity and by healthcare reform. In order to address workforce capacity issues that impact access to care, the field must engage in extensive planning; however, these efforts are limited by the lack of timely and useable data on the behavioral health workforce. One method for standardizing data collection efforts is the adoption of a Minimum Data Set. This article describes workforce data limitations, the need for standardizing data collection, and the development of a behavioral health workforce Minimum Data Set intended to address these gaps. The Minimum Data Set includes five categorical data themes to describe worker characteristics: demographics, licensure and certification, education and training, occupation and area of practice, and practice characteristics and settings. Some data sources align with Minimum Data Set themes, although deficiencies in the breadth and quality of data exist. Development of a Minimum Data Set is a foundational step for standardizing the collection of behavioral health workforce data. Key challenges for dissemination and implementation of the Minimum Data Set are also addressed. This article is part of a supplement entitled The Behavioral Health Workforce: Planning, Practice, and Preparation, which is sponsored by the Substance Abuse and Mental Health Services Administration and the Health Resources and Services Administration of the U.S. Department of Health and Human Services. ",0
6471,29779620,Evaluation of fine needle aspiration cytology in the diagnosis of cervical lymph node lymphomas,"""Surgical biopsy examination is the gold standard for the diagnosis of lymph node lymphomas. Fine-needle aspiration cytology (FNAC) is a quick and safe method in the management of cervical lymph nodes. Its value in confirming recurrent or residual lymphoma is well established. However, its role in the primary diagnosis of lymph node lymphoma remains controversial. The aim of this study was to assess, in our experience, the reliability of FNAC in the diagnosis of cervical lymph node lymphomas. This was a retrospective study carried out over a 6-year period (January 2011 to December 2016) and conducted at the Cytology Unit in our Pathology Department (Charles Nicolle Hospital, Tunisia). The measures of diagnostic accuracy of FNAC in the diagnosis of cervical lymph node lymphomas were calculated taking histopathology as the gold standard. A total of 937 FNA samples were obtained from 851 patients. The diagnosis of lymphoma was obtained in 65 cases (6.9%). Cytological diagnoses of lymphoma were as follows: 28 (44%) Hodgkin lymphoma, 17 (25%) high-grade lymphoma, 15 (23%) low-grade lymphoma, and 5 (8%) """"suggestive of lymphoma."""" FNAC of cervical lymph nodes had a sensitivity of 95.5%, specificity of 98.7%, positive predictive value (PPV) of 97.7%, and negative predictive value (NPP) of 97.5%. The present study demonstrated that cytology is capable to detect nodes suspicious for the presence of lymphoma precisely, in terms of low- or high-grade lymphoma, which is a relevant and very achievable first step in the management of patients with cervical lymph node lymphoma. """,0
6472,29780574,Synchronous nephrectomy and cavoatrial tumor thrombectomy under normothermic extracorporeal circulation and beating heart,"Formation of tumor thrombus is an occasional manifestation of renal cell carcinoma (RCC). Intravascular invasion of the renal vein and thereafter the inferior vena cava (IVC) might in very rare cases extend into the cardiac chambers. The subtle course and symptoms of such cases alongside with the engagement of vital anatomical structures marks them as a diagnostic and therapeutic challenge. Aggressive surgical intervention has proven to be critical for survival rates in such cases; however total synchronous resection remains a challenge for the surgical team and a debate for the medical community. Following we report the case of a 66-year-old male who was diagnosed with a RCC of the right kidney accompanied by a tumor thrombus extending into the right atrium, after he suffered a presyncope episode. The patient underwent a radical en bloc nephrectomy and tumor thrombectomy under extracorporeal circulation with beating heart. ",0
6473,29780584,Opening the black box of spring water microbiology from alpine karst aquifers to support proactive drinking water resource management,"Over the past 15 years, pioneering interdisciplinary research has been performed on the microbiology of hydrogeologically well-defined alpine karst springs located in the Northern Calcareous Alps (NCA) of Austria. This article gives an overview on these activities and links them to other relevant research. Results from the NCA springs and comparable sites revealed that spring water harbors abundant natural microbial communities even in aquifers with high water residence times and the absence of immediate surface influence. Apparently, hydrogeology has a strong impact on the concentration and size of the observed microbes, and total cell counts (TCC) were suggested as a useful means for spring type classification. Measurement of microbial activities at the NCA springs revealed extremely low microbial growth rates in the base flow component of the studied spring waters and indicated the importance of biofilm-associated microbial activities in sediments and on rock surfaces. Based on genetic analysis, the autochthonous microbial endokarst community (AMEC) versus transient microbial endokarst community (TMEC) concept was proposed for the NCA springs, and further details within this overview article are given to prompt its future evaluation. In this regard, it is well known that during high-discharge situations, surface-associated microbes and nutrients such as from soil habitats or human settlements-potentially containing fecal-associated pathogens as the most critical water-quality hazard-may be rapidly flushed into vulnerable karst aquifers. In this context, a framework for the comprehensive analysis of microbial pollution has been proposed for the NCA springs to support the sustainable management of drinking water safety in accordance with recent World Health Organization guidelines. Near-real-time online water quality monitoring, microbial source tracking (MST) and MST-guided quantitative microbial-risk assessment (QMRA) are examples of the proposed analytical tools. In this context, this overview article also provides a short introduction to recently emerging methodologies in microbiological diagnostics to support reading for the practitioner. Finally, the article highlights future research and development needs. This article is categorized under: 1Engineering Water > Water, Health, and Sanitation2Science of Water > Water Extremes3Water and Life > Nature of Freshwater Ecosystems. ",0
6474,29780821,A Role for Postoperative Negative Pressure Wound Therapy in Multitissue Hand Injuries,"In this study, we compared outcomes in patients with acute hand injury, who were managed with or without negative pressure wound therapy (NPWT) after reconstructive surgery. All of the patients who sustained acute and multitissue injuries of the hand were identified. After reconstructive surgery, a conventional dressing was applied in Group 1 and NPWT was applied in Group 2. The dressing and NPWT were changed every 3 days. The mean age and Hand Injury Severity Scoring System score of both groups were not significantly different. Disabilities of the Arm, Shoulder, and Hand (DASH) scores were evaluated 1 month after all the sutures were removed and 1 year postoperatively, which were both significantly lower in Group 2. Applying NPWT to the hand promoted wound healing by reducing edema, stabilizing the wound, and providing immobilization in a functional position. Early wound healing and decreased complications enabled early rehabilitation, which led to successful functional recovery, both objectively and subjectively. ",0
6475,29781188,Inhibition of Cyclic GMP-AMP Synthase Using a Novel Antimalarial Drug Derivative in Trex1-Deficient Mice,"Type I interferon (IFN) is strongly implicated in the pathogenesis of systemic lupus erythematosus (SLE) as well as rare monogenic interferonopathies such as Aicardi-Goutières syndrome (AGS), a disease attributed to mutations in the DNA exonuclease TREX1. The DNA-activated type I IFN pathway cyclic GMP-AMP (cGAMP) synthase (cGAS) is linked to subsets of AGS and lupus. This study was undertaken to identify inhibitors of the DNA-cGAS interaction, and to test the lead candidate drug, X6, in a mouse model of AGS. Trex1 On the basis of the efficacy-to-toxicity ratio established in vitro, drug X6 was selected as the lead candidate for treatment of Trex1 This study demonstrates that X6 is superior to HCQ for the treatment of an experimental autoimmune myocarditis mediated in vivo by the cGAS/stimulator of IFN genes (cGAS/STING) pathway. The findings suggest that drug X6 could be developed as a novel treatment for AGS and/or lupus to inhibit activation of the cGAS/STING pathway. ",0
6476,29781627,"Triple trajectories of alcohol use, tobacco use, and depressive symptoms as predictors of cannabis use disorders among urban adults","Heavy cannabis use is associated with a wide array of physical, mental, and functional problems. Therefore, cannabis use disorders (CUDs) may be a major public health concern. Given the adverse health consequences of CUDs, the present study seeks to find possible precursors of CUDs. The current study consisted of 5 waves of data collection from the Harlem Longitudinal Development Study. Among 816 participants, about half are African Americans (52%), and the other half are Puerto Ricans (48%). We used Mplus to obtain the triple trajectories of alcohol use, tobacco use, and depressive symptoms. Logistic regression analyses were then conducted to examine the associations between the trajectory groups and CUDs. The 5 trajectory groups were (1) moderate alcohol use, high tobacco use, and high depressive symptoms (MHH; 12%); (2) moderate alcohol use, high tobacco use, and low depressive symptoms (MHL; 26%); (3) moderate alcohol use, low tobacco use, and low depressive symptoms (MLL; 18%); (4) low alcohol use, no tobacco use, and high depressive symptoms (LNH; 11%); and (5) low alcohol use, no tobacco use, and low depressive symptoms (LNL; 33%). The MHH, MHL, MLL, and LNH trajectory groups were associated with an increased likelihood of having CUDs compared to the LNL trajectory group after controlling for a number of confounding factors (e.g., CUDs in the late 20s). The findings of the current longitudinal study suggest that treatments designed to reduce or quit drinking as well as smoking and to relieve depressive symptoms may reduce the prevalence of CUDs. (PsycINFO Database Record ",0
6477,29781780,Physical Therapists Know Function: An Opinion on Mobility and Level of Activity During Hospitalization for Adult Inpatients,"Negative consequences of immobility during hospitalization are widely known and remain undisputed. Evidence of low mobility for general medicine adult inpatients persists. Patients who experience hospital acquired functional decline due to low mobility require costly post-acute care services. The impact of immobility on post-acute care physical function and quality of life is directly at odds with value-based care. New Medicare payment models emphasize value-based care to promote care improvement and better patient outcomes. Quality improvement projects show promise in changing clinical practice using clinical champions, interprofessional collaboration, and teamwork. Physical therapists have a distinct expertise acutely focused on mobility and physical activity during hospitalization. Patients need acute care team members to develop sustainable clinical practice changes and to accept collective responsibility for a culture of mobility. Partnering with physical therapists and using their expertise to direct mobility, executed by the appropriate support personnel, can achieve the Quadruple Aim. ",0
6478,29781869,Utilizing Facebook and Automated Telephone Calls to Increase Adoption of a Local Smoke Alarm Installation Program,"Innovative strategies are needed to improve the prevalence of working smoke alarms in homes. To our knowledge, this is the first study to report on the effectiveness of Facebook advertising and automated telephone calls as population-level strategies to encourage an injury prevention behavior. We examine the effectiveness of Facebook advertising and automated telephone calls as strategies to enroll individuals in Baltimore City's Fire Department's free smoke alarm installation program. We directed our advertising efforts toward Facebook users eligible for the Baltimore City Fire Department's free smoke alarm installation program and all homes with a residential phone line included in Baltimore City's automated call system. The Facebook campaign targeted Baltimore City residents 18 years of age and older. In total, an estimated 300 000 Facebook users met the eligibility criteria. Facebook advertisements were delivered to users' desktop and mobile device newsfeeds. A prerecorded message was sent to all residential landlines listed in the city's automated call system. By the end of the campaign, the 3 advertisements generated 456 666 impressions reaching 130 264 Facebook users. Of the users reached, 4367 individuals (1.3%) clicked the advertisement. The automated call system included approximately 90 000 residential phone numbers. Participants attributed 25 smoke alarm installation requests to Facebook and 458 to the automated call. Facebook advertisements are a novel approach to promoting smoke alarms and appear to be effective in exposing individuals to injury prevention messages. However, converting Facebook message recipients to users of a smoke alarm installation program occurred infrequently in this study. Residents who participated in the smoke alarm installation program were more likely to cite the automated call as the impetus for their participation. Additional research is needed to understand the circumstances and strategies to effectively use the social networking site as a tool to convert passive users into active participants. ",0
6479,29782172,Assembly Dynamics of Plasmonic DNA-Capped Gold Nanoparticle Monolayers,"The self-assembly of nanoparticles in aqueous solutions promises wide applications but requires the careful balance of many parameters not present in organic solvents. While the presence of long-range electrostatic interactions in aqueous solutions may complicate such assemblies, they provide additional parameters through which to control self-assembly. Here, with DNA-capped gold nanoparticles and through the variation of the ionic strength in aqueous solutions, we explored the influence of electrostatic interactions on the adsorption of negatively charged nanoparticles on a positively charged surface. Specifically, we studied the kinetics of nanoparticle adsorption from solution using the quartz crystal microbalance with dissipation (QCM-D). We also characterized the structure of the adsorbed monolayers employing a combination of grazing incidence small-angle X-ray scattering (GISAXS) and scanning electron microscopy. We discovered that adsorption kinetics and monolayer structure were under the control of the DNA ligand length, solution ionic strength, and salt species. We also precisely fit the kinetics to a modified Langmuir model, which converged to the simple Langmuir model at high ionic strengths of magnesium chloride. We demonstrated that increasing the ionic strength and decreasing the DNA ligand lengths increased the surface coverage while decreasing the nanoparticle-nanoparticle spacing. The DNA-capped nanoparticle system reported here provides a readily applicable platform for controlling nanoparticle self-assembly in aqueous solution. Finally, we employ this tunability to create a system with a tunable plasmonic response. Our kinetics studies of the assembly process and further characterizations undertaken will facilitate the construction of nanoparticle arrays with precise structure, and such control will aid in the design of future plasmonic and optoelectronic devices. ",0
6480,29782196,"A Randomized Clinical Trial of Topical Diclofenac, Fluorometholone, and Dexamethasone for Control of Inflammation After Strabismus Surgery","To evaluate the comparative effects and safety of topical diclofenac sodium, fluorometholone, and dexamethasone for controlling inflammation after routine strabismus surgery. This was a randomized clinical trial. Ninety-nine patients admitted for surgery to treat intermittent exotropia were randomly assigned to receive 1 of 3 postoperative eye drops between January 2015 and February 2016. The primary efficacy outcomes were pain and conjunctival injection. Pain score from 0 to 10 was evaluated in each patient at postoperative days 1, 2, 3, and 5, in addition to weeks 1, 2, and 4. Conjunctival injection was graded from 1 to 4 at postoperative weeks 1, 2, and 4. We also evaluated intraocular pressure (IOP), discomfort attributed to the drops, and development of any other side effects. Conjunctival injection grade was the lowest in the diclofenac sodium group at postoperative weeks 1 and 2 (P < 0.001 and P = 0.03). There was no significant difference in pain score among the 3 groups. Mean IOP was the highest in the dexamethasone group at postoperative weeks 1, 2, and 4 (P < 0.001, P < 0.001, and P = 0.02). Significant IOP elevation (≥10 mmHg relative to preoperative IOP) was observed in 6 patients in the dexamethasone group. There was no difference in discomfort upon administration of the drops among the 3 groups, and no other adverse events developed. Diclofenac sodium was more effective against conjunctival injection than the 2 topical corticosteroids tested, but had a similar effect on postoperative pain as them. IOP elevation developed only in the dexamethasone group. ",0
6481,29782209,Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology,"Purpose To provide guidance regarding the practical assessment and management of vulnerabilities in older patients undergoing chemotherapy. Methods An Expert Panel was convened to develop clinical practice guideline recommendations based on a systematic review of the medical literature. Results A total of 68 studies met eligibility criteria and form the evidentiary basis for the recommendations. Recommendations In patients ≥ 65 years receiving chemotherapy, geriatric assessment (GA) should be used to identify vulnerabilities that are not routinely captured in oncology assessments. Evidence supports, at a minimum, assessment of function, comorbidity, falls, depression, cognition, and nutrition. The Panel recommends instrumental activities of daily living to assess for function, a thorough history or validated tool to assess comorbidity, a single question for falls, the Geriatric Depression Scale to screen for depression, the Mini-Cog or the Blessed Orientation-Memory-Concentration test to screen for cognitive impairment, and an assessment of unintentional weight loss to evaluate nutrition. Either the CARG (Cancer and Aging Research Group) or CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) tools are recommended to obtain estimates of chemotherapy toxicity risk; the Geriatric-8 or Vulnerable Elders Survey-13 can help to predict mortality. Clinicians should use a validated tool listed at ePrognosis to estimate noncancer-based life expectancy ≥ 4 years. GA results should be applied to develop an integrated and individualized plan that informs cancer management and to identify nononcologic problems amenable to intervention. Collaborating with caregivers is essential to implementing GA-guided interventions. The Panel suggests that clinicians take into account GA results when recommending chemotherapy and that the information be provided to patients and caregivers to guide treatment decision making. Clinicians should implement targeted, GA-guided interventions to manage nononcologic problems. Additional information is available at www.asco.org/supportive-care-guidelines . ",0
6482,29782440,Management of Simultaneous Patellar Tendon and Anterior Cruciate Ligament Ruptures-A Systematic Review of Available Literature,"Combined rupture of the anterior cruciate ligament (ACL) and patellar tendon (PT) is a rare injury pattern. Currently, little evidence exists to help guide management decisions for these patients. A systematic literature search was conducted using PubMed (MEDLINE) and Scopus (EMBASE and MEDLINE) for all articles reporting on combined rupture of the ACL and PT. The characteristic injury mechanisms, common presentation findings, and outcomes of simultaneous and staged treatment strategies were determined to provide guidance for the management of this uncommon injury pattern. An additional case report from our institution is also reported. Overall, 17 studies met the inclusion criteria and were included in our qualitative review. The mean age at injury was 30 years (range, 15-50 years). A high-energy injury with a rapid deceleration event through a flexed knee on a fixed foot is commonly described as the mechanism of injury. Anterior cruciate ligament rupture was missed on initial clinical examination in 24.1% compared with 17.2% for PT rupture. Injuries to the medial collateral ligament and menisci occured in 65.5% of cases. Outcome scores were reported in 41.4% (12/22) of patients undergoing staged or simultaneous repair. The Lysholm score postoperatively was 96 ± 3.3 for the staged group compared with 85.3 ± 18.6 for simultaneous repair. There were no clear differences between range of motion, time to return to sport, and complication rates between the groups. A high index of suspicion is required to detect concomitant ACL injuries when assessing high-energy PT ruptures. Simultaneous or staged protocols to address both injuries are safe and effective management strategies for this rare combined injury pattern. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. ",0
6483,29782517,Importance of software version for measurement of arterial stiffness: Arteriograph as an example,"Current guidelines recommend the measurement of arterial stiffness in terms of aortic pulse wave velocity (PWV) as an important cardio-vascular risk marker. Both aortic PWV and the aortic augmentation index (AIxao) can be measured using different techniques, e.g., the Arteriograph and SphygmoCor. A new version of the software for the Arteriograph (v. 3.0.0.1, TensioMed, Budapest, Hungary; Arteriograph II) is now available. We wanted to determine whether this improved software differs from the previous version (Arteriograph v. 1.9.9.12; Arteriograph I). We compared the estimated aortic PWV (ePWVao) and AIxao measured with both versions of Arteriograph software and analysed the agreement of these values with those measured by SphygmoCor (v. 7.01, AtCor Medical, Sydney, Australia). Eighty-seven subjects without known cardio-vascular disease (23 men and 64 women) aged 54.2 ± 8.7 years (mean ± standard deviation; range 33-68 years) were included in the study. Estimated PWVao and AIxao were measured by both Arteriograph and SphygmoCor. We compared Arteriograph I and Arteriograph II with each other and with SphygmoCor. Estimated PWVao measured by Arteriograph II was lower than that measured by Arteriograph I, while the AIxao was higher. Divergence in ePWVao values was especially noted above 9 m/s. Estimated PWVao measured by Arteriograph II (7.2 m/s, 6.6-8.0 [median, 25th-75th percentile]) did not differ from that measured by SphygmoCor (7.1 m/s, 6.7-7.9 [median, 25th-75th percentile]). However, the AIao measured by Arteriograph II was significantly higher (P < 0.001). Regularly upgraded software versions resulting from continuous technical development are needed for quality improvement of methods. However, the changes in software, even if the basic patented operational algorithm has not changed, may influence the measured values as shown in the present study. Therefore, attention should be paid to the software version of the method used when comparing arterial stiffness results in clinical settings or when performing scientific studies. ",0
6484,29782595,The clinical value of xSPECT/CT Bone versus SPECT/CT. A prospective comparison of 200 scans,"To prospectively evaluate the clinical utility of xSPECT/CT Bone, a new reconstruction algorithm for single photon emission tomography (SPECT), and compare it with standard SPECT/CT reconstruction. Sequential reporting of SPECT/CT followed by xSPECT/CT images in 200 sequential cases commencing August 2015. Differences between the initial SPECT/CT and the final report (after xSPECT/CT reconstruction) were documented and analysed. 12-18 months after the initial study follow-up, clinical data was sought from a subset of cases in which xSPECT/CT changed the primary diagnosis and imaging correlation undertaken in all patients who subsequently had MRI or CT scans of the same region. A majority of the 200 cases were related to assessment of musculoskeletal complaints. The final (scan) diagnosis was changed after reviewing the xSPECT/CT images in 40 (20%) of cases. The reporting physician (Iain Duncan) assessed that the xSPECT/CT had provided more diagnostic information in 71% of cases. A total of 470 additional lesions were found, equivalent to 2.4 lesions per case. In 33 cases of imaging follow-up there was a high degree of correlation with bone scan findings and xSPECT correlated better than SPECT in regard to detailed findings. In only 15/40 cases of diagnostic change could the outcome be verified and in 12/15 the xSPECT/CT revised diagnosis was confirmed. In this observational evaluation xSPECT/CT Bone reconstruction offers identifiable imaging improvements over standard SPECT/CT reconstruction algorithms. xSPECT/CT Bone provides an improvement in diagnostic confidence and identifies a greater number of lesions. ",0
6485,29783965,"Unmet basic needs negatively affect health-related quality of life in people aging with HIV: results from the Positive Spaces, Healthy Places study","Basic needs (e.g., food security and stable housing) are important determinants of health and well-being, yet their impact on health-related quality of life (HRQoL) in the context of HIV and aging has not been systematically investigated. Multiple linear regression models examined the relationship between unmet basic needs, and physical and mental HRQoL by age strata (20-34, 35-49 and 50+) in a cross-sectional sample of 496 people living with HIV in Ontario, Canada. An overwhelming majority of participants (87%) reported unmet needs related to food, clothing or housing. The prevalence of unmet basic needs in the two older groups appeared to be lower than among younger participants, but the difference did not reach statistical significance. The presence of unmet basic needs predicted substantially lower mean physical health and mental health summary scores in the two oldest groups. Notably, age moderated the influence of unmet basic needs on HRQoL. The availability and accessibility of food security, appropriate clothing and stable housing for people living with HIV who are aging need to become a higher priority for program planners and decision makers. ",0
6486,29783985,The doses of plasmid backbone plays a major role in determining the HBV clearance in hydrodynamic injection mouse model,"Hepatitis B virus (HBV) chronically infects approximately 350 million people worldwide, causing a major risk of liver disease and hepatocellular carcinoma (HCC). Many mouse models have been tried to establish HBV infection through injection with various HBV-containing plasmids. However, it is not well understood that different plasmids, all of which contain the similar HBV genome, even the same plasmids with different dose, results in opposite immune responses toward HBV. In this study, we investigated the role of HBV-containing plasmid backbones and the HBcAg in determining the HBV persistence. C57BL/6 mice were injected hydrodynamically with 6 μg or 20 μg of WT pAAV/HBV1.2 plasmid, e/core-null pAAV/HBV1.2 plasmid, or none-HBV genome pAAV/control plasmid. Serum levels of HBV-related markers were measured by quantitative immunoradiometric assay (IRMA). Liver HBcAg expression was detected by immunohistochemical staining. The mRNA levels of cytokines and Th1-related immune factors were quantified by qRT-PCR. All mice injected with 6 μg of the pAAV/HBV1.2 plasmid shows HBsAg positive at week 6 after hydrodynamic injection (AHI) as previously investigated. However, the mice injected with 20 μg pAAV/HBV1.2 or 6μgpAAV/HBV1.2 plus 14μgpAAV/control plasmid results in HBV clearance within 4 weeks AHI, indicating the anti-HBV activity is induced by 20 μg plasmid DNA, but not by the inserted viral genome. This anti-HBV activity is independent of HBcAg and Toll like receptor (TLR) signaling pathway, since the lack of HBcAg in pAAV/HBV1.2 plasmid or stimulation with TLRs agonists does not influence the kinetics of serum HBsAg in mice. The mRNA levels of t-bet and cxcr3 were dramatically up-regulated in the liver of the mice injected with 20 μg plasmid DNA. Our studies demonstrate that plasmid backbones are responsible for modulating immune responses to determine HBV persistence or clearance in our HBV mouse model by hydrodynamic injection of HBV-containing plasmid, and Th1 cells play key roles on HBV clearance. ",0
6487,29783997,Graft protective effect and induction of CD4,"Thrombomodulin (TM) is a promising therapeutic natural anti-coagulant, which exerts the effects to control disseminated intravascular coagulation. However, little is known whether TM on micro-vessels could play an important role in the regulation of intimal hyperplasia. We investigated the vessel-protective effect of TM in the survival of fully major histocompatibility complex (MHC)-mismatched murine cardiac allograft transplantation. CBA recipients transplanted with a C57BL/6 heart received intraperitoneal administration of normal saline or 0.2, 2.0, and 20.0 μg/day of TM for 7 days (n = 5, 7, 11, and 11, respectively). Immunohistochemical and fluorescent staining studies were performed to determine whether CD4 Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 7 days). CBA recipients exposed with the above doses had significantly prolonged allograft survival (MSTs, 17, 24 and 50 days, respectively). Morphometric assessment showed that intimal hyperplasia was clearly suppressed in the left and right coronary arteries or allografts from TM-exposed recipients 2 and 4 weeks. Immunohistochemical studies at 2 weeks showed more CD4 TM may prolong the survival of fully MHC-mismatched cardiac allografts through suppressing intimal hyperplasia and inducing the accumulation of regulatory CD4 ",0
6488,29784192,Differential Gene Expression in Prostate Tissue According to Ejaculation Frequency,"In a prospective study of 31 925 men with 18 yr of follow-up, higher ejaculation frequency (EF) throughout adulthood was associated with lower rates of prostate cancer. To further explore this association, we evaluated whole transcriptome gene expression in the prostate tissue from study participants who developed prostate cancer between 1992 and 2004 (n=157 tumor tissue, n=85 adjacent normal). We tested for trends in gene expression according to the level of EF as self-reported in 1992 for ages 20-29 yr, 40-49 yr, and the year prior to the questionnaire, 1991. There were no associations between EF and gene expression in areas of tumor after accounting for multiple testing. In contrast, in the adjacent normal tissue, 409 genes and six pathways were differentially expressed at a false discovery rate ≤0.2 across categories of EF in 1991. These results suggest that ejaculation affects the expression of genes in the normal prostate tissue. The identified genes and pathways provide potential biological links between EF and prostate tumorigenesis. To explore previous findings that men who ejaculate more frequently have lower risk of prostate cancer, we evaluated molecular alterations in the prostate tissue according to each man's frequency of ejaculation prior to diagnosis. We identified biological processes that could link ejaculation frequency and prostate cancer. ",0
6489,29784239,Paraneoplastic syndromes in ophthalmology,"Paraneoplastic syndromes involving the visual system are a heterogeneous group of disorders occurring in the setting of systemic malignancy. They are unrelated to local tumor invasion or metastasis and unexplained by nutritional, metabolic, infectious or iatrogenic causes. The presence of antibodies may aid in the diagnosis of a paraneoplastic syndrome, although this is not an absolute requirement. Chorioretinal involvement is seen in CAR (cancer-associated retinopathy) syndrome, MAR (melanoma-associated retinopathy) syndrome, paraneoplastic vitelliform maculopathy, and bilateral diffuse uveal melanocytic proliferation. Paraneoplastic neurological syndromes with ophthalmologic involvement include optic neuropathy, opsoclonus-myoclonus, Eaton-Lambert myasthenic syndrome, paraneoplastic cerebellar degeneration (PCD) and rhombencephalitis. ",0
6490,29784260,Severe Obesity and Sleep-Disordered Breathing as Risk Factors for Emergence Agitation in Pediatric Ambulatory Surgery,"Sleep-disordered breathing (SDB) may be a critical risk factor for emergence agitation (EA). We hypothesized that SDB diagnosis is a predictor of EA in children after general anesthesia for ambulatory surgery. Prospective, observational, cohort study. Children aged 4 to 17 years were assessed for the occurrence of EA. Differences in probability of EA were assessed using multivariable logistic regression analyses. Of 1,076 children, 66 (6.1%) had EA. Compared with those without EA, children with EA were younger (P < .001), more likely to have had mask induction (P < .001) and a preoperative diagnosis of SDB (P = .008). On multivariable analysis, SDB, severe obesity, decreasing age in years, increasing first arousal pain score, and intraoperative use of sevoflurane were independently associated with EA. SDB and severe obesity may be critical independent predictors of EA in children. Mechanisms underlying these observations deserve further elucidation. ",0
6491,29784600,Breast Reconstruction After Mastectomy: A Survey of Surgeons' and Patients' Perceptions,"""Breast reconstruction after mastectomy is important in breast cancer care. A cross-sectional study was designed to assess surgeons' and patients' perceptions toward breast reconstruction. Questionnaires were distributed to general and breast surgeons in East Coast Malaysian hospitals and Hospital Kuala Lumpur and to postmastectomy patients with and without breast reconstruction at the Hospital Universiti Sains Malaysia and Hospital Raja Perempuan Zainab II. The response rates were 82.5% for the surgeons (n = 33), 95.4% for the patients with reconstruction (n = 63), and 95.5% for the patients without reconstruction (n = 278). The median surgeon age and experience was 42 and 6 years, respectively. Each surgeon saw an average of 20 new breast cancer cases annually. Most surgeons (86.7%) discussed reconstruction options with their patients but had only referred an average of 4 patients for reconstruction during a 3-year period. Surgeons' concerns regarding the qualitative outcome increased the likelihood of a breast reconstruction discussion (β = 4.833; P = .044). The women who underwent breast reconstruction were younger (mean age, 42 vs. 50 years), were more often working (69.4% vs. 42.2%), and more often had previous awareness of the option (90.3% vs. 44.3%). The most common reasons for undergoing breast reconstruction were """"to feel more balanced"""" (92.1%) and """"surgeon's strong recommendation"""" (92.1%). Previous knowledge of breast reconstruction increased the likelihood of reconstruction (odds ratio, 5.805; P = .026). Although 70% of surgeons thought that patients would not be interested in reconstruction, only 37.9% of patients with previous awareness reported having no interest. The low reconstruction rate (20.6%) can be attributed to the low referral rate. Patients' likelihood to undergo reconstruction with their surgeon's recommendation and with previous awareness were reflective of the surgeons' strong influence on their patients. Thus, clarification of surgeons' hypothetical criticisms could conceivably increase the reconstructive surgery rate. """,0
6492,29785515,Prostate-specific antigen flare induced by ,"Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer, but its impact during radium-223 dichloride ( We conducted a retrospective study of 168 patients with mCRPC (median age 69; median PSA 29.7) receiving  Immediate PSA decline was observed in 49 patients (29.2%), whereas no PSA response was observed in 59 patients (35.1%). PSA flare (defined as rise after the first cycle followed by decrease below the baseline) was observed in 20 patients (11.9%) and PSA flare followed by a decrease from peak but not below baseline was observed in 40 (23.8%). The first flare subgroup had a median PFS and OS of 20.8 and 23.9 months, respectively. These outcomes were not significantly different from patients with immediate PSA decrease, but were significantly better than in patients with persistent PSA elevation (3.1 months for PFS and 11.5 months for OS, p < 0.001). Moreover, the PSA flare group showed an alkaline phosphatase (ALP) decrease significantly greater than non-responders (p = 0.003). Metabolic  This report suggests that a flare does not necessarily indicate lack of response to  ",0
6493,29785674,Assembly of a complete genome sequence for Gemmata obscuriglobus reveals a novel prokaryotic rRNA operon gene architecture,"Gemmata obscuriglobus is a Gram-negative bacterium with several intriguing biological features. Here, we present a complete, de novo whole genome assembly for G. obscuriglobus which consists of a single, circular 9 Mb chromosome, with no plasmids detected. The genome was annotated using the NCBI Prokaryotic Genome Annotation pipeline to generate common gene annotations. Analysis of the rRNA genes revealed three interesting features for a bacterium. First, linked G. obscuriglobus rrn operons have a unique gene order, 23S-5S-16S, compared to typical prokaryotic rrn operons (16S-23S-5S). Second, G. obscuriglobus rrn operons can either be linked or unlinked (a 16S gene is in a separate genomic location from a 23S and 5S gene pair). Third, all of the 23S genes (5 in total) have unique polymorphisms. Genome analysis of a different Gemmata species (SH-PL17), revealed a similar 23S-5S-16S gene order in all of its linked rrn operons and the presence of an unlinked operon. Together, our findings show that unique and rare features in Gemmata rrn operons among prokaryotes provide a means to better define the evolutionary relatedness of Gemmata species and the divergence time for different Gemmata species. Additionally, these rrn operon differences provide important insights into the rrn operon architecture of common ancestors of the planctomycetes. ",0
6494,29785750,Cellulose membrane modified with polypyrrole as an extraction device for the determination of emerging contaminants in river water with gas chromatography-mass spectrometry,"In this study, a simple, efficient, and reusable device based on cellulose membranes modified with polypyrrole was developed to extract 14 emerging contaminants from aqueous matrices. For chemical polymerization, a low-cost cellulose membrane was immersed in 0.1 mol/L pyrrole and 0.5 mol/L ammonium persulfate for 40 min in an ice/water bath. The cellulose membranes modified with polypyrrole were accommodated in a polycarbonate holder suitable for solid-phase extraction disks. Solid-phase extraction parameters that affect extraction efficiency, such as sample volume, pH, flow rate, and desorption were optimized. Subsequently, determination of target compounds was performed by gas chromatography with mass spectrometry. The linear range for analytes ranged from 0.05 to 500 μg/L, with coefficients of determination above 0.990. The limits of quantification varied between 0.05 and 10 μg/L, with relative standard deviations lower than 17%. The performance of the proposed cellulose membranes modified with polypyrrole device for real samples was evaluated after extraction of emerging contaminants from a river water sample from the city of Curitiba, Brazil. Bisphenol A (6.39 μg/L), caffeine (17.83 μg/L), and paracetamol (19.28 μg/L) were found in these samples. ",0
6495,29785878,Five-Year Outcomes with PCI Guided by Fractional Flow Reserve,"BACKGROUND: We hypothesized that fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) would be superior to medical therapy as initial treatment in patients with stable coronary artery disease. METHODS: Among 1220 patients with angiographically significant stenoses, those in whom at least one stenosis was hemodynamically significant (FFR, ?0.80) were randomly assigned to FFR-guided PCI plus medical therapy or to medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy and were entered into a registry. The primary end point was a composite of death, myocardial infarction, or urgent revascularization. RESULTS: A total of 888 patients underwent randomization (447 patients in the PCI group and 441 in the medical-therapy group). At 5 years, the rate of the primary end point was lower in the PCI group than in the medical-therapy group (13.9% vs. 27.0%; hazard ratio, 0.46; 95% confidence interval [CI], 0.34 to 0.63; P<0.001). The difference was driven by urgent revascularizations, which occurred in 6.3% of the patients in the PCI group as compared with 21.1% of those in the medical-therapy group (hazard ratio, 0.27; 95% CI, 0.18 to 0.41). There were no significant differences between the PCI group and the medical-therapy group in the rates of death (5.1% and 5.2%, respectively; hazard ratio, 0.98; 95% CI, 0.55 to 1.75) or myocardial infarction (8.1% and 12.0%; hazard ratio, 0.66; 95% CI, 0.43 to 1.00). There was no significant difference in the rate of the primary end point between the PCI group and the registry cohort (13.9% and 15.7%, respectively; hazard ratio, 0.88; 95% CI, 0.55 to 1.39). Relief from angina was more pronounced after PCI than after medical therapy. CONCLUSIONS: In patients with stable coronary artery disease, an initial FFR-guided PCI strategy was associated with a significantly lower rate of the primary composite end point of death, myocardial infarction, or urgent revascularization at 5 years than medical therapy alone. Patients without hemodynamically significant stenoses had a favorable long-term outcome with medical therapy alone. (Funded by St. Jude Medical and others; FAME 2 ClinicalTrials.gov number, NCT01132495 .).",0
6496,29785879,"Blood and hair mercury concentrations among Cree First Nations of Eeyou Istchee (Quebec, Canada): time trends, prenatal exposure and links to local fish consumption","To describe exposure to methylmercury among Cree, focusing on women of childbearing age, we used data from 2 studies. Multiple regression was employed to examine associations between blood and hair mercury concentrations and consumption of locally harvested fish. Approximately 9.9% of non-pregnant women aged 15-44 y and 3.9% of pregnant women required follow-up according to Health Canada's blood mercury guidance value of 40 nmol/L. 8% of hair mercury observations in the non-pregnant women and 2.5% among pregnant women exceeded the equivalent threshold of 10 nmol/g. The geometric mean blood mercury concentration was 12.7 nmol/L in 1,429 persons aged 8 and over, and 17.7 nmol/L in adults aged 18 and older. The proportion of hair mercury concentrations greater than 12.5 nmol/g decreased in all age-sex groups when comparing the 2002-2009 data to published values for 1993-1994. Among women of childbearing age, local fish consumption was associated with increased blood and hair mercury concentrations. While over 90% of women of childbearing age in this population have acceptable levels of mercury, ongoing intake of mercury suggests that their consumption of fish with known high mercury content be minimised. Reducing consumption of fish known to be high in mercury content needs to be balanced with promoting ongoing connection to Cree culture and land-based activities that are also important determinants of health. ",0
6497,29785884,Morphological changes and myocardial function assessed by traditional and novel echocardiographic methods in preadolescent athlete's heart,"Background Athlete's heart is a term used to describe the morphological and functional changes in the hearts of athletes. Recent studies suggest that these changes may occur even in preadolescent athletes. This study aims to improve our understanding of the changes occurring in the preadolescent athlete's heart. Design and methods Cardiac morphology and function in 76 preadolescent cross-country skiers (aged 12.1 ± 0.2 years) were compared with 25 age-matched non-competing preadolescents. Echocardiography was performed in all subjects, including 2D speckle-tracking strain echocardiography and 3D echocardiography. All participants underwent cardiopulmonary exercise testing to assess oxygen uptake and exercise capacity. Results Athletes had greater indexed VO ",0
6498,29785907,The fatty acid composition of Estonian and Latvian retail milk; implications for human nutrition compared with a designer milk,"The study reported in this Research Communication compared retail milks' FA profiles from two neighbouring countries, estimated the potential contributions of these milks and a designer milk (achieved by changing the diet of the dairy cow) to the recommended human dietary intake of FA, and predicted (based on the milk FA profile) methane emission from dairy cows. Retail milks in Estonia and Latvia were purchased from supermarkets monthly for one year. To compare the FA composition of retail milk with designer milk with an increased PUFA content, the bulk milk FA profile from a separate field trial was used. Milk FA concentrations of the two neighbouring countries were affected by state, season and their interaction, while the main influence on all these factors were different feeding practices (grazing availability, forage to concentrate ratio and legume-rich silages vs. maize silages). Three cups (600 mL; fat content 2·5 g/100 g) of Estonian, or Latvian retail milk or designer milk per day contributed more to the recommended intakes of saturated FA (SFA) (42·5, 42·7, 38·7%, respectively) than other FA. Compared to the retail milks, α-linolenic acid estimated intake was almost doubled by designer milk consumption (19·7% of adequate intake) without influencing summed intakes of SFA and trans FA. There were state and seasonal differences in the predicted methane outputs of dairy cattle based on retail milk FA. Although the FA profiles of retail milks in the two neighbouring countries were affected by state and season, an appreciable increase in human dietary intakes of beneficial fatty acids from milk, and concomitant reduction in methane emissions from dairy cows, can be achieved only by targeted feeding. ",0
6499,29786020,"Use of international foundations of medicine clinical sciences examination to evaluate students' performance in the local examination at the University of Sharjah, United Arab Emirates","Several medical schools around the world are moving away from isolated, locally developed in-house assessments to the introduction of external examinations into their curriculum. Although the objective varies, it is typically done to evaluate, audit, and compare students' performance to international standards. Similarly, the International Foundations of Medicine-Clinical Sciences Examination (IFOM-CSE) was introduced in the College of Medicine at the University of Sharjah as an external assessment criterion in addition to the existing in-house assessments. The aim of this study was to compare the student performance in this newly introduced IFOM-CSE examination and the existing in-house final examination in the college. The scores of three consecutive final-year undergraduate medical student batches (2013-2015) who took both the IFOM-CSE and the existing in-house final examination were analyzed. Pearson correlation and one-way analysis of variance test were conducted using SPSS 22. The students' scores in the IFOM-CSE and in the final examination prepared locally were highly correlated with Pearson correlation coefficients of 0.787 for batch 2013, 0.827 for batch 2014, and 0.830 for batch 2015 (P < 0.0005). Interestingly, while the mean scores of the IFOM-CSE among the three batches in the years 2013, 2014, and 2015 (475, 492, and 513, respectively) showed improvement with borderline significance (F[2226] = 2.73, P = 0.067), local examination scores showed a significant improvement during the study period (F[2277] = 52.87, P < 0.0005). The findings of this study showed that students' scores in the local examination were consistently correlated with their scores in the IFOM-CSE over all the three batches. Thus, introduction of external examination can be an important evaluation tool to a comprehensive internal assessment system providing evidence of external validity. ",0
6500,29786049,Lipoxin A4 Ameliorates Lipopolysaccharide-Induced A549 Cell Injury through Upregulation of N-myc Downstream-Regulated Gene-1,"Lipoxin A4 (LXA4) can alleviate lipopolysaccharide (LPS)-induced acute lung injury (ALI) and acute respiratory distress syndrome through promoting epithelial sodium channel (ENaC) expression in lung epithelial cells. However, how LXA4 promote ENaC expression is still largely elusive. The present study aimed to explore genes and signaling pathway involved in regulating ENaC expression induced by LXA4. A549 cells were incubated with LPS and LXA4, or in combination, and analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) of ENaC-α/γ. Candidate genes affected by LXA4 were explored by transcriptome sequencing of A549 cells. The critical candidate gene was validated by qRT-PCR and Western blot analysis of A549 cells treated with LPS and LXA4 at different concentrations and time intervals. LXA4 receptor (ALX) inhibitor BOC-2 was used to test induction of candidate gene by LXA4. Candidate gene siRNA was adopted to analyze its influence on A549 viability and ENaC-α expression. Phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was utilized to probe whether the PI3K signaling pathway was involved in LXA4 induction of candidate gene expression. The A549 cell models of ALI were constructed and subjected to transcriptome sequencing. Among candidate genes, N-myc downstream-regulated gene-1 (NDRG1) was validated by real-time-PCR and Western blot. NDRG1 mRNA was elevated in a dose-dependent manner of LXA4, whereas BOC-2 antagonized NDRG1 expression induced by LXA4. NDRG1 siRNA suppressed viability of LPS-treated A549 cells (treatment vs. control, 0.605 ± 0.063 vs. 0.878 ± 0.083, P = 0.040) and ENaC-α expression (treatment vs. control, 0.458 ± 0.038 vs. 0.711 ± 0.035, P = 0.008). LY294002 inhibited NDRG1 (treatment vs. control, 0.459 ± 0.023 vs. 0.726 ± 0.020, P = 0.001) and ENaC-α (treatment vs. control, 0.236 ± 0.021 vs. 0.814 ± 0.025, P < 0.001) expressions and serum- and glucocorticoid-inducible kinase 1 phosphorylation (treatment vs. control, 0.442 ± 0.024 vs. 1.046 ± 0.082, P = 0.002), indicating the PI3K signaling pathway was involved in regulating NDRG1 expression induced by LXA4. Our research uncovered a critical role of NDRG1 in LXA4 alleviation of LPS-induced A549 cell injury through mediating PI3K signaling to restore ENaC expression. ",0
6501,29786151,Time dependent loss of trabecular bone in human tibial plateau fractures,"We investigated if time between injury and surgery affects cancellous bone properties in patients suffering tibial plateau fractures (TPF), in terms of structural integrity and gene expression controlling bone loss. A cohort of 29 TPF, operated 1-17 days post-injury, had biopsies from the fracture and an equivalent contralateral limb site, at surgery. Samples were assessed using micro-computed tomography and real-time RT-PCR analysis for the expression of genes known to be involved in bone remodeling and fracture healing. Significant decreases in the injured vs control side were observed for bone volume fraction (BV/TV, -13.5 ± 6.0%, p = 0.011), trabecular number (Tb.N, -10.5 ± 5.9%, p = 0.041) and trabecular thickness (Tb.Th, -4.6 ± 2.5%, p = 0.033). Changes in these parameters were more evident in patients operated 5-17 days post-injury, compared to those operated in the first 4 days post-injury. A significant negative association was found between Tb.Th (r = -0.54, p < 0.01) and BV/TV (r = -0.39, p < 0.05) in relation to time post-injury in the injured limb. Both BV/TV and Tb.Th were negatively associated with expression of key molecular markers of bone resorption, CTSK, ACP5, and the ratio of RANKL:OPG mRNA. These structure/gene expression relationships did not exist in the contralateral tibial plateau of these patients. This study demonstrated that there is a significant early time-dependent bone loss in the proximal tibia after TPF. This bone loss was significantly associated with altered expression of genes typically involved in the process of osteoclastic bone resorption but possibly also bone resorption by osteocytes. The mechanism of early bone loss in such fractures should be a subject of further investigation. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2865-2875, 2018. ",0
6502,29786648,Utilizing Optimized Tools to Investigate PTM Crosstalk: Identifying Potential PTM Crosstalk of Acetylated Mitochondrial Proteins,"Post-translational modification (PTM) crosstalk is recognized as a major cell-regulatory mechanism, and studies of several proteins have validated the premise that PTMs work in concert. Previous work by our group investigated the potential PTM crosstalk on proteins in the EGFR-Ras-c-Fos axis by utilizing a comprehensive set of PTM reagents termed Signal-Seeker toolkits. In this study, these tools were used to investigate the potential PTM crosstalk that occurs in acetylated mitochondrial proteins in response to a mitochondrial stress-inducing agent hydrogen peroxide (H₂O₂). Mitochondrial protein acetylation has been shown to participate in PTM crosstalk as exemplified by the regulation of the pyruvate dehydrogenase complex via kinase, phosphatase, acetyltransferase, and deacetylase activities. Changes in the acetylated state of mitochondrial proteins were investigated, in response to H₂O₂, using a novel anti acetyl lysine (Ac-K) antibody. Signal-Seeker PTM detection tools were used to validate the acetylation state of ten mitochondrial targets, as well as their endogenous acetylation state in response to H₂O₂. Importantly, the endogenous acetylation, ubiquitination, SUMOylation 2/3, and tyrosine phosphorylation state of four target mitochondrial proteins were also investigated with the toolkit. Each of the four proteins had unique PTM profiles, but diverging acetylation and ubiquitin or SUMO 2/3 signals appeared to be a common theme. This proof-of-concept study identifies the Signal-Seeker toolkits as a useful tool to investigate potential PTM crosstalk. ",0
6503,29786793,A Method for Prostate and Breast Cancer Cell Spheroid Cultures Using Gelatin Methacryloyl-Based Hydrogels,"Modern tissue engineering technologies have delivered tools to recreate a cell's naturally occurring niche in vitro and to investigate normal and pathological cell-cell and cell-niche interactions. Hydrogel biomaterials mimic crucial properties of native extracellular matrices, including mechanical support, cell adhesion sites and proteolytic degradability. As such, they are applied as 3D cell culture platforms to replicate tissue-like architectures observed in vivo, allowing physiologically relevant cell behaviors. Here we review bioengineered 3D approaches used for prostate and breast cancer. Furthermore, we describe the synthesis and use of gelatin methacryloyl-based hydrogels as in vitro 3D cancer model. This platform is used to engineer the microenvironments for prostate and breast cancer cells to study processes regulating spheroid formation, cell functions and responses to therapeutic compounds. Collectively, these bioengineered 3D approaches provide cell biologists with innovative pre-clinical tools that integrate the complexity of the disease seen in patients to advance our knowledge of cancer cell physiology and the contribution of a tumor's surrounding milieu. ",0
6504,29786967,Developmental Chromatin Restriction of Pro-Growth Gene Networks Acts as an Epigenetic Barrier to Axon Regeneration in Cortical Neurons,"Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018. ",0
6505,29786973,Amniotic fluid lactic acid and matrix metalloproteinase-8 levels at the time of fetal surgery for a spine defect: association with subsequent preterm prelabour rupture of membranes,"In utero fetal surgery to correct incomplete closure of the spinal cord lessens the extent of permanent damage but is associated with preterm prelabour rupture of membranes (PPROM). We determined whether compounds in amniotic fluid collected at the time of surgery predicted subsequent development of PPROM. Prospective study. Hospitals in Sao Paulo, Brazil. Twenty-four consecutive pregnant women at 24-26 weeks of gestation seen between February and October 2017 with a singleton pregnancy underwent in utero surgery to correct an open spinal defect in their fetus. Amniotic fluid was tested for lactic acid, matrix metalloproteinase 2 (MMP-2), MMP-8, MMP-9 and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. Clinical data were collected after completion of all laboratory studies. Amniotic fluid concentration of compounds in women with or without PPROM. Preterm prelabour rupture of membranes occurred in seven (29.2%) women. There were no differences in maternal age, gravidity, parity, race, history of caesarean sections or fetal gender between women with or without PPROM. Length of surgery, days of wound healing and length of hospital stay were also indistinguishable. The median concentrations of MMP-8 (1.7 versus 0.6 ng/ml; P = 0.0041) and lactic acid (7.1 versus 5.9 mm; P = 0.0181) were higher in women with PPROM. The amniotic fluid MMP-8 level was also negatively correlated with gestational age at delivery (Spearman r = -0.4217, P = 0.0319). Differences in susceptibility to develop PPROM are present before fetal surgery. An increase in anaerobic glycolysis, evidenced by the intra-amniotic lactic acid level, may enhance MMP-8 production and weaken maternal and fetal membranes. Matrix metalloproteinase-8 and lactic acid in amniotic fluid predict preterm prelabour rupture of membranes. ",0
6506,29786990,Methylprednisolone sodium succinate reduces spinal cord swelling but does not affect recovery of dogs with surgically treated thoracolumbar intervertebral disk herniation,"The effect of methylprednisolone sodium succinate (MPSS) therapy was studied in 50 dogs with surgically treated Hansen type I thoracolumbar intervertebral disk herniation (TL-IVDH). Administration of MPSS significantly reduced the swelling of the spinal cord. The sensitivity of localization of disk extrusion using myelography in the MPSS group was 92.3%, and in the non-administration group was 83.3%. No significant difference in recovery rate or length of recovery time was found between the two groups. Administration of MPSS reduced spinal cord swelling, but has no effect on recovery in dogs after surgery for TL-IVDH. ",0
6507,29787236,Investigation of the Viability of Cells upon Co-Exposure to Gold and Iron Oxide Nanoparticles,"Cell lines were exposed either to mixtures of gold and iron oxide nanoparticles, or to a hybrid nanoparticle with gold and iron oxide domain. In the case of simultaneous exposure to gold and iron oxide nanoparticles, enhanced toxicity as compared to the exposure to only one type of nanoparticles was observed. An indication was found that, at equivalent concentrations, the hybrid nanoparticles may slightly reduce cell viability more strongly than mixtures of both nanoparticle types. The results suggest that composite nanomaterials, in which different materials are present in particle form, need to be analyzed carefully, as not only the concentration of the respective materials but also their arrangement may influence their toxicity. ",0
6508,29787364,Effect of respiratory Achromobacter spp. infection on pulmonary function in patients with cystic fibrosis,"Cystic fibrosis (CF) patients are susceptible to infection with Achromobacter spp., although its clinical significance remains controversial. The aim of this study was to investigate the clinical impact of infection with Achromobacter spp. in CF patients. CF outpatients with multiple sputum cultures and follow-up lung function tests were assigned to the case group (infected with Achromobacter spp.) or the control group (never infected with Achromobacter spp.) according to the isolation of Achromobacter spp. The Achromobacter spp. group included two subgroups, taking into consideration whether the isolation of Achromobacter spp. was intermittent or chronic. Baseline lung function tests and longitudinal behaviour were examined in relation to Achromobacter spp. status. A total of 190 CF patients were treated from January 2003 to December 2015 in the CF unit and 21 (11 %) had at least one positive culture for Achromobacter spp. Of these, 11/21 (52.4 %) patients were chronically infected with Achromobacter spp. An analysis of changes during follow-up showed the annual rate of FEV1 decline: -2.3±1.6 % in the Achromobacter spp. group compared to -1.1±0.9 % (P=0.02) in the control group. The chronically infected group also had a significantly greater decline in FEV1 compared to the control group (-2.9±1.9 vs -1.1±0.9; P=0.04). The mean number of annual pulmonary exacerbations during the study period was significantly higher in the case group (1.9±0.9 vs 1.1±0.8; P=0.03). The Achromobacter spp. status in CF shows a trend towards more severe airflow obstruction and an association with accelerated decline in lung function parameters. ",0
6509,29787473,Factors Contributing to Medial Tibial Stress Syndrome in Runners: A Prospective Study,"Medial tibial stress syndrome (MTSS) is one of the most common overuse injuries sustained by runners. Despite the prevalence of this injury, risk factors for developing MTSS remain unclear. The purpose of this study was to prospectively evaluate differences in passive range of motion, muscle strength, plantar pressure distributions, and running kinematics between runners who developed MTSS and those who did not. Twenty-four National Collegiate Athletic Association Division 1 cross-country runners participated in this study. Participants underwent a clinical examination documenting passive range of motion and muscle strength at the hips and ankles. Plantar pressure analysis was used to quantify mediolateral pressure balances while walking and 3D motion capture was used to quantify running kinematics. Participants were followed up for a 2-yr period during which time any runners who developed MTSS were identified by the team's certified athletic trainer. Runners who developed MTSS demonstrated tighter iliotibial bands (P = 0.046; effect size [ES] = 1.07), weaker hip abductors (P = 0.008, ES = 1.51), more pressure under the medial aspect of their foot at initial foot contact (P = 0.001, ES = 1.97), foot flat (P < 0.001, ES = 3.25), and heel off (P = 0.034, ES = 1.30), greater contralateral pelvic drop (P = 0.021, ES = 1.06), and greater peak amounts (P = 0.017, ES = 1.42) and durations (P < 0.001, ES = 2.52) of rearfoot eversion during stance phase. A logistic regression (χ = 21.31, P < 0.001) indicated that every 1% increase in eversion duration increased odds of developing MTSS by 1.38 (P = 0.015). These findings demonstrate that the development of MTSS is multifactorial, with passive range of motion, muscle strength, plantar pressure distributions, and both proximal and distal kinematics all playing a role. We suggest that coaches or sports medicine professionals screening runners for injury risk consider adopting a comprehensive evaluation which includes all these areas. ",0
6510,29787533,High-volume hospitals are associated with lower mortality among high-risk emergency general surgery patients,"We have previously demonstrated that Emergency General Surgery (EGS) patients treated at high-volume hospitals experience lower mortality rates than those treated at low-volume hospitals. However, EGS comprises a wide spectrum of diseases. Our goal was to determine which EGS diseases had better outcomes at high-volume hospitals. We undertook a retrospective analysis of the National Inpatient Sample database for 2013 (a nationwide representative sample). Patients with EGS diseases were identified using American Association for the Surgery of Trauma definitions. A hierarchical logistic regression model was used to measure risk-adjusted probability of death, adjusting for age, sex, race, ethnicity, insurance type, and comorbidities. Patients were then grouped into 16 risk groups based upon their predicted probability of death. We then compared observed mortality rates at high- versus low-volume hospitals within each risk group. Nationwide, 3,006,615 patients with EGS diseases were treated at 4,083 hospitals in 2013. Patients with predicted risk of death of 4% or higher (275,615 patients, 9.2%) had lower observed mortality rates at high-volume hospitals than at low-volume hospitals (7.7% vs. 10.2%, p < 0.001). We estimated that 1,002 deaths were potentially preventable if high-risk patients who were treated at low-volume hospitals were instead transferred to high-volume hospitals. EGS patients with predicted risk of death of 4% or higher experience lower mortality rates at high-volume hospitals than at low-volume hospitals. A regional system of EGS care that enables rapid transfer of high-risk patients to high-volume hospitals may prevent several deaths. Prognostic and epidemiological, level III; Therapeutic/Case Management, level IV. ",0
6511,29787777,Examination of the effects of cannabinoid ligands on decision making in a rat gambling task,"Although exposure to delta-9-tetrahydrocannabinol (THC) is perceived to be relatively harmless, mounting evidence has begun to show that it is associated with a variety of cognitive deficits, including poor decision making. THC-induced impairments in decision making are thought to be the result of cannabinoid CB1 receptor activation, and although clinical literature suggests that chronic activation via THC contributes to perturbations in decision making, acute CB1 receptor modulation has yielded mixed results. Using an animal model to examine how CB1-specific ligands impact choice biases would provide significant insight as to how recruitment of the endocannabinoid system may influence decision making. Here, we used the rat gambling task (rGT), a validated analogue of the human Iowa Gambling Task, to assess baseline decision making preferences in male Wistar rats. After acquisition rGT performance was measured. Animals were challenged with the CB1 receptor antagonist rimonabant, the partial agonist THC, and the synthetic agonist WIN55,212-2. Animals were also treated acutely with the fatty acid amide hydrolase (FAAH) inhibitor URB597 to selectively upregulate the endocannabinoid anandamide. Blockade of the CB1 receptor produced a trend improvement in decision making in animals who preferred the advantageous task options, yet left choice unaffected in risk-prone rats. Neither CB1 receptor agonist had strong effects on decision making, but a high dose THC decreased premature responses, whereas WIN55,212-2 did the opposite. URB597 did not affect task performance. These results indicate that although chronic CB1 receptor activation may be associated with impaired decision making, acute modulation has modest effects on choice and instead may play a substantive role in regulating impulsive responding. ",0
6512,29788165,Physical activity in relation to risk of prostate cancer: a systematic review and meta-analysis,"Prostate cancer (PCa) is one of the most common cancers among men, yet little is known about its modifiable risk and protective factors. This study aims to quantitatively summarize observational studies relating physical activity (PA) to PCa incidence and mortality. Published articles pertaining to PA and PCa incidence and mortality were retrieved in July 2017 using the Medline and EMBASE databases. The literature review yielded 48 cohort studies and 24 case-control studies with a total of 151 748 PCa cases. The mean age of the study participants at baseline was 61 years. In random-effects models, comparing the highest versus the lowest level of overall PA showed a summary relative risk (RR) estimate for total PCa incidence close to the null [RR = 0.99, 95% confidence interval (CI) = 0.94-1.04]. The corresponding RRs for advanced and non-advanced PCa were 0.92 (95% CI = 0.80-1.06) and 0.95 (95% CI = 0.85-1.07), respectively. We noted a statistically significant inverse association between long-term occupational activity and total PCa (RR = 0.83, 95% CI = 0.71-0.98, n studies = 13), although that finding became statistically non-significant when individual studies were removed from the analysis. When evaluated by cancer subtype, an inverse association with long-term occupational activity was noted for non-advanced/non-aggressive PCa (RR = 0.51, 95% CI = 0.37-0.71, n studies = 2) and regular recreational activity was inversely related to advanced/aggressive PCa (RR = 0.75, 95% CI = 0.60-0.95, n studies = 2), although these observations are based on a low number of studies. Moreover, PA after diagnosis was related to reduced risk of PCa mortality among survivors of PCa (summary RR based on four studies = 0.69, 95% CI = 0.55-0.85). Whether PA protects against PCa remains elusive. Further investigation taking into account the complex clinical and pathologic nature of PCa is needed to clarify the PA and PCa incidence relation. Moreover, future studies are needed to confirm whether PA after diagnosis reduces risk of PCa mortality. ",0
6513,29790698,Inhibition of migration and invasion by berberine via inactivation of PI3K/Akt and p38 in human retinoblastoma cell line,"As a clinically important natural isoquinoline alkaloid, berberine has been reported to possess various pharmacological effects. This study was aimed to investigate the effect of berberine on cell migration and invasion in human retinoblastoma (Rb) cells. The cytotoxicity of berberine was estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. After being stimulated with berberine under various concentrations, the cell migration and invasion were evaluated by transwell assay. Then, the expression levels of epithelial-mesenchymal transition (EMT) markers were determined by quantitative reverse transcription PCR (qRT-PCR) and western blot analysis. Furthermore, the phosphorylation levels of protein kinase B (Akt) and p38 were detected by western blot analysis. Finally, the effect of phosphatidylinositol-3-kinase (PI3K) and p38 inhibitors on cell migration and invasion was estimated by transwell assay. Untreated cells acted as control for all the experiments. The concentrations of berberine for further studies were controlled in a range of 0 to 100 μM. The cell migration and invasion were both suppressed by berberine in a dose-dependent manner compared to the control (p < 0.05 or p < 0.001). Berberine remarkably down-regulated expression of E-cadherin and up-regulated expression of vimentin and α-SMA compared to the control (p < 0.01 or p < 0.001). Furthermore, the phosphorylation levels of Akt and p38 were both down-regulated by berberine in comparison to the control. Furthermore, the addition of berberine accompanied by LY294002 or SB203580 significantly suppressed cell migration and invasion compared to the addition of berberine alone (p < 0.05). Berberine suppressed cell migration and invasion via inactivation of PI3K/Akt and p38. ",0
6514,29790836,Minocycline promotes posthemorrhagic neurogenesis via M2 microglia polarization via upregulation of the TrkB/BDNF pathway in rats,"Intracerebral hemorrhage (ICH) is a devastating disease worldwide with increasing mortality. The present study investigated whether minocycline was neuroprotective and induced M2 microglial polarization via upregulation of the TrkB/BDNF pathway after ICH. ICH was induced via injection of autologous blood into 150 Sprague-Dawley rats. A selective TrkB antagonist [N2-2-2-oxoazepan-3-yl amino] carbonyl phenyl benzo (b) thiophene-2-carboxamide (ANA 12)] and agonist [ N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC)] were used to investigate the mechanism of minocycline-induced neuroprotection. Minocycline improved ICH-induced neurological deficits and reduced M1 microglia marker protein (CD68, CD16) expression as well as M2 microglial polarization (CD206 and arginase 1 protein). Minocycline administration enhanced microglia-neuron cross talk and promoted the proliferation of neuronal progenitor cells, such as DCX- and Tuj-1-positive cells, 24 h after ICH. Minocycline also increased M2 microglia-derived brain-derived neurotrophic factors (BDNF) and the upstream TrkB pathway. ANA 12 reversed the neuroprotective effects of minocycline. HIOC exhibited the same effects as minocycline and accelerated neurogenesis after ICH. This study demonstrated for the first time that minocycline promoted M2 microglia polarization via upregulation of the TrkB/BDNF pathway and promoted neurogenesis after ICH. This study contributes to our understanding of the therapeutic potential of minocycline in ICH. NEW & NOTEWORTHY The present study gives several novel points: 1) Minocycline promotes neurogenesis after intracerebral hemorrhage in rats. 2) Minocycline induces activated M1 microglia into M2 neurotrophic phenotype. 3) M2 microglia secreting BDNF remodel the damaged neurocircuit. ",0
6515,29790842,Reviewing the WHO guidelines for antibiotic use for sepsis in neonates and children,"Background Guidelines from 2005 for treating suspected sepsis in low- and middle-income countries (LMIC) recommended hospitalisation and prophylactic intramuscular (IM) or intravenous (IV) ampicillin and gentamicin. In 2015, recommendations when referral to hospital is not possible suggest the administration of IM gentamicin and oral amoxicillin. In an era of increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for treating sepsis (taking into account susceptibility patterns, cost and risk of adverse events) in neonates and children is necessary. Methods Systematic literature review and international guidelines were used to identify published evidence regarding the treatment of (suspected) sepsis. Results Five adequately designed and powered studies comparing antibiotic treatments in a low-risk community in neonates and young infants in LMIC were identified. These addressed potential simplifications of the current WHO treatment of reference, for infants for whom admission to inpatient care was not possible. Research is lacking regarding the treatment of suspected sepsis in neonates and children with hospital-acquired sepsis, despite rising antimicrobial resistance rates worldwide. Conclusions Current WHO guidelines supporting the use of gentamicin and penicillin for hospital-based patients or gentamicin (IM) and amoxicillin (oral) when referral to a hospital is not possible are in accordance with currently available evidence and other international guidelines, and there is no strong evidence to change this. The benefit of a cephalosporin alone or in combination as a second-line therapy in regions with known high rates of non-susceptibility is not well established. Further research into hospital-acquired sepsis in neonates and children is required. ",0
6516,29790913,Impact of Implementing Antibiotic Stewardship Programs in 15 Small Hospitals: A Cluster-Randomized Intervention,"Studies on the implementation of antibiotic stewardship programs (ASPs) in small hospitals are limited. Accreditation organizations now require all hospitals to have ASPs. The objective of this cluster-randomized intervention was to assess the effectiveness of implementing ASPs in Intermountain Healthcare's 15 small hospitals. Each hospital was randomized to 1 of 3 ASPs of escalating intensity. Program 1 hospitals were provided basic antibiotic stewardship education and tools, access to an infectious disease hotline, and antibiotic utilization data. Program 2 hospitals received those interventions plus advanced education, audit and feedback for select antibiotics, and locally controlled antibiotic restrictions. Program 3 hospitals received program 2 interventions plus audit and feedback on the majority of antibiotics, and an infectious diseases-trained clinician approved restricted antibiotics and reviewed microbiology results. Changes in total and broad-spectrum antibiotic use within programs (intervention versus baseline) and the difference between programs in the magnitude of change in antibiotic use (eg, program 3 vs 1) were evaluated with mixed models. Program 3 hospitals showed reductions in total (rate ratio, 0.89; confidence interval, .80-.99) and broad-spectrum (0.76; .63-.91) antibiotic use when the intervention period was compared with the baseline period. Program 1 and 2 hospitals did not experience a reduction in antibiotic use. Comparison of the magnitude of effects between programs showed a similar trend favoring program 3, but this was not statistically significant. Only the most intensive ASP intervention was associated with reduction in total and broad-spectrum antibiotic use when compared with baseline. NCT03245879. ",0
6517,29791047,Cell-Surface Engineering for Advanced Cell Therapy,"Stem cells opened great opportunity to overcome diseases that conventional therapy had only limited success. Use of scaffolds made from biomaterials not only helps handling of stem cells for delivery or transplantation but also supports enhanced cell survival. Likewise, cell encapsulation can provide stability for living animal cells even in a state of separateness. Although various chemical reactions were tried to encapsulate stolid microbial cells such as yeasts, a culture environment for the growth of animal cells allows only highly biocompatible reactions. Therefore, the animal cells were mostly encapsulated in hydrogels, which resulted in enhanced cell survival. Interestingly, major findings of chemistry on biological interfaces demonstrate that cell encapsulation in hydrogels have a further a competence for modulating cell characteristics that can go beyond just enhancing the cell survival. In this review, we present a comprehensive overview on the chemical reactions applied to hydrogel-based cell encapsulation and their effects on the characteristics and behavior of living animal cells. ",0
6518,29791212,Indian novice nurses' perceptions of their role in caring for women who have experienced intimate partner violence,"intimate partner violence (IPV) is a significant health problem and a gross violation of the human rights of women. Nurses play an important role in providing support for these women. There is limited research on nurses' understanding and perceptions of their role in caring for women with IPV issues in India. to assess novice nurses' perceptions of self-efficacy, educational preparedness and their role in this area. this was a cross-sectional descriptive survey carried out among a convenience sample of novice nurses (n=83) at a tertiary care centre using self-reported questionnaires. a majority of the subjects were confident and had adequate knowledge in dealing with women who have experienced IPV. A significantly positive relationship was found between educational preparedness and self-efficacy and attitudes towards nurses' roles in caring for these women. novice nurses were confident and held positive attitudes towards women who experienced IPV. Yet their self-efficacy in caring for these patients could be improved through continuing education and there is an urgent need to integrate comprehensive training on IPV to improve clinical competencies, including how to refer women for further support. ",0
6519,29791233,Association of a Chromosome Locus 9p21.3 CDKN2B-AS1 Variant rs4977574 with Hypertension: The TAMRISK Study,"Chromosome locus 9p21.3 CDKN2B antisense RNA 1 (CDKN2B-AS1) has been found to contain multiple genetic markers for coronary artery disease (CAD) by genome-wide association studies (GWAS). Of these, the association of variants rs4977574, rs10757274, and rs2383206 with hypertension was studied in the Tampere adult population cardiovascular risk study (TAMRISK). A Finnish cohort of 336 subjects diagnosed with hypertension and 444 controls was analyzed. Samples were genotyped for the CDKN2B-AS1 polymorphisms using Kompetitive Allele Specific PCR (KASP) or TaqMan techniques. Individuals with the minor genotype GG of rs4977574 had less hypertension compared to the other genotypes (p = 0.048, OR 1.58, 95% CI 1.01-2.48). The variants rs2383206 and rs10757274 were not associated with hypertension. Our findings suggest that the GG genotype of the CDKN2B-AS1 gene variant rs4977574, which has been previously associated with an increased CAD risk, is also associated with a decreased susceptibility to the development of hypertension. ",0
6520,29791441,The impact of young maternal age at birth on neonatal mortality: Evidence from 45 low and middle income countries,"This study explores the impact of early motherhood on neonatal mortality, and how this differs between countries and regions. It assesses whether the risk of neonatal mortality is greater for younger adolescent mothers compared with mothers in later adolescence, and explores if differences reflect confounding socio-economic and health care utilisation factors. It also examines how the risks differ for first or subsequent pregnancies. The analysis uses 64 Demographic and Health Surveys collected between 2005 and 2015 from 45 countries to explore the relationship between adolescent motherhood (disaggregated as <16 years, 16/17 years and 18/19 years) and neonatal mortality. Both unadjusted bivariate association and logistic regression are used. Regional level multivariate models that adjust for a range of socio-economic, demographic and health service utilisation variables are estimated. Further stratified models are created to examine the excess risk for first and subsequent births separately. The risk of neonatal mortality in all regions was markedly greater for infants with mothers under 16 years old, although there was marked heterogeneity in patterns between regions. Adjusting for socio-economic, demographic and health service utilisation variables did not markedly change the odds ratios associated with age. The increased risks associated with adolescent motherhood are lowest for first births. Our findings particularly highlight the importance of reducing adolescent births among the youngest age group as a strategy for addressing the problem of neonatal mortality, as well ensuring pregnant adolescents have access to quality maternal health services to protect the health of both themselves and their infants. The regional differences in increased risk are a novel finding which requires more exploration. ",0
6521,29860917,Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer,"BACKGROUND: The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS: We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS: Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS: Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).",0
6522,29874542,Clinical Trial Participants' Views of the Risks and Benefits of Data Sharing,"Background Sharing of participant-level clinical trial data has potential benefits, but concerns about potential harms to research participants have led some pharmaceutical sponsors and investigators to urge caution. Little is known about clinical trial participants' perceptions of the risks of data sharing. Methods We conducted a structured survey of 771 current and recent participants from a diverse sample of clinical trials at three academic medical centers in the United States. Surveys were distributed by mail (350 completed surveys) and in clinic waiting rooms (421 completed surveys) (overall response rate, 79%). Results Less than 8% of respondents felt that the potential negative consequences of data sharing outweighed the benefits. A total of 93% were very or somewhat likely to allow their own data to be shared with university scientists, and 82% were very or somewhat likely to share with scientists in for-profit companies. Willingness to share data did not vary appreciably with the purpose for which the data would be used, with the exception that fewer participants were willing to share their data for use in litigation. The respondents' greatest concerns were that data sharing might make others less willing to enroll in clinical trials (37% very or somewhat concerned), that data would be used for marketing purposes (34%), or that data could be stolen (30%). Less concern was expressed about discrimination (22%) and exploitation of data for profit (20%). Conclusions In our study, few clinical trial participants had strong concerns about the risks of data sharing. Provided that adequate security safeguards were in place, most participants were willing to share their data for a wide range of uses. (Funded by the Greenwall Foundation.).",0
6523,29885402,Evaluation of miRNAs expression in medullary thyroid carcinoma tissue samples: miR-34a and miR-144 as promising overexpressed markers in MTC,"Medullary thyroid carcinoma (MTC) is a rare neoplasia derived from neural parafollicular C cells. MicroRNAs (miRNAs) are small regulatory RNAs with essential roles in the biology of cancers such as MTC and can be applied as diagnostic markers. According to previous studies, miR-144 and miR-34 and their two oncogenes target, mammalian target of rapamycin (mTOR) and AXL receptor tyrosine kinase (AXL), were selected for further investigations in our study. Thirty MTC samples as well as thirty adjacent normal thyroid tissues were applied in this study including 28 formalin-fixed, paraffin-embedded (FFPE) and 2 fresh-frozen MTC samples. RNA extraction and complementary DNA (cDNA) synthesis were performed for all samples. After primer pairs and probes were designed, real-time polymerase chain reaction (real-time PCR) method was used, and the results were analyzed using 2 ",0
6524,29885582,Understanding the synergistic effect and the main factors influencing the enzymatic hydrolyzability of corn stover at low enzyme loading by hydrothermal and/or ultrafine grinding pretreatment,"A thorough assessment of the microstructural changes and synergistic effects of hydrothermal and/or ultrafine grinding pretreatment on the subsequent enzymatic hydrolysis of corn stover was performed in this study. The mechanism of pretreatment was elucidated by characterizing the particle size, specific surface area (SSA), pore volume (PV), average pore size, cellulose crystallinity (CrI) and surface morphology of the pretreated samples. In addition, the underlying relationships between the structural parameters and final glucose yields were elucidated, and the relative significance of the factors influencing enzymatic hydrolyzability were assessed by principal component analysis (PCA). Hydrothermal pretreatment at a lower temperature (170 °C) combined with ultrafine grinding achieved a high glucose yield (80.36%) at a low enzyme loading (5 filter paper unit (FPU)/g substrate) which is favorable. The relative significance of structural parameters in enzymatic hydrolyzability was SSA > PV > average pore size > CrI/cellulose > particle size. PV and SSA exhibited logarithmic correlations with the final enzymatic hydrolysis yield. ",0
6525,29885588,"""Differentiating RNA from DNA by a molecular fluorescent probe based on the """"door-bolt"""" mechanism biomaterials""","Although excellent florescent probes have been developed for DNA, good probes for RNA remain lacking. The shortage of reported and commercial RNA probes is attributable to their severe interference from DNA. As DNA and RNA have similar structures but different functions, it has been an imperative challenge to develop RNA probes that differentiate from DNA. In this study, an NIR fluorescent probe, NBE, is described, which contains a bulky julolidine group that can fit in a spacious RNA pocket and emit intense fluorescence. However, NBE has no response to DNA, as it cannot intercalate into the double strands or even in the DNA minor groove. The sensing mechanism is similar to the effect of a door-bolt. NBE shows excellent performance in RNA sensing (outstanding photostability, high selectivity and fast response), whether in aqueous buffers, fixed cells or living cells. These findings might provide not only a potential imaging tool but also a new design strategy for the recognition of RNA while avoiding interference from DNA. ",0
6526,29885796,"ICEAplChn1, a novel SXT/R391 integrative conjugative element (ICE), carrying multiple antibiotic resistance genes in Actinobacillus pleuropneumoniae","SXT/R391 integrative conjugative elements (ICEs) are capable of self-transfer by conjugation and highly prevalent in various aquatic bacteria and Proteus species. In the present study, a novel SXT/R391 ICE, named ICEAplChn1, was identified in the multidrug resistant (MDR) Actinobacillus pleuropneumoniae strain app6. ICEAplChn1 was composed of the typical SXT/R391 backbone and insertion DNA at eight hotspots, including HS1, HS2, HS3, HS4, HS5, VRII, VRIII and a new variation region VRVI. Many of the insertion contents were not present in other reported SXT/R391 family members, including ICEApl2, a recently identified SXT/R391 ICE from a clinical isolate of A. pleuropneumoniae. Remarkably, the VRIII region had accumulated seven resistance genes tet(A), erm(42), floR, aphA6, strB (two copies), strA and sul2. Of them, erm(42) and aphA6 emerged for the first time not only in the SXT/R391 elements but also in A. pleuropneumoniae. Phylogenetic analysis showed considerable variation of the backbone sequence of ICEAplChn1, as compared to those of other SXT/R391 ICEs. A circular intermediate form of ICEAplChn1 was detected by nested PCR. However, the conjugation experiments using different bacteria as recipients failed. These findings demonstrated that SXT/R391 ICEs are able to adapt to a broader range of host bacterial species. The presence of the MDR gene cluster in ICEAplChn1 underlines that SXT/R391 ICE could serve as an important vector for the accumulation of antibiotic resistance genes. ",0
6527,29885872,The Views of Homeless People and Health Care Professionals on Palliative Care and the Desirability of Setting Up a Consultation Service: A Focus Group Study,"Palliative care for homeless people is often given late, if at all. Professionals in both palliative care and shelter care are often insufficiently equipped to provide this complex care. To provide insights into the palliative care experiences of professionals and homeless people, including barriers and facilitators to care, and to investigate whether a consultative function can help improve palliative care for homeless people. Six focus groups were included; four with professionals (n = 19) and two with severely ill homeless people (n = 15). Professionals were sampled purposively in organizations providing (palliative) care to the homeless. Homeless people were recruited by opportunity sampling. Palliative care for homeless people is especially complex and differs substantially from regular palliative care. It differs greatly among professionals, institutions, and cities. Homeless people get less autonomy than they would like. Homeless people and professionals have different perceptions of the care provided. Trusting relationships between professionals and homeless people is essential and easily accessible, and flexible care is needed. Consultation, in particular involving exchange of expertise between professionals, can provide added value to professionals. Homeless people consider consultation primarily as an opportunity to train professionals to show more understanding, provide tailored palliative care, and enhance professional collaboration. The local situation, characteristics of a consultant, and role of a consultant in providing information and education must be considered when developing the consultation process. Consultation can play an important role in improving palliative care by linking disciplines, providing support to professionals and appropriate palliative care to homeless people. ",0
6528,29885934,Global evolution of glycosylated polyene macrolide antibiotic biosynthesis,"Antibiotics are the most marvelous evolutionary products of microbes to obtain competitive advantage and maintain ecological balance. However, the origination and development of antibiotics has yet to be explicitly investigated. Due to diverse structures and similar biosynthesis, glycosylated polyene macrolides (gPEMs) were chosen to explore antibiotic evolution. A total of 130 candidate and 38 transitional gPEM clusters were collected from actinomycetes genomes, providing abundant references for phenotypic gaps in gPEM evolution. The most conserved parts of gPEM biosynthesis were found and used for phylogeny construction. On this basis, we proposed ancestral gPEM clusters at different evolutionary stages and interpreted the possible evolutionary histories in detail. The results revealed that gPEMs evolved from small rings to large rings and continuously increased structural diversity through acquiring, discarding and exchanging genes from different evolutionary origins, as well as co-evolution of functionally related proteins. The combination of horizontal gene transfers, environmental effects and host preference resulted in the diversity and worldwide distribution of gPEMs. This study is not only a useful exploration on antibiotic evolution but also an inspiration for diversity and biogeographic investigations on antibiotics in the era of Big Data. ",0
6529,29885954,Cognitive Deficits and Related Brain Lesions in Patients With Chronic Heart Failure,"This study sought to determine the spectrum of brain lesions seen in heart failure (HF) patients and the extent to which lesion type contributes to cognitive impairment. Cognitive deficits have been reported in patients with HF. A total of 148 systolic and diastolic HF patients (mean age 64 ± 11 years; 16% female; mean left ventricular ejection fraction 43 ± 8%) were extensively evaluated within 2 days by cardiological, neurological, and neuropsychological testing and brain magnetic resonance imaging (MRI). A total of 288 healthy, sex- and age-matched subjects sampled from the Austrian Stroke Prevention Study served as MRI controls. Deficits in reaction times were apparent in 41% of patients and deficits in verbal memory in 46%. On brain MRI, patients showed more advanced medial temporal lobe atrophy (MTA) (Scheltens score) compared to controls (2.1 ± 0.9 vs. 1.0 ± 0.6; p < 0.001). The degree of MTA was strongly associated with the severity of cognitive impairment, whereas the extent of white matter hyperintensities was similar in patients and controls. Moreover, patients had a 2.7-fold increased risk for presence of clinically silent lacunes. HF patients exhibit cognitive deficits in the domains of attention and memory. MTA but not white matter lesion load seems to be related to cognitive impairment. ",0
6530,29886382,Detection of semi-volatile compounds in cloud waters by GC×GC-TOF-MS. Evidence of phenols and phthalates as priority pollutants,"Although organic species are transported and efficiently transformed in clouds, more than 60% of this organic matter remains unspeciated. Using GCxGC-HRMS technique we were able to detect and identify over 100 semi-volatile compounds in 3 cloud samples collected at the PUY station (puy de Dôme mountain, France) while they were present at low concentrations in a very small sample volume (<25 mL of cloud water). The vast majority (∼90%) of the detected compounds was oxygenated, while the absence of halogenated organic compounds should be specially mentioned. This could reflect both the oxidation processes in the atmosphere (gas and water phase) but also the need of the compounds to be soluble enough to be transferred and dissolved in the cloud droplets. Furans, esters, ketones, amides and pyridines represent the major classes of compounds demonstrating a large variety of potential pollutants. Beside these compounds, priority pollutants from the US EPA list were identified and quantified. We found phenols (phenol, benzyl alcohol, p-cresole, 4-ethylphenol, 3,4-dimethylphenol, 4-nitrophenol) and dialkylphthalates (dimethylphthalate, diethylphthalate, di-n-butylphthalate, bis-(2-ethylhexyl)-phthalate, butylbenzylphthalate, di-n-octyl phthalate). In general, the concentrations of phthalates (from 0.09 to 52 μg L ",0
6531,29886412,Use of non-invasive ventilation in cerebral palsy,"Patients with cerebral palsy (CP), especially those at the severe end of the spectrum (Gross Motor Function Classification System levels IV-V equivalent), frequently suffer from sleep disturbance and sleep-disordered breathing (SDB). Non-invasive ventilation (NIV) is increasingly used in this patient group, albeit with little published evidence of its effectiveness in CP. This article aims to review the current evidence in the use of NIV in children with CP, highlighting areas of uncertainties, as well as the balance of potential risks, challenges and benefits. We would also share our experience and practical considerations in using NIV to manage SDB in this group of patients. Between January 2010 and December 2016, 21 patients (median age 11.1 (range 1.7-16.1) years) with CP were initiated on NIV at Great Ormond Street Hospital for Children following diagnosis of moderate to severe SDB on cardiorespiratory polygraphy. Over half of our patients with CP (n=11) failed to establish on NIV either due to intolerance of mask and/or ventilation pressure at the initial trial in hospital, or poor adherence during follow-up, in contrast to the overall failure rate of 8.7% among total patient population commenced on NIV. Children with CP constitute a relatively small but challenging group of patients. Decision to undertake NIV should be individualised, based on benefit outweighing the risk and burden of the treatment. ",0
6532,29886943,"Evaluation of the environmental quality of Parangipettai, Southeast Coast of India, by using multivariate and geospatial tool","The anthropogenic pressure in recent years has driven us to investigate the environmental quality at 22 stations in Parangipettai by collecting seawater samples monthly from 2014 to 2015. The sampling stations were grouped into three different environments, namely, Vellar Estuary (VE), Coleroon Estuary (CE), and Open Sea (OS). Factor analysis showed a total variance of 65.63% and exhibited a strong factor loading for atmospheric temperature (0.914), water temperature (0.917), ammonia (0.767), inorganic phosphate (0.897), total phosphorus (0.783), and phytoplankton (0.829). The index value showed water quality was good in OS (74.18), whereas it was moderate in VE (69.73) and CE (68.47). The visual model developed using Geographical Information System (GIS) displayed a spatial pattern of water temperature and phytoplankton dispersion in a distinct manner. The results obtained through multivariate analysis and GIS-based model are imperative to establish reference for a comparative study with other similar ecosystem for better planning and management of tropical seawaters. ",0
6533,29887184,"Percutaneous Cryoablation of Solitary, Sporadic Renal Cell Carcinoma: Outcome Analysis Based on Clear-Cell versus Papillary Subtypes","To evaluate treatment outcomes with percutaneous cryoablation (PCA) based on renal cell carcinoma (RCC) histology. Patients treated with PCA for a solitary, sporadic stage T1a RCC from 2003 to 2016 were identified from a single institution's renal ablation registry. Patients with multiple tumors, history of RCC, or genetic syndromes associated with RCC (n = 60); no specific RCC subtype determined from core biopsy (n = 66); RCC subtype other than clear-cell or papillary (n = 7); or less than 3 mo of follow-up imaging (n = 5) were excluded. In total, 173 patients met study inclusion criteria. Oncologic outcomes, clinical outcomes, and complications were evaluated based on tumor subtype. Of the 173 patients who underwent PCA for a stage T1a RCC, 130 (75%) had clear-cell RCC (ccRCC) and 43 (25%) had papillary RCC (pRCC). Median tumor size was 2.9 cm (range, 1.3-4.0 cm). Technically successful cryoablation was achieved in all 173 patients. Local tumor recurrence developed in 6 patients with ccRCC (4.6%), new renal tumors developed in 1 patient (0.8%), and metastatic RCC developed in 1 patient (0.8%) who also had local tumor recurrence. No patients with pRCC showed local tumor recurrence, new renal tumors, or metastatic disease. The 5-year disease-free survival rate in patients with ccRCC was 88%, compared with 100% in patients with pRCC (P = .48). Nine patients (5.2%), all with ccRCC, experienced major complications (P = .11). Percutaneous ablation is a viable treatment option for patients with clinical stage T1a pRCC and ccRCC. Percutaneous ablation may be a very favorable treatment strategy particularly for pRCC. ",0
6534,29887297,Influence of BMI in nephrolithiasis in an Appalachian pediatric population: A single-center experience,"The prevalence of pediatric nephrolithiasis has increased significantly in the past 20 years. Metabolic abnormalities predisposing adults to nephrolithiasis in obese patients include increased urinary sodium and uric acid excretion as well as low urine pH; however, limited data are available in the pediatric population. The aim was to investigate whether obese pediatric patients presenting with nephrolithiasis have a unique metabolic profile similar to reported findings in obese adults with nephrolithiasis. A retrospective chart review was performed in children aged 1-18 years seen at Kentucky Children's Hospital between 2010 and 2016. Inclusion criteria included all patients with documented stones confirmed by ultrasonography or computed tomography. A total of 111 patient charts were reviewed in the study with a mean age of 11.8 ± 4.2 years. Seventy patients (63%) had a normal BMI and 41 patients (37%) were considered overweight/obese. There was no statistically significant relationship between BMI and stone recurrence. Obese patients had significantly decreased levels of urinary citrate, oxalate, magnesium, and potassium with significant elevations of urinary urea nitrogen, ammonia, and low urine pH compared with normal weight patients (Summary Figure). Several groups have reported on metabolic findings within obese and non-obese pediatric patients. A Turkish study reported increased oxalate excretion and hypocitraturia in obese patients while a Korean study also reported increased rates of hypocitraturia in recurrent stone formers. Similar to these studies, we did find significant differences in citrate within our study population; however, we found significantly lower levels of urinary oxalate in obese patients. The majority of these studies do not report an association with BMI and urine pH although this has been reported in the adult population and our findings support an inverse relationship between body mass index (BMI) and pH. Our group found a higher level of calcium phosphate stones, supporting of Eisner's findings that high BMI is associated with increased supersaturation of calcium phosphate. Limitations of our study include being a single center and retrospective in nature. Our study demonstrates differences in types of stones and urinary metabolites in an obese pediatric population suggestive of different metabolic profiles contributing to stone disease. We report similar association between BMI and urine pH, urinary potassium, and citrate. This study confirmed our primary hypothesis that obese pediatric patients would have a different urinary mineral profile as evidenced by lower levels of citrate and potassium and low urine pH; however, obese patients did not exhibit significantly elevated urinary sodium and uric acid when normalized to weight, as described in the adult population. Our study did not confirm our secondary hypothesis that stone composition would be associated with BMI status or stone recurrence. ",0
6535,29887611,Effectiveness of outreach chest camps in detection of missed TB cases in Pakistan,"To determine the effectiveness of outreach chest camp intervention for detection of missed tuberculosis cases in Pakistan and to evaluate the demographic profile of those who are dependent on such doorstep healthcare services. This retrospective study was carried out using data from the outreach chest camp intervention organised by Greenstar Social Marketing company from August 2015 till December 2016 in Lahore, Gujrat and Sheikhupura districts of Pakistan's Punjab province. The intervention involved a set of community mobilisation events in hard-to-reach areas and in healthcare facilities which are deprived of suitable settings, followed by free medical camps where medical consultation and tuberculosis diagnostic facility of sputum smear microscopy were provided to the camp attendees. The data was taken as per set variables and analysed using SPSS 23. A total of 399chest camps were conducted, where 22,399 patients were clinically assessed for the presence or absence of tuberculosis. Overall, 12,319(55%) of the attendees were females and 10,080(45%) were males. Of the total, 5,226(24.6%) had signs and symptoms of tuberculosis and were declared as tuberculosis presumptive cases. After diagnostic investigations, 831(3.7%) individuals were declared confirmed tuberculosis patients. Amongst the total confirmed cases, 439(52.8%) were diagnosed through sputum smear microscopy with percent bacteria positivity of 8. (95% confidence interval [CI] 7.54 - 9.02). Chest camp intervention was found to have great potential to detect missed tuberculosis cases, thus limiting the spread of disease in the community. ",0
6536,29887718,Abdominal Wall Endometriosis Mimicking Metastases,"Abdominal wall lesions can be broadly divided into nontumorous and tumorous conditions. Nontumorous lesions include congenital lesion, abdominal wall hernia, inflammation and infection, vascular lesions, and miscellaneous conditions like hematoma. Tumorous lesions include benign and malignant neoplasms. Here, we report an unusual case of abdominal wall endometriosis mimicking metastases in a patient with breast carcinoma. ",0
6537,29887978,Evaluation of serum extracellular vesicle isolation methods for profiling miRNAs by next-generation sequencing,"Extracellular vesicles (EVs) are intercellular communicators with key functions in physiological and pathological processes and have recently garnered interest because of their diagnostic and therapeutic potential. The past decade has brought about the development and commercialization of a wide array of methods to isolate EVs from serum. Which subpopulations of EVs are captured strongly depends on the isolation method, which in turn determines how suitable resulting samples are for various downstream applications. To help clinicians and scientists choose the most appropriate approach for their experiments, isolation methods need to be comparatively characterized. Few attempts have been made to comprehensively analyse vesicular microRNAs (miRNAs) in patient biofluids for biomarker studies. To address this discrepancy, we set out to benchmark the performance of several isolation principles for serum EVs in healthy individuals and critically ill patients. Here, we compared five different methods of EV isolation in combination with two RNA extraction methods regarding their suitability for biomarker discovery-focused miRNA sequencing as well as biological characteristics of captured vesicles. Our findings reveal striking method-specific differences in both the properties of isolated vesicles and the ability of associated miRNAs to serve in biomarker research. While isolation by precipitation and membrane affinity was highly suitable for miRNA-based biomarker discovery, methods based on size-exclusion chromatography failed to separate patients from healthy volunteers. Isolated vesicles differed in size, quantity, purity and composition, indicating that each method captured distinctive populations of EVs as well as additional contaminants. Even though the focus of this work was on transcriptomic profiling of EV-miRNAs, our insights also apply to additional areas of research. We provide guidance for navigating the multitude of EV isolation methods available today and help researchers and clinicians make an informed choice about which strategy to use for experiments involving critically ill patients. ",0
6538,29887991,Modern Corneal Eye-Banking Using a Software-Based IT Management Solution,"Increasing government legislation and regulations in manufacturing have led to additional documentation regarding the pharmaceutical product requirements of corneal grafts in the European Union. The aim of this project was to develop a software within a hospital information system (HIS) to support the documentation process, to improve the management of the patient waiting list and to increase informational flow between the clinic and eye bank. After an analysis of the current documentation process, a new workflow and software were implemented in our electronic health record (EHR) system. The software takes over most of the documentation and reduces the time required for record keeping. It guarantees real-time tracing of all steps during human corneal tissue processing from the start of production until allocation during surgery and includes follow-up within the HIS. Moreover, listing of the patient for surgery as well as waiting list management takes place in the same system. The new software for corneal eye banking supports the whole process chain by taking over both most of the required documentation and the management of the transplant waiting list. It may provide a standardized IT-based solution for German eye banks working within the same HIS. ",0
6539,29888686,Correlation of human papillomavirus infection and clinical parameters with five-year survival in oral squamous cell carcinoma,"This study associated Human Papillomavirus (HPV) infection and other clinical parameters with five-year survival of oral squamous cell carcinoma patients at a tertiary care hospital in Karachi, Pakistan. A total of 140 patients diagnosed with oral squamous cell carcinoma were enlisted. HPV status and subtypes were established through polymerase chain reaction performed in a previously published study. Clinical data including five-year survival were obtained through institutional medical records. Ninety-five patients (67.9 per cent) were positive for HPV. Of these, 85 patients were HPV 16 positive while 2 patients were HPV 18 positive. The mean survival time for HPV positive patients was 44.3 months, whereas survival time for HPV negative patients was 46.9 months. Univariate analysis showed that HPV status in oral squamous cell carcinoma was not a statistically significant factor in determining five-year survival rate (p = 0.386). There is a high prevalence of HPV positive oral squamous cell carcinoma in Pakistan; however, there is no difference in the five-year survival rate when compared to HPV negative oral squamous cell carcinoma. ",0
6540,29888731,Mammographic findings of breast cancer screening in patients with positive family history in South-East Nigeria,"A positive family history of breast cancer is an important risk factor associated with the development of breast cancer in women. Early detection required regular screening in these women. To determine the mammographic findings of breast cancer screening in patients with a positive family history in Iyienu, Southeast Nigeria. Forty-three consenting females with a positive family history of breast cancer who underwent mammographic screening at Radiology Department, Iyienu Mission Hospital, Anambra State, were enrolled in the study. Mammographic findings were compared with those of females with a negative family history. The mean age was 49.6 years with a range of 35-69 years. The mammographic findings were asymmetric density, nipple retraction, tissue retraction, skin thickening, lymphadenopathy, and calcification within a mass with varying frequency for the right and left breasts. A significant statistical difference was found in lymphadenopathy and calcification for the right and left breasts, respectively, when compared with those without positive family history. ",0
6541,29888739,The Environment and Reproductive Health (EARTH) Study: A Prospective Preconception Cohort,"The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional, and lifestyle factors among both women and men on fertility and pregnancy outcomes. The EARTH Study recruits women 18 to 45 years and men 18 to 55 years seeking fertility evaluation and treatment at the Massachusetts General Hospital (MGH) Fertility Center, Boston, USA. Women and men are eligible to join either independently or as a couple. Participants are followed from study entry throughout each fertility treatment cycle, once per trimester of pregnancy (for those achieving pregnancy), and up to labor and delivery, or until they discontinue treatment or withdraw from the study. The study collects biological samples, self-reported questionnaire data (including a food frequency questionnaire) and clinically abstracted information. As of June 2017, the study cohort included 799 women and 487 men (447 couples; 40 men joined without female partners). Women were on average 34.7 years old at time of enrolment and predominantly Caucasian (81%), educated (49% have a graduate degree), and nulliparous (83%). Men were on average 36.6 years at baseline and mostly Caucasian (86%) and never-smokers (67%). The EARTH Study is one of the few cohorts designed to examine multiple potentially critical windows of vulnerability, including the paternal and maternal preconception windows and the periconception and prenatal windows in pregnancy. It is also one of the few human studies that has assessed potential interactions between environmental exposures and dietary factors. ",0
6542,29889317,The socioeconomic burden of patients affected by hemophilia with inhibitors,"Hemophilia is associated with a high financial burden on individuals, healthcare systems, and society. The development of inhibitors significantly increases the socioeconomic burden of the diseases. This study aimed to review and describe the burden of hemophilia with inhibitors, providing a reference scenario to assess the impact of new products in the real word. Two systematic literature reviews were performed to collect data on (i) health economics and (ii) health-related quality of life evidences in hemophilic patients with inhibitors. The costs associated with patients with hemophilia and inhibitors are more than 3 times greater than the costs incurred in those without inhibitors, with an annual cost per patient that can be higher than €1 000 000. The costs of bypassing agents account for the large majority of the total healthcare direct costs for hemophilia treatment. The quality of life is more compromised in patients with hemophilia and inhibitors compared to those without inhibitors, in particular the physical domains, whereas mental domains were comparable to that of the general population. The development of an inhibitor has a high impact on costs and quality of life. New treatments have the potential to change positively the management and socioeconomic burden of hemophilia with inhibitors. ",0
6543,29889371,CHRONIC PANCREATITIS AS A PREDICTOR OF OSTEOPOROSIS FORMATION,"The issues of formation of secondary osteoporosis in patients with chronic pancreatitis (CP) were discussed in this paper. It was shown that the chronic relapsing nature of the disease process in the pancreas leads to hypokalemia due to malabsorption of calcium and vitamin D as the result of maldigestion. As well as the redistribution of ionized and total calcium blood between the body fluids, which can be a consequence of long-term nature of pain. At the same time, the study of the content of enzymes bone found their decline to a greater extent characteristic index tartrate resistant acid fosfatazy-marker of bone resorption. Changes in bone metabolism were confirmed by ultrasound bone (densitometry) at which proved the development of osteoporosis in 47,7% of cases, and osteopenia in 35,7% of patients. The conclusions about the need for pre-clinical diagnosis of osteoporotic states in patients with CP, correction of diet and administration of appropriate therapy were made. ",0
6544,29889434,THE EFFECTIVENESS OF GOLIMUMAB IN SEVERE ULCERATIVE COLITIS WITH EXTRAINTESTINAL MANIFESTATIONS,"A clinical case of severe ulcerative colitis vvith extraintestinal manifestations, development of steroid dependence and inefficiency of basic therapy is presented. A good effect of therapy with golimumabis demonstrated. ",0
6545,29889629,Laparoscopic ovariectomy with a single-port multiple-access device in seven African lionesses (Panthera leo),"CASE DESCRIPTION 7 privately owned female African lions (Panthera leo) that had been bred for public exhibition and were housed in outdoor pens were evaluated prior to undergoing elective ovariectomy. CLINICAL FINDINGS All animals were healthy. Median age was 15 months (range, 9 to 34 months), and median body weight was 71 kg (156 lb; range, 48 to 145 kg [106 to 319 lb]). TREATMENT AND OUTCOME Surgical sterilization by means of single-incision laparoscopic ovariectomy was elected. A 2- to 3-cm-long skin incision was made just caudal to the umbilicus, and a single-port multiple-access device was bluntly inserted through the incision. Traction was maintained with stay sutures to provide counterpressure, and three 5-mm-diameter cannulae were introduced through the device's access channels with a blunt trocar. The abdomen was insufflated to a pressure of 12 mm Hg with CO ",0
6546,29889760,Risk of Spontaneous Abortion After Inadvertent Human Papillomavirus Vaccination in Pregnancy,"To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink. Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12-27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models. We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion. ",0
6547,29889905,Risk of introduction of lumpy skin disease in France by the import of vectors in animal trucks,"The lumpy skin disease virus (LSDV) is a dsDNA virus belonging to the Poxviridae family and the Capripoxvirus genus. Lumpy skin diseases (LSD) is a highly contagious transboundary disease in cattle producing major economic losses. In 2014, the disease was first reported in the European Union (in Cyprus); it was then reported in 2015 (in Greece) and has spread through different Balkan countries in 2016. Indirect vector transmission is predominant at small distances, but transmission between distant herds and between countries usually occurs through movements of infected cattle or through vectors found mainly in animal trucks. In order to estimate the threat for France due to the introduction of vectors found in animal trucks (cattle or horses) from at-risk countries (Balkans and neighbours), a quantitative import risk analysis (QIRA) model was developed according to the international standard. Using stochastic QIRA modelling and combining experimental/field data and expert opinion, the yearly risk of LSDV being introduced by stable flies (Stomoxys calcitrans), that travel in trucks transporting animals was between 6 x 10-5 and 5.93 x 10-3 with a median value of 89.9 x 10-5; it was mainly due to the risk related to insects entering farms in France from vehicles transporting cattle from the at-risk area. The risk related to the transport of cattle going to slaughterhouses or the transport of horses was much lower (between 2 x 10-7 and 3.73 x 10-5 and between 5 x 10-10 and 3.95 x 10-8 for cattle and horses, respectively). The disinsectisation of trucks transporting live animals was important to reduce this risk. The development of a stochastic QIRA made it possible to quantify the risk of LSD being introduced in France through the import of vectors that travel in trucks transporting animals. This tool is of prime importance because the LSD situation in the Balkans is continuously changing. Indeed, this model can be updated to process new information on vectors and the changing health situation, in addition to new data from the TRAde Control and Expert System (TRACES, EU database). This model is easy to adapt to different countries and to other vectors and diseases. ",0
6548,29890011,The Extraction and Recovery Efficiency of Pure DNA for Different Types of Swabs,"The extraction and recovery efficiency of swabs used to collect evidence at crime scenes is relatively low (typically <50%) for bacterial spores and body fluids. Cell-free deoxyribonucleic acid (DNA) is an interesting alternative compared to whole cells as a source for forensic analysis, but extraction and recovery from swabs has not been tested before using pure DNA. In this study cotton, foam, nylon flocked, polyester and rayon swabs are investigated in order to collect pure DNA isolated from saliva samples. The morphology and absorption capacity of swabs is studied. Extraction and recovery efficiencies are determined and compared to the maximum theoretical efficiency. The results indicate that a substantial part of DNA is not extracted from the swab and some types of swab seem to bind effectively with DNA. The efficiency of the different types of swab never exceeds 50%. The nylon flocked 4N6FLOQSwab used for buccal sampling performs the best. ",0
6549,29890116,"Ultra-processed food consumption among infants in primary health care in a city of the metropolitan region of São Paulo, Brazil","To analyze the prevalence of ultra-processed food intake among children under one year of age and to identify associated factors. A cross-sectional design was employed. We interviewed 198 mothers of children aged between 6 and 12 months in primary healthcare units located in a city of the metropolitan region of São Paulo, Brazil. Specific foods consumed in the previous 24h of the interview were considered to evaluate the consumption of ultra-processed foods. Variables related to mothers' and children's characteristics as well as primary healthcare units were grouped into three blocks of increasingly proximal influence on the outcome. A Poisson regression analysis was performed following a statistical hierarchical modeling to determine factors associated with ultra-processed food intake. The prevalence of ultra-processed food intake was 43.1%. Infants that were not being breastfed had a higher prevalence of ultra-processed food intake but no statistical significance was found. Lower maternal education (prevalence ratio 1.55 [1.08-2.24]) and the child's first appointment at the primary healthcare unit having happened after the first week of life (prevalence ratio 1.51 [1.01-2.27]) were factors associated with the consumption of ultra-processed foods. High consumption of ultra-processed foods among children under 1 year of age was found. Both maternal socioeconomic status and time until the child's first appointment at the primary healthcare unit were associated with the prevalence of ultra-processed food intake. ",0
6550,29890213,Pathologic role of nitrergic neurotransmission in mood disorders,"Mood disorders are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although over the past 40 years the biogenic amine models have provided meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders, there is still a need to examine the contribution of other systems to the neurobiology and treatment of mood disorders. This article reviews the current literature describing the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby the treatment of mood disorders. The hypothesis has arisen from several observations including (i) altered NO levels in patients with mood disorders; (ii) antidepressant effects of NO signaling blockers in both clinical and pre-clinical studies; (iii) interaction between conventional antidepressants/mood stabilizers and NO signaling modulators in several biochemical and behavioral studies; (iv) biochemical and physiological evidence of interaction between monoaminergic (serotonin, noradrenaline, and dopamine) system and NO signaling; (v) interaction between neurotrophic factors and NO signaling in mood regulation and neuroprotection; and finally (vi) a crucial role for NO signaling in the inflammatory processes involved in pathophysiology of mood disorders. These accumulating lines of evidence have provided a new insight into novel approaches for the treatment of mood disorders. ",0
6551,29890875,"Variation in Men's Dietary Intake Between Occupations, Based on Data From the Japan Environment and Children's Study","There has been increasing interest in dietary health promotion in the workplace. Although many previous studies have focused on dietary habits in specific occupations, variation between occupational groups requires clarification. The present study aimed to examine differences in food and nutrient intake between occupational groups, using detailed classification. A cross-sectional study was conducted using data from the Japan Environment and Children's Study. The study included 38,721 employed Japanese expectant fathers aged between 20 and 65 years. Dietary intake was assessed using a food frequency questionnaire. Occupations were categorized into 11 categories according to the Japan Standard Occupational Classification. Analysis of variance and analysis of covariance were performed to compare dietary intake of occupational groups. Logistic regression analysis was performed to examine the differences in adherence to dietary recommendations across occupations. Dietary intake differed significantly between occupations. Specific dietary intake was observed in security and agricultural workers, who tended to exhibit higher consumption levels for numerous foods and nutrients. In addition, relative to other workers, security workers showed higher intake of dairy products and calcium, and agricultural workers consumed larger amounts of pickles and salt. The study categorized occupations into detailed categories using the Japan Standard Occupational Classification, which facilitated the clarification of overall dietary trends across occupations and identification of specific dietary characteristics in individual occupations. The findings could aid in workplace health promotion. ",0
6552,29890921,"""""""Everybody's Really Close-Knit"""": Disconnections Between Helping Victims of Intimate Partner Violence and More General Helping in Rural Communities""","Social support is key to well-being for victims of intimate partner violence (IPV), and bystanders have an important role to play in preventing IPV by taking action when there is risk for violence. The current study used qualitative interviews to explore young adults' perspectives on helping in situations of IPV, and more general helping, in the rural communities in which they resided. Participants were 74 individuals between the ages of 18 and 24 years from 16 rural counties across the eastern United States. Participants generally described their communities as close-knit and helpful, especially around daily hassles (e.g., broken down car) and unusual circumstances (e.g., house fire). Although participants generated ways in which community members help IPV victims, these mostly focused on providing support or taking action in the aftermath of IPV as opposed to more preventive actions. Lack of financial resources were uniquely cited as a barrier to more general helping, whereas concerns about privacy and lack of deservingness of help were barriers to both general helping and helping in IPV situations, although these were more pronounced in IPV situations than general helping situations. Taken together, these results suggest that although people generally see their communities as helpful and close-knit, these perceptions and scripts did not necessarily translate to helping in situations of IPV. Bystander intervention programs are needed that provide more specific helping scripts for IPV. ",0
6553,29891151,Using process net-map to analyse governance challenges: A case study of livestock vaccination campaigns in Zambia,"The outbreak of livestock diseases in Sub-Saharan African countries is the most critical challenge affecting the development potential of the livestock sector. Vaccination campaigns are one of the most important strategies to deal with this challenge. However, such campaigns are difficult to implement due to major governance challenges, such as delays in the procurement of vaccines and the disbursement of funds. This paper presents an in-depth analysis of these governance challenges, based on a case study of a Livestock Development Animal Health Project in Zambia. The goal was to examine in detail why these problems occur and how they are linked to the implementation procedure. A novel qualitative research tool called Process Net-Map, which is a visual participatory mapping technique was applied. The tool made it possible to develop an understanding of the exact implementation mechanism and to identify the different actors involved, including government officials, private sector companies, and farmers. The study revealed that the complex design of the procurement procedure, the limited capacity of the procuring entity, and a lack of urgency among the actors involved, resulted in the procurement delays. The findings also indicate that the delay in the release of funds arises because of a diversion of funds. Some strategies to improve the efficiency of the procurement process were identified, such as increasing the sense of urgency, building staff capacity, using e-procurement and entering into framework contracts with suppliers. Building sustainable financial capacity in the overall management of public funds seems essential to deal with the challenge of fund diversion. Use of Citizen Report Cards and lobbying political decision markers are some of the mechanisms that farmers can employ to increase their capacity to hold the animal health service providers accountable and demand better services. The problems identified are not only relevant for vaccination programs but are general implementation challenges encountered in developmental programs that involve the distribution of publicly procured inputs. ",0
6554,29891772,Cytotoxicity of Plant-Mediated Synthesis of Metallic Nanoparticles: A Systematic Review,"In the field of medicine, nanomaterials, especially those derived using the green method, offer promise as anti-cancer agents and drug carriers. However, the biosafety of metallic nanoparticles used as anti-cancer agents remains a concern. The goal of this systematic review was to compare the cytotoxicity of different plant-mediated syntheses of metallic nanoparticles based on their potency, therapeutic index, and cancer cell type susceptibility in the hopes of identifying the most promising anti-cancer agents. A literature search of electronic databases including Science Direct, PubMed, Springer Link, Google Scholar, and ResearchGate, was conducted to obtain research articles. Keywords such as biosynthesis, plant synthesis, plant-mediated, metallic nanoparticle, cytotoxicity, and anticancer were used in the literature search. All types of research materials that met the inclusion criteria were included in the study regardless of whether the results were positive, negative, or null. The therapeutic index was used as a safety measure for the studied compound of interest. Data from 76 selected articles were extracted and synthesised. Seventy-two studies reported that the cytotoxicity of plant-mediated synthesis of metallic nanoparticles was time and/or dose-dependent. Biosynthesised silver nanoparticles demonstrated higher cytotoxicity potency compared to gold nanoparticles synthesised by the same plants ( ",0
6555,29891898,Changes in retinal nerve fiber layer thickness measurements in response to a trifocal intraocular lens implantation,"To determine the changes produced on the peripapillary retinal nerve fiber layer (RNFL) thickness, measured by an spectral-domain optical coherence tomography (OCT), after the implantation of a trifocal diffractive intraocular lens (IOL) and compare them with the variations produced by a monofocal IOL implantation. A prospective, double masked study in which 50 eyes belonging to 50 patients with bilateral cataract were enrolled. Sequentially, the first 25 patients were bilaterally implanted with the trifocal diffractive IOL AT LISA® Tri 839 MP and the following 25 patients with the monofocal IOL CT ASPHINA® 409 M/MP. RNFL thickness measurements were performed by Cirrus HD®-OCT before and six months after the second eye surgery. Mean patient age was 69.5 ± 6.1 years. In response to surgery, the average RNFL thickness increased 7.29 ± 10.51 µm at the AT LISA® Tri group and 1.96 ± 2.90 µm at the monofocal IOL group from the baseline (p = 0.017). Statistically significant differences in thickness variations were also detected in the superior sector (7.86 ± 7.70 µm at the AT LISA® Tri group vs 1.73 ± 5.74 µm at the monofocal group). Statistically significant differences between the pre and the postsurgery measurements were found in all sectors except the inferior one with the trifocal IOL and in two of the studied sectors (average and temporal) with the monofocal IOL. The IOL implantation produce changes in the RNFL thickness, which are larger in case of a trifocal diffractive IOL. ",0
6556,29892089,Introducing medical genetics services in Ethiopia using the MiGene Family History App,"Almost all low-income countries and many middle-income countries lack the capacity to deliver medical genetics services. We developed the MiGene Family History App (MFHA), which assists doctors with family history collection and population-level epidemiologic analysis. The MFHA was studied at St. Paul's Hospital in Addis Ababa, Ethiopia. A needs assessment was used to assess Ethiopian physicians' experience with genetics services. The MFHA then collected patient data over a 6-month period. The majority of doctors provide genetics services, with only 16% reporting their genetics knowledge is sufficient. A total of 1699 patients from the pediatric ward (n = 367), neonatal intensive care unit (NICU) (n = 477), and antenatal clinic (n = 855) were collected using the MFHA with a 4% incidence of a MFHA-screened condition present. The incidence was 11.7% in the pediatric ward, 3% in the NICU, and 0.5% in the antenatal clinic. Heart malformations (5.5% of patients) and trisomy 21 (4.4% of patients) were the most common conditions in the pediatric ward. Medical genetics services are needed in Ethiopia. As other countries increase their genetics capacity, the MFHA can provide fundamental genetics services and collect necessary epidemiologic data. ",0
6557,29892110,"Effect of freeze- and spray-drying on physico-chemical characteristics, phenolic compounds and antioxidant activity of papaya pulp","The effect of freeze- and spray-drying on physico-chemical characteristics, phenolics compounds and antioxidant activity of papaya pulp was investigated. The frozen pulp was freeze dried at - 62 °C during 48 h. Papaya pulp with 14% DE maltodextrin was also dried in a spray dryer. The organic acids, sugars, color, total soluble solids, pH, carotenoids, phenolic and flavonoid compounds, and antioxidant capacity values were determined. The changes in color, pH and lycopene were negligible. However, lower retention (86.5%) of vitamin C and sugars (glucose-79.7% and fructose-66.1%) was observed in spray dried products. Phenolic and flavonoid compounds were identified and quantified in dried papaya products by UHPLC-QqQ-MS/MS. Spray dried products presented a higher retention of phenolic and flavonoid compounds compared to the freeze dried products. Despite some variations in the parameters studied, the use of freeze- and spray-drying has proven viable options for the drying of papaya pulp. ",0
6558,29892803,Differential expression of photosynthesis-related genes in pentaploid interspecific hybrid and its decaploid of Fragaria spp,"Polyploidization always induces a series of changes in genome, transcriptome and epigenetics, of which changes in gene expression are the immediate causes of genotype alterations of polyploid plants. In our previous study on strawberry polyploidization, genes related to photosynthesis were found to undergo changes in gene expression and DNA methylation. Therefore, we chose 11 genes that were closely related to plant photosynthesis and analysed their expression during strawberry hybridization and chromosome doubling. Most genes of pentaploids showed expression levels between parents and were more similar to F. × ananassa. Gene expression levels of decaploids were higher than those of pentaploids and F. × ananassa. Different types of photosynthesis-related genes responded differently to hybridization and chromosome doubling. Chloroplast genes and regulatory genes showed complex responses. Structural genes of the photosynthetic system were expressed at a constant level and displayed a clear dosage effect. The methylation levels of one CG site on SIGE, which regulates expression of chloroplast genes, were negatively correlated with gene expression. In pentaploids and decaploids, more transcripts were from F. × ananassa than from F. viridis. The ratio of transcripts from from F. × ananassa to those from F. viridis was close to the ratio (4:1) of the genome of F. × ananassa to that of F. viridis in pentaploids and decaploids, but there were also some exceptions with obvious deviation. ",0
6559,29892950,Obese rats supplemented with bitter melon display marked shifts in the expression of genes controlling inflammatory response and lipid metabolism by RNA-Seq analysis of colonic mucosa,"Obesity is known to induce pathological changes in the gut and diets rich in complex carbohydrates that resist digestion in the small bowel can alter large bowel ecology. The purposes of this study were to identify the effects of bitter melon powder (BMP) on the global gene expression pattern in the colon mucosa of obese rats. Obese rats were fed a high-fat diet and treated without or with BMP for 8 weeks. Genome-wide expression profiles of the colon mucosa were determined by RNA sequencing (RNA-Seq) analysis at the end of experiment. A total of 87 genes were identified as differentially expressed (DE) between these two groups (fold change > 1.2). These results were further validated by quantitative RT-PCR, confirming the high reliability of the RNA-Seq. Interestingly, DE genes implicated in inflammation and lipid metabolism were found to be downregulated by BMP in the colon. Network between genes and the top 15 KEGG pathways showed that PRKCβ (protein kinase C beta) and Pla2g2a (phospholipase A2 group IIA) strongly interacted with surrounding pathways and genes. Results revealed that BMP supplement could remodel key colon functions by altering transcriptomic profile in obese rats. ",0
6560,29893339,An atypical presentation of POEMS syndrome with IgG kappa type M protein and normal VEGF level: Case report and review of literature,"POEMS syndrome is a multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. We present an atypical case of POEMS syndrome with subclinical polyneuropathy, splenomegaly, hypogonadism, and myeloma of immunoglobulin G kappa type. The typical osteosclerotic lesions and skin lesions were absent, and vascular endothelial growth factor (VEGF) level was normal. Our patient also had chronic kidney disease due to focal segmental glomerulosclerosis. The patient died due to multisystem complications nine months after presenting with acute on chronic renal failure. POEMS syndrome is an uncommon, potentially fatal paraneoplastic syndrome presenting with plasma cell neoplasm and multisystem involvement. Despite the normal VEGF level, our patient was diagnosed to have possible POEMS syndrome due to other clinical manifestations. It may be reasonable to expand the diagnostic criteria of POEMS syndrome if further atypical cases are reported in the future. ",0
6561,29893408,"Crocin, a natural molecule with potentially beneficial effects against skin ageing","Oxidative stress and low-grade chronic inflammation stand out as key features of physiological skin ageing. The aim of this study was to examine in normal human epidermal keratinocytes (NHEK) and human dermal fibroblasts (HDF) grown in vitro, the antioxidant and anti-inflammatory properties of crocin, a carotenoid glycoside responsible for the colour of saffron. Moreover, considering the newly emerging field of skin glycobiology and the presence of two gentiobiosyl moieties in crocin, the effect of crocin on NHEK glycosylation pathways was for the first time investigated. The anti-inflammatory and antioxidant activities of crocin were evaluated by in vitro assays of antioxidation activities, ELISA and microarray analysis. The effect of crocin on keratinocyte glycobiology was evaluated by proprietary GLYcoDiag lectin technologies and microarray analysis. Crocin is endowed with antioxidant potential against reactive oxygen species, protects squalene against UVA-induced peroxidation and prevents the release of inflammatory mediators. The expression of NF-kB-related genes and glycosylation-related genes is modulated in the presence of crocin. Results could designate this molecule as a promising skin ageing prevention cosmetic agent. Of note, some of these effects could be mediated by protein O-glycosylation and interaction of crocin with osidic receptors of keratinocytes. ",0
6562,29893439,Nursing home resident relationship types: What supports close relationships with peers & staff?,"""To describe from the nursing home resident perspective (a) the types and dimensions of relationships residents develop with others in the nursing home and (b) the conditions that influence the development of close relationships. Close relationships are considered the fundamental building block of person-centred care. Prior studies have examined the various types of relationships residents develop with peers and staff, but few have focused specifically on articulating the characteristics and dimensions of a close relationship or the factors that can support or detract from their development. Grounded theory. Fifteen cognitively intact residents from two nursing homes were recruited for one-on-one, unstructured interviews. Interview questions started broadly and became more focused as the study progressed. Data were analysed using open, axial and selective coding. Residents described developing a range of relationships with peers and staff (adversarial, utilitarian, and friendly). Residents used """"friendly"""" to describe many different types of relationships including acquaintanceships, casual friendships and close friendships. Few residents had close relationships with peers or staff. Several conditions promoted development of positive and friendly relationships. Physical proximity and access to peers with similar interests, who could communicate clearly, fostered friendly peer relationships. Spending noncare time, providing little extras, treating residents as special and responding positively to care requests fostered friendly staff relationships. Findings add new evidence regarding nuances in resident relationships and demonstrate how development of close relationships may be limited in practice. Careful assessment of resident relationship needs and goals may be critical to setting appropriate social goals. Nurses can be intentional about resident placements in the facility to promote social interactions and keep social goals in mind when making medical or staffing decisions to prevent interruption of important relationships. """,0
6563,29893643,Regional Cerebral Blood Flow in Children and Young Adults with Chronic Kidney Disease,"""Purpose To investigate the pathophysiologic effects of chronic kidney disease (CKD) on brain function in children with CKD by correlating cerebral blood flow (CBF) with clinical and behavioral indexes. Materials and Methods In this prospective study, 73 pediatric patients with CKD (mean age, 15.80 years ± 3.63; range, 9-25 years) and 57 control subjects (mean age, 15.65 years ± 3.76; range, 9-25 years) were recruited. CBF measurements were acquired with an MRI arterial spin labeling scheme. Neurocognitive measurements were performed with traditional and computerized neurocognitive batteries. Clinical data were also collected. Group-level global and regional CBF differences between patients with CKD and control subjects were assessed. Regression analyses were conducted to evaluate the associations among regional CBF, clinical variables, and cognitive performance. Results Patients with CKD showed higher global CBF compared with control subjects that was attributable to reduced hematocrit level (mean, 60.2 mL/100 g/min ± 9.0 vs 56.5 mL/100 g/min ± 8.0, respectively). White matter CBF showed correlation with blood pressure (r = 0.244, P = .039), a finding suggestive of altered cerebrovascular autoregulation. Regional CBF differences between patients and control subjects included regions in the """"default mode"""" network. In patients with CKD, positive extrema in the precuneus showed a strong correlation with executive function (ρ = 0.608, P = .001). Conclusion Systemic effects of estimated glomerular filtration rate, hematocrit level, and blood pressure on CBF and alterations in regional CBF may reflect impaired brain function underlying neurocognitive symptoms in CKD. These findings further characterize the nature of alterations in brain physiologic features in children, adolescents, and young adults with CKD. """,0
6564,29893661,Individuals seeking gender reassignment: marked increase in demand for services,"Aims and methodTo describe the pattern of referrals and characteristics of people aged over 18 seeking gender reassignment in Oxfordshire over a 6-year period (2011-2016). A total of 153 individuals attended for assessment (of 162 referred); 97 (63.4%) were natal males and 56 (36.6%) were natal females. Mean age at referral was markedly different between the two groups, with females being younger. The number of referral significantly increased over the time period, by an average of 18% per year (95% CI 1.08-1.30). Eighty-seven patients sought transition from male to female, and 46 from female to male, while a smaller group (n = 13) had non-binary presentations. Twelve patients (7.8%) had autism spectrum disorder.Clinical implicationsThere are various possible reasons for the increased demand for services for people with gender dysphoria, which we discuss here. When planning services in the UK, both the increase in overall referral rates and the apparent earlier age at referral should be taken into account.Declaration of interestNone. ",0
6565,29893785,Is Episodic Future Thinking Important for Instrumental Activities of Daily Living? A Study in Neurological Patients and Healthy Older Adults,"Episodic future thinking is the ability to mentally project oneself into the future. This construct has been explored extensively in cognitive neuroscience and may be relevant for adaptive functioning. However, it has not been determined whether the measurement of episodic future thinking might be valuable in a clinical neuropsychological setting. The current study investigated (1) the relationship between episodic future thinking and instrumental activities of daily living (IADLs); and (2) whether episodic future thinking is related to IADLs over and above standard measures of cognition. Sixty-one older adults with heterogeneous neurological conditions and 41 healthy older adults completed a future thinking task (the adapted Autobiographical Interview), a performance-based measure of instrumental activities of daily living (the Independent Living Scales), and standard clinical measures of memory and executive functioning. Episodic future thinking significantly predicted IADLs after accounting for age, education, gender, and depression (increase in R2 = .050, p = .010). Episodic future thinking significantly predicted IADLs over and above executive functioning (increase in R2 = .025, p = .030), but was not predictive of IADLs over and above memory (p = .157). This study suggests that episodic future thinking is significantly associated with IADLs, beyond what can be accounted for by executive functioning. However, episodic future thinking did not predict IADLs over and above memory. Overall, there is limited evidence for the clinical utility of episodic future thinking. The findings suggest that an episodic future thinking task does not provide enough valuable information about IADLs to justify its inclusion in a clinical neuropsychological setting. ",0
6566,29893796,Clinical utility of exhaled carbon monoxide in assessing preoperative smoking status and risks of postoperative morbidity after esophagectomy,"Whereas smoking constitutes a significant risk factor for postesophagectomy morbidity, there is no reliable method to assess the smoking status of patients prior to the procedure. Since exhaled carbon monoxide (CO) is an indicator of recent smoking, this paper hypothesizes that this is a useful parameter in assessing current smoking status and may help predict morbidity following esophagectomy. Sixty-nine patients, who had undergone elective three-incision esophagectomy with two- or three-field lymphadenectomy for esophageal cancer, were prospectively studied between February 2015 and September 2017. At surgical admission, they were asked about their smoking history, their exhaled CO levels were evaluated, and they were grouped into three based on their CO levels. These were 0 parts per million (ppm), >0 and <7 ppm, and ≥7 ppm. Their postoperative morbidity was also assessed. Approximately 13.5% of the patients showed high levels of exhaled CO ≥ 7 ppm, despite preoperatively reporting smoking cessation for over a month. Morbidities of the Clavien-Dindo classification (CDc) ≥ II increased as exhaled CO levels increased and severe morbidity of CDc ≥ IIIb frequently was observed in patients with exhaled CO levels ≥7 ppm. The logistic regression analysis showed that exhaled CO level ≥7 ppm was an independent risk factor for severe postesophagectomy morbidity. Overall, the results of this study suggest that exhaled CO levels may be useful in estimating current smoking status and that it may also help give an estimation of the risk of postesophagectomy morbidity. ",0
6567,29893854,Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting,"Mutations in a number of genes cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) and parkin genes. In this study, we identify a novel functional interaction between parkin and VPS35. We demonstrate that parkin interacts with and robustly ubiquitinates VPS35 in human neural cells. Familial parkin mutations are impaired in their ability to ubiquitinate VPS35. Parkin mediates the attachment of an atypical poly-ubiquitin chain to VPS35 with three lysine residues identified within the C-terminal region of VPS35 that are covalently modified by ubiquitin. Notably, parkin-mediated VPS35 ubiquitination does not promote the proteasomal degradation of VPS35. Furthermore, parkin does not influence the steady-state levels or turnover of VPS35 in neural cells and VPS35 levels are normal in the brains of parkin knockout mice. These data suggest that ubiquitination of VPS35 by parkin may instead serve a non-degradative cellular function potentially by regulating retromer-dependent sorting. Accordingly, we find that components of the retromer-associated WASH complex are markedly decreased in the brain of parkin knockout mice, suggesting that parkin may modulate WASH complex-dependent retromer sorting. Parkin gene silencing in primary cortical neurons selectively disrupts the vesicular sorting of the autophagy receptor ATG9A, a WASH-dependent retromer cargo. Parkin is not required for dopaminergic neurodegeneration induced by the expression of PD-linked D620N VPS35 in mice, consistent with VPS35 being located downstream of parkin function. Our data reveal a novel functional interaction of parkin with VPS35 that may be important for retromer-mediated endosomal sorting and PD. ",0
6568,29893981,The association of adolescent spinal-pain-related absenteeism with early adulthood work absenteeism: A six-year follow-up data from a population-based cohort,"Objectives Spinal (ie, back and neck) pain often develops as early as during adolescence and can set a trajectory for later life. However, whether early-life spinal-pain-related behavioral responses of missing school/work are predictive of future work absenteeism is yet unknown. We assessed the association of adolescent spinal-pain-related work or school absenteeism with early adulthood work absenteeism in a prospective population-based cohort. Methods Six year follow-up data from the Western Australian Pregnancy Cohort (Raine) study were used (N=476; with a 54% response rate). At age 17, participants reported spinal pain (using the Nordic questionnaire) and adolescent spinal-pain-related work/school absenteeism (with a single item question). Annual total and health-related work absenteeism was assessed with the Health and Work Performance questionnaire distributed in four quarterly text messages during the 23rd year of age. We modelled the association of adolescent spinal-pain-related absenteeism with work absenteeism during early adulthood, using negative binomial regression adjusting for sex, occupation and comorbidities. Results Participants with adolescent low-back or neck pain with work/school absenteeism reported higher total work absenteeism in early adulthood [148.7, standard deviation (SD) 243.4 hours/year], than those without pain [43.7 (SD 95.2) hours/year); incidence rate ratio 3.4 (95% CI 1.2-9.2)]. Comparable findings were found when considering low-back and neck separately, and when considering health-related absenteeism. Conclusions We found a more than three-fold higher risk of work absenteeism in early adulthood among those with adolescent spinal-pain-related absenteeism, compared to those without. These findings suggest that, to keep a sustainable workforce, pain prevention and management should focus on pain-related behaviors as early as in adolescence. ",0
6569,29894005,Possible roles of basophils in chronic itch,"Basophils are blood granulocytes and normally constitute <1% of blood peripheral leucocytes. Basophils share some morphological and functional similarities with mast cells, and basophils were once regarded as redundant and negligible circulating mast cells. However, recent studies reveal the indispensable roles of basophils in various diseases, including allergic and pruritic diseases. Basophils may be involved in itch through the mediation of a Th2 immune response, interaction with other cells in the skin and secretion of a wide variety of itch-related mediators, for example histamine, cytokines and chemokines (IL-4, IL-13, IL-31 and TSLP), proteases (cathepsin S), prostaglandins (PGE2 and PGD2), substance P and platelet-activating factor. Not only pruritic skin diseases (eg, atopic dermatitis, irritant contact dermatitis, chronic urticaria, prurigo, papulo-erythroderma of Ofuji, eosinophilic pustular folliculitis, scabies, tick bites and bullous pemphigoid) but also pruritic systemic diseases (eg, primary sclerosing cholangitis and polycythemia vera) may be affected by basophils. ",0
6570,29894745,A secretary bi-cistronic baculovirus expression system with improved production of the HA1 protein of H6 influenza virus in insect cells and Spodoptera litura larvae,"A bi-cistronic baculovirus expression vector was constructed to facilitate the expression, detection, and isolation of the hemagglutinin (HA) fragment HA1 of H6N1 avian influenza virus (AIV) in an insect and a culture of its cells. In this construct, the GP67sp signal peptide promoted the secretion of the recombinant protein into the culture medium, and improved protein expression and purification. Enhanced green fluorescent protein, co-expressed through an internal ribosome entry site, served as a visible reporter for protein expression detection. The hemolymph of Spodoptera litura larvae infected with the bi-cistronic baculovirus was collected for the purification of the recombinant HA1, which was found to be glycosylated, and monomeric and trimeric forms of the recombinant HA1 were identified. Proteins expressed in both the cell culture and larvae served as effective subunit vaccines for the production of antiserum against HA. The antiserum recognized the H6 subtype of AIV but not the H5 subtype. ",0
6571,29895183,Is smartphone addiction really an addiction?,"""Aims In light of the rise in research on technological addictions and smartphone addiction in particular, the aim of this paper was to review the relevant literature on the topic of smartphone addiction and determine whether this disorder exists or if it does not adequately satisfy the criteria for addiction. Methods We reviewed quantitative and qualitative studies on smartphone addiction and analyzed their methods and conclusions to make a determination on the suitability of the diagnosis """"addiction"""" to excessive and problematic smartphone use. Results Although the majority of research in the field declares that smartphones are addictive or takes the existence of smartphone addiction as granted, we did not find sufficient support from the addiction perspective to confirm the existence of smartphone addiction at this time. The behaviors observed in the research could be better labeled as problematic or maladaptive smartphone use and their consequences do not meet the severity levels of those caused by addiction. Discussion and conclusions Addiction is a disorder with severe effects on physical and psychological health. A behavior may have a similar presentation as addiction in terms of excessive use, impulse control problems, and negative consequences, but that does not mean that it should be considered an addiction. We propose moving away from the addiction framework when studying technological behaviors and using other terms such as """"problematic use"""" to describe them. We recommend that problematic technology use is to be studied in its sociocultural context with an increased focus on its compensatory functions, motivations, and gratifications. """,0
6572,29895279,Relationship between the geometry patterns of vertebrobasilar artery and atherosclerosis,"The plaques at the dorsal or lateral wall of basilar artery (BA) are associated with pontine infarcts. We sought to explore the correlations between vertebrobasilar artery geometry and BA plaque locations. We retrospectively analyzed the imaging and clinical data of 84 patients with BA atherosclerosis. On three-dimensional time-of-flight images, a side to side diameter difference of bilateral vertebral artery (VA) and BA bending were assessed. The vertebrobasilar artery geometry was qualitatively classified into four basic configurations: Walking, Tuning Fork, Dominant-Lambda, and Hypoplasia-Lambda. On high-resolution magnetic resonance imaging, the plaques were categorized based on the involvement of the ventral, dorsal, or lateral sides of BA wall. The relationships between vertebrobasilar artery geometry parameters and plaque locations were analyzed. Left VA dominance was identified in 28(33%) patients, and right VA dominance in 22(26%) patients. BA bending were detected in 49 patients. There were no significant correlations between the diameter difference/ratio of VA diameters and plaque locations, or between BA bending and plaque locations. BA plaques were evenly distributed in the vertebrobasilar arteries with Tuning Fork and Dominant-Lambda configurations. In Hypoplasia-Lambda group, however, plaques were more frequently located at the dorsal wall (58.57%) than at the ventral (14.43%) and lateral wall (26.71%; P = 0.001). In Walking group, the plaques more likely occurred at the lateral (49.79%) and dorsal (35.07%) wall than at the ventral wall (14.86%, P = 0.02). The geometric configurations of vertebrobasilar artery strongly influence the BA plaque locations. Further prospective studies are warranted to testify whether Hypoplasia-Lambda and Walking configurations are independent risk factors for pontine infarcts. ",0
6573,29895734,Briefing Note: Proceedings of the Singapore National Clinical Pharmacy Colloquium-Health Manpower Development Planning,"The nation of Singapore highly values its health service as well as the component of healthcare delivery that includes clinical pharmacy and administration. The Ministry of Health (MOH) engaged the services of Dr. Richard Parrish to better understand the relationship between the Singaporean citizenry and its clinical pharmacists. Through a series of five lectures, structured from the national to local unit level, four roundtables, two hands-on sessions, and three workshops, clinical pharmacists and administrative leadership participated in &ldquo;open-mic&rdquo; style lectures, discussed the issues facing Singapore pharmacy in its current provision of healthcare services, and deliberated on the future resources required to meet projected healthcare needs. From three distinct perspectives, these discussions were very frank, transparent, and passionate about what practitioners and administrators thought Singaporean health leadership needed to address in terms of (1) what programs and practices to continue; (2) what ones to start; and (3) what ones to evaluate. Each of the areas below will be framed using these three perspectives in order to clearly reflect the ideas and suggestions expressed in each of the 14 group sessions. These recommendations are forwarded to MOH pharmacy leadership for consideration and action. In addition, we met with MOH leaders regarding non-medical prescribing (NMP), and discussed strategies and tactics that seemed successful as well as unsuccessful in other jurisdictions when adopting expanded scope models for clinical pharmacists and other qualified healthcare providers that include prescribing of medications. ",0
6574,29895851,Evaluation of polygenic risk models using multiple performance measures: a critical assessment of discordant results,"The area under the receiver operating characteristic curve (AUC) is commonly used for evaluating the improvement of polygenic risk models and increasingly assessed together with the net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We evaluated how researchers described and interpreted AUC, NRI, and IDI when simultaneously assessed. We reviewed how researchers described definitions of AUC, NRI, and IDI and how they computed each metric. Next, we reviewed how the increment in AUC, NRI, and IDI were interpreted, and how the overall conclusion about the improvement of the risk model was reached. AUC, NRI, and IDI were correctly defined in 63, 70, and 0% of the articles. All statistically significant values and almost half of the nonsignificant were interpreted as indicative of improvement, irrespective of the values of the metrics. Also, small, nonsignificant changes in the AUC were interpreted as indication of improvement when NRI and IDI were statistically significant. Researchers have insufficient knowledge about how to interpret the various metrics for the assessment of the predictive performance of polygenic risk models and rely on the statistical significance for their interpretation. A better understanding is needed to achieve more meaningful interpretation of polygenic prediction studies. ",0
6575,29896083,Annexin A7 Levels Increase in Rats With Traumatic Brain Injury and Promote Secondary Brain Injury,"The incidence of traumatic brain injury (TBI) has been increasing annually. Annexin A7 is a calcium-dependent phospholipid binding protein. It can promote melting of the cell membrane. Recent studies have shown that it plays an important role in atherosclerosis, other cardiovascular diseases, and a variety of tumors. However, few studies of ANXA7 in TBI have been performed. We here observed how ANXA7 changes after TBI and discuss whether brain injury is associated with the use of ANXA7 antagonist intervention.  ",0
6576,29896101,Activation of A2A Receptor by PDRN Reduces Neuronal Damage and Stimulates WNT/β-CATENIN Driven Neurogenesis in Spinal Cord Injury,"Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination. In the last few years, adenosine receptors have been studied as a target for many diseases, including neurodegenerative conditions. The aim of this study was to investigate the effects of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate the Wnt pathway, we wanted to study PDRN effects on Wnt signaling following SCI. Spinal trauma was induced by extradural compression of spinal cord at T5-T8 level in C57BL6/J mice. Animals were randomly assigned to the following groups: Sham ( ",0
6577,29896852,Interleukin (IL)-8 and IL-36γ but not IL-36Ra are related to acrosyringia in pustule formation associated with palmoplantar pustulosis,"Palmoplantar pustulosis (PPP) is a refractory, nonbacterial impetigo confined to the palms and soles. Its pathogenesis is still obscure, but it may be associated with the large eccrine sweat glands and pores of palmoplantar skin. PPP is considered to be a localized pustular psoriasis. Interleukin (IL)-8, IL-36γ and IL-36Ra play important roles in the pathogenesis of pustular psoriasis, but their role in PPP is unclear. To evaluate IL-8, IL-36γ and IL-36Ra expression in PPP, and their relationship with acrosyringia and pustule formation. mRNA expression was quantified in skin samples from patients with PPP (n = 7), patients with psoriasis vulgaris (PSV; n = 8) and healthy controls (HCs) (n = 6) by reverse-transcription-real-time PCR. Protein expression was characterized by immunohistochemistry (PPP, n = 17; PSV, n = 14; HCs, n = 12). Sweat ducts, including acrosyringia, were stained for epithelial membrane antigen (EMA). IL-8 mRNA and protein were markedly increased in PPP lesions compared with PSV lesions or HC skin. IL-36γ mRNA and protein were significantly more abundant in PPP lesions than in HC skin. IL-36Ra mRNA was significantly overexpressed in PPP lesions compared with HC skin, but there was no difference in IL-36Ra protein between PPP, PSV and HCs. IL-8 was abundantly expressed by neutrophils in PPP pustules, while IL36Ra was localized in the keratinocytes of PPP, PSV and HC skin. IL-36γ and EMA were colocalized in cells surrounding PPP pustules, and IL-36γ was also expressed in sweat duct cells in the dermis. IL-8, IL-36γ and IL-36Ra are overexpressed in PPP lesions. IL-8, IL-36γ and acrosyringia, rather than IL-36Ra, are associated with pustule formation in PPP. ",0
6578,29897076,Honey protects against cisplatin-induced hepatic and renal toxicity through inhibition of NF-κB-mediated COX-2 expression and the oxidative stress dependent BAX/Bcl-2/caspase-3 apoptotic pathway,"The protective effects of both manuka and talh honeys were assessed using a rat model of cisplatin (CISP)-induced hepatotoxicity and nephrotoxicity. The results revealed that both honeys exerted a protective effect against CISP-induced hepatotoxicity and nephrotoxicity as demonstrated by decreasing liver and kidney function. Manuka honey also prevented CISP-induced histopathological changes observed in the liver and decreased the changes seen in the kidneys. Talh honey decreased CISP-induced liver histopathological changes but had no effect on CISP-induced kidney histopathological changes. Both honeys reduced the oxidative stress in the liver. Conversely, they have no effect on kidney oxidative stress, except that manuka honey increased CAT activity. GC-MS analysis showed the presence of the antioxidant octadecanoic acid in talh honey while heneicosane and hydrocinnamic acid were present at a higher content in manuka honey. The molecular mechanism was to limit the expression of inflammatory signals, including COX-2 and NF-κB, and the expression of the apoptotic signal, BAX and caspase-3 while inducing Bcl-2 expression. ",0
6579,29897429,Anaortic coronary surgery using the Π-circuit is associated with a low incidence of perioperative neurological complications,"Our goal was to compare the observed and the expected rates of postoperative cerebrovascular accidents (CVA) in a large cohort of consecutive patients undergoing off-pump coronary artery bypass grafting (CABG) using the ∏-circuit as a no-touch technique. From January 2001 to May 2016, 3081 patients were consecutively submitted to an off-pump CABG operation using the ∏-circuit. A CVA was defined as a neurological deficit, lasting less (transient ischaemic attack) or more (stroke) than 24 h, diagnosed by a neurologist and confirmed by a computed tomography or magnetic resonance imaging scan of the brain. The primary end point was to compare the observed and the expected rates of CVAs; the latter was obtained using the Society of Thoracic Surgeons' calculator. The secondary end point was to compare the observed and the expected mortality rates using the Society of Thoracic Surgeons' calculator and the prevalence of postoperative complications. Moreover, we identified some subgroups at higher risk. The postoperative rate of CVAs was 0.5% (14 cases): 2 (0.1%) were transient ischaemic attacks and 12 (0.4%) were strokes. The mean expected CVA rate (1.6%) was significantly higher than the observed rate (P < 0.001). None of patients who experienced postoperative CVAs died. The observed mortality was 1.3% (40 patients) vs the expected mortality (2.6%), which was significantly higher (P < 0.001). Multivariable analysis identified age >70 years old, diabetes, extracardiac vasculopathy and chronic renal failure as risk factors for postoperative CVAs. However, in all the subgroups of risk, except for those with chronic renal failure, the use of the ∏-circuit was associated with a low rate of CVAs. The ∏-circuit should be included as a possible choice among no-touch techniques. The observed rate of CVAs of 75% is lower than the expected rate. ",0
6580,29897481,Association Between Autologous Stem Cell Transplant and Survival Among Californians With Multiple Myeloma,"Autologous hematopoietic stem cell transplant (aHSCT) is an efficacious treatment for newly diagnosed multiple myeloma patients. However, as rapid advances have resulted in other highly efficacious and less intensive therapies, the role of aHSCT has been questioned. We utilized population-based data to identify 13 494 newly diagnosed patients younger than age 80 years between 1998 and 2012. Patient characteristics of aHSCT and non-aHSCT groups were balanced using inverse probability weighting of a propensity score predicting aHSCT use. Multivariable models adjusted for baseline comorbidities, demographics, and socioeconomic status estimated the adjusted hazard ratio (aHR) and 95% confidence intervals (CIs) of death. Twenty point eight percent (2807) of patients underwent aHSCT, and this rate increased over time from 15.4% in 1998-2002 to 23.9% in 2008-2012. aHSCT was utilized among 37.6% and 11.5% of patients younger than age 60 years and 60 to 79 years, respectively. The median time to aHSCT was 9.4 months, and 89% of all aHSCTs occurred within two years of diagnosis. The median overall survival from time of aHSCT was 72.9 months (95% confidence interval [CI] = 68 to 78). Autologous HSCT at any time was associated with improved survival (aHR = 0.83, 95% CI = 0.75 to 0.92). Among aHSCT recipients, transplant more than 12 months after diagnosis (vs ≤12 months) was associated with worse survival (aHR = 1.33, 95% CI = 1.16 to 1.51). The positive effect of aHSCT on overall survival was similar across study time periods and age groups. In the era of highly efficacious induction therapies, aHSCT remained infrequently used but continued to be associated with improved survival for multiple myeloma patients and should be considered for newly diagnosed patients. ",0
6581,29897969,Gene expression analysis of nidus of cerebral arteriovenous malformations reveals vascular structures with deficient differentiation and maturation,"Arteriovenous malformations (AVMs) are characterised by tangles of dysplastic blood vessels which shunt blood from arteries to veins with no intervening capillary bed. It is not known at what stage of development and differentiation, AVM vessels became aberrant. To address this, we have analysed the expression of vascular differentiation, vascular maturation and brain capillary specific genes in AVM nidus. We performed immunohistochemistry and western blot analysis of vascular differentiation (HEY2, DLL4, EFNB2, and COUP-TFII), vascular maturation (ENG and KLF2) and brain capillary specific genes (GGTP and GLUT1) on ten surgically excised human brain AVMs and ten normal human brain tissues. Immunohistochemical analysis revealed that AVM vessels co-express both artery and vein differentiation genes. H-score analysis revealed that there is statistically significant (P < 0.0001) increase in expression of these proteins in AVM vessels compared to control vessels. These findings were further confirmed by western blot analysis and found to be statistically significant (P < 0.0001 and P < 0.001) for all proteins except Hey2. Both immunostaining and western blot analysis revealed that AVM vessels express GGTP and GLUT1, markers specific to brain capillaries. Immunofluorescent staining demonstrated that expression of KLF2, a vascular maturation marker is significantly (P <0.001) decreased in AVM vessels and was further confirmed by western blot analysis (P < 0.001). Immunohistochemical and western blot analysis demonstrated that another vascular maturation protein Endoglin had high expression in AVM vessels compared to control vessels. The results were found to be statistically significant (P < 0.0001). Our findings suggest that vascular structures of AVMs co-express markers specific for arteries, veins and capillaries. We conclude that AVM nidus constitutes of aberrant vessels which are not terminally differentiated and inadequately matured. ",0
6582,29898002,"QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications","To investigate the prevalence and risk factors of acquired long QT syndrome (LQTS) on admission to a general Intensive Care Unit (ICU), and to assess the risk of LQTS associated with prescribed medications. Prospective observational, cross-sectional study approved by the Institutional Review Board. Between May 2014 and July 2016, 412 patients >18 years-old consecutively admitted to the ICU of a university hospital were included. LQTS was defined as a QT interval on the admission electrocardiogram corrected using Bazett's formula (QTc) >460 ms for men and >470 ms for women. All medications administered within 24 hours before admission were recorded. Logistic regression was used. LQTS prevalence was 27.9%. In LQTS patients, 70.4% had ≥ 1 LQTS-inducing drug prescribed in the 24 hours prior to ICU admission versus 70.4% in non-LQTS patients (p = 0.99). Bradycardia and Charlson morbidity index score are independent risk factors for LQTS. Haloperidol (OR 4.416), amiodarone (OR 2.509) and furosemide (OR 1.895) were associated with LQTS, as well as another drug not yet described, namely clopidogrel (OR 2.241). The LQTS is highly prevalent in critically ill patients, ICU patients are often admitted with LQTS-inducing medications, and patients with slow heart rate or with high Charlson comorbidity index should be evaluated for LQTS. ",0
6583,29898269,Metastatic pancreatic ductal adenocarcinoma: diagnosis and treatment with a view to the future,"Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5-year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental. This review discusses the evidence behind the currently used regimens, while introducing the potential future of pancreatic cancer care. ",0
6584,29898479,Is irritable bowel syndrome also present in dogs?,"Irritable bowel syndrome (IBS) in humans is described as the recurrent presence of gastrointestinal signs, without gross histopathologic evidence of inflammation and of other morphologic lesions; however, it is a syndrome not unanimously defined in veterinary medicine. There is some evidence that dysmotility could be related to stressors in some dogs that present with clinical signs (e.g. chronic idiopathic large-bowel diarrhea) that share overlapping aspects with human IBS. The authors hypothesize that an IBS-like condition, similar to that described in humans, might also be present in dogs. Nevertheless, the diagnostic path for canine IBS needs to be further elucidated and its pathogenesis better defined for a more rational therapeutic approach. In der Humanmedizin beschreibt der Begriff Reizdarmsyndrom das Auftreten wiederkehrender gastrointestinaler Symptome ohne ausgeprägte entzündliche oder andere morphologische Veränderungen in Darmbioptaten. In der Veterinärmedizin ist dieses Syndrom nicht einheitlich definiert. Es gibt jedoch Hinweise, dass bei Hunden Motilitätsstörungen des Magen-Darm-Trakts aufgrund verschiedener Stressfaktoren zu klinischen Symptomen (z. B. chronische idiopathische Dickdarmdiarrhö) führen, die in einigen Aspekten dem Reizdarmsyndrom des Menschen entsprechen. Die Autoren vermuten, dass beim Hund ein klinisches Äquivalent des Reizdarmsyndroms des Menschen vorliegt. Die Pathogenese dieses Syndroms und Kriterien zur Diagnosestellung müssen jedoch besser definiert werden. ",0
6585,29898596,Metabolomics Reveals How Cucumber ( Cucumis sativus) Reprograms Metabolites To Cope with Silver Ions and Silver Nanoparticle-Induced Oxidative Stress,"Due to their well-known antifungal activity, the intentional use of silver nanoparticles (AgNPs) as sustainable nanofungicides is expected to increase in agriculture. However, the impacts of AgNPs on plants must be critically evaluated to guarantee their safe use in food production. In this study, 4-week-old cucumber ( Cucumis sativus) plants received a foliar application of AgNPs (4 or 40 mg/plant) or Ag ",0
6586,29898646,Pure bone marrow aspirate injection for chronic greater trochanteric pain syndrome: a case report,"There are limited treatment options for patients with a chronic refractory greater trochanteric pain syndrome. Orthobiologic interventions may stimulate tendon healing and improve pain and function in patients who fail the standard conservative treatment. Since the US FDA's new position statement regarding the centrifugation of bone marrow aspirate products as a potentially 'more than minimally manipulated' product, there is a growing concern about the most common bone marrow aspirate concentrate technique. In this case, a 57 year old female with a debilitating chronic greater trochanteric pain syndrome was treated with a pure autologous bone marrow aspirate injection using a novel aspiration technique. The patient showed significant improvements in pain and function without recurrence at 1-year follow-up. This is the first case report to illustrate this novel technique for aspirating pure bone marrow that should comply with the new FDA regulations. ",0
6587,29898728,Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic,"Subfertile women are at increased risk of glucose intolerance in pregnancy. Based on epidemiologic studies, exposure to certain phthalates is associated with diabetes, elevated glucose, and increased insulin resistance. To evaluate the association between urinary phthalate metabolites and pregnancy glucose levels in women seeking medically assisted reproduction. We evaluated 245 women participating in a prospective cohort study based at a large fertility clinic who delivered live births and had data on pregnancy urinary phthalate metabolite concentrations and blood glucose levels. Urinary phthalate metabolite concentrations were from single spot urine samples collected in 1st and 2nd trimesters. Blood glucose data was abstracted from medical records for non-fasting 50-g glucose challenge tests at 24-28 weeks gestation. Multivariable linear regression models were used to evaluate associations between 7 urinary phthalate metabolites in quartiles and mean glucose adjusted for potential confounders. Eighteen percent of women had glucose levels ≥ 140 mg/dL. Second trimester monoethyl phthalate (MEP) concentrations were positively associated with glucose levels, with adjusted mean (95%CI) glucose levels of 121 mg/dl (114, 128) vs. 109 mg/dL (103, 116) for women in highest and lowest quartiles, respectively. Women in the highest quartile of second trimester mono-isobutyl phthalate (MiBP) concentrations had a mean glucose level 14 mg/dL lower compared to women in the lowest quartile. No other urinary phthalate metabolites were associated with glucose levels. MEP and MiBP-metabolites of diethyl phthalate and dibutyl phthalate, respectively-were associated with higher pregnancy glucose in subfertile women-a population at high risk of glucose intolerance in pregnancy. ",0
6588,29898873,"Effectiveness and safety of local anesthetic, semi-flexible pleuroscopy - experience from a peripheral hospital","If the seemingly less invasive semi-flexible pleuroscopes are combined with strategies of conscious sedation and local anesthesia the pleuroscopy has the potential to reach an increasing number of hospital settings. Local experiences can provide valuable information pertaining to the reproducibility of this technique in different scenarios. We performed a retrospective analysis of the clinical records of all patients that had undergone local anesthetic semi-flexible pleuroscopy in our unit between February 2015 and July 2017. Data on demographics, previous biochemical, cytological and histopathological analysis, procedure details, diagnostic and therapeutic results, complications and mortality were collected from all patients. Statistical analysis was performed using SPSS v23. A total of 30 patients were included. They were mainly male (66.7%), with a median age of 72 years (minimum 19 years, maximum 87 years). All presented with exudative pleural effusions and the exam was performed for diagnostic reasons. Pleural tissue was obtained in all patients and the overall diagnostic accuracy was 93.3%. Malignancy was the chief group of diagnosis (66.7%), followed by pleural tuberculosis (13.3%). The procedure was well tolerated and self-limited subcutaneous emphysema was the only complication registered (13.3%). No deaths were associated with the procedure. Our results globally overlap those of wider series and reinforce the perception that local anesthetic semi-flexible pleuroscopy is a well-tolerated, safe and highly accurate diagnostic and therapeutic tool which has proved to be both feasible and effective in our experience. ",0
6589,29899179,Involvement of Intracellular Cholesterol in Temozolomide-Induced Glioblastoma Cell Death,"Glioblastoma (GBM) still carries a poor prognosis due to the refractoriness against antitumor drugs. Temozolomide (TMZ), one of the few standard therapy drugs against GBM worldwide, has only limited effect due to acquired TMZ resistance of GBM. Therefore, development of novel therapeutic methods to overcome the TMZ resistance of GBM is urgent. The brain is the most cholesterol-rich organ in the human body, so modulation of cholesterol in tumor cells originating from the brain including GBM may be a tumor-specific therapeutic strategy including enhancement of TMZ effects. The unique lipid metabolism of glioma has recently been reported, but the involvement of intracellular cholesterol in TMZ therapy is yet to be fully elucidated. This review summarizes the effect of modulation of intracellular cholesterol level on cancer therapy including GBM treatment and the implications for TMZ therapy. Our recent findings about the involvement of intracellular cholesterol in TMZ-induced GBM cell death are described. ",0
6590,29899218,Rapid Colorimetric Detection of Cartap Residues by AgNP Sensor with Magnetic Molecularly Imprinted Microspheres as Recognition Elements,"The overuse of cartap in tea tree leads to hazardous residues threatening human health. A colorimetric determination was established to detect cartap residues in tea beverages by silver nanoparticles (AgNP) sensor with magnetic molecularly imprinted polymeric microspheres (Fe₃O₄@mSiO₂@MIPs) as recognition elements. Using Fe₃O₄ as supporting core, mesoporous SiO₂ as intermediate shell, methylacrylic acid as functional monomer, and cartap as template, Fe₃O₄@mSiO₂@MIPs were prepared to selectively and magnetically separate cartap from tea solution before colorimetric determination by AgNP sensors. The core-shell Fe₃O₄@mSiO₂@MIPs were also characterized by FT-IR, TEM, VSM, and experimental adsorption. The Fe₃O₄@mSiO₂@MIPs could be rapidly separated by an external magnet in 10 s with good reusability (maintained 95.2% through 10 cycles). The adsorption process of cartap on Fe₃O₄@mSiO₂@MIPs conformed to Langmuir adsorption isotherm with maximum adsorption capacity at 0.257 mmol/g and short equilibrium time of 30 min at 298 K. The AgNP colorimetric method semi-quantified cartap ≥5 mg/L by naked eye and quantified cartap 0.1⁻5 mg/L with LOD 0.01 mg/L by UV-vis spectroscopy. The AgNP colorimetric detection after pretreatment with Fe₃O₄@mSiO₂@MIPs could be successfully utilized to recognize and detect cartap residues in tea beverages. ",0
6591,29899250,Molecular Pathways Underlying Cholesterol Homeostasis,"Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern. ",0
6592,29899406,"LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation","Colorectal cancer (CRC) is one of the most common aggressive malignancies. Like other solid tumors, inactivation of tumor suppressor genes and activation of oncogenes occur during CRC development and progression. Recently, a novel tumor suppressor, LACTB, was proposed to inhibit tumor progression, but the functional and clinical significance of this tumor suppressor in CRC remains unexplored. Herein, we found LACTB was significantly downregulated in CRC due to promoter methylation and histone deacetylation, which was associated with metastasis and advanced clinical stage. CRC patients with low LACTB expression had poorer overall survival and LACTB also determined to be an independent prognostic factor for poorer outcome. Ectopic expression of LACTB suppressed CRC cells proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and inhibited CRC growth and metastasis in vivo, while knockout of LACTB by CRISPR/Cas9 gene editing technique resulted in an opposite phenotype. Interestingly, LACTB could exert antitumorigenic effect only in HCT116 and HCT8 cells harboring wild-type TP53, but not in HT29 and SW480 cells harboring mutant TP53 or HCT116 p53 ",0
6593,29899462,Phytochemicals-mediated production of hydrogen peroxide is crucial for high antibacterial activity of honeydew honey,"Honeydew honey is increasingly valued due to its pronounced antibacterial potential; however, the underlying mechanism and compounds responsible for the strong antibacterial activity of honeydew honey are still unknown. The aim of this study was to investigate the inhibition of bacterial growth of 23 honeydew honey samples. Activity of bee-derived glucose oxidase (GOX) enzyme, the content of defensin-1 (Def-1) and hydrogen peroxide (H ",0
6594,29899502,Development of a consent resource for genomic data sharing in the clinical setting,"Data sharing between clinicians, laboratories, and patients is essential for improvements in genomic medicine, but obtaining consent for individual-level data sharing is often hindered by a lack of time and resources. To address this issue, the Clinical Genome Resource (ClinGen) developed tools to facilitate consent, including a one-page consent form and online supplemental video with information on key topics, such as risks and benefits of data sharing. To determine whether the consent form and video accurately conveyed key data sharing concepts, we surveyed 5,162 members of the general public. We measured comprehension at baseline, after reading the form and watching the video. Additionally, we assessed participants' attitudes toward genomic data sharing. Participants' performance on comprehension questions significantly improved over baseline after reading the form and continued to improve after watching the video. Results suggest reading the form alone provided participants with important knowledge regarding broad data sharing, and watching the video allowed for broader comprehension. These materials are now available at http://www.clinicalgenome.org/share . These resources will provide patients a straightforward way to share their genetic and health information, and improve the scientific community's access to data generated through routine healthcare. ",0
6595,29899878,Prostaglandins in the pathogenesis of kidney diseases,"Prostaglandins (PGs) are important lipid mediators produced from arachidonic acid via the sequential catalyzation of cyclooxygenases (COXs) and specific prostaglandin synthases. There are five subtypes of PGs, namely PGE2, PGI2, PGD2, PGF2α, and thromboxane A2 (TXA2). PGs exert distinct roles by combining to a diverse family of membrane-spanning G protein-coupled prostanoid receptors. The distribution of these PGs, their specific synthases and receptors vary a lot in the kidney. This review summarized the recent findings of PGs together with the COXs and their specific synthases and receptors in regulating renal function and highlighted the insights into their roles in the pathogenesis of various kidney diseases. ",0
6596,29900357,Indicators to compare and assess the institutional strength of voluntary sustainability standards in the global coffee industry,"""The data presented in this article are related to the research article entitled """"The Voluntary Coffee Standard Index (VOCSI). Developing a composite Index to Assess and Compare the Institutional Strength of Mainstream Voluntary Sustainability Standards in the Global Coffee Industry"""" (Dietz et al., 2018) in press) [1]. The VOCSI presents the most detailed comparison all major voluntary sustainability standards (VSS) that currently exist in global coffee production. This Data in Brief contains the database that we have generated to set up the VOCSI. We publish this dataset in order to facilitate further critical or extended analyzes. """,0
6597,29900527,Mortality in schizophrenia: 30-year nationwide follow-up study,"Recent reports suggest that the mortality gap between persons with schizophrenia and the general population is increasing. We investigated the mortality, age at death, and causes of death among persons diagnosed with schizophrenia and the general population in Finland during 1984-2014. All persons with schizophrenia in Finland were identified from hospital discharge register, and compared with the Finnish population aged 16 years and older during 1984-2014, based on data from Statistics Finland. Age at death and standardized mortality ratio (SMR) were calculated for each follow-up year. Mean age at death increased from 57.6 years in 1984 to 70.1 years in 2014 in persons with schizophrenia, and from 70.9 to 77.5 years in the general population. All-cause SMR remained stable during the follow-up (2.6 in 1984 and 2.7 in 2014). A major change was observed in SMR for suicides which decreased from 11.0 in 1984 to 6.6 in 2014 (-40%). The SMRs for cardiovascular and cancer deaths showed increasing trends. The longevity of persons with schizophrenia is improving at approximately the same rate as the general population but suicide rates have declined substantially. However, there is still a major disparity in mortality compared with general population. ",0
6598,29900546,Role of MEKK1 in the anterior-posterior patterning during planarian regeneration,"Planarians have established a unique body pattern along the anterior-posterior (AP) axis, which consists of at least four distinct body regions arranged in an anterior to posterior sequence: head, prepharyngeal, pharyngeal (containing a pharynx), and tail regions, and possess high regenerative ability. How they reconstruct the regional continuity in a head-to-tail sequence after amputation still remains unknown. We use as a model planarian Dugesia japonica head regeneration from tail fragments, which involves dynamic rearrangement of the body regionality of preexisting tail tissues along the AP axis, and show here that RNA interference of the gene D. japonica mek kinase 1 (Djmekk1) caused a significant anterior shift in the position of pharynx regeneration at the expense of the prepharyngeal region, while keeping the head region relatively constant in size, and accordingly led to development of a relatively longer tail region. Our data suggest that DjMEKK1 regulates anterior extracellular signal-regulated kinase (ERK) and posterior β-catenin signaling pathways in a positive and negative manner, respectively, to establish a proper balance resulting in the regeneration of planarian's scale-invariant trunk-to-tail patterns across individuals. Furthermore, we demonstrated that DjMEKK1 negatively modulates planarian β-catenin activity via its serine/threonine kinase domain, but not its PHD/RING finger domain, by testing secondary axis formation in Xenopus embryos. The data suggest that Djmekk1 plays an instructive role in the coordination between the establishment of the prepharyngeal region and posteriorizing of pharynx formation by balancing the two opposing morphogenetic signals along the AP axis during planarian regeneration. ",0
6599,29900943,Association Between Joint Hypermobility and Gastroesophageal Reflux Disease: An Observational Analytical Cross Sectional Study,"This study aims to assess the association between joint hypermobility (JHM) and gastroesophageal reflux disease (GERD). This cross sectional study included 100 consecutive Iraqi patients (43 males, 57 females; mean age 30±6.6 years; range 18 to 40 years) with GERD diagnosed by a gastroenterologist according to the guidelines for diagnosis and management of GERD and age and sex matched 100 healthy controls (36 males, 64 females; mean age 30±5.2 years; range 20 to 40 years). JHM was measured using Beighton score method by a blinded observer. A score of 4 or more was considered hypermobile. Joint hypermobility values were significantly higher in GERD patients than in controls [46 (71.9%) vs 18 (28.1%), p<0.001, odds ratio=3.88; 95% confidence interval=2.04-7.39]. Multiple logistic regression analysis to detect predictors of GERD in JHM patients revealed that patients with high total mobility score (7- 9) had the highest risk for developing GERD [about 41 fold compared to those with normal mobility score (<4), P model <0.001, and overall prediction accuracy of 68%]. There is a significant association between JHM and GERD. The high total mobility score (7-9) was associated with a significantly high risk for developing GERD, indicating that early recognition of JHM may assist in early diagnosis and treatment of GERD. ",0
6600,29900978,Coexistence of Familial Mediterranean Fever With Ankylosing Spondylitis and Sjogren's Syndrome: A Rare Occurrence,"Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent episodes of fever, peritonitis, synovitis, pleuritis, and erysipelas-like skin lesions. Sjogren's syndrome is a chronic autoimmune disorder characterized by dry eyes, dry mouth, and musculoskeletal involvement. Ankylosing spondylitis is an autoinflammatory rheumatic disease which affects mainly the axial skeleton. To our knowledge, coexistence of familial Mediterranean fever with ankylosing spondylitis and Sjogren's syndrome has not been reported previously in the literature. In this article, we report an unusual case of three autoinflammatory diseases in one patient. ",0
6601,29901413,Melatonin as a Treatment after Traumatic Brain Injury: A Systematic Review and Meta-Analysis of the Pre-Clinical and Clinical Literature,"Traumatic brain injury (TBI) is common; however, effective treatments of the secondary brain injury are scarce. Melatonin is a potent, nonselective neuroprotective and anti-inflammatory agent that is showing promising results in neonatal brain injury. The aim of this study was to systematically evaluate the pre-clinical and clinical literature on the effectiveness of melatonin in improving outcome after TBI. Using the systematic review protocol for animal intervention studies (SYRCLE) and Cochrane methodology for clinical studies, a search of English-language articles was performed. Eligible studies were identified and data were extracted. Quality assessment was performed using the SYRCLE risk of bias tool. Meta-analyses were performed using standardized mean differences (SMD). Seventeen studies (15 pre-clinical, 2 clinical) met inclusion criteria. There was heterogeneity in the studies, and all had moderate-to-low risk of bias. Meta-analysis of pre-clinical data revealed an overall positive effect on neurobehavioural outcome with SMD of 1.51 (95% CI: 1.06-1.96). Melatonin treatment had a favorable effect on neurological status, by an SMD of 1.35 (95% CI: 0.83-1.88), and on cognition by an SMD of 1.16 (95% CI: 0.4-1.92). Melatonin decreased the size of the contusion by an SMD of 2.22 (95% CI: 0.8--3.59) and of cerebral edema by an SMD of 1.91 (95% CI: 1.08-2.74). Only two clinical studies were identified. They were of low quality, were used for symptom management, and were of uncertain significance. In conclusion, there is evidence that melatonin treatment after TBI significantly improves both behavioral outcomes and pathological outcomes; however, significant research gaps exist, especially in clinical populations. ",0
6602,29901534,Risk Factors for Loss of Lung Sliding in a Medical Intensive Care Population With Acute Respiratory Failure,"Point of care bedside ultrasound is widely utilized as a rapid technique to evaluate patients with acute pulmonary emergencies, including acute pneumothorax. The presence of a pneumothorax is a known cause of loss of lung sliding by ultrasound examination, but no other risk factors have been clearly identified. We attempted to identify demographic and patient characteristics that are risk factors for loss of ultrasonographic lung sliding in the absence of a pneumothorax. Data were collected on 159 patients admitted to the medical intensive care unit with acute respiratory failure, undergoing routine admission lung ultrasound. The lung ultrasound examination consisted of 3 views of each hemithorax using a phased array abdominal probe. There were 4 confirmed pneumothoraces out of 20 patients with loss of lung sliding at ≥1 ultrasound interrogation points on either hemithorax. Hypercarbic respiratory failure [odds ratio (OR), 5.59] and low body mass index (OR, 0.88) were statistically significant risk factors for the loss of lung sliding in the absence of pneumothorax. There was a trend toward significance in patients with a known history of a decreased forced expiratory volume 1/forced vital capacity ratio (OR, 0.02), COPD/asthma exacerbation as the cause of their respiratory failure (OR, 4.52) and previous pneumothorax (OR, 11.53). Common diagnoses and comorbidities are associated with the loss of ultrasonographic lung sliding, in the absence of pneumothorax. ",0
6603,29901552,Low Insulin-like Growth Factor-1 Influences Fatigue and Quality of Life in Children With Inflammatory Bowel Disease,"""Fatigue is common among patients with inflammatory bowel disease (IBD). Proinflammatory cytokines are elevated in chronic inflammation and can induce """"sickness behaviors,"""" such as fatigue. Chronic inflammatory states also lead to growth hormone resistance, demonstrated by low levels of insulin-like growth factor (IGF-1) and elevated growth hormone. This study evaluated the relationship between IGF-1, proinflammatory cytokine levels, and fatigue in patients with IBD. In this prospective study children with IBD, ages 10 to 16 years, were recruited from a subspecialty ambulatory clinic. Participants and their parents completed age-appropriate generic and disease-specific health-related quality of life (HRQOL) instruments. Serum samples obtained at the same encounter were analyzed for Th17 cytokine and IGF-1 levels. HRQOL scores were compared to a healthy sample and HRQOL scores and cytokine levels were compared by IGF-1 z score quartiles. A total of 67 patients with IBD were recruited, median age of 13.7 years (interquartile range, 11.7-15.3). Forty-eight (72%) had inactive disease based on Physician Global Assessment. Patients with IBD reported lower generic HRQOL (P = 0.0006) and more fatigue (P = 0.0004) than a healthy sample. Patients with IGF-1 z scores in the lowest quartile had significantly lower disease-specific HRQOL (P = 0.01) and more fatigue (P = 0.02) than the remainder of the cohort. Serum interleukin (IL)-10, IL-17A, IL-6, and interferon-γ were significantly higher in patients with IBD with IGF-1 z scores in the lowest quartile (P < 0.05). Children with subclinical IBD experience more fatigue and lower generic HRQOL than healthy children. Lower IGF-1 z scores are associated with more fatigue, and this relationship may be mediated through proinflammatory cytokines. """,0
6604,29901572,Association of Financial Literacy With Hospitalization in Community-dwelling Older Adults,"Lowering the likelihood of hospitalization in older adults is a major public health goal for modern health care systems. Emerging data suggest that financial literacy is an important determinant of health outcomes in old age, but the relationship with hospitalization has not been explored. To test the hypothesis that better financial literacy is related to lower risk of hospitalization in older persons. Prospective cohort study. Data came from community-dwelling older adults (n=388) without dementia enrolled in the Rush Memory and Aging Project. Participants underwent detailed assessment of financial literacy and cognition. Data on hospitalizations were obtained from linked Medicare claims records (MedPAR file). Over an average of 1.8 years, 117 participants (30%) were hospitalized, and a third of those hospitalized experienced multiple hospitalizations. In a modified Poisson regression model adjusted for age, sex, education, and cognition, better financial literacy was associated with lower risk of hospitalization. In a model further adjusted for income, physical activity, body mass index, smoking, social network size, chronic conditions, basic and instrumental activities of daily living disability, and depressive symptoms, the association was unchanged. Secondary analyses showed the association was primarily driven by conceptual knowledge rather than numeracy. Higher financial literacy is related to a lower risk of hospitalization in older persons without dementia, after adjusting for cognitive, health, functional, and socioeconomic factors. The ability to understand and utilize financial concepts may represent a potentially modifiable risk factor for hospitalization in later life. ",0
6605,29901702,YebC controls virulence by activating T3SS gene expression in the pathogen Edwardsiella piscicida,"Edwardsiella piscicida is an infectious Gram-negative bacterium that causes great losses to the aquaculture industry worldwide. Based on pattern analysis of conditional essentiality (PACE), a new method for transposon insertion sequencing (Tn-seq) data analysis, we investigated the genome-wide genetic requirements during the dynamic process of infection and colonization in turbot in this study. As a result, disruption of ETAE_1437 was discovered to lead to substantially reduced colonization, which was similar to the in vivo dynamic patterns of the mutants of T3SS or T6SS. Bioinformatics analysis indicated that ETAE_1437 is a YebC/PmpR family regulator. Moreover, we found that ETAE_1437 not only regulated quorum sensing by directly binding to the edwR promoter region but also activated T3SS expression by directly binding to the promoter region of the T3SS gene ETAE_0873. In addition, ETAE_1437 mutants exhibited substantial colonization defects and significantly decreased virulence in turbot. Overall, this study identified ETAE_1437 as a novel virulence regulator in E. piscicida and enriched our understanding of the pathogenesis of E. piscicida in fish. We thus reannotated ETAE_1437 as YebC. ",0
6606,29902468,Intravenous immunoglobulin ameliorates motor and cognitive deficits and neuropathology in R6/2 mouse model of Huntington's disease by decreasing mutant huntingtin protein level and normalizing NF-κB signaling pathway,"Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive movement disorders and cognitive deficits, which is caused by a CAG-repeat expansion encoding an extended polyglutamine (polyQ) tract in the huntingtin protein (HTT). Reduction of mutant HTT levels and inhibition of neuroinflammation has been proposed as a major therapeutic strategy in treating HD. Intravenous immunoglobulin (IVIg) therapy has been firmly established for the treatment of several autoimmune or inflammatory neurological diseases, either as adjunctive treatment or as first-line therapy. However, whether IVIg has therapeutic potential on HD remains unclear. Here we for the first time demonstrated that IVIg treatment remarkably rescued motor and cognitive deficits, prevented synaptic degeneration, attenuated neuroinflammation and oxidative stress in R6/2 mouse model. Further investigation showed that the beneficial effects of IVIg resulted from the reduced levels of mutant HTT and inhibition of NF-κB signalling pathway. These findings suggest that IVIg is a promising therapeutic potential for HD. ",0
6607,29902492,Analytical validation of viral CNS Flow Chip kit for detection of acute meningitis and encephalitis,"A new molecular assay (Viral CNS Flow Chip kit, Master Diagnóstica, Spain) has been developed for the detection of eight viruses causing acute meningitis and encephalitis, i.e. herpes simplex viruses 1-2, varicella zoster virus, human enterovirus, human parechovirus, Toscana virus, human cytomegalovirus and Epstein Barr virus. The new assay is a multiplex one-step RT-PCR followed by automatic flow-through hybridization, colorimetric detection and image analysis. The limit of detection was 50 copies/reaction, and 10 copies/reaction for human enterovirus and the other seven viruses, respectively. The analytical validation was performed with nucleic acids extracted from 268 cerebrospinal fluid samples and the results were compared with routine molecular assays. An excellent coefficient of agreement was observed between V-CNS and routine assays [kappa index: 0.948 (95%CI: 0.928-0.968)]. The overall sensitivity and specificity was 95.9% (95%CI: 91.2-98.3%) and 99.9% (95%CI: 99.6-100%), respectively. Viral CNS Flow Chip kit is an efficient multiplex platform for the detection of the main viruses involved in acute meningitis and encephalitis. The inclusion of a TOSV genome target may improve the laboratory diagnosis of viral neurological infections in endemic areas. ",0
6608,29902496,Penicisteroid C: New polyoxygenated steroid produced by co-culturing of Streptomyces piomogenus with Aspergillus niger,"Penicisteroid C, a new polyoxygenated steroid was isolated from co-cultivation of Streptomyces piomogenus AS63D and Aspergillus niger using solid-state fermentation on rice medium. Additional diverse eleven known metabolites were identified: Fumigaclavine C, fumiquinazoline C, physcion, methylsulochrin, methyllinoleate, glycerol linoleate, cerebroside A, thymine, adenine, thymidine and adenosine. The structure of penicisteroid C was determined by HRESIMS, 1D and 2D NMR data. The antimicrobial and in vitro cytotoxic activities of the microbial extract and penicisteroid C were reported as well. ",0
6609,29906252,Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial,"Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety. Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators. Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%). Pembrolizumab showed encouraging antitumor activity in patients with advanced TET. Given the high incidence of autoimmunity, additional studies are needed to identify those who can benefit from pembrolizumab without immune-related adverse events. ",0
6610,29906596,Are we missing respiratory viral infections in infants and children? Comparison of a hospital-based quality management system with standard of care,"Hospital-based surveillance of influenza and acute respiratory infections relies on International Classification of Diseases (ICD) codes and hospital laboratory reports (Standard-of-Care). It is unclear how many cases are missed with either method, i.e. remain undiagnosed/coded as influenza and other respiratory virus infections. Various influenza-like illness (ILI) definitions co-exist with little guidance on how to use them. We compared the diagnostic accuracy of standard surveillance methods with a prospective quality management (QM) programme at a Berlin children's hospital with the Robert Koch Institute. Independent from routine care, all patients fulfilling pre-defined ILI-criteria (QM-ILI) participated in the QM programme. A separate QM team conducted standardized clinical assessments and collected nasopharyngeal specimens for blinded real-time quantitative PCR for influenza A/B viruses, respiratory syncytial virus, adenovirus, rhinovirus and human metapneumovirus. Among 6073 individuals with ILI qualifying for the QM programme, only 8.7% (528/6073) would have undergone virus diagnostics during Standard-of-Care. Surveillance based on ICD codes would have missed 61% (359/587) of influenza diagnoses. Of baseline ICD codes, 53.2% (2811/5282) were non-specific, most commonly J06 ('acute upper respiratory infection'). Comparison of stakeholder case definitions revealed that QM-ILI and the WHO ILI case definition showed the highest overall sensitivities (84%-97% and 45%-68%, respectively) and the CDC ILI definition had the highest sensitivity for influenza infections (36%, 95% CI 31.4-40.8 for influenza A and 48%, 95% CI 40.5-54.7 for influenza B). Disease-burden estimates and surveillance should account for the underreporting of cases in routine care. Future studies should explore the effect of ILI screening and surveillance in various age groups and settings. Diagnostic algorithms should be based on the WHO ILI case definition combined with targeted testing. ",0
6611,29906630,A rare occurrence of viability of both small and large bowel in ileosigmoid knotting: A case report,"Ileosigmoid knot is an uncommon cause of acute intestinal obstruction where the ileum wraps around the base of a redundant sigmoid colon. We present an unusual case of a 45-year-old male patient who presented with signs and symptoms of intestinal obstruction. Exploratory laparotomy revealed an ileosigmoid knot. Both the small and large bowels were viable. The sigmoid colon was resected an end to end anastomosis was done. His post-operative period was uneventful. Preoperative diagnosis of the condition is difficult. Diagnostic delays coupled with the infrequent occurrence of the condition often results in patients commonly presenting with gangrene of the ileum, sigmoid loop or both. There is considerable controversy regarding the optimal management of this rare condition. Management involves preoperative resuscitation, empirical antibiotics and prompt relief of the obstruction. The anatomical and pathological changes of the involved loops of bowel dictate the definitive surgical procedure. The vast majority of cases present with gangrenous loops of ileum, the sigmoid colon or both. To identify the presence of the ileum and sigmoid colon being viable on exploration is a rarity. The management of a patient who has both viable loops of bowel on exploration is a contentious issue. Traditional teaching dictates that untying of the knot should be coupled with resection of the sigmoid colon to negate the risk of a recurrence. Some case reports suggest that resection may not be necessary as the risk of recurrence is believed to be low. ",0
6612,29906667,The high cost of critical care unit over-utilization for patients with NSTE ACS,"There is substantial variability among hospitals in critical care unit (CCU) utilization for patients admitted with non-ST-Segment Elevation Acute Coronary Syndromes (NSTE ACS). We estimated the potential cost saving if all hospitals adopted low CCU utilization practices for patients with NSTE ACS. National hospital claims data were used to identify all patients with a primary diagnosis of NSTE ACS initially admitted to an acute care hospital between 2007 and 2013. Hospital CCU utilization was classified as low (<30%), medium (30-70%), or high (>70%). Among the 270,564 NSTE ACS hospitalizations (71.6% non-ST-segment elevation myocardial infarction; 28.4% unstable angina) admitted to 261 hospitals, 41.9% (inter-hospital range 0.3%-95.1%) were admitted to a CCU. The proportion of patients admitted to a CCU in low, medium and high utilization hospitals was 16.3%, 49.5%, and high 81.1%, respectively. No differences in adjusted inpatient mortality were observed by hospital CCU utilization. The overall inpatient costs of caring for NSTE ACS were $1.1 billion. CCU care accounted for 45.2% of all hospitalization costs including 22.6%, 49.9%, and 69.0% (P < .001) of costs in low, medium and high utilization centers. The national potential direct cost savings of medium and high CCU utilization centers adopting low NSTE ACS CCU utilization practices was $113.4 million over the study period. In a population-based contemporary cohort, CCU utilization for patients with NSTE ACS varied widely and in-hospital mortality was similar between low, medium and high utilization centers. CCU care accounted for 45% of hospitalization costs; thus, implementing policies and admission practices to align hospital resources with patient care needs have the potential to reduce overall health care costs. ",0
6613,29906750,"Naringenin attenuates behavioral derangements induced by social defeat stress in mice via inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines","The effects of naringenin; a dietary flavonoid, with potent anti-oxidant and anti-inflammatory activities on social defeat stress (SDS)-induced neurobehavioral and biochemical changes were evaluated in mice using resident-intruder paradigm. The intruder male mice were distributed into 6 groups (n = 6). Mice in group 1 (control) received vehicle (3% DMSO, i.p), group 2 (SDS-control) were also given vehicle, groups 3-5 received naringenin (10, 25 and 50 mg/kg, i.p.) while group 6 had ginseng (50 mg/kg, i.p) daily for 14 days. However, 30 min after treatment on day 7, mice in groups 2-6 were exposed to SDS for a period of 10 min confrontation with aggressive counterparts for 7 consecutive days. Neurobehavioral phenotypes: spontaneous motor activity (SMA), memory, anxiety and depression were then evaluated on day 14. Malondialdehyde (MDA), glutathione (GSH), catalase and superoxide dismutase (SOD) were then estimated in the brain tissues. Acetylcholinesterase (AChE) activity and the concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) were also determined. SDS-induced neurobehavioral deficits were significantly (p < 0.05) attenuated by naringenin. The increased brain level of MDA (13.00 ± 0.63 μmol/g tissue) relative to vehicle-control (6.50 ± 0.43 μmol/g tissue) was significantly (p < 0.05) reduced to 5.50 ± 0.22 μmol/g tissue by naringenin (50 mg/kg). Mice exposed to SDS had decreased brain GSH level (5.17 ± 0.40 μmol/g tissue) relative to control (11.67 ± 0.84 μmol/g tissue). However, naringenin (50 mg/kg) significantly (p < 0.05) elevated GSH content (13.33 ± 0.88 μmol/g tissue) in the brains of SDS-mice. Moreover, 50 mg/Kg of naringenin (38.13 ± 2.38 ρg/mL) attenuated (p < 0.05) increased TNF-α level when compared with SDS (49.69 ± 2.81 ρg/mL). SDS-induced increase in brain level of IL-1β (236.5 ± 6.92 ρg/mL) was significantly (p < 0.05) reduced by naringenin (219.90 ± 15.25 ρg/mL). Naringenin also elevated antioxidant enzymes and decreased AChE activity in the brains of mice exposed to SDS (p < 0.05). These findings suggest that naringenin attenuates SDS-induced neurobehavioral deficits through inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines. ",0
6614,29907116,Intermittent oral levetiracetam reduced recurrence of febrile seizure accompanied with epileptiform discharge: a pilot study,"In previous study, we have found intermittent oral levetiracetam (LEV) can effectively prevent recurrence of febrile seizure (FS). This study aimed to analyze the effects of the preventive on the patients with frequent FS accompanied with epileptiform discharge. Patients with frequent FS were assigned to undergo Electroencephalogram (EEG). At the onset of fever, the patients who presented epileptiform discharge were orally administered with LEV with a dose of 15-30 mg/kg per day twice daily for 1 week, thereafter, the dosage was gradually reduced until totally discontinued in the second week. The seizure frequency associated with febrile events and FS recurrence rate during a 48-week follow-up were analyzed. among the 19 patients presented epileptiform discharge on EEG, 31.58% (6 of 19) had complex FS, 68.42% (13 of 19) had simple FS. Up to 57.89% (11 of 19) had a family history of seizure disorder and 36.84% (7 of 19) had a family history of FS in first-degree relatives. 42.11% (8 of 19) happened the first FS episode at the age < 18 months. 36.84% (7/19) presented generalized spikes, 63.16% (12/19) showed focal spikes. During the 48-week follow-up period, the patients experienced 26 febrile episodes, none of them presented seizure recurrence. Intermittent oral LEV can prevent the seizure recurrence of FS accompanied with epileptiform discharge in 48-week. However, further randomized controlled trials should be conducted. ChiCTR-IPR-15007241 ; Registered 1 January 2014 - Retrospectively registered. ",0
6615,29907193,Diagnostic potential of low molecular weight excretory secretory proteins of Paramphistomum epiclitum for caprine amphistomosis,"In the present study, the 75% alcoholic fractionation of excretory-secretory (ES) antigen isolated from 200 to 300 live P. epiclitum was assessed for its diagnostic potential for the detection of caprine amphistomosis by using antibody detection enzyme immunoassay. Prior to enzyme immunoassay, 75% alcoholic fractionation of excretory-secretory (ES) antigen was subjected to SDS- PAGE and western blot analysis for the presence of immunoreactive polypeptides. SDS-PAGE analysis of ES antigen resolved a total 7 polypeptides bands of size 56, 27, 25, 22.5, 12, 11 and 10 kDa. Western blot analysis revealed only two immunoreactive polypeptides (11 kDa and 12 kDa) when polypeptides resolved in SDS-PAGE were probed with known positive pooled serum. None of the polypeptides showed reactions with pooled known negative serum. The working dilutions of antigen, sera and conjugates were determined by checkerboard titration for employing ELISA and cut-off O.D. was calculated 0.616 by using the mean absorbance value of 11 negative kid sera. The sensitivity and specificity of ELISA was found to be 100% and 86.76%, respectively. As per kappa value estimation, the strength of agreement was found to be good. Antibodies to 75% alcoholic fractionation of ES antigen was detected in 20% goats (n = 160) of either sex, although faecal examination detected 10.6% goats to be infected with amphistomosis. The study confirmed that 75% alcoholic fractionation of ES antigen of P. epiclitum based ELISA had good value for serodiagnosis of caprine amphistomosis. ",0
6616,29907413,Development and optimization of a solid-phase microextraction gas chromatography-tandem mass spectrometry methodology to analyse ultraviolet filters in beach sand,"A methodology based on solid-phase microextraction (SPME) followed by gas chromatography-tandem mass spectrometry (GC-MS/MS) has been developed for the simultaneous analysis of eleven multiclass ultraviolet (UV) filters in beach sand. To the best of our knowledge, this is the first time that this extraction technique is applied to the analysis of UV filters in sand samples, and in other kind of environmental solid samples. Main extraction parameters such as the fibre coating, the amount of sample, the addition of salt, the volume of water added to the sand, and the temperature were optimized. An experimental design approach was implemented in order to find out the most favourable conditions. The final conditions consisted of adding 1 mL of water to 1 g of sample followed by the headspace SPME for 20 min at 100 °C, using PDMS/DVB as fibre coating. The SPME-GC-MS/MS method was validated in terms of linearity, accuracy, limits of detection and quantification, and precision. Recovery studies were also performed at three concentration levels in real Atlantic and Mediterranean sand samples. The recoveries were generally above 85% and relative standard deviations below 11%. The limits of detection were in the pg g ",0
6617,29907424,Repurposing drugs to treat l-DOPA-induced dyskinesia in Parkinson's disease,"In this review, we discuss the opportunity for repurposing drugs for use in l-DOPA-induced dyskinesia (LID) in Parkinson's disease. LID is a particularly suitable indication for drug repurposing given its pharmacological diversity, translatability of animal-models, availability of Phase II proof-of-concept (PoC) methodologies and the indication-specific regulatory environment. A compound fit for repurposing is defined as one with appropriate human safety-data as well as animal safety, toxicology and pharmacokinetic data as found in an Investigational New Drug (IND) package for another indication. We first focus on how such repurposing candidates can be identified and then discuss development strategies that might progress such a candidate towards a Phase II clinical PoC. We discuss traditional means for identifying repurposing candidates and contrast these with newer approaches, especially focussing on the use of computational and artificial intelligence (AI) platforms. We discuss strategies that can be categorised broadly as: in vivo phenotypic screening in a hypothesis-free manner; in vivo phenotypic screening based on analogy to a related disorder; hypothesis-driven evaluation of candidates in vivo and in silico screening with a hypothesis-agnostic component to the selection. To highlight the power of AI approaches, we describe a case study using IBM Watson where a training set of compounds, with demonstrated ability to reduce LID, were employed to identify novel repurposing candidates. Using the approaches discussed, many diverse candidates for repurposing in LID, originally envisaged for other indications, will be described that have already been evaluated for efficacy in non-human primate models of LID and/or clinically. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'. ",0
6618,29907694,HMGB1-induced autophagy facilitates hepatic stellate cells activation: a new pathway in liver fibrosis,"High-mobility group box-1 (HMGB1) plays a context-dependent role in autophagy, which is required for hepatic stellate cells (HSCs) activation. However, the significance of HMGB1-induced HSCs autophagy in liver fibrosis has not been elucidated. Here, we first documented an enrichment of peripheral and intrahepatic HMGB1 signal in hepatitis B virus (HBV)-related liver fibrosis progression, and presented a direct evidence of anatomic proximity of HMGB1 with a-SMA (a marker for HSCs activation) in cirrhotic liver specimens. Then, we demonstrated the autophagy-inducing effects by serum-sourced HMGB1 in both primary murine HSCs and human HSCs cell line (LX-2), reflected by increased number of autophagic vacuoles (AVs) under the transmission electron microscope (TEM) and up-regulated protein expression of lipidated microtubule-associated light chain 3 (LC3-II) (a marker for autophagosome) in Western blot analysis. Intriguingly, there is a possible translocation of endogenous HMGB1 from the nucleus to cytoplasm to extracellular space, during exogenous HMGB1-induced HSCs autophagy. Meanwhile, the dose- and time-dependent effects by recombinant HMGB1 (rHMGB1) in enhancing LX-2 autophagy and fibrogenesis have been revealed with activated extracellular regulated protein kinase (ERK)/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) and restrained mammalian target of rapamycin (mTOR)/STAT3 signaling pathways. Additionally, the ERK or JNK inhibitor could not only inhibit rHMGB1-induced autophagy and fibrogenesis in LX-2 cells, but also restore the suppressed mTOR and STAT3 pathways. Furthermore, using LC3-siRNA transfected LX-2, we found HMGB1-induced fibrogenesis is dependent on its autophagy-inducing effects. Finally, we elucidated the involvement of extracellular HMGB1-receptor for advenced glycation end product (RAGE) axis and endogenous HMGB1 in exogenous HMGB1-induced effects. Our findings could open new perspectives in developing an antifibrotic therapy by targetting the HSCs autophagy. ",0
6619,29907801,Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions,"To compare the pattern of gene-specific involvement and the spectrum of variants observed in prenatal and postnatal (mean ± SD, 8.9 ± 9.4 years) cohorts tested for Noonan syndrome and related conditions. Outcomes of sequencing panel testing were compared between prenatal (n = 845) and postnatal (n = 409) cohorts. PTPN11 and SOS1 harbored the majority of observed variants in both prenatal and postnatal cohorts, and BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, and SHOC2 had similarities in their pattern of involvement in both cohorts. PTPN11 was the largest contributor of pathogenic variants and had the lowest frequency of variants of uncertain significance (VUS). SOS1 had the highest VUS frequency in both cohorts. The overall VUS frequency was twice as high in prenatal specimens (58.1 vs. 29.3%). PTPN11 and SOS1 had a 1.5-fold higher VUS frequency in the prenatal cohort (10.7 vs. 7.4% and 95 vs. 61.1%, respectively). The diagnostic yield was 3.7% for prenatal samples, with a higher yield of 12.3% in fetuses with cystic hygroma as a sole finding, and 21.3% for postnatal. Comparison of prenatal versus postnatal specimens demonstrates that the pattern of specific gene involvement is similar, whereas the classification spectrum of observed variants differs considerably. ",0
6620,29908088,Influence of suturing technique on wound healing and patient morbidity after connective tissue harvesting. A randomized clinical trial,"The aims of this randomized clinical trial were to investigate the influence of the suturing technique and the thickness of the pre- and postoperative palatal and flap mucosa on the early healing of the palate after harvesting a connective tissue graft. Furthermore, patient pain perception was evaluated. A subepithelial connective tissue graft was obtained from the palate with a single horizontal incision technique. Patients were randomly assigned to continuous interlocking suture group or criss-cross suture group. The thickness of the palatal mucosa and residual palatal flap was measured; however, these variables were not randomized. One week postoperatively, the donor site wound healing was recorded by the modified rate of early healing index (EHI). Patient's pain perception was assessed by a visual analogue scale. Thirty-six patients were evaluated. No statistically significant differences were found between suturing technique and wound healing (p = 0.215). Statistically significant differences were found between postoperative flap thickness and EHI at 1, 3 and 6 mm from the incision line (p < 0.001). Negative correlations reaching statistical significance were found between the number of days of discomfort and residual flap thickness measured at 1, 3 and 6 mm. No association between the suture technique and the EHI was observed. Moreover, postoperative palatal flap thickness was associated with early wound healing of the donor site. Finally, the greater the postoperative palatal flap thickness, the less intensity of the pain perceived by patients. ",0
6621,29908291,"Tumor necrosis factor-α, interleukin-8 and eosinophil cationic protein as serum markers of glucocorticoid efficacy in the treatment of bronchial asthma","Bronchial asthma (BA) is a common chronic respiratory disease that has exhibited a rising global incidence in recent years. Glucocorticoids are used for the treatment of BA. Emerging evidence has demonstrated the roles of tumor necrosis factor (TNF-α), interleukin-8 (IL-8) and eosinophil cationic protein (ECP) in BA. The present study investigated whether TNF-α, IL-8 and ECP were associated with the clinical stages and severity of BA and the efficacy of glucocorticoids in the treatment of BA. A total of 199 patients with BA and 174 healthy individuals were included in this study. Patients with BA underwent glucocorticoid treatment, and the TNF-α, IL-8 and ECP levels and lung functions of the subjects were measured. The correlations of the TNF-α, IL-8 and ECP levels with BA severity, clinical staging and lung functions were assessed. We investigated whether the TNF-α, IL-8 and ECP levels aided in evaluating the efficacy of using glucocorticoids for the treatment of BA. TNF-α, IL-8 and ECP exhibited high levels in patients with BA, and glucocorticoid treatment notably decreased these levels. The TNF-α, IL-8 and ECP levels were positively correlated with the clinical stages and severity of BA and negatively correlated with lung function. TNF-α, IL-8 and ECP can be used as serum markers to predict the efficacy of glucocorticoids in the treatment of BA. The key findings of this study collectively support a role for TNF-α, IL-8 and ECP in BA development, and TNF-α, IL-8 and ECP can be used as serum markers of glucocorticoid efficacy in BA. ",0
6622,29908313,A magnetic resonance multi-atlas for the neonatal rabbit brain,"The rabbit model has become increasingly popular in neurodevelopmental studies as it is best suited to bridge the gap in translational research between small and large animals. In the context of preclinical studies, high-resolution magnetic resonance imaging (MRI) is often the best modality to investigate structural and functional variability of the brain, both in vivo and ex vivo. In most of the MRI-based studies, an important requirement to analyze the acquisitions is an accurate parcellation of the considered anatomical structures. Manual segmentation is time-consuming and typically poorly reproducible, while state-of-the-art automated segmentation algorithms rely on available atlases. In this work we introduce the first digital neonatal rabbit brain atlas consisting of 12 multi-modal acquisitions, parcellated into 89 areas according to a hierarchical taxonomy. Delineations were performed iteratively, alternating between segmentation propagation, label fusion and manual refinements, with the aim of controlling the quality while minimizing the bias introduced by the chosen sequence. Reliability and accuracy were assessed with cross-validation and intra- and inter-operator test-retests. Multi-atlas, versioned controlled segmentations repository and supplementary materials download links are available from the software repository documentation at https://github.com/gift-surg/SPOT-A-NeonatalRabbit. ",0
6623,29908387,Epilepsy mortality trends in Cuba compared with England and Wales: 1987-2010,"There are limited epilepsy mortality data from developing countries and Latin America in particular. We examined national epilepsy mortality data from Cuba and contrasted them with comparable data from England and Wales. National epilepsy mortality data for Cuba between the years 1987 and 2010 were obtained from the Medical Records and Health Statistics Bureau of the Cuban Public Health Ministry (www.sld.cu/sitios/dne/) with the corresponding mortality data from England and Wales obtained from the UK Office of National Statistics (ONS, www.ons.gov.uk). Indirect standardization with calculation of a standardized mortality ratio (SMR) was used to compare trends. The overall trend was of a slight decrease in mortality rates over the 23 years in Cuba, with higher mortality rates primarily occurring in young people. Annual age-adjusted rates were consistently lower in Cuba than those seen in England and Wales, with the SMR ranging from 0.35 (95% confidence interval (CI): 0.30 to 0.48) in 2007 to 1.00 (95% CI: 0.85 to 1.15) in 1994. Cuban epilepsy mortality rates are consistently lower than those of England and Wales. Reasons for this disparity in mortality rates are not immediately apparent but are likely to be multifactorial. ",0
6624,29908469,Simultaneous determination of six bioactive saponins from Rhizoma Panacis Japonici in rat plasma by UHPLC-MS/MS: Application to a pharmacokinetic study,"A specific, sensitive and rapid ultra high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method was developed and validated for simultaneous determination of six major bioactive constituents in Rhizoma Panacis Japonici (RPJ), including oleanolic acid-type chikusetsusaponin V, IV, hemsgiganoside B, damarane-type ginsenoside Rb1, Rg1 and Re in rat plasma, using estazolam as the internal standard (IS). Plasma samples were pretreated with methanol/acetonitrile (1:1, V/V) for protein precipitation. Chromatographic separation was performed on an Agilent Eclipse Plus C ",0
6625,29908495,Phytol shows anti-angiogenic activity and induces apoptosis in A549 cells by depolarizing the mitochondrial membrane potential,"In the present study, the antiproliferative activity of phytol and its mechanism of action against human lung adenocarcinoma cell line A549 were studied in detail. Results showed that phytol exhibited potent antiproliferative activity against A549 cells in a dose and time-dependent manner with an IC ",0
6626,29908900,"Molecular mechanisms of bi-directional ion transport in the Malpighian tubules of a lepidopteran crop pest, Trichoplusia ni","Classical studies have described in detail the complex and regionalized morphology of the Malpighian tubule (MT) in larval Lepidoptera. Recent studies revealed unusual aspects of ion transport in the Malpighian tubules of the larva of the cabbage looper, Trichoplusia ni. These included: cation reabsorption via secondary cells (SC); coupling of SCs to neighbouring PCs via gap junctions to enable reabsorption; and a reversal from cation secretion to reabsorption by the principal cells in the distal ileac plexus region of the in situ tubule in response to dietary ion loading. The current paper aimed to identify molecular components of ion transport in the MTs of T. ni and to describe their role in the recently reported reversal of ion transport in ion-loaded animals. Using a combination of molecular, immunohistochemical and electrophysiological techniques, we assigned roles to Na ",0
6627,29909233,Phenotype analyses of IL-10-producing Foxp3,"The mechanisms of allergen immunotherapy are not fully elucidated. Here, we sought to develop a murine model to demonstrate the effectiveness of subcutaneous immunotherapy (SCIT) for allergic responses. As excessive antigen dosages may induce immune tolerance in sensitized mice, the effects of SCIT were assessed by varying the antigen dosage. The mechanisms of SCIT were analyzed by focusing on the induction of Foxp3 Ovalbumin (OVA) + Al(OH) The maximum effects of SCIT were observed with 1 mg/animal of OVA for airway inflammation induced by 5 μg/animal of OVA, in which airway eosinophilia and Th2 cytokine production were markedly suppressed. The increase in the OVA-specific IgE level was significantly suppressed by SCIT. The development of bronchial epithelial thickening and mucus accumulation were also suppressed by SCIT. Concomitantly, IL-10-producing Foxp3 We successfully developed an airway allergic model for SCIT. It was suggested that most of IL-10-producing Foxp3 ",0
6628,29909404,Aortic Arch Width and Cardiovascular Disease in Men and Women in the Community,"We sought to determine whether increased aortic arch width (AAW) adds to standard Framingham risk factors and coronary artery calcium (CAC) for prediction of incident adverse cardiovascular disease (CVD) events in community-dwelling adults. A total of 3026 Framingham Heart Study Offspring and Third Generation cohort participants underwent noncontrast multidetector computed tomography from 2002 to 2005 to quantify CAC. We measured AAW as the distance between the centroids of the ascending and descending thoracic aorta, at the level of main pulmonary artery bifurcation or the right pulmonary artery. We determined sex, age group, and body size specific cut points for high (≥90th percentile) AAW from a healthy referent group (N=1471) and dichotomized AAW as high or not high across all study participants. Clinical covariates were obtained at Offspring cycle 7 (1998-2001) or Third Generation cycle 1 (2002-2005) examinations. The primary CVD outcome was a composite of myocardial infarction, coronary insufficiency, cerebrovascular accident, first hospitalization for heart failure, or CVD death. Cox proportional hazards models were used to estimate hazard ratio of high AAW on time-to-incident CVD after adjustment for Framingham risk factors and CAC. Net reclassification improvement was used to assess the effect of adding AAW to the baseline Framingham risk factor+CAC model. A total of 2826 participants (aged 51±11 years, 48% women) had complete covariates and were free of CVD at multidetector computed tomography. Over a median 8.9 years of follow-up, there were 135 incident CVD events. High AAW was independently predictive of CVD events (hazard ratio, 1.55;  AAW augments traditional CVD risk factors and CAC for prediction of incident adverse CVD events among community-dwelling adults. ",0
6629,29909447,Towards automation of glycomic profiling of complex biological materials,"Glycosylation is considered one of the most complex and structurally diverse post-translational modifications of proteins. Glycans play important roles in many biological processes such as protein folding, regulation of protein stability, solubility and serum half-life. One of the ways to study glycosylation is systematic structural characterizations of protein glycosylation utilizing glycomics methodology based around mass spectrometry (MS). The most prevalent bottleneck stages for glycomic analyses is laborious sample preparation steps. Therefore, in this study, we aim to improve sample preparations by automation. We recently demonstrated the successful application of an automated high-throughput (HT), glycan permethylation protocol based on 96-well microplates, in the analysis of purified glycoproteins. Therefore, we wanted to test if these developed HT methodologies could be applied to more complex biological starting materials. Our automated 96-well-plate based permethylation method showed very comparable results with established glycomic methodology. Very similar glycomic profiles were obtained for complex glycoprotein/protein mixtures derived from heterogeneous mouse tissues. Automated N-glycan release, enrichment and automated permethylation of samples proved to be convenient, robust and reliable. Therefore we conclude that these automated procedures are a step forward towards the development of a fully automated, fast and reliable glycomic profiling system for analysis of complex biological materials. ",0
6630,29909687,Comparative Efficacy of Autologous Stromal Vascular Fraction and Autologous Adipose-Derived Mesenchymal Stem Cells Combined With Hyaluronic Acid for the Treatment of Sheep Osteoarthritis,The current study explored whether intra-articular (IA) injection of autologous adipose mesenchymal stem cells (ASCs) combined with hyaluronic acid (HA) achieved better therapeutic efficacy than autologous stromal vascular fraction (SVF) combined with HA to prevent osteoarthritis (OA) progression and determined how long autologous ASCs combined with HA must remain in the joint to observe efficacy. OA models were established by performing anterior cruciate ligament transection (ACLT) and medial meniscectomy (MM). Autologous SVF (1×10 ,0
6631,29909780,Sinonasal papilloma: what influences the decision to request a magnetic resonance imaging scan?,"Computed tomography is the standard pre-operative imaging modality for sinonasal papilloma. The complementary use of magnetic resonance imaging as an additional investigation is debated. This study aimed to establish whether magnetic resonance imaging can accurately detect tumour extent and is a useful adjunct to computed tomography. A retrospective review was conducted on 19 patients with sinonasal papilloma. The interpretation of computed tomography and magnetic resonance imaging scans, by three clinicians, was conducted by comparing prediction of tumour extent. The perceived necessity of magnetic resonance imaging was compared between clinicians. The addition of magnetic resonance imaging improved accuracy of pre-operative interpretation; specifically, this finding was significant in cases with frontal sinus involvement. Surgeons were more likely than a radiologist to request magnetic resonance imaging, particularly when computed tomography indicated frontal sinus disease. Pre-operative combined magnetic resonance imaging and computed tomography helped predict disease in the frontal sinus better than computed tomography alone. A close working relationship between the ENT and radiology departments is important for accurate tumour localisation. ",0
6632,29909974,Cervical laminectomy and micro resection of the posterior venous plexus in Hirayama disease,"Hirayama disease is a rare cervical myelopathy predominantly affecting young adults and mainly found in Asia. It results in a pure motor distal lesion of the upper limbs with slow progression. Dynamic magnetic resonance imaging (MRI), which allows the diagnosis to be made, shows a typical appearance of anterior compression of the cervical spinal cord associated with enlargement of the posterior epidural spaces due to a dilated venous plexus. Surgery is considered when conservative treatment has failed. However, the type of surgery is not well standardized in this compressive myelopathy. We report on three patients with Hirayama disease operated using an original method: cervical decompressive laminectomy and coagulation of the posterior epidural plexus without fixation. The clinical, radiological and surgical data of these three patients were analyzed. Each patient underwent postoperative MR imaging. The mean age at diagnosis was 18.6 years (16-20 years) with a history of progressive symptoms lasting 1 to 4 years before treatment. Follow-up was 21 to 66 months after surgery. Neurological and electrophysiological improvement was noted in two patients; the third had stabilized. Postoperative MRI confirmed normalization of flexion imaging on MRI. None of the three patients complained of disabling neck pain. Posterior cervical decompression with coagulation of epidural venous plexus is a technique that seems effective in Hirayama disease in young subjects. It effectively treats patients by avoiding permanent cervical fixation. ",0
6633,29910053,Genetic burden and associations with adverse neurodevelopment in neonates with congenital heart disease,"""Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information. A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses. A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with """"neurotransmitters,"""" """"axon guidance,"""" and those incorporating """"RASopathy"""" genes in the development of NDD in CHD patients. These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group. """,0
6634,29910056,Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial,"SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome. ",0
6635,29910407,Exploring Motivation and Barriers to Physical Activity among Active and Inactive Australian Adults,"Physical inactivity is a major global public health issue associated with a range of chronic disease outcomes. As such, the underlying motivation and barriers to whether or not an individual engages in physical activity is of critical public health importance. This study examines the National Heart Foundation of Australia Heart Week Survey conducted in March 2015. A total of 894 (40% female) Australian adults aged 25⁻54 years completed the survey, including items relating to motivation and barriers to being physically active. The most frequently selected responses regarding motivation for physical activity among those categorised as active ( ",0
6636,29910490,Attenuation of the pressor responses to laryngoscopy and endotracheal intubation with intravenous dexmedetomidine versus magnesium sulphate under bispectral index-controlled anaesthesia: A placebo-controlled prospective randomised trial,"Laryngoscopy and intubation cause sympathetic stimulation and arousal reactions. We evaluated the role of dexmedetomidine and magnesium sulphate on pressor responses to laryngoscopy and intubation as compared to placebo, when depth of anaesthesia was maintained at a constant bispectral index (BIS) range 40-50 (±5). One hundred and twenty patients were randomised to receive either dexmedetomidine 1 μg/kg (Group DS), magnesium sulphate 30 mg/kg diluted in 100 ml saline (Group MS) or 100 ml normal saline (Group NS) 15 min before induction of anaesthesia in a double blind manner. After achieving BIS 40-50 (±5), laryngoscopy and intubation were performed. Heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded pre-drug, after drug, at intubation, at intervals of 1 min till 5 min, then every 2 min till 10 min and every 10 min for 30 min. Statistical analysis was done using Chi-square test and one way analysis of variance. SBP, DBP and HR fell in the DS and MS groups. No significant changes in BP were seen in the NS group at induction and after intubation. HR rose in the NS group ( At BIS levels 40-50 (±5) there was no pressor response to intubation in the NS Group. Dexmedetomidine and magnesium sulphate significantly reduced the heart rate and blood pressure from baseline. ",0
6637,29910727,Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression,"Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy) and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A ",0
6638,29911075,Trace element status in type 2 diabetes: A meta-analysis,"Type 2 diabetes is a chronic metabolic disorder that has been associated with alterations in the status of trace elements, including zinc, copper, iron and manganese. However, clinical studies reporting statuses of these trace elements in type 2 diabetes patients compared to controls have shown conflicting results. This meta-analysis aimed to summarize the existing literature on the statuses of zinc, copper, iron, and manganese in Type 2 diabetes mellitus patients. A literature search of Embase, PubMed, EBSCOHost, ScienceDirect, Scopus, Cochrane library and Web of Science electronic databases was conducted to find studies published from 1970 to November 2016 that compared the trace elements of interest between type 2 diabetic patients and healthy controls. Keywords used were type 2 diabetes, diabetes, hyperglycemia, insulin, glucose, HbA1c, trace elements, micronutrients, zinc, manganese, copper, ceruloplasmin, iron and ferritin. The bias corrected Hedges' g, was utilized as the effect sizes. Due to the biological interaction between trace elements, it is important to collectively evaluate the statuses of these minerals in type 2 diabetes. Thus, the robust variance estimation method was chosen to handle dependency between multiple outcomes. A total of 52 studies met the inclusion criteria, amounting to 98 effect sizes. Diabetic patients (n=20183) had significantly lower zinc status when compared to controls (effect size = -1.73, p<0.01); whereas copper (effect size = 1.10, p<0.05) and ferritin levels (effect size = 1.05, p<0.01) were significantly higher. Although not significant, ceruloplasmin (effect size = 1.85, p=0.06) and iron (effect size = 1.42, p=0.06) levels were higher, and manganese (effect size = 0.27, p=0.34) was lower in patients. Results from this meta-analysis indicate lower zinc status accompanied by increased copper and ferritin levels in patients with type 2 diabetes when compared to controls. ",0
6639,29911309,What women think about consent to research at the time of an obstetric emergency: a qualitative study of the views of a cohort of World Maternal Antifibrinolytic Trial participants,"The World Maternal Antifibrinolytic (WOMAN) Trial was the first in the UK to use the option of waiver of informed consent at the time of an obstetric emergency. This qualitative study aimed to investigate participants' views of the acceptability of the recruitment methods used. Qualitative study using in-depth interviews with women who did and did not give consent at the time of their recruitment to the WOMAN Trial. Highest UK recruitment site for the WOMAN Trial (129/569). Interviews were conducted in participants' homes. About 40 of the 129 women who were recruited to the WOMAN Trial at one UK site were invited to take part, 15 women were interviewed. Qualitative, interview study. Facilitators and barriers to successful recruitment during obstetric emergencies. Guidance for future researchers. Findings revealed that what is important is not so much the consent process used or a signature on a form, but the way in which consent is obtained. Clinicians who successfully negotiate consent to research during childbirth emergencies engage in a 'humane choreography' of words and actions. This emphasises the importance of prompt decision-making and treatment, while respecting the woman's personal situation and experience. Our findings do not support a single pathway to consent in the context of an obstetric emergency. Women understand that consent to research in an emergency is complex. Clinicians' skills in considering the clinical, ethical, and emotional aspects within the context of the clinical emergency can hamper or promote women's satisfaction. Study reports on women's views of consent to research in an obstetric emergency. Why and how was the study carried out? We undertook this study to find out what women thought about being included in a research study called the WOMAN Trial at the time they were being treated for heavy bleeding after giving birth. Some women had been asked if they wanted to be a part of the research at the time they were bleeding. Others were asked later, after they had recovered. We conducted interviews with 15 women who had been involved and asked what they thought about the way they had been asked, their preferences and ideas for improvements in future similar studies What were the main findings? Women understood how difficult it was for their doctors and midwives to ask them about the research study. They were pleased to have been included in the research and were mostly happy with the way they gave consent. Women's views were similar whether they were asked about the research at the time of the bleeding or after they had recovered. The most important thing was that doctors and midwives carefully thought about the situation the woman found herself in and how this might make her feel, so they could tailor their approach accordingly. What are the limitations of the work? This study only involved women from one hospital. The WOMAN Trial included women from many areas of the UK and other countries around the world. We do not know how their experiences or views may differ. What is the implication for professionals? Careful use of actions and words by birth attendants was the difference between a good or bad experience for the woman and her family. This is an important skill that could be developed as part of professional training. ",0
6640,29911376,Oncological Outcomes of Radical Cystectomy for Transitional Cell Carcinoma of Bladder,"To investigate the oncological outcome of radical cystectomy for muscle invasive bladder (MIBC) on cancerspecific survival. A consecutive series of patients undergoing radical cystectomy from 2004 to 2012 were recorded. The prognostic significance of several clinicopathologic factors in these patients were analyzed. The endpoint of oncological outcome was cancer-specific survival (CSS). The effect of clinical variables on CSS were statistically analysed by a log-rank test or Cox regression with hazard ratios. All analyses were performed using a 0.05 level of significance. One hundred eleven patients were analyzed. The average patient age when cystectomy was carried out was 65 (35 - 84) years. The 5-year cancer-specific survival rate was 36% for all 111 patients. The 5-year cancers-specific survival rates for patients with clinical T1, T2, T3 and T4 were 89%, 32%, 30% and 11.6%, respectively. Positive lymph nodes were found in 26 patients (23.4%) who had a 5-year cancer-specific survival 12.9%. Of several factors examined, univariate analysis identified tumor stage, nodal status, metastasis, margin positive and lymphovascular invasion (LVI) as significant predictors of OS, of which tumor stage and nodal status appeared to be independently related to overall survival on multivariate analysis. Radical cystectomy is a standard treatment for muscle invasive bladder cancer. Oncologic outcomes of radical cystectomy is generally favorable, however, surgery alone had no more potential to prolong survival of patients with invasive cancer, multimodal treatment approaches might need. ",0
6641,29911397,Transient Hyperthyroidism Induced by Thyroid Ultrasound,"Transient hyperthyroidism has been documented following surgical manipulation or direct trauma to the normal thyroid gland. This has best been studied in patients following parathyroidectomy and also reported following trauma to the neck, strangulation, and vigorous palpation of the thyroid gland. It has not previously been reported following a thyroid ultrasound. We report the case of a 58-year-old euthyroid woman with a large nontoxic multinodular goiter who developed transient hyperthyroidism following an ultrasound of the thyroid gland. She was not treated with anti-thyroid medications. Two weeks later, her free T3 and free T4 were normal, and 11 weeks after the ultrasound, all thyroid tests, including her TSH, were within the reference range. We believe this is the first report of a euthyroid individual who developed hyperthyroidism caused by thyroid ultrasonography. We hypothesize that pressure from the ultrasound probe during the examination compressed her large nodules, releasing stored hormone. ",0
6642,29912623,Saxagliptin Upregulates Nesfatin-1 Secretion and Ameliorates Insulin Resistance and Metabolic Profiles in Type 2 Diabetes Mellitus,"Saxagliptin as one of dipeptidyl peptidase-4 (DPP-4) inhibitors can effectively improve glycaemic control in type 2 diabetes mellitus, and nesfatin-1 is regarded as a very important factor in regulating feeding behavior and energy homeostasis. In this trial, we observed the effect of saxagliptin on regulating nesfatin-1 secretion and ameliorating insulin resistance and metabolic profiles in type 2 diabetes mellitus. One hundred two type 2 diabetes participants (M/F = 48/54) were investigated. Fifty-one (M/F = 24/27) of them as the treatment group were treated with oral glucose-lowering agents including saxagliptin, the other 51 (M/F = 24/27) as the control group were treated with oral glucose-lowering agents excluding any DPP-4 inhibitors. The parameters of serum nesfatin-1, C-peptide, homeostasis model assessment-β (HOMA-β) function, HOMA insulin resistance (HOMA-IR), glycosylated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), and blood pressure (BP) at baseline, month 3, 6, and 12 were observed and compared respectively. Saxagliptin significantly upregulated nesfatin-1 secretion (P < 0.001 at 3-, 6-, and 12-months vs. baseline), increased serum C-peptide (P < 0.05, 0.001, and 0.001 at 3-, 6-, and 12-months vs. baseline), improved HOMA-IR and function of HOMA-β (P < 0.001 at 3-, 6-, and 12-months vs. baseline) and metabolic profiles (P < 0.001 with HbA1c at 3-, 6- and 12-months; P < 0.001 with LDL-C at 6- and 12-months; P < 0.001 and 0.01 with HDL-C at 6- and 12-months vs. baseline), declined BMI (P < 0.05 at 6- and 12-months vs. baseline) and BP (P < 0.001 with systolic BP (SBP), and mean BP at 6- and 12-months, P < 0.01 with diastolic BP at 6- and 12-months vs. baseline). Saxagliptin could upregulate nesfatin-1 secretion and ameliorate insulin resistance and metabolic profiles in type 2 diabetes mellitus. Saxagliptin had the potential to play fundamental by upregulating nesfatin-1 secretion besides lowering glucose by inhibiting the degradation of glucagon-like peptide-1. ",0
6643,29912656,Neurological impairments in hypoxic neonates and lactate levels,"Metabolic acidosis with increasing lactate concentration develops due to the lack of oxygen in the tissues. The effect of lactic acidosis on neurological development in the first year of life. Our study included 50 newborns with perinatal hypoxia requiring oxygen therapy and 50 healthy newborns. pH, pCO2, pO2, base excess (BE) and lactates from arterialized capillary blood were determined in both groups of newborns, in the first and second hours after birth, and neurological development in the first year of life was estimated. pH, pCO2, pO2, BE and lactates differed significantly between the groups in the first and second hours after birth p < 0.01. Hypotonia was recorded in 20/50 cases and hypertonia was recorded in 10/50 cases in the first year of life. Lactate concentration may be an indicator of neurological damage in neonates with perinatal hypoxia. ",0
6644,29912839,Greater Reductions in Readmission Rates Achieved by Urban Hospitals Participating in the Medicare Shared Savings Program,"Accountable Care Organizations in the Medicare Shared Savings Program (MSSP) have financial incentives to reduce the cost and improve the quality of care delivered to Medicare beneficiaries that they serve. However, previous research about the impact of the MSSP on readmissions is limited and mixed. To examine the association between hospital participation in the MSSP during the 2012-2013 period and reductions in 30-day risk-standardized readmission rates for Medicare patients initially admitted for acute myocardial infarction, heart failure (HF), pneumonia, or any cause. Difference-in-differences estimation to compare the change in readmission rates for hospitals participating in the MSSP with that of other hospitals. Acute care hospitals that either participated in the MSSP or did not participate in any of Medicare Accountable Care Organization programs (for acute myocardial infarction, n=1631; for HF, n=1889; for pneumonia, n=1896; for any cause, n=2067). Compared with nonparticipating hospitals, MSSP-participating hospitals showed greater reductions in readmission rates for Medicare patients originally admitted for HF by 0.47 percentage points [95% confidence interval (CI), -0.76 to -0.17] and for pneumonia by 0.26 percentage points (95% CI, -0.49 to -0.03). MSSP-participating hospitals also showed more reductions in hospital-wide all-cause readmission by 0.10 percentage points (95% CI, -0.20 to 0.01), relative to nonparticipating hospitals during the first year of MSSP. MSSP-participating hospitals showed slightly greater reductions in readmissions during postimplementation years for Medicare patients initially admitted for HF or pneumonia, compared with other hospitals. ",0
6645,30021090,Evaluation of Medicare's Bundled Payments Initiative for Medical Conditions,"BACKGROUND: The Center for Medicare and Medicaid Innovation (CMMI) launched the Bundled Payments for Care Improvement (BPCI) initiative in 2013. A subsequent study showed that the initiative was associated with reductions in Medicare payments for total joint replacement, but little is known about the effect of BPCI on medical conditions. METHODS: We used Medicare claims from 2013 through 2015 to identify admissions for the five most commonly selected medical conditions in BPCI: congestive heart failure (CHF), pneumonia, chronic obstructive pulmonary disease (COPD), sepsis, and acute myocardial infarction (AMI). We used difference-in-differences analyses to assess changes in standardized Medicare payments per episode of care (defined as the hospitalization plus 90 days after discharge) for these conditions at BPCI hospitals and matched control hospitals. RESULTS: A total of 125 hospitals participated in BPCI for CHF, 105 hospitals for pneumonia, 101 hospitals for COPD, 88 hospitals for sepsis, and 73 hospitals for AMI. At baseline, the average Medicare payment per episode of care across the five conditions at BPCI hospitals was $24,280, which decreased to $23,993 during the intervention period (difference, -$286; P=0.41). Control hospitals had an average payment for all episodes of $23,901, which decreased to $23,503 during the intervention period (difference, -$398; P=0.08; difference in differences, $112; P=0.79). Changes from baseline to the intervention period in clinical complexity, length of stay, emergency department use or readmission within 30 or 90 days after hospital discharge, or death within 30 or 90 days after admission did not differ significantly between the intervention and control hospitals. CONCLUSIONS: Hospital participation in five common medical bundles under BPCI was not associated with significant changes in Medicare payments, clinical complexity, length of stay, emergency department use, hospital readmission, or mortality. (Funded by the Commonwealth Fund.).",0
6646,30137644,Tracking Fenestrae Dynamics in Live Murine Liver Sinusoidal Endothelial Cells,"The fenestrae of liver sinusoidal endothelial cells (LSECs) allow passive transport of solutes, macromolecules, and particulate material between the sinusoidal lumen and the liver parenchymal cells. Until recently, fenestrae and fenestrae-associated structures were mainly investigated using electron microscopy on chemically fixed LSECs. Hence, the knowledge about their dynamic properties has remained to date largely elusive. Recent progress in atomic force microscopy (AFM) has allowed the study of live cells in three dimensions (X, Y, and Z) over a prolonged time (t) and this at unprecedented speeds and resolving power. Hence, we employed the latest advances in AFM imaging on living LSECs. As a result, we were able to monitor the position, size, and number of fenestrae and sieve plates using four-dimensional AFM (X, Y, Z, and t) on intact LSECs in vitro. During these time-lapse experiments, dynamic data were collected on the origin and morphofunctional properties of the filtration apparatus of LSECs. We present structural evidence on single laying and grouped fenestrae, thereby elucidating their dynamic nature from formation to disappearance. We also collected data on the life span of fenestrae. More especially, the formation and closing of entire sieve plates were observed, and how the continuous rearrangement of sieve plates affects the structure of fenestrae within them was recorded. We observed also the dawn and rise of fenestrae-forming centers and defenestration centers in LSECs under different experimental conditions. Conclusion: Utilizing a multimodal biomedical high-resolution imaging technique we collected fine structural information on the life span, formation, and disappearance of LSEC fenestrae; by doing so, we also gathered evidence on three different pathways implemented in the loss of fenestrae that result in defenestrated LSECs.",0
6647,30184445,Quality of Care in the United Kingdom after Removal of Financial Incentives,"BACKGROUND: The benefits of pay-for-performance schemes in improving the quality of care remain uncertain. There is little information on the effect of removing incentives from existing pay-for-performance schemes. METHODS: We conducted interrupted time-series analyses of electronic medical record (EMR) data from 2010 to 2017 for 12 quality-of-care indicators in the United Kingdom's Quality and Outcomes Framework for which financial incentives were removed in 2014 and 6 indicators for which incentives were maintained. We estimated the effects of removing incentives on changes in performance on quality-of-care measures. RESULTS: Complete longitudinal data were available for 2819 English primary care practices with more than 20 million registered patients. There were immediate reductions in documented quality of care for all 12 indicators in the first year after the removal of financial incentives. Reductions were greatest for indicators related to health advice, with a reduction of 62.3 percentage points (95% confidence interval [CI], -65.6 to -59.0) in EMR documentation of lifestyle counseling for patients with hypertension. Changes were smaller for indicators involving clinical actions that automatically update the EMR, such as laboratory testing, with a reduction of 10.7 percentage points (95% CI, -13.6 to -7.8) in control of cholesterol in patients with coronary heart disease and 12.1 percentage points (95% CI, -13.6 to -10.6) for thyroid-function testing in patients with hypothyroidism. There was little change in performance on the 6 quality measures for which incentives were maintained. CONCLUSIONS: Removal of financial incentives was associated with an immediate decline in performance on quality measures. In part, the decline probably reflected changes in EMR documentation, but declines on measures involving laboratory testing suggest that incentive removal also changed the care delivered.",0
6648,30207912,Essential Role of BRCA2 in Ovarian Development and Function,"The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the BRCA2 gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, which resulted in chromosomal breakage and the failure of RAD51 to be recruited to double-stranded DNA breaks. The sisters also had microcephaly, and one sister was in long-term remission from leukemia, which had been diagnosed when she was 5 years old. Drosophila mutants that were null for an orthologue of BRCA2 were sterile, and gonadal dysgenesis was present in both sexes. These results revealed a new role for BRCA2 and highlight the importance to ovarian development of genes that are critical for recombination during meiosis. (Funded by the Israel Science Foundation and others.).",0
6649,30220337,Role of L-selectin on leukocytes in the binding of sialic acids on sperm surface during the phagocytosis of sperm in female reproductive tract,"In either natural fertilization or artificial insemination, hundreds of millions of sperm are ejaculated or inseminated and then deposited in the female reproductive tract, but only a few sperm reach the ampulla or the site of fertilization. This dramatic reduction in numbers clearly highlights the obstacles that sperm must overcome in order to reach the destination for egg fertilizing. Phagocytosis of sperm by leukocytes are repeatedly observed and generally considered to be one of the most important barriers, but the mechanism of the phagocytosis of sperm remains unclear. L-selectin is constitutively expressed on leukocytes, which can influence the behaviors of leukocytes when bind to ligands. Sialic acids are found as the outer most monosaccharide, capping the majority of glycans at the sperm surface, can act as recognition molecule. Since the sialic acids are considered as ligands of L-selectin, we propose that leukocytes bind to the sperm through the L-selectin on leukocytes and sialic acid on sperm surface during the sperm phagocytosis in female reproductive tract. ",0
6650,30220447,Evaluation of the nurse triage at the ophtalmology emergency department of Pierre-Paul-Riquet Hospital],"""The steady increase in the number of visits to the various emergency services combined with the decrease in medical demographics, make it necessary to optimize triage of patients to improve their care. The purpose of this study was to evaluate the pertinence of our triage questionnaire in the classification of ophthalmologic emergencies by severity. We used a monocentric cross-sectional study. From September 5 through September 25 2017, 858 patients who had all been seen in the ophthalmology emergency department of Pierre Paul Riquet Hospital of Toulouse university medical center and had responded to the triage nurse questionnaire were included. According to the symptoms presented or not by the patient, a color code was attributed (GREEN, ORANGE or RED) in order of increasing level of emergency. For each patient, we compared the severity of the final diagnosis by Base Score with the level of emergency established by our questionnaire. There were 118 """"GREEN"""" patients, 606 """"ORANGE"""" patients and 134 """"RED."""" We were able to analyze 822 patients. 21.65% of patients were correctly classified, 73.36% were overestimated (of which 87.06% by one level and 12.94% by two levels of severity), and 4.99% were underestimated (of which 90.24% by one level and 9.76% by two levels). Our current triage questionnaire is not sufficiently discriminating for effective triage of ophthalmologic emergencies. It often overestimates minor emergencies, causing a delay in treating other emergencies. We propose a new questionnaire modified according to the results obtained during our study. """,0
6651,30220839,Addressing Weight Suppression to Improve Treatment Outcome for Bulimia Nervosa,"Cognitive behavioral therapy (CBT) is regarded as the gold-standard treatment for bulimia nervosa (BN), yet despite impressive empirical support for its effectiveness, over 50% of patients fail to achieve abstinence from binge eating and purging by the end of treatment. One factor that may contribute to reduced efficacy rates in CBT is weight suppression (WS; the difference between a person's highest weight ever at their adult height and current weight). A growing body of research indicates that WS in patients with BN may have a clinically significant effect on symptomatology and prognosis. However, the current cognitive behavioral framework for BN does not explicitly acknowledge the role of WS in the onset or maintenance of BN symptoms and does not provide guidance for clinicians on how to address WS during treatment. The relationship between WS, biological pressure to regain lost weight, and the maintenance of BN symptoms suggest that current cognitive behavioral models of BN may be improved by considering the role of WS and exploring needed treatment modifications. Indeed, a reconceptualization of existing models may offer insight into potential strategies that can be used to reduce the susceptibility to treatment dropout, nonresponse, and relapse. It is therefore necessary to consider whether, and how, clinicians' consideration of WS during case conceptualization and treatment planning could serve to improve CBT outcomes. The current review explores ways in which high WS could contribute to poor CBT outcomes, provides preliminary clinical recommendations for incorporating WS into existing cognitive behavioral treatments based on extant data and clinical wisdom, and proposes suggestions for future research needed in this domain. ",0
6652,30220894,Finding the Integrated Care Evidence Base in PubMed and Beyond: A Bibliometric Study of the Challenges,"Integrated care research evidence should be optimally visible and accessible to stakeholders. This study examines the contribution of specific databases to the discovery of integrated care evidence, and tests the usefulness of Medical Subject Heading (MeSH) indexing of this literature within PubMed. We used bibliometric methods to analyse the integrated care literature indexed within six databases between 2007 and 2016. An international expert advisory group assessed the relevance of citations randomly retrieved from PubMed using MeSH term 'Delivery of Health Care, Integrated'. Integrated care evidence is diffuse, spread across many journals. Between 2007 and 2016, integrated care citations grew substantially, with the rate of increase highest in Embase. PubMed contributes the largest proportion of unique citations (citations not included in any of the other databases analysed), followed by Embase, PsycINFO and CINAHL. On average, expert reviewers rated 42.5% of citations retrieved by MeSH term 'Delivery of Health Care, Integrated' as relevant to integrated care. When these citations were dual reviewed, inter-rater agreement was low. MeSH terms alone are insufficient to retrieve integrated care content from PubMed. Embase and CINAHL contain unique content not found in PubMed that should not be overlooked. A validated search filter is proposed to simplify the process of finding integrated care research for clinicians, managers and decision-makers. ",0
6653,30221226,Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro,"A series of chalcone and heterocyclic isosteres, in which the enone moiety was replaced with an isoxazole and pyrazole ring system, was synthesized and their affinities for alpha synuclein (Asyn), amyloid beta (Aβ), and tau fibrils were measured in vitro. The compounds were found to have a modest affinity and selectivity for Asyn versus Aβ fibrils and low affinity for tau fibrils. Insertion of a double bond to increase the extendable surface area resulted in an increase in affinity and improvement in selectivity for Asyn versus Aβ and tau fibrils. The results of this study indicate that compound  ",0
6654,30221463,"The different perspectives of patients, informal caregivers and professionals on patient involvement in primary care teams. A qualitative study","Patient involvement in the decision-making process, especially for chronically ill elderly patients, has become an important element of patient-centred primary care in many countries, including the Netherlands. This study openly explores different perspectives of patients, informal caregivers and primary care professionals on patient involvement in primary care team interactions. Sixty-four qualitative semi-structured interviews with chronically ill elderly patients, informal caregivers and primary care professionals from various disciplines. Underpinned by a phenomenology approach, this study used conventional content analysis for data analysis. Participants have different views of the roles of patients and informal caregivers in the primary care team and thus different expectations of the extent and level of patient involvement. Three challenges impact patient involvement in the team: (a) patients feel misunderstood and less involved that they would like when professionals take control, (b) patients have to balance the conflicting opinions of different professionals and (c) informal caregivers act undesirably as team leaders due to their own view of the level of patient involvement. Patient involvement is formed in complex interactions between patients, informal caregivers and multiple professionals whose perspectives and expectations can be misaligned. Recognizing the value of patients and informal caregivers on the team could help professionals to understand them better and thus limit the likelihood of challenges arising in team interactions. ",0
6655,30221467,Role of social cognition in post-traumatic stress disorder: A review and meta-analysis,"Social functioning is a key component of recovery after a potentially traumatic experience, and the buffering role of the social support in trauma resilience and recovery has been very well documented. Factors contributing to resilience and recovery are notable because although most people will experience a traumatic event during their lifetimes, only 6% to 10% are diagnosed with post-traumatic stress disorder (PTSD). The relationship between an individual and their social environment is determined both by the quality of the social environment itself, and by the individual's perception and understanding of information conveyed by the other people around them. However, little research has considered the contribution of these internal social cognitive processes to PTSD risk or resilience. The current review draws on the existing literature on social cognitive functioning in trauma exposure and PTSD, identifying key questions and themes for future research. We utilized a meta-analytic approach to assess the evidence for alterations in social cognition in PTSD, finding a consistent large deficit in social cognitive performance in PTSD groups relative to trauma-exposed and healthy controls. We then reviewed the literature on the interaction of genes and the social environment, supporting the hypothesis that social cognitive deficits are a preexisting risk factor for PTSD. Finally, we reviewed relevant neuroimaging findings, which suggest that alterations in social cognition affect the perception of threat cues in PTSD. Overall, research on social cognition and PTSD is still emerging, but existing findings suggest this is an important and understudied area for the understanding of PTSD. ",0
6656,30221822,Family environment and traumatic dental injuries in adolescents,"No comprehensive assessment of the influence of the home environment on traumatic dental injuries (TDI) has been conducted to date. The aim of this study was to explore the relationship between family environment and TDI among adolescents from East London. This cross-sectional study used data from 646 adolescents who participated in phase III of the Research with East London Adolescents Community Health Survey (RELACHS). Family environment was measured with four indicators (non-nuclear family, discordant parental relationship and levels of parental support and parental punishment) measured through a self-administered questionnaire. Clinical examinations were performed for TDI, overjet and lip coverage. Logistic regression was used to test the crude and adjusted (controlling for sociodemographic and clinical factors) association of each family environment characteristic with TDI prevalence. Twenty-nine percent of adolescents were from non-nuclear families, and 52.3% reported a discordant parental relationship. The mean score for parental support was -0.01 (SD: 0.90, range: -0.11 to 0.08), and the mean parental punishment score was 0.03 (SD: 0.86, range: -0.04 to 0.10). Adolescents from non-nuclear families had 1.63 (95% confidence interval: 1.06-2.53) greater odds of having TDI than those from nuclear families. However, this association was fully attenuated after adjusting for sociodemographic and clinical factors. The other three indicators of family environment were not associated with TDI either in crude or adjusted regression models. This study found weak evidence of an association between family environment and TDI. ",0
6657,30221986,Arthroscopic Meniscopexy for the Treatment of Nontraumatic Osteochondritis Dissecans in the Knee Joint of Adult Patients,"Objective The etiology of osteochondritis dissecans (OCD) is still uncertain. Recently, it has been hypothesized that instability of the anterior horn of the meniscus is an important cause for the development of a nontraumatic OCD in adolescents with good results after surgical stabilization. This case series aims to evaluate the treatment results after meniscus stabilization in adults with nontraumatic OCD. Design Ten patients with magnetic resonance imaging (MRI)-confirmed OCD of the knee joint, meniscal instability, and closed epiphyseal plates were enrolled in this study. The instable meniscus was stabilized by direct suturing of the anterior horn of the meniscus. MRI examinations were performed preoperative and 6 and 12 months postoperative. The OCD was classified arthroscopically according to Guhl and according to Hughes in the MRI. The overall knee function was evaluated by the Lysholm score before treatment and 12 months postoperative. Results Four women and 6 men with a mean age of 20.6 ± 1.9 years were included in this study. Preoperatively 60% of the patients showed a grade II or III lesion arthroscopically and 70% a grade III or IVa lesion in the MRI examination. After arthroscopic meniscus stabilization the Lysholm score increased in average from 48.1 ± 14.12 before treatment to 97.5 ± 3.1 postoperative. At final follow-up after 12 months, an improvement of the OCD in the MRI could be demonstrated in all patients (100%). In 80% of the patients a complete healing of the OCD could be noted. Conclusion The clinical concept of an instable anterior horn of the meniscus as a cause for the development of a nontraumatic OCD seems to be transferable to adults and arthroscopic stabilization can lead to a sufficient healing of this knee pathology. ",0
6658,30222139,Entering the spotlight: hepatitis B surface antigen-specific B cells,"Hepatitis B virus-specific (HBV-specific) T cells have been identified as main effector cells in HBV clearance. In contrast, B cells producing neutralizing antibodies against the HBV surface antigen (HBsAg) have been studied in little detail, mainly due to methodical limitations. In this issue of the JCI, two reports use a new technique to specifically detect and characterize HBsAg-specific B cells ex vivo. Indeed, these cells are present, but show phenotypic alterations and impaired function during acute and chronic HBV infection. Thus, HBsAg-specific B cells are a novel attractive target for antiviral strategies toward functional cure of chronic HBV infection. ",0
6659,30222236,Factors associated with first thrombosis in patients presenting with obstetric antiphospholipid syndrome (APS) in the APS Alliance for Clinical Trials and International Networking Clinical Database and Repository: a retrospective study,"To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. Retrospective study. The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository. Women with Ob-APS. Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM). Risk factors for thrombosis and aGAPSS. Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4-16) versus 9 (4-13); P = 0.0089]. Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity. ",0
6660,30226642,A Roadmap for Value-Based Payment Models Among Patients With Cirrhosis,"Healthcare reimbursement is shifting from fee-for-service to fee-for-value. Cirrhosis, which costs the U.S. healthcare system as much as heart failure, is a prime target for value-based care. This article describes models in which physician groups or health systems are paid for improving quality and lowering costs for a given population of patients with cirrhosis. If done correctly, we believe that such frameworks, once adopted, could help reduce burnout by freeing physicians of the burden of checking boxes in the electronic medical record so that they can devote their energies to managing populations. Conclusion: Value-based payment models for cirrhosis have the potential to benefit patients, physicians, and healthcare insurers.",0
6661,30251414,The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease,"The use of pluripotent stem cells (PSCs) has transformed the investigation of liver development and disease. Clinical observations and animal models have provided the foundations of our understanding in these fields. While animal models remain essential research tools, long experimental lead times and low throughput limit the scope of investigations. The ability of PSCs to produce large numbers of human hepatocyte-like cells, with a given or modified genetic background, allows investigators to use previously incompatible experimental techniques, such as high-throughput screens, to enhance our understanding of liver development and disease. In this review, we explore how PSCs have expedited our understanding of developmental mechanisms and have been used to identify new therapeutic options for numerous hepatic diseases. We discuss the future directions of the field, including how to further unlock the potential of the PSC model to make it amenable for use with a broader range of assays and a greater repertoire of diseases. Furthermore, we evaluate the current weaknesses of the PSC model and the directions open to researchers to address these limitations. Conclusion: The use of PSCs to model human liver disease and development has and will continue to have substantial impact, which is likely to further expand as protocols used to generate hepatic cells are improved.",0
6662,30276829,Letter to Editor: Response to AASLD Editorial/Message from the President,A commentary [1] criticized our systematic review regarding the use of direct-acting agents (DAAs) in chronic hepatitis C [2]. The following represents our major disagreements. Sustained virological response (SVR) is a non-validated surrogate outcome. The principles of evidence-based medicine require that it be validated in randomized clinical trials (RCTs) by showing parallel benefits in clinical outcomes [3]. This article is protected by copyright. All rights reserved.,0
6663,30281992,Acceleration of BMI in Early Childhood and Risk of Sustained Obesity,"""BACKGROUND: The dynamics of body-mass index (BMI) in children from birth to adolescence are unclear, and whether susceptibility for the development of sustained obesity occurs at a specific age in children is important to determine. METHODS: To assess the age at onset of obesity, we performed prospective and retrospective analyses of the course of BMI over time in a population-based sample of 51,505 children for whom sequential anthropometric data were available during childhood (0 to 14 years of age) and adolescence (15 to 18 years of age). In addition, we assessed the dynamics of annual BMI increments, defined as the change in BMI standard-deviation score per year, during childhood in 34,196 children. RESULTS: In retrospective analyses, we found that most of the adolescents with normal weight had always had a normal weight throughout childhood. Approximately half (53%) of the obese adolescents had been overweight or obese from 5 years of age onward, and the BMI standard-deviation score further increased with age. In prospective analyses, we found that almost 90% of the children who were obese at 3 years of age were overweight or obese in adolescence. Among the adolescents who were obese, the greatest acceleration in annual BMI increments had occurred between 2 and 6 years of age, with a further rise in BMI percentile thereafter. High acceleration in annual BMI increments during the preschool years (but not during the school years) was associated with a risk of overweight or obesity in adolescence that was 1.4 times as high as the risk among children who had had stable BMI. The rate of overweight or obesity in adolescence was higher among children who had been large for gestational age at birth (43.7%) than among those who had been at an appropriate weight for gestational age (28.4%) or small for gestational age (27.2%), which corresponded to a risk of adolescent obesity that was 1.55 times as high among those who had been large for gestational age as among the other groups. CONCLUSIONS: Among obese adolescents, the most rapid weight gain had occurred between 2 and 6 years of age; most children who were obese at that age were obese in adolescence. (Funded by the German Research Council for the Clinical Research Center """"Obesity Mechanisms"""" and others; ClinicalTrials.gov number, NCT03072537 .).""",0
6664,30345907,MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease,"BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7�10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7�10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3�10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4�10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5�10(-6)). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Soci�t� Fran�aise de Rhumatologie and others.).",0
6665,30380364,Immune Escape of Relapsed AML Cells after Allogeneic Transplantation,"BACKGROUND: As consolidation therapy for acute myeloid leukemia (AML), allogeneic hematopoietic stem-cell transplantation provides a benefit in part by means of an immune-mediated graft-versus-leukemia effect. We hypothesized that the immune-mediated selective pressure imposed by allogeneic transplantation may cause distinct patterns of tumor evolution in relapsed disease. METHODS: We performed enhanced exome sequencing on paired samples obtained at initial presentation with AML and at relapse from 15 patients who had a relapse after hematopoietic stem-cell transplantation (with transplants from an HLA-matched sibling, HLA-matched unrelated donor, or HLA-mismatched unrelated donor) and from 20 patients who had a relapse after chemotherapy. We performed RNA sequencing and flow cytometry on a subgroup of these samples and on additional samples for validation. RESULTS: On exome sequencing, the spectrum of gained and lost mutations observed with relapse after transplantation was similar to the spectrum observed with relapse after chemotherapy. Specifically, relapse after transplantation was not associated with the acquisition of previously unknown AML-specific mutations or structural variations in immune-related genes. In contrast, RNA sequencing of samples obtained at relapse after transplantation revealed dysregulation of pathways involved in adaptive and innate immunity, including down-regulation of major histocompatibility complex (MHC) class II genes ( HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) to levels that were 3 to 12 times lower than the levels seen in paired samples obtained at presentation. Flow cytometry and immunohistochemical analysis confirmed decreased expression of MHC class II at relapse in 17 of 34 patients who had a relapse after transplantation. Evidence suggested that interferon-? treatment could rapidly reverse this phenotype in AML blasts in vitro. CONCLUSIONS: AML relapse after transplantation was not associated with the acquisition of relapse-specific mutations in immune-related genes. However, it was associated with dysregulation of pathways that may influence immune function, including down-regulation of MHC class II genes, which are involved in antigen presentation. These epigenetic changes may be reversible with appropriate therapy. (Funded by the National Cancer Institute and others.).",0
6666,30383299,Letter to Editor: Using Proper Methods to Identify Patients With Cirrhosis in Administrative Databases Is Crucial to Correctly Predict Outcomes,"We would like to congratulate Mumtaz et�al.(1) for their important study attempting to develop and validate a risk score to predict 30-day hospital readmission in decompensated cirrhosis patients using the US nationwide readmission database (NRD). The identification of cirrhosis patients at high-risk for readmission is critical for developing processes to effectively address this problem. However, flaws in patient identification challenge the utility of the risk-score outlined in this study. This article is protected by copyright. All rights reserved.",0
6667,30398671,"Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013-2016","Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in the United States, causing substantial morbidity and mortality and costing billions of dollars annually. To update the estimated HCV prevalence among all adults aged ?18 years in the United States, we analyzed 2013-2016 data from the National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of HCV in the noninstitutionalized civilian population and used a combination of literature reviews and population size estimation approaches to estimate the HCV prevalence and population sizes for four additional populations: incarcerated people, unsheltered homeless people, active-duty military personnel, and nursing home residents. We estimated that during 2013-2016 1.7% (95% confidence interval [CI], 1.4-2.0%) of all adults in the United States, approximately 4.1 (3.4-4.9) million persons, were HCV antibody-positive (indicating past or current infection) and that 1.0% (95% CI, 0.8-1.1%) of all adults, approximately 2.4 (2.0-2.8) million persons, were HCV RNA-positive (indicating current infection). This includes 3.7 million noninstitutionalized civilian adults in the United States with HCV antibodies and 2.1 million with HCV RNA and an estimated 0.38 million HCV antibody-positive persons and 0.25 million HCV RNA-positive persons not part of the 2013-2016 NHANES sampling frame. Conclusion: Over 2 million people in the United States had current HCV infection during 2013-2016; compared to past estimates based on similar methodology, HCV antibody prevalence may have increased, while RNA prevalence may have decreased, likely reflecting the combination of the opioid crisis, curative treatment for HCV infection, and mortality among the HCV-infected population; efforts on multiple fronts are needed to combat the evolving HCV epidemic, including increasing capacity for and access to HCV testing, linkage to care, and cure.",0
6668,30403942,Daratumumab for Delayed Red-Cell Engraftment after Allogeneic Transplantation,"Daratumumab, a human IgG1? monoclonal antibody targeting CD38, is used to treat multiple myeloma. We describe successful treatment with daratumumab in a case of treatment-refractory pure red-cell aplasia after ABO-mismatched allogeneic stem-cell transplantation. The patient was a 72-year-old man with the myelodysplastic syndrome who received a transplant from an HLA-matched, unrelated donor with a major ABO incompatibility (blood group A in the donor and blood group O in the recipient). The patient had persistent circulating anti-A antibodies and no red-cell recovery 200 days after transplantation. Standard treatments had no effect. Within 1 week after the initiation of treatment with daratumumab, he no longer required transfusions.",0
6669,30485780,Attention Deficit-Hyperactivity Disorder and Month of School Enrollment,"BACKGROUND: Younger children in a school grade cohort may be more likely to receive a diagnosis of attention deficit-hyperactivity disorder (ADHD) than their older peers because of age-based variation in behavior that may be attributed to ADHD rather than to the younger age of the children. Most U.S. states have arbitrary age cutoffs for entry into public school. Therefore, within the same grade, children with birthdays close to the cutoff date can differ in age by nearly 1 year. METHODS: We used data from 2007 through 2015 from a large insurance database to compare the rate of ADHD diagnosis among children born in August with that among children born in September in states with and states without the requirement that children be 5 years old by September 1 for enrollment in kindergarten. ADHD diagnosis was determined on the basis of diagnosis codes from the International Classification of Diseases, 9th Revision. We also used prescription records to compare ADHD treatment between children born in August and children born in September in states with and states without the cutoff date of September 1. RESULTS: The study population included 407,846 children in all U.S. states who were born in the period from 2007 through 2009 and were followed through December 2015. The rate of claims-based ADHD diagnosis among children in states with a September 1 cutoff was 85.1 per 10,000 children (309 cases among 36,319 children; 95% confidence interval [CI], 75.6 to 94.2) among those born in August and 63.6 per 10,000 children (225 cases among 35,353 children; 95% CI, 55.4 to 71.9) among those born in September, an absolute difference of 21.5 per 10,000 children (95% CI, 8.8 to 34.0); the corresponding difference in states without the September 1 cutoff was 8.9 per 10,000 children (95% CI, -14.9 to 20.8). The rate of ADHD treatment was 52.9 per 10,000 children (192 of 36,319 children; 95% CI, 45.4 to 60.3) among those born in August and 40.4 per 10,000 children (143 of 35,353 children; 95% CI, 33.8 to 47.1) among those born in September, an absolute difference of 12.5 per 10,000 children (95% CI, 2.43 to 22.4). These differences were not observed for other month-to-month comparisons, nor were they observed in states with non-September cutoff dates for starting kindergarten. In addition, in states with a September 1 cutoff, no significant differences between August-born and September-born children were observed in rates of asthma, diabetes, or obesity. CONCLUSIONS: Rates of diagnosis and treatment of ADHD are higher among children born in August than among children born in September in states with a September 1 cutoff for kindergarten entry. (Funded by the National Institutes of Health.).",0
6670,30575473,Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up,"BACKGROUND: Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term follow-up is sparse. METHODS: We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model. RESULTS: By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer). CONCLUSIONS: Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer. (Funded by the Swedish Cancer Society and others.).",0
6671,30586159,"Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus","Hepatitis B virus (HBV) infection is a major health concern worldwide. To prevent HBV-related mortality, elimination of viral proteins is considered the ultimate goal of HBV treatment; however, currently available nucleos(t)ide analogs rarely achieve this goal, as viral transcription from episomal viral covalently closed circular DNA (cccDNA) is not prevented. HBV regulatory protein X was recently found to target the protein structural maintenance of chromosomes 5/6 (Smc5/6) for ubiquitination and degradation by DDB1-CUL4-ROC1 E3 ligase, resulting in enhanced viral transcription from cccDNA. This ubiquitin-dependent proteasomal pathway requires an additional ubiquitin-like protein for activation, neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8). Here, we show that pevonedistat, a NEDD8-activating enzyme inhibitor, works efficiently as an antiviral agent. Pevonedistat significantly restored Smc5/6 protein levels and suppressed viral transcription and protein production in the HBV minicircle system in in vitro HBV replication models and in human primary hepatocytes infected naturally with HBV. Conclusion: These results indicate that pevonedistat is a promising compound to treat chronic HBV infection.",0
6672,30586518,Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis,There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).,0
6673,30614547,A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A,"Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na(+) /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-? (IFN-?) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-? on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-? treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.",0
6674,30650324,The Structural Violence of Hyperincarceration - A 44-Year-Old Man with Back Pain,"Mr. M., an uninsured, 44-year-old Puerto Rican man with chronic back pain, diabetes, hypertension, asthma, and a history of incarceration presented to a free clinic with acute exacerbation of back pain triggered by carrying heavy loads of trash at work. A premedical student acting as his health care advocate accompanied him. Mr. M. was hesitant to seek health care because he had no health insurance and mistrusted institutions as a result of his extensive negative experiences with the criminal justice system. He was visibly nervous in the unfamiliar institutional environment of the clinic, which had no Latino staff and was located in a middle-class neighborhood far from his home. The advocate reassured him in Spanish that the doctor was trustworthy and urged him to speak frankly about his health problems, including his challenges in obtaining medication. Embarrassed, Mr. M. reported that during recent back-pain exacerbations he occasionally resorted to purchasing one or two 5-mg oxycodone tablets in the open-air drug market operating on the inner-city block where he lived. The physician gave Mr. M. ibuprofen and a prescription for five 5-mg oxycodone tablets, enrolled him in the clinic�s diabetes and hypertension programs, and scheduled a follow-up visit. Mr. M. never filled the prescription and did not return to the clinic, despite repeated entreaties by the advocate both in person and over the phone. Mr. M.�s pain had eased, and he claimed to be managing his diabetes, hypertension, and asthma by splitting medication with insured family members. To stretch their supply, they rationed their doses for use only on the days when they �felt symptoms.� Finally, 8 months later, Mr. M. admitted that he had not dared fill his prescription or return to the clinic for fear of being rearrested after admitting to the doctor that he had purchased oxycodone illegally.",0
6675,30661248,"Lymphocyte Antigen 6 Complex, Locus C(+) Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice","To understand the mechanism(s) of age-dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age-related HBV mouse model in which 6-week-old (N6W) C3H/HeN mice exhibited virus tolerance whereas 12-week-old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C-C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)(+) monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF-?-secreting Ly6C(+) monocytes and fewer IL-10-secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon-?(+) TNF-?(+) CD8(+) T cells at D7 was only seen in the older cohort. The enhanced Ly6C(+) monocyte induction in N12W mice resulted from elevated C-C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C(+) monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C(+) monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C(+) monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV-related liver diseases.",0
6676,30664279,Direct Inhibition of Hepatitis B e Antigen by Core Protein Allosteric Modulator,"Hepatitis B e antigen (HBeAg) is an important immunomodulator for promoting host immune tolerance during chronic hepatitis B (CHB) infection. In patients with CHB, HBeAg loss and seroconversion represent partial immune control of CHB infection and are regarded as valuable endpoints. However, the current approved treatments have only a limited efficacy in achieving HBeAg seroconversion in HBeAg-positive patients. Hepatitis B virus (HBV) core protein has been recognized as an attractive antiviral target, and two classes of core protein allosteric modulator (CpAM) have been discovered: the phenylpropenamides (PPAs) and the heteroaryldihydropyrimidines (HAPs). However, their differentiation and potential therapeutic benefit beyond HBV DNA inhibition remain to be seen. Here, we show that in contrast to PPA series compound AT-130, a HAP CpAM, HAP_R01, reduced HBeAg levels in multiple in vitro and in vivo HBV experimental models. Mechanistically, we found that HAP_R01 treatment caused the misassembly of capsids formed by purified HBeAg in vitro. In addition, HAP_R01 directly reduces HBeAg levels by inducing intracellular precore protein misassembly and aggregation. Using a HAP_R01-resistant mutant, we found that HAP_R01-mediated HBeAg and core protein reductions were mediated through the same mechanism. Furthermore, HAP_R01 treatment substantially reduced serum HBeAg levels in an HBV mouse model. Conclusion: Unlike PPA series compound AT-130, HAP_R01 not only inhibits HBV DNA levels but also directly reduces HBeAg through induction of its misassembly. HAP_R01, as well as other similar CpAMs, has the potential to achieve higher anti-HBeAg seroconversion rates than currently approved therapies for patients with CHB. Our findings also provide guidance for dose selection when designing clinical trials with molecules from HAP series.",0
6677,30693544,An Efficient Combination Immunotherapy for Primary Liver Cancer by Harmonized Activation of Innate and Adaptive Immunity in Mice,"Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. In previous experiments, we unexpectedly identified a robust liver tumor-preventive effect of a synthetic double-stranded RNA, polyinosinic-polycytidylic acid (polyIC), in mice. Herein we further demonstrate that polyIC given at the precancer stage effectively prevented liver tumorigenesis by activating natural killer cells, macrophages, and some T-cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced programmed death ligand 1 (PD-L1) expression in liver sinusoid endothelial cells, which prompted us to test a combined treatment of polyIC and PD-L1 antibody (Ab). Although injecting PD-L1 Ab alone did not show any therapeutic effect, injection of polyIC sensitized the hepatic response to PD-L1 blockade. Combination of polyIC and PD-L1 Ab resulted in sustained accumulation of active cluster of differentiation 8 cytotoxic T cells and robust liver tumor suppression and conferred a survival advantage in mice. These preclinical data in animal models suggest that, despite the low efficacy of PD-L1/PD-1 blockade alone, careful design of mechanism-based combinatorial immunotherapeutic protocols may shift the paradigm in liver cancer treatment by coordinating maximal activation of multiple innate and adaptive immune functions. Conclusion: We provide proof of principle for the development of an efficient prevention strategy of liver tumorigenesis and a powerful combination immunotherapy for primary liver cancer.",0
6678,30699320,"New Neuroscience of Homeostasis and Drives for Food, Water, and Salt","Well-being requires the maintenance of energy stores, water, and sodium within permissive zones. The brain, as ringleader, orchestrates their homeostatic control. It senses disturbances, decides what needs to be done next, and then restores balance by altering physiological processes and ingestive drives (i.e., hunger, thirst, and salt appetite). But how the brain orchestrates this control has been unknown until recently � largely because we have lacked the ability to elucidate and then probe the underlying neuronal �wiring diagrams.� This has changed with the advent of new, transformative neuroscientific tools. When targeted to specific neurons, these tools make it possible to selectively map a neuron�s connections, measure its responses to various homeostatic challenges, and experimentally manipulate its activity. This review examines these approaches and then highlights how they are advancing, and in some cases profoundly changing, our understanding of energy, water, and salt homeostasis and the linked ingestive drives.",0
6679,30706949,Liver Expression of a MiniATP7B Gene Results in Long-Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice,"Gene therapy with an adeno-associated vector (AAV) serotype 8 encoding the human ATPase copper-transporting beta polypeptide (ATP7B) complementary DNA (cDNA; AAV8-ATP7B) is able to provide long-term copper metabolism correction in 6-week-old male Wilson disease (WD) mice. However, the size of the genome (5.2 kilobases [kb]) surpasses the optimal packaging capacity of the vector, which resulted in low-yield production; in addition, further analyses in WD female mice and in animals with a more advanced disease revealed reduced therapeutic efficacy, as compared to younger males. To improve efficacy of the treatment, an optimized shorter AAV vector was generated, in which four out of six metal-binding domains (MBDs) were deleted from the ATP7B coding sequence, giving rise to the miniATP7B protein (?57-486-ATP7B). In contrast to AAV8-ATP7B, AAV8-miniATP7B could be produced at high titers and was able to restore copper homeostasis in 6- and 12-week-old male and female WD mice. In addition, a recently developed synthetic AAV vector, AAVAnc80, carrying the miniATP7B gene was similarly effective at preventing liver damage, restoring copper homeostasis, and improving survival 1 year after treatment. Transduction of approximately 20% of hepatocytes was sufficient to normalize copper homeostasis, suggesting that corrected hepatocytes are acting as a sink to eliminate excess of copper. Importantly, administration of AAVAnc80-miniATP7B was safe in healthy mice and did not result in copper deficiency. Conclusion: In summary, gene therapy using an optimized therapeutic cassette in different AAV systems provides long-term correction of copper metabolism regardless of sex or stage of disease in a clinically relevant WD mouse model. These results pave the way for the implementation of gene therapy in WD patients.",0
6680,30723923,Exosomal Interferon-Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti-Hepatitis B Virus Efficacy of Exogenous Interferon Alpha,"The negative regulators in the interferon (IFN) signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to IFN? treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti-HBV (hepatitis B virus) efficacy of IFN?. From the Gene Expression Omnibus (GEO) database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to IFN? (GSE54747), and found that innate immune status was associated with the IFN?-based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of IFN-induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of IFN? mRNA in peripheral blood mononuclear cells (PBMCs) of CHB patients with suboptimal response to IFN? treatment. Increased IFITM2 protein was also found in the serum of IFN? nonresponsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous IFN? synthesis by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3); knocking out IFITM2 enhanced activation of the endogenous IFN? synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled by exosomes to dendritic cells (DCs), the main source of endogenous IFN?. Exosome-mediated transport of IFITM2 inhibited synthesis of endogenous IFN? in DCs whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of IFN? against HBV. Conclusion: Exosome-mediated transport of IFITM2 to DCs inhibits IFN? pathway activation and blocks anti-HBV efficacy of exogenous IFN?. The findings provide an explanation to the suboptimal response of CHB patients to IFN? treatment.",0
6681,30741017,Primary neurolymphomatosis of the trigeminal nerve,"We report a case of a primary malignant lymphoma of the trigeminal nerve that was associated with facial pain. A 65-year-old man was examined at another hospital for unilateral facial pain. Carbamazepine was prescribed, but his symptoms did not improve. Magnetic resonance imaging (MRI) revealed swelling of the trigeminal nerve and a mass lesion in Meckel's cave. The patient was referred to our hospital at this point. Gadolinium-enhanced MRI and F18-Fluorodeoxyglucose-position emission tomography suggested a likely malignant tumour and a biopsy was performed. Histopathological examination showed diffuse a large B cell lymphoma. The patient was treated with high-dose methotrexate (HD-MTX) and radiotherapy. Despite responding well to initial treatment, the patient relapsed, with lymphoma observed throughout the body. He died of pneumonia 18 months after the initial diagnosis. Facial pain is a symptom that is commonly managed in general practice. If symptoms do not improve, repeated imaging studies, including contrast MRI, is warranted. This is the first reported case of primary neurolymphomatosis (NL) of the trigeminal nerve associated with facial pain alone. Furthermore, HD-MTX and radiotherapy may be considered for the management of primary NL of a cranial nerve. ",0
6682,30741575,"Appraisal of the relationship between tooth inclination, dehiscence, fenestration, and sagittal skeletal pattern with cone beam computed tomography","To examine the relationship between sagittal facial pattern and dehiscence/fenestration presence in conjunction with buccolingual tooth inclination by using cone beam computed tomography. The study was carried out on the cone beam computed tomography scans of the following three groups of patients (n = 20 in each group): Class I, Class II, Class III. Buccolingual tooth inclination, buccal dehiscence/fenestration presence, and lingual dehiscence/fenestration presence were evaluated on each tooth. Analysis of variance, Kruskall-Wallis H, Scheffe, and chi-square tests were used for statistical comparisons. Differences ( Orthodontists must consider concealed alveolar defects in treatment planning to avoid gingival recession or tooth mobility. ",0
6683,30741732,"""Socioeconomic """"Distressed Communities Index"""" Improves Surgical Risk-adjustment""","We hypothesize the Distressed Communities Index (DCI), a composite socioeconomic ranking by ZIP code, will predict risk-adjusted outcomes after surgery. Socioeconomic status affects surgical outcomes; however, the American College of Surgeons National Surgery Quality Improvement Program (ACS NSQIP) database does not account for these factors. All ACS NSQIP patients (17,228) undergoing surgery (2005 to 2015) at a large academic institution were paired with the DCI, which accounts for unemployment, education level, poverty rate, median income, business growth, and housing vacancies. Developed by the Economic Innovation Group, DCI scores range from 0 (no distress) to 100 (severe distress). Multivariable regressions were used to evaluate ACS NSQIP predicted risk-adjusted effect of DCI on outcomes and inflation-adjusted hospital cost. A total of 4522 (26.2%) patients came from severely distressed communities (top quartile). These patients had higher rates of medical comorbidities, transfer from outside hospital, emergency status, and higher ACS NSQIP predicted risk scores (all P < 0.05). In addition, these patients had greater resource utilization, increased postoperative complications, and higher short- and long-term mortality (all P < 0.05). Risk-adjustment with multivariate regression demonstrated that DCI independently predicts postoperative complications (odds ratio 1.1, P = 0.01) even after accounting for ACS NSQIP predicted risk score. Furthermore, DCI independently predicted inflation-adjusted cost (+$978/quartile, P < 0.0001) after risk adjustment. The DCI, an established metric for socioeconomic distress, improves ACS NSQIP risk-adjustment to predict outcomes and hospital cost. These findings highlight the impact of socioeconomic status on surgical outcomes and should be integrated into ACS NSQIP risk models. ",0
6684,30741804,Noninvasive Prenatal Whole Genome Sequencing: Pregnant Women's Views and Preferences,"""To assess pregnant women's views and preferences on noninvasive prenatal whole genome sequencing. A survey was offered to 805 pregnant women receiving prenatal care in practices affiliated with a large, tertiary care maternity hospital. Respondents were asked to envision undergoing prenatal whole genome sequencing and discuss their preferences and reasons for receiving different categories of genomic results, organized by actionability, severity, prevalence, and age of onset. The survey also queried respondents on their preferred role for clinicians in prenatal whole genome sequencing decision-making, and on their demographics and genetic literacy. From June to August 2017, a total of 553 respondents returned the survey (response rate=68.7%). Respondents were most likely to want information regarding serious treatable childhood-onset conditions (89.7%) and least likely to want to receive information about nonmedical traits from prenatal whole genome sequencing (40%). The most frequently cited reason for wanting medical prenatal whole genome sequencing results was """"to prepare financially, medically, or psychologically for a child with special needs."""" In total, 10.5% of respondents wanted clear recommendations from clinicians about the categories of information that are most appropriate to test for, 44.7% wanted clear recommendations plus all options presented, 26.2% wanted all options presented and joint decision-making, and 13.2% wanted all options presented and independent decision-making. Respondents generally preferred to receive all categories of genetic results pertaining to medical conditions and wanted the information to prepare. More than half of respondents wanted (at minimum) clear recommendations from clinicians when deciding which prenatal whole genome sequencing results to receive. """,0
6685,30741848,"Risk Factors for Complications and Nondiagnostic Results following 1,155 Consecutive Percutaneous Core Renal Mass Biopsies","The purpose of this study was to evaluate patient, tumor and technical factors associated with procedural complications and nondiagnostic findings following percutaneous core renal mass biopsy. We reviewed core renal mass biopsies from 2000 to 2017. Complications at 30 days or less were graded using the Clavien-Dindo system. Univariate and multivariable analyses were done to evaluate associations between clinical characteristics and the risk of complications or nondiagnostic findings. Of the 1,155 biopsies performed in a total of 965 patients procedural complications were identified in 24 patients (2.2%), including 5 (0.4%) with major complications (Clavien 3a or greater). No patients were identified with tumor seeding of the biopsy tract. Patient age, body mass index, gender, Charlson comorbidity index, smoking, mass diameter, nephrometry score, number of cores and prior biopsy were not associated with complication risk (p = 0.06 to 0.53). Complications were not increased for patients on aspirin or those with low platelets (25,000 to 160,000/μl blood) or a mildly elevated INR (international normalized ratio) (1.2 to 2.0, p = 0.16, 0.07 and 0.50, respectively). The complication risk was not increased during the initial 50 cases of a radiologist or when a trainee was present (p = 0.35 and 0.12, respectively). Nondiagnostic findings were present in 14.6% of biopsies. Independent predictors included cystic features, contrast enhancement, mass diameter and skin-to-mass distance (p <0.001, 0.002, 0.02 and 0.049, respectively). Radiologist experience was not associated with the nondiagnostic rate (p = 0.23). Prior nondiagnostic biopsy was not associated with an increased nondiagnostic rate on subsequent attempts (19.2% vs 14.2%, p = 0.23). Procedural complications following biopsy are rare even with low serum platelets, a mildly elevated INR or when the patient remains on aspirin. Cystic features, hypo-enhancement on imaging, a smaller mass diameter and a longer skin-to-tumor distance increase the risk of nondiagnostic findings. ",0
6686,30742736,A cohort study of local excision followed by adjuvant therapy incorporating a contact X-ray brachytherapy boost instead of radical resection in 180 patients with rectal cancer,"Recent data have suggested near-equivalent oncological results when treating early rectal cancer by local excision followed by radio- ± chemotherapy rather than salvage radical surgery. The aim of this retrospective study was to assess the use of contact X-ray brachytherapy within this paradigm. All patients had undergone local excision and were referred to our radiotherapy centre for treatment with contact X-ray brachytherapy. Postoperative (chemo)radiotherapy was also given in their local hospital in most cases. Variables assessed were local excision method, postoperative therapy received, follow-up duration, disease-free survival, salvage surgery and stoma-free survival. In total, 180 patients with a median age of 70 (range 36-99) years were assessed. Following local excision, pT stages were pT1 = 131 (72%), pT2 = 44 (26%), pT3 = 5 (2%). All patients received contact X-ray brachytherapy boosting at our centre and, in addition, 110 received chemoradiotherapy and 60 received radiotherapy alone. After a median follow-up of 36 months (range 6-48), 169 patients (94%) remained free of local recurrence. Of the 11 patients with local recurrence (three isolated nodal), five underwent salvage abdominoperineal excision. Eight patients developed distant disease, of whom five underwent metastasis surgery. At last included follow-up 173 (96%) patients were free of all disease and 170 (94%) were stoma free. Contact therapy can be offered in addition to external beam radio (±chemo) therapy instead of radical surgery as follow-on treatment after local excision of early rectal cancer. This combination can provide equivalent outcomes to radical surgery. The added value of contact therapy should be formally assessed in a clinical trial. ",0
6687,30742761,Poor People and Poor Health: Examining the Mediating Effect of Unmet Healthcare Needs in Korea,"The purpose of this study was to estimate the mediating effect of subjective unmet healthcare needs on poor health. The mediating effect of unmet needs on health outcomes was estimated. Cross-sectional research method was used to analyze Korea Health Panel data from 2011 to 2015, investigating the mediating effect for each annual dataset and lagged dependent variables. The magnitude of the effect of low income on poor health and the mediating effect of unmet needs were estimated using age, sex, education level, employment status, healthcare insurance status, disability, and chronic disease as control variables and selfrated health as the dependent variable. The mediating effect of unmet needs due to financial reasons was between 14.7% to 32.9% of the total marginal effect, and 7.2% to 18.7% in lagged model. The fixed-effect logit model demonstrated that the existence of unmet needs raised the likelihood of poor self-rated health. However, only a small proportion of the effects of low income on health was mediated by unmet needs, and the results varied annually. Further studies are necessary to search for ways to explain the varying results in the Korea Health Panel data, as well as to consider a time series analysis of the mediating effect. The results of this study present the clear implication that even though it is crucial to address the unmet needs, but it is not enough to tackle the income related health inequalities. ",0
6688,30742904,Immunosenescence in honey bees (Apis mellifera L.) is caused by intrinsic senescence and behavioral physiology,"Young honey bee workers (0 to 2-3 weeks old) perform tasks inside the colony, including brood care (nursing), whereas older workers undergo foraging tasks during the next 3-4 weeks, when an intrinsic senescence program culminates in worker death. We hypothesized that foragers are less able to react to immune system stimulation than nurse bees and that this difference is due to an inefficient immune response in foragers. To test this hypothesis, we used an experimental design that allowed us to uncouple chronological age and behavior status (nursing/foraging). Worker bees from a normal age demography colony (where workers naturally transit from nursing to foraging tasks as they age) and of a single-cohort colony setup (composed of same-aged workers performing nursing or foraging tasks) were tested for survival and capability of activation of the immune system after bacterial injection. Expression of an antimicrobial peptide gene, defensin-1 (def-1), was used to assess immune system activation. We then checked whether the immune response includes changes in the expression of aging- and behavior-related genes, specifically vitellogenin (vg), juvenile hormone esterase (jhe), and insulin-like peptide-1 (ilp-1). We found a significant difference in survival rate between bees of different ages but carrying out the same tasks. Our results thus indicate that the bees' immune response is negatively affected by intrinsic senescence. Additionally, independent of age, foragers had a shorter lifespan than nurses after bacterial infection, although both were able to induce def-1 transcription. In the normal age demography colony, the immune system activation resulted in a reduction in the expression of vg, jhe and ilp-1 genes in foragers, but not in the nurse bees, demonstrating that age and behavior are both important influences on the bees' immune response. By disentangling the effects of age and behavior in the single-cohort colony, we found that vg, jhe and ilp-1 response to immune system stimulation was independent of behavior. Younger bees were able to mount a stronger immune response than older bees, thus highlighting age as an important factor for immunity. Taken together, our results provide new insights into how age and behavior affect the honey bee's immune response. ",0
6689,30743035,Pediatric Cranial Fasciitis: Discussion of Cases and Systematic Review of the Literature,"Cranial fasciitis is a rare benign mass that typically presents in pediatric patients from 3 weeks to 6 years of age. It is classified as a subset of nodular fasciitis and was first reported in 1980. This study evaluates the literature for common characteristics that may affect diagnosis and treamtent. We describe the case of a 13-month-old girl with a history of accidental head trauma 7 months before presentation and the case of a 5-month-old girl with an expansile skull lesion. We also performed a systematic review of the reported data on cranial fasciitis, including a total of 57 reported studies with 80 unique cases. There were 80 total cases reviewed in the literature. There was a male predominence, 1.75:1. The average age at presentation was 5.2 years. The most common causes for this lesion were idiopathic (65%), blunt trauma (14%) and radiation therapy (7%). Overall, there was a 9% recurrence rate following treatment. We report the characteristics at presentation, including, to the best of our knowledge, the first account of gender differences, and the treatment modalities used in the included studies and the implications in relation to the recurrence rates. ",0
6690,30743066,Effect of deuteration on the phase behaviour and structure of lamellar phases of phosphatidylcholines - Deuterated lipids as proxies for the physical properties of native bilayers,"Deuteration of phospholipids is a common practice to elucidate membrane structure, dynamics and function, by providing selective visualisation in neutron scattering, nuclear magnetic resonance and vibrational spectroscopy. It is generally assumed that the properties of the deuterated lipids are identical to those of the protiated lipids, and while a number of papers have compared the properties of different forms, to date this has been no systematic study of the effects over a range of conditions. Here we present a study of the effects of deuteration on the organisation and phase behaviour of four common phospholipids (DSPC, DPPC, DMPC, DOPC), observing the effect of chain deuteration and headgroup deuteration on lipid structure and phase behaviour. For saturated lipids in excess water the gel-fluid phase transition temperature is 4.3 ± 0.1 °C lower for lipids with deuterated chains compared to protiated chains, consistent with previous work. Despite this significant change, well away from the transition structural changes as measured by powder small angle X-ray scattering are small and within errors. To investigate this further, measurements were carried out on oriented multilamellar stacks of DOPC in the fluid phase at reduced hydration. Neutrons are used in conjunction with contrast variation to elucidate the role of the deuteration explicitly. It is found that deuterated chains cause a reduction in the lamellar repeat spacing and bilayer thickness, but deuterated headgroups cause an increase. Consequences for the interpretation of Neutron Scattering data with deuterated lipids are discussed. ",0
6691,30743138,Therapeutic strategies for eosinophilic dermatoses,"Eosinophil infiltration is observed in a broad spectrum of skin diseases of various origins. Eosinophils are thought to actively contribute to pathogenesis as they are able to defend against microbes, to regulate inflammation, cause tissue damage, promote remodeling and fibrosis, and initiate pruritus. Therefore, targeting eosinophils would seem a worthwhile therapeutic approach. A promising strategy is to target the production, activation and survival of eosinophils, example with antibodies directed against IL-5 or its receptor, and Siglec-8. Dexpramipexole and tyrosine kinase inhibitors have been shown to reduce eosinophil numbers in patients with hypereosinophilia. Janus kinase inhibitors block signal transduction and thus activation of inflammatory cells including eosinophils. A further approach is to target cells and cytokines acting on or mediators released by eosinophils, for example, CD52, IL-13, IL-31, TSLP, and eotaxins. This review summarizes current therapeutic strategies, including novel agents affecting eosinophils directly that are under clinical investigation. ",0
6692,30743214,Hypermethylation of miR-205-5p by IR Governs Aggressiveness and Metastasis via Regulating Bcl-w and Src,"Although radiotherapy has been successfully applied to treat many cancer types, surviving cancer cells often acquire therapeutic resistance, leading to increased risk of local recurrence and distant metastases via modification of the tumor microenvironment. Previously, we reported that high expression of Bcl-w in cancer patients is significantly correlated with poor survival as well as malignant activity. However, the relationship between ionizing radiation (IR)-induced resistance and Bcl-w expression in cancer cells is currently unclear. We showed that IR-induced Bcl-w contributes to EMT (epithelial-mesenchymal transition), migration, angiogenesis, stemness maintenance, and metastasis by promoting the expression of factors related to these phenotypes, both in vitro and in vivo. Meanwhile, IR enhanced hypermethylation of miR-205-5p CpG islands through Src activation, leading to decreased miR-205-5p expression and, in turn, potentially stimulating Bcl-w-mediated malignant activity and metastasis. The clinical applicability of Bcl-w and miR-205-5p from cells or animal models was confirmed using tissues and plasma of breast carcinoma patients. Based on the collective findings, we propose that miR-205-5ps as important negative mediators of resistance in radiotherapy could serve as useful potential targets of concurrently applied genetic therapy aimed to inhibit tumor aggressiveness and enhance the efficiency of radiotherapy in cancer patients. ",0
6693,30743590,Evaluation of Verticillium Wilt Resistance in Mentha arvensis and M. longifolia Genotypes,"Verticillium wilt, caused by Verticillium dahliae, is a major constraint to mint (Mentha spp.) production in the United States, and the use of resistant cultivars is an important component of Verticillium wilt management. Two Mentha arvensis and four M. longifolia genotypes were evaluated for resistance to Verticillium wilt in the greenhouse using V. dahliae isolates obtained from different hosts and belonging to different vegetative compatibility groups. Isolates of V. dahliae obtained from peppermint (M. × piperita) caused significantly higher disease severity, plant mortality, and yield reduction than isolates obtained from other hosts. Disease severity, plant mortality, and pathogen incidence in aboveground stems were higher and yields lower in peppermint, the susceptible standard, compared with the resistant standard, native spearmint (M. spicata). Root-dip inoculations of M. arvensis and M. longifolia with isolates of V. dahliae obtained from peppermint produced severe symptoms; however, both species displayed the ability to recover from infection and produce asymptomatic growth from rhizomes. Both M. arvensis cultivars exhibited lower mean disease severity ratings following cutback and regrowth and were not significantly different than native spearmint. The restriction of pathogen movement in aboveground tissue and ability to recover from infection may be important components of V. dahliae resistance in perennial mint cropping systems. ",0
6694,30743617,Influence of Temperature and Wetness Periods on the Development of Stemphylium Blight on Lentil,"Stemphylium blight of lentil (Lens culinaris subsp. culinaris) caused by Stemphylium botryosum has become more prevalent in the Canadian prairies. Germination of conidia, appressorium formation, and infection of lentil plants were evaluated under controlled conditions at temperatures from 5 to 30°C and increasing incubation periods under wet conditions to elucidate the epidemiology of this disease. On glass slides, conidial germination increased steadily with temperature up to 25 and 30°C, and reached more than 80% after 20 h at these temperatures, compared with around 30% at 5°C. The response of germination on glass slides to temperature was nonlinear, as evident in significant linear, quadratic single factor, and linear, quadratic, and cubic cross factor temperature effects in the model. On lentil leaves, 18% of conidia had germinated after 2 h of incubation at 25°C, and a few germ tubes penetrated into the tissue through stomata. Germination reached 89% after 12 h, and 12% of germ tubes had penetrated into the leaves. Stemphylium blight severity reached more than 80% at 25 and 30°C with leaf wetness periods of 48 h. A simple logistic model with linear temperature, leaf wetness period, and cross factor effects described disease development on lentil plants. ",0
6695,30744760,Improvement of Hepatic Functions by Spheroids Coculture with Fibroblasts in 3D Silica Nonwoven Fabrics,"In order to realize organ-on-a-chip as an effective tool for regenerative medicine and drug development, tissue-mimic cell culture methods which promote liver-specific function for long period have been developed. We have previously demonstrated that coculture of hepatocyte spheroids on fibroblasts using micropatterned substrate improved the hepatic functions due to the heterotypic cell-cell interactions and paracrine signaling from each other. In addition, hepatocyte function cultured as monolayer was also promoted in separately coculture with fibroblasts cultured as monolayer, and it is more improved in separately coculture with fibroblasts in 3D silica nonwoven fabrics. In this study, separately coculture of hepatocyte spheroids with fibroblasts cultured on 3D silica nonwoven fabrics was estimated for further improvement of hepatocyte functions. The hepatic function cocultured with fibroblast was more promoted than mono spheroids culture. The functional enhancement was significantly most improved in separately coculture with fibroblast in 3D silica nonwoven fabrics. Thus, these results were suggested that 3D culture of fibroblasts in 3D silica nonwoven fabrics increased the heterotypic secretion of paracrine factors, and it is essential for improved hepatic performance. ",0
6696,30744761,Comparative Studies on the Aqueous Synthesis and Biocompatibility of L-Cysteine and Mercaptopropionic Acid Capped CdSe/CdS/ZnS Core/Shell/Shell Quantum Dots,"Quantum dots have now become the most important candidates and widely exploited as promising architectures for use as diagnostic and imaging agents in biomedicine and as semiconductors in the electronics industry. This article emphasizes on the aqueous synthesis of water soluble CdSe/CdS/ZnS core/shell/shell quantum dots with L-cysteine and mercaptopropionic acid as capping agent and their observed properties have been compared. The biocompatibility of the assynthesized quantum dots have also been analyzed through the cytotoxicity study using MTT assay. The structural, morphological and optical properties of these quantum dots have been examined through X-ray diffraction (XRD), high resolution transmission electron microscopy (HRTEM), UV-Visible absorption spectroscopy (UV-Vis) and Photoluminescence spectroscopy (PL). The capping of L-cysteine and mercaptopropionic acid on the quantum dots has been confirmed from Fourier transform infrared spectroscopy (FTIR). XRD results demonstrated the formation of hexagonal wurtzite structure for L-cysteine and cubic zinc blende structure for mercaptopropionic acid capped CdSe/CdS/ZnS quantum dots. From the optical measurements, it is observed that there is a considerable increase in the photoluminescence intensity of L-cysteine capped quantum dots than MPA. The HRTEM images revealed the narrow size distribution and in addition, L-cysteine capped quantum dots were found to be more biocompatible than mercaptopropionic acid capped quantum dots which would provide new opportunities for applications in bioimaging and biolabelling. ",0
6697,30744806,Defining host-pathogen interactions employing an artificial intelligence workflow,"For image-based infection biology, accurate unbiased quantification of host-pathogen interactions is essential, yet often performed manually or using limited enumeration employing simple image analysis algorithms based on image segmentation. Host protein recruitment to pathogens is often refractory to accurate automated assessment due to its heterogeneous nature. An intuitive intelligent image analysis program to assess host protein recruitment within general cellular pathogen defense is lacking. We present HRMAn (Host Response to Microbe Analysis), an open-source image analysis platform based on machine learning algorithms and deep learning. We show that HRMAn has the capacity to learn phenotypes from the data, without relying on researcher-based assumptions. Using  This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). ",0
6698,30744886,Identification and functional analysis of a cytochrome P450 gene involved in imidacloprid resistance in Bradysia odoriphaga Yang et Zhang,"Insect cytochrome P450 monooxygenases played an important role in detoxifying insecticides which potentially contributed to the metabolic resistance to insecticides. Bradysia odoriphaga, as a major pest of Chinese chive, was reported to be highly tolerant to neonicotinoid insecticides imidacloprid. In this study, a novel P450 gene, CYP6FV12, was cloned from B. odoriphaga. The full-length cDNA sequence of CYP6FV12 is 2520 bp long and its open reading frame (ORF) encodes 519 amino acids. Quantitative real-time PCR showed that the highest expression of CYP6FV12 was observed in fourth-instar larvae, which is 154.32-fold higher than that of eggs. Highest expression of CYP6FV12 was observed in the midgut, followed by fat body, which was 13.67 and 5.42-fold higher than that in cuticle, respectively. The expression of CYP6FV12 was significantly up-regulated in B. odoriphaga larvae after exposed to imidacloprid at the concentrations of 10, 30, 50, and 70 mg/L. Moreover, RNAi mediated silencing of CYP6FV12 increased mortality by 28.62% when the fourth-instar larvae were treated with imidacloprid. This is the first systematic study on isolated P450s gene involved in imidacloprid resistance in B. odoriphaga and increased our understanding of the molecular mechanisms of insecticide detoxification in this pest insect. ",0
6699,30745170,"Identification of novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide","Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least partly genetic. Ordinal genome-wide association study of suicidality in the UK Biobank cohort comparing: 'no suicidality' controls (N = 83,557); 'thoughts that life was not worth living' (N = 21,063); 'ever contemplated self-harm' (N = 13,038); 'act of deliberate self-harm in the past' (N = 2498); and 'previous suicide attempt' (N = 2666). We identified three novel genome-wide significant loci for suicidality (on chromosomes nine, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (r These findings provide new information about genetic variants relating to increased risk of suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level. FUND: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217). MRC Doctoral Training Programme Studentship at the University of Glasgow (MR/K501335/1). MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh. UKRI Innovation Fellowship (MR/R024774/1). ",0
6700,30745219,Pharmacological and non-pharmacological treatments for the Neonatal Abstinence Syndrome (NAS),"Neonatal abstinence syndrome is defined by signs and symptoms of withdrawal that infants develop after intrauterine maternal drug exposure. All infants with documented in utero opioid exposure, or a high pre-test probability of exposure should have monitoring with a standard assessment instrument such as a Finnegan Score. A Finnegan score of >8 is suggestive of opioid exposure, even in the absence of declared use during pregnancy. At least half of infants in most locales can be treated without the use of pharmacologic means. For this reason, symptom scores will drive the decision for pharmacologic therapy. Nevertheless, all infants, regardless of initial manifestations, should be first be managed with non-pharmacologic approaches which in turn, should not be considered as the sole alternative to drug therapy, but rather, as the base upon which all patients are treated. Those who continue to have symptoms despite supportive care should be pharmacologically treated, which in the most severe cases, is life-saving. ",0
6701,30745354,Access to primary health care for asylum seekers and refugees: a qualitative study of service user experiences in the UK,"Asylum seekers and refugees (ASR) face difficulty accessing health care in host countries. In 2017, NHS charges for overseas visitors were extended to include some community care for refused asylum seekers. There is growing concern that this will increase access difficulties, but no recent research has documented the lived experiences of ASR accessing UK primary health care. To examine ASR experiences accessing primary health care in the UK in 2018. This was a qualitative community-based study. ASR were recruited by criterion-based sampling through voluntary community organisations. A total of 18 ASR completed face-to-face semi-structured recorded interviews discussing primary care access. Transcripts underwent thematic analysis by three researchers using Penchansky and Thomas's modified theory of access. The qualitative data show that participants found primary care services difficult to navigate and negotiate. Dominant themes included language barriers and inadequate interpretation services; lack of awareness of the structure and function of the NHS; difficulty meeting the costs of dental care, prescription fees, and transport to appointments; and the perception of discrimination relating to race, religion, and immigration status. By centralising the voices of ASR and illustrating the negative consequences of poor healthcare access, this article urges consideration of how access to primary care in the UK can be enhanced for often marginalised individuals with complex needs. ",0
6702,30745565,Precision dosing of warfarin: open questions and strategies,"Warfarin has a very narrow therapeutic window and obvious interindividual variability in its effects, with many factors contributing to the body's response. Algorithms incorporating multiple genetic, environment and clinical factors have been established to select a precision dose for each patient. A number of randomized controlled trials (RCTs) were conducted to explore whether patients could benefit from these algorithms; however, the results were inconsistent. Some questions remain to be resolved. Recently, new genetic and non-genetic factors have been discovered to contribute to variability in optimal warfarin doses. The results of further RCTs have been unveiled, and guidelines for pharmacogenetically guided warfarin dosing have been updated. Based on these most recent advancements, we summarize some open questions in this field and try to propose possible strategies to resolve them. ",0
6703,30746244,Anesthesia and enhanced recovery in subxiphoid video-assisted thoracoscopic surgery,"Subxiphoid video-assisted thoracoscopic surgery (VATS) is a surgical approach in minimally invasive thoracic surgery that aims to aid enhanced recovery by reducing postoperative pain by avoiding instrumentation of the intercostal spaces. Access through a subxiphoid port presents challenges for both the surgeon and anaesthetist. Particularly for left sided procedures, the heart can be compressed resulting in arrhythmia and haemodynamic compromise. The anaesthetic team play an important role in ensuring the success of subxiphoid VATS procedures. The key is continuous and comprehensive monitoring for circulatory disturbance and arrhythmia intraoperatively. Should arrhythmia develop it is important that it is managed rapidly and effectively in such a manner to minimize haemodynamic disturbance. In this article, important considerations for anaesthesia in subxiphoid VATS procedures is presented and solutions presented. ",0
6704,30747397,Improved Long-term Survival with Remote Limb Ischemic Preconditioning in a Rat Fixed-Pressure Hemorrhagic Shock Model,"We investigated whether bilateral, lower limb remote ischemic preconditioning (RIPC) improved long-term survival using a rat model of hemorrhagic shock/resuscitation. Rats were anesthetized, intubated and ventilated, and randomly assigned to RIPC, induced by inflating bilateral pressure cuffs around the femoral arteries to 200 mmHg for 5 min, followed by 5-min release of the cuffs (repeated for 4 cycles), or control group (cuffs were inflated to 30 mmHg). Hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure of 30 mmHg for 30 min, followed by 30 min of resuscitation with shed blood. Rats remained anesthetized for 1 h during which hemodynamics were monitored then they were allowed to survive for 6 weeks. The percentage of estimated total blood volume withdrawn to maintain a level of 30 mmHg was similar in both groups. RIPC significantly increased survival at 6 weeks: 5 of 27 (19%) rats in the control group and 13 of 26 (50%; p = 0.02) rats in the RIPC group survived. Blood pressure was higher in the RIPC group. The diastolic internal dimension of the left ventricle, an indicator of circulating intravascular blood volume, was significantly larger in the RIPC group at 1 h after initiation of resuscitation compared to the control group (p = 0.04). Left ventricular function assessed by fractional shortening was comparable in both groups at 1 h after initiation of resuscitation. Blood urea nitrogen (BUN) was within normal range in the RIPC group (17.3 ± 1.2 mg/dl) but elevated in the control group (22.0 ± 1.7 mg/dl) at 48 h after shock. RIPC significantly improved short-term survival in rats that were subjected to hemorrhagic shock, and this benefit was maintained long term. RIPC led to greater circulating intravascular blood volume in the early phase of resuscitation and improved BUN. ",0
6705,30748048,Factors influencing colonoscopy behaviour among Koreans with a positive faecal occult blood tests,"Colonoscopy is important for colorectal cancer (CRC) screening in individuals with a positive faecal occult blood test (FOBT). The purpose of the present study was to identify factors affecting the colonoscopy screening behaviour of FOBT-positive individuals, based on the health belief model (HBM). This study involved a cross-sectional survey of 213 individuals aged 50 years or older who underwent CRC screening at a general hospital in Seoul, Korea, as part of the Korean National Cancer Screening Programme and who tested positive on FOBT. The questionnaire was created based on HBM instruments. The collected data were analysed using descriptive statistics, and factors associated with adherence to colonoscopy were examined using logistic regression analysis. Of the FOBT-positive individuals, 44.1% adhered to colonoscopy. Three of the six evaluated HBM-driven factors (perceived seriousness, perceived barriers and health motivation) significantly differed between colonoscopy-adherent and non-adherent subjects. Perceived seriousness and perceived barriers were the most important factors influencing colonoscopy screening behaviour. For early detection and prevention of CRC, colonoscopy screening behaviour should improve among FOBT-positive individuals. To this aim, education on the graveness of CRC should be provided, and barriers to CRC screening should be addressed. ",0
6706,30753160,Diffuse massive adenomyosis and infertility. Is it possible to treat this condition?,"Background Severe forms of adenomyosis are a serious gynecological problem. In most cases, conservative treatment of this pathology is unsuccessful. Adenomyomectomy by Osada's approach seems to be the most promising solution. The present study evaluated the follow-up results of this type of surgery in patients with adenomyosis and infertility. Materials and methods The prospective study included 26 patients with severe forms of adenomyosis who underwent an adenomyomectomy using Osada's approach. In 18 patients (69%), infertility was the main indication for surgical treatment. The follow-up period lasted from July 2012 to January 2018. Results The median post-operative follow-up period was 18 months. For the first 12 months patients received hormonal therapy. In all postoperative patients, the menstrual cycle had normalized, and other symptoms of the disease had disappeared. Seven patients continue to receive postoperative hormonal treatment. Three individuals got spontaneously pregnant; two of them delivered full-term babies by cesarean section. Six patients are planning a pregnancy with assisted reproductive technology. Conclusion In the present study, the organ-preserving surgery of severe adenomyosis performed using Osada's method appeared to be a good alternative to hysterectomy. It stopped the development of pathological symptoms of the disease and restored the patient's reproductive function. ",0
6707,30753169,Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in regulatory T cells,"Chimeric antigen receptor (CAR) technology can be used to engineer the antigen specificity of regulatory T cells (Tregs) and improve their potency as an adoptive cell therapy in multiple disease models. As synthetic receptors, CARs carry the risk of immunogenicity, particularly when derived from nonhuman antibodies. Using an HLA-A*02:01-specific CAR (A2-CAR) encoding a single-chain variable fragment (Fv) derived from a mouse antibody, we developed a panel of 20 humanized A2-CARs (hA2-CARs). Systematic testing demonstrated variations in expression, and ability to bind HLA-A*02:01 and stimulate human Treg suppression in vitro. In addition, we developed a new method to comprehensively map the alloantigen specificity of CARs, revealing that humanization reduced HLA-A cross-reactivity. In vivo bioluminescence imaging showed rapid trafficking and persistence of hA2-CAR Tregs in A2-expressing allografts, with eventual migration to draining lymph nodes. Adoptive transfer of hA2-CAR Tregs suppressed HLA-A2+ cell-mediated xenogeneic graft-versus-host disease and diminished rejection of human HLA-A2+ skin allografts. These data provide a platform for systematic development and specificity testing of humanized alloantigen-specific CARs that can be used to engineer specificity and homing of therapeutic Tregs. ",0
6708,30753196,"Acute rhinosinusitis among pediatric patients with allergic rhinitis: A nationwide, population-based cohort study","While chronic rhinosinusitis is a common complication of allergic rhinitis, the link between acute rhinosinusitis and allergic rhinitis is unclear. The aim of this study was to evaluate the risk of incident acute rhinosinusitis among pediatric patients with allergic rhinitis, using a nationwide, population-based health claims research database. Newly diagnosed allergic rhinitis patients aged 5-18 years were identified from the health claim records of the Longitudinal Health Insurance Database 2000 of Taiwan's National Health Insurance Research Database. A comparison cohort was assembled by randomly selecting patients from the same database with frequency matching by sex, age group, and index year. All patients were followed until a diagnosis of acute rhinosinusitis or the end of the follow-up period. Cox proportional hazards model was used to assess the association between allergic rhinitis and acute rhinosinusitis. Of the 43,588 pediatric patients included in this study, 55.4% were male and 43.9% were between the ages of 5.0-7.9 years. The risk of acute rhinosinusitis was significantly higher in pediatric patients with allergic rhinitis compared to those without the condition (adjusted hazard ratio = 3.03, 95% confidence interval = 2.89-3.18). Similar hazard ratios were observed between male and female pediatric patients. This secondary cohort study using a nationwide, population-based health claim data of the Taiwan's NHIRD showed that allergic rhinitis was significantly associated with a higher risk of acute rhinosinusitis among pediatric patients. ",0
6709,30753220,Leukemia multiclass assessment and classification from Microarray and RNA-seq technologies integration at gene expression level,"In more recent years, a significant increase in the number of available biological experiments has taken place due to the widespread use of massive sequencing data. Furthermore, the continuous developments in the machine learning and in the high performance computing areas, are allowing a faster and more efficient analysis and processing of this type of data. However, biological information about a certain disease is normally widespread due to the use of different sequencing technologies and different manufacturers, in different experiments along the years around the world. Thus, nowadays it is of paramount importance to attain a correct integration of biologically-related data in order to achieve genuine benefits from them. For this purpose, this work presents an integration of multiple Microarray and RNA-seq platforms, which has led to the design of a multiclass study by collecting samples from the main four types of leukemia, quantified at gene expression. Subsequently, in order to find a set of differentially expressed genes with the highest discernment capability among different types of leukemia, an innovative parameter referred to as coverage is presented here. This parameter allows assessing the number of different pathologies that a certain gen is able to discern. It has been evaluated together with other widely known parameters under assessment of an ANOVA statistical test which corroborated its filtering power when the identified genes are subjected to a machine learning process at multiclass level. The optimal tuning of gene extraction evaluated parameters by means of this statistical test led to the selection of 42 highly relevant expressed genes. By the use of minimum-Redundancy Maximum-Relevance (mRMR) feature selection algorithm, these genes were reordered and assessed under the operation of four different classification techniques. Outstanding results were achieved by taking exclusively the first ten genes of the ranking into consideration. Finally, specific literature was consulted on this last subset of genes, revealing the occurrence of practically all of them with biological processes related to leukemia. At sight of these results, this study underlines the relevance of considering a new parameter which facilitates the identification of highly valid expressed genes for simultaneously discerning multiple types of leukemia. ",0
6710,30753597,27-Hydroxycholesterol Alters Synaptic Structural and Functional Plasticity in Hippocampal Neuronal Cultures,"This study aimed to explore the neurotoxic effects of 27-hydroxycholesterol (27-OHC), a major circulating cholesterol active derivative in brain on synaptic structural and functional plasticity in primary hippocampal neurons. Newborn SD rat primary hippocampal neurons were treated with 0, 1, 3, 10, and 30 μM 27-OHC for 24 hours. MTT and CCK-8 assays were used to monitor the cell viability of neurons with different treatments. Neurite morphology was assessed by staining for microtubule-associated protein-2 (MAP2) and analyzed by immunofluorescence. Synaptic ultrastructure was evaluated by transmission electron microscopy. Real-time polymerase chain reaction and Western blot analyses were used to evaluate the expression of key synaptic proteins: synaptophysin (SYP), postsynaptic density protein-95 (PSD-95), synaptosomal-associated protein 25 (SNAP-25), growth-associated protein-43 (GAP-43), MAP2, and activity-regulated cytoskeleton-associated protein (Arc). Treatment with 27-OHC at various doses stimulated cell death and resulted in significant decreases in neurite number and length, alteration of synaptic ultrastructure, and downregulated expression of synaptic proteins in a dose-dependent manner. These results suggest that 27-OHC is deleterious for synaptic structural and functional plasticity, which may partially account for its neurotoxic effects. ",0
6711,30753670,Rutin attenuates inflammatory responses induced by lipopolysaccharide in an in vitro mouse muscle cell (C2C12) model,"White striping (WS) and woody breast (WB) are 2 of the major myopathies in the modern poultry industry. Even though the exact etiology for WS and WB is still unknown, differentially expressed genes in broiler breast muscle affected by WS and WB indicate that oxidative stress and inflammation could be involved in their occurrences. Therefore, it is very important to identify natural compounds with anti-oxidative stress and anti-inflammation properties that can reduce the occurrences of WS and WB in broiler chickens. Rutin is a polyphenol antioxidant that has been reported to be present in several plant extracts. In the current study, we established an in vitro inflammation model by using mouse muscle cells (C2C12) and evaluated the effects of rutin on lipopolysaccharide (LPS)-induced inflammatory responses in the muscle cells. Interleukin 6 (IL-6) secretion was measured by enzyme-linked immunosorbent assay. The mRNA abundance of cytokines and inducible nitric oxide synthase (iNOS) was measured by real-time PCR. Nuclear factor kappa B (NF-κB) activation was detected by electrophoretic mobility shift assay. The results showed that LPS (25 ng/ml) stimulation quickly activated NF-κB and induced significant IL-6 expression on both mRNA and protein levels (P < 0.05) in cells when compared with control cells without the LPS treatment. The rutin treatment decreased IL-6 mRNA abundance induced by LPS in a dose-dependent manner (P < 0.05). LPS-induced tumor necrosis factor-alpha and iNOS gene expression was significantly attenuated by 100 μM of rutin (P < 0.05). Moreover, LPS induced reactive oxygen species (ROS) production, and NF-κB activation was significantly blocked by 100 μM of rutin. These results suggest that rutin can attenuate LPS-induced inflammation in muscle cells and supplementation of rutin or rutin-containing plant extracts may present a promising approach to control WS and WB in broiler chickens. ",0
6712,30754068,Higher Axial Tibiofemoral Rotation and Functional Outcomes with Mobile-Bearing Compared with Fixed-Bearing Total Knee Arthroplasty at 1- but Not at 2-Year Follow-Up - A Randomized Clinical Trial,"The objective of this study was to determine in vivo knee kinematics and clinical outcomes of patients who underwent fixed- and mobile-bearing total knee arthroplasty (TKA) at 1- and 2-year follow-up. This prospective double-blinded randomized controlled trial was performed from November 2011 to December 2012. A total of 64 patients were randomized to fixed- and mobile-bearing TKA groups (32 patients in each group). All patients were evaluated with the following: three-dimensional in vivo knee kinematics analysis during gait, stepping up and stepping down stair steps, and getting up from and sitting on a chair; and knee range of motion and patient-reported outcome measures (Knee Outcome Survey Activities of Daily Living Scale [KOS-ADLS] and pain visual analog scale [VAS]) at 1- and 2-year follow-up. Descriptive statistics (means, standard deviations, and percentages) were calculated for all variables. The Kolmogorov-Smirnov test was used to test if variables were normally distributed. A Student's  ",0
6713,30754321,First Report of Postharvest Fruit Rot in Persimmon Caused by Phacidiopycnis washingtonensis in Italy,"Persimmon (Diospyros kaki L.) is widely grown in Italy, the leading producer in Europe. In the fall of 2009, a previously unknown rot was observed on 3% of fruit stored at temperatures between 5 and 15°C in Torino Province (northern Italy). The decayed area was elliptical, firm, and appeared light brown to dark olive-green. It was surrounded by a soft margin. The internal decayed area appeared rotten, brown, and surrounded by bleached tissue. On the decayed tissue, black pycnidia that were partially immersed and up to 0.5 mm in diameter were observed. Light gray conidia produced in the pycnidia were unicellular, ovoid or lacriform, and measured 3.9 to 6.7 × 2.3 to 3.5 (average 5.0 × 2.9) μm. Fragments (approximately 2 mm) were taken from the margin of the internal diseased tissues, cultured on potato dextrose agar (PDA), and incubated at temperatures between 23 and 26°C under alternating light and darkness. Colonies of the fungus initially appeared ash colored and then turned to dark greenish gray. After 14 days of growth, pycnidia and conidia similar to those described on fruit were produced. The internal transcribed spacer (ITS) region of rDNA was amplified using the primers ITS4/ITS6 and sequenced. BLAST analysis (1) of the 502-bp segment showed a 100% similarity with the sequence of Phacidiopycnis washingtonensis Xiao & J.D. Rogers (GenBank Accession No. AY608648). The nucleotide sequence has been assigned the GenBank Accession No. GU949537. Pathogenicity tests were performed by inoculating three persimmon fruits after surface disinfesting in 1% sodium hypochlorite and wounding. Mycelial disks (10 mm in diameter), obtained from PDA cultures of one strain were placed on wounds. Three control fruits were inoculated with plain PDA. Fruits were incubated at 10 ± 1°C. The first symptoms developed 6 days after the artificial inoculation. After 15 days, the rot was very evident and P. washingtonensis was consistently reisolated. Noninoculated fruit remained healthy. The pathogenicity test was performed twice. Since P. washingtonensis was first identified in the United States on decayed apples (2), 'Fuji', 'Gala', 'Golden Delicious', 'Granny Smith', 'Red Chief', and 'Stark Delicious', apple fruits also were artificially inoculated with a conidial suspension (1 × 10 ",0
6714,30754555,First Report of Brown Ring Patch Caused by Waitea circinata var. circinata on Poa annua in Pennsylvania,"In late May and early June of 2008, bright yellow, thin, irregular-shaped rings that were 10 to 15 cm in diameter were observed on 30% of an annual bluegrass (Poa annua L.) putting green in Coopersburg, PA. The 46-year-old silt-loam soil green was mowed at a 3.1-mm height and consisted of 80% annual bluegrass and 20% creeping bentgrass (Agrostis stolonifera L., unknown cultivar). During the appearance of ring symptoms, the overall minimum and maximum daily air temperature ranged from 19.9 to 31.1°C, respectively, along with 40.3 mm of total rain accumulation. In late May, only individual affected annual bluegrass plants exhibited a bright yellow chlorosis of upper and lower leaf blades and crown. By early June, affected annual bluegrass plants appeared dark brown and water soaked, turning reddish brown and then tan as they dessicated, wilted, and died. Fungal mycelium, similar in appearance to Rhizoctonia spp., was found among affected leaf blades and within the thatch layer. A single fungal isolate was obtained from affected annual bluegrass tissue and grown on potato dextrose agar (PDA) plus 0.1 g of chloramphenicol per liter. Fungal colony morphology and sequencing of the ITS1F/ITS4-amplified rDNA internal transcribed spacer (ITS) region confirmed the isolate as Waitea circinata var. circinata, with ≥90% similar homology match to published W. circinata var. circinata ITS sequences (GenBank Accession No. DQ900586) (2,4). To confirm pathogenicity, the isolate was inoculated onto 6-week-old annual bluegrass (0.001 g of surface-sterilized seed per cm ",0
6715,30754720,Dose-Dependent Toxic Effect of Cotinine-Verified Tobacco Smoking on Systemic Inflammation in Apparently Healthy Men and Women: A Nationwide Population-Based Study,"Chronic exposure to tobacco smoke leads to chronic low-grade systemic inflammation; however, little is known about the dose-dependent toxic effect of objective tobacco smoking on systemic inflammation. We examined the dose-dependent toxic effect of cotinine-verified tobacco smoking on leukocyte count in a representative sample of Korean adults, including 8655 men and 10,432 women aged 19⁻65 years from the Korean National Health and Nutrition Examination Survey. The participants were categorized into five groups by the level of urine cotinine (Ucot) as follows: A non-smoker group (<50.00 ng/mL) and four quartile groups for smokers for both men and women. The odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific high leukocyte count (≥75th percentile) were calculated across five groups of Ucot concentrations using multiple logistic regression analyses. The mean values of leukocyte count gradually increased according to the grade of Ucot concentration in both sexes. The ORs (95% CIs) for high leukocyte count in the 4th Ucot quartile concentrations versus the non-smokers were 4.09 (3.39⁻4.94) for men and 3.91 (2.82⁻5.41) for women after adjusting for confounding variables. The present study confirmed the dose-response toxic effect of tobacco smoking on chronic low-grade systemic inflammation. ",0
6716,30755021,Left ventricular hypertrophy in world class elite athletes is associated with signs of improved cardiac autonomic regulation,"In this study we sought to assess whether in elite athletes the physiological increase in cardiac mass attending severe long-term training leading to athlete's heart is accompanied by an improvement of autonomic performance, as assessed by post exercise vagal indices and a novel unitary Autonomic Nervous System Index for sports (ANSIs). The study involved 500 elite athletes (23.9 ± 6.4 years) participating in a screening organised by the National Italian Olympic Committee. All subjects underwent a complete medical examination, rest and stand autonomic assessment (heart rate variability) as well as bicycle exercise. ANSIs was also derived as radar plot from rest, stand and heart rate recovery individual proxies of autonomic nervous system regulation. All subjects were grouped into those with left ventricular hypertrophy present (LVH(+)), or not (LVH(-)), according to recognised thresholds. We observed that LVH(+) athletes (24.8%) showed a marked increase of post-exercise vagal indices ( p < 0.001) and of ANSIs ( p < 0.001), while no difference was observed for heart-rate variability indices. These changes were contingent upon sport intensity categories. Elite athletes with physiological cardiac hypertrophy (LVH(+)) present a selective profile of indices of autonomic nervous system performance, characterised by increases of markers of vagal recovery and of the novel unitary autonomic index for sports while RR variance and spectral indices seem to be unmodified. Athlete's heart may be characterised by a specific combination of anatomical and neurocardiac remodeling. This approach might furnish potential warning signs differentiating normal training induced physiology from pathological adaptation. ",0
6717,30755497,Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP,"Oxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown. Diagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome. Nuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival. Nrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group. ",0
6718,30755559,Comparison between Glyceryl Trinitrate and Trimetazidine in Ischaemic Cardiomyopathy Patients,"Ischaemic cardiomyopathy (ICM) remains a major health problem, both in developed and developing countries like Bangladesh where it causes a significant number of morbidity and mortality. The treatment and outcome of ICM chiefly depends on the presence and extent of hibernating myocardium. In this regard addressing anginal symptoms is the key to patients' comfort as well to achieving the goal of treatment. Glyceryl trinitrate (GTN) and trimetazidine (TMZ) are two widely used drugs for relieving angina. This pilot study was designed to answer some of the confusions and controversies regarding their use and to bring precision in decision making in the treatment of ICM. Here, comparison of GTN and trimetazidine were done by assessing the symptoms by NYHA and CCS class following their use in ICM patients, admitted in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from 15th October, 2015 to 15th April, 2016, who were randomly placed in two groups in a prospective manner. Most of the patients were in age group 51-60 years and were male in both the groups. It was observed that there was no significant difference in NYHA and CCS class at base line and at discharge between two groups (p>0.05). But statistically significant (p<0.05), improvement noted at 6 weeks and 12 weeks in GTN group in comparison to trimetazidine group. GTN stood out to be a better option than TMZ in the treatment of ICM. Moreover GTN is a cheaper option than TMZ. ",0
6719,30755636,Ventricular-Subventricular Zone Contact by Glioblastoma is Not Associated with Molecular Signatures in Bulk Tumor Data,"Whether patients with glioblastoma that contacts the ventricular-subventricular zone stem cell niche (VSVZ + GBM) have a distinct survival profile from VSVZ - GBM patients independent of other known predictors or molecular profiles is unclear. Using multivariate Cox analysis to adjust survival for widely-accepted predictors, hazard ratios (HRs) for overall (OS) and progression free (PFS) survival between VSVZ + GBM and VSVZ - GBM patients were calculated in 170 single-institution patients and 254 patients included in both The Cancer Genome (TCGA) and Imaging (TCIA) atlases. An adjusted, multivariable analysis revealed that VSVZ contact was independently associated with decreased survival in both datasets. TCGA molecular data analyses revealed that VSVZ contact by GBM was independent of mutational, DNA methylation, gene expression, and protein expression signatures in the bulk tumor. Therefore, while survival of GBM patients is independently stratified by VSVZ contact, with VSVZ + GBM patients displaying a poor prognosis, the VSVZ + GBMs do not possess a distinct molecular signature at the bulk sample level. Focused examination of the interplay between the VSVZ microenvironment and subsets of GBM cells proximal to this region is warranted. ",0
6720,30755731,Prostate cancer promotes a vicious cycle of bone metastasis progression through inducing osteocytes to secrete GDF15 that stimulates prostate cancer growth and invasion,"Bone is the most frequent site of prostate cancer (PCa) metastasis; however, little is known about the role of the most common cell in bone, the osteocyte (OCy), in cancer biology. In this study we explored the crosstalk between PCa cells and OCys to determine if it contributes to PCa progression. PCa cells induced OCys to promote PCa proliferation, migration and invasion. A chemokine screen revealed that PCa cell induced OCys to produce growth-derived factor 15 (GDF15). Knockdown of GDF15 in OCys demonstrated that PCa cells conferred the ability on OCys to promote PCa proliferation, migration and invasion through GDF15. Consistent with this finding was the observation that the GDF15 receptor, GFRAL, was expressed on multiple PCa cell lines. Transcription factor array screening of PCa cells exposed to OCys with or without knockdown of GDF15 revealed that GDF15 in OCys promoted early growth response 1 (EGR1) expression in the PCa cells. Knockdown of EGR1 expression in PCa cells revealed it was required for the OCy-derived GDF15-mediated induction of in vitro PCa cell proliferation, migration and invasion. Subcutaneous co-injection of PCa cells and OCys into mice revealed that OCys promoted tumor growth in vivo, which was diminished by knockdown of GDF15 in the OCys. Knockdown of GDF15 in the tibiae diminished growth of PCa cancer cells injected into the tibiae, which was accompanied by decreased tumor cell proliferation and EGR1 expression. These results shed light on a novel mechanism through which PCa cells educate OCys to promote progression of PCa bone metastasis. They also suggest that targeting of GDF15-based and EGR1-based signaling pathways should be further explored for their potential to diminish progression of PCa bone metastasis. ",0
6721,30755887,Simultaneous Acute Pulmonary Embolism and Isolated Septal Myocardial Infarction in a Young Patient,"We report the case of a young patient with a simultaneous isolated septal myocardial infarction (MI) and pulmonary embolism (PE). The aim was to describe a rare clinical entity and to explain why these two pathologies were present at the same time in a young patient. A review of literature was performed. An interventional cardiologist, an interventional radiologist and a lung specialist were consulted. The diagnostic workup revealed only heterozygous Factor Leiden V mutation. This presentation was probably fortuitous, but worth reporting in our opinion. To our knowledge, the simultaneous presentation of an isolated septal MI and PE in a young patient has never been reported.Isolated septal MI should be considered in the presence of right bundle branch block (RBBB) at sub-occlusion of a large septal branch. The final diagnosis can optimally be confirmed by cardiac magnetic resonance (CMR).An increasing number of asymptomatic PE are being detected due to advances in computed tomography (CT) scanning. This is important because, if left untreated, incidental PE may be associated with higher recurrence rate and mortality. ",0
6722,30755978,Systemic Sarcoidosis Associated with Exposure to ,"Here we describe a rare case of systemic sarcoidosis in a healthy young man with neuroborreliosis as a putative trigger. A 21-year-old forestry worker was diagnosed with systemic sarcoidosis involving his lungs, kidneys and skin. Additional diagnostics revealed signs indicative of a recent infection with  Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. This case suggests that an infection with  We should maintain a high index of suspicion for underlying infectious processes like neuroborreliosis in patients with new-onset sarcoidosis before starting immunosuppressive regimens. ",0
6723,30756115,Utilization of Observational Data as a Proxy Cohort for Comparison Purposes with Open-Label Study Results: An Example from Alzheimer's Disease,"Randomized placebo-controlled trials in the development of disease-modifying treatments for Alzheimer's disease are typically of short duration (12-18 months), and health economic modeling requires extrapolation of treatment effects beyond the trial period. To investigate whether observational data can be used to extrapolate data from open-label trials, we compared outcomes (cognition, function, behavior) over 36 months for patients with mild Alzheimer's disease dementia in the GERAS observational study (proxy for placebo control) with those of the mild Alzheimer's disease population on active treatment (solanezumab) in two 18-month randomized placebo-controlled trials (EXPEDITION and EXPEDITION2) and the additional 18-month open-label extension study (EXPEDITION-EXT). Analysis of longitudinal data from patients with mild Alzheimer's disease dementia in the GERAS observational study (conducted in France, Germany and the United Kingdom) and the EXPEDITION program (conducted in Europe, North America, South America, Asia and Australia). European and North American community-living patients, aged ≥55 years, with probable Alzheimer's disease dementia and their caregivers. Mild Alzheimer's disease dementia was defined as a Mini-Mental State Examination score of 20-26 in EXPEDITION and 21-26 in GERAS. Active treatment in both randomized placebo-controlled trials and the open-label extension study was intravenous solanezumab 400 mg every 4 weeks. Patients in GERAS were receiving treatment as part of standard care. Between-group differences for changes from baseline over 36 months in cognitive function, ability to perform activities of daily living, and behavioral and psychological symptoms of dementia were assessed using models stratified by propensity score. At baseline, patients and caregivers participating in GERAS were significantly older than those in the EXPEDITION studies, and the GERAS patient cohort had fewer years of education and a shorter time since diagnosis of Alzheimer's disease. The baseline mean Mini-Mental State Examination score of the GERAS cohort was significantly higher (indicating better cognition) than that of patients receiving placebo or active treatment in the pooled EXPEDITION studies Baseline functional ability scores were significantly lower for the GERAS cohort, indicating poorer functioning. Propensity score stratification achieved a good balance in the baseline variables between GERAS and the two EXPEDITION arms. Over 18 months, least squares mean changes from baseline in outcome measures were similar in the GERAS cohort and the pooled placebo groups from the randomized controlled trials. Also, the 18-month results for the comparison between the GERAS cohort and the pooled active treatment groups from the randomized controlled trials were generally similar to those reported for the comparison with the control group in the randomized trial. Comparison of active treatment (EXPEDITION-EXT) and observational study (GERAS, as proxy control) results over 36 months of the open-label trial showed a significantly smaller decline in activities of daily living (instrumental and basic) in the active treatment group, reflecting better functioning, but no between-group differences at 36 months for cognitive function or behavioral and psychological symptoms of dementia. Comparing results from clinical trials and observational studies (real-world data) may be a useful methodological approach for informing long-term outcomes in Alzheimer's disease drug development and could be used to inform health economic modeling. Further research using this methodological approach is needed. ",0
6724,30757918,Characterization of membrane vesicles released by Mycobacterium avium in response to environment mimicking the macrophage phagosome,"To investigate the formation of Mycobacterium avium membrane vesicles (MVs) within macrophage phagosomes. A phagosome model was utilized to characterize proteomics and lipidomics of MVs. A click chemistry-based enrichment assay was employed to examine the presence of MV proteins in the cytosol of host cells. Exposure to metals at concentrations present in phagosomes triggers formation of bacterial MVs. Proteomics identified several virulence factors, including enzymes involved in the cell wall synthesis, lipid and fatty acid metabolism. Some of MV proteins were also identified in the cytosol of infected macrophages. MVs harbor dsDNA. M. avium produces MVs within phagosomes. MVs carry products with potential roles in modulation of host immune defenses and intracellular survival. ",0
6725,30758027,A smart molecular probe for selective recognition of nitric oxide in 100% aqueous solution with cell imaging application and DFT studies,"Herein, a simple, least-cytotoxic as well as an efficient fluorescent sensor HqEN480 was prepared from (quinolin-8-yloxy)-acetic acid ethyl ester (L1) and N,N-dimethylethylene diamine to recognize NO in 100% aqueous solution. Its marked selectivity and sensitivity towards NO, makes it a highly suitable probe for nitric oxide under in vitro conditions with the possibility of in vivo monitoring of NO. Upon addition of 3.5 equivalents of NO, there is an approximately 7 fold enhancement in fluorescence intensity in aqueous solution with a corresponding Kf value of (1.75 ± 0.07) × 104 M-1. Quantum yields of HqEN480 and [HqEN480-NO] compounds are determined to be 0.04 and 0.22, respectively, using acidic quinine sulphate as a standard. In terms of the 3σ method, the LOD for nitric oxide was found to be 53 nM thus, making the probe suitable for tracking NO in biological systems. ",0
6726,30758201,"Astratides: Insulin-Modulating, Insecticidal, and Antifungal Cysteine-Rich Peptides from Astragalus membranaceus","Astragalus membranaceus root, Huang Qi in Chinese, is a popular medicinal herb traditionally used to regulate blood glucose. Herein, the identification and characterization of two families of cysteine-rich peptides (CRPs), designated α- and β-astratides, from A. membranaceus roots are reported. Proteomic analysis showed that α-astratide aM1 and β-astratide bM1 belong to two distinct CRP families. The six-cysteine-containing and proline-rich α-astratide aM1 displayed high sequence identity to Pea Albumin 1 Subunit b (PA1b), while the eight-cysteine-containing β-astratide bM1 showed sequence similarity to plant defensins. An antifungal assay revealed that bM1 possessed potent antifungal activity. In contrast, aM1 showed a cytotoxic effect against insect Sf9 cells. More importantly, aM1 decreased insulin secretion in mouse pancreatic β cells, suggesting it could interfere in glucose homeostasis, which accounts for the adaptogenic property of A. membranaceus. Phylogenetic clustering analysis suggested that the proline-rich aM1 is a putative prolyl oligopeptidase inhibitor and belongs to a novel subfamily of PA1b-like peptides, while bM1 belongs to a new subfamily of plant defensins. Together, the study reveals that astratides are multifunctional CRPs in plants, which expand the existing library of PA1b-like peptides and plant defensins and further our understanding of their roles in host-defense system and leads as peptidyl therapeutics. ",0
6727,30758400,Allele and haplotype frequencies of human platelet and leukocyte antigens in platelet donors,"To described the allele and haplotype frequencies of human leukocyte antigen genes at the -A, -B loci and human platelet antigen genes for human platelet antigen systems 1 to 9, 11 and 15 in blood. We included 867 healthy unrelated volunteer donors who donated platelets between January 2011 and December 2014. Microarray genotyping was performed using a BeadChip microarray. Medium resolution typing of the human leukocyte antigen at loci A and B was carried out using sequence-specific oligonucleotide probe hybridization. We used multivariate analysis and our human leukocyte antigen population was compared to data from the United States national bone marrow donor program. Human platelet antigen results were compared to a literature review and data from around the world. Our human leukocyte antigen haplotype results were more similar to those of hispanics, followed by caucasians. Likewise, our human platelet antigen sample is more similar to those of Argentina, Rio Grande do Sul and Italy. This was the first article that discusses human platelet antigen and human leukocyte antigen data together. Rare genotypes or antibody associations can make patient management difficult. A blood bank with genotyped donors allows for optimal transfusion and can contribute to better results. Our information can serve as basis for a database of platelet antigen polymorphisms. ",0
6728,30758760,Demographic and Clinical Characteristics of 5294 Jaw Cysts: A Retrospective Study of 38 Years,"The aim of the present study is to report the demographic and clinical characteristics of all jaw cysts diagnosed in a single Oral Pathology Department. 5294 cases of jaw cysts diagnosed during a 38-year period were retrospectively collected and classified according to the latest classification of Head and Neck Tumors of the World Health Organization. The patients' gender and age, as well as the main clinical features of the cysts were retrieved from biopsy report forms. Jaw cysts were more common in male patients, with a male to female ratio of 1.6:1. Most patients were in the 4th-6th decade of life, with a mean age of 42.3 ± 16.1 years. There was no jaw predilection and the majority of lesions were more commonly encountered in the anterior region of the maxilla, followed by the molar region of the mandible. The most common jaw cyst was radicular cyst followed by dentigerous cyst, residual cyst and odontogenic keratocyst. The majority of jaw cysts are of inflammatory origin and represent a sequale of pulp necrosis. However, other type of jaw cysts may also be found. ",0
6729,30759144,The use of arthrocentesis in patients with temporomandibular joint disc displacement without reduction,"The aim of this study was to evaluate the efficacy of the use of the arthrocentesis in patients with disc displacement without reduction (DDWOR). Two hundred and thirty-four (234) patients with DDWOR were evaluated and the following data collected: gender; affected side; age (years); duration of the pain (months); patient's perception of pain (measured by Visual Analogue Scale [VAS 0-10]); maximal interincisal distance (MID) (mm); and joint disc position, determined by magnetic resonance imaging. Data were obtained in two different moments: before the arthrocentesis (M1) and three or four months later (M2). Paired t-Student Test, Scores Test and Wilcoxon Test showed a statistical significant difference (p<0.0001) between the M1 and M2 for the variables VAS and MID. There was an alteration in the joint disc position in 93.88% of the cases after arthrocentesis. There was no association between the general characteristics of the patients on the M1 and the results of the arthrocentesis (p>0.05). It can be concluded that the arthrocentesis is efficient in reducing the pain, in increasing interincisal distance, and altering the joint disc position in patients with DDWOR regardless gender, age side and pain duration. ",0
6730,30759329,Risk Perceptions Toward Drinking Water Quality Among Private Well Owners in Ireland: The Illusion of Control,"In rural areas where no public or group water schemes exist, groundwater is often the only source of drinking water and is extracted by drilling private wells. Typically, private well owners are responsible for the quality and testing of their own drinking water. Previous studies indicate that well owners tend to underestimate the risks of their well water being contaminated, yet little is known about why this is the case. We conducted a qualitative study by interviewing private well owners in Ireland to investigate their beliefs surrounding their water quality, which, in turn, inform their risk perceptions and their willingness to regularly test their water. Based on our findings we designed a theoretical model arguing that perceived control is central in the perceived contamination risks of well water. More specifically, we argue that well owners have the illusion of being in control over their water quality, which implies that people often perceive themselves to be more in control of a situation than they actually are. As a result, they tend to underestimate contamination risks, which subsequently impact negatively on water testing behaviors. Theoretical and practical implications are highlighted. ",0
6731,30759417,In vitro and In vivo toxicity assessment of phytofabricated ZnO nanoparticles showing bacteriostatic effect and larvicidal efficacy against Culex quinquefasciatus,Murraya koenigii berry extract based zinc oxide nanoparticles (Mk-ZnO NPs) were synthesized by simple co-precipitation method and examined for bacteriostatic and larvicidal efficiency. Synthesized Mk-ZnO NPs were characterized by UV-Vis spectroscopy at 336 nm. X-Ray diffraction (XRD) showed crystalline nature as hexagonal. Fourier transform infrared spectroscopy (FTIR) spectrum exhibited strong peak at 3442.80 cm ,0
6732,30759441,Maternal Influence and Murine Housing Confound Impact of NLRP1 Inflammasome on Microbiome Composition,"The NLRP1 inflammasome attenuates inflammatory bowel disease (IBD) progression and colitis-associated tumorigenesis. A possible mechanism postulates that the lack of the NLRP1 inflammasome creates permissive niches in the gut for pathogenic bacteria to flourish, causing dysbiosis and increased IBD susceptibility. To evaluate this hypothesis, we characterized the gut microbiome of wild-type, Nlrp1b-/-, and Asc-/- mice under naïve conditions by sequencing the V3 region of the 16s rRNA gene. For both genetically modified mouse lines, the microbiome composition reflected overrepresentation of bacteria associated with dysbiosis relative to wild-type animals. Measurement of short- and medium-chain fatty acids by mass spectrometry further revealed significant differences between genotypes. However, prior to concluding that the NLRP1 inflammasome plays a role in regulating the composition of the microbiome, we evaluated two additional strategies for cohousing wild-type and Nlrp1b-/- mice: breeding homozygous parents and cohousing at weaning, and breeding from heterozygous parents and cohousing littermates. We found that maternal influence was the greater predictor of microbiome composition rather than genotype. With the rise in microbiome research across disciplines, our study should be viewed as a cautionary example that illustrates the importance of careful breeding and housing strategies when evaluating host-microbiome interactions. ",0
6733,30759616,Assessing the role of CAP for more sustainable and healthier food systems in Europe: A literature review,"Today, the European food system is characterized by unhealthy dietary trends, environmentally unsustainable production, and a dependency on an ageing farming population. The ongoing reform of the Common Agricultural Policy (CAP) represents an opportunity to redress these issues. This literature review highlights trends in how academic and grey literature have received CAP attempts in addressing the (i) environmental issues, (ii) nutritional outcomes, and (iii) rural livelihoods. Additionally, future policy and research directions relating to the CAP have been identified from the selected literature. The reviewed literature varies in approach and perspective. In particular, since the environment and rural development are already part of the CAP, the reviewed studies analyze and propose improvements to existing mechanisms. While for nutrition, the reviewed studies assessed possible policy strategies for integrating this sphere within the CAP, highlighting both the complexity of this task as well as its potential benefits. Despite these differences, a clear commonality emerged from the policy recommendations: the CAP should promote the European Union (EU) policy integration and multi-disciplinary and participatory research as key strategies to meet food system sustainability targets. ",0
6734,30759753,Therapeutic Radiometals: Worldwide Scientific Literature Trend Analysis (2008⁻2018),"Academic journals have published a large number of papers in the therapeutic nuclear medicine (NM) research field in the last 10 years. Despite this, a literature analysis has never before been made to point out the research interest in therapeutic radionuclides (RNs). For this reason, the present study aims specifically to analyze the research output on therapeutic radiometals from 2008 to 2018, with intent to quantify and identify global trends in scientific literature and emphasize the interdisciplinary nature of this research field. The data search targeted conventional ( ",0
6735,30759884,Shift Work Including Night Work and Long Working Hours in Industrial Plants Increases the Risk of Atherosclerosis,"There is an abundance of literature reporting an association between shift work and cardiovascular disease (CVD). Few studies have examined early manifestation of CVD using advanced modern methodology. We established a group of 65 shift workers and 29 day workers (controls) in two industrial plants. For the shift workers, the shift schedule includes rotating shifts with day, evening and nightshifts, some day and nightshifts lasting for 12 h. The current paper describes cross-sectional data in a study running for three years. We collected background data by questionnaire and measured blood pressure, heart rate, lipids, glycosylated hemoglobin (HbA1c) and C-reactive protein (CRP). We examined arterial stiffness (central blood pressure, augmentation pressure and index, and pulse wave velocity) by the use of SphygmoCor ",0
6736,30760208,PmiRDiscVali: an integrated pipeline for plant microRNA discovery and validation,"MicroRNAs (miRNAs) constitute a well-known small RNA (sRNA) species with important regulatory roles. To date, several bioinformatics tools have been developed for large-scale prediction of miRNAs based on high-throughput sequencing data. However, some of these tools become invalid without reference genomes, while some tools cannot supply user-friendly outputs. Besides, most of the current tools focus on the importance of secondary structures and sRNA expression patterns for miRNA prediction, while they do not pay attention to miRNA processing for reliability check. Here, we reported a pipeline PmiRDiscVali for plant miRNA discovery and partial validation. This pipeline integrated the popular tool miRDeep-P for plant miRNA prediction, making PmiRDiscVali compatible for both reference-based and de novo predictions. To check the prediction reliability, we adopted the concept that the miRNA processing intermediates could be tracked by degradome sequencing (degradome-seq) during the development of PmiRDiscVali. A case study was performed by using the public sequencing data of Dendrobium officinale, in order to show the clear and concise presentation of the prediction results. Summarily, the integrated pipeline PmiRDiscVali, featured with degradome-seq data-based validation and vivid result presentation, should be useful for large-scale identification of plant miRNA candidates. ",0
6737,30760241,Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial,"Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. Netherlands Trial Register NTR5100 . Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7. ",0
6738,30760286,TOP2A as marker of response to pegylated lyposomal doxorubicin (PLD) in epithelial ovarian cancers,"Relapsed epithelial ovarian cancer (EOC) is frequently treated with pegylated liposomal doxorubicin (PLD). Unfortunately, most patients do not benefit from treatment. Prediction of response is crucial to optimize PLD use and avoid unnecessary toxicities. We aimed at assessing the value of topoisomerase II alpha (TOP2A) expression as predictive marker of response to PLD-based therapy in patients with relapsed EOCs. We retrospectively analyzed Formalin Fixed Paraffin Embedded (FFPE) tissues from 101 patients with platinum resistant (PR) or partially platinum-sensitive (PPS) EOCs treated with PLD-based chemotherapy beyond second line in three referral cancer centers between January 2010 and June 2018. TOP2A expression was measured by immunohistochemistry (IHC): images of each sample were acquired by optical microscope and analyzed by using automatic counter software. Correlation between TOP2A expression and response to PLD was assessed. Since no cut-off for positivity has been validated yet, we dichotomized TOP2A expression based on a cut-off of 18% (mean value in this study). TOP2A expression beyond cut-off was not prognostic for primary platinum-free interval in our series (p = 0.77) neither for optimal cytoreduction (p = 0.9). TOP2A > 18% was associated with a longer time to progression (TTP) following PLD-treatment, although not statistically significant (p = 0.394). No difference was observed between PR and PPS patients' groups (p = 0.445 and p = 0.185, respectively). Not unexpectedly, patients with TOP2A expression > 18% treated with PLD monotherapy achieved a longer TTP compared with PLD-doublet therapy (p = 0.05). Our data suggest that TOP2A status might predict activity of PLD in patients with PR/PPS EOCs. ",0
6739,30760527,Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation,"T cell activation is tightly regulated by both stimulatory and inhibitory co-receptors and has been a focus in the development of interventions for managing cancer or autoimmune diseases. Targeting the inhibitory co-receptors programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) has successfully eradicated tumors but induced immune-related adverse events in humans and mice. The beneficial and adverse effects of targeting these co-receptors highlight their importance in cancer immunity and also autoimmunity. Although the therapeutic potencies of other inhibitory co-receptors are under extensive investigation, their inhibitory mechanisms and their functional differences are not well understood. Here we analyzed the inhibitory mechanisms of lymphocyte activation gene-3 (LAG-3), another inhibitory co-receptor, by using an  ",0
6740,30760653,Body mass index and C-peptide are important for the promptly differential diagnosis of maturity-onset diabetes from familial type 2 diabetes in outpatient clinic,"Type 2 diabetic patients are becoming younger and having a tendency to family aggregation, they are easily suspected as maturity-onset diabetes of young (MODY) in the outpatient clinic and send to genetic testing. 9 diabetic families were compared in our outpatient clinic who met the primary diagnosis criteria of MODY. Detailed clinical features and laboratory data including gene sequence were collected and analyzed. The patients met the primary clinical diagnostic criteria of MODY for genetic testing at the first look. However, members of families A1 to A3 had normal Body mass index (BMI) and a lower C-peptide level which indicated impaired pancreatic islet function. In contrast, the members with diabetes of families B1 to B6 had normal or increased C-peptide level which indicated insulin resistance and were overweight with BMI. Genetic testing showed that the mutations in HNF1A, INS, KCNJ11 and so on in families A were consistent with the diagnosis of MODY. No pathogenic mutation was found in the members of families B which were diagnosed with familial T2D. Before the clinical laboratory testing and the further gene test, BMI and the concentration of C-peptide are important for the promptly differential diagnosis of MODY from familial type 2 diabetes and medication instruction in the outpatient clinic which could help to alleviate the burden of genetic testing for them. ",0
6741,30760686,A case of cerebral salt wasting syndrome caused by minor head injury],"An 80-year-old woman who was hospitalized due to small subarachnoid hemorrhaging caused by a bruise in the left temporal region of the brain. Nausea/vomiting and malaise appeared after dinner on the fourth day of the illness. Head computed tomography showed that the post-traumatic status was almost normal; however, the sodium ion (Na ",0
6742,30761202,Ergogenic Effect of Neuromuscular Electrical Stimulation During Rest and Submaximal Exercise,"The primary aim of this investigation was to determine the ergogenic effect of neuromuscular electrical stimulation (NMES) amongst twenty apparently healthy males during submaximal exercise. In Session 1, 20 participants (Age = 35.0 ± 15.0 yrs; Height = 179.9 ± 8.5 cm; Body Mass = 85.4 ± 12.0 kg) were familiarized with all equipment. Sessions 2-4 included the following randomized 5-min trials a) Rest and Rest+NMES, b) Rest, Arms-Only, Arms+NMES, and c) Rest, Arms+Legs, Arms+Legs+NMES. Physiological variables collected during rest and submaximal exercise were volume of oxygen (VO ",0
6743,30761590,Rising rates of cesarean delivery in Ecuador: Socioeconomic and institutional determinants over two decades,"Ecuador's cesarean delivery rate far exceeds that recommended by the Pan American Health Organization (PAHO) and the World Health Organization (WHO). Using data from three iterations of Ecuador's nationally representative, population-based survey Encuesta Nacional de Salud y Nutrición (ENSANUT/ENDEMAIN), spanning 23 years, this study examines women's mode of delivery outcomes by sociodemographic characteristics and hospital type (private, public, social security) in light of Ecuador's major health care reform over the past two decades. Using data from the 1994, 2004, and 2012 iterations of the data set, we analyzed trends in cesarean delivery based on province, year, and institution of care. Logistic regression was used to test the odds of cesarean delivery based on hospital type, sociodemographics, and birth complications for the full sample and primiparous women. Predicted probabilities were derived from this model. Ecuador's cesarean rate increased from 22% in 1989 to 41% in 2012. From 2008 to 2012, the probability of cesarean delivery in private centers was significantly higher than in public centers, and from 2009 to 2012, the probability of cesarean delivery in social security centers was significantly higher than in public centers. Higher maternal age, income, education, and parity, earlier prenatal care initiation, and more prenatal visits were associated with risk for cesarean delivery. To decrease the adverse effects of cesarean delivery for women and their babies, cesarean delivery should be reduced. Future research should investigate how incentive structures are used and how medical indication is defined within health institutions in Ecuador. ",0
6744,30761772,Endogenous circulating testosterone and sex hormone-binding globulin levels and measures of myocardial structure and function: the Framingham Heart Study,"The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. To determine the cross-sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community-dwelling men across a wide age range. A total of 720 men from the Framingham Heart Study Offspring Cohort (age range 37-82, mean = 59.6 years) who underwent cardiac magnetic resonance imaging and had hormone levels measured. Total testosterone (measured using liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (measured using an immunofluorometric assay), and calculated free testosterone levels were assessed in male participants of the Framingham Heart Study Offspring Cohort at examination 7. Cardiac magnetic resonance imaging was performed between examinations 7 and 8 (2002-2006). Age-adjusted linear regression models showed statistically significant association between total testosterone levels and left ventricular mass (p = 0.009), left ventricular mass index (p = 0.006), cardiac output (p = 0.001), and main pulmonary artery diameter (p = 0.008); the association between total testosterone and these cardiac magnetic resonance measures was weak and was not significant after adjustment for established risk factors-age, body mass index, diabetes, and hypertension. Furthermore, calculated free testosterone level was not significantly associated with any measure of myocardial mass or function. Sex hormone-binding globulin level was significantly associated with left ventricular mass (p = 0.002), left ventricular mass index (p = 0.004), cardiac output (p = 0.003), left ventricular ejection fraction (p = 0.039), and main pulmonary artery diameter (p = 0.042) in age-adjusted models; these associations were also rendered non-significant after adjusting for cardiovascular risk factors. Neither testosterone nor sex hormone-binding globulin levels in men are associated significantly with myocardial mass and function independent of established cardiovascular risk factors. ",0
6745,30761815,Current perspectives for the treatment of chronic myeloid leukemia,"With an annual incidence of 1-2 in a million, Ph*(+) chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disease that makes myeloid neoplastic cells breed out of control. This BCR-ABL(+) myeloproliferative disease makes up about 15%-20% of all leukemia cases in adults. CML is seen more in males than females, with a rate of three to two. However, it does not show differences in prevalence in terms of age. CML consists of three clinical phases. The first one is the chronic phase, defined by rising white blood cell levels and also by myeloid proliferation and bone marrow maturation. While this phase does not exhibit complications, in diagnosis, it comprises most of the patients. The second phase is the accelerated phase, which the disease progresses to if it is not treated or does not respond to treatment. This usually takes about 3 years. The third phase is the blastic phase. The chronic phase can still progress to the next two phases within the first 2 years, with a rate of 10%. In the following years, the possibility increases by 15%-20% each year. Tyrosine kinase inhibitors (TKIs) are revolutionary drugs for the management of disease course in CML. The aim of this review is to assess current approaches to CML patients' follow-up and treatment with TKIs. A literature search on CML and TKIs was made in PubMed, Web of Science, and Scopus with particular focus on randomized clinical trials, recommendations, guidelines, and expert opinions. In managing CML, various treatment methods have been utilized for many decades. Prior to the development of TKIs, interferon alpha was the primary tool, which was then complemented by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT was successful in slowing the disease down in the long term and curing up to 50% of patients. Then the coming of the imatinib era opened up different treatment perspectives. For the patients resistant or intolerant to imatinib, second- and third-generation TKIs are successfully used in distinct CML disease states. The survival benefits of TKIs including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib for CML patients are outstanding. TKI-related adverse events could impact the clinical course, especially in long-term drug administrations. The current aim for CML disease management in the TKI era is to provide age- and sex-matched normal life duration to CML patients. ",0
6746,30761951,Do socioeconomic factors influence households' solid waste disposal systems? Evidence from Ghana,"Solid waste management remains a major challenge in Ghana, especially in the peri-urban and urban areas. The implications from this bottleneck are widely acknowledged. Nonetheless, fundamental issues such as the factors that drive households into the adoption of a particular solid waste disposal system have not been explored. This study applied a multinomial logit approach using 16,767 households in the Ghana Living Standard Survey round six data to examine whether or not socioeconomic factors influence households' decision to adopt a particular solid waste disposal system. The results established that a number of the hypothesised socioeconomic factors drive households into the use of a particular solid waste disposal system. For instance, education of households on solid waste management is important to increase households' decision into collecting wastes other than open dumping or burning. The characteristics of houses and the location of households also influence waste disposal systems in Ghana. We conclude that solid waste disposal at unapproved places was largely influenced by socioeconomic characteristics other than income or welfare of households. We recommend continuous advocacy programmes on improved solid waste management systems, led by the various decentralised governance structures such as the District Assemblies, to curb the menace. ",0
6747,30762239,DNA methylation and allergic sensitizations: A genome-scale longitudinal study during adolescence,"The presence of allergic sensitization has a major influence on the development and course of common childhood conditions such as asthma and rhinitis. The etiology of allergic sensitization is poorly understood, and its underlying biological mechanisms are not well established. Several studies showed that DNA methylation (DNAm) at some CpGs is associated with allergic sensitization. However, no studies have focused on the critical adolescence period. We assessed the association of pre- and postadolescence genome-wide DNAm with allergic sensitization against indoor, outdoor and food allergens, using linear mixed models. We hypothesized that DNAm is associated with sensitization in general, and with poly-sensitization status, and these associations are age- and gender-specific. We tested these hypotheses in the IoW cohort (n = 376) and examined the findings in the BAMSE cohort (n = 267). Via linear mixed models, we identified 35 CpGs in IoW associated with allergic sensitization (at false discovery rate of 0.05), of which 33 were available in BAMSE and replicated with respect to the direction of associations with allergic sensitization. At the 35 CpGs except for cg19210306 on C13orf27, a reduction in methylation among atopic subjects was observed, most notably for cg21220721 and cg11699125 (ACOT7). DNAm at cg10159529 was strongly correlated with expression of IL5RA in peripheral blood (P-value = 6.76 × 10 In adolescence, the status of allergic sensitization was associated with DNAm differentiation and at some CpGs the association is likely to be age-specific. ",0
6748,30763314,Assessing effects of germline exposure to environmental toxicants by high-throughput screening in C. elegans,"Chemicals that are highly prevalent in our environment, such as phthalates and pesticides, have been linked to problems associated with reproductive health. However, rapid assessment of their impact on reproductive health and understanding how they cause such deleterious effects, remain challenging due to their fast-growing numbers and the limitations of various current toxicity assessment model systems. Here, we performed a high-throughput screen in C. elegans to identify chemicals inducing aneuploidy as a result of impaired germline function. We screened 46 chemicals that are widely present in our environment, but for which effects in the germline remain poorly understood. These included pesticides, phthalates, and chemicals used in hydraulic fracturing and crude oil processing. Of the 46 chemicals tested, 41% exhibited levels of aneuploidy higher than those detected for bisphenol A (BPA), an endocrine disruptor shown to affect meiosis, at concentrations correlating well with mammalian reproductive endpoints. We further examined three candidates eliciting aneuploidy: dibutyl phthalate (DBP), a likely endocrine disruptor and frequently used plasticizer, and the pesticides 2-(thiocyanomethylthio) benzothiazole (TCMTB) and permethrin. Exposure to these chemicals resulted in increased embryonic lethality, elevated DNA double-strand break (DSB) formation, activation of p53/CEP-1-dependent germ cell apoptosis, chromosomal abnormalities in oocytes at diakinesis, impaired chromosome segregation during early embryogenesis, and germline-specific alterations in gene expression. This study indicates that this high-throughput screening system is highly reliable for the identification of environmental chemicals inducing aneuploidy, and provides new insights into the impact of exposure to three widely used chemicals on meiosis and germline function. ",0
6749,30763631,"Prescription opioid misuse among middle-aged and older adults in the United States, 2015-2016","Adults ≥50 years of age have high rates of prescription opioid use. The purpose of this study is to estimate the prevalence and correlates of prescription opioid misuse among middle-aged and older adults in the United States who use prescription opioids. Data from adults age ≥ 50 from the two most recent cohorts (2015 and 2016) of the National Survey of Drug Use and Health were examined (N = 17,608). Characteristics of past-year prescription opioid misusers, including demographics, substance use, depression, chronic disease, and emergency department (ED) use, were compared to adults who used prescription opioids as prescribed in the past year and non-users. We used multivariable logistic regression to determine correlates of prescription opioid misuse among adults who used prescription opioids. Among the entire sample, 61.4% reported no past-year prescription opioid use, 36.0% reported past-year prescription opioid use without misuse, and 2.5% reported past-year prescription opioid misuse. Among past-year prescription opioid users, 6.6% reported misuse. Past-year misuse was higher among males, adults age 50-64, misusers of prescription sedatives, stimulants, and tranquilizers, users of other substances (i.e., tobacco, marijuana, cocaine), and those with alcohol use disorder. Past-year misuse was lower among adults with 2 or more chronic diseases. Past-year prescription misuse of sedatives (AOR 4.08 [95% CI 2.05-8.12]), stimulants (AOR 3.88 [95% CI 2.00-7.53]), and tranquilizers (AOR 10.02 [95% CI 6.48-15.50]) were all associated with past-year opioid misuse. Characteristics of opioid misusers determined in this study-particularly misuse of other substances-may help determine middle-aged and older adults at risk for prescription opioid misuse. ",0
6750,30763746,Efficacy and Safety of Gamma Knife Radiosurgery for Meningiomas in Patients with Neurofibromatosis Type 2: A Long-Term Follow-Up Single-Center Study,"To explore the efficacy and safety of Gamma Knife radiosurgery (GKRS) for meningiomas in patients with neurofibromatosis type 2 (NF2). A series of 35 consecutive patients with 99 meningiomas in our department were retrospectively included from January 2000 to December 2015. Clinical records, magnetic resonance images, and follow-up data were reviewed. A total of 35 patients (25 women and 10 men) with 99 NF2-associated meningiomas were identified. All patients initially received GKRS. The patients' median age at the time of GKRS was 40 years (range, 16-61 years). The median prescription dose at the tumor margin was 13 Gy (range, 12-15 Gy). The median follow-up time was 96 months (range, 25-224 months). Twenty-nine patients received GKRS only once, and 6 patients received it multiple times. Six patients (17.1%) had radiation-related complications 7.5 ± 2.4 months after GKRS. Local control rates at 1, 3, and 5 years were 100%, 97.1%, and 90.6%, respectively. Distant control rates at 1, 3, and 5 years were 88.5%, 55.9%, and 45.5%, respectively. Five patients died of concomitant neurologic symptoms. No malignant transformation was observed during the follow-up periods in all 35 patients. GKRS represents an effective and safe management strategy with minimal invasion for patients with NF2-associated meningiomas. Our data showed a high local control rate of NF2-associated meningiomas by GKRS; however, the distant control rate is low, especially in young patients. For these patients, retreatment with GKRS may still be the advisable method. ",0
6751,30763776,Clinical evaluation of submental intubation as an alternative airway management technique in midface osteotomy,"The conventional endonasal intubation would not allow precise intra-operative assessment of the changes to the nasolabial soft tissue complex. Submental intubation allows accurate measurement of nasolabial soft tissue complex with no interference with the occlusion. A clinical prospective study was carried on 20 patients visiting the Oral and Maxillofacial Surgery department diagnosed of dentofacial deformity requiring orthognathic surgery. The patient were intubated by the submental route of anaesthesia. Intraoperatively time taken to perform intubation and bleeding during the surgery was noted. Post-operatively infection, presence or absence of any complications were noted along with the measurement of scar by Vancouver scar scale. Out of 20 patients 17 patients required only maxillary osteotomies whereas 3 patients required bimaxillary osteotomy. The mean time taken for intubation was 5.68 ± 1.257 minutes. In all the cases the scar was measured as minimum. 2 patients showed infection at the site of submental intubation after 7th day while after 14th day there was no infection present. No other complication was noted. 19 out of 20 cases showed no interference during the procedure whereas in 1 case mild interference during mandibular movement. The submental intubation is a very good alternative to nasotracheal intubation in the patients undergoing bimaxillary surgeries or maxillary surgeries. Submental intubation can be chosen whenever possible, as it is easy, takes little time and follow-up is simple, does not result in bleeding or other complications and more importantly does not result in any unaesthetic scar after 3rd month follow up. ",0
6752,30763832,"A critical review of risks, characteristics, and treatment strategies for potentially toxic elements in wastewater from shale gas extraction","Shale gas extraction via horizontal drilling and hydraulic fracturing (HF) has enhanced gas production worldwide, which has altered global energy markets and reduced the prices of natural gas and oil. Water management has become the most challenging issue of HF, as it demands vast amounts of freshwater and generates high volumes of complex liquid wastes contaminated by diverse potentially toxic elements at variable rates. This critical review focuses on characterizing HF wastewater and establishing strategies to mitigate environmental impacts. High prioritization was given to the constituents with mean concentrations over 10 times greater than the maximum contamination level (MCL) guidelines for drinking water. A number of potentially harmful organic compounds in HF wastewaters were identified via the risk quotient approach to predict the associated toxicity for freshwater organisms in recipient surface waters. Currently, two options for HF wastewater treatment are preferred, i.e., disposal by deep well injection or on-site re-use as a fracturing fluid. Supplementary treatment will be enforced by increasingly rigorous regulations. Partial treatment and reuse remain the preferred method for managing HF wastewater where feasible. Otherwise, advanced technologies such as membrane separation/distillation, forward osmosis, mechanical vapor compression, electrocoagulation, advanced oxidation, and adsorption-biological treatment will be required to satisfy the sustainable requirements for reuse or surface discharge. ",0
6753,30764121,First Report of Phaeoacremonium parasiticum Causing Petri Disease of Grapevine in Peru,"Since 2005, symptoms of grapevine decline have been observed on 4- to 8-month-old grapevines (cvs. Red globe and Crimson) grafted onto 1103 P rootstock in Ica and Pisco valleys in southern Peru. Affected plants exhibited weak growth, interveinal chlorosis, necrosis and wilting of leaves, and death. Dark brown-to-black streaking of the xylem was seen when transverse or longitudinal cuts were made in the trunk and shoots. Symptomatic plants were collected and sections (5 cm long) were cut from the zone between the rootstock and the scion, surface sterilized for 1 min in a 1.5% sodium hypochlorite solution, and washed twice with sterile distilled water. The sections were split longitudinally, and small pieces of discolored tissues were placed onto potato dextrose agar (PDA) supplemented with oxytetracycline (500 mg liter ",0
6754,30764516,"CHADS₂, CHA₂DS₂ASc, and New ABCD Scores Predict the Risk of Peripheral Arterial Disease in Patients with Sleep Apnea","The association between sleep apnea (SA) and peripheral artery disease (PAD) remains debatable, and there is no clinical tool to predict incident PAD in SA patients. The CHADS₂ score has been found useful in predicting PAD risk. This study was designed to investigate the association between these diseases and the usefulness of CHADS₂ and CHA₂DS₂ASc scores in predicting subsequent PAD in SA patients. From a population-based database of one-million representative subjects, adult patients with SA diagnosis were enrolled as the suspected SA group, and those having SA diagnosis after polysomnography were further extracted as the probable SA group. Twenty sex- and age-matched control subjects were randomly selected for each SA patients. The occurrence of PAD after SA was taken as the primary endpoint. Totally, 10,702 and 4242 patients were enrolled in the suspected and probable SA groups, respectively. The cumulative incidence of PAD was similar between SA patients and the corresponding control groups. Multivariable Cox regression analyses showed that SA was not an independent risk factor for subsequent PAD. Sensitivity analyses using propensity score-matched cohorts showed consistent results. Furthermore, in stratifying the SA patients by CHADS₂, CHA₂DS₂ASc, or a newly-proposed ABCD (composed of Age, high Blood pressure, Cerebral vascular disease, and Diabetes mellitus) score, patients with higher scores predicted higher risks of subsequent PAD, while the ABCD score appeared to be the most robust. Aggressive risk modification is suggested to reduce the subsequent PAD risk in SA patients with a higher CHADS₂, CHA₂DS₂ASc, or ABCD score. ",0
6755,30764751,Useful lessons for the provision of services in long-term care facilities in South Korea: operators' experiences illuminate the phenomenon of working with the elderly in the field,"""The aim of this study was to gain a deeper understanding of elderly long-term care facilities by focusing on insights provided by the operators of these facilities. In this phenomenological study, 10 participants who operated nursing home businesses were interviewed. Of the 10 participants, seven had graduated from a nursing programme and three had studied social welfare. The experiences of facility operators could be organized into four themes: """"Starting as a facility operator"""", """"Dream of an ideal long-term care facility"""", """"Struggling desperately in practice"""", and """"Obtaining hope by providing care"""". These four themes were divided into 18 subthemes, constituting 96 meaningful statements. Despite the obvious gap between reality and ideals with regard to caring for residents, operators used a person-centred care strategy for the elderly at their facilities. Our findings indicate that, despite diverse barriers and hardships, participants were encouraged when they offered person-centred healthcare services for the elderly under their care, based on a philosophy of a holistic understanding of humans and respect for human life and dignity. Facility operators who are leaders in the practical field should be involved in the decision/policy-making process, to support health and well-being in the elderly in institutionalized settings. """,0
6756,30764895,Survey of Behavioral Indices of Welfare in Research Chimpanzees (,"Chimpanzees demand specialized housing and care and the highest degree of attention to animal welfare. The current project used a survey method to collate information on chimpanzee housing and behavioral indices of welfare across all 6 of the chimpanzee research facilities in the United States. Data were compiled on 701 chimpanzees ranging from 2 to 62 y old (mean age, 26.0 y). All chimpanzees except for one were socially housed; the median group size was 7 animals, and group sizes ranged from 1 to 14. All of the subjects had access to outdoor spaces each day. Daily access to a natural substrate in the chimpanzee's enclosure was available for 63.8% of the subjects. Overall, 94.1% of the chimpanzees used tools to acquire food, 48.1% built nests, 75.8% copulated, and 83.3% initiated grooming bouts. The following atypical behaviors were reported most often: rocking (13.0%), coprophagy (10.0%), and stereotyped behaviors other than rocking (9.4%). There was widespread evi- dence of positive animal training techniques, with nearly all (97.7%) subjects reported to generally voluntarily cooperate with shifting in their enclosure, and 72.2% were reported to present for an injection of anesthetic. We include some comparison between these findings and data describing zoo-housed chimpanzees. In addition, we discuss survey findings in reference to recommendations made by the NIH Working Group on the Use of Chimpanzees in NIH-supported Research. The current survey assessed a larger sample of chimpanzees living under human care than has been published previously. This broad analysis can help to guide future improvements in behavioral management to address behavioral problems or deficits. ",0
6757,30764939,A Comparative Analysis of ZnO Nanorods and Nanopencils Towards Amperometric Biosensing Applications,"In this work, ZnO Nanorods (ZNR) and Nanopencils (ZNP) were synthesized over Platinum (Pt) coated glass substrate by simple and low-temperature hydrothermal process for large-scale fabrication towards biosensing applications. The two types of morphologies have been obtained by using strong oxidizing agent viz KMnO₄ as an additive and replenishing the growth solution during the hydrothermal growth process. It was observed that incorporation of additive and replacement of growth solution has greatly influenced structural and electrochemical properties of ZNR/ZNP in terms of morphology, aspect ratio, and charge transfer hindrance. The aspect ratio has been found to increase by approximately three times from ZNR to ZNP which facilitated higher enzyme loading over ZNP as compared to ZNR. Moreover, electrochemical charge transport resistance was found to decrease by 36 times with changes in morphology and aspect ratio. Hence, significant variation in performance of as-fabricated enzymatic biosensor was observed. Amidst both the types of biosensors four-fold increment in sensitivity was found from ZNR to ZNP along with fast response time of 5s and a linear range of operation of 0.5-7.5 mM. The obtained results revealed that aspect ratio could be tuned efficiently by replacing the growth solution during hydrothermal growth which cognitively effects enzyme loading thereby influencing different figure of merits of the biosensor. ",0
6758,30765128,Three-dimensional hierarchical frameworks based on molybdenum disulfide-graphene oxide-supported magnetic nanoparticles for enrichment fluoroquinolone antibiotics in water,"Recently, water pollution caused by antibiotics is rapidly increasing. Thus, developing efficient, fast and sensitive detection methods for environmental antibiotics monitoring are still remaining elusive. Herein, a method for antibiotics analysis including lecofloxacin, pazcofloxacin and gatifloxacin in water by high performance liquid chromatography (HPLC) using molybdenum disulfide-graphene oxide-supported magnetic nanoparticles (Fe ",0
6759,30765256,Exploring issues relating to disability cultural competence among practicing physicians,"""Many factors contribute to the well-recognized health care disparities experienced by persons with disability, including failure of physicians to understand the lives of individuals with disability. Disability cultural competence considers physicians' ability to meet the social, cultural, and linguistic needs of this population. To assess physicians' understanding of disability cultural competence and attitudes towards patients with disability. Qualitative analyses of open-ended individual interviews averaging 41 min with 20 Massachusetts physicians from 5 different subspecialties, in practice for 8-51 years. Interview recordings were transcribed verbatim for conventional content analysis. Most participants defined disability using medically-focused concepts rather than concepts that recognize how social factors contribute to disability. All participants used disability culturally-competent language, such as """"person-first language,"""" at some points throughout their interviews. However, most participants also employed language that is now considered unacceptable or archaic, such as variations on the word """"handicap,"""" """"wheelchair-bound,"""" describing persons with disability as """"suffering,"""" and calling persons by their health condition (e.g., """"COPDer""""). Participants mentioned persons with mental illness and intellectual disability as particularly challenging, especially around communication and performing even routine tests or examinations. Recommendations for improving care included better listening to patients with disability and seeking their views about their care. In this exploratory study, most participants used language that is considered disability culturally competent at times but also employed many terms and concepts that are considered outdated and may be troubling to some persons with disability. """,0
6760,30765335,Glucose Metabolism Is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes,"Patients with type 1 diabetes mellitus (T1DM) have increased thrombosis and platelet activation. The mechanisms for platelet hyperactivation in diabetes are incompletely understood. T1DM is accompanied by hyperglycemia, dyslipidemia, and increased inflammation in addition to an altered hormonal milieu. In vitro analysis of platelets revealed that normal glucose reduces platelet activation whereas hyperglycemic conditions increase platelet activation. We therefore hypothesized that hyperglycemia increases platelet glucose utilization, which increases platelet activation to promote thrombosis. Glucose uptake and glycolysis were increased in platelets isolated from mice given streptozotocin (STZ) to induce T1DM in concert with induction of GLUT3. Platelets from STZ-induced diabetic mice exhibited increased activation after administration of protease-activated receptor 4 peptide and convulxin. In contrast, platelets isolated from GLUT1 and GLUT3 double-knockout (DKO) mice, which lack the ability to use glucose, failed to increase activation in hyperglycemic mice. Diabetic mice displayed decreased survival in a collagen/epinephrine-induced pulmonary embolism model of in vivo platelet activation relative to nondiabetic controls. Survival after pulmonary embolism was increased in diabetic DKO mice relative to nondiabetic controls. These data reveal that increased platelet glucose metabolism in vivo contributes to increased platelet activation and thrombosis in a model of T1DM. ",0
6761,30765408,Causes of albuminocytological dissociation and the impact of age-adjusted cerebrospinal fluid protein reference intervals: a retrospective chart review of 2627 samples collected at tertiary care centre,"We set out to test the discriminative power of an age-adjusted upper reference limit for cerebrospinal fluid total protein (CSF-TP) in identifying clinically relevant causes of albuminocytological dissociation (ACD). We reviewed the charts of 2627 patients who underwent a lumbar puncture at a tertiary care centre over a 20-year period. Samples with CSF-TP above 45 mg/dL (0.45 g/L) were included. Samples with white cell count >5×10 The presence of ACD was associated with a broad range of neurological diagnoses. Among all 2627 patients with ACD, a clinical diagnosis explaining CSF-TP elevation was identified in 57% of cases. 'True' ACD was associated with a suitable diagnosis in 75% of cases, whereas patients with 'pseudo' ACD showed an appropriate diagnosis in only 51% of cases. Use of an age-adjusted upper reference limit favoured the detection of polyneuropathy patients (13.5% proportionate increase) and excluded a larger number of patients with isolated headache (10.7% proportionate decrease; p<0.0001). Elevated CSF-TP is a common finding, with a range of underlying causes. Use of an age-adjusted upper reference limit for the CSF-TP value improves diagnostic specificity and helps to avoid overdiagnosis of ACD. ",0
6762,30765508,"A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis","Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs.  ",0
6763,30765800,Terrestrial mammalian wildlife responses to Unmanned Aerial Systems approaches,"Unmanned Aerial Systems (UAS) are increasingly being used recreationally, commercially and for wildlife research, but very few studies have quantified terrestrial mammalian reactions to UAS approaches. We used two Vertical Take-off and Landing (VTOL) UAS to approach seven herbivore species in the Moremi Game Reserve, Botswana, after securing the relevant permissions. We recorded responses to 103 vertical and 120 horizontal approaches, the latter from three altitudes above ground level (AGL). We ran mixed logistic regressions to identify factors triggering (i) any response and (ii) an evasive response. We included effects of activity, altitude, direction of approach, distance, habitat, herd type, herd size, other species, target species, time, VTOL type and wind strength. Response triggers were linked to altitude, distance, habitat and target species. Elephant (Loxodonta africana), giraffe (Giraffa camelopardalis), wildebeest (Connochaetes taurinus) and zebra (Equus quagga) were most affected by VTOL approach, impala (Aepyceros melampus) and lechwe (Kobus leche) were least responsive, and tsessebe (Damaliscus lunatus) displayed intermediate sensitivity. VTOLs flown lower than 60 m AGL and closer than 100 m horizontal distance from target animals triggered behavioural responses in most species. Enforced regulations on recreational UAS use in wildlife areas are necessary to minimise disturbance to terrestrial mammals. ",0
6764,30765952,Perceptions and Career Expectation in Ophthalmology among Saudi Undergraduate Medical Students,"To assess the perceptions about ophthalmology as a career among undergraduate medical students and to investigate the determinants of career choice in ophthalmology. A questionnaire was administered to all medical students (from 4 Among 519 included students, ophthalmology was the first career choice of 5.6% and in the top three choices of 13.5% of students. Students from Group A had female preponderance and comparable academic skills, by reference to Group B. Group A reported to have a better experience in ophthalmology, including conference attendance, research activity, and community services related to ophthalmology, as well as greater advantage from ophthalmology rotation. Determinants of career choice in ophthalmology included giving importance for workload during their residency (odds ratio [OR] = 3.38;  Students who aspire for a career in ophthalmology showed to have an early involvement in related academic activities and less concern about instrumental and intellectual challenges, as compared to their counterparts. The formal ophthalmology rotation is the key step to recruit future ophthalmologists by correcting misconceptions and enhancing interest about the specialty. ",0
6765,30766461,Oestrogen receptor alpha PvuII polymorphism and uterine fibroid incidence in Caucasian women,"Uterine fibroids (UFs) are benign, monoclonal tumours of the female genital tract that originate from the myometrium. They may be diagnosed in as many as 80% of women depending on the selected population. UFs depend mostly on steroid hormones. Elevated levels of oestrogens and progesterone are believed to be among the most important factors inducing their formation and growth. These facts suggest that oestrogen (ESR) and progesterone receptors are crucial in UF pathophysiology as well. Previous studies have shown that, in some populations, polymorphisms in ESR genes (e.g. PvuII) constitute an important risk factor for UFs. The aim of our study was to investigate whether ESRα PvuII polymorphism is associated with an increased risk of UFs in Caucasian women of Polish origin. A total of 197 patients (114 UF-positive and 83 controls) were included in this retrospective cohort study. ESRα gene polymorphism PvuII (rs2234693) was assayed with PCR and restriction fragment length polymorphism (RFLP). Our study found no significant difference in the occurrence of ESR PvuII polymorphism between women with UFs and UF-free controls in the selected population. Our results did not indicate a significant association between ESRα gene PvuII polymorphism and the risk of UFs in Caucasian women of Polish origin. More studies and comparisons between races are necessary to clarify the role of ESRα in the development and progression of UFs. ",0
6766,30766551,Screening for diabetes among tuberculosis patients: a nationwide population-based study in Egypt,"The prevalence of type 2 diabetes mellitus (DM) is increasing rapidly in Egypt and considered one of the major health problems in the Eastern Mediterranean region. To measure the prevalence of diabetes and detect the undiagnosed cases of diabetes mellitus among patient with tuberculosis. Study Design: Nationwide population-based study. To diagnose DM among TB patients, we used a fasting blood sugar level of ≥ 126 mg/dl and a post-prandial blood glucose test result of ≥ 200 mg/dl. Screening for DM among 1435 TB patients' with no history of DM detected 30 new cases of DM, with a case detection rate of 2.09%. The highest screening yields were among TB patients aged ≥ 40 years, females and those with pulmonary TB. The number needed to screen (NNS) TB patients for detecting one new case of DM was 48 while the lowest values were for older age (NNS=27) and females (NNS=29). Older age and being females and those with pulmonary type of TB were more prone to the double burden of TB and DM. Identifying cases with double burden of diseases will improve the proper management of both diseases and prevent complications. ",0
6767,30766694,Confronting the challenges of the menopausal transition,"Canada's Generation X is now entering the menopausal transition and pursuing effective therapy for bothersome vasomotor symptoms. They do so at a time when confusion about the safe and appropriate use of menopausal hormone therapy (MHT) has never been greater. Misplaced fears among women and their health care providers about MHT have, in many circumstances, led them to abandon this most effective therapy. This review discusses the physiology of the menopausal transition, the nature of symptoms related to withdrawal of ovarian estrogen production, and the potential benefits and risks of MHT. It is now clear that for most recently menopausal women the benefits of MHT outweigh the risks. The rationale for choosing different dosages, formulations, and regimens is reviewed. ",0
6768,30767046,A reliable method to avoid contamination during cartilage graft preparation in septorhinoplasty,"The aim of the study is to determine the risk of contamination in the cartilage graft materials prepared on the swester table and those prepared in a sterile package, and to reveal a more reliable method by performing the microbiological examination of these materials. Cartilages removed from the nasal septum were divided into four pieces. The first part (Sample A) was directly placed into the medium. Sample B was prepared by being crushed in a sterile package. Sample C was prepared on the auxiliary swester table, and Sample D was prepared on the main swester table actively used by surgery team. All samples were transferred in a 1 ml brain heart(BH) liquid medium. From each BH medium, 100 µl culture was performed on blood agar, eosin-methylene blue-lactose-sucrose agar and chocolate agar. Bacterial growth was detected in 2 of the samples A, in 4 of the samples B, in 24 of the samples C, and in 36 of the samples D. The number of patients with bacterial growth in the samples C and/or D despite no growth in the sample B was 35. When the samples A/B and C/D were compared in terms of bacterial growth, a significant difference was found in all matchings (p < 0.001 for all comparisons).  CONCLUSION: These findings showed that preparation of the cartilage grafts on the swester table was extremely risky for microbiological contamination. Arslan and his colleagues suggest that preparing a graft material in a sterile package is extremely simple, cheap, and it also reduces contamination risk significantly. ",0
6769,30767056,Negative effects of stripe conchotomy on intranasal conditioning],"""Partial resection of the caudal part of the inferior turbinate including the head is still performed in rhinosurgery (""""stripe conchotomy""""). However, extensive resections of the turbinate affect nasal airflow and intranasal conditioning. The aim of this study was to determine the effect of partial resection of the inferior turbinate including its head on intranasal air flow as well as warming and humidification of the inspired air by means of computational fluid dynamics. A bilateral, realistic nasal model was created based on the CT scan of a patient. A unilateral partial resection of the lower turbinate on the right side had been performed externally. A numerical simulation was performed to analyze intranasal air flow patterns, temperature, and humidity distribution of the inspired air. Due to the partial resection of the lower turbinate on the right side, the flow pattern was significantly altered compared to the opposite side. Resection leads to a centered and higher velocity in the inferior nasal meatus as well as to reduced heating and humidification of the inhaled air compared to the untouched left nasal cavity. Partial resection of the caudal part of the inferior turbinate may lead to disturbed intranasal conditioning of inspired air if performed too radically. Therefore, if possible, this procedure should be avoided and a more gentle mucosal procedure chosen. """,0
6770,30767286,Home Parenteral and Enteral Nutrition During Natural Disasters: A Guide for Clinicians and Consumers,"""Natural disasters are most often weather related but can also be unrelated to weather. Either way, these disrupt """"normal"""" life for a short or extended period of time. When someone depends on electricity, clean water, and transportation services for life-sustaining therapies such as home nutrition support, it is important to have a plan in place-even if it is never used. Understanding supply needs, access to home utilities, and when to change location should be discussed, determined, and defined. In this article, the authors strive to provide this information for home parenteral and enteral nutrition support patients (consumers), caregivers, and clinicians. """,0
6771,30767377,Impact on renal resistive index of diabetes in renal transplant donors and recipients: A retrospective analysis of 1827 kidney transplant recipients,"High renal resistive index (RI) is observed in diabetes and is associated with poor patient survival, but whether it is primarily due to renal vascular resistance or systemic vascular alterations is unclear. The respective impact of kidney transplant from diabetic donors or to diabetic recipients on RI would shed some light on this issue. The objective of the study was to analyze the impact of donor and recipient diabetes on RI in order to understand the respective impact of the kidney and the vascular environment. The authors conducted a retrospective study in 1827 renal transplant recipients who received a kidney between 1985 and 2017, and had Doppler measurements at 3 months after transplant. Donor and recipient characteristics at the time of transplant and at 3 months were reviewed. Both donor diabetes and recipient diabetes were associated with RI in univariate analysis, but only recipient diabetes remained significantly associated in stepwise multivariate analyses (effect estimate on RI: +0.03 ± 0.005, P < 0.001). These findings were confirmed when RI was expressed as a binary variable using a cutoff of 0.75 (OR = 2.50 [1.77, 3.54], P < 0.001). Other determinants of RI were recipient characteristics (age, sex, systolic and diastolic blood pressure, and duration of dialysis). Donor characteristics were not associated with RI. Our results suggest that high RI observed in diabetic recipients shortly after transplant is primarily due to the new vascular environment, rather than to characteristics of the transplanted kidney. Therefore, RI reflects systemic rather than intra-renal changes. ",0
6772,30767757,Targeting Chromatin Remodeling for Cancer Therapy,"Epigenetic alterations comprise key regulatory events that dynamically alter gene expression and their deregulation is commonly linked to the pathogenesis of various diseases, including cancer. Unlike DNA mutations, epigenetic alterations involve modifications to proteins and nucleic acids that regulate chromatin structure without affecting the underlying DNA sequence, altering the accessibility of the transcriptional machinery to the DNA, thus modulating gene expression. In cancer cells, this often involves the silencing of tumor suppressor genes or the increased expression of genes involved in oncogenesis. Advances in laboratory medicine have made it possible to map critical epigenetic events, including histone modifications and DNA methylation, on a genome-wide scale. Like the identification of genetic mutations, mapping of changes to the epigenetic landscape has increased our understanding of cancer progression. However, in contrast to irreversible genetic mutations, epigenetic modifications are flexible and dynamic, thereby making them promising therapeutic targets. Ongoing studies are evaluating the use of epigenetic drugs in chemotherapy sensitization and immune system modulation. With the preclinical success of drugs that modify epigenetics, along with the FDA approval of epigenetic drugs including the DNA methyltransferase 1 (DNMT1) inhibitor 5-azacitidine and the histone deacetylase (HDAC) inhibitor vorinostat, there has been a rise in the number of drugs that target epigenetic modulators over recent years. We provide an overview of epigenetic modulations, particularly those involved in cancer, and discuss the recent advances in drug development that target these chromatin-modifying events, primarily focusing on novel strategies to regulate the epigenome. ",0
6773,30767877,The mortality rate and causes of death among juvenile idiopathic arthritis patients in Finland,"To explore mortality rates and causes of death in juvenile idiopathic arthritis (JIA) patients in Finland compared with the general population. All incident patients with JIA (age <16 years at the index day) during 2000-2014 were collected from the nationwide register maintained by the Social Insurance Institution of Finland and The National Population Registry identified three age-, sex- and residence-matched controls for each case. They were followed up together until 31st Dec 2015. Altogether 4,180 JIA patients (62% females) were identified. Mean age at diagnosis was 8.3 years. The average follow-up time was 6.6 years (IQR 3.1-10.5). The patients were compared with 12,511 controls. During 28,941 follow-up years, 11 JIA patients (6 females, 5 males) and 23 controls (12 females, 11 males) died. The mean age at death was 20.3 (range: 11-30) in JIA patients and 23.1 (range: 9-29) years in the control group, (p=0.17). Cumulative mortality in JIA was 0.6% (95% Cl 0.3-1.2) compared to 0.6% (95% Cl 0.4-1.0) in the controls; (hazard ratio 1.44, 95% Cl 0.70-2.95). Accidents were the most common (54%) cause of death in JIA, whereas suicide (39%) in the controls. Substance abuse and depression contributed more to deaths in the controls (39%) than in the JIA patients (10%), (p=0.053). The mortality rate was not elevated in patients with juvenile idiopathic arthritis. ",0
6774,30768225,A New Suggested Strategy for Safe Injection of Ozurdex,"Ozurdex intravitreal injection is performed via a patented injection device. However, there is a common misconception among ophthalmologists regarding the relation between the speed of applicator button depression and the speed of pellet injection. Six dexamethasone intravitreal implants were injected into a calibrated ex vivo water bath. Three of the pellets were injected via rapid compression, whereas the other three implants were injected using a 3-second compression technique. The procedures were recorded using high-speed photography followed by calculation of pellet velocity and impact force. The mean impact velocity and force of the pellet insertion is significantly higher in the fast injection group compared to the slow injection group. By depressing the Ozurdex implant injector during a 3-second time interval, the impact force of the implant pellet is reduced by about 95%. This new technique will theoretically reduce the risk of retinal injury and vitreous hemorrhage from Ozurdex injections. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e23-e25.]. ",0
6775,30768257,Mitigation of Hydrophobicity-Induced Immunotoxicity by Sugar Poly(orthoesters),"Polymeric nanoparticles (NPs) derived from self-assemblies of amphiphilic polymers have demonstrated great potential in clinical applications. However, there are challenges ahead. Notably, immunotoxicity remains a major roadblock that deters the NPs from further applications. Studies suggested that the hydrophobic component is a primary cause, yet biocompatible hydrophobic carbohydrate-based polymers may help mitigate this issue. Herein we design and synthesize novel NP systems having glucose poly(orthoesters) hydrophobic scaffold and polyethylene glycol (PEG) hydrophilic shell. The new NPs exhibited low immunotoxicity both in vitro and in vivo, as measured by the induced cytokine levels. In contrast, when other polymers, such as polylactide (PLA) or polycaprolactone (PCL), were used as the hydrophobic scaffold, the cytokine levels were orders of magnitude higher. Results from our multiple immunological studies indicate that carbohydrate-based polymers can largely mitigate the hydrophobicity-induced immunotoxicity, and thereby they may be good candidate polymers to engineer low immunotoxic biomaterials for various biomedical studies. ",0
6776,30768414,Trajectories of Symptom Change in the Treatment for Adolescents With Depression Study,"Depression is the most prominent mental health disorder among youth and has a profound impact with respect to morbidity and mortality if not addressed. The Treatment for Adolescent Depression Study (TADS) is one of the largest randomized controlled trials that compared the effectiveness of four treatments: cognitive-behavioral therapy (CBT); fluoxetine (FLX); combined cognitive-behavioral and fluoxetine treatment (COMB); and placebo (PBO). However, meaningful heterogeneous treatment courses are masked by these group mean comparisons of treatment impact. The present study sought to characterize the acute phase symptom trajectories of the depressed teens enrolled in TADS and to explore predictors of these trajectories, including TADS treatment condition. The TADS sample of 439 adolescent participants diagnosed with major depressive disorder was subjected to growth mixture modeling (GMM) to evaluate subgroups of adolescents with unique trajectories of depression symptom change. Growth mixture modeling revealed three unique classes of adolescents: (1) a high-severity class with early significant improvement; (2) a high-severity class with limited symptom change; and (3) a moderate severity class with late significant improvement. Baseline predictors of class membership included treatment condition, sex, age, stage of change, depression severity, number of comorbid disorders, hopelessness, melancholia, suicidality, and cognitive distortions. Results of this study may have implications for the selection of which treatment to use for which depressed adolescent. Treatment for Adolescents With Depression Study (TADS); https://clinicaltrials.gov/; NCT00006286. ",0
6777,30768615,The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial,"The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, where artemisinin resistance is prevalent. After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. ClinicalTrials.gov NCT01872702. ",0
6778,30769039,Medicinal plants with concomitant anti-diabetic and anti-hypertensive effects as potential sources of dual acting therapies against diabetes and hypertension: A review,"""Diabetes and hypertension are pathophysiologically related diseases that co-exist with a wider complex of metabolic diseases having similar set of risk factors. There are numerous ethnopharmacological evidences on the anti-diabetic and/or anti-hypertensive properties of medicinal plants from various parts of the world, which are used as therapies to concomitantly manage diabetes and hypertension. This article reviewed findings on medicinal plants with both anti-diabetic and anti-hypertensive effects reported in same experimental study to facilitate the development of dual-acting therapies against diabetes and hypertension. A literature search was carried out on different scientific search engines including, but not limited to """"PubMed"""", """"Google Scholar"""", """"Scopus"""" and ScienceDirect to identify published data in which plants in same experimental studies were reported to possess both anti-hyperglycemic and anti-hypertensive effects. Subsequently, the anti-diabetic/anti-hypertensive potency ratio (ψ) of the medicinal plants was computed. Sixty-four studies with 102 plant species matched the selection criteria. Members of the Fabaceae family were the most investigated plants, while the ψ greatly varied across the plants, with only 11 plants having a ψ ≃ 1. Withania somnifera Dunal was the only plant reported to show blood glucose-lowering and diuretic effects in humans, comparable to daonil. Caffeic acid, chlorogenic acid, caftaric acid, cichoric acid, verbascoside, leucosceptoside A, isoacteoside, fucoxanthin and nicotinamide were the reported dual acting anti-diabetic and anti-hypertensive compounds identified and/or isolated in the plants. This review suggests that medicinal plants possess varied therapeutic dynamics against hypertension and diabetes that could be exploited for the discovery of therapeutic preparation(s) or agent(s) for treating the two diseases. """,0
6779,30769079,Molecular characteristics and function study of TNF receptor-associated factor 5 from grouper (Epinephelus coioides),"Tumor necrosis factor receptor-associated factor 5 (TRAF5) is a key adapter molecule that participates in numerous signaling pathways. The function of TRAF5 in fish is largely unknown. In the present study, a TRAF5 cDNA sequence (EcTRAF5) was identified in grouper (Epinephelus coioides). Similar to its mammalian counterpart, EcTRAF5 contained an N-terminal RING finger domain, a zinc finger domain, a C-terminal TRAF domain, including a coiled-coil domain and a MATH domain. The EcTRAF5 protein shared relatively low sequence identity with that of other species, but clustered with TRAF5 sequences from other fish. Real-time PCR analysis revealed that EcTRAF5 mRNA was broadly expressed in numerous tissues, with relatively high expression in skin, hindgut, and head kidney. Additionally, the expression of EcTRAF5 was up-regulated in gills and head kidney after infection with Cryptocaryon irritans. Intracellular localization analysis demonstrated that the full-length EcTRAF5 protein was uniformly distributed in the cytoplasm; while a deletion mutant of the coiled-coil domain of EcTRAF5 was observed uniformly distributed in the cytoplasm and the nucleus. After exogenous expression in HEK293T cells, TRAF5 significantly activated NF-κB. The deletion of the EcTRAF5 RING domain or of the zinc finger domain dramatically impaired its ability to activate NF-κB, implying that the RING domain and the zinc finger domain are required for EcTRAF5 signaling. ",0
6780,30769273,Social contents in dreams: An empirical test of the Social Simulation Theory,"Social Simulation Theory (SST) considers the function of dreaming to be the simulation of social events. The Sociality Bias and the Strengthening hypotheses of SST were tested. Social Content Scale (SCS) was developed to quantify social events. Additionally, we attempted to replicate a previous finding (McNamara et al., 2005, Psychological Science) of REM dreams as predisposed to aggressive, and NREM dreams to prosocial interactions. Further, we investigated the frequency and quality of interactions in late vs early REM and NREM dreams. Data consisted of wake, REM and NREM home dream reports (N = 232, 116, 116, respectively) from 15 students. Dreams overrepresented social events compared to wake reports, supporting the Sociality Bias hypothesis. However, the Strengthening Hypothesis was not supported. We weren't able to replicate the McNamara et al. finding, and no time of night effect was found. While SST gained partial support, further research on social contents in dreams is required. ",0
6781,30769364,Evaluation of BioFoam for Anastomotic Bleeding in Cardiovascular Surgery," Hemostatic agents are increasingly used as an adjunct to standard methods of controlling anastomotic bleeding in surgical procedures. The purpose of this study was to investigate the safety and effectiveness of BioFoam Surgical Matrix used as an adjunct for anastomotic hemostasis following cardiovascular surgery.  A prospective, multicenter, single arm study was conducted with 75 subjects treated with BioFoam following a total of 105 elective cardiovascular surgical procedures. Time to hemostasis was recorded following a single application of BioFoam in 74 subjects. Safety evaluations included intraoperative administration of a blood product, requirement for alternative means to achieve hemostasis, and the incidence of reoperation for bleeding.  Hemostasis within 3 minutes was achieved in 62 (84%) of the 74 subjects and within 10 minutes in 69 (93%) of these subjects. BioFoam was well tolerated. Twelve (16%) of the 75 enrolled subjects each experienced one adverse event, and 13 serious adverse events were reported in 10 (13.3%) of the subjects. None of the adverse events was considered by the Investigators to be related to BioFoam. Blood products were administered to 14 (18.6%) of the 75 subjects, banked autologous blood was given to 5 (6.6%) subjects, and 57 (75.7%) subjects required only a cell saver. Four (5.3%) of the 75 subjects required reoperation for bleeding within 24 hours of surgery. There were no observations of bleeding in any subject at discharge and no reoperation for bleeding following discharge. The mean operation time was 218.2 (±72.2) minutes.  This study demonstrates the effectiveness of BioFoam Surgical Matrix when used as an adjunct for anastomotic hemostasis following a broad range of cardiovascular surgical procedures. The safety outcomes were within the normal limits for the types of procedures performed. ",0
6782,30769473,First Report of Impatiens necrotic spot virus Infecting Lettuce in California,"Impatiens necrotic spot virus (INSV; family Bunyaviridae, genus Tospovirus) is an important pathogen of ornamental plants in North America and Europe, particularly in the greenhouse industry (2,3). However, INSV is now emerging as a pathogen of vegetable crops. During the 2006 and 2007 growing seasons, lettuce (Lactuca sativa) in Monterey County, CA showed necrotic spotting, leaf chlorosis, and plant stunting typical of symptoms induced by Tomato spotted wilt virus (TSWV). Significant and damaging outbreaks of these disease symptoms were found in numerous romaine, greenleaf, redleaf, butterhead, and iceberg lettuce fields in Monterey and San Benito counties. Samples from symptomatic plants from 21 of 27 fields in Monterey County were negative when tested with TSWV immunostrips (Agdia, Elkhart, IN); however, tests of the TSWV-negative samples with INSV immunostrips were positive. In most fields where INSV was detected, disease development was limited to the edges of fields and disease incidence was <5%; however, some fields had incidences >50% and crop loss was experienced. The virus causing the tospovirus symptoms in the TSWV-negative lettuce was sap transmitted to Nicotiana benthamiana and lettuce, where it induced chlorosis and necrosis. Symptoms in N. benthamiana were consistent with INSV infection, and those in lettuce were similar to symptoms observed in the field. Immunostrip tests confirmed that symptomatic N. benthamiana and lettuce plants were infected with INSV. To further confirm the identity of this virus, reverse transcription (RT)-PCR analysis was conducted with an INSV primer pair that directs the amplification of a ~1.3-kb fragment from the small RNA of INSV (4). The 1.3-kb fragment was amplified from RNA from symptomatic lettuce plants that were INSV positive with immunostrips, and not from asymptomatic lettuce. A total of 38 of 54 samples showing tospovirus-like symptoms were confirmed to be infected with INSV by RT-PCR. Sequences of two representative 1.3-kb DNA fragments were 98 to 99% identical with sequences of INSV isolates from Japan, Italy, and The Netherlands (GenBank Accession Nos. AB109100, DQ425096, and X66972). Taken together with the previous identification of the INSV vector, the western flower thrips (Frankliniella occidentalis), in central California lettuce (1), these results confirm that INSV induced tospovirus symptoms in lettuce fields in Monterey County in 2007. To our knowledge, this is the first report of the occurrence of INSV infecting lettuce in California. References: (1) W. E. Chaney. Annu. Rep. California Lettuce Res. Board. 2006. (2) M. Daughtrey et al. Plant Dis. 81:1220, 1997. (3) M. D. Law and J. W. Moyer. J. Gen. Virol. 71:933, 1990. (4) R. A. Naidu et al. Online publication. doi: 10.1094/PHP-2005-0727-01-HN. Plant Health Progress, 2005. ",0
6783,30769685,Isolation and Variation in Virulence of Single-Spore Isolates of Plasmodiophora brassicae from Canada,"Clubroot of crucifers, caused by Plasmodiophora brassicae, is emerging as an important disease of canola (Brassica napus) in Alberta, Canada. Populations of the pathogen often consist of a mixture of different pathotypes. Therefore, a simple and efficient method to isolate single resting spores of P. brassicae was developed, based on serial dilution of spore suspensions. The virulence of 24 single-spore isolates, representing five populations of the pathogen from Alberta, Ontario, and British Columbia, was characterized on the differentials of Williams and Somé et al. Symptoms were rated 6 weeks after inoculation and Fisher's least significant difference (P < 0.05) was used to differentiate resistant from susceptible host reactions. The pathotype composition of P. brassicae in Canada appeared more diverse when single-spore isolates were examined rather than populations of the pathogen. In Alberta, at least three and possibly four pathotypes were identified among the 14 isolates tested, whereas a maximum of only two pathotypes had been reported previously when populations of the pathogen were examined. Pathotype 3 or P ",0
6784,30769691,Phenotypic and Genetic Analysis of Epiphytic Pseudomonas syringae Populations from Sweet Cherry in Michigan,"A severe outbreak of bacterial canker occurred on sweet cherry in Michigan in 2002. Blossom infection and subsequent canker formation was observed following a prolonged freeze event during bloom. Epiphytic blossom isolates of Pseudomonas syringae were recovered from 39 orchards from the three major cherry-growing areas (southwest [SW], west-central [WC], and northwest [NW]) of Michigan in 2003 and 2004. Average P. syringae populations over 2 years were 4.0, 5.1, and 4.8 log ",0
6785,30769762,"First Report of Rubus yellow net virus on Rubus idaeus in Alberta, Canada","In North America, Rubus yellow net virus (RYNV), a member of the genus Badnavirus, family Caulimoviridae, is vectored in a semipersistent manner by the large raspberry aphid (Amphorophora agathonica Hottes) and is responsible for producing net-like chlorosis of tissue along the leaf veins (2). Red raspberry (Rubus idaeus L.) is commonly grown in Canada and after the dry, hot summer of 2006 in southern Alberta, a group of garden raspberry plants located near Lethbridge, Alberta exhibited interveinal chlorosis resembling viral symptoms. Nonenveloped, 140 × 30 nm, bacilliform particles typical of badnaviruses were observed in infected leaves by transmission electron microscopy. The presence of RYNV was confirmed by immunocapture of virions from extracts of symptomatic leaves using Sugarcane bacilliform virus polycolonal antiserum (Agdia Incorporated, Elkhart, IN) followed by PCR amplification of a 451-bp fragment with RYNV-specific primers based on the highly conserved region of the reverse transcriptase and ribonuclease H genes (5'-ATCCTCAAAGGGTTACGTAGCTGGTT-3' and 5'-TTCAAGCCACCTTACCCTCGAAGGTTT-3'). Sequence of clones from the PCR product (GenBank Accession No. EU327346) showed 87% identity to a previously sequenced isolate of RYNV (GenBank Accession No. AF468454) (1). To our knowledge, this is the first report of RYNV in Alberta, Canada, and as an important component of raspberry veinbanding disease, it poses a new threat to the Alberta raspberry industry. References: (1) A. T. Jones et al. Ann. Appl. Biol. 141:1, 2002. (2) R. Stace-Smith. Can. J. Bot. 33:269, 1955. ",0
6786,30770283,Management of fetal tumors,"In this review article, we discuss the most common fetal tumors, their prenatal management, and outcomes. Overall, the most important outcome predictors are tumor histology, size, vascularity, and location. Very large lesions, lesions causing cardiac failure, and hydrops and lesions obstructing the fetal airway have the poorest outcome, as they may cause fetal death or complications at the time of delivery. Fetal therapy has been developed to improve outcomes for the most severe cases and can consist of transplacental therapy (sirolimus for rhabdomyomas or steroids for hemangiomas and microcystic lung lesions) or surgical intervention (shunting of cystic masses, tumor ablation, occlusion of blood flow or airway exploration, and protection). Given the rarity of fetal tumors, patients should be referred to expert centers where care can be optimized and individualized to allow the best possible outcomes. ",0
6787,30770612,Nested case-control study investigating the diagnostic role of tissue eosinophilia in adverse cutaneous drug reactions,"Although tissue eosinophilia has traditionally been considered diagnostically supportive of adverse cutaneous drug reactions (ACDRs), studies have suggested it is neither a sensitive nor a specific finding in drug eruptions (DEs). Determining whether skin tissue eosinophilia is a reliable indicator of ACDR. A nested case-control retrospective study conducted in a cohort of 170 patients at a single institution. Tissue eosinophilia (number of eosinophils per high-power field (HPF)) was investigated in skin biopsies obtained from the following groups of patients who demonstrated: (i) in vitro assay and telephone interview-validated cutaneous drug reactions (true DE); (ii) initial clinical diagnosis of ACDR but drug aetiology was excluded by in vitro assay and telephone interview (false DE); and (iii) non-drug-associated cutaneous eruptions, skin tumours and nevi, randomly selected for evaluation (control). Significantly higher number of eosinophils per HPF was observed in the false DE compared to the true DE group (P = 0.02). The false DE group demonstrated a higher number of eosinophils (P < 0.001) while the true DE group eosinophils' number was not significantly higher as compared to control (P = 0.2032). Tissue eosinophilia is not a reliable indicator of ACDRs. ",0
6788,30770675,Translocation of Zymomonas mobilis pyruvate decarboxylase to periplasmic compartment for production of acetaldehyde outside the cytosol,"Acetaldehyde, a valuable commodity chemical, is a volatile inhibitory byproduct of aerobic fermentation in Zymomonas mobilis and in several other microorganisms. Attempting to improve acetaldehyde production by minimizing its contact with the cell interior and facilitating its removal from the culture, we engineered a Z. mobilis strain with acetaldehyde synthesis reaction localized in periplasm. For that, the pyruvate decarboxylase (PDC) was transferred from the cell interior to the periplasmic compartment. This was achieved by the construction of a Z. mobilis Zm6 PDC-deficient mutant, fusion of PDC with the periplasmic signal sequence of Z. mobilis gluconolactonase, and the following expression of this fusion protein in the PDC-deficient mutant. The obtained recombinant strain PeriAc, with most of its PDC localized in periplasm, showed a twofold higher acetaldehyde yield, than the parent strain, and will be used for further improvement by directed evolution. ",0
6789,30770784,Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling,"Mesangial cell proliferation has been identified as a major factor contributing to glomerulosclerosis, which is a typical symptom of diabetic nephropathy (DN). Lysophosphatidic acid (LPA) levels are increased in the glomerulus of the kidney in diabetic mice. LPA is a critical regulator that induces mesangial cell proliferation; however, its effect and molecular mechanisms remain unknown. The proportion of α-SMA ",0
6790,30770999,H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo,"Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome. The resulting transcriptional changes recapitulate expression signatures from K27M primary DIPG tumors and are strongly enriched for genes associated with nervous system development. Integrated analysis of ChIP-seq and expression data showed that genes upregulated by the mutation are overrepresented in apparently bivalent promoters. Many of these targets are associated with more immature differentiation states. Expression profiles indicate K27M knockdown decreases proliferation and increases differentiation within lineages represented in DIPG. These data suggest that K27M-mediated loss of H3K27me3 directly regulates a subset of genes by releasing poised promoters, and contributes to tumor phenotype and growth by limiting differentiation. The delayed tumor growth associated with knockdown of H3 K27M provides evidence that this highly recurrent mutation is a relevant therapeutic target. ",0
6791,30771020,Postoperative Treatment of Oropharyngeal Cancer in the Era of Human Papillomavirus,"Despite an overall decline in the incidence of tobacco-related cancers, human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) of the oropharynx is on the rise. The prognosis of HPV-related oropharynx cancer (HPV-OPC) is generally favorable even in locoregionally advanced disease, and a variety of treatment options are available. Though the primary treatment modality of choice remains definitive radiation (RT), surgical resection followed by appropriate adjuvant therapy remains an option, especially in those patients who may not be favorable candidates for definitive radiotherapy, particularly when concurrent chemotherapy is warranted. Upfront resection may offer a chance to avoid the well-described acute toxicity and long-term morbidity associated with concurrent chemoradiotherapy (CRT) in select patients. Despite the overall favorable prognosis of HPV-OPC, indications for therapy remain unchanged from the recommendations for treatment in tobacco-related OPC and other anatomic sites of HNSCC. Ongoing studies assessing deintensification strategies in HPV-OPC are focused on maintaining high cure rates while improving treatment-related toxicities. Currently, no clear guidelines exist for the choice of primary therapy, surgical resection, or RT in patients with HPV-OPC, highlighting the need for multidisciplinary discussion and review of the individual patient before selecting the most appropriate curative modality. This review seeks to present the data for postoperative therapy in HPV-related oropharyngeal HNSCC. ",0
6792,30771153,Preliminary report of microwave ablation for the primary papillary thyroid microcarcinoma: a large-cohort of 185 patients feasibility study,"To assess the safety and efficacy of microwave ablation (MWA) for primary papillary thyroid microcarcinoma (PTMC) with a large sample of 185 patients. A total of 185 patients underwent MWA for 206 primary PTMC nodules. They received ultrasound follow-up at 1, 3, 6, and 12 months after MWA and every 6 months thereafter. Nodule volumes were calculated at each follow-up and compared with those before MWA. Additionally, the volume reduction rate (VRR) of the nodules was calculated. Patients' thyroid functions were tested before and 1 month after MWA. The mean follow-up time of the 185 patients was 20.7 ± 8.8 months (range 12-36 months). During the follow-up period, the mean volume of the 206 nodules was 100.1 ± 92.9 mm This preliminary study suggests that MWA is safe and effective in the treatment of primary PTMC and offers a new alternative for clinical treatment. ",0
6793,30771165,Assays for Neuronal Defects Caused by Early Formation of α-Synuclein Inclusions in Primary Cultured Neurons,"Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by intracellular inclusions composed mostly of α-synuclein (Baba et al., Am J Pathol 152:879-884, 1998). How inclusion formation impacts neuronal function prior to death is key to understanding disease progression and identifying therapeutic windows. In the α-synuclein fibril model, exposure of primary neurons to α-synuclein fibrils induces endogenously expressed α-synuclein to form inclusions which closely resembles pathologic mechanisms in humans with PD and DLB (Volpicelli-Daley et al., Neuron 72, 57-71, 2011). In this model, at 7 days after exposure of neurons to fibrils, when there is no neuron death, inclusions in the axon selectively impair axonal transport of endosomes carrying the TrkB receptor and LC3-positive autophagosomes (Volpicelli-Daley et al., Mol Biol Cell 25:4010-4023, 2014). In addition, the frequency and amplitude of spontaneous Ca ",0
6794,30855740,Patient Safety Outcomes under Flexible and Standard Resident Duty-Hour Rules,"BACKGROUND: Concern persists that extended shifts in medical residency programs may adversely affect patient safety. METHODS: We conducted a cluster-randomized noninferiority trial in 63 internal-medicine residency programs during the 2015-2016 academic year. Programs underwent randomization to a group with standard duty hours, as adopted by the Accreditation Council for Graduate Medical Education (ACGME) in July 2011, or to a group with more flexible duty-hour rules that did not specify limits on shift length or mandatory time off between shifts. The primary outcome for each program was the change in unadjusted 30-day mortality from the pretrial year to the trial year, as ascertained from Medicare claims. We hypothesized that the change in 30-day mortality in the flexible programs would not be worse than the change in the standard programs (difference-in-difference analysis) by more than 1 percentage point (noninferiority margin). Secondary outcomes were changes in five other patient safety measures and risk-adjusted outcomes for all measures. RESULTS: The change in 30-day mortality (primary outcome) among the patients in the flexible programs (12.5% in the trial year vs. 12.6% in the pretrial year) was noninferior to that in the standard programs (12.2% in the trial year vs. 12.7% in the pretrial year). The test for noninferiority was significant (P?=?0.03), with an estimate of the upper limit of the one-sided 95% confidence interval (0.93%) for a between-group difference in the change in mortality that was less than the prespecified noninferiority margin of 1 percentage point. Differences in changes between the flexible programs and the standard programs in the unadjusted rate of readmission at 7 days, patient safety indicators, and Medicare payments were also below 1 percentage point; the noninferiority criterion was not met for 30-day readmissions or prolonged length of hospital stay. Risk-adjusted measures generally showed similar findings. CONCLUSIONS: Allowing program directors flexibility in adjusting duty-hour schedules for trainees did not adversely affect 30-day mortality or several other measured outcomes of patient safety. (Funded by the National Heart, Lung, and Blood Institute and Accreditation Council for Graduate Medical Education; iCOMPARE ClinicalTrials.gov number, NCT02274818.).",0
6795,30855741,Sleep and Alertness in a Duty-Hour Flexibility Trial in Internal Medicine,"BACKGROUND: A purpose of duty-hour regulations is to reduce sleep deprivation in medical trainees, but their effects on sleep, sleepiness, and alertness are largely unknown. METHODS: We randomly assigned 63 internal-medicine residency programs in the United States to follow either standard 2011 duty-hour policies or flexible policies that maintained an 80-hour workweek without limits on shift length or mandatory time off between shifts. Sleep duration and morning sleepiness and alertness were compared between the two groups by means of a noninferiority design, with outcome measures including sleep duration measured with actigraphy, the Karolinska Sleepiness Scale (with scores ranging from 1 [extremely alert] to 9 [extremely sleepy, fighting sleep]), and a brief computerized Psychomotor Vigilance Test (PVT-B), with long response times (lapses) indicating reduced alertness. RESULTS: Data were obtained over a period of 14 days for 205 interns at six flexible programs and 193 interns at six standard programs. The average sleep time per 24 hours was 6.85 hours (95% confidence interval [CI], 6.61 to 7.10) among those in flexible programs and 7.03 hours (95% CI, 6.78 to 7.27) among those in standard programs. Sleep duration in flexible programs was noninferior to that in standard programs (between-group difference, -0.17 hours per 24 hours; one-sided lower limit of the 95% confidence interval, -0.45 hours; noninferiority margin, -0.5 hours; P?=?0.02 for noninferiority), as was the score on the Karolinska Sleepiness Scale (between-group difference, 0.12 points; one-sided upper limit of the 95% confidence interval, 0.31 points; noninferiority margin, 1 point; P<0.001). Noninferiority was not established for alertness according to the PVT-B (between-group difference, -0.3 lapses; one-sided upper limit of the 95% confidence interval, 1.6 lapses; noninferiority margin, 1 lapse; P?=?0.10). CONCLUSIONS: This noninferiority trial showed no more chronic sleep loss or sleepiness across trial days among interns in flexible programs than among those in standard programs. Noninferiority of the flexible group for alertness was not established. (Funded by the National Heart, Lung, and Blood Institute and American Council for Graduate Medical Education; ClinicalTrials.gov number, NCT02274818.).",0
6796,30865797,Mendelian Randomization Study of ACLY and Cardiovascular Disease,"BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P?=?4.0�10(-14)) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P?=?3.9�10(-19)) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).",0
6797,30865798,"Initial Opioid Prescriptions among U.S. Commercially Insured Patients, 2012-2017","BACKGROUND: The United States is undergoing a crippling opioid epidemic, spurred in part by overuse of prescription opioids by adults 25 to 64 years of age. Of concern are long-duration and high-dose initial prescriptions, which place the patients and their friends and relatives at heightened risk for long-term opioid use, misuse, overdose, and death. METHODS: We estimated the incidence of initial opioid prescriptions in each month between July 2012 and December 2017 using administrative-claims data from across the United States (accessed through Blue Cross-Blue Shield [BCBS] Axis); monthly incidence was estimated as the percentage of enrollees who received an initial opioid prescription among those who had not used opioids (i.e., no opioid prescription or a diagnosis of opioid use disorder in the 6 months before a given month). We then estimated the percentage of enrollees initiating opioid therapy who received a long-duration or high-dose initial opioid prescription in each month during this period. We also calculated the number of providers who initiated opioid therapy in any patient who had not used opioids in each month and examined monthly trends in the duration and dose of initial opioid prescriptions in prescriber and patient subgroups. Our study sample included 63,817,512 enrollees who had not used opioids (mean, 15,897,673 per month). RESULTS: The monthly incidence of initial opioid prescriptions among enrollees who had not used opioids declined by 54%, from 1.63% in July 2012 to 0.75% in December 2017. This decline was accompanied by a decreasing number of providers (from 114,043 in July 2012 to 80,462 in December 2017) who initiated opioid therapy in any patient who had not used opioids. Nonetheless, among the shrinking subgroup of physicians who initiated opioid therapy in such patients, high-risk prescribing (i.e., prescriptions for more than a 3-day supply or for a dose of 50 morphine milligram equivalents per day or higher) persisted at a monthly rate of 115,378 prescriptions per 15,897,673 enrollees who had not used opioids. CONCLUSIONS: As the opioid crisis progressed between July 2012 and December 2017, many providers stopped initiating opioid therapy. Although the number of initial opioid prescriptions declined, a subgroup of providers continued to write high-risk initial opioid prescriptions. (Funded by the National Institute on Aging and a gift from Owen and Linda Robinson.).",0
6798,30873635,Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S-Mediated Noncanonical Mechanism,"Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)-mediated autophagy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch-like ECH-associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62-dependent autophagy in SPD-mediated liver protection was confirmed using a carbon tetrachloride-induced liver fibrosis model in wild-type, Nrf2(-/-) , p62(-/-) and Nrf2(-/-) ;p62(-/-) mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Conclusion: Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.",0
6799,30883052,A Fully Magnetically Levitated Left Ventricular Assist Device - Final Report,"BACKGROUND: In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device. METHODS: We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years. RESULTS: This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P<0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group. CONCLUSIONS: Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).",0
6800,30893535,Vitamin D-Binding Protein Deficiency and Homozygous Deletion of the GC Gene,"A 58-year-old woman with debilitating ankylosing spondylitis who was born to consanguineous parents was found to have an apparent severe vitamin D deficiency that did not respond to supplementation. Liquid chromatography-tandem mass spectrometry showed the absence of circulating vitamin D-binding protein, and chromosomal microarray confirmed a homozygous deletion of the group-specific component (GC) gene that encodes the protein. Congenital absence of vitamin D-binding protein resulted in normocalcemia and a relatively mild disruption of bone metabolism, in this case complicated by severe autoimmune disease. (Funded by the National Institutes of Health and the University of Washington.).",0
6801,30957056,Ambulatory Clinic Exam Room Design with respect to Computing Devices: A Laboratory Simulation Study,"""Challenges persist regarding how to integrate computing effectively into the exam room, while maintaining patient-centered care. Our objective was to evaluate a new exam room design with respect to the computing layout, which included a wall-mounted monitor for ease of (re)-positioning. In a lab-based experiment, 28 providers used prototypes of the new and older """"legacy"""" outpatient exam room layouts in a within-subject comparison using simulated patient encounters. We measured efficiency, errors, workload, patient-centeredness (proportion of time the provider was focused on the patient), amount of screen sharing with the patient, workflow integration, and provider situation awareness. There were no statistically significant differences between the exam room layouts for efficiency, errors, or time spent focused on the patient. However, when using the new layout providers spent 75% more time in screen sharing activities with the patient, had 31% lower workload, and gave higher ratings for situation awareness (14%) and workflow integration (17%). Providers seemed to be unwilling to compromise their focus on the patient when the computer was in a fixed position in the corner of the room and, as a result, experienced greater workload, lower situation awareness, and poorer workflow integration when using the old """"legacy"""" layout. A thoughtful design of the exam room with respect to the computing may positively impact providers' workload, situation awareness, time spent in screen sharing activities, and workflow integration. """,0
6802,30957068,Effects of anastomotic technique on early postoperative outcome in open right-sided hemicolectomy,"Despite recent improvements in colonic cancer surgery, the rate of anastomotic leakage after right hemicolectomy is still around 6-7 per cent. This study examined whether anastomotic technique (handsewn or stapled) after open right hemicolectomy for right-sided colonic cancer influences postoperative complications. Patient data from the German Society for General and Visceral Surgery (StuDoQ) registry from 2010 to 2017 were analysed. Univariable and multivariable analyses were performed. The primary endpoint was anastomotic leakage; secondary endpoints were postoperative ileus, complications and length of postoperative hospital stay (LOS). A total of 4062 patients who had undergone open right hemicolectomy for colonic cancer were analysed. All patients had an ileocolic anastomosis, 2742 handsewn and 1320 stapled. Baseline characteristics were similar. No significant differences were identified in anastomotic leakage, postoperative ileus, reoperation rate, surgical-site infection, LOS or death. The stapled group had a significantly shorter duration of surgery and fewer Clavien-Dindo grade I-II complications. In multivariable logistic regression analysis, ASA grade and BMI were found to be significantly associated with postoperative complications such as anastomotic leakage, postoperative ileus and reoperation rate. Handsewn and stapled ileocolic anastomoses for open right-sided colonic cancer resections are equally safe. Stapler use was associated with reduced duration of surgery and significantly fewer minor complications. ",0
6803,30957221,"Bushmeat trade consequences predict higher anxiety, restraint, and dominance in chimpanzees","More data are needed for a better understanding of the long-term influence of wider and combined stressful events in chimpanzee personality development. We evaluated the effects of bushmeat trade outcomes on the personality development in 84 African sanctuary chimpanzees. The chimpanzees presented different backgrounds regarding maternal care, social exposure, and abuse. We evaluated personality traits in chimpanzees using the Cattell 16PF personality questionnaire, the first application of this questionnaire in this species. We found that chimpanzees were rated as higher in anxiety after long social deprivation during infancy and juvenility, and if high human exposure was experienced. Mother-reared chimpanzees were rated as lower in restraint than hand-reared chimpanzees. Finally, mother-reared chimpanzees were rated as less dominant than hand-reared chimpanzees and rated higher when they had experienced severe mistreatment. Results suggest a wide range of possible stressful events could be potentially shaping rescued chimpanzees' personality and demonstrating the detrimental outcomes and consequences of the bushmeat and pet trade. ",0
6804,30969506,Tau Positron-Emission Tomography in Former National Football League Players,"BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied. METHODS: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group. RESULTS: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P?=?0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease. CONCLUSIONS: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).",0
6805,30970186,Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease,"BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ?-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (A?). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P?=?0.67 for the comparison between the 12-mg group and the placebo group and P?=?0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).",0
6806,31004519,p300 Acetyltransferase Is a Cytoplasm-to-Nucleus Shuttle for SMAD2/3 and TAZ Nuclear Transport in Transforming Growth Factor ?-Stimulated Hepatic Stellate Cells,"Nuclear translocation of mothers against decapentaplegic homolog 2/3 (SMAD2/3), core transcription factors of transforming growth factor ? (TGF-?) signaling, is critical for hepatic stellate cell (HSC) differentiation into metastasis-promoting myofibroblasts. SMAD2/3 have multiple coactivators, including WW domain-containing transcription regulator protein 1 (WWTR1 or TAZ) and p300 acetyltransferase. In the nucleus, TAZ binds to SMAD2/3 to prevent SMAD2/3 nuclear export. However, how TAZ and SMAD2/3 enter the nucleus remains poorly understood because neither contains a nuclear localization signal (NLS), an�amino acid�sequence tagging proteins for�nuclear transport. p300 is an NLS-containing large scaffold protein, so we hypothesized that SMAD2/3 and TAZ may undergo nuclear import through complexing with p300. Coimmunoprecipitation, immunofluorescence, and nuclear fractionation assays revealed that TGF-?1 promoted binding of SMAD2/3 and TAZ to p300 and that p300 inactivation disrupted TGF-?1-mediated SMAD2/3 and TAZ nuclear accumulation. Deleting the p300 NLS blocked TGF-?1-induced SMAD2/3 and TAZ nuclear transport. Consistently, p300 inactivation suppressed TGF-?1-mediated HSC activation and transcription of genes encoding tumor-promoting factors, such as connective tissue growth factor, Tenascin C, Periostin, platelet-derived growth factor C, and fibroblast growth factor 2, as revealed by microarray analysis. Chromatin immunoprecipitation-real-time quantitative PCR showed that canonical p300-mediated acetylation of histones also facilitated transcription in response to TGF-?1 stimulation. Interestingly, although both TGF-?1-mediated and stiffness-mediated HSC activation require p300, comparison of gene expression data sets revealed that transcriptional targets of TGF-?1 were distinct from those of stiffness-p300 mechanosignaling. Lastly, in tumor/HSC coinjection and intrasplenic tumor injection models, targeting p300 of activated-HSC/myofibroblasts by C646, short hairpin RNA, or cre-mediated gene disruption reduced tumor and liver metastatic growth in mice. Conclusion: p300 facilitates TGF-?1-stimulated HSC activation by both noncanonical (cytoplasm-to-nucleus shuttle for SMAD2/3 and TAZ) and canonical (histone acetylation) mechanisms. p300 is an attractive target for inhibiting HSC activation and the prometastatic liver microenvironment.",0
6807,31077406,CD8(+) T Cells Promote Maturation of Liver-Resident NK Cells Through the CD70-CD27 axis,"Liver-resident natural killer (LrNK) cells are a unique subset of NK cells that are distinct from conventional NK cells. However, little is known about the mechanisms by which LrNK cells mature. In this study, we discovered that LrNK cells exhibit a relatively immature phenotype and impaired cytotoxic capacity in the absence of CD8(+) T cells. The provision of CD8(+) T cells to Cd8(-/-) or Rag1(-/-) mice led to the restoration of LrNK cell maturation. Furthermore, co-culture with CD8(+) T cells induced immature CD27(+) LrNK cells to convert into mature CD27(-) LrNK cells, whereas blocking the interaction of CD70 and CD27 abrogated the ability of CD8(+) T cells to promote the maturation of LrNK cells. Conclusion: Our findings indicate that CD8(+) T cells promote the maturation of LrNK cells through the CD70-CD27 axis, and therefore highlight a previously unknown mechanism responsible for the mediation of LrNK cell maturation.",0
6808,31091367,The Hospital Readmissions Reduction Program - Time for a Reboot,"The Hospital Readmissions Reduction Program (HRRP) was established by the Centers for Medicare and Medicaid Services (CMS) in 2010 with a goal of reducing preventable hospitalizations by imposing financial penalties on hospitals with higher-than-expected 30-day readmission rates. After the program was created, readmission rates appeared to decrease nationwide for patients hospitalized with heart failure, acute myocardial infarction, and pneumonia, the three conditions it originally targeted.",0
6809,31102415,Rat Organic Anion Transport Protein 1A1 Interacts Directly With Organic Anion Transport Protein 1A4 Facilitating Its Maturation and Trafficking to the Hepatocyte Plasma Membrane,"Organic anion transport proteins (OATPs) on the basolateral surface of hepatocytes mediate uptake of a number of drugs and endogenous compounds. Previous studies showed that rat OATP1A1 (rOATP1A1) has a postsynaptic density protein, drosophila disc large tumor suppressor, zonula occludens-1 protein (PDZ) consensus binding motif at its C-terminus and binds to PDZ domain containing 1 (PDZK1), which is required for its cell-surface localization. PDZK1 associates with rOATP1A1-containing endocytic vesicles within cells, mediating recruitment of motor proteins required for microtubule-based trafficking to the plasma membrane. rOATP1A4 also traffics to the plasma membrane, although it lacks a PDZ binding consensus sequence. The current study was designed to test the hypothesis that trafficking of rOATP1A4 to the plasma membrane requires its direct interaction with rOATP1A1 resulting in a complex that traffics through the cell in common subcellular vesicles in which the cytosolic tail of rOATP1A1 is bound to PDZK1. We found that 74% of rOATP1A4-containing rat liver endocytic vesicles (n�=�12,044) also contained rOATP1A1. Studies in transfected HEK293 cells showed surface localization of rOATP1A1 only when coexpressed with PDZK1 whereas rOATP1A4 required coexpression with rOATP1A1 and PDZK1. Studies in stably transfected HeLa cells that constitutively expressed PDZK1 showed that coexpression of rOATP1A4 with rOATP1A1 resulted in more rapid appearance of rOATP1A4 on the plasma membrane and faster maturation to its fully glycosylated form. Similar results were observed on immunofluorescence analysis of single cells. Immunoprecipitation of rat liver or transfected HeLa cell lysates with rOATP1A1 antibody specifically co-immunoprecipitated rOATP1A4 as determined by western blotting. Conclusion: These studies indicate that optimal rOATP1A4 trafficking to the cell surface is dependent upon coexpression and interaction with rOATP1A1. As rOATP1A1 binds to the chaperone protein, PDZK1, rOATP1A4 functionally hitchhikes through the cell with this complex.",0
6810,31136002,Blocking Sodium-Taurocholate Cotransporting Polypeptide Stimulates Biliary Cholesterol and Phospholipid Secretion in Mice,"Active secretion of bile salts into the canalicular lumen drives bile formation and promotes biliary cholesterol and phospholipid output. Disrupting hepatic bile salt uptake, by inhibition of sodium-taurocholate cotransporting polypetide (NTCP; Slc10a1) with Myrcludex B, is expected to limit bile salt flux through the liver and thereby to decrease biliary lipid excretion. Here, we show that Myrcludex B-mediated NTCP inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid secretion. Induction of cholesterol secretion was not a consequence of increased ATP-binding cassette subfamily G member 5/8 activity given that NTCP inhibition still promoted cholesterol excretion in Abcg8(-/-) mice. Stimulatory effects of NTCP inhibition were maintained in Sr-b1(-/-) mice, eliminating the possibility that the increase in biliary lipids was derived from enhanced uptake of high-density lipoprotein-derived lipids. NTCP inhibition shifts bile salt uptake, which is generally more periportally restricted, toward pericentral hepatocytes, as was visualized using a fluorescently labeled conjugated bile salt. As a consequence, exposure of the canalicular membrane to bile salts was increased, allowing for more cholesterol and phospholipid molecules to be excreted per bile salt. Conclusion: NTCP inhibition increases biliary lipid secretion, which is independent of alterations in bile salt output, biliary bile salt hydrophobicity, or increased activity of dedicated cholesterol and phospholipid transporters. Instead, NTCP inhibition shifts hepatic bile salt uptake from mainly periportal hepatocytes toward pericentral hepatocytes, thereby increasing exposure of the canalicular membrane to bile salts linking to increased biliary cholesterol secretion. This process provides an additional level of control to biliary cholesterol and phospholipid secretion.",0
6811,31157962,Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer,"BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (�SE) rate of distant recurrence at 9 years was less than 5% (?1.8�0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7�1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3�2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2�3.3%). CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).",0
6812,31167051,Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up,"BACKGROUND: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up. METHODS: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome. RESULTS: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P?=?0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75). CONCLUSIONS: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).",0
6813,31216398,Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease,"BACKGROUND: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established. METHODS: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points. RESULTS: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P?=?0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P?=?0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P?=?0.21). CONCLUSIONS: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.).",0
6814,31237366,An Aging Population of Chronic Hepatitis B With Increasing Comorbidities: A Territory-Wide Study From 2000 to 2017,"Patients with chronic hepatitis B (CHB) are aging because of improved survival under better health care. This has an important implication on the choice of antiviral treatment (AVT), given that long-term safety would be a concern in the presence of multiple comorbidities. We aimed to determine the prevalence of key comorbidities and concomitant medications in a territory-wide CHB cohort in Hong Kong in 2000-2017. CHB patients who have been under the care at primary, secondary, and tertiary medical centers in the public sector were identified through the Clinical Data Analysis and Reporting System of the Hospital Authority, Hong Kong. The demographics and prevalence of key comorbidities, including diabetes mellitus, hypertension, chronic kidney disease, osteopenia/osteoporosis based on diagnosis codes, relevant medications, and/or laboratory parameters, were determined according to CHB patients' first appearance in four time periods: 2000-2004, 2005-2009, 2010-2013, and 2014-2017. In the final analysis, 135,395 CHB patients were included; the mean age increased with time: 41���15 years in 2000-2004; 46���17 years in 2005-2009; 51���16 years in 2010-2013; and 55���15 years in 2014-2017. There was a trend of increasing prevalence of several common comorbidities over the four periods: hypertension 25.5%, 23.8%, 27.2%, and 28.6%; diabetes mellitus 10.6%, 12.5%, 16.1%, and 20.1%; cardiovascular disease 12.5%, 16.9%, 20.9%, and 22.2%; and malignancy 7.0%, 13.2%, 17.3%, and 23.6%, respectively (all P�<�0.001). Conclusion: CHB patients are getting older with increasing prevalence of common comorbidities. These comorbidities should be taken into account when choosing AVT.",0
6815,31278760,Hepatitis B Virus Virions Produced Under Nucleos(t)ide Analogue Treatment Are Mainly Not Infectious Because of Irreversible DNA Chain Termination,"Nucleos(t)ide analogues (NAs) have been widely used for the treatment of chronic hepatitis B (CHB). Because viral DNA polymerase lacks proofreading function (3' exonuclease activity), theoretically, the incorporated NAs would irreversibly terminate viral DNA synthesis. This study explored the natures of nascent hepatitis B virus (HBV) DNA and infectivity of progeny virions produced under NA treatment. HBV infectivity was determined by infection of HepG2-NTCP cells and primary human hepatocytes (PHHs). Biochemical properties of HBV DNA in the progeny virions were investigated by qPCR, northern blotting, or Southern blotting hybridization, sucrose gradient centrifugation, and in vitro endogenous DNA polymerase assay. Progeny HBV virions produced under NA treatment were mainly not infectious to HepG2-NTCP cells or PHHs. Biochemical analysis revealed that under NA treatment, HBV DNA in nucleaocapsids or virions were predominantly short minus-strand DNA with irreversible termination. This finding was supported by the observation of first disappearance of relaxed circular DNA and then the proportional decline of HBV-DNA levels corresponding to the regions of PreC/C, S, and X genes in serial sera of patients receiving NA treatment. Conclusion: HBV virions produced under NA treatment are predominantly replication deficient because the viral genomes are truncated and elongation of DNA chains is irreversibly terminated. Clinically, our results suggest that the viral loads of CHB patients under NA therapy vary with the different regions of genome being detected by qPCR assays. Our findings also imply that NA prevention of perinatal and sexual HBV transmission as well as infection of transplanted livers works not only by reducing viral loads, but also by producing noninfectious virions.",0
6816,31291834,Simvastatin-induced erythromelalgia: less is more,"We describe a case of a woman with uncomplicated Type 2 diabetes mellitus, presenting with severe burning pains and intense redness of the legs, for which only cooling could provide relief. Although the description was classic of erythromelalgia, the lack of familiarity of the disorder caused considerable doctor's delay as well as the erroneous advice to start pain killers and amitriptyline. However, empirical discontinuation of simvastatin made all symptoms disappear. Erthyromelalgia is a rare but debilitating disease which is diagnosed by exclusion only. It usually occurs as a secondary feature to (hematologic) malignant disorders, autoimmune diseases or, infections or, most notoriously, to pharmacological agents. One of the latter might be simvastatin, and possibly all HMG CoA Reductase inhibitors. ",0
6817,31291967,"Combined supplementation of Lactobacillus fermentum and Pediococcus acidilactici promoted growth performance, alleviated inflammation, and modulated intestinal microbiota in weaned pigs","Probiotics are important for pigs to enhance health and intestinal development, which are potential alternative to antibiotics. Many studies have reported the functions of single bacterial strain as probiotic on the animals. In this study, we evaluated effects of combined probiotics on growth performance, inflammation and intestinal microbiota in weaned pigs. One hundred and eight pigs, weaned at 28 day old (7.12 ± 0.08 kg), were randomly divided into the 3 dietary treatments with 6 pens and 6 pigs per pen (half male and half female). The experimental period lasted for 28 days and treatments were as follows: i. basal diet; ii. Antibiotic: the basal diet plus 75 mg· kg Supplementation probiotics improved average daily gain over the entire 28 days (P < 0.01) and feed efficiency in the last 14 days (P < 0.05) compared with the other two groups. Both probiotics and antibiotic supplementation decreased concentrations of serum pro-inflammatory cytokines interleukin-6 (P < 0.05) and interferon-γ (P < 0.01). Probiotics group had greater abundance of Lactobacillus in the caecal digesta and Firmicutes in the colonic digesta, while both probiotics and antibiotic supplementation inhibited Treponema_2 and Anaerovibrio in the caecal digesta. Caecal acetic and propionic acid (P < 0.05) of probiotics group were higher than the other two groups, whereas concentrations of colonic lactic acid and propionic acid (P < 0.05) of antibiotic group were lower than control and probiotics groups. These findings suggest that combined supplementation of Lactobacillus fermentum and Pediococcus acidilactici regulate the gut health and improve the host ADG and F/G by decreasing serum pro-inflammatory factors (IL-6, IFN-γ), promoting beneficial bacteria (Lactobacillus in the caecal digesta and Firmicutes in the colonic digesta), enhancing production of short chain fatty acids, and inhibiting pathogens (Treponema_2, Anaerovibrio in the caecal digesta). ",0
6818,31291989,The effect of visual support strategies on the quality of life of children with cerebral palsy and cerebral visual impairment/perceptual visual dysfunction in Nigeria: study protocol for a randomized controlled trial,"Cerebral visual impairment (CVI), including perceptual visual dysfunction (PVD), is common in children with cerebral palsy (CP). Inventories of questions relating to practical aspects of visual perception in everyday life, in particular the closed-ended Insight Questions Inventory (IQI), can be used to assess CVI/PVD. Studies linking responses to the inventory with specific visual support strategies, aimed at modifying the child's environment and/or behaviour to minimize the impact of the CVI/PVD, have been piloted. The IQI and tailored strategies have not been used in an African population, nor have they been tested in a controlled trial. This trial will compare the effectiveness of the IQI and linked visual support strategies versus general supportive treatments on the quality of life of children with CVI/PVD and CP through a randomized controlled trial. This is a prospective, double-blind, parallel-arm, randomized controlled trial. The primary outcome is change in quality of life scores between the two arms of the trial at 6 weeks, assessed using the Paediatric Quality of Life Inventory (PedsQL) generic 4.0 and CP 3.0 module. All children will undergo baseline assessment including the Open Questions Inventory, IQI, PedsQL 3.0, PedsQL 4.0 generic, and the Strengths and Difficulties Questionnaire (SDQ). Eligible children with CP aged 4 years to < 16 years will be stratified and blocked by the age groups 4-9 and 10 to < 16 years and by Gross Motor Function Classification System (GMFCS) levels 1-3 and 4-5. Families in the intervention arm will receive tailored insight visual support strategies and telephone calls during the 6-week trial period. The control arm will receive standard treatment and the intervention after the 6-week trial period. Follow-up interviews will be performed in both arms at 6 weeks with a repeat administration of the PedsQL CP 4.0 and 3.0, the IQI and the SDQ. Secondary outcomes include a change in functional vision. This randomized controlled trial will provide evidence of the effectiveness of this intervention for children with CP in a resource-poor setting. Pan African Clinical Trials Registration, PACTR201612001886396 . Registered on 3 December 2016. ",0
6819,31292048,No one ever asked us. Young people's evaluation of their residential child care facilities in three different programs,"Residential child care is a very complex measure and has been the subject of heated debate in many countries. However, there is a paucity of studies that examine quality assessments of these services, much less that have asked the children and young people receiving those services about their own evaluations. This study interviewed 209 young people between 11 and 20 years of age, in 21 residential facilities, about their degree of satisfaction with the care they receive. These residential facilities are differentiated into three types of programs that will be compared: preparation for adult life (PAL), therapeutic care for behavioral problems (TRC) and general programs for children and young people without any specific profile (GRC). The instrument used is an interview that includes both quantitative and qualitative assessments. The results show a trend toward positive average scores on practically all aspects, highlighting the support from as well as the connection they feel with the educators who care for them. On the other hand, young people in TRC displayed lower scores on almost all aspects evaluated while those in PAL were the most positive. The main implications for the practice will be discussed from these youths&rsquo; perspective. ",0
6820,31292088,Prevalence of Incidentally Identified Thoracic Aortic Dilations: Insights for Screening Criteria,"Systematic screening for ascending thoracic aortic aneurysms and dilations does not exist currently with unknown prevalence and diagnostic yields. We evaluated the prevalence of ascending thoracic aortic dilation. Computed tomography scans including the chest in adult patients carried out during 2016 were reviewed at our institution. Aortic dilation was defined as the ascending thoracic aorta diameter ≥ 4.0 cm, with sensitivity analyses using height-indexed values and thresholds of 3.5, 4.25, and 4.5 cm. The prevalence of aortic dilation was evaluated by age and sex. Potential diagnostic yield along the continuum of age threshold was calculated by sex. Of the 5662 scans from unique patients, the prevalence of aortic dilation was 2.1% overall, 3.2% for males and 0.9% for females. Patients with aneurysms were significantly older (70.2 ± 9.9 vs 58.3 ± 16.4 years, P < 0.001) and more likely to be male (81.0% vs 54.2%, P < 0.001). The highest diagnostic yield of aneurysm ≥ 4.5 cm in females occurred at the age threshold of ≥ 73 years, with the yield of 0.5%. The highest diagnostic yield of aneurysm ≥ 4.5 cm in males occurred at age ≥ 84 years, with the yield of 5.7%. In males, the diagnostic yields at age thresholds of ≥ 50, ≥ 60, and ≥ 70 years were 1.3%, 1.6%, and 2.2%, respectively. Aortic dilation was identified in 2.8% of individuals with age ≥ 50 years. In females, aneurysm was uncommon. In males, there was an incremental increase in the diagnostic yield with age. Male patients with age ≥ 50 years may be the demographic group with a high prevalence of dilation. ",0
6821,31292269,Fracture Risk in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study,"Aromatase inhibitors (AIs) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk. Using a population-based BMD registry, we identified women aged at least 40 years initiating AIs for breast cancer with at least 12 months of AI exposure ( At baseline, AI users had higher body mass index (BMI), higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women from the general population or women with breast cancer without AI use (all  Higher baseline BMI, BMD, and lower prevalence of prior fracture at baseline may offset the adverse effects of AI exposure. Although confirmatory data from large cohort studies are required, our findings challenge the view that all women with breast cancer initiating AI therapy should be considered at high risk for fractures. In a population-based observational registry that included 1,775 patients initiating long-term aromatase inhibitor therapy, risk for major osteoporotic fracture, hip fracture, or any fracture was similar to the general population. Higher baseline body mass index, bone mineral density, and lower prevalence of prior fracture at baseline may offset the adverse effects of aromatase inhibitor exposure. ",0
6822,31292517,Adjuvant chemotherapy in rectal cancer patients who achieved a pathological complete response after preoperative chemoradiotherapy: a systematic review and meta-analysis,"This study evaluated the prognostic impact of ACT in patients who achieved a pathological complete response (pCR). Articles published from January 1990 to September 2018 were searched in EMBASE, PubMed, Ovid, Web of Science, and Cochrane Library. Hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS) were extracted. Thirteen observational studies were included. There were four National Cancer Database studies with overlapping study periods, thus individual pooled analyses of four different datasets were conducted (n = 3,182, 3,330, 3,575, and 4,739 for pooled analysis sets including Dossa et al., Polanco et al., Xu et al., and Shahab et al., respectively). Although a trend toward improved OS with ACT was observed, statistical significance was not proven (P = 0.09, P = 0.03, P = 0.12, and P = 0.10, respectively). When we performed a stratified analysis comparing the results from single institution and multicenter studies, there was no significant prognostic benefit of ACT. Publication bias was not observed. Routine use of ACT in patients with a pCR could not be warranted from the present meta-analysis. Further study of individual patient data from randomized trials is needed to clarify the role of ACT. ",0
6823,31292734,High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer's disease,"Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer's disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [ ",0
6824,31292738,Radiofrequency Ablation for Management of Shoulder Pain,"The treatment options for the management of shoulder pain are broad but evolving process. Modalities for controlling shoulder pain have commonly focused on pharmacotherapy, physical therapy, rehabilitation, and invasive procedures (surgical procedures, surgical, intra-articular steroid injections, many times, being sub-optimal). The use of radiofrequency ablation (RFA) for managing shoulder pain is on the rise. Our review investigated the evidence for the use of RFA in the management of shoulder pain. In our investigation, a review of the literature was conducted using Medline, PubMed, and Cochrane Database of Systematic Reviews from 1966 to 2018. Our study included RCTs, open non-randomized control studies, prospective studies, retrospective studies, case series, and case reports. We limited our search to patients with chronic shoulder pathologies. Our initial search identified 96 articles for initial review. This was narrowed down to 31 articles, which met our inclusion criteria, with only 18 articles remaining after our exclusion criteria was applied. This systematic review suggests that shoulder RFA may provide a safe and significant benefit in the management of chronic shoulder pain. There were a few high-quality RCTs included in our study, which supports the findings of several case reports and case series. ",0
6825,31292793,"The transcript expression levels of HNRNPM, HNRNPA0 and AKAP17A splicing factors may be predictively associated with ageing phenotypes in human peripheral blood","Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population. ",0
6826,31293170,Health-Related Quality of Life Among Vietnamese Breast Cancer Women,"The aim of the study was to investigate health-related quality of life among Vietnamese breast cancer women who were treated at National Cancer Hospital, Hanoi, Vietnam, in 2018. Information about physical functioning, Role Physical, Bodily Pain, General Health, vitality, Social Functioning, Role Emotional, and Mental Health of 200 patients with breast cancer was collected through face-to-face interview, using short form-36 questionnaire. We found that the older patients (older than 50 years) had higher score of Mental Health than patients at age 50 and lower ( ",0
6827,31293267,The postoperatıve effects of use of trimetazidine before the coronary artery bypass graft surgery,"In this study, postoperative cardiac functions were observed in patients undergoing coronary artery bypass grafting (CABG) surgery following preoperative administration of the anti-ischemic drug trimetazidine. The study included a total of 50 CABG patients; 25 were administered with trimetazidine preoperatively and 25 did not receive trimetazidine. A retrospective evaluation was made of the parameters of age, gender, preoperative echocardiography (ECHO) results, cross-clamping durations, postoperative inotropic requirements, and postoperative 4 There was no statistically significant difference determined between the 2 groups in respect of the data of age, gender, comorbidity, preoperative ECHO signs [(ejection fraction (EF), left ventricle end systolic diameter (lvsd), left ventricle end diastolic diameter (lvdd), left atrium diameter (LA), and intraventricular septum thickness (IVS)], inotropic requirements, and postoperative troponin-I levels. In the control group, a positive correlation was determined between postoperative troponin-I levels and DM (r: 0.597, p: 0.002). There was no correlation determined in the trimetazidine group (r:-0.042, p: 0.844). The results of this study demonstrated a positive correlation between postoperative troponin-I levels and DM in the group not administered with trimetazidine. There was no such correlation determined in the group administered with trimetazidine. This result may suggest that DM may increase troponin-I levels in the absence of trimetazidine, and therefore that the drug may be cardioprotective in such cases. Further studies on more extensive patient populations are required to confirm these results. ",0
6828,31293276,A retrospective case series of 12 patients with chronic reactive arthritis with emphasis on treatment outcome with biologics,"Patients with reactive arthritis frequently present to dermatologists. However, there is paucity of information regarding its clinical aspects and management in dermatological literature. To review the clinical features and management of patients with chronic reactive arthritis admitted to the dermatology department of a teaching hospital. This was a retrospective analysis of patients with reactive arthritis admitted to the Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India from January 2016 to February 2018. There were 12 males (disease duration 9-180 months). Biologics were used in 9 (75%) patients on 16 different occasions, the most frequent being infliximab (n = 10 times), followed by adalimumab (n = 3), etanercept, secukinumab and itolizumab (n = 1 each), in combination with other systemic agents. Response rate with treatment regimens including biologics (69% responders, 31% partial responders) was statistically significantly better than those without biologics (27% responders, 46% partial responders, 27% nonresponders; P = 0.036), using a composite measure assessing improvement in skin and joint symptoms. Biologics were discontinued on 50% of the occasions, after a median of 3.5 months (range 1.5-7.5 months) because of satisfactory response (n = 4), therapeutic fatigue (n = 3) or adverse event (n = 1). After biologic discontinuation, the response was sustained for a median of 5 months (range 3-6 months) before disease exacerbation. The number of treatment switches increased with the follow-up duration (median three switches per patient, range 1-8). The median follow-up duration was 10.5 months (range 4-76 months). Biologics produce rapid improvement in skin and joint symptoms in chronic reactive arthritis, but the response is not long-lasting. Patients with chronic reactive arthritis have a waxing and waning course despite regular treatment. The limitations are retrospective design, small sample size and lack of a validated outcome measure. ",0
6829,31293714,Physical energies to the rescue of damaged tissues,"Rhythmic oscillatory patterns sustain cellular dynamics, driving the concerted action of regulatory molecules, microtubules, and molecular motors. We describe cellular microtubules as oscillators capable of synchronization and swarming, generating mechanical and electric patterns that impact biomolecular recognition. We consider the biological relevance of seeing the inside of cells populated by a network of molecules that behave as bioelectronic circuits and chromophores. We discuss the novel perspectives disclosed by mechanobiology, bioelectromagnetism, and photobiomodulation, both in term of fundamental basic science and in light of the biomedical implication of using physical energies to govern (stem) cell fate. We focus on the feasibility of exploiting atomic force microscopy and hyperspectral imaging to detect signatures of nanomotions and electromagnetic radiation (light), respectively, generated by the stem cells across the specification of their multilineage repertoire. The chance is reported of using these signatures and the diffusive features of physical waves to direct specifically the differentiation program of stem cells  ",0
6830,31293735,"Renewing accessible heptazine chemistry: 2,5,8-tris(3,5-diethyl-pyrazolyl)-heptazine, a new highly soluble heptazine derivative with exchangeable groups, and examples of newly derived heptazines and their physical chemistry","We have prepared 2,5,8-tris(3,5-diethyl-pyrazolyl)-heptazine, the first highly soluble heptazine derivative possessing easily exchangeable leaving groups. We present its original synthesis employing mechanochemistry, along with a few examples of its versatile reactivity. It is, in particular, demonstrated that the pyrazolyl leaving groups can be replaced by several secondary or primary amino substituents or by three aryl- or benzyl-thiol substituents. In addition to being a synthetic platform, 2,5,8-tris(3,5-diethyl-pyrazolyl)-heptazine is fluorescent and electroactive, and its attractive properties, as well as those of the derived heptazines, are briefly presented. ",0
6831,31293885,Mitogen-Activated Protein Kinase Pathway: A Critical Regulator in Tumor-associated Macrophage Polarization,"The notion that inflammation is a critical component of cancer has been researched extensively. Tumor-associated macrophages (TAMs) are among the inflammatory cells that greatly influence cancer. In the tumor microenvironment (TME), macrophages can either stimulate or inhibit tumorigenesis. TAMs that stimulate tumor cell proliferation (M2-phenotype) enrich the TME with growth factors and immunosuppressive molecules, whereas tumor inhibitory TAMs (M1-phenotype) initiate the immune response to dampen tumor progression. Shifting between phenotypes is controlled by several components of the TME. Targeting macrophages, specifically inhibiting M2 TAMs, has been introduced successfully in cancer immunotherapy. However, signaling mechanisms underlining TAM polarization are largely unknown. This review analyzed studies of the role of mitogen-activated protein kinase (MAPK) as a determinant of macrophage polarization. It is proposed that activation of MAPK, particularly extracellular signal-regulated kinase 1/2 and p38, might favor the differentiation into M2 TAMs. Thus, pharmacological modification of MAPK pathways will potentially offer exciting new targets in cancer immunotherapy. ",0
6832,31294131,"Genomic analysis of Korean patients with advanced prostate cancer by use of a comprehensive next-generation sequencing panel and low-coverage, whole-genome sequencing","To analyze the characteristics of somatic mutations and copy number alterations (CNAs) in Korean patients with advanced prostate cancer (PCa) by use of the Oncomine Comprehensive Panel (ThermoFisher Scientific) and low-coverage, whole-genome sequencing (LC-WGS). We retrospectively analyzed PCa tissues obtained from 14 patients with advanced PCa (metastatic tumor, 12 [85.7%]; nonmetastatic castration-resistant PCa, 1 [7.1%]; pT3b, 1 [7.1%]) from 2009 to 2017. The Oncomine Comprehensive Panel included a total of 143 genes. Moreover, LC-WGS was performed to detect CNAs of the entire genome. Two plasma samples matched with tumor tissues were analyzed using LC-WGS to compare the chromosomal aberration patterns between circulating tumor DNA and tumor tissue. Genetic alterations were most frequently observed in the androgen receptor ( Our data showed that the characteristics of mutations and CNAs in Korean patients with advanced PCa were similar to those observed in previous studies. ",0
6833,31294387,The Impact of Inflammatory Bowel Disease in Canada 2018: Extra-intestinal Diseases in IBD,"The burden of extra-intestinal disease is high in patients with IBD, some of whom respond to or are prevented by treating the bowel inflammation, whereas others require specific treatment because they are independent of the underlying bowel inflammation. Among the most common extra-intestinal manifestations are other chronic immune-mediated diseases such as erythema nodosum, ankylosing spondylitis and primary sclerosing cholangitis. Patients with IBD are at higher risk of complications in other organ systems such as osteoporosis, venous thromboembolism and cardiovascular disease. In addition, patients with IBD have a higher risk of cancer, including colon cancer. Mental health comorbidity is important and common in IBD though not always recognized and managed. Consequently, patients and care providers need to be vigilant in the surveillance of extra-intestinal manifestations and complications of IBD. The burden of extra-intestinal disease is high in patients with IBD.Immune-mediated inflammatory diseases (IMIDs) commonly coexist with patients with IBD and the activity of IMIDs can be either dependent or independent of bowel inflammation.Patients with IBD can be diagnosed with coexisting diseases that affect every organ, including bones, blood, heart, liver, and others.Patients with IBD are at increased risk of cancer, including colon cancer, caused by their bowel inflammation, cholangiocarcinoma due to primary sclerosing cholangitis, and rarely lymphoma related to immunosuppressive medications.The best way to prevent or reduce the burden of many of the extra-intestinal disease is to treat the inflammation of IBD, however some extra-intestinal inflammatory diseases run courses that are independent of the intestinal disease activity. Patients with IBD are often burdened with extra-intestinal manifestations, some of which respond to or are prevented by treating the bowel inflammation whereas others require specific treatment because they are independent of the underlying bowel inflammation.Other immune-mediated inflammatory diseases (IMIDs) can coexist with IBD.Some IMIDs run an independent course from the bowel inflammation of IBD, such as ankylosing spondylitis, iritis, and primary sclerosing cholangitis.Immune-mediated inflammatory diseases that often have courses that match the bowel inflammation of IBD include erythema nodosum and peripheral arthritis.Immune-mediated inflammatory diseases such as multiple sclerosis and psoriasis have been associated with IBD. However, these conditions may also emerge as complications of therapy for IBD.Patients with IBD are at risk for venous thromboembolic disease, which occurs at a rate of one per 200 person-years.Venous thromboembolic disease can be reduced by treating patients admitted to hospital with an IBD diagnosis with venous thromboembolism prophylaxis.Arterial vascular disease is also increased in IBD patients, including both coronary artery disease and cerebrovascular disease.Osteoporosis is more prevalent in IBD patients and translates to a 40% increased risk of fracture. While corticosteroids increase the risk of osteoporosis, patients with IBD can also develop metabolic bone disease independent of corticosteroid use.Persons with IBD are more likely to be infected with  Patients with IBD are often burdened with extra-intestinal disease. Future research should determine the collective frequency and added costs of living with extra-intestinal disease.Immune-mediated inflammatory diseases are commonly codiagnosed with IBD. Future research should focus on the pathogenesis connecting coexisting IMIDs with IBD.Care pathways that support the investigation and mitigation of extra-intestinal disease are needed. For example, when and how ambulatory patients with IBD should receive prophylaxis against venous thromboembolic disease is unknown.With an aging IBD population, the burden of extra-intestinal disease should be studied in the context of comorbidities of advancing age.Increasing mental health screening and access to mental health care should be a goal of IBD management. ",0
6834,31294446,Osteosarcoma cell-derived exosomes affect tumor microenvironment by specific packaging of microRNAs,"Bone microenvironment provides growth and survival signals essential for osteosarcoma (OS) initiation and progression. OS cells regulate communications inside tumor microenvironment through different ways and, among all, tumor-derived exosomes support cancer progression and metastasis. To define the contribution of OS-derived exosomes inside the microenvironment, we investigated the effects induced in bone remodelling mechanism and tumor angiogenesis. We demonstrated that exosomes promoted osteoclasts differentiation and bone resorption activity. Furthermore, exosomes potentiated tube formation of endothelial cells and increased angiogenic markers expression. We therefore investigated the miRNA cargo from exosomes and their parental cells by performing small RNA sequencing through NGS Illumina platform. Hierarchical clustering highlighted a unique molecular profile of exosomal miRNA; bioinformatic analysis by DIANA-mirPath revealed that miRNAs identified take part in various biological processes and carcinogenesis. Among these miRNAs, some were already known for their involvement in the tumor microenvironment establishment, as miR-148a and miR-21-5p. Enforced expression of miR-148a and miR-21-5p in Raw264.7 and Huvec cells recapitulated the effects induced by exosomes. Overall, our study highlighted the importance of OS exosomes in tumor microenvironment, also by a specific packaging of miRNAs. ",0
6835,31318976,A Metallomic Approach to Assess Associations of Serum Metal Levels With Gallstones and Gallbladder Cancer,"BACKGROUND AND AIMS: Exposure to metals may promote the risk for cancers. We evaluated the associations of a broad spectrum of metals with gallbladder cancer (GBC) and gallstones. APPROACH AND RESULTS: A total of 259 patients with GBC, 701 patients with gallstones, and 851 population-based controls were enrolled in Shanghai, China. A metallome panel was used to simultaneously detect 18 metals in serum through inductively coupled plasma-mass spectrometry. Logistic regression models were used to estimate crude or adjusted odds ratios (OR(adj) ) with 95% confidence intervals (CIs) for the association between metal levels and gallbladder disease. Among the 18 metals tested, 12 were significantly associated with GBC and six with gallstones (P(corrected) �<�0.002). Boron, lithium, molybdenum, and arsenic levels were associated with GBC compared to gallstones as well as with gallstones compared to population-based controls. Elevated levels of cadmium, chromium, copper, molybdenum, and vanadium were positively associated with GBC versus gallstones; and the OR(adj) for the highest tertile (T3) compared to the lowest tertile (T1) ranged from 1.80 to 7.28, with evidence of dose-response trends (P�<�0.05). Arsenic, boron, iron, lithium, magnesium, selenium, and sulfur were inversely associated with GBC, with the T3 versus T1 OR(adj) ranging from 0.20 to 0.69. Arsenic, boron, calcium, lithium, molybdenum, and phosphorus were negatively associated with gallstones, with the T3 versus T1 OR(adj) ranging from 0.50 to 0.75 (P�<�0.05). CONCLUSIONS: Metals were associated with both GBC and gallstones, providing cross-sectional evidence of association across the natural history of disease. Longitudinal studies are needed to evaluate the temporality of metal exposure and gallbladder diseases and to investigate the mechanisms of disease pathogenesis.",0
6836,31381163,Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice,"BACKGROUND AND AIMS: Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation, and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response. APPROACH AND RESULTS: Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including interleukin (IL)-1?, IL-6, and tumor necrosis factor ?. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages by protecting against ER stress and promoting anti-inflammatory polarization. Co-culture with VDR-activated bone marrow-derived macrophages suppresses UPR target genes in primary hepatocytes treated with ER stress inducers. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice. CONCLUSIONS: VDR signaling in macrophages regulates a shift between proinflammatory and anti-inflammatory activation during ER stress-induced inflammation to promote hepatic ER stress resolution.",0
6837,31383558,Pulmonary versus aortic pressure behavior of a bovine pericardial valve,"The Carpentier Edwards Perimount Magna Ease aortic valvular prosthesis (Edwards Lifesciences, Irvine, Calif) has been among the most frequently and successfully used tissue prosthetic cardiac valves. Furthermore, this prosthesis has been used off-label in the pulmonary position. Until now, there has been a paucity of data regarding the functioning of tissue prosthetic valves under pulmonary conditions. Using a pulse duplicator, hydrodynamic characteristics of a 21-mm and 25-mm Magna Ease valve were evaluated. Among parameters evaluated were leakage orifice area, closing time (ie, time required to close), and leakage duration. This procedure was performed under different pulmonic pressure conditions (15/5 mm Hg, 28/11 mm Hg, 73/32 mm Hg) and normal aortic pressure (120/80 mm Hg) as a reference. Moving images were obtained using a Phantom MIRO M320S high-speed camera (Vision Research Inc, Wayne, NJ) at 600 frames per second and used to analyze valve area in closed position. Under normal pulmonic conditions (28/11 mm Hg) the leakage orifice area was 0.020 ± 0.012 mm Under normal pulmonary pressure conditions, the hydrodynamic characteristics of Magna Ease valves are significantly different compared with aortic conditions. Further research is needed to determine whether these results are associated with prosthetic valve failure. ",0
6838,31383564,Long term effect of spa therapy combined with patient education program on subjects with overweight and obesity - A controlled study,"The aim of this single center prospective controlled study in volunteers with obesity and overweight was to evaluate the effect of a patient therapeutic education program (PTE group) combined with spa therapy on weight, physical activity, eating habits and quality of life versus spa therapy alone (control group). The main endpoint was weight change at 5 months after the end of the program. The PTE group of 151 subjects with obesity or overweight followed a 3-week program combining patient education with spa therapy and 189 attended a course of spa therapy alone. At 5 months significant loss was observed in the PTE group compared to controls (-2.69kg vs -1.24kg, p=0.008), a relative weight loss of -2.8% vs -1.3%. At 11 months after spa therapy, only the PTE group maintained a weight loss in addition to the weight loss obtained during spa therapy. The control group returned to the weight they had at the end of spa therapy. In both groups, a significant increase in physical activity was observed at 5 (p<0.001) and 11 months (p<0.001) with a significant better improvement in the PTE group. In addition, while in both groups some quality of life parameters and dietary choices were improved, the improvement (more fruit, vegetables, fish and water) was significantly higher in the PTE group, at both 5 and 11 months after spa therapy. In conclusion, while spa therapy alone initiated positive changes in weight loss, physical activity and some quality of life parameters, the PTE program enhanced this effect. ",0
6839,31383601,Holistic approach of the care of the infant with hypoxic-ischaemic encephalopathy in Spain],"There is not much information about the care of infants with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) in Spain. This includes whether protocols are routinely used, the type of neuro-monitoring performed, and how information on the neurological prognosis is presented to families. The answers to these would allow to detect and implement areas of improvement. A cross-sectional analysis was performed on the responses to structured questionnaires sent to all the Spanish neonatal units that were performing TH in June 2015. Questions were divided into 5sections: 1) the availability of protocols and technological resources, 2) the use of neuro-monitoring tools, 3) the knowledge and training of the professionals; 4) the prognostic information given to the parents; and 5) the discharge report and the follow-up plan. Most centres (95%) use servo controlled whole-body cooling methods and have specific management protocols. Sedation is used in 70% of centres, and in 68% of them the onset of enteral feeding is delayed until the end of the cooling period. Amplitude-integrated electroencephalography monitoring is used in more than 80% of the centres, although only in 50% are nurses able to interpret it. Cerebral oxygen saturation is not often monitored (16%). As regards diagnostic-prognostic studies, neuroimaging is universal, but brain damage biomarkers are hardly used (29%). Prognostic information is offered within the first 72 posnatal hours in 21% of the centres, and is given without the presence of the nurse in 70% of the centres. Follow-up is performed by a neuro-paediatrician (84%), with an uneven duration between centres. The care of infants with HIE treated with TH in Spain is generally adequate, although there are areas for improvement in neuromonitoring, sedation, prognostic information, teamwork, and duration of follow-up. ",0
6840,31383749,Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells,"A group of cytoprotective genes is regulated by heterodimers composed of the cap'n'collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay system will be a powerful tool to specifically examine the function of other CNC-sMaf heterodimers. ",0
6841,31383837,Specific Biomarkers of Prostate Cancer-Associated Ischemic Stroke: A Case-Control Study,"<strong>BACKGROUND</strong> Ischemic stroke in cancer patients is associated with poor prognosis. However, the specific biomarkers of cancer-associated ischemic stroke (CaIS) have not been well defined. <strong>MATERIAL AND METHODS</strong> A retrospective study was conducted on PCaIS patients. Clinical data and laboratory and imaging findings were collected. Multivariable logistic regression analysis was used to analyze the independent risk factors for PCaIS. A multiple model combining the independent risk factors of PCaIS was developed using the receiver operating characteristic (ROC) and area under the ROC curve (AUC). <strong>RESULTS</strong> A total of 83 PCaIS patients and 83 prostate cancer (PCa) patients were included. PCaIS patients had higher levels of D-dimer, neutrophil-to-lymphocyte ratio (NLR), and total prostate-specific antigen (T-PSA). In the multivariate analysis, D-dimer [OR=1.001, 95% CI: 1.00,1.00, <i>P</i>=0.002], NLR [OR=1.12, 95% CI: 1.04,1.22, <i>P</i>=0.005], and T-PSA [OR=6.275, 95% CI: 2.57,15.31, <i>P</i><0.001] were independent risk factors of PCaIS. Additionally, the AUC of the multiple model of PCaIS was 0.815 (95% CI, 0.750-0.869), with sensitivity of 81.71% and specificity of 70.21%. <strong>CONCLUSIONS</strong> Elevated levels of D-dimer and T-PSA and increased NLR are independent risk factors of PCaIS. The multiple model of PCaIS can be a specific biomarker and is a reliable predictor of development of PCaIS. ",0
6842,31384428,An unusual presentation of acute cholecystitis: gallbladder volvulus,"Gallbladder volvulus is a rare condition with similar presentation to acute cholecystitis. It is caused by the gallbladder twisting upon its mesentery leading to potential ischemia and biliary obstruction. A 77-year-old female presented with symptoms of right upper quadrant pain and nausea. She was found to have an elevated leukocytosis and a palpable right upper quadrant abdominal mass on exam. Imaging revealed a severely distended gallbladder with pericholecystic fluid and wall thickening without gallstones. Intraoperatively, an extremely distended, ischemic gallbladder was noted to have twisted upon its mesentery. The structures were able to be identified and the gallbladder was able to be safely removed with a laparoscopic approach despite its large size. Gallbladder volvulus is important to consider in the differential of acute cholecystitis because delay in intervention could lead to gallbladder necrosis and possible perforation, increasing the patient's morbidity and mortality. ",0
6843,31384458,Dedifferentiated liposarcoma of the thyroid gland: A case report,"Liposarcoma is one of the most common soft tissue tumors that affect adults. Liposarcoma is typically identified in the retroperitoneum, trunk and extremities as a slow-growing mass, yet is rare in the thyroid gland. Herein, we report a case of dedifferentiated liposarcoma that developed in the thyroid gland, and performed a literature review. A 66-year-old male with a history of well-differentiated liposarcoma in the thymus presented with a rapidly enlarging mass in the thyroid gland. Malignancy was suspected due to the local extension of the tumor, and complete resection of the tumor was achieved. Tissue diagnosis from the tumor following surgery revealed that dedifferentiated liposarcoma, and tumor progression was difficult to control with adjuvant radiation and chemotherapy. This is, to the best of our knowledge, the first case to report dedifferentiated liposarcoma in the thyroid gland, and the difficulty in initial diagnosis as well as the aggressive features of dedifferentiated liposarcoma are highlighted. ",0
6844,31384580,Cross-reactivity of pink peppercorn in cashew and pistachio allergic individuals,"The Pink peppercorn belongs to the same Anacardiaceae family as cashew and pistachio. However, the cross-reactivity of pink peppercorn with cashew and pistachio has yet to be studied. To date, there has been a single case report of anaphylaxis to pink peppercorn in a cashew and pistachio allergic individual. We aim to demonstrate cross-sensitization to pink peppercorn in cashew and/or pistachio allergic children. A small descriptive cohort study looking at cross-sensitization of pink peppercorn in cashew and/or pistachio allergic children was conducted. Children with a history of reaction to pistachio and/or cashew nut underwent skin prick tests to the pink peppercorn species  Out of the 21 cashew and/or pistachio allergic subjects, 16 (76.2%) demonstrated cross-sensitization to pink peppercorn. None of the subjects had any knowledge of previous exposure or allergic reactions to pink peppercorn. This study demonstrates potential cross-reactivity between pink peppercorn and cashew and pistachio. While an oral food challenge to pink peppercorn would have been important in demonstrating clinical cross-reactivity, this was not performed due to ethical constraints. We hope to increase the awareness of pink peppercorn as a potential and hidden source of allergen and encourage further studies to demonstrate the clinical cross-reactivity and to better delineate the major allergen involved. ",0
6845,31384599,The Effect of Arginine Intake on Colorectal Cancer: a Systematic Review of Literatures,"Colorectal cancer (CRC) is one of the major reasons of mortality in the worldwide. There is clear evidence that some amino acids such as arginine can improve CRC and its complications. Hence, in this systematic review we evaluated the association between arginine intake and CRC improvement. We searched the PubMed, Scopus, ISI Web of Science, Cochrane library, and Google Scholar databases by using proper keywords to find the relevant literatures, published to March 2019. Nine human studies of 523 screened articles were included in present systematic review. The majority of studies have found a positive association between consumption of arginine and CRC improvement. Increased inducible nitric oxide (NO) synthase expression and subsequently increasing the NO concentration in the tumor and/or serum, after arginine intake may be responsible for these protective effects. Also, arginine consumption may reduce cell proliferation in CRC and it can enhance immune function after remove the tumor. Although the benefits of arginine consumption in CRC patients were reported in previous trials, the finding need replication in well-designed studies before final conclusion. ",0
6846,31384748,Shaping markets to benefit global health - A 15-year history and lessons learned from the pentavalent vaccine market,"Market shaping for health products used in lower-income countries strives to benefit public health. As a funder of vaccines, Gavi, The Vaccine Alliance (Gavi) has goals for its market shaping efforts, achieved through a strategy developed and implemented by the Gavi Secretariat, UNICEF, the World Health Organization (WHO) and the Bill & Melinda Gates Foundation (BMGF). A case-study of Gavi's fifteen-year engagement with a vaccine against diphtheria, tetanus, pertussis, hepatitis B and  ",0
6847,31384822,Multiple analytical methods for determination of formoterol and glycopyrronium simultaneously in their novel combined metered dose inhaler,"One of the major causes of mortality all over the world is chronic obstructive pulmonary disease (COPD). Recently approved combined inhaler of formoterol fumarate (FF) and glycopyrronium bromide (GLY) has been used in very low concentrations (µg level/actuation) doses in COPD patients. The first spectrophotometric and advanced highly sensitive liquid chromatography has been achieved successfully throughout this study, permitting validated analysis of dual combined inhaler in raw material as well as pharmaceutical inhaled dosage form. Three sensitive analytical methods were carried out for the simultaneous assay of FF and GLY in their novel combined Metered dose inhaler (MDI). The first method depends on measuring the first derivative amplitudes at 208.27 nm for FF and at 213.27 nm and 239.86 nm for GLY, respectively. The second method depends on measurement of the first derivative of the ratio spectra at 214 or 229 nm for FF and 240 or 259 nm for GLY, respectively. For the spectrophotometric methods, the linearity ranges were 0.48-9.6 µg/mL for FF and 0.9-18 µg/mL for GLY. For the third method, valid ion-pairing chromatographic method was carried out applying C ",0
6848,31385896,Should I Plan to Open? Predicting the Need For Open Reduction in the Treatment of Developmental Dysplasia of the Hip,"Closed reduction is generally attempted on children under 18 months of age who present as older infants or who fail nonoperative management for developmental dysplasia of the hip (DDH). However, many of these patients will not achieve concentric reduction by closed means and will ultimately require open reduction (OR). Limited evidence exists to predict which patients can be adequately closed reduced versus those who will need open treatment. Prospectively collected data from 4 select centers of an international multicenter study group sharing a common treatment approach were reviewed for all DDH infants under 18 months old that required operative management. Patients were categorized into 2 groups: those whose hips were successfully closed reduced or those who ultimately required OR. Factors were compared between the closed reduction and OR groups for 2 separate cohorts-those presenting early in life with ultrasound (US) data, and those presenting later with radiographic data. A total of 154 patients (166 hips) were included in the analysis. Overall, 87.3% were female. In the early-presenting cohort, purposeful entry multivariate regression revealed that patients with Graf IV hips on US had 3.8 times higher odds of requiring an OR. For the later cohort, hips that were clinically irreducible (ie, negative Ortolani sign) had 3.3 times higher odds of requiring OR. Patients with International Hip Dysplasia Institute (IHDI) grade IV hips had 2.5 times higher odds of needing an OR versus those with grade III hips and 15.4 times higher odds than those with grade II hips. Children with an IHDI grade IV hip and a negative Ortolani sign had 4.4 times higher odds of needing OR. Children younger than 18 months with dislocated hips who require OR are more likely to have a high-grade radiographic dislocation (IHDI grade IV), negative preoperative Ortolani sign, and a Graf IV classification on initial US. This information may help surgeons budget the use of operating room time and better counsel parents about intraoperative expectations. Level III-Prognostic. ",0
6849,31386108,Complete Sequence of Succinamopine Ti-Plasmid pTiEU6 Reveals Its Evolutionary Relatedness with Nopaline-Type Ti-Plasmids,"Agrobacterium tumefaciens is the etiological agent of plant crown gall disease, which is induced by the delivery of a set of oncogenic genes into plant cells from its tumor-inducing (Ti) plasmid. Here we present the first complete sequence of a succinamopine-type Ti-plasmid. Plasmid pTiEU6 is comprised of 176,375 bp with an overall GC content of 56.1% and 195 putative protein-coding sequences could be identified. This Ti-plasmid is most closely related to nopaline-type Ti-plasmids. It contains a single T-region which is somewhat smaller than that of the nopaline-type Ti-plasmids and in which the gene for nopaline synthesis is replaced by a gene (sus) for succinamopine synthesis. Also in pTiEU6 the nopaline catabolic genes are replaced by genes for succinamopine catabolism. In order to trace the evolutionary origin of pTiEU6, we sequenced six nopaline Ti-plasmids to enlarge the scope for comparison to this class of plasmids. Average nucleotide identity analysis revealed that pTiEU6 was most closely related to nopaline Ti-plasmids pTiT37 and pTiSAKURA. In line with this traces of several transposable elements were present in all the nopaline Ti plasmids and in pTiEU6, but one specific transposable element insertion, that of a copy of IS1182, was present at the same site only in pTiEU6, pTiT37, and pTiSAKURA, but not in the other Ti plasmids. This suggests that pTiEU6 evolved after diversification of nopaline Ti-plasmids by DNA recombination between a pTiT37-like nopaline Ti-plasmid and another plasmid, thus introducing amongst others new catabolic genes matching a new opine synthase gene for succinamopine synthesis. ",0
6850,31386217,Early pubertal maturation and risk of childhood asthma: A mendelian randomization and longitudinal study,"Studies on early puberty and incident asthma have reported inconsistent results and are mainly performed in females. In this longitudinal study, we investigated the causal relationship between pubertal maturation and asthma through Mendelian randomization (MR) and explored the joint effect of overweightness and early pubertal maturation on asthma. We used data from the Taiwan Children Health Study with longitudinal follow-ups of 2991 children aged 11-17 years. Six puberty-related single-nucleotide polymorphisms (combined into a weighted allelic score) were used to yield genetic instrumental variables for early puberty. Early pubertal maturation was defined as reaching a certain pubertal stage earlier than the median age for that stage. Incident asthma cases were calculated by excluding children with a history of asthma prior to that age. The results of MR analysis revealed that early pubertal maturation was associated with active asthma (OR = 1.18; 95% CI: 1.08-1.28); this effect was significant in male children. Early pubertal maturation significantly increased the risk of incident asthma outcomes at 12 and 17 years of age in both sexes (hazard ratio = 2.15; 95% CI: 1.21-3.84). Taking non-overweight and non-early puberty children as the reference group, we observed a synergistic effect of overweightness and early pubertal maturation on asthma risk (OR = 1.08; 95% CI: 1.04-1.11) in children of both sexes. Early screening and intervention for obesity are recommended to prevent future early pubertal onset and asthma occurrence. ",0
6851,31386306,Improving the Rate of Translation of Tissue Engineering Products,"Over 100 000 research articles and 9000 patents have been published on tissue engineering (TE) in the past 20 years. Yet, very few TE products have made their way to the market during the same period. Experts have proposed a variety of strategies to address the lack of translation of TE products. However, since these proposals are guided by qualitative insights, they are limited in scope and impact. Machine learning is utilized in the current study to analyze the entire body of patents that have been published over the past twenty years and understand patenting trends, topics, areas of application, and exemplifications. This analysis yields surprising and little-known insights about the differences in research priorities and perceptions of innovativeness of tissue engineers in academia and industry, as well as aids to chart true advances in the field during the past twenty years. It is hoped that this analysis and subsequent proposal to improve translational rates of TE products will spur much needed dialogue about this important pursuit. ",0
6852,31387368,First Clinical Application of Polyurethane Meniscal Scaffolds with Mesenchymal Stem Cells and Assessment of Cartilage Quality with T2 Mapping at 12 Months,"Complex meniscal lesions often require meniscectomy with favorable results in the short term but a high risk of early osteoarthritis subsequently. Partial meniscectomy treated with meniscal substitutes may delay articular cartilage degeneration. To evaluate the status of articular cartilage by T2 mapping after meniscal substitution with polyurethane scaffolds enriched with mesenchymal stem cells (MSC) and comparison with acellular scaffolds at 12 months. Seventeen patients (18-50 years) with past meniscectomies were enrolled in 2 groups: (1) acellular polyurethane scaffold (APS) or (2) polyurethane scaffold enriched with MSC (MPS). Patients in the MPS group received filgrastim to stimulate MSC production, and CD90+ cells were obtained and cultured in the polyurethane scaffold. The scaffolds were implanted arthroscopically into partial meniscus defects. Concomitant injuries (articular cartilage lesions or cartilage lesions) were treated during the same procedure. Changes in the quality of articular cartilage were evaluated with T2 mapping in femur and tibia at 12 months. In tibial T2 mapping, values for the MPS group increased slightly at 9 months but returned to initial values at 12 months ( Meniscal substitution with polyurethane scaffold maintains normal T2 mapping values in adjacent cartilage at 12 months. The addition of MSC did not show any advantage in the protection of articular cartilage over acellular scaffolds ( ",0
6853,31387383,The American Academy of Pediatrics hypertension guidelines identify obese youth at high cardiovascular risk among individuals non-hypertensive by the European Society of Hypertension guidelines,"Two different systems for the screening and diagnosis of hypertension (HTN) in children currently coexist, namely, the guidelines of the 2017 American Academy of Pediatrics (AAP) and the 2016 European Society for Hypertension (ESH). The two systems differ in the lowered cut-offs proposed by the AAP versus ESH. We evaluated whether the reclassification of hypertension by the AAP guidelines in young people who were defined non-hypertensive by the ESH criteria would classify differently overweight/obese youth in relation to their cardiovascular risk profile. A sample of 2929 overweight/obese young people (6-16 years) defined non-hypertensive by ESH (ESH Using the AAP criteria, 327/2929 (11%) young people were categorized as hypertensive (ESH The reclassification of hypertension by the AAP guidelines in young people overweight/obese defined non-hypertensive by the ESH criteria identified a significant number of individuals with high blood pressure and abnormal cardiovascular risk. Our data support the need of a revision of the ESH criteria. ",0
6854,31387576,Oncologic outcome of marginal mandibulectomy in squamous cell carcinoma of the lower gingiva,"There is a large amount of controversy about the best management of the mandible in oral squamous cell carcinoma (SCC), mainly owing to the inability to acquire accurate bone invasion status. Therefore, our goal was to analyse the oncologic safety in patients undergoing marginal mandibulectomy (MM) for cT1-2 N0 SCC of the lower gingiva. Patients undergoing MM for untreated cT1-2 N0 SCC of the lower gingiva were retrospectively enrolled. The main endpoints of interest were locoregional control (LRC) and disease-specific survival (DSS). A total of 142 patients were included in the analysis, and a pathologic positive node was noted in 27 patients. Cortical invasion was reported in 23 patients, and medullary invasion was reported in 9 patients. The 5-year LRC and DSS rates were 85 and 88%, respectively. Patients with bone invasion had a significantly higher risk for recurrence than patients without bone invasion. However, the DSS was similar in patients with versus without bone invasion. Patients with a high neutrophil lymphocyte ratio had a higher risk for worse prognosis. The oncologic outcome in patients undergoing MM for cT1-2 N0 SCC of the lower gingiva was favourable; bone invasion was not uncommon, but it significantly decreased the prognosis in patients undergoing MM. ",0
6855,31387603,"Long-chain vitamin K2 production in Lactococcus lactis is influenced by temperature, carbon source, aeration and mode of energy metabolism","Vitamin K2 (menaquinone, MK-n) is a lipid-soluble vitamin that functions as a carboxylase co-factor for maturation of proteins involved in many vital physiological processes in humans. Notably, long-chain vitamin K2 is produced by bacteria, including some species and strains belonging to the group of lactic acid bacteria (LAB) that play important roles in food fermentation processes. This study was performed to gain insights into the natural long-chain vitamin K2 production capacity of LAB and the factors influencing vitamin K2 production during cultivation, providing a basis for biotechnological production of vitamin K2 and in situ fortification of this vitamin in food products. We observed that six selected Lactococcus lactis strains produced MK-5 to MK-10, with MK-8 and MK-9 as the major MK variant. Significant diversities between strains were observed in terms of specific concentrations and titres of vitamin K2. L. lactis ssp. cremoris MG1363 was selected for more detailed studies of the impact of selected carbon sources tested under different growth conditions [i.e. static fermentation (oxygen absent, heme absent); aerobic fermentation (oxygen present, heme absent) and aerobic respiration (oxygen present, heme present)] on vitamin K2 production in M17 media. Aerobic fermentation with fructose as a carbon source resulted in the highest specific concentration of vitamin K2: 3.7-fold increase compared to static fermentation with glucose, whereas aerobic respiration with trehalose resulted in the highest titre: 5.2-fold increase compared to static fermentation with glucose. When the same strain was applied to quark fermentation, we consistently observed that altered carbon source (fructose) and aerobic cultivation of the pre-culture resulted in efficient vitamin K2 fortification in the quark product. With this study we demonstrate that certain LAB strains can be employed for efficient production of long-chain vitamin K2. Strain selection and optimisation of growth conditions offer a viable strategy towards natural vitamin K2 enrichment of fermented foods, and to improved biotechnological vitamin K2 production processes. ",0
6856,31387766,A randomized controlled trial of public messaging to promote safe firearm storage among U.S. military veterans,"""The objectives of this study were to determine whether short-term exposure to firearm safety messaging significantly improved (1) firearm storage practices, and (2) attitudes of safe firearm storage behaviors among U.S. veterans, a group at elevated risk for firearm suicide. A three-arm, parallel-group RCT was conducted online in the U.S. nationwide from December 2015 to January 2016. A national random sample of U.S. veterans (N = 358) was recruited from the GfK KnowledgePanel, a probability-based internet panel representative of U.S. adults. All study activities were administered online over a three-week study period. Participants were randomized and exposed three times (once per week) to either (a) firearm safety message only (n = 115); (b) firearm safety and mental health promotion messages (n = 133); or (c) active control group exposed to mental health promotion message only (n = 110). Each message was less than two minutes long. Assessments were completed at baseline (pre-randomization) and at end-of-trial. Changes in awareness of risk for injuries, attitudes/beliefs related to safe storage practices, behavioral intentions, and storage practices were measured using self-reported surveys. Linear mixed effect models with weighted generalized estimating equations were used to test for exposure effects. Analyses were conducted February 2018. Analyses restricted to those with baseline firearm access (n = 195) identified no significant changes for intentions or safe storage practices across exposure groups. At baseline, participants' attitudes and beliefs were generally supportive of safe firearm storage. The Firearm Safety message yielded small increases in agreement with the concept that secure storage is """"important during emotional or stressful times"""" (0.36; 95% CI = 0.08, 0.64). Other significant changes in awareness and beliefs were found, but across all study conditions. Results reinforce the critical need for considerable research and testing prior to the widespread implementation of public messages to increase the likelihood for desired exposure effects. """,0
6857,31388404,Deficiency or activation of peroxisome proliferator-activated receptor α reduces the tissue concentrations of endogenously synthesized docosahexaenoic acid in C57BL/6J mice,"Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the  The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among PPARα homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate (PPARα agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA. PPARα ablation reduced the hepatic  LCPUFA enzyme expression was altered by PPARα. Either PPARα deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance. ",0
6858,31388772,Exercise in Pregnant Women with Diabetes,"Diabetes affects an increasing number of pregnancies. Regular exercise is recommended for pregnant women without diabetes, but whether exercise during pregnancy also benefits women with gestational diabetes (GDM) or preexisting (type 1 or type 2) diabetes or if these women have any specific risks is unclear. Recent evidence suggests that low- to moderate-intensity exercise improves blood glucose and may delay insulin initiation for women with GDM. Exercise is also safe, with no reports of increased maternal or neonatal complications. Few studies evaluated exercise as adjunct therapy for pregnant women with preexisting diabetes, precluding a thorough assessment in this population. Low- to moderate-intensity exercise during pregnancy safely improves glycemic control among women with GDM. More studies are needed to evaluate the impact of exercise in pregnant women with preexisting diabetes. Whether a specific type, volume, or timing of activity is most effective is not known. ",0
6859,31388849,Repetitive Head Impact Exposure in College Football Following an NCAA Rule Change to Eliminate Two-A-Day Preseason Practices: A Study from the NCAA-DoD CARE Consortium,"Repetitive head impact exposure sustained by athletes of contact sports has been hypothesized to be a mechanism for concussion and a possible explanation for the high degree of variability in sport-related concussion biomechanics. In an attempt to limit repetitive head impact exposure during the football preseason, the NCAA eliminated two-a-day practices in 2017, while maintaining the total number of team practice sessions. The objective of this study was to quantify head impact exposure during the preseason and regular season in Division I college football athletes to determine whether the 2017 NCAA ruling decreased head impact exposure. 342 unique athletes from five NCAA Division I Football Bowl Subdivision (FBS) programs were consented and enrolled. Head impacts were recorded using the Head Impact Telemetry (HIT) System during the entire fall preseasons and regular seasons in 2016 and 2017. Despite the elimination of two-a-day practices, the number of preseason contact days increased in 2017, with an increase in average hourly impact exposure (i.e., contact intensity), resulting in a significant increase in total head impact burden (+ 26%) for the 2017 preseason. This finding would indicate that the 2017 NCAA ruling was not effective at reducing the head impact burden during the football preseason. Additionally, athletes sustained a significantly higher number of recorded head impacts per week (+ 40%) during the preseason than the regular season, implicating the preseason as a time of elevated repetitive head impact burden. With increased recognition of a possible association between repetitive head impact exposure and concussion, increased preseason exposure may predispose certain athletes to a higher risk of concussion during the preseason and regular season. Accordingly, efforts at reducing concussion incidence in contact sports should include a reduction in overall head impact exposure. ",0
6860,31388883,Safety and Feasibility of Robotic Reduced-Port Distal Pancreatectomy: a Multicenter Experience of a Novel Technique,"A reduced-port approach including single-site surgery has been used for distal pancreatectomy. However, triangulation is difficult in reduced-port laparoscopic distal pancreatectomy, and instrument crowding, and collision may occur, so this approach has not been widely used. Recently, an innovative technique for distal pancreatectomy using a robotic single-site surgical system was introduced. Herein, we evaluate the safety and feasibility of this technique. Twenty-seven patients with a pancreatic tail mass underwent robotic single-site plus one-port distal pancreatectomy at six centers. We collected clinicopathologic data and evaluated the short-term perioperative outcomes of robotic single-site plus one-port distal pancreatectomy. We evaluated 26 patients who underwent robotic single-site plus one-port distal pancreatectomy excluding one patient who needed more ports because of fatty abdomen. The mean age and body mass index were 47.3 years (range 21-74) and 22.6 kg/m Robotic single-site plus one-port distal pancreatectomy is safe and feasible in terms of short-term outcomes. This technique could be performed in select cases to expand the surgical boundaries of the robotic single-site platform. Further studies are needed with more cases to investigate long-term outcomes. ",0
6861,31388915,Comparative Effectiveness of Combining MTX with Biologic Drug Therapy Versus Either MTX or Biologics Alone for Early Rheumatoid Arthritis in Adults: a Systematic Review and Network Meta-analysis,"Comparative effectiveness of early rheumatoid arthritis (RA) treatments remains uncertain. Compare benefits and harms of biologic drug therapies for adults with early RA within 1 year of diagnosis. English language articles from the 2012 review to October 2017 identified through MEDLINE, Cochrane Library and International Pharmaceutical Abstracts, gray literature, expert recommendations, reference lists of published literature, and supplemental evidence data requests. Two persons independently selected studies based on predefined inclusion criteria. One reviewer extracted data; a second reviewer checked accuracy. Two independent reviewers assigned risk of bias ratings. We identified 22 eligible studies with 9934 participants. Combination therapy with tumor necrosis factor (TNF) or non-TNF biologics plus methotrexate (MTX) improved disease control, remission, and functional capacity compared with monotherapy of either MTX or a biologic. Network meta-analyses found higher ACR50 response (50% improvement) for combination therapy of biologic plus MTX than for MTX monotherapy (relative risk range 1.20 [95% confidence interval (CI), 1.04 to 1.38] to 1.57 [95% CI, 1.30 to 1.88]). No significant differences emerged between treatment discontinuation rates because of adverse events or serious adverse events. Subgroup data (disease activity, prior therapy, demographics, serious conditions) were limited. Trials enrolled almost exclusively selected populations with high disease activity. Network meta-analyses were derived from indirect comparisons relative to MTX due to the dearth of head-to-head studies comparing interventions. No eligible data on biosimilars were found. Qualitative and network meta-analyses suggest that the combination of MTX with TNF or non-TNF biologics reduces disease activity and improves remission when compared with MTX monotherapy. Overall adverse event and discontinuation rates were similar between treatment groups. PROSPERO (available at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017079260 ). ",0
6862,31389272,Is vitamin-D supplementation not useful in patients at risk of fractures and falls?,"To evaluate numerous publications that question the bone and extraosseous benefits of vitamin D diet supplementation based on results, which often transcend to public opinion, but are not well interpreted. This may have negative consequences on compliance of patients under vitamin D supplementation. Critical appraisal of several articles on vitamin D supplementation and its relationship with fractures, falls, cardiovascular diseases, and cancer incidence. Such publications have certain limitations (i.e. patients excluded because of a diagnosis of osteoporosis, or at a higher risk for fractures and falls, or because they have a vitamin D deficiency, etc.), and conclusions and/or subsequent recommendations should be approached with caution. Our research shows that patients with osteoporosis, vitamin D deficiency, and at high risk of fractures and falls should not discontinue vitamin D supplementation (often associated with calcium). It is becoming increasingly evident that patients with hypovitaminosis D are those that gain a maximal benefit from vitamin D supplementation. ",0
6863,31389606,LncRNA CADM1-AS1 serves as a new prognostic biomarker for gastric cancer,"To investigate the expression of the long non-coding RNA CADM1-AS1 (lncRNA CADM1-AS1) in gastric cancer and its clinical significance. The real time fluorescence quantitative polymerase chain reaction (qRT-PCR) was performed to detect the expression difference of lncRNA CADM1-AS1 between gastric cancer and its adjacent normal tissues. Then, the correlation between the expression of CADM1-AS1 in gastric cancer and the clinicopathological characteristics was analyzed by the Chi-square test. Moreover, the potential of lncRNA CADM1-AS1 in predicting the prognosis of patients with GC after the operation was assessed by the Log-rank test and the Cox's proportional hazards regression model. The expression of lncRNA CADM1-AS1 was significantly decreased in tumor tissues. According to the mean expression of lncRNA CADM1-AS1, the patients were divided into a high expression group and a low expression group, and the expression of lncRNA CADM1-AS1 in gastric cancer was significantly correlated with tumor differentiation, N stage, M stage, and TNM stage. Moreover, the gastric cancer patients with higher expression of lncRNA CADM1-AS1 had a statistically better overall survival (OS) time and progression-free survival (PFS) time. In univariate analyses and multivariate analyses, the expression of lncRNA CADM1-AS1 was an independent prognosis index of patients with gastric cancer. LncRNA CADM1-AS1 might be a new prognostic biomarker for gastric cancer. ",0
6864,31389960,Harnessing combinational phototherapy via post-synthetic PpIX conjugation on nanoscale metal-organic frameworks,"Nanomaterial-mediated phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is an effective anticancer intervention that relies on light activation of photoactive nanomaterials localized in tumors. Recently, combinational PDT/PTT offered a practical pathway to relieve resistance of monotherapy, surmount undesirable side effects and provide a synergistic effect to enhance phototherapeutic efficiency. Herein, we report a facile strategy to integrate protoporphyrin IX (PpIX) into nanoscale metal-organic frameworks (NMOFs) and control their photoactive properties for combinational cancer PDT and PTT. With optimized PpIX conjugation, the as-fabricated nanoparticles (nPCU NPs) exhibit (1) improved dispersibility and particle stability, (2) simultaneous generation of reactive oxygen species and heat effectively through activation by a single-wavelength laser of 635 nm, and (3) maintenance of porosity for further application as drug delivery vehicles. Moreover, in vitro investigation of nPCU NPs demonstrates effective cellular uptake, successful endosomal escape and enhanced phototherapeutic efficacy under both normoxic and hypoxic conditions. Therefore, this study developed a novel type of phototherapeutic nanoplatform with optimal properties for applicable cancer phototherapy. ",0
6865,31390332,Does Rectocele on Defecography Equate to Rectocele on Physical Examination in Patients With Defecatory Symptoms?,"Our primary objective was to determine the association between rectocele size on defecography and physical examination in symptomatic patients. Our secondary objective was to describe the associations between both defecography and physical examination findings with defecatory symptoms and progression to surgical repair of rectocele. We performed a retrospective review of all patients referred to a female pelvic medicine and reconstructive surgery clinic with a diagnosis of rectocele based on defecography and/or physical examination at a single institution from 2003 to 2017. Patients who did not have defecatory symptoms, did not undergo defecography imaging, or did not have a physical examination in a female pelvic medicine and reconstructive surgery clinic within 12 months of defecography imaging were excluded. Of 200 patients, 181 (90.5%) had a rectocele diagnosed on defecography and 170 (85%) had a rectocele diagnosed on physical examination. Pearson and Spearman tests of correlation both showed a positive relationship between the rectocele size on defecography and rectocele stage on physical examination; however, one was not reliable to predict the results of the other (Pearson correlation = 0.25; Spearman ρ = 0.29). The strongest predictor of surgery was rectocele stage on physical examination (P < 0.001). Size of rectocele on defecography was not a strong independent predictor for surgery (P = 0.01), although its significance improved with the addition of splinting (P = 0.004). Our results suggest that rectocele on defecography does not necessarily equate to rectocele on physical examination in patients with defecatory symptoms. Rectocele on physical examination was more predictive for surgery than rectocele on defecography. ",0
6866,31390344,Measuring Cognitive Reserve (CR) - A systematic review of measurement properties of CR questionnaires for the adult population,"The aim of this systematic review was to summarize and critically appraise the quality of published literature on measurement properties of questionnaires assessing Cognitive Reserve (CR) in adults (>18 years). We systematically searched for published studies on MEDLINE, PsycINFO, and Web of Science through August 2018. We evaluated the methodological quality of the included studies and the results on measurement properties based on a consensus-based standard checklist. The search strategy identified 991 publications, of which 37 were selected evaluating the measurement properties of six different questionnaires. Construct validity of the Cognitive Reserve Index questionnaire was most extensively evaluated, while evaluation of the remaining measurement properties of this questionnaire was scarce. Measurement properties of the Cognitive Reserve Questionnaire and the Cognitive Reserve Scale were assessed more completely. While the Lifetime of Experience Questionnaire seems to be the most thorough instrument, a finale recommendation for one specific questionnaire cannot be drawn, since about half of the measurement properties for each questionnaire were poorly or not assessed at all. There is a need of high quality methodological studies assessing measurement properties of CR questionnaires, especially regarding content validity, structural validity, and responsiveness. PROSPERO Registration number CRD42018107766. ",0
6867,31390629,Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature,"Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs. ",0
6868,31390921,Sirt1 modulates H3 phosphorylation and facilitates osteosarcoma cell autophagy,Abnormal histone modifications have been recognized as an important contributing factor to the initiation and progression of osteosarcoma. Sirtuin 1 (Sirt1) up-regulation has been discovered in osteosarcoma cells. This study tested the influence of Sirt1 on histone H3 phosphorylation at threonine 3 (H3 ,0
6869,31391356,LncRNA AK077216 is downregulated in diabetic retinopathy and inhibited the apoptosis of retinal pigment epithelial cells by downregulating miR-383,"LncRNA AK077216 is a novel lncRNA with critical role in osteoclastogenesis and bone resorption. Our preliminary RNA-seq data suggested its downregulated expression pattern in diabetic retinopathy (DR). We therefore further investigated the function of AK077216 in DR. Plasma samples used in this study were derived from blood, which was extracted from 60 diabetic retinopathy patients. AK077216 in plasma of DR patients, diabetic patients (DB) and controls (Control) was detected by RT-qPCR. ROC curve analysis was performed to evaluate the diagnostic value of plasma AK077216 for DR. It was found that plasma AK077216 was downregulated only in DR patients but not in diabetic patients (no obvious complications) comparing to healthy controls. Downregulation of AK077216 distinguished DR patients from diabetic patients and healthy controls. High glucose treatment failed to significantly affect AK077216 expression in cells of human retinal pigment epithelial cell line ARPE-19. MiR-383 was inversely correlated with AK077216 in DR patients. AK077216 overexpression caused miR-383 downregulation, but miR-383 overexpression did not significantly alter AK077216 expression. AK077216 overexpression inhibited ARPE-19 cell apoptosis, while miR-383 overexpression played an opposite role and attenuated the effects of AK077216 overexpression. Therefore, AK077216 is downregulated in diabetic retinopathy and inhibited the apoptosis of ARPE-19 cells by downregulating miR-383. ",0
6870,31391465,Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing,"Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 3272-26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 3272-26A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases. ",0
6871,31392259,"Determinants of Antenatal Care Visit Utilization of Child-Bearing Mothers in Kaffa, Sheka, and Bench Maji Zones of SNNPR, Southwestern Ethiopia","Antenatal care (ANC) is a preventive obstetric health-care program aimed at optimizing maternal fetal outcome through regular monitoring of pregnancy. Even if World Health Organization recommends a minimum of 4 ANC visits for normal pregnancy, existing evidence from developing countries including Ethiopia indicates there are few women who utilize it due to different reasons. The purpose of this article is to identify determinants significantly influencing the ANC visit utilization of child-bearing mothers in the Kaffa, Sheka, and Bench-Maji zones of Southern Nation Nationalities and Peoples Region, Ethiopia. A total of 1715 child-bearing mothers were selected. Several count models such as Poisson, negative binomial, zero-inflated Poisson, zero-inflated negative binomial, hurdle Poisson, and hurdle negative binomial regression models were fitted to select the model which best fits the data. The parameters were estimated by maximum likelihood. Measures of goodness of fit were based on the Rootogram. The data were found zeros (8.1%); the variance (3.794), which is less than its mean (3.91). Hurdle Poisson regression model was found to be better fitted with the data given. Variables are selected by backward selection method, through the analysis, zones, residence, age at first pregnancy, source of information, knowledge during danger sin, willingness, time of visit, and satisfaction, which were major predictors of ANC service utilization. The estimated odds that the number of ANC visits those child-bearing mothers made (mothers who lived in urban) are 3.52 times more likely than mothers who lived in rural keeping others variables constant and the like. Based on our findings, a lot of effort needs to be made by health offices to create awareness, maternal health-care programs should be expanded and intensified in rural areas, improve women's knowledge and awareness about the risk factor of late visit, the necessary investigations and follow-up throughout the antenatal period to promote regular attendance for ANC, and fulfill the client's satisfaction. ",0
6872,31392442,"Age, Sex, Race, Ethnicity, Sexual Orientation: Intersectionality of Marginalized-Group Identities and Enacted HIV-Related Stigma Among People Living with HIV in Florida","HIV-related stigma is associated with many negative health outcomes among people living with HIV (PLHIV). The theory of intersectionality suggests that the interactions of social identities affect PLHIV's experiences of stigma. This study aims to identify individual and interactive marginalized-group identities correlated with enacted HIV-related stigma among PLHIV in Florida. The sample (n = 932) was majority male (66.6%), Black (58.5%), and non-Latino (80.2%) with 53% reporting experiences of HIV-related stigma. In multinomial regression models, the interaction between race and ethnicity was significant where non-White Latinos had higher odds of experiencing high levels of enacted stigma [AOR (CI) 7.71 (2.41, 24.73), p < 0.001] compared to white non-Latinos. Additionally, racial minorities were less likely to have experienced moderate or high levels of enacted stigma [AOR (CI) 0.47 (0.31, 0.72), p < 0.001; AOR (CI) 0.39 (0.22, 0.70), p = 0.002, respectively]. Moreover, women had higher odds of experiencing high levels of enacted stigma [AOR (CI) 2.04 (1.13, 3.67), p = 0.018]. The results suggest that intersectionality is important to consider in HIV-related stigma research and future interventions. ",0
6873,31392834,Association between socioeconomic status and small-for-gestational-age in Japan: A single center retrospective cohort study,"Small-for-gestational-age (SGA) status has negative health consequences in neonates and later life. Low socioeconomic status (SES) is a reported risk factor for adverse birth outcomes, such as SGA and preterm birth (PTB). The present study investigated whether maternal SES is associated with adverse outcomes in Japanese pregnant women. Retrospective data were collected for 1970 Japanese women with singleton pregnancies who delivered between January 2007 and December 2011 at a single center: low SES group (n = 197); and controls (n = 1773). Low SES was defined according to the criteria of the Japanese pregnant-childbirth hospitalization support policy system. The low SES group included a significantly higher proportion of young women, women with single marital status, greater parity, pre-pregnancy smoking and a lack of regular employment (P < 0.001, respectively). The crude odds ratio (OR) for the association between low maternal SES and SGA was 1.80 (95% confidence interval [CI] 1.15-2.82, P = 0.010). After adjustment for baseline maternal age, parity, body mass index, smoking and gestational weight gain, the adjusted OR for the association between low maternal SES and SGA was 1.92 (95% CI 1.17-3.17, P = 0.010). No significant association was found between maternal SES and PTB. The present results suggest that low maternal SES is associated with SGA births in the Japanese population. Mitigation of low maternal SES could be urgent public health to prevent disadvantage birth outcome. ",0
6874,31393045,Cardamonin induces G2/M arrest and apoptosis via activation of the JNK-FOXO3a pathway in breast cancer cells,"Cardamonin (CD), a naturally occurring chalcone isolated from large black cardamom, was previously reported to suppress the proliferation of breast cancer cells. However, its precise molecular anti-tumor mechanisms have not been well elucidated. In this study, we found that CD markedly inhibited the proliferation of MDA-MB 231 and MCF-7 breast cancer cells through the induction of G2/M arrest and apoptosis. Reactive oxygen species (ROS) plays a pivotal role in the inhibition of CD-induced cell proliferation. Treatment with N-acetyl-cysteine (NAC), an ROS scavenger, blocked CD-induced G2/M arrest and apoptosis in this study. Quenching of ROS by overexpression of catalase also blocked CD-induced cell cycle arrest and apoptosis. We showed that CD enhanced the expression and nuclear translocation of Forkhead box O3 (FOXO3a) via upstream c-Jun N-terminal kinase, inducing the expression of FOXO3a and its target genes, including p21, p27, and Bim. This process led to the reduction of cyclin D1 and enhancement of activated caspase-3 expression. The addition of NAC markedly reversed these effects, knockdown of FOXO3a using small interfering RNA also decreased CD-induced G2/M arrest and apoptosis. In vivo, CD efficiently suppressed the growth of MDA-MB 231 breast cancer xenograft tumors. Taken together, our data provide a molecular mechanistic rationale for CD-induced cell cycle arrest and apoptosis in breast cancer cells. ",0
6875,31393094,SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus,"Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery. WES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression. A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis. ",0
6876,31393305,Control of Walking Speed in Children With Cerebral Palsy,"Children's ability to control the speed of gait is important for a wide range of activities. It is thought that the ability to increase the speed of gait for children with cerebral palsy (CP) is common. This study considered 3 hypotheses: (1) most ambulatory children with CP can increase gait speed, (2) the characteristics of free (self-selected) and fast walking are related to motor impairment level, and (3) the strategies used to increase gait speed are distinct among these levels. A retrospective review of time-distance parameters (TDPs) for 212 subjects with CP and 34 typically developing subjects walking at free and fast speeds was performed. Only children who could increase their gait speed above the minimal clinically important difference were defined as having a fast walk. Analysis of variance was used to compare TDPs of children with CP, among Gross Motor Function Classification System (GMFCS) levels, and children in typically developing group. Eight-five percent of the CP group (GMFCS I, II, III; 96%, 99%, and 34%, respectively) could increase gait speed on demand. At free speed, children at GMFCS I and II were significantly faster than children at GMFCS level III. At free speed, children at GMFCS I and II had significantly greater stride length than those at GMFCS levels III. At free speed, children at GMFCS level III had significantly lower cadence than those at GMFCS I and II. There were no significant differences in cadence among GMFCS levels at fast speeds. There were no significant differences among GMFCS levels for percent change in any TDP between free and fast walking. Almost all children with CP at GMFCS levels I and II can control the speed of gait, however, only one-third at GMFCS III level have this ability. This study suggests that children at GMFCS III level can be divided into 2 groups based on their ability to control gait speed; however, the prognostic significance of such categorization remains to be determined. Diagnostic level II. ",0
6877,31393877,The trend in blood pressure and hypertension prevalence in the general population of South Kivu between 2012 and 2016: Results from two representative cross-sectional surveys-The Bukavu observational study,"Data on blood pressure trends are scarce or unavailable in Sub-Saharan Africa in general and especially in the Democratic Republic of the Congo. This work addresses this gap by analyzing the dynamics in the prevalence and control of hypertension in a cohort of Congolese adults in South Kivu. Two phases of data collection were conducted including a baseline at the beginning in 2012 and a follow up in 2016. The subjects were ≥ 18 years old living in urban (n = 4413) or rural areas (n = 6453). Hypertension was defined as a blood pressure ≥ 140/90 mmHg and/or taking antihypertensive medications. The crude prevalence of hypertension was age-adjusted to the WHO population. Between 2012 and 2016, there was a significant increase in blood pressure (+2.5/+1.4 mmHg; p = 0.001), age standardized prevalence of hypertension [19.0% vs. 18.0%; OR = 1.05 (1.02-1.08); p<0.0001], and obesity (7.9% to 9.8%; p<0.0001) as well as the proportion of subjects > 60 years old (8.8% to 11.3%; p<0.0001) and those with tachycardia (10.5% to 14.4%; p<0.0001). The number of subjects under treatment of hypertension were statistically non-significant [16.1% vs. 14.3%; p = 0.29), but the level of control of hypertension was significantly reduced by 32.4% in 2016 compared in 2012 (43.5% vs. 64.4%; p = 0.0008). There was an increase in the prevalence of hypertension as well as cardiovascular-associated risk factors in the population. However, this trend did not increase for treated subjects with no improvements in the level of AHT control. Therefore, improved strategies for the prevention and management of non-communicable diseases are very important in Sub-Saharan Africa. ",0
6878,31394012,Longitudinal analysis of pre- and post-treatment measurements with equal baseline assumptions in randomized trials,"For continuous variables of randomized controlled trials, recently, longitudinal analysis of pre- and posttreatment measurements as bivariate responses is one of analytical methods to compare two treatment groups. Under random allocation, means and variances of pretreatment measurements are expected to be equal between groups, but covariances and posttreatment variances are not. Under random allocation with unequal covariances and posttreatment variances, we compared asymptotic variances of the treatment effect estimators in three longitudinal models. The data-generating model has equal baseline means and variances, and unequal covariances and posttreatment variances. The model with equal baseline means and unequal variance-covariance matrices has a redundant parameter. In large sample sizes, these two models keep a nominal type I error rate and have high efficiency. The model with equal baseline means and equal variance-covariance matrices wrongly assumes equal covariances and posttreatment variances. Only under equal sample sizes, this model keeps a nominal type I error rate. This model has the same high efficiency with the data-generating model under equal sample sizes. In conclusion, longitudinal analysis with equal baseline means performed well in large sample sizes. We also compared asymptotic properties of longitudinal models with those of the analysis of covariance (ANCOVA) and t-test. ",0
6879,31394072,Contraception across the transmasculine spectrum,"The field of transgender health continues to expand rapidly, including research in the area of family planning. While much attention has been given to fertility preservation and the parenting intentions of transgender individuals, far less has been paid to pregnancy prevention and contraceptive needs of people along the transmasculine gender spectrum (transgender men and gender-nonbinary persons who were assigned female at birth). Existing research illustrates that many clinicians and transmasculine individuals falsely believe that there is no risk of pregnancy while amenorrheic. These studies also show inconsistent counseling practices provided to transmasculine persons surrounding contraception and pregnancy while falling short of providing robust clinical guidance for improvement. Clinicians report a lack of adequate training in transgender reproductive health, and consequently, many do not feel comfortable treating transgender patients. The aim of this publication is to consolidate the findings of these prior studies and build upon them to offer comprehensive clinical guidance for managing contraception in transmasculine patients. To do so, it reviews the physiologic effects of testosterone on the sex steroid axis and current understanding of why ovulation and pregnancy may still occur while amenorrheic. Gender-inclusive terminology and a suggested script for eliciting a gender-affirming sexual history are offered. Common concerns (such as the effects on gender dysphoria and gender affirmation) and side effects of available contraceptive methods are subsequently addressed and how these may have a unique impact on transmasculine persons as compared with cisgender women. Lastly, a model is provided for approaching contraceptive counseling in the transmasculine population to assist clinicians and patients in determining the need for and selection of the type of contraception. To center transmasculine voices, the development of this publication's guidelines have been led by reproductive care clinicians of transgender experience. ",0
6880,31394671,Resveratrol Regulation of PI3K-AKT Signaling Pathway Genes in MDA-MB-231 Breast Cancer Cells,"Resveratrol (RSVL), a natural compound found in grapes and other food products, has been described to exert cancer chemopreventive activities. However, the cellular and molecular basis of its anticancer activity is largely undefined. The aim of the present study was to identify RSVL target genes in the MDA-MB-231 breast cancer cell line using cDNA arrays representing genes of the PI3K/AKT signaling pathway. Total RNA from control and RSVL-treated cells was used to synthesize biotinylated cDNA probes. cDNA arrays were hybridized with the probes and signals were detected with a chemiluminescent method. Western blotting analysis was used to validate the arrays' gene expression. At the cDNA level, 13 genes were altered (at least 2-fold difference) by RSVL treatment. At the protein level, both c-fos and P70S6K were also regulated. Using gene arrays it was shown for the first time that c-fos and p70S6 kinase were regulated by RSVL. ",0
6881,31395205,Reliability of three common fecal egg counting techniques for detecting strongylid and ascarid infections in horses,"The detection and quantification of nematode eggs using fecal egg count techniques have an irreplaceable role in equine parasitic control. The reliability, particularly precision and accuracy, of individual techniques have been described only for strongylid infections. The aim of this study was to compare three fecal egg count techniques used for the detection of the two most common equine nematode infections: strongylid and ascarid. The Simple McMaster, Concentration McMaster and Mini-FLOTAC techniques were tested on spiked fecal samples with various levels of egg concentration (50, 100, 200, 500, 1000 and 3000 eggs per gram) and naturally infected mixed strongylid-ascarid samples with 30 replicates. The Simple McMaster, Concentration McMaster and Mini-FLOTAC techniques had precision coefficients of variation of 44.33, 35.64 and 18.25% for the strongylid infection and 62.95, 35.71 and 18.95% for the ascarid infection, and percent accuracies (mean count/number of eggs spiked) of 97.53, 88.39 and 74.18% for the strongylid infection and 65.53, 83.18 and 90.28% for the ascarid infection, respectively. Accuracy depended greatly on the type of nematode, but precision did not. The Mini-FLOTAC technique was more precise than the Simple and Concentration McMaster techniques regardless of nematode type. Simple McMaster was the most accurate technique for detecting strongylid eggs, and Mini-FLOTAC was the most accurate technique for detecting ascarid eggs. Our results indicated that none of the current techniques were universally and sufficiently reliable for the simultaneous quantification of both of these common equine nematodes. ",0
6882,31395449,Effect of the addition of thiourethane oligomers on the sol⿿gel composition of BisGMA/TEGDMA polymer networks,"Thiourethane oligomers have been shown to increase the fracture toughness and reduce the polymerization stress of methacrylate-based materials. However, network formation has not been elucidated in these materials yet. The aim of this study was to evaluate how the addition of a thiourethane oligomer (TU) influences the sol/gel composition and network structure of methacrylate-based materials using dynamic mechanical analysis and extraction methods. BisGMA/TEGDMA at systematically varied mass ratios (20/80 to 80/20wt%) were mixed with pre-polymerized thiourethane oligomers at 0 (control) or 20wt%, synthesized by combining pentaerythritol tetra-3-mercaptopropionate with dicyclohexylmethane 4,4⿲-Diisocyanate, at 1:2 isocyanate:thiol. 0.1wt% of 2,2-Dimethoxy-2-phenylacetophenone was added as the photoinitiator and 0.3wt% of 2,6-di-tert-butyl-4-methylphenol was added as a free radical inhibitor. Disk specimens (0.8ÿ10mm in diameter, n=3) were photoactivated at 270mW/ (320⿿500nm) for 1min. The degree of conversion (DC) was measured in near-IR (˿6165cm In general, the presence of TU increased the overall conversion. The WS was similar for all groups, but the SL decreased by 2-fold with the addition of the TU oligomer for all compositions, except BisGMA/TEGDMA 80/20. The BisGMA concentration of the leachates increased with increasing BisGMA in the initial mixture, and with the presence of thiourethane. This compositional drift of the gel with the presence of TU was attributed to the preferential dissolution of TEGDMA into the TU network. Tg and ν decreased with the addition of TU, as expected. The addition of TU produced more homogeneous networks, as evidenced by narrower breadth of the tan delta curve. The addition of TU affected the composition of the sol/gel in crosslinked networks, which were more homogeneous and presented 2-fold less potentially toxic leachates than the methacrylate controls. The addition of TU may produce less cytotoxic materials based on the increased conversion and reduced amount of unreacted extractables from its network after water storage. ",0
6883,31395532,Theoretical Value of Deceleration Capacity Points to Deceleration Reserve of Fetal Heart Rate,"The interpretation of Average Acceleration and Deceleration Capacities (AC/DC), computed through Phase-Rectified Signal Averaging (PRSA), in intrapartum fetal heart rate (FHR) monitoring is still matter of investigation. We aimed to elucidate some behaviours of AC/DC. We derived the theoretical value of PRSA for stationary stochastic Gaussian processes and proved that for these time series AC and DC are necessarily identical in absolute value. The difference between DC and AC, termed Deceleration Reserve (DR), was introduced to detect signals' asymmetric trends. DR was tested on FHR signals from: near-term pregnant sheep model of labor consisting of chronically hypoxic and normoxic fetuses with both groups developing acidemia due to umbilical cord occlusions (UCO); and the CTU-UHB dataset containing fetal CTG recordings collected during labor of newborns that resulted acidotic and non-acidotic, respectively. DR was compared with AC and DC in terms of discriminatory power (AUC), between the groups, after correcting for signals' power or deceleration area, respectively. DR displayed higher discriminatory power on the animal model during severe acidemia, with respect to AC/DC (p<0.05$ but also distinguished correctly all chronically hypoxic from normoxic fetuses at baseline prior to UCO. DR also outperformed AC/DC on the CTU-UHB dataset in distinguishing acidemic fetuses at birth (AUC: 0.65). Theoretical results motivated the introduction of DR, that proved to be superior than AC/DC for risk stratification during labor. DR, measured during labor, might permit to distinguish acidemic fetuses due to their different autonomic regulation, paving the way for new monitoring strategies. ",0
6884,31395793,Frailty in middle age is associated with frailty status and race-specific changes to the transcriptome,"Frailty is an aging-associated syndrome resulting from diminished capacity to respond to stressors and is a significant risk factor for disability and mortality. Although frailty is usually studied in old age, it is present in mid-life. Given the increases in mortality statistics among middle-aged Americans, understanding molecular drivers of frailty in a younger, diverse cohort may facilitate identifying pathways for early intervention. We analyzed frailty-associated, genome-wide transcriptional changes in middle-aged blacks and whites. Next generation RNA sequencing was completed using total RNA from peripheral blood mononuclear cells (n = 16). We analyzed differential gene expression patterns and completed a parametric analysis of gene set enrichment (PAGE). Differential gene expression was validated using RT-qPCR (n = 52). We identified 5,082 genes differentially expressed with frailty. Frailty altered gene expression patterns and biological pathways differently in blacks and whites, including pathways related to inflammation and immunity. The validation study showed a significant two-way interaction between frailty, race, and expression of the cytokine  ",0
6885,31395920,Mating of escaped domestic pigs with wild boar and possibility of their offspring migration after the Fukushima Daiichi Nuclear Power Plant accident,"The 2011 Tohoku earthquake drastically changed human activities in some regions of Fukushima Prefecture, Japan. The subsequent tsunami damage and radioactive pollution from the Fukushima Daiichi nuclear power plant resulted in the evacuation of humans, and abandonment of agricultural lands, allowing population expansion of wildlife into areas formally inhabited by domesticated livestock. Unintentional escape of domesticated pigs into wildlife inhabited environments also occurred. In this study, we tested the possibility of introgression between wild boar and domesticated pigs in Fukushima and neighboring prefectures. We analyzed mitochondrial DNA sequences of 338 wild boar collected from populations in the Tohoku region between 2006 and 2018. Although most boar exhibited Asian boar mitochondrial haplotypes, 18 boar, phenotypically identified as wild boar, had a European domesticated pig haplotype. Frequencies of this haplotype have remained stable since first detection in 2015. This result infers ongoing genetic pollution in wild boar populations from released domesticated pigs. In 2018, this haplotype was detected outside of evacuated areas, suggesting migration and successful adaptation. The natural and anthropocentric disasters at Fukushima gave us the rare opportunity to study introgression processes of domestic genes into populations of wild boar. The present findings suggest a need for additional genetic monitoring to document the dispersal of domestic genes within wild boar stock. ",0
6886,31395925,Steroid receptors and their regulation in avian extraembryonic membranes provide a novel substrate for hormone mediated maternal effects,"Exposure of the vertebrate embryo to maternal hormones can have long-lasting effects on its phenotype, which has been studied extensively by experimentally manipulating maternal steroids, mostly androgens, in bird eggs. Yet, there is a severe lack of understanding of how and when these effects are actually mediated, hampering both underlying proximate and ultimate explanations. Here we report a novel finding that the embryo expresses androgen receptor (AR) and estrogen receptor (ERα) mRNA in its extraembryonic membranes (EMs) as early as before its own hormone production starts, suggesting a novel substrate for action of maternal hormones on the offspring. We also report the first experimental evidence for steroid receptor regulation in the avian embryo in response to yolk steroid levels: the level of AR is dependent on yolk androgen levels only in the EMs but not in body tissues, suggesting embryonic adaptation to maternal hormones. The results also solve the problem of uptake of lipophilic steroids from the yolk, why they affect multiple traits, and how they could mediate maternal effects without affecting embryonic sexual differentiation. ",0
6887,31396498,Why Children's Hospitals Are Unique and So Essential,"Children's hospitals were created in the nineteenth century, first in France and then in England. They were designed to provide optimal care to infants, children, and adolescents in a specific environment where parents were admitted and where the special needs of children were catered for. No other system currently offers so many advantages as the multidisciplinary teams with their pediatricians, surgeons, anesthetists, intensive care specialists, and all the allied health professionals who can add their knowledge to the quality of care. From the beginning, they played a major role in caring for socially disadvantaged children. They brought together more than 95% of tertiary care, including cancer care and organ transplantations. They represent the best blend for the study of pediatric medicine and physiology, for high-level preventive medicine, and for research in all fields of pediatrics. This probably explains why they have developed everywhere around the world. This article explains the paramount importance of children's hospitals for providing safe and effective multidisciplinary pediatric care. ",0
6888,31397535,"""Perspectives regarding what constitutes a """"good death"""" among Thai nurses: A cross-sectional study""","""Palliative care is a crucial component in improving peoples' end-of-life period. It is important to understand the wishes of people at the end of life and the perceptions of their healthcare providers regarding these wishes. As nurses play a key role in patient care, in this study we set out to determine nurses' perceptions regarding what constitutes a """"good death"""", comparing what they thought their older patients would prefer to their own preferences for their own end-of-life care. Questionnaires asking about various options of end-of-life care were distributed to nurses, and they were asked how they thought older people would respond to each of the questions and what their own preferences would be if they were terminally ill. In total, 656 participants were enrolled and they rated relief from suffering as the most important component, both for themselves and for those in their care. More than 80% of nurses agreed with all of the statements on the questionnaire. However, some of the nurses' preferences for their own end of life differed from those they expected their patients to value. """,0
6889,31397837,Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR26b-5p and miR-140-3p binding to Gata4,"Circular RNAs (circRNAs) are involved in gene regulation in a variety of physiological and pathological processes. The present study aimed to investigate the effect of circRNA_000203 on cardiac hypertrophy and the potential mechanisms involved. CircRNA_000203 was found to be upregulated in the myocardium of Ang-II-infused mice and in the cytoplasma of Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Enforced-expression of circRNA_000203 enhances cell size and expression of atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC) in NMVCs. In vivo, heart function was impaired and cardiac hypertrophy was aggravated in Ang-II-infused myocardium-specific circRNA_000203 transgenic mice (Tg-circ203). Mechanistically, we found that circRNA_000203 could specifically sponge miR-26b-5p, -140-3p in NMVCs. Further, dual luciferase reporter assay showed that miR-26b-5p, -140-3p could interact with 3'UTRs of Gata4 gene, and circRNA_000203 could block the above interactions. Additionally, Gata4 expression is transcriptionally inhibited by miR-26b-5p, -140-3p mimic in NMVCs, but enhanced by over-expression of circRNA_000203 in vitro and in vivo. Functionally, miR-26b-5p, -140-3p, and Gata4 siRNA, could reverse the hypertrophic growth in Ang-II-induced NMVCs, as well as eliminate the pro-hypertrophic effect of circRNA_000203 in NMVCs. Furthermore, we demonstrated that NF-κB signaling mediates the upregulation of circRNA_000203 in NMVCs exposed to Ang-II treatment. Our data demonstrated that circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p leading to enhanced Gata4 levels. ",0
6890,31398176,Perspective for evaluation of microrna in plasma and bile for differential diagnosis of obstructive biliary tract disease,"Introduction: Cholelithiasisis diagnosed in 10-25% of the adult population. The manifestation of cholelithiasis in the form of acute cholecystitis, cholangitis, jaundice etc. occurs with a probability of 2-3% or more per year depending on the risk factors. Most often, it manifests it self as acute calculous cholecystitis. Up to 20% of such patients have additional calculi in extrahepatic bile ducts requiring simultaneous surgical intervention. Currently, the algorithm for diagnosis of concomitant choledocholithiasis in acute cholecystitis is multilevel and it needs to be simplified and improved. Conventional non-invasive diagnostic techniques have low specificity and sensitivity. A new safe diagnostic test is needed for the diagnosis of choledocholithiasis in cholecystitis in order to improve the results of surgical treatment of patients. The aim of the study - to determine the prospects for diagnosis of microRNA for differential diagnosis of obstructive diseases of the biliary tract on the basis of the literature data. Materials and methods: The analysis of the selected international literature in the period of 1991-2018 concerning the studies of microRNA in cholestatic liver diseases was carried out. The search for literature was conducted using Google Scholar and PubMed search engines for the following keywords: microRNA, cholestasis, choledocholithiasis, acute cholecystitis, biliary obstruction in their various combinations. Review: MicroRNA is a specific post-transcriptional regulator of gene expression in all organs and systems of the body. There are specific types of miRNAs for different tissues. The most studied type of liver miRNA is miR-122. The studies showed better sensitivity and specificity of the detection of miR-122 both in the plasma and in the bile for the diagnosis of pathological liver conditions compared with conventional liver tests (aminotransferase, alkaline phosphatase, gamma-glutamyltransferase). Regarding the cholestatic hepatocyte injury occurring in choledocholithiasis, the following types of miRNA were identified: 122, 21, 29, 125, 222, let-7, 98 etc. Their concentrations in plasma and bile can be used as a diagnostic test for the presence of concomitant benign cholestasis in acute cholecystitis. Moreover, these markers can be used for the differential diagnosis of cholestasis of different etiology. Conclusions: Quantitative and qualitative characteristics of microRNA in bile and plasma can be used as an additional non-invasive method for diagnosis of cholestasis induced by choledocholithiasis in acute calculous cholecystitis. Further studyis needed to identify the most optimal algorithm for the administration of microRNA in clinical practice. ",0
6891,31398230,Perceptions of physicians in Saudi Arabia on the use of international clinical guidelines for managing primary insomnia,"While there are no national clinical guidelines for managing primary insomnia in Saudi Arabia, there are also no published studies of physicians' perceptions of and attitudes towards using international guidelines. The objective of this study was to explore the knowledge, perceptions, and attitudes of physicians practising in Saudi Arabia about using international guidelines for managing insomnia. A qualitative study using in-depth, face-to-face, and semi-structured interviews with 15 physicians held in July 2017 at a tertiary care hospital in Jazan, the distal south-western province in Saudi Arabia. Interviews were audio-recorded, transcribed verbatim, coded using the qualitative software NVivo11 and analysed thematically. Data saturation was assumed as no new understandings of the broad thematic issues were produced by the last three interviews. Themes identified were: Knowledge, Resistance, Barriers and Facilitators. Participants acknowledged their lack of awareness of available guidelines and their lack of training and education about Cognitive Behavioural Therapy for Insomnia (CBT-I). They highlighted a lack of education for patients about insomnia and its treatment. Beliefs about dependence on hypnotics and the inappropriateness of international guidelines for Saudi Arabia inclined many to resist using them. Inability to document diagnosis and consultations due to limited time and lack of suitable electronic systems, lack of suitably trained practitioners for referral for CBT-I, and lack of accountability for practice were identified as key barriers to following international guidelines. Development of national guidelines was the most important facilitator suggested by participants. The health authorities in the government of the Kingdom of Saudi Arabia (KSA) should improve general public awareness about sleep disorders and provide focused training for specialists and technologists. Above all, KSA needs its own nationwide guidelines for treating sleep-disorders based on evidence-based clinical trials, consistent with its history, culture, socioeconomic conditions and traditions. ",0
6892,31398452,"Measles transmission at an international airport - Taiwan, March-April 2018","During March-April 2018, an infectious measles index case traveling from Thailand led to two successive generations of measles transmission in Taiwan, with 21 cases confirmed. The median patient age was 30.5 years (range 22-47 years); six (27%) had documented receipt of one (n=3) or more (n=3) previous measles-containing vaccine doses at age ≥12 months. Epidemiological investigation and sequence analysis found that most (n=16, 76%) measles transmissions had occurred in airport and flight settings; secondary and tertiary cases included cabin crew (n=7), airport staff (n=2), and passengers who had been at the same airport or on the same flight (n=7). This investigation serves as a reminder that an international airport can be a hotspot for measles transmission. International travelers, airline cabin crew, and airport employees are recommended to check their vaccination status and ensure that they are fully vaccinated against measles. Furthermore, it is recommended that airline and airport employers have an occupational health vaccination program in place to ensure appropriate pre-employment assessment of measles immunity and vaccination. ",0
6893,31398490,A case of pyoderma gangrenosum in hand surgery,"Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that can take many clinical forms. Its diagnosis is difficult and often delayed. We report the case of a 36-year-old man with PG complicating a chemical burn of the wrist. This mode of atypical onset delayed the diagnosis and the initiation of appropriate treatment. This was not sufficient since the patient's hand was amputated at his request because of unbearable pain, and failed treatment. Surgeons should be aware of this pathology in cases of rapidly progressing ulcers, especially if aggravated by repeated debridement. ",0
6894,31398963,Evaluation of Integrated Interventional Radiology Residency Websites,"In the transition to the integrated interventional radiology residency model, residency websites are important resources of program information for prospective applicants. The objective of this investigation was to evaluate the availability and comprehensiveness of integrated interventional radiology residency websites. A complete list of programs participating in the 2018 integrated interventional radiology match was collected using the online Fellowship and Residency Electronic Interactive Database and Electronic Residency Application Service. Residency program websites were evaluated for the presence of 19 variables related to resident education and recruitment, and the percent comprehensiveness of each website was calculated based on the number of variables present. The effect of program size and geographic region on website availability and comprehensiveness was assessed. Of the 69 programs participating in the 2018 match, 18 (26%) programs did not have any locatable website. Of the 51 programs with websites, 30 (59%) had stand-alone interventional radiology websites distinct from the associated diagnostic radiology website. Large programs were more likely to have a residency website than small programs (91% versus 54%, p=0.001). Across all categories, the mean website comprehensiveness was 33%. Mean website comprehensiveness of programs in the Midwest (43%) and Northeast (37%) was significantly greater than mean website comprehensiveness of programs in the West (19%) (p=0.005). Overall, 1 in 4 integrated interventional radiology residency programs did not have locatable websites. Many integrated interventional radiology residency websites lack important content variables. Efforts should be made to improve the residency websites and digital training resources for prospective interventional radiology applicants and to help showcase programs in the best light. ",0
6895,31398985,The most recent recommendations for the surgical treatment of inguinal hernia,"The publication of new guidelines in recent years shows that surgical treatment of inguinal hernia remains topical. The main goal is to improve patient outcomes, specifically to decrease recurrence rates and reduce chronic pain. The main purpose of this article is to summarize the latest recommendations in surgical treatment of the groin hernias, especially in the case of strangulation. The authors made literature review of all the guidelines published by the hernia societies, including related articles, in the last ten years. The use of the EHS classification system is suggested. In elective operations, mesh repair is recommended. The Lichtenstein technique is the standard in open inguinal hernia repair. Transabdominal preperitoneal and totally extraperitoneal approach have comparable outcomes. Their clear advantages include minimal invasiveness. Mesh repair is recommended also in the case of strangulation, but only in clean and clean-contami-nated operations. A laparoscopic approach should be considered as well. Inter alia, it allows an assessment of bowel viability during the whole procedure. The need of bowel resection is hence lower compared to open surgery. If it is not possible to use the mesh, the Shouldice method is regarded as the best non-mesh repair technique. If there is concern about bowel viability, visualization, either by formal laparoscopy, hernia sac laparoscopy or laparotomy, is recommended. Hernioscopy is a simple and safe procedure that uses the hernia sac for insertion of a port following insufflation and diagnostic examination. It requires less advanced laparoscopic skills than does emergency laparoscopic hernia repair. It can be performed even by surgeons who lack sufficient experience with laparoscopy. In elective procedures, the mesh repair is recommended. It is recommended also in the case of strangulation, but not in a contaminated-dirty surgical field. If there is concern about bowel viability, visualization, either by formal laparoscopy, hernia sac laparoscopy or laparotomy, is needed. ",0
6896,31399030,Cost-effectiveness of childhood pneumococcal vaccination program in Ethiopia: results from a quasi-experimental evaluation,"Ethiopia was among the 15 countries that, together accounted for 64% of the world's severe episodes of pneumonia among children below the age of 5 in 2011. To reduce this burden, the 10-valent pneumococcal conjugate vaccine (PCV 10) was introduced into the general childhood national immunization program in Ethiopia in 2011. However, there is little evidence on its cost-effectiveness, and the aim of this study was to estimate the cost-effectiveness of the introduction of PCV 10 vaccination in the Ethiopian setting. The cost-effectiveness analysis was carried out based on a quasi-experimental evaluation of implementing PCV 10 at the Butajira rural health program site in Ethiopia. The intervention and the control groups consisted 876 and 1010 children, respectively. Using data from program site's surveillance system database as a framework, health outcome and vaccination data were collected from medical records, immunization registration books and reports. Disability- Adjusted Life Year (DALY) was a main health outcome metric complimented by incidence of acute lower respiratory infection/1000-person years. Vaccination and treatment costs were collected by document review and cross-sectional household survey. In the intervention cohort, 626 of 876 (71.5%) children received PCV 10 vaccination. Until the first year of life, the incidence of acute lower respiratory infection was higher in the intervention group. After the first year of life, the incidence rate was 35.2 per 1000-person years in the intervention group compared to 60.4 per 1000-person years in the control group. The incremental cost-effectiveness ratio (ICER) per averted DALY for the intervention group during the total follow-up period was (2013 US$) 394.3 (undiscounted) and 413.8 (discounted). The ICER per averted DALY excluding the first year of life was (2013 US$) 225 (undiscounted) and 292.7 (discounted). Compared to the WHO's suggested cost-effectiveness threshold value, the results indicate that the general childhood PCV 10 vaccination was a cost-effective intervention in the Butajira rural health program site. ",0
6897,31399066,Chart validation of an algorithm for identifying hereditary progressive muscular dystrophy in healthcare claims,"Muscular dystrophies (MDs) are a group of inherited conditions characterized by progressive muscle degeneration and weakness. The rarity and heterogeneity of the population with MD have hindered therapeutic developments as well as epidemiological and health outcomes research. The objective of the study was to develop and validate a case-finding algorithm utilizing administrative claims data to identify and characterize patients with MD. This retrospective cohort study used medical chart validation to evaluate an ICD-9/10 coding algorithm in a large commercial claims database. Patients were identified who had ≥2 office visits with a diagnosis of hereditary progressive MDs from January 1, 2013 through December 31, 2016, were male, and younger than 18 years at the time of first MD diagnosis. Cases who met the algorithm were then validated against medical charts. Diagnoses of MD and specific type (Duchenne, Becker, or other MD) were confirmed by medical chart review by trained reviewers. Positive predictive value (PPV) and 95% confidence intervals (CI) were calculated using a 2 × 2 contingence table. Patient demographic, clinical, and health utilization characteristics were summarized using basic descriptive statistics. Charts were obtained and reviewed for 109 patients who met the algorithm. The PPV of the case-identifying algorithm for MD was 95% (95% CI 88-98%). Of the 103 confirmed MD cases, 87 patients (85%, 95% CI 76-91%) had Duchenne or Becker MD; 76 patients (74%, 95% CI 64-82%) had Duchenne MD, and 11 patients (11%, 95% CI 5-18%) had Becker MD. A total of 74 (67.9%) patients had ≥1 pediatric complex chronic condition (other than neurologic/neuromuscular disease); 54 (49.5%) had cardiovascular conditions; 14 (12.8%) had respiratory conditions; 50 (45.9%) had bone-related issues; 11 (10.1%) had impaired growth; and 6 (5.5%) had puberty delay. The results of this study demonstrate that the case-finding algorithm accurately identified patients with MD, primarily Duchenne MD, within a large administrative database. The algorithm, which was constructed using a few items easily accessible from claims, can be used to facilitate epidemiological and health outcomes research in the Duchenne patient population. ",0
6898,31399391,"GRADE: Using evidence to decision frameworks for adoption, adaptation and de novo generation of trustworthy guideline recommendations - GRADE-ADOLOPMENT]","""Guideline developers can: (1) adopt existing recommendations from others; (2) adapt existing recommendations to their own context; or (3) create recommendations de novo. Monetary and nonmonetary resources, credibility, maximization of uptake, as well as logical arguments should guide the choice of the approach and processes. To describe a potentially efficient model for guideline production based on adoption, adaptation, and/or de novo development of recommendations utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision (EtD) frameworks. We applied the model in a new national guideline program producing 22 practice guidelines. We searched for relevant evidence that informs the direction and strength of a recommendation. We then produced GRADE EtDs for guideline panels to develop recommendations. In two waves, a total of 80 EtD frameworks was produced approximately 4 months and 146 EtDs in about 6 months. Use of the EtD frameworks allowed panel members to understand judgments of other guideline groups about the criteria that bear on guideline recommendations and then make their own judgments about those criteria in a systematic approach. The """"GRADE-ADOLOPMENT"""" approach to guideline production combines adoption, adaptation, and, as needed, de novo development of recommendations. If guideline developers apply EtD criteria more widely and make their work publically available, this approach should prove even more useful. """,0
6899,31399861,Laser-assisted prevention of enamel caries: a 10-year review of the literature,"Since the invention of lasers in dentistry, investigations in caries prevention by the use of laser radiation have been proposed. There are several mechanisms stated for this purpose such as photothermal and/or photochemical interaction processes with the enamel. Alone or in conjugation with topical fluoride application, this treatment modality may improve enamel acid resistance in high-caries-risk populations. Data collection was done by searching the keywords caries, prevention, and laser in PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar. Lasing protocols of the collected literature and their effectiveness as well as examination methods used to verify treatment outcomes have been evaluated. One hundred eighteen publications were found for the last 10 years. The wavelengths investigated for caries prevention are mainly located in the near and the mid-infrared spectral range. In the evaluated period of time, investigations using CO ",0
6900,31399936,Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma,"We conducted a phase Ib study (NCT02345824) to determine whether ribociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), penetrates tumor tissue and modulates downstream signaling pathways including retinoblastoma protein (Rb) in patients with recurrent glioblastoma (GBM). Study participants received ribociclib (600 mg QD) for 8-21 days before surgical resection of their recurrent GBM. Total and unbound concentrations of ribociclib were measured in samples of tumor tissue, plasma, and cerebrospinal fluid (CSF). We analyzed tumor specimens obtained from the first (initial/pre-study) and second (recurrent/on-study) surgery by immunohistochemistry for Rb status and downstream signaling of CDK4/6 inhibition. Participants with Rb-positive recurrent tumors continued ribociclib treatment on a 21-day-on, 7-day-off schedule after surgery, and were monitored for toxicity and disease progression. Three participants with recurrent Rb-positive GBM participated in this study. Mean unbound (pharmacologically active) ribociclib concentrations in plasma, CSF, MRI-enhancing, MRI-non-enhancing, and tumor core regions were 0.337 μM, 0.632 μM, 1.242 nmol/g, 0.484 nmol/g, and 1.526 nmol/g, respectively, which exceeded the in vitro IC This study suggests that ribociclib penetrated recurrent GBM tissue at concentrations predicted to be therapeutically beneficial. Our study was unable to demonstrate tumor pharmacodynamic correlates of drug activity. Although well tolerated, ribociclib monotherapy seemed ineffective for the treatment of recurrent GBM. ",0
6901,31399987,Urinary Biomarkers of Renal Fibrosis,"Renal fibrosis is the common pathological pathway of progressive CKD. The commonly used biomarkers in clinical practice are not optimal to detect injury or predict prognosis. Therefore, it is crucial to develop novel biomarkers to allow prompt intervention. Urine serves as a valuable resource of biomarker discovery for kidney diseases. Owing to the rapid development of omics platforms and bioinformatics, research on novel urinary biomarkers for renal fibrosis has proliferated in recent years. In this chapter, we discuss the current status and provide basic knowledge in this field. We present novel promising biomarkers including tubular injury markers, proteins related to activated inflammation/fibrosis pathways, CKD273, transcriptomic biomarkers, as well as metabolomic biomarkers. Furthermore, considering the complex nature of the pathogenesis of renal fibrosis, we also highlight the combination of biomarkers to further improve the diagnostic and prognostic performance. ",0
6902,31400086,Preserved expressive language as a phenotypic determinant of Mosaic Angelman Syndrome,"Angelman Syndrome (AS) is a neurodevelopmental disorder with core features of intellectual disability, speech impairment, movement disorders, and a unique behavioral profile. Typically, AS results from absent maternal expression of UBE3A, but some individuals have imprinting defects in a portion of their cells. These individuals are mosaic for normal and defective UBE3A expression, resulting in mosaic AS (mAS) with a partial loss of gene expression. This study aims to contrast the mAS phenotype to that of AS. Clinical characteristics of mAS were obtained from a parental survey of 22 mAS patients and from the Angelman Natural History study. These were contrasted with those of AS using historical data. Developmental delay was present in nearly all mAS patients, whereas the core features of AS were reported in less than 40%. While language and ability to manage activities of daily living were markedly improved over that expected in AS, mAS patients demonstrated a high incidence of behavioral challenges. Clinical work-up of an individual with developmental delay, hyperactivity, anxiety, and an uncharacteristically happy demeanor should prompt methylation studies to rule out mAS. We expand the phenotypic spectrum of AS to include features that overlap with Prader-Willi such as hyperphagia. ",0
6903,31400100,An Online Geographic Data Visualization Tool to Relate Preterm Births to Environmental Factors,"Preterm birth (<37 weeks gestation) continues to be a significant cause of disease and death in the United States. Its complex causes are associated with several genetic, biological, environmental, and sociodemographic factors. Organizing and visualizing various data that may be related to preterm birth is an essential step for pattern exploration and hypothesis generation and presents an opportunity to increase public and stakeholder involvement. In this article, we describe a collaborative effort to create an online geographic data visualization tool using open software to explore preterm birth in Fresno County, where rates are the highest in California. The tool incorporates information on births, environmental exposures, sociodemographic characteristics, the built environment, and access to care. We describe data sets used to build the tool, the data-hosting platform, and the process used to engage stakeholders in its creation. We highlight an important example of how collaboration can increase the utility of geographic data visualization to improve public health and address health equity in birth outcomes. ",0
6904,31400297,The contraceptive and reproductive history and planning goals of trans-masculine adults: a mixed-methods study,"This study aims to identify factors associated with the reproductive planning of trans-masculine adults. Between 2015 and 2016, providers enrolled 150 trans-masculine adults in a sexual health study assessing sociodemographics, social support, gender affirmation, sexual partnering, and reproductive history and planning. A brief clinical interview assessed contraceptive use and concerns. Bivariate and multivariable logistic regression analyses examined associations between participant characteristics and three outcomes: current contraceptive use, lifetime pregnancy history and reproductive planning. Overall, 37.3% are currently using contraceptives; 5.3% have been pregnant; and 20.0% plan to have biological children (9.3% plan to become pregnant; 12.0% plan to use their oocytes with a surrogate). Participants are less likely to use contraceptives if they are students vs. not, have socially affirmed their gender vs. not and have a partner vs. are single. Greater number of sexual partners is associated with the increased odds of contraceptive use. Further, as social support increases, the odds of having been pregnant decreases. Participants with a nonbinary gender identity are more likely to want to become pregnant than those with a binary gender identity, whereas those who have socially affirmed their gender are less likely to want to become pregnant than those who had not. Finally, participants of color more commonly planned to use their oocytes with a surrogate than white participants. Sociodemographic, gender affirmation, social support and sexual partner factors are associated with contraceptive use and reproductive history among trans-masculine patients. Healthcare providers must be aware of the diverse reproductive histories and pregnancy goals of trans-masculine individuals in order to provide comprehensive reproductive healthcare counseling and provision. More research is needed to better understand contraception and reproduction desires in trans-masculine individuals. ",0
6905,31400500,Cell-intrinsic survival signals. The role of autophagy in metastatic dissemination and tumor cell dormancy,"Metastasis is the main cause of cancer-related deaths. Disseminated tumor cells (DTCs), which seed metastasis, can remain undetected in a dormant state for decades after treatment of the primary tumor and their persistence is the main cause of late relapse and death in a substantial proportion of cancer patients. Understanding the mechanisms underlying the survival of dormant DTCs is of utmost importance to develop new therapies that effectively kill DTCs while in a quiescent state, therefore preventing metastatic disease and minimizing the chance of future relapses. Besides key interactions with the local microenvironment, dormant DTCs must integrate survival mechanisms to remain viable for long periods of time. Here, the pro-survival role of autophagy in tumor cell dissemination and dormant DTC maintenance are discussed, as well as the implications of the current knowledge for future research efforts. ",0
6906,31400955,Organ preservation by chemoradiation for bladder cancer],"When localized, the reference treatment of urothelial, muscle-invasive bladder tumours relies on radical cystectomy with reconstruction by enterocystoplasty if possible or Bricker bypass. Trimodal therapy combining transurethral resection of the tumour followed by concomitant chemotherapy may be considered as a therapeutic alternative to radical cystectomy in well-selected patients with unifocal tumours, stage T2, non-diverticular location, without in situ carcinoma or hydronephrosis and with macroscopically complete transurethral resection. The functional prognosis of the bladder and quality of life should be discussed with the patient as well as the need for salvage surgery for persistent tumour at a 45-Gy dose level, the latter being a highly unfavourable prognosis factor. On the other hand, this trimodal treatment is the reference in case of surgical contraindication. This article details the methods and results of the main series available in the literature in terms of local control, survival, bladder preservation rates and complications, as well as study prospects. ",0
6907,31400959,Electroacupuncture relieved visceral and referred hindpaw hypersensitivity in colitis rats by inhibiting tyrosine hydroxylase expression in the sixth lumbar dorsal root ganglia,"Irritable bowel syndrome patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting the involvement of an exaggerated signaling process in both visceral and somatic sensory pathways. Increasing evidence has shown that sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibers toward sensory neurons in dorsal root ganglia maintains and exacerbates the neuropathic and inflammatory pain, as well as colonic inflammation. The aim of the present study was to determine whether electroacupuncture could alleviate the visceral and secondary somatic hyperalgesia in colitis rats by suppressing the TH-IR expression in related dorsal root ganglia. After trinitrobenzene sulfonic acid irritation, rats developed inflammatory tissue damage in the distal colon, which was accompanied by visceral hypersensitivity and secondary hind paw hyperalgesia, as indicated by enhanced visceromotor response to colorectal distension and decreased mechanical and thermal withdrawal latency of the hind paw. Additionally, excessive TH-IR fibers sprouted toward calcitonin gene-related peptide immunoreactive sensory neurons, and TH-IR neurons also increased in the sixth lumbar dorsal root ganglia of colitis rats. Both electroacupuncture and guanethidine attenuated visceral and referred hind paw hyperalgesia by inhibiting the over-expression of TH-IR neurons and fibers in the sixth lumbar dorsal root ganglia. Moreover local inflammatory damage in the distal colon was restored after 7 days of electroacupuncture intervention. These results suggest that electroacupuncture relieved visceral and referred hind paw hypersensitivity in colitis rats by inhibiting TH expression in the sixth lumbar dorsal root ganglia. ",0
6908,31401122,Proteomics analysis of blood plasma in HIV-infected patients with chronic kidney disease,"Patients treated for human immunodeficiency virus (HIV) infection are prone to developing chronic kidney disease (CKD). Current methods used in assessing kidney function suffer inaccuracy in HIV-infected patients. This study aims to identify biomarkers that could complement existing methods of kidney assessment among HIV-infected subjects. Plasma protein profiling was performed for HIV patients with CKD presented with negative/trace proteinuria (non-proteinuric) (n = 8) and their matched non-CKD controls, using two-dimensional gel electrophoresis (2DE); selected protein candidates were identified using mass spectrometry. Subsequently, altered plasma abundance of protein candidates were verified using Western blotting in HIV-infected subjects with non-proteinuric CKD (n = 8), proteinuric CKD (n = 5), and their matched non-CKD controls, as well as in HIV-uninfected subjects with impaired kidney function (n = 3) and their matched controls. Analysis of 2DE found significantly altered abundance of five protein candidates between HIV-infected patients with non-proteinuric CKD and without CKD: alpha-1-microglobulin (A1M), serum albumin (ALB), zinc-alpha-2-glycoprotein (AZGP1), haptoglobin (HP), and retinol binding protein (RBP4). Western blotting showed an increased abundance of A1M and HP in HIV-infected patients with non-proteinuric CKD compared to their non-CKD controls, whereas A1M, AZGP1, and RBP4 were significantly increased in HIV-infected patients with proteinuric CKD compared to their non-CKD controls. Such pattern was not found in HIV-uninfected subjects with impaired kidney function. The data suggests four proteins that may be used as biomarkers of CKD in HIV-infected patients. Further validation in a larger cohort of HIV-infected patients is necessary for assessing the clinical use of these proposed biomarkers for CKD. ",0
6909,31401330,Responses in the crucian carp (Carassius auratus) exposed to environmentally relevant concentration of 17α-Ethinylestradiol based on metabolomics,"17α-ethynylestradiol (EE2), a ubiquitous synthetic endocrine disrupting chemical, was the principal component of contraceptive drugs and one of common hormone medications. The detrimental impact of EE2 on the reproduction of organisms was widely recognized. However, the underlying mechanisms of physiological and metabolome effects of EE2 on freshwater fish are still unclear. This study investigated the toxic effects and related mechanisms of EE2 on freshwater fish crucian carp (Carassius auratus) based on metabolomics. Crucian carp were exposed to EE2 at environmentally relevant concentration for 9 days, 18 days, and 27 days, and the biological responses were explored through analysis of the physiological endpoints, steroid hormones, and metabolome. The physiological endpoints of crucian carp had no distinct change after EE2 exposure. However, metabolomics analysis probed significant deviation based on chemometrics, indicating that the metabolomics approach was more sensitive to the effects of EE2 at environmentally relevant concentration to freshwater fish than the traditional endpoints. The alterations of 24 metabolites in gonad and 16 metabolites in kidney were induced by treatment with EE2, respectively, which suggesting the perturbations in amino acid metabolism, lipid metabolism, energy metabolism, and oxidative stress. Moreover, EE2 exposure could induce the disruption of lipid metabolism and then broke the homeostasis of endogenous steroid hormones. Metabolomics provided a new strategy for the studies on contaminant exposure at a low dose in the short term and gave important information for the toxicology and mechanism of EE2. ",0
6910,31401731,Prothrombin Complex Concentrates are Superior to Fresh Frozen Plasma for Emergency Reversal of Vitamin K Antagonists: A Meta-Analysis in 2606 Subjects,"Urgent reversal of vitamin K antagonists (VKAs) is required for major bleeding or urgent surgery by intravenous vitamin K with either prothrombin complex concentrates (PCCs) or fresh frozen plasma (FFP). However, there is lack of consensus regarding the superiority of either reversal agent. We sought to compare the performance of PCC and FFP in urgent reversal of VKA. A meta-analysis was conducted up to November 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Seventeen studies comprising 2606 participants met the inclusion criteria. Compared with FFP treatment, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.60, 95% CI 0.40-0.90, p = 0.01), better reversal of INR (OR 7.36, 95% CI 4.18-12.98; p < 0.00001) and lower risk of at least one treatment-related adverse event (OR 0.45, 95% CI 0.26-0.80, p = 0.006). Among patients with VKA-associated intracranial haemorrhage, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.58, 95% CI 0.35-0.94, p = 0.03) and better reversal of INR (OR 6.52, 95% CI 1.66-25.59, p = 0.007). There were no differences between these two agents in thrombogenicity, requirement for and quantity of red blood cell transfusions, all adverse events, fluid overload or disability on discharge or at 90 days. As an agent for urgent reversal of VKA, PCC outperforms FFP in 90-day all-cause mortality including those with VKA-related intracranial haemorrhage, INR reversal and treatment-related adverse events. ",0
6911,31402168,Interaction effects of FTO rs9939609 polymorphism and lifestyle factors on obesity indices in early adolescence,"The rs9939609 SNP in fat mass and obesity-associated (FTO) gene influence obesity, whose effects might be mediated by lifestyle factors. However, evidence was lacked in early adolescents. This study aimed to investigate the interactions effects of FTO rs9939609 and lifestyle factors on obesity indices in early adolescence. The study included 1149 children aged 10-12 years. Their body mass index (BMI) and body fat percentage (BF%) were measured, and lifestyle factors were surveyed through questionnaires. The rs9939609 SNP in the FTO gene was genotyped. Significant associations were found between FTO rs9939609 and obesity indices after adjusting for confounding factors. An interaction effect between rs9939609 and soft drinks was observed with p=0.019 for BMI after adjustment for confounding factors. The children carrying risk allele A had a significantly higher mean BMI (mean=19.67kg/m FTO rs9939609 had an obvious and independent effect on obesity-related indices in early adolescents. Soft drinks may exert a modifying effect on the relationship between FTO rs9939609 and BMI. ",0
6912,31402286,Salvage Re-irradiation With Single-modality Interstitial Brachytherapy for the Treatment of Recurrent Gynaecological Tumours in the Pelvis: A Multi-institutional Study,"Recurrent gynaecological tumours can cause significant morbidity with limited salvage options. This study investigates the strategy of salvage single-modality interstitial brachytherapy (SM-ISBT) for recurrent gynaecological pelvic cancer at two specialised ISBT centres. Patients who had received salvage SM-ISBT for pelvic recurrence of gynaecological cancers from September 2008 to January 2017 were included. None had distant metastasis at the time of recurrence. Local control, progression-free and overall survival and long-term toxicities were evaluated. Twenty-six patients with a median follow-up of 24 months (range 2.5-106.3 months) after SM-ISBT were included. Primary cancer sites were endometrium (20), cervix (4), vulva (1) and vagina (1). All patients had prior whole-pelvic external beam irradiation and 16 had prior brachytherapy. The median disease-free survival prior to SM-ISBT was 20.3 months (interquartile range 9.9-30.5). SM-ISBT was delivered with high dose rate technique over three to six fractions. The median high-risk clinical target volume was 34.6 cm Salvage SM-ISBT re-irradiation for pelvic recurrence of gynaecological malignancies was feasible and safe. With limited salvage options, the local control obtained in more than a quarter of patients seems reasonable. Further efforts are needed to establish a consensus about the optimal patient selection, dose fractionation, implant technique and combination with systemic therapies. ",0
6913,31402330,Solitary pulmonary nodules caused by Mycobacterium avium complex,"The prevalence of Mycobacterium avium complex (MAC) pulmonary disease (PD) is increasing significantly in Japan. Among the patterns of MAC-PD, a solitary pulmonary nodule (SPN) is less common and often resembles lung cancer. The aim of this study was to identify the clinical features of MAC-SPN. SPNs culture-positive for MAC (definite cases) and culture-negative SPNs showing nucleic acid amplification test (NAAT)-positive status (probable cases) that presented between January 2007 and December 2017 were enrolled. The patients' clinical, laboratory, radiological, and microbiological findings and outcomes were investigated. This study included 28 patients (median age, 66 years; 16 men, 12 women). All patients were asymptomatic when the disease was detected. Median SPN size was 23.5 mm. Twenty-six patients underwent video-assisted thoracoscopic surgery, while the others underwent percutaneous needle biopsy for diagnosis. Granulomatous inflammation was confirmed in all cases. Microbiologically, the 28 cases were divided into 17 in the definite group and 11 in the probable group. In both groups, M. avium was predominant. There were no significant differences in clinical and radiological findings and follow-up periods between the 2 groups. After diagnosis, 6 patients received medical treatment, while the others did not. The median follow-up period was 42 months, and no recurrence was observed in both groups. MAC should be considered in the differential diagnosis of SPNs in asymptomatic patients. To overcome the difficulties in diagnosing MAC-SPN, this study underscores the importance of diagnostic interventions and identification of MAC by culture and/or NAAT in biopsied specimens. ",0
6914,31403202,Sense of Filial Obligation and Caregiving Burdens Among Chinese Immigrants in the United States,"Focusing on Chinese immigrants, this study examined (1) whether filial obligation, the core social norm in the Chinese culture, is related to caregiving burdens; and (2) whether level of acculturation of the caregivers moderates the above relationships. Cross-sectional. Chicago, Illinois. A purposive sample of 393 Chinese adult immigrants who were primary caregivers of parents aged 60 years or older. Sense of filial obligation was captured by felt responsibility toward parents in six domains (respect, make happy, care, greet, obey, and provide financial support). Caregiving burdens were measured by the Caregiver Burden Inventory. Acculturation was measured by 12 questions about respondents' language preference in different settings and ethnicity of individuals they interact with. A stronger sense of filial obligation was significantly associated with lower levels of developmental (β = -.15), emotional (β = -.18), social (β = -.20), and physical (β = -.10) burdens. For subjective burdens (developmental, social burdens), such a protective effect of filial obligation was stronger among caregivers with lower acculturation levels. For more objective burdens (time-dependent, physical burdens), stronger filial obligation was actually associated with greater burdens among caregivers with higher acculturation levels. Programs focusing on celebrating the cultural heritage of immigrants and improving the relationship between the parents and children may be helpful to reduce caregiving burdens. Intervention programs that help Chinese immigrant caregivers to find the most appropriate way to balance traditional and new social norms are important to provide successful care to aging Chinese immigrants. J Am Geriatr Soc 67:S564-S570, 2019. ",0
6915,31403489,Information and Training Needs of Pediatric Oncologists in Complementary and Integrative Medicine: A Cross-Sectional Study,"More than one third of all German pediatric patients with cancer use complementary and integrative medicine (CIM). Parents want to discuss the topic of CIM with their pediatric oncologists (POs); however, POs mostly do not feel confident discussing these topics. POs report openness to receiving further information and training, but CIM training opportunities in medical education seem rare. We investigated POs' information and training needs and preference patterns regarding CIM training content with a paper-based or online survey. A total of 101 POs from Germany completed the survey. Only 11.4% agreed to being sufficiently informed of CIM. The participants stated needing further CIM information very often (8.6%), often (38.7%), or occasionally (44.1%). They considered an overview of CIM therapies and information about relaxation methods, herbal remedies, and acupuncture for cancer-related symptoms such as lack of appetite, nausea, or vomiting as most important in CIM training material, and also the topics of adverse effects and summary of evidence. Finally, POs reported on clinical situations in which a need for further information on CIM emerged. The results of our study indicate that there is a need for a structured training that offers knowledge and skills on the subject of patient counseling on CIM in pediatric oncology. ",0
6916,31404020,"SpHincterotomy for Acute Recurrent Pancreatitis Randomized Trial: Rationale, Methodology, and Potential Implications","In patients with acute recurrent pancreatitis (ARP), pancreas divisum, and no other etiologic factors, endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) is often performed to enlarge the minor papillary orifice, based on limited data. The aims of this study are to describe the rationale and methodology of a sham-controlled clinical trial designed to test the hypothesis that miES reduces the risk of acute pancreatitis. The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a multicenter, international, sham-controlled, randomized trial comparing endoscopic ultrasound + ERCP with miES versus endoscopic ultrasound + sham for the management of ARP. A total of 234 consented patients having 2 or more discrete episodes of acute pancreatitis, pancreas divisum confirmed by magnetic resonance cholangiopancreatography, and no other clear etiology for acute pancreatitis will be randomized. Both cohorts will be followed for a minimum of 6 months and a maximum of 48 months. The trial is powered to detect a 33% risk reduction of acute pancreatitis frequency. The SHARP trial will determine whether ERCP with miES benefits patients with idiopathic ARP and pancreas divisum. Trial planning has informed the importance of blinded outcome assessors and long-term follow-up. ",0
6917,31404313,An Unusual Presentation of Postpartum Spontaneous Coronary Artery Dissection,"The postpartum population is one with a unique physiologic profile that predisposes these patients to rare and often life-threatening conditions. Herein, we discuss a case of a 37-year-old, multiparous female who presented to the emergency department with vague chest discomfort 14 days after delivering her sixth child via vaginal delivery. The patient was found to have elevated cardiac biomarkers and was ultimately diagnosed with pregnancy-related spontaneous coronary artery dissection (P-SCAD). This case report discusses the evaluation, pathophysiology, workup, and management of P-SCAD. ",0
6918,31404529,"Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice","Maternal smoking of conventional or vapor cigarettes during pregnancy, a form of developmental nicotine exposure (DNE), enhances the risk of neurodevelopmental disorders such as ADHD, autism, and schizophrenia in children. Modeling the multigenerational effects of smoking during pregnancy and nursing in the first- (F1) and second- (F2) generation adolescent offspring of oral nicotine-treated female C57BL/6J mice, we have previously reported that DNE precipitates intergenerational transmission of nicotine preference, hyperactivity and impulsivity-like behaviors, altered rhythmicity of home cage activity, corticostriatal nicotinic acetylcholine receptor and dopamine transporter dysfunction, and corticostriatal global DNA methylome deficits. In aggregate, these DNE-evoked behavioral, neuropharmacological, and epigenomic anomalies mirror fundamental etiological aspects of neurodevelopmental disorders including ADHD, autism, and schizophrenia. Expanding this line of research, the current study profiled the multigenerational neurotrophic and neuroendocrine consequences of DNE. Results reveal impaired proBDNF proteolysis as indicated by proBDNF-BDNF imbalance, downregulation of the proBDNF processing enzyme furin, atypical glucocorticoid receptor (GR) activity as implied by decreased relative nuclear GR localization, and deficient basal plasma corticosterone (CORT) levels in adolescent DNE offspring and grandoffspring. Collectively, these data recapitulate the BDNF deficits and HPA axis dysregulation characteristic of neurodevelopmental disorders such as ADHD, autism, and schizophrenia as well as the children of maternal smokers. Notably, as BDNF is a quintessential mediator of neurodevelopment, our prior findings of multigenerational DNE-induced behavioral and neuropharmacological abnormalities may stem from neurodevelopmental insults conferred by the proBDNF-BDNF imbalance detected in DNE mice. Similarly, our findings of multigenerational GR hypoactivity may contribute to the increased risk-taking behaviors and aberrant circadian rhythmicity of home cage activity that we previously documented in first- and second-generation DNE mice. ",0
6919,31404604,Antioxidant and antibacterial activities of omega-3 rich oils/curcumin nanoemulsions loaded in chitosan and alginate-based microbeads,"Omega-3 fatty acids can be considered as potential alternative therapeutic agents because of their antimicrobial and antioxidant properties. Two investigated omega-3 rich oils (flaxseed or fish) have been nanoemulsified with and without the natural antioxidant (curcumin, Cur) followed by their incorporation into crosslinked polymeric microbeads. The microbeads were developed from chitosan (CS), alginate (AL) and their combination (CSAL). Results indicated that the mean droplet diameter of the plain and Cur-loaded nanoemulsions ranged from 62.3 to 111.29 nm. The microbeads produced from AL, CS and their combination without Cur had predominantly shriveled surfaces compared to Cur-loaded ones. Addition of Cur was found to enhance oxidative stability, encapsulation efficiency, loading capacity, and antioxidant activity of the formulated microbeads. Plain fish oil revealed more antibacterial activity than plain flaxseed oil. Fish oil nanoemulsion-in-AL microbeads had more antibacterial activity than nanoemulsions of flaxseed oil-in-AL, fish oil-in-CS and the combined (CSAL) microbeads. However, flaxseed oil nanoemulsion-in-CS microbeads showed higher antibacterial activity than nanoemulsions of fish oil-in-CS, flaxseed oil-in-AL and the combined microbeads. The obtained results suggested the suitability of the formulated nanoemulsions-loaded microbeads to be used in food and pharmaceuticals products. ",0
6920,31404798,Tyrosine-based asymmetric urea ligand for prostate carcinoma: Tuning biological efficacy through in silico studies,"In this article, we have explored the chemical interactions of tyrosine-based asymmetric urea ligands in the binding pockets of prostate specific membrane antigen (PSMA) through in silico studies. The S1 pocket of the PSMA protein offers better scope for modifications in the urea ligands to improve the binding affinity. Accordingly, tyrosine-based (S)-2-(3-((S)-1-carboxy-2-(4-(carboxymethoxy)phenyl)ethyl)ureido)pentanedioic acid (CYUE, 3) ligand was designed, synthesized and predicted to possess inhibition constant (Ki) of 55 nM with PSMA protein. The CYUE (3) ligand was further elaborated into a fluorescent diagnostic probe for detection of PSMA ",0
6921,31404859,The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease,"The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review. ",0
6922,31404895,Geographical and Temporal Variation in the Incidence and Mortality of Hepato-Pancreato-Biliary Primary Malignancies:1990-2017,"Hepatic, pancreas, and biliary (HPB) cancers pose serious challenges to global health care systems. These malignancies demonstrate great geographical variations with shifting trends over time. The aim of the present study was to determine the recent trends in incidence, prevalence, and mortality of primary HPB malignancies to guide the further development of effective strategies for prevention, screening, and treatment. The Global Burden of Disease (GBD) dataset 1990-2017 was interrogated for end point variables by age, sex, year, and geography. Epidemiologic data were modeled in DisMod-MR 2.1, a Bayesian meta-regression tool that pools data points from different sources and adjusts for known sources of variability. Global Burden of Disease data were extracted from 284 country-year, and 976 subnational-year combinations from 27 countries in North America, Latin America, Europe, India, and New Zealand. Although the global incidence of primary HPB malignancies increased by 1.43% from 1990 to 2017 (1,400,739 cases), the incidence of extrahepatic biliary and gallbladder malignancies decreased by -0.32% (210,878 cases) over the same period. There was significant variability in the incidence, prevalence, and mortality of HPB cancers by the sociodemographic index (SDI), as well as by geography. The largest incidence increase of primary liver and pancreas cancers was seen in the high-income Asia-Pacific group, followed by the high-income North America and Western Europe groups. The highest incidences and prevalence of extrahepatic biliary and gallbladder malignancies were observed in Asia-Pacific, Southern Latin American, and Andean Latin American regions. In general, mortality rates of HPB malignancies were larger in the low SDI when compared with the high SDI group in all geographical regions. The global incidence and prevalence of primary liver and pancreatic malignancies continue to increase with great geographical variation. The mortality trends mirror those of the incidence. Although the global incidence and prevalence of extrahepatic biliary and gallbladder malignancies has decreased, the mortality rate has not significantly changed. The results of this article can assist local and regional authorities in policy development to improve health care access for screening, early detection, and treatment of HPB malignancies. ",0
6923,31405064,Use of Simple Telemetry to Reduce the Health Impacts of Fuel Poverty and Living in Cold Homes,"""In Great Britain, roughly half of people with at least one long-standing illness (LSI) live in low-income households. Lower-income households are at risk of fuel poverty and living in a colder house, which can worsen certain health conditions, causing related morbidity and mortality. This pilot study aimed to assess whether raising occupants' awareness of indoor temperatures in the home could initiate improved health and well-being among such vulnerable residents. Thermometers were placed inside a manufactured bamboo brooch to be worn or placed within homes during the winter of 2016/17. These devices were supplied to households (n = 34) already assisted by Community Energy Plus, which is a private social enterprise in Cornwall, United Kingdom (UK), using initiatives aimed at maintaining """"healthy homes"""". Questionnaires were supplied to households before devices were supplied, and then again at the end of a three-month period, with further questions asked when devices were collected. Temperatures were recorded automatically every half-hour and used to draw inference from questionnaire responses, particularly around health and well-being. Questionnaires were completed by 22 households. Throughout the winter, those declaring the poorest health when supplied with devices maintained homes at a higher average temperature. There were also indications that those with raised awareness of interior temperatures sought fewer casual medicines. Simple telemetry could play a role in the management of chronic health conditions in winter, helping healthcare systems become more sustainable. The need for higher indoor temperatures among people with an LSI highlights the need to consider this approach alongside more sustainable household energy-efficiency improvements. A larger study is needed to explore this further and quantify the cost benefit of this approach. """,0
6924,31405314,The multiple roles of exosomes in Parkinson's disease: an overview,"The extracellular vesicles (EVs) represent a relatively new field of research in neurodegenerative disease and they are thought to be one of the ways that neurodegenerative pathologies, such as Parkinson's Disease (PD), spread in the brain. EVs are membrane vesicles released from cells into the extracellular space and they are produced by all cells of the nervous tissue. The classification of the vesicle subtypes comprises exosomes, microvesicles/microparticles, apoptotic bodies. EVs change in number and content in response to environmental conditions and may function as shuttles for the delivery of cargo between cells. Recent data suggest that exosomes secreted by both activated microglia and neurons play an important role in α-synuclein (α-syn) spreading and increase of neuroinflammation, thus exacerbating neuronal dysfunction and disease progression. α-syn is a presynaptic protein secreted by neurons in small amounts, and it is the main component of Lewy bodies, one of the histopathological features of PD. Several factors have shown to induce and/or modulate α-syn structure and oligomerization  ",0
6925,31405315,"Prognostication Accuracy, Confidence, and Decisional Conflict Across Training Levels of Internal Medicine Providers","Providing patient care at the end of a patient's life is a humbling and sacred experience for both patient and provider. Without a truthful and meaningful conversation about end-of-life care preferences, the care that is delivered may not be the care that the patient prefers. Determine if there is a relationship between level of training, confidence, and presence of decisional conflict in making an accurate prognosis for 2 standardized cases. Additionally, we evaluated the correctness of the prognosis as measured against survival outcomes for patients with similar diagnoses. Decisional conflict was measured with the SURE tool, a validated 4-item tool that has been used in assessing for the presence of decisional conflict. Following analysis of data, it was found that providers with no decisional conflict were much more likely to be attendings with more than 5 years' experience. Providers were more conflicted overall when confronted with a case with a more grave prognosis. It was determined that providers with a lower level of training were more likely to have decisional conflict. Provider confidence increases and decisional conflict decreases as one increases their level of training. However, the degree in which the provider is correct in their prognosis does not change as one increases their level of training. These findings have broad implications on patients, providers, and the health-care system. ",0
6926,31405350,Predictors of Wound Healing Following Revascularization for Chronic Limb-Threatening Ischemia,"""After surgical or endovascular revascularization, some ischemic lesions will not heal, while some others will heal at a variable period of time from the intervention, indicating a multifactorial interaction between local and systematic """"wound healing-promoting"""" factors. Our objective was to identify predictors of wound healing following revascularization for chronic limb-threatening ischemia (CLTI). A literature review was performed to identify published research concerning clinical, biochemical, and noninvasive methods as predictors of wound healing time and wound-free period after surgical and endovascular revascularization for CLTI. Our review indicated that potential predictors included local wound factors, wound depth, patient's comorbidities, medications, smoking and alcohol abuse, poor vessel runoff, and direct versus indirect revascularization. Among the clinical biomarkers, platelet-derived growth factor, transforming growth factor β, basic fibroblast growth factor, tumor necrosis factor α, interleukin (IL) 1, and IL-6 have been proposed as potential predictors. Furthermore, the potential of noninvasive microcirculation assessment to predict proper wound healing has been the topic of extensive investigation. Among the novel methods, transcutaneous measurement of oxygen partial pressure, skin perfusion pressure, oxygen-to-see method, indocyanine green fluorescence imaging, and multispectral optoacoustic tomography have shown promising results. The risk factor profile of an ischemic lesion in the lower extremities with a delayed/failed healing response, following a successful revascularization, is not fully clarified. Although many predictors have been assessed so far, further research needs to be done to identify the optimal clinical and biochemical indices and the noninvasive technique assessing the microcirculation that is associated with complete wound healing. """,0
6927,31405378,Drug metabolite synthesis by immobilized human FMO3 and whole cell catalysts,"Sufficient reference standards of drug metabolites are required in the drug discovery and development process. However, such drug standards are often expensive or not commercially available. Chemical synthesis of drug metabolite is often difficulty due to the highly regio- and stereo-chemically demanding. The present work aims to construct stable and efficient biocatalysts for the generation of drug metabolites in vitro. In this work, using benzydamine as a model drug, two easy-to-perform approaches (whole cell catalysis and enzyme immobilization) were investigated for the synthesis of FMO3-generated drug metabolites. The whole cell catalysis was carried out by using cell suspensions of E. coli JM109 harboring FMO3 and E. coli BL21 harboring GDH (glucose dehydrogenase), giving 1.2 g/L benzydamine N-oxide within 9 h under the optimized conditions. While for another approach, two HisTrap HP columns respectively carrying His The results presented in this work provides new possibilities for the drug-metabolizing enzymes-mediated biocatalysis. ",0
6928,31405428,Visceral Kaposi Sarcoma Presenting as Small Bowel Intussusception: A Rare Presentation and Call to Action,"Surgical emergencies related to visceral involvement of Kaposi sarcoma (KS) are rare complications of the disease. In this report, we describe a case of visceral KS causing small bowel intussusception in a young, previously undiagnosed human immunodeficiency virus (HIV)-positive patient. Southern surgeons should be particularly attentive to HIV/AIDS-related disease as a cause of surgical pathology, particularly in the southeast, and can play a significant advocacy role for improved access to HIV/AIDS diagnostic and treatment services. ",0
6929,31405485,"Stimulatory effect of dopamine derivative, salsolinol, on pulsatile luteinizing hormone secretion in seasonally anestrous sheep: Focus on dopamine, kisspeptin and gonadotropin-releasing hormone","In the present study, there was testing of the hypothesis that a centrally administered dopamine (DA) derivative, salsolinol, could affect pulsatile luteinizing hormone (LH) secretion in seasonally anestrous sheep by affecting the neuronal components of the estradiol (E2) negative feedback. In two experiments performed during early spring (increasing day length - March/April), salsolinol or Ringer-Locke solution (control) were administered into the third brain ventricle (IIIv): 1) in several injections for three consecutive days; and 2) in several hour-long infusions. In addition to determining the LH concentration (in both experiments), the abundances of gonadotropin-releasing hormone (GnRH) and kisspeptin mRNA were examined in the hypothalamus and LHβ subunit mRNA in the pituitary (Experiment 1). In Experiment 2, concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in perfusates collected from the infundibular nucleus/median eminence (IN/ME) by the push-pull method. In both experiments, salsolinol increased both LH pulse frequency (P < 0.05) and plasma LH concentration (P < 0.001) compared to controls. The injected salsolinol also increased (P < 0.05) the abundance of GnRH mRNA in the mediobasal hypothalamus and kisspeptin mRNA in the arcuate nucleus. The two doses of infused salsolinol decreased DA to undetectable concentrations and DOPAC concentration by 60% in perfusates collected from the IN/ME. In conclusion, exogenous salsolinol functioning centrally stimulates pulsatile LH secretion in sheep during seasonal anestrus. It is suggested that salsolinol may have this effect by reducing the activity of the hypothalamic neuroendocrine dopaminergic system, which results in an increase in both kisspeptin and GnRH neurons activity. ",0
6930,31405569,"Burden of Persistent Vomiting With Cannabis Use Disorder: Report From 55,549 Hospitalizations in the United States","With increase in incidence rate of persistent vomiting (PV) in the post-legalization period it is important to understand adverse effects of cannabis use and its relationship with PV. We investigated the relationship between cannabis use disorder (CUD) and PV-related hospitalization. A Nationwide Inpatient Sample was analyzed from 2010 to 2014 for patients (aged 15-54 y) with a primary diagnosis of PV (N = 55,549), and a comparison was made between patients with the International Classification of Diseases, Ninth Edition classification of CUD versus non-CUD cohorts. We used logistic regression to study the odds ratio between CUD and PV. The number of PV-related hospitalizations with CUD had a significantly increased trend (P < 0.001), with a 286% increase over 5 years. A higher proportion of these patients with CUD were younger (15-24 y), female, and African American/Hispanic. In regression analysis, cannabis was associated with a seven-fold higher odds (95% confidence interval: 6.931-7.260) of PV-related hospitalization. This study found that CUD was independently associated with a 609% increased likelihood of PV-related hospitalization, and this association persisted even after adjusting for known risk factors and other substances. ",0
6931,31405680,"Evaluation of illness perceptions and their associations with glycaemic control, medication adherence and chronic kidney disease in type 2 diabetes mellitus patients in Malaysia","Illness perceptions (IP) involve coping strategies and behavioural responses that can influence glycaemic control. Despite the importance of good glycaemic control, the majority of patients in Asia are not achieving glycaemic targets. An evaluation of IP in association with glycaemic control, medication adherence and chronic kidney disease (CKD) in Type 2 diabetes mellitus patients (T2DM) was carried out in an outpatient setting in Malaysia METHOD: A cross-sectional study was conducted using the Revised Illness Perception Questionnaire in a purposive sample of 384 T2DM patients. There were 55.7% females, median age was 58.2 years and median duration of diabetes was 13 years. The majority (79.4%) of patients had poor diabetes control (HbA1c ≥ 7.0%) and 39.6% of patients had low medication adherence. Patients with good glycaemic control had a higher Timeline Acute/Chronic and Emotional Representations score, hence they held the correct belief that diabetes is chronic and experienced negative emotions. Highly adherent patients had a higher Illness Coherence (χ2 = 21.385, p < 0.001) score but a lower Consequences (χ2 = 17.592, p < 0.001) and Emotional Representations (χ2 = 16.849, p < 0.001) score indicating good understanding and less negative perceptions of disease burden. Patients in a more advanced stage of CKD had a significantly higher Timeline Cyclical score (χ2 = 18.718, p = 0.001), believing that diabetes was unpredictable. Dimensions of IP have been shown to be significantly associated with the assessed variables, therefore intervention studies with education, support and counselling should be conducted in Asia with the ultimate aim of empowering patients through IP-targeted management. ",0
6932,31405748,Incidence and risk factors for cyclops syndrome after anterior cruciate ligament reconstruction: A systematic literature review,"Cyclops syndrome after anterior cruciate ligament (ACL) reconstruction is due to a fibrous nodule that develops in the anterior part of the intercondylar notch and prevents full knee extension. The primary objective of this systematic literature review was to evaluate the incidence of symptomatic cyclops lesion after ACL reconstruction. The secondary objective was to identify risk factors for cyclops syndrome. Cyclops syndrome is common after ACL reconstruction and has several risk factors reported in the literature. A systematic literature review was performed by searching the PubMed, Medline, CINAHL, Cochrane, and Embase databases with the key terms 'cyclops' and 'ACL reconstruction'. The data thus retrieved were evaluated independently by two investigators. All articles in English or French that reported the incidence and risk factors of cyclops syndrome after ACL reconstruction were included. The search retrieved the titles and abstracts of 79 articles, of which 20 were selected to be read in full; among these, 10 were included in the study. The incidence of symptomatic cyclops lesion ranged from 1.9% to 10.9%. Identified risk factors were as follows: pre-operatively, knee inflammation and/or motion restriction at the time of ACL reconstruction; intra-operatively, narrow intercondylar notch and excessively anterior position of the tibial tunnel; and post-operatively, persistent hamstring muscle spasm. Development of a cyclops lesion is common after ACL reconstruction, occurs early, and may require further surgery. The knowledge of the risk factors provided by this study may improve the ability to devise effective preventive measures. II, systematic literature review. ",0
6933,31405759,MiR-3653 inhibits the metastasis and epithelial-mesenchymal transition of colon cancer by targeting Zeb2,"Aberrant expression of microRNAs (miRNAs) has been widely recognized to play critical roles in the pathogenic processes of colon cancer. However, the expression and functions of miR-3653 in colon cancer remain uncovered. This study revealed for the first time that miR-3653 expression was significantly decreased in colon cancer tissues and cell lines. MiR-3653 overexpression led to decreased migration and invasion of HCT116 cells while miR-3653 knockdown resulted in opposite influence of the metastatic behaviors of HT29 cells. qRT-PCR and western blot demonstrated that miR-3653 suppressed the epithelial-mesenchymal transition (EMT) of colon cancer cells using both gain- and loss- of function assay. Mechanically, miR-3653 was found to interact with the 3'-UTR of Zeb2 through the complementary sequences and inhibited the expression of Zeb2 in colon cancer cells. Rescue experiments demonstrated that the inhibitory effect of miR-3653 overexpression on cell metastasis and EMT was abrogated by forced expression of Zeb2. This study demonstrates that miR-3653 suppresses the metastasis and EMT of colon cells by targeting Zeb2, and serves as a promising biomarker and therapeutic target in colon cancer. ",0
6934,31405828,Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis,"Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio [IRR] 0·49, 95% CI 0·36 to 0·66; p<0·0001). We also found that macrolide treatment improved the time to first exacerbation (adjusted hazard ratio 0·46, 0·34 to 0·61; p<0·0001) and was associated with improved quality of life measured by the SGRQ (mean improvement 2·93 points, 0·03 to 5·83; p=0·048). Macrolides were not associated with a significant improvement in FEV Long-term macrolide treatment significantly reduces the frequency of exacerbations in patients with bronchiectasis, with similar benefits observed in all subgroups based on patient characteristics. This finding suggests that macrolides might be considered in patients in whom macrolides are not indicated according to the current guidelines, particularly if alternative approaches to reduce exacerbations have been unsuccessful. However, downsides of long-term macrolide treatment must also be taken into account. European Respiratory Society. ",0
6935,31406038,"Pyogenic Spondylitis: Clinical Features, Diagnosis and Treatment","Although pyogenic spondylitis is an infrequent infection, its incidence is increasing because of the growing number of elderly people and immunocompromised patients. Diagnosis is often difficult and appropriate imaging, blood cultures and/or biopsy are essential in making an early diagnosis. Most of the cases can be treated non-operatively. Surgical treatment is indicated in patients with spinal cord or cauda equine compression with progressive neurological deficits and/or patients who have failed conservative treatment. Early and accurate diagnosis of pyogenic spondylitis is important for timely and effective management, in order to reduce the occurrence of spinal deformity and dysfunction. ",0
6936,31406145,Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis,"Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons leading to muscle paralysis and death. While a link between dysregulated lipid metabolism and ALS has been proposed, lipidome alterations involved in disease progression are still understudied. Using a rodent model of ALS overexpressing mutant human Cu/Zn-superoxide dismutase gene (SOD1-G93A), we performed a comparative lipidomic analysis in motor cortex and spinal cord tissues of SOD1-G93A and WT rats at asymptomatic (~70 days) and symptomatic stages (~120 days). Interestingly, lipidome alterations in motor cortex were mostly related to age than ALS. In contrast, drastic changes were observed in spinal cord of SOD1-G93A 120d group, including decreased levels of cardiolipin and a 6-fold increase in several cholesteryl esters linked to polyunsaturated fatty acids. Consistent with previous studies, our findings suggest abnormal mitochondria in motor neurons and lipid droplets accumulation in aberrant astrocytes. Although the mechanism leading to cholesteryl esters accumulation remains to be established, we postulate a hypothetical model based on neuroprotection of polyunsaturated fatty acids into lipid droplets in response to increased oxidative stress. Implicated in the pathology of other neurodegenerative diseases, cholesteryl esters appear as attractive targets for further investigations. ",0
6937,31406406,Antileishmanial activity and immune modulatory effects of benzoxonium chloride and its entrapped forms in niosome on ,"Benzoxonium chloride is an anti-infective agent that is used as anti-septic drugs for disinfection of the mucus membrane, skin surface and anti-bacterial, and it is also found to be effective against cutaneous leishmaniasis. The present study aims to evaluate the leishmanicidal activity of benzoxonium chloride and niosomal forms against  ",0
6938,31407113,Lipid nanoparticles as vehicles for oral delivery of insulin and insulin analogs: preliminary ex vivo and in vivo studies,"Subcutaneous administration of insulin in patients suffering from diabetes is associated with the distress of daily injections. Among alternative administration routes, the oral route seems to be the most advantageous for long-term administration, also because the peptide undergoes a hepatic first-pass effect, contributing to the inhibition of the hepatic glucose output. Unfortunately, insulin oral administration has so far been hampered by degradation by gastrointestinal enzymes and poor intestinal absorption. Loading in lipid nanoparticles should allow to overcome these limitations. Entrapment of peptides into such nanoparticles is not easy, because of their high molecular weight, hydrophilicity and thermo-sensitivity. In this study, this objective was achieved by employing fatty acid coacervation method: solid lipid nanoparticles and newly engineered nanostructured lipid carriers were formulated. Insulin and insulin analog-glargine insulin-were entrapped in the lipid matrix through hydrophobic ion pairing. Bioactivity of lipid entrapped peptides was demonstrated through a suitable in vivo experiment. Ex vivo and in vivo studies were carried out by employing fluorescently labelled peptides. Gut tied up experiments showed the superiority of glargine insulin-loaded nanostructured lipid carriers, which demonstrated significantly higher permeation (till 30% dose/mL) compared to free peptide. Approximately 6% absolute bioavailability in the bloodstream was estimated for the same formulation through in vivo pharmacokinetic studies in rats. Consequently, a discrete blood glucose responsivity was noted in healthy animals. Given the optimized ex vivo and in vivo intestinal uptake of glargine insulin from nanostructured lipid carriers, further studies will be carried out on healthy and diabetic rat models in order to establish a glargine insulin dose-glucose response relation. ",0
6939,31407153,Exploratory relationships between cognitive improvements and training induced plasticity in hippocampus and cingulum in a rat model of mild traumatic brain injury: a diffusion MRI study,"Traumatic brain injury (TBI) is a major cause of long-term cognitive deficits, even in mild TBI patients. Computerized cognitive training can help alleviate complaints and improve daily life functioning of TBI patients. However, the underlying biological mechanisms of cognitive training in TBI are not fully understood. In the present study, we utilised for the first time a touchscreen cognitive training system in a rat model of mild TBI. Moreover, we wanted to examine whether the beneficial effects of a cognitive training are task-dependent and selective in their target. Specifically, we examined the effect of two training tasks, i.e. the Paired Associate Learning (PAL) task targeting spatial memory functioning and 5-Choice Continuous Performance (5-CCP) task loading on attention and inhibition control, on the microstructural organization of the hippocampus and cingulum, respectively, using diffusion tensor imaging (DTI). Our findings revealed that the two training protocols induced similar effects on the diffusion MRI metrics. Further, in the TBI groups who received training microstructural organization in the hippocampus and cingulum improved (as denoted by increases in fractional anisotropy), while a worsening (i.e., increases in mean diffusivity and radial diffusivity) was found in the TBI control group. In addition, these alterations in diffusion MRI metrics coincided with improved performance on the training tasks in the TBI groups who received training. Our findings show the potential of DTI metrics as reliable measure to evaluate cognitive training in TBI patients and to facilitate future research investigating further improvement of cognitive training targeting deficits in spatial memory and attention. ",0
6940,31407251,"Carbamazepine, a Histone Deacetylase Inhibitor Induces Apoptosis in Human Colon Adenocarcinoma Cell Line HT-29",Colon cancer ranks fourth and is responsible for causing 10% cancer-related mortality in western countries. Its incidence is rising in many countries due to widespread adoption of the Western diet and lifestyle. Carbamazepine (CBZ) is a FDA-approved antiepileptic drug and a histone deacetylase inhibitor. The aim of this study is to evaluate the cytotoxic potentials of CBZ in human colon cancer cells (HT-29 cells). HT-29 cells were treated with 36 and 76 μg/ml of CBZ for 24 h. The cytotoxic effect was evaluated by MTT assay. The intracellular reactive oxygen species (ROS) expression was evaluated through dichloro-dihydro-fluorescein diacetate staining. Morphological changes related to apoptosis were evaluated by dual staining with acridine orange and ethidium bromide. Mitochondrial membrane potential was evaluated by rhodamine 123 staining. Immunofluorescence analysis of caspase 3 was done with confocal microscopy. CBZ caused significant cytotoxicity in HT-29 cells and the effect was concentration dependent. CBZ treatments also caused significant expression of ROS in HT-29 cells. Dual staining showed early and late apoptotic cells and morphological alterations induced by the CBZ. Confocal microscopic studies confirmed the increased caspase 3 expression in CBZ-treated cells. CBZ induced apoptosis in HT-29 cell through ROS generation and caspase 3 expression and these results pave the way for further in vivo studies. ,0
6941,31407399,Regulation of the firing activity by PKA-PKC-Src family kinases in cultured neurons of hypothalamic arcuate nucleus,"The cAMP-dependent protein kinase A family (PKAs), protein kinase C family (PKCs), and Src family kinases (SFKs) are found to play important roles in pain hypersensitivity. However, more detailed investigations are still needed in order to understand the mechanisms underlying the actions of PKAs, PKCs, and SFKs. Neurons in the hypothalamic arcuate nucleus (ARC) are found to be involved in the regulation of pain hypersensitivity. Here we report that the action potential (AP) firing activity of ARC neurons in culture was up-regulated by application of the adenylate cyclase activator forskolin or the PKC activator PMA, and that the forskolin or PMA application-induced up-regulation of AP firing activity could be blocked by pre-application of the SFK inhibitor PP2. SFK activation also up-regulated the AP firing activity and this effect could be prevented by pre-application of the inhibitors of PKCs, but not of PKAs. Furthermore, we identified that forskolin or PMA application caused increases in the phosphorylation not only in PKAs at T197 or PKCs at S660 and PKCα/βII at T638/641, but also in SFKs at Y416. The forskolin or PMA application-induced increase in the phosphorylation of PKAs or PKCs was not affected by pre-treatment with PP2. The regulations of the SFK and AP firing activities by PKCs were independent upon the translocation of either PKCα or PKCβII. Thus, it is demonstrated that PKAs may act as an upstream factor(s) to enhance SFKs while PKCs and SFKs interact reciprocally, and thereby up-regulate the AP firing activity in hypothalamic ARC neurons. ",0
6942,31407640,"Association between hours worked in paid employment and diet quality, frequency of eating out and consuming takeaways in the UK","To examine associations between hours worked and diet quality, frequency of eating out and consuming takeaways. Data were taken from the National Diet and Nutrition Survey (2008-2014). Associations between hours worked in paid employment and diet quality, assessed using the Diet Quality Index (DQI) and selected foods and nutrients, were tested using linear regression models. Associations between hours worked and frequency of eating out and consuming takeaways were tested using ordinal logistic regression models. All models were adjusted for sex, age, equivalised household income, household composition and household food role. UK. Adults (n 2154) aged 19-64 years in employment. Mean (95 % CI) hours worked per week was 36·1 (35·6, 36·6) and mean DQI score was 41·9 (41·2, 42·5) %. Hours worked was not associated with DQI score, frequency of eating out or consuming takeaways. Hours worked was positively associated with consuming red meat, processed meat and alcohol intake. Adults working more hours had lower intake of fibre but higher total fat and saturated fat intakes if they lived in households with children. Working hours may not be the main factor driving poor-quality diets among this sample of UK adults in employment. Focusing on consumption of foods prepared outside the household may not be the most efficient way to improve diet quality as effort is needed at all levels. Although it is unclear what is driving the differences in nutrient intakes according to household composition, they are important to consider when developing interventions to improve healthy eating. ",0
6943,31408101,Classification of Unmedicated Bipolar Disorder Using Whole-Brain Functional Activity and Connectivity: A Radiomics Analysis,"The aim of this study was to develop and validate a method of disease classification for bipolar disorder (BD) by functional activity and connectivity using radiomics analysis. Ninety patients with unmedicated BD II as well as 117 healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). A total of 4 types of 7018 features were extracted after preprocessing, including mean regional homogeneity (mReHo), mean amplitude of low-frequency fluctuation (mALFF), resting-state functional connectivity (RSFC), and voxel-mirrored homotopic connectivity (VMHC). Then, predictive features were selected by Mann-Whitney U test and removing variables with a high correlation. Least absolute shrinkage and selection operator (LASSO) method was further used to select features. At last, support vector machine (SVM) model was used to estimate the state of each subject based on the selected features after LASSO. Sixty-five features including 54 RSFCs, 7 mALFFs, 1 mReHo, and 3 VMHCs were selected. The accuracy and area under curve (AUC) of the SVM model built based on the 65 features is 87.3% and 0.919 in the training dataset, respectively, and the accuracy and AUC of this model validated in the validation dataset is 80.5% and 0.838, respectively. These findings demonstrate a valid radiomics approach by rs-fMRI can identify BD individuals from healthy controls with a high classification accuracy, providing the potential adjunctive approach to clinical diagnostic systems. ",0
6944,31408174,Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones,"The age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset. We sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones. Longitudinal observational study. In 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling. Mean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events. Hormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease. ",0
6945,31408289,Human Chorionic Gonadotropin monotherapy for the treatment of hypogonadal symptoms in men with total testosterone > 300 ng/dL,"The 2018 American Urological Association guidelines on the Evaluation and Management of Testosterone Deficiency recommended that 300 ng/dL be used as the threshold for prescribing testosterone replacement therapy (TRT). However, it is not uncommon for men to present with signs and symptoms of testosterone deficiency, despite having testosterone levels greater than 300 ng/dL. There exists scant literature regarding the use of hCG monotherapy for the treatment of hypogonadism in men not interested in fertility. We sought to evaluate serum testosterone response and duration of therapy of hCG monotherapy for men with symptoms of hypogonadism, but total testosterone levels > 300 ng/dL. We performed a multi-institutional retrospective case series of men receiving hCG monotherapy for symptomatic hypogonadism. We evaluated patient age, treatment indication, hCG dosage, past medical history, physical exam findings and serum testosterone and gonadotropins before and after therapy. Descriptive analysis was performed and Mann Whitney U Test was utilized for statistical analysis. Of the 20 men included in the study, treatment indications included low libido (45%), lack of energy (50%), and erectile dysfunction (45%). Mean testosterone improved by 49.9% from a baseline of 362 ng/dL (SD 158) to 519.8 ng/dL (SD 265.6), (p=0.006). Median duration of therapy was 8 months (SD 5 months). Fifty percent of patients reported symptom improvement. Treatment of hypogonadal symptoms with hCG for men who have a baseline testosterone level > 300 ng/dL appears to be safe and effi cacious with no adverse events. ",0
6946,31408505,Cost-effectiveness analysis of universal varicella vaccination in Turkey using a dynamic transmission model,"In 2013, Turkey introduced one-dose universal varicella vaccination (UVV) at 12 months of age. Inclusion of a second dose is being considered. We developed a dynamic transmission model to evaluate three vaccination strategies: single dose at 12 months (1D) or second dose at either 18 months (2D-short) or 6 years of age (2D-long). Costs and utilization were age-stratified and separated into inpatient and outpatient costs for varicella and herpes zoster (HZ). We ran the model including and excluding HZ-related costs and impact of exogenous boosting. Five years post-introduction of UVV (1D), the projected varicella incidence rate decreases from 1,674 cases pre-vaccine to 80 cases/100,000 person-years. By 25 years, varicella incidence equilibrates at 39, 12, and 16 cases/100,000 person-years for 1D, 2D-short, and 2D-long strategies, respectively, using a highly effective vaccine. With or without including exogenous boosting impact and/or HZ-related costs and health benefits, the 1D strategy is least costly, but 2-dose strategies are cost-effective considering a willingness-to-pay threshold equivalent to the gross domestic product. The model predicted a modest increase in HZ burden during the first 20-30 years, after which time HZ incidence equilibrates at a lower rate than pre-vaccine. Our findings support adding a second varicella vaccine dose in Turkey, as doing so is highly cost-effective across a wide range of assumptions regarding the burden associated with varicella and HZ disease. ",0
6947,31408570,Evaluation of structural changes and intracellular substance leakage of Escherichia coli O157:H7 induced by ohmic heating,"To investigate the effects of ohmic heating (OH) and water bath heating (WB) on the membrane permeability, membrane structure, intracellular organization and leakage of intracellular substances of Escherichia coli O157:H7 at the same inactivation level and at a heating temperature of 72°C. Flow cytometry analysis indicated that membrane permeability of E. coli O157:H7 by OH was comparable to WB at 72°C. Scanning electron microscopy analysis showed that the OH-treated E. coli O157:H7 had greater morphological changes than those of WB-treated ones both at the same inactivation level and the same heating temperature. Transmission electron microscopy analysis showed that both OH and WB caused severe damage on the intracellular organization of E. coli O157:H7 at 72°C. Moreover, OH-treated E. coli O157:H7 had more leakage of intracellular substances than those treated with WB due to the electroporation caused by OH. OH presents considerable potential in inactivation of E. coli O157:H7, especially OH at 10 V cm The nonthermal effect of OH had a greater effect on the cell membrane of E. coli O157:H7, resulting in more pores and more leakage of intracellular substances out of the E. coli O157:H7 cells. These results could promote the application of OH in food processing. ",0
6948,31408725,Opposing action of NCoR1 and PGC-1α in mitochondrial redox homeostasis,"The ability to respond to fluctuations of reactive oxygen species (ROS) within the cell is a central aspect of mammalian physiology. This dynamic process depends on the coordinated action of transcriptional factors to promote the expression of genes encoding for antioxidant enzymes. Here, we demonstrate that the transcriptional coregulators, PGC-1α and NCoR1, are essential mediators of mitochondrial redox homeostasis in skeletal muscle cells. Our findings reveal an antagonistic role of these coregulators in modulating mitochondrial antioxidant induction through Sod2 transcriptional control. Importantly, the activation of this mechanism by either PGC-1α overexpression or NCoR1 knockdown attenuates mitochondrial ROS levels and prevents cell death caused by lipid overload in skeletal muscle cells. The opposing actions of coactivators and corepressors, therefore, exert a commanding role over cellular antioxidant capacity. ",0
6949,31408745,Effectiveness of laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy for morbid obesity in achieving weight loss outcomes,"Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are commonly performed weight loss procedures worldwide. Unfortunately, few studies have compared percentage total weight loss (%TWL) following these procedures. This research compared short-term, mid-term and long-term %TWL by LRYGB and LSG. Selected databases were searched for original articles that compared %TWL by LSG and LRYGB. Review manager 5.3 was used for data analysis. Effect summary was presented by forest plot. A significantly better %TWL in 5 years was shown by LRYGB than LSG; pooled mean difference (MD) 1.87 (95% CI 0.27-3.48, z statistics = 2.28, p < 0.05). Subgroup analysis showed better %TWL by LRYGB than LSG at 24 months pooled MD 6.47 (95% CI 1.22-11.72, z statistics = 2.42, p < 0.05), however, better %TWL by LSG was noted after 36 months (pooled MD -0.23; 95% CI -0.39-0.06, z statistics = 2.65, p < 0.05). Finally, significantly better %TWL was noted for LRYGB at 60 months. This study shows %TWL of 70.4% by LRYGB and 59.8% following LSG in at least half of patients from selected cohort. A significantly greater %TWL by LRYGB in short and long term, while higher %TWL by LSG in mid-term is reported. ",0
6950,31409039,"Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes","The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis. ",0
6951,31409050,Challenges Facing the Detection of Colonic Polyps: What Can Deep Learning Do?,"""Colorectal cancer (CRC) is one of the most common causes of cancer mortality in the world. The incidence is related to increases with age and western dietary habits. Early detection through screening by colonoscopy has been proven to effectively reduce disease-related mortality. Currently, it is generally accepted that most colorectal cancers originate from adenomas. This is known as the """"adenoma-carcinoma sequence"""", and several studies have shown that early detection and removal of adenomas can effectively prevent the development of colorectal cancer. The other two pathways for CRC development are the Lynch syndrome pathway and the sessile serrated pathway. The adenoma detection rate is an established indicator of a colonoscopy's quality. A 1% increase in the adenoma detection rate has been associated with a 3% decrease in interval CRC incidence. However, several factors may affect the adenoma detection rate during a colonoscopy, and techniques to address these factors have been thoroughly discussed in the literature. Interestingly, despite the use of these techniques in colonoscopy training programs and the introduction of quality measures in colonoscopy, the adenoma detection rate varies widely. Considering these limitations, initiatives that use deep learning, particularly convolutional neural networks (CNNs), to detect cancerous lesions and colonic polyps have been introduced. The CNN architecture seems to offer several advantages in this field, including polyp classification, detection, and segmentation, polyp tracking, and an increase in the rate of accurate diagnosis. Given the challenges in the detection of colon cancer affecting the ascending (proximal) colon, which is more common in women aged over 65 years old and is responsible for the higher mortality of these patients, one of the questions that remains to be answered is whether CNNs can help to maximize the CRC detection rate in proximal versus distal colon in relation to a gender distribution. This review discusses the current challenges facing CRC screening and training programs, quality measures in colonoscopy, and the role of CNNs in increasing the detection rate of colonic polyps and early cancerous lesions. """,0
6952,31409425,"Effectiveness of a home-based re-injury prevention program on motor control, return to sport and recurrence rates after anterior cruciate ligament reconstruction: study protocol for a multicenter, single-blind, randomized controlled trial (PReP)","Although anterior cruciate ligament (ACL) tear-prevention programs may be effective in the (secondary) prevention of a subsequent ACL injury, little is known, yet, on their effectiveness and feasibility. This study assesses the effects and implementation capacity of a secondary preventive motor-control training (the Stop-X program) after ACL reconstruction. A multicenter, single-blind, randomized controlled, prospective, superiority, two-arm design is adopted. Subsequent patients (18-35 years) with primary arthroscopic unilateral ACL reconstruction with autologous hamstring graft are enrolled. Postoperative guideline rehabilitation plus Classic follow-up treatment and guideline rehabilitation plus the Stop-X intervention will be compared. The onset of the Stop-X program as part of the postoperative follow-up treatment is individualized and function based. The participants must be released for the training components. The endpoint is the unrestricted return to sport (RTS) decision. Before (where applicable) reconstruction and after the clearance for the intervention (aimed at 4-8 months post surgery) until the unrestricted RTS decision (but at least until 12 months post surgery), all outcomes will be assessed once a month. Each participant is consequently measured at least five times to a maximum of 12 times. Twelve, 18 and 24 months after the surgery, follow-up-measurements and recurrence monitoring will follow. The primary outcome assessement (normalized knee-separation distance at the Drop Jump Screening Test (DJST)) is followed by the functional secondary outcomes assessements. The latter consist of quality assessments during simple (combined) balance side, balance front and single-leg hops for distance. All hop/jump tests are self-administered and filmed from the frontal view (3-m distance). All videos are transferred using safe big content transfer and subsequently (and blinded) expertly video-rated. Secondary outcomes are questionnaires on patient-reported knee function, kinesiophobia, RTS after ACL injury and training/therapy volume (frequency - intensity - type and time). All questionnaires are completed online using the participants' pseudonym only. Group allocation is executed randomly. The training intervention (Stop-X arm) consists of self-administered home-based exercises. The exercises are step-wise graduated and follow wound healing and functional restoration criteria. The training frequency for both arms is scheduled to be three times per week, each time for a 30 min duration. The program follows current (secondary) prevention guidelines. Repeated measurements gain-score analyses using analyses of (co-)variance are performed for all outcomes. German Clinical Trials Register, identification number DRKS00015313 . Registered on 1 October 2018. ",0
6953,31409522,Perinatal outcomes in 521 gestations after fresh and frozen cycles: a secondary outcome of a randomized controlled trial comparing GnRH antagonist versus GnRH agonist protocols,"Are perinatal outcomes different after treatment with the gonadotrophin-releasing hormone (GnRH) antagonist versus the long GnRH agonist protocol for IVF? Perinatal outcomes were secondary outcomes in a large Phase IV, dual-centre, open-label, randomized controlled trial to compare GnRH antagonist and long GnRH agonist protocols in women <40 years undergoing their first assisted reproductive technology treatment. Women (n = 1050) were randomized in a ratio 1:1 from January 2009 to December 2013 and followed until December 2016. All fresh and frozen embryo transfer (FET) cycles from a single oocyte aspiration, resulting in a gestation (human chorionic gonadotrophin >10 IU/l) were included (n = 521). Data were analysed to compare preterm birth [PTB] (<37 weeks), very PTB (<32 weeks), low birthweight [LBW] (<2500 g) and very LBW (<1500 g) rates among singleton live births in GnRH antagonist versus agonist protocol. Similar perinatal outcomes were found after both protocols. In singletons after fresh embryo transfer, mean gestational age at delivery was 39.1 ± 2.49 versus 39.3 ± 1.90 (P = 0.67) and very PTB rates 1.9% versus 0% (P = 0.17). Mean birthweight was 3264 ± 662 g in the antagonist and 3341 ± 562 g in the agonist group (P = 0.37). LBW was found in 12.4% versus 7% (P = 0.19) and very LBW in 2.9% versus 1% (P = 0.34). In FET cycles, the perinatal outcomes were similar. Small for gestational age and large for gestational age rates were similar in both protocols for singleton live births after fresh and FET. Perinatal outcomes are similar after the GnRH antagonist versus GnRH agonist protocols for IVF. The choice of the GnRH analogue in ovarian stimulation should be based solely on optimizing the chance of pregnancy and not on risks in perinatal outcomes. ",0
6954,31409532,The effect of tranexamic acid on wound complications in primary total Hip Arthroplasty: A meta-analysis,"Allogeneic blood transfusion has been linked with an increase in the risk of surgical site infections (SSIs) through the mechanism of immunomodulation. However, no studies to date have investigated the direct relationship between blood conserving strategies including antifibrinolytics and wound complications after total hip arthroplasties (THA). A systematic review and meta-analysis of published randomised controlled trials (RCTs) to investigate the effect of tranexamic acid (TXA) on wound complications after THAs has been conducted. We identified 25 clinical trials which were suitable for detailed data extraction. There were no trials which utilised TXA in revision THA. All studies reported on wound complications including a total of 1608 patients. Using TXA led to a 2% reduction in the risk of developing wound complications compared to the control group with no significant statistical heterogeneity among the study groups (Risk Difference -0.02, 95%, confidence interval CI -0.04 to -0.00, P = 0.01, Heterogeneity I TXA reduced blood loss and transfusion rates after primary THA surgery. It also reduced wound complication rates but the clinical significance of this needs further investigation through well designed and adequately powered RCTs. ",0
6955,31409848,Transcriptomic Profiling of Adipose Derived Stem Cells Undergoing Osteogenesis by RNA-Seq,"Adipose-derived stromal/stem cells (ASCs) are multipotent in nature that can be differentiated into various cells lineages such as adipogenic, osteogenic, and chondrogenic. The commitment of a cell to differentiate into a particular lineage is regulated by the interplay between various intracellular pathways and their resultant secretome. Similarly, the interactions of cells with the extracellular matrix (ECM) and the ECM bound growth factors instigate several signal transducing events that ultimately determine ASC differentiation. In this study, RNA-sequencing (RNA-Seq) was performed to identify the transcriptome profile of osteogenic induced ASCs to understand the associated genotype changes. Gene ontology (GO) functional annotations analysis using Database for Annotation Visualization and Integrated Discovery (DAVID) bioinformatics resources on the differentially expressed genes demonstrated the enrichment of pathways mainly associated with ECM organization and angiogenesis. We, therefore, studied the expression of genes coding for matrisome proteins (glycoproteins, collagens, proteoglycans, ECM-affiliated, regulators, and secreted factors) and ECM remodeling enzymes (MMPs, integrins, ADAMTSs) and the expression of angiogenic markers during the osteogenesis of ASCs. The upregulation of several pro-angiogenic ELR+ chemokines and other angiogenic inducers during osteogenesis indicates the potential role of the secretome from differentiating ASCs in the vascular development and its integration with the bone tissue. Furthermore, the increased expression of regulatory genes such as CTNNB1, TGBR2, JUN, FOS, GLI3, and MAPK3 involved in the WNT, TGF-β, JNK, HedgeHog and ERK1/2 pathways suggests the regulation of osteogenesis through interplay between these pathways. The RNA-Seq data was also validated by performing QPCR on selected up- and down-regulated genes (COL10A1, COL11A1, FBLN, FERMT1, FN1, FOXF1, LAMA3, LAMA4, LAMB1, IGF1, WNT10B, MMP1, MMP3, MMP16, ADAMTS6, and ADAMTS14). ",0
6956,31409963,Results of switchback from ranibizumab to aflibercept in patients with exudative age-related macular degeneration,"Intravitreal injection of anti-VEGF drugs has become standard therapy for patients with exudative age-related macular degeneration (AMD). However, some patients do not exhibit sufficient response to the drugs for suppression of choroidal neovascularization activity. We investigated the efficacy of switchback from ranibizumab to aflibercept in patients with AMD who could not achieve further benefit beyond initial therapy of aflibercept injection. Eleven eyes of eleven patients were included in this study. Two patients were nonresponders, and nine exhibited tachyphylaxis to aflibercept. All patients received three monthly injections of ranibizumab as an initial phase of switching and received aflibercept as a switchback drug. We investigated changes in injection interval, visual acuity, and central retinal thickness. In four patients (36.4%), injection interval was extended. The interval was 6.73 weeks before switch and 9.27 weeks after switchback ( A switchback from ranibizumab to aflibercept may be beneficial in some patients with AMD who exhibit tachyphylaxis to aflibercept. ",0
6957,31410296,Analysis of Dexmedetomidine on the Quality of Awakening During Neurosurgery,"Dexmedetomidine has a dose-dependent sedative and analgesic effect. To further evaluate the wake-up quality of dexmedetomidine in patients undergoing neurosurgery, a meta-analysis of dexmedetomidine in a randomized controlled trial of general anesthesia was performed. Firstly, an experimental algorithm was proposed, and then the data fusion algorithm was used to conduct randomized controlled trials. The clinical efficacy and safety of dexmedetomidine in the acupuncture of neurosurgical patients were evaluated one by one for quality evaluation and data extraction. The effect of different input variables on the depth of anesthesia was studied by using a multi-data fusion approach. The results show that the data fusion algorithm proposed can effectively connect redundant information and complementary information in multiple data, and estimate the real parameters of the measured object. In addition, data fusion brings great convenience to the design of control algorithms and controllers, and provides an effective basis for system simplification. Experiments have shown that dexmedetomidine is effective and safe in the operation of neurosurgical motor function, and the management of the recovery period is safe and effective. Based on the research, it can provide some reference for the awakening of patients undergoing neurosurgery, and promote the progress and development of medicine. ",0
6958,31410417,Controlled synthesis of PEGylated surface protein-imprinted nanoparticles,"High recognition selectivity has been the main object in developing protein-imprinted materials. Here, we demonstrate a novel strategy for the controlled synthesis of PEGylated surface protein-imprinted nanoparticles with reduced nonspecific binding, which is based on sequential two steps of surface-initiated reversible addition-fragmentation chain transfer aqueous precipitation polymerization (SI-RAFT APP). Click chemistry was employed to construct hydrophilic nanocores with both high-density RAFT chain transfer agents and template-capturing groups. Through the first-step SI-RAFT APP, protein-imprinted nanoshells were formed over the nanocores using lysozyme as a model template. By the second-step SI-RAFT APP, nonlinear PEG chains were grafted from the core-shell imprinted nanoparticles before the removal of the template. Both the thickness of the imprinted nanoshells and the length of the grafted chains could be readily controlled by the polymerization time. Thus the obtained PEGylated core-shell particles exhibited greatly improved template binding selectivity compared with the non-PEGylated controls, typically with the imprinting factor increasing from 2.1 to 9.1. Meanwhile, the PEGylation process did not impair but significantly enhance the protein binding capacity. The generality of the established approach was preliminarily proved by imprinting another template protein, bovine hemoglobin. This work represents the first example for the controlled synthesis and post-imprinting functionalization of surface protein-imprinted nanoparticles via SI-RAFT polymerization. ",0
6959,31410923,The effect of knowledge and health beliefs about colorectal cancer on screening behaviour,"To determine the effect of the knowledge and health beliefs of individuals about colorectal cancer on their screening behaviour. Colorectal cancer ranks third among the most common cancers both worldwide and in Turkey. Colorectal cancer plays an important role in cancer mortality but can be prevented by promoting healthy behaviour and participation in early screening programmes. This descriptive study was completed with 114 women and 121 men. The study data were collected using the 'Data collection form' and 'Health Belief Model Scale for Protection from Colorectal Cancer'. Potential risk factors were investigated using logistic regression analyses. The AGREE checklist was completed. The colorectal cancer screening tests were known by 23.0% of the subjects and 17% had undergone one of these tests. The score medians obtained from the confidence-benefit subscale of Health Belief Model Scale for Protection from Colorectal Cancer were found to be significantly higher in those who had undergone colorectal cancer screening. Logistic regression analysis revealed that having knowledge of the relevant tests was associated with undergoing colorectal cancer screening. Having knowledge on colorectal cancer screening tests increases the relevant confidence-benefit perception regarding the tests and the behaviour of participating in screening programmes. Regular training on colorectal cancer and early diagnosis should therefore be provided by healthcare professionals to both women and men aged 50-70 years to increase the rate of undergoing early screening tests. Increasing the rate of early screening is among the responsibilities of health workers working in primary health centres. Therefore, problems that prevent individuals from participating in these programmes need to be identified. In this way, health workers will develop suggestions and initiatives that change the individual's health beliefs and increase motivation. ",0
6960,31411376,Effect of Meal Acceptability on Postprandial Appetite Scores and Hormones of Male Participants with Varied Adiposity,"This study portrays the effect of hedonic manipulation (high acceptability [HA] vs. low acceptability [LA]) on postprandial hormones and appetite scores in healthy males. Thirty participants (15 with normal weight and 15 with obesity) were recruited for a randomized, crossover design. They were randomly assigned to the HA or LA (with acesulfame-K) custard. Blood samples were drawn before the meals and for 4 hours after the meals and were analyzed for glucose, insulin, ghrelin, and glucagonlike peptide 1 (GLP-1). Appetite scores and subsequent energy intake were recorded. Postprandial glucose, insulin, and ghrelin were different according to adiposity, whereas meal acceptability did not correspond to any significant difference in postprandial glucose, insulin, ghrelin, and GLP-1 concentrations. Appetite scores showed lower hunger, higher satiety, and fullness after the HA meal without a significant difference between the meals. Subsequent energy intake, expressed as a percentage of the resting energy expenditure, was higher in participants with obesity but did not reflect postprandial hormones and appetite scores; there was no significant difference between meals. Hedonic properties and palatability do not affect gut hormones, mainly ghrelin and GLP-1. Moreover, their postprandial concentrations were not paralleled by similar changes in appetite scores, and both were not found to affect subsequent intake. ",0
6961,31411973,There Is No Way to Avoid Systematic Prostate Biopsies in Addition to Multiparametric Magnetic Resonance Imaging Targeted Biopsies,"Whether or not adding systematic biopsies (transrectal ultrasound-guided biopsy [TRUS-Bx]) to targeted cores in patients with a lesion detected at multiparametric magnetic resonance imaging (mpMRI) is still a debated topic. To identify patients who can avoid TRUS-Bx at the time of mpMRI targeted biopsy (MRI-TBx) relying on individual patient probability to harbour clinically significant prostate cancer (csPCa) outside the index lesion (IL). A total of 339 European and 441 North American patients underwent fusion MRI-TBx and concomitant TRUS-Bx at two tertiary care referral centres between 2013 and 2017. The study outcome was csPCa, defined as a Gleason score at biopsy of ≥7, outside the IL. Multivariable logistic regression analyses (MVAs) were performed to develop a predictive model for the study outcome. Multivariable-derived coefficients were used to develop a novel risk calculator in each cohort. The models were evaluated using the area under the curve (AUC), calibration plot, and decision-curve analyses. In the European cohort, csPCa detection rate was 55%. The csPCa detection rate for TRUS-Bx was 41%. At MVAs, prostate volume, previous negative biopsy, and Prostate Imaging Reporting and Data System versions 4 and 5 were independent predictors for the presence of csPCa outside the IL. The multivariable model had an AUC of 0.78. Omitting TRUS-Bx in patients with a calculated risk of <15% would have spared 16% of TRUS-Bx at the cost of missing 7% of csPCa. Similar findings were obtained when the same analyses were performed in the North American cohort. No net benefit was observed for low-threshold probabilities (<15%) of the each model relative to the standard of care (performing TRUS-Bx in addition to MRI-TBx to all patients) in both cohorts. The study is limited by its retrospective design. We failed to identify those patients who might safely benefit from MRI-TBx alone. The combination of MRI-TBx and TRUS-Bx should strongly be considered the best available approach. In the presence of positive multiparametric magnetic resonance imaging (mpMRI) of the prostate, physicians should always perform systematic sampling of the prostate in addition to mpMRI targeted biopsy. ",0
6962,31412001,Cost-effectiveness of Pembrolizumab as Second-line Therapy for the Treatment of Locally Advanced or Metastatic Urothelial Carcinoma in Sweden,"Urothelial carcinoma (UC) is the most common subtype of bladder cancer. The randomized phase 3 KEYNOTE-045 trial showed that pembrolizumab, used as second-line therapy significantly prolonged overall survival with fewer treatment-related adverse events than chemotherapy for advanced UC. Pembrolizumab has been approved by the European Medicines Agency for the treatment of locally advanced or metastatic UC in adults who have received platinum-containing chemotherapy. Many European countries use cost-effectiveness analysis to inform reimbursement decisions. To assess the cost-effectiveness of pembrolizumab as second-line therapy for the treatment of advanced UC from a Swedish health care perspective. We developed a partitioned-survival model to assess the costs and effectiveness of pembrolizumab compared with vinflunine (base case), paclitaxel, or docetaxel monotherapy in patients with advanced UC over a 15-yr time horizon. We obtained Kaplan-Meier estimates for survival endpoints, adverse events, and utility data from KEYNOTE-045. We performed parametric extrapolations to estimate overall and progression-free survival beyond the clinical trial period. Swedish costs and utility weights were used to estimate total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We performed deterministic and probabilistic sensitivity analyses to assess the robustness of the model results. In the base-case analysis, pembrolizumab resulted in a mean survival gain of 1.66 years (1.38 QALYs) at an incremental cost of €69852 and an ICER of €50529/QALY gained versus vinflunine monotherapy. ICERs for other chemotherapies were €81356/QALY for pembrolizumab versus paclitaxel or docetaxel monotherapy, and €71924/QALY for pembrolizumab versus paclitaxel, docetaxel, or vinflunine monotherapy. Long-term follow-up from KEYNOTE-045 and real-world data are needed to validate the extrapolations. The results indicate that pembrolizumab improves survival, increases QALYs, and is cost-effective as second-line therapy at a willingness-to-pay threshold of €100000/QALY for the treatment of advanced UC. To date, pembrolizumab is the only treatment associated with a significant overall survival benefit compared with chemotherapy in a randomized controlled trial as second-line therapy for advanced urothelial carcinoma. Our trial-based cost-effectiveness analysis suggests that pembrolizumab is a cost-effective option over chemotherapy in patients with advanced urothelial carcinoma after platinum-based therapy in Sweden. ",0
6963,31412091,Pain on the first postoperative day after tonsillectomy in adults: A comparison of metamizole versus etoricoxib as baseline analgesic,"To compare the effect of metamizole versus etoricoxib as baseline analgesic for treating postoperative pain after tonsillectomy. Single centre prospective cohort study. Two consecutive cohorts of tonsillectomy patients. 124 patients (n = 55 treated with etoricoxib, n = 69 with metamizole); median age 30.5 years; 50% women. Patients rated their pain on first postoperative day using the questionnaires of the German-wide project Quality Improvement in Postoperative Pain Treatment (QUIPS) including numeric rating scales (NRS, 0-10) for pain determination. The influence of preoperative and postoperative parameters on patients' pain was estimated by univariate and multivariate statistical analysis. The demographic parameters showed no differences between the patients in the metamizole group and the etoricoxib group (all p>0.05) with one exception: Patients in the metamizole group had significantly more preoperative pain than patients in the etoricoxib group (p = 0.001). The metamizole group had a mean postoperative pain in activity of 4.4 ± 2.1 and the etoricoxib group of 4.5 ± 2.2. Maximal pain for the metamizole group and the etoricoxib group were 5.6 ± 2.2 and 6.1 ± 1.9, respectively. Pain in activity, maximal pain and minimal pain were not different between both groups (p = 0.652, p = 0.113, p = 0.276, respectively). Patients of the etoricoxib group received more frequently piritramide in recovery room as demand medication (p = 0.046). In the whole cohort, patients with peritonsillar abscess had more preoperative pain in comparison to chronic tonsillitis (p<0.001). Patients under 30.5 years reported higher maximal pain than older patients (p = 0.049). On the other hand, a significant influence of patients' age on the pain in activity and minimal pain could not be demonstrated (p = 0.368, p = 0.508, respectively). Men reported lower minimal pain than women (p = 0.041). Also, patients with ASA status I had lower minimal pain than patients with higher ASA status (p = 0.019). The multivariate analysis did not show an association between postoperative pain in activity and preoperative counseling on postoperative pain management (p = 0.588, p = 0.174, respectively). Special preoperative counseling on postoperative pain management resulted in lower levels of maximal pain (p = 0.024). Linear regression demonstrated an independent association of higher pain in activity with higher mobility impairment (p = 0.034) and respiratory impairment (p = 0.002). The linear regression of minimal pain identified female gender (p = 0.005) as an independent influencing factor with higher pain levels. In terms of satisfaction, no preoperative pain therapy (p = 0.016) could be found as an independently significant influencing factor with higher satisfaction. Etoricoxib does not have an advantage as baseline analgesic for post tonsillectomy pain in comparison to metamizole. ",0
6964,31412806,The 2018 UK NHS Digital annual report on the Improving Access to Psychological Therapies programme: a brief commentary,"This commentary examines publicly available information on 2017-2018 outcomes in the UK government's Improving Access to Psychological Therapies (IAPT) programme, a National Health Service (NHS) primary care mental health programme in England. In that year there were 1.4 million referrals into IAPT and over 500,000 people completed a course of treatment. The IAPT database collects routine session-by-session outcome monitoring data for this population, including outcomes for depression and anxiety in a stepped care model which includes a range of psychological therapies, among them Cognitive Behavioural Therapy (CBT) and Person-centred Experiential Therapy, known in the IAPT programme as Counselling for Depression (CfD).In 2017-18, 32% of all referrals were for anxiety and stress disorders, 26% for depression, and 35% were unspecified. The definition of treatment completion is receipt of 2 sessions or more and on this basis 60% of all referrals in 2017-18 did not complete treatment, predominantly because they failed to attend the initial appointment, or ended after only one session. Four years of data on outcomes for CBT and CfD suggests these therapies are broadly comparable in terms of both recovery rate and average number of sessions, though the number of referrals to each therapy varied widely. Data on treatment choice and satisfaction was favourable but there were issues with low return rates and invalid data. Information on outcomes for ethnicity, sexual orientation, disability and religion, as well as a measure of local economic deprivation, indicate lower outcomes for a number of patient groups. Data on employment status outcomes suggest little overall change, including for the category of those on benefits payments.The data published alongside the annual IAPT reports mean there is an increasing amount of information in the public domain about IAPT performance, but it is time consuming to extract and evaluate. This report highlights a number of points of concern which suggest the need for improvement on multiple axes. We suggest that improved researcher access to the huge IAPT dataset can allow for more detailed evaluations of IAPT that can inform policy/decision-making to improve outcomes for clients. ",0
6965,31412840,Psychometric properties of fertility desire scale (FDS) developed for Iranian parents,"Fertility choice is a critical women's right. Although researchers have studied the positive effects of fertility desire, its different components have, unfortunately, been neither established nor implemented for parents. A reliable and valid scale is required to measure this vital aspiration of a couple. This study aims to develop and evaluate the psychometric properties of the Fertility Desire Scale (FDS), which is designed to assess fertility desire among Iranian parents. A multi-phase instrument developmental approach was used to develop this scale in 2017. The items for the questionnaire were generated using three approaches: a qualitative study, an interview with an expert panel, and a comprehensive literature review. To provide a draft form of the questionnaire, we performed face and content validity analyses. The questionnaire validation was conducted on a sample of married women and men, recruited from public places affiliated with the Mazandaran province. Finally, measurement and analyses of exploratory and confirmatory factors, internal consistency reliability, item-scale correlation, and test-retest reliability of the questionnaire were performed to complete the validation process. Thirty-five items were initially developed on the basis of the interviews with the expert panel and the literature review. The questionnaire was subsequently reduced to include 27 items after performing the content and face validity testing. The exploratory factor analysis (EFA) identified four factors (positive childbearing motivations, preferences, childbearing worries, and social beliefs) comprising 19 items that jointly accounted for 55.44% of the observed variance. The confirmatory factor analysis (CFA) also revealed the suitable model fit for the data. The Cronbach's alpha coefficient for the subscales ranged from .83 to .86, and the intraclass correlation coefficient (ICC) ranged from .88 to .92; these coefficients are well above the acceptable thresholds. Results from this validation study demonstrated that the FDS is a valid and reliable questionnaire for measuring fertility desire that can be used in clinical practice, as well as in similar future studies. ",0
6966,31412861,Taking note: A qualitative study of implementing a scribing practice in team-based primary care clinics,"Though much is known about the benefits attributed to medical scribes documenting patient visits (e.g., reducing documentation time for the provider, increasing patient-care time, expanding the roles of licensed and non-licensed personnel), little attention has been paid to how care workers enact scribing as a part of their existing practice. The purpose of this study was to perform an ethnographic process evaluation of an innovative medical scribing practice with primary care teams in Veterans Health Administration (VHA) clinics across the United States. The aim of our study was to understand barriers and facilitators to implementing a scribing practice in primary care. At three to six months after medical scribing was introduced, we used semi-structured interviews and direct observations during site visits to five sites to describe the intervention, understand if the intervention was implemented as planned, and to record the experience of the teams who implemented the intervention. This manuscript only reports on semi-structured interview data collected from providers and scribes. Initial matrix analysis based on categories outlined in the evaluation plan informed subsequent deductive coding using the social-shaping theory Normalization Process Theory. Through illustrating the slow accumulation of interactions and knowledge that fostered cautious momentum of teams working to normalize scribing practice in VHA primary care clinics, we show how the practice had 1) an organizing effect, as it centered a shared goal (the creation of the note) between the provider, scribe, and patient, and 2) a generative effect, as it facilitated care workers developing relationships that were both interpersonally and inter-professionally valuable. Based on our findings, we suggest that a scribing practice emphasizes the complementarity of existing professional roles, which thus leverage the interactional possibilities already present in the primary care team. Scribing, as a skill, forged moments of interprofessional fit. Scribing, in practice, created opportunities for interpersonal connection. Our research suggests that individuals will notice different benefits to scribing based on their professional expectations and organizational roles related to documenting patient visits. ",0
6967,31412918,Inhibitor of apoptosis proteins are potential targets for treatment of granulosa cell tumors - implications from studies in KGN,"Granulosa cell tumors (GCTs) are derived from proliferating granulosa cells of the ovarian follicle. They are known for their late recurrence and most patients with an aggressive form die from their disease. There are no treatment options for this slowly proliferating tumor besides surgery and chemotherapy. In a number of tumors, analogs of the second mitochondria-derived activator of caspases (SMAC), alone or in combination with other molecules, such as TNFα, are evolving as new treatment options. SMAC mimetics block inhibitor of apoptosis proteins (IAPs), which bind caspases (e.g. XIAP), or activate the pro-survival NF-κB pathway (e.g. cIAP1/2). Expression of IAPs by GCTs is yet not fully elucidated but recently XIAP and its inhibition by SMAC mimetics in a combination therapy was described to induce apoptosis in a GCT cell line, KGN. We evaluated the expression of cIAP1 in GCTs and elucidated the effects of the SMAC mimetic BV-6 using KGN as a model. Employing immunohistochemistry, we observed cIAP1 expression in a tissue microarray (TMA) of 42 GCT samples. RT-PCR confirmed expression of cIAP1/2, as well as XIAP, in primary, patient-derived GCTs and in KGN. We therefore tested the ability of the bivalent SMAC mimetic BV-6, which is known to inhibit cIAP1/2 and XIAP, to induce cell death in KGN. A dose response study indicated an EC Taken together, the results show that BV-6 is able to induce apoptosis in KGN cells. This approach may therefore offer a promising therapeutic avenue to treat GCTs. ",0
6968,31413421,Effect of modified Soxhlet (Soxtec) and Folch extraction method selection on the total lipid determination of aged beef,"This study compared the modified Soxhlet (Soxtec) and Folch extraction methods for determining the total lipid or intramuscular fat (IMF) content of aged beef samples. Ageing periods tested were 0, 5, 8, 10 and 12 weeks during which samples were held in vacuo and at ~ 1.0 °C. Prior to solvent extraction, all samples were freeze-dried and ground. The Folch method was found to result in higher IMF values and therefore higher extraction efficiency when compared to the Soxtec. A linear relationship was evident between the two methods that described 80.9% of the variation between IMF values. An interaction between ageing period and extraction method was identified, although ageing period did not independently impact on averaged IMF findings. Based on these observations and reagent toxicity not being a limiting factor, it is recommended that the Folch extraction method be used to determine beef IMF, although it is acknowledged that the Soxtec method IMF results were strongly aligned with those found using the Folch extraction method and tended towards comparability for beef aged < 5 weeks. ",0
6969,31433921,Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy,"BACKGROUND: The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. METHODS: Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. RESULTS: CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P?=?0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death. CONCLUSIONS: The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.).",0
6970,31465556,A Bile Duct-on-a-Chip With Organ-Level Functions,"BACKGROUND AND AIMS: Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are frequently associated with damage to the barrier function of the biliary epithelium. Here, we report on a bile duct-on-a-chip that phenocopies not only the tubular architecture of the bile duct in three dimensions, but also its barrier functions. APPROACH AND RESULTS: We showed that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, that the permeability of the cholangiocyte monolayer was comparable to ex vivo measurements, and that cholangiocytes in the device were mechanosensitive (as demonstrated by changes in calcium flux under applied luminal flow). Permeability decreased significantly when cells formed a compact monolayer with cell densities comparable to those observed in vivo. This device enabled independent access to the apical and basolateral surfaces of the cholangiocyte channel, allowing proof-of-concept toxicity studies with the biliary toxin, biliatresone, and the bile acid, glycochenodeoxycholic acid. The cholangiocyte basolateral side was more vulnerable than the apical side to treatment with either agent, suggesting a protective adaptation of the apical surface that is normally exposed to bile. Further studies revealed a protective role of the cholangiocyte apical glycocalyx, wherein disruption of the glycocalyx with neuraminidase increased the permeability of the cholangiocyte monolayer after treatment with glycochenodeoxycholic acid. CONCLUSIONS: This bile duct-on-a-chip captured essential features of a simplified bile duct in structure and organ-level functions and represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.",0
6971,31475793,Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease,"BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P?=?0.01 for superiority). CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).",0
6972,31509667,CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia,"The safety of CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because CCR5-null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated CCR5 persisted for more than 19 months without gene editing-related adverse events. The percentage of CD4+ cells with CCR5 ablation increased by a small degree during a period of antiretroviral-therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR-edited HSPCs, the percentage of CCR5 disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. (Funded by the Beijing Municipal Science and Technology Commission and others; ClinicalTrials.gov number, NCT03164135.).",0
6973,31535726,Near-Infrared Spectroscopy Reveals Brain Hypoxia and Cerebrovascular Dysregulation in Primary Biliary Cholangitis,"BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease linked to symptoms including fatigue and altered mood/cognition, indicating that chronic liver inflammation associated with PBC can impact brain function. We employed near-infrared spectroscopy (NIRS), a noninvasive neuroimaging technique, to determine whether patients with PBC exhibit reduced cerebral oxygen saturation (StO(2) ) and altered patterns of microvascular cerebral blood perfusion and whether these alterations were associated with clinical phenotype. This observational case-control study was conducted at a tertiary hospital clinic (University of Calgary Liver Unit). APPROACH AND RESULTS: Thirteen female patients with noncirrhotic PBC, seven female patients with cirrhotic PBC, and 11 healthy female controls were recruited by physician referral and word of mouth, respectively. NIRS was used to measure cerebral hemoglobin and oxygen saturation. A wavelet phase coherence method was used to estimate the coherent frequency coupling of temporal changes in cerebral hemodynamics. The PBC group demonstrated significantly reduced cerebral StO(2) (P�=�0.01, d�=�0.84), indicating cerebral hypoxia, significantly increased cerebral deoxygenated hemoglobin concentration (P�<�0.01, d�=�0.86), and significantly reduced hemodynamic coherence in the low-frequency band (0.08-0.15 Hz) for oxygenated hemoglobin concentration (P�=�0.02, d�=�0.99) and total hemoglobin (tHb) concentration (P�=�0.02, d�=�0.50), indicating alterations in cerebrovascular activity. Complete biochemical response to ursodeoxycholic acid (UDCA) therapy in early patients with PBC was associated with increased cerebral tHb concentration and decreased hemodynamic coherence. CONCLUSIONS: Using NIRS, patients with PBC were found to have hypoxia, increased cerebral hemoglobin concentration, and altered cerebrovascular activity, which were reversed in part in UDCA responders. In addition, symptoms and quality-of-life measures did not correlate with brain hypoxia or cerebrovascular dysregulation in patients with PBC.",0
6974,31553835,Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma,"BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 ?g twice a day) was compared with adding salmeterol (50 ?g twice a day) and doubling the fluticasone (to 100 ?g twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P?=?0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P?=?0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P?=?0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).",0
6975,31778583,Endothelial Bone Morphogenetic Protein 2 (Bmp2) Knockout Exacerbates Hemochromatosis in Homeostatic Iron Regulator (Hfe) Knockout Mice but not Bmp6 Knockout Mice,"BACKGROUND AND AIMS: Bone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain. APPROACH AND RESULTS: We therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes. CONCLUSIONS: These data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.",0
6976,31804707,Economic and Health Care Burdens of Hepatitis Delta: A Study of Commercially Insured Adults in the United States,"BACKGROUND AND AIMS: The paucity of data regarding the extent of hepatitis delta virus (HDV) associated health care burden in the United States is an important obstacle to assessing the cost-effectiveness of potential intervention strategies. In this study, we characterized the health care use and cost burdens of HDV in the United States using real-world claims data. APPROACH AND RESULTS: We conducted a case-control study using the Truven Health MarketScan Commercial Claims databases from 2011-2014. A total of 2,727 HDV cases were matched 1:1 by sociodemographic characteristics and comorbidities to chronic hepatitis B virus (HBV) controls using propensity scores. The HDV group had significantly higher prevalence of substance abuse, sexually transmitted diseases, decompensated cirrhosis, cirrhosis, and hepatitis C virus compared to patients with chronic HBV. First HDV diagnosis was associated with significant increases in the total number of health care claims (25.61 vs. 28.99; P�<�0.0001) and total annual health care costs ($19,476 vs. $23,605; P�<�0.0001) compared with pre-HDV baseline. The case-control analysis similarly indicated higher total claims (28.99 vs. 25.19; P�<�0.0001) and health care costs ($23,605 vs. $18,228; P�<�0.0001) in HDV compared with HBV alone. Compared with HBV controls, HDV cases had an adjusted incident rate ratio of 1.16 (95% confidence interval: 1.10, 1.22) times the total number of annual claims and an adjusted incident rate ratio 1.32 (95% confidence interval 1.17, 1.48) times the total annual health care cost. CONCLUSIONS: HDV is associated with higher health care use and cost burden than HBV alone, underscoring the need for improved screening and treatment.",0
6977,31907954,Applying Machine Learning in Liver Disease and Transplantation: A Comprehensive Review,"Machine learning (ML) utilizes artificial intelligence to generate predictive models efficiently and more effectively than conventional methods through detection of hidden patterns within large data sets. With this in mind, there are several areas within hepatology where these methods can be applied. In this review, we examine the literature pertaining to machine learning in hepatology and liver transplant medicine. We provide an overview of the strengths and limitations of ML tools and their potential applications to both clinical and molecular data in hepatology. ML has been applied to various types of data in liver disease research, including clinical, demographic, molecular, radiological, and pathological data. We anticipate that use of ML tools to generate predictive algorithms will change the face of clinical practice in hepatology and transplantation. This review will provide readers with the opportunity to learn about the ML tools available and potential applications to questions of interest in hepatology.",0
6978,31940700,Suicide,"Throughout the world, approximately 800,000 people die by suicide every year, accounting for 1.5% of all deaths. Suicide is the 10th leading cause of death in North America and the foremost cause of death worldwide among persons 15 to 24 years of age.",0
6979,31950520,Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging,"BACKGROUND AND AIMS: Older patients with obesity/type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; however, their link to NASH has not been explored. APPROACH AND RESULTS: Shc expression increased in livers of older patients with NASH, as assessed by real time quantitative PCR (RT-qPCR) or western blots. Fibrosis, Shc expression, markers of senescence, and nicotinamide adenine dinucleotide phosphate, reduced form oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice, lentiviral (LV)-short hairpin Shc versus control-LV were used during FFD. For hepatocyte-specific effects, floxed (fl/fl) Shc mice on FFD were injected with adeno-associated virus 8-thyroxine-binding globulin-Cre-recombinase versus control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation, and fibrosis. To study NOX2 activation, the interaction of p47(phox) (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation and coimmunoprecipitations. Palmitate-induced p52Shc binding to p47(phox) , activating the NOX2 complex, more so at an older age. Kinetics of binding were assessed in Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) domain deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47(phox) interaction using RosettaDock was generated. CONCLUSIONS: Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47(phox) subunit that results in redox stress and accelerated fibrosis in the aged.",0
6980,31978945,"A Novel Coronavirus from Patients with Pneumonia in China, 2019","In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).",0
6981,31990985,The Histone Methyltransferase G9a Promotes Cholangiocarcinogenesis Through Regulation of the Hippo Pathway Kinase LATS2 and YAP Signaling Pathway,"BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a highly malignant epithelial tumor of the biliary tree with poor prognosis. In the current study, we present evidence that the histone-lysine methyltransferase G9a is up-regulated in human CCA and that G9a enhances CCA cell growth and invasiveness through regulation of the Hippo pathway kinase large tumor suppressor 2 (LATS2) and yes-associated protein (YAP) signaling pathway. APPROACH AND RESULTS: Kaplan-Meier survival analysis revealed that high G9a expression is associated with poor prognosis of CCA patients. In experimental systems, depletion of G9a by small interfering RNA/short hairpin RNA or inhibition of G9a by specific pharmacological inhibitors (UNC0642 and UNC0631) significantly inhibited human CCA cell growth in vitro and in severe combined immunodeficient mice. Increased G9a expression was also observed in mouse CCA induced by hydrodynamic tail vein injection of notch intracellular domain (NICD) and myr-Akt. Administration of the G9a inhibitor UNC0642 to NICD/Akt-injected mice reduced the growth of CCA, in vivo. These findings suggest that G9a inhibition may represent an effective therapeutic strategy for the treatment of CCA. Mechanistically, our data show that G9a-derived dimethylated H3K9 (H3K9me2) silenced the expression of the Hippo pathway kinase LATS2, and this effect led to subsequent activation of oncogenic YAP. Consequently, G9a depletion or inhibition reduced the level of H3K9me2 and restored the expression of LATS2 leading to YAP inhibition. CONCLUSIONS: Our findings provide evidence for an important role of G9a in cholangiocarcinogenesis through regulation of LATS2-YAP signaling and suggest that this pathway may represent a potential therapeutic target for CCA treatment.",0
6982,31997380,A Single-Cell Perspective of the Mammalian Liver in Health and Disease,"The liver contains heterogeneous cell types that exhibit distinct spatial, molecular, and functional properties. The cells in the liver communicate with each other via a network of ligands and receptors and undergo cell type-specific transcriptomic reprogramming in disease. The advance of single-cell genomics has provided a powerful tool for unraveling the complexity of liver cells in health and disease with unprecedented resolution. In this review, we discuss insights gained from the recent single-cell RNA sequencing studies that shed new light on the molecular nature of liver cell heterogeneity, intercellular crosstalk, and disease-associated reprogramming.",0
6983,32023372,Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction,"BACKGROUND: We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze. METHODS: In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children's sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D(3) per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D(3) per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups. RESULTS: There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance. CONCLUSIONS: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).",0
6984,32101664,Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation,"BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).",0
6985,32130814,"MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis","BACKGROUND: The use of 12-core systematic prostate biopsy is associated with diagnostic inaccuracy that contributes to both overdiagnosis and underdiagnosis of prostate cancer. Biopsies performed with magnetic resonance imaging (MRI) targeting may reduce the misclassification of prostate cancer in men with MRI-visible lesions. METHODS: Men with MRI-visible prostate lesions underwent both MRI-targeted and systematic biopsy. The primary outcome was cancer detection according to grade group (i.e., a clustering of Gleason grades). Grade group 1 refers to clinically insignificant disease; grade group 2 or higher, cancer with favorable intermediate risk or worse; and grade group 3 or higher, cancer with unfavorable intermediate risk or worse. Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens were recorded. Secondary outcomes were the detection of cancers of grade group 2 or higher and grade group 3 or higher, cancer detection stratified by previous biopsy status, and grade reclassification between biopsy and radical prostatectomy. RESULTS: A total of 2103 men underwent both biopsy methods; cancer was diagnosed in 1312 (62.4%) by a combination of the two methods (combined biopsy), and 404 (19.2%) underwent radical prostatectomy. Cancer detection rates on MRI-targeted biopsy were significantly lower than on systematic biopsy for grade group 1 cancers and significantly higher for grade groups 3 through 5 (P<0.01 for all comparisons). Combined biopsy led to cancer diagnoses in 208 more men (9.9%) than with either method alone and to upgrading to a higher grade group in 458 men (21.8%). However, if only MRI-target biopsies had been performed, 8.8% of clinically significant cancers (grade group ?3) would have been misclassified. Among the 404 men who underwent subsequent radical prostatectomy, combined biopsy was associated with the fewest upgrades to grade group 3 or higher on histopathological analysis of surgical specimens (3.5%), as compared with MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%). CONCLUSIONS: Among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. However, MRI-targeted biopsy alone underestimated the histologic grade of some tumors. After radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy. (Funded by the National Institutes of Health and others; Trio Study ClinicalTrials.gov number, NCT00102544.).",0
6986,32145089,Activation of the liver X receptor pathway inhibits HBV replication in primary human hepatocytes,"Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigens production upon agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7?-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with siRNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSION: We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly via sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting LXR pathway for the treatment of chronic HBV infection.",0
6987,32191342,The emergence of zoonotic rat hepatitis E virus infection,"We noted the identification of further rat hepatitis E virus (HEV) cases in humans in Hong Kong (1). This emergence, infection of a Canadian UN worker in Africa (2) and serological evidence of exposure in German foresters (3) and hospitalized Vietnamese patients (4), raises the question of how widespread rat HEV infection is globally.",0
6988,32222998,Regional differences in human biliary tissues and corresponding in vitro derived organoids,"BACKGROUND: Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (Extrahepatic Bile Ducts or EHBDs) or inside the liver (Intrahepatic bile ducts or IHBDs). These organoids share many characteristics including the expression of cholangiocyte markers such as KRT19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown. METHODS/RESULTS: Organoids were derived from human gallbladder, common bile duct, pancreatic duct and intrahepatic bile ducts using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers LGR5/PROM1 and ductal markers KRT19/KRT7. However, RNA-sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, downregulation of biliary markers and upregulation of cell cycle genes was observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling and only IHBD were able to express a low-level of hepatocyte markers under differentiation conditions. CONCLUSIONS: Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify new targets for therapeutic development.",0
6989,32242357,Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes,"BACKGROUND: Efforts to prevent Clostridioides difficile infection continue to expand across the health care spectrum in the United States. Whether these efforts are reducing the national burden of C. difficile infection is unclear. METHODS: The Emerging Infections Program identified cases of C. difficile infection (stool specimens positive for C. difficile in a person ?1 year of age with no positive test in the previous 8 weeks) in 10 U.S. sites. We used case and census sampling weights to estimate the national burden of C. difficile infection, first recurrences, hospitalizations, and in-hospital deaths from 2011 through 2017. Health care-associated infections were defined as those with onset in a health care facility or associated with recent admission to a health care facility; all others were classified as community-associated infections. For trend analyses, we used weighted random-intercept models with negative binomial distribution and logistic-regression models to adjust for the higher sensitivity of nucleic acid amplification tests (NAATs) as compared with other test types. RESULTS: The number of cases of C. difficile infection in the 10 U.S. sites was 15,461 in 2011 (10,177 health care-associated and 5284 community-associated cases) and 15,512 in 2017 (7973 health care-associated and 7539 community-associated cases). The estimated national burden of C. difficile infection was 476,400 cases (95% confidence interval [CI], 419,900 to 532,900) in 2011 and 462,100 cases (95% CI, 428,600 to 495,600) in 2017. With accounting for NAAT use, the adjusted estimate of the total burden of C. difficile infection decreased by 24% (95% CI, 6 to 36) from 2011 through 2017; the adjusted estimate of the national burden of health care-associated C. difficile infection decreased by 36% (95% CI, 24 to 54), whereas the adjusted estimate of the national burden of community-associated C. difficile infection was unchanged. The adjusted estimate of the burden of hospitalizations for C. difficile infection decreased by 24% (95% CI, 0 to 48), whereas the adjusted estimates of the burden of first recurrences and in-hospital deaths did not change significantly. CONCLUSIONS: The estimated national burden of C. difficile infection and associated hospitalizations decreased from 2011 through 2017, owing to a decline in health care-associated infections. (Funded by the Centers for Disease Control and Prevention.).",0
6990,32259305,E2F7 is a potent inhibitor of liver tumor growth in adult mice,"Upregulation of the E2F-dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F-dependent transcription. They are atypical in that they do not bind to dimerization partner (DP) proteins and are not controlled by pRb. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking. Here, we generated transgenic mice with doxycycline-controlled transcriptional activation of E2f7 and E2f8 and induce their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and to lesser extendE2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity and cell proliferation in DEN-induced liver tumors. CONCLUSION: Collectively, our findings demonstrate that atypical E2Fs can override cell-cycle entry and progression governed by other E2F-family members, and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.",0
6991,32281670,Adaptive Natural Killer Cell Functional Recovery in Hepatitis C Virus Cured Patients,"BACKGROUND AND AIMS: Current evidence suggests that dysfunctional natural killer (NK) cell responses during hepatitis C virus (HCV) infection can be restored after viral eradication with direct acting antivirals (DAAs). However, the fate of the recently described adaptive NK cell population, endowed with increased ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), during HCV infection is poorly defined, while no study has explored the effects of DAAs on this NK subset. APPROACH AND RESULTS: We performed multicolor flow cytometry to investigate CD57(+) Fc?RI?(neg) adaptive and Fc?RI?(pos) conventional NK cell phenotype and function before and after DAA treatment in 59 patients chronically infected with HCV, 39 with advanced liver fibrosis, and 20 with mild-moderate liver fibrosis. Moreover, bulk NK cell phenotype and function were analyzed after cytokine activation following contact with K562 target cells. The proportion of Fc?RI?(neg) NK cells in patients with HCV was associated with increased HCV load at baseline, and it was significantly reduced after treatment. Patients with an advanced fibrosis stage displayed increased NK cell activation and exhaustion markers that normalized after therapy. Of note, adaptive NK cells from patients with HCV were characterized by increased programmed death receptor 1 expression and reduced ADCC activity at baseline. DAA treatment restored ADCC ability and reduced programmed death receptor 1 expression. CONCLUSIONS: HCV profoundly affects the frequency, phenotype, and function of adaptive NK cells. DAA therapy restores a normal adaptive NK phenotype and enhances interferon-gamma production by this cell subset.",0
6992,32286709,Functional consequences of metabolic zonation in murine livers: New insights for an old story,"BACKGROUND & AIMS: Zone-dependent differences in the expression of metabolic enzymes along the porto-central axis of the acinus are a long-known feature of liver metabolism. A prominent example is the preferential localization of the enzyme glutamine synthetase in pericentral hepatocytes, where it converts potentially toxic ammonia to the valuable amino acid glutamine. However, with the exception of a few key regulatory enzymes, a comprehensive and quantitative assessment of zonal differences in the abundance of metabolic enzymes and much more importantly, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far. APPROACH & RESULTS: We addressed this problem by establishing a new method for the separation of periportal and pericentral hepatocytes that yields sufficiently pure fractions of both cell populations. Quantitative shotgun proteomics identified hundreds of differentially expressed enzymes in the two cell populations. We used zone-specific proteomics data for scaling of the maximal activities to generate portal and central instantiations of a comprehensive kinetic model of central hepatic metabolism (Hepatokin1). CONCLUSION: The model simulations revealed significant portal-to-central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids and detoxification.",0
6993,32289214,Spread of SARS-CoV-2 in the Icelandic Population,"BACKGROUND: During the current worldwide pandemic, coronavirus disease 2019 (Covid-19) was first diagnosed in Iceland at the end of February. However, data are limited on how SARS-CoV-2, the virus that causes Covid-19, enters and spreads in a population. METHODS: We targeted testing to persons living in Iceland who were at high risk for infection (mainly those who were symptomatic, had recently traveled to high-risk countries, or had contact with infected persons). We also carried out population screening using two strategies: issuing an open invitation to 10,797 persons and sending random invitations to 2283 persons. We sequenced SARS-CoV-2 from 643 samples. RESULTS: As of April 4, a total of 1221 of 9199 persons (13.3%) who were recruited for targeted testing had positive results for infection with SARS-CoV-2. Of those tested in the general population, 87 (0.8%) in the open-invitation screening and 13 (0.6%) in the random-population screening tested positive for the virus. In total, 6% of the population was screened. Most persons in the targeted-testing group who received positive tests early in the study had recently traveled internationally, in contrast to those who tested positive later in the study. Children under 10 years of age were less likely to receive a positive result than were persons 10 years of age or older, with percentages of 6.7% and 13.7%, respectively, for targeted testing; in the population screening, no child under 10 years of age had a positive result, as compared with 0.8% of those 10 years of age or older. Fewer females than males received positive results both in targeted testing (11.0% vs. 16.7%) and in population screening (0.6% vs. 0.9%). The haplotypes of the sequenced SARS-CoV-2 viruses were diverse and changed over time. The percentage of infected participants that was determined through population screening remained stable for the 20-day duration of screening. CONCLUSIONS: In a population-based study in Iceland, children under 10 years of age and females had a lower incidence of SARS-CoV-2 infection than adolescents or adults and males. The proportion of infected persons identified through population screening did not change substantially during the screening period, which was consistent with a beneficial effect of containment efforts. (Funded by deCODE Genetics-Amgen.).",0
6994,32298473,Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement,"BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19), the illness caused by the SARS-CoV-2 virus, is rapidly spreading throughout the world. Hospitals and healthcare providers are preparing for the anticipated surge in critically ill patients, but few are wholly equipped to manage this new disease. The goals of this document are to provide data on what is currently known about COVID-19, and how it may impact hepatologists and liver transplant providers and their patients. Our aim is to provide a template for the development of clinical recommendations and policies to mitigate the impact of the COVID-19 pandemic on liver patients and healthcare providers. APPROACH AND RESULTS: This article discusses what is known about COVID-19 with a focus on its impact on hepatologists, liver transplant providers, patients with liver disease, and liver transplant recipients. We provide clinicians with guidance for how to minimize the impact of the COVID-19 pandemic on their patients' care. CONCLUSIONS: The situation is evolving rapidly, and these recommendations will need to evolve as well. As we learn more about how the COVID-19 pandemic impacts the care of patients with liver disease, we will update the online document available at https://www.aasld.org/about-aasld/covid-19-and-liver.",0
6995,32304327,Molecular targets in cholangiocarcinoma,"Cholangiocarcinoma (CCA) encompasses a heterogeneous collection of malignancies for which diagnostic biomarkers are lacking and population screening is otherwise infeasible due its status as a rare disease. Coupled with high post-surgical recurrence rates among the minority of patients diagnosed at resectable stages, systemic clinical management will inevitably be required for the majority of CCA patients with recurrent and advanced disease. In this review, we discuss the therapeutic potential of different classes of molecular targets at various stages of development in CCA, including those targeted at the tumor epithelia (oncogenic, developmental, metabolic, epigenomic) and the tumor microenvironment (angiogenesis, checkpoint regulation). Further, we discuss the successes and failures of CCA targeted therapies, emphasizing key lessons learned that should pave the way for future molecular target evaluation in this uncommon yet bona fide target-rich disease.",0
6996,32374916,C(24) -Ceramide Drives Gallbladder Cancer Progression through Directly Targeting PIP4K2C to Facilitate mTOR Signaling Activation,"The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and novel therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with gallbladder cancer has not been investigated. In present study, we revealed aberrant gene expressions (e.g. SPTLC1 and CERS2) of de novo ceramide biosynthesis and length-specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy control, gallbladder stone and GBC patients identified C24-Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2 and its product C24-Ceramide were associated with tumor staging, distal metastasis and worse prognosis. In line with this, C(24) -Ceramide promoted GBC cell proliferation and migration in vitro and in vivo. Mechanistically, C24-Ceramide directly bound to PIP4K2C, a regulator of mTOR, to facilitate mTOR complex formation and activation. C6-Ceramide, an analogue of natural ceramide, competed with C24-Ceramide for PIP4K2C binding, thereby abrogating C24-Ceramide -mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6-Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells in vitro and in vivo, which was dependent on PIP4K2C. Conclusion: Our findings highlights the clinical relevance of ceramide metabolism with GBC progression, and identify C24-Ceramide as a novel diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6-Ceramide as potential therapeutic intervention for GBC through a direct competition with C24-Ceramide.",0
6997,32459923,FDA Initiative for Drug Facts Label for Over-the-Counter Naloxone,"""BACKGROUND: The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use. METHODS: In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval. RESULTS: The results for performance on six primary end points met or exceeded thresholds, including the steps """"Check for a suspected overdose"""" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and """"Give the first dose"""" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of """"Call 911 immediately,"""" but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of """"Check, give, and call 911 immediately"""" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9). CONCLUSIONS: Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales.""",0
6998,32484955,Reply Letter to: 20-0173.R1,"We appreciate the interest in our report and the comments in the correspondence from Drs. Kumar and Kulkarni who express concerns about SGLT2-inhibitors (SGLT2-I) being nothing more than loop diuretics and from Dr. Patoulias et al who express concerns about weight reduction with SGLT2-I being more due to fat loss, with volume loss being an only transient effect.",0
6999,32502295,Have the starting lineup of five for HBV cccDNA synthesis been identified?,"The persistence of covalently closed circular (ccc) DNA after a long-term therapy of viral DNA polymerase inhibitors attributes to their failure of curing chronic hepatitis B virus (HBV) infection. However, lack of knowledge on the molecular mechanism of cccDNA biosynthesis, metabolic stability and transcriptional regulation impedes the discovery of therapeutics for selective eradication or silencing of cccDNA minichromosomes.",0
7000,32516515,Telomere Dysfunction Activates p53 and Represses HNF4? Expression Leading to Impaired Human Hepatocyte Development and Function,"BACKGROUND AND AIMS: Telomere attrition is a major risk factor for end-stage liver disease. Due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in patients with telomere syndromes remain elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cells (hESCs) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol that resembles hepatocyte development in vivo. APPROACH AND RESULTS: Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-regulation, immediately after endoderm differentiation and completely absent in in vitro-derived hepatocytes, similar to what is observed in human primary hepatocytes. While endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction impaired hepatic endoderm formation. Consequently, hepatocyte derivation, as measured by expression of specific hepatic markers as well by albumin expression and secretion, is severely compromised in telomerase mutant cells with short telomeres. Interestingly, this phenotype was not caused by cell death induction or senescence. Rather, telomere shortening prevents the up-regulation and activation of human hepatocyte nuclear factor 4 alpha (HNF4?) in a p53-dependent manner. Both reactivation of telomerase and silencing of p53 rescued hepatocyte formation in telomerase mutants. Likewise, the conditional expression (doxycycline-controlled) of HNF4?, even in cells that retained short telomeres, accrued DNA damage, and exhibited p53 stabilization, successfully restored hepatocyte formation from hESCS. CONCLUSIONS: Our data show that telomere dysfunction acts as a major regulator of HNF4? during hepatocyte development, pointing to a target in the treatment of liver disease in telomere-syndrome patients.",0
7001,32557755,Letter to the Editor: Sodium-glucose cotransporter 2 inhibitors (SGLT2-I) ameliorate ascites and peripheral edema in patients with cirrhosis and diabetes,"We read with great interest the observations made by Montalvo-Gordon and colleagues regarding the potential of SGLT-2 inhibitors to ameliorate ascites and peripheral edema in patients with cirrhosis and concomitant type 2 diabetes mellitus (T2DM), serving also as an alternative treatment option in patients with diuretic-resistant or diuretic-intractable ascites. Interestingly, all 3 patients remained free of ascites and edema 12-26 months after diuretics' discontinuation, replaced by a SGLT-2 inhbitor.",0
7002,32558469,Systematic or Test-Guided Treatment for Tuberculosis in HIV-Infected Adults,"BACKGROUND: In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. METHODS: We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. RESULTS: A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment. CONCLUSIONS: Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. (Funded by the Agence Nationale de Recherches sur le Sida et les H�patites Virales; STATIS ANRS 12290 ClinicalTrials.gov number, NCT02057796.).",0
7003,32563203,Letter to Editor: Congenital extrahepatic portosystemic shunts (Abernethy malformation): A new variant,"We read with interest the article by Baiges et al [1] which shed light on the rare entity of Abernethy malformation and gives a working algorithm for extrahepatic shunts. We commend all the authors for the effort to put together a large series and have a follow-up up to the age of 30 years, missed by previous series.",0
7004,32623738,Hemostatic Changes of Acute Kidney Injury in Patients With Cirrhosis: What Do They Mean?,"Historically, patients with liver disease were considered to have a bleeding tendency that was a consequence of changes in their hemostatic system. An important consequence of this concept is the ever-ongoing policy of prophylactic blood product transfusion prior to invasive procedures aimed to reduce bleeding risk. However, it is increasingly acknowledged that although bleeding in patients with liver diseases can be the consequence of a (temporal) hypocoagulable state, it is frequently unrelated to hemostatic failure and rather caused by portal hypertension (e.g., variceal bleeding) or inadvertent laceration of a blood vessel (e.g., during liver biopsy or paracentesis).",0
7005,32654263,Intestinal Virome in Patients With Alcoholic Hepatitis,"BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.",0
7006,32687649,Letter to the Editor: Use of Pre-genomic HBV RNA and HBcrAg to Predict Cure of Hepatitis B Virus Infection,"I read with great interest the article by Carey and colleagues on the dynamics of pregenomic hepatitis B virus (HBV) RNA and hepatitis B core related antigen (HBcrAg) among patients on nucleos(t)ide analogue (NA) therapy(1). Both HBcrAg and HBV RNA are products of transcriptional activities of covalently closed circular DNA (cccDNA). Although HBcrAg is a test for 3 HBV proteins, it measures primarily hepatitis B core antigen in hepatitis B e antigen (HBeAg)-negative patients. Carey and colleagues reported that patients who developed severe flare after stopping NA tend to have detectable and higher HBV RNA and HBcrAg levels than those who have milder flares.",0
7007,32692457,Next-generation immunosequencing reveals pathological T cell architecture in autoimmune hepatitis,"BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease that regularly relapses when immunosuppression is tapered. It is thought to be driven by T cells while the etiologic impact of an apparently deregulated B lineage system, as evidenced by hypergammaglobulinemia and autoantibodies, remains elusive. We set out to investigate T and B cell repertoires supporting chronic inflammation in AIH. APPROACH & RESULTS: T and B cell receptor (TCR/BCR) repertoire and HLA next-generation sequencing were used to record immune signatures from a cohort of 60 AIH patients and disease controls. Blood and liver B lineage immune metrics were not indicative of a dominant directional antigen selection apart from a slight skewing of IGHV-J genes. More importantly, we found strong AIH-specific TRBV-J skewing not attributable to the HLA-DRB1-specificities of the cohort. This TCR repertoire bias was generated as a result of peripheral T cell (de)selection and persisted in disease remission. Using a clustering algorithm according to antigenic specificity, we identified liver TCR clusters that were shared between patients with AIH but were absent or deselected in patients with other liver pathologies. CONCLUSIONS: AIH patients show profound and persisting T cell architectural changes that may explain high relapse rates after tapering immunosuppression. Liver T cell clusters shared between patients may mediate liver damage and warrant further study.",0
7008,32706533,Duodenal Microbiota in Stunted Undernourished Children with Enteropathy,"BACKGROUND: Environmental enteric dysfunction (EED) is an enigmatic disorder of the small intestine that is postulated to play a role in childhood undernutrition, a pressing global health problem. Defining the incidence of this disorder, its pathophysiological features, and its contribution to impaired linear and ponderal growth has been hampered by the difficulty in directly sampling the small intestinal mucosa and microbial community (microbiota). METHODS: In this study, among 110 young children (mean age, 18 months) with linear growth stunting who were living in an urban slum in Dhaka, Bangladesh, and had not benefited from a nutritional intervention, we performed endoscopy in 80 children who had biopsy-confirmed EED and available plasma and duodenal samples. We quantified the levels of 4077 plasma proteins and 2619 proteins in duodenal biopsy samples obtained from these children. The levels of bacterial strains in microbiota recovered from duodenal aspirate from each child were determined with the use of culture-independent methods. In addition, we obtained 21 plasma samples and 27 fecal samples from age-matched healthy children living in the same area. Young germ-free mice that had been fed a Bangladeshi diet were colonized with bacterial strains cultured from the duodenal aspirates. RESULTS: Of the bacterial strains that were obtained from the children, the absolute levels of a shared group of 14 taxa (which are not typically classified as enteropathogens) were negatively correlated with linear growth (length-for-age z score, r?=?-0.49; P?=?0.003) and positively correlated with duodenal proteins involved in immunoinflammatory responses. The representation of these 14 duodenal taxa in fecal microbiota was significantly different from that in samples obtained from healthy children (P<0.001 by permutational multivariate analysis of variance). Enteropathy of the small intestine developed in gnotobiotic mice that had been colonized with cultured duodenal strains obtained from children with EED. CONCLUSIONS: These results provide support for a causal relationship between growth stunting and components of the small intestinal microbiota and enteropathy and offer a rationale for developing therapies that target these microbial contributions to EED. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02812615.).",0
7009,32722908,Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates,"BACKGROUND: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. METHODS: Nonhuman primates received 10 or 100 ?g of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. RESULTS: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID(50)) geometric mean titers of 501 in the 10-?g dose group and 3481 in the 100-?g dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-?g dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. CONCLUSIONS: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.).",0
7010,32740969,Clinical Research in Hepatology in the COVID-19 Pandemic and Post-Pandemic Era: Challenges and the Need for Innovation,"The SARS-CoV-2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C, and studying the natural history of many forms of chronic liver disease. NIH, foundation and industry funding has provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all non-essential research activities were halted when the pandemic started, forcing those involved in clinical research to re-think their research strategy, including a shift to COVID-19 research while endeavoring to maintain their pre-existing agenda. Strategies to maintain the integrity of ongoing studies, including patient follow up, safety assessments and continuation of investigation products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a re-vamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the pre-determined time frame and the need to re-program career path timelines. Real world databases, biomarker and long term follow up studies, and research involving special groups (children, the homeless and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research.",0
7011,32745283,IgG 4 Autoimmune hepatitis presenting as idiopathic hypereosinophilia syndrome,"Autoimmune Hepatitis (AIH) and Idiopathic Hypereosinophilia Syndrome (HES) are viewed as distinct diseases. Our patient presented with hepatic and serum IgG4+ plasma cell infiltration, in addition to a marked bone marrow and peripheral eosinophilia with colonic involvement, raising the diagnosis of IgG4-related disease (IgG4-RD) and HES. This is the first reported case of IgG4 - AIH presenting with HES, both of which resolved with immune suppressive therapy.",0
7012,32750152,"A novel circular RNA, circ-CCAC1, contributes to CCA progression, induces angiogenesis, and disrupts vascular endothelial barriers","Circular RNAs (circRNAs) and extracellular vesicles (EVs) are involved in various malignancies. We aimed to clarify the functions and mechanisms of dysregulated circRNAs in the cells and EVs of cholangiocarcinoma (CCA). CircRNA microarray was used to identify circRNA expression profiles in CCA tissues and bile-derived EVs. Cholangiocarcinoma-associated circular RNA 1 (circ-CCAC1) expression was measured by qRT-PCR. The clinical importance of circ-CCAC1 was analyzed by receiver operating characteristic curves, Fisher's exact test, Kaplan-Meier plots, and Cox regression model. The functions of circ-CCAC1 and exosomal circ-CCAC1 were explored in CCA cells and HUVECs, respectively. Different animal models were used to verify the in vitro results. RNA sequencing, bioinformatics, RNA immunoprecipitation, RNA pulldown, chromatin immunoprecipitation followed by sequencing, and luciferase reporter assays were used to determine the regulatory networks of circ-CCAC1 in CCA cells and HUVECs. Circ-CCAC1 levels were increased in cancerous bile-resident EVs and tissues. The diagnostic and prognostic values of circ-CCAC1 were identified in patients with CCA. For CCA cells, circ-CCAC1 increased cell progression by sponging miR-514a-5p to upregulate YY1. Meanwhile, YY1 directly bound to the promoter of CAMLG to activate its transcription. Moreover, circ-CCAC1 from CCA-derived EVs was transferred to endothelial monolayer cells, disrupting endothelial barrier integrity and inducing angiogenesis. Mechanistically, circ-CCAC1 increased cell leakiness by sequestering EZH2 in the cytoplasm, thus elevating SH3GL2 expression to reduce the levels of intercellular junction proteins. In vivo studies further showed that increased circ-CCAC1 levels in circulating EVs and cells accelerated both CCA tumorigenesis and metastasis. CONCLUSION: Circ-CCAC1 plays a vital role in CCA tumorigenesis and metastasis and may be an important biomarker/therapeutic target for CCA.",0
7013,32767793,The majority of patients with chronic HDV infection need better treatment options,"We read with interest the letter to the editor by Oynur et al., we agree that the substantial difference in the interferon (IFN) treatment duration between the two cohorts may have caused difference in some results.(1,2) As we have pointed out in the discussion section of our study, the median duration of 8.7 months was shorter than the currently recommended duration of at least 48 weeks according to guideline of European Association for the Study of the Liver (EASL).",0
7014,32767857,"""Letter to Editor: Response to Commentary """"Midodrine for Hepatic Hydrothorax""""""","We agree with Kulkarni et al on the potential role of splanchnic and peripheral vasoconstrictors in the treatment of HH. In our review (1), we summarize the sparse data on octreotide and terlipressin in HH management. However, there are currently no large studies or randomized trials on the use of these medications in HH, and evidence for their use is limited to case reports and case series. Most of the studies cited by Kulkarni et al examine these pharmacologic agents in the control of ascites, not HH per se.",0
7015,32772387,Reply to Letter to the Editor: Why serum HBV DNA has higher frequency of rtM204I/V mutation than serum HBV RNA in the same individual?,"We appreciate the interest in our publication from Dr. Liao who explained why serum HBV DNA has higher frequency of rtM204I/V mutation than serum HBV RNA in chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogs (NAs). Our study demonstrated that the emergence of serum HBV RNA rtM204I/V mutation was generally delayed compared to that of serum HBV DNA, and both of them would ultimately become nearly 100% mutant forms under continuous NA therapy.",0
7016,32780882,Esophageal Stenting as Bridge Therapy to Direct Intrahepatic Portocaval Shunt for Refractory Variceal Bleeding,"Variceal bleeding is the most severe complication of portal hypertension in patients with cirrhosis. Management of refractory variceal bleeding is a challenging but commonplace scenario, in which usual endoscopic therapies including variceal ligation and/or sclerotherapy are unsuccessful in controlling the bleed. Portosystemic shunt creation is one effective treatment in prevention of treatment failure and rebleeding. We present a unique case of refractory esophageal varices in which an esophageal stent was placed as a temporizing measure to stop bleeding prior to creation of an alternative portosystemic shunt.",0
7017,32794259,The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in Nonalcoholic Steatohepatitis,"BACKGROUND & AIMS: The composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. Here we report the effect of aldafermin, an analog of the gut hormone FGF19, versus placebo on the gut microbiota in a prospective, phase 2 study in patients with NASH. APPROACH & RESULTS: 176 patients with biopsy-confirmed NASH (NAS ?4), fibrosis (F1-F3 by NASH CRN criteria) and elevated liver fat content (?8% by MRI-PDFF) received 0.3 mg (n=23), 1 mg (n=49), 3 mg (n=49), 6 mg (n=28) aldafermin or placebo (n=27) for 12 weeks. Stool samples were collected on day 1 and week 12 and profiled using 16S rRNA gene sequencing; 122 patients had paired stool microbiome profiles at both day 1 and week 12. Overall, the state of the gut microbial community was distinctly stable in patients treated with aldafermin, with all major phyla and genera unaltered during therapy. Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile. CONCLUSIONS: Veillonella may be a bile acid-sensitive bacteria whose enrichment is enabled by aldafermin-mediated suppression of bile acid synthesis and in particular, decreases in toxic bile acids. This study provides an integrated analysis of gut microbiome, serum bile acid metabolome, imaging and histological measurements in clinical trials testing aldafermin for NASH. Our results reveal novel biology and provide better understanding of the intricacies of microbiome-host interactions.",0
7018,32813947,Evinacumab for Homozygous Familial Hypercholesterolemia,"BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).",0
7019,32865232,Reply to Letter to the Editors: Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy Allowing Liver Regeneration and Survival by Induction of H2-Bl/HLA-G,We would like to provide information that address the Letter to Editors submitted on 17 July 2020 by Lin and Yan regarding our publication.(1) We have provided a response to each point raised by the authors below.,0
7020,32905674,BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A,"BACKGROUND: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours � IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours � IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (?51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).",0
7021,32918286,Integrating Patient Reported Outcomes within Routine Hepatology Care: A Prompt to Action,"Chronic liver disease (CLD) and its complications account for significant morbidity and mortality worldwide. Traditionally, clinical measures such as histologic stage of fibrosis and MELD (Model for End Stage Liver Disease) scores are used as surrogates of clinical outcomes to inform medical care. In contrast, measures assessing patients' experience with their liver disease and its treatment (Patient Reported Outcomes/PROs) are rarely used in hepatology practices.",0
7022,32946672,Reproductive Health�and Liver Disease: Practice�Guidance by the American Association for the Study of Liver Diseases,"This first Practice Guidance on Reproductive Health from the American Association for the Study of Liver Diseases (AASLD) is intended to be a comprehensive reference on adolescents and adults with chronic liver disease. The Guidance specifically (1) addresses management of reproductive health�in women and men from puberty to senescence and (2) summarizes the natural history, risk factors, evaluation, and optimal management of liver diseases during pregnancy and after birth.",0
7023,32955740,DNA Methylation of CNRIP1 Promotes Pathogenesis of Intrahepatic Cholangiocarcinoma Through Suppressing Parkin-Dependent PKM2 Ubiquitination,"Methylation landscape is important for maintaining the silence of cannabinoid receptor-interacting protein 1 (CNRIP1) in some tumors. However, the role of CNRIP1 in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. In our study, we showed that CNRIP1 was down-regulated in ICC tissues and low expression of CNRIP1 was significantly associated with poor prognosis of ICC patients in 3-year overall survival (OS) and tumor-free survival (TFS). Investigating the genomic DNA methylation profile, we disclosed a novel CpG island site named CNRIP1 MS-2 (CNRIP1 methylation site-2) contributing to the down-regulation of CNRIP1. In addition, the methylation level of CNRIP1 MS-2 was correlated to the pathological grade, metastasis, and tumor-node-metastasis (TNM) classification in ICC. Notably, we observed that CNRIP1 suppressed tumor cell migration, invasion, and proliferation by inhibiting the activity of pyruvate kinase M2 (PKM2). The sustained overexpression of CNRIP1 suppressed the in vivo tumor growth in a mouse xenograft model. It was also found that CNRIP1 overexpression activated Parkin (a novel E3 ubiquitin [Ub] ligase), which resulted in the protein degradation of PKM2 in ICC cells. Conclusion: We identified that CNRIP1 acted as a putative tumor suppressor in ICC, which suggested that CNRIP1 could be a candidate biomarker for predicting tumor recurrence in ICC patients. Furthermore, these findings highlight a potential therapeutic approach in targeting the CNRIP1/Parkin/PKM2 pathway for the treatment of ICC.",0
7024,32978989,Oligonucleotide-Based Therapeutics: An Emerging Strategy for the Treatment of Chronic Liver Diseases,"Chronic liver disease is an important cause of morbidity and mortality in the United States. Despite significant advances, the treatment options for many chronic liver diseases are limited. Recently, oligonucleotide-based therapeutics emerged as a novel treatment approach for a number of liver diseases. Therapeutic oligonucleotides comprised of 15 to 30 nucleotides in length that work in complementary to a specific region of a messenger RNA (mRNA) encoding a disease-related protein or a regulatory non-coding RNA and interfere with the target gene expression. These oligonucleotides can bind with high affinity and specificity through RNA-RNA or RNA-DNA base-pairing and targets the expression of mRNA leading to the disease control. A large number of druggable targets including miR-122, miR-132, miR-34, HSP 47, PNPLA3, STK25 etc., have emerged as susceptible molecular targets in the liver to treat various diseases. Thus, chronic liver diseases may be treated effectively by modulating these susceptible molecular targets using novel therapeutic oligonucleotides. Currently, several preclinical and clinical studies are underway to evaluate the clinical effectiveness and safety of different oligonucleotide therapies in the treatment of chronic liver diseases. In order to optimize its clinical effectiveness, various strategies have been explored including chemical modifications of the oligonucleotides and developing effective drug delivery systems such as oligonucleotide -ligand conjugates, oligonucleotide-polymer conjugates, and lipid or polymer-based nano-carriers. In this review, we provide an overview of the historical perspectives, the mechanism of action, delivery technologies, and clinical experience of using oligonucleotide-based therapies in treating liver diseases.",0
7025,32997909,Physician Work Hours and the Gender Pay Gap - Evidence from Primary Care,"BACKGROUND: The gender gap in physician pay is often attributed in part to women working fewer hours than men, but evidence to date is limited by self-report and a lack of detail regarding clinical revenue and gender differences in practice style. METHODS: Using national all-payer claims and data from electronic health records, we conducted a cross-sectional analysis of 24.4 million primary care office visits in 2017 and performed comparisons between female and male physicians in the same practices. Our primary independent variable was physician gender; outcomes included visit revenue, visit counts, days worked, and observed visit time (interval between the initiation and the termination of a visit). We created multivariable regression models at the year, day, and visit level after adjustment for characteristics of the primary care physicians (PCPs), patients, and types of visit and for practice fixed effects. RESULTS: In 2017, female PCPs generated 10.9% less revenue from office visits than their male counterparts (-$39,143.2; 95% confidence interval [CI], -53,523.0 to -24,763.4) and conducted 10.8% fewer visits (-330.5 visits; 95% CI, -406.6 to -254.3) over 2.6% fewer clinical days (-5.3 days; 95% CI, -7.7 to -3.0), after adjustment for age, academic degree, specialty, and number of sessions worked per week, yet spent 2.6% more observed time in visits that year than their male counterparts (1201.3 minutes; 95% CI, 184.7 to 2218.0). Per visit, after adjustment for PCP, patient, and visit characteristics, female PCPs generated equal revenue but spent 15.7% more time with a patient (2.4 minutes; 95% CI, 2.1 to 2.6). These results were consistent in subgroup analyses according to the gender and health status of the patients and the type and complexity of the visits. CONCLUSIONS: Female PCPs generated less visit revenue than male colleagues in the same practices owing to a lower volume of visits, yet spent more time in direct patient care per visit, per day, and per year. (Funded in part by the Robert Wood Johnson Foundation.).",0
7026,33118625,Reply to Letter to the Editor: Use of pre-genomic HBV RNA and HBcrAg to predict cure of hepatitis B virus infection,"We thank Professor Chan for his interest in our paper(1). We agree that pgRNA and HBcrAg appear to be clinically informative markers of residual cccDNA transcriptional activity in HBeAg-negative patients receiving NA. As pointed out, we did not detect HBcrAg or pgRNA in serum in a minority of patients with detectable HBV DNA before therapy. PgRNA concentrations are lower than HBV DNA in treatment na?ve patients, which may explain this dichotomy.",0
7027,PubMedID,Title,Abstract,1
7028,17418,"Pharmacological properties of 2,3-dihydro-9H-isoxazolo [3,2-b] quinazolin-9-one (W-2429. Part 1: Analgesic, antipyretic and antiedema activity",,1
7029,21610,Hepatotoxicity of erythromycin estolate during pregnancy,"Women in the second half of pregnancy, who were infected with genital mycoplasmas and who gave written informed consent, were randomly assigned to receive capsules of identical appearance containing erythromycin estolate, clindamycin hydrochloride, or a placebo for 6 weeks. Levels of serum glutamic oxalacetic transaminase (SGOT) were determined before and during treatment by a fluorometric method. All pretreatment levels of SGOT were normal (<41 units). Participants who received erythromycin estolate had significantly more abnormally elevated levels of SGOT (16/161, 9.9%) than did those who received clindamycin (4/168, 2.4%, P < 0.01) or those who received placebo (3/165, 1.8%, P < 0.01). Elevated levels of SGOT ranged from 44 to 130 U. Serum bilirubin levels were normal. Gamma-glutamyl transpeptidase activity was abnormal in six of six participants who had abnormal levels of SGOT while receiving erythromycin estolate. There were few associated symptoms, and all levels of SGOT returned to normal after cessation of treatment. The treatment of pregnant women with erythromycin estolate may be inadvisable.",1
7030,25167,Loxapine: a review of its pharmacological properties and therapeutic efficacy as an antipsychotic agent,"Loxapine is a dibenzoxazepine, tricyclic compound recommended for the treatment of acute and chronic schizophrenia. In its therapeutic effectiveness and profile and incidence of side-effects, loxapine closely resembles the traditional antipsychotic agents. Although loxapine has tended to be less effective than some standard antipsychotic drugs in a few short-term (3 to 4 weeks) studies, it has been superior to a placebo and about as effective as chlorpromazine, haloperidol, trifluoperazine or thiothixene when evaluated after 4 to 12 weeks. Like the phenothiazine (e.g. chlorpromazine) and butyrophenone (e.g. haloperidol) antipsychotic agents, loxapine causes a high incidence of extrapyramidal reactions. Sedation occurs frequently, especially during early stages of treatment. Other, less common side-effects such as anticholinergic effects (dry mouth, blurred vision, etc.), hypotension, tachycardia and precipitation of epileptic seizures, which occur with the older antipsychotic drugs, have also been reported with loxapine.",1
7031,27155,Hypersensitivity to salicylazosulfapyridine: renal and hepatic toxic reactions,"Salicylazosulfapyridine has been used for a number of years as therapy for ulcerative colitis. Reported toxicities are usually minor. This case report represents an acute allergic reaction to the drug. Characterized by fever, rash, eosinophilia, nephritis, and hepatitis. Resolution occurred with discontinuation of salicylazosulfapyridine. Although similar reactions have been reported with the antimicrobial sulfonamides, none has been fully described with salicylazosulfapyridine, a combination of a sulfonamide and salicylate.",1
7032,28568,Granulomatous hepatitis associated with salicylazosulfapyridine therapy,"Granulomatous hepatitis has been associated with many conditions, including chronic ulcerative colitis and sulfonamide therapy. We report a patient with ulcerative colitis in whom hepatic granulomatosis was associated with salicylazosulfapyridine (Azulfidine). Sulfonamides should be considered a possible cause of hepatotoxicity when used therapeutically in inflammatory bowel disease.",1
7033,30045,Tricyclic antidepressants (first of two parts),,1
7034,31085,Azulfidine- (sulfasalazine-) induced hepatic injury,"A patient with Azulfidine-related hepatotoxicity in which prompt recurrence of symptoms, fever skin rash, and laboratory evidence of hepatocellular injury occurred upon readministration of Azulfidine is reported. The clinical and biochemical features support the fact that this was an example of an acquired hypersensitivity reaction to Azulfidine.",1
7035,43669,Hepatotoxicity of salicylazosulfapyridine: a case report and review of the literature,"A case report of a patient with biopsy-proven hepatitis which occurred while that patient was receiving Azulfidine which recurred after a rechallenge is presented. Toxic hepatitis, an apparent drug hypersensitivity reaction can result from Azulfidine therapy and must be considered in the differential diagnosis of hepatic abnormalities in patients with inflammatory bowel disease who are taking this drug. The literature concerning toxic reactions to the drug is reviewed.",1
7036,45581,Hypersensitivity reaction to sulfasalazine with severe hepatotoxicity,"Sulfasalazine hepatotoxicity has been poorly documented in the literature. We report a case of a young female with inflammatory bowel disease who developed severe hepatotoxicity as part of a systemic hypersensitivity reaction to sulfasalazine. The clinical, biochemical, and histopathological features resemble those of sulfonamide-induced hepatic injury. Although rare, our case as well as previous reports indicate the serious nature of the illness.",1
7037,47110,Letter: hepatoma associated with androgenic steroids,,1
7038,48362,Quinidine hepatitis,"Long-term administration of quinidine was associated with persistent elevation of serum concentrations of SGOT, lactic acid dehydrogenase, and alkaline phosphatase. Liver biopsy showed active hepatitis. Discontinuance of quinidine therapy led to normalization of liver function tests. A challenge dose of quinidine caused clinical symptoms and abrupt elevation of SGOT, alkaline phosphatase, and lactic acid dehydrogenase values. We concluded that this patient had quinidine hepatotoxicity and believe that this is the first case reported with liver biopsy documentation. This report also suggests that, even after long-term administration, the hepatic toxicity is reversible.",1
7039,48918,Letter: Toxicity of asparaginases,,1
7040,50605,Hepatic complications of antituberculous therapy,"Drug hepatitis occurred in 0-32 per cent of 7492 patients receiving antituberculous therapy, while the overall incidence of drug reactions was estimated at 9 per cent. PAS was the most common cause of drug hepatitis among the 38 patients analysed. The clinical, biochemical and haematological picture of antituberculous drug hepatitis was found to be fairly uniform. However, the patients with definite PAS hepatitis had lower SGOT values than those in whom there was uncertainty whether PAS or INH was implicated. Premonitory symptoms were present in all but four patients before the onset of jaundice. One or more of the features associated with dry hypersensitivity reactions, such as fever, rashes, lymphadenopathy, arthralgia, leucocytosis, eosinophilia and atypical monocytes were present in 89 per cent of cases so that confusion with viral hepatitis seldom arose. Sensitization time was less than three months in all except three patients, who were considered to be suffering from viral hepatitis. While no patients with PAS hepatitis died, the overall mortality was 17 per cent. A review of the literature stresses the frequency of asymptomatic elevations of SGOT, the value of clinical surveillance during the early months of therapy and the importance of stopping all therapy immediately warning symptoms appear.",1
7041,53401,Letter: Saralasin bolus test,,1
7042,54713,Letter: Immunoblactic lymphadenopathy associated with phenytoin (diphenylhydantoin),,1
7043,55736,Letter: Oral contraceptives and malignant hepatoma,,1
7044,57491,Letter: Renal autotransplantation in the treatment of renovascular hypertension,,1
7045,59509,The relation of HL-A antigens to liver histology in methotrexate-treated psoriatics,"A total of 45 patients with severe psoriasis vulgaris treated with Methylaminopterin NFN (Methotrexate Lederle) were HL-A typed in order to seek a possible correlation between HL-A antigens and the histological abnormalities in post-Methotrexate (MTX) liver biopsies. Highly significantly increased frequencies of w17 and TY (P less than 0.0001) were found, while HL-A13 Was only slightly increased. No statistically significant correlations were found between HL-A antigens and liver histology. HL-A typing does not seem to be of any predictive value in the pre-MTX screening of psoriatics in order to rule out patients with a high risk of liver damage during long-term MTX therapy.",1
7046,63711,Genetic factors in the development of chronic active hepatitis,"In 14 of 16 patients with chronic active hepatitis (C.A.H.) who did not have HLA antigens B8 and/or B12 an external triggering factor (drug or virus) could be demonstrated at onset of symptoms. In contrast external factors were involved in only 11 of 25 cases of C.A.H. in patients with HLA-B8 and/or B12. In the latter group antinuclear antibodies were less common in cases possible triggered by external agents compared with cases in which no such factor was demonstrated. The results suggest that there are at least two pathogenetically different types of C.A.H.---one genetically determined type in which no external factor is involved and in which autoimmune phenomena are common, and another type triggered by environmental agents and not involving predisposing genetic factors.",1
7047,63959,Discovery of clinical effect of bleomycin and its further development,,1
7048,65331,Fetuin. In vitro effect on sheep erythrocyte rosette formation with human T lymphocytes,Peripheral blood lymphocytes from six healthy control subjects were incubated in vitro with fetuin and enumerated for sheep erythrocyte rosette forming T cells. Significant enhancement of rosette-forming T lymphocytes was observed in a dose-related manner. The physical presence of fetuin is not required for this effect. Incubation of lymphocytes with human AB serum has no significant effect on the rosette formation. This enhancing effect of fetuin appears to be secondary to alteration in T lymphocyte surface receptors for sheep erythrocytes.,1
7049,66682,Cell-cycle-related changes of 3':5'-cyclic GMP levels in Novikoff hepatoma cells,"Intracellular and extracellular levels of 3':5'-cyclic GMP and 3':5'-cyclic AMP were studied in synchronized Novikoff rat hepatoma cells. Intracellular levels of cyclic GMP increased spontaneously from 2-fold (without colcemid) to 10-fold (with colcemid), in proportion to the number of cells in mitosis. As cells entered mitosis, cellular cyclic AMP declined simultaneously with the rise in cyclic GMP. These reciprocal changes in cyclic nucleotide levels were reversed as cells passed out of metaphase and through anaphase. Maximum cyclic AMP and minimum cyclic GMP concentrations occurred during G-1. Less marked reciprocal fluctuations in both cyclic nucleotides were also found in S-phase and early G-2, where the ratio of cyclic AMP to cyclic GMP concentrations first fell and then increased. These changes in cyclic nucleotide ratios were closely correlated with major cell-cycle transitions at the boundaries between G-1/S-phase, S-phase/G-2, G-2/prophase, and metaphase/anaphase. Most, but not all, of the extracellular cyclic nucleotides were extruded when cells traversed mitosis. Colcemid or vinblastine completely prevented the appearance of extracellular cyclic AMP but augmented the appearance of extracellular cyclic GMP in parallel with the accumulation of mitotic cells. These results reflected changes in intracellular cyclic nucleotides and indicated that increased intracellular turnover of cyclic GMP and cyclic AMP occurred before and after metaphase, respectively. Elevated cyclic GMP levels during mitosis and S-phase are consistent with potential modulatory roles for this cyclic nucleotide in proliferation.",1
7050,67817,Immunosuppressive and cytotoxic chemotherapy: long-term complications,"Cytotoxic drugs, which are widely used as immunosuppressive and antiinflammatory agents in patients with neoplastic conditions, and cancer chemotherapy preparations, are of long-range concern due to the problem of cumulative organ toxicity which is not manifested until damage is extensive. These considerations have arisen because of their widespread use in recent years. Those involved in hepatic toxicity are the antimetabolites methotrexate and 6-mercaptopurine. Bisulfin, bleomycin, and methotrexate have been linked to pulmonary toxicity. Daunomycin and adriamycin, used as anticarcinogens, are examined for their cardiac toxicity. Cyclophosphamide and streptozotocin affect the urinary tract. These drugs have specific toxic effects on fertility in both males, through its disruption of the testicular function, and in females, for ovarian disruptions. Antifolics, 6-mercaptopurine, azathioprine, and alkylating agents, used for therapy in pregnant women, particularly in the first 4 months, are linked to the appearance of fetal abnormalities. The process of carcinogenesis is examined for clues to possible chemotherapy-related 2nd tumors, which appear during the course of treatment.",1
7051,69876,Liver damage from long-term methyltestosterone,"Of 60 patients (42 female transsexuals and 18 impotent males) receiving long-term therapy with methyltestosterone 50 mg three times a day, 19 had abnormal liver-function tests and 33 out of 52 had abnormal liver scans, particularly those who had been treated for more than a year. Liver biopsy specimens showed accumulation of hepatocytes in the liver cords and within the walls of centrilobular veins, and early peliosis hepatis. One patient had a hepatic adenoma. Of the androgens, only 17alpha-alkylated steroids seem to be implicated in the development of cholestatic jaundice, peliosis hepatis, and liver tumours.",1
7052,73812,Oral contraceptives and malignant hepatoma,,1
7053,74285,Treatment of refractory adult acute nonlymphoblastic leukemia with subcutaneous 5-azacytidine,,1
7054,74627,Hepatic sinusoidal dilatation after chenodeoxycholic-acid therapy,,1
7055,74931,Nonalcoholic fatty liver with alcoholic hyalin after long-term glucocorticoid therapy,"Alcoholic hyalin was found in liver of a nonalcoholic patient with fatty liver after long-term glucocorticoid therapy for systemic lupus erythematosus. Hepatocytes including hyalin bodies showed fatty change or vesiculated degeneration. Occasionally, basophilic substance which was recognized in the hepatocytes with or without hyalin was noticed showing the feature quite similar to delicate alcoholic hyalin.",1
7056,75498,Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma,"""Thirty (30) patients with advanced metastatic malignant melanoma refractory to DTIC (NSC-45388) and a nitrosourea were treated with 5-azacytidine (NSC-102816). 5-Azacytidine was administered subcutaneously at a dosage of 100 mg/m2/day for 10 days. Twenty-six (26) patients were evaluable for toxicity and response. Major organ toxicities were hematologic, gastrointestinal, and cutaneous; no antitumor activity was noted.""",1
7057,76779,Severe rifampicin-associated liver failure in patients with compensated cirrhosis,,1
7058,79123,Clofibrate and the liver,,1
7059,81065,[The role of recently identified proteins in rheumatoid inflammation],,1
7060,83833,The measurement of permeability in single capillaries,,1
7061,87291,Development of antinuclear antibodies during acebutolol therapy,"Eleven patients were studied while taking the beta blocker acebutolol for a period ranging from 12 to more than 24 wk. Control titers for fluorescent antinuclear antibody (ANA) were obtained in all. Serial testing was performed over the duration of the therapy and following its discontinuation. Additional immunologic testing was performed in most patients. The patients were observed closely for the development of clinical autoimmune disease. Using a sensitive assay, fluorescent ANA developed in 8 of 9 patients with negative values in the control period. In no patient has evidence of clinical autoimmune disease developed. In general, the titers of ANA tended to rise with increasing duration of therapy and decline after its discontinuation. Positive lupus erythematosus cell preparations were also observed in several patients. These data suggest that autoantibodies are frequently induced by acebutolol and, although no evidence of clinical autoimmune disease has been reported, immunologic surveillance is warranted.",1
7062,89510,New pathways of nitrogen excretion in inborn errors of urea synthesis,"The defect in nitrogen excretion in patients with inborn errors of urea synthesis can be controlled by exploiting the biosynthetic pathways of readily excretable non-urea metabolites which contain nitrogen derived from ammonium, alanine, glutamate, and glutamine. Two classes of such metabolites are the urea-cycle intermediates--including citrulline, argininosuccinic acid, and arginine--and the aminoacid acylation products--hippuric acid (the glycine conjugate of benzoic acid) and phenylactylglutamine (the glutamine conjugate of phenylactic acid). Thus the urea cycle may serve as a model for the development of excretion pathways of toxic precursors which accumulate in inborn errors of metabolism.",1
7063,91781,"Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers","""34 patients treated with cyclosporin A received 36 cadaveric organ allografts (32 kidneys, 2 pancreases, and 2 livers), 26 kidneys are still supporting life, 3 after more than a year; the pancreases and livers are also functioning. 20 patients are not receiving steroids, and 15 of these have not had any additional immunosuppressive agents. In these patients infectious complications have not been severe, but a gastroduodenal lymphoma has developed in 1 patient. 6 patients were given 'Cytimum' (a cyclophosphamide derivative) and steroids in addition to cyclosporin A: 5 of these died of infections and 1 also had a lymphoma. 11 patients received additional steroids: 1 of these died from septicaemia and lymphoma. Nephrotoxicity can be avoided by perioperative hydration and forced diuresis. Cyclosporin A is effective on its own and is a very potent immunosuppressive drug. Additional immunosuppressive agents may lead to severe complications.""",1
7064,92158,Liver injury following administration of 8-methoxypsoralen during PUVA therapy,"A case of liver injury caused by 8-methoxypsoralen given orally during PUVA therapy is presented. The reaction, manifested by elevated serum alanine-aminotransferase and serum aspartate-aminotransferase, was provoked on three consecutive occasions, on the last one with 8-MOP only. The liver injury seems to be of the hepatocellular and nonpredictable type.",1
7065,99584,[Emergency care and nursing. 18. Diagnostic tests and treatment necessary for emergency patients],,1
7066,102752,Intrahepatic cholestasis after gold therapy in juvenile rheumatoid arthritis,,1
7067,110184,U.S. Public Health Service Cooperative trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis,"A total of 822 patients with newly diagnosed pulmonary tuberculosis were assigned randomly to one of 3 daily rifampin-isoniazid (RIF-INH) regimens: 450, 600, or 750 mg of RIF in combination with 300 mg of INH. After an initial 20 weeks of therapy with RIF-INH, patients recieved 300 mg of INH and 15 mg of ethambutol (EMB) per kg of body weight for either 12 or 18 months after their sputum cultures became negative. The rate of bacteriologic conversion of sputum among the 3 RIF-INH regimens was compared for 552 patients who completed the 20 weeks of RIF-INH therapy. Apporximately 60 per cent of these patients also completed their assigned INH-EMB therapy and were examined for relapse for at least one year after therapy was stopped. There was no significant difference in the rate of sputum conversion or rate of relapse between the group of patients who received 600 mg of RIF and those who received 750 mg of RIF. However, the 450-mg RIF regimen was significantly less effective than the other 2 regimens, as manifested by a lower rate of sputum conversion and a higher rate of treatment failures. Further analysis showed that RIF dosages of less than 9 mg per kg of body weight per day may be inadequate for treatment of pulmonary tuberculosis. The acceptability of these regimens was high, and the incidence of adverse reactions requiring discontinuation of RIF-INH therapy was quite low (3.3 per cent). A large proportion of patients (44 per cent) developed increased concentrations of transaminase during therapy with RIF-INH. These abnormalities were usually transient and, in most cases, of no clinical significance. In the relapse analysis, 12 months of chemotherapy after sputum conversion was shown to be as effective as 18 months of therapy after conversion of these RIF-containing regimens.",1
7068,115078,Cholestatic hepatitis induced by gold,A patient with rheumatoid arthritis developed an acute intrahepatic cholestasis after 100 mg of sodium aurothiomalate. Hepatotoxicity in rheumatoid arthritis is well described following a variety of anti-inflammatory preparations but is now a rare complication of gold therapy and the literature on the subject is reviewed.,1
7069,122652,Preparation of and clinical experiences with trien for the treatment of Wilson's disease in absolute intolerance of D-penicillamine,,1
7070,128640,Chlorpropamide-induced granulomas. A probable hypersensitivity reaction in liver and bone marrow,"Anicteric hepatitis, associated with fever and exfoliative dermatitis, developed in a diabetic patient two weeks after intake of a long-acting sulfonylurea, chlorpropamide (Diabinese). Granulomas showing heavy infiltration with eosinophils were found in the liver and bone marrow. These were interpreted as manifestations of an allergic reaction. The clinical signs, abnormal laboratory findings, and hepatic lesions subsided spontaneously on withdrawal of the drug. Bone marrow changes, however, persisted seven months after cessation of the drug. To our knowledge, this is the first report of a patient with liver and bone marrow inflammation characterized by granulomas with eosinophilic infiltration following intake of chlorpropamide.",1
7071,131731,Intrahepatic cholestasis after griseofulvin administration,"The occurrence of cholestatic jaundice in a patient receiving griseofulvin is described. The clinical manifestations, laboratory features, and pathological lesion of drug-induced hepatotoxicity are discussed. Complete recovery followed the discontinuation of drug administration. The potential hepatotoxicity of griseofulvin and the importance of close monitoring of liver function studies in patients receiving this drug are emphasized.",1
7072,132924,Diphenylhydantoin sensitivity. a syndrome resembling infectious mononucleosis with a morbilliform rash and cholestatic hepatitis,"A ten-year-old boy presented with an illness resembling infectious mononucleosis associated with an unusual skin rash and marked cholestatic hepatitis. This combination represents a rare reaction to diphenylhydantoin. Few reported cases have been published. The illness commences from three to seven weeks after starting therapy. Although one death has been reported, other cases have shown complete recovery. Early recognition of the combination of symptoms and cessation of drug therapy is essential.",1
7073,136506,200 years of occupational medicine in the U.S,,1
7074,141494,Medical problems associated with arsenic exposure,,1
7075,149490,Adverse reactions with methyldopa--a decade's reports,"During 1966-75 the Swedish Adverse Drug Reaction Committee received some 300 reports of reactions to methyldopa. As the Swedish rules for reporting adverse reactions emphasize the importance of severe and unexpected reactions, the relative incidence of various adverse effects differs greatly from what would be found in an intensive study. The three most commonly reported reactions are fever, hemolysis and hepatic effects. Two-thirds of these patients were women. The median age of the groups differed, from 57 years (hepatic effects) to 69 years (hemolysis). The clinical picture of the different reactions was consistent, in the main, with what has been described previously. Between 70 and 85% of the patients in these groups were admitted to hospital because of the adverse reaction.",1
7076,150825,Cholestatic hepatitis after administration of furan derivatives,A patient developed cholestatic hepatitis while being treated with nitrofurantoin. A second episode of jaundice followed the intravaginal administration of a mixture of furazolidone and nifuroxime. It is important to consider possible cross-sensitivity of chemically related compounds even when they are administered by different routes.,1
7077,154997,Idiopathic portal hypertension and chronic arsenic poisoning. Report of a case,We report a case of idiopathic portal hypertension which is related to chronic arsenic poisoning. Only 7 cases have been reported previously. The patient presented with bleeding esophageal varices. Splenomegaly and hyperkeratosis of palms and soles were later noted and led to the discovery of chronic arsenic poisoning. The hemodynamic studies revealed a gradient between the splenic pulp pressure and hepatic wedge pressure which is consistent with presinusoidal hypertension. The liver histology revealed only mild portal fibrosis. Arsenic poisoning is one cause of idiopathic protal hypertension.,1
7078,156393,Penicillamine in rheumatoid arthritis: adverse effects,"The use of penicillamine in rheumatoid arthritis (RA) is limited by the incidence of adverse effects, some of which are potentially hazardous. However, adverse effects are dose-related and the advantages and disadvantages of different fixed and flexible dose regimes are discussed. The incidence of adverse effects is significantly greater in patients previously treated with gold who developed toxicity to that drug--no such increase being found in gold treated patients whose only reason for stopping gold was ineffectiveness. Rashes which develop after several months of treatment are variants of pemphigus and their various presentations are described. Fatal reactions, fortunately rare, are predominantly associated with aplasia of the bone marrow. Monthly haematological checks coupled with meticulous charting of the results may reveal trends as well as numerical changes and serve as an early warning of marrow damage.",1
7079,159491,Severe hypersensitivity reactions to allopurinol,"The frequency of severe reactions to allopurinol has probably been underestimated. A retrospective study encompassing a five-year period has yielded 20 patients with severe hypersensitivity reactions to allopurinol. Patients with preexisting renal impairment or who were receiving concomitant thiazide diuretics appeared to be especially predisposed. Cutaneous reaction patterns included maculopapular eruptions, exfoliative dermatitis, and toxic epidermal necrolysis. eosinophilia was uncommon. Forty percent of the patients developed hepatic involvement and 45% had renal involvement. Hepatic and renal changes usually were reversible and were not unique to any one cutaneous reaction pattern. Three patients with renal involvement required prolonged administration of systemic steroids. Complications included sepsis, decubitus ulcers, and thromboembolism. Two patients required hyperalimentation. Sequelae included dry eyes, pigmentary disturbances, and keloids. Three patients died as a result of their reaction. It is concluded that allopurinol should be used only in select patients, and the dosage should be modified if renal disease exists.",1
7080,160967,"[Fever, skin and liver reactions in a patient treated with Paraflex comp]",,1
7081,162813,Hemoperitoneum from liver cell adenoma in a patient on oral contraceptives,"A case of hemoperitoneum from ruptured benign liver cell adenoma in a young woman with a long history of oral contraceptive use is presented. The importance of recognizing the cause of this intra-abdominal emergency is stressed, and comment is made about the entity occurring in women on contraceptive drugs.",1
7082,168333,Hepatic adenoma in Fanconi anemia treated with oxymetholone,,1
7083,168654,Hepatic dysfunction in recipients of renal allografts,,1
7084,169340,Hepatotoxicity of chemotherapy following nephrectomy and radiation therapy for right-sided Wilms tumor,"Two children developed hepatotoxicity during treatment for right-sided Wilms Tumor. Treatment consisted of nephrectomy, irradiation, and chemotherapy with actinomycin D and vincristine. Hepatic enlargement, thrombocytopenia, and abnormalities in liver function and seen on the liver scan occurred at the time of the course of chemotherapy administered 20 days after completion of irradiation. These abnormalities disappeared when treatment was temporarily suspended. Vincristine and actinomycin D were subsequently reintroduced without evidence of hepatotoxicity. Actinomycin D after irradiation for right-sided Wilms tumor may produce severe liver toxicity.",1
7085,170431,Liver cell adenoma and oral contraceptives. Double tumor development,,1
7086,171048,Multiple neoplasms in two siblings with a variant form of Fanconi's anemia,"Two siblings with a variant form of Fanconi's anemia developed multiple neoplasms after prolonged survival and treatment with androgens. One of the siblings developed two separate oral squamous cell carcinomata, and the other developed acute leukemia and hepatoma. Androgens may have had a carcinogenic role in the appearance of the hepatic neoplasm. There is an increased incidence of neoplasm associated with Fanconi's anemia. This may be related to frequent spontaneous chromosomal abberations and/or to increased cellular susceptibility to viral transformation.",1
7087,172187,Histological evidence of carcinoma in a hepatic tumour associated with oral contraceptives,"""A primary hepatic tumour occurred in a 21-year-old woman who had been taking oral contraceptives for two years; she was treated by partial hepatectomy. Part of the neoplasm showed features suggestive of focal nodular hyperplasia, while the remainder had the histological characteristics of a well-differentiated hepatocellular carcinoma. This is the first report of malignant transformation of a tumour in a patient taking oral contraceptives.""",1
7088,173996,Liver-cell adenomas associated with use of oral contraceptives,"During the past six years an increasing number of liver-cell adenomas in women were diagnosed, and we undertook a study of possible etiologic factors, including use of oral contraceptives, in 42 women. There was a significant difference between cases and matched controls in mean months of oral-contraceptive use: 73.4 as compared to 36.2 (P less than 0.001). The women with adenomas took mestranol-containing pills much more commonly than the controls (P less than 0.0001). Hemorrhage into the tumor was often associated with the onset of menstruation in women taking oral contraceptives. Long-term use of oral contraceptives, especially those containing a high total dose of steroids or mestranol as the synthetic estrogen, should be balanced against risks of side effects of the drugs.",1
7089,175178,Hepatic changes in young women ingesting contraceptive steroids. Hepatic hemorrhage and primary hepatic tumors,"""Primary hepatic tumors developed in 13 young women who had been ingesting contraceptive steroids. Nine tumors were benign, and four malignant. Six tumors ruptured spontaneously and caused life-threatening hemorrhage. Benign tumors were successfully resected in eight women. One woman died during hepatic resection for malignant hepatoma; in two other cases of hepatocellular carcinoma, tumors were nonresectable. In two patients, the tumor was left in situ after neoplasm had been excluded by biopsy. The increase of such tumors in women of childbearing age warrants the suspicion that these contraceptive steroid hormones play an etiologic role.""",1
7090,178577,Successful treatment of a malignant gastrinoma with streptozotocin,"The treatment with streptozotocin of a patient with metastatic gastrinoma is described. Two courses of intravenous streptozotocin were without effect. However, three months after two doses of 4 g streptozotocin were given into the coeliac axis, there was a marked reduction in hepatic size and a fall in fasting plasma gastrin levels from 1430 pmol/l to 240 pmol/l. Seven months after treatment fasting plasma gastrin levels were 125 pmol/l.",1
7091,179194,Multiple hepatocellular tumours in a patient treated with oral contraceptives,"A case of multiple hepatic tumours in a patient treated for four years with high doses of oral contraceptives is described. Solitary hepatocellular lesions associated with conventional doses of oral contraceptives have been reported previously in twenty nine cases. Haemorrhage has been a common mode of presentation and is attributed to the marked vascularity of the lesions, an appearance referred to as peliosis hepatis. Radiographic studies show this term to be inappropriate as the vessels are of arterial origin. Another finding not previously reported is the presence of diffuse hyperplasia in the non-tumourous parts of the liver.",1
7092,180859,Editorial: Systemic contraceptives and liver tumors,"Since 1973 more than 100 cases of benign liver tumors occuring in association with oral contraceptive (OC) use have been reported. These tumors have varied in histologic appearance. Recent reports have identified 5 women with hepatocellular carcinoma nad 1 with hepatoblastoma occurring in association with use of systemic contraceptives. Before 1960 these tumors were rare. There are probably a larger number of unrecognized cases as many patients with these tumors have been asymptomatic. A significant difference in duration of OC use by patients and controls has been noted (p more than .01). The mean duration of OC use of 6 years before clinical appearance of liver cell adrenomas has been determined. The number of women entering the high-risk group for formation of liver cell adenomas may increase in the future. Unresectable tumors have been observed to decrease in size when OCs habe been discontinued and such tumors have recurred in patients in whom OC use was continued after resection. Other factors may also be important. The Armed Forces Institute of Pathology (AFIP) has instituted an epidemiologic survey that will review cases of hepatocellular tumors occurring in young women. Physicians may refer documented cases to Dr. Kamal G. Ishak at AFIP in Washington, D.C. A national registry for these tumors is recommended to establish the magnitude of the problem. Basic research into the effects of OCs on liver structure is needed. Funding agencies are urged to cooperate.",1
7093,182106,Hepatic adenoma. Observations after estrogen withdrawal,"A case of ruptured, benign hepatic adenoma occurred in a young woman taking oral contraceptives. Our observation of this patient after biopsy and control of hemorrhage is the subject of this report. We support the concept that these tumors may regress or remain dormant after estrogen withdrawal, and question the need for routine resection of benign hepatic adenomas. Further observations of growth patterns after estrogen withdrawal are needed.",1
7094,184729,Benign liver tumors: what is their relationship to oral contraceptives?,"A series of eight cases of benign hepatocellular tumors from the New Orleans area is presented. Clinical and histological features of these unusual tumors are discussed. Also, a series of 56 similar cases reported in the literature is reviewed. We conclude that these tumors have shown definite evidence of hormonal sensitivity and there is strong circumstantial evidence that oral contraceptive medications have contributed to their recent increased incidence. Although the risk of this problem in the overall population of women taking oral contraceptives seems to be quite small, further clinical and experimental research on this problem is clearly indicated.",1
7095,188336,Benign hepatic tumors and oral contraceptive pills,"""In order to consider possible environmental factors related to the development of benign hepatic tumors, all reports of this disorder in the case records of five different hospitals in Rochester, New York, during the past 10 years were reviewed. Seven patients with benign hepatic tumors of the liver and two with peliosis hepatis were identified. Among the seven with a benign hepatic tumor, four were women currently receiving oral contraceptives; one had been receiving this medication in the past, and two had no history of exposure to any steroid whatsoever. The two patients with peliosis hepatis were receiving long-term androgenic anabolic steroids. Dilated, thin-walled vessels and vascular spaces were a more prominent feature of the tumor seen in four patients receiving oral contraceptive pills. It is emphasized in this report that benign hepatic tumors do occur in men and in patients with cirrhotic liver without the use of any kind of steroids.""",1
7096,189044,Liver tumors and contraceptive steroids: experience with the first one hundred registry patients,,1
7097,189576,Treatment of malignant metastatic pancreatic insulinoma with streptozotocin. Review of 21 cases described in detail in the literature and report of complete remission of a new case,"The possibilities of treating different types of pancreatic islet cell cancer with the active drug streptozotocin have been studied in reports of 21 patients published during the last 8 years. The unusual features of the symptomatology, dosage and injection methods, side-effects after different infusion schedules and complications of streptozotocin therapy, are compared. A new case with pancreatic carcinoma and liver metastases was treated with a total dose of 14 g streptozotocin, divided into 7 injections with an increasing interval between them. This patient underwent a marked amelioration of the disease, without serious side-effects of the streptozotocin treatment. She has been apparently well for the 22 months which have now elapsed since the beginning of treatment. This seems to be one of the longest remission periods yet published in the insulinoma literature.",1
7098,192659,Benign hepatic lesions and orally administered contraceptives. A report of seven cases and a critical analysis of the literature,"A consecutive series of 12 benign hepatic lesions in women consisted of six cases of focal nodular hyperplasia and six cases of liver cell adenoma. Five of the six women with liver cell adenoma and two of the six with focal nodular hyperplasia had taken orally active contraceptive hormones. These few cases reflect a similar impression gained from a critical analysis of the literature, namely, that focal nodular hyperplasia may be unrelated to the oral administration of contraceptive hormones, whereas the increase in liver cell adenoma reported in recent years is probably related to such therapy. Two women with liver cell adenomas were asymptomatic six and four years after incomplete resection of the tumor. These are the longest intervals thus far reported for uncomplicated survival in incompletely resected liver cell adenoma.",1
7099,194813,Hepatic tumors: possible relationship to use of oral contraceptives,,1
7100,196746,Hepatocellular carcinoma in a woman on long-term oral contraceptives,"A 32-year-old woman on oral contraceptives for 12 years developed a hepatocellular carcinoma, which resulted in death 15 months after initial diagnosis. The possible association between this malignant hepatic tumor and the long-term use of oral contraceptives is reviewed.",1
7101,198105,Benign liver-cell adenoma associated with long-term administration of an androgenic-anabolic steroid (methandienone),"A 19-year-old man with paroxysmal nocturnal hemoglobinuria treated for 3 years with Methandienone was admitted to the hospital with hemoperitoneum due to the rupture of an hepatic tumor. Histology revealed that it was a benign liver cell adenoma, with a pathologic appearance and mode of clinical presentation closely resembling those of cases observed to develop in association to contraceptive steroids.",1
7102,199056,Multiple hepatic tumors and peliosis hepatis in Fanconi's anemia treated with androgens,"""We report the case of a 13-year-old boy who was known to have Fanconi's anemia for five years. For treatment of this condition he was given androgens and corticosteroids. Two months before his death, severe varicella developed complicated by pneumonia, jaundice, and prolonged fever; all of which resolved during a five-week hospitalization. Three weeks later he died of Clostridium septicum sepsis caused by necrotizing enterocolitis. At autopsy he was found to have multiple hepatocellular neoplasms. A striking feature of the neoplasms was cholestasis. The liver also showed peliosis hepatis. The association of the use of certain androgenic steroids with hepatic neoplasms histologically resembling hepatocarcinomas, but characterized by lack of metastases and apparent reversibility, suggests the desirability of a new nomenclature for these hepatocellular lesions.""",1
7103,199136,Multiple tumors after androgen therapy,"A case of multiple small well-differentiated hepatomas with early peliosis hepatis, multiple pancreatic islet cell tumors, and a renal medullary interstitial cell tumor following five years of androgen and prednisone therapy for idiopathic aplastic anemia is reported in a patient who died shortly after allogeneic bone marrow transplantation. The hepatic tumors were well differentiated, and the pancreatic tumors were of mixed ribbon and islet cell pattern. Therapeutic and experimental implications and the relevant literature are briefly summarized.",1
7104,200767,Hepatoma in a child with methotrexate-induced hepatic fibrosis,"""During autopsy, an 11-year-old girl with acute lymphocytic leukemia was found to have hepatic fibrosis with a 2.5-cm nodule of hepatocarcinoma. For 5 1/2 of the six years of treatment, chemotherapy consisted of daily orally administered methotrexate with monthly doses of vincristine sulfate and prednisone. The cumulative dose of methotrexate was 2.5 g. To our knowledge, this report constitutes the first association of hepatoma with methotrexate-induced hepatic fibrosis. A careful follow-up of patients receiving methotrexate for malignant neoplasms is urged; caution is suggested in the prolonged use of methotrexate when treating benign disease.""",1
7105,209068,Xanthoma formation by human beta-lipoprotein immune complexes in rabbit blood stream,,1
7106,217519,Anabolic steroid therapy and intrahepatic cholangiocarcinoma,"A 47-year-old man who had been treated with an anabolic steroid for refractory anemia developed an intrahepatic cholangiocarcinoma with metastases to abdominal lymph nodes and lungs. Microscopically, the tumor showed mucin production and was devoid of hepatocellular elements. Previous reports have suggested a possible relationship between anabolic steroid therapy and hepatocellular carcinoma. In many such cases, there are doubts about the histological diagnosis, malignant potential, and the nature of the association between the steroids and the tumors. The presence of distant metastases attests to the malignant nature of the tumor in the present case. Despite the apparent temporal eligibility of the steroid as an etiologic agent, a causative relationship between therapy and tumor is not established.",1
7107,223536,Liver disease associated with chronic arsenic ingestion,"""The association of chronic liver disease with long-standing arsenic ingestion is well documented, although the spectrum and incidence of liver disease due to arsenic remain uncertain. We report two patients with chronic liver disease and arsenical skin changes that followed previous chronic arsenic ingestion. One patient developed macronodular cirrhosis and the other non-cirrhotic portal hypertension with perisinusoidal fibrosis. The latter patient developed a primary liver cell cancer. There is only one previously reported case of malignant hepatoma in a non-cirrhotic liver complicating chronic arsenicism. Lack of awareness of this uncommon but well described cause of chronic liver disease may account for a small proportion of patients with """"cryptogenic"""" liver disease. Previous arsenic administration should be considered as a cause of chronic liver disease, especially when typical skin changes or internal neoplasia develop.""",1
7108,225026,"Therapeutic trials with VP-16-213 and VM-26: active agents in small cell lung cancer, non-Hodgkin's lymphomas, and other malignancies",,1
7109,227234,Streptozotocin treatment of a pancreatic tumour producing VIP and gastrin associated with Verner-Morrison syndrome,A 57-year-old male patient with metastasizing non-beta islet cell carcinoma of the pancreas is described. Both gastrin and VIP levels were elevated and the patient suffered from a syndrome of pancreatic cholera and hyperacidity. The tumour contained gastrin and VIP as demonstrated by immunofluorescence. The patient also had a history of familial renal stone formation and parathyroid nodular hyperplasia. Resection of pancreatic tumour in 1973 resulted in four years without symptoms. In 1977 definite signs of multiple hepatic metastases appeared. These signs disappeared after streptozotocin given in a dosage of 2 g three times at weekly intervals. The patient had remained well for 20 months after this treatment. The causative agents for the clinical syndrome in this case are discussed in view of circulating hormone levels.,1
7110,228707,The respiratory chain of Paramecium tetraurelia in wild type and the mutant Cl1. I. Spectral properties and redox potentials,"1. Purified mitochondria have been prepared from wild type Paramecium tetraurelia and from the mutant Cl1 which lacks cytochrome aa3. Both mitochondrial preparations are characterized by cyanide insensitivity. Their spectral properties and their redox potentials have been studied. 2. Difference spectra (dithionite reduced minus oxidized) of mitochondria from wild type P. tetraurelia at 77 K revealed the alpha peaks of b-type cytochrome (s) at 553 and 557 nm, of c-type cytochrome at 549 nm and a-type cytochrome at 608 nm. Two alpha peaks at 549 and 545 nm could be distinguished in the isolated cytochrome c at 77 K. After cytochrome c extraction from wild type mitochondria, a new peak at 551 nm was unmasked, probably belonging to cytochdrome c1. The a-type cytochrome was characterized by a split Soret band with maxima at 441 and 450 nm. The mitochondria of the mutant Cl1 in exponential phase of growth differed from the wild type mitochondria in that cytochrome aa3 was absent while twice the quantity of cytochrome b was present. In stationary phase, mitochondria of the mutant were characterized by a new absorption peak at 590 nm. 3. Cytochrome aa3 was present at a concentration of 0.3 nmol/mg protein in wild type mitochondria and ubiquinone at a concentration of 8 nmol/mg protein both in mitochondria of the wild type and the mutant Cl1. Cytochrome aa3 was more susceptible to heat than cytochromes b and c,c1.",1
7111,247023,[Public health nursing activity based on the close tie with the local residents--answer to the letter by Ms. Yamazaki],,1
7112,252305,What an RN should know about copyright law,,1
7113,265379,Transoral resection of a condylar osteochondroma: report of case,"""A rare case of osteochondroma (osteocartilaginous exostosis) of the mandibular condyle is described; this represents the seventh documented case in the English language literature. Treatment consisted of transoral surgical resection which maintained condylar integrity. No maxillomandibular fixation was placed and the patient's mandibular function was undisturbed. Postoperatively, mandibular deviation was minimal.""",1
7114,267312,[Portal hypertension without liver cirrhosis in chronic vitamin A intoxication],"The ysmptoms and findings in a patient after prolonged intake of excessive amounts of vitamin A for treatment of psoriasis are presentd. All the characteristic signs of chronic intoxication were reversible after withdrawal of the medication. Initially portal hypertension could be demonstrated, although histologically there was no cirrhosis of the liver. During the period of observation the disturbed liver function returned to normal and the signs of portal hypertension disappeared completely. Reversibility of portal hypertension is a unusual observation and is discussed in relation to similar situations in toxic liver disease.",1
7115,272174,Drug-induced hepatic injury,,1
7116,276660,Stevens-Johnson syndrome plus toxic hepatitis due to ibuprofen,,1
7117,282477,Erythromycin estolate-induced hepatitis. Ultrastructural study of liver,,1
7118,290813,Undesirable effects of gold salts,A review of recent studies of undesirable effects of gold salts is presented. Marrow aplasia is potentially the most serious side effect with a poor prognosis. Its prevalence is undetermined but may have been overestimated. Gold nephropathy and thrombocytopenia although more common usually have a good prognosis. Both can be satisfactorily treated without prolonged morbidity or mortality. Mucocutaneous reactions although more common are rarely of serious importance and need not necessarily prevent completion of a therapeutic course of gold salts. When indicated the side effects of gold salts can be adequately treated by cessation of therapy and use of corticosteroids. The value of chelating agents is desirable.,1
7119,296787,Hepatotoxicity in the treatment of acute lymphoblastic leukaemia,"Serial liver function tests and percutaneous liver biopsies were performed on 21 children receiving treatment for acute lymphoblastic leukaemia (ALL). The patients received continuing chemotherapy either with daily 6-mercaptopurine and weekly methotrexate or with five-day pulses of these drugs every three weeks. Liver function tests were transiently abnormal in the majority of children, but the abnormalities bore no relationship to the histology of the liver biopsy. Mild inflammatory and fatty changes were commonly seen, and early portal fibrosis was found in three out of 16 patients biopsied at between 108-130 weeks on treatment. There was no correlation between treatment regime and results of biopsy. Three patients showed possible progression of abnormalities on repeat biopsy. The risk of development of portal fibrosis appears low after 2-3 years of continuing chemotherapy, but examination of liver histology may be indicated if more prolonged therapy is contemplated.",1
7120,302237,Morphologic changes in adverse drug reactions in infants and children,"""The morphologic findings in 102 validated cases of adverse drug reactions classified in the """"causative"""" and """"probable"""" category are reported. All of them are well documented cases of drug associated reactions. The patterns of tissue reactions in these cases are divided into the following categories: inflammation, degeneration and infiltration, hypoplasia and aplasia, hyperplasia, necrosis, circulatory disturbances and vascular abnormalities, and teratogenesis. Degeneration and infiltration constitute the most common tissue reaction pattern present in these cases. The liver is the organ most frequently affected. Anti-infective drugs were associated with the highest number of adverse drug reactions, followed by antineoplastic drugs.""",1
7121,303561,[Small-nodular liver cirrhosis with marked portal hypertension due to vitamin A intoxication resulting from psoriasis treatment (author's transl)],"Clinical and histological signs of small nodular liver cirrhosis with portal hypertension were present in a 36-year-old man, three-and-a-half years after a seven-week course of treatment of psoriasis vulgaris with high doses of vitamin a (70 X 10(6) IU orally). Although there is no increase in serum level of vitamin A now, increased deposits of vitamin A in the perisinusoidal lipid storage cells (Ito cells) are still demonstrated by fluorescencespectrophotometry and under the electron microscope. Fundectomy with resection of the terminal oesophagus was necessary because of bleeding from oesophageal varices.",1
7122,306216,Isoniazid induction of antinuclear antibodies. A prospective study,"We prospectively studied 102 patients admitted to the Chest Service with tuberculosis. Four patients (4%) had antinuclear antibodies before therapy and 22 patients (21.6%) developed antinuclear antibodies after treatment. None developed lupus erythematosus cells or signs or symptoms of systemic lupus erythematosus. Age and race were not related to the induction of antinuclear antibodies. The percent of positive sera was similar during and after 3 months of treatment, with higher titers after 3 months of therapy. Although patients were treated with various antituberculosis drugs, isoniazid alone or in combination with other drugs induced antinuclear antibodies.",1
7123,309537,[Hepatotoxicity during treatment of juvenile rheumatoid arthritis and rheumatic diseases using salicylates],,1
7124,314042,Evaluation of overall toxicity of high-dosage methotrexate regimens,"""The occurrence of overall toxicity was analyzed for 43 patients with osteosarcoma who received 349 high-dosage courses of methotrexate (HD-MTX) with citrovorum factor (Leukovorin) """"rescue"""" (CF). The dosages of HD-MTX ranged from 50 to 350 mg/kg. Overall toxicity was assessed on the basis of five manifestations of toxicity: stomatitis, dermatitis, myelosuppression, liver dysfunction, and kidney function abnormalities. The great majority (91.4%) of the infusions were well tolerated, but 8.6% were associated with moderate or severe toxicity. Stomatitis and serum glutamic-oxaloacetic transaminase (SGOT) changes were the most frequent postinfusion findings. Three patients died from causes related to MTX toxicity. Dose, age, sex, and number of prior infusions were investigated by logistic regression analysis for prognostic effect on frequency of moderate to severe overall toxicity. Age and number of prior infusions had significant (P less than 0.06) effects on overall toxicity. Patients older than 15 years with greater than 10 prior infusions constituted the """"high risk"""" group with a risk of moderate to severe toxicity 6.3 times that of the younger patients with fewer than 10 infusions.""",1
7125,317034,Lymphocyte-mediated cytotoxicity in isoniazid-associated hepatitis,"The release of lymphotoxin (LT) from peripheral blood lymphocytes of patients with isoniazid (INH)-induced hepatitis was studied, using L929 fibroblast target cells, as was the cytotoxic effect of these lymphocytes on murine hepatoma cells (L1469) and L929 fibroblasts, using a 3H-proline cytotoxicity assay. Evidence for LT release was found in five out of six patients, following stimulation of the peripheral blood lymphocytes with INH or isonicotinic acid (INA) conjugated to human serum albumin. In the direct cytotoxicity assay, cytotoxic effects on the hepatoma cells were enhanced by preincubation of the target cells with INH in five out of six patients tested. Although specificity with regard to the drug was demonstrable, tissue specificity was less certain in that enhanced killing of the fibroblast cell line was also found to occur following preincubation of the L929 cells with INH.",1
7126,317969,[Benign drug jaundice during treatment combining rifampicin and triacetyloleandomycin],,1
7127,323097,Drug-induced chronic liver disease,,1
7128,332099,Isoniazid chemoprophylaxis. Association with detection and incidence of liver toxicity,"The hepatotoxicity of isoniazid was studied in a double blind fashion in 120 adult patients receiving the drug for chemoprophylaxis. The incidence of abnormal SGOT values was significantly higher in those on the drug, 18.3% having elevated values as compared to 6.7% of those on placebo during the three-month study period. There was no statistical difference in the frequency of symptoms suggestive of liver diseases between the isoniazid and placebo groups. Furthermore, there was no significant relationship between symptoms and elevated SGOTs. Therefore, symptomatology would not appear to be a sensitive method for detecting early isoniazid liver toxicity. From available evidence, biochemical monitoring would appear to detect liver toxicity at an earlier and more reversible stage.",1
7129,337270,Nature and incidence of unwanted effects with atenolol,,1
7130,340145,Tricyclic antidepressants: a review of their toxicology,"The tricyclic antidepressants have a complex interaction with several tissues both in experimental animals and in man. Side effects exerted by these drugs may be so severe as to justify a careful management of each individual depressed patient. The clinician must be aware of these effects above all in treating overdose poisoning and suicide attempts. This paper reviews the tricyclic-induced organic and psychologic disturbances, attention being paid to the antidepressant pharmacodynamics and the importance of biogenic amines-reuptake inhibition. Further studies on the pharmacokinetics of tricyclic antidepressants are needed however to clarify the mechanisms of their side effects. In this situation, increased drug levels should be tried only after lower dosages have proved ineffective in relieving the depressive symptomatology. In any case, the greatest caution should be used in the treatment of patients with cardiovascular diseases, severe hypertension, glaucoma, or a tendency to retain urine. Nevertheless, at present no new antidepressant has been found which may offer more selective therapeutic advantages than the classical tricyclic thymoleptics (imipramine-like drugs).",1
7131,345189,[Ship physician pirates and marine accident insurance in the 17th century],,1
7132,349093,Efficacy and safety of cefamandole plus either gentamicin or tobramycin in therapy of severe gram-negative bacterial infections,"""Thirty-one patients with severe gram-negative bacterial infections were treated successfully with a combination of cefamandole nafate plus gentamicin or tobramycin. The patients were divided into two treatment groups: group 1 received low-dose therapy (80--100 mg of cefamandole nafate/kg per 24 hr plus 3 mg of either gentamicin or tobramycin/kg per 24 hr), and group 2 patients, who had suspected bacteremia, received high-dose therapy (170 mg of cefamandole nafate/kg per 24 hr plus 5 mg of either gentamicin or tobramycin/kg per 24 hr). All of the patients were clinically and bacteriologically cured of their primary infections. All four episodes of bacteremia were cleared within 24 hr after therapy was initiated. There was a uniform decrease in the rate of creatinine clearance which was slightly greater in group 2 patients; however, all creatinine clearance values were within the normal range and actually improved during therapy. There was no difference between the clearance values of the tobramycin-treated patients and gentamicin-treated patients. A few transient abnormalities in results of liver function tests occurred during the study. In one patient whose serum was positive for hepatitis-associated antigen, the alkaline phosphatase, aspartate aminotransferase, and bilirubin values were elevated on admisssion of the patient to the hospital, increased fivefold during therapy, and decreased to the base-line admission values six days after therapy; however, it is difficult to establish that this reaction was antibiotic-induced hepatic toxicity.""",1
7133,356251,Report on a long-term tolerability study of up to two years with diclofenac sodium (Voltaren),,1
7134,362234,Baclofen for spasticity in multiple sclerosis. Double-blind crossover and three-year study,"Baclofen is a safe and effective means for treating spasticity associated with multiple sclerosis. We found no toxic effects on hepatologic, hematopoietic, or renal function, acutely or for over 3 years of follow-up. A statistically significant reduction was noted in frequency of spasms, and clonus, and there was improved range of joint movement, which enabled patients to maintain functional status for prolonged periods. For the more disabled patients, treatment with baclofen gave symptomatic relief of painful spasms and made immobility more tolerable. Optimum effect was achieved when baclofen was administered in the early stages of disease, before major disabilities became permanent.",1
7135,369367,Drug therapy reviews: nitrofurantoin,"Mechanism of action, antimicrobial spectrum, pharmacology, adverse reactions and therapeutic uses of nitrofurantoin, a broad-spectrum antimicrobial agent, are discussed. The frequency and potential severity of reactions attributed to nitrofurantoin, plus its inability to achieve therapeutic blood concentrations, relegate this drug to a position of secondary importance. Nitrofurantoin compares favorably with other standard agents for the therapy of acute and recurrent urinary tract infections in women which may be caused by susceptible organisms, and it is an effective chemoprophylactic agent for patients with recurrent urinary tract infections. The compound has no apparent adverse effects on the developing fetus and can be used in pregnant women. This is not sanctioned by the package insert, however. Nitrofurantoin should not be administered when the possibility of bacteremia exists, as the drug does not achieve therapeutic serum levels when administered orally. Nitrofurantoin is contraindicated for patients with renal insufficiency. The value of this compound for men with acute urinary tract infection, recurrent urinary tract infection, acute bacterial prostatitis or chronic bacterial prostatitis has not been established. There are no indications for prescribing parenteral nitrofurantoin.",1
7136,371565,Complications of chrysotherapy: a review of recent studies,"Chrysotherapy has become a cornerstone in the treatment program of patients with rheumatoid arthritis. Unfortunately, approximately one third of these individuals will experience an adverse drug reaction at some time. Cutaneous manifestations are most commonly recognized and do not necessarily preclude reinstitution of gold after their resolution. Other complications involving the hematopoietic and renal systems are less frequent but may be severe. Recently, investigators have described serious toxic reactions involving the liver and lungs. The pathophysiologic mechanism of these untoward effects appears to be immunologic, although there are conflicting data. Treatment is primarily supportive, and the role of corticosteroids and chelating agents remains controversial. Emphasis should be placed primarily on early detection of adverse reactions through patient education and careful monitoring of blood and urine values.",1
7137,372803,Acute hepatic failure associated with the use of sodium valproate,,1
7138,375787,Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis,"""In a study in Singapore, Chinese, Malay, and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed either by daily treatment with isoniazid, rifampin, and pyrazinamide (SHRZ/HRZ regimen) or by daily administration of isoniazid and rifampin (SHRZ/HR regimen) allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli before treatment had a favorable bacteriologic response during chemotherapy. During the first 6 months after the end of chemotherapy, there was only a single bacteriologic relapse among 84 SHRZ/HRZ and 80 SHRZ/HR patients treated for 6 months, but 8 (10 per cent) of 80 SHRZ/HRZ and 4 (5 per cent) of 74 SHRZ/HR patients treated for 4 months relapsed. Of a total of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs before treatment, only one had an unfavorable response during chemotherapy, and none of 31 patients relapsed during the first 6 months after stopping chemotherapy. The incidence of adverse reactions was low; 11 (3 per cent) of 397 patients had hepatitis, but not all episodes were attributable to drug toxicity, and one patient had thrombocytopenic purpura.""",1
7139,377449,Clinical comparative evaluation of choline magnesium trisalicylate and acetylsalicylic acid in rheumatoid arthritis,"""A multicentre double-blind comparison of choline magnesium trisalicylate (CMT) and acetylsalicylic acid (ACSA) compared the two medications for seven weeks in rheumatoid arthritis patients. Investigators measured the number of painful and swollen joints and the duration of morning stiffness, and assessed the overall condition of each patient. Both medications were highly effective in significantly reducing the severity of symptoms flaring after interruption of prior therapy. CMT achieved a greater reduction in the number of swollen joints than did ACSA (P less than 0.05). The incidence of adverse side-effects per patient was significantly less with CMT (P less than 0.05) (ACSA 32.1%; CMT, 16.3%. A larger percentage of ACSA patients (50.8%) reported adverse side-effects than did CMT patients 28.4%) (P less than 0.02).""",1
7140,378348,Improved remission rates and remission duration in young women with metastatic breast cancer following combined oophorectomy and chemotherapy: a study of Cancer and Leukemia Groupe B,"One hundred fifty-seven premenopausal women with metastatic breast cancer were prospectively randomized to treatment consisting of oophorectomy + vincristine, prednisone, cyclophosphamide, methotrexate, 5-fluorouracil (VPCMF) (Reg. I) or oophorectomy + cyclophosphamide (Reg. II) or oophorectomy followed by an observation period (Phase 1), followed by VPCMF (Phase 2) (Reg. III). Complete plus partial response rates were 72% on Reg. I, 65% on Reg. II, 18% on Reg. III, Phase 1 and 50% on Reg. III, Phase 2. Median duration of response for Reg. I was 17 months, for Reg. II 16 months, and for Phase 1 and Phase 2 of Reg. III, respectively, 5 months and 8 months. The response rate for patients treated with oophorectomy plus chemotherapy is significantly higher than the response rate achieved with oophorectomy alone as first treatment following the appearance of metastases in premenopausal women.",1
7141,382938,Trimethoprim-sulfamethoxazole in the United States,"After approximately 5 years of clinical use in Great Britain and other European countries, trimethoprim-sulfamethoxazole in fixed-dose combination was introduced into the United States in 1973. As a result of sequential blockade in the biosynthesis of tetrahydrofolic acid, the antimicrobial activity of the combination exceeds that of either agent alone. Although the drug is approved for use in only chronic urinary-tract infection, otitis media, shigellosis, and Pneumocystis carinii pneumonia, many experimental clinical trials suggest that this agent may be useful in a number of other infectious disorders. Trimethoprim-sulfamethoxazole is generally well tolerated even with long-term administration, but its potential for hematologic toxicity and nephrotoxicity must be monitored.",1
7142,391117,Ibuprofen,"Ibuprofen was introduced in England in 1967 and in the United States in 1974 as an anti-inflammatory drug in humans. It has weak but definite anti-inflammatory properties similar to those of aspirin, milligram for milligram, but with considerably less adverse effect on the stomach. Ibuprofen is chemically related to fenoprofen and naproxen, but lack of effect for any one in this chemical class of propionic-acid derivatives does not necessarily mean lack of effect for any other in an individual patient. The drug has analgesic properties, probably related to its anti-inflammatory effect. It inhibits prostaglandin synthesis and has no effect on the adrenopituitary axis, making it a nonsteroidal agent. Ibuprofen has been shown to be effective in rheumatoid arthritis and osteoarthritis and is probably effective in ankylosing spondylitis, gout, and Bartter's syndrome.",1
7143,393287,A multicentre open trial of labetalol in New Zealand,"""1 In a multicentre open trial, labetalol was given to 128 patients in ten centres. Forty-three patients had not previously received antihypertensive therapy; the remainder (85 patients) had been on antihypertensive therapy with either unsatisfactory BP control or troublesome side-effects. 2 Thirty-two patients were withdrawn from the trial in the first 6 months of therapy, 24 (19% of the total) because of side-effects. 3 Control of BP was generally satisfactory or considerably improved. Other drugs (usually a diuretic) had to be added in 23 patients. 4 There was an abnormality of liver function in one patient; otherwise there were no biochemical or haematological problems.""",1
7144,404619,"A comparison of fasting plasma insulin and growth hormone concentrations in marasmic, kwashiorkor, marasmic-kwashiorkor and underweight children","Fasting plasma insulin and growth hormone concentrations were measured in 24 marasmic, 11 kwashiorkor, 16 marasmic-kwashiorkor, and 4 underweight children. Hormone measurements were made by a special modification of the Hales and Randle double antibody immunoassay with increased sensitivity in the concentration range 0-25 micronU/ml. Fasting plasma insulin was low in marasmus, kwashiorkor, and marasmic-kwashiorkor children, and increased to normal levels after recovery. Fasting plasma growth hormone was elevated in all groups during malnutrition and was significantly decreased to normal levels after recovery. There were no significant differences in plasma insulin or growth hormone levels between the different clinical types of severe protein energy malnutrition. These hormonal changes in severe protein energy malnutrition are of complex and not fully understood etiology. However, recovered children appear to have a hormonal pattern similar to that described in normal control infants and children.",1
7145,407169,Serological study of listeriosis in domestic animals in S?o Paulo-Brazil,"A serological examination was carried out for L. monocytogenes antibodies on 9,318 domestic animal--7,809 bovine, 838 horses and 671 swine--in S?o Paulo, Brazil. Serum agglutination in tubes was the method used. Only somatic antigens from serotypes 1, 2, 3, 4a and 4b were employed. It was considered reagent all sera reacting in a titer 1/20 while as positive only sera with 1/320 or above. According this criteria the results showed showed that in cattle 17.8% were reagent but only 8 sera were positive for types 1, 2 and 4b. Only type 1 was found in horses in a rate of 22.7% reagent, and 11 positive samples. For swine the percentage of reagent was 13.3% but none serum was positive, since the highest titer was 1/160.",1
7146,412451,Hepatic toxicity associated with gold therapy,"Three patients with rheumatoid arthritis developed jaundice after initiation of chrysotherapy. Gold sodium thiomalate had been administered in dosages of 37.5, 60, and 110 mg in these patients before the onset of jaundice. Liver function studies indicated a cholestatic jaundice in all subjects. One patient underwent exploratory laparotomy because of progressive jaundice. Liver biopsy was done in two patients. In one patient significant bile stasis and thrombi were seen in the biliary tree. In another patient liver biopsy showed ballooning of hepatocytes with minimal cholestasis. All patients recovered spontaneously. Awareness of this rare complication may prevent unnecessary diagnostic and surgical procedures in patients with rheumatoid arthritis who may develop jaundice while receiving chrysotherapy.",1
7147,416737,Gold and liver biopsy,,1
7148,424836,Cryptogenic cirrhosis associated with methyldopa,"A 55-year-old woman developed cirrhosis with portal hypertension while taking methyldopa. No other cause for the cirrhosis was evident. In view of the known hepatotoxic effects of methyldopa, a causal relationship is implied. Possible mechanisms of drug toxicity include both immunologic reactions and direct hepatocellular damage by the drug or its metabolites.",1
7149,425510,"Lithium poisoning. Report of a case with neurologic, cardiac and hepatic sequelae",,1
7150,426429,Oxacillin and hepatotoxicity,,1
7151,427109,Pyrenesulfonyl azide: a marker of acetylcholine receptor subunits in contact with membrane hydrophobic environment,,1
7152,433466,Lethal orphenadrine intoxication: report of a case,A case of lethal orphenadrine intoxication is reported. Included are the anatomical and toxicological findings. Most conspicuous histologically was the centrilobular necrosis of the liver.,1
7153,434706,Oxacillin and hepatitis,,1
7154,436393,Loxapine fatalities,,1
7155,440869,Accidental childhood iron poisoning: a problem of marketing and labeling,"Accidental iron poisoning still represents a significant hazard in children less than 5 years of age. The problem is compounded by the attractiveness of dosage forms, their high availability, and ambiguities in product labeling. Manufacturers accentuate label ambiguity by not specifically designating the iron as being total elemental iron or iron compound. A list of products that contain iron has been prepared to help clarify this issue.",1
7156,442549,The sensitivity of binocular rivalry to changes in the nondominant stimulus,,1
7157,445081,Hepatotoxicity of erythromycin derivatives,,1
7158,446297,[Anabolic agents and liver neoplasms],,1
7159,448845,Aplastic anemia and agranulocytosis in patients using methazolamide for glaucoma,"Carbonic anhydrase inhibitors used in the treatment of glaucoma, seizure disorders, and hypertension are rarely associated with blood dyscrasias. Several case reports of aplastic anemia with use of acetazolamide, and two cases with use of methazolamide, have appeared in the literature. This article describes two cases of aplastic anemia, at least one of which was almost certainly induced by the use of methazolamide, and one case of agranulocytosis related to the use of methazolamide.",1
7160,449328,Hepatotoxicity in disulfiram-treated patients,"Thirty-five alcoholics receiving disulfiram for 3 weeks showed no dose-related hepatotoxicity compared with controls, but 9 did exhibit non-dose-related subclinical hepatotoxicity.",1
7161,453894,Clofazimine in the treatment of pyoderma gangrenosum,"Ten patients with pyoderma gangrenosum, seven female and three male, 25 to 94 years old, mainly with multiple lesions, have been treated with clofazimine, 100 mg three times daily. Associated disease was registered in three patients: diabetes mellitus, a previous adenocarcinoma of the colon treated by hemicolectomy, and pustulosis palmoplantaris. In a further patient, M-component was found in the serum. In seven cases the lesions were completely healed by two to five months of therapy, and in three cases the ulcers healed partially. Side effects were redness of the skin in seven cases and dryness of the skin in two patients. No hematological side effects occurred. The working mechanism is still obscure.",1
7162,455188,Salicylate hepatitis in a case of juvenile dermatomyositis,,1
7163,457302,Acute copper intoxication,,1
7164,460061,Quantum fluctuations in radiographic screen-film systems,"With the recent introduction of fast rare-earth screens into the market, the question of noise and how it influences image quality becomes particularly important. In this paper a compact formula involving familiar and measurable quantities is derived for the specification of the noise arising from the spatial fluctuations of the x-ray quanta absorbed in the screens. Experimental evidence in support of this concept is also given.",1
7165,463905,Nitrofurantoin: another cause of drug-induced chronic active hepatitis? A report of a patient with HLA-B8 antigen,"Nitrofurantoin, an agent used extensively in chronic urinary tract infections, is rarely incriminated as a hepatotoxin. In this 27 year old women chronic active hepatitis first developed during exposures to nitrofurantoin, and she later suffered exacerbations. Earlier reported cases are reviewed which describe a spectrum of hepatotoxic reactions. This patient has HLA-B8, an antigen associated with autoimmune forms of chronic active hepatitis. It is postulated that the antigen may be associated with liver injury initiated by drugs such as nitrofurantoin.",1
7166,468068,Chronic oral arsenic intoxication as a possible aetiological factor in idiopathic portal hypertension (non-cirrhotic portal fibrosis) in India,"Estimates were made of the arsenic concentration in liver specimens from nine patients having idiopathic portal hypertension (IP), and in four livers these were found to be significantly higher than those in patients with cirrhosis and in control subjects. The splenovenogram revealed extensive portosystemic collateral circulation. Corrected sinusoidal pressure and blood flow studies showed higher levels in four patients than in normal subjects. Microscopic examination of liver tissues revealed periportal fibrosis. The higher hepatic arsenic levels that were found were due to the inadvertent drinking of water contaminated with arsenic, adulterated opium, and indigenous medicines. A history of opium intake was not forthcoming but two patients had drunk water contaminated with arsenic and two others had taken bhasams (Ayurvedic medicines prepared by repeated oxidation of ores). Though the aetiology of idiopathic portal hypertension is not known, it is possible that arsenic intake may be one of the factors.",1
7167,471729,[Hepatitis during indapamide therapy],,1
7168,479996,Acute hepatic failure in severe iron poisoning,,1
7169,482995,Noncirrhotic portal hypertension after arsenic ingestion,"Five years after arsenic therapy, the patient described had noncirrhotic portal hypertension, for which he had splenectomy and anastomosis of the splenic vein to the left renal vein. During the 12-year postoperative period he had Bowen's disease (skin carcinoma), but has had normal liver function and no further gastrointestinal bleeding. Arsenic exposure in humans is common throughout the world and may lead to late complications such as noncirrhotic portal hypertension and skin carcinoma, as well as malignancies of the lungs, liver, and lymphatic systems. It may also lead to severe arteriosclerosis with involvement of the heart and extremities.",1
7170,483555,[Prevention of sterility in cows on western Sibirian farms],,1
7171,484983,Sulindac and jaundice,,1
7172,492816,Clinical hepatotoxicity of isoniazid in children,A patient is presented with reversible clinical and biochemical hepatocellular injury secondary to isoniazid (INH). This apparently rare drug reaction in children is compared with the more common transient hypertransaminasemia induced by isoniazid. A review of the clinical literature and basic pharmacologic mechanisms of isoniazid-induced hepatotoxicity has led to a rational plan for monitoring and managing children who are treated with INH.,1
7173,496138,[Cholestatic hepatitis during treatment with I.N.H. and rifampicin: arguments in favour of the hepatotoxicity of rifampicin (author's transl)],"It is generally accepted that hepatitis occurring during treatment with INH and rifampicine results from the hepatotoxicity of INH metabolites. A case is reported of cholestatic hepatitis occurring during such treatment, in which there was a previous history of an isolated hepatic affection. The administration of INH and rifampicin caused cholestasis alone, which reoccurred after rifampicin administration only. No immuno-allergic phenomenon has been shown to be involved in rifampicin toxicity. This observation suggests that rifampicin may be hepatotoxic itself, especially in patients with previous hepatic affections.",1
7174,500344,Hepatic dysfunction in tuberculous patients treated with rifampicin and isoniazid,,1
7175,505359,Acute septicaemic melioidosis with pulmonary hilar prominence: a case report with a unique chest radiographic pattern,,1
7176,510025,The side effects and interactions of antituberculosis drugs,,1
7177,512520,Salicylate induced hepatotoxicity in juvenile rheumatoid arthritis--a case report,,1
7178,514726,Complete biliary obstruction due to erythromycin estolate administration in an infant,,1
7179,519312,Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning,"One hundred cases of severe paracetamol poisoning were treated with intravenous N-acetylcysteine (acetyl-cysteine). There was virtually complete protection against liver damage in 40 patients treated within eight hours after ingestion (mean maximum serum alanine transaminase activity 27 IU/1). Only one out of 62 patients treated within 10 hours developed severe liver damage compared with 33 out of 57 patients (58%) studied retrospectively who received supportive treatment alone. Early treatment and acetylcysteine also prevented renal impairment and death. The critical ingestion-treatment interval for complete protection against severe liver damage was eight hours. Efficacy diminished progressively thereafter, and treatment after 15 hours was completely ineffective. Intravenous acetylcysteine was more effective than cysteamine and methionine and noticeably free of adverse effects. It is the treatment of choice for paracetamol poisoning.",1
7180,522604,Unnecessary laparotomy for abdominal pain and fever due to clofazimine,,1
7181,524495,[Liver involvement in propylthiouracil treatment of juvenile thyrotoxicosis],,1
7182,531746,Symposium on morbid obesity,,1
7183,547161,Hepatic toxicity of adjuvant chemotherapy for carcinoma of the breast,"Four patients developed abnormal liver function tests and focal defects on liver scan while receiving cyclophosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy following mastectomy for breast cancer. Liver biopsies showed severe focal inflammation. The biopsy findings and the subsequent clinical course of the patients strongly suggest that these abnormalities were due to hepatic toxicity of the chemotherapy and not metastic breast cancer. A review of serial liver function tests performed on 24 patients in that chemotherapy program revealed that four out of eight patients with elevated alkaline phosphatase prior to therapy developed early metastatic cancer. Elevated alkaline phosphatase occurring during chemotherapy on the other hand was quite common but more likely due to hepatic toxicity of the drugs. The development of abnormal liver function tests even in association with focal defects on liver scan is not sufficient to diagnose metastatic breast cancer in patients receiving adjuvant chemotherapy.",1
7184,553260,Sicca complex and cholangiostatic jaundice in two members of a family probably caused by thiabendazole,"An entire family (father, mother, and three daughters) were given thiabendazole because one of the children had acquired pinworm infestation. The mother and one daughter (non-infected) developed a sicca complex (keratoconjunctivitis sicca and xerostomia) accompanied by cholangiostatic jaundice. Sjogren's syndrome is an autoimmune disease and presents many immune mechanism aberrancies. An association between autoimmune liver disease and sicca complex has been reported. Labeled mitochondrial antibodies bound to the parotid duct have been noted in patients with autoimmune cholangiostatic jaundice and such antibodies may be similar to the antibody against salivary duct found in Sjogren's syndrome. It is suggested that in these two patients, thiabendazole may have acted as a hapten and by binding to the body protein induced the production of autoantibodies which may have acted against the biliary epithelium, the salivary duct epithelium, and the lacrimal gland ducts.",1
7185,556610,Liver disease in vineyard sprayers,"""Liver disease with inclusions of copper was recognized among 30 rural workers with """"vineyard sprayer's lung."""" The pathological findings were varied: focal or diffuse swelling and proliferation of Kupffer cells; histiocytic and sarcoid-like granulomata; fibrosis of variable degree in the perisinusoidal, portal, and subcapsular areas, accompanied by atypical proliferation of the sinusoidal lining cells; micronodular cirrhosis; angiosarcoma of the liver; idiopathic portal hypertension. Abundant deposits of copper were revealed by histochemical techniques within hepatic and pulmonary lesions in these patients. The observations on the human and experimental material suggest an etiological relationship between exposure to copper sulfate and the lesions described. A morphological resemblance was noted between the """"liver disease of vineyard sprayers"""" and the hepatic lesions reported in workers exposed to inorganic arsenic and to vinyl chloride. The identification of the inhaled foreign material within the liver lesions raises important etiological considerations.""",1
7186,560985,Desmosomal abnormalities in the liver of methotrexate-treated psoriatics,Electron microscopy of the liver of methotrexate-treated psoriatic patients revealed junctional abnormalities consisting of detachment of desmosomal plaques between hepatocytes. Mitochondria anchoring desmosomal microfilaments were frequently noted.,1
7187,567014,"Development of hepatic angiosarcoma in man induced by vinyl chloride, thorotrast, and arsenic. Comparison with cases of unknown etiology","Examples of human angiosarcoma following exposure to vinyl chloride, Thorotrast, or arsenic (medicinal and industrial) and cases, including children, of unknown etiology were studied to establish diagnostic criteria and to study their evolution. The uniform evolution suggests an environmental factor also in the cases of unknown etiology, which may be established by epidemiologic studies. A precursor stage is charaterized by areas of combined hyperlasia of hepatocytes and a variety of sinusoidal and perisinusoidal cells associated with excess of reticulin and with sinusoidal dialation. The diagnostically useful picture in silver impregnations indicated reticulum formation by the perisinusoidal cells, presumably the libocytes. The hepatocytic proliferation suggests a hepatocarcinogenic but usually not fully expressed potential. The mixed hyperplasia of the various sinusoidal cells proceeds to an overgrowth of angiosarcoma cells, presumably derived from endothelial cells. In early stages they are usually in contact with hepatocytes (intralobular growth). A trabecular arrangement results from loosening of the lobular plate arrangement by dilatation of sinusoids, leading to primary peliosis. With disappearance of the hepatocytes, various growth patterns develop, terminating in nodular, solid angiosarcoma composed of either spindle-shaped or polyhedral cells which undergo necrosis or hemorrhage (secondary peliosis). The interaction between hepatocytes and sinusoidal cells requires elucidation.",1
7188,571981,Bromocriptine in Parkinson disease: further studies,"""Bromocriptine was administered to 66 patients with advanced Parkinson disease (PD) and increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Forty-five patients tolerated at least 25 mg per day of bromocriptine (the """"adequately treated"""" group) in addition to Sinemet and had significantly decreased rigidity, tremor, bradykinesia, gait disturbance, and total score, but increased involuntary movements. Twenty-five of these 45 patients improved by at least one stage. Among the 45 patients, 27 had """"on-off"""" effects, and in 19 the """"on-off"""" effects decreased on bromocriptine. The mean dose of bromocriptine in adequately treated patients las 47 mg, permitting a 10 percent reduction in the dose of levodopa. Twelve adequately treated patients received bromocriptine for at least 1 year, and 8 continued for longer than this. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). All adverse effects were reversible. Despite adverse effects, expense, and scarcity, bromocriptine, when added to levodopa, is useful in patients with advanced disease who no longer respond satisfactorily to levodopa, and for whom no other treatment is available.""",1
7189,574201,Phenytoin hypersensitivity: 38 cases,"To determine the frequency and severity of hypersensitivity reactions to phenytoin, we reviewed 38 cases of proven reactions. Patients were included only if no other drugs, including other anticonvulsants, were in use at the time of the reaction. Rashes were most frequent, followed by fever, lymphadenopathy, eosinophilia, abnormal liver function tests, blood dyscrasias, serum sickness, renal failure, and polymyositis. The pseudolymphoma syndrome, (fever, rash, and lymphadenopathy) occurred in nine patients. Thirty-five of the 38 reactions occurred within 2 months of the start of therapy. Phenytoin sensitivity accounted for 467 inpatient days during the 14 years of study. Early recognition of phenytoin reactions, prompt drug withdrawal, and appropriate therapeutic measures were necessary to prevent serious morbidity from phenytoin hypersensitivity.",1
7190,576881,Massive hepatic necrosis in a patient receiving allopurinol concomitant medication,,1
7191,577673,Peliosis hepatis. Twelve cases associated with oral androgen therapy,"Peliosis hepatis was encountered in 12 patients treated with high-dose oxymetholone or fluoxymesterone therapy. In three cases liver failure was the primary cause of death. In one case, the diagnosis was established by biopsy, the androgen therapy was discontinued, and the lesion was absent at autopsy two years later. In eight cases peliosis hepatis was an incidental finding at postmortem examination. The clinical and anatomic features of these cases are described, and previously reported cases of peliosis are briefly reviewed. A hypothesis is offered to explain the association of this peculiar lesion with anabolic androgen therapy.",1
7192,581569,Updating the side effects of the penicillins,"Use of the penicillins in patients may result in a variety of side effects in addition to the well known occasional allergic reactions. Some of these side effects may be quite serious. Treatment with the various penicillins, expecially in the large amounts presently prescribed, may be attended by immunologic reactions, such as nephritis, and by direct toxic effects which may involve the blood platelets, the neurones of the central nervous system, and perhaps the parenchymal cells of the liver.",1
7193,593197,[Drug-induced chronic aggressive hepatitis],,1
7194,594300,Aplastic anaemia: a study of prognosis and the effect of androgen therapy,"One hundred and twenty-nine Chinese patients with aplastic anaemia, were studied. In ten it was induced by drugs, one followed hepatitis and the remainder were of unkown cause. Mortality within the first six months was 47.3 per cent. Features associated with poor prognosis included a short duration of symptoms of three months or less, neutropenia of less than 0.5 x 10(9)/l and severe thrombocytopenia. On the other hand, some preservation of erythroid activity of the bone marrow was associated with long survival. Remission occurred in 47 patients and this was associated with androgen therapy in 33. Remission was complete in 18 and partial in 29. In the latter group, persistent thrombocytopenia was the main abnormality and treatment with calusterone led to an increase in platelets although the effect was not sustained after its withdrawal. Hepatotoxicity was seen in 16.0 per cent of patients treated with androgens and this occurred even with non-17alpha-alkylated compounds. It is concluded that androgen therapy was useful and should be started as early as possible after diagnosis. Hepatic intolerance to androgens may be an indication for bone marrow transplantation.",1
7195,594785,The other side of the coin,,1
7196,598417,Hepatic injury and drug metabolism in patients with alpha-methyldopa-induced liver damage,,1
7197,602767,Liver ultrastructure in psoriatics related to methotrexate therapy. 2. Findings in bile ducts from 11 methotrexate treated psoriatics and 2 controls,To determinate what damage occurred in the bile ducts of psoriatics receiving Methotrexate (MTX) therapy liver biopsies from 11 patients were studied with the light and electron microscope and compared with normal material. Thick sections (1 micrometer) showed light and dark cells in biliary epithelium and lipofuscin granules. At the ultrastructural level these were confirmed. The lumen of the bile ducts contained debris. The microvilli were decreased in number and damaged forms appeared. Damage to the biliary epithelial mitochondria was widespread and there were foci of intracellular oedema. The Golgi apparatus was hypertrophied and dilated. Atrophic cells were seen. The lateral intercellular spaces were dilated and contained debris and the basement membrane showed zones of duplication. Similar changes were found in the ducts of Hering.,1
7198,612620,Isoniazid hepatotoxicity: report of two cases,,1
7199,615837,Hyperplasia and prolapse of hepatocytes into hepatic veins during longterm methyltestosterone therapy: possible relationships of these changes to the developement of peliosis hepatis and liver tumours,"We report the pathological changes in liver biopsies from 10 patients (four female transexuals and six impotent males) after treatment with 150 mg methyltestosterone daily for periods of up to 3 years, and in a hemihepatectomy specimen from a female transexual who developed a liver adenoma after 37 months of this treatment. Hepatocyte hyperplasia and mild focal sinusoidal dilatation was found in most cases. In some cases there were microcysts and dissociation of hepatocytes. In nine patients there was accumulation of hepatocytes between the endothelium and the supporting collagen of hepatic veins which often resulted in either partial occlusion of their lumina or disruption of their walls. These vascular changes do not appear to have been reported before. It is postulated that a single pathological process-hyperplasia, perhaps related to the anabolic effect of methyltestosterone--could be partly responsible both for the formation of cysts through mechanical obstruction of hepatic veins and for the formation of nodules and tumours.",1
7200,622225,Effect of pregnancy on liver tumor associated with oral contraceptives,Four cases of liver adenoma associated with oral contraceptives complicating pregnancy are reported. All patients were symptomatic during pregnancy and 2 were admitted with rupture of the adenoma. One subsequently died. Increased growth and vascularity of adenomas during pregnancy is highly likely. The potential for development of lethal complications is considerable.,1
7201,626188,A fatal case of peliosis of the liver and spleen,,1
7202,628065,Chenotherapy for gallstone dissolution. II. Induced changes in bile composition and gallstone response,"""Changes in bile saturation and biliary bile acid composition in patients with gallstones who received chenodeoxycholic (""""chenic"""") acid, cholic acid, or placebo were measured. Chenodeoxycholic induced bile desaturation; this effect was attributable solely to a decrease in the proportion of cholesterol. By gas chromatography, chenodeoxycholic acid increased substantially in the biliary bile acids of patients receiving it, and by mass spectrometry, no unusual bile acids were detected in appreciable amounts. Changes in bile saturation and biliary bile acid composition were then related to chenodeoxycholic acid dosage, and all of these variables were, in turn, related to gallstone response. In general, patients whose gallstones dissolved ingested a higher dose of chenodeoxycholic acid or had bile that contained a higher proportion of this acid and it was more unsaturated, but there were many exceptions, casting doubt on the value of a single analysis of fasting-state bile for predicting gallstone dissolutions. The major factor influencing response, provided dosage is adequate, appears to be gallstone type. Nonetheless, the proportion of chenodeoxycholic acid in biliary bile acids can probably be used to infer patient compliance.""",1
7203,629612,Cholestatic jaundice caused by D-penicillamine,"D-penicillamine is not generally considered to cause hepatic damage. Cholestatic jaundice developed in a patient with rheumatoid arthritis 4 weeks after penicillamine was added to his regimen, and he died in acute renal failure. The probability that penicillamine caused the cholestasis is discussed.",1
7204,629894,Arsenic exposure and mortality: a case-referent study from a Swedish copper smelter,"An increased mortality from lung cancer, cardiovascular disease, haematolymphatic malignancy and cirrhosis of the liver has been reported among smelter workers and others exposed to arsenic. This study uses the case-referent (case-control) technique and is concerned with workers in a copper smelter in a complex work environment, characterised by the presence of trivalent arsenic in combination with sulphur dioxide and copper, and also with other agents. Lung cancer mortality was found to be increased about five-fold and cardiovascular disease about two-fold, showing a dose-response relationship to arsenic exposure. Mortality from malignant blood disease (leukaemia and myeloma) and cirrhosis of the liver was also slightly increased. This mortality pattern among the smelter workers is consistent with earlier reports. An increased mortality from cardiovascular disease in this type of industry is of particular interest as it has been reported only once before.",1
7205,630623,[Treatment of various complications of photocoagulation in cataract extraction],,1
7206,636413,Cirrhosis due to hypervitaminosis A,,1
7207,645691,Tolazamide-induced hepatic dysfunction,"A case of tolazamide-induced hepatic injury is reported. Injury was documented by abnormal liver tests, including an elevated alkaline phosphatase, 5' nucleotidase and serum glutamic oxaloacetic transaminase. Liver biopsy confirmed the degree and type of injury which consisted of severe portal inflammation, bile duct proliferation and early fibrosis. The case is reported to further establish tolazamide as a drug capable of producing hepatic injury and to report a new form of hepatic injury attributable to a sulfonylurea agent.",1
7208,646570,Allopurinol-induced granulomatous hepatitis with cholangitis and a sarcoid-like reaction,"""A 36-year-old man had pain in both knees and an elevated uric acid concentration; his liver function was normal. Allopurinol therapy was started, 100 mg twice daily. After one month fever, lethargy, and severe polyarthralgia developed. On admission to our hospital liver function was abnormal, and a liver biopsy specimen showed granulomas with cholangitis and pericholangitis. He also had lymphopenia with a reduced number of T cells and granulomas in the bone marrow. One month after discontinuation of allopurinol therapy the patient was clinically well with normal liver function and a normal lymphocyte count. A repeated liver biopsy specimen showed normal liver tissue with no granulomas. The onset of the symptoms and findings shortly after the initiation of allopurinol therapy, and their disappearance after the discontinuation of therapy suggest a drug-induced hypersensitivity.""",1
7209,648827,Mechanisms of chlorpromazine cholestasis: hypersensitivity or toxic metabolite?,,1
7210,651333,Cimetidine cholestatic jaundice in children,,1
7211,661938,Possible association of granulomatous hepatitis with clofibrate therapy,,1
7212,666111,Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study,"""After an outbreak of hepatitis in Washington, D.C. in 1970 among a group of persons taking isoniazid to prevent tuberculosis, an isoniazid surveillance study was conducted among 13,838 persons in 21 participating health departments. Age appeared to be the predominant factor influencing the risk of developing isoniazid-related hepatitis, i.e., increasing age was associated with an increasing risk. Drinking alcohol, especially on a daily basis, also seemed to enhance the risk of hepatitis among persons concurrently taking isoniazid. In general, case rates among males and females of the same race, and rates among different races, were not markedly different; however, there were striking differences in the case rates among males of different races. The incidence of hepatitis varied greatly among the 21 cities, but was not unique to any geographic region, nor was it related to a specific manufacturer of isoniazid. The onset, in most cases, occurred within the first few months of treatment. Eight fatalities were reported by the 21 participating health departments, 7 occurring in one city. Black females accounted for 5 of the 8 deaths. This information provides a basis for weighing the benefits of isoniazid in preventing tuberculosis against the risk of its causing hepatitis. Close monitoring for overt signs or symptoms of hepatitis among persons receiving isoniazid preventive therapy is indicated, especially for persons greater than or equal to 35 years of age and those who drink alcoholic beverages on a daily basis.""",1
7213,667811,Hepatopathy following irradiation and adriamycin,"This report describes two cases of hepatopathy following irradiation and adriamycin at doses and volumes of irradiation ordinarily considered within the tolerance of hepatic function. In one case fatal hepatopathy followed 2400 rad/17 fractions/28 days to the entire liver with preceding and concurrent adriamycin. In the second case moderate clinical changes occurred after treatment in which much of the right lobe of the liver was shielded following 2500 rad/23 fractions/32 days with adriamycin administered before, during, and after irradiation. The locally enhancing effects of adriamycin on hepatic tolerance to irradiation are discussed.",1
7214,671139,Salicylate-induced hepatotoxicity: a review,,1
7215,673548,Clinical pharmacology and efficacy of ticarcillin in infants and children,"Ticarcillin was evaluated in 82 neonates and young infants with suspected sepsis and in 16 older children with chronic Pseudomonas infection of the mastoids. The infants also received kanamycin. Individual ticarcillin doses of 75 or 100 mg/kg were given every four, six, or eight hours by intramuscular injection or by a 30-minute intravenous infusion. Mean plasma concentrations one hour after a dose were from 125 to 189 microgram/ml, depending on dosage, age, and maturity. Mean plasma half-lives were approximately 5 hours in the first week of life, 2 hours in infants from 1 to 8 weeks, and 0.9 hours in older children. Volume of distribution was approximately twice as great in infants as in children, and plasma clearance rates correlated inversely with age. Limited efficacy data suggest that ticarcillin is a suitable alternative to ampicillin or carbenicillin, when given concurrently with an aminoglycoside, for newborn infections. When given for several days before mastoidectomy and tympanoplasty, ticarcillin sterilized the mastoids in the majority of patients. A new dosage schedule for ticarcillin in pediatric patients is proposed.",1
7216,673817,[Elevation of glutamic-pyruvic transaminases under procetofene treatment of idiopathic hyperlipemia: incidence and significance in 443 treated cases],,1
7217,677132,Fenoprofen-induced hepatotoxicity,,1
7218,684947,[Acetylsalicylic acid and liver damage],,1
7219,685927,Clofibrate therapy and gallstone induction,,1
7220,689968,Zinc phosphide poisoning in dogs,,1
7221,695571,Analgesic hepatotoxicity,,1
7222,696433,Intrahepatic jaundice due to warfarin therapy,,1
7223,698699,Diflunisal-induced cholestatic jaundice,,1
7224,707874,Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis,"""Seventy-five patients who developed mild hepatic reactions (serum transaminase concentrations of 45 to 149 units per liter) and 50 patients who showed more serious liver damage (serum transaminase values greater than 150 units per liter) were compared with 261 consecutive patients who had no liver reactions during treatment with rifampin and isoniazid. Generally, liver toxicity occurred in 18 per cent of patients receiving combined anti-tuberculous drug therapy. Small increases in transaminase occurred in 14 per cent of the patients; large increases occurred in 4 per cent. Elderly women comprised a risk group. Among patients exhibiting a more serious hepatic lesion (transaminase values greater than 150 units per liter), alcoholics, mostly men, formed another risk group, together with other patients with a history of previous liver or biliary disease. Of 261 patients who did not develop a liver reaction, 57 per cent were slow INH acetylators. In this study, the groups with small and large increases in transaminase were clearly separated; in the former group there was no preponderance of phenotype, whereas in the latter group, slow acetylators clearly dominated among early (first 4 weeks of treatment) hepatic reactions (P less than 0.01). Studies of single-drug regimens of isoniazid have shown that neither slow nor rapid acetylation has any causal influence on isoniazid-induced hepatitis. Because the metabolism of rifampin is independent of the acetylation process, rifampin and isoniazid in combination seem to cause a toxic hepatitis that differs from the hepatitis induced by either drug separately.""",1
7225,710735,Fine structural changes in the liver of methotrexate-treated psoriatics,"Ultrastructure of 55 liver biopsies obtained from 52 patients, all but 1 with psoriasis and all but 5 treated with methotrexate (MTX), have been studied. In MTX-treated psoriatics, liver cell nuclei showed reduced electron opacity with frequent cytoplasmic invaginations and glycogen inclusions. In the mitochondria nonspecific changes, such as pleomorphism, gigantism, paracrystalline inclusions, compartmentalization, signs of division and sequestration via autophagosomy were noted. The pericanalicular ectoplasm exhibited widening with accumulation of microfilaments. Detachment of desmosomal plaques between hepatocytes was common. A striking finding was the hyperplasia of fat-storing perisinusoidal (Ito) cells. No definite correlation was found between morphology, duration of disease, treatment as well as cumulative dose of MTX.",1
7226,712504,Liver functions in children receiving carbamazepine,,1
7227,719380,"Genetic basis of rheumatoid disease: HLA antigens, disease manifestations, and toxic reactions to drugs",Ninety-five patients with rheumatoid arthritis and 200 healthy controls were examined for HLA-D-related (HLA-DR) alloantigens. HLA-DRW4 was significantly more prevalent among the patients and was particularly common in those with a family history of the disease (77% of such patients had DRW4 compared with 34% of controls). Significantly fewer patients than controls had DRW2: patients with this antigen had rheumatoid nodules less frequently and significantly lower titres of rheumatoid factor than patients without DRW2. In contrast DRW3 was significantly more prevalent among severely affected patients with rheumatoid factor titres exceeding 1/1280 and in patients with nodules. There was a significant association between DRW2 and DRW3 and toxic reactions to sodium aurothiomalate and penicillamine. The results suggest that the HLA-DR phenotype is associated not only with susceptibility to rheumatoid arthritis but also with severity of the disease and whether certain toxic reactions to drugs occur.,1
7228,719602,"o,p'-DDD (mitotane) therapy of adrenal cortical carcinoma: observations on drug dosage, toxicity, and steroid replacement","Four patients with adrenal cortical carcinoma were treated with standard doses of o,p'-DDD. Plasma levels of o,p'-DDD and its metabolites o,p'-DDA and o,p'-DDE were measured. o,p'-DDD was measurable for up to 8 months after stopping therapy, and trace levels of metabolites were detectable at 18 months. Although 2 of 3 patients with measurable disease had objective tumor response and one patient achieved a complete response, severe drug toxicity occurred in all patients and signs of adrenal insufficiency occurred in three. Low dose therapy with o,p'-DDD is suggested, together with full gluco and mineralocorticoid replacement. Measurement of o,p'-DDD and its metabolites in plasma may prove clinically useful in developing effective but less toxic dosage schedules.",1
7229,722447,Pyrrolizidine (Senecio) intoxication mimicking Reye syndrome,,1
7230,724343,"""Chronic salicylate administration in juvenile rheumatoid arthritis: aspirin """"hepatitis"""" and its clinical significance""","Salicylates provide the backbone of therapy in juvenile rheumatoid arthritis. They are effective in controlling the disease approximately 75% of the time if they are properly used. Salicylate administration is relatively safe if carefully done. Serum salicylate levels should not exceed 30 mg/dl routinely. Patients, physicians, and parents should be alert to early clinical signs of toxicity. Chief hazards of chronic salicylate administration other than salicylism (which should be uniformly preventable) include gastric irritation with questionable relationship to peptic ulcer disease, and rare serious hepatotoxicity, bleeding diatheses, or hypersensitivity reactions.",1
7231,727408,[Technical contribution to the surgical treatment of bilateral laryngeal paralysis],,1
7232,735735,Negligible hepatotoxicity of chlorpromazine in long-term therapy,,1
7233,740454,[Severe hepatitis induced by chemotherapy with antitubercular agents in childhood. 2 cases],,1
7234,742878,Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans: possible factor in 5-fluorocytosine clinical toxicity,"A gas chromatographic-mass spectrometric method for detecting 5-fluorouracil (5-FU) in serum at concentrations as low as 10 ng/ml was used to determine to what extent 5-FU was present in the serum of patients taking oral 5-fluorocytosine (5-FC). Preliminary studies in two patients and two healthy volunteers given an initial 2-g oral dose of 5-FC demonstrated sustained serum 5-FU levels (>100 ng/ml) during the 5 h after ingestion of drug. Pharmaceutical preparations of 5-FC used in these studies were shown to be insignificantly contaminated with 5-FU (<0.03%), suggesting in vivo conversion of 5-FC to 5-FU had occurred. Serum samples from seven patients with cryptococcal meningitis treated with amphotericin B and 5-FC were examined for 5-FU. Five of these patients had experienced hematological or other toxicity attributed to 5-FC at some time during the course of therapy. Of 41 serum samples, 20 were observed to have 5-FU levels greater than 1,000 ng/ml in the range observed with cancer chemotherapeutic doses of 5-FU known to be associated with hematological toxicity. It is concluded that conversion of 5-FC to 5-FU occurs in humans and furthermore that 5-FU may account for some of the toxicity observed with 5-FC.",1
7235,746229,[Acute hepatitis caused by erythromycin],,1
7236,751721,A case of liver toxicity following cis-dichlorodiammineplatinum(II) treatment,,1
7237,761834,Hepatitis from dantrolene sodium,"The clinical course and histological changes in the liver during a presumed adverse reaction to the drug dantrolene sodium are described in four patients. After a typical prodrome one developed a moderately severe hepatitis-like illness. Another also had a prodrome but never became jaundiced. In the other two, abnormal liver function tests were detected on routine screening. In each case liver biopsy showed changes typical of an acute hepatitis, but the severity was unrelated to the clinical presentation. In addition, there were also changes in the portal tracts resembling ascending cholangitis. In each case liver function tests returned to normal after withdrawing treatment with dantrolene.",1
7238,763309,Severe reaction associated with sulindac administration,,1
7239,772461,"An evaluation of baclofen treatment for certain symptoms in patients with spinal cord lesions. A double-blind, cross-over study","""Baclofen (a gamma aminobutylic acid derivative) and a placebo were compared for their efficacy in relieving certain symptoms in patients with long-standing spinal cord lesions and """"spinal spasticity."""" In a double-blind, cross-over clinical investigation, 22 patients with chronic spinal cord disease were studied. Baclofen regularly alleviated involuntary flexor or extensor spasms and increased resistance to passive movement of the legs but did not alter strength, gait, stretch reflexes, or clonus. Side effects were mild and transient. This study demonstrates that (1) baclofen is useful for the treatment of flexor spasms and (2) in evaluating a new mode of therapy, one must consider selectively the response of individual components of such global syndromes as """"spasticity.""""""",1
7240,781229,"Fenoprofen calcium in steroid treated rheumatoid arthritis: efficacy, safety, and steroid-sparing effect","Twenty-one patients with active rheumatoid arthritis on maintenance corticosteroids were studied during a double-blind, crossover trial with fenoprofen. Fenoprofen showed significantly greater effect than did placebo on several subjective and objective measurements. In addition, patients were able to reduce their dose of corticosteroid to a level significantly lower than that during placebo periods. Though three patients dropped out of the study with gastrointestinal complaints while on fenoprofen, only one of these was believed to be drug-related. No serious adverse effects were encountered.",1
7241,786007,Aspirin-induced hepatic dysfunction in a patient with adult rheumatoid arthritis,"A patient with classical rheumatoid arthritis receiving high doses of aspirin developed significant elevation of serum glutamic oxaloacetic transaminase. This patient had recently been on phenylbutazone and an initial liver biopsy, at the time of elevation of the transaminase revealed nonspecific mild fatty infiltration of the liver compatible with the pathology seen with rheumatoid disease. Because of the severity and activity of her rheumatoid arthritis, and thus the need to know whether aspirin was the etiologic factor in liver dysfunction, the patient was challenged with aspirin. SGOT elevation occurred after a 4-6 day lag period, which promptly remitted when salicylates were discontinued. A liver biopsy at this time revealed evidence for degeneration, regeneration, and mild focal mononuclear infiltration. Although previous reports note salicylate-related hepatocellular dysfunction in patients with systemic lupus erythematosus and juvenile rheumatoid arthritis, these data clearly demonstrate the relationship of ASA to liver dysfunction in a patient with adult onset rheumatoid arthritis. This histologic picture as well as the clinical course of this patient's hepatic abnormality suggest a toxic rather than hypersensitivity etiology for this syndrome.",1
7242,788271,[Psoriasis vulgaris. Treatment with carbon-arc light baths and 8-methoxypsoralen. A double-blind investigation],,1
7243,790035,Tetracycline hepatotoxicity. A review,,1
7244,793592,Neurotransmitter release from viable purely cholinergic Torpedo synaptosomes,,1
7245,797593,"A double-blind study comparing Daktacort, miconazole and hydrocortisone in inflammatory skin infections","In a 4-week double-blind trial, Daktacort cream was compared with each of its constituents (i.e. miconazole 2% and hydrocortisone 1%) in a total of 63 patients (aged 12-60 years) with inflamed skin infections of bacterial or mycotic origin. Daktacort treatment induced a significant improvement of all symptoms within 1 week and was superior to both miconazole and hydrocortisone in suppressing the inflammation. This tendency persisted throughout the trial but at the end miconazole treatment proved also superior to hydrocortisone.",1
7246,808198,Hepatic rupture from anticoagulant therapy,,1
7247,817630,Computer files and analyses of laboratory data from tuberculosis patients. II. Analyses of six years' data on sputum specimens,"""Laboratory data on sputum specimens from patients with pulmonary mycobacterioses between 1968 and 1973 were analyzed. Specimens were cultured on Middlebrook 7H10 and/or 7H11 medium; blue light fluorescence microscopy was used to examine specimen smears. An admission series of 6 sputum specimens detected 94.7 per cent of all culture-positive patients. Only 62 per cent of patients who were culture positive in the admission series would have been detected by smear alone. Quantitative agreement of smear and culture results was seen only in the smear-numerous (more than 2 bacilli per high-power field), culture-numerous (more than 100 colonies per plate) category. Qualitative agreement of smear and culture was 71 per cent. A total of 123 smear-positive and culture-negative specimens, representing 9 per cent of the total number of positive smears, was found among 6,251 sputum specimens from 270 culture-positive ptients. At least one smear-positive and culture-negative specimen was obtained from 23 per cent of the patients evaluated. During this period, improved housekeeping measures and drying of culture plates reduced the culture contamination rate from 9.8 to less than 5 per cent.""",1
7248,819639,Isoniazid hepatitis in adolescents,"Prophylactic isoniazid therapy is currently recommended for adolescents with positive tuberculin reactions because of the risk of activation of tuberculosis in this age group. Since this drug has been associated with hepatic dysfunction in adults, the present study was undertaken to evaluate its effect on liver function in teen-agers. Accordingly, liver function tests were performed on 178 adolescents prior to and following administration of INH. Abnormalities in SGPT values were encountered in 10% of these patients and occurred in the main within the first 10 weeks of testing, suggesting INH maybe hepatotoxic. However, jaundice was notably absent in the patients with enzyme elevations and prompted a further investigation into the possible effect of INH on bilirubin metabolism. Thus, Sprague-Dawley rats were given four daily injections of INH. These animals manifested increased hepatic bilirubin glucuronyl transferase activity when compared with control rats, supporting the hypothesis that enzymatic induction may be responsible for the absence of jaundice in our adolescent subjects.",1
7249,824116,Pimozide: a review of its pharmacological properties and therapeutic uses in psychiatry,"Pimozide 1-(1-[4,4-bis(4-fluorophenyl)butyl]-4-peperidinyl)-2-benzimidazolone, is the first of a new series of psychotropic drugs, the kiphenylbutylpiperidines. It is advocated for once-daily use as maintenance therapy in chronic schizophrenia and for the treatment of psychic and functional disorders induced by personality traits. Published data suggest that in chronic schizophrenia, pimozide 4 to 6mg daily is indistinguishable from maintenance doses of chlorpromazine, fluphenazine, flupenthixol, perphenazine, or thioidazine. Patient groups have usually been to small to allow statistically significant differences to be apparent, but in some trials pimozide was significantly superior to trifluoperzine and to haloperidol. On present evidence, pimozide has no place in the hyperactive, aggressive type of patient or in treating the acute phase of schizophrenia, probably because of its relative lack of sedative properties compared with many antipsychotic drugs. The incidence and severity of extrapyramidal reactions with pimozide are low, but suitably designed controlled studies are needed to determine whether its use leads to a reduction in the requirement for antiparkinsonian medication. In anxious patients, pimozide seems to offer no advantages over currently available anxiolytic agents, either in terms of efficacy or incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven.",1
7250,825355,Long-term study of molindone hydrochloride in chronic schizophrenics,,1
7251,829608,[Psychiatric nosology and indication of psychopharmaceuticals],,1
7252,833445,"Leprosy in the United States, 1971-1973",,1
7253,835915,Isoniazid-related hepatotoxicity,,1
7254,835940,Aspirin hepatotoxicity and disseminated intravascular coagulation,"""A 17-year-old girl with a clinical diagnosis of adult-type juvenile rheumatoid arthritis developed a severe hepatotoxic reaction to 3.6 g of aspirin per day. This was associated with a microangiopathic anemia and transient congestive cardiac failure. She responded well to steroids, and when all laboratory test findings were back to normal, she was """"challenged"""" with five divided doses of aspirin (total, 3.0 g). This produced a salicylate level of 9.1 g/dl and was associated with an immediate deterioration in liver function test findings and a return of microangiopathic blood features with elevation of fibrin split products and a prolonged prothrombin time. These changes were again reversed by promptly starting steroid therapy. This case suggests that disseminated intravascular coagulation, and its rare association with hepatotoxicity, is a potentially fatal side effect of aspirin therapy.""",1
7255,836694,Treatment of servere psoriasis with pyrimethamine,"""Pyrimethamine, a folate antagonist similar to methrotrexate without known hepatotoxcity in man, was administer orally, once a week, to seven patients with severe, long-standing psoriasis. Four patients obtained a good to excellent response; a fifth withdrew from the study early after a partial response; a sixth had minimal response to high doses, and the seventh was withdrawn due to a probable drug-induced hepatotoxic reaction. Hepatotoxic reaction was suspected in another patient with abnormal liver biopsy and experienced severe gastrointestinal toxic reactions and two developed significant thrombocytopenia, which resolved after oral treatment with folic acid or discontinuation of the drug. These did not recur at lower doses. Pyrimethamine appears to be effective in severe psoriasis, but offers no advantage, and several disadvantages over methotrexate. Pyrimethamine is probably hepatotoxic. It should be used with caution in patients with liver disease or impaired renal function; pretreatment liver biopsy is recommended.""",1
7256,838229,Salicylate hepatitis,"Two patients developed acute hepatic injury as a result of salicylate therapy. In each patient serum salicylate levels were below 25 mg per 100 ml during the development of hepatic dysfunction. Liver biopsies, obtained a few days after the peak abnormalities in serum transaminases, revealed nonspecific acute hepatitis. Normal liver tissue was found before the beginning of salicylate treatment in 1 patient, who had systemic lupus erythematosus and drug rechallenge was not attempted. In the other patient, who had rheumatoid arthritis, rechallenge with salicylate evoked hepatic dysfunction and recurrent symptoms. Salicylate-induced liver injury should be considered in the differential diagnosis of hepatic disease occurring in patients receiving high dose salicylate therapy, regardless of serum salicylate levels.",1
7257,839638,[Therapy for severe anaerobic infections with clindamycin (author's transl)],"""Ten adult patients with severe Bacteroides infections were treated with 0.9 approximately 1.8 g/day of parenteral or oral clindamycin, and a child was treated with 0.3 g/day orally. Remarkable responses and cures were obtained in all the patients, who had no underlying diseases and pure anaerobic infections; a case of sepsis, two cases of liver abscess, a case of subcutaneous abscess and a case of spinal epidural abscess. The other six patients who had ultimately fatal underlying diseases or mixed infections did not respond well to the combination of clindamycin and the other antibiotics therapy, althought bacteriological cures were obtained in all but two cases. Clindamycin was well tolerated and generally nontoxic, nevertheless it was administrated for long term (34 approximately 49 days). But transient development of transaminase was seen in a patient. The data suggested that clindamycin should be considered a first choice antibiotic for the treatment of an aerobic, especially, Bacteroides infections.""",1
7258,841390,Close monitoring is essential during isoniazid prophylaxis,"""A three-year prospective study during the entire course of preventive therapy with isoniazid (INH) for recently infected hospital employees was undertaken to evaluate the risk of developing INH-related hepatic injury. Results of clinical and laboratory tests at 1, 2, 6, and 12 months were correlated to ascertain the significance and value of monitoring procedures. Thirty-two (32%) of 100 employees developed elevated SGOT levels: one (1%) patient developed clinical hepatitis in the first month of therapy; four (4%) subjects with SGOT elevations (82-378 units) became clinically symptomatic at one to four months and INH was discontinued; one (1%) individual with minimal increases in serum bilirubin and SGOT levels was symptomatic at eight months and the drug was stopped. Twenty-four (24%) otherwise asymptomatic subjects who developed SGOT elevations (70-480 units) were followed at closer intervals to complete INH therapy without further progression of liver function abnormality. The intervals between the beginning of treatment and the elevation of SGOT levels varied widely, with elevations occurring throughout the 12-month course of isoniazid therapy.""",1
7259,848977,Phenytoin-induced pseudolymphoma syndrome: an immunologic study,"""In vitro and in vivo immunologic studies were performed on a 28-year-old woman with phenytoin sodium-induced pseudolymphoma syndrome. During the acute phase of the syndrome, the patient appeared immunologically depressed. Six months after resolution of lymphadenopathy, repeat studies demonstrated a return to immunologic competence. In vitro studies of the patient's lymphocytes when incubated with phenytoin failed to indicate a delayed hypersensitivity reaction to the drug; These findings suggest that the patient developed a clinical lymphatic proliferation at a time when she was immunologically depressed. This may result in an increased chance of a mutant malignant clone developing at a time when the immunosurveillance system is impaired and explains why a rare patient with this syndrome may develop a frank malignant lymphoma.""",1
7260,858271,The safety and value of naloxone as a therapeutic aid,"The safety and value of naloxone as a therapeutic aid was demonstrated in a large population of narcotic dependent persons over a two-year period. Naloxone was used to precipitate the narcotic withdrawal syndrome. This withdrawal syndrome was rated according to a previously developed scale. Retrospectively, naloxone rating scores were correlated with the patients' initial dose of methadone. With patients who received 0.8 mg naloxone, good correlation was obtained between the naloxone test score and the optimum methadone dose (mg), as indicated by the patients' physical status during the initial three days of methadone treatment. Three hundred and sixty-three tests were administered to 343 persons and no individuals developed any serious effects such as convulsions, syncope or cardiovascular collapse.",1
7261,859490,Amodiaquine agranulocytosis,A case of profound neutropenia and severe infection after the administration of amodiaquine is presented. The recommended dose for malaria prophylaxis was administered.,1
7262,864273,Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial,"Extensive psoriasis in 1,308 patients has been treated two or three times a week with oral 8-methoxypsoralen followed by high intensity, long-wave ultraviolet light (PUVA). Excluding 169 patients still under early treatment, psoriasis cleared in 88% and failed to clear in 3%. One percent dropped out due to complications of treatment, and 8% for other reasons. The twice-a-week schedule was superior for patients with lighter skin types. Once a remission was induced, there was no difference in its maintenance when patients were treated once a week, once every other week, or once every third week. Each of these schedules was superior to no maintenance treatment. Immediate side effect of the 45,000 treatments administered in the first 18 months of this study were uncommon, temporary, and generally mild. No clinically significant changes in laboratory screening or eye examinations attributable to PUVA have been uncovered.",1
7263,868818,Aspirin-induced hepatotoxicity and its effect on juvenile rheumatoid arthritis,"Evidence of hepatic disease was sought in 102 children with juvenile rheumatoid arthritis (JRA) who were treated with aspirin. Serum glutamic oxaloacetic transaminase level was elevated (greater than 39 IU/liter) in 59% of the children. The degree and prevalence of SGOT elevations correlated with aspirin dose and serum salicylate level. Nevertheless, increased SGOT values were frequently present in children receiving moderate aspirin doses and having serum salicylate levels less than 25 mg/100 ml. Elevated SGOT values decreased in proportion to the degree of reduction in aspirin dose. The SGOT values above the 100 IU/liter were statistically associated with reduced sedimentation rates. Concomitant improvement in the clinical manifestations of JRA was noted in some children.",1
7264,869341,[Toxic hepatitis caused by rifampin and isoniazid in treatment of tuberculosis (author's transl)],"Five children with tuberculosis were treated with isoniazid (20 mg./Kg./day) and rifampin (15 mg./Kg./day). After five to twenty seven days of treatment they presented anorexia, vomiting and jaundice. Hepatomegaly was found in two of them. High indirect bilirubin, S.G.O.T. and S.G.P.T. and low prothrombin levels were present in all of them. Eight to thirty one days after withdrawal of rifampin, all patients were well and their laboratory data was normal.",1
7265,871808,Disulfiram hepatotoxicity,,1
7266,873137,Hepatic veno-occlusive disease due to pyrrolizidine (Senecio) poisoning in Arizona,"An infant with documented hepatic veno-occlusive disease due to ingestion of pyrrolizidine alkaloids is presented. The alkaloids were ingested in the form of an herbal tea commonly used as a folk remedy among the Mexican-American population. Among these people, this herb is known as gordolobo yerba. The patient presented with acute hepatocellular disease and portal hypertension which progressed over 2 months to extensive hepatic fibrosis. Other potential causes of hepatic venous occlusion were absent.",1
7267,874990,Evaluation of clinical skills for a specialty board during residency training,"Since 1971 the directors of residency training programs in internal medicine have had the responsibility for evaluating the clinical skills of their trainees for the American Board of Internal Medicine. Satisfactory performance is required by the board as a qualification for admission to its written certifying examination. This report presents the board's experience with the evaluation of clinical skills through June 1975 based on visits with the administrators of 166 residency training programs. Described are the evaluative methods employed by the programs, the delineation and observation of acceptable minimum standards of performance, and the benefits to training in internal medicine accruing from the institution of these evaluation procedures and from the related visits to hospitals by representatives of the board.",1
7268,876909,Acute renal failure following copper sulphate intoxication,"Eleven out of a series of twenty-nine patients (37-9%) with acute copper sulphate poisoning developed acute renal failure. Intravascular haemolysis appeared to be the chief factor responsible for renal lesions in these patients. Histological lesions observed in the kidney varied from those of mild shock to well established acute tubular necrosis. In one case, granulomatous lesions were seen in response to tubulorrhexis. Renal failure was the chief indication for dialysis in ten patients, whereas one patient was dialysed primarily for removal of copper. Notwithstanding the adequate control of uraemia by dialysis, only six of the eleven patients recovered. Septicaemia was responsible for death in three, hepatic failure in one and methaemoglobinaemia in another. It is postulated that release of copper from haemolysed red cells during acute haemolytic episodes may initiate, or contribute to, the development of renal damage.",1
7269,877782,Raised serum transaminase levels in patients with rheumatic fever treated with salicylates,"Of 11 patients with acute rheumatic fever, 9 were treated with a total daily salicylate dosage of 3,6 g or less, 1 patient required a total daily dosage of 5,4 g and another required 9,0 g daily. Six of the 11 patients had elevated serum transaminase levels, and all were asymptomatic. The elevated transaminase levels appear to bear a direct relationship to the serum salicylate level, and a serum salicylate level of 19,2 mg/100 ml appears to be the critical point. In 5 out of the 6 patients with elevated transaminases, the serum salicylate level exceeded 19,2 mg/100 ml, while in the 5 patients with normal transaminases the serum salicylate level did not exceed 19,2 mg/100 ml. Also, in 10 of the 11 patients eosinophilia was noted, but this decreased despite continued or increased salicylate administration. A narrow margin thus appears to exist between therapeutic serum salicylate levels and hepatotoxic levels, and serial serum transaminase estimations are advocated in patients on long-term salicylate therapy.",1
7270,879128,Budd-chiari syndrome after taking oral contraceptives. A case report and review of 14 reported cases,"A case of Budd-Chiari syndrome in a young woman taking oral contraceptives is described. Her main complaints were abdominal pain and ascites without hepatosplenomegaly and the subsequent development of shock. Diagnosis was established by selective hepatic arteriogram and vena cavagram. She was treated with supportive measures, anticoagulants and neomycin. At the time of this report, the patient is slowly convalescing, taking coumadin, diuretics and Aldactone, as well as supplementary vitamins. Reviewed are 14 cases of Budd-Chiari syndrome occurring while patients were taking oral contraceptives.",1
7271,879147,The spectrum and causes of liver diseases in narcotic addicts,"Fifty charts of patients discharged with a diagnosis of liver disease from the acute care service of a hospital for the treatment of addiction were analyzed. Among 42 active heroin users or former heroin addicts maintained on methadone, 79% were heavy alcohol abusers. Seventeen cases of cirrhosis were encountered. All occurred in those abusing alcohol. Reversible liver disease was seen in both alcohol abusers and nonalcoholics. This study suggests that alcohol is a major factor in the development of irreversible liver disease in active heroin addicts and ex-addicts on methadone maintenance.",1
7272,896955,Back stabilization during knee strengthening exercise,"Twenty normal women were tested for maximal isometric contraction of the right knee extensor muscles. The knee was positioned in 60 degrees of extension and the hip at 120 degrees of extension, with and without a backrest. The purpose of the study was to determine whether the use of a backrest resulted in greater force than when not using a backrest when the angle of back inclination was held constant and the support was varied. The results indicated that the addition of a backrest, when the body assumes an optimal position, enables the knee extensors to generate greater force then when no backrest is used. A backrest adds to the comfort and support of the subject performing resistive knee exercise and should be incorporated into the design of knee exercise units.",1
7273,906375,[Achievements and prospects in the field of upbringing and development of young children],,1
7274,908562,Hirschsprung's disease and congenital deafness. Familial assocation,A family is described showing deafness in three consecutive generations. Hirshchsprung's disease was present in at least two of the affected patients and a history of bowel dysfunction was present in the third. The assocation of the two disorders in this family may be due to a single autosomal dominant gene and in this regard differs from previously reported isolated patients with Hirschsprung's disease and deafness.,1
7275,910708,Truncus arteriosus communis,,1
7276,916211,[A case of alpha-methyldopa-induced hemolytic anemia with cholestasis (author's transl)],,1
7277,920711,Spectrum of methyldopa liver injury,"""The administration of alpha methyldopa resulted in serious liver injury to seven patients, requiring hospitalization. All patients presented with symptoms indistinguishable from viral hepatitis. Histological changes ranged from those compatible with acute hepatitis to chronic active hepatitis and subacute hepatic necrosis. One patient with subacute hepatic necrosis rapidly progressed to hepatic failure and died; autopsy revealed postnecrotic cirrhosis. Inadvertent rechallenge after recovery resulted in dramatic recurrence of symptoms in one patient, confirming the fact that a hypersensitivity phenomenon is involved. A high state of awareness among physicians of this unpredictable toxic effect of the drug may reduce its unrecognized perpetuation.""",1
7278,921828,Allopurinol hepatotoxicity. Case report and literature review,"""Significant hepatotoxicity due to allopurinol seems to be rare. Only 6 such cases have been recorded in the literature. The clinical and histopathologic findings of allopurinol-induced liver injury are variable in the previously reported cases. Described herein is another patient with allopurinol hepatotoxicity. Of interest is the similar histopathology between the present case and the two previously reported cases of allopurinol-induced granulomatous hepatitis; thus this is the third such recorded case. Allopurinol should be suspected when liver abnormalities occur following use of this drug.""",1
7279,923468,[Cholestatic hepatosis under Cimetidine],,1
7280,926189,Liver lesions and oral contraceptive steroids,"Two strains of mice, CF-LP and Swiss-Webster random-bred, were evaluated for liver neoplasia after administration of oral contraceptive steroids. No increased incidence of hepatocellular tumors was found beyond the variation expected by chance. The overall tumor incidence in treated and untreated groups was identical. No significant increase in tumor size was observed in the treated animals. Liver weights progressively increased in several of the treated groups. In both treated and untreated animals hepatocellular neoplasia was usually accompanied by intracytoplasmic inclusions similar to those observed in human liver tumors. Vascular lesions were observed in some of the animals receiving large doses of contraceptive steroids. While these may be the result of local toxicity, their similarity to lesions observed in benign liver tumors warrants further investigation. No evidence was found to suggest that contraceptive steroids act as initiators of liver neoplasia.",1
7281,933027,Renal handling of phenol red. II. The mechanism of substituted phenolsulphophthalein (PSP) dye transport in rabbit kidney tubules in vitro,"1. The uptake of various substituted phenolsulphophthalein dyes by cortical slices of rabbit kidney has been studied in detail in order to obtain more information on the secretory system for organic anions. 2. The rate of initial uptake of dyes and the accumulation after incubation for 2 hr under aerobic conditions increased in the order: phenol red (PR) greater than bromophenol blue (BPB) greater than bromocresol green (BCG) greater than bromothymol blue (BTB), while the reverse order of uptake was observed under anaerobic conditions. There was no difference between the uptake of BTB under aerobic and anaerobic conditions. 3. The accumulation of dyes under anaerobic conditions could be accounted for by binding to tissue constituents. In comparison with PR (Sheikh, 1972), the substituted dyes were found to interact extensively with the 700 G (cell membranes) and cytosol fractions of renal homogenates. 4. Low concentrations of the substituted dyes efficiently inhibited the accumulation of rho-aminohippurate (PAH). The concentration of dye resulting in 50% inhibition of PAH accumulation (KI) agreed well with concentrations estimated to sustain 50% of maximal dye transport (KM). On this basis the affinity of the dyes for the transport system increases in the order: PR less than BPB less than BCG less than BTB. 5. Probenecid, 2,4-dinitrophenol, PAH, octanoate and succinate affected to a smaller extent the uptake and binding of BPB and BCG by renal tissue than that previously shown for PR (Sheikh, 1972). No inhibitory effect of these substances on the accumulation of BTB by kidney tissue was observed. 6. The binding of PSP dyes by phospholipid vesicles (liposomes) and a representative binding protein, human serum albumin, exhibited close similarity to that of binding by renal tissue. Partition experiments involving octanol-water phases indicated that the hydrophobicity of the dyes increased in the order: PR less than BPB less than BCG less than BTB. 7. The results indicate that BTB, despite its inhibitory potency, is not transported by the organic anion system. BPB and BCG are transported to a lesser extent, and interact more strongly with the transport system than does PR. It is suggested that the substituted dyes by virtue of hydrophobic interaction with the transport system reduce the movement of the mobile part of the transport system.",1
7282,937290,Letter: Aspirin hepatitis,,1
7283,937897,Letter: Isoniazid and liver injury,,1
7284,939378,Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?,"A family study was prompted by the presence of benign recurrent intrahepatic cholestasis in three members and probably in a fourth. Pruritus and/or jaundice occurred during pregnancy in nine members. Two additional members suffered from pruritus while using oral contraceptives. The literature on benign recurrent intrahepatic cholestasis since 1959 describes at least 57 cases. A familial form of this condition proved to be fairly common. There seems to be a relation to the intrahepatic cholestasis sometimes seen during pregnancy and during oral contraceptive use. The data of the family study are suggestive for an interrelation of the three types of intrahepatic cholestasis, although a common denominator remains obscure.",1
7285,942146,Letter: Fever from ibuprofen in a patient with lupus erythematosus,,1
7286,946110,Letter: Quinidine hepatotoxicity,,1
7287,946302,Letter: Death after use of cupric sulfate as emetic,,1
7288,946467,An unusual reaction to chloroquine-primaquine,,1
7289,950417,Molecular orbital studies of enzyme activity. 2. Nucleophilic attack on carbonyl systems with comments on orbital steering,,1
7290,954339,Accidental iron poisoning in childhood. Six cases including one fatality,"Between 1962 and 1973, six children were admitted to the Massachusetts General Hospital because of accidental iron poisoning. Intoxication was life-threatening in two children whose serum iron concentrations exceeded their iron binding capacities. One of these patients died despite intensive supportive care and desferoxamine therapy. Although iron poisoning appears to be relatively uncommon, it can produce life-threatening and fatal intoxication in children.",1
7291,958755,Commentaries: A first priority--childhood automobile safety,,1
7292,959886,"Leprosy in the United States, 1950-1969: an epidemiologic review",,1
7293,959916,Herb use and necrodegenerative hepatitis,"Twelve patients with herbally-induced hepatitis are described and the clinicopathological features of their illness, which seem to present a recognisable spectrum, are discussed. The nature and the severity of the histological changes seem to correlate with the clinical manifestations and the immediate prognosis. Laboratory tests, especially liver function studies, are of limited diagnostic and prognostic value. The plants which contain the responsible toxins, have been identified in this country and in other parts of Southern Africa. A short list is provided of, apparently, the commonest medicinal plants in Lesotho. Many more toxic plants, however, are used in food and in diverse traditional medications. Senecio species are the principal source of hepatotoxic alkoloids, especially pyrrolizidines. Experimental studies ann evidence of similar disorders in animals, have thrown some light on the pathogenic mechanisms of these hepatotoxic and possibly hepatocarcinogenic agents. The disease in humans probably results from a combination of factors.",1
7294,961676,Allopurinol-induced granulomatous hepatitis,,1
7295,962233,Letter: Preventing isoniazid hepatotoxicity,,1
7296,967392,Aspirin hepatotoxicity in adults with rheumatoid arthritis,,1
7297,968972,[Treatment of psoriasis with 8-methoxypsoralen and long-wave ultraviolet light],,1
7298,977780,A case of veno-occlusive disease of the liver in Britain associated with herbal tea consumption,"Veno-occlusive disease of the liver with clinical and pathological features similar to those of the condition occurring in the Caribbean is described in a young woman resident in Britain. The diagnosis was made from liver biopsies and hepatic venography and was confirmed at necropsy. Small amounts of pyrroliziding alkaloids were recovered from a sample of mate (Paraguay) tea, owned by the patient, to which she was addicted. It seems probable that the consumption of large amounts of this tea over a period of years was the cause of the hepatic disease.",1
7299,980021,Acute meprobamate poisoning with gastrotomy and removal of a drug-containing mass,,1
7300,980605,Serum enzyme abnormalities in juvenile rheumatoid arthritis,"""Elevated serum transaminases, particularly SGOT, as a result of acetylsalicylic acid (ASA) therapy have been reported in patients with juvenile rheumatoid arthritis (JRA). In order to evaluate the possibilities that these elevated transaminases may result from JRA itself or from concomitant muscle injury, we correlated liver function tests and a specific test for muscle damage, creatine phosphokinase (CPK), with ASA therapy in 37 patients. These JRA patients were evaluated serially; 20 took ASA continuously, 6 took it intermittently, and 11 were on no therapy. Thirty-five healthy children were also studied to establish normal control values for the serum enzyme tests. Mean SGOT and SGPT in the 11 untreated subjects were significantly (P less than.001) higher than normal controls while CPK and alkaline phosphatase (AP) were not elevated. Mean SGOT and SGPT were also significantly (P less than .001) elevated in 20 children receiving ASA continuously; CPK was normal and AP less (P less than .05) than normal. CPK was elevated in 13 patients. Elevation of enzymes was sporadic and there was no correlation with serum salicylate, sex, age, disease duration, type, or activity. We conclude that mild abnormalities of SGOT and SGPT in JRA patients are common, but that they occur sporadically and elevated values appear to be unrelated to ASA therapy.""",1
7301,989134,Colitis and hepatitis caused by methyldopa,"Acute, severe colitis and hepatitis developed in a 55-year-old man on two occasions in relation to administration of methyldopa. He also had fever, skin rash, and eosinophilia, suggesting drug allergy. All symptoms and signs remitted after he stopped taking the drug. It appears that this agent is capable of producing acute colitis as well as the previously recognized hepatitis.",1
7302,992650,Veno-occlusive disease of the liver associated with oral contraceptives: case report and review of literature,"This report concerns a young woman who, after taking a contraceptive preparation orally for three years, developed the Budd-Chiari syndrome as the result of a widespread chronic obliterative process involving the intrahepatic efferent venous system. Her prolonged course, which failed to respond to an end-to-side portacaval shunt procedure, mimicked chronic hepatitis evolving to cirrhosis. Additional noteworthy features were the presence of two small benign hepatic adenomas, observed both at biopsy and at necropsy, a lesion recently recognized as a complication of anovulatory drugs, and widespread hepatic calcifications found at autopsy.",1
7303,1008656,[Hepatitis due to erythromycin propionate (author's transl)],,1
7304,1020119,Plasma 5alpha androstanediol: an androgen marker of hirsuitism in women,,1
7305,1028823,Methyldopa liver injury,,1
7306,1030283,Isoniazid-associated hepatitis,,1
7307,1035522,[Present status of clinical neurology in Japan. (3) Polyradiculoneuopathy],,1
7308,1057088,Stevens-Johnson syndrome with hepatitis following therapy with ampicillin and cephalexin,The Stevens-Johnson syndrome is rarely associated with hepatitis and neither entity is commonly seen following the use of ampicillin or cephalexin. An infant is described in whom both entities appeared simultaneously following therapy with these drugs.,1
7309,1068643,Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases,"Two adult male patients with acute leukemia developed a fatal Budd-Chiari-like illness while receiving 6-thioguanine. Both had previously received cytosine arabinoside. Antemortem and postmortem specimens of liver showed changes characteristic of toxic veno-occlusive disease. Similar findings have been described after ingestion of certain plant alkaloids and after treatment with arsphenamine, urethane, and ionizing radiation to the liver. We are unaware of any published reports of veno-occlusive disease of the liver after treatment with either 6-thioguanine or cytosine arabinoside. Although 6-thioguanine was most likely responsible for this syndrome, it is not possible to eliminate cytosine arabinoside as the causative agent. Since both drugs are occasionally used for benign conditions, physicians should be aware of this possible complication.",1
7310,1069234,"[Evaluation in children of the clinical, biological and electroencephalographic side effects of L-asparaginase]",,1
7311,1073405,Technique clinic. Hygiene around the 3-3 retainer,,1
7312,1079531,Hepatotoxicity of rifampicin and isoniazid in children,,1
7313,1086057,Idiopathic portal hypertension,"Idiopathic portal hypertension is reported in five cases including one case of chronic arsenical intake and one case of chronic industrial vinyl chloride exposure. In all five cases the patients presented with gastrointestinal bleeding as the chief complaint. Physical examination was within normal limits except for splenomegaly in all. Results of liver function tests were normal, except for the relative clearance of sulfobromophtalein. A surgical liver biopsy specimen was obtained in all cases and showed moderate degrees of portal fibrosis, but no cirrhosis. Combined umbilicoportal, hepatic vein and superior mesenteric artery catheterization was performed in all cases. Hepatoportographies showed distortion of the intrahepatic portal venous system and cut-off of small portal venules. Porto-hepatic gradients ranged from 14.0 to 20.5 mm Hg. The portal hypertension was both sinusoidal and presinusoidal in nature but mainly presinusoidal. Hepatic extraction of indocyanine green and of albumin microaggregates was normal, thereby suggesting normal functional portal blood supply to the liver. The patients with arsenical or vinyl chloride exposure could not be differentiated from the other three patients with idiopathic portal hypertension. These results suggest that idiopathic portal hypertension may be related to domestic or industrial exposure to other hepatotoxins.",1
7314,1088626,"""[Chronic intrahepatic cholestasis following chlorpromazine; treated using phenobarbital]""",,1
7315,1090103,A double-blind trial with baclofen (Lioresal) and diazepam in spasticity due to multiple sclerosis,"In 17 in-patients suffering from spasticity due to multiple sclerosis, the effect and tolerability periods were 4 weeks each. As to efficacy, the variables: spasticity, clonus, flexor spasms, gait and bladder function were evaluated clinically. No significant difference was found between the two drugs. As far as side-effects are concerned, sedation was specifically inquired about. Apart from that, spontaneoulsy reported side-effects were recorded. Sedation was more often seen during treatment with diazepam, while the side-effects during baclofen treatment were more varied. The total number and severity of side-effects were equal in the two treatment groups. A preference for one of the two treatment periods was stated by the investigator before the code was broken. A significant difference (p less than 0.001) in favor of Lioresal was found. This is discussed in the light of the fact that no significant difference was found for the individual symptoms or side-effects.",1
7316,1092973,Double blind evaluation of long acting diethylpropion hydrochloride in obese patients from a general practice,"Obese patients encountered in general practice were studied in order to determine whether a long-acting form of diethylpropion hydrochloride (Tenuate Dospan) was more effective than placebo for weight loss. One hundred and two patients completed this double blind, 16-week crossover study. During the first eight weeks, the patients treated with diethylpropion hydrochloride lost significantly (P smaller than 0.001) more weight than the patients treated with placebo (an average of 11-1 lb or 6-4% of their initial weight as compared with 6-2 lb or 3-6% of their initial weight). When the group taking diethylpropion hydrochloride crossed over to placebo for a second eight weeks, they lost an average of 1-5 lb (0-9% of their weight at the start of the second period), while the group who crossed from placebo over to diethylpropion hydrochloride lost an average of 6-7 lb (3-8%). The advantages of diethylpropion hydrochloride over placebo are statistically significant.",1
7317,1096840,Treatment of fungal infections with flucytosine,"Treatment with flucytosine of 20 patients with fungal infections gave favorable results in four patients with crytococcal infections, two of four patients with disseminated candidiasis, eight of ten patients with urinary tract infections due to Candida albicans and Torulopsis glabrata, and tow of three patients with miscellaneous infections due to Calbicans. Two patients with crytococcal meningitis and altered host resistance and one patient with an aorto femoral graft infection due to C albicans were treated with flucytosine and smphotericin B. The infection was eradicated in one of the patients with meningitis, and cultures from an infected arterial graft became negative. Adverse side effects of flucytosine included mild leukopenia and thrombocytopenia, a transient increase in alkaline phosphatase and glutamic oxaloacetic transaminase, and nausea and diarrhea.",1
7318,1098955,Hepatic veno-occlusive disease in a renal transplant patient receiving azathioprine,"""Central vein phlebitis and occlusion developed in a patient who was receiving immunosuppressive therapy with azathioprine (Imuran) and prednisone after renal transplantation. He had been well for 1 year before evidence of liver disease was noted; once begun, it progressed to hepatocellular failure in spite of a change in immunosuppressants from azathioprine to cyclophosphamide. Several known causes of venoocclusive disease and the possible causes in this patient are discussed.""",1
7319,1100953,A controlled clinical trial of continuous and intermittent rifampicin therapy during an initial three months period in lepromatous leprosy: final analysis,,1
7320,1104856,A container for processing small volumes of cell suspensions for critical point drying,"The attachment of lymphocytes to glass or filters, in order to facilitate handling for processing prior to scanning electron microscopy, may introduce artefacts in surface topography. A container has therefore been adapted, from an embedding capsule, for the preparation of small volumes of cell suspensions.",1
7321,1107728,Multicentre controlled comparative trial of clofazimine and dapsone in low dosages,,1
7322,1115455,Letter: Quinidine and granulomatous hepatitis,,1
7323,1121178,Another health care crisis,,1
7324,1126603,Noncirrhotic presinusoidal portal hypertension associated with chronic arsenical intoxication,"""A 39-year-old male with bleeding esophageal varices due to portal hypertension was observed. The patient had taken an arsenical preparation during a period of 12 yr because of psoriasis and subsequently developed keratotic changes of the palms and soles of his feet and an epithelioma of the scrotum. Physical examination was unremarkable except for splenomegaly and skin lesions. Liver function tests were normal; a needle biopsy of the liver (right lobe) showed nonspecific changes. Combined hepatic and umbilicoportal catheterization revealed, on splenography and portography, huge esophageal varices and patent portal vein; dilation, distortion, and cut-off of many intrahepatic portal branches were found. A marked gradient existed between the free portal venous pressure (25 mm Hg) and the wedged hepatic venous pressure (9.5 mm Hg). Hepatic blood flow, portal PO2, cardiac output, cardiac index, and blOOD volume were within normal range. Arteriographies did not reveal arteriovenous shunts in the splanchnic or splenic vessels. A splenorenal shunt were performed and a wedged biopsy of the liver (left lobe) revealed nonspecific changes. Three years later the patient had not experienced any episode of hemorrhage or hepatic encephalopathy but developed an epithelioma of the tongue. No known cause could be incriminated in the pathogenesis of the portal hypertension. However, there was unequivocal chronic arsenic intoxication. Toxic hepatitis, cirrhosis, noncirrhotic portal hypertension, and hemangiosarcoma of the liver have been reported with the intake of arsenicals. Thus, it is suggested that in this patient, presinusoidal portal hypertension was secondary to chronic arsenical intake associated with marked intrahepatic vascular changes seen on portography.""",1
7325,1128758,Ineffectiveness of hemodialysis in copper sulphate poisoning,"A fatal case of severe copper sulphate poisoning is reported in whom hemodialysis was performed 13 h after ingestion. At autopsy a significant amount of copper was found in the brain, heart, liver, kidney, spleen and adrenals. This case indicates sopper is nondialysable and that hemodialysis is ineffective in the treatment of acute copper sulphate poisoning.",1
7326,1130813,Letter: Paraben-induced dermatitis,,1
7327,1132819,[Liver damage following salicylate intake],,1
7328,1136073,[Utero-placental circulation in the pregnant woman studied using In113m. Preliminary results],,1
7329,1138146,[Metrological basis of optimal radiometry of the whole body],,1
7330,1142648,[Certain problems of pathogenesis and surgical tactics in pancreatic cysts],,1
7331,1147734,Liver disease caused by propylthiouracil,"This report presents the clinical, laboratory, and light and electron microscopic observations on a patient with chronic active (aggressive) hepatitis caused by the administration of propylthiouracil. This is an addition to the list of drugs that must be considered in the evaluation of chronic liver disease.",1
7332,1150039,Isoniazid-associated hepatitis in 114 patients,"""Analysis of the overt hepatic disease that developed in 114 patients while taking isoniazid for chemoprophylaxis of tuberculosis showed it to be mainly hepatocellular. The severity of the hepatic injury was manifested by the 13 fatalities (12.3%) and by the histological demonstration of submassive necrosis in 9 and massive necrosis in 4 patients. The 20 other patients from whom hepatic tissue was available for study included 16 with moderately severe acute hepatocellular injury (4 had a mixed hepatocellular-cholestatic pattern), and 4 with chronic hepatic diseases (1 had cirrhosis). Clinical manifestations of hepatic disease prior to the onset of jaundice included vague digestive complaints in 55% of the group and """"viral' disease-like complaints in 35%, some with and some without gastrointestinal symptoms. Jaundice was the presenting complaint in 10% of patients. Fever and rash were reported in very few patients (less than 4%) and eosinophilia of modest degree was noted in approximately 10%. Hepatic injury was recognized during the 1st month of isoniazid administration in 15% and during the 2nd month in an additional 31%. In the remaining 54% of patients, the drug had been administered for periods of 2 to 11 months before hepatic injury was noted. Analyses of variables suggested that hepatic injury which presented after 2 months, especially with bilirubin levels that exceeded 20 mg per 100 ml, was more likely to have a fatal outcome than disease that presented during the first 2 months even with higher bilirubin levels. The case fatality rate was significantly higher in black females than in black males or in whites of either sex. The observations of the present study offer no support for the view that isoniazid-induced hepatic disease results from hypersensitivity to the drug. Other data that support the view that hepatotoxic metabolites of isoniazid may be responsible for the injury are considered.""",1
7333,1153692,Halothane-related hepatitis. A clinical study of twenty-six cases,"Twenty-six patients are described who had otherwise unexplained hepatitis after halothane anaesthesia. Twenty-four (92 per cent) had multiple exposures, and 11 (42 per cent) died. In eight patients a characteristic pattern of delayed postoperative pyrexia has been found. Obesity was common, but the clinical features and complications were those of any severe hepatitis. Obesity, early onset of jaundice after anaesthesia, and low thrombotest, were associated with a fatal outcome. None of those who were followed up after recovery developed clinical or biochemical evidence of chronic liver disease. The differential diagnosis of postoperative jaundice is discussed, and it is shown that halothane patients with hepatic encephalopathy are significantly older (25.4 plus or minus 11.6 years) than those referred to this unit with viral hepatitis of equal severity (34.1 plus or minus 16.4 years). Unexplained jaundice or delayed pyrexia after a previous administration of halothane should be a contraindication to its further use.",1
7334,1155430,"Reye's syndrome: epidemiologic and viral studies, 1963-1974","Fifty-eight children with Reye's syndrome (RS) confirmed by liver biopsy were treated at the University of Cincinnati between 1963 and 1974. Cases were clustered in the winter and spring with the peak in February and March. These coincided with the occurrence of influenza and, numerically, were associated more closely with influenza B than with influenza A. Six of the 58 cases were associated with chickenpox. Twenty-six children with RS were seen from 1963 to 1971, before the beginning of a systematic epidemiologic and virologic study. Viral infection was documented in either the patient or a contact in only 19% of those studied. Between 1971 and 1973, after the study was initiated, 16 cases of RS were diagnosed and viral infection was confirmed in 56% of these. In 1974, an epidemic of RS occurred during an influenza B epidemic and viral infection was found in either the patient or a contact in 81% of 16 cases. This study demonstrates that an association with viral infection can be proven in the majority of cases of RS when an intensive investigation is undertaken. During this study no significant environmental toxic exposures could be idenified. Most children had taken aspirin and other medications, and seven children had a history of excessive aspirin ingestion.",1
7335,1166986,Letter: Severe hypersensitivity to diphenylhydantoin with circulating antibodies to the drug,,1
7336,1169181,Angiosarcoma of the liver associated with Fowler's solution (potassium arsenite),"A patient with an angiosarcoma of the liver associated with the chronic ingestion of Fowler's solution (potassium arsenite) is described. The patient's clinical course was characterized by upper gastrointestinal hemorrhage, recurrent hemoperitoneum, hepatic failure, and, subsequently, the appearance of an angiosarcoma of the skin. Selective angiography demonstrated features consistent with both hepatoma and cavernous hemangioma. The hepatic toxicity and the carcinogenicity of arsenic are reviewed, with particular reference to Fowler's solution, which previously has been widely used for the treatment of psoriasis. The long latency period for the development of the malignancies is emphasized.",1
7337,1172014,[Long term analgesic effects of intermittent alcohol injection into subarachnoid space for pains caused by neoplasms],,1
7338,1172923,Letter: Hepatitis and propylthiouracil,,1
7339,1173187,Hepatitis caused by amitriptyline therapy,,1
7340,1175893,Effects of clofibrate in primary biliary cirrhosis hypercholesterolemia and gallstones,"A patient with primary biliary cirrhosis is reported in whom the administration of clofibrate in a dose of 1 g per day for 2 months resulted in a marked increase in hypercholesterolemia, and endoscopic retrograde cholangiography showed multiple intrahepatic gallstones. The stones disappeared 3 months after stopping clofibrate and starting chenodeoxycholic acid in a dose of 125 mg daily. These observations are discussed in relation to the known effects of clofibrate on bile composition.",1
7341,1181510,Cholestatic jaundice possibly due to benzodiazepine-type drugs,,1
7342,1188303,Liver disease with periportal sinusoidal dilatation. A possible complication to contraceptive steroids,"Four women of fertile age on long-term treatment with contraceptive steroids developed moderate liver damage and hepatomegaly. The liver histology showed a conspicuous periportal sinusoidal dilatation as the only abnormality. The clinical course of the liver damage was benign. The aetiology and pathogenic mechanisms of these changes, which were localized predominantly to Rappaport's Zone I, are unknown. Haemodynamic studies revealed no abnormalities. The connection to possible long-term action of oestrogens and gestagens on the liver, and the relation to peliosis and benign hepatic adenomas, are discussed.",1
7343,1189911,Acute liver failure and encephalopathy (Reye's syndrome?) during salicylate therapy,A case of hepatotoxicity and encephalopathy (Reye's syndrome?) associated with salicylate therapy is presented and the aetiology of this syndrome is discussed. Hepatotoxicity developed with salicylate serum concentrations not exceeding therapeutic serum levels. The importance of controlling serum salicylate concentration and transaminase activity particularly during the first fourteen days of therapy is emphasized.,1
7344,1199984,Aspirin hepatitis,"Adverse reactions to aspirin, a potentially hepatotoxic drug, are believed to be dose related. This article reviews the medical literature and described two children with aspirin hepatitis. Hepatic dysfunction recurred in one of these patients at salicylate concentrations in serum previously considered nontoxic.",1
7345,1200504,Letter: Disulfiram hepatotoxicity,,1
7346,1204341,Delayed hepatotoxicity from methyldopa,,1
7347,1218401,[Prospects of drug production in the USSR],,1
7348,1235590,"""State intervention on behalf of """"neglected"""" children: a search for realistic standards""",,1
7349,1242064,The homebound aged: a medically unreached group,,1
7350,1244795,Letter: Salicylate hepatotoxicity in Reiter's syndrome,,1
7351,1249068,Proton magnetic resonance studies of glutamate-alanine transaminase-catalyzed deuterium exchange. Evidence for proton conservation during prototropic transfer from the alpha carbon of L-alanine to the C4-position of pyridoxal 5'-phosphate,"""Pulsed Fourier transform proton magnetic resonance spectroscopy was used to study the glutamate-alanine transaminase-catalyzed incorporation of deuterium from solvent deuterium oxide into the alpha and beta positions of L-alanine. It was found that the beta proton resonance signal initially disappears slightly faster than the signal due to the alpha proton, but whereas the alpha proton signal decays exponentially, that due to the beta proton signal does not. Eventually, the rate of decrease of the alpha proton signal becomes greater than that for the beta proton. This change in the relative rates is ascribed to a deuterium isotope effect upon substitution of an alpha proton by a deuteron. Furthermore, as deuterium begins to replace hydrogen, two classes of alanine become distinguishable, i.e. alanine which contains deuterium in the alpha position and hydrogen in the beta position, and alanine which contains hydrogen in the alpha position and deuterium in the beta position. Thus, removal of all 3 beta protons is not contingent upon loss of an alpha proton from the same molecule. The two classes of deuterated alanine may conceivably arise by a scrambling mechanism in which protons are transferred from the alpha to the beta position and vice versa. Present evidence excludes this scramblong mechanism and leads to the conclusion that deuterium incorporation into L-alanine involves, (a) the reversible enzymatic conversion of the classical ketimine enzymes intermediate to an enaminetype structure, and (b) considerable conservation of label during the prototropic shift from the alpha carbon of L-alanine to the C4-position of pyridoxal 5'-phosphate. It is also postulated that alanine binds at the active site in such a way as to bring the beta protons into close contact with a basic group on the enzyme surface. This group is distinct from that used in abstraction of an alpha proton. The beta protons of glutamate are not enzymatically removed; presumably glutamate binds in such a way that the beta protons cannot effectively interact with an enzyme base. Similar studies were carried out on soluble glutamate-aspartate transaminase; no evidence was found for significant enzyme-catalyzed deuterium incorporation into the beta position of L-glutamate, L-aspartate, and L-alanine.""",1
7352,1251251,Clinicopathologic conference: a case of multiple myeloma followed up for 15 years,,1
7353,1252262,Correlations between transaminase concentrations and serum salicylate concentration in juvenile rheumatoid arthritis,"Simultaneous measurements of serum salicylate, SGPT, and SGOT concentrations were made on 92 children receiving salicylates for arthritis during a 13-month period. Statistical correlations were found between salicylate and transaminase concentrations in patients with juvenile rheumatoid arthritis when in active stages. However elevated transaminase levels occurred with low salicylate levels and during inactive stages, and were inconstant in individual patients. Marked transaminase abnormalities were transient and appeared unpredictably in individual patients. Some factor in addition to salicylate concentration must be involved in raising serum transaminase levels. No evidence of chronic hepatotoxicity was noted.",1
7354,1254146,Letter: The isoniazid problem,,1
7355,1258704,A nitrofurantoin-induced disorder simulating chronic active hepatitis. A case report,"A 78-year-old woman with liver damage resembling chronic active hepatitis and occuring during long-term nitrofurantoin treatment is described. On admission to hospital she displayed jaundice, ascites and high serum levels of GOT, GPT, bilirubin and gamma-globulin as well as high titres of ANF and antibodies against smooth muscle cells. After withdrawal of nitrofurantoin the clinical and laboratory picture normalized without corticosteroid treatment, suggesting that the liver reaction was drug-induced.",1
7356,1259798,Effect of aspirin on liver tests in patients with RA or SLE and in normal volunteers,"Aspirin was given to 20 patients with RA, 16 patients with SLE, and 3 normal volunteers. Four of the RA patients, 7 of the SLE patients, and 1 normal volunteer developed abnormal liver tests, during the study. The abnormalities (elevated transaminases) were most frequent and of rapid onset in patients with cliniclaly active SLE. Increases in BUN and creatinine related to aspirin were observed in several subjects. In a retrospective survey of 80 patients with SLE, aspirin appeared responsible for two-thirds of episodes of liver test abnormalities in 19 patients.",1
7357,1261772,Fulminant hepatitis and lymphocyte sensitization due to propylthiouracil,"Fulminant hepatic failure developed in a 24-year-old black woman who had been treated with propylthiouracil and propranolol for hyperthyroidism. Clinical and biochemical recovery followed discontinuation of drug therapy. Liver biopsy disclosed submassive hepatic necrosis. During the acute phase of the disease, lymphocyte transformation studies revealed sensitization of the patient's lymphocytes to propylthiouracil but not to propranolol. Sensitization remained demonstrable 2 months after cessation of the former drug. Lymphocytes obtained from a hyperthyroid patient treated with propylthiouracil without complications failed to show evidence of sensitization. These observations indicate that submassive hepatic necrosis may result from treatment with propylthiouracil and are consistent with the notion that sensitization mechanisms may be responsible for the hepatic injury induced by this drug.",1
7358,1263732,A long term trial with clofazimine in reactive lepromatous leprosy,,1
7359,1269875,Quinidine hepatotoxicity. A report of a case and review of the literature,"A case is described of presumed quinidine hepatotoxicity, characterized by the development of fever, abnormal serum transaminase values, which improved after cessation of the drug but recurred after a challenge dose, and centrizonal hepatocellular necrosis detected on liver biopsy. Morphological changes on electron microscopy, consistent with a drug reaction, are also described. Pertinent features of previous case reports are analyzed, and the histological findings by light microscopy of the present and past cases are discussed. It is suggested that the development of unexplained fever within 1 month of quinidine administration should lead to consideration of possible hepatotoxicity.",1
7360,1271388,Liver dysfunction and polymyalgia rheumatica. A case report,"Hepatic dysfunction may be a manifestation of polymyalgia rheumatica. We present a second patient with the polymyalgia rheumatica syndrome and a significantly elevated alkaline phosphtase who, on liver biopsy, demonstrated granuloma formation and massive infiltration of the portal spaces with lymphocytes. The alkaline phosphatase elevation was favorably influenced by low dose steroid therapy.",1
7361,1274590,Liver biopsies from psoriatics related to methotrexate therapy. 1. Findings in 123 consecutive non-methotrexate treated patients,"""A prospective study was started in 1969 to describe morphological features of liver biopsies from patients with severe psoriasis. Among 123 patients evaluated for possible MTX therapy, liver biopsies disclosed pathological histology (maninly fatty change and/or non-specific reactive hepatitis) in 51 per cent. The incidence of pathological liver histology did not statistically correlate with psoriasis parameters such as duration and extent. However, statistically significant correlations (p less than 0.0001) were found between the frequency of pathological liver histology and other factors such as age, obesity, and daily alcholic intake. Comparison of liver histology with SGOT value at the time of liver biopsy showed that while the diagnostic specificy of this test high (1.00), the diagnostic was low (0.17). Normal values of SGOT should not be relied upon to indicate all types of liver pathology. A """"risk index"""" indicating the probability of pathological liver histology was developed. It is calculated as follows: two times the height (cm) minus weight (kg) minus age (years) minus 50 (in case of daily alcoholic intake) minus 50 (in case of elevated SGOT). To elucidate liver histology and particularly to rule out fibrosis and cirrhosis, a liver biopsy should be performed in every psoriatic patient with a low score in the risk index prior to beginning MTX therapy.""",1
7362,1274671,Liver biopsies in epileptics during anticonvulsant therapy,"Liver function tests, performed in 11 epileptics under antiepileptic treatment for 10-35 years, showed a slight increase in serum alanine amino-transferase in six patients and a marked increased level of serum alkaline phosphatases in four. Liver biopsies revealed few uni- or paucicellular necroses in five patients. Granulomatous hepatitis was found in one patient in whom sarcoidosis was later diagnosed. None of the biopsies showed signs of permanent liver damage.",1
7363,1276848,Letter: Chronic active hepatitis induced by nitrofurantoin,,1
7364,1284748,"Case report: acute renal failure, thrombocytopenia and nonhemolytic icterus probably caused by mefenamic acid (Parkemed)-dependent antibodies","A 65-year-old, previously healthy man developed acute renal failure, severe thrombocytopenia and hepatic icterus after a small dose of mefenamic acid (Parkemed). Drug-dependent antibodies reacting against platelets could be identified as the most probable cause for this acute and rapidly reversible disorder. A concomitant hemolytic reaction was not observed and accordingly no drug-dependent red cell antibodies could be demonstrated. The drug-specific antibodies were found only during the acute phase using the platelet immunofluorescence test and a solid-phase immunoassay but not with the monoclonal antibody specific immobilization of platelet antigens assay. After discontinuation of the drug the patient steadily improved and fully recovered until day 22 after admission and drug removal. The clinical course strongly suggests that drug-dependent antibodies against mefenamic acid and/or its metabolites reacting by immune complex mechanism were responsible not only for the thrombocytopenia but also for the renal and hepatic failure.",1
7365,1289197,[Cimetidine hepatitis],"A 41-year-old man with rheumatoid arthritis developed severe acute hepatitis 3 days after starting cimetidine for duodenal ulcer. Other causes were ruled out and he recovered after cimetidine was discontinued. Mild transient elevations of hepatic enzymes have been reported in 3.6% of patients taking cimetidine. However, only 12 cases of severe acute hepatitis associated with cimetidine, mostly secondary to idiosyncrasy, have been reported in the English literature. This rare but serious complication of cimetidine should be kept in mind.",1
7366,1297340,Binding of pp60v-src to membranes: evidence for multiple membrane interactions,"Membrane association of pp60v-src, the myristylated transforming protein of Rous sarcoma virus, has been shown to be a receptor-mediated process, which is inhibited by myristylated src peptides containing the N-terminal 11 amino acids of the v-src sequence (MGYsrc). By cross-linking radiolabelled MGYsrc peptide to fibroblast membranes, a 32-kilodalton membrane protein was identified as a candidate src receptor. To elucidate the potential role of p32 in binding pp60v-src, we studied the relationship between binding of MGYsrc peptide and pp60v-src polypeptide to cellular membranes. The subcellular membrane distribution of p32 was distinct from that of pp60v-src in transformed cells. Moreover, under certain defined in vitro conditions, it was possible to inhibit peptide cross-linking to p32 without significantly affecting pp60v-src membrane binding. However, when internal sequences were removed from pp60v-src, the binding characteristics of the src deletion polypeptide and MGYsrc peptide became identical. These data indicate that the presence of internal membrane binding domains influences the interaction of myristylated N-terminal src sequences with p32, and suggest that accessory binding factors might be involved in establishing stable contact between pp60v-src and the membrane phospholipid bilayer.",1
7367,1303612,A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer,"""To decrease the toxicity of hepatic arterial fluorodeoxyuridine (FUDR) administered through an Infusaid pump (Shiley Infusaid, Inc., Norwood, MA), 50 patients with liver metastases from colorectal cancer were selected randomly to receive FUDR, 0.3 mg/kg/d, for 14 of 28 days, with or without a total dose of 20 mg of hepatic arterial dexamethasone for 14 of 28 days. Patients were stratified according to the percentage of liver involvement by tumor and the perfusion pattern on macroaggrated albumin perfusion scan (MAA) scan. There was a trend toward decreased frequency of bilirubin levels in the group receiving dexamethasone plus FUDR versus the group receiving FUDR alone (9% and 30%, respectively, had a 200% or greater increase from baseline; P = 0.07). Patients in the group treated with dexamethasone and FUDR received higher doses of FUDR in the second, third, fifth, and sixth months than those receiving FUDR alone; however, this was statistically significant only in the fifth month (percentages of planned dose received: 42% and 19%, respectively; P = 0.05), and there was no overall difference for the total 6-month period. The complete and partial response rates were increased in patients receiving dexamethasone and FUDR versus FUDR alone (8% and 63% versus 4% and 36%, respectively; P = 0.03), and there was a trend toward increased survival with the addition of dexamethasone (median, 23 months and 15 months, respectively; P = 0.06). In conclusion, the use of hepatic arterial dexamethasone is associated with an increased response rate and a trend toward increased survival and decreased bilirubin levels. Therefore, the authors recommend additional investigation of the use of dexamethasone with chemotherapy to treat hepatic metastases.""",1
7368,1309865,"Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication","""We examined the efficacy and safety of meso-2,3-dimercaptosuccinic acid (DMSA) in children with markedly elevated blood lead (BPb) concentrations. Among 19 children with BPb concentrations of 50 to 69 micrograms/dl (2.41 to 3.33 mumol/L) who received a 5-day inpatient oral course of DMSA (1050 mg/m2 per day), the mean BPb concentration decreased by 61%; in four who received calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) (1000 mg/m2 per day intravenously), it decreased by 45% (p less than 0.0007). Urinary lead excretion was comparable in both groups. Treatment with DMSA was more effective than treatment with CaNa2EDTA in restoring metabolic activity to the heme pathway and was well tolerated even among nine patients who received concomitant iron supplementation and two who had homozygous deficiency of glucose-6-phosphate dehydrogenase. On discharge, these 19 children received either no chelation therapy or DMSA, 350 or 700 mg/m2 per day for 14 days on an outpatient basis. After 14 days the mean BPb values for the no-chelation, low-DMSA, and high-DMSA groups were 73%, 66%, and 50% of the pretreatment values, respectively. We conclude that a 5-day oral course of DMSA is effective in the treatment of children with severe lead poisoning. In addition, on an outpatient basis the administration of DMSA, 700 mg/m2 per day, is capable of delaying the typical rebound in BPb values and should ultimately reduce the need for repeated hospitalizations.""",1
7369,1311212,Reproductive factors in the etiology of hepatocellular carcinoma. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives,"Data from a hospital-based case-control study conducted in four developing countries were analyzed to evaluate the role of reproductive factors in the etiology of liver cancer. Eighty-three patients newly diagnosed with primary liver cancer and 596 matched controls between the ages of 15 and 56 years completed study interviews. The relative risk of hepatocellular carcinoma was elevated significantly in women of high gravidity, an association that was attributable to the effects of full-term pregnancies. The adjusted relative-risk estimate in women who had ever had a full-term pregnancy was 1.6 (95 percent confidence interval = 0.6-4.1), and risk increased directly with the number of full-term pregnancies (P for trend = 0.03), rising to 3.8 among women with seven or more births compared to women with one to two births. Induced abortions and a history of miscarriage were unrelated to risk. These findings were unchanged after adjustment for a history of jaundice, lifetime number of sexual partners, or age at first sexual intercourse--variables which may be related to hepatitis B virus (HBV) exposure. Serum samples to determine HBV status were not collected, however, and it is not known whether the observed associations are independent of prior HBV infection.",1
7370,1316028,Are oral contraceptive-associated liver cell adenomas premalignant?,"""From January 1977 to June 1990, 1,670 patients with a liver mass or masses underwent transabdominal fine needle aspiration biopsy of the liver. Of those cases, 99 were diagnosed cytologically as """"hepatocellular carcinoma"""" and 9 as """"consistent with liver cell adenoma."""" Among the 99 patients with hepatocellular carcinoma, 3 were users of oral contraceptives. The nine patients with liver cell adenoma were all users of oral contraceptives. Of them, two developed foci or areas of liver cell dysplasia within the adenomas. The mean periods of oral contraceptive use among these three groups of patients were different. It appeared that patients started to develop liver cell adenoma after five years of oral contraceptive use (mean, 6.3 years). Foci or areas of liver cell dysplasia began to arise within liver cell adenomas after 8 years of oral contraceptive use (mean, 9 years), and the patients started to develop hepatocellular carcinoma after 10 years of contraceptive use (mean, 11 years). The cytologic features of liver cell dysplasia strikingly mimicked those of hepatocellular carcinoma. From this study, the foci or areas of liver cell dysplasia appear to be the missing link responsible for the transformation of liver cell adenoma to carcinoma. It is believed that liver cell adenomas are not premalignant and may undergo reversible change after withdrawal of causative agents, whereas foci or areas of liver cell dysplasia within the adenomas are irreversible, premalignant changes and may transform into hepatocellular carcinoma.""",1
7371,1318951,Carboplatin and etoposide chemotherapy regimen for recurrent malignant glioma: a phase II study,"PURPOSE: A phase II study that used combination chemotherapy with carboplatin (CBDCA) and etoposide (VP 16) (CE) was performed on patients with recurrent malignant glioma to investigate tumor control and toxicity. PATIENTS AND METHODS: Thirty-eight patients were treated with CBDCA 300 mg/m2 on days 1 to 3 and VP 16 100 mg/m2 on days 1 to 5. A minimum of three courses were required unless the patient had a rapid progression of disease (PD). Courses were repeated every 4 weeks. RESULTS: We observed partial responses (PRs) in eight of 38 patients (21%), stable disease (SD) in 12 of 38 (32%), whereas 18 of 38 (47%) patients had PD. The median time to tumor progression (TTP) for PR and SD patients was 42.5 weeks, whereas the median survival time (MST) for PR and SD patients was 47.5 weeks. Three groups of toxicities were observed: hematologic, gastrointestinal, and hepatic. No grade 4 Eastern Cooperative Oncology Group toxicity was observed. CONCLUSIONS: This regimen has shown at least comparable results with other series that used platinum-based agents. Further studies that use these agents in various-dose schedules and drug combinations are warranted.",1
7372,1344831,[Omeprazole and liver functions],"""Omeprazole is the first of a new class of drugs (proton pump blockers) approved in the United States and in Europe for its high efficiency as an inhibitor of gastric acid secretion. Omeprazole is a drug for short term use in patients with acid-peptic disease. A limited prevalence of hepatotoxic effects is reported by some authors (transitory rise in serum aminotransferase level) and it may be prescribed in patients with chronic liver disease although slower metabolism and greater bioavailability are observed. Omeprazole interacts with the cytochrome P-450 system in the liver: inhibition of several liver mono-oxygenases activities (inhibitory effect on diazepam, phenytoin and R-warfarin metabolism with prolonged elimination); induction of P-450 (IA1 and IA2) enzymes that may potentiate the hepatotoxic effect of phenacetin and acetaminophen or increase the tumorigenic effect of chemical carcinogens (polycyclic aromatic hydrocarbons, arylamines, aflatoxin). This latter concern is unfounded as based on a false extrapolation from the results of in vitro studies to those of in vivo situations. However, although omeprazole has proved to be remarkably free of side effects, postmarketing surveillance is recommended for potential interaction with other drugs that are known to be metabolized by the same liver enzymes.""",1
7373,1345869,"Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group",,1
7374,1346249,Liver enzyme levels in arthritis patients treated with long-term bolus methotrexate,,1
7375,1347364,Flucloxacillin jaundice,,1
7376,1349790,Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients,"PURPOSE: The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide. PATIENTS AND METHODS: Liver function tests, namely measurement of serum aspartate amino-transferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function. RESULTS: An increase in AST and ALT at fourfold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals. CONCLUSION: Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.",1
7377,1353083,Terazosin: a new alpha adrenoceptor blocking drug,"""Terazosin (Hytrin; Abbott Laboratories, North Chicago, IL) is a new, selective alpha 1-adrenoceptor blocking agent used on once-a-day basis for therapy of mild-to-moderate hypertension. Its pharmacologic properties are similar to those of prazosin. Terazosin however, differs from prazosin in that its water solubility is 25 times greater than that of prazosin and its elimination half-life is about three times that of prazosin. Greater water solubility facilitates intravenous formulation, and longer half-life allows once-daily administration of terazosin. Terazosin is effective in lowering blood pressure and has a beneficial effect on plasma lipid profile. The major advantage of terazosin compared with prazosin, however, is its long duration of action. Terazosin is safe and effective when used in combination with diuretics and other antihypertensive agents, and in the long-term treatment of patients with mild to moderate essential hypertension.""",1
7378,1353389,Acute renal failure after ecstasy,,1
7379,1353554,"""Toxicity and deaths from 3,4-methylenedioxymethamphetamine (""""ecstasy"""")""","""The risk of adverse reactions to 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as """"ecstasy"""", is now widely known in both the USA and UK, but the patterns of illness remain varied. We report our experience during 1990 and 1991. There has been a recent increase in cases of severe toxicity following recreational misuse of small amounts of MDMA. Among 7 fatalities, the pattern of toxicity included fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Until now, there have been few reports of this type of toxicity from MDMA, which may be related both to the potential of the drug to alter thermoregulation and to the circumstances of misuse. In addition, we have monitored 7 cases of hepatotoxicity and suspect that the frequency of this complication is increasing; a history of MDMA misuse should be sought in young people presenting with unexplained jaundice or hepatomegaly. We also describe 5 subjects involved in road traffic accidents in whom MDMA was identified. Misuse of MDMA can have severe acute toxic effects; few data are available concerning long-term morbidity, and this deserves close monitoring in future.""",1
7380,1355200,Multiorgan failure and disseminated intravascular coagulation in severe convulsive seizures,,1
7381,1355234,Fatal hepatitis after herbal tea,,1
7382,1355567,Ecstasy-fueled 'rave' parties become dances of death for English youths,,1
7383,1356543,Misuse of ecstasy,,1
7384,1357248,New treatment for tyrosinaemia,,1
7385,1357995,Liver adenomatosis with granulomas in two patients on long-term oral contraceptives,"""We report two cases of liver cell adenomatosis associated with granulomatous hepatitis, both developed in white women (52 and 39 years of age) on long-term oral contraceptives (for 18 and 12 years, respectively). The first patient underwent surgery for five hepatic tumors 1-7 cm in diameter; the other patient had a partial segmentectomy for a 4-cm hepatic nodule of the right lobe. In both cases, dissection of the liver showed many other diffuse and smaller nodules. Histologically, all tumors were benign liver cell adenomas, with cellular atypia in the largest tumor and associated in both cases with granulomatous hepatitis, with numerous noncaseating epithelioid and giant cell granulomas located either only in the tumors (case 1) or diffusely in the tumoral and nontumoral hepatic parenchyma (case 2). During follow-up, ultrasound showed new nodular lesions in case 2, whereas in case 1 evolution was uneventful. In estroprogestative-associated liver diseases, adenomas are common, but adenomatosis and granulomas are rare. An association of these latter two conditions would seem to be exceptional. The prognosis for adenomatosis remains uncertain.""",1
7386,1359218,Ginkgo biloba,,1
7387,1361136,Podophyllotoxin intoxication: toxic effect of Bajiaolian in herbal therapeutics,"Bajiaolian (Dysosma pleianthum), one species in the Mayapple family, has been widely used as a general remedy and for the treatment of snake bite, weakness, condyloma accuminata, lymphadenopathy and tumours in China for thousands of years. However, the textbooks of traditional Chinese medicine mention little about the toxicity of Bajiaolian. Within 1 year, the authors saw five people who manifested nausea, vomiting, diarrhoea, abdominal pain, thrombocytopenia, leucopenia, abnormal liver function tests, sensory ataxia, altered consciousness and persistant peripheral tingling or numbness after drinking infusions made with Bajiaolian. The herb was recommended by either traditional Chinese medical doctors or herbal pharmacies for postpartum recovery and treatment of a neck mass, hepatoma, lumbago and dysmenorrhoea. Podophyllotoxin is one of the main ingredients of the Bajiaolian root. The clinical manifestations observed in our patients were consistent with podophyllum intoxication. Podophyllotoxin intoxication usually results from the accidental ingestion or topical application of podophyllum resin. However, these cases of Bajiaolian intoxication were iatrogenic and results from 'therapeutic doses' of Bajiaolian cited in the textbooks of traditional Chinese medicine.",1
7388,1361304,Reversible hepatic injury induced by long-term vitamin A ingestion,,1
7389,1362531,The three week sulphasalazine syndrome,"We report a 53-year-old man with sero-negative rheumatoid arthritis who developed a fever, rash and hepatitis 3 weeks after starting sulphasalazine therapy. This was associated with a T cell lymphocytosis, eosinophilia and evidence of classical complement pathway activation. He responded to high dose corticosteroids. This is a rare but characteristic reaction which is likely to be encountered by rheumatologists more frequently with the increasing use of sulphasalazine. It should be recognized promptly as it may be fatal and can be confused with other systemic diseases.",1
7390,1367623,Yeast systems for the commercial production of heterologous proteins,"""Yeasts are attractive hosts for the production of heterologous proteins. Unlike prokaryotic systems, their eukaryotic subcellular organization enables them to carry out many of the post-translational folding, processing and modification events required to produce """"authentic"""" and bioactive mammalian proteins. In addition, they retain the advantages of a unicellular microorganism, with respect to rapid growth and ease of genetic manipulation. The vast majority of yeast expression work has focused on the well-characterized baker's yeast Saccharomyces cerevisiae. However, with the development of DNA transformation technologies, a growing number of non-Saccharomyces yeasts are becoming available as hosts for recombinant polypeptide production. These include Hansenula polymorpha, Kluyveromyces lactis, Pichia pastoris, Schizosaccharomyces pombe, Schwanniomyces occidentalis and Yarrowia lipolytica. The performance of these alternative yeast expression systems is reviewed here relative to S. cerevisiae, and the advantages and limitations of these systems are discussed.""",1
7391,1369795,Histologic changes in liver allograft biopsies associated with elevated whole blood and tissue cyclosporine concentrations,"""Cyclosporine is used in the postoperative management of rejection in liver allograft recipients. Despite its efficacy in the treatment of allograft rejection, the drug exhibits toxicity at elevated whole blood concentrations including nephrotoxicity with associated histologic changes, and evidence of hepatotoxicity as determined by liver function studies. To date, there have been few published reports describing histologic changes in liver biopsies from patients with elevated blood cyclosporine levels. In the present study, we retrospectively examined biopsies from 16 liver allograft recipients, seven patients with elevated whole blood cyclosporine levels (> 1000 ng/ml) and nine control patients who had whole blood cyclosporine levels in the therapeutic range (558 to 993 ng/ml). In each case, frozen liver biopsy tissue was available to measure tissue levels of cyclosporine and metabolites. The blood and tissue drug levels were then correlated with the histologic changes present in the biopsy specimens. Patients with increased cyclosporine levels displayed histologic changes consisting of hypertrophy of the bile ductal epithelium with cytoplasmic vacuoles and the presence of """"foamy"""" material within the hepatic sinusoids that were either absent or occurred less frequently in the control group. The histologic changes correlated best with cyclosporine metabolite levels rather than tissue levels of native drug. When liver function studies were correlated with cyclosporine levels, only gamma glutamyl transpeptidase (GGT) demonstrated a significant positive correlation with the histologic changes.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
7392,1376585,Hepatotoxicity of high dose salicylate therapy in acute rheumatic fever,"""Liver function tests, including serum alanine aminotransferase (ALT) activity, serum bilirubin, alkaline phosphatase, serum proteins, blood ammonia levels and intravenous glucose utilization, were monitored in 50 children with acute rheumatic fever receiving anti-rheumatic doses of aspirin. There was a significant increase in blood ammonia levels and serum ALT after aspirin therapy. A significant fall in glucose utilization coefficient was also recorded. Serum alkaline phosphatase, bilirubin and total proteins did not change significantly. Twenty-two of the 50 children recorded a rise in serum ALT; in 12, the rise was five- to tenfold. These 12 children developed adverse symptoms to aspirin. Also, all had a marked rise in blood ammonia levels. The children improved clinically and biochemically on withdrawal of aspirin. There was no constant relationship between hepatocellular function and serum salicylate levels.""",1
7393,1380630,Finasteride for benign prostatic hypertrophy,,1
7394,1382939,Enoxaparin. A review of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disorders,"""Enoxaparin (PK 10169) belongs to the group of low molecular weight heparins which have a greater bioavailability and longer half-life than unfractionated heparin, permitting less frequent subcutaneous administration. In well controlled trials in surgical patients at high risk of deep venous thrombosis (DVT), enoxaparin has demonstrated prophylactic efficacy against venographically confirmed DVT at least equal to that observed with unfractionated heparin. Efficacy has also been demonstrated in patients at moderate risk and in limited investigations using 125I-fibrinogen scanning in nonsurgical patients at risk of DVT; in addition, enoxaparin appears to provide effective treatment of established DVT. In clinical studies, enoxaparin has also prevented coagulation of extracorporeal circulation, maintaining the patency of the circuit in patients undergoing haemodialysis. Thus, enoxaparin represents an effective alternative in the prophylaxis and treatment of thrombosis, with the convenience of less frequent administration than unfractionated heparin and the possible advantage of a lesser propensity for bleeding complications.""",1
7395,1387992,[Acute hepatitis associated with etodolac therapy],,1
7396,1389551,[Cholestasis caused by hypersensitivity to flurbiprofen],,1
7397,1393073,Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports,"OBJECTIVE: To examine the possible contribution of sedation with propofol in the deaths of children who were intubated and required intensive care. DESIGN: Case note review. SETTING: Three intensive care units. SUBJECTS: Five children with upper respiratory tract infections aged between 4 weeks and 6 years. RESULTS: Four patients had laryngotracheo-bronchitis and one had bronchiolitis. All were sedated with propofol. The clinical course in all five cases was remarkably similar: an increasing metabolic acidosis was associated with brady-arrhythmia and progressive myocardial failure, which did not respond to resuscitative measures. All children developed lipaemic serum after starting propofol. These features are not usually associated with respiratory tract infections. No evidence was found of viral myocarditis, which was considered as a possible cause of death. CONCLUSION: Although the exact cause of death in these children could not be defined, propofol may have been a contributing factor.",1
7398,1397750,Safety experience from long-term treatment with omeprazole,"Omeprazole was administered for up to 6 years in 859 patients for 'prevention of relapse in patients with poorly responsive peptic ulcer or reflux oesophagitis'. The pattern of adverse events reported during long-term treatment was similar to the adverse-event profile in short-term treatment with omeprazole (n = 2,818), ranitidine (n = 1,572) and cimetidine (n = 891). Omeprazole had essentially the same adverse-event profile as the two H2-receptor antagonists. The adverse-event profile for omeprazole during long-term treatment did not differ from that seen during short-term treatment with either omeprazole or the H2-receptor antagonists. The rate of occurrence of any specific adverse event decreased with time, and no previously unidentified adverse event occurred with long-term omeprazole therapy. There were no serious adverse events that were considered to be causally related to omeprazole therapy. Thus, omeprazole has been shown to be well tolerated in both short- and long-term treatment.",1
7399,1397860,[Cytolytic hepatitis induced by cisapride],,1
7400,1404819,A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group,"OBJECTIVE: To compare efficacy and safety of tacrine hydrochloride with placebo in patients with probable Alzheimer's disease. DESIGN: A 12-week, double-blind, placebo-controlled, parallel-group study. SETTING: Outpatients at 23 centers. PATIENTS: Men and women with probable Alzheimer's disease, at least 50 years old, mildly to moderately impaired, without other significant medical conditions. INTERVENTIONS: In the initial 6 weeks, patients received placebo, 20 mg/d of tacrine, or 40 mg/d of tacrine. In the second 6 weeks, half received the same treatment and half increased tacrine dose: those receiving placebo increased to 20 mg/d, those receiving 20 mg/d increased to 40 mg/d, and those receiving 40 mg/d increased to 80 mg/d. PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale (ADAS) cognitive component and clinician-rated Clinical Global Impression of Change (CGIC). RESULTS: Four hundred sixty-eight patients entered. After 12 weeks, dose-related improvement was significant on the ADAS cognitive (P = .014), clinician-rated CGIC (P = .014), and caregiver-rated CGIC (P = .006). Comparison of 80 mg/d with placebo showed significant improvement on the ADAS cognitive (P = .015), clinician-rated CGIC (P = .016), and caregiver-rated CGIC (P = .028). Significant effects appeared as early as 6 weeks on the ADAS cognitive and caregiver-rated CGIC. Among patients receiving 80 mg/d of tacrine, 51% achieved a four-point or greater improvement of the ADAS cognitive component after 12 weeks of treatment. Reversible asymptomatic transaminase elevations greater than three times normal occurred in 25% of patients. Other treatment-related events included nausea and/or vomiting (8%), diarrhea (5%), abdominal pain (4%), dyspepsia (3%), and rash (3%). CONCLUSIONS: These results confirm the efficacy and safety of tacrine in some patients with Alzheimer's disease. After 12 weeks, the magnitude of the treatment effect is clinically important and recognized by the physician and caregiver. Liver toxicity is reversible and easily detected by weekly alanine aminotransferase determinations.",1
7401,1410910,[Hepatotoxicity of cyproterone acetate],,1
7402,1412047,[Dentist and physician integrated training at the Health Sciences Faculty at Copenhagen],,1
7403,1414241,Six-year follow-up study on the efficacy and safety of vigabatrin in patients with epilepsy,"Twenty-five patients with epilepsy (mostly with partial seizures) who had responded favourably to a short-term trial of add-on vigabatrin entered maintenance treatment. After 52 to 78 months, 15 patients continue to take the drug with good therapeutic response. Median monthly seizure frequency during the last 2 months on vigabatrin in all patients, including drop-outs, was 3.5 (range 0-74) as compared with 10 (range 3-98) during an initial placebo period (p < 0.01). Drop-outs were caused by adverse events in 2 cases (ataxia and psychotic symptoms respectively), seizure breakthrough in 4 cases and reasons unrelated to treatment in 4 patients. In most patients, side effects were absent or mild, the most frequent complaint being weight gain. It is concluded that the antiepileptic efficacy and good clinical tolerability of vigabatrin are generally maintained during long-term treatment for up to 6 years.",1
7404,1419017,Postoperative elevation of serum transaminases following isoflurane anesthesia,"Halogenated inhalational anesthetics have been implicated in hepatotoxicity. Halothane hepatitis results from the biotransformation of the drug to a metabolite that binds to liver proteins, which creates a hapten, which, in turn, causes an immunologic response in the liver. Case reports of hepatic injury resulting from isoflurane, which has a decreased biotransformation compared with that of halothane, have received much criticism. We describe a patient who had elevated liver enzymes and a positive trifluoroacetyl antibody titer following an anesthetic regimen that included isoflurane.",1
7405,1423181,Phase III double-blind comparison of intravenous ondansetron and metoclopramide as antiemetic therapy for patients receiving multiple-day cisplatin-based chemotherapy,"BACKGROUND: Ondansetron hydrochloride is a selective serotonin subtype 3 (5HT3) receptor antagonist that has been shown to be an effective antiemetic in patients receiving cisplatin chemotherapy. METHODS: This double-blind study compared the safety and efficacy of intravenous ondansetron with metoclopramide in patients receiving a 4- or 5-day regimen of cisplatin (20-40 mg/m2/day) combination chemotherapy. Forty-five patients were enrolled, and efficacy of the drug therapy could be studied for all 45. Patients were randomly assigned (1:1) to receive three daily intravenous doses of either 0.15 mg/kg ondansetron or 1 mg/kg metoclopramide. All patients were monitored daily for the number of emetic episodes (vomiting or retching), severity of nausea, adverse events, and laboratory safety parameters. RESULTS: Seven (30%) patients who received ondansetron had no emetic episodes throughout the entire study period compared with two (9%) who received metoclopramide (P = 0.077). The greatest difference in antiemetic efficacy was seen on day 1, when 18 (78%) patients who received ondansetron had no emetic episodes compared with 3 (14%) patients who received metoclopramide (P < 0.001). Significantly fewer antiemetic treatment failures (more than five emetic episodes or withdrawal from the study) occurred with patients given ondansetron (9%) than with those given metoclopramide (50%) during the entire study period (P = 0.002). The most commonly reported adverse event associated with ondansetron therapy was headache (controlled with acetaminophen), whereas diarrhea and restlessness were the most commonly reported adverse events associated with metoclopramide therapy. Extrapyramidal symptoms were judged to have occurred in 13 patients who received metoclopramide and 1 patient who received ondansetron. However, the patient who received ondansetron subsequently was judged to have had an anxiety attack. In patients with low or normal baseline transaminase values, a greater percentage who received ondansetron had transient increases as great as twice the upper limit of normal in aspartate transaminase (5% versus 0%) and alanine transaminase (17% versus 6%) than those who received metoclopramide. CONCLUSIONS: Ondansetron is superior to metoclopramide as antiemetic therapy for multiple-day cisplatin-based chemotherapy.",1
7406,1434065,[Non-Hodgkin's lymphoma in an elderly patient complicated by cyclophosphamide-induced allergic hepatic dysfunction],"A 77-year-old male presented at our Department of Urology in August 1990 with a gradually enlarging swelling in the right scrotum. On August 21, right high orchietomy was performed. This was diagnosed histologically as non-Hodgkin's lymphoma (diffuse large cell type), and the patient was transferred to our department on September 11 for further examination and treatment. As enlargement of the lymph nodes around the abdominal aorta was evident, it was diagnosed as stage IIA according to the Ann Arbor Classification. Beginning on September 21, three courses of COP-BLAM therapy (CPM, VCR, PDN, BLM, ADR, PCZ) were administered (the third course started on November 8) to achieve complete remission. Hepatic dysfunction appeared, however, from November 16, and by November 19, GOT and GPT increased to 6700 and 2120, respectively, with aggravation of jaundice. PDN therapy was instituted, and GOT and GPT improved gradually, but jaundice did not improve. On December 22, laparoscopy was performed, and liver biopsy produced histologic findings of drug-induced hepatitis. Further, lymphoblastic response was positive for CPM. Hepatic failure occurred on December 29, and plasma exchange was performed, but it failed to improve the condition, and the patient died on January 15. We described a case of non-Hodgkin's lymphoma complicated by hepatic dysfunction, probably induced by CPM, in an elderly patient who died to hepatic failure.",1
7407,1440084,[Gold-induced severe cholestatic jaundice in rheumatoid arthritis patient and effect of repeated steroid pulse therapy],"A 32-year-old female with early stage of rheumatoid arthritis (RA) developed anorexia, pruritus, dark urine, pale stool and jaundice 3 weeks after initiation of chrysotherapy. She was administered a total of 35mg of gold sodium thiomalate (GST) intramuscularly and auranofin 6mg per day orally. Liver function tests and biopsy specimens showed severe cholestatic jaundice. Prednisolone 30mg per day and plasma exchange were started. No response however was obtained and the total bilirubin level gradually increased. Steroid pulse therapy, 1000mg methylprednisolone for successive 3 days as one therapy unit, was repeated 4 times. Liver functions were then gradually improved. Gold induced hepatotoxicity is a rare complication. We concluded that the hepatotoxicity in this case was caused by allergic reaction against GST and repeated steroid pulse therapy was very effective to these conditions.",1
7408,1445654,Cerebellar stimulation as an unconditioned stimulus in classical conditioning,"Rabbits were implanted with chronic stimulating electrodes in white matter underlying lobule HVI of the cerebellar cortex. Stimulation elicited movements of the face or neck and, when paired with a tone conditioned stimulus (CS), produced learning comparable to that seen with peripheral unconditioned stimuli (USs). CS-alone trials produced extinction. Reinstatement of paired trials produced reacquisition with savings. Additional groups received either explicitly or randomly unpaired CS-US trials before paired conditioning. Low-frequency responding during these sessions indicated that the paired training results were associative and not due to pseudoconditioning or sensitization. Explicitly unpaired sessions retarded learning on subsequent paired trials compared with groups that received either randomly unpaired or no CS-US preexposure. These results are interpreted in terms of the role of the cerebellum and associated pathways in classical conditioning of motor responses.",1
7409,1449165,Hepatotoxicity of 6-mercaptopurine in Crohn's disease,,1
7410,1453702,Kava: an overview,"Since the first significant contact with Europeans in the 18th century, the Oceanic plant, Piper methysticum Forst. (Piperaceae) and the beverage prepared from it, both of which are called kava, have become familiar to much of the outside world through both the written and visual media. The ceremonial preparation and consumption of the beverage are probably its most conspicuous and spectacular features. Kava continues to occupy a central place in everyday life in the islands concerned, although its role has been somewhat diminished by time and outside influences. Despite the large body of literature on kava--about 800 entries are listed in a recent bibliography by Singh (1986)--there has been no comprehensive review on the subject. Earlier contributions by Keller and Klohs (1963) and Shulgin (1973) were selective in treatment and dealt primarily with chemical and pharmacological aspects. The monograph by Steinmetz (1960) remains a standard reference but understandably some of the information in it has become dated. The attention of the reader is also drawn to two excellent additions to the recent kava literature, by Lebot and Cabalion (1988) and Brunton (1989), which are, although somewhat restricted in focus, are very significant contributions to the subject. The present review paper provides an updated and a multidisciplinary overview of the subject. It was prepared on the basis of the author's personal experience--he is a native of Fiji and lived in that country for about 30 years--as well as the relevant literature listed in the Singh (1986) bibliography and some more recent publications.",1
7411,1456591,Isoniazid-associated hepatitis deaths: a review of available information,,1
7412,1458761,Clinical pharmacokinetics of ketorolac tromethamine,"""Ketorolac is a new chiral nonsteroidal anti-inflammatory drug (NSAID) which is marketed for analgesia as the racemate. The drug is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular injection. The absorption of ketorolac is rapid, Cmax being attained between 20 to 60 min. Its oral bioavailability is estimated to range from 80 to 100%. The drug is extensively bound (> 99%) to plasma proteins and has a volume of distribution (0.1 to 0.3 L/kg) comparable with those of other NSAIDs. Only small concentrations of ketorolac are detectable in umbilical vein blood after administration to women in labour. The elimination half-life is between 4 and 6h and is moderate in comparison with other NSAIDs. The area under the plasma concentration-time curve of ketorolac is proportional to the dose after intramuscular administration of therapeutic doses to young healthy volunteers. Ketorolac is extensively metabolised through glucuronidation and oxidation; little if any drug is eliminated unchanged. Most of the dose of ketorolac is recovered in the urine as conjugated drug. Although ketorolac is excreted into the breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Little stereoselectivity was present in the pharmacokinetics of ketorolac in a healthy volunteer receiving single intravenous or oral doses. The elderly exhibit reduced clearance of the drug. Renal insufficiency appears to cause an accumulation of ketorolac in plasma, although hepatic disease may not affect the pharmacokinetics.""",1
7413,1460759,[A case of postoperative hepatic injury after sevoflurane anesthesia],"A 63 year old man underwent MCA aneurysmal neck clipping under O2-N2O-enflurane anesthesia. On the 46th postoperative day after the first operation, he had cranioplasty under O2-N2O-sevoflurane anesthesia. Hepatic injury occurred after the operation, and GOT, GPT and bilirubin increased above 700 IU.l-1, 800 IU.l-1 and 15.0 mg.dl-1 respectively but consciousness disturbance, hyperammonemia and DIC did not appear. His hepatic injury improved on conservative therapy. It seems that his hepatic injury was not caused by hepatitis viruses or hepatotoxicity of any drugs, but caused by cross sensitization between halogenated inhalation anesthetics, especially enflurane and sevoflurane, judging from drug induced lymphocyte stimulating test (DLST). We have to select an anesthetic method considering potential hepatic injury by halogenated anesthetics in a case of repeated anesthesia and operations during a short-term.",1
7414,1464366,Fulminant hepatic failure after high-dose cytosine arabinoside and mitoxantrone treatment for relapse of acute myelogenous leukaemia,,1
7415,1471553,Controlled trials of Antabuse in alcoholism: the importance of supervision and adequate dosage,Methods of using Antabuse have changed since its introduction over 40 years ago. Several randomised controlled trials have shown that Antabuse can make a statistically and clinically significant contribution to treatment outcome in alcoholism but only if its administration is carefully supervised. The recent literature is reviewed. Adequate dosage is important and the recommended maximum in some countries is often insufficient. Both prescribers and supervisors of Antabuse need to be aware of the ways in which some patients try to evade medication.,1
7416,1474535,Worldwide safety experience with nabumetone,"Nabumetone has undergone human clinical premarketing and postmarketing testing for efficacy and safety for about 10 years. In the United States and elsewhere, 7,241 patients were evaluated in clinical trials and comparative information with placebo, aspirin, and other nonsteroidal antiinflammatory drugs (NSAID) was gathered. Postmarketing surveillance information was gathered for 37,712 patients in the United Kingdom and Germany. Withdrawal rates due to adverse effects ranged from 3 to 13%. The cumulative incidence of nabumetone-induced perforations, ulcers, or bleeds varied from 0.02 to 0.95%. In all patients evaluated, only 2 deaths and 15 hospitalizations could be attributed to nabumetone therapy. Bone marrow suppression, liver necrosis, serious central nervous system conditions, or life-threatening dermatologic reactions did not occur. No increase in toxicity was noted with increased dose (up to 2000 mg/day) or age. Nabumetone was determined to be a safe NSAID that causes a low incidence of ulcers.",1
7417,1478415,[Cytolytic hepatitis and wild Germander: a new case with reintroduction],,1
7418,1486190,Gall-bladder sludge: lessons from ceftriaxone,"Ceftriaxone-associated sludge has been a fascinating story. The occurrence is novel and unique. It has produced a model of gall-bladder sludge in humans. This phenomenon has taught us a great deal about biliary lipid and organic anion excretion by the liver, and the physical chemistry of calcium and calcium sensitive anions. It has added further insights into the pathophysiology of gall-bladder sludge formation. It points to a combination of a hepatic effect where the liver secretes a biochemically abnormal bile, and a gall-bladder effect which provides an environment for precipitation, in order for sludge to develop. The precipitated calcium ceftriaxone has prompted us to re-evaluate the imaging criteria for the diagnosis of gall-bladder sludge versus gallstones. Above all, the rapid onset and rapid disappearance of ceftriaxone sludge has mirrored in a compressed, encapsulated form, the natural history of gall-bladder sludge. It has reminded us that, like gallstones, biliary sludge is usually benign and asymptomatic. However just because it is smaller than gallstones does not mean it cannot cause problems. It can disappear or it can become a calcium ceftriaxone gallstone.",1
7419,1493887,[Fulminant hepatitis caused by wild germander],,1
7420,1494520,Hepatic and pulmonary complications of herbal medicines,,1
7421,1496647,Toxicity of high-dose busulfan and cyclophosphamide as a preparative regimen for bone marrow transplantation,,1
7422,1504402,Hypersensitivity immune reaction as a mechanism for dilevalol-associated hepatitis,"OBJECTIVE: To assess lymphocyte reactivity to dilevalol and to serum containing putative ex vivo dilevalol antigens or metabolites in a case of dilevalol-induced liver injury. PATIENT: A 58-year-old woman with a clinical diagnosis of dilevalol-induced liver injury. METHODS: Peripheral blood mononuclear cells collected from the patient were cultured in the presence of a solution of dilevalol and also with sera collected from a volunteer before and after dilevalol intake. A similar protocol was performed with lymphocytes from a healthy subject. RESULTS: No lymphocyte proliferation was observed either in the patient or in the healthy volunteer in the presence of dilevalol solutions. A significant proliferative response to serum collected after dilevalol intake was observed in the case of the patient compared with the proliferative response to the serum collected before the drug intake. No reactivity was found when lymphocytes from the healthy subject were tested under similar conditions. CONCLUSIONS: The methodology used allowed the detection of lymphocyte sensitization to sera containing ex vivo-prepared dilevalol antigens, suggesting the involvement of an immunologic mechanism in dilevalol-induced liver injury.",1
7423,1505913,Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial,"The efficacy and safety of ursodeoxycholic acid for the treatment of primary sclerosing cholangitis were evaluated in a prospective, randomized, double-blind, placebo-controlled trial. Fourteen patients with primary sclerosing cholangitis documented by cholestatic serum enzyme pattern, liver histological appearance and endoscopic retrograde cholangiography were included in the trial. Six patients received ursodeoxycholic acid (13 to 15 mg/kg body wt/day), and eight patients received placebo. Two patients had to be withdrawn from the study, one because of UDCA-related diarrhea and the other because of worsening of the disease during placebo treatment. Patients in the ursodeoxycholic acid group improved significantly during 1 yr of treatment with respect to serum levels of bilirubin (median = -50%), alkaline phosphatase (median = -67%), gamma-glutamyltransferase (median = -53%), AST (median = -54%) and ALT (median = -36%) compared with the placebo group, but not with respect to serum levels of hydrophobic bile acids. During ursodeoxycholic acid treatment, histopathological features also improved significantly, as evaluated by multiparametric score. Expression of human leukocyte antigen class I molecules appeared to be markedly reduced on liver cells after ursodeoxycholic acid treatment. We conclude that ursodeoxycholic acid is beneficial in reducing disease activity in patients with primary sclerosing cholangitis.",1
7424,1506809,Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987,"""The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected during the last 2 years of the decade. Based on consumption data, the incidence of hepatic injury due to sulindac was estimated to be 18-fold higher than that due to ibuprofen. Paracetamol was reported to induce acute cytotoxic as well as cholestatic reactions in non-alcoholic subjects taking therapeutic doses.""",1
7425,1510353,"The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study","To find out whether treatment with 4-aminopyridine is beneficial in multiple sclerosis (MS), 70 patients with definite MS entered into a randomized, double-blind, placebo-controlled, cross-over trial in which they were treated with 4-aminopyridine and placebo for 12 weeks each (maximum dose, 0.5 mg/kg of body weight). The estimated effect of the treatment as measured with the Kurtzke expanded disability status scale, which was the main evaluation parameter, was 0.28 point (p = 0.001). A significant decrease in the scale score (1.0 point or more) was encountered in 10 patients (16.4%) during oral treatment with 4-aminopyridine whereas it was not seen during placebo treatment (p less than 0.05). A significant subjective improvement (defined as an improvement that significantly affected the activities of normal daily life) was indicated by 18 patients (29.5%) during 4-aminopyridine treatment and by 1 patient (1.6%) during placebo treatment (p less than 0.05). Significant improvements related to 4-aminopyridine occurred in a number of neurophysiological parameters. No serious side effects were encountered. However, subjective side effects such as paresthesias, dizziness, and light-headedness were frequently reported during 4-aminopyridine treatment. Analysis of subgroups revealed that there was no difference in efficacy between those patients randomized to receive 4-aminopyridine and then placebo and those randomized to receive placebo and then 4-aminopyridine or between patients with and those without subjective side effects. Especially patients with temperature-sensitive symptoms and patients characterized by having a longer duration of the disease and being in a progressive phase of the disease were likely to show clear clinical benefit.",1
7426,1515637,Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin's lymphoma: a double-blind placebo-controlled trial,"The toxicity of autologous bone marrow transplantation (ABMT) is correlated to neutropenia. Although recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) seems to hold promise in accelerating neutrophil recovery, few analyses from randomized studies are presently available. Ninety-one patients with non-Hodgkin's lymphoma receiving high-dose ablative chemotherapy followed by ABMT with unpurged or purged marrow were included in a randomized, double-blind, placebo-controlled trial. Forty-four patients received 250 micrograms rhu GM-CSF (Escherichia coli)/m2 and 47 patients received placebo. Treatment was administered daily as continuous infusion from day of ABMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/L for 7 days or until day 30, whichever was first. With rhu GM-CSF, 50% of the patients reached an ANC count greater than 0.5 x 10(9)/L at day 14 as opposed to day 21 with placebo (P less than .0001). Patients transplanted with marrow purged by mafosfamide also recovered earlier when treated with rhu GM-CSF (16 v 20.5 days, P = .013). The hospitalization duration was shorter in the rhu GM-CSF group (median, 23 v 28 days, P less than .05). No difference was observed in fever, number of infections, and antibiotic administration between the two groups. The major adverse event ascribed to rhu GM-CSF was a capillary leak syndrome in three patients graded as severe in two patients, moderate in one, and reversible in all three patients. In addition, one patient in the rhu GM-CSF group died suddenly with no explanation. In long term follow-up, the relapse rate was identical in both groups and there was no significant difference in the number of deaths at 1 year (12 with rhu GM-CSF v 9 with placebo), although deaths seemed to occur slightly earlier in the rhu GM-CSF group. We conclude that after ABMT with purged or unpurged marrow, rhu GM-CSF (E coli) significantly reduces neutropenia duration and hospitalization stay. A positive causative relation between the study drug and/or its mode of application with an increased toxicity as compared with GM-CSF from other sources and/or other modes of application cannot be deduced from the experiences in this study. Additional randomized trials would be necessary for an appropriate answer.",1
7427,1520752,Hepatotoxicity of hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors,"The first clinical studies on hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors reported a low incidence of liver toxicity. The personal observation of a case of simvastatin-induced acute cholestatic hepatitis prompted us to evaluate the true incidence of hepatic side effects of these drugs in a large Italian population. One hundred patients taking simvastatin and ninety patients treated with pravastatin were followed-up six months with periodical evaluation of serum lipid levels and liver function test. In 5% of simvastatin-treated patients and 4.5% of pravastatin-treated patients significant liver toxicity was observed, which required drug discontinuation. The mechanism of liver damage was direct, idiosyncratic, but immunological features of drug toxicity could be hypothesized in one patient.",1
7428,1526188,Adverse effects associated with intravenous pentamidine isethionate as treatment of Pneumocystis carinii pneumonia in AIDS patients,"To evaluate the adverse effects of intravenous pentamidine isethionate, a retrospective study was carried out over a four-year period. Twenty-one acquired immunodeficiency syndrome (AIDS) patients received intravenous pentamidine as treatment of Pneumocystis carinii pneumonia (PCP). This was 13% of the total number of patients with PCP in the department during that period. Four patients died during treatment and were not evaluated for side effects. Thirteen patients (13/17 = 76%) suffered from one or more minor side effects. The most common of these were gastrointestinal discomfort, pancreatitis, nephro- and hepatotoxicity. Five patients (5/17 = 29%) experienced a major adverse effect. These were cardiac arrest (one patient), severe hypoglycaemia (one patient) and severe pancreatitis (three patients). In two patients, discontinuation of treatment was necessary due to adverse reactions. As long as pentamidine isethionate is the second drug of choice in the treatment of acute PCP, careful biochemical and cardial monitoring of patients during treatment is recommended.",1
7429,1526409,[Atrium-induced hepatitis with autoimmune pattern],,1
7430,1530700,Hepatotoxicity of fluorouracil with N-phosphonacetyl-L-aspartate,,1
7431,1531828,The safety profile of paroxetine,"Side effects remain one of the most important clinical issues in antidepressant therapy. Patients may not be able to take appropriate treatment or may not tolerate their medication in adequate doses or for an adequate length of time to manage their depressive illness. This article reviews the extensive safety data from 6705 patients treated with paroxetine. These data indicate that paroxetine has no significant cardiovascular effects, few significant drug interactions, and no clinically significant effects on the ECG or EEG. Furthermore, paroxetine is relatively safe in overdose and has very little anticholinergic activity. Psychomotor performance is not impaired by paroxetine and there is no evidence of any zimelidine-like hypersensitivity reactions or increase in suicidal ideation. As with other selective serotonin reuptake inhibitors (SSRIs), the most common side effect is gastrointestinal upset, especially nausea. This is usually very well tolerated and rarely leads to drug discontinuation. As with other SSRIs, monoamine oxidase inhibitors should not be prescribed concurrently or soon after discontinuing paroxetine because of the risk of a lethal interaction. Paroxetine may be less likely than currently available SSRIs to cause agitation. In general, paroxetine has a very favorable side effect profile and should be an important alternative in the medical treatment of depressive illness.",1
7432,1532509,Zoladex (goserelin) in the treatment of benign gynaecological disorders: an overview of safety and efficacy,,1
7433,1535676,Liver pathology associated with the use of anabolic-androgenic steroids,"This review examines the liver-damaging side effects of anabolic-androgenic steroids (AAS). It seems that AAS can cause development of peliosis hepatis, subcellular changes of hepatocytes, hepatocellular hyperplasia and hepatocellular adenomas. On the other hand, it has not been convincingly proved that AAS can cause development of hepatocellular carcinomas when used in the usual therapeutic doses. Tumours reported as hepatocellular carcinomas caused by AAS seems to be hyperplastic lesions of a benign nature able to regress with withdrawal of the putative agent. The effects of untraditional combinations and high-dose AAS are not yet known, leaving the possibility of a carcinogenic effect in those cases.",1
7434,1536695,Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update,"""The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)""",1
7435,1536917,"Population density and cancer incidence differentials in New York State, 1978-82","Patterns of cancer incidence within five population density quintiles in New York State, exclusive of New York City, were investigated between 1978 and 1982. Sex-specific, standardized incidence ratios were calculated within each population density quintile for all cancer cases combined and for site-specific cancers based on cancer incidence patterns exhibited by the general population of New York State, exclusive of New York City. Areas with the highest population density demonstrated a 13 percent excess of cancer cases among males and a seven percent excess among females. In contrast, areas with the lowest population density exhibited lower cancer incidence, among both males (12 percent less) and females (12 percent less). Males demonstrated a significant, direct linear relationship between increasing population density and all cancer sites combined, and for cancers of the oral cavity and pharynx, esophagus, stomach, colon, rectum, liver, pancreas, larynx, lung, bladder, brain, and nervous system, and for Hodgkin's disease and multiple myelomas. Among females, a significant, direct linear relationship was observed between increasing population density and all cancer sites combined, and for cancers of the buccal cavity and pharynx, esophagus, stomach, lung, breast, and kidney. Malignant melanomas of the skin, and in situ and invasive cancers of the cervix exhibited unusual incidence patterns across the population density quintiles. These data are most useful in generating hypotheses for further studies to define specific etiologic factors operating within population density groupings. Population density, as measured in this investigation, may represent a surrogate measure for other factors which are related to cancer morbidity.",1
7436,1537473,[Augmentin hepatotoxicity: responsibility of clavulanic acid? Apropos of a case],,1
7437,1538215,"Frequency of central lesions in polyneuropathy associated with IgM monoclonal gammopathy: an MRI, neurophysiological and immunochemical study","CNS lesions were studied in polyneuropathy associated with IgM monoclonal gammopathy. Eleven out of 12 patients with IgM MGUS and one patient with Waldenstrom's disease had clinical and electrophysiological features indicating a demyelinating polyneuropathy. MRI showed CNS white matter lesions in two cases. Antibodies reacting against glycolipids present in CNS white matter were present in five cases, two of which had abnormal MRI. Central conduction times cortex-C7, obtained by magnetic stimulation, were prolonged in 3/8 patients, of which two patients had anti-CNS glycolipid antibodies.",1
7438,1539293,Treatment with poly- and monoclonal antilymphocyte antibodies: assessment of efficacy and safety in transplantation,,1
7439,1545730,Low-dose methotrexate therapy and hepatotoxicity,,1
7440,1548414,Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenge,,1
7441,1551543,Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome,"Serious carbamazepine hepatotoxicity is being recognized more frequently and is usually manifest as an acute granulomatous hepatitis that is self-limiting if the drug is withdrawn. The case of a 59-year-old man who developed the vanishing bile duct syndrome after 2 months of treatment with carbamazepine for glossopharyngeal neuralgia is reported. The characteristic histological features of this syndrome may also be seen in primary biliary cirrhosis, primary sclerosing cholangitis, graft-vs.-host disease after allogeneic bone marrow transplantation, chronic liver allograft rejection, and other drug reactions. The progress of this patient to date suggests that irreversible liver injury resulting in chronic liver disease is likely, in keeping with the clinical course of the vanishing bile duct syndrome in most cases.",1
7442,1551549,Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C,"""The case of a 68-year-old man with chronic hepatitis C who developed worsening of liver disease with jaundice when he was treated with alpha interferon is described. His disease activity appeared to improve when interferon was stopped but flared again with reinstitution of treatment. Subsequent treatment with prednisone resulted in partial resolution of disease. The patient had antibody to hepatitis C virus and hepatitis C virus RNA detectable in serum; titers of these viral markers did not change with treatment. In addition, he had insulin-dependent diabetes and antinuclear antibodies, suggesting that he had a pre-existing autoimmune diathesis that may have predisposed him to developing an autoimmune hepatitis with interferon therapy.""",1
7443,1553942,Fulminant hepatic failure related to omeprazole,Omeprazole is a new hydrogen-potassium adenosine triphosphatase antagonist with indications for severe reflux esophagitis and Zollinger-Ellison syndrome. Side effects involving the liver have consisted of minimal elevations of hepatocellular enzymes with higher dosages. We present what we believe is the first reported case of fulminant hepatic failure related to omeprazole.,1
7444,1554954,Labetalol hepatotoxicity,,1
7445,1556848,[Perspectives in pediatrics in united Germany],,1
7446,1559791,Lovastatin-induced hepatitis,,1
7447,1568667,Liver fibrosis in a patient with familial homozygous hypobetalipoproteinaemia: possible role of vitamin supplementation,"A case of apolipoprotein B-related disorder is reported in which liver fibrosis developed without long term administration of medium chain triglycerides, previously incriminated in the pathogenesis of this lesion. The patient was a young woman in whom the diagnosis of familial homozygous hypobetalipoproteinaemia was made at the age of 21. A first liver specimen taken at diagnosis revealed steatosis, hypertrophic Golgi apparatus and proliferating smooth endoplasmic reticulum. The patient was treated with vitamin A and E supplementation only. Two years later, a second liver biopsy, carried out because of increased serum alanine aminotransferase concentrations, showed fibrosis, mild cytolysis and marked mitochondrial alterations. Hepatic level of vitamin A was increased. This finding supports the hypothesis that liver disease observed in our patient might be an adverse effect of vitamin supplementation. Our observation underlines the importance of including liver function tests in the follow up of patients with apolipoprotein B-related disorders.",1
7448,1576399,Comment: ketoconazole hepatotoxicity,,1
7449,1579800,[Hepatic involvement in the course of ovarian hyperstimulation syndrome],"The authors report the case of hepatic damage with a favorable outcome, occurring during severe ovarian stimulation which had anatomico-clinical features which distinguished it from the three cases previously reported due to its exclusively cytolytic nature and the histological lesions produced. The physiopathological mechanisms involved are discussed.",1
7450,1582111,Hepatotoxicity to several nonsteroidal anti-inflammatory drugs with diclofenac induced histological changes,,1
7451,1583956,[Cholestatic jaundice induced by captopril],,1
7452,1587437,Prolonged cholestasis due to trimethoprim sulfamethoxazole,"""Drug-induced liver injury due to trimethoprim sulfamethoxazole is rare and classified as an unpredictable or idiosyncratic type of hepatotoxic reaction. Early reports suggested that the pattern of liver injury in the majority of cases is mixed hepatocellular-cholestatic. The current report describes two cases of severe, prolonged cholestasis after treatment with trimethoprim sulfamethoxazole; intractable pruritus and abnormal liver test results lasted for 1-2 years after discontinuation of the drug. Liver biopsy specimens showed a cholestatic pattern of liver injury and only minimal hepatocellular necrosis or inflammation. Recent case reports suggest that cholestasis alone may occur after the use of trimethoprim sulfamethoxazole; these two additional cases show that cholestasis may be quite prolonged.""",1
7453,1591420,Fulminant hepatic failure possibly related to ciprofloxacin,"OBJECTIVE: To report a case of hepatic failure in a patient who was receiving oral ciprofloxacin. DATA SOURCES: Case reports, review articles, and relevant laboratory studies identified by MEDLINE. DATA EXTRACTION: Data were abstracted from pertinent published sources by one author and reviewed by the remaining authors. DATA SYNTHESIS: A 66-year-old man was admitted for hip arthroplasty and developed fulminant hepatic failure during oral ciprofloxacin therapy. Ciprofloxacin was started on postoperative day 13 for treatment of a urinary tract infection. Over the next three days he became confused and hypoglycemic. His prothrombin time increased to greater than 90 s. Serum aspartate aminotransferase and alanine aminotransferase concentrations were markedly elevated. The patient died on postoperative day 20. Postmortem examination of the liver revealed extensive centrilobular necrosis. A skin biopsy was consistent with a drug reaction. It is unknown whether the patient had received a quinolone compound in the past or had a history of exposure to hepatotoxins. CONCLUSIONS: It cannot be concluded that ciprofloxacin directly caused hepatic failure in this patient. It is possible that the drug evoked a hypersensitivity reaction or exacerbated a preexisting hepatotoxicity. A detailed patient history and evaluation of hepatic function should be obtained prior to initiating ciprofloxacin therapy. A nonquinolone antimicrobial may be a safer alternative for patients with hepatic dysfunction.",1
7454,1592342,Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy,"""The efficacy and safety of ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy was investigated in an open pilot study. Five patients received 1 gm/day of ursodeoxycholic acid during 20 days and another three patients received two identical periods of treatment separated by a 14-day interval free of the drug. Pruritus and serum levels of total bile salts and glutamic-pyruvic transaminase improved significantly during treatment with ursodeoxycholic acid. In the three patients who received two periods of treatment with ursodeoxycholic acid, pruritus and the laboratory alterations relapsed in the second week after the drug was discontinued, but they improved again when ursodeoxycholic acid was readministered. No adverse reactions were detected in the mothers or in their babies. All newborns were thriving normally during a follow-up period that lasted 5 mo after delivery. It is concluded that UDCA appears to be safe when administered in late pregnancy; its promising efficacy in the treatment of intrahepatic cholestasis of pregnancy should now be confirmed in controlled clinical trials.""",1
7455,1594365,Comparison of pediatric poisoning hazards: an analysis of 3.8 million exposure incidents. A report from the American Association of Poison Control Centers,"This analysis of life-threatening and fatal pediatric poisonings was conducted to aid poison prevention educational efforts, guide product reformulations and aversive agent use, reassess over-the-counter status for selected pharmaceuticals, and identify research areas for clinical advances in the treatment of pediatric poisonings. A hazard factor was devised to assess more objectively the pediatric poisoning hazard posed by pharmaceutical and nonpharmaceutical products. By considering the frequency and extent of injury following actual exposures, the hazard factor reflects more than the acute toxicity of individual ingredients and is also influenced by such variables as packaging, accessibility, availability (as a reflection of marketing), formulations, and closure types. Of the 3,810,405 exposures involving children younger than 6 years of age reported to poison centers in 1985 through 1989, 2117 patients experienced a major outcome (life-threatening effect or residual disability) and an additional 111 fatalities occurred. The three most commonly implicated substance categories, accounting for 30.4% of reported exposures, include cosmetics and personal care products, cleaning substances, and plants. All had low hazard factors, with significant hazards being limited to a small number of products identified herein. Thus this analysis of hazard factors demonstrates that frequent exposure does not imply toxicity. Iron supplements were the single most frequent cause of pediatric unintentional ingestion fatalities, accounting for 30.2% of reported pediatric pharmaceutical unintentional ingestion fatalities reported over an 8-year period. Antidepressants, cardiovascular medications, and methyl salicylate follow in frequency of pediatric pharmaceutical deaths. Hydrocarbons (including five lamp oil deaths) and pesticides were each implicated in 12 pediatric ingestion fatalities during the 8-year period.(ABSTRACT TRUNCATED AT 250 WORDS)",1
7456,1597556,The effect on liver transaminases of phototoxic drugs used in systemic photochemotherapy,,1
7457,1600269,Two fatal cases of hepatitis B virus carriers after corticosteroid therapy for bronchial asthma,We report two hepatitis B virus (HBV) carriers who had liver failure after withdrawal of corticosteroids (steroids) administered for treatment of serious asthmatic attacks. Liver functions deteriorated 1 to 2 wk after withdrawal of the steroid therapy and liver failure occurred. Steroid readministration and intensive therapy for liver failure did not prevent death. An excessive immune response provoked by steroid withdrawal and decreased reserve capacity due to underlying chronic liver disease were thought to be factors in the liver failure. Caution must be exercised in the administration of steroids to patients with underlying chronic HBV infection to prevent exacerbation of hepatitis. Prompt readministration of steroids is indicated if evidence of liver failure develops.,1
7458,1603212,A case of labetalol-induced hepatitis,,1
7459,1605432,The myth of beneficent nature: the risks of herbal preparations,,1
7460,1608854,"Liver disease associated with diclofenac, naproxen, and piroxicam","Based on information derived from computers used by general practitioners in the United Kingdom, we identified all patients with any recorded diagnosis of a liver disorder within 90 days of a prior prescription for diclofenac, naproxen, or piroxicam, three nonsteroidal antiinflammatory drugs (NSAIDs). The follow-up cohort consisted of 102,644 persons who used one or more of these drugs. A case history was requested from the physician to provide a description of the liver disorder and its relation to NSAID exposure. One case of clinically important liver disease was likely to have been caused by a study drug and another appeared to be caused by use of numerous NSAIDs. In 10 additional patients a causal connection between a study NSAID and the liver disorder seemed unlikely but could not be fully ruled out. We conclude that serious liver disease caused by diclofenac, naproxen, or piroxicam appears to be uncommon.",1
7461,1612350,Hepatotoxicity associated with piroxicam use,,1
7462,1616571,Effect of context on the rating of students by faculty and housestaff in a clinical clerkship,,1
7463,1617065,Severe cholestatic jaundice caused by mezlocillin,,1
7464,1626557,Hepatotoxicity associated with sustained-release niacin,"Niacin (nicotinic acid) is a widely used agent in the treatment of hyperlipidemias characterized by elevated low-density lipoprotein and very-low-density lipoprotein. The tendency of the conventional crystalline niacin to cause flushing has limited its use in many patients. Sustained-release (SR) niacin preparations are increasingly utilized due to a lower incidence of flushing and convenient dosing frequency. Although gastrointestinal and hepatotoxic side effects are common to both formulations, they are more frequent and occasionally more severe with the SR preparations. We describe a patient who developed an acute illness characterized by hypothermia, hypotension, metabolic acidosis, and severe hepatic dysfunction 2 days after substitution of an SR preparation for a previously well-tolerated crystalline niacin.",1
7465,1629393,Abnormal liver function tests associated with lithium treatment,,1
7466,1629819,Clinical liver disease in patients with rheumatoid arthritis taking methotrexate,"Between 1981 and 1989, 3 of 134 patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) developed clinically significant hepatic dysfunction and showed histologic evidence of severe liver disease (fibrosis and cirrhosis). Factors identified in these patients that may have been linked to liver toxicity included diabetes, congestive heart failure and Felty's syndrome. In the patient group that received a post-MTX liver biopsy, pulmonary fibrosis and obesity were significantly associated with hepatic fibrosis/cirrhosis. Severe liver disease may occur in patients with RA treated with low dose MTX (less than 3%). Early liver biopsy is recommended in selected cases.",1
7467,1632349,"""Disappearing """"gallstones"""": biliary pseudolithiasis complicating ceftriaxone therapy""",,1
7468,1635536,Neurotoxicity of phenytoin administered to newborn mice on developing cerebellum,"To examine the neurotoxic effects of phenytoin (PHT) on cerebellar development, we administered 50 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-14 and determined plasma PHT concentrations at designated intervals during the administration period. In the treated group, walking reflex and negative geotaxis were poorly developed on postnatal day 14. Pyknotic cells in the external granular layer (EGL) significantly increased and were prominent in the vermis area compared with controls on postnatal day 14. Plasma PHT levels were 34-36 micrograms/ml on the 3rd day of PHT treatment and approached a steady-state situation. Total brain weight, size of the cerebellum, and cerebellar weight were significantly reduced in the treated group on postnatal day 56. Accordingly, oral administration of PHT in the neonatal period induced neurotoxic damage on the developing cerebellum.",1
7469,1641399,Idiosyncratic reactions to antidepressants: a review of the possible mechanisms and predisposing factors,"Antidepressants, a widely used group of drugs, are associated with a range of idiosyncratic reactions affecting in particular the liver, skin and both the hematological and central nervous systems. These reactions seem to be mediated by chemically reactive metabolites formed by the cytochrome P450 enzyme system, the toxicity occurring either directly or indirectly via an immune mechanism. Individual susceptibility is determined by factors, both genetic and environmental, which result in inadequate detoxication of the chemically reactive metabolite. Prevention of such reactions will depend on either the development of new compounds which are not converted to toxic metabolites or by prediction of individual susceptibility prior to drug administration.",1
7470,1645424,[Small sized non-small cell lung cancer in advanced stage],"Eighteen cases of non-small cell, small sized advanced lung cancer, out of 362 operated cases for 6 years excluding 7 cases of small cell lung cancer, 60 of preoperative treated and 27 of inoperable cases, were discussed. A small sized tumor was defined as a tumor within 8,000 mm3 in its volume, calculated by multipling three lengths measured on the resected specimens. There were fourteen cases with stage 3 and 4 (A), and four cases with N1 disease (B). In group A, three cases of twelve with N2 diseases showed the tiny skipping lesion in the mediastinum with negative regional nodes. Remaining two had a lesion of dissemination and pulmonary metastasis. In group B, they showed unusual way of N1 spread, in which two of them with left upper lobectomy had metastatic lymph nodes on the non-bearing lobe, the lower lobe, and other two cases took regional lymph nodes metastasis without invasive growth of the main tumor. Predominant histologic type was adenocarcinoma, but the subtype and the differentiation of it were not specific. The level of CEA was low below 5 ng/dl in most of them except three cases, in which it suggested massive positive nodes and pulmonary metastasis. Seven patients died of the disease in two years. Remainders are alive, 4 with and 7 free from the tumor with the longest period of 3 years and a half. N2 diseases of small sized tumor were found in the cases with the volume of 3 cm3 and more at almost same ratio.(ABSTRACT TRUNCATED AT 250 WORDS)",1
7471,1649062,[Hepatocellular carcinoma in a patient with psoriasis and methotrexate-induced cirrhosis],,1
7472,1656742,Clinical toleration and safety of azithromycin,"""The toleration and safety profile of the azalide antibiotic, azithromycin, has been assessed in 3,995 patients aged 2-94 (mean, 36) years, comprising 1,644 females and 2,351 males. Patients with infections of the respiratory tract or skin/skin structure received 1.5 g azithromycin over 5 days; patients with urethritis/cervicitis caused by Chlamydia were treated with 1 g as a single dose. Assessments of side effects and laboratory safety test abnormalities were made pretreatment and approximately 7-14 and 30 days after the start of therapy. Twelve standard antibiotics have been used for comparison. Overall, side effects were recorded in 12.0% of patients, significantly less (p less than 0.05) than with comparative drugs (14.2%). The most common side effects were diarrhea (3.6%), abdominal pain (2.5%), and other gastrointestinal symptoms. Ninety-three percent of side effects were classed as mild or moderate, and only 0.7% of patients withdrew from treatment, significantly less (p less than 0.001) than with comparative agents (2.6%). The frequency of side effects was not affected by patient age. Azithromycin had no marked or consistent effect on laboratory safety parameters. Treatment-related laboratory abnormalities were rare, the most common being transient increases of ALT and AST in 1.7% and 1.5% of patients, respectively. Specific tests revealed no neurologic, audiometric, or ophthalmologic abnormalities, or evidence of phospholipidosis. There were no pharmacokinetic interactions observed with theophylline, warfarin, cimetidine, carbamazepine, or methylprednisolone, but coadministration with food altered the absorption of the drug. Coadministration with antacids decreased the peak serum concentration of azithromycin, but did not affect its overall absorption. Azithromycin was well tolerated in the presence of a wide variety of concurrent illnesses and medications.""",1
7473,1663298,Hepatocellular carcinoma coexisting with hepatic adenoma. Incidental discovery after long-term oral contraceptive use,"In March 1989, ultrasonography revealed a hepatic mass in a 40 year old nulliparous woman who was then referred to the University of Southern California--Los Angeles (UCLA) Liver Unit. She exhibited no symptoms of a liver condition. From 19-28 years old, she took the combined oral contraceptive (OC) Ovulen 21 for irregular menses. After a brief period of taking Ortho Novum 1/80, she took Demulen 1/35-24 between ages 28-34. Her physician diagnoses endometriosis at 34. He stopped OC therapy and prescribed the progestin Norlutate. She had no history of hepatitis, toxin exposure, and previous liver disease. Further no one in her family had had liver disease or neoplasms. Computer tomography identified a 6.5 cm x 3.5 cm mass in the right lobe of the liver which matched a cold defect on a liver scan using technetium Tc 99m sulfur colloid. The mass selectively took up gallium. Arteriography revealed the mass to be a vascular tumor, but it did not exhibit a typical vascular pattern of an adenoma or the neovascularity of hepatocellular carcinoma. Physicians at UCLA used peritoneoscopy to take percutaneous needle biopsies of the right lobe which confirmed a hepatic adenoma. they then removed the right lobe of the liver. The remaining part of the liver was normal. Histologic examinations of the removed section showed features of a well differentiated hepatocellular carcinoma. Further tumor cells had invaded normal hepatic parenchyma. The physicians believed that hepatic adenoma was in the process of transforming into hepatocellular carcinoma in this patient. They thought that long term OC use, and possibly long term progestin use, may have contributed to the formation of the liver neoplasms. They emphasized the need for a pilot study to develop guidelines on surveillance ultrasonography of women taking OCs over a long period.",1
7474,1671276,Hepatitis after chronic abuse of senna,,1
7475,1673721,Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis,"The toxicity profiles of 7 disease modifying antirheumatic drugs (DMARD) (hydroxychloroquine, intramuscular (im) gold, D-penicillamine, oral gold, methotrexate (MTX), azathioprine and cyclophosphamide) were evaluated in 2,479 patients with rheumatoid arthritis consecutively enrolled at 5 centers in the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) program. Incidence rates for side effects are reported as events/1000 patient-years. Our descriptive study revealed an individual profile of prevalent toxicities for each drug. Oral gold was characterized by substantial lower gastrointestinal (GI) toxicity (diarrhea 391 events/1000 patient-years, loose bowel movement 148, lower abdominal pain 76), MTX by hepatotoxicity (47) while D-penicillamine had the only clinically significant incidence of altered taste (40). MTX users reported the most mucosal ulcers (87), followed by oral gold (76), im gold (55) and D-penicillamine (38). Rash was frequently seen with gold compounds and D-penicillamine, while upper GI toxicity was common with immunosuppressive agents. Cyclophosphamide had 48% discontinuations within 6 months. MTX had the lowest discontinuation rate in the first 6 months, but then showed little difference from im gold. A preliminary similarity index was developed to compare the toxicity profiles of various DMARD. Close similarities were found between toxicity profiles of im gold and D-penicillamine, and between azathioprine and MTX. Oral gold had a unique toxicity pattern. Knowledge of these different toxicity patterns can enable more appropriate selection of agents for particular patients.",1
7476,1676027,Hepatic safety of erythromycin acistrate in 1549 patients with respiratory tract or skin infections,"Erythromycin acistrate is a new 2'-acetyl esther prodrug of erythromycin, whose structure resembles that of erythromycin estolate. However, in toxicological studies, it does not have the problems of hepatotoxicity. To assess its effects on hepatic functions in clinical practice, the liver parameters of patients with respiratory tract or skin infections were monitored during therapy. In total 1549 patients were treated for 7-14 days. In addition, 127 patients with suspected viral infections served as controls. There were no significant differences in serum aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyltransferase (gamma-GT) or alkaline phosphatase (APHOS) values between the erythromycin acistrate or control groups at the beginning or end of therapy. ASAT values increased moderately in 2.4% and clearly in 0.3% of patients treated, but also decreased in 2.0%. ALAT values were moderately increased in 9.9%, clearly increased in 0.6% and normalized in 3.5% of the patients. gamma-GT values increased moderately in 3.5% and and clearly in 0.3%, but decreased to normal in 3.3% of the patients. APHOS was moderately elevated in 1.0% of the patients and normalized in 1.3%. The correlation of changes between the different liver enzymes was poor. Only ten patients (0.6%) had two or more clearly elevated liver enzyme values by the end of the therapy, of whom five had increased liver enzyme activities before the treatment, two had underlying disease explaining the changes and in only three patients out of 1549 (0.2%) could hepatic changes be attributed to erythromycin acistrate therapy. These changes were reversible. The results demonstrate the hepatic safety of erythromycin acistrate in clinical practice. Concomitant food intake did not affect the safety profile.",1
7477,1678206,[Fatal hepatic necrosis due to a treatment course of rheumatoid arthritis with gold salts],"Gold salts are still a first choice for treatment of rheumatoid arthritis. Although adverse reactions are relatively frequent, hepatic abnormalities are rare. They consist largely of reversible cholestasis, and, exceptionally, the evolution can prove rapidly fatal due to extensive hepatic necrosis. We present an additional case of this kind which occurred after a total dose of 450 mg intramuscular Aurothiopropanol over 6 weeks. The pathogenetic mechanism is complex, toxic and/or immuno-allergic. Nevertheless, regular hepatic enzyme testing is not recommended.",1
7478,1681387,Fatal hepatotoxicity of anti-tubercular chemotherapy,,1
7479,1684328,[Atrium-related hepatitis. Report of four cases],"Four patients developed acute hepatitis after receiving Atrium, an association of phenobarbital, febarbamate and difebarbomate, for the treatment of tremor or for the prevention of alcohol withdrawal symptoms. Hepatitis occurred 1 to 3 months after treatment. Asthenia was the unique clinical manifestation. Marked increase in serum aminotransferases and gamma-glutamyltranspeptidase levels were the main biological features. Histological examination showed liver cell necrosis in two cases, prominent in the centrolobular area in one case. There was no case of hepatic failure. Atrium withdrawal was followed by complete recovery within 6 to 12 weeks. The mechanism of Atrium hepatotoxicity remains unknown.",1
7480,1702143,Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies,"Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.",1
7481,1706982,"Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis","""The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.""",1
7482,1710761,Granulocyte colony-stimulating factors,,1
7483,1715157,Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings,"Liver tissue from 16 patients with rheumatoid arthritis was studied. The patients had received low dose methotrexate weekly for a minimum of 12 months between two liver biopsies. The progression of pericellular fibrosis was measured by computerised image analysis. Extracts of these liver biopsy specimens were pooled into five samples according to the progression of hepatic fibrosis and analysed by high performance liquid chromatography. The concentrations of methotrexate, 2,4 diamino-N(10)-methylpteroic acid, and methotrexate polyglutamate were markedly increased in the samples obtained from the three patients who recorded the greatest increase in fibrosis. These preliminary data suggest that progression of hepatic fibrosis is related to the retention of methotrexate and metabolites in the liver.",1
7484,1723369,"Idarubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer","Idarubicin is a 4-demethoxy-anthracycline analogue of daunorubicin which, when administered intravenously in combination with cytarabine, has therapeutic efficacy superior to that of standard induction and salvage treatment regimens in acute myelogenous leukaemia. Idarubicin alone or in combination regimens has also been effective in limited studies in patients with other acute leukaemias, advanced breast cancer, multiple myeloma and non-Hodgkin's lymphoma. Idarubicin is more lipophilic than its parent drug daunorubicin. It intercalates DNA, induces DNA strand breaks and delays cell cycle progression. Leucopenia is often dose-limiting in patients with solid tumours treated with idarubicin, and most other adverse effects are similar in incidence and severity to those experienced with other anthracycline cytotoxic agents, except for alopecia which appears to occur with a reduced incidence and severity. Cardiotoxic effects have been reported with idarubicin as with other anthracyclines, but animal data and preliminary clinical findings suggest the possibility of reduced cardiotoxicity with idarubicin--a potentially important advantage if confirmed on further study. A maximum cumulative dose of idarubicin beyond which the incidence of cardiotoxicity rapidly increases has not been determined. Thus, intravenous idarubicin is a useful alternative to other anthracyclines (particularly in combination with cytarabine) in the treatment of acute myelogenous leukaemia, and there is some evidence that it is less cardiotoxic than other anthracycline drugs. Further studies are required to establish the use of intravenous idarubicin as a replacement for other intravenous anthracyclines, especially its effect on response duration and survival, and to confirm the evidence of reduced cardiotoxic effects. The role of idarubicin as consolidation and maintenance therapy for various malignancies requires further investigation, as does the potential use of oral idarubicin which is currently under development.",1
7485,1727095,Autoimmune chronic hepatitis exacerbated by alpha-interferon,,1
7486,1728522,Granulomatous hepatitis due to combination of amoxicillin and clavulanic acid,"We report the case of a patient with amoxicillin-clavulanic acid-induced hepatitis with histologic multiple granulomas. This type of lesion broadens the spectrum of liver injury due to this drug combination, mainly represented by a benign cholestatic syndrome. The association of granulomas and eosinophilia favor an immunoallergic mechanism. As penicillin derivatives and amoxicillin alone are known to induce such types of lesions, the amoxicillin component, with or without a potentiating effect of clavulanic acid, might have a major role.",1
7487,1731512,"Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group","PURPOSE: To evaluate the safety and efficacy of anagrelide when used to reduce platelet counts in patients with thrombocytosis. PATIENTS AND METHODS: Five hundred seventy-seven patients were treated with anagrelide to control the thrombocytosis of chronic myeloproliferative diseases. Three hundred thirty-five patients had primary thrombocythemia, 114 chronic granulocytic leukemia, 68 polycythemia vera, and 60 undifferentiated myeloproliferative diseases. Of the 577 patients, 504 were known to have been previously treated unsuccessfully with other modalities. RESULTS: Of the 577 patients treated, 424 were evaluable for response. Anagrelide in doses of 0.5 mg to 1.0 mg four times a day reduced the platelet count by 50%, or to less than 600,000/mm3, for at least 28 days in 396 of the 424 (93%) evaluable patients. Acquired resistance to the drug was not observed. Major side effects were neurologic, gastrointestinal, and cardiac. In more than 5 years, 16% of patients discontinued treatment because of side effects. CONCLUSIONS: Our experience suggests that anagrelide should become a useful agent in controlling the thrombocythemia seen in chronic myeloproliferative diseases and can be effective in patients in whom treatment with currently available agents has failed.",1
7488,1731528,Cytolytic T lymphocytes and antibodies to myocytes in adriamycin-treated BALB/c mice. Evidence for immunity to drug-induced antigens,"Female BALB/c mice were given a single intravenous injection of between 0.1 and 10 mg adriamycin/kg body weight and were killed between 2 and 16 days later. Natural killer (NK) cell activity in the spleen was measured using YAC cell targets. Natural killer cell activity was slightly elevated 2 to 5 days after drug injection and significantly depressed by day 9 compared with spleen cells from untreated animals. Adriamycin-treated mice developed both cytolytic T lymphocytes (CTL) and antibodies to drug-treated myocytes. Peak CTL response occurred between days 9 and 13, whereas antibody reactivity continued to increase throughout the observation period. The effector cell belonged to the CD8+ T lymphocyte subpopulation, because cytolytic activity could be reduced by treating the cells with anti-Lyt 2 antibody and complement, whereas anti-L3T4 (CD4+ cell-specific) treatment either had no effect or increased cytotoxicity. Both CTL and antibody reactivity could be absorbed with adriamycin-treated myocyte monolayers but not by non-drug-treated myocytes. Furthermore CTL reactivity could be only partly removed by adriamycin-treated skin fibroblasts. Adriamycin concentrations in the heart were measured by flourometry and demonstrated only a gradual decrease in the drug over the 16-day period. Immunofluorescent staining of myocardial sections demonstrated increased numbers of both T lymphocytes and macrophages in the hearts of adriamycin-treated mice compared with untreated controls.",1
7489,1734901,Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update,"""OBJECTIVE: To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: Eighty-four-month open prospective trial at a single academic rheumatology center. RESULTS: Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity. CONCLUSION: The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.""",1
7490,1735527,Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia,"""Drug-induced acute hepatitis may be followed by prolonged cholestasis despite the withdrawal of the drug. Eight patients suffering from prolonged cholestasis caused by several drugs were investigated with sequential liver biopsies. At the early stage, lesions of acute cholangitis were observed in most patients; at the chronic phase, ductopenia, defined by the absence of interlobular bile ducts in at least 50% of small portal tracts, was demonstrated in all patients. Ductopenia might be the consequence of acute cholangitis; the degree of ductopenia and the chronicity of the disease might be directly related to the severity of the early acute damage of bile ducts. Consequently, in patients with severe cholestasis related to drugs, research of early morphological signs of acute cholangitis and then of ductopenia seems to be important.""",1
7491,1736919,Anaphylaxis from administration of intravenous thiamine,"The routine administration of intravenous thiamine in the emergency department has become widespread. Although anaphylaxis from intravenous thiamine is felt to be uncommon, it can be life threatening. The authors present such a case and review the literature regarding this clinical entity. This case of anaphylactic reaction appears to be the first instance reported since 1946 in the US literature. However a review revealed that cases of anaphylaxis from thiamine have been reported with some regularity in the non-US literature. Given the large number of patients treated without side effects, it seems that thiamine is relatively safe. However, this case illustrates that the assumption that thiamine is a drug with a completely innocuous nature is not totally accurate.",1
7492,1743173,Routine laboratory monitoring for serious adverse effects of antiepileptic medications: the controversy,"Rare, serious adverse effects of antiepileptic drugs (AEDs) include hepatotoxicity and bone marrow suppression. Current management includes routine laboratory monitoring during therapy with AEDs, a practice, however, that is controversial, as some clinicians believe that such monitoring is ineffective and that clinical monitoring is sufficient. Unfortunately, routine laboratory monitoring cannot predict acute idiosyncratic drug reactions, which will remain unpreventable until specific markers are available to identify susceptible patients. Nevertheless, routine laboratory monitoring may be helpful for early detection of chronic adverse reactions such as subclinical hepatotoxicity, leukopenia, or thrombocytopenia, which are usually mild and clinically insignificant but are occasionally more severe. Routine liver function tests may be especially important during valproate therapy because pathologic data suggest that some cases of valproate (VPA)-induced hepatic failure are the result of chronic liver damage and cirrhosis. Although levels of hepatic enzymes may be elevated during an early reversible stage of VPA toxicity, by the time clinical symptoms develop, hepatic failure may be irreversible.",1
7493,1746792,Adjunctive antimicrobials in surgery of soft tissue infections: evaluation of cephalosporins and carbapenems,"""The authors report three trials of B-lactams and carbapenems for soft tissue infections treated on a surgical service: 1) cefmetazole versus cefoperazone, n = 44; 2) cefotetan versus cefoxitin, n = 24; and 3) meropenem versus imipenem, n = 44. A total of 138 hospitalized patients were enrolled with 112 meeting evaluability criteria. Four hundred twenty-three isolates were cultured (mean, three/patient) of which 67 per cent were aerobes and 33 per cent anaerobes. Cure rates for each trial were: 1) 93 per cent; 2) 92 per cent; 3) 100 per cent. Failures were caused by resistant organisms (Streptococcus group D, Bacteroides fragilis and Pseudomonas) appearing in incompletely drained infection sites. Three patients receiving meropenem had adverse effects (headache, nausea) and one receiving cefoxitin (truncal rash). Operative drainage and debridement remain the critical elements in therapy. Agents with longer half lives allowing twice daily dosing (cefmetazole and cefotetan) were as effective and less expensive than multiple doses of short-acting agents. The extended spectrum carbapenems are most useful for severe infections or resistant organisms.""",1
7494,1749125,[Interaction between visual and auditory memories in repetitive learning],"""A serial recall experiment under same- and cross-modality conditions was carried out according to Hebb's (1961) paradigm. Subjects memorized strings of nine digits in 18 trials, which were divided into early trials and late ones. Under the same-modality condition the strings used in the 18 trials were presented through the same modality, i.e., visual or auditory, whereas under the cross-modality condition the strings used in the early and late trials were presented through two different modalities. A repeated string and unrepeated strings were presented 3 and 6 times respectively in both early and late trials. The results showed that (1) repetitive learning in the same-modality occurred for both visual and auditory; (2) there was a non-additivity of cross-modal repetitive learning from auditory to visual, whereas there was an additivity of cross-modal repetitive learning from visual to auditory. We inferred that the visual inputs received both visual coding and auditory coding through an audio-transformation so as to be separately memorized in visual and auditory memories, whereas the auditory inputs were memorized in the auditory memory through the auditory coding alone.""",1
7495,1749296,"Tetracyclines, chloramphenicol, erythromycin, clindamycin, and metronidazole","""The tetracyclines are effective in the treatment of Chlamydia, Mycoplasma pneumoniae, and rickettsial infections and also can be used for gonococcal infections in patients unable to tolerate penicillin. These drugs may cause gastrointestinal irritation, diarrhea, phototoxic dermatitis, and vestibular damage, and fatal reactions due to hepatotoxicity have occurred in pregnant women. Chloramphenicol has a broad spectrum of bacteriostatic activity, but its association with suppression of the bone marrow and aplastic anemia has relegated it to a historical role. Erythromycin is the drug of choice for the treatment of infections caused by M. pneumoniae, Legionella species, group A beta-hemolytic streptococci, and Streptococcus pneumoniae. The frequency of serious adverse effects associated with the use of erythromycin is low; dose-related epigastric distress may occur. Clindamycin is bactericidal to most nonenterococcal gram-positive aerobic bacteria and many anaerobic microorganisms. Although historically it was a frequent cause of antibiotic-associated diarrhea and colitis, clindamycin is considered an excellent alternative to beta-lactam antibiotics for treatment of many staphylococcal infections, and it has therapeutic utility in anaerobic infections and in several protozoan infections in immunosuppressed patients. Metronidazole is efficacious for treating nonpulmonary anaerobic infections, various parasitic infections (trichomoniasis, amebiasis, and giardiasis), nonspecific vaginitis, and Clostridium difficile-mediated colitis. With use of metronidazole, mild side effects such as epigastric discomfort, diarrhea, reversible neutropenia, and allergic-type cutaneous reactions may occur.""",1
7496,1750433,Familial occurrence of hypersensitivity to phenytoin,"PURPOSE: Therapy with anticonvulsants such as phenytoin, phenobarbital, and carbamazepine can be complicated by severe hypersensitivity reactions. Previous work has suggested that the predisposition to such reactions is based on an inherited abnormality in the detoxification of reactive metabolites of the drugs. However, there are no reports of familial occurrence of the reactions in the literature. In the current study, we examined a family in which three siblings developed hypersensitivity reactions to phenytoin, confirming the inheritance of a predisposition to the reactions. Detoxification of reactive metabolites of the anticonvulsants was studied in cells from the patients and their siblings. PATIENTS AND METHODS: Three siblings from a family of 12 siblings developed hypersensitivity reactions to phenytoin characterized by fever, rash, lymphadenopathy, and anicteric hepatitis. All recovered completely after discontinuation of treatment. One sibling tolerated phenobarbital without toxic sequelae. Peripheral blood mononuclear cells from the three patients and five additional siblings who had never taken anticonvulsants were exposed to oxidative metabolites of phenytoin, phenobarbital, and carbamazepine generated by a hepatic microsomal drug-metabolizing system in vitro. The toxicity of metabolites in the cells from the siblings was compared with that in cells from control subjects. RESULTS: Cells from each of the patients who had experienced a hypersensitivity reaction exhibited increased toxicity from metabolites of phenytoin and carbamazepine, while the cellular response to metabolites of phenobarbital was within normal limits. Cells from four of the other siblings showed an abnormal response to phenytoin metabolites, while cells from the final sibling detoxified phenytoin metabolites normally. CONCLUSION: Our observations on the patients confirm the inherited nature of phenytoin hypersensitivity reactions in vivo. In vitro studies demonstrated abnormal metabolite detoxification in the patients and several of their siblings. The detoxification defect included metabolites of phenytoin and carbamazepine but not of phenobarbital. A family history of a drug hypersensitivity reaction should alert physicians to the probability of a markedly increased risk of an adverse reaction in family members. In vitro assays to confirm adverse reaction risks may ultimately be able to provide individualized risk assessment for patients who must take anticonvulsants.",1
7497,1752554,[Acute fulminant hepatic failure after short-term amiodarone],Acute liver failure occurred in a 59-year-old man with congestive heart failure within 4 days of oral loading with amiodarone. Hepatic toxicity of amiodarone leads to 2 histologic pictures: pseudo-alcoholic hepatitis and phospholipoidosis. Immune mechanisms are possible in amiodarone hepatotoxicity.,1
7498,1754488,Gastrotomy and whole bowel irrigation in iron poisoning,"Ipecac and gastric lavage are questionable interventions for the overdose patient, and activated charcoal does not absorb iron. Gastrotomy and whole bowel irrigation have been described as unique interventions for this poisoning. We describe a patient who was treated with each of these. Because less than half of the iron was removed during surgery, and because the chelation requirement was modest, it is likely that whole bowel irrigation removed a significant amount of iron. We believe that this combined approach contributed to our patient's positive outcome.",1
7499,1763547,Methyldopa-induced granulomatous hepatitis,,1
7500,1767803,Overview of fluoroquinolone safety,"The safety of the fluoroquinolone antimicrobial agents is reviewed, discussing documented and potential clinical and laboratory adverse effects and drug-drug interactions. In prospective, randomized, double-blind clinical trials comparing fluoroquinolones to nonquinolone drugs or placebo, the fluoroquinolones were not significantly different (22 studies) or were superior (5 studies) to comparison agents but were only rarely more toxic (2 studies). Adverse effects included mild gastrointestinal toxicities and less common but more problematic central nervous system toxicities. Clinically important interactions occurred with coadministration of antacids and all fluoroquinolones and with theophylline and enoxacin and to a lesser extent ciprofloxacin and pefloxacin but not other fluoroquinolones. Potential adverse effects such as cartilage damage, DNA damage, teratogenicity, and crystalluria, while of concern, have not as yet been shown to be of clinical importance. Therapy of bacterial infections in children and adolescents is relatively contraindicated, but growing clinical experience with treatment of these patients has not so far revealed serious bone or cartilage toxicity. The fluoroquinolones thus far have exhibited a favorable safety profile, but our clinical experience is still limited, and monitoring for as yet unappreciated toxicities is warranted.",1
7501,1771253,The European core curriculum on radiotherapy,,1
7502,1788551,"Colchicine intoxication: clinical pharmacology, risk factors, features, and management","The use of colchicine for acute gouty arthritis dates to ancient times. In recent years, colchicine also has been used successfully for various other rheumatic and nonrheumatic conditions. Colchicine is a safe drug when used according to established therapeutic guidelines. However, toxicity can be considerable if ingested intentionally or if the recommended doses are exceeded. Colchicine intoxication is characterized by multi-organ involvement and by the poor prognosis associated with administration of large amounts of the drug. Therapy is basically supportive and symptomatic because of the rapid distribution and binding of colchicine to the affected tissues. Use of anticolchicine antibodies is a novel approach that has shown promise in experimental models. Important research questions pertain to the effect of liver and kidney disease on colchicine metabolism, use of colchicine levels in the diagnosis of intoxication and for prognostication, and application of immunotoxicotherapy for colchicine poisoning in humans.",1
7503,1790429,"Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy","Twenty-four patients between the ages of 8 and 48 years (median 27.5) with high-risk for relapse hematologic malignancy received a marrow transplant from an HLA and MLC compatible sibling donor after chemotherapy with busulfan, 4 mg/kg/day for 4 days by mouth, cyclophosphamide 60 mg/kg/day i.v. for 2 days, and etoposide 60 mg/kg i.v. over 4 h on the first day of cyclophosphamide treatment (BU/CY/VP). Toxicity consisted of mucositis, skin rash, and nausea and vomiting in all patients, transient fever thought to be due to etoposide administration in 16/24 (67%) patients, and clinical veno-occlusive disease (VOD) of the liver in 4/24 (17%). There were nine deaths from causes other than recurrent disease in the first 100 days after transplant and two deaths after day 100, a total transplant mortality of 11/24 (46%). Three patients relapsed, but 10/24 (40%) remain alive and disease free 26-182 weeks (median 60 weeks) from transplant. These results compare favorably with results in a group of 12 similar risk patients treated with total body irradiation (TBI) containing regimens during an overlapping time period. Six of the TBI patients have had persistent or recurrent disease and only two (17%) are currently alive and disease free. The probability of disease persistence or relapse is 67% in the TBI group and 20% in the BU/CY/VP group (p less than 0.02).",1
7504,1794009,The problems and pitfalls of NSAID therapy in the elderly (Part I),"""Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide when grouped by generic categories and account for 3 to 9% of total prescription numbers in various countries. While NSAIDs are responsible for approximately 25% of all reported adverse drug reactions, aging may substantially increase the risk of NSAID-induced reactions. Several factors may contribute to NSAID-related toxicity in the elderly. The increase in morbidity associated with aging may result in consumption of a wide range of potent drugs, while inappropriate drug therapy and aberrant compliance are also capable of contributing to adverse drug reactions in geriatric patients. Age-related alterations in pharmacokinetics may influence the handling of NSAIDs in the elderly; in particular, dosage reduction is appropriate for azapropazone (apazone), naproxen, ketoprofen and salicylates administered to healthy aged patients, whereas the presence of renal disease may also necessitate dosage reduction of diflunisal, indomethacin, sulindac and mefenamic acid. Changes in NSAID pharmacodynamics with aging, such as increased CNS sensitivity to NSAIDs and impaired homeostasis, also predispose the elderly to NSAID-related adverse effects. It is undisputed that gastrointestinal toxicity due to NSAID therapy is a class effect. A significant association has been found between aspirin and uncomplicated gastric, but not uncomplicated duodenal ulcer, while nonaspirin NSAIDs are significantly associated with both uncomplicated gastric and duodenal ulceration. The use of NSAIDs is accompanied by a 2- to 5-fold risk of serious complications of peptic ulcer disease, i.e. haemorrhage or perforation, which increases in the elderly, particularly women. A broad range of renal side effects has been ascribed to NSAIDs, of which acute renal impairment is the most common in the elderly. Although most NSAIDs have been reported to cause hepatotoxicity, serious abnormalities of liver function are rare and are largely unpredictable. Other adverse effects due to NSAIDs have also been described, some of which (e.g. cardiovascular, CNS and haematological effects) may be more common in the elderly.""",1
7505,1806630,Toleration and safety of sertraline: experience worldwide,"The clinical trial programme of sertraline, a selective serotonin re-uptake inhibitor, has shown the drug to have a favourable safety and toleration profile. In contrast, the tricyclic antidepressant, amitriptyline, produced a significant level of side effects, particularly anticholinergic. The side-effect profile of sertraline was similar in young and old, and individual side effects did not make a notable contribution to the discontinuation rate. The incidence of side effects was related to both dosage and dosage regimen. An initial dose of 50 mg increased at 2-weekly intervals to 100 mg and then 200 mg daily produced a very low incidence, no side effect occurring with a frequency greater than 10%. In the long term (after 8 weeks' study), sertraline was well tolerated with little difference in side-effect reporting from placebo. There were no significant problems with safety. Sertraline was without effect on vital signs or electrocardiogram, and had no clinically relevant effects on laboratory values. In contrast to amitriptyline there was no significant effect on body weight. The overall incidence of mania was 0.4% and skin rash less than 2%. There were no cases of drug-related convulsions. Overdose with sertraline (four cases) was satisfactorily overcome with no significant sequelae and without the need for intensive monitoring.",1
7506,1815425,Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis,"""Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.""",1
7507,1824554,"A new syndrome: ascites, hyperbilirubinemia, and hypoalbuminemia after biochemical modulation of fluorouracil with N-phosphonacetyl-L-aspartate (PALA)","OBJECTIVE: To report a new syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia after treatment with N-phosphonacetyl-L-aspartate (PALA) and fluorouracil for metastatic colorectal cancer. DESIGN: Retrospective analysis. SETTING: Regional cancer treatment center. PATIENTS: Forty-four previously untreated patients with metastatic colorectal cancer in a phase I-II trial of PALA-fluorouracil. MEASUREMENTS AND MAIN RESULTS: One or more transient hepatic abnormalities frequently occurred in 15 of the 17 responding patients. Within the first 10 weeks of treatment, 5 patients developed ascites, 12 had a decrease in the serum albumin level, 6 developed bilirubin elevations, and 7 had transaminase elevations, all in the presence of a complete or partial tumor response. Prolongations of the prothrombin time and elevations of serum glucose levels were also seen. CONCLUSIONS: An unusual syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia is associated with a PALA-fluorouracil regimen. These abnormalities, which may be related to decreased hepatic protein synthesis, occurred more often in patients whose tumor was responding to chemotherapy. Clinicians must recognize that in patients undergoing chemotherapy with these agents, ascites and elevated liver function tests may be secondary to drug administration and are not necessarily due to disease progression.",1
7508,1825232,Doxazosin for treatment of hypertension,,1
7509,1825596,An observational study of isotretinoin recipients treated for acne in a health maintenance organization,"""From September 1982 to June 1987, all members (N = 513) of the Group Health Cooperative of Puget Sound, Seattle, Wash, who were prescribed isotretinoin for acne were observed throughout the first 4- to 5-month course of therapy for effectiveness and adverse effects. The highest rates of use were among male subjects aged 15 to 24 years. Excluding 47 subjects whose prescriptions were stopped because of noncompliance or who left the care of Group Health Cooperative physicians, 39 (8.4%) of the remaining 466 discontinued taking the drug because of the following adverse effects: mucous/skin/musculoskeletal effects (17); elevated triglyceride levels (eight); headaches (five); increased liver enzyme levels (three); amenorrhea (two); and other (four). One subject, excluded from the 466 because of noncompliance, became pregnant while using medication from a previous prescription and had a therapeutic abortion; she was not under the care of a physician at the time of pregnancy. Most subjects (97%) developed a mucocutaneous symptom, and 42% developed musculoskeletal symptoms. Moderate elevations in liver enzyme levels developed in six (1.8%) of 341 subjects with normal baseline values. Of 389 subjects with normal baseline triglyceride values (less than 2.25 mmol/L), nine (2.3%) developed moderate elevations (4.5 to 9.0 mmol/L), and one (0.3%) developed a severe elevation (greater than or equal to 9.0 mmol/L). Of 24 subjects with elevated baseline triglyceride levels, three (12.5%) developed moderate elevations. Of an additional 53 subjects whose baseline serum triglyceride levels were not determined, two developed elevations during therapy, one up to 13.4 mmol/L. Subjects who were overweight or had elevated baseline serum triglyceride values had an increased risk of developing elevations in triglyceride levels during therapy (odds ratio, 6.0; 95% confidence interval, 1.6 to 22.0; and odds ratio, 4.35; 95% confidence interval, 0.9 to 20.2, respectively). Acne was improved for at least 94.0% of subjects.""",1
7510,1827039,Severe hepatocellular dysfunction following cyproterone acetate therapy,"Cyproterone acetate (CPA) is a widely used drug in the treatment of advanced prostatic carcinoma. Although it is generally well tolerated, liver toxicity has been recognised as a complication of long-term use. We report 3 patients with severe hepatocellular damage due to CPA therapy, 2 with fatal fulminant hepatitis.",1
7511,1828327,Methotrexate and histologic hepatic abnormalities: a meta-analysis,"STUDY OBJECTIVE: To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. DESIGN: A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. PATIENTS: A total of 636 patients from 15 studies. RESULTS: The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02). CONCLUSIONS: The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.",1
7512,1828773,A case of hepatitis related to etretinate therapy and hepatitis B vaccine,"""The case of a 41-year-old male patient is described who developed acute reversible hepatitis related to etretinate therapy. During the course of etretinate he received 2 doses of hepatitis B vaccine; this and his HLA typing A1, A2, Bw57, Cw6 may have predisposed him to develop this reaction.""",1
7513,1830919,Etodolac,,1
7514,1832694,Ketoconazole-induced fulminant hepatitis necessitating liver transplantation,"The most serious side effect of ketoconazole is hepatitis, which has proved fatal in seven reported cases. We present a case of fulminant hepatic failure in a 45-year-old Oriental woman that probably would have been fatal except for a successful liver transplant. A review of the literature of fatalities associated with ketoconazole is presented.",1
7515,1834445,[Experimental replacement of the trachea by dacron-silicone rubber prosthesis],"Experimental results of trachea replacement by dacron-silicone rubber tube in rabbits and dogs were presented. The techniques for anastomosis of the prosthesis to the host trachea, prevention of obstruction by granulation and the dynamic effects of air current during cough reflex caused by the artificial trachea were also investigated. Experiments showed that the use of artificial trachea with right size (inner diameter) was the key to maintain expectoration mechanism. When the artificial trachea was constructed on proper selected cases, complications resulting from use of Nevilles are preventable.",1
7516,1837260,Double-blind comparison of etodolac and piroxicam in patients with rheumatoid arthritis,"A study was carried out to compare the efficacy and tolerability of etodolac and piroxicam in patients with rheumatoid arthritis. Sixty patients entered this double-blind, parallel study and after a wash-out period of up to 2 weeks were randomly assigned to receive 200 mg etodolac twice daily or 20 mg piroxicam once daily for 12 weeks. Efficacy and tolerability assessments were made after 2, 4, 6, 8 and 12 weeks. Patients in the etodolac group demonstrated statistically significant improvement in the number of tender joints and the duration of morning stiffness after 12 weeks, as did the piroxicam-treated patients. In addition, the etodolac-treated patients had significant improvement according to the patients' and physician's global evaluations, pain intensity, number of swollen joints, and grip strength. There were significant differences between therapies favouring etodolac for the assessments of the number of tender joints and the physician's global evaluation by the end of the study. Forty-seven percent (47%) of 15 etodolac-treated patients compared with 7% of 15 piroxicam-treated patients showed improvement according to the physician's global evaluation at Week 12. Similarly, the patients' global evaluation showed that 40% of etodolac-treated patients and 19% of piroxicam-treated patients had improved by the end of therapy. Both therapies were well tolerated. There were no significant differences between groups in the incidence of any adverse reactions or the frequency of withdrawals.",1
7517,1846405,Hepatopathy-thrombocytopenia syndrome--a complication of dactinomycin therapy for Wilms' tumor: a report from the United Kingdom Childrens Cancer Study Group,"""We have observed hepatopathy, associated with thrombocytopenia, in children receiving chemotherapy for Wilms' tumor. We have studied this hepatopathy-thrombocytopenia syndrome (HTS) in patients enrolled in the United Kingdom Childrens' Cancer Study Group (UKCCSG) Wilms' tumor trials (UKW1 and UKW2). At the time of this study, 501 patients had completed therapy. Treatment flow sheets were examined for evidence of hepatopathy (hepatomegaly with abnormal liver function tests) and severe thrombocytopenia (platelet count less than 25 x 10(9)/L). No child who developed the syndrome had received irradiation. HTS was seen in five of 355 (1.4%) of patients treated with combination chemotherapy but in none of the 146 patients treated with vincristine alone. In each instance, the onset was less than 10 weeks after diagnosis. In two children, hepatopathy was severe with jaundice, ascites, transaminases greater than 1,000 IU/L, and prolongation of prothrombin time. On average, HTS lasted 12 days, and resolved with supportive treatment. After recovery, the children tolerated chemotherapy, mostly at reduced dosage, without recurrence. There was no evident long-term morbidity. Dactinomycin is the probable cause of this syndrome. We conclude that the HTS is a rare but important complication of dactinomycin-containing combination chemotherapy for Wilms' tumor. Children developing """"isolated"""" thrombocytopenia following dactinomycin are """"at risk"""" of developing the full-blown syndrome and should have their treatment modified accordingly.""",1
7518,1848454,Hepatocellular carcinoma and treatment with cyproterone acetate,,1
7519,1849346,Delayed subcapsular hematoma after percutaneous liver biopsy as a manifestation of warfarin toxicity,"Guidelines for the management of patients receiving chronic anticoagulation therapy who require liver biopsy are not clearly defined. In patients with normal coagulation, liver biopsy is a relatively safe procedure with a morbidity of less than 0.1% and a mortality of less than 0.01%. We report a patient with a prosthetic aortic valve who developed a large subcapsular hematoma 12 days after a percutaneous liver biopsy as a consequence of warfarin toxicity. Based on the experience with this patient, reinstitution of anticoagulant therapy should be avoided for at least 72 h after a percutaneous liver biopsy. Intravenous heparin should be resumed first, and warfarin added if no bleeding has occurred after an additional 48-72 h. The prothrombin time should be maintained at 1.5 times the baseline.",1
7520,1860646,Interferon-induced chronic active hepatitis?,"""A 54-year-old man with chronic B hepatitis was treated with interferon alfa. Despite resolution of the hepatitis B viral infection, he experienced severe jaundice, ascites, and encephalopathy. Further work-up showed hyperglobulinemia, chiefly immunoglobulin G, and positive smooth muscle and anti-nuclear antibodies. Because of these """"autoimmune"""" features, the patient was treated with prednisone. One month later, a significant clinical and biochemical improvement was observed. A possible autoimmune mechanism induced by interferon alfa is proposed as the cause for the perpetuation of the necroinflammatory activity.""",1
7521,1863194,Multisystem failure and hepatic microvesicular fatty metamorphosis associated with tolmetin ingestion,"Multisystem toxicity including both renal and hepatic failure has been reported with the use of nonsteroidal anti-inflammatory drugs. We report a fatal case of multisystem failure associated with tolmetin ingestion in a 15-year-old girl. Microvesicular fatty change was found in the liver at autopsy. To our knowledge, this is the first reported case of nonsteroidal anti-inflammatory drug-associated multisystem failure to have this histopathologic finding.",1
7522,1872757,Diclofenac hepatitis,"We report five cases of biopsy-proven hepatitis developing between six and 20 weeks after administration of diclofenac. In one patient jaundice had previously developed following use of ibuprofen. In another the clinical, biochemical and histopathological features were those of chronic active hepatitis and treatment with corticosteroids was required. All patients recovered from their liver injury without sequelae. Resolution of symptoms occurred between three and 12 weeks following cessation of the drug, while liver function tests returned to normal between seven and 16 weeks after drug withdrawal, except in the patient with chronic active hepatitis who remained biochemically abnormal for eight months. Three of the five patients developed transient circulating autoantibodies, suggesting immune mechanisms may be important in the pathogenesis of this injury. The incidence of severe hepatic dysfunction related to the use of diclofenac appears low and is probably in the order of one case per 50-100,000 prescriptions.",1
7523,1877853,Two methods of assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis,"Serial liver biopsy specimens from 18 patients with rheumatoid arthritis receiving a weekly dose of methotrexate 7.5-20 mg for a minimum of 12 months were assessed semiquantitatively and by a microcomputer image analysis system. The semiquantitative histological method showed a significant increase in pericellular collagen and in overall disease while morphometry showed a significant increase in pericellular, perivenular, and portal tract collagen. There was a significant correlation between the two methods, but morphometry had the advantage of objectivity and efficiency. There was no correlation between the increase in collagen and the accumulated dose of methotrexate, which suggests that other factors in addition to methotrexate may contribute to liver injury.",1
7524,1880254,Serum aminoterminal propeptide of type III procollagen in psoriasis and psoriatic arthritis: relation to liver fibrosis and arthritis,"Levels of serum aminoterminal propeptide of type III procollagen were measured in 170 patients with psoriasis (49% with coexistent psoriatic arthritis) who had liver biopsies performed during or before treatment with methotrexate or, in some cases, with retinoids. Psoriasis patients with fibrosis or cirrhosis in their liver biopsy specimens had a significantly higher mean serum aminoterminal propeptide of type III procollagen than did patients without fibrosis and without arthritis. Only 4% of patients without cirrhosis or fibrosis and no arthritis had an elevated serum aminoterminal propeptide of type III procollagen. In contrast, 38% of patients with psoriatic arthritis had an increased aminoterminal propeptide of type III procollagen in the absence of detectable liver fibrosis. It is concluded that the number of liver biopsies performed on methotrexate-treated psoriasis patients with or without arthritis may be reduced to a minimum as long as serum aminoterminal propeptide of type III procollagen is normal. Increased serum aminoterminal propeptide of type III procollagen in the absence of arthritis is a strong indicator of liver fibrogenesis and suggests the need for liver biopsy to monitor possible methotrexate-induced toxicity. In patients with psoriatic arthritis an increased aminoterminal propeptide of type III procollagen may be related to the joint disease. Patients with psoriatic arthritis and increased levels of aminoterminal propeptide of type III procollagen should therefore follow the established guidelines for the use of methotrexate in psoriasis.",1
7525,1880490,Enalapril-induced immunologic impairment of hepatic function,,1
7526,1883690,"Methotrexate: mechanism of action, pharmacokinetics, clinical indications, and toxicity",Methotrexate has become a standard therapy for the treatment of rheumatoid arthritis. This review summarizes the recent literature on low-dose methotrexate in the rheumatologic illnesses. The effect of methotrexate on in vivo rheumatoid factor production and suppression of ex vivo leukotriene B4 generation is reviewed. New information on drug interactions and pharmacokinetics is highlighted. The efficacy and toxicity of the drug in rheumatoid arthritis and other diseases are further defined. The effects of methotrexate on liver histology are also summarized.,1
7527,1891078,4-Aminopyridine in multiple sclerosis: prolonged administration,"In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76%) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4-AP lasted a mean of 7.07 hours (83% of the average 8.53-hour treatment-observation period) compared with 2.36 hours for placebo (26% of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.",1
7528,1892143,Niacin revisited: clinical observations on an important but underutilized drug,"""STUDY OBJECTIVE: To evaluate the efficacy and side effects of niacin therapy in dyslipidemic individuals. DESIGN: A retrospective analysis of patients' charts. SETTING: An outpatient referral-based clinic specializing in the treatment of lipid disorders. PATIENTS: All patients with dyslipidemia treated by niacin (n = 82) at the Atherosclerosis Detection and Prevention Clinic during 1987 to 1990, including a subgroup of 17 dyslipidemic heart transplant recipients. RESULTS: Niacin was well tolerated in 83% of the nontransplant group (n = 65) at an average dose of 2.5 +/- 0.9 g/day. Similar beneficial lipoprotein effects were found in the transplant and nontransplant patients. The high-density lipoprotein cholesterol (HDL-C) response to niacin therapy was independent of the baseline (HDL-C level. In the transplant group, 11 patients (65%) discontinued treatment, primarily because of hyperglycemia; this was especially prominent in those patients with pretreatment diabetes mellitus. Of the 15 patients using sustained-release niacin, eight cases of hepatitis were recorded, some during therapy with relatively low niacin doses. Several different sustained-release preparations were responsible for this phenomenon, suggesting that the cause was not a contaminant in the preparation. No cases of hepatitis were documented in the 67 patients using regular niacin. One case of hepatitis was recently observed in a patient who switched from one type to regular niacin to another; however, we have data to suggest that the substituted preparation was not an immediate-release niacin. A familial predisposition to hepatitis is suggested by the occurrence of this side effect in identical twin brothers and two sisters. A pharmacy survey disclosed that most pharmacists are unaware of the relationship of sustained-release niacin to hepatitis, have a negative impression of regular niacin, and do not stock this formulation. Finally, we found that in this small sample of patients, niacin used with lovastatin is a particularly effective drug combination and appears to have few side effects beyond those seen with niacin alone. CONCLUSIONS: Our experience supports the fact that regular niacin is a useful lipid-modifying drug. When used appropriately, patients can usually tolerate adequate doses for prolonged periods and achieve meaningful results. However, this requires a certain amount of physician skill and patient motivation. The use of sustained-release preparations to overcome this problem can lead to harmful consequences and should only be done under strict medical supervision. In our opinion, the availability of sustained-release niacin as a nonprescription drug is unjustified and should be reexamined. Finally, we have observed that reduction of very-low-density lipoprotein cholesterol (VLDL-C) with niacin alone leads to an elevation in low-density lipoprotein cholesterol in many patients; this indicates to us that the mechanism whereby niacin lowers VLDL-C and total cholesterol is not solely the result of a decreased synthesis of VLDL-C.""",1
7529,1903847,Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer,"""BACKGROUND: The period of neutropenia after autologous bone marrow transplantation results in substantial morbidity and mortality. The results of previous phase I-II clinical trials suggest that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) may accelerate neutrophil recovery and thereby reduce complications in patients after autologous bone marrow transplantation. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at three institutions. The study design and treatment schedules were identical, and the results were pooled for analysis. One hundred twenty-eight patients were enrolled. Sixty-five patients received rhGM-CSF in a two-hour intravenous infusion daily for 21 days, starting within four hours of the marrow infusion, and 63 patients received placebo. RESULTS: No toxic effects specifically ascribed to rhGM-CSF were observed. The patients given rhGM-CSF had a recovery of the neutrophil count to 500 x 10(6) per liter 7 days earlier than the patients who received placebo (19 vs. 26 days, P less than 0.001), had fewer infections, required 3 fewer days of antibiotic administration (24 vs. 27 days, P = 0.009), and required 6 fewer days of initial hospitalization (median, 27 vs. 33 days; P = 0.01). There was no difference in the survival rate at day 100. CONCLUSIONS: In patients undergoing autologous bone marrow transplantation for lymphoid neoplasia, rhGM-CSF significantly lessens morbidity. Further studies will be required to establish its optimal dosage and schedule of administration.""",1
7530,1904700,Hepatotoxicity of rifampin and isoniazid. Is it all drug-induced hepatitis?,"Serologic markers for hepatitis viruses were studied in 40 children who developed acute hepatitis during antituberculosis therapy with rifampin and isoniazid, with the aim of assessing the contributory role of these viruses toward producing hepatic injury. Hepatitis A and B were confirmed in 7.5 and 35% patients, respectively, by IgM antibodies. Epidemiologic evidence suggested the possibility of non-A, non-B hepatitis in at least a few of the remaining 23 children. Hepatitis B was seen more often in children with severe tubercular disease (72%) and was largely (92.8%) parenterally transmitted. The study highlights that the endemicity of viral hepatitis in developing countries, among other factors, could also be responsible for the reported higher incidence of hepatotoxicity from developing countries and also for the increased risk of hepatotoxicity seen in severe tubercular disease.",1
7531,1906693,"Fulminant hepatic failure associated with 2',3'-dideoxyinosine (ddI)",,1
7532,1908340,"Hepatic veno-occlusive disease post-bone marrow transplantation in children conditioned with busulfan and cyclophosphamide: incidence, risk factors, and clinical outcome","""We performed a retrospective analysis of the incidence, risk factors, and clinical outcome of hepatic veno-occlusive disease (VOD) in 50 children prepared for bone marrow transplantation with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). The overall incidence of VOD was 28% (14/50). The incidence of VOD among patients transplanted for leukemia was 36% (14/39). In contrast, no patient transplanted for a genetic disease developed VOD. Neither patient age, sex, remission status, type of graft (i.e. allogeneic or autologous), past history of liver disease nor pretransplant liver function tests were associated with an increased risk of VOD. In addition, 23 of 50 patients had pretransplant samples available for antihepatitis C virus (HCV) testing; 3/23 were reactive (two of nine patients with VOD and one of 14 patients without VOD were positive for anti-HCV). We found a high incidence of pleural effusion in patients with VOD (7/14), an association that has previously not been described. VOD was manageable and resolved in all patients.""",1
7533,1913229,Fatal thrombocytopenia and liver failure associated with carboplatin therapy,"A patient with fatal severe thrombocytopenia and acute hepatic necrosis complicating carboplatin (JM8, CBDCA, NSC 241240) therapy is described. The patient, an 18-year-old man with acute lymphocytic leukemia, was given high-dose carboplatin as a part of a phase I trial of this agent for the treatment of leukemia. Carboplatin (270 mg/m2/day) was administered as an intravenous infusion on five consecutive days, and the patient died 10 days after his last dose of carboplatin from complications of thrombocytopenia and acute liver necrosis. Autopsy revealed hemorrhage into the substance of the myocardium and hemorrhagic centrilobular liver necrosis. The temporal relationship between the initial rise in this patient's liver function tests and treatment with carboplatin suggests that this patient's liver failure was in part due to carboplatin. The autopsy findings of hemorrhage into the substance of the myocardium and centrolobular liver necrosis suggest that, in addition to its direct effects, carboplatin may have also contributed indirectly to this patient's liver failure through the complications of thrombocytopenia.",1
7534,1916139,[Nilutamide-induced acute hepatitis],,1
7535,1918429,Lithium-induced hyperbilirubinemia in an adolescent,,1
7536,1921807,Low-dose methotrexate therapy and hepatotoxicity. The view of the hepatologist,,1
7537,1926651,Single-dose fosfomycin trometamol (Monuril) versus multiple-dose norfloxacin: results of a multicenter study in females with uncomplicated lower urinary tract infections,"The results of an open, randomized study comparing the efficacy and safety of Fosfomycin trometamol (Monuril), 3-gram single dose, and Norfloxacin (Noroxine 400), 400 mg twice daily for 5 days, are reported. Clinical and bacteriological assessments were performed before and 3-4 (short-term) and 25-30 days (long-term) after treatment. Only female patients with uncomplicated lower urinary tract infection were eligible for inclusion in the study: 33 cases were given Fosfomycin trometamol and 30 cases Norfloxacin. In the overall etiology, Escherichia coli (74% of the strains found), Proteus mirabilis (6%) and Klebsiella pneumoniae (6%) are highly predominant. With regard to bacteriological efficacy, the percentages of eradication in the two groups were similar: after the short-term test, 93.9% (31 of 33 patients) in the Fosfomycin trometamol group and 86.6% (26 of 30) in the Norfloxacin group, and after the long-term tests, 73.3% (22 of 30) in the Fosfomycin trometamol group and 77.89% (21 of 27) in the Norfloxacin group. There are no statistically significant differences. The duration of the reported side effects was significantly lower in the Fosfomycin trometamol group. The simplified dosage regimen (single dose) and its favorable benefit/risk ratio justifies the use of Fosfomycin trometamol as a treatment for uncomplicated urinary tract infections in female patients.",1
7538,1928075,National cooperative rHu erythropoietin study in patients with chronic renal failure: a phase IV multicenter study. Report of National Cooperative rHu Erythropoietin Study Group,"""Initial experience with recombinant human erythropoietin (rHuEPO, epoetin alfa) was gained through research protocols in which patient selection and management were tightly controlled. When epoetin alfa was approved for use by the Food and Drug Administration (FDA) these constraints were removed. The present study was designed to examine the medical and social impact of epoetin alfa therapy, as well as to document its safety and efficacy as it is used in clinical practice. From 1,000 to 2,000 patients at 100 to 200 centers will be enrolled and monitored for 1 year. Two groups of patients are being studied--those already receiving epoetin alfa at study entry and those new to epoetin alfa therapy. Demographic data are collected initially and detailed outcome data are collected monthly. This interim report presents data from 68 participating dialysis centers on 447 enrolled patients. To date, 89% of the patients are on in-center hemodialysis, while 9% are on home dialysis (79% continuous ambulatory peritoneal dialysis [CAPD], 14% continuous cyclic peritoneal dialysis [CCPD]). Preliminary analyses suggest this population is similar in age and cause of chronic renal failure to the overall US dialysis population, although whites and males are somewhat underrepresented. Of those already on epoetin alfa at study entry, 62% were receiving 3,000 to 9,000 U/wk. In addition, those already on epoetin alfa had better self-rated general health than those new to therapy. Outcomes and epoetin alfa usage patterns are currently being fully analyzed. Three-month follow-up data on a cohort of patients new to epoetin alfa indicate that the average dose in these patients is less than 100 U/kg/wk; two thirds of the doses were administered intravenously. Hematocrit levels increased over the 3 months from a level of 25.1% at entry to 30.6% by month 3. The percentage of cohort patients who were transfusion-independent increased from 85.1% at study entry to 95.7% by month 3. No increases in the incidence of adverse events occurred in the cohort group and no changes in the safety profile were indicated. These preliminary findings suggest that low doses of rHuEPO are being used in general, with a resultant low mean hematocrit. Thus, patients do not seem to be realizing the full potential beneficial effects of this remarkable agent.""",1
7539,1929040,Ceftriaxone-induced cholelithiasis,,1
7540,1932674,Cholestatic jaundice associated with captopril therapy,"""Captopril has attained widespread use as an effective agent in the treatment of heart failure and hypertension. Dermatological, renal and haematological toxicity associated with its use has been widely described and is usually well recognized. There have been comparatively few reports implicating it as causing hepatic drug reactions. Most descriptions have emphasized strongly cholestatic features, although a mixed hepatocellular cholestatic picture and predominant hepatocellular reactions have been reported. Between November 1972 and June 1990 only five cases of possible Captopril-associated hepatic dysfunction were reported to the Australian Adverse Drug Reaction Advisory Committee. Cases reported suggest equal sex distribution, latent period to development of abnormality between 1 week and 20 months, with slow resolution of jaundice and biochemical abnormality from 1 week to 6 months after withdrawal of the drug. One case of hepatic coma and death with massive acute hepatic necrosis on biopsy has been reported. Not uncommonly the accompanying systemic features suggest a syndrome of drug hypersensitivity. We report a case of Captopril-induced cholestatic jaundice in which the abnormality occurred 2 weeks after commencement of the drug and resolved slowly upon discontinuation. The case illustrates two important points: first, the importance of taking a full history, obtaining detailed information about previous drug administration in patients admitted with jaundice; and second, in the case of Captopril-induced liver disease, the jaundice may persist for many weeks after drug withdrawal.""",1
7541,1938056,Tinea capitis in adults in southern Taiwan,"""We report the clinicomycologic study of 27 culture-proven cases of tinea capitis from southern Taiwan during the years 1988 to 1990. The series is notable for its predominance of adults (63%), of women (89%), and of Trichophyton violaceum infection (74%). The age distribution was clearly bimodal; the median age was 6 years for children and 56 years for adults (older than 18 years). Whether or not these findings represent a new trend of tinea capitis in southern Taiwan remains to be determined. Clinically, our cases of black-dot ringworm caused by T. violaceum often presented with subtle changes of scaling, hair loss, and black dots. The keys to the correct diagnosis are (1) a high clinical index of suspicion with careful inspection of the scalp for the presence of black dots, and (2) microscopic examination and culturing of the black dots or plucked hairs.""",1
7542,1940255,Cocaine and the liver,,1
7543,1941835,Gold induced hepatitis and pure red cell aplasia. Complete recovery after corticosteroid and N-acetylcysteine therapy,"A 54-year-old man developed severe cholestatic jaundice and pure red cell aplasia shortly after beginning treatment with gold sodium thiomalate. Although the hepatic toxicity began to spontaneously improve, the pure red cell aplasia was progressive. Treatment with prednisone and N-acetylcysteine (NAC) infusions was followed by prompt and complete hematologic recovery. Gold induced pure red cell aplasia should be added to the list of gold induced hematologic toxicities that can be potentially reversed with NAC infusion therapy.",1
7544,1943250,Vancomycin,"Vancomycin is a glycopeptide antibiotic that is active against staphylococci, streptococci, and other gram-positive bacteria. It is the drug of choice for the treatment of infections due to methicillin-resistant staphylococci, Corynebacterium jeikeium, and multiply resistant strains of Streptococcus pneumoniae. Vancomycin is an alternative treatment for serious staphylococcal and streptococcal infections, including endocarditis, when allergy precludes the use of penicillins and cephalosporins. Vancomycin is bactericidal against most strains of staphylococci and nonenterococcal streptococci. Although rare strains of staphylococci and enterococci that are resistant to vancomycin have been reported, bacterial resistance has thus far not emerged as a major clinical problem despite widespread use of vancomycin. When therapy is monitored by periodic determinations of serum concentrations of the drug and rapid infusion rates are avoided, vancomycin is rarely associated with serious toxicity.",1
7545,1949968,Phenytoin hypersensitivity syndrome: a case report,"""We report a life-threatening case of phenytoin hypersensitivity syndrome, a rare reaction primarily characterized by fever, skin eruptions, lymphadenopathy, eosinophilia, and hepatotoxicity. The reaction developed in a 27-year-old black man with surgically corrected tetralogy of Fallot who was treated with phenytoin for one month for exercise-induced sustained ventricular tachycardia. Phenytoin therapy was discontinued and the patient was treated with intravenous methylprednisolone; the therapy was later converted to oral prednisone. Clinical improvement was noted five days after admission and the patient was discharged on hospital day 14. This adverse reaction usually develops within six weeks of starting phenytoin therapy and may be fatal in up to 40 percent of the patients who develop hepatotoxicity. Early recognition of this relatively rare reaction is essential to prevent serious and potentially fatal complications.""",1
7546,1954449,Tobacco and the European common agricultural policy,,1
7547,1955140,Severe cholestatic jaundice associated with piroxicam,"A 62-year-old man with rheumatoid arthritis developed jaundice while taking piroxicam. A full evaluation including ultrasound, computerized tomography, endoscopic cholangiography, and liver biopsy confirmed the diagnosis of intrahepatic cholestasis. The patient's jaundice and all other liver function abnormalities normalized 4 months after he discontinued taking piroxicam. This is the first case report in the United States of severe liver toxicity associated with piroxicam. The six cases in the English-language literature are reviewed, featuring the presentation, patterns of liver injury, and outcome in each. Piroxicam should be considered as a potential cause of cholestatic jaundice when other more common etiologies have been excluded.",1
7548,1959977,Detection of antidrug IgG antibodies in patients with adverse drug reactions to amodiaquine,Antidrug IgG antibodies have been detected in some patients receiving amodiaquine (AQ). Antidrug antibodies were detected in 6/7 patients who experienced serious well-defined adverse drug reactions during malaria prophylaxis and in 7/22 patients who received comparable doses of the drug (at least 400 mg weekly x 6) but did not present with clinical adverse drug reactions. In contrast antidrug antibodies were not detected in 7 patients who received the drug for treatment (1.0-1.2 g total over 3 days). The specificity of the IgG response was defined by hapten inhibition experiments (IC50 value for AQ ranged between 0.050 and 0.282 microM) which suggest that the antibody recognised the drug linked to cysteine residues in protein via the 4-hydroxyanilino side chain. The data show that AQ is immunogenic in man and are consistent with the hypothesis that idiosyncratic adverse reactions to the drug have an immunological aetiology.,1
7549,1969613,Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine,"2-Chlorodeoxyadenosine is a simple purine nucleoside that has previously been shown to be effective in the treatment of low-grade malignant disorders of lymphoid tissue, including chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Because of these encouraging results, we treated 12 patients with another low-grade B-cell neoplasm, hairy-cell leukemia. The patients received 2-chlorodeoxyadenosine (0.1 mg per kilogram of body weight per day) by continuous infusion for seven days. All the patients responded to treatment. Eleven had complete remissions characterized by the normalization of peripheral blood and bone marrow and disappearance of tumor masses. The longest remission has been 3.8 years. None of the patients have relapsed, and the median duration of remission has been 15.5 months. No serious toxic reactions occurred as a result of 2-chlorodeoxyadenosine therapy. These results suggest that 2-chlorodeoxyadenosine may be the most effective therapy available for hairy-cell leukemia. The administration of 2-chlorodeoxyadenosine resulted in a higher rate of complete remission than is observed with interferon alfa, and it required no maintenance therapy. Its toxicity may be lower than that of deoxycoformycin, and the responses were achieved with single courses of treatment.",1
7550,1971860,[Therapy of inflammatory intestinal diseases from the viewpoint of internal medicine],,1
7551,1972297,Mesalazine: a global safety evaluation,"""The potential benefit of sulphasalazine in inflammatory bowel disease is limited by the wide variety of side effects that occur in about one-third of treated patients. Most of the side effects of sulphasalazine are due to the sulphapyridine moiety. Claversal has the advantage of delivering the active ingredient of sulphasalazine--mesalazine--without the undesirable effects of sulphapyridine. Four international multicentre trials involving 932 patients with ulcerative colitis or Crohn's disease compared 0.75 g/day or 1.5 g/day mesalazine, 1.5 g/day or 3.0 g/day sulphasalazine, or placebo. Forty-seven (14%) of 331 patients receiving mesalazine reported adverse events, whereas 33 (23%) of 144 patients receiving sulphasalazine and 23 (19%) of 123 patients receiving placebo reported adverse effects. When lower doses of both mesalazine (0.75 g/day) and sulphasalazine (1.5 to 2.0 g/day) were evaluated in a maintenance trial, the percentage of adverse events was similar for both drugs--14% and 12%, respectively. In these trials the incidence of adverse effects was similar with both doses of mesalazine; however, doubling the sulphasalazine dose resulted in a twofold increase in adverse effects. In contrast, mesalazine appeared not to induce dose-related effects, suggesting that patients may be able to tolerate even higher mesalazine doses than those studied. The withdrawal rate owing to adverse events in all four controlled trials was similar for patients treated with mesalazine (6%) and sulphasalazine (8%). Results of an open postmarketing sampling trial of just over 1700 patients in Germany showed a low overall incidence of adverse effects (3%) with mesalazine and none of the rare, more serious effects, such as hepatoxicity, agranulocytosis, or pulmonary complications.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
7552,1974701,Brain tissue elasticity and CSF elastance,"In the analysis of the pressure-volume relationship of the intracranial system, the concept of brain elastance, sometimes called tissue elastance or CSF elastance, is often used. It is generally designated as Ecsf and is calculated as the slope of the pressure-volume curve of the system. Variations in Ecsf are related to, for example, changes in the buffering capacity of the system which, however, could be influenced by the cerebral vascular volume, compressibility of the meningeal membranes, and compressibility of the subpial brain tissue. Our interest is in isolating the effect of controlled changes in the intracranial system with changes in the subpial tissue only. Here we discuss the measurement of brain tissue elasticity and describe two experimental conditions in which simultaneous measurements showed distinct differences between the behaviour of the system CSF elastance and brain tissue elastic behaviour.",1
7553,1975057,Fluconazole-induced jaundice,,1
7554,1977339,Whole-bowel irrigation as treatment for zinc sulfate overdose,"""A 16-year-old boy ingested approximately 50 zinc sulfate tablets (ZnSO4; 500-mg tablets). After spontaneous emesis, ipecac-induced emesis, and orogastric lavage, an abdominal radiograph performed four hours after ingestion still demonstrated approximately 50 ZnSO4 tablets within the stomach and three pills within the colon. Whole-bowel irrigation was begun with a polyethylene glycol lavage solution (PEG; Golytely) that was administered through a nasogastric tube; within one hour, the patient began producing a rectal effluent that contained pills. The patient remained asymptomatic throughout whole-bowel irrigation. Stool guaiac tests were negative. The serum chloride, however, increased from 105 to 127 mEq/L. Follow-up kidney, ureter, and bladder studies demonstrated the clearance of the zinc tablets from the gastrointestinal tract during the next 24 hours.""",1
7555,1982004,Liver abnormality in ovarian hyperstimulation syndrome,"Ovarian hyperstimulation syndrome (OHSS) is a potentially fatal condition associated with the therapeutic induction of ovulation in infertility. Liver function abnormality has been previously reported in four patients, one of whom had ultrastructural abnormalities on liver biopsy. This paper describes a patient presenting with severe OHSS 16 days after ovulation had been induced. Liver function abnormality was apparent 11 days later, with a sustained rise in alkaline phosphatase and aspartate aminotransferase (AST) which lasted up to 2 months. A liver biopsy performed during the second month of her protracted hospital admission showed marked zonal fatty change (acinar zone 1) and associated inflammation, with mitochondrial crystalline inclusions and rough endoplasmic reticulum dilatation on electron microscopy. This report discusses the clinical features and possible aetiological factors.",1
7556,1985608,Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia,"In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P less than .001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein-cholesterol level (24% to 40%), increased high-density lipoprotein-cholesterol level (6.6% to 9.5%), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein-cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P less than .001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia.",1
7557,1986415,Captopril-induced cholestatic jaundice,"I have reported a case of captopril-induced cholestatic jaundice. This drug is being used with increasing frequency, so it is important that physicians recognize this adverse effect. Captopril-induced jaundice resolves after cessation of captopril therapy.",1
7558,1988755,Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin,"Hepatitis developed in five patients who were taking low dosages (3 g/day or less) of time-release niacin. In four of the five patients, clinical symptoms of hepatitis developed after the medication had been taken for a relatively short time (2 days to 7 weeks). This manifestation of hepatotoxicity seems to differ from that previously reported in association with use of crystalline niacin, which occurred with high dosage and prolonged usage of the medication. In view of the recent increased frequency of prescribing niacin for the treatment of hyperlipidemia, physicians should be aware of the potential for hepatotoxicity with even low-dose and short-term use of time-release niacin.",1
7559,1992890,"Acetaminophen, isoniazid, and hepatic toxicity",,1
7560,2000613,[Fulminating hepatitis after treatment with naproxen and/or disulfiram?],"A 49 year old female was started on disulfiram. Six weeks later she was given naproxen because of epicondylitis. After 5 days' treatment with naproxen she complained of nausea, anorexia and jaundice. At admission, bilirubin was 452 mumol/l, aspartate aminotransferase (ASAT) 1925 U/I, alanine aminotransferase (ALAT) 2815 U/I and prothrombin time measured as Normotest was 27%. The patient developed a fulminant hepatitis and died in hepatic coma almost four weeks after the introduction of naproxen. Postmortem examination disclosed a small liver (1,100 g) and histological examination showed massive necrosis and collapse of the lobules. The naproxen was the most probable cause of death, but it is impossible to exclude disulfiram as causative agent.",1
7561,2007774,Etoposide (VP 16-213) induced hepatitis. Report of three cases following standard-dose treatments,"Acute hepatitis is a potential, although rare, complication following administration of high doses of Etoposide (VP 16-213). We report three cases of severe hepatocellular necrosis following administration of standard doses of this antineoplastic agent.",1
7562,2010080,[A case of hepatitis caused by simvastatin],,1
7563,2017635,Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins,"""Charts were reviewed for 63 patients whose chronic pseudomonas osteomyelitis was treated with high doses of extended-spectrum penicillins for prolonged periods. The incidence of untoward drug reactions was significantly higher than expected. Carbenicillin evoked adverse reactions in 22.8% of patients. However, most of these reactions were mild, and a change of drug was required in only 5.7% of cases. No adverse drug reactions were observed with cumulative doses of less than 750 g. In contrast to carbenicillin, the ureidopenicillins were associated with adverse reactions in 67.7% of patients; most reactions were moderate to severe in intensity; a cumulative dose of greater than 250 g produced adverse reactions; and discontinuation or change of therapy was required in 51.6% of cases. The main adverse reactions to both carbenicillin and the ureidopenicillins included rash, drug fever, leukopenia, eosinophilia, thrombocytopenia, and hepatic damage.""",1
7564,2019372,Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate,"Ceftriaxone, a third-generation cephalosporin, is partially excreted into bile. With its clinical use, the formation of gallbladder sludge detected by ultrasonography has been reported. Four surgical specimens were examined and no gallstones were found. Instead, fine precipitates of 20-250 microns were present. Microscopically, there was a small number of cholesterol monohydrate crystals and bilirubin granules among an abundant amount of granular-crystalline material that was not morphologically cholesterol monohydrate crystals. The chemical composition of the precipitates (n = 4) was determined. There was a small amount of cholesterol (1.7% +/- 0.8%) and bilirubin (13.9% +/- 0.74%). The major component of the precipitate was a residue. On further analysis using thin-layer chromatography, high-performance liquid chromatography, and electron microprobe analysis, the residue was identified as a calcium salt of ceftriaxone. The residue also had identical crystal morphology and chromatographic elution profile as authentic calcium-ceftriaxone standards. It is concluded that ceftriaxone, after excretion and being concentrated in the gallbladder bile, can form a precipitate. The major constituent has been identified as a ceftriaxone-calcium salt.",1
7565,2022163,Long-term efficacy of oral cisapride in symptomatic upper gut dysmotility,"""We conducted a 12-month trial of cisapride (10 mg three times a day) in 21 patients with gastric stasis due to clinically and manometrically diagnosed gastroparesis (N = 9; seven due to diabetes) or chronic intestinal pseudo-obstruction (N = 12). Radionuclide solid-liquid gastric emptying tests were performed at baseline and at the end of the 12-month period. Symptoms were assessed monthly by diary and every three months by the investigators; frequency and severity of symptoms were scored in a standardized manner. For the whole group of 21 patients, gastric emptying of both solids and liquids improved significantly after one year of cisapride (P less than 0.05). Among chronic intestinal pseudoobstruction patients, there was predominantly an improvement in gastric emptying of solids; in contrast, patients with gastroparesis had a greater improvement in liquid emptying. Total symptom score improved significantly in the gastroparesis group (median score: 8 at baseline vs 6 at one year, P less than 0.05) but not in the chronic intestinal pseudoobstruction patients (median score at baseline 10 vs 9 at one year). Similarly, body weight showed a trend towards improvement in the gastroparesis group. No significant side effects were noted. We conclude that during a 12-month open trial, cisapride was effective in improving gastric emptying in patients with gastric stasis and consistently improved symptoms in those with gastroparesis.""",1
7566,2025579,The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation,"The toxicity of the conditioning regimen of high dose busulphan (Bu) (16 mg/kg) and cyclophosphamide (Cy) (120 mg/kg) has been compared to cyclophosphamide (Cy) (120 mg/kg) and fractionated total body irradiation (TBI) 12-14 Gy. Since 1985, 67 patients have received conditioning of Bu and Cy for HLA-identical sibling bone marrow transplants. 166 patients have received Cy and TBI since 1981. Veno-occlusive disease of the liver occurred in 19% in the Bu-Cy group and was fatal in 1/12 cases, but only in 1.3% of Cy-TBI group (P less than 0.0005) and was fatal in 1/2. 30% of evaluable patients developed haemorrhagic cystitis in the Bu-Cy group and 14% in the Cy-TBI group (P = 0.008). A multiple logistic regression analysis demonstrated the preparative regimen as the only significant risk factor for the development of veno-occlusive disease or haemorrhagic cystitis. Interstitial pneumonia was diagnosed in 12/56 evaluable patients (21%) in the Bu-Cy group and was fatal in 75%. It occurred in 39/137 evaluable patients (28%) in the Cy-TBI group with a 54% case mortality. Within the Bu-Cy group, the incidence of veno-occlusive disease and haemorrhagic cystitis was similar in chronic myeloid leukaemia (CML) and acute leukaemia (AL) groups, but there was a significant (P = 0.003) incidence of interstitial pneumonia in the CML group 36% as compared to 7% in the AL group. Preparative regimen and age were significant risk factors in the development of interstitial pneumonia in patients with CML. A flexural and acral rash ranging from pigmentation to severe erosion was noted in the Bu-Cy group, but not in the Cy-TBI group. Thus, veno-occlusive disease, haemorrhagic cystitis and cutaneous changes were more common in patients receiving Bu-Cy. Interstitial pneumonia was more common in patients receiving Bu-Cy for CML than for AL.",1
7567,2026392,Acute amiodarone-induced hepatitis,"Two fatal cases of amiodarone-induced acute, confluent, necrotic hepatitis are described. The patients, aged 28 and 60, had received a high loading dose of amiodarone. After the first and second day respectively following the administration of amiodarone, the patients developed jaundice, hepatomegaly, high serum transaminases, a prolonged prothrombin time and low cholesterol concentration. They died of hepatic coma and acute renal failure on the fourteenth and fourth day respectively. Needle liver biopsy, performed immediately after death, revealed lesions of acute drug-induced hepatitis with confluent and bridging necrosis. It is proposed that rapid administration of a high loading dose of amiodarone can cause acute confluent necrotic hepatitis. The mode of administration and the dosage of the drug should be re-considered.",1
7568,2034154,Augmentin-induced jaundice,"OBJECTIVE: To alert clinicians to the hepatotoxic potential of Augmentin (amoxycillin and clavulanic acid), a widely prescribed antibiotic, in susceptible patients, and to point out that the hepatic illness may be delayed but serious and protracted. DESIGN AND SETTING: Case reports of patients with Augmentin-induced jaundice referred to the gastroenterology departments in three major teaching hospitals, and a review of cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). PATIENTS: Eight patients with nine episodes of Augmentin-induced jaundice personally treated by the authors from March 1988 to February 1990 are described. A further 19 patients reported to ADRAC from May 1987 to November 1989 are discussed. All patient histories were carefully reviewed to ensure that there was a temporal relationship between the course of Augmentin and the onset of the hepatitic illness and that other causes of jaundice were reasonably excluded. RESULTS: Jaundice developed in some of these patients several weeks after drug treatment was completed. The illness may be protracted over many weeks. As yet, there has been no case of progressive disease leading to the liver failure. CONCLUSIONS: The data suggest that a hypersensitivity reaction to clavulanic acid is the likely cause of the jaundice. Therefore, Augmentin, although an important antibiotic, should be reserved for severe infections for which amoxycillin is unsuitable.",1
7569,2040172,"Side effects during recombinant human erythropoietin therapy in 2,000 ESRD patients",,1
7570,2040198,The safety of epoetin-alpha: results of clinical trials in the United States,,1
7571,2043287,Side effects of ranitidine,"""Ranitidine was first marketed in 1981; since then many patients have been treated such that much experience has been accumulated on the safety of this histamine H2-receptor antagonist in the treatment of gastroduodenal disease. A wide array of ranitidine-associated side effects has been described, but infrequently. As so much information is now available, the aim of this review is to assess the weight of evidence for a causal link between ranitidine and the reported side effects. Overall, ranitidine is well tolerated. The incidence of general side effects at less than 2% is very similar to placebo. Headaches, tiredness, dizziness and mild gastrointestinal disturbance (e.g. diarrhoea, constipation and nausea) are among the most frequent complaints, but have very seldom resulted in stopping treatment. Cardiovascular side effects are extremely rare and unpredictable with the usual doses of oral ranitidine (at most 1 in 1 million patients). They mostly comprise sinusal bradycardia and atrioventricular blockade, especially after rapid intravenous administration, receding after cessation of the drug. Clinical studies, however, have not shown a significant pharmacological effect of ranitidine on the cardiovascular system via H2-receptors, even though individual sensitivities cannot be ruled out in a few isolated reports. Ranitidine is unlikely to be directly hepatotoxic: a transient change in liver function tests has been noted in only 1 in 100 to 1 in 1000 patients. Several cases of mixed hepatitis have been reported, but very few were fully documented. The incidence of ranitidine-associated acute hepatitis has been estimated to be less than 1 in 100,000 patients. Neuropsychiatric complications may be less common and clinically quite similar to those reported with cimetidine, i.e. confusion, disorientation, hallucinations, delirium. These side effects have occurred especially in critically ill and multiple-therapy patients, or patients with chronic renal or hepatic failure, so that the direct causal link with ranitidine treatment was often difficult to ascertain. Even though an H2-receptor-mediated effect is an attractive hypothesis (since similar complications were noted with other H2-receptor antagonists), other mechanisms have been suggested to play a role, e.g. cholinergic or histaminic effects. The overall incidence of neuropsychiatric complications is probably markedly less than 1%. White cell injury (i.e. agranulocytosis) appears to be the most frequent haematological complication, even though case reports are very few and poorly documented.(ABSTRACT TRUNCATED AT 400 WORDS)""",1
7572,2044610,"N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication","We report the 9-year follow-up of a patient suffering from N-acetylglutamate synthetase deficiency, an urea cycle disorder leading to severe neonatal hyperammonaemia. Hitherto two patients from two families with this inborn error of metabolism had been observed. Our management consisted mainly of a protein-restricted diet and oral treatment with N-carbamylglutamate, an activator of carbamylphosphate synthetase, together with arginine or citrulline. The somatic development was normal whereas a moderate psychomotor retardation was diagnosed. The patient died after an episode of coma and prolonged generalized convulsions at the age of 9.5 years.",1
7573,2046117,Hepatoxic reaction to antituberculous drugs: Adjustments to therapeutic regimen,,1
7574,2050339,Even isoflurane,,1
7575,2053502,Effects of tetrahydroaminoacridine on liver function in patients with Alzheimer's disease,"Detailed liver function test analysis is reported for 30 patients with Alzheimer's disease who were treated with tetrahydroaminoacridine. Results show that a benign elevation of aspartate transaminase occurs in up to 50% cases, that the reaction can be a symptomatic one and that clinical hepatitis can occasionally result. Liver function test changes appear dose-dependent and normalize within 2-4 weeks of stopping the drug or of reducing the dose. Women appear more likely to develop hepatotoxicity than men. Rechallenge with THA in patients previously showing abnormalities in liver function shows that some patients are able to tolerate the drug a second time.",1
7576,2056805,[Hepatitis due to etretinate: a case report],,1
7577,2060127,Cyclosporine toxicity to organs other than the kidney,"""The molecular basis for CsA toxicity is unknown, and several fundamental questions remain. First, it is still unclear whether the toxicity of CsA is a consequence of its mechanism of action (and therefore perhaps inevitable) or is separate from its beneficial (immunosuppressive) effects. Second, several organs appear to be at greater risk for CsA toxicity, but the mechanisms involved in this increased susceptibility (increased membrane binding of the drug, increased intracellular transport, increased intracellular binding, different metabolism, inefficient protective mechanisms, etc.) have not been studied. Third, and equally important, it is possible that many of the toxicities of CsA are not related to CsA itself (or its metabolites) but to secondary mediators produced in the presence of CsA. This would imply that the study of CsA toxicity in vitro would necessitate the presence of these cells (in addition to the """"target"""" cells) under conditions in which these toxic mediators are formed. There are few answers to these questions at present, and, whilst answers to the first two questions may be obtained from the in vitro study of cell culture systems, the answer to the third requires the development and study of suitable in vivo models of CsA toxicity.""",1
7578,2064763,"A case of Stevens-Johnson syndrome, cholestatic hepatitis and haemolytic anaemia associated with use of mefenamic acid","A woman with a history of drug allergy, renal impairment and carcinoma of the breast with pulmonary micrometastases developed haemolytic anaemia and Stevens-Johnson syndrome following the use of mefenamic acid, paracetamol (acetaminophen) and furosemide (frusemide). In addition there was severe cholestatic hepatitis in the absence of clinical evidence of sepsis, biliary obstruction or recurrent metastases. The rash resolved on steroid therapy but the patient eventually died from both renal and liver failure. Acute tubular necrosis with a background of chronic tubulointerstitial nephritis was also found at autopsy. Although in the presence of multiple drug therapy the causative agent cannot be identified with absolute certainty, the association of these severe idiosyncratic hepatic and dermatological reactions with haemolytic anaemia strongly suggests mefenamic acid as the most likely culprit.",1
7579,2067448,Liver side effects associated with simvastatin therapy,,1
7580,2068577,Long-term methotrexate therapy for rheumatoid arthritis,"A retrospective review of methotrexate (MTX) treatment assessed the clinical course in 124 rheumatoid arthritis (RA) patients. After 5 years, 39 (31%) patients continued MTX with clinical benefit. Although patients continuing MTX after 5 years were younger (45 +/- 13 v 54 +/- 12 yrs, P less than .001) and had a shorter disease duration of RA (9.3 +/- 8.1 v 14 +/- 11 yrs, P less than .05) than patients who discontinue the drug, these differences were not considered clinically significant. MTX was discontinued in 20 patients for a lack of clinical benefit, in 21 patients for non-drug-related reasons, and in 44 patients for suspected adverse drug reactions. The adverse drug reactions requiring permanent discontinuation of MTX were nausea, stomatitis, hair loss, rash, pulmonary reactions, elevated liver enzymes, hematologic abnormalities, and hepatic fibrosis. At least one adverse drug reaction was reported by 115 (93%) patients receiving MTX, but the majority did not require permanent drug discontinuation. Although the prevalence of adverse reactions increased with longer duration of therapy, no differences existed in the type of reactions reported over 5 years of treatment. There were no risk factors identified that were clearly associated with the development of toxicity. Long-term therapy was primarily limited by adverse reactions rather than loss of efficacy.",1
7581,2070975,[Pentamidine-related acute hepatitis during pneumocystosis treatment in acquired immunodeficiency syndrome],,1
7582,2074065,[Acute hepatitis and pneumonitis associated with nitrofurantoin],"Nitrofurantoin is widely used in the prophylaxis and treatment of urinary tract infections. Most untoward side-effects are mild and due to gastrointestinal intolerance. More severe side-effects consist of acute and chronic pulmonary reactions, liver damage, blood dyscrasias and peripheral neuropathy. Nitrofurantoin is a rare cause of hepatic injury, with a spectrum of toxic reactions ranging from acute, self-limited, hepatocellular or cholestatic injury to chronic active hepatitis. We present a case of acute hepatic injury and pneumonitis related to nitrofurantoin. When this drug is given periodic clinical and laboratory monitoring is important.",1
7583,2081138,Acute hepatitis after a loading dose of intravenous amiodarone,,1
7584,2084236,Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis,"Adverse experience occurred with a high frequency in a longterm (greater than 3 years), prospective, double blind, followed by an open trial of methotrexate (MTX) therapy in 45 patients with rheumatoid arthritis (RA). Adverse experiences occurred in 96% of patients, and the discontinuation rate was 44% over 176 weeks. No hepatic or pulmonary fibrosis occurred. Unusual toxicities included weight loss (2 patients), systemic fungal infections (2 patients), and transient noncirrhotic ascites (1 patient). Baseline white blood cell counts and creatinine may help predict adverse experiences. The full dose-toxicity spectrum of MTX RA is not yet fully defined.",1
7585,2090674,Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil,"A female newborn whose mother was taking propylthiouracil (PTU) for Graves' disease, presented with transient thyrotoxicosis (serum triiodothyronine 1,710 ng/dl) and signs of acute hepatic injury. Jaundice and choluria were evident on her fourth day of life. Serum total bilirubin reached 14 mg/dl, with a direct fraction of 11 mg/dl. Serum alanine aminotransferase and aspartate aminotransferase showed moderate elevations (110 IU/l and 61.5 IU/l, respectively), as well as the alkaline phosphatase which increased to about twice the upper limit of normal. When incubated with PTU, the patient's cultured peripheral lymphocytes underwent transformation to more than twice the values found in 2 controls, with a stimulation index (SI) of 3.19, compared to SI of 1.45 and 1.15 for the controls, suggesting a hypersensitivity mechanism involved in the hepatic injury. Although about 20 cases of PTU induced hepatic damage were reported in the medical literature, this is, as far as we know, the first description of neonatal liver injury probably caused by placental transfer of this drug.",1
7586,2099434,Bleeding oesophageal varices associated with anabolic steroid use in an athlete,"A 30 year old bodybuilder who had been taking anabolic steroids for 18 months presented with bleeding oesophageal varices. Serious liver disease secondary to anabolic steroids including peliosis hepatis, nodular hyperplasia and malignant change is well recognized. We report what is, to our knowledge, the first case of bleeding oesophageal varices associated with the use of anabolic steroids.",1
7587,2100991,Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients,"""BACKGROUND: A sudden increase in the incidence of post-transplantation lymphoproliferative disorder among the patients in our cardiac-transplantation program was temporally related to introduction of the immunosuppressive drug OKT3. This monoclonal antibody has come to be widely used in recent years both to prevent and to treat rejection after cardiac transplantation. METHODS: In order to identify variables that predict the development of post-transplantation lymphoproliferative disorder, we analyzed retrospectively a series of 154 consecutive cardiac-transplant recipients at a single institution. Univariate analyses and multivariate analysis by logistic regression were performed. RESULTS: Among 75 patients who did not receive OKT3, post-transplantation lymphoproliferative disorder developed in 1 (1.3 percent), as compared with 9 of 79 patients who received the drug (11.4 percent); the incidence among the OKT3-treated patients was ninefold higher (odds ratio, 9.5; 95 percent confidence interval, 1.6 to 54.7). According to multivariate analysis, the only factor significantly associated with the development of post-transplantation lymphoproliferative disorder was the use of OKT3 (P = 0.001). A significant increase in risk with increasing doses was also apparent: 4 of 65 patients who received a cumulative dose of 75 mg of OKT3 or less (6.2 percent) had post-transplantation lymphoproliferative disorder, whereas 5 of 14 patients who received more than 75 mg had the disorder (35.7 percent; P less than 0.001). CONCLUSION: The addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder after cardiac transplantation, and the risk increases sharply after cumulative doses greater than 75 mg. We suggest that the risks and benefits of prophylactic OKT3 administration be reassessed in the light of these findings, particularly since the value of prophylactic immunotherapy in cardiac-transplant recipients remains to be clearly established.""",1
7588,2103414,Hepatic toxicity of vitamin A and synthetic retinoids,Vitamin A and synthetic retinoids have recently been used increasingly in a variety of health related concerns. Hepatic toxicity is an uncommon but serious side-effect of several Vitamin A derivatives which may lead to cirrhosis. This review will focus on the clinical and pathologic findings of hepatic involvement in chronic hypervitaminosis A and on the evidence concerning the potential hepatotoxicity of currently available synthetic retinoids.,1
7589,2107856,Lyme disease: a review,"In the last decade, Lyme borreliosis has emerged as a complex new infection whose distribution is worldwide. The multisystem disorder, which primarily affects the skin, joints, heart and nervous system at different stages, is caused by the tick-borne spirochaete Borrelia burgdorferi. After the first weeks of infection almost all patients have a positive antibody response to the spirochaete and serological determinations are currently the most practical laboratory aid in diagnosis. Treatment with appropriate antibiotics is usually curative.",1
7590,2108017,Markedly increased omega-oxidation of valproate in fulminant hepatic failure,"Using gas chromatography-mass spectrometry, we showed that the urinary metabolite profile of valproate (VPA) in a subject receiving VPA and phenobarbital (PB) who died of fulminant hepatic failure was quite different from those of reported patients with Reye's syndrome or fatal hepatic failure. Only 2-n-propylglutarate, the end product of omega-oxidation of VPA, was excreted in markedly increased amounts, while other VPA metabolites were undetectable. Although the primary cause of fulminant hepatitis and the mechanism of enhanced VPA metabolism by the hepatic P-450 system in this patient are not clear, our findings suggest that P-450-mediated reactions become the predominant metabolic pathway of VPA in a stage of fulminant hepatic failure.",1
7591,2112245,Long term treatment of myasthenia gravis with azathioprine,"Twenty-seven patients with myasthenia gravis have been treated with azathioprine in conjunction with pyridostigmine and prednisolone for a total of 138 patient years. Side effects necessitated discontinuation of treatment in only four patients. Treatment with azathioprine was associated with marked clinical improvement in all the remaining 23 patients, resulting in reduction in the dose of pyridostigmine and prednisolone. The number of hospital admissions as well as the number of episodes of respiratory failure were markedly reduced.",1
7592,2113424,The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects,"The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.",1
7593,2116345,"Chronic cholestasis, paucity of bile ducts, red cell aplasia, and the Stevens-Johnson syndrome. An ampicillin-associated case",The unique case of severe chronic cholestasis with paucity of bile ducts accompanied by pure red cell aplasia and the Stevens-Johnson syndrome in a 35-year-old woman after ampicillin ingestion is presented. The patient improved gradually and is asymptomatic 4 years later. Sequential histological and clinical follow-up substantiate the course of her disease.,1
7594,2118858,"Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group","""The safety and efficacy of leuprolide acetate (LA) for depot suspension (Lupron depot; TAP Pharmaceuticals, North Chicago, IL), 3.75 mg versus placebo, in the treatment of pain associated with endometriosis was assessed in a randomized, double-blind, multicenter study involving 52 patients. Dysmenorrhea, pelvic pain, and pelvic tenderness all responded significantly to LA treatment in comparison with placebo. Menses were suppressed in all of the LA patients. Estradiol decreased significantly to menopausal levels in the LA group. There were small to moderate changes in a variety of laboratory parameters, but these were not clinically significant. The most common adverse event was vasodilatation, occurring significantly more frequently in the LA group. Lupron depot was shown to be safe and effective in inducing a hormonal and menstrual suppression in patients with endometriosis, resulting in alleviation of pain symptoms.""",1
7595,2125388,Vascular hepatotoxicity related to heroin addiction,"""The hepatotoxic effect of heroin has been demonstrated in liver biopsies by morphometric analysis of four groups of patients: twenty-one drug abusers (DA) at the time of the biopsy, eighteen patients who had stopped drug consumption for at least six months (ex-DA), twelve patients with post-transfusional chronic active hepatitis (PTCAH), and eleven controls (CONTROL). Semiquantitative assessment showed the extent of sinusoidal dilatation and the inflammatory and fibrotic reaction in the terminal hepatic vein (THV). Thickening and cellularity of the venular wall and the volume density of sinusoidal lumen (Vsl) in the Zone I and III of the hepatic acinus, were also evaluated. The morphometric analysis used computerized measurements. In DA, the sinusoidal dilatation (100% of cases), the sinusoidal and THV inflammation (81% and 67.7%, respectively), localized mainly in the centrilobular zone, were more pronounced than in ex-DA, in patients with PTCAH and in CONTROL (significantly different P less than 0.0001). Conversely, the fibrotic reaction (perisinusoidal fibrosis--44.4% and perivenular fibrosis--61.1%) was more frequent in ex-DA. The THV inflammation in DA was replaced by a fibrotic matrix deposit in the THV wall (wall surface/internal surface = 2.72 +/- 0.37 in ex-DA; 1.38 +/- 0.32 in DA; 0.87 +/- 0.14 in PTCAH and 0.45 +/- 0.03 in CONTROL--significantly different P less than 0.001), associated with a perisinusoidal fibrosis, after drug withdrawal. Moreover, there was significantly decreased venular wall cellularity in ex-DA (wall surface/mesenchymal cells = 949 +/- 158 in ex-DA; 622 +/- 40 in DA; 619 +/- 61 in PTCAH; 547 +/- 23 in CONTROL--P less than 0.001). Semiquantitative and morphometric data suggest that these vascular lesions and their reversibility may be due to the direct hepatotoxic effects of heroin.""",1
7596,2130580,[Drug-induced hepatitis due to benzarone (Fragivix): apropos of a clinical case report],"""A 46-year-old woman with a previous history of thyroiditis but without clinical evidence of preexisting liver disease presented with severe acute hepatitis while under benzarone therapy (Fragivix, 400 mg per day, p.o.). Because of negative serological work-up, a tentative diagnosis of """"sporadic"""" non-A, non-B hepatitis was considered. Two months after resolution, a relapse of clinical and biochemical features of hepatitis occurring 10 days after the spontaneous resumption of therapy led to the diagnosis of drug-induced liver damage. This case represents the third reported case of severe hepatitis related to benzarone. The mechanism of liver toxicity was likely due to hypersensitivity.""",1
7597,2135589,[Cholestatic hepatitis caused by erythromycin propionate],,1
7598,2136905,Trimetrexate-leucovorin dosage evaluation study for treatment of Pneumocystis carinii pneumonia,"""To determine the maximal tolerable dosage of trimetrexate for treatment of pneumocystis pneumonia, 25 patients were treated each day with 45 mg/m2 of trimetrexate and 80 mg/m2 of leucovorin; 10 received 60 mg/m2 and 80 mg/m2; 12 received 60 mg/m2 and 160 mg/m2; and 6 received 90 mg/m2 and 160 mg/m2, respectively. Leucovorin was increased twofold and trimetrexate reduced by 50% or suspended briefly for various levels of neutropenia and thrombocytopenia until blood counts increased. Dosage-modifying hematologic toxicity occurred in 12 (46%), 8 (80%), 9 (75%), and 4 (67%) patients with the respective groups. Cytopenias were in each case reversible and other toxicities were well tolerated. All survivors but one were able to receive a full 21 doses of trimetrexate. Twenty-four (92%), 10 (100%), 7 (58%), and 4 (80%) of patients in the respective groups survived. Thus, the 45 mg/m2/day dosage of trimetrexate with 80 mg/m2/day of leucovorin resulted in the least dosage-modifying toxicity and excellent efficacy. This combination should be selected for studies to compare trimetrexate with other therapies for pneumocystis pneumonia.""",1
7599,2138674,"Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain","All reports of adverse reactions with pyrimethamine-sulphadoxine (Fansidar), pyrimethamine-dapsone (Maloprim), and amodiaquine spontaneously reported through the UK national post-marketing system were reviewed. Retrospective reporting rates of serious reactions associated with these drugs were analysed using prescription data from the Department of Health, derived from the Prescription Pricing Authority, and relevant pharmaceutical companies. Whilst interpretation of these data requires caution, they allowed comparison with reporting rates from other studies. The reported rate for all serious reactions to pyrimethamine-sulphadoxine was 1:2100 prescriptions, and for cutaneous reactions was 1:4900 prescriptions, with a fatality rate of 1:11,100. The reported rate for serious reactions to pyrimethamine-dapsone was 1:9100 prescriptions, and for blood dyscrasias was 1:20,000 prescriptions, with a fatality rate of 1:75,000. The reported rate of blood dyscrasias associated with amodiaquine was 1:2100 users with a fatality rate of 1:31,000. Serious hepatic disorders occurred in 1:11 1000 pyrimethamine-sulphadoxine prescriptions, 1:75,200 pyrimethamine-dapsone prescriptions, and in 1:15,650 amodiaquine users. 35% of cases received these drugs needlessly as they were not exposed to drug resistant strains of Plasmodium falciparum. Since few serious reactions have been reported to chloroquine plus proguanil, these data support guidelines which restrict the use of reviewed drugs for those at greatest risk of infection. Dosage data indicated that fatalities had taken higher doses and continued prophylaxis after onset of symptoms. Two thirds of serious reactions to the compound antimalarials were reported in females.",1
7600,2142236,"Effect of toremifene on clinical chemistry, hematology and hormone levels at different doses in healthy postmenopausal volunteers: phase I study","Toremifene was given within the dose range of 3-680 mg as a single dose or on five consecutive days to 72 postmenopausal volunteers. Blood samples for clinical chemistry were taken hourly up to 7 h and 1, 2, 3, 7, 10 and 15 days after the last dose of toremifene. The concentrations of serum bilirubin, creatinine, amylase, free thyroxine, cortisol, prolactin, electrolytes and blood glucose remained unchanged at all dose levels. A statistically significant decrease was observed in liver enzymes (ASAT, ALAT, ALP) at the dose levels of 220-680 mg, whereas gamma-GT remained unchanged. A decrease in the concentration of LH and FSH was observed at the dose levels of 46 mg or higher and 220 mg or higher, respectively. These hormonal changes including the increase of SHBG at the dose levels of 220-680 mg and the decrease of antithrombin III (220-680 mg) may be attributed to a weak estrogen-like effect of toremifene. Side effects were minimal: pulse rate, blood pressure and ECG remained unchanged during the test period. Only two patients on 680 mg dose suffered from nausea and vertigo, and one of them discontinued the medication.",1
7601,2144387,[Mononucleosis syndrome with hypersensitivity hepatitis following carbamazepine administration],,1
7602,2146132,An updated safety profile of etodolac in several thousand patients,"The safety of etodolac, a new nonsteroidal anti-inflammatory drug (NSAID), was reviewed by examining data from 3,302 patients enrolled in double-blind and open-label clinical trials and from 8,334 patients taking etodolac in post-marketing surveillance studies. The review determined that gastrointestinal disturbances are the most frequently reported side effects, followed by headache, dizziness, rash, and pruritus. The rate of abdominal pain and dyspepsia is similar to that observed with several other NSAIDs but is lower than that seen with aspirin. Gastrointestinal ulceration occurs in less than 0.3% of patients taking etodolac, and drug-related hepatic, renal, and hematologic dysfunctions are rare. The elderly appear to be no more at risk of experiencing adverse effects than the general population. Overall, the review confirmed the excellent safety profile of etodolac reported previously.",1
7603,2147707,Severe hepatotoxic reaction with progression to cirrhosis after use of a novel retinoid (acitretin),"We report the case of a 50-year-old female who suffered from severe palmar and plantar pustulosis. During treatment with acitretin, a novel oral retinoid, which is the main derivative of etretinate, the patient developed a severe hepatotoxic reaction. Subsequent histological studies strongly suggested the development of liver cirrhosis. Reversible elevation of serum aminotransferase values during treatment with acitretin has been reported. However, the present observation indicates that severe hepatotoxic injury may also follow treatment with this agent.",1
7604,2150568,Global safety of etodolac: reports from worldwide postmarketing surveillance studies,"Etodolac is a new nonsteroidal anti-inflammatory drug (NSAID) that has shown a favorable safety profile in clinical trials in osteoarthritis (OA) and rheumatoid arthritis (RA). Four postmarketing surveillance studies were conducted with patients who had OA and RA to further assess the safety of etodolac. One study also had patients with ankylosing spondylitis (AKS). These studies were conducted in Italy, Switzerland, the United Kingdom, and France. A total of 8334 patients received oral doses of 200 to 600 mg/day for periods ranging from 4 weeks to 1 year. The incidence of study events was low, 77% of the patients treated in these postmarketing surveillance studies reported no study events. Only 9% of all the patients treated withdrew from these studies because of adverse effects. Gastrointestinal events were the most commonly reported among the study events that did occur, as expected for an NSAID. These results further support the safety of etodolac that was previously established in clinical trials.",1
7605,2153087,Histopathology of cocaine hepatotoxicity. Report of four patients,"Although cocaine is believed to be hepatotoxic for humans, the hepatic histopathology has been reported in only 1 patient. That patient had zone-1 necrosis. We have encountered 4 patients with liver injury secondary to cocaine use, 1 of whom died. The biopsies from two patients showed well-demarcated zone-3 necrosis identical to that seen with acetaminophen toxicity. The patient who died had necrosis of almost all hepatocytes as found at biopsy and autopsy. Biopsy was performed on another patient after resolution of the illness, and showed hyperplastic endoplastic reticulum but no necrosis. All patients had mild large- and small-droplet steatosis in surviving hepatocytes. Inflammation was mild. Drug screenings performed on all patients showed the presence of a cocaine metabolite and the absence of acetaminophen, alcohol, and other potential toxins. Patients typically had early marked increase and rapid decrease of serum aminotransferases, mild-to-moderate increase in prothrombin time, myoglobinuria, and moderate azotemia. The predominant pattern of zone-3 necrosis is similar to that reported of mice given cocaine.",1
7606,2155569,"USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results","""STUDY OBJECTIVE: To determine the effectiveness, toxicity, and acceptability of a 6-month antituberculous regimen compared with a 9-month regimen. DESIGN: A nonblinded, unbalanced, randomized, multicenter clinical trial. SETTING: Twenty-two tuberculosis clinics in public health departments and hospitals in the United States. PATIENTS: Patients were eligible if Mycobacterium tuberculosis, isolated from sputum cultures, was susceptible to study drugs. Of 1451 patients enrolled, 75% (617 of 823) assigned to the 6-month regimen and 71% (445 of 628) assigned to the 9-month regimen were eligible. INTERVENTIONS: Patients took self-administered isoniazid and rifampin daily for 24 weeks (6-month regimen) or 36 weeks (9-month regimen). In addition, patients assigned to the 6-month regimen took self-administered pyrazinamide daily during the first 8 weeks. RESULTS: Patients on the 6-month regimen converted more rapidly than patients on the 9-month regimen (94.6% compared with 89.9% after 16 weeks of therapy, with a difference of 4.7% [95% CI, 0.7% to 8.7%]); had similar rates of adverse drug reactions (7.7% compared with 6.4%, with a difference of 1.3% [95% CI, 0.0% to 4.6%]); had lower noncompliance rates (16.8% compared with 29.2%, with a difference of 12.4% [95% CI, 6.8% to 18.0%]); and had similar relapse rates 96 weeks after completing therapy (3.5% compared with 2.8%, with a difference of 0.7% [95% CI, 0.0% to 3.9%]). A significantly greater proportion of patients assigned to the 6-month regimen successfully completed therapy (61.4% compared with 50.6%; chi 2 = 11.976). CONCLUSIONS: Our results suggest that this 6-month regimen is similar in effectiveness, toxicity, and acceptability to the 9-month regimen for treating pulmonary tuberculosis.""",1
7607,2166418,Reversible liver injury possibly due to roxithromycin therapy,,1
7608,2167951,Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study,"To evaluate the effect of dactinomycin (AMD) dose and schedule on the frequency of severe hepatic toxicity in unirradiated National Wilms' Tumor Study-4 (NWTS-4) patients, we reviewed the records of 154 children randomized to single-dose AMD and 176 children randomized to divided-dose AMD administration. All the children also received vincristine in identical dose schedules for the first 10 weeks. The frequency of severe hepatic toxicity encountered in the early weeks of therapy was 14.3% (five of 35) among patients treated with 60 micrograms/kg of AMD, 3.7% (four of 108) among patients given 45 micrograms/kg, and 2.8% (five of 176) among patients treated with 15 micrograms/kg per dose times five doses (P = .025). The data suggest an increased frequency of severe hepatic toxicity with the higher, single-dose schedule of administration. However, the frequency of severe hepatic toxicity among the patients in the two remaining groups is markedly higher than the 0.4% observed among similar unirradiated patients in NWTS-3. The relationship of this toxicity to factors such as anesthetic agents, blood transfusions, intercurrent viral infection, or other presently unrecognized causes can be further evaluated only with a detailed investigation such as a case-control study.",1
7609,2172073,Fulminant hepatitis after lisinopril administration,"A case of fulminant hepatitis in a patient taking lisinopril for 5 weeks for arterial hypertension is reported. Jaundice, fever, myalgia, and marked increase in serum aminotransferase activities occurred after 2 weeks of treatment. Continuation of lisinopril administration for 3 weeks after the onset of jaundice was associated with the development of grade III encephalopathy and a marked decrease in prothrombin and proaccelerin levels. This case strongly suggests that lisinopril may induce acute hepatitis and that continuation of the treatment after the onset of jaundice can lead to life-threatening hepatic failure.",1
7610,2175192,G-proteins and the inositol cycle in Dictyostelium discoideum,"The inositol cycle in Dictyostelium discoideum was studied both in vitro and in vivo. The results are compared to the inositol cycle as it is known from higher eukaryotes. Although there is a strong resemblance the cycles are different at some essential points. In comparison to higher eukaryotes, in the cycle in D. discoideum the inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] kinase appears to be absent and there are additional phosphatases which hydrolyse Ins(1,4,5)P3 via inositol 4,5-bisphosphate [Ins(4,5)P2] to inositol 4-phosphate (Ins4P). The function of the receptor-stimulated inositol cycle was elucidated using mutants from the fgd A complementation group, which are defective in the G-protein alpha-subunit, responsible for the activation of phosphoinositidase C. These mutants show defects in both chemotaxis and differentiation, suggesting that the stimulation of phosphoinositidase C is the major sensory transduction pathway in D. discoideum.",1
7611,2183495,Penbutolol: a new beta-adrenergic blocking agent,"Penbutolol is a new beta-adrenergic blocking drug approved for the treatment of hypertension. It is a noncardioselective beta-blocker and has intrinsic sympathomimetic activity. The drug is approximately four times as potent as propranolol when taken orally. After oral administration, it is almost completely absorbed and peak plasma concentrations are achieved within 1.0 to 2.25 hours. Penbutolol is extensively metabolized in the liver by hydroxylation and glucuronidation. Active metabolites have not been identified. Only four to six percent of the parent drug is eliminated in the urine unchanged and dosage adjustment in renal insufficiency does not appear to be necessary. The mean terminal half-life of penbutolol is 17.6 to 26.5 hours. The duration of the hypotensive effect is approximately 24 hours. Current dosing guidelines recommend initiating therapy with 20 mg/d administered once a day. Optimum hypotensive effect occurs at dosages of 20-40 mg/d with little additional benefit observed above this range. Penbutolol appears to be well tolerated. The adverse effect profile is similar to other beta-blockers.",1
7612,2184010,Pergolide. A review of its pharmacological properties and therapeutic potential in Parkinson's disease,"When used to treat patients with Parkinson's disease pergolide acts at dopamine receptors in the corpus striatum to improve locomotor activity, reducing the tremor, gait disturbances, bradykinesia or akinesia and rigidity experienced by such patients. Treatment with pergolide often allows substantial reductions in concomitant levodopa dosage, and occasionally levodopa can be completely replaced by pergolide therapy in short term use. Pergolide has a long duration of action, thus reducing the wearing-off and end-of-dose phenomena frequently seen with long term levodopa therapy, suppressing fluctuations in levodopa response, and increasing total 'on' time. Despite a lack of well controlled studies comparing this drug with other dopamine agonist agents, pergolide appears to result in adverse effects and anti-Parkinson responses similar to those of bromocriptine and lisuride. Thus, pergolide would appear to be at least as useful as other dopamine agonists such as bromocriptine or lisuride for the management of patients with Parkinson's disease when administered in combination with levodopa. Future research should be directed towards establishing which patients are most likely to benefit from pergolide therapy, and clarifying the relative efficacy and safety of the anti-Parkinsonian drugs available to the clinician. If pergolide does provide clinical benefit when substituted for levodopa-adjunct drugs that are producing less than optimal control, this will be an advantage in a disease area which at present has few therapeutic options.",1
7613,2187948,"""Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study""","""The Swedish Ticlopidine Multicentre Study (STIMS) was a double-blind placebo-controlled trial designed to determine whether ticlopidine, a platelet antiaggregatory agent, reduces the incidence of myocardial infarction, stroke and transitory ischaemic attacks in patients with intermittent claudication. A total of 687 patients was monitored for a minimum of 5 years or until an end-point was reached. The number of end points (99 vs. 89), analysed according to the intention-to-treat principle, was 11.4% lower in the ticlopidine group (P = 0.24). The mortality rate was 29.1% lower in the ticlopidine group (64 vs. 89, P = 0.015); this observation could be accounted for by a reduced mortality from ischaemic heart disease. On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group (47 vs. 76, P = 0.017). Diarrhoea was the most common side-effect. Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine. It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine.""",1
7614,2189592,"High-dose carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support: excessive hepatic toxicity","Intensive doses of carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support were given to four patients with advanced melanoma. Three developed clinically diagnosed, severe veno-occlusive liver disease, which was fatal in two cases. The dose of carboplatin (450 mg/m2) was comparable with that used in ambulatory regimens. At the doses and schedule employed, this three-drug combination produced excessive hepatic toxicity. Caution is suggested when giving carboplatin in combination with intensive doses of other chemotherapeutic agents with known hepatotoxic potential.",1
7615,2189950,Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16,"""The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.""",1
7616,2191851,Diltiazem. A reappraisal of its pharmacological properties and therapeutic use,"Diltiazem is a calcium antagonist effective in the treatment of stable, variant and unstable angina pectoris and mild to moderate systemic hypertension, with a generally favourable adverse effect profile. It is also effective in terminating supraventricular tachycardia and in controlling the ventricular response to atrial fibrillation/flutter. Atrioventricular block, the risk of which may be exacerbated by concomitant beta-adrenoceptor antagonist therapy, occurs rarely as an adverse effect of diltiazem treatment. Diltiazem appears to exert complex cardioprotective effects which have been of benefit after intracoronary administration to patients undergoing coronary angiography and bypass procedures. In addition, long term diltiazem treatment has produced a significant reduction in subsequent cardiac events in patients with non-Q wave myocardial infarction. Thus, diltiazem is an effective and well-tolerated first-line or alternative treatment of patients with ischaemic heart disease, systemic hypertension, and supraventricular arrhythmias, with possible potential in limiting ischaemia-induced myocardial damage.",1
7617,2192616,Vitamin B6 safety issues,,1
7618,2196079,Methotrexate side-effects,"""Methotrexate is by far the most widely used cytotoxic drug in psoriasis. Treatment requires normal kidney, liver and bone-marrow function, and pregnancy and alcohol abuse are absolute contraindications. Serious toxic reactions are recognized, but can be avoided if the drug is used correctly. The most important side-effects are haematopoietic and hepatotoxic. It is well established that long-term methotrexate can induce liver damage which, in a number of patients, may lead to fibrosis or cirrhosis. Recent studies have, however, documented that the methotrexate-induced liver cirrhosis is not aggressive. Interaction can occur with a number of drugs; serious problems in particular may arise with concomitant use of sulphonamides and salicylates. The recommended guidelines for methotrexate use in psoriasis should be followed and patients given clear instructions.""",1
7619,2196621,Naltrexone in autistic children: a double-blind and placebo-controlled study,"A double-blind, placebo-controlled study was designed to assess critically the effects of naltrexone on behavioral symptoms and learning in autistic children, and its safety. This is a preliminary report on 18 children, ages 3.08 to 7.99 years, who completed this ongoing study. Subjects were randomly assigned to naltrexone or placebo and received daily doses over a period of 21 days. Naltrexone was superior to placebo according to blind Clinical Global Consensus Ratings (unpublished scale). However, other behavioral rating measures did not confirm this result. There was only a suggestion that naltrexone reduced fidgety and hyperactive behavior and tended to alleviate overall symptomatology in older children. Naltrexone did not appear to affect discrimination learning. Results are preliminary and, owing to the small sample size, can be considered only suggestive until this study is completed or replication is obtained from independent research.",1
7620,2197323,Iron poisoning: report of three cases and a review of therapeutic intervention,"Although the acute ingestion of iron-containing preparations can produce very serious consequences, the majority of reported exposures are not associated with significant morbidity or mortality. We present 3 cases of acute iron ingestion and review the aspects of general management, with an emphasis on the appropriate choice of a gastrointestinal decontamination procedure.",1
7621,2202319,[Drug-induced liver damage from the clinical viewpoint],"Extensive drug-induced hepatic injury leading up to jaundice occurs relatively rarely. Generally it is not predictable, independent on dosage and irreproductible in animals. As a rule you find it in less than 0.1% of the patients taking the drug, whereas the degree may range up to heavy or lethal (e.g. for isoniazid, methyldopa, halothane). Pathogenetically reactive metabolites capable of producing cytotoxic and/or immune reactions may play a role. Obviously higher age, female sex and endogenous or exogenous alterations in hepatocellular drug metabolism are disposing factors. Drugs, to which our patients most frequently reacted, were dihydralazine alone or in combination with propranolol, and ketophenylbutazone. The lymphocyte transformation test proved diagnostically valuable although it cannot be considered to represent a generally reliable testing method for drug-induced liver disease. Clinical, laboratory and histological findings are typical with a wider range of drugs, but liver biopsy provides the most reliable criteria. Clinical suspicion and stopping the intake of potentially noxious drugs are of importance. The reexposition test should be reserved to exceptional cases.",1
7622,2203305,Apparent biliary pseudolithiasis during ceftriaxone therapy,"""Biliary pseudolithiasis has been reported in patients who received ceftriaxone therapy. To examine this phenomenon further, serial gallbladder sonograms were evaluated in 44 adult patients who received intravenous ceftriaxone at 2 g or a placebo daily for 14 days in a double-blind controlled study. Ultrasound examinations of gallbladders were performed on days 1 and 14 of therapy and 2 weeks posttherapy if abnormalities were observed on day 14. Eight patients were unevaluable because of abnormal base-line gallbladder sonograms. Thirty-six patients (ceftriaxone, n = 28; placebo, n = 8) demonstrated normal baseline gallbladder sonograms and were evaluated for the development of change. A total of 6 of 28 (21.4%) ceftriaxone-treated patients and 1 of 8 (12.5%) patients who received the placebo demonstrated abnormal gallbladder sonograms on day 14 (P = 0.491). Four of the six ceftriaxone-treated patients demonstrating abnormal sonograms were clinically asymptomatic, while two patients reported vomiting. The abnormal sonograms of gallbladders of patients treated with ceftriaxone returned to normal between 9 and 26 days posttherapy. These data suggest an association between ceftriaxone treatment and the development of gallbladder abnormalities on ultrasound examination which resolve spontaneously on discontinuation of ceftriaxone therapy.""",1
7623,2208575,A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors,"A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was greater than 95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing's sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.",1
7624,2215004,[Erythromycin caused liver injury and gallbladder inflammation],,1
7625,2220897,Pyrrolizidine poisoning,,1
7626,2227290,Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility,"""Ceftriaxone, a semisynthetic third-generation cephalosporin, has recently been associated with biliary sludge formation. Analysis of the biliary concretions induced by this agent shows a calcium salt of ceftriaxone. The present in vitro studies were undertaken to provide insight into the pathogenesis of ceftriaxone-associated biliary sludge formation by evaluating possible interactions that may exist between calcium, bile salts, and ceftriaxone. Ceftriaxone possessed high calcium-binding affinity. The formation constant for the calcium ceftriaxone salt at 37 degrees C was about 157.3 L/mol; stoichiometry of the salt was 1:1, i.e., calcium ceftriaxone. The calcium-binding property of ceftriaxone was observed to be additive to that of taurocholate in mixed taurocholate-ceftriaxone solutions. Although the solubility product constant for calcium ceftriaxone was only 1.62 x 10(-6) mol/L2, marked metastability was observed; neither visible nor microscopic precipitates developed until the [Ca2+] x [ceftriaxone] ion product exceeded the solubility product constant by a factor of 10.4. Metastability of the calcium ceftriaxone salt was also observed in human gallbladder bile in vitro. Estimates of human biliary calcium ceftriaxone solubility in vivo were than calculated from previously-reported values for biliary [Ca2+], [ceftriaxone], and from the solubility product constant as defined in this study. Calculated saturation indices for calcium-ceftriaxone in human bile generally increased (corresponding to a decrease in solubility) with increasing ceftriaxone dose. At doses less than or equal to 1 g, saturation index was well within the metastable range of this calcium-salt. However, at doses greater than or equal to 2 g, the saturation index surpassed the metastable limit. Under these conditions, precipitation of ceftriaxone could occur. It was concluded that the development of ceftriaxone-induced biliary sludge is a solubility problem that occurs in patients receiving high-dose treatment (greater than or equal to 2 g). This study proposes that the risk of developing ceftriaxone-associated biliary """"pseudolithiasis"""" increases with increasing ceftriaxone dose and in patients with impaired gallbladder emptying.""",1
7627,2232043,Diclofenac-associated hepatotoxicity,"Diclofenac sodium, a phenylacetic acid-derived nonsteroidal anti-inflammatory drug (NSAID) recently released in the United States, was associated with the development of significant hepatitis in seven patients, with one associated death. Signs and symptoms developed within several weeks of initiation of drug use and generally resolved 4 to 6 weeks following discontinuation of use of the drug. The only patient rechallenged with the drug developed a recurrence of her hepatic abnormalities. In one patient, fatal, fulminant hepatitis developed despite early withdrawal of the drug. Review of the European literature disclosed three additional fatalities associated with diclofenac therapy. It is unclear whether the incidence of hepatotoxicity is higher with this drug compared with other nonsteroidal anti-inflammatory drugs. Careful patient monitoring is advised, and prompt discontinuation of the drug is suggested when signs or symptoms of liver disease develop.",1
7628,2239806,Mitoxantrone and constant infusion etoposide for relapsed and refractory acute myelocytic leukemia,"""In an effort to search for new, synergistic and non-cross-resistant antileukemic regimens, the Cancer and Leukemia Group B (CALGB) investigated the activity and toxicity of mitoxantrone in combination with etoposide for the reinduction of patients with relapsed or refractory acute myelocytic leukemia (AML). Mitoxantrone, 12 mg/m2 daily for 3 days, was combined with three dose levels of etoposide, 100, 150 and 200 mg/m2 daily by constant infusion for 5 days. There were 19 male and 13 female patients, with a median age of 46 (range, 21-74). Of these, nine were primarily refractory to daunorubicin and ara-C; 17 had one prior complete remission (CR), five had two prior CR, and one had three prior CR. Thirteen patients were entered at the first dose level, 11 were entered at the second, and eight at the third. All but one patient, whose death occurred within the first 2 days of treatment, are evaluable for toxicity. There were five CR (four at the first and one at the second dose level) and six partial remissions (PR) (three at the first dose level and three at the second). Unmaintained responses lasted 6-33 weeks. Median survival for all patients was 12.6 weeks. Anti-leukemic effects with severe marrow hypoplasia were observed in all patients; severe nausea and vomiting were seen in four. Severe mucositis, often indistinguishable from superimposed candidiasis, occurred in 40% of all patients; it was associated with dose-limiting esophagitis (three of seven evaluable patients) at the highest etoposide dose. Hepatic and renal dysfunction was severe in three patients; no treatment-related severe pulmonary or cardiac toxicity was observed. Posttreatment infectious complications were severe in 11 patients. In three cases, they were fatal--an incidence not dissimilar from that of other reinduction regimens in heavily pretreated patients. The regimen appears to be active; the combination of mitoxantrone, 12 mg/m2 daily for 3 days, with etoposide, 150 mg/m2/day for 5 days, by constant intravenous infusion is now being explored by the CALGB in a randomized phase II study against mitoxantrone plus diazoquinone and diazoquinone plus etoposide.""",1
7629,2242059,"Aspirin, hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis","Levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in patients with rheumatoid arthritis from 5 centers involved in the Arthritis, Rheumatism, and Aging Medical Information System were correlated with the use of specific antirheumatic medications. Elevated levels of SGOT and SGPT were most frequent in patients taking salicylates and methotrexate (MTX) and least frequent in patients taking hydroxychloroquine. The combination of MTX and salicylates greatly increased the frequency of abnormal liver enzyme values. In contrast, the addition of hydroxychloroquine to a regimen of either MTX or aspirin essentially eliminated the SGOT and SGPT abnormalities. Results from all 5 centers were consistent and remained so after adjustment for age, sex, and disease duration. Knowledge of these important drug interactions may permit continuation of MTX therapy in patients in whom the drug might otherwise be discontinued.",1
7630,2246687,Late-onset ornithine transcarbamylase deficiency in male patients,"We report on 21 male patients who presented after 28 days of age with ornithine transcarbamylase (OTC) deficiency, which we define as late-onset OTC deficiency. These patients appeared normal at birth, but irritability, vomiting, and lethargy, which were often episodic, later developed. The age at presentation ranged from 2 months to 44 years. Biochemical testing revealed hyperammonemia, hyperglutaminemia, hypocitrullinemia, increased urinary orotate excretion, and decreased liver OTC activity measured in vitro, which ranged from 0% to 15% of normal. Male patients who were older at presentation had a somewhat different pattern of presenting symptoms and were more likely to die. These data illustrate the phenotypic variability of OTC deficiency. Unexplained episodes of repetitive or protracted vomiting in association with progressive alterations in behavior or neurologic findings should suggest the diagnosis of a urea cycle defect (or another symptomatic inborn error of metabolism), regardless of the age or medical history of the patient.",1
7631,2254636,Norfloxacin-induced hepatotoxicity,,1
7632,2257004,"Methotrexate, liver abnormalities and RA",,1
7633,2259936,Hepatic granulomas--an experience over the last 8 years,"Twenty cases of hepatic granulomas seen in the Department of Medicine over the period of 8 years from 1981-1988 were reviewed. Prolonged fever and jaundice were the commoner presentations. While the aetiology was varied, patients with tuberculosis and idiopathic causes formed the major groups. There were also 2 rare causes, one due to cytomegalovirus infection and the other a result of allopurinol hypersensitivity. The idiopathic group of cases fared well but those with tuberculosis did badly and 2 out of 6 died. The absence of pulmonary involvement and the high incidence of jaundice and liver dysfunction in the patients with tuberculosis were the other striking features.",1
7634,2262129,[Hepatitis caused by benzarone: a second case],,1
7635,2271847,Cholestasis associated with cinnarizine,,1
7636,2279511,Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breast-feeding,"We report a 3-week-old boy with cholestatic hepatitis, most likely due to carbamazepine exposure during pregnancy and breastfeeding. Cholestasis resolved after cessation of nursing. Liver function test results and histological findings were compatible with a drug-induced hepatitis. Other causes were excluded. While carbamazepine-induced hepatitis is well known in children and adults, it has never been described in association with prenatal exposure and/or breast-feeding.",1
7637,2291149,[Hemolytic anemia induced by Chelidonium majus. Clinical case],"A case of haemolytic anaemia secondary to oral ingestion of a Chelidonium majus extract is presented. It coursed with intravascular haemolysis, renal failure, liver cytolysis and thrombocytopenia. The direct Antiglobulin test was positive (4+), IgG+C'. The patient was treated with steroids, red cell and platelet transfusion and also twice with an haemodialytic treatment, with complete resolution of the clinical features about the 12th day. A complete bibliographic revision from 1966-1989 was performed and no cases like this one were found during that period, so this could the first one reported.",1
7638,2297290,Fulminant hepatic failure associated with intravenous erythromycin lactobionate,"Fatal fulminant hepatic failure accompanied by brisk hemolysis developed in an elderly man after intravenous administration of erythromycin lactobionate for a lower respiratory infection. To our knowledge, this is the first case of fatal hepatotoxicity associated with intravenous erythromycin therapy. Erythromycin should be added to the list of drugs that can cause fulminant hepatic failure.",1
7639,2301746,Antibody assays for the detection of patients sensitized to halothane,"Sera from patients with a clinical diagnosis of halothane hepatitis have been shown to contain antibodies that react with liver microsomal proteins (100, 76, 59, 57, and 54 kDa) covalently altered by the trifluoroacetyl (TFA) halide metabolite of halothane. In the present study, rapid and sensitive enzyme-linked immunosorbent assays for the detection of these antibodies have been evaluated. A recently described method that utilizes TFA-rabbit serum albumin as test antigen was studied employing a large population of halothane hepatitis and control patients. Several problems were discovered with the assay that were not previously recognized. The assay was then compared directly with methods that utilize as test antigens either liver microsomes or purified TFA proteins from halothane-treated rats. Sixty-seven percent of patients with a clinical diagnosis of halothane hepatitis tested positive for antibodies when the test antigens were either TFA-rabbit serum albumin or liver microsomes. This value was increased to 79% when the purified TFA-57 kDa, TFA-76 kDa, and TFA-100 kDa proteins were used as test antigens. These results indicate that the specificity and sensitivity of enzyme-linked immunosorbent assay methods for the detection of patients' antibodies may be increased significantly by utilizing the purified TFA microsomal proteins as test antigens.",1
7640,2306066,Fulminant hepatitis as a consequence of reactivation of hepatitis B virus infection after discontinuation of low-dose methotrexate therapy,,1
7641,2307948,Thioridazine-induced non-icteric hepatotoxicity. Report of a case,,1
7642,2311846,[A case of acute hepatitis caused by flutamide],,1
7643,2317014,Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis,"4-Aminopyridine (4-AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4-AP on both visual and motor signs in MS. Twenty temperature-sensitive male MS patients were given either 10 to 25 mg of 4-AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4-AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4-AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration.",1
7644,2322916,Cholestatic jaundice associated with lovastatin (Mevacor) therapy,,1
7645,2324442,[Fatal toxic hepatitis in pregnancy. A discussion of the role of methyldopa],"The authors report a case of toxic hepatitis in a woman of 22 years of age in the third trimester of her first pregnancy treated by methyldopa for hypertension of pregnancy which was diagnosed at 33 weeks of amenorrhoea. The prodromal symptoms were mild and consisted of nausea, vomiting and rise in temperature and this phase was associated with febrile jaundice without pruritus and it was only associated with coagulation disorders in the third stage of labour. This was a case of mixed cytolytic hepatitis (ASAT x 3N) and cholestasis (x 1.5N). The outcome was fatal. The patient died three days after delivery following haematemesis and renal failure as well as hepatic encephalopathy. The main diagnostic feature was acute hepatic stasis in spite of the absence of pruritus and the presence of a raised temperature after hematolytic, viral and obstructive causes had been eliminated. Histology confirmed that there was toxic hepatitis. This aetiology was suggested by the timing of the symptoms after MD (methyldopa) had been taken. Elkington described methyldopa hepato-toxicity in 1969. Fatal cases in the literature were in patients who were over 40 years of age. Methyldopa is used in pregnant women because of its safety as far as the fetus is concerned. Mechanism by which it causes toxic hepatitis is a combination of abnormal metabolism (the cytochrome P450 chain produces an antigen) and an immune reaction in response to this antigen and these explain why such severe and potentially fatal forms of the condition exist.(ABSTRACT TRUNCATED AT 250 WORDS)",1
7646,2324882,Hepatic hypervitaminosis A: a familial observation,"Four siblings with hepatic fibrosis are described. The liver damage in these patients was secondary to chronic ingestion of massive doses of vitamin A for congenital ichthyosis. Although the extrahepatic manifestations were helpful in the diagnosis of hypervitaminosis A, the distinctive features of hepatic histopathology were confirmatory. The plasma concentrations of vitamin A and retinol-binding protein were misleading. The recovery from the liver damage in these patients was slow despite a complete withdrawal of the vitamin A intake. These cases show the importance of hepatic vitamin A assessment in the diagnosis of hepatic fibrosis.",1
7647,2324894,Efficacy and safety of a diazepam and meperidine combination for pediatric gastrointestinal procedures,"""Little has been published about outpatient sedation for pediatric patients. We designed a study to evaluate the efficacy and adverse effects of diazepam and meperidine in combination for sedation in ambulatory pediatric patients undergoing endoscopy, colonoscopy, or liver biopsy. Thirty patients (7 months-20 years) were observed. Each patient received a single combined dose of intravenous diazepam and meperidine. The standard dose was 0.1 mg/kg for diazepam and 2.0 mg/kg for meperidine. In patients weighing greater than 100 lb, set doses of meperidine (100 mg) and diazepam (5 mg) were used. The time to achieve sedation and the vital signs were measured; cooperation, emotional state, and drowsiness were rated before, during, and after procedures. The amnesic effect was noted, as were any adverse effects. Diazepam and meperidine were effective in 26 of 30 patients, with sedation generally produced within 2-3 min. Cooperation and emotional state improved significantly following drug administration (p less than 0.05). When a prospective 24-h telephone follow-up study was instituted in 40 consecutive patients receiving diazepam and meperidine no significant adverse effects were noted. Only 20% of patients old enough to be questioned remembered the procedure. Diazepam and meperidine in combination appear to be effective and safe in pediatric patients undergoing gastrointestinal procedures. Prolonged monitoring of patients does not appear necessary in this patient population.""",1
7648,2326558,"[Erythema multiforme, aplasia, cholestatic hepatitis during treatment with Augmentin (amoxicillin + clavulanic acid)]",,1
7649,2327233,Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system,"A survey was made of 505 reports on 713 adverse reactions to carbamazepine submitted to the Swedish Adverse Drug Reactions Advisory Committee from 1965-1987. For the period after 1972, the relation between the reports and sales statistics could be investigated. The total incidence of reported adverse reactions to carbamazepine was 4.5 per million defined daily doses (DDD), corresponding to 2.7 per million prescribed daily doses (PDD). Most often reported were skin reactions (48%), but reports on haematological (12%) and hepatic disorders (10%) were also frequent. Virtually all hepatic disorders and severe skin reactions, as well as the majority (60%) of the haematological reactions, occurred within the first 2 months of treatment. In view of the very low incidence of reported serious blood dyscrasias, such as pancytopenia (0.04/million PDD) and agranulocytosis (0.06/million PDD), continuous haematological monitoring seems to be of little value. The elderly appear to be at increased risk of developing blood dyscrasias and liver reactions, and alcohol abusers seem to represent a high-risk group for developing serious skin reactions.",1
7650,2327391,Fatal submassive necrosis of the liver associated with piroxicam,"A 64-yr-old woman developed acute hepatitis after 3 wk of treatment with 40 mg/day of piroxicam (Feldene). Jaundice was preceded by a skin rash associated with eosinophilia. Despite withdrawal of the drug, she developed severe hepatocellular failure and died 53 days after the onset. Hepatitis was attributed to piroxicam because of the absence of other etiological factors.",1
7651,2327848,Methotrexate-induced cirrhosis requiring liver transplantation in three patients with psoriasis. A word of caution in light of the expanding use of this 'steroid-sparing' agent,"Methotrexate has been used for many years to treat refractory psoriasis. Three cases of methotrexate-induced cirrhosis requiring orthotopic liver transplantation are presented to emphasize the importance of strict adherence to published criteria for patient selection, monitoring of cumulative drug dosages, and the performance of serial liver biopsies. Each patient had been treated with long-term methotrexate therapy (cumulative doses far in excess of 1.5 g) without undergoing serial liver biopsies, contrary to well-established treatment guidelines. Caution must be exercised in using methotrexate as a steroid-sparing agent in the treatment of inflammatory diseases because of its potential to cause severe hepatotoxic effects with long-term usage and cumulative doses above 1.5 g. Patients easily become psychologically dependent on the drug, and physicians need to guard against the false sense of security engendered by normal results on liver function studies.",1
7652,2330646,[Adverse effects of propofol (Diprivan)],,1
7653,2331957,Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis,"""In a double-blind, randomized, comparative trial of the prokinetic drug cisapride and the H2-blocker cimetidine, mucosal healing and changes in symptoms of gastroesophageal reflux were evaluated in patients with erosive reflux esophagitis. The patients were treated with either cisapride, 10 mg four times a day (N = 36) or cimetidine, 400 mg four times a day (N = 37) for six weeks, or for 12 weeks if mucosal healing was not obtained by week 6. Upon entry, two thirds of the patients in each group had grade I (Savary-Miller) esophagitis, and the remainder grade II or III. At the end of treatment, endoscopy showed mucosal healing in 56% (38-72%; 95% confidence interval) of cisapride and 57% (39-73%; 95% confidence interval) of cimetidine patients. After six weeks, both drugs significantly (P less than 0.01) decreased the intensity and frequency of heartburn, regurgitation, and the postural syndrome. No significant intergroup differences were found regarding endoscopic parameters or the improvement of heartburn and regurgitation. Concomitant antacid use was also comparable. Adverse effects were reported by four cisapride and nine cimetidine patients. These results indicate that the effects of cisapride compare well with those of cimetidine in terms of both esophageal mucosal healing and symptom relief.""",1
7654,2332596,Phenobarbital hepatotoxicity in an 8-month-old infant,"Severe hepatotoxicity from phenobarbital occurred in an infant boy who had a complicated illness with chronic bilateral subdural hematomas and sepsis. Skin rash began after 2 weeks of treatment, and signs of hepatocellular failure developed 3 weeks after phenobarbital had been started. Signs of severe liver disease included elevated aminotransferases, conjugated hyperbilirubinemia, significant coagulopathy, hepatosplenomegaly and ascites. Other features of this adverse drug reaction were unremitting fever, leukocytosis with eosinophilia and atypical lymphocytosis, and proteinuria. Sepsis, viral hepatitis, and metabolic liver disease were excluded. The child was on no other medication and had been previously well. In-vitro rechallenge of the patient's lymphocytes with cytochrome P-450 generated metabolites of phenobarbital showed extensive cytotoxicity compared to control. These data support the hypothesis that a defect in drug detoxification was responsible for the child's susceptibility to this drug hepatotoxicity.",1
7655,2337515,Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia,"""In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT] during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT less than or equal to 40 IUl-1. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r greater than 0.70, P less than 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk). Patients with a mATMT greater than 40IUl-1 had a lower risk of relapse than patients with a mATMT less than or equal to 40IUl-1 (4.5 year CCR: 0.70 and 0.50, P = 0.06; and 4.5 year haematological remission: 0.83 and 0.63, P = 0.03). The favourable outcome for patients with hepatoxicity could be demonstrated for all risk groups.""",1
7656,2339451,High-dose intravenous naloxone for the treatment of acute ischemic stroke,"""To evaluate the safety and possible efficacy of high-dose naloxone for the treatment of acute cerebral ischemia, 38 patients received a loading dose of 160 mg/m2 over 15 minutes followed by a 24-hour infusion at the rate of 80 mg/m2/hr. Nausea and/or vomiting were common side effects. Naloxone was discontinued in seven patients (because of hypotension in one, bradycardia and hypotension in two, myoclonus in one, focal seizures in two, and hypertension in one); all seven patients responded to treatment and no permanent sequelae to naloxone were noted. Twelve of the 38 patients showed early neurologic improvement (by completion of the naloxone loading dose). However, there was no correlation between such a loading dose response and clinical outcome at 3 months. Our experience suggests that naloxone is safe at the dose used, but data for efficacy are inconclusive.""",1
7657,2343506,[Fatal hepatitis caused by disulfiram],"A case of fatal fulminant hepatitis following treatment with disulphiram in a man aged 34 year is reported. Acute toxic hepatitis produced by disulphiram is a rare but serious side effect with a lethality about 40%. In the case reported here, immediate withdrawal of disulphiram administration on the earliest signs of hepatitis did not prevent toxic development of severe hepatic necrosis.",1
7658,2344115,Busulfan and veno-occlusive disease of the liver,,1
7659,2344802,Liver injury from cyclosporine A,"To assess the incidence of cyclosporine A-induced hepatotoxicity, we retrospectively analyzed liver biochemical test results in 59 patients with endogenous uveitis who received cyclosporine A. All patients had normal liver tests before treatment and had at least six determinations during a 6- to 36-month course of therapy with cyclosporine A at a dose of 2-10 mg/kg/day. Thirty-four (58%) patients developed at least one abnormality of liver tests, and 19 (32%) had a prolonged pattern of abnormalities. The usual abnormalities consisted of a mild, transient increase in alkaline phosphatase levels occasionally accompanied by slight elevations in serum bilirubin and aminotransferase activities. Peak alkaline phosphatase levels ranged from 125 to 243 units/liter and persisted for seven days to 48 months. Thus, biochemical evidence of mild cholestatic liver injury was common in patients receiving cyclosporine A. These abnormalities are usually self-limited and asymptomatic but may cause diagnostic difficulty if a preexisting liver disease is present.",1
7660,2346127,Frequency of veno-occlusive disease of the liver in bone marrow transplantation with a modified busulfan/cyclophosphamide preparative regimen,"Veno-occlusive disease (VOD) of the liver is a major complication of bone marrow transplantation (BMT). The overall frequency of VOD has ranged from 20 to 30%, with a mortality rate greater than 40%, as reported by centers utilizing cyclophosphamide (Cy) and total body irradiation (CyTBI) or various chemotherapeutic regimens, including the busulfan (Bu) (4 mg/kg for 4 days) and Cy (50 mg/kg for 4 days) (BuCy4) combination. Since 1986, Hahnemann University (HU) has primarily used the BuCy2 regimen, i.e., Bu (4 mg/kg for 4 days) followed by Cy (60 mg/kg for 2 days). We reviewed 74 consecutive patients who received either an autologous or allogeneic BMT for various malignancies from January 1986 through October 1988 to determine the frequency of VOD. Seven of 74 consecutive patients met clinical criteria for VOD, for a total frequency of 9.5%. Fifty-five patients were conditioned with various other regimens. Only 5 of the patients conditioned with BuCy2 developed VOD (9.1%). This is less than the 25% reported frequency of VOD in patients who received CyTBI (1,000 rads) and less than the 24% reported frequency of VOD in patients who received BuCy4. Only one of seven patients who developed VOD died from the disease. One patient died of sepsis after the VOD had almost completely resolved. The remaining five completely recovered. We conclude that the total Cy dose, and not Bu, is the major factor in the occurrence of VOD in Bu/Cy BMT preparative regimens, and the BuCy2 regimen reduces the frequency of VOD in autologous and allogeneic graft recipients when compared to CyTBI or the BuCy4 regimens.",1
7661,2348423,Treatment of rheumatoid arthritis with higher dose intravenous methotrexate,"""A pilot study evaluated intravenous methotrexate (MTX) (initial dose 40 mg/m2; final dose, 26 mg/m2), weekly for 12 weeks in 10 patients with rheumatoid arthritis who failed oral MTX. Statistically significant differences were noted for all the response variables examined: joint count (p = 0.0017), morning stiffness (p = 0.014), global assessment (patient, p = 0.0032, physician, p = 0.029), Arthritis Impact Measurement Scale (p = 0.0004), erythrocyte sedimentation rate (p = 0.012), grip strength (right p = 0.044, left p = 0.011). All 7 patients who completed the 12-week treatment period fulfilled the predetermined criteria for response. Intravenous MTX at these doses has potential efficacy in this patient group.""",1
7662,2355439,Acute hepatic failure associated with the use of low-dose sustained-release niacin,,1
7663,2357675,Cholestatic jaundice associated with lovastatin (mevacor) therapy,,1
7664,2362104,Acute hepatitis after tetrahydroaminoacridine administration for Alzheimer's disease,"Tetrahydroaminoacridine administration has been proposed as a treatment for Alzheimer's disease. Although recent studies have shown that tetrahydroaminoacridine administration can be associated with mild or moderate liver dysfunction, to our knowledge, no case of symptomatic hepatitis with severe liver lesions has heretofore been reported. We describe a patient who developed jaundice after receiving tetrahydroaminoacridine for three weeks. Histologic examination showed extensive hepatocellular necrosis. Tetrahydroaminoacridine withdrawal was followed by the disappearance of jaundice within a few days and complete recovery within 5 weeks. This case shows that tetrahydroaminoacridine administration can induce marked liver cell necrosis resulting in symptomatic acute hepatitis.",1
7665,2365984,Flutamide-induced liver failure,"Two cases of clinically manifest liver failure in patients with metastatic prostatic cancer treated with the non-steroidal antiandrogen flutamide combined with a luteinizing hormone-releasing hormone analogue are described. One patient developed severe hepatic insufficiency with jaundice, ascites and hepatic coma. The condition reversed after discontinuation of flutamide. The other patient only became jaundiced with a biochemical cholestatic pattern. Previous reports of hepatic adverse reactions only include elevated transaminase levels without clinical manifestations. The morphological lesions in the liver biopsy and the clinical condition may be due to a reversible interaction with metabolic processes in the hepatocytes.",1
7666,2369419,Hepatitis with bridging fibrosis and reversible hepatic insufficiency in a woman with rheumatoid arthritis taking methotrexate,"A patient with seropositive rheumatoid arthritis developed ascites while taking weekly doses of methotrexate (MTX). Her serum transaminase and albumin levels were normal. A liver biopsy revealed chronic hepatitis with bridging fibrosis and piecemeal necrosis. Upon discontinuation of MTX, her ascites resolved, and her arthritis became more active. This is the third report of reversible hepatic decompensation associated with prolonged MTX therapy in patients with rheumatoid arthritis.",1
7667,2371992,Piroxicam hepatotoxicity,,1
7668,2374409,An infant fatality due to hydroxychloroquine poisoning,"A 2 1/2-year-old boy was hospitalized following ingestion of an estimated 60 tablets of 200-mg hydroxychloroquine. Upon death from cardiorespiratory arrest, analytes from the stomach, small intestine, liver, and plasma were examined using UV spectroscopy, thin-layer chromatography, and gas chromatography/mass spectrometry. Results indicate modest drug amounts in the stomach and small intestine, but much higher levels in the blood and liver extracts, suggesting that a considerable overdose was consumed.",1
7669,2375560,Polymyalgia and minoxidil,,1
7670,2375835,Accidental overdose of insufflated colchicine,"""An accidental overdose of colchicine by nasal insufflation occurred when the colchicine was mistaken for methamphetamine. Colchicine insufflation is not believed to be a common practice among drug abusers; however, its physical appearance was similar enough to methamphetamine for it to be mistaken for that drug of abuse. In this case a 29-year-old White man presented to the emergency room 3 days after he 'snorted' approximately 200mg of colchicine powder. The colchicine was used as a 'root stimulator' in gardening by the patient's brother and stored in the same cabinet as the methamphetamine. Within 24 hours of exposure the patient began experiencing gastrointestinal distress and myalgia, which eventually prompted him to seek medical attention. The clinical course included hypocalcaemia (69 mg/L--day 5), hypophosphataemia (10 mg/L--day 5) and thrombocytopenia (19 X 10(3)/mm3 - day 8), all of which are consistent with colchicine toxicity. The patient improved with supportive care and electrolyte replacement, and was discharged after an 8-day hospitalisation.""",1
7671,2388211,Hepatic fibrosis with the use of methotrexate for juvenile rheumatoid arthritis,"Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. One complication of MTX is hepatotoxicity. Although liver function tests may be abnormal with its use, in this setting they do not correlate well with the development of hepatic fibrosis. Periodic liver biopsy is required to monitor for the hepatotoxic changes secondary to MTX. We describe and discuss the case of a 17-year-old woman who developed evidence of hepatic fibrosis after 3 years of MTX therapy.",1
7672,2392230,Dantrolene sodium and hepatic injury,"This is a report on hepatic adverse events associated with dantrolene therapy. All cases reported to the manufacturer are included, from all sources, through 1987. Of 122 cases containing sufficient data to analyze, 47 patients had asymptomatic transaminase elevations, 12 had additional mild (less than or equal to 2.5 mg/dl) hyperbilirubinemia, 36 had jaundice, and 27 patients died. There is an overrepresentation of women over 35 years and patients with multiple sclerosis in the fatal group compared with the study population as a whole (not statistically significant). Mean dantrolene dose was 582 mg/d in fatal cases and 263 mg/d in the nonfatal group. Generally, at least 2 months of therapy was given before injury occurred. Concomitant drugs and nonhepatic, drug-independent disease were associated with a fatal outcome. Serum bilirubin may be predictive for death (mean of 17.0 mg/dl in the fatal group compared with 6.5 mg/dl in nonfatal cases). Of available biopsy reports, 68% included chronic active hepatitis or precirrhotic/cirrhotic lesions. Physicians should monitor liver function in patients taking dantrolene.",1
7673,2396863,Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis,"""The liver histology of 52 patients treated with intermittent low dose pulse methotrexate for rheumatoid arthritis was evaluated using a modification of the Roenigk grading system. Patients studied had had an average of 3.2 years of treatment or had received 1.7 g methotrexate. No patient had cirrhosis; 15 (29%) patients had evidence of mild fibrosis. Histological abnormalities were not predicted by liver function test changes, with the exception that hypoalbuminaemia occurred in 60% of those with grade IV (modified criteria) findings. The need for liver biopsy in patients with rheumatoid arthritis treated with methotrexate before two years or 1500 mg of treatment has not been established. Whether serial liver biopsies will be needed beyond this time has yet to be determined.""",1
7674,2397873,[Hepatic cholestasis probably due to the combination of amoxicillin and clavulanic acid],,1
7675,2400216,Trends in the incidence of Reye's syndrome and the use of aspirin,"In 1986 there was a public warning in the United Kingdom about a link between the consumption of aspirin and Reye's syndrome. To find out if the use of aspirin and paracetamol in children had altered, and whether the incidence of Reye's syndrome had changed since a previous study, parents were interviewed in Belfast and London, and the British Reye's Syndrome Surveillance System data were reviewed. Children with febrile illnesses were 17 times more likely to have received aspirin before admission to hospital in 1985/6 compared with 1988/9. Only 21 Belfast parents (40%) and 13 London parents (27%) had heard of Reye's syndrome and only 12 in Belfast (23%) and seven in London (15%) knew of its association with aspirin, suggesting a continuing need for public education. Cases of Reye's syndrome declined both in numbers (from a peak of 79 in 1983/4 to 19 in 1988/9) and in median age. Of the 418 reported cases, the diagnosis was subsequently revised in 89, most often (in 31 of 89, 36%) to 'inborn errors of metabolism'.",1
7676,2402650,Acetaminophen hepatotoxicity in the alcoholic,"In a retrospective review from 1987 to 1989, we identified seven alcoholics who had severe acute hepatocellular injury soon after using acetaminophen for therapeutic purposes and who had no suicidal intent. All had markedly elevated serum transaminase values (aspartate aminotransferase greater than 4000 U/L) and prolonged prothrombin times. Three died. Use of acetaminophen by the alcoholic patient is potentially lethal.",1
7677,2403975,Histopathologic analysis of suspected amiodarone hepatotoxicity,"This analysis of the morphology of suspected amiodarone (AD) liver disease is based on a study of liver specimens from 17 individuals. Changes similar to alcoholic liver injury were commonly seen. Steatosis, both macrovesicular and microvesicular, was the most frequent histopathologic feature. Ballooning of hepatocytes, Mallory bodies, and fibrosis were also common. Other changes included nuclear unrest, acidophilic bodies, foam cells, glycogenated nuclei, and portal inflammation. Characteristic lamellar lysosomal inclusion bodies representing phospholipidosis were found in two of 14 specimens studied ultrastructurally. These changes of pseudoalcoholic hepatitis and/or phospholipidosis were present in liver specimens from asymptomatic, anicteric patients with mild elevations in serum aminotransferase or alkaline phosphatase values with or without hepatomegaly, as well as in patients with clinically overt symptoms of hepatotoxicity. Phospholipidosis appears to be a generalized systemic effect of cationic amphophilic compounds, such as AD. The cytotoxic pseudoalcoholic changes appear to be an independent phenomenon in susceptible patients, whom we speculate may have been unable or less able to metabolize AD through normal pathways. The true incidence of hepatic injury from AD remains to be determined from prospective evaluations of pretreatment and follow-up liver biopsies.",1
7678,2404445,Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety,"""STUDY OBJECTIVE: To determine the efficacy of stepwise incremental doses, to compare twice- with thrice-daily administration of the same total daily dosage of the long-acting somatostatin analog SMS 201-995 (octreotide, Sandoz Australia, Sydney, Australia), and to evaluate the risk for cholelithiasis after long-term therapy for acromegaly. DESIGN: Nonrandomized, controlled trial. SETTING: Tertiary care center at a medical research institute. PATIENTS: Sequential sample of 19 patients with active acromegaly. Twenty-five age-matched normal subjects were also studied to establish the normal range for growth hormone (GH) and insulin-like growth factor 1 (IGF-1). INTERVENTIONS: Eight patients (group 1) were treated with 100, 250, and 500 micrograms twice daily of octreotide, then switched to 333 micrograms three times daily, whereas 11 patients (group 2) were treated with 100, 200, 300, and 500 micrograms three times daily. Each treatment stage lasted 6 to 12 weeks. MEASUREMENTS AND MAIN RESULTS: Octreotide, 100 micrograms administered twice or thrice daily, significantly reduced mean 12-hour and nadir GH (P less than 0.01), IGF-1 (P less than 0.05), and hand volume (P less than 0.05). Dose increment to 500 micrograms in both groups did not further reduce mean 12-hour GH, nadir GH, or hand volume. Switching from 500 micrograms twice daily to 333 micrograms thrice daily resulted in significant (P less than 0.05) reduction of mean 12-hour GH, IGF-1, and hand volume. Normalization of mean 12-hour GH and IGF-1 occurred in 8 of 19 patients; 7 of the 8 patients had pretherapy mean 12-hour GH below 20 mIU/L. The pretherapy mean blood glucose was a significant negative predictor (r = -0.89) of the change in mean blood glucose during therapy. Gallstones were present in 9 of 18 patients after therapy. CONCLUSION: Thrice-daily was more effective than twice-daily administration of octreotide, and dose increments above 100 micrograms thrice daily did not confer additional benefit. Biochemical remission was achieved in 40% of patients and was dependent on the GH concentration at initiation of treatment. Cholelithiasis is a risk of octreotide therapy. Octreotide is effective and can be considered as a first-line therapy in patients with acromegaly with mean pretherapy GH concentrations below 20 mIU/L. In patients with mean GH over 20 mIU/L, octreotide may be used as an adjuvant to surgery or radiotherapy.""",1
7679,2406933,Long-term buspirone therapy for chronic anxiety: a multicenter international study to determine safety,"""This report presents results from an international multicenter trial of the safety of buspirone in the treatment of anxiety disorders for periods up to one year, if needed; 424 patients were treated for six months, and 264 patients completed a full year of treatment. Chronic use of buspirone for up to 52 weeks was associated with emergence of no new or unexpected side effects that were not previously reported during shorter periods of treatment. Most patients were successfully managed on daily doses ranging from 15 to 30 mg/day. When buspirone therapy was abruptly discontinued after more than six months of therapy, assessments of patients yielded no evidence of a withdrawal syndrome or unusual events. Although long-term anxiolytic drug therapy is not generally recommended, this open study provides evidence of the potential usefulness of buspirone when used for up to one year. As a general guideline, when an anxiolytic agent is used for several months or longer to treat chronic anxiety, the need for drug therapy should be reevaluated periodically.""",1
7680,2412930,Liver adenomatosis. An entity distinct from liver adenoma?,"""From 1979 to 1984, we followed the cases of 3 men (aged 13, 31, and 75 yr) and 2 women (aged 38 and 45 yr who had never used oral contraceptives) suffering from liver adenomatosis, an uncommon lesion consisting of numerous benign adenomas in an otherwise normal hepatic parenchyma. During the same period, we observed 20 cases of liver adenoma (one tumor in 18 patients and two tumors in 2 patients). From these cases and the review of previously reported cases of liver adenomatosis and series of liver adenoma, the following distinctive characteristics of these two benign conditions of the liver can be outlined: liver adenomatosis affects men and women, whereas liver adenoma predominantly affects women; liver adenomatosis is unrelated, whereas liver adenoma is closely related, to oral contraceptive use; increases in serum alkaline phosphatase and gamma-glutamyl transpeptidase are common in liver adenomatosis, but are uncommon in liver adenoma.""",1
7681,2418169,Clinical toxicity of interferons in cancer patients: a review,"""All major types of human interferons (IFNs) have been purified and clinically administered as antitumor agents. We summarize here experience to date with toxicity of IFNs in cancer patients. The acute syndrome consists of fever, chills, myalgias, arthralgias, and headache, with some variation according to type of IFN, route of administration, schedule, and dose. Fatigue, perhaps reflecting CNS toxicity, is the most prevalent nonacute symptom. At high doses, IFNs are neurotoxic; the abnormalities seen by EEG resemble those in diffuse encephalitis. Hematologic toxicity consists mainly of leukopenia, but anemia and thrombocytopenia occur in some patients. Nausea, vomiting, and diarrhea are the main gastrointestinal symptoms. Elevation of serum transaminases seems to reflect liver toxicity. Renal function is well preserved, except for rare instances of acute renal failure. Cardiac toxicity remains questionable, although heart failure and arrhythmias have been associated with the administration of IFNs. Most, if not all, of these effects are reversible or can be ameliorated. With IFN alpha, the type most widely used in clinical studies, doses of 1 million to 9 million units (MU) are generally well tolerated, but doses greater than or equal to 18 MU yield moderate to severe toxicity. Doses greater than or equal to 36 MU can induce severe toxicity and significantly alter the performance status of the patient.""",1
7682,2427090,Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates,"Serum and red blood cell methotrexate (MTX) levels, as well as hepatic levels of MTX and folate, were analyzed in 24 patients who had received long-term oral MTX weekly for the treatment of rheumatoid arthritis. The serum MTX level peaked rapidly and was insignificant after 24 hours. The red blood cell MTX level was not related to the interval from the last MTX dose. In hepatic tissue obtained by liver biopsy, MTX was found in a predominantly polyglutamated form with depleted hepatic folate stores when compared with baseline specimens. A brief period of therapy with oral folinic acid repleted hepatic folate. It is possible that MTX hepatotoxicity is related to reduced hepatic folate levels and formation of MTX polyglutamates.",1
7683,2427948,Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue,"""We studied the effects of a long-acting analogue of somatostatin (SMS 201-995, Sandoz) in 25 patients with histologically proved metastatic carcinoid tumors and the carcinoid syndrome. This drug was self-administered by subcutaneous injection at a dose of 150 micrograms three times daily. Flushing and diarrhea associated with the syndrome were promptly relieved in 22 patients. All 25 patients had an elevated 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) (mean, 265 mg per 24 hours; range, 14 to 1079), which served as an objective indicator of disease activity. Eighteen of the 25 patients (72 percent) had a decrease of 50 percent or more in their urinary 5-HIAA levels, as compared with the pretreatment values. The median duration of this biochemical response was more than 12 months (range, 1 to greater than 18). Since no serious toxicity was observed, we conclude that SMS 201-995 may be appropriate for use as early therapy in patients with symptoms due to the carcinoid syndrome who have not responded to simpler measures.""",1
7684,2442561,The safety and tolerability of lisinopril in clinical trials,"""The safety and tolerability of lisinopril were assessed in 1,476 patients [1,165 hypertensives and 311 patients with congestive heart failure (CHF)] and 211 normal volunteers. The duration of lisinopril therapy ranged from 1 day to 16 months, with a mean duration of 105 days. In the hypertensive population, the most frequent clinical adverse experiences on lisinopril alone were headache, dizziness, cough, and diarrhea. Not all of these adverse experiences were thought to be drug related. Five percent of patients were discontinued because of adverse clinical experiences; cough and dizziness were the most common reasons for discontinuation. Two of 1,165 (0.17%) hypertensive patients treated with lisinopril died, compared to 0.41% of hypertensive patients on other therapies. Neither case was considered to be drug related. In patients with CHF, the most frequent clinical adverse experiences were dizziness, diarrhea, hypotension, fatigue, headache, and rash. Not all of these adverse experiences were thought to be drug related. The percent of CHF patients discontinuing because of an adverse clinical experience was 7.4%; the most frequent causes for discontinuation were hypotension, dizziness, or renal impairment. Twelve deaths occurred in 311 CHF patients treated with lisinopril (3.9%) compared to 4/104 (3.8%) of CHF patients treated with placebo and 2/65 (3.1%) treated with captopril. Hypotension, orthostatic effects, or dizziness following the initial lisinopril dose occurred infrequently in patients treated with lisinopril. In hypertensive patients with normal renal function, including those treated previously or concomitantly with diuretic therapy, a first-dose hypotensive episode was reported in six of 955, or 0.6%. The incidence was higher (6.7%) in hypertensive patients with impaired renal function.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
7685,2445154,Methotrexate hepatotoxicity and concentrations of methotrexate and folate in erythrocytes--relation to liver fibrosis and cirrhosis,"Assessment of folate and methotrexate concentrations in erythrocytes has been suggested as criterion for when to institute liver biopsy surveillance during methotrexate treatment of psoriasis. We report an investigation of these parameters in thirty psoriatics on long-term methotrexate treatment. The patients were six psoriatics with histologically verified methotrexate-induced liver cirrhosis, eleven patients in which a blind histological evaluation had established a liver fibrosis in progression during treatment, and thirteen patients, who either had no liver fibrosis or no progression in the degree of fibrosis. There was no statistically significant difference in erythrocyte folate between the groups. When the two groups with progression were combined and compared with the group without progressive hepatic disease, erythrocyte methotrexate was found significantly higher in the patients with progression. Individual data, however, did not support the idea that assessment of folate and methotrexate in erythrocytes can limit the number of necessary liver biopsies during methotrexate treatment.",1
7686,2446754,Phase II study of fludarabine phosphate in previously untreated patients with colorectal carcinoma: a Southwest Oncology Group Study,,1
7687,2464794,Fludarabine therapy in chronic lymphocytic leukemia (CLL),"Fludarabine (9-beta-D-arabinofuranosyl 2-fluoro-adenine monophosphate) is a fluorinated analogue of adenine which is relatively resistant to deamination by adenosine deaminase. Phase I clinical trials disclosed significant antitumor activity in lymphoid malignancies. Fludarabine has been used in the treatment of CLL since March, 1985, at a dose of 25-30 mg/m2/day x 5 days each 3-4 weeks by short intravenous infusion. Sixty-eight previously treated patients with CLL are evaluable for response. The median age was 60 years, 50 were male the median number of prior chemotherapy regimens was 2, and the median time from initial chemotherapy to fludarabine was 45 months. Forty-three (63%) were Rai stages 3 and 4, 31 (46%) were Binet Stage C. Twenty patients (29%) obtained a complete remission (CR), defined as peripheral lymphocytes less than 4,000/microliters, no clinical evidence of disease, less than 30% of lymphocytes in the bone marrow (with no residual nodules), or a nodular partial remission, NPR (CR except for residual lymphoid nodules), and 19 (28%) a partial remission (less than 50% reduction in tumor in nodes, liver, spleen and bone marrow and greater than 1 log reduction in the lymphocyte count). The complete remission rate for the various involved sites were blood (69%), liver (52%), spleen (55%), and nodes (48%). The bone marrow was the least responsive site with 16% CR and 44% PR. The number of prior regimens did not have a significant response rate or survival. The serum albumin , alkaline phosphatase, platelet and hemoglobin level all were associated with survival from the start of fludarabine.(ABSTRACT TRUNCATED AT 250 WORDS)",1
7688,2473207,Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate,"Ten histological criteria were evaluated semiquantitatively in the liver biopsies of 60 patients with rheumatoid arthritis (RA) before initiation of methotrexate (MTX) and were compared with 40 biopsies taken during MTX treatment (mean cumulative dose 1.322 mg). Mesenchymal changes (Kupffer cell proliferation, portal tract infiltration) and parenchymal alterations (nuclear variability, ballooning, fatty infiltration) were very common without statistically significant difference between the 2 groups. Slight periportal and/or portal fibrosis was present in 25% of patients without statistical difference between groups. Central fibrosis occurred in 13.5-12.5%. We conclude that liver abnormalities in RA are not related to MTX treatment.",1
7689,2484903,Unusual complications of antithyroid drug therapy: four case reports and review of literature,"Two cases of propylthiouracil-associated acute hepatitis, one case of fatal methimazole-associated hepatocellular necrosis and one case of propylthiouracil-associated lupus-like syndrome are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism.",1
7690,2488482,[Jaundice caused by rifampicin: 3 cases],Three cases are reported of cholestatic hepatitis occurring during treatment with rifampicin for staphylococcal septicemia (2) and tuberculosis (1). There was no previous history of hepatic affection. The administration of rifampicin caused cholestasis alone. No immunoallergic phenomenon has been shown.,1
7691,2491596,[Transaminase elevation and captopril],,1
7692,2493922,Chronic active hepatitis associated with cimetidine,,1
7693,2496789,Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial,"OBJECTIVE: To determine the efficacy of oral nimodipine in reducing cerebral infarction and poor outcomes (death and severe disability) after subarachnoid haemorrhage. DESIGN: Double blind, placebo controlled, randomised trial with three months of follow up and intention to treat analysis. To have an 80% chance with a significance level of 0.05 of detecting a 50% reduction in an incidence of cerebral infarction of 15% a minimum of 540 patients was required. SETTING: Four regional neurosurgical units in the United Kingdom. PATIENTS: In all 554 patients were recruited between June 1985 and September 1987 out of a population of 1115 patients admitted with subarachnoid haemorrhage proved by the results of lumbar puncture or computed tomography, or both. The main exclusion criterion was admission to the neurosurgical units more than 96 hours after subarachnoid haemorrhage. There were four breaks of code and no exclusions after entry. One patient was withdrawn and in 130 treatment was discontinued early. All patients were followed up for three months and were included in the analysis, except the patient who had been withdrawn. INTERVENTIONS: Placebo or nimodipine 60 mg was given orally every four hours for 21 days to 276 and 278 patients, respectively. Treatment was started within 96 hours after subarachnoid haemorrhage. END POINTS: Incidence of cerebral infarction and ischaemic neurological deficits and outcome three months after entry. MEASUREMENTS: Demographic and clinical data, including age, sex, history of hypertension and subarachnoid haemorrhage, severity of haemorrhage according to an adaptation of the Glasgow coma scale, number and site of aneurysms on angiography, and initial findings on computed tomography were measured at entry. Deterioration, defined as development of a focal sign or fall of more than one point on the Glasgow coma scale for more than six hours, was investigated by using clinical criteria and by computed tomography, by lumbar puncture, or at necropsy when appropriate. All episodes of deterioration and all patients with a three month outcome other than a good recovery were assessed by a review committee. MAIN RESULTS: Demographic and clinical data at entry were similar in the two groups. In patients given nimodipine the incidence of cerebral infarction was 22% (61/278) compared with 33% (92/276) in those given placebo, a significant reduction of 34% (95% confidence interval 13 to 50%). Poor outcomes were also significantly reduced by 40% (95% confidence interval 20 to 55%) with nimodipine (20% (55/278) in patients given nimodipine v 33% (91/278) in those given placebo). CONCLUSIONS: Oral nimodipine 60 mg four hourly is well tolerated and reduces cerebral infarction snd improves outcome after subarachnoid haemorrhage.",1
7694,2502367,Exaggerated cholestasis and hepatic fibrosis following simultaneous administration of chlorpromazine and sodium valproate,,1
7695,2513032,Hepatotoxicity of herbal remedies,,1
7696,2521370,Trimetrexate for Pneumocystis carinii pneumonia,,1
7697,2521845,Floxuridine-associated sclerosing cholangitis. A dog model,"The authors developed a dog model for the biliary sclerosis that occurs as a severe complication of protracted hepatic arterial floxuridine (FUDR) infusions (using implanted drug delivery systems) in patients with hepatic cancers. Infusaid pumps attached to hepatic arterial catheters were used for protracted infusions in ten mixed breed hounds. To allow repeated cholangiograms, the animals' gallbladders were removed and catheters connected to subcutaneous infusion ports were positioned in the cystic ducts. Five treated dogs received FUDR 0.3 mg/kg/day through the pump for a total of 30 days. Five control dogs received only saline through the pump. Cholangiograms were obtained before and after treatment in all animals. In the control group, serum liver function test results and the cholangiographic appearance of the biliary tree remained within normal limits. By contrast, in the FUDR-treated group, serum glutamic-pyruvic transaminase and alkaline phosphatase progressively rose above normal, starting 2-3 weeks into FUDR infusion, followed by hyperbilirubinemia (7-28 mg/dl peak levels) beginning 4 to 6 weeks after initiation of the drug infusion. Cholangiograms revealed focal strictures involving the central bile ducts (five dogs) and diffuse attenuation of the intrahepatic ducts (four dogs). Thus, the liver function abnormalities and the cholangiographic findings in this dog model mimic the hepatobiliary toxicity in sensitive patients receiving similar treatment.",1
7698,2523611,Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma,"""Two multicenter, open, randomized phase III clinical trials were conducted in the United Kingdom to compare the effectiveness and safety of the depot formulation of the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex, ICI Pharma, Wilmington, Delaware), 3.6 mg sc/28 d, with orchiectomy and with diethylstilbestrol (DES), 1 mg tid, in the treatment of advanced prostatic cancer. In the Zoladex versus orchiectomy trial, there was no significant difference between the treatment groups with regard to subjective and objective responses (British Prostate Group criteria), endocrine responses, clinical effects and side effects, time to treatment failure and death, or survival after similar median follow-up periods. It was concluded that depot Zoladex had behaved as a truly medical alternative to orchiectomy. In the Zoladex versus DES trial, subjective and objective responses (British Prostate Group and National Prostatic Cancer Project criteria), response duration and survival were similar. However, there was a more rapid response to treatment in the depot Zoladex group. Side effects from Zoladex such as flare symptoms during the initial stages of treatment required no discontinuation of therapy; in contrast, 15 percent of patients receiving DES required cessation of therapy during the first three months because of side effects. It was concluded that depot Zoladex was superior to DES in its attainment of an early objective response and in its absence of side effects, and that Zoladex was comparable with DES in terms of response rates and survival.""",1
7699,2525986,A global safety evaluation of etodolac,"Etodolac has previously been reported to have an excellent safety profile. Results of recent clinical trials and of a clinical practice study were compared with the previously reported safety data for etodolac. The total incidence of patient complaints and of laboratory abnormalities continues to be low, with no apparent increase in side effects with increasing patient age. In the clinical practice study, 60% of study events occurred early in therapy (before 10 weeks). These data support an excellent safety profile for etodolac.",1
7700,2527068,Acute hepatitis and exfoliative dermatitis associated with minocycline,,1
7701,2530251,"A double-blind, placebo-controlled trial of acitretin for the treatment of psoriasis","""Acitretin, the active metabolite of etretinate, has the clinical advantage of a much shorter terminal elimination half-life. We report the results of a double-blind, placebo-controlled trial of acitretin (Soriatane) in 15 patients with moderate to severe psoriasis. Patients received 25 mg or 50 mg daily of acitretin or placebo in a double-blind fashion for 8 weeks and then were given 25 to 75 mg acitretin daily during an open study. Only two placebo patients completed the double-blind phase; one patient's psoriasis worsened, and one showed no significant change. All 15 patients then completed at least 8 weeks with 25 to 75 mg acitretin daily, with a moderate change in erythema, scaling, and induration (mean 28% to 37% improvement) but with minimal change in the percentage of body surface area involved. Prolonged treatment (greater than or equal to 20 weeks) with acitretin resulted in further significant improvement and a 44% reduction of involved surface area from baseline.""",1
7702,2537593,Transformation of hepatic cell adenoma to hepatocellular carcinoma due to oral contraceptive use,"Unlike the proven causal association between oral contraceptive (OC) use and hepatic cell adenoma, the link between OCs and hepatocellular carcinoma remains speculative. The case history of a 53-year-old US woman suggests, however, that hepatic cell adenomas may transform into hepatocellular carcinoma. The patient, who had used Ovral continuously since 1966, presented in 1985 with vague abdominal pain and a palpable right upper quadrant mass. Computed tomography revealed a 12 x 8 cm mass in the right hepatic lobe and 2 small lesions in the left lobe. Serum alpha-fetoprotein and ferritin levels were normal and tests for hepatitis B were negative. A needle biopsy of the right lobe mass indicated benign hepatic adenoma. OC use was discontinued and the patient was examined at bimonthly intervals. Although she continued to report vague pain, there were no significant changes in radiologic findings or levels of alpha-fetoprotein over the next 18 months. At the 18-month follow-up visit, the alpha-fetoprotein level showed an increase to 227 mcg/L and had risen to 2300 mcg/L by the 30-month follow-up visit. At this time, computed tomography showed slight enlargement of the right lobe mass and inhomogeneity, while biopsy revealed sclerosing hepatocellular carcinoma. This is the 3rd case reported in the literature in which there is evidence of a transformation of hepatic cell adenomas into hepatocellular carcinoma in longterm OC users. Thus, the premalignant potential of hepatic cell carcinomas in OC users should be considered by physicians who follow such cases.",1
7703,2554724,Oral contraceptive use and liver cancer,"""The risk of liver cancer in relation to use of oral contraceptives was evaluated in a hospital-based case-control study conducted in five US cities from 1977 to 1985. Twelve new cases of liver cancer were identified in women aged 19-54 years; five controls selected from among patients hospitalized for acute conditions unrelated to oral contraceptive use were matched to each case on age (five-year categories), date of interview (three-year categories), and geographic location of the hospital. Among nine cases classified as having hepatocellular carcinoma, eight (89%) had used oral contraceptives; only 16 (36%) of 45 matched controls had used oral contraceptives. Among three other cases (two with cholangiocarcinomas and one with liver cancer of undetermined type), all had used oral contraceptives, compared with four of 15 matched controls. The results confirm the strong positive association between oral contraceptive use and hepatocellular carcinoma observed in earlier studies. Such an association is consistent with evidence that oral contraceptive use is associated with benign hepatic tumors in young women. However, the number of cases of liver cancer in the United States that are attributable to oral contraceptive use is probably small, because liver cancer is extremely rare in the United States.""",1
7704,2560267,[Pancreatitis and hepatitis in a patient treated with enalapril maleate. A case report],,1
7705,2561186,Toxicological profile and safety evaluation of antifungal azole derivatives,"For the development of new systemically acting, oral antifungal azoles, it is of key importance to compare them with ketoconazole, the first available drug in this therapeutic class. Ketoconazole is a major breakthrough although hepatic side-effects as well as interactions with mammalian steroids might rarely occur during prolonged treatment. The prediction of these side-effects is difficult but the potential to interact with mammalian cytochrome P-450 enzymes is considered to be important. Therefore, for the selection of itraconazole a multidisciplinary approach was applied to study this potential. The present paper deals with the toxicological profile of itraconazole and its safety evaluation. In addition, a further comparison with ketoconazole and also with fluconazole is provided, in so far sufficient information is available. For the liver as a potential target organ, the available data indicate that itraconazole is not a predictable hepatotoxic drug in man. The major endocrine targets for overdosing with antifungal azoles are the adrenal cortex and the gonads. Endocrine studies show that itraconazole is not bearing a potential to interfere with steroid hormones in patients, which is a major improvement when compared to ketoconazole. In rats, elevation of serum cholesterol is observed especially after chronic exposure to itraconazole. This species-specific phenomenon leads at toxic dose levels to secondary events, especially in the long-term toxicity studies. In man, including those with existing hypercholesterolemia, serum cholesterol is not adversely affected by itraconazole. In pregnant rats, ketoconazole was shown to be teratogenic at high, toxic doses. The same observation has been made for itraconazole and this also might be true for fluconazole.(ABSTRACT TRUNCATED AT 250 WORDS)",1
7706,2563116,Fulminant hepatitis due to cyproterone acetate,,1
7707,2563951,Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial,"""OBJECTIVE: To assess the safety and efficacy of a preparation of mesalazine (5-aminosalicylic acid) coated with a pH dependent resin (Eudragit L) as compared with sulphasalazine in patients with active mild to moderate ulcerative colitis. DESIGN: Eight week randomised double blind parallel group study. SETTING: Forty six gastroenterology outpatient clinics in seven countries. PATIENTS: Two hundred and twenty patients aged 18-70 who met the following criteria: clinical activity index greater than or equal to 6 and endoscopic index greater than or equal to 4; no concomitant treatment for ulcerative colitis; no hypersensitivity to salicylates or sulphonamides. Of the 164 patients eligible for efficacy analysis, 87 received the coated preparation of mesalazine and 77 sulphasalazine. Most of the remaining patients (28 in each group) were ineligible for the efficacy analysis because of treatment with steroid enemas. All pretrial characteristics were comparable in the two treatment groups. INTERVENTIONS: Coated mesalazine (Mesasal) 1.5 g daily or sulphasalazine 3.0 g daily for eight weeks. Compliance monitored by pill counts. END POINT: Clinical and endoscopic remission. MEASUREMENTS AND MAIN RESULTS: Clinical activity measured by daily diary cards, assessment by investigators, and laboratory findings. Endoscopic evaluation at week 8. After four weeks 50 of 70 patients (71%) taking coated mesalazine and 38 of 58 (66%) taking sulphasalazine had achieved remission of their disease by eight weeks remission rates were 74% (37/50 patients) and 81% (35/43) in the two treatment groups respectively. Endoscopic remission at eight weeks was recorded in 20 of 41 patients (49%) taking coated mesalazine and 18 of 38 (47%) taking sulphasalazine. There was a higher incidence of adverse events among patients taking sulphasalazine (25/105; 24%) than among those taking coated mesalazine (16/115; 14%). CONCLUSION: Mesalazine coated with Eudragit L is a safe, logical alternative to sulphasalazine.""",1
7708,2564563,Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS,"In a randomised, double-blind study the efficacy and toxicity of oral fluconazole 50 mg daily and ketoconazole 200 mg daily were compared for the treatment of oropharyngeal candidiasis in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC). 20 episodes (18 patients) were treated with fluconazole and 20 episodes (19 patients) with ketoconazole. Pretreatment clinical features and laboratory test results were similar in both groups. 17 episodes (85%) in the fluconazole group and 16 (80%) in the ketoconazole group could be evaluated. There was clinical cure at the end of therapy in all fluconazole-treated and 12 of 16 (75%) ketoconazole-treated episodes. Cultures were negative at the end of therapy in 87% of the fluconazole group and 69% of the ketoconazole group. 1 patients stopped taking fluconazole because of severe nausea. 1 of 18 fluconazole-treated and 4 of 19 ketoconazole-treated patients had transient rises in alanine or aspartate aminotransferase. Fluconazole seemed more effective than ketoconazole in the treatment of oral thrush among AIDS and ARC patients.",1
7709,2566778,The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke,"""The Canadian American Ticlopidine Study (CATS) is a randomised, double-blind, placebo-controlled trial to assess the effect of ticlopidine (250 mg twice daily) in reducing the rate of subsequent occurrence of stroke, myocardial infarction, or vascular death in patients who have had a recent thromboembolic stroke. Twenty-five centres entered 1072 patients into the study between 1 week and 4 months after their qualifying stroke. The patients were treated and followed for up to 3 years (mean 24 months). In the efficacy analysis, the event rate per year for stroke, myocardial infarction or vascular death, considered together, was 15.3% in the placebo group and 10.8% in the ticlopidine group, representing a relative risk reduction with ticlopidine of 30.2% (95% confidence interval 7.5-48.3%; p = 0.006). Ticlopidine was beneficial for both men and women (relative risk reductions 28.1%, p = 0.037, and 34.2%, p = 0.045, respectively). Analysis by intention-to-treat gave a smaller estimate of risk reduction (23.3%, p = 0.020) for stroke, myocardial infarction, or vascular death. Adverse experiences associated with ticlopidine included neutropenia (severe in about 1% of cases) and skin rash and diarrhoea (severe in 2% of cases each); all were reversible. This study provides evidence of a beneficial effect of ticlopidine in both men and women with a recent thromboembolic stroke.""",1
7710,2570229,Captopril and the liver,,1
7711,2571851,Hazards of interferon therapy for HBV-seronegative chronic hepatitis,,1
7712,2572625,Clotiazepam-induced acute hepatitis,"We report the case of a patient who developed acute hepatitis with extensive hepatocellular necrosis, 7 months after the onset of administration of clotiazepam, a thienodiazepine derivative. Clotiazepam withdrawal was followed by prompt recovery. The administration of several benzodiazepines, chemically related to clotiazepam, did not interfere with recovery and did not induce any relapse of hepatitis. This observation shows that clotiazepam can induce acute hepatitis and suggests that there is no cross hepatotoxicity between clotiazepam and several benzodiazepines.",1
7713,2578590,An apparent danazol-induced primary hepatocellular carcinoma: case report,"This paper presents an apparent case of danazol-induced primary hepatocellular carcinoma in a 49-year-old patient, following two years of continuous therapy with this inhibitor of pituitary gonadotrophin. Discontinuation of the drug failed to cause regression of the tumour.",1
7714,2585411,"Acute, reversible hepatic failure associated with methotrexate treatment of rheumatoid arthritis",We describe 2 patients who developed reversible decompensated liver disease while taking pulse dosed methotrexate (MTX) for rheumatoid arthritis. One of the patients was available for biopsy and had chronic active hepatitis--a lesion not previously described with MTX. This appears to be a unique and unusual manifestation of MTX hepatotoxicity.,1
7715,2591002,Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation,"""Busulfan is an alkylating agent that is widely used in preparative regimens for bone marrow transplantation (BMT). We developed a high-performance liquid chromatographic (HPLC) assay for the determination of plasma busulfan concentrations in 30 patients who received oral doses of 1 mg/kg. Concentrations were fit by a one-compartment pharmacokinetic model with first-order absorption. The pattern of absorption and elimination varied widely between patients, with peak concentrations ranging from 1.2 to 10.4 mumol/l (mean, 4.25 +/- 2.49). The elimination half-life ranged from 58 to 433 min (harmonic mean, 140 min). The AUC contributed by a single oral dose ranged from 606 to 5,144 mumol-min/l (mean, 2,012 +/- 1,223). Patients were evaluated for the development of veno-occlusive disease (VOD), a treatment complication that occurs in 20% of patients undergoing BMT and causes 10% of transplantation-related deaths. All six patients who developed VOD had an AUC greater than the mean, and five of them had an AUC that was greater than 1 SD above the mean. The occurrence of VOD was highly correlated with an increased AUC (greater than 1 SD above the mean) (X2 = 18; P less than 0.0001). Using multivariate logistic regression, no other statistically significant pharmacokinetic predictor of VOD was found. The tenfold variability in the busulfan AUC and the statistical association of increased AUC with the development of VOD suggest a possible role for therapeutic monitoring in this setting.""",1
7716,2593049,Animal model of margosa oil ingestion with Reye-like syndrome. Pathogenesis of microvesicular fatty liver,"The aetiology and pathogenesis of Reye's syndrome (RS) are incompletely understood. A number of environmental toxins and biological agents, including viruses, have been postulated to cause RS, either acting alone or synergistically. Most investigations have suggested that the primary insult is in the liver mitochondria, leading to a complex biochemical catastrophe, with death from encephalopathy. Margosa oil (MO), a long-chain fatty acid compound, has been shown to cause a Reye-like syndrome with death from hepatoencephalopathy, in children in Malaysia and India. The present time-course study performed in MO-administered mice showed the development of hepatic lesions with many features of RS. MO acts rapidly, within 30 min, on the nuclei of hepatocytes inducing mitoses and binucleated cells. This is followed by mitochondrial injury, with swelling, rarefaction of matrix, loss of dense bodies, pleomorphism, and loss of ribosomes starting at 60 min. There is loss of liver glycogen, and proliferation and hypertrophy of the endoplasmic reticulum (ER), followed by the presence of lipid droplets in the hyaloplasm, and globules within dilated cisterns of the ER. Additional fatty acids from lipolysis of body adipocytes, and fat globules from intestinal MO ingestion further aggravate the liver fatty change. There is evidence of fat globule ingestion by endocytosis into hepatocytes at the level of the sinusoids. The development of microvesicular liver steatosis and glycogen depletion due to involvement of liver cell organelles occur rapidly as in RS.",1
7717,2596461,Fulminant liver failure and pancreatitis associated with the use of sulfamethoxazole-trimethoprim,"We report the case of a 26-yr-old patient with fulminant liver failure and acute hemorrhagic pancreatitis secondary to the use of trimethoprim-sulfamethoxazole (Bactrim DS). Our patient presented with skin rash and decreased C3 and C4 levels, which we believed was due to a hypersensitivity reaction secondary to the sulfonamide component (sulfamethoxazole). To our knowledge, this is the first case reported in which sulfamethoxazole-trimethoprim has been implicated as a cause of fulminant liver failure and acute hemorrhagic pancreatitis simultaneously, and emphasizes the need of discontinuing this medication as soon as there is evidence of liver and pancreatic dysfunction.",1
7718,2608608,Acute hepatic dysfunction following parenteral amiodarone administration,,1
7719,2612124,Cholestasis and pneumonitis induced by gold therapy,The authors describe the association of gold salt-induced cholestasis and lymphocytic alveolitis proved by liver biopsy and broncho-alveolar lavage. To our knowledge this is the third case report on the combination of liver disease and pulmonary infiltration induced by gold compounds.,1
7720,2615929,"Analysis of individual symptoms in generalized anxiety--a pooled, multistudy, double-blind evaluation of buspirone","""Pooled data for 427 patients with generalized anxiety disorders were analyzed retrospectively from six double-blind trials evaluating buspirone, a nonbenzodiazepine anxiolytic, in the treatment of generalized anxiety disorder. After a 4- to 7-day washout period, patients were allocated at random to receive treatment over a 4-week period. Buspirone dose ranged from 10 to 60 mg. Patients were assessed on entry and at weekly intervals using the 14 symptom groups (items) of the Hamilton Anxiety Rating Scale (HAM-A). Buspirone improved all symptom groups significantly; onset of anxiolytic activity was observed at week 1 in 3 groups of psychic symptoms of anxiety. Within 2 weeks, 8 of the 14 symptom groups were improved significantly by buspirone versus placebo, and symptoms of anxiety improved further up to the 4-week end point. Psychic symptoms of anxiety improved earlier in general than the somatic symptoms of anxiety. At the end of treatment, analyses of the HAM-A scores indicated that all of the 14 symptom groups (individual items), the total HAM-A score, and the 2 composite Psychic and Somatic Anxiety Factors were significantly improved with buspirone as compared to placebo. The beneficial effects of buspirone were not compromised by any significant side effects.""",1
7721,2619253,[Cholestatic hepatitis and acute kidney insufficiency during treatment with diclofenac],,1
7722,2625154,[The hepatotropic properties of nonsteroidal anti-inflammatory agents],"The hepatotropic effect of nonsteroidal anti-inflammatory drugs (NSAID) such as indomethacin, voltaren, piroxicam, phenylbutazon, mefenamic acid was studied. It was found that according to their level of the pharmacological protection of the liver against tetrachlormethan these agents may be arranged in the following sequence: mefenamic acid, phenylbutazon, voltaren, piroxicam. The hepatoprotective effect of NSAID correlates with the antioxidant properties and fails to correlate with the antioxidant ones. The hepatotoxic effect of NSAID was determined by their ability to suppress synthesis of prostaglandins.",1
7723,2629632,Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency,A 24 day old girl with homocystinuria and hypomethioninaemia caused by methylenetetrahydrofolate reductase deficiency presented with rapidly progressing encephalopathy and myopathy. An almost complete recovery was achieved by treatment with betaine.,1
7724,2637609,[Hypoplastic left heart syndrome due to aortic and mitral atresias: report of one case],"""A three-day-old female infant was transferred to the Pediatric Intensive Care Unit with chief presenting problems of progressive change of cyanosis and respiratory distress. Physical examination revealed tachypnea, acrocyanosis, hepatomegaly, undetectable pulse of extremities and oozing over the place of venous puncture. Chest roentgenograms revealed slight cardiomegaly; other X-rays were within normal limits. Complete electrocardiograms showed right axis deviation and right ventricular hypertrophy. Because of an impression of neonatal sepsis, the patient was put in an incubator with oxygen and antibiotics were given. Persistent anuria appeared associated with sighs of cardiac and renal failure; the ventilator was applied; dopamine and lasix were also given. Unfortunately, the cyanosis worsened progressive. Despite several attempts at resuscitations, the infant expired eight hours later. Pathology disclosed the heart size as normal; hypoplasia of ascending aorta as 0.4 cm in diameter; a PDA with 1 cm in diameter; a diminutive bean-sized left ventricle; hypertrophy of right ventricle and atresias of aortic and mitral valves. There was no evidence of septicemia.""",1
7725,2643228,Hydralazine-induced cholestatic jaundice following liver transplantation,,1
7726,2645120,"A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy","""Two hundred and thirty-five patients suffering from newly diagnosed epilepsy were randomly allocated to treatment with either oxcarbazepine or carbamazepine in a double-blind multi-centre study. After a titration phase (between 4 and 8 weeks), the optimal individual dose of trial medication was determined and treatment with that dose was continued for another 48 weeks. The criteria for assessment were: efficacy--seizure frequency, EEG tracings, global evaluation; tolerability--side effects observed by the patient or the investigator, laboratory tests; other assessments--blood pressure and heart rate, carbamazepine and 10,11-dihydro-10-hydroxycarbamazepine trough serum levels. The results of the study showed the following: no significant difference in seizure frequency between oxcarbazepine and carbamazepine; no correlation between the therapeutic effect and the EEG findings in either treatment group; oxcarbazepine caused significantly fewer (P = 0.04) 'severe' side effects than carbamazepine; global evaluation of tolerability demonstrated a trend towards the better tolerability of oxcarbazepine; no correlation was observed between either efficacy or tolerability and the actual serum trough levels of antiepileptic drugs; clinically relevant abnormal laboratory test findings were observed in 2 patients, both on carbamazepine. The authors consider oxcarbazepine to be a valuable alternative to carbamazepine, particularly in patients who develop side effects which prevent optimal seizure control.""",1
7727,2645587,Liver toxicity of retinoid therapy,,1
7728,2646364,Fatal liver failure due to disulfiram,"We present the case of a 30-year-old man with disulfiram-induced hepatitis complicated by fatal liver failure. The disease followed a protracted course with an interval of 25 days between the onset of jaundice and the onset of encephalopathy. In this patient, the severity of the liver disease might have been due to reingestion of disulfiram shortly after the onset of jaundice.",1
7729,2652087,Nitrofurantoin toxicity in children,,1
7730,2653624,Review of clinical studies of bile acid sequestrants for lowering plasma lipid levels,"Both alone and in combination with other lipid-lowering drugs, the bile acid sequestrants cholestyramine and colestipol, are excellent agents for lowering circulating low-density lipoprotein (LDL) cholesterol levels. They have been shown to lower the incidence of new coronary events and to retard the progression of coronary atherosclerosis. They also induce qualitative changes in lipoproteins whose significance requires further investigation but may be of significance in coronary disease prevention. While side effects may be bothersome for some patients, they can generally be managed effectively. In particular, modest lowering of dosage may preserve considerable LDL cholesterol lowering and virtually eliminate side effects. Sequestrants appear to be among the safest and most effective drugs in the cholesterol-lowering armamentarium.",1
7731,2655052,[Severe mixed hepatitis caused by fenofibrate? A review of the literature apropos of a case],,1
7732,2658555,"Atenolol for prevention of rebleeding from esophageal varices in hepatic cirrhosis: results of a controlled, randomized pilot study",,1
7733,2663415,"Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease","Nimodipine is a dihydropyridine calcium antagonist which has been shown to dilate cerebral arterioles and increase cerebral blood flow in animals and humans. It has potential in the treatment of a range of cerebrovascular disorders. Major interest to date, however, has focused on its use in the prevention and treatment of the delayed ischaemic neurological deficits that frequently occur in patients with subarachnoid haemorrhages as a result of sustained cerebral vasospasm. Initial studies in which patients were treated with an intravenous infusion of nimodipine for up to 2 weeks, followed by oral treatment for 7 days, indicated that a higher proportion of patients than would normally be expected recovered with little or no permanent neurological damage. In a number of controlled studies oral nimodipine treatment for 3 weeks significantly decreased mortality rates and increased the number of patients who had a 'good' neurological outcome as compared with placebo treatment. In some of these trials fewer of the nimodipine-treated patients developed neurological deficits during the treatment period, but in none was there a significant effect on the incidence of angiographic vasospasm. It would seem that other pharmacological actions, such as increasing collateral blood flow to underperfused regions or a direct anti-ischaemic effect at the cellular level, may contribute to the clinical benefits obtained with nimodipine treatment. Preliminary results suggest that nimodipine is potentially useful in other cerebrovascular disorders, particularly ischaemic stroke. To date, nimodipine has been well-tolerated, the only adverse effects of any significance being reductions in the blood pressure of some patients and reversible increases in liver enzymes during intravenous therapy. Thus, nimodipine has significant potential in the treatment of patients with subarachnoid haemorrhage. Wider clinical use should confirm its value as a significant addition to the very limited range of therapeutic choices currently available for patients with this disorder.",1
7734,2665225,Orthotopic liver transplantation resulting in amitriptyline toxicity in the recipient,,1
7735,2666321,Griseofulvin and ketoconazole in the treatment of dermatophyte infections,,1
7736,2671624,Erythropoietin for anemia,,1
7737,2678162,Double blind study of a valerian preparation,"Valerian root contains two substances of special pharmacological interest--valepotriates and sesquiterpenes. The former, which has been used for standardization of the drug, is cytotoxic. The latter has no such effect. Both have sedative effects. A double blind test has been carried out on a preparation (VALERINA NATT) containing primarily sesquiterpenes. When compared with placebo it showed a good and significant effect on poor sleep (p less than 0.001). Forty-four percent reported perfect sleep and 89% reported improved sleep from the preparation. No side effects were observed.",1
7738,2680380,Neoantigens associated with halothane hepatitis,,1
7739,2682510,The use of aztreonam in the cystic fibrosis patient,"""Eradication of pulmonary infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients has long presented a significant challenge to the medical community. Many antimicrobial agents have proved incompletely effective against this persistent pathogen, and even the aminoglycosides, which represent the traditional therapy for such infections, have been associated with considerable toxicity and resistance. The monobactam antibacterial agent aztreonam is used both as single-agent therapy and in combination with other drugs. Several controlled, clinical trials have demonstrated the efficacy of aztreonam in the treatment of CF patients with pulmonary exacerbations caused by P. aeruginosa. The only side effect of aztreonam therapy commonly encountered in these studies was elevation of hepatic transaminase concentrations; this effect was of uncertain significance. It was concluded that aztreonam may offer clinical efficacy comparable to that provided by the combination of tobramycin plus azlocillin. Further, there does not seem to be any appreciable difference in the development of resistance to aztreonam compared with traditional therapies.""",1
7740,2686432,Safety of oral ciprofloxacin. An update based on clinical trial results,"""The safety of ciprofloxacin was established on a data base (compiled through the end of 1988) of 9,473 well-documented treatment courses world-wide. The daily dosages ranged between 200 and 2,000 mg orally. Thirty-eight percent of the patients received doses between 1 and 10 mg/kg body weight, 46 percent between 11 and 20 mg/kg, and the remaining 16 percent more than 20 mg/kg body weight daily. Ciprofloxacin was administered to 4,214 women (45 percent) and 5,252 men (55 percent). The duration of treatment ranged from less than two days to more than 90 days. A 600-mg daily dose of ciprofloxacin was used mostly in Japan (2,341 patients). The daily dose of 1,000 mg was administered chiefly in the United States and Europe (2,288 patients). The age of the patients ranged from less than one year to 99 years (mean, 50.6 years). More than 38 percent were older than 60 years. According to COSTART terminology, the following drug-related side effects were observed in the different organ systems: digestive, 4.9 percent; metabolic-nutritional, 4.4 percent; central nervous system, 1.5 percent, skin, 1.1 percent; hemic and lymphatic, 0.9 percent; urogenital, 0.8 percent; body as a whole, 0.5 percent; cardiovascular, 0.2 percent; special senses, 0.2 percent; musculoskeletal, 0.1 percent; and respiratory, 0.1 percent. Several patients had more than one reaction. The total incidence of side effects for the treated patients was 9.3 percent. The vast majority of adverse reactions were mild or moderate (94 percent). Serious side effects were reported for 55 patients (6 percent). Based on the 9,473 courses, the incidence of severe reactions was 0.6 percent. Ciprofloxacin treatment was discontinued due to side effects in 146 patients (1.5 percent), mostly due to gastrointestinal reactions (80 patients). The worldwide data from clinical trials with oral ciprofloxacin clearly demonstrate that the drug is relatively safe, and the side effects are usually mild or moderate in intensity and are reversible.""",1
7741,2688507,Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial,"""STUDY OBJECTIVE: To determine the effectiveness and safety of recombinant human erythropoietin (rHuEpo). PATIENTS: Hemodialysis patients (333) with uncomplicated anemia (hematocrit less than 0.30). All received rHuEpo intravenously, three times per week at 300 or 150 U/kg body weight, which was then reduced to 75 U/kg and adjusted to maintain the hematocrit at 0.35 +/- 0.03 (SD). RESULTS: The baseline hematocrit (0.223 +/- 0.002) increased to 0.35, more than 0.06 over baseline within 12 weeks in 97.4% of patients. Erythrocyte transfusions (1030 within the 6 months before rHuEpo therapy) were eliminated in all patients within 2 months of therapy. Sixty-eight patients with iron overload had a 39% reduction in serum ferritin levels after 6 months of therapy. The median maintenance dose of rHuEpo was 75 U/kg, three times per week (range, 12.5 to 525 U/kg). Nonresponders had complicating causes for anemia, myelofibrosis, osteitis fibrosa, osteomyelitis, and acute or chronic blood loss. Adverse effects included myalgias, 5%; iron deficiency, 43%; increased blood pressure, 35%; and seizures, 5.4%. The creatinine, potassium, and phosphate levels increased slightly but significantly. The platelet count increased slightly but there was no increase in clotting of vascular accesses. CONCLUSIONS: The anemia of hemodialysis patients is corrected by rHuEpo resulting in the elimination of transfusions, reduction in iron overload, and improved quality of life. Iron stores and blood pressure must be monitored and treated to maintain the effectiveness of rHuEpo and to minimize the threat of hypertensive encephalopathy.""",1
7742,2694294,[Granulomatous hepatitis secondary to ingestion of carbamazepine. Report of a case],"""A 51-year-old man with epilepsy received carbamazepine during three weeks. He developed fever, jaundice, dark urine and pale stools. Laboratory data showed hepatocellular injury and cholestasis; six weeks after withdrawal of the drug these abnormalities returned to normal limits. The liver biopsy showed acute cholangitis, bile duct injury, granulomas and eosinophils in the portal areas.""",1
7743,2694823,Reappraisal of the risk/benefit of nitrofurantoin: review of toxicity and efficacy,,1
7744,2707742,Hepatic vascular toxicity of dacarbazine (DTIC): not a rare complication,,1
7745,2712618,Azathioprine induced hepatic veno-occlusive disease in rheumatoid arthritis,"A patient with rheumatoid arthritis developed hepatic veno-occlusive disease following the use of azathioprine. Although azathioprine induced veno-occlusive disease is suspected to occur more frequently in patients with autoimmune dysfunction, it has not previously been reported as a complication of treatment in rheumatoid arthritis. The mechanism responsible for this condition remains unknown.",1
7746,2719021,Transient hepatitis due to low dose neuroleptic medication,,1
7747,2721325,Micronodular cirrhosis after thiabendazole,"Hepatotoxicity secondary to the administration of thiabendazole has been rare since this drug was produced in 1964. In 14 of 15 patients reported previously in the literature, severe intrahepatic cholestasis resolved within seven months of the onset of illness. A recent report documented the progression to cirrhosis in a 15th patient. We report the second case of a patient with intrahepatic cholestasis that developed after treatment with thiabendazole and progressed to severe micronodular cirrhosis.",1
7748,2723568,Isoniazid-rifampicin-induced submassive hepatic necrosis,"A 58-year-old woman with tuberculosis received antituberculous drugs which included isoniazid, rifampicin, and ethambutol. Nausea and anorexia were initial symptoms while jaundice and abdominal pain were late manifestations. She became comatose and died 7 weeks after therapy. Autopsy revealed submassive necrosis of the liver and active advanced pulmonary tuberculosis. It is, thus, necessary for the physician to be alert for this serious complication in prescribing a combination of these antituberculous drugs.",1
7749,2726592,Follow-up study of tolmetin users,"A follow-up study of 8370 outpatients who filled over 24,000 prescriptions for tolmetin revealed no hospital admissions for acute allergic, blood, skin, or central nervous system illness within 90 days of filling a prescription or refill for the drug. There were two cases of liver disease and two cases of nephrotic syndrome in which an etiologic relationship to tolmetin seemed unlikely but could not be entirely ruled out. In addition, 11 patients were hospitalized for peptic ulcer disease and its complications. In all but two patients other risk factors were present that could readily explain the illness. The rate of hospitalization for peptic ulcer disease and its complications among tolmetin recipients appears to be of the same magnitude as that in patients who take other nonsteroidal antiinflammatory drugs in this population, and close to that of the population at large.",1
7750,2731688,[Acute cholestatic hepatitis after ingestion of roxithromycin],,1
7751,2734725,"[Cholestatic hepatitis caused by quinidine phenylethylbarbiturate, and sarcoidosis. Apropos of a case]",,1
7752,2735960,Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment,"In an effort to understand the prognostic features that may influence the probability of a patient's continuing to take methotrexate (MTX) over time, we studied 152 rheumatoid arthritis patients treated with MTX between 1981 and 1986. The overall probability of continuing to take MTX was 71.2% at 1 year, 55.5% at 3 years, 50% at 5 years, and 49% at 6 years. By univariate analysis, patients who started MTX therapy later in the study, American blacks, younger patients, those with less severe disease, and those with less frequent or less severe toxic events appeared to have a better probability of continuing the drug therapy. When these parameters were evaluated by multivariate analysis, only the time when MTX was started and the occurrence of toxic effects independently influenced the probability of continuing MTX. Thus, by current practice standards, toxic effects emerge as the main reason for MTX discontinuation.",1
7753,2739957,Cholestatic hepatitis after therapy with amoxicillin/clavulanate potassium,,1
7754,2741990,Comfrey herb tea-induced hepatic veno-occlusive disease,,1
7755,2746881,[Acute leukemia complicated by hyperbilirubinemia due to high dose cytosine arabinoside therapy],"A 58-year-old man was admitted to our hospital because of low grade fever and purpura in September. 1987. On admission, his bone marrow aspiration showed nucleated cell count of 48 x 10(4)/mm3 with 94.6% of promyelocyte-like leukemic cells. A diagnosis of acute promyelocytic leukemia was made and he was treated with high dose cytosine arabinoside (HDAra C). After this therapy, serum bilirubin, especially direct bilirubin was increased and hyperbilirubinemia was progressed with normal transaminase levels. He had complicated by pneumonia and died of respiratory failure. Autopsy revealed only cholestasis in the liver with neither hepatic cell necrosis nor cell infiltration. This case was though to be a rare case with cholestatic liver injury due to HDAra C.",1
7756,2752877,Amoxycillin/clavulanic acid (Augmentin)-induced intrahepatic cholestasis,"A 75-year-old man developed a biopsy-proven, drug-induced intrahepatic cholestasis after use of amoxycillin trihydrate combined with the beta-lactam inhibitor potassium clavulanate (Augmentin). Cholestatic liver injury is an uncommonly recognized, probably immunologically based adverse reaction to therapy with penicillin and its derivatives.",1
7757,2753313,[Is buprenorphine hepatotoxic?],,1
7758,2757062,Fatal labetalol-induced hepatic injury,,1
7759,2757903,Efficacy and safety of vigabatrin in the long-term treatment of refractory epilepsy,"""1. The long term safety and efficacy of vigabatrin has been studied in 254 patients with refractory epilepsy (82% with partial seizures) in 23 different clinics in eight European countries. 2. This was an open multicentre study in which patients who had experienced a significant benefit from vigabatrin and had continued to take the drug for 1 year or longer were eligible for evaluation. The mean duration of therapy in the 254 patients was 22.7 months; 72 patients received vigabatrin for more than 2 years. 3. Patients were severely affected by epilepsy with a median monthly seizure frequency of 15.7 despite taking an average of 2.2 antiepileptic drugs. On vigabatrin, the median seizure frequency was about 35% of baseline, remaining stable over time despite a 10% reduction in the number of concurrent medications. 4. The lack of tachyphylaxis to the antiepileptic effect of vigabatrin is shown by the small number of patients who discontinued for insufficient efficacy (11%), two thirds of them during the first 6 months of follow-up. Maintenance of efficacy is also clearly demonstrated by analysis of 2 year and 3 year cohorts of patients. 5. Clinical and biological tolerability was excellent. There was a very low rate of drop out for adverse events (1.6%). Adverse events, mainly sedation, irritation and weight gain were mostly mild and transient. 75% of patients reported no adverse event at all. 6. Safety evaluation included serial neurological, ophthalmological and general examinations: no new abnormal clinical feature or adverse event emerged with long term therapy.""",1
7760,2758719,Massive levothyroxine ingestion. Conservative management,"The clinical course of a 29-month-old girl who was referred for evaluation after ingesting ninety 0.2-mg tablets of levothyroxine is reported. Despite an initial thyroxine (T4) level of 282 micrograms/dl and a triiodothyronine (T3) level of 1,837 ng/dl at 48 hours postingestion, her symptoms were mild and included irritability, vomiting, tremor, and tachycardia. Treatment was limited to activated charcoal and propranolol. Thyroid hormone levels fell to normal by 13 days postingestion. The child's clinical course was benign. Even after massive acute ingestions of levothyroxine, children's symptoms are usually mild and may be controlled with propranolol. This conservative approach should be considered before expensive and potentially dangerous therapies are undertaken.",1
7761,2761587,A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group,"We report the results of the Ticlopidine Aspirin Stroke Study, a blinded trial at 56 North American centers that compared the effects of ticlopidine hydrochloride (500 mg daily) with those of aspirin (1300 mg daily) on the risk of stroke or death. The medications were randomly assigned to 3069 patients with recent transient or mild persistent focal cerebral or retinal ischemia. Follow-up lasted for two to six years. The three-year event rate for nonfatal stroke or death from any cause was 17 percent for ticlopidine and 19 percent for aspirin--a 12 percent risk reduction (95 percent confidence interval, -2 to 26 percent) with ticlopidine (P = 0.048 for cumulative Kaplan-Meier estimates). The rates of fatal and nonfatal stroke at three years were 10 percent for ticlopidine and 13 percent for aspirin--a 21 percent risk reduction (95 percent confidence interval, 4 to 38 percent) with ticlopidine (P = 0.024 for cumulative Kaplan-Meier estimates). Ticlopidine was more effective than aspirin in both sexes. The adverse effects of aspirin included diarrhea (10 percent), rash (5.5 percent), peptic ulceration (3 percent), gastritis (2 percent), and gastrointestinal bleeding (1 percent). With ticlopidine, diarrhea (20 percent), skin rash (14 percent), and severe but reversible neutropenia (less than 1 percent) were noted. The mean increase in total cholesterol level was 9 percent with ticlopidine and 2 percent with aspirin (P less than 0.01). The ratios of high-density lipoprotein and low-density lipoprotein to total cholesterol were similar in both treatment groups. We conclude that ticlopidine was somewhat more effective than aspirin in preventing strokes in this population, although the risks of side effects were greater.",1
7762,2773535,[Clozapine-induced cholestatic jaundice: a case report],"""We report on a patient who became jaundiced during treatment with clozapine (Leponex). Histologically, cholestatic hepatitis with single-cell necroses of hepatocytes and infiltration of the portal zones with eosinophilic granulocytes were found. The patient recovered after discontinuation of clozapine, and liver function tests returned to normal within 4 weeks. This adverse effect of clozapine suggests that this """"atypical"""" tricyclic neuroleptic resembles the phenothiazines both with regard to therapeutic spectrum and side effects.""",1
7763,2773977,Labetalol hepatotoxicity,,1
7764,2774596,Detection of hepatotoxicity associated with methotrexate therapy for psoriasis,"""To determine whether liver function tests and clinical and demographic information would predict methotrexate-associated hepatotoxicity, we identified 78 patients who had undergone 147 liver biopsies associated with methotrexate therapy for psoriasis. The joint sensitivity of aspartate aminotransferase, alkaline phosphatase, and total bilirubin values in detecting abnormal results from a biopsy specimen obtained after treatment was .86; the predictive value of negative test results was .93. A logistic regression model significantly predicted the presence of abnormal (grade III or higher) liver biopsy specimen results. The concordance index was .92 (perfect, 1.0). Regression coefficients may be used along with information from a specific patient to calculate the predicted probability of an abnormal result from a liver biopsy specimen after treatment. We conclude that this multivariate risk estimation model significantly predicts the likelihood of positive findings from liver biopsy specimens in this patient population. The clinical use of this model awaits further validation.""",1
7765,2774703,Fatal aplastic anaemia and liver toxicity caused by D-penicillamine treatment of rheumatoid arthritis,"A 65 year old woman with rheumatoid arthritis developed marrow aplasia and jaundice owing to D-penicillamine treatment. Recovery of bone marrow was ineffective, and the patient finally died despite intensive therapeutic measures. The rare coexistence of myelotoxicity and hepatotoxicity is presented and discussed.",1
7766,2782732,If a tree falls in the middle of the forest. Isoniazid and hepatitis,,1
7767,2785079,Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients,"""The prevalence of apparent amiodarone-related hepatic injury in 104 patients followed prospectively is compared to that reported in the literature. Asymptomatic elevation of serum aminotransferase levels was detected in approximately one-fourth of the patients, a figure similar to the average of reported cases. The frequency of extrahepatic organ toxicity was increased in patients with elevated levels. Symptomatic """"hepatitis"""" developed in 3% of this series and in less than 1% of cases in the literature. Evidence of hepatic phospholipidosis and the development of pseudoalcoholic liver injury is most likely due to the biochemical effects of the drug and to possible metabolic idiosyncrasy, respectively. Serial blood enzyme measurements, as recommended by the manufacturer, may offer some protection against the development of more serious liver injury. However, levels of amiodarone may persist in various tissues for weeks to months following withdrawal, and stopping the drug does not guarantee the prompt reversal of any organ toxicity. Accordingly, the risks posed and benefits offered by amiodarone should be carefully weighed prior to discontinuing the drug, as the risk of sudden cardiac death may outweigh the hazards of ongoing hepatic, pulmonary or other toxicity.""",1
7768,2794330,Surveying optometry school alumni: a multifaceted approach,"Surveying alumni of a college of optometry provides vital information on the effectiveness of academic and clinical programs which prepare students for the practice of optometry and for advancement of the profession. This University of Houston College of Optometry (UHCO) alumni study took a multifaceted approach, asking graduates of recent years--1984, 1985, 1986--to evaluate program areas and to tell how they practiced in the first years out. Although most young optometrists worked for someone else in the year after graduation, within 2 years, two-thirds of men and women were self-employed and located primarily in urban/suburban areas. A striking finding was the difference in type of practice entered by women and men: women far more often entered solo practice or, if employed, worked for a health maintenance organization (HMO), while men more often entered partnerships or worked for another optometrist. And, women reported much lower incomes than men regardless of type of practice. These differences merit attention, as does the familiar finding that alumni, although satisfied with their optometric training overall, rated their training in practice management most inadequate.",1
7769,2797021,Amiodarone hepatotoxicity: progression from steatosis to cirrhosis,,1
7770,2797298,[Liver damage during use of busulfan],,1
7771,2799042,[Hepatotoxicity caused by ketoconazole],,1
7772,2803323,Electron microscopic analysis of sequential liver biopsy samples from patients with rheumatoid arthritis. Correlation with light microscopic findings,"We used electron microscopy (EM) to analyze 52 biopsy samples from 22 patients who were receiving long-term weekly oral doses of methotrexate (MTX) for the treatment of rheumatoid arthritis. Forty-eight biopsy samples were obtained after 2-6 years of continuous treatment, and 4 samples were obtained before treatment was begun. Specimens were graded for neutral fat, secondary and tertiary lysosomes, and smooth endoplasmic reticulum (SER) in hepatocytes, and for collagen in the perisinusoidal space (Disse's space). We examined the correlations between the EM findings and the light microscopic (LM) findings in the same biopsy specimens, and between the EM findings and the results of simultaneous monthly measures of aspartate transaminase, alkaline phosphatase, bilirubin, and albumin levels, as well as history of alcohol consumption before MTX treatment and monthly assessments of clinical status during the course of treatment. The presence of collagen was minimally increased in these sequential biopsy samples, whereas fat, lysosomes, and SER were decreased. The SER decrease was statistically significant. EM findings of collagen in the space of Disse did not correlate with early fibrotic changes observed with LM. Thus, after as long as 6 years of weekly oral treatment with MTX, hepatic ultrastructural changes are minimal and are not clinically significant. The use of EM for sequential biopsy studies allows the quantitation of long-term hepatic changes that may be more limited than the impression gained after LM analysis.",1
7773,2806096,[Noncirrhotic liver fibrosis after chronic arsenic poisoning],"A 67-year-old woman with portal hypertension, splenomegaly without portal vein thrombosis, leucopenia and thrombocytopenia of splenic origin had repeated episodes of life-threatening haemorrhage from esophageal varices. Since childhood she had suffered from psoriasis and had been treated over a period of 15 years with Fowler's solution (in all about 25 g of arsenic trioxide). She had the characteristic skin lesions of arsenical poisoning-palmar hyperkeratoses and two basal cell carcinomas on the trunk. Histological examination of a wedge biopsy from the liver showed definite structural changes with fibrosis around the central veins and in the portal tracts. There was no evidence of cirrhotic alteration. The hepatocytes were normal by light microscopy and electron microscopy. This case of noncirrhotic hepatic fibrosis is considered to have been caused by chronic arsenical poisoning.",1
7774,2809168,Cholestatic hepatitis due to an amoxycillin/clavulanic acid preparation,Two cases of reversible cholestatic hepatitis after treatment with an amoxycillin/clavulanic acid preparation (Augmentin) are described.,1
7775,2813671,Side effects of clozapine,"""In addition to the low risk of agranulocytosis, several more frequent side effects are associated with clozapine therapy. We tried to estimate the incidence of these side effects. We analysed 391 treatments in 315 inpatients, who received clozapine alone or combined with other neuroleptic and antidepressant drugs. Two thirds were combined treatments, one third were treatments with clozapine alone (i.e., no other neuroleptic, antidepressant or anticonvulsive drugs were allowed). The numbers in brackets show the incidence based on the analysis of the treatments with clozapine alone. In 49% (61%) of the treatments a rise in the liver enzyme values was observed. However, counting only the cases in which a two-fold increase over the normal values was observed, the incidence was reduced to 20% (31%). Increase in temperature was observed in 4% (6%) and leukopenia (leukocyte count under 3500/microliters) was recorded in 2% (2%). Hypotensive dysregulation (systolic blood pressure under 90 mm Hg) was observed in 25% of all treatments and pharmacogenic delirium in 8%. No cases of agranulocytosis were observed. Mean treatment duration was 56 days, mean daily dosage 257 mg. The mean age of the patients was 34 years. In the overall evaluation 71% of the treatments were classified as successful; clozapine therapy was continued after discharge in 68% of the treatments. Adverse reactions (delirium, rise in temperature, hypotension, fatigue, rise in liver enzymes) necessitated a change of medication in 17% of the treatments. Changeover to another neuroleptic drug due to ineffectiveness of clozapine was necessary in 7% of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
7776,2824032,Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors,"A Phase I-II clinical trial of high dose single agent busulfan (16-20 mg/kg) administered over a 4-day period was undertaken. Pharmacokinetic measurements reveal that steady state total plasma busulfan levels between 2 and 10 microM were achieved by the second day and maintained through the remaining treatment period. Urinary excretion of mutagenic activity monitored by the Salmonella mutagenesis assay persisted for up to 48 h following the last dose of busulfan. The treatment showed specificity for myelocytic precursors as evidenced by selective depression of granulocytes with relative sparing of lymphocytic elements, and by differences in DNA damage as measured by a nucleoid sedimentation assay. Dose limiting toxicity was mucositis, anorexia, and hepatic toxicity. Transient autoimmune disorders were observed in three of the six patients. Partial responses were seen in two of five patients with melanoma, but these lasted for only 2 and 3 months. High dose busulfan represents an alkylating agent with marked myelocytic selectivity and may be useful for inclusion in intensive combination regimens.",1
7777,2830841,"Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution","""Azithromycin (CP-62,993), a new acid-stable 15-membered-ring macrolide, was well absorbed following oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of azithromycin over erythromycin was shown through efficacy in a series of animal infection models. Azithromycin was orally effective in treating middle ear infections induced in gerbils by transbulla challenges with amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae; erythromycin failed and cefaclor was only marginally active against the H. influenzae challenge. Azithromycin was equivalent to cefaclor and erythromycin against Streptococcus pneumoniae. In mouse models, the new macrolide was 10-fold more potent than erythromycin and four other antibiotics against an anaerobic infection produced by Fusobacterium necrophorum. Similarly, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle); erythromycin failed against both infections. The oral and subcutaneous activities of azithromycin, erythromycin, and cefaclor were similar against acute systemic infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas azithromycin was more potent than erythromycin and cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of azithromycin over erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus infection. These properties of azithromycin strongly support the further evaluation of this new macrolide for use in community-acquired infections of skin or soft tissue and respiratory diseases.""",1
7778,2834121,Liver diseases related to oral contraceptives,,1
7779,2838151,Severe hepatic toxicity after treatment with single-dose dactinomycin and vincristine. A report of the National Wilms' Tumor Study,"Dactinomycin is an antitumor antibiotic with known activity against many pediatric solid tumors. Administration of dactinomycin using a single-dose schedule was incorporated into the design of the National Wilms' Tumor Study 4 (NWTS-4). This was done to determine whether laboratory and preliminary clinical data, suggesting that such a schedule was associated with increased antitumor effect and/or decreased normal tissue toxicity, could be validated in a large clinical trial. Five patients treated with regimens EE-4 or K-4, regimens that included single-dose dactinomycin and no abdominal irradiation, experienced severe hepatic toxicity. The clinical courses of these patients suggested that multiple factors, including the administration of other hepatotoxic agents, contributed to the toxicity observed. The study has been modified by decreasing the dose of dactinomycin from 60 micrograms/kg to 45 micrograms/kg. Further evaluation of other potential contributing factors, such as the use of halogenated hydrocarbon inhalational anesthetic agents, is needed.",1
7780,2840226,Acute renal failure induced by foscarnet: 4 cases,"Foscarnet (FC) is a new antiviral agent which has been recently proposed for the treatment of severe cytomegalovirus (CMV) infections in immunocompromised patients. When used intravenously (i.v.), main adverse effects of FC are a fall in hemoglobin, and an increase in liver enzymes and serum calcium. Although increased serum creatinine have been noted in several patients, deterioration of renal function is often accounted for by the concomitant use of other nephrotoxic drugs, the severity of underlying disease or the presence of graft rejection. Consequently FC is often considered as a non or poorly nephrotoxic drug. We report 4 cases of acute renal failure (ARF) which can be exclusively attributed to FC. FC was used for CMV chorioretinitis in 3 AIDS patients and in one non-immunocompromised patient. ARF was diagnosed between the 6th and 15th day of treatment, with oligoanuria in two patients (one of whom required two hemodialysis periods). ARF was most likely secondary to acute toxic tubulopathy. Three patients did not receive any other nephrotoxic drug. The fourth patient received concomitantly sulfadiazine but renal function returned to baseline value after FC completion although sulfadiazine was continued. In conclusion, our 4 observations suggest that FC may be responsible for acute tubulopathy. We suggest that in these patients renal function should be carefully monitored and dehydration promptly corrected to limit the risk of nephrotoxicity.",1
7781,2841021,Carboplatin: current status and future prospects,,1
7782,2845778,Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients,"""PURPOSE: Cryptococcus neoformans causes infections in up to 10 percent of patients with the acquired immunodeficiency syndrome (AIDS). Nearly 50 percent of AIDS patients with previously treated cryptococcal meningitis will experience a relapse within six months. To reduce the likelihood of relapse, a maintenance regimen of amphotericin B is often administered weekly. However, the drug's intravenous route of administration and considerable toxicity have led to a search for alternative antifungal agents. In this report, we document our experience with fluconazole, a new oral triazole antifungal agent. PATIENTS AND METHODS: Twenty-two patients with AIDS and various forms of cryptococcosis were treated in an open-label study with 50 to 400 mg/day of fluconazole. The following laboratory studies were done on a monthly basis: complete blood cell count, liver function tests, serum creatinine level, serum cryptococcal antigen level, and serum fluconazole level. Lumbar puncture was performed in patients with meningitis every four to eight weeks to evaluate cerebrospinal fluid cryptococcal antigen, India ink preparation findings, fungal culture, fluconazole level, and protein, glucose, and cell count. RESULTS: Of seven patients with active culture-positive infections, four showed clinical and microbiologic responses (three of four with meningitis, one of three with extraneural cryptococcosis). Fifteen patients who had already undergone successful amphotericin B therapy for either meningitis (n = 14) or pneumonia (n = 1) received fluconazole as prophylaxis against relapse. Fourteen patients remained free of infection during 11 to 64 weeks of suppressive therapy; one patient with meningitis experienced relapse after 26 weeks of treatment. Reverse reactions were limited to increases in hepatic enzyme levels in four patients. CONCLUSION: These results appear sufficiently encouraging to warrant further trials of this oral agent in the suppression of chronic cryptococcosis and perhaps in the treatment of acute infection.""",1
7783,2853857,[Hepatotoxicity with etoposide-ifosfamide combination therapy],"Combination chemotherapy with etoposide and ifosfamide in 2 patients with advanced bronchial carcinomas caused hepatotoxic side effects. Hepatotoxicity was observed during and immediately after the 5-day therapy and was characterised by a massive rise in direct bilirubin, drop in cholinesterase, as well as a rise in the alkaline phosphatase and to a lesser extent in gGT and GOT. Hepatotoxicity was lethal in one case and reversed to normal in the other. Hepatotoxicity was most likely caused by ifosfamide, since this drug was applied for the first time in both cases. Nonetheless, a contribution of etoposide in this regard can not be excluded since there were liver enzyme alterations in one case after a previous course of chemotherapy using etoposide and cis-platinum.",1
7784,2857299,Ranitidine and hepatotoxicity,,1
7785,2857709,"A comparative trial of the antidepressant, anxiolytic, and cardiovascular effects of trimipramine and doxepin in depressed hospitalized patients","""After a 1-week placebo washout, 25 depressed hospitalized patients were treated for 4 weeks with trimipramine or doxepin in a fixed equivalent dosage schedule ending in 150 mg h.s. The study used a parallel group double-blind design. Comparisons over time revealed that both drugs improved patients' overall well-being as indicated by the rating scales studied. Significant (p less than .05) differences between the treatments favored trimipramine over doxepin: the Hamilton scale diurnal variation cluster at Week 1 and the sleep disturbance factor at Week 4; the Clinical Global Impressions improvement index at Week 1; and the Anxiety Status Inventory somatic symptoms cluster at Week 4. No differences in blood pressure, heart rate, PVCs, or PACs were observed in any of the comparisons. The total number of side effects reported was greater in the doxepin-treated patients.""",1
7786,2858698,Valproic acid associated abnormalities of carnitine metabolism,,1
7787,2859803,Chlorpropamide-induced cholestatic jaundice and pseudomembranous colitis,"A previously healthy 59-year-old man received chlorpropamide 250 mg/day for adult-onset diabetes. Within 1 month of starting the drug, he developed cholestatic jaundice and pseudomembranous colitis. The colitis worsened during subsequent treatment with multiple antibiotics and sulfasalazine. Oral vancomycin produced a prompt and total remission. One similar case of chlorpropamide toxicity manifested by jaundice and colitis has been previously reported. It is possible that the sulfonamide moiety of the chlorpropamide was implicated in the development of the colitis.",1
7788,2860483,Ranitidine hepatotoxicity in renal transplant patient,,1
7789,2864011,Terfenadine and hepatitis,,1
7790,2865199,"Hepatic metabolic function in patients receiving long-term methotrexate therapy: comparison with topically treated psoriatics, patient controls and cirrhotics","Standard biochemical liver function tests and the clearances of antipyrine and indocyanine green have been compared in psoriatic patients taking methotrexate, psoriatic patients on topical treatment, patient controls and patients with hepatic cirrhosis. The methotrexate-treated patients showed significant elevations in alkaline phosphatase (p less than 0.025) and gamma glutamyl transpeptidase activities (p less than 0.05) compared to topically treated psoriatics and patient controls. The clearance of antipyrine was reduced in the methotrexate treated group but not significantly (p less than 0.1 greater than 0.05). In contradistinction, the weight-adjusted clearance of indocyanine green was significantly impaired in the methotrexate group in comparison with the topically treated psoriatics (p less than 0.01). The clearance of both antipyrine and indocyanine green were markedly lowered in the cirrhotics (p less than 0.001 against all other groups). These data suggest that the serial measurement of alkaline phosphatase and indocyanine green clearance may provide a non-invasive indicator of the development and progression of methotrexate-related liver injury.",1
7791,2866493,Comparison of buspirone and diazepam in generalized anxiety disorder,"""A total of 66 outpatients meeting Diagnostic and Statistical Manual (DSM-III) criteria for generalized anxiety disorder began treatment in a randomized double-blind study that compared the efficacy and safety of buspirone and diazepam. Thirty-nine outpatients completed the 4-week trial. Both drugs were administered in a 1:1 dosage ratio; the daily prescribed dose did not exceed 40 mg. The mean daily dose of buspirone prescribed throughout the study was significantly higher than that of diazepam. Diazepam had a significantly earlier onset of efficacy than buspirone, although both drugs were equivalent after 4 weeks of treatment. Adverse reactions were more frequent in the diazepam group. Total scores from the Hamilton anxiety scale and physician's global ratings show that diazepam was significantly superior to buspirone during the initial 2 weeks of treatment. These findings are further corroborated by the results of patients' self-rated scales.""",1
7792,2868682,[Hepatotoxicity of drugs commonly used in rheumatology],,1
7793,2869702,A case of alprazolam-related hepatitis,,1
7794,2870463,Iron poisoning,"Iron poisoning continues to be a major toxicologic problem, with major impact on the gastrointestinal and circulatory systems. Failure to recognize the severity of iron intoxication may result in an inappropriate level of intervention. By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine. In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume. Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage. Under rare circumstances in which large numbers of iron tablets are present in the gastrointestinal tract, surgical removal may be indicated. In addition, measures such as hemodialysis and exchange transfusion should be reserved for those unusual poisonings in which more conservative therapy is unsuccessful. In rare cases of iron intoxication, late sequelae such as hepatic necrosis and gastrointestinal scarring with obstruction may occur. The prompt recognition and initiation of management of children with acute iron poisoning is the single most critical element in decreasing the morbidity and mortality associated with these products.",1
7795,2871452,Naltrexone and hepatotoxicity,,1
7796,2871605,[Hepatitis and mononucleosis syndrome related to the ingestion of salazosulfapyridine],"The authors report the case of a patient treated by salazosulfapyridine and presenting with hepatitis and mononucleosis. The clinical pattern was similar to infectious mononucleosis including pharyngitis and lymphadenopathy but infection by Epstein Barr virus or cytomegalovirus has been ruled out by serological tests. Responsibility of salazosulfapyridine was highly suggested by the following facts: hepatocellular necrosis was sharply centrolobular, plasmocytosis was the main finding in the white blood cells count and all abnormalities rapidly improved after treatment withdrawal. The authors point out that salazosulfapyridine intolerance could mimic infectious mononucleosis and viral hepatitis. In such cases the drug must be rapidly withdrawn to avoid massive hepatic necrosis.",1
7797,2872666,Acute sulphasalazine hepatotoxicity,We describe a case of severe sulphasalazine hepatotoxicity. The features described are those of an acute hypersensitivity reaction which responded to drug withdrawal alone as steroids were withheld. Supportive treatment only is recommended for this potentially fatal condition.,1
7798,2874203,Effects of anticonvulsive drugs on the activity of gammaglutamyltransferase and aminotransferases in serum,"A cross-sectional study was performed to define patients at risk of developing liver disease due to long-term treatment with anticonvulsive drugs. The activities of gamma-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase and the concentrations of primidone, phenobarbital, phenytoin, and valproic acid in serum were estimated. Epileptic children before therapy were used as controls. The results indicated enzyme induction due to phenobarbital and both enzyme induction and liver cell damage or plasma membrane leakage due to phenytoin. Gamma-glutamyltransferase may be an early indicator of liver disease due to valproic acid.",1
7799,2876632,"Marked atypical lymphocytosis, hepatitis, and skin rash in sulfasalazine drug allergy","A 38-year-old man presented with a generalized pruritic maculopapular rash, fever, myalgias, and edema of the face and neck. Laboratory examination revealed eosinophilia, atypical lymphocytosis, and abnormal liver function results. The clinical course was characterized by rapid resolution after initiation of steroid therapy and withdrawal of sulfasalazine, which had been started three weeks earlier for abdominal cramping and diarrhea. This clinical picture suggests a drug-induced hypersensitivity reaction to a drug commonly used for inflammatory bowel disease, sulfasalazine.",1
7800,2878646,Sulphasalazine hepatotoxicity: lack of a hypersensitivity response,,1
7801,2881002,'Eve' and 'Ecstasy'. A report of five deaths associated with the use of MDEA and MDMA,"""3,4-Methylenedioxymethamphetamine (MDMA, """"Ecstasy""""), a synthetic analogue of 3,4-methylenedioxyamphetamine, has been the center of recent debate over its potential for abuse vs its use as a psychotherapeutic agent. Following its emergency classification in Schedule 1 by the Drug Enforcement Administration in 1985, 3,4-methylenedioxyethamphetamine (MDEA, """"Eve"""") has appeared as MDMA's legal replacement. MDMA is thought to be safe by recreational users and by psychotherapists who support its use. The details of five deaths associated with the use of MDMA and MDEA are reported. In three patients, MDMA or MDEA may have contributed to death by the induction of arrhythmias in individuals with underlying natural disease. In another patient, use of MDMA preceded an episode of bizarre and risky behavior that resulted in accidental death. In another patient, MDMA was thought to be the immediate cause of death. Death as a consequence of the use of these drugs appears to be rare, but it does occur; this outcome may be more common in individuals with underlying cardiac disease.""",1
7802,2881417,Modifications of liver enzymes during heparin therapy,,1
7803,2884090,[Clozapine-induced cholestatic liver lesions. A case study],"During neuroleptic treatment with clozapine, transitory reversible rise in transaminases is not rare, while severe parenchymal damage with icterus has not previously been reported. Such a case is now described: a 54-year-old woman developed clozapine-induced cholestasis with severe liver damage.",1
7804,2884855,An open one-year comparison of doxazosin and prazosin for mild to moderate essential hypertension,"The long-term safety, efficacy and effect on serum lipid profile of doxazosin, a new alpha 1-adrenoceptor inhibitor administered once daily, were compared with those of prazosin, administered twice daily, in 104 patients with essential hypertension treated for 1 year. Doxazosin produced clinically significant decreases in standing and supine blood pressures over a period of 1 year. These decreases were similar to those produced after an initial period of 12 weeks of double-blind therapy. The reductions in blood pressure produced by doxazosin were greater than those produced by prazosin. Minor and clinically nonsignificant changes in heart rate were observed with both drugs. The favorable changes from baseline in plasma lipid concentrations observed after 12 weeks of double-blind therapy were maintained throughout the 1-year open study. These were average increases in the mean high density lipoprotein cholesterol concentration and the derived high density lipoprotein/total cholesterol ratio, and average decreases in total cholesterol and total triglyceride concentrations. The incidence of side effects reported was similar for doxazosin and prazosin. Most were rated as being mild or moderate in severity and were tolerated or disappeared with continued therapy. Results of laboratory tests, electrocardiograms, ophthalmoscopy and body weight measurements revealed only minor changes from baseline, and none was judged to be of clinical significance. These findings demonstrate that doxazosin is a safe and effective antihypertensive agent suitable for once-daily dosing, and has favorable effects on the serum lipid profile.",1
7805,2885169,"Terazosin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in essential hypertension","Terazosin is a post-synaptic alpha 1-adrenoceptor antagonist with a similar pharmacodynamic profile to prazosin. It differs from prazosin in having a longer duration of action, with an elimination half-life some 2 to 3 times that of prazosin, allowing the convenience of once daily administration. Moreover, its absorption from the gastrointestinal tract is more complete and predictable than that of prazosin which may facilitate dose titration. Terazosin therapy results in a significant reduction in blood pressure in patients with mild to moderate essential hypertension, with little influence on heart rate. The drug is an effective antihypertensive when administered as monotherapy or in combination with a range of antihypertensive agents including beta-blockers, diuretics and combinations of the two. In the few patients with congestive heart failure studied, terazosin produced an increase in cardiac output with a reduction in ventricular filling pressure and systemic vascular resistance, but no studies have been performed to assess the therapeutic potential of terazosin in this indication. Reductions in total plasma cholesterol and low density plus very low density lipoprotein cholesterol fractions have been reported after terazosin therapy, while high density lipoprotein cholesterol concentrations have tended to increase. Should such beneficial changes be confirmed in long term clinical studies they would suggest a therapeutic advantage of terazosin over some other antihypertensive drugs, particularly diuretics, which have been reported to adversely affect the plasma lipid profile. The most common side effects associated with terazosin treatment are dizziness, headache, asthenia and nasal congestion, but these are usually mild and do not require treatment discontinuation. Terazosin is normally administered once daily, starting at a dose of 1 mg/day and gradually titrating upwards as the blood pressure stabilises at each new dose, until blood pressure is adequately controlled or to a maximum dose of 20mg daily. First-dose syncope occurs rarely after terazosin, and can largely be avoided by giving the first dose at bedtime. Thus, terazosin offers a useful alternative to the drugs currently available for the management of mild to moderate essential hypertension either as monotherapy or in combination with other antihypertensive drugs.",1
7806,2886672,Multiple severe complications from recreational ingestion of MDMA ('Ecstasy'),,1
7807,2889256,Famotidine: postmarketing clinical experience,"""A postmarketing survey of famotidine usage (phase IV survey) tracked 6346 patients at 602 locations from August 1985 to April 1986. Through the survey, the efficacy and the safety of famotidine were studied. The patients included 4618 cases of peptic ulcer, 106 cases of reflux esophagitis, 1006 cases of upper gastrointestinal tract bleeding, 343 cases of bleeding and ulcer prophylaxis, and 273 cases of gastritis and other diseases, totalling 6346 patients. Efficacy was analyzed by type of disease in terms of overall improvement; results of intermittent hemostatic efficacy were obtained for upper gastrointestinal tract bleeding; and safety was assessed. Overall, the results were good; the 8-week healing rate was 92.4%, and 72.3% of patients had their bleeding controlled within 7 days of beginning famotidine therapy. Side effects occurred in only 0.43% of patients, and abnormalities in laboratory test results were observed in less than 1% of patients. Gastrointestinal side effects, especially constipation, occurred most frequently. Most side effects were mild. The results of this postmarketing survey indicate that famotidine is a safe and effective H2-receptor antagonist.""",1
7808,2889964,Oesophageal varices associated with busulphan-thioguanine combination therapy for chronic myeloid leukaemia,"5 patients receiving continuous busulphan and 6-thioguanine for chronic myeloid leukaemia (CML) were found to have oesophageal varices associated with abnormal liver function tests. 3 of these cases presented with gastrointestinal haemorrhage and 1 patient died. The 2 other cases had varices discovered at endoscopy. Nodular regenerative hyperplasia (NRH) of the liver was identified as the cause of portal hypertension in the 4 patients on whom liver biopsies were done. The administration of busulphan and thioguanine in combination is likely to be associated with the development of NRH, with portal hypertension and oesophageal varices occurring in a substantial proportion of cases.",1
7809,2892253,Safety of nizatidine in clinical trials conducted in the USA and Europe,"The safety of nizatidine as treatment for active duodenal or gastric ulcer disease or as maintenance therapy following ulcer healing was assessed in 3800 nizatidine-treated individuals in clinical trials conducted in the USA and Europe. Safety parameters included physical examinations, electrocardiograms, eye examinations, serum chemistries and testosterone, hematology, and urinalyses. Adverse events were recorded without judgment of causality. Early discontinuations and adverse events, including complications of active duodenal ulcer disease, occurred more frequently in placebo-treated patients than in those given nizatidine. No differences were observed between the nizatidine and ranitidine treatment groups in regard to adverse event incidence or severity. Minimal changes in uric acid values were observed during ranitidine and nizatidine therapy. Abnormal liver function tests occurred infrequently and to an equal extent in nizatidine and placebo treatment groups. No clinically relevant differences in laboratory test results were observed between treatment groups in studies conducted in Europe.",1
7810,2893228,Dangers of methotrexate/etretinate combination therapy,,1
7811,2896139,Comparison of delayed-release 5-aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis,"To assess the safety and efficacy of delayed-release mesalazine (5-aminosalicylic acid) as maintenance treatment for patients with ulcerative colitis, 100 patients with quiescent colitis were randomly grouped to receive either delayed-release mesalazine or an equivalent dose of enteric-coated sulfasalazine in a 48-wk trial. Groups were comparable for age, sex, and duration and extent of disease. Relapse rates at 48 wk were as follows: sulfasalazine 38.6% (95% confidence limits, 24%-54%) and mesalazine 37.5% (95% confidence limits, 24%-53%), chi 2 = 0.01, p greater than 0.90. Mean time to relapse, cumulative relapse rate, and relapse severity were similar in the two groups. Headaches and upper gastrointestinal symptoms--common at trial entry--improved to a greater extent in patients receiving mesalazine. Delayed-release mesalazine is an effective treatment for maintaining ulcerative colitis remission and is associated with fewer side effects than equivalent doses of enteric-coated sulfasalazine.",1
7812,2898027,A multicenter comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. The Lovastatin Study Group III,"""This study compares lovastatin and cholestyramine resin therapy in patients with severe primary hypercholesterolemia. Two hundred sixty-four patients on lipid-lowering diets were randomized equally to receive 12 g of cholestyramine resin, 20 mg of lovastatin, or 40 mg of lovastatin, each twice a day. The mean reductions among the three groups after 12 weeks' treatment in levels of total plasma cholesterol (-17%, -27%, and -34%, respectively) and low-density lipoprotein cholesterol (-23%, -32%, and -42%, respectively) and the median reductions in apolipoprotein B levels (-21%, -28%, and -33%, respectively) were all significantly different between groups. Similar mean increases in high-density lipoprotein cholesterol levels (8%, 9%, and 8%, respectively) and median increases in apolipoprotein A-1 levels (7%, 6%, and 11%, respectively) were observed in all treatment groups. Cholestyramine resin treatment had no significant effect on very low-density lipoprotein cholesterol and apolipoprotein A-II levels and produced a median 11% increase in plasma triglyceride concentration; in contrast, administration of either 20 or 40 mg of lovastatin twice a day was associated with median reductions in very low-density lipoprotein cholesterol levels (-34% and -31%, respectively) and plasma triglyceride levels (-21% and -27%, respectively) and median increases in levels of apolipoprotein A-II (8% and 13%, respectively). Adverse events in all treatment groups were preponderantly in the gastrointestinal tract; gastrointestinal tract symptoms that could be attributed to therapy with a specific drug occurred in 58% of the cholestyramine resin group, 13% of the 20-mg lovastatin group, and 14% of the 40-mg lovastatin group. The only drug-attributable serious adverse event was a reversible myopathy in a patient taking 40 mg of lovastatin twice a day. We conclude that lovastatin is both more effective and better tolerated than cholestyramine resin in the treatment of primary hypercholesterolemia.""",1
7813,2899219,Deterioration in primary biliary cirrhosis in patient on ursodeoxycholic acid,,1
7814,2901299,Liver-function studies in heart-transplant recipients treated with cyclosporin A,"Cyclosporine (CsA) hepatotoxicity has been reported but has not been studied systematically. This study includes 17 patients undergoing heart transplantation (HTx) and being treated with CsA, azathioprine, and corticosteroids. We assessed liver function in these patients before HTx and during the following month by five biological tests: total bile acids (BA), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), and total bilirubin in serum, and the aminopyrine breath test (ABT). With these tests we could classify the patients into three groups before HTx: normal (group I), mildly altered (group II), and severely altered (group III) liver function. During CsA therapy we did not observe any changes in any test results except for BA and GGT, and these only in group III. The ABT improved significantly in this group. During kinetic studies in patients without liver dysfunction, we confirmed a direct interference of CsA on BA secretion mechanism, but not the GGT increase, which remains to be explained.",1
7815,2904533,Reversible ceftriaxone-associated biliary pseudolithiasis in children,"Serial abdominal ultrasonography was performed in 37 children being treated with ceftriaxone for serious infections. Biliary concrements developed in 16 patients, causing symptoms in 3, one of whom also had urolithiasis with renal colic and obstructive ureteropyelectasia. After cessation of ceftriaxone treatment, ultrasound abnormalities and symptoms gradually disappeared, with complete sonographic resolution after 2 to 63 days.",1
7816,2904748,A multicenter study of doxazosin in the treatment of severe essential hypertension,"The antihypertensive efficacy and safety of doxazosin, a selective alpha 1-inhibitor, were assessed in 33 severely hypertensive patients. The study involved three phases: a 1-day baseline period, a 32-day period in which patients received doxazosin, 1 to 16 mg, once daily, and a 4-week maintenance period. All patients were considered therapy successes (sitting diastolic blood pressure either less than or equal to 90 mm Hg or greater than or equal to 10 mm Hg reduction) at a mean daily dose of 8.1 mg. Twenty-seven patients (82%) achieved good blood pressure control (sitting diastolic blood pressure less than or equal to 90 mm Hg) at a mean dose of 6.7 mg once daily. By the final treatment visit, mean systolic/diastolic blood pressures in the sitting and supine positions were significantly reduced by 40/29 and 37/28 mm Hg from a mean baseline of 180/121 and 181/121 mm Hg to final visit values of 140/91 and 144/92 mm Hg, respectively (p less than 0.05). Eleven patients experienced one or more side effects that were mild or moderate and disappeared or were tolerated with continued therapy. During the study no abnormal laboratory test findings were identified by the investigators. The investigators' global assessment of the efficacy and toleration of once-daily doxazosin therapy was excellent or good for 31 (94%) patients and fair for the remaining two patients.",1
7817,2905941,Phenothiazine-induced cholestatic jaundice,"""Proposed mechanisms, clinical features, prevalence, and treatment of phenothiazine-induced cholestatic jaundice are reviewed, and interactions between phenothiazines and other drugs that could theoretically alter the risk of cholestasis are described. Phenothiazine-induced jaundice is classified as a form of cholestatic hepatocanalicular hepatotoxicity and as an acute liver disease. Occasionally cholestatic jaundice may progress to chronic liver disease. The mechanism of hepatotoxicity is not completely understood but may involve a combination of physiochemical, immune, and direct toxic effects. Based on proposed mechanisms, concomitant use of drugs that alter microsomal hepatic enzyme function or have metabolic pathways that interfere with or overlap with those of the phenothiazines could be expected to potentiate or reduce the risk of cholestasis. The estimated prevalence of jaundice with chlorpromazine is 1-2%. The prevalence of jaundice with other phenothiazines is probably similar. The onset of jaundice usually occurs during the first one to four weeks of therapy. In most cases, discontinuation of the offending drug is the only treatment required. Jaundice usually resolves without sequelae two to eight weeks later. Pruritus can be relieved by topical corticosteroid or analgesic therapies or by oral antihistamines or bile acid sequestrants if topical therapy is ineffective. Whenever possible, reinstitution of neuroleptic therapy should be delayed until the reaction has resolved. Selection of a nonphenothiazine neuroleptic agent may be preferred. Phenothiazine-induced cholestatic jaundice occurs relatively infrequently and is usually self-limited; topical agents and oral antihistamines can alleviate the discomfort associated with the reaction.""",1
7818,2908831,Zidovudine-induced hepatotoxicity,,1
7819,2909202,Recombinant human erythropoietin treatment in pre-dialysis patients. A double-blind placebo-controlled trial,"""STUDY OBJECTIVE: To determine the efficacy and safety of recombinant human erythropoietin (r-HuEPO) in predialysis renal patients. DESIGN: Randomized, double-blind, placebo-controlled trial for 8 weeks. SETTING: Inpatient and outpatient facility in the Clinical Research Center of a university-based hospital. PATIENTS: Fourteen adult subjects with renal insufficiency (mean serum creatinine, 473 mumol/L +/- 61 [6.2 +/- 0.8 mg/dL]) and anemia (mean hematocrit, 0.27 +/- 0.01). INTERVENTIONS: Recombinant human erythropoietin, 50, 100, or 150 IU/kg body weight or placebo given intravenously three times per week. MEASUREMENTS AND MAIN RESULTS: Subjects who received active r-HuEPO showed a dose-dependent rise in hematocrit; mean hematocrit increased 41% from 0.27 +/- 0.01 to 0.38 +/- 0.01. At the same time, erythrocyte mass rose 43% from 13.7 +/- 0.6 mL/kg in the baseline state to 19.6 +/- 1.0 mL/kg after treatment. Maximal oxygen consumption during exercise increased 9% from 16.0 mL/min.kg +/- 1.8 to 17.5 mL/min.kg +/- 1.9. CONCLUSIONS: Recombinant human erythropoietin is effective and safe in ameliorating the anemia of pre-dialysis patients.""",1
7820,2912522,Jaundice and intrahepatic cholestasis following high-dose megestrol acetate for breast cancer,"""High-dose megestrol acetate, a synthetic progestin, has been advocated recently in treating patients with metastatic breast carcinoma; no significant increase in adverse effects has been reported. This report describes a patient with jaundice and intrahepatic cholestasis after high-dose megestrol acetate therapy. This cholestatic lesion may have a pathogenesis similar to that observed with estrogens and oral contraceptives.""",1
7821,2917307,High-dose cytosine arabinoside and daunorubicin as primary therapy in elderly patients with acute myelogenous leukemia. A phase I-II study of the Southeastern Cancer Study Group,"""We undertook a phase I-II trial in elderly (age greater than or equal to 60 years) untreated acute myelogenous leukemia (AML) patients using brief, intensive therapy to improve induction rates and overall survival in older AML patients. Twenty-one patients ranging in age from 60 to 81 years (median, 66 years) were treated using either a 4- or 5-day course of high-dose cytosine arabinoside, 3 g/m2 intravenously (IV) every 12 hours; followed by daunorubicin, 45 mg/m2/d IV bolus for 3 consecutive days. Thirteen patients were entered at the first dose level (a 4-day course or eight doses of cytosine arabinoside), whereas eight patients underwent therapy at the second dose level (a 5-day course or ten doses). Patients who achieved a complete remission received a repeat course of high-dose cytosine arabinoside and daunorubicin within 4 weeks of attaining remission. Seven patients had an antecedant history of a myelodysplastic syndrome. Infection was the major complication experienced by this elderly patient group, and included ten episodes of bacteremia or fungemia (four of which were fatal) and five cases of pneumonia (one fatality). Nine of the 21 patients (three of 13 at the first dose level and six of eight at the second dose level) achieved a complete remission. Median remission duration was 9 months (range, 4-19+ months). Although high-dose cytosine arabinoside plus daunorubicin was an effective antileukemic therapy, it is too toxic to recommend for most elderly leukemic patients.""",1
7822,2919623,Allopurinol hepatotoxicity,,1
7823,2920047,Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples,"""Twenty-nine patients with active rheumatoid arthritis receiving long-term oral weekly methotrexate (MTX) therapy were studied to determine the extent of their hepatic architectural changes. Liver biopsies (n = 101) were performed in all patients before the initiation of MTX therapy, after 2 years, and annually thereafter (mean duration of therapy 53 months). The hepatic histologic grade (5-point scale) in 25 patients increased (worsened) (mean +/- SEM change 0.84 +/- 1.02; P = 0.001). Fibrosis, confirmed by trichrome staining, developed in 14 of 27 patients (52%). A history of alcohol consumption prior to starting MTX correlated significantly with subsequent worsening of the liver biopsy grade (r = 0.55, P = 0.0054). Alcohol intake prior to study entry, elevated weight at MTX initiation, and dose and duration of MTX were significantly associated with the development of fibrosis. Elevations in serum aspartate aminotransferase levels at 29-53 months of therapy correlated with the increase in hepatic histologic grade at the 3-year biopsy (r = 0.50, P = 0.04) and 4-year biopsy (r = 0.58, P = 0.03). We conclude that long-term MTX therapy in rheumatoid arthritis patients results in a statistically significant worsening in hepatic histologic grade, with common development of mild fibrosis. We do not consider these changes to be clinically significant at present.""",1
7824,2927200,[Risk of liver reactions after treatment with flucloxacillin],,1
7825,2930715,Oral contraceptives and primary liver cancer,"The relative risk for developing primary liver cancer in northern Italian users of oral contraceptives, compared to matched controls was calculated based on reported cases in hospitals in the greater Milan area from 1984-1987. The incidence of and mortality from primary liver cancer, as well as the prevalence of oral contraceptive usage, have both been rising to Italy since the late 1950s. 21 cases of liver cancer, in women aged 32-59 (median 50), occurred in the Milan area during the study period. These women, and 145 controls matched for age but admitted to hospitals for a variety of non-neoplastic diseases, were interviewed with a structured questionnaire covering socio-demographics, life style, diet, medical history, and history of use of oral contraceptives and other drugs. 19.0% of the cases had used oral contraceptives compared to 7.6% of controls, a relative risk of 1.8 for up to 5 years' use, and 8.3 for 5 years. History of hepatitis was associated with 14% of cases and 7% of controls. Italians have a higher incidence of liver neoplasms that northern Europeans and Americans, probably because of higher incidence of risk factors, such as hepatitis and alcohol use. The attributable risk for oral contraception, however, is lower in this population.",1
7826,2933968,Acute cholecystitis associated with hepatic arterial infusion of floxuridine,"In a 1 year period, 13 patients underwent pump implantation for liver metastasis from a primary colorectal tumor. The gallbladders were not removed at the time of pump implantation in the initial six patients. In these patients, chemotherapy consisted of floxuridine given every 2 weeks followed by a 2 week rest period and cisplatin over 1 hour by way of the side portal on day 8 of the cycle. The treatment was repeated every 28 days. All patients whose gallbladders were not removed at the time of pump implantation required reoperation for acute or chronic acalculous cholecystitis from 1 to 9 months (mean 5.4 months) after pump implantation. At operation, all patients were found to have various degrees of inflammation and fibrosis. In one patient, significant sclerosing cholangitis was documented that involved the entire intrahepatic ductal system and hepatic duct bifurcation. Cholecystectomy and operative cholangiography are recommended in all patients who undergo pump implantation for metastatic disease to the liver.",1
7827,2934836,Biliary sclerosis associated with hepatic artery infusion of floxuridine,"We report the clinical and radiologic findings and course of two patients who developed drug-related biliary sclerosis during hepatic artery infusion of floxuridine. If severe and persistent jaundice develops during the course of regional hepatic infusion of floxuridine, and obstructive component in the biliary tree must be suspected and investigated by endoscopic retrograde cholangiography. Regional infusion therapy should be stopped immediately. Surgical treatment of the obstructing lesion is avoided unless cholangitis occurs or jaundice persists for more than 3 months and a surgically correctable lesion exists.",1
7828,2935680,Common duct stricture associated with hepatic artery infusion of FUDR,"A case report is presented giving the first detailed description of a benign common duct stricture occurring in a patient receiving hepatic artery infusion of FUDR for metastatic colon cancer. It is postulated that the stricture results from a combination of drug toxicity, and hypoxemia of the duct, with the lesion occurring more often than is recognized. A guide is given for the evaluation of the FUDR-infused patient with suspected nonmalignant duct stricture, and for the methods of alleviating extrahepatic blockage in these individuals.",1
7829,2937274,Sclerosing cholangitis associated with hepatic arterial FUDR chemotherapy: radiographic-histologic correlation,"During a 2-year period, cholangiography was performed on 17 patients with clinical evidence of cholestasis who were receiving hepatic intraarterial floxuridine (IA-FUDR) infusions for treatment of metastatic colorectal adenocarcinoma. The development of cholestasis was associated with persistently elevated alkaline phosphatase, but serial CT examinations of the liver showed no progression of the tumor. All patients had cholangiographic abnormalities (by endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, or operative cholangiography) of the biliary ductal system similar to those in idiopathic sclerosing cholangitis. Certain features, however, appear specific to IA-FUDR-induced cholestasis. All patients studied had segmental involvement at the common hepatic duct bifurcation. The cystic duct and gallbladder were often involved, but the distal common bile duct was spared. Histologic features of periportal and periductal fibrosis were present in specimens obtained from percutaneous liver biopsy in three patients, cholecystectomy in four patients, and autopsy in two patients. When clinical signs of hepatic dysfunction occur in the absence of tumor progression, biliary sclerosis must be suspected.",1
7830,2939001,[Sclerosing cholangitis after chemotherapy by continuous hepatic intra-arterial infusion of fluorodeoxyuridine],"A case of sclerosing cholangitis after a two-month treatment by hepatic artery infusion of FUDR is reported. The patient presented with jaundice and a marked increase in serum alkaline phosphatase activity which persisted after withdrawal of FUDR infusion. Endoscopic retrograde cholangiogram revealed a stricture of the middle part of the common bile duct, which was treated by endoprosthesis insertion. From this report, as well as those previously published, it is concluded that sclerosing cholangitis may complicate continuous hepatic artery infusion with FUDR. This lesion could be secondary to an FUDR-induced arteritis in the branches of hepatic artery which supply bile ducts.",1
7831,2940954,Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome,"All patients with the acquired immunodeficiency syndrome and a first episode of Pneumocystis carinii pneumonia seen at the San Francisco General Hospital between November 1984 and April 1985 were evaluated for oral treatment with dapsone (100 mg/d) plus trimethoprim (20 mg/kg body weight X d). All 15 patients who met the entry criteria improved clinically and radiographically within 3 to 10 days after starting treatment. Repeat pulmonary function tests and gallium lung scans after 3 weeks of therapy also showed improvement. Although side effects occurred in 14 patients, in only 2 were they severe enough to require stopping therapy. Both of these patients had worsening skin rash, and dapsone-trimethoprim therapy was stopped after 10 days. When compared with trimethoprim-sulfamethoxazole or pentamidine used to treat P. carinii pneumonia in similar patients, oral dapsone-trimethoprim is at least as effective, seems to be better tolerated, and may have a lower frequency of serious side effects.",1
7832,2941626,Cholecystitis secondary to infusion chemotherapy,"This report centers on a patient with metastatic colorectal cancer who developed acute and chronic cholecystitis secondary to the infusion of FUDR (fluoro-deoxyuridine) into the hepatic artery. This was documented by sonography, cholescintigraphy, and, ultimately, pathologically on the surgically removed specimen. Undoubtedly, with increasing cumulative treatment days made possible through technological advances in delivery systems, this complication will be seen more frequently. Prophylactic removal of the gallbladder, at the time of pump placement, which does not significantly prolong the operative time nor increase the operative mortality, should be performed to prevent this complication from occurring.",1
7833,2946507,Antihypertensive activity of isradipine in humans: a new dihydropyridine calcium channel antagonist,"""Isradipine (Sandoz PN 200-110), a new dihydropyridine calcium channel antagonist, was evaluated in a randomized, double-blind, placebo-controlled trial for antihypertensive efficacy in 24 patients with essential hypertension. Two groups were studied: one received placebo throughout the entire study (n = 12) and the other received isradipine (n = 12), 2.5 mg b.i.d., for the first week, 5 mg b.i.d. the second week, and 10 mg b.i.d. the third week after an initial 3-week baseline placebo period. Blood pressure was measured approximately 3 hours after dosing. Isradipine, at a total daily dose of 10 mg, lowered average supine diastolic blood pressure 11.8 mm Hg, with only a 3.5 mm Hg decrease in systolic blood pressure compared with baseline. At a total daily dose of 20 mg, average supine diastolic blood pressure decreased 14.8 mm Hg and supine systolic blood pressure declined 13.9 mm Hg; both were significantly decreased compared with placebo or baseline. Heart rate was increased only minimally by isradipine. Renin level activity was increased slightly by isradipine. No serious adverse clinical or laboratory experiences were noted. Isradipine appears to be effective in lowering blood pressure without reflex tachycardia.""",1
7834,2948451,Etretin therapy for severe psoriasis. Evaluation of initial clinical responses,"We have investigated the clinical responses of 21 patients with severe psoriasis to therapy with etretin, a metabolite of etretinate. In a preliminary double-blind dose-finding study, the optimum dose of etretin was determined to be 50 mg/d (mean, 0.66 mg/kg/d). In an open study, patients receiving etretin therapy were followed up for a minimum of six months. An excellent or good response (greater than 50% clearance) was obtained in 18 of 21 patients. The incidence of mucocutaneous side effects from etretin therapy was similar to that previously reported with etretinate therapy. As a group, patients who received etretin therapy for six or more months showed no significant aberrations from normal levels of serum lipids or serum liver enzymes. However, five patients had mild elevation of liver enzymes or blood lipids, which were corrected by dose reduction. Etretin showed equivalent efficacy to that previously reported with etretinate in severe recalcitrant plaque psoriasis vulgaris. Taken with the reportedly more rapid clearance of etretin from the body, there may be clinical advantages of the use of etretin over the use of etretinate.",1
7835,2950200,Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent,"The therapy of Pneumocystis carinii (PC) pneumonia is often unsuccessful, particularly in patients with acquired immune deficiency syndrome (AIDS). Because of difficulties in growing the organism in vitro or obtaining purified organisms, current treatment choices have been made with little information on the metabolic effects of therapeutic agents on PC. This report quantitates the effects of the commonly used antifolates as well as the classic antineoplastic antifolate methotrexate and a lipid-soluble analogue, trimetrexate, on the target enzyme, dihydrofolate reductase (DHFR), in the PC organisms. Trimethoprim and pyrimethamine were found to be weak inhibitors (ID50 = 39,600 and 2,800 nM, respectively), while methotrexate and trimetrexate were potent reductase inhibitors (ID50 = 1.4 and 26.1 nM, respectively). transport studies with radiolabeled compounds showed that compounds with the classic folate structure (methotrexate and leucovorin) were not taken up by the intact PC organisms. In contrast, trimetrexate exhibited rapid uptake. These results suggest a major therapeutic advantage may be gained by combining a potent, readily transported PC DHFR inhibitor such as trimetrexate with the reduced folate leucovorin to achieve a highly potent antiprotozoan effect while preventing toxicity to mammalian cells.",1
7836,2950752,Hepatitis in patients receiving intraarterial chemotherapy for metastatic colorectal carcinoma,"Fifty-one patients with metastatic colorectal carcinoma confined to the liver received intraarterial chemotherapy through the hepatic artery via a subcutaneous pump. The chemotherapy consisted of sequential 14-day infusions of floxuridine (FUDR) and dichloromethotrexate (DCMTX) or a 14-day infusion of FUDR and bolus mitomycin (MMC). Twenty-four patients (47%) developed hepatitis with an elevation of hepatic serum transaminase (serum glutamic oxaloacetic transaminase, SGOT, or serum glutamic-pyruvic transaminase, SGPT). The median time to develop hepatitis was 11 weeks after initiation of chemotherapy. The morphologic effects of chemotherapy were evaluated in eight patients with hepatitis. All the patients with hepatitis had normalization of the serum transaminases after temporary cessation of chemotherapy. There was a trend toward a greater chance of remission in patients who developed hepatitis. Sixty-seven percent of the patients with a therapeutic response had hepatitis, whereas only 33% of the patients without a response had hepatitis. However, this difference was not statistically significant. The occurrence of hepatitis was not related to FUDR dose, drug program (FUDR-DCMTX vs. FUDR-MMC), pump flow rate, hepatic arterial anatomy, sex, or age of the patients.",1
7837,2952797,Toxicity of longterm low dose D-penicillamine therapy in rheumatoid arthritis. Cooperative Systematic Studies of Rheumatic Disease Group,"After a controlled, double blind multicenter trial of D-penicillamine in the treatment of rheumatoid arthritis, 148 patients were followed for an additional year in an open label trial. Complications of longterm D-penicillamine included rash, gastrointestinal manifestations, proteinuria, bone marrow depression, myasthenia gravis, myositis, acute febrile reaction and pemphigus foliaceus. With the exception of one patient with myasthenia gravis, all adverse reactions resolved after withdrawal of D-penicillamine. While the complications of D-penicillamine therapy are usually dose related, these reactions can occur at any time and at any dose. Continued and frequent longterm monitoring of D-penicillamine therapy is required.",1
7838,2957048,Pediatric phase I trial and pharmacokinetic study of trimetrexate,"Trimetrexate, a new nonclassical antifolate, was evaluated in a phase I trial in children with refractory cancer including nine with acute leukemia and 21 with solid tumors. The drug was administered as an i.v. bolus injection weekly for three doses, and courses were repeated every 28 days. The dose ranged from 35 to 145 mg/m2. Thirty patients who received a total of 33 courses were evaluable for toxicity, including 19 who were evaluable for hematological toxicity. The maximally tolerated dose for patients with a solid tumor and leukemia was 110 mg/m2. The dose-limiting toxicities were myelosuppression, mucositis and a pruritic, diffuse maculopapular rash. Other side effects observed included transient, mild elevations of serum transaminases, mild nausea and vomiting, and a local phlebitis at the site of injection at higher dose levels. A single patient with delayed drug clearance had evidence of renal toxicity with a transient increase in serum creatinine. The pharmacokinetics of trimetrexate were studied in 25 patients over the entire dose range. There was considerable interpatient variability in total drug clearance (range 9.2 to 215 ml/min/m2) and half-life (2.1 to 20 h). There was a suggestion of a correlation between plasma concentration at 24 h and the development of hematological toxicity at the highest dose level. Trimetrexate was cleared primarily by biotransformation with renal clearance accounting for only 10% of total clearance. Two metabolites of trimetrexate which inhibit the enzyme dihydrofolate reductase were identified in the urine. One of these appears to be a glucuronide conjugate.",1
7839,2958709,Pneumocystis carinii pneumonitis,,1
7840,2960788,Trimetrexate: a second generation folate antagonist in clinical trial,"Trimetrexate is a promising new lipophilic antifolate with antitumor and antimicrobial activity, which is currently undergoing clinical trials. It differs from methotrexate in its transport and intracellular retention, and may be useful against tumors resistant to methotrexate because of impaired transport or deficient polyglutamylation. In preclinical studies, it has demonstrated a broader spectrum of antitumor activity than methotrexate, and appears to have synergistic antitumor activity when combined with a number of other agents. In clinical trials, the primary toxicity has been hematologic, with rapid recovery and no evidence of cumulative dose effect. Nonhematologic toxicity has been sporadic. Preliminary results of phase II trials indicate activity against breast, non-small-cell lung, and head and neck tumors. In addition, trimetrexate with simultaneous leucovorin rescue appears to be a promising new treatment for pneumocystis pneumonia in AIDS patients, with minimal toxic side effects.",1
7841,2966038,Reported adverse reactions to and consumption of nonsteroidal anti-inflammatory drugs in Denmark over a 17-year period,"""Over the 17-year period 1969-1985, 2,721 reports of 3,521 suspected adverse drug reactions (ADRs) associated with non-steroidal anti-inflammatory drugs (NSAIDs) were submitted to the Danish Committee on ADRs. The results are presented together with the consumption of each drug during the same period. The total sale of NSAIDs showed a four-fold increase during the 17 years, the average corresponding to a permanent intake by 2.2% of the population. The number of reported ADRs per defined daily dose (DDD) sold was markedly lower for """"older"""" drugs like the butazones, indomethacin, ibuprofen, naproxen, ketoprofen, and fenoprofen than for the drugs marketed during the last decade. These differences could not be accounted for by the well-known biases attached to spontaneous ADR reporting. Of 67 fatal reactions, 25 were due to bleeding or perforation of a gastric ulcer, mostly during treatment with indomethacin and naproxen, and in elderly people, and 27 were caused by bone marrow depression or leukaemia, begun mostly during treatment with butazones, but some with indomethacin and naproxen as well. It is pointed out that all reports on fatal bone marrow depression associated with butazones were submitted before 1976 and that the fact that none have been received since that time could be a result of better understanding of the proper dosage of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
7842,2967101,Three cases of diflunisal hypersensitivity,,1
7843,2967780,A multicentre placebo-controlled study in general practice to evaluate the efficacy and safety of tizanidine in acute low-back pain,"Patients (112) with acute low-back pain of recent onset were recruited to this double-blind, randomized, placebo-controlled parallel group study in general practice to evaluate the efficacy and tolerability of the muscle relaxant, tizanidine. They were treated for 7 days with tizanidine (4 mg three times daily) or matching placebo. Aspirin tablets (300 mg) were taken as required as 'rescue' medication. Symptoms were assessed by the patient and doctor before treatment, and after 3 and 7 days. Patients recorded pain and aspirin consumption in a daily diary. Both treatments were effective. In patients who had taken no medication prior to entry, aspirin consumption was almost halved in the first 3 days of taking tizanidine compared with placebo (P = 0.037). Results for pain at rest, pain at night, restriction of movement and pain on movement suggest that tizanidine may give greater improvement, earlier. No serious drug-related adverse events or abnormal biochemistry or haematology were observed in either group. Drowsiness occurred in 22% of patients taking tizanidine although, in patients with severe acute low-back pain, sedation, analgesia and bed rest might be beneficial and desired. Considerably more patients given aspirin/placebo had gastro-intestinal side-effects (P = 0.018). In conclusion, tizanidine may reduce the need for analgesics and be useful in the treatment of acute low-back pain.",1
7844,2968261,Clinical and endocrine effects of cyproterone acetate in postmenopausal patients with advanced breast cancer,"A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.",1
7845,2970126,"[Anuria, hepatocellular insufficiency and bone marrow aplasia after the administration of streptozocin and fluorouracil]",,1
7846,2971818,Trimetrexate: predictors of severe or life-threatening toxic effects,"In four phase II trials of trimetrexate given iv daily for 5 days, we noted marked variability among patients in the development of severe or life-threatening toxic effects. In an effort to define which of 15 patient characteristics were associated with toxic effects of this degree, we have carried out single-factor and multifactor analyses on toxic effects during the first cycle of therapy in 68 patients. The final logistic regression model identified both low pretreatment serum protein levels and metastatic liver disease as significant correlates of severe toxic effects (P = .02 and P = .0005, respectively). While drug dose was an important element of the best logistic model, its statistical significance was only borderline. Trimetrexate is extensively protein bound and is cleared primarily by hepatic metabolism, so it is not unreasonable to believe that alteration in protein binding of the drug or in metabolic capacity of the liver could produce enhanced toxic effects. Although the validity of these predictors should be confirmed, it seems prudent to recommend lower starting doses of trimetrexate for patients with metastatic liver disease and/or low protein levels and dose escalation if toxic effects allow it.",1
7847,2983208,Etoposide (VP-16-213). Current status of an active anticancer drug,,1
7848,2984149,Liver carcinoma in an athlete taking anabolic steroids,,1
7849,2996384,Hepatic necrosis associated with herpes virus after isoflurane anesthesia,,1
7850,2997324,Multiple hepatic adenomas after long-term therapy with testosterone enanthate. Review of the literature,"We report a case of multiple hepatic adenomas developed in a 32-year-old man with renal allograft after long-term therapy with testosterone enanthate. Histological assessment showed a benign hepatocellular adenoma, which has not regressed over a 6-month follow-up since androgen withdrawal. A review of primary hepatic tumors associated with androgenic-anabolic steroid therapy published in the English literature has been carried out, concentrating on the more relevant recent publications. No previous case of hepatic adenoma with possible relationship to the use of non-17-alpha alkylated compounds has been reported.",1
7851,3002916,Ten year's experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease,"Methotrexate and folinic acid was administered as primary therapy in 185 patients with gestational trophoblastic disease between 1974 and 1984. Methotrexate and folinic acid induced complete remission in 147 (90.2%) of 163 patients with nonmetastatic disease and in 15 (68.2%) of 22 patients with low-risk metastatic disease. Sustained remission was achieved in 132 (81.5%) patients following only one course of chemotherapy. All patients with methotrexate resistance subsequently achieved remission with Actinomycin D or combination chemotherapy. Methotrexate when administered with folinic acid was associated with granulocytopenia, thrombocytopenia, and hepatotoxicity in 11 (5.9%), 3 (1.6%), and 26 (14.1%) patients, respectively. The human chorionic gonadotropin (hCG) regression curve served as a reliable guide for the administration of chemotherapy and enabled the attainment of a high remission rate while limiting chemotherapy exposure. Methotrexate and folinic acid achieves an excellent therapeutic outcome with limited chemotherapy exposure and effectively limits systemic toxicity.",1
7852,3007684,"Teniposide (VM-26), an overlooked highly active agent in small-cell lung cancer. Results of a phase II trial in untreated patients","""Teniposide, VM-26 (Vumon), was administered in a dose of 60 mg/m2 on days 1 to 5 every third week to 36 patients with histologically confirmed small-cell lung cancer. None had previously received chemotherapy or radiotherapy. The median age was 73 years (range, 52 to 79). Thirty-three patients were evaluable; 21 of these had local disease. Five patients had bone marrow metastases, four had liver involvement, and one CNS metastases. All patients had a performance status less than or equal to 2 before the start of treatment. Thirty patients obtained a response (90%), ten of whom had a complete remission (30%). The median duration of remission was 8+ months (range, 1.1 to 17+ months), whereas the median survival was 8.7 months (range, 1.9 to 20 months). Toxicity was primarily hematologic, with leukopenia the only dose-limiting effect. Besides alopecia, all other side effects were minimal including nausea and vomiting. We find these results provocative in regard to the response rate and the duration of response obtained as well as in reference to the dismal results that prior investigations in previously treated patients have shown. These data may indicate the need for reconsideration of the usual strategy for performing phase II trials.""",1
7853,3009383,"Pharmacokinetics, safety and preliminary clinical experiences using foscarnet in the treatment of cytomegalovirus infections in bone marrow and renal transplant recipients","Fifty seven episodes of severe cytomegalovirus (CMV) infection were treated with iv foscarnet in 13 bone marrow and 33 renal graft recipients. The ranges of the daily dose, duration, average steady state level and total dose were 23-268 mg/kg, 2-46 days, 42-400 mg/l and 2-399 g, respectively. Adverse effects, such as decreased haemoglobin, decreased renal function and increased serum calcium, were observed in a few patients only. Increased liver enzymes, hallucinations and tremor were seen in one uraemic patient and coincided with foscarnet plasma concentrations above 400 mg/l. Among 25 patients evaluated for clinical efficacy, 12 died. Improvements, such as eradication of CMV (8/14 assessable patients), resolution of fever (11/22), and improved laboratory values (13/23) were noted in 17/24 (70%). Controlled trials are warranted on the basis of this study.",1
7854,3011186,Cancer of the liver and the use of oral contraceptives,"A case-control study of the use of oral contraceptives was conducted among women certified as having died from cancer of the liver in the period 1979-82 and in the age range 20-44 years. An age matched group of women who died from other causes, not related to use of oral contraceptives, in the same period were used as controls. Information about use of oral contraceptives was obtained from the general practitioners' notes for both cases and controls. Information was obtained for 30 women with histologically confirmed liver cancer, 19 with hepatocellular carcinoma and 11 with cholangiocarcinoma, and for 147 controls. The results were analysed after adjusting for age at diagnosis and year of birth and showed that use of oral contraceptives was associated with a significantly (p less than 0.05) raised relative risk for hepatocellular carcinoma of 3.8 (95% confidence interval 1.0 to 14.6) and use for eight years or more was associated with a significantly (p less than 0.01) increased relative risk of 20.1 (2.3 to 175.7). There were no apparent increases in risk for cholangiocarcinoma. Despite the small number of cases in this study and the methodological problems in assessing use of oral contraceptives from general practitioners' notes, the results were consistent with other similar studies. Although in the United Kingdom primary liver cancer remains an exceptionally rare disease, especially in young women, further research on the role of oral contraceptives is needed in those countries where it is a much more common disease.",1
7855,3013057,"Isoniazid, rifampin, and hepatotoxicity",,1
7856,3019201,Resolution of a contraceptive-steroid-induced hepatic adenoma with subsequent evolution into hepatocellular carcinoma,"The very rare event of 3 types of liver neoplasia occurring at different times and locations in a user or oral contraceptives is reported. The woman developed benign hepatic adenoma at 36 years of age in 1977 after using pills for 14 years. She had taken a combination of norethindrone and mestranol for the last 7 years. The tumor was 13 cm in diameter and extensively involved the inferior suface of the right lobe. She discontinued pills, the tumor resolved, and she remained well. In 1984 a necrotic hemorrhagic mass with a thick fibrous capsule was then found at the same site. It was a poorly differentiated hepatocellular carcinoma. During a second laparotomy 2 months later for curative resection, another nodular mass 2 cm in diameter was found on the left lobe, apparently a focal nodular hyperplasia. 9 months later several tumor implants appeared on the serosal surface of the transverse colon, metastatic hepatocellular carcinoma. After partial colectomy the woman has been free of tumors for 2 years. The literature on the few cases of malignant transformation of adenomas associated with contraceptive steroids is discussed. Even though such adenomas usually resolve after discontinuation of the pill, patients should probably be followed with ultrasound over several years.",1
7857,3026019,Sulbactam plus ampicillin: interim review of efficacy and safety for therapeutic and prophylactic use,"""The efficacy and safety of sulbactam/ampicillin has been evaluated in 39 studies of therapeutic use and six studies of prophylaxis. Studies of therapy were conducted in 899 patients: 751 seriously ill, many of whom had multiple concurrent diseases, and 148 with gonorrhea. Overall clinical and bacteriologic success was achieved in 92% of assessable cases; 88% of 768 pathogens in these patients were eradicated. Of these pathogens, 43% were resistant to ampicillin; eradication rates of 91% and 85% were achieved in ampicillin-resistant and ampicillin-sensitive organisms, respectively. In 388 patients who received prophylactic sulbactam/ampicillin, efficacy was similar to that of comparative agents and better than that of a placebo in preventing wound infections after appendiceal, biliary, upper-gastrointestinal, or gynecologic surgery. Adverse reactions were infrequent with the exception of injection-site pain, which occurred mainly after intramuscular injection and was reduced in incidence by concurrent administration of lidocaine.""",1
7858,3033852,De novo hepatocellular carcinoma without chronic liver disease but with 17 years of azathioprine immunosuppression,,1
7859,3034543,[Epidemiological and clinical aspects of focal nodular hyperplasia of the liver. An assessment of 886 cases],"""The objective of this study was to check whether there is a link between focalnodular hepatic hyperplasia of the liver and use of birth control pills, and if so, what it is. Focalnodular hepatic hyperplasias consists of hepatocytes, Kupffer's cells, proliferating hepatic ducts, connective tissue and vessels. Characteristically, on the cut surface of a focalnodular hyperplasia specimen is central, star shaped scar tissue with radial branches. The nodular tissue is sharply delineated from the surrounding liver tissue without actually forming an anatomic capsule. Based on the literature and authors' observations 886 cases were assembled for analysis. Results are as follows: Roughly 20% of tumors occur in children and adolescents, barely 18% in males. Use of steroid hormones for contraceptive purposes was found in only 27.8% of patients. Tumor size does not correlate with length of use of birth control pills. In males and patients under 20, tumors are on the average larger than in women and patients over 19. On the other hand, birth control pills are assumed to promote growth of an existing focalnodular hyperplasia for the following reason: Women using oral contraceptives on the average have larger tumors than non-users; oral contraceptive users are younger than the comparison group when the diagnosis is made; symptoms occur more frequently among pill user; however, it is concluded that oral contraceptives can be precluded as a causal pathogenetic factor in focalnodular hyperplasia.""",1
7860,3034850,Clinical efficacy and safety of sulbactam/ampicillin in patients suffering from chronic liver disease,"""Sulbactam is a new beta-lactamase inhibitor with pharmacokinetic characteristics in humans similar to those of ampicillin. A total of 41 patients hospitalized in the Clinic of Infectious Diseases, University of Naples, for chronic liver diseases, were treated with sulbactam/ampicillin (ratio 1:2) for urinary, respiratory, biliary tract or soft tissue infections. Sulbactam/ampicillin was administered im or iv at a dosage of 3-9 g/day depending on the site and severity of the infection. All the patients treated with sulbactam/ampicillin had clinical signs and symptoms of infection, and all the organisms isolated were sensitive to sulbactam/ampicillin (MIC less than 16 mg/l). For both Gram-positive and Gram-negative bacteria the sulbactam/ampicillin MICs were much lower than the ampicillin MICs. In agreement with the favourable in-vitro results, we observed good therapeutic efficacy. 85% of the patients recovered or improved within a few days of therapy, with no clinical relapses, and in 81% of the infections the responsible bacteria were completely eradicated. We observed a low number of side effects (3/41 oral candidosis; 3/41 pain at the im injection site) and no change in the blood chemistry tests.""",1
7861,3041245,Hepatotoxicity of methotrexate in rheumatic diseases,"""Methotrexate-induced hepatotoxicity is well recognised in the treatment of leukaemia, psoriasis and rheumatoid arthritis. The pathological lesions are non-specific, consisting of fatty change, nuclear pleomorphism, hepatocyte necrosis, portal chronic inflammatory infiltrate, fibrosis and cirrhosis. The mechanism of liver injury is poorly understood; intracellular accumulation of methotrexate polyglutamate and consequent folate depletion are suspected to play a role. Early studies in psoriasis clearly established a relationship of the hepatic injury with the frequency of methotrexate administration. With weekly low dose therapy, however, consensus is lacking regarding the incidence of hepatotoxicity because studies have had disparate control groups, used variable dosage regimens and often failed to document pre-existing liver disease or categorised patients at risk, i.e. elderly patients, alcoholics and obese diabetics. Moreover, current methods of assessing the degree of hepatic injury are subjective, relying on interpretation by an experienced histopathologist. Preliminary evidence suggests less frequent and less severe hepatotoxicity occurs in patients with rheumatoid arthritis, probably as a result of lower methotrexate doses and better patient selection. Nevertheless, until the risk of serious liver disease is better defined it is recommended that patients have a pretreatment liver biopsy, a follow-up biopsy after a cumulative dose of 1500 mg, and then biopsies approximately every 2 years in the absence of other evidence of liver disease or risk factors.""",1
7862,3045164,Liver toxicity of retinoid therapy,"Vitamin A metabolism involves storage in the liver. Hypervitaminosis A results in liver abnormalities, including fibrosis and cirrhosis. Ito cells are increased and promote fibrogenesis, which results in cirrhosis. Retinoids (Accutane and Tegison) are used clinically for the treatment of a variety of skin diseases. Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some abnormalities in the liver in about 25% of patients treated. Liver biopsy studies have included isolated case reports and two retrospective and one prospective liver biopsy study of retinoids in humans. Although some increase in histologic liver changes have been noted, most liver biopsy specimens showed no change or improvement. Retinoids do not appear to produce consistent toxic liver abnormalities.",1
7863,3047224,Indomethacin-associated cholestasis,"A patient with no prior history of liver disease developed mild cholestasis, with a moderate elevation of the serum alkaline phosphatase level, several days after instituting indomethacin therapy. The cholestasis resolved soon after the medication was discontinued. An extensive workup, including liver biopsy, revealed no alternative cause. Despite extensive use, indomethacin therapy has been associated with hepatic injury in only nine previously reported cases, as near as we can tell.",1
7864,3048471,"Veno-occlusive disease of the liver following high-dose chemotherapy and autologous bone marrow transplantation in children with solid tumors: incidence, clinical course and outcome","Two hundred and thirty-six consecutive courses of high-dose chemotherapy with autologous bone marrow transplantation in children with solid tumors were reviewed in order to assess the incidence, clinical presentation and outcome of veno-occlusive disease (VOD) of the liver. Patients conditioned with total body irradiation were excluded from this study. Eleven patients (4.6%) met the diagnostic criteria for VOD. The clinical course included sudden weight gain, jaundice, hepatomegaly and ascites. Renal dysfunction and refractoriness to platelet transfusions occurred in the most severe forms. Seven patients recovered within 7-29 days of onset and four patients died, all with renal failure and fluid overload. The time of onset appeared to determine two patterns of outcome: mild forms with early onset (before day 11) and more severe forms with onset after day 17. Analysis of pretransplant factors revealed no significant association with an increased risk of VOD. However, all the patients with severe VOD had received a conditioning regimen containing cyclophosphamide which might be involved in the pathogenesis of VOD.",1
7865,3052053,Hydroxychloroquine treatment of rheumatoid arthritis,"A variety of placebo-controlled and open studies have demonstrated the effectiveness of hydroxychloroquine in the treatment of rheumatoid arthritis. The excellent responses to recurrent treatment in a sample patient illustrate the value of hydroxychloroquine. Because low daily doses of hydroxychloroquine are associated with greater ophthalmologic safety, it would be advantageous to use the smallest effective daily dose, but there are no published controlled efficacy studies using daily doses of less than 400 mg. Hydroxychloroquine may best be employed to treat patients with new onset of disease or those in whom disease is not rapidly progressive. Great potential exists for the use of hydroxychloroquine in combination therapy, but optimal utilization of combination regimens will require performances of additional controlled studies.",1
7866,3054039,Propylthiouracil hepatotoxicity: two pediatric cases and review of the literature,"We have observed isolated hepatotoxicity in two children treated with propylthiouracil (PTU) for hyperthyroidism. Neither patient had risk factors for or clinical evidence of preexisting liver disease. In one patient the drug was promptly discontinued when signs of liver disease were noted. This patient quickly recovered. The second patient continued to receive PTU for several days after developing symptoms. Her illness progressed to fulminant hepatic failure with encephalopathy, and she died. These are the third and fourth pediatric cases reported, and there have been 10 cases reported in adults in the English language literature. Thirteen of the 14 patients are female. The literature regarding all these patients is reviewed. Propylthiouracil may cause lethal hepatic damage. This drug should be discontinued immediately if signs or symptoms of hepatic injury are detected.",1
7867,3055031,Erythromycin-induced hepatitis: simulator of malignancy,"A 67-year-old patient was admitted with a 2-week history of epigastric discomfort that began after an episode of upper respiratory tract infection treated with erythromycin. Results of liver function tests were abnormal. Abdominal ultrasound (US) and computed tomography showed multiple, poorly demarcated irregular lesions in both hepatic lobes, suggestive of diffuse metastatic invasion. Histologic examination of the biopsy specimen revealed drug-induced hepatitis. Ten weeks after withdrawal of the erythromycin, US showed complete resolution of the hyperechogenic liver lesions.",1
7868,3057873,Methotrexate-induced chronic liver injury: guidelines for detection and prevention. The ACG Committee on FDA-related matters. American College of Gastroenterology,,1
7869,3060893,Cyclophosphamide-induced liver necrosis: a possible interaction with azathioprine,"Cyclophosphamide is a valuable drug for the treatment of vasculitis and hepatic toxicity resulting from its use has been reported rarely. We describe four patients in whom cyclophosphamide was associated with liver injury when its administration had been preceded by azathioprine. Microscopy of hepatic biopsy material in three of these cases showed liver cell necrosis. In two of the patients, cyclophosphamide had been given previously without earlier azathioprine and hepatic damage had not been noted. An apparent interaction of cyclophosphamide with azathioprine to cause liver cell necrosis has important implications for the treatment of patients with vasculitis and related disorders.",1
7870,3063490,Safety profiles of the angiotensin-converting enzyme inhibitors,"This review will discuss the safety profiles of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril and lisinopril in patients with hypertension. In general, the safety profiles of ACE inhibitors compare favourably with those of other agents used for the treatment of hypertension. Adverse effects are not common when ACE inhibitors are used at the currently recommended doses. The adverse experiences that do occur with ACE inhibitors can be divided into 3 categories. Hypotension, hyperkalaemia and renal impairment are related directly to the blockade of the angiotensin-converting enzyme. Attention to the clinical condition, including concomitant therapy, reduces the risk of these adverse effects of ACE inhibition. Other adverse effects such as cough and angioedema also occur with all ACE inhibitors. The mechanisms are poorly understood, making it difficult to predict in which patients they will occur. Adverse effects such as rash, dysgeusia, neutropenia and proteinuria, which were reported relatively frequently in the early experience with captopril, are reported less frequently with lower doses of captopril and do not appear to be a problem with other ACE inhibitors such as enalapril and lisinopril.",1
7871,3066276,Adverse hepatic reactions associated with etretinate in patients with psoriasis--analysis of 22 cases,"In a retrospective study of 533 patients with psoriasis treated with etretinate in several centers in the United States, 22 adverse drug reactions related to hepatic dysfunction were reported. On analysis, 6 of these adverse hepatic reactions were probably drug related, 7 possibly related, 6 unlikely to be related and in 3 there was insufficient evidence to implicate or associate the reported event as a hepatic adverse reaction. Most of the adverse drug reactions were asymptomatic changes in liver function test (LFT). No death occurred which could be attributed to adverse hepatic reaction from etretinate.",1
7872,3070713,[Hepatitis secondary to current non-steroidal anti-inflammatory agents],"The authors report 83 cases of acute hepatitis secondary to non steroid anti-inflammatory drugs (NSAID), published in the literature. The NSAID in question are: niflumic acid, tolfenamic acid, diclofenac, fenoprofen, ibuprofen, indomethacin, naproxen, piroxicam, pirprofen and sulindac. Six deaths are directly ascribed to NSAID: although rare, these forms of hepatitis deserve therefore to be reported. They are usually mixed immuno-allergic forms of hepatitis (cytolytic as well as cholestatic). They often affect elderly women taking multiple medications. Monitoring of the liver function tests is necessary, during prolonged treatment with NSAID, especially during the first six months.",1
7873,3078905,Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of clinical experience,"Cyclobenzaprine hydrochloride became available for the treatment of acute skeletal muscle spasm ten years ago. The initial clinical trials conducted during the premarketing evaluation of this drug showed that it was significantly superior to placebo in relieving the signs and symptoms of acute skeletal muscle spasm. In addition, cyclobenzaprine was found to have a more rapid onset of action than diazepam. Data obtained both in controlled clinical investigations and in a postmarketing surveillance program indicated that cyclobenzaprine treatment was associated with few serious adverse experiences. Cyclobenzaprine represents a cost-effective approach to the management of acute muscle spasm, primarily because of the rapid symptomatic relief that it provides.",1
7874,3081740,Preventive therapy with isoniazid. Cost-effectiveness of different durations of therapy,"Daily administration of isoniazid for one year to persons infected with Mycobacterium tuberculosis is effective in considerably reducing the risk of disease. From a practical viewpoint, this approach to prevention is less than ideal because it results in considerable costs as health care providers monitor for possible hepatotoxic effects and because it is difficult to maintain compliance for 12 months. The efficacy and toxicity of isoniazid preventive therapy regimens of 12, 24, and 52 weeks' duration were recently assessed in a study conducted in Eastern Europe. We used data from this study to conduct a cost-effectiveness analysis of the three alternative regimens. The results indicate that over a wide range of assumptions, a regimen of 24 weeks' duration is more cost-effective than either the 12- or 52-week regimen. Using base case estimates, the cost per case prevented for the 24-week regimen was $7,112, compared with $16,024 for the 52-week regimen. Among a cohort of 1,000 persons treated, each additional case prevented by the 52-week regimen would cost $80,807. Thus, a shorter course of isoniazid preventive therapy is relatively cost-effective compared with current policy.",1
7875,3082727,[Chrysotherapy induced hepatic damage],,1
7876,3085648,Hepatitis and neutropenia secondary to gold thiomalate therapy for rheumatoid arthritis,A 37 year old female with rheumatoid arthritis developed clinical and biochemical evidence of hepatitis after receiving 80 mg of sodium aurothiomalate. Inadvertent rechallenge with sodium aurothiomalate led to recurrence of the biochemical abnormalities and a profound neutropenia and eosinophilia.,1
7877,3089267,Hepatic effects of amiodarone,,1
7878,3092712,Auranofin or D-penicillamine in the treatment of rheumatoid arthritis,"""Ninety patients were entered into a randomized, controlled, double-blind trial lasting 12 months to compare auranofin (6 mg/d), and D-penicillamine (250 mg/d for 4 weeks, 500 mg/d for 4 weeks, then 750 mg/d thereafter) in the treatment of rheumatoid arthritis. Most patients in both groups completed the trial with significant improvement in all quantitative measures of efficacy. Patients treated with D-penicillamine were more likely to have """"important improvement"""" in physician global assessment, swollen joint count, and score and grip strength. The overall frequency of side effects was similar between the two groups; however, more patients were withdrawn for adverse effects from the D-penicillamine group, and proteinuria (greater than or equal to 2+) and thrombocytopenia (less than 100 000 mm3) occurred significantly more frequently with D-penicillamine than auranofin (p = 0.028). These results suggest that in the dosage regimen used, auranofin is safer than D-penicillamine but that D-penicillamine tends to show greater clinical effectiveness in patients with rheumatoid arthritis.""",1
7879,3093213,Serum carnitine during valproic acid therapy,"This study was initiated to examine the influence of valproic acid (VPA) on serum carnitine, as well as the possible etiological role of carnitine in VPA-induced fatal hepatotoxicity. Free, total, and short-chain acylcarnitine were measured in the serum of 21 pediatric patients receiving VPA therapy, 21 healthy matched controls, and 21 patients receiving various antiepileptic drugs other than VPA. The free carnitine level was lowest in the VPA group (p less than 0.05), and the short-chain acylcarnitine/free carnitine ratio was highest in the VPA group (p less than 0.01). Patients receiving VPA polytherapy had lower total carnitine values than patients receiving VPA monotherapy (p less than 0.05). No correlation was found between serum ammonia and VPA drug levels. A 3 1/2-year-old girl developed hepatic failure under VPA therapy. Her serum carnitine values were normal. Despite the oral intake of L-carnitine this patient died. In this case, apparently VPA-induced hepatotoxicity was not associated with carnitine deficiency. The reduction of carnitine in the serum of VPA-treated patients is most probably due to alterations of fatty acid metabolism. However, neither primary carnitine deficiency nor VPA-induced secondary carnitine deficiency can be the only reason for the VPA-induced fatal hepatotoxicity.",1
7880,3094778,Hepatic cholestasis induced by trimethoprim,,1
7881,3098946,Reversible valproate fulminant hepatic failure,"Valproate fulminant hepatotoxicity, usually fatal, is believed to be idiosyncratic and metabolic without an immunologic basis. There are no previous reports of a hypersensitivity reaction among numerous cases of fatal valproate fulminant hepatitis. Little is known about the electron microscopical features of valproate hepatitis. We report a case of reversible fulminant hepatitis attributable to valproate with clinical and histological characteristics of a hypersensitivity reaction. Electron microscopical findings included microvesicular steatosis with normal-appearing mitochondria.",1
7882,3102998,Valproic acid hepatic fatalities: a retrospective review,"We reviewed all US cases of fatal hepatotoxicity coincident with valproate anticonvulsant therapy that were reported between 1978 and 1984. Thirty-seven hepatic fatalities were determined to have occurred coincident with the use of valproate. All but one patient had such other medical conditions as mental retardation, developmental delay, congenital abnormalities, and other neurologic diseases. The primary risk of fatal hepatic dysfunction (1/500) was found to be in children 0 to 2 years old receiving valproate as polytherapy. The risk declined with age and was low in patients receiving valproate as monotherapy (1/37,000). No hepatic fatalities occurred in patients above the age of 10 years receiving valproate as monotherapy.",1
7883,3106402,Drugs used in ovulation induction. Safety of patient and offspring,"Data on the safety of agents used to induce ovulation in women are presented, with a special reference to the normality of children at birth and puberty. No overall increase in anomalies has been found after the use of clomiphene citrate. This drug has been given up to day 35 of pregnancy, and its safety in these circumstances requires further analysis. More studies will also be needed on offspring as they pass through puberty, to ensure there are no defects in their M?llerian system. No increase in anomalies has been noted after the use of human menopausal gonadotrophins (HMG). The onset of menstrual rhythms and other parameters in the offspring appear to be normal. No increase in various cancers has been identified following the use of clomiphene or HMG, although most treated women have yet to enter the high risk years.",1
7884,3111687,High-dose i.v. thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer,"Twenty-five patients with malignancies resistant to conventional chemoradiation therapy or for which no effective therapy is known were treated with escalating doses of thiotepa (135-1215 mg/m2 iv over 3 days) followed by reinfusion of previously cryopreserved autologous bone marrow. The hematological and nonhematological toxic effects, therapeutic effects, and pharmacokinetics of this regimen were evaluated. Granulocyte (greater than 500/microliter) and platelet (greater than 20,000/microliter) count recovery occurred at a median of 16 (range, 11-38) and 18.5 (range, 11-40) days after marrow reinfusion, respectively. Six patients experienced severe infection, four of which were fatal. One patient died due to intracranial hemorrhage. Toxicity to the gastrointestinal and central nervous systems was dose-limiting, and the maximum tolerated dose of thiotepa was 1005 mg/m2. Objective tumor regression occurred in six of the patients. Serum thiotepa concentration peaked immediately after infusion and declined rapidly in a biphasic manner. No relationship between thiotepa serum concentration or pharmacokinetic parameter estimates was observed for tumor response or toxicity. High-dose thiotepa and autologous bone marrow transplantation may represent an alternative therapeutic modality for patients with advanced cancer.",1
7885,3114679,Hepatic vascular disease after kidney transplantation: report of two cases and review of the literature,"Severe hepatic vascular disease developed in two patients 4 and 8 years after kidney transplantation, while receiving combined immunosuppressive therapy with prednisone and azathioprine. Portal hypertension and marked liver failure were observed in both cases. The diagnosis was established by histological examination of liver biopsies showing typical veno-occlusive disease of the liver associated with peliosis in both cases. Azathioprine was discontinued. Two years later one patient was asymptomatic and liver function tests were normal. The second patient died 3 years later from liver failure. Early recognition of hepatic vascular disease arising in kidney transplant recipients would be of utmost importance, as substitution of another immunosuppressive agent for azathioprine could halt the process leading to portal hypertension.",1
7886,3115370,Veno-occlusive disease of the liver secondary to ingestion of comfrey,,1
7887,3128767,Controlled trial of aztreonam vs. tobramycin and azlocillin for acute pulmonary exacerbations of cystic fibrosis,"The efficacy of aztreonam was compared to that of standard therapy consisting of tobramycin and azlocillin in the treatment of acute pulmonary exacerbations of cystic fibrosis in a randomized, open trial. Fifteen patients were randomized to each treatment. Responses were assessed based on changes in pulmonary and clinical scores, white blood cell counts, pulmonary function tests and quantitative bacteriology of sputum which were performed before, every 5 to 7 days during and on the last day of therapy. Patients in both groups responded to therapy and there were no statistically significant differences in changes in the above indicators of response with therapy between the two groups (P greater than 0.05). The incidence of detection of Pseudomonas aeruginosa isolates resistant to all three study antibiotics increased with therapy. Side effects were limited to transient elevations of liver enzymes (both groups) and rash and fever in one patient treated with azlocillin. Aztreonam represents effective therapy for pulmonary exacerbations of cystic fibrosis associated with susceptible pathogens.",1
7888,3130483,Liver dysfunction in ovarian hyperstimulation syndrome. A case report,"""Ovarian hyperstimulation syndrome (OHS) is one of the potential complications associated with the use of human menopausal gonadotropin therapy. We recently dealt with a case of severe OHS presenting features of liver dysfunction; such a case has not been reported on before.""",1
7889,3133277,[Hepatitis probably secondary to the massive ingestion of fluvoxamine],,1
7890,3137017,Fatal liver failure in 16 children with valproate therapy,"""The data of 16 children who died while receiving valproate (VPA) therapy in West Germany were analyzed. Five were normally developed, 5 were receiving VPA-monotherapy, and only 2 patients were aged less than 3 years. The first clinical symptoms of impending hepatotoxicity usually included nausea, vomiting, and apathy; pathologic laboratory tests reflected liver failure. Liver histology revealed microvesicular steatosis, cell necrosis, and bile duct proliferation of varying degree. An abnormal metabolite, 4-ene-VPA, was detected in all examined patients (six of six) and persisted after drug withdrawal. The pathogenesis of fatal liver failure during VPA treatment remains unknown. World-wide, approximately 100 fatalities have been reported in relation to VPA treatment. More than 90% were aged less than 20 years, 95% developed their first symptoms within the first 6 months of treatment, and 16 were treated with VPA alone. Since it is difficult precisely to define a group at risk for fatalities with VPA, careful clinical and laboratory monitoring with a special focus on vomiting and apathy, liver enzymes, and coagulation tests seem mandatory during the first 6 months after introduction of VPA. Taking into account the considerable number of fatalities during VPA treatment, the indication for its use requires careful reevaluation.""",1
7891,3140108,Three cases of nodular regenerative hyperplasia of the liver following renal transplantation,"We report three cases of nodular regenerative hyperplasia of the liver: the clinical onset of hepatic disease occurred between 24 and 30 months after renal transplantation. Nodular regenerative hyperplasia was associated with peliosis hepatitis in two cases, and with veno-occlusive disease in one case. Two patients developed portal hypertension, but are doing well. The third patient developed jaundice and died of septic shock. We discuss the aetiological role of renal transplantation, cytomegalovirus infection, and azathioprine in the development of nodular regenerative hyperplasia of the liver.",1
7892,3140956,Ceftriaxone and reversible cholelithiasis,,1
7893,3145882,Hyperamino-acidaemia and hyperammonaemia in epileptic children treated with valproic acid,"Serum amino acid pattern, blood ammonia, and serum valproic acid (VPA) levels were estimated in 75 epileptic children with and without VPA therapy. The incidence of patients with hyperammonaemia (greater than 60 mumol/l) in patients treated with only VPA or with a combination of VPA and other antiepileptic drugs was 19% and 20% respectively. Hyperammonaemia was not observed in patients receiving other drugs. Elevated levels of serum glycine, alanine and serine were more common in epileptic patients treated with VPA alone and with VPA in combination with other drugs than in patients receiving other drugs. A significant positive correlation was found between the serum levels of glycine and alanine, of glycine and serine, and of serine and alanine. These findings may indicate a mitochondrial dysfunction caused by VPA.",1
7894,3154674,The pharmacology of nisoldipine,"Nisoldipine is a calcium antagonist that specifically blocks the slow or voltage-dependent calcium channel up to the highest concentrations. This mode of action has been confirmed in pharmacological studies on isolated organs, electrophysiological and binding studies, and by the measurement of transmembrane calcium transport. As with other dihydropyridine calcium antagonists, an interaction with intracellular calcium reservoirs and calmodulin seems to be of minor importance. The drug exhibits higher potency, longer duration of action, and a higher binding affinity in vitro and in vivo than nifedipine. In contrast to its vasodilating and spasmolytic activity, its negative inotropic effect occurs in vitro only after higher concentrations than after nifedipine. In whole animals a secondary positive inotropic effect occurs regularly owing to sympathetic counter-regulation. The influence of nisoldipine on cardiac stimulus formation and conduction is also very slight in anesthetized animals, and is completely eliminated in awake animals and humans by counter-regulation up to very high doses. The cardiac anti-ischemic action of nisoldipine has been demonstrated in various ischemia models and is probably based predominantly on its afterload-reducing properties in addition to its spasmolytic effect on the coronary arteries. Various other suspected effects, for which there are isolated indications, e.g., inhibition of thromboxane synthesis, preload reduction, interaction with the transport of adenosine, and normalization of the sarcolemmal Na+, K(+)-ATPase activity, are probably of subordinate importance. Its antihypertensive effect is explained primarily by lowering of the peripheral resistance. There are, however, some indications that nisoldipine exerts certain effects over and above pure vasodilation. The prevention of postischemic calcium overloading in the renal tubule epithelium and the natriuretic effect are probably of importance in the therapeutic action. Clinically, nisoldipine was found more potent and prolonged in its action in comparison with nifedipine. In comparative studies, nisoldipine, 10 mg once a day, was found equieffective with nifedipine 10 mg three times or 20 mg twice a day in angina or hypertension, respectively.",1
7895,3155793,Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump,"Sixty-two patients with metastatic colorectal carcinoma involving the liver were treated by hepatic intra-arterial chemotherapy using an implantable infusion pump. The 53 patients with metastases confined to the liver had a median survival (MS) of 17 months and an objective response rate of 32%. Four patients (8%) demonstrated a complete response (CR), with normal abdominal computed tomography (CT) scan results and plasma carcinoembryonic antigen (CEA) levels, and 13 patients (25%) demonstrated a partial response (PR), with at least a 50% decrease in the liver lesions by CT scan and at least a 50% decrease in CEA levels. Thirty patients (57%) had stable disease (S), and six patients (11%) had no response (NR). Nine patients with extrahepatic tumor plus hepatic metastases had an MS of only 4.9 months. None of these patients had an objective response, and only four patients had S. Quality of response was clearly associated with longevity. Forty patients treated with floxuridine (FUDR) and mitomycin (M) (F + M) showed a 20% objective response rate, while the 13 patients treated with FUDR and dichloromethotrexate (DCMTX) (F + D) attained a 69% objective response rate. Although F + D treatment appears to be superior, there may have been selection biases that make such an observation only preliminary. Twenty-six (49%) of the 53 patients developed hepatitis during infusion chemotherapy, which resolved after temporary cessation of the chemotherapy. Of the 17 patients with CR or PR, 12 patients (71%) had hepatitis, whereas only 14 (39%) of the 36 patients with S or NR had hepatitis. Eleven patients had evidence of peptic ulceration by endoscopic examination during the infusion chemotherapy. All the ulcers healed after chemotherapy was discontinued.",1
7896,3158386,Synthetic retinoids in dermatology,"The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively non-toxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited.",1
7897,3160062,Iatrogenic sclerosing cholangitis following hepatic arterial chemotherapy infusion,"A case of common hepatic duct stricture secondary to hepatic artery chemotherapy infusion is described. CT and endoscopic retrograde cholangiopancreatography (ERCP) may be used in concert to differentiate this entity from other causes of jaundice--namely, hepatic replacement by tumor, porta hepatis adenopathy, and chemotherapy hepatotoxicity.",1
7898,3160268,[Acute fatal hepatorenal failure during treatment with mithramycin],"""A case of fatal hepato-renal failure occurring during mithramycin treatment is reported. A 64 year-old female patient was admitted to hospital in a state of acute renal failure. She also presented with hypercalcaemia and bilateral pulmonary metastases. She had been operated on 10 years previously of a parathyroid cancer. Despite treatment with mithramycin (total dose 8.25 mg) and haemodialysis, the hypercalcaemia returned; it was then decided to remove the secretory lung metastases (parathormone 420 micrograms X ml-1). 48 hours before surgery, the patient was again given 1.25 mg mithramycin. Immediately after surgery, she developed hepatic failure with massive cell destruction and anuria. The patient died 48 h after the operation. The hepatic and renal complications of mithramycin are discussed.""",1
7899,3161347,Three cases of carbamazepine toxicity,"The growing number of psychiatrists who prescribe carbamazepine therapy should be alert to the drug's potential complications. The authors report three such cases: one of hepatitis, one of a fatality due to aplastic anemia, and one of a severe dermatological reaction.",1
7900,3173196,"Cocaine abuse with hyperthermia, seizures and fatal complications","The case of a previously-healthy woman who developed marked hyperthermia after the intravenous self-administration of cocaine is described. Status epilepticus and a prolonged period of hypotension were followed by the development of rhabdomyolysis, disseminated intravascular coagulation, acute renal failure, impaired cerebral function and hepatic dysfunction. The pathophysiology of these events and their relationship to cocaine overdose is discussed.",1
7901,3177432,Treatment of primary Sjogren's syndrome with hydroxychloroquine,"""Sjogren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of the salivary/lacrimal glands, autoantibody production, and polyclonal hyperglobulinemia. In view of the efficacy and relative safety of hydroxychloroquine in other autoimmune disorders, the potential benefit of hydroxychloroquine (200 mg per day for 12 months) in 10 patients with Sjogren's syndrome was evaluated. Changes in levels of total immunoglobulin, antibody against Sjogren's syndrome-associated antigen B, rheumatoid factor, and in vitro production of immunoglobulin in the serum were evaluated. For comparison, 10 patients matched according to age and sex, who did not receive hydroxychloroquine were studied. In the hydroxychloroquine-treated group, the following observations were made: (1) significantly decreased total immunoglobulin G (IgG) and IgA levels with little change in IgM levels; (2) significant decrease in IgA-rheumatoid factor with a smaller decrease in IgM-rheumatoid factor; (3) decreased IgG anti-Sjogren's syndrome-associated antigen B autoantibody; and (4) decreased erythrocyte sedimentation rate and increased hemoglobin level. Further, a specific idiotype present on their rheumatoid factor (defined by monoclonal antibody 17-109) was significantly decreased, with disappearance of detectable circulating paraprotein in two hydroxychloroquine-treated patients. Finally, rheumatoid factor production in vitro by lymphocytes from hydroxychloroquine-treated patients using a T cell-dependent mitogen was significantly decreased. These results suggest that hydroxychloroquine modulates lymphoproliferation in patients with Sjogren's syndrome and may prevent progression to extraglandular sites of neoplastic transformation.""",1
7902,3178321,Changing the class of NSAID in cases of hepatotoxicity,,1
7903,3181214,A case of hepatitis associated with carbamazepine therapy,,1
7904,3182029,Jaundice due to albendazole,,1
7905,3189370,Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases,"""PURPOSE: The syndrome of idiopathic hyperammonemia occurs in patients who have received high-dose cytoreductive therapy for the treatment of hematologic malignancy. It is characterized by abrupt alteration in mental status and respiratory alkalosis associated with markedly elevated plasma ammonium levels in the absence of any identifiable cause, and frequently results in intractable coma and death. Our goal was to survey clinical and pathologic manifestations of the disorder and discuss treatment options. PATIENTS AND METHODS: Plasma ammonium levels were measured in patients on the acute leukemia service or on the bone marrow transplant service at The Johns Hopkins Hospital, and a level more than twice normal was considered diagnostic of hyperammonemia. The syndrome was identified in nine patients; in eight, hyperammonemia occurred after administration of intensive cytoreductive therapy that resulted in profound leukopenia. The disorder occurred in the ninth patient two months after allogeneic bone marrow transplantation. RESULTS: Three of the nine patients survived an episode of idiopathic hyperammonemia; one patient subsequently died of leukemia and one of recurrent idiopathic hyperammonemia. The one long-term survivor is currently alive and well without neurologic sequelae 250 days after autologous bone marrow transplantation. CONCLUSION: Because neurologic function can deteriorate rapidly, early recognition of this disorder and close monitoring of the patient's neurologic status are critical.""",1
7906,3192186,Cocaine-induced hepatotoxicity,,1
7907,3195601,Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis,"""PURPOSE: Beginning in the 1980s, methotrexate has been used successfully to treat rheumatoid arthritis. The magnitude and severity of short- and long-term methotrexate toxicity, however, have not been adequately investigated. Our study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis receiving long-term methotrexate therapy. PATIENTS AND METHODS: We conducted a retrospective, computer-assisted review of all Duke University Medical Center patients undergoing liver biopsy for methotrexate monitoring from January 1979 to January 1988. A total of 538 biopsies were performed in 399 patients, 259 of whom had inflammatory arthritis (210 with rheumatoid arthritis, 47 with psoriatic arthritis, and two with seronegative spondyloarthropathy). RESULTS: No evidence of cirrhosis was defined in the cohort with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic changes of fibrotic liver disease (prevalence of 2.9 percent in the group with rheumatoid arthritis) while taking methotrexate. Five of the six patients were obese and three had glucose intolerance or overt diabetes mellitus, and one person admitted to alcohol usage. Only one patient with fibrotic liver disease had elevated liver function test results, and no person showed a declining serum albumin level at the time of biopsy. Sixty-one patients with rheumatoid arthritis underwent multiple samplings (44 with two, 13 with three, and four with four biopsies). Fourteen of these patients showed progressive hepatic disease, whereas four patients improved. CONCLUSION: Although the prevalence of methotrexate hepatotoxicity in this large cohort of patients with rheumatoid arthritis was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening, still exists.""",1
7908,3196365,Hepatic ultrastructure after methotrexate therapy for rheumatoid arthritis,"Twenty-six patients receiving long-term oral methotrexate (MTX) therapy for rheumatoid arthritis (24 patients) or psoriasis (2 patients) were prospectively evaluated for alterations in liver morphology by light microscopy, electron microscopy, and immunofluorescence microscopy. Although only 4 MTX-treated patients had light microscopic evidence of mild fibrosis, all had evidence of collagen deposition in the space of Disse near Ito cells and changes in hepatocyte lysosomes on electron microscopy. These findings were absent from control livers. Fibrinogen, fibronectin, and type IV collagen were identified by immunofluorescence in both MTX-treated patients and controls. We conclude that long-term MTX therapy for rheumatoid arthritis is associated with alterations in hepatic ultrastructure, including collagen deposition in the space of Disse and changes in hepatocyte lysosomes.",1
7909,3198757,Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk,"""Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis of a hypersensitivity reaction was corroborated by in vitro rechallenge for each drug (phenytoin, n = 34; phenobarbital, n = 22; carbamazepine, n = 25) when cytotoxicity (% dead cells) exceeded 3 SD above the mean result for controls. Cross-reactivity among the drugs was noted. 7 out of 10 patients who had received all three anticonvulsants had adverse reactions to each. 40 out of 50 patients tested to all three drugs in vitro were positive to each. Adverse reactions were indistinguishable among anti-convulsants. Skin rash (87%), fever (94%), hepatitis (51%), and hematologic abnormalities (51%) were common clinical features of each drug. 62% of reactions involved more than two organs. Cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients. In vitro testing can help diagnose hypersensitivity to anticonvulsants. Cells from patients may also be used for prospective individualization of therapy to decrease risk of adverse reaction. Cross-reactivity among the major anticonvulsants is common and should be considered before deciding on alternative therapy.""",1
7910,3219687,The safety and usefulness of buspirone as an anxiolytic drug in elderly versus young patients,"Buspirone, the prototype of the new azaspirodecanedione series of antianxiety drugs, was studied in over 6,000 patients in an open, multicenter trial to confirm its safety and usefulness for anxiety in a typical medical practice setting. Non-psychotic patients with clinically manifest anxiety that required anxiolytic drug therapy were enrolled to receive four weeks of treatment with a fixed dose of buspirone (15 mg/day). Patient data were analyzed according to age: the elderly group comprised 605 patients aged 65 years or older, and the younger group included 5,969 patients less than 65 years old. Both the elderly and younger patients achieved similar relief of anxiety within four weeks based on the Hamilton Anxiety Scale and global assessments of improvement. Most patients (80%) in both groups reported no side effects. Further, the side effect profile in the elderly differed little from that in the younger patients. Overall, the data indicate that buspirone may be administered to patients aged 65 years or older without any special adjustment in dose, does not cause unusual adverse age-related phenomena, and relieves moderate-to-severe symptoms of anxiety in elderly patients.",1
7911,3229345,Carbamazepine-induced severe systemic hypersensitivity reaction with eosinophilia,"Skin rash, fever, and eosinophilia developed in a previously healthy 35-year-old woman three weeks after starting carbamazepine. Fulminant respiratory and renal failure ensued. Autopsy showed pneumonitis, nephritis, serositis, pancreatitis, hepatitis, and carditis, characterized by an infiltrate of eosinophils and lymphocytes. The severity, duration, and extensive organ involvement of the reaction make this case unique.",1
7912,3230599,Hepatotoxicity due to Atractylis gummifera-L,"The authors describe an intoxication by Atractylis gummifera in a 7-year old boy who drunk an extract made from the plant's root as traditional medicine. He was admitted to the Hospital 2 days after ingestion, in coma stage II, with epigastric pain, vomiting and general anxiety. Laboratory findings showed severe hepatocellular damage and acute renal failure. In spite of all treatment and therapeutic efforts, the boy died 8 days after admission. A postmortem histopathological study of the liver confirmed the panlobular hepatic necrosis and allowed the differential diagnosis of the intoxication from Reye syndrome.",1
7913,3246320,[Digitalis intoxication in the presence of amiodarone-induced acute hepatitis],"In this report, we describe a case of acute atypical hepatitis during chronic treatment with amiodarone in a patient in which symptoms of digitalis toxicity also developed. The sudden onset of these side effects, whose mechanisms are herein discussed, stresses the importance of a careful monitoring of patients treated with amiodarone.",1
7914,3261125,Re-treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum,"""Twenty-two patients with aplastic anemia were treated with antilymphocyte serum or antithymocyte globulin at Vanderbilt University and affiliated hospitals from 1980 to 1986. The median age was 42 (eight to 73 years); the male:female ratio was 8:14. Nineteen patients had severe aplastic anemia, and three had moderate disease. Twenty patients received antilymphocyte serum initially while two patients received antithymocyte globulin. Fifteen patients received fluoxymesterone 10 mg by mouth three times a day with antilymphocyte serum, and all received prednisone during the course of antilymphocyte serum or antithymocyte globulin. There were seven responses (31.8 percent) to the first course with four complete responses and three partial responses. Six of 15 patients who received fluoxymesterone showed a response, compared with zero of five treated without androgens (p less than 0.05). Eight patients with no initial response and a patient who experienced a relapse after a complete response were re-treated with either antithymocyte globulin (six) or antilymphocyte serum (three), with four of nine patients (44 percent) having a response (three complete responses, one partial response). Overall, 10 of 22 patients (45 percent) had a response (six complete responses, four partial responses). Median survival for those without a response is six months. Median survival for those with a response has not been reached, with follow-up ranging from 18 to 70 months. This study shows the benefit of a second cycle of antilymphocyte serum or antithymocyte globulin and a possible role for concomitant androgens in this treatment of aplastic anemia.""",1
7915,3263401,Treatment of cutaneous T cell lymphoma with 2'-deoxycoformycin (pentostatin),"2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered to three patients with cutaneous T cell lymphoma refractory to multiple treatment modalities. Patient 1, who received 5 mg/m2/day for 3 days at 35- to 71-day intervals, has achieved a complete remission greater than 16 months in duration. Patient 2 had progressive disease despite two courses of 2'-deoxycoformycin at a dose of 5 mg/m2/day for 3 days at 28-day intervals. The third patient, who was treated with 4 mg/m2 2'-deoxycoformycin weekly to biweekly, had an initial response, but the disease progressed after eight treatments. Only one patient had any side effects: Patient 1 developed reversible episcleritis, mild elevation of liver enzymes, and persistent nausea and vomiting. In red blood cells of all patients, there was near complete inhibition of adenosine deaminase (91% to 96%) and S-adenosylhomocysteine hydrolase (89% to 95%) activities with treatment. In peripheral blood lymphocytes, adenosine deaminase was inhibited by 85% to 98% and S-adenosylhomocysteine hydrolase by 51% to 88%. The deoxyadenosine triphosphate level, reflected by the total cellular adenine deoxyribonucleotide measurement in erythrocytes, was noted to be modestly elevated during treatment, with the highest level in the patient who demonstrated the only complete response and the only toxic effects. Low-dose 2'-deoxycoformycin appears to be safe but may be an insufficiently intensive regimen to treat refractory cutaneous T cell lymphoma. With proper biochemical monitoring, higher doses may be both safe and more effective.",1
7916,3265396,[Crossed hepatotoxicity of erythromycin propionate and troleandomycin?],,1
7917,3275523,A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts,"The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty-five patients were randomized to receive either sublingual buprenorphine or oral methadone under double-dummy and double-blind conditions to study the pharmacology of buprenorphine in a 90-day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between-group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self-report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.",1
7918,3279499,Adverse effects of the fluoroquinolones,"Data on adverse reactions due to the quinolone antibacterial agents--ciprofloxacin, ofloxacin, pefloxacin, norfloxacin, and enoxacin--observed in a patient sample of approximately 30,000 are reviewed. Overall rates of adverse reactions were 4.0%-8.0%, and adverse reactions necessitated discontinuation of therapy in 1.0%-2.6% of patients. Patterns of organ-system involvement and of signs and symptoms were quite similar, with gastrointestinal effects predominating (nausea, vomiting, diarrhea, or abdominal pain in 1.0%-5.0% of the patients), followed by effects on the central nervous system (dizziness, headache, and/or insomnia in 0.1%-0.3% of the patients) and skin (0.5%-2.2% of the patients). Elevation in levels of hepatic enzymes occurred in 1.8%-2.5% of the patients, azotemia in 0.2%-1.3%, and eosinophilia in 0.2%-2.0%. These adverse effects were reversible after drug withdrawal and were generally not dose-dependent. Within the constraints of the relatively small number of well-documented patients and the unique mechanism of action of these antimicrobial agents, the safety profile of these drugs seems to make them acceptable for use when their administration is well directed and specific. In addition, close surveillance for new phenomena should be maintained.",1
7919,3280080,Flutamide versus stilboestrol in the management of advanced prostatic cancer. A controlled prospective study,"In a prospective randomised study the effect of flutamide 750 mg daily was compared with that of stilboestrol 3 mg daily in the treatment of 40 previously untreated patients with advanced prostatic cancer. There was a good subjective response to both treatments. After 12 months, a response was demonstrated in 13 of 20 patients treated with flutamide and 8 of 20 patients treated with stilboestrol. The difference was not statistically significant. Treatment with stilboestrol caused more frequent, and more severe, side effects than flutamide.",1
7920,3280746,Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial,"A multicenter, randomized placebo-controlled double-blind trial of nimodipine in poor-grade aneurysm patients was carried out in 17 Canadian hospitals. Of 188 patients enrolled in the trial, 32 were excluded for protocol violations and two were excluded due to statistical considerations, leaving 154 patients for valid outcome analysis. Nimodipine treatment was associated with a significantly better outcome (p less than 0.001): 21 (29.2%) of 72 nimodipine-treated patients had a good outcome at 3 months after subarachnoid hemorrhage (SAH) compared to eight (9.8%) of 82 placebo-treated patients. Delayed ischemic deficits from vasospasm alone were significantly less frequent in the nimodipine group (p less than 0.05) with permanent deficits occurring in five nimodipine-treated patients (6.9%) and in 22 placebo-treated patients (26.8%). Improvement in the good outcome rate and reduction in delayed ischemic deficits from vasospasm alone occurred in both Grade 3 and 4 patients, with no difference between nimodipine- and placebo-treated patients being found in Grade 5 patients. Repeat angiography after Day 4 was carried out in 124 patients. There was no significant difference in the incidence of moderate or severe diffuse spasm, which was seen in 64.3% of nimodipine-treated patients and 66.2% of placebo-treated patients. The authors conclude that nimodipine treatment in poor-grade patients with SAH results in an increase in the number of good outcomes and a reduction in the incidence of delayed neurological deterioration due to vasospasm. This effect occurs by a mechanism other than prevention of large-vessel spasm as visualized on angiography.",1
7921,3286128,"Multi-centre, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis","A multi-centre, double-blind study was carried out in 100 patients suffering from chronic spasticity due to multiple sclerosis to compare the effectiveness of tizanidine hydrochloride with that of baclofen. Patients were allocated at random to receive treatment initially with daily doses of either 6 mg tizanidine or 15 mg baclofen and the dose was increased during the first 2 weeks up to a maximum of 24 mg tizanidine or 60 mg baclofen per day. Patients were then treated with the optimum dose for 6 weeks. Efficacy and tolerability parameters were evaluated after 2 and 8 weeks. Tizanidine and baclofen improved the functional status of patients in 80% and 76% of cases, respectively, but there were no significant differences between the two drugs. The antispastic efficacy of tizanidine was greater after 8 weeks than after 2 weeks, whereas the efficacy of baclofen decreased slightly with time. Both drugs showed good overall tolerability in more than 60% of patients. Thus, tizanidine is a well tolerated and effective muscle relaxant, the antispastic efficacy of which is well maintained over time, and it promises to be particularly useful in the treatment of spasticity due to multiple sclerosis.",1
7922,3287015,High dose cytarabine: a review,"""High dose cytarabine (HDARAC) therapy is used increasingly to treat hematologic malignancies. Recent data indicate that HDARAC at doses of 2-3 g/M2 every 12 hr x 10-12 doses is of comparable or greater efficacy in remission induction as standard doses of cytarabine in acute myelogenous leukemia. HDARAC can also produce remissions in individuals resistant to conventional doses. HDARAC-containing regimens are reported to result in substantially higher long-term, disease-free survival than previous approaches to post-remission therapy, but this has not yet been confirmed in controlled trials. HDARAC is also active in acute lymphocytic leukemia. Because intravenous HDARAC achieves high levels in the spinal fluid, it is useful to treat central nervous system leukemia and may provide adequate CNS prophylaxis in acute lymphocytic leukemia. HDARAC is reported to be active in advanced non-Hodgkin lymphomas and chronic myelogenous leukemia in acute phase; optimal use in these settings is under study. HDARAC has also been combined with other drugs. Randomized trials are needed to determine whether these combinations are more effective than HDARAC alone. Apart from potent myelosuppression, the dose-limiting toxicity of HDARAC is cerebellar damage. This occurs with increased frequency in patients greater than 50 years old. HDARAC is active in hematologic malignancies and may further improve therapeutic results if combined with other drugs.""",1
7923,3291396,Medical risks of cocaine use,"This discussion was selected from the weekly Grand Rounds in the Department of Medicine, Oregon Health Sciences University School of Medicine, Portland. Taken from a transcription, it has been edited by George A. Porter, MD, Professor and Chair, Department of Medicine.",1
7924,3293002,Ceftriaxone-associated cholecystitis,,1
7925,3297125,Captopril: 4 years of post marketing surveillance of all patients in New Zealand,"The Intensive Medicines Monitoring Programme (IMP), a specialised part of the New Zealand Post Marketing Surveillance system, has been used to monitor captopril since it was first approved for marketing for the treatment of hypertension and heart failure. Monitoring has consisted of (1) spontaneous reporting for which doctors have been encouraged to report all clinical events, (2) a specific event recording survey at the end of the first year and (3) a controlled patient survey of taste disturbance. The IMP gathers prescription information on about 85% of all patients. There were 4,124 patients at the end of the first 4 years. Reported events involved 4% of patients, the majority being cutaneous (1%) and gastrointestinal (0.7%). The event recording survey gave an overall rate of adverse events of 2.2 per patient year. The taste survey showed a remarkably high incidence of taste disturbance in the control population and only taste loss was significantly higher (P less than 0.01) for captopril. This ongoing study has so far demonstrated a low incidence of adverse effects due to captopril, which is reassuring in view of its increasing use for mild hypertension and early cardiac failure.",1
7926,3297909,Progressive bile duct injury after thiabendazole administration,"""A 27-yr-old man developed jaundice 2 wk after exposure to thiabendazole. Cholestasis persisted for 3 yr, at which time a liver transplant was performed. Two liver biopsy specimens and the hepatectomy specimen were remarkable for almost complete disappearance of interlobular bile ducts. Prominent fibrosis and hepatocellular regeneration were also present; however, the lobular architecture was preserved. This case represents an example of """"idiosyncratic"""" drug-induced liver damage in which the primary target of injury is the bile duct. An autoimmune pathogenesis of the bile duct destruction is suggested.""",1
7927,3299090,"The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial","""We conducted a double-blind, placebo-controlled trial of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Although significant clinical benefit was documented (N Engl J Med 1987; 317:185-91), serious adverse reactions, particularly bone marrow suppression, were observed. Nausea, myalgia, insomnia, and severe headaches were reported more frequently by recipients of AZT; macrocytosis developed within weeks in most of the AZT group. Anemia with hemoglobin levels below 7.5 g per deciliter developed in 24 percent of AZT recipients and 4 percent of placebo recipients (P less than 0.001). Twenty-one percent of AZT recipients and 4 percent of placebo recipients required multiple red-cell transfusions (P less than 0.001). Neutropenia (less than 500 cells per cubic millimeter) occurred in 16 percent of AZT recipients, as compared with 2 percent of placebo recipients (P less than 0.001). Subjects who entered the study with low CD4 lymphocyte counts, low serum vitamin B12 levels, anemia, or low neutrophil counts were more likely to have hematologic toxic effects. Concurrent use of acetaminophen was also associated with a higher frequency of hematologic toxicity. Although a subset of patients tolerated AZT for an extended period with few toxic effects, the drug should be administered with caution because of its toxicity and the limited experience with it to date.""",1
7928,3301251,Hepatotoxicity associated with choline magnesium trisalicylate: case report and review of salicylate-induced hepatotoxicity,"A case of a 21-year-old woman who had developed mild hepatotoxicity while receiving choline magnesium trisalicylate therapy is described. She presented with fever and mild hepatic enzyme elevations before salicylate therapy was instituted. Liver function tests (LFT) returned to normal within five days of hospitalization but she continued to develop daily fevers. Blood, urine, and throat cultures were negative. An acute viral illness or reactivation of systemic lupus erythematosus were the suspected diagnoses. Choline magnesium trisalicylate was then administered in an effort to control her fever, and was successful. After three days of salicylate therapy her LFT values began to rise. They continued to rise for five more days before salicylate hepatotoxicity was suspected. Choline magnesium trisalicylate was discontinued after eight days and the patient's LFT quickly returned to normal. The source of fever was never identified, although infection with cytomegalovirus was considered the most likely cause. Salicylate-induced hepatotoxicity is reviewed.",1
7929,3304049,Emergency liver transplantation for fulminant hepatitis,"""Orthotopic liver transplantation was done in 17 patients with fulminant hepatitis. The cause of the liver disease was infection with hepatitis B virus, or co-infection with hepatitis B virus and hepatitis D virus, or infection with hepatitis A virus in 6 patients; drug hepatotoxicity in 5; and indeterminate in 6. Grafts from incompatible blood groups, steatotic grafts, or reduced-size grafts were used in 5, 4, and 4 patients, respectively. Of the 17 patients, 5 died: 2 of early liver failure due to the poor quality of the graft, 1 presumably of accidentally transmitted acute infection with the human immunodeficiency virus, and 2 of decerebration occurring during or immediately after surgery. The 12 other patients were alive 2 to 15 months after transplantation.""",1
7930,3305969,Severe hepatotoxicity from Escherichia coli L-asparaginase,"""A 51-year-old black woman with diabetes mellitus developed severe hepatotoxicity after receiving high-dose L-asparaginase (Elspar) for acute lymphatic leukemia. Patients with diabetes should be given this drug cautiously. Glutaminase-free L-asparaginase from Vibrio succinogenes has been reported to be less hepatotoxic in mice; it might be a safer product for this group of patients.""",1
7931,3307498,Liver toxicity encountered in the Veterans Administration trial of disulfiram in alcoholics,"Alcoholic subjects (453) were randomly assigned to disulfiram or placebo therapy and followed for up to 12 months for drinking. Drinking status was determined from interviews of the subject and a household contact each 2 months and from the analysis of eight blood samples or 39 urines submitted at intervals during the year. Liver status was monitored each 2 months by obtaining serum alkaline phosphatase, bilirubin, and AST. Sensitive criteria were arbitrarily selected to identify about 1/5 of the patients with episodic elevations of liver tests. There was no relationship of liver test elevations to disulfiram treatment. However, the elevated AST related significantly to drinking status (p = 0.004) as did elevated bilirubin (p = 0.044), but not elevated alkaline phosphatase (p = 0.146). Two hundred one patients had liver test elevations at least one time and were continued on drug, four were dropped. One hundred seventy-nine of these patients were drinking, 22 were abstinent, and four were indeterminant. It is concluded that patients on disulfiram with minor liver test abnormalities are usually drinking.",1
7932,3312846,Low dose cytosine arabinoside in myelodysplasia and acute myelogenous leukemia: a review,"We analyzed clinical trials of low dose cytosine arabinoside (LDARA-C) in 324 patients with acute myelogenous leukemia (AML) and 129 patients with myelodysplasia (MDS). Complete and partial remission rates were 31% and 18%, respectively, in patients with AML, and 24% and 27% in patients with MDS. Toxicity was primarily hematologic. Although in vitro data suggested that LDARA-C acts as a differentiating agent, clinical data generally indicate a cytotoxic mechanism. Given the lack of effective therapeutic options in MDS and high risk AML (patients greater than 65 years old, secondary AML), these data are encouraging. LDARA-C warrants further study, comparing continuous infusion with intermittent subcutaneous administration and comparing LDARA-C to conventional dose therapy.",1
7933,3317860,Hepatotoxic effects of the anabolic/androgenic steroids,,1
7934,3318422,Safety evaluation of nabumetone in United States clinical trials,"""A total of 1,924 persons (rheumatoid arthritis, 835; osteoarthritis, 1,073; volunteers, 16) received nabumetone in United States clinical trials. Nine hundred eighty-eight patients have received nabumetone treatment for periods of more than one year, and 375 patients have received treatment for longer than two years. Four hundred eighty patients over 65 years of age have received treatment with nabumetone, and 224 of these elderly patients have received treatment for periods of more than one year. The nabumetone dose most commonly used in all double-blind trials was 1,000 mg at night. In long-term, open-label studies, which were usually extensions of the double-blind trials, patients could increase the dose to 2,000 mg per day. Nine hundred nineteen patients received doses of more than 1,000 mg per day. Adverse experience information was collected at each visit, including information for some patients receiving treatment for more than three years. Laboratory data were collected periodically throughout the trials, and the data were assessed for trends over time. The adverse experience pattern observed for nabumetone is similar to that described for clinical trial data for other nonsteroidal anti-inflammatory drugs. However, it is noteworthy that the pattern observed for nabumetone is from clinical trials with approximately 1,000 patients receiving treatment for periods of one year or more. This long-term patient exposure in clinical trials far exceeds long-term clinical trial data for other agents. The types and frequencies of adverse experiences reported by persons treated with nabumetone are relatively constant over the long time period covered by these trials. Also, the adverse experience patterns remained generally constant over time for various populations: all patients, patients 65 or older, female patients, male patients, and patients who received an increased dose of nabumetone. Although some statistically significant trends were detected for some laboratory parameters, there was little indication of significant clinical patterns. Although there were patients with individually important laboratory values, nabumetone was not associated with clinically important adverse laboratory patterns. Overall, the adverse experience data and laboratory data indicate that nabumetone is safe for the treatment of adult patients with rheumatoid arthritis or osteoarthritis.""",1
7935,3321587,Venoocclusive disease of the liver following bone marrow transplantation,"Review of 235 consecutive patients undergoing bone marrow transplantation was performed in order to define the clinical syndrome of venoocclusive disease of the liver (VOD) in these patients. Analysis of all patients with histologically proven VOD revealed a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. This was characterized by hyperbilirubinemia peaking at greater than or equal to 2 mg/dl with at least 2 of 3 other findings: hepatomegaly, ascites, and 5% or greater weight gain. VOD developed in 22% (52 of 235). A persistently elevated aspartate aminotransferase (SGOT) prior to transplant was associated with an increased risk of developing VOD by multivariate analysis (P = 0.0003), and acute leukemia in first remission was associated with a decreased risk (P = 0.02). Neither the preparative regimen (busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation) nor the type of graft (allogeneic versus autologous) influenced the occurrence. Twenty-four of these 52 patients (47%) died with VOD (10% of the entire group). This makes VOD the third leading cause of death in our allogeneic graft recipients, and the second leading cause in our patients receiving autologous transplants. VOD is a common complication of bone marrow transplantation and has a specific clinical presentation, which usually allows diagnosis without the need of liver biopsy.",1
7936,3323262,A comparative double-blind controlled study of trimipramine and amitriptyline in major depression: lack of correlation with 5-hydroxytryptamine reuptake blockade,"Thirty-four hospitalized patients with major depression were enrolled in a 3-week double-blind parallel comparative study of trimipramine and amitriptyline. Following a 1-week washout period, patients randomly received one of the two drugs up to 100 mg twice daily on a fixed increment dosage schedule. Both treatments produced a rapid significant clinical improvement that occurred in a predominantly linear fashion. The pattern of improvement was very similar with both drugs. There was no significant correlation between plasma levels of trimipramine and desmethyl-trimipramine and clinical improvement. A negative correlation between amitriptyline plasma levels and clinical improvement was found, whereas a positive correlation occurred with the nortriptyline levels. Amitriptyline, and to a lesser extent trimipramine, prolonged intracardiac conduction. In the amitriptyline group only, this effect was accompanied by significant increases of heart rate and blood pressure. Platelet serotonin content was decreased by 57% by the amitriptyline treatment but remained unchanged in the trimipramine group. This finding constitutes the first clinical evidence that trimipramine does not exert its antidepressant effect through 5-hydroxytryptamine reuptake blockade. It is proposed that neuronal sensitization to 5-hydroxytryptamine might mediate the therapeutic effect of tricyclic antidepressant drugs.",1
7937,3327676,Clinical pharmacokinetics of felodipine. A summary,"Felodipine is completely absorbed from the gastrointestinal tract. However, the amount reaching the systemic circulation is reduced to about 15% because of first-pass degradation. The bioavailability is constant within the dose interval of 5 to 40mg orally. The frequency histogram of the area under the plasma concentration-time curve (AUC) seems to be normally distributed. The disposition of felodipine is independent of the administered dose over the intravenous dose interval (1-3 mg). The plasma concentration-time curve declines in 3 distinct phases. The mean elimination half-life of felodipine is approximately 25h. Felodipine is extensively distributed to extravascular tissues. The volume of distribution of felodipine is about 10 L/kg, implying that less than 1% of the amount of drug in the body is localised in the blood. Felodipine is more than 99% bound to plasma proteins. Mean total clearance from the blood is 1 to 1.5 L/min and, therefore, felodipine is considered a high clearance drug. Felodipine is metabolised completely and no unchanged drug is eliminated in the urine. The first step in the metabolism involves oxidation to the corresponding pyridine derivative by the cytochrome P-450 system. Identified metabolites in plasma and urine are devoid of vasodilating activity. Long term treatment, and the presence of hypertension and impaired renal function do not affect the disposition of felodipine. Elderly people may have higher plasma levels than the young and middle-aged. Impaired liver function significantly decreases systemic clearance. Cimetidine and food affect felodipine kinetics, but with negligible clinical implications. Therapeutic concentrations of felodipine do not interact with highly protein-bound drugs and these drugs have no effect on the binding of felodipine to human plasma proteins in vitro. Plasma levels of digoxin and metoprolol tended to increase during felodipine treatment. There is a significant correlation between plasma concentrations of felodipine and haemodynamic effects in both healthy subjects and hypertensive patients during short term as well as during long term treatment.",1
7938,3335168,Safety and efficacy of amiodarone. The low-dose perspective,"Amiodarone has been reported to be a remarkably safe and effective drug in the European and South American experience but American investigators have published conflicting data. Since this disparity may be explained by a different dosing schedule, we prospectively evaluated the safety and efficacy of a low dose regimen in a group of 68 patients with cardiac arrhythmia resistant to conventional therapy, of whom 57 had manifested either ventricular tachycardia or fibrillation. All were loaded either intravenously (17) or orally, and maintained on an oral dose of 200 to 600 mg/day (mean daily dose 317 +/- 114 mg) and followed for 4 to 58 months (22 +/- 11). Results indicated that amiodarone was a safe and effective antiarrhythmic drug when used in lower doses.",1
7939,3337519,Metoprolol-induced hepatitis: rechallenge and drug oxidation phenotyping,,1
7940,3340642,Lovastatin alone and in combination for treatment of primary hypercholesterolemia,,1
7941,3341340,Fatal amiodarone hepatoxicity,"The antiarrhythmic agent amiodarone is associated with numerous adverse effects, but clinically significant liver disease is rare. A patient is described who presented with muscle weakness, hepatomegaly, and ascites following 28 months of amiodarone usage. His condition deteriorated despite discontinuation of amiodarone therapy. A postmortem liver biopsy demonstrated necrosis, fibrosis, hyalin, and phospholipid-laden lysosomal lamellar bodies. Resolution of hepatic dysfunction may not necessarily occur on withdrawal of amiodarone if irreversible damage is already established. We speculate as to the reasons for the reportedly low incidence of overt liver disease, and suggest that hepatic enzyme levels, as well as other indicators of hepatic function, such as the serum albumin concentration, be monitored indefinitely in all patients while taking amiodarone.",1
7942,3346531,Amodiaquine-induced fulminant hepatitis,"Three patients suffered from fulminant hepatitis within 23, 59 and 22 weeks after having ingested a total dose of 16, 26 and 15 g, respectively, of amodiaquine for the prophylaxis of malaria. Amodiaquine administration was continued for 44, 21 and 25 days after the onset of jaundice, respectively. One patient underwent emergency orthotopic liver transplantation and survived. The other two died. Fulminant hepatitis threatens patients in whom amodiaquine administration is protracted for several months and not interrupted when jaundice occurs.",1
7943,3347339,Autoimmunity in multiple sclerosis,"Multiple sclerosis reportedly coexists with disorders of autoimmune origin. The prevalence with which such disorders occur in the MS population has not been adequately investigated. We reviewed the medical records of 828 patients with definite MS and found that 4.8% had a past or present associated disorder in which autoimmune mechanisms presumably play a role. The cumulative prevalence of these disorders was no higher than that estimated for the general population. Serum from 105 patients, without clinical evidence of an associated autoimmune disorder, was tested for the presence of antinuclear, thyroid, parietal cell, smooth muscle, and mitochondrial antibodies. A significantly higher prevalence (p less than 0.01) of generally low titers of one or more autoantibodies was found in serum from the MS group, compared with a control group of 105 patients with other neurologic disorders. The increased frequency of serum autoantibodies probably reflects the existence of a nonspecific B cell overactivity in MS.",1
7944,3354178,Multiple vitamins and vitamins with iron: accidental poisoning in children,"To insure adequate nutrition, parents and pediatricians often advocate vitamin and mineral supplementation in young children. A retrospective review of 275 pediatric cases (6 mo-6 yr) involving multiple vitamins and vitamins with iron was conducted. Six cases with co-ingestants were excluded. The product ingested was the child's own dietary supplement in 93% of the cases. Fifty-six percent were children's multiple vitamins and 44% were children's multiple vitamins with iron. Adult vitamin preparations accounted for 7% of the ingestions. The average amount of vitamin A ingested by history was 43,300 IU (1,500-225,000) while the mean ingestion of iron was 16.8 mg/kg (0.9-77.5 mg/kg). Fifty ingestions (18.2%) involved more than one child. The mean time since ingestion was 15.8 min (0-150 min). Management data showed 246 (89.5%) being treated in the home setting with dilution (83%) or syrup of ipecac induced-emesis (10%). Medical intervention including emesis, serum iron/TIBC, and oral complexation was needed in 10.5% of the cases. The mean serum iron levels were 204.6 mcg/dl (81-414 mcg/dl). No patient needed admission. This review revealed 100% of patients showed no significant toxic effects. We conclude that early recognition and prompt treatment of pediatric overdoses involving multiple vitamins with and without iron significantly reduces morbidity.",1
7945,3358644,"Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety","In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.",1
7946,3359400,Fatal hepatic vascular toxicity of DTIC. Is it really a rare event?,"A fatal massive hepatic necrosis with widespread thrombotic occlusion of the small hepatic veins developed in two of 68 patients treated with DTIC for advanced melanoma in a randomized study. Thirteen similar reactions, in patients treated with single-agent DTIC, are reported in the literature. Several clinical and pathologic features distinguish this DTIC toxicity from Budd-Chiari syndrome and veno-occlusive disease (both well-known types of possibly drug-related hepatic vascular disease) and make it a distinctive syndrome. We were impressed by the repeated occurrence of this complication in a relatively small set of patients, in contrast with the rarity of the literature reports. We suggest that this dramatic complication could occur more frequently than commonly thought. Therefore, caution should be used with DTIC, particularly in curable patients.",1
7947,3364416,Anticonvulsant-induced liver damage,A case of iterated clonazepam-induced liver injury is described. It is suggested that the damage was of the metabolic idiosyncrasy type.,1
7948,3366514,"Deleterious effects of anabolic steroids on serum lipoproteins, blood pressure, and liver function in amateur body builders","The effects of self-administered anabolic steroids (AS) on lipoproteins, liver function, and blood pressure were studied in male amateur body builders. Twenty body builders were studied at the end of a course of AS (group 1) and 42 body builders were studied after discontinuation of the AS for a mean of 5 months (group 2). Sixteen body builders were studied after discontinuation of AS for at least 2 months and at the end of a 9-week course of AS (group 3). A group of 13 body builders who never used AS served as a control group. Both groups 1 and 2 showed higher levels of transaminas and a higher systolic blood pressure than the controls (P less than 0.05). Group 3 showed an increase of the transaminases an a slight but significant increase of systolic blood pressure (+3 mm Hg) and heart rate (+7 bts/min) after one course of AS (P less than 0.05). Group 1 showed a considerably lower high-density lipoprotein cholesterol (HDLC) (P less than 0.001), a higher low-density lipoprotein cholesterol (LDLC) (P less than 0.05), and a lower apoprotein A-l/B ratio (Apo A-l/ApoB) (P less than 0.001) than the controls and group 2. The ratio of LDLC/HDLC in group 1 was fourfold higher than in the controls (P less than 0.01). In group 3 HDLC decreased from 1.18 +/- 0.05 to 0.60 +/- 0.08 mmol/l (P less than 0.001) and LDLC increased from 3.97 +/- 0.39 to 5.74 +/- 0.71 mmol/l (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)",1
7949,3371237,[Chronic drug-induced hepatitis caused by dihydralazine],"Two cases are described, which revealed the picture of a dihydralazine-induced chronic aggressive hepatitis bioptically. One case was laparotomized under the clinical diagnosis of obstruction jaundice, the other exhibited no symptoms and was detected by elevated transaminases only. The time of exposure was 2-3 years. After withdrawal of dihydralazine the patients recovered within 2-3 months. Elevated transaminases (more than 1 mumol) should given occasion for withdrawing the drug or for performing of liver biopsy. In a total of 6,581 liver biopsies within five years an acute dihydralazine-hepatitis was seen more frequent than a chronic one (ratio 77:2).",1
7950,3371877,Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases,"""Fifty cases of nitrofurantoin-associated hepatic injury and two cases of nifurtoinol (hydroxymethylnitrofurantoin)-associated hepatic injury reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs were analyzed in detail. In 38 cases, a causal relationship was considered likely [i.e., """"highly probable"""" (n = 4), """"probable"""" (n = 23) or """"possible"""" (n = 11)]. In 25 cases, hepatic injury was of the acute type whereas 13 cases presented a chronic type of reaction. Both types were more common in the elderly. Eighty per cent of the acute reactions appeared within the first 6 weeks of treatment and were sometimes accompanied by fever (28%), rash (12%) and eosinophilia (16%). Biochemically, the pattern was mainly hepatocellular (32%), whereas mixed cholestatic-hepatocellular (4%) and cholestatic (4%) patterns were uncommon. Although mild to moderate liver enzyme elevations (60%) were common, these were primarily symptomatic. The reaction was fatal in one """"acute"""" and one """"chronic"""" case. In the chronic cases, nuclear (82%) and smooth muscle (73%) antibodies and LE cells (50%) were frequently present. HLA typing showed no increase of the HLA B8 or HLA DRw3 haplotype. HLA DR2 (56%) and HLA DRw6 (56%) were more frequent than in controls (both 29%), but this was not statistically significant. Histology showed mainly necrosis, varying from spotty to massive, in the acute cases and a pattern consistent with chronic active hepatitis in the chronic cases.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
7951,3375535,[Cholestatic hepatitis caused by D-penicillamine],,1
7952,3376924,Busulfan-induced hepatitis,"A 61-yr-old man with chronic myelocytic leukemia treated continuously for 8 yr with busulfan presented with fever, abdominal pain, and elevated liver enzymes in a cholestatic pattern. Evaluation of his liver and biliary tract with ultrasound and computerized tomography disclosed no structural abnormality. A percutaneous needle liver biopsy revealed cellular cholestasis with focal liver cell necrosis accompanied by a mild inflammatory infiltrate. Busulfan was discontinued, with subsequent normalization of liver enzymes and resolution of fever. These findings are interpreted as being compatible with busulfan-induced hepatitis.",1
7953,3380061,Mitoxantrone in relapsed or refractory acute nonlymphocytic leukemia,"""Seventeen patients with relapsed or refractory acute nonlymphocytic leukemia were treated with 14 mg/m2 of mitoxantrone given in a 30-minute infusion daily for three days. If the day fourteen bone marrow showed residual leukemia, a second course was given at the same dose for two days. Eight patients (47%) entered complete remission. Three patients (17%) had a partial response, four (24%) did not respond, and two (12%) died with hypoplastic marrows during treatment. Seven of the 12 relapsed patients entered a complete remission, as did one of the five refractory patients. Toxicity was acceptable; prolonged myelosuppression, moderate hepatic toxicity, and stomatitis were the only problems. Several dose schedules of mitoxantrone have been studied by other investigators with varying results. The three-day schedule in the present study is similar to the schedule used for common induction regimens employing anthracycline drugs. On the basis of its activity and acceptable toxicity in relapsed and refractory ANLL patients, we feel that this schedule could be safely combined with other agents in future studies.""",1
7954,3384112,Transient liver function tests abnormalities in ovarian hyperstimulation syndrome,,1
7955,3390984,Scintigraphic demonstration of hepatocellular damage after verapamil toxicity,,1
7956,3395527,Acute hepatitis after parenteral amiodarone administration,Amiodarone is believed to have caused acute hepatitis 24 hours after intravenous administration in two patients in whom no other alternative cause of hepatitis was found.,1
7957,3412385,Acute rhabdomyolysis associated with cocaine intoxication,"""Because an increasing number of patients were arriving at our emergency room with cocaine intoxication and rhabdomyolysis, we reviewed our experience with such patients. We identified 39 patients seen at our institution over an eight-year period with acute rhabdomyolysis after cocaine use. The patients' mean creatine kinase level was 12,187 U per liter (range, 1756 to 85,000). Thirteen of the 39 patients (33 percent) had acute renal failure; 6 of them died. In comparison to the patients with normal renal function, those with renal failure were more often admitted with profound hypotension (46 vs. 4 percent; P less than 0.001), hyperpyrexia (69 vs. 15 percent; P less than 0.001), and markedly elevated serum creatine kinase levels (mean, 28,084 vs. 7931 U per liter; P less than 0.01). Disseminated intravascular coagulation developed in seven patients with renal failure. All six deaths were in this group. Severe hepatic dysfunction was found in 11 patients with renal failure. We conclude that cocaine intoxication can cause acute rhabdomyolysis with acute renal failure, severe liver dysfunction, and disseminated intravascular coagulation and that the mortality rate among patients with this syndrome is high.""",1
7958,3414648,Reye's syndrome-like illness in a patient receiving amiodarone,"A 16-yr-old boy who was receiving amiodarone for ventricular arrhythmias developed a Reye's syndrome-like illness several days after an upper respiratory infection. Liver biopsy revealed microvesicular fat and spotty hepatocellular necrosis, typical of Reye's syndrome. Recovery was complete. This case report suggests that medications other than aspirin may predispose to Reye's syndrome, and that children receiving amiodarone should receive prophylaxis against influenza B and chicken pox.",1
7959,3418094,Anabolic steroid-induced cholestasis: choleretic response to corticosteroids,,1
7960,3428300,"Sudden death of a child with juvenile chronic arthritis, probably due to indomethacin",,1
7961,3435325,Nifedipine hepatitis,"An 80-year-old woman developed acute hepatitis following her first exposure to nifedipine. This adverse effect was characterised by fever, chills, anorexia, nausea, liver tenderness, hepatitic liver function tests and peripheral blood eosinophilia. On liver biopsy the portal tracts were expanded with a mixed inflammatory cell infiltrate rich in eosinophils. The potential for the occurrence of this adverse effect must increase with the current expansion of indications for the use of nifedipine.",1
7962,3440439,Some adverse effects of disulfiram in the treatment of nickel-allergic patients,"A retrospective follow-up study is reported of 58 women and 3 men with nickel allergy and hand eczema, of at least 4 months duration, treated with 50 to 400 mg disulfiram per day for 4 to 56 weeks. 2 patients were given 2 treatment series, making a total of 63 treatment series. 11 patients (20%) developed biochemical evidence of hepatotoxicity. 5 of them developed clinical evidence of hepatitis, which, for 4, was verified by liver biopsy. The patients with hepatotoxcity were significantly older than those who did not have this side effect. No correlation could be seen between the cumulative or maximum dose of disulfiram, the duration of the therapy and whether or not the patients showed evidence of hepatotoxicity. In 29 treatment series the dermatitis healed, while improvement was seen in 19 and no change in 15. There was no difference in the results whether maximum daily doses of 50, 200 or 400 mg were given. Follow-up examinations showed that the eczema recurred within a month after termination of therapy in 50% of the patients who improved during disulfiram therapy. Recurrence was seen within 6 months for another 40% of the patients.",1
7963,3444715,Drug hepatitis of cholestatic type in association with a FAC-regimen for breast cancer,"""The case of a 36 year old patient in whom breast cancer was diagnosed in February 1983 is reported. At the time of the diagnosis bone metastases, were already present. Therapy was started on the basis of a FAC-regimen (Ftorofur-, Adriamycin-Cyclophosphamide), where after the patient developed clinical and laboratory signs of hepatic lesion. At the time of the first FAC-course the suspicion of viral hepatitis of cholestatic type was raised; HBsAg was consistently negative. In the 3rd week after completion of the second FAC-course clinical signs of cholestatic hepatitis with high fever and leucopenia of increasing severity were suggestive of drug-induced hepatitis. Cyclophosphamide was incriminated, therefore, this component was omitted from the subsequent FAC-course. Nevertheless, the clinical manifestations reappeared in a more pronounced form. This time, too steroids were administered, with beneficial effect. In view of the complaints pointed to bone-metastases further cytostatic treatment, Vepesid monotherapy was started, but after the first course the patient developed hepatitis and died. Necropsy revealed, in addition to extensive bone-metastases, microscopic signs of drug-induced hepatitis. The types of liver damage caused by the cytostatic agents used in this study are reviewed. No hepatitis has been reported in connection with these drugs (Adriamycin + Ftorofur or Vepesid) thus far. The diagnostic criteria of drug-induced hepatitis are outlined. It is pointed out that with the eves more extensive use of cytostatic therapy a growing incidence of this complication should be taken into account.""",1
7964,3449308,Low dose pulse methotrexate in rheumatoid arthritis: an 8-year experience with hepatotoxicity,"The clinical utility of standard liver function tests for monitoring low dose pulse methotrexate therapy is reviewed in 163 rheumatoid arthritis patients over an eight-year period. Abnormalities of hepatic enzymes were seen in 58% of patients but led to cessation of therapy in only 5%. Moderate alcohol intake did not affect the frequency of liver test abnormalities. Abnormalities were seen more frequently in patients with longer duration of methotrexate therapy and in those with higher total dose. There was no correlation between liver test abnormalities and day of serum sampling relative to day of methotrexate dosing, nor was a correlation seen between liver test abnormalities and total weekly dose of methotrexate. Methotrexate has been demonstrated to be an effective drug in the treatment of rheumatoid arthritis. The clinical utility of standard liver tests to predict the potential for hepatotoxicity is questionable.",1
7965,3460168,Safety aspects of omeprazole,"Omeprazole has been given to more than 2500 subjects, mostly in short-term studies for 2-4 weeks, but also to some patients for more than 2 years. An analysis of side-effects has so far not shown a specific pattern that could be attributed to the drug.",1
7966,3463209,Phase I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia,"""Sixty-four patients with refractory acute leukemia were treated with high-dose cytosine arabinoside given at a dosage of 3 g/m2 intravenously over two hours every 12 hours for four to 12 doses, repeated at two- to three-week intervals. Complete remissions were observed in 16 patients (25 percent), and the median duration of remission was three months (range, one to 10 months). Remission rates were similar for patients with acute myelogenous and acute lymphocytic leukemia (24 and 27 percent, respectively). Response rates were significantly higher in patients with initial remission durations of more than six months than in those with shorter remissions or those in whom there was no response to front-line therapy (41 and 9 percent; p less than 0.01). Similarly, patients with disease sensitive to conventional cytosine arabinoside had higher response rates than did those with resistant disease (54 and 17 percent; p = 0.03). Serial in vivo measurements of intracellular concentrations of the active metabolite of cytosine arabinoside in peripheral blasts following the initial dose demonstrated considerable individual variation. Favorable intracellular pharmacology of this active metabolite, manifested by its higher intracellular concentrations 12 hours after the first dose, by longer half-lives of active metabolite levels, and by higher values of the measured area under the curve of its accumulation and retention, was associated with higher response rates. Central nervous system toxicity occurred in 24 percent of patients, and pulmonary toxicity occurred in 22 percent; both were dose-limiting and dose-related. Other toxicities included nausea, vomiting, diarrhea, conjunctivitis, photophobia, cytosine arabinoside fever, skin rashes, and hepatic dysfunction. Response rates were similar for schedules utilizing four to six doses at two-week intervals or nine doses at three-week intervals (27 percent versus 25 percent). The schedule of 12 doses had a more rapid antileukemic effect but resulted in significantly higher toxicity and mortality rates during therapy with a similar overall response rate (21 percent). Thus, high-dose cytosine arabinoside is an effective regimen with substantial toxicity in patients with acute leukemia.""",1
7967,3477654,Possible zidovudine-induced hepatotoxicity,,1
7968,3486211,Does propranolol precipitate hepatic encephalopathy?,A 52-year-old woman with primary biliary cirrhosis who had never had hepatic coma developed it while taking propranolol. The coma receded when the propranolol was stopped and 2 days later gastrointestinal bleeding did not precipitate hepatic coma. This raises the question whether propranolol and other beta blockers lead to hepatic encephalopathy.,1
7969,3493172,"Treatment of aplastic anemia with antithymocyte globulin, high-dose corticosteroids, and androgens","""A total of 46 patients with aplastic anemia (34 severe; 12 moderate) were treated with antihuman thymocyte globulin (ATG), high-dose methylprednisolone, and oxymetholone. Early symptoms of ATG toxicity included fever, rash, and bronchospasm. Signs of serum sickness also developed in 23 patients. Complications associated with high doses of steroids were hyperglycemia, hypertension, fluid retention, gastrointestinal hemorrhage, and aseptic necrosis of the hip. Other morbidity possible associated with steroid administration included seizures, arrhythmias, and headache with papilledema. Studies of elevated liver function necessitated discontinuation of androgen therapy in eight patients. A complete or partial hematological response was noted in 19 patients (41%). Of these, three have had recurrent cytopenias, of whom one has developed a myelodysplastic syndrome. There are currently 34 patients surviving, and 12 who have died. Actuarial survival at three years is 65%. These response and survival data are comparable to those of previous trials using ATG and androgens without high-dose steroids. A prospective, randomized trial is needed to determine whether the addition of high-dose corticosteroids to ATG does significantly increase the rate and frequency of response in order to justify the toxicity of this additional immunosuppressive therapy in the treatment of aplastic anemia.""",1
7970,3504404,Comparison of oxcarbazepine and carbamazepine: a double-blind study,"The antiepileptic efficacy and side-effects of oxcarbazepine (OXC), a new carbamazepine derivate, were evaluated in a double-blind study. Forty ambulatory epileptics with unsatisfactory seizure control or unwanted effects due to phenytoin monotherapy were changed to OXC or carbamazepine (CBZ) and were then followed for 48-50 weeks. Thirty-four of the patients completed the study. The seizure frequencies on the trial drugs were not significantly different and the antiepileptic efficacy of OXC was comparable to CBZ. The incidence of side-effects during the initiation phase was lower with OXC suggesting better tolerability of OXC compared to CBZ.",1
7971,3510146,Azathioprine and hepatic venocclusive disease in renal transplant patients,"We report 3 cases of hepatic venocclusive disease occurring in renal transplant patients receiving azathioprine and combine our experience with 4 other previously reported cases. The data suggest a clinical syndrome characterized by (a) delayed clinical onset, (b) striking male predominance, (c) presentation with jaundice followed by evidence of portal hypertension, and (d) poor prognosis. One of our patients, who is still alive 40 mo after the first onset of symptoms of liver disease, showed striking clinical improvement with discontinuation of azathioprine and subsequent deterioration on reinstitution. We suggest that azathioprine may be closely linked with the development of venocclusive disease in renal transplant patients and that the frequency of this disorder may be more common than previously reported. To attempt to prevent a fatal outcome, this group of patients should be closely monitored for the earliest signs of hepatic venocclusive disease through periodic serum bilirubin and alkaline phosphatase determinations. Patients with abnormal tests should undergo liver biopsy. If hepatic venocclusive disease is found, prompt withdrawal of azathioprine is indicated.",1
7972,3511825,Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure,"""We have treated 6 chronic alcoholics and identified an additional 19 reported in the literature who developed severe hepatotoxicity from acetaminophen taken in apparently moderate doses. The clinical disease in these 25 patients had a characteristic pattern: mild to moderate jaundice; mild to severe coagulopathy; and strikingly abnormal aminotransferase levels, values inconsistent with either acute alcoholic hepatitis or viral hepatitis. The possible causes for the injury from ostensibly nontoxic drug levels appear to be either the induction by chronic alcohol intake of the cytochrome P-450 system responsible for converting acetaminophen to a toxic metabolite, or the effect of alcoholism and the associated malnutrition in reducing the glutathione concentration, responsible normally for preventing hepatotoxicity by conjugation with the toxic metabolite. The research data pertaining to the apparent enhanced toxicity from chronic alcoholism are reviewed. Despite the low frequency of ethanol-potentiated acetaminophen hepatotoxicity, alcoholics should be cautioned about the use of acetaminophen while they persist in heavy consumption of alcohol.""",1
7973,3517744,Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction,"A double-blind placebo-controlled study was conducted to evaluate the efficacy of orally administered pilocarpine in treating oral dryness caused by salivary gland hypofunction. At low dosages, pilocarpine increased the production of saliva by parotid and submandibular and/or sublingual glands and relieved the sensation of oral dryness. The quantity and composition of pilocarpine-stimulated secretions were similar to saliva produced in response to gustatory stimulation with citrate. In appropriate patients, pilocarpine is a safe, easily administered, effective therapy to relieve xerostomia by increasing natural salivary function.",1
7974,3521429,Mitoxantrone: a new anticancer drug with significant clinical activity,"Clinical studies using mitoxantrone, an anthraquinone, were begun in the United States in 1979. Subsequent phase II and III trials have shown that mitoxantrone has significant clinical activity in patients with breast cancer, acute leukemia, and lymphoma. The drug has antiviral, antibacterial, antiprotozoal, immunomodulating, and antineoplastic properties and is mutagenic in some animal systems. Its mechanism of action seems to involve both DNA intercalation and nonintercalative electrostatic interactions. The dose-limiting toxicity is myelosuppression when the drug is given on a single-dose, every-3-week schedule and mucositis when it is given daily for 5 days. Other toxicities include gastrointestinal and cardiac effects, the gastrointestinal toxicity being less severe and less frequent than that with the anthracycline anticancer drugs. Because of its low incidence of serious toxicities and effectiveness in treating certain solid tumors and leukemias, mitoxantrone is a promising new agent in the treatment of cancer.",1
7975,3524334,"A controlled clinical trial of 3- and 5-month regimens in the treatment of sputum-positive pulmonary tuberculosis in South India. Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Bangalore","""A controlled comparison of 3 short-course regimens was undertaken in patients with newly diagnosed, sputum-positive, pulmonary tuberculosis in South India. The regimens were: R3: rifampin plus streptomycin plus isoniazid plus pyrazinamide daily for 3 months; 5: the same as regimen R3 followed by streptomycin plus isoniazid plus pyrazinamide twice weekly for 2 months; Z5: the same as regimen R5 but without rifampin. The distributions of various pretreatment characteristics were similar in the 3 series. At the end of treatment, 6 patients (3 R3, 3 Z5) of 694 (228 R3, 230 R5, 236 Z5) with drug-sensitive organisms initially were classified as having an unfavorable response. By 24 months (21 months of follow-up for the R3 regimen and 19 months for the R5 and Z5 regimens), a bacteriologic relapse requiring treatment occurred in 20% of 200 R3, 4% of 187 R5, and 13% of 199 Z5 patients, the difference between the R3 and R5 series being highly significant (p = 0.00001). Considering patients with cultures initially resistant to isoniazid, 4 of 57 in the R3 and R5 series combined had an unfavorable response to treatment compared with 13 of 26 in the Z5 series (p less than 0.0001). Of the 4 patients with an unfavorable response in the R3 and R5 series combined, resistance to rifampin emerged in 2. Complaints of arthralgia were made by 45% of the R3 and R5 patients combined and 70% of the Z5 patients (p less than 0.00001). However, chemotherapy was modified in only 5 and 12%, respectively. Jaundice occurred in 7% of the R3 and R5 patients and 1% of the Z5 patients (p less than 0.00001).""",1
7976,3528517,Propylthiouracil-induced cholestatic jaundice,"The typical propylthiouracil (PTU)-linked hepatotoxicity, is known to manifest itself by hepatocellular injury with greatly increased serum transaminase values and evidence of hepatic necrosis on liver biopsy. Herewith presented is a 33-year old, thyrotoxic woman who developed cholestatic jaundice two weeks after initiation of PTU therapy. The diagnosis was confirmed by liver biopsy. A causal link between PTU treatment and the cholestatic jaundice was suggested by: the time of onset, typical skin rash and a positive migration inhibition factor (MIF) test to PTU. Awareness of this rare complication of PTU treatment may prevent the performance of unnecessary, expensive and possibly harmful diagnostic procedures.",1
7977,3531450,Course of nephropathic cystinosis after age 10 years,"We identified 80 patients with nephropathic cystinosis older than age 10 years in the United States and Canada. The oldest reported individual was 26 years of age. Ninety percent of patients had received at least one renal allograft. Age at the time of first transplant varied between 7 and 17 years (mean 10.0 years). Almost three fourths of the patients required thyroid replacement, 27% had splenomegaly, and 42% had hepatomegaly. Photophobia was noted in 86% of patients, decreased visual acuity in 32%, and corneal ulcerations in 15%. Neurologic involvement, renal osteodystrophy, and diabetes mellitus were unusual. All these late complications of nephropathic cystinosis contribute to a description of the natural history of the disease and provide a rationale for the therapeutic use of cystine-depleting agents after renal transplantation.",1
7978,3537786,Medical complications of cocaine abuse,,1
7979,3541320,Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients,"""Two hundred twenty-eight patients from a total of 466 (49%) receiving renal allografts under cyclosporine/prednisone (CsA/Pred) immunosuppression experienced at least one episode of posttransplant hepatotoxicity. All patients were documented to have normal serum bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), lactic acid dehydrogenase (LDH), and alkaline phosphatase (AP), as well as negative results of biliary ultrasound and upper gastrointestinal contrast examinations prior to transplantation. Hepatotoxic episodes usually were self-limited (82%), and generally occurred during the very early posttransplant period (76%). Liver function abnormalities included hyperbilirubinemia (48% of patients), elevated SGOT (47%), SGPT (73%), LDH (84%), and AP (59%). The CsA serum trough radioimmunoassay (RIA) was relatively high among hepatotoxic patients with a mean value of 225 +/- 17 ng/ml. Pharmacokinetic parameters, including bioavailability and drug clearance, were significantly altered among this group of patients. The management strategy of CsA dose reduction was effective; however, 11 patients (2.4%) developed biliary calculous disease posttransplant while under CsA/Pred immunosuppression. Seven patients had cholelithiasis, and two patients underwent choledochoduodenostomy because of primary choledocholithiasis. The results contrast with 279 renal transplant recipients from an overlapping nonrandomized group treated with azathioprine (Aza)/Pred in whom cholelithiasis was not identified. Pancreatic abnormalities were relatively common, but clinical pancreatic disease occurred in only six patients. There were two episodes of acute pancreatitis, three patients developed pancreatic abscess, and one patient developed a pancreatic pseudocyst. The apparent proclivity of CsA-treated patients to develop biliary calculous disease, and the occurrence of serious pancreatic complications in a small percentage of patients did not affect the majority of CsA-treated patients. They may, however, represent important problems associated with the use of this immunosuppressive agent.""",1
7980,3544376,Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years,"""The therapeutic efficacy of cyclosporine (CsA) as an immunosuppressive agent was complemented by a modest, long-term incidence of toxic complications in 402 renal allograft recipients engrafted one to five years prior to analysis. The overall patient and graft survivals at one year were 97% and 84% (actual), and at five years 92% and 67% (actuarial). The immunosuppressive therapeutic index was excellent: only 12% of allografts were lost from rejection, with 5% of patients succumbing to infection. While infections were common, tending to emanate in the urinary tract or to be viral in etiology, they were generally mild and readily controlled. Only four patients displayed malignancies; none succumbed to this cause. The most common toxic complication was hypertrichosis, which was accentuated in pediatric patients. While tremors occurred in 20% of patients, primarily during the first three months, other neuroectodermal complications of parethesias, depression, somnolence, and seizures were rare. Hepatotoxicity, which was noted in 50% of patients, particularly recipients of cadaveric grafts, generally was first seen as a transaminase elevation, at least partially reversible by dose-reduction and abating by the third year. Associated disturbances of cholelithiasis and pancreatitis were occasionally observed. Nephrotoxicity was the only persistent, long-term complication. Hypertension occurred in 72% of patients during the first month, 36% in the second year, and about 15% thereafter. Hyperuricemia, which occurred in about 30% of recipients during the first two years, was occasionally associated with symptomatic gout. The mean serum creatinine level remained elevated throughout the follow-up period at 1.8-1.9 mg/dl, suggesting persistent, but nonprogressive, drug-induced renal injury. The present analysis documents the relative safety of CsA for long-term therapy, and highlights the need for new approaches to ameliorate drug-induced nephrotoxicity.""",1
7981,3550461,Cysteamine therapy for children with nephropathic cystinosis,"""We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months. This agent is known to be effective in depleting cells of cystine. In our study, the mean cystine depletion from leukocytes was 82 percent. A historical control group of 55 children received either ascorbic acid (27 children) or placebo (28). At age six, 2 of 17 controls had a serum creatinine level less than 1.0 mg per deciliter, as compared with 17 of 27 patients treated with cysteamine for at least one year (odds ratio, 12.8; 95 percent confidence interval, 2.1 to 33.9). At the end of the study, creatinine clearance was higher in the cysteamine group than in the control group (38.5 vs. 29.7 ml per minute per 1.73 m2; 95 percent confidence limits on the difference, 1.8 and 15.8), even though the cysteamine group was on average 1.4 years older than the control group. Cysteamine also improved growth; those in the cysteamine group between two and three years of age grew at 93 percent of the normal velocity, as compared with 54 percent in the control group. Fourteen percent of the patients could not tolerate the taste and smell of cysteamine. Concurrent controls treated in a blinded fashion with a placebo were not included in this study. With this limitation in mind, we conclude that oral cysteamine, by depleting cells of cystine, helps maintain renal glomerular function, improves growth, and constitutes the current treatment of choice for nephropathic cystinosis.""",1
7982,3554879,The treatment of spasticity in multiple sclerosis: a double-blind clinical trial of a new anti-spastic drug tizanidine compared with baclofen,"""The anti-spastic effect of a new drug, tizanidine, was compared with that of baclofen in a double-blind clinical trial; 40 seriously handicapped patients with multiple sclerosis (MS) were randomly allocated treatment with one or the other drug for a 6-week period. The antispastic effect was evaluated by clinical criteria. The optimal daily dose of both drugs varied considerably from patient to patient, and was on the average 23 mg for Tizanidin and 59 mg for baclofen. To the extent an antispastic effect was observed, the 2 drugs appeared to be equally effective when given at a 1:2 ratio (mg tizanidine: mg baclofen). Side effects of both drugs were sleepiness, muscular weakness and dry mouth. Tizanidine had a mild depressive effect on blood pressure. Sudden withdrawal of both drugs was accompanied by a transient relative increase of spasticity in approximately half the patients. There were no other changes suggesting physical or psychological dependence. The present study underscores that neither baclofen nor tizanidine are ideal antispastic drugs, and emphasize the need for further research.""",1
7983,3559100,Prolonged cholestasis after cyproheptadine-induced acute hepatitis,"We report a patient in whom cyproheptadine-induced hepatitis was followed by prolonged cholestasis marked by elevation of serum alkaline phosphatase levels, gammaglutamyltransferase and bile acid levels, and disappearance of small bile ducts. Chlorpromazine and imipramine, which can induce a similar acute hepatitis followed by protracted cholestasis, have a close chemical structure (i.e., a tricyclic ring). We suggest that this structure might be involved in this type of hepatotoxicity.",1
7984,3563038,[Cimetidine and toxic hepatitis],,1
7985,3568943,Carbamazepine-induced acute cholangitis,We report the case of a patient with carbamazepine-induced cholestasis in whom histologic examination showed acute cholangitis. This type of lesion broadens the spectrum of carbamazepine-induced liver injury which also includes granuloma and hepatocellular necrosis. Its association with marked hypereosinophilia suggests that carbamazepine may cause acute cholangitis through an immunoallergic mechanism.,1
7986,3572936,Salicylate toxicity in elderly patients with rheumatoid arthritis,"Using the American Rheumatism Association Medical Information System, we studied the effect of age upon salicylate toxicity in elderly patients with rheumatoid arthritis. Data were gathered from 545 patients by self-reported questionnaires for the 6 months and also the 7 days before the visit of interest. With one week data and weight adjusted doses in 253 patients in whom data were available, age related differences in lower gastrointestinal symptoms (p = 0.05) and tinnitus (p = 0.01) were found, despite the fact that elderly patients (E) took less salicylate than younger ones (y)--E [39.1 +/- 2.4 (SD) mg/kg/day] vs Y [49.8 +/- 3.89 mg/kg/day] (p = 0.02). Our data indicate a difference in salicylate dynamics among the elderly (i.e., increased toxicity in the face of decreased salicylate doses).",1
7987,3578211,Copper toxicity following massive ingestion of coins,"Two hundred seventy-five United States coins were discovered in the stomach of a mentally disturbed individual at autopsy. Many coins containing copper were corroded by prolonged contact with gastric juice, with subsequent absorption and deposition of copper in the liver and kidneys. The patient died from complications related to the acute toxic phase of chronic copper poisoning. A discussion of the case, foreign-body ingestion, gastric bezoars and the mechanism of copper toxicity is presented. To our knowledge, this is the first death due to copper intoxication following a massive ingestion of coins.",1
7988,3578231,Cholestatic jaundice due to derivatives of oxacillin,,1
7989,3581546,"The aminopyrine breath test, an inadequate early indicator of methotrexate-induced liver disease in patients with psoriasis","The aminopyrine breath test has been shown to be a sensitive noninvasive indicator of liver cell dysfunction. In a search for a noninvasive method of monitoring the effects of methotrexate therapy, we have investigated the use of the aminopyrine breath test in patients receiving methotrexate for the treatment of severe psoriasis. The [14C]-aminopyrine breath test was performed in 20 normal control subjects, 32 patients with psoriasis receiving methotrexate therapy, and 8 patients with histologically confirmed cirrhosis of differing etiology. Eighteen patients on methotrexate had liver biopsies classified as grade I changes, 6 patients as grade II, and 8 patients as grade III. The normal value for the breath test was 11.0 +/- 1.6% (mean +/- 1 SD). The mean [14C]-CO2 excretion (8.3 +/- 4.4%) of the 8 patients with grade III liver disease was significantly different from the control subjects (p less than 0.02), and those with grade I liver changes (p less than 0.04). The aminopyrine breath test was only able to detect the later severe stages of methotrexate hepatotoxicity, grade III, when fibrosis occurs, before established cirrhosis was present. Our data suggests that the aminopyrine breath test is not a sensitive indicator for the detection of early methotrexate-induced hepatotoxicity, (stages I and II), but will detect the precirrhotic stage III change. Consequently, we recommend that a liver biopsy should be performed annually in all psoriatic patients receiving methotrexate, to detect histological damage, especially when the aminopyrine breath test score falls below the 95% confidence limits of normal.",1
7990,3584485,Granular cells as a marker of early amiodarone hepatotoxicity: a pathological and analytical study,"Two contrasting cases of amiodarone hepatotoxicity are described. In one, perivenular collections of swollen cells, probably macrophages, with granular cytoplasm in an otherwise nearly normal liver were observed. Transmission electron microscopy showed that the cytoplasmic granularity was due to lysosomal bodies of various sizes. X-ray energy and wavelength spectroscopic analysis showed a high iodine content in these lysosomal bodies, good presumptive evidence of the presence of amiodarone or one of its metabolites. In the second case there was a micronodular cirrhosis, and similar granular cells also containing iodine were seen in the fibrous connective tissue. These cases seem to represent the very early and late stages of amiodarone hepatotoxicity. In a patient taking this drug aggregates of swollen granular cells may be a sensitive and histopathologically useful marker of early amiodarone toxicity.",1
7991,3586729,[Hepatotoxicity of ketoconazole in patients with adrenal pathology],,1
7992,3588112,Efficacy of aztreonam in pulmonary exacerbations of cystic fibrosis,"A noncomparative pilot study was conducted to assess the potential usefulness of aztreonam in pulmonary exacerbations of cystic fibrosis. Of 27 patients initially enrolled 25 received sufficient courses of aztreonam therapy to be evaluable. All patients received 200 mg/kg/day of aztreonam in 4 equally divided doses administered intravenously. Of 57 isolates of Pseudomonas aeruginosa from pretherapy sputum cultures, 48 were susceptible to aztreonam in vitro as were 11 of 18 strains isolated at the conclusion of therapy. With treatment colony counts of P. aeruginosa in sputum were reduced by 3 log10 or more in 15 patients. It was totally (but temporarily) eradicated in 11 of these patients. Clinical scores and white blood cell counts improved significantly (P less than 0.05). Side effects of aztreonam were limited to transient elevations of liver enzymes occurring in 16 patients. Aztreonam merits further evaluation in a randomized, comparative trial with standard antibiotic therapy for cystic fibrosis.",1
7993,3596172,Cyclosporin A-induced cholestasis. The mechanism in a rat model,"Cyclosporin A (CyA) causes cholestasis in a significant proportion of transplant patients. Doses of 5, 10, and 15 mg CyA/kg body wt or the Miglyol 812 vehicle were administered intraperitoneally for 1, 2, and 3 wk to separate groups of rats to investigate the mechanism of this cholestasis. At 1 wk a dose-response relationship between serum CyA levels and increasing CyA doses was noted. A maximum CyA blood level was achieved by 2 wk with the 10- and 15-mg/kg doses. Subsequent studies were performed using the smaller (10 mg/kg) dose administered for 3 wk. This dose resulted in a marked increase in serum bile acid levels compared with vehicle-treated controls (24.6 +/- 4.0 vs. 4.3 +/- 1.2 mumol/L, p less than 0.001) without inducing significant changes in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, bilirubin, alkaline phosphatase, and albumin levels or hepatic architectural alterations. With CyA treatment, baseline bile flow decreased by 35% and bile salt secretion decreased by 25% compared with vehicle-treated animals. Cyclosporin A and vehicle-treated rats were infused intravenously with taurocholate (4 mumol/min X kg) for 2 h and then depleted of bile salts over the next 24 h. Bile samples collected over this period were graphed as bile salt secretion versus bile flow. The mean slope of the linear regression for the CyA-treated rats was 62% of the control, demonstrating a decrease in bile salt-dependent flow. Extrapolation of the linear regression to the ordinate demonstrated a 22% decrease in bile-independent flow with CyA treatment. Therefore, in our experimental model of CyA-induced cholestasis, the decrease in flow observed was the result of a decrease in both bile salt-dependent and bile salt-independent flows and occurred in the absence of significant biochemical or histologically evident hepatotoxicity.",1
7994,3602573,[Acute hepatitis caused by indomethacin],,1
7995,3605968,[Cholestatic hepatitis: a rare complication of the treatment with D. penicillamine],,1
7996,3613879,Malignancies following long-term azathioprine treatment in chronic liver disease. A report from the Copenhagen Study Group for Liver Diseases,"One hundred and fifty-four patients with histologically verified non-alcoholic chronic liver disease were randomized to azathioprine or prednisone treatment. After a median of 91 months observation time, the cause of death was assessed retrospectively. Autopsy was performed in 82% of 71 deaths. In the azathioprine group 33% (13/39) died from malignant neoplasia, and in the prednisone group (13%) (4/32) (p = 0.08). Considering a possible fatal outcome as a consequence of treatment, this finding urges caution in the long-term application of azathioprine at the usual dose level.",1
7997,3617201,Albendazole in hydatid disease--hepatocellular toxicity,,1
7998,3622187,Disulfiram and fulminant hepatitis,,1
7999,3623575,Accidental poisoning in childhood: a multicentre survey. 1. General epidemiology,"""As background to a study of the effectiveness of packaging in preventing childhood poisoning, the National Poisons Information Service coordinated a prospective survey, in which 9 Accident and Emergency (A & E) departments and 5 paediatric departments, between July 1982 and February 1984, recorded 2043 cases of suspected accidental poisoning in children aged 0-60 months. The products implicated were drugs (59%), household products (37%) and plants (3%). The drugs most frequently implicated were analgesics, anxiolytics, cough medicines, oral contraceptives and drugs to supplement diet or treat dietary disorders. The most frequently implicated household products were cleaners such as bleach, detergent and disinfectant, and petroleum distillate. Seventy-five per cent of the children were 2 and 3-year-olds. Fifty-six per cent were male. Only 22% of the children had signs or symptoms on admission. In only 2 cases were these serious. Treatment other than ipecacuanha and/or oral fluids was seldom required. Of the cases where outcome was recorded, 56% were discharged from A & E. The rest were admitted to a ward; only 7 children were admitted to intensive care units. No child died. Comparison with HASS and other epidemiological surveys shows that these results are representative of national trends.""",1
8000,3624504,The hepatic injury of monoamine oxidase inhibitors,,1
8001,3629206,"Hepatotoxicity associated with low-dose, long-term methotrexate treatment of rheumatoid arthritis","""Liver biopsies were performed in 17 patients with therapy-refractory rheumatoid arthritis who were treated successfully with 5-15 mg/week methotrexate (mtx). The average duration of exposure to mtx therapy for each patient was 2.8 years (range 1.5-5 years). Total cumulative mtx doses ranged between 633 and 1,655 mg (mean 1,060 mg). The biopsies revealed 16 cases of normal histology, of which 3 showed nuclear variability in the hepatocytes; 4 with mild fatty infiltration, 2 with mild fatty infiltration and portal round cell infiltration. Portal fibrosis was found in one patient who had psoriasis in addition to clinical RA.""",1
8002,3653467,Methotrexate-induced liver cirrhosis. A follow-up,"Studies on serial liver biopsies from 25 patients with methotrexate-induced liver cirrhosis, taken from 1 to 13 years after cirrhosis was established, confirm that this type is not of aggressive nature. When evaluated blind no progression was found in most of the later biopsies. Alcohol and previous use of hepatotoxic drugs such as the combination of arsenics and vitamin A seem to have been contributing factors to cirrhosis formation.",1
8003,3658544,Inhibition of mitochondrial functions by margosa oil: possible implications in the pathogenesis of Reye's syndrome,"""Margosa oil (MO), a fatty acid-rich extract of the seeds of the neem tree and a reported cause of Reye's syndrome, has been used in the induction of an experimental model of Reye's syndrome in rats. It has been reported that MO causes a decrease in in vivo mitochondrial enzyme activity similar to that seen in Reye's syndrome. We have attempted to uncover some of the biochemical mechanisms of MO's toxicity by examining its effect in vitro on isolated rat liver mitochondria. Male rat liver mitochondria were isolated by centrifugation; oxygen uptake, reduced forms of cytochrome b, c + c1, a + a3, and flavoprotein, intramitochondrial concentrations of acetyl coA, acid-soluble coA, acid-insoluble coA, and ATP content were measured after incubation with and without MO. Our results reveal that MO is a mitochondrial uncoupler. State 4 respiration was increased while the respiratory control ratio was decreased. The intramitochondrial content of ATP was also decreased. There were substantial changes in the reduction of the respiratory chain components after incubation of mitochondria with MO. This decelerative effect on mitochondrial electron transport was alleviated by the addition of coenzyme Q and/or carnitine. These effects of MO on mitochondrial respiration may be due to changes in fatty acid metabolism caused by MO as MO caused a shift in the proportion of acid-soluble or acid-insoluble coA esters. Supplementary therapy with L-carnitine and coenzyme Q may be useful in the management of MO-induced Reye's syndrome.""",1
8004,3662087,A report of hepatic necrosis and death following isoflurane anesthesia,,1
8005,3669125,Leucopenia and abnormal liver function in travellers on malaria chemoprophylaxis,"Of 2887 travellers between the years 1984-1985, 451 on prophylactic antimalarials were studied retrospectively for adverse haematological or hepatic drug reactions and compared to 296 drug non-users. Travellers using amodiaquine, chloroquine, or pyrimethamine for less than 10 weeks had significantly lower total leucocyte counts than non-users. This was due to diminution of lymphocytes, not neutrophils. Travellers using amodiaquine for less than 10 weeks also had significantly higher serum aspartate aminotransferase (SGPT) levels than non-users. Amodiaquine was associated with a 3.1-times increased risk (95% confidence limits 1.8-5.4) of abnormal SGPT values. We consider toxic products, including metabolites of amodiaquine, the most likely cause of amodiaquine-related hepatotoxicity in travellers.",1
8006,3672282,Ketoconazole induced hepatitis,,1
8007,3676923,Treatment of spasticity with tizanidine in multiple sclerosis,"Spasticity is a frequent and often disabling symptom in MS patients. Current drugs used as antispastic agents include Dantrolene Sodium, Baclofen and Diazepam. Tizanidine (5-chloro-4-(2imidazolin-2 yl amino)-2,1,3-benzothialdiazole) is a new antispasticity agent that has purported central action. A double blind placebo controlled trial was performed to study the efficacy of this drug in MS patients. Sixty-six patients entered an eight week therapeutic trial and fifty-nine completed the trial. Patients were assessed at 0, 2, 3 and 8 weeks of therapy for clinical effects. Electrophysiologic tests were performed at 0 and 8 weeks. A statistically significant benefit was noted in spastic muscle groups in the legs with concomitant significant reduction in hyperactive stretch reflexes and ankle clonus. Side effects most frequently cited included dry mouth and drowsiness. Two patients developed elevated liver function test that decreased with cessation of therapy. Other clinical details, side effects and electrophysiologic data will be presented. Tizanidine appears to reduce clinical spasticity and hyperreflexia in MS patients although no change in functional status was detected. Tizanidine may well serve as an alternate antispastic agent, alone or in combination with other agents.",1
8008,3680580,Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist,"""The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model-independent pharmacokinetic analysis of the plasma concentration-time data showed that nalmefene was rapidly absorbed and had an elimination half-life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a beta-glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50-mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven-day administration period.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
8009,3683638,[Fatal liver damage during use of diclofenac],,1
8010,3690249,Fatal toxicity of antidepressant drugs in overdose,"A fatal toxicity index (deaths per million National Health Service prescriptions) was calculated for antidepressant drugs on sale during the years 1975-84 in England, Wales, and Scotland. The tricyclic drugs introduced before 1970 had a higher index than the mean for all the drugs studied (p less than 0.001). In this group the toxicity of amitriptyline, dibenzepin, desipramine, and dothiepin was significantly higher, while that of clomipramine, imipramine, iprindole, protriptyline, and trimipramine was lower. The monoamine oxidase inhibitors had intermediate toxicity, and the antidepressants introduced since 1973, considered as a group, had significantly lower toxicity than the mean (p less than 0.001). Of these newer drugs, maprotiline had a fatal toxicity index similar to that of the older tricyclic antidepressants, while the other newly introduced drugs had lower toxicity indices, with those for mianserin, nomifensine, trazodone, and viloxazine reaching significance. Provided that these drugs are equally effective clinically, serious consideration should be given to prescribing antidepressants with a lower fatal toxicity.",1
8011,3694926,A case of hyperbilirubinemia during treatment with chenodeoxycholic acid,"This is a report of a 27-year-old female with hyperbilirubinemia during treatment with chenodeoxycholic acid (CDCA) for the resolution of gallstones. After CDCA administration, serum bilirubin increased markedly without an apparent obstruction of bile ducts. The histological findings of the liver were compatible with toxic liver injury. Bile acids analysis, however, did not reveal the increment of lithocholic acid, toxic metabolite of CDCA in the serum and the hepatic tissue. The bile acids sulfation and the 6 alpha-hydroxylation of CDCA were also normal. Her jaundice disappeared quickly after discontinuation of CDCA. Presumably, in this case, the stagnation of bile acids in the liver caused by choledochal sands facilitated the toxic effect of CDCA on the damaged hepatocytes.",1
8012,3701014,Cholestatic hepatitis after dicloxacillin-sodium therapy,,1
8013,3704507,[Liver complications caused by D-penicillamine. Apropos of a case],"The complications of D-penicillamine are rare. It generally consists of reversible cholestatic hepatitis which may, however, be fatal. The authors report a typical case with a benign outcome and with concomitant signs of cutaneous intolerance with eosinophilia. The definite role of D-penicillamine was confirmed by the re-introduction of the drug.",1
8014,3705214,[Glipizide induced toxic hepatitis],,1
8015,3706949,Piroxicam and pancreatitis,,1
8016,3709082,Chronic salicylism in a patient with juvenile rheumatoid arthritis,"A patient who developed chronic salicylism associated with salicylate therapy for treatment of juvenile rheumatoid arthritis is described, and the clinical presentation and treatment of chronic salicylism are reviewed. A 5 1/2-year-old boy was receiving aspirin 150/mg/kg/day for treatment of juvenile rheumatoid arthritis. While on salicylate therapy, the patient developed tachypnea and became increasingly hyperthermic, lethargic, and disoriented. The patient developed a maculopapular rash, weakness, and a decreased level of consciousness during the 11 days before admission to the hospital. Physical examination and laboratory determinations revealed that the patient had hypoprothrombinemia, hypoglycemia, and severe hepatic encephalopathy secondary to long-term salicylate toxicity. The patient was treated for hypoglycemia, electrolyte imbalances, thrombocytopenia, and anemia and was discharged after 24 days. Diagnosing chronic salicylism with hepatic dysfunction was difficult because the symptoms are similar to those of stage I to stage II Reye's syndrome. Liver enzymes, including aspartate aminotransferase (also called SGOT), alanine aminotransferase (also called SGPT), alkaline phosphatase, and lactate dehydrogenase, may be elevated in juvenile arthritis patients with hepatic dysfunction. Liver dysfunction usually improves when salicylate therapy is discontinued. Supportive therapy should always be used in symptomatic patients. Children on long-term, high-dose salicylate therapy should be monitored closely, and baseline liver function tests should be performed. The clinical effectiveness of administering sodium bicarbonate in attempts to alkalinize urine and increase salicylate elimination is controversial. In patients with juvenile rheumatoid arthritis who develop chronic salicylism, careful analysis of the patient's medication history, laboratory values, and clinical presentation are necessary to rule out Reye's syndrome.",1
8017,3713591,Methyldopa: an often overlooked cause of fever and transient hepatocellular dysfunction,"The clinical features and laboratory findings of 78 cases of methyldopa fever are reported. This drug reaction masqueraded as a variety of acute infectious diseases including septicaemia, meningitis, hepatitis and gastroenteritis, occurred within five weeks of starting the drug and appeared to be unrelated to its dosage. Eosinophilia and skin rashes were conspicuous by their absence. In the majority of patients, symptoms were relieved within 48 hours of the withdrawal of the drug. Sixty-one per cent of patients had biochemical evidence of liver damage but jaundice was uncommon. This pattern of mild hepatotoxicity in patients with early febrile reactions to methyldopa contrasts with the later more serious viral hepatitis-like illness due to the drug.",1
8018,3715186,[Cholestatic fatty liver of probably iatrogenic origin],,1
8019,3717792,Danazol and cholestatic hepatitis,,1
8020,3717976,Methotrexate pharmacokinetics in psoriatic patients developing hepatic fibrosis,"""Methotrexate sodium is a well-established therapeutic agent for severe psoriasis, but its use may be associated with hepatic fibrosis. We studied the pharmacokinetics of oral and intramuscular methotrexate in two groups of patients--those who did and those who did not develop hepatic fibrosis while receiving methotrexate therapy. Our results showed no difference between the two groups for peak or 24-hour methotrexate concentrations; for area under the curve to 24, 144, and 24 to 144 hours; or in total-body methotrexate clearance. Measurement of methotrexate plasma levels after drug administration is therefore unlikely to help in identifying those patients at risk of developing fibrosis.""",1
8021,3722044,Safety of ticarcillin disodium/potassium clavulanate,"Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously. No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man. Safety evaluation studies carried out in the animals established as suitable for studying the toxicology of ticarcillin have shown no unexpected synergistic or antagonistic toxic effects of Timentin not predicted from the toxicological evaluation of clavulanate alone. Reproductive mutagenic, cardiovascular and general pharmacological studies have shown no significant hazard from Timentin. Clinical experience with ticarcillin has been reviewed, and impairment of platelet function, seen at supratherapeutic doses, has been shown in an animal model not to be influenced by clavulanate. The assessment of the safety of ticarcillin and clavulanate for therapeutic use in man is thus comprised of the clinical experience with ticarcillin and parenteral clavulanate in clavulanate potentiated amoxycillin, animal safety evaluation studies, and the clinical experience with Timentin reported in this symposium.",1
8022,3726630,[Effect of disulfiram on liver function],,1
8023,3729286,[The hepatotoxicity of ethionamide remains a topical subject. Apropos of a case of acute hepatitis],"The authors discuss the case of a 22 year-old patient treated for lepromatous leprosy who developed acute hepatitis 2 years after beginning polychemotherapy associating thalidomide, rifampin, ethionamide and clofazimine. Besides the ethionamide, there was no hepato-toxic factor and the hepatic anomalies quickly disappeared upon termination of treatment with this product. This again draws attention to the hepato-toxicity of ethionamide.",1
8024,3732752,[Is amodiaquine (Flavoquine) hepatotoxic?],,1
8025,3734150,Hepatic reaction to carbamazepine,,1
8026,3737441,Acute hepatotoxicity after excessively high doses of carbamazepine on two occasions,"A 2 1/2-year-old child being treated with carbamazepine (CBZ) for a seizure disorder on two separate occasions experienced elevated CBZ serum concentrations (28 and 23.2 mg/L), severe liver damage (SGOT greater than 6000 IU, SGPT greater than 5000 IU), and central nervous system manifestations (coma, lethargy, seizures). During the first episode, the time course of CBZ concentrations exhibited a nonlinear decline and was accompanied by CBZ-10,11-epoxide concentrations that were elevated 4-fold compared to normal values. Cerebrospinal fluid concentrations of CBZ and CBZ-10,11-epoxide were also elevated, although their ratios to serum concentrations did not suggest enhanced permeability of the central nervous system to these substances. The concentrations of CBZ-10,11-epoxide but not CBZ were elevated for the duration of time that the patient was comatose, suggesting that this metabolite may contribute to the neurotoxic side effects observed with CBZ therapy.",1
8027,3740585,Refractory shock secondary to copper sulfate ingestion,"Presented is the case of a 62-year-old man with refractory shock secondary to copper sulfate ingestion. The patient's history was complicated by the presence of peptic ulcer disease, myocardial disease, and a known abdominal aortic aneurysm. Despite the presence of such characteristic signs and symptoms as hemorrhagic gastroenteritis, hemolytic anemia, and refractory hypotension, the diagnosis of copper sulfate ingestion was delayed for several days after ingestion, when the family first volunteered that the patient had vomited blue-green material the day before his admission to the hospital. This delay contributed significantly to the patient's ultimate demise.",1
8028,3740693,Amodiaquine and hepatitis,,1
8029,3742311,[Hepatitis caused by fenofibrate],,1
8030,3743526,Evaluation of heparin toxicity in the isolated and perfused rat liver,"A plasma increase of liver enzymes has been recently reported in patients receiving heparin therapy. In this study we have evaluated the toxic effect of heparin infusion in the whole rat and in the isolated and perfused rat liver. No variation of plasma enzymes was observed in heparin-treated rats (10 IU per gram body weight, daily for 12 days). The heparin addition in the perfusion medium (5,000 IU in all) has shown no difference in the kinetics of hepatic enzymes release and in the other parameters of liver function. These data do not confirm a liver-toxic effect of heparin in the rat.",1
8031,3754231,[Fatal fulminant hepatitis probably due to Plethoryl],,1
8032,3755329,Acute intoxication due to ibuprofen overdose,"A male patient ingested a single overdose of ibuprofen (greater than 20 g). The serum ibuprofen levels were 185 mg/L (897 mumol/L) and 51.6 mg/L (250 mumol/L) at ten hours and 67 hours, respectively, after ingestion. There was also an accumulation of metabolites (2-carboxyibuprofen and 2-hydroxyibuprofen) in the plasma. The patient became unresponsive and developed severe metabolic acidosis, acute renal failure, acute liver-cell injury, acute cholestasis, and thrombocytopenia. Although his course was complicated by respiratory failure, hypotension, and upper gastrointestinal tract bleeding, the patient had complete resolution of multiple organ failure.",1
8033,3758905,Hepatic angiosarcoma among Egyptian farmers exposed to pesticides,"A greatly increased incidence of hepatic angiosarcoma (H.A.S.) among Egyptian farmers involved in pest-control spraying operations attracted our attention. Fourteen patients were diagnosed at Ain Shams University Hospital between the years 1980-1984 as having H.A.S. Eleven were males and 3 females with an average age of 49 years, and a male:female ratio of 3.8:1. Eleven patients reside in Lower Egypt and 3 in Upper Egypt. Ten out of the 14 patients had a definite history of a direct chronic recurrent exposure to agricultural pesticides of variable chemical nature, throughout the year. The period of exposure ranged from 11-20 years with an average of 14 years. The other 4 patients had no history of exposure to any of the known carcinogenic factors. This significant increase in angiosarcoma among farmers involved in pesticide spraying suggests that agricultural pesticides might play a role in the genesis of H.A.S. in Egypt.",1
8034,3759835,D-penicillamine induced cholestatic jaundice,,1
8035,3764142,[Cholestatic hepatitis secondary to propylthiouracil],,1
8036,3767121,Isoniazid prophylaxis in hepatitis B carriers,"Both tuberculosis and hepatitis B are endemic in southeast Asia and are common among refugees to the United States from that region. Isoniazid, used for the prophylactic treatment of tuberculosis, is a potentially hepatotoxic drug. Carriers of the hepatitis B virus are likely to have some degree of liver damage due to their chronic infection. We hypothesized that prophylactic treatment of carriers with isoniazid would cause greater liver damage, as measured by serum alanine aminotransferase (ALT) levels, than would such therapy of noncarriers. Cross-sectional and longitudinal studies of the southeast Asian refugee population in Philadelphia failed to support this hypothesis. Isoniazid did not cause greater hepatotoxicity in hepatitis B carriers than in noncarriers. Although carriers had higher ALT levels than noncarriers, both groups experienced transient ALT elevations during the first 2 months of isoniazid prophylactic therapy. Therefore, we concluded that chronic infection with hepatitis B virus is not a contraindication to the prophylactic use of isoniazid.",1
8037,3767174,Mitoxantrone and hepatic toxicity,,1
8038,3773178,The age threshold for isoniazid chemoprophylaxis. A decision analysis for low-risk tuberculin reactors,"""Isoniazid chemoprophylaxis recommendations include its use in persons who have positive tuberculin reactions, but neither recent conversion nor other activation risk factors, only if they are under age 35 years. Above this threshold, the isoniazid hepatitis risk is said to outweigh the benefit of preventing activation. Because this policy is controversial, we performed a decision analysis contrasting those who take with those who decline isoniazid therapy according to three outcome measures: life expectancy, likelihood of illness (isoniazid hepatitis and active tuberculosis), and likelihood of fatal illness. We found no threshold between ages 10 and 80 years by the measures of life expectancy and likelihood of fatal illness; isoniazid benefits outweigh risks for all, though the margin is small for the elderly. A threshold exists only in the likelihood of illness: isoniazid risks outweigh benefits for those aged 50 to 65 years. Only extreme variations of assumptions affect these findings. Chemoprophylaxis recommendations should include low-risk tuberculin reactors over age 35 years.""",1
8039,3776959,Cloxacillin-induced cholestatic jaundice,A case of cholestatic jaundice after cloxacillin treatment is presented. Hepatotoxicity due to the drug was confirmed by inadvertent rechallenge and strongly positive tests for macrophage migration inhibitory factor and mast cell degranulation. The recognition of cholestatic hepatotoxicity due to oxacillin derivatives should help to avoid unnecessary invasive procedures in the evaluation of this reversible condition.,1
8040,3776999,Phenytoin hypersensitivity: a case of severe acute rhabdomyolysis,"A 22-year-old black man was hospitalized with fever, rash, myalgias, and marked periorbital and facial edema three months after beginning phenytoin therapy. His hospital course was marked by an initial serum creatine phosphokinase level of 85,000 IU/liter, which rose to a peak value of 242,000 IU/liter on the third hospital day and a striking eosinophilia (8,400/microliter). Muscle biopsy revealed only early fiber necrosis with partial dissolution of the sarcoplasm without evidence of inflammation, vasculitis, regeneration, or parasitic infection. When therapy with phenobarbital, a structural congener of phenytoin, was begun, the patient had an exacerbation of his rash and became febrile again.",1
8041,3778077,Reye's syndrome in adults. A case report and review of the literature,Adult Reye's syndrome (ARS) is an infrequently diagnosed condition that typically affects patients younger than age 35 years. We describe a 61-year-old man with ARS occurring after influenza B-USSR infection and aspirin use. The diagnosis of ARS was confirmed by oil-red-O stain of liver biopsy tissue and subsequent electron microscopy. We review the literature on ARS and compare the clinical features and management of ARS with pediatric Rye's syndrome. This case is of interest to practitioners treating adult patients because it demonstrates that the patient population at risk for Reye's syndrome is broader than generally believed.,1
8042,3782631,Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin,"""The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.""",1
8043,3785321,Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone),"We studied the effects of the progesterone antagonist RU 486 in 100 women with early, unwanted pregnancy (within 10 days of the expected onset of the missed menstrual period). Thirty-four women received oral doses of 400 mg (in four days), 26 received 600 mg (in four days), and 40 received 800 mg (in two days). Uterine bleeding occurred in all patients within four days of the first dose and continued for 5 to 17 days. In 85 of the women, a dramatic decrease in the plasma chorionic gonadotropin level was observed on day 6, and an empty uterus was confirmed by ultrasonography on day 13. Hence, these women were considered to have had a complete abortion. Fifteen subjects had persistently elevated plasma chorionic gonadotropin levels on day 6 and were considered not to have responded to RU 486. They all had uterine evacuation, which was facilitated by a softening of the cervix. The percentage of women with complete abortion was similar in all dosage groups. Furthermore, plasma levels of immunoreactive RU 486 were similar in subjects with and without complete abortion. The only important side effect observed in the responders was prolonged uterine bleeding in 18 percent, but neither blood transfusion nor curettage was required. We conclude that RU 486 is an effective and safe method for termination of very early pregnancy but that it should be used only under close medical supervision.",1
8044,3791261,High-dose carmustine and high-dose etoposide: a treatment regimen resulting in enhanced hepatic toxicity,,1
8045,3792922,Fatal hepatitis associated with diclofenac,"Non-steroidal anti-inflammatory agents (NSAIDS) are a well recognised cause of hepatotoxicity. Diclofenac, a relatively new NSAID, was first introduced into the UK in 1979. Five cases of hepatitis have recently been reported, principally in the French literature. We report the first fulminant case of hepatitis in the English literature in a patient taking diclofenac and indomethacin.",1
8046,3794303,Chronic liver disease after low daily doses of amiodarone. Report of three cases,"A few cases of alcohol-like chronic liver disease have recently been described in patients on high daily doses of amiodarone (400-600 mg) for 5-24 months. We report here 3 cases in which similar lesions were observed after low daily doses of amiodarone. Daily dosage was 200 mg in 2 cases, 400 mg then 200 mg in the third one, and duration of therapy ranged between 36 and 60 months. Symptomatology was limited to hepatomegaly and/or mild elevation of serum aminotransferases. Liver biopsy showed alcohol-like lesions with fibrosis in 2 cases and cirrhosis in 1 case. Electron microscopy disclosed hepatic phospholipidosis. These cases indicate that chronic liver disease may be observed even when amiodarone is prescribed at low daily dosage, provided that duration of treatment is long. They also suggest that rather than the daily dosage, the cumulative dose of amiodarone is a major factor in the development of hepatic injury.",1
8047,3796103,[Ketoconazole hepatotoxicity],,1
8048,3799705,Treatment of Wilson's disease with zinc. II. Validation of oral 64copper with copper balance,"The efficacy of zinc as a therapeutic agent to control copper balance in Wilson's disease patients has been previously documented with balance studies. In an attempt to develop a simpler and faster tool for evaluating the adequacy of zinc therapy, a technique that measures the uptake into blood of a small oral dose of 64copper was studied in conjunction with copper balance. The mean peak 64copper uptake into blood of nine Wilson's disease patients on D-penicillamine, trien, or no medication was 6.04 +/- 2.74%, comparable with normal controls. Seven patients on zinc therapy had a markedly and significantly reduced mean uptake of 0.79 +/- 1.05% after treatment. The data demonstrate that the prevention of copper uptake into blood in Wilson's disease patients by zinc therapy can be evaluated by 64copper uptake and that peak uptakes of less than 1% occur in patients with neutral or negative copper balance.",1
8049,3803829,[Acute hepatitis caused by Plethoryl],,1
8050,3803831,[Amodiaquine (Flavoquine) is hepatotoxic],,1
8051,3805669,Cimetidine hepatitis,"A 62-year-old man developed asymptomatic anicteric hepatitis during cimetidine therapy for duodenal ulcer disease. Liver biopsy revealed zonal (centrolobular) necrosis, bile stasis, and mononuclear cell infiltration. Electron microscopy featured mitochondrial hyperplasia, giant mitochondria, and liver cell bile inclusions. The diagnosis of cimetidine-related hepatitis was confirmed by re-exposure to cimetidine, which prompted a rapid rise in serum transaminases while under observation in the hospital. Cimetidine hepatitis is rarely reported, and routine monitoring of the patient's liver tests during therapy does not seem cost-effective as a general practice.",1
8052,3807865,Cholestatic jaundice associated with methyldopa,,1
8053,3812421,Propylthiouracil-induced fatal hepatic necrosis,"We present a fatal case of acute submassive hepatic necrosis occurring in a 42-yr-old black woman treated for hyperthyroidism with propylthiouracil for 1 yr. Alcohol and drug abuse were ruled out and all serological tests for hepatitis A and B, cytomegalovirus, and Epstein-Barr virus infection were negative. At autopsy the liver was shrunken and presented a yellow granular appearance. Microscopy disclosed submassive necrosis with bile stasis and severe chronic inflammation, as well as mild bile duct proliferation. Although non-A, non-B hepatitis cannot be ruled out (there was no transfusion of blood or its products), this is considered to be the third fatal case and ninth instance of propylthiouracil-induced hepatic necrosis.",1
8054,3814977,"Pulmonary oedema, jaundice and renal impairment with naproxen",,1
8055,3818992,Amoxapine associated with hepatotoxicity,,1
8056,3820024,Emergency gastrotomy: treatment of choice for iron bezoar,"""The authors believe that gastrotomy and surgical removal of tablets is the treatment of choice in massive iron ingestion with development of an """"iron bezoar"""" unresponsive to gastric lavage. Prompt surgical treatment in such cases may be lifesaving.""",1
8057,3821321,[Sulindac--a review of adverse effects. Liver reactions are the most characteristics],,1
8058,3831362,Methotrexate and the liver,"The findings of liver studies in 29 patients who were treated with low dose pulse methotrexate for rheumatoid arthritis (RA) are described. The biopsy specimens of 22 patients (76%) showed liver abnormalities, but cirrhosis did not develop in any patient. There were no statistically significant differences in age, duration of treatment, or cumulative dose between patients in whom abnormal liver histology developed and those in whom it did not. Our findings showed that isolated elevations of the aminotransferase enzymes or alkaline phosphatase levels did not predict liver disease, nor did the absence of elevation of these enzymes assure the absence of liver disease. Serial elevations of the aminotransferase and/or alkaline phosphatase enzyme levels and the development of hypoalbuminemia during treatment were specific indicators of the development of liver disease. In the patients studied, significant liver disease did not develop before 2 years of therapy or with a cumulative dose of methotrexate of less than 1500 mg.",1
8059,3834715,[Peliosis hepatis with liver rupture],"The case of a 50-year-old woman with a ruptured liver caused by peliosis hepatis is presented. Death occurred three days after laparotomy for an acute abdomen with a clinical diagnosis of intra-abdominal hemorrhage. Autopsy findings including histology are presented and the possible pathogenetic mechanisms are discussed. There was neither evidence of a tumor nor of drug or toxin exposure. Known etiologic factors for this disorder are discussed on the basis of the medical literature. These include consumptive primary disorders, anabolic agents and oral contraceptives. The pathogenetic sequence involves damage to the endothelial cells of the hepatic sinuses and to the reticular fiber network. This case should make physicians aware of this infrequent iatrogenic disorder which is apparently increasing in its occurrence.",1
8060,3836862,Ticarcillin-clavulanic acid therapy in severe infections,"""Twenty patients with severe infections were treated with a fixed combination of ticarcillin + clavulanic acid. Nineteen of them had severe underlying diseases. Fifteen were bacteraemic; four of these were in shock. Eleven were infected with microorganisms resistant in vitro to ticarcillin. Eleven were clinically cured, 6 improved and 3 failed to respond, the latter being infected with ticarcillin-resistant microorganisms (2 E. coli, 1 P. mirabilis). Six patients experienced side-effects, which were usually mild and reversible, consisting mainly of moderate elevation of serum transaminases. In one patient ticarcillin-clavulanic acid was stopped due to worsening of a pre-existing drug hepatitis.""",1
8061,3852637,Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients,"""The safety and effectiveness of Timentin were evaluated in 34 adult patients with symptomatic complicated urinary tract infections, principally due to multiply-drug-resistant bacteria. Although a wide variety of organisms, particularly gram-negative bacilli, were found, Escherichia coli was the most frequent, accounting for 14 of 45 (31 percent) pathogens isolated. Ten (22 percent) isolates were Pseudomonas aeruginosa; 11 (24 percent) were Proteus or Morganella species; three (7 percent) were Citrobacter; one (2 percent) was Klebsiella pneumoniae; two (4 percent) were Staphylococcus aureus; and two (4 percent) were enterococci. Ninety-three percent of all pathogens isolated produced a beta-lactamase. Eight (24 percent) infections were polymicrobial; seven (21 percent) were associated with bacteremia. Clinical improvement occurred in 30 of 34 (86 percent) patients. All bacteremias were cured. Although bacteriologic cure occurred in only 32 percent of patients, control of sepsis and temporary eradication of bacteria (bacteriologic improvement) occurred in 96 percent. Not surprisingly, the rates of relapses and reinfections were high. It was concluded that Timentin is a useful agent in the management of complicated urinary tract infection and offers clinicians an alternative to more toxic antibiotics, such as aminoglycosides.""",1
8062,3866535,Sulindac hepatotoxicity: effects of acute and chronic exposure,"Sulindac (Clinoril), an anti-inflammatory drug increasingly used in Australia for the treatment of rheumatological conditions, is unpredictably associated with a cholestatic hepatitis. We present three cases of sulindac hepatitis. The first case exemplifies acute sulindac hepatitis, the second, continuously exposed to sulindac for 18 months, had chronic sulindac hepatotoxicity, and in the third case, the long-term histological outcome after cessation of sulindac is described. The clinical, biochemical, and histopathological characteristics are those of a cholestatic hepatitis which resolves on withdrawal of the drug. We report marked anisonucleosis with cytoplasmic invaginations into the nucleus and binuclearity of hepatocytes as additional histological features of sulindac hepatitis. There is no evidence that sulindac hepatitis progresses to irreversible structural liver damage, although nuclear changes may persist for up to two months after cessation of the drug. The clinical and biochemical features of all reported cases of sulindac hepatitis are summarised.",1
8063,3871563,Increased hepatic density and phospholipidosis due to amiodarone,"Amiodarone is an amphiphilic iodinated compound that is used as a treatment for refractory ventricular arrhythmias. During evaluation for possible pulmonary toxicity, a patient receiving amiodarone was noted to have an increase in the density of his liver as seen on computed tomographic (CT) scanning of the abdomen. Six additional patients who were receiving amiodarone were subsequently evaluated to ascertain the frequency of this finding. The CT density of the liver was increased in all patients. Values obtained varied from 95 to 145 H, with a mean of 117 +/- 8.9 (normal, 30-70). The alkaline phosphatase was elevated in four patients, but only one had an elevation of either the alanine or aspartate aminotransferase. Two patients underwent liver biopsies, and both revealed membranous lamellar phospholipid-containing structures within hepatocytes. Animal studies done to recreate these findings revealed that amiodarone accumulated in the liver at concentrations 175-500 times greater than those found in serum. Quantitative measurements of iodine in samples from the same liver showed that the iodine levels were correspondingly elevated. In the treated animals, there was a small but statistically significant increase in the CT density of the liver, whereas the values for untreated animals were unchanged. Treatment with amiodarone leads to an accumulation in the liver of this iodinated compound and hence an increase in the CT density of the liver. This accumulation of the drug in hepatic lysosomes apparently causes a secondary phospholipidosis.",1
8064,3875307,[A new case of lupus induced by acebutolol],"Few such observations of beta-blocker-induced lupus have been published in the medical literature. In the index case, the usual criteria were present. Acebutolol withdrawal resulted in rapid clinical improvement. Antinuclear antibodies are still present after nine months follow up. Pathogenic hypotheses are discussed.",1
8065,3877284,A review of the safety and tolerance of propofol ('Diprivan'),,1
8066,3881069,Captopril-associated cholestatic jaundice,"""Captopril, the competitive inhibitor of angiotensin-converting enzyme, is of considerable benefit in difficult-to-manage forms of hypertension. Its use has been associated with various untoward effects, but hepatic injury has not been widely reported. We treated a patient with captopril-associated cholestatic jaundice; a review of cases reported to the drug manufacturer and a review of the literature showed 13 additional cases of hepatic injury associated with captopril. In 9 of these the jaundice was categorized as cholestatic, and in 4 of the remaining 5 as mixed cholestatic-hepatocellular. These findings show that jaundice may be an idiosyncratic side effect of captopril, and that captopril-associated jaundice characteristically has strongly cholestatic features.""",1
8067,3883172,Efficacy of low-dose methotrexate in rheumatoid arthritis,"""Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.""",1
8068,3883500,Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments,"The pharmacokinetics of heparin differ markedly from those of its fractions both in man and in experimental animal models. The route of administration determines the relative availability of different molecular species that exert the anti-Xa, anti-IIa, fibrinopeptide A generation inhibiting actions and the release of tissue plasminogen activator-like activity from the endothelial cell lining. The bioavailability of heparin fractions has proved to be much greater than heparin after subcutaneous or intraperitoneal administration. Most of the low molecular weight heparin fractions exhibit sustained antiprotease and antithrombotic actions. The pharmacokinetics of the specific anti-IIa and anti-Xa actions of heparin and its fractions is dependent on the molecular composition of these agents. Even if the fractions are standardized for identical potencies by the in vitro assays, the elimination rate of anti-Xa and anti-IIa actions are significantly different for each fraction. The antithrombotic actions of heparin and its fractions also vary widely in the rabbit stasis thrombosis model. Different fractions show variable antithrombotic actions against defined thrombogenic challenges. Moreover, selection and potency of a thrombogenic agent is of crucial importance in these studies. The primate (Macaca mulatta) model offers a useful preclinical model for the pharmacologic evaluation of the low molecular heparin fractions. Since the coagulation system and heparinizability index of this model approximate a human response, the data may be used to reflect therapeutic and prophylactic responses, as well as to assess toxic effects, such as bleeding.",1
8069,3888101,Clinical trial of the efficacy and safety of ticarcillin and clavulanic acid,"""Forty-three hospitalized patients were treated with a new antibiotic combination containing ticarcillin plus the beta-lactamase inhibitor, clavulanic acid, in a fixed combination for intravenous use. A variety of infections were treated, including pneumonia, bacteremia, urinary tract infection, and osteomyelitis. Of 50 episodes of infection in 43 patients, 44 clinical cures were obtained, with 5 patients improving and 1 patient failing to respond to treatment. In vitro susceptibility testing of 101 clinical isolates was notable for the rarity of resistance to the combination antibiotic. Of specific interest, all 14 isolates of Staphylococcus aureus were susceptible to ticarcillin plus clavulanic acid, whereas only 2 of the 14 isolates were susceptible to ticarcillin alone. Adverse reactions to the study drug were minimal; eosinophilia, unaccompanied by other allergic phenomena, and oral candidiasis were most frequent. Overall, the combination of ticarcillin with the beta-lactamase inhibitor, clavulanic acid, appears to be a safe and effective drug for the treatment of infections caused by susceptible organisms.""",1
8070,3890924,A comparative double blind study of ketoconazole and griseofulvin in dermatophytosis,"The merits of oral ketoconazole and griseofulvin in dermatophytosis have been compared in a double blind study on 74 patients with 152 infected sites. The initial daily doses were 200 mg and 500 mg respectively, but these were doubled after 3 months if there was an inadequate clinical response. Treatment was continued either until clinical and mycological remission was achieved or a year of therapy had been given. Seventy-five per cent (total 80) and 74% (total 72) of all infected sites treated with ketoconazole and griseofulvin respectively were cleared of infection. However, in toe nail infections the respective cure rates were only 21% and 17%. Ketoconazole appeared to act more rapidly in curing tinea corporis or tinea cruris due to Trichophyton rubrum, whereas griseofulvin was superior in T. interdigitale infections. No serious side-effects were encountered in either treatment group. In view of the slight risk of drug-induced hepatitis, ketoconazole is best reserved as a second-line drug for toe nail infections unless there are specific indications, such as griseofulvin intolerance. In these cases liver function tests should be monitored regularly throughout therapy.",1
8071,3893441,Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial,"One hundred eighty-nine patients with rheumatoid arthritis were entered into a prospective, controlled, double-blind multicenter trial comparing placebo and methotrexate (MTX). One hundred ten patients completed 18 weeks of therapy. No remissions were seen, but patients able to tolerate low-dose pulse MTX therapy were significantly improved, compared with patients receiving placebo therapy, for all clinical variables measured, including joint pain/tenderness and swelling counts, rheumatoid nodules, and patient and physician assessment of disease activity. MTX treatment demonstrated statistically significant improvement over placebo in patients with anemia, elevated erythrocyte sedimentation rate, and rheumatoid factor. However, nearly one-third of the patients receiving MTX were withdrawn for adverse drug reactions, of which elevated levels of liver enzymes was the most common. Pancytopenia occurred in 2 patients taking MTX. All adverse drug effects resolved without sequelae. MTX appears to be effective in the treatment of active rheumatoid arthritis but requires close monitoring for toxicity.",1
8072,3895175,Prospective comparative trial of ceftriaxone vs. conventional therapy for treatment of bacterial meningitis in children,"""Fifty children with bacterial meningitis were prospectively evaluated in a randomized comparative trial of twice daily ceftriaxone with conventional ampicillin and chloramphenicol therapy. The groups were comparable in age, sex, days of illness before admission, severity of illness at admission, etiology and admission cerebrospinal fluid (CSF) parameters and bacterial colony counts. The pathogens were Haemophilus influenzae type b (34 beta-lactamase-negative, 8 beta-lactamase-positive); Streptococcus pneumoniae (4); Neisseria meningitidis (3); and Streptococcus agalactiae (1). Initial CSF colony counts ranged from 2.5 X 10(2) to 1 X 10(10) colony-forming units/ml. In 44 children a lumbar puncture was repeated 10.5 to 18 hours after starting treatment; 16 of 24 (67%) ceftriaxone patients and 12 of 20 (60%) conventional therapy patients had sterile cultures. The reduction in the CSF bacterial colony counts (6.3 log10 colony-forming units/ml) was similar in both groups. Ceftriaxone CSF levels ranged from 1.0 to 8.0 micrograms/ml, representing a mean CSF penetration of 11.3% (range, 3.0 to 24.5%) of the simultaneous serum concentration. The median ceftriaxone bactericidal titer in CSF was 1:1024 compared with 1:4 achieved with conventional therapy. There were no significant differences in clinical responses or in frequency of complications, except for diarrhea which occurred in 59% of the ceftriaxone group and in 22% of the other (P less than 0.01). Despite one H. influenzae type b relapse occurring in the ceftriaxone group, ceftriaxone appears to be safe and as effective as conventional therapy for bacterial meningitis in children older than 2 months of age.""",1
8073,3895557,[Toxic hepatitis caused by captopril],,1
8074,3899005,Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia,"""A prospective, randomized study was undertaken to compare the efficacy and safety of ceftazidime with those of a combination of ticarcillin and tobramycin in the treatment of 40 nonneutropenic patients with pneumonia or bacteremia. Altogether, 93% of the patients receiving ceftazidime for pneumonia were cured, and 87% of those with bacteremia responded favorably. Of the subjects who were treated with ticarcillin and tobramycin ceftazidime developed significant superinfection, and one individual treated with the aminoglycoside and carboxypenicillin developed reversible azotemia. Ceftazidime appears to be as efficacious as the ticarcillin-tobramycin combination and is probably safer with regard to oto-and nephrotoxicity; however, superinfections did occur more frequently in the group treated with ceftazidime.""",1
8075,3901212,Imipenem/cilastatin in the treatment of serious bacterial infections,"""Imipenem (N-formimidoyl thienamycin) is a new carbapenem beta-lactam antibiotic with a broad antibacterial spectrum. Forty-five patients were treated with either 500 or 1,000 mg of imipenem/cilastatin four times daily, the duration varying according to clinical response. The diagnoses were urinary tract infection, 10 patients; septicemia, six; intraabdominal sepsis, six; pneumonia, six (two cases of Legionnaires' disease); skin and soft tissue infection, four; and other diagnoses, 13. Of the 32 clinically assessable patients, 17 were cured, nine improved, three died, and three were withdrawn from the trial. Of 21 patients who were microbiologically assessable, 13 were cured. In six cases of complicated urinary tract infection, the organism--which had been eradicated from the urine during treatment--reappeared after completion of antibiotic therapy. Two patients developed adverse clinical reactions that were thought to be drug-related (drug-induced fever and nausea plus vomiting, respectively). Both patients had mildly abnormal results in liver function tests, and one developed a positive direct Coombs' test. Fifty-seven percent of the patients developed some degree of phlebitis, which was moderate to severe in 19%. In this study imipenem/cilastatin proved to be a highly effective agent for the treatment of a variety of serious bacterial infections.""",1
8076,3903180,Sulindac hepatotoxicity: a case report and review,"A 44 year old female, previously on propranolol, phenytoin and phenobarbital, developed hepatotoxicity while on sulindac and acetaminophen containing analgesic. A limited review of hepatotoxicity and drug interactions of sulindac is presented. The possible mechanism of hepatotoxicity and its treatment is suggested.",1
8077,3905530,Antibody mediated hepatocyte injury in methyl dopa induced hepatotoxicity,"To investigate the mechanisms underlying the hepatotoxicity induced by methyl dopa, we have examined sera from nine patients with liver damage following the use of the drug for evidence of sensitisation to drug altered liver cell membrane antigens using both immunofluorescence and antibody dependent cell mediated cytotoxicity. Five sera induced significant cytotoxicity to hepatocytes isolated from rabbits pretreated with methyl dopa after exposure to the mixed function oxidase inducer, Arachlor 1254. Sera from 10 patients on methyl dopa but with normal liver function and 32 patients with other drug and viral induced liver damage, gave normal cytotoxicity values. Two of the antibody positive sera gave a specific immunofluorescence pattern at the periphery of human hepatocytes when tested on liver biopsy specimens taken from patients taking methyl dopa. These findings are consistent with the view that immune mechanisms directed against drug associated antigens are involved in severe liver damage from methyl dopa administration and that metabolic activation of the drug is implicated in the generation of drug associated antigen. The need for a combination of immune and metabolic factors may explain the rarity of this condition.",1
8078,3906673,Baclofen versus diazepam for the treatment of spasticity and long-term follow-up of baclofen therapy,"Baclofen (25 to 60 mg per day) and diazepam (10 to 40 mg per day) were evaluated for spasticity reduction in a double-blind, crossover study in 13 patients over a period of 19 weeks. Both drugs produced overall improvement and there was no significant difference in preference for one or other treatment. Side-effects, especially excessive daytime sedation, were more common in the diazepam group. In a companion baclofen long-term study, 18 spastic patients were treated with baclofen for an average of 4 years. Baclofen discontinuation in this group resulted in a worsening of spastic signs and symptoms in 16 patients, with no evidence of drug tolerance even after many years of baclofen therapy.",1
8079,3909341,Clinical studies of aztreonam in Japan,"""Clinical studies of aztreonam were undertaken by 220 investigators in 86 university and general hospitals in Japan. A total of 1,447 patients were treated by investigators in various fields. Satisfactory clinical responses were achieved in 67% of all patients. Efficacy rates by field of specialty were: internal medicine, 67%; urology, 61%; general surgery, 73%; and surgical patients in other fields (obstetrics-gynecology, otorhinolaryngology, and ophthalmology), 78%. Among 364 patients with complicated urinary tract infections, the efficacy rate was 60%. Seventy-four percent of 1,122 gram-negative aerobic organisms were eradicated after treatment with aztreonam. Adverse reactions occurred in 2.1% of patients; none were serious. Mild elevations of serum aminotransferases were observed in approximately 4% of patients for whom test results were reported. In conclusion, aztreonam demonstrated remarkable effectiveness in the treatment of gram-negative infections in hospitalized patients.""",1
8080,3912190,Baclofen in the elderly stroke patient its side-effects and pharmacokinetics,"""A double blind crossover trial of baclofen against placebo in elderly stroke patients was discontinued because the drug produced an unacceptably high level of drowsiness. In a subsequent study baclofen 10 mg was given orally to 12 elderly stroke patients, and drug concentrations measured from a series of plasma samples. A group of healthy subjects given the same dose in a previous study were used as controls. Elderly patients took longer to achieve peak plasma baclofen concentrations, but healthy controls had higher peak values and eliminated the drug more rapidly; areas under the curve were similar in the two groups. Simulations based on mean data suggest that increased drowsiness in the elderly was probably not due to changes in the drug's pharmacokinetic behaviour.""",1
8081,3913457,Ultrasound as a screening procedure for methotrexate-induced hepatic damage in severe psoriasis,"Methotrexate has been of proven value in the management of patients with severe psoriasis. Its long-term use, however, can be complicated by progressive hepatic damage which has necessitated regular liver biopsies. We have looked into the efficacy of liver ultrasonography as a non-invasive screening procedure to select those patients who may be developing liver changes. Eighty-seven investigations on 82 patients were performed, comparing liver ultrasound results with liver biopsy. Eight of these showed a degree of hepatic damage which was sufficient to indicate cessation of methotrexate, and all of these were detected by ultrasonography. Our results indicate that patients whose last liver biopsy was normal could be allowed an extended interval between biopsies provided their intervening ultrasound scans remained normal.",1
8082,3918052,When to leave well enough alone--two cases,,1
8083,3923075,Fatal anaphylactic reaction to oral penicillin: report of case,A report of a fatal anaphylactic reaction to oral penicillin is presented and the unusual set of circumstances leading to its fatal outcome is reviewed. The initial signs and symptoms are analyzed and the use of the proper and immediate treatment is advised.,1
8084,3925290,Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin,"""To minimize the cutaneous flushing symptoms associated with niacin use, a time-release capsule form of niacin has been formulated. Thus study compares the effects of time-release niacin with those of unmodified niacin on lipoprotein lipids, including HDL2 and HDL3, apoproteins A-I and A-II, clinical chemistries, symptomatic side effects, and adherence to the medication regimen. Seventy-one primarily hypercholesterolemic subjects were randomized to either unmodified niacin or time-release niacin ad took medication for a six-month period. The two groups were closely matched on anthropomorphic and lipid variables. Adherence to the therapeutic regimen at a dose of 1.5 g/d in the first month of treatment was similar in the two groups. Thereafter, at a dose of 3.0 g/d, adherence was in excess of 90% among subjects taking unmodified niacin but only 64% among those taking time-release niacin, chiefly because of aggravated gastrointestinal symptoms; cutaneous flushing side effects, however, were slightly less common with time-release niacin. At these levels of adherence, LDL cholesterol (C) was reduced 21% by unmodified niacin and 13% by the time release form. Plasma total triglyceride was reduced more with unmodified niacin (27%) than with time-release niacin (8% maximum), and HDL-C and HDL2-C were increased significantly with unmodified niacin (26% and 36%) and were not significantly changed by time-release niacin. Increased to a similar degree on both regimens were HDL3-C (approximately 35%) and apoA-I (approximately 12%). ApoA-II was not affected by either drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
8085,3932253,Gold-induced granulomatous hepatitis,,1
8086,3934499,Homocystinuria due to cystathionine beta-synthase deficiency--the effects of betaine treatment in pyridoxine-responsive patients,"""Homocystinuria due to cystathionine beta-synthase deficiency may be responsive to pyridoxine, a precursor of the cofactor pyridoxal phosphate, and the amount of residual enzyme activity present is the probable determinant of this. In six treated pyridoxine-responsive patients whose biochemical control of fasting plasma amino acid levels appeared optimal, we assessed the effects on plasma amino acids of standard oral methionine loads (4g/m2 of body area) before and after adding betaine (trimethylglycine) 6 g/d, to the treatment regimen of pyridoxine and folic acid. Our aim was to define the capacity of these patients to metabolize methionine and to determine whether betaine would effect a reduction in postload homocysteine levels. During the 24 hours after the methionine challenge all patients had higher plasma methionine and homocysteine and lower cysteine than did 17 normal subjects. After betaine these homocysteine responses were reduced to near normal, and there was a trend toward increased methionine. There was a direct correlation between premethionine fasting homocysteine and mean homocysteine responses during the 24 hours following the methionine load, both before (r = 0.79) and after betaine (r = 0.71). Betaine also increased plasma cysteine levels in patients with the more severe biochemical abnormalities. After betaine there were modest increases in plasma serine (mean increase 25%; P less than 0.025). Since the vascular complications of homocystinuria are related to increased plasma homocysteine, betaine therapy may reduce this risk in patients receiving a standard pyridoxine and folic acid regimen in whom there are abnormal homocysteine responses after a standard methionine load.""",1
8087,3939748,Valproate hepatotoxicity,,1
8088,3940466,Is enflurane hepatotoxic?,"""We evaluated 88 cases of hepatic injury that followed, and were attributed to, enflurane anesthesia. In 30 of the cases, data were insufficient to assess the role of enflurane vs other variables as causal factors. In 43 (""""unlikely"""") patients, factors known to produce hepatic injury were clearly present; in the remaining 15 (""""possible""""), such factors were not evident. No consistent pathologic change was found in liver specimens from either the unlikely or the possible group of cases. A syndrome suggested to be associated with enflurane-induced hepatic injury was present in both groups and did not differ between groups. We conclude that the data do not demonstrate a causal relationship between enflurane anesthesia and subsequent liver injury and that if severe injury is caused by enflurane anesthesia, it is an extremely rare event.""",1
8089,3940497,A non-C17-alkylated steroid and long-term cholestasis,,1
8090,3941781,Azathioprine toxicity in neuromuscular disease,"""Azathioprine toxicity was examined in 64 consecutively treated patients with various neuromuscular diseases. Reversible leukopenia was seen in 14 patients (22%). Hepatotoxicity developed in six patients (9%), and a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurred in eight patients (12%). Toxic effects limited the dose of azathioprine in 27 patients (42%) and led to discontinuation of therapy in 13 (20%). Macrocytosis developed in 20% of patients, but did not require an adjustment in the dose. Two patients received allopurinol and azathioprine; both developed reversible leukopenia and macrocytosis. Patients with hematologic and hepatic toxicity, but not those with systemic toxicity, successfully tolerated retreatment with azathioprine. Toxicity was delayed as long as 56 weeks after starting azathioprine in some patients.""",1
8091,3943237,Erythromycin hepatotoxicity. A rare cause of a false-positive technetium-99m DISIDA study,"An unusual cause of a cholescintigraphic, false-positive, erythromycin-induced hepatotoxicity is presented. This occurred in the presence of preservation of hepatic uptake and the normal appearance of gut activity. Serial scintigraphy and serum chemistries documented underlying gallbladder normalcy.",1
8092,3944744,Hepatomegaly following short-term high-dose steroid therapy,"Children treated with large doses of corticosteroids were found to develop hepatomegaly within a few days. No relationship could be established between the condition for which steroids were given and the liver enlargement. Liver biopsy was thought to be indicated, and thus was performed in three children because of diagnostic uncertainty. The light and electron microscopic examinations revealed normal liver architecture, without edema, sinusoid engorgement, or inflammatory changes. The hepatocytes were distended by increased amounts of glycogen. In a pattern reminiscent of some glycogen storage diseases, mitochondria and other cytosol components were displaced toward the cell membrane or around the nucleus, which occasionally contained glycogen. Moderate sinusoidal compression, interhepatocytic free glycogen particles, and mild increase in lipid droplets were also found. It is concluded that the hepatomegaly noted in patients given short-term, high-dosage steroid therapy is due to excessive glycogen accumulation within parenchymal cells. This finding is in accordance with observations in animals, as well as with biochemical studies demonstrating hepatocytic glycogen deposition after steroid therapy. Being benign and reversible, early hepatomegaly following administration of high-dose corticosteroids should not influence the initial therapeutic plan required by the basic disease.",1
8093,3947418,The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality,"""Patients receiving allopurinol are at risk of developing the allopurinol hypersensitivity syndrome, an immunologic reaction to the drug, characterized by multiple abnormalities such as fever, rash, decreased renal function, hepatocellular injury, leukocytosis, and eosinophilia. The records of 8 patients with the allopurinol hypersensitivity syndrome evaluated at the Downstate Medical Center hospitals and an additional 72 patients described in the literature were reviewed. All were seriously ill. Three of the 8 patients at the Downstate Medical Center hospitals died as a result of allopurinol hypersensitivity; 19 of the 72 previously described patients also died from consequences of taking the drug. Only 1 of our 8 patients with allopurinol hypersensitivity was given allopurinol for an appropriate reason. Eight of the 59 previously described patients on whom there was adequate information had legitimate indications for allopurinol therapy. Severe, often fatal iatrogenic disease occurred unnecessarily in the others.""",1
8094,3949113,Risk of hepatic vein thrombosis in relation to recent use of oral contraceptives. A case-control study,"In a case-control study, we evaluated the relative risk of hepatic vein thrombosis among recent oral contraceptive users as compared with nonusers. Thirty-three cases of hepatic vein thrombosis affecting women aged 15-45 yr were collected between 1970 and 1983, and individually matched to 3 or 4 controls interviewed in 1982-1984. There were 18 recent oral contraceptive users among the 33 cases, and 44 recent oral contraceptive users among the 128 case-matched controls. The relative risk of hepatic vein thrombosis was 2.37 (95% confidence interval: 1.05-5.34, p less than 0.02). The relative risk of hepatic vein thrombosis is close to that of stroke, myocardial infarction, and venous thromboembolism among oral contraceptive users as compared with nonusers.",1
8095,3950462,[Hepatic injury caused by methyldopa in a pre-eclamptic patient],,1
8096,3953883,The side effects of carbamazepine,,1
8097,3957235,Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype,"""Of 143 patients with pulmonary tuberculosis receiving isoniazid therapy, 52 (36%) had a transient elevation in serum aminotransferases. Among 74 patients taking isoniazid, rifampicin and streptomycin, 35 (47%) had such an increase, while of 69 patients taking isoniazid, amino-salicylic acid and streptomycin, 17 (24%) did; this difference was significant. Isoniazid therapy could be continued in all patients with the abnormal test results. In 36 of the patients receiving isoniazid, rifampicin and streptomycin, isoniazid and its metabolites were studied in the serum and urine using high-performance liquid chromatography after the oral administration of 10 mg per kg of isoniazid. We had chosen for this test 18 patients with normal aminotransferase levels and 18 with abnormal levels. There were 14 rapid acetylators in the patients with abnormal aminotransferase levels and 7 rapid acetylators in the patients with normal levels; this difference was significant. These results indicate that liver dysfunction is more often caused by an isoniazid/rifampicin regimen, and patients who are rapid acetylators are more susceptible.""",1
8098,3962737,Hepatotoxicity of amiodarone,"Amiodarone has proved very effective in the treatment of otherwise resistant cardiac tachyarrhythmias. The use of amiodarone has, however, been limited due to its serious side-effects. A patient with cholestatic hepatitis due to amiodarone treatment is presented below and a review of the hepatotoxicity of amiodarone is given. It is concluded that solid evidence exists of hepatic injury due to amiodarone treatment, including steatosis, alterations resembling alcoholic hepatitis, cholestatic hepatitis and micronodular cirrhosis of the liver. Patients receiving amiodarone should be regularly screened with respect to hepatic enzyme levels. Therapy should be discontinued on the suspicion of cholestatic injury or hepatomegaly.",1
8099,3963977,Liver involvement in the sulfone syndrome,"""A patient being treated with dapsone developed a hypersensitivity reaction with typical features of the """"sulfone syndrome,"""" including fever, malalse, and hepatitis. All abnormalities rapidly reversed with discontinuance of the dapsone regimen and institution of prednisone therapy. Hepatic involvement may be a prominent feature of the sulfone syndrome and may be of the hepatocellular or cholestatic type. Based on our review of the Food and Drug Administration reports, this syndrome appears to be relatively uncommon, but physicians need to recognize that expression of this syndrome may be incomplete. More clinical data are necessary to better define the incidence and pathogenesis of sulfone-induced liver disease.""",1
8100,3965874,Hepatic reactions to nifedipine,"Two cases in which abnormal liver function tests were associated with the use of nifedipine are reported. In both cases, liver function returned to normal after withdrawal of the drug. Evidence suggests that the toxic effect of nifedipine on the liver is due to hypersensitivity.",1
8101,3967557,"Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis. An acceptable risk/benefit ratio","Thirty patients with psoriasis or other nonmalignant diseases had liver biopsies done before treatment with low-dose methotrexate, 15 mg/week, and then at one- to two-year intervals as long as they continued the methotrexate. All patients were symptomatically improved on this regimen. The 15 patients who had normal liver biopsies at the start of the study had normal biopsies after methotrexate. Fifteen others had minor hepatic histologic abnormalities before treatment. Eleven patients had fatty infiltration. Ten showed no significant change after treatment while one had increased fat and portal fibrosis on a fourth liver biopsy done seven years after MTX was begun. This last patient, a former alcohol abuser, continued methotrexate and showed no further worsening at 8 years. The remaining four had portal fibrosis before treatment. One patient had less fibrosis after methotrexate, two patients slightly more fibrosis, and one a marked increase in portal fibrosis. No patient developed cirrhosis or clinical liver disease. Our results suggest that in the absence of alcohol consumption, low-dose weekly methotrexate treatment rarely causes clinically significant liver damage.",1
8102,3970484,Amiodarone and the liver,,1
8103,3971296,Experience with continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. A prospective randomized study,"Sixty-five patients with hepatic metastases from colorectal primaries were studied in a prospective randomized fashion. The five patients with solitary metastases all had resection of metastases and 50% were randomized to pump therapy. Of the 16 patients with multiple resectable metastases, 7 had pump only and 9 had resection plus pump. Although the difference was not significant, there was a trend of improved survival for the patients with resection plus pump. For the patients with unresectable disease, those patients with positive portal nodes had poor survival matching those patients with extra hepatic metastases. Patients with unresectable disease treated with pump had a 73% therapeutic response rate and a median survival of 22 months. Significant complications included chemical hepatitis and biliary stenosis. The long-term efficacy of continuous hepatic artery infusion versus the hazards of treatment and the financial cost will need further investigation.",1
8104,3972228,Clinical and morphologic effects of amiodarone on the liver,,1
8105,3975725,Cyclophosphamide-associated hepatotoxicity,"Cyclophosphamide, a potent alkylating agent, is effective therapy for some rheumatic diseases. Despite primary hepatic activation of the drug, hepatic toxicity has been reported only in one case. We have reported two episodes of hepatic dysfunction associated with oral cyclophosphamide administration in patients with systemic rheumatic diseases.",1
8106,3979751,Diltiazem and granulomatous hepatitis,"A case of granulomatous hepatitis proven by biopsy and related to diltiazem use is described. Clinicians should be alert to the possible presence of this complication in patients who develop fever, laboratory abnormalities, or clinical evidence of hepatic injury while taking diltiazem.",1
8107,3981309,"Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection","Seven children with juvenile rheumatoid arthritis had a syndrome characterized by hemorrhage and neurologic, hepatic, hematologic, and metabolic manifestations. The disease did not seem to conform clearly to the characteristics of Reye syndrome or any other well-known entity. This severe complication may be induced by macrophage activation secondary to a drug or intercurrent infection. Our data suggest that a sudden fall in erythrocyte sedimentation rate or in platelet and fibrinogen levels may mark the start of this complication and may be an indication for rapid steroid therapy.",1
8108,3984967,Salicylate-induced hepatitis in rheumatic fever,"In a 4 1/2-year retrospective study of hospitalized patients with rheumatic fever treated with salicylates, we determined that five of 34 children manifested salicylate-induced hepatitis. The average serum salicylate level in those patients with hepatotoxicity was 30.9 mg/dL, while the average serum salicylate level in the rest of the patients was 19.7 mg/dL. An awareness of this potential complication is important when treating children with salicylates at doses previously considered to be nontoxic. Serum salicylate levels should be maintained at approximately 15 to 25 mg/dL during such therapy.",1
8109,3990620,Tinidazole and hepatitis,,1
8110,3992352,Three dimensional analysis of right thoracic idiopathic scoliosis,,1
8111,3994088,Multiple organ failure resulting from intravenous abuse of methylphenidate hydrochloride,"A 32-year-old woman who abused methylphenidate hydrochloride developed complications including hepatic, renal, pancreatic, pulmonary, and CNS toxicities. These were manifested by abnormal liver function enzymes, poor urine output, hypotension, tachypnea, tachycardia, abnormal blood gases, rising serum BUN and creatinine, and hyperactive deep-tendon reflexes. All were reversible with medication withdrawal and supportive therapy. Toxicities of this medication and their implications are discussed.",1
8112,3997313,A case of cholestatic hepatitis associated with D-penicillamine therapy for rheumatoid arthritis,"A male aged 72 years suffering from erosive seropositive rheumatoid arthritis developed jaundice after one month on D-penicillamine after a cumulative dose of 5.625 g. The biological abnormalities were characteristic of cholestasis. There were no gall-stones. The liver biopsy showed severe intrahepatocellular cholestasis with a slight degree of cellular cholangitis and with eosinophils in the portal tracts. There was no sign of cellular necrosis. After cessation of D-penicillamine, the jaundice cleared within three weeks and the enzymes were normalized within two months. The aetiology is discussed and the cases of the literature are reviewed. This case represents a further instance of D-penicillamine-induced cholestatic hepatitis.",1
8113,4000989,Hepatotoxic reactions in children with severe tuberculosis treated with isoniazid-rifampin,"The incidence and degree of liver injury was prospectively evaluated in 44 children, ages between 4 months and 14 years (mean age, 4.5 years) treated for tuberculosis with 15 to 20 mg isoniazid/kg/day and 15 mg rifampin/kg/day (INH-RIF). None of the patients had hepatic dysfunction before initiation of treatment. Elevation of the serum alanine aminotransferase (ALT) concentration (greater than 100 units) occurred in 36 patients (82%). One patient with an increase in the ALT value had coincidental infection with hepatitis B. The incidence of hepatotoxicity did not correlate with the patients' age or sex. Fifteen of the 36 patients developed clinical hepatitis with jaundice. In 7 patients liver enlargement and prolongation of the prothrombin time were also observed. In all but one patient liver dysfunction was recognized 6 to 30 days (mean, 14 days) after start of treatment. Biochemical signs of hepatic injury in the 35 surviving patients regressed completely without alteration of the INH-RIF regimen in 22 patients. These facts suggest the possibility that hepatocellular damage may be due to the effect of tubercle bacilli products liberated in the liver after their destruction by antituberculous drugs. However, the high rate of hepatotoxic reactions warns that the dose of 10 mg INH/kg/day should not be exceeded when that drug is combined with RIF.",1
8114,4005158,Chronic active hepatitis associated with etretinate therapy,"Acute hepatitis developed in a patient taking etretinate for severe psoriasis. Discontinuation of therapy was followed by progression of the histological changes to chronic active hepatitis, despite improvement of his clinical and laboratory status. This is the third reported case of chronic active hepatitis associated with etretinate therapy, and the second patient in our group of twenty-two etretinate-treated patients with severe psoriasis to develop clinically significant hepatic disease. Immunological evaluation revealed a marked increase in the patient's OKMI-staining population of peripheral mononuclear cells and augmentation of Con A-induced lymphocyte blastogenesis in the presence of etretinate.",1
8115,4006738,Hepatitis associated with allopurinol,"When adverse reactions occur, it is important to identify the etiologic drug. We describe a case of hepatitis associated with allopurinol. A 66-year-old female was admitted for rehabilitation of a cerebral hemorrhage on September 11, 1981. Allopurinol, clofibrate, and baclofen were administered. Severe hepatitis developed on November 13. The clinical laboratory data returned to normal on November 30. Challenge tests were conducted on clofibrate, allopurinol, and baclofen. The challenge test was positive after the administration of allopurinol. Allopurinol hepatitis is most likely a hypersensitivity reaction, as is suggested by the symptoms of eosinophilia and rash. Renal dysfunction may predispose one to develop hepatitis associated with allopurinol.",1
8116,4007605,Ketoconazole-induced fulminant hepatitis,"We report the cases of two adult patients in whom fulminant hepatitis developed after 17 and 103 days of ketoconazole administration. Histologic administration showed massive, predominantly centrilobular necrosis. Clinical manifestations of hypersensitivity and eosinophilia were absent in both patients, which suggests that ketoconazole hepatotoxicity is not mediated through an immunoallergic mechanism.",1
8117,4008991,Potential toxicity of ketoconazole,,1
8118,4022509,Maternal liver impairment associated with prolonged high-dose administration of terbutaline for premature labor,"Widespread use of beta 2-sympathomimetic therapy for premature labor has resulted in a diverse number of serious maternal complications, ie, pulmonary edema, myocardial ischemia, etc. However, to the authors' knowledge, there has been only one previous report of mild maternal liver impairment associated with this therapy. Recently, a patient developed marked elevation of liver enzymes (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase) during therapy with terbutaline sulfate for premature labor.",1
8119,4022885,Ergotamine abuse and extra-hepatic portal hypertension,"Arterial complications following ergotamine therapy have been well recognized since the beginning of this century. Venous complications, however, have only rarely been reported. A 48 year old Nigerian woman developed extra-hepatic portal hypertension coincident with a chronic overdosage of ergotamine. The literature elucidating the possible mechanisms involved is reviewed.",1
8120,4024960,Changes in liver histology during methotrexate therapy of psoriasis correlated to the concentration of methotrexate and folate in erythrocytes,"To investigate, whether an assessment of the folate and methotrexate concentrations in erythrocytes could be used to indicate incipient histological liver changes, these 2 parameters were related to liver histology in series of liver biopsies (means 4.3 biopsies) from 31 long-term methotrexate-treated psoriasis patients. Logistic regression analysis showed that the probability of changes in liver histology during methotrexate therapy increased significantly with increasing erythrocyte methotrexate concentrations and with decreasing erythrocyte folate concentration. The application of these variables as a decisive criterion when to institute liver biopsy surveillance needs further studies, but can probably help reduce the number of liver biopsies to be taken during long-term methotrexate therapy considerably.",1
8121,4025314,Complications of heparin administration in normal individuals,"The incidence, severity, and pathogenic mechanism of heparin-associated thrombocytopenia with both bovine and porcine heparin administration were studied in forty normal males randomized to one of four treatment groups: beef lung heparin #1, beef lung heparin #2, porcine gut heparin, and saline control. All of the subjects receiving heparin developed a reversible increase in serum transaminases (SGOT, SGPT). However, other measurements of liver function were normal. Thirty-three percent of these heparinized normals had decreased platelet counts. The incidence of platelet count decrease was similar for both bovine and porcine heparins, but 4 of the 20 normals receiving bovine heparin had platelet counts less than 150,000/microliters. Immune pathogenesis was investigated by analyzing plasma from the volunteers for both platelet antibody and immune complexes. None of the men had increased platelet-associated IgG. Among the ten subjects with decreased platelet counts, IgG immune complexes were detected in three and C1q in seven. The heparin-associated thrombocytopenia appears not to be mediated by a platelet antibody. More probably it reflects a direct effect of the heparin on platelets.",1
8122,4028427,Chronic active hepatitis induced by nitrofurantoin,,1
8123,4029887,Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies,"""A study from five hepatology units documenting 157 cases of drug-induced hepatitis and a second study from a laboratory of immunology which tested more than 100,000 sera permitted us to establish the frequency of antiorganelle antibodies and their diagnostic value in drug-induced hepatitis. In drug-induced hepatitis caused by a heterogenous group of drugs consisting of ajmaline, aminopterine, isaxonine, isoniazid, perhexiline, phenylbutazone and troleandromycine, antiorganelle antibodies were absent or rare. In drug-induced hepatitis caused by another heterogenous group of drugs, including clometacin, fenofibrate, oxyphenisatin and papaverine, antismooth muscle, antinucleus and antimitochondria antibodies were found in isolation or in different combinations in 70% of cases. From the presence of antismooth muscle antibodies in sera, we could trace 30 cases of clometacin-induced hepatitis. The third group included drug-induced hepatitis with special antibody:iproniazid-induced hepatitis with antimitochondrial antibody 6 and tienilic acid (ticrynafen)-induced hepatitis with antiliver/kidney microsome antibody 2 (anti-LKM2). These two antibodies are rare in routine sera and were absent in patients who received the drug and had no liver damage. From the presence of corresponding antibodies, we detected six cases of iproniazid-induced hepatitis and 67 cases of tienilic acid-induced hepatitis. Antiorganelle antibodies found in high titers disappeared in 2 to 24 months following withdrawal of the offending drug. The fourth group was represented by halothane-induced hepatitis; antiliver/kidney microsome antibody 1 was weak and infrequent. Similarities between drug-induced hepatitis of the second group and lupoid hepatitis suggest that drugs may reveal this spontaneous disorder.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
8124,4036534,Enflurane hepatitis. A report of a case with a previous history of halothane hepatitis,"Enflurane hepatitis has only recently been accepted as a disease entity. As far as the authors know, this paper is the first report on enflurane hepatitis in a patient with a previous history of halothane hepatitis. Our conclusion is that a potent halogenated inhalation agent should never be given to a patient if a prior administration of another such agent has led to the development of hepatic injury.",1
8125,4037565,Ranitidine and hepatitis,,1
8126,4038421,Hepatosplenic peliosis after danazol and glucocorticoids for ITP,,1
8127,4042525,Effects of long-term therapy with naltrexone on body weight in obesity,"""The endogenous opiate system is thought to be associated with the regulation of food intake and body weight. Opiate antagonists decrease food intake in animals, but there are no controlled studies in obese man to evaluate body weight response to naltrexone. Sixty obese people were randomized into three groups and given 0, 50, or 100 mg of the opiate antagonist naltrexone for 8 weeks in an outpatient, double-blind study. Weight loss was not significant in either the 50 or 100 mg groups as compared with placebo. However, when broken down by sex, women had a significant (P less than 0.05) weight loss of 1.7 kg, while men did not lose weight. Side effects were modest, but six subjects had one or more abnormal liver function test results; in one subject these abnormalities appeared to be clinically significant. The effects of naltrexone on weight loss were less than expected in light of prior animal studies, but further studies with a wider dose range of naltrexone may be indicated.""",1
8128,4053978,Hepatitis associated with propylthiouracil treatment,"A 12-year-old girl with hyperthyroidism who had started treatment with propylthiouracil (PTU) 100 mg tid developed hepatitis. The drug was stopped, and the clinical and laboratory findings of hepatitis disappeared within a week. She was not receiving other drugs that could cause hepatic damage, and investigations for various viral agents were negative. This is the ninth report of PTU-induced hepatitis. The clinical picture is similar to that of viral hepatitis. Recovery usually occurs after withdrawal of the drug, but there have been two fatal cases of PTU-induced hepatitis.",1
8129,4056348,Cimetidine-induced liver injury. Report of three cases,"Cimetidine-induced liver injury has only very rarely been reported. Three patients are described who developed signs of hepatic damage after the institution of cimetidine therapy. Transient signs of acute liver failure were noticed in one patient. Histologically, a cytotoxic type of injury with centrilobular confluent and bridging portal-central necrosis, accompanied by a mixed mono- and polymorphonuclear infiltrate with signs of cholangiolitis in the portal tracts was observed in two patients, whereas a hepatocanalicular type of cholestatic hepatitis was noticed in another patient. It is proposed that the mechanism of cimetidine-induced liver injury may vary in different patients: it may be due either to a 'metabolic idiosyncrasy' because of the production of hitherto unknown toxic metabolites or to a hypersensitivity reaction.",1
8130,4057311,Whole bowel irrigation for toxic ingestions,"Eight children aged eleven months to sixteen years who ingested toxic substances were treated with whole bowel irrigation. This procedure involves the rapid infusion of fluids per nasogastric tube in order to flush the toxic substance out from the gastrointestinal tract thereby preventing its absorption into the bloodstream. The infusion is terminated when the rectal effluent takes on the characteristics of the infusate. The toxic substances included miniature disc batteries, iron, tricyclic antidepressant and paraquat. No significant changes in serum sodium, serum potassium or hematocrit were observed. Whole bowel irrigation was felt to be efficacious in this series. It requires additional study as a therapeutic approach to the patient who has ingested a toxic substance.",1
8131,4061998,Gastrotomy--a surgical approach to iron overdose,"""Emesis and lavage often are ineffective in providing complete emptying of the stomach after an ingestion. With a locally corrosive and systemically toxic agent such as iron, surgical intervention with emergency gastrotomy may be required. We recently treated a 19-year-old man in the ED and in the departments of surgery and medicine who required a gastrotomy to remove a large amount of elemental iron inaccessible to removal by emesis, lavage, or gastroscopy. At gastrotomy the stomach showed full-thickness inflammation; the entire mucosal surface was hemorrhagic in nature. Gastrotomy was successful in allowing the removal of a large amount of the retained corrosive material. The severity of the findings at gastrotomy and the dramatic clinical improvement and recovery in our patient strongly support this approach if traditional methods fail.""",1
8132,4065499,[Hepatitis caused by ranitidine],,1
8133,4067758,Fatal hepatic failure and encephalopathy associated with amiodarone therapy,,1
8134,4073095,Clinical pharmacology and safety evaluation of Timentin,,1
8135,4073101,Comparative study of ticarcillin plus clavulanate potassium versus piperacillin in the treatment of hospitalized patients with urinary tract infections,"""The efficacy and safety of ticarcillin plus clavulanate potassium and piperacillin were compared in a clinical trial of 78 hospitalized patients with urinary tract infections. There were 37 evaluable patients in the ticarcillin plus clavulanate potassium-treated group and 39 in the piperacillin-treated group. The 43 infection sites in each group were primarily complicated pyelonephritis or complicated cystitis; six patients in the ticarcillin plus clavulanate potassium-treated group and four in the piperacillin-treated group also had septicemia. Both ticarcillin (3 g) plus clavulanate potassium (200 mg) and piperacillin (125 to 200 mg/kg per day) were administered intravenously. The 43 most common pathogens in each treatment group were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from the urinary tract and E. coli from the blood. Eight pathogens in the ticarcillin plus clavulanate potassium-treated group and 11 in the piperacillin-treated group were resistant to ticarcillin in vitro. Eradication was achieved for 39 of the 43 (91 percent) pathogens in the ticarcillin plus clavulanate potassium group, including all six organisms isolated from the blood and eight (89 percent) of the ticarcillin-resistant pathogens. In the piperacillin-treated group, 33 of the 43 (77 percent) pathogens were eradicated, including three of the four blood isolates but only eight (73 percent) of the ticarcillin-resistant pathogens. The rate of reinfection or relapse was similar in both groups. Clinical cure or improvement occurred in 97 percent of the patients in each group. Mild and transient increases in levels of liver enzymes or eosinophilia was reported for 11 patients in the ticarcillin plus clavulanate potassium-treated group and for seven in the piperacillin-treated group. In one patient in the ticarcillin plus clavulanate potassium-treated group, a drug-related rash and nausea developed, and treatment was discontinued.""",1
8136,4077446,Dense liver in a 72-year-old woman with congestive heart failure,"Amiodarone is a cardiac antiarrhythmic agent now undergoing clinical trials in the United States. Its most important side effect is pulmonary toxicity, which may present radiographically in two forms. One is similar to eosinophilic pneumonia with peripheral alveolar opacities but without any of the laboratory or pathologic findings. A second presentation is as a bilateral interstitial pattern resembling interstitial pulmonary edema. This is often mistaken for heart failure in the clinical and radiographic setting. Amiodarone also causes a phospholipidosis of the liver, which is usually asymptomatic but on occasion may present as hepatitis. On abdominal CT the liver will have an abnormally high attenuation (80-140 HU), which appears to be due to accumulation of an amiodarone metabolite in hepatocytes. This appearance is usually distinguishable from the other causes of increased hepatic attenuation by virtue of other CT criteria and clinical history. However, from a radiographic standpoint alone, the combination of acute congestive heart failure and an abnormally dense liver may result in at least an initial misdiagnosis of advanced primary hemochromatosis.",1
8137,4078724,Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans,"The plasma concentrations of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine and diacetylhydrazine, were measured by gas chromatography-mass spectrometry in 12 healthy subjects after the ingestion of 300 mg of isoniazid. The area under the plasma concentration-time curve of acetylisoniazid and diacetylhydrazine increased with increasing rate of acetylation of isoniazid. In contrast, the area under the plasma concentration-time curve of acetylhydrazine, the postulated precursor of a toxic metabolite formed from isoniazid, was greater in slow acetylators. This occurred even though rapid acetylators generated more acetylisoniazid and thus more acetylhydrazine from isoniazid, because the rapid acetylators also acetylated acetylhydrazine faster to diacetylhydrazine than did the slow acetylators. Due to this complex relationship between area under the plasma concentration-time curve of acetylhydrazine and the rate of isoniazid acetylation (i.e., a faster rate of formation of acetylhydrazine is accompanied by a faster clearance to diacetylhydrazine), the rate of acetylation of isoniazid minimally influences the exposure of most patients to acetylhydrazine. This pharmacokinetic analysis, however, also shows that the apparent plasma half-life of acetylhydrazine is about five times longer than the plasma half-life of isoniazid, and thus repeated doses of isoniazid should lead to an accumulation of acetylhydrazine in the slowest acetylators in which the plasma half-life of acetylhydrazine is 20-plus hr.(ABSTRACT TRUNCATED AT 250 WORDS)",1
8138,4085166,D-penicillamine-induced acute hypersensitivity pneumonitis and cholestatic hepatitis in a patient with rheumatoid arthritis,"Acute hypersensitivity pneumonitis is not a known side effect of D-penicillamine. Also, there are only a few reports of cholestatic hepatitis caused by this drug. The present report describes a case of rheumatoid arthritis where these manifestations appeared in the same patient ten days after the institution of D-penicillamine therapy. The etiological relationship with the drug was established, inadvertantly, by its accidental intake by the patient 5 months later with the reproduction of the same manifestations.",1
8139,4092653,[The so-called dihydralazine hepatitis. A contribution to the pathogenesis],"Liver injuries following application of dihydralazine in 14 patients, ten of them with the typical pattern of perivenous liver cell necrosis, are reported. The other 4 patients, all having been exposed to additional hepatotoxic substances, histologically showed mixed patterns of tissue injury in liver biopsy. Moreover, in 6 of 14 patients there were diseases in the upper abdomen and/or metabolic disorders as well as an exposition to chemical hepatotoxic substances, or an additional application of potential hepatotoxic drugs. 9 of 14 patients had been treated with propranolol and dihydralazine simultaneously. One female patient showed the typical morphologic pattern of 'dihydralazine-damage' after application of propranolol only. In 3 cases with reexposition of dihydralazine merely one of them developed the typical histological behaviour documented in the literature. Distinct fibrosis of the liver remained in 2 cases. Consequently, to the hitherto existing pathogenetic concept of dihydralazine-caused liver injury as a metabolic-toxic-allergic one, there is to be added the new aspect of summing up of the actions of various additional noxious agents.",1
8140,4094082,"[A case of autoimmune hemolytic anemia, interstitial pneumonia and liver injury occurred during one month's medication of small dose of alpha-methyldopa]",,1
8141,4100063,Hepatic artery infusion for metastatic malignancy using percutaneously placed catheters,,1
8142,4103033,Liver biopsy in methotrexate treatment,,1
8143,4108488,"Hepatitis, arthritis and lupus cell phenomena caused by methyldopa",,1
8144,4116869,Abdominal pain and erythromycin estolate,,1
8145,4117807,Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma,,1
8146,4118649,Hepatic damage and death from overdose of paracetamol,,1
8147,4119402,Androgens and hepatocellular carcinoma,,1
8148,4120232,Evaluation of a new antituberculous agent. Capreomycin sulfate (capastat sulfate),,1
8149,4123858,Androgenic-anabolic steroid therapy and hepatocellular carcinoma,,1
8150,4126107,Mithramycin in Paget's disease of bone,,1
8151,4126381,Clinical trials of cis-diamminedichloroplatinum (NSC-119875),,1
8152,4127562,Letter: Benign hepatomas and oral contraceptives,,1
8153,4130278,Letter: Liver-cell carcinoma after long-term oestrogen-like drugs,,1
8154,4130500,Letter: Benign hepatomas and oral contraceptives,,1
8155,4131429,Rifampicin hepatitis. A clinical and histological study,,1
8156,4132843,Letter: Liver tumours and steroid hormones,,1
8157,4133693,Letter: Jaundice associated with naproxen,,1
8158,4136079,Letter: Hepatomas and oral contraceptives,,1
8159,4139002,Treatment of pulmonary tuberculosis,,1
8160,4143738,Chloramphenicol and jaundice in a baby,,1
8161,4146729,Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype,,1
8162,4154834,Baclofen: a preliminary report of its pharmacological properties and therapeutic efficacy in spasticity,,1
8163,4159865,Tetracyclines and the liver in pregnancy,,1
8164,4167452,The clinical use of antilymphocyte globulin in renal homotransplantation,"Twenty patients were treated with antilymphocyte globulin (ALG) which was prepared from the serum of immunized horses. The ALG was used as an adjuvant to azathioprine and prednisone and its use limited to 4 months. The surviving patients are now 1 to 7 months postoperative. There was 1 death, the consequence of a technical accident. The function in the remaining 19 patients is excellent, despite reduced doses of azathioprine and especially prednisone. Biopsies were obtained in the first 8 consecutive cases from 108 to 145 days after operation. There was no evidence in the specimens of either Masugi-like or serum sickness nephritis.",1
8165,4176152,Treatment of multiple-hormone-producing malignant islet-cell tumour with streptozotocin,,1
8166,4188135,Hepatic reaction to nitrofurantoin,,1
8167,4189787,Hereditary haemorrhagic telangiectasia: aggravation by oral contraceptives?,,1
8168,4190565,Hereditary haemorrhagic telangiectasia and oral contraceptives,,1
8169,4194539,Triethylene tetramine,,1
8170,4197287,Encephalopathy and fatty degeneration of viscera: Reye's syndrome,,1
8171,4206176,[Hypoglycemia caused by oral antidiabetic agents],,1
8172,4209436,Multiple complications and death following protriptyline overdose,,1
8173,4210892,Preliminary clinical experience with ticarcillin (BRL 2288) in 101 patients treated for severe respiratory infections,,1
8174,4214658,A double-blind comparison of pimozide vs. trifluoperazine in schizophrenic outpatients,,1
8175,4234079,Lethal hepatic necrosis after therapy with imipramine and desipramine,,1
8176,4243752,Parenteral methotrexate in psoriasis. A report on the efficacy and toxicity of long-term intermittent treatment,,1
8177,4253251,Hepatocellular damage due to methyldopa,,1
8178,4255439,Toxicity form rifampicin plus isoniazid and rifampicin plus ethambutol therapy,,1
8179,4266968,Isoniazid administration and liver injury,,1
8180,4271305,Clinical experience with adverse reactions to trimethoprim-sulfamethoxazole,,1
8181,4290387,Comparative study of methods of administering mitomycin C,,1
8182,4296504,Norethisterone jaundice in two sisters,,1
8183,4319181,Streptozotocin therapy for metastatic insulinoma,,1
8184,4324228,Hepatoma and peliosis hepatis developing in a patient with Fanconi's anemia,"Fanconi's anemia is a rare genetic disorder associated with congenital deformities, infections, chromosomal abnormalities, and leukemia. This brief article describes the case of a 20 year old man affected with the disease, who was given 100 mg daily of oxymetholone to cure leukopenia and thrombocytopenia. 10 months later he died of hepatic failure. Autopsy revealed hepatoma and liver peliosis, a rare condition of unknown etiology characterized by blood-filled cysts in the liver. It is possible that in the case reported here the hepatoma could have been related to the oxymetholone treatment, which conceivably could have initiated hepatic damage.",1
8185,4329505,Therapeutic effect and toxicity of adriamycin in patients with neoplastic disease,,1
8186,4334088,Clinical experience with mitomycin C (NSC-26980),,1
8187,4339534,Hepatic dysfunction after renal transplantation in children,,1
8188,4348410,Arsenic intoxication from well water in the United States,,1
8189,4352019,Adriamycin--an antitumor antibiotic in the treatment of neoplastic diseases,,1
8190,4355081,Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature,,1
8191,4361338,Use of oxandrolone for growth stimulation in children,,1
8192,4364925,Focal nodular hyperplasia of the liver. Possible relationship to oral contraceptives,,1
8193,4366047,Hepatic cell adenoma: A report of four cases,Four patients with hepatic cell adenoma have been treated at the UCLA Hospital since 1965. The most recent was a 22-year-old woman who underwent subtotal resection of a giant hepatic cell adenoma after an unusual and confusing clinical presentation. The tumor may be the largest reported to date and may have excreted metabolically-active substances. Increased familiarity with the varying clinical and radiographic presentations of these rare tumors may facilitate earlier diagnosis and management.,1
8194,4371075,Clinical antitumor activity and toxicity of streptozotocin (NSC-85998),,1
8195,4399967,Halothane hepatitis: a critical review,,1
8196,4406795,Cephalexin nephrotoxicity. Reversible nonoliguric acute renal failure and hepatotoxicity associated with cephalexin therapy,,1
8197,4409491,[Erythromycin estolate and liver toxicity],,1
8198,4413117,Effects of blood levels of tetracycline and oxytetracycline on hepatic and renal functions in normal subjects,,1
8199,4414663,Methyldopa liver damage,"""Twenty patients are described in whom liver damage appeared to be directly related to the administration of methyldopa. Sixteen had hepatitic syndromes from which they recovered on stopping methyldopa; four of these patients had recurrences of jaundice after a second course of the drug. Features suggestive of active chronic hepatitis were found in two patients. There were two deaths attributed to methyldopa, one of these being in a patient with pre-existing undiagnosed macronodular cirrhosis.""",1
8200,4417152,Iron intoxication in two adult patients,,1
8201,4418777,Salicylate hepatitis. A case report,,1
8202,4423214,Peliosis hepatis associated with androgenic-anabolic steroid therapy. A severe form of hepatic injury,,1
8203,4424638,Hepatic necrosis caused by furosemide,,1
8204,4429278,Letter: Isoniazid and the liver,,1
8205,4433082,Quinidine-induced granulomatous hepatitis,,1
8206,4452168,[Liver damage during erythromycin therapy in 3 children],,1
8207,4453809,Sulfonamide-induced chronic liver disease,,1
8208,4473289,[2 cases of liver diseases caused by thyroid antagonists],,1
8209,4479092,Disulfiram hypersensitivity hepatitis,,1
8210,4515688,Liver injury by salicylates,,1
8211,4518740,Side effects of rifampicin. A clinical study,,1
8212,4522067,A trial of intermittent rifampicin and ethambutol in retreatment regimens,,1
8213,4531928,Intrahepatic cholestasis due to alpha-methyldopa: a case report,,1
8214,4546042,[Non-cirrhotic portal fibrosis (hepatoportal sclerosis) after chronic arsenic poisoning: clinical and morbid-anatomical findings (author's transl)],,1
8215,4550304,Clofazimine in leprosy,,1
8216,4562099,Irreversible liver damage after azathioprine,,1
8217,4567104,Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels,"Tamoxifen (ICI 46474) is the trans-isomer of 1(p-beta-dimethylaminoethoxy-phenyl)-1, 2-diphenylbut-1-ene. In several but not all mammal species it is a potent anti-estrogen. It is thought to act by blocking estrogen receptors. Patients were 68 women with advanced primary carcinoma of the breast, recurrences in the chest wall or soft tissue metastases. The oral dose of tamoxifen was either 10 mg or 20 mg twice daily. Patients were seen and laboratory tests done monthly for 6 months. Side effects were usually trivial and their incidence was the same at both dose levels. Of 26 patients who showed a reduction in tumor size to half or less, 5 had been in remission for over a year and another 10 for over 6 months. Some tumor responses were spectacular. The drug was less effective for bone deposits. In this study 12 of 33 patients (36%) receiving 10 mg of tamoxifen twice daily showed a definite response while a futher 8 (24%) showed a partial response. A definite response was seen in 14 out of 35 (40%) receiving 20 mg twice daily and a partial response in a further 13 (37%). The total response for low dosage was 60% and for high dosage 77%.",1
8218,4574197,Acute ferrous sulfate hepatotoxicity in rats. An electron microscopic and biochemical study,,1
8219,4577390,Liver disease in kidney transplant patients receiving azathioprine,,1
8220,4581906,Late toxicity to hydralazine resembling systemic lupus erythematosus or rheumatoid arthritis,,1
8221,4586083,Acute hepatic necrosis and fulminant hepatic failure,,1
8222,4589978,Evaluation of loxapine succinate in chronic schizophrenia,,1
8223,4590715,Tetracycline hepatotoxicity in the differential diagnosis of postoperative jaundice,,1
8224,4595936,Benign cholestatic jaundice of pregnancy and benign cholestatic jaundice from oral contraceptives,"A discussion of benign cholestatic jaundice of pregnancy and from oral contraceptives is presented. It has been established that recurrent cholestatic jaundice of pregnancy is caused by interference with liver secretory processes such that conjugated bilirubin accumulates in the blood stream. The condition maybe caused by a possible inherited metabolic effect resulting in an increased secretion of estrogen and progesterone. Women with a history of cholestatic jaundice of pregnancy may experience generalized pruritus or cholestatic jaundice if they are on an oral contraceptive regimen. Pruritus may be a symptomatic sign of the onset of cholestatic jaundice and in women using oral contraceptives, the condition indicates the possible development of choletic jaundice during pregnancy. Cholestatic jaundice will usually disappear 1 to 8 weeks after parturition or the cessation of oral contraceptive therapy.",1
8225,4601671,Toxicity study of BCNU (NSC-409962) given orally,,1
8226,4606798,Medical therapy for gallstones,,1
8227,4617720,"Controlled long-term therapy of leprosy with B663 (lamprene, clofazimine) compared with DDS",,1
8228,4629449,Liver damage and estrogen therapy of prostatic cancer. Case report,,1
8229,4633722,Intrahepatic cholestasis due to therapy of rheumatoid arthritis,,1
8230,4641958,Chronic adult hypervitaminosis A with hypercalcemia,,1
8231,4642675,Cyclophosphamide in the treatment of childhood nephrotic syndrome,,1
8232,4648805,Structural and functional abnormalities of the liver in psoriasis before and during methotrexate therapy,,1
8233,4662281,[Cholestatic syndrome following massive chrysotherapy],,1
8234,4680015,[Liver disorders in Inderal therapy],,1
8235,4685515,Disseminated intravascular coagulation associated with tetracycline-induced hepatorenal failure during pregnancy,,1
8236,4688569,Drug-induced active chronic hepatitis,,1
8237,4692124,Psoriasis with hydroxyurea. An 18-month study of 60 patients,,1
8238,4692711,Active chronic hepatitis after chlorpromazine ingestion,,1
8239,4694908,Quinidine hepatotoxicity?,,1
8240,4697675,Validity of serum glutamic oxalacetic transaminase determinations in isoniazid recipients,,1
8241,4704507,Hypersensitivity hepatitis associated with administration of cyclizine,,1
8242,4706137,Hydralazine disease associated with transient granulomas in the liver. A case report,,1
8243,4711784,"Clindamycin, endocarditis, hepatotoxicity",,1
8244,4716739,Methotrexate therapy for psoriasis. Guideline revisions,,1
8245,4719544,Oxymetholone in myelofibrosis and chronic lymphocytic leukemia,,1
8246,4721174,Isoniazid hepatitis,,1
8247,4729773,Liver ultrastructure in methotrexate treatment of psoriasis,,1
8248,4739612,Thioridazine toxicity. Agranulocytosis and hepatitis with encephalopathy,,1
8249,4739987,Methyldopa-induced submassive hepatic necrosis,,1
8250,4741351,The erythromycins. A further report from the Australian Drug Evaluation Committee,,1
8251,4749163,Abnormalities in liver function tests during long-term diphenylhydantoin therapy in epileptic out-patients,,1
8252,4751738,Letter: Disturbed hepatic function during isoniazid chemoprophylaxis,,1
8253,4758150,Liver injury associated with methotrexate therapy for psoriasis,,1
8254,4783020,Hepatotoxicity of long-term methotrexate therapy for psoriasis,,1
8255,4800332,Oxacillin-induced hepatic dysfunction,,1
8256,4808582,Spontaneous rupture of the liver in patient using contraceptive pills,,1
8257,4810329,Editorial: Aspirin-induced hepatic injury,,1
8258,4810337,Letter: Isoniazid hepatitis,,1
8259,4810349,Hypercalcemia and skeletal effects in chronic hypervitaminosis A,,1
8260,4811806,Letter: Isoniazid hepatoxicity,,1
8261,4812384,Hepatotoxicity to isoniazid. A case report,,1
8262,4816197,Letter: Isoniazid hepatitis,,1
8263,4827607,[A case of hepatocellular jaundice during treatment with ibuprofen],,1
8264,4832164,Letter: Aspirin hepatotoxicity,,1
8265,4834576,Proceedings: Liver damage in patients taking methyldopa,,1
8266,4834945,Chemical structure of erythromycin and hepatotoxicity,,1
8267,4835153,Occurrence of hepatic impairment in women jaundiced by oral contraceptives and in their mothers and sisters,,1
8268,4835475,Jaundice in acute pustular psoriasis,,1
8269,4841570,Arene oxides: a new aspect of drug metabolism,,1
8270,4843577,The effect of isoniazid on transaminase levels,,1
8271,4843589,Letter: Isoniazid,,1
8272,4847042,Severe intrahepatic cholestasis due to thiabendazole,,1
8273,4851012,Chloroquine poisoning,,1
8274,4852220,Halothane hepatitis--a report of five cases,,1
8275,4853200,Methotrexate induced liver disease in psoriasis,,1
8276,4859632,Letter: Hepatic necrosis after enflurane anesthesia,,1
8277,4863509,Clinical trial of protriptyline (Vivactil),,1
8278,4873914,Lupoid hepatitis following administration of penicillin. Case report and immunological studies,,1
8279,4881878,A controlled comparison between imipramine and protriptyline,,1
8280,4891127,Methotrexate and the liver,,1
8281,4903304,The many effects of griseofulvin,,1
8282,4904933,L-asparaginase in treatment of acute leukaemia and lymphosarcoma,"""L-Asparaginase was used to treat 40 patients with acute leukaemia or lymphosarcoma. Fifteen with acute lymphoblastic leukaemia either untreated or in relapse after previous therapy were given """"Squibb,"""" """"Bayer,"""" or """"Porton"""" L-asparaginase. Five of these patients had complete remission of their disease, and four had good partial remission. Eleven patients with acute myeloid leukaemia were treated for a short period with L-asparaginase alone. None of them went into remission though a pronounced fall in the numbers of circulating white cells was seen. Six patients with lymphosarcoma received L-asparaginase, two of them having good partial remissions.The toxic side-effects of the L-asparaginase from the three sources seemed to vary, and L-asparaginase from Erwinia carotovora appeared to be antigenically different from the enzyme produced by Escherichia coli.The way in which leukaemic cells become resistant to the action of the enzyme requires further investigation. To overcome this resistance asparaginase should be used in combination with other drugs in the treatment of acute leukaemia.""",1
8283,4905153,Toxicity of E. coli L-asparaginase in man,,1
8284,4913866,Thalidomide in the treatment of erythema nodosum leprosum. With a note on selected laboratory abnormalities in erythema nodosum leprosum,,1
8285,4924590,Some aspects of the interaction between natural and synthetic female sex hormones and the liver,,1
8286,4926242,Clinical studies with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037),,1
8287,4933014,The use of dantrolene sodium in disorders of the central nervous system,,1
8288,4937796,Carbenicillin therapy for pseudomonas infections,,1
8289,4940540,Cyclophosphamide and whole organ transplantation in human beings,,1
8290,4945997,L-asparaginase (NSC-109229) plus azaserine (NSC-742) in acute lymphatic leukemia,,1
8291,4946082,"Clinical studies with a new podophyllotoxin derivative, epipodophyllotoxin, 4'-demethyl-9-(4,6-O-2-thenylidine- -D-glucopyranoside) (NSC-122819)",,1
8292,4949165,Some clinical observations on the treatment with L-asparaginase of the acute leukemias,,1
8293,4952749,Cholestatic jaundice associated with chlordiazepoxide hydrochloride (Librium) therapy. Report of a case and review of the literature,,1
8294,4968193,A toxicologic study of mithramycin,,1
8295,4969672,"Double-blind comparison of efficacy, safety, and side effects of Bionamin, phentermine compound, and placebo in the treatment of exogenous obesity",,1
8296,4993672,Isoniazid treatment for tuberculosis,,1
8297,5006919,Dissolution of cholesterol gallstones by chenodeoxycholic acid,,1
8298,5009403,Hypogastric artery infusion and radiation therapy for advanced squamous cell carcinoma of the cervix,,1
8299,5015292,Methotrexate hepatotoxicity in psoriasis--comparison of different dose regimens,"Liver histological appearances were studied in 44 patients treated for psoriasis with methotrexate. Cirrhosis was found in six and hepatic fibrosis in another 11. Of these 17 patients 12 had received methotrexate by a regimen of frequent small dosage, two had been treated by a regimen of intermittent large dosage, while three had been treated at different times by both methods. The prevalence of cirrhosis and fibrosis was significantly greater in patients treated by frequent small dosage than in those treated by intermittent large dosage, though the dose level (mg/month) was similar in both groups. Hepatic fibrosis, sometimes preceding cirrhosis, seems to develop invariably if treatment with small frequent dosage is sufficiently prolonged. In the few circumstances in which this drug is indicated for psoriasis intermittent large dosage is the treatment regimen of choice.",1
8300,5017281,Hepatic injury associated with the phenothiazines. Clinicopathologic and follow-up study of 36 patients,,1
8301,5019446,Acute copper intoxication. A hazard of hemodialysis,,1
8302,5023985,[Collateral effects of gold salts in the therapy of rheumatoid arthritis],,1
8303,5032153,Hepatotoxicity in rifampin-isoniazid treated patients related to their rate of isoniazid inactivation,,1
8304,5036092,Effect of rifampicin on liver function in man,"Liver function and serum concentrations of rifampicin, a highly cholephilic antibiotic, have been studied after ingestion of a single dose of 600 mg of rifampicin in 12 patients, six of them having a normal liver and six a cirrhotic, and during treatment with 600 mg of rifampicin per day for 17 days in eight patients, four of them having a normal liver and four a cirrhotic. Rifampicin produced competition for the elimination of bilirubin and bromsulphalein by the liver. This competition, which seemed to involve mainly the uptake by the liver cell, was always rapidly reversible when treatment was discontinued. It makes it impossible, however, to interpret a bromsulphalein test during treatment with rifampicin. In the eight patients treated for 17 days, apart from the competition already mentioned, no clinical, biological, or morphological abnormalities of the liver were ascertained. But in this limited number of patients it is not possible to exclude the fact that rifampicin could provoke jaundice by idiosyncrasy in a small percentage of cases. The serum concentrations of rifampicin were higher in cirrhotic patients than in patients with normal livers, especially after one or two weeks of treatment. It is suggested that efficient blood concentrations of rifampicin would be achieved with small doses in case of previous hepatocellular insufficiency.",1
8305,5050316,"Pregnancy, oral contraceptives, and chronic familial jaundice with predominantly conjugated hyperbilirubinemia (Dubin-Johnson syndrome)",,1
8306,5052728,Adverse reactions during rifampicin treatment,,1
8307,5055057,[Intrahepatic cholestasis following chlordiazepoxide--contribution to the differential diagnosis of drug jaundice],,1
8308,5059424,Granulomatous hepatitis in a patient receiving allopurinol,,1
8309,5063168,5-fluorocytosine: an oral antifungal compound. A report on clinical and laboratory experience,,1
8310,5067581,Isoniazid toxicity. A prospective study in secondary chemoprophylaxis,,1
8311,5074970,[Diffuse liver necrosis in treatment with 5-fluorouracil],,1
8312,5083381,Blood dyscrasias attributed to chloramphenicol. A review of 576 published and unpublished cases,,1
8313,5090795,Liver damage and methotrexate,,1
8314,5095674,Colchicine intoxication. A reappraisal of its pathology based on a study of three fatal cases,,1
8315,5098212,Hepatitis induced by methyldopa (aldomet). Report of a case and a review of the literature,,1
8316,5108642,Methotrexate and hepatic disease,,1
8317,5109448,Duration and severity of fatty metamorphosis of the liver following L-asparaginase therapy,,1
8318,5111743,5-fluorouracil given once weekly: comparison of intravenous and oral administration,,1
8319,5129618,Chronic arsenical poisoning and non-cirrhotic portal hypertension--a case for diagnosis,,1
8320,5146732,[Hepatitis induced by combination of rifampicin and isoniazid],,1
8321,5150312,[A case of icterus in the course of treatment with rifampicin. Histological records],,1
8322,5151819,Forty-four months' experience in the treatment of leprosy with clofazimine (Lamprene (Geigy)),,1
8323,5195777,[Hepatitis caused by erythromycin],,1
8324,5215561,Acute iron poisoning. Clinical and laboratory observations with deferoxamine,,1
8325,5232672,Severe liver toxicity after methyldopa,,1
8326,5235587,Treatment of acute iron intoxication with deferoxamine: a report of six cases. Chelating agent proves effective in management of acute iron poisoning,,1
8327,5262259,Prolonged infusion of arabinosyl cytosine in childhood leukemia,,1
8328,5264814,[Treatment of acute leukemia with the L-asparaginase. Preliminary results based on 84 cases],,1
8329,5278225,Comparison of daily versus weekly L-asparaginase for the treatment of childhood acute leukemia,,1
8330,5286443,Cytosine arabinoside in acute leukemia of childhood,,1
8331,5292724,A summary of the clinical status of asparaginase,,1
8332,5296945,[Hepatic function in the course of therapy with indomethacin],,1
8333,5301748,Portal hypertension in a case of acute leukemia treated with antimetabolites for ten years,,1
8334,5310706,Pentamidine: clinical pharmacologic correlations in man and mice,,1
8335,5314582,Acute hepatic dysfunction in juvenile rheumatoid arthritis,,1
8336,5315135,Still's disease in the adult,,1
8337,5315548,Toxic and therapeutic effects of methotrexate-folinic acid (Leucovorin) in advanced cancer and leukemia,,1
8338,5320547,"A controlled trial with trimipramine, a new anti-depressant drug",,1
8339,5327471,Chronic chlorpromazine cholangiolitic hepatitis. Report of a case with immunofluorescent studies,,1
8340,5332484,The effect of oral contraceptives on the liver,,1
8341,5339123,A comparative trial of amitriptyline and trimipramine in the treatment of depression,,1
8342,5350402,Cirrhosis caused by methotrexate in the treatment of psoriasis,,1
8343,5352203,Hepatic necrosis associated with halothane anesthesia,,1
8344,5361410,Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid,,1
8345,5369623,Thiabendazole for the treatment of trichinosis in humans,,1
8346,5383009,[Jaundice during treatment with rifampicin (12 cases)],,1
8347,5402667,[Influence of chlorpromazine on the hepatic functions],,1
8348,5410161,"Granulocytopenia, lupus-like syndrome, and other complications of propylthiouracil therapy",,1
8349,5410273,Vasculitis with allopurinol therapy,,1
8350,5410643,Anicteric hepatitis induced by diphenylhydantoin,,1
8351,5412191,Hepatitis after isoniazid administration,,1
8352,5420239,"Clofibrate, serum enzymes, and muscle pain","""Serum creatine kinas (C.K.), aspartate amino-transferase (G.O.T.), and alkaline phosphatase (A.P.) activities were measured in 211 men with serum cholesterol concentrations in the upper one-third of the normal distribution. Of these, 110 were receiving clofibrate and 101 were given identical capsules containing olive oil. These investigations were also carried out on 85 healthy men with low serum cholesterol levels not receiving clofibrate.No differences were observed in C.K. and G.O.T. activities between any of these groups; A.P. was significantly lower in the clofibrate-treated group. No significant alterations in C.K. occurred during serial observations made in 15 patients with ischaemic heart disease over a period of five months. No instance of myalgia or muscle stiffness was recorded in 452 men who had received clofibrate for one year.It is concluded that raised C.K. and G.O.T. concentrations and the occurrence of myalgia are uncommon accompaniments of clofibrate treatment.""",1
8353,5423891,Recurrent hepatitis in patients receiving multiple halothane anesthetics for radium treatment of carcinoma of the cervix uteri,,1
8354,5432630,Jaundice after rifampicin,,1
8355,5435667,Malignant lymphoma associated with hydantoin drugs,,1
8356,5438429,Abnormal serum transaminase levels after parenteral ampicillin and carbenicillin administration,,1
8357,5452049,Prolonged survival after portal decompression of patients with non-cirrhotic intrahepatic portal hypertension,"In a series of 251 good-risk patients undergoing portal decompression for intrahepatic portal hypertension, one fifth have been found not to have hepatic cirrhosis. Of these, 44 had only minor changes in hepatic architecture, and the clinical features and subsequent course have been compared and contrasted with a group of 201 cirrhotic patients who underwent portal decompression for similar indications. The degree of portal hypertension was comparable in both groups and it was not possible confidently to differentiate the condition from hepatic cirrhosis on either clinical or biochemical grounds in the individual case. The histological lesion was not progressive in the non-cirrhotic group and this was reflected in the far better survival of these patients. After five years 83% (30 of 36) of this group were alive compared with 43% (65 of 152) of the cirrhotic patients. After 10 years the cumulative survival was 77% (20 of 26) for those without cirrhosis, contrasted with 22% (19 of 87) for the cirrhotic patients.",1
8358,5455931,[Atypical picture of pityriasis versicolor],,1
8359,5457518,Hemangiomatosis of the liver with thrombosis following use of an oral contraceptive,,1
8360,5460240,Long-term monitoring during clofibrate therapy,,1
8361,5467301,"Toxic epidermal necrolysis, azotemia, and death after allopurinol therapy",,1
8362,5467807,[Hepatotoxicity of caffeine and theophylline],,1
8363,5469272,[Liver damage during methotrexate treatment of psoriasis],,1
8364,5474111,Liver disease associated with methotrexate treatment of psoriatic patients,,1
8365,5483428,Peliosis hepatis: case report and review of pathogenesis,,1
8366,5489326,Tolbutamide jundice associated with multiple drug therapy,,1
8367,5492248,Ultrastructure of the liver in non-cirrhotic portal fibrosis with portal hypertension,"The aetiology of the ultrastructural abnormalities of non-cirrhotic portal fibrosis is not known. In an attempt to elucidate the pathophysiology of this condition, the hepatic ultrastructure in nine cases of non-cirrhotic portal fibrosis with portal hypertension has been studied.",1
8368,5501902,Evaluation of possible chronic hepatotoxicity from methotrexate for psoriasis,,1
8369,5510316,"[Jaundice epidemiology in 1,974 hospitalized tubercular patients, treated or untreated by rifampicin]",,1
8370,5539574,Budd-Chiari syndrome in women taking oral contraceptives,,1
8371,5548272,Hepatotoxicity of methotrexate in the treatment of psoriasis,,1
8372,5549745,Anabolic action and side effects of oxandrolone in 34 mental patients,,1
8373,5555178,Lethal orphenadrine intoxications. A report of five cases,,1
8374,5558887,"Treatment of advanced Hodgkin's disease with (1,3 bis (2-chloroethyl)-1-nitrosourea) BCNU",,1
8375,5564809,Hepatorenal toxicity of tetracycline,,1
8376,5576002,Serum transaminases during salicylate therapy,"""In 8 out of 32 juvenile patients suffering from chronic polyarthritis and in one patient with dermatomyositis, raised transaminase levels were found; the salicylate level was above 35 mg/100 ml in all except one. Reduction in the salicylate level led to a prompt fall in the serum transaminases. Despite a rise in alkaline phosphatase in three cases there was no other evidence of liver dysfunction in the children. Only one of the adults showed a rise in transaminase levels, and she had mild cirrhosis.""",1
8377,5576148,Self-poisoning with colchicine,,1
8378,5583132,Prolonged chlorpromazine jaundice,,1
8379,5634821,Budd-Chiari syndrome after oral contraceptives,,1
8380,5635646,Prevention of Wilson's disease in asymptomatic patients,,1
8381,5641439,Acute iron poisoning in children: role of chelating agents,,1
8382,5643729,Budd-Chiari syndrome after oral contraceptives,,1
8383,5648509,Acute copper sulphate poisoning,,1
8384,5656682,"""Impaired secretion of triglycerides by the liver; a cause of tetracycline-induced fatty liver""",,1
8385,5658873,Syndrome of heaptitis and aplastic anemia,,1
8386,5677140,Hepatic microanatomy in hypervitaminosis A in man and rat,,1
8387,5694455,Hepatic disorder and severe bleeding diathesis following nitrofurantoin ingestion,,1
8388,5694615,Tetracycline toxicity in a nonpregnancy woman,,1
8389,5694750,Mitomycin C therapy in advanced gastrointestinal cancer,,1
8390,5696234,"Encephalopathy and fatty degeneration of the viscera in childhood: I. Review of cases at the Hospital for Sick Children, Toronto (1954-1966)",,1
8391,5701926,Colchicine toxicity,,1
8392,5708633,Biochemical changes in blood in cases of acute copper sulphate poisoning,,1
8393,5720561,[Accidental iron sulfate poisoning in a 3-year-old child],,1
8394,5721976,Liver disease in narcotic addicts. II. The role of the needle,,1
8395,5747401,[Jaundice in diabetics treated with sulfonylureas. On a clinical case of jaundice caused by tolazamide],,1
8396,5754834,Cholestatic jaundice during imipramine therapy,,1
8397,5764450,Recurrent hepatitis attributable to halothane sensitization in an anesthetist,,1
8398,5773660,Hepatic lipidosis associated with L-asparaginase treatment,,1
8399,5778839,Methotrexate liver toxicity,,1
8400,5781951,Jaundice associated with amitriptyline,,1
8401,5800713,Liver function during amantadine hydrochloride medication in compensated liver disease,,1
8402,5805238,Hepatic fibrosis following long acting nicotinic acid therapy: a case report,,1
8403,5809690,"""Obliterative portal venopathy of the liver and """"idiopathic portal hypertension""""""",,1
8404,5817464,Clinical studies with mithramycin,,1
8405,5818983,Statewide study of chloramphenicol therapy and fatal aplastic anemia,,1
8406,5833579,Acute copper sulfate poisoning,,1
8407,5841222,Acute hepatic necrosis following treatment with amitriptyline and diazepam,,1
8408,5841675,Acute iron intoxication,,1
8409,5844831,[Jaundice due to chlorpromazine],,1
8410,5858571,"Clinical trials with 1,3-bis(2-chloroethyl)-1-nitrosourea, NSC-409962",,1
8411,5895147,[Chronic toxic hepatitis caused by aspirin],,1
8412,5898078,Abnormal liver function and synthetic estrogens,,1
8413,5905463,Mitomycin-C in the therapy of far-advanced malignant tumors,,1
8414,5907470,Hepatic fibrosis in a child possibly due to prolonged methotrexate,A case is described in which marked hepatic fibrosis probably resulted from the prolonged treatment of acute leukaemia with methotrexate.,1
8415,5911317,Deferoxamine in the treatment of acute iron poisoning. Clinical experiences with 172 children,,1
8416,5913085,Liver damage and impaired glucose tolerance after paracetamol overdosage,,1
8417,5917425,Study of the excretion in bile and concentration in the gall bladder wall of rifamide,,1
8418,5919490,Fatty liver associated with administration of tetracycline in pregnant and nonpregnant women,,1
8419,5923599,"Adrenal cortical carcinoma. Results of treatment with o,p'DDD in 138 patients",,1
8420,5926937,Biliary cirrhosis induced by chlorpromazine,,1
8421,5933578,Bone marrow depression associated with acute colchicine toxicity in the presence of hepatic dysfunction,,1
8422,5934994,Hepatic toxicity of tetracycline in pregnancy,,1
8423,5936929,Comparison of ethionamide with isoniazid in original treatment cases of pulmonary tuberculosis. XIV. A report of the Veterans Administration--Armed Forces cooperative study,,1
8424,5939019,Tetracycline toxicity. A clinicopathologic study with special reference to liver damage and its relationship to pregnancy,,1
8425,5947216,[Liver damage caused by carbamazepine],,1
8426,5950894,Nine years' experience with tolbutamide in the treatment of diabetes,,1
8427,5953369,Suggestive evidence of hepatotoxicity concomitant with thioridazine hydrochloride use,,1
8428,5963841,[Physiopathology of icterus caused by chlorpromazine],,1
8429,5978248,Subicterus following the administration of thioridazine and chlordiazepoxide,,1
8430,6007094,Isoniazid jaundice during the treatment of genitourinary tuberculosis,,1
8431,6018455,Postoperative massive liver necrosis. A clinical and pathological study,,1
8432,6022777,Fatal reaction to acetazolamide,,1
8433,6023693,Side-effects of indomethacin,,1
8434,6028103,Hepatocellular damage with ethacrynic acid,,1
8435,6029314,Case records of the Massachusetts General Hospital. Case 32-1967,,1
8436,6034795,Chelation therapy in acute iron poisoning,,1
8437,6037940,Agranulocytosis and jaundice associated with chlorpromazine,,1
8438,6046676,Sulfonamide hepatic injury. Review of the literature and report of a case due to sulfamethoxazole,,1
8439,6054829,Infective hepatitis and toxic jaundice in a municipal hospital during a five-year period. Incidence and prognosis,,1
8440,6059263,Budd-Chiari syndrome after taking oral contraceptives,,1
8441,6065567,Evaluation of hepatic function during long-term Chlorpropamide therapy,,1
8442,6071455,Toxicity of indomethacin. Report of a case of acute pancreatitis,,1
8443,6071832,Chronic hypervitaminosis A in an adult,,1
8444,6072491,Meprobamate overdosage. Evaluation of its severity and methods of treatment,,1
8445,6087460,Hepatic tumors induced by sex steroids,"Our study of more than 250 women with hepatic tumors, accessioned in our tumor registry at the University of Louisville, disclosed three types of tumor: FNH , HCA, and HCC. The ingestion of sundry kinds of sex steroids by the majority of these women, chiefly for purposes of preventing conception, warrants the suspicion that such hormones induced these different types of hepatic tumors. Publications by others reporting similar hepatic tumors in men using male sex steroids lends support to this hypothesis. Rupture of the hepatic tumor and consequent hemorrhage, producing hemoperitoneum, is a major risk factor. Other presenting symptoms are pain and palpable mass. Symptomatic women using OCs should be subjected to a CT or technetium hepatic scan as an initial screening assessment. Because of the imminent possibility of rupture, large turgid vascular tumors should be resected without biopsy. Biopsy-proved HCC should also be removed surgically. All other tumors, including small multiple tumors, will usually regress when exogenous sex steroids are withdrawn and pregnancy avoided. Other significant hepatic changes observed in this study are peliosis hepatis, periportal sinusoidal dilation, and vascular lesions. The branches of the hepatic artery and the tributaries of the portal vein show combinations of intimal and smooth muscle proliferation, vascular thickening, occlusive intimal thickening, and, at times, obstructing thrombosis. Similar smooth muscle proliferation in the afferent vessels of the livers of animals treated with sex steroids suggests that there is a cause and effect relationship in women using OCs.",1
8446,6090021,Clinical evaluation of ceftriaxone,"Seventy-seven patients with acute bacterial infections were treated with ceftriaxone (1 gm administered intravenously every 12 hours). The 58 patients evaluable for efficacy had 60 infections, including 39 of the respiratory tract, 14 of the urinary tract, and seven of soft tissue. Five patients were bacteremic. The mean duration of ceftriaxone treatment was eight days for patients with respiratory and urinary tract infections and 13 days for patients with other types of infections. A satisfactory clinical response occurred in 56 (93%) of the infections. Eighty-four (94%) of the 89 pretherapy pathogens were bacteriologically eradicated. Included were all 19 isolates of Haemophilus influenzae, all 15 of Streptococcus pneumoniae, all 12 of Escherichia coli, 22 of the 23 isolates of other Enterobacteriaceae species, three of five isolates of Pseudomonas aeruginosa, and three of four isolates of Staphylococcus aureus. Two cases of superinfection (one with bacteremia) occurred with P aeruginosa. There were two cases each of reinfection and colonization with Streptococcus faecalis. One patient developed manifestations of culture-documented S pneumoniae meningitis eight hours after the first dose was administered. Peak and trough plasma levels of ceftriaxone were 142 and 64 micrograms/ml. Ceftriaxone achieved therapeutic levels in infected cerebrospinal fluid and in the abscess fluid of selected patients. Adverse effects, which were mild, included diarrhea in 4% of the patients and elevated transaminase levels in 10%.",1
8447,6093526,Clinical adverse effects during ceftriaxone therapy,"""The clinical safety of ceftriaxone administered at various doses for time periods ranging from a single injection to up to six weeks was evaluated in 2,640 patients treated in 153 individual studies. The incidence of clinical adverse effects was greatest for gastrointestinal (3.45 percent), hypersensitivity (2.99 percent), and local (1.86 percent) reactions. When the pediatric population was analyzed separately, the incidence of gastrointestinal and hypersensitivity reactions was 5.63 and 3.3 percent, respectively; all other reactions occurred in fewer than 1 percent of patients. The frequency of adverse effects for the once-daily and twice-daily dosing regimens was comparable, except for a statistically significant increase in local reactions when ceftriaxone was administered twice daily. When ceftriaxone was compared directly with other antibiotic regimens, the incidence of clinical adverse effects was similar. Ceftriaxone appears to be safe and well tolerated from a clinical standpoint.""",1
8448,6094851,Hepatic angiosarcoma and bronchioloalveolar carcinoma induced by Fowler's solution,,1
8449,6097111,Cholesteryl ester storage disease and Wolman disease: phenotypic variants of lysosomal acid cholesteryl ester hydrolase deficiency,"The lysosomal enzyme responsible for cholesteryl ester hydrolysis, acid cholesteryl ester hydrolase, or acid lipase (E.C.3.1.1.13) plays an important role in cellular cholesterol metabolism. Loss of the activity of this enzyme in tissues of individuals with both Wolman disease and cholesteryl ester storage disease is believed to play a causal role in these conditions. The objectives of our studies were not only to directly compare and contrast the clinical features of Wolman disease and cholesteryl ester storage disease but also to determine the reasons(s) for the varied phenotype expression of acid cholesteryl ester hydrolase deficiency. Although both diseases manifest a type II hyperlipoproteinemic phenotype and hepatomegaly secondary to lipid accumulation, a more malignant clinical course with more significant hepatic and adrenal manifestations was observed in the patient with Wolman disease. However, the acid cholesteryl ester hydrolase activity in cultured fibroblasts in both diseases was virtually absent. In addition, fibroblasts from both Wolman disease and cholesteryl ester storage disease were able to utilize exogenously supplied enzyme, suggesting that neither disease was due to defective enzyme delivery by the mannose-6-phosphate receptor pathway. Coculture and cell fusion of fibroblasts from Wolman disease and cholesteryl ester storage disease subjects did not lead to correction of the enzyme deficiency, indicating that these disorders are allelic. However, the activities of the hepatic acid and neutral lipase in these two clinical variants were quite different. Hepatic acid lipase activity was only 4% normal in Wolman disease, but the activity was 23% normal in cholesteryl ester storage disease. The hepatic neutral lipase activity was normal in Wolman disease but increased more than twofold in cholesteryl ester storage disease. These combined results indicate that the clinical heterogeneity in acid cholesteryl ester hydrolase deficiency can be explained by a varied hepatic metabolic response to an allelic mutation.",1
8450,6098506,"[Regenerative nodular hyperplasia, hepatocellular carcinoma and oral contraceptives]",,1
8451,6101735,Oral-contraceptive-associated liver tumours: occurrence of malignancy and difficulties in diagnosis,"Seven of ten women with oral-contraceptive-associated liver tumours were found to have hepatocellular carcinoma. The diagnosis was often delayed, although hepatomegaly was always present on examination, and liver-function tests and erythrocyte sedimentation-rates were abnormal in most cases. Other investigations, including routine technetium liver scans and biopsy, were sometimes misleading. There were important differences in alpha-fetoprotein concentration, vascularity on angiography, and survival between liver tumours in pill users and non-users.",1
8452,6102641,Danazol and liver damage,,1
8453,6103924,The effects of phenobarbital and diphenylhydantoin on liver function and morphology,"Sixty-three children with seizure disorders receiving phenobarbital and/or diphenylhydantoin for more than 12 months had liver function tests evaluated. All 56 whose serum anticonvulsant concentrations were in the therapeutic range had elevations of their serum gamma glutamyl transpeptidase activity. Of the 11 who had elevated SGOT and SGPT concentrations initially, six had persistent transaminase abnormalities for more than 20 weeks. Liver tissue from these six patients revealed by light microscopy uniform swelling of the hepatocytes without cell necrosis, inflammation, fibrosis, or disturbance of hepatic architecture. Electron microscopy demonstrated proliferation of the smooth endoplasmic reticulum without other ultrastructural alterations. All six patients were maintained on the same dosages of PB and/or DPH, and their transaminase activities returned to normal within eight to 14 months. The clinical well being of these patients, the transient nature of their SGOT and SGPT elevations, and the absence of specific histopathology suggest that chronic treatment with PB and/or DPH does not result in hepatotoxicity but rather in enzyme induction. The data indicate that liver biopsies are not warranted in such children and that PB and DPH may be continued despite mild elevations of SGOT and SGPT, without concern for hepatic damage.",1
8454,6107120,"Nadolol, a once daily treatment for hypertension: multi-centre clinical evaluation",,1
8455,6107747,Toxic pyrrolizidine alkaloids in comfrey,,1
8456,6108201,[Transaminase increase: a largely unknown side-effect of heparin treatment (author's transl)],"GOT, GPT and some other enzyme levels were measured systematically in 46 patients receiving subcutaneous heparin treatment. The heparin dosage varied between 5,000 and 15,000 IU, given every eight hours. During heparinisation a rise in GPT (average maximal values 67.0 +/- 7.3 U/l on the eighth treatment day) occurred in 89% of patients, while a rise in GOT (mean maximal values 39.7 +/- 3.9 U/l on the fifth treatment day) occurred in 82%. On reaching maximal value, enzyme activity decreased to the initial value despite continuing heparin treatment. A certain dependence of the incidence and (or) extent of the transaminase increase on heparin dosage was noted, especially comparing low-dose and full heparinisation. An increase in gamma-GT during subcutaneous heparinisation occurred in 37% of patients, while there was no significant change in alkaline phosphatase and lactate dehydrogenase.",1
8457,6110100,Margosa oil poisoning as a cause of Reye's syndrome,"Vomiting, drowsiness, metabolic acidosis, polymorphonuclear leucocytosis, and encephalopathy developed in thirteen infants within hours of ingestion of margosa oil. Liver biopsy of one infant and necropsy examination of ICR strain mice after experimentally induced margosa-oil poisoning demonstrated pronounced fatty infiltration of the liver and proximal renal tubules as well as cerebral oedema. Electron microscopy demonstrated mitochondrial damage. These findings indicate that margosa oil may be involved in the aetiology of Reye's syndrome among Indians in Malaysia.",1
8458,6112544,"Obstructive jaundice, pancytophenia and hydralazine",,1
8459,6115316,Nadolol: a new beta-adrenoceptor antagonist,,1
8460,6116111,Hyperbilirubinaemia and cyclosporin A levels in renal transplant patients,,1
8461,6117575,The efficacy and safety of nabilone (a synthetic cannabinoid) in the treatment of anxiety,"""The anxiolytic properties of nabilone, a synthetic cannabinoid resembling the natural cannabinoids, were studied in 25 outpatients suffering from anxiety. The drug was compared with a placebo in a double-blind manner over a 28-day treatment period. Patients were seen weekly by the physician and were rated by the Hamilton Rating Scale for Anxiety and the Patient's Global Evaluation as well as by patient-rated evaluations. The results of the study showed a dramatic improvement in anxiety in the nabilone group when compared with placebo (P less than 0.001). Side effects reported were dry mouth, dry eyes, and drowsiness. Patients did not report any of the subjective """"altered state"""" experience of marihuana.""",1
8462,6118798,Hyperbilirubinaemia and cyclosporin A levels,,1
8463,6119776,Ranitidine: a pilot study in Japan,"Twenty-four patients with gastric ulcer and 18 with duodenal ulcer diagnosed by endoscopy were treated with ranitidine, 300 mg day-1, for 8 consecutive weeks, or until the ulcer was found endoscopically healed. Of the 24 with gastric ulcer, 50% were healed within 4 weeks, and 83% within 8 weeks. Of 18 cases with duodenal ulcer, 50% were healed within 2 weeks and 94% within 4 weeks. Therapeutic effect of ranitidine was statistically significant compared with placebo. Side effects due to ranitidine administration were few and consisted of a rash in one case and slight increase of transaminase in a few patients.",1
8464,6122089,Ketoconazole and the liver,,1
8465,6123306,Combined hepatotoxicity and neurotoxicity following sulphasalazine administration,"Two cases of hepatotoxicity following sulphasalazine administration are reported. Each patient became ill after her initial exposure to sulphasalazine and after being re-exposed to the drug. In both instances there was an interval of three weeks between receiving the drug for the first time and the onset of the toxic reaction. In the first patient, hepatotoxicity occurred after initial exposure and following the second course of sulphasalazine. Mild neurotoxicity was seen following second exposure to sulphasalazine. In the second patient, hepatotoxicity occurred following the initial exposure to sulphasalazine but after reexposure the only abnormality in liver function tests present was a slight rise in the serum level of gamma glutamyl transpeptidase. In this patient, life-threatening neurotoxicity occurred each time that the patient received sulphasalazine.",1
8466,6127497,Serious reactions during malaria prophylaxis with pyrimethamine-sulfadoxine,,1
8467,6128216,Ranitidine: a review of its pharmacology and therapeutic use in peptic ulcer disease and other allied diseases,"Ranitidine is a new histamine H2-receptor antagonist which, unlike cimetidine, does not contain an imidazole group. On a weight basis, ranitidine is 4 to 10 times more potent than cimetidine in inhibiting stimulated gastric acid secretion in humans. Therapeutic trials comparing ranitidine and cimetidine have demonstrated that ranitidine 150 mg twice daily is an effective alternative to cimetidine 1000 mg daily in 4 divided doses in increasing the rate of healing of duodenal and gastric ulcers over a period of 4 to 6 weeks. Ranitidine, given as a single 150 mg dose at night, decreases the incidence of ulcer recurrence. Preliminary studies in the Zollinger-Ellison syndrome and in patients intolerant of, or unresponsive to cimetidine, indicate that ranitidine controls the gastric hyperacidity and heals most ulcers, including those which failed to respond to months of treatment with cimetidine 1 to 1.6 g daily. Ranitidine, unlike cimetidine, has no antiandrogenic effects and does not alter hepatic metabolism of drugs. Ranitidine is well tolerated. Preliminary reports of the resolution of cimetidine-induced adverse effects following substitution of ranitidine, suggest that ranitidine may be of value in patients intolerant of cimetidine. However, wider clinical experience with ranitidine is needed to determine the clinical relevance of these reports.",1
8468,6129799,Hepatic reactions during ketoconazole treatment,"Silent and symptomatic hepatic reactions have occurred during ketoconazole treatment. The silent reactions (transient asymptomatic elevations of serum transaminase or alkaline phosphatase levels) may occur at any time during ketoconazole treatment. Asymptomatic increases in liver enzymes may also occur in a sizeable number of patients with fungal disease without any treatment. Symptomatic hepatic reactions have occurred mainly during the first few months of treatment. The estimated incidence of symptomatic reactions is of the order of 1 in 10,000.",1
8469,6132132,Carbamazepine-induced non-hereditary acute porphyria,"Acute intermittent porphyria has hitherto been recognised as an autosomal dominant inborn error of haem metabolism characterised by a depressed activity of the enzyme uroporphyrinogen I synthase (URO.S). A case of non-hereditary acute porphyria, similar to acute intermittent porphyria, following treatment of epilepsy with carbamazepine is reported. Subsequent measurements of erythrocyte URO.S activity in a group of epileptic patients treated with various combinations of anticonvulsant drugs suggest that carbamazepine exerts a direct suppressant effect on URO.S in addition to its indirect enzyme-inducing properties.",1
8470,6134567,Sulphasalazine hepatotoxicity after 15 years' successful treatment for ulcerative colitis,,1
8471,6135690,"A placebo-controlled, double-blind comparison of clobazam and diazepam in the treatment of anxiety","""In a randomized, placebo-controlled, double-blind study, the efficacy and safety of clobazam and diazepam were compared in 114 anxious outpatients. During the 4-week double-blind phase of the study, the mean daily dose was 59 mg for clobazam and 25 mg for diazepam. Results indicate statistically significant efficacy, measured by both patient and physician rating scales, for both active drugs compared to placebo. The incidence of sedation was similar for the two active treatment groups; dizziness was more frequent in the diazepam group.""",1
8472,6136396,Sulfasalazine. Adverse effects and desensitization,,1
8473,6137258,Sulphasalazine hepatotoxicity after 15 years' treatment,,1
8474,6138013,The effects of valproic acid on liver function,"To study a possible enzyme-inducing potency of valproic acid (VPA) in children, serum gamma-glutamyltranspeptidase (GGT) activity in serum and D-glucaric acid (GLA) excretion in urine were measured in 32 epileptic children who were on sodium valproate monotherapy (29.6 +/- 10.3 mg/kg/day). VPA did not affect GGT activity, but it selectively enhanced GLA excretion. To approach this phenomenon experimentally an attempt was made to induce a similar effect in animals. In guinea pigs it was possible to provoke a VPA induced rise in GLA excretion. In addition, vacuolisation of the cytoplasm of the hepatic parenchymal cells was observed. The question of the possible relationship between VPA hepatotoxicity and stimulation of GLA excretion remains to be answered.",1
8475,6138592,Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial,"""In a multicentre trial conducted in eight European centres, 232 recipients of cadaveric renal allografts were randomly allocated to receive either cyclosporin (117 patients) or azathioprine and steroids (115 patients) for immunosuppression. All patients have now been followed up for at least a year. 1-year graft survival was 72% in the cyclosporin group and 52% in the control group. 24 of the 84 patients in the cyclosporin group with functioning grafts at 1 year had been changed to azathioprine and steroids, and 1 patient had had prednisolone added to cyclosporin therapy; the other 59 patients were receiving cyclosporin as their sole immunosuppressive agent. 16 patients on cyclosporin treatment never received steroids. 1-year patient survival was 94% in the cyclosporin group and 92% in the control group. There was no difference between the two treatment groups in the prevalence of infection. Lymphoma did not develop in any patient. At 1 year post-transplantation, renal function was poorer in patients on cyclosporin than in those on conventional therapy. Thus the 1-year graft-survival rate is higher with cyclosporin alone as a first-line immunosuppressive agent than with azathioprine and steroids.""",1
8476,6141674,[Ketoconazole-induced hepatitis. Case report],"Since Oct. 1981 a new systemic antifungal drug Ketoconazole is available in the Federal Republic of Germany that has proven effective even in severe cases with fungal infections. This case-study will call attention on a rare but important side effect, namely Ketoconazole induced hepatitis. As an acute icteric viral hepatitis, type Non-A-Non-B-hepatitis possibly misdiagnosed only a carefully compiled history of the recent intake of drugs points at the real cause of hepatitis. In our case-report we observed a considerable increase in serum enzymes, especially GOT, GPT and GLDH after a drug-challenge with two tablets. We recommend so-called liver functions tests 2 to 3 weeks after beginning of therapy and further-on in monthly intervals. Histologically at that time toxic hydropic changes of the liver cells and a mesenchymal reaction with portal and intralobular mainly eosinophilic infiltration could be established. The serum enzymes came to normal only after 12 weeks.",1
8477,6143933,Absence of cross-reactivity between captopril and enalapril,,1
8478,6144896,Isolation of Crimean-Congo haemorrhagic fever and Rift Valley fever viruses in Upper Volta,,1
8479,6145039,Omeprazole: no evidence for frequent hepatic reactions,,1
8480,6148170,Acute iron poisoning in children,"Acute accidental iron poisoning is a common serious and potentially fatal intoxication in the young child. Approximately 1 per cent of such poisoning have a fatal outcome, and outcome is closely related to the early onset of coma or shock. Long-term prognosis is excellent for all survivors of the acute episode, although there are occasional obstructive complications occurring four to six weeks later.",1
8481,6151783,"Nonicteric liver damage with a gamma-glutamyl transpeptidase level of 5,609 units/l in a renal-transplant recipient receiving azathioprine","""A 26-year-old male with renal allograft, who received immunosuppressive treatment with azathioprine, presented marked elevations of serum biliary tract enzymes, such as gamma-glutamyl transpeptidase (5,609 units/l) and alkaline phosphatase (60.5 Bessey-Lowry units), 14 months after transplantation. Two months later the patient became icteric; he died of respiratory failure 19 months after the renal allograft. Postmortem examination revealed intrahepatic cholestasis with minimal inflammatory cell infiltration, indicating drug hepatotoxicity.""",1
8482,6170307,Methotrexate accumulation and folate depletion in cells as a possible mechanism of chronic toxicity to the drug,"Methotrexate has been associated with chronic toxicities such as cirrhosis and neurological impairments ranging from mild learning disorders to a fatal leucoencephalopathy. The mechanism(s) for this toxicity is not completely understood. Certain tissues can convert methotrexate to polyglutamates. This results in a more persistent intracellular form of the drug. In this study the intracellular levels of folate and methotrexate were measured in the erythrocytes and liver of patients treated chronically with methotrexate. These tissues showed an accumulation of methotrexate as polyglutamates and a concomitant loss of folate. Folate concentrations were below normal in nine of 12 red cell and three of five liver samples. It is proposed that persistent methotrexate concentrations and/or the associated folate deficiency may be related to the toxicity of methotrexate, especially in time of cellular stress.",1
8483,6183902,Methotrexate in psoriasis with and without leucovorin: effect of different dosage schedules on acute liver toxicity,"Studies on thirty-six psoriatics revealed no differences in acute liver toxicity of four different intermittent dosage schedules of methotrexate with or without addition of leucovorin, as judged by daily determinations of SGOT for one week. Three patients with psoriatic erythroderma receiving high-dosage methotrexate (100 mg i.v.) with leucovorin rescue responded extremely well to treatment and did not distinguish themselves from the other patients with regard to acute liver toxicity.",1
8484,6185805,Hepatic and cerebral pathology findings in children with fatal salicylate intoxication: further evidence for a causal relation between salicylate and Reye's syndrome,Histology or necropsy records of 13 children with accidental or therapeutically induced salicylate intoxication were examined for the presence of hepatic and cerebral pathology findings characteristic of Reye's syndrome. Liver sections stained with haematoxylin and eosin showed intrahepatocytic microvesiculation (10 of 12 children) and absence of significant inflammation or necrosis (10 of 12 children). All 6 specimens of liver tissue stained with oil red O showed intrahepatocytic microvesicular fat with central hepatocytic nuclei distributed either diffusely throughout the lobule or more prominently in the lobular periphery. Liver tissue stained with the periodic-acid/Schiff method showed complete absence of stainable glycogen in 5 of 6 children. 9 of 12 children for whom information was available had cerebral oedema. It is concluded that the light-microscopy hepatic findings and the gross cerebral findings for the majority of these children with salicylate intoxication are the same as those for children with Reye's syndrome.,1
8485,6197014,Salicylate hepato toxicity in rheumatic fever,Two children with rheumatic fever developed anicteric hepatitis while on high-dose aspirin therapy. The striking chemical abnormality was an elevation of serum glutamic oxalacetic transaminase (SGOT) [aspartate aminotransferase (AST)]. A percutaneous liver biopsy obtained from one of the patients showed ultrastructural abnormalities consistent with a toxic hepatitis and hepatic congestion. An awareness of this potential complication is important when treating children with aspirin at doses previously considered to be non-toxic.,1
8486,6210671,Comparison of the efficacy and safety of mezlocillin and ticarcillin in the treatment of patients with serious systemic infections,,1
8487,6212004,Diphenylhydantoin-induced hepatitis,,1
8488,6215008,Piperacillin v Carbenicillin in the therapy for serious infections,"""One hundred seven patients were treated with either piperacillin (56) or carbenicillin (51) in an open randomized trial of hospitalized patients with pleuropulmonary (40), urinary tract (26), gynecologic (21), skin and soft-tissue (eight), joint (five), bone (three), and miscellaneous other infections (four). Patients with urinary tract infections were given 150 mg/kg/day of piperacillin sodium or 200 mg/kg/day or carbenicillin sodium in divided doses every six hours intravenously. Patients with other infections were given 250 mg/kg/day of piperacillin sodium and 450 mg/kg/day of carbenicillin sodium; 53/56 (95%) patients treated with piperacillin and 45/51 (88%) patients treated with carbenicillin were cured clinically. In general, the drugs were well tolerated. There were, however, more adverse experiences in the groups taking carbenicillin. Of special interest was the finding of liver function test abnormalities in 17/78 (21%) carbenicillin recipients (evaluative and nonevaluative cases). We concluded that piperacillin was effective and safe. It has potential for use in a great variety of infections.""",1
8489,6219616,Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981,"A retrospective chart review of 98 patients treated with 100 courses of intravenous vancomycin was undertaken to better define its toxicity. Most of the patients carried diagnoses of Staphylococcus aureus or Staphylococcus epidermidis infection. Auditory toxicity was not seen, and fever and rash occurred in only 1 to 3% of the subjects. Phlebitis was noted in 13% of the cases and required discontinuation of therapy in 2%. Therapy was complicated by neutropenia (polymorphonuclear leukocyte count, less than or equal to 1,000 cells per cm3) in 2% of the patients but was rapidly reversible. Nephrotoxicity was uncommon (5%) and reversible in subjects receiving vancomycin alone, even when the therapy was continued. However, 35% of the patients receiving vancomycin with an aminoglycoside developed significant elevations in serum creatinine. Although this high incidence may have been due to the patient population selected or to the aminoglycoside therapy alone, the possibility of additive toxicity between vancomycin and the aminoglycosides should be considered.",1
8490,6223674,High-dose cytosine arabinoside therapy for refractory leukemia,"""Fifty-seven patients with refractory acute leukemia were treated with high-dose cytosine arabinoside to establish the maximum tolerated dose and duration and to determine the antileukemic activity. The maximum tolerated regimen was found to be 3 g/sq m every 12 hr for 6 days. At this dose, nonhematologic toxicity was limited to conjunctivitis in approximately half of the patients, and liver toxicity (transient elevations in transaminase, alkaline phosphatase, or bilirubin) was frequently observed, but neither was dose-limiting. Extending the duration of treatment to 8 days resulted in excessive diarrhea and skin toxicity (painful erythema with bullae), while increasing the dose to 4.5 g/sq m q. 12 hr for 6 days resulted in severe cerebellar toxicity. Myelosuppression was severe, but was not related to the intensity of treatment; granulocyte recovery occurred a median of 28 days (range 22-40 days) after initiating therapy, and platelet recovery occurred after a median of 25 days (range 16-41 days). Antileukemic activity was evaluable in the 46 patients who survived at least 3 wk. Complete remissions were obtained in 1 of 6 patients with chronic myelogenous leukemia (CML) in accelerated phase and 1 of 3 acute lymphoblastic leukemia (ALL) patients. A more detailed analysis of response was possible for the 37 evaluable patients with acute nonlymphoblastic leukemia: 70% of these patients responded, with 51% complete remissions. The median unmaintained response was 4 mo (range 2-26+ mo). The complete response rate was higher in patients who received at least 12 doses of high-dose cytosine arabinoside compared to shorter regimens [17/28 (61%) versus 2/9 (22%), p less than 0.05]. Resistance to cytosine arabinoside in conventional doses was documented in 11 patients, 5 of whom responded (2 complete remissions) to high-dose regimens. We conclude that high-dose cytosine arabinoside in the maximally tolerated regimen of 3 g/sq m every 12 hr for 6 days has substantial antileukemic activity in patients refractory to standard therapy. Durable unmaintained remissions can be achieved, even in patients who fail to respond to cytosine arabinoside in conventional doses.""",1
8491,6224935,"Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac therapy","We report 2 patients who had serious adverse effects after taking sulindac. One of these patients developed toxic hepatitis and Stevens-Johnson/toxic epidermal necrolysis syndrome which resulted in death. Such fatal reaction to sulindac therapy has not been reported previously. There was temporal relation of ingestion of sulindac to 2 episodes of acute pancreatitis in the 2nd patient, strongly suggesting drug induction. Recent reports of similar side effects with other nonsteroidal antiinflammatory drugs suggest that these drugs may have potentially more serious toxicity than has been recognized.",1
8492,6225634,"Carbamazepine-induced thrombocytopenia, rash, and hepatic dysfunction","Carbamazepine is an anticonvulsant agent that has been found clinically useful in the treatment of refractory seizure disorders. Its mechanism of action is not well understood. The drug also has been associated with several serious side-effects. These include bone marrow suppression, liver and renal dysfunction, water intoxication, and ocular lens opacities. A 33-year-old white female developed elevated liver enzymes, a rash, and thrombocytopenia following the short-term use of carbamazepine for temporal lobe seizures. All of these findings are consistent with literature reports. Other etiologic factors also are discussed. This case is presented to illustrate the importance of monitoring blood counts and liver function tests when carbamazepine is part of a particular treatment regimen. Clinicians must be aware that a variety of hematological disorders can occur with this drug. Liver dysfunction is usually first noted, with an elevation of liver function tests. When thrombocytopenia is noted, prompt withdrawal of the drug is required. The platelet count should return to normal within a few days.",1
8493,6226335,Possible hepatotoxicity of zimelidine,,1
8494,6230976,Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome,"""We reviewed the charts of 38 patients with the acquired immunodeficiency syndrome who were treated for Pneumocystis carinii pneumonia. Only 5 of 37 patients started on trimethoprim-sulfamethoxazole were able to complete treatment; in 29 patients drug toxicity occurred and in 19 treatment was changed due to adverse reactions that included rash, fever, neutropenia, thrombocytopenia, and transaminase elevation. Pentamidine was given to 30 patients (1 as initial treatment); toxicity occurred in 13 but only 4 required a change in drug. Adverse reactions from pentamidine included fever, rash, neutropenia, transaminase elevation, azotemia, and hypoglycemia. Patients received trimethoprim-sulfamethoxazole a median of 9.5 days, and pentamidine, a median of 12.5 days. Toxicity from trimethoprim-sulfamethoxazole appeared earlier than toxicity associated with pentamidine (7.5 versus 9.5 days of treatment). In patients with the acquired immunodeficiency syndrome, trimethoprim-sulfamethoxazole has a higher incidence of adverse reactions than pentamidine (p less than 0.005).""",1
8495,6233335,Isotretinoin therapy for acne: results of a multicenter dose-response study,"One hundred fifty patients with treatment-resistant nodulocystic acne were entered into a double-blind clinical study. Three different dosing levels (0.1, 0.5, 1.0 mg/kg/day) were used in equal-sized groups. In addition to the clinical response, the clinical side effects, the laboratory abnormalities, and the duration of the induced remissions were evaluated with each dose of the drug. There was a highly significant clinical response to treatment with all three dosages of isotretinoin. There was no significant difference in the clinical response between dosages. However, 42% of the patients who received 0.1 mg/kg/day of isotretinoin required retreatment with the drug. This finding, coupled with only minor differences in the clinical side effects and the laboratory abnormalities, indicates that higher dose levels of isotretinoin are indicated for treatment of nodulocystic acne.",1
8496,6235745,Safety profile: fifteen years of clinical experience with ibuprofen,"Since its introduction in the United States in 1974, ibuprofen (Motrin, Upjohn) has been shown to be safe and effective for the treatment of pain, dysmenorrhea, inflammation, and fever. A careful review of pre-registration and postmarketing data from both patients and normal subjects clearly indicates ibuprofen's remarkable safety profile compared with that of aspirin and other commonly prescribed nonsteroidal anti-inflammatory agents. Continued safety can be anticipated on the basis of the past 15 years of review experience.",1
8497,6236451,[Diclofenac hepatitis. A case],,1
8498,6238672,Hepatic toxicity of low doses of mithramycin in hypercalcemia,"The medical records of patients receiving mithramycin for the treatment of hypercalcemia at The Johns Hopkins Oncology Center were reviewed. Of 67 evaluable patients, 11 (16%) developed hepatic toxicity when graded using standard criteria. The pattern of laboratory abnormalities noted suggested mild hepatocellular damage that was reversible within 2 weeks. Review of these patients did not identify factors which predispose to hepatic toxicity, although failure to do so may reflect the limited number of toxic patients evaluated. Mild, reversible hepatic dysfunction appears to be a more common sequela of mithramycin administration than has previously been recognized.",1
8499,6245986,Copper and the liver,,1
8500,6252466,Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma,"To evaluate the treatment of advanced islet-cell carcinoma, we randomly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil. Each regimen was given in five-day courses. The most frequent toxic effects were nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression with the combination regimen. The combination had advantages over streptozocin alone in overall rate of response (63 vs. 36 per cent) and in rates of complete response (33 vs. 12 per cent). There was no evidence of a preferential response among types of functional tumors. Objective responses were generally of long duration (median, 17 months) and of substantive clinical benefit. Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone (medians, 26 and 16 1/2 months), but this difference is not statistically significant. In spite of gastrointestinal side effects, streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma.",1
8501,6256879,[Neurological and hepatic complications in chrysotherapy (author's transl)],"The authors report the case of two neurologic complications and one hepatic complication gold salt induced. They study the prevalence, the clinical features, biological data and mechanisms of these complications.",1
8502,6259092,[Liver cell carcinoma following juvenile acute lymphoblastic leukemia. Case contribution],"""The case history of a boy suffering from acute lymphoblastic leukemia (ALL) and carcinoma of the liver as secondary malignoma is reported. After completion of the combined ALL-therapy, a splenogenous thrombocytopenia emerged which was successfully treated by splenectomy. In the biopsy material liver cirrhosis and HBsAg-positive hepatitis could be detected; these proved to be progressive in the course of the following year. At the end of another year, a hepatocellular carcinoma was diagnosed, causing the patient's death, who was still in complete hematological remission 5 7/12 years after the onset and 2 9/12 years after the end of the ALL-therapy. Only two cases of hepatocellular carcinoma following ALL in childhood have been described in the literature so far.""",1
8503,6269238,Cyclosporin A and steroid therapy in sixty-six cadaver kidney recipients,"From nine to 18 months ago, 66 patients were given 67 randomly matched cadaveric kidneys with cyclosporin A and steroid therapy. Nine of the recipients were undergoing retransplantation. The over-all kidney survival rate to date has been 77.6 per cent, and 78.8 per cent of the recipients are dialysis-free. The patient mortality in this learning phase was 13.3 per cent. Nephrotoxicity, hepatotoxicity and other side-effects of cyclosporin A could usually be dealt with by dosage adjustments, making feasible the chronic use of this agent. One B-cell immunoblastic sarcoma was encountered which was monoclonal. It was not responsible for death. Another patient had a perforation of the intestine from a lympho-proliferative reaction in which the B cells were polyclonal. After jejunal resection a year ago, there were no further complications. This lesion was not classified as a lymphoma. Both lympho-proliferative lesions were associated with a rise in antibody to viral capsid antigen of Epstein-Barr virus. Results of this study have verified the effectiveness and relative safety of cyclosporin A with steroids for immunosuppression in human recipients of cadaveric kidneys.",1
8504,6271328,Toxic hepatis during ketoconazole treatment,,1
8505,6271517,Complete regression of hepatocellular adenoma after withdrawal of oral contraceptives,"A 28-year-old woman who complained of mild abdominal pain was found to have a large liver tumor. Angiography and needle biopsy established the diagnosis of hepatocellular adenoma. The tumor was felt to be unresectable because of its size, and no treatment was given other than withdrawal of oral contraceptives. Subsequent hepatic scintiscans documented compete resolution of the tumor over a 12-month period.",1
8506,6274509,Oral contraceptives and hepatocellular carcinoma,"A 23-year-old woman was seen with an acute hemoperitoneum caused by rupture of a hepatocellular carcinoma. She died two years after hepatic artery ligation. The patient had been taking oral contraceptives for periods of one year and ten months, separated by a pregnancy. The association between oral contraceptive steroids and hepatocellular carcinoma is briefly reviewed.",1
8507,6275283,Androgen-associated hepatoma in a hemodialysis patient,"A patient on hemodialysis treatment developed hepatocellular carcinoma (HCC) after long-term therapy with androgenic anabolic steroids. The tumor progressed very rapidly, and there was no evidence of regression despite discontinuation of the drug. In view of the evidence of an increased of malignancy in patients with chronic uremia and hemodialysis, and of the higher frequency of HCC correlated to treatment with C17-alkylated anabolic steroids, it is necessary to further evaluate the efficiency of this treatment in the aforementioned group of patients.",1
8508,6277724,Regression of liver cell adenoma. A follow-up study of three consecutive patients after discontinuation of oral contraceptive use,"Three consecutive young female patients with unresected liver cell adenoma and a history of contraceptive use of several years' duration were followed up over a period of 2-4.5 yr after withdrawal of hormonal medication. One patient presented multiple adenomas and in another, the adenoma was associated with a Budd-Chiari syndrome due to bilateral thrombotic hepatic vein occlusion. Complete regression of the adenomas was documented in all 3 patients by ultrasonography, liver radionuclide scan, laparoscopy, or computerized tomography. It is concluded that, in selected cases, conservative management after withdrawal of hormonal contraception may be a valid alternative to surgical therapy.",1
8509,6281318,Ketoconazole and the liver,,1
8510,6282377,"Adverse reactions to nitrofurantoin in the United Kingdom, Sweden, and Holland","A study was carried out comparing the reporting of adverse reactions to nitrofurantoin in Sweden, Holland, and the United Kingdom. The Swedish drug regulatory authorities receive more reports of adverse reactions to nitrofurantoin than to any other drug, and the annual reporting rate is increasing despite a steady fall in the prescription of nitrofurantoin. In the United Kingdom the total number of adverse reaction to nitrofurantoin reported to the Committee on Safety of Medicines has been steadily falling for many years, as has the number of prescription. Lung reactions and liver damage are more commonly reported in Sweden than in the UK, where gastrointestinal symptoms and peripheral neuropathy are more common. Such figures as were available in Holland showed an intermediate picture. The incidences of blood dyscrasias and allergic reactions are similar in the three countries. The causes for such differences are unresolved, but it is disturbing that the incidence and range of adverse reactions to such a common drug as nitrofurantoin reported to the national authorities can differ so much in countries that have close ethnic, dietary, and economic similarities. Thus great caution must be observed when data on adverse drug reactions from the country are extrapolated to another.",1
8511,6283980,Hepatic dysfunction and ketoconazole therapy,,1
8512,6284630,Hepatocellular carcinoma in women: probable lack of etiologic association with oral contraceptive steroids,"""To investigate the possibility of an association between oral contraceptive steroids (CS) and hepatocellular carcinoma (HCC), we reviewed 128 cases of HCC in women collected between 1953 and 1980. There were 48 cases under the age of 40, and 13 of these (27%) had used CS. However, 62% of HCC associated with CS and 58% of HCC in women under 40 not using CS were classified histologically as """"fibrolamellar"""" carcinoma. This subtype of HCC occurs predominantly in young people, both male and female. The apparent increase in HCC in young women can be explained by the presence of cases of fibrolamellar carcinoma in this age group, an the apparent association with CS is probably coincidental.""",1
8513,6287413,[Hepatocellular carcinoma in an African after 10 years of treatment of Waldenstrom's disease with chlorambucil],,1
8514,6289734,Ceftriaxone: in vitro studies and clinical evaluation,"The in vitro activity of ceftriaxone against 437 clinical isolates of gram-negative bacilli was determined. Ceftriaxone was found to have high in vitro activity against Enterobacteriaceae, with the exception of Enterobacter cloacae. Ceftriaxone was only minimally active against Pseudomonas aeruginosa and Acinetobacter calcoaceticus. We evaluated the clinical efficacy and toxicity of ceftriaxone in 55 adult patients. Bacterial infection was confirmed by the isolation of etiological bacteria in 30 patients. Infectious disorders treated included 10 pneumonias, 13 urinary tract infections, and 7 soft tissue or bone infections. Pathogens identified were 25 isolates of gram-negative bacilli, 5 isolates of Staphylococcus aureus, 5 isolates of pneumococci, and 4 isolates of other streptococci. The overall efficacy of ceftriaxone was excellent. The clinical cure rate was 93%, and the bacteriological cure rate was 93%. A total of 30 adverse reactions were noted in 22 of 55 patients receiving ceftriaxone, but only one necessitated discontinuation of treatment. Adverse effects frequently noted were elevated hepatic enzymes (16%), thrombocytosis (16%), and eosinophilia (8%). Ceftriaxone is an effective and well-tolerated antimicrobial agent that appears promising for the treatment of serious gram-negative bacillary infections.",1
8515,6291807,Side effects of long-term amiodarone therapy,,1
8516,6296542,Hepatomas in young women on oral contraceptives: report of two cases and review of the literature,"""Hepatocellular carcinoma (HCC) developed in two women who had ingested oral contraceptives for prolonged duration. One of the patients had hepatoma restricted to the liver, and it was successfully resected. The other patient presented with metastatic HCC to the sacrum and lung, and she died after an initial response to chemotherapy in 12 months. Review of literature showed 23 previously reported cases of HCC associated with """"pill"""" use since 1973. Although the reported instances of HCC in pill users are few in number, the majority of affected females were in their 20s and early 30s, without any preexisting liver disease. Even though the risk of developing HCC on oral contraceptives is low, this association adds to the list of complications induced by oral contraceptives in premenopausal women. Two cases are reported and literature reviewed.""",1
8517,6299502,Androgen related primary hepatic tumors in non-Fanconi patients,Three cases of androgen related primary hepatic tumor in non-Fanconi patients are described in whom detailed information is available concerning histologic changes and clinical course over long periods. Two patients presented with hepatic rupture and hemoperitoneum requiring surgical intervention. In one case histologic assessment showed a hepatic adenoma which has almost completely regressed over four years since androgen withdrawal. In two patients there was a degree of nuclear pleomorphism not seen in 'spontaneous' adenomas and following androgen withdrawal there has been no evidence of progression or of metastases although the tumor has not regressed over a follow-up period of two years.,1
8518,6304923,Ketoconazole and hepatic reactions,,1
8519,6307616,Hepatitis induced by drugs used as alcohol aversion therapy,"We report here on the hepatic lesions produced in 17 alcoholic patients who had received Cyanamide or Disulfiram as aversion therapy. The characteristic lesion consists of cytoplasmic inclusions, similar to Lafora bodies. They are found predominantly in periportal hepatocytes, including those lining the cholangioles. They appear to be persistent but are lost after death of the inclusion-bearing liver-cell when both the inclusion body and the dead hepatocyte are removed by macrophages. As well as the inclusion bodies, portal or periportal inflammation and necrosis of isolated liver-cells are seen. The inflammatory infiltrate is usually denser in the periportal areas and is associated with liver-cell destruction. The inflammation is usually followed by portal fibrosis which can be severe if treatment is prolonged. In one case, in which two biopsies were performed, cirrhosis developed while that patient was on Cyanamide.",1
8520,6308447,Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome,"""We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption. Four were severely disabled; all improved after withdrawal. Weakness was not a feature of this condition, and the central nervous system was clinically spared. Although consumption of large doses of pyridoxine has gained wide public acceptance, this report indicates that it can cause sensory neuropathy or neuronopathy syndromes and that safe guidelines should be established for the use of this widely abused vitamin.""",1
8521,6311129,Successful ketoconazole treatment of protothecosis with ketoconazole-associated hepatotoxicity,"A 46-year-old woman had a chronic, unresponsive wrist infection that was proved to be due to the algaelike organism Prototheca wickerhamii. Treatment with ketoconazole resulted in prompt improvement and ultimate healing. Therapy was complicated by hepatitis that was ketoconazole-related. Ketoconazole may be effective and easily administered therapy for this generally unresponsive infection.",1
8522,6315228,Etoposide-induced hepatic injury: a potential complication of high-dose therapy,"Two cases of toxic hepatitis developing in patients receiving high-dose etoposide (VP-16-213) for refractory germinal neoplasms are described. Each patient received a total cumulative dose of at least 6800 mg/m2. Liver function abnormalities, including hyperbilirubinemia, elevated transaminases, and elevated alkaline phosphatase, became clinically apparent approximately 3 weeks following the last dose of VP-16-213. These abnormalities resolved spontaneously without sequelae over 12 weeks. High-dose VP-16-213 may be associated with hepatic injury.",1
8523,6318466,[Side effects of ketoconazole],"""Ketoconazole, a new orally active broad-spectrum antimycotic, is usually well tolerated. Liver changes have been observed with an incidence rate below 1:10 000; they are idiosyncratic reactions independent from duration of treatment or dosage. Ketoconazole given in a dosage of 400 mg daily or more may inhibit testosterone biosynthesis.""",1
8524,6319220,Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases,"Ketoconazole has only recently been recognized as a cause of hepatic injury, with most reports coming from outside the United States. In order to characterize more fully the U.S. experience, we undertook an analysis of 54 reports of alleged ketoconazole-induced liver injury submitted to the Food and Drug Administration from the time of initial marketing in 1980. Thirty-three reports were considered likely instances of ketoconazole-induced hepatitis. The majority of these cases occurred in women more than 40 yr of age. Jaundice was recorded in 27 individuals after therapy of 11-168 days with an average daily dose of 200 mg. Anorexia, malaise, nausea, and vomiting accompanied liver injury in one-third of cases. No instances of rash or eosinophilia were recorded. Serum transaminase and alkaline phosphatase values were consistent with acute hepatocellular injury in 18 patients, with primarily cholestatic injury in 5 patients, and with a mixed pattern in 9 individuals. Only one death seemed attributable to ketoconazole. In that patient, the drug was continued after the appearance of clinical and biochemical evidence of hepatic injury and massive hepatocellular necrosis was present at autopsy. The incidence of symptomatic, potentially serious hepatic injury appears to be very low, perhaps 1 in 15,000 exposed individuals. The presumed mechanism of injury is metabolic idiosyncrasy, although hypersensitivity has not been completely dismissed in some cases reported in the literature. The incidence of mild, asymptomatic, reversible elevations in serum transaminases occurring in ketoconazole recipients has been estimated to be 5%-10%. Periodic biochemical testing and monitoring for symptoms of hepatitis during ketoconazole therapy is recommended to help prevent the development of serious or fatal hepatic injury.",1
8525,6320760,Benign hepatocellular tumors in the young. A clinicopathologic spectrum,"""Hepatic tumors unassociated with cirrhosis were encountered in seven patients aged 10 to 19 years. Four patients had received androgens for aplastic anemia. Two patients had transfusional hemosiderosis. One patient had had a renal transplant 2 1/2 years ago. Two patients are alive at 2 3/4 and 2 1/2 years after surgical resections. Nodules were found at autopsy in the others. The tumors were well differentiated and, in the androgen-related cases, differed from the others in the following features: canalicular bile retention, mild nuclear atypia, and acinar formation. No mitoses, vascular invasion, or metastatic tumor were evident. The clinical setting was variable; different factors, including iron overload and androgen therapy, played a role in the development of tumor. Although the androgen-related cases showed mild cellular atypia, biologic evidence of malignancy was lacking as in most previous reports.""",1
8526,6321289,[Hepatitis during treatment with ketoconazole],,1
8527,6322251,[Hepatic adenomas and oral contraceptives],,1
8528,6325285,[Adenoma of the liver in man],"""The authors report the case of a 28-year-old man with a solitary adenoma of the liver. The tumor was detected because of a raised erythrocyte sedimentation rate and serum fibrinogen. Review of the literature shows that adenoma of the liver is an uncommon tumor in man since only 30 other cases have been reported. The tumor is often multiple (55 p. 100) and the clinical manifestations are quite different from those observed in women: the adenoma is often asymptomatic (45 p. 100) and rupture is rare (10 p. 100). Androgens seem to be implicated in the development of adenoma in man since 8 out of 31 patients had received androgens for a long period of time; androgens also seem to favor the tumor's rupture.""",1
8529,6327784,Systemic ketoconazole in tinea versicolor: a double-blind evaluation and 1-year follow-up,"A 4-week, double-blind comparison of ketoconazole and placebo was conducted in sixty-six patients with tinea versicolor. Two hundred milligrams of ketoconazole in a daily oral dose was effective in producing a clinical and mycologic cure: lesions in thirty-three of thirty-four patients on active drug were completely healed (97%), and one patient had a mild residual effect. Only three patients on placebo were considered to have responded, and none experienced complete healing. Potassium hydroxide (KOH) examinations were negative in all but one of the patients given ketoconazole. All patients receiving ketoconazole who were KOH-negative at week 4 also showed negative results when reexamined 8 weeks later. Patients who did not respond (virtually all of the patients given placebo) were subsequently treated with a topical imidazole lotion. Safety evaluation, including blood chemistry tests and a comprehensive liver function battery, showed no differences between the ketoconazole and placebo groups. Ketoconazole was well tolerated and produced no significant adverse effects. Follow-up after 1 year revealed that 64% of patients given ketoconazole were still clear, whereas only 11% of patients who received placebo (later treated with imidazole topically) were clear after 1 year.",1
8530,6328973,Long-term survival after resection of a hepatocellular carcinoma with lymph node metastasis and discontinuation of oral contraceptives,"The occurrence of a hepatocellular carcinoma is described in a young woman who had been taking oral contraceptives for 2 1/2 years. She was treated by wedge excision of the tumor. At the time of operation, lymph node metastasis was present. After the operation oral contraceptives were discontinued. No evidence of residual or recurrent tumor could be demonstrated during a follow-up period of 6 years. This is the first report on long-term survival after nonradical resection of metastasized hepatocellular carcinoma associated with the use of birth control pills.",1
8531,6331241,Possible ranitidine hepatotoxicity,,1
8532,6332892,Immunologic aspects of phenobarbital hypersensitivity,"Seven patients with hypersensitivity reactions to phenobarbital are described. Clinical manifestations consisted of fever and pruritic skin rash, often associated with adenopathy and conjunctivitis. Reexposure to phenobarbital or other anticonvulsants resulted in redevelopment of symptoms. In vitro lymphocyte stimulation studies with anticonvulsant drugs suggested a cell-mediated hypersensitivity reaction to phenobarbital.",1
8533,6334376,[Acebutolol and a lupus syndrome. Apropos of a case],,1
8534,6334741,D-Penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR3,"""Sulphoxidation of carbocysteine, a drug structurally similar to D-penicillamine, displays a skewed distribution within a population. In 66 patients with rheumatoid arthritis (RA) a significant association between impaired sulphoxidation and toxicity (p less than 0.001) was found; HLA-DR3, although associated with toxicity (p less than 0.05), appeared to be an independent risk factor of most importance in the group with extensive sulphoxidation. The relative risk of toxicity in a patient possessing either DR3 or impaired sulphoxidation was 25. The prevalence of poor sulphoxidizers within this group of RA patients was increased compared to that in a previous population study and requires further investigation. Our findings explain a number of the toxic phenomena associated with D-penicillamine administration in RA.""",1
8535,6338383,Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage,"We enrolled 125 neurologically normal patients with intracranial aneurysms in a multi-institution, prospective, double-blind, randomized, placebo-controlled trial within 96 hours of their subarachnoid hemorrhage, to determine whether treatment with the calcium blocker nimodipine would prevent or reduce the severity of ischemic neurologic deficits from arterial spasm. A deficit from cerebral arterial spasm that persisted and was severe or caused death by the end of the 21-day treatment period occurred in 8 of 60 patients given placebo and in 1 of 56 given nimodipine (P = 0.03, Fisher's exact test). Analysis of the amount of basal subarachnoid blood on pre-entry CAT scans in patients with deficits from spasm showed that an increase in subarachnoid blood was not associated with a worse neurologic outcome among patients who received nimodipine, unlike the situation in patients given a placebo. There were no side effects from nimodipine. We conclude that nimodipine should be given to patients who are neurologically normal after subarachnoid hemorrhage in order to reduce the occurrence of severe neurologic deficits due to cerebral arterial spasm.",1
8536,6339039,Kinetic analysis of hepatotoxicity associated with antineoplastic asparaginases,,1
8537,6340972,Fentiazac in rheumatoid arthritis: comparison with sulindac and long-term tolerance,"Forty patients with definite or classical rheumatoid arthritis were entered for 3 months in a double-blind trial, 20 patients on 400 mg fentiazac or 200 mg sulindac daily. Statistically significant improvements on fentiazac were reported during the course of the study for 3 of 7 parameters: pain score, total joint score and number of swollen joints, while for sulindac a significant improvement was reported for 6 parameters: pain score, grip strength, joint size, total joint score, number of swollen joints and erythrocyte sedimentation rate. Side-effects were reported during the 3-month comparative period for 3 patients receiving fentiazac, consisting of rash, headache, epigastric pain, and for 1 patient receiving sulindac who suffered from gastro-intestinal intolerance. Because of ineffectiveness and/or side-effects, the treatment had to be discontinued for 5 patients in the fentiazac group and for 3 in the sulindac treatment group. The results support earlier evidence that fentiazac and sulindac have analgesic and anti-inflammatory properties controlling disease activity in rheumatoid arthritis, sulindac being the more effective. During a long-term tolerance study, 3 of 33 patients continued on fentiazac developed a reversible hepatotoxicity possibly due to the drug.",1
8538,6342492,New data on preventive treatment with isoniazid,,1
8539,6347792,[Hepatitis caused by various derivatives of erythromycin],,1
8540,6348949,Low dose oral methotrexate in rheumatoid arthritis: an uncontrolled trial and review of the literature,"New therapeutic alternatives are needed for patients with progressive RA unresponsive to gold or D-penicillamine. Azathioprine and cyclophosphamide can be effective but have been linked with the development of lymphoreticular malignancies. In an effort to exploit a less toxic agent, we have been impressed by the results and minimal toxicity of low dose oral MTX. Extensive application of this regimen in psoriasis and psoriatic arthritis indicates that low dose MTX does not have an unusual risk for developing cancer. In addition, prior experience with other rheumatic disorders and preliminary studies on the mechanism of action suggest a potential value in RA. We present our initial retrospective results in 28 patients with refractory RA given low dose oral MTX over the past 2.5 yr. An apparent positive response was noted in 19 of these patients (67%) and is similar to the experience of other clinicians. At the same time, the toxicity has been low and, with one exception, amenable to dose modification. Methotrexate in various regimens is being increasingly employed in refractory RA. Issues concerning the pharmacology and potential toxicity are, therefore, important. These topics are reviewed with emphasis on low dose therapy and hepatotoxicity. Despite the encouraging preliminary results it is unclear whether MTX can prevent erosions or improve long-term function and quality of life in RA. There are still no controlled perspective studies comparing MTX to placebo or other immunosuppressive agents in RA. Although short-term toxicity is low, long-term toxicity, especially hepatic, is uncertain. As a result, a controlled, long-term prospective study is necessary.",1
8541,6350878,A randomized clinical trial of cyclosporine in cadaveric renal transplantation,"In a randomized multicenter trial, 209 recipients of cadaveric renal transplants were treated either with cyclosporine and prednisone or with standard therapy that included azathioprine and prednisone. Predicted graft survival at one year was 80.4 per cent in patients receiving cyclosporine and 64.0 per cent in those receiving standard therapy (P = 0.003). Predicted patient survival at one year was 96.6 per cent in patients given cyclosporine and 86.4 per cent in those given standard therapy. A detrimental effect on predicted graft survival at one year was seen in patients treated with cyclosporine if they received kidneys that were perfused by machine for longer than 24 hours (70 vs. 88 per cent, P = 0.005) or if the time used to perform the surgical anastomosis was longer than 45 minutes (60 vs. 89 per cent, P = 0.002). In the group receiving standard therapy, predicted graft survival was better in patients who had had five or more blood transfusions than in those who had had two to four transfusions (77 vs. 55 per cent, P = 0.05). Serum creatinine was 2.6 mg per deciliter in patients receiving cyclosporine 90 days after transplantation and 2.0 mg per deciliter in those receiving standard therapy (P = 0.03). Lymphoma developed in one patient receiving cyclosporine. We conclude that cyclosporine is preferable to azathioprine in preventing renal transplant rejection. Further studies will be required to determine the optimal regimen with this agent.",1
8542,6352169,"""Treatment of nickel dermatitis with Antabuse; a double blind study""","""A double blind, placebo-controlled treatment with Antabuse was carried out in 24 patients with hand eczema and nickel allergy. The amount of Antabuse given was gradually increased from 50 to 200 mg daily. The maximum dose was given for 6 weeks. During the treatment period, the dermatitis of 5 out of 11 patients in the group treated with Antabuse healed, compared with 2 out of 13 in the group receiving the placebo. A statistical analysis was made of changes observed during the study, through the parameters: scaling, frequency of flares, erythema, area involved and number of vesicles. Differences in results obtained with Antabuse and the placebo were statistically significant only for the parameters scaling and frequency of flares (p less than 0.05). The difference between the sums of parameters following the 2 forms of treatment was not statistically significant (p = 0.11). 2 patients treated with Antabuse showed signs of hepatic toxicity; 1 of them had toxic hepatitis. No other significant side effects were seen.""",1
8543,6354303,Antithymocyte globulin reacts with many normal human cell types,"Antithymocyte globulin (ATG) is frequently effective therapy for aplastic anemia. Its mechanism of action is often assumed to be upon a lymphocyte inhibitor of hematopoiesis. However, specificity for T lymphocytes would not be anticipated from consideration of the method of preparing ATG. In fact, using flow microfluorometry and fluorescence immunohistochemistry, we have found that ATG binds to virtually all circulating lymphocytes, granulocytes, and platelets, as well as to bone marrow cells. Extensive absorption of ATG with either granulocytes or lymphocytes does not eliminate reactivity with the opposite cells, indicating that ATG recognizes some distinct antigens on each cell type. Treatment of cells with ATG blocks the binding of monoclonal antibodies directed against either lymphocyte differentiation or histocompatibility antigens. ATG also binds to visceral tissues, including thymus and testis cell membranes and the nuclear and cytoplasmic components of tonsil, kidney, liver, breast, lung, and intestine. In vitro cytotoxicity of ATG was demonstrated for both T and non- T lymphocytes and platelets. Despite its name, ATG is not specific for a particular cell type, and it would be premature to conclude that its effect is mediated through a specific lymphocyte population.",1
8544,6354826,Comparative efficacy and side effects of ursodeoxycholic and chenodeoxycholic acids in dissolving gallstones. A double-blind controlled study,"In a double-blind controlled study of ursodeoxycholic acid (400 and 800 mg/day) and chenodeoxycholic acid (375 and 750 mg/day), in comparison with placebo, ursodeoxycholic acid was significantly more effective than chenodeoxycholic acid in dissolving gallstones after 12 mo of treatment. Although there continued to be better dissolution during ursodeoxycholic acid treatment (dissolution complete in 30% and partial in another 30% of the patients) than during chenodeoxycholic acid treatment (dissolution complete in 7% and partial in 40%) at 24 mo, this difference between the treatment groups was no longer statistically significant. The incidence of floating stones was significantly higher in the patients who dissolved their stones than in those who did not (p less than 0.001). The three failures of dissolution of floating stones during bile acid treatment were associated with chenodeoxycholic acid therapy--two of them with the 750-mg and the third with the 375-mg doses. Gallstone dissolution with ursodeoxycholic acid occurred in spite of a rise in biliary cholesterol saturation, which was consistent with a nonmicellar mechanism of cholelitholysis. Furthermore, more than threefold serum elevations of L-alanine aminotransferase were observed only during chenodeoxycholic acid therapy. They occurred in 2 patients treated with 375 and 750 mg/day, respectively. The enzyme levels normalized after discontinuation of chenodeoxycholic acid and have remained normal for 13 and 8 mo, respectively, after the institution of treatment with 800 mg/day of ursodeoxycholic acid. There was no correlation between the liver tests and biliary levels of lithocholic acid. Of all the symptoms studied, only constipation showed changes that approached statistical significance (p = 0.0681). There was a significant improvement of constipation in the combined chenodeoxycholic acid groups when they were compared with the combined ursodeoxycholic acid groups. The total bile acid pool expanded significantly in both the chenodeoxycholic acid and in the 800-mg ursodeoxycholic acid treatment groups. The marked increases of biliary ursodeoxycholic acid and chenodeoxycholic acid, respectively, indicated compliance with the treatment in all but 1 bile acid-treated patient. Neither serum triglycerides nor serum cholesterol showed significant changes in any of the treatment groups. The study shows that ursodeoxycholic acid dissolves gallstones faster and with fewer side effects than chenodeoxycholic acid. The results of the study are also consistent with the view that ursodeoxycholic acid is cholelitholytic at a lower dose than is chenodeoxycholic acid.",1
8545,6356901,Multicenter clinical evaluation of long-term efficacy and safety of labetalol in treatment of hypertension,"""The long-term efficacy and safety of labetalol, an antihypertensive agent with combined beta- and alpha-blocking activity, were evaluated alone (number = 193) and in combination with a diuretic (number = 144) in an open-label multicenter trial of 337 hypertensive patients aged 21 to 75 years, including initially 205 (61 percent) men and 219 (65 percent) Caucasians. There were 219 (65 percent) mild, 85 (25 percent) moderate, and 33 (10 percent) severe hypertensive patients. Labetalol (100 to 1,200 mg twice a day) alone or in combination with a diuretic reduced the mean standing blood pressure by 13/11 and 25/16 mm Hg to 135/88 and 130/91 mm Hg, respectively (p less than 0.01), and supine blood pressure by 6/7 and 18/13 mm Hg to 141/86 and 138/90 mm Hg (p less than 0.01), respectively. Blood pressure reductions observed at one month were maintained after one year; 206 (62 percent) patients had 10 mm Hg or greater reductions and 184 (56 percent) patients were maintained at diastolic blood pressures less than 90 mm Hg. Most frequently reported drug-related side effects included fatigue (14 percent), dizziness (12 percent), nausea (11 percent), nasal stuffiness (8 percent), headache (4 percent), and male sexual dysfunction (14 percent). Side effects were generally of mild to moderate intensity and often transient. In addition, in 27 (8 percent) patients reversible asymptomatic transaminase elevations to greater than twice normal developed at some time during the study. In 13 (4 percent) patients these alterations resolved during continued labetalol therapy, but in five (2 percent) patients these marked elevations led to discontinuation of the drug. A total of 32 (9.5 percent) patients were terminated prematurely due to side effects (most commonly genitourinary or gastrointestinal) possibly attributable to the drug. These findings indicate that labetalol with or without a diuretic is a potentially effective, safe, and relatively well-tolerated long-term antihypertensive therapy.""",1
8546,6361299,The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease,"The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point--definite CHD death and/or definite nonfatal myocardial infarction--reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v 8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.",1
8547,6363397,Double-blind comparison of amoxapine and imipramine in the treatment of depressed patients,"""A 5-week double-blind study compared amoxapine to imipramine (2:1 dosage ratio) in the treatment of depressed outpatients. The two agents were similar in anti-depressant efficacy and rapidity of action. The most common adverse reactions to both drugs were anticholinergic effects and sedation; cardiovascular effects were minimal. A few amoxapine-treated patients developed adverse effects typical of neuroleptic drugs: some experienced extrapyramidal signs, one developed galactorrhea, and most showed elevated plasma prolactin concentrations. Amoxapine was associated with significant neuroleptic activity in plasma. No correlation was found between blood levels of either drug and therapeutic response.""",1
8548,6365496,Captopril-induced cholestatic jaundice,"A 50-year-old black female developed hepatic dysfunction secondary to captopril therapy, 25 mg tid for one month. Liver biopsy showed primarily cholestasis, with secondary hepatocellular elements. Symptoms consisted of jaundice, pruritus, anorexia and weight loss, hepatomegaly, and abdominal tenderness. Total bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH), and serum glutamic-oxaloacetic transaminase (SGOT), reached highs of 506 mumol/L, 737 U/L, 319 U/L, and 100 U/L, respectively. Recovery was slow, but complete, after discontinuation of the drug.",1
8549,6367747,Cocaine-mediated hepatotoxicity. A critical review,,1
8550,6368760,High-dose VP-16-213 monotherapy for refractory germinal malignancies: a phase II study,"VP-16-213 at standard dose is one of the more active agents for the treatment of germ cell tumors. In previous phase I studies, VP-16-213 has been investigated in suprastandard dose when hematopoietic reconstitution was assured by autologous bone marrow transplantation (ABMT). This phase II study was performed to explore the possibility that an augmented dose of VP-16-213 may be more active than standard dose against germ cell tumors. Eleven patients with progressive refractory germ cell tumors were treated with high-dose VP-16-213: 2,400 mg/m2 with ABMT every three to four weeks followed by 1,200 mg/m2 without ABMT. Seven patients had received VP-16-213 at standard dose prior to high-dose VP-16-213. Toxicity to high-dose VP-16-213 included severe myelosuppression, nausea, vomiting, alopecia, mucositis, and hepatitis. Of 10 evaluable patients, two complete responses and four partial responses, all of short duration, were obtained. However, some patients unresponsive to standard-dose VP-16-213 exhibited responses to the augmented-dose VP-16-213. Therefore, although more myelosuppressive, VP-16-213 may have increased activity against germ cell tumors when administered at augmented dose. High-dose VP-16-213 may be considered in designing new approaches for initial management of patients with germ cell tumors not expected to be cured with standard chemotherapy.",1
8551,6373099,Hepatic toxicity of nonsteroidal anti-inflammatory drugs,"The hepatic toxicity associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is reviewed. NSAIDs include agents in more than 10 classes of compounds, many of which are capable of producing hepatic injury. When NSAIDs are used to treat rheumatic disease, the hepatic effects of the disease itself may complicate the diagnosis of NSAID-induced hepatic injury. Hepatotoxicity caused by drugs may be either intrinsic or idiosyncratic in nature and may be manifested by hepatocellular injury, cholestasis, or a combination of both types of injury. Intrinsic hepatotoxins, such as salicylates, produce injury in a large percentage of exposed individuals that is often dose related and occurs after a short, fixed latent period. Idiosyncratic injury, such as that caused by sulindac, occurs in unusually susceptible persons, usually after a variable latent period. Injury is not dose related. In most cases of hepatocellular injury, the prognosis of those patients who survive the acute phase of injury is good. Fatalities rarely result from cholestatic injury. Monitoring of serum hepatic-enzyme concentrations is recommended for patients receiving NSAIDs from the indole, pyrazolone, and propionic acid classes since these agents have been associated with the greatest incidence of adverse hepatic reactions. Enzyme monitoring is advisable for high-risk individuals receiving NSAIDs from other classes. Enhance vigilance on the part of clinicians, patients, and pharmaceutical manufacturers is needed to reduce the incidence of hepatotoxicity associated with the use of NSAIDs.",1
8552,6375139,Intestinal and liver toxicity of antineoplastic drugs,"This discussion was selected from the weekly Grand Rounds in the Department of Medicine, University of Washington, Seattle. Taken from a transcription, it has been edited by Drs Paul G. Ramsey, Assistant Professor of Medicine, and Philip J. Fialkow, Professor and Chairman of the Department of Medicine.",1
8553,6375618,Peliosis hepatis after renal transplantation,,1
8554,6379462,Liver and hypervitaminosis,,1
8555,6380348,"Trental 400 in the treatment of intermittent claudication: results of long-term, placebo-controlled administration","""A double-blind, randomized, placebo-controlled long-term clinical study of Trental 400 was carried out, partly under cross-over design, partly as a parallel-group study, in 36 patients suffering from chronic arterial obstructive disorders in the lower limbs, associated with intermittent claudication, in order to evaluate the effectiveness and the safety of this drug administered t.i.d. over a period of 6 months. This controlled period was preceded by a placebo run-in period of 3 months. The clinical results under Trental 400 showed a statistically significant within group improvement of painfree and maximum walking parameters (p less than 0.05) corresponding to an increase to baseline by +96% to +139% respectively and also in comparison to placebo (p less than 0.05). The alterations of walking parameters within the placebo groups, ranging between -25% and +28% were not significant. The subjective parameters (rest pain, paraesthesias, muscular cramps and sensation of heaviness in the legs) paralleled the course of the walking parameters. Under Trental 400, 24 out of 36 patients reported an improvement of these symptoms compared to 7 under placebo. Trental 400 was well tolerated. Minor side effects were mentioned by 7 out of 36 patients. One patient had to stop the drug treatment because of persisting prickling sensation and subsequent insomnia. Drug-related changes in the laboratory findings could not be detected; vital signs varied in function of age, concomitant drug treatments and seasonal factors. The results obtained in these studies suggest Trental 400 as a drug of choice for treating patients with intermittent claudication due to peripheral arterial obstruction according to stage II or III after Fontaine.""",1
8556,6380350,"Double-blind, crossover study of the clinical efficacy and the hemorheological effects of pentoxifylline in patients with occlusive arterial disease of the lower limbs","The effect of a 3 month daily administration of 800 mg pentoxifylline (Trental 400 bds) or placebo was assessed under double blind crossover design in 18 patients (12 males and 6 females) with peripheral occlusive arterial disease in respect of painfree walking distance and various hemorheological and hemostasiological variables, platelet aggregation, serum cholesterol and triglycerides. In first treatment period walking distance significantly increased with pentoxifylline by 46% from baseline 121 +/- 15 m and by 4% with placebo from baseline 134 +/- 18 m. Pentoxifylline administration furthermore yielded significant decrease in whole blood and plasma viscosity and significant increase in erythrocyte deformability. This was paralleled by distinct reduction of fibrinogen, platelet aggregation and euglobulin lysis time, also plethysmographic variables showed positive changes pointing to improvement of limb perfusion. The results of the study suggest that treatment of peripheral occlusive vascular disease by a drug improving blood fluidity through correction of hemorheological and hemostasiological factors turns especially promising and beneficial since the action centers finally on the languishing microcirculation in the ischemic tissue.",1
8557,6384381,Once monthly rifampicin (1200 mg) plus daily dapsone (100 mg) and clofazimine (100 mg) in the initial treatment of lepromatous leprosy,"The therapeutic effect of rifampicin 1200 mg once monthly and 100 mg clofazimine daily for the first six months of treatment was evaluated in 30 patients of bacteriologically positive lepromatous leprosy patients. Moderate to marked clinical improvement was seen in all the patients and a very rapid bacteriological regression as indicated by the decrease in bacteriological and morphological indices of the skin within one week. Seven patients become MI negative at one month and three months and 13 at the end of nine months. Two patients became MI and BI negative at the end of six months and six at the end of nine months. These observations clearly establish the high therapeutic efficacy and practicability of the three drug regimen. Once monthly rifampicin is highly effective and well tolerated, and has many advantages like low cost, better patient compliance and reliability of the treatment. Addition of clofazimine to rifampicin and dapsone prevents the emergence of E.N.L. reactions which were seen during treatment with once monthly rifampicin and daily dapsone. This regimen is thus ideal for initial, intensive treatment of lepromatous leprosy and may help in preventing the spread of the disease and development of dapsone resistance.",1
8558,6385799,Cyclosporine: a new immunosuppressive agent for organ transplantation,"Cyclosporine, a cyclic endecapeptide of fungal origin, has recently been released for use in clinical transplantation. Trials in kidney, heart, liver and bone marrow recipients were encouraging: 1-year graft survival rates were 70% to 80% for kidney and heart recipients, and 60% to 65% for liver allograft recipients. Cyclosporine is also effective in treating bone marrow recipients with acute graft-versus-host disease. The drug selectively inhibits T-helper cell production of growth factors essential for B cell and cytotoxic T-cell differentiation and proliferation, while allowing expansion of suppressor T-cell populations. Drug absorption varies greatly, necessitating monitoring of drug level and individualization of therapy. Nephrotoxicity is the most frequent side effect of cyclosporine. An increased incidence of B-cell lymphomas seen when cyclosporine was used in conjunction with cytotoxic agents or anti-lymphocyte globulin has very rarely been observed when concomitant immunosuppression has been limited to low-dose corticosteroids. Lower initial doses of cyclosporine, followed by more rapid tapering may reduce the incidence of nephrotoxicity without compromising improved graft outcome.",1
8559,6389237,"Favourable outcome of hepatic veno-occlusive disease in a renal transplant patient receiving azathioprine, treated by portacaval shunt. Report of a case and review of the literature","Veno-occlusive disease (VOD) developed in a 45-year-old white male 2 years after cadaveric kidney transplantation while receiving combined immunosuppressive therapy with prednisone and azathioprine. Early clinical signs at presentation included ascites and tender hepatomegaly. The diagnosis of VOD was established at laparoscopy and by histological examination of liver biopsies. Azathioprine was discontinued. Gross ascites refractory to medical treatment and decreasing liver function required surgical treatment by portacaval shunt. Transient postoperative complications were hepatic encephalopathy and considerable hyperbilirubinaemia. 8 months later the patient is well, with stable renal function and no clinical signs of hepatic disease.",1
8560,6395272,Cefonicid: an overview of clinical studies in the United States,"""Cefonicid, an investigational cephalosporin with a half-life just under 5 hr, was studied by more than 100 investigators in the United States. Of 1,060 cefonicid-treated patients for whom the clinical efficacy of the compound could be evaluated, 91.7% were cured or improved; 95% received a single daily dose. Rates of bacteriologic cure were equal for infections due to gram-positive cocci (89.9%) and gram-negative bacilli (93.2%). Overall rates of favorable response to cefonicid therapy, by disease, were 88.4%, urinary tract infections; 91.4%, lower respiratory tract infections; 95.1%, skin and skin-structure infections; and 91.3%, bone and joint infections. Prophylaxis with cefonicid administered 1 hr before surgery was as effective as that with control antibiotic in reducing the incidence of perioperative infection. For 795 patients who received cefonicid or control drug who underwent gynecologic surgery, prosthetic arthroplasty, cesarean section, or intraabdominal surgery, the reduction in incidence of perioperative infections were equivalent. Resistance to cefonicid developed infrequently (1.3%). Overall safety of cefonicid was comparable with that of control agents except for the frequency of occurrence of diarrhea, which was lower among patients who received cefonicid than among those who received a control drug.""",1
8561,6397677,Double-blind placebo-controlled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids,"In order to investigate the effectiveness of microporous cholestyramine in the pharmacological management of intra- and extrahepatic cholestasis, a double-blind placebo-controlled study was carried out in 10 patients. Microporous cholestyramine or placebo 3 g t.i.d. were given orally over a four-week period. The active drug resulted statistically superior to the placebo in reducing itching intensity (p less than 0.01) and serum bile acids (p less than 0.01). A positive linear relationship between itching and serum bile acids (p less than 0.01) was also demonstrated.",1
8562,6402064,Quinine-induced granulomatous hepatitis,"""Many adverse reactions to quinine have been reported. A 65 year old woman taking quinine sulphate for nocturnal leg cramps presented for investigation of episodes of malaise, fever, nausea, vomiting, and polyarthralgia. Granulomatous hepatitis was diagnosed, for which no common cause was found. She was challenged with quinine sulphate; within hours her temperature had risen and her symptoms returned; transaminase activities rose within 48 hours, as did erythrocyte sedimentation rate. After withdrawal of the drug symptoms abated and transaminase activities returned to normal. The biochemical response to challenge with quinine implicates the drug as the cause of the liver disturbances. Quinine should be added to the list of drugs known to cause granulomatous hepatitis and should be considered in cases where symptoms are episodic or where no other cause is apparent.""",1
8563,6402993,HLA DR antigens and gold toxicity,"One hundred and thirty-two patients with rheumatoid arthritis treated with gold have been studied for possible associations between HLA DR antigens and different adverse reactions occurring during such therapy. Patients possessing HLA DR3 had a significantly greater frequency of side effects than patients lacking this antigen. It was particularly noticed that DR3 positive patients on gold treatment had an 11 times higher risk of getting proteinuria than those without DR3. The lowest frequency of side effects was seen in DR7 positives. No significant differences between the DR antigen groups with respect to skin eruptions, liver reactions, or leucopenia were evident.",1
8564,6406465,Preclinical toxicology of bupropion: an overview,"""In preclinical studies, the toxicologic profile of bupropion was determined in laboratory animals using exaggerated doses of drug in a variety of toxicologic assays. Under overdose conditions, clinical signs primarily referable to the central nervous system were seen in rats, mice, rabbits, and dogs. Very mild, reversible hepatotoxicity and anemia occurred in dogs with chronic dosing; lifetime administration in rats caused hepatocellular hypertrophy and focal hepatic hyperplasia. In both rats and dogs, there was an increase in liver weight related to hepatic enzyme induction. Appropriate tests indicated that bupropion is unlikely to have the potential to cause teratogenic, mutagenic, or carcinogenic effects in man.""",1
8565,6409240,Adverse reactions during treatment with amiodarone hydrochloride,"Amiodarone was administered to 80 patients with recurrent cardiac tachyarrhythmias previously resistant to drug treatment. Forty nine patients were treated for ventricular tachycardia or fibrillation and 31 for supra-ventricular arrhythmias. The mean (range six days to 51 months), permitting a total of 100 patient years of observation. Adverse reactions were observed in 69 patients. Severe side effects were encountered in 13: four patients developed interstitial pneumonitis, four patients developed incessant ventricular tachycardia, three patients taking amiodarone and digoxin sustained sinus node arrest with depression of escape foci, one patient developed hepatitis, and one patient developed hypercalcaemia with renal failure. Furthermore, a rise in the serum concentration of digoxin and potentiation of warfarin anticoagulation occurred in cases in which these agents were combined with amiodarone. Amiodarone was stopped in 14 patients because of side effects. Although amiodarone is effective in suppressing arrhythmias in most patients in whom extensive use of antiarrhythmic drugs has been unsuccessful, it is associated with diverse and serious toxicity. These observations suggest that at present the use of amiodarone should be reserved for patients with life threatening or seriously disabling arrhythmias in whom longer established drugs have been ineffective or are contraindicated.",1
8566,6411235,Precipitation of hepatic encephalopathy by propranolol in cirrhosis,,1
8567,6412580,Reye-like syndrome associated with valproic acid,"A case of a Reye-like syndrome during the course of treatment with VPA was reported. Hyperammonemia and severe liver damage as well as diffuse small droplets in the liver biopsy material were demonstrated. On analysis by gas chromatography/mass spectrometry of the urine immediately after the onset, the metabolites of VPA were detected together with lactate and other substances, and electron microscopic observation of liver biopsy material revealed deformation of mitochondria, disappearance of cristae and electron dense deposits in the matrix.",1
8568,6419928,Liver damage from verapamil,,1
8569,6424398,"Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy","""Side effects of carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) are rare during long-term use but rather common and usually transient during the early phases of treatment. The usual side effects of CBZ are drowsiness, dizziness, and diplopia, which are dose dependent in long-term use, but CBZ does not seem to cause cognitive disturbances, as do phenobarbital and phenytoin. Other reactions to CBZ may include leukopenia, hyponatremia, disturbances of vitamin D metabolism and fortunately rarely, agranulocytosis and hepatitis. Use of VPA can lead to gastrointestinal discomfort, weight gain, hair loss, tremor and sedation, but these side effects are rather uncommon, mild, and transient during VPA monotherapy. Potentially hazardous reactions such as hepatitis and pancreatitis have occurred in a few patients on VPA, generally with multidrug therapy. Some of the side effects are dose related. They infrequently lead to withdrawal of VPA. Side effects limited to initiation of CZP therapy include drowsiness, ataxia, and behavioral changes; they are usually transient but can lead to dose reduction or even withdrawal of the drug. Except for development of tolerance, CZP seems to be practically free of long-term side effects.""",1
8570,6428548,"Oral contraceptives, pregnancy, and endogenous oestrogen in gall stone disease--a case-control study","A case-control study of gall stone disease in women in relation to use of contraceptives, reproductive history, and concentrations of endogenous hormones was undertaken. The study population comprised 200 hospital patients with newly diagnosed gall stone disease, 182 individually matched controls selected from the community, and 234 controls who were patients in hospital. Use of oral contraceptives was associated with an increased risk of developing gall stones among young subjects but a decreased risk among older subjects. The risk of developing gall stone disease increased in association with increasing parity, particularly among younger women. The risk fell with increasing age at first pregnancy, independent of parity. Mean urinary excretion over 24 hours of oestrone, but not of pregnanediol, was significantly (p less than 0.05) greater for postmenopausal patients than controls. The age dependence of the relative risk associated with exposure to oral contraceptives and pregnancy suggests that there are subpopulations of women susceptible to early formation of gall stones after exposure to either oral contraceptives or pregnancy.",1
8571,6429329,Liver dysfunction associated with gold therapy for RA,,1
8572,6430441,Tamoxifen and liver damage,,1
8573,6434025,Acute cholecystitis and thiazides,"Drugs purchased by a random sample (17 000) of the population of J?mtland county, Sweden, are continuously monitored. Patients who had been admitted to the county's only hospital with acute cholecystitis and who were part of this sample were studied, and controls matched for age and sex were drawn from the sample. The purchase of thiazides and other drugs prescribed to the patients with acute cholecystitis was compared with that of the controls. The estimated relative risk of developing acute cholecystitis in patients who had purchased thiazides in the year before admission to hospital, as compared with those who had not, was 2.1 (95% confidence limit 1.1-3.9). As it has been reliably reported that the use of thiazides is not itself associated with cholelithiasis, the association found between thiazides and cholecystitis suggests that thiazides may increase the risk of acute cholecystitis developing in a patient with gall stones.",1
8574,6435654,A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients,"The antipyrine clearance and the urinary excretion of D-glucaric acid (D-GA) were determined in 122 patients receiving chronic anticonvulsant drug treatment and in 21 drug-free control subjects. Patients treated with carbamazepine (CBZ), phenytoin (DPH), primidone (PMD) and phenobarbitone (PB), either alone or in combination, showed higher values of antipyrine clearance and excreted larger amounts of D-GA as compared to controls. While antipyrine clearance values did not differ significantly from one drug group to another, D-GA excretion was significantly higher in patients treated with CBZ than in those treated with DPH. In patients treated with sodium valproate antipyrine clearance did not differ from control values. There was a trend for D-GA excretion to be higher in these patients but the difference was not statistically significant. Significant positive correlations were found between the dosage of CBZ, DPH, PMD and PB and both indices of enzyme induction. These data demonstrate a dose-dependent degree of enzyme induction in patients receiving therapeutic doses of these anticonvulsants. The relative potency at average dose levels for antipyrine clearance was PB (1), DPH (0.92), CBZ (0.84), PMD (0.82) and for log D-GA excretion was PB (1), CBZ (0.96), PMD (0.95), DPH (0.90).",1
8575,6438309,Fatal intrahepatic cholestasis and interstitial lung fibrosis following gold therapy for rheumatoid arthritis,,1
8576,6442056,[Undesirable effects of gold therapy],"In about 20 to 30% of patients receiving intramuscular gold salts untoward side-effects of variable severity are known to occur with resultant discontinuation of treatment in a high percentage of cases to be on the safe side. Among the most common, albeit harmless side-effects are those affecting the skin and the mucous membranes. These are followed by renal symptoms. Grave complications affecting the hemopoietic system (leucopenia, thrombocytopenia, aplastic anaemia) are rarely seen. Other potential side effects (pulmonary fibrosis, liver damage, neuropathies, vasomotor reactions, loss of hair, nail changes) are extremely uncommon or no more than anecdotal). Meticulous follow-ups at regular intervals are imperative to minimize the associated risks.",1
8577,6443775,Cefsulodin therapy for infections due to Pseudomonas aeruginosa in patients with burns,"""This multicenter trial compared treatment with either cefsulodin or reference antibiotics (gentamicin, tobramycin, amikacin, or ticarcillin) in 67 patients with Pseudomonas aeruginosa infection and burn injury. Safety of treatment was evaluated for all 67 patients; clinical efficacy, for 29; and bacteriologic efficacy, for 26. The average daily dose and duration of treatment for the 37 cefsulodin-treated patients were 5.6 g and 10.3 days, respectively. The percentage of total body surface burned was greater than or equal to 50% for 40% and greater than or equal to 25% for 85% of the patients. Rates of bacteriologic cure for 30 sites of infection were 64% (7/11) for skin and skin-structure infections treated with cefsulodin or reference antibiotics; 100% (1/1) for respiratory tract infections treated with cefsulodin and 33% (2/6) for those treated with reference antibiotics; and 100% (1/1) for septicemia treated with a reference antibiotic. Overall bacteriologic and clinical efficacy for cefsulodin treatment was 67% (8/12) and 73% (11/15), respectively, and for treatment with a reference antibiotic was 56% (10/18) and 64% (9/14), respectively. Cefsulodin was found to be safe and comparable in efficacy to reference antibiotics in this patient population.""",1
8578,6445305,Triethylene tetramine dihydrochloride toxicity in primary biliary cirrhosis,"Triethylene tetramine dihydrochloride (trien) is a copper chelating agent used as the alternative drug of choice in the treatment of Wilson's disease. Because of its apparent safety, we have used the drug in 4 patients with primary biliary cirrhosis in whom penicillamine had to be withdrawn because of serious side effects. Trien is an effective cupruretic drug in primary biliary cirrhosis, but its use is limited by the occurrence of side effects that occurred in all 4 patients. Three patients developed gastrointestinal side effects, and one of these patients developed a skin rash. The 4th patient developed acute rhabdomyolysis within 48 hr of receiving the first dose of the drug. One patient tolerated therapy for 20 wk, and, although her liver copper concentration did not show a marked fall, aspartate transaminase levels fell, and her IgM concentration fell to normal. Trien is an unsuitable copper chelating drug in primary biliary cirrhosis, although it remains the alternative drug of choice in Wilson's disease.",1
8579,6448525,[Gold therapy in chronic polyarthritis. Differentiation of allergic and toxic side effects],"""The data from 310 patients treated with gold were analysed. The occurrence of side effects is lower than the average data in the literature: with """"Solganal"""" 21.5%, with """"Tauredon"""" 21%. The clinical importance of the differentiation of toxic and allergic side effects is pointed out. It seems possible to differentiate between the toxic-allergic and the dosage dependent, actually toxic side effects. In cases of toxicity caused by retarded metabolisation the use of the barbiturate enzyme induction made it possible to continue treatment.""",1
8580,6453500,Toxic hepatitis induced by disulfiram in a non-alcoholic,A reversible toxic liver damage was observed in a non-alcoholic woman treated with disulfiram. The causative relationship was proven by challenge.,1
8581,6455409,Disulfiram toxicity--a review of the literature,,1
8582,6460738,Piperacillin: a review of clinical experience,,1
8583,6461677,Isotretinoin versus placebo in the treatment of cystic acne. A randomized double-blind study,"Thirty-three patients with treatment-resistant cystic and conglobate acne entered a randomized, double-blind protocol testing the efficacy of isotretinoin versus placebo. There was an overall 57% increase in the number of cystic lesions in seventeen patients who initially received placebo. Sixteen of these seventeen patients then received isotretinoin, with a resultant 98% improvement. The sixteen patients who had been randomly assigned to receive initial therapy with isotretinoin had a 95% improvement. Twenty-seven of the thirty-two patients treated with isotretinoin cleared completely. The average maximum dosage of isotretinoin received by these patients was 1.2 mg/kg/day. Eighteen patients received only one 4-month course of isotretinoin. Fifteen patients received two courses. These included twelve patients with predominantly truncal acne who responded partially to the first course, and three patients who had cleared completely after one course of therapy but had mild relapses after an average of six months off of treatment. All patients are now in remission averaging 38 months in duration. Skin biopsies and quantitative measurement of sebum production during therapy indicated a profound inhibition of sebaceous gland size and function, which may be central to the mechanism of action of isotretinoin in acne.",1
8584,6465090,Acetaminophen overdose with fetal demise,"A case of fetal demise and maternal recovery after acetaminophen overdose is presented, to our knowledge the first reported. Fetal liver and maternal serum concentrations indicate overdose to be the cause of fetal death. Maternal disseminated intravascular coagulation (DIC) may have been related to maternal acetaminophen-induced liver disease alone or to a combination of liver disease and the presence of a dead fetus.",1
8585,6466024,Drug-induced liver injury. In vitro demonstration of hypersensitivity to both phenytoin and phenobarbital,"Fever, lymphadenopathy, exfoliative dermatitis, and evidence of drug-induced liver injury developed in a 16-year-old girl three weeks after beginning therapy with phenytoin and phenobarbital. This clinical syndrome can be caused by either of these structurally related drugs but has been more frequently attributed to phenytoin. In vitro studies disclosed marked reactivity of this patient's lymphocytes to concentrations of both drugs, which encompassed their measured serum levels. The demonstration of dual reactivity raises concerns about continuing administration of phenobarbital during an apparent phenytoin-induced reaction. Whether this potential risk is greater than the risk of stopping all anticonvulsant medications in a patient with a seizure disorder is not known and remains to be established.",1
8586,6475904,Chlorpropamide hepatotoxicity: report of a case and review of the literature,"Chlorpropamide, a sulfonylurea compound used in the treatment of diabetes mellitus, type II, has been implicated as the cause of untoward reactions involving the hematopoietic, cutaneous, and gastrointestinal systems. The hepatotoxic reactions induced by this drug generally present as hepatocanalicular cholestatic reactions, in contrast to the hepatocellular reactions induced by the older sulfonylurea compounds. An unusual presentation of chlorpropamide toxicity, presenting as a mixed hepatocanalicular reaction, is reported, along with a review of the literature.",1
8587,6483640,Fluphenazine decanoate-induced cholestatic jaundice and thrombocytopenia,,1
8588,6483711,Disulfiram-induced hepatitis--report of a case and review of the literature,"Disulfiram has been used as an adjunct to the treatment of chronic alcoholism since 1948. We report a young woman who developed clinical, biochemical and histopathological signs of a liver hypersensitivity reaction. A review of the literature is also presented.",1
8589,6486141,Side effects of systemic cyclosporine in patients not undergoing transplantation,"Twenty-six patients with ocular inflammatory disorders of presumed autoimmune origin were treated with oral cyclosporine. Cyclosporine is a potent T cell regulatory agent that has been utilized extensively in organ transplantation. In general, the patients in this study did not have chronic debilitating illnesses that are observed in organ transplant recipients, did not receive corticosteroids in addition to cyclosporine, and did not undergo any surgical procedure during their treatment. This study describes the observed adverse reactions in this group of patients not undergoing transplantation. The reported side effects of cyclosporine in organ transplant recipients have included nephrotoxicity, hepatotoxicity, infections, lymphoma, hirsutism, gingivitis, and central nervous system toxicity. Side effects were observed that were similar to those in previous reports, but the severity of the nephrotoxicity and hepatotoxicity appeared to be less. Nephrotoxicity occurred in eight patients and hepatotoxicity occurred in one patient. No lymphomas were seen. Hypertension and anemia each were observed in six patients. In addition, previously unreported effects of hyperuricemia, elevated sedimentation rate, and hidradenitis were observed. However, the overall severity of the side effects did not seriously affect the usage of cyclosporine in the patients in this study. Cyclosporine may be useful in the treatment of other autoimmune diseases.",1
8590,6490982,Histologic changes in the liver during etretinate treatment,"Histologic changes in the liver were evaluated in thirty-two patients with different dyskeratotic dermatoses treated with etretinate (Tigason) during an average of 24.9 months. Fatty infiltration, nuclear variability, periportal inflammation, focal necrosis, fibrosis, and cholestasis were estimated. The usual dose was 50-75 mg/day, with reduction according to efficacy and side effects. No statistically significant differences were found between a control group of thirty-five liver biopsies from psoriasis patients who had not received systemic therapy and biopsies from the patients treated with etretinate. Among the thirty-two etretinate-treated patients, six had two serial biopsies, and eight had pretreatment biopsies. No significant changes appeared during therapy.",1
8591,6497443,Outbreak of fatal arsenic poisoning caused by contaminated drinking water,"""An outbreak of subacute poisoning occurred among nine members of a family; eight were ill with gastrointestinal symptoms, four developed encephalopathy, and two died. Abnormal liver function tests and leukopenia were common laboratory findings. Epidemiologic and environmental investigations traced the source of arsenic exposure to a farm well with water containing 108 ppm arsenic. The soil adjacent to the well was also contaminated with arsenic, possibly from waste pesticide. Presumably, arsenic gained access to the well through obvious leaks in the well's casing. To our knowledge, this is only the second reported outbreak of fatal arsenic poisoning from contaminated drinking water and one of few instances where illness followed exposure to a toxic substance which was disposed of, or possibly disposed of, in an indiscriminate manner.""",1
8592,6500549,Peliosis-like ultrastructural changes of the hepatic sinusoids in human chronic hypervitaminosis A: report of three cases,"""In addition to hypertrophy of Ito cells and perisinusoidal fibrosis, previously unrecognized ultrastructural abnormalities of the hepatic sinusoids were observed in three patients with chronic hypervitaminosis A: 1) large areas of communication between the sinusoidal lumina and the perisinusoidal spaces, allowing extravasation of blood cells; 2) marked dilation of the perisinusoidal spaces; and 3) swelling and clarification of endothelial cells. Most of these changes, along with some other sinusoidal barrier alterations previously reported in chronic hypervitaminosis A (i.e., bleb formation on the sinusoidal membrane of the hepatocytes and the presence of multiple cellular layers lining the sinusoids), are strikingly similar to those observed in peliosis hepatis. The present findings suggest that sinusoidal barrier abnormalities might constitute a major event in the pathophysiology of vitamin A-induced liver injury as well as of peliosis hepatis.""",1
8593,6506005,[Evaluation of drug-induced hepatic complications collected by the French drug surveillance organization],,1
8594,6510817,[Liver damage due to reserpine hypersensitivity],,1
8595,6510880,Severe liver injuries due to sulfamethoxazole-trimethoprim and sulfamethoxydiazine,"Two cases of severe sulfonamide liver injury are described. In one patient, fulminant liver failure developed after two days of taking sulfamethoxazole-trimethoprim. The patient was treated with resin hemoperfusion and recovered completely. Another patient became jaundiced after using sulfamethoxydiazine for ten days. Very severe intrahepatic cholestasis developed and cleared up only after high-dose prednison treatment. Marked hyperbilirubinemia persisted for four months and aminotransferase activity had not normalized ten months after the onset of the disease.",1
8596,6512351,[Two cases of carbamazepine induced hepatitis],,1
8597,6519409,"[Hepatitis due to non-steroidal anti-inflammatory agents : a new involved molecule, piroxicam (Feldene) ?]",,1
8598,6526232,[Acute cholestatic hepatitis due to carbamazepine],,1
8599,6527401,Hepatotoxicity due to disulfiram,,1
8600,6527958,Deterioration of liver function during PUVA therapy,,1
8601,6538153,[Hepatic fibrosis and portal hypertension in chronic vitamin A poisoning],"""The authors report the case of a 36-year-old man who was hospitalized for portal hypertension. The patient had been receiving 200 millions units of vitamin A for ten years duration as treatment of psoriasis. There were no extrahepatic signs of hypervitaminosis A and the serum concentration of vitamin A was low. Microscopic examination of a liver specimen showed: a) spontaneous fluorescence due to vitamin A accumulation in sinusoidal cells; b) portal, periportal and perisinusoidal fibrosis; c) hyperplasia and hypertrophy of Ito cells. Hepatic vitamin A concentration was markedly increased. Hemodynamic study showed increased wedged hepatic venous pressure. Low serum concentration of retinol binding protein, which could be due to severe denutrition, explained the low serum vitamin A. This case report emphasizes that severe hepatic injury due to chronic hypervitaminosis A may be observed in the absence of extrahepatic signs of vitamin A intoxication and increase in serum vitamin A concentration. In such cases, histologic examination of a liver specimen and determination of hepatic vitamin A concentration are the only means of diagnosis.""",1
8602,6541672,Treatment of serious gram-negative infections with aztreonam,"Aztreonam (SQ 26,776) is the first parenteral monobactam agent to be used in patient trials. The agent has significant activity in vitro against facultative aerobic gram-negative bacteria but not against gram-positive or anaerobic bacteria. Aztreonam was used for a year to treat 106 hospitalized patients with a total of 131 documented gram-negative infections. Important exclusion criteria included granulocytopenia, hyperbilirubinemia, meningitis, patients less than 13 years of age, pregnancy, and history of anaphylaxis to penicillin. In this study of 35 men and 71 women, there were 67 cases of pyelonephritis (25% bacteremic), 19 of pneumonia (16% bacteremic), 10 of skin or soft-tissue infections, 9 cases of osteomyelitis, and 6 cases of postpartum endometritis. During the study period, 159 facultative aerobic gram-negative bacteria were tested for aztreonam susceptibility, and 144 (91%) were found to be susceptible. Eighty percent of infections were cured by both clinical and microbiological criteria and each of the other 26 infections showed clinical improvement. Eradication of the infecting organism was achieved in 89% of infections without adverse reaction or drug toxicity.",1
8603,6549301,[Acute hepatitis probably due to Plethoryl],,1
8604,6578867,Veno-occlusive disease of the liver in children following chemotherapy for acute myelocytic leukemia,"""Three children developed acute veno-occlusive disease of the liver following combination chemotherapy for acute myelocytic leukemia. The clinical presentation was similar in all three, with acute onset of hepatomegaly and thrombocytopenia in the absence of significant transaminasemia or icterus. In all three patients, radionuclide imaging with technetium-99m sulfur colloid showed hepatosplenomegaly, decreased liver uptake, and increased splenic activity. The results of liver biopsy established the diagnosis, revealing marked centrilobular congestion with hemorrhage into the spaces of Disse, atrophy of central hepatic cords, and edema of the walls of the central and sublobular veins. Each patient showed marked improvement following temporary cessation of chemotherapy. The diagnosis of veno-occlusive disease is suggested by the triad of: (1) clinical signs and symptoms; (2) scintigraphic findings; and (3) temporal relationship to chemotherapy.""",1
8605,6586251,Toxic and adverse reactions encountered with new beta-lactam antibiotics,,1
8606,6594184,Reversible hepatotoxicity related to amphotericin B,"Hepatotoxicity is regarded as a rare side effect of amphotericin B therapy. A patient with acute myelogenous leukemia who had normal liver function was treated with amphotericin B for fungal pneumonia. While he was receiving the drug at high dosages asymptomatic elevation of the levels of alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, lactic dehydrogenase and bilirubin was noted. The levels returned to normal when the drug was discontinued. Rechallenge with a lower dosage prompted a rapid rise in the levels, with subsequent return to normal when the medication was withdrawn.",1
8607,6600661,Trimethoprim-sulfamethoxazole-induced intrahepatic cholestasis,,1
8608,6601598,[Acute hepatitis caused by erythromycin esters (propionate and ethylsuccinate)],,1
8609,6604257,Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis,"""To estimate rates of hepatotoxicity in the United States among children treated for tuberculosis, we conducted a retrospective survey of health departments and individual practitioners. We received 874 reports suitable for analysis of children treated during 1977 to 1979. A total of 16 hepatotoxic reactions were reported; 14/430 (3.3%) children receiving isoniazid and rifampin had a hepatotoxic reaction, which approximates the rate seen in adults taking these drugs. Half of the reactions occurred during the first month of therapy, and all of the well-documented reactions were noted during the first 10 weeks. Because the likelihood of hepatotoxicity may be increased with higher drug doses, limiting the dose of isoniazid to 10 mg/kg and that of rifampin to 15 mg/kg may help minimize hepatotoxic reactions. Because more serious disease, especially disseminated tuberculosis, may further increase the risk of hepatotoxicity, close monitoring of such children receiving isoniazid and rifampin should help minimize serious hepatotoxicity. Routine biochemical monitoring may not be necessary for all children, eg, those with mild forms of disease and those with normal pretreatment liver function who are treated with lower drug doses.""",1
8610,6608933,Propylthiouracil and hepatitis. Two cases and a review of the literature,"Propylthiouracil-induced hepatitis is an uncommon entity. Two further cases are reported herein, and the clinical and laboratory features of the other six cases in the English literature are reviewed. The initial appearance of the disease is similar to that of viral hepatitis, characterized by nausea, vomiting, and jaundice. The biochemical pattern of injury is predominantly hepatocellular, with marked elevation of transaminase valves and less striking elevation of alkaline phosphatase values. Recovery is usually complete after withdrawal of the drug, but there have been at least two fatalities, including the first patient (to our knowledge) whose case is reported herein. Despite its rarity, the disease should be suspected in any patient receiving propylthiouracil in whom clinical or laboratory evidence of hepatocellular injury develops.",1
8611,6609640,Cholestatic hepatitis from erythromycin ethylsuccinate. Report of two cases,"Cholestatic hepatitis developed in two patients while they were receiving erythromycin ethylsuccinate. Both patients had received the drug without apparent problem within two months of the episode of drug-related cholestatic injury. In both, there was complete resolution of the hepatic injury upon withdrawal of the drug. Erythromycin ethylsuccinate should be added to the list of drugs causing cholestatic hepatitis.",1
8612,6613213,[Hepatocellular drug reaction caused by mebendazole therapy in cystic echinococcosis],"A 76 years-old male patient received mebendazole, 500 mg four times a day (appr. 29 mg per kg body weight) for treatment of sonographically and serologically proven cystic echinococcosis of the liver. On day 49 of this therapy he developed an exanthema, and mebendazole-administration was interrupted. At the same time a striking rise of serum transaminases was observed. When enzyme levels normalized, a reexposure using a low dose of mebendazole lead to a new more pronounced rise of transaminases suggesting a drug-induced hepatocellular damage. No measurable change of the Echinococcus cyst was observed during treatment.",1
8613,6614680,Oral zinc therapy for Wilson's disease,"Wilson's disease is an inherited disorder of copper accumulation that is fatal if untreated. Because penicillamine, the established treatment, is toxic in a substantial number of patients, we studied the efficacy of zinc treatment. We induced a negative or neutral copper balance in five out of five patients with Wilson's disease who were receiving no therapy other than zinc. Zinc acetate was given every 4 hours during the day, and the patient was not allowed to eat for 1 hour before and 1 hour after each dose. Oral zinc therapy, used according to our regimen, may now be considered in the treatment of patients with penicillamine intolerance. However, it is premature to convert patients to zinc therapy if they tolerate penicillamine well. The efficacy of zinc therapy in the initial removal of the copper burden in acutely ill patients with Wilson's disease has not yet been evaluated.",1
8614,6619028,Comparison of azlocillin and ticarcillin in the treatment of urinary tract infection,"This prospective, controlled, randomized double blind study compared the safety and effectiveness of intravenous azlocillin at a dosage of 6 g/day in three divided doses with that of intravenous ticarcillin at 8 g/day in four divided doses for the treatment of urinary tract infections in 35 patients. The clinical and bacteriological responses among the 26 courses evaluable for drug effectiveness (13 in each group) appeared to be somewhat more favourable in the azlocillin treatment group (92.3%) than the ticarcillin group (69.2%). However, statistically, both treatment groups did not differ in a significant manner in regard to effectiveness or adverse reactions. Of the patients who were followed for relapses for three-four weeks after treatment, 66.7% of the azlocillin group and 45.5% of the ticarcillin group remained free of the original infecting organism. Local and systemic tolerance for both drugs was excellent.",1
8615,6625282,Severe iron poisoning treated with enteral and intravenous deferoxamine,"An 18-month-old boy ingested approximately 18 g FeSO4, equivalent to 336 mg/kg elemental Fe. He rapidly developed severe gastroenteric symptoms, obtundation, and transient hypotension. The serum iron level two hours after ingestion was 6,798 micrograms/dL. He was treated with deferoxamine intravenously, enterally, and as a lavage solution. His hospital course was notable for lack of severe neurologic, hepatic, metabolic, or cardiovascular complications acutely with apparent complete recovery, although he returned six weeks after ingestion with intestinal obstruction due to a jejunal stricture.",1
8616,6627877,Hepatic dysfunction following nafcillin and cephalothin therapy in a patient with a history of oxacillin hepatitis,,1
8617,6634153,"[An unusual side effect of quinidine: liver damage, pneumonia]",,1
8618,6637896,A case of peliosis hepatis in association with tamoxifen therapy,,1
8619,6644413,Hepatotoxicity of cysteamine?,,1
8620,6658826,Hepatic arsenic in non-cirrhotic portal fibrosis,,1
8621,6660241,Methotrexate therapy in rheumatoid arthritis: 15 years experience,"An increasing amount of clinical data indicates that low-dose methotrexate therapy for rheumatoid arthritis is both effective and free of serious side effects. Since 1967 we treated 78 patients with definite or classic rheumatoid arthritis who showed inadequate response to conventional therapy. Up to 15 mg of methotrexate was given weekly by the intramuscular route. Morning stiffness, severity of pain at rest and with activity, extent of active synovitis, functional capacity, change in steroid dosage, complete blood count, erythrocyte sedimentation rate, and gamma glutamyl transpeptidase were monitored. Overall assessment indicated that 45 of the 78 (58 percent) patients showed marked improvement or complete remission, usually within four weeks. When maximum improvement was obtained, most patients were switched to oral therapy with a variable degree of success, and dosage was decreased as tolerated. No serious toxicity was noted. In 34 patients a total of 67 liver biopsy specimens were obtained, some after as long as 15 years of therapy. Minor changes observed are the same as in patients with rheumatoid arthritis not treated with methotrexate. Because the risks did not appear justified, routine annual biopsies were discontinued. In contrast to other cytotoxic drugs, no carcinogenesis has been demonstrated with methotrexate. It appears that methotrexate is approximately as effective as intramuscular gold and D-penicillamine but that it has a quicker onset of response and less serious toxicity.",1
8622,6668931,The effect of clofazimine on liver function tests in lepra reaction (ENL),Twenty patients with suspected DDS resistance and repeated attacks of lepra reactions were selected for the study. Clofazimine was administered in different doses over a period of 12 months. Elevated levels of transaminases and Alkaline phosphatase prior therapy attained values to near normalcy. Progressive fall in serum Bilirubin and Proteins with normal A/G ratio at the end of therapy was also observed. Clofazimine by its anti-inflammatory and antibacterial action could inhibit the process of liver damage and happened to have minimal deleterious effect on liver by studying the liver function tests.,1
8623,6672506,The liver in fatal exertional heatstroke,"We describe the chronology of hepatic histopathologic alterations in 50 cases of fatal exertional heatstroke related to military training. Five patients who died in the field demonstrated the earliest alterations: fatty change (sometimes microvacuolar), amitotic hepatocellular regeneration, accumulation of hemosiderin, and congestion. In addition, the sinusoids contained polymorphonuclear leukocytes, immature erythroid and granulocytic cells, megakaryocytes, and lymphocytes. Fibrin was not evident. The other 45 patients, who survived up to 8 days following hospitalization, also demonstrated these findings. Microvacuolar fatty change was common in this group of patients, and degenerated hepatocytes resembled Councilman bodies. Coagulative degeneration and submassive necrosis were uncommon. Of those surviving over 12 h, more than half had bile stasis (sometimes ductal), frequently associated with acute cholangitis and ductular proliferation. Regeneration and pigmentary alterations have not been recognized as early hepatic findings in heatstroke, nor have intrasinusoidal bone marrow elements, ductal bile stasis, and acute cholangitis been described. Possible pathogenic factors, other than hyperthermia and sequellae of shock, include obesity, recent illnesses and immunizations, bacterial toxemia, hemolysis, and bone marrow injury.",1
8624,6678827,Effects of oral methoxy-psoralen photochemotherapy (PUVA) on liver function and antipyrin kinetics,"Standard liver function tests and antipyrin kinetics were studied in 19 non-alcoholic patients before and after a four-week PUVA treatment with oral methoxy-psoralen. Whereas liver function remained normal in all subjects, antipyrin clearance was significantly reduced at the end of PUVA therapy. Although the mechanism of this pharmacological effect remains unclarified, these results suggest that there is considerable potential for interactions to occur with other drugs metabolized by the same hepatic pathways (cytochrome P 450) in patients undergoing PUVA therapy.",1
8625,6684283,"""Vitamin A supplementation. Subclinical overdose """"unmasked"""" by hepatitis""",,1
8626,6689558,[Case of Hashimoto's disease with thyroxine induced allergic hepatitis],,1
8627,6690948,Betaine in the treatment of homocystinuria,,1
8628,6691707,Hepatotoxic reactions in a patient treated with etretinate,"""Hepatotoxic reactions and eosinophilia developed in a 74-year-old woman who had been treated with an aromatic retinoid compound, etretinate, for severe psoriasis palmaris et plantaris. Rapid improvement in her condition followed discontinuation of the drug therapy. Liver enzyme elevations recurred after reinstitution of etretinate therapy; these levels quickly returned to normal after the drug therapy was again discontinued. Our patient's reaction to etretinate may have been a hypersensitivity reaction.""",1
8629,6694278,Reye's syndrome associated with long-term aspirin therapy,Reye's syndrome has been infrequently described in children receiving long-term salicylate therapy. We report the clinical and laboratory findings of two children in whom Reye's syndrome developed while taking salicylates for systemic inflammatory disorders. Monitoring of hepatocellular function should be considered in children who are receiving long-term salicylate therapy.,1
8630,6695234,Hepatitis as a manifestation of phenobarbital hypersensitivity,,1
8631,6698264,Etretinate (Tigason) hepatitis in 2 patients,"A histologically confirmed, clinically inapparent and reversible hepatitis occurred in 2 patients (1 psoriasis, 1 basal cell nevus syndrome) within the first months after introduction of etretinate therapy. Causes of hepatitis other than etretinate were not found. Reintroduction of etretinate resulted in reactivation and/or persistence of the hepatitis in both patients. These data strongly suggest that the hepatitis in both patients was caused by etretinate. Later the basal cell nevus syndrome patient was given 13-cis-retinoic acid, which caused no liver test disturbances during a follow-up period of 6 months.",1
8632,6698350,[Cirrhosis induced by vitamin A],"The case of a 75-year-old woman who had been treated for 12 years by vitamin A (250,000 UI/day) for psoriasis is presented. During the hospitalisation, hepatic cirrhosis was detected and attributed to hypervitaminosis A based on disease history, clinical hypervitaminosis A features, increased vitamin A blood values and histological patterns, i. e. perisinusoidal fibrosis and spontaneous fluorescence of lipid vacuoles within fat-storing cells. Thus, although rare, vitamin A intoxication can be responsible for cirrhosis.",1
8633,6700042,"Oral contraceptives, pregnancy, and focal nodular hyperplasia of the liver","There is uncertainty regarding the role, if any, of oral contraceptive steroids in the development of focal nodular hyperplasia of the liver. In a 36-year-old woman, a large left hepatic lobe tumor developed that was detected after 11 years of using these drugs. The tumor regressed when administration of the drug was stopped but began to increase in size during a subsequent pregnancy. A left hepatic lobectomy during the second trimester disclosed focal nodular hyperplasia. Both contraceptive steroids and pregnancy, with high levels of endogenous sex steroids, favored tumor growth in this patient, suggesting that focal nodular hyperplasia can be steroid related.",1
8634,6703837,Hepatic infarction related to oral contraceptive use,"The first case of oral contraceptive (OC)-related common hepatic artery thrombosis with subsequent hepatic infarction is reported. Hepatic complications of OC use are enumerated and the clinical manifestation of hepatic infarction is described. Propranolol hydrochloride, because of its effect on liver blood flow, may have contributed to this disease process.",1
8635,6706074,"Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies","The hepatic morphological findings in 3 patients treated with amiodarone, a potent and effective antiarrhythmic drug, are reported. An enlarged liver and mild elevation of hepatic enzymes were the most important clinical findings. Fibrosis, cholangitis, mixed inflammatory infiltrate, and cytoplasmic granularity of the hepatocytes were the main histologic changes common to all cases. In 2 of the cases the presence of Mallory bodies was confirmed by electron microscopy. In 1 of these 2 cases, Mallory bodies were also confirmed by immunostaining. Ultrastructurally, numerous cytoplasmic inclusions with a membranous or lamellar structure identical to those described in phospholipidosis were the most striking features seen in hepatocytes, biliary epithelial cells, Kupffer cells, and endothelial cells.",1
8636,6710648,[Heparin-induced increase in serum aminotransferase],,1
8637,6712030,Transaminase elevations in patients receiving bovine or porcine heparin,"Eighty-six patients who required heparin therapy were randomly assigned to receive bovine or porcine heparin. Abnormal concentrations of alanine transaminase and aspartate transaminase developed during treatment in 59.3% and 26.7% of patients, respectively. Patient characteristics that significantly influenced the development of abnormal alanine transaminase concentrations were male sex and higher baseline enzyme values. Transaminase concentrations returned to normal in 80% of patients after heparin therapy was discontinued and in 20% during therapy. Analysis of transaminase concentrations in all 86 patients showed that 95% had some increase in enzymes during treatment. Mean maximal increase over baseline for all patients was 3.6 for alanine transaminase and 3.1 for aspartate transaminase (range, 1.0 to 15). Lactate dehydrogenase concentrations became abnormal in 35.7% of patients. Lactate dehydrogenase isoenzyme determinations in 6 patients showed elevated hepatic fractions. No clinical symptoms of hepatic dysfunction were seen.",1
8638,6715854,Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride,"Methylphenidate-induced hepatic injury was documented by abnormal liver function tests including a markedly elevated serum bilirubin, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase. Liver biopsy confirmed portal inflammation and hepatocellular disarray. Enzyme changes were reproducible with rechallenge of the drug (Ritalin). The drug is capable of producing hepatic injury, particularly when given in nonstandard doses intravenously.",1
8639,6723229,Hepatic enzyme elevations associated with baclofen,,1
8640,6729767,[Median- and long-term tolerability of diltiazem],,1
8641,6731219,Chlorpropamide hepatitis,,1
8642,6732411,Acute hepatic injury associated with minocycline,"Minocycline hydrochloride hepatotoxic effect occurred in one patient. Unlike the usual histologic features of tetracycline-induced hepatic injury, fatty metamorphosis was predominantly macrovesicular . The patient recovered when drug therapy was withdrawn. Close observation of liver function variables is recommended in patients treated with high parenteral doses of minocycline, particularly in cases of pregnancy or renal disease.",1
8643,6739935,[Hepatitis caused by isoniazid: study of 9 cases],,1
8644,6741977,Phencyclidine-induced malignant hyperthermia causing submassive liver necrosis,"This report describes three male patients arrested for aggressive and combative behavior, characteristic of phencyclidine intoxication, in whom severe hyperthermia, respiratory failure, and coma developed. Two days after the malignant hyperthermic event, serum transaminase levels rose acutely to extremely high levels with concomitant elevations in bilirubin levels and a fall in prothrombin activity. Liver biopsy specimens in two patients showed marked perivenular necrosis and collapse. No specific treatment was directed at the phencyclidine intoxication. Two of the three patients survived. Submassive liver necrosis caused by malignant hyperthermia is an unusual complication of phencyclidine abuse.",1
8645,6748800,[Cholestasis hepatitis caused by erythromycin propionate],,1
8646,6751834,Tizanidine in the treatment of spasticity,"A double-blind crossover trial compared tizanidine with baclofen in 36 patients with spasticity. Tizanidine appeared to reduce lower limb spasticity more effectively and to have fewer side effects, but no statistically significant differences emerged when the two drugs were compared. An additional open study of tizanidine confirmed the beneficial action in a selected minority of patients with spasticity. This drug may have an important role in the management of spasticity, but further studies are required.",1
8647,6753681,Cimetidine: II. Adverse reactions and patterns of use,"""Numerous adverse reactions have been attributed to cimetidine, which is understandable in view of the attention and scrutiny the drug has received, its widespread use, and its systemic effects. The reported frequency of side effects has differed considerably but is surprisingly low in all studies. The drug has caused an array of central nervous system disturbances, gynecomastia, and, rarely, hepatotoxicity, interstitial nephritis, bradycardia, hypotension, and even cardiac arrest. The last complication has occurred with rapid-bolus intravenous injection. Blood dyscrasias have also been rare and usually associated with serious underlying disease or multiple drugs, making it difficult to establish cause and effect in most cases. The drug is used widely to treatment conditions for which it is not approved. Some of these conditions are now believed to respond to cimetidine (gastric ulcer); others are known not to respond (acute upper gastrointestinal bleeding and acute pancreatitis).""",1
8648,6758252,Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report: the results up to 24 months. Hong Kong Chest Service/British Medical Research Council,"Five 6-month antituberculosis regimens, allocated at random to patients with acid-fast bacilli in their sputum on microscopy, were studied. Four, given 3 times a week throughout, contained isoniazid and rifampicin together with 1. streptomycin, pyrazinamide and ethambutol, 2. streptomycin and pyrazinamide, but no ethambutol, 3. streptomycin and ethambutol, but no pyrazinamide, 4. pyrazinamide and ethambutol, but no streptomycin. The fifth was a daily regimen of isoniazid, rifampicin, pyrazinamide and ethambutol. All 833 patients with drug-sensitive strains of tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy, and the bacteriological relapse rate during 18 months after stopping chemotherapy was 1% for the three-times-weekly regimens containing streptomycin and pyrazinamide in addition to isoniazid and rifampicin (regimens 1 and 2, above) and for the daily regimen, 2% for the regimen of isoniazid, rifampicin, pyrazinamide and ethambutol three times a week (regimen 4), but 8% for the only regimen which did not contain pyrazinamide (regimen 3). The results achieved by the 4 pyrazinamide regimens were practically as good for the 110 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment as they were for the patients with drug-sensitive strains.",1
8649,6762682,[Hepatitis during captopril combination therapy],,1
8650,6769385,Fatal Reye-like syndrome associated with valproic acid,,1
8651,6770287,Seizure management in acute hepatic porphyria: risks of valproate and clonazepam,"Seizures may occur in acute intermittent porphyria or other hepatic porphyrias. Management is difficult, because barbiturates and hydantoins exacerbate the porphyric state. We studied one patient with major motor seizures and acute intermittent porphyria. The seizure disorder was exacerbated by phenytoin and did not respond to a high-carbohydrate diet or to intravenous hematin. Clonazepam was ineffective in treating the seizures and, in high doses, seemed to exacerbate the porphyria. Both clonazepam and valproate were porphyrinogenic in experimental test systems. Because both drugs may exacerbate the acute hepatic porphyrias, bromide remains the drug of choice to treat these seizures.",1
8652,6771598,[Dacarbazine (DTIC) therapy and the Budd-Chiari syndrome],"A case of a 58 years old female is presented, who died because of a Budd-Chiari-syndrome. This complication had developed during treatment with Dacarbazine (DTIC), which was given after surgical removal of a malignant melanoma. The causative relation between the Budd-Chiari-syndrome and this cytostatic drug is discussed, even though the influence of other drugs cannot be excluded.",1
8653,6776355,[Hypersensitivity vasculitis and granulomatous hepatitis induced by glybenclamide: a case report (author's transl)],"The second case in the medical literature of hypersensitivity vasculitis induced by glybenclamide is reported, and for the first time vasculitic lesions are demonstrated in the histopathological study of liver tissue. The case was a male patient admitted because of a febrile illness and generalized malaise of long duration. He had diabetes mellitus that was being treated with glybenclamide. Physical examination disclosed fever, poor general condition, hepatomegaly, and red nodes in the finger-tips of both hands. Abnormal laboratory parameters included normochromic normocytic anemia, leukocytosis with a high eosinophil count, and markedly elevated erythrocyte sedimentation rate. There was as well slight cytolysis and marked elevation of cholestatic serum enzymes without hyperbilirubinemia. Biopsy of the skin lesions demonstrated anular granulomata, a common lesion in diabetics. The histopathological study of the liver revealed a vasculitic hypersensitivity reaction with conspicuous granulomata located in the vicinity of blood vessels and in the wall of portal arterioles, the endothelium of the latter being disrupted at different levels. Glybenclamide withdrawal resulted in a clinical, biological and histopathological cure of the disease. Unlike the previously reported case, the patient remains alive, and this may partly have been due to early institution of corticosteroid therapy.",1
8654,6779941,Mistletoe hepatitis,"A 49-year-old woman presented with nausea, general malaise, and a dull ache in the right hypochondrium. Liver biopsy showed slight inflammatory-cell infiltration, and results of liver function tests suggested hepatitis. Hepatitis B surface antigen was not detected, and a cholecystogram was normal. Two years later she presented with similar symptoms, and both illnesses were found to have occurred after ingestion of a herbal remedy containing kelp, motherwort, skullcap, and mistletoe. A challenge test established this to be the cause of the illness. Mistletoe is the only constituent of the tablets known to contain any potential toxin and thus was probably the cause of the illness. Mistletoe is widely used in herbal remedies, whose ingestion may therefore cause hepatitis.",1
8655,6784611,Accidental ingestion of liquid zinc chloride: local and systemic effects,"The case of a 24-year-old man who accidentally ingested liquid zinc chloride is presented. Local caustic effects included erosive pharyngitis and esophagitis. Nausea, vomiting and abdominal pain, as well as hypocalcemia and hyperamylasemia, suggested acute pancreatitis. Microhematuria occurred, but renal function did not deteriorate. Lethargy and confusion, noted previously in another case of hyperzincemia, were present. Chelation therapy was instituted, with reversal of the clinical and biochemical effects of zinc poisoning.",1
8656,6786601,Hepatic vascular lesions associated with dacarbazine treatment,"Dacarbazine is widely used in the treatment of melanoma. Transient abnormalities of liver function tests are well-recognised side effects of the drug, but acute liver failure due to vascular occlusion in patients receiving single-agent chemotherapy with dacarbazine has been noted only rarely. Two cases are reported in which hepatic vascular lesions developed during treatment with dacarbazine and were confirmed at necropsy. Hepatic vascular occlusion due to treatment with dacarbazine may be less rare than was previously thought. Greater caution may be needed when dacarbazine is prescribed, particularly as an adjuvant agent in stage I and II disease.",1
8657,6791819,Phase I trial of pentamethylmelamine: a clinical and pharmacologic study,"""Pentamethylmelamine (PMM) is a water-soluble monodemethylated derivative of hexamethylmelamine and has a similar spectrum of activity against murine tumors. Unlike hexamethylmelamine, it is suitable for parenteral administration. We conducted a phase I trial of PMM given as a weekly 1-hour iv infusion to 34 extensively pretreated patients with advanced solid tumors. Eight dose levels ranging from 80 to 1500 mg/m2 were studied. A median of three infusions (mean, 4.2; range, 1-24) were given to each patient. Severe nausea and vomiting was dose-limiting at 1500 mg/m2; it was unresponsive to antiemetics and persisted up to 48 hours. Mild to moderately depressed levels of consciousness were seen in one third of the patients at dose levels of greater than or equal to 750 mg/m2. Consistent dose-related myelosuppression was not observed. Hepatocellular toxicity manifested by elevated serum transaminases occurred sporadically, usually in patients with liver metastases, but could not be unequivocally attributed to the drug. No complete or partial tumor responses were noted. At each dose level, the pharmacokinetics of PMM disappearance from plasma were studied in one to three patients with a gas chromatograph-mass spectrometer assay which exclusively measured the unmetabolized drug. The data obtained wee consistent with a two-compartment model of drug distribution, with a mean dose-independent terminal half-life of 143 minutes (range, 43-370). Peak drug levels were directly proportional to dose. The relative lack of myelotoxicity would make PMM an attractive candidate for addition to combination regimens if antitumor activity at tolerable doses could be documented. On this schedule, the recommended dose is 100 mg/m2 for phase II trials.""",1
8658,6796404,A case of fatal toxic hepatitis: recommendations for the administration of sodium valproate,,1
8659,6799876,Tube feeding reconsidered,,1
8660,6805622,Diclofenac hepatitis,,1
8661,6807326,Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment,"""The effects of long-term gemfibrozil (Lopid) therapy on human liver structure are not known. Studies of this nature are becoming essential in determining the risk/benefit ratio since gemfibrozil is an effective agent for the control of hyperlipoproteinemia types IIa, IIb, and IV. Particularly, gemfibrozil is effective when dietary management or available therapeutic control fail to reduce serum cholesterol and triglycerides as well as normalizing the lipoprotein pattern. Percutaneous liver biopsies of 9 patients on long-term gemfibrozil therapy were evaluated by light microscopy, interference contrast optics and transmission electron microscopy. The distribution of patients according to lipoprotein phenotype was 3 Type IIa, 3 Type IIb, and 3 Type IV. Their lipoprotein patterns approached normal and the serum lipids were controlled during gemfibrozil therapy. By light microscopy, the lobular architecture and other parameters were within normal limits. Varying degrees of fatty change were found as would be expected. No preferential lobular disposition of the fat globules was evident. Coalescence of fat droplets, nuclear displacement and fatty cysts were noted. Differential interference contrast microscopy revealed several degrees of contrast amplitude in these droplets suggesting a heterogeneous lipid deposition in hepatocytes. The subcellular analysis revealed a moderate degree of glycogen deposition, absence of nuclear abnormalities and unremarkable mitochondria; the rough endoplasmic reticulum was not significantly altered and smooth surfaced membranes appeared proliferated. Detailed analysis of the peroxisome population showed matrix rarefaction, marginal plate formation and spurious densities though no significant proliferation occurred. Distribution of peroxisomes in hepatocytes varied widely from cell to cell and in different lobular areas. This study confirmed the association of hepatic fatty change with hyperlipoproteinemia irrespective of the pattern observed in circulating lipoproteins. Peroxisome proliferation, as seen in rodents when receiving gemfibrozil, did not occur and the structure of these subcellular organelles was not compromised. It was concluded that the long-term administration of this compound did not show adverse effects on the hepatocyte in hyperlipoproteinemia.""",1
8662,6811394,Valproate-induced hepatic injury: analyses of 23 fatal cases,"Analyses of 23 fatal instances of hepatic injury in patients taking valproic acid reveals that all but three were less than 20 years old, and all but four had been taking the drugs for more than 1 month. Convulsions, facial edema, lassitude, and vomiting were prominent clinical features. Hypoglycemia was recorded in six patients. Rash and eosinophilia were not seen. Values for transaminases were modestly elevated in most patients. Most levels of SGOT were below 500 IU, and SGPT levels were below 200 IU. Livers showed microvesicular steatosis in most patients, usually accompanies by necrosis. Four patients had cirrhosis. Overt valproic acid-induced hepatic injury appears to be rare and hence, by definition, idiosyncratic. That it may be an idiosyncratic exaggeration of a much more frequent phenomenon is suggested by the higher incidence of seemingly trivial injury. The idiosyncrasy appears to be metabolic rather than immunologic, and the available information leads to the plausible hypothesis that a metabolite is responsible for the microvesicular steatosis seen in most fatal cases. The steatosis resembles that of Reye's syndrome and Jamaican vomiting sickness, and there is reason to believe that the metabolite responsible for the steatosis resembles the agent responsible for Jamaican vomiting sickness. A different metabolite is presumably responsible for the necrosis seen in many of the cases.",1
8663,6813444,Carnitine deficiency and hyperammonemia associated with valproic acid therapy,"""Plasma carnitine and blood ammonia concentrations were measured in 25 severely handicapped patients, ages 3 to 21 years, and 27 age-matched control subjects. Fourteen of the handicapped patients were treated with anticonvulsant drugs including valproic acid; the remaining 11 patients were treated with drugs excluding valproic acid. Plasma carnitine concentrations were lower and blood ammonia values were higher in patients treated with valproic acid than in the untreated patients and control subjects. A significant inverse relationship was found between plasma carnitine concentrations and the dosage of valproic acid, and between plasma carnitine and blood ammonia values. After oral administration of D,L-carnitine (50 mg/kg/day) for four weeks, both carnitine deficiency and hyperammonemia were corrected.""",1
8664,6817146,[Liver damage caused by valproic acid],,1
8665,6819143,Decreased serum carnitine in valproate induced Reye syndrome,"A 3-year-old girl developed acute liver disease after treatment with valproate for 6 months. She developed the typical features of Reye syndrome. Serum free carnitine was decreased as well as 3-keto-valproic acid, the main metabolite of beta-oxidation of valproate. The serum valproate concentration was at the upper limit of the therapeutic range. The possible importance of carnitine in the pathogenesis of valproate induced liver disease is discussed.",1
8666,6824189,Placebo controlled double blind study with pentoxifylline of walking performance in patients with intermittent claudication,"A double blind placebo-controlled randomised crossover study was performed with Pentoxifylline (Trental 400 tablets with 400 mg active ingredient) in 24 patients (19 males, 5 females, aged between 40 and 71 years) suffering from peripheral occlusive arteriopathy of stage II severity (Fontaine's classification). In 12 patients (group I) the treatment was started with placebo, and in another 12 subjects with Pentoxifylline (group II). The dosage was 3 tablets of either formulation t.d.s., the treatment periods were 8 weeks each with a two week washout between. The standardised walking test (120 steps/min under metronome control) was used for the assessment of the walking capacity. There was a significant 60% increase in pain-free walking distance in either Pentoxifylline treatment periods, whereas there were no clinically relevant changes in the placebo periods. When comparing the two starting periods only, there was an increase in the Pentoxifylline group from 223 to 359 m on average and in the placebo group from 208 to 215 m, patients in both groups being comparable at basal level as to the distribution of sex, age, location of occlusion, duration of disease as well as in respect to the walking capacity. No adverse reactions were recorded during the trial.",1
8667,6830396,Methyldopa-induced immune hemolytic anemia and chronic active hepatitis,Immune hemolytic anemia and chronic active hepatitis developed concurrently in a 76-year-old man after prolonged therapy with methyldopa. Both complications disappeared following cessation of treatment with the offending drug and a short course of a high-dose corticosteroid (prednisone). Inhibition of T-suppressor lymphocyte function by methyldopa may be instrumental in the emergence of autoimmune complications following usage of the drug.,1
8668,6842343,Veno-occlusive disease of the liver associated with cysteamine treatment of nephropathic cystinosis,,1
8669,6844981,Carbamazepine-induced liver injury,"""Two patients had carbamazepine-induced liver injury. The clinical, biochemical, and histologic data suggest hepatitis of the idiosyncratic hypersensitivity type with granulomas in one patient; in the other, the liver injury resembles that caused by a hepatotoxin. Both patients showed prompt recovery upon discontinuation of the drug.""",1
8670,6848304,Acetaminophen in chronic liver disease,"The safety of acetaminophen in therapeutic doses was evaluated in subjects with stable chronic liver disease. Six subjects with chronic liver disease were given 4.0 gm daily for 5 days. Although the mean half-life (t 1/2) acetaminophen was 3.42 hr, there was no evidence of drug cumulation or hepatotoxicity. A double-blind, two-period crossover design was also used to evaluate acetaminophen in 20 subjects. Acetaminophen, at a dose of 4.0 gm daily for 13 days, was well tolerated by these subjects with stable chronic liver disease. One subject developed symptoms, which worsened and were associated with deterioration in the results of laboratory studies, while taking acetaminophen. Subsequent challenges with 4.0 gm acetaminophen daily for periods of 10 and 14 days were well tolerated, which indicates that the deterioration was not related to the drug. During this study there were no abnormalities indicative of an adverse reaction to acetaminophen. There is, therefore, no contraindication to the use of acetaminophen in therapeutic doses in the presence of stable chronic liver disease.",1
8671,6849209,"Prospective, randomized comparison of metronidazole and clindamycin, each with gentamicin, for the treatment of serious intra-abdominal infection","Metronidazole (M) has potent bactericidal activity against anaerobic bacteria. This study was designed to compare its efficacy and safety when combined with gentamicin (M + G) to those of an accepted regimen, clindamycin plus gentamicin (C + G), for the treatment of intra-abdominal infection. Patients were randomly allocated to receive 500 mg of M or 600 to 800 mg of clindamycin (C) each combined with G, 1.5 mg/kg, all administered intravenously every 8 hours. Of 186 patients enrolled, 45 were excluded from analysis (22, M + G). Of the remaining 141 patients, 72 had been allocated to the M + G group. Data refer to M + G and C + G groups, respectively. Infections included abscess in 37 and 30 patients and peritonitis in 30 and 31. Appendicitis was the most common underlying disease, causing intra-abdominal infection in 21 and 22 patients, with diverticulitis occurring next most frequently, seven and 10 patients. Both anaerobic and aerobic bacteria were isolated from abdominal pus in 32 and 27 patients, anaerobes alone in seven and four, and aerobes alone in 24 and 25. In six and seven patients, pus was not cultured. Anaerobic bacteremia occurred in 10/66 and 6/64 patients from whom blood was cultured. Patients were classified as cured, improved, or treatment failures. These ratios were 60:8:4 and 58:8:3. Median trough serum concentrations of M and C were 13.0 and 3.7 micrograms/ml, respectively, and at 15 minutes after infusion, 15 and 10.7 micrograms/ml, respectively. The frequencies of rash, diarrhea, and superinfection were not different in the two treatment groups although abnormal serum tests of liver function occurred more commonly in the C+G group. M+G and C+G are not different in efficacy and acceptability for the therapy of serious intra-abdominal infections in adults.",1
8672,6851057,"Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias","Ninety-six patients with recurrent, drug-refractory tachyarrhythmias were treated with amiodarone for 8.0 +/- 7.5 months (range 1 day to 27 months): 77 for recurrent ventricular tachycardia or ventricular fibrillation (VT/VF), two for complex ventricular ectopy, and 17 for supraventricular tachyarrhythmias. The actuarial incidence of successful amiodarone therapy was 52 +/- 7% at 12 months and 28 +/- 9% at 24 months for patients with VT/VF. Neither patient with complex ventricular ectopy was successfully treated. Among the patients with supraventricular tachyarrhythmias, 64.7% were successfully treated for 7.7 +/- 7.6 months (range 1 to 22 months). Amiodarone toxicity occurred in 66 of 91 patients (72.5%) treated for more than 1 week. Fourteen patients had therapy-limiting toxicity. Of these 14, six had pulmonary toxicity, four had arrhythmia exacerbation, one had hepatitis, one had renal toxicity, one had rash, and one had erythema nodosum. The actuarial incidence of therapy-limiting side effects was 27 +/- 7% at 15 months. We conclude that amiodarone is useful in the treatment of refractory tachyarrhythmias but that the rate of efficacy in VT/VF is lower and the incidence of significant toxicity is higher than has been generally appreciated.",1
8673,6852419,[Hepatitis caused by diclofenac],,1
8674,6853130,Hepatic lesions in patients on anabolic androgenic therapy,"The histopathological changes in the livers of 11 patients treated with alkylated and nonalkylated anabolic androgenic steroids are presented. The histological changes in the liver included: proliferation of the bile ducts with or without cystic dilatation (9/11), peliosis (8/11), atypical hyperplasia of liver cells (2/11), and tumors (3/11). The latter included one case of cholangiocarcinoma, one of hepatocellular carcinoma, and one of combined cholangiocellular and hepatocellular carcinoma. The pathological changes in the liver in this series suggest a possible relationship between anabolic androgenic steroids and bile duct proliferation and/or cholangiocarcinoma.",1
8675,6857425,Hepatic complications of antituberculosis therapy revisited,"""Since 1973, when the incidence and pattern of adverse reactions to antituberculosis therapy were described by Rossouw and Saunders, para-amino-salicylic acid, the major cause of drug-induced hepatitis, has been withdrawn from the regimen used in Cape Town and replaced with pyrazinamide (PZA). Our study in the same hospital indicates that although the substitution has resulted in a significant reduction in the incidence of all side-effects (4,1% v. 9%; P less than 0,001), the incidence of hepatitis is unchanged (0,3%). PZA is currently the major cause of hepatitis associated with antituberculosis therapy.""",1
8676,6859708,Enflurane hepatotoxicity. A clinicopathologic study of 24 cases,"Analysis of 24 cases of enflurane anesthesia-associated hepatic injury shows that the clinical, biochemical, and histologic features are similar to those seen with halothane- and methoxyflurane-related hepatitis. Postoperative fever was the presenting symptom in 19 patients. Jaundice occurred in 19 patients after a mean latent period of 8 days. Sixteen patients had been previously exposed to enflurane or halothane, and the latent period from exposure to the onset of symptoms or jaundice was shortened in these patients. There were five fatalities among the entire group. Liver biopsy most characteristically showed centrilobular necrosis, occasionally with ballooning degeneration and fatty change. The presumed mechanism of injury is metabolic idiosyncracy, and prior exposure to a haloalkane anesthetic may increase the risk of hepatic injury after enflurane administration.",1
8677,6860059,Fulminant hepatitis associated with disulfiram. Report of a case,"Disulfiram is used commonly as reinforcement in the treatment of chronic alcoholism. Although the drug is generally considered safe, there are reports of side effects including psychosis and hepatitis. We report a case of fatal fulminant hepatitis caused by the use of disulfiram in a man with previously normal hepatocellular function.",1
8678,6871924,Effects of long-term administration of diltiazem hydrochloride in hypertensive patients,"""The efficacy and safety of long-term administration of diltiazem hydrochloride were investigated in eight patients with essential hypertension given the drug for approximately five years. Subjective symptoms improved within one to two months after therapy was begun, and no new symptoms appeared. A generally satisfactory blood pressure reducing effect was achieved with no evidence of the escape phenomenon developing over the course of long-term therapy. No exacerbations in ECG findings, cardiothoracic index, or heart rate were observed. Long-term administration of diltiazem had no adverse effects on urinalysis; hematological values; metabolism of protein, lipids, and glucose; renal or hepatic function; or electrolytes. It is thus concluded that diltiazem hydrochloride can be safely given for long periods to patients with hypertension.""",1
8679,6873616,Intrahepatic cholestasis and sicca complex after thiabendazole. Report of a case and review of the literature,"Thiabendazole is a relatively safe and effective agent with a wide range of activity against nematodes infesting the gastrointestinal tract. A 55-yr-old man developed prolonged jaundice and sicca complex after a course of thiabendazole therapy. Endoscopic retrograde cholangiopancreatography demonstrated normal biliary tree and pancreatic ducts. Liver biopsy was consistent with a drug-induced intrahepatic cholestatic reaction. The patient recovered completely from his liver injury, but the sicca complex persisted 1 yr after the drug was given. The literature on thiabendazole-induced cholestasis and its association with sicca complex is reviewed.",1
8680,6874749,[Renodigestive fistulas. Apropos of 3 cases],"Two cases of left renocolic fistula and one case of a double renogastric and left renocutaneous fistula are reported. Diagnostic difficulties are encountered in these affections, their origin being usually from the kidney. Enlarged nephrectomy appears to be the only possible treatment in the majority of cases, the attitude adopted in respect of the digestive viscera involved varying according to local conditions.",1
8681,6876886,Acute toxicity after excessive ingestion of colchicine,"A 15-year-old girl was admitted to a hospital in Rochester, Minnesota, 40 hours after the ingestion of 24 mg of colchicine. She suffered severe cardiovascular, pulmonary, hematologic, gastrointestinal, renal, metabolic, and neuromuscular complications but ultimately survived. Colchicine is an uncommon but potentially serious source of acute toxicity. An overdose warrants prompt attention in a setting where intensive medical support is available.",1
8682,6879565,[Quinidine-induced hepatitis. A case report and review of the literature],,1
8683,6883354,Acute liver dystrophy with thrombosis of hepatic veins: a fatal complication of dacarbazine treatment,"In the course of adjuvant single-agent chemotherapy with dacarbazine after extirpation of malignant melanoma, a fatal complication was observed in four of our patients. During the second cycle of therapy liver failure due to massive hepatic necrosis supervened, with widespread thrombosis of liver veins. The clinical and pathologic features of our patients are compared with the findings in eight published cases. The possible pathogenesis is discussed in detail, and Budd-Chiari syndrome caused by an allergic thrombophlebitis with secondary liver cell necrosis seems to be most probable.",1
8684,6884586,Dihydralazine hepatitis: report of a case and review of the literature,"The authors report the case of a patient with hepatitis after the administration of dihydralazine, an analogue of hydralazine which is widely used in Europe. Hepatitis occurred during the administration of dihydralazine, quickly improved when the administration of dihydralazine was interrupted, and worsened again when it was resumed. Hepatitis was severe with hepatic encephalopathy and prolonged prothrombin time. There was centrizonal and bridging necrosis. After interruption of the drug administration, the outcome was favorable, but fibrotic sequelae were observed on a follow-up histologic examination.",1
8685,6885713,Arsenic and liver,,1
8686,6886083,Zinc toxicity in ruminants,"Four natural occurrences of zinc toxicity in sheep and one in calves were studied. To assist in the confirmation of a diagnosis of zinc toxicity, 2 experiments were conducted in which sheep were given toxic amounts of zinc. The clinical findings, clinical pathology, and gross and microscopic pathology are given. Clinical manifestations included inappetance, loss of condition, diarrhoea with dehydration or subcutaneous oedema, profound weakness and jaundice. Significant rises in the concentration of zinc were usually found in the liver, kidney and pancreas, but occasionally in only 1 or 2 of these organs. Many affected sheep were anaemic. Pathological changes were found in the pancreas, kidney, liver, rumen, abomasum, small intestine and adrenal gland. Lesions in the kidney and abomasum apparently made the most significant contribution to the deterioration in health of affected animals, but the pancreas was the only organ consistently affected. The degenerative changes in the pancreas were mainly restricted to the exocrine portion of the organ, and regeneration of the damaged tissue was observed although exposure to toxic amounts of zinc continued. Attention is drawn to the importance of the pancreas in the diagnosis of zinc toxicity and in estimating the period of exposure.",1
8687,6888059,[Carbamazepine and methyldopa: a hepatotoxic combination?],,1
8688,6891179,Arsenic-related hepatic angiosarcoma,"Data from several small autopsy series in German vintners in the 1940s and 1950s and a number of case reports have previously suggested that arsenic is a cause of hepatic angiosarcoma (HAS). In a nationwide review of deaths from HAS in the United States, we identified seven cases with a history of prolonged use of Fowler's solution (inorganic potassium arsenite), which provide further support for the association of arsenic exposure and HAS. An epidemiologic study of a cohort of individuals treated long-term with Fowler's solution might confirm this association.",1
8689,6894634,Methsuximide for refractory complex partial seizures,"The efficacy and safety of methsuximide were evaluated for 12 weeks in 21 patients with complex partial (psychomotor) seizures refractory to conventional anticonvulsants. After addition of methsuximide to the previous anticonvulsant regimens, the number of complex partial seizures per patient decreased from a weekly average of 5.8 to 0.9 seizures. A 90 to 100% control of complex partial seizures was achieved in 15 (71%) of the patients. Dose reduction or discontinuation of one or more previous medications was possible in 42%. Seizure control was optimal at methsuximide doses of 9.5 to 11.0 mg per kilogram per day and plasma levels of 20 to 24 micrograms per milliliter. Adverse experiences, particularly somnolence and lethargy, were reported by 12 patients. Methsuximide appeared to be an effective and generally well tolerated adjunct medication in the management of complex partial seizures.",1
8690,6929214,High rate of long-term survivals in AML treated by chemotherapy and androgenotherapy: a pilot study,"An unexpectedly high rate of long-term survivors in acute myeloid leukemia (AML) has been observed in a group of patients who achieved a first complete remission (CR) after induction of a therapeutic regimen including daunorubidomycine, vincristine, prednisone and stanozolol, and anabolizing steroid. The rate of CR was 52%. Maintenance therapy was very simple and the only association with stanozolol during this period suggested to us that an androgen, at low dosages, might be responsible for the unusual long-term survival time (45 months with a 95% confidence limit from 30 to 86 months). On the basis of our first observation, high dosages of the androgen were used during the induction phase of treatment but failed to demonstrate any advantage when associated with a drug regimen, including cytosine arabinoside (ARA-C). The reevaluation of each parameter for our group of patients did not allow selection of patients in terms of their age or the hematologic data obtained at presentation. Effects of androgen on the socalled normal hemopoietic cells and on the leukemic cells are discussed, particularly the possible antagonistic effect with ARA-C. A prospective statement is made concerning the possible condition of the prolongation of the complete remission in AML according to some experimental data which enforce the stimulative activity of androgen on the myeloid proliferation.",1
8691,6937637,Life-threatening neuropathy and hepatotoxicity in infants during induction therapy for acute lymphoblastic leukemia,,1
8692,6948549,Phenytoin induced granulomatous hepatitis,,1
8693,6954286,An unusual case of hypersensitivity vasculitis probably due to allopurinol,,1
8694,6959544,Adverse reactions of L-asparaginase,"Adverse reactions to L-asparaginase in children undergoing induction therapy for acute lymphocytic leukemia have previously been described and have been noted to include hypersensitivity reactions, pancreatitis, hepatic dysfunction, nephrotoxicity, and central nervous system dysfunction. Recently, however, newly described abnormalities in hematological and hemostatic function have resulted in intracranial hemorrhage and thrombosis of the extremities, immune hemolytic anemia and abnormal collagen stimulated platelet aggregation. The coagulopathy appears to be a result of a combination of events related to decreased synthesis of fibrinogen, antithrombin III and plasminogen. Implications for future modifications of L-asparaginase therapy are further discussed.",1
8695,6965509,Erythromycin ethylsuccinate hepatotoxicity,,1
8696,6968680,Hepatotoxicity of rifampicin and isoniazid in children treated for tuberculosis,"In order to determine the hepatotoxicity of rifampicin in children treated for tuberculosis, a survey was performed of 18 children receiving this medicine in combination with isoniazid. Fifteen of the 18 children (83%) showed a rise in ASAT values and 11 (61%) in ALAT values exceeding 29U/L. Seven children with maximal ASAT values between 40 and 100 U/L were treated without any changes in the regimen and the transaminases normalized later in the treatment. Six out of the eight children with ASAT values over 100 U/L were allowed a three-week pause in their therapy, one was given the same dose of rifampicin, and in one the treatment was discontinued entirely. The therapy was discontinued in an additional three children because of a second high rise in the transaminase values. Liver injury can occur at any time during treatment, and thus makes continuous follow-up tests necessary.",1
8697,6973390,Phase I study of 2'-deoxycoformycin in acute lymphoblastic leukemia,"2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2'-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2'-dCF which were not associated with limiting toxicities. These results suggest that 2'-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.",1
8698,6979924,Erythromycin ethylsuccinate-induced cholestasis,,1
8699,6980110,Hepatotoxicity to both erythromycin estolate and erythromycin ethylsuccinate,"Two patients experienced hepatotoxicity associated with erythromycin estolate (Ilosone) usage, followed 13 and 15 years later by an hepatotoxic reaction with administration of erythromycin ethylsuccinate (E.E.S.). These cases provide further evidence for erythromycin ethylsuccinate-associated hepatotoxicity and demonstrate erythromycin cross-sensitivity after previous erythromycin estolate liver injury. Hepatotoxicity to both sensitivity after previous erythromycin estolate liver injury. Hepatotoxicity to both estolate and ethylsuccinate preparations of erythromycin stimulates speculation regarding the potentially hepatotoxic moiety of the erythromycin molecule. Furthermore, these cases suggest that all erythromycin preparations should be avoided or used only with careful monitoring in patients with previous erythromycin-associated liver injury.",1
8700,6981160,Adverse reactions to trimethoprim-sulfamethoxazole in hospitalized patients,"Of 1,121 hospitalized recipients of trimethoprim-sulfamethoxazole, 91 (8%) experienced reactions that were attributed to this drug. The most common adverse effects were gastrointestinal upset (3.9%) and skin reactions (3.3%). Serious toxicity attributable to the drug was rare.",1
8701,6984402,[Hepatitis due to erythromycin ethylsuccinate],,1
8702,6988202,Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis,"Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It has been studied in osteoarthritis, pain resulting from musculoskeketal sprains and strains and from minor surgery and cancer. The duration of its analgesic effect is longer than that of aspirin and diflunisal is effective when given twice daily. Diflunisal is not metabolised to salicylic acid and has a lesser effect than aspirin on platelet function in vivo. In osteoarthritis, diflunisal appears comparable in efficacy to moderate doses of aspirin (2 to 3g daily), but is better tolerated. It has not been compared with the most active phenylalkanoic acid derivatives such as naproxen in adequate numbers of patients. Diflunisal is comparable with glafenine in pain and with propoxyphene/paracetamol combinations and oxyphenbutazone in pain and in musculoskeletal strains and sprains. As with other non-steroidal agents, gastrointestinal complaints are the most frequently reported side effects.",1
8703,6997146,[Quinidine-induced subclinical hepatitis],,1
8704,6998337,Rifampin-isoniazid therapy of alcoholic and nonalcoholic tuberculous patients in a U.S. Public Health Service Cooperative Therapy Trial,"A history of alcoholism is often regarded as a relative contraindication to the use of isoniazid and rifampin in patients with tuberculosis. To test the validity of this assumption the outcome of 6 months of rifampin-isoniazid therapy was analyzed for the first 531 eligible patients enrolled in a U.S. Public Health Service Cooperative Trial of Short-Course Chemotherapy of Pulmonary Tuberculosis. In this study, data were available to classify a patient as an alcoholic in the following 2 ways: (1) patient's statement that he was a moderate, heavy, or excessive user of alcohol, or (2) patient's score of 6 or more on a Brief Michigan Alcoholism Screening Test (MAST). Based on their statements, 58% of the patients were classified as alcoholic, whereas only 17.9% were thus classified by their MAST scores. Although alcoholics had more abnormal concentrations of aspartate aminotransferase (AST) before and during therapy, there was no significant difference between the alcoholics and non-alcoholics in the incidence of adverse reactions, including hepatotoxic reactions, including hepatotoxic reactions, attributed to the drugs. We concluded that in the absence of clinically significant and persistent pretreatment abnormalities of hepatic function tests, rifampin and isoniazid are not contraindicated in patients categorized as alcoholic by our 2 commonly used methods.",1
8705,7000451,Methotrexate therapy of psoriasis. Effect and side effects with particular reference to hepatic changes. A survey,,1
8706,7002704,An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation,"In order to assess the prevalence of venocclusive disease in autopsied recipients of bone marrow transplantation, we reviewed coded liver histology from 204 consecutive autopsied recipients transplanted for leukemia (142), other malignancies (5), or aplastic anemia (57). Twenty-seven patients with leukemia, 2 with carcinoma, and 3 with aplasia had venocclusive disease and survived 2-86 days post-transplant. Early lesions showed subintimal edema and hemorrhage within small central venules and centrilobular congestion with hepatocyte degeneration. Later lesions showed subtotal to complete fibrous obliteration of the central venule lumina and centrilobular sinusoidal fibrosis. Thirteen patients had a subclinical course, and 19 were symptomatic. Venocclusive disease was life-threatening or lethal in 13. Typical symptoms developed 1-3 wk post-transplant and consisted of sudden weight gain, hepatic enlargement, ascites, high bilirubin, and encephalopathy. Statistical analyses showed a significantly higher prevalence of venocclusive disease associated with transplantation for leukemia (P = 0.014), pretransplant conditioning with more rigorous chemoradiotherapy regimens (P < 0.001) and three- to fourfold increase of venocclusive disease in patients whose conditioning included dimethyl busulfan (P < 0.005). Abnormal liver tests before transplant were also more prevalent among patients with venocclusive disease. No factors predicted the clinical outcome of established venocclusive disease. Venocclusive disease showed no association with hepatic graft-versus-host disease even among prolonged cases with severe periportal hepatitis and cholestasis. Other centrilobular lesions (hepatocyte degeneration, sinusoidal fibrosis, and phlebosclerosis) were identified in 23 patients. These non-specific changes may occur with viral hepatitis, graft-versus-host disease or chemoradiotherapy effects.",1
8707,7005620,The use and misuse of androgens,"Because testosterone is rapidly metabolized by the liver, it is necessary either to administer androgens by injection in the form of testosterone esters that are absorbed slowly into the circulation or to administer by mouth derivatives that are slowly metabolized by the liver. The later derivatives, however, have deleterious side effects that limit their usefulness. Long-acting parenteral androgen esters are the treatment of choice in the replacement therapy of male hypogonadism. Because these esters must be hydrolyzed to the free hormone prior to exerting their cellular actions the effectiveness of therapy can be monitored by following plasma testosterone levels. All known effects of the endogenous hormone can be duplicated except for the induction and maintenance of normal spermatogenesis. Androgens have been tried in a variety of clinical situations other than male hypogonadism in the hopes that the nonvirilizing actions would outweigh any detectable side effects. The only disorders in which a salutary effect has been documented are hereditary angioneurotic edema and some patients with anemia due to failure off the bone marrow.",1
8708,7010713,Regression on oxymetholone-induced hepatic tumors after bone marrow transplantation in aplastic anemia,"Treatment of acquired aplastic anemia with androgens has been occasionally associated with the development of hepatic tumors. We have studied a 13-year-old boy with idiopathic aplastic anemia in whom oxymetholone treatment was associated with a partial hematological remission. Thirty-four months later, however, the patient developed multiple hepatic tumors. When oxymetholone therapy was discontinued, the aplastic anemia relapsed. He then underwent bone marrow transplantation from his HLA-A, B, and D-compatible sibling. This was followed by hematological and immunological reconstitution. The hepatic tumors underwent progressive regression after bone marrow transplantation. The patient is now 3 years post-bone marrow transplantation and is in complete remission of his aplastic anemia with no evidence of detectable liver tumors.",1
8709,7011347,Hepatitis associated with captopril treatment,,1
8710,7016449,"A double-blind comparative trial of new muscle relaxant, tizanidine (DS 103-282), and baclofen in the treatment of chronic spasticity in multiple sclerosis","A double-blind trial with two parallel groups was carried out to compare the antispastic effect and tolerability of a new muscle relaxant, tizanidine (DS 103-282), with those of baclofen in the treatment of spasticity due to multiple sclerosis. Twenty-one hospitalized patients with stable spasticity participated in the 6-week trial. Eleven received tizanidine and 10 baclofen in gradually increasing daily doses. The optimal daily dose of tizanidine was between 8 and 36 mg and that of baclofen between 10 and 80 mg. Overall spastic state, spasms and clonus were similarly improved with both medications. In contrast, muscle strength, bladder function and the activities of daily living were more improved on tizanidine than on baclofen. Tiredness was the most frequent side-effect on tizanidine and muscle weakness on baclofen. The laboratory tests did not show any pathological changes with either medication. According to these results, tizanidine provides a new therapeutic alternative in the treatment of spasticity.",1
8711,7021122,Piroxicam: a review of its pharmacological properties and therapeutic efficacy,"Piroxicam is an N-heterocyclic carboxamide of 1,2 benzothiazine 1,1 dioxide with analgesic and anti-inflammatory activity. It has an extended half-life of about 40 hours and is suitable for once daily administration. Published studies indicate that piroxicam 20mg daily is comparable with aspirin 3 to 6g. indomethacin 75 to 150mg, phenylbutazone 400mg, naproxen 500mg, ibuprofen 1200 to 2400mg and diclofenac 75mg in rheumatoid arthritis. In osteoarthritis, piroxicam 20mg daily is comparable in efficacy with aspirin 2.6 to 3.9g, indomethacin 75mg, naproxen 500mg and fenbufen 600mg but is generally better tolerated than aspirin or indomethacin in patients with arthritic diseases. Piroxicam 20mg was at least as effective as indomethacin 75mg in a study in ankylosing spondylitis. As with other non-steroidal anti-inflammatory drugs gastrointestinal complaints are the most frequently reported side effects and their frequency and severity appears to be dose-related.",1
8712,7023307,Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: the National Cooperative Gallstone Study. A controlled trial of efficacy and safety,"A double-masked study was conducted to determine the efficacy and safety of randomly allocated chenodiol (chenodeoxycholic acid, 750 mg/d or 350 mg/d) or placebo administered for 2 years to 916 patients for dissolution of radiolucent gallstones. There was confirmed complete dissolution in 13.5% of patients (750 mg/d), 5.2% (375 mg/d), and 0.8% (placebo), p less than 0.0001. Partial (over 50%) or complete dissolution (by validated roentgenographic metrology) occurred in 40.8% (750 mg/d), 23.6% (375 mg/d), and 11.0% (placebo), p less than 0.0001. Dissolution occurred more frequently in women, thin patients, or patients with small or floating gallstones or serum cholesterol greater than or equal to 227 mg/dL. Clinically significant hepatotoxicity occurred in 3% of patients (750 mg/d), 0.4% (375 mg/d), and 0.4% (placebo), p less than 0.007, and always was reversible biochemically. Elevations of 10% or more of serum cholesterol, mostly low-density lipoproteins, occurred in 85.2% of patients (750 mg/d), 82.8% (375 mg/d), and 67.0% (placebo), p less than 0.001. Chenodiol, 750 mg/d for up to 2 years, is appropriate therapy for dissolution of gallstones in selected patients who are informed of the risks and benefits.",1
8713,7029276,Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study,"It has been suggested that because propranolol decreases portal venous pressure, it may prevent gastrointestinal bleeding associated with portal hypertension. We randomly assigned 74 patients with cirrhosis, who were admitted because of gastrointestinal bleeding, to either oral propranolol given in doses that reduced the heart rate by 25 per cent (38 patients) or to a placebo (36 patients). The proportion of patients free of recurrent gastrointestinal bleeding one year after inclusion in this study was 96 per cent in the propranolol group and 50 per cent in the placebo group (P less than 0.0001). We conclude that continuous administration of propranolol by mouth is effective in preventing recurrent gastrointestinal bleeding in patients with cirrhosis.",1
8714,7033784,Medical intelligence drug therapy: captopril,,1
8715,7037877,Methotrexate guidelines--revised,,1
8716,7041349,Cyclosporin A hepatotoxicity in 66 renal allograft recipients,"Liver functional abnormalities were seen in 13 (19.7%) of 66 recipients of cadaveric renal homografts treated with cyclosporin A and prednisone. However, such presumed hepatotoxicity was a minor problem in the use of cyclosporin A. The complication was less frequent than that of nephrotoxicity, was as easily manageable with reductions in the cyclosporin A dosage, and generally did not cause clinical illness. In an occasional case, late hepatotoxicity can force a therapeutic change from cyclosporin A to azathioprine, but careful consideration should be given to the dangers of subsequent rejection.",1
8717,7042484,Liver disease after bone marrow transplantation,"Liver dysfunction occurs after bone marrow transplantation but the relative importance of graft versus host disease and other factors, such as infection, radiation, and drugs, has not been clearly established. We have studied liver status before and after bone marrow transplantation in 43 consecutive patients and have related this to survival and factors that are recognised to cause liver injury. Minor abnormalities of liver tests occurred in 21% of patients before grafting but this did not influence survival or the development of liver disease after transplantation. During the first 50 days after grafting, 83% of patients had abnormal liver tests which were more severe in patients who subsequently died. Alanine transaminase was significantly higher in non-survivors and appeared to predict survival early after transplantation. Only non-survivors developed clinical signs of liver disease. Severe liver disease was always associated with graft versus host disease and atypia of the small bile ducts was the most useful histological marker of hepatic involvement with this disease. Two of the patients with hepatic graft versus host disease also has hepatic veno-occlusive disease and three fatalities had opportunistic infection of the liver, although, in the latter, death was not due primarily to liver dysfunction. Previous hepatitis and androgen therapy could not be implicated as important causes of hepatic damage but chemotherapy for acute leukaemia and conditioning regimens for bone marrow transplantation appear to be the most important factors in the development of hepatic veno-occlusive disease.",1
8718,7044735,Diltiazem hydrochloride,,1
8719,7045360,Aspirin and fenoprofen (Nalfon) in the treatment of juvenile rheumatoid arthritis results of the double blind-trial. A segment II study,"We compared efficacy and safety of aspirin (ASA) and fenoprofen in the treatment of JRA. Ninety-nine children with JRA were given ASA or fenoprofen in a 12-wk, multicentered, double-blind, parallel study. Initial fenoprofen dosage was 900 mg/m2/d increased to 1800 mg/m2/d (3200 mg/d-max). Initial ASA dosage was 1500 mg/m2/d increased to 3000 mg/m2/d (5450 mg/d-max). Adverse reactions forced removal of 14% of ASA treated patients from the trial, whereas no fenoprofen patient was removed for this reason. Forty of 50 ASA patients, and 47 of 49 fenoprofen patients completed at least 10 wk of therapy and analysis showed that the 2 drugs were nearly identical in efficacy, but toxicity was considerably less among fenoprofen treated patients.",1
8720,7048664,Evaluation of antithymocyte globulin for human bone marrow transplantation. Antihematopoietic and immunosuppressive activity,Antihematopoietic stem cell activity and immunosuppressive activity were evaluated before and after absorption of horse antihuman thymocyte globulin (ATG) with mature granulocytes and fetal liver cells. Unabsorbed ATG was cytotoxic to committed myeloid-macrophage progenitors (CFU-C). Absorption of ATG removed cytotoxicity to CFU-C. The immunosuppressive potentials of absorbed ATGs were identical to those of unabsorbed ATG in several tests. Primary response to trinitrophenyl (TNP)-modified autologous and allogeneic cells could be suppressed by treatment with ATG alone whereas suppression of secondary and cytotoxic responses required treatment with ATG and complement. These data indicate that unsensitized or undifferentiated T cells may be more sensitive to ATG than are sensitized or differentiated T cells.,1
8721,7049659,Amoxapine: a review of its pharmacology and efficacy in depressed states,"Amoxapine is an N-demethylated dibenzoxazepine closely related in the neuroleptic loxapine. Its tricyclic structure appears to give it antidepressant properties resembling imipramine and amitriptyline. In uncontrolled trials it was shown to have antidepressant activity in usual doses up to 200 to 400mg daily. In placebo and double-blind controlled studies comparing amoxapine with the standard tricyclic antidepressants imipramine and amitriptyline, it was shown to be comparable in efficacy with a possibly somewhat faster onset of improvement of selected symptoms of depression in some studies. Because of the small study groups and lack of placebo control, many reports do not show statistically significant differences of treatment over standard drugs. To date there have been no studies comparing amoxapine with electroconvulsive therapy. Side effects were qualitatively similar to standard drugs with a suggestion that in standard doses or overdose myocardial effects are mild. However, the final place of amoxapine in the therapy of depressed states is still to be decided.",1
8722,7051241,Adverse reactions to trimethoprim-sulfamethoxazole,"A comprehensive review is presented of the world literature on adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMZ) since its first use in 1968, when concern was expressed about possible hematologic toxicity. Serious toxicity is a rare event, but when it occurs severe skin lesions and thrombocytopenia/leukopenia are the most likely complications. Like other antibacterial agents, TMP-SMZ is associated with gastrointestinal upset, but adverse reactions affecting the kidney, liver, and fetus are rare. If the use of TMP-SMZ in pregnant women and in those known to be sensitive to the drug is avoided and if there is an awareness of possible drug interactions, therapy with the combination in the usual clinical setting is not associated with serious toxicity.",1
8723,7053705,Hepatic veno-occlusive disease caused by 6-thioguanine,"Clinically reversible veno-occlusive disease of the liver developed in a 23-year-old man with acute lymphocytic leukemia after 10 months of maintenance therapy with 6-thioguanine. Serial liver biopsies showed the development and resolution of intense sinusoidal engorgement. Although this disease was clinically reversible, some subintimal fibrosis about the terminal hepatic veins persisted. This case presented a unique opportunity to observe the histologic features of clinically reversible hepatic veno-occlusive disease over time, and may be the first case of veno-occlusive related solely to 6-thioguanine.",1
8724,7056156,[Salicylate induced disturbances of liver function (author's transl)],,1
8725,7060471,[Hepatotoxicity of acetylsalicylic acid],,1
8726,7062188,Use of ticarcillin following carbenicillin-associated hepatotoxicity,,1
8727,7065742,Rheumatoid arthritis: treatment with azathioprine (IMURAN (R)). Clinical side-effects and laboratory abnormalities,"A retrospective review of the literature has been carried out to determine laboratory abnormalities occurring in patients with rheumatoid arthritis (RA) treated with azathioprine, in order to establish a profile for this agent in the treatment of this disease. A total of 542 patients in 24 studies, reported in the literature, were given a range of doses of azathioprine for up to four years. Fifteen percent of patients were withdrawn because of toxicity. The two major toxic effects were gastrointestinal symptoms and alteration in blood counts. Clinically significant leucopenia (less than 2500/mm3) occurred in 14 of the total of 93 patients reported to have developed leucopenia. Some adverse reactions, which would have been expected from the use of azathioprine in other diseases, were uncommon, namely significant infections, hepatotoxicity and pancreatitis. Adverse experience with azathioprine in rheumatoid arthritis compares well with other slow-acting, or disease modifying, drugs.",1
8728,7068113,A prospective morphologic evaluation of hepatic toxicity of chenodeoxycholic acid in patients with cholelithiasis: the National Cooperative Gallstone Study,"""A sample of 126 patients with cholelithiasis was treated with chenodeoxycholic acid (CDCA) (375 or 750 mg g.d.) for 2 years. Hepatotoxicity was assessed by sequential light (LM) and electron microscopic (EM) analysis of liver biopsies obtained before and after 9 and 24 months of therapy. Patients were without symptoms of biliary colic for 3 months prior to biopsy, less than 70 years old, and had normal tests of liver function. All light microscopy was read blindly by two morphologists, and electron microscopy by one. Only four biopsies (3%) showed severe (3+) abnormalities preventing admission to the study. On evaluation, moderate (2+) LM changes were present in less than 12% of biopsies, while milder changes (1+) were seen more frequently. No severe, dose-related abnormalities were seen in LM over the 2 years of study. However, mild changes (hepatocyte ballooning and lipofuscin, binucleate cells, glycogen nuclei, ductular proliferation, enlarged and fibrotic triads, and sinusoidal congestion) became more prevalent with time (p less than or equal to 0.01) regardless of CDCA dose, according to 1 of the 2 morphologists. Because patients with """"proven"""" cholelithiasis for greater than 2 years (33% of the study population) did not have a greater incidence of morphologic abnormalities than those with the diagnosis for less than 2 years, it is unlikely that these changes were due to the natural history of gallstone disease. Furthermore, electron microscopic findings demonstrated worsening intrahepatic cholestasis and a lesion in two patients which was identical to that produced in animals administered lithocholic acid, the 7-alpha-dehydroxylated metabolite of CDCA. the possibility that clinically significant hepatotoxicity could develop with CDCA therapy greater than 24 months thus cannot be excluded by this study.""",1
8729,7068976,A study of potential hepatotoxicity of etretinate used in the treatment of psoriasis,"Etretinate was used to treat twenty patients who had severe, disabling psoriasis and an increased risk of liver damage. Potential hepatotoxicity was evaluated by obtaining liver biopsies prior to starting therapy and after a 6-month course on a dosage of 0.75 mg/kg/day. In comparing pretreatment biopsies to posttreatment biopsies, five of twenty patients demonstrated a morphologic change in their liver. Three showed progressive fatty metamorphosis, and two showed liver cell necrosis and progressive fibrosis. One of these was due to heavy alcohol intake. Based on our 6-month evaluation, etretinate does not produce a consistent toxic effect on the liver.",1
8730,7070561,Flucloxacillin-associated liver damage,,1
8731,7074431,Liver lesions and oral contraceptives,"The association of cavernous hemangioma, focal nodular hyperplasia, and hemangiomatosis of the liver has not previously been described in the literature. A case report of a patient who presented with these 3 lesions simultaneously is reviewed. The 32-year-old obese woman presented with upper abdominal pain of recent onset. No liver abnormality had been noted at the times of cholecystectomy and cesarean section, each performed some years before. She had taken oral contraceptives (OCs) 6 years earlier for about 6 months. Now the liver was enlarged and contained a firm, nontender mass that extended to 1 handsbreadth below the right costal margin and across the epigastrium. No bruit was noted. Results of hematologic and biochemical investigations were within normal limits. Ultrasonography revealed a solic mass, and selective celiac arteriography showed that the mass occupied the right lobe of the liver and was predominantly avascular, with small areas of pooling of contrast material. An operation revealed, in addition to the mass, many irregular purplish areas 2-4 mm in diameter in both lobes of the liver. Close to the free edge of the left lobe was a yellowish brown and slightly modular firm mass. The pathological report listed a giant cavernous hemangioma of the right lobe, several disseminated cavernous hemangiomata, multiple disseminated vascular ectasiae (hemangiomatosis) and 1 lesion of focal nodular hyperplasia in the left lobe. 27 days after the operation, scintiscanning revealed evidence of good liver regeneration. Another scan 3 years later revealed regeneration of the liver to normal size and no focal abnormalities. Due to the fact that increasing numbers of cases of focal nodular hyperplasia and liver cell adenomas have been reported in association with OCs and in view of the possible association between these drugs and hemangioma, caution in prescribing these drugs is recommended.",1
8732,7077803,Aspirin as a risk factor in Reye's syndrome,,1
8733,7078580,Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion,"""Children with inborn errors of urea synthesis accumulate ammonium and other nitrogenous precursors of urea, leading to episodic coma and a high mortality rate. We used alternative pathways for the excretion of waste nitrogen as substitutes for the defective ureagenic pathways in 26 infants. These pathways involve synthesis and excretion of hippurate after sodium benzoate administration, and of citrulline and argininosuccinate after arginine supplementation. The children were treated for seven to 62 months; 22 survived. The mean plasma level of ammonium ( +/- S.E.) was 36 +/- 2 mumol per liter, and that of benzoate was 1.5 +/- 1.0 mg per deciliter. Alternative pathways accounted for between 28 and 59 per cent of the total """"effective"""" excretion of waste nitrogen. Nineteen infants had normal height, weight, and head circumference, and 13 had normal intellectual development. Activation of alternative pathways of waste nitrogen excretion can prolong survival and improve clinical outcome in children with inborn errors of urea synthesis.""",1
8734,7080870,Myocarditis and methyldopa,,1
8735,7081289,Hepatitis following cimetidine administration,There have been only two reports of cimetidine-induced hepatitis. Such a low incidence suggests a hypersensitivity type of reaction. The case of an adult who developed both hepatic dysfunction and an impaired macrophage migration after exposure to cimetidine is discussed.,1
8736,7083715,Pleural effusion and ascites: unusual presenting features in a pediatric patient with vitamin A intoxication,"The usual presenting features of vitamin A intoxication are pseuotumor cerebri, skeletal pain, desquamative dermatitis, and hepatic inflammation. Our patient was a nine-year-old female who had increasing cough, dyspnea, and abdominal distention for a short time prior to admission. She was said to have been treated with 10,000 units of vitamin A per day for skin rashes. Radiographic studies revealed a very large right sided pleural effusion, ascites, demineralized bones, and retarded skeletal maturation. The diagnosis of hypervitaminosis A was made. More detailed medical history confirmed that the child had, in actuality, received up to 300,000 units/day of vitamin A plus desiccated liver pills and carrot juice for the previous year. Clinical symptoms completely abated following acute medical treatment for ascites and cessation of vitamin A intake. Several months later, a sample of liver, obtained and preserved at the time of exploratory laparotomy, was homogenized and extracted with ethanol/hexane. The retinyl palmitate level was significantly elevated and consistent with vitamin A poisoning.",1
8737,7091946,Reversible hepatic veno-occlusive disease and 6-thioguanine,,1
8738,7092282,The dapsone syndrome,,1
8739,7093923,Secondary treatment of polycythemia rubra vera with 6-thioguanine,"6-thioguanine, an antimetabolite not potentiated by allopurinol, has been used in the treatment of 29 patients with polycythemia vera. All but two of the patients had been treated previously by venesection and/or radioactive phosphorus (32p) and/or alkylating agents. The usual dose was 40-160 mg daily alternate weeks according to individual response. The treatment period varied from 6-66 months (mean, 31 months). Of 27 evaluable patients 24 (89%) responded to treatment and at one year there was a significant fall in all blood count parameters. Seven patients relapsed while on treatment and four were withdrawn because of side effects. 6-thioguanine merits further evaluation in the management of polycythemia vera, particularly in those patients who have received large cumulative doses of 32p and/or alkylating agents and in whom an alternative mode of therapy is desirable.",1
8740,7095372,Haloperidol-induced chronic cholestatic liver disease,"A 15-yr-old patient with chronic cholestatic liver disease associated with haloperidol therapy is presented. Emphasis is placed on the pattern of biochemical abnormalities and on the histologic features observed in the four serial biopsies which demonstrated a pronounced injury to the bile duct epithelium, correlating well with the clinical and biochemical abnormalities. During the early stage of illness, the clinicopathologic features simulated obstructive jaundice, whereas a resemblance to chronic chlorpromazine-induced cholestasis or primary biliary cirrhosislike syndrome was striking as the chronicity developed. Comparison is made of the features in our patient with those in 2 patients with biopsy-documented, acute haloperidol-induced liver disease reported for the first time in 1977. Despite the lack of concrete evidence, both the clinical and morphologic features, and the close temporal relationship between the medication and onset of illness in this patient led to the reasonable inference that haloperidol was responsible for the chronic cholestatic reaction on a hypersensitivity basis.",1
8741,7107495,Hepatic failure following mebendazole administration to a dog,,1
8742,7112492,[Ticlopidine: blood and liver involvement?],,1
8743,7114646,Nitrofurantoin and chronic active hepatitis,,1
8744,7116312,Benign hepatic cyst in a patient on antiestrogen therapy for metastatic breast cancer,,1
8745,7117772,[Cholestatic jaundice associated with ingestion of ticlopidine: apropos of the first 2 cases],,1
8746,7118708,Hepatic cirrhosis associated with long-term anticonvulsant drug therapy in dogs,"Advanced chronic hepatic disease was observed in 5 dogs that had received anticonvulsant drug therapy for 2 to 3 years. Clinical signs included anorexia, weakness, and restlessness, and 2 dogs also had ascites. There were remarkable increases in the serum activities of alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. The total serum bile acid concentration was high in 3 of 4 dogs that were tested. Sulfobromophthalein excretion was delayed in all dogs. Histologic examination of liver specimens from 4 of the dogs demonstrated macronodular or micronodular cirrhosis.",1
8747,7129022,"""[Hepatitis due to Sulindac; a case with review of 3 precedents]""",,1
8748,7130740,Complications in methotrexate treatment of psoriasis with particular reference to liver fibrosis,"All patients taking methotrexate for treatment of psoriasis over the past 5 yr have been reviewed. Thirty-eight patients have had pretreatment liver biopsies and at least 1 repeat liver biopsy. Of the 38, nine (24%) have developed significant liver fibrosis or cirrhosis, and have stopped treatment. The high incidence of fibrosis is attributed to synergism between methotrexate and other hepatotoxic factors, particularly alcohol, the use of a baseline biopsy to identify subsequent changes, and the early detection of fibrosis by sensitive histological techniques.",1
8749,7136416,Benign liver tumors and oral contraceptives,"""The article presents the case of a healthy 30 year old patient, parity 2, who had been on oral contraception (OC) for 15 years. She sought medical advice for an egg-sized, mobile abdominal mass; when the patient noted that the mass had considerably increased in size laparotomy was performed. The operation revealed a slightly nodular, pedunculated tumor the size of an orange; it was classified as a well differentiated benign hepatic adenoma. About 2/3 of benign liver neoplasms thought to be the results of estrogen/progestogen treatment can be defined as true hepatic cell adenomas; the remainder are known as focal nodular hyperplasia. The lesions are probably the reaction of the normal hepatocyte to the metabolic changes induced by chronic administration of estrogen or progesterone; they are usually aggravated by smoking. In the cases reported in the published literature the time of exposure varies from 6 months to 12 years; the risk is greater with longer exposure, age over 30, """"older"""" high potency OC containing mestranol, and smoking. A detailed patient's history is essential for correct diagnosis, together with manual examination; liver scans, ultrasound examination and arteriography are very useful. Treatment consists in discontinuing OC. Hemorrhage from the tumor carries a mortality of 6-8%. Surgery should be performed if regression of the tumor does not occur within a few months after withdrawal of OC. About 10% of these benign tumors undergo malignant changes.""",1
8750,7143157,Complete hematologic and hepatic recovery in a patient with chloramphenicol hepatitis-pancytopenia syndrome,,1
8751,7148508,Fatal hepatitis following irradiation and vincristine,"The increasing use of combination therapy with irradiation and cytostatics in malignant disease increases the risk of toxicity. An account is given of a patient with liver toxicity terminating fatally, in whom increased radiosensitivity may have been induced by vincristine.",1
8752,7157374,Hepatotoxicity and pulmonary toxicity of pennyroyal oil and its constituent terpenes in the mouse,,1
8753,7172968,"Adverse effects of methicillin, nafcillin and oxacillin in pediatric patients","68 patients (from newborns to 18 years of age) were studied prospectively for adverse effects associated with methicillin, nafcillin and oxacillin. Hematologic, liver and renal function tests were monitored before and during therapy. 3 of 28 patients receiving methicillin developed eosinophilia within 5-8 days. Of 32 patients on nafcillin, 2 had neutropenia within 4-13 days, 3 had eosinophilia within 1-4 days and 1 elevated liver enzymes on day 3. Of 8 patients receiving oxacillin, 1 developed neutropenia on day 11 and another showed elevation of liver enzymes on day 15. All abnormalities were reversible with the discontinuation of therapy. Appropriate laboratory tests should be monitored to detect an occurrence of adverse reaction to methicillin, nafcillin and oxacillin.",1
8754,7189278,Chronic vitamin A intoxication in infants fed chicken liver,"Twin female infants were fed 120 gm of chicken liver homogenate daily for four months. They developed irritability, vomiting, and bulging anterior fontanelles. Computed tomograms of the brain revealed enlarged ventricles in both infants and dilated subarachnoid spaces in one. Plasma vitamin A concentrations were elevated. After all sources of vitamin A intake were stopped, the infants recovered without sequelae. The chicken liver homogenate contained 36,000 IU of vitamin A per 120 gm. Since infants often receive 4,000 units of vitamin A daily from fortified milk and vitamin supplements, they probably cannot be fed 60 gm of chicken liver safely more often than once weekly.",1
8755,7191664,Cephalosporin hepatitis,,1
8756,7194443,Safety of anticonvulsants in hepatic porphyrias,"Because acute attacks of porphyria may be precipitated by anticonvulsants, a therapeutic dilemma arises when seizures complicate hepatic porphyria. The list of unsafe agents includes barbiturates, primidone, phenytoin, mephenytoin, ethotoin, ethosuximide, methsuximide, phensuximide, and trimethadione. Agents are considered unsafe if they induce experimental porphyria in animals, and short trials in patients are unreliable for screening. Using drug incubation in chick-embryo hepatocyte culture, we found that porphyrin was increased by carbamazepine, clonazepam, and valproate. These agents should probably be avoided or used with caution in porphyric patients. Alternative approaches to acute porphyric attacks with seizures are discussed.",1
8757,7195872,Precursor stage of hepatocellular neoplasm following long exposure to orally administered contraceptives,"Hepatic neoplasms and peliosis are known to occur in women taking contraceptives orally. We observed hyperplasia of hepatocytes combined with hypertrophy of sinusoidal lining cells and sinusoidal dilatation with progression to peliosis in the liver of a patient who had been taking such contraceptives for 10 years. These changes resembled the precursor stage in the development of hepatic angiosarcoma induced by vinyl chloride, Thorotrast, and arsenic. In users of orally administered contraceptives these findings may precede the development of hepatocellular neoplasms.",1
8758,7196210,Methazolamide-induced hepatitis and pure RBC aplasia,,1
8759,7197395,Multiform quinidine toxicity,,1
8760,7198070,Hypervitaminosis A unmasked by acute viral hepatitis,"""A case of acute hypervitaminosis A complicating viral hepatitis is reported. Twenty days after presenting with hepatitis B, a 42-yr-old vegetarian developed acute hypervitaminosis A in the absence of recent, massive exposure to the vitamin. Findings included headache, confusion, skin desquamation, and hypercalcemia. Prior to developing hepatitis, he had ingested supplemental vitamin A without recognized ill effect. Liver and serum vitamin A without recognized ill effect. Liver and serum vitamin A levels were both elevated; the liver biopsy showed abundant, lipid-filled Ito cells and perisinusoidal fibrosis. This case demonstrates that patients with excessive hepatic stores of vitamin A may develop hypervitaminosis A during acute, intercurrent liver disease. Levels of retinol binding protein are reduced in hepatitis. This phenomenon may account for the findings in this case, since vitamin A is more toxic when not specifically bound to retinol binding protein. The size of the population at risk for this complication of hepatitis in unknown, but presumably it is growing with the widespread use of supplemental vitamin A.""",1
8761,7199426,Epidemiology of hepatic angiosarcoma in the United States: 1964-1974,"""A nationwide survey of hepatic angiosarcoma (HAS) in the United States during the years 1964 through 1974 identified 168 cases. Of these, 42 cases (25%) were associated with known etiologic factors, such as vinyl chloride monomer exposure during preparation of poly(vinyl chloride), use of Thorotrast in angiography, exposure to inorganic arsenic, and treatment with androgenic-anabolic steroids; 126 cases (75%) are of uncertain etiology. HAS most often affects males (ratio of approximately 3:1), peaks in the sixth and seventh decades of life (somewhat earlier than other sarcomas of the liver) and appears to occur more often in the industrialized Northeast and Midwest (although reporting artifact may be a factor). There is an extraordinary relative risk for poly(vinyl chloride) polymerization workers; there may also be other chemical-industrial associations that require further investigation. Prospective epidemiologic studies of HAS should be considered as a means of identifying other causative factors (e.g., chemicals or drugs) related to HAS.""",1
8762,7200783,"Comparative evaluation of the effects of tetracycline, rolitetracycline and doxycycline on some blood parameters related to liver function","A comparative study was made on the effects of tetracycline (TC), rolitetracycline (RTC), and doxycycline (DC) at doses of 10-100 micrograms/g i.v. on serum GOT, GPT, bilirubin and urea levels of male and female mice. All tetracyclines at doses of 50-100 micrograms/g caused an increase of serum GOT and GPT activities in females after 2-8 h. This effect was less pronounced in males. The serum urea levels were markedly raised by TC and DC (50-100 micrograms/g) and RTC (10-100 micrograms/g). This effect was produced only in females. It was long-lasting (up to 8 h) after TC and RTC and more transient after DC. Likewise the tetracyclines affected the serum bilirubin only in females but not in males. All tetracyclines (25-100 micrograms/g) increased the amount of unconjugated and total bilirubin. This effect was most pronounced after TC, which also reduced the level of conjugated bilirubin.",1
8763,7203370,Prevalence of liver disease in patients taking salicylates for arthropathy,"110 patients with various arthropathies, mostly rheumatoid arthritis, treated with salicylates, were investigated for the presence of signs of liver disease attributable to this drug. An increased serum alkaline phosphatase level was observed in 9 of 96 ASA-treated patients with rheumatoid arthritis. However, this alteration could not be related to the use of salicylates, nor to the ingestion of any other antirheumatic drug. The hyperphosphatasemia persisted during a three-year follow-up in five of the nine patients.",1
8764,7203455,"""Nodular transformation (nodular """"regenerative"""" hyperplasia) of the liver. A clinicopathologic study of 30 cases""","""Nodular transformation, a rare hyperplastic condition of the liver, has been reported in patients with rheumatoid arthritis, Felty's syndrome, the CRST syndrome, and myeloproliferative disorders. Associated disorders in the present clinicopathologic study of 30 cases included the foregoing as well as extrahepatic neoplasms, endocrine disorders, and other diseases producing immune dysfunction; some patients had received drug therapy for a prolonged time. Clinically nodular transformation may be confused with cirrhosis; histologic evaluation of liver biopsy material is essential for diagnosis. Complications include portal hypertension, hepatic failure, and rupture of the liver. Histologic and experimental evidence suggests that nodular transformation is preneoplastic, possibly giving rise to hepatocellular adenomas or carcinomas. Experimental and clinical data suggest that drugs should be considered as possible etiologic factors in the development of the nodules.""",1
8765,7207544,Acute cholecystitis and thiazides,,1
8766,7212507,Hepatotoxicity due to treatment with verapamil,,1
8767,7214289,Cholestatic jaundice induced by flurazepam hydrochloride,,1
8768,7218735,[Veno-occlusive syndrome with acute liver dystrophy following decarbazine therapy of malignant melanoma (author's transl)],"Case report about death due to veno-occlusive liver disease following Dacarbazine treatment: 9 years after surgical treatment of malignant melanoma of the trunk a 68-years old patient developed lymph node metastases in the right axilla, which were removed immediately by surgical excision. One month before the patient had undergone surgical treatment of empyema of the gallbladder: Cholecystectomy and appendectomy were performed, postoperative recovery was uncomplicated. On account of the second lymph node metastasis within nine months adjuvant treatment with Dacarbazine was agreed and started one month later. After having performed the first course of treatment without any hints to intolerance the patient suddenly exhibited severe shock symptoms on the fourth day of the second course. Clinically residual myocardial infarct or pulmonary embolism were assumed, but could not be verified. The patient delivered increasing hepatomegaly. A massive increase in transaminase values was noted. Hemostasiologic changes with decreased Quick value occurred. The patient died of cerebral hemorrhage five days after beginning the second Dacarbazine cycle. Autopsy findings were severe liver cell necroses as well as liver vein thromboses, no metastases of melanoma could be found. Hepatotoxicity of Dacarbazine and the mechanism of liver vein thrombosis are discussed with special regards to possible hemostasiologic changes and sensibilisation due to Dacarbazine and/or previous liver cell damage.",1
8769,7224271,"Acute phencyclidine intoxication: incidence of clinical findings in 1,000 cases","""In 1,000 cases of phencyclidine (PCP) intoxication evaluated at the time of first examination in an emergency department, the incidence of """"typical"""" findings was found to be lower than has been reported previously. Nystagmus and hypertension occurred in only 57% of our cases; some patients had only one of these findings and many had neither. The incidence of violence was 35%; bizarre behavior, 29%; and agitation, 34%. Changes in sensorium consisted of coma, lethargy/stupor, and acute brain syndrome; however, 46% of patients were alert and oriented. Motor signs included grand mal seizures, generalized rigidity, localized dystonias, catalepsy, and athetosis. Profuse diaphoresis, hypersalivation, bronchospasm, and urinary retention occurred in less than 5%. A small percentage had severe disturbances in vital signs, including three cases (0.3%) of cardiac arrest and 28 cases (2.8%) of apnea. Hypoglycemia and elevated serum CPK, uric acid, and SGOT/SPGT were common. Urine PCP levels did not correlate with the severity of the clinical findings.""",1
8770,7230149,"Tetracycline-associated fatty liver of pregnancy, including possible pregnancy risk after chronic dermatologic use of tetracycline","Two cases of tetracycline-associated fatty liver of pregnancy are reported. In one, the history was negative for antibiotic use, yet autopsy revealed typical gross and microscopic bone fluorescence of tetracycline. Tissue extraction and chemical analysis showed qualitative evidence of tetracycline, whereas quantitation revealed 60 microgram/gm of wet bone tissue. Findings in our cases and in those from the literature indicate that the association of tetracycline use and fatty liver of pregnancy is even more common than has been suggested.",1
8771,7235421,Fatal reaction to dapsone during treatment of leprosy,"""A Burmese boy being treated with dapsone (diaminodiphenylsulfone [DDS]), 100 mg daily, for lepromatous leprosy had a fatal reaction to the drug 3 weeks after therapy was started. The clinical symptoms and progression of illness conform well to a """"DDS syndrome"""" first described in the early 1950s. Although the syndrome clinically resembles infectious mononucleosis, neither Epstein-Barr virus nor cytomegalovirus was implicated as an etiologic agent in this case. The syndrome has been recognized during initiation of dapsone therapy for lepromatous leprosy and has led to the use of a prolonged induction period with initial dosages as low as 25 mg/week. However, because dapsone resistance has been recognized in some strains of Mycobacterium leprae, slow induction of therapy has been replaced with the schedule used for this patient. This report of a fatal reaction to dapsone emphasizes the need for caution when initiating therapy with the drug at full dosage.""",1
8772,7235427,Evaluating isoniazid preventive therapy: the need for more data,,1
8773,7238251,Cimetidine-induced hepatitis. Electron microscopic observations and clinical pattern of liver injury,,1
8774,7247130,Granulomatous hepatitis secondary to carbamazepine,"Three cases of carbamazepine-induced granulomatous hepatitis are reported. Each patient had ingested carbamazepine for less than 1 month before presenting with a febrile illness suggestive of biliary tract infection. After withdrawal of carbamazepine, symptoms disappeared rapidly. Histologically, all patients had granulomatous hepatitis. Two patients also had acute cholangitis. Carbamazepine-induced liver injury can be confused clinically and pathologically with biliary tract infection.",1
8775,7253120,Cholestatic hepatitis caused by penicillamine,,1
8776,7256343,Intrahepatic cholestasis due to trimethoprim-sulfamethoxazole,,1
8777,7260802,Oral contraceptives and liver disease,"""Case reports are presented that link the use of oral contraceptives (OCs) to liver disease, particularly to the Budd-Chiari syndrome. This syndrome is caused by occlusion of hepatic veins and although a causative relation between OC use and this syndrome is not proven, these facts support an association: 1) the known increased incidence of venous thrombosis in women using OCs; 2) data from a review of 164 cases of the syndrome showed that in 1959 men and women suffered the syndrome about equally, but since 1975 after the introduction of OCs another study reported women contracting the disease twice as often as men; 3) the syndrome is associated with pregnancy; and 4) since the 1975 study, association with the pill was found in 16 reported cases. Clinically, the average age of these 16 women with OC-associated Budd-Chiari syndrome was 32 years. Length of time before onset of symptoms after beginning OC therapy varied from 2 weeks to 8 years (mean 23.8 months). In most cases, abdominal pain, nausea, vomiting, and abdominal distension were present. Hepatomegaly and ascites were described in most cases and splenomegaly in less than half. Liver function abnormalities were nonspecific. Prognosis is not good, and management techniques for the syndrome have been largely unsuccessful. Metabolic alterations of steroids as they pass through the liver may account for the syndromes associated with OC use. 3 major diseases or effects are linked with OCs: hepatic dysfunction, cholestatic jaundice, and benign hepatic tumors and peliosis hepatis; these, however, are benigh complications compared with the severity of contracting Budd-Chiari syndrome, and the clinician should respect a woman's decision not to use the pill in the face of such disease-inducing possibilities.""",1
8778,7262995,Role of arsenic and copper in the pathogenesis of Indian childhood cirrhosis,,1
8779,7267501,Complications of baclofen overdosage,"A 39-year-old female patient who had been receiving 30 mg of baclofen daily for 5 months was admitted to the hospital about 12 hr after overdose of this drug (450 mg). On admission, she was comatose, flaccid, and in respiratory failure. Later she developed muscle twitchings and had several epileptic fits. She was treated symptomatically and became conscious within 36 hr. However, approximately 65 hr after the overdose she developed sinus tachycardia which was successfully treated with oral propranolol. Plasma concentrations, as measured on days 2 and 3, were within the therapeutic range but the elimination half-life was prolonged.",1
8780,7270563,Salicylate hepatitis: a complication of the treatment of Kawasaki's disease,"""A case of salicylate hepatitis in a seven-week-old boy with Kawasaki's disease, mucocutaneous lymph node syndrome, is reported. The infant was admitted to the hospital with fever and a diffuse maculopapular petechial rash. He was treated with antibiotics for 72 hours for presumed septicemia. His condition deteriorated and he developed mucous membrane lesions and edema in his hands and feet. When the cultures of spinal fluid, blood, and urine were found to be negative, the antimicrobial therapy was discontinued; however, the cyanosis of his extremities progressed and gangrenous regions developed in his toe and finger pads. Oral aspirin therapy was started at a dosage of 100 mg/kg/day, every six hours. After five days, the rash, membrane lesions, and swelling in his hands and feet resolved. The cyanosis regressed. Liver enzyme tests revealed mild elevations of SGOT and LDH, and on the 12th hospital day these values peaked to a level consistent with salicylate hepatitis. The aspirin therapy was discontinued and within four days the liver function test results were normal. Aspirin therapy was reinstituted at a single daily dose of 30 mg/kg with no recurrence of hepatitis. The careful monitoring of liver function tests is recommended for children with Kawasaki's disease receiving aspirin therapy to avoid salicylate-induced hepatitis.""",1
8781,7276230,Drug-induced liver disease,,1
8782,7281269,[Disulfiram hepatitis],,1
8783,7283297,Cholestasis and toxic epidermal necrolysis associated with phenytoin sodium ingestion: the role of bile duct injury,,1
8784,7286784,Oxidative metabolism of halothane in the production of altered hepatocyte membrane antigens in acute halothane-induced hepatic necrosis,"Previous investigations have shown that patients with fulminant hepatic failure after halothane anaesthesia have a circulating antibody which reacts with an antigen present on the surface of halothane-altered hepatocytes. In the present study, it has been shown that the expression of the antigen is associated with the oxidative metabolism of halothane, in contrast with results of other groups which have shown that the reductive route is involved in the direct hepatotoxic reaction attributed to halothane.",1
8785,7292431,"[Fenofibrate, efficacy and tolerance in long-term treatment (author's transl)]",,1
8786,7300940,[Massive liver cell necrosis following administration of indomethacin in combination with aminophenzone],,1
8787,7305153,Spironolactone hepatitis in primary hyperaldosteronism,,1
8788,7307596,Preliminary results of six-month regimens studied in the United States and in Poland,,1
8789,7323715,Morphologic alterations in patients with alpha-methyldopa-induced liver damage after short- and long-term exposure,"Alpha-methyldopa-induced histologic alterations were investigated in 21 patients with hepatic injury after short- and long-term exposure. Seven patients developed liver injury within 6 months and 24 after several years (mean, 5 years) of exposure. Histologic findings and clinical and biochemical data differed significantly in the two groups. Morphologic analysis of the short-term-treated group revealed marked parenchymatous degeneration, focal, confluent and massive necrosis, and inflammation. Fatty accumulation and increased fibrous trabeculae were characteristic for the patients treated for long term. All patients in the short-term-exposed group had acute and severe hepatitis. Four of them had icterus. Two patients died of hepatic coma. Patients in the long-term-treated group had for several months initially mild but increasing discomfort, dyspepsia, nausea, and colics. Liver function tests in these groups revealed differences in serum albumin, bilirubin, and transferase levels. No changes were observed in alkaline phosphatase and Thrombotest. Fat accumulation and fibrous trabeculae suggest that the alterations precede the clinical symptoms and biochemical signs of hepatitis. The findings show that alpha-methyldopa may induce hepatocellular injury after short- and long-term exposure.",1
8790,7325149,Trimethoprim-sulfamethoxazole-induced cholestasis,A 52-year old woman developed severe cholestasis seven days after the administration of trimethoprim-sulfamethoxazole (RMP-SMZ) The clinical and pathologic features are discussed as well as the various mechanisms of liver injury following TMP-SMZ use.,1
8791,7327913,Hypertransaminasemia with subcutaneous heparin therapy,"An elevation of serum aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) may be produced in patients treated with i.v. full-dose HEPARIN. We studied the influence of low-dose s.c. HEPARIN (5,000 IU X 2) in 34 patients with acute myocardial infarction (AMI) and in 7 with cerebrovascular accidents or calf thrombophlebitis. Twelve patients (all males) with AMI showed a secondary elevation of GOT and GPT at about the sixth or seventh day after the commencement of therapy that persisted throughout the period of treatment. Four patients (two males and two females) with cerebrovascular accidents or thrombophlebitis showed similar increases of GOT and GPT.",1
8792,7336507,[Penicillamine induced liver involvement],,1
8793,7339949,[Intoxication with promethazine as a cause to liver damage],,1
8794,7346919,[Acetylsalicylic acid-induced hepatotoxicity],,1
8795,7350855,Nitrofurantoin and chronic active hepatitis,,1
8796,7350873,Nitrofurantoin-induced chronic active hepatitis,"Two patients developed a syndrome closely simulating the 'lupoid' form of chronic active hepatitis during prolonged therapy with macrocrystalline nitrofurantoin. Symptoms and biochemical indices of hepatocellular necrosis abated rapidly after discontinuation of drug therapy, but smooth muscle and antinuclear antibodies remained detectable more than 1 year later. The serologic features of the disease and a strongly positive lymphocyte transformation test in one of the patients suggest that the disorder may have been immunologically mediated.",1
8797,7359700,Herbal abortifacients,"3 cases of severe intoxication through the use of pennyroyal oil as an abortifacient agent are reported. The women, all residents in the Denver area, probably acted independently and did not seek advice from a common source. The women's nonuse of the local physician was not due to ignorance or nonavailability of abortion services, but seems to be part of a relatively widespread move away from conventional medicine. Needless to say, herbal preparation can be very harmful, and the public should be continually educated regarding the most popular forms of self-treatment.",1
8798,7362156,Trimethoprim-sulfamethoxazole-induced intrahepatic cholestasis,,1
8799,7364735,A comparison of trimipramine and imipramine: a controlled study,"Trimipramine, a new tricyclic antidepressant, was compared to imipramine in 38 hospitalized depressives. Both groups improved, with no major differences seen between the drugs. Analysis of the power of the statistical analysis shows that it is very unlikely that a true difference was present and not detected. There were fewer adverse reactions to trimipramine.",1
8800,7368395,[Liver involvement after treatment with naproxen],,1
8801,7369769,Methotrexate hepatotoxicity in psoriasis. Consideration of liver biopsies at regular intervals,"Fibrosis of the liver developed to a degree that contraindicated further treatment with methotrexate in 11 of 43 patients who had been receiving maintenance therapy with methotrexate for psoriasis. Liver biopsy had been performed prior to initiation of methotrexate therapy and was repeated at 12- to 18-month intervals. In this retrospective study, age of the patient and duration of therapy have been found to be significant factors in those patients receiving only the weekly oral dosage schedule. Yearly biopsies of the liver are recommended for patients who receive methotrexate throughout their courses of therapy.",1
8802,7374520,Hydroxyurea induced hepatitis,A case of hydroxyurea-induced self-limited hepatitis with an influenza-like reaction to hydroxyurea therapy is presented. The association was supported by recurrence of the symptoms on rechallenge with the drug.,1
8803,7379000,Hepatic veno-occlusive disease due to DTIC,"A case of fulminant hepatic failure leading to death in a patient receiving DTIC for metastatic melanoma is presented. Autopsy revealed widespread centrilobular necrosis secondary to a veno-occlusive process. There was no evidence of a similar process in other organs, and common causes of similar pathology were ruled out. It is likely that in this patient the hepatic failure was due to DTIC alone. Similar cases have been reported in patients receiving other chemotherapeutic agents. Physicians using these drugs should be aware of this side-effect of therapy, since it is often fatal.",1
8804,7382094,Life-threatening hypersensitivity to sulindac,,1
8805,7383683,[2 cases of acute liver damage caused by indomethacin],,1
8806,7385109,[Hepatic damages caused by allopurinol],,1
8807,7387883,Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment,,1
8808,7389973,A case of centrolobular toxic necrosis of the liver due to aromatic retinoid--Tigason (Ro 10-9359),"A woman aged 54 years developed toxic necrosis of liver cells during treatment with aromatic retinoid (Ro 10-9359) for erythrodermia ichthyosiformis non-bullosa. Her skin was almost normalized when liver function tests and liver biopsy disclosed severe damage. The treatment was stopped, but 4 months later ALAT and ASAT were still elevated.",1
8809,7395459,Toxic encephalopathy with hyperammonaemia during high-dose salicylate therapy,"High-dose, long-term aspirin therapy easily overloads the patient's individual capacity to metabolize salicylates and may lead to complex metabolic disturbances including fulminant hepatic failure, hyperammonemia and toxic metabolic encephalopathy. In the two cases presented there was a severe outbreak of hepatotoxic encephalopathy despite the fact that the dosage of salicylates did not exceed that generally recommended for children with rheumatic diseases. The justification of high-dose salicylate therapy is discussed, taking into account the fact that children with juvenile rheumatoid arthritis and allied conditions may have increased susceptibility to liver damage from drugs. EEG abnormalities in these two cases corresponded to those described in other metabolic encephalopathies including Reye's syndrome. The quality of the EEG changes gives prognostic signs, but is of restricted value in establishing the etiology without the anamnestic data of salicylate ingestion. Active therapeutic measures including exchange transfusions are needed to prevent irreversible metabolic and pressure changes in the brain.",1
8810,7396606,Coumarin-associated hepatitis. Report of two cases,"We investigated two cases of recurrent jaundice, both involving repeated exposure to phenprocoumon and suggestive of coumarin-induced hepatitis. The first patient showed the histologic picture of cholestasis during the second bout of jaundice, the other that of chronic aggressive hepatitis. In both patients, the hepatitis appearance disappeared after termination of the first exposure to the coumarin drug, in the first case without additional drug therapy. In the second case, prednisone therapy was instituted when phenprocoumon administration was withdrawn. In both cases, hepatopathy recurred after reexposure to the drug. In one of these patients, and with his consent, a third bout of jaundice was provoked with phenprocoumon.",1
8811,7398153,Drugs and the hepatic porphyrias,,1
8812,7400373,Trimethobenzamide HCl in the treatment of nausea and vomiting associated with antineoplastic chemotherapy,Fifty-five patients undergoing chemotherapy for various neoplastic processes were treated with trimethobenzamide or placebo to control nausea and vomiting. Trimethobenzamide was shown to be significantly better than placebo in relieving periodic and total nausea over the 48-hour study. Vomiting incidence was also reduced in the group receiving trimethobenzamide. Differences were noted in the degree of emetic stimulus associated with different chemotherapeutic regimens. No side effects attributable to trimethobenzamide were recorded.,1
8813,7402257,Fever secondary to triamterene therapy,,1
8814,7405322,[Rare liver damage caused by an antihypertensive and anti-arrhythmic agents],"It is reported on lesions of the liver parenchyma after the application of dihydralazin and detajmium bitartrate with description of the clinical and morphological findings. By means of the morphological findings got in liver biopsy a clinically supposed acute virus hepatitis could be excluded. After the application of dihydralazin group cell necroses and an inflammation of the periportal fields, after detajmium bitartrate a typical intrahepatic cholestasis was in the front. The knowledge of medicamentous side-effects may avoid diagnostic and therapeutic errors in the individual case.",1
8815,7416129,Fluphenazine jaundice. Report of a case,"The management of an agitated schizophrenic was complicated by the onset of severe hepatocellular dysfunction concomitant with the administration of fluphenazine, a drug which has rarely been implicated in phenothiazine jaundice. Since neuroleptics did lead to a dramatic improvement, the patient was treated with an antipsychotic from an alternative drug class. The differential diagnosis, approach to management and natural history are presented, along with a brief review of phenothiazine jaundice, with special emphasis on fluphenazine.",1
8816,7420331,Low dose pulse methotrexate therapy in rheumatoid arthritis,Thirty-two patients with definite or classical rheumatoid arthritis were treated with low dose pulse methotrexate (MTX). A therapeutic response was shown in 2/3 of the patients by statistically significant joint changes and improved global response. Greater than one-half of those who improved demonstrated a drop in sedimentation rate. Eight patients discontinued treatment because of inefficacy and 2 because of gastrointestinal distress. One patient died of neoplasm. Five liver biopsies performed in patients with abnormal liver enzymes demonstrated no MTX related changes. We conclude that MTX may be an effective alternative to other more toxic immunosuppressive regimens and should undergo future evaluation.,1
8817,7421712,Salicylate hepatotoxicity in rheumatoid arthritis,,1
8818,7424826,Hepatic injury associated with diphenylhydantoin therapy. A clinicopathologic study of 20 cases,"Although the toxicity of diphenylhydantoin in a number of target organs is discussed in numberous reports, hepatotoxic reactions are quite rare. The hepatic lesion has mostly been described as necrosis or hepatitis. Tissue sections from 20 patients who had validated diphenylhydantoin hepatotoxicity were reviewed to define this entity. The morphologic lesions included ground-glass transformation of liver cells, hepatocellular degeneration and/or necrosis (with changes resembling those occurring in viral hepatitis or infectious mononucleosis), granulomatous reactions with or without associated hepatocellular injury or vasculitis, and infiltration by malignant cells of reticuloendothelial origin. The interval between the beginning of therapy and the adverse drug reaction varied from one to eight weeks. Clinically, 75% of the patients had fever, 62.5% had rash, and 89% had eosinophilla. Most patients recovered after the drug was discontinued. The clinical and morphologic differential diagnosis includes a number of diseases, such as granulomatous hepatitis, infectious mononucleosis, and viral hepatitis.",1
8819,7429116,Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy,"This report describes a middle-aged female who received imipramine for 7 days, developed severe cholestatic jaundice with features similar to primary biliary cirrhosis, and then improved clinically over the next 12 mo. Biochemical and histologic abnormalities persisted over a 14-yr period of follow-up, though subsequent administration of haloperidol may have influenced the long-term course. High levels of circulating immune complexes were also found 14 yr later, which raises questions about the relationship of primary biliary cirrhosis to drug-induced liver injury. A review of the literature on imipramine- and phenothiazine-related hepatic injuries reveals multiple similarities, and this case provides further evidence for a common hepatic reaction to the two drugs.",1
8820,7437797,Lymphocyte sensitisation in nifedipine-induced hepatitis,,1
8821,7438960,Hydralazine-induced liver injury,"A 68-year-old man developed hepatic injury with no hypersensitivity reaction after three years of hydralazine therapy. The liver injury histologically showed centrilobular zonal necrosis. Clinical, biochemical, and histological recovery followed discontinuation of the drug. Challenge tests and serial liver biopsies revealed that this liver injury was induced by hydralazine.",1
8822,7443602,Jaundice associated with naproxen,"Hepatic injury in association with naproxen therapy is described and documented by liver biopsy in one patient. Histological findings were consistent with a drug-induced hepatitis, and cessation of therapy led to reversal of the clinical and biochemical changes. Circumstantial evidence is in favour of a hypersensitivity response to the drug rather than direct hepatotoxicity. Increased awareness of clinicians of this probably rare side effect of naproxen may help prompt identification of similar cases.",1
8823,7446211,Granulomatous hepatitis in a patient receiving carbamazepine,"A 60-year-old woman, previously in good health, received carbamazepine in a total dose of 10 g during 1 month. Fever, upper abdominal pain and abnormal liver function appeared after 3 weeks. Liver biopsy showed non-caseating granulomas. One week after withdrawal of carbamazepine the patient was clinically well with normal liver function. Carbamazepine was then reinstituted for 4 days, resulting in fever, upper abdominal pain and deteriorating liver function. One month after this provocation test the patient was clinically well with normal liver function and normal liver biopsy showing only slight fatty vacuolization but no granulomas. A reversible positive mitochondrial antibody test was seen.",1
8824,7450449,Sulindac (Clinoril) hepatitis,"A patient with Sulindac-induced hepatitis is presented. Sulindac was confirmed as the cause of the patient's liver disease when hepatic dysfunction abruptly recurred after an inadvertent reexposure to Sulindac and quickly resolved when the drug was withdrawn. The prompt reappearance of fever, chills, pruritus, rash, tender hepatomegaly, and abnormal liver tests after only two doses of Sulindac suggested a hypersensitivity reaction.",1
8825,7451927,Salicylate hepatotoxicity: the potential role of hypoalbuminemia,"Seventeen patients suffering from an initial attack of acute rheumatic fever were studied during treatment with phenoxymethyl penicillin and salicylates (600 mg orally every 4 or 6 hours). Elevated transaminase (SGOT) levels occurred in nine patients. The SGOT levels were directly related to serum salicylate levels (r = 0.668) and inversely to the serum albumin level (r = -0.418). SGOT response was greater in patients with a serum albumin of less than 3.5 g/dl (P < 0.001). In hypoalbuminemia, the ratio of free salicylate to bound salicylate rises and the free salicylate might be more active and thus more hepatotoxic even at relatively low total serum salicylate levels. In all patients with hypoalbuminemia of less than 3.5 g/dl, close monitoring the SGOT is advisable, especially if the level of total serum salicylate is 15 mg/dl or higher.",1
8826,7453791,N-acetylglutamate synthetase deficiency: a disorder of ammonia detoxication,,1
8827,7464961,[Chronic active hepatitis caused by nitrofurantonin],,1
8828,7468146,[Fatal toxic hepatitis associated with administration of dantrolene (author's transl)],"A 50 year-old female diabetic patient with disseminated sclerosis presented fatal cholestatic hepatitis about ten weeks after the initiation of dantrolene therapy (600 mg/day). Clinical findings, biochemical results and the appearance of hepatic biopsy are described and compared with other cases reported to date. Hypotheses regarding the hepatotoxicity of dantrolene and essential precautions to be taken when using this medication are deduced.",1
8829,7468565,Barbiturate-induced submassive hepatic necrosis. Report of a case and review of the literature,"A case of barbiturate-induced submassive hepatic necrosis is presented and the literature is reviewed. The patient's clinical presentation, histologic features on liver biopsy and favorable course after stopping the drug suggest that barbiturates can be added to the list of agents which can cause submassive hepatic necrosis.",1
8830,7469629,Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment,"Six hundred sixty-two consecutive patients with acetaminophen overdoses were evaluated. Those at risk on the basis of their acetaminophen blood levels, as plotted on the study nomogram, were treated with oral acetylcysteine. Statistically significant differences in severity of hepatic toxicity were observed between patients treated within 16 hours after ingestion and those treated between 16 and 24 hours after ingestion. No deaths occurred among patients treated within 24 hours of ingestion, except for one patient who was an alleged gunshot homicide. Seven percent of patients with plasma acetaminophen levels in the potentially toxic range and treated with acetylcysteine within ten hours of ingestion showed transient SGOT level elevations, whereas 29% of those treated between ten and 16 hours after ingestion and 62% of those treated between 16 and 24 hours after ingestion showed such transient toxicity. No consistent difference in hepatotoxicity could be demonstrated between those patients with a history of chronic alcohol use and those patients with no history of chronic alcohol use. Acute alcohol use resulted in less severe toxic reactions than in those patients without acute alcohol use.",1
8831,7475613,Hepatitis B reactivation after lamivudine,,1
8832,7477143,Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group,"""BACKGROUND: Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS: We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS: The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS: Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.""",1
8833,7483723,[Cholestasis in imipenem/cilastatin treatment],The case report on a 22-year-old female patient shows how the treatment with Imipenan/Cilastatin resulted in a severe intrahepatic cholestasis. The serum-bilirubin rapidly decreased after discontinuation of the antibiotic. The laboratory findings were no longer conspicuous four weeks after discharge from hospital.,1
8834,7486167,Hepatotoxicity after desflurane anesthesia,,1
8835,7486483,"Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial","OBJECTIVE: To evaluate ribavirin, an oral antiviral agent, as therapy for chronic hepatitis C. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical Center of the National Institutes of Health, a tertiary referral research hospital. PATIENTS: 29 patients with chronic hepatitis C who received oral ribavirin (600 mg twice daily) for 12 months and 29 controls with chronic hepatitis C who received placebo for 12 months. MEASUREMENTS: Effects of therapy were evaluated by measuring serum aminotransferase and hepatitis C virus (HCV) RNA levels before, during, and for 6 months after therapy and by histologic examination of liver specimens before and at the end of treatment. RESULTS: Patients treated with ribavirin had a prompt decrease in serum aminotransferase levels (54% overall) compared with levels before treatment and levels in controls (5% decrease). Serum aminotransferase levels became normal or nearly normal in 10 patients treated with ribavirin (35% [95% CI, 18% to 54%]) but in no controls (0% [CI, 0% to 12%]). Aminotransferase levels remained normal in only 2 patients after ribavirin therapy was discontinued (7% [CI, 1% to 23%]). Serum HCV RNA levels did not change during or after therapy. Liver biopsy specimens showed a decrease in hepatic inflammation and necrosis among ribavirin-treated patients whose aminotransferase levels became normal. CONCLUSIONS: Ribavirin has beneficial effects on serum aminotransferase levels and histologic findings in the liver in patients with chronic hepatitis C, but these effects are not accompanied by changes in HCV RNA levels and are not sustained when ribavirin therapy is discontinued. Thus, ribavirin alone for periods as long as 12 months is unlikely to be of value as therapy for chronic hepatitis C.",1
8836,7487684,Flucloxacillin hepatitis--an Australian epidemic,,1
8837,7490837,Flutamide hepatotoxicity,"PURPOSE: Observed and expected reporting rates were compared in patients who died or were hospitalized due to hepatotoxicity associated with the use of flutamide. MATERIALS AND METHODS: Case series were submitted to the MedWatch Spontaneous Reporting System of the Food and Drug Administration. Reporting rates for serious hepatotoxicity due to flutamide were calculated and compared to rates for hospitalized patients with acute idiopathic hepatitis in the medical literature. RESULTS: After the marketing of flutamide in the United States, between February 1989 and December 1994 the Food and Drug Administration received reports of 20 patients who died and 26 who were hospitalized for hepatotoxicity due to flutamide. The rate of approximately 3 per 10,000 flutamide users exceeds by 10-fold or more the expected rate of hospitalizations for acute noninfectious liver injury of 2.5 per 100,000 men 65 years and older. Autopsies in 6 cases revealed marked to massive hepatic necrosis as the predominant feature. CONCLUSIONS: Flutamide is a potent hepatotoxin in certain patients. Serial blood aminotransferase levels should be monitored during the first few months of flutamide treatment. Before beginning use of this drug patients should be instructed to report immediately to physicians any episodes of nausea, vomiting, fatigue and jaundice so that flutamide can be promptly discontinued to avoid progression of possible liver injury.",1
8838,7491336,[Pseudolithiasis caused by ceftriaxone in children: a case report],"""Recently, there are in literature some reports concerning the sonographic observation of transient gallbladder precipitates in children and adults during ceftriaxone treatment. The condition is defined as ceftriaxone-reversible """"pseudolithiasis"""" and the gallbladder precipitates resolve spontaneously after cessation of therapy. We present a case of a 1 year old children treated with ceftriaxone who presented asymptomatic pseudolithiasis that resolved partially two weeks after cessation of treatment. The sonographic observation performed four months after cessation of therapy show a normally gallbladder, without precipitates or sludge.""",1
8839,7495252,Safety of antioxidant vitamins and beta-carotene,"""Epidemiologic evidence links high antioxidant status with low risk of degenerative disease. Optimal intakes of antioxidants may not be achievable by diet alone; supplements may be taken, particularly in subgroups of the population at high risk. It is thus necessary to ensure that antioxidant supplements are safe and free from side effects. The toxicity of vitamin E is low; no mutagenic, teratogenic, or carcinogenic effects are known and in double-blind studies in which large amounts of vitamin E were used in humans, no side effects occurred. High concentrations are contraindicated in subjects with vitamin K-associated blood coagulation disorders, and the toxicity in normal subjects ingesting large amounts of vitamin E over long periods requires additional investigation. Toxicity of beta-carotene also is low. Evidence from human toxicity trials is not available but there is much circumstantial evidence that 15-50 mg/d is without side effects except for hypercarotenemia in some subjects at high intakes. The findings of more lung cancer in subjects who smoked and who were given 20 mg beta-carotene/d than in those given a placebo could be influenced by the cancer being well advanced before beta-carotene administration. Massive anecdotal evidence exists that vitamin C (at > or = 1 g/d) is safe. Exhaustive literature searches have failed to reveal a controlled study of vitamin C toxicity in human subjects. Anxiety exists about oxalate stone formation, uricosuria, vitamin B-12 destruction, mutagenicity, and iron overload, but the consensus is that adverse effects do not occur in healthy subjects ingesting large amounts of vitamin C.""",1
8840,7501229,[Acute hepatotoxicity from amiodarone],"The functional and histological liver alterations induced by amiodarone treatment have been well known for some time and often consist in isolated increases in transaminase levels during long-term treatment. Secondary phospholipidosis was observed in these cases, an alteration which suggests the presence of toxic damage. Reports in the literature also indicate acute liver intoxication, including a number of fatal cases. This paper reports the finding of acute alterations of laboratory parameters indicative of hepatocytonecrosis with alterations of protein synthesis capacity following the first dose of the drug and which regressed after its suspension. On the basis of a review of the literature the authors propose that, in addition to a dose-dependent toxic mechanism, immunogenic or idiosyncratic mechanisms may also play a role in the onset and manifestation of acute liver intoxication by amiodarone.",1
8841,7504976,Toxic hepatitis induced by antithyroid drugs: four cases including one with cross-reactivity between carbimazole and benzylthiouracil,"OBJECTIVE: This study was conducted to assess the occurrence of hepatic adverse effects encountered with antithyroid drugs. METHODS: Retrospective review of medical records of 236 patients with hyperthyroidism admitted in our department (in- or out-patients) from 1986 to 1992. RESULTS: Four patients (1.7%) were identified with toxic hepatitis which could reasonably be attributed to the use of antithyroid agent. Two patients had a cholestatic hepatitis induced by carbimazole (Neomercazole). Two others had a mixed (cholestatic and cytolytic) hepatitis following carbimazole. One of the latter two patients further experienced a cytolytic hepatitis which appeared after Benzylthiouracil (Basdene) had replaced carbimazole. Biological features of hepatitis disappeared in all cases after cessation of the incriminated drug, while biliary, viral and immunological searches were negative. Only 2 patients of our retrospective study experienced a mild or severe neutropenia. CONCLUSION: Toxic hepatitis is a potential adverse effect of antithyroid drugs which warrants, as for haematological disturbances, a pre-therapeutic determination and a careful follow-up of relevant biological markers. Moreover, hepatotoxicity may not be restricted to one class of antithyroid agents.",1
8842,7505717,Drug formulary review process for sargramostim and filgrastim: focus on analysis of adverse drug reactions,"""Selection of a drug for formulary inclusion involves evaluation of safety, efficacy, and cost. The colony-stimulating factors (CSFs) sargramostim and filgrastim have a broad range of potential indications and represent a costly formulary addition when acquisition price alone is considered; their comparative safety is unclear. These factors suggest that the CSFs should be closely scrutinized prior to formulary addition. In the absence of direct comparative studies, an assessment of the safety of CSFs involves evaluation of information provided in the product circular, official drug compendia, adverse biologic reports submitted to the United States Food and Drug Administration, and data from key clinical trials. Data in the product circulars report on adverse events in small numbers of patients treated for chemotherapy-induced neutropenia (filgrastim) or neutropenia subsequent to bone marrow transplantation (sargramostim). The official compendia and clinical trials include experience with CSFs produced in a variety of expression systems; these data are not limited to sargramostim and filgrastim. Importantly, there was a similar incidence of adverse events in patients who received sargramostim or filgrastim and in those who took placebo reported in the product circulars and the pivotal trials, suggesting that the underlying disease may have an important role in determining the side-effect profile of these agents. Adverse biologic reports represent experience with sargramostim and filgrastim obtained under actual clinical conditions and suggest that the same types of adverse events are seen with sargramostim as with filgrastim. This analysis suggests that a decision to select filgrastim over sargramostim for formulary inclusion based on the safety profile is not appropriate because currently available data are equivocal and that such decisions would more appropriately be based on efficacy and cost.""",1
8843,7505877,"Randomized study for the treatment of adult advanced Hodgkin's disease: epirubicin, vinblastine, bleomycin, and dacarbazine (EVBD) versus mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD)","Seventy patients with previously untreated advanced Hodgkin's disease and without bulky disease were entered in a prospective randomized clinical trial comparing epirubicin in combination with vinblastine, bleomycin, and dacarbazine (EVBD) with a regimen containing mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD). Both groups were comparable for the variables of age, sex, stage, and presence of B symptoms and histology. Thirty-one (88%) of EVBD-treated patients achieved a pathologically documented complete remission (CR) compared to the 24 cases (68%) of the MVBD-treated group. After a median follow-up of 36 months, duration of CR is better in the EVBD-treated patients with an actuarial 5-year duration of CR of 80%, statistically different to the MVBD group: 53% (P < 0.01). Both regimens showed the same gastrointestinal toxicity, but the patients treated with the MVBD regimen shown most and severe hematological and cardiac toxicities. Also, biochemical alterations in hepatic test were observed in these patients. The alternative use of epirubicin in combination chemotherapy appears to be as effective in advanced Hodgkin's disease without bulky disease, with reduced clinical toxicity. Mitoxantrone containing regimen was not found to have an equivalent efficacy and clinical toxicity was most frequent and severe. We felt that mitoxantrone could be consider a second-line drug in the treatment of advanced Hodgkin's disease.",1
8844,7508362,Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis,"""We report three patients who experienced hepatotoxic reactions in association with acetaminophen ingestion while undergoing treatment for active tuberculosis with isoniazid, rifampin, and other agents. All were young adult women. One patient intentionally took a large amount of acetaminophen and had typical signs and symptoms of acetaminophen overdosage; another took acetaminophen in combination form for a minor upper respiratory illness. She experienced no symptoms. The remaining patient took acetaminophen to ameliorate the symptoms of fever and malaise that were subsequently attributed to tuberculosis. She had the rapid onset of signs and symptoms of isoniazid hepatotoxicity. The patterns of liver function abnormalities were similar: each patient experienced pronounced serum elevations of hepatocellular enzymes with at most only modest rises in those of bilirubin. All antituberculous drugs were withheld until symptoms resolved and laboratory values became normal; then treatment for tuberculosis was resumed without isoniazid and was successfully completed in all three patients. These cases plus similar reports in the literature suggest that isoniazid or rifampin, or both, may potentiate the hepatotoxicity of acetaminophen, perhaps by induction of cytochrome P450 isozymes that oxidize acetaminophen to its toxic metabolites.""",1
8845,7515217,Acute zinc chloride ingestion in a child: local and systemic effects,"A 16-month-old boy ingested liquid zinc chloride/ammonium chloride soldering flux. He developed severe local burns, metabolic acidosis, hepatic damage, hyperamylasemia, lethargy, and hypertension. Peak measured plasma zinc was 1,199 micrograms/dL. Because of persistent signs of systemic toxicity, he was chelated with dimercaprol (BAL) and EDTA. Although clinical improvement was noted coincident with the initiation of chelation, there was no apparent increase in urinary zinc excretion. Scarring in the gastric antrum necessitated an antrectomy. The child recovered without other apparent complications.",1
8846,7517215,Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate,"""Intravenous arginine butyrate has been shown to increase fetal hemoglobin (HbF) in sickle cell and thalassemia patients. Recently, we observed that sodium 4-phenylbutyrate, a drug administered orally to treat urea cycle disorders, increases HbF production in nonanemic children and adults. We treated six subjects with sickle cell disease over a period of 14 to 179 days. All subjects received their initial therapy of 9 to 13 g/m2/day as 0.5-g tablets of sodium 4-phenylbutyrate as inpatients. All subjects showed a rapid increase in the percentage of F-reticulocytes (pretreatment, 1% to 20%; posttreatment, 10% to 44%). Four subjects were treated only 11 to 25 days as inpatients. Two of these four subjects failed to respond to the outpatient component because of their inability to maintain an intake of 30 to 40 tablets per day. One subject (C) developed a rash at day 10 and discontinued treatment at day 14. Another subject (B) was transfused for a painful crisis on day 25. Subject A, treated for 179 days, has an increased percentage of F cells, from 54% to 77%, and increased HbF levels, from 10.6% to 18%. Subject F, treated for 154 days, has an increased percentage of F cells, from 59% to 73%, and an increased percentage of HbF, from 10.4% to 16%. All subjects showed some increase in weight. Subject A developed mild transient ankle edema. Myelotoxicity was not seen in any treated patient. Oral administration of sodium 4-phenylbutyrate rapidly increases F-cell production in sickle cell disease.""",1
8847,7519800,Reversal of severe FK506 side effects by conversion to cyclosporine-based immunosuppression,,1
8848,7524888,High dose busulphan/cyclophosphamide for autologous bone marrow transplantation is associated with minimal non-hemopoietic toxicity,"We retrospectively reviewed the regimen-related toxicity associated with busulphan (1 mg/kg orally QID days -7 to -4) and cyclophosphamide (60 mg/kg IV days -3 and -2) (Bu/Cy) chemotherapy in 69 consecutive patients who underwent autologous bone marrow transplantation (ABMT). Twenty-four patients received bone marrow (BM) alone, 22 received BM plus post-transplant granulocyte-colony stimulating factor (G-CSF) and 23 received peripheral blood progenitor cells (PBPC) +/- BM plus post-transplant G-CSF. Toxicity was scored using the criteria of Bearman. Grade II and III toxicities included mucosa (38%), liver (8%), central nervous system (5%), kidney (5%), heart (3%), pericardium (2%), bladder (2%) and lung (2%). There were five treatment related deaths (7%) from pneumonitis (2) and veno-occlusive disease, pulmonary hemorrhage and sepsis (1 each). Post-transplant G-CSF (+/- PBPC) resulted in a trend (p = 0.07) towards a reduction in post-transplant stomatitis, but did not impact on the already low incidence of other organ toxicities. As Bu/Cy for ABMT is associated with minimal non-hemopoietic toxicity, the addition of other cytotoxic agents is justified in an attempt to augment the anti-tumour effect of this conditioning regimen.",1
8849,7538237,"A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group","OBJECTIVES: To compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer. METHODS: Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 x 2 factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). RESULTS: With a median duration of follow-up of 49 weeks, time to treatment failure, the primary endpoint, was significantly (P = 0.005) better for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group. Patients in the flutamide plus LHRH-A group were 34% more likely to fail treatment over the given time period, as indicated by the hazard ratio of 0.749 (95% confidence interval, 0.61 to 0.92) for bicalutamide plus LHRH-A to flutamide plus LHRH-A. Results for secondary endpoints (survival, quality of life, and subjective response) were similar between groups. Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group, compared with 10% of patients in the bicalutamide plus LHRH-A group (P < 0.001). CONCLUSIONS: In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is well tolerated and provides superior efficacy to flutamide plus LHRH-A with respect to time to treatment failure. Assessment of the effects of these regimens on longer term survival requires additional time for follow-up.",1
8850,7545495,Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I,"Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.",1
8851,7549833,"A phase I-II study of high-dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for autologous transplantation for malignant lymphoma","Thirty-four adults with malignant lymphoma at high-risk for relapse were treated on a Phase I-II study of high-dose thiotepa (THIO), busulfan (BU) and cyclophosphamide (CYC) with autologous marrow or peripheral blood stem cell support. Four patients were in untreated relapse, 7 had stable or progressive disease, 12 were in partial remission, and 11 were in complete remission after reinduction chemotherapy before proceeding to the preparative regimen. Median follow-up time is 22 months. Grades 3-4 regimen-related toxicity occurred in 3 (14%) of 22 patients treated with THIO 250 mg/m2 x 3, BU 1 mg/kg x 10 and CYC 50 mg/kg x 3, and this was considered the maximal tolerated dose-schedule. Of the 23 patients with active disease at the time of transplantation, 52% (95% CI 31-73%) achieved a complete response, and 26% (95% CI 10-48%) achieved a partial response. For all patients, median time to progression was 13 months, median survival was 16 months, and disease-free survival at 18 months was 34% (95% CI 18-51%). The combination of THIO, BU and CYC is tolerable as a preparative regimen for lymphoma and has a high response rate, but further measures are needed to reduce the relapse rate for patients with advanced disease.",1
8852,7556332,Ceftriaxone-associated gallbladder lithiasis in children,,1
8853,7565008,[Fatal hepatitis due to allopurinol in Dakar],,1
8854,7566002,Natural history of paroxysmal nocturnal hemoglobinuria,"""BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH), which is characterized by intravascular hemolysis and venous thrombosis, is an acquired clonal disorder associated with a somatic mutation in a totipotent hematopoietic stem cell. An understanding of the natural history of PNH is essential to improve therapy. METHODS: We have followed a group of 80 consecutive patients with PNH who were referred to Hammersmith Hospital, London, between 1940 and 1970. They were treated with supportive measures, such as oral anticoagulant therapy after established thromboses, and transfusions. RESULTS: The median age of the patients at the time of diagnosis was 42 years (range, 16 to 75), and the median survival after diagnosis was 10 years, with 22 patients (28 percent) surviving for 25 years. Sixty patients have died; 28 of the 48 patients for whom the cause of death is known died from either venous thrombosis or hemorrhage. Thirty-one patients (39 percent) had one or more episodes of venous thrombosis during their illness. Of the 35 patients who survived for 10 years or more, 12 had a spontaneous clinical recovery. No PNH-affected cells were found among the erythrocytes or neutrophils of the patients in prolonged remission, but a few PNH-affected lymphocytes were detectable in three of the four patients tested. Leukemia did not develop in any of the patients. CONCLUSIONS: PNH is a chronic disorder that curtails life. A spontaneous long-term remission can occur, which must be taken into account when considering potentially dangerous treatments, such as bone marrow transplantation. Platelet transfusions should be given, as appropriate, and long-term anticoagulation therapy should be considered for all patients.""",1
8855,7575712,Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables,"OBJECTIVE: To describe liver histopathologic features and ultrastructural changes in a prospectively studied cohort of rheumatoid arthritis (RA) patients receiving long-term methotrexate (MTX) therapy, and to seek correlations between these changes and simultaneously measured laboratory indices of liver function. METHODS: This was a long-term, prospective, open observational study. Twenty-seven outpatients with RA who began therapy with MTX and continued treatment for extended periods underwent baseline and followup liver biopsies. One hundred seventy liver biopsy specimens were analyzed by light microscopy (LM) and assessed according to a modified Roenigk score and a newly devised numerical grading system. Ninety-three biopsy specimens were also analyzed by electron microscopy (EM). Blood samples were obtained at 4-6-week intervals for determination of bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), and albumin levels, and the weekly dosage of MTX was adjusted if there were abnormalities in the AST or albumin level. A mean of 6.3 liver biopsies per patient were obtained over a mean followup period of 8.2 years (range 2-13 years). RESULTS: The modified Roenigk score was significantly different from baseline at year 3, when it increased from a mean of 1.8 to 2.3 (P = 0.05) and at year 6, when it increased to 2.4 (P = 0.04), but this was not considered clinically meaningful. No other significant changes from baseline were observed by either LM grading system. No significant progression was observed by EM over the course of the investigation. Increases in serial measurements of AST correlated with both the modified Roenigk score (r = 0.21, P = 0.016) and the numerical rating score (r = 0.19, P = 0.027). CONCLUSION: Patients with RA who are receiving weekly single-dose oral MTX therapy exhibit little deterioration in hepatic architecture by LM or EM when the dosage of the drug is adjusted for abnormalities in AST and serum albumin, monitored at frequent intervals.",1
8856,7577112,[Acute pancreatitis associated with hepatotoxicity induced by amoxicillin-clavulanic acid],"A 25-year old man suffered from acute pancreatitis and cholestatic acute hepatitis simultaneously after 4 weeks of an antibiotic treatment withdrawal (amoxicillin plus clavulanic acid) which was given for pharyngitis. Other potential etiological causes of both acute pancreatitis and liver disease, were excluded. The causal relationship between amoxicillin plus clavulanic acid and cholestatic hepatitis is well know, but no data has been reported regarding acute pancreatitis. The medical literature is reviewed and the mechanisms of toxicity are discussed.",1
8857,7577576,Abnormalities of serum type III procollagen aminoterminal peptide in methotrexate-treated psoriatic patients with normal liver histology do not correlate with hepatic ultrastructural changes,"In a previous study, it was shown that the serum levels of type III procollagen aminoterminal peptide (P3NP) were significantly greater in patients receiving methotrexate (MTX) treatment for psoriasis than in untreated control patients with psoriasis. Although levels were highest in patients with hepatic fibrosis and cirrhosis, serum P3NP concentrations in those patients with normal liver histology on light microscopy were also shown to be significantly higher than in controls. In the present study, liver biopsies from 22 such 'normal' patients were examined by electron microscopy, in order to determine whether P3NP levels correlated with ultrastructurally demonstrable fibrosis. Fibrosis in the perisinusoidal space of Disse was present in as many as 82% of biopsies. Although the prevalence of such fibrosis in psoriasis patients who have not received MTX is unknown, the high prevalence of Disse space fibrosis and of raised P3NP in MTX-treated patients suggests that MTX causes subtle liver damage in a majority of treated patients. However, we were unable to show a statistical correlation between P3NP and the degree of Disse space fibrosis.",1
8858,7583074,Long-term treatment of Wilson's disease with triethylene tetramine dihydrochloride (trientine),"""Long-term treatment with triethylene tetramine dihydrochloride, (trientine, TETA) was evaluated in 19 patients with Wilson's disease (WD). Two were given the drug as first choice and 17 after treatment with penicillamine. The change was made because of side-effects, lack of improvement or worsening of neurological symptoms. All penicillamine-induced side-effects reverted. Thirteen patients still receive trientine, and the mean total observation time on this treatment is 8.5 years/patient. Seven of the 13 are free from symptoms related to WD, five have mild to moderate neurological symptoms, mainly dysarthria. One patient with neurological symptoms who received trientine from the start of treatment deteriorated rapidly and is now severely dystonic. The symptoms initially worsened and later improved in one patient. All other patients improved during trientine treatment. Three patients died: two from a multifocal cancer including the liver and one non-complier from a ruptured spleen. Two patients underwent liver transplantation for progressive liver failure: one non-complier and one with liver cirrhosis whose liver function deteriorated despite treatment; both are now free from symptoms. Unexpectedly, two patients developed a serious colitis, one with duodenitis as well, that improved after withdrawal of the drug. No other unfavourable effects of trientine were recorded.""",1
8859,7585087,Mitochondrial toxicity of antiviral drugs,"Long-term treatment with antiviral nucleoside analogue drugs, such as AZT, can give rise to delayed and at times severe mitochondrial toxicity. Although these toxic effects are manifest in many tissues, a common disease mechanism can explain the diverse clinical events. A better understanding of these disorders will shed light on genetic mitochondrial diseases and lead to the design of safer and more effective antiviral drugs.",1
8860,7587776,Development of granulomatous hepatitis during treatment with interferon-alpha 2b,,1
8861,7588026,[Phenprocoumon-induced necrotizing hepatitis],,1
8862,7590650,Efficacy and safety of interferon alfa therapy in chronic hepatitis C with autoantibodies to liver-kidney microsomes,"Interferon alfa (IFN) therapy is efficacious in chronic viral hepatitides. It may, however, cause adverse immunologic reactions in patients with concomitant autoimmune phenomena. A minority of patients with chronic type C hepatitis have antibodies against liver and kidney microsomes (anti-LKM) in serum. We therefore carried out this study to find out whether IFN is safe and efficacious also in this subgroup. We treated 92 consecutive cases of chronic hepatitis C with IFN. Twelve patients had anti-LKM< and the remaining 80 tested negative to the anti-LKM. The hepatitis C virus (HCV) infection was diagnosed on the basis of positive anti-HCV and HCV-RNA tests. We compared the clinical and virological virological results of the therapy and the side effects found in the two groups. We found that the response to therapy and the outcome after 1 year of follow-up were similar. Treatment was discontinued in one anti-LKM-positive patient because of a drastic increase in ALT levels at the fourth month of therapy. No untoward effect was observed in the other cases. Hepatitis C patients with anti-LKM may be exposed to an increased risk of an adverse hepatitic reaction while being treated with IFN. However, we found that the extent of the risk was minimal compared with the expected benefits of the therapy. IFN is therefore recommended as the first therapy to choose in these patients. They must, however, be monitored more closely for possible liver dysfunction than the ordinary hepatitis C patient.",1
8863,7593434,Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis,"""Primary hypothyroidism is a known complication of nephropathic cystinosis, a lysosomal storage disorder characterized by renal failure as well as deterioration of other organs. The drug cysteamine depletes lysosomes of cystine and helps preserve renal function and enhance growth in cystinosis patients. To determine whether cysteamine also prevents hypothyroidism, we retrospectively divided 101 patients into group A (n = 28; well treated), group B (n = 26; partially treated), and group C (n = 47; poorly treated). Lifetable analysis indicated a significantly higher probability of remaining free of L-T4 replacement in group A vs. group B (P = 0.09) or group C (P = 0.004). Cysteamine therapy also improved mean height z-scores (-2.17 in group A, -3.04 in group B, and -4.07 in group C) and reduced the bone age deficit (i.e. chronological age minus bone age) by 1.5 yr for every 10 yr of previous cysteamine therapy. We conclude that in addition to its other salutary effects, oral cysteamine therapy helps prevent hypothyroidism and enhances growth in patients with nephropathic cystinosis.""",1
8864,7598311,Tamoxifen-induced steatohepatitis,,1
8865,7599407,Hepatic failure due to massive iron ingestion successfully treated with liver transplantation,"A 3-year-old female had fulminant hepatic and renal failure due to massive iron ingestion, despite gastric lavage, deferoxamine administration, hemodialysis and continuous arteriovenous hemofiltration. She underwent a successful emergency liver transplantation on 5th day after ingestion and was discharged 25 days later with excellent liver and renal function.",1
8866,7601945,The safety of etretinate as long-term therapy for psoriasis: results of the etretinate follow-up study,"BACKGROUND: Etretinate is an aromatic retinoid given orally to treat severe psoriasis, a chronic disease that often requires long-term therapy. OBJECTIVE: We assessed the safety of long-term therapy with etretinate for psoriasis. METHODS: This 5-year prospective study of a cohort of 956 patients with psoriasis treated with etretinate assessed the frequency of adverse events in relation to total use and in relation to the frequency of these events in control populations. RESULTS: Our data do not provide evidence for an increased risk of cardiovascular disease, cancer, diabetes, or inflammatory bowel disease in association with long-term etretinate use. Although some patients reported that joint problems improved with the use of etretinate, a greater number associated the use of etretinate with joint problems. CONCLUSION: With proper patient selection and monitoring, long-term etretinate therapy (up to 4 years) does not appear to be accompanied by a substantial increased risk of major adverse effects.",1
8867,7602656,Drug-induced liver disease--a review of 14 cases,"The clinical and pathological features of 14 cases of acute drug-induced liver disease (DILD) were analyzed using the French group method for drug reaction assessment. Among them, 8 were of the cytotoxic type, 4 were of the cholestatic type and 2 were of the mixed type. Serum alkaline phosphatase (ALP) levels of the cytotoxic type DILD were all < 1.8 times the normal value, while those of the cholestatic type DILD > 1.8 times (P < 0.05). The alanine aminotransaminase and aspartate aminotransaminase (ALT and AST) levels of the cholestatic type were all < 13.1 times the normal value, while those of the cytotoxic type varied from 2.2 to 118 times the normal value. We found that steatosis was the major feature in the cytotoxic type with ALT and AST < 2.5 times the normal value. Piecemeal necrosis was noted only in all the cases with ALT and AST > 20 times the normal value. In the cholestatic type, the pathological features of the oral contraceptive-related DILD showed mainly cholestasis, whereas chlorpromazine-related DILD revealed additional portal inflammation. Meticulous taking of patient history and clinical assessment are mandatory for the diagnosis of DILD. The ALP levels were helpful in distinguishing different types of DILD. There are some correlations between biochemical changes and pathological features, and both are helpful in distinguishing different etiologies of DILD when the inciting drug is in doubt.",1
8868,7603374,Risk factors for the development of amoxycillin-clavulanic acid associated jaundice,"""OBJECTIVES: To identify risk factors for the development of amoxycillin-clavulanic acid associated jaundice. DESIGN: Retrospective case-control study. Cases were selected from those reported to the Adverse Drug Reactions Advisory Committee from the time of introduction of amoxycillin-clavulanic acid to Australia in 1986 until December 1993. SUBJECTS: Thirty-four cases, defined as individuals who developed jaundice within eight weeks of starting amoxycillin-clavulanic acid, with a biochemical picture of cholestasis, normal calibre bile ducts and no other recognised causes of jaundice or recent use of other hepatotoxic drugs, were selected. For each case, four controls who had been prescribed amoxycillin-clavulanic acid without developing jaundice were randomly selected from the patient register of the prescribing doctor. RESULTS: Increasing age was a risk factor for amoxycillin-clavulanic acid associated jaundice; patients over 55 years had an odds ratio of 16.1 (95% confidence interval [CI], 2.9-88.9) compared with patients less than 30 years. Men had an odds ratio of 2.5 (95% CI, 1.1-5.4) compared with women, although the proportion of men in the study group was larger than in the reported cases overall. History of serious medical illness, drug dose, route and duration of therapy, other medications, smoking and previous drug allergies or use of amoxycillin-clavulanic acid were not significantly associated with jaundice. CONCLUSIONS: Because of the higher risk of jaundice with increasing age, the risk-benefit ratio of amoxycillin-clavulanic acid should be carefully considered in older patients. Further assessment is necessary to clarify the association between jaundice and male sex.""",1
8869,7606070,Suspected ciprofloxacin-induced hepatotoxicity,"OBJECTIVE: To report a case of probable ciprofloxacin-induced hepatotoxicity. CASE SUMMARY: A 44-year-old woman developed severe hepatitis 3 weeks after initiation of a 7-day course of oral ciprofloxacin therapy. Liver biopsy showed severe hepatic necrosis, and other causes of liver injury were excluded. Liver function test results returned to normal 4 months after the appearance of jaundice. DISCUSSION: The time course of events suggested that ciprofloxacin was the cause of severe hepatitis in this patient, and other causes of hepatitis were ruled out. Hepatotoxicity has been reported with other fluoroquinolone antibiotics, and there have been previous unpublished reports to the manufacturer of possible hepatotoxicity caused by ciprofloxacin. CONCLUSIONS: It is suggested that ciprofloxacin can cause severe hepatic injury and that healthcare providers should be aware of this possible adverse drug reaction.",1
8870,7608823,Hepatic toxicity associated with 2'-3' dideoxyinosine in children with AIDS,"Among 34 children with AIDS enrolled in a trial with 2'-3' dideoxyinosine (ddI), six (aged 1-6 years) developed liver abnormalities within 2-18 months after institution of ddI. Two children died of fulminant hepatic failure (one had also an adenovirus infection), and four had a striking elevation of alkaline phosphatases (AP: 1120-7000 IU/L). All of them received sulfa drugs and antifungic treatment with ketoconazole or fluconazole. Three had a serology positive for hepatitis C virus. The evolution of liver enzymes following withdrawal and rechallenge with ddI in the children with elevated AP was an indication of drug-induced toxicity in two patients. In both of the others, readministration of ddI did not cause any subsequent problems. Liver histology in the patients with fulminant hepatitis showed an extensive hepatic necrosis. Liver biopsy done in two other patients revealed a mild granulomatous hepatitis in one and nonspecific changes (i.e., steatosis and a mild inflammation) in the other. Hepatic toxicity has been described with ddI and other nucleoside analogs in adult patients. These six children had many potential causes of liver disease. It may be that ddI is not hepatotoxic per se but that it precipitates liver disease in predisposed patients. We recommend that liver functions be carefully monitored when using this drug.",1
8871,7612373,[NSAID-induced hepatotoxicity: aceclofenac and diclofenac],"Diclofenac (Voltaren, Geigy) and aceclofenac (Falcol, Bayer) belong to a chemical subgroup of nonsteroidal antiinflammatory drugs (NSAID) that are arylalkanoic groups of phenylacetic acid. Hepatotoxicity has been reported with the majority of NSAID although its incidence is not known. We describe two patients who presented hepatic injury after diclofenac and aceclofenac therapy. Recognition of cholestasis associated with NSAID may prevent invasive investigations in jaundiced patients. Clinically liver injury associated with NSAID is not prevalent but we think it is interesting to report those patients for recognition of the role of certain risk factors and to suggest close monitoring.",1
8872,7616816,Fatal aplastic anaemia associated with lisinopril,,1
8873,7618323,Hepatotoxic reaction to chloroquine phosphate in a patient with previously unrecognized porphyria cutanea tarda,,1
8874,7621289,[Hepatic angiosarcoma: a report of a case associated with treatment with arsenic salts and a review of the literature],Hepatic angiosarcoma is an infrequent neoplasm representing 1-3% of all the primary liver cancers. One fourth of the cases have demonstrated a relation with chemical carcinogens with the most frequent being thorium dioxide (thorotrast) and vinyl chloride. The case of an hepatic angiosarcoma which presented as an intraperitoneal hemorrhage in a patient who had undergone treatment with Neosalvarsan (dioxidiaminoarsenobenzol) 46 years beforehand is reported. The previous published reports include 6 cases of hepatic angiosarcoma related with treatment with arsenic salts and 4 cases in whom exposure was environmental.,1
8875,7625419,Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling,"BACKGROUND: The effects of the aminobisphosphonate alendronate sodium on bone mass and markers of bone remodeling were investigated. PATIENTS AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, 2-year study, 188 postmenopausal women, aged 42 to 75 years, with low bone mineral density (BMD) of the lumbar spine were randomly assigned to 1 of 6 daily treatment groups: placebo for 2 years, alendronate 5 or 10 mg for 2 years, alendronate 20 or 40 mg for 1 year followed by placebo for 1 year, or alendronate 40 mg for 3 months followed by 2.5 mg for 21 months. All subjects were given 500 mg/d of elemental calcium as calcium carbonate. RESULTS: At each dose, alendronate produced significant reductions in markers of bone resorption and formation, and significantly increased bone mass at the lumbar spine, hip, and total body, as compared with decreases (significant at lumbar spine) in subjects receiving placebo. In the 10-mg group, mean urinary deoxypyridinoline/creatinine had declined by 47% at 3 months, and mean serum osteocalcin by 53% at 6 months. Mean changes in BMD over 24 months with 10 mg alendronate were +7.21% +/- 0.49% for the lumbar spine, +5.27% +/- 0.70% for total hip, and +2.53% +/- 0.68% for total body (each P < 0.01) compared to changes of -1.35% +/- 0.61%, -1.20% +/- 0.64% and -0.31% +/- 0.44% at these sites, respectively, with placebo treatment. Progressive increases in BMD of both lumbar spine and total hip were observed in the second year of treatment with 10 mg alendronate (both P < 0.05). CONCLUSION: Alendronate, a potent inhibitor of bone resorption, reduces markers of bone remodeling and significantly increases BMD at the lumbar spine, hip, and total body, and is well tolerated at therapeutic doses (5 or 10 mg daily) in the treatment of osteoporosis in postmenopausal women.",1
8876,7626305,[Ticlopidine-induced cholestatic hepatitis],,1
8877,7630846,"Niacin for lipid disorders. Indications, effectiveness, and safety","Niacin can be very effective and safe in lowering low-density lipoprotein cholesterol and triglyceride levels and also in increasing high-density lipoprotein cholesterol levels. In combination with other lipid-lowering drugs (eg, bile acid sequestrants), it has reduced the incidence of cardiovascular events and stopped the progression of coronary artery lesions. It may be the most cost-effective lipid-lowering agent currently available. At lower doses, sustained-release forms of niacin may also improve patient compliance.",1
8878,7631226,Medicinal arsenic poisoning: 27-year follow-up,,1
8879,7636666,"Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. The Multicenter Fluconazole Study Group","""OBJECTIVE: To compare the efficacy, safety, and tolerance of fluconazole suspension versus nystatin in the treatment of oropharyngeal thrush in immunocompromised children. DESIGN: Multicenter, randomized, observer-masked trial. SETTING: Thirty-two centers participated, including hospitals and ambulatory care clinics. PATIENTS: We enrolled 182 immunocompromised infants and children, ages 5 months to 14 years, with signs of oral thrush and presence of yeasts on potassium hydroxide- or gram-stained preparations. Subjects were randomly assigned to receive a single daily dose of fluconazole suspension, 2 to 3 mg/kg per day, or nystatin, 400,000 units four times daily for 14 days; 159 patients, who had culture confirmation of thrush and received at least 7 days of study drug, were evaluated for efficacy; all patients were evaluated for safety. RESULTS: Clinical cure was demonstrated in 91% of the subjects in the fluconazole group and 51% of the subjects in the nystatin group (p < 0.001), and eradication of the organism cultured at entry occurred in 76% and 11% (p < 0.001), respectively. Gastrointestinal conditions developed in six patients who received fluconazole and in three who received nystatin; two fluconazole recipients were subsequently withdrawn from the study. Laboratory abnormalities occurred with equal frequency in both groups. Clinical relapse rates were similar in both groups at 2 weeks (18% and 24% for fluconazole and nystatin, respectively) and 1 month (28% and 27%, respectively) after the completion of study drug. CONCLUSIONS: Fluconazole suspension is more effective than nystatin in the treatment of thrush in immunocompromised children. Both regimens were well tolerated.""",1
8880,7639808,Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients,"""OBJECTIVE: To test the usefulness and cost savings resulting from application of the new American College of Rheumatology (ACR) guidelines for assessing the risk for the development of clinically significant liver disease in rheumatoid arthritis (RA) patients treated with methotrexate (MTX). METHODS: One-hundred twelve MTX-treated RA patients were prospectively followed up for MTX hepatotoxicity and underwent liver biopsies according to modified guidelines of the Psoriatic Task Force (PTF). All biopsies were graded according to the Roenigk classification. The new ACR recommendations were then retrospectively applied to test their usefulness and cost-effectiveness in this cohort. RESULTS: Based on the PTF guidelines, 66 patients underwent liver biopsies; a total of 110 liver biopsies were performed. Two patients had biopsy-related complications. Five patients were found to have Roenigk grade IIIB or IV histologic abnormalities. The total cost for this group was $111,380. Applying the new ACR criteria, only 15 patients would have undergone liver biopsies; there would have been a total of 18 biopsies, with no complications. Four of the 5 patients with Roenigk grade IIIB or IV liver abnormalities would have been identified. One patient with insulin-dependent diabetes mellitus (IDDM) who was found to have cirrhosis (Roenigk grade IV) on liver biopsy as a result of use of the PTF guidelines would have been missed with use of the ACR guidelines. The total cost for the group receiving biopsies based on the ACR guidelines would have been $16,956. Overall, the new ACR guidelines had 80% sensitivity and 82% specificity and resulted in a cost savings of $1,430 per patient. CONCLUSION: The new ACR guidelines on MTX monitoring and biopsy surveillance appear to be clinically useful and result in considerable cost savings. However, 1 IDDM patient with significant liver histologic abnormalities would have been missed. We suggest that IDDM be added to the ACR guidelines as a risk factor for MTX hepatotoxicity.""",1
8881,7641903,"Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes, and androgen receptor behavior","OBJECTIVE: To investigate the long-term effects of treatment with low doses of flutamide on clinical and hormonal parameters, as well as on the androgen receptor status, in hirsute women. DESIGN: Eighteen hirsute patients with regular menses were studied basally and during treatment with 125 mg flutamide, three times per day for 12 months. Barrier or intrauterine contraception was used during the study in sexually active women. Safety parameters were assessed throughout the study. Hirsutism, graded by the modified Ferriman-Gallwey score, and hormonal parameters were evaluated basally and at 4-month intervals during treatment. Gonadotropin-releasing hormone and ACTH stimulation tests were performed before and after 3 to 4 months of therapy. In addition, the concentration of androgen receptors in mononuclear leukocytes was measured, in both the follicular and luteal phases of the menstrual cycle, basally and after 4 months of flutamide treatment. RESULTS: Flutamide was well tolerated in all women, with the noticeable exception of one patient who presented increased serum transaminase after 8 months of therapy. Hirsutism markedly improved in all women during the treatment (Ferriman-Gallwey score after 1 year: 4.1 +/- 0.5 versus 14.1 +/- 0.9). A reduction of serum androgens was found, whereas no change was observed in either basal or GnRH-stimulated gonadotropins or in the cortisol and 17 alpha-hydroxyprogesterone response to ACTH. Cycles remained ovulatory. Before treatment, the number of androgen receptors was higher in the luteal than in the follicular phase. This rhythmic differentiation disappeared after the patients had been given the antiandrogen drug. CONCLUSIONS: Flutamide is effective in the treatment of hirsutism but requires constant surveillance of liver function. Androgen receptor blockade might be potentiated by a reduction of serum androgens. Flutamide affects androgen receptor behavior during the menstrual cycle. The meaning of this finding remains to be elucidated.",1
8882,7644398,Antituberculosis treatment-induced hepatotoxicity: role of predictive factors,"Antituberculosis drug-induced hepatotoxicity is quite common. However, factors predicting its development are still controversial. The objective of the present study was to evaluate the role of certain factors (age and sex of the patient, alcoholism, chronic liver disease, hepatitis B virus carrier status, acetylator status, nutritional status and antituberculosis treatment (ATT) regimen) in predicting the development of ATT-induced hepatitis. In a case-control study, 60 consecutive patients with evidence of ATT-induced hepatitis were studied to assess the possible association of the above-mentioned factors with ATT-induced hepatitis. Body mass index was found to be significantly lower in ATT-induced hepatitis patients (17.2 +/- 2.7) than in controls (19.5 +/- 3.3) (p < 0.05). Pyrazinamide was used in addition to isoniazid and rifampicin in a significantly higher percentage of patients in the ATT-induced hepatitis group (70%) as compared with those in the control group (42%). No significant differences were observed between the two groups with regard to the rest of the parameters.",1
8883,7650341,Liver transplantation for severe acute liver failure after herbal medicine (Teucrium polium) administration,,1
8884,7654902,[Phenytoin hypersensitivity syndrome],"Diphenylhydantoine is a drug frequently used in the treatment of epilepsia. In rare occasions, it produces a mulsisystemic manifestation characterized by fever, lymphadenopathy, hepatitis, eosinophilia and desquamative cutaneous eruption, which typically develops within 4-8 weeks after the beginning of the treatment. Mortality rates may reach up to 40% in patients with severe hepatic affection, although the response to steroid therapy is usually frequent. We present the case of a patient which developed a syndrome of hypersensibility to diphenylhydantoine with mononucleosic manifestations, icteric hepatitis and exfoliative dermatitis, who completely recovered a few days after his hospitalization.",1
8885,7655135,Piperacillin/tazobactam: a new beta-lactam/beta-lactamase inhibitor combination,"OBJECTIVE: To discuss the antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effect profile of piperacillin/tazobactam, a new beta-lactan/beta-lactamase inhibitor combination. DATA SOURCES: Literature was identified by MEDLINE search of the medical literature, review of selected references, and data provided by the manufacturer. STUDY SELECTION: In vitro susceptibility data were surveyed from studies following the methods of the National Committee for Clinical Laboratory Standards. Data evaluating clinical efficacy were selected from all published trials and abstracts. Additional information concerning safety, chemistry, and pharmacokinetics was reviewed. DATA SYNTHESIS: The antimicrobial activity of piperacillin is enhanced by addition of tazobactam against gram-positive, gram-negative, and anaerobic bacteria. Tazobactam is active against a broad spectrum of plasmid and chromosomally mediated enzymes and has minimal ability to induce class I chromosomally mediated beta-lactamase enzymes. Piperacillin/tazobactam's expanded activity appears encouraging in the treatment of mixed aerobic and anaerobic infections. Direct comparisons of ticarcillin/clavulanate and piperacillin/tazobactam for the treatment of lower respiratory tract infections showed piperacillin/tazobactam to be clinically superior, and in the treatment of skin and soft tissue infections the 2 agents were comparable. For the treatment of intraabdominal infections, piperacillin/tazobactam was at least as effective as imipenem/cilastatin and clindamycin plus gentamicin. CONCLUSIONS: The combination of tazobactam with piperacillin results in an antimicrobial agent with enhanced activity against most beta-lactamase-producing organisms. Preliminary data indicate that piperacillin/tazobactam has proven clinical efficacy in the treatment of a variety of infections, especially polymicrobic infections.",1
8886,7657281,Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure,"""Hepatic injury in alcoholics due to intake of acetaminophen (APAP or acetylparaaminophenol) with therapeutic intent has been reported, but the extent of the phenomenon is not clear, pertinent details of the association remain insufficiently clarified, and the importance of the phenomenon is not widely appreciated. The present report describes 67 patients who developed hepatic injury after ingestion of APAP with therapeutic intent. All were regular users of alcohol. Sixty-four percent of the patients were considered to be """"alcoholic"""" or reported intakes greater than 80 g/d, 35% took 60 g/d or less, and the remainder were vague in their reporting. Doses of APAP were in the """"nontoxic"""" range ( < 6 g/d) in 60% of the group, within the recommended range ( < 4 g/d) in 40%, and at 4.1 to 6 g/d in 20%. Characteristic feature was the towering level reached by aspartate transaminase (AST) with figures ranging from 3,000 to 48,000 IU in more than 90% of cases. Almost 20% of the patients died. The data on these patients were similar to 94 cases of injury from APAP taken with therapeutic intent reported in the literature. This study provides further evidence of hepatic injury in regular uses of alcohol, especially chronic alcoholics, who take APAP with therapeutic intent. Susceptibility is presumably caused by induction of cytochrome P-4502EI by ethanol and by depletion of glutathione (GSH) because of the effects of alcohol, the malnutrition often associated with alcoholism, and the depletion associated with chronic use of APAP and impaired glucuronidation caused by fasting perhaps as well. The syndrome of liver injury is distinctive, marked by uniquely elevated levels of AST, and poses a significant threat.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
8887,7661164,Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy,"BACKGROUND: A syndrome of hepatomegaly with severe steatosis has been described in case reports and case series in HIV-infected patients receiving nucleoside analog antiretroviral therapy. We wished to quantitate the incidence of this syndrome in a well characterized, demographically heterogeneous cohort of HIV-infected patients followed longitudinally. METHODS: All patients enrolled into a comprehensive primary care HIV Clinic from July 1989 through July 1994 (N = 1836) were screened for evidence of steatosis and liver disease by assessment of hospital discharge diagnoses, pathology reports, out- and in-patient laboratory data, and clinic records. RESULTS: A total of 322 (18%) patients had evidence of a liver abnormality. In these patients, viral hepatitis and alcohol-induced liver disease were the most common diagnoses. Only two patients had hepatomegaly with moderate to severe steatosis and acidosis. Both cases occurred in white men with very advanced HIV disease who were receiving nucleoside analog antiretroviral therapy. The incidence of the syndrome was 1.3 per 1000 person-yr of follow-up in antiretroviral users in our cohort (95% confidence interval: 0.2, 4.5 per 1000 person-yr). CONCLUSION: The hepatic steatosis syndrome manifesting as a severe, potentially fatal complication of antiretroviral therapy in HIV disease is rare. Both men and women and patients in early and late stages of HIV infection appear to be susceptible. It is not currently known whether a milder form of this syndrome is occurring in a larger population.",1
8888,7662428,[Aceclofenac-induced hepatitis],,1
8889,7663041,Ticlopidine-induced granulomatous hepatitis,,1
8890,7663283,Safety of complementary medicines should be monitored,,1
8891,7671785,[Lupus erythematosus and liver diseases],,1
8892,7674492,Chaparral and liver toxicity,,1
8893,7674494,Chaparral and liver toxicity,,1
8894,7677802,Fatal acute hepatic necrosis due to fluconazole,,1
8895,7680764,Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma,"""BACKGROUND: CHOP is a first-generation, combination-chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone that has cured approximately 30 percent of patients with advanced stages of intermediate-grade or high-grade non-Hodgkin's lymphoma in national cooperative-group trials. However, studies at single institutions have suggested that 55 to 65 percent of such patients might be cured by third-generation regimens such as ones consisting of low-dose methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD); prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue (ProMACE-CytaBOM); and methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). METHODS: To make a valid comparison of these regimens, the Southwest Oncology Group and the Eastern Cooperative Oncology Group initiated a prospective, randomized phase III trial. The study end points were the response rate, time to treatment failure, overall survival, and incidence of severe or life-threatening toxicity. Dose intensity was calculated and analyzed. RESULTS: Of the 1138 patients registered for the trial, 899 were eligible. Each treatment group contained at least 218 patients. Known prognostic factors were equally distributed among the groups. There were no significant differences among the groups in the rates of partial and complete response. At three years, 44 percent of all patients were alive without disease; there were no significant differences between the groups (41 percent in the CHOP and MACOP-B groups and 46 percent in the m-BACOD and ProMACE-CytaBOM groups; P = 0.35). Overall survival at three years was 52 percent (50 percent in the ProMACE-CytaBOM and MACOP-B groups, 52 percent in the m-BACOD group, and 54 percent in the CHOP group; P = 0.90). There was no subgroup of patients in which survival was improved by a third-generation regimen. Fatal toxic reactions occurred in 1 percent of the CHOP group, 3 percent of the ProMACE-CytaBOM group, 5 percent of the m-BACOD group, and 6 percent of the MACOP-B group (P = 0.09). CONCLUSIONS: CHOP remains the best available treatment for patients with advanced-stage intermediate-grade or high-grade non-Hodgkin's lymphoma.""",1
8896,7682911,"Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy","""Mefloquine is an orally administered blood schizontocide. Initial dose-finding and comparative studies performed between 1977 and 1989 demonstrated efficacy of mefloquine as prophylaxis in nonimmune individuals and in the suppression and treatment of malaria in adults and children caused by multidrug-resistant Plasmodium falciparum. It was also effective against P. vivax infection, while data concerning the treatment of P. ovale and P. malariae infections were limited. In an attempt to delay the emergence of resistance to this promising antimalarial agent, mefloquine was combined with sulfadoxine and pyrimethamine. Although initial clinical trials indicated that this regimen was effective in preventing and treating falciparum malaria, recent treatment failures, the potential for severe dermatological reactions and lack of therapeutic advantage over mefloquine alone has prompted the World Health Organization to recommended that the combination be no longer used for treatment or prophylaxis of malaria. Mefloquine is generally well tolerated in both adults and children, with nausea, vomiting, diarrhoea, headache, dizziness, rash, pruritus and abdominal pain being the most common adverse effects, although it is difficult to distinguish between disease- and treatment-related events. The incidence of these adverse effects is similar to or lower than those observed with other antimalarial agents. Cardiovascular changes, such as bradycardia, occasionally occur. The most notable adverse effects associated with mefloquine are neuropsychiatric disturbances; precipitation of such events should be closely monitored and requires termination of prophylaxis or therapy. The eventual emergence of resistance to mefloquine, as with many other antimalarial agents, was inevitable. Mefloquine resistance is established in certain areas of Thailand and may be becoming a growing problem in other regions of the world. In order to preserve the efficacy of mefloquine in non-resistant areas, this useful agent should be used with care and only prescribed for prophylaxis in travellers and treatment in areas of multidrug-resistant plasmodia. Future options to combat mefloquine resistance may include the combination of mefloquine with other antimalarial agents such as qinghaosu derivatives. Thus, with cautious use and possible combination with other agents, mefloquine is likely to remain an important treatment option for falciparum malaria, a widespread parasitic disease for which an increasing number of drugs have proved inadequate.""",1
8897,7694924,Dystonia and drug-induced hepatitis in a patient treated with clozapine,,1
8898,7699252,High doses of aminoglycoside antibiotics do not induce liver toxicity because uptake is limited,,1
8899,7701468,Hepatotoxicity caused by the combined action of isoniazid and rifampicin,"A 35 year old black Somalian woman with miliary tuberculosis developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol. After withdrawal of all drugs the liver profile returned to normal and remained so after challenge with isoniazid. Hepatotoxicity recurred when rifampicin was added, but it was well tolerated when reintroduced without isoniazid.",1
8900,7705574,[Chronic active hepatitis associated with antinuclear antibodies induced by fenofibrate],,1
8901,7707128,Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukemia,"PURPOSE: To evaluate the clinical efficacy and safety of 2-chlorodeoxyadenosine (CdA) when administered by subcutaneous injection to patients with symptomatic hairy cell leukemia (HCL), and to evaluate predictive factors for response. PATIENTS AND METHODS: Seventy-three patients were given CdA as a subcutaneous injection once daily for 7 days. Complete remission (CR) required normalized blood counts and the absence of B-ly 7-positive bone marrow cells by flow cytometry. CdA concentrations in plasma following the first injection were analyzed by high-pressure liquid chromatography. RESULTS: Fifty-nine patients (81%) achieved a durable CR after one (n = 55) or two courses, and 10 had a partial remission (PR). With a median follow-up duration of 20 months, no patient had a clinical relapse. Neutropenic fever that required intravenous antibiotics occurred in 28 patients (38%). No toxicity at injection sites was observed. Incomplete response was predicted by an elevated lymphocyte count and serum beta 2-microglobulin level, and by a high percentage of hairy cells in the bone marrow. Plasma CdA levels were similar to those achieved from intravenous administration. CONCLUSION: Subcutaneous injection of CdA is safe and as effective as continuous infusion without problems associated with the mode of administration. Our schedule simplifies CdA treatment and can be generally recommended.",1
8902,7711343,Probable ticlopidine-induced cholestatic hepatitis,"OBJECTIVE: To report a case of probable ticlopidine-induced cholestatic hepatitis. CASE SUMMARY: A 76-year-old man with no known history of liver disease developed painless jaundice approximately 3 weeks after starting ticlopidine 250 mg bid. After ticlopidine was discontinued, the jaundice resolved and serum liver enzyme concentrations returned toward normal. A diagnosis of probable ticlopidine-induced cholestatic hepatitis was made. The patient was not rechallenged with ticlopidine. DISCUSSION: A literature search produced 6 case reports describing 7 patients in whom probable ticlopidine-induced cholestatic hepatitis had been diagnosed. Only 1 of these reports appeared in the North American literature. Jaundice developed within 1 to 3 months of starting ticlopidine at less than or equal to the recommended daily dose. In all cases, jaundice resolved and serum liver enzyme concentrations normalized over a period of months after drug discontinuation. CONCLUSIONS: Routine monitoring of serum liver enzyme concentrations is not recommended. However, patients should be instructed to watch for signs and symptoms of liver injury. Should they occur, patients should stop taking the ticlopidine and consult their physician immediately.",1
8903,7714072,Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole,,1
8904,7715639,Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia,"BACKGROUND: In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. METHODS: In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. RESULTS: Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. CONCLUSIONS: Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.",1
8905,7717345,Intrahepatic cholestasis due to ticarcillin-clavulanate,,1
8906,7717793,Prolonged use of methotrexate for sarcoidosis,"BACKGROUND: To determine the safety and efficacy of methotrexate as a steroid-sparing agent in patients with symptomatic sarcoidosis, a nonrandomized interventional study of patients with chronic sarcoidosis treated with methotrexate for at least 2 years was performed. Efficacy was assessed for all patients after 2 years of treatment. Toxicity was assessed for all patients receiving therapy for the entire time (a total of 150 patient-years). METHODS: Patients were treated in a subspecialty ambulatory clinic at a university hospital. Patients with biopsy-confirmed sarcoidosis who had persistent symptoms and who were eager to avoid or reduce corticosteroid therapy were selected for study. A total of 50 patients completed at least 2 years of methotrexate therapy. Patients were treated with oral methotrexate once a week. Dosage was adjusted based on the patient's white blood cell count. Clinical response was measured in the affected organ, including the lung (measurement of vital capacity), skin (regression of skin lesions), and central nervous system (magnetic resonance imaging). Also noted was the initial and subsequent dosage of prednisone used as therapy for sarcoidosis. RESULTS: Improvement in vital capacity or other affected symptomatic organ was noted in 33 of 50 treated patients. Corticosteroids were discontinued in an additional six patients who remained stable with clinical or symptomatic improvement. The major toxic effects noted in 150 patient-years of therapy were hepatic (six patients), leukopenia requiring hospitalization (one patient), and cough (one patient). Forty-one liver biopsy procedures were performed in 33 patients. Of these, six demonstrated significant changes related to methotrexate that led to drug discontinuation. CONCLUSION: Methotrexate is a well-tolerated therapeutic agent with significant steroid sparing and efficacy for the treatment of chronic symptomatic sarcoidosis.",1
8907,7720737,Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea,"Veno-occlusive disease was diagnosed in an 18-month-old boy who had regularly consumed a herbal tea mixture since the 3rd month of life. The boy developed portal hypertension with severe ascites. Histology of the liver showed centrilobular sinusoidal congestion with perivenular bleeding and parenchymal necrosis without cirrhosis. The tea contained peppermint and what the mother thought was coltsfoot (Tussilago farfara). The parents believed the tea aided the healthy development of their child. Pharmacological analysis of the tea compounds revealed high amounts of pyrrolizidine alkaloids. Seneciphylline and the corresponding N-oxide were identified as the major components by thin-layer chromatography, mass spectrometry and NMR spectroscopy. We calculated that the child had consumed at least 60 micrograms/kg body weight per day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles alliariae (Alpendost) had been erroneously gathered by the parents in place of coltsfoot. The two plants can easily be confused especially after the flowering period. The child was given conservative treatment only and recovered completely within 2 months. CONCLUSION: In all cases of veno-occlusive disease pyrrolizidine alkaloids ingestion should be excluded. The identity of collected plant material should be verified by pharmaceutically trained experts and information of composition, dosage and mode of administration should be included in guidelines for herbal preparations.",1
8908,7730690,Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS,"""The effects of dronabinol on appetite and weight were evaluated in 139 patients with AIDS-related anorexia and > or = 2.3 kg weight loss in a multi-institutional study. Patients were randomized to receive 2.5 mg dronabinol twice daily or placebo. Patients rated appetite, mood, and nausea by using a 100-mm visual analogue scale 3 days weekly. Efficacy was evaluable in 88 patients. Dronabinol was associated with increased appetite above baseline (38% vs 8% for placebo, P = 0.015), improvement in mood (10% vs -2%, P = 0.06), and decreased nausea (20% vs 7%; P = 0.05). Weight was stable in dronabinol patients, while placebo recipients had a mean loss of 0.4 kg (P = 0.14). Of the dronabinol patients, 22% gained > or = 2 kg, compared with 10.5% of placebo recipients (P = 0.11). Side effects were mostly mild to moderate in severity (euphoria, dizziness, thinking abnormalities); there was no difference in discontinued therapy between dronabinol (8.3%) and placebo (4.5%) recipients. Dronabinol was found to be safe and effective for anorexia associated with weight loss in patients with AIDS.""",1
8909,7733122,"Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus","BACKGROUND: Acarbose delays release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, thereby attenuating postprandial increments in blood glucose and insulin. This multicenter, double-blind, placebo-controlled study compared the efficacy and safety of diet alone, acarbose, tolbutamide, and acarbose-plus-tolbutamide in non-insulin-dependent diabetes mellitus (NIDDM) patients. PATIENTS AND METHODS: A total of 290 patients with NIDDM and fasting plasma glucose levels of at least 140 mg/dL were randomized to receive treatment TID with acarbose 200 mg, tolbutamide 250 to 1,000 mg, a combination of both drugs, or placebo. A 6-week run-in period was followed by double-blind treatment for 24 weeks, then a 6-week follow-up period. RESULTS: All active treatments were superior (P < 0.05) to placebo in reducing postprandial hyperglycemia and HbA1c levels. The ranking in order of efficacy was: acarbose-plus-tolbutamide, tolbutamide, acarbose, and placebo. The postprandial reductions in glucose were approximately 85 mg/dL for acarbose-plus-tolbutamide, 71 mg/dL for tolbutamide, 56 mg/dL for acarbose, and 13 mg/dL for placebo. Tolbutamide was associated with increases in body weight and postprandial insulin levels when taken alone, but these were ameliorated when tolbutamide was taken in combination with acarbose. Acarbose alone or in combination with tolbutamide caused significantly more gastrointestinal adverse events (mainly flatulence and soft stools or diarrhea) than tolbutamide or placebo, but these were generally well tolerated. Clinically significant elevations in hepatic transaminase levels occurred in 3 patients in the acarbose group and 2 in the acarbose-plus-tolbutamide group. Transaminase levels returned to normal when therapy was discontinued. CONCLUSIONS: Acarbose was effective and well tolerated in the treatment of NIDDM. Control of glycemia was significantly better with acarbose compared with diet alone. Acarbose-plus-tolbutamide was superior to tolbutamide alone.",1
8910,7734010,Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group,"""BACKGROUND: HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. METHODS AND RESULTS: Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). CONCLUSIONS: In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.""",1
8911,7734692,[Cholestatic hepatitis associated with tenoxicam],,1
8912,7741903,Acute hepatitis associated with jin bu huan,,1
8913,7744141,"A randomised trial comparing the safety and efficacy of the Zoladex 10.8-mg depot, administered every 12 weeks, to that of the Zoladex 3.6-mg depot, administered every 4 weeks, in patients with advanced prostate cancer. The Dutch South East Cooperative Urological Group","A new longer-acting depot formulation containing 10.8 mg Zoladex administered every 12 weeks was compared to the 3.6-mg Zoladex depot administered every 28 days, in a randomised trial in patients with advanced prostatic carcinoma in which pharmacodynamic efficacy and safety were assessed. Effective induction of mean serum testosterone suppression into the surgically castrate range by 21 days and maintenance of suppression for the duration of therapy was achieved with both the 3.6-mg and the 10.8-mg depot formulations. The Zoladex 10.8-mg depot was well tolerated both locally and systemically. This new formulation which is equivalent to three successive 3.6-mg depots will provide a more convenient dosing regime for both patient and doctor in this indication.",1
8914,7746823,[Acute liver disease during treatment with pipobroman and allopurinol],,1
8915,7748712,[Cholestatic hepatitis caused by glybenclamide in a patient with hepatitis C virus],"We report the case of a 68-year-old male HVC+ diagnosed as cholestatic hepatitis induced by glybenclamide, following a non-insulin dependent diabetes mellitus treatment. When the drug was discontinued normal analytic parameters were obtained. However, HVC may induce more cholestatic and cytolysic changes on the hepatitis due to glybenclamide. When reviewing the literature only one similar case has been previously reported, although several disturbances in liver function tests have been described in other reports. Routine biochemical tests including liver function are indicated in patients receiving antidiabetic agents in order to make an early diagnosis of liver toxicity.",1
8916,7755793,Hepatic injury and vitamin A ingestion,,1
8917,7756636,The syndrome of hepatic veno-occlusive disease after marrow transplantation,"The clinical syndrome of VOD is a frequent cause of nonrelapse mortality among patients receiving high-dose cytoreductive regimens. Patients likely to develop VOD have existing liver dysfunction, evidence of infection before conditioning, tend to receive more intensive preparative regimens, and often receive marrow from alternative donors. Therapeutic drug monitoring of busulfan and pharmacokinetic dose adjustments appear to be useful in reducing the incidence of VOD in patients receiving this agent. Data are contradictory as regards whether pharmacologic prophylaxis is effective. Patients who will develop severe VOD are characterized by a rapid increase in serum bilirubin as well as weight. Supportive management of these patients should attempt to preserve respiratory as well as renal function, sometimes a very difficult task. Treatment with recombinant tissue plasminogen activator has promise. However, given its potential for toxicity, a prospective randomized trial should be performed. Hopefully, as more data regarding the molecular and cellular mechanisms of this illness are elucidated, more thoughtful prevention strategies will be developed. This will be necessary, particularly as newer, more intensive preparative regimens are being developed, as access to alternative donors increases, and as more diseases will be treated with this approach.",1
8918,7767184,Use of chloramphenicol as topical eye medication: time to cry halt?,,1
8919,7769203,Possible nizatidine-induced subfulminant hepatic failure,Subfulminant hepatic failure has not been reported to occur with the histamine-2 receptor antagonists. We report a possible case of nizatidine-induced subfulminant hepatic failure leading to the eventual development of cirrhosis.,1
8920,7774090,High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis,"OBJECTIVE: To assess the response to and safety of long term, high dose (> or = 1 mg/kg/week or > or = 15 mg/m2/week) methotrexate (MTX) administration, in a cohort of 21 children with longstanding, severe juvenile rheumatoid arthritis (JRA). METHODS: Children received MTX at an average weekly dose of 27 mg for a mean of 15.2 months. Outcome was assessed using a disease activity score based on changes in concomitant therapy, laboratory parameters, physician's global assessment, and radiologic evaluation. RESULTS: Seven patients (33%) improved, including one child who achieved complete remission, while 14/21 children (67%) did not benefit from high dose MTX. Subsequently, 6/14 (43%) of the non-responders discontinued high dose MTX and began cyclosporine. Radiologic progression, regardless of clinical outcome, was documented in 10/15 (67%) of the patients. The drug was well tolerated despite mild gastrointestinal symptoms and transient liver enzyme elevation. CONCLUSION: The results of this open retrospective pilot trial suggest that high dose MTX is well tolerated, but that its role in the treatment of children with refractory JRA may be limited. Radiologic progression, despite improvement in the clinical status or in the laboratory parameters, supports the hypothesis that MTX acts as a potent antiinflammatory agent.",1
8921,7774760,Zolpidem in insomnia: a 3-year post-marketing surveillance study in Switzerland,"""A multicentre post-marketing surveillance study was conducted in Switzerland in routine practice and involved 1972 insomniac patients treated with zolpidem, an imidazopyridine hypnotic agent. The patients were representative of the general insomniac population (65% women; mean age 55 years; 29% over 65). Of the patients, 87% were treated with a zolpidem dosage of 10 mg/day and the median treatment duration was 30 days. All adverse events were collected through spontaneous reporting. A total of 175 patients (8.9%) reported 343 adverse events, and 102 (5.2%) of them discontinued treatment. CNS (central nervous system)-related adverse events accounted for 66% of the total, the most common events being residual daytime sedation and insufficient efficacy in 3.7% and 1.6%, respectively; confusion, disorientation, nervousness, nightmares, amnesia, impaired concentration and anxiety were observed in a lower proportion. Gastro-intestinal symptoms, headache and skin reactions were the most frequent non-CNS related effects. No serious adverse event was reported and no new risk factors or at-risk populations were identified. The safety profile of zolpidem is thus consistent with its known pharmacological properties, the results of previous clinical trials, and the cumulative international experience gained with this short-acting hypnotic drug.""",1
8922,7781437,Exacerbation of primary biliary cirrhosis during interferon-alpha 2b therapy for chronic active hepatitis C,"A 60-year-old woman with chronic active hepatitis C was treated with 6 million units of rIFN-alpha 2b daily for two weeks and subsequently three times weekly for several months. Histological examination proved a severe form of chronic active hepatitis C unexpectedly complicated with primary biliary cirrhosis (PBC). Before treatment, levels of serum alkaline phosphatase (ALP) or gammaglutamyltranspeptidase (GGT) had remained within normal limits over six months, although anti-mitochondrial antibody (AMA) was shown to be positive. After eight weeks of therapy, the daily dose of rIFN was reduced to 3 million units because of a marked increase of ALP and GGT, although the serum alanine aminotransferase (ALT) was normalized. Four months later, IFN treatment was suspended because of continuous elevation of the ALP and GGT levels, and administration of ursodeoxycholic acid was substituted. Two months later, the ALP and GGT levels returned to the normal range, although ALT was not normalized and HCV-RNA remained positive. This is the first report case that demonstrates IFN treatment potentially exacerbates PBC associated with chronic active hepatitis C. It is important for treating physicians to keep this association in mind.",1
8923,7784827,Hypersensitivity hepatitis due to pyrazinamide,"Pyrazinamide hepatotoxicity is considered secondary to a direct and dose-related toxic effect. At currently used doses, pyrazinamide provides effective short-term treatment and is free from serious side effects. We report a case of pyrazinamide-induced hepatitis for which the rechallenge data strongly suggest a hypersensitivity mechanism.",1
8924,7787212,Methotrexate therapy and liver fibrosis: are human prolyl hydroxylase and type IV collagen reliable and sensitive markers?,,1
8925,7794322,Possible coumarin hepatotoxicity,,1
8926,7797836,"""Hepatotoxicity and accelerated fibrosis following 3,4-methylenedioxymetamphetamine (""""ecstasy"""") usage""","""3,4-Methylenedioxymetamphetamine (""""ecstasy"""") has previously been reported to cause an acute hepatitis that may progress to liver failure. We present the first recorded case of ecstasy-induced accelerated hepatic fibrosis.""",1
8927,7805928,Clinical assessment of recombinant human follicle-stimulating hormone in stimulating ovarian follicular development before in vitro fertilization. Recombinant Human FSH Study Group,"OBJECTIVE: To compare the efficacy and the safety of recombinant human FSH (hFSH) with urinary hFSH for stimulating follicular development in women undergoing IVF-ET. DESIGN: Multicenter, prospective, randomized, open, parallel group, clinical study. SETTING: Eight European academic IVF units and one private IVF unit. PATIENTS: Infertile female patients aged 18 to 38 years suffering from tubal disease, mild endometriosis, or unexplained infertility. INTERVENTIONS: Pretreatment with buserelin acetate was followed by recombinant or urinary hFSH treatment started at an initial dose of 225 IU FSH/d. Dose adjustment was allowed after 5 days of FSH. After administration of hCG, a standard IVF-ET procedure was performed. MAIN OUTCOME MEASURES: Follicular development, oocyte retrieval, fertilized oocytes, duration and dose of FSH, and pregnancy. The hypothesis formulated before the study was that no difference was expected between the two FSH preparations. RESULTS: Sixty patients were treated with recombinant hFSH and 63 with urinary hFSH. The mean number (+/- SD) of growing follicles (mean diameter > 10 mm) was 10.3 +/- 4.9 and 11.2 +/- 5.2, of follicles (mean diameter > 14 mm) was 7.8 +/- 3.6 and 9.2 +/- 4.5, of retrieved oocytes was 9.3 +/- 5.0 and 10.7 +/- 5.3, and of fertilized oocytes was 5.6 +/- 3.8 and 6.5 +/- 4.3, for recombinant and urinary hFSH, respectively. The duration of FSH treatment was 9.9 +/- 2.3 and 9.4 +/- 1.8 days and the average total dose was 2270 +/- 714 and 2095 +/- 591 IU of FSH, for recombinant and urinary hFSH, respectively. Thirteen pregnancies were recorded in the recombinant hFSH group and 11 in the urinary hFSH group. Nine patients delivered 13 live infants in the recombinant hFSH group and eight delivered 13 live infants in the urinary hFSH group. In terms of safety, no difference was recorded between the groups and no anti-FSH antibodies were found in any of the patients. CONCLUSIONS: This clinical study shows that recombinant hFSH is as safe and effective as urinary hFSH in stimulating ovarian follicular development.",1
8928,7814188,Transient hepatic dysfunction in two brothers receiving heparin and streptokinase: a genetic predisposition?,"Two brothers with acute myocardial infarction are presented. Subsequent to a standard thrombolysis treatment with streptokinase and heparin, both developed abnormal liver tests, with elevated transaminases only. This liver dysfunction resolved promptly. The occurrence of such side-effects in two siblings raises the question of genetic predisposition to the otherwise uncommon hepatic complications of thrombolysis treatment.",1
8929,7820043,The Scripps Clinic experience with 2-chlorodeoxyadenosine in the treatment of hairy cell leukemia,"Follow-up data is now available on 144 patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine (2-CdA) at the Scripps Clinic. Of 144 patients followed for a median of 14.2 months, 123 (85%) obtained complete responses, 17 (12%) partial responses, 3 (2%) did not respond and 1 patients was unevaluable. So far, only 4 patients have relapsed at a median of 36 months. Fever was the major toxicity occurring in 43% of patients. Five patients resistant (3 patients) or intolerant (2 patients) to 2'-deoxycoformycin were also treated. Of these 5 patients, 4 obtained complete responses, including 2 patients resistant to 2'-deoxycoformycin, and 1 patient a partial response, suggesting a possible lack of cross-resistance between 2'-deoxycoformycin and 2-CdA in hairy-cell leukemia. More than 200 patients have been treated with 2-CdA worldwide with 82% obtaining complete remission and 12% partial remissions. Serial peripheral blood immunophenotypic analyses have documented the absence of circulating hairy cells. When bone marrow biopsies were examined using sensitive immunohistochemical staining techniques, residual hairy cells were detected in 25-50% of morphologic complete responders. Patients will need to be observed longitudinally to determine if this staining is predictive of relapse. A double-blind, placebo-controlled study of pentoxifylline, a modulator of tumor necrosis factor-alpha and other cytokines, was performed in 2-CdA-treated hairy cell leukemia patients to determine whether the incidence of neutropenic fever would be reduced. Although pentoxifylline resulted in less febrile, hospital and antibiotic therapy days than placebo, only the number of days in the hospitalized patients achieved statistical significance. 2-CdA is emerging as the treatment of choice for hairy cell leukemia given the high percentage of long-lasting, complete responses that follow a single course of therapy.",1
8930,7823379,Spironolactone and hepatic toxicity,,1
8931,7825090,Exacerbation of liver disease during interferon-alpha therapy for chronic hepatitis C,,1
8932,7830880,Metronidazole-associated hepatotoxicity in a hemodialyzed patient,,1
8933,7837315,Survival after a severe iron poisoning treated with intermittent infusions of deferoxamine,"Iron poisoning is the most common cause of overdose mortality in children under six years of age and there are no reports of survival with iron levels > 2687 mumol/L (> 15,000 micrograms/dL). A 22-month-old male was brought to the emergency department by his parents after ingesting an estimated 50 ferrous sulfate tablets (60 mg elemental iron/tablet) several hours earlier. Despite spontaneous emesis and gastric lavage his condition deteriorated and he was found to have a serum iron of 2992 mumol/L (16,706 micrograms/dL). During the first four days in the intensive care unit, he developed coma, metabolic acidosis, hypovolemic and cardiogenic shock, liver failure, coagulopathy and adult respiratory distress syndrome. He was treated with a unique deferoxamine dosage schedule (25 mg/kg/h for 12 h/d x 3 d), mechanical ventilation, Swan-Ganz catheter monitoring, dopamine/nitroprusside therapy, blood product, bicarbonate, electrolyte and volume replacement. After a prolonged hospital course complicated primarily by gastric outlet obstruction he was dismissed on full oral feedings, gaining weight, and neurologically intact. Swan-Ganz catheter monitoring guided the management of this patient's shock, iron-induced cardiac failure, and deferoxamine mesylate induced adult respiratory distress syndrome. Further experience and research is required to determine the most appropriate deferoxamine mesylate dosing schedule and our experience expands the range for possible survival after massive iron overdose.",1
8934,7840371,Clozapine-induced toxic hepatitis,,1
8935,7841570,Possible ciprofloxacin-induced acute cholestatic jaundice,"""OBJECTIVE: To report a case of acute cholestatic jaundice in a patient who was receiving oral ciprofloxacin. CASE SUMMARY: An 84-year-old woman residing in a long-term care facility developed acute cholestatic jaundice while being treated with ciprofloxacin for a urinary tract infection. On day 6 of ciprofloxacin therapy, she was noted to have an erythematous, pruritic rash over her chest and abdomen. At this point ciprofloxacin treatment was discontinued, as an allergy was suspected. Three days later she was noted to have jaundiced sclera and skin, and liver function test results were markedly elevated. The plasma cholesterol concentration was increased substantially; there was no decrease in plasma albumin concentration or increase in prothrombin time. The patient was treated with intravenous fluids. Within the next month, the liver function test results decreased to near normal and the patient was asymptomatic. Follow-up liver test results three months later were normal. DISCUSSION: To our knowledge, there are only a few other case reports in the literature of a possible ciprofloxacin-induced liver injury. Enoxacin, a fluorinated quinolone antibiotic similar to ciprofloxacin, was reported to cause cholestatic liver injury in one patient. The exact mechanism by which fluoroquinolones may cause liver injury is unknown. CONCLUSIONS: We believe that this is only the second reported case of acute cholestatic jaundice resulting from ciprofloxacin therapy. Although this reaction seems to occur rarely, it is prudent to be alert for the signs and symptoms of cholestasis when administering ciprofloxacin.""",1
8936,7844372,Biliary complications in the treatment of unsubstantiated Lyme disease,"""Treatment of unsubstantiated Lyme disease has led to serious complications in some cases. Two case-control studies, based on information in clinical records of patients discharged with a diagnosis of Lyme disease during 1990-1992, were conducted at a central New Jersey hospital. Twenty-five patients with biliary disease were identified, and 52 controls were selected from 1352 patients with suspected Lyme disease. Only 3% of 71 evaluatable subjects met the study criteria for disseminated Lyme disease. Patients with biliary disease were more likely than were antibiotic controls to have received ceftriaxone and more likely than ceftriaxone controls to have received a daily ceftriaxone dose > or = 40 mg/kg and to be < or = 18 years old. Fourteen of 25 biliary case-patients underwent cholecystectomy; all had histopathologic evidence of cholecystitis and 12 had gallstones. Thus, treatment of unsubstantiated diagnoses of Lyme disease is associated with biliary complications.""",1
8937,7847600,"A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence","A dozen studies have been published showing that opiate antagonists suppress alcohol drinking in animals, and two independent placebo-controlled, double-blind clinical trials of naltrexone found this agent was associated with decreased alcohol craving and consumption in alcohol-dependent patients. Nalmefene is a newer opiate antagonist that has a number of potential advantages over naltrexone in the treatment of alcoholism, including no dose-dependent association with liver toxicity and more effective binding to central opiate receptors. Consequently, a double-blind pilot study was conducted to gather preliminary data on the safety and efficacy of nalmefene for reducing alcohol consumption in alcohol-dependent subjects. Twenty-one alcohol-dependent subjects meeting admission criteria were randomly assigned to 12 weeks of double-blind treatment with 40 mg nalmefene, 10 mg nalmefene, or placebo, resulting in 7 patients/treatment group. Nalmefene was well tolerated, with no serious adverse drug reactions. The 40 mg group had a significantly lower rate of relapse (p < or = 0.05), and a greater increase in the number of abstinent days/week (p < or = 0.09), than the other treatment groups. A significant decrease in the number of drinks/drinking day was noted for both nalmefene groups (p < or = 0.04), but not for placebo. These results were supported by parallel decreases in ALT. These pilot data provide preliminary support for the hypotheses that nalmefene can be safely given to alcoholics, and that nalmefene may have a role in reducing alcohol consumption and preventing relapse, particularly at the 40 mg level. A full-scale study is underway to confirm these preliminary findings.",1
8938,7851193,Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group,"This 12-month, double-blind, placebo-controlled study randomized 205 ulcerative colitis patients in remission to placebo or controlled-release mesalamine at 4 g/day for 12 months. Patients were stratified to either pancolitis or left-sided disease, based on previous diagnosis. Maintenance of remission was defined as a sigmoidoscopic index of < 5, less than five stools per day, and the absence of rectal bleeding. A significantly greater number of patients maintained remission on mesalamine 4 g/day than on placebo at each of five study visits, following the first one-month visit (P < 0.05). The estimated 12-month remission rates for the mesalamine group were 64% (38% for placebo, P = 0.0004). Baseline subgroups (disease location, time since last flare of active disease, and previous response to oral/rectal steroids or sulfasalazine) did not influence remission rates. Treatment-related adverse events were rare. Controlled-release mesalamine is a safe and efficacious single agent for maintaining remission of ulcerative colitis.",1
8939,7852133,Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials,"""PURPOSE: Pilocarpine hydrochloride administered in either a fixed-dose or in a dose-titration protocol three times a day for 12 weeks was evaluated for its ability to relieve symptoms of postradiation xerostomia and to improve saliva production. The studies were randomized, double-blind, placebo-controlled, multicenter clinical trials. A total of 369 patients who had received at least 40 Gy of radiation to the head and neck with clinically significant xerostomia were enrolled in the two studies. In the dose-titration study, 162 patients were enrolled and they received a thrice daily regimen of 2.5 mg tablets for first 4 weeks, 5.0 mg tablets for the second 4 weeks, and 10.0 mg tablets for last 4 weeks of a 12-week study. Patients in the titration study were allowed to down titrate following at least one dose escalation to alleviate bothersome side effects, if any. In the fixed dose study, 207 patients received either placebo, 5.0 mg, or 10.0 mg tablets t.i.d. for 12 weeks. METHODS AND MATERIALS: Patients were evaluated for symptomatic relief by responding to questionnaires using visual analog scales and categorical questions; and, for saliva production by sialometry. Questionnaires measured relief of intraoral dryness, improvement in overall condition (global response), oral discomfort, difficulty in speaking, chewing and swallowing, denture wearing, and usage of artificial saliva. Evaluations were conducted at baseline, and weeks 4, 8, and 12. RESULTS: There were statistically significant improvements in salivary flow in pilocarpine treatment groups vs. placebo. There was a significant improvement in the overall """"global"""" condition of xerostomia associated with the use of pilocarpine in both studies. In the fixed-dose study, there were significant improvements in oral dryness, mouth comfort, ability to speak, and reduction in the use of oral comfort agents. The dose-titration study showed improvements in dryness that approached significance (p = 0.057) and a decreased use of oral comfort agents (p = 0.045). All pilocarpine dosages (2.5, 5.0, and 10.0 mg three times a day) were judged to be safe. Adverse experiences were those expected for a cholinergic agonist, with the most common being mild to moderate sweating. The incidence of these events increased by dose. CONCLUSION: It is concluded that in these studies pilocarpine produced clinically significant benefits with acceptable side effects and risks for the treatment of symptomatic postradiation xerostomia. The incidence of most adverse events increased with dose. Best results may require continuous treatment for more than 8 weeks with doses greater than 2.5 mg three times a day. A 5.0 mg thrice daily regimen produced the best clinical results when both efficacy and side effects were taken into consideration. There may be some patients who would experience some additional benefit by increasing the dose to 10 mg thrice daily.""",1
8940,7858459,Acute confusion induced by a high-dose infusion of 5-fluorouracil and folinic acid,"A 61-year-old man was treated with combination chemotherapy incorporating cisplatinum, etoposide, high-dose 5-fluorouracil (2,250 mg/m2/24 hours) and folinic acid for an inoperable gastric adenocarcinoma. He developed acute neurologic symptoms of mental confusion, disorientation and irritability, and then lapsed into a deep coma, lasting for approximately 40 hours during the first dose (day 2) of 5-fluorouracil and folinic acid infusion. This complication reappeared on day 25 during the second dose of 5-fluorouracil and folinic acid, which were then the only drugs given. Because folinic acid was unlikely to be associated with this condition, neurotoxicity due to high-dose 5-fluorouracil was highly suspected. The pathogenesis of 5-fluorouracil neurotoxicity may be due to a Krebs cycle blockade by fluoroacetate and fluorocitrate, thiamine deficiency, or dihydrouracil dehydrogenase deficiency. High-dose 5-fluorouracil/folinic acid infusion therapy has recently become a popular regimen for various cancers. It is necessary that both oncologists and neurologists be fully aware of this unusual complication.",1
8941,7871583,Reversible nitrofurantoin-induced chronic active hepatitis and hepatic cirrhosis in a patient awaiting liver transplantation,,1
8942,7872282,"Cisapride for gastroesophageal reflux disease: a placebo-controlled, double-blind study","OBJECTIVES: To evaluate the safety and efficacy of cisapride in patients with gastroesophageal reflux disease. METHODS: Patients (N = 177) were randomized to double-blind treatment with cisapride (10 or 20 mg q.i.d.) or placebo for 12 wk. Efficacy was determined by pre- and poststudy endoscopies, symptom assessments by patient and physician, and Maalox consumption. Safety evaluations included vital signs, electrocardiograms, clinical laboratory tests, and reports of adverse events. RESULTS: Cisapride 10 mg significantly reduced daytime and nighttime heartburn at 4 wk compared with placebo. Cisapride 20 mg reduced both daytime and nighttime heartburn at 4, 8, and 12 wk, compared with placebo, and was also significantly superior to the 10-mg dose at 12 wk. The percent of patients with endoscopic healing was significantly higher with cisapride 20 mg than with placebo [healing: 51 vs 36% (p < or = 0.044)]. Maalox usage declined significantly with cisapride 20 mg compared with placebo. No clinically significant changes in safety variables occurred with cisapride. The most frequently reported adverse events in the cisapride group were diarrhea, headache, and sinusitis. CONCLUSIONS: Cisapride 10 and 20 mg q.i.d. were safe and well tolerated in a population of patients with mild-to-moderate gastroesophageal reflux disease. Both symptoms and endoscopic grade improved after 12 wk of treatment with cisapride 20 mg q.i.d.",1
8943,7872756,Single-dose fosfomycin trometamol versus 5-day cephalexin regimen for treatment of uncomplicated lower urinary tract infections in women,"A randomized study was conducted to assess the clinical and microbiological efficacies of a single 3-g dose of fosfomycin trometamol for the treatment of uncomplicated lower urinary tract infections in women compared with a 5-day regimen of cephalexin at 0.5 g four times daily. One hundred twelve women, all of whom had documented infections with bacteria sensitive to both antibiotics, were included. Fifty-eight women received fosfomycin trometamol, and 54 women received cephalexin. The two groups did not differ in age, severity, or duration of current urinary tract infection, menstrual status, sexual activity, or use of contraceptives. Ninety percent of pathogens in the fosfomycin trometamol group and 81% in the cephalexin group were Escherichia coli (the difference is not significant [NS]). A clinical evaluation at the 5-day follow-up showed that 91% of the women in each group were free of symptoms, while five women in each group were considered therapy failures and were treated by another antibiotic course. A microbiological evaluation at the 5-day follow-up showed a 91% eradication rate in the fosfomycin trometamol group and an 83% eradication rate in the cephalexin group (NS). At the 1-month follow-up, a clinical evaluation demonstrated prolonged resolution in 86 and 78%, respectively, of the participating women (NS). A microbiological evaluation at 1 month demonstrated prolonged eradication in 47 (81%) women treated with fosfomycin trometamol and in 37 (68%) women treated with cephalexin (NS). Three and six women, respectively, had relapsed. No adverse reactions were reported by the fosfomycin trometamol-treated women, while three women treated with cephalexin reported mild adverse reactions but completed the study period. Fosfomycin trometamol in a single 3-g dose is as effective as a 5-day regimen of cephalexin for the treatment of uncomplicated lower urinary tract infection in women.",1
8944,7875406,[Severe hepatitis caused by phenobarbital],,1
8945,7878605,[Heparins and transaminases: an enigma without importance in 1994?],,1
8946,7880186,The cost-effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate,"OBJECTIVE: To assess the cost-effectiveness of liver biopsy in monitoring rheumatoid arthritis (RA) patients for methotrexate (MTX)-induced cirrhosis. METHODS: A decision analytic model was used to compare a strategy of no biopsy versus strategies of biopsy after 5 years or 10 years of MTX treatment. RESULTS: Biopsy after 5 years of MTX treatment had a cost-effectiveness ratio of $1,891,830 per year of life saved, while biopsy after 10 years of treatment had a cost-effectiveness ratio of $52,374 per year of life saved. Sensitivity analyses revealed that the cost-effectiveness of biopsy was most dependent on the probability of cirrhosis. CONCLUSION: Liver biopsy to monitor for MTX-induced cirrhosis in RA patients is not cost effective after 5 years of treatment, and even biopsy after 10 years has a high cost.",1
8947,7884025,Clozapine rechallenge after marked liver enzyme elevation,,1
8948,7884429,Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy,"""PURPOSE: To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. RESULTS: The overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesions. The median response duration for patients who achieved a CR has not been reached, but was 19.0 months for those who achieved a PR. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was the only predictive prognostic factor for response to IL-2. While treatment was associated with severe acute toxicities, these generally reversed rapidly after therapy was completed. However, 4% of patients died of adverse events judged to be possibly or probably treatment-related. CONCLUSION: High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment-associated toxicities, IL-2 should be considered for initial therapy of patients with appropriately selected metastatic renal cell carcinoma.""",1
8949,7885528,Chronic hepatitis caused by lisinopril,"""ACE inhibitors are used world-wide for treatment of hypertension and cardiac failure; liver damage is a rare but potentially severe side-effect of these drugs. In this case report we describe a patient with chronic liver damage due to lisinopril.""",1
8950,7890903,Disulfiram-induced hepatitis. Report of four cases and review of the literature,"Liver test abnormalities following disulfiram therapy are common. However, overt disulfiram-induced hepatitis is rare but has a high mortality rate, specially when the etiologic role of disulfiram is not suspected and treatment is not discontinued. We report four cases of disulfiram-induced acute hepatitis with different degrees of severity and review the cases reported in the literature. The clinical spectrum of disulfiram hepatotoxicity ranges from minor elevation of serum aminotransferases to fulminant hepatitis. Although some patients with disulfiram-induced hepatitis have manifestations of hypersensitivity, recent clinical and experimental data suggest that disulfiram hepatotoxicity is produced by the accumulation of toxic metabolites.",1
8951,7892168,Veno-occlusive disease of the liver induced by low-dose cyclophosphamide,"A 2-yr-old child with idiopathic pulmonary hemosiderosis and autoimmune thrombocytopenia developed hepatic veno-occlusive disease after being treated with long-term, low-dose cyclophosphamide. The authors believe that the injury was induced by cyclophosphamide. Although transplant dosages of cyclophosphamide alone or in conjunction with other drugs have been shown to induce hepatic venocclusive disease, this is the first case of hepatic venocclusive disease associated with nontransplant dosages of cyclophosphamide. Histopathologically, the injury was characterized by occlusive lesions of intrahepatic veins, both the terminal hepatic venules and portal veins branches, together with necrosis (predominately involving Zones 3 and 2) and hemorrhages. An added risk factor could have been release of platelet-derived growth factor that in turn activated and promoted proliferation of fibroblasts and smooth muscle cells in the vessels. Previously reported cases of cyclophosphamide-related injury are reviewed.",1
8952,7896655,"Naltrexone in young autistic children: a double-blind, placebo-controlled crossover study","""OBJECTIVE: This study evaluated the efficacy and safety of naltrexone, an opiate blocker, in the treatment of autism. METHOD: Thirteen children with autistic disorder, aged 3.4 to 8.3 years (mean 5.4), were studied in home, school, and outpatient laboratory. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, placebo-controlled crossover design. Dependent measures included parent and teacher Clinical Global Impressions (CGI), Conners Rating Scales, and Naltrexone Side-Effects (SE) Rating Scale; laboratory CGI, movement actometer readings, and a 10-second interval recording system analysis of on-task, communication initiations, disruptive behavior, and self-stimulation. RESULTS: Eight of 13 subjects improved in two or more settings. Changes in parent measures (CGI, Conners Impulsivity-Hyperactivity Factor, and SE-Restlessness) and Teacher CGI achieved statistical significance. Teacher SE-Restlessness and initiation of communication in the clinic showed a trend toward improvement. Actometer readings improved in two children who were very active at baseline. Adverse side effects were behavioral, mild, and transient. Administering the bitter tablet was a challenge. CONCLUSIONS: Naltrexone offers promise as an agent for modest improvement of behavior and social communication in young children with autism. Parent and teacher measures can be useful in outpatient trials to evaluate change.""",1
8953,7901585,Randomised controlled trial of efficacy of albendazole in intra-abdominal hydatid disease,"""The efficacy of albendazole in hydatid disease is still unclear, because there has been no study that assessed the status of the parasite after treatment. The significance of albendazole-induced echographic changes in the cyst therefore cannot be judged. We did a prospective, controlled, randomised, open study of albendazole in patients with liver hydatid disease, and assessed parasite viability after treatment. 18 patients received no albendazole treatment (controls), 18 received albendazole (10 mg/kg daily) for 1 month (group A), and 19 received the drug for about 3 months (group B). Echography was done before and during treatment; all patients underwent surgery on completion. Parasite (protoscolex viability and development of cysts in mice) and ultrastructure studies were done for all cysts removed. 8 (50%) of cysts in the control group, 13 (72%) in group A, and 16 (94%) in group B were non-viable (p = 0.015). Protoscolex and cyst viability were significantly (p = 0.039 and p = 0.018, respectively) lower in treated patients than in controls. Treatment was also significantly associated with total cyst membrane disintegration. 68% of cysts treated for 3 months showed echographic changes, and only 1 of 20 cysts showing echographic changes during treatment was judged viable. The efficacy of albendazole at a dose of 10 mg/kg daily for 3 months suggests that it is a suitable alternative to surgery in uncomplicated hydatid liver disease, as initial treatment.""",1
8954,7907714,Fatal hepatic failure associated with ciprofloxacin,,1
8955,7910028,"Comparison of a new vasodilating beta-blocker, carvedilol, with atenolol in the treatment of mild to moderate essential hypertension","Carvedilol is a new cardiovascular compound with the combined pharmacologic properties of nonselective beta-blockade and vasodilation. The aim of this study was to compare the safety and antihypertensive efficacy of 25 to 50 mg carvedilol once daily with 50 to 100 mg atenolol once daily in patients with mild to moderate essential hypertension. This was a multicenter study conducted in Europe. After a single-blind placebo run-in phase, 325 eligible patients with stable hypertension were randomized to receive 25 mg carvedilol once daily (161 patients) or 50 mg atenolol (164 patients) in a double-blind 8-week treatment phase. After 4 weeks, the dosage was doubled if there was inadequate response. The primary index of efficacy (response) was the reduction of mean sitting diastolic blood pressure to 90 mg Hg or less (normalized) or by at least 10 mm Hg from baseline. At each of three to six run-in phase visits and after 2, 4, and 8 weeks of treatment, sitting blood pressure and heart rate at trough were measured in triplicate, and body weight, adverse experiences, compliance, and use of concomitant medications were assessed. Laboratory tests, including fasting serum lipids, and electrocardiograms were also monitored during the trial. After 8 weeks of treatment, response rates in the carvedilol and atenolol treatment groups were 75% and 82%, respectively. Compared to baseline, the mean sitting blood pressure was significantly (P < .05) reduced by carvedilol from 165/104 mm Hg to 147/89 mm Hg. With atenolol, mean sitting blood pressure was significantly (P < .05) reduced from 167/104 mm Hg to 150/90 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)",1
8956,7912347,Cladribine in treatment of chronic progressive multiple sclerosis,"Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.",1
8957,7912472,Sequential liver and bone biochemical changes in hyperthyroidism: prospective controlled follow-up study,"OBJECTIVE: To reexamine the prevalence and sequential changes of liver and bone biochemical abnormalities in patients with hyperthyroidism. METHODS: A consecutive series of 95 patients with hyperthyroidism and 66 controls with euthyroid goiter seen during same period were studied. The patients were treated with propylthiouracil (PTU) 300 mg/day for 2 months, followed by 100-150 mg/day for 3 months and a subsequent maintenance dose of 100 mg/day. Serum aspartate amino-transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin, ALP isoenzymes, and hepatitis markers were studied before therapy and at 2 and 5 months after PTU therapy was begun. RESULTS: Seventy-two [75.8%, confidence interval (CI) 67.2-84.4%] of the 95 patients had at least one biochemical abnormality. AST, ALT, ALP, GGT, and bilirubin were elevated in 27.4%, 36.8%, 64.2%, 16.8%, and 5.3%, respectively. Of the 34 patients with ALT elevation, 62% showed gradual normalization of ALT, whereas 38% (CI 21.9-54.5%) showed transient, asymptomatic, but significant (p < 0.025) further elevation of ALT during PTU therapy. Overt hepatitis developed in one patient. None of these changes was due to hepatitis A, B, C, or delta virus infection or autoimmune hepatitis. Changes of serum GGT parallel those of ALT. In contrast, serum ALP (primarily bone isoenzyme) rose significantly (p < 0.01) as T4 and T3 levels declined at 2 months after therapy. CONCLUSIONS: The results suggest that hyperthyroidism is often associated with abnormal biochemical tests, particularly ALP elevation, and thus may pose diagnostic confusion. The increase of bone isoenzyme accounts for the elevations in total ALP level before and during therapy. Serum ALT and GGT abnormalities usually subside during PTU therapy, but transient asymptomatic PTU hepatotoxicity occurs in one-third of the patients. Discontinuation of PTU is not required unless overt hepatitis develops.",1
8958,7914595,Multisystem adverse reaction to lamotrigine,,1
8959,7915924,Fatal hepatic necrosis associated with trazodone and neuroleptic drugs,,1
8960,7923316,Alpha 1-blockade for the treatment of hypertension: a megastudy of terazosin in 2214 clinical practice settings,"""The purpose of this study was to evaluate the effects of the alpha 1-blocking agent terazosin on blood pressure (BP) and blood lipids in a large, variant population of patients with hypertension. A total of 16,917 patients with hypertension were evaluated at 2214 primary and community care facilities; 7808 of these patients had not been treated previously for hypertension; 3928 were switched to terazosin from another antihypertensive agent; and 5181 received terazosin in addition to an agent that had not controlled their hypertension. Terazosin produced highly significant reductions in systolic (-18.2 +/- 0.2 mm Hg) and diastolic (-13.2 +/- 0.1 mm Hg) BP when used as monotherapy (mean dose, 3.1 mg; range, 2 to 10 mg) without causing a significant increase in heart rate. Equal antihypertensive efficacy was demonstrated in men, women, blacks, and whites of all ages, with particular benefit to elderly patients (> or = 65 years of age) with systolic hypertension. Comparative studies indicated that terazosin had equal antihypertensive efficacy in combination with diuretics, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. Patients who had not responded to monotherapy with one of these classes of antihypertensive drugs showed significant reductions of BP after terazosin, in the following average doses, was added to diuretics, 3.1 mg; beta-blockers, 3.4 mg; calcium channel blockers, 3.3 mg; and ACE inhibitors, 3.4 mg. Terazosin produced highly significant reductions in blood levels of total cholesterol (-5.0%), triglycerides (-6.1%), and low-density lipoprotein cholesterol (-7.6%) without change in high-density lipoprotein cholesterol when used as monotherapy. Similar favorable effects on blood lipid levels were demonstrated when terazosin was used in combination with all other classes of antihypertensive drugs. The greatest reductions in blood cholesterol (-9.2%) were observed among patients with hyperlipidemia (total cholesterol > or = 240 mg/dL). Terazosin maintained its antihypertensive efficacy and was well tolerated by patients with a variety of concomitant diseases, including congestive heart failure, peripheral vascular disease, chronic obstructive pulmonary disease, benign prostatic hyperplasia, diabetes, and obesity. Adverse effects occurred in 17.9% of patients and caused 2.2% to drop out of the study. The most frequent adverse effects were dizziness (4.8%), headache (2.5%), and asthenia (2.4%). Only 0.4% suffered syncope and 0.2% impotence. These data demonstrate the usefulness of terazosin as monotherapy or add-on therapy for treatment of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
8961,7925143,Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities,"""Since our last report on valproate (VPA)-related hepatotoxicity in 1988, 8 other children have died of VPA-associated liver failure in Germany and Switzerland. We compared the clinical course of these children with that of 6 children with a reversible outcome of severe hepatotoxicity related to VPA. Thirty-five percent of patients with fatal liver failure were normally developed, 23.5% were receiving VPA monotherapy, and 35.3% were aged < or = 2 years. The initial clinical symptoms of VPA-related hepatotoxicity were nausea, vomiting, apathy or coma, and increasing seizures in more than 50% of patients, in combination with febrile infections at onset of symptoms. As compared with the series of German patients reported in 1988, one third of the fatalities occurred after the first 6 months of therapy as compared with 6% in the 1988 series. Clinical symptoms and laboratory findings were the same in patients with reversible and with fatal outcome. Early or immediate withdrawal of VPA after the first signs of VPA-associated hepatotoxicity may be responsible for the increased number of children who recovered after VPA-related severe liver failure. The pathogenesis of liver failure during VPA treatment remains unknown; metabolic defects and cofactors such as polypharmacy or infections have become increasingly likely to contribute by depleting intracellular CoA. Worldwide, 132 patients have died of VPA-associated liver failure and/or pancreatitis. Because a group at risk for fatalities with VPA cannot be defined precisely, patients treated with VPA and their families must be made well aware of the clinical symptoms of hepatotoxicity such as apathy, vomiting, or increased seizure frequency, especially in the presence of febrile infections. Laboratory tests and clinical controls during the first 6 months of therapy should not be neglected.""",1
8962,7930488,Subfulminant hepatitis requiring liver transplantation after benzarone administration,,1
8963,7936805,Biliary pseudolithiasis in a child associated with 2 days of ceftriaxone therapy,"Ceftriaxone, a third-generation cephalosporin, is known to induce reversible precipitations in the gallbladder of children. In general, radiologic signs and symptoms will develop after 9-11 days of treatment. The authors report a case where 48 h of therapy were sufficient to develop a biliary pseudolithiasis. Clinicians and radiologists should be aware of this complication which mimics true cholelithiasis.",1
8964,7940829,Incidence and etiology of hepatic dysfunction in heart transplant recipients receiving a cyclosporine-based triple immunosuppressive therapy,,1
8965,7942916,More ticlopidine-induced cholestatic jaundice,,1
8966,7944058,"Bitter herbs: mainstream, magic, and menace",,1
8967,7950687,Potential risks of health food products containing yohimbe extracts,,1
8968,7955931,Oxymetholone hepatotoxicity enhanced by concomitant use of cyclosporin A in a bone marrow transplant patient,,1
8969,7958700,Tetracycline-induced bile duct paucity and prolonged cholestasis,"Acute self-limited liver disease has been associated with tetracycline use. However, severe prolonged cholestatic hepatitis and bile duct paucity have not been previously attributed to tetracyclines. Hepatitis, characterized by prolonged jaundice, severe pruritus, and moderate increased transaminase values, occurred within 2 months of ingesting tetracyclines in two female patients. Serum bilirubin levels normalized 12 and 34 months after tetracycline ingestion. Liver histology revealed bile duct paucity, severe cholestasis, and minimal necrosis and inflammation. Tetracyclines may infrequently induce bile duct paucity and prolonged, severe, and reversible cholestasis.",1
8970,7963356,Serum lactic dehydrogenase in the differential diagnosis of acute hepatocellular injury,"Acute hepatocellular injury, whether due to viral hepatitis, hepatic ischemia, or drug hepatotoxicity, results in elevated levels of serum aminotransferases (AST and ALT). Serum lactate dehydrogenase (LD) is reported to be markedly elevated in ischemic hepatitis. Thus, comparisons of the degree of elevation of serum levels of LD, ALT, and AST may be helpful in the differential diagnosis of acute liver injury. To study this, we reviewed serum enzyme patterns early in the course of acute liver injury in patients with acute viral hepatitis A and B (n = 51), ischemic hepatitis (n = 20), and acetaminophen injury (n = 26). All patients had serum ALT and/or AST at least five times the upper limit of normal. For a given ALT and AST level, LD was higher in ischemic hepatitis and acetaminophen injury than in viral hepatitis. The mean ALT/LD ratio for acute viral hepatitis was 4.65, for ischemic hepatitis 0.87, and for acetaminophen injury 1.46. Mean ALT/LD ratio for viral hepatitis was significantly higher (p < 0.0001) than for the other two groups combined. An ALT/LD ratio of 1.5 differentiated acute viral hepatitis from ischemic hepatitis and acetaminophen injury with a sensitivity of 94% and a specificity of 84%.",1
8971,7964712,"A comparison of clonidine, cyproheptadine and baclofen in spastic spinal cord injured patients","In twenty-five SCI subjects, antispasticity effects of three putative antispasticity agents [clonidine (an alpha-2 noradrenergic agonist), cyproheptadine (a 5-HT2 antagonist) and baclofen (a GABA-B agonist)] were tested in terms of changes in leg tone as graded by the Ashworth scale (AS), in terms of the vibratory inhibition of the H-reflex (VII) and in terms of the ability of the knee to swing passively in the pendulum test as quantified by video motion analysis. When compared to the no drug period, all three drug treatments showed an antispasticity effect on the AS, the VII and the amplitude of the first swing and the relaxation index of the pendulum test, p. < 0001. Surprisingly, cyproheptadine and baclofen produced a greater reduction in the VII than clonidine, p. < 01. The amplitude of the first swing in the pendulum test correlated well with the AS, r = .88, and the antispasticity effects of the drugs produced improvements in both measures, a reduced AS and increased amplitude of knee swing in the pendulum test. Therefore, video motion analysis of the pendulum test is as valid a measure of spasticity as the Ashworth scale and is not limited by subjectivity of the examiner.",1
8972,7970342,Herbal medicine and toxic hepatitis,,1
8973,7979840,Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus,"BACKGROUND: Acarbose delays the release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, attenuating postprandial increments in blood glucose and insulin. This multicenter double-blind study compared the efficacy and safety of acarbose with placebo in the treatment of obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) managed by diet. METHODS: Two hundred twelve obese subjects with NIDDM who had not received any diabetic medication for at least 12 weeks were randomized to receive acarbose or placebo. The subjects were stratified by fasting glucose level above or below 11.1 mmol/L (200 mg/dL). Based on the subject's therapeutic response and tolerance, the acarbose dosage was titrated from 50 to 300 mg three times per day. This 36-week study consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week posttreatment period. RESULTS: Ninety-one subjects given acarbose and 98 subjects who received placebo were evaluable for efficacy. During a standard meal tolerance test at the double-blind end point, the differences between treatment groups in mean change from baseline were as follows: 0.9 mmol/L (16 mg/dL) for fasting plasma glucose level, approximately 2.8 mmol/L (50 mg/dL) for postprandial plasma glucose level, and 0.59% (P < .0001) for hemoglobin A1c concentration (for all three measurements, values decreased in the acarbose group and increased in the placebo group). CONCLUSIONS: Acarbose improved both fasting and postprandial hyperglycemia and improved overall glycemic control as measured by the hemoglobin A1c level. These findings suggest a beneficial role for acarbose in combination with diet in the treatment of obese subjects with NIDDM.",1
8974,7980246,A reversible parkinsonian syndrome and hepatotoxcity following addition of carbamazepine to sodium valproate,,1
8975,7982642,Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis,"We describe a 33-yr-old pregnant woman in whom a primary biliary cirrhosis-like syndrome developed after 2 wk of chlorpromazine therapy. The clinical course was characterized by severe jaundice lasting 22 mo, intense pruritus, fever, steatorrhea, high alkaline phosphatase levels and hypercholesterolemia. Jaundice resolved with initiation of ursodeoxycholic acid therapy, but subclinical cholestasis and low-level inflammatory activity persisted and ultimately evolved into biliary cirrhosis. The pathological substrate of this severe and prolonged cholestatic reaction was found to be the vanishing bile duct syndrome with a marked transient pseudoxanthomatosis.",1
8976,7983646,Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus,"OBJECTIVE: To compare the relative safety and efficacy of hydroxychloroquine (HCQ) and placebo (Pl) in the treatment of the articular complaints of systemic lupus erythematosus (SLE). METHODS: Seventy-one patients with mild SLE requiring < or = 10 mg of prednisone or equivalent daily and with arthritis or arthralgias were entered into a 48-week prospective, controlled, double blind multicenter trial and randomly assigned to either HCQ or Pl. RESULTS: Both HCQ and Pl were well tolerated in the 48-week trial. There were no remissions. With the exception of the patient assessment of joint pain, all other joint measures were similar between the groups. Twenty-nine patients withdrew before the end of the trial although only 2 patients withdrew for adverse drug effects. CONCLUSION: Our study found subjective pain relief as the only statistically significant difference in joint count variables from HCQ in the treatment of the articular manifestations of SLE.",1
8977,7983964,Liver tumours in women on oral contraceptives,,1
8978,7985487,Marked but transitory elevation of hepatic transaminases after subcutaneous calcium heparin administration,,1
8979,7990219,Association of acetaminophen hepatotoxicity with fasting and ethanol use,"OBJECTIVES: To evaluate the association of fasting and alcohol use with hepatotoxicity from acetaminophen ingested for therapeutic reasons. DESIGN: Retrospective case series. SETTING: Hospitals of the University of Pittsburgh (Pa) Medical Center. PATIENTS: A total of 126,779 discharge summaries from January 1987 to July 1993 were reviewed using a comprehensive, whole-text-indexed medical database to identify all patients with acetaminophen ingestion and hepatotoxicity. These patients were categorized according to the intended acetaminophen use and dose of acetaminophen ingested. MAIN OUTCOMES MEASURED: The independent variables of chronic alcohol use, recent alcohol use, and recent fasting were determined for all patients. RESULTS: Forty-nine patients with acetaminophen hepatotoxicity (aspartate aminotransferase > 1000 U/L) were identified. Twenty-one patients (43%) ingested acetaminophen for therapeutic purposes. All patients with hepatotoxicity took more than the recommended limit of 4 g/d. Recent fasting was more common than recent alcohol use among those who suffered hepatotoxicity after a dose of 4 to 10 g of acetaminophen per day (P = .02). Recent alcohol use was more common in the group who took more than 10 g/d than in those who took 4 to 10 g/d (P = .004). CONCLUSION: Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use. Patients who developed hepatoxicity after taking acetaminophen doses of greater than 10 g/d for therapeutic purposes were alcohol users. Acetaminophen hepatotoxicity after an overdose appears to be enhanced by fasting in addition to alcohol ingestion.",1
8980,7994270,"Phase I trial of high-dose melphalan, high-dose etoposide and autologous bone marrow re-infusion in solid tumors: an Eastern Cooperative Oncology Group (ECOG) study","""The purpose of this work was to determine the maximum tolerated (phase II) dose of melphalan and etoposide that can be given in conjunction with autologous BM re-infusion in patients who have refractory or relapsed solid tumors. Twenty-six patients with refractory or relapsed breast cancer (n = 15), small cell lung cancer (n = 1), ovarian cancer (n = 3), colorectal cancer (n = 3) or malignant melanoma (n = 4) were enrolled and treated in this phase I study. Patients ranged in age from 31 to 60 years (median 44.5 years). Melphalan 180 mg/m2 (60 mg/m2/day for 3 consecutive days i.v. over 30 min) and etoposide 1200-3600 mg/m2 (400-1200 mg/m2/day for 3 consecutive days i.v. over 4 h) were given followed by autologous BM infusion 60-72 h after completion of chemotherapy. Ten patients received GM-CSF or G-CSF therapy after marrow re-infusion. Regimen-related toxicities included fever, pancytopenia, mucositis, nausea, vomiting, diarrhea, esophagitis, hepatic dysfunction and infection. Neutrophils recovered to > 500 x 10(6)/l and platelets recovered to > 20 x 10(9)/l (without transfusions) a median of 17 days and 20.5 days after marrow infusion, respectively. Dose-limiting toxicity occurred at an etoposide dose of 3600 mg/m2, since 4 of 6 patients treated at this dose level experienced grade 4 NCI Common Toxicity Criteria (mucositis (n = 3) and infection (n = 1)). Complete responses were noted in 7 patients (breast cancer (n = 5), colorectal cancer (n = 1) and melanoma (n = 1)); partial responses were observed in 5 patients. Melphalan 180 mg/m2 and etoposide 3000 mg/m2 is a potent high-dose chemotherapy regimen with significant antineoplastic activity, particularly for breast cancer, and has acceptable toxicity when administered in conjunction with autologous BM re-infusion.""",1
8981,7995584,[Sonographic demonstration of pseudo-cholelithiasis after ceftriaxone],"""The term biliary pseudolithiasis was coined by Schaad (1988) to describe the appearance of gallbladder sludge following treatment with ceftriaxone. After cessation of the drug the condition resolves, hence the term """"pseudolithiasis."""" The third generation cephalosporin, cefatriaxone, is a very potent, broad spectrum antibiotic indicated in meningitis, osteomyelitis, pyelonephritis, Lyme disease and many other severe infectious diseases. Up to 46% of those receiving this antibiotic develop gallbladder sludge. Most are asymptomatic, but a small proportion may develop right upper quadrant pain, nausea, vomiting and even cholecystitis. Ultrasonography may demonstrate many, small, echogenic particles within the gallbladder, as well as larger echogenic foci casting acoustic shadows. However, it can not differentiate these pseudostones from real stones. There are reports of surgical intervention in such cases. 2 boys, aged 5 and 10 years, respectively, treated with ceftriaxone for meningitis are presented. Both developed symptoms during treatment and in both gallbladder sludge was identified by ultrasonography. In 1 intraluminal gallbladder findings were identical with the appearance of surgical stones. Follow-up ultrasonography after the drug was stopped showed no evidence of pseudostones in either case. Awareness of this phenomena might save many unnecessary operations.""",1
8982,7997079,Flucloxacillin-associated hepatic injury,"Eleven cases of hepatic injury attributed to the intake of flucloxacillin were reported to the Netherlands Center for Monitoring of Adverse Reactions to Drugs between 1982 and 1992. They concerned four men and seven women, with a mean age of 57 years, treated for 2-28 days with an oral dose varying from 1500-4000 mg per day. Symptoms mostly appeared 10 to 30 days after starting treatment with flucloxacillin. Biochemically, the pattern was compatible with cholestatic hepatitis in seven cases, with a mixed cholestatic-hepatocellular type of injury in one case, a hepatocellular pattern in two cases, and mild liver enzyme elevations in one patient. Two patients died, one due to fatal bleeding from the liver after biopsy, and the second patient to a combination of hepatic and cardiac failure. The other patients recovered, on average 72 days after peaking of serum aminotransferase values. Histology in seven cases showed cholestatic hepatitis in five, with cholangitis or cholangiolitis in four of these patients. In the other two patients, there was centrilobular cholestasis with extensive bridging fibrosis and portal-central bridging necrosis, respectively.",1
8983,8002862,Profound suppression of plasma alanine aminotransferase activity in children taking vigabatrin,,1
8984,8005129,Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study,"We report the results of a randomized single-centre study designed to assess the effects of simvastatin on blood lipids, blood biochemistry, haematology and other measures of safety and tolerability in preparation for a large-scale multicentre mortality study. Six hundred and twenty-one individuals considered to be at increased risk of coronary heart disease were randomized, following a 2-month placebo 'run-in' period, to receive 40 mg daily simvastatin, 20 mg daily simvastatin or matching placebo. Their mean age was 63 years, 85% were male, 62% had a history of prior myocardial infarction (MI), and the mean baseline total cholesterol was 7.0 mmol.l-1. Median follow-up in the present report is 3.4 years. Eight weeks after randomization, 40 mg daily simvastatin had reduced non-fasting total cholesterol by 29.2% +/- 1.1 (2.03 +/- 0.08 mmol.l-1) and 20 mg daily simvastatin had reduced it by 26.8% +/- 1.0 (1.87 +/- 0.07 mmol.l-1). Almost all of the difference in total cholesterol at 8 weeks was due to the reduction in LDL cholesterol (40.8% +/- 1.6 and 38.2% +/- 1.4 among patients allocated 40 mg and 20 mg of simvastatin daily respectively), but simvastatin also reduced triglycerides substantially (19.0% and 17.3%) and produced a small increase in HDL cholesterol (6.4% and 4.8%). These effects were largely sustained over the next 3 years, with 40 mg daily simvastatin producing a slightly greater reduction in total cholesterol at 3 years (25.7% +/- 1.9 reduction) than did 20 mg daily simvastatin (22.2% +/- 1.8). There were no differences between the treatment groups in the numbers of reports of 'possible adverse effects' of treatment or of a range of different symptoms or conditions (including those related to sleep or mood) recorded at regular clinic follow-up. Mean levels of alanine aminotransferase, aspartate aminotransferase and creatine kinase were slightly increased by treatment, but there were no significant differences between the treatment groups in the numbers of patients with significantly elevated levels. A slightly lower platelet count in the simvastatin group was the only haematological difference from placebo, with no difference in the numbers of patients with low platelet counts. In summary, the simvastatin regimens studied produced large sustained reductions in total cholesterol, LDL cholesterol and triglyceride and small increases in HDL cholesterol. They were well tolerated, with no evidence of serious side-effects during the first 3 years of this study.(ABSTRACT TRUNCATED AT 400 WORDS)",1
8985,8006430,The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification,"""The nosology of severe bullous erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) remains controversial. To conduct a prospective case-control study of the etiologic factors of these diseases, we needed to define criteria for classifying the cases. After having reviewed photographs of the skin lesions of more than 200 patients, an international group of dermatologists proposed a classification based on the pattern of """"EM-like lesions"""" (categorized as typical targets, raised or flat atypical targets, and purpuric macules) and on the extent of epidermal detachment. The """"consensus"""" classification in five categories was as follows: bullous erythema multiforme, detachment below 10% of the body surface area (BSA) plus localized typical targets or raised atypical targets; SJS, detachment below 10% of the BSA plus widespread erythematous or purpuric macules or flat atypical targets; overlap SJSTEN, detachment between 10% and 30% of the BSA plus widespread purpuric macules or flat atypical targets; TEN with spots, detachment above 30% of the BSA plus wide-spread purpuric macules or flat atypical targets; TEN without spots, detachment above 10% of the BSA with large epidermal sheets and without any purpuric macules or target. Whether all five categories proposed represent distinct etiopathologic entities will require further epidemiologic and laboratory investigations.""",1
8986,8014445,Fulminant hepatitis after flutamide treatment,"Two cases of severe acute hepatitis in patients taking flutamide for metastatic prostatic carcinoma are reported. Jaundice and marked increase in aminotransferases occurred after 6-8 weeks of treatment. Continuation of flutamide administration was associated with the development of hepatic encephalopathy and a marked prolongation of prothrombin time. One of the patients died of acute liver failure and the other survived after prolonged hospitalization. Rechallenge was not performed because of the severity of the clinical picture. Liver histology showed extensive hepatic necrosis. These two cases strongly suggest that flutamide, in addition to its cholestatic side effects, can induce acute hepatitis potentially with a fulminant and lethal course. Journal of Hepatology.",1
8987,8015513,Intranasal budesonide for allergic rhinitis,,1
8988,8017740,Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery. Enoxaparin Clinical Trial Group,"""OBJECTIVE: To determine the most effective and safe dose of enoxaparin to prevent deep venous thrombosis in high-risk surgical patients. DESIGN: A double-blind, randomized, multicenter clinical trial. SETTING: Private, university, and government hospitals in the United States. PATIENTS: 572 patients having elective hip replacement surgery, 568 of whom received study medication and had efficacy data available for evaluation. INTERVENTIONS: Patients were randomly assigned to one of three subcutaneous enoxaparin regimens: 10 mg once daily (161 patients); 40 mg once daily (199 patients); and 30 mg every 12 hours (208 patients). Treatment was initiated within 24 hours after surgery and continued for as long as 7 days. Treatment with 10 mg enoxaparin once daily was discontinued prematurely after an interim analysis showed an increased deep venous thrombosis incidence in this treatment group. MEASUREMENTS: Efficacy was determined by bilateral lower extremity venography, noninvasive vascular imaging methods, or clinical evidence on day 7 of treatment or earlier if clinically indicated. RESULTS: Deep venous thrombosis occurred in 25% (40 of 161) of the patients who received 10 mg of enoxaparin once daily; in 14% (27 of 199) of those receiving 40 mg of enoxaparin once daily; and in 11% (22 of 208) in those receiving 30 mg of enoxaparin every 12 hours. The incidence of deep venous thrombosis was significantly higher in patients who received 10 mg of enoxaparin once daily compared with those who received 40 mg of enoxaparin once daily (P = 0.02) or those who received 30 mg of enoxaparin every 12 hours (P < 0.001). The difference between the patients who received 40 mg once daily and those who received 30 mg every 12 hours was not significant. Only two cases of pulmonary embolism were diagnosed, one in patients receiving 40 mg of enoxaparin and one in those receiving 10 mg once daily. The incidence of hemorrhagic complications differed significantly between patients who received 10 mg of enoxaparin once daily (5%, 8 of 161 patients) and those who received 30 mg of enoxaparin every 12 hours (13%, 26 of 208; P < 0.05). CONCLUSIONS: After surgery, enoxaparin, 40 mg once daily or 30 mg every 12 hours, is more effective than a regimen of 10 mg once daily to prevent deep venous thrombosis in patients having elective hip replacement surgery. The regimens of 40 mg once daily and 30 mg every 12 hours provided prophylaxis similar to the most effective drug treatments previously reported. The incidence of hemorrhagic episodes with the regimens of 40 mg once daily and 30 mg twice daily was higher than that observed with 10 mg once daily; however, major hemorrhage occurred in only 4% to 5% of patients receiving the higher-dose regimens. The risk-to-benefit ratio supports the use of enoxaparin as a therapeutic agent to prevent deep venous thrombosis in these patients.""",1
8989,8020662,Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C,"BACKGROUND/AIMS: The effects of corticosteroids on chronic hepatitis B have provided insight into the mechanism of liver cell injury caused by hepatitis B. In this study, this model was applied to investigate the effects of prednisone on alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels in chronic hepatitis C. METHODS: Ten patients with chronic hepatitis C who had increased levels of ALT and HCV RNA detectable in serum were given a 7-week course of a tapering dose of prednisone. Quantitation of serum HCV RNA was determined by polymerase chain reaction (PCR) and by branched-chain DNA amplification. RESULTS: ALT levels decreased in 8 of 10 patients during therapy. Mean ALT levels of all 10 patients decreased from 184 to 84 U/L (P = 0.002) and then rebounded in 7 of the 8 patients after discontinuation of prednisone. HCV RNA was detectable by the branched DNA technique in 9 of 10 patients. These values increased in all 9 patients during prednisone therapy. The mean serum HCV RNA levels increased from 40.9 before treatment to 414.3 Eq/mL x 10(5) during treatment (P = 0.043). Using PCR, HCV RNA titers increased one log-fold in 8 of 10 patients (geometric mean of 1:4420 to 1:23410). HCV RNA levels decreased to pretreatment values within a mean of 2.8 weeks (range, 1-5) after discontinuation of prednisone. CONCLUSIONS: These responses in ALT and HCV RNA suggest the participation of an immune-mediated mechanism in the liver cell injury in chronic hepatitis C.",1
8990,8021361,Cholestatic hepatitis occurring shortly after etretinate therapy,,1
8991,8026248,Open label study of long-term effectiveness of cisapride in patients with idiopathic gastroparesis,"Cisapride induces acetylcholine release in cells of the myenteric plexus, thus promoting gastrointestinal motility. We studied the effects of cisapride on 11 patients with idiopathic gastroparesis. All had negative gastrointestinal endoscopy, normal glucose, and took no drugs capable of influencing motility. Most (9/11) were prior metoclopramide treatment failures. Patients' symptoms were scored (0-60) for pain, satiety, bloating, nausea, vomiting, and heartburn. All underwent a solid gastric emptying study using a Technetium-99-labeled egg meal and received placebo prior to cisapride. There were 10 females and one male with a mean (+/- SE) age of 37.8 +/- 2.6 years. Disease duration was 7.9 +/- 2.8 years. The dose of cisapride was 30-60 mg/day and the duration of therapy was 12.6 +/- 2.6 months (range 2.5-25 months). The symptom score improved on cisapride from 30.9 +/- 3.6 to 14.4 +/- 2.7 (P < 0.002 signed rank test). Emptying half-time improved from 113 +/- 4 min to 94 +/- 6 min, and 46.9 +/- 2.4% food remaining at 120 min decreased to 35.5 +/- 3.6% (both P < 0.05). Emptying half-time in normals was 68 +/- 5 min with 16.9 +/- 2.9% remaining at 120 min. Nine of 11 patients gained weight, with a mean increase of 6.7 +/- 1.6 lb (range 2-12 lb). We conclude that cisapride significantly reduces gastrointestinal symptoms and promotes weight gain in patients with idiopathic gastroparesis and is associated with improvement in solid gastric emptying. The drug is useful in patients who previously failed metoclopramide.",1
8992,8034946,Niacin-induced hepatitis and thrombocytopenia after 10 years of niacin use,,1
8993,8040106,Hepatic side-effects of antibiotics,"Although the liver is particularly exposed to drugs and their metabolites, hepatic side-effects of antibiotics are far less frequent than other adverse effects such as gastrointestinal disorders or cutaneous reactions. However, the potential severity of hepatic side-effects for some drugs is stressed. Antibiotic related liver injuries cover most of the clinical and pathological expressions of hepatic dysfunction, including cytotoxic hepatitis (isoniazid), intrahepatic cholestasis (macrolides, penicillins, clavulanic acid), mixed hepatitis (sulphonamides), chronic active hepatitis (nitrofurantoin), or microvesicular steatosis (tetracycline). In most cases, toxicity is idiosyncratic, reactions occurring only in some susceptible individuals. The mechanisms underlying toxicity may be primarily metabolite-dependent (isoniazid), hypersensitivity-mediated (beta-lactams), or result from both processes (sulphonamides, erythromycin derivatives). In some cases, the liver is not the primary target organ for toxicity but appears to mediate the clinical expression of some adverse effects induced by antibiotics. The most significant example of this is hypoprothrombinaemia due to the inhibition of hepatic gamma-carboxylation of vitamin K-dependent clotting factors by sulphydryl group-containing cephalosporins. Inhibition of bilirubin conjugation or transport by rifampicin or fusidic acid may also be viewed as hepatic side-effects of antibiotics. Ascertaining the casual relationship of a given drug to an hepatic adverse effect may prove particularly difficult, because of the potential contribution of host status and concurrent medications. Diagnosis is based mainly on circumstantial evidence, i.e. the temporal relationship between drug administration (or withdrawal) and the time-course of liver dysfunction. Improving morbidity related to drug hepatotoxicity relies on a free flow of information between manufacturers and practitioners in order to optimize detection of potentially serious liver damage, and advances in pharmacogenetics toward a better identification of those at particular risk for developing drug-related liver toxicity.",1
8994,8041531,A prospective study of symptomatic gallstones in women: relation with oral contraceptives and other risk factors,"""OBJECTIVE: To examine the relation between oral contraceptives (OCs), body mass index (BMI), weight change, alcohol use, parity, smoking, and symptomatic gallstones in women less than 45 years of age. METHODS: In this prospective study, associations between the various self-reported exposures and symptomatic gallstones were assessed in 96,211 female United States nurses with 425 cases of gallstones, using multiple logistic regression. RESULTS: We found little relation between ever-use of OCs and symptomatic gallstones (relative risk [RR] 1.2, 95% confidence interval [CI] 0.9-1.6), although there was a modest elevation in risk for long-term use (RR 1.5, 95% CI 1.0-2.2 for 10-14 years; RR 1.6, 95% CI 1.0-2.4 for 15 or more years). There was also an increased risk in current users of OCs (RR 1.6, 95% CI 1.1-2.4). The risk of symptomatic gallstones increased with increasing BMI and weight gain since age 18. Women with four or more births had an elevated risk of symptomatic gallstones (RR 2.0, 95% CI 1.3-3.2), and current cigarette smokers had a slightly higher risk than never-smokers (RR 1.3, 95% CI 1.0-1.7). The risk decreased with increasing alcohol intake. CONCLUSION: We found no substantial increase in the risk of symptomatic gallstones among ever-OC users, although current and long-term users had somewhat elevated risks. Body mass index remains the strongest predictor of symptomatic gallstones among young women.""",1
8995,8046321,High-dose methotrexate treatment and liver function in patients with osteosarcoma,"OBJECTIVES: To study the effects of short-term high-dose methotrexate therapy on liver function in patients with osteosarcoma. DESIGN: Open prospective study. SETTING: Department of Internal Medicine and Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy. SUBJECTS: Fourteen patients with osteosarcoma, with no evidence of previous or actual liver disease at the time of diagnosis. INTERVENTIONS: All patients received a cumulative dose of 30-57 gm-2 of methotrexate within 6 months as neo-adjuvant chemotherapy (pre- and post-surgery). Each course of chemotherapy included methotrexate at a dose of 8-12 gm-2 and, in addition, adriamycin and cisplatinum. MAIN OUTCOME MEASURES: Galactose elimination capacity and antipyrine clearance were measured at baseline, after the first course of chemotherapy, at the end of the pre-operative period and at the end of chemotherapy. In each case they were carried out after transaminase levels had returned to normal. RESULTS: Galactose elimination capacity decreased from 2.45 (+/- 0.48) mM min-1 to 2.04 (+/- 0.60) mM min-1 after the five planned courses of chemotherapy (P = 0.013, Wilcoxon signed-rank test), without any change in routine liver function tests. No differences in antipyrine clearance and half-life were demonstrated (n = 8). CONCLUSIONS: The data are consistent with a decreased reserve capacity of the liver after short-term, high-dose methotrexate. Long-term survivors deserve monitoring of liver function for safer methotrexate use, in the light of progressive dosage increments to improve prognosis in neoplastic diseases.",1
8996,8052321,[Cholestatic jaundice caused by amoxicillin-clavulanic acid in 4 patients],"In four patients, two men and two women aged 73, 68, 84 and 72 years respectively, reversible cholestatic liver injury was seen 28-35 days after the start of treatment with amoxycillin-clavulanic acid (Augmentin). This rare complication of amoxycillin-clavulanic acid treatment is characterized by a relatively long latent period before the onset of symptoms or biochemical abnormalities, which makes early recognition difficult. The mechanism responsible for this idiosyncratic cholestasis is unknown.",1
8997,8055207,Fatal cholestatic hepatitis caused by D-penicillamine,"A 37-yr-old woman with RF-positive RA developed cholestatic hepatitis after 10 days of D-penicillamine therapy. This was discontinued immediately. The cholestasis persisted for the remaining 14 months of her life. Severe hypercholesterolemia developed with xanthelasmata and eventually pancytopenia, which was caused by a massive infiltration of the bone marrow by lipid-containing foam cells. The patient died of sepsis. Review of the literature shows intrahepatic cholestasis to be a rare and idiosyncratic complication of D-penicillamine therapy. To our knowledge, ours is the first documented case of persistent cholestatic icterus.",1
8998,8057403,Hepatocellular damage following amphetamine intoxication,,1
8999,8060560,"Metabolic, hepatic and muscular changes during zidovudine therapy: a drug-induced mitochondrial disease?",,1
9000,8065199,Cyclophosphamide-induced hepatitis in Wegener's granulomatosis,,1
9001,8068426,[An intrahepatic hematoma secondary to peliosis hepatis in a female patient treated with oral contraceptives],"The case of a patient is reported, who developed peliosis hepatis during contraceptive steroid therapy. This was clinically manifested as a spontaneous hepatic hematoma. No underlying liver tumor could be detected by both invasive and non-invasive investigations. Oral contraceptives should be listed among the potential albeit exceptional cases of liver hematoma, and this clinical presentation of peliosis hepatis added to the possible manifestations of that obscure condition.",1
9002,8074603,"Severe episode of high fever with rash, lymphadenopathy, neutropenia, and eosinophilia after minocycline therapy for acne","""Minocycline is a tetracycline agent frequently used for acne therapy. It has a few rare but severe side effects that are not widely known but should be recognized early as drug related. These include acute hepatitis and liver failure; a Loffler-like syndrome with pulmonary infiltrates, wheezing, fever, and eosinophilia; skin eruptions, eosinophilic cellulitis, and pustular folliculitis with eosinophilia; and a lupuslike syndrome. Side effects that are better known and recognized include photosensitization, skin exanthema with pruritus, and pseudotumor cerebri.""",1
9003,8078987,The side-effects of clozapine: a four year follow-up study,"Clozapine, as the model agent for the atypical antipsychotic drugs, is currently recommended as effective regarding negative symptoms of schizophrenia and treatment-resistant schizophrenic patients. This study focuses on the clozapine-induced side-effects in 100 hospitalized schizophrenic patients (negative and therapy-resistant forms), followed-up for a four year period. Clinically relevant side-effects occurred in 73% of all patients. Tachycardia (67%), the increase of liver enzymes (36%), hypotension (29%) and sedation (27%) were most frequent. Tachycardia, hypotension and sedation disappeared during the initial phase of treatment (i.e. 4-6 weeks), as tolerance developed with continuation of therapy. The increase of liver enzymes appeared to be dose related, since the reduction of daily clozapine dose led to the normalization of transaminases values. The other side-effects (constipation, nausea and vertigo) were rare and transient. Leucopenia was not registered in any patient during the follow-up period. Therefore, clozapine is efficient and, with some precautions concerning hepatotoxicity, is safe for in- and outpatient long-term treatment in appropriately selected patients.",1
9004,8083706,Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study,"""PURPOSE: To evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite with activity against solid tumours. PATIENTS AND METHODS: Eighty-two patients with unresectable stage IIIa to IV non-small-cell lung cancer (NSCLC) were entered. The first 54 patients received gemcitabine 800 mg/m2, and subsequent patients 1,000 mg/m2, as a 30-minute intravenous infusion on days 0, 7, and 14. Courses of therapy were repeated every 28 days. Twenty percent dosage escalation was permitted after course no.1 if World Health Organization (WHO) toxicity was < or = 1. RESULTS: Sixteen (20%; 95% confidence interval [CI], 12% to 31%) of 79 patients assessable for response had independently validated partial responses, with a median duration of 7 months. The overall median survival duration was 7 months. Gemcitabine improved disease-related symptoms (70% patients) and increased WHO performance status (44%). Toxicity was generally mild and reversible. Patients experienced little WHO grade 3 and 4 toxicity, with anemia in four (5%), thrombocytopenia in one (1%), leukopenia in six (7%), and neutropenia in 18 (22%). Infection occurred in nine patients (12%) during the study (four were neutropenic), but there were no episodes of WHO grade 3 or 4 infection. WHO grade 3 and 4 biochemical toxicity occurred with transient elevations of transaminases in 10 patients (12%). Two patients had transient WHO grade 3 elevation of serum creatinine levels, and two developed acute renal failure 4 and 6 weeks after the last dose of gemcitabine. There was no WHO grade 4 symptomatic toxicity. WHO grade 3 vomiting occurred in 31 patients (38%) and grade 3 alopecia in one (1%). Flu-like symptoms were associated with gemcitabine administration in 36 patients (44%). Twenty-six patients (32%) experienced fever (1% WHO grade 3), 33 (40%) ankle edema not associated with cardiac failure, 31 (38%) lethargy, and 11 (13%) dyspnea. CONCLUSION: Gemcitabine is an active new agent in the treatment of NSCLC. This schedule was associated with little alopecia or myelosuppression. Gemcitabine warrants further investigation in other malignancies and in combination with other agents.""",1
9005,8086558,Temafloxacin syndrome: review of 95 cases,"""Four months after its approval in the United States, temafloxacin was withdrawn from the market worldwide because of frequent reports of serious hemolysis with or without other organ system dysfunction. We describe this """"temafloxacin syndrome"""" on the basis of a review of 95 spontaneous reports of hemolysis sent to the Food and Drug Administration. Patients typically presented with fever, chills, and jaundice a mean of 6.4 days after starting therapy. A moderate degree of hemolysis was reflected by the mean drop in hemoglobin level (by 42 g/L) and by the mean lowest concentration of hemoglobin (97 g/L). New-onset renal dysfunction was noted in 54 cases (57%), and dialysis was required in 34 cases (63%). Coagulopathy was noted in 33 cases (35%), and 48 cases (51%) met the criteria for hepatic dysfunction. Four patients developed central nervous system complications, and two patients died. Prior quinolone use was more common among patients who developed hemolysis after only one dose as opposed to two or more doses (P < .001). These data suggest that temafloxacin causes immune hemolytic anemia, most likely secondary to immune complex formation.""",1
9006,8088258,The long-term safety and efficacy of gabapentin (Neurontin) as add-on therapy in drug-resistant partial epilepsy. The US Gabapentin Study Group,"This is the 2-year interim report of results from a multicenter, open-label study evaluating the long-term efficacy and safety of gabapentin (Neurontin) as add-on therapy in patients with refractory partial seizures who had had a therapeutic response to gabapentin in a preceding 12-week double-blind trial or 12-week open-label extension. A total of 240 patients continued to receive gabapentin as add-on therapy at dosages of 600-2400 mg/day for an average of 342 days (range 10-784 days). Efficacy analyses compared seizure frequency during consecutive 12-week treatment periods with seizure frequency during the 12-week baseline. During the nine treatment periods evaluated, the percent of patients with a 50% or greater reduction in seizure frequency ranged from 35% to 71%, and the median percent change in seizure frequency ranged from -33% to -60%. At the time of data cutoff, 30% of patients had withdrawn from the study due to lack of efficacy, and 4% due to adverse events. In 225 patient-years of gabapentin treatment in this study, CNS adverse events reported by more than 10% of patients were nystagmus, somnolence, diplopia, tremor, ataxia, and dizziness. No consistent changes in clinical laboratory values were associated with gabapentin. Gabapentin as add-on therapy at dosages up to 2400 mg/day is safe during long-term treatment in patients with refractory partial seizures. Subgroup analyses of patients who remained in the study over the long term confirmed that gabapentin maintained efficacy for up to 2 years.",1
9007,8091264,Hepatotoxicity from propylthiouracil,"Propylthiouracil is a drug used commonly to treat hyperthyroidism. Among its side effects, hepatotoxicity is one of the rarest but one of the most serious. This complication may be due to an immune mechanism. However, particular risk factors associated with the development of hepatotoxicity are not known, and its occurrence is unpredictable. I report a case of acute hepatitis developing during propylthiouracil therapy for Graves' disease and review the literature related to this problem.",1
9008,8093301,Adverse events after triazolam substitution,,1
9009,8095649,Hepatic toxicity of liposomal encapsulated doxorubicin,,1
9010,8096597,Roxithromycin-induced or herpes hepatitis?,,1
9011,8098447,Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa,"There is much confusion over which malaria chemoprophylaxis should be used in areas such as East Africa. We did two consecutive studies between 1985 and 1991 to assess the efficacy and side-effects of malaria chemoprophylaxis in short-term travellers to East Africa. All passengers returning from Kenya to Europe received an in-flight questionnaire and a second one three months later. Any report of documented malaria or of admission to hospital for possible side-effects was verified with the physician. 145 003 travellers completed questionnaires. Among the 139 164 who stayed in East Africa for less than one year, 296 cases of confirmed malaria were reported (275 due to P falciparum). In people who used no chemoprophylaxis, the incidence of falciparum malaria was 1.2% per month. Prophylactic effectiveness was 91% (95% Cl 85 to 94) for mefloquine, 82% (71 to 89) for pyrimethamine and sulfadoxine, 72% (56 to 82) for chloroquine plus proguanil, and 10 to 42% for chloroquine at various doses. Rates of side-effects, which were usually mild, were 18.8% for mefloquine users, 17.1% and 18.6% for chloroquine 300 mg and 600 mg base per week, respectively, 30.1% for chloroquine plus proguanil, and 11.7% for sulfadoxine and pyrimethamine. Mefloquine is significantly more effective than chloroquine plus proguanil for malaria prophylaxis in short-term tourists visiting East Africa and has a tolerance similar to that of chloroquine used alone.",1
9012,8109254,Two cases of recurrent hepatic injury associated with early pregnancy: hCG on hepatocytes is a suspected target antigen for lymphocyte attack,"Two cases of recurrent hepatic injury which appeared in the first trimester of pregnancy were studied. Case 1 was a 35 year old woman, gravida 4, para 0, who suffered repeatedly from hepatic injury requiring induced abortions. The patient was healthy before the pregnancies and the plasma aminotransferases increased after 8 weeks gestation and promptly returned to normal after the abortions. No fluctuation of aminotransferases was observed in the menstrual cycle. A liver biopsy immediately after abortion showed spotty necrosis of hepatocytes with mononuclear cell infiltration. Most of the infiltrating cells were cytotoxic T cells that were directly in contact with hepatocytes. Numerous lymphocytic infiltrations were also found in the decidua of the uterine curettage material. The patient's lymphocytes showed conspicuous blast transformation in culture with human chorionic gonadotropin (hCG). The hCG was detected in close vicinity to the injured hepatocytes by immunostaining. Case 2 was a 23 year old woman, gravida 2, para 0, who underwent an induced abortion due to hepatic dysfunction in the first pregnancy. Although hepatic dysfunction reappeared from 10 weeks gestation during the second pregnancy, her health gradually improved with conservative therapy and resulted in a full-term delivery. She lacked allergies to drugs or foods and was healthy when she was not pregnant. These two cases suggest that some hepatotoxic materials appeared transiently in the first trimester. The results of Case 1 suggest strongly that hCG on the hepatocytes was recognized as an antigen and evoked lymphocytic attack.",1
9013,8117876,[Hepatotoxicity and flutamide],,1
9014,8121527,[Liver cell necrosis during administration of clozapine],"A 38-year-old woman was treated for mutism with clozapine. After a week liver function disturbances developed, which disappeared when the treatment was discontinued. Histopathological investigation of a liver biopsy specimen revealed extensive liver cell necrosis. So far two patients have been described with cholestatic jaundice induced by clozapine, and one patient with toxic hepatitis due to clozapine.",1
9015,8122946,Cholesterol lowering in the elderly. Results of the Cholesterol Reduction in Seniors Program (CRISP) pilot study,"""BACKGROUND: Total and lipoprotein cholesterol levels continue to be predictors of coronary heart disease risk in men and women over 65 years old. Cholesterol-lowering trials, however, while sometimes including such subjects, have not concentrated on this age group. The Cholesterol Reduction in Seniors Program was a five-center pilot study to assess feasibility of recruitment and efficacy of cholesterol lowering in this age group. METHODS: The study was a randomized, double-masked clinical trial with placebo, 20-mg lovastatin, and 40-mg lovastatin arms. Major efforts were made to recruit women and minorities. Participants were followed up for 1 year on a cholesterol-lowering diet plus placebo or study drug. End points were changes in blood lipid levels. Data on other blood chemistry values, as well as quality-of-life measures and coronary heart disease morbidity and mortality, were also collected. RESULTS: Four hundred thirty-one subjects with low-density lipoprotein cholesterol levels greater than 4.1 and less than 5.7 mmol/L (159 and 221 mg/dL) were randomized, of whom 71% were women and 21% were African Americans; the mean age was 71 years. In the 20- and 40-mg lovastatin groups, total cholesterol levels fell 17% and 20%; low-density lipoprotein cholesterol levels fell 24% and 28%; triglyceride levels fell 4.4% and 9.9%, respectively. High-density lipoprotein cholesterol levels rose 7.0% and 9.0%, respectively. No changes were observed in the placebo group. Gender, race, and age did not significantly affect responses. Coronary heart disease morbidity and mortality data were collected but not analyzed for this study. CONCLUSION: Older subjects of both genders and a variety of racial and ethnic groups can be successfully recruited into a cholesterol-lowering trial. Lovastatin has effects similar to those reported in younger subjects in previous controlled trials. There is little advantage to the higher lovastatin daily dose. Side effects were remarkably low in all groups.""",1
9016,8123956,Hepatitis following treatments with famotidine and then cimetidine,"OBJECTIVE: To report a case of hepatitis induced by two histamine (H2)-receptor blockers, famotidine and cimetidine. CASE SUMMARY: A 51-year-old obese woman with a duodenal ulcer developed symptomatic, famotidine-induced hepatitis. Other causes for hepatitis were ruled out. Famotidine was discontinued and the patient took omeprazole for a month without incident. Cimetidine therapy was then initiated and shortly thereafter, the patient developed another episode of symptomatic hepatitis that resolved upon drug discontinuation. Two abdominal ultrasound examinations six months apart and an abdominal computed tomography scan obtained later showed what appeared to be a stable, fatty liver. DISCUSSION: This appears to be the first reported case of clinical hepatitis related to famotidine and the first reported case where clinical hepatitis followed the administration of two different H2-receptor blockers. The fatty liver probably was secondary to obesity and incidental to the hepatitis episodes. CONCLUSIONS: Famotidine can cause clinical hepatitis, and drug-induced hepatitis can occur after the administration of two different H2-receptor blockers.",1
9017,8124850,Intrahepatic cholestasis during nicotinic acid therapy,"""BACKGROUND: Nicotinic acid, widely used to lower serum cholesterol levels, may rarely cause cholestatic jaundice. SUMMARY: A 61-year-old white man with hypercholesterolemia complained of marked pruritus and became jaundiced after taking 3.0 g of crystalline nicotinic acid daily for 13 months. His total serum bilirubin level was increased at 144 mumol/L (8.4 mg/dL) and his alkaline phosphatase level was markedly elevated at 35.00 mukat/L (2100 U/L). Endoscopic retrograde cholangiopancreatography failed to demonstrate an obstructive lesion in the extrahepatic biliary system, computed tomography showed no intrahepatic dilatation, and ultrasonographic studies of the liver, gallbladder, and pancreas were normal; these factors all suggest intrahepatic cholestasis. Symptoms improved and liver function test results returned to normal within 51 days after stopping the drug. CONCLUSIONS: Nicotinic acid-induced cholestatic jaundice may not be as rare as previously thought, and physicians should observe their patients for it.""",1
9018,8127168,[Syndrome of allopurinol hypersensitivity. Report of a new case and review of the Spanish literature],Allopurinol is a drug of wide clinical use and good tolerance. Some patients develop severe hypersensitivity due to immunologic reaction to the drug. A new case which fulfills all the diagnostic criteria of the syndrome of allopurinol hypersensitivity with associated clinical manifestations of multiple mononeuritis and evidence of granulomas and vasculitis in liver biopsy as the most significant data is reported. The syndrome was favorably resolved following withdrawal of the drug without need for corticoid therapy. The characteristics of the cases described in the Spanish literature over the last few years are globally reviewed. The absence of mortality is of note. The inconvenience of prescribing allopurinol to patients with asymptomatic hyperuricemia is emphasized.,1
9019,8129642,4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety,"""OBJECTIVE: To study the long-term efficacy and safety of 4-aminopyridine in patients with multiple sclerosis. DESIGN: Case series, follow-up varying from 6 to 32 months. SETTING: University referral center. PATIENTS: Thirty-one patients with definite MS, 23 of them being exposed to long-term administration (6 to 32 months) of 4-aminopyridine, since they showed a favorable initial response to the drug. INTERVENTIONS: Long-term oral treatment with 4-aminopyridine in daily doses of up to 0.5 mg/kg of body weight. MAIN OUTCOME MEASURES: Neurologic functions and symptoms as reported by the patients; side effects. RESULTS: Twenty of 23 patients who showed a favorable initial response benefited from long-term administration. Ambulation and fatigue (each in 13 patients) and visual function (in five patients) were most frequently reported to be improved. Three major side effects did occur during a follow-up of 406 patient months: a generalized epileptic seizure in two patients and hepatitis in one. CONCLUSIONS: Although a substantial proportion of patients with multiple sclerosis seem to benefit from long-term administration of 4-aminopyridine, additional studies are needed to clarify the exact value of the drug.""",1
9020,8133559,Short course chemotherapy for tuberculosis in children,"In order to determine the efficacy of short course chemotherapy (SCC) for tuberculosis in children, 83 newly diagnosed cases in children < 12 years old were given SCC and were prospectively followed for 1-3 years. Seventy-one cases were treated for 6-9 months as they had mild to moderate involvement. Twelve cases were treated for 12 months as they had meningitis (7), disseminated tuberculosis (2), or miliary tuberculosis (3). The results showed that none of the children, at the end of follow up, showed evidence of active tuberculosis. All children tolerated the drugs well, with side effects noticed being mild, namely transient hepatitis (4), vomiting (1), and skin rash (1). It is suggested that SCC for 6-9 months using isoniazid (INH) and rifampicin along with other drugs when necessary is highly effective in most cases of tuberculosis in children and has several advantages over conventional chemotherapy of 18 months or longer duration.",1
9021,8135028,[Carbamazepine poisoning: protracted course with development of intestinal atony and hepatic toxicity],"A 43 year-old female patient with a history of manic-depressive illness and prophylactic carbamazepine (CBZ) medication ingested a potentially lethal overdose of 20 g of the substance. Neurotoxic symptoms reached full intensity after about 24 hours. Subsequently, the patient developed a gastrointestinal atony, which proved to be refractory to treatment for several days. Moreover, there was an increase of bilirubin. Parallel to this we observed the persistence-and even intermittent re-increase--of toxic serum CBZ concentrations for one week with corresponding protracted clinical symptomatology.",1
9022,8139083,A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group,"""OBJECTIVE: To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. DESIGN: A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. SETTING: Outpatients at 33 US centers. PATIENTS: Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. INTERVENTIONS: Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. PRIMARY OUTCOME MEASURES: Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale--Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA). RESULTS: A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P < or = .05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P < or = .001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P < or = .002) and ADAS-Cog and FCCA (P < or = .001), as well as caregiver-global and quality-of-life assessments (P < or = .05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine. CONCLUSIONS: Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.""",1
9023,8139647,Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis,,1
9024,8149124,Concurrent agranulocytosis and hepatitis secondary to clomipramine therapy,"A 67-year-old man developed concurrent severe agranulocytosis and elevation of hepatic transaminases as a result of treatment with clomipramine. Although such adverse drug reactions can be considered rare events, the potentially serious nature of these reactions vindicate the routine monitoring of blood picture, and liver function tests, after initiation of treatment with tricyclic antidepressants.",1
9025,8153703,Augmentin-induced cholestatic jaundice--a case report,A case of cholestatic jaundice following treatment with Augmentin is reported. The awareness of hepatotoxicity due to drug should help to avoid unnecessary invasive procedures in the evaluation of this reversible condition.,1
9026,8157475,VM-26 in gastric cancer. A Southwest Oncology Group study,"The Southwest Oncology Group conducted a trial of VM-26 (teniposide) in patients with advanced gastric cancer. VM-26 60 mg/m2 i.v. infusion over 30-45 minutes was given daily for 5 days every 21 days. Twenty-one eligible patients with measurable disease and a SWOG performance status of 0-2 were analyzed for response and toxicity. Partial responses were seen in 2 of the 21 eligible patients (9.5%). Median survival was 3.8 months. Severe of life-threatening toxicity was observed in 13/21 (62%) patients. This included two drug related deaths related to neutropenic sepsis and seven other patients with grade 4 granulocytopenia (< 500/mm3). Liver dysfunction and hypotension were seen less often and were not dose limiting. Although the modest activity seen was comparable to that of VP-16 (etoposide) as a single agent, the hematologic toxicity observed in this trial would likely preclude further trials of VM-26 (teniposide) in advanced gastric cancer.",1
9027,8161767,"Hepatotoxicity of antituberculosis therapy (rifampicin, isoniazid and pyrazinamide) or viral hepatitis","SETTING: Department of Chest Diseases, Gazi University Faculty of Medicine and Atat?rk Chest Diseases Hospital, Ankara, Turkey. OBJECTIVE: The primary purpose of this study was to assess the contributory role of viral hepatitis in antituberculosis drug hepatotoxicity. DESIGN: Serologic markers for viral hepatitis were studied in 57 patients who developed acute hepatitis during antituberculosis therapy with rifampicin and isoniazid. RESULTS: Among 705 adult tuberculous patients, 57 (8.1%) developed acute hepatitis during therapy with rifampicin and isoniazid. Serologic markers confirmed the presence of hepatitis B in 6 (10.5%) and hepatitis C in 4 (7%) of the 57 patients. Acute hepatitis A was not diagnosed in any of the patients. CONCLUSION: Hepatitis occurring during antituberculosis therapy may not be drug-induced in all patients. Apart from the other factors mentioned above the endemicity of viral hepatitis in developing countries could be responsible for the higher incidence of antituberculosis-drug hepatitis.",1
9028,8165461,[Technical aspects of ultrasonography of the fetal hip joint],"Recent advances in ultrasound technology now permit direct access to foetal structures with visualisation of foetal hip development. Since early diagnosis and treatment of congenital hip dislocation significantly influence outcome of the disease, ultrasound screening of newborn infants proved to be the most effective method. In our study assessment of the foetal hip has been carried out to provide basic knowledge on foetal hip development from 14.-40. weeks of gestation. Technique of foetal hip ultrasound is presented. Diagnosis should include qualitative and quantitative descriptions of foetal hip structures. Alpha and Beta angles according to Graf's classification are frequently measurable from the 21st week of gestation, but tend to be more reliable towards the end of pregnancy.",1
9029,8170206,Hepatotoxicity of 6-mercaptopurine and azathioprine,,1
9030,8172156,Terbutaline hepatitis in pregnancy: report of two cases and literature review,,1
9031,8175002,Fulminant hepatic failure secondary to hydroxychloroquine,Hydroxychloroquine is widely used in rheumatological disease but hepatic side effects have not been reported previously. Two cases are described of fulminant hepatic failure developing after the start of hydroxychloroquine treatment for a chronic rheumatological disorder. In both cases the symptoms of liver disease developed within two weeks of starting hydroxychloroquine and rapidly progressed to fulminant hepatic failure and in neither case was there any pre-existing liver disease. One patient had emergency orthotopic liver transplantation and the other died before a donor organ became available.,1
9032,8175136,The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis,"""Ursodeoxycholic acid, a dihydroxyl bile acid normally present in human beings in minimal amounts, becomes incorporated into the bile salt pool when taken orally. In cholestasis, bile acids are retained in the liver and are hepatotoxic. Ursodeoxycholic acid is the least-known hepatotoxic bile acid, has choleretic properties and is reported to benefit patients with chronic cholestasis. In a nationwide Canadian controlled trial, 222 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (14 mg/kg/body wt/day) or placebo for 24 mo. Only patients with a diagnosis confirmed by liver biopsy and serum positive for antimitochondrial antibodies were enrolled; 88% were symptomatic on entry. The primary outcome measure was percent change in total serum bilirubin from baseline to final follow-up. Treated patients (111) and controls (111) were comparable with regard to age, gender, biochemical parameters and liver histological condition. Although treatment was not associated with any improvement in symptoms, ursodeoxycholic acid therapy caused the bilirubin to fall significantly within the first 3 mo of therapy (p < 0.001). Significant falls in serum alkaline phosphatase, aminotransferases, cholesterol and IgM levels were also noted in the treated group. Improvement in some histological features was observed but there was no difference between the groups in the number of patients who reached the endpoints of death or liver transplantation. Ursodeoxycholic acid, given to patients with primary biliary cirrhosis, leads to an improvement in serum markers of cholestasis. A larger sample size is needed to determine whether ursodeoxycholic acid therapy has a beneficial effect on the survival of patients with primary biliary cirrhosis.""",1
9033,8180029,Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients,"Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metastatic adrenocortical carcinoma, although a favourable effect of this drug on survival has never been documented. We evaluated the efficacy of mitotane treatment of 96 patients with adrenocortical carcinoma followed up in our department between 1959 and 1992. Complete tumour resection was the goal of the initial treatment. Mitotane treatment was classified according to serum trough concentrations on maintenance therapy: low (< 14 mg l-1) or high (> or = 14 mg l-1). Total tumour resection was feasible in 47 patients (49%), and subtotal resection was performed in 37 patients (39%). Patients who underwent total tumour resection survived significantly longer than those who did not (P < 0.001). Adjuvant mitotane therapy (n = 11) did not influence survival after total resection. Sixty-two patients were given mitotane treatment at some time during their illness, only 30 of whom reached high maintenance serum levels. Mitotane treatment with high serum levels had an independently favourable influence on patient survival, using univariate (P < 0.01) and multivariate analysis (P = 0.01). Mitotane treatment resulting in low serum levels was tantamount to not giving mitotane at all. We conclude that mitotane treatment in adrenocortical carcinoma is effective only when high serum levels can be achieved.",1
9034,8181926,Fatal fulminant hepatitis from cyproterone acetate,,1
9035,8183002,[Hepatotoxicity due to flutamide],,1
9036,8186115,One-year follow up of children treated with Chinese medicinal herbs for atopic eczema,"The opportunity to continue treatment was offered to the parents of 37 children who had completed a double-blind placebo-controlled trial of a specific formulation of Chinese medicinal herbs for atopic eczema. The parents elected for continued treatment in every case, and the progress of the children was monitored over the following 12 months. The aim was to achieve a substantial clinical improvement, and thereafter to reduce treatment frequency progressively while maintaining this benefit. At the end of the year, 18 enjoyed at least 90% reductions in eczema activity scores, and five showed lesser degrees of improvement. Fourteen children withdrew from the study, 10 due to lack of response, and four because of unpalatability of treatment or difficulty in the preparation of treatment. By the end of the year, seven of the children were able to discontinue treatment without relapse. The other 16 required treatment to maintain control of their eczema, but only four of these still required daily treatment. Asymptomatic elevation of serum aspartate aminotransferase to 7-14 times normal values was noted on one occasion in two children whose eczema was so well controlled that the therapy was stopped. Liver function tests were normal 8 weeks later. We conclude that Chinese medicinal herbs provide a therapeutic option for children with extensive atopic eczema which has failed to respond to other treatments. In the medium term, it proved helpful for approximately half the children who originally took part in our placebo-controlled trial. The possibility that it may provoke hepatic abnormalities requires further study.(ABSTRACT TRUNCATED AT 250 WORDS)",1
9037,8191137,[Major adverse reactions to propylthiouracil in 586 cases of hyperthyroidism],"Aiming to know the incidence and evolution of major adverse reactions to propylthiouracil in patients with hyperthyroidism, we performed a retrospective analysis of 586 patients treated between 1982 and 1992. All known complications associated to the use of propylthiouracil were considered major adverse reactions, when other causes were discarded. Eight patients (1.4% of the sample) had major adverse reactions: three had agranulocytosis, 3 hepatitis, 1 cholestasis and 1 vasculitis. All had a good evolution after discontinuing the drug. The patients with agranulocytosis were treated with antibiotics and the patient with cholestasis received prednisone. We conclude that major adverse reactions to propylthiouracil are infrequent, that they occur preferentially during the first months of treatment, earlier after reexposure and that there was no associated mortality.",1
9038,8197999,Acute hepatic injury after treatment with diltiazem,,1
9039,8198020,Combination therapy with fluvastatin and niacin in hypercholesterolemia: a preliminary report on safety,"A double-blind, randomized study was undertaken to evaluate the efficacy and safety of fluvastatin as monotherapy and as combination therapy with niacin in the treatment of hypercholesterolemia refractory to diet. Seventy-four patients with plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 160 mg/dL were treated with fluvastatin, 20 mg/d, or placebo for 6 weeks. Thereafter, immediate-release niacin, at a dosage titrated to a maximum of 3 g/d, was added to both regimens for another 9 weeks. All adverse events were monitored, with particular attention to the evaluation of liver and muscle enzymes. Initial analysis of the data shows that fluvastatin and its combination with niacin was well tolerated and was not associated with any serious adverse events. Small, transient, asymptomatic rises in aspartate aminotransferase (AST) occurred in 28.9% of fluvastatin-niacin treated patients compared to 8.3% in the niacin-placebo control arm (p < 0.05). These were considered clinically insignificant in that no transaminase elevations > 3 times the upper limit of normal occurred. No evidence of myopathy, creatine kinase levels exceeding 10 times the upper limit of normal, myositis, or rhabdomyolysis were demonstrated in this short-term trial. The majority of adverse events resulting in patient withdrawals were ascribed to niacin therapy and included cutaneous vasodilatation, flushing, itching, and rash. These preliminary results suggest that fluvastatin, both alone and combined with niacin, is an effective, safe, and well-tolerated treatment for hypercholesterolemia.",1
9040,8198460,A case report of drug-induced allergic hepatitis probably due to the N-methyltetrazolethiol group cephalosporin,Drug-induced allergic hepatitis occurred in a patient being treated with cefpiramide sodium. A lymphocyte blast transformation test suggested that the N-methyltetrazolethiol group of the drug was responsible for the induction of acute hepatitis. A detailed case report and discussion of the relevant literature are presented in this paper.,1
9041,8200006,A randomized clinical trial of single-dose versus fractionated-dose dactinomycin in the treatment of Wilms' tumor. Results after extended follow-up. Brazilian Wilms' Tumor Study Group,"BACKGROUND: To verify the adequacy of a simplified chemotherapeutic regimen for the treatment of Wilms' tumor (WT), the authors conducted a clinical trial to compare the standard fractionated dose (15 mcg/kg x 5 days) of dactinomycin (AMD) with a single dose (60 mcg/kg x 1 day) administration of the drug. METHODS: From October 1986 to December 1988, 176 WT patients were enrolled in a randomized, multicentric clinical trial conducted by the Brazilian WT Study Group in 38 institutions from 8 states. Patients were randomly assigned to treatment arm A (standard 5-day fractionated AMD administration) or arm B (single high dose AMD administration) in the schedules most appropriate for their stage and histology. Except for the differences in AMD administration, patients were managed by the Third U.S. National WT Study protocol. The endpoints of interest were relapse free and overall survival. Complete follow-up information was obtained until December 1992. RESULTS: After a median follow-up of 47 months, there were no significant differences in survival distributions between treatment arms, using data for all patients or data stratified by disease stage. Relapse free and overall 4-year rates were similar in both groups: 67% and 72%, respectively, in arm A, and 67% and 75%, respectively, in arm B (P = 0.839 and 0.710, respectively). Patients assigned to the simplified arm had cumulatively 1921 fewer hospital days as compared with those receiving the fractionated dose. Hepatic toxicity was observed in only one patient assigned to the divided dose regimen and in none of the single dose group. CONCLUSIONS: WT can be treated using a single dose regimen for AMD administration, thus minimizing the inconvenience for the children and their parents and reducing considerably health care delivery costs.",1
9042,8201211,"Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis","We report cases of amoxycillin- and flucloxacillin-induced liver damage associated with an acute vanishing bile duct syndrome. Ductopenia was present at the time of first liver biopsy, 3 weeks and 3 months after administration of the two drugs, respectively. Ductopenia apparently occurred as the primary lesion, with no evidence of accompanying portal tract inflammation. Subsequent biopsies showed a persistent paucity of ducts, accompanied by increasing features of chronic cholestasis. Biochemical dysfunction persists at 2 year's follow-up and late prognosis remains guarded.",1
9043,8203031,[Methyldopa-induced hepatitis: 3 case reports],,1
9044,8211464,Treatment of tuberculosis in patients with pre-existing liver disease or following hepatotoxic drug reactions,,1
9045,8214760,"Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane","BACKGROUND: Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. METHODS: Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. RESULTS: The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevoflurane defluorination was also highly correlated with that of enflurane (r = 0.93), which is known to be metabolized by human P450 2E1. Diethyldithiocarbamate, a selective inhibitor of P450 2E1, produced a concentration-dependent inhibition of sevoflurane, methoxyflurane, and isoflurane defluorination. No other isoform-selective inhibitor diminished the defluorination of sevoflurane, whereas methoxyflurane defluorination was inhibited by the selective P450 inhibitors furafylline (P450 1A2), sulfaphenazole (P450 2C9/10), and quinidine (P450 2D6) but to a much lesser extent than by diethyldithiocarbamate. CONCLUSIONS: These results demonstrate that cytochrome P450 2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of sevoflurane. P450 2E1 is the principal, but not exclusive enzyme responsible for the metabolism of methoxyflurane, which also appears to be catalyzed by P450s 1A2, 2C9/10, and 2D6. The data also suggest that P450 2E1 is responsible for a significant fraction of isoflurane metabolism. Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.",1
9046,8216376,Association of anti-58 kDa endoplasmic reticulum antibodies with halothane hepatitis,"We recently showed that when rats were administered the inhalation anesthetic halothane, a 58 kDa liver endoplasmic reticulum protein became covalently trifluoroacetylated by the trifluoroacetyl chloride metabolite of halothane. Although the 58 kDa protein showed 99% identity to that of the deduced amino acid sequence of a cDNA reported to correspond to phosphatidylinositol-specific phospholipase C-alpha, it did not have phosphatidylinositol-specific phospholipase C activity. It was concluded that the reported cDNA of phosphatidylinositol-specific phospholipase C-alpha actually encoded for the 58 kDa endoplasmic reticulum protein of unknown function. Other researchers have come to the same conclusion and have shown that the 58 kDa protein has protein disulfide-isomerase and protease activities. We now report that patients with halothane hepatitis have serum antibodies that react with both purified trifluoroacetylated and native rat liver 58 kDa proteins. These results suggest that when patients are exposed to halothane a human liver orthologue of the rat liver trifluoroacetylated-58 kDa protein is formed. In certain patients, this protein may become immunogenic and lead to the formation of specific antibodies and or specific T-cells, which may react with both trifluoroacetylated and native 58 kDa proteins, and ultimately be responsible, at least in part, for the hepatitis caused by halothane.",1
9047,8219452,"Trimethoprim/sulfamethoxazole-induced rash, fever, abnormal liver function tests, leukopenia, and thrombocytopenia",,1
9048,8225213,Resolution of liver biopsy alterations in three siblings with bile acid treatment of an inborn error of bile acid metabolism (delta 4-3-oxosteroid 5 beta-reductase deficiency),"""Identical male twins and their brother, cholestatic from birth, with delta 4-3-oxosteroid 5 beta-reductase deficiency, were studied by serial liver biopsy. Spectrometry documented defective primary bile acid synthesis and markedly increased levels of atypical oxo and allo bile acids in urine and serum. Hepatocellular cholestasis and giant-cell transformation resolved in parallel with clinical and biochemical recovery during oral bile acid administration. In the twins, portal fibrosis stabilized at a mild level; they are well as 5-yr-olds at this writing. Follow-up biopsy in their brother at 8 mo was normal, and he is doing well at 3 yr of age. Hepatic ultrastructural alterations in all three were characterized by abnormalities of bile canaliculi including small bile plugs, diverticulae and latticelike elaborations of hepatocellular membranes adjacent to bile canaliculi that were shown to have resolved completely on subsequent biopsies. Eight additional cases have been detected on urine screening; only two of these patients have survived, on bile acid therapy. Early diagnosis and treatment improves the prognosis of this otherwise lethal inborn error of bile acid synthesis.""",1
9049,8227497,The rise of serum aminotransferases in a patient treated with bupropion,,1
9050,8229232,Comparison of methods for identifying early methotrexate-induced hepatotoxicity in patients with rheumatoid arthritis,"Hepatotoxicity may complicate therapy with methotrexate in patients with rheumatoid arthritis. Prevention of cirrhosis may depend upon early identification of liver damage, usually accomplished by serial biopsy. To determine the adequacy of noninvasive methods for identifying hepatotoxicity, 22 sets of data were obtained in patients undergoing therapy with methotrexate for rheumatoid arthritis. Comparisons were made between liver biopsy, hepatocellular enzymes and two noninvasive radioisotopic methods that have been shown to be abnormal in hepatocellular disease: the rate constant of excretion of the 14C-aminopyrine and the time from injection to peak hepatic activity of 99mTc-diisopropylimidodiacetic acid. The hepatocellular enzymes and the time-to-peak-activity of diisopropylimidodiacetic acid were not useful predictors of methotrexate-induced hepatotoxicity. The aminopyrine breath test was abnormal in approximately half the patients with hepatotoxicity but showed poor specificity. Noninvasive methods remain inferior to biopsy for the detection of mild to moderate methotrexate-induced hepatotoxicity in patients with rheumatoid arthritis.",1
9051,8232701,Phenprocoumon-induced liver failure,,1
9052,8235718,Intrahepatic cholestasis of pregnancy: an estrogen-related disease,"In the recent years new avenues have been opened in the treatment of ICP, a complex disorder that seems to represent a maladaptation of some young and otherwise healthy women, to estrogens or other sex hormones. New drugs have been shown capable of providing promising therapeutic effects either on pruritus, the main distressing symptoms of cholestasis (such as epomediol, silymarin) or both on pruritus and some biochemical abnormalities (such as UDCA). Future clinical and experimental studies should provide better insight into the pathogenesis of cholestasis, the mechanisms of bile formation and secretion, and the metabolism of estrogens and other sex hormones and their alteration relationship to cholestasis, a disorder that is highly prevalent in humans.",1
9053,8240157,Cyclophosphamide related hepatotoxicity,,1
9054,8243938,[Fatal fulminant hepatitis induced by nilutamide (Anandron)],"The first case of fatal fulminant hepatitis probably caused by nilutamide, a non steroidal antiandrogen derivative, is reported. Nilutamide administration had been continued for 6 days after the occurrence of jaundice, 52 days after beginning of treatment. The rapidly fatal outcome might have been promoted by coadministration of phenobarbital.",1
9055,8246027,Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy,"PURPOSE: To determine the frequency and nature of hepatic toxicity associated with fluorouracil (5-FU) plus levamisole adjuvant therapy. PATIENTS AND METHODS: All patients had resection of stage II or stage III colon cancer and were randomized to receive observation only, levamisole alone, or 5-FU plus levamisole. Serial liver function studies were documented in 1,025 patients who did not develop recurrence during the year of therapy. RESULTS: One hundred forty-nine (39.6%) of 376 patients treated with 5-FU plus levamisole showed laboratory abnormalities consistent with hepatic toxicity, compared with 16.3% of 251 patients treated with levamisole alone and 16.1% of 398 untreated controls. Most common was elevation of alkaline phosphatase, frequently accompanied by elevations of transaminase or serum bilirubin. Characteristically, these changes were mild, not associated with symptoms, and resolved when therapy was stopped. In some instances, they were associated with elevated carcinoembryonic antigen (CEA) tests or with fatty liver seen on computed tomographic (CT) scan or liver biopsy. CONCLUSION: Mild and reversible hepatotoxicity is a common consequence of 5-FU plus levamisole adjuvant therapy, but this is only rarely symptomatic. However, the oncologist should be alert to this phenomenon, since the associated laboratory and imaging findings may simulate those associated with hepatic metastasis.",1
9056,8247912,A follow-up safety study of ciprofloxacin users,"""We followed 37,233 outpatients for 45 days after receiving a prescription for ciprofloxacin to identify any newly diagnosed, important illnesses that might have been caused by the drug. For 29 users the role of ciprofloxacin in the etiology of the illness could not be confidently ruled out (7.79/10,000 persons; 95% CI 5.42-11.18). In only seven was a causal relation to ciprofloxacin considered likely: three skin reactions and one case each of thrombocytopenia, """"headache, nausea, and shakes,"""" hallucinations, and palpitations. No fatal illnesses occurred, and all patients recovered after discontinuing the drug. In addition, few cases of photosensitivity were associated with the agent. We conclude that important adverse reactions attributable to ciprofloxacin are uncommon.""",1
9057,8251685,Endstage liver disease associated with nitrofurantoin requiring liver transplantation,"OBJECTIVE: To report the apparent development of endstage liver disease secondary to nitrofurantoin administration. PATIENT: A 40-year-old woman developed hepatic failure after receiving nitrofurantoin 200 mg po bid for one month for prophylaxis against urinary-tract infections. Symptoms first occurred after two weeks of nitrofurantoin therapy. Other causes of hepatic failure (e.g., viral infection, autoimmune disorder, concomitant medications, cancer, Wilson's disease, ethanol abuse, pregnancy) were ruled out. CONCLUSIONS: Acute and chronic hepatic injury has previously been reported with the use of nitrofurantoin. The proposed mechanism may be immunoallergic or metabolic in origin. On evaluating concomitant diseases and medications in our patient as well as the temporal sequence of her signs and symptoms, it appears that she developed hepatic failure secondary to the use of nitrofurantoin, ultimately necessitating orthotopic liver transplantation. The potential for the development of such a severe adverse reaction warrants careful evaluation of symptoms that may potentially be caused by hepatic damage as well as immediate discontinuation of nitrofurantoin in patients presenting with jaundice.",1
9058,8253329,[Chronic active cirrhogenic hepatitis induced by fenofibrate],,1
9059,8254467,"Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. The Multicenter Study Group","A total of 334 HIV-infected patients with oral candidiasis were randomly assigned to receive 14 days of treatment with either 100 mg of oral fluconazole once daily or 10 mg clotrimazole five times daily. Both treatments were clinically effective: 98% of evaluable fluconazole-treated patients and 94% of evaluable clotrimazole-treated patients were cured or showed improvement (p = NS). Fluconazole was more effective than clotrimazole in eradicating Candida from the oral flora by the end of therapy (65% versus 48%) (p = 0.005). In addition, patients in the fluconazole-treated group were more likely to remain asymptomatic through the second week of follow-up (82.3% versus 50.0%) (p < 0.001). This difference was no longer evident by the post-therapy visit during week 4. Seven patients treated with clotrimazole and two patients treated with fluconazole discontinued therapy because of side effects. Two patients in the fluconazole group were withdrawn from therapy because of elevated serum glutamic-oxaloacetic transaminase levels, one considered possibly related to drug therapy. Fluconazole was as effective as clotrimazole in the treatment of oral candidiasis and temporarily provided a more prolonged disease-free state. Future studies are needed to define the optimal regimen for both the treatment and prevention of recurrent oral candidiasis in HIV-infected patients, addressing special attention to the issue of compliance, cost, and emergence of resistance.",1
9060,8256699,Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris,"The efficacy and safety of extended-release isosorbide mononitrate tablets were evaluated in patients with stable effort angina. In a double-blind study, 313 patients with stable effort-induced angina were randomized to receive placebo or extended-release isosorbide mononitrate: 30, 60, 120 or 240 mg once daily in the morning. Serial exercise testing was performed using the standard Bruce treadmill protocol on days 1, 7, 14, 28 and 42 immediately before morning drug administration, and 4 and 12 hours after administration. After initial dosing, all groups that received extended-release isosorbide mononitrate had significant (p < 0.01) increases in mean total exercise time of approximately 30 to 50 seconds in relation to placebo 4 and 12 hours after administration. On day 42, mean changes from baseline in total exercise time of patients who received 120 or 240 mg of extended-release isosorbide mononitrate exceeded placebo by approximately 50 to 60 seconds 4 hours after dosing (p < 0.01), and by 30 to 35 seconds 12 hours after dosing (p < or = 0.05). No significant difference was detected between responses to extended-release isosorbide mononitrate and placebo 24 hours after administration (i.e., immediately before the next dose). Thus, there was neither significant activity nor demonstrable rebound of effort-induced angina (zero-hour effect) at the end of the dosing interval. Transient headache was the most prevalent adverse experience. Extended-release isosorbide mononitrate (120 and 240 mg administered orally once daily) significantly prolonged exercise time to development of moderate effort-induced angina 4 and 12 hours after dosing during long-term therapy, without development of nitrate tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)",1
9061,8261063,Hepatotoxicity due to verapamil hydrochloride,,1
9062,8265236,Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy,The histological appearances of liver biopsies of 13 patients who developed cholestasis following courses of flucloxacillin are presented. In most of the cases jaundice and pruritus were protracted and in nearly all cases liver function tests are yet to return to normal after mean follow-up of 18 mths. One patient died after 7 mths of jaundice and another shows clinical evidence of secondary biliary cirrhosis. Biopsies typically showed hepatocellular and canalicular bile stasis with minimal or no hepatitis. Mild portal fibrosis and a patchy portal lymphocytic infiltrate were usually present. In 4 cases bile ducts were reduced in number and in 6 cases reduced in size. Bile duct epithelium showed degenerative changes but only occasional infiltration by inflammatory cells. Ductular proliferation was quite variable and in some cases--most noticeably the fatal case--was inconspicuous despite depletion of bile ducts. The appearances suggested damage not only of hepatocytes but also of bile ducts and proliferating ductules. This may explain the prolonged and occasionally irreversible hepatic disease associated with the use of flucloxacillin. Flucloxacillin should be included amongst the causes of vanishing bile duct syndrome.,1
9063,8268277,The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs,"We conducted a nested case-control study to estimate and compare the relative risks for hospitalizations for newly diagnosed acute liver injury associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) and other hepatotoxic drugs and their interaction. The source population comprised 228,392 members of the Saskatchewan Health Plan from 1982 to 1986. We used hospital records and the databases of the Department of Health. Thirty-four cases with confirmed liver injury were hospitalized. We randomly selected 500 controls from the source population. Crude risks ranged from 1 case per 100,000 prescriptions in current users of methyldopa, ampicillin, or NSAIDs to 14 cases per 100,000 prescriptions in current users of erythromycin estolate. The age-adjusted odds ratios for current users of NSAIDs was 1.8 [95% confidence interval (CI) = 0.8-3.7] and for other hepatotoxic drugs 5.9 (95% CI = 2.8-12.4). The adjusted relative excess risk due to the interaction between current exposure to both categories of drugs was 3.6, accounting for 31% of the cases of acute liver injury among those with exposure to both types of drugs. We conclude that the risk of hospitalization for acute noninfectious liver injury is different among users of various individual potentially hepatotoxic drugs. Concomitant current exposure to two or more drugs increases this risk above what would merely be expected from the sum of the individual risks.",1
9064,8276346,Hepatic venular stenosis after orthotopic liver transplantation,"""Fibrous stenosis of hepatic venules and other features of venous outflow obstruction, including zone 3 congestion and hemorrhage, are sometimes seen after orthotopic liver transplantation. similar changes associated with endothelial damage have recently been ascribed to azathioprine toxicity and may be forerunners of chronic rejection. Other potential causative agents such as viral hepatitis have yet to be considered. We reviewed 49 liver biopsy specimens from 21 consecutive patients after orthotopic liver transplantation, in whom full data including further follow-up biopsy samples were available. Hepatic venous stenosis was identified in seven patients who had received azathioprine and two additional patients in whom this change could not be ascribed to azathioprine. Stenosis was always associated with zone 3 hemorrhage and congestion and was first noted between 5 and 30 days after transplantation in all but two cases; in these two patients they were first noted after 72 and 133 days. Cellular rejection, including endotheliitis involving terminal hepatic venules, was found in five of the seven patients who had received azathioprine. Chronic (ductopenic) rejection was not seen during a follow-up period of between 97 and 540 days. In three of the nine patients with hepatic venular stenosis, zone 3 changes persisted, and in two of these azathioprine could not be held responsible. Of the 12 patients without hepatic venular stenosis, 10 had received azathioprine. Two of these 12 patients had peliosis-like foci but no other vascular abnormalities. Both also had moderate cellular rejection. Hepatic venular stenosis was found in 43% of patients after liver transplantation; this was usually associated with azathioprine administration and concomitant cellular rejection.(ABSTRACT TRUNCATED AT 250 WORDS)""",1
9065,8279152,Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis,"Isoniazid chemoprophylaxis has long been known to be a highly effective means of preventing silent tuberculous infections from spreading to active disease. There has been much controversy, however, about the risk it carries for fatal hepatotoxicity. In this article I review the rate of fatal isoniazid-induced hepatitis during chemoprophylaxis that is done according to current monitoring guidelines. Information was obtained from a MEDLINE literature search and a survey of tuberculosis control officers in large metropolitan areas throughout the country. Data were included of patients who were monitored according to the American Thoracic Society's guidelines or who were treated after 1983 when the guidelines were published. The pooled results of the published studies showed no hepatotoxic deaths in 20,212 patients in whom prophylaxis was started. The unpublished data showed 2 deaths in 182,285 patients, for a combined rate of 0.001% (2 of 202,497). The death rate for those older than 35 years was estimated to be 0.002% (1 of 43,334). This rate is significantly lower than was previously estimated and should be used to reevaluate the benefit of preventive therapy for tuberculin-reactive patients older than 35. The risk of fatal isoniazid-induced hepatitis is negligible for all ages when patients are routinely monitored for liver toxicity.",1
9066,8280426,Patterns of multiple-drug hypersensitivities in HIV-infected patients,,1
9067,8286822,Enalapril-induced hepatotoxicity,,1
9068,8288093,[Acute hepatic involvement during ingestion of acitretin],,1
9069,8290850,[Fatal sub-fulminant hepatitis due to diclofenac],,1
9070,8297198,Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors,"BACKGROUND: Hospitalizations for acute liver injury in the absence of a viral infection or any other well-defined pathologic finding that could have caused it is rare. In this study, we included both outpatients and hospitalized patients with acute liver injury to estimate the risk of clinically important acute liver injury associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to study the role of certain risk factors. METHODS: This was a retrospective cohort study with secondary case-control analysis. The study included 536 general practitioners' practices in England and Wales for the period October 1987 through August 1991. A total of 625,307 persons who received more than 2 million prescriptions for one of 12 NSAIDs were followed up to estimate the risk of newly diagnosed acute liver injury. RESULTS: There were 23 cases of acute liver injury. The incidence of acute liver injury was 3.7 per 100,000 NSAID users or 1.1 per 100,000 NSAID prescriptions. None of the cases had a fatal outcome. Sulindac was the only NSAID with a substantially greater risk than that for the overall NSAID group. Users of NSAIDs who had rheumatoid arthritis had a 10-fold increased risk of acute liver injury compared with NSAID-treated patients with osteoarthritis. Concomitant exposure to other hepatotoxic medications also increased the risk. Transient minor increases in liver test values were not a useful predictor of diagnosed NSAID-associated acute liver injury. CONCLUSIONS: Although NSAIDs have been found to be associated with acute liver injury in a small number of persons, the risk is sufficiently small as to be of minimal concern for most NSAIDs.",1
9071,8297290,Acute hepatitis induced by ingestion of the herbal medication chaparral,,1
9072,8299912,Hepatotoxicity of germander in mice,BACKGROUND/AIMS: An epidemic of hepatitis due to germander teas or capsules recently occurred in France. The aim of the present study was to show the hepatotoxicity of germander and determine its mechanism in mice. METHODS: A germander tea lyophilisate and a fraction that isolated and concentrated 10-fold the furano neo-clerodane diterpenoids of the lyophilisate were prepared. RESULTS: (1) Intragastric administration of the lyophilisate (1.25 g/kg) or the furano neo-clerodane diterpenoid fraction (0.125 mg/kg) produced similar midzonal liver cell necrosis at 24 hours in mice. (2) Toxicity was prevented by pretreatment with a single dose of troleandomycin (a specific inhibitor of cytochromes P4503A) and enhanced by pretreatment with dexamethasone or clotrimazole (two inducers of cytochromes P4503A). (3) Toxicity was attenuated by pretreatment with butylated hydroxyanisole or clofibrate (two inducers of microsomal epoxide hydrolase) and markedly increased by phorone-induced glutathione depletion. CONCLUSIONS: We conclude that germander constituents (probably its furano neo-clerodane diterpenoids) are transformed by cytochromes P450 (particularly P4503A) into hepatotoxic metabolites. The metabolites (probably epoxides) are partly inactivated by glutathione and probably epoxide hydrolase.,1
9073,8308218,Fulminant hepatic failure after methotrexate and PUVA therapy for psoriasis,"Acute hepatic failure developed after 8-methoxypsoralen and ultraviolet irradiation for psoriasis in a patient with prior methotrexate-induced cirrhosis. Review of the literature and the temporal relationship between 8-methoxypsoralen and hepatic injury in our patient suggests it may be a direct hepatotoxin. In our report, submassive necrosis superimposed on cirrhosis appears to have produced hepatic failure.",1
9074,8309029,A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients,"""OBJECTIVE: To compare escalating doses of immediate-release (IR) and sustained-release (SR) niacin for effectiveness in reducing levels of low-density lipoprotein cholesterol and triglycerides and increasing levels of high-density lipoprotein cholesterol, and for the occurrence of adverse reactions, especially hepatotoxicity. DESIGN: Randomized, double-blind, parallel comparison of IR and SR niacin administered sequentially at 500, 1000, 1500, 2000, and 3000 mg/d, each for 6 weeks. SETTING: Cholesterol research center. PATIENTS: Forty-six adults, 23 in each group, with low-density lipoprotein cholesterol levels greater than 4.14 mmol/L (160 mg/dL) after 1 month of a step 1 National Cholesterol Education Program diet. OUTCOME MEASURES: Fourteen-hour fasting lipid and lipoprotein cholesterol levels, results of clinical laboratory tests, a symptom questionnaire, and withdrawal rates. RESULTS: The SR niacin lowered low-density lipoprotein cholesterol levels significantly more than IR niacin did at the dosage of 1500 mg/d and above, while IR niacin increased high-density lipoprotein cholesterol levels significantly more than SR niacin did at all dosage levels. The reduction in triglyceride levels was similar with IR and SR niacin. Nine (39%) of the 23 patients assigned to the IR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were vasodilatory symptoms, fatigue, and acanthosis nigricans. Eighteen (78%) of the 23 patients assigned to the SR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were gastrointestinal tract symptoms, fatigue, and increases in levels of liver aminotransferases, often with symptoms of hepatic dysfunction. None of the patients taking IR niacin developed hepatotoxic effects, while 12 (52%) of the 23 patients taking SR niacin did. CONCLUSION: The SR form of niacin is hepatotoxic and should be restricted from use. The IR niacin is preferred for the management of hypercholesterolemia but can also cause significant adverse effects and should be given only to patients who can be carefully monitored by experienced health professionals.""",1
9075,8315062,Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions,"The purpose of this article is to review the risk/benefit ratio of the oral antifungals: griseofulvin, ketoconazole, fluconazole, itraconazole, and terbinafine. The reported side effects of each drug have been listed with particular emphasis on the possibility of hepatic damage. All oral antifungal agents cause minor gastrointestinal upset, as well as headache and skin reactions. There is also a rare incidence of reversible hepatic damage. Although the incidence of abnormal liver function tests from oral antifungal therapy is extremely low, patients should be advised to inform their physician if any warning symptoms are noticed.",1
9076,8320810,[A case of suspected liver dysfunction induced by sevoflurane anesthesia],"We report a case of suspected liver dysfunction after general anesthesia with sevoflurane. A 30 day old male infant underwent inguinal herniorrhaphy under sevoflurane anesthesia (sevoflurane concentration: 1.3-1.5% with 50% oxygen and nitrous oxide). Two days after the operation, he developed frequent vomiting, anorexia and fever. GOT, GPT and LDH values were 242 Ku, 326 Ku and 901 Wu, respectively and peaked at 520 Ku, 709 Ku and 1000 Wu 12-16 days after the operation. Clinical symptoms and the laboratory data became normal within 2 months. The antibody titers of EB-virus, cytomegalo-virus and HA-virus were all within normal ranges and HBs antigen was negative. There were no blood transfusion or antibiotics administration before the onset, and no epidemic of hepatitis around him. His mother had no history of hepatitis during her pregnancy. Lymphocyte stimulation test for indication of sevoflurane allergy was also negative. From these evidences, toxic (not allergic) liver dysfunction due to exposure to sevoflurane was considered to be the most probable diagnosis.",1
9077,8336198,Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcemia,"PURPOSE: A randomized, double-blind, dose-ranging study of single-dose intravenous (IV) therapy with alendronate sodium (aminohydroxybutylidene bisphosphonate) was performed in patients with cancer-associated hypercalcemia. PATIENTS AND METHODS: Patients with hypercalcemia who had not received antitumor therapy in the preceding 7 days were treated with 48 hours of IV hydration. Patients with persistent hypercalcemia (albumin-corrected serum calcium concentration [CSCC] > or = 11.5 mg/dL) were randomly assigned to receive 2.5, 5, 10, or 15 mg of alendronate infused over 2 hours, or 10 mg of alendronate infused over 24 hours. Fifty-nine patients were treated and 50 patients were assessable for the dose-response relationship. RESULTS: Normalization of CSCC (< or = 10.5 mg/dL) was achieved in 22%, 82%, 75%, and 90% of assessable patients in the 2.5-, 5-, 10- (2- and 24-hour groups pooled), and 15-mg dose groups, respectively, within 8 days of therapy. Doses > or = 5 mg were significantly superior to the 2.5-mg dose level (P < .05). There was no significant difference in the minimum CSCC achieved between the 2- and 24-hour infusions of the 10-mg dose. Based on an intent-to-treat analysis of all randomized patients, the overall complete response rate was 74% for dose levels greater than 2.5 mg. For assessable patients who responded to > or = 5 mg of alendronate, the estimated median duration of normocalcemia was 10 days (range, 1 to 25). The estimated median time to relapse (CSCC > 11.5 mg/dL) was 15 days from initial treatment and 12 days from initial response, respectively. Adverse events included a transient febrile response in 34% of patients and eight episodes of reversible elevations in serum transaminase levels among treated patients. CONCLUSION: While a statistically significant dose-response relationship was not clearly evident at doses greater than 5 mg, single doses of > or = 5 mg alendronate sodium effectively lowered serum calcium concentrations and were well tolerated in the treatment of cancer-associated hypercalcemia.",1
9078,8338425,[Fulminant hepatitis with encephalopathy in acute articular rheumatism treated with acetylsalicylic acid],,1
9079,8342719,Oral contraceptives and the risk of gallbladder disease: a meta-analysis,"OBJECTIVES: This study was designed to assess the risk of gallbladder disease due to oral contraceptive use by conducting a thorough literature review. METHODS: Controlled epidemiologic studies published through March 1992 were systematically searched and evaluated. Of 25 studies (27 publications), 9 could stand the test of critical appraisal with respect to validity. Restriction to these studies was judged to circumvent publication bias at the same time. RESULTS: Oral contraceptive use is associated with a slightly and transiently increased rate of gallbladder disease. The results of six selected studies in which asymptomatic women were screened for gallstones were strikingly similar. Pooling of these results yielded an odds ratio, for ever vs never oral contraceptive use, of 1.36. A dose-effect relationship was indicated, suggesting that modern low-dose oral contraceptives are safer than older formulas, but an effect cannot be excluded. CONCLUSIONS: Considering the large efforts already devoted to this exposure-disease relationship, the probably weak effect, and the rapidly changing formulas of oral contraceptives, the authors suggest that the safety of new oral contraceptives be evaluated by studying bile saturation and biliary function rather than by waiting for gallbladder disease to develop.",1
9080,8349085,[Acute cytolytic hepatitis caused by amoxapine],,1
9081,8354979,Liver damage from low-dose oral contraceptives,"OBJECTIVE: To study whether the decrease in the content of oestrogen and gestagen in modern low-dose oral contraceptives (OC) has yielded a lower incidence of adverse liver reactions, and to describe the biochemical pattern of the adverse liver reactions from low-dose OC. DESIGN: We surveyed all liver reactions from OC reported to SADRAC (Swedish Adverse Drug Reactions Advisory Committee) from 1966 to 1989. MAIN OUTCOME MEASURE: Incidence of reported adverse liver reactions (number of reported adverse reactions/OC sales in defined daily dose [DDD]). RESULTS: There was a sharp decline in the number of reports during the studied period, suggesting changes in reporting habits. However, there was also a significantly lower incidence of reports for medium-compared to high-oestrogen dose OC, and a further decrease, albeit non-significant, in incidence with low-oestrogen dose OC. Furthermore, in three comparisons of pairs of OC that differed only in the gestagen dose, there was a strong trend towards a higher reporting rate with higher gestagen dose. Cholestatic and hepatocellular liver enzyme patterns were equally frequent in patients with adverse reactions from low-dose oestrogen OC. There was no report of liver tumours related to use of low-oestrogen dose OC. CONCLUSION: There seems to be a decrease in the incidence of adverse liver reactions related to lower contents of both oestrogen and gestagens in OC of the combined-preparation type.",1
9082,8357116,Levothyroxine therapy in patients with thyroid disease,"PURPOSE: To review the indications for and the proper monitoring of levothyroxine therapy in patients with thyroid disease. DATA SOURCES: Relevant English language articles published from 1966 to 1992 were identified through a MEDLINE search and manual searches of both identified articles and selected endocrinology texts. STUDY SELECTION: Studies, case reports, and review articles that contained data on the pathophysiologic aspects of relevant thyroid disorders and on the pharmacologic aspects of, indications for, and administration of levothyroxine therapy. DATA EXTRACTION: Data on the epidemiology, clinical manifestations, complications, and treatment of thyroid disorders were analyzed with respect to patient selection, methods, diagnostic criteria, and conclusions. These data were used to develop a rational approach to the management of such patients. RESULTS OF DATA SYNTHESIS: Levothyroxine is a reliable and commonly prescribed drug to treat thyroid disease, but excessive dosage may have adverse effects. In patients with hypothyroidism, levothyroxine is used as replacement therapy. For most patients, therapy can be initiated with a full replacement dosage (1.6 micrograms/kg body weight), which is usually 75 to 100 micrograms/day for women and 100 to 150 micrograms/d for men. The goal is to normalize the serum thyroid-stimulating hormone concentration. Levothyroxine is also used to suppress the serum thyroid-stimulating hormone concentration. A trial of thyroid-stimulating hormone suppressive therapy is indicated for most patients with benign solitary nonfunctioning thyroid nodules and for those with a history of thyroid cancer. Levothyroxine in non-thyroid-stimulating hormone-suppressive doses may also be indicated for patients with nontoxic multinodular goiter and for certain patients after lobectomy for benign thyroid nodules. CONCLUSIONS: With proper patient monitoring, levothyroxine replacement therapy should be effective, inexpensive, and free of complications. Recommendations for thyroid-stimulating hormone suppression with levothyroxine are based on risk-benefit considerations of the biologic characteristics of the thyroid disorder and the individual patient.",1
9083,8358058,Transient hyperammonemia related to chemotherapy with continuous infusion of high-dose 5-fluorouracil,"Hyperammonemic encephalopathy has been reported in patients receiving chemotherapy (CT). It is characterized by abrupt alteration in mental status with markedly elevated plasma ammonium levels in the absence of obvious liver disease. This paper reports seven patients who developed transient hyperammonemia during chemotherapy. The regimens all included continuous infusion of high-dose 5-fluorouracil (5-FU). The onset of hyperammonemic encephalopathy was 1.5-4 days after the start of CT. Five cases had infection and six had prerenal azotemia at the time of hyperammonemia. After management, plasma ammonium levels all returned to the normal range within 2 days. Except for one persistent coma, status of consciousness cleared completely. The true mechanism of transient hyperammonemia is unclear. The excess production of ammonium due to metabolites of 5-FU added to precipitating factors such as infection, hypovolemia or constipation may be the explanation for transient hyperammonemia in our study.",1
9084,8361861,Liver disorders in patients receiving chlorpromazine or isoniazid,"Based on information derived from computers and clinical records obtained from general practitioners in the United Kingdom, we estimated the frequency of liver toxicity associated with two known hepatotoxins, chlorpromazine and isoniazid. Among the cohort of 10,502 users of chlorpromazine, 14 had illnesses compatible with drug-induced liver disease, a frequency of 1.3/1000 users (95% Cl 0.8, 2.2). Four presumed cases of the disorder occurred among 921 users of isoniazid, for a frequency of 4/1000 users (95% Cl 1.7, 11.1). This study provides population-based quantification of the frequency of liver disorders associated with the use of these two agents.",1
9085,8368468,Anaphylactic reaction to ranitidine,Ranitidine is a well-tolerated H2-receptor antagonist with a furan ring as nucleus. Anaphylactic reactions are seldom reported despite the wide use of the drug. We report a patient who presented an anaphylactic reaction with ranitidine (Zantac). The positive skin prick test and oral challenge suggest type I hypersensitivity. Specific IgE determination by RAST technique and histamine release test with ranitidine were negative. The patient did not react to other H2-receptor antagonists or to another furan-derivative (nitrofurantoin).,1
9086,8374097,Portal vein thrombosis associated with prolonged ingestion of oral contraceptive steroids,"The case is described of a 38 year old woman who developed severe right upper quadrant abdominal pain that was associated with partial portal vein occlusion, as confirmed by flow Doppler ultrasonography and dynamic contrast computed tomography. The patient was a cigarette smoker and had taken combined oestrogen/progestagen oral contraceptive steroids (OCS) continuously for 24 years. There were no other risk factors for portal vein thrombosis or for thromboembolic disease. Following anticoagulant therapy and discontinuation of OCS complete recovery occurred. The case is reported to draw attention to portal vein thrombosis as an extremely rare complication of OCS.",1
9087,8377697,Norfloxacin-induced hepatitis,,1
9088,8380490,[Liver damage during administration of itraconazole (Trisporal)],"Three case histories are described of patients, two women aged 62 and 57 and a man aged 75 years, who developed symptomatic hepatic injury five to six weeks after starting itraconazole treatment. In two of them the biochemical pattern of liver injury was cholestatic. Other causes of hepatic injury were excluded. Monitoring serum liver enzymes is advisable in patients treated with itraconazole for one month or longer.",1
9089,8382515,Female hormone utilisation and risk of hepatocellular carcinoma,"The relationship between female hormone use and primary liver cancer was analysed using data from a case-control study conducted between 1984 and 1992 in Milan on 82 female incident cases with histologically or serologically confirmed hepatocellular carcinoma and 368 controls admitted to hospital for acute non-neoplastic, non-hormone-related diseases. An elevated relative risk (RR) or primary liver cancer was observed in oral contraceptive (OC) users (RR 2.6, for ever versus never users, 95% confidence interval, CI 1.0-7.0). The RR was directly related to duration of use (RR 1.5 for < or = 5 years and 3.9 for > 5 years) and persisted for longer than 10 years after stopping use (RR 4.3%, 95% CI 1.0-18.2). The RR were below unity, although not significantly, for women ever using oestrogen replacement therapy (RR 0.2, 95% CI 0.03-1.5) and female hormones for indications other than contraception and menopausal therapy (RR 0.4, 95% CI 0.1-1.5). The long-lasting, association between risk of hepatocellular carcinoma and OC use has potential implications on a public health scale, since primary liver cancer is a relatively rare disease among young women, but much more common at older ages. This study provides limited but reassuring evidence on the possible relationship between oestrogen replacement treatment and subsequent risk of hepatocellular carcinoma.",1
9090,8383659,The efficacy and safety of piperacillin/tazobactam in the therapy of bacteraemia,"""The efficacy of the combination of piperacillin plus tazobactam was studied in 142 patients who had a bacteriologically proven bacteraemia. Seventy-three patients were bacteriologically evaluable and, of these, 55 had a follow-up blood culture; there was no follow-up culture in the other 18 patients, so that any cure could only be presumptive. Of the 55 patients who were fully followed up, 32 received only piperacillin and tazobactam and 23 also received an aminoglycoside. Overall, there were 67 cures and six failures out of 73 evaluable cases (three Staphylococcus aureus, two Staphylococcus epidermidis and one Streptococcus bovis). There were 11 deaths, eight of which occurred in neutropenic patients. In no case was death drug related. Side-effects were mild; the commonest adverse events noted were mild elevations of liver enzymes. Piperacillin plus tazobactam appeared efficacious and safe in the therapy of bacteraemia.""",1
9091,8384172,Ephedrine in the treatment of obesity,,1
9092,8385884,Hepatocellular carcinoma arising in a focus of multilobular adenoma. A case report,This report presents a case of hepatocellular carcinoma arising in a large multilobulated adenoma in the noncirrhotic liver of a 29-year-old woman. This unusual case demonstrates the potential for a benign proliferative process in the liver to evolve into a malignant neoplasm.,1
9093,8392242,Acute cholestatic hepatitis with rash and hypereosinophilia associated with ranitidine treatment,"We report a case of acute cholestatic hepatitis associated with rash and hypereosinophilia, in which the absence of transfusion, intercurrent viral infection, alcohol consumption or other hepatotoxic drugs are suggestive of ranitidine-induced hepatotoxicity. The pathogenesis of the disorder is unknown, but the lack of a dose-effect relationship, the rarity and unpredictability of the reaction, as well as the clinical signs suggest that hypersensitivity is involved. Physicians should be aware of this rare and idiosyncratic side-effect of ranitidine.",1
9094,8397892,"The current role of 2,3-dimercaptosuccinic acid (DMSA) in the management of childhood lead poisoning","2,3-Dimercaptosuccinic acid (DMSA) is an orally active chelating agent used in the treatment of lead and other heavy metal poisonings. In animals, DMSA chelates lead from soft tissues, including the brain, without clinically evident adverse effects or histopathological changes. In lead-poisoned children and adults, DMSA significantly increases urinary lead excretion, and, at least transiently, reduces the blood lead concentration. The safety profile of DMSA in both children and adults is encouraging, with few clinically apparent or biochemical adverse effects reported. However, clinical experience with DMSA is limited, and is not sufficient to exclude the possibility that other more serious drug-related adverse events including hypersensitivity or idiosyncratic reactions may occur. No data currently exist to determine whether drug-enhanced lead excretion with DMSA (or any other chelating agent) is beneficial in reducing lead-related neurotoxicity. The efficacy of DMSA in reducing neuropsychological morbidity, and additional safety data, are key areas requiring additional study before DMSA can be clearly recommended as the chelating agent of choice for the treatment of lead-poisoned children.",1
9095,8404476,[Fulminant hepatitis caused by disulfiram],"""After undergoing withdrawal treatment for alcoholism as an in-patient for one year a 49-year-old woman was started on disulfiram, 250 mg daily, her liver function tests being normal. Except for vitamin B1 she received no further medication. Jaundice developed 13 days after onset of treatment and acute liver failure was diagnosed on the 18th day after a total disulfiram dose of 4.5 g (Quick value < 10%; bilirubin 460 mumol/l; GPT 5099 U/l; GOT 4142 U/l), as well as early renal failure (creatinine 300 mumol/l). An acute viral infection, autoimmune hepatitis and a metabolic liver disease were excluded by biochemical, serological and molecular biology tests. All toxicological tests were negative. The patient died 25 days after the onset of disulfiram treatment in hepatic coma due to a fulminant hepatitis with hepatorenal syndrome. Both a liver biopsy and the autopsy showed the signs of an acute hepatic dystrophy without cirrhosis. The temporal relationship between the disulfiram intake and onset of the illness, the exclusion of other causes of the fulminant hepatitis and the liver histology, which was compatible with a chemical-toxic hepatitis, indicate that this was a case of disulfiram-induced hepatitis. The hepatotoxicity of disulfiram is a very rare idiosyncratic reaction which is often fatal. Disulfiram administration must be discontinued at once if there is a rise in liver enzyme activity or jaundice occurs.""",1
9096,8406314,Spontaneous liver hematomas induced by anti-coagulation therapy. A case report and review of the literature,"We report on a case of massive bleeding into the liver parenchyma during treatment with a combination of warfarin sodium and trimethoprim-sulfamethoxazole. A fifty-five-year-old woman was put on long-term anticoagulant therapy with warfarin sodium. Two years later a course of trimethoprim-sulfamethoxazole was given to treat bronchitis. Following a bout of severe epigastric pain, ultrasonography and computed tomography (CT) then showed an enlarged liver containing several large hematomas. Subsequent CT scans, after tentative treatment only, showed regression of the liver hematomas, with almost complete disappearance after eight months. Bleeding complications and drug interactions related to this case are discussed, together with a review of the only six previous reports in the world literature of liver hematomas following anticoagulant therapy. Also mentioned are five patients in whom thrombolytic therapy gave rise to the same adverse reaction.",1
9097,8410125,Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia,"PURPOSE: To determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population. PATIENTS AND METHODS: In a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine. RESULTS: Severe, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in 35% of those who received 70 to 80 mg/m2 of mitoxantrone. Other extramedullary toxicity, including cardiac dysfunction, was mild. Myelosuppression was universal and the median time to complete remission (CR) was 28 days (range, 19 to 77). The CR rate for previously untreated and relapsed patients with AML was 85% (17 of 20) and 38% (seven of 18), respectively. Eighty-three percent (15 of 18) of patients with ALL achieved a CR, including all patients with previously untreated disease. Eight of 12 patients with advanced-phase CML achieved a CR. No significant changes in mean mitoxantrone plasma elimination rates (ie, terminal plasma half-life and total-body clearance rate) occurred as the mitoxantrone dose doubled, indicating linear pharmacokinetics. CONCLUSIONS: The recommended phase II dose of mitoxantrone is 80 mg/m2 administered over 15 minutes as a single intravenous infusion in combination with cytarabine 3 g/m2/d for 5 days. At this dose, high concentrations of mitoxantrone are achievable in vivo to levels that have been shown to be extremely cytotoxic in vitro.",1
9098,8418405,"Unconventional medicine in the United States. Prevalence, costs, and patterns of use","""BACKGROUND: Many people use unconventional therapies for health problems, but the extent of this use and the costs are not known. We conducted a national survey to determine the prevalence, costs, and patterns of use of unconventional therapies, such as acupuncture and chiropractic. METHODS: We limited the therapies studied to 16 commonly used interventions neither taught widely in U.S. medical schools nor generally available in U.S. hospitals. We completed telephone interviews with 1539 adults (response rate, 67 percent) in a national sample of adults 18 years of age or older in 1990. We asked respondents to report any serious or bothersome medical conditions and details of their use of conventional medical services; we then inquired about their use of unconventional therapy. RESULTS: One in three respondents (34 percent) reported using at least one unconventional therapy in the past year, and a third of these saw providers for unconventional therapy. The latter group had made an average of 19 visits to such providers during the preceding year, with an average charge per visit of $27.60. The frequency of use of unconventional therapy varied somewhat among socio-demographic groups, with the highest use reported by nonblack persons from 25 to 49 years of age who had relatively more education and higher incomes. The majority used unconventional therapy for chronic, as opposed to life-threatening, medical conditions. Among those who used unconventional therapy for serious medical conditions, the vast majority (83 percent) also sought treatment for the same condition from a medical doctor; however, 72 percent of the respondents who used unconventional therapy did not inform their medical doctor that they had done so. Extrapolation to the U.S. population suggests that in 1990 Americans made an estimated 425 million visits to providers of unconventional therapy. This number exceeds the number of visits to all U.S. primary care physicians (388 million). Expenditures associated with use of unconventional therapy in 1990 amounted to approximately $13.7 billion, three quarters of which ($10.3 billion) was paid out of pocket. This figure is comparable to the $12.8 billion spent out of pocket annually for all hospitalizations in the United States. CONCLUSIONS: The frequency of use of unconventional therapy in the United States is far higher than previously reported. Medical doctors should ask about their patients' use of unconventional therapy whenever they obtain a medical history.""",1
9099,8419773,Hepatotoxicity due to erythromycin ethylsuccinate,,1
9100,8420443,Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients,"""OBJECTIVE: To determine the incidence and clinical course of veno-occlusive disease of the liver (VOD) after bone marrow transplantation and to analyze risk factors for severe VOD. DESIGN: Cohort study of 355 consecutive patients. SETTING: A bone marrow transplantation center. MEASUREMENTS: Each patient was prospectively evaluated for VOD, and many risk factors for severe VOD were analyzed using logistic regression models. The relation of VOD to renal and cardiopulmonary failure was analyzed using time-dependent proportional hazards models. RESULTS: Veno-occlusive disease developed in 190 of 355 patients (54%; 95% CI, 48% to 59%): Fifty-four patients had severe VOD and 136 had mild or moderate VOD. Independent variables derived from a multivariate model for predicting severe VOD included elevated transaminase values before transplantation (relative risk, 4.6; P < 0.0001); vancomycin therapy during cytoreductive therapy (relative risk, 2.9; P = 0.003); cytoreductive therapy with a high-dose regimen (relative risk, 2.8; P = 0.01); acyclovir therapy before transplantation (relative risk, 4.8; P = 0.02); mismatched or unrelated donor marrow (relative risk, 2.4; P = 0.02); and previous radiation therapy to the abdomen (relative risk, 2.2; P = 0.04). Vancomycin therapy was a marker for persistent fever. Multiorgan failure was more frequent among patients with VOD and usually followed the onset of liver disease. CONCLUSIONS: Veno-occlusive disease, which developed in 54% of bone marrow transplant recipients, is frequently associated with renal and cardiopulmonary failure. Pretransplant transaminase elevations, use of high-dose cytoreductive therapy, and persistent fever during cytoreductive therapy are independent predictors of severe VOD.""",1
9101,8425685,Oral mesalamine (Pentasa) as maintenance treatment in Crohn's disease: a multicenter placebo-controlled study. The Groupe d'Etudes Th?rapeutiques des Affections Inflammatoires Digestives (GETAID),"""BACKGROUND: Mesalamine provides a new therapeutic approach in treating Crohn's disease. METHODS: To assess the efficacy and safety of slow-release mesalamine (Pentasa; Ferring AS, Vanl�se, Denmark) in maintaining remission in Crohn's disease, 161 patients with inactive disease were randomized to receive either Pentasa (2 g/day) or placebo in a 2-year double-blind, multicenter trial. Two strata were defined according to the duration of their remission: < 3 months (n = 64) or 3-24 months (n = 97), presumed to be high and a low relapse risk strata, respectively. RESULTS: The probability of relapse was higher in the short-remission placebo group than in the three other groups (P < 0.003), showing there was a significant benefit from Pentasa in the high relapse risk stratum. In this stratum, the 2-year ongoing remission rate was of 29% +/- 9% and 45% +/- 11% (mean +/- SD) in the placebo and Pentasa groups, respectively. The incidences of side effects were similar in both groups. CONCLUSIONS: Pentasa (2 g/day for 2 years) is a safe and effective maintenance treatment for Crohn's disease when given within 3 months of achieving remission.""",1
9102,8425713,Ursodeoxycholic acid treatment of intrahepatic cholestasis of pregnancy: observations on efficacy and safety,,1
9103,8426212,Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer,"""PURPOSE: To explore further the efficacy of high-dose toremifene in patients with advanced breast cancer who had failed to respond to tamoxifen or whose disease had progressed on tamoxifen. PATIENTS AND METHODS: One hundred two perimenopausal or postmenopausal women with metastatic breast cancer refractory to tamoxifen were entered onto a phase II clinical trial of toremifene at a dose of 200 mg/d. The study patients consisted of 28 primarily refractory patients; 43 patients who had relapsed after a prior tamoxifen response; and 31 patients who had relapsed while receiving adjuvant tamoxifen. This was a heavily pretreated group of patients, with 65% having failed chemotherapeutic attempts and 72% having failed two or more hormonal therapies. Forty-nine percent of patients had visceral dominant disease. RESULTS: The objective response rate was 5% (95% confidence interval [CI], 3% to 7%). The median time to treatment failure (TTF) was 10.9 months for the five responders. An additional 23% of patients had stable disease for a median TTF of 7.8 months, whereas the patients who experienced treatment failure had a median TTF of 2.1 months. Whether those patients with stable disease derived clinical benefit or simply had slow progression in an intrinsically indolent disease presentation is uncertain. Common toxicities were generally mild and similar to those encountered with tamoxifen. CONCLUSION: We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.""",1
9104,8429113,Nisoldipine: a new dihydropyridine calcium-channel blocker,"Nisoldipine is a new calcium-channel blocker of the dihydropyridine subclass, with a chemical structure similar to nifedipine. It has been used in clinical trials to assess its efficacy and safety in patients with hypertension, angina pectoris, and congestive heart failure. Similar to other dihydropyridines, nisoldipine is a potent peripheral and coronary dilator. The most optimal dosage regimen has not been established in clinical trials. The drug appears to have a favorable side-effect profile.",1
9105,8432484,Effect of octreotide on gall stone prevalence and gall bladder motility in acromegaly,"Octreotide therapy in acromegaly is associated with an increased prevalence of gall stones, which may be the result of an inhibition of gall bladder motility. Gall stone prevalence in untreated acromegalic patients relative to the general population is unknown, however, and the presence of gall stones and gall bladder motility in these patients and in acromegalic patients receiving octreotide was therefore examined. Thirty four percent of 39 patients who had taken octreotide for a mean of 20 months had gall stones compared with 16% of 38 patients who had not been treated with octreotide (p < 0.005). In a subgroup of 21 patients studied prospectively over 4 to 18 months, two patients developed stones. No patient had symptoms referrable to their gall stones. In 31 untreated acromegalic patients, the mean fasting gall bladder volume was similar to that in normal subjects. Maximal percentage emptying, however, was impaired (34 v 64%, p < 0.001) and the mean postprandial residual gall bladder volume increased (21.7 v 9.0 ml, p < 0.001). Treatment with octreotide increased the mean postprandial residual volume further to 36.8 ml (p < 0.001). Gall bladder emptying in untreated acromegalic subjects is impaired. Octreotide further increases postprandial residual gall bladder volume and this may be a factor in the increased gall stone prevalence seen in these patients.",1
9106,8435326,Acquired sideroblastic anaemia during treatment of Wilson's disease with triethylene tetramine dihydrochloride,"We report one case of acquired sideroblastic anaemia in a patient treated for Wilson's disease with triethylene tetramine dihydrochloride (TTH). No other cause of acquired sideroblastic anaemia was found, and neither iron nor pyridoxine therapy could correct this anaemia. In contrast, decreasing the dose of TTH led to disappearance of ringed sideroblasts. Thus TTH should be added as a further cause of secondary acquired sideroblastic anaemia. The pathophysiology of this finding, probably linked to an abnormality of mitochondrial iron metabolism, is briefly discussed.",1
9107,8436346,Amiodarone-associated cirrhosis with hepatic and lymph node granulomas,,1
9108,8438828,Meprobamate dependence secondary to carisoprodol (Soma) use,,1
9109,8439116,Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism. A cohort study,"""OBJECTIVE: To evaluate the incidence, severity, and course of propylthiouracil-induced hepatic injury in patients with hyperthyroidism. DESIGN: Cohort study. SETTING: Outpatient clinic of a university-based hospital. PATIENTS: Fifty-four patients with normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values and a definite diagnosis of hyperthyroidism. INTERVENTION: Treatment with propylthiouracil, 300 mg/d for 2 months followed by 100 to 150 mg/d for 3 months and a subsequent maintenance dose of 100 mg/d. MEASUREMENTS: Liver biochemical tests were studied before therapy and 2 months and 5 months after starting propylthiouracil therapy. The patients were monitored with clinical evaluation and weekly liver biochemical tests after AST or ALT levels became abnormal. Serologic markers of hepatitis A, B, C, and delta virus infection were also studied when appropriate. RESULTS: Fifteen (28%; 95% CI, 16% to 42%) of the 54 patients showed ALT elevations 2 months after propylthiouracil therapy. The mean peak ALT level for these patients was 1.35 mu kat/L (range, 0.65 3.85 mu kat/L). None of these patients had symptoms or hyperbilirubinemia. Liver biopsy in three patients showed mild perivenular focal necrosis or ill-defined granuloma composed of foamy histiocytes with ceroid pigment and mild fatty metamorphosis. Despite continued propylthiouracil therapy at a reduced dose, ALT levels returned to normal in 13 of 15 patients in the following 3 months. None of these ALT elevations resulted from hepatitis A, B, C, or delta virus infection. No statistical difference was seen in the pretreatment characteristics between patients with and those without ALT elevation, except that the former had a higher pretreatment T4 level (270 +/- 12.9 compared with 237 +/- 7.72 nmol/L, P = 0.027) and T3 level (7.22 +/- 0.72 compared with 5.85 +/- 0.39 nmol/L, P = 0.048). CONCLUSIONS: Propylthiouracil-induced subclinical liver injury is common and is usually transient and asymptomatic. Therapy with propylthiouracil may be continued with caution in the absence of symptoms and hyperbilirubinemia.""",1
9110,8443520,Risk factors for development of flucloxacillin associated jaundice,"OBJECTIVES: To identify risk factors predisposing to the development of flucloxacillin associated jaundice. DESIGN: Case-control study. Medical records of cases and controls were reviewed and information recorded on standard data collection forms. SETTING: Alfred Hospital recruiting subjects from Melbourne, Sydney, and Brisbane. SUBJECTS: Cases were defined as patients who had developed jaundice within eight weeks of stopping flucloxacillin, biochemical test results suggesting cholestasis, normal calibre bile ducts, and not been taking recognised hepatotoxic drugs. 51 of the 53 patients referred were included in the study. Four controls for each case were randomly selected from the patient register of the prescribing doctor. These were defined as patients who had been prescribed flucloxacillin without developing jaundice. MAIN OUTCOME MEASURES: Demographic characteristics, medical history, indication for flucloxacillin, dose, route and duration of treatment, other drugs, smoking, and previous drug allergies or use of flucloxacillin. RESULTS: Increasing age and a prolonged duration of flucloxacillin treatment were found to be risk factors for the development of jaundice. Patients aged over 55 years had an odds ratio of 18.61 (95% confidence interval 5.16-67.17) compared with patients under 30. The odds ratio for patients prescribed flucloxacillin for over 14 days was 7.13 (2.90 to 17.58) compared with patients treated for 14 days or less. Dose and route of administration were not related to the risk of jaundice. CONCLUSIONS: Older patients and those receiving flucloxacillin for longer than two weeks are at a substantially greater risk of jaundice. Careful consideration of the risk-benefit ratio is required when flucloxacillin is used in these settings.",1
9111,8452577,Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis,"OBJECTIVE: To assess the risk of serious liver disease in patients with rheumatoid arthritis (RA) taking methotrexate (MTX). METHODS: We surveyed members of the American College of Rheumatology to determine previous use of MTX in the treatment of rheumatoid arthritis and to identify cases of cirrhosis and liver failure. Cases were confirmed by review of pathology specimens, findings from diagnostic testing, and clinical presentations. A case-control study was then conducted to ascertain prognostic factors. Case and control medical records were reviewed for information on MTX therapy as well as other possible determinants of serious liver disease. RESULTS: Twenty-four cases of cirrhosis and liver failure were identified, giving a 5-year cumulative incidence of approximately 1/1,000 treated patients. Six of the 24 patients had died: 4 died of the initial liver disease, 1 of hepatic complications of another illness, and 1 of unrelated causes. Two patients continue to have active liver disease. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease. CONCLUSION: Serious liver disease is an uncommon, age- and dose-related complication of low-dose MTX therapy for RA.",1
9112,8453944,Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity,"Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4-ene-VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA-associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA-associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the inter-individual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA beta-oxidation and increase of metabolites of alternative metabolic pathways (omega- and omega 1-hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2-n-propyl-4-pentenoic acid metabolite of VPA (4-ene-VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life-threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as-yet-unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.",1
9113,8456759,A multicenter comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia. The Lovastatin Pravastatin Study Group,"""A randomized, controlled, double-blind trial in 672 hypercholesterolemic patients evaluated the efficacy and safety profile of lovastatin and pravastatin across their usually recommended dosage ranges (lovastatin 20 to 80 mg/day and pravastatin 10 to 40 mg/day). After a 7-week placebo and diet run-in period, patients with low-density lipoprotein (LDL) cholesterol > 160 mg/dl (4.1 mmol/liter) were randomized to 20 mg/day of lovastatin, or 10 mg/day of pravastatin for 6 weeks. The doses were then increased to 40 and 80 mg/day of lovastatin, and 20 and 40 mg/day of pravastatin at weeks 6 and 12, respectively. Efficacy and safety evaluations were performed at weeks 6, 12 and 18. The mean percent changes from baseline in LDL cholesterol at weeks 6, 12 and 18 were -28, -33 and -39%, respectively, with lovastatin, and -19, -25 and -27%, respectively, with pravastatin. All changes were significantly different from 0 (p < 0.001), and the between-group differences were highly significant (p < 0.001). The frequency of adverse events leading to discontinuation was low (2.9% with lovastatin, and 2.4% with pravastatin), with no significant differences between groups. Across the recommended dosage ranges, lovastatin was more effective than pravastatin in reducing total and LDL cholesterol; however, both agents had similar safety profiles.""",1
9114,8462373,Phenytoin-induced chronic hepatitis,"Phenytoin has been associated with acute hepatotoxicity. Chronic liver enzyme abnormalities associated with phenytoin have been attributed to enzyme induction. There have been no reports of phenytoin-induced chronic hepatitis. We describe an asymptomatic 52-year-old woman who received phenytoin sodium for 11 years and was found to have elevated serum aminotransferases. Assays for hepatitis A, B, and C were negative. Liver biopsy was performed and showed chronic persistent hepatitis. This documentation of phenytoin-induced chronic persistent hepatitis was proven by histology and its etiology confirmed by drug withdrawal and by rechallenge. Although uncommon, this entity is important to recognize in the differential diagnosis of asymptomatic chronic hepatic enzyme dysfunction.",1
9115,8463863,Chromium in human nutrition: a review,"""This review summarizes the results of 15 controlled studies supplementing defined Cr(III) compounds to subjects with impaired glucose tolerance. Three of these (3-4 mumol Cr/d for > 2 mo) produced no beneficial effects: serum glucose, insulin and lipid concentrations remained unchanged. The remaining 12 interventions improved the efficiency of insulin or the blood lipid profile of subjects (ranging from malnourished children and healthy middle-aged individuals to insulin-requiring diabetics). In addition, three cases of impaired glucose tolerance after long-term total parenteral alimentation responding to Cr supplementation have been reported. Chromium potentiates the action of insulin in vitro and in vivo; maximal in vitro activity requires a special chemical form, termed Glucose Tolerance Factor and tentatively identified as a Cr-nicotinic acid complex. Its complete structural identification is a major challenge to chromium research. The development and validation of a procedure to diagnose chromium status is the second challenge. Such a test would allow the assessment of incidence and severity of deficiency in the population and the selection of deficiency in the population and the selection of chromium-responsive individuals. The third challenge is the definition of chromium's mode of action on parameters of lipid metabolism that have been reported from some studies but not others. Future research along these lines might establish whether chromium deficiency is a factor in the much discussed """"Syndrome X"""" of insulin resistance.""",1
9116,8470208,"Fulminant hepatic failure, hepatorenal syndrome, and necrotizing pancreatitis after minocycline hepatotoxicity",,1
9117,8470644,Acetaminophen hepatotoxicity: potentiation by isoniazid,"Potentiation of acetaminophen hepatotoxicity has previously been associated with a history of alcohol abuse. Presented here is the case of a 21-yr-old Philippino female with rapidly deteriorating hepatic functions. She had been on isoniazid, 300 mg daily, as prophylaxis against tuberculosis due to a positive tuberculin skin test. She took 3.25 g of acetaminophen for abdominal cramping and subsequently had rapid deterioration of liver function manifested by prolongation of the prothrombin time, elevated ammonia, marked elevation of transaminases, and hyperbilirubinemia. Over the course of 1 wk, these values essentially normalized and she was discharged. Isoniazid induces the cytochrome P-450 system, resulting in increased metabolism of acetaminophen, formation of toxic metabolites, depletion of glutathione stores, and subsequent hepatocellular injury. Patients on isoniazid should use caution when taking acetaminophen since the potentially hepatotoxic effects may be amplified due to induction of the cytochrome P-450 system.",1
9118,8471200,Hepatomegaly with severe steatosis in HIV-seropositive patients,"""OBJECTIVE: To describe death attributed to severe hepatomegaly and macrovesicular steatosis without inflammation or necrosis in HIV-seropositive patients without AIDS. PATIENTS: Patients from the AIDS Clinical Trials Group (ACTG) Adverse Reactions and the Food and Drug Administration's (FDA) Spontaneous Report databases. RESULTS: Six fatal and two non-fatal cases in which no known cause of hepatic steatosis could be found were identified. With one possible exception, none of the six fatal cases had a diagnosis of AIDS and all were in reasonable nutritional status (as indicated by weight and/or serum albumin); the majority were mildly to moderately overweight. All had received at least 6 months of antiretroviral therapy, and all had gastrointestinal complaints without other non-hepatic abdominal pathology. At least three out of the six had no history of progressively abnormal liver function tests until a few weeks prior to the onset of symptoms and subsequent death. Further investigation of the FDA and ACTG databases identified two similar but non-fatal cases in which abnormalities resolved after cessation of antiretroviral therapy. CONCLUSIONS: The cases described represent a degree of hepatic abnormalities that has not been reported previously in HIV-seropositive patients, and are probably an underestimate of actual incidence, since patients with possible etiologies of liver disease were excluded from the clinical history, laboratory, microbiologic, or histologic examination. The etiology of hepatic disease may be associated with antiretroviral therapy, HIV, or an unidentifiable infection, and requires further investigation.""",1
9119,8475694,Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment,"""Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 mumol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51-66%, 32-48% had a decrease, and 1-10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live-born, first trimester oxcarbazepine-exposed children.""",1
9120,8476468,Assessment of acute iron poisoning by laboratory and clinical observations,"""A survey of medical records at a tertiary children's medical center was performed to determine whether selected laboratory and clinical observations and the serum iron concentration exceeding the total iron-binding capacity serve as indicators of acute iron poisoning. Patients were hospitalized for treatment of iron poisoning during January 1976 through June 1992. A total of 128 patients were identified; 92 met selection criteria and 65 had a serum iron concentration and total iron-binding capacity obtained simultaneously. The present study was unable to confirm that vomiting, diarrhea, leukocytosis, hyperglycemia, and radiopacities were associated with a serum iron concentration in excess of 300 micrograms/dL (54 mumol/L); only one observation, coma, was associated (P < .02) with a serum iron greater than 500 micrograms/dL (90 mumol/L). Coma, radiopacities, leukocytosis, and an elevated anion gap will be concurrently present (predictive value positive = 100%) when the serum iron concentration is greater than 500 micrograms/dL; moreover, they will be absent collectively (predictive value negative = 95%) when the serum iron concentration is below 500 micrograms/dL. Individually, these signs and symptoms have a low positive predictive value, but the absence of any one of these variables is likely to be associated with serum iron concentrations less than 500 micrograms/dL (predictive value negative > or = 93%). The ratio of serum iron concentration to the total iron-binding capacity was not associated with symptoms of systemic iron toxicity or presence of vin ros? urine after parenteral deferoxamine administration. A serum iron concentration in excess of the total iron-binding capacity may not identify patients with serious iron poisoning.""",1
9121,8477575,Drug intolerance to high-dose clarithromycin among elderly patients,"We treated 13 elderly patients with chronic mycobacterial lung disease with clarithromycin using 1000 mg b.i.d. as monotherapy. Patients had a mean age of 70 years, and 12 of 13 had creatinine clearances of 31-71 ml/min. Adverse events were seen in 100% of patients, with the most common being bitter taste (92%), nausea (92%), vomiting (54%) and central nervous system symptoms (54%). Elevated liver enzymes developed in five (38%) of 13 patients at weeks 1-6 of therapy. Mean serum levels of clarithromycin plus its 14-OH metabolite were 12.9 +/- 3.6 micrograms/ml (SD). There were 11 patients (85%) who discontinued the high dose within 3 months because of side effects. Serum drug levels of clarithromycin plus its 14-OH metabolite consistently exceeded 12 micrograms/ml in six of six patients who discontinued drug (10 of 10 values) compared with neither of two patients who tolerated the high dose (0 of 6 values). A dose reduction to 500 mg b.i.d. was well tolerated (nine of 10 patients). Future trials with clarithromycin in this population should use lower doses with attention to body mass and renal function to minimize side effects.",1
9122,8479375,Erythromycin-associated cholestatic hepatitis,"OBJECTIVE: To estimate the risk of cholestatic hepatitis of uncertain origin in patients who had recently received erythromycin, a drug which is known to cause this disorder. DESIGN: A retrospective cohort study using data automatically recorded on general practitioners' office computers. SETTING: Some 600 general practices in the United Kingdom. SUBJECTS: 366,064 people who received erythromycin. MAIN OUTCOME MEASURE: Clinically documented cholestatic hepatitis of uncertain origin diagnosed 1-45 days after a prescription for erythromycin. RESULTS: There were 13 cases of cholestatic hepatitis of uncertain origin diagnosed within 45 days of receiving erythromycin which were either characteristic of or consistent with a syndrome previously described as being associated with this drug. CONCLUSION: The risk of cholestatic jaundice associated with erythromycin is estimated to be in the range of 3.6 per 100,000 users (95% confidence interval, 1.9-6.1).",1
9123,8482178,"Objective and subjective results of a randomized, double-blind, placebo-controlled trial using cisapride to treat gastroparesis","""Cisapride, a relatively new gastrointestinal prokinetic agent, has been reported to increase gastric emptying and improve symptoms of gastroparesis. We investigated these effects of cisapride in patients with severe idiopathic and diabetic gastroparesis during an eight-week trial. The study design was a two-week single-blind placebo run in period to exclude placebo responders, followed by a six-week randomized, double-blind, placebo-controlled treatment phase. Delayed gastric emptying of solids on radionuclide scan and a minimum symptom intensity score were inclusion criteria. Forty-three patients were entered: four placebo responders and one other patient were excluded, leaving 19 patients randomized to cisapride (20 mg per os three times a day before meals), and 19 patients to placebo. Seven individual symptoms of gastroparesis were scored in a daily diary and reviewed at two-week visits. Sixteen patients in the cisapride group were able to complete the trial compared to 12 on placebo. The gastric emptying study was repeated at the end of treatment or at the time of withdrawal for those who dropped out. Cisapride significantly increased solid gastric emptying relative to baseline (P = 0.005) whereas placebo did not (P > 0.10). Cisapride did not significantly improve any symptom of gastroparesis relative to baseline or to placebo. We conclude that in a population of severe, refractory gastroparetic patients cisapride significantly accelerates gastric emptying of a solid meal without significantly reducing symptoms during a short-term treatment trial compared to placebo. Further trials of cisapride in less advanced and """"end-stage"""" gastroparetics than studied here or combining cisapride with other prokinetic agents or antiemetics, are warranted.""",1
9124,8489815,[Hepatotoxicity induced by Droxicam: presentation of 4 cases],"Hepatotoxicity has been reported with most of the nonsteroidal antiinflammatory drugs (NSAID). We describe four patients who presented hepatic injury after of treatment with Droxicam, a new NSAID prodrug of piroxicam. Hepatitis was attributed to Droxicam because of the absence of other etiological factors, temporal relation with drug administration, clinical, laboratory and histological picture and evolution favorable after the drug suppression. The hepatic injury was manifested as cholestasis and withdrawal of the drug was followed by biochemical and clinical improvement until the complete normalization in three of the four patients. Postmarketing surveillance is necessary in new drugs with unknown hepatotoxicity.",1
9125,8491409,Early acute hepatitis with parenteral amiodarone: a toxic effect of the vehicle?,"A 72 year old white man developed acute hepatic impairment and renal failure within 24 hours of starting intravenous amiodarone for paroxysmal ventricular tachycardia. After normal initial investigations, there was a noticeable rise in serum transaminases as well as an increase in clotting times, a decrease in renal function and a thrombocytopenia. These changes returned to normal within seven days of withdrawal of the drug without specific treatment, and the patient was later treated with oral amiodarone without any further evidence of hepatotoxicity. Intravenous amiodarone has been implicated in acute hepatic disease on four previous occasions, but it is suggested that polysorbate 80, an organic surfactant added to the intravenous infusion, is a more likely cause of this complication. Similar reactions have been described with polysorbate 80 in association with the 'E-ferol' syndrome in infants. The occurrence of acute hepatic impairment with intravenous amiodarone does not necessarily preclude the use of this drug by mouth.",1
9126,8494085,Toxic hepatitis by clozapine treatment,,1
9127,8497745,[Acute cholestatic hepatitis due to roxithromycin],,1
9128,8498900,Adverse events of subcutaneous recombinant human erythropoietin therapy: results of a controlled multicenter European study,"In a controlled European multicenter study, clinical tolerance of subcutaneously administered recombinant human erythropoietin (rh-EPO) therapy and its influence on the course of illness in 362 hemodialyzed patients (162 males, 200 females) from 16 European dialysis centers was studied. Of these, 181 patients served as a control group in the first year and received rh-EPO therapy in the second year. Of the 837 adverse events that occurred, 277 were classified as serious and 560 as nonserious. Thirty-two deaths have been reported for the study population: 18 in the control group and 14 in the therapy group. The individual analysis of the serious adverse events including death demonstrates a protective effect of rh-EPO on the high-risk cardiovascular situation of dialysis patients. Hypertension was no problem, and under rh-EPO therapy an increase in resistance to infection was observed. Subcutaneous rh-EPO treatment might have an even better safety profile than intravenous application.",1
9129,8505497,Transient focal hepatic defects related to sustained-release niacin,"Hepatotoxicity is a potential side effect of niacin therapy for hypercholesterolemia, ranging from mild aminotransferase elevation to fulminant hepatic failure. Although uncommon with plain forms, liver dysfunction has increasingly been associated with sustained-release preparations. This case illustrates transient focal liver defects seen on computed tomography with symptomatic elevation of liver-associated enzymes during treatment with sustained-release niacin. The masses were not evident on radionuclide liver scan, suggesting focal fatty liver. After niacin was discontinued, these abnormalities resolved, and aminotransferases returned to normal. This is the first such reported case.",1
9130,8507122,Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Pravastatin Multicenter Study Group II,"BACKGROUND: Treatment of severe hypercholesterolemia often requires high-dose therapy with a hydroxymethylglutaryl-coenzyme A reductase inhibitor alone or in combination with bile acid-binding resin. We evaluated the efficacy and safety of pravastatin, a new hydroxymethylglutaryl-coenzyme A reductase inhibitor with hydrophilic selectivity, alone and in combination with cholestyramine. METHODS: Pravastatin was studied at doses of 20 or 40 mg twice daily alone or 20 mg twice daily with cholestyramine, 12 g twice daily, vs placebo in a randomized, double-blind multicenter study of 311 patients for 8 weeks and in continued therapy through 24 weeks. RESULTS: After 8 weeks of therapy, pravastatin in a dosage of 20 mg twice daily reduced low-density lipoprotein cholesterol levels by 31%, whereas a dosage of 40 mg twice daily reduced low-density lipoprotein cholesterol levels by 38%. Cholestyramine, 24 g daily alone, reduced low-density lipoprotein cholesterol levels by 32%. Cholestyramine combined with 40 mg of pravastatin reduced the level by 51%. Pravastatin, 40 or 80 mg daily, reduced the triglyceride level by 13% to 19%, resin alone increased the triglyceride level by 21%, and no change was seen with combined therapy. High-density lipoprotein cholesterol levels increased by about 5% regardless of regimen. Similar effects were seen at 24 weeks. Symptoms reported were indistinguishable among placebo and pravastatin users and were less than with cholestyramine alone or cholestyramine in combination with pravastatin. Elevations of liver enzyme levels were small in all groups, indistinguishable between resin and pravastatin, and were highest when the two drugs were combined. Plasma creatine kinase levels did not increase in any treatment group. CONCLUSIONS: Pravastatin treatment of hypercholesterolemia is highly effective and well tolerated alone and in combination with bile acid-binding resin and shows no tendency to increase muscle enzyme levels.",1
9131,8507221,"Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial","""OBJECTIVE: To determine whether the side effects of methotrexate can be decreased by the concurrent use of leucovorin, without affecting the efficacy of the methotrexate. METHODS: We conducted a multicenter randomized, double-blind, placebo-controlled trial of leucovorin administration, 2.5-5.0 mg orally, to be given 24 hours after the single, weekly, oral dose of methotrexate. Every 3 weeks for 52 weeks, patients were evaluated for rheumatic disease activity and side effects. Dosage adjustments for both methotrexate and leucovorin were made as needed, according to a defined protocol. The primary outcome evaluated was the frequency of study withdrawals because of side effects and/or inefficacy. Secondary outcomes evaluated included the frequency of side effects and the relative efficacy of methotrexate in the leucovorin and placebo treatment groups. RESULTS: Ninety-two evaluable patients were analyzed (44 took leucovorin and 48 placebo). Twenty-two patients withdrew early because of side effects unresponsive to our protocol, and 1 because of inefficacy; 17 had been taking placebo and 6 had been taking leucovorin (35% versus 14%, P < 0.02). The number of visits during which side effects were reported was reduced by almost 50% in the leucovorin treatment group (P < 0.001). There were significant reductions in the frequencies of all common side effects. At 52 weeks, disease activity was similar in both patient groups. CONCLUSION: The methotrexate-leucovorin protocol used significantly reduces common side effects of methotrexate therapy without significantly altering efficacy.""",1
9132,8514044,Hepatic fibrin-ring granulomas in giant cell arteritis,"Hepatic fibrin-ring granulomas were found in a 70-year-old man with prolonged fever and inflammatory syndrome. Diagnosis of giant cell arteritis was confirmed by temporal artery biopsy. Other diseases usually associated with fibrin-ring granulomas in liver, such as Q fever, cytomegalovirus hepatitis, infectious mononucleosis, Hodgkin's disease, non-Hodgkin's lymphoma, allopurinol treatment, and visceral leishmaniasis, were ruled out. This report suggests that giant cell arteritis should be considered as an additional cause of hepatic fibrin-ring granulomas.",1
9133,8515719,Interferon beta-1B for multiple sclerosis,,1
9134,8519541,[Ticlopidine-induced cholestatic hepatitis. A case report],"A 74-year-old man with cholestatic hepatitis after 3 months of taking ticlopidine is presented herein. Viral serology and autoantibodies were negative. There was no evidence of biliary tree obstruction. After ticlopidine was discontinued, liver tests were normal in 3 months. We review the other cases published in the literature.",1
9135,8522133,[Acute cytolytic hepatitis caused by cefazolin and metronidazole],,1
9136,8527549,Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease,"""We initiated a multidrug trial that included high-dose rifabutin for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. Twenty-six patients received rifabutin (600 mg/d) in combination with ethambutol, streptomycin, and either clarithromycin (500 mg b.i.d.; 15 patients) or azithromycin (600 mg/d; 11 patients). Rifabutin-related adverse events occurred in 77% of patients. Fifty-eight percent of patients required a dosage adjustment or discontinuance of rifabutin therapy. The most common adverse event was a reduction in the mean total white blood cell (WBC) count, which decreased from 8,600 +/- 2,800/mm3 before treatment to 4,500 +/- 2,100/mm3 during treatment (P = .0001). Although all patients had some decrease in WBC count, only three patients (12%) required a dosage adjustment for this reason. Other common adverse events included gastrointestinal symptoms (nausea, vomiting, or diarrhea; 42%) and abnormal liver enzyme levels (12%). Eight of 11 patients (73%) with gastrointestinal symptoms, including one patient with abnormal liver enzyme levels, required a rifabutin-dosage adjustment. The most severe adverse events, always requiring an adjustment of therapy, were a diffuse polyarthralgia syndrome (19%) and anterior uveitis (8%). The latter toxicity has previously been reported to occur only in patients with AIDS and was seen only in patients who also were receiving clarithromycin. On the basis of the current findings, we recommend that rifabutin be used at a dose of 300 mg/d in multidrug regimens that include a macrolide for treatment of MAC lung disease.""",1
9137,8532025,A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension,"""BACKGROUND: Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. METHODS: We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). RESULTS: Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. CONCLUSIONS: As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.""",1
9138,8533995,"An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. The Mesalamine Study Group","OBJECTIVE: To compare the safety and efficacy of a pH-sensitive, polymer-coated oral formulation of mesalamine (Asacol, Procter & Gamble Pharmaceuticals, Cincinnati, Ohio) with those of placebo in maintaining remission in patients with ulcerative colitis. DESIGN: Multicenter, double-blind, placebo-controlled, randomized clinical trial. SETTING: Eight private practices, five university-based medical centers, and four hospitals or clinics. PATIENTS: 264 patients with ulcerative colitis that had been maintained in remission for at least 1 month while the patients were receiving stable doses of sulfasalazine or any oral mesalamine product. INTERVENTION: Coated mesalamine at oral dosages of 0.8 g/d or 1.6 g/d or matching placebo for 6 months. MEASUREMENTS: Treatment success, defined as maintenance of remission after 6 months, and treatment failure, defined as relapse during the study (as indicated by proctosigmoidoscopy at 1, 3, or 6 months of treatment) or withdrawal due to adverse events. Safety was assessed on the basis of laboratory analyses and patient- and investigator-noted adverse events. RESULTS: 189 patients were compliant with the protocol for 6 months or stopped receiving therapy because of relapse or adverse events. Of these 189 patients, 25 of the 63 patients (39.7%) in the placebo group had treatment success compared with 40 of the 68 patients (58.8% [95% CI, 46.4% to 71.3%]) in the group receiving mesalamine, 0.8 g/d (P = 0.036) and 38 of the 58 patients (65.5% [CI, 52.4% to 78.6%]) in the group receiving mesalamine, 1.6 g/d (P = 0.006). In the intention-to-treat analysis of all patients, 42 of the 87 patients (48.3%) in the placebo group had treatment success compared with 57 of the 90 patients (63.3% [CI, 52.8% to 73.8%]) in the group receiving mesalamine, 0.8 g/d (P = 0.050) and 61 of the 87 patients (70.1% [CI, 59.9% to 80.3%]) in the group receiving mesalamine, 1.6 g/d (P = 0.005). Age, sex, and race were not found to predict treatment success or failure. The mesalamine tablet was well tolerated, and no clinically significant changes were seen in hematologic, hepatic, or renal laboratory profiles. CONCLUSION: Coated mesalamine at oral dosages of 0.8 g/d and 1.6 g/d is safe and effective in maintaining remission in patients with quiescent ulcerative colitis.",1
9139,8536519,Chronic active hepatitis and liver cirrhosis in association with combined tamoxifen/tegafur adjuvant therapy,"Two female breast cancer patients who received combined tamoxifen and tegafur as postsurgical adjuvant therapy developed severe hepatotoxicity after being treated for three and eight months, respectively. Shortly after the cessation of the treatment, routine liver tests showed gradual recovery, but liver biopsies revealed chronic active hepatitis in one patient and liver cirrhosis in the other. Four and five years, respectively, after the cessation of the treatment, the results of liver tests were normal and distinct histological improvement was observed in both patients. Because these patients had no viral and immunoserological markers nor any history of alcohol abuse, this study suggested that the tamoxifen and tegafur regimen induced reversible chronic active liver disease.",1
9140,8545299,Fatal hepatotoxicity associated with 6-mercaptopurine therapy,,1
9141,8545387,"[Pseudo-cholangitis, a form of erythromycin-induced hepatitis]",,1
9142,8547735,"Shock, metabolic acidosis, and coma following ibuprofen overdose in a child","OBJECTIVE: To report a child who developed shock, loss of consciousness, and metabolic acidosis following an ibuprofen overdose. CASE SUMMARY: A 6-year-old boy with no prior medical problems ingested approximately thirty 200-mg tablets of ibuprofen. The patient developed shock, coma, and metabolic acidosis. He was treated successfully with intubation and mechanical ventilation, fluid resuscitation, and decontamination with activated charcoal. The patient was discharged without any clinical sequelae. DISCUSSION: Serious adverse complications following ibuprofen overdose have been reported rarely in children. We reviewed literature pertaining to the etiology, pharmacology, pathophysiology, and management of complications following ibuprofen overdoses, as well as other case reports. CONCLUSIONS: Coma, metabolic acidosis, and shock were noted in a child who ingested a large quantity of ibuprofen. These complications have been described rarely in children. We attribute his favorable clinical outcome to early and aggressive intervention consisting of tracheal intubation, fluid resuscitation, and decontamination with activated charcoal. Although ibuprofen overdoses are usually benign, healthcare professionals should be aware of the various potentially serious complications that may occur.",1
9143,8549000,Azathioprine hypersensitivity-like reactions--a case report and a review of the literature,"""Azathioprine is used in a variety of dermatological conditions. However, because of its side-effect profile, azathioprine is limited for use in patients with severe disease. An unpredictable, rare and potentially fatal side-effect of azathioprine is the development of a hypersensitivity reaction, often consisting of fever, hypotension and oliguria. We describe a 17-year-old patient with leucocytoclastic vasculitis who was placed on azathioprine; within 15 days of start of therapy, she developed a fever. Azathioprine was discontinued and an evaluation for sepsis was undertaken; all cultures were negative and the fever abated. Azathioprine was restarted 5 days later. After a single dose, fever, nausea and vomiting, diarrhoea, hypotension, tachycardia and oliguria developed and the patient was admitted to an intensive care unit. Azathioprine was discontinued and investigations revealed no sign of an infection. All the above signs and symptoms abated within 24 h and the patient was discharged from hospital in 7 days. A review of 28 case reports in the literature of azathioprine-induced hypersensitivity reactions suggest that most commonly a fever and gastrointestinal symptoms occurred on initial presentation. In addition, a maculopapular rash, urticaria, vasculitis, erythema multiforme or erythema nodosum may occur. Hepatotoxicity and nephritis have also been reported. The aetiology of the reaction is unknown but sudden onset of fever and hypotension suggests that this reaction may be due to cytokine or mediator release induced by azathioprine. As azathioprine is metabolized to 6-MP, rechallenges to both should be avoided in patients who experienced an azathioprine hypersensitivity-like reaction.""",1
9144,8550028,Ganciclovir treatment of hepatitis B virus infection in liver transplant recipients,"""To determine the safety and efficacy of ganciclovir treatment of hepatitis B virus (HBV) infection after liver transplantation, nine patients (seven males, two females; mean age, 38 years) with posttransplant HBV infection were treated with ganciclovir for 3 to 10 months. Ganciclovir was administered intravenously at an initial dose of 5 mg/kg/d and then increased to 10 mg/kg/d. Immunosuppressive drug therapy was maintained at low levels. There were no major side effects of ganciclovir therapy. Serum HBV DNA levels decreased by a mean of 90% (range, 42% to 100%), and four of nine patients had no measurable HBV DNA at the completion of therapy. Mean serum alanine aminotransferase levels decreased by 83%. Hepatic expression of HBV antigens and HBV DNA was assessed before and after therapy in six patients and found to be reduced in three patients. The histology activity index was also stabilized or improved in all patients. After discontinuation of therapy, four of nine patients underwent retreatment for 4- to 12-fold elevation of serum HBV DNA and/or biochemical and clinical relapse, that was severe in one patient. This pilot study shows the safety and efficacy of ganciclovir therapy for reducing HBV replication in patients with HBV infection after liver transplantation.""",1
9145,8554969,Phase II study of gemcitabine in patients with advanced pancreatic cancer,"The efficacy and safety of gemcitabine at a starting dose of 800 mg m2 administered once a week for 3 weeks with 1 week's rest was investigated in chemonaive patients with advanced and/or metastatic pancreatic cancer. Of 34 patients, 32 were evaluable for efficacy, 20 patients had metastatic stage IV disease, 25 had a performance status of 1 and 26 (76%) patients has significant pain on presentation. All responses were independently validated by an external oncology review board: two patients achieved a partial response that lasted 5.8 and 5.2 months (6.3%) and six patients were stable for at least 4 weeks. The median duration of survival for evaluable patients was 6.3 months (range 1.6-19.2 months). The tumour markers, CEA, CA 19-9 and CA 195 were serially measured in 16 patients. There was a good correlation with tumour response when all three markers were significantly decreased. In 4 of 16 patients, tumour marker levels decreased by > or = 60%, including the two responders, one patient who survived for 12 months and one patient who showed objective tumour shrinkage but was deemed ineligible for response evaluation because the disease was considered not to be bidimensionally measurable. Symptomatic benefits included improvement in performance status (17.2%), analgesic requirement (7.4%), pain score (28.6%) and nausea (27.3%). The mean number of cycles administered was 2.5 and the mean dosage received was 890 mg m2 per injection. Seventy-four per cent of dose administrations were given on schedule. Toxicity, particularly haematological toxicity, reported as the maximum WHO grade experienced by patients was mild. Infective episodes were rare and limited to WHO grade 2 (6.7%). Nausea and vomiting was generally modest (WHO grade 3, 26.7%). Other side-effects included mild transient flu-like symptoms (seven patients) and peripheral oedema (three patients), which was not associated with abnormal cardiac hepatic or renal function. Gemcitabine has modest activity in pancreatic cancer, a limited positive improvement on a range of patient benefit parameters and has a mild toxicity profile. For these reasons and because of its novel mode of action, gemcitabine warrants further investigation in combination studies in pancreatic cancer.",1
9146,8561126,Subacute mitochondrial liver disease in a patient with AIDS: possible relationship to prolonged fluconazole administration,"Azole-derived antifungal medications are particularly involved in drug-induced hepatic injury encountered in patients with AIDS. Fluconazole may induce multiple hepatic abnormalities usually characterized by asymptomatic and reversible mild hepatic necrosis. We here describe severe subacute liver damage occurring in a patient with AIDS who was receiving fluconazole maintenance therapy for a cryptococcosis. Hepatotoxicity was essentially characterized by mixed cytolytic and cholestatic liver tests abnormalities which improved after fluconazole discontinuation and worsened on fluconazole rechallenge. Optical microscopy demonstrated nonspecific abnormalities including granular aspect of the cytoplasm of the hepatocytes. In contrast, analysis of electron microscopy revealed unusual unreported features characterized by giant mitochondria with paracrystalline inclusions and enlarged smooth endoplasmic reticulum. All microscopic abnormalities were reversed after discontinuation of fluconazole. We suggest that persistent increased hepatic enzymes in HIV-infected patient taking fluconazole should prompt suspension of the treatment. Prospective studies are needed to determine whether careful monitoring of hepatic tests should be recommended in AIDS patients on prolonged fluconazole maintenance therapy.",1
9147,8565024,"Double-blind, placebo-controlled comparison of the safety and efficacy of orally administered etodolac and nabumetone in patients with active osteoarthritis of the knee","""This 4-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study was designed to compare the efficacy and safety of etodolac and nabumetone in the treatment of patients with active osteoarthritis (OA) of the knee. Ninety-one patients received etodolac 400 mg twice daily, 89 received nabumetone 1500 mg once daily, and 90 received placebo. Both active treatments significantly improved the patients' condition relative to baseline (P < or = 0.001) at all evaluations during treatment and relative to placebo (P < or = 0.05) by visit 4. Improvement relative to placebo in investigator's global assessments was earlier in the etodolac group (ie, by visit 3) than in the nabumetone group. At visit 4, improvement in investigator's and patient's global assessment scores, and in the distribution of investigator's assessment scores, was significantly (P < or = 0.05) greater in the etodolac group than in the nabumetone group. Other than hypokalemia, which occurred only in three patients in the nabumetone group (P = 0.035), there were no significant differences among the groups in the frequency of study events or premature discontinuation from the study as a result of study events. Study events considered at least possibly treatment related were reported for 26 patients in the etodolac group (28.6%), 20 in the nabumetone group (22.5%), and 23 in the placebo group (25.6%). The most frequently reported symptoms for all groups were dyspepsia, nausea, and headache. Four patients treated with nabumetone (4.5%) had elevations in aspartate aminotransferase or alanine aminotransferase during treatment. The results of this study show that etodolac 400 mg twice daily is at least as effective as nabumetone 1500 mg once daily and is equally well tolerated in the treatment of patients with active OA of the knee; etodolac may have an earlier onset of action and/or a relatively greater efficacy in patient and investigator global assessments than nabumetone.""",1
9148,8565754,Nafcillin-associated hepatotoxicity. Report of a case and review of the literature,"Nafcillin is a semisynthetic penicillin that is generally well tolerated with few side effects. Hepatic complications are rare but have a potential for serious liver dysfunction. This unusual complication causes a predominantly cholestatic injury, which can persist for prolonged periods even after discontinuing the medication. The pathophysiology may include direct cytotoxicity or an immune-mediate hypersensitivity. Treatment is generally supportive, except for severely symptomatic patients who may require steroids. We report a case of nafcillin-associated hepatotoxicity and review the literature of this disorder.",1
9149,8569826,Metformin,,1
9150,8572837,"Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components","BACKGROUND: Angiotensin II acts at the cellular level through specific angiotensin II subtype I, AT-1 receptors. Losartan is the first of a new class of antihypertensive agents that specifically block angiotensin II at AT-1 receptors. By acting on complementary and different pharmacologic mechanisms, the concomitant use of low doses of hydrochlorothiazide with losartan may offer an additive antihypertensive activity with fewer adverse experiences. METHODS: This double-blind study evaluated losartan concomitantly administered with hydrochlorothiazide as initial therapy in 703 patients with essential hypertension. RESULTS: The greatest reduction in blood pressure was observed in the 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide group (17.2 mm Hg in sitting systolic blood pressure and 13.2 mm Hg in sitting diastolic blood pressure [P < or = .001]), and the effects of the two components appeared to be additive. Seventy-eight percent of the patients treated with 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide had an excellent or good antihypertensive response (sitting diastolic blood pressure < 90 mm Hg or > or = 90 mm Hg with a reduction of 10 mm Hg or more). Peak (6 hours after dosing) and trough placebo-adjusted ratios for the losartan-hydrochlorothiazide groups ranged from 62% to 85%, indicating that there was a smooth reduction in sitting diastolic blood pressure that was sustained over 24 hours. The most common clinical adverse experiences (> or = 4%) that occurred with an incidence slightly greater than that reported by the placebo-treated patients were headache, asthenia or fatigue, dizziness, sinusitis, and upper respiratory infection. CONCLUSION: The concomitant administration of losartan potassium, 50 mg, with 12.5 mg of hydrochlorothiazide once daily produced an additive reduction in trough sitting systolic and diastolic blood pressure and was well tolerated.",1
9151,8587082,A multicenter study of nabumetone and diclofenac SR in patients with osteoarthritis,"OBJECTIVE: To conduct the first Canadian study of the comparative efficacy and safety of nabumetone and diclofenac SR in patients with primary osteoarthritis (OA) of the hip, knee and shoulder. METHODS: Nabumetone 1000-1500 mg po daily was compared to diclofenac SR 100-150 mg po daily in a 6-month, double blind, randomized, controlled, multicenter, parallel trial. Initial starting doses were nabumetone 1000 mg daily and diclofenac SR 100 mg daily, with optional subsequent one-level dose titration permitted after 2 weeks on lower dose up to 1500 mg nabumetone and 150 mg diclofenac SR. The primary outcome measures were overall pain and disease activity as assessed by physician and patient. Secondary efficacy measures included tenderness, swelling, limitation of motion, duration of morning stiffness, acetaminophen consumption, physician and patient global assessment, and patient evaluation of efficacy and tolerability. Following an initial screening visit and a 2 to 7 day nonsteroidal antiinflammatory drug free washout period (i.e., randomization), patients were assessed at Weeks 2, 8, 14, 20, and 26. RESULTS: In all, 382 patients [nabumetone (n = 192), diclofenac SR (n = 190)] participated in the trial. Improvement in all efficacy variables was noted, but there was no statistically significant difference between drugs. Significantly fewer (p = 0.01) patients reported upper gastrointestinal (GI) adverse experiences in the nabumetone group. Significantly fewer (p < 0.04) patients withdrew from the study for adverse experiences in the nabumetone (14%) than the diclofenac SR (23%) group, particularly from upper abdominal pain (p < 0.04) and dyspepsia (p = 0.02). Three patients treated with diclofenac SR and none with nabumetone developed upper GI ulcers or bleeds. The number of patients experiencing clinically important elevations in transaminases (p < 0.04) or BUN/creatinine (p < 0.03) was significantly lower in the nabumetone group. CONCLUSION: Nabumetone is efficacious and well tolerated in patients with OA of the hip, knee or shoulder. In this group of patients it was similar in efficacy and superior in tolerability to diclofenac SR.",1
9152,8588783,Probable ciprofloxacin induced cholestasis,,1
9153,8596376,"Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393","BACKGROUND: The frequency of thromboembolism after major orthopaedic surgery continues to be high despite prophylaxis. New agents such as CGP 39393, a recombinant form of hirudin, may be more effective than existing therapies. METHODS: In this double-blind, multicentre, European study the efficacy of three doses of CGP 39393, in comparison with unfractionated heparin, were examined in 1119 patients undergoing elective hip surgery. Patients were randomly allocated to receive by subcutaneous injection either 10, 15, or 20 mg of CGP 39393 twice daily or 5000 IU of heparin three times daily. All treatments were started just before surgery and continued for 8-11 days, until bilateral venography was performed. FINDINGS: The occurrence of thromboembolism was significantly reduced in patients treated with CGP 39393 compared to heparin. The frequency of deep-vein thrombosis was 34.2% in the heparin group as compared to 23.9% (p=0.0113), 18.4% (p=0.0003), and 17.7% (p=0.0001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. At all dose levels, CGP 39393 was more effective than heparin in preventing proximal deep-vein thrombosis. The frequency of proximal thrombosis was 19.6% in the heparin group as compared to 8.5% (p<0.001), 3.1% (p<0.001), and 2.4% (p<0.001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. All treatments were well tolerated. INTERPRETATION: This study indicates that specific inhibition of thrombin by prophylactic CGP 39393 significantly reduces thromboembolic complications in patients undergoing total hip replacement.",1
9154,8598621,"Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group","OBJECTIVE: To study the effect of 3 months of treatment with zileuton, an inhibitor of the enzymatic pathway (5-lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma. DESIGN: Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks. SETTING: Asthma study clinics in university hospitals and private practices. PATIENTS OR OTHER PARTICIPANTS: Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV1], 40% to 80% of predicted) whose only treatment was inhaled beta-agonists. INTERVENTIONS: Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily.) MAIN OUTCOME MEASURES: Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled beta-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events. RESULTS: Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo (P=.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group (P=.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group (P=.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients (P=.03 vs placebo), three patients (P=.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively. CONCLUSIONS: Three months of 5-lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma.",1
9155,8600877,Carbamazepine-induced hepatitis in a patient with cervical myelopathy,"Carbamazepine is a drug commonly used in the treatment of neuropathic pain. It is an iminostilbene derivative that is extensively metabolized by the liver. We describe a 66-year-old man with dysesthetic pain from cervical myelopathy who developed cholestatic hepatitis, skin rash, and eosinophilia after carbamazepine was administered for 5 weeks (total dose of 18.9gm). Withdrawal of carbamazepine led to complete resolution of both clinical and biochemical abnormalities within 3 weeks. Clinicians should be alert to this rare complication because it can be confused clinically with biliary tract sepsis and viral hepatitis.",1
9156,8604150,"Comparative studies on the toxicity of mercury, cadmium, and copper toward the isolated perfused rat liver","""The toxic effects of cadmium, mercury, and copper were compared over the over range 0.01, 0.03, and 0.1 mM using the isolated perfused rat liver preparation. All metals caused similar changes in various parameters used to describe general toxicity. Thus reductions in oxygen consumption, perfusion flow, and biliary secretion were found, while lactate dehydrogenase release into the perfusate, as well as liver weight, increased also in a dose-dependent fashion. Each metal caused similar magnitudes of changes and exerted similar potency. Measurement of other parameters indicating more specific injury revealed a number of differences. Although all metals reduced hepatic ATP concentration, mercury and cadmium were more potent than copper in this respect. Cadmium was the most potent at decreasing reduced glutathione levels. Mercury was most effective at increasing tissue calcium content, while copper was less so, and cadmium ineffective. Only copper significantly increased tissue malondialdehyde (MDA) content, while all metals increased its release into perfusate. Furthermore, whereas cadmium seemed the most potent metal in increasing MDA release, it was least efficacious, while copper was the most. Antioxidants such as superoxide dismutase, catalase, and Trolox C only reduced cadmium's influence on MDA in perfusate; however, they did not affect cadmium's ability to alter most other parameters of vitality. Albumin reversed the toxic effects of copper and mercury, but not cadmium. While metal-induced reductions in perfusion flow accounted for some of the toxic effects of the metals investigated, the results as a whole supported the suggestion that all metals exerted toxicity at the mitochondria, since ATP levels were reduced in a manner that could not be reproduced by perfusion flow reduction alone. Lipid peroxidation appears to play little role in determining toxicity induced by any of these metals. Furthermore, albumin may play an important physiological role in preventing hepatic injury that might otherwise be induced through acute metal intoxication.""",1
9157,8607519,Fulminant hepatic failure associated with clarithromycin,,1
9158,8610937,Hepatic injury caused by acarbose,,1
9159,8610959,Tamoxifen-induced steatohepatitis,,1
9160,8614514,Valproic acid hepatic fatalities. III. U.S. experience since 1986,"We report the results of a third retrospective study of the U.S. experience with fatal hepatotoxicity associated with valproic acid (VPA). In the United States, over one million patients received new prescriptions for VPA during the years 1987 to 1993, and 29 patients developed fatal hepatotoxicity. Decreased alertness, jaundice, vomiting, hemorrhage, increased seizures, anorexia, and edema were the most common presenting signs. Risk factors included young age, polytherapy, developmental delay, and coincident metabolic disorders. Patients less than 2 years old receiving VPA as polytherapy were at the greatest risk (1:600) of developing this complication.",1
9161,8617554,A comparative clinical trial of albendazole versus metronidazole in children with giardiasis,"The adverse effects and treatment failures to some of the currently recommended drugs for giardia infection have given rise to the need for alternative antigiardial agents. In an open, randomized parallel group study, the safety and efficacy of albendazole was compared with metronidazole for the treatment of giardiasis in children. Sixty four children of age ranging from 2-12 years was randomized to receive either albendazole suspension 400 mg daily for 5 days or metronidazole suspension 400 mg daily for 5 days or metronidazole suspension 7.5 mg/Kg thrice daily for 5 days. The mean days required for cure, as evident by absence of cysts and/or trophozoites in the stool specimen, were 3.7 +/- 1.4 and 4.5 +/- 1.1 days, respectively for children on albendazole and metronidazole therapy. Six children on metronidazole therapy developed anorexia 2 to 4 days after the treatment. Albendazole proved as effective as metronidazole in the treatment of giardia infection in children with the added advantage of the absence of anorexia.",1
9162,8624173,Safety of antioxidant vitamins,"As a result of the many scientific and popular press reports of the benefits of antioxidant vitamins (vitamin A, beta-carotene, vitamin E, and ascorbic acid), it is estimated that 40% of the US population is consuming vitamin supplements. The efficacy of these supplements is not yet proved, and some have questioned their safety. Approximately 10 to 15 cases of vitamin A toxic reactions are reported per year in the United States, usually at doses greater than 100,000 IU/d. No adverse effects have been reported for beta-carotene. The frequency of vitamin E toxic reactions is not well delineated, but case reports are few at dosages less than 3200 mg/d. Ascorbic acid toxic reactions are rare at dosages less than 4 g/d. Despite a lack of clinical trial data, it seems that antioxidant vitamins are safe, although prudence might dictate their avoidance by women of childbearing potential, persons with liver disease or renal dysfunction, and those taking certain medications or undergoing specific laboratory tests.",1
9163,8626361,The safety profile of nefazodone,"""Comprehensive review of safety data from approximately 3500 patients who received nefazodone in premarketing clinical trials demonstrates the drug to be very well tolerated, with a favorable side effect profile compared with other antidepressant drugs. Nefazodone treatment was associated with fewer side effects than were the control drugs. The incidence of side effects was generally low, and treatment discontinuations for adverse effects were less frequent with nefazodone than with imipramine and comparable with fluoxetine. No late-appearing side effects or toxicity emerged during the long-term treatment (1 year or longer) of several hundred patients. There were no drug-related fatalities and no evidence that nefazodone caused specific organ toxicity, although some cardiovascular side effects were noted (e.g., asymptomatic reduced systolic blood pressure, asymptomatic sinus bradycardia). Experience in 488 elderly patients treated with nefazodone yielded no evidence of increased susceptibility of older patients to nefazodone-associated adverse experiences, including those pertaining to the cardiovascular system. However, treatment should be initiated at a reduced dose in elderly patients because of reduced hepatic clearance of nefazodone in this age group. Final dose range may be similar in healthy younger and older patients. Although nefazodone may interact with some other medications (e.g., increases at steady state in AUC: alprazolam, twofold; triazolam, fourfold), drug-drug interactions involving patients have been clinically minor. On the basis of the inhibition of cytochrome P450 3A4 isoenzyme by nefazodone in vitro, coadministration of terfenadine or astemizole with nefazodone is contraindicated because nefazodone can increase the plasma levels of these two drugs. Extensive clinical experience provides substantial evidence that nefazodone is an extremely safe and effective treatment for depression, with important advantages over existing therapies. Therapeutic benefits include a low incidence of clinically troublesome side effects and lack of unwanted psychic activation, sexual dysfunction, weight change, and the cardiotoxicity of other antidepressants.""",1
9164,8628066,[A case report. Thrombocytopenia and granulomatous hepatitis caused by quinine],,1
9165,8628357,Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding,"""BACKGROUND: Patients who have bleeding from esophageal varices are at high risk for rebleeding and death. We compared the efficacy and safety of endoscopic sclerotherapy with the efficacy and safety of nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. METHODS: Eighty-six hospitalized patients with cirrhosis and bleeding from esophageal varices diagnosed by endoscopy were randomly assigned to treatment with repeated sclerotherapy (43 patients) or nadolol plus isosorbide-5-mononitrate (43 patients). The primary outcomes were rebleeding, death, and complications. The hepatic venous pressure gradient was measured at base line and after three months. RESULTS: Base-line data were similar in the two groups, and the median follow-up was 18 months in both. Eleven patients in the medication group and 23 in the sclerotherapy group had rebleeding. The actuarial probability of remaining free of rebleeding was higher in the medication group for all episodes related to portal hypertension (P = 0.001) and variceal rebleeding (P = 0.002). Four patients in the medication group and nine in the sclerotherapy group died (P = 0.07 for the difference in the actuarial probability of survival). Seven patients in the medication group and 16 in the sclerotherapy group had treatment-related complications (P = 0.03). Thirty-one patients in the medication group underwent two hemodynamic studies; 1 of the 13 patients with more than a 20 percent decrease in the hepatic venous pressure gradient had rebleeding, as compared with 8 of the 18 with smaller decreases in the pressure gradient (P = 0.04) for the actuarial probability of rebleeding at two years). CONCLUSIONS: As compared with sclerotherapy, nadolol plus isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices.""",1
9166,8630641,Safety of meloxicam: a global analysis of clinical trials,"Meloxicam is a new preferential cyclooxygenase-2 (COX-2) inhibitor for the treatment of rheumatic disease. This paper presents a global safety analysis of data from meloxicam clinical studies, focusing on gastrointestinal (GI) adverse events. Meloxicam 7.5 and 15 mg (n = 893 and 3282) were compared with piroxicam 20 mg (n = 906), diclofenac 100 mg slow release (n = 324) and naproxen 750-1000 mg (n = 243). With respect to all GI adverse events, meloxicam 7.5 and 15 mg were significantly better than all comparators in a pooled analysis of double-blind studies in rheumatoid arthritis (RA) and osteoarthritis (OA). When examining non-serious GI events, severe GI events, discontinuous due to GI events, dyspepsia, abdominal pain and upper GI events, both meloxicam doses were significantly better than comparator non-steroidal anti-inflammatory drugs (NSAIDs) in most cases. Where statistical significance was not demonstrated, there was generally a trend in favour of meloxicam. With respect to upper GI perforations, ulcerations and bleedings, the most serious of NSAID-associated side-effects, meloxicam was better tolerated than the comparators, reaching statistical significance for piroxicam and naproxen. Meloxicam's improved GI safety profile is likely to be due to its preferential inhibition of inducible COX-2 relative to constitutive COX-1.",1
9167,8633815,"Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators","""OBJECTIVE: To study the addition of a third human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, nevirapine, to the combination of zidovudine and didanosine. DESIGN: A 48-week, randomized, double-blind, placebo-controlled trial at 16 AIDS (acquired immunodeficiency syndrome) Clinical Trials Units. PATIENTS: 398 adults who had HIV-1 infection, had 350 or fewer CD4+ T lymphocytes/mm3, and had had more than 6 months of previous nucleoside therapy. INTERVENTION: 1) Either nevirapine or placebo (200 mg/d for 2 weeks, then 400 mg/d thereafter) and 2) open-label zidovudine (600 mg/d) and didanosine (400 mg/d for patients weighing > or = 60 kg). MEASUREMENTS: CD4+ T lymphocyte counts, time to first HIV-1 disease progression event or death, adverse events, and nevirapine levels in plasma samples taken at random were measured in all patients. Plasma levels of HIV-1 RNA HIV-1 infectivity titer in peripheral blood mononuclear cells; serum p24 antigen levels; and plasma levels of zidovudine and didanosine were measured in patients enrolled at half the study sites. RESULTS: After 48 weeks of study treatment the patients assigned to the triple-combination regimen (nevirapine, zidovudine, and didanosine) had an 18% higher mean absolute CD4 cell count (95% Cl, 7% to 29%; P = 0.001), a 0.32 log10 lower mean infectious HIV-1 titer in peripheral blood mononuclear cells (Cl, 0.05 to 0.59 log10 infectious units per million cells; P = 0.023), and a 0.25 log10 lower mean plasma HIV-1 RNA level (Cl, 0.03 to 0.48 log10 RNA copies/mL; P = 0.028) than did patients assigned to the double-combination regimen (zidovudine and didanosine). Severe rashes were more common among patients assigned to receive the triple combination (9% compared with 2%; P = 0.002). Risk for disease progression did not differ between the two groups (relative hazard of the triple-combination group, 1.24 [Cl, 0.75 to 2.06]; P > 0.2), although the study had only moderate power to detect a major difference. CONCLUSIONS: Adding nevirapine to zidovudine and didanosine improved the long-term immunologic and virologic effects of therapy and was associated with severe rash among the patients studied, who had had extensive previous therapy. These results support 1) the continuing development of combinations of more than two antiretroviral drugs to increase and prolong HIV-1 suppression and 2) the potential utility of nevirapine in combination regimens.""",1
9168,8637535,The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men,"""BACKGROUND: Athletes often take androgenic steroids in an attempt to increase their strength. The efficacy of these substances for this purpose is unsubstantiated, however. METHODS: We randomly assigned 43 normal men to one of four groups: placebo with no exercise; testosterone with no exercise; placebo plus exercise; and testosterone plus exercise. The men received injections of 600 mg of testosterone enanthate or placebo weekly for 10 weeks. The men in the exercise groups performed standardized weight-lifting exercises three times weekly. Before and after the treatment period, fat-free mass was determined by underwater weighing, muscle size was measured by magnetic resonance imaging, and the strength of the arms and legs was assessed by bench-press and squatting exercises, respectively. RESULTS: Among the men in the no-exercise groups, those given testosterone had greater increases than those given placebo in muscle size in their arms (mean [+/-SE] change in triceps area, 424 +/- 104 vs. -81 +/- 109 square millimeters; P < 0.05) and legs (change in quadriceps area, 607 +/- 123 vs. -131 +/- 111 square millimeters; P < 0.05) and greater increases in strength in the bench-press (9 +/- 4 vs. -1 +/- 1 kg, P < 0.05) and squatting exercises (16 +/- 4 vs. 3 +/- 1 kg, P < 0.05). The men assigned to testosterone and exercise had greater increases in fat-free mass (6.1 +/- 0.6 kg) and muscle size (triceps area, 501 +/- 104 square millimeters; quadriceps area, 1174 +/- 91 square millimeters) than those assigned to either no-exercise group, and greater increases in muscle strength (bench-press strength, 22 +/- 2 kg; squatting-exercise capacity, 38 +/- 4 kg) than either no-exercise group. Neither mood nor behavior was altered in any group. CONCLUSIONS: Supraphysiologic doses of testosterone, especially when combined with strength training, increase fat-free mass and muscle size and strength in normal men.""",1
9169,8645078,"""Captopril-associated """"pseudocholangitis'. A case report and review of the literature""","""Captopril, a competitive inhibitor of angiotensin-converting enzyme, is widely used in the treatment of hypertension and heart failure. Captopril is known to be associated with dermatologic, hematologic, and pulmonary adverse effects. However, hepatotoxicity is extremely rare. A patient with severe cholestatic jaundice induced by captopril is presented. On admission to the hospital, the patient was diagnosed and treated as having cholangitis. Review of the literature showed similar occurrences in other patients. Patients treated with captopril who develop """"atypical cholangitis"""" should be suspected of having captopril-associated liver damage.""",1
9170,8646427,Methotrexate in rheumatoid arthritis: toxicity issues,,1
9171,8651842,Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid,"BACKGROUND: Amoxicillin-clavulanic acid combination-associated hepatitis and jaundice was first identified in 1988. Numerous case reports and case series have been published since then, but there is no precise estimate of this risk. METHODS: A retrospective cohort study in the United Kingdom to estimate the risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid and compare it with the one of amoxicillin alone. Data were derived from a cohort of 93,433 users of the combination drug amoxicillin-clavulanic acid and 360,333 users of amoxicillin alone who were aged between 10 and 79 years and who were followed up from 1991 through 1992. After reviewing the information on subjects with suspected liver injury that was recorded on computer files, the clinical records of 177 patients from the attending general practitioners were requested. RESULTS: They were 35 cases of idiopathic acute liver injury. None was fatal. There were 14 cases of acute liver injury among users of amoxicillin alone. The type of liver injury was hepatocellular in half the cases. There were 21 cases of acute liver injury among users of amoxicillin and clavulanic acid together. The type of liver injury was cholestatic in three quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of developing acute liver injury associated with the combination of amoxicillin and clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (.02-0.5) per 10 000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver injury for amoxicillin and clavulanic acid together compared with amoxicillin alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients presenting with jaundice. Among users of amoxicillin and clavulanic acid together, the risk of developing acute liver injury was more than 3 times greater after a course of 2 or more consecutive prescriptions than after a single course of therapy. The risk also increased with age among users of amoxicillin and clavulanic acid together. The combination of advancing age and repeated prescriptions resulted in a risk of developing acute liver injury greater than 1 per 1000 users of amoxicillin and clavulanic acid together.",1
9172,8655682,"""Pathology of deaths associated with """"ecstasy"""" and """"eve"""" misuse""","AIMS: To study the postmortem pathology associated with ring substituted amphetamine (amphetamine derivatives) misuse. METHODS: The postmortem findings in deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl-amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve) were studied in seven young white men aged between 20 and 25 years. RESULTS: Striking changes were identified in the liver, which varied from foci of individual cell necrosis to centrilobular necrosis. In one case there was massive hepatic necrosis. Changes consistent with catecholamine induced myocardial damage were seen in five cases. In the brain perivascular haemorrhagic and hypoxic changes were identified in four cases. Overall, the changes in four cases were the same as those reported in heart stroke, although only two cases had a documented history of hyperthermia. Of these four cases, all had changes in their liver, three had changes in their brains, and three in their heart. Of the other three cases, one man died of fulminant liver failure, one of water intoxication and one probably from a cardiac arrhythmia associated with myocardial fibrosis. CONCLUSIONS: These data suggest that there is more than one mechanism of damage in ring substituted amphetamine misuse, injury being caused by hyperthermia in some cases, but with ring substituted amphetamines also possibly having a toxic effect on the liver and other organs in the absence of hyperthermia.",1
9173,8665360,[Cholestatic hepatitis and anemia induced by ticlopidine],"A new case of acute cholestatic hepatitis in a 70-years-old woman treated with ticlopidine following stroke occurred 2 months previously is presented. The patient also presented anemia which became more severe during admission, but which was resolved following withdrawal of the drug with no involvement of the other 2 series. This is the first case reported with isolated anemia related to ticlopidine.",1
9174,8667468,"Increased matrix proteins, collagen and transforming growth factor are early markers of hepatotoxicity in patients on long-term methotrexate therapy","BACKGROUND: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. DESIGN: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 +/- 0.25 g (n = 20) and 3 +/- 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. CONCLUSIONS: Immunohistochemical quantification of matrix proteins and collagens type III and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate.",1
9175,8668280,[Clinically manifest liver lesions during use of simvastatin],"Symptomatic hepatic damage was diagnosed in six patients, three males and three females, during treatment with simvastatin. All patients recovered after discontinuation of the drug. One patient used the drug again, which led to another increase of serum liver enzyme activity. The period between the start of the treatment with simvastatin and the first symptoms of hepatic damage varied between 1 month and 3 years. If serum liver enzyme activities increase in patients using simvastatin, a causative relation should be considered.",1
9176,8668793,Flutamide-associated liver toxicity during treatment with total androgen suppression and radiation therapy for prostate cancer,"""PURPOSE: To examine the frequency and severity of toxicity associated with flutamide inpatients treated with total androgen suppression before and during pelvic radiation therapy (RT) for prostate cancer. MATERIALS AND METHODS: Sixty-five patients with T2b-T4 prostate cancer received flutamide and goserelin acetate for 4 months, with RT beginning at the 3rd month. Treatment records including liver function test (LFT) results at baseline and during treatment were reviewed and toxicities noted. RESULTS: In 30 (46%) of 65 patients, flutamide was discontinued prematurely. Primary reasons included elevation in LFT levels (n=14); gastro-intestinal toxicity (n=9); decreased hemoglobin level (n=2); patient refusal (n=2); and arthralgia, rash, and malaise (n=1 each). Hepatotoxicity generally was manifest as asymptomatic transaminase level elevation. Grade 3-4 hepatotoxicity was noted in four of 65 patients. Mean aspartase aminotransferase increased from 23 (baseline) to 67 U/L (during flutamide treatment) (P<.02); mean alanine aminotransferase level increased from 26 (baseline) to 94 U/L (during flutamide treatment) (P<.005). CONCLUSION: Flutamide toxicity was common. LFTs should be monitored during flutamide therapy. The role of flutamide in this treatment regimen may need to be reevaluated.""",1
9177,8671272,Elevated liver function tests in a case of moderate ovarian hyperstimulation syndrome,"Ovarian hyperstimulation syndrome is a recognized complication of ovulation induction. Abnormalities in liver function have been considered to be a rare manifestation of the severe form of ovarian hyperstimulation syndrome (OHSS). A 28 year old woman with primary infertility underwent ovulation induction and intrauterine insemination. She was diagnosed with moderate OHSS and was followed as an outpatient. Early in her course of treatment she complained of upper right quadrant pain. Her work-up included an upper right quadrant ultrasound which showed only moderate ascites. Liver function tests at that time were elevated in a hepatocellular damage pattern. Liver function test elevations, as well as the ovarian hyperstimulation, resolved spontaneously in 10 days. Transient abnormalities in liver function do not appear to be limited to the most sever forms of OHSS.",1
9178,8675168,Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis,"""Liver disease is increasingly recognized as a major cause of morbidity in cystic fibrosis (CF). Preliminary data suggest that ursodeoxycholic acid (UDCA) may be beneficial for treatment of this manifestation. We performed a double-blind, multicenter trial in these patients to establish efficacy and safety of UDCA in terms of the improvement of clinical and nutritional indicators besides standard liver function tests. We also intended to establish whether taurine supplementation has a beneficial effect in patients receiving UDCA. From June to December 1990, we enrolled in 12 centers 55 CF patients with liver disease (39 male subjects; median age, 13.8 years). They were randomly assigned to receive for 1 year one of the following treatments: UDCA (15 mg/kg body weight daily) plus taurine (30 mg/kg body weight daily), UDCA plus placebo, placebo plus taurine, or double placebo. Clinical and laboratory evaluations were performed every 3 months. After 1 year, deterioration of overall clinical conditions, as indicated by the Shwachman-Kulczycki score (SKS), occurred in patients who received placebo but not in those who received UDCA (P = .025). Patients treated with UDCA also showed an improvement in gamma-glutamyl transpeptidase (GGT) (P = .004) and 5'-nucleotidase (P = .006) levels. Treatment with taurine was followed by a significant increase in serum prealbumin levels (P = .053), a trend toward a reduction in fat malabsorption, and no effect on the biochemical profile. No severe side effects occurred with any treatment. Thus, we concluded that UDCA administration improves clinical and biochemical parameters in CF patients with liver disease. Taurine supplementation may be indicated in patients with severe pancreatic insufficiency and poor nutritional status.""",1
9179,8676932,"Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group","""BACKGROUND: Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS: We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS: In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS: For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.""",1
9180,8678010,"Acute hepatitis associated with the use of a Chinese herbal product, ma-huang","Herbal medicines are widely perceived by the public as being healthful and innocuous. A number of herbal medicines have now been linked with hepatotoxicity. We report a case of acute hepatitis associated with the use of ma-huang, a herbal product derived from plants of the Ephedra species, which is advertised as being useful for causing weight loss and enhancing energy levels. Given the lack of reports in the literature of hepatotoxicity with ma-huang and ephedrine, we speculate that the ma-huang product our patient took contained some other ingredient or contaminant or was misidentified. Our report and others in the literature, which we review, indicate that the clinician should consider herbal medicines as a possible cause of unexplained liver injury.",1
9181,8687355,Peliosis hepatis associated with oral contraceptive use,A 35 year old woman with right upper quadrant abdominal pain was found to have peliosis hepatis. This was attributed to oral contraceptive use and 6 month follow up after cessation of oral contraceptives showed these lesions to have reduced in extent.,1
9182,8688983,Fatal course of toxic epidermal necrolysis under treatment with lamotrigine,"We report on the first fatal course of toxic epidermal necrolysis (Lyell's disease) occurring under treatment with lamotrigine, following the development of a skin rash caused by carbamazepine.",1
9183,8693545,A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation,"""In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.""",1
9184,8707404,Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy--long-term follow-up of a Swedish cohort,"We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow-up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen-progestin combined brand was associated with an increasing relative risk of breast cancer with follow-up time, the SIR reaching 1.4 (95% CI 1.1-1.8) after 10 years of follow-up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6-5.9) in women prescribed estrogens alone, whereas those given an estrogen-progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol-progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow-up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow-up time. We conclude that hormone replacement increases the endometrial-cancer risk after unopposed estrogens and the breast-cancer risk-notably after estrogen-progestin combined therapy-and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.",1
9185,8711637,Hepatotoxicity of antituberculosis drugs,,1
9186,8712091,"[Phase I study of bicalutamide (Casodex), a nonsteroidal antiandrogen in patients with prostatic cancer]","""A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.""",1
9187,8712879,A 10 year follow up of parenteral gold therapy in patients with rheumatoid arthritis,"OBJECTIVES: To study the long term tolerance of parenteral gold and subsequent drug treatment in patients with rheumatoid arthritis, including prediction of outcome and 'survival' of sequential treatments. METHODS: A retrospective cohort study of 376 patients was made, including a detailed screening of 237 patients treated in 1989. Reasons for discontinuing treatment were analysed in life table analyses, which were used to compare patients receiving parenteral gold treatment in 1985 and 1989, and two groups of patients receiving disease modifying antirheumatic drugs after parenteral gold treatment. The causes of discontinuation were followed in sequential treatments. RESULTS: The estimated probability of discontinuation of parenteral gold treatment was 29% after six months and 42%, 55%, 74%, and 92% after 1, 2, 5, and 10 years, respectively. Mucocutaneous side effects were the main cause of discontinuation of parenteral gold treatment during the first three years, while the probability of discontinuation because of inefficacy dominated after four years. Side effects also constituted the main cause of discontinuation of treatments given after parenteral gold treatment during the first three years of follow up. No significant differences were found when comparing the termination rates between the first and the second and subsequent treatments after parenteral gold treatment. The main reasons for discontinuing one treatment could not predict the cause of discontinuation of the next treatment. CONCLUSION: Mucocutaneous side effects dominated initially, while inefficacy was the dominating cause of discontinuation of long term parenteral gold treatment. No serious side effects were registered. The cause of discontinuation of one treatment did not predict the cause of discontinuation of the following drug. Drug 'survival' was the same in both treatments after parenteral gold treatment.",1
9188,8718422,Safety profile of gemcitabine,"This paper reviews the toxicity profile of gemcitabine in a large group of patients (up to 790) from pivotal phase II studies, in which the drug was given intravenously as a 30 min infusion, in a schedule once a week for 3 weeks followed by a week of rest. The safety profile of gemcitabine is unusually mild for such an active agent in solid tumours. Haematological toxicity is mild and short-lived with modest WHO grades 3 and 4 for haemoglobin (6.4% and 0.9% of patients), leukocytes (8.1% and 0.5%), neutrophils (18.7% and 5.7%) and platelets (6.4% and 0.9%). The incidence of grade 3 and 4 infection associated with this level of myelosuppression was low (0.9% and 0.2%). Transaminase elevations occurred frequently, but they were usually mild, and rarely dose limiting. Mild proteinuria and haematuria were seen but were rarely clinically significant. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting was mild, rarely dose limiting, and generally well controlled with standard antiemetics. Flu-like symptoms were experienced in a small proportion of patients but were of short duration. Where oedema/peripheral oedema was experienced there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare, with WHO grade 3 alopecia reported in 0.5% of patients. There was no grade 4 alopecia. Furthermore, gemcitabine displayed minimal toxicity in elderly patients, and the side-effect profile does not seem to be affected by patient age. The adverse events typically experienced with cytotoxic agents, namely myelosuppression, nausea and vomiting and alopecia, are not seen to such a degree with gemcitabine, and this nonoverlapping toxicity profile suggests that gemcitabine is a promising agent for incorporation into combination chemotherapy regimens.",1
9189,8724260,Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy,"""The clinical profile of antituberculosis treatment (ATT)-induced hepatotoxicity is variable, and the reintroduction of ATT in patients who have developed such injury is controversial. We conducted a prospective study to determine the clinical profile in patients with ATT-induced hepatotoxicity and to test a predefined strategy of reintroduction of ATT. Seventy-two consecutive patients with clinical evidence of ATT-induced hepatotoxicity were included. Jaundice was the presenting symptom in 44 (61%) patients; prodromal symptoms were present in 28 (39%). Serious complications developed in 12 (16.6%) patients (fulminant hepatic failure in seven, subacute hepatic failure in four, hepatic encephalopathy in one). Nine patients (three males, six females) died from these complications. The mean duration of treatment before the onset of hepatitis was significantly longer in the group that died (53.22 +/- 36.22 days) than in the rest of the patients (31.07 +/- 30.30 days; p < 0.01). Malnutrition was present in 37 of the 72 patients. After resolution of drug induced hepatitis, reintroduction of isoniazid and rifampicin was possible in 41 of 44 patients. Thus, our results showed that ATT-induced hepatitis carried significant morbidity and mortality, that malnutrition was common in patients with ATT-related hepatitis, and that potentially hepatotoxic antituberculosis agents could be safely reintroduced after recovery from hepatitis.""",1
9190,8727770,Dilantin hypersensitivity reaction,"""Dilantin hypersensitivity syndrome is characterized by fever, rash, lymphadenopathy, facial edema, and hepatitis. Anemia, pharyngitis, diarrhea, and nephritis may also be present. The eruption may present as the classic erythematous follicular papules and pustules; or it may be pleomorphic, presenting as a morbilliform eruption, erythroderma, or toxic epidermal necrolysis. Early recognition and discontinuation of the medication are necessary to prevent a potentially fatal outcome. A case is presented and the literature reviewed.""",1
9191,8729209,Rifabutin versus placebo in combination with three drugs in the treatment of nontuberculous mycobacterial infection in patients with AIDS,"The aim of this double-blind, randomized, placebo-controlled, 12-week study was to assess the efficacy of rifabutin (450 or 600 mg/d) in the treatment of disseminated nontuberculous mycobacterial infection in patients with AIDS. Companion drugs in both arms of the study were ethambutol, clofazimine, and isoniazid. Because of low accrual, the study was prematurely terminated when a total of 382 patients had been enrolled, of which 200 were eligible (i.e., their specimens were culture-positive for Mycobacterium avium complex [MAC] or Mycobacterium xenopi at baseline) and 102 were evaluable (i.e., they were eligible, were treated for a minimum of 6 weeks, and had at least one culture assessment after baseline). The original protocol called for a total of 220 evaluable patients. At week 12, rifabutin treatment was associated with higher, although nonsignificant, rates of bacteriologic conversion than was the placebo arm, with regard to both the eligible patients (25% vs. 18%) and the evaluable patients (45% vs. 38%). Corresponding median times to culture conversion were 42 vs. 63 days (eligible patients) and 43 vs. 69 days (evaluable patients). No significant difference was observed in clinical improvement, mortality, or toxicity between the two treatment arms. The addition of rifabutin to a triple-drug regimen may contribute to the clearance of disseminated MAC infection in patients with AIDS, without causing additional toxicity.",1
9192,8731582,[Acquired sideroblastic anemia and cholestasis in a hyperthyroid patient treated with methimazole and atenolol],"The authors describe a 62 year-old white male who was diagnosed as autoimmune hyperthyroidism and treated with methimazole and atenolol. Ten days later he showed itching, jaundice and choluria. All drugs were discontinued. The patient was given radioactive iodine. Two months later direct serum bilirubin levels reached 35 mg%. Endoscopic retrograde cholangiogram evidenced normal extrahepatic biliary ducts. The percutaneous liver biopsy showed marked cholestasis specially in the centrolobular zone with a slight infiltrate of mononuclear cells in the portal areas. Together with the liver disease the patient presented an anemic syndrome. Bone marrow aspiration showed rich cellularity, Perls staining showed 70% sideroblasts, with 10% ringed sideroblasts and increased extracorpuscular iron. The patient's evolution was satisfactory. Twenty months after the beginning of the disease clinical and biochemical tests were normal. A new bone marrow aspiration rendered normal. Hepatic cholestasis suffered by our patient was probably due to an adverse reaction of methimazole. Physiopathology of reversible sideroblastic anemia is discussed.",1
9193,8733373,Safety of long-term high-dose minocycline in the treatment of acne,"Minocycline is widely used as a second-line antimicrobial for acne vulgaris. Some patients require doses of up to 200 mg daily to control their acne. To assess the long-term safety of minocycline when used at higher doses, 700 patients treated with minocycline at doses of 100 mg daily, 100/200 mg on alternate days and 200 mg daily, were recruited. The mean duration of treatment was 10.5 months. Side-effects were monitored and full blood count, blood urea, electrolytes and liver function tests were carried out on 200 of the 700 patients. Side-effects were recorded in 13.6%, and included vestibular disturbance, candida infection, gastrointestinal disturbance, cutaneous symptoms (pigmentation, pruritus, photosensitive rash and urticaria) and benign intracranial hypertension. Pigmentation was the only side-effect found to be significantly increased in patients taking higher doses of minocycline, as compared with lower doses (P < 0.01). All patients with pigmentation had taken a total cumulative dose of over 70 g. No significant abnormalities were found in any of the haematological and biochemical profiles. We conclude that minocycline, at doses of up to 200 mg/day, is safe, long-term, for acne, when such doses are clinically necessary.",1
9194,8734324,[Fulminant hepatitis caused by flutamide],,1
9195,8739974,Treatment of two children with hereditary tyrosinaemia type I and long-standing renal disease with a 4-hydroxyphenylpyruvate dioxygenase inhibitor (NTBC),,1
9196,8741026,Hepatic failure associated with imipramine therapy,"Imipramine is an antidepressant drug that is rarely associated with mild liver function abnormalities. These are usually minor and transient liver enzyme elevations which return to normal levels upon discontinuation of the drug. We describe a 48-year-old male who developed subfulminant hepatic failure after imipramine usage, with complete recovery within three months after discontinuation of the drug.",1
9197,8744394,[Acute hepatitis caused by intravenous amiodarone],Amiodarone is an antiarrhythmic agent very often used in clinical practice in spite of its large array of adverse effects. We report one patient case with acute hepatitis following intravenous amiodarone treatment and its possible etiology. Our conclusion is the importance of a strict control of parameters in the hepatic functions in patients who require amiodarone therapy.,1
9198,8747629,Meperidine: therapeutic use and toxicity,"Meperidine is a synthetic opioid analgesic frequently prescribed in the emergency department. Meperidine is most often administered intramuscularly or intravenously, due to its poor oral bioavailability, and is metabolized extensively by the liver. Analgesic effects usually last 3-4 hours with parenteral administration, and some adverse effects such as nausea may be reduced when meperidine is combined with antiemetic or antihistaminic medications. Although meperidine is often a preferred analgesic by both patients and physicians in the treatment of disorders such as migraine headaches, its analgesic efficacy has rarely proven superior to alternative parenteral pain medications in controlled trials. In addition, meperidine can precipitate monoamine oxidase inhibitor reactions, and during metabolism it is demethylated to normeperidine, a compound with significant central nervous system (CNS) toxicity. Meperidine should be considered a second line agent in the treatment of pain when opioid analgesics are required.",1
9199,8749905,"Hepatotoxicity of antimicrobial, antifungal, and antiparasitic agents","""Several antibiotics are known to be hepatotoxic. Apart from subtle, reversible, and often inconsequential abnormalities, cholestasis is the predominant presentation that has a protracted and disabling course. Hepatitis, like illness, is characteristic of some drugs, and chronic liver disease may evolve. It is important to recognize if a patient has an adverse reaction to a drug because continuing use of the drug in the face of hepatitis can have disastrous consequences. Chronic liver disease may ensue and progress onto cirrhosis; this has typically been seen following use of isoniazid and nitrofurantoin. Cholestatic liver disease can progress into a chronic form of a ductopenic state; this is particularly seen after antibiotic-related cholestasis.""",1
9200,8749908,Hepatotoxicity of transplant immunosuppressive agents,Hepatotoxicity from transplant immunosuppressive agents is infrequent but recognized. Most of the published literature emphasizes hepatotoxicity from cyclosporine and azathioprine. Cyclosporine is associated with cholestasis and possibly biliary calculi. Azathioprine has been associated with a variety of hepatic abnormalities. This article reviews the frequency and pattern of hepatotoxicity associated with these agents.,1
9201,8750181,Severe cholestasis and sicca syndrome after thiabendazole,,1
9202,8757175,Terfenadine-induced cholestatic hepatitis,,1
9203,8758509,[Acute hepatitis related to the ingestion of terbinafine],,1
9204,8759678,Minocycline-induced liver injury,"""Tetracycline may cause fatty infiltration of the liver; more recently, it has been reported to cause intrahepatic cholestasis with bile duct depletion. However, minocycline, a derivative of tetracycline, is not generally recognized to be hepatotoxic. We report a series of six cases of presumed minocycline-induced liver injury; five of these patients had acute hepatitic illness, whereas one had a more prolonged course with histological evidence of chronic hepatitis. In addition, three patients demonstrated abnormal anti-nuclear antibody levels, and one had positive double-stranded DNA.""",1
9205,8764622,Isoniazid-related fatal hepatitis,"To describe the clinical and demographic characteristics of fatal hepatitis due to single-drug isoniazid preventive therapy for tuberculosis, we did a survey of cases from state health departments, published case reports, and reports to the Centers for Disease Control and Prevention from 1970 to 1992. Of 108 reported cases, some clinical information was available for 76. A medical review panel judged 39 of these deaths as probably due to isoniazid hepatitis and 23 deaths as possibly due to isoniazid hepatitis. Of the 62 probable and possible cases combined, 50 (81%) were female, 49 (79%) were non-Hispanic black or Hispanic, and 19 (31%) were younger than 35 years. The median duration of isoniazid preventive therapy before symptom onset was 16 weeks. Of the 60 cases with symptom information, 54 (90%) presented with jaundice. Of the 62 cases, 26 (42%) were monitored monthly in accordance with current recommendations, and 6 of the patients were younger than 35 years. We estimate that the rate of fatal isoniazid hepatitis among patients in the public sector was no greater than 4.2 per 100,000 persons beginning therapy and no greater than 7 per 100,000 persons completing therapy. Adherence to isoniazid preventive therapy guidelines apparently reduces, but does not eliminate, the risk of fatal hepatitis. Careful patient selection, education, and monitoring are critical for minimizing that risk.",1
9206,8774209,The clinical spectrum of Jin Bu Huan toxicity,"Herbal medications and other nontraditional medical therapies are becoming increasingly popular in the United States. We describe three children and three adults in whom severe toxic effects developed after ingestion of a Chinese herbal medication, jin bu huan, which is sold as Jin Bu Huan Anodyne Tablets. Jin bu huan produced distinct clinical syndromes after acute ingestion in children and long-term use in adults. A single, acute ingestion in children rapidly produced life-threatening neurologic and cardiovascular manifestations, while long-term jin bu huan use in adults was associated with hepatitis. Jin bu huan contains levo-tetrahydropalmatine, a potent neuroactive substance. The constituents of jin bu huan are misidentified on the package, resulting in significant delay in identifying the plant alkaloid responsible for its toxicity. Although perceived as innocuous, jin bu huan may produce major health effects. The highly concentrated formulation, the lack of childproof packaging, and the product insert listing indications for the treatment of serious medical conditions may all contribute to the development of toxic reactions.",1
9207,8776005,Liver disfunction due to ciprofloxacin,,1
9208,8777552,Methsuximide therapy of juvenile myoclonic epilepsy,"Currently valproic acid is considered to be the drug of first choice for juvenile myoclonic epilepsy (JME) resulting in a 70-90% control rate for all seizure types associated with JME. In those situations where valproic acid fails to control seizure activity, results in unacceptable side-effects, or is declined due to potential side-effects, an alternative effective monotherapy would be desirable. Five adolescent female patients were placed on methsuximide for JME. All five patients have been seizure free with the use of methsuximide and four out of five are now on methsuximide monotherapy with good success. C.L. has now had complete seizure control on methsuximide monotherapy, a total of 1200 mg a day, for 7 years with the exception of one seizure event occurring on an attempted discontinuation of methsuximide after being 5 years seizure free. Methsuximide monotherapy as demonstrated in these five patients is an effective treatment for JME.",1
9209,8778603,Long-term treatment of girls with ornithine transcarbamylase deficiency,"BACKGROUND: Ornithine transcarbamylase is an X-linked mitochondrial enzyme that catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine. A deficiency of this enzyme leads to hyperammonemia and hyperglutaminemia. In boys the disease is often fatal when its onset occurs during the neonatal period, but it is milder when onset occurs later in childhood. Heterozygous girls may be normal or may have episodes of hyperammonemic encephalopathy and decline in cognitive function. We report here on the long-term outcome in girls with ornithine transcarbamylase deficiency enrolled in studies of treatments designed to activate new pathways of waste-nitrogen excretion. METHODS: We studied 32 girls (age, 1 to 17 years) with ornithine transcarbamylase deficiency who had had at least one episode of encephalopathy. The patients were assigned to treatment that consisted of sodium benzoate, alone or in combination with sodium phenylacetate or sodium phenylbutyrate, or sodium phenylbutyrate alone. Collaborating physicians provided clinical, metabolic, and developmental data at specified intervals. RESULTS: Patients treated according to these protocols had greater than 90 percent survival at five years and maintained appropriate weight for height. The frequency of hyperammonemic episodes decreased with increasing age and with sodium phenylacetate or sodium phenylbutyrate treatment. Although the mean IQ before treatment was in the low average range, 19 of the 23 girls in whom intelligence was tested longitudinally had stable test scores. CONCLUSIONS: Girls with symptomatic ornithine transcarbamylase deficiency who are treated with drugs that activate new pathways of waste-nitrogen excretion have fewer hyperammonemic episodes and a reduced risk of further cognitive decline.",1
9210,8780466,Tolerance of mefloquine chemoprophylaxis in Dutch military personnel,"""From June until October 1993, a battalion of Dutch marines was stationed in Cambodia for a United Nations deployment. In 73 volunteers who used mefloquine as malaria chemoprophylaxis, possible mefloquine-related adverse events were monitored with special emphasis on QT prolongation. All participants started mefloquine chemoprophylaxis with a loading dose (250 mg a day for three days) one week before departure, followed by a weekly dose (250 mg) for approximately 25 weeks. One month before (t - 1) and one (t + 1) and three (t + 3) months after mefloquine prophylaxis was started, an at rest electrocardiogram was made. Frequency, PR-, and QT-intervals were measured; blood samples for liver transaminases, total white blood cell count, and mefloquine concentration were obtained after one and three months. Adverse events such as dizziness, headache, coordination problems, and nausea were spontaneously reported in one (1.4%) and three (4.1%) persons at t + 1 and t + 3, respectively, while specific questioning revealed adverse events in nine (12.3%) and five (6.9%) persons, respectively, at the same time point. Three months after starting chemoprophylaxis, the heart rate at rest and total white blood cell count were lower (P < 0.05), while the QTc-interval was longer and levels of liver transaminases increased (P < 0.05), although both were still within the normal range. There was no extreme prolongation of the QTc-interval or increased levels of liver transaminases that resulted in a need to stop the chemoprophylaxis. No accumulation of mefloquine in the serum occurred, and no relationship was observed between the incidence of adverse events and serum mefloquine concentrations. The incidence of self reported mefloquine-related adverse events was low. In conclusion, mefloquine chemoprophylaxis was safe and well-tolerated in this group.""",1
9211,8789977,Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers,"""OBJECTIVE: To compare the frequency of adverse events, particularly neuropsychiatric effects, from mefloquine and from chloroquine plus proguanil as used for malaria chemoprophylaxis. DESIGN: Retrospective questionnaire to travellers taking either regimen between November 1993 and February 1995; telephone interview with those reporting pronounced side effects. SETTING: Travellers from Britain who consulted an advisory helpline. SUBJECTS: 1214 adults taking mefloquine and 1181 taking chloroquine plus proguanil. MAIN OUTCOME MEASURES: Reported presence of and degree of disability from 12 neuropsychiatric and other symptoms, as assessed by the subjects and by referees and on the basis of behaviour change. RESULTS: There were equal rates of any side effects (40%) and of stopping or changing medication. Overall, neuropsychiatric adverse events were significantly more common in travellers taking mefloquine. In all, 333 neuropsychiatric adverse events were reported by 1214 travellers taking mefloquine, compared with 189 such events in 1181 travellers taking proguanil plus chloroquine (P < 0.001). In all, 0.7% of travellers taking mefloquine had disabling neuropsychiatric adverse effects, compared with 0.09% of those taking proguanil plus chloroquine (P = 0.021). Two travellers taking mefloquine (1 in 607) were admitted to hospital as a result of the adverse event, compared with 1 in 1181 travellers taking proguanil plus chloroquine. CONCLUSION: There is a significant excess of adverse neuropsychiatric events of intermediate degrees of severity associated with the use of mefloquine compared with proguanil plus chloroquine. This finding may also explain the discrepant findings between earlier studies and clinical experience.""",1
9212,8792011,Gemcitabine: once-weekly schedule active and better tolerated than twice-weekly schedule,"This paper reviews the toxicity profile of gemcitabine, a novel anticancer drug. Gemcitabine has been administered using two different treatment schedules: once weekly or twice weekly for 3 weeks followed by a week of rest (one cycle). It was well tolerated and alopecia was not a problem. Toxicity was greater in the twice-weekly schedule. Comparing the once-weekly with the twice-weekly schedule, WHO grade 3 or 4 thrombocytopenia was reported in 4.7 and 25.6% of patients, respectively. Other hematological toxicity was minimal. Transient WHO grade 3 or 4 elevations of ALT and AST occurred in 9.2 and 7.2% of patients, respectively, in the once-weekly schedule. For the twice-weekly schedule the corresponding percentages were 12.2 and 13.8%. Symptomatic toxicity was greater in patients who received twice-weekly gemcitabine. Nausea and vomiting was mild and generally well controlled without 5HT3 antagonists. However, there was a greater incidence of nausea and vomiting on the twice-weekly schedule. Flu-like symptoms were documented in 19.8% of patients receiving once-weekly and 63.3% of patients receiving twice-weekly gemcitabine. Peripheral edema, not related to cardiac, hepatic or renal failure, was seen more often in patients on twice-weekly treatment. As the efficacy of gemcitabine in non-small cell lung cancer was equivalent when using both regimens, the better tolerated and more easily administered once-weekly schedule is recommended.",1
9213,8795565,Cross-reactivity in fixed drug eruptions to tetracyclines,,1
9214,8800186,Risks of parenteral deferoxamine for acute iron poisoning,"OBJECTIVE: To review the adverse effects and risks of deferoxamine for the treatment of iron poisoning. METHODS: A literature search of deferoxamine induced adverse effects was used to identify pertinent articles. The references of these articles served as the source of other references not previously identified. RESULTS: Deferoxamine is a relatively safe antidote for iron intoxication, but adverse effects have been recognized with increased usage, particularly with prolonged intravenous dosing. This paper focuses on deferoxamine induced cardiovascular, pulmonary, ocular and auditory toxicity as well as its potential to increase the risk of infection. Information on iron's toxicology and toxicokinetics and deferoxamine's pharmacology and pharmacokinetics are reviewed. With this background information a hypothesis is generated to maximize deferoxamine benefit while minimizing deferoxamine induced pulmonary toxicity. The hypothesis is based upon a stoichiometric approach to maximal chelation during the first 24 h following iron ingestion. CONCLUSION: Deferoxamine is a relatively safe antidote for iron poisoning but the potential for pulmonary and cardiovascular toxicity should be respected. Studies defining maximum regimens over defined periods of time will allow a more logical utilization of deferoxamine, optimizing benefit and minimizing risk.",1
9215,8800624,Ocular chloramphenicol and aplastic anaemia. Is there a link?,"The question of a link between the use of topical ocular chloramphenicol and the incidence of aplastic anaemia continues to be a controversial issue in ophthalmological spheres. At present topical ocular chloramphenicol is widely used in the UK for the treatment of conjunctivitis, whereas it is very rarely prescribed for this indication in the U.S. Individual policies vary around the rest of the world. The evidence for and against any association between topical and ocular chloramphenicol and an increased risk of aplastic anaemia is reviewed, and the reasons behind the current prescribing policies are clarified. The discussion generated in the literature over the past 2 years over this issue is considered, along with the published debate from the past 3 decades. The debate is not conclusive, but by presenting or referencing the specific case reports and the published opinions of various experts, we hope to enable the reader to make his or her own informed decision as to whether use of the topical preparation of chloramphenicol should be considered by the ophthalmological community.",1
9216,8813989,Riluzole,,1
9217,8816722,Drug associated hepatic reactions in New Zealand: 21 years experience,"AIMS: To review spontaneous reports of drug-associated adverse hepatic reactions. METHODS: Reports of drug-associated adverse hepatic reactions received by the New Zealand Centre for Adverse Reactions Monitoring over the 21 year period January 1974 to December 1994 were reviewed. Subdivision into three 7 year periods was undertaken to compare patterns. RESULTS: Of a total of 22,455 adverse medicine reaction (AMR) reports there were 943 reports of liver injury (4.2%). Two hundred and five drugs were associated with hepatic reactions. The top 20 drugs accounted for 57% of all liver reactions. Fifty-seven percent were reported in females. Hepatotoxicity was most commonly reported among patients 50-80 years old. Liver reactions were associated with a 3.3% mortality, but were responsible for 7.4% of all fatal occurrences. There was a steady increase in the number of reports over the 21 years. Although the largest number of reports of liver injury were received between 1988 and 1994, mortality was lowest during this period. There were substantial differences in the medicines associated with hepatic reactions during each of the three periods, although erythromycin was the commonest cause throughout. Erythromycin was associated with two deaths. Halothane and perhexilene were the most frequent cause of death and were two of the most important causes of liver injury during the first and second periods. Diclofenac, Augmentin and flucloxacillin were important causes of hepatotoxicity during period 3 but were not associated with a fatal outcome. CONCLUSION: Hepatic reactions accounted for 4.2% of all adverse medicine reactions and 7.4% of all fatal occurrences. The top 20 drugs were responsible for 57% of all liver reactions. Despite a steady increase in the number of reports during the 21 years, mortality was lowest during the last 7 years. Differences in the medicines causing liver injury during the three periods influenced the number of fatalities. Erythromycin was the most commonly reported cause of hepatic reactions but was usually associated with a favourable outcome. There were no reported deaths with diclofenac, Augmentin or flucloxacillin.",1
9218,8817448,"Methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis","Cholestatic jaundice caused by imidazole derivates is a rare complication of antithyroid therapy. Only 20 such cases have been reported in the literature since the introduction of methimazole in 1949 and of carbimazole in 1953. We present a further case of methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis, where the etiology has been proven by a clear chronological relationship and the lack of other causative factors.",1
9219,8820478,Acute encephalopathy attributed to 5-FU,"Acute encephalopathy attributable to 5-fluorouracil (5-FU) is rare. A patient experienced this reaction associated with a continuous 5-FU infusion. The etiology of the event remains uncertain, but it is generally reversible and does not preclude retreatment with 5-FU at reduced dosages. Steroids and thiamine may expedite neurologic recovery.",1
9220,8823335,Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group,"""PURPOSE: Bone metastases are a major cause of morbidity in breast cancer, resulting in complications that include pain, loss of mobility, pathologic fracture, and tumor-induced hypercalcemia (TIH). Inhibition of osteoclast-mediated bone destruction using bisphosphonates represents a promising new management approach. PATIENTS AND METHODS: Breast cancer patients with bone metastases were randomly allocated to receive chemotherapy alone (152 patients) or chemotherapy plus pamidronate 45 mg in 250 mL of saline as a 1-hour intravenous infusion every 3 weeks (143 patients). Whenever possible, treatment continued until progression of disease (PD) in bone appeared on radiographs or bone scan. Time to PD in bone and pain reduction according to a self-assessment six-point scale were selected as primary end points. PD in bone was verified during extramural review (EMR) of all imaging studies by blinded observers, and these data were used as the main efficacy criterion. Analgesic intake, World Health Organization (WHO) performance status, and complications of bone metastases (radiotherapy, TIH, fractures, orthopedic surgery) were also compared in the two groups. RESULTS AND CONCLUSION: At EMR, median time to PD in bone was increased by 48% in patients who received pamidronate (249 v 168 days; P = .02, Wilcoxon test). Marked pain relief, defined as a two-point decrease lasting for > or = 6 weeks, was reported by 44% of pamidronate patients and by 30% of controls (P = .025, chi 2 test). The infusions (median, nine per patient; range, 0 to 39) were well tolerated, with no major toxicities reported. Pamidronate by repeated infusion can significantly slow the progression of bone metastases and reduce attendant morbidity.""",1
9221,8828996,"Zolpidem in the treatment of short-term insomnia: a randomized, double-blind, placebo-controlled clinical trial","""Zolpidem was evaluated in this double-blind, randomized, placebo-controlled study for efficacy and safety in patients with short-term insomnia related to problems with work, marriage, family, or financial matters. One hundred and thirty-eight patients ranging in age from 20 to 55 years were evaluated for safety. Of these, 136 patients were included in the analysis of efficacy. Patients received zolpidem 10 mg or placebo nightly for 7-10 nights. Patients completed a morning questionnaire daily, reported their global impressions of therapy, and completed a Profile of Mood States (POMS) at the start and end of the study. Nine patients (three zolpidem and six placebo) discontinued before completing the study; three (one zolpidem and two placebo) due to adverse events. Compared to placebo, zolpidem significantly reduced subjective latency to sleep on all nights of treatment and patients rated that falling asleep was easier with zolpidem than with placebo (p < 0.01) throughout the study. Compared to placebo, the zolpidem-treated patients reported longer total sleep time, fewer awakenings after sleep onset, shorter time spent awake after sleep onset and better quality of sleep. All of these differences were significant during at least part of the study. No morning sleepiness or impairment in the ability to concentrate were recorded among patients taking zolpidem. Each item on the patient's global impression of zolpidem therapy was rated significantly better than that of placebo. No changes in mood (including anxiety) were detected using the POMS scale. Side effects occurred with a similar frequency in the zolpidem and placebo groups. Zolpidem was found to be more effective than placebo and was well tolerated in the management of stress-induced short-term insomnia.""",1
9222,8832011,"Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis","""Veno-occlusive disease continues to be a significant cause of morbidity and early mortality following bone marrow transplantation. This study retrospectively analyzes the incidence and risk factors for severe VOD in 350 patients treated with 4 days of busulfan (total 16 mg/kg) and 2 days of cyclophosphamide (120 mg/kg) at four marrow transplant centers. Using the criteria defined by McDonald et al (Hepatology 1984; 4: 116-122), 93/350 (27%) developed VOD (11% mild, 5% moderate and 11% severe). Multivariate analysis revealed the following risk factors to be significantly associated with severe VOD: pretransplant transaminase and alkaline phosphatase elevation, ciprofloxacin antibiotic prophylaxis, use of estrogen/progestins or vancomycin during the peritransplant period and methotrexate for GVHD prophylaxis. Mild to moderate grades of VOD were not associated with significantly increased mortality but mortality was higher in patients with severe VOD (31%, P = 0.0013). These data suggest that risk factors for VOD may depend on the preparative regimen used and suggest that use of these risk factors may identify a subgroup of patients that can be targetted for studies of prevention of VOD.""",1
9223,8832983,Significant changes in serum AST across hepatic histological biopsy grades: prospective analysis of 3 cohorts receiving methotrexate therapy for rheumatoid arthritis,"OBJECTIVE: To describe the statistical association between serum AST and liver biopsy grade in patients with rheumatoid arthritis. METHODS: 94 patients from 3 prospectively followed cohorts underwent a total of 354 biopsies graded according to Roenigk. Blood samples for serum aminotransferase (AST) were obtained every 37.7 + or - 32.7 days (mean + or - SD) and 15.2 + or - 7.1 samples were obtained before each biopsy. For each prebiopsy interval, 4 AST functions were calculated: (1) mean, (2) maximum, (3) percentage abnormal, and (4) the presence or absence of at least one abnormality. Analysis of variance was performed to determine the effect of each of these variables on liver biopsy score. RESULTS: AST increased across biopsy grades: 26.5 IU + or - 10.7 IU (mean + or - SD) in Grade I biopsies, 28.4 + or - 10.9 in Grade II, and 35.4 + or - 21.1 in Grade IIIA (p = 0.0006, overall difference between classes). The percentage of abnormal prebiopsy AST values increased across biopsy grades: 8.7 + or - 13.9 (mean + or - SD) in Grade I biopsies, 12.3 + or - 17.5 in Grade II, and 18.6 + or - 27.1 in Grade IIIA samples [(p = 0.0014) overall difference between classes.] A mean prebiopsy AST in the abnormal range was more likely to be associated with a more abnormal liver biopsy grade (p = 0.01, Wilcoxon's rank sum test). AST values abnormal <49% of the time had a 97% specificity for a normal biopsy grade. CONCLUSION: Regular AST measurements are useful markers of hepatic histologic outcome, within the range of mostly normal histology reported here, in patients with RA receiving longterm weekly MTX.",1
9224,8834428,Risperidone-associated hepatotoxicity,,1
9225,8838473,Massive hepatic necrosis and death following repeated isoflurane exposure: case report and review of the literature,"Multiple exposures to halothane have been shown to produce hepatic injury and subsequent hepatic failure often leading to death. Isoflurane, a related haloalkane, is considered a nonhepatotoxic alternative to halothane and its potential to cause injury has been greeted with skepticism. Described is a 30-year-old woman who developed hepatic failure and died after being exposed twice to isoflurane. Recent exposure to anesthetic agents must be considered when death is caused by massive hepatic necrosis.",1
9226,8841740,Cidofovir,"Cidofovir is a nucleotide analogue which inhibits viral DNA polymerase and is effective against human cytomegalovirus (CMV) infection. It is phosphorylated to its active form by cellular enzymes. With the long intracellular half-life of its metabolites, cidofovir can be administered weekly during induction and every other week during maintenance therapy. Viral resistance has not been documented in patients treated with cidofovir to date, but has developed in vitro. Immediate cidofovir therapy delayed progression of CMV retinitis compared with deferred treatment in patients with AIDS. Cidofovir also delayed the progression of CMV retinitis relapsing after previous treatment. To avoid nephrotoxicity, probenecid and intravenous saline hydration must be administered with each dose of cidofovir.",1
9227,8851452,The tolerability and safety profile of famotidine,"Famotidine is a specific, long-acting histamine2-receptor antagonist. It is indicated for the treatment of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. Since its introduction for the treatment of acid-related disorders in 1985, an estimated 18.8 million patients worldwide have been treated with famotidine. We present a comprehensive safety profile of oral famotidine, incorporating data from investigational trials, postmarketing studies, and reports of marketed use. The excellent tolerability profile of famotidine observed during investigational trials has remained substantially unchanged during postmarketing experience. Famotidine does not notably bind to cytochrome P-450 or gastric alcohol dehydrogenase and therefore has not been associated with clinically significant drug interactions. It is generally well tolerated in patients with cardiovascular, renal, or hepatic dysfunction or with Zollinger-Ellison syndrome who have tolerated doses up to 800 mg daily.",1
9228,8862101,Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study,"BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.",1
9229,8862966,"Antibacterial-induced hepatotoxicity. Incidence, prevention and management","Hepatotoxic reactions to antibacterials are rare, occurring with an estimated frequency of between 1 and 10 per 100,000 drug prescriptions for most antibacterials. Although many antibacterial-induced hepatotoxic reactions have a characteristic clinical and biochemical pattern e.g. cholestatic hepatitis (flucloxacillin) or fatty liver (tetracycline), many can also present with a variety of clinicopathological patterns e.g. nitrofurantoin is associated with the development of acute hepatitis, granulomatous hepatitis and chronic active hepatitis. Almost all reactions are idiosyncratic, with no diagnostic laboratory tests to aid the diagnosis. Early diagnosis is essential and requires a vigilant physician to elicit a detailed drug history. Although the outcome is usually good when the offending antibacterial is withdrawn, morbidity may persist for years and fatalities have occurred, particularly when there is a delay in recognising the hepatotoxic antibacterial. There is no specific treatment for antibacterial-induced hepatotoxicity other than withdrawing the implicated drug. For severe disease, however, liver transplantation should be considered.",1
9230,8876856,Propylthiouracil-induced hepatic damage,"OBJECTIVE: To report a case of propylthiouracil-induced hepatic damage. CASE SUMMARY: A 64-year-old white woman with hyperthyroidism received propylthiouracil 250 mg/d for 1 year. She developed hepatitis after 1 year of therapy. Alcohol and drug abuse were ruled out and all serologic tests for hepatitis A, B, and C were negative. Cytomegalovirus and Epstein-Barr virus infection were also ruled out. Antinuclear antibody, antimitochondrial antibody, and antismooth muscle antibody were negative. The clinical picture was similar to that of viral hepatitis characterized by nausea, vomiting, and jaundice. Histologic examination of a liver biopsy specimen showed chronic active hepatitis. The patient developed cirrhosis during follow-up. DISCUSSION: Propylthiouracil is widely used in the treatment of hyperthyroidism. Despite its widespread use, there have been only a few reported cases of propylthiouracil-induced hepatotoxicity. The precise mechanism of the injury is unknown, although immunologic factors are suggested. CONCLUSIONS: Hepatic damage induced by propylthiouracil is a rare complication. However, the danger of permanent hepatic damage should be kept in mind. The best way of preventing propylthiouracil hepatotoxicity is careful screening of patients considered for treatment.",1
9231,8878246,Influence of biochemical parameters of liver function on vancomycin pharmacokinetics,"""The influence of biochemical parameters of hepatic function on vancomycin pharmacokinetics was retrospectively evaluated in 76 adult patients (age 18 to 81 years), from biochemistry data gathered during routine therapeutic drug monitoring. All subjects had normal serum creatinine levels. Vancomycin concentrations were determined by fluorescence polarization immunoassay in 101 paired serum samples. All data for vancomycin concentration versus time were fitted to a one-compartment model using the bayesian approach. Bilirubin, transaminases (n = 101), gamma-glutamyl transferase (n = 97), alkaline phosphatase (n = 95), albumin (n = 92) and lactate dehydrogenase (n = 42) were determined. No strong correlation was seen between any of the pharmacokinetic and biochemistry parameters studied. In patients with hyperbilirubinaemia, the mean Vss and t1/2 were increased (Vss: 0.75 +/- 0.31 versus 0.92 +/- 0.42 1.kg-1, p = 0.020; t1/2 5.93 +/- 3.30 versus 7.48 +/- 4.44 hr, p = 0.049). When liver function was evaluated according to hepatic profile (normal, mildly altered and severely altered), no significant differences were observed in vancomycin pharmacokinetics among the groups. In conclusion, vancomycin pharmacokinetics are only weakly influenced by the biochemistry parameters of liver function.""",1
9232,8893879,Gemcitabine safety overview,"The novel nucleoside analog, gemcitabine, appears to be exceptionally well tolerated. To examine gemcitabine's toxicity profile in detail, an analysis of safety data from 18 single-agent gemcitabine studies has been performed. The studies were across a range of tumor types, but all used a dose regimen of 800 to 1,250 mg/ m2 once a week for 3 weeks followed by a week of rest. Seven hundred ninety patients were included in the analysis. Myelosuppression was found to be mild and short-lived: World Health Organization grades 3 and 4, respectively, were recorded in 6.4% and 0.9% of patients for hemoglobin, in 8.1% and 0.5% for leukocytes, in 18.7% and 5.7% for neutrophils, and in 3.7% and 1.0% for platelets. There was little associated infection or hemorrhage. Mild transaminase increases were common but were rarely dose limiting. In general, renal toxicity was mild, but a few cases of renal failure of uncertain etiology were reported. There was little symptomatic toxicity, with low incidences of the gastrointestinal and hair toxicities normally associated with cytotoxic drugs. However, there was a higher incidence than expected of flu-like symptoms and edema, although these were rarely serious. When the safety data from non-small cell lung cancer studies were analyzed separately, the toxicity findings were similar. Therefore, these analyses in large numbers of patients confirm gemcitabine's favorable safety profile.",1
9233,8902272,Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis,"Autoantibodies against specific human cytochrome P450s have been found in the sera of patients suffering from a variety of diseases, including those caused by drugs. In the cases of tienilic acid- and dihydralazine-induced hepatitis, patients have serum autoantibodies directed against cytochromes P450 2C9 and P450 1A2, respectively. In the present study, we have found that 25 of 56 (45%) patients diagnosed with halothane hepatitis have autoantibodies that react with human cytochrome P450 2E1 that was purified from a baculovirus expression system. The autoantibodies inhibited the activity of cytochrome P450 2E1 and appeared to be directed against mainly conformational epitopes. In addition, because cytochrome P450 2E1 became trifluoroacetylated when it oxidatively metabolized halothane, it is possible that the covalently altered form of cytochrome P450 2E1 may be able to bypass the immunologic tolerance that normally exists against cytochrome P450 2E1. A similar mechanism may explain the formation of autoantibodies that have been found against other cellular targets of the reactive trifluoroacetyl chloride metabolite of halothane.",1
9234,8909490,Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants,"BACKGROUND: Hepatic and neurologic injury developed in two infants after ingestion of mint tea. Examination of the mint plants, from which the teas were brewed, indicated that they contained the toxic agent pennyroyal oil. METHODS: Sera from each infant were analyzed for the toxic constituents of pennyroyal oil, including pulegone and its metabolite menthofuran. RESULTS: Fulminant liver failure with cerebral edema and necrosis developed in the first infant, who died. This infant was positive only for menthofuran (10 ng/mL). In the other infant, who was positive for both pulegone (25 ng/mL) and menthofuran (41 ng/mL), hepatic dysfunction and a severe epileptic encephalopathy developed. CONCLUSION: Pennyroyal oil is a highly toxic agent that may cause both hepatic and neurologic injury if ingested. A potential source of pennyroyal oil is certain mint teas mistakenly used as home remedies to treat minor ailments and colic in infants. Physicians should consider pennyroyal oil poisoning as a possible cause of hepatic and neurologic injury in infants, particularly if the infants may have been given home-brewed mint teas.",1
9235,8915142,Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients,"This study was designed to establish whether measurement of a serological marker of fibrosis might reduce the need for liver biopsy in psoriatic patients receiving methotrexate (MTX). Levels of type III procollagen aminopeptide (PIIINP-O and PIIINP-B) and laminin P1 (LamP1-B) were measured in 147 serum samples taken at the time of liver biopsy in 87 patients receiving long-term MTX treatment for severe psoriasis. Biopsies were classified as: (1) normal, (2) steatosis, (3) inflammation, (4) fibrosis, or (5) cirrhosis. Groups 3-5 were considered to show clinically relevant abnormality. Compared with controls, PIIINP-O was significantly raised in the group of MTX-treated psoriatics (P < 0.001). Within this group, levels were significantly higher in patients with inflammation, fibrosis or cirrhosis compared with those with normal histology or steatosis alone (P < 0.0001). In contrast, PIIINP-B and LamP1-B did not distinguish between controls and MTX-treated patients or between histological groups. Forty-two patients had two or more biopsies with simultaneous PIIINP-O measurement. PIIINP-O levels at the time of the first biopsy were normal in six of the seven patients whose histology was initially normal and subsequently became abnormal. A single measurement of PIIINP-O thus did not predict which patients might develop abnormal histology following further MTX. In a group of 17 patients, PIIINP-O was measured 3-monthly for up to 6 years during MTX treatment. PIIINP-O was elevated at some time during follow-up in all three patients who developed abnormal histology but was consistently normal in eight of the 11 patients whose histology remained or became normal. Our findings indicate that PIIINP-O is of value in detecting liver damage and, particularly if measured serially, may reduce the need for liver biopsy in MTX-treated patients. Although the test does not detect all patients with fibrosis, it would appear that the risk of missing significant liver damage in patients with persistently normal PIIINP-O is low.",1
9236,8927291,Hepatic necrosis,,1
9237,8929007,Subfulminant liver failure and severe hepatotoxicity caused by loratadine use,,1
9238,8931426,Isoflurane hepatotoxicity: a case report and review of the literature,"Isoflurane, hailed as the anesthetic of the 1980s, is less hepatotoxic than its predecessors, halothane and enflurane. Since its release by the Food and Drug Administration in 1979, controversy has existed about the extent to which isoflurane is capable of producing hepatotoxic effects. In this report, we provide direct evidence that isoflurane can induce liver injury and should therefore be considered as a potential cause of serum transaminase elevations in any patient who is exposed to this anesthetic.",1
9239,8931446,Acute cholestasis by fluoxetine,,1
9240,8935375,Risk factors leading to ceftriaxone-associated biliary pseudolithiasis in children,"Between July, 1992 and June, 1994, 151 pediatric patients who had ceftriaxone therapy for probable or definite bacterial enteritis were prospectively evaluated by serial abdominal ultrasonography. All patients received a dose of > or = 50 mg/kg/day and for a duration of 3 or more days. Five patients developed gallbladder precipitates or pseudolithiasis during treatment. Fasting and patients older than 24 months were probably the significant risk factors associated with this phenomenon (p < 0.05). However, no significant differences in sex, dose (50 vs. > 50 mg/kg/day) or duration of therapy (< 5 vs. > 5 day) were observed between patients who received ceftriaxone with and without the development of this gallbladder abnormality.",1
9241,8938559,A case of tizanidine-induced hepatic injury,"The case history is presented of a woman who developed serious liver injury while taking 36 mg tizanidine daily. Other causes of hepatic injury were excluded. Symptoms resolved after discontinuation of tizanidine, and the liver enzyme levels were nearly normal 6 weeks after discontinuation of the drug. Rechallenge with 4 mg tizanidine caused a relapse. The temporal relationship between the symptoms and liver enzyme elevations, the absence of other potential causes, and the reaction to rechallenge, strongly implicate tizanidine as the cause of hepatic injury. As we are not aware of similar case histories, this seems to be the first reported case of tizanidine-induced hepatic injury.",1
9242,8941257,Sodium phenylbutyrate for urea cycle enzyme deficiencies,,1
9243,8942832,Oral contraceptives and primary liver cancer: temporal trends in three countries,"OBJECTIVE: To determine if vital statistics support a temporal association between the introduction of oral contraceptives (OC) and the incidence of, and mortality from, primary liver cancer in three countries from different regions of the world. METHODS: We used Cancer Incidence in Five Continents, volumes I-VI, for incidence data on primary liver cancer in the United States and Japan. The Centre for Epidemiology in Stockholm provided the incidence data for Sweden. We obtained mortality data for the U.S. from Vital Statistics of the United States, for Japan from The World Health Statistics Annual, and for Sweden from Swedish government sources. We compiled data on the prevalence of OC use in all three countries from multiple sources, including the National Survey of Family Growth, The Population Council, and original articles. RESULTS: Despite several hundred million woman-years of exposure to OCs, primary liver cancer incidence and mortality rates among women have not changed substantially in the United States. In Sweden, another country with extensive OC use, the primary liver cancer incidence trends in women paralleled those of men. The incidence of, and mortality rate from, primary liver cancer is gradually rising in Japan, where OC use has been negligible. CONCLUSION: Population-based data from three industrialized countries with very different patterns of oral contraceptive use provide no support for a measurable effect of OCs on primary liver cancer. Although case-control studies from developed countries have suggested an increase in risk, if such an effect does exist, the public health impact appears to be negligible.",1
9244,8943975,Flutamide-induced toxic hepatitis. Potential utility of ursodeoxycholic acid administration in toxic hepatitis,"Flutamide is a nonsteroidal antiandrogen commonly used in the treatment of prostate cancer. Hepatic toxicity associated with flutamide has been reported with an incidence from less than 1% to about 5%. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been widely used in the treatment of cholesterol gallstones and of several liver diseases, but few data are now available concerning its use in the management of drug-induced hepatitis. The case of a patient who presented severe hepatitis with jaundice following use of flutamide is reported. UDCA treatment was started on admission and, contemporaneously, flutamide was withdrawn. Clinical and biochemical improvement was progressively observed, and the patient was discharged six weeks after the admission. Since fatal flutamide-related hepatitis has been reported, monitoring of serum liver tests is advocated during flutamide administration, and the effectiveness of UDCA in the treatment of drug-induced hepatotoxicity requires further study.",1
9245,8947978,Serum iron concentrations and symptoms of acute iron poisoning in children,"""STUDY OBJECTIVE: To determine whether serum iron concentrations correlate with the development of symptoms of iron poisoning in children. DESIGN: A retrospective study of medical records from January 1976 through June 1992. SETTING: A tertiary care children's medical center. PATIENTS: Criteria for patient selection included an acute ingestion of iron-containing drugs, measurement of serum iron prior to deferoxamine administration, and a serum iron concentration (obtained within 2-9 hours of exposure) that was greater than 150 micrograms/dl (27 mumol/L). Of the 128 children who were hospitalized for acute iron poisoning, 92 patients (mean age 2.3 +/- 2.2 years) met the selection criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean (+/-SD) serum iron concentrations (microgram/dl) of patients who exhibited cardiovascular instability (725 +/- 555, n = 6; p < 0.001) differed from those categorized with central nervous system changes (373 +/- 77, n = 30), gastrointestinal symptoms (334 +/- 83, n = 44), and no symptoms (368 +/- 102, n = 12). Serum iron concentrations in patients with cardiovascular instability ranged from 205-500 micrograms/dl (37-269 mumol/L), whereas those with no symptoms ranged from 170-513 micrograms/dl (30 to 92 mumol/L) demonstrating considerable overlap of ranges. CONCLUSIONS: Serum iron concentrations do not necessarily relate to acute toxicity, and further study is needed to demonstrate the value of serum iron concentrations and to identify alternative strategies in the emergency assessment of the acutely poisoned child.""",1
9246,8956353,Reversible hepatotoxicity of paroxetine in a patient with major depression,"Selective serotonin reuptake inhibitors (SSRIs) are becoming widely used because of their favorable side-effect profile and their safety in overdose. We report about a patient with recurring major depression (DSM-IIIR) who was treated with paroxetine and developed a severe hepatotoxic reaction, which was reversed after withdrawal of the drug. Individual, patient-related causes for this side-effect were not found. To our knowledge, this is the first published case of a probably paroxetine-induced severe hepatotoxicity. Hepatotoxicity should be taken into account as a rare complication that may occur not only with tricyclic antidepressants (TCAs) but also with SSRIs.",1
9247,8959957,"Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses","Thalidomide, a hypnosedative drug introduced in the 1950s, has been used in a variety of dermatologic conditions during the past few decades. Although originally withdrawn from the world market on discovery of its teratogenic effect, it has since been selectively reintroduced for use in various disorders thought to have an autoimmune or inflammatory basis. A review of the literature focused on clinical uses of thalidomide in the treatment of dermatologic diseases was performed. Diseases for which thalidomide has been found effective include erythema nodosum leprosum, prurigo nodularis, actinic prurigo, discoid lupus erythematosus, aphthous stomatitis, Beh?et's syndrome, and graft-versus-host disease. Side effects such as teratogenicity and peripheral neuropathy remain its limiting factor. Thalidomide is a useful addition to the therapeutic armamentarium for treatment-resistant dermatoses as long as proper vigilance for adverse effects is maintained.",1
9248,8961591,Lamotrigine-induced toxic epidermal necrolysis treated with intravenous cyclosporin: a discussion of pathogenesis and immunosuppressive management,"""There is growing evidence that the final common pathway of toxic epidermal necrolysis (TEN) is mediated by the cellular immune system which targets drug altered epithelial antigens. This provides a rationale for immunosuppressive therapy. The ideal regimen for quickly turning off epidermal damage in TEN has not yet been determined and the use or benefit of routine immunosuppression remains highly controversial. This article reviews recent advances in the pathogenesis of TEN along with the theoretical benefits of early immunosuppressive treatment in severe cases, specifically utilizing cyclosporin. We describe a 29-year-old woman with TEN due to the anticonvulsant lamotrigine whose successful management included intravenous cyclosporin. The extension of her lesions ceased within 24 hours of initiating cyclosporin (day 7 of her admission). Complications included: scarring alopecia; Enterococcus faecalis septicaemia due to an infected central line; and ulceration and squamous metaplasia of conjunctivae. The potential role of lamotrigine as a cause of TEN is discussed.""",1
9249,8968230,Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience,"""OBJECTIVE: The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. SUMMARY BACKGROUND DATA: To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. METHODS: In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. RESULTS: A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. CONCLUSIONS: In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.""",1
9250,8968694,Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status,"The standard antitubercular regimen currently includes a combination of 3 antitubercular agents: isoniazid, rifampicin (rifampin) and pyrazinamide. Administration of a fourth agent, ethambutol, is recommended when isoniazid resistance is suspected. Two of these 4 agents (isoniazid and pyrazinamide) are major hepatotoxins. The remaining 2 agents (rifampicin and ethambutol) are rarely or not hepatotoxic. However, rifampicin, which is a powerful enzyme inducer, may enhance the hepatotoxicity of isoniazid. In patients receiving a combination of isoniazid, rifampicin and pyrazinamide, 2 patterns of fulminant liver injury can be observed. The first pattern is characterised by an increase in serum transaminase activity that occurs soon (usually within the first 15 days) after initiation of treatment. This pattern is likely to be caused by rifampicin-induced isoniazid hepatotoxicity. The prognosis is good in most cases. The second pattern is characterised by an increase in serum transaminase activity that occurs late (usually more than 1 month) after the initiation of treatment. It has been suggested that this pattern may be related to pyrazinamide hepatotoxicity. The prognosis of this type of hepatitis is generally poor. In order to reduce the risk of severe hepatic adverse effects during antitubercular treatment, several measures are proposed. First, patients with underlying liver test abnormalities should not be given pyrazinamide. Second, isoniazid and pyrazinamide should be administered at the lowest dosage within their respective therapeutic ranges. Third, serum transaminase levels should be determined twice weekly during the first 2 weeks of treatment, every 2 weeks during the rest of the first 2 months, and every month thereafter. When serum transaminase levels increase to greater than 3 times the upper limit of normal, therapy with isoniazid, rifampicin and pyrazinamide should be stopped. After serum transaminase levels have returned to normal, isoniazid can be re-introduced at a low daily dose, without rifampicin. Pyrazinamide may not be re-introduced because of the risk of recurrence and the poor prognosis of pyrazinamide-induced hepatitis. Although it is nephrotoxic, streptomycin is an alternative in patients with liver test abnormalities during antitubercular treatment.",1
9251,8971372,Melphalan alone prior to allogeneic bone marrow transplantation from HLA-identical sibling donors for hematologic malignancies: alloengraftment with potential preservation of fertility in women,"Melphalan has rarely been used as a single agent for conditioning prior to allogeneic marrow transplantation. Twenty-eight patients (median age 19.5 years) undergoing allogeneic BMT for acute leukemia (n = 26) or lymphoblastic lymphoma (n = 2) in first remission (n = 10) or beyond (n = 18) from HLA-identical siblings received 240 mg/m2 melphalan. Death due to primary graft failure was seen in two patients. Sustained hematopoietic recovery was seen in all the others (n = 22) not dying early due to toxicity (n = 2) or persistent active disease (n = 2). The 3-year probabilities of transplant-related mortality and relapse were 35% and 62%, respectively. Seven patients are alive and well at 103-163 months (median 136) with Karnofsky scores of 100% (10-year disease-free survival, 25%). Of the 16 patients with donors of the opposite sex, seven underwent cytogenetic studies after BMT and showed complete chimerism with donor cells. Amongst the four women who were 15-30 years at the time of the transplant, there were seven pregnancies over 297 months of follow-up beyond 2 years from transplant. In contrast, no pregnancies were seen in 53 women with hematologic malignancies who were conditioned with other regimens over 3524 months of follow-up beyond 2 years from transplant. The pregnancy rate was significantly higher (P < 0.001) for women conditioned with melphalan alone (three of four) than for those conditioned with other regimens (0 of 53). We conclude that pre-transplant conditioning with melphalan alone permits alloengraftment of marrow from HLA-identical siblings, and may preserve fertility better than other regimens in some women.",1
9252,8977730,Is methotrexate liver toxicity modest worldwide?,,1
9253,8981129,Severe ovarian hyperstimulation syndrome (OHSS) and icterus,"Severe ovarian hyperstimulation syndrome (OHSS) leads to changes in laboratory analyte concentrations. Whereas elevated aminotransferase activity is often observed, a cholestatic course with hyperbilirubinaemia and icterus seldom occurs. In this report, the case of a 33 year old patient with polycystic ovary syndrome (PCOS) is described who, after stimulation with human menopausal gonadotrophin (HMG), developed severe OHSS with haemoconcentration, ascites, hydrothorax, elevated aminotransferases, hyperbilirubinaemia and icterus. The patient did not become pregnant and the OHSS regressed, together with the normalization of laboratory and clinical parameters and disappearance of the icterus. During the course of an OHSS cholestasis with icterus may occur, which could be explained by a reactive cholestatic hepatosis as a reaction to the hormonal changes induced by the stimulation therapy.",1
9254,8985273,Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study,"""To evaluate the incidence, severity, and course of ketoconazole-associated hepatic injury, 211 patients with onychomycosis were randomized by a ratio of 2:1 to receive either ketoconazole (137 patients) or griseofulvin (74 patients). All of them were seronegative for hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) and had no biochemical abnormality before therapy. The two groups were comparable in age, sex, and pretherapy liver biochemical tests. Liver biochemical tests were followed up biweekly for 3 months, and then at monthly intervals during the remaining course of therapy. No biochemical abnormality or hepatic injury was found in patients during griseofulvin treatment. Of the patients treated with ketoconazole, 24 (17.5%; 95% confidence interval [CI], 11.1% to 23.9%) showed asymptomatic transaminase elevation. Ketoconazole was discontinued immediately after overt hepatitis developed in another 4 patients (2.9%; 95% CI, 0.1% to 5.7%) who did not succumb to hepatic decompensation. The abnormal biochemical changes in patients with overt hepatitis returned to normal after discontinuing ketoconazole. Elderly patients were more prone to develop overt hepatitis. In patients with asymptomatic liver injury, the abnormal biochemical changes gradually returned to normal despite continuing ketoconazole therapy. The results of this cohort study suggest that ketoconazole-induced overt hepatitis is more common than previously believed and that transient subclinical injury is much more common than overt hepatitis. Therapy with ketoconazole may be continued with caution in the absence of symptoms and/or hyperbilirubinemia, but should be discontinued if overt hepatitis occurs.""",1
9255,8989225,Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide,"Somatostatin analogs are an alternative treatment to pituitary surgery and radiotherapy in acromegalic patients. Recently, a depot long-lasting formulation of slow release (SR) lanreotide has been shown to be effective in the short-term control of GH hypersecretion in acromegalic patients. We report the long-term follow-up of a cohort of 22 acromegalic patients treated with SR lanreotide during 1-3 yr. Thirteen females and 9 males, age 51 +/- 3 yr, presented with macroadenomas (n = 12), microadenomas (n = 8), or empty sella (n = 2). Seven patients previously had undergone a partial surgical removal of their adenomas, and 21 of them had mean plasma GH levels less than 5 micrograms/L during a previous octreotide treatment. According to GH values recorded after 3 months of twice monthly 30 mg SR lanreotide im injection, SR lanreotide was administered every 14 days (n = 13) or every 10 days (n = 9). At the 6-month visit, mean GH values were 5 micrograms/L or less in 68% and 2.5 micrograms/L or less in 27% of patients, and these results remained unchanged during the 1-3 yr follow-up period. During SR lanreotide treatment, the mean insulin-like growth factor I (IGF-I) concentrations remained in the normal range in 63% of patients. No escape from the treatment occurred in any of the cases. A significant decrease of the pituitary tumor volume was observed in 3 (13%) patients. The main side effect consisted of minor digestive problems during 48 h after each injection and was reported by 13 patients. Biannual gallbladder echographies revealed the occurrence of gallstones in 4 (18%) patients. In conclusion, these data confirm the efficacy and the tolerance of the long-term SR lanreotide administration (30 mg im every 10-14 days) in the control of acromegaly.",1
9256,8991155,[Fatal sub-fulminant hepatitis caused by cyproterone acetate. A new case],,1
9257,8995955,Acute hepatitis and drug-related lupus induced by minocycline treatment,"Minocycline is widely prescribed for long-term treatment in acne. Major side effects are rare and include hepatitis and drug-related lupus. Hepatitis can be early and acute or late and chronic, whereas lupus presents as a tardive and insidious disease. We report a case of minocycline-induced lupus initially presenting as acute hepatitis, evolving to chronic cytolysis, in a young man treated for facial acne.",1
9258,8996150,Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy,"""PURPOSE: To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS: Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS: Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION: CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.""",1
9259,8998667,[Severe hepatotoxicity of tuberculostatic agents. Increase in the incidence],"Hepatotoxicity by antituberculous drugs is well known. Nonetheless, severe liver involvement is infrequent. Several series of fulminant hepatitis by antituberculous drugs have recently been reported with a much greater frequency than previously reported. The present study describes the authors' experience which, similar to other groups, has shown a marked increase with respect to previous experience. During 1994 5 patients with acute severe hepatitis associated to antituberculous drugs were admitted to the authors' unit. The mean age of the patients was 43 years (range: 25-62). Two patients were healthy HBsAg carriers, one undergoing enzymatic inducer treatment and was anti-HIV positive. Another patient presented compensated liver cirrhosis by HCV. The 5 cases received combined isoniazid and rifampicin and four had also received pyrazinamide. Four patients presented hepatic encephalopathy. Of these cases, three could not undergo emergency liver transplantation because of contraindications and died due to complications of acute severe liver failure. Another patient evolved favorably following emergency liver transplantation. The only patient who presented good evolution with conservative treatment and who did not present hepatic encephalopathy had discontinued isoniazid because of the finding of slight hypertransaminasemia during a routine analytical control. Several risk factors have been reported for the appearance of hepatotoxicity by antituberculous drugs. The factor of greatest clinical importance for the development of severe hepatotoxicity is probably continuation of the treatment once hepatic dysfunction has initiated. The important increase in cases of severe toxicity urges the need for strict analytical monitoring following initiation of treatment.",1
9260,8999497,[Liver injury caused by coumarin anticoagulants: experience of the IKS (Intercanton Monitoring Station) and the SANZ (Swiss Center for Drug Monitoring)],"Drug-induced liver diseases are potentially avoidable. Hepatotoxic drugs can mimic virtually any form of liver disease. Among all voluntary adverse drug reaction reports to central registries, 4-7% refer to drug-induced liver diseases. We analyze all cases of coumarin-induced hepatic injuries reported on a voluntary basis to the Swiss Drug Monitoring Centre (SANZ) and the Pharmacovigilance Centre (IKS) from 1981 to 1995. During this period the SANZ collected 9720 reports, 674 of which (6.9%) referred to the liver and the biliary tract. In only 11 reports an oral anticoagulant was involved. In 8 cases we assumed at least a possible causal relationship. 2 more cases were reported directly to the IKS. Among these 10 cases 7 were related to phenprocoumon and 3 to acenocoumarol. In 4 cases elevated concentrations of liver enzymes were measured 2-7 days after the beginning of therapy. In the remaining 6 cases the clinical picture was so severe that the patients had to be hospitalized. These 10 cases are discussed and compared with the cases published in the literature. According to our data, hepatic disorders induced by coumarin-anti-coagulants are rare. If hepatitis is diagnosed in a patient treated with oral anticoagulants, the differential diagnosis of a coumarin-induced hepatic injury has to be considered. Crossreactions between the coumarin derivatives phenprocoumon and acenocoumarol are possible.",1
9261,9004792,[Toxic hepatitis caused by aceclofenac],,1
9262,9009137,Cholestatic jaundice induced by ciprofloxacin,,1
9263,9015207,"Angiotensin I-converting enzyme, blood groups, and a local marrow-specific renin-angiotensin system",,1
9264,9021715,Hepatocellular carcinoma in long-term oral contraceptive use,"Hepatocellular carcinoma (HCC) is one of the most common malignancies in certain parts of the world, particularly in Africa and Asia, but it is less commonly encountered in the United States. It is closely associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and almost always develops in a cirrhotic liver. In non-cirrhotic livers, HCC is found in about 20% of asymptomatic carriers of HBV and rarely in patients taking androgenic-anabolic or oral contraceptive (OC) steroids. We report four patients, who developed HCC after prolonged use of OC steroids. Whether OC steroids act as mutagen or co-carcinogen in hepatocarcinogenesis is not clear. To exclude latent HCV and HBV infections which may occur in the absence of their serological markers, we employed polymerase chain reaction for the detection of HBV and HCV sequences in the tumor and non-tumorous liver tissue. Viral sequences of HBV and HCV were undetectable in all four cases. These findings suggest OC use as the only known risk factor in these cases and, therefore, strengthen its possible role in hepatocarcinogenesis.",1
9265,9024733,The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day,"""The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to <100 mg/dl. However, in some patients this cannot be achieved using monotherapy with simvastatin 40 mg/day, the current maximal recommended dose. To evaluate the effectiveness of extending the dosage range, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80, and 160 mg/day in a 26 week, double-blind, 3-period, complete block crossover study. Each active treatment period was 6 weeks in duration with intervening 2 week washout periods. Median reductions from baseline in LDL cholesterol were 41%, 47%, and 53% in the 40-, 80-, and 160-mg groups, respectively. The corresponding reductions in plasma TG were 21%, 23%, and 33%. High-density lipoprotein (HDL) cholesterol increased by 6% to 8% in each group. One patient (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg, and 3 (2.1%) taking 160 mg had transaminase elevations > 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.""",1
9266,9025882,Propylthiouracil-induced fulminant hepatitis: case report and review of the literature,"Propylthiouracil (PTU), a thyroid hormone inhibitor, is widely used for the treatment of hyperthyroidism. Rarely, the drug has been associated with severe hepatotoxicity. We present the case of a 13-year-old girl who developed jaundice and profound liver dysfunction with rapid progression to metabolic encephalopathy while receiving PTU therapy. She died despite extensive therapeutic measures including orthotopic liver transplantation. Her rapid clinical course and fatal outcome show that in spite of regular monitoring, severe, rare, rapidly occurring complications of PTU therapy may still occur.",1
9267,9033862,[Painful acute liver involvement related to ingestion of fenofibrate],,1
9268,9034423,Antibiotic-associated hepatitis: update from 1990,"OBJECTIVE: To review the literature on the recent available evidence of antibiotic-associated acute liver injury. DATA SOURCES: All published articles from January 1990 to July 1995 were extracted from the monthly updated HEPATOX database. Additional articles were found using MEDLINE, EMBASE, and PASCAL searches. Hepatic injuries associated with antituberculous, antimycotic, antiviral, antiprotozoal, and antiseptic compounds were excluded form this review. STUDY SELECTION: As the amount of literature was large, only case reports, series and epidemiologic data were used. Results from clinical trials were reviewed only when other information was available. DATA EXTRACTION: Original articles were reviewed to select relevant material. Information regarding the clinical description, histologic features, severity, outcome, and possible risk factors was extracted. Data on incidence were provided by epidemiologic studies or spontaneous reporting to regulatory agencies. DATA SYNTHESIS: Antibiotic-associated acute injury is rare, with an incidence not exceeding 1 case 10,000 users for most drugs. Among beta-lactams, amoxicillin/clavulanic acid and penicillinase-resistant penicillins are associated with predominant and sometimes protracted cholestasis. The hepatotoxic potential of all available erythromycin salts is confirmed, and recent evidence suggests that roxithromycin could be added to the list of antibiotic-induced liver injury. Among fluoroquinolones, only ciprofloxacin has been associated with serious hepatitis. Trimethoprim/sulfamethoxazole-induced hepatitis often reported, but trimethoprim alone also appears as a possible cause of acute liver injury. Finally, acute bile duct injuries and ductopenia have been described with several antibiotics. CONCLUSIONS: The most important recent information is the possibility of protracted liver cholestasis with bile duct injuries induced by several antibiotics, particularly penicillinase-resistant penicillins, and the identification of new potentially hepatotoxic antibiotics, namely, roxithromycin, ciprofloxacin, and trimethoprim.",1
9269,9036306,The effect of digoxin on mortality and morbidity in patients with heart failure,"""BACKGROUND: The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial. METHODS: In the main trial, patients with a left ventricular ejection fraction of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting-enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo. RESULTS: In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P=0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P=0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P<0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial. CONCLUSIONS: Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.""",1
9270,9036798,"Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Studies of Ocular complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group","""BACKGROUND: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). OBJECTIVE: To evaluate intravenous cidofovir as a treatment for CMV retinitis. DESIGN: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. SETTING: Ophthalmology and AIDS services at tertiary care medical centers. PATIENTS: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). INTERVENTION: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. MEASUREMENTS: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. RESULTS: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.02), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mumol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. CONCLUSIONS: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity.""",1
9271,9038603,"Treatment of recurrent malignant supratentorial gliomas with ifosfamide, carboplatin and etoposide: a phase II study","Thirty-six patients previously treated with surgery, radiation therapy and chemotherapy with a nitrosourea for malignant supratentorial gliomas received a combination of ifosfamide, carboplatin and etoposide (ICE) at tumour progression. Carboplatin and etoposide were both given at a dose of 75-100 mg/m2/day for 3 days, whereas ifosfamide doses ranged from 750 mg/m2/day to 1500 mg/m2/ day for 3 days, according to haematological tolerance. Treatment was repeated every 4 weeks. A minimum of three courses was required to evaluate the response unless the patient had rapid tumour progression. Grade III and IV haematological toxicity occurred in 15 patients (42%) and was lethal in one patient. Grade II hepatic toxicity was observed in one patient. Five complete (CR) and five partial responses (PR) were noted. 9 patients had stable disease (SD) after a minimum of three courses. CR + PR + SD was 53% (19/36). The median time to tumour progression (MTTP) was 13 weeks. Median survival (MST) was 29 weeks (44 weeks for R + S patients and 17 weeks for patients with progressing disease). This study suggests that the ICE combination is active in recurrent supratentorial malignant gliomas after failure of surgery, radiation therapy and chemotherapy, but at the cost of substantial haematological toxicity.",1
9272,9040190,Liver toxicity does not have to follow methotrexate therapy of patients with rheumatoid arthritis,,1
9273,9041931,Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs,"OBJECTIVE: To quantify the risk of symptomatic hepatic injury associated with nonsteroidal antiinflammatory drugs (NSAIDs). METHODS: Five population-based studies were summarized to evaluate information on more than 1,000,000 patients using NSAIDs. RESULTS: The risk of clinically apparent liver injury was approximately 1 case per 10,000 patient-years of NSAID use. Only sulindac, associated with a 5-10-fold higher incidence of hepatic injury, differed significantly from other NSAIDs. Patients using diclofenac showed no higher incidence of serious liver disease than did patients using other NSAIDs. CONCLUSION: Symptomatic hepatic effects attributable to most NSAIDs are extremely rare and usually mild.",1
9274,9048269,"Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study","N-methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood-brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid-induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose-limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self-limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half-life of 117.5 minutes (+/-53.2), and a clearance of 38.8 L/hr (+/-17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.",1
9275,9049513,Doppler flow and echocardiography in functional cardiac insufficiency: assessment of nisoldipine therapy. Results of the DEFIANT-II Study. The DEFIANT-II Research Group,"AIMS: A multicentre, double-blind, placebo-controlled trial was conducted in 542 patients, randomized 7-10 days after myocardial infarction, to study the effect of nisoldipine coat-core (nisoldipine-CC) on exercise after 6 months. Secondary endpoints included exercise-induced ischaemia, left ventricular function measured by Doppler echocardiography, adverse cardiac events and clinical outcome. METHODS AND RESULTS: Patients had reduced left ventricular ejection fraction between 25 and 50%, but no heart failure. Exercise time was not different in the two groups. Nisoldipine-CC prolonged time to 1 mm ST deviation (P = 0.03). There was an effect of nisoldipine-CC of +3.6 cm.s-1 on early peak velocity (P = 0.01) and of -6.2 ms on isovolumic relaxation time (P = 0.005), but no effects on left ventricular volumes or ejection fraction. There was a trend towards reduced mortality (one death in the nisoldipine-CC group vs seven in the placebo group. P < 0.07) and the combined end-point of mortality and cardiac events (P = 0.09). Peripheral oedema occurred in 49 patients assigned to nisoldipine-CC and two assigned to placebo (P < 0.001). There were no differences in non-cardiac events. CONCLUSIONS: Nisoldipine-CC did not improve exercise time but increased time to 1 mm ST deviation, and improved diastolic left ventricular function. It is safe and well tolerated in post-infarction patients with impaired left ventricular function.",1
9276,9053491,Prospective randomized placebo-controlled study of granulocyte-macrophage colony-stimulating factor without stem-cell transplantation after high-dose melphalan in patients with multiple myeloma,"""PURPOSE: To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days. RESULTS: GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients. CONCLUSION: GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.""",1
9277,9058614,Cidofovir: a new therapy for cytomegalovirus retinitis,"""Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, formerly known as HPMPC, is the first antiviral nucleotide analogue available for the treatment of cytomegalovirus (CMV) retinitis. Because cidofovir does not require viral activation, it has two advantages over nucleoside analogues such as ganciclovir and acyclovir. Cidofovir is active in uninfected cells and may act preemptively, and it may retain activity against ganciclovir-resistant strains. Preclinical studies showed the major toxicity of cidofovir to be dose-, schedule-, and species-dependent nephrotoxicity. These studies also showed that concomitant administration of probenecid protects animal models against cidofovir-induced nephrotoxicity. Two phase I-II studies were undertaken in HIV-positive patients with asymptomatic CMV excretion to evaluate several dose-escalation regimens. Data from both phase I-II studies showed that in patients receiving cidofovir at > or =3 mg/kg, the virologic response rate (> or =2 log reduction in CMV titer) was 93% for urine and 74% for semen. In addition, four treatment modifications were indicated to reduce the incidence of cidofovir-related nephrotoxicity: (a) dose reduction or interruption for changes in renal function; (b) concomitant administration of probenecid; (c) administration of 1 L of normal saline 1 h before infusion of cidofovir; and (d) extension of the dosing interval.""",1
9278,9059967,Drug-induced hepatocellular liver injury due to benzylpenicillin with evidence of lymphocyte sensitization,"BACKGROUND/AIMS: Reports on drug-induced liver injury due to benzylpenicillin are scarce and predominantly describe cases of intrahepatic cholestasis. To our knowledge, no immunologically documented case of hepatocellular liver injury due to benzylpenicillin has been reported so far. CASE REPORT: A previously healthy man required long-term therapy with benzylpenicillin because of vertebral spondylitis. After 4 weeks of treatment, liver tests showed a marked increase in transaminases associated with high peripheral eosinophil counts. Discontinuation of benzylpenicillin resulted in gradual recovery. INVESTIGATIONS: Levels of eosinophil cationic protein were elevated, indicating eosinophil activation and the presence of an immunoallergic reaction. Skin tests and assays for specific Ig E-antibodies to benzylpenicillin were negative, but lymphocyte transformation tests demonstrated T-cell sensitization to benzylpenicillin. CONCLUSIONS: According to current causality assessment schemes, our report constitutes a probable case of drug-induced hepatocellular liver injury due to benzylpenicillin.",1
9279,9065147,Fenoterol-induced hepatitis in a pregnant woman: a case report,The case of a pregnant woman in whom hepatitis developed after administration of high-dose fenoterol during the third trimester of a second pregnancy is described.,1
9280,9070519,"Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement","""Specific inhibition of thrombin is a new method for the prevention of postoperative deep-vein thrombosis. The objective of this multicenter, randomized, double-blind study was to compare the efficacy and safety of desirudin (Revasc, CGP 39393; fifteen milligrams two times a day) with that of unfractionated heparin (5000 international units three times a day) in patients having a primary elective total hip replacement. The medications were administered subcutaneously, starting preoperatively and continuing for eight to eleven days. The primary end point was a confirmed thromboembolic event during the treatment period. The presence of deep-vein thrombosis was evaluated with bilateral venograms, which were centrally assessed by two independent radiologists. A total of 445 eligible patients were randomized: 220, to management with heparin, and 225, to management with desirudin. A per-protocol analysis of efficacy was performed for the 351 patients (79 per cent) for whom an adequate bilateral venogram had been made within eight to eleven days after the operation or who had had a proved thromboembolic event. The prevalence of confirmed deep-vein thrombosis was thirteen (7 per cent) of 174 patients who had received desirudin and forty-one (23 per cent) of 177 patients who had received heparin, a significant difference (p < 0.0001). The prevalence of proximal deep-vein thrombosis was also significantly reduced (p < 0.0001), by 79 per cent, in the group that had received desirudin (six [3 per cent] of 174 patients) compared with in the group that had received heparin (twenty-nine [16 per cent] of 177). There were no confirmed pulmonary embolisms or deaths during the period of prophylaxis. During a six-week follow-up period, pulmonary embolism was confirmed in four patients, all of whom had received heparin. There was no significant difference between the treatment groups with respect to bleeding variables or bleeding complications. These data demonstrate that a fixed dose of fifteen milligrams of desirudin, started preoperatively and administered subcutaneously twice daily for at least eight days, provided effective, safe prevention of thromboembolic complications, with no specific requirements for laboratory monitoring, in patients who had a total hip replacement.""",1
9281,9075493,Tramadol: a new centrally acting analgesic,"""The pharmacology, pharmacokinetics, efficacy, adverse effects, and dosage and administration of tramadol are reviewed. Tramadol is a synthetic analogue of codeine that binds to mu opiate receptors and inhibits norepinephrine and serotonin reuptake. It is rapidly and extensively absorbed after oral doses and is metabolized in the liver. Analgesia begins within one hour and starts to peak in two hours. In patients with moderate postoperative pain, i.v. or i.m. tramadol is roughly equal in efficacy to meperidine or morphine; for severe acute pain, tramadol is less effective than morphine. Oral tramadol can also be effective after certain types of surgery. Tramadol and meperidine are equally effective in postoperative patient-controlled analgesia. In epidural administration for pain after abdominal surgery, tramadol is more effective than bupivacaine but less effective than morphine. In patients with ureteral calculi, both dipyrone and butylscopolamine are more effective than tramadol. For labor pain, i.m. tramadol works as well as meperidine and is less likely to cause neonatal respiratory depression. Oral tramadol is as effective as codeine for acute dental pain. In several types of severe or refractory cancer pain, tramadol is effective, but less so than morphine; for other types of chronic pain, such as low-back pain, oral tramadol works as well as acetaminophen-codeine. Common adverse effects of tramadol include dizziness, nausea, dry mouth, and sedation. The abuse potential seems low. The recommended oral dosage is 50-100 mg every four to six hours. Tramadol is an effective, if expensive, alternative to other analgesics in some clinical situations.""",1
9282,9075803,"Effects of pramlintide, an analog of human amylin, on plasma glucose profiles in patients with IDDM: results of a multicenter trial","The effects of subcutaneous administration of 10, 30, or 100 microg q.i.d. pramlintide, an analog of human amylin, on plasma glucose regulation in patients with IDDM were evaluated in a multicenter trial. The plasma glucose response to a Sustacal test meal was significantly reduced compared with placebo both after 1 week and after 2 weeks of administration of 30 or 100 microg pramlintide. In addition, 24-h mean plasma glucose concentrations were significantly lowered in patients receiving 30 microg of pramlintide for 2 weeks compared with placebo, while the 100-microg pramlintide dose did not reach statistical significance for the 24-h glucose profiles. At 10 microg, pramlintide had no effect on the 24-h glucose profile or on the plasma glucose response to a Sustacal test meal. The reduction in 24-h glucose concentrations and glucose concentrations after the Sustacal test meal observed at the 30-microg pramlintide dose was not accompanied by an increased incidence of hypoglycemic events. The most frequent adverse events were dose-related and involved transient upper gastrointestinal symptoms. A majority (>80%) of the patients who reported these adverse events during week 1 did not report them in week 2. These data indicate that pramlintide effectively reduces plasma glucose concentrations as reflected in both a 24-h glucose profile and a Sustacal test meal while maintaining an acceptable safety profile.",1
9283,9078205,Acarbose-induced acute severe hepatotoxicity,,1
9284,9083705,Acarbose: a review of US clinical experience,"Postprandial hyperglycemia and elevations in glycated hemoglobin A1c (HbA1c) levels have been associated with long-term complications of diabetes. Because not all patients with type II, or non-insulin-dependent diabetes mellitus (NIDDM), respond adequately to diet, exercise, or treatment with oral sulfonylurea drugs, alternate therapies have been investigated. Acarbose, the first alpha-glucosidase inhibitor available in the United States, exerts its activity in the gastrointestinal tract. By reversibly inhibiting the enzymatic cleavage of complex carbohydrates to simple absorbable sugars, treatment with acarbose results in a reduction in postprandial blood glucose and, subsequently, reductions in HbA1c levels. Acarbose may be given as monotherapy with diet or in combination with diet and a sulfonylurea drug. The results of several controlled clinical studies conducted in the United States are reviewed here. Acarbose, in doses of up to 100 mg three times daily for periods of up to 16 weeks, was statistically significantly superior to placebo with respect to the mean reduction in HbA1c levels and mean 1-hour postprandial glucose levels. Adverse events were nonsystemic and primarily gastrointestinal in nature. Acarbose represents a new approach to the management of NIDDM, modulating gastrointestinal carbohydrate metabolism to control postprandial hyperglycemia and to maximize long-term glycemic control.",1
9285,9091557,[Hepatic encephalopathy induced by flutamide administered for the treatment of prostatic cancer],"A 72-year-old male treated with flutamide for metastatic prostate cancer developed lethargy and confusion. He was noted to be icteric and his liver enzymes were elevated. Within a week of discontinuing the medication, the patient's mental status and liver function returned to normal. Although flutamide-induced near fatal liver dysfunction has been described, progression to encephalopathy is a rare occurrence. Based on a review of the literature, management guidelines for the use of flutamide are suggested.",1
9286,9093098,Quinolones may induce hepatitis,,1
9287,9095290,Albendazole in treatment of human cystic echinococcosis: 12 years of experience,"This review paper examines the evidence from published and previously unpublished sources for the efficacy and safety of albendazole (ABZ) obtained in the last 12 years. Benzimidazole treatment alone is not ideal, requiring prolonged administration over many weeks, with an unpredictable outcome in terms of response rates in individuals. However, studies have shown that treatment with albendazole in E. granulosus infection can result in an apparent cure in up to 30% of cases, with a further 40-50% showing objective evidence of response when followed in the short term. Some studies have demonstrated that even patients who do not show obvious initial evidence of response may be found to be cured when followed up over several years. Duration of therapy and dose are also important, and with ABZ, efficacy seems to increase with exposure up to 3 months in the commoner cyst sites. Formal dose ranging and minimal effective dose studies have not been performed, but the current dose of 800 mg daily appears to be adequate. The issue of cyclical versus continuous treatment still has to be resolved. Data on ABZ safety has been accumulated over the past 12 years of marketing. The profile shows that liver function abnormalities are common although rarely treatment limiting, while occasional hematological changes affecting the white cells may be more serious. The safety data supplies the rationale for monitoring of patients during treatment. On balance ABZ has been shown to be a useful advance in the management of cystic echinococcosis both when used as sole treatment or as an adjunct to surgery or other treatments.",1
9288,9098261,Stevens-Johnson syndrome associated with methazolamide treatment reported in two Japanese-American women,"BACKGROUND: Systemic acetazolamide treatment has been reported in association with Stevens-Johnson syndrome (SJS). This is the first report of this syndrome associated with methazolamide treatment. The association is reported in two Japanese-American women. METHOD AND RESULTS: Two patients with SJS, which developed during treatment with methazolamide, are described. Other potential associations are discussed. CONCLUSIONS: Systemically administered carbonic anhydrase inhibitors, including both acetazolamide and methazolamide can be associated with SJS.",1
9289,9098664,"Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections","Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3 g oral dose, peak urinary concentrations occur within 4 hours and remain high (> 128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. beta-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication.",1
9290,9101008,Oral terbinafine: a new antifungal agent,"""OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of terbinafine. Available comparative data of terbinafine and other antimycotic agents are described for understanding the potential role of terbinafine in patient care. DATA SOURCES: A MEDLINE search restricted to English language during 1966-1996 and extensive review of journals was conducted to prepare this article. MeSH headings included allylamines, terbinafine, SF 86-327, dermatophytosis, dermatomycosis. DATA EXTRACTION: The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled single- or double-blind studies were evaluated to describe the efficacy of terbinafine in the treatment of various fungal infections. DATA SYNTHESIS: Terbinafine is the first oral antimycotic in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. Terbinafine demonstrates excellent in vitro activity against the majority of dermatophyte species including Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum; less activity is seen against Dematiaceae and the filamentous fungi. It is least active against the pathogenic yeast and this correlates with the relatively poor efficacy against these organisms in vivo. High concentrations of terbinafine are achieved in keratinous tissues, the site of superficial infections, and these concentrations are maintained for up to 3 months. The clinical efficacy of terbinafine against a number of dermatophyte infections exceeds that of the current standard of therapy, griseofulvin. The efficacy of terbinafine may be as good or better than that of the azole antifungals. Additional studies are required to confirm these observations. Terbinafine demonstrates a good safety profile, and relatively few drug interactions have been identified. CONCLUSIONS: Terbinafine is more effective than the gold standard, griseofulvin, in the treatment of tinea pedis and tinea unguinum, with considerably shorter treatment duration in the latter. It has been proven as effective as griseofulvin in the treatment of tinea capitis, tinea corporis, and tinea cruris. Terbinafine does not appear to offer any advantage in the treatment of nondermatophyte infections; its utility in the treatment of systemic infections has yet to be established. Depending on individual institutional costs, terbinafine may be a front-line drug for some superficial infections responding poorly to the current standard of therapy.""",1
9291,9107080,Acute hepatic toxicity during cyclic chemotherapy in non Hodgkin's lymphoma,"""BACKGROUND AND OBJECTIVE: Hepatic toxicity directly related to the drugs administered in cyclic chemotherapy (CT), although sometimes serious, does not limit the treatment of non-Hodgkin's lymphoma (NHL). Nevertheless, reports of reactivation of viral hepatitis in NHL patients with B virus (HBV) infection are becoming more frequent. The recent observation of two cases of severe liver toxicity directly correlated to CT and a case of fatal hepatic failure due to HBV replication prompted us to evaluate the hepatic toxicity of CT in 98 consecutive B-cell NHL patients treated with relatively homogeneous cyclic CT. METHODS: Acute hepatic toxicity was retrospectively evaluated in 98 consecutive B-cell NHL patients who received induction CT. HBV and HCV markers were checked at presentation. All patients were tested for ALT and bilirubin before every CT course, while tests for HBV-DNA and/or for HCV-RNA were performed with PCR only when hepatitis occurred. RESULTS: At presentation 22 patients (22.4%) were positive for HBsAg, and 11 (15.9%) were positive for anti-HCV. Acute hepatitis developed in 12 (12.2%) NHL patients: 8 (out of 22) in HBsAg-positive and anti-HCV-negative patients, 3 (out of 76) in HBsAg-negative patients, and 1 (out of 11) in anti-HCV-positive patients. Hepatitis was attributed to reactivation of chronic B hepatitis in 3 patients and to drug toxicity in 3 others; hepatitis was undefined in 6 cases. INTERPRETATION AND CONCLUSIONS: Drug-related liver toxicity is not a rare occurrence in NHL patients. Reactivation of HBV replication is responsible for a relevant number of the hepatitis cases observed. We did not detect acute hepatitis due to the reactivation of HCV replication (in chronic C hepatitis carriers).""",1
9292,9110927,Ischemic hepatitis associated with toxic epidermal necrolysis in a cirrhotic patient treated with cefuroxime,Ischemic hepatitis is rare in patients with liver cirrhosis and is usually precipitated by hypotension due to gastrointestinal bleeding. We describe a cirrhotic patient who developed ischemic hepatitis as a consequence of toxic epidermal necrolysis (TEN) caused by cefuroxime.,1
9293,9115061,Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan,"""The adulteration by synthetic therapeutic substances of traditional Chinese medicines has been reported on various occasions and has been a public health concern in Taiwan over the past several years. A large-scale effort was initiated in 1992 to screen traditional Chinese medicines that were suspected of adulteration with synthetic therapeutic substances. The term """"adulteration"""" refers to traditional Chinese medicines that are tested and found to contain chemical substances not prescribed or labeled as part of the intended use. A total of 2,609 samples were collected by eight major general hospitals in Taiwan. Samples were collected through physicians' referrals during patients visits. The samples were analyzed by hospital pharmacists following the established standard procedures in comparison to references by thin-layer chromatography. An average of 23.7% (n = 618) of the samples collected from the eight hospitals were adulterated. Four samples with either a rheumatoid or an antiinflammatory indication contained six different kinds of adulterants. More than half (52.8%) of the adulterated traditional Chinese medicines contained two or more adulterants. The sources of adulterated samples and their claimed indications, as well as the most frequently detected synthetic therapeutic substances, are presented in this report. The controversies regarding the combination of synthetic therapeutic substances and traditional Chinese medicines without adequate labeling should be resolved through regulatory actions for better safety of drug use.""",1
9294,9121201,[Hepatitis and Ecstasy],,1
9295,9123721,Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder,"OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.",1
9296,9128330,Autoimmune hepatitis triggered by administration of an herbal medicine,"Although herbal medicines are believed to be safe with few side effects, there are several reports on drug-induced liver injury caused by them. However, there are no reports of autoimmune hepatitis triggered by herbal medicines. We report here the case of a patient with autoimmune hepatitis that became clinically apparent after administration of Dai-saiko-to (Da-Chai-Hu-Tang), an herbal medicine that is used as a standard medicine in Japan.",1
9297,9131951,The risk of acute liver injury associated with cimetidine and other acid-suppressing anti-ulcer drugs,"AIMS: The objective of this study was to estimate the risk of acute liver injury associated with individual acid-suppressing drugs and assess the role of dose and duration of treatment. METHODS: We used a nested case-control study design within a cohort of over 100,000 users of cimetidine, famotidine, omeprazole and ranitidine. The primary source of information was the General Practitioners Research Database. We identified 108,981 persons aged 20-74 years who received at least one prescription for cimetidine, famotidine, omeprazole, or ranitidine during 1990-93, and we ascertained the first occurrence of clinically acute liver injury referred to a specialist or admitted to a hospital. RESULTS: After review of medical records, 33 patients were considered eligible cases of idiopathic acute liver injury with no fatal cases. The type of liver injury was hepatocellular in almost half of the cases, and 80% of all cases presented with jaundice. Twelve cases occurred among current users of cimetidine, five among ranitidine users and one in an omeprazole user. The absolute risk of acute liver injury associated with cimetidine was estimated to be slightly greater than one per 5000 users of cimetidine. The adjusted relative risk (RRs) and 95% CI of developing acute liver injury associated with current use of cimetidine compared to non-use was 5.5 (1.9-15.9), with omeprazole 2.1 (0.2-19.2) and with ranitidine 1.7 (0.5-5.8). In the absence of concomitant use of other hepatotoxic drugs, the RR with cimetidine was 14.4 (2.9-73.7). Among users of cimetidine, the risk was especially high in the first 2 months of starting therapy (RR: 11.3, 3.7-35.1) and at daily doses of 800 mg or greater (RR: 8.8, 3.0-26.0). CONCLUSIONS: Cimetidine was the individual anti-ulcer drug with the highest risk of developing symptomatic acute liver disease. Further data are required to confirm this finding. Our study indicates that there is a dose relationship and a short latent period between cimetidine treatment and acute liver injury.",1
9298,9134282,Double-blind randomized multicenter study on the efficacy of trapidil versus isosorbide dinitrate in stable angina pectoris,"BACKGROUND: Trapidil is an inhibitor of phosphodiesterase I-IV with resulting positive lusitropic, vasodilating, and antiplatelet effects. HYPOTHESIS: This study was undertaken to compare the antianginal efficacy of trapidil with that of isosorbide dinitrate (ISDN) in patients with stable angina pectoris. METHODS: We studied 95 patients with stable angina pectoris who were randomized into a double-blind parallel group study with either oral trapidil or ISDN. After a 1-week run-in period and a 2-week wash-out phase, the patients received either trapidil 200 mg t.i.d. (n = 48) or ISDN 20 mg t.i.d. (n = 47) for 12 weeks. All antianginal medication, except sublingual glyceryl trinitrate (GTN), was discontinued during the study. Patients underwent an exercise electrocardiogram on an ergometer bicycle according to a modified Bruce protocol before and at 6 and 12 weeks during treatment. RESULTS: The workload capacity increased from 583 +/- 281 W.min before treatment to 833 +/- 444 W.min after 12 weeks of treatment in the trapidil group (p < 0.01) and from 555 +/- 276 W.min to 827 +/- 361 W.min in the ISDN group (p < 0.01). The anginal attacks per week as well as the use of GTN decreased significantly in both groups. After 12 weeks of therapy, the cumulative ST-segment depression during exercise decreased by 67% in the trapidil patients and by 23% in the ISDN patients. Compared with baseline, the double product at the 75 W level was reduced in both groups after 12 weeks of treatment. Blood pressure and heart rate at rest remained nearly unchanged. Overall, no statistical difference was found between the two study groups. The tolerability was good. CONCLUSION: Oral trapidil therapy is safe and effective in stable angina pectoris and is equivalent to standard therapy with ISDN.",1
9299,9136851,Fatal acute fulminant liver failure due to clozapine: a case report and review of clozapine-induced hepatotoxicity,"Clozapine-induced hepatotoxicity is not well known and is usually of no clinical significance. This report describes fatal acute fulminant liver failure caused by clozapine in a 39-year-old man with chronic paranoid schizophrenia. The hepatotoxicity of clozapine is reviewed. Asymptomatic elevation of transaminase levels is observed most commonly, affecting between 30% and 50% of patients. Icteric hepatitis is uncommon, noted in 84 of 136,000 patients (0.06%). Fatal acute fulminant hepatitis has been documented in 2 patients (0.001%). The mechanism of clozapine hepatotoxicity is unknown. Although serious toxicity is rare, prescribers of clozapine should be aware of the hepatotoxic potential.",1
9300,9140164,Liver reactions to oral low-dose tetracyclines,"BACKGROUND: We report on a case of severe liver reaction associated with doxycycline in a previously healthy subject. Furthermore, we estimate the incidence of oral low-dose tetracycline-related liver reactions in relation to sales figures in Sweden and study the clinical and biochemical features of low-dose tetracycline-associated liver injury, on the basis of reports to SADRAC (Swedish Adverse Drug Reactions Advisory Committee) and on the reports in the literature. METHODS: All liver reactions reported to SADRAC from 1965 to 1995 were surveyed, and articles on liver reactions resulting from tetracycline published during the period 1966-95 were reviewed. RESULTS: During this 30-year period, 23 liver reactions with a suspected casual relationship to oral, low-dose tetracycline derivatives were reported to SADRAC. A causal relationship was considered likely in 3 and possible in 8 cases, giving an incidence of roughly 1 in 18 million DDD (defined daily doses). No deaths were observed from these liver reactions, and liver enzyme activities normalized in all cases without any serious clinical consequences. A total of three cases of reported tetracycline liver damage were found in the literature. Of these, two were classified as having a likely relationship, and in one a causal relationship was not determinable because of other concomitant drug administration. The liver injury was designated as cholestatic, hepatocellular, and mixed, with similar frequencies. CONCLUSIONS: Low-dose, oral tetracyclines constitute a likely cause of acute liver damage with a variable biochemical profile. Such reactions are probably very rare.",1
9301,9146570,Minocycline-related lupus erythematosus with associated liver disease,"A young woman developed minocycline-related lupus erythematosus with associated autoimmune hepatitis. All clinical and laboratory abnormalities returned to normal when the drug was stopped. The symptoms worsened dramatically upon rechallenge, strongly suggesting the reaction was related to the minocycline.",1
9302,9153299,Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression,"The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.",1
9303,9158528,Reduction of flutamide-induced alanine aminotransferase elevation after replacement by bicalutamide in a patient with N+ disease treated with maximal androgen blockade as a primary treatment,,1
9304,9160206,Tenoxicam-associated hepatic injury: a case report and review,"A 51-year-old woman developed jaundice while taking tenoxicam. A full evaluation, including ultrasound, computed tomography, endoscopic cholangiography and liver biopsy, confirmed the diagnosis of mixed hepatic injury. The patient's jaundice and all other liver function abnormalities normalized 1 month after she discontinued taking tenoxicam. This is the first case report of mixed hepatic injury, confirmed with biopsy, associated with tenoxicam. Tenoxicam should be considered as a potential cause of hepatic injury when other more common aetiologies have been excluded.",1
9305,9161499,[Acute cytolytic hepatitis caused by coumarin. 2 cases],"Coumarin is a drug which is extensively used to treat lymphedema. We report two cases of acute hepatitis probably due to coumarin. Two women, 40 year and 45 year-old, were treated with 90 mg/d of coumarin for 5 months. Clinical features included jaundice, pruritus, and diarrhea. A marked increase in serum aminotransferases was observed (ALT: 30 and 100 times the upper limit of normal, respectively). Coumarin withdrawal was rapidly followed by a favorable outcome in both cases. Rechallenge in one case induced a relapse of symptoms and liver test abnormalities. Coumarin can induce acute cytolytic hepatitis.",1
9306,9162532,[Cholestasis associated with ticlopidine],"The case of a 56-years-old male with cholestasis associated with ticlopidine is presented. Cholestasis is an infrequent adverse effect of this drug. The patient was admitted to hospital because of jaundice, choluria, and itching of one month of evolution. The patient had taken ticlopidine twice a day for 3 months up to one week prior to admission for peripheral arteriopathy. Biopsy was performed showing acinar cholestasis and portal inflammatory infiltrate compatible with cholestasis due to hypersensitivity. Ticlopidine was discontinued by the patient himself one week prior to admission. The drug was not readministered and the evolution of the clinical and biochemical parameters of cholestasis decreased. The patient was asymptomatic and laboratory data were normal 4 months later.",1
9307,9162542,[Hepatic toxicity caused by aceclofenac],,1
9308,9164179,Randomized trial showing equivalent efficacy of filgrastim 5 micrograms/kg/d and 10 micrograms/kg/d following high-dose chemotherapy and autologous bone marrow transplantation in high-risk lymphomas,"""PURPOSE: To evaluate the effect of two filgrastim dosages after autologous bone marrow transplantation (ABMT) in patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Eighty-six patients were enrolled onto a multicenter, randomized, open-label study. The study compared the efficacy and safety of two different doses of filgrastim, 5-microgram/kg/d subcutaneous (SC) bolus injection and 10-microgram/kg/d SC continuous infusion, starting on day 1 following ABMT. RESULTS: Both patient groups were well matched in terms of demography and disease. The results showed no statistical difference in the median time to reach an absolute neutrophil count (ANC) of 0.5 x 10(9)/L (11 days; P = .685) and no difference in the median duration of neutropenia (10 v 11 days, respectively; P = .567) between either dose of filgrastim. The incidence and duration of fever and neutropenic fever were the same in both groups. The number and mean duration of clinically and documented infections, duration of intravenous (IV) antibiotics, time to discharge from hospital, and tumor response also were similar in both groups. CONCLUSION: This study demonstrates that a dose of filgrastim 5 micrograms/kg/d administered as a daily SC bolus injection has a similar efficacy and safety profile compared with the 10-microgram/kg/d dose administered as a SC continuous infusion. The lower dose of filgrastim has potential cost-saving implications in terms of both the dose of drug administered and the ease of administration. Based on these findings, the recommended dose of filgrastim after ABMT should be 5 micrograms/kg/d.""",1
9309,9164222,"Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group","""PURPOSE: To assess activity and toxicity of topotecan in previously treated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients with measurable SCLC, progressive after one first-line regimen, were eligible for the study. Two groups of patients were selected: (1) patients who failed first-line treatment < or = 3 months from chemotherapy discontinuation (refractory group); and (2) patients who responded to first-line treatment and progressed greater than 3 months after chemotherapy discontinuation (sensitive group). Topotecan was administered as a 30-minute daily infusion at a dose of 1.5 mg/m2 for 5 consecutive days, every 3 weeks. RESULTS: One hundred one patients were entered onto the study and 403 courses were administered. Ninety-two patients (47 refractory and 45 sensitive) were eligible and assessable for response. Among refractory patients, there were two partial responses (PRs) and one complete response (CR), for an overall response rate of 6.4% (95% confidence interval [CI], 1.3% to 17.6%), whereas in the sensitive group, there were 11 PRs and six CRs, for an overall response rate of 37.8% (95% CI, 23.8% to 53.5%). Overall median duration of response was 7.6 months. Median survival was 5.4 months; median survival of refractory patients was 4.7 months, whereas that of sensitive patients was 6.9 months (P = .002). Median survival of responding patients was 12.5 months. Toxicity was mainly hematologic. Leukopenia, although short-lived, was universal, with grade III and IV neutropenia occurring in 28% and 46.8% of cycles, respectively. Nonhematological toxicity was mild. Fatigue/malaise was reported in 39.3% of cycles and transient elevation of liver enzymes in 17%. CONCLUSION: Topotecan has significant activity in SCLC, particularly in patients sensitive to prior chemotherapy, with predictable and manageable toxicity. The incorporation of topotecan in combination chemotherapy regimens for future treatment of SCLC is warranted.""",1
9310,9173469,[2 cases of acute cholestasis caused by ticlopidine],"""We report the case of two patients suffered from cholestatic jaundice occurred 3-4 weeks after starting ticlopidine therapy. In both cases the diagnosis was made by ruling out any other known cause of acute hepatitis or cholestasis. One patient underwent liver biopsy, which showed a typical intralobular cholestatic pattern and a slight lymphocytic infiltration of the portal tracts. The other patient, a 29 year-old woman, was taking ticlopidine as the sole drug, further to an ischemic stroke occurred while she was taking oral contraceptives; she presented a diffuse itchy dermatitis, fever and slight eosinophilia besides cholestasis. In both patients ticlopidine was discontinued and liver tests returned to normal values within 4-8 weeks; no rechallenge was attempted and ticlopidine was replaced with another antiplatelet drug. To the best of our knowledge 19 cases of ticlopidine-related cholestatic disease have been described so far in the literature. Its pathogenesis is still unknown, although some clinical findings and experimental results from patients with acute enteropathy or agranulocytosis induced by ticlopidine suggest that the drug may act through a toxic mechanism, perhaps mediated by prostaglandins.""",1
9311,9179740,Liver tests in hyperthyroidism: effect of antithyroid therapy,"Changes in liver biochemical test results have been described in hyperthyroid patients before and after antithyroid therapy. In the present study, we analyzed liver tests at diagnosis and after 6 weeks of treatment with propylthiouracil (PTU) in 43 patients with hyperthyroidism. At diagnosis, 60.5% of the patients had at least one liver abnormality. Elevations of alkaline phosphatase, alanine and aspartate aminotransferase, and gamma-glutamyl transpeptidase levels were observed in 19 (44.2%), 10 (23.3%), six (14%), and six (14%) of the patients, respectively. At the end of the 6-week treatment with PTU, elevations in liver test values, possibly induced by PTU, were found in seven (16.3%) patients. Age, sex, type of goiter (either diffuse or multinodular), and presence or absence of abnormal liver biochemical tests at diagnosis were not significant in determining the possibility of PTU-induced elevations in liver tests. These data suggest that liver test abnormalities are frequently found at the time of diagnosis of hyperthyroidism. However, the presence or absence of these abnormalities does not predict elevations in liver test results, which are possibly induced by PTU during therapy.",1
9312,9186345,"Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group","PURPOSE: We studied the long-term efficacy and tolerability of nilutamide, a nonsteroidal antiandrogen, combined with orchiectomy in patients with advanced prostate cancer. MATERIALS AND METHODS: A large double-blind trial was done on 457 patients randomized to receive nilutamide or placebo after orchiectomy. RESULTS: At 8.5 years of followup significant benefits were found for progression and survival in favor of patients receiving nilutamide and orchiectomy. In addition, normalized prostate specific antigen levels at 3 months from the start of therapy were predictive of good long-term outcome. Moreover, combined androgen blockade with nilutamide increased the chance of patients having normal prostate specific antigen levels at 3 months. Nilutamide was well tolerated in the long term with no increase in the incidence of drug specific adverse events. CONCLUSIONS: With long-term followup of patients with advanced prostate cancer, the combination of nilutamide and orchiectomy has significant benefits in interval to progression and improved survival compared to orchiectomy and placebo.",1
9313,9189054,"Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study","A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA.",1
9314,9190513,[Severe hepatitis attributed to paroxetine (Seroxat)],"A 52-year-old man suffering from chronic hepatitis B related liver cirrhosis was treated for depression with paroxetine (Serotax) 5 mg and subsequently 15 mg once daily. A severe hepatitis with liver failure (jaundice, hypoalbuminaemia, edemas, and ascites) developed. After the drug was withdrawn the patient recovered completely. The adverse reaction may be explained by a change in the pharmacokinetics of the drug caused by the liver cirrhosis. Caution is required in prescribing long-term paroxetine therapy for patients with documented liver cirrhosis. The liver function should be monitored and administration of the drug should be discontinued when functional disturbances are noticed.",1
9315,9193350,"Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial","PURPOSE: A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS: Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS: Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION: The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.",1
9316,9193771,"Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up","BACKGROUND AND DESIGN: Methotrexate (MTX) hepatotoxicity in psoriatic patients is well recognized, but there are discrepancies in the reported incidence and associated risk factors. This retrospective study describes 104 Nova Scotian patients with psoriasis seen between 1979 and 1990. Patients received MTX over one to 11 years (mean 3.38), with baseline and annual follow-up liver biopsies. Clinical data were obtained by chart review. Statistical analysis evaluated the risks associated with obesity, diabetes, alcohol consumption and duration of therapy, with the histological grade of liver biopsies. RESULTS: Of the 104 patients, 35 were obese, 10 were diabetic and 37 occasionally consumed alcohol. At the end of the study, 21 patients had developed severe hepatic fibrosis (grade IIIB), and three developed liver cirrhosis (grade IV). Significant risk of severe hepatotoxicity is related to diabetes (P = 0.02) but not to obesity (P = 0.12) or alcohol consumption (P = 0.12). All patients with cirrhosis took MTX for two years in standard doses of 20 to 25 mg/week. CONCLUSIONS: In this first Canadian study evaluating MTX hepatotoxicity in psoriatics, the incidence of severe hepatotoxicity is high: 23.1% (24 of 104 patients). This study shows that diabetic patients are particularly at increased risk of MTX hepatotoxicity. Occasional alcohol consumption is not associated with increased risk. Three patients who developed cirrhosis over two years of standard MTX therapy may represent a subset of psoriatics with increased hepatic susceptibility to MTX. Another three patients whose severe hepatic fibrosis had regressed upon discontinuation of MTX, but who developed accelerated recurrence of the severe hepatic fibrosis upon resumption of MTX therapy, also suggest the possibility of unusual sensitivity to the drug. These cases emphasize the need for continuing surveillance, with regular liver biopsies, of psoriatic patients on MTX.",1
9317,9195083,Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions,"""A total of 167 human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis were randomly assigned to receive 14 days of therapy with liquid suspension fluconazole (100 mg once daily) or liquid nystatin (500,000 U four times daily). At day 14, 87% of the fluconazole-treated patients were clinically cured, as opposed to 52% in the nystatin-treated group (P < .001). Fluconazole eradicated Candida organisms from the oral flora in 60%, vs. a 6% eradication rate with nystatin (P < .001). The fluconazole group had fewer relapses noted on day 28 (18%, vs. 44% in the nystatin group; P < .001). This relapse difference no longer existed by day 42. Fluconazole oral suspension as a systemic therapy was more effective than liquid nystatin as a topical therapy in the treatment of oral candidiasis in HIV-infected patients and provided a longer disease-free interval before relapse.""",1
9318,9195115,Clinical pharmacokinetics of sulindac. A dynamic old drug,"""Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the indene acetic acid class. The absorption of sulindac is rapid when given orally. Sulindac is reversibly metabolised to sulindac sulphide which has anti-inflammatory and analgesic properties and is irreversibly metabolised to sulindac sulphone which has been suggested to possess antiproliferative effects against tumours. Sulindac and its sulphide and sulphone metabolites bind extensively to plasma albumin. Sulindac is eliminated following bio-transformation; sulindac and sulindac sulphone and their respective glucurooconjugated metabolites are excreted in urine; however only a small amount of the sulindac sulphide metabolite is eliminated in urine. Following long term twice daily administration both sulindac and its metabolites accumulate in plasma. Both patients with cirrhosis and the elderly demonstrate elevated concentrations of all species upon long term sulindac administration as compared with a single dose. The disposition of sulindac and its metabolites may be tied to renal function. In end-stage renal disease, increased free fractions of all species and accumulation of the sulphide and sulphone metabolites, and to a lesser extent sulindac, occurs. Significant drug interactions have been demonstrated for dimethylsulphoxide, cyclosporin, furosemide (frusemide), hydrochlorothiazide, methotrexate and cholestyramine.""",1
9319,9204073,Phenytoin-like hypersensitivity associated with lamotrigine,,1
9320,9211083,Troglitazone,"Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM). Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone. In clinical trials, troglitazone 200 to 800 mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas). Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.",1
9321,9212766,Azathioprine-induced lymphoma manifesting as fulminant hepatic failure,"""Azathioprine and rheumatoid arthritis are known to be associated with an increased risk of the development of non-Hodgkin's lymphoma; however, the manifestation of fulminant hepatic failure is extremely uncommon in patients with non-Hodgkin's lymphoma. In this article, we describe a patient with rheumatoid arthritis who was taking azathioprine, in whom fulminant hepatic failure occurred because of massive lymphomatous infiltration of the liver.""",1
9322,9214235,[Toxic effects of the second dose of sodium aurothiomalate in childhood systemic chronic arthritis],,1
9323,9215610,Severe adverse skin reaction to chlorambucil in a patient with chronic lymphocytic leukemia,,1
9324,9217693,Glatiramer acetate for relapsing multiple sclerosis,,1
9325,9217846,Cholestatic jaundice due to terbinafine,,1
9326,9219808,Chronic hepatitis related to use of fluoxetine,,1
9327,9222185,"Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study","""We compared the efficacy, safety, an tolerability of pramipexole, an aminobenzathiazol-derived dopamine agonist with novel properties, with those of placebo in advanced PD patients with motor fluctuations under levodopa treatment. Pramipexole improved motor function of patients during """"on"""" and """"off"""" periods, decreased the time spent in """"off"""" periods, reduced the severity of """"off"""" periods, decreased disability and PD severity during """"on"""" and """"off"""" periods, as assessed by the Unified Parkinson Disease Rating Scale, and permitted a reduction in levodopa dosage. Adverse effects related to the central nervous system were similar to those reported with other dopamine agonists, and the gastrointestinal and cardiovascular tolerability of the compound was satisfactory.""",1
9328,9226250,Hyperbilirubinemia in a renal transplant patient due to cyclosporin A therapy,,1
9329,9230022,Protracted cholestatic hepatitis after the use of prostata,,1
9330,9234577,Idarubicin in patients with diffuse large cell lymphomas: a randomized trial comparing VACOP-B (A = doxorubicin) vs VICOP-B (I = idarubicin),"""BACKGROUND AND OBJECTIVE: Idarubicin is an effective drug in acute leukemia but its use in non-Hodgkin lymphomas (NHLs) is not yet well established. We evaluated its efficacy in patients with diffuse large cell lymphoma (DLCL) by means of a randomized trial comparing two 12-week regimens (VACOP-B and VICOP-B) which differed only in the anthracycline drug used (doxorubicin vs idarubicin). METHODS: From January 1992 to December 1994, 104 patients aged less than 65 years with de novo advanced stage DLCL were enrolled. Fifty-two patients were treated with VACOP-B (doxorubicin 50 mg/sqm) and 52 with VICOP-B (idarubicin initially 8 mg/sqm and thereafter 10 mg/sqm). RESULTS: Clinical characteristics of the two groups were not significantly different. One HBsAg+ patient died of hepatic necrosis in the VICOP-B arm, and severe (WHO grade > 2) toxicities occurred in 7 patients treated with VACOP-B and in 5 treated with VICOP-B; the only significant difference was for mucositis (p = 0.02). Complete remission (CR) was obtained in 79% of patients receiving VACOP-B and in 56% (idarubicin 8 mg/sqm) and 75% (idarubicin 10 mg/sqm) of those in the VICOP-B group (p = n.s.). Prognostic factors that negatively affected CR were advanced stage in VACOP, bone marrow infiltration in both schedules. At a median follow-up of two years, overall survival (67% VACOP and 61% VICOP) and disease-free survival (65% and 67%, respectively) were not significantly different. INTERPRETATION AND CONCLUSIONS: Idarubicin is slightly less toxic than doxorubicin; at a dose of 10 mg/sqm the former is easily tolerated and shows the same efficacy as doxorubicin in the treatment of DLCL.""",1
9331,9241012,Hepatotoxicity of clozapine,"Two hundred thirty-eight patients treated with either haloperidol or clozapine were investigated to shed more light on the incidence and severity of antipsychotic-induced liver enzyme increase. Serum glutamic-pyruvic transaminase (SGPT) increase was most frequently seen in both treatment groups. When analyzing the incidence rates for patients with increased liver enzyme values (serum glutamic-oxaloacetic transaminase, SGPT, gamma-glutamyl transpeptidase) that were higher than twice the upper limit of the normal range, clozapine-treated patients showed an SGPT increase (37.3%) significantly more frequently than patients treated with haloperidol (16.6%). Both patients with higher clozapine plasma levels and male patients were at a higher risk for an SGPT increase. At least 60% of the increase of the different enzymes remitted within the first 13 weeks of treatment. In general, the authors conclude that clozapine-induced liver enzyme elevation seems to be a common and mostly transient phenomenon.",1
9332,9246051,Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts,"The antifungal drug terbinafine has infrequently been incriminated in the occurrence of acute liver injury. We report a case of prolonged cholestasis that occurred in a 75-year-old woman, following terbinafine administration. Jaundice followed by pruritus appeared after four weeks of therapy and was associated with mixed hepatocellular and cholestatic liver tests abnormalities. Following drug withdrawal, serum bilirubin returned to normal values within three months, but anicteric cholestasis persisted for over six months. A liver biopsy performed after six months showed centrilobular cholestasis, discrete portal fibrosis, and a reduction in the number of interlobular biliary ducts. Terbinafine should be added to the list of drugs that can cause reduction in interlobular bile ducts.",1
9333,9250549,A review of epidemiologic research on drug-induced acute liver injury using the general practice research data base in the United Kingdom,"Drug hepatotoxicities have been evaluated in case histories, surveys based on retrospective record reviews, and spontaneous adverse drug reactions reported to national pharmacovigilance systems, but in relatively few epidemiologic studies. To identify and quantify the risk of acute liver injury associated with individual drugs, we reviewed and integrated all the published epidemiologic research on the subject. The source population for the eight studies was general population registered on a single large general practice-based computerized data base. All were retrospective cohort studies, but some had a case-control design nested within the source cohort. Participants were selected according to their use of selected agents (nonsteroidal antiinflammatory drugs [NSAIDs], antibiotics, acid-suppressing drugs, other drugs suspected of being hepatotoxic) during the study period. Among the agents, we found a group of important hepatotoxic drugs with an associated incidence rate of acute liver injury greater than 100/100,000 users, including chlorpromazine and isoniazid. Agents with less risk but greater than 10/100,000 users were amoxicillin-clavulanic acid and cimetidine. A third group of drugs had an associated incidence rate of acute liver injury of less than 10/100,000 users. Our results provide evidence of relative safety for commonly administered agents such as NSAIDs, amoxicillin, omeprazole, and ranitidine. We also quantified important suspected liver toxicity, providing a reasonable precise risk estimate of clinical liver injury associated with chlorpromazine, isoniazid, and amoxicillin-clavulanic acid.",1
9334,9251655,Severe hepatitis in patients with AIDS and haemophilia B treated with indinavir,,1
9335,9251900,Griseofulvin-induced hepatopathy due to abnormalities in heme pathway,"""1. The effect of long-term griseofulvin (GRIS) topical administration on some indicators of liver damage was examined. 2. Liver porphyrin accumulation was significant; however, no porhyrin crystals were observed under light microscopy. 3. An earlier onset of hepatopathy was established (3-fold) increase of direct bilirubin values after 7 days of treatment; hepatic injury was confirmed by measuring a 6-fold increase of free bilirubin. 4. Enhanced values of alkaline phosphatase and glutamic oxalacetic transaminase (GOT) confirmed the onset of cholestasis. 5. Topical application of GRIS induced measurable hepatopathy. Nevertheless, we cannot discard the possibility that this hepatopathy could also be attributed in part to a direct reaction to xenobiotics.""",1
9336,9252857,Severe hepatotoxicity on beginning propylthiouracil therapy,"We report a case of propylthiouracil (PTU)-induced cholestatic hepatotoxicity in Graves' disease that developed 1 day after beginning PTU. After clinical recover, liver abnormalities persisted for 5 years. Percutaneous liver biopsy and the eventual normalization of enzyme levels excluded permanent liver damage as a result of PTU therapy. Thus prolonged elevation of serum enzymes is consistent with the diagnosis of PTU-induced hepatotoxicity, which may recover completely.",1
9337,9256183,Central venulitis in the allograft liver: a clinicopathologic study,"""BACKGROUND: Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity. METHODS: We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression. RESULTS: No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution. CONCLUSIONS: These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.""",1
9338,9258971,Valproate-induced liver failure in one of two siblings with Alpers disease,"Alpers disease is a neurodegenerative disorder of childhood characterized by early developmental delay, intractable seizures, and death in childhood. Neuropathologic changes are most severe in the gray matter and consist of diffuse neuronal loss, spongiform changes, and astrocytosis. We report 2 siblings with Alpers disease who were discordant for exposure to valproate (VPA). Both had developmental delay, and a progressive seizure disorder beginning at 5 years of age. The proband died at age 8 years of complications of ongoing seizures, including epilepsia partialis continua, with only minimal liver abnormalities. Her younger brother was treated with VPA for new-onset seizures and developed fulminant liver failure 6 months later, which led to his death at 5 years of age. Neuropathologic abnormalities of both siblings were consistent with Alpers disease. These observations support classification of Alpers disease and Alpers disease with liver cirrhosis as a single disease. They also confirm previous reports indicating that VPA may accelerate fulminant liver failure in Alpers disease. We recommend that a diagnosis of Alpers disease be considered in children with unexplained early developmental delay, cerebellar signs, or partial seizures, especially epilepsia partialis continua. When Alpers disease is strongly suspected, use of VPA should be avoided.",1
9339,9263133,Monitoring for methotrexate hepatotoxicity in patients with rheumatoid arthritis: another hepatologist's perspective,,1
9340,9266107,Hepatic toxicity caused by adjuvant CMF/CNF in breast cancer patients and reversal by tamoxifen,"The purpose of the study was to determine the effect of adjuvant chemotherapy on liver enzymes in breast cancer patients. Furthermore, the effect of tamoxifen on liver enzymes was analyzed. Liver function tests from 194 breast cancer patients who received adjuvant chemotherapy with or without tamoxifen (TAM) were reviewed. Statistically very significant increases were seen in alkaline phosphatase, aspartate acetyl transferase, and gamma glutamyl transferase levels in these patients receiving adjuvant chemotherapy. No statistical changes were noticed in bilirubin levels. If tamoxifen was given together with adjuvant chemotherapy, no changes in liver function tests were detected. Hepatic toxicity was induced in breast cancer patients by adjuvant CMF/CNF therapy (cyclophosphamide, methotrexate, 5-fluorouracil, mitoxantrone). These changes were mostly mild. Adjuvant tamoxifen reduced the increase in liver enzymes caused by adjuvant chemotherapy.",1
9341,9267134,"[A case of fulminant hepatitis caused by antiandrogen, flutamide in a patient with prostate cancer]","Luteinizing hormone-releasing hormone analogue, 3.6 mg goserelin acetate and flutamide, 375 mg per day were used to treat metastatic prostate cancer in a 66-year-old male. Marked increase in serum aminotransferases and total bilirubin levels was noted after 7 weeks of treatment. The enzyme levels returned to normal at 2 months following discontinuation of the treatment. Though incidences of severe hepatotoxicity are rare (0.003-0.18%), cases of flutamide-induced death have been reported. Careful monitoring of patients is mandatory while administering flutamide.",1
9342,9269384,Ticlopidine induced cholestatic jaundice,Ticlopidine hydrochloride (Ticlid) has been increasingly used as an antiplatelet agent. Some studies showed that it has higher efficacy in reducing stroke recurrence when compared to conventional aspirin. Side effects like gastrointestinal disturbances and blood dyscrasias are common but ticlopidine-induced cholestatic jaundice has been reported only rarely. We present a case report on a patient who has ticlopidine-induced cholestatic jaundice.,1
9343,9269750,Ropivacaine--a new local anesthetic,,1
9344,9280793,[Acute hepatitis associated with treatment with minocycline],,1
9345,9283542,Adverse effects of low dose amiodarone: a meta-analysis,"""OBJECTIVES: We sought to assess the odds of experiencing adverse effects with low dose amiodarone therapy compared with placebo. BACKGROUND: An estimate of the likelihood of experiencing amiodarone-related adverse effects with exposure to low daily doses of the drug is lacking in the published reports, and little information is available on adverse effect event rates in control groups not receiving the drug. METHODS: Data from four published trials involving 1,465 patients were included in a meta-analysis design. The criteria for inclusion were 1) double-blind, placebo-controlled design; 2) absence of a crossover design between patient groups; 3) mean follow-up of at least 12 months; 4) maintenance amiodarone dose < or = 400 mg/day; and 5) presence of an explicit description of adverse effects. Data were pooled after testing for homogeneity of treatment effects across trials, and summary odds ratios were calculated by the Peto-modified Mantel-Haenszel method for each adverse effect. RESULTS: The mean amiodarone dose per day ranged from 152 to 330 mg; 738 patients were randomized to receive amiodarone and 727 placebo. Exposure to amiodarone in this dose range, for a minimal duration of 12 months, resulted in odds similar to those of placebo for hepatic and gastrointestinal adverse effects, but in significantly higher odds than those of placebo (p < 0.05) for experiencing thyroid (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.0 to 8.7), neurologic (OR 2.0, 95% CI 1.1 to 3.7), skin (OR 2.5, 95% CI 1.1 to 6.2), ocular (OR 3.4, 95% CI 1.2 to 9.6) and bradycardic (OR 2.2, 95% CI 1.1 to 4.3) adverse effects. A trend toward increased odds of pulmonary toxicity was noted (OR 2.0, 95% CI 0.9 to 5.3), but this did not reach statistical significance (p = 0.07). The unadjusted total incidence of drug discontinuation was 22.9% in the amiodarone group and 15.4% in the placebo group. The odds of discontinuing the drug in the amiodarone group was approximately 1.5 times that of the placebo group (OR 1.52, 95% CI 1.2 to 1.9) (p = 0.003). CONCLUSIONS: Compared with placebo, there is a higher likelihood of experiencing several amiodarone-related adverse effects with exposure to low daily doses of the drug. Thus, although low dose amiodarone may be well tolerated, it is not free of adverse effects.""",1
9346,9287227,A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team,"""BACKGROUND: The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.""",1
9347,9294990,Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia,"No monotherapy is able to tackle effectively all atherogenic features of familial combined hyperlipidemia: high low-density lipoprotein (LDL) cholesterol, triglycerides (TG), and plasma fibrinogen, as well as low high-density lipoprotein (HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or simvastatin with gemfibrozil or ciprofibrate treatment on total cholesterol, LDL, TG, plasma fibrinogen, and apoproteins B and A-I in patients with refractory familial combined hyperlipidemia, with or without coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to pravastatin + gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively), simvastatin + gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin + ciprofibrate (n = 124, 20 and 100 mg). Lipid parameters, apoproteins B and A-I, and plasma fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited myopathy or rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high transaminases (more than threefold the upper normal limit). Five nonfatal coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing lipid profile than any monotherapy in the past. Simvastatin + ciprofibrate was more effective than pravastatin + gemfibrozil in reducing LDL, TG, and plasma fibrinogen levels. Simvastatin + gemfibrozil increased HDL levels more than the other 2. The apoprotein B decrease was analogous to the LDL reduction by all combinations, whereas apoprotein A-I was increased more with simvastatin + gemfibrozil. The data suggest that the statin-fibrate combinations used in the study are safe and have a favorable effect on all major coronary artery disease risk factors in patients with refractory familial combined hyperlipidemia with or without coronary artery disease. Early detection of the rare drug-induced reversible hepatotoxicity calls for close monitoring of patients.",1
9348,9300571,Activity of gemcitabine in the treatment of patients with non-small cell lung cancer: a multicenter phase II study,"Gemcitabine is a novel nucleoside analog with unique activity against a wide range of solid tumors. We initiated a multicenter phase II study in patients with non-small cell lung cancer (NSCLC) to evaluate the efficacy and safety of gemcitabine. Eligible patients had stage III and IV, previously untreated with chemotherapy, age range from 18 to 80 years, and ECOG performance status 0 2. Gemcitabine was administered at 1000 mg/m2 as a continuous i.v. infusion once a week for a consecutive 3 week period, followed by 1 week of rest. Of the 69 patients enrolled, 67 patients were eligible for efficacy evaluation. The overall response rate was 20.9% with a 95% confidence interval of 11.9-32.6%. The median survival time was 9.0 months and the 12 month survival rate was 31.3%. Grade 3 or 4 toxicities included neutropenia in 22.7%, anemia in 13.4%, leukopenia in 10.4%, anorexia in 10.4%, malaise in 7.5% and nausea/vomiting in 6.0%. Serious toxicities were septic shock and interstitial pneumonia (one patient each). Gemcitabine, administered weekly for three consecutive weeks followed by 1 week of rest, is an active agent for NSCLC. Gemcitabine is currently being evaluated in combination with cisplatin and other agents.",1
9349,9301500,Oral budesonide is as effective as oral prednisolone in active Crohn's disease. The Global Budesonide Study Group,"""BACKGROUND: The use of corticosteroids in active Crohn's disease often becomes limited by side effects. Budesonide is a potent corticosteroid with low systemic bioavailability due to an extensive first pass liver metabolism. AIMS: To compare the efficacy and safety of two dosage regimens of budesonide and prednisolone in patients with active Crohn's disease affecting the ileum and/or the ascending colon. PATIENTS AND METHODS: One hundred and seventy eight patients were randomised to receive budesonide controlled ileal release (CIR) capsules 9 mg once daily or 4.5 mg twice daily, or prednisolone tablets 40 mg once daily. The treatment period was 12 weeks. The primary efficacy variable was clinical remission, defined as a Crohn's Disease Activity Index (CDAI) of 150 or less. RESULTS: After eight weeks of treatment, remission occurred in 60% of patients receiving budesonide once daily or prednisolone and in 42% of those receiving budesonide twice daily (p = 0.062). The presence of glucocorticoid associated side effects was similar in all groups; however, moon face was more common in the prednisolone group (p = 0.0005). The highest frequency of impaired adrenal function, as measured by a short ACTH test, was found in the prednisolone group (p = 0.0023). CONCLUSIONS: Budesonide CIR, administered at 9 mg once daily or 4.5 mg twice daily, is comparable to prednisolone in inducing remission in active Crohn's disease. The single dose administration is as promptly effective as prednisolone and represents a simpler and safer therapeutic approach, with a considerable reduction in side effects.""",1
9350,9303518,Ketoconazole-induced hepatotoxicity,,1
9351,9305331,"Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group","A total of 335 patients with early Parkinson's disease (PD) were enrolled in a multicenter, randomized, double-blind trial designed to assess the efficacy and safety of pramipexole. Entry was restricted to patients with idiopathic PD who were not receiving levodopa. Pramipexole was administered according to an ascending dose schedule up to 4.5 mg/d. During the 7-week dose-escalation phase, each subject was titrated to his or her maximally tolerated dose of study medication. This was followed by a 24-week period of maintenance therapy. The mean daily dose during the maintenance period was 3.8 mg. Pramipexole significantly reduced the severity of PD symptoms and signs compared with placebo, as measured by decreases in parts II (Activities of Daily Living) and III (Motor Examination) of the Unified Parkinson's Disease Rating Scale at week 24 compared with baseline (p < or = 0.0001). Differences between the active drug and placebo groups emerged at week 3 (1.5 mg/d) in the ascending-dose interval and persisted throughout the maintenance phase (p < or = 0.0001). The majority of patients completed the study (pramipexole 83%, placebo 80%). In the assessment of adverse events, nausea, insomnia, constipation, somnolence, and visual hallucinations occurred more frequently in the pramipexole treatment group compared with placebo patients. No clinically significant changes were noted in blood pressure or pulse rate. Overall, these results indicate that pramipexole is safe and effective in the treatment of early PD.",1
9352,9309372,Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group,"The possible adverse effects of chronic, high-dose fluconazole therapy are detailed from analysis of a multicenter, dose-escalating study of the therapy of invasive mycoses. Ninety-three adult patients were studied, 48 of these received > or = 6 months therapy and 20 received > or = 1 year. Fifty-eight patients received > or = 300 mg/day, and 7 received > or = 600 mg/day. One patient received 1,997 g over 86 months. Twenty-seven percent experienced possible symptomatic side effects, which resulted in 2 patients discontinuing therapy, and 42% had asymptomatic laboratory abnormalities, none of which were progressive. Headache, hair loss and anorexia were the most common symptoms experienced (each by 3% of patients), and eosinophilia and aspartate aminotransferase increases were the most common laboratory findings (12 and 10%, respectively). Fluconazole appears well tolerated and safe in these doses and durations.",1
9353,9315493,"Double-blind, placebo-controlled safety and efficacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction","""This double-blind, placebo-controlled clinical trial of yohimbine hydrochloride included 86 patients with erectile dysfunction and without clearly detectable organic or psychologic causes. The patient group fulfilled all entry criteria; 85 of these could be considered for the Safety-respectively 83 for the Intention-to-treat (ITT)-analysis. Yohimbine was administered orally in a dosage of 30 mg a day (two 5 mg tablets three times daily) for eight weeks. Patients were seen for follow-up after four weeks' treatment, and for a final visit after eight weeks. Efficacy evaluation was based on both subjective and objective criteria. Subjective criteria included improvement in sexual desire, sexual satisfaction, frequency of sexual contacts, and quality of erection (penile rigidity) during sexual contact/intercourse. Objective criteria of outcome were based on improvement in penile rigidity determined by use of polysomnography in the sleep laboratory. Overall Yohimbine was found significantly more effective than placebo in terms of response rate: 71 vs 45%. Yohimbine was well-tolerated: Only 7% of patients rated tolerability fair or poor, and most adverse experiences were mild. There was no serious adverse event.""",1
9354,9317091,Lamivudine-stavudine-induced liver failure in hepatitis B cirrhosis,,1
9355,9324030,Effect of combination therapy with cyclosporine and methotrexate on liver function test results in rheumatoid arthritis,,1
9356,9324896,[Liver failure caused by flutamide],"""Flutamide is a non-steroidal anti-androgen used in the treatment of prostate cancer, usually in combination with LHRH-analogs. Incidence of hepatotoxicity associated to Flutamide in the literature is very low and does not exceed 0.18%. Between February 1989 and December 1994, the FDA was reported 20 cases of patients who had died and 26 who had been hospitalized due to hepatotoxicity secondary to Flutamide. We contribute two cases of patients diagnosed with prostate adenocarcinoma following treatment with flutamide and LHRH-analogs who presented liver failure; one with signs and symptoms of acute hepatitis that recovered after discontinuation of the drug, and a second one who developed micronodular cirrhosis and later died of icteroascitic decompensation and hepatorenal syndrome. Including a review of the literature, the paper comments on the likely biological mechanisms for liver toxicity caused by Flutamide. The authors conclude that clinical and laboratory monitoring of patients who either will receive or are receiving treatment with Flutamide is necessary, and withdrawal of drug imperative as soon as certain symptoms of hepatic dysfunction become apparent.""",1
9357,9330929,Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine,"OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.",1
9358,9332048,[Terbinafine-induced cholestatic liver injury],"""A 43-year-old man presented with weakness, pruritus, skin rash and jaundice 2 weeks after treatment for onychomycosis with terbinafine (Lamisil) was started. Liver function tests showed combined hepatocellular and cholestatic injury. Ultrasound examination, computerized tomography and ERCP excluded extrahepatic obstruction. Serology was negative for HBV, HCV, HAV, CMV, and EBV. Liver biopsy was consistent with drug-induced cholestatic injury. Since the clinical picture did not improve when terbinafine was stopped, corticosteroids were started and resulted in complete clinical and laboratory recovery; liver function tests were normal 8 months after corticosteroids were discontinued.""",1
9359,9335511,"The taxoids: same roots, different drugs","The discovery and development of the taxoid class of antitumor compounds, most notably paclitaxel, originally extracted from the Pacific yew, and its semisynthetic analog docetaxel, represent significant advances in the treatment of patients with a variety of malignancies. Although paclitaxel and docetaxel have a similar chemical root, extensive research and clinical experience indicate that important biological and clinical differences exist between the two compounds. Although the mechanism by which they disrupt mitosis and cell replication is novel and unique to this class of compounds, there are small but important differences in the formation of the stable, nonfunctional microtubule bundles and in the affinity of the two compounds for binding sites. These differences may explain the lack of complete cross-resistance observed between docetaxel and paclitaxel in preclinical and clinical studies. The two taxoids also exhibit slightly different toxicity and clinical efficacy profiles. Docetaxel-induced adverse events have been shown to occur most frequently in patients with impaired liver function, and a reduction in dosage in patients with raised levels of transaminases and alkaline phosphatase is recommended to improve the tolerability of the drug in these patients. The incidence and severity of problematic adverse effects such as hypersensitivity, skin reactions, and a cumulative fluid retention syndrome are minimized with the routine administration of a 3- to 5-day corticosteroid-based premedication regimen with each docetaxel infusion. The results of ongoing studies of taxoid-based monotherapies and combination regimens will further optimize the benefits achievable with these drugs, and new preclinical findings also may lead to new clinical uses for these and future drugs of the taxoid class.",1
9360,9347819,Fatal iron intoxication in an infant,"Iron ingestion continues to be one of the major contributors to pediatric poisoning deaths. In 1995, more than 22,000 children unintentionally received preparations containing iron. Despite child-resistant packaging and education of both the public and medical personnel, the number of deaths has not significantly declined. Our patient, a 13-month-old child, ingested prenatal vitamins and despite aggressive efforts died 13 hours after his initial presentation. The patient's 3-year-old sibling had been evaluated at a local hospital 12 hours earlier for iron ingestion. Although there have been previous reports of death from iron ingestion, this case report is important because of the sibling's presentation and medical evaluation 12 hours before our patient's presentation. This case illustrates the need for physicians to inquire about other children in the home, possibly preventing further tragic outcomes.",1
9361,9352959,"Newer anticonvulsant drugs: role of pharmacology, drug interactions and adverse reactions in drug choice","""In the last few years a number of new anticonvulsants have been introduced into clinical practice mainly as add-on therapy in patients who do not become seizure-free while receiving established anticonvulsants. Up to now, no single drug has been shown to be more effective at controlling seizures of a particular type than another, so other factors such as mechanism of action, pharmacokinetics, dosage regimens or the spectrum of adverse drug reactions and interactions are used when making a choice between one agent and another. The mechanism of action of tiagabine and vigabatrin is very specific; both agents increase gamma-aminobutyric acid (GABA) levels through inhibition of reuptake and catabolism respectively. However, the mechanism of action of gabapentin is unknown and those of felbamate, lamotrigine and topiramate are not sufficiently clarified as yet, and may be multiple. Great advances have been made in improving the pharmacokinetic characteristics of these newer anticonvulsants. Gabapentin and vigabatrin exhibit relatively ideal pharmacokinetic properties as they are not bound to proteins, are excreted mostly unchanged in the urine and show linear pharmacokinetics. Lamotrigine possesses a highly variable elimination half-life depending on the co-medication. Tiagabine is highly protein bound and zonisamide shows nonlinear pharmacokinetics; both these drugs are extensively metabolised. Problematic drug interactions between newer anticonvulsants and other drugs in general occur rarely when these agents are given concomitantly. However, in common with most new drugs, there are very few data on the use of the newer anticonvulsants in women of childbearing age. Studies done so far on interactions with oral contraceptives used low anticonvulsant dosages for a very short time. The newer anticonvulsants elicit adverse reactions that, while not being unique, are particularly associated with that drug. For example, felbamate may cause aplastic anaemia and fulminant liver failure, lamotrigine is prone to cause skin rash, and oxcarbazepine may cause symptomatic hyponatraemia. Topiramate and zonisamide cause kidney stones, and vigabatrin may induce psychiatric syndromes. Although highly diverse in structure and activity, these newer drugs offer new possibilities for treating refractory epilepsy. However, since no single factor can dictate the choice of drug nor predict the success of treatment, prescribing of these rather expensive drugs has to depend upon careful consideration of the aims of treatment, the characteristics of the drug and the needs of the individual patient.""",1
9362,9358134,Antithrombotic agents and thromboembolic disease,,1
9363,9360061,Topiramate. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy,"""Topiramate is a sulphamate-substituted monosaccharide derived from D-fructose and is structurally unrelated to other antiepileptic drugs. It acts by multiple mechanisms that suggest it may be effective in several types of epilepsy. In double-blind placebo-controlled trials, add-on therapy with topiramate 400 to 1000 mg/day reduces the seizure rate by > or = 50% in 35 to 52% of adult patients with resistant partial epilepsy (with or without secondarily generalised seizures) compared with 0 to 19% of placebo recipients; a 200 mg/day dosage was less effective. Topiramate has also been shown to be superior in efficacy to placebo in well controlled trials in patients with generalised tonic-clonic seizures, Lennox-Gastaut syndrome and in paediatric patients with partial epilepsy. Efficacy has been maintained for 7 years and some patients may also be satisfactorily treated with topiramate monotherapy. Further study is needed to follow up on the promising results of topiramate use in other paediatric epilepsies. Adverse CNS events are the most common untoward effects during topiramate therapy and are most likely to lead to withdrawal of the drug. However, most adverse events are mild to moderate in severity and lessen with continued drug therapy. In clinical trials, most adverse events which were dose limiting or led to discontinuation of treatment occurred during the titration phase. The overall incidence of adverse events may be reduced by slower upward dosage titration. In summary, topiramate appears to be a suitable agent for add-on therapy in adult patients with partial epilepsy. Preliminary reports support the use of add-on topiramate in adults with generalised epilepsy, in childhood epilepsies and in patients with Lennox-Gastaut syndrome, as well as the use of topiramate monotherapy in patients with partial epilepsy. Thus, topiramate can be considered an important new drug for the management of patients with refractory epilepsy.""",1
9364,9360412,Fever caused by hydroxyurea: a report of three cases and review of the literature,"Hydroxyurea (HU) is generally regarded as an effective and well-tolerated drug for the treatment of the chronic myeloproliferative syndromes. It has rarely been implicated as a cause of drug fever. We report two patients with primary thrombocythaemia and one patient with polycythaemia vera who developed fever and shaking chills during treatment with HU. Infection was highly suspected and all patients were examined extensively. The fever subsided after discontinuation of therapy with this drug. However, the fever recurred within 1 day after rechallenge. The mechanism of HU-induced fever remained unclear, but the experience in our patients and the reviewed cases in the literature are highly suggestive of a hypersensitivity reaction. Clinicians should be aware of this rare adverse effect.",1
9365,9363868,Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin,"""PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.""",1
9366,9370501,Losartan-induced hepatotoxicity,,1
9367,9371937,Multiorgan dysfunction and disseminated intravascular coagulation in children receiving lamotrigine and valproic acid,"Two children developed multiorgan dysfunction with disseminated intravascular coagulation 9 days after lamotrigine was added to their antiepileptic therapy, which included valproic acid. During the episodes, rhabdomyolysis was detected in one of them, while being seizure-free, suggesting that this adverse reaction may involve muscular tissue.",1
9368,9375713,Phenprocoumon-induced hepatitis delaying precise diagnosis in a thrombophilic patient with activated protein C resistance due to factor V R506Q mutation,,1
9369,9377242,[Severe acute hepatitis due to cyproterone],,1
9370,9379999,Tamsulosin for benign prostatic hyperplasia,,1
9371,9381745,[Hepatotoxicity of flutamide],,1
9372,9382559,"Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients","""OBJECTIVE: To broaden the safety database for oral terbinafine by determining the incidence of adverse events, particularly rare risks, that accompany its uncontrolled use in actual clinical practice. DESIGN: Four open, prospective, uncontrolled, postmarketing surveillance studies were conducted in unselected patients in 4 countries. No exclusion criteria were applied. The only treatment instructions participating physicians received were the manufacturer's product information. Physicians monitored patients for adverse events at baseline, during treatment, and at the end of treatment. Serious events were identified according to study protocol, which was consistent for all 4 studies, allowing data to be pooled and analyzed collectively. SETTING: Patients were recruited from dermatology, general, and family practices in the United Kingdom, the Netherlands, Germany, and Austria. PATIENTS: Of the 25884 patients who entered the study, 38.6% had concomitant diseases, 42.8% were taking other medications, and 22.7% were older than 60 years. The predominant indication for terbinafine treatment was onychomycosis (72.2%). INTERVENTIONS: Data on treatment duration was available for 25091 patients. Median duration of treatment was 12 weeks (mean, 13.2 weeks). Treatment extended beyond 6 weeks in 76.0% of patients and for at least 12 weeks in 59.3%. MAIN OUTCOME MEASURES: The incidence of adverse events as reported by physicians, with their opinions regarding relationship to terbinafine therapy. RESULTS: The incidence of adverse events was 10.5%; the majority involved the gastrointestinal system (4.9%) or skin (2.3%). These tended to be mild, transient, and reversible. Terbinafine was considered a possible or probable cause of 11 (0.04%) serious adverse events. No drug interactions were reported, even in patients taking oral antidiabetic agents, astemizole, terfenadine, or cimetidine hydrochloride. CONCLUSIONS: The positive safety profile established during controlled clinical trials of oral terbinafine extends to its uncontrolled use in clinical practice. No previously unrecognized risks were identified.""",1
9373,9384334,Adverse reactions to trimethoprim-sulfamethoxazole among children with human immunodeficiency virus infection,"BACKGROUND: The clinical course of HIV infection is frequently different among infants and children from that in adults. In adults among the most common sources of morbidity related to therapy are adverse drug reactions, notably to trimethoprim-sulfamethoxazole. Although there are case reports of serious adverse reactions to trimethoprim-sulfamethoxazole among infants and children with HIV infection, the precise rate and clinical characteristics of these adverse reactions among HIV-infected children are unknown. METHODS: We reviewed the clinical records of all children referred to a regional HIV clinic in a 6-year period. Therapy and suspected adverse drug reactions to therapy were reviewed by one of the investigators not involved in patient care. Adverse drug reactions were identified and characterized according to previously established criteria. RESULTS: During this time 78 children were referred for assessment of possible HIV infection, 45 of whom were ultimately determined to have the infection. Twenty-five were treated with trimethoprim-sulfamethoxazole, 15 (60%) of whom tolerated therapy and 10 (40%) of whom had adverse reactions. The most common type of adverse reaction was erythema multiforme (70%), followed by neutropenia (20%) and Stevens-Johnson syndrome (10%). In two patients a serious adverse reaction to trimethoprim-sulfamethoxazole led to the diagnosis of HIV infection. CONCLUSIONS: The overall incidence and type of serious adverse reactions to trimethoprim-sulfamethoxazole among infants and children with HIV infection appear to be similar to those among adults.",1
9374,9386869,A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group,"Efficacy and safety of toremifene 60 and 240 mg daily (TOR60 and TOR240) are compared to 40 mg tamoxifen daily (TAM40) in postmenopausal women with advanced estrogen receptor (ER) positive or ER unknown breast cancer. The study is randomized and open label in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safety was reported according to WHO criteria. Altogether 463 patients were randomized (157 to TOR60, 157 to TOR240, and 149 to TAM40). By data cut-off, after 20.5 months median follow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7%, and 20.8% in TOR60. TOR240, and TAM40, respectively. TOR60 and TAM40 show statistically equivalent efficacy and the difference between TOR240 and TAM40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR60), 6.1 (TOR240), and 5.0 (TAM40) months and the corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40 are statistically equivalent and the difference between TOR240 and TAM40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion, TOR60 and TAM40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not statistically significantly improves response rate and time to progression. In postmenopausal women, toremifene 60 mg daily is an effective and safe treatment of advanced ER-positive or ER-unknown breast cancer.",1
9375,9391686,Baclofen toxicity in patients with severely impaired renal function,"""OBJECTIVE: To report the toxic effects of baclofen in patients with severely impaired renal function. DATA SOURCES: From 1991 to 1995, nine patients with severely impaired renal function (2 not receiving dialysis, 1 undergoing continuous ambulatory peritoneal dialysis [CAPD], and 6 receiving maintenance hemodialysis), who exhibited clinical toxicity after baclofen therapy at our hospital were included for analysis. Another seven cases from the literature obtained by computerized (MEDLINE) and manual (Index Medicus) search methods published between 1980 and 1995 were also reviewed. INTERVENTION: Among our nine patients, the six undergoing chronic hemodialysis and one not undergoing dialysis received early (< 48 h) hemodialysis after toxic symptoms developed. The patient undergoing CAPD received late hemodialysis (> 72 h), and the other patient who had not undergone dialysis received only supportive care. RESULTS: A review of these 16 cases revealed that most patients received only small doses and very short-term baclofen therapy. Altered consciousness was the major presenting feature. Severe acute complications, such as seizures and respiratory depression, were relatively uncommon among patients with severely impaired renal function. However, abdominal pain, which has previously rarely been reported, was noted in five of our nine patients. Most patients showed clinical improvement after hemodialysis. An analysis of these nine patients revealed that those who received early hemodialysis had a shorter recovery time than the patient who received only supportive care (2.71 +/- 0.42, respectively, vs. 9 d; p < 0.01). A lag of several hours between the end of the hemodialysis session and an improvement in the level of consciousness was noted. DISCUSSION: As most patients with severely impaired renal function developed toxic symptoms soon after initiating a low-dose baclofen regimen, the accumulated dosage was small and severe complications were less common. Abdominal pain may have occurred as a result of the gamma-aminobutyric acid-mediated cholinergic effect exerted by baclofen. The delay in conscious recovery after hemodialysis may be due to a delay in the clearance of baclofen from the central nervous system. CONCLUSIONS: Patients with severely impaired renal function generally develop baclofen intoxication soon after the initiation of low-dose therapy. Thus, the administration of baclofen, regardless of the dosage, in these patients is not appropriate. Abdominal pain, in addition to altered consciousness, is a common presenting feature in patients with renal failure who have baclofen intoxication. Hemodialysis is effective in alleviating the clinical symptoms and shortening the recovery time for such patients.""",1
9376,9392962,Boldly they rode ... into the mouth of hell. Pennyroyal oil toxicity,,1
9377,9396337,"[A case of drug induced hepatitis and interstitial pneumonia caused by a herbal drug, Dai-saiko-to]",,1
9378,9402173,A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer,"""BACKGROUND: To compare protracted venous infusion (PVI) 5-fluorouracil (5-FU) with and without mitomycin C (MMC) in a prospectively randomised study and analyse for tumour response, survival, toxicity and quality of life (QL). PATIENTS AND METHODS: Two hundred patients with advanced colorectal cancer received PVI 5-FU 300 mg/m2/day for a maximum of 24 weeks and were randomised to PVI 5-FU alone or PVI 5-FU + MMC 10 mg/m2 (7 mg/m2 from June 1995) 6 weekly for 4 courses. RESULTS: Overall response was 54% (95% confidence interval [CI] 44.1%-63.9%) with PVI 5-FU + MMC compared to 38% (95% CI: 28.3%-47.7%) for PVI 5-FU alone (P = 0.024). The median failure free survival was 7.9 months in PVI 5-FU plus MMC and 5.4 months with PVI 5-FU alone (P = 0.033) and at one year 31.9% for the combination compared to 17.7% for PVI 5-FU alone. Median survival was 14 months with MMC and 15 months in 5-FU alone; one-year survival 51.7% vs. 57.2%. PVI 5-FU + MMC caused more overall haematological toxicity but CTC grades 3/4 was increased only for thrombocytopaenia. Two patients treated with a cumulative dose of MMC of 40 mg/m2 developed haemolytic uraemic syndrome warranting the reduction in cumulative MMC dose to 28 mg/m2. The global QL scores were better for PVI 5-FU + MMC arm at 24 weeks, but the remaining QL data showed no differences. CONCLUSIONS: PVI 5-FU + MMC results in failure-free survival and response advantage, tolerable toxicity and better QL when compared to PVI 5-FU alone but no overall survival advantage. There is no irreversible toxicity with MMC at a cumulative dose of 28 mg/m2.""",1
9379,9402409,Fatal acute hepatic necrosis due to dose-dependent fluconazole hepatotoxicity,,1
9380,9404924,High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma,"Eighteen patients with poor risk Ewing's sarcoma (including 11 patients with metastatic disease at presentation) received consolidation therapy of busulphan and melphalan with autologous stem cell rescue. There were nine females. The median age at diagnosis was 14.2 years (range 2.75-30 years). There was one early death due to cytomegalovirus pneumonitis. One patient developed a single generalised convulsion during busulphan therapy. Severe renal toxicity was not encountered. One patient developed veno-occlusive disease of the liver (VOD) which eventually resolved. With a median follow up of 2 years, 13 patients survive including six with initial metastatic disease. We conclude that high-dose busulphan/melphalan is well-tolerated and should be evaluated for efficacy in a larger series of patients with high risk Ewing's sarcoma.",1
9381,9406047,Toxicology of melatonin,"""Despite the fact that melatonin has been released for public use in the United States by the Food and Drug Administration and is available over the counter nationwide, there currently is a total lack of information on the toxicology of melatonin. In Europe, melatonin has a completely different status in that it is considered a """"neurohormone"""" and cannot be sold over the counter. Even though administration of melatonin in humans, as well as in animals (even at supraphysiological doses), has not shown evidence of toxicological effects (i.e., no deaths), a drug toxicological file still would need to be prepared and approved by the regulatory authorities. Several features that are specific to this neurohormone need to be taken into consideration. Whatever the species concerned, melatonin is secreted during the night; it is the """"hormone of darkness."""" It presents a circadian rhythm and a circannual rhythm (in photoperiodic species). The duration of these secretions could have an impact on the reproductive system, for example, showing the importance of the pharmacodynamics of melatonin. An inappropriate time schedule of melatonin administration could induce supraphysiological concentrations of the neurohormone and a desensitization of melatonin receptors. A long duration of exposure to melatonin also could mimic an """"artificial darkness"""" condition when a circadian rhythm with a basal zero level during the day needs to be conserved for a physiological function. Furthermore, administration of large doses of melatonin could induce high concentrations of melatonin and of different metabolites that could have deleterious effects per se. Numerous books, magazines, and articles have praised melatonin as a """"miraculous cure-all"""" for ailments ranging from sleeplessness, to aging, without any clinical evidence of efficacy (with the exception of its chronobiotic and resynchronizing effect). Very little attention has been paid to the possible side effects of melatonin. Nightmares, hypotension, sleep disorders, abdominal pain, etcetera, have been reported. In fact, analysis of the known pharmacological profile of melatonin and/or of its metabolites, based on scientific preclinical studies, constitutes a basis for prediction of adverse drug reactions or side effects. These include (1) the central nervous system, (2) the cardiovascular system and platelet aggregation, (3) glucose metabolism, (4) immunology, and (5) cancer. The knowledge of the fundamental mechanism of action of melatonin, including molecular biology, also needs to be taken into account for evaluation of possible side effects. Two types of melatonin receptors have been cloned (related to cyclic AMP), and the possibility of intracellular action of melatonin cannot be excluded. Melatonin receptors are present in the periphery and also at the level of the central nervous system, particularly on the suprachiasmatic nucleus that """"drives"""" a circadian rhythm to many other areas on which it projects. Among those, the hypothalamus (which has melatonin receptors) plays a fundamental role in the hormonal homeostasis and modulation control of the organism. Special preclinical and pharmacological studies that take into account all these parameters need to be designed for safety evaluation and risk assessment of this specific neurohormone.""",1
9382,9407743,Probable ticlopidine-induced severe aplastic anemia and cholestatic hepatitis,,1
9383,9416861,The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis,"""OBJECTIVE: To determine if the long-term use of methotrexate (MTX) in juvenile rheumatoid arthritis (JRA) is associated with the development of significant liver fibrosis, and to describe the presence of risk factors for liver fibrosis in patients with JRA. METHODS: Needle biopsies of the liver were performed on a cross-section cohort of 14 patients with JRA who had received a total cumulative dose of MTX that was either > 3,000 mg or > 4,000 mg/1.73 m2 of body surface area. Biopsy samples were independently graded according to the Roenigk Classification Scale by 2 pathologists. The presence of risk factors for MTX hepatotoxicity, especially biochemical abnormalities reflective of liver injury and alcohol consumption, were assessed. RESULTS: Thirteen biopsy samples (93%) were classified as grade I, and 1 (7%) as grade II; none demonstrated significant fibrosis. However, histologic abnormalities were found in 13 biopsy samples (93%). Only 2 patients (14%) consumed more than 1 alcoholic drink per month. Thirteen patients (93%) had biochemical abnormalities while being treated with MTX, but only 5 patients (36%) had at least 1 determination in which the aspartate or alanine aminotransferase elevation was > 3 times the upper limit of normal. CONCLUSION: Long-term use of MTX for JRA does not appear to be associated with the development of significant liver fibrosis. Although nearly all patients had minor histologic changes, no significant clinical consequences were apparent. A prospective study of a larger population will more accurately define the incidence of MTX-related liver fibrosis and appropriate monitoring guidelines in JRA.""",1
9384,9422046,Anagrelide for essential thrombocythemia,,1
9385,9424151,[Cholestatic hepatitis due to ticlopidine: a report of a new case],,1
9386,9428213,Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group,"""BACKGROUND & AIMS: Aminosalicylates are widely used in the treatment of ulcerative colitis (UC). Balsalazide is a novel mesalamine prodrug, activated by colonic bacteria. The aim of this study was to compare the efficacy and safety of balsalazide with that of a pH-dependent formulation of mesalamine in active UC. METHODS: A randomized, double-blind study was performed comparing balasalazide, 6.75 g daily, with mesalamine, 2.4 g daily, administered for 4, 8, or 12 weeks to 101 (99 evaluable) patients with symptomatic, sigmoidoscopically verified UC. RESULTS: More patients treated with balsalazide achieved symptomatic remission after 2 (64% [balsalazide] vs. 43% [mesalamine]), 4 (70% vs. 51%), 8 (78% vs. 45%), and 12 weeks (88% vs. 57%) and complete remission (none/mild symptoms, sigmoidoscopy grade 0/1, no rectal steroid use within 4 days) after 4 (38% vs. 12%), 8 (54% vs. 22%), and 12 weeks (62% vs. 37%). Patients taking balsalazide experienced more asymptomatic days (4 weeks, 24% vs. 14%) and achieved the first asymptomatic day more rapidly (median, 10 vs. 25 days). Fewer patients in the balsalazide group reported adverse events (48% vs. 71%); four serious adverse events occurred in the mesalamine group. CONCLUSIONS: Balsalazide is more effective and better tolerated than mesalamine as treatment for acute UC.""",1
9387,9435929,Efficacy and safety of docetaxel in clinical trials,"The efficacy and safety of docetaxel in clinical trials in patients with a variety of malignancies are reviewed. The overall response rate for docetaxel as a first-line treatment for metastatic breast cancer is 59%. Docetaxel in combination with doxorubicin or vinorelbine has proved particularly effective in the first-line treatment of metastatic breast cancer. Docetaxel is also one of the most active single agents in the treatment of non-small-cell lung cancer (NSCLC), producing an overall response rate of 27% when used as a first-line agent. Docetaxel plus cisplatin was more effective against NSCLC than either drug used alone, yielding response rates of 33-48%. Docetaxel has shown activity against a variety of other tumors, including ovarian cancer (response rate in second-line therapy, 34%), head-and-neck cancer (response rate in first-line therapy, 35%), and soft-tissue sarcoma (response rate in first-line therapy, 32%). The main toxic effect is grade 3-4 neutropenia, which occurs in 57% of treatment cycles but is brief and manageable. The dosage of docetaxel should be reduced from 100 mg/m2 to 75 mg/m2 if patients have neutropenia lasting more than one week, febrile neutropenia, or impaired liver function. Other adverse effects include severe fluid retention and asthenia. Some adverse effects can be avoided by administering corticosteroid premedication. Docetaxel has shown efficacy against a wide range of cancers in clinical trials and has a manageable adverse-effect profile.",1
9388,9439900,Isoniazid-related hepatitis,"Conclusive evidence of isoniazid (INH)-related hepatotoxicity ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure resulting in liver transplantation and/or death has been firmly established. Anticipation of the widespread usage of INH in the prevention and treatment of tuberculosis is expected due to the recent increasing incidence of tuberculosis. The aim of this article is to review the current concepts of pathogenesis, histopathology, risk factors and clinical features of INH-related hepatitis, emphasizing the need for vigilance.",1
9389,9443132,Sulfasalazine-induced fulminant hepatitis in pediatric Crohn's disease: report of two cases,,1
9390,9445740,[Acute hepatitis associated with terbinafine],Oral terbinafine is a recently introduced antifungal drug with slight side effects that rarely includes liver involvement. A case of toxic hepatitis secondary to terbinafine administration in a patient with no previous history of liver disease and in whom other possible causes of liver damage and histologic study were performed is reported. A mixed lesion was presented with predominance of cholestasis. The initial worsening following discontinuation of the drug is of note as are the prolonged course of the enzymatic alterations which normalized at one year. The precise mechanism by which terbinafine produced liver damage is unknown and is probably due to an idiosyncratic type reaction.,1
9391,9448194,A rare case of hepatic injury associated with ovarian hyperstimulation syndrome,"A 26-year-old married woman was admitted to our hospital because of massive ascites and hepatic injury. The patient had been treated with human menopausal gonadotropin and clomiphene citrate to prevent recurrence of spontaneous abortions. About 1 month later, she developed upper abdominal pain and noticed dark urine. On admission, she had elevated concentrations of serum transaminases with an asparate aminotransferase of 127 IU/L and alanine aminotransferase of 194 IU/L. An abdominal ultrasound showed massive ascites. Her serum concentration of estradiol was high at 12,100 pg/mL, which was much greater than the value of early stage of pregnancy (2,279-7,353 pg/mL). She was thus diagnosed as having ovarian hyperstimulation syndrome. Following a period of bed rest, her liver function normalized and the ascites disappeared. Based on the above findings, the patient was considered to have suffered from ovarian hyperstimulation syndrome, complicated by hepatic injury.",1
9392,9451703,Bentazepam-induced hepatic bridging necrosis,,1
9393,9456265,Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy,,1
9394,9468033,Impaired liver function tests in patients treated with antithymocyte globulin: implication for liver transplantation,"""Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day -1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 +/- 37.7 U/l pre-treatment to 1394.4 +/- 488.7 U/l 3 days post-treatment (n = 16; p < 0.029), and then declined to 561.4 +/- 61.3 U/l 10 days post-treatment (n = 16; p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 +/- 11.3 U to 184.6 +/- 74.6 U (n = 16; p < 0.036), and then declined to 121.9 +/- 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 + 5.7 U to 152.0 +/- 67.0 U (n = 16; p < 0.44) and then declined to 46.0 +/- 14 (n = 16; p < 0.049). The mean tau-glutamyltransferase (GTP) levels increased from 93.0 +/- 34 to 188.0 +/- 36 (n = 16; p < 0.02), and were 168.0 +/- 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 +/- 1.9 microM l(-1) to 22.7 +/- 2.8 (n = 16); NS), at day +3 and to 31.9 +/- 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.""",1
9395,9475762,The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group,"""BACKGROUND: Finasteride is known to improve urinary symptoms in men with benign prostatic hyperplasia, but the extent to which the benefit is sustained and whether finasteride reduces the incidence of related events, including the need for surgery and the development of acute urinary retention, is not known. METHODS: In this double-blind, randomized, placebo-controlled trial, we studied 3040 men with moderate-to-severe urinary symptoms and enlarged prostate glands who were treated daily with 5 mg of finasteride or placebo for four years. Symptom scores (on a scale of 1 to 34), urinary flow rates, and the occurrence of outcome events were assessed every four months in 3016 men. Prostate volume was measured in a subgroup of the men. Complete data on outcomes were available for 2760 men. RESULTS: During the four-year study period, 152 of the 1503 men in the placebo group (10 percent) and 69 of the 1513 men in the finasteride group (5 percent) underwent surgery for benign prostatic hyperplasia (reduction in risk with finasteride, 55 percent; 95 percent confidence interval, 41 to 65 percent). Acute urinary retention developed in 99 men (7 percent) in the placebo group and 42 men (3 percent) in the finasteride group (reduction in risk with finasteride, 57 percent; 95 percent confidence interval, 40 to 69 percent). Among the men who completed the study, the mean decreases in the symptom score were 3.3 in the finasteride group and 1.3 in the placebo group (P<0.001). Treatment with finasteride also significantly improved urinary flow rates and reduced prostate volume (P<0.001). CONCLUSIONS: Among men with symptoms of urinary obstruction and prostatic enlargement, treatment with finasteride for four years reduces symptoms and prostate volume, increases the urinary flow rate, and reduces the risk of surgery and acute urinary retention.""",1
9396,9487641,[Successful therapy of persistent androgen-induced cholestasis with ursodeoxycholic acid],"Drug-induced cholestasis can rarely persist for a considerable time period even after withdrawal of the drug. We report the case of a 55-year-old man with progressive jaundice after oral therapy with 17-alpha-methyltestosterone. Under empiric therapy with ursodeoxycholic acid the condition resolved completely. According to this observation, we suggest a therapeutic trial with ursodeoxycholic acid in cases of prolonged androgen-induced cholestasis.",1
9397,9492630,[Fatal outcome in allopurinol hypersensitivity syndrome],"A 76 year-old otherwise healthy man was treated with allopurinol after a single episode of gout. He developed allopurinol hypersensitivity syndrome with epidermal necrolysis, dermal vasculitis, impaired renal function, fever, gastrointestinal bleeding, and possibly pulmonary vasculitis. The outcome was lethal. Controlling allopurinol therapy according to renal function is emphasized.",1
9398,9493165,[Hepatotoxicity from flutamide],,1
9399,9496518,Hemorrhage caused by ruptured liver cell adenoma following long-term oral contraceptives: a case report,"A 41-year-old woman who had taken oral contraceptives for 14 years was admitted to the hospital with pain in the left shoulder region and epigastrium arising after regurgitation. Sonography and CT revealed a ruptured liver tumor with sealed-off liver hemorrhage. The resected specimen revealed a ruptured and partially necrotic liver cell adenoma. This paradigmatic case illustrates a rare but well known entity: liver cell adenomas prone to necrosis and hemorrhage, requiring emergency intervention, in women on long-term oral contraceptive therapy.",1
9400,9498464,Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients coinfected with HIV,"The impact of human immunodeficiency virus (HIV) protease inhibitors on hepatitis C (HCV) viremia was assessed in 19 patients infected with both HIV and HCV. HIV and HCV RNA levels were measured before and during treatment with protease inhibitors. Before treatment, mean levels of HCV RNA were 5.3 log for HCV RNA and 5.0 log for HIV RNA. CD4 lymphocyte counts were 63/mm3. After 6 weeks of treatment, a mean reduction of 2.1 log10 in HIV RNA (P < .001) and a mean (+/-SE) increase of 73 (+/-21) CD4 and 296 (+/-70) CD8 cells were observed (P < .05). In contrast, both HCV viremia (+0.4 log +/- 0.1) and alanine aminotransferase increased (P < .04). HCV RNA levels returned to baseline after 17 and 32 weeks of treatment. Thus, potent anti-HIV regimens with protease inhibitors may temporarily worsen HCV status despite improvement of HIV parameters.",1
9401,9504521,Tamoxifen-induced fatty liver in patients with breast cancer,,1
9402,9505953,[Ticlopidine-induced acute cholestatic hepatitis],"HISTORY AND ADMISSION FINDINGS: A 52-year-old man who had sustained a cerebellar infarct was given the platelet inhibitor ticlopidine (2 x 250 mg/d) to prevent further thromboses. 28 days after starting the medication he complained of itchings, feeling unwell and diarrhoea. He had also noted darkened urine and faecal discoloration. Physical examination revealed marked jaundice and multiple scratch marks over the entire body. INVESTIGATIONS: The activities in serum of alkaline phosphatase (420 U/l) and of gamma-GT (470 U/l) were markedly elevated and total bilirubin concentration was maximally 26.4 mg/dl. Activities of GPT (197 U/l) and GOT (44 U/l) were slightly increased. No cause was found for any extra- or intrahepatic cholestasis with or without mechanical obstruction (e.g. viral or autoimmune hepatitis). A biopsy, which showed centro-acinar cholestasis also suggested drug-induced liver damage. TREATMENT AND COURSE: Despite discontinuing ticlopidine, the signs of cholestatic hepatitis had only disappeared 2 1/2 months after the onset of symptoms. CONCLUSION: Changes in the blood picture, allergic skin reactions and gastrointestinal disorders are among the significant clinical side effects of ticlopidine. As this drug is increasingly being prescribed world-wide, the possibility of toxic liver damage should be taken into account.",1
9403,9516220,Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group,"""BACKGROUND: Troglitazone is a new oral antidiabetic drug that increases the sensitivity of peripheral tissues to insulin. It may therefore increase the efficacy of exogenous insulin in patients with insulin-resistant diabetes mellitus. METHODS: We studied the effect of troglitazone or placebo in 350 patients with poorly controlled non-insulin-dependent (type 2) diabetes mellitus (glycosylated hemoglobin values, 8 to 12 percent; normal, 4.3 to 6.1 percent) despite therapy with at least 30 U of insulin daily. The patients were randomly assigned to receive 200 mg of troglitazone (116 patients), 600 mg of troglitazone (116 patients), or placebo (118 patients) daily for 26 weeks. Insulin doses were not increased and were reduced only to prevent hypoglycemia. Glycosylated hemoglobin, serum glucose while fasting, serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured 5 times during an 8-week base-line period and 10 times during the 26-week treatment period. Daily insulin doses were recorded during both periods. RESULTS: Ninety percent of the patients completed the study. The adjusted mean glycosylated hemoglobin values decreased by 0.8 and 1.4 percentage points, respectively, in the group given 200 mg of troglitazone and the group given 600 mg of troglitazone, and fasting serum glucose concentrations decreased by 35 and 49 mg per deciliter (1.9 and 2.7 mmol per liter), respectively, despite decreases in the insulin dose of 11 percent and 29 percent (P<0.001 for all comparisons with the placebo group). Serum total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations increased slightly and serum triglyceride concentrations decreased slightly in the troglitazone-treated patients. CONCLUSIONS: When given in conjunction with insulin, troglitazone improves glycemic control in patients with type 2 diabetes mellitus.""",1
9404,9517278,[Verapamil-associated liver injury],"Hepatotoxicity due to verapamil is very rare and to the best of our knowledge only 10 cases have been reported. A 54-year-old woman developed cholestatic liver injury and pruritus following treatment with sustained-release verapamil (240 mg/day) for arterial hypertension. The pruritus and all hepatic biochemical abnormalities completely resolved after withdrawal of the drug. Similar to previously reported cases, the pathogenic mechanism of verapamil-associated liver injury in our patient was, most probably, idiosyncratic. These cases emphasize the need for awareness of the possibility that verapamil may occasionally induce liver injury, sometimes severe and potentially fatal.",1
9405,9517669,Acarbose-induced acute hepatitis,,1
9406,9518284,Hepatic dysfunction associated with troglitazone,,1
9407,9520032,Methotrexate in psoriasis: consensus conference,,1
9408,9522791,Relation of aplastic anaemia to use of chloramphenicol eye drops in two international case-control studies,,1
9409,9525435,"Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS","To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.",1
9410,9529516,Raloxifene for postmenopausal osteoporosis,,1
9411,9537855,Chronic hepatitis induced by Jin Bu Huan,"BACKGROUND/AIMS: Jin Bu Huan and other Chinese herbal products are widely taken remedies. They have been developed as a natural alternative to traditional drugs in the treatment of various ailments. Their ability to induce several side effects such as acute hepatitis has already been described. We report a case of chronic hepatic damage following administration of Jin Bu Huan Anodyne tablets. METHODS: The patient, a 49-year-old man, developed biochemical signs of liver damage 2 months after beginning Jin Bu Huan intake (3 tablets/daily) including biopsy-proven chronic hepatitis with moderate fibrosis. Virological, autoimmune, metabolic or other hepatotoxic causes were excluded. Liver function impairment was resolved by discontinuing Jin Bu Huan intake. CONCLUSIONS: This case reinforces the already known hepatotoxicity of this product and should make us think more about the uncontrolled use of alternative products.",1
9412,9542866,[Side effects of minocycline in the treatment of acne vulgaris],"Minocycline is the most commonly used systemic antibiotic in the long-term treatment (weeks to months) of severe acne vulgaris. Currently much attention is being paid in the Dutch and international literature to the safety of minocycline, after several reports on serious adverse events. The clinical efficacy of minocycline in the treatment of acne vulgaris is better than that of tetracycline and equal to that of doxycycline. The serious adverse events of minocycline therapy described consist of hyperpigmentation of various tissues, autoimmune disorders (systemic lupus erythematosus, autoimmune hepatitis) and serious hypersensitivity reactions (hypersensitivity syndrome reaction, pneumonitis and eosinophilia, and serum sickness-like syndrome). In relation to the number of prescriptions, the number of serious adverse events of minocycline described is small. However, it is very important that prescribing doctors should be aware of the possibility of these adverse events occurring during long-term minocycline therapy and able to recognize the characteristic symptoms at an early stage.",1
9413,9549187,[Acute hepatocellular lesion induced by amoxicillin-clavulanic acid],"Since first description in 1988, numerous cases of amoxycillin-clavulanic acid hepatotoxicity have been reported. Most of them are cholestatic hepatitis. A case of acute hepatocellular injury by amoxycillin-clavulanic acid is reported in a 23-years-old male, with a favourable outcome after 18 weeks.",1
9414,9558894,Niacin. Help for your cholesterol--harm for your liver,,1
9415,9562580,Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group,"""BACKGROUND: Most trials of immunomodulators in metastatic renal-cell carcinoma have been uncontrolled and subject to selection bias. The objective of this blinded, placebo-controlled study was to compare overall response rates, time to disease progression, and survival of patients with metastatic renal-cell carcinoma treated with recombinant human interferon gamma-1b or placebo. METHODS: Patients with biopsy-proved metastatic renal-cell carcinoma were randomly assigned to receive interferon gamma-1b (60 microg per square meter of body-surface area subcutaneously once weekly) or placebo. The primary tumor had been treated by nephrectomy or angioinfarction at least three weeks previously. Patients were evaluated for radiologic evidence of progression, and all responses were independently reviewed by a committee that was unaware of the treatment. RESULTS: A total of 197 patients with metastatic renal-cell carcinoma were enrolled at 17 centers in Canada. One hundred eighty-one patients could be evaluated; of these, 91 were assigned to receive interferon gamma-1b and 90 were given placebo. The groups were well balanced in terms of prognostic factors. Two thirds of all patients had Karnofsky scores of 90 or 100, and more than half had two or more metastatic sites. Grade I and II toxicity, mostly chills, fever, asthenia, or headaches, was reported in 91 percent and 61 percent, respectively, of the patients in the interferon group, as compared with 76 percent and 63 percent in the placebo group. Life-threatening drug-related events were rare, occurring in 1 percent of patients in the interferon group. No significant differences between groups were observed in overall response rates, time to disease progression, or survival. The overall response rate was 4.4 percent (3.3 percent complete response and 1.1 percent partial response) in the interferon group and 6.6 percent (3.3 percent complete response and 3.3 percent partial response) in the placebo group (P=0.54), with a rate of durable complete response of 1 percent in both groups. The median time to disease progression was 1.9 months in both groups (P=0.49), and there was no significant difference in median survival (12.2 months with interferon vs. 15.7 months with placebo, P=0.52). CONCLUSIONS: No difference in outcome was observed in patients with metastatic renal-cell carcinoma who were treated with interferon gamma-1b as compared with placebo. These results emphasize the necessity of testing the efficacy of immunomodulators in randomized studies.""",1
9416,9568923,Acute hepatic failure in a child treated with lamotrigine,"An 8-year-old boy with a known seizure disorder that was being treated with lamotrigine developed acute hepatic failure. The patient, who had been well previously, presented with jaundice, elevated liver enzymes, and a coagulopathy. After discontinuation of lamotrigine and aggressive resuscitation, the patient made an uneventful recovery. We believe that the hepatic failure in our patient was secondary to the use of lamotrigine. We recommend careful monitoring of liver function when lamotrigine is administered.",1
9417,9576446,Cisapride 20 mg b.i.d. provides symptomatic relief of heartburn and related symptoms of chronic mild to moderate gastroesophageal reflux disease. CIS-USA-52 Investigator Group,"""OBJECTIVE: We evaluated the efficacy and safety of a twice-daily dosage regimen of cisapride 20 mg in relieving the symptoms of mild-moderate gastroesophageal reflux disease (GERD) in patients with moderate intensity heartburn and no history of erosive esophagitis. METHODS: After a 2-wk, single-blind, placebo run-in period, 398 patients who continued to experience moderate intensity heartburn were randomized to either placebo (n = 196) or cisapride 20 mg (n = 202) twice daily for 4 wk. RESULTS: Compared with placebo, cisapride significantly reduced scores for daytime and nighttime heartburn (p < 0.001), total regurgitation (p < 0.001), eructation (p = 0.04), and early satiety (p = 0.04). Cisapride 20 mg b.i.d. was also superior to placebo in reducing total use of rescue antacid medication (p < 0.001); reducing, in concordance analyses, daytime and nighttime heartburn with antacid usage (p < 0.001); increasing the percentage of heartburn-free days and antacid-free nights (p < 0.5); and increasing the percentage of patients self-rated as having minimal or better symptomatic improvement (p = 0.01). Cisapride 20 mg b.i.d. was well tolerated. The most common adverse event in the cisapride group was diarrhea, reported by 10% of patients, compared with an incidence of 4% in the placebo group. CONCLUSION: Cisapride 20 mg b.i.d. was shown to be effective and safe for the short-term treatment of daytime and nighttime heartburn and for other symptoms associated with mild-moderate GERD.""",1
9418,9580395,[Amoxicillin-clavulanic acid hepatotoxicity],,1
9419,9580744,Toremifene and letrozole for advanced breast cancer,,1
9420,9584675,Glibenclamide-induced cholestasis,,1
9421,9587501,[Hepatic transplantation for severe ductopenia related to ingestion of thiabendazole],"We report a case of severe cholestasis and sicca syndrome after thiabendazole administration for Strongyloides stercoralis infection in a 26-year-old patient. Liver biopsy, performed 15 days after the onset of jaundice, revealed a marked paucity of bile ducts, and cholestasis rapidly progressed to biliary cirrhosis. Because of the progression of jaundice and the development of esophageal varices, orthotopic liver transplantation was performed, 18 months after the beginning of disease. The mechanism responsible for thiabendazole-induced biliary injury is unknown. The association between sicca syndrome and biliary disease suggests an immunoallergic mechanism against an antigen which could be common to the biliary, lacrimal and salivary duct epithelium.",1
9422,9587562,[Lactic acidosis and hepatic mitochondrial changes during a treatment with zidovudine],"Adverse effects of zidovudine, which mainly result in myopathies and hematological disorders, could be due to multitissular mitochondrial toxicity of the drug. During zidovudine treatment, most cases of lactic acidosis have been attributed to mitochondrial myopathy. We report a case of hepatocellular failure with lactic acidosis in a 33 year-old patient with the human immunodeficiency virus infection and treated with zidovudine for 8 months. Liver biopsy showed massive macrovacuolar steatosis and ultrastructural mitochondrial abnormalities similar to those previously described in the skeletal muscle. This is the second reported case of lactic acidosis and hepatocellular failure which is probably related to hepatic mitochondrial dysfunction caused by zidovudine.",1
9423,9591521,Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. Tolcapone Stable Study Group,"In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.",1
9424,9592619,Pharmacokinetics and pharmacodynamics of hydroxyurea,"Hydroxyurea is used in the treatment of various forms of cancer, sickle-cell anaemia and HIV infection. Oral absorption of the drug is virtually complete, the volume of distribution is equivalent to total body water and elimination is through both renal and nonrenal mechanisms. Nonrenal elimination of hydroxyurea is characterised by Michaelis-Menten kinetics. Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination. The recent development of improved assays for hydroxyurea should have benefits for future pharmacokinetic studies.",1
9425,9597236,Tritherapy for human immunodeficiency virus infection does not modify replication of hepatitis C virus in coinfected subjects,"Triple antiretroviral therapy combining reverse transcriptase and protease inhibitors modifies the prognosis for human immunodeficiency virus (HIV) infection, with dramatic improvement in immune status. In an attempt to evaluate the impact of anti-HIV triple combination therapy on the course of hepatitis C virus (HCV)-related chronic hepatitis and on HCV replication, we studied the biological and virological characteristics of 22 HCV/HIV-coinfected patients who were given triple combination therapy. In comparison with baseline values, there was (1) a significant increase in the CD4 and CD8 cell counts and a decrease in the HIV RNA load and (2) no significant variation in aminotransferase activities or the HCV RNA load at 3, 6, or 9 months of tritherapy. Antiretroviral tritherapy seems to modify neither the biological activity of HCV-related chronic hepatitis nor the HCV load, despite immune restoration. Hepatic histopathologic analysis is warranted to assess the impact of immune restoration on liver lesions.",1
9426,9604732,Liver toxicity profile in gold-treated Egyptian rheumatoid arthritis patients,"The objective was to evaluate the rationale for liver needle biopsy versus blood liver functional tests in monitoring the incidence of hepatotoxicity in Egyptian rheumatoid arthritic patients treated with gold compounds. Forty patients (12 males, 28 females) were randomly selected out of 258 Egyptian rheumatoid arthritic patients treated with sodium auro-thiomalate during the past 4 years. The minimum duration of treatment was 40 weeks. The methods used were firstly, liver function tests (serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, total serum bilirubin and total serum albumin) before, weekly during and after administration of sodium auro-thiomalate. Secondly, a needle liver biopsy was conducted by using the tru-cut needle. Then liver histology was graded according to Roenigk for grading liver toxicity. Viral hepatitis markers (hepatitis B surface antigen, anti-hepatitis C virus were done for monitoring viral hepatitis. Finally, the liver tissue contents of heavy metals were counted in the cases that showed grade IIIB histological changes. The results showed that none of the studied cases developed any clinically significant liver disease during the course of chrysotherapy. Blood liver function tests were of normal value throughout the course of drug administration. According to Roenigk grading, 20 patients (50%) showed grade I liver changes, and the other 20 patients showed liver changes of grades II and III (four grade II, eight grade IIIA, and another eight grade IIIB). None of the patients showed grade IV liver changes. It was concluded that blood liver tests are not the most sensitive methods to detect hepatotoxicity in gold-receiving Egyptian rheumatoid arthritic patients. Needle liver biopsy is not superior in detecting liver toxicity, compared with routine laboratory liver function tests, because of its complications. Rheumatoid arthritic patients with a potential risk of clinically significant liver disease should not be exposed to the risk of gold salt therapy. Pretreatment HLA-DR genetic typing may be a good detector for rheumatoid arthritic patients with potential risk of hepatotoxicity.",1
9427,9607293,[Hepatitis associated with treatment with lovastatin. Presentation of 2 cases],"Two women of 57 and 59 years of age, presented anicteric hepatitis at 9 months and 3 years, respectively, of the initiation of treatment with lovastatin (20 mg/day) for hypercholesterolemia. In both cases other causes of liver damage were excluded and the analytical alterations normalized within a few weeks following discontinuation of the medication.",1
9428,9609675,Olanzapine in treatment-resistant bipolar disorder,"BACKGROUND: We evaluated the response to olanzapine in 14 consecutive patients with bipolar I disorder who were inadequately responsive to standard psychotropic agents. METHODS: Fourteen patients with bipolar I disorder by DSM-IV criteria experiencing persistent affective symptoms inadequately responsive to at least one standard mood stabilizer were treated with open-label olanzapine by one of the authors. Response was assessed with the Clinical Global Impression Scale modified for use in bipolar disorder (CGI-BP). RESULTS: The 14 patients received olanzapine at a mean (SD dosage of 14.1+/-7.2 (range 5-30) mg/day for a mean+/-SD of 101.4+/-56.3 (range 30-217) days of treatment. Of the 14 patients, 8 (57%) displayed much or very much overall improvement in their illness. In general, olanzapine was well tolerated. The most common side effects were sedation, tremor, dry mouth, and appetite stimulation with weight gain. LIMITATIONS: Data were obtained nonblindly and without a randomized control group, and olanzapine was added to ongoing psychotropic regimens. CONCLUSION: Olanzapine may have antimanic and mood-stabilizing effects in some patients with bipolar disorder, and is generally well tolerated. Controlled studies of olanzapine in bipolar disorder appear warranted.",1
9429,9613910,Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study,"""CONTEXT: Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. OBJECTIVE: To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinics in Texas. PARTICIPANTS: A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). INTERVENTION: Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. MAIN OUTCOME MEASURES: First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. RESULTS: After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. CONCLUSIONS: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.""",1
9430,9619824,Antiretroviral triple therapy decreases HIV viral load but does not alter hepatitis C virus (HCV) serum levels in HIV-HCV-co-infected haemophiliacs,,1
9431,9624310,Management of anaphylactoid reactions to intravenous N-acetylcysteine,"STUDY OBJECTIVE: To develop management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetylcysteine (NAC) and to assess the safety of restarting the infusion after a reaction. METHODS: In phased 1, we used a 6-year retrospective case series of hospitalized patients and a review of the literature to develop the management guidelines for anaphylactoid reactions to intravenous NAC. In phase 2, these guidelines were evaluated prospectively in our poison-control center. RESULTS: In phase 1, the charts of 11 patients with anaphylactoid reactions (9 cutaneous and 2 systemic) were reviewed. In most cases, no treatment or treatment with diphenhydramine alone or with salbutamol was sufficient to continue or restart NAC infusion safely. On the basis of our findings in those patients and on published experience, we concluded that anaphylactoid reactions to intravenous NAC are dose-related and the antihistamines are useful in controlling and in preventing recurrence of anaphylactoid symptoms. We developed the following guidelines: flushing requires no treatment, urticaria should be treated with diphenhydramine, and NAC infusion should be continued in both cases. Angioedema and respiratory symptoms each require the administration of diphenhydramine and symptomatic therapy. In these cases, NAC infusion should be stopped but, when necessary, can be started 1 hour after the administration of diphenhydramine in the absence of symptoms. In phase 2, 50 patients (31 cutaneous and 19 systemic reactions) were treated prospectively with the use of these guidelines. Recurrence of symptoms occurred in only one case involving a deviation from the guidelines. The NAC infusion was restarted immediately after the administration of diphenhydramine in a patient who sustained a systemic reaction. CONCLUSION: Non-life-threatening anaphylactoid reactions to intravenous NAC are treated easily and the infusion may be continued or restarted safely after the administration of diphenhydramine.",1
9432,9625135,Nitrofurantoin-induced hepatotoxicity mediated by CD8+ T cells,"Nitrofurantoin is a synthetic nitrofuran commonly used for the treatment and prophylaxis of urinary tract infections. We describe the case of a 75-yr-old woman who was taking nitrofurantoin as prophylaxis against recurrent urinary tract infections, and who subsequently developed pulmonary and hepatic toxicity. We postulate that a breakdown product of the drug or the drug itself complexed to an endogenous peptide is presented by the class I HLA antigen on the hepatocyte cell membrane, inducing cytotoxic T cell activation and subsequently, hepatocyte death.",1
9433,9625138,Liver transplantation for disulfiram-induced hepatic failure,"Fulminant hepatitis is a rare but potentially fatal adverse reaction that may occur after the use of disulfiram. A patient without a known history of liver disease was transplanted for fulminant hepatic failure secondary to disulfiram. A high index of suspicion and aggressive therapeutic approaches are essential for the prompt diagnosis and treatment of disulfiram-induced hepatic failure. The clinical presentation, histopathology, treatment, and all cases of disulfiram-induced hepatic failure reported in the English literature are reviewed. The role of orthotopic liver transplantation in a case of disulfiram-induced hepatic failure is discussed.",1
9434,9625400,"Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group","""OBJECTIVES: To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more. DESIGN: Randomized, multicenter, double-blind, placebo-controlled, parallel-group study. A 2-week, single-blind, placebo run-in period was followed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg, or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period. SETTING/PATIENTS: Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled beta-agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled beta-agonist use. Twenty-three percent of the patients used concomitant inhaled corticosteroids. PRIMARY END POINTS: Forced expiratory volume in 1 second and daytime asthma symptoms. RESULTS: Montelukast improved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, """"as-needed"""" beta-agonist use, nocturnal awakenings) (P<.001 compared with placebo). Montelukast provided near-maximal effect in these end points within the first day of treatment. Tolerance and rebound worsening of asthma did not occur. Montelukast improved outcome end points, including asthma exacerbations, asthma control days (P<.001 compared with placebo), and decreased peripheral blood eosinophil counts (P<.001 compared with placebo). The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups. CONCLUSIONS: Montelukast, compared with placebo, significantly improved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo.""",1
9435,9626034,Metformin-induced acute hepatitis,,1
9436,9627768,Felodipine extended release versus conventional diuretic therapy for the treatment of systolic hypertension in elderly patients. The National Trial Group,"""OBJECTIVE: To compare 8 weeks of monotherapy using either felodipine extended release (ER) or a conventional diuretic therapy, triamterene/hydrochlorothiazide (HCTZ), in elderly patients with systolic hypertension. DESIGN: Prospective, randomized, single-blind screening, double-blind treatment, parallel group comparison. SETTING: Twenty-nine general and family practice sites across Canada. PARTICIPANTS: Men and post-menopausal women aged 60 to 85 years, with mild to moderate primary systolic hypertension (systolic blood pressure > 160 mm Hg or blood pressure > 140/ > 90 mm Hg). INTERVENTIONS: Daily doses of either felodipine ER (2.5 mg) or triamterene/HCTZ (25/12.5 mg) for 8 weeks. After the first 4 weeks, the patients who responded to the initial dosage (a reduction in systolic blood pressure of at least 15 mm Hg) or whose blood pressure was controlled on the dosage (systolic blood pressure < 140 mm Hg) continued to take the low dose. Among the others, the daily doses were doubled for the final 4 weeks. OUTCOME MEASURES: Systolic blood pressure before beginning treatment and at the end of the study, as well as adverse events and results of heart rate measurement, clinical chemistry tests, electrocardiograms and physical examinations before and after therapy. RESULTS: Sufficient data for analysis were obtained from 216 patients (86 men and 130 women). Mean seated blood pressure was reduced significantly in both the felodipine group (from 168/91 to 151/84 mm Hg) and the diuretic group (from 168/92 to 147/84 mm Hg). The difference in mean reductions in systolic blood pressure between the groups was 2.2 mm Hg (with a 95% confidence interval of-1.7 to 6.0 mm Hg), which was not significant. Clinical chemistry measurements taken before treatment and at the end of the study showed that more patients in the diuretic group developed abnormal values for blood urea nitrogen, uric acid and creatinine. Other changes were unremarkable. The incidence of adverse events was similar in both groups, but more patients in the felodipine group (9) than in the diuretic group (3) discontinued treatment owing to an adverse event. CONCLUSIONS: Felodipine ER (2.5 to 5 mg daily) is as effective in reducing systolic blood pressure as triamterene/HCTZ (25/12.5 mg to 50/25 mg daily). More patients discontinued felodipine treatment than triamterene/HCTZ treatment owing to adverse events. However, patients receiving triamterene/HCTZ tended to have abnormal levels in clinical chemistry tests; these should be monitored.""",1
9437,9628257,Methotrexate hepatotoxicity: what is the evidence?,,1
9438,9630737,"Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity","""Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint, to mercury in the atmosphere, in dental amalgams and in seafood, and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compound s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances.""",1
9439,9632999,New antiretrovirals and new combinations,"The appearance in the clinic of two to three new antiretroviral agents yearly since 1995 has permitted unprecedented advances in HIV treatment. This remarkable pace of drug development is a testimony to an extraordinary international effort involving scientists, clinicians, governments, community activists and industry dedicated to the rapid and safe development of novel therapies. New drugs present the opportunity to improve HIV therapy. They also create an enormous challenge to the clinician, who must constantly assimilate data on new drugs and incorporate this information into practical management strategies. Combination therapy has proven the most effective approach to treat HIV disease. The profound and sustained viral suppression achievable with combinations such as indinavir (IDV), lamivudine (3TC) and zidovudine (ZDV) have resulted in a dramatic shift in HIV treatment paradigms over the last year. The full potential of combination therapy with available drugs has yet to be realized as only a limited number of the possible combinations incorporating new drugs have been fully tested. Even drugs available for many years may have untapped potential. Didanosine (ddI) and stavudine (d4T), once thought to be contraindicated in combination because of their overlapping peripheral neuropathy toxicity, have proven well tolerated and effective. Combination therapy can increase antiviral suppression, prevent drug resistance, optimize drug exposure and simplify dosing, but it can also result in pharmacologic antagonism, subtherapeutic drug concentrations and unexpected toxicities. Clinical studies have confirmed in vitro studies showing pharmacologic antagonism for the combination of ZDV and d4T. Combining protease inhibitors with each other or with non-nucleoside reverse transcriptase inhibitors is complicated by effects both classes of drugs have on drug metabolism and clearance. These observations underline the importance of carefully conducted clinical studies to characterize safety, pharmacokinetics and efficacy of combination therapies. In this review, we will first summarize the clinical profile of new drugs which either became commercially available last year [nelfinavir, nevirapine, delavirdine (DLV)] or are in the late stages of clinical development (DMP-266, abacavir and 141W94). Later we will summarize new data on nucleoside, protease inhibitor and non-nucleoside reverse transcriptase combination regimens. Finally, we will briefly mention new drugs in early stages of development.",1
9440,9638415,Diphenylhydantoin-induced hepatitis: a case report,"This case report is of a 25-year old man with severe diphenylhydantoin-induced hepatitis, fever, rash and generalized lymphadenopathy. Hepatic histology and lymphocyte transformation tests strongly supported the diagnosis. He made an uneventful recovery with supportive therapy.",1
9441,9643663,A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer,"OBJECTIVES: To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer. METHODS: A total of 1,453 patients with either confirmed metastatic disease (M1), or T3/T4 non-metastatic disease with elevated prostate-specific antigen (M0) were recruited into one of two identical, multicentre, randomised studies to compare 'Casodex' 150 mg/day with castration. The protocols allowed for combined analysis. RESULTS: At a median follow-up period of approximately 100 weeks for both studies, 'Casodex' 150 mg was found to be less effective than castration in patients with metastatic disease (M1) at entry (hazard ratio of 1.30 for time to death) with a difference in median survival of 6 weeks. In symptomatic M1 patients, 'Casodex' was associated with a statistically significant improvement in subjective response (70%) compared with castration (58%). Analysis of a validated quality-of-life questionnaire proved an advantage for 'Casodex' in sexual interest and physical capacity. 'Casodex' had a substantially lower incidence of hot flushes compared to castration (6-13% compared with 39-44%) and the most commonly reported adverse events were those expected for a potent antiandrogen. However, in patients with M0 disease at entry, the data are still immature with only 13% of M0 patients having died. An initial analysis of this immature data has suggested that the results in these patients may be different to those obtained in patients with M1 disease. A further survival analysis in patients with M0 disease is therefore planned when the data are more mature. CONCLUSIONS: 'Casodex' 150 mg is less effective than castration in patients with M1 disease. However, 'Casodex' has shown a benefit in terms of quality of life and subjective response when compared to castration and has an acceptable tolerability profile. Thus 'Casodex' 150 mg monotherapy is an option for patients with M1 prostate cancer for whom surgical or medical castration is not indicated or is not acceptable.",1
9442,9650153,A review of the effectiveness of Cimicifuga racemosa (black cohosh) for the symptoms of menopause,"In this review of eight human studies on the effectiveness of an extract of Cimicifuga racemosa on alleviating menopausal symptoms, it is apparent that it is a safe, effective alternative to estrogen replacement therapy for those patients in whom estrogen replacement therapy is either refused or contraindicated.",1
9443,9652559,Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group,"""BACKGROUND: Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients. METHODS: 380 adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4-6 weeks (n=193), or to receive placebo (n=187). Both groups received baseline dual immunosuppressive therapy with cyclosporin and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study. FINDINGS: 376 patients were eligible for intention-to-treat analysis (basiliximab, n=190; placebo, n=186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8%) of 171 in the basiliximab group compared with 73 (44.0%) of 166 in the placebo group (32% reduction; 14.2% difference [95% Kaplan-Meier CIs 3% to 24%], p=0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10% vs 23.1%, 13.1% difference [5.4% to 20.8%], p<0.001). At weeks 2 and 4 post-transplantation, the mean daily dose of steroids was significantly higher in the placebo group (p<0.001 with one-way analysis of variance). The incidence of graft loss at 12 months post-transplantation was 23 (12.1%) of 190 in the basiliximab group and 25 (13.4%) of 186 in the placebo group (1.3% difference [-5% to 9%], p=0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. 14 deaths (basiliximab n=9; placebo n=5; -2.0% difference [-6% to 2%], p=0.293) occurred during the 12-month study and a further three deaths (basiliximab n=1; placebo n=2) occurred within the 380-day cut-off period. One post-transplantation lymphoproliferative disorder was recorded in each group. INTERPRETATION: Prophylaxis with 40 mg basiliximab reduces the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns.""",1
9444,9652997,Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone,,1
9445,9654706,[Diclofenac-associated acute cholestatis hepatitis],"Diclofenac is an anti-inflammatory analgesic which is widely used in the therapy of inflammatory joint pain. Diclofenac hepatotoxicity ranges from asymptomatic elevation of transaminase activity to significant liver disease. 31 cases of diclofenac-induced hepatitis with five associated deaths have been already reported in the English, French and Spanish literature. We report the case of a 64-year-old patient who was admitted to the hospital with an icteric hepatitis of sudden onset. The only drug that was taken before admission was diclofenac in a daily dose of 150-200 mg because of a spondylodiscitis. Work-up of the patient included ERCP, laparoscopy and liver biopsy and excluded other reasons of a cholestatic hepatitis. Discontinuation of diclofenac resulted in normalization of transaminase activity and bilirubin concentration within four months. The frequent use of diclofenac and the possibility of fatal liver damage highlights the need that diclofenac-toxicity should be considered in the differential diagnosis of acute cholestatic hepatitis.",1
9446,9656761,[Acute cholestatic hepatitis secondary to flutamide],,1
9447,9660045,Amiodarone-induced severe hepatitis mediated by immunological mechanisms,A 64-year-old man developed a fulminant hepatitis 4 days after initiation of amiodarone treatment and a total dose of 7.1 g. The direct Coombs test was positive and became negative again soon after stopping treatment. Immediately after stopping treatment the extremely increased parameters of hepatic failure returned to normal again. A rechallenge with 200 mg of amiodarone was accompanied by a positive Coombs test which again became negative after several days. We conclude that the occurrence of an acute hepatitis soon after initiation of amiodarone treatment is mediated by immunological mechanisms. There should be high vigilance with respect to this rare life-threatening adverse drug reaction.,1
9448,9663368,"Long-term efficacy, tolerability, and safety of the combination of enalapril and felodipine ER in the treatment of hypertension. Enalapril-Felodipine ER Factorial Study Group","""A recent 8-week, double-masked, placebo-controlled, 3 x 4 factorial-design study demonstrated that enalapril-felodipine extended-release (ER) combinations had statistically significant additive effects for reducing both sitting systolic blood pressure (SiSBP) and sitting diastolic blood pressure (SiDBP) and were generally well tolerated in hypertensive patients with SiDBPs ranging from 95 to 115 mm Hg. The present open-label study was undertaken to assess the long-term efficacy, tolerability, and safety of such combinations. Patients from the factorial study were eligible for the 1-year, open-label extension. Initially, all patients received enalapril 5 mg-felodipine ER 2.5 mg once daily; if SiDBP was not controlled (< 90 mm Hg) after 4 weeks of treatment, the dose was titrated upward at 2- to 4-week intervals to a maximum of enalapril 10 mg-felodipine ER 10 mg. Hydrochlorothiazide (HCTZ) 12.5 mg was added to the regimen of patients whose hypertension was not controlled at the highest enalapril-felodipine ER dose. A total of 507 patients were enrolled, of whom 502 were assessable. At their last study visit, 391 (78%) of the assessable patients were receiving only an enalapril-felodipine ER combination. The enalapril-felodipine ER combinations resulted in mean trough SiDBPs of 85 to 89 mm Hg (decreases of 13 to 16 mm Hg from baseline) and SiSBPs of 137 to 140 mm Hg (decreases of 13 to 21 mm Hg). Overall, 407 (81%) of the 502 assessable patients achieved an SiDBP < 90 mm Hg or a reduction from baseline > or = 10 mm Hg (responders); such a response was recorded in 331 patients (66%) taking a combination of enalapril-felodipine ER alone and 76 patients (15%) taking the combination with the addition of HCTZ 12.5 mg. Blood pressure reductions were maintained throughout the treatment period. Drug-related adverse events were relatively infrequent, often transient, usually mild, and apparently not dose related. The most frequently reported drug-related adverse events were edema/swelling, asthenia/fatigue, dizziness, cough, and headache. These results suggest that combination therapy with enalapril-felodipine ER is effective for long-term blood pressure reduction, has an excellent safety profile, and is generally well tolerated. Addition of low-dose HCTZ to the enalapril-felodipine ER combination appears to provide further blood pressure control without increasing drug-related adverse events.""",1
9449,9670588,[Hepatotoxicity caused by captopril],,1
9450,9672188,Severe idiosyncratic acute hepatic injury caused by paracetamol,,1
9451,9677182,Hepatotoxicity after introduction of highly active antiretroviral therapy,,1
9452,9680339,Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population,"""Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.""",1
9453,9681106,Rapid onset of risperidone-induced hepatotoxicity,,1
9454,9683215,Severe cutaneous reaction due to terazosin,,1
9455,9686348,Alternative pathway therapy for urea cycle disorders,"""In man the major pathway for the disposal of waste nitrogen is the urea cycle; in inborn errors of this pathway, nitrogen flux is reduced. As a result there is accumulation of ammonia and glutamine with disordered metabolism of other amino acids. Nitrogen homeostasis can be restored in these patients with a low-protein diet combined with compounds that create alternative pathways for nitrogen excretion. The introduction of these compounds has been a major advance in the management of these inborn errors and as a result the outcome, particularly for those treated early, has improved.""",1
9456,9686768,"A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group","""Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.""",1
9457,9692168,Successful treatment of human fascioliasis with nitazoxanide,,1
9458,9692692,Oral budesonide as maintenance therapy in Crohn's disease--results of a 12-month study. Global Budesonide Study Group,"BACKGROUND: Budesonide is a corticosteroid with high topical anti-inflammatory activity and low systemic activity due to rapid inactivation. We have assessed the efficacy and safety of an oral controlled ileal release (CIR) preparation of budesonide for maintenance of remission in patients with ileal or ileocaecal Crohn's disease. METHODS: In a double-blind, multicentre trial, 75 patients in clinical remission (Crohn's Disease Activity Index, CDAI, < or = 150) were randomly assigned to receive placebo, budesonide 3 mg or budesonide 6 mg daily for 12 months. Trial drugs were given at a fixed dose and without concomitant medication. The primary outcome measure was relapse, defined as a CDAI > 150 together with an increase of at least 60 units from entry. A patient was also considered to have a relapse if withdrawn from the study due to clinical deterioration, whether or not a CDAI value could be calculated at that time. RESULTS: There were no statistically significant differences in the relapse rate at any time-point throughout the study. By 12 months the proportion of patients having relapsed were 48, 46 and 60% in those patients treated with budesonide 6 mg, 3 mg and placebo, respectively (N.S.). Treatments were well tolerated, and the proportion of patients with suppressed adrenal function (according to predetermined criteria) were 50% (6 mg), 26% (3 mg) and 17% (placebo) (P = 0.096). CONCLUSIONS: In the present study, relapse rate and time to relapse were similar in the patients treated with budesonide CIR, 6 mg daily or 3 mg daily or with placebo, throughout 12 months. This is in contrast to the two previous trials with identical design, where a significant effect of budesonide CIR in prolonging the median time to relapse was found. Possible reasons for the negative results of the present study include small sample size, and the fact that there was a high placebo response.",1
9459,9696502,Nimesulide-induced acute hepatitis: evidence from six cases,"""BACKGROUND/AIMS: A number of nonsteroidal anti-inflammatory drugs have been reported to provoke hepatic injury. Nimesulide is a new agent of the sulfonanilide class, and is a more selective inhibitor of cyclooxygenase type 2 than of type 1. Well-documented cases of acute hepatitis have not yet been reported with this drug. We report on six patients who developed acute liver damage after initiation of nimesulide. METHODS: Between April 1996 and January 1997, six patients with apparent nimesulide-induced liver injury were admitted. Clinical, laboratory, serologic, radiological, and histologic data of all six cases were extensively analyzed. The causal relationship between nimesulide and liver injury was assessed, using a scoring system elaborated by the French and International consensus meeting group. RESULTS: Four women developed a centrilobular (three) or panlobular (one) bridging necrosis, whereas two men showed a bland intrahepatic cholestasis. Jaundice was the presenting symptom in five of the six cases. One patient with hepatocellular necrosis and one with cholestasis had hallmarks of hypersensitivity with an increased blood and tissue eosinophilia. The causal relationship could be designated as """"highly probable"""" in one, """"probable"""" in four, and """"possible"""" in one patient. One patient died from a pancreatic tumor 5 months after the diagnosis of toxic liver injury. In all other patients, liver tests returned to completely normal values within a late follow-up period of 6 to 17 months. CONCLUSIONS: Nimesulide-induced liver injury can present with hepatocellular necrosis or with pure cholestasis. From clinical and histologic data, it appears that both immunologic and metabolic idiosyncratic reactions can be invoked as the pathogenic mechanisms of nimesulide-induced liver disease.""",1
9460,9706284,Recombinant interleukin-11 for chemotherapy-induced thrombocytopenia,,1
9461,9707067,An unusual case of amoxicillin/clavulanic acid-related hepatotoxicity,"Amoxicillin/clavulanic acid is a widely used antibiotic. Hepatic dysfunction is a rare adverse reaction associated with this combination antibiotic. We report the case of a 40-yr-old woman with a somewhat unusual presentation of amoxicillin/clavulanate-related cholestatic hepatotoxicity and multiple duodenal erosions whose diagnosis was delayed until inadvertent rechallenge with the antibiotic combination. The relevant literature is also reviewed and discussed. The diagnosis may be missed because the onset of signs/symptoms may occur several weeks after the cessation of therapy. The hepatic dysfunction, which may be severe and is more prevalent in elderly patients, is usually reversible, although chronic liver disease and deaths have been reported. Immunological hypersensitivity is considered to be the most likely mechanism resulting in liver injury. Amoxicillin/clavulanate should be used with caution in patients with underlying liver disease and in the elderly.",1
9462,9713096,Ketoconazole-induced liver damage,"Five cases (four females, one male) of ketoconazole-related liver damage are presented, two of whom died. All patients received ketoconazole (400 mg/day) for various mycoses. In the four women the first signs of hepatotoxicity appeared after four weeks of therapy. One fatal case developed massive necrosis with fulminant liver failure and the other, submassive necrosis. In four cases cholestasis was a prominent finding. Biochemical evidence of biliary stasis may persist for several months, as occurred in the three surviving patients of our series. The two fatal cases continued receiving the drug in spite of its adverse effects. Consequently, repeated evaluation is recommended to detect early signs of liver environment.",1
9463,9718630,Management of the adverse effects of clozapine,"Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.",1
9464,9722388,Tramadol hydrochloride: an overview of current use,"Tramadol's two enantiomers produce analgesia, in acute and chronic pain states, by combining synergistically, weak opioid and monoaminergically-mediated mechanisms. Tramadol is interesting, being free of some of the clinically significant side-effects seen with other opioids of comparable efficacy.",1
9465,9726336,Colchicine: 1998 update,"""OBJECTIVE: To present an update of the use of colchicine in patients with familial Mediterranean fever (FMF) and other rheumatic and nonrheumatic diseases. DATA SOURCES: Published studies on colchicine retrieved from MEDLINE searches from 1987 to 1997 and reports presented at national and international meetings. STUDIES SELECTION AND EXTRACTION: All studies were reviewed by the authors. Reports addressing the topics of colchicine pharmacokinetics, biological effects, indications for use, and side effects were selected. DATA SYNTHESIS: Colchicine is an alkaloid that may interfere with microtubule formation, thereby affecting mitosis and other microtubule-dependent functions. It has a bioavailability of 25% to 50% when administered orally. Colchicine and its metabolites are excreted through the urinary and biliary tracts. It may be used while breast feeding; however, amniocentesis should be performed when used in pregnancy. The drug may be given to children with FMF. The efficacy of colchicine has been proved in FMF, gout, Behcet's disease, and cirrhosis. Its place in the treatment of scleroderma, sarcoidosis, and skin disorders remains to be determined. Gastrointestinal side effects occur early and are most common manifestations of colchicine toxicity. Severe colchicine toxicity results in multiple organ failure, convulsions, coma, and death. Potentially, effective treatment with Fab anti-colchicine antibodies unfortunately is unavailable; therefore, treatment is supportive. CONCLUSIONS: Colchicine is a relatively safe and effective medication for several disorders when used in appropriate dosage in patients with normal kidney and liver function.""",1
9466,9727726,Safety and tolerance of zolpidem in the treatment of disturbed sleep: a post-marketing surveillance of 16944 cases,"""The subjective response to treatment with zolpidem, an imidazopyridine hypnotic, was assessed in patients with insomnia under normal treatment conditions in an outpatients' practice in Germany. The uncontrolled clinical surveillance study included 16944 outpatients with subjective difficulties in initiating and/or maintaining sleep. Office-based neurologists, psychiatrists, internists and general practitioners were asked individually to adjust the dosage of zolpidem (age < or = 65 years, 10-20 mg; age > 65 years, 5-10 mg) over a recommended period of 3-4 weeks. In total, 82.8% of patients completed the survey (36% men, 64% women, mean age 58.8 +/- 14.9 years; 58.6% without previous hypnotic medication; duration of sleep complaints > 6 months in 40.6%, 1-6 months in 27.8%). Most patients (63.9%) took zolpidem on a daily basis. The average dose was 10 mg zolpidem per night in 74.8%, 5 mg in 19.8%, 20 mg in 2.4% and > 20 mg in 10 cases. Most physicians (87.6%) rated the efficacy of zolpidem as 'very good' or 'good'. One hundred and eighty-two (1.1%) of the 16 944 patients reported 268 adverse events (one adverse event in 113 cases, two adverse events in 53 cases and more than two adverse events in 16 cases). One hundred and eighteen (64.8%) of these patients (0.006% of all participating patients) discontinued treatment because of adverse events. Nausea (n = 36), dizziness (n = 35), malaise (n = 23), nightmares (n = 20), agitation (n = 19), and headache (n = 18) were the most common adverse events. There was one serious adverse reaction in a 48-year-old women who developed paranoid symptoms during the documentation phase. No life-threatening adverse event occurred. The adverse event profile reflected the pharmacological properties of zolpidem and underlined the cumulative good experience with the drug internationally.""",1
9467,9731048,Long-term follow-up of patients with hairy cell leukemia after cladribine treatment,"""Hairy cell leukemia is a chronic B-cell disorder that follows an indolent, but progressive course. Cladribine (2-chlorodeoxyadenosine) induces complete remissions in the majority of patients after a single course. We report the long-term outcomes, including response rates and their duration; time-to-treatment failure (TTF) rates; retreatment results; toxicities; and survival rates of patients treated at Scripps Clinic (La Jolla, CA). A total of 358 patients with hairy cell leukemia were treated with cladribine at 0.087 or 0.1 mg/kg body weight per day by continuous intravenous infusion for 7 days. The expected number of second neoplasms was based on the National Cancer Institute's Surveillance Epidemiology and End Results data. Of 349 evaluable patients, 319 (91%) achieved an initial complete response and 22 (7%) a partial response with an overall median duration of response follow-up of 52 months. Ninety patients (26%) had relapsed at a median of 29 months. The TTF rate for all 341 responders was 19% at 48 months, 16% for complete responders, and 54% for partial responders. Of 53 evaluable patients treated with second courses of cladribine at first relapse, 33 (62%) achieved complete responses and 14 (26%) partial responses. Twenty-seven patients (8%) developed second neoplasms (only 1 hematopoietic) with an observed-to-expected ratio of 1.88 (95% confidence interval, 1.24 to 2.74). The overall survival rate was 96% at 48 months. Single courses of cladribine induced long-lasting complete responses in the vast majority of patients. Relapse rates for complete responders were low. Patients who relapse can be successfully retreated with cladribine. Cladribine has high efficacy and a favorable acute and long-term toxicity profile when administered to patients with hairy cell leukemia.""",1
9468,9732947,Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series,Hepatitis C is a common chronic infection. Nonsteroidal anti-inflammatory drugs are commonly ingested both over-the-counter and by prescription. This case report describes three cases where ibuprofen use leads to a marked rise in hepatic transaminases with one case repeating on rechallenge. These cases support the recommendation of acetaminophen over nonsteroidal antiinflammatory drug use in patients with chronic hepatitis C.,1
9469,9740115,Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Ropinirole Study Group,"""OBJECTIVE: To evaluate ropinirole hydrochloride as dopaminergic monotherapy in patients with early Parkinson disease. DESIGN: A 6-month extension of a double-blind, placebo-controlled study. SETTING: Ambulatory care at 22 different sites in the United States. PATIENTS: Patients who successfully completed the initial 6-month study could enter the 6-month extension study (ropinirole, n = 70; placebo, n = 77). INTERVENTION: Use of ropinirole or placebo therapy. MAIN OUTCOME MEASURES: The efficacy variables were the number of patients who successfully completed the 12-month study and did not require supplemental levodopa, the number of patients requiring supplemental levodopa, and the proportion of patients having an insufficient therapeutic response. RESULTS: Significantly fewer ropinirole-treated patients met criteria for insufficient therapeutic response (23 [19.8%] of 116) or required the initiation of levodopa therapy (22 [19%] of 116) compared with placebo-treated patients (60 [48%] of 125 patients for insufficient therapeutic response; 57 [45.6%] of 125 patients for additional levodopa). Significantly more ropinirole-treated patients (51 [44.0%] of 116) successfully completed the 12-month study and did not require supplemental levodopa compared with placebo-treated patients (28 [22.4%] of 125). The incidence of adverse experiences and patient withdrawals was low. CONCLUSION: Ropinirole was effective and well tolerated as monotherapy for 12 months in patients with early Parkinson disease.""",1
9470,9742783,[The hepatotoxicity of flutamide],,1
9471,9744703,Cholestatic hepatitis due to ticlopidine: clinical and histological recovery after drug withdrawal. Case report and review of the literature,A 72-year-old housewife presented with clinical and laboratory signs of acute cholestatic hepatitis. Symptoms had appeared 6 months after she was started on ticlopidine 250 mg/day. Infectious aetiologies were excluded by serology and there was no history of alcohol abuse or use of other drugs. Clinical findings were confirmed by liver biopsy. The drug was discontinued and symptoms gradually subsided. A second biopsy obtained during this phase documented complete resolution of the hepatic damage. A review of the literature shows that the late onset of hepatic toxicity in this case is unique and this is the first report to include histological documentation during the acute phase and after recovery.,1
9472,9747868,Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study,"""BACKGROUND: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. METHODS: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. RESULTS: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. CONCLUSIONS: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.""",1
9473,9752821,Tolcapone and fulminant hepatitis,,1
9474,9757261,[Regression of a focal nodular hyperplasia after stopping oral contraceptives],The complete regression of a focal nodular hyperplasia of the liver with typical MRI patterns 5 years after withdrawal of oral contraceptives was observed. Effects of oral contraceptives on this tumor's evolution and appropriate imaging by MRI are discussed.,1
9475,9759603,Flutamide-induced acute hepatitis: investigation on the role of immunoallergic mechanisms,"Flutamide is a nonsteroidal antiandrogen drug used in the treatment of prostatic cancer. Hepatotoxic reactions due to flutamide have been reported with an incidence ranging from 1% to 5%. These reactions are usually reversible upon withdrawal of the drug but can occasionally be life-threatening. The mechanism of flutamide-associated hepatotoxicity is not well established. We report a case of a 69-year-old man with prostatic carcinoma in whom flutamide induced an acute hepatitis which resolved completely soon after drug withdrawal. In this patient, we have studied the possible involvement of an immunological mechanism in causing flutamide hepatitis by investigating the presence of circulating antibodies directed against reactive metabolites of flutamide bound to liver proteins with enzyme-linked immunosorbent assay technique. Although, in the present case, we have failed to detect IgG reacting with rat liver microsomes incubated in vitro with flutamide, this does not completely rule out the possibility of an immunological involvement in flutamide hepatotoxicity. The possibility of severe flutamide-related injury, independently of the underlying pathogenic mechanism, strongly suggests the need for careful monitoring of liver enzymes in patients taking this drug.",1
9476,9762291,[Autoimmune hepatitis induced by fibrates],"AIM: Long term treatment by fibrates could induce chronic hepatitis associated with auto-antibodies. The aim of this study was to assess the features of this hepatitis. METHODS: Baseline clinical and biological features, and liver biopsy in 5 patients with fibrate-induced chronic hepatitis were studied, as well as their outcome. RESULTS: At enrollment, patients (4 men, mean age 65 years) had highly (n = 3) or mildly (n = 2) increased serum aminotransferase activity, hypergammaglobulinemia and high titers of anti-nuclear antibodies (with homogenous fluorescence in 3 cases). Liver biopsies demonstrated a lympho-plasmocytic infiltrate in all cases. Hepatocellular necrosis was multilobular in 2 cases, and mild to moderate, located in lobular and periportal areas in 3 cases. Cirrhosis was found at presentation in 3 cases and developed within a few months in the 2 other patients. After discontinuation of fibrates, aminotransferase activity normalized within 6 weeks either spontaneously (n = 3) or under immunosuppressive treatment (n = 2). Immunosuppression was rapidly withdrawn in 2 patients (< 18 months) without relapse, while one patient was treated for 4 years because of relapse after early withdrawal. A second liver biopsy performed 6 months after discontinuation of fibrates in an untreated-patient showed no inflammation or necrosis. CONCLUSION: These observations suggest that fibrates could trigger chronic liver disease resembling type I auto-immune chronic hepatitis, which resolves after drug withdrawal.",1
9477,9764966,Terfenadine and risk of acute liver disease,"AIMS: To estimate the risk of idiopathic acute liver disease among users of terfenadine. METHODS: We conducted a population-based cohort study based on the General Practice Research Database (GPRD) in the U.K. All persons who received at least one prescription for terfenadine during the period 1991 through 1995 were eligible for the study. Among these patients we identified all those with a diagnosis of a liver disorder requiring hospitalization or referral to a consultant within 60 days of a prior prescription for terfenadine. We obtained clinical records, including hospital discharge summaries, consultant reports and relevant laboratory results in order to identify a potentially drug-inducible liver illness. RESULTS: From a cohort of 210683 recipients of terfenadine, we found only three cases of acute liver disease where a causal connection to terfenadine could not be ruled out, yielding a risk estimate of 1.4/100000 users (95% CI 0.5, 4.2) and 0.5/100000 prescriptions (95% CI 0.2, 1.4). All cases were receiving a concomitant hepatotoxic drug and all had a full recovery. CONCLUSION: The use of terfenadine is rarely associated with idiopathic acute liver disease.",1
9478,9767974,[Acute hepatitis due to ecstasy],"BACKGROUND: Ecstasy is a synthetic amphetamine which causes a wide variety of adverse effects. Hepatic toxicity was only recently demonstrated but can be quite severe. CASE REPORT: A 27-year-old male with no past medical or surgical history developed jaundice without fever. He was a regular user of ecstasy and had recently increased the number of doses consumed. No evidence of a viral, alcoholic, metabolic or autoimmune mechanism was found which could explain the hepatitis. Complete cure was obtained by discontinuing ecstasy. DISCUSSION: Few cases of ecstasy hepatic toxicity have been reported. Ecstasy was undoubtedly the causal agent in this case since other known causes of acute hepatitis were excluded, confirming the hepatotoxicity of ecstasy reported in the literature. The liver disease has been reported to range form acute regressive hepatitis to fatal liver failure. Iterative exposure can lead to fibrosis. The pathophysiological mechanism of this toxic effect is not well elucidated. Ischemia alone cannot explain all the clinical forms described, particularly cases without hyperpyrexia. Ecstasy must be added to the list of potential causes of acute hepatitis. Exposure must always be searched for in cases of acute hepatitis in young subjects.",1
9479,9772944,"[Study of the efficacy and safety of fosinopril in general practice in 19,435 hypertensive patients (FLIGHT Study)]","The efficacy and good safety of fosinopril, an angiotensin converting enzyme inhibitor recently made available to the medical profession in France, has been demonstrated by several controlled studies versus placebo and reference antihypertensives. A phase IV multicentre clinical trial was conducted among general practitioners in order to assess, on a larger scale and under conditions of daily practice, the results obtained in terms of blood pressure control and quality of life as well as the clinical and laboratory safety of the drug. This analysis was based on 19,435 hypertensive patients, 989 of whom were over the age of 75 years, followed for 12 weeks after introduction of fosinopril either as monotherapy or in combination with the antihypertensive treatment(s) already prescribed. Under these conditions, after 12 weeks of treatment, blood pressure was controlled in 79.8% of patients, with improvement of all items of the quality of life scale. The very low incidence of clinical and laboratory adverse events, even among the oldest patients, confirms the safety of use of fosinopril, predictive of good long-term compliance with treatment.",1
9480,9774964,New monoclonal antibodies to prevent transplant rejection,,1
9481,9779711,Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel,"""PURPOSE: Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel. PATIENTS AND METHODS: Topotecan 1.5 mg/m2 daily was administered as a 30-minute infusion for 5 consecutive days on a 21-day cycle. Eligibility criteria included bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal function. Efficacy was assessed by independent radiologic review. RESULTS: One hundred thirty-nine patients were treated; 81% were platinum resistant. Sixty-two patients had received one prior regimen and 77 patients had received two prior regimens. Nine patients were not assessable for response; however, all patients were included in the response analysis. The overall response rate was 13.7%; 12.4% in platinum-resistant and 19.2% in platinum-sensitive patients. Stable disease lasted at least 8 weeks in 27.3% of the patients. The median duration of response and time to progression were 18.1 and 12.1 weeks, respectively. The median survival was 47.0 weeks. Grade 4 neutropenia occurred in 82% of the patients (34% of the courses) and thrombocytopenia in 30% of the patients (9% of the courses). Infectious complications occurred in 6% of the courses. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION: As a single agent, topotecan has modest activity in women with advanced epithelial ovarian carcinoma who have progressed or not responded after one or two prior regimens with platinum and paclitaxel. Further investigation of combination regimens is indicated in the primary therapy for ovarian cancer based on the mechanism of action and tolerability.""",1
9482,9781550,Lamotrigine-associated anticonvulsant hypersensitivity syndrome,"""We systematically reviewed and analyzed published and unpublished cases of lamotrigine-associated adverse drug reactions consistent with the features of the anticonvulsant hypersensitivity syndrome (AHS) to identify characteristics of the syndrome. We identified 26 cases (mean age, 28+/-18 years; range, 3.5 to 74 years; 54% female), of which nine were published. The characteristics of the syndrome associated with lamotrigine are comparable to AHS induced by older aromatic anticonvulsants.""",1
9483,9786476,Efficacy and safety profile of long-term nitrofurantoin in urinary infections: 18 years' experience,"""Case records from 219 female patients between 1975 and 1992 who were given long-term prophylaxis (1 year) with nitrofurantoin for the prevention of recurrent urinary infections have been reviewed. Patients' age ranged from 9 to 89 years (median 31-35 years, mode 26-30 years); most (61%) were < 40 years old. The median number of symptomatic episodes in the 12 months immediately before prophylaxis was six (mode 4, mean 6.9). 14.4% of the patients were allergic to an antibiotic, and 23.6% had an imaging abnormality. Three regimens were used: group A (43 patients), 50 mg microcrystalline nitrofurantoin, bd; group B (110 patients), 100 mg macrocrystalline nitrofurantoin (Macrodantin), od; group C (66 patients), 50 mg Macrodantin, od. There were no obvious differences in efficacy between the patient groups (173 assessable patients). The mean incidence of symptomatic episodes decreased 5.4-fold during prophylaxis. Four-fifths of the 43 breakthrough infections (mostly due to Escherichia coli), were caused by nitrofurantoin-sensitive strains. An important finding was that patients with an imaging abnormality responded as well as those with no such abnormalities. In 16% of patients, prophylaxis was not helpful, objectively or subjectively, for no obvious reasons. In most patients where prophylaxis was successful, clinical improvement was maintained for at least 6 months after the end of prophylaxis. Nausea was more common in group A (P < 0.001), as were 'all adverse events'. Of those in group A 25.6% stopped prematurely as a result of an adverse event of any type, compared with 13% of those taking Macrodantin (P < 0.01). Older patients (> 65 years) did not report more adverse events than younger patients. No adverse event was life-threatening. Faecal flora analysis showed neither overgrowth by nitrofurantoin-resistant bacteria nor elimination of sensitive coliforms. Thus, macrocrystalline nitrofurantoin 50 mg at bedtime is appropriate for use in the long-term (12 months) prophylaxis of recurrent urinary infections, in view of its efficacy and favourable safety and tolerability profile. Patients can be managed by their family doctor.""",1
9484,9790457,Ticlopidine-induced cholestatic hepatitis: report of three cases and review of the literature,,1
9485,9792403,Acute clinical hepatitis in an HIV-seropositive hepatitis B carrier receiving protease inhibitor therapy,,1
9486,9794697,Treatment of Wilson's disease with zinc: XV long-term follow-up studies,"""Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.""",1
9487,9795794,Acute hepatitis in a patient treated with saquinavir and ritonavir: absence of cross-toxicity with indinavir,,1
9488,9798669,"Early ticlopidine-induced hepatic dysfunction, dermatitis and irreversible aplastic anemia after coronary artery stenting",,1
9489,9802764,Acarbose-associated hepatotoxicity,,1
9490,9806110,5-Methoxypsoralen. A review of its effects in psoriasis and vitiligo,"""5-Methoxypsoralen, a naturally occurring linear furocoumarin, has been successfully used in combination with ultraviolet (UV) A irradiation [psoralen plus UV (PUVA)] to manage psoriasis and vitiligo. In patients and volunteers, PUVA 5-methoxypsoralen causes a dose-related increase in cutaneous photosensitivity. However, mean minimum phototoxic doses (MPD) were 30 to 50% greater with 5-methoxypsoralen than with 8-methoxypsoralen within individuals; this suggests lower photoactivity with 5-methoxypsoralen. In comparative clinical trials of parallel design, psoriasis clearance rates of > 90% or > 97% were observed in similar numbers of patients (60 to 77%) receiving oral PUVA 5-methoxypsoralen (typically 1.2 mg/kg) or oral PUVA 8-methoxypsoralen (0.6 mg/kg) treatment. Generally, 5-methoxypsoralen recipients required a greater total UVA exposure than 8-methoxypsoralen recipients to achieve end-point. However, study end-point was achieved sooner with oral or topical PUVA 5-methoxypsoralen in a small number of patients with psoriasis who received both treatments simultaneously and contralaterally. Up to 56% of patients with vitiligo achieved > 75% repigmentation with 5-methoxypsoralen (oral or topical) combined with UV irradiation (lamp or sun); the face and trunk were the most responsive areas. Lack of response to PUVA 5-methoxypsoralen treatment was observed in up to 16% of patients with psoriasis and, in 1 trial, in 22% of those with vitiligo. Lesion spreading during treatment of vitiligo was also observed in 7 (19%) patients in 1 study. The incidence and severity of adverse events was generally lower in PUVA 5-methoxypsoralen 1.2 mg/kg than in PUVA 8-methoxypsoralen 0.6 mg/kg recipients. Nausea and/or vomiting, pruritus and erythema were the most commonly reported adverse events in the short term; they occurred about 2 to 11 times more frequently in 8-methoxypsoralen than 5-methoxypsoralen recipients within clinical trials. Adverse hepatic events after oral administration of the drug were uncommon. Long term tolerability data for PUVA 5-methoxypsoralen are scarce; however, carcinogenicity was not reported during a 14-year observation period of 413 patients with psoriasis. CONCLUSION: Similar lesion clearance rates were observed with oral 5- or 8-methoxypsoralen plus UVA exposure in patients with vitiligo or psoriasis, although patients given 5-methoxypsoralen often required a greater total UV exposure than 8-methoxypsoralen recipients. The incidence of short term cutaneous and gastrointestinal adverse effects is markedly less with 5-methoxypsoralen than with 8-methoxypsoralen, which is an advantage, although the long term tolerability of 5-methoxypsoralen has yet to be fully established. Nevertheless, in appropriately selected patients, PUVA 5-methoxypsoralen therapy may be recommended as an alternative first-line systemic treatment option for the management of vitiligo or psoriasis.""",1
9491,9811293,Minocycline-related autoimmune hepatitis: case series and literature review,"BACKGROUND: Minocycline is an antibiotic commonly used in the treatment of adolescent acne. OBJECTIVES: To describe the clinical, laboratory, and histological features in 3 cases of minocycline-related autoimmune hepatitis and to review the literature of similar cases in the adolescent population. DESIGN: Case series. SETTING: Patients were cared for in the Division of Gastroenterology, Children's Hospital, Boston, Mass. RESULTS: Three adolescents (age, 15-16 years), while being treated with therapeutic doses of minocycline for periods of 12 to 20 months, met the 1993 International Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had a positive antinuclear antibody titer. Other features included hypergammaglobulinemia and a positive anti-smooth muscle antibody titer. Two patients underwent liver biopsy that revealed severe chronic lymphoplasmacytic inflammation, necrosis, and fibrosis. All other causes of liver disease were excluded. One patient had resolution of symptoms with withdrawal of the drug, while 2 required immunosuppression therapy. A review of the literature yielded only 18 similar cases, none in the pediatric literature, the majority of which contained incomplete pertinent data. CONCLUSIONS: Minocycline is related to the development of autoimmune hepatitis in some adolescents. Pediatricians who use this drug for treatment of acne should be aware of this serious potential relation and stop the drug immediately when suspicion is raised.",1
9492,9814369,Trastuzumab and capecitabine for metastatic breast cancer,,1
9493,9815810,Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients,"We conducted a Phase IB trial of antidisialoganglioside chimeric 14. 18 (ch14.18) antibody and interleukin 2 (IL-2) to determine the maximal tolerated dose (MTD), immunological effects, antitumor effects, and toxicity of this treatment combination. Twenty-four melanoma patients received immunotherapy with ch14.18 antibody and a continuous infusion of Roche IL-2 (1.5 x 10(6) units/m2/day) given 4 days/week for 3 weeks. The ch14.18 antibody (dose level, 2-10 mg/m2/day) was scheduled to be given for 5 days, before, during, or following initial systemic IL-2 treatment. The ch14.18 MTD was 7.5 mg/m2/day, and 15 patients were treated with the ch14.18 MTD. Immunological effects included the induction of lymphokine-activated killer activity and antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells. In addition, serum samples obtained following ch14.18 infusions were able to facilitate in vitro antibody-dependent cellular cytotoxicity. Antitumor activity included one complete response, one partial response, eight patients with stable disease, and one patient with >50% decrease of hepatic metastases in the face of recurrence of a s.c. lesion. Dose-limiting toxicities were a severe allergic reaction and weakness, pericardial effusion, and decreased performance status. Most patients treated at the MTD had abdominal, chest, or extremity pain requiring i.v. morphine. One patient had an objective peripheral neuropathy. This IL-2 and ch14.18 treatment combination induces immune activation in all patients and antitumor activity in some melanoma patients. We are attempting to enhance this treatment approach by addition of the anti-GD3 R24 antibody to this IL-2 and ch14.18 regimen.",1
9494,9818693,High-dose thiotepa and etoposide-based regimens with autologous hematopoietic support for high-risk or recurrent CNS tumors in children and adults,"The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range 8-37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10-37) than for PBPC (median 9.5 days, range 8-10). Platelet engraftment >50 x 10(9)/l was 24 days (range 14-53 days) in children. In adults, platelet engraftment >20 x 10(9)/l was 12 days (range 9-65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.87, P = 0.009) and platelet engraftment (rho = -0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n = 4). Median time to tumor progression (TTP) was 7 months, with an overall median survival of 12 months. These TE-based BCNU or carboplatin three-drug combination HDC regimens are safe and tolerable with promising response rates in both children and older adults.",1
9495,9820309,Raloxifene-associated hepatitis,,1
9496,9825098,Hepatotoxicity due to ticlopidine,,1
9497,9827291,DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy,,1
9498,9829158,Candesartan cilexetil. A review of its use in essential hypertension,"Candesartan cilexetil is completely converted to the nonpeptide angiotensin II receptor blocker candesartan during absorption from the gastrointestinal tract. Candesartan selectively blocks and dissociates slowly from the angiotensin II subtype 1 (AT1) receptor which mediates most of the known activities of angiotensin II. When administered once daily, oral candesartan cilexetil 8 to 32 mg dose-dependently and effectively reduces blood pressure in patients with mild to moderate essential hypertension. In comparative studies, candesartan cilexetil 8 mg/day was as effective as usual therapeutic dosages of enalapril, losartan potassium, hydrochlorothiazide and amlodipine. One study showed candesartan cilexetil 16 mg/day to be more effective than losartan potassium 50 mg/day. Furthermore, the combination of candesartan cilexetil with either hydrochlorothiazide or amlodipine resulted in additive antihypertensive effects. Preliminary evidence suggests that the blood pressure-lowering effects of candesartan cilexetil are associated with the prevention or improvement of end-organ damage in patients with hypertension. However, this requires further confirmation in clinical studies. Candesartan cilexetil improves insulin sensitivity in patients with hypertension and does not affect glucose homeostasis or the serum lipid profile in those with coexisting type 2 (non-insulin-dependent) diabetes mellitus. Candesartan cilexetil is well tolerated in patients with hypertension. Pooled data indicate that the tolerability profile of the drug is not significantly different from that of placebo, with headache being the most commonly reported event. Adverse events are not dose related and are mostly mild to moderate in severity. Candesartan cilexetil is better tolerated than enalapril, primarily because of a reduced incidence of cough, and was not associated with the hypokalaemia or hyperuricaemia seen with hydrochlorothiazide in a study in patients aged > or = 75 years. The drug has an adverse events profile similar to that of losartan potassium in patients with mild to moderate hypertension. CONCLUSIONS: once daily candesartan cilexetil is effective and well tolerated when used once daily (as monotherapy or in combination with other antihypertensive agents) in patients with mild, moderate or severe hypertension. Initially, however, the drug is likely to be used as an alternative to other agents in patients not responding to or intolerant of their current drug therapy.",1
9499,9833921,Expression of autoantibodies to specific cytochromes P450 in a case of disulfiram hepatitis,"BACKGROUND/AIMS: Immunological mechanisms are involved in many adverse drug reactions. In certain forms of drug-induced hepatitis, patients have been reported to express specific autoantibodies to hepatic drug-metabolising enzymes. The alcohol deterrent disulfiram is associated with a low frequency of severe liver toxicity, including hepatitis, but the mechanism of the toxicity is unknown. We investigated whether autoantibodies to cytochrome P450 enzymes were expressed in the serum of a 28-year-old male patient, who developed hepatitis after 7 weeks of disulfiram treatment and in whom possible causes of hepatitis other than disulfiram had been ruled out. METHODS: Patient serum IgG reactivity was analysed by immunoblotting or ELISA against test antigens consisting of recombinant/purified human or rat liver P450 enzymes, or isolated rat liver microsomes. RESULTS: A significant serum reactivity was found in immunoblotting against human cytochromes P450 1A2 and rat P450 3A1, using serum dilutions of up to 1:900 and 1:2400, respectively. In contrast, the reactivity against cytochromes P450 2E1, 2C9, 2D6, 3A4, and rat liver P450 reductase was either very low or undetectable. ELISA reactivity was low in general, indicating that the P450 epitopes were not surface exposed. Immunoblotting of rat liver microsomes revealed that autoantibodies recognised one major polypeptide corresponding to P450 3A. Autoantibody titres remained stable for at least 6 months after acute hepatitis. A similar reactivity was not found in any of ten control sera. CONCLUSIONS: The expression of autoantibodies directed against specific cytochromes P450 in a case of disulfiram hepatitis suggests that immunological mechanisms are involved in this adverse drug reaction, and that these P450 proteins should be evaluated as possible diagnostic test antigens in disulfiram hepatotoxicity.",1
9500,9836214,Propofol infusion syndrome in children,"The use of propofol infusions to sedate children in intensive care units has decreased after reports of deaths from myocardial failure. More recently it has been suggested that propofol might have been prematurely condemned. Information about 18 children who had received propofol infusions and suffered serious unwanted effects was used to define their common features. Three of the deaths occurred in one intensive care unit where propofol infusions had been used between 1987 and 1993. During this period 44 children with respiratory tract infections had been admitted to this unit and sedated for at least 48 h. Nine had received long-term (> 48 h), high-dose (> 4 mg.kg-1.h-1) propofol infusions and three had developed progressive myocardial failure and died. There was a significant association between receiving a long-term, high-dose propofol infusion and developing progressive myocardial failure (Fisher's Exact Test, two-tailed hypothesis, P = 0.0128) although a causative relationship could not be proved.",1
9501,9841583,Short-course prophylaxis against tuberculosis in HIV-infected persons. A decision and cost-effectiveness analysis,"BACKGROUND: Isoniazid prophylaxis for 12 months effectively prevents tuberculosis in HIV-infected persons and may decrease the incidence of other HIV-related disease and mortality. Recent clinical trials have found that some short-course regimens also effectively prevent tuberculosis. OBJECTIVE: To compare the benefits, risks, and cost-effectiveness of isoniazid prophylaxis and short-course prophylaxis regimens. DESIGN: Decision and cost-effectiveness analysis. SETTING: United States. PATIENTS: Hypothetical patients who are HIV-infected and have CD4 counts of 200 cells/mm3 or less and positive results on tuberculin skin tests. INTERVENTIONS: Isoniazid prophylaxis lasting 12 months and six short-course prophylaxis regimens of isoniazid, rifampin, and pyrazinamide alone or in combination. MEASUREMENTS: 5-year survival rate, life expectancy, lifetime incidence of tuberculosis, and cost per quality-adjusted life-year saved. RESULTS: Compared with no prophylaxis, the 12-month isoniazid regimen increased 5-year survival rates by 9% and life expectancy by 8.7 months, decreased incidence of tuberculosis by 27%, and saved 4 medical care dollars for every 1 spent on prophylaxis. Regimens of isoniazid for 6 months, isoniazid and rifampin for 3 months, and rifampin and pyrazinamide for 2 months had similar results: 6.2- to 8.6-month increases in life expectancy, 19% to 26% reductions in incidence of tuberculosis, and 1 to 7 medical care dollars saved for every 1 spent on prophylaxis. A 3-month regimen of isoniazid, rifampin, and pyrazinamide resulted in fewer clinical benefits and was the only regimen tested that did not save medical care dollars. CONCLUSIONS: Prophylaxis decreases the incidence of tuberculosis and increases life expectancy for HIV-infected patients. Some regimens save medical care dollars, and some short-course regimens have clinical and economic benefits similar to those of the 12-month isoniazid regimen. Short-course prophylaxis is a reasonable alternative to the 12-month isoniazid regimen.",1
9502,9847957,Hydroxyurea-induced fever and hepatitis,,1
9503,9849287,Gallstones and isoflurane hepatitis,"This report is of a case of a previously fit 65-year-old woman who developed postoperative liver dysfunction following an anaesthetic involving isoflurane. Biliary ultrasound demonstrated gallstones. However, serum antibodies to trifluoroacetylated proteins were detected, suggesting that immune sensitisation to the anaesthetic could have contributed to the impaired liver function.",1
9504,9851383,Trial of oral miltefosine for visceral leishmaniasis,"""BACKGROUND: There is no effective oral treatment for visceral leishmaniasis (kala-azar), a disseminated intracellular protozoal infection that occurs worldwide. Miltefosine, an alkyl phospholipid developed as an oral antineoplastic agent, is active against visceral infection in animal models. We tested safety, tolerance, and efficacy of miltefosine in kala-azar. METHODS: Oral doses of miltefosine were given to six groups of five Indian men for 28 days: 50 mg every second day (group 1), 100 mg every second day (group 2), 100 mg/day (group 3), 150 mg/day (group 4), 200 mg/day (group 5), and 250 mg/day (group 6). Assessment for apparent cure--taken as an afebrile state with decreased spleen size and a splenic-aspirate parasite-density score of 0--was done on days 14 and 28. Definitive cure at 8 months required a parasite-free bone-marrow aspirate and no clinical evidence of relapse. FINDINGS: 21 of 30 patients were apparently cured on day 14. Transient episodes of vomiting and diarrhoea, were common during weeks 1-2 and were seen in 22 patients. Four other patients in groups 5 and 6 had miltefosine withdrawn after 7-10 days because of vomiting. One patient in group 6 developed renal insufficiency and severe diarrhoea and died on day 21. On day 28, all 29 remaining patients were apparently cured. By 8 months, seven of ten patients in groups 1 and 2 had relapsed; however, 18 of 19 patients treated daily (groups 3-6) appeared to be cured. Among the 21 definitive cures were the four patients treated for 10 days or less and 12 for whom previous therapy with pentavalent antimony had failed. INTERPRETATION: Treatment with miltefosine at 100-150 mg/day for 4 weeks has promise as an effective oral treatment of visceral leishmaniasis including antimony-resistant infection.""",1
9505,9854210,[Dexchlorpheniramine-induced acute hepatitis: a case with positive rechallenge],,1
9506,9855171,"Nonsteroidal anti-inflammatory drug-associated toxicity of the liver, lower gastrointestinal tract, and esophagus","Although upper gastrointestinal (GI) adverse events are the most common consequences of nonsteroidal anti-inflammatory drug (NSAID) use, there are other GI side effects that can contribute to the morbidity and mortality associated with these drugs. NSAID-associated toxicity of the large and small bowel is increasingly recognized in clinical practice, as enteroscopic procedures become more frequently used. This lower GI toxicity may have several different manifestations: ulcerations, strictures, colitis, or exacerbation of inflammatory bowel disease. Hepatic injury, most likely due to an idiosyncratic reaction resulting from an immunologic response or altered metabolic pathways, is another sequela of NSAID use that is usually reversible. Although hepatotoxicity is listed as a class warning for NSAIDs, aspirin, diclofenac, and sulindac are most commonly associated with this problem. Surveillance for hepatic injury is not always reliable, and the low frequency of both hepatic and lower GI toxicity in NSAID users renders these events difficult to characterize. An increase in awareness, surveillance, and reporting of these events can lead to a better understanding of the risk factors and etiology associated with NSAID toxicity.",1
9507,9861942,New warnings on the use of isotretinoin (Roaccutane),,1
9508,9863784,Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group,"BACKGROUND: Influenza affects many people worldwide each year and has many troublesome symptoms. We investigated the efficacy and safety of the inhaled antiviral agent zanamivir as a treatment for influenza A and B infection. METHODS: In a randomised, double-blind, placebo-controlled trial, we recruited 455 patients aged 12 years and older with influenza-like symptoms of 36 h duration or less who lived in Australia, New Zealand, and South Africa. Eligible patients were randomly assigned 10 mg inhaled zanamivir (n=227) or placebo (n=228) twice daily for 5 days. All patients recorded symptoms on diary cards four times daily during treatment and twice daily for 9 days after treatment. We analysed all patients by intention to treat, influenza-positivity, and high risk of developing complications. FINDINGS: Compared with placebo, zanamavir relieved influenza symptoms a median of 1.5 days earlier in the intention-to-treat (p=0.011) and influenza-positive (p=0.004) populations, and 2 days earlier in patients who were febrile at entry [corrected]. In high-risk patients treated with zanamivir, symptoms were alleviated a median of 2.5 days earlier (p=0.048), fewer had complications (p=0.004), and fewer used complication-associated antibiotics (p=0.025) compared with placebo. The adverse event profiles were similar for zanamivir and placebo. INTERPRETATION: Zanamivir was well-tolerated and effective in decreasing the duration and severity of symptoms. Complications were also decreased in high-risk patients but these findings need to be confirmed in future studies due to the limited number of patients [corrected].",1
9509,9864540,[Acute hepatocytic necrosis during ketoconazole therapy for treatment of onychomycosis. National Foundation for Registry and Evaluation of Adverse Effects],"The imidazole derivative ketoconazole is approved in the Netherlands for treatment of local and systemic fungal infections. Despite the risk of major hepatic damage, this antimycotic drug is still being used in daily practice for the oral treatment of patients with onychomycosis. Since April 1986, 18 cases of relatively severe hepatic damage in the Netherlands were ascribed to the oral use of ketoconazole for the treatment of onychomycosis, skin infection or vaginal candidiasis. Given the potential risk for the patients concerned, ketoconazole should no longer be prescribed for relatively mild cosmetic disorders such as onychomycosis.",1
9510,9865671,Safety and efficacy of Omacor in severe hypertriglyceridemia,"BACKGROUND: Severe hypertriglyceridemia is a risk factor for acute pancreatitis, therefore decreasing serum triglyceride concentrations is an important component of risk management. Omega-3 fatty acids are well known hypotriglyceridemic agents, but their efficacy in severe forms of the disorder is not well documented. Our objective was to examine the effects of Omacor, a drug composed of 85% omega-3 fatty acid ethyl esters. METHODS: Forty-two patients with triglyceride concentrations between 5.65 and 22.60 mmol/l (500 and 2000 mg/dl) were studied in a prospective, double-blind, placebo-controlled trial of Omacor (4 g/day for 4 months). RESULTS: Compared with baseline values, Omacor significantly reduced mean triglyceride concentrations by 45% (P<0.00001), cholesterol by 15% (P< 0.001), very-low-density lipoprotein cholesterol by 32% (P< 0.0001) and cholesterol:high density lipoprotein (HDL) cholesterol ratio by 20% (P=0.0013), and increased HDL cholesterol by 13% (P=0.014) and low-density lipoprotein cholesterol by 31% (P=0.0014). The placebo had no effect on these parameters. Omacor was well tolerated and no patient discontinued medication because of side effects. CONCLUSIONS: Four capsules of Omacor per day markedly decreased triglyceride concentrations in patients with severe hypertriglyceridemia. The availability of a potent and safe omega-3 fatty acid preparation for this patient population should diminish the risk for acute pancreatitis, and may also reduce the long-term risk for cardiovascular disease.",1
9511,9867776,Fatal hepatotoxicity associated with troglitazone,,1
9512,9870876,Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist,"OBJECTIVE: To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS: Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS: A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigator's assessment of disease activity, patient's assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION: This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.",1
9513,9872479,Coexistent minocycline-induced systemic lupus erythematosus and autoimmune hepatitis,"""OBJECTIVES: This study was performed to raise awareness among rheumatologists about two autoimmune disorders associated with long-term minocycline therapy that can coexist in the same patient. We provide an update on the occurrence of these disorders, their main characteristics, and the current knowledge of potential pathogenic mechanisms. METHODS: We searched the medical literature in English indexed in MEDLINE from 1966 through April 1998 for the term minocycline combined with each of the following: autoimmune hepatitis (AIH), chronic hepatitis, lupus, systemic lupus erythematosus (SLE), anti-myeloperoxidase (anti-MPO), arthritis, vasculitis, and toxicity. We also reviewed relevant references cited in the articles our search uncovered. RESULTS: We identified over 60 minocycline-induced cases of SLE and 24 cases of minocycline-induced AIH. Both autoimmune disorders coexisted in the same patient in 12 cases reported in the literature and in one case seen at our clinic. These 13 patients were characterized by symmetrical polyarthralgias/polyarthritis, elevated liver enzymes, and positive antinuclear antibodies (ANA); they also were generally anti-histone-negative, and only two patients had perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). After withdrawal of minocycline, their symptoms resolved, and abnormal laboratory results normalized or markedly improved. CONCLUSIONS: Although data on the actual prevalence of autoimmune disorders induced by minocycline are not available, numerous case reports or small series deal with such disorders. Probable pathogenic mechanisms for each of these conditions are discussed.""",1
9514,9874468,Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice,"""BACKGROUND: Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. METHODS: All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. RESULTS: Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. CONCLUSIONS: Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.""",1
9515,9875925,Lactic acidemia and bradyarrhythmia in a child sedated with propofol,"OBJECTIVES: To describe a severe adverse reaction in a child who received an infusion of propofol for sedation in the intensive care unit (ICU). To describe the management and further investigation of this patient and review similar published reports. DESIGN: Case report and literature review. SETTING: Community hospital ICU and tertiary pediatric ICU. PATIENT: Infant with upper respiratory obstruction secondary to an esophageal foreign body who required tracheal intubation and mechanical ventilation. INTERVENTIONS: Conventional cardiovascular and respiratory support. Continuous veno-venous hemofiltration (CVVH) and plasmapheresis. MEASUREMENTS AND MAIN RESULTS: The patient received a propofol infusion at a mean rate of 10 mg/kg/hr for 50.5 hrs. He developed lipemia and green urine and subsequently, a progressive severe lactic acidemia and bradyarrhythmias unresponsive to conventional treatment. These abnormalities resolved with CVVH. He was encephalopathic and developed liver and muscle necrosis histologically compatible with a toxic insult. Examination of homogenized muscle tissue demonstrated a reduction in cytochrome C oxidase activity. There was no evidence of systemic infection or underlying metabolic disease. He eventually recovered completely. CONCLUSION: Propofol has been associated with severe adverse reactions in children receiving intensive care. The biochemical and histologic abnormalities described in this patient may guide further investigation. We advise against prolonged use of propofol for sedation in children.",1
9516,9876823,Liver injury with the use of ticlopidine,,1
9517,9878991,Telmisartan,"Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation. Oral telmisartan dose-dependently reduced blood pressure (BP) in various animal models of hypertension. In transgenic rats, telmisartan reduced cardiac hypertrophy and glomerulosclerosis. When administered at dosages of 40 to 160 mg once daily to patients with mild to moderate hypertension, telmisartan significantly reduced systolic and diastolic BP compared with placebo and was at least as effective as atenolol 50 or 100 mg and lisinopril 10 to 40 mg. One study showed telmisartan 80 mg/day to be more effective than enalapril 20 mg/day. In 2 studies that used ambulatory BP monitoring, once daily telmisartan provided better control of diastolic BP for the full dosing interval than losartan potassium 50 mg or amlodipine 5 or 10 mg. In a single study in patients with severe hypertension, a telmisartan-based regimen had antihypertensive efficacy similar to that of an enalapril-based regimen. Telmisartan had a tolerability profile similar to that of placebo in clinical studies.",1
9518,9880448,The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis,"""OBJECTIVE: To examine the relationship between hepatotoxic risk factors and liver histopathology in patients with juvenile rheumatoid arthritis (JRA) treated with methotrexate (MTX). STUDY DESIGN: We graded the histology of 33 percutaneous liver biopsy specimens from 25 patients with JRA treated at Children's Hospital Medical Center, Cincinnati, Ohio, using the Roenigk Classification Scale. Stepwise linear and logistic regression analyses were performed to examine the relationship of the Roenigk grade and presence of liver fibrosis of biopsy specimens with potential risk factors. RESULTS: Twenty-seven biopsy specimens (82%) were classified as grade I, 4 (12%) as grade II, and 2 (6%) as grade IIIA; none demonstrated significant fibrosis. The frequency of biochemical abnormalities (P <.001) and body mass index (P =.05) were the only risk factors found to significantly relate to the Roenigk grade. The following factors were not significantly associated with the Roenigk grade: age, gender, disease duration, JRA subtype and course, duration of MTX administration, weekly MTX dose, cumulative dose of MTX, route of MTX administration, use of folic acid supplementation, concurrent use of other medications, and potential hepatotoxic comorbidities. CONCLUSIONS: Serial biochemical abnormalities are significantly associated with Roenigk grade and the presence of liver fibrosis. These findings concur with studies of patients with rheumatoid arthritis, suggesting that guidelines for monitoring MTX hepatotoxicity in rheumatoid arthritis may be applicable to patients with JRA.""",1
9519,9882028,Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group,"""BACKGROUND: Despite widespread use of aminosalicylates as maintenance treatment for ulcerative colitis (UC), patients still report troublesome symptoms, often nocturnally. AIM: To compare the efficacy and safety of balsalazide (Colazide) with mesalazine (Asacol) in maintaining UC remission. METHODS: A randomized, double-blind comparison of balsalazide 3 g daily (1.04 g 5-ASA) and mesalazine 1.2 g daily for 12 months, in 99 (95 evaluable) patients in UC remission. RESULTS: Balsalazide patients experienced more asymptomatic nights (90% vs. 77%, P=0.0011) and days (58% vs. 50%, N.S.) during the first 3 months. Balsalazide patients experienced more symptom-free nights per week (6.4+/-1.7 vs. 4.7+/-2.8; P=0.0006) and fewer nights per week with blood on their stools or on the toilet paper, mucus with their stools or with sleep disturbance resulting from symptoms or lavatory visits (each P < 0.05). Fewer balsalazide patients relapsed within 3 months (10% vs. 28%; P=0.0354). Remission at 12 months was 58%, in both groups. Similar proportions of patients reported adverse events (61% balsalazide vs. 65% mesalazine). There were five serious adverse events (two balsalazide, three mesalazine) and four withdrawals due to unacceptable adverse events (three balsalazide, one mesalazine), of which one in each group was also a serious adverse event. CONCLUSIONS: Balsalazide 3 g/day and mesalazine 1.2 g/ day effectively maintain UC remission and are equally well tolerated over 12 months. At this dose balsalazide prevents more relapses during the first 3 months of treatment and controls nocturnal symptoms more effectively.""",1
9520,9893628,Efficacy and toxicity of 2-Chlorodeoxyadenosine (Cladribine)--2 h infusion for 5 days--as first-line treatment for advanced low grade non-Hodgkin's lymphoma,"""2-Chlorodeoxyadenosine (Cladribine) is a new purine analogue with high activity in pretreated low grade non-Hodgkin's lymphoma (NHL). To evaluate the efficacy of this drug in untreated patients with advanced NHL, we performed a prospective multicentre trial. Cladribine (0.12 mg/kg) was administered intravenously daily for 5 consecutive days in an out-patient setting. The treatment was repeated every 28 days for four cycles. Included were patients with a histological diagnosis of low grade NHL according to the Kiel classification and stage III or IV disease. Stage II patients were included when radiotherapy had failed. 55 patients were entered into the study. 50 patients were evaluable. The remission rate was 44/50 (88%; 95% confidence interval 82-100%), including complete remissions (CR) in 14 (28%) patients. Only 2 patients showed progression while on Cladribine treatment. The estimated overall survival, and time to treatment failure (TTF) were 85% and 51%, respectively, after a median observation time of 92 weeks. 11 (22%) patients showed grade 3 or 4 toxicity according to the WHO grading. Haematological toxicity was responsible for 86% of the overall toxicity and 100% of grade 3 and 4 toxicity. 7 patients (14%) had an infection, two of which were opportunistic. 12 (24%) patients did not experience any toxicity during the treatment. The results of this study clearly demonstrate the safety and considerable activity of this regimen. Cladribine is very effective even at lower doses than have been used so far.""",1
9521,9915660,"A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients","""Immediate-release niacin manifests beneficial effects in cardiovascular disease with respect to dyslipidemic states. It lowers low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a), and apoprotein B; at the same time, it increases high-density lipoprotein (HDL) cholesterol, HDL2, and apoprotein A-I. However, use of crystalline niacin has drawbacks: therapy requires multidose regimens, and side effects include flushing and pruritus. Slowing absorption with sustained-release formulations succeeds in decreasing flushing and increasing tolerance, but increases in hepatic enzyme levels have raised safety concerns. A new extended-release, once-daily formulation of niacin (Niaspan) shows promise in minimizing flushing while avoiding hepatotoxicity. A multicenter, randomized, double-blind clinical trial of Niaspan enrolled 122 patients with confirmed diagnosis of primary dyslipidemia (LDL cholesterol >4.14 mmol/L [160 mg/dL] and triglycerides <9 mmol/L [800 mg/dL]) into 3 treatment groups: (1) Niaspan 1,000 mg/day; (2) Niaspan 2,000 mg/day; and (3) placebo. The primary treatment endpoint was LDL-cholesterol level. This endpoint was not significantly affected by placebo (0.2% increase), but Niaspan decreased LDL cholesterol by 5.8% (1,000 mg/day) and 14.6% (2,000 mg/day) (p <0.001). Likewise, with placebo there were significant changes in total cholesterol, triglycerides, lipoprotein(a), and apoprotein B, whereas both Niaspan 1,000 and 2,000 mg/day significantly (p <0.001) decreased these parameters. In addition, both Niaspan groups showed significant (p <0.001) increases in HDL cholesterol (17% and 23%, respectively), including HDL subfractions. With respect to flushing, 20% of the placebo group reported at least 1 episode, whereas 88% and 83% of the Niaspon 1,000- and 2,000-mg/day groups, respectively, reported episodes. There was no hepatotoxicity as liver enzyme levels remained within clinically accepted limits in all treatment groups. However, Niaspan 2,000 mg/day showed a significant increase in aspartate aminotransferase compared with baseline and placebo. This trial demonstrated a cholesterol-modifying effect of Niaspan consistent with those reported for niacin, but demonstrated a better tolerance for flushing. Moreover, in contrast to sustained-release formulations, Niaspan showed relatively mild hepatic effects.""",1
9522,9916603,"Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection","Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor widely used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus disease. To establish its safety profile, we conducted a review of data from prospective US and international clinical trials involving a total of 906 adult patients and 468 pediatric patients treated with NVP. Drug-related adverse events were similar in adults and children, with rash and nausea most frequently reported in adults and rash and granulocytopenia most frequently reported in children. A separate analysis of rash based on data from adult patients in controlled trials demonstrated a 16% rate of NVP-attributable rash in these patients. Of patients with NVP-associated rash, 65% developed rash within the first 6 weeks of therapy, and it has been shown that a lower lead-in dose (200 mg/d vs the standard 400 mg/d) for the first 2 weeks of NVP treatment reduces the frequency of drug-associated rash. Serious rash (Stevens-Johnson syndrome [SJS] or SJS/toxic epidermal necrolysis transition syndrome) occurred with an incidence of 0.3% and clinical hepatitis with an incidence of 1.0% among NVP-treated patients in clinical trials. Adverse event data from long-term clinical trials demonstrated a lower incidence of NVP-related adverse events than in short-term trials of NVP therapy. An analysis of abnormal laboratory findings using thresholds similar to those found in the prescribing information for other commonly used antiretroviral agents and data from controlled trials in adults showed that the most frequently observed laboratory abnormalities were elevations in liver function test results. Approximately 50,000 patients in the United States had been treated with marketed NVP at the time of writing, and postmarketing surveillance has supported the overall safety profile observed in clinical trials. NVP has been shown to be well tolerated in both adult and pediatric patients.",1
9523,9919455,Omeprazole and the development of acute hepatitis,"Omeprazole has been used with increasing frequency for the treatment of conditions such as reflux oesophagitis, peptic ulcer disease, and Zollinger-Ellison syndrome. Several sequelae have been documented in the literature, but there has been limited indication of significant hepatotoxicity. We present a unique case of acute hepatitis secondary to the use of omeprazole that was resolved spontaneously with discontinuation of the drug.",1
9524,9927101,"Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sj�gren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group","BACKGROUND: Patients with Sj�gren syndrome (SS) experience slowly progressive infiltration of lacrimal and salivary glands by mononuclear cells. This leads to diminished secretions, with resultant symptoms of xerostomia and xerophthalmia. Although pilocarpine hydrochloride tablets are currently indicated for the treatment of radiation-induced xerostomia, their effects on dry mouth or dry eyes in patients with SS are unclear. OBJECTIVE: To assess the safety and efficacy of pilocarpine (Salagen) tablets as symptomatic treatment for dry mouth and dry eyes caused by SS in a multicenter, doubleblind, placebo-controlled trial. METHODS: After providing written informed consent, 373 patients with primary or secondary SS and clinically significant dry mouth and dry eyes were randomized to receive 2.5-mg pilocarpine, 5-mg pilocarpine, or placebo tablets 4 times daily for 12 weeks. Symptoms were assessed by questionnaires with visual analog scales or categorical checkboxes. Whole-mouth salivary flow rates were measured. RESULTS: A significantly greater proportion of patients in the 5-mg pilocarpine group showed improvement compared with the placebo group (P< or =.01) in global assessments of dry mouth, dry eyes, and other symptoms of dryness (P< or =.05). Salivary flow was significantly increased 2- to 3-fold (P<.001) after administration of the first dose and was maintained throughout the 12-week study. The most common adverse effect was sweating, and no serious drug-related adverse experiences were reported. CONCLUSION: Administration of 5-mg pilocarpine tablets 4 times daily (20 mg/d) was well tolerated and produced significant improvement in symptoms of dry mouth and dry eyes and other xeroses in patients with SS.",1
9525,9927163,"Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion","Zidovudine is known to be responsible for a mitochondrial myopathy with ragged-red fibres and mitochondrial DNA depletion in muscle. Lactic acidosis alone or associated with hepatic abnormalities has also been reported. A single report mentioned the concomitant occurrence of muscular and hepatic disturbances and lactic acidosis in a patient receiving zidovudine, but muscle and liver tissues were not studied. A 57-year-old man with AIDS, who had been treated with zidovudine for 3 years, developed fatigue and weight loss. Serum creatine kinase and hepatic enzyme levels were high. Lactic acidosis was present. Liver biopsy showed diffuse macrovacuolar and microvacuolar steatosis. After withdrawal of zidovudine, creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels normalised within 5 days, and lactacidaemia decreased. Acidosis persisted. The patient became confused and febrile and died 8 days after detection of high blood lactic acid. A muscle sample obtained at autopsy showed mitochondrial abnormalities with ragged-red fibres and lipid droplet accumulation. Southern blot analysis showed depletion of mitochondrial DNA, affecting skeletal muscle and liver tissue. No depletion was found in myocardium and kidney. This case emphasises that zidovudine treatment can induce mitochondrial multisystem disease, as revealed in our case by myopathy, liver steatosis and lactic acidosis.",1
9526,9927799,[Toxic hepatitis caused by flutamide],,1
9527,9929017,"Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group","""BACKGROUND: Phase II trials of leflunomide, an inhibitor of de-novo pyrimidine synthesis, have shown efficacy in rheumatoid arthritis. This double-blind randomised trial compared leflunomide with placebo and sulphasalazine in active rheumatoid arthritis. METHODS: 358 patients were randomly assigned leflunomide (100 mg daily on days 1-3, then 20 mg daily), placebo, or sulphasalazine (0.5 g daily, titrated progressively to 2.0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigator's and patient's overall assessments. Analyses were by intention to treat. FINDINGS: The mean changes in the leflunomide, placebo, and sulphasalazine groups were -9.7, -4.3, and -8.1 for tender joint count; -7.2, -3.4, and -6.2 for swollen joint count; -1.1, -0.3, and -1.0 for physician's overall assessment; and -1.1, -0.4, and -1.1 for patient's overall assessment. Leflunomide and sulphasalazine were significantly superior to placebo (p=0.0001 for joint counts; p<0.001 for assessments). Radiographic disease progression was significantly slower with leflunomide and sulphasalazine than with placebo (p<0.01). Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%). Transiently abnormal liver function was seen in three leflunomide-group patients and five sulphasalazine-group patients. There were two cases of reversible agranulocytosis in the sulphasalazine group. INTERPRETATION: Leflunomide was more effective than placebo in treatment of rheumatoid arthritis and showed similar efficacy to sulphasalazine. Leflunomide was well tolerated. This drug may be a useful option as a disease-modifying antirheumatic drug.""",1
9528,9930641,Risperidone-induced hepatotoxicity,,1
9529,9934769,Simultaneous pancreatitis and hepatitis associated with trimethoprim-sulfamethoxazole,"A 34-yr-old woman developed simultaneous pancreatitis and hepatitis following exposure to trimethoprim-sulfamethoxazole (TMP/SMX). The episode occurred 4 yr after a previous episode of hepatitis associated with TMP/SMX. This patient represents the second case of concurrent TMP/SMX-induced pancreatitis and hepatitis reported in the literature. However, it is the first in which the adverse reaction was documented following an inadvertent rechallenge with the drug.",1
9530,9951955,Ibandronate,"Ibandronate (ibandronic acid) is a third generation bisphosphonate which inhibits hone resorption in human and animal studies. It also inhibits bone formation only at high doses (10 microg/kg/day) in animal studies. In animal models, ibandronate was more potent than etidronate, clodronate, pamidronate and alendronate and equivalent in potency or more potent than risedronate in inhibiting induced hypercalcaemia and bone resorption. In clinical studies, single-dose ibandronate (0.2 to 6 mg intravenously) significantly reduced albumin-corrected serum calcium levels and urinary markers of bone resorption in patients with hypercalcaemia of malignancy, and in those with bone metastases. Serum calcium levels were normalised in 50 and 67% of ibandronate 2 mg recipients and in about 76% of 4 mg recipients. In postmenopausal women with osteoporosis or osteopenia. ibandronate (0.5 to 5 mg/day orally or 0.5 to 2 mg every 3 months intravenously) dose-dependently increased bone mineral density, with parallel reductions in the biochemical markers of bone turnover. In preliminary studies in patients with Paget's disease a single intravenous ibandronate dose (2mg) decreased serum alkaline phosphatase levels and urinary markers of bone turnover. Adverse events associated with the use of ibandronate in the management of hypercalcaemia of malignancy include increased body temperature, hypocalcaemia and hypophosphataemia. Less commonly, flu-like symptoms and gastrointestinal intolerance may occur.",1
9531,9972382,Quinine-induced hepatotoxicity,"OBJECTIVE: To report a case of quinine-induced hepatotoxicity presenting within 24 hours following the ingestion of the first dose. DATA SOURCES: Case report information was obtained from the medical record, the patient, and the physicians involved in this patient's case. MEDLINE and Index Medicus were searched to obtain relevant published literature from January 1942 to May 1997 using the terms quinine, muscle cramps, liver disease, and hepatotoxicity. CASE SUMMARY: A 57-year-old Native American woman presented with symptoms of nausea, vomiting, generalized myalgia, headache, fever, chills, and rigor. The alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase concentrations were dramatically elevated. Quinine was suspected as the cause after several days of hospitalization and continued therapy. With discontinuation of the quinine, the patient's symptoms resolved within 48 hours and the liver enzyme concentrations declined within 72 hours. CONCLUSIONS: Documented hepatotoxicity has occurred with quinidine, the optical isomer of quinine. Limited awareness of quinine-induced hepatotoxicity may result in an unrecognized adverse effect.",1
9532,9990571,Grand mal seizures with liver toxicity in a case of clozapine treatment,,1
9533,10023790,Hepatic enzyme abnormalities in children on triple therapy for tuberculosis,"""Standard chemotherapy for tuberculosis (TB) in children uses hepatotoxic drugs. Published data and guidelines on monitoring of liver function during TB treatment are often contradictory and not directly relevant to the pediatric population. We carefully monitored 43 children (age 6.6 years, 0.7-15.1 [median, range]; 49% male; 72% Caucasian) being treated for TB infection (n = 8) or disease (n = 35) with triple therapy, using pyrazinamide, rifampicin, and isoniazid in standard recommended doses. Children on other hepatotoxic drugs were excluded. Measurements of liver function tests (LFT) included aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin, and they were checked before and a median of 5 times (1-23) during treatment. Only one child had mildly abnormal LFTs pretreatment. Thirteen children (n = 13, [30%]; age 7.6 years, 1.8-10.9; 54% male; 77% Caucasian) developed abnormal LFTs (> mean + 2 SD) and of these 10 had TB disease. Eight of the 13 had mildly elevated enzymes (< twice upper limit of normal) while in five, all with disease, the enzymes were more markedly raised. In the group with normal LFTs (n = 30, [70%]; age 6.6 years 0.7-15.1; 47% male; 70% Caucasian) 25 had disease (83%). Liver enzyme elevation occurred early (1.65 weeks, 0.6-16.6). Only two children had symptoms (one jaundice, one pruritus) with treatment being stopped temporarily only in the jaundiced child. Otherwise, LFTs normalized without interrupting treatment. We conclude that elevated liver enzymes are not uncommon in children receiving triple therapy for TB, generally occurring early in treatment. Symptoms are rare. Current British Thoracic Society and American Thoracic Society guidelines (that if LFTs are normal prior to treatment then further monitoring should only be performed if clinically indicated) seem adequate for children.""",1
9534,10023957,COX 2 inhibitor and fulminant hepatic failure,,1
9535,10030780,Suspected carbamazepine-induced hepatotoxicity,"Carbamazepine is a potent anticonvulsant agent with proven efficacy in the treatment of partial and tonic-clonic seizures. An epileptic child treated with therapeutic dosages of carbamazepine developed severe hepatitis and hepatic insufficiency. She had a positive response to withdrawal of the drug and administration of corticosteroids. The Roussel UCLAF method for estimating causality of the adverse event was applied for an acute hepatocellular problem, with a final score of 8. This method has advantages over other tools because it involves many clinical factors that give additional guides to clinicians in patients with liver injury, but it must be adapted for adverse events in the pediatric population.",1
9536,10047618,Sotalol: An important new antiarrhythmic,"""Sotalol, the most recently approved oral antiarrhythmic drug, has a unique pharmacologic profile. Its electrophysiology is explained by nonselective beta-blocking action as well as class III antiarrhythmic activity (including fast-activating cardiac membrane-delayed rectifier current blockade), which leads to increases in action potential duration and refractory period throughout the heart and in QT interval on the surface electrocardiogram. Its better hemodynamic tolerance than other beta-blockers may be a result of enhanced inotropy associated with class III activity. Sotalol's ability to suppress ventricular ectopy is similar to that of class I agents and better than that of standard beta-blockers. Unlike class I agents, its use in a postinfarction trial was not associated with increased mortality rate. Therapeutically, it has shown superior efficacy for prevention of recurrent ventricular tachycardia and ventricular fibrillation, which was the basis for its approval. In a randomized study, the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial, sotalol was associated with an increased in-hospital efficacy prediction rate (by Holter monitor or electrophysiologic study), reduced long-term arrhythmic recurrence rate with superior tolerance, and lower mortality rate than class I (""""standard"""") antiarrhythmic drugs. Sotalol was 1 of 2 drugs selected for comparison with implantable defibrillators in the recent National Institutes of Health Antiarrhythmics versus Implantable Defibrillator (AVID) study. Sotalol appears to be a preferred drug for use with implantable defibrillators; unlike some other agents (eg, amiodarone) it does not elevate and, indeed, may lower defibrillation threshold. Although unapproved for this use, sotalol is active against atrial arrhythmias. It has shown efficacy equivalent to propafenone and quinidine in preventing atrial fibrillation recurrence, but it is better tolerated than quinidine and provides excellent rate control during recurrence. Sotalol's major side effects are related to beta-blockade and the risk of torsades de pointes (acceptably small if appropriate precautions are taken). Unlike several other antiarrhythmics (eg, amiodarone), it has no pharmacokinetic drug-drug interactions, is not metabolized, and is entirely renally excreted. Initial dose is 80 mg twice daily, with gradual titration to 240 to 360 mg/day as needed. The daily dose must be reduced in renal failure. On the basis of favorable clinical trials and practice experience, sotalol has shown a steadily growing impact on the treatment of arrhythmias during its 5 years of market availability, a trend that is likely to continue.""",1
9537,10063482,The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia,"Administration of noncompetitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in nonhuman subjects. In this review, the usefulness of PCP administration as a potential animal model of schizophrenia is considered. To support the contention that NMDA receptor antagonist administration represents a viable model of schizophrenia, the behavioral and neurobiological effects of these drugs are discussed, especially with regard to differing profiles following single-dose and long-term exposure. The neurochemical effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Future directions for the application of NMDA receptor antagonist models of schizophrenia to preclinical and pathophysiological research are offered.",1
9538,10066203,Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial,"OBJECTIVES: To assess the effects of rivastigmine on the core domains of Alzheimer's disease. DESIGN: Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks. SETTING: 45 centres in Europe and North America. PARTICIPANTS: 725 patients with mild to moderately severe probable Alzheimer's disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. OUTCOME MEASURES: Cognitive subscale of the Alzheimer's disease assessment scale, rating on the clinician interview based impression of change incorporating caregiver information scale, and the progressive deterioration scale. RESULTS: At the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer's disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events. CONCLUSIONS: Rivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer's disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population.",1
9539,10068372,Severe hepatotoxicity associated with troglitazone,,1
9540,10068399,Troglitazone-associated hepatic failure,,1
9541,10072411,Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group,"BACKGROUND: In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity. METHODS: We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy. RESULTS: The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001). CONCLUSIONS: Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.",1
9542,10075273,Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial,"The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.",1
9543,10080612,"Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer","PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.",1
9544,10086436,Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic,"""CONTEXT: Isoniazid preventive therapy for latent tuberculosis (TB) infection has been debated because of the risk of hepatotoxicity. The frequency of hepatotoxicity was 0.5% to 2.0% in early studies but may have changed with new criteria for diagnosis and patient selection. OBJECTIVE: To determine the rate of isoniazid hepatotoxicity in patients managed according to current guidelines and practice standards. DESIGN: Prospective cohort study. SETTING: A public health clinic operated by the TB control program of a city-county public health agency. PATIENTS: A total of 11141 consecutive patients who started a regimen of isoniazid preventive therapy for latent TB infection from January 1989 through December 1995. MAIN OUTCOME MEASURES: The rate of developing symptoms and signs of hepatotoxicity among all persons starting isoniazid preventive therapy, among all those completing therapy, and by age, sex, and race. RESULTS: Eleven patients (0.10% of those starting, and 0.15% of those completing treatment) had hepatotoxic reactions to isoniazid during preventive treatment. The rate of hepatotoxicity in persons receiving preventive therapy increased with increasing age (chi2 for linear trend = 5.22, P=.02) and there were trends toward increased rates in women (odds ratio [OR], 3.30; 95% confidence interval [CI], 0.87-12.45; chi2 = 3.28; P=.07) and in whites (OR, 2.60; 95% CI, 0.75-8.95; chi2 = 3.08; P=.08). CONCLUSIONS: The rate of isoniazid hepatotoxicity during clinically monitored preventive therapy was lower than has been reported previously. Clinicians should have greater confidence in the safety of isoniazid preventive therapy.""",1
9545,10086516,Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature,"Cholestasis has been reported as a rare presentation among patients with severe liver injury secondary to amiodarone hepatic toxicity. We report an unusual case of amiodarone-induced cholestatic hepatotoxicity occurring after amiodarone had been discontinued and the initial abnormal liver function findings had improved. The patient, without jaundice at the initial presentation, developed severe jaundice about 4 months after withdrawal of amiodarone. Light and transmission electron microscopic examination of a specimen secured by computed tomographically guided liver biopsy was consistent with amiodarone hepatic toxicity as the cause of intrahepatic cholestasis. An abdominal ultrasound, endoscopic retrograde cholangiography, and dimethyl iminodiacetic acid and computed tomographic scans of the abdomen all failed to demonstrate any other causes for jaundice other than amiodarone toxicity. Thus, amiodarone hepatic toxicity may occur after drug withdrawal even if results of liver function tests improve. Histopathologic examination of a liver biopsy specimen is of value for diagnosis and prognosis. The liver biopsy findings, clinical course, and liver function test results are discussed, and the English-language literature on amiodarone cholestatic hepatotoxicity is reviewed.",1
9546,10090926,Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party,"""We report the results of the first prospective randomized multicenter study of immunosuppressive treatment in patients with previously untreated nonsevere aplastic anemia (AA) as defined by a neutrophil count of at least 0.5 x 10(9)/L and transfusion dependence. Patients were randomized to receive cyclosporin (CSA) alone or the combination of horse antithymocyte globulin ([ATG] Lymphoglobuline; Merieux, Lyon, France) and CSA. The endpoint of the study was the hematologic response at 6 months. One hundred fifteen patients were randomized and assessable with a median follow-up period of 36 months; 61 received CSA and 54 ATG and CSA. In the CSA group, the percentage of complete and partial responders was 23% and 23%, respectively, for an overall response rate of 46%. A significantly higher overall response rate of 74% was found in the ATG and CSA group, with 57% complete and 17% partial responders (P =. 02). Compared with CSA alone, the combination of ATG and CSA resulted in a significantly higher median hemoglobin level and platelet count at 6 months. Fewer patients required a second course of treatment before 6 months due to a nonresponse. In the CSA group, 15 of 61 (25%) patients required a course of ATG before 6 months because of disease progression, compared with only 3 of 54 (6%) in the ATG and CSA group. The survival probabilities for the two groups were comparable, 93% (CSA group) and 91% (ATG and CSA group), but at 180 days, the prevalence of patients surviving free of transfusions, which excluded patients requiring second treatment because of nonresponse, death, disease progression, or relapse, was 67% in the CSA group and 90% in the ATG and CSA group (P =.001). We conclude that the combination of ATG and CSA is superior to CSA alone in terms of the hematologic response, the quality of response, and early mortality, and a second course of immunosuppression is less frequently required.""",1
9547,10091111,Severe hepatitis in a HIV-positive subject under treatment with protease inhibitor,,1
9548,10096345,Effects of niacin therapy that simulate neoplasia: hepatic steatosis with concurrent hepatic dysfunction,"Niacin, a widely used antihyperlipidemic agent, can produce hepatic steatosis and clinical hepatic abnormalities that together simulate the presentation of hepatobiliary neoplasia. We describe a patient initially suspected of having hepatobiliary neoplasia for whom imaging studies played a pivotal role in reaching the correct diagnosis of niacin-induced hepatotoxicity. Radiologists should become knowledgeable of these niacin-related effects, add niacin effects to the differential diagnosis of hepatic steatosis, and understand the value of correlative imaging in distinguishing these effects from hepatobiliary neoplasia.",1
9549,10102941,Review article: mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications,"The social use of ecstasy (methylenedioxymethampheta-mine, MDMA) and amphetamines is widespread in the UK and Europe, and they are popularly considered as 'safe'. However, deaths have occurred and hepatotoxicity has featured in many cases of intoxication with amphetamine or its methylenedioxy analogues such as ecstasy. Recreational use of these drugs presents an important but often concealed cause of hepatitis or acute liver failure, particularly in young people. The patterns of liver damage and multiple putative mechanisms of injury are discussed. Recognition of the aetiological agent requires a high index of suspicion. Optimum management of the resultant liver damage, including the controversial role of liver transplantation for fulminant hepatic failure, is also discussed.",1
9550,10186943,"Tizanidine treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam","""To conduct a meta-analysis of the antispastic efficacy and tolerability of tizanidine, we reviewed records of the European sponsor of tizanidine trials and selected double-blind, randomized studies of moderate duration in which oral tizanidine was compared with baclofen or diazepam. Studies were required to have individual patient data; three key outcome measures (Ashworth Rating Scale for muscle tone, a measure of muscle strength, and Global Tolerability to Treatment Rating); and patients with multiple sclerosis or cerebrovascular lesions. Ten trials involving 270 patients met these criteria. Seven studies used baclofen as the positive control; three used diazepam. As measured by Total and Lower Body Ashworth scores, tizanidine and similar spasticity-reducing effects to both baclofen and diazepam. Muscle strength was affected less by tizanidine than by either comparator, and investigators judged tizanidine to have greater tolerability. Within the limits of these comparisons, tizanidine, baclofen, and diazepam were equally effective in decreasing excessive muscle tone in patients with multiple sclerosis or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but improvement was greatest with tizanidine.""",1
9551,10191871,Antimalarial prophylaxis--use and adverse events in visitors to the Kruger National Park,"OBJECTIVES: To determine the use of antimalarial prophylaxis and the relative frequency of adverse events with different regimens in visitors to the Kruger National Park. DESIGN: Retrospective postal survey of a cohort of 7,397 visitors during April 1996. Telephonic interviews were conducted with all respondents who reported neuropsychiatric adverse events necessitating medical attention, and their medical caregivers. RESULTS: The most commonly used regimens were chloroquine and proguanil in combination (C&P) (35.6%) and mefloquine (18.4%). However, non-recommended regimens were also used by travellers to this chloroquine-resistant area, including chloroquine alone (15.7%). Adverse events were reported by 23.8% of travellers and were more common in the C&P group than the mefloquine group (28.9% v. 25.0%, P = 0.0100). Gastro-intestinal side-effects were significantly more common in the C&P group (nausea (P = 0.0170), diarrhoea (P = 0.0008), mouth ulcers (P = 0.0000)), while neuropsychiatric side-effects were more common in the mefloquine group (depression (P = 0.0000), light-headedness (P = 0.0009), anxiety (P = 0.0060)). Only 30% of travellers reported using antimalarial drugs both regularly as prescribed and for 4 weeks after leaving the malaria area. The most commonly reported reason for changing prophylaxis was advice from a physician or pharmacist (41.9%). CONCLUSIONS: Health professionals providing medical advice to prospective travellers to malarious areas must tailor recommendations based on the balance between malaria risk in a specific geographical area and the benefits and tolerance of protective measures. Mosquito-avoidance measures should always be advocated, but counselling on antimalarial prophylaxis will be guided by the malaria/prophylaxis (serious adverse events) risk ratio. Where drug measures are indicated, the importance of their correct use should be emphasised.",1
9552,10192972,Valaciclovir-induced hepatitis,,1
9553,10193097,[Hepatoxicity by enalapril],,1
9554,10197329,Fentanyl dosage,,1
9555,10199359,Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema,,1
9556,10200868,Acute liver damage possibly related to sertraline and venlafaxine ingestion,,1
9557,10201510,Acute hepatitis related to omeprazole,,1
9558,10206223,Ultrasonographic findings in niacin-induced hepatitis,,1
9559,10209973,Propofol-infusion syndrome in children,,1
9560,10212898,Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials,"The preliminary results of a clinical safety review that partly used the Cochrane methodology are presented. Despite methodological limitations including incomplete databases, this review collated evidence corroborating the benign safety profile of the artemisinin type of compounds. No difference was apparent amongst the various derivatives. At the time the workshop was held, 188 studies had been identified of which 108 (enrolling 9,241 patients) fulfilled criteria for analyses. These included both uncomplicated and severe malaria patients enrolled in either controlled and non-controlled studies as well as healthy volunteers. Safety was assessed by analysing adverse events, as well as clinical laboratory (haematology assessed in 4,062, blood chemistry in 3,893 patients), electrocardiographic (2638 patients) and neurological assessments as reported in the papers. No serious adverse event or severe significant toxicity was reported. Overall, the most commonly reported adverse experiences were gastro-intestinal. Occasional neutropenia (1.3%), reticulocytopenia (0.6%), elevated liver enzymes (0.9%) were reported. Transient bradycardia and prolonged QT interval were reported in circa 1.1% of patients monitored. A neurological assessment was performed primarily in the severe malaria patients. No difference was apparent with respect to quinine. In addition, four cases of neuropsychiatric adverse events were reported in patients receiving concomitant mefloquine.",1
9561,10215503,Terbinafine and fulminant hepatic failure,,1
9562,10216414,[Hepatotoxic reaction associated with metformin and chlorpropamide treatment],,1
9563,10217058,Criteria and recommendations for vitamin C intake,"Recommendations for vitamin C intake are under revision by the Food and Nutrition Board of the National Academy of Sciences. Since 1989 when the last recommended dietary allowance (RDA) of 60 mg was published, extensive biochemical, molecular, epidemiologic, and clinical data have become available. New recommendations can be based on the following 9 criteria: dietary availability, steady-state concentrations in plasma in relationship to dose, steady-state concentrations in tissues in relationship to dose, bioavailability, urine excretion, adverse effects, biochemical and molecular function in relationship to vitamin concentration, direct beneficial effects and epidemiologic observations in relationship to dose, and prevention of deficiency. We applied these criteria to the Food and Nutrition Board's new guidelines, the Dietary Reference Intakes, which include 4 reference values. The estimated average requirement (EAR) is the amount of nutrient estimated to meet the requirement of half the healthy individuals in a life-stage and gender group. Based on an EAR of 100 mg/d of vitamin C, the RDA is proposed to be 120 mg/d. If the EAR cannot be determined, an adequate intake (AI) amount is recommended instead of an RDA. The AI was estimated to be either 200 mg/d from 5 servings of fruits and vegetables or 100 mg/d of vitamin C to prevent deficiency with a margin of safety. The final classification, the tolerable upper intake level, is the highest daily level of nutrient intake that does not pose risk or adverse health effects to almost all individuals in the population. This amount is proposed to be less than 1 g of vitamin C daily. Physicians can tell patients that 5 servings of fruits and vegetables per day may be beneficial in preventing cancer and providing sufficient vitamin C intake for healthy people, and that 1 g or more of vitamin C may have adverse consequences in some people.",1
9564,10219621,[A new drug responsible for microvesicular steatosis: ticlopidine],,1
9565,10221943,Hepatotoxicity associated with zolpidem treatment,,1
9566,10227334,Long-term safety and efficacy of zafirlukast in the treatment of asthma: interim results of an open-label extension trial,"""BACKGROUND: Current guidelines recommend anti-leukotriene agents as alternative treatments for mild persistent asthma; however, information on their long-term safety and efficacy is needed. OBJECTIVE: To evaluate long-term safety and efficacy of and compliance with oral zafirlukast (Z; 20 mg BID) during the first 39 weeks of ongoing, multicenter, open-label extension (OLE) of a previously reported 13-week, randomized (2:1), double-blind (DB), placebo (P)-controlled trial in mild-to-moderate asthmatic patients treated previously with beta2-agonists alone. METHODS: Patients (12 to 76 years; FEV1 > or = 55% predicted) elected to enter OLE after completing the DB trial. Safety evaluated by adverse events (AEs), laboratory tests, and physical and electrocardiographic examinations. Efficacy assessed by spirometry measurements [FEV1, FEV1 % predicted, personal-best (post-bronchodilator) FEV1] and treatment failure rates. Compliance was calculated as percentage of treatment dispensed. After a visit at OLE week 3 (week 16), patients had visits every 12 weeks. RESULTS: A total of 443 patients (nz-->z = 310, np-->z = 133) entered the OLE. Results through the OLE period showed that 80% of patients overall reported AEs. Of patients randomized to Z and P during DB period, 68% and 67%, respectively, reported AEs during quarter I (Q1); percentage of Z-treated patients reporting AEs during the OLE ranged from 66% (Q2) to 44% (Q4). Review by quarters showed occurrence of AEs in Z-treated groups (Q2-4) was similar to that in P group (Q1). Compared with baseline (week 0), modest yet significant improvements (P < or = .02) in all spirometry measurements were noted in Z --> Z and P --> Z groups at OLE week 3, with sustained effects noted during OLE period. Treatment failure rates during OLE ranged from 7.2% (Q2) to 3.3% (Q4). Mean compliance ranged from 98% (OLE week 3) to 95% (OLE week 39). CONCLUSIONS: Long-term treatment with zafirlukast was safe and well tolerated in asthmatic patients. Sustained efficacy and asthma control and good compliance were observed over extended treatment period. Results demonstrate long-term safety and effectiveness of and compliance with this anti-leukotriene agent.""",1
9567,10230761,Herbal toxicity and fatal hepatic failure,,1
9568,10235223,Acute cholestatic hepatitis associated with pravastatin,"A 57-yr-old man presented with clinical and laboratory signs of acute cholestatic hepatitis. Symptoms had appeared 7 wk after he was started on pravastatin 20 mg/day for hypercholesterolemia. A full evaluation including ultrasound, computed tomography, endoscopic cholangiography, and liver biopsy confirmed the diagnosis of intrahepatic nonobstructive jaundice. The liver function abnormalities normalized 7 wk after cessation of therapy. Pravastatin should be considered as a potential cause of cholestatic hepatitis with favorable clinical outcome after drug withdrawal.",1
9569,10321506,A phase II study of irinotecan and infusional cisplatin with recombinant human granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer,"PURPOSE: We administered chemotherapy consisting of a combination of 5-day continuous infusion of cisplatin (20 mg/m2 per day) plus irinotecan (160 mg/m2 per day, as a bolus, on day 1) with recombinant human granulocyte colony-stimulating factor (rG-CSF) support to previously untreated advanced non-small-cell lung cancer (NSCLC) patients, and evaluated the effectiveness and safety of this therapy. PATIENTS: Enrolled in the study were 41 NSCLC patients. RESULTS: Of the 41 patients, 24 achieved a partial response. The response rate was 58.5% (95% confidence interval, 42.2% to 74.8%), with a median response duration of 32.1 weeks. The median survival time was 44.8 weeks and the 1-year survival rate was 44%. A total of 100 courses of therapy were given. The major toxic effects were grade 3 or 4 diarrhea (23%), granulocytopenia (20%), thrombocytopenia (15%) and anemia (15%). There were no treatment-related deaths. CONCLUSIONS: Combination chemotherapy with irinotecan plus infusional cisplatin with rG-CSF support was well tolerated and effective in patients with advanced NSCLC.",1
9570,10323894,Mesalazine (5-aminosalicylic acid) induced chronic hepatitis,"BACKGROUND: Treatment of ulcerative colitis or Crohn's disease with sulphasalazine causes several adverse effects, including hepatitis. Sulphasalazine is cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine. Received wisdom was that 5-aminosalicylic acid was topically active, whereas sulphapyridine was absorbed and caused immunoallergic side effects. Mesalazine, a slow release formulation of 5-aminosalicylic acid, was expected to be a safe alternative. However, several cases of acute hepatitis have been reported. CASE REPORT: A 65 year old man had increased liver enzymes, anti-nuclear and anti-smooth muscle autoantibodies and IgG levels, and lesions of chronic hepatitis after 21 months of mesalazine treatment. Although liver dysfunction had been identified eight months earlier, simvastatin rather than mesalazine had been withdrawn, without any improvement. In contrast, liver enzyme and IgG levels became normal and autoantibodies disappeared after discontinuation of mesalazine administration. CONCLUSION: Contrary to initial expectations, mesalazine can cause most of the sulphasalazine induced adverse effects, and hepatic side effects may be almost as frequent. When liver dysfunction occurs, mesalazine administration should be discontinued to avoid the development of chronic hepatitis and liver fibrosis.",1
9571,10327032,Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection,"From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma ammonium level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma ammonium levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma ammonium levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU.",1
9572,10327225,Liver damage induced by coumarin anticoagulants,"""Except for bleeding complications, relevant adverse effects of coumarin anticoagulants are comparatively rare considering the widespread use of these substances. Here we present the case of a 56-year-old woman who developed recurrent episodes of severe hepatitis following repeated exposure to phenprocoumon (Marcumar; Roche, Grenzach-Wyhlen, Germany) and warfarin (Coumadin; DuPont Pharma, Bad Homburg, Germany) after replacement of the mitral valve with a mechanical prosthesis. The diagnosis of """"coumarin-induced hepatitis"""" is compatible with the time relationship between start of the drug and the onset of hepatopathy (first episode 8 months, second episode 4 weeks, and third episode 7 days), the rapid improvement following discontinuation of the drug, recurrence of liver dysfunction after re-exposure to the drug, and liver histology. After anticoagulant therapy was changed to heparin and acenocoumarol (Sintrom; Ciba-Geigy, Basel, Switzerland), the patient's general state was markedly improved and her liver values became almost normal. This case will be discussed and compared with other reports of coumarin-induced hepatic lesions. Although liver damage induced by coumarin derivates is rare, it is important to be aware of the hepatotoxic potential of these drugs, which, in most cases, mimics the clinical presentation of viral hepatitis.""",1
9573,10333116,Cirrhosis in a child with hypothalamic syndrome and central precocious puberty treated with cyproterone acetate,"Before the advent of gonadotropin-releasing-hormone analogues, cyproterone acetate (CPA) had been widely prescribed for the treatment of precocious puberty. Although it is usually well tolerated, liver toxicity has been recognized as a complication of its long-term use. We report the occurrence of cirrhosis in a 10-year-old boy with hypothalamic syndrome and precocious puberty who was treated with CPA for over 50 months. Despite discontinuation of the medication, the liver disease progressed. The patient died of sepsis and multiorgan failure at the age of 14 years. This is the first paediatric report of substantial liver damage and liver toxicity progressing to cirrhosis associated with CPA treatment. CONCLUSION: Prolonged cyproterone acetate treatment may induce cirrhosis. Monitoring of liver function both during treatment and for several months after discontinuation of therapy is recommended.",1
9574,10334121,Nitrofurantoin-induced immune-mediated lung and liver disease,"""A 60-year-old woman with multiple sclerosis and recurrent urinary tract infections (UTI) was evaluated for the recent onset of a dry cough, dyspnea on exertion, and jaundice. Investigation demonstrated interstitial lung disease with bilateral infiltrates and unilateral effusion, as well as a severe chronic active hepatitis with marked fibrosis. Other notable features were positive antinuclear antibodies and anti-smooth-muscle antibodies and the absence of any possible cause except for nitrofurantoin treatment (Macrodantin, 100 mg/day), which the patient had been taking for the previous 3 years as a prophylactic measure against UTI. The patient died of pneumococcal septicemia less than 30 days after presentation. Pulmonary or hepatic injury caused by nitrofurantoin treatment is rare; their combined occurrence is hardly ever described. Combined drug-induced pulmonary and hepatic toxicity is reviewed and should be considered early in the differential diagnosis to allow reversibility and avoid serious outcomes.""",1
9575,10347994,Atorvastatin-induced acute hepatitis with absence of cross-toxicity with simvastatin,,1
9576,10348093,Safety issues concerning the use of disulfiram in treating alcohol dependence,"""Disulfiram is known to cause hepatitis, which is sometimes fatal. The best estimate of the frequency of disulfiram-induced fatal hepatitis is 1 case in 30,000 patients treated/year. Its appears to be more common in patients given disulfiram for the treatment of nickel sensitivity. Frequent blood testing for liver function is probably not necessary, but patients taking disulfiram should be in regular contact with a physician. There are rare reports of psychosis and confusional states in conjunction with disulfiram treatment and peripheral neuropathy and optic neuritis have been reported; these effects are dose-related. Psychiatric complications appear to be more common with the use of disulfiram in India than in Western countries. Of the less serious adverse effects, tiredness, headache and sleepiness are the most common. Deaths from the disulfiram-alcohol (ethanol) interaction have not been reported in recent years, possibly because the dosages used are lower than those used 40 years ago, and patients with cardiac disease are now excluded from treatment. There is no evidence to suggest that disulfiram causes cancer. Of note, there are drug interactions with compounds that utilise the cytochrome P450 enzyme system. Disulfiram can be viewed as a drug with a moderate record of adverse effects. Alcohol dependence, for which it can be a helpful treatment, is associated with a high morbidity and mortality.""",1
9577,10349787,[Non-immunoallergic hepatotoxicity due to mesalazine],Mesalazine is an aminosalicillic derivative considered as a safe alternative to the relative frequency (5-55%) of adverse effects observed with sulfasalazine. The well known hepatoxicity associated with sulfasalazine and attributed to its sulfamidic fraction is limited to few cases described in the treatment with mesalazine. We herein present a new case of hepatoxicity by mesalazine in a patient with lymphocytic colitis. The possible pathogenic mechanism is also commented upon.,1
9578,10356381,Successful treatment with gabapentin in the presence of hypersensitivity syndrome to phenytoin and carbamazepine: a report of three cases,"We report three consecutive patients with hypersensitivity syndrome (HSS) due to phenytoin and carbamazepine and successful treatment with gabapentin. HSS is a rare but potentially fatal reaction to multiple drugs including several anticonvulsants. Cross-reactivity among drugs may occur. Immediate withdrawal of the offending drug is the most important step in treatment. Benzodiazepines acutely and, after resolution of the hepatitis, valproic acid have been successfully used for seizure control in patients with HSS. Our cases indicate that gabapentin is also a safe anticonvulsant in HSS.",1
9579,10357054,"Prospective, randomized dose-ranging open phase II pilot study of quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related staphylococcal bacteremia","Two different doses of quinupristin/dalfopristin were compared with intravenous vancomycin with regard to the efficacy and safety in the treatment of catheter-related staphylococcal bacteremia. A total of 39 patients were enrolled from 13 centers. For all treated patients with a baseline pathogen, outcome was comparable for all antibiotic study regimens. Discontinuation of the antibiotic for an adverse clinical event occurred in 12% of patients receiving quinupristin/dalfopristin and in 15% of those receiving vancomycin. Quinupristin/dalfopristin may have the potential to serve as an alternative agent in the treatment of catheter-related staphylococcal bacteremia. However, larger prospective randomized trials are required.",1
9580,10357972,Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men,"In order to evaluate the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH) in combination with urinary human chorionic gonadotrophin (HCG) to induce spermatogenesis and fertility in gonadotrophin-deficient men, we conducted a prospective, open, non-comparative multicentre study in two Australian academic medical centres. Ten men with gonadotrophin deficiency requiring induction of spermatogenesis and fertility were treated with HCG for 3-6 months followed by the s.c. self-administration of injections of r-hFSH in combination with HCG for 18 months. Among the eight men who commenced r-hFSH treatment, seven demonstrated sperm output at a median of 6 months and five achieved the target sperm output of 1. 5x10(6) per ml at a median of 9 months of FSH treatment. Mean testicular volume increased by 4.2 ml during FSH treatment. Three men produced pregnancies in their partners, two of which resulted in the birth of healthy babies and a third patient's partner had a miscarriage. We conclude that r-hFSH is well tolerated and effective in inducing testis growth, spermatogenesis and fertility in gonadotrophin-deficient men. The efficacy of r-hFSH seems comparable with urinary FSH at restoring normal fertility in gonadotrophin-deficient men.",1
9581,10363248,[Ticlopidine and hepatic adverse reactions. Data from the Spanish drug surveillance system],,1
9582,10366933,[Acute hepatitis after phytotherapy],,1
9583,10369424,Repaglinide versus glyburide: a one-year comparison trial,"This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-na?ve patients suggest that patients given repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.",1
9584,10372018,The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review,"Tamoxifen has become one of the most widely used drugs in the treatment of breast cancer, and concerns about its long-term safety and efficacy are being raised. Investigations in rats have suggested an association between the administration of tamoxifen and the development of hepatocellular carcinoma. However, no studies to date have demonstrated an increased incidence of hepatocellular carcinoma in women treated with tamoxifen. In the case reported, a 56-year-old woman presented with hepatocellular tumours after 6 years of tamoxifen therapy for breast cancer. The patient had no other risk factors for the development of hepatocellular carcinoma. She underwent successful resection of the lesions, and subsequent pathological studies confirmed hepatocellular carcinoma with a trabecular growth pattern similar to the histologic pattern seen in tamoxifen-induced hepatocellular carcinoma occurring in rat models.",1
9585,10375350,Venlafaxine-associated hepatitis,,1
9586,10376571,The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation,"""CONTEXT: Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. OBJECTIVE: To determine whether women taking raloxifene have a lower risk of invasive breast cancer. DESIGN AND SETTING: The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe. PARTICIPANTS: A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded. INTERVENTION: Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets. MAIN OUTCOME MEASURES: New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review. RESULTS: Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7). CONCLUSION: Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.""",1
9587,10376651,Propofol-infusion syndrome in children,,1
9588,10381993,"Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose","""STUDY OBJECTIVES: To compare the efficacy, safety, and withdrawal symptoms in emergency department patients with suspected narcotic overdose treated with nalmefene, an opioid antagonist with a 4- to 10-hour duration of action, with those treated with naloxone. METHODS: Adults in 9 centers who would otherwise receive naloxone for altered consciousness levels were randomly assigned to receive intravenous study drug (1 mg nalmefene, or 2 mg nalmefene or 2 mg naloxone, double-blinded) every 5 minutes as needed for up to 4 doses in a 4-hour study. Outcomes were 20-minute and 4-hour posttreatment changes in respiratory rates, Neurobehavioral Assessment Scale scores, Opioid Withdrawal Scale scores, and incidences of adverse events. RESULTS: Opioid positivity was recorded for 30 of 63 (1-mg nalmefene), 23 of 55 (2-mg nalmefene), and 24 of 58 (naloxone) cases, 75% of whom also had nonopioid central nervous system depressants. Most patients received only 1 dose of study drug. Similar, clinically meaningful improvements in respiratory rates and Neurobehavioral Assessment Scale scores were seen with all treatments. No statistical differences in efficacy or withdrawal outcomes were seen between treatment groups, and no significant overall time-treatment interactions occurred, in either the entire patient group or among opioid-positive cases (P >.21, all comparisons). Adverse events occurred in 30.9% (2 mg nalmefene), 15.9% (1 mg nalmefene), and 15.5% (naloxone) of patients (P >.08); none were associated with morbidity. CONCLUSION: In this study of patients with varied potential causes of altered consciousness, nalmefene (1 mg and 2 mg) and naloxone (2 mg) appeared to be efficacious, safe, and to yield similar clinical outcomes.""",1
9589,10383883,Treatment of copper associated liver disease in childhood,"BACKGROUND/AIMS: Copper associated liver disease is accompanied with high liver copper concentrations and progressive liver disease in infancy or childhood. The disease is thought to be due to excessive dietary copper overload (copper-enriched water supply) and in addition to be based on a genetic predisposition. Treatment with penicillamine in Indian childhood disease, which probable has the same etiology, is effective when it is started early enough as well as in Wilson's disease. We aimed to describe the clinical features of copper associated liver disease and report our experience with different treatment options in German children. METHODS/RESULTS: Two boys presented at the age of 6 and 10 months with abdominal distension due to hepatosplenomegaly. The diagnosis of copper associated liver disease was made based on feeding history, standard liver function parameters, liver biopsy and assessment of dry weight copper concentration and urinary excretion of copper. Both had micronodular cirrhosis, ballooning of hepatocytes and Mallory bodies. In child A improvement of liver function was observed after introduction of penicillamine therapy and copper-reduced diet. The treatment was stopped after 18 months, when normalisation of copper concentration in the liver had occured. In child B acute liver failure developed despite initiation of treatment. The boy was transplanted successfully. Both children are presently healthy 10 years after transplantation and 4 years after begin of chelating therapy, respectively. CONCLUSIONS: We conclude, that early chelating therapy with penicillamine can be successful in children with copper associated liver disease. In case of delayed diagnosis and acute liver failure liver transplantation is necessary. Our case reports highlight the urgent need of rapid diagnosis of copper associated liver disease in order to initiate early chelating therapy. Copper associated liver disease should obviously be considered in liver disease of unknown origin. Possible causes of excessive dietary copper intake should be ascertained.",1
9590,10388026,Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer,"This review compares the tolerability profiles of the three currently available nonsteroidal antiandrogens, flutamide, bicalutamide and nilutamide. Pharmacological effects associated with blockade of the androgen receptor are frequent with all three drugs. Gynecomastia and breast pain are seen more frequently during antiandrogen monotherapy than during combination with medical or surgical castration or castration alone, and the reverse is true for hot flashes, which are a side effect of castration. Gastrointestinal symptoms are also common to all three drugs, but diarrhea occurs more frequently in flutamide studies than in bicalutamide or nilutamide studies. Hepatotoxicity has been seen with all three antiandrogens, but acute, reversible hepatitis and fatal fulminant hepatitis have also been reported with both nilutamide and flutamide. All three drugs have been associated with asymptomatic elevations in aminotransferases and may reduce hemoglobin levels. Adverse events that have been reported with nilutamide include interstitial pneumonitis, delayed adaptation to darkness after exposure to bright light and alcohol intolerance. To date, bicalutamide appears to have some advantage over flutamide and nilutamide in terms of tolerability.",1
9591,10394348,[Fatal liver failure after corticosteroid treatment of a hepatitis B virus carrier],"HISTORY AND ADMISSION FINDINGS: A 69-year-old man, a known carrier of hepatitis B virus (HBV) after blood transfusion, developed increasingly severe jaundice with high transaminase levels after receiving steroids in high doses. Significant preceding conditions included chronic obstructive pulmonary disease, coronary heart disease, ulcerative colitis in remission and diabetes mellitus. On admission he was jaundiced and experienced pain on pressure below the right costal margin. INVESTIGATIONS: Serology demonstrated reactivated hepatitis B with an increase of the HBV-DNA concentration in serum, as well as seroconversion with HBe antigen, anti-HBc-IgM antibodies and absence of anti-HBe antibodies. DIAGNOSIS, TREATMENT AND COURSE: The history and serological findings indicated reactivation of the hepatitis B by the steroid treatment. Progressive liver failure developed. A marked reduction of virus particles in the blood occurred after a therapeutic trial with the nucleoside analog lamivudine, but the patient died of liver failure 30 days after admission. CONCLUSION: Steroids should be given to known hepatitis B carriers only if strictly indicated, because of the danger of acute deterioration of liver functions by reactivation of the disease with possibly fatal consequences. If steroids are administered, liver functions and serological hepatitis markers should be closely monitored so that any necessary treatment can be quickly initiated.",1
9592,10396113,[Acute flutamide-induced hepatitis],,1
9593,10400405,Rosiglitazone,"Rosiglitazone, a thiazolidinedione antidiabetic agent, improves insulin resistance, a key underlying metabolic abnormality in most patients with type 2 (non-insulin-dependent) diabetes mellitus. In animal models of insulin resistance, rosiglitazone decreased plasma glucose, insulin and triglyceride levels and also attenuated or prevented diabetic nephropathy and pancreatic islet cell degeneration. In contrast with troglitazone, rosiglitazone does not induce cytochrome P4503A4 metabolism. It does not interact significantly with nifedipine, oral contraceptives, metformin, digoxin, ranitidine or acarbose. In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone 2 to 12 mg/day (as a single daily dose or 2 divided daily doses) improved glycaemic control, as shown by decreases in fasting plasma glucose and glycosylated haemoglobin (HbA1c). Addition of rosiglitazone 2 to 8 mg/day to existing sulphonylurea, metformin or insulin therapy achieved further reductions in fasting plasma glucose and HbA1c. Oral combinations improved insulin sensitivity and beta-cell function according to a homeostasis model assessment. Consistent with its mechanism of action, rosiglitazone appears to be associated with a low risk of hypoglycaemia (<2% of patients receiving monotherapy). There is no evidence to date that rosiglitazone shares the hepatotoxicity of troglitazone.",1
9594,10404850,"A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group","We assessed efficacy and safety of a new anti-ischemic agent, ranolazine, during a randomized, double-blind, placebo-controlled crossover study. In the qualifying phase, we withdrew at least 1 antianginal drug from the drug regimen of 312 patients with chronic stable angina while they took placebo. After exercise time had shortened by > or =1.0 minute, we randomly assigned patients to receive either immediate-release ranolazine in 3 dosing regimens or placebo during each treatment period. After each week of treatment, we measured exercise tolerance and ranolazine plasma concentrations at both peak and trough. All exercise parameters significantly (p< or =0.02) improved (intention-to-treat analysis) with ranolazine (all regimens combined) at mean peak plasma concentrations ranging from 1,576 to 2,492 ng/ml compared with placebo without differences in double product. Although similar trends persisted at mean trough, plasma concentrations (range 275 to 602 ng/ml), only the time to 1.0 mm ST-segment depression remained statistically significant. In conclusion, immediate-release ranolazine is effective and well tolerated. However, this immediate-release short-acting formulation with this dosing regimen is not adequate for continuous protection. Either larger or more frequent doses or a sustained-release formulation would be required for clinical use.",1
9595,10405699,Acute hepatitis due to fluoxetine therapy,"Fluoxetine-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. Asymptomatic increases in liver enzyme values have been observed in 0.5% of patients who take long-term fluoxetine therapy. This report details 2 cases of acute hepatitis believed to be caused by fluoxetine. Three cases of acute hepatitis caused by fluoxetine have been reported previously. The mechanism of fluoxetine-induced hepatotoxicity is unknown. Although routine monitoring of liver function may not be cost-effective, physicians should be alert to the possibility of fluoxetine-associated hepatitis and consider early discontinuation of the drug if this condition is suspected.",1
9596,10406406,Minocycline-induced autoimmune syndromes: an overview,"""OBJECTIVE: To increase awareness of minocycline-induced autoimmune syndromes. METHODS: Review of relevant publications from the American and European literature. RESULTS: Four minocycline-induced syndromes have been described in 82 patients: serum sickness, drug-induced lupus, autoimmune hepatitis, and vasculitis. Aside from sporadic cases of serum sickness, all other syndromes occurred in patients treated for acne. Drug-induced lupus and hepatitis were by far the most common events (66 cases). Except for serum sickness, which presented shortly (mean, 16 days) after minocycline, the autoimmune syndromes manifested after protracted use (mean, 25.3 months). As expected, the patients with acne were young (mean, 19.7 years). The most frequent symptoms were arthralgia, followed by arthritis, fever, and rash (73, 45, 38, and 29 patients, respectively). Serologically, antinuclear antibodies were the most common finding (63 positive of 68 tests); perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA), when assayed, were similarly frequent (20 of 24 tests). Surprisingly, anti-histone antibodies were uncommon, even among patients with drug-induced lupus (4 of 31 tests). The clinical and serological features of the separate syndromes may overlap. The diagnostic value of pANCA, as well as its possible role in minocycline-induced autoimmunity, are discussed. CONCLUSIONS: Minocycline has the potential to evoke a variety of clinical and serological autoimmune expressions. The number of published reports may underestimate the frequency of this condition, which should be suspected and investigated in young patients with autoimmune manifestations.""",1
9597,10410179,Hepatotoxicity possibly caused by amphotericin B,"OBJECTIVE: To report a case of possible amphotericin B-induced hepatotoxicity in a patient with pulmonary blastomycosis. SUMMARY: A 26-year-old white man with life-threatening pulmonary blastomycosis developed elevation of his liver enzymes after the addition of amphotericin B to his initial itraconazole therapy. The hepatotoxicity resolved rapidly with discontinuation of the amphotericin B, and the blastomycosis was successfully treated with itraconazole alone. DISCUSSION: This case illustrates an unusual occurrence of hepatotoxicity associated with a short course of amphotericin B. Liver biopsy was compatible with drug-induced changes and showed no evidence of blastomycosis. Discontinuation of amphotericin B with no other therapeutic changes resulted in a rapid resolution of hepatotoxicity. A possible adverse drug interaction with itraconazole and amphotericin B is postulated based on the mechanism of action of each drug. CONCLUSIONS: Amphotericin B therapy can be associated with many adverse effects, but reports of hepatotoxicity are rare. Closer monitoring of liver enzymes in patients receiving amphotericin B, especially in combination with potentially hepatotoxic agents, including azole antifungal drugs, would be prudent.",1
9598,10410273,Hepatotoxicity of parenteral gold therapy in rheumatoid arthritis: a case report and review of the literature,We report a case of severe hepatotoxic reaction during gold therapy for rheumatoid arthritis. The previous literature on this condition is reviewed and the possible mechanisms of gold-induced hepatotoxicity are discussed.,1
9599,10414925,Adverse drug reactions associated with the administration of amphotericin B lipid complex (Abelcet),,1
9600,10418941,Ticlopidine-induced prolonged cholestasis: a case report,"We report a case of ticlopidine-induced prolonged cholestasis in a 60-year-old man with no previous hepatobiliary disease who presented with sudden right upper abdominal pain, jaundice and pruritus three months after starting ticlopidine therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. The liver biopsy showed a cholestatic hepatitis with bile duct damage. The disease ran a severe and protracted course, but symptoms and jaundice eventually subsided five months after drug withdrawal. More than a year later, relevant abnormalities of liver function tests consistent with anicteric cholestasis still persist, fulfilling criteria for a minor form of drug-induced prolonged cholestasis. This syndrome has been reported infrequently in relation to several drugs, mainly chlorpromazine, and only once with ticlopidine.",1
9601,10427794,Meloxicam-induced liver toxicity,"We report the case of a female patient with rheumatoid arthritis who developed acute cytolytic hepatitis due to meloxicam. Recently introduced in Belgium, meloxicam is the first nonsteroidal antiinflammatory drug with selective action on the inducible form of cyclooxygenase 2. The acute cytolytic hepatitis occurred rapidly after meloxicam administration and was associated with the development of antinuclear antibodies suggesting a hypersensitivity mechanism. This first case of meloxicam related liver toxicity demonstrates the potential of this drug to induce hepatic damage.",1
9602,10429550,[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners],"""Evaluation and treatment of insomnia are frequent procedures in the physician's everyday practice, since many patients seek medical treatment for this condition. Knowledge of pharmacological therapeutical alternatives is therefore decisive, in order to identify the most efficaceous and safe therapy for the patient among the available hypnotics. The short-acting hypnotic zolpidem has been investigated in Switzerland in two multicenter safety studies in ambulatory practice. In the first study 8.9% (n = 125 of 1,972 treated patients), and in the second 7.2% of the patients (n = 175 of 1,833 treated patients) reported an adverse event. The most frequent events were related to the central nervous system (CNS) (somnolence, headache, confusion, vertigo); gastrointestinal and cutaneous symptoms were the most frequent non CNS-dependent effects. New, unknown or serious adverse events were not found and no specific risk factor or population at risk was identified. The safety profile of zolpidem is consistent with its known pharmacological properties, the results of previous clinical trials and the international experience obtained in large patients groups.""",1
9603,10432757,[Cholestatic hepatitis from ticlopidine],,1
9604,10433603,Hydroxyurea-induced hepatitis in human immunodeficiency virus-positive patients,,1
9605,10444232,The systemic safety of fexofenadine HCl,"Fexofenadine is a highly specific, H1-receptor antagonist with a safety profile similar to placebo. In placebo-controlled trials of seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU), the type and incidence of adverse events were comparable in fexofenadine and placebo recipients. Fexofenadine does not impair performance in tests of driving or psychomotor performance and has been shown to improve quality of life in patients with SAR. Fexofenadine has a high margin of safety and is also well tolerated in subjects with renal or hepatic impairment, in children and the elderly. No clinically significant drug interactions have been identified. Fexofenadine is not associated with cardiotoxicity. Unlike some other antihistamines, such as loratidine or cetirizine [1, 2], fexofenadine is truly non-sedating, showing no dose-related increase in sedation, even at high doses [3, 4]. Fexofenadine is formulated and marketed as the hydrochloride salt. The recommended dose of fexofenadine HC1 is 120 mg daily for SAR (either as 120 mg once daily or 60 mg twice daily) or 180 mg once daily for CIU.",1
9606,10449123,"Pergolide monotherapy in the treatment of early PD: a randomized, controlled study. Pergolide Monotherapy Study Group","""OBJECTIVE: To determine whether pergolide monotherapy provides symptomatic relief in early PD. BACKGROUND: Early treatment with dopamine agonists may reduce the risk of motor fluctuations, which are most likely linked to levodopa therapy. Pergolide, a D1-D2 dopamine agonist, has been studied as """"add on"""" therapy in PD, but no controlled clinical trial studying the efficacy of pergolide monotherapy is available. METHODS: The efficacy and tolerability of pergolide were evaluated in a multicenter, double-blind, randomized, parallel-group, 3-month trial versus placebo. Patients with a diagnosis of idiopathic PD, a modified Hoehn & Yahr score of 1 to 3, and a score greater than 14 points on the Unified Parkinson's Disease Rating Scale (UPDRS) part III at baseline were enrolled in the study (pergolide, n = 53; placebo, n = 52). RESULTS: Patient characteristics at study entry were comparable in the two study groups. The pergolide group showed a significantly greater percent of responders (defined as a -30% decrease in UPDRS part III score at end point) compared with placebo (57% versus 17%; p < 0.001). Pergolide-treated patients experienced a significantly greater improvement than placebo-treated patients (p < 0.001) in UPDRS (overall, part II, and part III) score, Schwab & England score, and Clinical Global Impression improvement score. By the study end the mean dose of pergolide was 2.06 mg/day. Six patients in the pergolide group versus two patients in the placebo group discontinued the study because of treatment emergent side effects. CONCLUSION: This study suggests that pergolide monotherapy may be an efficacious and well-tolerated first-line treatment in patients with early-stage PD.""",1
9607,10451758,COMT inhibitors in Parkinson's disease,"""The COMT inhibitors, tolcapone and entacapone, are a new class of Parkinson's medications. By inhibiting the enzyme catechol-o-methyl-transferase (COMT), they prevent peripheral degradation of levodopa, allowing a higher concentration to cross the blood-brain barrier. Pharmacokinetic studies have shown that both tolcapone and entacapone significantly prolong the elimination half life, and increase the area under the curve of levodopa without increasing C max. Clinical studies with COMT inhibitors have shown benefit in both stable and fluctuating PD patients with improvement in motor function with lower levodopa doses. Fluctuating patients also had increased """"on"""" time and reduced """"wearing off"""". Side effects were most commonly related to increased dopaminergic stimulation. Specific side effects included diarrhea and elevated liver enzymes. The recent reports of three cases of fulminant hepatitis with the use of tolcapone has led many countries to remove this compound from their market. Concerns about a possible class effect should impose close monitoring of liver function tests with the use of any of the nitrocatechols.""",1
9608,10452668,"Two episodes of acute renal failure, rhabdomyolysis, and severe hepatitis in an AIDS patient successively treated with ritonavir and indinavir",,1
9609,10453975,Delayed-onset ticlopidine-induced cholestatic jaundice,"An 86-year-old man experienced a rash approximately 2 weeks after starting ticlopidine therapy, necessitating discontinuation of the drug. About 1 month later, despite discontinuation, he developed jaundice and liver test abnormalities. These resolved gradually over the next few months. Based on case reports and the drug's pharmacokinetic profile, a high index of suspicion for ticlopidine-induced jaundice is prudent in patients with recent exposure to the agent who have evidence of liver damage.",1
9610,10459140,Acitretin in psoriasis: an overview of adverse effects,"Oral retinoids are among the drugs of choice for pustular and erythrodermic psoriasis. In addition, retinoids are effective in combination with other topical and systemic agents for the treatment of plaque-type psoriasis. Acitretin, the active retinoid metabolite, has replaced etretinate in retinoid therapy of psoriasis because of its more favorable pharmacokinetic profile, including a significantly shorter half-life. Retinoids, including acitretin, are potent teratogens, leading to strict requirements for pregnancy prevention during and after their use. Other retinoid side effects are generally preventable or manageable through proper patient selection, dose adjustments, and routine monitoring. Mucocutaneous side effects such as cheilitis and hair loss are the most common dose-dependent side effects, requiring dose reduction in some patients. Less common effects such as hepatotoxicity, serum lipid alterations, pancreatitis, and possible skeletal effects are also discussed.",1
9611,10459914,Fulminant liver failure associated with flutamide therapy for hirsutism,,1
9612,10461819,Risperidone-induced hepatotoxicity in children and adolescents? A chart review study,"""Risperidone is an atypical antipsychotic drug that has been used in the treatment of numerous psychiatric disorders in children and adolescents. The question of whether risperidone-induced weight gain is associated with steatohepatitis has recently been raised. The purpose of this chart review was to ascertain: (1) the rate of liver dysfunction observed during risperidone treatment in children and adolescents; and (2) the clinical factors associated with liver dysfunction. For purposes of this chart review study, abnormal liver function was defined by serum transaminase or bilirubin values falling outside the normal laboratory ranges. Chart reviews were completed on 38 youths with ages ranging from 5-17 years with a variety of psychiatric diagnoses. The mean length of risperidone treatment was 15.2 months at a mean dose of 2.5 mg/day. It was found that 37 of the 38 youths treated with risperidone had no liver enzyme abnormalities at the end of study. One subject had an alanine aminotransferase (ALT) level of 46 U/L which was 7 U/L above the upper limit of normal for this laboratory test. This isolated value was not considered clinically significant. These data were noted in spite of weight gain and the use of numerous concomitant psychotropic medications. These findings suggest that risperidone in short term treatment does not commonly lead to evidence of abnormal liver function at therapeutic doses in children and adolescents. Larger-scale, prospective studies are needed in order to confirm these findings.""",1
9613,10468156,Ferrous sulfate toxicity: a review of autopsy findings,"""Ferrous sulfate is the leading cause of accidental pediatric poisonings. Despite the requirement for child-resistant packaging for any oral iron product with 250 mg or more per container, the incidence has continued to increase. Although the clinical presentation of iron toxicity has been well described, pathologic findings in human tissue and correlation with clinical data are scant. We reviewed autopsies from the Armed Forces Institute of Pathology of 11 children who died from ferrous sulfate toxicity. Clinical data, morphologic changes, and iron levels in tissue were evaluated. The children's ages ranged from 11 to 36 mo. Prominent iron deposition in gastric and small intestinal mucosa was associated with necrosis, with some cases demonstrating prominent vascular iron deposition. The clinical courses were rapid and progressed from Stage I to Stage III. These observations were correlated with increased levels of iron in various tissues, as determined by analytical atomic absorption spectrophotometry. The morphologic and chemical analysis data provide information on the pathogenesis of ferrous sulfate poisoning; the vascular iron deposition may be related to subsequent hemorrhage. In the liver the periportal necrosis is probably a direct cytopathic effect of the highest levels of iron carried to these cells by the portal blood flow.""",1
9614,10473024,Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS,"Cidofovir is an antiviral nucleotide analogue with significant activity against cytomegalovirus (CMV) and other herpesviruses. The drug is indicated for the treatment of CMV retinitis, a sight-threatening condition, in patients with AIDS. Cidofovir has a long intracellular half-life which allows for a prolonged interval (2 weeks) between maintenance doses. In contrast, other intravenous treatment options for patients with CMV retinitis (i.e. ganciclovir and foscarnet) must be administered on a daily basis. The efficacy of intravenous cidofovir has been demonstrated in patients with AIDS and previously untreated CMV retinitis in multicentre randomised trials, and in a dose-finding study of cidofovir in patients with AIDS and previously treated relapsing CMV retinitis. Clinical trials have been relatively small (n < or = 100 patients) and no studies have been conducted directly comparing intravenous cidofovir with the more established intravenous agents, ganciclovir or foscarnet. Indirect comparisons of clinical trial data suggest that intravenous cidofovir may have similar efficacy to intravenous ganciclovir or foscarnet in delaying progression of CMV retinitis. However, such comparisons must be made with caution because of potential differences in patient populations, data analysis techniques and interobserver variability in the masked assessment of retinal photographs. Nevertheless, intravenous cidofovir offers a less intrusive administration regimen than intravenous ganciclovir or foscarnet because of its prolonged dosage interval. Since therapy is life-long, patients receiving daily intravenous ganciclovir or foscarnet (but not cidofovir) usually require an indwelling central venous catheter and are therefore at increased risk of serious infection. The relatively long dosage interval for cidofovir may also have favourable implications in terms of overall treatment costs and patient quality of life, although specific data are very limited. Potentially irreversible nephrotoxicity is the major treatment-limiting adverse event associated with intravenous cidofovir in patients with AIDS-related CMV retinitis. Anterior uveitis/iritis has been reported frequently with intravenous cidofovir in postmarketing reports and a small number of patients have developed hypotony. Other treatment options for CMV retinitis are also associated with serious adverse events, and selection of pharmacotherapy will depend on a number of factors including retinitis lesion characteristics, patient quality-of-life issues and efficacy and tolerability profiles of available therapies. CONCLUSION: Although the extent of its use may be limited by its adverse event profile, cidofovir offers a useful addition to the limited number of drugs available for the treatment of CMV retinitis in patients with AIDS.",1
9615,10473987,Antiandrogen hepatotoxicity in patients with chronic viral hepatitis,"OBJECTIVE: To assess whether patients with chronic viral hepatitis are at an increased risk for antiandrogen hepatotoxicity. METHODS: We retrospectively reviewed 121 prostate cancer patients who received long-term antiandrogen, either flutamide (n = 56) or cyproterone acetate (n = 65), and had normal pretreatment serum alanine aminotransferase (ALT) levels. Serological markers of hepatitis B and C viruses (HBV and HCV) were checked in 42 of the 121 patients. RESULTS: Twenty-two (18%) of the 121 patients had ALT elevations during antiandrogen therapy. Thirteen (59%) of the 22 patients were positive for either one of the two viral markers, including 7 for HBV, 4 for HCV, and 2 for both. This percentage was higher than the combined prevalence rate of positivity for HBV and/or HCV markers (<20%) in Taiwan. There was no significant differences in the percentage of positive makers among the two antiandrogen groups (p = 0.092). Although a higher incidence of hepatotoxicity was noted in the flutamide (13/56, 23%) than in the cyproterone acetate group (9/65, 14%), there were no significant differences between the two groups (p = 0.27). The time period between initiation of antiandrogen and first ALT elevation varied significantly (from 4 to 1,398 days with a median of 151 days). Half of the 14 HBV carriers and all of the 6 patients with anti-HCV developed antiandrogen hepatotoxicity. CONCLUSION: Our limited data suggested that patients with chronic viral hepatitis probably are at a higher risk of developing antiandrogen hepatotoxicity. Close monitoring of liver functions in patients with chronic viral hepatitis is advised if antiandrogen therapy is necessary. However, a large-scale study is necessary for a definitive conclusion.",1
9616,10476768,Severe hepatic failure related to nevirapine treatment,,1
9617,10482436,Paracetamol overdose in a liver transplantation centre: an 8-year experience,"""BACKGROUND: Paracetamol is a readily available, widely used analgesic that can cause serious hepatic injury when taken in overdose. The aims of this study were to assess the frequency of attendance at the Austin and Repatriation Medical Centre for paracetamol overdose, the frequency of referral to the Victorian liver transplant unit after serious overdoses, the morbidity and mortality rates in all patients treated and the appropriateness of treatment. METHODS: A review of the Austin and Repatriation Medical Centre medical records and of the Victorian liver transplant unit database of all patients attending because of paracetamol overdose from 1988-1995 was undertaken. One hundred and fifty-two patients (103 females, 49 males) files were reviewed. RESULTS: One hundred and thirty-one patients presented directly from the community and 21 were referred specifically for consideration for possible transplantation. The most important predictor of liver injury was time between overdose and arrival at hospital (P< 0.01). Thirteen patients developed fulminant hepatic failure, one of whom received a liver transplant; this patient died post-transplantation and was the only death in the series. CONCLUSIONS: We found that serious liver injury following overdose was uncommon, liver transplantation was rarely needed and death was rare. Although inappropriate delay in instituting N-acetylcysteine treatment after admission to hospital or failure to treat still occurred in a number of cases, delay in presentation to hospital was the main predictor of liver damage.""",1
9618,10485752,Short-term propofol infusions in children,,1
9619,10487399,Felbamate in epilepsy therapy: evaluating the risks,"Felbamate demonstrates a unique therapeutic profile and often results in seizure control when other agents fail. Its use has been associated with risks for aplastic anaemia and hepatic failure. A number of confounding factors makes the actual incidence rate for each adverse effect difficult to determine. However, certain risk factors are common in reported cases. In order to minimise the risk, at the present time, it is necessary to rely on the clinical profile of the patients reporting these adverse effects. The patient reporting aplastic anaemia is usually female, Caucasian, and an adult. The dose did not appear to be a factor and the time to onset of aplastic anaemia was less than 1 year for all patients. Concomitant medications and diseases may play an important role. Patients with reported aplastic anaemia generally had a history of a serious allergy or toxicity to other anticonvulsants and/or a background of having had a cytopenia due to other anticonvulsants, and a diagnosis or serological evidence of concomitant immune disorder. The demographics associated with hepatic failure are less well defined. Patients were also predominantly female, were equally divided among adult and paediatric patients, and had a broad range of time to presentation of hepatotoxicity following felbamate therapy. Concomitant medications again play an important role with, in this case, valproic acid (sodium valproate), phenytoin and carbamazepine being the most frequent. In 50% of the population, hepatic failure was not felt to be due to felbamate but associated with confounding factors including status epilepticus, paracetamol (acetaminophen) toxicity, hepatitis and shock liver. Initial research has failed to provide a diagnostic indicator. However, work on a potential intermediate felbamate metabolite has suggested the formation of a reactive aldehyde whose end products have been detected in the urine of felbamate treated patients. Until these data are confirmed, the medical history, clinical picture, and laboratory testing, should be used to identify patients at risk. The risks for toxicity with felbamate should be evaluated before starting treatment. In addition, liver function tests and complete blood count (CBC) prior to therapy and at clinically rational intervals should be conducted. Patients must be educated in the likely prodromal symptoms of potential marrow/liver toxicity. Felbamate is too valuable an anticonvulsant to be relegated to the therapeutic scrap heap. With monitoring, patient education, and continued research to further elucidate risk factors, felbamate can be a viable therapeutic agent for patients with epilepsy.",1
9620,10489985,Cholestatic liver dysfunction,,1
9621,10492496,Oxaprozin-induced symptomatic hepatotoxicity,"OBJECTIVE: To describe a case of symptomatic hepatotoxicity attributed to oxaprozin use. CASE SUMMARY: A 41-year-old white woman was admitted to the hospital with malaise, anorexia, and right upper quadrant pain. The patient was found to have severe jaundice with liver enzyme elevation. Laboratory test results for potential etiologies were negative, except for the use of oxaprozin for the preceding six weeks. Diagnosis of drug-induced hepatotoxicity was made by liver biopsy. The patient's symptoms resolved and liver enzymes normalized after oxaprozin was discontinued. DISCUSSION: Symptomatic hepatic effects attributable to most nonsteroidal antiinflammatory drugs (NSAIDs) are rare and usually mild. Oxaprozin has been shown to cause mild elevation of liver enzymes in clinical studies. This is the second reported case of presumed oxaprozin-induced icteric hepatitis. The mechanism of oxaprozin-induced hepatotoxicity is unclear, but is thought to be due to metabolic idiosyncrasy. Most NSAID reactions are hepatocellular and occur because of individual susceptibility (idiosyncrasy). In general, people aged >40 years and women are more predisposed to NSAID-induced liver injury. CONCLUSIONS: Although this toxicity is rare, clinicians should be aware of the potential for oxaprozin to cause hepatotoxicity and use caution when prescribing this medication. This case also stresses the importance of careful inquiry regarding drug or toxin exposure in cases of unexplained hepatitis.",1
9622,10493319,"Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects","OBJECTIVES: To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. METHODS: Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. RESULTS: Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. CONCLUSIONS: Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.",1
9623,10495371,"Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases","BACKGROUND: The perception of pruritus is modified by endogenous opiates via central opiate receptors in a histamine-independent manner. OBJECTIVE: The aim of this pilot study was to evaluate the efficacy and safety of naltrexone, an orally active opiate antagonist, in the treatment of severe, otherwise intractable pruritus of different origin in an open-label clinical trial. METHODS: A total of 50 patients with pruritus caused by internal diseases, hydroxyethyl starch, contact with water, cutaneous lymphoma, atopic dermatitis, xerosis cutis, macular amyloidosis, psoriasis, and other skin disorders as well as with pruritus of unknown origin were randomly selected to receive naltrexone 50 mg daily. The pruritus intensity was rated by the patients before and during therapy in a visual analogue scale. RESULTS: A significant therapeutic response was achieved in 35 of the 50 patients within 1 week (confidence limits of 0.55 and 0.82 at a confidence level of 0. 95). Naltrexone was of high antipruritic effect in 9 of 17 cases of prurigo nodularis and contributed to healing of the skin lesions. Tachyphylaxis was infrequent (6/50), occurred late, and could be counterbalanced by raising the dosage in 2 patients. Adverse drug effects were restricted to the first 2 weeks of treatment and included nausea (11/50), fatigue (3/50), dizziness, heartburn, and diarrhea (1/50 each). CONCLUSION: The study suggests that oral opiate antagonists might be a well-tolerated and effective therapy for pruritic symptoms in many diseases.",1
9624,10500075,Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial,"""BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is used for treatment of primary biliary cirrhosis. Previous studies showed that, compared with UDCA monotherapy, bile salts plus prednisolone had no further effect on laboratory data but improved liver histology. Thirty percent of these patients had prednisolone-related side effects. Budesonide is a glucocorticoid with a high receptor affinity and a high first-pass metabolism. In this study we investigated whether budesonide and UDCA are superior to UDCA monotherapy. METHODS: A 2-year prospective, controlled double-blind trial was performed. Twenty patients (mainly with early-stage disease) were treated with UDCA at a dose of 10-15 mg/kg daily in addition to 3 mg budesonide 3 times daily (group A), and 19 patients (1 dropped out for personal reasons) were treated with UDCA plus placebo (group B). Liver biopsy specimens were taken before, after 12 months, and at the end of study. Glucose tolerance tests, serum cortisol levels, and adrenocorticotropin-stimulated cortisol secretion were assessed at regular intervals. Bone mass density was measured by dual-energy photon absorptiometry. RESULTS: Compared with pretreatment values, liver enzyme and immunoglobulin M and G levels decreased significantly in both groups. Improvement in group A was significantly more pronounced (P < 0.05) than in group B. Titers of antimitochondrial antibodies did not change. In group A, the point score of liver histology improved by 30.3%; in group B, it deteriorated by 3.5% (P < 0.001). Changes in bone mineral density after 2 years were -1.747% in group A and -0.983% in group B (P = 0.43). Budesonide had little influence on the hypothalamic-pituitary-adrenal axis. One patient in group A had budesonide-related side effects; in 3 patients in group B, complications of liver disease developed. CONCLUSIONS: Combination therapy with UDCA and budesonide is superior to UDCA and placebo.""",1
9625,10501791,Clodronate as a cause of aminotransferase elevation,"Adverse events (AEs) associated with bisphosphonates are usually gastrointestinal, but elevation of aminotransferases (alanine and aspartate aminotransferase) has also been described in many cases. The frequency of such elevation is, however, poorly investigated. The Probone study is a continuing phase II trial of 610 osteopenic women randomized for 3 years to receive placebo or clodronate at the following clodronate doses: 65 mg, 400 mg and 800 mg daily, and 400 mg for 15 days out of 90 (intermittent group). During the first study year, gastrointestinal AEs were reported by 20-26% of the patients in the five study groups, but no differences appeared between groups. The high-dose clodronate groups (400 mg and 800 mg daily) had no more hepatic side-effects than the low-dose groups, and no serious AE due to liver disease was reported. These higher doses of clodronate caused, however, a mean alanine aminotransferase (ALT) elevation of 5.4-5.8 U (25-24%) which differed significantly from the change in the placebo group (p = 0.002 and p<0.0001, respectively). In those volunteers with initially normal aminotransferase values the risk ratio for an aminotransferase increase to an above-normal value (compared with the placebo group) during the study year was up to 1.8 in the clodronate 400 mg group and up to 2.5 in the clodronate 800 mg group. Among these groups an elevation above the normal limits occurred in up to 11.7% of the volunteers for aspartate aminotransferase (AST) and up to 17.7% for ALT. The respective percentages in the placebo group were 6.2% and 7. 2%. All analyzed bilirubin values were normal. We conclude that oral clodronate use may elevate serum aminotransferase levels, and that these enzymes most likely come from the liver. This elevation has also been described for several other bisphosphonates. However, clinically significant liver injury is unlikely.",1
9626,10504728,Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site,"Various classes of nucleotidyl polymerases with different transcriptional roles contain a conserved core structure. Less is known, however, about the distinguishing features of these enzymes, particularly those of the RNA-dependent RNA polymerase class. The 1. 9 A resolution crystal structure of hepatitis C virus (HCV) nonstructural protein 5B (NS5B) presented here provides the first complete and detailed view of an RNA-dependent RNA polymerase. While canonical polymerase features exist in the structure, NS5B adopts a unique shape due to extensive interactions between the fingers and thumb polymerase subdomains that serve to encircle the enzyme active site. Several insertions in the fingers subdomain account for intersubdomain linkages that include two extended loops and a pair of antiparallel alpha-helices. The HCV NS5B apoenzyme structure reported here can accommodate a template:primer duplex without global conformational changes, supporting the hypothesis that this structure is essentially preserved during the reaction pathway. This NS5B template:primer model also allows identification of a new structural motif involved in stabilizing the nascent base pair.",1
9627,10506840,[Severe cholestasis with kidney failure from anabolic steroids in a body builder],"HISTORY AND ADMISSION FINDINGS: A 28-year-old body builder was admitted because of jaundice. For 80 days, until 3 weeks before hospitalization, he had been taking moderately high doses of anabolic steroids: metandienone (methandienone), 10-50 mg daily by mouth, and stanozolol, 50 mg intramuscularly every other day. Physical examination was unremarkable except for yellow discoloration of the skin and sclerae. INVESTIGATIONS: Bilirubin concentration was raised to 4.5 mg/dl, cholestasis enzymes were normal, while transaminase activities were raised. Liver biopsy was compatible with cholestasis induced by anabolic steroids. TREATMENT AND COURSE: Although the steroids had been discontinued, the patient's general condition deteriorated over 7 weeks. Serum bilirubin rose up to a maximum of 77.9 mg/dl. In addition renal failure developed with a creatinine concentration of 4.2 mg/dl. The patient's state improved simultaneously with the administration of ursodeoxycholic acid and the biochemical values gradually reached normal levels after several weeks. CONCLUSION: Anabolic steroids can cause severe cholestasis and acute renal failure. In this case there was a notable temporal coincidence between the administration of ursodeoxycholic acid and the marked clinical improvement.",1
9628,10511396,Safety and tolerability of quinupristin/dalfopristin: administration guidelines,"""The safety and tolerability of quinupristin/dalfopristin were assessed in both comparative and non-comparative trials (2298 quinupristin/dalfopristin-treated patients). In comparative clinical trials, the most frequent systemic adverse events related to quinupristin/dalfopristin were nausea (4.6%), diarrhoea (2.7%), vomiting (2.7%) and skin rash (2.5%). The comparator group showed similar rates, except that nausea was significantly more common (7.2%; P = 0.01). In non-comparative trials, arthralgia and myalgia were reported most frequently but were reversible upon treatment discontinuation. The renal, inner ear, cardiovascular and central nervous systems were not implicated as significant target organs for toxicity. The most frequent local adverse events related to infusion of quinupristin/dalfopristin were inflammation, pain, oedema, infusion site reaction and thrombophlebitis. Results of laboratory tests while on therapy were comparable for quinupristin/dalfopristin and comparator groups, except that increases in conjugated bilirubin of >5 x the upper limit of normal were reported in 5.5% of quinupristin/dalfopristin recipients; increases in total bilirubin of >5 x the upper limit of normal occurred in 1.5%. Comparator recipients more frequently had increases in alanine aminotransferase and alkaline phosphatase. Quinupristin/dalfopristin inhibits the cytochrome P450 3A4-mediated metabolism of drugs including midazolam, nifedipine, terfenadine and cyclosporin. Therefore, plasma drug monitoring and/or dosage reduction of these agents is prudent. Concomitant administration of drugs that can prolong the electrocardiographic QTc interval should be avoided. Quinupristin/dalfopristin is visually and chemically compatible with commonly used drugs of various classes, but it is not compatible with sodium chloride solution and certain other drugs, including some antimicrobials. Therefore, when prescribing quinupristin/dalfopristin, clinicians should be aware of the potential for peripheral venous intolerance, arthralgias and myalgias, increases in conjugated bilirubin, interactions with drugs metabolized by the cytochrome P450 3A4 isoenzyme and certain physico-chemical incompatibilities. However, multiple studies have shown that the safety and tolerability of quinupristin/dalfopristin are generally favourable, and that it provides clear benefits to ill patients with severe gram-positive infections.""",1
9629,10514019,Zanamivir: a review of clinical safety,"Preclinical and clinical studies have clearly demonstrated that zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neuraminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinical studies completed up to the 17 July 1998 involving over 6000 adult and adolescent patients from North America, Europe and the Southern Hemisphere. Serious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequencies and was found to have a comparable safety profile with placebo when given for both the treatment and prophylaxis of influenza-like illness. These findings were independent of age and underlying medical condition. 4152 patients received zanamivir and the most commonly reported adverse events were consistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of zanamivir and placebo recipients reported a serious adverse event. In addition, 490 healthy volunteers received zanamivir in clinical pharmacology studies. It was well tolerated and the incidence of adverse events was similar in zanamivir and placebo recipients. In addition, no clinically significant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 197 times the current therapeutic dose (20 mg/day). The characteristics of the molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intravenous doses were well tolerated in healthy volunteers. The observed safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine and amantadine, as well as GS4104, a neuraminidase inhibitor currently in phase III development. This may be attributed to the low systemic bioavailability of zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a reduced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver. Therefore, the safety profile of zanamivir supports its use in the management of influenza.",1
9630,10517569,Acute zolpidem overdose--report of two cases,"""This report describes two cases of acute zolpidem overdose. The decedent in the first case was a 36-year-old female found dead in bed in her secured home. She had a history of psychiatric illness, including paranoid disorder, depression with panic episodes, and post-traumatic stress disorder. She was treated with risperidone and sertraline. Nine months prior to her death, the decedent was also prescribed zolpidem (Ambien). The postmortem examination revealed white foam within the larynx and upper trachea, which is indicative of pulmonary edema. Toxicological analyses of the urine showed the presence of caffeine, risperidone, and zolpidem. Subsequent quantitation of postmortem iliac serum revealed 5.6 microg/L of 9-hydroxyrisperidone and the following zolpidem concentrations: blood (subclavian), 4.5 mg/L; blood (iliac), 7.7 mg/L; vitreous humor, 1.6 mg/L; bile, 8.9 mg/L; urine, 1.2 mg/L; liver, 22.6 mg/kg; and gastric contents, 42 mg. The second case involved a 58-year old female, also found dead in bed, with white foam around her mouth. The decedent had a 25-year history of hypertension and mental illness--manic depression and schizophrenia. She was medicated with carbamazepine, naproxen, risperidone, and zolpidem. The postmortem examination revealed cardiomegaly, pulmonary edema, hepatomegaly, mild coronary atherosclerosis, and no signs of trauma. Toxicological analyses of the urine showed the presence of zolpidem and carbamazepine and metabolite. Zolpidem concentrations were as follows: blood (iliac), 1.6 mg/L; vitreous humor, 0.52 mg/L; bile, 2.6 mg/L; liver, 12 mg/kg; and gastric contents, 0.9 mg. The zolpidem blood concentrations of these cases are consistent with those of the previously published fatalities. The blood/vitreous humor ratios of zolpidem were 2.81 (subclavian) and 4.81 (iliac) in the first case and 3.08 (iliac) in the second case. These ratios, along with the sampling times of blood and vitreous humor for both cases, are not conclusive to indicate a definitive presence or absence of postmortem drug redistribution of zolpidem. The cause of death for both cases was determined to be acute zolpidem overdose, and manner of death was suicide.""",1
9631,10520659,Non-alcoholic steatohepatitis,,1
9632,10523732,Continuous itraconazole treatment for onychomycosis and dermatomycosis: an overview of safety,"Over the past 10 years, itraconazole has been used to treat more than 34 million patients worldwide. We present a review of the safety of various continuous itraconazole schedules used in the treatment of dermatomycosis and onychomycosis. Data from controlled clinical trials and extensive post-marketing surveillance show that itraconazole has an impressive safety profile at a dose of 50-200 mg/day for 1-4 weeks for dermatomycosis and 200 mg/day for 3 months for onychomycosis. In addition, itraconazole is safe to use in diabetic patients with dermatomycosis or onychomycosis. Short-term, intermittent itraconazole regimens, which may offer additional benefits in terms of safety and cost, have now been introduced.",1
9633,10525830,"Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-FLAG) for treatment of refractory, relapsed, and secondary AML","""The current phase-II trial was initiated to assess the efficacy and toxicity of the Ida-FLAG regimen in patients with poor-risk acute myeloid leukemia (AML). Three subgroups of patients with AML were eligible for the study: (a) refractory, (b) first relapse, or (c) secondary AML (i.e., signs of trilineage myelodysplasia at diagnosis or the history of a myelodysplasia or myeloproliferative disorder). Fifty-seven fully evaluable patients were included in the study. Twenty patients received a second course of Ida-FLAG. Complete remission was achieved by 1/14 patients with refractory AML, 12/15 patients with relapsed AML, and 17/28 patients with secondary AML. The median duration of ANC <1000/microl was 17 days (10-36); of platelets <30,000/microl 23 days (9-65); of days with fever >38.0 degrees C 6 days (1-33). Thirteen patients (22.8%) died within 42 days of severe infection or hemorrhage. Overall survival at 20 weeks in the subgroups was 24% for patients with refractory, 78% for patients with relapsed, and 55% for patients with secondary AML. The toxicity of the first cycle of Ida-FLAG is moderate. The feasibility and subjective tolerance of the Ida-FLAG regimen are acceptable. There is no evidence for an increase of atypical infections. The efficacy for patients with secondary AML and especially those with first relapse of AML is good, with a high rate of complete remissions. Remission duration seems to be short. Therefore, an intensified post-remission therapy seems necessary.""",1
9634,10528036,A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis,"""BACKGROUND AND METHODS: Patients with idiopathic pulmonary fibrosis have progressive scarring of the lung and usually die within four to five years after symptoms develop. Treatment with oral glucocorticoids is often ineffective. We conducted an open, randomized trial of treatment with a combination of interferon gamma-1b, which has antifibrotic properties, and an oral glucocorticoid. We studied 18 patients with idiopathic pulmonary fibrosis who had not had responses to glucocorticoids or other immunosuppressive agents. Nine patients were treated for 12 months with oral prednisolone alone (7.5 mg daily, which could be increased to 25 to 50 mg daily), and nine with a combination of 200 microg of interferon gamma-1b (given three times per week subcutaneously) and 7.5 mg of prednisolone (given once a day). RESULTS: All the patients completed the study. Lung function deteriorated in all nine patients in the group given prednisolone alone: total lung capacity decreased from a mean (+/-SD) of 66+/-8 percent of the predicted value at base line to 62+/-6 percent at 12 months. In contrast, in the group receiving interferon gamma-1b plus prednisolone, total lung capacity increased (from 70+/-6 percent of the predicted value at base line to 79+/-12 percent at 12 months, P<0.001 for the difference between the groups). In the group that received interferon gamma-1b plus prednisolone, the partial pressure of arterial oxygen at rest increased from 65+/-9 mm Hg at base line to 76+/-8 mm Hg at 12 months, whereas in the group that received prednisolone alone it decreased from 65+/-6 to 62+/-4 mm Hg (P<0.001 for the difference in the change from baseline values between the two groups); on maximal exertion, the value increased from 55+/-6 to 65+/-8 mm Hg in the group that received combined treatment and decreased from 55+/-6 mm Hg to 52+/-5 mm Hg in the group given prednisolone alone (P<0.001). The side effects of interferon gamma-1b, such as fever, chills, and muscle pain, subsided within the first 9 to 12 weeks. CONCLUSIONS: In a preliminary study, 12 months of treatment with interferon gamma-1b plus prednisolone was associated with substantial improvements in the condition of patients with idiopathic pulmonary fibrosis who had had no response to glucocorticoids.""",1
9635,10534534,Dihydropyridine calcium channel blockers: a rare and reversible cause of hepatotoxicity with cholestasis in a CAPD patient,,1
9636,10535888,Acute hepatitis induced by greater celandine (Chelidonium majus),"The hepatotoxic potential of conventional drugs is well known, but herbal medicines are often assumed to be harmless. In the last 2 years, we have observed 10 cases of acute hepatitis induced by preparations of greater celandine (Chelidonium majus), which are frequently prescribed to treat gastric and biliary disorders. The course of hepatitis was mild to severe. Marked cholestasis was observed in 5 patients, but liver failure did not occur. Other possible causes of liver disease (viral, autoimmune, hereditary, alcohol, and secondary biliary) were excluded by laboratory tests and imaging procedures, and liver biopsy specimens were consistent with drug-induced damage. After discontinuation of greater celandine, rapid recovery was observed in all patients and liver enzyme levels returned to normal in 2-6 months. Unintentional rechallenge led to a second flare of hepatic inflammation in 1 patient. Greater celandine has to be added to the list of herbs capable of inducing acute (cholestatic) hepatitis. A significant proportion of unexplained cases of hepatitis may be caused by greater celandine.",1
9637,10542998,[Ticlopidine-induced cholestasis],"UNLABELLED: We report a case of ticlopidine-induced cholestatic hepatitis. CASE SUMMARY: An 82-year-old man suffered a myocardial infarction in February 1998. Because of persistent angina pectoris a coronary stent was implanted in May 1998. At this time medication with 1 x 250 mg ticlopidine was started in addition to the preexistent medication of aspirin 1 x 100 per day, metoprolol fumarate 1 x 95 mg per day and isosorbide dinitrate 1 x 100 mg per day. Three weeks after starting ticlopidine the patient complained of itching, and on day 28 painless jaundice developed. At this time, the serum activities of alkaline phosphatase (923 U/l), gamma-GT (823 U/l) and total bilirubin concentration (129 mumol/l) were markedly elevated, whereas the activities of the transaminases (AST 131 U/l, ALT 194 U/l) were slightly increased. An extra- or intrahepatic biliary obstruction was ruled out, and there were no signs of a toxic, infectious or immunological cause for the hepatic injury. Liver biopsy showed centro-acinar cholestasis. After drug discontinuation the itching stopped after 4 weeks and jaundice disappeared after 2 weeks. Eight months after the onset of symptoms, the activities of alkaline phosphatase (226 U/l) and gamma-GT (213 U/l) were still elevated but the patient was asymptomatic. CONCLUSIONS: Ticlopidine-induced mild serum liver enzyme elevations have been observed in some studies (incidence 1-2%). The incidence of severe hepatitis has been estimated at 0.0013%. Only a few cases (in approximately 20 patients receiving ticlopidine) of a severe cholestatic pattern of injury have been reported. In all cases the jaundice resolved and serum liver enzyme concentrations normalised over a period of months. Characteristically, liver biopsies demonstrated centro-acinar cholestasis. Monitoring of serum liver enzyme concentrations is not recommended. When itching or jaundice occur in a patient taking ticlopidine, the possibility of toxic liver damage should be taken into account.",1
9638,10550734,"Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis","""BACKGROUND: Fexofenadine hydrochloride (HCl) is a new H(1) antihistamine used twice daily in some countries. OBJECTIVE: A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of fexofenadine HCl (120 and 180 mg administered once daily) and cetirizine (10 mg once daily) in the treatment of seasonal allergic rhinitis. METHODS: After a 3- to 5-day run-in period, patients meeting entrance criteria were randomized to receive placebo, fexofenadine HCl 120 mg once daily, fexofenadine HCl 180 mg once daily, or cetirizine 10 mg once daily (active control) for 2 weeks. Eight hundred twenty-one patients comprised the intention-to-treat population and 722 patients completed the study. Symptom assessments were conducted 12 hours after the dose for the previous 12 hours and again at 24 hours after the dose for the previous 12 hours. In addition, assessment was made immediately before dosing in the morning for the previous 30 minutes. Total symptom score was calculated as the sum of scores for the 4 individual symptoms: (1) sneezing, (2) rhinorrhea, (3) itchy nose, palate, or throat, and (4) itchy, watery, or red eyes; the nasal congestion score was also recorded. RESULTS: Both doses of fexofenadine HCl were superior to placebo in reducing the total symptom score. Efficacy was maintained for the entire dosing interval (ie, for 24 hours). There were no differences in efficacy between the 2 doses of fexofenadine HCl or between either dose of fexofenadine HCl and cetirizine. There was no major side effect, but the combined incidence of drowsiness or fatigue was greater with ce-tirizine (9%) than with placebo (4%) (P =.07) or fexofenadine (4%) (P =.02). CONCLUSIONS: Once-daily fexofenadine is thus a valuable addition to the nonsedating group of H(1) receptor antagonists currently available for the treatment of seasonal allergic rhinitis.""",1
9639,10558963,Increase in hepatitis C virus load in hemophiliacs during treatment with highly active antiretroviral therapy,"The effect of highly active antiretroviral therapy (HAART) on liver function and viral load of hepatitis C virus (HCV) was studied in 21 hemophilic men coinfected with HCV and human immunodeficiency virus (HIV). HCV RNA polymerase chain reaction was measured by branched DNA Quantiplex assay on frozen plasma samples obtained at baseline and at 24, 48, and 96 weeks after initiation of HAART. HCV RNA increased at 48 and 96 weeks after initiation of HAART therapy (198x105 Eq/mL [P=.03] and 227x105 Eq/mL [P<.0001], respectively, compared with baseline [141x105 Eq/mL]). This increase was associated with an increase in CD4 cell count and reduction in HIV viral load but no change in hepatic transaminases. With discontinuation of HAART, HCV RNA decreased as HIV RNA rebounded. Further study is required to clarify the histopathologic significance of this finding.",1
9640,10561265,High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993,"""PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.""",1
9641,10561345,Phase II study of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer,"""PURPOSE: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non-small-cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m(2)) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m(2)) after CPT-11 administration on day 1. RESULTS: Fifty-two patients were enrolled, including 33 men and 19 women. The median age was 61 years (range, 29 to 79 years). Southwest Oncology Group performance status was 0 in 12 patients, 1 in 32 patients, and 2 in eight patients. Eleven and 41 patients had stage IIIB and IV disease, respectively. Objective responses occurred in 28.8% of patients (15 of 52; 95% confidence interval, 16.5% to 41.2%). The median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%. Grade 3/4 adverse events consisted primarily of nausea (32. 7% ) or vomiting (13.5%), late-onset diarrhea (17.3%), and neutropenia (46.1%). The study design led to preferential modification of CPT-11 doses, resulting in CPT-11 dose attenuations to < or = 40 mg/m(2) in the majority of patients (31 of 52; 60%), whereas dose reductions of cisplatin were uncommon. CPT-11 pharmacokinetic parameters were comparable to those reported previously in single-agent studies. CONCLUSION: CPT-11/cisplatin is an active combination regimen with manageable toxicity in the therapy of stage IIIB/IV NSCLC. Future studies should be designed with schedules and dose modification provisions that avoid unnecessary CPT-11 dose reductions to exploit more directly the therapeutic synergy of these agents.""",1
9642,10561911,Hepatic tumor rupture following effectual treatment with irinotecan in a patient with highly refractory malignant lymphoma,"We describe a patient with highly refractory malignant lymphoma who died of hepatic tumor rupture following treatment with irinotecan (CPT-11). This 60-year-old man with non-Hodgkin's lymphoma (diffuse large B-cell lymphoma) demonstrated disease recurrence in the liver and the vertebrae following high-dose chemotherapy and autologous hematopoietic stem cell transfusion. He was treated with CPT-11 at a dose of one third of the conventional dose used for non-Hodgkin's lymphoma in Japan. The tumor in the liver markedly decreased in size but then ruptured. Although pathologic hepatic tumor rupture is a rare complication in patients with malignant lymphoma of the liver, this case demonstrates that hepatic tumor rupture may occur in refractory malignant lymphomas that reveal extensive degradation by this new, effective salvage therapy.",1
9643,10562933,[Nimesulide acute hepatitis: description of 3 cases],,1
9644,10566234,[Porphyria cutanea tarda after antineoplastic drugs],"Chronic hepatic porphyria is in some cases a paraneoplasia, in others part of the neoplastic disease. Sometimes it is, on the other hand manifested during antineoplastic treatment. Its development may be associated with this therapy. The presented case-history describes a female patient with breast cancer treated with antineoplastic agents, who developed a sporadic form of late cutaneous porphyria with a classical clinical and laboratory picture. The authors contemplate on the possible porphyrinogenic effect of antineoplastic agents, in particular cyclophosphamide and tamoxifen, which in the latter preparation was not described so far.",1
9645,10568423,Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid,"Sixty-six rheumatoid arthritis (RA) patients were analyzed retrospectively to assess the incidence and risk factors for elevation of serum hepatic aminotransferases during methotrexate (MTX) therapy. The effect of folate supplementation on serum ALT and RA activity was evaluated prospectively in 14 patients who showed a sustained high serum level of ALT. The frequency of elevation of serum AST or ALT was 4-5 times greater than in patients taking other DMARDs. Multivariate linear regression analysis demonstrated that elevation of ALT was independently associated with sex (female), obesity, baseline ALT, MTX dose, and gastrointestinal side effects. Folate supplementation caused ALT levels to decrease in all patients within 3 months. Eleven patients showed no change of RA activity, but 3 patients dropped out of the study because of the exacerbation of RA. These results suggest that careful monitoring of serum hepatic aminotransferases is necessary in patients with predisposing factors, especially those receiving more than 0.15 mg/kg of MTX weekly. Folate supplementation can reverse the sustained elevation of ALT, but might cause exacerbation of RA in some patients.",1
9646,10570561,Hepatitis from 5-methoxypsoralen occurring in a patient with previous flucloxacillin hepatitis,A 55-year-old woman with psoriasis vulgaris was treated with oral 5-methoxypsoralen and UVA photochemotherapy. After 40 treatments over 3 months she became unwell with hepatitis attributable to the psoralen. Six years earlier she developed cholestatic hepatitis to flucloxacillin. A previous history of drug-induced reactions should be sought before prescribing further drugs with similar adverse effects.,1
9647,10573201,"Phase I trial of gemcitabine (Gemzar), 24 h infusion 5-fluorouracil and folinic acid in patients with inoperable pancreatic cancer","Gemcitabine (Gemzar) has a significant impact upon survival and quality of life for patients with pancreatic cancer, compared with 5-fluorouracil (5-FU). This phase I study was initiated to define the recommended dose of 5-FU delivered as a 24 h infusion in combination with gemcitabine (1000 mg/m2) and folinic acid (200 mg/m2) in patients with inoperable pancreatic cancer, treated on an outpatient basis. Drugs were administered weekly for 4 weeks out of 6 weeks. Sixteen chemonaive patients (median age 59 years, range 51-66) were enrolled, 15 had stage IV and one stage III disease. The median Karnofsky performance score (KPS) was 70 (range 60-80). Six patients received 5-FU 750 mg/m2, eight received 5-FU 1000 mg/m2 and two received 5-FU 1250 mg/m2. The maximum tolerated dose of 5-FU was 1000 mg/m2. Hepatotoxicity was dose limiting. One patient who received 5-FU 1250 mg/m2 died as a result of hepatorenal failure. There was one partial response, nine patients had stable disease for more than 3 months and 13 patients had improved KPS. The median time to progressive disease was 31 weeks (range 5-50 weeks). A phase 11 trial is underway to further assess the activity of this combination at the recommended dose of 750 mg/m2 5-FU.",1
9648,10580751,Levothyroxine-induced liver dysfunction in a primary hypothyroid patient,"Here we report a case of levothyroxine-induced liver dysfunction. T4 (levothyroxine) has been more commonly used for the treatment of hypothyroidism than T3 active hormone (triiodothyronine), because with the former drug a stabler plasma concentration is obtained after oral administration. Although there are few reports on levothyroxine-induced liver dysfunction, we treated a primary hypothyroid patient with high serum aminotransferase after administration of levothyroxine. Liver dysfunction was improved after cessation of the drug administration. Antibody to T4 was found in the serum of the patient after this event. From clinical course and laboratory data of the patient, the episode of liver damage was considered to be induced by levothyroxine. We then administrated triiodothyronine, and it did not induce liver dysfunction. Changing levothyroxine to triiodothyronine resulted in a successful clinical course in this case, as re-administration of the doubtful drug is strictly limited.",1
9649,10584584,Three new herbal hepatotoxic syndromes,,1
9650,10587720,[Acute hepatitis in the course of cyclosporine therapy of Crohn's disease],"BACKGROUND: Cyclosporin is used for the treatment of corticosteroid-resistant inflammatory bowel disease. Secondary liver disease is a risk. CASE REPORT: Acute hepatitis with predominant major transaminase elevation occurred in a patient treated with cyclosporin for corticosteroid-resistant Crohns disease. No viral, alcoholic, autoimmune or metabolic cause could be incriminated. Complete cure was achieved after withdrawal of cyclosporin. DISCUSSION: Only one case of cholestatic hepatitis has been reported in chronic inflammatory bowel disease. Cyclosporin was the probable cause in our case as other causes of acute hepatitis were ruled out and withdrawal led to cure. Cyclosporin can induce abnormal liver tests in 25% of cases. If reducing dose does not lead to improvement, it may be necessary to discontinue cyclosporin. Regular liver tests would thus be required for patients given cyclosporin for chronic inflammatory bowel disease.",1
9651,10592073,Ceftriaxone-associated nephrolithiasis and biliary pseudolithiasis,"Biliary pseudolithiasis has been reported in patients who received ceftriaxone therapy. In addition to biliary sludge formation occasional reports of ceftriaxone-induced nephrolithiasis have been published. In general, these adverse effects will develop after seven to ten days of treatment. We report on a seven-year-old boy with ceftriaxone-associated biliary pseudolithiasis and nephrolithiasis four days after initiation of treatment. Patients receiving a high dose of ceftriaxone and developing colicky abdominal pain should be considered for ultrasound and a change in antibiotic therapy if appropriate.",1
9652,10594489,A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs,"AIMS: The aim of this cohort study was to estimate the risk of clinical acute liver injury among users of oral antifungals identified in the general population of the General Practice Research Database in UK. METHODS: The cohort included 69 830 patients, 20-79 years old, free of liver and systemic disease, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine between 1991 and 1996. RESULTS: Sixteen cases of acute liver injury were identified and validated. Ten cases occurred during nonuse of oral antifungals with a background rate of 0.6 per 100,000 person-months (95% confidence interval 0.3,1.1). Five cases occurred during current use of oral antifungals. Two were using ketoconazole, another two itraconazole, and one terbinafine. Incidence rates of acute liver injury were 134.1 per 100 000 person-months (36.8,488.0) for ketoconazole, 10.4 (2.9-38.1) for itraconazole, and 2.5 (0.4,13. 9) for terbinafine. The remaining case was associated with past use of fluconazole. Ketoconazole was the antifungal associated with the highest relative risk, 228.0 (95% confidence interval 33.9,933.0), when compared with the risk among nonusers, followed by itraconazole and terbinafine with relative risks of 17.7 (2.6,72.6) and 4.2 (0.2, 24.9), respectively. CONCLUSIONS: Ketoconazole and itraconazole were the two oral antifungal associated with a marked increase of clinical acute liver injury. The risk associated with ketoconazole should be taken into account when prescribing it as initial treatment for uncomplicated fungal infections.",1
9653,10599404,[Carbamazepine-induced hepatitis. A case report],"A 59 years old man jaundice, haemathologic disturbances and Splenomegaly, with epilepsy treated by Carbamazepine in the last 3 weeks is reported. He had a positive response to withdrawal carbamazepine and corticotherapy.",1
9654,10604263,Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results,"""Previous chemotherapy trials in hormone refractory prostate cancer have resulted in low response rates and minimal survival impact. Clearly, better agents are needed to improve outcomes in such patients. Microtubule inhibitors have been a recent focus of investigation as chemotherapeutic agents in prostate cancer; in tissue culture, docetaxel (Taxotere; Rhone-Poulenc Rorer, Collegeville, PA) appears to be the most active of these drugs. Patients enrolled in this trial had hormone refractory prostate cancer and were required to have progressive disease despite hormonal therapy and, if previously treated with antiandrogens, have progressive disease despite antiandrogen withdrawal. Patients had not been exposed to any prior chemotherapy. Testosterone suppression was continued during the trial when patients received docetaxel at 75 mg/m2 every 21 days. Thirty-five patients with ages ranging from 49 to 85 years (median age, 70 years) were enrolled in the trial. Three hundred twelve treatments have been given (median, six treatments), with a minimum follow-up of 4 months. The median prostate-specific antigen (PSA) at the time of entry was 96 ng/mL (range, 24 to 2,070 ng/mL). Seven patients (20%) have had a more than 80% decline in PSA and 16 (46%) have had a more than 50% decline. Six additional patients have had a PSA decline of 40% to 50%. Soft tissue disease was seen in 25 of 35 patients. One patient had a complete response; three others had a nearly complete response. Three patients met criteria for a partial response, yielding a 28% response rate with measurable disease. Three additional patients had substantial shrinkage and 12 had prolonged stable disease. Combining both PSA and soft tissue responses, one complete response and five partial responses were seen. Substantial responses, defined as a more than 40% PSA decline and a more than 50% reduction of bidimensional cross-products in patients with measurable disease, were seen in 17 of 35 patients enrolled. Responses were maintained for a median of 9 months (range, 2 to 24 months). The median overall survival was 27 months. Three patients remain under therapy. Toxicity remained tolerable throughout the treatment. Grade 4 toxicities requiring discontinuation of treatment included stomatitis, small bowel obstruction, and a gluteal abscess. There were two deaths during the study: one due to lung toxicity/pneumonia and one due to pulmonary embolus. The patient with lung toxicity had markedly elevated transaminases with marked involvement of the liver with tumor. Six patients stopped voluntarily due to fatigue or edema Other common toxicities were neutropenia, anemia, mild edema and hyperglycemia (due to steroids), anorexia, myalgias, and mild alopecia The responses seen in this population are very encouraging and suggest substantial durable activity for docetaxel as single-agent therapy for hormone refractory prostate cancer.""",1
9655,10606333,Severe cholestasis related to intraconazole for the treatment of onychomycosis,"We describe a case of prolonged cholestasis temporally associated with the use of itraconazole for onychomycosis. Peak bilirubin level of 32.0 mg/dl was documented approximately 2 months after discontinuation of the patient's itraconazole therapy, with symptoms of cholestasis persisting more than 1 month after the peak in bilirubin. Physicians should be aware of the potential for severe cholestasis associated with itraconazole usage.",1
9656,10607813,Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group,"BACKGROUND: Immune responses mediated by IgE are important in the pathogenesis of allergic asthma. A recombinant humanized monoclonal antibody (rhuMAb-E25) forms complexes with free IgE and blocks its interaction with mast cells and basophils. We studied the efficacy of rhuMab-E25 as a treatment for moderate-to-severe allergic asthma. METHODS: After a 4-week run-in period, we randomly assigned 317 subjects (age range, 11 to 50 years) who required inhaled or oral corticosteroids (or both) to receive either placebo or one of two regimens of rhuMAB-E25: high-dose rhuMAb-E25 (5.8 microg per kilogram of body weight per nanogram of IgE per milliliter or low-dose rhuMAb-E25 (2.5 microg per kilogram per nanogram of IgE per milliliter) intravenously on days 0 (half a dose), 4 (half a dose), and 7 (full dose) and then once every 2 weeks thereafter for 20 weeks. For the first 12 weeks of the study, the subjects continued the regimen of corticosteroids they had received before enrollment. During the following eight weeks, the doses of corticosteroids were tapered in an effort to discontinue this therapy. The primary outcome measure was an improvement in the asthma symptom score at 12 weeks, according to a 7-point scale, in which a score of 1 indicated no symptoms and a score of 7 the most severe symptoms. RESULTS: A total of 106 subjects were assigned to receive a high dose of rhuMAb-E25, 106 were assigned to receive a low dose, and 105 were assigned to receive placebo. At base line, the mean asthma symptom score was 4.0. After 12 weeks of therapy, the mean (+/-SE) scores were 2.8+/-0.1 in the high-dose group (P=0.008) and 2.8+/-0.1 in the low-dose group (P=0.005), as compared with 3.8+/-0.1 in the placebo group. At 20 weeks, the mean scores were 2.7+/-0.1 in both the high-dose group (P=0.048) and the low-dose group (P=0.14), as compared with 2.9+/-0.1 in the placebo group. More subjects in the two rhuMAb-E25 groups were able to decrease or discontinue their use of corticosteroids than in the placebo group, but only some of the differences were significant. After 20 weeks, serum free IgE concentrations decreased by a mean of more than 95 percent in both rhuMAb-E25 groups. The therapy was well tolerated. After 20 weeks, none of the subjects had antibodies against rhuMAb-E25. CONCLUSIONS: A recombinant humanized monoclonal antibody directed against IgE has potential as a treatment for subjects with moderate or severe allergic asthma.",1
9657,10612272,"Anticonvulsant hypersensitivity syndrome: incidence, prevention and management","""Although the anticonvulsant hypersensitivity syndrome was first described in 1950, confusion still abounds regarding the syndrome. The triad of fever, rash and internal organ involvement occurring 1 to 8 weeks after exposure to an anticonvulsant heralds this rare (1 in 1,000 to 10,000 exposures) but serious reaction. Aromatic anticonvulsants [phenytoin, phenobarbital (phenobarbitone) and carbamazepine] are the most frequently involved drugs; however, there have also been several cases of anticonvulsant hypersensitivity syndrome associated with lamotrigine. Fever, in conjunction with malaise and pharyngitis, is often the first sign. This is followed by a rash which can range from a simple exanthem to toxic epidermal necrolysis. Internal organ involvement usually involves the liver, although other organs such as the kidney, CNS or lungs may be involved. Hypothyroidism may be a complication in these patients approximately 2 months after occurrence of symptoms. The aromatic anticonvulsants are metabolised to hydroxylated aromatic compounds, such as arene oxides. If detoxification of this toxic metabolite is insufficient, the toxic metabolite may bind to cellular macromolecules causing cell necrosis or a secondary immunological response. Cross-reactivity among the aromatic anticonvulsants may be as high as 75%. In addition, there is a familial tendency to hypersensitivity to anticonvulsants. Discontinuation of the anticonvulsant is essential in patients who develop symptoms compatible with anticonvulsant hypersensitivity syndrome. A minimum battery of laboratory tests, such as liver transaminases, complete blood count and urinalysis and serum creatinine, should be performed. Corticosteroids are usually administered if symptoms are severe. Patients with anticonvulsant hypersensitivity syndrome should avoid all aromatic anticonvulsants; benzodiazepines, valproic acid (sodium valproate) or one of the newer anticonvulsants can be used for seizure control. However, valproic acid should be used very cautiously in the presence of hepatitis. There is no evidence that lamotrigine cross-reacts with aromatic anticonvulsants. In addition, family counselling is a vital component of patient management.""",1
9658,10615231,A double-blind comparison of fluconazole and nystatin in the prevention of candidiasis in patients with leukaemia. Antifungal Prophylaxis Study Group,"""In this multicentre, randomised, double-blind study, the safety and efficacy of oral fluconazole (200 micrograms/day) and nystatin suspension (6,000,000 IU/day) for the prevention of fungal infections were compared in patients with leukaemia undergoing remission induction chemotherapy. Antifungal prophylaxis was initiated at the time chemotherapy was started and continued throughout the hospital stay or the period of neutropenia to a maximum of 42 days. Prophylaxis was successful (no evidence of fungal infection or fever of unknown origin unresponsive to antibiotics) in 38 of 56 (68%) fluconazole-treated and 25 of 53 (47%) nystatin-treated patients (P = 0.03). 2 patients (4%) in the fluconazole group and 6 (11%) patients in the nystatin group developed systemic fungal infections (P = 0.15). The overall frequency of adverse events was similar among fluconazole-treated (29%) and nystatin-treated (32%); most events in both treatment groups involved the gastrointestinal tract. These results indicated fluconazole was more effective than nystatin in preventing Candida infections in patients with leukaemia; fluconazole was well tolerated.""",1
9659,10619755,Lactic acidosis associated with stavudine administration: a report of five cases,"""Type """"B"""" lactic acidosis has been described in patients receiving the nucleoside analogs zidovudine, didanosine, and fialuridine. Lactic acidosis has also been described in 4 patients receiving combination therapy with stavudine and lamivudine. We describe the development of chronic type """"B"""" lactic acidosis in 3 patients receiving stavudine as a single agent and in 2 patients receiving combination therapy with stavudine and either lamivudine or delavirdine, a nonnucleoside analog. All patients presented with abdominal pain, vomiting, and hepatic steatosis. Other signs of mitochondrial toxicity included pancreatitis and myopathy (2 cases). The mean duration of stavudine therapy was 9.4 months, and the mean observed peak lactate level+/-SD was 10.3+/-5 mmol/L. After discontinuation of stavudine treatment, lactic acidosis improved in 4 patients after 4-60 weeks, and 1 patient died. Evaluations for other causes of lactic acidosis, including hypoxemia, malignancy, sepsis, and cardiogenic shock, were negative.""",1
9660,10620103,Chronic intoxication by doxycycline use for more than 12 years,"We report the clinical case of a 12-years' intoxication by doxycycline. A patient with a depersonalization and derealization syndrome took 1 g doxycycline per day. In addition to hepatocellular necrosis with cholestasis, nephrotoxicity, leukopenia, anaemia and skin hyperpigmentation he suffered from hitherto unreported adverse cardiac events as intermittent supraventricular tachycardia and sporadic Wenckebach heart block. Despite a long period of self-medication these side-effects were reversible.",1
9661,10626521,Incidence of ceftriaxone-associated gallbladder pseudolithiasis,"We prospectively evaluated the incidence of gallbladder pseudolithiasis in children treated with high doses of ceftriaxone for a variety of serious infections. We also monitored the time interval needed for this phenomenon to develop and resolve completely after initiation and cessation of treatment, respectively. Included in this study are 44 children treated with ceftriaxone 100 mg/kg/d divided into 2 equal intravenous doses and followed by serial abdominal sonography. Eleven children developed pseudolithiasis of gallbladder 2-9 d after initiation of ceftriaxone therapy. Six children (54.5%) developed this complication within the first 3 d. Lithiasis completely resolved 8-23 d after the end of treatment. In conclusion, pseudolithiasis of the gallbladder developed in 25% of sick children and completely resolved in all patients. Early development of this complication was not exceptional. It occurred in more than half of these children.",1
9662,10630451,Minocycline-induced hepatitis,,1
9663,10631475,"Hepatic toxicity from cyclophosphamide, methotrexate, fluorouracil (CMF regimen)",,1
9664,10632283,Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection,"""CONTEXT: Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus. OBJECTIVES: To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development. DESIGN: Prospective cohort study. SETTING: University-based urban HIV clinic. PATIENTS: A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively. MAIN OUTCOME MEASURE: Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy. RESULTS: Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9% -44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir(6.8%; 95% CI, 3.0%-13.1 %). Although chronicviral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05 x 10(9)/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity. CONCLUSIONS: Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus.""",1
9665,10636987,Rapidly progressive cholestasis: An unusual reaction to amoxicillin/clavulanic acid therapy in a child,Hepatotoxity associated with amoxicillin/clavulanic acid is usually a self-limited disease with complete recovery. We report a rapidly progressing liver disease with ductopenia and portal fibrosis in a 3-year-old boy treated with Augmentin.,1
9666,10638597,Tamoxifen-induced transient multifocal hepatic fatty infiltration,"Tamoxifen is one of the most commonly used anticancer medications. Hepatic damage secondary to tamoxifen treatment is rare. Tamoxifen-induced multifocal hepatic fatty infiltration has not been reported previously. This report describes one case of steatohepatitis caused by tamoxifen in an elderly woman with a history of breast cancer. The patient had multifocal hepatic fatty infiltration secondary to tamoxifen therapy. After tamoxifen was discontinued, the features of multifocal hepatic fatty infiltration on CT improved dramatically, and hepatic transaminases normalized.",1
9667,10642628,[Acute severe fibrosing hepatitis associated with ciprofibrate treatment],,1
9668,10643355,[Hepatic toxicity of nitrofurantoin. Cases reported to the Center for Monitoring Adverse Drug Reactions 1968-1998],"""Forty-four cases of nitrofurantoin-associated hepatic injury were reported to the Danish Center for Monitoring of Adverse Drug reactions from 1968 to 1998. Forty-one were women with a median age of 69 years. They had been treated with nitrofurantoin for median one year (two days-seven years), and all had biochemical and clinical signs of hepatitis. In five cases the injury had been provoked by a rechallenge. Twenty-seven liver biopsies showed an equal amount of acute and chronic histopathological changes. Cirrhosis was diagnosed in seven cases. Four died in liver failure; the others apparently recovered without long-term symptoms. In rare cases, nitrofurantoin can cause toxic hepatitis. Apparently elderly women in long-term treatment are more sensitive to develop this adverse reaction. The drug should be withdrawn if the patient shows any signs of hepatitis during treatment and the patient should be informed about the possible relationship to nitrofurantoin exposure. Rechallenge should not be performed.""",1
9669,10644272,Hepatic failure in a patient taking rosiglitazone,"BACKGROUND: Rosiglitazone maleate is the second approved oral hypoglycemic agent of the thiazolidinedione class. The first, troglitazone, has been associated with liver failure, occasionally resulting in liver transplantation or death. There have been no reports to date of rosiglitazone-associated elevations in the alanine aminotransferase level or hepatotoxicity. OBJECTIVE: To report the clinical characteristics of liver failure developing in a patient receiving rosiglitazone. DESIGN: Case report. SETTING: University hospital. PATIENT: 69-year-old man taking rosiglitazone, 4 mg/d. INTERVENTION: Discontinuation of rosiglitazone therapy and treatment with lactulose, vitamin K, fresh frozen plasma, ventilatory assistance, and intensive care unit support. MEASUREMENTS: Blood test monitoring, including toxicology screening, liver function tests, coagulation studies, serum chemistries, and complete blood counts. RESULTS: After 21 days of rosiglitazone therapy, hepatic failure developed. Other causes of hepatic failure, such as viruses and toxins, were excluded, although it is possible that congestive heart failure was also a causative factor. The patient recovered fully with supportive care. CONCLUSION: Rosiglitazone may be associated with hepatic failure.",1
9670,10644281,Rosiglitazone and hepatic failure,,1
9671,10647752,St John's wort for depression: a systematic review,"To address whether St John's wort is useful for the treatment of depression we attempted to retrieve all English-language articles with data on the efficacy, safety, and availability of St John's wort. Randomized, controlled, double-blind trials were selected and assessed for methodological quality using a standardized checklist, and data on pharmacology, cost, regulation, and safety were extracted. Eight studies were identified, found to be of generally good methodological quality, and determined to provide a modest amount of data to suggest that St John's wort is more effective than placebo in the treatment of mild to moderate depression. The absolute increased response rate with the use of St John's wort ranged from 23% to 55% higher than with placebo, but ranged from 6% to 18% lower compared with tricyclic antidepressants. More data are required to assess both its use in severe depression and its efficacy compared with other antidepressants. Rates of side effects were low. As a dietary supplement, St John's wort is currently largely unregulated, but the Food and Drug Administration is reviewing plans to tighten its regulatory oversight.",1
9672,10653871,Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients,"""PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program. PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m(2) every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis. RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P <. 05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction. CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.""",1
9673,10656221,Gliclazide-induced acute hepatitis,"There are few reports in the literature related to sulfonylurea-induced hepatotoxicity. We describe the case of acute hepatitis induced by gliclazide, a second generation sulfonylurea. A 60-year-old woman with diabetes mellitus (type 2) developed an acute icteric hepatitis-like illness 6 weeks after the initiation of gliclazide therapy. Other causes of acute hepatocellular necrosis were excluded. Liver histology showed marked portal inflammation with lymphocytes, monocytes and eosinophils, associated with lobular inflammation (indicative of a histological pattern consistent with drug-induced hepatitis). The drug was immediately withdrawn and the patient was given glibenclamide. The patient recovered clinically and, in less than 4 weeks, her serum bilirubin and aminotransferases returned to normal levels. We believe that this is the first description of acute hepatitis caused by an idiosyncratic adverse reaction to gliclazide or to one of its metabolites. In conclusion, this case strongly suggests that gliclazide can induce acute icteric liver necro-inflammation which may be misdiagnosed clinically as acute viral hepatitis. In patients who show abnormal liver function tests, the immediate discontinuation of gliclazide is recommended.",1
9674,10660405,Acute eosinophilic hepatitis from trovafloxacin,,1
9675,10663024,"[Stevens-Johnson syndrome with transition to toxic epidermal necrolysis after carbamazepine administration, heroin and alcohol abuse]","A 28 year old patient developed a severe bullous exanthem and enanthem combined with hepatitis, fever and blood count abnormalities after taking carbamazepine and consumption of heroin and alcohol. After discontinuing carbamazepine, prednisolone was given over a five day period accompanied by intravenous fluid and electrolyte substitution and local therapy which lead to improvement. Severe bullous skin reactions nowadays are classified into erythema exsudativum multiforme majus (EEMM), Stevens-Johnson syndrome (SJS), overlap Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS/TEN), TEN with maculae and TEN on large erythema, and they are most often caused by antibiotics and anticonvulsant drugs. Heroin and alcohol abuse alters host immunity which subsequently may increase susceptibility to allergic reactions. There is a high (40%) mortality rate for TEN, and patients with organ involvement are at increased risk.",1
9676,10669183,Toxic epidermal necrolysis associated with acetaminophen ingestion,"OBJECTIVE: To report a case of toxic epidermal necrolysis (TEN) associated with acetaminophen ingestion. SUMMARY: A seven-year-old girl developed TEN after acetaminophen ingestion. The diagnosis was based on clinical evaluation and skin biopsy. A later acetaminophen challenge, undertaken by an allergist who questioned the diagnosis, resulted in a similar skin reaction. DISCUSSION: TEN is a severe disease with a high mortality rate. TEN may be either idiopathic or associated with several clinical conditions, such as viral infections, autoimmune disorders, malignancy, and drug hypersensitivity. Because of the rarity of its association with acetaminophen, the diagnosis in our patient was questioned by an allergist who performed an oral acetaminophen rechallenge test despite the potential risk. This caused a severe skin reaction that required rehospitalization. CONCLUSIONS: TEN can be caused by over-the-counter medications such as acetaminophen. Rechallenge with the causative drug carries a risk of severe complications and should be avoided.",1
9677,10669206,Potential hepatotoxicity of lamotrigine,"""Lamotrigine is a new antiepileptic drug that is effective for a broad range of seizures in adults and children. Three children with seizures of different causes who were treated with lamotrigine and developed reversible hepatotoxicity are reported. In one child, this therapy led to relatively severe hepatic failure that required and responded to aggressive therapy. Unlike most of the previously reported six patients with similar severe hepatic involvement, this patient's liver function and blood hepatic enzymes became normal. All three patients were on multiple drugs, and two were in epilepsia partialis continua secondary to encephalitis. Two of the patients had relatively rapid medication titration schedules. The close time relationship between the initiation of the lamotrigine therapy and the reversal of the liver abnormalities with lamotrigine discontinuation argues against a cause other than the lamotrigine; however, because of the complexity of the reported cases, the causality remains an assumption. Review of the literature revealed six other previously reported patients (five adults and one child) who had hepatotoxicity during lamotrigine therapy, with or without associated multisystem failure, and similar patient profiles. Lamotrigine is generally a safe and effective medication; however, it should be used with caution in patients on polytherapy and in those with complicated acute systemic and central nervous system conditions, such as fever, status epilepticus, epilepsia partialis, and encephalitis.""",1
9678,10671757,Flucytosine: correlation between toxicity and pharmacokinetic parameters,"Flucytosine (5-fluorocytosine, 5-FC) is a systemic antimycotic drug the major toxicities of which are bone marrow depression and hepatotoxicity. The purpose of this observational and retrospective study was to assess a possible relationship between toxicity and 5-FC pharmacokinetics within a group of 53 intensive care unit patients. The presented results reveal that thrombocytopenia is associated with a decreased 5-FC clearance and that the thrombocyte nadir is linearly related to the 5-FC clearance. Furthermore, patients experiencing 5-FC levels exceeding 100 mg 5-FC/l were found to be at a higher risk of developing thrombocytopenia and hepatotoxicity as compared to those not exceeding this level.",1
9679,10673086,Fatal hepatitis associated with nimesulide,,1
9680,10677134,Multiple organ failure related to pantoprazole,,1
9681,10682129,Acute hypersensitivity with delavirdine,,1
9682,10685763,Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity,"Trazodone (Desyrel) is a second-generation, nontricyclic antidepressant that has been in use in North America since the early 1980s. It has the advantage of being more sedating and having less anticholinergic side effects than other secondary amines in the piperazine class, namely, desipramine and nortriptyline. Five previous cases of trazodone hepatotoxicity have been reported in the literature, one describing chronic damage and the others, more acute cellular and cholestatic injury. We describe a case of acute reversible liver injury with the use of trazodone. This case is unique in that injury occurred after protracted (18 months) drug use and while the patient was on corticosteroids. Moreover, the diagnosis was confirmed by an inadvertent challenge with trazodone. This case reports not only a well documented instance of trazodone-induced liver injury, but also serves as a basis for a brief discussion of mechanisms, clinical monitoring, and therapy in drug-induced hepatotoxicity.",1
9683,10685778,Fatal hepatitis associated with ranitidine,,1
9684,10686190,"""A double-blind, randomized study to compare recombinant human follicle stimulating hormone (FSH; Gonal-F) with highly purified urinary FSH (Metrodin) HP) in women undergoing assisted reproductive techniques including intracytoplasmic sperm injection. The French Multicentre Trialists""","""This prospective, double-blind, randomized, multicentre study compared the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH; Gonal-F((R))) versus highly purified urinary FSH (u-hFSH HP; Metrodin((R)) HP) in women undergoing ovarian stimulation for in-vitro fertilization, including intracytoplasmic sperm injection. A total of 278 patients began a long gonadotrophin-releasing hormone agonist protocol, then 139 received r-hFSH and 139 u-hFSH HP, 150 IU/day administered s.c., for the first 6 days of treatment. On day 7, the dose was adjusted, if necessary, according to ovarian response. Human chorionic gonadotrophin (HCG, 10 000 IU, s.c.) was administered once there was more than one follicle 18 mm in diameter and two others >/=16 mm. Oocyte retrieval was performed 36-38 h after HCG injection: 128 patients (92%) receiving r-hFSH and 113 (81%) receiving u-hFSH HP had at least one oocyte retrieved. Among patients receiving r-hFSH, there was a significantly higher mean (+/- SD) number of oocytes retrieved (11.0 +/- 5.9 versus 8.8 +/- 4.8 with u-hFSH HP; P = 0. 002) and mean number of embryos obtained (5.1 +/- 3.7 versus 3.5 +/- 2.9 with u-hFSH HP; P = 0.0001). With r-hFSH, significantly fewer FSH treatment days (11.7 +/- 1.9 versus 14.5 +/- 3.3) and 75 IU ampoules (27.6 +/- 10.2 versus 40.7 +/- 13.6) were required than with u-hFSH HP (P = 0.0001). Embryo replacement on day 2-3 after oocyte retrieval resulted in 36 liveborn children in the Gonal-F((R)) group and 33 in the Metrodin HP((R)) group (not significant). There were seven cases (5.0%) of ovarian hyperstimulation syndrome in the r-hFSH group and three (2.2%), in the u-hFSH HP group (not significant). It is concluded that r-hFSH is more effective than u-hFSH in inducing multiple follicular development.""",1
9685,10687989,An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer,"PURPOSE: The administration of gonadotropin hormone-releasing hormone agonists is well established for treating metastatic prostate cancer. In an ongoing study we evaluated the effect of a long acting implant that releases the gonadotropin hormone-releasing hormone agonist histrelin ([ImBzl]D-His6,Pro9-Net) in 15 patients with disseminated prostate cancer. MATERIALS AND METHODS: The 2.6 cm. implant releasing 60 microg. histrelin daily is inserted subcutaneously into the upper arm using local anesthesia. Of the patients 8 received 1 and the remainder received 2 implants. Treatment with the antiandrogen flutamide or cyproterone acetate began 2 weeks before implant insertion and continued for up to 12 weeks. Testosterone, luteinizing hormone (LH) and prostate specific antigen were determined monthly, and a metastatic evaluation was performed every 6 months. RESULTS: LH and testosterone increased after flutamide administration and decreased after implant insertion. By day 28 LH and testosterone were completely suppressed. LH and testosterone decreased immediately after cyproterone acetate administration. Prostate specific antigen began to decrease during antiandrogen therapy and decreased further after implant insertion. One patient requested implant removal after 1 year for personal reasons and 1 died of an unrelated cause 18 months after insertion. Escape was demonstrated in 4 cases at 5, 10, 12 and 19 months, although LH and testosterone remained suppressed. Duration of treatment in the remaining 9 patients was between 21 and 30 months. LH and testosterone remained completely suppressed and prostate specific antigen levels were in the normal range. The clinical and biochemical response was identical in those who received 1 or 2 implants. At 12 months 8 patients were challenged at intermittent intervals for up to 24 months with a bolus of 100 microg. gonadotropin hormone-releasing hormone followed by 2 weeks of flutamide. The response was compared with that in untreated controls recently diagnosed with prostate cancer. Unlike controls there was complete LH suppression in the 8 challenged patients. CONCLUSIONS: A histrelin implant suppresses LH and testosterone in prostate cancer for up to 30 months. This finding represents a significant improvement over existing preparations, which must be administered at 1 to 3-month intervals.",1
9686,10690140,"Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies","Metoclopramide has been used for almost 40 yr to prevent postoperative nausea and vomiting (PONV). We have reviewed the efficacy and safety of metoclopramide for the prevention of PONV. A systematic search (MEDLINE, EMBASE, manufacturers' databases, hand searching, bibliographies, all languages, up to June 1998) was performed for full reports of randomized comparisons of metoclopramide with placebo in surgical patients. Relevant end-points were prevention of early PONV (within 6 h after operation), late PONV (48 h) and adverse effects. Combined data were analysed using relative benefit/risk and number-needed-to-treat/harm. In 66 studies, 3260 patients received 18 different regimens of metoclopramide, and 3006 controls received placebo or no treatment. There was no evidence of dose-responsiveness with oral, i.m., intranasal or i.v. metoclopramide in children and adults. In adults, the best documented regimen was 10 mg i.v. There was no significant anti-nausea effect. The numbers-needed-to-treat to prevent early and late vomiting were 9.1 (95% confidence intervals 5.5-27) and 10 (6-41), respectively. In children, the best documented regimen was 0.25 mg kg-1 i.v. The number-needed-to-treat to prevent early vomiting was 5.8 (3.9-11). There was no significant late anti-vomiting effect. Minor drug-related adverse effects (sedation, dizziness, drowsiness) were not significantly associated with metoclopramide. There was one adult who experienced extrapyramidal symptoms with metoclopramide.",1
9687,10691596,Venlafaxine-associated hepatitis,,1
9688,10695637,Hepatic injury due to troglitazone,,1
9689,10696231,Entacapone for Parkinson's disease,,1
9690,10697032,Paclitaxel/gemcitabine administered every two weeks in advanced breast cancer: preliminary results of a phase II trial,"""The purpose of this study was to evaluate the toxicity and efficacy of paclitaxel/gemcitabine administered every 2 weeks in the first-line treatment of advanced breast cancer. Forty-three chemonaive patients with histologically confirmed metastatic breast carcinoma were enrolled. Patients received paclitaxel 150 mg/m2 followed by gemcitabine 2,500 mg/m2, both on day I of a 14-day cycle, for a maximum of eight cycles. Thirty-four patients were evaluable for toxicity; 38 were evaluable for efficacy. The median age at the time of diagnosis was 54 years, the median performance status was 90, and the median number of lesions was three. Most patients (71%) had received prior adjuvant therapy. Grade 3 and 4 toxicity was limited to leukocytes (14% and 18%, respectively). Grade 3 toxicities (5% each) were thrombocytopenia, nausea and vomiting, elevation of aspartate transaminase, neurosensory, and constipation. One patient had neutropenia and fever. The objective response rate was 68% (21% complete response and 47% partial response); 18% had stable disease and 13% had partial disease. The preliminary evaluation of paclitaxel/gemcitabine given as a 2-week schedule to patients with untreated advanced breast carcinoma shows encouraging activity and a favorable toxicity profile.""",1
9691,10699540,How useful is docusate in patients at risk for constipation? A systematic review of the evidence in the chronically ill,"The effectiveness of docusate for constipation has not been studied in the terminally ill. Controversy also exists concerning its effectiveness in the chronically ill. Because chronically ill patients and terminally ill patients have several risk factors for constipation in common, we undertook a systematic review of prospective controlled trials of oral docusate in the chronically ill to clarify the utility of this drug in populations with advanced disease. The data sources were Medline 1966-April 1997, CINAHL 1982-April 1997, Current Contents August 1996-April 1997, Cochrane Library, a hand search of Index Medicus 1940-1966, three palliative care journals, references in relevant articles and texts, and direct contact with experts. Prospective controlled trials evaluating oral docusate in humans with chronic illness and identifiable risk factors for, or preexisting, constipation were selected. Only materials abstracted in English or French were considered. Information was collected by two independent reviewers and included patient demographic data, study design, dose of docusate, outcomes of stool consistency, stool frequency, need for other laxatives, and assessment of methodologic and reporting quality. Of nine identified studies, four were eligible. These incorporated three different designs and sample sizes that ranged from 15 to 74. Quality assessment scores were low (range 0.46-0.52 with a perfect score being 1.0). Three studies were flawed in blinding of treatment allocation and the use of co-interventions. All studies showed a small trend toward increased stool frequency on docusate. Because of significant clinical heterogeneity in the identified studies, pooled data analysis was not feasible. At present, the use of docusate for constipation in palliative care is based on inadequate experimental evidence. Randomized controlled trials with chronically ill patients and patients with advanced disease are needed to determine its role in prevention and treatment of constipation.",1
9692,10702207,Oral contraceptive use and focal nodular hyperplasia of the liver,"""BACKGROUND & AIMS: Because most patients with focal nodular hyperplasia (FNH) are young women, an important decision is whether to discontinue oral contraceptive (OC) use. The aims of this study were to evaluate (1) the number and size of FNH lesions in women with various patterns of OC use and in women without OC use and (2) the modifications in the number and size of FNH lesions during follow-up, according to OC use. METHODS: In a 9-year study in 216 women with FNH, the diameter and number of lesions documented by magnetic resonance (MR) imaging were evaluated (1) at diagnosis according to OC use as follows: group A, no OC use (n = 28); group B, high-dose OC use (n = 46); group C, low-dose OC use (n = 98); group D, successive use of high-dose and low-dose OCs (n = 33); and group E, use of progestogens only (n = 11); and (2) during follow-up in 136 women, 14 of whom were OC nonusers who stayed off OCs, 89 discontinued OC use, 26 took low-dose OCs, and 7 stayed on a progestogen only. Twelve women became pregnant. In 168 women, the diagnosis of FNH was made based on a combination of rigorously defined MR criteria. In the remaining 48 patients, diagnosis was by surgical biopsy (n = 36) or resection (n = 12). Mean diameter and number of lesion(s) per patient were assessed by MR imaging using the same protocol in all study patients. RESULTS: No significant differences in the number or size of lesions were found in the 5 patient groups. During follow-up, a change in lesion diameter occurred in only 4 women; this event was not influenced by OC use. In the 12 patients who became pregnant, lesion size was unchanged after delivery, pregnancy was uneventful, and delivery occurred spontaneously. CONCLUSIONS: These data suggest that (1) neither the size nor the number of FNH lesions are influenced by OC use; (2) size changes during follow-up are rare and do not seem to depend on OC use; and (3) pregnancy is not associated with FNH changes or complications.""",1
9693,10707883,Fatal lactic acidosis and liver steatosis associated with didanosine and stavudine treatment: a respiratory chain dysfunction?,,1
9694,10710110,Cumulative hepatotoxicity induced by continuous low-dose cyclophosphamide therapy,,1
9695,10714568,Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study,"OBJECTIVE: To study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen. DESIGN: The ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection. METHODS: HIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected. RESULTS: Seven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time. CONCLUSIONS: The quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory.",1
9696,10715303,Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas,"""PURPOSE: This multicenter phase II study evaluated the efficacy, dosimetry methodology, and safety of iodine-131 tositumomab in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients received a dosimetric dose that consisted of 450 mg of anti-B1 antibody followed by 35 mg (5 mCi) of iodine-131 tositumomab. Serial total-body gamma counts were then obtained to calculate the patient-specific millicurie activity required to deliver the therapeutic dose. A therapeutic dose of 75 cGy total-body dose (attenuated to 65 cGy in patients with platelet counts of 101,000 to 149,000 cells/mm(3)) was given 7 to 14 days after the dosimetric dose. RESULTS: Forty-five of 47 patients were treated with a single dosimetric and therapeutic dose. Twenty-seven patients (57%) had a response. The response rate was similar in patients with low-grade (57%) or transformed low-grade (60%) NHL. The median duration of response was 9.9 months. Fifteen patients (32%) achieved a complete response (CR; 10 CRs and five clinical CRs), including five patients (50%) with transformed low-grade NHL. The median duration of CR was 19.9 months, and six patients have an ongoing CR. Treatment was well tolerated, with the principal toxicity being hematologic. The most common nonhematologic toxicities that were considered to be possibly related to the treatment included mild to moderate fatigue (32%), nausea (30%), fever (26%), vomiting (15%), infection (13%), pruritus (13%), and rash (13%). Additionally, one patient developed human-antimouse antibodies. CONCLUSION: Iodine-131 tositumomab produced a high overall response rate, and approximately one third of patients had a CR despite having chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL.""",1
9697,10720292,Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group,"OBJECTIVE: This is one of two separate clinical trials to evaluate the efficacy and safety of modafinil, a novel wake-promoting agent, in patients with excessive daytime sleepiness (EDS) associated with narcolepsy. METHODS: In this 9-week, randomized, placebo-controlled, double-blind, 21-center clinical trial, patients were randomized to receive fixed daily doses of modafinil 200 mg, modafinil 400 mg, or placebo. A placebo-controlled, 2-week treatment discontinuation phase was included to evaluate the effects of withdrawal on patients who had been receiving modafinil. A total of 271 patients who were naive to modafinil received study medication in the 9-week trial and 240 patients received study medication in the discontinuation phase. RESULTS: Treatment with modafinil resulted in significant improvement in two objective measures of EDS: the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Additionally, patient self-assessment of sleepiness was significantly improved, as measured by the Epworth Sleepiness Scale, and level of illness was significantly reduced on the independent clinician assessment, the Clinical Global Impression of Change. Nighttime sleep, monitored by nocturnal polysomnography, was not adversely effected with modafinil treatment compared with placebo treatment. The most frequent adverse experience was headache, which was not significantly greater for modafinil than placebo. During treatment discontinuation, individuals who had been receiving modafinil experienced a return of their EDS to baseline levels. During treatment discontinuation, patients did not experience symptoms associated with amphetamine withdrawal syndrome. For up to 9 weeks of daily use there was no evidence for the development of dependence at the dose levels studied. CONCLUSION: The data indicate that modafinil has an excellent safety profile and is very well tolerated. Modafinil is an effective treatment for excessive daytime sleepiness in narcolepsy and shows continued efficacy with up to 9 weeks of daily use.",1
9698,10726736,Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro,"""BACKGROUND: The anticonvulsant lamotrigine has been associated with severe adverse events such as the hypersensitivity syndrome and severe bullous reactions. So far, specific immunologic tests have rarely been performed to demonstrate specific sensitization. METHODS: A 36-year-old man suffering from epilepsy was concomitantly treated with high doses of sodium valproate and lamotrigine. About 1 month later, a severe hypersensitivity syndrome occurred affecting skin, lymph nodes, and liver. Three months later, skin tests and lymphocyte stimulation tests with anticonvulsants were performed. RESULTS: Skin tests were negative with all drugs; lymphocyte stimulation tests were twice positive with lamotrigine. Later re-exposure to sodium valproate was tolerated. CONCLUSIONS: Lamotrigine may elicit a severe hypersensitivity syndrome. Particularly high initial doses and concomitant treatment with sodium valproate increase the risk of cutaneous reactions. The lymphocyte stimulation test was used to identify the culprit drug. Lymphocyte sensitization to the drug or a metabolite may be involved in the pathogenesis.""",1
9699,10726966,Subfulminant hepatitis requiring liver transplantation following ibuprofen overdose,,1
9700,10731303,Nimesulide-induced hepatitis and acute liver failure,"BACKGROUND: Nimesulide is a relatively new non-steroidal anti-inflammatory drug that is gaining popularity in many countries because it is a selective cyclooxygenase 2 inhibitor. Occasionally, treatment is associated with mild elevation of liver enzymes, which return to normal upon discontinuation of the drug. Several cases of nimesulide-induced symptomatic hepatitis were also recently reported, but these patients all recovered. OBJECTIVES: To report the characteristics of liver injury induced by nimesulide. PATIENTS AND METHODS: We report retrospectively six patients, five of them females with a median age of 59 years, whose aminotransferase levels rose after they took nimesulide for joint pains. In all patients nimesulide was discontinued, laboratory tests for viral and autoimmune causes of hepatitis were performed, and sufficient follow-up was available. RESULTS: One patient remained asymptomatic. Four patients presented with symptoms, including fatigue, nausea and vomiting, which had developed several weeks after they began taking nimesulide (median 10 weeks, range 2-13). Hepatocellular injury was observed with median peak serum alanine aminotransferase 15 times the upper limit of normal (range 4-35), reversing to normal 2-4 months after discontinuation of the drug. The remaining patient developed symptoms, but continued taking the drug for another 2 weeks. She subsequently developed acute hepatic failure with encephalopathy and hepatorenal syndrome and died 6 weeks after hospitalization. In none of the cases did serological tests for hepatitis A, B and C, Epstein-Barr virus and cytomegalovirus, as well as autoimmune hepatitis reveal findings. CONCLUSIONS: Nimesulide may cause liver damage. The clinical presentation may vary from abnormal liver enzyme levels with no symptoms, to fatal hepatic failure. Therefore, monitoring liver enzymes after initiating therapy with nimesulide seems prudent.",1
9701,10733264,Comparative tolerability of the newer generation antiparkinsonian agents,"In recent years, the treatment of Parkinson's disease has undergone an immense amount of research, resulting in the development of multiple new medications. This has largely been fuelled by dissatisfaction over the development of motor complications secondary to long term levodopa therapy. Different treatment approaches are applied depending on the stage of Parkinson's disease. In early and mild Parkinson's disease, selegiline offers a limited symptomatic effect. Its neuroprotective effect, although at present theoretical, has questionable clinical relevance. Increased mortality associated with selegiline has been reported, although a meta-analysis of 5 different trials did not support this finding. The newer, non-ergoline dopamine agonists, pramipexole and ropinirole, have undergone extensive studies to evaluate their efficacy as monotherapy in early Parkinson's disease. These newer agonists are ideal initial symptomatic medications, primarily because they delay the onset of levodopa-induced motor fluctuations. Efficacy of the newer dopamine agonists in advanced disease seems to be comparable to that of the older agents, bromocriptine and pergolide. Adverse effects can be reduced by starting the medication at a very low dose and then slowly titrating upward. Catechol-O-methyl transferase (COMT) inhibitors are indicated for the treatment of motor fluctuations in advanced disease, particularly the 'wearing-off' phenomenon. Tolcapone, a peripheral and central COMT inhibitor, appears to be quite effective, producing a 47% reduction in 'off' time. Unfortunately, 3 deaths have been observed, which are presumably secondary to tolcapone therapy. The drug has been withdrawn in many countries, and liver enzyme testing is mandatory in the US. Entacapone, a purely peripheral COMT inhibitor with a lower potency than tolcapone, has also proved to be effective and has not been associated with liver damage, obviating the need for testing.",1
9702,10736599,Hepatotoxicity of salicylate therapy in acute rheumatic fever,,1
9703,10741116,[Evaluation of hepatic toxicity following high-dose 5-FU arterial infusion chemotherapy: analysis of 42 cases of colorectal liver metastases],"""The regional toxicity of an anticancer agent for normal liver tissue following hepatic arterial infusion chemotherapy (HAI) was evaluated in terms of morphology, function, and histopathology. Forty-two patients(M:F = 30:12; mean age, 59.9 years) with liver metastases from colorectal cancer were treated with HAI using a totally implantable vascular access port system from July 1994 to March 1999. The regimen used here was so-called weekly high-dose 5-fluorouracil(5-FU) infusion(5-FU, 1,000 mg/m2/week). Volume measurement of the liver demonstrated not only whole liver atrophy including the tumor but also volume reduction of the non-tumorous lobe. Atrophic change of the liver was seen in patients who were administered over 20 g/m2 of 5-FU(p < 0.01). The CT attenuation values of the liver were examined, and fatty infiltration was seen in six patients. Histologic examination of liver biopsies from the non-tumorous part revealed steatosis and infiltration of inflammatory cells in the portal triad, which were not seen in specimens prior to HAI. On clinical laboratory findings, enzymes representing bile duct, including alkaline phosphatase, leucine amino peptidase, and gamma-glutamyltranspeptidase, were increased in 22 patients. In terms of regional toxicity for long-term HAI, 20 g/m2 of 5-FU, is the key dose at which to consider temporary cessation or dose reduction.""",1
9704,10743694,Treatment of tacrolimus-related adverse effects by conversion to cyclosporine in liver transplant recipients,"""When tacrolimus side effects persist despite dose reduction, conversion to cyclosporine-based immunosuppression (CyA) is necessary. We characterized tacrolimus side effects that warranted discontinuation of the drug, and outcomes after conversion. Of 388 liver recipients who received tacrolimus as primary immunosuppression, 70 required conversion to CyA. We recorded indication for conversion, whether conversion was early or late after transplantation, tacrolimus dose and trough blood level at conversion, and incidence of rejection after conversion. Conversion was early in 29 patients (41.4%) and late in 41 (58.6%). Indications for early conversion were neurotoxicity (20), (insulin-dependent) diabetes mellitus (IDDM) (5), nephrotoxicity (3), gastrointestinal (GI) toxicity (6), and cardiomyopathy (1), and for late conversion were neurotoxicity (15), IDDM (12), nephrotoxicity (3), GI toxicity (5), hepatotoxicity (6), post-transplant lmphoproliferate disease (PTLD) (2), cardiomyopathy (1), hemolytic anemia (1), and pruritus (1). All early-conversion patients showed improvement/resolution of symptoms. Among late-conversion patients, 37 (90.2%) had improvement/resolution; in 4 (9.8%), adverse effects persisted. The overall rejection rate was 30%. Sixty-two patients (88.6%) are alive with functioning grafts 686 +/- 362 days (range, 154-1433 days) after conversion. When tacrolimus side effects are unresponsive to dose reduction, conversion to CyA can be accomplished safely, with no increased risk of rejection and excellent long-term outcome.""",1
9705,10749332,Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group,"The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.",1
9706,10750660,Ursodeoxycholic acid (UDCA) for the treatment of amoxycillin-clavulanate potassium (Augmentin)-induced intra-hepatic cholestasis: report of two cases,"This report describes two patients who developed jaundice within two weeks of receiving an amoxycillin-clavulanate potassium combination. Causes of jaundice, other than drug administration, were excluded. The patients' jaundice and clinical symptoms did not respond to stopping the drug. Ursodeoxycholic acid (750 mg/day) led to a prompt and sustained improvement in their hyperbilirubinaemia and symptoms such as pruritus and fatigue. These cases suggest that ursodeoxycholic acid may be an effective treatment for drug-associated cholestasis.",1
9707,10751736,Sonographic assessment of ceftriaxone-associated biliary pseudolithiasis in children,"PURPOSE: Ceftriaxone is a widely used third-generation cephalosporin. In this prospective study, we used sonography to investigate the incidence and outcome of biliary complications in children receiving ceftriaxone therapy. METHODS: Ceftriaxone was administered intravenously at a dosage of 100 mg/kg/day for 1-3 weeks to 118 children hospitalized for severe infection. Serial gallbladder sonograms were obtained on days 1, 5-7, and 10-14 of therapy and the day after therapy ended if it had lasted more than 2 weeks. When sonographic abnormalities were found, additional sonograms were obtained every 3 days until the abnormalities had completely resolved. RESULTS: Twenty patients (17%), all asymptomatic, demonstrated sonographic abnormalities: 8 had gallbladder sludge, defined as echogenic material without associated acoustic shadowing, and 12 had pseudolithiasis, defined as echogenic material with acoustic shadowing. These abnormalities spontaneously resolved within 2 weeks of stopping the ceftriaxone (mean time to disappearance, 8.2 +/- 3.4 days). No significant differences were found between patients with normal versus abnormal sonographic findings in sex, age, duration of treatment, or other risk factors for drug precipitation. CONCLUSIONS: Ceftriaxone-associated biliary pseudolithiasis is usually asymptomatic and was rapidly reversible after cessation of therapy in this group of Turkish children.",1
9708,10759225,Sho-saiko-to: Japanese herbal medicine for protection against hepatic fibrosis and carcinoma,"Herbal medicines, which have been used in China for thousands of years, are now being manufactured in Japan, in standardized form in terms of quality and quantities of ingredients. The Chinese herbal medicine Sho-saiko-to is a mixture of seven herbal preparations, which is widely administered in Japan to patients with chronic hepatitis and cirrhosis. In a prospective study, this herbal medicine was found to play a chemopreventive role in the development of hepatocellular carcinoma in cirrhotic patients. However, little is known about the mechanism by which Sho-saiko-to protects against hepatic fibrosis and carcinoma. Several laboratories, including ours, have clearly demonstrated the preventive and therapeutic effects of Sho-saiko-to on experimental hepatic fibrosis, as well as its inhibitory effect on the activation of hepatic stellate cells, which are the major types of collagen-producing cells. We provided evidence that Sho-saiko-to functions as a potent anti-fibrosuppressant via the inhibition of oxidative stress in hepatocytes and hepatic stellate cells and that its active components are baicalin and baicalein. In addition, Sho-saiko-to has anti-carcinogenic properties in that it inhibits chemical hepatocarcinogenesis in animals, acts as a biological response modifier and suppresses the proliferation of hepatoma cells by inducing apoptosis and arrests the cell cycle. Among the active components of Sho-saiko-to, baicalin, baicalein and saikosaponin-a have the ability to inhibit cell proliferation. It should be noted that baicalin and baicalein are flavonoids with chemical structures very similar to silybinin, which shows anti-fibrogenic activities. This may provide valuable information on the search for novel anti-fibrogenic agents.",1
9709,10766693,Rapid-onset subfulminant liver failure associated with troglitazone,,1
9710,10767651,"A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy","""Objective: To assess the continued efficacy of modafinil in the treatment of excessive daytime somnolence (EDS) of narcolepsy.Background: Modafinil has been shown to be a safe and effective treatment for the EDS presented by patients with narcolepsy. However, the duration of treatment has been relatively brief, particularly considering the chronic nature of the disease.Methods: Sixty-nine patients with narcolepsy, who completed a 6-week crossover study of modafinil continued on modafinil for 16 weeks of open-label treatment (300+/-100 mg). This was followed by 2 weeks during which patients were randomly and blindly allocated to continue modafinil (M) at the same dose (n=30), or placebo (P; n=33).Results: A mean dose of 330 mg of modafinil continued to produce a significant decrease in EDS as measured by the Maintenance of Wakefulness Test (9.7+/-7.9 for P; 16.4+/-13.7 for M; P=0.009), the Epworth Sleepiness Scale (15.4+/-5.8 for P; 13.2+/-5.7 for M; P=0.023), and the number of episodes of severe somnolence and sleep reported in patient diaries (8.2+/-7.2 for P; 4.2+/-5.2 for M; P=0.017). Modafinil had no significant effects on nocturnal sleep, blood pressure, heart rate, the electrocardiogram (ECG), weight, or mood.Conclusion: Modafinil continues to be an effective and well-tolerated drug after 16 weeks of treatment.""",1
9711,10770552,The impact of co-infection with hepatitis C virus and HIV on the tolerability of antiretroviral therapy,,1
9712,10771467,Alfuzosin-induced hepatotoxicity,"Drug-induced hepatic injury is a potential complication of virtually all drugs because the liver is central to the metabolic disposition of almost all drugs, although precise mechanisms often are unknown. We report a case of severe acute mixed hepatitis (cholestatic and hepatocellular), probably induced by alfuzosin. This event has not been reported previously (MEDLINE 1990, March 1999). Viral causes, autoimmune hepatitis and biliary tree obstruction were excluded. After discontinuation of the drug, liver function test results returned to normal.",1
9713,10772444,Recurrent NNRTI-induced hepatotoxicity in an HIV-HCV-coinfected patient,,1
9714,10776834,Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus,"Miglitol, the first pseudomonosaccharide alpha-glucosidase inhibitor, smooths postprandial peak plasma glucose levels and thus improves glycaemic control, which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral antihyperglycaemic agent is indicated for the treatment of patients with type 2 diabetes mellitus. Miglitol is generally well tolerated and, unlike the sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia when administered as monotherapy. The drug is systemically absorbed but is not metabolised and is rapidly excreted via the kidneys. Clinical trials with miglitol (usually 50 or 100 mg 3 times daily) in patients with type 2 diabetes mellitus consistently demonstrated a significant improvement in glycaemic control for periods of 6 to 12 months. There were also marked reductions in postprandial serum insulin levels, although miglitol generally had no effect on fasting insulin levels. In comparative studies miglitol had similar efficacy to acarbose, but at lower therapeutic doses (50 and 100 mg 3 times daily, respectively). In addition, although sulphonylurea agents provided superior reductions in HbA1c levels, miglitol provided similar or superior reductions in fasting and postprandial plasma glucose levels. In combination with other oral antidiabetic agents or insulin, miglitol improved glycaemic control in patients in whom metabolic control was suboptimal despite dietary and pharmacological intervention. Most adverse events associated with miglitol treatment involve disturbances of the gastrointestinal tract (most common effects are flatulence, abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to moderate in severity, occur at the onset of treatment, decline with time and resolve promptly on discontinuation of the drug or with dosage adjustment. As monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use with other oral antidiabetic agents may necessitate dosage adjustment of the other agents. Miglitol had no significant effects on renal, cardiovascular, respiratory or haematological parameters in long term studies. No dosage adjustments are required in elderly patients, in those with hepatic impairment or in those with mild to moderate renal insufficiency. CONCLUSIONS: In long term, well designed trials miglitol reduces fasting and postprandial plasma glucose levels, thus improving glycaemic control, which is reflected in a reduced HbA1c level in patients with type 2 diabetes mellitus. Most adverse events associated with miglitol involve disturbances of the gastrointestinal tract. This agent is a useful first-line therapy in patients with type 2 diabetes mellitus insufficiently controlled by diet alone and as second-line or as adjuvant therapy in those insufficiently controlled with diet and sulphonylurea agents. Miglitol may prove particularly beneficial in elderly patients and those with hepatic impairment or mild to moderate renal impairment, in whom other oral antidiabetic agents are contraindicated or need to be used with caution.",1
9715,10779420,Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload,"""We compared 48-hour urinary iron excretion after a twice-daily subcutaneous bolus injection of deferoxamine and after 12 hours of subcutaneous continuous infusion of the drug in 27 patients with iron overload (mean age, 55.7 years). In most patients, the iron overload was due to multiple transfusions administered during chemotherapy or as part of supportive care for a hematologic or oncologic disorder. One patient had sickle cell anemia and 1 had hereditary hemochromatosis and spherocytosis. Similar urinary iron excretion was observed with the 2 methods of administration; mean +/- SD values were 6935.3 +/- 3832.3 microg/48 hours with subcutaneous bolus injection and 6630.4 +/- 3606.9 microg/48 hours with subcutaneous continuous infusion (P =.3). Twenty-six patients (96.3%) chose to continue therapy with bolus injection. The long-term efficacy of bolus injection was evaluated by measuring the serum ferritin concentration at regular intervals for a follow-up time of 20.1 +/- 4.5 months. Ferritin concentration decreased to below 1000 microg/L in 73% of the patients and to below 500 microg/L in 42% and became normal in 26%. Best results were obtained in patients who were no longer receiving blood transfusions when chelation therapy was initiated. Three of 26 patients (11.5%) had mild, transient side effects after bolus injection. Larger prospective, randomized studies must be conducted before deferoxamine bolus injection can be routinely recommended for patients with iron overload. (Blood. 2000;95:2776-2779)""",1
9716,10784544,"""Sedation with """"non-sedating"""" antihistamines: four prescription-event monitoring studies in general practice""","""OBJECTIVES: To investigate the frequency with which sedation was reported in post-marketing surveillance studies of four second generation antihistamines: loratadine, cetirizine, fexofenadine, and acrivastine. DESIGN: Prescription-event monitoring studies. SETTING: Prescriptions were obtained for each cohort in the immediate post-marketing period. SUBJECTS: Event data were obtained for a total of 43 363 patients. MAIN OUTCOME MEASURES: Reporting of sedation or drowsiness. RESULTS: The odds ratios (adjusted for age and sex) for the incidence of sedation were 0.63 (95% confidence interval 0.36 to 1.11; P=0.1) for fexofenadine; 2.79 (1.69 to 4.58; P<0.0001) for acrivastine, and 3.53 (2.07 to 5.42; P<0.0001) for cetirizine compared with loratadine. No increased risk of accident or injury was evident with any of the four drugs. CONCLUSIONS: Although the risk of sedation was low with all four drugs, fexofenadine and loratadine may be more appropriate for people working in safety critical jobs.""",1
9717,10788961,Bexarotene (Targretin) for cutaneous T-cell lymphoma,,1
9718,10795774,Severe but reversible hepatitis induced by troglitazone,,1
9719,10800057,The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity,"""Busulphan and cyclophosphamide (Bu/CP) are widely used in preparative regimens for bone marrow transplantation. Many studies have shown a wide variation in busulphan pharmacokinetics. Moreover, higher rates of liver toxicity were reported in Bu/CP protocols than in a total body irradiation (TBI)-containing regimen. In the present paper we investigated the effect of the time interval between the last dose of busulphan and the first dose of cyclophosphamide on the pharmacokinetics of CP and its cytotoxic metabolite 4-hydroperoxycyclophosphamide (4-OHCP). Thirty-six patients undergoing bone marrow transplantation (BMT) were included in the study. We also investigated the occurrence of veno-occlusive disease, mucositis and graft-versus-host disease. Ten patients conditioned with CP followed by TBI served as a control group (TBI). Twenty-six patients were conditioned with Bu/CP. The patients received Bu (1 mg/kg x 4 for 4 days), followed by CP (60 mg/kg for 2 days) administered as a 1-h infusion. Patients received their CP therapy either 7-15 h (group A, n = 12) or 24-50 h (group B, n = 14) after the last dose of Bu. None of the patients were given phenytoin or any other drug known to enhance CP metabolism. The administration of CP less than 24 h after the last dose of Bu resulted in: (1) a significantly (P = 0.003) lower clearance for cyclophosphamide was observed in group A (0.036 l/h/kg) compared to 0.055 and 0.055 l/h/kg, in the B and TBI groups, respectively; (2) significantly (P = 0.002) longer elimination half-life in group A (10.93 h) than in groups B and TBI (6.87 and 7.52 h, respectively); (3) significantly (P < 0.001) lower exposure to the cytotoxic metabolite (4-OHCP), expressed as the ratio AUC4-OHCP/AUCCP, in group A (0.0053) than that obtained in group B (0.013) and group TBI (0.012); (4) the patients in group A had a significantly (P < 0.05) higher incidence of VOD (seven of 12) than the other groups, B and TBI (2/14 and 1/10, respectively); and (5) mucositis was significantly higher in group A patients (8/12), being seen in only one patient in group B and none in the TBI group. The present study has shown that the interval between busulphan and cyclophosphamide administration can negatively affect the pharmacokinetics of cyclophosphamide and its cytotoxic metabolite. We conclude that the timing of CP administration must be considered in order to improve drug efficacy and reduce conditioning-related toxicity.""",1
9720,10801054,Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia,"Intravenous sodium benzoate and sodium phenylacetate have been used successfully in the treatment of acute hyperammonaemia in patients with urea cycle disorders. They provide alternative pathways for waste nitrogen disposal and help maintain nitrogen homeostasis. However, we report three patients with hyperammonaemia who received inappropriate doses of intravenous sodium benzoate and sodium phenylacetate that resulted in severe complications. Ambiguous medical prescriptions and inadequate cross-checking of drug dosage by physicians, nurses and pharmacists were the main causes of these incidents. All the patients presented with alteration in mental status, Kussmaul respiration and a partially compensated metabolic acidosis with an increased anion gap. Two patients developed cerebral oedema and hypotension and died. The third survived after haemodialysis. Plasma levels of benzoate and phenylacetate were excessively high. The possible mechanisms of toxicity, management and safety measures are discussed.",1
9721,10804039,Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections,"UNLABELLED: Valaciclovir is an aciclovir prodrug used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus, and for prophylaxis against cytomegalovirus (CMV). Oral valaciclovir provides significantly better oral bioavailability than oral aciclovir itself, contributing to the need for less frequent administration. Several studies have demonstrated the efficacy of long term (> 90 days) therapy with valaciclovir for the suppression of genital HSV disease in otherwise healthy individuals with HSV infection. In 1 randomised, double-blind trial, once daily valaciclovir (1000 mg, 500 mg and 250 mg) produced statistically significant suppression of disease recurrence, as did twice daily valaciclovir 250 mg and aciclovir 400 mg. Valaciclovir dosages of > or = 500 mg daily are recommended for suppression of genital herpes recurrences in immunocompetent individuals. This disease occurs frequently in patients with human immunodeficiency virus (HIV) infection and, in a single randomised double-blind trial, prophylactic valaciclovir (1000 mg once daily or 500 mg twice daily) and aciclovir (400 mg twice daily) were found to be of similar efficacy in the suppression of genital herpes. However, a higher than expected dropout rate indicated that more studies of valaciclovir in patients with HIV are required. In a randomised trial of patients undergoing renal transplant, valaciclovir 2 g 4 times daily for 90 days significantly reduced the incidence and delayed the onset of CMV disease: the incidence in valaciclovir-treated patients who were CMV-seronegative at baseline, and recieived a kidney from a CMV-seropositive donor, was 3% versus 45% for placebo after 90 days of treatment. Acute graft rejection was also reduced in the valaciclovir-treated group. A small study in heart transplant patients compared valaciclovir (2 g 4 times daily) with aciclovir (200 mg 4 times daily) and found a significant reduction in CMV antigenaemia favouring valacilovir at the end of the treatment period. Additional reductions in other indices of CMV in those given valaciclovir compared with aciclovir were also noted. In a preliminary study of prophylaxis for CMV disease in bone marrow transplant recipients valaciclovir (2 g 4 times daily) was superior to aciclovir (800 mg 4 times daily) in terms of time to CMV viraemia or viruria. Although valaciclovir (8 g/day for approximately 30 weeks) reduced the incidence and time to CMV disease compared with aciclovir (3.2 g/day) in patients with advanced HIV disease, valaciclovir was associated with more gastrointestinal complaints and an increased risk of death, leading to premature termination of the study. As yet, no trials comparing the efficacy of valaciclovir with famciclovir (the oral prodrug for penciclovir) in the suppression of recurrent episodes of genital herpes have been published, nor have direct comparisons been made, between valaciclovir with ganciclovir in patients with CMV disease. Valaciclovir is well tolerated at dosages used to suppress recurrent episodes of genital herpes (500 to 1000 mg/day) in immunocompetent and HIV seropositive individuals, with headache being reported most often. However, a potentially fatal thrombotic microangiopathy (TMA)-like syndrome has been reported in some immunocompromised patients receiving high-dose prophylactic valaciclovir therapy (8 g/day) for CMV disease for prolonged periods, and the risk of this syndrome appears to be higher in patients with advanced HIV disease. While the clinical benefits of valaciclovir in some immunocompromised patients may outweigh the risk of TMA, close monitoring for symptoms of TMA is indicated in all immunocompromised patients receiving high-dose valaciclovir. CONCLUSION: Oral valaciclovir is an effective drug for the suppression of recurrent episodes of genital herpes in immunocompetent and immunocompromised individuals. (ABSTRACT TRUNCATED)",1
9722,10804771,[Stevens-Johnson syndrome due to nevirapine],,1
9723,10811239,Risperidone side effects,"The overall effectiveness of traditional antipsychotics has been hindered by their extrapyramidal side effects, which contribute to noncompliance and relapse in patients with schizophrenia. The side effects associated with traditional antipsychotic treatment are generally minimal in patients who take risperidone, a combined 5-HT2/D2 antagonist, but the literature is sparse on adverse events among the newer atypical antipsychotics. Risperidone is associated with relatively few motor side effects compared with the traditional antipsychotics, and weight gain is less likely with risperidone than with either clozapine or olanzapine. While increased prolactin levels have been reported in patients taking risperidone, little correlation has been found between prolactin levels and adverse events. As antipsychotic treatment options expand to include the new agents, it is important for clinicians to anticipate side effects and to query patients about specific adverse events.",1
9724,10811241,Review of quetiapine side effects,"The newest atypical antipsychotic medication to be approved by the U.S. Food and Drug Administration, quetiapine is a drug that awaits a wide range of clinical and head-to-head comparisons. Nevertheless, clinical trials currently available suggest that quetiapine has a beneficial side effect profile, particularly with regard,to extrapyramidal symptoms. To date, quetiapine has also proved effective in the treatment of schizophrenia, but its efficacy, while clearly superior to that of placebo, seems no greater than that of haloperidol or chlorpromazine. Clinical trials have supported the use of quetiapine in treating elderly patients. Further research is necessary to establish the clinical profile of quetiapine.",1
9725,10815112,Elevated liver enzymes following initiation of antiretroviral therapy,,1
9726,10817685,Quinupristin/Dalfopristin therapy for infections due to vancomycin-resistant Enterococcus faecium,"""The efficacy and safety of quinupristin/dalfopristin for treatment of infections due to vancomycin-resistant Enterococcus faecium were evaluated in 24 hospitalized patients with documented infections (19 bacteremias, 5 localized infections) caused by vancomycin-resistant E. faecium that was susceptible to quinupristin/dalfopristin in vitro. Patients received iv quinupristin/dalfopristin at a dosage of either 7.5 mg/kg every 8 h or 5 mg/kg every 8 h. A favorable clinical response (cure or improvement) occurred in 19 (83%) of 23 evaluable patients; bacteriologic eradication occurred in 17 (74%) of 23 evaluable patients. A favorable clinical response was observed in 12 (80%) of 15 patients who were treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h and in 7 (88%) of 8 patients treated with 5 mg/kg of quinupristin/dalfopristin every 8 h. Two of four treatment failures were associated with a decrease in the in vitro susceptibility of vancomycin-resistant E. faecium to quinupristin/dalfopristin. Superinfections developed in 6 patients (26%), but only one was caused by Enterococcus faecalis that was resistant to quinupristin/dalfopristin. Myalgias and arthralgias were the only adverse events related to quinupristin/dalfopristin. These conditions occurred in 8 (33%) of 24 patients and were dose-related (8 cases in 16 patients treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h, no cases in 8 patients treated with 5 mg/kg every 8 h). Mortality associated with vancomycin-resistant E. faecium infection was 17% (4 of 23 patients), whereas mortality from other causes was 52% (12 of 23 patients). These results suggest that quinupristin/dalfopristin is effective as treatment for vancomycin-resistant E. faecium infections in critically ill patients with serious underlying conditions. Except for myalgias and arthralgias at higher dosages, the drug is well-tolerated.""",1
9727,10824052,Hypersensitivity syndrome caused by amitriptyline administration,"Adverse cutaneous manifestations are among the most common side effects associated with psychotropic drugs. Skin reactions due to amitriptyline (a tricyclic antidepressant agent) include rashes and hypersensitivity reactions (for example, urticaria and photosensitivity) as well as hyperpigmentation. Hypersensitivity syndrome is a specific severe idiosyncratic reaction causing skin, liver, joint, and haematological abnormalities, which usually resolve after the discontinuation of the implicated drug. A case of a 24 year old woman who experienced hypersensitivity syndrome three weeks after the initiation of amitriptyline is reported.",1
9728,10828434,Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy,"Objectives: To assess the long-term efficacy and safety of modafinil in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.Background: Modafinil has been shown to be effective and well tolerated for treating EDS associated with narcolepsy in two large-scale, well-controlled, 9-week clinical trials.Methods: Four hundred and seventy eight adult patients with a diagnosis of narcolepsy who had completed one of two 9-week, double-blind, placebo-controlled, multicenter, clinical trials of modafinil were enrolled in two 40-week, open-label, extension studies. A flexible-dose regimen (i.e. 200, 300, or 400 mg daily) was followed in one study. In the second study, patients received 200 mg/day for 1 week, followed by 400 mg/day for 1 week. Investigators then prescribed either 200- or 400-mg doses for the duration of the study. Efficacy was evaluated using Clinical Global Impression of Change (CGI-C) scores, the Epworth Sleepiness Scale (ESS), and the 36-item Medical Outcomes Study health survey (SF-36). Adverse events were recorded. Data from the two studies were combined.Results: The majority of patients ( approximately 75%) received 400 mg of modafinil daily. Disease severity improved in >80% of patients throughout the 40-week study. At weeks 2, 8, 24, and 40, disease severity was 'much improved' or 'very much improved' in 49, 58, 59, and 58% of patients, respectively. The mean (+/-SEM) ESS score improved significantly from 16.5+/-0.2 at open-label baseline to 12.4+/-0.2 at week 2 and remained at that level through week 40 (P<0.001). Quality of life scores at weeks 4, 8, 24, and 40 were significantly improved versus open-label baseline scores for six of the eight SF-36 domains (P<0.001). The most common treatment-related adverse events were headache (13%), nervousness (8%), and nausea (5%). Most adverse events were mild to moderate in nature. A total of 341 patients (71%) completed the studies. Forty-three patients (9.0%) discontinued treatment because of adverse events.Conclusions: Modafinil is effective for the long-term treatment of EDS associated with narcolepsy and significantly improves perceptions of general health. Modafinil is well tolerated, with no evidence of tolerance developing during 40 weeks of treatment.",1
9729,10831533,Safety and effectiveness of dofetilide for conversion of atrial fibrillation and nesiritide for acute decompensation of heart failure: a report from the cardiovascular and renal advisory panel of the Food and Drug Administration,,1
9730,10835757,[Hepatotoxicity by amoxicillin/clavulanic acid: case report],"We report a 72 years old diabetic male that, after the use of combined amoxicillin-clavulanic acid, developed pruritus and jaundice. Liver function tests showed serum total bilirubin of 4.3 mg/dL aspartate aminotransferase 140 U/l (normal < 35 U/L), alanine aminotransferase 470 U/L (normal < 40) and alkaline phosphatases of 400 U/L (normal < 100). Serology for hepatitis A, B and C viruses was negative, ERCP showed a normal biliary tree and liver biopsy disclosed a cholestatic hepatitis. Ursodeoxycholic was started to relieve pruritus. Liver function tests improved shortly thereafter, suggesting that this drug may be useful in the treatment of drug induced cholestasis.",1
9731,10837187,Liver damage and kinetics of hepatitis C virus and human immunodeficiency virus replication during the early phases of combination antiretroviral treatment,"""In order to assess the relationship between human immunodeficiency virus (HIV) RNA, hepatitis C virus (HCV) RNA, CD4, CD8, and liver enzymes during combination antiretroviral therapy, these parameters were measured in 12 HIV-HCV-coinfected patients (who were naive for antiretrovirals) on the day before and 3, 7, 14, 28, 56, and 84 days after initiating the following treatments: stavudine and lamivudine in all patients, indinavir in 6 patients, and nevirapine in 6 patients. HIV RNA declined rapidly, CD4 cells increased slowly, and CD8 cells and liver enzymes were stable. HCV RNA showed a transient significant increase at days 14 and 21 (7.33+/-0.16 [mean +/- SE] and 7.29+/-0.2 log copies/mL vs. 7+/-0.2 log copies/mL at baseline; P<.05). These changes were similar in both treatment groups. A 2-fold alanine aminotransferase increase was observed in 4 of 12 patients; 4 of 4 patients showed increased HCV RNA. The relationship between HCV RNA increase and HIV RNA decrease indicates virus-virus interference. An HCV RNA increase may cause significant liver damage only in a minority of patients.""",1
9732,10844292,[Fatal subfulminant hepatitis probably due to the combination benazepril-hydrochlorothiazide (Briazide)],,1
9733,10845730,"A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy","The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase. Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05] and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily. Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose.",1
9734,10845767,Yohimbine in erectile dysfunction: the facts,"Yohimbine, a pharmacologically well-characterized alpha-2-adrenoceptor antagonist with activity in the central and peripheral nervous system, has been used for over a century in the treatment of erectile dysfunction. In-depth, systematic studies in animals have shown that the drug has a remarkable positive effect on sexual performance. Meta-analyses of the few controlled, randomized human studies have consistently shown an advantage of yohimbine over placebo. Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigorous human clinical trials. Although relevant basic pharmacological and animal research information has been available for over 15 y, recent studies were designed with a lack of insight and complete disregard of those fundamental studies. Currently, dose-response investigations are not available, alternative routes of administration (i.e. sublingual) have not been investigated, nor has continuous versus 'on-demand' administration been explored. Synergistic activity with other drugs was last studied nearly four decades ago. Assessment of various populations was carried out in very limited cohorts and only in most general terms. In short, properly designed trials in humans have not been done. Why? Yohimbine is an old drug. As such it does not enjoy patent protection or commercial viability. Until molecular/formulation changes can be brought about (as recently happened with two other agents: phentolamine and apomorphine), serious investigations of yohimbine will remain in limbo. It could be that the nay sayers are right and yohimbine, indeed, lacks clinical activity as a treatment for men with erectile dysfunction. As long as it remains an orphan drug, we will never know.",1
9735,10847432,Acute hepatic failure: a Western perspective,"Acute hepatic failure (AHF) is an uncommon, devastating syndrome, which results in death or the need for liver transplantation in more than 50% of cases. While AHF has numerous causes, most cases are due to viral hepatitis and drug toxicity or idiosyncratic reactions. A significant group with indeterminate causation remains, despite careful investigation. In many of these cases a viral aetiology is suspected, although yet not proven. Major differences exist in the aetiology of AHF between the West and Eastern countries. A wider range of aetiologies exists in the West. Common causes include acetaminophen toxicity and idiosyncratic drug reactions, while viral hepatitis is less frequent. Hepatitis E infection is rarely seen in Western countries in contrast to its high prevalence in the East. The mainstay of AHF management is supportive care in an intensive care unit. Liver transplantation is now the standard of care in many Western liver units for individuals who have a less than 20% probability of survival. Lack of availability of donor livers at short notice remains a significant problem. Methods of liver support used while waiting for a donor liver or for the native liver to regenerate include bioartificial livers, extracorporeal liver-assist devices, extracorporeal whole organ perfusion (human and transgenic pig) and hepatocyte transplantation. The effectiveness of these methods remains unproven and awaits controlled clinical trials. Both transplantation and liver-support methods require specialized units and expensive and complicated equipment. Further research is necessary to identify modalities of therapy that would be effective as well as widely accessible.",1
9736,10852648,Irbesartan: an updated review of its use in cardiovascular disorders,"""Irbesartan interrupts the renin-angiotensin system via selective blockade of the angiotensin II subtype 1 receptor; the latter being responsible for the pressor related effects of angiotensin II. As treatment for mild to moderate hypertension, irbesartan 150 mg/day controlled diastolic BP in 56% of patients according to pooled data from several phase III studies and 77% of patients in a large phase IV study. in comparative trials, irbesartan was significantly more effective than losartan and valsartan as treatment for mild to moderate essential hypertension and as effective as enalapril or atenolol. Results from many studies show an additive antihypertensive effect when hydrochlorothiazide is added to irbesartan monotherapy. The drug also induces statistically significant regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy, and preliminary evidence suggests it has beneficial haemodynamic effects in patients with heart failure. Irbesartan is very well tolerated, exhibiting an adverse event profile similar to that seen with placebo in comparative trials. In conclusion, although the role of irbesartan as a treatment for heart failure is little clearer than it was 2 years ago, the place of the drug in the management of hypertension is now better established. There is evidence to suggest the drug may have a role as initial therapy for hypertension, although formal recommendation in management guidelines will almost certainly not occur until long term morbidity and mortality benefits are established.""",1
9737,10857986,Late-onset troglitazone-induced hepatic dysfunction,,1
9738,10859983,[Acute necrotizing hepatitis: an unusual side effect of oral anticoagulants],"We report the case of a severe relapsing phenprocoumon-induced hepatitis. The first episode of hepatitis was thought to be caused by another drug (Verapamil). The anticoagulation with Phenprocoumon was therefore continued after healing of liver inflammation. The relapse typically developed after a shorter exposition-time supporting the hypothesis of an allergic etiology. Fortunately we didn't find any cross-reaction between Phenprocoumon and Acenocoumarol. The patient could thus be anticoagulated orally without complications. If long term anticoagulation is absolutely essential, it is reasonable to prescribe a different Coumarin-derivate. In the case of a cross-reaction, the therapy should be continued with low-molecular weight heparin.",1
9739,10863862,[Hepatotoxicity induced by non-steroidal anti-inflammatory drugs],,1
9740,10866439,Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group,"""BACKGROUND: Use of some antiviral drugs for influenza infection is limited by potential rapid emergence of resistance. We studied the efficacy and safety of oseltamivir, the oral prodrug of the neuraminidase inhibitor GS4071, in adults with naturally acquired laboratory-confirmed influenza. METHODS: We did a randomised controlled trial of 726 previously healthy non-immunised adults with febrile influenza-like illness of up to 36 h duration. Patients were assigned oral oseltamivir 75 mg (n=243), oseltamivir 150 mg (n=245), or placebo (n=238) twice daily for 5 days. We assessed recovery by questionnaire and temperature recordings. The primary endpoint was time to resolution of illness in influenza-infected patients. FINDINGS: 475 (66%) patients had confirmed infection. Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87.4 h [95% CI 73.3-104.7], p=0.02) with oseltamivir 75 mg and by 35 h (30%, 81.8 h [68.2-100.0], p=0.01) with oseltamivir 150 mg than with placebo (116.5 h [101.5-137.8]). The effect of oseltamivir was apparent within 24 h of the start of treatment. In patients treated within 24 h of symptom onset, symptoms were alleviated 43 h (37% reduction) and 47 h (40%) earlier with oseltamivir 75 mg and 150 mg, respectively, compared with placebo (75 mg 74.5 h [68.2-98.0], p=0.02; 150 mg 70.7 h [54.0-89.4], p=0.01; placebo 117.5 h [103.0-143.8]). Oseltamivir was associated with lower [corrected] symptom scores, less viral shedding, and improved health, activity, and sleep quality, and was well tolerated. INTERPRETATION: Oseltamivir was effective and well tolerated in the treatment of natural influenza infection in adults. The efficacy, tolerability, and ease of administration warrant further investigation in children, elderly patients, and at-risk patients.""",1
9741,10868832,Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia,"""OBJECTIVE: The objective of the study was to assess the efficacy and safety of four fixed doses of nateglinide compared with placebo in the treatment of patients with type 2 diabetes with focus on the prandial state. RESEARCH DESIGN AND METHODS: This randomized double-blind placebo-controlled multicenter study was conducted in 289 patients who received either nateglinide at doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), or 180 mg (n = 57) or placebo (n = 60) before three main meals for 12 weeks. Levels of HbA1c, fasting plasma glucose (FPG), fructosamine, and plasma lipids were measured at predetermined intervals, and the effects of nateglinide on prandial glucose insulin, C-peptide, and triglyceride levels were measured after a liquid standard meal (Sustacal; Mead Johnson, Evansville, IN). Adverse events and hypoglycemic episodes were recorded. RESULTS: After a liquid meal challenge, nateglinide rapidly increased mealtime insulin levels within 30 min of drug intake and reduced mealtime glucose excursions without affecting triglyceride levels. At study end point, reduction of HbA1c levels was statistically significantly greater with nateglinide at doses of 60, 120, and 180 mg than placebo (-0.45, -0.62, and -0.64%, respectively; P<0.05). The mean level of FPG was significantly reduced versus placebo in the nateglinide 120-mg group only (-1.14 mmol/l P<0.01). Overall, nateglinide was well tolerated. CONCLUSIONS: This study demonstrated that nateglinide improves mealtime and mean glycemic control in a dose-dependent manner by restoring early insulin secretion phase. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes.""",1
9742,10873183,Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose,"We studied the relationship between alcohol consumption and hepatotoxicity related to paracetamol ingestion both in cases of overdose with suicidal intent and in cases where paracetamol was apparently taken for therapeutic reasons. In a retrospective study of 553 patients admitted to a specialist liver unit between January 1987 and December 1993 with paracetamol-induced hepatotoxicity, there was no difference in the severity of the hepatotoxicity following either a deliberate or an inadvertent overdose. Heavy alcohol consumption was more common in males than females and more commonly associated with deliberate overdoses of >15 g. There was no correlation between alcohol consumption and severity of hepatotoxicity (mean INR and the serum creatinine levels over the first 7 days after the overdose). The significantly lower platelet count in heavy drinkers was probably the consequence of direct alcohol toxicity to the marrow. Overall there was a greater incidence of heavy alcohol consumption amongst therapeutic misadventure compared to deliberate overdose cases, but there was no difference between the two groups when amounts of <10 g/day were involved. Eleven (29%) patients in the therapeutic misadventure group were depressed, 10 of whom had previously attempted suicide. In conclusion, we were unable to demonstrate that heavy drinkers develop more severe hepatotoxicity following paracetamol overdose than non-drinkers, and from the material reported in this study, accidental overdose is a better defining term than therapeutic misadventure.",1
9743,10877016,Co-trimoxazole-induced liver and renal failure. Case report,,1
9744,10877225,Erythromycin-induced primary biliary cirrhosis,,1
9745,10881762,Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society,"""This statement provides new recommendations for targeted tuberculin testing and treatment regimens for persons with latent tuberculosis infection (LTBI) and updates previously published guidelines (1,2). This statement is issued in recognition of the importance of these activities as an essential component of the TB Elimination Strategy promoted by the U.S. Public Health Service Advisory Council on the Elimination of Tuberculosis, and reports the deliberations of expert consultants convened by the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Isoniazid for 6-12 mo has been the mainstay of treatment for LTBI in the United States for more than 30 yr. However, the application of isoniazid for LTBI has been limited because of poor adherence, due to the relatively long duration of treatment required, and because of concerns about toxicity. Therefore, there has been interest in the development of shorter, rifampin-based regimens as alternatives to isoniazid for the treatment of LTBI. During the past decade, a series of studies of """"short-course"""" treatment of LTBI in persons with human immunodeficiency virus (HIV) infection has been undertaken. The results of these trials have recently become available, and the in-depth analyses of these and prior studies of isoniazid form the scientific basis of the treatment guidelines presented in this report. In addition, many changes to previous recommendations regarding testing for and treatment of LTBI are presented (Table 1).""",1
9746,10885091,Aloe vera: a systematic review of its clinical effectiveness,"BACKGROUND: The use of aloe vera is being promoted for a large variety of conditions. Often general practitioners seem to know less than their patients about its alleged benefits. AIM: To define the clinical effectiveness of aloe vera, a popular herbal remedy in the United Kingdom. METHOD: Four independent literature searches were conducted in MEDLINE, EMBASE, Biosis, and the Cochrane Library. Only controlled clinical trials (on any indication) were included. There were no restrictions on the language of publication. All trials were read by both authors and data were extracted in a standardized, pre-defined manner. RESULTS: Ten studies were located. They suggest that oral administration of aloe vera might be a useful adjunct for lowering blood glucose in diabetic patients as well as for reducing blood lipid levels in patients with hyperlipidaemia. Topical application of aloe vera is not an effective preventative for radiation-induced injuries. It might be effective for genital herpes and psoriasis. Whether it promotes wound healing is unclear. There are major caveats associated with all of these statements. CONCLUSION: Even though there are some promising results, clinical effectiveness of oral or topical aloe vera is not sufficiently defined at present.",1
9747,10888712,A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis,"""OBJECTIVE: To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group. RESULTS: After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide. CONCLUSIONS: Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.""",1
9748,10891757,[Severe acute hepatitis probably induced by nimesulide],,1
9749,10894614,Nefazodone-induced acute liver failure,,1
9750,10895374,Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis,"OBJECTIVE: To examine the safety of the use of disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with chronic viral hepatitis (CVH). METHODS: Records of 600 Chinese patients satisfying the ARA criteria for RA in two rheumatology centers were reviewed. Patients with CVH were studied. Liver enzymes were checked before (baseline) and during DMARD use at 3-month intervals or more frequently if necessary. Drug-episodes (D-Ep), defined as the continuous use of DMARD, singly or in combination, for more than 6 months in a patient, were analysed. Changes in serum liver alanine transaminase (ALT) levels as multiples of the upper range of normal were taken to reflect the severity of hepatotoxicity. Changes of ALT to > or = 1.5 times the upper range of normal if they were measured at baseline or > or = 2 times the upper range of normal if they were measured during and after the use of DMARD were considered as abnormal. Control patients included those with CVH alone (n = 623) or RA without CVH (n = 62) matched for age, sex and D-Ep. RESULTS: 30 RA patients were found to have concomitant CVH. One patient was excluded because of use of NSAID alone (n = 1). Among the 29 patients, 23 were HBsAg +ve and 6 were anti-HCV Ab +ve. A total of 47 D-Ep were analysed. 20/47 (42.6%) of D-Ep in 16/29 (55.2%) RA + CVH patients developed abnormal ALT levels after a mean 1.9-year duration of DMARD use. This was statistically significant when compared with 13/94 (13.8%) of D-Ep which ended with abnormal ALT levels in 13/62 (21%) patients with RA alone (p < 0.0001 for D-Ep which ended up with abnormal ALT, and p < 0.02 for the number of patients who developed abnormal ALT) and 128/623 (20.5%) patients with CVH alone (p < 0.005). 53% (9/17) of hydroxychloroquine (HCQ) D-Ep were associated with an abnormal outcome. Corresponding figures for sulphasalazine (SAZP) and oral or intramuscular gold preparations were 55.6% (5/9) and 0% (0/3) respectively. Two patients on methotrexate, used either singly or in combination, had normal ALT levels throughout the study period. One patient on azathioprine developed reactivation of hepatitis B infection. When D-Ep of the RA + CVH group were further analysed, 16/43 (37.2%) and 4/4 (100%) D-Ep which started with normal and abnormal baseline ALT respectively developed further liver enzyme derangement. CONCLUSION: The use of DMARD in RA + CVH patients is associated with a high incidence of hepatotoxicity. The effect is likely to be synergistic. This includes drugs such as HCQ, which is generally believed to be less hepatotoxic.",1
9751,10897581,[Changes in liver function induced by flutamide in patients with prostate cancer (studies in patients treated with total androgen blockage)],"OBJECTIVES: The incidence of flutamide-induced liver toxicity was studied in 30 consecutive patients with prostate cancer who were treated with total androgen blockage (TAB) therapy (luteinizing hormone releasing hormone [LHRH] analogue and flutamide) in our hospital during the last 3 years and in 20 consecutive patients with prostate cancer who were treated by partial androgen blockage (PAB) therapy (LHRH analogue alone). METHODS: Liver function test, including measurement of serum levels of aspartate aminotransferase (AST) alanine aminotransferase (ALT), total cholesterol, total bilirubin, gamma-glutamyl transpeptidase (gamma-GTP), and cholinesterase were performed at regular interval. RESULTS: The incidence of liver toxicity in patients receiving TAB (10 cases of 25 patients) was significantly higher than in patients receiving PAB (2 of 18 patients). Two patients in whom severe liver toxicity developed after receiving TAB were hospitalized. However, after flutamide was discontinued all patients with liver damage recovered with normalization of AST and ALT levels. Levels of total cholesterol and gamma-GTP did not differ significantly in either patient group. In two patients receiving TAB total bilirubin levels showed slight, transient elevations after maximum elevations of AST and ALT. In 80% of patients receiving TAB serum levels of cholinesterase were significantly higher than those in patients receiving PAB. CONCLUSION: These data suggest that the risk of flutamide-induced liver toxicity is significant in patients receiving TAB. However, this damage can be normalized after flutamide has been discontinued. Serum levels of cholinesterase also increase significantly in patients receiving TAB. This previously unreported phenomenon suggests an unknown effect of flutamide on liver function in patients with prostate cancer.",1
9752,10902281,[Toxic hepatitis caused by flutamide and hirsutism],,1
9753,10906833,Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases,"""BACKGROUND: An association between use of zidovudine and didanosine and a rare but life-threatening syndrome of hepatic steatosis, lactic acidosis, and myopathy has been reported. OBJECTIVE: To describe the syndrome of hepatic steatosis, lactic acidosis, and myopathy in four patients taking stavudine. DESIGN: Case series. SETTING: A community hospital in Washington, D.C., and National Institutes of Health Clinical Center, Bethesda, Maryland. PATIENTS: Two men and two women with HIV-1 infection who were taking stavudine presented with lactic acidosis and elevated levels of aminotransferases. All patients required intensive care. MEASUREMENTS: Levels of lactic acid, alanine aminotransferase, aspartate aminotransferase, amylase, and lipase; computed tomography of the abdomen; liver biopsy (two patients); and muscle biopsy (two patients). RESULTS: Histologic findings consistent with mitochondrial injury confirmed the diagnosis of hepatic or muscle abnormality. CONCLUSION: Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of elevated hepatic aminotransferase levels among patients taking stavudine.""",1
9754,10907999,Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease,,1
9755,10908683,"Leflunomide, a new disease-modifying anti-rheumatic drug and the never ending rheumatoid arthritis story",,1
9756,10914251,[Hepatic injury associated with use of nitrofurantoin],,1
9757,10916496,[Asymptomatic diclofenac-induced acute hepatitis],"HISTORY AND ADMISSION FINDINGS: After removal of an herniated intervertebral disc a 49-year-old man had recurrent pain in the lumbar region, treated with diclofenac and flupirtine. 4 months postoperatively he was referred to the author's hospital because of progressive rise in transaminase levels and in cholestasis parameters. Physical examination on admissions was unremarkable, except for jaundice. INVESTIGATIONS: Laboratory tests showed an increases in transaminases (GPT 769 U/l [normal: < 23 U/l], GOT 285 U/l [normal: < 19 U/l]) and in cholestasis-related values (gamma-GT 172 U/l [Norm 6-28 U/l], alkaline phosphatase 207 U/l [normal < 175 U/l], total bilirubin: 2.5 mg/dl [Norm < 1.1 mg/dl]). This corresponded to the histological finding of toxic damage to the liver parenchyma. Viral, autoimmune and metabolic causes had been excluded. DIAGNOSES, TREATMENT AND COURSE: The history as well as laboratory and histological findings indicated diclofenac-induced toxic hepatitis. The drug was discontinued and without any treatment all laboratory values returned to normal within 9 weeks. CONCLUSION: Diclofenac, a frequently prescribed non-steroid anti-inflammatory drug, is generally thought to be relatively safe. But it can produce toxic hepatitis which may be asymptomatic (but this patient was jaundiced) and may take an unforeseeable course. This should be taken account of by regularly monitoring liver functions.",1
9758,10918425,"High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors","Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.",1
9759,10923237,Cholelithiasis in a newborn following treatment with the somatostatin analogue octreotide,"We report the case of a newborn infant affected by congenital hyperinsulinism who developed cholelithiasis associated with cholestatic jaundice following treatment with octreotide, a somatostatin analogue.",1
9760,10925723,[Clinic-epidemiological significance of drug hepatotoxicity in liver disease consultation],"""To assess epidemiological and clinical significance of drug hepatotoxicity in the setting of liver diseases consultation, ten thousand and three hundred forty two prospectively designed clinical records from patient cared for in our Liver Unit in the period 1988-1998 were incorporated into the study; 58 out of 10,342 (prevalence = 5.6%) fulfilled at least the first three of the following causality requirements: 1.--Liver injury associated in time to drug exposition; 2.--Negative evaluation of more common other etiologies; (alcohol, viruses, immunologic, metabolic, etc) 3.--Favourable response to drug withdrawal (ALT < 50% of baseline in 8 to 30 days in acute hepatitis type, and alkaline phosphatase and/or total bilirubin < 50% of baseline up to 6 months, in acute cholestasis) 4.--Inadverted or rarely prescribed positive challenge. Acute hepatitis type of injury were considered when serum ALT rise 8 times or more above normal superior level with alkaline phosphatase (APh) below 3 times; """"pure"""" cholestasis when APh rise 3 times or more above normal with ALT below 8 times; mixed acute injury or cholestatic hepatitis when both ALT and APh were elevated above 8 and 3 times respectively, and indeterminate type when both enzymes were below the referred levels. Chronic injury were considered when six or more month of evolution and compatible liver histology happens. Clinical severity were expressed as mild (absence of major clinical complications, serum bilirubin < 5 mg/dl and prothrombin concentration > 75%), moderate (presence of clinical complications, bilirubin > 5 mg/dl and prothrombin concentration between 50-75%), and severe (major clinical complications with bilirubin > 5 mg/dl and prothrombin concentration < 50%). Female/male ratio was 1.4:1, with age average 39 years (R = 15-77) and major concentration of cases above 40. More than 50% of cases received 2 or more drugs. Jaundice was present in 60.4%, and systemic manifestations of hypersensibility (fever, adenomegalies, rush, mononucleosis like syndrome, eosinophilia) in 29.3%. Acute injury represented 91.4% of the cases: 41.4% acute hepatitis, 15.5% """"pure"""" cholestasis, 24.1% cholestatic hepatitis, and 10.3% indeterminate type. Four patients (4.5% of acute injury cases) were presented as severe acute liver failure, leading to liver transplant in one of them, drug association (INH-rifampicin and carbamazepine-phenobarbital) and inadverted challenge (sulphonamides and pemoline) were associated to clinical severity. Chronic injury were found in five patient (8.6%), four of them associated to chronic hepatitis and the other one to a ductopenic syndrome. Six drugs represented 53.4% of our cases; oral contraceptives (7 cases), INH alone or combined with rifampicin (6 cases), sulfonamides and clorpropamida (5 cases each), carbamazepine and amiodarone (4 cases each). Normalization of liver enzymes after drug suppression took 2 to 8 weeks in acute hepatitis type (X = 4 weeks), 4 to 20 in """"pure"""" cholestasis (X = 12 weeks) and 8 to 24 weeks in cholestatic hepatitis or mixed type (X = 16 weeks). Two cases of chronic hepatitis normalize the histological activity index in 20 and 18 month respectively, one case remains as chronic hepatitis at 10 month and the other one progress to cirrhosis; the ductopenic syndrome normalize histology in 19 months receiving urso-deoxicolic acid, 10 mg/k/day.""",1
9761,10928391,Frequency of cutaneous reactions on rechallenge with nevirapine and delavirdine,"OBJECTIVE: To determine the frequency of cutaneous reactions in a group of HIV-infected adults attending a public hospital HIV clinic who received nevirapine, delavirdine, or both, as well as the consequences of rechallenge with the same or alternative agent. DESIGN: The medical records of patients who had received either or both agents between March 1997 and July 1998 were reviewed, including 69 patients who initially received nevirapine and 20 who initially received delavirdine. Gender, ethnicity, HIV status, and plasma HIV RNA concentrations were analyzed as risk factors for the development of rash. RESULTS: The overall incidence of rash attributed to the initial use of one of these drugs was 37.1%. While rash due to delavirdine occurred more often, the rash due to nevirapine was more severe and resulted in hospitalization more frequently. There was a trend toward a higher frequency of rash in Latinos and possibly in women, but HIV status, CD4+ cell counts, and plasma HIV RNA were not risk factors for the development of rash. Drug therapy was temporarily or permanently discontinued because of rash in 19 of 69 (28%) and in five of 20 (25%) patients initially receiving nevirapine or delavirdine, respectively. Rash recurred in six of eight (75%) patients rechallenged with the same agent, and in seven of 10 (70%) who were crossed over to the alternative agent because of rash. Fever, in the absence of any apparent cause, was a significant predictor for the development of rash in patients receiving nevirapine. CONCLUSIONS: There is probably little value in attempting to retreat patients with cutaneous reactions, even with the alternative agent, except in patients with limited treatment options.",1
9762,10929166,Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes,"""BACKGROUND: Troglitazone promotes adipocyte differentiation in vitro and increases insulin sensitivity in vivo. Therefore, troglitazone may have therapeutic benefit in lipoatrophic diabetes. OBJECTIVE: To determine whether troglitazone ameliorates hyperglycemia and hypertriglyceridemia or increases fat mass in lipoatrophic patients. DESIGN: Open-labeled prospective study. SETTING: United States and Canada. PATIENTS: 20 patients with various syndromes associated with lipoatrophy or lipodystrophy. INTERVENTION: 6 months of therapy with troglitazone, 200 to 600 mg/d. MEASUREMENTS: Levels of hemoglobin A1c triglycerides, free fatty acids, and insulin; respiratory quotient; percentage of body fat; liver volume; and regional fat mass. RESULTS: In the 13 patients with diabetes who completed 6 months of troglitazone therapy, hemoglobin A1c levels decreased by a mean of 2.8% (95% CI, 1.9% to 3.7%; P < 0.001). In all 19 study patients, fasting triglyceride levels decreased by 2.6 mmol/L (230 mg/dL) (CI, 0.7 to 4.5 mmol/L [62 to 398 mg/dL]; P = 0.019) and free fatty acid levels decreased by 325 micromol/L (CI, 135 to 515 micromol/L; P = 0.035). The respiratory quotient decreased by a mean of 0.12 (CI, 0.08 to 0.16; P < 0.001), suggesting that troglitazone promoted oxidation of fat. Body fat increased by a mean of 2.4 percentage points (CI, 1.3 to 4.5 percentage points; P = 0.044). Magnetic resonance imaging showed an increase in subcutaneous adipose tissue but not in visceral fat. In one patient, the serum alanine aminotransferase level increased eightfold during the 10th months of troglitazone treatment but normalized 3 months after discontinuation of treatment Liver biopsy revealed an eosinophilic infiltrate, suggesting hypersensitivity reaction as a cause of hepatotoxicity. CONCLUSION: Troglitazone therapy improved metabolic control and increased body fat in patients with lipoatrophic diabetes. The substantial benefits of troglitazone must be balanced against the risk for hepatotoxicity, which can occur relatively late in the treatment course.""",1
9763,10930052,"Safety and efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) in children with elevated blood lead concentrations","""OBJECTIVE: To evaluate the safety and efficacy of meso-2,3-dimercaptosuccinic acid in the treatment of children with lead toxicity. DESIGN: This was an open-label study in 59 children 12-65-months old, with pretreatment whole-blood lead levels of 25-66 microg/dL, who received 116, 26-28 day courses of oral dimer-captosuccinic acid, while residing either in the Pediatric Clinical Research Unit of the Johns Hopkins Hospital or in lead-safe housing during the outpatient portion of the study. RESULTS: All, who completed the study, showed sharp decreases in blood lead concentration during therapy, but 2-3 weeks following completion of drug therapy, blood lead concentration rebounded to an average of 58% (23 microg Pb/dL of whole blood) of their average pretreatment blood lead concentration (40 microg Pb/dL of whole blood). There were no adverse reactions attributable to dimercaptosuccinic acid; however, 2 of the 59 patients were reexposed to defective lead paint and experienced sharp increases in blood lead concentration while on therapy. In one instance, the child's blood lead concentration increased from 20 to 90 microg Pb/dL whole blood in 1 week. Other unexpected events were discussed in the text. CONCLUSIONS: Dimercaptosuccinic acid is apparently safe and does mobilize lead into the urine, but not the essential metals, zinc and copper. Reexposure is always a danger; therefore, all children, while on therapy, should be monitored for their blood lead concentration at weekly intervals during and immediately after therapy. No conclusions can be drawn from this study regarding long-term beneficial effects, if any, of this drug on late neurocognitive outcome.""",1
9764,10931801,Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS),"""BACKGROUND: Combination therapy with the ADP receptor antagonist ticlopidine plus aspirin has emerged as standard care after coronary stenting. Clopidogrel, a new ADP receptor antagonist, has greater molar potency than ticlopidine and better safety/tolerability. METHODS AND RESULTS: Patients (n=1020) were randomized after successful stent placement and initiated on a 28-day regimen of either (1) 300-mg clopidogrel loading dose and 325 mg/d aspirin on day 1, followed by 75 mg/d clopidogrel and 325 mg/d aspirin; (2) 75 mg/d clopidogrel and 325 mg/d aspirin; or (3) 250 mg BID ticlopidine and 325 mg/d aspirin. The primary end point consisted of major peripheral or bleeding complications, neutropenia, thrombocytopenia, or early discontinuation of study drug as the result of a noncardiac adverse event during the study-drug treatment period. The primary end point occurred in 9.1% of patients (n=31) in the ticlopidine group and 4.6% of patients (n=31) in the combined clopidogrel group (relative risk 0.50; 95% CI 0.31 to 0.81; P=0.005). Overall rates of major adverse cardiac events (cardiac death, myocardial infarction, target lesion revascularization) were low and comparable between treatment groups (0.9% with ticlopidine, 1.5% with 75 mg/d clopidogrel, 1.2% with the clopidogrel loading dose; P=NS for all comparisons). CONCLUSIONS: The safety/tolerability of clopidogrel (plus aspirin) is superior to that of ticlopidine (plus aspirin) (P=0.005). The 300-mg loading dose was well tolerated, notably with no increased risk of bleeding. Secondary end point data are consistent with the hypothesis that clopidogrel and ticlopidine have comparable efficacy with regard to cardiac events after successful stenting.""",1
9765,10933271,Oral contraceptive and benign ovarian tumors,"Whether use of combined oral contraceptives (OC) protects against benign ovarian tumors is unknown. A case-control study of pathologically confirmed benign ovarian tumors was conducted in the New York City area and included cases diagnosed from January 1, 1992, to December 31, 1993, and controls identified by random digit dialing. There were 196 cases with serous adenomas, 176 with teratomas, 311 with endometriomas, and 65 with mucinous adenomas. Interview data were used to determine contraceptive use. Ever use of OC was associated with a decreased risk of these benign tumors (age- and hospital-adjusted odds ratio = 0.79, 95% confidence interval: 0.60, 1.05). In histologic subgroup analyses, the risk of ovarian tumors was reduced for both current and past OC users. Among tumor subtypes, the risk reduction was greatest for women who had endometriotic lesions. The risk reduction also was greater for women who had used OC for more than 24 months. Protection against benign ovarian tumors may be an additional noncontraceptive benefit of OC use.",1
9766,10933615,Change in transaminases in hepatitis C virus- and HIV-coinfected patients after highly active antiretroviral therapy: differences between complete and partial virologic responders?,"Patients with HIV and hepatitis C virus (HCV) coinfection have more severe hepatitis-related disease than do patients with HCV infection alone. Highly active antiretroviral therapy (HAART) with protease inhibitor appears to restore pathogen-specific immune responses, especially in patients with persistent undetectable HIV viral load. To evaluate the potent impact of immune restoration induced by HAART on the course of HCV-related disease, HCV viremia and levels of transaminases were compared between two groups of patients: 10 HIV/HCV-coinfected patients with persistently undetectable HIV viremia (group A) and 12 HIV/HCV-coinfected patients with persistent detectable HIV viremia. No difference was detected in HCV viral load in either group. An increase in transaminases was found only in patients with persistent undetectable HIV viral load, which was correlated with the increase in CD8+ T cells. This may suggest that the restoration of CD8+ T cell cytotoxicity could lead to an enhancement of hepatitis C-related disease in HCV/HIV-coinfected patients receiving HAART.",1
9767,10945507,The safety profile of the fluoroquinolones,"BACKGROUND: Premarketing trials showed the fluoroquinolone agents to have a favorable side-effect profile, with treatment-related adverse events comprising gastrointestinal, central nervous system, and dermatologic effects that were generally mild and reversible on cessation of treatment. However, postmarketing surveillance studies have identified severe adverse events, including severe anaphylaxis, QTc-interval prolongation, and potential cardiotoxicity, associated with 3 quinolone agents that either resulted in the removal of the agent from the market (temafloxacin and grepafloxacin) or significantly restricted its use due to substantial mortality and morbidity associated with liver toxicity (trovafloxacin). To date, there have been no such significant adverse events associated with the older fluoroquinolone agents, including ciprofloxacin, ofloxacin, norfloxacin, and levofloxacin. However, there are fewer data from postmarketing surveillance studies on the most recently approved agents, such as moxifloxacin and gatifloxacin, or agents awaiting approval, such as gemifloxacin. OBJECTIVE: This paper examines safety data from the premarketing trials and postmarketing surveillance studies of fluoroquinolones available in the United States. METHODS: A MEDLINE search was performed to identify all English-language studies published since 1980 concerning the safety profiles of the fluoroquinolones. CONCLUSIONS: The fluoroquinolone antibacterial agents offer broad-spectrum therapy in patients with a variety of infections. Given similar spectra of activity, the choice between quinolones may be based on differences in efficacy and safety or tolerability profiles. Most drug reactions involving these agents are minor and reversible on discontinuing treatment, but adverse effects can be associated with significant mortality and morbidity, as was seen in the case of trovafloxacin and temafloxacin.",1
9768,10948380,Hepatotoxicity of botanicals,"OBJECTIVE: Hepatic impairment resulting from the use of conventional drugs is widely acknowledged, but there is less awareness of the potential hepatotoxicity of herbal preparations and other botanicals, many of which are believed to be harmless and are commonly used for self-medication without supervision. The aim of this paper is to examine the evidence for hepatotoxicity of botanicals and draw conclusions regarding their pathology, safety and applications. DESIGN: Current literature on the hepatotoxicity of herbal drugs and other botanicals is reviewed. The aetiology, clinical picture and treatment of mushroom (Amanita) poisoning are described. RESULTS: Hepatotoxic effects have been reported for some Chinese herbal medicines (such as Jin Bu Huan, Ma-Huang and Sho-saiko-to), pyrrolizidine alkaloid-containing plants, germander (Teucrium chamaedrys), chaparral (Larrea tridentata), Atractylis gummifera, Callilepsis laureola, and others. The frequency with which botanicals cause hepatic damage is unclear. There is a lack of controlled treatment trials and the few studies published to date do not clarify the incidence of adverse effects. Many plant products do not seem to lead to toxic effects in everyone taking them, and they commonly lack a strict dose-dependency. For some products, such as Sho-saiko-to, the picture is confused further by demonstrations of hepatoprotective properties for some components. Mushroom poisoning is mostly due to the accidental consumption of Amanita species. Treatment with silymarin, thioctic acid, penicillin and liver transplantation have been shown to be effective but require early diagnosis. CONCLUSIONS: Severe liver injury, including acute and chronic abnormalities and even cirrhotic transformation and liver failure, has been described after the ingestion of a wide range of herbal products and other botanical ingredients, such as mushrooms. It is concluded that in certain situations herbal products may be just as harmful as conventional drugs.",1
9769,10950090,Didanosine-induced hepatitis,,1
9770,10950478,Hepatic encephalopathy associated with combined clozapine and divalproex sodium treatment,,1
9771,10955785,A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver,"""There are no satisfactory treatment options for patients with ocular melanoma metastatic to liver, and after liver metastases are identified, median survival is only between 2 and 7 months. Because liver metastases are the sole or life-limiting component of disease in the vast majority of patients who recur, we reasoned that complete vascular isolation and perfusion of the liver might result in clinically meaningful regression of disease. Between September 1994 and July 1999, 22 patients (13 women and 9 men; mean age, 49 years) with ocular melanoma metastatic to liver were treated with a 60-min hyperthermic isolated hepatic perfusion (IHP) using melphalan alone (1.5-2.5 mg/kg, n = 11) or with tumor necrosis factor (TNF, 1.0 mg, n = 11). Via a laparotomy, IHP inflow was via the hepatic artery alone (n = 17) or hepatic artery and portal vein (n = 5) and outflow from an isolated segment of inferior vena cava. Most patients had advanced tumor burden with a mean percentage of hepatic replacement of 25% (range, 10-75%) and a median number of metastatic nodules of 25 (range, 5 to >50). Complete vascular isolation was confirmed in all patients using a continuous intraoperative leak monitoring technique with 131I radiolabeled albumin. There was one treatment mortality (5%). The overall response rate in 21 patients was 62% including 2 radiographic complete responses (9.5%) and 11 partial responses (52%). The overall median duration of response was 9 months (range, 5-50) and was significantly longer in those treated with TNF than without (14 versus 6 months, respectively; P = 0.04). Overall median survival in 22 patients was 11 months. These data indicate that a single 60-min IHP can result in significant regression of advanced hepatic metastases from ocular melanoma. TNF appears to significantly prolong the duration of response.""",1
9772,10958225,Fatal hepatotoxicity after re-exposure to isoflurane: a case report and review of the literature,"A 76-year-old Caucasian woman developed fulminant hepatic necrosis 6 days after an uneventful operation under isoflurane anaesthesia. Laboratory findings included elevated bilirubin, grossly elevated transaminases and prolonged prothrombin time. Radiological investigation showed no evidence of extra-hepatic disease. Serological studies were negative for acute viral hepatitis and autoimmune disease. The patient may have been previously sensitized by exposure to isoflurane 3 years previously but antibodies to tri-fluoro acetate, present in 70% of cases of halothane hepatitis, were not detected in pre-operative or postoperative samples of blood. On the seventh postoperative day the patient died and postmortem examination demonstrated centrilobular necrosis of the liver, with a histological pattern similar to changes associated with halothane hepatitis.",1
9773,10962217,Valproate metabolism during valproate-associated hepatotoxicity in a surviving adult patient,"The plasma profiles of valproate (VPA), its beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA and its terminal desaturation metabolite 4-en-VPA, have been measured in a patient receiving NaVPA 1000 mg twice per day from early in the course of serious hepatotoxicity and for 2 weeks after the drug was stopped. Concurrent profiles of liver, renal and haematological function parameters were available. Relative to concurrent plasma VPA concentrations, E-2-en-VPA concentrations were not different to those of the VPA-treated epileptic population at any stage of the illness, whereas 3-oxo-VPA concentrations relative to concurrent VPA concentrations were abnormally high early in the toxicity, abnormally low at its peak (3-5 days later), and comfortably within normal limits for the treated epileptic population late in the recovery phase (9-13 days from the onset). When measurable, plasma 4-en-VPA concentrations were not elevated. The elimination half-life of VPA during the recovery phase was 100 h, which is some 6-12 times greater than values reported for this parameter in normal patients. These data clearly define, in this patient, a link between idiosyncratic VPA-associated hepatotoxicity at its onset and peak and the later stages of VPA beta-oxidation. Whether the beta-oxidation abnormalities are causative or a consequence of an as yet undefined defect is unknown. In this patient, 4-en-VPA was unlikely to have been involved in the pathogenesis of the toxicity.",1
9774,10962947,[Symptomatic pseudolithiasis caused by Rocephalin],"Treatment with ceftriaxone may be accompanied by precipitation of ceftriaxone calcium salts in the gallbladder, called pseudolithiasis. We present a case, in which a formerly healthy five year-old girl developed symptomatic pseudolithiasis during treatment with Rocephalin. The symptoms and pseudolithiasis disappeared after a few days with symptomatic treatment and change of antibiotics.",1
9775,10966298,Death related to propofol use in an adult patient,"OBJECTIVE: To report an adult trauma patient fatality related to propofol administration. DESIGN: Retrospective case review. SETTING: Trauma intensive care unit (ICU) in a level one trauma center. PATIENT: An 18-yr-old man involved in a motor vehicle crash. INTERVENTIONS: Treatment for multiple trauma injuries and propofol sedation. MEASUREMENTS AND MAIN RESULTS: Posttrauma ICU monitoring was performed. The patient developed cardiac arrhythmia, metabolic acidosis, and cardiac failure, which resulted in death. CONCLUSION: Death related to propofol infusion can occur in adults as well as in pediatric patients.",1
9776,10969344,Mortality for liver disease in patients with HIV infection: a cohort study,"""We undertook this study to assess the association between the various potential causes of liver disease in HIV-seropositive patients and mortality due to liver failure. Three hundred and eight in-hospital deaths were observed from 1987 to December 1995 in a prospectively followed cohort of 1894 HIV-seropositive patients. For each study subject, clinical data were evaluated to assess whether liver failure had substantially contributed to mortality. A case control study nested in the cohort was then performed, which compared demographic and clinical variables observed at enrollment and during follow-up between patients who died for liver disease as the main or concurrent cause of death (cases) and those who died as a result of illness related to AIDS or other causes (controls). Among 308 in-hospital deaths, liver failure was found the cause of death in 35 patients (12%); in 16 cases, it was the primary cause and in 19 cases it was concurrent. Multivariate analysis showed that in-hospital liver-disease-related mortality was independently associated with hepatitis B surface antigen reactivity (odds ratio [OR], 9; 95% confidence interval [CI], 3.8-21.7) and history of alcohol abuse (OR, 2.3; 95% CI, 1-5.2). Prevention and treatment of hepatitis B virus infection and alcohol intake are management priorities in HIV-seropositive patients.""",1
9777,10969925,Experience with cyproterone acetate in the treatment of precocious puberty,"The authors review their experience (1967-present) in the use of cyproterone acetate (CPA) in precocious puberty. CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg b.i.d. (70-100 mg/d). After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial stimulatory effect of the GnRHa as well as an adjunct drug in case of very active adrenarche causing advanced bone age during GnRHa treatment. The final heights of girls treated with CPA and girls treated with D-Trp6-LHRH were found comparable: 157.8+/-5.1 cm vs 159.6+/-6.3 cm, respectively. The main adverse effects were occasional fatigue due to partial adrenal insufficiency with CPA and gynecomastia in a few boys. Liver function tests were normal in all patients with the exception of one boy with severe hypothalamic disease, including precocious puberty, who developed liver cirrhosis 3 years after stopping CPA following 5 years treatment. Other indications for CPA treatment during childhood and adolescence, such as fast puberty, congenital adrenal hyperplasia and acne, are also mentioned.",1
9778,10976903,Anabolic steroid-induced hepatic adenomas with spontaneous haemorrhage in a bodybuilder,,1
9779,10979796,Alendronate for the treatment of osteoporosis in men,"""BACKGROUND: Despite its association with disability, death, and increased medical costs, osteoporosis in men has been relatively neglected as a subject of study. There have been no large, controlled trials of treatment in men. METHODS: In a two-year double-blind trial, we studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis. Approximately one third had low serum free testosterone concentrations at base line; the rest had normal concentrations. Men with other secondary causes of osteoporosis were excluded. All the men received calcium and vitamin D supplements. The main outcome measures were the percent changes in lumbar-spine, hip, and total-body bone mineral density. RESULTS: The men who received alendronate had a mean (+/-SE) increase in bone mineral density of 7.1+/-0.3 percent at the lumbar spine, 2.5+/-0.4 percent at the femoral neck, and 2.0+/-0.2 percent for the total body (P<0.001 for all comparisons with base line). In contrast, men who received placebo had an increase in lumbar-spine bone mineral density of 1.8+/-0.5 percent (P<0.001 for the comparison with base line) and no significant changes in femoral-neck or total-body bone mineral density. The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites (P<0.001). The incidence of vertebral fractures was lower in the alendronate group than in the placebo group (0.8 percent vs. 7.1 percent, P=0.02). Men in the placebo group had a 2.4-mm decrease in height, as compared with a decrease of 0.6 mm in the alendronate group (P=0.02). Alendronate was generally well tolerated. CONCLUSIONS: In men with osteoporosis, alendronate significantly increases spine, hip, and total-body bone mineral density and helps prevent vertebral fractures and decreases in height.""",1
9780,10979889,Rosiglitazone and liver failure,,1
9781,10981257,Ceftriaxone-associated nephrolithiasis,,1
9782,10983737,Pioglitazone,"Pioglitazone is an orally administered insulin sensitising thiazolidinedione agent that has been developed for the treatment of type 2 diabetes mellitus. Pioglitazone activates the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma), which leads to the increased transcription of various proteins regulating glucose and lipid metabolism. These proteins amplify the post-receptor actions of insulin in the liver and peripheral tissues, which leads to improved glycaemic control with no increase in the endogenous secretion of insulin. In placebo-controlled clinical trials, monotherapy with pioglitazone 15 to 45 mg/day has been shown to decrease blood glycosylated haemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus. The addition of pioglitazone 30 mg/day to preexisting therapy with metformin, or of pioglitazone 15 or 30 mg/day to sulphonylurea, insulin or voglibose therapy, has been shown to decrease HbA1c and fasting blood glucose levels significantly in patients with poorly controlled type 2 diabetes mellitus. Pioglitazone has also been associated with improvements in serum lipid profiles in randomised placebo-controlled clinical studies. The drug has been well tolerated by adult patients of all ages in clinical studies. Oedema has been reported with monotherapy, and pooled data have shown hypoglycaemia in 2 to 15% of patients after the addition of pioglitazone to sulphonylurea or insulin treatment. There have been no reports of hepatotoxicity.",1
9783,10987009,Quinupristin/dalfopristin,,1
9784,10989325,Troglitazone-induced fulminant hepatitis: report of a case with autopsy findings,"""Troglitazone is an insulin-sensitizing agent used to treat type 2 diabetes mellitus. Several cases have been reported of troglitazone-induced hepatic injury; some requiring transplantation, others resulting in death. We here present a case of troglitazone-induced fulminant hepatic necrosis that led to the death of the patient.""",1
9785,10992732,Injectable gold-induced hepatitis and neutropenia in rheumatoid arthritis,"Gold salts have been used for many years in the treatment of rheumatoid arthritis. The common side effects are mucocutaneous reactions, but hepatotoxic reaction and isolated neutropenia are rare complications. We report a 62-year-old woman with rheumatoid arthritis who had developed hepatitis and neutropenia simultaneously after receiving 137.5 mg of sodium aurothiomalate.",1
9786,10997508,Clinical features and risk factors of lactic acidosis following long-term antiretroviral therapy: 4 fatal cases,"""Our objective was to describe clinical features and predisposing factors attributed to lactic acidosis in 4 HIV-infected patients on long-term nucleoside reverse transcriptase inhibitor (NRTI) therapy. All patients had received at least 6-20 months of NRTI-containing antiretroviral therapy: all used stavudine (d4T), in one combined with lamivudine (3TC), in the other 3 with didanosine (ddI); in one hydroxyurea was added. In all, the initial symptoms were gastrointestinal (nausea and vomiting), followed by tachypnoea preceding the lactic acidosis; death followed 6-22 days after admission (liver failure and uncontrollable arrhythmias). Treatment with riboflavin was unsuccessful in one patient. The only definite risk factor in all cases was NRTI-induced mitochondrial toxicity; one patient was concomitantly treated for Kaposi's sarcoma (with bleomycin and vinblastine) and one just recovered from pneumococcal sepsis. None of the patients had a history of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. In all patients, some sort of toxicity to other previously used NRTIs had occurred earlier. Lactic acidosis occurred after months of NRTI therapy in patients who had already suffered other forms of NRTI toxicity. Concomitant diseases or comedication might have aggravated the mitochondrial toxicity of the NRTIs. Screening methods to detect mitochondrial toxicity are necessary, since lactic acidosis occurs rather unexpectedly, with a rapid, fatal course.""",1
9787,10999171,Phenytoin induced severe agranulocytosis and hepatitis,,1
9788,10999594,Anaphylaxis from intravenous thiamine--long forgotten?,,1
9789,11007105,Acetaminophen hepatoxicity,"To determine the influence of psychosocial factors in accidental and deliberate acetaminophen overdose, we reviewed the charts of 207 overdose patients, and 48 met our criteria for acetaminophen toxicity. Two patients died. A psychiatric history was present in 75%, and 25% had a previous or subsequent suicide attempt. A substance abuse history was elicited from 46% and 36% of adolescent teenagers had a teen pregnancy. The mean time to starting N-acetylcysteine was 18.5 hr. Delayed N-acetylcysteine administration led to higher transaminase levels. Alcohol abuse was associated with a longer hospital stay. Mean AST was 8,860 IU/liter in the accidental and 3,013 IU/liter in the suicide groups. We concluded that management of acetaminophen toxicity can be optimized by early identification, obtaining a complete drug screen, starting N-acetylcysteine early or whenever toxic acetaminophen levels or elevated transaminases are identified, and referring patients with acetaminophen toxicity to a liver center.",1
9790,11007239,A pilot study of pentoxifylline for the treatment of primary sclerosing cholangitis,"""OBJECTIVE: There is no effective therapy for patients with primary sclerosing cholangitis (PSC). Rats with experimental small bowel bacterial overgrowth develop hepatobiliary injury similar to PSC. The hepatobiliary injury results from peptidoglycan-polysaccharide-mediated activation of Kupffer cells, release of cytokines such as tumor necrosis factor (TNF-alpha), and is prevented by pentoxifylline. Our aims were to assess the safety and effects of pentoxifylline on symptoms and biochemical liver tests in patients with PSC. METHODS: A total of 20 patients with clinical, cholangiographic, and histological features of PSC of varying severity were treated with pentoxifylline sustained release (SR) tablets (400 mg q.i.d.) for < or = 1 yr. Serum alkaline phosphatase, aspartate aminotransferase, and bilirubin were monitored every 3 months for 1 year; serum TNF-alpha and TNF receptor subtypes I and II were assessed at baseline and 1 year. RESULTS: Of 20 patients, 16 tolerated pentoxifylline and completed the study. Two patients were withdrawn because of severe nausea, and two patients were noncompliant with medication and withdrew. Pentoxifylline did not significantly alter symptoms of fatigue or pruritus, serum liver tests, serum TNF-alpha or TNF receptor levels. CONCLUSIONS: In the current regimen, pentoxifylline alone does not significantly improve symptoms or liver tests in patients with PSC.""",1
9791,11012560,The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies,"""AIMS: To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. METHODS: In prescription-event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. RESULTS: The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0. 18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0. 17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age-response relationship. CONCLUSIONS: Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.""",1
9792,11020010,Budd-Chiari syndrome: combination of genetic defects and the use of oral contraceptives leading to hypercoagulability,"A young female, who had been in excellent health and had used third-generation oral contraceptives, was admitted to hospital because of abdominal pain and ascites. Budd-Chiari syndrome (BCS) was diagnosed by radiographic and histological examination. Tests for myeloproliferative disease, deficiency of coagulation inhibitors and paroxysmal nocturnal haemoglobinuria were negative. DNA investigation showed a double heterozygous defect: the Arg506Gln mutation in the factor V gene (factor V Leiden) and G20210A nucleotide substitution in the prothrombin gene. This double defect was also found in the patient's father, who had never experienced an episode of venous thromboembolism. Genetic and acquired thrombogenic risk factors are being detected increasingly in patients with BCS. With the discovery of new genetic defects leading to hypercoagulabiulity an increasing number of patients with serious thrombotic manifestations, such as BCS, will exhibit concurrence of hereditary and acquired risk factors for thrombosis.",1
9793,11032933,Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients,"Adjuvant tamoxifen has become the treatment of choice against estrogen receptor-positive breast cancer. Adverse effects are rarely observed and since symptoms of hepatic steatosis, non-alcoholic steatohepatitis and cirrhosis are usually negligible, such effects are not well characterized despite large cohort studies of adjuvant tamoxifen. This issue remains to be systematically studied. The present study consisted of 136 breast cancer patients treated with or without tamoxifen. Patients had laboratory tests once each month and underwent abdominal computed tomography (CT) annually for 5 years. The extent of hepatic steatosis was assessed by CT as the liver/spleen ratio. While receiving adjuvant tamoxifen, 40 of 105 patients developed hepatic steatosis (liver/spleen ratio <0.9) without obvious changes in body mass index. Twenty-one had a liver spleen ratio of <0.5, whereas none of the 31 patients treated without tamoxifen had a ratio <0.9 or <0.5 (p<0.0001 and p<0.0001, respectively). Hepatic steatosis was recognized in 35 of the 40 patients within the first 2 years of receiving adjuvant tamoxifen and 21 of the 40 had increased transaminase levels. Liver biopsy revealed NASH in 6 of 7 patients among the 21 with a liver/spleen ratio of <0.5. A subset of individuals given adjuvant tamoxifen developed progressive hepatic steatosis without significant changes in the body mass index. We suggest a liver/spleen ratio of <0.5 as a criterion upon which liver biopsy should be recommended since NASH frequently occurred in such patients.",1
9794,11034006,Granular cells as a marker of early amiodarone hepatotoxicity,"Hepatotoxicity due to chronic amiodarone (AD) use is well described. However, hepatitis occurring after acute administration of AD has only occasionally been reported and the pathologic findings in the liver in this condition have not been well characterized. We describe an idiosyncratic reaction, in a 40-year-old man after 6 weeks of oral AD therapy, consisting of acute hepatitis, which resolved after withdrawal of the drug. The liver biopsy showed clusters of cells with granular cytoplasm. These cells were characterized as macrophages, and phospholipid membranous inclusions were demonstrated ultrastructurally in the granular cells and in the hepatocytes. Pathologists and clinicians should be aware of this subtle histologic finding when looking for evidence to support AD hepatotoxicity.",1
9795,11034591,Co-amoxiclav jaundice: clinical and histological features and HLA class II association,"""BACKGROUND AND AIMS: Jaundice associated with co-amoxiclav has been increasingly recognised. We aimed to characterise its clinical and histological features and to investigate linkage with human leucocyte antigen class II haplotypes. METHODS: We identified cases in the west of Scotland in the period 1991-1997 and performed polymerase chain reaction amplification and oligonucleotide probing on whole blood. RESULTS: Twenty two cases were identified (10 male, mean age 59.1 years). Jaundice occurred a median of 17 days after drug commencement, with a median peak bilirubin level of 225 micromol/l (range 84-598) and median duration of jaundice 69 days (range 29-150). Two patients had primary biliary cirrhosis and two other patients had persistently abnormal liver biochemistry on follow up. One death occurred in a frail elderly woman despite resolving jaundice. The frequency of jaundice was 1 in 78 209 co-amoxiclav prescriptions. Liver biopsy, available in 12 patients, showed perivenular bilirubinostasis, accompanying reactive ceroid laden macrophages, and portal inflammation with focal injury to interlobular bile ducts. Fourteen of 20 patients had DRB1*1501 compared with 27 of 134 controls (p<2.5 x 10(-6); odds ratio (OR) 9.25; relative risk (RR) 6.43). Of these, seven patients were homozygous for DRB1*1501(p< 10(-8); OR 35.54; RR=8.68) compared with two of 134 controls. All patients with DRB1*1501 had the extended haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602. There were no clinical or histological differences between genotypes. CONCLUSIONS: Co-amoxiclav associated hepatotoxicity may have a genetic basis and be delayed, severe, and prolonged, although complete recovery is usual.""",1
9796,11036799,Hepatic glycogenosis: reversible hepatomegaly in type 1 diabetes,"""OBJECTIVE: To describe the aetiology, clinical features and appropriate treatment for hepatic glycogenosis in poorly controlled type 1 diabetes. METHODS: A review of three adolescents with poor diabetes control, hepatomegaly and elevated serum liver transaminase concentrations. RESULTS: Symptoms included abdominal pain, anorexia, nausea and vomiting. All had tender hepatomegaly; two had splenomegaly. Liver biopsy was performed on two patients. Histology revealed hepatic glycogenosis in both; one also demonstrated macrovesicular steatosis. With improved glycaemic control, all three showed resolution of their symptoms, organomegaly and elevated serum liver transaminase concentrations. CONCLUSIONS: Insulin-reversible hepatic glycogenosis is the most common cause of hepatomegaly and raised serum liver transaminase concentrations in children and adolescents with type 1 diabetes. Having excluded other causes of hepatic dysfunction, a 4 week therapeutic trial of improved glycaemic control is recommended prior to more invasive investigations.""",1
9797,11041902,"Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam Osteoarthritis Investigators","""BACKGROUND: Meloxicam (Mobic; Boehringer Ingelheim, Ridgefield, Conn) is an enolic acid derivative of the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs) whose mechanism of action may be related to prostaglandin (cyclooxygenase) synthetase inhibition. In previous studies, meloxicam has been found to be safe and effective in the treatment of osteoarthritis (OA) at doses of 7.5 to 15 mg daily. To evaluate a lower dose and a different patient population, we evaluated the efficacy and safety of 3 doses of meloxicam vs placebo and diclofenac for the treatment of OA among patients with symptom exacerbations. METHODS: In this double-blind, double-dummy, parallel-group, multicenter study, 774 patients with confirmed OA of the hip or knee and a flare were randomized and treated with daily oral administration of meloxicam tablets (at dosages of 3.75, 7.5, or 15 mg/d), diclofenac (100 mg [50 mg twice daily]), or placebo. Treatment was for 12 weeks, with regular assessments for drug safety and efficacy. Safety was assessed by evaluation of adverse events, vital signs, and laboratory data. Primary efficacy variables included the Western Ontario and McMaster University Osteoarthritis (WOMAC) index, the patient's overall assessment of pain, and the patient's and investigator's overall assessment of disease activity. RESULTS: The incidence of all adverse events was lower at each dosage of meloxicam than for diclofenac but greater than for placebo. However, the incidence of gastrointestinal adverse events and dropout rates because of such events was the same for meloxicam as for placebo and lower than for diclofenac. Meloxicam, at 7.5 and 15 mg/d, and diclofenac were statistically significantly more effective than placebo for all end points, while the 3.75-mg/d dosage of meloxicam did not always reach statistical significance for all end points. Efficacy was evident after 2 weeks of treatment, improved with increasing doses, and was maintained until the end of the trial. CONCLUSIONS: Meloxicam is a safe and effective medication for the symptomatic treatment of OA. The data support consideration of 7.5 to 15 mg of meloxicam once daily to treat the pain and stiffness of OA, with gastrointestinal tolerability comparable to that of placebo. Arch Intern Med. 2000;160:2947-2954""",1
9798,11045912,Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal,"""The long-term efficacy and safety of oral Viagra (sildenafil citrate), a selective phosphodiesterase 5 inhibitor, and the effect of withdrawing treatment were evaluated in men with erectile dysfunction (ED). In 233 men with ED of psychogenic or mixed organic/psychogenic aetiology, 16 weeks of open-label, flexible-dose sildenafil treatment (10-100 mg) was followed by eight weeks of double-blind, fixed-dose, randomised withdrawal to placebo or continued treatment with sildenafil. Sildenafil was taken as needed (not more than once daily) approximately 1 h prior to sexual activity. The main outcome measures were a global efficacy question, a sexual function questionnaire, an event log of erections, and adverse event recording. In the open-label phase, 200 of 216 patients (93%) reported improved erections with sildenafil; 28 patients (12%) discontinued treatment. In the double-blind phase, the significant improvements in the frequency and duration of erections were maintained in the sildenafil group but returned to pre-treatment values in patients on placebo (P values < 0.0001 versus placebo). The most frequent adverse events in the sildenafil group during the double-blind phase were flushing (7%), headache (6%), and dyspepsia (5%). Of the 192 patients enrolled in the 1-y extension, 90% completed the study; only two patients (1%) were withdrawn due to lack of efficacy. In men with ED of psychogenic or mixed aetiology, oral sildenafil is effective and well-tolerated both at the initiation of therapy and during long-term treatment. For most patients, sildenafil treatment must be continued for improvements in erectile function to be maintained.""",1
9799,11052334,Acute hepatitis induced by bupropion,"As an antidepressant, bupropion is considered to be a safe agent that usually causes infrequent and mild increase of serum liver enzymes. Asymptomatic elevation of serum transaminases was previously reported only in a single case. We describe a patient who developed typical acute hepatitis after receiving six weeks of bupropion for depression. His presentation was characterized with acute onset of symptoms associated with significantly elevated ALT, AST, and LDH and acute hepatic inflammation. The clinical course of our patient, including incubation period, pattern of liver enzyme elevation, and time of recovery, was similar to, but much more severe than, the case reported by Oslin and Duffy. Discontinuation of bupropion was followed by a rapid resolution of clinical symptoms and liver enzymes. The incidence of bupropion-induced hepatitis remains to be defined even though it appears to be relatively low. Since the clinical application of bupropion is broader, we must be aware of the clinical entity of bupropion-induced hepatitis.",1
9800,11052337,Tolcapone-related fulminant hepatitis: electron microscopy shows mitochondrial alterations,,1
9801,11054441,Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors,"""PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-na?ve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg.min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m(2) and carboplatin AUC 6 mg.min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m(2))/carboplatin AUC (mg.min/mL) of 67.5/6, 81/6, 94.5/6, 67. 5/7.5, and 67.5/9, respectively. In chemotherapy-na?ve patients, one of 17 developed DLT at paclitaxel 81 mg/m(2) and carboplatin AUC 6 mg/mL.min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was >/= 0.05 micromol/L, ranging from 16.6 +/- 6.7 hours to 41.5 +/- 9.8 hours for paclitaxel doses of 54.5 mg/m(2) to 94.5 mg/m(2), respectively. CONCLUSION: The recommended phase II dose in chemotherapy-na?ve patients is paclitaxel 81 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.""",1
9802,11055239,Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors,"Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive cytotoxic chemotherapy and may result in varying degrees of liver damage. As chemotherapy is used increasingly in cancer patients, HBV reactivation during cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during chemotherapy. However, corresponding data for patients with other malignancies undergoing cytotoxic chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received cytotoxic chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during chemotherapy. It is concluded that in patients with chronic HBV infection under chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.",1
9803,11060765,An assessment of levetiracetam as an anti-epileptic drug,"A brief review of epilepsy as a disease, anti-epileptic drugs (AEDs) and methods of evaluation of AEDs are presented as a background for the assessment of levetiracetam which has been approved by the FDA as add-on therapy for the treatment of partial seizures with or without secondary generalisation in adults. The exact mechanism of action of levetiracetam is not known but its action differs from that of other anti-epileptic drugs. A specific binding site for levetiracetam has been identified and is possibly related to anticonvulsant activity. Levetiracetam offers an effective and broad spectrum treatment of epileptic seizures, partial as well as generalised epilepsy. Levetiracetam has been shown to be effective in genetic and kindled animal models of epilepsy and against chemoconvulsant-induced partial epileptic seizures. Levetiracetam has a near perfect pharmacokinetic profile, with rapid absorption following oral administration, excellent bioavailability, quick attainment of steady-state concentrations, linear kinetics and minimal plasma protein binding. Levetiracetam does not interact with commonly used drugs and other AEDs. In recent Phase III clinical trials, the responder rate was 39.4 - 42.1% on 3000 mg dose, compared with placebo rates of 10.9 - 16.7%. Levetiracetam has a favourable safety profile and the most frequently reported adverse events were somnolence, asthenia and dizziness. Overall, levetiracetam is considered to have several advantages over current AEDs.",1
9804,11061618,Hepatocellular carcinoma after long-term tamoxifen therapy,"We describe a case of hepatocellular carcinoma (HCC) after long term tamoxifen therapy in a 71-year-old woman. The patient was prescribed tamoxifen for 12 years following right mastectomy and axillary node clearance for breast carcinoma in 1985. In 1997, she complained of abdominal pain and fullness. An abdominal ultrasound scan showed lesions in the right lobe of liver which were thought to be metastases. However, a biopsy showed primary HCC. Studies in rats suggest that tamoxifen is involved in hepatic carcinogenesis but studies in humans have failed to show any increased risk. However, these studies followed up patients for less than five years. An increased risk of HCC may not become apparent until after a decade or more of tamoxifen therapy. In addition, HCC in tamoxifen treated patients may be under-reported since there may be reluctance to biopsy liver tumours which are assumed to be secondary carcinoma of the breast.",1
9805,11062197,Treatment of methicillin-resistant staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency-Use Study Group,"Safety and efficacy of quinupristin-dalfopristin (an injectable streptogramin antibiotic) were evaluated in the treatment of a variety of infections due to methicillin-resistant Staphylococcus aureus (MRSA) in patients either intolerant of or failing prior therapy. The influence of resistance phenotypes on treatment outcome was also assessed. This worldwide, multicentre, open-label, non-comparative, emergency-use clinical study enrolled patients with one or more of nine predefined, culture-confirmed infections with MRSA, who had no clinically appropriate alternative antibiotic therapy. The recommended quinupristin-dalfopristin dose was 7.5 mg/kg administered iv every 8 h for a duration judged appropriate by the investigator. There were no restrictions on prior or concomitant treatment with other antibiotics. Clinical, microbiological and laboratory assessments were performed at baseline, during study drug treatment, within 24 h after the last dose, and 7-21 days post-therapy. Ninety patients [age (mean +/- S.D.) 57.4 +/- 18.5 years] with significant underlying medical illnesses were treated at 63 centres in five countries. The most common indications were bone and joint infection (44.4% of patients) and skin and skin structure infection (16.7%). The mean (+/- S.D.) daily dose and treatment duration was 20.2 +/- 2.9 mg/kg/day for 28.5 +/- 22.3 days, most frequently administered every 8 h. The overall success rate (defined as a clinical outcome of either cure or improvement and a bacteriological outcome of eradication or presumed eradication) was 71.1% in the all-treated population (n = 90) and 66.7% in patients who were both clinically and bacteriologically evaluable (n = 27). Success rates for endocarditis, respiratory tract infection and bacteraemia of unknown source were below the population mean. The macrolide-lincosamide-streptogramin type B resistance phenotype did not appear to alter the response rate. The most common non-venous adverse events related to study medication were arthralgias (10.8%), myalgias (8.6%) and nausea (8.6%). Quinupristin-dalfopristin should be considered as a treatment option for infections caused by MRSA, especially in patients intolerant of or failing alternate therapy.",1
9806,11063865,Hepatic steatosis and lactic acidosis caused by stavudine in an HIV-infected patient,"Lactic acidosis and hepatic steatosis caused by mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI) is a rare cause of liver disease with a high mortality rate. This report describes a male, HIV-positive patient with a 4-week history of nausea, vomiting and abdominal pain. His medication consisted of prednisone 5 mg od (because of auto-immune thrombocytopenia), didanosine (for 2 years) and stavudine (for 3 months). Laboratory studies showed cholestasis and elevation of aminotransferases. Lactic level was not measured. Liver biopsy revealed steatosis and cholestatic hepatitis. In the absence of other causes of liver disease a probable diagnosis of stavudine-induced hepatic toxicity was made. After discontinuation of NRTI, he recovered completely. Because lactic acidosis had not been confirmed, stavudine was restarted and within 1 week the lactate level increased significantly. Therefore stavudine was discontinued again. One year later the patient is doing well on a double protease inhibitor regimen. In conclusion, clinicians treating patients with NRTI should be aware of the risk of lactic acidosis and hepatic steatosis. When this is suspected, all NRTI must be stopped. The diagnosis can be made when elevated lactate levels and hepatic steatosis are present in the absence of other causes of liver disease.",1
9807,11067793,Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study,"""BACKGROUND: This double-blind, multicenter, placebo-controlled study determined the efficacy and safety of dofetilide in converting atrial fibrillation (AF) or atrial flutter (AFl) to sinus rhythm (SR) and maintaining SR for 1 year. METHODS AND RESULTS: Patients with AF or AFl (n=325) were randomized to 125, 250, or 500 microgram dofetilide or placebo twice daily. Dosages were adjusted for QTc response and, after 105 patients were enrolled, for calculated creatinine clearance (Cl(Cr)). Pharmacological cardioversion rates for 125, 250, and 500 microgram dofetilide were 6.1%, 9.8%, and 29.9%, respectively, versus 1.2% for placebo (250 and 500 microgram versus placebo; P=0.015 and P<0.001, respectively). Seventy percent of pharmacological cardioversions with dofetilide were achieved in 24 hours and 91% in 36 hours. For the 250 patients who successfully cardioverted pharmacologically or electrically, the probability of remaining in SR at 1 year was 0.40, 0.37, 0.58 for 125, 250, and 500 microgram dofetilide, respectively, and 0.25 for placebo (500 microgram versus placebo, P=0.001). Two cases of torsade de pointes occurred, 1 on day 2 and the other on day 3 (0.8% of all patients given active drug); 1 sudden cardiac death, classified as proarrhythmic, occurred on day 8 (0.4% of all patients given active drug). CONCLUSIONS: Dofetilide, a new class III antiarrhythmic agent, is moderately effective in cardioverting AF or AFl to SR and significantly effective in maintaining SR for 1 year. In-hospital initiation and dosage adjustment based on QTc and Cl(Cr) are necessary to minimize a small but nonnegligible proarrhythmic risk.""",1
9808,11069031,A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation,"""Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.""",1
9809,11071104,Interferon beta-1b treatment in patients with relapsing--remitting multiple sclerosis under a standardized protocol in Spain,"""OBJECTIVE: A protocol system is being used in Spain for the prescription of innovative drugs including interferon beta-1b (IFNbeta-1b). Petitions for dispensing and reimbursement are based on the inclusion and exclusion criteria of pivotal trials, and are reviewed individually for approval by specialist committees. To estimate the performance of IFNbeta-1b in the clinical setting, data collected by the INSALUD and regional health services of Andalusia and Catalonia, together responsible for the healthcare of nearly 30 million individuals, were compiled in a common database for analysis. METHODS: Data comprise demographic and disease characteristics at the time of petition and at follow-up 3 months after treatment initiation and every 6 months thereafter. Efficacy was estimated by mean number of relapses per year, proportion of relapse-free patients, and disease progression as measured by the Expanded Disability Status Scale (EDSS). Safety parameters included adverse events and laboratory analyses. RESULTS: Between September 1995 and database cutoff in mid-1998, petitions of 1419 patients were approved for IFNbeta-1b treatment. Patients were homogenous across the three databases and in the subgroups of patients completing 1 year (n = 940) and 2 years (n = 302) of treatment. There was a marked decrease in the mean number of relapses in the first 12 months of IFNbeta-1b treatment for the 938 patients documented for 12 months, with a mean of 0.4 (+/- 0.7 SD) relapses per patient and year, and a 2-year mean of 0.9 (+/- 1.20 SD) in the 302 patients documented for 24 months. Of the 938 patients followed for > or = 12 months, 505 (53.8%) were documented as being relapse-free during 12 months of treatment, and 146 (48.3%) of the 302 patients followed for > or = 24 months, were relapse-free during 24 months of treatment. There were no differences in mean or median EDSS scores between baseline and months 12 and 24. Skin disorders were the most frequent adverse events, reported in over one-third of all patients; there were 159 injection site events, most frequently erythema (115 events). Systemic AEs pointing towards flu-like symptoms were reported in 288 of 1419 patients (20.3%). Leukopenia was the most frequently reported laboratory event. Elevations in liver transaminases were noted for 12 patients (0.8%) with SGOT increase and 7 (0.5%) with SGPT increase. CONCLUSION: The protocol system has helped make IFN treatment available to 8-10% of the estimated 15,000-18,000 MS patients in the regions studied. In terms of efficacy, IFNbeta-1b performed in line with the pivotal study results. The safety profile of IFNbeta-1b was consistent with the published findings and the drug labelling, and no new side effects or increased incidence of known side effects was observed.""",1
9810,11074748,Cholestatic liver reaction and heparin therapy,,1
9811,11074926,Isolated elevation of alkaline phosphatase level associated with rosiglitazone,,1
9812,11080238,Late onset heterozygous ornithine transcarbamylase deficiency mimicking complex partial status epilepticus,"A 57 year old woman with post-traumatic complex partial seizures was admitted because of recurrent episodes of altered mental state over the preceding 4 years, each lasting up to 5 days. There was a history of dietary protein intolerance since childhood and two of her daughters had died in the neonatal period from unexplained encephalopathies. In hospital she developed fluctuating confusion, amnesia, and sudden episodes of unresponsiveness. An EEG was consistent with complex partial status epilepticus but there was no response to benzodiazepines. Nasogastric feeding and sodium valproate were given and shortly afterwards she lapsed into a deep coma. Blood ammonia and urinary orotate were raised, and genetic testing confirmed that she was a carrier of a mutation in exon 3 of the ornithine transcarbamylase gene (C to T at position 92). Treatment with protein restriction, carnitine, and sodium phenylbutyrate led to a full recovery over a period of 3 months. To our knowledge this is the oldest age of onset yet described in a manifesting carrier. She is the fifth patient with heterozygous ornithine transcarbamylase deficiency reported to have had a severe reaction to sodium valproate. Hyperammonaemic encephalopathy should be considered in patients of any age who experience fluctuating confusion.",1
9813,11081995,"Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica","Centella asiatica is a medicinal plant that has been in use since prehistoric times. Its active constituents include pentacyclic triterpene derivatives. Studies have been conducted in particular to investigate the madecassosides and asiaticosides. In common with most traditional phytotherapeutic agents, Centella asiatica is used in folk medicine to treat a wide range of indications. In contrast to other medicinal plants, however, Centella asiatica has been subjected to quite extensive experimental and clinical investigations. Studies done in accordance with standardized scientific criteria have shown it to have a positive effect in the treatment of venous insufficiency and striae gravidarum. Centella asiatica also appears to be effective in the treatment of wound healing disturbances. At the present time, clinical studies aimed at investigating the sedative, analgesic, antidepressive, antimicrobial, antiviral and immunomodulatory effects that have been demonstrated experimentally, are still lacking. However, the therapeutic potential of this plant in terms of its efficacy and versatility is such that further detailed research would appear worthwhile.",1
9814,11083648,Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections,"""This randomized, double-blind, multicenter trial compared the efficacy and safety of linezolid, an oxazolidinone, with those of oxacillin-dicloxacillin in patients with complicated skin and soft tissue infections. A total of 826 hospitalized adult patients were randomized to receive linezolid (600 mg intravenously [i.v.]) every 12 h or oxacillin (2 g i.v.) every 6 h; following sufficient clinical improvement, patients were switched to the respective oral agents (linezolid [600 mg orally] every 12 h or dicloxacillin [500 mg orally] every 6 hours). Primary efficacy variables were clinical cure rates in both the intent-to-treat (ITT) population and clinically evaluable (CE) patients and microbiological success rate in microbiologically evaluable (ME) patients. Safety and tolerability were evaluated in the ITT population. Demographics and baseline characteristics were similar across treatment groups in the 819 ITT patients. In the ITT population, the clinical cure rates were 69.8 and 64.9% in the linezolid and oxacillin-dicloxacillin groups, respectively (P = 0.141; 95% confidence interval -1.58 to 11. 25). In 298 CE linezolid-treated patients, the clinical cure rate was 88.6%, compared with a cure rate of 85.8% in 302 CE patients who received oxacillin-dicloxacillin. In 143 ME linezolid-treated patients, the microbiological success rate was 88.1%, compared with a success rate of 86.1% in 151 ME patients who received oxacillin-dicloxacillin. Both agents were well tolerated; most adverse events were of mild-to-moderate intensity. No serious drug-related adverse events were reported in the linezolid group. These data support the use of linezolid for the treatment of adults with complicated skin and soft tissue infections.""",1
9815,11084438,[Acute pseudoangiocholitic hepatitis probably induced by azithromycin],,1
9816,11092117,Fatal cholestatic jaundice associated with amitriptyline,"A 75-year-old woman was admitted with a two-week history of anorexia and vague abdominal pain. She had been taking amitriptyline 75 mg at night for depression for four months before her admission. On presentation she was jaundiced, but with no stigmata of chronic liver disease. Initial liver function tests showed a slightly raised bilirubin, but were otherwise normal. Over the next three weeks her bilirubin concentration continued to rise without evidence of biliary obstruction on ultrasound examination. Her condition continued to deteriorate, and she later developed renal failure consistent with hepatorenal syndrome. Seven weeks after admission she died following a large gastrointestinal bleed. At autopsy, liver histology confirmed pure cholestasis consistent with amitriptyline ingestion.",1
9817,11093966,"A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse","""The opioid antagonist, naltrexone, is reported, in single centre studies, to improve the clinical outcome of individuals with alcohol dependence participating in outpatient psychosocial programmes. This is the first multicentre controlled study to evaluate the efficacy and safety of naltrexone as adjunctive treatment for alcohol dependence or abuse. Patients who met criteria for alcohol dependence (n = 169) or alcohol abuse (n = 6) were randomly assigned to receive double-blind oral naltrexone 50 mg daily (n = 90) or placebo (n = 85) for 12 weeks as an adjunct to psychosocial treatment. The primary efficacy variable was time to first episode of heavy drinking; secondary efficacy assessments included time to first drink, alcohol consumption, craving, and changes in the serum biological markers gamma-glutamyl transferase (GGT), and aspartate and alanine aminotransferases. Compliance was assessed by tablet counts and, in the naltrexone-treated group, by measurement of urinary concentrations of 6-ss-naltrexol. Forty-nine (58%) patients randomized to placebo and 53 (59%) randomized to naltrexone did not complete the study. In intention-to-treat analyses, there was no difference between groups on measures of drinking. The median reduction from baseline of serum GGT (P: < 0.05) and the reductions in alcohol craving (Obsessive and Compulsive Drinking Scale: OCDS) were greater in the naltrexone group (P: < 0.05), from approximately half-way through the study. Of 70 patients (35 placebo; 35 naltrexone) who met an a priori definition of compliance (80% tablet consumption, attendance at all follow-up appointments), those allocated to naltrexone reported consuming half the amount of alcohol (P: < 0.05), had greater median reduction in serum GGT activity (P: < 0.05), and greater reduction in alcohol craving (OCDS total score: P: < 0.05; Obsessive subscale score: P: < 0.05), compared to patients in the placebo group. Use of naltrexone raised no safety concerns. Naltrexone is effective in treating alcohol dependence/abuse in conjunction with psychosocial therapy, in patients who comply with treatment.""",1
9818,11098345,Miglitol: assessment of its role in the treatment of patients with diabetes mellitus,"""OBJECTIVE: To evaluate miglitol, a new oral alpha-glucosidase inhibitor, and discuss its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy. DATA SOURCES: A MEDLINE English-language only database search using the keywords miglitol, glyset, and Bay m 1099 (1985 to December 1999), was completed to identify relevant articles including reviews, recent studies, and abstracts; American Diabetes Association 1999 Annual Meeting abstracts; Pharmacia & Upjohn data on file and product information. STUDY SELECTION: The clinical trials that were selected to be reviewed in detail were randomized, double-blind studies with at least 100 patients in the intention-to-treat group. DATA EXTRACTION: All articles and abstracts were reviewed along with the product labeling from Pharmacia & Upjohn. DATA SYNTHESIS: Miglitol is an alpha-glucosidase inhibitor that exerts its effect through the delayed absorption of complex carbohydrates in the small intestine, resulting in a decrease in postprandial glucose concentrations that are directly correlated with the dietary carbohydrate content. Both small, short-term trials and large, clinical trials show a decrease in postprandial glucose concentrations and a modest decrease in glycosylated hemoglobin of approximately 0.5-1.0% as a result of miglitol's action. The adverse effects of miglitol are mild and transitory and include flatulence, diarrhea, and abdominal pain. The incidence of gastrointestinal problems may be reduced with a small initial dose, which is slowly titrated as tolerated. CONCLUSIONS: Miglitol is an effective and safe treatment option in patients with type 2 diabetes mellitus who are inadequately controlled with diet or oral sulfonylurea therapy. Miglitol is a good choice of therapy in Hispanic, African-American, and elderly patients, or any patients in whom hypoglycemia, weight gain, or lactic acidosis are risks. No published studies comparing miglitol with acarbose have been published, but there appears to be no major clinical or financial advantages to using one agent over the other.""",1
9819,11105176,Adverse effects associated with use of nevirapine in HIV postexposure prophylaxis for 2 health care workers,,1
9820,11111124,Hydroxyurea as a cause of drug fever,"We report on a patient with essential thrombocythemia treated with hydroxyurea who became febrile 3 weeks after the treatment was started. After drug withdrawal, the fever resolved but after rechallenge there was recurrence of the fever. Although hydroxyurea-induced fever is rare, this drug must be added to the list of drugs that produce fever and the physicians should be aware of this possibility.",1
9821,11113103,Pentoxifylline and alcoholic hepatitis,,1
9822,11118394,Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy,"We describe 2 patients who were initially positive for antibodies to hepatitis B surface antigen and who experienced a strong and sudden increase of hepatitis B virus (HBV) replication during highly active antiretroviral therapy (HAART). We found that reactivation of HBV replication during HAART can occur independently of lamivudine resistance or withdrawal of lamivudine, and in spite of increasing CD4(+) cell counts.",1
9823,11119397,Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast,"BACKGROUND: In registration trials, zafirlukast, an asthma medication, caused asymptomatic elevated aminotransferase levels in up to 5% of participants. Until now, however, no cases of severe hepatitis attributed to zafirlukast have been reported. OBJECTIVE: To report the clinical characteristics of three patients with severe hepatitis due to zafirlukast. DESIGN: Case report. SETTING: One community hospital and two university hospitals. PATIENTS: Three middle-aged women taking zafirlukast, 20 mg twice per day. INTERVENTION: Discontinuation of zafirlukast therapy in three patients, steroid therapy in two patients, and orthotopic liver transplantation in one patient. MEASUREMENTS: Serum aminotransferase and bilirubin levels, standard blood tests for causes of hepatitis other than drug toxicity, and liver biopsy in two patients. RESULTS: Patient 1 recovered spontaneously, had a severe relapse after inadvertent rechallenge with the medication, and ultimately made a complete recovery. Patient 2 developed subfulminant hepatic failure and required liver transplantation. Patient 3 developed severe hepatitis that improved after treatment with corticosteroids. Liver tissue was available from two patients and showed histologic changes commonly associated with drug reactions. CONCLUSION: Patients receiving zafirlukast may develop severe liver injury and should be observed for signs and symptoms of hepatitis.",1
9824,11125891,Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy,"BACKGROUND: Fatal lactic acidosis is a serious complication of therapy with nucleoside analogues. OBJECTIVE: To examine symptomatic hyperlactataemia in HIV-infected adults treated with antiretroviral drugs. METHODS: In this prospective study, arterial blood lactate levels were measured in patients presenting with unexplained clinical symptoms. When these levels were high, functional respiratory tests (FRT) were carried out. Liver or muscle biopsies were further proposed. Incidences were calculated by comparison with the entire cohort of patients treated in the department. RESULTS: Fourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered. Clinical symptoms included abnormal fatigue, tachycardia, abdominal pain, weight loss, peripheral neuropathy, and more specifically exercise-induced dyspnoea occurring despite effective antiretroviral treatment. FRT showed a metabolic deviation towards anaerobiosis with a high lactate/pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction. Evolution was favourable in 13 patients, probably because of an early diagnosis. CONCLUSIONS: Potentially fatal adverse events occurring during antiretroviral treatment may be avoided by close monitoring of clinical signs and blood lactate levels. If other studies confirm that the cumulative long-term toxicity of antiretroviral drugs results from mitochondrial dysfunction, the incidence of hyperlactataemia and its clinical consequences may become more important.",1
9825,11129758,Fulminant chemical hepatitis possibly associated with donepezil and sertraline therapy,"OBJECTIVE: To describe a case of fulminant hepatitis possibly related to concomitant donepezil and seratriline therapy. PATIENT AND SETTING: An 83-year-old woman treated in a dementia care facility and later in a tertiary medical center. INTERVENTION AND MANAGEMENT: Discontinuation of donepezil and sertraline therapy with subsequent improvement evidenced by liver biopsy and liver function tests. RESULTS: An older woman with Alzheimer's disease was admitted to a dementia care facility because of aggressive behavior. Treatment with sertraline was initiated in February 1998. Sertraline doses were increased gradually to 200 mg daily by May 1998, and some improvement in behavior was seen. Concomitant therapy with donepezil 5 mg qhs was initiated June 26, 1998. Ten days later, confusion and jaundice were noted. Total bilirubin was 5.6 mg/dL, GGTP was 1,208 IU/L, and alkaline phosphatase was 369 IU/L. Computed tomography revealed cholelithiasis without ductal dilation. Liver, spleen, and pancreas seemed normal. Donepezil and sertraline were discontinued. The patient was admitted to our institution and treated for dehydration. A liver biopsy revealed scattered portal eosinophils and prominent cholestasis consistent with acute chemical hepatitis. The GGTP and total bilirubin of this patient peaked at 2,235 IU/L and 22.6 mg/dL, respectively. The patient improved, and her liver function tests normalized over the next 2 months.",1
9826,11130224,Mefloquine-induced acute hepatitis,"Mefloquine is an effective drug for prophylaxis and treatment of malaria caused by Plasmodium falciparum. It is generally well tolerated with few side effects. Minimal elevation of liver function tests has been reported after exposure to mefloquine, especially in susceptible individuals with prior abnormal liver function tests. Our patient, who had had elevated liver function tests attributed to heart failure, experienced an acute elevation of liver transaminases 6 weeks after exposure to mefloquine 250 mg/week. Cessation of the drug caused test results to return to normal. Mefloquine should be prescribed cautiously in patients with liver disease.",1
9827,11136881,Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis,"""OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).""",1
9828,11141435,[Acute hepatitis induced by candesartan],,1
9829,11142494,A fatal case of cholestatic liver failure probably related to gemcitabine,,1
9830,11143546,[Toxic liver damage caused by HMG-CoA reductase inhibitor],"CASE REPORTS: We report on 4 patients who were referred to the clinic with suspected acute hepatitis and to investigate high transaminase values. After exclusion of specific hepatitis, unspecific virus hepatitis, autoimmune hepatitis, a metabolic disorder damaging the liver and extrahepatic cholestasis, a toxic liver damage remained as the probable cause and was histologically verified. Since other drugs and alcoholics could be eliminated as possible causes of the damage, the toxicity had to be attributed to statin ingestion. CLINICAL COURSE: After discontinuation of the medication with continuation of all other therapeutic agents of the general practitioners, the transaminase values normalized within a few weeks. Renewed administration of statin was not prescribed for ethical reasons. CONCLUSION: Therefore, when prescribing a HMG-CoA-reductase inhibitor, the possibility of liver damage should be mentioned and regular checks of the transaminase values should be performed.",1
9831,11144948,[Meloxican-induced cholestasis],"The cholestasis by meloxicam has not been often described. However, we present here the clinic, laboratory, histologic and follow up of a patient with cholestatic hepatitis produced by this drug.",1
9832,11147510,COMT inhibitors and liver toxicity,"This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.",1
9833,11148549,Alternative pathway therapy for urea cycle disorders: twenty years later,"Alternative pathway therapy is currently an accepted treatment approach for inborn errors of the urea cycle. This involves the long-term use of oral sodium phenylbutyrate, arginine supplements, or both, depending on the specific enzyme deficiency, and treatment of acute hyperammonemic crises with intravenous sodium benzoate/sodium phenylacetate plus arginine. A review of 20 years of experience with this approach illustrates the strengths and limitations of this treatment. It has clearly decreased the mortality and morbidity from these disorders, but they remain unacceptably high. The medications are generally well tolerated, but severe accidental overdosage has been reported because of the infrequent use of the medication. There is also a difference in their metabolism between newborns and older children that must be addressed in determining dosage. To avoid these complications it is recommended that drug levels in blood be monitored routinely and that very specific treatment protocols and oversight be followed to avoid overdoses. Finally, it must be acknowledged that alternative pathway therapy has limited effectiveness in preventing hyperammonemia and must be combined with effective dietary management. Therefore in children with neonatal-onset disease or in those with very poor metabolic control, liver transplantation should be considered. There should also be the continued search for innovative therapies that may offer a more permanent and complete correction, such as gene therapy.",1
9834,11149228,[Nimesulide toxic hepatitis in pregnancy],,1
9835,11151906,Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity,"Herbal medicines are gaining widespread popularity. Much of the public believes that botanical herbs are both harmless and useful for the treatment of a variety of symptoms. This belief stands in contrast with the fact that many herbal therapies have been shown to be toxic. In the present case report, cascara sagrada (CS) has been associated with the development of cholestatic hepatitis, complicated by portal hypertension. CS is a mixture of ingredients, among which is anthracene glycoside--an herbal agent that previously has been associated with chronic hepatitis. The liver injury in the case herein reported is believed to be related to either anthracene glycoside or one of the other constituents of CS.",1
9836,11151926,Acute cholestatic hepatitis in a child treated with famotidine,,1
9837,11153671,Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection,"OBJECTIVE: To investigate the risk of hepatotoxicity after initiation of protease inhibitor-containing highly active antiretroviral therapy (HAART) for HIV-1 infected patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection. DESIGN: Retrospective study with 394 HIV-1-infected patients initiating HAART at a single university clinic. METHODS: Liver enzyme elevation (LEE) was defined as alanine aminotransferase or aspartate aminotransferase at least five times the upper limit of normal and an absolute increase of > 100 U/l. Relative risks for time to LEE were estimated using Cox proportional hazards models. RESULTS: Of 394 patients 7% were hepatitis B surface antigen (HBsAg)-positive and 14% were anti-HCV-positive. Patients with chronic hepatitis had a higher risk for LEE compared with patients without co-infection: 37% versus 12% respectively. After adjustment for higher baseline transaminases, the presence of HBsAg or anti-HCV remained associated with an increased risk of LEE - relative risk 2.78 (95% confidence interval, 1.50-5.16) and 2.46 (95% confidence interval, 1.43-4.24) respectively. In patients with LEE, transaminases declined whether HAART was continued or modified. Of patients with chronic HBV infection 38% lost HBeAg or developed anti-HBe after initiation of HAART, and one seroconverted from HBsAg-positive to anti-HBs-positive. However, there was no clear relationship with LEE. CONCLUSIONS: HIV-1-infected patients co-infected with HBV or HCV were at considerably higher risk of developing LEE when HAART was initiated compared with patients without co-infection, but it is usually not necessary to modify antiretroviral therapy.",1
9838,11155780,Ticlopidine-induced cholestatic hepatitis with anti-nuclear antibody in serum,"We describe a case of severe cholestatic hepatitis following administration of ticlopidine. A 57-year-old man without known liver disease developed jaundice approximately 3 weeks after initiation of ticlopidine for secondary prevention of stroke. Hyperbilirubinemia and abnormal liver function test values resolved 5 months after withdrawal of ticlopidine. The diagnosis of ticlopidine-induced cholestasis was made after thorough investigations had excluded other causes of jaundice. He was not retreated with ticlopidine. This case may serve to illustrate the possibility of ticlopidine hepatotoxicity, which has rarely been reported. Furthermore, to the best of our knowledge, ticlopidine-induced cholestatic hepatitis accompanied by autoantibody has not been previously reported. This case suggests that regular assessment of liver function should be performed in the initial 3 months of ticlopidine treatment due to the potential risk of adverse effects. In patients with abnormal biochemical test results, autoantibodies should be assessed.",1
9839,11159570,"Hepatitis associated with Kava, a herbal remedy for anxiety",,1
9840,11167689,The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up,"BACKGROUND: Methotrexate (MTX) -induced liver damage is an important complication in patients treated with this drug for skin disease. Reliable non-invasive monitoring tests would have considerable importance. OBJECTIVES: This retrospective study was designed in order to evaluate if serial normal serum levels of amino-terminal propeptide of type III procollagen (PIIINP) might indicate that no significant fibrosis is taking place in the liver, and thereby reduce the need for repeated liver biopsies in psoriatic patients treated with MTX. METHODS: The clinical records of 70 patients with psoriasis, who in the years 1989/90 were on MTX and had both a liver biopsy without fibrosis and a normal PIIINP, were examined and followed until the patient stopped taking the drug. The follow-up time was from 1 to 11 years. RESULTS: A total of 189 liver biopsies and 329 analyses of PIIINP were recorded. Twenty-one patients had only one and no further biopsies, but their data included at least two to three PIIINP samples obtained within a year around the time of the biopsy, and at least two were taken either prior to or at the time of the biopsy. The remaining patients had from two to seven liver biopsies each and a total of 267 analyses of PIIINP. In the study period only four patients developed fibrosis of the liver as shown by liver biopsies, and all four of these patients developed elevated serum PIIINP levels. In addition two further patients, one of them with psoriatic arthritis, had elevated PIIINP, but normal liver biopsy. Thus no liver fibrosis was missed in the 63 patients with consistently normal PIIINP levels. CONCLUSIONS: Present data support the view that, as long as PIIINP is consistently normal in serial investigations, there is minimal risk of development of substantial liver fibrosis.",1
9841,11167954,"Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged > or = 6 years","""OBJECTIVE: Montelukast is a leukotriene receptor antagonist administered orally once daily for treatment of chronic asthma in adults and children. A comprehensive analysis of safety data from double-blind, randomized, placebo-controlled trials with montelukast has not been previously reported. PATIENTS AND METHODS: A pooled analysis of safety data from 11 multicentre, randomized, controlled montelukast Phase IIb and III trials and five long-term extension studies was performed. A total of 3386 adult patients (aged 15-85 years) and 336 paediatric patients (aged 6-14 years) were enrolled in the trials; 2031 adults received montelukast for up to 4.1 years, and 257 children received montelukast for up to 1.8 years. Summary statistics comparing incidences of adverse events among treatment groups were calculated. RESULTS: The overall incidence of clinical and laboratory adverse events among montelukast-treated patients, both adult and paediatric, was similar to that among patients receiving placebo. There were no clinically relevant differences in individual adverse events, including infectious upper respiratory conditions and transaminase elevations, between montelukast and placebo groups. Discontinuations due to adverse events occurred with similar frequencies during placebo, montelukast and inhaled beclomethasone therapy. No dose-related adverse effects of montelukast were observed in adults treated with dosages as high as 200 mg per day (20 times the recommended dose) for 5 months. This tolerability profile montelukast observed in clinical trials has been generally reflected in the post-marketing safety experience seen to date. CONCLUSIONS: These data indicate a tolerability profile for montelukast similar to placebo during both short-term and long-term administration, even at doses substantially higher than the recommended clinical dose of 10 mg once daily for adults and 5 mg once daily for children aged 6-14 years.""",1
9842,11170959,Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection,"""Highly active antiretroviral therapy has decreased human immunodeficiency virus (HIV)-associated mortality; other comorbidities, such as chronic liver disease, are assuming greater importance. We retrospectively examined the causes of death of HIV-seropositive patients at our institution in 1991, 1996, and 1998-1999. In 1998-1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996 (P=.003). In 1998-1999, 55% of patients had nondetectable plasma HIV RNA levels and/or CD4 cell counts of >200 cells/mm(3) within the year before death. Most of the patients that were tested had detectable antibodies to hepatitis C virus (75% of patients who died in 1991, 57.7% who died in 1996, and 93.8% who died in 1998-1999; P=NS). In 1998-1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.""",1
9843,11173046,Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs,"The use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with upper gastrointestinal bleeding and perforation (UGIB), acute liver injury, acute renal injury, heart failure, and adverse reproductive outcomes. This article summarizes the effects of various factors, such as NSAID dose, duration of treatment, patient age, and ulcer history, on the incidences of these adverse side effects. We used the UK General Practice Research Database to study further the principal safety concern related to NSAIDs, namely, UGIB.",1
9844,11173739,[Acute cholestatic hepatitis induced by glimepiride],,1
9845,11177221,Nebulized budesonide for asthma in children,,1
9846,11181293,[Cholestatic hepatitis by ticlopidin],,1
9847,11186000,Hydroxyurea-induced fever in a patient with chronic myelogenous leukemia,,1
9848,11188053,[Arsenic as an environmental problem],"Chronic exposure to arsenic through drinking water is known in different continents. Arsenic compounds from disintegrating rock may be solubilized after reduction by organic material, and harmful concentrations of arsenic may be found in surface water as well as in water from drilled wells. Because of well drilling since the sixties in the Ganges delta numerous millions of people have been exposed to toxic amounts, and hundreds of thousands demonstrate signs of chronic poisoning. A changed water technology and chemical precipitation of arsenic in the drinking water can reduce the size of the problem, but the late sequelae i.e. malignant disease are incalculable. Indications for antidotal treatment of exposed individuals have not yet been outlined.",1
9849,11191729,Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparin-induced hepatotoxicity,"""Enoxaparin, a low-molecular-weight heparin (LMWH), is widely used for the treatment and prophylaxis of thromboembolic disorders, such as deep vein thrombosis. Low-molecular-weight heparin products have smaller and more uniform molecular weights than unfractionated heparin, allowing them to exhibit a much greater affinity for factor Xa than factor IIa. Compared with traditional unfractionated heparin, LMWHs have proved to be equally efficacious and may be safer. The distinctive characteristics of LMWHs have resulted in decreased rates of bleeding and equivalent rates of thrombocytopenia compared with unfractionated heparin. This favorable safety profile has been identified in several studies and may have led clinicians to believe that LMWHs have lower frequencies of all common side effects. A 66-year-old woman developed increased hepatic transaminases during treatment with enoxaparin for a deep vein thrombosis; they returned to normal after enoxaparin discontinuation. A causal relationship between unfractionated heparin and asymptomatic, transient increases in hepatic transaminase levels has been documented; these increased levels also appear to be an underrecognized, adverse effect of LMWH therapy.""",1
9850,11194222,Failure to develop hepatic injury from rosiglitazone in a patient with a history of troglitazone-induced hepatitis,,1
9851,11197401,Long-term propofol infusion and cardiac failure in adult head-injured patients,"Five adult patients with head injuries inexplicably had fatal cardiac arrests In our neurosurgical intensive-care unit after the introduction of a sedation formulation containing an increased concentration of propofol. To examine the possible relation further, we did a retrospective cohort analysis of head-injured adults admitted to our unit between 1996 and 1999 who were sedated and mechanically ventilated. 67 patients met the inclusion criteria, of whom seven were judged to have died from propofol-infusion syndrome. The odds ratio for the occurrence of the syndrome was 1.93 (95% CI 1.12-3.32, p=0.018) for every mg/kg per h increase in mean propofol dose above 5 mg/kg per h. We suggest that propofol infusion at rates higher than 5 mg/kg per h should be discouraged for long-term sedation in the intensive-care unit.",1
9852,11198946,"Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures--worldwide, 1997-2000","In September 2000, two instances of life-threatening hepatotoxicity were reported in health-care workers taking nevirapine (NVP) for postexposure prophylaxis (PEP) after occupational human immunodeficiency virus (HIV) exposure. In one case, a 43-year-old female health-care worker required liver transplantation after developing fulminant hepatitis and end-stage hepatic failure while taking NVP, zidovudine, and lamivudine as PEP following a needlestick injury (1). In the second case, a 38-year-old male physician was hospitalized with life-threatening fulminant hepatitis while taking NVP, zidovudine, and lamivudine as PEP following a mucous membrane exposure. To characterize NVP-associated PEP toxicity, CDC and the Food and Drug Administration (FDA) reviewed MedWatch reports of serious adverse events in persons taking NVP for PEP received by FDA (Figure 1). This report summarizes the results of that analysis and indicates that healthy persons taking abbreviated 4-week NVP regimens for PEP are at risk for serious adverse events. Clinicians should use recommended PEP guidelines and dosing instructions to reduce the risk for serious adverse events.",1
9853,11204814,Risperidone-induced cholestatic hepatitis,"Risperidone, a widely used atypical and potent neuroleptic drug, is assumed to induce fewer hepatic side-effects than phenothiazine anti-psychotics. Recently, we observed a case of risperidone-induced cholestatic hepatotoxicity. A 37-year-old male developed a rapid increase in liver enzymes and cholestatic parameters after starting treatment with risperidone for paranoid psychosis. Work-up for other potential aetiologies was negative. The results of a percutaneous liver biopsy were consistent with drug-induced liver injury and cholestasis. Over the course of one month after the discontinuance of all anti-psychotic agents, the liver function test results returned to near-normal values. This observation supports the need to monitor cholestatic parameters in addition to liver function enzymes during initiation and the first weeks of risperidone intake.",1
9854,11207356,Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 6-2001. A 17-year-old girl with marked jaundice and weight loss,,1
9855,11211898,Orlistat associated subacute hepatic failure,,1
9856,11214790,Candesartan and acute liver injury,,1
9857,11217818,A case report of olanzapine-induced hypersensitivity syndrome,"Hypersensitivity syndrome is defined as a drug-induced complex of symptoms consisting of fever, rash, and internal organ involvement. The hypersensitivity syndrome is well recognized as being caused by anticonvulsants. Olanzapine is an atypical antipsychotic agent whose side effects include sedation, weight gain, and increased creatinine kinase and transaminase levels. To date, there have been no reports of hypersensitivity syndrome related to this drug. A 34-year-old man developed a severe generalized pruritic skin eruption, fever, eosinophilia, and toxic hepatitis 60 days after ingestion of olanzapine. After termination of olanzapine treatment, the fever resolved, the skin rash was reduced, eosinophil count was reduced to normal, and the transaminase levels were markedly reduced. Clinical features and the results of skin and liver biopsies indicated that the patient developed hypersensitivity syndrome caused by olanzapine.",1
9858,11220297,Possible liver damage by biosynthetic human insulin,,1
9859,11229464,Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient,"A 75-year-old female rheumatoid arthritis patient who was positive for hepatitis B surface antigen and for antibodies to hepatitis Be antigen showed liver dysfunction, and therefore methotrexate (MTX) therapy was discontinued. Her drug lymphocyte stimulation test indicated positivity for MTX. Her liver dysfunction improved briefly, but she developed fulminant hepatitis with elevated levels of hepatitis B virus (HBV)/DNA polymerase and subsequently died. HBV/DNA analysis performed with polymerase chain reaction-mutation site-specific assay revealed that the fulminant hepatitis was caused by a precore mutant virus. Sudden reactivation of the immune system by discontinuation of MTX may have led to the attack on infected cells. Even when hepatitis Be antibodies are present, MTX should not be used in patients who have chronic infection with HBV.",1
9860,11235818,Troglitazone and liver function abnormalities: lessons from a prescription event monitoring study and spontaneous reporting,"OBJECTIVES: To investigate whether there were any cases of liver function abnormalities possibly associated with troglitazone use in general practice in England. DESIGN: A prescription-event monitoring (PEM) study was undertaken between October 1997 and December 1997. SETTING: Data from prescriptions were obtained electronically for the troglitazone cohort in the immediate postmarketing period. STUDY PARTICIPANTS: Event data were obtained for a total of 1344 patients. RESULTS: Troglitazone was effective in 394 (75%) of the 529 patients for whom an opinion was given. The most frequent reasons for stopping treatment related to drug tolerability were malaise/lassitude (16 reports), abnormal liver function tests (II reports) and nausea/vomiting (9 reports). The major cause of stopping troglitazone was because the drug was withdrawn from the market (1101 reports). 30 patients with liver dysfunction were identified from the cohort. In 9 of these patients there were alternative explanations for the liver dysfunction and hence these patients were not followed up further. 21 patients were followed up, for whom 19 questionnaires were returned. In 5 patients their liver dysfunction was assessed as possibly related to troglitazone, in 6 patients the liver dysfunction was unlikely to be attributed to troglitazone, while in 7 patients it was difficult to assess the causality because of limited information and confounding factors. The remaining patient was not included as this individual did not fit the inclusion criteria of the study. CONCLUSION: Although the cohort is small (the drug was available for only 3 months in the UK), 5 patients with abnormal liver function, considered possibly related to troglitazone were detected in this PEM study. It is possible for PEM to contribute to the elucidation of safety signals in the UK.",1
9861,11236773,Efficacy and safety of recombinant human activated protein C for severe sepsis,"""BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.""",1
9862,11244324,Phase II trial of systemic recombinant interleukin-2 in the treatment of refractory nasopharyngeal carcinoma,"BACKGROUND: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. METHODS: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5-6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-alpha, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. RESULTS: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3x) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. CONCLUSION: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.",1
9863,11247598,Hypersensitivity syndrome associated with azithromycin,,1
9864,11249557,"Miglitol, a new alpha-glucosidase inhibitor","Miglitol (Bay m 1099, Bayer) is a second generation alpha-glucosidase inhibitor. It is a derivative of 1-desoxynojirimycin, and binds reversibly to the brushborder alpha-glucosidase enzymes. In contrast to its parent drug (acarbose, Bay g 5421, Bayer), miglitol is almost completely absorbed in the small intestine. It has to be taken with each main meal, and through its effect on carbohydrate digestion it blunts the postprandial blood glucose increase. Miglitol has no or a very small effect on fasting blood glucose levels. The blood-glucose lowering effects of miglitol in patients with Type 2 diabetes are lower than those of the frequently-used sulphonylurea compounds. Long-term studies show that a moderate average reduction of HbA1c of 0.3-0.7% point from baseline can be achieved. An advantage over sulphonylurea is the effect on serum insulin levels: miglitol therapy leads to slightly lower postprandial levels of serum insulin, whereas chronic sulphonylurea treatment usually increases serum insulin levels. This insulin-sparing effect may, in theory, lead to a lesser weight gain or even no weight gain and reduced risk of hypoglycaemia during chronic treatment. Long-term experience in Type 1 diabetic patients is limited. Similarly, miglitol may lead to reduced postprandial glucose excursions, slightly reduced insulin requirements and perhaps, as a consequence, a lower risk of hypoglycaemia. More long-term data are needed to fully assess to the clinical use of miglitol in these patients.",1
9865,11255340,The drug hypersensitivity syndrome: what is the pathogenesis?,,1
9866,11258350,Long-term outcome in treated combined methylmalonic acidemia and homocystinemia,"PURPOSE: To describe the clinical and biochemical features and long-term outcome of a cohort of eight patients with methylmalonic acidemia and homocystinuria (cblC). METHODS: Documentation of clinical features at birth and longitudinal follow-up of the biochemical and clinical response to treatment with daily oral carnitine and intramuscular hydroxocobalamin observed during continuous follow-up for an average of 5.7 years. RESULTS: Our patients had an increased incidence of congenital malformations including microcephaly (<5%) at birth (2 of 8), congenital heart disease (2 of 8), dysmorphic facial features (1 of 8), and thyroglossal duct cyst (1 of 8). Postnatal hydrocephalus (2 of 8) and hip dislocation caused by ligament laxity (1 of 8) were also noted. One patient had profound visual impairment before 6 months of age secondary to cblC retinopathy, and two patients had abnormal retinal pigmentation with normal visual function. All patients presented with poor growth, feeding problems, and/or seizures. No patients had acute acidotic crises before or after treatment. All patients had dramatic reduction of plasma free homocystine and urine methylmalonic acid excretion after initiation of therapy with carnitine, intramuscular (IM) hydroxocobalamin (OHcbl) and, in two cases, oral betaine. Growth was significantly improved in most cases after the initiation of therapy, and microcephaly was resolved in one patient. All patients were developmentally delayed regardless of age of treatment onset, although two patients had relatively mild developmental delay. CONCLUSION: cblC patients may have an increased incidence of congenital malformations suggesting prenatal effects of abnormal cbl metabolism. Treatment with IM OHcbl and carnitine successfully corrects the biochemical abnormalities and improves growth. Developmental delay of variable severity is always present regardless of age at diagnosis or treatment onset.",1
9867,11261323,Hepatic veno-occlusive disease in two patients with relapsed acute myeloid leukemia treated with anti-CD33 calicheamicin (CMA-676) immunoconjugate,"Monoclonal antibodies recognizing hematopoietic antigens are increasingly being used to target therapy directly at leukemic cells, with the aim of achieving sustained remission with little systemic toxicity. Administration of anti-CD33 calicheamicin immunoconjugate is commonly regarded as being safe, with only moderate systemic non-hematological side effects. We report on two cases of hepatic veno-occlusive disease in heavily pretreated patients presenting with relapsed acute myeloid leukemia (AML). Since significant liver toxicity prevented further specific therapy in both patients, we recommend that antibody therapy with anti-CD33 immunoconjugate should be applied with caution in patients presenting with risk factors for the development of hepatic veno-occlusive disease.",1
9868,11263519,The management of anti-tuberculosis drug-induced hepatotoxicity,"SETTING: A tuberculosis ward in a chest disease teaching hospital. OBJECTIVE: To compare the efficacy of two different retreatment protocols on hepatotoxicity recurrence in tuberculosis treatment. DESIGN: In a prospective, randomised study, 45 patients with new tuberculosis developed hepatotoxicity after anti-tuberculosis treatment. Patients in Group I (n = 20) were retreated with a drug regimen consisting of isoniazid, rifampicin, ethambutol and streptomycin administered by gradually increasing the number and dosage of the drugs. Patients in Group II (n = 25) were retreated with the same regimen (isoniazid, rifampicin, pyrazinamide and ethambutol) in the same dosages throughout. RESULTS: Hepatotoxicity recurred in respectively zero and six (24%) patients in Groups I and II (P = 0.021). Of the six patients with recurrence of hepatitis, one could not be followed up. The other five received the same retreatment protocol as Group I. By the end of retreatment, all patients were cured. CONCLUSION: The recurrence rate of hepatotoxicity in the retreatment of tuberculosis is higher in the reintroduction of a full-dose regimen including pyrazinamide, which causes more hepatotoxicity than gradual reintroduction of a regimen without pyrazinamide.",1
9869,11265073,Captopril-associated cholestasis complicating the management of pancreatic cancer,"Cholestatic jaundice is a rare complication associated with the use of the angiotensin -converting enzyme inhibitor captopril. The severity of the disease may range from cholestasis on liver histology to overt fulminant hepatic failure. This diagnosis is seldom considered in patients with pancreatic or biliary tract malignancy. We present a patient with unresectable adenocarcinoma of the pancreas whose jaundice decreased slowly over many weeks despite establishment of adequate endoscopic biliary drainage. The presence of captopril-associated cholestasis confounded confirmation of adequate biliary drainage. The absence of observed hepatic bile secretion at duodenoscopy, as seen in this patient, is a previously unreported endoscopic feature of this syndrome.",1
9870,11276273,Treatment of elderly patients with nabumetone or diclofenac: gastrointestinal safety profile,"GOALS: To evaluate the efficacy and gastrointestinal safety of nabumetone and diclofenac in the treatment of elderly patients with osteoarthritis, participating in a 3-month efficacy trial. BACKGROUND: Elderly patients have an elevated risk for developing gastrointestinal complications with chronic use of nonsteroidal anti-inflammatory drugs. STUDY: This was a randomized, double-blind, parallel-group, multicenter study with a 3-to 14-day placebo washout period and a 12-week active treatment phase. Patients 65 years or older with moderate-to-severe osteoarthritis of the knee or hip were randomized to receive 1,000 to 2,000 mg/d of nabumetone or 100 to 150 mg/d of diclofenac. The primary efficacy parameters were the percent of patients improved using a Patients' and Physicians' Global Assessment at endpoint. Gastrointestinal safety was assessed by the incidence of gastrointestinal symptoms and adverse events. RESULTS: Three hundred thirty-five patients (mean age = 72 years) with active osteoarthritis were enrolled. There were no statistically significant differences between the two treatment groups in any of the primary efficacy variables. However, differences between the groups were apparent in the frequency of adverse gastrointestinal events. Two patients in the diclofenac group had evidence of gastrointestinal bleeding and/or ulcer compared with none in the nabumetone group. In addition, significantly more (p < 0.05) patients (4%) receiving diclofenac had alanine transaminase values more than twice the upper limit of normal at endpoint compared with patients receiving nabumetone (0%). CONCLUSIONS: Nabumetone was as effective as diclofenac in the treatment of elderly patients with moderate-to-severe osteoarthritis. However, the gastrointestinal safety profile of nabumetone was superior to that of diclofenac with respect to elevation of liver enzymes.",1
9871,11276298,The efficacy and safety of comfrey,"Herbal medication has gathered increasing recognition in recent years with regard to both treatment options and health hazards. Pyrrolizidine alkaloids have been associated with substantial toxicity after their ingestion as tea and in the setting of contaminated cereals have led to endemic outbreaks in Jamaica, India and Afghanistan. In Western Europe, comfrey has been applied for inflammatory disorders such as arthritis, thrombophlebitis and gout and as a treatment for diarrhoea. Only recently was the use of comfrey leaves recognized as a substantial health hazard with hepatic toxicity in humans and carcinogenic potential in rodents. These effects are most likely due to various hepatotoxic pyrrolizidine alkaloids such as lasiocarpine and symphytine, and their related N-oxides. The mechanisms by which toxicity and mutagenicity are conveyed are still not fully understood, but seem to be mediated through a toxic mechanism related to the biotransformation of alkaloids by hepatic microsomal enzymes. This produces highly reactive pyrroles which act as powerful alkylating agents. The main liver injury caused by comfrey (Symphytum officinale) is veno-occlusive disease, a non-thrombotic obliteration of small hepatic veins leading to cirrhosis and eventually liver failure. Patients may present with either acute or chronic clinical signs with portal hypertension, hepatomegaly and abdominal pain as the main features. Therapeutic approaches include avoiding intake and, if hepatic failure is imminent, liver transplantation. In view of the known serious hazards and the ban on distributing comfrey in Germany and Canada, it is difficult to understand why comfrey is still freely available in the United States.",1
9872,11280657,Acute hepatic steatosis complicating massive insulin overdose and excessive glucose administration,"OBJECTIVE: To describe a case of acute hepatic steatosis due to excessive administration of glucose in the setting of massive insulin overdose, a complication which is rapidly and completely reversible if glucose infusion is rapidly tapered. DESIGN: Case report, clinical. SETTING: Intensive care unit, university hospital. PATIENT: A single patient admitted to the ICU. INTERVENTION: Intravenous glucose after insulin overdose. MEASUREMENTS AND MAIN RESULTS: On the 3rd day, increases in transaminase (ASAT 420 IU/l, ALAT 610 IU/l), bilirubin (147 mmol/l) and lactate (6.8 mmol/l), a decrease in arterial pH (7.32) and slightly increased liver size on ultrasound examination suggested acute hepatic steatosis. Clinical and laboratory abnormalities resolved rapidly after discontinuation of excessive glucose infusions (1,400 g/day for 3 days). CONCLUSIONS: Very large amounts of glucose after massive insulin overdose are potentially dangerous. Even though the fear of hypoglycemia-induced neurologic damage should be a constant preoccupation in this situation, glucose administration should be titrated on closely monitored blood glucose levels.",1
9873,11281569,Hepatitis after intravenous buprenorphine misuse in heroin addicts,"BACKGROUND: Sublingual buprenorphine is used as a substitution drug in heroin addicts. Although buprenorphine inhibits mitochondrial function at high concentrations in experimental animals, these effects should not occur after therapeutic sublingual doses, which give very low plasma concentrations. CASE REPORTS: We report four cases of former heroin addicts infected with hepatitis C virus and placed on substitution therapy with buprenorphine. These patients exhibited a marked increase in serum alanine amino transferase (30-, 37-, 13- and 50-times the upper limit of normal, respectively) after injecting buprenorphine intravenously and three of them also became jaundiced. Interruption of buprenorphine injections was associated with prompt recovery, even though two of these patients continued buprenorphine by the sublingual route. A fifth patient carrying the hepatitis C and human immunodeficiency viruses, developed jaundice and asterixis with panlobular liver necrosis and microvesicular steatosis after using sublingual buprenorphine and small doses of paracetamol and aspirin. CONCLUSIONS: Although buprenorphine hepatitis is most uncommon even after intravenous misuse, addicts placed on buprenorphine substitution should be repeatedly warned not to use it intravenously. Higher drug concentrations could trigger hepatitis in a few intravenous users, possibly those whose mitochondrial function is already impaired by viral infections and other factors.",1
9874,11285002,Autoimmune hyperthyroidism in multiple sclerosis under treatment with glatiramer acetate--a case report,,1
9875,11286949,Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia,"""PURPOSE: To examine the efficacy and safety of colesevelam hydrochloride, a novel, nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin in a multicenter, randomized, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL] cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose, n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34), colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with simvastatin 20 mg (n = 37), for 6 weeks. RESULTS: Mean LDL cholesterol levels decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61 mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone (P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride levels were similar to those for simvastatin alone. Side effects were similar among treatment groups, and there were no clinically important changes in laboratory parameters. CONCLUSION: Coadministration of colesevelam and simvastatin was effective and well tolerated, providing additive reductions in LDL cholesterol levels compared with either agent alone.""",1
9876,11291233,Drug- and chemical-induced cholestasis,"Cholestasis resulting from drugs is an increasingly recognized cause of liver disease. It produces a broad clinical-pathologic spectrum of injury that includes simple jaundice, cholestatic hepatitis, and bile duct injury that can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis. Although the risk of drug-induced cholestasis leading to a fatal outcome is quite rare, knowledge and recognition of the various forms of cholestatic injury assumes an importance whenever clinicians are confronted with jaundice or other manifestations of liver disease in patients receiving medicinal or chemical agents.",1
9877,11293449,Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report,"We report a case of fosinopril-induced prolonged cholestatic jaundice and pruritus in a 61-year-old man, with no previous hepatobiliary disease, who presented with asthenia, jaundice and itching 3 weeks after starting fosinopril therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. Liver biopsy showed cholestasis without bile duct damage. The disease ran a severe course during the 2 months of hospitalization, with prolonged itching for 6 months, eventually controlled with oral naltrexone. Jaundice subsided after 4 months, with anicteric cholestasis persisting for more than 18 months. Similar occurrences have been reported with other inhibitors of angiotensin-converting enzyme (mostly captopril), but this is the first case of an important adverse reaction to fosinopril.",1
9878,11302345,Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer,"BACKGROUND: Management of patients with recurrent epithelial ovarian cancer is difficult. Although several agents are active, responses are short-lived and observed in only a small number of patients. Side effects of these drugs are substantial. There is a need for more effective and less toxic therapies. Altretamine is a well tolerated oral agent with minimal toxicity. There are only a few trials evaluating its efficacy as a single agent in recurrent epithelial ovarian cancer. METHODS: We prospectively studied patients with recurrent epithelial ovarian cancer who were able to take oral medication and had adequate bone marrow, liver and renal functions. All had been previously treated with at least one platinum-based chemotherapy regimen and had either relapsed or failed to achieve an adequate response. RESULTS: Seventeen patients were studied. The commonest histological subtype was serous adenocarcinoma. Seven patients had platinum refractory disease. The mean duration of therapy was 6.1 months. Six patients (35%) achieved complete or partial remission, time to progression was 6.0 months and mean overall survival was 15.1 months. Toxicity was primarily nausea, vomiting and asthenia and was easily manageable. CONCLUSION: Altretamine is an acceptable and apparently less toxic alternative to other cytotoxic drugs used for palliation of patients with recurrent epithelial ovarian cancer.",1
9879,11304783,Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine,"""PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.""",1
9880,11305380,Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment,"""OBJECTIVE: To evaluate the efficacy, safety and side-effects of methotrexate (MTX) in psoriasis. DESIGN: A 26-year retrospective study. SETTING: Department of Dermatology, Leipzig University, Leipzig, Germany. PATIENTS: One hundred and fifty-seven patients with extensive plaque psoriasis, erythrodermic, pustular and arthropathic forms, were treated with low-dose methotrexate (15-20 mg maximum weekly dosage [Weinstein schedule]), the majority for long-term periods. The mean cumulative dose was 3394 mg, the mean duration 237 weeks. RESULTS: The effect of MTX treatment was good in 76%, moderate in 18% and poor in 6% of subjects; 61% experienced side-effects, most frequently due to liver function abnormalities, bone marrow suppression, nausea, gastric complaints and hair loss. In 20% of cases the subjects were forced to discontinue therapy; 9% refused therapy due to physical and psychological discomfort, 2% wanted to become pregnant, 16% were lost to follow-up, 6% died from multimorbidity and old age. Three subjects (2%) developed cancer of the lung, breast or cervix uteri, possibly in relation to long-term MTX treatment. Altogether there were no deaths or life-threatening side-effects attributable to MTX treatment, and no cases of progressive liver cirrhosis apart from two extensive skin necroses due to overdosage (misunderstanding, suicidal attempt) that were treated successfully with citrovorum factor. CONCLUSION: Low-dose MTX (<15-20 mg/week) is an effective therapy for extensive and severe forms of psoriasis if patients are selected carefully and monitored regularly, particularly with respect to liver and bone marrow toxicity. This helps to reduce severe side-effects even during long-term treatment. Drug interactions must be avoided. MTX therapy according to the guidelines is relatively safe and still has a place in the systemic treatment of psoriasis with 40 years of experience and an acceptable safety record.""",1
9881,11307364,[Clozapine-induced toxic hepatitis],"A case of clozapine-induced toxic hepatitis in a 49-year old woman with schizophrenia is described. The daily clozapine dose was clinically titrated to 300 mg. Subsequently, the patient experienced lethargy and anorexia, and fever, eosinophilia, leucocytosis and abnormal liver parameters were found. The serum concentration of clozapine was 8595 nmol/l, and treatment was discontinued. After eight days, the condition stabilised, and low-dose clozapine treatment was successfully reinstituted with serum monitoring (TDM).",1
9882,11309550,The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions,"""BACKGROUND: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. METHODS: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P <.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, approximately 12 micromol/L) and metabolites (inhibition constant, approximately 8.5 micromol/L for metabolite Ro 47-8634). CONCLUSIONS: These results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.""",1
9883,11310525,Possible atypical cross-sensitivity between phenytoin and carbamazepine in the anticonvulsant hypersensitivity syndrome,"Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening reaction that occurs in response to common anticonvulsants in predisposed individuals. It is often characterized by fever, rash, lymphadenopathy, hepatitis, and laboratory abnormalities. Consequently, it often is overlooked or even misdiagnosed by practitioners unfamiliar with AHS. Cross-sensitivity manifests frequently between phenytoin, phenobarbital, and carbamazepine as an exacerbation of presenting signs and symptoms. We report a case of AHS in a patient whose clinical features changed significantly when switching from phenytoin to carbamazepine. Physicians and pharmacists must become aware of the extreme variability in AHS manifestation so that the offending anticonvulsant regimen can be discontinued in a timely manner.",1
9884,11315774,Acute cholestatic hepatitis caused by a probable allergic reaction to paracetamol in an adolescent,We reported on an adolescent who suffered from cholestatic hepatitis after taking a low dose of paracetamol. It was suspected that the condition was brought about by an allergic reaction to paracetamol. Paracetamol is one of the representative intrinsic hepatotoxic drugs. There have been only a few reports on liver damage due to an allergic reaction to paracetamol. There is a need to call attention to this particular reaction.,1
9885,11317062,Chronic acetaminophen overdosing in children: risk assessment and management,"Acetaminophen is currently the pediatric analgesic and antipyretic of choice. Although children appear to tolerate single, high-dose ingestions well, the literature is replete with reports of significant morbidity and mortality after repeated supra-therapeutic dosing. Proposed risk factors for injury with chronic use include age, total dose, duration, presence of intercurrent febrile illness, starvation, co-administration of cytochrome P450-inducing drugs, underlying hepatic disease, and unique genetic makeup. Evaluation of these children should include serum acetaminophen concentration, prothrombin time, and serum bilirubin and transaminase concentrations. The Rumack-Mathew nomogram should not be used to estimate the risk of hepatotoxicity in cases of chronic ingestion. Based on history, clinical examination, and laboratory findings, patients may be placed in three categories: those without hepatic injury and with no residual acetaminophen to be metabolized, those without injury but with some acetaminophen to be metabolized, and those with hepatotoxicity. Those without injury and no residual acetaminophen need not be treated or followed. Patients with hepatotoxicity or potential for hepatotoxicity based on residual acetaminophen should be treated with N-acetylcysteine. Most importantly, because so many parents are unaware of the potential risk of inappropriate dosing, education is the key to preventing future cases.",1
9886,11317164,The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib,"Celecoxib is a cyclooxygenase- (COX)-1-sparing inhibitor of COX-2 that is indicated for the treatment of osteoarthritis and rheumatoid arthritis. Many agents used for treating these diseases, both symptom-modifying and disease-modifying, are associated with the potential for hepatotoxicity. This article presents an analysis of the hepatic effects of celecoxib in 14 controlled studies of patients with arthritis (2 to 24 weeks' duration), in a long-term, open-label safety study (as long as 2 years), in 11 studies of patients receiving treatment for pain after oral or orthopedic surgery (up to 5 days' duration), and in five pharmacology studies. The overall incidence of hepatic adverse events in arthritis patients receiving celecoxib was similar to that for placebo but significantly lower than in the combined group of patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). The most commonly reported hepatic adverse events were elevations in liver transaminase levels, most of which occurred in patients receiving diclofenac. Similarly, clinically significant elevations of transaminase levels occurred more frequently with NSAIDs than with celecoxib. A pharmacology study performed in patients with mild or moderate hepatic impairment showed that celecoxib did not produce any clinically relevant changes from baseline in creatinine clearance, alanine aminotransferase, or bilirubin values in these settings. In the four interaction studies performed with drugs metabolized in the liver, none of the adverse events was hepatic in nature, and no clinically relevant liver function test abnormalities occurred. In conclusion, this analysis suggests that celecoxib has a very low potential for hepatic toxicity, even after exposures of as long as 2 years at therapeutic doses.",1
9887,11318519,Aspirin-related hepatotoxicity in a child after liver transplant,,1
9888,11319447,[Acute cholestatic hepatitis due to chlorambucil],,1
9889,11322018,[Liver damage and nonsteroidal anti-inflammatory drugs: case non-case study in the French Pharmacovigilance Database],"This study investigates the relationship between exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and liver injuries using the French Pharmacovigilance Database. We use the case/non-case methodology, where 'cases' were reports of the reactions of interest (liver injuries as recorded in the database according to the WHO-ART classification including cytolytic and cholestatic hepatitis, acute hepatitis, liver enzyme elevations). 'Non-cases' were all reports of reactions other than these being studied. Amineptine and acetaminophen were used as 'positive controls'. Among the 42,913 adverse drug reactions recorded in the database between January 1995 and December 1997, 5708 (13 per cent) were liver injuries. In comparison with other drugs in the database, liver injuries were inversely associated with exposure to NSAIDs, whatever the class of the drugs (OR 0.3 [0.3-0.4]). In contrast, liver injuries were significantly related to acetaminophen (OR 2.1 [1.9-2.3]), and amineptine (OR 14.0 [10.5-18.7]). Naproxen and diclofenac were associated with a higher frequency of liver injuries, respectively 15.7 per cent and 11.5 per cent. The risk associated with NSAIDs alone significantly decreased when the analysis was performed after exclusion of hepatotoxic drugs associated with NSAIDs (except for naproxen). The present results show the low frequency of liver damage associated with NSAIDs. The main factor appears to be concomitant exposure to other hepatotoxic drugs.",1
9890,11330435,Trovafloxacin hepatotoxicity,"A 19-year-old woman was treated for recurrent sinusitis with oral trovafloxacin and developed acute hepatitis and peripheral eosinophilia, with hepatosplenomegaly and ascites. Laparoscopic liver biopsy showed extensive centrilobular hepatocyte necrosis, likely causing venooclusive disease-like signs and symptoms. Clinical and laboratory abnormalities resolved completely after prolonged treatment with steroids. The temporal relationship between trovafloxacin and the onset of hepatitis favors this drug as a culprit.",1
9891,11330653,Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of 'sulfa' allergy,"""Celecoxib, a selective cyclo-oxygenase-2 inhibitor, is a diaryl-substituted pyrazole derivative containing a sulfonamide substituent. Because of this structural component, celecoxib is contraindicated for use in patients who have demonstrated allergic reactions to sulfonamides. However, there is a lack of data demonstrating cross-reactivity among sulfonamide medications. A sulfonamide is any compound with an SO2NH2 moiety. The major difference between sulfonamide antimicrobials and other sulfonamide-containing medications such as furosemide, thiazide diuretics and celecoxib, is that sulfonamide antimicrobials contain an aromatic amine group at the N4 position. This allows for division of the sulfonamides into 2 groups: aromatic amines (i.e., sulfonamide antimicrobials) and nonaromatic amines. In addition, sulfonamide antimicrobials contain a substituted ring at the N1-position; this group is not found with nonaromatic amine-containing sulfonamides. Adverse reactions to sulfonamide antimicrobials include type I, or immunoglobulin (Ig) E-mediated reactions, hypersensitivity syndrome reactions, and severe skin reactions such as toxic epidermal necrolysis. The aromatic amine portion of the sulfonamide antimicrobial is considered to be critical in the development of latter 2 reactions. In susceptible individuals, the hydroxylamine metabolite is unable to be detoxified leading to a cascade of cytotoxic and immunological events that eventually results in the adverse reaction. Since celecoxib does not contain the aromatic amine, adverse reactions such as hypersensitivity syndrome reactions and toxic epidermal necrolysis would not be expected to occur at the same frequency as they do with sulfonamide antimicrobials. Similarly, for IgE-mediated reactions, the N1-substituent and not the sulphonamide moiety is important in determining specificity to antibodies. Celecoxib and other nonaromatic amine-containing sulfonamide medications do not contain the N1-substituent. Cross-reactivity among the various sulfonamide-containing medications has also not been substantiated by published case reports. In fact, conflicting information exists in the literature. Reports showing lack of cross-reactivity balance the few case reports suggesting cross-reactivity. Cross-reactivity between sulfonamide medications should be based on scientific data, including chemistry, metabolism, immune responses and clinical data. Based on the current information, there is no documentation for cross-reactivity between sulfonamide antimicrobials and other sulfonamide medications, such as celecoxib.""",1
9892,11333662,"[Hirsutism, flutamide and hepatotoxicity]",,1
9893,11336467,Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study,"""The efficacy and toxicity of combined paclitaxel and gemcitabine was evaluated in 54 chemotherapy-naive patients with metastatic non-small cell lung cancer (NSCLC). Gemcitabine i.v. 1000 mg/m(2)was administered on days 1 and 8 and paclitaxel 200 mg/m(2)as a continuous 3-hour infusion on day 1. Treatment was repeated every 21 days. Patients had a median age of 53 years. ECOG performance status was 0 or 1 in 48 patients. 41 patients (75.9%) had initial stage IV disease; histology was mainly adenocarcinoma (46.3%). 2 patients (4.3%) achieved a complete response and 15 (31.9%) achieved a partial response giving an overall response rate of 36.2% (95% CI: 22.4-49.9%); 19 patients (40.4%) had stable disease and 10 (21.3%) had progressive disease. The median survival time was 51 weeks (95% CI: 46.5-59.3), with a 1-year survival probability of 0.48 (95% CI: 0.34-0.63). Grade 3/4 neutropenia and febrile neutropenia occurred in 15.2% and 2.2% of courses, respectively. Grade 3/4 thrombocytopenia was rare (1.8% of courses). Peripheral neurotoxicity developed in 25 patients (47.2%), mostly grade 1/2. Arthalgia/myalgia was observed in 30 patients (56.6%), generally grade 1 or 2. Grade 3 abnormal levels of serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT) occurred in 5 patients (9.4%) and 1 patient (1.9%), respectively. Combined paclitaxel and gemcitabine is an active and well-tolerated regimen for the treatment of advanced NSCLC, and warrants further investigation in comparative, randomized trials.""",1
9894,11343055,"Mitochondrial DNA depletion, near-fatal metabolic acidosis, and liver failure in an HIV-infected child treated with combination antiretroviral therapy","A child with controlled human immunodeficiency virus infection presented with neurologic deterioration, lactic acidosis, and organic aciduria. Muscle biopsy revealed abnormal mitochondrial (mt) morphology, reduced mt enzyme activities, and mtDNA depletion. After adjustment of antiretroviral therapy to a regimen free of nucleoside analogs, marked improvement was seen in clinical status and mt abnormalities.",1
9895,11346336,Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma,"""OBJECTIVES: To determine the safety and efficacy of oral bexarotene (Targretin capsules; Ligand Pharmaceuticals Incorporated, San Diego, Calif). DESIGN: The effects of 2 randomized doses of 6.5 mg/m(2) per day (with crossover for progression) vs 650 mg/m(2) per day (later modified to 300 mg/m(2) per day) were evaluated in an open-label, multicenter, phase 2 and 3 study conducted between February 1997 and November 1998. SETTING: Eighteen international cutaneous T-cell lymphoma clinics at academic referral centers. PATIENTS: Fifty-eight patients with biopsy-proven stage IA through IIA cutaneous T-cell lymphoma that was refractory to (or patients were intolerant of) treatment or had reached at least a 6-month response plateau under at least 2 forms of prior therapy (median of 3.5 prior therapies). INTERVENTION: Bexarotene (Targretin capsules) administered once daily with meal for 16 weeks or longer. MAIN OUTCOME MEASURES: Primary end point classification of overall response rate of complete and partial remissions determined by either the Physician's Global Assessment of Clinical Condition or the objective Composite Assessment of Index Lesion Severity. Body surface area, time to response, duration of disease control, time to disease progression, individual index lesion signs and symptoms, and quality of life parameters were secondary outcomes. RESULTS: Responses (> or = 50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m(2) per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m(2) per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m(2) per day (95% CI, 43%-91%). The rate of progressive disease was 47%, 21%, and 13% at the same dose levels, respectively. Eight (73%) of 11 patients crossing over from 6.5 mg/m(2) per day to higher doses subsequently responded. The median duration of response from start of therapy could not be estimated for the 15 patients at 300 mg/m(2) per day owing to low relapse rates in 2 patients (13%); at higher doses it was 516 days. The following drug-related adverse effects were reversible and treatable: hypertriglyceridemia (46 patients [79%]), hypercholesterolemia (28 patients [48%]), headache (27 patients [47%]), central hypothyroidism (23 patients [40%]), asthenia (21 patients [36%]), and leukopenia (16 patients [28%]). No cases of drug-related neutropenic fever, sepsis, or death occurred. Pancreatitis occurred in 3 patients with triglyceride levels higher than 14.69 mmol/L (1300 mg/dL), all of whom were taking 300 mg/m(2) or more of oral bexarotene per day. CONCLUSIONS: Bexarotene (Targretin capsules) (the first retinoid X receptor-selective rexinoid) was well tolerated and effective as an oral treatment for 15 (54%) of 28 patients with refractory or persistent early-stage cutaneous T-cell lymphoma at doses of 300 mg/m(2) per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication.""",1
9896,11346902,[Fulminant hepatocellular necrosis following administration of docetaxel],,1
9897,11353925,"""Erythropoietin (Procrit; Epogen) revisited""",,1
9898,11360450,[Phenprocoumon-induced necrotizing hepatitis],"CLINICAL PRESENTATION: A 52-year-old female patient presented at our hospital with right upper abdominal pain and impaired general condition. During the previous 7 months, the patient had received anticoagulation treatment with phenprocoumon due to a prosthetic aortic valve replacement. TESTS: Serological tests for virologic, autoimmune or metabolic causes of hepatitis were negative. The histologic examination of liver biopsies showed necrotizing hepatocellular injury in zone 3 of the acinus without relevant fibrosis. Initially, a lymphocyte transformation test with phenprocoumon was negative. A second test after one week turned out to be positive. DIAGNOSIS AND CLINICAL COURSE: After withdrawal from phenprocoumon therapy and switching to anticoagulation with a low molecular weight heparin, liver tests gradually became normal. Aminotransferase levels rapidly increased when phenprocoumon treatment was resumed. Phenprocoumon-associated necrotizing hepatitis was diagnosed by clinical course, liver histology and the positive lymphocyte transformation test. After immunosuppressive treatment with prednisolone was started again, liver enzymes gradually normalized. Anticoagulation was further performed with low molecular weight heparin. CONCLUSION: This case stresses the fact that an adequate and detailed history on concomitant medication is mandatory in patients who present with cryptic hepatitis. Though severe hepatic adverse effects of phenprocoumon are rare, physicians should consider coumarin derivatives as a potential source of hepatitis.",1
9899,11364758,Hepatitis in an HIV-infected man,"A case study is presented of a 28-year-old, HIV-infected male with hepatic dysfunction of unknown etiology. After failure on AZT and 3TC, the patient was prescribed d4T, 3TC, and nevirapine. After three weeks of treatment, the patient had poor appetite, bloating, and fever. Blood chemistries, diagnostic imaging, and hepatitis and CMV serologies were all performed, with no clear findings. Since there had been reports of liver dysfunction from nevirapine, all medications were ceased, and the patient's condition improved. The role of antiretroviral agents, particularly nevirapine, in liver dysfunction is explored. Contraindications in prescribing this drug, particularly for patients with impaired liver function or current alcohol or drug abuse, are also discussed.",1
9900,11371686,Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy,"OBJECTIVE: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. DESIGN: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. RESULTS: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. CONCLUSIONS: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.",1
9901,11374701,Jaundice and hepatocellular damage associated with nevirapine therapy,"OBJECTIVE: Nevirapine is a nonnucleoside reverse transcription inhibitor that is used as part of highly active antiretroviral therapeutic combinations. Nevirapine has been associated with a skin rash in 32 to 48% of patients. Recent reports indicate that hepatic toxicity also occurs. METHODS: We describe four instances of reversible hepatocellular damage associated with the use of nevirapine in patients with HIV infection. Two of the four patients were also coinfected with the hepatitis C virus. RESULTS: Evidence of malaise, skin rash, and icteric hepatitis with pruritus occurred 4-6 wk after the beginning of nevirapine therapy. No evidence of metabolic acidosis was present in any of our patients. In all cases, liver test results declined to normal or near normal levels, and pruritus disappeared 4-6 wk after discontinuation of the medication. No patient was rechallenged with the drug. CONCLUSION: Nevirapine can be associated with icteric hepatitis, which appears to be reversible after withdrawal of the drug.",1
9902,11374713,Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus,"Troglitazone is currently approved for the treatment of diabetes mellitus. Hepatic abnormalities have been reported in up to 1.9% of patients receiving the drug. Severe hepatotoxicity, including the need for liver transplantation, has also been reported in patients treated with troglitazone. Troglitazone has been reported to be beneficial in a small group of patients with nonalcoholic steatohepatitis (NASH). We present a patient with nonalcoholic steatohepatitis and diabetes mellitus who developed severe cholestasis after treatment with troglitazone. The exact mechanism of troglitazone toxicity is unknown, and whether preexisting liver abnormalities increase the incidence of toxicity is speculative. Further data are needed before more widespread use of troglitazone can be recommended for patients with nonalcoholic steatohepatitis.",1
9903,11375358,The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes,"""OBJECTIVE: To investigate the efficacy and safety of miglitol in combination with metformin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently controlled by diet alone. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind, placebo-controlled study, 324 patients with type 2 diabetes were randomized, after an 8-week placebo run-in period, to treatment with either placebo, miglitol alone, metformin alone, or miglitol plus metformin for 36 weeks. The miglitol was titrated to 100 mg three times a day and metformin was administered at 500 mg three times a day. The primary efficacy criterion was change in HbA(1c) from baseline to the end of treatment. Secondary parameters included changes in fasting and postprandial plasma glucose and insulin levels, serum triglyceride levels, and responder rate. RESULTS: A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean placebo-subtracted HbA(1c) of -1.78% was observed with miglitol plus metformin combination therapy, which was significantly different from treatment with metformin alone (-1.25; P = 0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone for fasting plasma glucose (-44.8 vs. -20.4 mg/dl; P = 0.0025), 2-h postprandial glucose area under the curve (-59.0 vs. -18.0 mg/dl; P = 0.0001), and responder rate (70.6 vs. 45.52%; P = 0.0014). All therapies were well tolerated. CONCLUSIONS: In type 2 diabetic patients, miglitol in combination with metformin gives greater glycemic improvement than metformin monotherapy.""",1
9904,11376200,Effect of L-carnitine treatment for valproate-induced hepatotoxicity,"The authors analyzed the association of L-carnitine treatment with hepatic survival in 92 patients with severe, symptomatic, valproate-induced hepatotoxicity. Forty-eight percent of the 42 patients treated with L-carnitine survived, but only 10% of the 50 patients treated solely with aggressive supportive care survived (p < 0.001). Early intervention with IV rather than enteral L-carnitine was associated with the greatest hepatic survival. Specifically, all 10 patients who were diagnosed in <5 days and treated with IV L-carnitine survived. Most patients had features of chronic illness and most children appeared to be malnourished.",1
9905,11381301,Acute hepatitis induced by alpha-interferon in a patient with chronic hepatitis C,"Hepatic adverse effects occur very rarely with alpha-interferon therapy. A case of acute hepatitis induced by alpha-interferon in a 33-year-old man with chronic hepatitis C is described. The patient developed acute hepatitis with very high aminotransferase activity and jaundice. After discontinuing alpha-interferon therapy, hepatitis resolved rapidly. The immune-mediated mechanism is the most probable cause of this hepatitis.",1
9906,11387849,[Early hepatopathy induced by ticlopidine],,1
9907,11395686,[Acute hepatitis following intravenous buprenorphine injection as a substitute drug in a drug-addict],,1
9908,11400273,"[A case of fulminant hepatitis, possibly caused by benzbromarone]",,1
9909,11402259,Ziprasidone (Geodon) for schizophrenia,,1
9910,11407955,Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood,"The efficacy and safety of methsuximide (MSM) was evaluated in children with intractable epilepsies in a prospective uncontrolled study. MSM was added to the therapeutic regimen of 112 children with intractable epilepsy under inpatient conditions, all of whom were therapeutically refractory to various first-line antiepileptic drugs (AED) or combinations of other AED. Titration of MSM was performed following a uniform protocol. Administration of MSM resulted in a 50% or greater reduction in seizure frequency in 40 patients after a short-term observation period (mean 9.1 weeks). After a mean of 3.7 years, the rate of seizures and side effects were re-evaluated in 39 patients who were still receiving MSM as part of their antiepileptic regimen. Twenty two of these patients derived long-term benefit from MSM. In patients with good seizure control, fasting plasma levels of N-desmethylmethsuximide, the principal active metabolite of MSM, were 25.3-44.7 mg l(-1)(mean 36.0 mg l(-1)). Thus effective plasma levels of N-desmethylmethsuximide in children were found to be higher than previously described. Forty one of 112 patients (28.9%) developed side effects during MSM treatment. No serious or irreversible side effects were seen. Our study demonstrates the value of MSM as an 'add-on' drug in intractable epilepsies.",1
9911,11409000,Benzylpenicillin-induced prolonged cholestasis,,1
9912,11410481,Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia,"""PURPOSE: Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML). In this study, we review the preclinical and clinical profiles of this immunoconjugate and the regulatory review that led to marketing approval by the United States Food and Drug Administration. EXPERIMENTAL DESIGN: From the literature and manufacturer's data, we review the activity, tolerability, and pharmacokinetics of gemtuzumab ozogamicin in preclinical and Phase I studies and its activity, efficacy, and side effects in three Phase 2 trials of 142 patients with relapsed AML. RESULTS: In Phase I studies, the major toxicity was myelosuppression, especially neutropenia and thrombocytopenia, resulting from the expression of CD33 on myeloid progenitor cells. The Phase 2 dose was 9 mg/m(2) infused i.v. over 4 h, repeated on day 14. A minority of patients experienced acute infusion-related symptoms, usually transient and occasionally requiring hospitalization. The complete response (CR) rate with full recovery of hematopoiesis was 16%. A subset of patients [CRs with incomplete platelet recovery (CRps)] was identified with blast clearance and neutrophil recovery but incomplete platelet recovery. The duration of responses of CRps appeared to be similar to those of the CRs, although the numbers were small. The question of the equivalence of these response groups was a central issue in the review of this new drug application (NDA). After considerable discussion, the Oncology Drugs Advisory Committee recommended allowing inclusion of CRps resulting in an overall response rate in the Phase 2 studies of 30%. In the subgroup of patients over 60 years of age, the overall response rate was 26%. Response duration was difficult to establish because of the high prevalence of postremission therapies. Tolerability and ease of administration may be improved compared with conventional chemotherapy, except for hepatotoxicity, with 31% of patients exhibiting abnormal liver enzymes. One patient died of liver failure in the Phase 2 trials. CONCLUSIONS: Marketing approval of gemtuzumab ozogamicin was granted on May 17, 2000 by the United States Food and Drug Administration under the Accelerated Approval regulations. Gemtuzumab ozogamicin is indicated for the treatment of patients with CD33 positive AML in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy. The approved dose was 9 mg/m(2) i.v. over 4 h and repeated in 14 days. Completion of the ongoing studies of gemtuzumab ozogamicin in relapsed AML and initiation of randomized clinical trials comparing the effects of gemtuzumab ozogamicin in combination with conventional induction chemotherapy to conventional chemotherapy alone on survival are mandated to confirm clinical benefit under the accelerated approval Subpart H regulations. Postmarketing reports of fatal anaphylaxis, adult respiratory distress syndrome (ARDS), and hepatotoxicity, especially venoocclusive disease (VOD) in patients treated with gemtuzumab ozogamicin, with and without associated hematopoietic stem cell transplantation (HSCT), have required labeling revisions and the initiation of a registration surveillance program. Tumor lysis and ARDS have been reported in patients with leukocytes above 30,000/ml treated with gemtuzumab ozogamicin; therefore, the reduction of leukocyte counts to below 30,000/ml is recommended prior to treatment. Patients should be carefully monitored for acute hypersensitivity, hypoxia, and delayed hepatotoxicity following treatment with gemtuzumab ozogamicin.""",1
9913,11411208,Fatal liver necrosis associated with the use of nitrofurantoin,,1
9914,11412594,[Alendronate-induced hepatocellular lesion],"Bisphosphonates are widely used in the treatment of metabolic bone disease. Bisphosphonate-induced hepatotoxicity is extremely infrequent. We present the case of a 76-year-old female patient with osteoporosis who was prescribed alendronate. A routine laboratory investigation carried out three months later revealed markedly elevated transaminase concentrations. Six weeks after withdrawal of treatment, laboratory parameters had returned to normal levels. We analyze this adverse reaction to alendronate as well as its possible pathogenic mechanisms.",1
9915,11422785,Cholangiopathy after short-term administration of piperacillin and imipenem/cilastatin,"We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was discharged 5 days after surgery in good clinical condition and with normal liver values except for a marginal elevation of alanine aminotransferase. Two weeks after discharge, he developed fatigue, fever and pruritus, necessitating rehospitalization. He was jaundiced and had elevated alkaline phosphatase and transaminases. After exclusion of an intra-abdominal fluid collection, a vascular problem, and infectious or autoimmune liver disease, a liver biopsy was performed. The biopsy revealed centrizonal bilirubinostasis, a portal infiltrate rich in eosinophils and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism for the observed hepatopathy. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 3 months. We conclude that short-term therapy with piperacillin, imipenem/cilastatin or the combination of these drugs can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Liver biopsy and positive lymphocyte transformation are compatible with an immunological mechanism.",1
9916,11426487,"Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study","""A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an """"S"""" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.""",1
9917,11426912,Safety of antileukotriene agents in asthma management,"OBJECTIVE: This article presents information on the safety of zafirlukast, montelukast, and zileuton, three antileukotrienes (anti-LTs) approved in the United States for the prophylaxis and treatment of asthma. After reading this article, readers should have an understanding both of the general safety of anti-LTs and their specific adverse effects. DATA SOURCES: Relevant and appropriate controlled clinical studies on the safety of anti-LTs in asthma were used. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals and appropriate reviews. RESULTS: Antiasthma agents, including corticosteroids, beta2-agonists, and methylxanthines, may be categorized into two classes: those used for the long-term control and prevention of persistent asthma and those used for the prompt relief of acute symptoms and exacerbations of the disease. Although most agents are safe and well tolerated when used properly, adverse effects may occur with use at higher dose levels. The anti-LTs, including zafirlukast, montelukast, and zileuton, are the first new pharmacologic class in the therapeutic armamentarium for asthma management to be approved in the United States in the past 20 years. Both zafirlukast and montelukast carry pregnancy category B classification whereas zileuton carries pregnancy category C classification. The most common adverse effects observed in clinical trials were headache, pharyngitis, abdominal pain, dyspepsia, and cough. CONCLUSIONS: The results of clinical trials and real-world experience indicate that these agents are generally safe and well tolerated, with an incidence of adverse effects comparable with placebo.",1
9918,11431595,Thiazolidinediones and liver toxicity,"Thiazolidinediones or glitazones specifically target insulin resistance. They have proven efficacy for reducing plasma glucose levels of type 2 diabetic patients treated with diet alone, sulphonylureas, metformin or insulin. In addition, they may be associated to some improvement of cardiovascular risk profile. However, troglitazone, the first compound approved by the FDA in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozens of deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy on blood glucose control of type 2 diabetic patients as compared to troglitazone. In controlled clinical trials, the incidence of significant increases in liver enzyme levels (ALT) was similar with rosiglitazone or pioglitazone as compared to placebo, whereas troglitazone was associated with a threefold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only two cases of severe reversible liver failure have been reported in patients treated with rosiglitazone, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. While regular monitoring of liver enzymes is still recommended and more long-term data are desirable, current clinical evidence supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.",1
9919,11433569,[DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome after sulfasalazine and carmazepine: report of two cases],"INTRODUCTION: To better individualize drug hypersensitivity reaction, Bocquet et al. have recently called this adverse drug reaction DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). EXEGESIS: We report two cases of DRESS and highlight the main characteristics of this syndrome. Two patients presented severe febrile skin eruption following drug intake (carbamazepine or sulfazalazine), with hypereosinophilia and hepatitis. All symptoms resolved after drug withdrawal and corticosteroid therapy. DRESS syndrome is an idiosyncratic reaction characterised by febrile eruption, occurring 2 to 6 weeks after the beginning of the treatment, accompanied by systemic symptoms and biological abnormalities (hypereosinophilia, hepatitis). Some complications can occur. This syndrome can be fatal. Numerous drugs can be responsible for this reaction to medication. The physiopathology has not yet been elucidated, and the treatment is not codified, but the triggering agent must immediately be stopped. Corticotherapy is sometimes used. CONCLUSION: It is important to recognize this entity recently named DRESS syndrome because it can mimic other pathologies, is potentially serious, and because withdrawal of the incriminating drug is imperative.",1
9920,11434605,Ornidazole-induced autoimmune hepatitis,"Ornidazole is a commonly prescribed antiparasitic drug for parasitic infestations, including amoebiasis, giardiasis and Trichomonas vaginalis. Several cases of antibiotic-induced autoimmune hepatitis (AIH) or AIH-like syndrome have been reported recently. In this report, we describe a 35-year-old woman with two relapses of AIH induced by ornidazole prescribed for diarrhoea and vaginal infection.",1
9921,11434754,Kava hepatotoxicity,,1
9922,11434897,Analysis of the cilostazol safety database,"""Cilostazol, a type III phosphodiesterase inhibitor, was approved in the United States in 1999 for the reduction of the symptoms of intermittent claudication. This article summarizes the safety data from 8 cilostazol phase 3 controlled clinical trials, involving 2,702 patients: 1,374 receiving cilostazol, 973 assigned to placebo, and 355 taking pentoxifylline. The trials ranged from 12 to 24 weeks in duration. There were a total of 475 patient-exposure years on cilostazol, 357 patient-exposure years on placebo, and 135 patient-exposure years on pentoxifylline. Headache, diarrhea, and other gastrointestinal complaints were seen more often in cilostazol-treated than placebo-treated patients; pharyngitis and nausea were more common in pentoxifylline-treated than placebo-treated patients. Headache requiring discontinuation occurred in 1.3% of patients taking cilostazol 50 mg bid and 3.7% of those receiving cilostazol 100 mg bid, compared with 0.3% of placebo-treated patients. Discontinuations due to diarrhea, palpitations, or myocardial infarction were similar in cilostazol-, placebo-, and pentoxifylline-treated patients. The rate of serious cardiovascular events was similar in all 3 treatment groups. Myocardial infarction occurred in 1.0% of cilostazol-treated, 0.8% of placebo-treated, and 1.1% of pentoxifylline-treated patients. The incidence of stroke was 0.5% in both cilostazol- and placebo-treated patients and 1.1% in pentoxifylline-treated patients. Total cardiovascular morbidity and all-cause mortality was 6.5% for cilostazol 100 mg bid, 6.3% for cilostazol 50 mg bid, and 7.7% for placebo. There were 16 deaths occurring in 0.6%, 0.5%, and 0.6% of cilostazol-, placebo-, and pentoxifylline-treated patients, respectively. The evaluations showed no trend toward increased cardiovascular morbidity or mortality risk in patients receiving cilostazol. In addition, postmarketing surveillance in the United States, representing 70,430 patient-years of cilostazol exposure, has shown minimal accounts of myocardial infarction, stroke, or death. The safety profile of cilostazol in doses of 50 mg bid and 100 mg bid appears to offer an acceptable risk-benefit ratio in patients with intermittent claudication.""",1
9923,11438043,"Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis","""Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed. This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 microg/kg of rhIL-11 or placebo twice per week or 5 or 15 microg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug. Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 microg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response. The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site.""",1
9924,11440232,"Acute, recurrent fosfomycin-induced liver toxicity in an adult patient with cystic fibrosis",We report a very unusual adverse effect--fosfomycin-induced repeat liver toxicity--in a female adult with cystic fibrosis (CF).,1
9925,11443569,"Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide","A prospective randomized, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of nitazoxanide in the treatment of diarrhea caused by Giardia intestinalis or Entamoeba histolytica and/or E. dispar in 89 adults and adolescents, 22 of whom were diagnosed with G. intestinalis, 53 with E. histolytica and/or E. dispar, and 14 with both G. intestinalis and E. histolytica and/or E. dispar. The study medication was administered as 1 nitazoxanide 500-mg tablet or a matching placebo twice daily for 3 days. Thirty-eight (81%) of 47 patients in the nitazoxanide treatment group resolved diarrhea within 7 days (median, 3 days) after initiation of treatment, versus 17 (40%) of 42 in the placebo group (P=.0002). With its efficacy in treating a broad spectrum of enteric protozoan pathogens, nitazoxanide could play an important role in the management of diarrhea caused by enteric protozoa, reducing morbidity and costs associated with these diarrheal illnesses.",1
9926,11444584,Possible roxithromycin-induced fulminant hepatic failure in a child,"A pediatric formulation of roxithromycin is a relatively new addition to the antibiotic market in Australia. A previously healthy 5-year-old boy with no significant medical history was treated with roxithromycin 50 mg twice/day for cough, fever, and anorexia. After completing a 5-day course of the agent, he developed a nonpruritic, nonurticarial, erythematous, maculopapular, generalized rash and occasional vomiting. Three days later his symptoms included jaundice, dark urine, and pale stools. Laboratory results revealed acute hepatitis, and the patient was admitted to the hospital. His hepatic function continued to deteriorate, so the boy was transferred to a tertiary pediatric hospital. His condition continued to worsen, and 6 days after transfer, he underwent liver transplantation. Clinicians should be aware of potential hepatic complications associated with the use of roxithromycin.",1
9927,11449876,Levetiracetam,"""The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of levetiracetam are reviewed. Levetiracetam is an adjunctive treatment for partial-onset epileptic seizures. This drug inhibits seizure activity via a mechanism that does not involve excitatory or inhibitory neuronal pathways. Oral bioavailability is about 100%, and food does not alter absorption. Levetiracetam is minimally plasma protein bound (10%). Peak time to absorption after oral administration is one hour, and steady state is achieved in two days with twice-daily administration. Three clinical studies have demonstrated levetiracetam's ability to reduce seizure frequency in patients with partial-onset epilepsy. The most commonly reported adverse effects in clinical trials were somnolence, dizziness, infection, and asthenia. The potential for interactions with medications that are hepatically metabolized is minimal. The starting dosage is 500 mg twice a day; the maximum dosage is 3000 mg/day within four weeks. Levetiracetam is effective as an adjunctive treatment of partial-onset epilepsy with or without secondary generalization.""",1
9928,11452755,Case of the month. Hepatic and renal failure in a patient taking troglitazone and metformin,"Troglitazone is a thiazolidinedione with insulin-sensitizing activities when administered to humans or animals with type 2 diabetes mellitus. It has been shown to have numerous desirable metabolic effects on glucose and lipid metabolism. A major adverse effect of troglitazone is the development of hepatotoxicity. In early clinical trials, elevations of serum aminotransferases (> 3 times upper normal limit) occurred in 48 of 2510 (1.9%) subjects receiving troglitazone. In December 1997 and again in August 1998, the United States Food and Drug Administration issued stronger warnings after getting reports of more than a hundred cases of liver damage, including liver failure requiring transplantation in three patients and death in another patient. Warner-Lambert Company announced on March 21, 2000 that it is voluntarily discontinuing the sale of Rezulin (troglitazone) tablets for the treatment of type 2 diabetes. Media reports sensationalizing the risks, associated with Rezulin therapy had created an environment in which patients and physicians were simply unable to make well-informed decisions regarding the safety and efficacy of Rezulin. Under these circumstances, and after discussions with the FDA, the company decided it was in the best interests of patients to discontinue marketing Rezulin. Concerns about the hepatotoxicity of troglitazone led the Medicine Control Agency of the United Kingdom to request voluntary withdrawal of the drug from the UK in December 1997.",1
9929,11464155,Risk factors for hepatotoxicity in patients treated with highly active antiretroviral therapy,,1
9930,11465701,"Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study","""OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.""",1
9931,11467664,Cholestatic jaundice associated with the use of metformin,"We report a patient who developed cholestatic jaundice shortly after initiation of treatment with metformin hydrochloride. Ultrasound of the liver and abdominal CT were normal. An ERCP showed normal biliary anatomy. A percutaneous liver biopsy was obtained showing marked cholestasis, with portal edema, ductular proliferation, and acute inflammation. Metformin hydrochloride was discontinued, and the patient's jaundice resolved slowly over a period of several months. Given the onset of his jaundice 2 wk after the initiation of metformin, we believe that this case represents an example of metformin-associated hepatotoxicity, the first such case reported.",1
9932,11468963,"Rosiglitazone (Avandia): hepatic, cardiac and hematological reactions",,1
9933,11472451,Comparison between repaglinide and glipizide in Type 2 diabetes mellitus: a 1-year multicentre study,"""AIMS: To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes. METHODS: Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily. RESULTS: Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively). CONCLUSIONS: Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.""",1
9934,11474633,"Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: a randomized, double-blind comparison with trovafloxacin","""This multicentre, randomized, double blind, parallel group study compared the efficacy and safety of gemifloxacin (320 mg once daily) with trovafloxacin (200 mg once daily) in 571 patients with community-acquired pneumonia (CAP). Although treatment was given routinely for 7 days it could be extended to 14 days; two-thirds of patients were treated for 7 days. High clinical success rates were noted at follow-up in the per-protocol population in both the gemifloxacin group (95.8%) and the trovafloxacin group (93.6%), non-inferiority with 95% CI. In the intent-to-treat population, the clinical success rate at follow-up was significantly superior for gemifloxacin (87.6%) compared with trovafloxacin (81.1%; 95% CI 0.5, 12.4). The pathogens identified most commonly at presentation were Mycoplasma pneumoniae and Streptococcus pneumoniae. Gemifloxacin eradicated 100% of S. pneumoniae. One bacteraemic isolate of S. pneumoniae was associated with clinical failure in the trovafloxacin group (MIC of trovafloxacin 8 mg/L). Gemifloxacin was well tolerated and the incidence of transient liver function abnormalities was very low. Gemifloxacin is an effective and well-tolerated treatment for patients with CAP.""",1
9935,11476450,Severe ciprofloxacin-induced acute hepatitis,,1
9936,11481613,Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy,"Hepatitis C virus (HCV)-related liver fibrosis progression is accelerated in human immunodeficiency virus (HIV)-infected patients. The effect of protease inhibitor (PI) therapy on liver fibrosis is unknown. The aim of this work was to analyze the impact of PI therapy on HCV-related liver fibrosis in HIV/HCV coinfected patients. We evaluated in a long-term follow-up retrospective cohort study the influence of antiretroviral therapy containing PI on liver fibrosis in 182 consecutive HIV/HCV coinfected patients. At liver biopsy, 63 patients had received PI and 119 patients had never been treated with PI. Relationships between liver histologic features, age, alcohol consumption, CD4 cell count, HIV-RNA load, and antiretroviral regimens were analyzed. Liver fibrosis stage was lower in patients receiving PIs by comparison with patients who had never received PIs (P =.03). The 5-, 15-, and 25-year cirrhosis rates were 2% versus 5%, 5% versus 18%, and 9% versus 27%, respectively, in patients who had received PIs compared with PI-untreated patients (P =.0006). Multivariate analysis identified 4 independent predictors of progression to cirrhosis: absence of protease inhibitor therapy (relative risk [RR] = 4.74, 95% confidence interval [CI], 1.34-16.67), heavy alcohol consumption (> or = 50 g daily) (RR = 4.71, 95% CI, 1.92-11.57), low CD4 cell count (<200/microL) (RR = 2.74, 95% CI, 1.17-6.41), and age at HCV contamination (> or = 20 years) (RR = 2.37, 95% CI, 1.04-5.38). In conclusion, protease inhibitor therapy might not accelerate progression to HCV-related cirrhosis. Furthermore, chronic use of antiretroviral therapy containing PI together with reduction of alcohol consumption and maintenance of high CD4 count could have a beneficial impact on liver fibrosis progression in HIV/HCV coinfected patients.",1
9937,11485143,Colesevelam hydrochloride: a novel bile acid-binding resin,"""OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. METHODS: MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. CONCLUSIONS: Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.""",1
9938,11487567,Enzyme therapy for lysosomal acid lipase deficiency in the mouse,"""Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of the triglycerides (TG) and cholesteryl esters (CE) delivered to lysosomes. Its deficiency produces two human phenotypes, Wolman disease (WD) and cholesteryl ester storage disease (CESD). A targeted disruption of the LAL locus produced a null (lal( -/-)) mouse model that mimics human WD/CESD. The potential for enzyme therapy was tested using mannose terminated human LAL expressed in Pichia pastoris (phLAL), purified, and administered by tail vein injections to lal( -/-) mice. Mannose receptor (MR)-dependent uptake and lysosomal targeting of phLAL were evidenced ex vivo using competitive assays with MR-positive J774E cells, a murine monocyte/macrophage line, immunofluorescence and western blots. Following (bolus) IV injection, phLAL was detected in Kupffer cells, lung macrophages and intestinal macrophages in lal( -/-) mice. Two-month-old lal( -/-) mice received phLAL (1.5 U/dose) or saline injections once every 3 days for 30 days (10 doses). The treated lal( -/-) mice showed nearly complete resolution of hepatic yellow coloration; hepatic weight decreased by approximately 36% compared to PBS-treated lal( -/-) mice. Histologic analyses of numerous tissues from phLAL-treated mice showed reductions in macrophage lipid storage. TG and cholesterol levels decreased by approximately 50% in liver, 69% in spleen and 50% in small intestine. These studies provide feasibility for LAL enzyme therapy in human WD and CESD.""",1
9939,11488711,Spironolactone-induced hepatitis,"There is widespread use of spironolactone in medical practice and the indications for its use well established and side effect profile well known. Herein, we present a case of drug-induced hepatitis occurring in a 50-year-old woman using spironolactone for the treatment of androgenetic alopecia. Six weeks after commencement of spironolactone the patient became unwell, complained of an extensive itch, but no icterus or jaundice. Liver function tests found abnormally elevated bilirubin and enzymes levels. After withdrawal of spironolactone, the patient's symptoms resolved and liver function improved. To date, there has only been one other report of spironolactone-induced hepatitis.",1
9940,11494710,Nevirapine-induced hepatitis: a case series and review of the literature,"Nevirapine, a nonnucleoside reverse transcriptase inhibitor used as part of combination antiretroviral therapy, can cause mild elevations in transaminase levels. Severe elevations in transaminase levels related to the use of nevirapine developed in 4 patients. Data on these patients were extracted via chart review, and a review of the literature was also completed. Nevirapine-induced hepatitis occurred shortly after drug initiation in patients with and without preexisting liver disease. Significant elevations in liver enzyme levels occurred but resolved promptly in most with discontinuation of the nevirapine. Close monitoring of liver enzyme levels in the early period after starting nevirapine is essential.",1
9941,11498145,Liver transplantation for ecstasy-induced fulminant hepatic failure,,1
9942,11501568,ACOG Practice Bulletin no. 28: Clinical Management Guidelines for Obstetrician-Gynecologists. Use of botanicals for management of menopausal symptoms,"Lack of confidence in the espoused benefits of hormone replacement therapy (HRT) coupled with a significant array of side effects of HRT, results in fewer than 1 in 3 women choosing to take HRT. The use of alternatives to conventional HRT has become more accessible and acceptable to many women. As more women choose these alternatives, physicians are confronted with the challenges of how to advise patients about alternative medicine and how to determine which therapies may be safe and effective. This document will examine available scientific information on alternative therapies for treatment of menopausal symptoms and provide recommendations on efficacy and potential adverse consequences.",1
9943,11506133,Fatal hepatitis associated with isoflurane exposure and CYP2A6 autoantibodies,,1
9944,11508453,"Hepatitis with interface inflammation and IgG, IgM, and IgA anti-double-stranded DNA antibodies following infliximab therapy: comment on the article by Charles et al",,1
9945,11509081,Twelve-month safety of entacapone in patients with Parkinson's disease,"The safety of entacapone combined with levodopa and a dopadecarboxylase (DDC) inhibitor was tested in a 12-month double-blind study of 326 patients with idiopathic Parkinson's disease (PD). The study population represented 'typical' PD outpatients, including patients with varying disease severity and with various concomitant medications. Two-thirds of the patients were randomized to receive 200 mg of entacapone with each of 2--10 daily levodopa doses, and one-third to receive placebo. All entacapone patients were included in the safety evaluation of adverse events (AEs), vital signs, ECG, and laboratory parameters. Entacapone was well tolerated with a discontinuation rate due to AEs of 14% compared with 11% with placebo (NS). As expected, due to dopaminergic enhancement, dyskinesia was more frequent as an AE with entacapone than with placebo. Dryness of mouth, urine discoloration and diarrhoea were more frequent non-dopaminergic AEs with entacapone than with placebo. Entacapone had no adverse effects on hepatic enzyme activity, ECG or haemodynamic parameters, and there was no evidence of any toxicity. As an indication of levodopa enhancement with entacapone, patients taking 5--10 doses of levodopa, most likely representing predominantly fluctuating patients, showed a significant decrease in their mean daily levodopa dose of 94 mg in the entacapone group compared with a decrease of 39 mg in the placebo group (P < 0.01). The interval between the first two morning doses of levodopa increased by 17% with entacapone, whereas with placebo no extension was observed (P < 0.05). Despite levodopa dose reduction, efficacy of entacapone was maintained. As further evidence of efficacy, Parkinsonian symptoms markedly worsened in all patients after withdrawal of entacapone. We conclude that entacapone is safe in optimizing levodopa in long-term treatment of idiopathic Parkinson's disease. Monitoring of liver or other safety parameters during entacapone treatment is not required.",1
9946,11511818,Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy,"""OBJECTIVES: Treatment of HIV infection with highly antiretroviral therapy (HAART) may be limited by liver toxicity. Its incidence and risk factors are not well known. PATIENTS AND METHODS: Retrospective chart review. Naive patients beginning HAART between January 1997 and January 2000. Severe transaminase elevation was defined as fivefold or higher rise over upper normal limits, or as > or =3.5-fold rise above abnormal baseline values. RESULTS: Of 222 study subjects, 38%, 5%, and 2% were coinfected with hepatitis C virus (HCV), hepatitis B virus, and hepatitis D virus, respectively. Besides two nucleoside reverse transcriptase inhibitors (NRTIs), 96 patients received protease inhibitors (PIs), 90 received nonnucleoside reverse transcriptase inhibitors (NNRTIs), and 35 received a PI + NNRTI combination. Severe hepatic injury developed in 21 (9%): 10% PI, 9%, and 9% PI + NNRTI. Both univariate and multivariate analyses identified alcohol abuse, HCV coinfection, and older age as independent risk factors. Predictor variables in the final multivariate model were: alcohol abuse (risk ratio [RR], 5.87; 95% confidence interval [CI], 1.49-23.15; p =.01], positive HCV serology (RR, 3.99; 95% CI, 1.32-12.10; p =.01], and older age (RR, 1.11; 95% CI, 1.04-1.18; p = 0.001). CONCLUSIONS: Nearly 10% of study subjects who start HAART experience severe transaminase elevation, irrespective of the treatment. Avoidance of alcohol abuse, especially in study subjects coinfected with HCV, will reduce the risk of hepatic injury after HAART. When possible, prior treatment for chronic HCV infection should be considered.""",1
9947,11513198,Severe hepatotoxicity with jaundice associated with paroxetine,"Hepatotoxicity due to paroxetine, a selective serotonin reuptake inhibitor, is very rare, and to the best of our knowledge, only five cases of liver injury in association with paroxetine have previously been reported in the medical literature. We describe the clinical, biochemical, and pathological findings in a patient with paroxetine hepatotoxicity, which was reversed after withdrawal of the drug. The present case and the others previously reported suggest that hepatotoxicity should be taken into account as a rare complication, sometimes severe, that may occur with paroxetine.",1
9948,11520938,Possible role of retinoids in hepatitis B virus-associated liver damage,"Liver damage following hepatitis B virus (HBV) infection may be due to the action of retinoids as modulators of viral replication. The reduced rate of survival of liver grafts in patients with HBV infection could also be due to the continued presence of the virus, stimulated by retinoids in the graft tissue. Subject to obtaining empirical support for this hypothesis, the use of retinoid-blocking agents could be explored to reduce the risk of liver damage in HBV infection and to enhance the survival of liver grafts. Continued use of such agents may need to be used in conjunction with anti-viral modalities such as HBV hyperimmune globulin and lamivudine to prevent recurrent liver damage and to increase the long-term viability of the graft.",1
9949,11528574,"Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study","""Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.""",1
9950,11535846,"Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis","PURPOSE: Familial adenomatous polyposis is an inherited colorectal cancer syndrome characterized by the presence of multiple adenomatous colorectal polyps. Molecular studies have revealed that germline mutations in the APC gene are the underlying cause of the disease. The nonsteroidal anti-inflammatory agent sulindac has been shown to reduce the number of colorectal adenomas. Most sulindac trials in the large bowel have focused on the distal colon and relatively little is known about its effect on the proximal colon. Moreover, it is unknown whether the site of the APC mutation affects the efficacy of sulindac. METHODS: This study investigated whether there were regional differences in the effect of sulindac on the colon and whether response to sulindac was dependent on the site of mutation in the APC gene. In an open prospective study 17 patients with familial adenomatous polyposis were treated with 300 mg oral sulindac daily for four months followed by a washout phase of six months. Ten of the patients had an intact colon and seven had rectal stumps only. The number, size, and the degree of dysplasia of the adenomas were evaluated by colonoscopy at entry, end of treatment and end of the study. RESULTS: Overall, a statistically significant decrease in the number of adenomas was observed (120 +/- 112 to 28 +/- 64, P = 0.007). After cessation of sulindac treatment the number of adenomas increased to 48 +/- 44.5, but remained significantly lower than the values observed at baseline. In the ten patients with intact colons, adenomas decreased by sevenfold in the proximal colon (103 +/- 73 to 15.1 +/- 47.4, P = 0.011) and twofold in the distal colon (80 +/- 52 to 29.6 +/- 37.2, P = 0.005). The size of adenomas and the grade of dysplasia also decreased. No correlation could be seen between the APC mutation site and the response to treatment. CONCLUSION: These data indicate that sulindac reduces the number of adenomas in the entire colon and that the effect seems to be more pronounced in the proximal colon.",1
9951,11544547,[Fulminant liver failure after administration of the herbal antidepressant Kava-Kava],"HISTORY AND CLINICAL FINDINGS: A 60 year-old woman was admitted to hospital because of jaundice, fatigue, weight loss over several months and icteric skin. Because of progressive liver failure, concomitant renal failure and progressive encephalopathy she was transferred to an intensive care unit. INVESTIGATIONS: Biochemical tests revealed acute liver failure with high levels of total and conjugated bilirubin (30 mg/dl) as well as aspartate aminotransferase (921 IU/l) and alanine aminotransferase (1350 IU/l) concentrations. Prothrombin time was less than 10 %. Serological tests could rule out viral hepatitis, metabolic or autoimmune causes of liver failure. On abdominal computed tomography and ultrasonography no pathological changes were detected. Above all portal vein thrombosis, ascites, focal lesions of the liver and extrahepatic cholestasis could be excluded. Liver histology showed extensive hepatocellular necrosis with intrahepatic cholestasis. TREATMENT AND CLINICAL COURSE: The patient's physical condition deteriorated. She had to be intubated because of respiratory insufficiency and encephalopathy stage IV. Because of progressive liver failure under conservative treatment the patient received an orthotopic liver transplant 11 days after admission. CONCLUSIONS: The exclusion of other causes and the histological diagnosis made Kava-Kava as the cause of acute liver failure most likely. This is the 18th case of Kava-Kava induced liver failure reported to the European regulatory authorities.",1
9952,11547496,High hepatotoxicity rate seen among HAART patients,"Evidence continues to mount showing that HIV patients receiving antiretroviral treatment are at high risk for hepatotoxicity. The National Institutes of Health presented findings on liver toxicity among 10,011 HIV patients at the first International AIDS Society conference. The retrospective analysis shows that liver toxicity is associated with all classes of antiretroviral medications in use, and not just with regimens containing nevirapine or hydroxyurea, the two drugs about which the FDA recently issued hepatotoxicity warnings.",1
9953,11549211,Fatal hepatoxicity secondary to nimesulide,"This report describes a 57-year-old female patient with chronic lumbago, who died from the sequelae of acute liver failure induced by nimesulide medication. Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclo-oxygenase 2 and has been associated with a total of 13 reported cases of severe liver injury including our case. On the basis of the literature reports, the following features of nimesulide-associated hepatotoxicity were identified: female sex (84% of cases), age (mean age 62 years), jaundice as a primary manifestation (90%) and the absence of peripheral blood eosinophilia. The average duration of therapy of the published cases was 62 days (range 7-180 days). Based on spontaneous reports to the World Health Organization, nimesulide induces a high proportion of severe adverse hepatic reactions compared with other NSAIDs registered in Switzerland. Hepatotoxicity thus represents an important risk factor of nimesulide usage.",1
9954,11549783,History of quinolones and their side effects,"Fluoroquinolone development from 1985 to the present was reviewed. Severe drug adverse events were noted for enoxacin, pefloxacin and fleroxacin, which were phototoxic. Temafloxacin was associated with severe hemolytic-uremic syndrome, lomefloxacin caused phototoxicity and central nervous system (CNS) effects, and sparfloxacin was associated with phototoxicity and QTc prolongation. Tosufloxacin caused severe thrombocytopenia and nephritis, and hepatotoxicity was reported for trovafloxacin. Grepafloxacin was withdrawn due to cardiovascular effects, and clinafloxacin was associated with phototoxicity and hypoglycaemia. The structure of the quinolones directly relates to both their activity and side-effect profiles. The relationship among specific substituents attached to the quinolone nucleus are clarified. The incidence of specific adverse events associated with individual fluoroquinolones was reviewed in a five-year post-marketing surveillance (PMS) study in Japan, in which a total adverse drug reaction (ADR) rate of 1.3% was found for levofloxacin, compared to total ADR rates of 3.3% for pazufloxacin, 3.6% for tosufloxacin, 4.5% for gatifloxacin and 5.4% for balofloxacin. Gastrointestinal effects were the most common adverse events for all fluoroquinolones. Levofloxacin had the lowest rate of CNS effects and skin adverse events among the agents listed.",1
9955,11550401,Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis,"Simvastatin, a hydroxymethyl glutarate coenzyme A (HMG-CoA) reductase inhibitor, is a commonly used cholesterol lowering agent. The long-term safety profile of simvastatin, established over ten-years of clinical use, is excellent. Both rhabdomyolysis and hepatitis, however, are recognized toxic effects of this medication, and generally occur when the patients are taking more than 40 mg of simvastatin a day. Potent inhibitors of the cytochrome P450 3A4 (CYP3A4) enzyme increase the incidence of simvastatin toxicity. Calcium channel blockers are weak inhibitors of the CYP3A4 enzyme. Diltiazem is known to increase the serum concentration of simvastatin. Many patients who take both simvastatin and diltiazem require lower doses of simvastatin to achieve the recommended reduction in cholesterol. Since diltiazem is known to increase plasma levels of lovastatin, a similar phenomenon may occur with simvastatin. Our patient had been stable for three years on simvastatin therapy. His rhabdomyolysis and hepatitis coincided with the addition of diltiazem. This is the first report of the combined toxicities of rhabdomyolysis and hepatitis being induced by the addition of diltiazem to simvastatin therapy. This patient serves as a reminder to the clinician of the potential interaction of these two commonly used drugs.",1
9956,11553264,Comparison between deferoxamine and deferiprone (L1) in iron-loaded thalassemia patients,"""INTRODUCTION: Iron-chelating therapy with deferoxamine in patients with thalassemia major has dramatically improved the prognosis of this disease. However, the limitations of this treatment have stimulated the design of alternative orally active iron chelators. OBJECTIVE: To compare the effectiveness and safety of, and compliance with, oral deferiprone (L1), and deferoxamine, in thalassemia major patients. METHODS: All patients were followed up in one center in Lebanon. Sixteen patients were on L1 (75 mg/kg/d), and 40 patients on subcutaneous deferoxamine (20-50 mg/kg/d). Serum ferritin level, urinary iron excretion (UIE) and side effects were monitored over a two year period. RESULTS: Patients on L1 had an initial serum ferritin concentration of 3663+/-566 microg/l (mean+/-SEM), that dropped to 2599+/-314 at 6 months (p<0.02; paired t-test), and stabilised at that level over the 24 months follow up. Patients on deferoxamine had an initial mean serum ferritin concentration of 3480+/-417 (NS compared to the L1 group), which dropped gradually to 3143+/-417 (p<0.05) and 2819+/-292 (p<0.02) at 6 and 24 months, respectively. The most common adverse reactions associated with L1 were arthralgia and nausea, but they did not necessitate stopping the drug. CONCLUSION: L1 had comparable efficacy as deferoxamine with minimal side effects and better compliance. Provided long term side effects are not encountered, L1 seems to be a valuable alternative iron chelator for patients unable or unwilling to use deferoxamine effectively.""",1
9957,11557646,"Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine","""OBJECTIVE: Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period. METHODS: 358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts. RESULTS: The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (-1.46 v -1.11, p=0.03) and patient (-1.61 v -1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Deltamean HAQ -0.65 v -0.36, p=0.0149; DeltaHAQ disability index -0.89 v -0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.""",1
9958,11561690,Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study,"A phase II trial of gemcitabine (Gemzar), a nucleoside analogue with broad activity in solid tumors, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. A total of 26 eligible patients were registered to receive a dose of 1250 mg/m2 weekly for 3 weeks, followed by a 1 week rest. Toxicity was evaluable in 26 patients. Nausea and vomiting occured in 11 and 6 patients, repectively. Grade 3 or 4 hematologic toxicities were infrequent. Two patients developed neutropenic infections. One patient developed fatal liver failure which was thought due to progressive liver metastases or infection 14 days after a single dose of gemcitabine. There were no objective treatment responses (95% CI 0-13%), with a median survival of 6 months in this highly resistant disease population. Gemcitabine is not considered active enough as monotherapy for further evaluation in this disease population.",1
9959,11564003,Antiretroviral hepatotoxicity in human immunodeficiency virus-infected patients,"""BACKGROUND: Drug hepatotoxicity is a potentially serious adverse reaction of antiretroviral therapy in human immunodeficiency virus-infected patients. The impact of this problem in the routine treatment of patients with human immunodeficiency virus infection is poorly defined. OBJECTIVES: Our aim was to determine what clinical features are associated with hepatotoxicity in human immunodeficiency virus-infected patients receiving antiretroviral therapy. METHODS: Consecutive patients in a primary care-based human immunodeficiency virus clinic were evaluated for hepatotoxicity. Clinic records were used to obtain patient characteristics, as well as independent variables including CD4+ count, coexisting hepatitis C and current alcohol use. RESULTS: Sixty-five patients taking antiretroviral therapy were evaluated. Twenty-four were identified to have antiretroviral hepatotoxicity. An age over 40 years (P=0.019), an absolute CD4+ count of less than 310 cells/mL (P=0.002) and coexisting hepatitis C infection (P=0.035) were significantly associated with hepatotoxicity. Patients older than 40 years had a sevenfold increased risk (risk ratio, 6.9; 95% confidence interval, 1.7-27.3) and those with an absolute CD4+ count of less than 310 cells/mL had a tenfold increased risk (risk ratio, 10.2; 95% confidence interval, 2.5-41.9) for antiretroviral hepatotoxicity, in comparison with those who were younger or who had a greater absolute CD4+ count. Of the eight patients documented to have coexisting hepatitis C infection, six (75%) were in the antiretroviral hepatotoxicity group. CONCLUSIONS: An age older than 40 years and an absolute CD4+ count of less than 310 cells/mL were significantly associated with antiretroviral-induced hepatotoxicity. The majority of our patients with chronic hepatitis C had hepatotoxicity from antiretroviral therapy.""",1
9960,11564966,Terbinafine-induced hepatic dysfunction,"A 41-year-old man developed severe hepatic dysfunction following a 3.5-week course of terbinafine (250 mg/day). He suffered marked pruritus, jaundice, malaise, anorexia and loin pain. Serum bilirubin rose to a peak value of 718 micromol/l with alkaline phosphatase at 569 U/l, alanine aminotransferase at 90 U/l, aspartate aminotransferase at 63 U/l and a prolonged prothrombin time of 21 s, unresponsive to vitamin K. Transjugular liver biopsy showed canalicular cholestasis consistent with a drug reaction. Symptoms resolved 11 months after drug cessation, with liver function tests returning to normal values after 15 months. This case represents the most severe cholestatic reaction reported to date, resulting in patient recovery without liver transplantation. A comprehensive literature review is provided.",1
9961,11569700,"Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study","""OBJECTIVES: No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH. METHODS: Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine. RESULTS: A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients. CONCLUSIONS: Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial.""",1
9962,11572578,Metolazone-induced cholestatic liver disease,,1
9963,11573856,Acute hepatitis induced by cyproterone acetate,"OBJECTIVE: To report a case of acute hepatitis resulting from the use of cyproterone acetate, an adjuvant treatment for prostate cancer. CASE SUMMARY: An 87 year-old white man, admitted to surgery for prostate cancer, received cyproterone acetate 300 mg/d orally and developed acute hepatitis, which initially was diagnosed clinically. A liver biopsy showed changes suggestive of acute cholestatic hepatitis. Cyprotorone was stopped immediately, and the patient was subsequently treated with corticosteroids. He then improved rapidly. DISCUSSION: Cyproterone acetate is thought to be well tolerated, but some authors have reported severe hepatic reactions, in particular acute hepatitis, fatal fulminant hepatic failure, and hepatocellular carcinoma. The above-mentioned hepatotoxicity represents an idiosyncratic drug reaction, probably due to the hepatomitogen action of cyproterone, causing an increase of hepatocytes expressing placental glutathione S-transferase, which are considered preneoplastic elements. CONCLUSION: This case suggests the possibility of hepatotoxicity from cyproterone.",1
9964,11575681,"Relationship of blood trace elements to liver damage, nutritional status, and oxidative stress in chronic nonalcoholic liver disease","""Trace elements are involved in chronic liver diseases because these elements may have a direct hepatic toxicity or may be decreased as a consequence of the impaired liver function, particularly in patients with alcoholic cirrhosis and/or malnutrition. In this study, we determined plasma and erythrocytes trace elements in 50 inpatients with nonalcoholic chronic liver disease (11 with biopsy-proven chronic hepatitis, 39 with cirrhosis [16 in stage A according to Child-Pugh criteria, 23 Child B+C]), and in a control group of 10 healthy subjects by the proton induced x-ray emission method. The relationship between trace element concentration and the extent of liver damage, the nutritional status (by anthropometric evaluations), and various blood markers of oxidative stress--reduced glutathione, total lipoperoxides and malonyldialdehyde--was investigated. We found that cirrhotics had a significant decrease of Fe, Zn, Se, and GSH levels in the plasma and of GSH and Se in the erythrocytes with respect to the control and chronic hepatitis groups. GSH levels were related to the degree of liver damage; a significant direct correlation was observed among Se, Zn, and GSH plasma values and between GSH and Se in the erythrocytes. The trace element decrease was, on the contrary, independent of the degree of liver function impairment and only partially affected by the nutritional status. Data indicate that liver cirrhosis, even if not alcohol related, induces a decrease of Se and Zn and that, in these patients, an oxidative stress is present, as documented by the significant correlation between Se and GSH. The plasma Br level was higher in cirrhotics with respect to the control and chronic hepatitis groups.""",1
9965,11578163,Severe liver injury,,1
9966,11579648,Hepatic and haematological adverse reactions associated with the use of multidrug therapy in leprosy--a five year retrospective study,"""This study analyses retrospectively some of the risks associated with the use of WHO-multidrug therapy (MDT) in Sri Lanka. Case records of 3,333 new cases of leprosy attending the Central Leprosy Clinic in Colombo during 1991-1995, were analysed for adverse drug reactions involving the liver and blood. There were 81 reports of suspected hepatic or haematological adverse reactions associated with the use of MDT, of which 39 were classified as haemolytic anaemia, 25 as toxic hepatitis, 2 as methaemoglobinaemia and 15 as anaemia. Dapsone, was incriminated in the majority of adverse reactions (72%). Adverse drug reactions were more common in female than male subjects (55% vs 45%; P < 0.5), but there was no significant differences between the age groups. Majority of adverse reactions was seen within the first three months of initiation of MDT. This study in no way undermines the benefits of MDT but highlights the risks and suggests measures to minimize these risks.""",1
9967,11580159,Hepatotoxicity induced by fosinopril,,1
9968,11583720,Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively,"""Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and safety of coadministration of colesevelam and atorvastatin, administration of these agents alone or in combination was examined in a double-blind study of 94 hypercholesterolemic men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the American Heart Association Step I diet, patients were randomized among five groups: placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8 g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 12-53% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin (38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%). Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05). Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected by colesevelam alone or in combination. The frequency of side effects did not differ among groups. At recommended starting doses of each agent, coadministration of colesevelam and atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol reductions comparable to those observed with the maximum atorvastatin dose.""",1
9969,11588504,Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART,"""BACKGROUND: Highly active antiretroviral therapy (HAART) is strongly effective in reducing morbidity and mortality in HIV-1-positive individuals. Its main drawback is the potential toxicity. Data on the frequency and determinants of severe hepatotoxicity in a clinical setting are still sparse. METHODS: This is a prospective study of HIV-1-positive individuals with known HBsAg and HCV-Ab serology. The study end point was progression to alanine aminotransferase (ALT) levels > or =200 IU/L after HAART initiation. Cumulative probability of progression to this end point was estimated by the Kaplan-Meier method. Crude and adjusted hazard ratios (HR) were estimated by proportional hazards regression model. RESULTS: One thousand two hundred fifty-five patients were included. HBsAg was found in 91 (7.2%), HCV-Ab in 578 (46.5%) patients; almost all injection drug users (451 of 482; 93.6%) were HCV-Ab positive. Sixty-one individuals progressed to the end point with a probability of 7.9% (95% confidence interval [CI], 5.6-10.0) of progression at 24 months from starting. Independent factors predicting progression to the end point were baseline ALT levels (HR, 5.29; 95% CI, 3.24-8.65; every 10 IU/L higher), HCV-Ab positivity (HR, 4.01; 95% CI, 1.48-10.85) or both HBsAg and HCV Ab positivity (HR, 3.85, 95% CI, 1.01-14.61), and previous non-HAART therapy (HR, 1.84, 95% CI, 1.04-3.42). Patients receiving stavudine-containing regimens had a lower risk than those receiving zidovudine-containing regimens (HR, 0.30, 95% CI, 0.12-0.71). CONCLUSIONS: There was a low risk of ALT > or =200 IU/L in our cohort. Hepatitis C coinfection and elevated ALT levels at HAART initiation are important predictors of progression to ALT > or =200 IU/L; stavudine-containing regimens were associated with a lower risk compared with zidovudine-containing regimens.""",1
9970,11592358,"Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group","""OBJECTIVE: Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS: The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS: In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION: The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.""",1
9971,11593148,[Acute hepatitis and drug dermatitis due to fenofibrate (Secalip)],,1
9972,11597664,Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study,"BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.",1
9973,11598552,[Is Exolise hepatotoxic?],,1
9974,11606755,Mechanism of indinavir-induced hyperbilirubinemia,"Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in approximately 10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (K(I) = 183 microM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher K(I) (360 microM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.",1
9975,11606952,Analysis of common side effects of isotretinoin,"Patients with severe recalcitrant nodular acne that is unresponsive to conventional therapy (including topical and systemic antibiotics) have few alternative effective treatment modalities other than the use of oral isotretinoin (Accutane). The cause of acne vulgaris is multifactorial, but the pathogenesis of this disorder of the pilosebaceous follicles arises mainly from endogenous factors. It is usually, but not always, associated with the onset of puberty. Severe acne, defined by the prevalence of facial and truncal inflammatory lesions, is a disfiguring disease that can often result in significant permanent scarring after the healing of deep inflammatory lesions and other disorders, such as systemic bacterial infections. Topical treatments are considered as the first line of therapy for less severe forms of acne, although systemic treatments such as antibiotics or antiandrogen agents are effective for either mild or moderate forms and sometimes effective for severe acne. However, in many patients with large numbers of nodules, longer treatment periods with these agents are required to reduce the count of inflammatory lesions. It has become increasingly evident that (because topical agents and antibiotic or antiandrogenic therapy have a slow onset of action) even mild or moderate acne that is treated in this way can result in scarring. In addition, the excessive use of systemic antibiotics has led to the detection of increasing numbers of antibiotic-resistant bacteria on the skin of patients with acne.(1) Therefore, because of its relatively rapid onset of action and its high efficacy with reducing more than 90% of the most severe inflammatory lesions, Accutane has a role as an effective treatment in patients with severe acne that is recalcitrant to other therapies.",1
9976,11665695,YMDD-mutant HBV strain as a cause of liver failure in an HIV-infected patient,,1
9977,11669307,Fulminant hepatitis B virus reactivation with concomitant listeriosis after fludarabine and rituximab therapy: case report,"Chronic hepatitis B infection poses a problem in patients with malignancies undergoing chemotherapy. Not uncommonly, hepatitis B virus (HBV) reactivates during or soon after chemotherapy. We report a case of a woman with acute prolymphocytic leukemia who received chemotherapy containing fludarabine and cyclophosphamide, followed by the CD 20 monoclonal antibody, rituximab. She developed fatal reactivation of hepatitis B with fulminant liver failure 3 months after completing treatment. Listeria monocytogenes was concomitantly isolated. This case indicates the importance of identifying all hepatitis B carriers and the need to closely monitor and detect reactivation early. Newer chemotherapeutic agents with potentially long-lasting effects on T cells, such as purine analogues, require extended vigilance for reactivation of HBV as well as opportunistic infections. Rituximab is increasingly used alone or in combination with other chemotherapy agents. Its possible contributory role in hepatitis B reactivation needs to be defined.",1
9978,11673194,Hepatotoxicity from rifampin plus pyrazinamide: lessons for policymakers and messages for care providers,,1
9979,11673741,[Ketoprofen-induced acute hepatitis],,1
9980,11674975,"[Ticlopidine, cholestasis and hepatic nodules]",,1
9981,11677951,Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer,"Hepatic arterial infusion of floxuridine is an effective treatment for unresectable hepatic metastases from colorectal cancer. Despite its pharmacological advantage of higher tumor drug concentration with minimal systemic toxicity, hepatic arterial infusion of floxuridine is characterized by regional toxicity, including hepatobiliary damage resembling idiopathic sclerosing cholangitis (5-29% of treated cases). Unlike previous reports describing biliary damage of both intrahepatic and extrahepatic ducts, a case series of extrahepatic biliary stenosis after hepatic arterial infusion with floxuridine is herein described. Between September 1993 and February 1999, 54 patients received intraarterial hepatic chemotherapy based on continuous infusion of floxuridine (dose escalation 0.15-0.30 mg/kg/day for 14 days every 28 days) plus dexamethasone 28 mg. Twenty-seven patients underwent laparotomy to implant the catheter into the hepatic artery, the other 27 patients receiving a percutaneous catheter into the hepatic artery through a transaxillary access. Five patients (9.2%) developed biliary toxicity with jaundice and cholangitis (3 cases), alterations of liver function tests and radiological features of biliary tract abnormalities. They received from 9 to 19 cycles (mean 14.5 +/- 6.3 cycles) of floxuridine infusion with a total drug delivered dose ranging from 20.3 to 41.02 mg/kg (mean: 31.4 +/- 13.5 mg/kg). Extrahepatic biliary sclerosis was discovered by computed tomography scan and ultrasound, followed by endoscopic retrograde cholangiopancreatography and/or percutaneous cholangiography in 3 cases. Radiological findings included common hepatic duct complete obstruction in 1 case, common hepatic duct stenosis in 2 cases, common bile duct obstruction in 1 case, and intrahepatic bile ducts dilation without a well-recognized obstruction in 1 case. Two patients were treated by sequentially percutaneous biliary drainage and balloon dilation while 1 patient had an endoscopic transpapillary biliary prosthesis placed. Percutaneous or endoscopic procedures obtained the improvement of hepatic function and cholestatic indexes without subsequent jaundice or cholangitis. In two patients suppression of floxuridine infusion allowed the improvement of hepatic function. The present series suggests that in some patients receiving hepatic arterial infusion of floxuridine extrahepatic biliary stenosis may represent the primary event leading to a secondary intrahepatic biliary damage that does not correlate with specific floxuridine toxicity but results from bile stasis and infection, recurrent cholangitis and eventually biliary sclerosis. Aggressive research for extrahepatic biliary sclerosis is advised, since an early nonsurgical treatment of extrahepatic biliary stenosis may prevent an irreversible intrahepatic biliary sclerosis worsening the prognosis of metastatic liver disease.",1
9982,11678619,Arsenic and liver disease,"""The hepatotoxic action of arsenic, when used as a therapeutic agent, has long been recognised. Data on liver involvement following chronic exposure to arsenic-contaminated water are scanty. The nature and degree of liver involvement are reported on the basis of hospital based studies in patients who consumed arsenic contaminated drinking water for one to 15 years. Two hundred forty-eight patients with evidence of chronic arsenic toxicity underwent clinical and laboratory examination including liver function tests and hepatitis B surface antigen (HBsAg) status. Liver biopsy was done in 69 cases; in 29 patients, liver arsenic content was estimated by neutron activation analysis. Hepatomegaly was present in 190 of 248 patients (76.6%). Non-cirrhotic portal fibrosis was the predominant lesion (91.3%) in liver histology. The maximum arsenic content in liver was 6 mg/kg (mean 1.46 [0.42], control value 0.16 [0.04]; p <0.001); it was undetected in 6 of 29 samples studied. The largest number of patients with liver disease due to chronic arsenicosis from drinking arsenic contaminated water are reported. Non-cirrhotic portal fibrosis is the predominant lesion in this population. Hepatic fibrosis has also been demonstrated due to long term arsenic toxicity in an animal model. Initial biochemical evidence of hepatic membrane damage, probably due to reduction of glutathione and antioxidant enzymes, may be seen by 6 months. Continued arsenic feeding resulted in fatty liver with serum aminotransferases elevated at 12 months and hepatic fibrosis at 15 months.""",1
9983,11682044,Acute hepatocellular injury associated with zafirlukast,,1
9984,11688919,Clinical experience with linezolid in the treatment of resistant gram-positive infections,"This study presents our clinical experience with linezolid in 19 patients with serious resistant gram-positive infections enrolled as part of the compassionate study. In this prospective, non-randomized, noncomparative study, 19 patients were enrolled as part of the National Compassionate Study Protocol conducted by Pharmacia-Upjohn. At the time of this writing, these patients had not been published in the literature. All of the patients had to have documented evidence of serious gram-positive infections in normally sterile sites and should have been unable to tolerate available antimicrobial therapy or be unresponsive to available drugs. Clinical characteristics, laboratory values, and pharmacokinetic and pharmacodynamic parameters were obtained. Patients were followed both short-term and long-term after completion of therapy. Nineteen patients were enrolled: 13 females and 6 males. The average age was 63 years. The average length of therapy with linezolid was 22 days. Methicillin-resistant Staphylococcus aureus (MRSA) was treated in eight patients, methicillin-resistant Staphylococcus epidermidis (MRSE) in two patients, vancomycin-resistant Enterococcus faecium (VREF) in eight patients, and coagulase-negative Staphylococcus in two patients. Co-infecting organisms include Enterococcus species colonization in six patients, Pseudomonas species in one patient, Serratia marcenens in one patient, and Candida albicans in one patient. Sterile sites that were infected included bone and joint (wounds and septic joints) in six patients, gastrointestinal system (hepatobiliary, liver abscess, Crohn's) in five patients, genitourinary (kidney and urine) in two patients, blood in five patients, respiratory in one patient, and aortic valve in 1 patient. Linezolid was given at 600 mg IV every 12 hours with a mean length of therapy of 22 days. Surgical drainage was used in combination with linezolid in 11 of the patients. Seventy nine percent of these patients achieved clinical and microbiologic cure, and none of the deaths reported in this series were related to the drug. Adverse events included skin rash in one patient, mild bone marrow suppression in two patients, and mild elevation in liver function tests in two patients. No life-threatening adverse events were noted. It appears that linezolid, along with surgical intervention (when necessary), appears to be an effective treatment option for resistant gram-positive infections. Long-term studies evaluating the possible resistance rates are necessary.",1
9985,11690719,Acute fatal hepatitis related to sertraline,,1
9986,11692304,Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases,"""We retrospectively investigated the clinical and histopathologic features of hospitalized patients infected with human immunodeficiency virus who had symptomatic lactic acidosis syndrome at a university teaching hospital during 1995-2000. Twelve patients were identified, 11 during 1998-2000; of these, 5 died with rapid progression to otherwise unexplained multiple-organ failure. All had extensive prior exposure to nucleoside analog reverse-transcriptase inhibitors (NRTIs). At presentation, the most commonly identified NRTI component of antiretroviral regimens was stavudine plus didanosine. Eleven patients presented with abdominal pain, nausea, and/or emesis. Eight patients had prior acute weight loss (mean [+/-SD], 12+/-5.3 kg). Median venous plasma lactate levels were > or =2-fold greater than the upper limit of normal (2.1 mmol/L). Serum transaminase levels were near normal limits at presentation. Histopathologic studies confirmed hepatic macrovesicular and microvesicular steatosis in 6 patients. Concurrent chemical pancreatitis was identified in 6 patients. The increasing number of cases identified during the study period suggests that physicians better recognize symptomatic lactic acidosis and/or that cumulative NRTI exposure may increase the risk for this syndrome.""",1
9987,11693467,Lansoprazole: an update of its place in the management of acid-related disorders,"""Lansoprazole is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against Helicobacter pylori in vitro. Current therapy for peptic ulcer disease focuses on the eradication of H. pylori infection with maintenance therapy indicated in those patients who are not cured of H. pylori and those with ulcers resistant to healing. Lansoprazole 30 mg combined with amoxicillin 1g, clarithromycin 250 or 500mg, or metronidazole 400 mg twice daily was associated with eradication rates ranging from 71 to 94%, and ulcer healing rates were generally >80% in well designed studies. In addition, it was as effective as omeprazole- or rabeprazole-based regimens which included these antimicrobial agents. Maintenance therapy with lansoprazole 30 mg/day was significantly more effective than either placebo or ranitidine in preventing ulcer relapse. Importantly, preliminary data suggest that lansoprazole-based eradication therapy is effective in children and the elderly. In the short-term treatment of patients with gastro-oesophageal reflux disease (GORD), lansoprazole 15, 30 or 60 mg/day was significantly more effective than placebo, ranitidine 300 mg/day or cisapride 40 mg/day and similar in efficacy to pantoprazole 40 mg/day in terms of healing of oesophagitis. Lansoprazole 30 mg/day, omeprazole 20 mg/day and pantoprazole 40 mg/day all provided similar symptom relief in these patients. In patients with healed oesophagitis. 12-month maintenance therapy with lansoprazole 15 or 30 mg/day prevented recurrence and was similar to or more effective than omeprazole 10 or 20 mg/day. Available data in patients with NSAID-related disorders or acid-related dyspepsia suggest that lansoprazole is effective in these patients in terms of the prevention of NSAID-related gastrointestinal complications, ulcer healing and symptom relief. Meta-analytic data and postmarketing surveillance in >30,000 patients indicate that lansoprazole is well tolerated both as monotherapy and in combination with antimicrobial agents. After lansoprazole monotherapy commonly reported adverse events included dose-dependent diarrhoea, nausea/vomiting, headache and abdominal pain. After short-term treatment in patients with peptic ulcer, GORD, dyspepsia and gastritis the incidence of adverse events associated with lansoprazole was generally < or = 5%. Similar adverse events were seen in long-term trials, although the incidence was generally higher (< or = 10%). When lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole adverse events included diarrhoea, headache and taste disturbance. In conclusion, lansoprazole-based triple therapy is an effective treatment option for the eradication of H. pylori infection in patients with peptic ulcer disease. Preliminary data suggest it may have an important role in the management of this infection in children and the elderly. In the short-term management of GORD, lansoprazole monotherapy offers a more effective alternative to histamine H2-receptor antagonists and initial data indicate that it is an effective short-term treatment option in children and adolescents. In adults lansoprazole maintenance therapy is also an established treatment option for the long-term management of this chronic disease. Lansoprazole has a role in the treatment and prevention of NSAID-related ulcers and the treatment of acid-related dyspepsia; however, further studies are needed to confirm its place in these indications. Lansoprazole has emerged as a useful and well tolerated treatment option in the management of acid-related disorders.""",1
9988,11700164,DRESS syndrome associated with nevirapine therapy,,1
9989,11704198,Hepatotoxicity with antiretroviral treatment of pregnant women,"""BACKGROUND: Hepatotoxicity in adults with human immunodeficiency virus (HIV) infection has been associated with all classes of antiretroviral drugs and coinfection with hepatitis B and C virus. We treated two HIV-infected pregnant women in whom hepatotoxicity developed after initiating antiretroviral therapy. CASES: The first woman developed icterus, jaundice, hyperbilirubinemia, and elevated serum aminotransferase levels approximately 5 months after beginning combination antiretroviral therapy with zidovudine, lamivudine, and efavirenz. Serum aminotransferase abnormalities improved after discontinuation of antiretroviral medications. The second woman had similar symptoms and laboratory abnormalities 3 months after initiation of zidovudine, lamivudine, and nelfinavir. Despite initial improvement after discontinuing her antiretroviral medications, fulminant hepatic failure developed and she died. Both patients tested negative for hepatitis A, B, and C; Epstein-Barr virus; and cytomegalovirus. There was no history of illicit drug use, alcohol use, or blood transfusions in either case. CONCLUSION: We emphasize the need for careful monitoring for hepatotoxicity after initiation of antiretroviral therapy.""",1
9990,11706664,Acute asymptomatic hepatitis in a healthy normal volunteer exposed to 2 oral doses of amodiaquine and artesunate,Combination antimalarial therapy is being explored to delay development of resistance to falciparum malaria. This report describes an unexpected drug-induced hepatitis in a previously healthy young woman exposed to 2 doses of amodiaquine and artesunate. Use of these combinations should be closely monitored.,1
9991,11711508,One-year study of felodipine or placebo for stage 1 isolated systolic hypertension,"Asubstantial number of older hypertensive patients have stage 1 isolated systolic hypertension (systolic blood pressure between 140 and 159 mm Hg and diastolic blood pressure <90 mm Hg), but there are currently no data showing that drug treatment is effective, safe, and/or beneficial. To compare the effects of active treatment compared with placebo on blood pressure, left ventricular hypertrophy, and quality of life among older stage 1 isolated systolic hypertensive patients, a randomized, double-blind, parallel-group, multicenter clinical trial comparing felodipine (2.5, 5, or 10 mg once daily) and matching placebo was performed in 171 patients (49% male, average age 66+/-7 years, with 49% white and 30% Hispanic) with a baseline blood pressure of 149+/-7/83+/-6 mm Hg. During 52 weeks of treatment, patients randomized to active treatment achieved significantly lower blood pressures (137.0+/-11.7/80.2+/-7.6 mm Hg for extended-release felodipine versus 147.5+/-16.0/83.5+/-9.7 mm Hg for placebo, P<0.01 for each), a reduced incidence of left ventricular hypertrophy (7% for extended release felodipine versus 24% for placebo, P<0.04), and improved quality of life (change in Psychological General Well-Being index, 3.0+/-6.8 for extended-release felodipine versus -0.8+/-10.3 for placebo, P<0.01) versus baseline. There were no clinically significant differences between treatments in tolerability or adverse effects. Stage 1 isolated systolic hypertension can be effectively and safely treated pharmacologically. Treatment reduced progression to the higher stages of hypertension, reduced the incidence of left ventricular hypertrophy, and improved an overall measure of the quality of life. Larger and longer studies will be needed to document any long-term reduction in cardiovascular event rates associated with treating stage 1 systolic hypertension.",1
9992,11712893,Severe liver injury associated with zafirlukast,,1
9993,11714476,[Acute hepatitis induced by valsartan],,1
9994,11719360,Thrombocytopenia caused by the development of antibodies to thrombopoietin,"""Thrombocytopenia developed in some individuals treated with a recombinant thrombopoietin (TPO), pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). Three of the subjects who developed severe thrombocytopenia were analyzed in detail to determine the cause of their thrombocytopenia. Except for easy bruising and heavy menses, none of these subjects had major bleeding episodes; none responded to intravenous immunoglobulin or prednisone. Bone marrow examination revealed a marked reduction in megakaryocytes. All 3 thrombocytopenic subjects had antibody to PEG-rHuMGDF that cross-reacted with endogenous TPO and neutralized its biological activity. All anti-TPO antibodies were immunoglobulin G (IgG), with increased amounts of IgG4; no IgM antibodies to TPO were detected at any time. A quantitative assay for IgG antibody to TPO was developed and showed that the antibody concentration varied inversely with the platelet count. Anti-TPO antibody recognized epitopes located in the first 163 amino acids of TPO and prevented TPO from binding to its receptor. In 2 subjects, endogenous TPO levels were elevated, but the TPO circulated as a biologically inactive immune complex with anti-TPO IgG; the endogenous TPO in these complexes had an apparent molecular weight of 95 000, slightly larger than the full-length recombinant TPO. None of the subjects had atypical HLA or platelet antigens, and the TPO cDNA was normal in both that were sequenced. Treatment of one subject with cyclosporine eliminated the antibody and normalized the platelet count. These data demonstrate a new mechanism for thrombocytopenia in which antibody develops to TPO; because endogenous TPO is produced constitutively, thrombocytopenia ensues.""",1
9995,11720317,Hepatitis B and C virus infection in Crohn's disease,"""Patients with Crohn's disease (CD) are at higher risk of hepatitis C (HCV) and B virus (HBV) infection, because of surgical and/or endoscopic procedures. However, the prevalence of HCV and HBV infection in CD is unknown. This issue may be relevant because of the growing use of immunomodulatory drugs in CD. The purpose of this study was to assess, in a multicenter study, the prevalence and risk factors of HCV and HBV infection in CD. The effect of immunomodulatory drugs for CD on the clinical course of hepatitis virus infections and of interferon-alpha (IFN-alpha) on the course of CD was examined in a small number of patients. Sera from 332 patients with CD and 374 control subjects (C) were tested for the following: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, HBeAg, HBeAb, anti-HCV, and HCV-RNA. An additional 162 patients with ulcerative colitis (UC) were tested as a disease control group. Risk factors were assessed by multivariate statistical analysis. Infection by either HCV or HBV was detected in 24.7% of patients with CD. In the age groups younger than 50 years, HCV prevalence was higher in CD than in C (p = 0.01). HCV infection in CD was associated with surgery (OR 1.71; 95% CI 1.00-2.93; p = 0.04), blood transfusions (OR 3.39; 95% CI 1.04-11.04; p = 0.04), and age (OR 2.3; 95% CI 1.61-3.56; p < 0.001). The event CD-related surgery appeared to be the main risk factor for HCV infection in CD. HCV prevalence was higher in CD (7.4%) than in UC (0.6%) (p = 0.001). HBcAb positivity was higher in CD (10.9%) and UC (11.5%) than in C (5.1%) (CD vs. C: p = 0.016; UC vs. C: p = 0.02), associated with age (OR 2.08; 95% CI 1.37-3.17; p = 0.001) and female gender (OR 2.68; 95% CI 1.37-3.17; p = 0.001) in CD and to UC duration (OR 1.20; 95% CI 1.06-1.36; p = 0.002). Immunomodulatory drugs did not influence the course of HBV or HCV infection in seven patients with CD, and IFN-alpha for chronic hepatitis C did not affect CD activity in six patients with CD. It is concluded that HBV prevalence is higher in CD than in C at all ages, whereas HCV prevalence is increased in young patients with CD, because of a greater need for surgery. The higher HCV (but not HBV) prevalence in CD than in UC suggests that the host immune response may influence the risk of HCV infection. Although a relatively high proportion of patients with CD showed HBV and/or HCV infections, this should not influence treatment strategies for CD.""",1
9996,11724106,Fatal hepatotoxicity associated with enalapril,,1
9997,11726569,The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain,"BACKGROUND: Until recently, human menopausal gonadotrophin (HMG), a urinary extract containing a fixed combination of LH and FSH, was the only source of exogenous LH for women with hypogonadotrophic hypogonadism undergoing ovulation induction with gonadotrophins. Recombinant human LH (rLH) is now available for clinical use, providing a new treatment option but clinical data on its use are scanty. Therefore, the aim of the present study was to investigate the efficacy and safety of rLH combined with recombinant FSH (rFSH) to induce follicular development and ovulation in World Health Organization (WHO) group I anovulatory women. METHODS: We included in this multicentre study 38 hypogonadotrophic anovulatory (WHO group I) women. Patients received 150 IU/day rFSH and 75 IU/day rLH (with the possibility of dose adjustment) as a single s.c. injection for up to three cycles with a total of 84 treatment cycles. RESULTS: Sufficient follicular growth was observed in 79 (94%) out of 84 initiated cycles. The 75 IU rLH dose was found to be effective in most treatment cycles (94%) and only five cycles in three patients required daily dose increase. Overall, HCG was administered to trigger ovulation in 67 (80%) of the 84 cycles while it was withheld in 12 cycles (14%) due to ovarian hyper-response and five cycles (6%) were cancelled for insufficient follicular growth. The pregnancy rate per started treatment cycle and per cycle given HCG was 18 and 22.4% respectively. Pregnancy was achieved by 15 (39.5%) of the 38 patients. Mild to moderate ovarian hyperstimulation syndrome occurred in three patients. Local tolerance was good. CONCLUSIONS: This study confirms that combined rFSH and rLH treatment induces follicular growth, ovulation and pregnancy in a good proportion of hypogonadotrophic anovulatory patients and is well tolerated. The doses of 150 IU rFSH and 75 IU rLH daily seem the most appropriate but in a small minority of patients doses >75 IU rLH/day may be necessary.",1
9998,11731945,"Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin and other commonly used antimicrobials","""This study compared adverse drug reactions (ADRs) to oxacillin with those to nafcillin and other antibiotics. We reviewed the medical records of 222 children receiving outpatient parenteral antimicrobial therapy (OPAT) from February 1995 through June 1999. The diagnosis, antibiotics used, ADRs, action taken, and patient demographics were recorded. The most common ADRs were neutropenia (9.8%), rash (8.5%), and hepatotoxicity (3.8%). ADRs occurred more frequently in the oxacillin group (58.5%) than in the nafcillin group (29.3%; P=.004), the clindamycin group (12.5%; P<.001) and the """"other"""" antibiotics group (14.4%; P<.001). Hepatotoxicity and rash occurred more frequently in the oxacillin group (22% and 31.7%, respectively) than in the nafcillin group (0% [P<.001] and 10.3% [P=.008]), the clindamycin group (1.4% [P<.001] and 8.3% [P=.001]), and the other antibiotics group (1.4% [P<.001] and 1.4% [P<.001]). On the basis of this retrospective analysis, oxacillin use in children was associated with a higher incidence of hepatotoxicity and rash, compared with the use of nafcillin and other intravenous antimicrobials.""",1
9999,11735663,Adverse drug reactions related to the use of NSAIDs with a focus on nimesulide: results of spontaneous reporting from a Northern Italian area,"OBJECTIVE: To analyse and compare the adverse drug reactions (ADRs) associated with the use of nimesulide with those associated with diclofenac, ketoprofen, and piroxicam, reported spontaneously in a northern Italian area (Veneto and Trentino). METHODS: Data were obtained from the spontaneous reporting system database of Veneto-Trentino, the principal contributor to the Italian spontaneous surveillance system. All case reports that occurred in association with all formulations of the nonsteroidal anti-inflammatory drugs (NSAIDs) under investigation during the period from January 1988 to December 2000, were analysed in detail. Sales data from June 1996 to May 1999 and prescription data, from 1997 to 2000 from the Veneto region were utilised to select the most widely used NSAIDs to be included in the study. The prescription data were also used to look at the drug use in relation to age. RESULTS: During the study period, 10 608 reports describing 16 571 adverse reactions were entered into the surveillance system. We found 207 case reports for nimesulide, 187 for diclofenac, 174 for ketoprofen, and 137 for piroxicam. Analysis of sales and prescription data revealed that in the Veneto region nimesulide was the most widely prescribed drug followed at a long distance by diclofenac, piroxicam and ketoprofen. No age-related difference in the use of the four drugs was found. Analysis of the case reports revealed significantly different toxicity profiles for the four drugs. In particular, nimesulide was associated with fewer and less severe gastrointestinal (GI) ADRs compared with the other NSAIDs. Nimesulide was associated with about half the number of GI reactions (10.4%) than the other three NSAIDs (21.2% for diclofenac, 21.7% for ketoprofen, 18.6% for piroxicam). Two previously unreported reactions were also found for piroxicam and ketoprofen. CONCLUSIONS: Nimesulide is the most frequently used NSAID in Italy. Spontaneous reporting data suggest that nimesulide has the most favourable GI tolerability profile of the NSAIDs investigated, with few reports of severe GI reactions. A few reports of hepatic and renal impairment associated with nimesulide suggest caution in patients at risk. Age-related reporting analysis suggests a higher toxicity for diclofenac and piroxicam in the elderly compared with nimesulide and ketoprofen. This analysis of the Veneto-Trentino database on spontaneous reporting confirms that NSAIDs differ in their tolerability profile, and this fact should be taken into account in the choice of drugs in relation to patient characteristics.",1
10000,11740411,Darbepoetin (Aranesp) - A long-acting erythropoietin,,1
10001,11743258,Acute cholestatic hepatitis caused by Teucrium polium (golden germander) with transient appearance of antimitochondrial antibody,,1
10002,11748416,Hepatocellular injury following the administration of propofol,,1
10003,11757206,Conventional treatment of hypercalcemia of malignancy,"Treatment of hypercalcemia of malignancy (HCM) is briefly reviewed, available treatments are compared, and treatment guidelines are presented. The most effective strategy is treatment of the underlying malignancy. For patients who have a poor prognosis and no viable treatment options, the most humane course may be no treatment at all since encephalopathy will cloud their consciousness. Patients with mild hypercalcemia (corrected serum calcium concentration < 12 mg/dL) may respond to oral hydration, salt restriction, and ambulation, which encourage the normal bone remodeling process. Patients with moderate (corrected serum calcium concentration 12.0-13.5 mg/dL) to severe (> 13.5 mg/dL) hypercalcemia may require rehydration with 0.9% sodium chloride injection. Furosemide may be indicated to counteract fluid overload from rehydration measures or in patients at risk of developing congestive heart failure. For patients with renal failure not caused by dehydration, dialysis with a calcium-free or low-calcium solution is the treatment of choice. The calciuric effect of rehydration lasts only two to three days, and antiresorptive therapy is indicated for patients who require a longer duration of effect. Calcitonin is useful if a rapid decrease in serum calcium is necessary, but tachyphylaxis limits its use. Corticosteroids should be used only in patients with tumors that produce 1,25-dihydroxycholecalciferol. The use of plicamycin is limited because of adverse effects. Before the availability of zolendronic acid, pamidronate disodium was the treatment of choice, because of its longer duration of action than etidronate disodium and potential safety advantages. Zolendronic acid (discussed elsewhere in this supplement) is likely to supercede pamidronate disodium as the drug of choice for HCM, but the presence of symptoms, the rate of rise in serum calcium concentration, and the overall status of the patient are important considerations in selecting therapy.",1
10004,11765309,Gatifloxacin-associated acute hepatitis,"Gatifloxacin, a fluoroquinolone with extended gram-positive activity, has become extensively used in both the community and hospital environments. Unfortunately, concerns have been raised about the use of certain fluoroquinolones because of adverse drug reactions. A 44-year-old woman developed acute hepatitis while receiving gatifloxacin for chronic sinusitis. After 5 days of receiving antibiotics, the patient developed nausea, lethargy, and abdominal pain, all of which progressed over the next few days. Liver function tests were elevated, with bilirubin peaking at 9.4 mg/dl. The patient also became jaundiced. A percutaneous liver biopsy showed acute hepatitis with eosinophilic infiltrates consistent with drug-induced hepatitis. All other drugs and disease processes were ruled out as likely causes of the patient's hepatitis. Clinicians should be alerted to the possibility that hepatitis may occur with gatifloxacin administration.",1
10005,11765835,Propofol-infusion syndrome,,1
10006,11767440,[Cholestatic hepatitis caused by gemfibrozil],,1
10007,11768836,"A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study","""BACKGROUND: The few published direct comparative studies of the tolerability and efficacy of atypical antipsychotic agents were performed in relatively homogeneous populations that may not be typical of patients seen in clinical practice. OBJECTIVE: The Quetiapine Experience with Safety and Tolerability (QUEST) study compared the relative safety, tolerability, and efficacy of quetiapine and risperidone in outpatients with a broad range of psychotic symptoms. METHODS: This was a multicenter, 4-month, open-label, randomized clinical trial. Patients were randomized in a 3:1 ratio to receive quetiapine or risperidone. Doses were adjusted to maximize efficacy and to minimize adverse events. Extrapyramidal symptoms (EPS) were assessed with an EPS checklist; adverse events were recorded. Efficacy was assessed using the Clinical Global Impression (CGI) scale, Positive and Negative Symptom Scale (PANSS), and Hamilton Rating Scale for Depression (HAM-D). RESULTS: A total of 728 patients were randomized, 553 to quetiapine and 175 to risperidone. Mean prescribed doses over the study period were 253.9 mg/d quetiapine and 4.4 mg/d risperidone. At the end of 4 months, EPS declined in both treatment groups, but quetiapine-treated patients were significantly less likely to require dose adjustment or concurrent anti-EPS medication (P < 0.001). The most common adverse events in the quetiapine and risperidone groups were somnolence (31.3% and 15.4%, respectively), dry mouth (14.5% and 6.9%), and dizziness (12.7% and 6.9%). Overall, tolerance to side effects with the 2 drugs, measured by dropout rates, was comparable. At each visit, a higher percentage of quetiapine-treated patients showed improvement on the CGI scale, but there were no significant between-group differences on the PANSS. At end point, quetiapine-treated patients had significantly lower HAM-D scores (P = 0.028). CONCLUSIONS: The results of this study suggest that quetiapine is as effective as risperidone for the treatment of psychotic symptoms, is more effective for depressive symptoms, may have a more favorable EPS profile, and has comparable overall tolerability.""",1
10008,11771523,Toxicity of methotrexate treatment in psoriasis and psoriatic arthritis--short- and long-term toxicity in 104 patients,"""Methotrexate (MTX) is an effective anti-psoriatic agent but there are major concerns about its long-term toxicity, in particular to the liver. Reported frequencies and recommendations for monitoring patients on MTX vary considerably. The aim of this study was to analyse the frequency and severity of MTX-associated adverse drug reactions (ADR) in patients with psoriasis and psoriatic arthritis. A retrospective analysis was performed of 104 psoriasis and psoriatic arthritis patients (60 male, 44 female) treated with MTX between October 1968 and October 1998. The severity of ADR was classified according to Common Toxicity Criteria (CTC). Acute ADR was defined as adverse effects within the first 90 days of MTX therapy. ADR seen later were classified as chronic. In 83 patients 165 ADR were noted within the beginning of MTX therapy. In five patients treatment was terminated because of ADR. During long-term therapy 23 patients received < or = 2000 mg MTX (group A); 81 received a cumulative dose greater than 2000 mg (group B). The total frequency of ADR in group B and the frequency of ADR CTC grade 3 or 4 in general was not significantly increased in group B (chi2 test; P = 0.468). Group B was characterised as follows: CTC grade 3 or 4 blood count changes led significantly more often to the termination of MTX (Fisher's exact test; P = 0.048), CNS side-effects (P = 0.016) and infections were more frequent (chi test; P<0.001). Liver changes and serum enzyme level increases were not significantly more frequent in group B. ADR are common in psoriasis patients on MTX therapy independent of the cumulative dose. In most cases they are temporary by nature and mild. Liver changes and serum enzyme level increases were not a major problem in our patients.""",1
10009,11772541,Hepatotoxic reactions induced by beta-lactamase inhibitors,"Since amoxicillin/clavulanate was first introduced in the UK in 1981, beta-lactamase inhibitors are used increasingly worldwide. Two more drugs of this class are currently available, sulbactam and tazobactam. Meanwhile, adverse drug reactions associated with amoxicillin/clavulanate occurring late after the end of therapy have been repeatedly published. In many cases, a cholestatic hepatitis was diagnosed that was most likely caused by the clavulanic acid component of the combination. Symptoms were mostly mild and reversible, whereas a number of cases showing a protracted, even fatal course of the disease have been documented. This article summarizes and analyzes all relevant studies and case reports dealing with hepatotoxicity caused by beta-lactamase inhibitors. The description of a typical case from our own patient population illustrates the clinical challenge associated with this adverse drug reaction.",1
10010,11774996,Toxic interaction of didanosine and acetaminophen leading to severe hepatitis and pancreatitis: a case report and review of the literature,,1
10011,11778670,Hepatotoxicity in acute iron poisoning,"Although hepatotoxicity is a known sequela of acute iron poisoning, the literature describing it is confined to sporadic reports. Key issues such as prognosis and whether this is a dose-related phenomenon are not addressed. Review of this literature and of experimental animal studies demonstrates that it occurs early in the clinical course and has a relatively high mortality. The lowest acute serum iron concentration associated with hepatotoxicity was 1700 microg/dL (304 micromol/L). Since this greatly exceeds the reference range of 50-150 microg/dL (9-27 micromol/L), it supports a dose-related etiology. Unlike most other hepatotoxins, the periportal areas of the hepatic lobule are the primary sites of injury. As this is the principle sitefor hepatic regeneration, this accountsfor the relatively high mortality rate. An understanding of the pathogenesis of the hepatotoxicity of acute iron poisoning is central to the identification of rational and effective interventions. From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation.",1
10012,11779293,Feasibility and safety of outpatient Bexxar therapy (tositumomab and iodine I 131 tositumomab) for non-Hodgkin's lymphoma based on radiation doses to family members,"Radioimmunotherapy with anti-CD20 antibodies is a promising treatment approach for relapsed low-grade non-Hodgkin's lymphoma. Under revised Nuclear Regulatory Commission regulations (May 1997), patients may be released following treatment provided the maximum dose to any individual is not likely to exceed 500 mrem. Non-Hodgkin's lymphoma patients have been studied to evaluate radiation exposure to caregivers/family members after outpatient treatment with tositumomab and iodine I 131 tositumomab (Bexxar therapy). Estimates of total radiation doses to individuals expected to be maximally exposed to patients posttreatment have revealed that the doses should be within revised guidelines. In a University of Nebraska Medical Center study, the predicted total radiation doses (based on patient dose rate at 1 meter) ranged from 95-423 mrem. Family members were provided radiation-monitoring devices to directly monitor radiation exposure. Measured doses ranged from 10-409 mrem. In this and other studies, estimated and measured dose equivalents to maximally exposed individuals were below 500 mrem. Measured doses were, in most instances, lower than those predicted by patient-specific calculations, thus confirming the validity of the calculated dose predictions. Therefore, radioimmunotherapy with tositumomab and iodine I 131 tositumomab can be safely conducted on an outpatient basis.",1
10013,11781652,Development of hepatic veno-occlusive disease after Mylotarg infusion for relapsed acute myeloid leukemia,"Mylotarg (gemtuzumab zogamicin) is a conjugated monoclonal antibody that has recently become available for use in patients with relapsing or refractory acute myeloid leukemia. Reversible hepatotoxicity is common after administration. We describe the first report of hepatic veno-occlusive disease (HVOD) developing after Mylotarg infusion in a patient who underwent hematopoietic stem cell transplantation 8 months earlier. Certain antineoplastic agents have been implicated as a cause of HVOD, but the disease is most commonly seen within 30 days after hematopoietic stem cell transplantation. The possible association between Mylotarg infusion and HVOD is discussed.",1
10014,11785026,[Acute hepatitis due to ticlopidine. A report of 12 cases and review of the literature],"OBJECTIVE: To analyze the characteristics of hepatotoxicity due to ticlopidine. PATIENTS AND METHODS: We describe all the case of hepatotoxicity attributed to ticlopidine and reported to the Register of drug associated hepatopathies. We also obtained data from MEDLINE and the Spanish Medical Index regarding cases reported during the period 1982 2001. RESULTS: We reported twelve cases of hepatopathy related to the use of ticlopidine. These made up 5% of all the cases notified to the Register. Eighty three percent of the patients were male, and of an average age of 68 years. Sixty six percent required hospital admission. The latent period varied between 2 and 13 weeks. The liver lesion was of cholestatic type in 75% of the cases, hepatocellular in 16.6% and mixed in 8.3%. Twenty five percent of the patients had received sub therapeutic doses. CONCLUSIONS: Ticlopidine is often related to hepatotoxicity. This seems to be due to an idiosyncratic mechanism and is mainly cholestatic. The use of lower dosage than that recommended means that the desired therapeutic effect is not attained but does not protect against the development of hepatotoxicity. Doctors who use this drug should be aware of this so as to establish the true risk benefit relation.",1
10015,11786975,Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections,"Hepatologists are frequently asked to evaluate human immunodeficiency virus (HIV)-infected patients with abnormal liver enzymes and to assess the causal role of medications, such as antiretroviral drugs. Recently, the use of HIV-1 specific non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine (NVP) and efavirenz (EFV), has been associated with severe hepatic injury. We prospectively studied the incidence of severe hepatotoxicity (grade 3 or 4 change in alanine or aspartate transaminase levels) among 568 patients receiving NNRTI-containing antiretroviral therapy, including 312 and 256 patients prescribed EFV and NVP, respectively. Hepatitis C virus (HCV) and hepatitis B virus (HBV) were detected in 43% and 7.7% of patients, respectively. Severe hepatotoxicity was observed in 15.6% of patients prescribed NVP and 8.0% of those prescribed EFV, but only 32% of NVP and 50% of EFV-associated episodes were detected during the first 12-weeks of therapy. The risk was significantly greater among persons with chronic viral hepatitis (69% of cases) and those prescribed concurrent protease inhibitors (PIs) (82% of cases). Nonetheless, 84% of patients with chronic HCV or HBV did not experience severe hepatotoxicity. Severe hepatotoxicity occurs throughout the course of NNRTI therapy and is more common among patients prescribed nevirapine, those coinfected with HCV or HBV, and those coadministered protease inhibitors.",1
10016,11788010,Hepatolithiasis (intrahepatic stone) during octreotide therapy for acromegaly: a case report,"We report a case of hepatolithiasis (intrahepatic stone) complicated by gram-negative sepsis in a 37 year old male with acromegaly being treated with octreotide. As a child, he had suffered a traumatic injury to his liver requiring the surgical repair of a laceration. This is the first reported case of hepatolithiasis during octreotide therapy. Gallstones and bile sludge are common side effects of octreotide therapy but rarely become symptomatic or require treatment. Hepatolithiasis is uncommon in western countries but is quite prevalent in East Asia and is often associated with a predisposing condition that causes intrahepatic bile stasis (eg. bile duct stricture). In addition to its known effect on gallbladder stasis, octreotide alters bile acid composition and may thus hasten intrahepatic sludge and stone formation. Extra caution should be taken in using octreotide or its long-acting analog in patients otherwise predisposed to intrahepatic bile stasis.",1
10017,11789021,Optimal treatment of nevirapine-associated hepatotoxicity remains uncertain,"The cases of 2 patients with nevirapine-associated hepatotoxicity in conjunction with rash and eosinophilia are reported here. Both patients' conditions improved following withdrawal of nevirapine. Previous case reports have described a variety of interventions other than drug withdrawal that might have contributed to resolution of drug-induced hepatitis. Until a better understanding of the clinical spectrum and pathophysiology of nevirapine-associated hepatotoxicity is realized, treatment will remain largely empiric.",1
10018,11792999,Liver transplantation for fulminant hepatic failure due to cocaine intoxication in an alcoholic hepatitis C virus-infected patient,,1
10019,11793641,Eosinophilic hepatitis associated with cefonicid therapy,,1
10020,11800507,"Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study","New treatment strategies are encouraged in insomnia and, in particular, discontinuous treatment. The aim of this double-blind study was to compare, in a large primary care population of chronic insomniacs (> 4 weeks duration) the efficacy and safety of zolpidem 10 mg 5 nights/week and placebo 2 nights/week, to that of nightly zolpidem. Seven hundred and eighty-nine drug-free insomniacs, with a Total Sleep Time (TST) of 3-6 h/night were enrolled in seven European countries. After a placebo run-in period, treatment lasted 14 days. The primary criterion was the Clinical Global Impression improvement score (CGI-II) which showed that 65.2% of patients in the continuous and 58.6% in the discontinuous groups were rated 'much' or 'very much' improved. Even though the non-inferiority test did not show the equivalence of both regimens, the difference of 7% in responder rates does not appear to be clinically relevant. Other sleep parameters such as TST, number of nocturnal awakenings and Quality of Life scales showed marked, not significantly different, improvements in both groups. Both regimens were well tolerated and no adverse event which could be related to non-treatment nights was reported in the discontinuous group. Non-nightly zolpidem appears to be a feasible and safe additional option for the management of chronic insomnia.",1
10021,11807147,CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma,"BACKGROUND: The standard treatment for patients with diffuse large-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, has therapeutic activity in diffuse large-B-cell lymphoma. We conducted a randomized trial to compare CHOP chemotherapy plus rituximab with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. METHODS: Previously untreated patients with diffuse large-B-cell lymphoma, 60 to 80 years old, were randomly assigned to receive either eight cycles of CHOP every three weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients). RESULTS: The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the CHOP-plus-rituximab group (P<0.001 and P=0.007, respectively). The addition of rituximab to standard CHOP chemotherapy significantly reduced the risk of treatment failure and death (risk ratios, 0.58 [95 percent confidence interval, 0.44 to 0.77] and 0.64 [0.45 to 0.89], respectively). Clinically relevant toxicity was not significantly greater with CHOP plus rituximab. CONCLUSIONS: The addition of rituximab to the CHOP regimen increases the complete-response rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma, without a clinically significant increase in toxicity.",1
10022,11807679,Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis,"""To evaluate the efficacy and safety of voriconazole in acute invasive aspergillosis (IA), an open, noncomparative multicenter study was conducted. Immunocompromised patients with IA were treated with intravenously administered voriconazole 6 mg/kg twice a day (b.i.d.) twice and then 3 mg/kg b.i.d. for 6-27 days, followed by 200 mg b.i.d. administered orally for up to 24 weeks. Response was assessed by clinical and radiographic change. A total of 116 patients were assessable. IA was proven in 48 (41%) and probable in 68 patients. Voriconazole was given as primary therapy in 60 (52%). Good responses were seen in 56 (48%); 16 (14%) showed complete response and 40 (34%) partial response. A stable response was seen in 24 patients (21%), and 36 (31%) of the infections failed to respond to therapy. Good responses were seen in 60% of those with pulmonary or tracheobronchial IA (n=84), 16% with cerebral IA (n=19), 58% with hematologic disorders (n=67), and 26% of allogeneic stem cell transplant recipients (n=23). Voriconazole is efficacious in treating acute IA.""",1
10023,11810037,Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial,"OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.",1
10024,11815724,Low-dose flutamide (125 mg/day) as maintenance therapy in the treatment of hirsutism,"OBJECTIVE: To evaluate the safety and efficacy of a low dose of flutamide (125 mg/day) in maintaining the clinical results already obtained using a higher dose (250 mg/day), in women suffering from hirsutism. METHOD: Forty-three women suffering from hirsutism of varying origin received 250 mg/day of flutamide as an initial treatment for 12 months and, subsequently, 125 mg/day of flutamide for an additional 12 months as a maintenance treatment. Hirsutism was evaluated by the Ferriman-Gallwey score, and hair diameter and hair growth rate were determined by a special image analysis processor. Biochemical, clinical and hormonal parameters were evaluated in basal conditions and every 2-6 months. RESULTS: The significant decrease in the hirsutism score, hair diameter and hair growth rate during the initial treatment period was confirmed at the end of the maintenance treatment period. Androgen levels decreased up to the end of the initial treatment period and partially decreased during the maintenance treatment. During the initial treatment period, 4 subjects showed an increase of aspartate aminotransferase and alanine aminotransferase and dropped out. During the maintenance treatment period, no side effects or complications were observed. CONCLUSION: Satisfactory management of hirsutism with flutamide seems to be represented by an initial treatment period using 250 mg/day to achieve satisfactory results, followed by a long maintenance treatment period using 125 mg/day.",1
10025,11816250,Possible ranitidine-induced cholestatic jaundice,,1
10026,11817238,[Toxic hepatitis caused by aceclofenac],,1
10027,11821453,Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer,"""PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.""",1
10028,11822934,Acute fulminant hepatitis after treatment with rabeprazole and terbinafine: is rabeprazole the culprit?,,1
10029,11825325,Sirolimus: a comprehensive review,"Sirolimus (Rapamune), Wyeth-Ayerst, Madison, NJ) is a new, potent, immunosuppressant that is emerging as a foundation for long-term immunosuppressive therapy in renal transplantation. The drug acts during both co-stimulatory activation and cytokine-driven pathways via a unique mechanism: inhibition of a multifunctional serine-threonine kinase, mammalian target of rapamycin (mTOR). Although there is no a priori reason to assume it, sirolimus displays a synergistic interaction to enhance the efficacy of cyclosporin A (CsA). In trials wherein the concentrations of CsA and sirolimus were tightly controlled, rates of acute rejection episodes were < 10%, despite markedly reduced exposures to each agent. In pivotal multi-centre blinded dose-controlled trials, the rates of acute rejection episodes within 12 months following administration of 2 or 5 mg/day sirolimus in combination with CsA and steroids were reduced to 19 and 14%, respectively. Since the inhibitory effect of sirolimus disables virtually all responses to cytokine mediators due to the widespread involvement of mTOR in multiple signalling pathways, the agent is likely also to retard proliferation of endothelial and vascular smooth muscle cells, an important component of the immuno-obliterative processes associated with chronic rejection. The advantages of this unique therapeutic action combined with an intrinsic lack of nephrotoxicity are counterbalanced by myelosuppressive and hyperlipidaemic side effects. Ongoing studies are assessing whether the long-term benefits of sirolimus to permit reduction in exposure to or elimination of calcineurin inhibitors ameliorate the progression of chronic nephropathy, the condition that erodes long-term renal transplant survival.",1
10030,11826672,[Acute hepatitis after use of a herbal preparation with greater celandine (Chelidonium majus)],"A 42-year-old woman developed jaundice due to acute hepatitis several weeks after ingestion of a herbal preparation containing greater celandine (Chelidonium majus) and curcuma root, which had been prescribed by an alternative therapist due to a skin complaint. After the medication had been withdrawn, clinical recovery was rapid and the hepatic functions returned to normal within 2 months. The hepatitis was ascribed to the known hepatotoxic effects of C. majus. In view of the increasing popularity of herbal remedies, greater awareness of side effects, such as hepatotoxicity, is needed. Quite a number of herbal preparations carry the risk of liver damage. The supposed clinical effectiveness of herbal remedies does not seem to always outweigh the potential risks. In the event of non-clarified liver function disturbances the ingestion of supposedly harmless, but potentially hepatotoxic, herbal products should be considered.",1
10031,11828837,Troglitazone (Rezulin) and hepatic injury,"PURPOSE: Analyze US rates of reported severe liver disease for the oral hypoglycemic agent troglitazone from March 1997 through February 2000 and the possible effects of publicity on reporting. METHODS: The number of troglitazone reports with liver failure and or hospitalization with jaundice or hyperbilirubinemia, made to the FDA and/or Parke-Davis are used as numerators. The denominators are numbers of patients and person-time estimates of exposure. Additionally, the amount of publicity about troglitazone during its marketing is quantified. RESULTS: Approximately 1.92 million patients were treated with troglitazone from March 1997 through the end of February 2000 resulting in 1.6 million person-years of exposure. Reports of 83 cases of liver failure associated with troglitazone were received (1 in 23,000 patients or 1 in 20,000 person-years). Of the 83 cases, only 49 (59%) were classified by a hepatologist to be 'possibly' or 'probably' attributed to troglitazone. For the first, second, and third years of marketing, rates of reported hepatic failure per 100,000 person years exposure to troglitazone were 8.3, 5.3, and 2.7 respectively. Rates of reported liver disease involving hospitalizations with mention of jaundice and hyperbilirubinemia per 100,000 person-years were 16.0, 6.1, and 3.6 respectively for these years. During the 3-year marketing history of troglitazone, there were 470 lay press and 158 medical literature articles with mentions of hepatotoxicity for the drug. CONCLUSIONS: Rates of reported severe liver disease declined substantially during the second and third years of marketing of troglitazone. The decline followed increasingly stringent requirements for liver function test monitoring and may have been due to improved patient selection and management as a result of the widely publicized association between troglitazone and hepatotoxicity.",1
10032,11830344,Acute liver failure associated with antiretroviral treatment for HIV: a report of six cases,"BACKGROUND/AIMS: Severe hepatotoxicity is a rare but potentially fatal side effect of all antiretrovirals. We report a series of six human immunodeficiency virus (HIV)-infected patients admitted with acute liver failure (ALF) over a 25-month period, of whom five died. All had been treated with a range of antiretroviral therapy and only two had had acquired immune deficiency syndrome (AIDS) defining illnesses. RESULTS: Median duration of antiretroviral therapy was 12.5 months (range 1-23). Median time from the introduction of new antiretroviral therapy to the onset of ALF was 8 weeks (range 2-12). The development of ALF was unrelated to duration of HIV treatment or type of antiretroviral therapy, and was not predicted by close out-patient supervision and monitoring of liver function. Biochemical investigations were variable but revealed a predominantly hepatocellular pattern. Liver biopsy revealed typical features of mitochondrial toxicity in only one case, with confluent hepatocellular necrosis, inflammation and cholestasis seen in the others. CONCLUSIONS: There is a need to increase awareness of the potential hepatotoxicity of antiretroviral therapy and to develop means of predicting its development. With increasing usage of antiretroviral therapy, severe hepatotoxicity and ALF may arise more frequently, and the outcome is poor despite intensive supportive therapy.",1
10033,11835952,The safety of triptans in the treatment of patients with migraine,"The introduction of the triptans (5-hydroxytryptophan [5-HT] (1B/1D) agonists) in the past decade has brought migraine-specific pain relief to those suffering from migraine. These drugs activate the serotonin receptors 5-HT(1B) and 5-HT(1D) on cerebral vessels. Concerns about their safety, particularly in patients with vascular risk factors, have been raised because triptans also activate the 5-HT(1B) receptors on coronary arteries. Although triptans are contraindicated in patients with cardiac or cerebrovascular disease, they are safer than many other medications used to treat patients with migraine, including the nonspecific serotonin-agonist ergot preparations.",1
10034,11837721,Efficacy of early immunosuppressive therapy in a child with carbamazepine-associated vanishing bile duct and Stevens-Johnson syndromes,,1
10035,11840435,Guidelines for the management of rheumatoid arthritis: 2002 Update,,1
10036,11844656,A pilot study of the safety and efficacy of cholestin in treating HIV-related dyslipidemia,"""OBJECTIVE: We collected preliminary safety and efficacy data on the effects of Cholestin, a statin-containing dietary supplement, in individuals with dsylipidemia related to human immunodeficiency virus. METHODS: Fourteen adults with dsylipidemia related to human immunodeficiency virus characterized by hypercholesterolemia, hypertriacylglycerolemia, or both participated in a randomized, double-blind, placebo-controlled pilot study in an infectious disease clinic based in an academic medical center. Participants were randomly assigned to receive 1.2 g of Cholestin twice daily (n = 7) or placebo (n = 7) for 8 wk. The main outcome measures were safety (hepatic function tests, plasma human immunodeficiency virus-1 RNA levels, CD4(+) cell counts, adverse effects) and efficacy (fasting serum cholesterol: total, high- and low-density lipoproteins, and fasting serum triacylglycerols). Safety and efficacy outcomes were evaluated at 2- and 8-wk intervals. RESULTS: Twelve participants (n = 6 per group) completed the 8-wk treatment protocol. After 8 wk of treatment with Cholestin, there were significant declines from baseline in mean (+/- standard error of the mean) fasting total cholesterol (-30.8 +/- 8.8 versus 7.7 +/- 5.6; P = 0.01) and low-density lipoprotein cholesterol (-32.2 +/- 7.2 versus 26.3 +/- 14.2; P = 0.01) versus placebo. Moreover, the decline in fasting total cholesterol was significant (-40.2 +/- 4.8 versus 2.8 +/- 11.9; P = 0.006) after 2 wk of therapy, at which time the low-density lipoprotein cholesterol approached significance (-30.2 +/- 7.4 versus 4.4 +/- 15.2; P = 0.068). High-density lipoprotein cholesterol and triacylglycerol levels did not change at either time point. No adverse effects were seen with Cholestin. CONCLUSIONS: Cholestin may safely lower total and low-density lipoprotein cholesterol in patients with dsylipidemia related to human immunodeficiency virus. Larger and longer-term trials of this approach are warranted.""",1
10037,11844898,"Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicentre, randomised, double-blind, placebo-controlled comparison","""The 5-HT(1B/1D/1F) agonist eletriptan, at an oral dose of 80 mg, has been shown to be more efficacious than sumatriptan 100 mg and placebo in the treatment of migraine attacks with or without aura. Another commonly prescribed oral treatment for migraine attacks is Cafergot (1 mg ergotamine tartrate with 100 mg caffeine per tablet). The efficacy, tolerability and safety of 40- and 80-mg doses of eletriptan and 2 tablets of Cafergot were compared in a double-blind, randomised, placebo-controlled, parallel-group trial involving 733 migraine patients. Patients recorded symptoms at baseline (before treatment) and 1, 2, 4 and 24 h after dosing. Headache intensity was assessed on a 4-point scale (3 = severe pain, 2 = moderate pain, 1 = mild pain, 0 = no pain). Significantly more eletriptan-treated patients (80 mg, 68%; 40 mg, 54%) than Cafergot-treated patients (33%; p < 0.001) reported headache response (improvement from moderate-to-severe to mild or no pain) at 2 h. Substantially more eletriptan recipients reported no pain (80 mg, 38%; 40 mg, 28%; Cafergot, 10%; placebo, 5%; p < 0.001). Eletriptan headache response rates at 1 h were significantly higher (80 mg, 39%; 40 mg, 29%; Cafergot, 13%; placebo, 13%; p < 0.002 for each comparison). Both doses of eletriptan were significantly more effective than Cafergot in reducing nausea (p < 0.0001), photophobia (80 mg, p < 0.0001; 40 mg, p < 0.002), phonophobia (80 mg, p < 0.0001; 40 mg, p < 0.003) and functional impairment (p < or = 0.001) at 2 h. Adverse events were generally mild or moderate and transient. This randomised trial shows that oral eletriptan is more efficacious in the acute treatment of migraine than oral Cafergot and is well tolerated.""",1
10038,11847945,Acute cholestatic hepatitis after exposure to isoflurane,"OBJECTIVE: To report a case of acute cholestatic hepatitis following exposure to the inhalational anesthetic isoflurane. CASE SUMMARY: A 70-year-old healthy woman from Iraq developed acute cholestatic hepatitis 3 weeks following repair of the right rotator cuff under general anesthesia. There was no evidence for viral, autoimmune, or metabolic causes of hepatitis. No other medications were involved except for dipyrone for analgesia. The alanine aminotransferase was elevated to a peak concentration of 1533 U/L and the serum bilirubin reached a peak of 17.0 mg/dL. There was slow improvement over 4 months. Accidental reexposure by the patient to dipyrone was uneventful. DISCUSSION: The clinical and histologic picture of this case resembles halothane hepatitis, which has a significant mortality rate. CONCLUSIONS: Isoflurane, a common anesthetic agent, can cause severe cholestatic hepatitis.",1
10039,11848652,Liver adenoma and focal nodular hyperplasia associated with oral contraceptives,"We report the case of a woman, with a 15-year history of high-dosage oral contraceptive use, who came to our center for a gynecological screening. Elevated liver enzymes were detected in blood samples and an abdominal ultrasound showed a hypoechogenic nodular image of 8 cm in the right hepatic lobe of the liver. Routine examinations, including hepatitis B surface antigen, hepatitis C viral antibody and alpha-fetoprotein, were all negative. Imaging studies, including computerized tomography scan, magnetic resonance imaging, sulfur colloid gammagraphy and hepatic angiography, were performed and confirmed the presence of the lesion, detecting the characteristic central scar structure of focal nodular hyperplasia. Discontinuation of oral contraceptives and follow-up showed no change in lesion size so that a surgical approach was adopted in order to remove the hepatocellular carcinoma. Pathological findings confirmed focal nodular hyperplasia.",1
10040,11850865,Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 12 cases and review of the literature,"""Lactic acidosis is a rare but often fatal complication reported in some human immunodeficiency virus (HIV)-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. We report a series of 12 patients with HIV infection treated with nucleoside analogues who developed unexplained metabolic acidosis. We have also reviewed 60 additional published cases. The aim of the present study is to describe the clinical picture, prognostic factors, and final outcome for nucleoside-associated lactic acidosis. The mortality rate is high: 33% for our patients, and 57% for the patients described in the literature. In the multivariate analysis, a lactate serum level of >10 mM (odds ratio [OR], 13.23; 95% confidence interval [CI], 2.96-59.25) was the only factor associated with higher mortality. The administration of specific therapy with cofactors against acidosis was associated with a lower mortality (OR, 0.17; 95% CI, 0.04-0.73). We conclude that specific therapy with cofactors may improve the outcome for patients with this syndrome.""",1
10041,11852289,Pergolide in the treatment of patients with early and advanced Parkinson's disease,"""Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.""",1
10042,11854634,Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study,"OBJECTIVE: A role of female hormones, including oral contraceptives, has been suggested in the etiology of focal nodular hyperplasia of the liver. There is, however, no epidemiologic quantification of this relationship. STUDY DESIGN: A hospital-based case-control study was conducted in Italy of 23 women with histologically confirmed focal nodular hyperplasia of the liver and 94 controls in the hospital for acute diseases. Odds ratios (ORs) were computed by use of multiple logistic regression models. RESULTS: Focal nodular hyperplasia was not associated with menstrual and reproductive factors. Ever oral contraceptive use was reported by 83% of cases and 59% of controls. The multivariate OR was 2.8 (95% confidence interval [CI], 0.8-9.4) for ever use, and 4.5 (95% CI, 1.2-16.9) for use > or = 3 years. The trend in risk with duration was statistically significant. CONCLUSIONS: This study confirms previous clinical observations, and provides a quantitative estimate of the association between use of oral contraceptives and focal nodular hyperplasia of the liver.",1
10043,11856080,"A double-blind comparison of balsalazide, 6.75 g, and sulfasalazine, 3 g, as sole therapy in the management of ulcerative colitis","BACKGROUND: Sulfasalazine is accepted therapy for active ulcerative colitis, but side-effects and intolerance are common. Balsalazide is an azo-bonded pro-drug which also releases 5-aminosalicylic acid into the colon, but uses an inert carrier molecule. AIM: To compare the safety and efficacy of sul- fasalazine, 3 g, with balsalazide, 6.75 g, in the initial daily treatment of mild to moderate ulcerative colitis. METHODS: A randomized, multicentre, double-blind, parallel group study was performed, with a treatment duration of 8 weeks. Patients on previous maintenance treatment were excluded. The trial medication was the sole treatment for the colitis. Efficacy was assessed by patient diaries, symptom assessment, sigmoidoscopic appearance and histology. RESULTS: Fifty patients were recruited: 26 allocated to the balsalazide group and 24 to the sulfasalazine group. More patients withdrew due to adverse events in the sulfasalazine group (nine patients vs. one patient in the balsalazide group, P=0.004). Improvement occurred in both groups, with a tendency to a faster response with balsalazide. Of the patients taking balsalazide, 61% achieved clinical and sigmoidoscopic remission. CONCLUSIONS: Balsalazide, 6.75 g, is effective as the sole treatment for patients with mild to moderately active ulcerative colitis, with significantly fewer withdrawals due to side-effects than in a similar group of patients taking sulfasalazine, 3 g.",1
10044,11857551,Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency,"Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 micromol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 micromol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control.",1
10045,11865828,"Treatment of severe intermittent claudication with pentoxifylline: a 40-week, controlled, randomized trial","The efficacy, safety, and cost of pentoxifylline (PXF) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a randomized 40-week study. A treadmill test was performed at inclusion and at the end of weeks 20 and 40. A progressive training plan and the control of risk factors (with antiplatelet treatment) were used in both groups. Of the 200 included patients, 178 completed the study: 88 in the PXF group and 90 in the placebo group. There were 22 dropouts. The two groups were comparable for age, sex distribution, and for the presence of risk factors and smoking. There was a significant increase in pain-free walking distance (PFWD) in both groups. The absolute and percent increase in PFWD was significantly greater in the PXF group (p<0.05). At 20 weeks, the increase was 360.5% in the PXF vs 252% in the placebo group. At 40 weeks, the increase was 386% in the PXF and 369% in the placebo group (p<0.02). Total walking distance (TWD) increased at 20 weeks (up to 254%) and up to 329% at 40 weeks. In the placebo groups the increase was 158% at 20 weeks and 183% at 40 weeks. The excess increase produced by PXF treatment was 30% at 20 weeks and 38% at 40 weeks (p<0.02). Unwanted effects treatment was well tolerated. No serious drug-related side effects were observed. In summary, between-group analysis favors PXF considering walking distance and costs. Results indicate good efficacy and tolerability.",1
10046,11866297,Clarithromycin use preceding fulminant hepatic failure,,1
10047,11867103,Adverse reactions to TNF-alpha inhibitors in rheumatoid arthritis,,1
10048,11870241,Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia,"BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.",1
10049,11873055,Subcellular localization of trifluoroacetylated liver proteins in association with hepatitis following isoflurane,,1
10050,11873540,Ecstasy-induced hepatitis in an active duty soldier,"""3,4-Methylenedioxymethamphetamine, or """"Ecstasy,"""" is a drug commonly used at """"rave"""" parties to heighten energy and intimacy. Although its complications have been well described in Europe, including less common side effects such as hepatic failure and rhabdomyolysis, physicians in the United States have less experience with this drug because of the shorter duration of its use in this country. We present a case of an active duty soldier who was admitted for acute hepatitis secondary to Ecstasy ingestion and describe its proposed pathophysiology. We believe that with the increased use of Ecstasy in the United States, especially among younger patients, including soldiers, military physicians will need to be more familiar with this potentially deadly drug.""",1
10051,11877262,Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study,"""Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.""",1
10052,11878166,[Asymptomatic hepatitis induced by propylthiouracil],"Propylthiouracil (PTU) is widely used to treat patients with hyperthyroidism. In rare cases this drug has been found to have toxic effects on the liver. We describe the second assymptomatic case, reported in the literature, of PTU induced hepatotoxicity. Sixteen cases have been published so far, all with clinical manifestations. A 20-year-old female patient developed an elevation of AST, ALT and GGT levels after 5 months of PTU (50 mg tid) therapy for Graves disease with hyperthyroidism. The patient showed normal levels of liver aminotransferases before starting PTU. She had no risk factors for or clinical evidence of pre-existing liver disease. She didn't take any regular medication. After stopping PTU, the plasma levels of hepatic enzymes normalised within 6 weeks. Thirteen days after the reinstitution of PTU (150 mg tid), because of the recurrence of hyperthyroidism, another episode of assymptomatic hepatotoxicity was documented. AST, ALT, GGT and AP levels rose again, but bilirrubin levels remained normal, which represents a very unusual laboratory constellation in this kind of patient. The serology for hepatitis A, B, C and for EBV and CMV was negative. After stopping PTU, methimazole (MMI) was started and the liver enzymes normalised within two weeks. After 12 months of MMI therapy, the patient is assymptomatic, with normal liver enzyme levels and normal thyroid function tests. This case is the second to be described where the diagnosis was confirmed by the rechallenge of PTU, being this a major diagnostic criteria. Despite its rarity the disease should be suspected in any patient receiving PTU in whom clinical or laboratorial evidence of hepatocellular injury develops. The drug should be discontinued immediately when the hepatic injury is detected. Recovery is usually complete after the withdrawal of the drug, but there were al least, three fatalities among the 17 cases described.",1
10053,11881318,Hepatic fibrin-ring granulomas in granulomatous hepatitis: report of four cases and review of the literature,"BACKGROUND: The differential diagnosis of hepatic fibrin-ring granulomas includes infective agents (Coxiella burneti, CMV, EBV,....), hypersensitivity to medication (allopurinol) and malignancy. METHODS: During a period of 6 months, four patients presented at our university hospital with a similar clinical picture of fever and abnormal liver tests, and fibrin-ring granulomas on liver biopsy. Clinical course, laboratory and imaging findings, and histopathological features were compared. RESULTS: Clinical manifestations, and laboratory and imaging findings were similar. Histopathological assessment of the hepatic fibrin-ring granulomas appeared not to be helpful in identifying the causative agent. Other histopathological features (e.g. sinusoidal rows of lymphocytes, eosinophilic polymorphonuclear infiltrate) were suggestive for the causative agent, yet conclusive identification was obtained by either serology (Q fever, CMV, EBV), or by exclusion with concomitant stop of medication (allopurinol). CONCLUSIONS: In the differential diagnosis of hepatic fibrin-ring granulomas, serologic titers remain the determining factor, since an infective agent is the most common cause. When hepatic fibrin-ring granulomas are present, other histopathological features may be helpful in making the differential diagnosis.",1
10054,11888078,Carisoprodol: an unrecognized drug of abuse,"During a 6-month monitoring period, carisoprodol was detected in the urine specimens of 19 patients for whom drug screening had been ordered for purposes of patient care. The clinical history suggested that in 7 cases the drug was abused or implicated in a suicide attempt or gesture. In another 7 cases, the drug was used primarily for medical purposes, and in 5 cases the reason for use could not be determined. One patient ingested homemade tablets that were found to contain carisoprodol. In an additional case, the drug was detected in breast milk. Physical findings, clinical history, and treatment are described, and the profile of a typical carisoprodol user is discussed. It seems that carisoprodol has become an unrecognized drug of abuse, at least in our community. This drug and its metabolite, meprobamate, should be included in comprehensive drug screening.",1
10055,11888656,Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors,"Clinical studies with tenofovir disoproxil fumarate, an oral prodrug of the nucleotide analog tenofovir, recently approved for the treatment of HIV, have demonstrated antiviral activity and good tolerability in HIV-infected patients. In order to better understand the cytotoxicity profile of tenofovir relative to the other nucleoside reverse transcriptase inhibitors (NRTIs), the in vitro effects of these agents were evaluated in various human cell types. Tenofovir inhibited the proliferation of liver-derived HepG2 cells and normal skeletal muscle cells with CC(50) values of 398 and 870 microM, respectively. In comparison, ZDV, ddC, ddI, d4T, and abacavir all showed lower CC(50) values in these two cell types. Evaluation of hematopoietic toxicity revealed that tenofovir was less cytotoxic towards erythroid progenitor cells (CC(50)>200 microM) than ZDV, d4T, and ddC (CC(50)=0.06-5 microM). Despite some degree of donor-to-donor variability, the inhibitory activity of the tested NRTIs against myeloid cell lineage, in the order of decreasing severity, was consistently ddC>ZDV>d4T>tenofovir>3TC. Finally, tenofovir showed substantially weaker effects on proliferation and viability of renal proximal tubule epithelial cells than cidofovir, a related nucleotide analog with the potential to induce renal tubular dysfunction. In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease.",1
10056,11893792,Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients,"BACKGROUND: Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase gamma. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. METHODS: Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy. RESULTS: Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68 percent lower than those of non-HIV-infected controls and 43 percent lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P=0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels. CONCLUSIONS: Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy.",1
10057,11897208,Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia,"""Combination therapy is increasingly recommended for patients with multiple lipid disorders, especially those at high risk for coronary events. We investigated the long-term safety and effectiveness of a new drug formulation containing once-daily extended-release niacin and lovastatin. A total of 814 men and women (mean age 59 years) with dyslipidemia were enrolled in a 52-week multicenter, open-label study. We used 4 escalating doses (niacin/lovastatin in milligrams): 500/10 for the first month, 1,000/20 for the second, 1,500/30 for the third, and 2,000/40 for the fourth month through week 52. Dose-dependent effects were observed for all major lipid parameters. At week 16, mean low-density lipoprotein (LDL) cholesterol and triglycerides were reduced by 47% and 41%, respectively; mean high-density lipoprotein (HDL) cholesterol was increased by 30% (all p <0.001). LDL/HDL cholesterol and total/HDL cholesterol ratios were also decreased by 58% and 48%, respectively. These effects persisted through week 52, except for the mean increase in HDL cholesterol, which had increased to 41% at 1 year. Lipoprotein (a) and C-reactive protein also decreased in a dose-related manner (by 25% and 24%, respectively, on 2,000/40 mg; p <0.01 vs baseline). Treatment was generally well tolerated. The most common adverse event was flushing, which caused 10% of patients to withdraw. Other adverse events included gastrointestinal upset, pruritus, rash, and headache. Drug-induced myopathy did not occur in any patient. The incidence of elevated liver enzymes to >3 times the upper limit of normal was 0.5%. Once-daily niacin/lovastatin exhibits substantial effects on multiple lipid risk factors and represents a significant new treatment option in the management of dyslipidemia.""",1
10058,11897929,"Important role of prodromal viral infections responsible for inhibition of xenobiotic metabolizing enzymes in the pathomechanism of idiopathic Reye's syndrome, Stevens-Johnson syndrome, autoimmune hepatitis, and hepatotoxicity of the therapeutic doses of acetaminophen used in genetically predisposed persons","Upper respiratory tract febrile illnesses caused by various viruses, mycoplasma, chlamydia infections, and/or inflammatory diseases are usually observed a few days to a few (several) weeks before the onset of Reye's syndrome, Stevens-Johnson syndrome, autoimmune hepatitis (hepatotropic virus infections), or hepatotoxicity associated with therapeutic administration of acetaminophen in persons with varying degrees of deficits of important enzymatic activity. Activation of systemic host defense mechanisms by inflammatory component(s) results in depression of various induced and constitutive isoforms of cytochrome P-450 mixed-function oxidase system superfamily enzymes in the liver and most other tissues of the body. Because several cytochrome P-450 enzymes activities important for biotransformation of many endogenous and egzogenous substances show considerable variability between individuals, in some genetically predisposed persons, even the administration of therapeutic doses of a drug may result in serious clinical mishaps, if an important concomitant risk factor (eg, acute viral infection) is involved. Several inflammatory cytokines, such as interleukins, transforming growth factor beta1, human hepatocyte growth factor, and lymphotoxin, downregulate gene expression of major cytochrome P-450 enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity observed with a given cytokine varying for each P-450 studied, thus eventually leading to metabolite-mediated adverse drug reactions and immunometallic diseases which sometimes result in tissue injury beyond the site(s) where metabolic bioactivation takes place. On the other hand, it must be emphasized that inhibition of metabolism of several drugs, as well as influence on the concentration and/or ratio of various cytokines in inflamed tissues, may exert beneficial effects in patients with different diseases, thus opening new therapeutic possibilities. Clinically relevant interactions may be exemplified by the effects of some fluoroquinolone antibiotics, such as pefloxacin and ciprofloxacin, which probably have a steroid-sparing effect in some patients with frequently relapsing nephrotic syndrome, and an increased bioavailability of several drugs following concomitant intake with freshly pressed grapefruit juice, eventually caused by inhibition of their metabolism, mediated mainly by CYP3A and specifically inhibited by naturally occurring flavonoids.",1
10059,11900502,Did this drug cause my patient's hepatitis? and related questions,,1
10060,11903461,Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy,"PURPOSE: To investigate ammonia and glutamine levels in valproate (VPA)-related hyperammonemic encephalopathy (VHE). METHODS: We reviewed the medical records and EEG recordings of seven adults diagnosed with VHE. RESULTS: Venous ammonia levels were elevated in five (71%) of the seven patients. Elevated serum or cerebrospinal fluid (CSF) glutamine levels were found in four (80%) of five cases tested, including two who had normal ammonia levels. Initial behavioral signs included violent outbursts in three patients, paranoid ideation severe enough to require restraint in two cases, and milder abnormalities in two instances. The severity of encephalopathy was not related to any particular serum VPA level. In four patients serum VPA levels did not exceed 100 microg/ml, and in one case, VHE developed after taking only one 250-mg dose. Symptoms eventually cleared after reducing the dose of, or discontinuing, VPA. Liver-function tests were normal. Each of six patients tested had EEG findings that supported the diagnosis of VHE and excluded nonconvulsive status epilepticus. The rate of normalization of one patient's serum glutamine level and the EEGs of two cases correlated better with the timing of their delayed clinical recovery than did the more rapid rate of decline of the serum ammonia levels. CONCLUSIONS: Serum or CSF glutamine levels are initially elevated in a majority of patients with suspected VHE, sometimes in the absence of hyperammonemia. Glutamine levels may be useful adjunctive laboratory tests for the diagnosis of VHE.",1
10061,11907376,Acute hepatitis associated with cetirizine intake,,1
10062,11908554,"Dose response and safety study of meloxicam up to 22.5 mg daily in rheumatoid arthritis: a 12 week multicenter, double blind, dose response study versus placebo and diclofenac","""OBJECTIVE: This Phase III, placebo and active controlled, multicenter trial evaluated the efficacy and safety of meloxicam 7.5, 15, and 22.5 mg daily for the treatment of rheumatoid arthritis (RA). METHODS: A 12 week, randomized, double blind, double dummy, parallel group trial compared daily oral meloxicam 7.5, 15, and 22.5 mg to placebo (negative control) and diclofenac 75 mg BID (positive control). A total of 894 patients (18 years of age with confirmed RA who flared following an NSAID-free period) were randomized to be treated. Baseline scores for all endpoints were similar among the treatment groups. Patient assessments were at 0, 2, 4, 8, and 12 weeks or early termination. RESULTS: All treatment groups demonstrated significant improvement from baseline (p < 0.001). Meloxicam 7.5 and 22.5 mg was significantly superior to placebo in all 5 primary efficacy endpoints (swollen joint count, tender joint count, patient pain, patient and physician global; all p < 0.05). Diclofenac 150 mg was superior to placebo for 4 of 5 primary efficacy measures (all but swollen joint count; p < 0.05) and meloxicam 15 mg was superior for 3 of 5 primary endpoints (patient pain and patient and physician global). AUC of patient global, patient pain, and modified Health Assessment Questionnaire demonstrated dose-response (p < 0.04), while AUC ACR20 showed a qualitative trend in the same direction. The rate of gastrointestinal (GI) events during the 12 week trial for all doses of meloxicam and diclofenac did not differ significantly from placebo (23.2-32.0%). GI withdrawals were comparable and not significantly different across all treatment groups (4.3-5.7%). CONCLUSION: This trial demonstrated a dose response relationship for meloxicam 7.5, 15, and 22.5 mg using AUC measurement of response for the treatment of RA. All 3 doses of meloxicam. and positive control, were effective in the treatment of RA. The overall incidence rate of GI events did not differ significantly from placebo in either the meloxicam treatment groups or the positive control.""",1
10063,11914150,"Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?","BACKGROUND: Mefloquine is a clinically important antimalaria drug, which is often not well tolerated. We critically reviewed 516 published case reports of mefloquine adverse effects, to clarify the phenomenology of the harms associated with mefloquine, and to make recommendations for safer prescribing. PRESENTATION: We postulate that many of the adverse effects of mefloquine are a post-hepatic syndrome caused by primary liver damage. In some users we believe that symptomatic thyroid disturbance occurs, either independently or as a secondary consequence of the hepatocellular injury. The mefloquine syndrome presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs) may be related to the development of severe or prolonged adverse reactions to mefloquine. IMPLICATIONS: We believe that people with active liver or thyroid disease should not take mefloquine, whereas those with fully resolved neuropsychiatric illness may do so safely. Mefloquine users should avoid alcohol, recreational drugs, hormonal contraception and co-medications known to cause liver damage or thyroid damage. With these caveats, we believe that mefloquine may be safely prescribed in pregnancy, and also to occupational groups who carry out safety-critical tasks. TESTING: Mefloquine's adverse effects need to be investigated through a multicentre cohort study, with small controlled studies testing specific elements of the hypothesis.",1
10064,11917243,"Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987-1999","To examine trends in the proportions of deaths with various diseases among deaths with HIV infection, we analyzed multiple-cause death certificate data for all deaths in the United States from 1987 through 1999. Disease proportions were adjusted to control for demographic changes. Deaths reported with HIV infection increased from 15,331 in 1987 to 47,977 in 1995 and then decreased to 16,061 in 1999. Among these reported deaths, new trends during the period from 1995 through 1999 included decreases in the proportions with cytomegalovirus disease (from 6.8% to 2.8%), wasting/cachexia (9.8% to 6.8%), and dementia/encephalopathy (6.3% to 3.9%) and increases in the proportions with septicemia/septic shock (from 9.2% to 13.4%) and diseases of the liver (4.9% to 11.6%), kidney (6.3% to 9.1%), and heart (4.2% to 6.9%). Continuations of pre-1995 trends included decreases in the proportions with nontuberculous mycobacteriosis (7.1% to 3.1%) and Kaposi sarcoma (5.3% to 2.6%). Advances in antiretroviral therapy probably caused deaths due to HIV infection to decrease after 1995. Consequently, the proportions of deaths with HIV that were caused by other conditions increased. Improved prophylaxis or treatment of some opportunistic infections could also have reduced the proportions of deaths with those diseases, whereas antiviral drug toxicity could have contributed to increases in the proportions with noninfectious organ diseases.",1
10065,11920411,"A double-blind, randomized, placebo-controlled study of cevimeline in Sj�gren's syndrome patients with xerostomia and keratoconjunctivitis sicca","OBJECTIVE: To evaluate the safety and efficacy of 2 dosages of cevimeline for the treatment of xerostomia and keratoconjunctivitis sicca in patients with Sj�gren's syndrome. METHODS: A 12-week double-blind, randomized, placebo-controlled study was performed. Patients were randomly assigned to receive either placebo, 15 mg of cevimeline 3 times daily, or 30 mg of cevimeline 3 times daily. Patients were evaluated at baseline and throughout the study for their global assessment of dryness (mouth, eyes, overall) as well as their subjective assessment of the specific symptoms of dry mouth and dry eyes. Total saliva and tear flow also were measured. RESULTS: Patients taking 30 mg of cevimeline 3 times daily had statistically significant improvements in their subjective global assessment of dry eyes (P = 0.0453), dry mouth (P = 0.0004), and increased salivary flow (P = 0.007). Patients receiving the 30-mg dosage also showed greater objective improvement (increased salivary and lacrimal flow rates, as measured by Schirmer's test) than did patients receiving placebo. Frequently reported adverse events included headache, increased sweating, abdominal pain, and nausea. CONCLUSION: Treatment with cevimeline at a dosage of 30 mg 3 times daily resulted in substantive improvement by increasing the rate of saliva and tear flow in patients with Sj�gren's syndrome, as well as improving subjective symptoms of dry mouth, dry eyes, and overall dryness. The 15-mg dosage relieved some symptoms, and both dosages were well tolerated.",1
10066,11922592,Severe cholestatic hepatitis in a patient taking acitretin,,1
10067,11924761,Recent findings of green tea extract AR25 (Exolise) and its activity for the treatment of obesity,"The green tea extract AR25 is an 80% ethanolic dry extract standardized at 25% catechins expressed as epigallocatechin gallate (EGCG). In vitro, green tea extract AR25 exerts a direct inhibition of gastric and pancreatic lipases and a stimulation of thermogenesis. In an open study, the effects of extract AR25 were evaluated in moderately obese patients. After 3 months, body weight was decreased by 4.6% and waist circumference by 4.48%. These results suggest the green tea extract AR25 to be a natural product for the treatment of obesity, which exerts its activity by several ways: inhibition of lipases and stimulation of thermogenesis.",1
10068,11926717,An open-label trial of citalopram for major depression in patients with hepatitis C,"""BACKGROUND: Hepatitis C affects nearly 4 million Americans. Depression is a common comorbid condition in this population and may be induced by interferon alfa, an approved treatment for hepatitis C. Depression is a major indicator for discontinuation of interferon therapy. This open-label study examines the effect of citalopram on measures of depression and quality of life and tests of liver function in subjects with hepatitis C and major depressive disorder. METHOD: Subjects were recruited by advertisement; those with DSM-IV major depressive disorder were included in the study. Subjects received citalopram for 8 weeks starting at 20 mg/day. Dosage adjustments were made as the physicians deemed clinically necessary. No dosages were increased prior to week 4 of the study. Hamilton Rating Scale for Depression (HAM-D) scores, Clinical Global Impressions-Severity of Illness scale (CGI-S) scores, Medical Outcomes Study Short Form Health Survey (SF-36) ratings, Symptom Checklist-90-Revised (SCL-90-R) scores, and liver function tests were obtained at baseline, 4 weeks, and 8 weeks. RESULTS: A total of 15 patients (10 men, 5 women) participated in this study. The mean daily dose of citalopram at endpoint was 26.67 mg. Mean HAM-D scores decreased significantly with treatment (F = 36.3, df = 2,42; p = .0001). Thirteen of the 15 subjects demonstrated a clinical response, defined as a 50% or greater reduction in HAM-D scores. CGI-Severity of Illness scores also improved significantly (p = .0001). Subjects demonstrated statistically significant improvement (p < .05) on all of the SF-36 subscales. Statistically significant improvements (p < .05) were also demonstrated on all subscales of the SCL-90-R. Tests of liver function showed no significant worsening of aspartate aminotransferase, alanine aminotransferase, or gamma-glutamyltransferase levels. CONCLUSION: These results suggest that depression in patients with hepatitis C may be effectively and safely treated with citalopram.""",1
10069,11928077,Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease),"The term veno-occlusive disease of the liver refers to a form of toxic liver injury characterized clinically by the development of hepatomegaly, ascites, and jaundice, and histologically by diffuse damage in the centrilobular zone of the liver. The cardinal histologic features of this injury are marked sinusoidal fibrosis, necrosis of pericentral hepatocytes, and narrowing and eventual fibrosis of central veins. Recent studies suggest that the primary site of the toxic injury is sinusoidal endothelial cells, followed by a series of biologic processes that lead to circulatory compromise of centrilobular hepatocytes, fibrosis, and obstruction of liver blood flow. Thus we propose a more appropriate name for this form of liver injury--sinusoidal obstruction syndrome. This review encompasses historical perspectives, clinical manifestations of sinusoidal obstruction syndrome in the setting of hematopoietic cell transplantation, histologic features of centrilobular injury, and a discussion of the pathophysiology of sinusoidal injury, based on both animal and clinical investigations.",1
10070,11931510,Hepatotoxicity caused by Breynia officinalis,"Breynia officinalis has the Chinese proprietary name, Chi R Yun, which means dizziness or vertigo for 7 d. In daily practice, it has been used to treat venereal diseases, contusion, heart failure, growth retardation and conjunctivitis in combination with other traditional Chinese medicines. Two hospital-based cases of Breynia officinalis poisoning have been reported to the Poison Control Center. Case 1 was a 43-y-old female who consumed a mixture of 1500 g lower stem and root of Ji Mu Ju in boiled water in a suicide attempt. Her AST reached 264 and ALT reached 2443. Case 2 was a 51-y-old female who consumed 20 pieces of lower stem and root of Ji Mu Ju stewed with meat and 100 ml of wine to treat chronic contact dermatitis. Her AST reached 3815 and ALT reached 6625. In both cases Breynia officinalis was identified as the cause of poisoning. Poisoning in humans involves the neurologic, gastrointestinal, hepatic, urinary and respiratory systems. Hepatotoxic effects have been reported for some Chinese herbal medicines, but not Breynia officinalis: Breynia officinalis poisoning causes hepatocellular liver injury rather than cholestatic liver injury.",1
10071,11936716,Evaluation of isolated case reports on hepatotoxicity,,1
10072,11938071,[Severe acute hepatitis induced by alendronate],,1
10073,11941553,Hepatotoxicity associated with antiretroviral therapy containing dual versus single protease inhibitors in individuals coinfected with hepatitis C virus and human immunodeficiency virus,"To determine the rates of patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who discontinued therapy as a result of protease inhibitor (PI)-related hepatotoxicity, a retrospective review was conducted. Baseline CD4 counts, plasma HIV RNA levels, and duration of therapy were comparable between single- and dual-PI-treated subjects and between subjects receiving ritonavir-containing therapy and those receiving ritonavir-sparing therapy. The proportions of patients with elevations in alanine aminotransferase level to > or =5 times the upper limit of normal (19% versus 26%) and hyperbilirubinemia (30% versus 38%) were similar between the dual-PI (n=27) and single-PI treatment groups (n=39), respectively. No difference in these characteristics was observed between ritonavir-containing (n=34) and ritonavir-sparing (n=32) treatment arms. Rates of treatment discontinuation due to hepatotoxicity were similar for single-PI and dual-PI therapy and for ritonavir-containing and ritonavir-sparing regimens. Dual-PI therapy and inclusion of ritonavir do not seem to increase the rates of hepatotoxicity in PI-treated, HIV-HCV coinfected subjects.",1
10074,11941968,Metronidazol as a probable cause of severe liver injury,"""Metronidazol, a commonly used antibiotic drug, has been very rarely associated with hepatotoxicity. In particular, no reports have appeared in the literature about cases of metronidazol-associated severe hepatotoxicity, leading to liver transplantation or death. We report on a case of acute fulminant liver failure in a young woman, who had, two years previously, developed jaundice after intake of metronidazol. During the current hospitalization, metronidazol treatment had been undertaken two weeks previously and also this time the patient developed severe hepatocellular injury and cholestasis. A viral etiology was ruled out as well as vascular, metabolic and malignant etiology. Although, the cause of the liver injury in this case is not proven, the relationship between this drug and two occasions of severe liver damage, suggests a positive challenge as well as rechallenge. An International algorithm was used for the assessment of the causality of a drug in this case of acute liver injury and a """"probable"""" classification was obtained.""",1
10075,11943262,Genetic variations in HLA-B region and hypersensitivity reactions to abacavir,"Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.",1
10076,11951073,Drug-induced liver damage -- a three-year study of patients from one gastroenterological department,"BACKGROUND: The aim of our study was to analyze drug-induced liver disease over a 3-year period in one gastroenterological department. MATERIAL/METHODS: International consensus standard definitions and criteria for assessing causality of adverse drug reactions were applied to all patients with abnormal hepatic test results. RESULTS: Drugs were implicated in hepatic injury in 14 patients (8 females) in whom causal relationship between drug and liver disease was definite or highly probable. The drugs responsible were amoxicillin with clavulanic acid (3 cases), fluvastatin and pravastatin (3 cases), antituberculous drugs (2 cases), estrogens, roxithromycin, asacol, satolol, enalapril and thiamazol. A total of 78.6% (11 cases) were classified as hepatocellular or mixed hepatitis, while cholestatic injury was found in 21.4% (3 cases). There were no lethal or severe (prothrombin < 50%) hepatic drug reactions. In 13 patients the course of liver disease after withdrawal of the offensive drug was either acute or protracted, while in one patient there was chronic cholestasis (>3 years) resulting from injury to interlobular bile ducts by amoxicllin with clavulanic acid. CONCLUSIONS: A thorough history of drug intake should be taken in all patients presenting with abnormal hepatic test results. Amoxicillin & clavulanic acid, cholesterol-lowering and antituberculin drugs were the most frequent hepatotoxic factors in our patients. In a majority of cases the liver injury was not severe, and resolved after prompt withdrawal of the responsible drug.",1
10077,11951124,Hepatic safety of itraconazole,"BACKGROUND: As the use of the newer oral antifungal agents for the treatment of superficial fungal infections becomes more widespread, the issue of safety surrounding their use is becoming an increasingly important consideration. Itraconazole is effective and well tolerated, with most side effects being minor and reversible. The most common adverse events are gastrointestinal upset, headache, and transient skin reaction. There have also been rare reports of hepatitis. OBJECTIVE: To assess the hepatic safety of pulse and continuous itraconazole in the treatment of onychomycosis. METHODS: An analysis was performed on all itraconazole clinical trials sponsored by Janssen Research Foundation in the treatment of onychomycosis, where there was an assessment of laboratory safety. A review of the published literature was also undertaken to assess the hepatic safety of itraconazole in common practice. RESULTS: The data indicate that itraconazole pulse treatment is safe, with no significant differences in the number of code 4 abnormalities (baseline value is in the normal range and at least two values, or the last testing in the observation period, exceed twice the upper limit of normal) in the liver function parameters studied: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. The incidence of all the code 4 abnormalities was below 2%. In the literature there are reports of symptomatic hepatitis with itraconazole continuous therapy but no published report of symptomatic hepatotoxicity using the pulse regimen. CONCLUSIONS: Itraconazole pulse therapy for onychomycosis appears to be safe, especially from the perspective of potential liver damage. In the itraconazole package insert liver function tests are recommended for patients receiving continuous itraconazole for periods of time exceeding 1 month. There is no such monitoring requirement for the pulse regimen unless the patient has a history of underlying hepatic disease, the liver function tests are abnormal at baseline, or at any time that there is the development of signs or symptoms suggestive of liver dysfunction.",1
10078,11955027,Severe hepatotoxicity associated with the dietary supplement LipoKinetix,"BACKGROUND: LipoKinetix (Syntrax, Cape Girardeau, Missouri) is a dietary supplement marketed for weight loss. OBJECTIVE: To describe a possible causal association between LipoKinetix and hepatotoxicity. DESIGN: Case series. SETTING: Outpatient clinic, tertiary care hospital, and U.S. Food and Drug Administration databases. INTERVENTION: Routine medical and supportive care. MEASUREMENTS: Clinical and laboratory evaluation. RESULTS: All patients developed acute hepatotoxicity within 3 months of starting LipoKinetix. At presentation, symptoms and results of laboratory tests were characteristic of acute hepatitis. All patients recovered spontaneously after LipoKinetix use was discontinued. Three of the seven patients, including one who developed fulminant hepatic failure complicated by cerebral edema, were taking LipoKinetix alone at the time of presentation. Of the four patients who were taking multiple supplements, two resumed taking supplements other than LipoKinetix without incident. CONCLUSIONS: The use of LipoKinetix may be associated with hepatotoxicity. Despite extensive evaluations, no other cause for hepatotoxicity could be identified in the seven patients studied.",1
10079,11955534,Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study,"BACKGROUND: Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis. Although results of studies have shown the efficacy of such drugs, including methotrexate, on rheumatoid arthritis morbidity measures, their effect on mortality in patients with the disease remains unknown. Our aim was to prospectively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis. METHODS: Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. We also obtained and recorded demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3.5 months). We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model. FINDINGS: 191 individuals died during follow-up. Patients who began treatment with methotrexate (n=588) had worse prognostic factors for mortality. After adjustment for this confounding by indication, the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0.4 (95% CI 0.2-0.8). Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality. The hazard ratio of methotrexate use for cardiovascular death was 0.3 (0.2-0.7), whereas that for non-cardiovascular deaths was 0.6 (0.2-1.2). INTERPRETATION: Our data indicate that methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease-modifying antirheumatic drugs could be compared.",1
10080,11957564,Allopurinol hypersensitivity syndrome and acute myocardial infarction--two case reports,"""INTRODUCTION: Allopurinol hypersensitivity syndrome is an idiosyncratic drug reaction characterised by an acute and severe multiorgan disease. It usually begins 2 to 6 weeks after starting allopurinol. The most important and critical characteristics are the presence of visceral involvement and haematological abnormalities; hepatitis, interstitial nephritis and eosinophilia are most frequently seen. However, cardiac involvement has not been previously reported. CLINICAL PICTURE: Two previously well young Chinese men presented with fever, rash and hepatitis 3 weeks after taking allopurinol. The clinicopathological presentation was typical of allopurinol hypersensitivity syndrome. TREATMENT AND OUTCOME: Both men received systemic corticosteroid therapy and had full recovery. A few months later, they each had an acute myocardial infarction with a fatal outcome, despite minimal cardiac risk factors and no family history of coronary artery disease. CONCLUSION: The immunologic process in allopurinol hypersensitivity syndrome may have caused coronary vasculitis and subsequent myocardial infarct. Alternatively, the idiosyncratic reaction may have damaged myocardium, with the resultant myocarditis masquerading as coronary artery disease. Patients with allopurinol hypersensitivity syndrome should be followed up for cardiac involvement.""",1
10081,11960076,Losartan-induced hepatic injury,"Losartan, an angiotensin II receptor antagonist, is widely used for the treatment of hypertension. Clinical experience with this drug has demonstrated that it is safe. Losartan-induced hepatic toxicity is extremely rare. We report a case of severe hepatic toxicity and fibrosis caused by losartan use, and we review four previously reported cases. Drug-induced hepatic injury may be seen during the treatment of hypertension by losartan and the clinician should be aware of this toxicity, especially during the initial phase of treatment.",1
10082,11970768,Acute and long-term toxicities associated with gemtuzumab ozogamicin (Mylotarg) therapy of acute myeloid leukemia,"""Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells that express CD33 by means of a humanized anti-CD33 monoclonal antibody conjugated to a modified antitumor antibiotic, calicheamicin. The effects of gemtuzumab ozogamicin (given intravenously at a dose of 9 mg/m2 for 2 doses separated by 2 weeks) have been evaluated in 3 phase II studies involving patients (n = 188) with acute myeloid leukemia (AML) in first relapse. Interim analysis has revealed that 30% of patients achieved remission, characterized by < or = 5% blasts in the marrow, neutrophil count > or = 1500/microL, hemoglobin > or = 9 g/dL, and independence from red blood cell and platelet transfusion. Grade 3/4 acute toxicities included nausea or vomiting (11%); elevated serum aminotransferase enzyme (16%) and bilirubin (26%) levels; and infusion-related chills (9%), fever (6%), and hypotension (5%). As predicted with CD33-targeted therapy, most patients had neutropenia (98%) and thrombocytopenia (99%). However, the incidence of grade 3/4 bleeding events (14%) and infection rates (pneumonia, 7%; sepsis, 15%) was low. No patients were reported to have treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Veno-occlusive disease (VOD) after gemtuzumab ozogamicin treatment (but prior to other therapies) occurred in 2% of patients (4/188), and the VOD-related death rate was < 1% (1/188). Prior hematopoietic stem cell transplant may be a risk factor for VOD (P = 0.002, univariate analysis). Gemtuzumab ozogamicin is a safe and effective treatment in carefully selected patients with AML in first relapse.""",1
10083,11975873,[Toxic hepatitis associated with tamoxifen use. A case report and literature review],"Tamoxifen is an antiestrogenic drug that acts by binding to the estrogen receptor. The drug is used as a co-adjuvant treatment in advanced breast cancer expressing the oestrogen-receptor protein. Clinical trials of tamoxifen have shown its efficacy in reducing mortality and recurrence rates over a five-year treatment. Cases of tamoxifen-associated hepatotoxicity have been described, including cholestasis with or without cytolysis and steatohepatitis. We report the case of a female patient who developed hepatic alterations while undergoing continuous tamoxifen treatment. We also present an overview of similar cases published to date and comment on the advisability of continuing or suppressing this treatment in patients with hepatotoxicity or after a five-year treatment period.",1
10084,11978164,Ziprasidone: the fifth atypical antipsychotic,"""OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of ziprasidone as a treatment for schizophrenia. DATA SOURCES: Information was selected from a MEDLINE search (July 2000-October 2001) of English-language medical literature using ziprasidone as the search term. Manual searches of pertinent journal article references, request for medical information from Pfizer, and access of the Web site of the Food and Drug Administration were also performed. STUDY SELECTION: All available published information regarding the pertinent characteristics of ziprasidone were considered for selection. DATA EXTRACTION: Pharmacology and pharmacokinetic studies were selected to provide a comprehensive description of these characteristics. Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. DATA SYNTHESIS: Ziprasidone is a benzisothiazolyl piperazine-type atypical antipsychotic that shares the serotonin(2A)/dopamine(2) (5-HT(2A)/D(2)) profile of the available atypical antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT(1A) receptor agonist and as a very weak inhibitor of serotonin and norepinephrine reuptake. These data do not support ziprasidone as being a clinically meaningful inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6-7 hours, and protein binding is extensive at >99%. Twelve metabolites have been identified, yet only 4 of these are considered to be primary metabolites. Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with potential pharmacologic activity; CYP3A4 also contributes to the metabolism of ziprasidone. Clinical studies support ziprasidone as efficacious for the treatment of patients with acute exacerbations of schizophrenia or schizoaffective disorder. Daily doses permitted in these clinical trials ranged from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to placebo. Future research efforts should be directed toward refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse effect characteristics of ziprasidone commonly include headache, nausea, and somnolence; infrequent effects include extrapyramidal symptoms and weight gain. Ziprasidone has been reported to cause an average QTc prolongation of approximately 20 msec; there have only been 2 patients (0.06%) reported by the manufacturer to have a measured QTc interval >500 msec. CONCLUSIONS: Ziprasidone is a safe and efficacious atypical antipsychotic for the acute management of schizophrenia. Efficacy data and most safety data for ziprasidone support its use as a first-line treatment for schizophrenia; however, its potential effects on ventricular repolarization relegate it to second-line status in patients with comorbid cardiovascular risks.""",1
10085,11978674,Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction,"OBJECTIVE: Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class. RESEARCH DESIGN AND METHODS: This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised > 6,000 patients aged 30-80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6- to 12-week intervals thereafter. Patients with at least one on-therapy ALT value >3 times the upper limit of the reference range were identified, and their case records examined in detail. RESULTS: At baseline, 5.6% of the patients with type 2 diabetes (mean HbA(1c) 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients ( approximately 83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value >3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulin-treated 0.40%. The respective rates of ALT values >3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64. CONCLUSIONS: No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 person-years. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-gamma agonist class effect. Poorly controlled patients with type 2 diabetes may have moderate elevations of serum ALT that will decrease with improved glycemic control during treatment with rosiglitazone or other antihyperglycemic agents.",1
10086,11983042,Acetaminophen toxicity: suicidal vs. accidental,"INTRODUCTION: Acetaminophen toxicity, which can lead to hepatotoxicity, is a burden on our health care system and contributes significantly to intensive care unit admissions and cost of hospitalization. The aim of our study was to determine the epidemiology of various types of acetaminophen poisoning and analyze their outcome compared with their admission characteristics. METHODS: We identified 93 consecutive patients, hospitalized for acetaminophen toxicity over a 52-month period from 1996 to 1999 in our urban county hospital. Retrospective case-control analysis was carried out using the data obtained from the medical records. RESULTS: Acetaminophen accounted for 7.5% of all cases of poisoning admitted during this period. Of the 93 patients, 80 were classified as suicidal and 13 had accidentally poisoned themselves in an attempt to relieve pain. The ratio of females to males was found to be 2:1. Of the 93 patients studied, 88 were admitted to the intensive care unit for initial 24-48 hours of monitoring. Peak acetaminophen levels were higher in the suicidal overdose group (mean 121.7 +/- 97.0 mg/l vs. 64.5 +/- 61.8 mg/l, P < 0.05) than in the accidental group. In spite of this, peak aminotransferase levels >1000 IU/l were more often seen in the latter (39% vs. 12%, P < 0.05). Hepatic coma and death were seen more often in the accidental overdose group (15% vs 0%, P < 0.05). Interestingly chronic alcohol abuse was also more frequent in the accidental overdose category (39% vs 18%, P = 0.05). DISCUSSION: Although the peak acetaminophen level in the suicidal group was significantly higher, cases of therapeutic misadventure had higher rates of morbidity and mortality. Peak acetaminophen levels correlate poorly with hepatic dysfunction, morbidity and mortality. CONCLUSION: We recommend that the patients with suicidal acetaminophen overdose, without any concomitant poisoning, can safely managed on the medical floors.",1
10087,11985370,Severe liver damage on terbinafine,,1
10088,11986204,Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study,"""Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.""",1
10089,11989110,[Ticlopidine-induced hepatitis. Report of a new case],,1
10090,11989525,Efficacy and safety of Herceptin in women with metastatic breast cancer: results from pivotal clinical studies,"Amplification of the human epidermal growth factor receptor-2 (HER2) gene and overexpression of the encoded protein are seen in 20-30% of breast cancers, and are associated with aggressive disease and relatively poor prognosis. Thus, HER2 represents an appropriate target for anticancer treatment and the humanized anti-HER2 monoclonal antibody Herceptin has been developed for this purpose. The efficacy of Herceptin has been confirmed in two pivotal trials-a monotherapy study in 222 women with HER2-positive metastatic breast cancer who had already received one or two chemotherapy regimens for metastatic disease and a study comparing Herceptin plus chemotherapy with chemotherapy alone in 469 patients previously untreated for metastatic disease. Herceptin monotherapy was associated with longer median response duration and survival than previous chemotherapy. Addition of Herceptin to chemotherapy increased response rates, time to disease progression and survival duration. Benefit was greatest in patients with high-level HER2 overexpression. Herceptin was well tolerated, with mild to moderate infusion-related reactions, usually seen with the first infusion only, being the most common event. Most patients respond to conventional supportive treatment. Cardiotoxicity, the most serious adverse event observed, occurred mainly in patients exposed to anthracyclines and was generally manageable. Thus, Herceptin represents a significant development in the management of HER2-positive breast cancer.",1
10091,11990713,Phase I study of irinotecan in pediatric patients with malignant solid tumors,"PURPOSE: To determine the dose-limiting toxicity, maximum tolerated dose, and potential efficacy of irinotecan in children with refractory malignant solid tumors. PATIENTS AND METHODS: In the present phase I clinical trial, 28 patients received irinotecan 50 to 200 mg/m2 per day by intravenous 2-hour infusion over the course of 3 days, repeated once after an interval of 25 days. Fifty-one treatment courses were administered to these patients. RESULTS: Dose-limiting toxicities were observed at the dose of 200 mg/m2 per day for 3 days. Diarrhea and hematopoietic toxicities were the dose-limiting factors, and the former required support with intravenous fluid administration. The occurrence of vomiting was variable. Decreases in clinical tumor marker levels were observed in the majority of patients who received two cycles of irinotecan 80 mg/m2 per day to 200 mg/m2 per day over the course of 3 days, and partial response was attained in four patients who received irinotecan in two cycles of 140 mg/m2 per day to 200 mg/m2 per day over the course of 3 days. Pharmacokinetic studies showed that the plasma concentration of irinotecan and its active metabolite SN-38 ranged from 93 to 2,820 ng/mL and 5.2 to 34.8 ng/mL, respectively, during 3-day infusions of irinotecan 200 mg/m2 per day. The mean clearance of irinotecan was 14.54 L/h per m2 (range 8.45-20.83 L/h per m2). CONCLUSION: The maximum tolerated dose was determined to be a dose of irinotecan between 160 mg/m2 per day and 180 mg/m2 per day administered over the course of 3 consecutive days on an inpatient basis, repeated once after 25 days off, and our results indicate that irinotecan is a promising anticancer agent that is worthy of phase II trials in pediatric solid tumors.",1
10092,11994179,Anticonvulsant hypersensitivity syndrome,"Anticonvulsant hypersensitivity syndrome is an acute, life-threatening, idiosyncratic drug reaction seen with the aromatic antiepileptic drugs, phenytoin, carbamazepine, phenobarbital, and primidone, with frequent cross sensitivity. It usually occurs 2-8 weeks after initiation of therapy and the hallmark clinical features are fever, rash, and lymphadenopathy. Hematologic abnormalities such as eosinophilia, atypical lymphocytes, and internal organ involvement also occur with varying severity. A case of hypersensitivity syndrome due to carbamazepine with cross sensitivity to phenytoin is reported. It is emphasized that this serious drug reaction with diverse clinical presentations should be recognized and treated promptly.",1
10093,12001285,Amphotericin B-induced hepatorenal failure in cystic fibrosis,"Although nephrotoxicity is a common and well-recognized side effect of amphotericin B, hepatotoxicity is rare. We report on a 9-year-old girl with cystic fibrosis who developed fulminant renal and hepatic dysfunction following a short course of intravenous amphotericin B for a suspected aspergillus infection, although she did not have clinical evidence of invasive aspergillosis. The toxicity became apparent after changing to liposomal amphotericin. This association of renal and hepatotoxicity with liposomal amphotericin B has not previously been reported in children.",1
10094,12004282,Budesonide-induced acute hepatitis in an HIV-positive patient with ritonavir as a co-medication,,1
10095,12006469,Death associated with rifampin and pyrazinamide 2-month treatment of latent mycobacterium tuberculosis,We present the case of an elderly patient who died of fulminant hepatic failure in the course of receiving 2 months of treatment with pyrazinamide and rifampin for his latent tuberculosis. This 2-month course of treatment for latent tuberculosis is one of four options recently recommended by the Centers for Disease Control and Prevention. We discuss the safety of using this two-drug regimen to treat latent tuberculosis in stable elderly patients.,1
10096,12011756,Pegfilgrastim (Neulasta) for prevention of febrile neutropenia,,1
10097,12014728,Prevalence and interaction of hepatitis B and latent tuberculosis in Vietnamese immigrants to the United States,"OBJECTIVES: Southeast Asian immigrants, with a high prevalence of both hepatitis B and latent tuberculosis, constitute a large proportion of immigrants to the United States. Isoniazid hepatotoxicity may be associated with hepatitis B. This study was conducted to document the prevalence and interaction of hepatitis B, latent tuberculosis, and isoniazid toxicity. METHODS: Hepatitis B surface antigen (HBsAg) and tuberculin skin testing was done on 743 Vietnamese immigrants to the Midwest between January, 1991 and December, 1999. HBsAg positive cases were tested for hepatitis B e antigen (HBeAg). All tuberculin skin test-positive patients were treated with isoniazid, unless contraindicated. Complications of isoniazid treatment and compliance with hepatitis B virus immunization recommendations were evaluated. RESULTS: One hundred three subjects (13.86%) had HBsAg, and 43 (5.7%) HBeAg. Prevalences of latent tuberculosis were similar in HBsAg positive (53%) and HBsAg negative (45%) subjects. Sixty-two percent of HBeAg positive versus 19% of HBeAg negative subjects had hepatotoxic side effects requiring discontinuation of treatment (relative risk [RR] = 11.38, CI = 5.49 < RR < 23.59, p < 0.001). Three cases of severe isoniazid hepatitis occurred in 21 HBeAg positive subjects, versus no cases in 121 HBeAg negative cases treated with isoniazid (RR = 7.72, CI = 5.02 < RR < 11.88, p < 0.001). Only 58% of subjects at risk of developing hepatitis B virus infection were appropriately immunized. CONCLUSIONS: Vietnamese immigrants have a high prevalence of hepatitis B and latent tuberculosis. HBeAg positive cases have a 7.7-fold increased risk of serious isoniazid toxicity and an 11.3-fold increased risk of isoniazid side effects requiring discontinuation of treatment. HBeAg represents an important risk factor for severe isoniazid hepatitis.",1
10098,12016548,"Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs","""Hepatotoxic adverse drug reactions have contributed to the decline of many promising therapies, even among mainstream medication classes (bromfenac and troglitazone are recent examples). The spectrum of nonsteroidal anti-inflammatory drug-related liver toxicity continues to expand, with reports in children, interactive toxicity in persons with hepatitis C, and recognition of the toxicity of both the preferential and selective cyclooxygenase-2 inhibitors. Of the antihypertensive agents, methyldopa is now rarely prescribed and adverse effects are reported infrequently, whereas cases of liver injury associated with the angiotensin receptor and converting enzyme inhibitors are increasingly reported. Of the antidiabetic agents, acarbose, gliclazide, metformin, and human insulin have been implicated in causing liver injury. To date, the newer thiazolidinediones do not appear to share the hepatotoxic potential of troglitazone, although a few reports of acute hepatitis have accrued. Although liver injury has been associated with the """"statins,"""" the frequency of such toxicity is lower than that of the background population and the value of biochemical monitoring remains unproved. Newer concepts in anticonvulsant hepatotoxicity have been the recognition of the reactive metabolite syndrome, delineation of the risk factors for valproic acid toxicity, the potential role of carnitine in preventing valproic acid hepatotoxicity, and the toxicity of second-line antiepileptic drugs. Liver injury associated with newer psychotropic agents, particularly the selective serotonin reuptake inhibitors, is also discussed. The focus of the review is the hepatotoxicity of commonly used drugs with particular reference to recent and novel reports of toxicity. Well-known causes of liver injury such as chlorpromazine, phenytoin, and methyldopa are not discussed.""",1
10099,12016550,Herbal hepatotoxicity,"""Herbal hepatotoxicity is increasingly recognized as herbal medicines become more popular in industrialized societies. Some herbal products may potentially benefit people with liver disease; however, these benefits remain generally unproved in humans, and a greater awareness of potential adverse effects is required. Herbal use is often not disclosed, and this may result in a diagnostic delay and perpetuation or exacerbation of liver injury. Female gender may predispose to hepatotoxicity, and concomitant agents that induce cytochrome P450 enzymes may also increase individual susceptibility. The range of liver injury includes minor transaminase elevations, acute and chronic hepatitis, steatosis, cholestasis, zonal or diffuse hepatic necrosis, hepatic fibrosis and cirrhosis, veno-occlusive disease, and acute liver failure requiring transplantation. In addition to the potential for hepatotoxicity, drug-drug interactions between herbal medicines and conventional agents may affect the efficacy and safety of concurrent medical therapy. This review focuses on emerging hepatotoxins and patterns of liver injury, potential risk factors for herbal hepatotoxicity, and herb-drug interactions. Appropriate reporting and regulatory systems to monitor herbal toxicity are required, in conjunction with ongoing scientific evaluation of the potential benefits of phytotherapy.""",1
10100,12021218,Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project,"""BACKGROUND: Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. METHODS AND RESULTS: The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3x the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. CONCLUSIONS: This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.""",1
10101,12021934,COX-2 inhibitor (nimesulide) induced acute liver failure,,1
10102,12027060,Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV,"""The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced substantial complexity into treatment regimens for persons infected with human immunodeficiency virus (HIV). In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for clinical management of HIV-infected adults and adolescents (CDC. Report of the NIH Panel To Define Principles of Therapy of HIV Infection and Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998;47[RR-5]:1-41). This report, which updates the 1998 guidelines, addresses 1) using testing for plasma HIV ribonucleic acid levels (i.e., viral load) and CD4+ T cell count; 2) using testing for antiretroviral drug resistance; 3) considerations for when to initiate therapy; 4) adherence to antiretroviral therapy; 5) considerations for therapy among patients with advanced disease; 6) therapy-related adverse events; 7) interruption of therapy; 8) considerations for changing therapy and available therapeutic options; 9) treatment for acute HIV infection; 10) considerations for antiretroviral therapy among adolescents; 11) considerations for antiretroviral therapy among pregnant women; and 12) concerns related to transmission of HIV to others. Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. Treatment should be offered to persons who have <350 CD4+ T cells/mm3 or plasma HIV ribonucleic acid (RNA) levels of >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase-polymerase chain reaction [RT-PCR] assays). The recommendation to treat asymptomatic patients should be based on the willingness and readiness of the person to begin therapy; the degree of existing immunodeficiency as determined by the CD4+ T cell count; the risk for disease progression as determined by the CD4+ T cell count and level of plasma HIV RNA; the potential benefits and risks of initiating therapy in an asymptomatic person; and the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. Treatment goals should be maximal and durable suppression of viral load, restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. Results of therapy are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0 log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months after treatment initiation. Failure of therapy at 4-6 months might be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Patients whose therapy fails in spite of a high level of adherence to the regimen should have their regimen changed; this change should be guided by a thorough drug treatment history and the results of drug-resistance testing. Because of limitations in the available alternative antiretroviral regimens that have documented efficacy, optimal changes in therapy might be difficult to achieve for patients in whom the preferred regimen has failed. These decisions are further confounded by problems with adherence, toxicity, and resistance. For certain patients, participating in a clinical trial with or without access to new drugs or using a regimen that might not achieve complete suppression of viral replication might be preferable. Because concepts regarding HIV management are evolving rapidly, readers should check regularly for additional information and updates at the HIV/AIDS Treatment Information Service website (http://www.hivatis.org).""",1
10103,12034651,Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia,"""BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.""",1
10104,12039422,"A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson's disease","BACKGROUND: To the extent that excitotoxicity may play a role in the pathogenesis of certain neurodegenerative disorders, antagonists of glutamate, an excitatory neurotransmitter, should exert neuroprotective effects in these disorders, including Parkinson's disease (PD). METHODS: Patients in early stages of PD, not previously treated with levodopa, were randomized to receive riluzole 50mg capsules orally, taken twice daily or a matching placebo. All subjects were evaluated at baseline (pre-treatment), at 1, 3 and 6 months (post-treatment), and following a 6-week washout. After the washout, all subjects were offered an enrollment in an open label, 1-year, extension study. The principal investigator (JJ), however, remained blinded to the original assignment during the entire study. The patients were assessed by the Unified Parkinson's Disease Rating Scale (UPDRS), Activities of Daily Living (ADL), Hoehn & Yahr (HY) stage, and Schwab and England (SE) ADL scale. The quantitative assessments included Movement Time (MT) and Reaction Time (RT). Additionally, the time to initiate dopaminergic therapy was assessed. Safety was determined at each visit by clinical history and examination, a panel of blood safety laboratory tests including complete blood count, chemistry profile, and liver function studies. RESULTS: Twenty patients with a mean age of 62+/-9.02 (range: 46-73) years and mean duration of symptoms of 18+/-9.53 (range: 6-36) months were enrolled. One patient withdrew from the study because he needed more aggressive treatment of his symptoms. Analysis of the efficacy variables showed no meaningful symptomatic effect of riluzole on UPDRS score. Likewise, there was no significant change in the median HY stage, SE ADL rating, or the MT/RT. Seventeen patients (mean age 62+/-9.26) elected to continue in the open label extension study. Although the observed deterioration in UPDRS scores seemed to be more pronounced in the placebo group than in the riluzole group, the difference did not reach statistical significance. There was no statistically significant difference in the latency between enrollment and start of symptomatic therapy when patients initially treated with riluzole were compared to those initially treated with placebo (8.3 vs 9 months). CONCLUSIONS: This pilot and extension study showed that riluzole, 100mg/day, was well tolerated in patients with early PD. No evidence of symptomatic effect of riluzole was observed. Because of the exploratory nature of the design and small size of the study, it was not possible to determine whether riluzole affected the natural history of PD. The encouraging results from our study, however, suggest that larger, longitudinal studies are warranted.",1
10105,12043957,Progressive cholestatic liver disease associated with clarithromycin treatment,"The authors report a case of an acute toxic cholestatic reaction to clarithromycin, proven by liver biopsy, in a patient with comorbid diseases, prior exposure to erythromycin and ultimate death. No autopsy was performed. A 59-year-old woman with diabetes mellitus and chronic renal insufficiency received clarithromycin 500 mg twice daily for 3 days for acute maxillary sinusitis and then developed a rash and jaundice. She was hospitalized 11 days after stopping clarithromycin. Progressive cholestatic jaundice accompanied by oligo-anuric renal failure requiring hemodialysis ensued. Liver biopsy showed pure bilirubinostasis without parenchymal inflammation. On the 22nd hospital day, after clinical deterioration, she died from an apparent cardiopulmonary death. This is the first report in the literature of a fatality associated with a short-term, low (1 g) daily dose of drug-induced pure cholestasis, an entity not previously identified with severe drug-induced hepatotoxicity.",1
10106,12044412,Safety concerns about kava,,1
10107,12048364,Role of hepatitis C virus genotype in the development of severe transaminase elevation after the introduction of antiretroviral therapy,"""OBJECTIVE: To assess the role of different hepatitis C virus (HCV) genotypes in the development of transaminase elevation after treatment with highly active antiretroviral therapy (HAART). DESIGN: Retrospective cohort study at one referral HIV outpatient clinic. METHODS: HCV genotype was determined in plasma samples from all consecutive HCV-HIV coinfected patients initiating HAART between March 1998 and January 2000. Clinical and laboratory data were recorded during the following 9 months. Severe transaminase elevation was defined as > or = fivefold increase over upper normal limits (AIDS Clinical Trials Group grades 3 or 4) when baseline alanine transaminase (ALT) and aspartate transaminase (AST) values were normal, and as > or = 3.5-fold increase above baseline ALT and AST values if they were abnormal. RESULTS: Twelve of 70 subjects (17%) developed severe transaminase elevation. Their HCV genotypes were distributed as follows: type 1, 5/39 (13%); type 2, 0/3 (0%); type 3, 7/21 (33%); and type 4, 0/7 (0%). The incidence of severe transaminase elevation was significantly higher among subjects with HCV genotype 3 (HCV-3) compared with those with non-type 3 (OR, 4.4 [95%CI, 1.2-16.1]; P =.02). In the multivariate analysis, HCV-3 remained associated with severe transaminase elevation when adjusted for baseline HCV viral load and degree of immune recovery seen during follow-up evaluation. CONCLUSIONS: HCV-3 is an independent risk factor for developing severe transaminase elevation after HAART. HCV genotyping before initiating antiretroviral therapy may be useful for assessing the risk of hepatotoxicity and for choosing the most appropriate drugs to prescribe for HIV-HCV coinfected patients. Given that the best response to interferon plus ribavirin occurs in patients with HCV-3, treatment should be specially encouraged in coinfected persons carrying HCV-3.""",1
10108,12056704,"Phase I, dose-finding study of capecitabine in combination with docetaxel and epirubicin as first-line chemotherapy for advanced breast cancer","PURPOSE: Capecitabine is an oral fluoropyrimidine with considerable activity and minimal myelosuppression and alopecia. This phase I study evaluated the addition of capecitabine to epirubicin/docetaxel combination therapy as first-line treatment for advanced breast cancer. PATIENTS AND METHODS: Twenty-three female patients with advanced breast cancer received capecitabine (765-1060 mg/m2 twice daily on days 1-14 of a 3-week treatment cycle) in combination with epirubicin and docetaxel (75 mg/m2 i.v. on day 1). RESULTS: The maximum tolerated dose of capecitabine was 985 mg/m2 and the principal dose-limiting toxicity was febrile neutropenia. No grade 3/4 anemia or thrombocytopenia occurred. There were no grade 4 non-hematological events and grade 3 events other than alopecia were rare. Alopecia occurred in all patients and treatment cycles, and asthenia occurred in all patients and in 84% of treatment cycles. Other frequent adverse events included nausea, vomiting, fever, paresthesia and elevated transaminase levels. An objective response to treatment was observed in 91% (95% confidence interval 72% to 99%) of patients. CONCLUSIONS: The addition of capecitabine to docetaxel/epirubicin combination therapy provides a well-tolerated and active first-line chemotherapy regimen in patients with advanced breast cancer, and merits phase II/III evaluation.",1
10109,12057729,"Comparison of the efficacy and safety of a highly purified human follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta for in vitro fertilization: a prospective, randomized study","""OBJECTIVE: To compare the efficacy and safety of Bravelle s.c., Bravelle i.m., and Follistim s.c. in patients undergoing controlled ovarian hyperstimulation for IVF-ET. DESIGN: Open-label, randomized, parallel group, multicenter study. SETTING: Eleven academic and private fertility clinics with experience in IVF-ET. PATIENT(S): Infertile premenopausal women with regular ovulatory menstrual cycles undergoing IVF-ET. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of Bravelle s.c. (n = 60), Bravelle i.m. (n = 59), or Follistim s.c. (n = 58); hCG administration, oocyte retrieval, and ET. MAIN OUTCOME MEASURE(S): Mean number of oocytes retrieved; patients with ET, chemical, clinical and continuing pregnancies; mean peak serum E2 levels; adverse events and injection site pain scores. RESULT(S): There were no significant differences among treatment groups in mean number of oocytes retrieved, peak serum E2 levels, patients with ET, continuing pregnancies, or live births. There were no significant differences among the treatment groups in the number, nature, or intensity of adverse events. Patients treated with Bravelle s.c. or Bravelle i.m. experienced significantly less injection site pain than patients treated with Follistim s.c. CONCLUSION(S): Bravelle s.c. and Bravelle i.m. are comparable in efficacy and safety to Follistim s.c. in patients undergoing controlled ovarian hyperstimulation for IVF-ET.""",1
10110,12058881,Tamoxifen-induced nonalcoholic steatohepatitis in breast cancer patients treated with adjuvant tamoxifen,"OBJECTIVE: The benefits of 5-year tamoxifen administration for patients with estrogen receptor-positive breast cancer undoubtedly outweigh the risk of any adverse effects. Massive hepatic steatosis is an example of its side effects. Here we show risk factors for the development of massive hepatic steatosis and describe a representative clinical course of these patients treated with fibrates for the first time. METHODS: Computed tomography (CT) numbers of the liver and spleen were measured and correlated to body mass index (BMI) and pregnanetriol/pregnanediol ratio in urine (P3/P2 ratio). PATIENTS: We enrolled 56 premenopausal women treated with breast conservation treatment. They received oral tamoxifen (40 mg/day for 2 to 3 years) as adjuvant endocrine therapy with systemic chemotherapy. RESULTS: Serum estradiol level in 48 of 56 patients treated with tamoxifen was less than 10 pg/ml. The ratio of hepatic CT number to splenic CT number<0.9 was related to increased BMI (>23.6 kg/sqm) and reduced P/P2 ratio (<1). Fibrates are potent enough to improve hepatic steatosis in tamoxifen-induced hepatic steatosis. CONCLUSION: P3/P2 ratio<1 was related to sufficient blockade of estrogen receptor proven by the development of massive hepatic steatosis. Therefore, we propose that tamoxifen is not a mere antagonist of estrogen, but it may also suppress estrogen synthesis when estrogen receptor is blocked sufficiently. The undetectable level of serum estrogen in tamoxifen-treated premenopausal women may partially explain why tamoxifen was so effective in estrogen receptor-positive early breast cancer.",1
10111,12062731,The liver and lovastatin,"The cholesterol-lowering agents, known as statins, have been in use for 15 years and are among the most commonly prescribed drugs. Animal studies and premarketing clinical trials have given signals of hepatotoxicity, primarily minor elevations in serum alanine aminotransferase enzyme (ALT) levels. For that reason, all of the cholesterol-lowering drugs have labeling that requires monitoring of liver enzymes. Postmarketing experience, however, suggests that hepatotoxicity is rare and thus it is timely to revisit the issue. The first of the statins, lovastatin, was approved in 1986 and has acquired 24 million patient-years of clinical experience. Minor elevations in liver enzymes, i.e., ALT 3 x the upper limit of normal (ULN) occur in 2.6% and 5.0% of patients on lovastatin doses of 20 and 80 mg/day, respectively. These elevations are reversible with continuing therapy, are dose related, and are probably related to cholesterol lowering per se. Rare cases of acute liver failure (ALF) have been reported with all of the cholesterol-lowering drugs. With lovastatin, the rate is approximately 1/1.14 million patient-treatment years, which is 9% of the background rate of all causes of ALF and approximately equal to the background rate of idiopathic ALF. Monitoring for hepatotoxicity has not been effective in preventing serious liver disease, largely because of its rarity and the poor predictive value of minor ALT elevations. In fact, it may increase patient risk because of needless discontinuation of cholesterol-lowering therapy for false-positive results in patients who are benefiting from treatment.",1
10112,12065350,"Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study","""STUDY OBJECTIVES: To evaluate the safety and efficacy of sitaxsentan, an endothelin-A receptor antagonist, in a 12-week, open-label trial of patients with pulmonary arterial hypertension (PAH). PATIENTS: Six children and 14 adults with New York Heart Association (NYHA) functional class II, III, or IV primary pulmonary hypertension or PAH associated with either congenital systemic-to-pulmonary shunts or collagen vascular disease were enrolled. MEASUREMENTS: Sitaxsentan was administered orally at 100 to 500 mg bid for 12 weeks. Cardiopulmonary hemodynamics via cardiac catheterization were obtained at baseline and week 12. Six-minute walk test distance was measured at baseline, week 6, and week 12. RESULTS: Sitaxsentan treatment resulted in significant improvement in exercise capacity as assessed by the 6-min walk distance (baseline [mean +/- SD], 466 +/- 132 m; week 12, 515 +/- 141 m, n = 20, p = 0.006). Mean pulmonary artery pressure and pulmonary vascular resistance index also improved (63 +/- 20 to 52 +/- 22 mm Hg, n = 17, p = 0.0002; and 20 +/- 11 to 14 +/- 13 U x m(2), n = 17, p = 0.008, respectively). Serious adverse events included two cases of acute hepatitis (fatal in one patient). CONCLUSIONS: Patients with NYHA functional class II, III, or IV PAH showed a significant improvement in exercise capacity and cardiopulmonary hemodynamics over a 12-week period of treatment with sitaxsentan, an endothelin-A receptor antagonist. Further investigation is warranted to evaluate the safety and efficacy of sitaxsentan in patients with PAH.""",1
10113,12066972,Levofloxacin-induced toxic epidermal necrolysis in an elderly patient,"Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are mild-to-life-threatening adverse reactions that have been described after exposure to fluoroquinolones. No published reports, however, exist of exfoliative disease after treatment with levofloxacin. A 78-year-old woman with many medical problems, including chronic obstructive pulmonary disease, was treated with parenteral levofloxacin for community-acquired pneumonia. She was discharged with oral levofloxacin to complete an additional 3 days of treatment as an outpatient. Two days after completing this regimen, the patient developed a rash with blistering. The rash progressed to TEN in 7 days, and she was transferred to a burn treatment center. She was treated with fluid resuscitation, wound dressing, and antibiotics. Her condition improved, and she was discharged after 22 days. To our knowledge, this case is the first published report of levofloxacin-induced TEN.",1
10114,12069536,Urea cycle disorders,"Most patients with urea cycle disorders who present as neonates, do so with deteriorating feeding, drowsiness and tachypnoea, following a short initial period when they appear well. The plasma ammonia should be measured at the same time as the septic screen in such patients. Ammonia levels above 200 micromol/l are usually caused by inherited metabolic diseases and it is essential to make a diagnosis for genetic counselling, even if the patients die. The aim of treatment is to lower the ammonia concentrations as fast as possible. Sodium benzoate, sodium phenylbutyrate and arginine can exploit alternative pathways for the elimination of nitrogen but haemodialysis or haemofiltration should be instituted if ammonia concentrations are >500 micromol/l or if they do not fall promptly. Long-term management involves drugs, dietary protein restriction and use of an emergency regimen during illness. Severe hyperammonaemia is usually associated with irreversible neurological damage, particularly if levels have been above 800 micromol/l for >24 hours, and the option of withdrawing treatment should be discussed with the family.",1
10115,12069710,[Kava-induced acute icteric hepatitis],,1
10116,12070418,[Unexplained increase in aminotransferases and obstructive sleep apnea syndrome],,1
10117,12073669,[Nimesulide-induced hepatotoxicity],,1
10118,12075742,"Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-na?ve patients with advanced non-small-cell lung cancer","""BACKGROUND: To evaluate the efficacy and safety of pemetrexed therapy for chemotherapy-na?ve patients with surgically incurable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients received pemetrexed 600 mg/m2 every 3 weeks. Restaging was performed after every two cycles of therapy and toxicity was assessed at each cycle of pemetrexed. In the absence of disease progression or undue toxicity, treatment was continued for a maximum of 12 cycles. RESULTS: Fifty-nine patients (median age 59 years; range 39-74 years) received a median of four cycles of pemetrexed. Nineteen patients (32%) had a ECOG performance status (PS) of two and 39 patients (66%) had stage IV disease. The most common histological sub-types were adenocarcinoma (20 patients, 34%) and large cell (18 patients, 31%). Sixteen patients (27%) had received prior radiotherapy. Nine patients achieved a partial response for an overall response rate of 15.8% (95% confidence interval CI 7% to 28%). The median duration of response was 4.9 months, and the median survival was 7.2 months. The principal toxicities were myelosuppression and rash. While grade 3 or 4 neutropenia was seen in 25 patients (42%), only two patients (3%) developed grade 3 infection. Eighteen patients (31%) developed grade 3 or 4 cutaneous toxicity, which improved with prophylactic oral dexamethasone administered for 3 days beginning the day before pemetrexed treatment. Asymptomatic elevations in hepatic biochemistry (especially alanine transaminase and aspartate transaminase) were seen in 47 patients (80%); however, these did not interfere with the dose or schedule of pemetrexed and returned to normal levels throughout the study. CONCLUSIONS: This is the largest study confirming the encouraging single-agent activity of pemetrexed in chemotherapy-na?ve patients with NSCLC. In addition, this study demonstrates that a dose of 600 mg/m2 can be delivered safely; however, treatment should be restricted to patients with a PS of 0 or 1. The results of combination studies are awaited with interest.""",1
10119,12079721,Terbinafine hepatotoxicity resulting in chronic biliary ductopenia and portal fibrosis,,1
10120,12081178,Lactic acidosis and abnormal liver function in advanced HIV disease,"""A 48 year old man receiving HAART presented with late stage HIV disease, non-specific symptoms, a normal sized liver, ascites, and lactic acidosis. Following a failed liver biopsy worsening acidosis developed, requiring ICU support. Progressive liver failure occurred. Endoscopy showed oesophageal varices and a transjugular liver biopsy showed non-cirrhotic cholestasis; findings that were ascribed to HAART.""",1
10121,12084041,Fulminant hepatic failure associated with benzbromarone treatment: a case report,,1
10122,12086547,Possible gatifloxacin-induced fulminant hepatic failure,"OBJECTIVE: To report a case of fulminant hepatic failure associated with the use of gatifloxacin. CASE SUMMARY: A 76-year-old white man was found to have an approximate 1-week history of worsening jaundice on the last day of a 10-day course of gatifloxacin for treatment of impetigo while at his skilled nursing facility. Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), international normalized ratio, activated partial thromboplastin time, and ammonia concentrations were found to be markedly elevated, consistent with hepatocellular necrosis commonly seen with fluoroquinolones. Screening for other causes of hepatotoxicity, including alcoholic or viral hepatitis, obstruction, or autoimmune-mediated processes, were negative. Other potential medication causes were less likely. The patient's liver function steadily declined, eventually resulting in multiple organ failure. The patient died 25 days after completing the course of gatifloxacin. DISCUSSION: This case of hepatotoxicity was associated with gatifloxacin. Other fluoroquinolones, most notably trovafloxacin, have been observed to cause variable degrees of hepatotoxicity, ranging from asymptomatic elevations of liver enzymes to fulminant hepatic failure. Fluoroquinolones are thought to cause hepatocellular necrosis, which results in elevated ALT and AST concentrations with a normal alkaline phosphatase concentration. A variable degree of hyperbilirubinemia is often seen, with the presence and degree of jaundice often correlating to a poorer prognosis. Hepatic encephalopathy and coagulopathy are also commonly present. CONCLUSIONS: Fluoroquinolones, including trovafloxacin, ciprofloxacin, ofloxacin, enoxacin, norfloxacin, and, in this case report, gatifloxacin, have been associated with hepatotoxicity. It is important that these medications be considered a possible cause when the patient being treated has liver disease.",1
10123,12088359,Ticlopidine-associated cholestatic hepatitis,,1
10124,12089658,Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy,"This retrospective cohort study investigated whether particular antiretroviral agents are associated with a higher risk for developing grade 4 liver enzyme elevations (LEEs) in patients with human immunodeficiency virus (HIV) type 1 infection who are starting to receive highly active antiretroviral therapy (HAART). Grade 4 LEE was defined as aminotransferase levels >10 times the upper limit of normal and >200 U above baseline levels. A multivariate Cox model was used to identify risk factors. The incidence of LEE was 6.3%. No patients died of LEE consequences. Risk factors were higher baseline alanine aminotransferase levels, chronic hepatitis B or C virus infection, antiretroviral therapy-naive patients undergoing their first HAART regimen, recent start of a regimen of nevirapine or high-dose ritonavir, and female sex. In hepatitis B virus (HBV)-coinfected patients, discontinuing lamivudine (3TC) use was a risk factor. In 97% of cases, >or=1 risk factor was present. In HBV-coinfected patients using 3TC, continued use of 3TC should be considered, even if 3TC-resistant HIV strains develop.",1
10125,12094857,"A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis","OBJECTIVE: Balsalazide is a new innovative, mesalamine-containing prodrug that is activated by bacteria in the colon. Balsalazide has been shown previously to be well tolerated and effective in the treatment of acute ulcerative colitis. The aim of this study was to determine the dose-response of balsalazide for efficacy and safety in active, mild-to-moderate ulcerative colitis and to compare this profile with that of mesalamine, pH-dependent, delayed-release tablets. METHODS: A multicenter, randomized, active control, double-blind, double-dummy, dose-response, parallel-group study was performed comparing balsalazide (6.75 g daily), balsalazide (2.25 g daily), and mesalamine (2.4 g daily), administered for 8 wk to 154 patients with active, mild-to-moderate ulcerative colitis as verified by sigmoidoscopy. RESULTS: Eight weeks of treatment with 6.75 g of balsalazide daily provided significantly greater improvement than did balsalazide (2.25 g daily) in rectal bleeding (64.7% [6.75-g balsalazide] vs 32.4% [2.25-g balsalazide], p < 0.006), stool frequency (58.8% vs 29.4%, p < 0.006), sigmoidoscopic score (78.9% vs 52.5%, p < 0.015), and Physician's Global Assessment (73.7% vs 51.3%, p < 0.03). The efficacy of balsalazide showed a significantly more rapid onset of action than that of mesalamine (2.4 g daily) (2-wk sigmoidocopic score improvement, 54.7% [6.75-g balsalazide] vs 29.4% [2.4-g mesalamine], p = 0.006) with numerically greater improvement at 8 wk in five of seven measured signs and symptoms. Balsalazide (6.75 g daily) was well tolerated, and the safety profile did not differ significantly from that of balsalazide (2.25 g daily) or mesalamine. CONCLUSIONS: Eight weeks of treatment with balsalazide (6.75 g daily) is significantly more effective than balsalazide (2.25 g daily) and more rapid in onset than mesalamine (2.4 g daily) in improving signs and symptoms of acute ulcerative colitis. Balsalazide (6.75 g daily) is well tolerated, and the safety profile does not differ from that of balsalazide (2.25 g daily) and mesalamine (2.4 g daily).",1
10126,12100170,"The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients","In 1997, the Italian Ministry of Health created a special programme for the controlled distribution of deferiprone to collect data and to evaluate its safety and effectiveness in long-term use. Five hundred and thirty-two thalassaemia patients from 86 treatment centres were enrolled in this programme. One hundred and eighty-seven patients (32%) experienced a total of 269 events that led to a temporary interruption or, in some cases, to a discontinuation of treatment. The incidence of agranulocytosis and milder neutropenias were 0.4/100 and 2.1/100 patient-years respectively. Neutropenia occurred predominantly in younger and non-splenectomized patients. Transient alanine transaminase increase, gastrointestinal discomfort and arthralgia were the other most commonly reported events. Ferritin levels showed a significant decrease in time after 3 years of therapy. This is the largest number of deferiprone-treated patients to have been reported to date. These data show that the drug was effective in reducing serum ferritin levels and the incidence of adverse events was not greater than the frequency reported in clinical trials.",1
10127,12110740,Cystinosis,,1
10128,12114036,"MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial","""BACKGROUND: Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. METHODS: 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These """"intention-to-treat"""" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. FINDINGS: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. INTERPRETATION: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.""",1
10129,12118965,Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS,"BACKGROUND: In patients with moderate to severe histoplasmosis associated with AIDS, the preferred treatment has been the deoxycholate formulation of amphotericin B. However, serious side effects are associated with use of amphotericin B. OBJECTIVE: To compare amphotericin B with liposomal amphotericin B for induction therapy of moderate to severe disseminated histoplasmosis in patients with AIDS. DESIGN: Randomized, double-blind, multicenter clinical trial. SETTING: 21 sites of the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. PATIENTS: 81 patients with AIDS and moderate to severe disseminated histoplasmosis. MEASUREMENTS: Clinical success, conversion of baseline blood cultures to negative, and acute toxicities that necessitated discontinuation of treatment. RESULTS: Clinical success was achieved in 14 of 22 patients (64%) treated with amphotericin B compared with 45 of 51 patients (88%) receiving liposomal amphotericin B (difference, 24 percentage points [95% CI, 1 to 52 percentage points]). Culture conversion rates were similar. Three patients treated with amphotericin B and one treated with liposomal amphotericin B died during induction (P = 0.04). Infusion-related side effects were greater with amphotericin B (63%) than with liposomal amphotericin B (25%) (P = 0.002). Nephrotoxicity occurred in 37% of patients treated with amphotericin B and 9% of patients treated with liposomal amphotericin B (P = 0.003). CONCLUSION: Liposomal amphotericin B seems to be a less toxic alternative to amphotericin B and is associated with improved survival.",1
10130,12119927,Hepatoma associated with androgen therapy for aplastic anemia,,1
10131,12126938,Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome,"Hermansky-Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency and, in patients with HPS1 gene mutations, a progressive, fatal pulmonary fibrosis. We investigated the safety and efficacy of an antifibrotic agent, pirfenidone (800 mg, t.i.d.), in treating 21 adult Puerto Rican HPS patients, including 20 homozygous for the same HPS1 mutation. Patients were examined every 4 months for up to 44 months in a randomized, placebo-controlled trial, with rate of change in pulmonary function values as outcome parameters. Using the complete data set of 130 patient admissions, a repeated measures model showed that 11 pirfenidone-treated patients lost FVC at a rate 5% of predicted ( approximately 400 mL) per year slower than 10 placebo-treated patients (p=0.001). A random coefficients model showed no significant difference. However, using data restricted to patients with an initial FVC >50% of predicted, both models showed the pirfenidone group losing FVC (p<0.022), FEV(1) (p<0.0007), TLC (p<0.001), and DL(CO) (p<0.122) at a rate approximately 8%/year slower than the placebo group. Clinical and laboratory side effects were similar in the two groups. Pirfenidone appears to slow the progression of pulmonary fibrosis in HPS patients who have significant residual lung function.",1
10132,12131221,Liver injury after beginning antiretroviral therapy in HIV/hepatitis C virus co-infected patients is not related to immune reconstitution,"Transaminase elevations occur more frequently after beginning antiretroviral therapy in HIV-positive patients co-infected with hepatitis C virus (HCV). The mechanism of liver injury in these individuals is unknown, although immune reconstitution phenomena have been postulated. In 42 HIV/HCV co-infected individuals followed after beginning potent antiretroviral therapy, the development of liver injury was not associated with significant changes in serum HCV-RNA levels nor with greater CD4 cell increases. Underlying chronic hepatitis may thus increase the risk of liver toxicity by other mechanisms.",1
10133,12132559,Esomeprazole: a clinical review,"The pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy, and adverse effects of esomeprazole are reviewed. Esomeprazole, a proton-pump inhibitor (PPI), is the S-isomer of omeprazole. Esomeprazole has FDA-approved labeling for use in the treatment of symptomatic gastroesophageal reflux disease (GERD), including healing and maintenance of healing of erosive esophagitis and as part of a triple-drug regimen for Helicobocter pylori infection. Esomeprazole is structurally similar to other PPIs but is the first PPI to include only the active isomer, which may lead to improved pharmacokinetic and pharmacodynamic characteristics. Esomeprazole maintains intragastric pH at a higher level and above 4 for a longer period than other PPIs. Clinical studies have shown that esomeprazole is at least equivalent in safety and efficacy to other drugs in the class. Esomeprazole has demonstrated efficacy in the treatment of erosive esophagitis, the maintenance of healing of erosive esophagitis, and the treatment of signs and symptoms of GERD. Effective dosages are 20 or 40 mg orally every day or as needed. Esomeprazole magnesium 40 mg once daily in combination with amoxicillin and clarithromycin is effective in eradicating H. pylori infection. The potential for interacting with other drugs is limited and is similar to that of omeprazole. The most common adverse effects are headache, respiratory infection, and abdominal symptoms. Esomeprazole has pharmacokinetic properties that may make it more effective than omeprazole in some patients.",1
10134,12135060,Moxifloxacin-induced acute liver injury,,1
10135,12137558,Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide,"Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with idiosyncratic hepatotoxicity in susceptible patients. The molecular mechanisms underlying this toxicity have not yet been fully elucidated. However, experimental evidence suggests that they include increased concentration of the drugs in the hepatobiliary compartment, formation of reactive metabolites that covalently modify proteins and produce oxidative stress, and mitochondrial injury. Genetic and/or acquired patient factors can either augment the pathways leading to hepatic toxicity or impede the protective and detoxifying pathways. An example is nimesulide, a selective cyclo-oxygenase-2 inhibitor widely used for the treatment of inflammatory and pain conditions, which has been recently associated with rare but serious and unpredictable adverse reactions in the liver (increases in serum aminotransferase activities, hepatocellular necrosis, and/or intrahepatic cholestasis). Similar to other drugs causing idiosyncratic hepatotoxicity, both the molecule and the patient contribute to the hazard. Here, the weakly acidic sulfonanilide drug undergoes bioreductive metabolism of the nitroarene group to reactive intermediates that have been implicated in oxidative stress, covalent binding, and mitochondrial injury. It is only in a small number of susceptible patients, however, that genetic or nongenetic factors will cause this potential toxicity to become clinically manifest. In view of the very large recipient population, the incidence of nimesulide-induced liver injury has been low (approximately 0.1 per 100,000 patients treated). Although this estimation is based on spontaneous reporting data versus sales units and needs correction due to the classical bias of this system, the type and incidence of these rare but severe hepatic adverse reactions are comparable to that of other NSAIDs.",1
10136,12141828,Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone,"Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and gamma-glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.",1
10137,12143055,Incidence of drug-induced hepatic injuries: a French population-based study,"""The incidence of hepatic adverse drug reactions (ADRs) remains unknown in the general population. The goal of this population-based study was to assess the incidence and seriousness of hepatic ADRs. All new cases of symptomatic drug-induced hepatic injuries were collected by 139 trained physicians (general practitioners [GPs] and specialists) between November 1997 and November 2000 in an area containing 81,301 inhabitants who could not go elsewhere for medical care. Over 3 years, 34 cases of hepatic ADRs were collected, 82% of them in outpatients. Global crude annual incidence rate was 13.9 +/- 2.4 per 100,000 inhabitants; corresponding standardized annual global rate was 8.1 +/- 1.5. There was no difference between urban and rural areas. Standardized incidence female/male ratio was 0.86 (0.26-2.90) until 49 years of age and 2.62 (1.00-6.92) after this age. Diagnosis was carried out by GPs in half of the cases. The outcome was recovery for 32 patients and death for 2. The main drugs implicated were anti-infectious, psychotropic, hypolipidemic agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). Our results suggest that the number of hepatic ADRs in the French population would be 16 times greater than the number noted by spontaneous reporting to French regulatory authorities. In conclusion, the incidence and seriousness of drug-induced hepatitis are largely underestimated in the general population. These results may be useful for further evaluation of drug-induced hepatotoxicity.""",1
10138,12145716,"A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients","""We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P<.001) in patients treated with ABCD. Rates of drug-related toxicity in patients receiving ABCD and AmB, respectively, were 53% versus 30% (chills), 27% versus 16% (fever), 1% versus 4% (hypoxia) and 22% versus 24% (toxicity requiring study drug discontinuation). ABCD appears to have equivalent efficacy and superior renal safety, compared with AmB, in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more frequently in patients receiving ABCD than in those receiving AmB.""",1
10139,12150482,Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore,"SETTING: The Singapore Tuberculosis (TB) Control Unit, a high volume national referral centre. OBJECTIVES: To determine the incidence, clinical course and outcome of TB drug-induced hepatitis (DH) and the risk factors associated with DH under general programme conditions. DESIGN: A retrospective review of adult patients started on TB treatment in 1998. RESULTS: There were 55 cases of DH in the cohort of 1036 patients treated in 1998. The median time to diagnosis of DH was 38 days. Factors significantly associated with DH were abnormal baseline transaminases/ bilirubin (OR 2.1, 95%CI 1.1-4.3, P = 0.02), age >60 years (OR 1.97, 95%CI 1.14-3.34, P = 0.01) and female sex (OR 1.9, 95%CI 1.07-3.4, P = 0.02). Ethnicity, self-reported alcohol consumption and body weight were not associated with development of DH. All three patients with fatal DH had received pyrazinamide-containing regimens. Treatment was re-introduced in 48 patients and successfully completed in 45 patients. The median time to reinstitution of TB treatment was 23 days. CONCLUSION: The incidence of TB drug-induced hepatitis was 5.3%. Age >60 years, abnormal baseline transaminase/bilirubin levels and female sex were risk factors associated with the development of TB drug-induced hepatitis.",1
10140,12160118,Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis,"""BACKGROUND: The current Canadian and US guidelines for the treatment of multidrug-resistant latent tuberculosis infection advocate the use of pyrazinamide and a fluoroquinolone as a first-line treatment option. However, there is very little information in the literature that describes the use of these agents together. This case series describes the probable association between multiple adverse events and the use of pyrazinamide and levofloxacin in the treatment of individuals with suspected latent multidrug-resistant tuberculosis infection. METHODS: We studied a case series of 17 individuals with suspected latent multidrug-resistant tuberculosis infection in Hamilton, Ont., who were being treated with pyrazinamide and levofloxacin. The Naranjo scale was used to assess patients for musculoskeletal, central nervous system, gastrointestinal and dermatological adverse events. Hepatocellular events were assessed and defined using criteria established by the Council for International Organizations of Medical Sciences. Laboratory abnormalities and adverse events that were documented during combination drug therapy were evaluated to determine the likelihood of an association. RESULTS: Fourteen individuals developed musculoskeletal adverse effects (11 were deemed to be probably related to combination therapy). There were 8 reports of central nervous system effects (5 of which were assessed as being probably associated with therapy). Hyperuricemia and gastrointestinal and dermatological effects were also common; the use of pyrazinamide and levofloxacin was believed to be probably responsible for the emergence of these adverse effects. There were 5 cases of hepatocellular injury. Therapy was discontinued in all individuals. INTERPRETATION: The combination of pyrazinamide and levofloxacin appears to be a poorly tolerated regimen. The mechanism of a possible interaction is not yet understood. Given the severity of some of the adverse events, a better understanding of dosing and clearer guidelines for monitoring therapy are imperative if these drugs are to be prescribed together.""",1
10141,12165183,Kava--the unfolding story: report on a work-in-progress,"""This paper, originated as a submission (now updated) to the U.K. Medicines Control Agency and Committee of Safety of Medicines (CSM) on January 11, 2002, in response to a report circulated by the German Federal Institute for Drugs and Medical Products (German initials are BfArM), a compilation of which is summarized in Appendix 2. This agency issued notification in late November 2001 of some thirty adverse events associated with the use of concentrated standardized preparations of kava (Piper methysticum, Forst. f.) reported from Germany and Switzerland. An analysis of the summary of the BfArM case reports (see Appendix 2) shows that these contain duplications among the cases cited. The original submission that was sent to the CSM January 2002 has been updated to the version published here. This new version was completed in April 2002. As a result of the alert from BfArM, the evaluation of kava's safety is now occurring on a worldwide basis and, being that this a matter of considerable importance to the public, the health care community, and regulatory authorities as well as to kava farmers throughout Polynesia, it is it important to depict this progress report. As such, this updated report does not provide final answers. The material released by the BfArM is lacking in detail; however, it is hoped that this report will shed light on the kava controversy. It is anticipated that there will be further updates shortly. This report, prepared on behalf of the Traditional Medicines Evaluation Committee, a subcommittee of the European Herbal Practitioners Association, argues that many of the adverse events cited by the BfArM should not be attributed to kava. In addition, the report states that the properties of concentrated standardized kava extracts - as opposed to preparations that closely approximate those created for traditional use - contribute to causing adverse events. This report proposes a number of simple measures that will ensure that safe kava preparations may continue to be available in the United Kingdom.""",1
10142,12167069,A new Poisson and Bayesian-based method to assign risk and causality in patients with suspected hepatic adverse drug reactions: a report of two new cases of ticlopidine-induced hepatotoxicity,"""OBJECTIVE: The diagnosis of drug-induced hepatotoxicity is based on circumstantial evidence and is often inaccurate. We have designed a method based on published data to assign causality to suspected cases of drug-induced hepatotoxicity. DESIGN: Forty-seven published cases of ticlopidine-induced hepatotoxicity were identified by a Medline-based literature search. Data regarding abnormal liver function in patients receiving ticlopidine were obtained from the only published placebo-ticlopidine clinical trial (the Canadian American Ticlopidine Study; CATS). Thus, we calculated the maximum number of expected hepatotoxicity cases in patients exposed to ticlopidine and those not exposed to the drug by means of the Poisson distribution. The calculated odds ratio was used as a prior odd for subsequent quantification, using a Bayesian-based approach, of individual ticlopidine-induced hepatotoxicity likelihood. Concretely, the prior odd is modified by several separate likelihood ratios: age; sex; AST level; ALT level; alkaline phosphatase level; total bilirubin level; latent period of adverse reaction appearance; and period of remission of adverse reaction. This methodology was applied to two new cases of suspected ticlopidine-induced hepatotoxicity. RESULTS: The prior probability of ticlopidine-induced hepatotoxicity derived from CATS data is 61.29%. This is in contrast with the 28.83% incidence rate of drug-induced liver alterations in the general population. Alkaline phosphatase levels and total bilirubin levels were six times the normal values among individuals with ticlopidine-induced hepatotoxicity than in the general population. They were the most relevant likelihood ratios of the Bayesian model to establish a high level of causality relationship between a hepatotoxicity event and ticlopidine use. CONCLUSIONS: The proposed method, which links information from clinical trials with the profile of clinical hepatotoxicity of a drug defined from published cases reported after a drug is marketed, can be a useful tool for drug postmarketing surveillance research.""",1
10143,12169989,A severe case of ovarian hyperstimulation syndrome with liver dysfunction and malnutrition,"""Ovarian hyperstimulation syndrome (OHSS) is a potentially fatal condition associated with the use of ovulation-inducing drugs. We describe a 28-year-old woman who presented with ascites, oliguria and vomiting. Over 2 weeks, the combination of intractable vomiting, intravenous rehydration, paracentesis, hypercatabolism and proteinuria led to severe hypoalbuminaemia with gross oedema and progressively worsening liver function. The patient's albumin dropped to 9 g/l with liver function abnormalities peaking at: alanine aminotransferase, 462 IU/l; alkaline phosphatase, 706 IU/l; bilirubin, 26 micromol/l; and prothrombin time, 19 s. The judicious use of paracentesis and commencement of total parenteral nutrition coincided with a rapid clinical improvement. One month after discharge, the patient was asymptomatic with normal liver function. This case demonstrates the severity of malnutrition and liver dysfunction that can occur with severe OHSS. Increasing use of in-vitro fertilization techniques makes it mandatory for clinicians to be aware of the clinical features, complications and treatment of this condition, and we would suggest that patients with severe OHSS should be jointly managed by physicians and obstetricians.""",1
10144,12171680,Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests?,"INTRODUCTION: Isotretinoin has been used to treat acne since 1982. Its current indications in the package insert are limited and many physicians still feel uncomfortable prescribing it because of its side effects. Serum levels of liver enzymes and lipids are carried out as a routine in most clinics both before and during treatment. AIMS: Our objective was to evaluate the effect of isotretinoin on serum lipids, liver function and other laboratory parameters in order to assess the necessity to perform routine laboratory tests. METHODS: Computerized medical files of 1292 patients in private practice that received isotretinoin for acne were analyzed. RESULTS: 907 patients completed a treatment course of 5 to 9 months. Serum levels of liver enzymes were not elevated to a degree necessitating discontinuation of treatment. Only 1.5% of the patients had serum triglyceride levels above 400 mg%. No laboratory abnormalities were a cause for discontinuation of treatment. During a 6-year follow up only 3.5% of patients received a second course of therapy with isotretinoin. CONCLUSIONS: Aside from its teratogenic effect, isotretinoin is a safe and excellent drug for acne therapy. It should be prescribed for any inflammatory acne and in our opinion there is no need for a routine laboratory follow-up in young, healthy patients aside from a pregnancy test in females. At present, isotretinoin should be considered as the drug of choice for moderate to severe acne.",1
10145,12172412,Cholestatic hepatitis related to use of irbesartan: a case report and a literature review of angiotensin II antagonist-associated hepatotoxicity,"We report a patient who developed cholestatic hepatitis shortly after starting therapy with irbesartan, one of the new, recently marketed angiotensin II antagonists. Serological studies and ultrasonography ruled out viral hepatitis and extrahepatic obstructive jaundice, respectively. A percutaneous liver biopsy showed a portal inflammatory infiltrate with eosinophils and marked cholestatic features in the perivenular area. Irbesartan was discontinued and the patient's jaundice resolved slowly over a period of several weeks, although mild biochemical cholestasis lasted for more than 1 year. There have been seven prior cases of angiotensin II antagonist-induced hepatotoxicity reported in the literature. A class warning for hepatotoxicity for these compounds should probably be considered.",1
10146,12173489,Safety and efficacy of ET-743: the French experience,"""Initial evidence of clinical benefit with ecteinascidin-743 (ET-743) in patients with sarcoma was provided during a Phase I pharmacokinetic study in which 52 patients received ET-743 at doses of 50-1800 micrograms/m2 as a 24 h continuous infusion every 3 weeks. Neutropenia and thrombocytopenia were the dose-limiting toxicities; liver toxicity (a severe but transient and reversible increase in transaminase concentrations) was not treatment limiting. In conjunction with results obtained with ET-743 in a compassionate-use program, these indications of activity in heavily pretreated patients with sarcoma prompted initiation of a French multicenter Phase II study of ET-743 in this population. From February 1999 to January 2001, 54 patients with advanced anthracycline-pretreated soft-tissue sarcoma (STS) received ET-743 at a dose of 1500 micrograms/m2 every 3 weeks by continuous 24 h infusion. The main histological subtype was leiomyosarcoma (37%); the majority of primary tumors were visceral (24%) or uterine (19%) sarcomas. In this Phase II population (> or = 25% negative prognostic or predictive factors of response to chemotherapy; > or = 50% anthracycline- and ifosfamide-resistant), safety data were comparable to those obtained in the Phase I and compassionate-use studies. Asymptomatic and reversible neutropenia and transaminitis (grade 3/4) were the most frequent toxicities (approximately 60% of patients); febrile neutropenia was infrequent (< 10%). No mucositis, alopecia, cardiac or neurotoxicity was observed. Two severe cases of rhabdomyolysis occurred. Side effects were non-cumulative, reversible and manageable. Of 52 evaluable patients, three (6%) achieved a long-lasting (8-13 months) partial response, four (8%) achieved a minor response (25-50% tumor reduction) and 22 (42%) achieved disease stabilization. With a 13-month median follow-up, median survival was almost 11 months. Progression-free survival at 6 months was 26.5% and the overall survival rate at 12 months was almost 50%. The response rate was uninfluenced by tumor metastatic site, size or anthracycline sensitivity status. These results, combined with the lack of cumulative toxicity, confirm the role of ET-743 in the treatment of advanced STS.""",1
10147,12176871,Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia,"""Patients with thalassemia major require lifelong chelation therapy to prevent iron-induced organ damage. The orally active chelator deferiprone has been proposed as an alternative for patients unable or unwilling to use deferoxamine. One report has concluded that deferiprone may worsen hepatic fibrosis in patients with thalassemia, whereas others have found no detrimental effect. A panel of 3 pathologists evaluated 112 coded liver biopsies obtained from 56 patients before and after deferiprone therapy. Fibrosis was scored with the Laennec and Ishak systems. The mean interval between liver biopsies was 3.1 years (range, 1.2-4.9 years). In 11 patients seronegative for hepatitis C, fibrosis scores before and after therapy were 1.12 +/- 1.07 and 0.97 +/- 0.84 (P =.42) with the use of the Ishak system, and 0.71 +/- 0.65 and 0.70 +/- 0.53 (P =.91) with the Laennec system. Among 45 patients seropositive for hepatitis C, fibrosis scores before and after therapy were 1.91 +/- 1.13 and 2.04 +/- 1.30 (P =.43) with the use of the Ishak system and 1.26 +/- 0.73 and 1.35 +/- 0.90 (P =.41) with the Laennec system. When the data set was limited to biopsies that each contained 6 or more portal tracts (31 patients), analysis still showed no significant change in fibrosis with time. With the use of the Laennec system, the fibrosis score did not increase by more than one level in any patients without hepatitis C; it increased by more than one level in 1 patient with hepatitis C; and it did not decrease by more than one level in any of the 56 patients. This analysis of the largest collection of liver biopsies reported to date in patients receiving deferiprone demonstrates no evidence of deferiprone-induced progression of hepatic fibrosis during long-term therapy.""",1
10148,12180481,Tamoxifen-related porphyria cutanea tarda,"""We report a case of porphyria cutanea tarda (PCT) in a patient with breast cancer following adjuvant tamoxifen. Cessation of tamoxifen resulted in a prompt decline in urinary porphyrins suggestive of a causative role. Tamoxifen is known to be hepatotoxic; however, its association with PCT is unclear. In this report, we discuss the porphyrinogenicity of tamoxifen and potential mechanisms.""",1
10149,12180714,Not yet time to change the guidelines for monitoring methotrexate liver toxicity: they have served us well,,1
10150,12185885,[Acute hepatic and renal failure due to piroxicam use],,1
10151,12189369,Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients,"""OBJECTIVE: Our objective was to clarify risk factors associated with the development of severe hepatotoxicity during antituberculosis chemotherapy in Japanese children. METHODS: In a retrospective analysis in a 350-bed referral children's hospital in a metropolitan area, the medical charts of all pediatric patients who received antituberculosis chemotherapy between January 1995 and November 1999 were surveyed. Univariate and multivariate analyses were performed to find any demographic parameters (ie, sex, age, height, and body weight), clinical characteristics (ie, nutritional or developmental status, co-infection with hepatitis viruses [B or C] or human immunodeficiency virus, presence of extrapulmonary tuberculosis, or medical history of liver disease), or individual antituberculosis agents used that would be associated with the likelihood of development of severe hepatotoxicity during antituberculous chemotherapy. Severe hepatotoxicity (defined as an elevation of ALT and AST levels that were greater than 5 times the respective reference values) was attributed to the chemotherapy when it developed in children with normal pretreatment values for these parameters and no other potential causes were identified. Those who had abnormal ALT or AST values before treatment were excluded from analysis. RESULTS: Among the 117 patients surveyed (58 males and 59 females; age range, 0 to 16 years), 18 were excluded from the analysis because of abnormal baseline ALT and AST values. Severe hepatotoxicity developed in 8 of the 99 eligible children, and all 8 of those children were younger than 5 years old. The univariate analysis revealed that the children in whom hepatotoxicity developed were significantly (P <.05) younger, were predominantly male, had extrapulmonary tuberculosis, and were given pyrazinamide more often than those who had no hepatotoxicity. However, the multivariate logistic regression analysis revealed that only age and the administration of pyrazinamide would have a significant contribution (P <.05) to the development of severe hepatotoxicity, with odds ratios of 143 (95% confidence interval, 4.2 to 4934.9) and 0.60 (95% confidence interval, 0.39 to 0.90), respectively: the estimated probability of development of hepatotoxicity in a typical pediatric patient at 1, 5, and 10 years receiving pyrazinamide with rifampin (INN, rifampicin) and isoniazid would be 0.95, 0.72, and 0.16, respectively. CONCLUSIONS: This study indicated that intensive monitoring of hepatotoxicity should be performed for younger children (<5 years) receiving pyrazinamide for antituberculosis chemotherapy.""",1
10152,12190207,Re: Lasso-de-la-Vega et al. gabapentin as a probable cause of hepatotoxicity and eosinophilia,,1
10153,12192206,Mirtazapine-induced hepatotoxicity,"We report two cases of hepatotoxicity induced by mirtazapine. Two women treated for depression with mirtazapine developed severe hepatotoxicity because of the drug. In the first case, mirtazapine was prescribed for 3 years and the patient developed derangement in liver function with prolonged jaundice, which improved after the withdrawal of mirtazapine. The use of mirtazapine in the second case was associated with prolonged jaundice, which only recovered 3 months after the withdrawal of mirtazapine. The cause of mirtazapine-induced liver toxicity was unknown, and to our knowledge, these are the first reported cases of mirtazapine-induced prolonged jaundice.",1
10154,12196081,Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies,"""BACKGROUND: Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments. METHODS: A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding. RESULTS: Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; P<.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P =.008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups. CONCLUSION: In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.""",1
10155,12203257,Khat: pharmacological and medical aspects and its social use in Yemen,"Fresh leaves of the khat tree (Catha edulis Forsk.) are chewed for their euphoric properties in East Africa and parts of the Middle East, such as The Yemen. This review describes the history, cultivation and constituents of khat, and the social aspects of khat chewing in Yemen. The major pharmacologically active constituent of the fresh leaves is (--)-S-cathinone. The pharmacology of (--)-S-cathinone in the central nervous system and the peripheral effects are described. (--)-S-Cathinone is regarded as an amphetamine-like sympathomimetic amine and this mechanism of action is discussed in relation to the central stimulant actions and the cardiovascular effects of increasing blood pressure and heart rate. The risk factors associated with khat chewing are described, with emphasis on the reported increased incidence of acute myocardial infarction.",1
10156,12212533,[Acute liver failure in nefazodone therapy? A case report],"Antidepressant-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. We report on a patient with recurrent major depression who was treated with nefazodone. Six weeks after initiation of therapy with nefazodone, he developed fatal liver failure. After cessation of the drug, the patient did not recover. He underwent liver transplantation but unfortunately died.",1
10157,12220974,Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals,"""To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study population.""",1
10158,12228210,Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine,"""PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.""",1
10159,12237619,Treprostinil (Remodulin) for pulmonary arterial hypertension,,1
10160,12243603,Rhabdomyolysis with concurrent atorvastatin and diltiazem,"""OBJECTIVE: To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and diltiazem. CASE SUMMARY: A 60-year-old African American man with a significant past medical history presented to the emergency department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 times normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication regimen that included atorvastatin. DISCUSSION: Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug interaction between atorvastatin and diltiazem. CONCLUSIONS: While optimizing the patient's lipid profile should be the primary factor in choosing one statin over another, the potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking medications that may interact.""",1
10161,12269386,Kava-kava and anxiety: growing knowledge about the efficacy and safety,"Kava-kava (Piper methysticum G. Forster) has been used in social and ceremonial life in the Pacific islands from ancient times for the soporific and narcotic effects. Today several extracts standardized in the biologically active constituents kavalactones are marketed both as herbal medicinal products for anxiety disorders and as dietary supplements to improve stress disorders, nervous tension and restlessness. Unlike other substances used for these purposes, kava-kava has been shown to have minimal negative effects, and possibly positive effects, on reaction time and cognitive processing. Furthermore, it decreases anxiety without the loss of mental acuity. Although kava-kava has been found to be very effective, well tolerated, and non-addictive at therapeutic dosages, potential side effects can occur when very high doses are taken for extended periods. In addition, in the last two years unexpected high liver toxicity has been reported in two patients. Until now no studies support the liver toxicity of kavalactones and it is unknown which compound could have provoked the liver disease. On the other hand, it should be possible that unknown or unexpected constituents are the responsible or contributed to the liver toxicity.",1
10162,12281005,[Peliosis hepatis and oral contraceptives: a case report],"Possible hepatic effects of oral contraceptives (OCs) include tumors, intrahepatic cholestasis, and less well known vascular lesions such as Budd-Chiari syndrome and peliosis, a disseminated pseudocystic dilatation of the sinusoid capillaries of the liver. A 29-year-old woman with a history of 4 pregnancies, hypertension and diabetes both requiring daily medication, and use since April 1983 of an oral contraceptive (OC) containing .15 mg levonorgestrel and .03 mg of ethinyl estradiol complained in March 1984 of epigastric pain and increased abdominal volume. Ascitis was diagnosed and the patient was hospitalized. She had experienced a generalized pruritus for several months and had lost weight. The bilirubin, alcaline phosphatase, and Gamma GT levels were slightly elevated. Sonography showed a hypertrophied liver. Incipient esophageal varices were seen with gastric fibroscopy. The small subhepatic venous branches had a cloudy aspect. The peliosis hepatis was diagnosed by a transjugular puncture biopsy of the liver. With discontinuation of the OCs, the ascites did not reappear after puncture and the perturbations of the liver functioning normalized. On follow-up in April 1985, slight hepatomagaly persisted but the patient reported no further symptoms. She continued her medication for hypertension and diabetes. Peliosis hepatis was 1st described in 1964 and several cases related to OC use have been reported since 1972. Peliosis has the aspect of multiple small congestive cavities of 1-3 mm in diameter in the parenchyma. The lesions consist of areas of hepatocellular necrosis secondarily filled with blood. The cysts may be voluminous and subcortical, creating a risk of hemoperitoneum. The lesions may also be associated with a benign or malignant liver tumor. Regression of the lesions is possible with termination of the etiologic agent. Clinically, hepatomegaly, painful or not, sometimes associated with splenomegaly, is often found with peliosis. Moderate jaundice is very frequent. Ascites or edema of the legs are observed. Hyperbilirubinemia and augmentation of phosphatases and Gamma GT are the main laboratory findings. Transaminases may be slightly elevated, and the rate of prothrombin may be diminished. The condition is sometimes diagnosed with laparoscopy, celiomesenteric arteriography, or phlebography, but hepatic puncture biopsy usually establishes the diagnosis. The contition may improve if the etiologic agent is removed or it may worsen because of liver failure or a complication such as hemoperitoneum or an associated tumor.",1
10163,12298421,Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation,"The antiepileptic drug (AED) carbamazepine is widely used in the treatment of different kinds of seizures as well as affective and behavioural disorders. This paper presents an epidemiological study of carbamazepine-induced hepatic injuries and death, and describes the possible mechanisms of its toxicity. A retrospective analysis of clinical data revealed that the likelihood of hepatic death was comparatively higher in children, particularly when they were receiving medication with multiple AEDs, whereas reversible hepatic injuries were more likely to be seen in elderly patients. As suggested in this paper, the development of carbamazepine hepatotoxicity is rare, and unpredictable with the present state of knowledge, but it is somehow related to disturbance of glutathione metabolism, although data in this regard are imperfect. There appear to be two types of carbamazepine-initiated idiosyncratic liver injury, hypersensitivity and toxin-induced. It is feasible that both are due to the accumulation of toxic metabolite(s), and arene oxides may probably be considered as damaging derivatives of carbamazepine metabolism. Despite the lack of clear-cut underlying clinical and experimental findings in those patients in whom an inherited weakness of drug eliminating capacity is present, those conditions that may deteriorate glutathione balance, may increase the possibility of the emergence of toxic events during carbamazepine therapy. Finally, some recommendations for carbamazepine therapy are presented.",1
10164,12351933,"A double-blind, placebo-controlled study of naltrexone in the treatment of alcohol-dependence disorder: results from a multicenter clinical trial","""BACKGROUND: A 12-week, multicenter, double-blind, randomized, parallel-group clinical trial to compare naltrexone and placebo was carried out to determine the efficacy, safety, and tolerability of naltrexone together with a psychosocial intervention in the treatment of alcoholism. METHODS: A total of 202 alcohol-dependent patients were assigned to 12 weeks' treatment with either naltrexone or placebo. The relapse rate was evaluated by means of intention-to-treat analyses. Alcohol consumption, craving, adverse events, and changes in the biochemical markers of heavy drinking and possible toxicity were evaluated in the 192 patients who were considered to be assessable. RESULTS: The survival function for patients who were treated with naltrexone was significantly better than that of the patients who were treated with placebo (Kaplan-Meier log rank = 4, df = 1, p < 0.05). In addition, 7.9% of patients who were treated with naltrexone relapsed as compared with 18.8% of those who received placebo [chi = 5.89, df = 2, p = 0.050]. In comparing naltrexone with placebo-treated patients, the most common adverse events were abdominal pain [8.6% vs. 1%; (chi = 6.1, df = 1, p < 0.05)] and headache [7.5% vs. 1% (chi = 5.1, df = 1, p < 0.05)]. CONCLUSIONS: Naltrexone was well-tolerated, as the rate of adverse events was low, and safe, as it did not interfere with the normalization of biochemical markers of heavy drinking or alter liver function markers. Naltrexone seemed to reduce relapse rate to heavy drinking, but we found no differences in other alcohol consumption variables between naltrexone- and placebo-treated groups. Although the naltrexone group showed a tendency to consume fewer drinks per drinking day and had a longer time to first drink, differences were not statistically significant.""",1
10165,12352223,Reversible vanishing bile duct syndrome induced by carbamazepine,"Carbamazepine, a widely used anticonvulsant, can induce hepatotoxicity, usually evolving with an acute hepatitis that ceases after drug withdrawal. Carbamazepine-induced vanishing bile duct syndrome (VBDS) is a rare complication and has seldom been reported in the medical literature. This report presents a case of a 26-year-old male who had onset of epilepsy at 12 months of age and was initially treated with phenobarbital. Carbamazepine (1200 mg/day) was added in June 1996 when he was 22 years old to control the frequency of seizures. Two years later, during a routine investigation, elevation of serum gamma-glutamyltransferase (GGT) levels was detected. For this reason, the patient was weaned off carbamazepine, followed 6 months later by complete withdrawal of the drug. The first liver biopsy disclosed total absence of interlobular bile ducts (IBD) in 30 portal tracts. Fourteen months later, a control biopsy showed the presence of IBD in eight of 14 portal tracts. There was also a decrease of GGT levels detected 27 months after withdrawal of carbamazepine. This case illustrates the ductopenic effect of carbamazepine when used for a prolonged time, as reported in three previous publications. However, this is the first case in which there was a remission of the VBDS and bile duct regeneration after withdrawal of the drug.",1
10166,12352386,Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses,"""PURPOSE: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg up to a maximum of once daily [DOSAGE ERROR CORRECTED] in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of """"yes"""" responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question. RESULTS: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Patients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in International Index of Erectile Function erectile function domain score from baseline (p <0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p <0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p <0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events. CONCLUSIONS: Tadalafil was effective and well tolerated in this patient population.""",1
10167,12353830,Fatal progressive hepatic necrosis associated with lamotrigine treatment: a case report and literature review,"We present a case of fatal, progressive hepatotoxicity in a patient treated with lamotrigine. After presenting with a rash and fever, she developed elevated liver function tests and clinical sequelae of hepatic failure. The subacute course of her progressive liver damage is documented in serial liver biopsies. While her initial biopsy showed approximately 50% hepatocyte necrosis, her post mortem examination performed three weeks later displayed massive hepatic necrosis with extensive bile duct proliferation. Although she was taking other antipsychotics at the time, her clinical course best parallels other reports of lamotrigine-associated hepatotoxicity. Here we discuss not only the clinicopathologic findings of this case but also review the pertinent literature.",1
10168,12357373,Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis,,1
10169,12361531,[Variability of the clinical expression of Ecstasy-induced hepatotoxicity],"3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, known as ecstasy. Because of its euphoric effects, the use of this substance as a drug of abuse is becoming increasingly widespread. The development of hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, cardiac arrhythmia and neurotoxicity have been described in association with the use of this drug. Moreover, in the last few years, cases of liver involvement, associated or not with the above-mentioned entities, have been described, ranging from mild acute hepatitis to fulminant hepatic failure and death. We present four cases of ecstasy-induced hepatotoxicity. Outcome was favorable in three patients while the fourth required liver transplantation. Consequently, ecstasy ingestion should be ruled out as a cause of acute non-viral hepat",1
10170,12361829,Multiorgan failure induced by atorvastatin,,1
10171,12362579,Immune-mediated drug-induced liver disease,"Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.",1
10172,12365478,Methotrexate-associated liver toxicity in a patient with breast cancer: case report and literature review,"A patient with breast cancer developed severe asthenia, accompanied with progressively increasing transaminases, during adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and 5-fluorouracil). Additional blood tests and imaging were negative. A liver biopsy revealed a grade II toxic hepatitis. Because methotrexate was suspected to be the cause of the hepatotoxicity, the administration of this drug was stopped and mitoxantrone was given instead. A recovery of clinical symptoms and normalisation of the liver function tests was observed afterwards. In that sense, mitoxantrone appears to be a valuable alternative to methotrexate in cases of hepatotoxicity in patients with breast cancer. An overview of the literature regarding methotrexate hepatotoxicity is presented.",1
10173,12374248,"Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study","""OBJECTIVE: To compare the upper gastrointestinal (GI) tract tolerability of once-weekly oral alendronate, 70 mg, and placebo. PATIENTS AND METHODS: This was a 12-week multicenter, randomized, double-blind, placebo-controlled study. The first patient initiated treatment on June 5, 2000, and the last patient completed treatment on March 1, 2001. The study enrolled 450 postmenopausal women and men with osteoporosis (224 took alendronate, 226 took placebo) who were ambulatory and community dwelling at 48 outpatient study centers in the United States. By design, approximately half of the patients were naive to bisphosphonates. The primary end point was upper GI tract tolerability based on the incidence of any upper GI tract adverse events. Secondary end points included the number of discontinuations due to drug-related upper GI tract adverse events and the change from baseline in bone resorption, assessed by the urinary N-telopeptide-creatinine ratio at 12 weeks. A subgroup analysis of the primary and secondary end points was performed on the patients stratified by prior bisphosphonate use. The safety and tolerability of the weekly alendronate and placebo regimens were captured as clinical and laboratory adverse events. RESULTS: A total of 11% of the alendronate patients and 13% of the placebo patients reported an upper GI tract adverse event. Discontinuations due to drug-related upper GI tract adverse events occurred in 3% of alendronate patients and 1% of placebo patients. The differences between the treatment groups for the primary and secondary end points were not significant. For the primary end point, the upper limit of the 95% confidence interval of the difference was well within the prespecified 14% comparability bound (-2.2%; 95% confidence interval, -8.3% to 3.9%). The overall incidence of upper GI tract adverse events was lower in the subgroup of patients with prior bisphosphonate exposure (8%) than in those who were bisphosphonate naive (16%). However, regardless of prior bisphosphonate exposure, the incidence of upper GI tract adverse events was similar between the alendronate and placebo patients. The urinary N-telopeptide-creatinine ratio showed a significant decrease in the alendronate patients (72% of baseline, P<.001) compared with a slight increase in the placebo patients (106% of baseline) at week 12. CONCLUSION: In this 3-month study, the incidence of upper GI tract adverse events in patients treated with once-weekly alendronate, 70 mg, was comparable to that with placebo.""",1
10174,12374454,"Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality","""Hepatic venoocclusive disease (HVOD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is a well-recognized dose-limiting toxicity of oral busulfan (Bu)-based preparative regimens. The unpredictable absorption of oral Bu from the gastrointestinal (GI) tract and hepatic first-pass effects have led to the development of an intravenous Bu preparation (i.v. Bu). The purpose of this retrospective comparison was to evaluate the incidence rate of HVOD and the 100-day mortality rate in patients treated with a busulfan/cyclophosphamide (BuCy2) regimen in which either oral Bu or i.v. Bu was administered. Data from 2 similar groups of patients treated between March 1995 and December 1997 were analyzed. Thirty patients were treated with oral Bu (1 mg/kg x 16 doses) at City of Hope and 61 patients were treated with i.v. Bu (0.8 mg/kg x 16 doses) in a multicenter trial involving 7 sites. Bu was followed by Cy (60 mg/kg x 2 days) and a histocompatible-sibling-donor HSCT. In the i.v. Bu treatment group, 48% of the patients were classified as heavily pretreated (> or = 3 prior chemotherapy regimens, prior radiation, or prior HSCT) with 13% having had a prior HSCT and 75% having active disease at the time of transplantation. According to the same classification criteria, 33% of the patients in the oral-Bu treatment group were considered heavily pretreated, with 23% having had a prior HSCT and 80% having active disease at the time of transplantation. The incidence rates of clinically diagnosed HVOD were 5/61 (8%) and 10/30 (33%) after i.v. and oral Bu, respectively. HVOD-related mortality occurred in 2 (3.3%) of 61 i.v. and 6 (20%) of 30 oral Bu patients. The (standardized) Jones criteria for HVOD were met by 4.9% of i.v. and 20% of oral Bu patients. Univariate logistic regression analysis identified oral versus i.v. Bu (P = .001) and a diagnosis of myelodysplastic syndrome (P = .04) as statistically significant factors in the development of HVOD, with prior extensive treatment identified as marginally significant (P = .25). No other demographic parameter was found to be significant. After adjustment for prior treatment, multivariate analyses showed that the use of oral versus i.v. Bu was the strongest predictor for development of HVOD (odds ratio, 7.5; 95% confidence interval, 2.1-27.2; P = .002). This study showed that the incidence rate of HVOD is significantly lower (P = .002) and the 100-day survival rate significantly higher (P = .002) in patients treated with i.v. Bu than in patients treated with oral Bu when Bu is used as part of a BuCy2 preparative regimen for allogeneic HSCT.""",1
10175,12375317,"Longitudinal measurement of methotrexate liver concentrations does not correlate with liver damage, clinical efficacy, or toxicity during a 3.5 year double blind study in rheumatoid arthritis","OBJECTIVES: In patients with rheumatoid arthritis (RA), we examined whether methotrexate (MTX) and MTX polyglutamate accumulation in the liver correlated with clinical efficacy or clinical/laboratory toxicity. We also began preliminary examination of a new histologic index of liver histology (the Iowa Score) relative to the Roenigk grading system. METHODS: Forty patients with RA participated in a prospective, double blind, 3.5 year study of MTX treatment. Liver biopsies, liver MTX and MTX polyglutamate concentrations, laboratory tests, evaluation of disease activity, and evaluation of adverse events were done prospectively at baseline and at 1, 2, and 3.5 years. Biopsies were examined using the Roenigk grading system and an additional histological scoring system. Radiochemical ligand binding assays and HPLC methods were used to measure MTX and MTX polyglutamates. Statistical analysis included ANOVA, linear regression, and logistic regression modeling. RESULTS: No significant changes in the mean values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, or hemoglobin occurred. A significant percentage of patients had at least one abnormal alkaline phosphatase, AST, or ALT (25 to 52%), although most abnormalities were small and transient. Histological abnormalities did not progress using either the Roenigk or the Iowa score. The last abnormal AST, the number of abnormal AST and ALT, and female sex correlated with histological liver abnormalities (r2 = 0.41) using a new preliminary histologic scoring system (the Iowa Score). Amount of alcohol use correlated with fatty change, and the MTX dose at biopsy was associated with liver histological abnormalities (p = 0.03 and 0.049, respectively). Total liver MTX concentrations were stable from Year 1 to Year 3.5 and the percentage of higher order polyglutamates was relatively high (38 to 56%) relative to monoglutamates. No correlation of these concentrations with clinical response or toxicity, histology, or liver function tests could be documented. CONCLUSION: This analysis describes the accumulation and stabilization of MTX concentrations in the liver and examined correlations between MTX liver concentrations, patient demographics, liver histology, concomitant medications, and disease activity. No such correlations were found, decreasing the likelihood that MTX concentrations in serum would be useful measures to predict significant hepatotoxicity.",1
10176,12379063,Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial,"""BACKGROUND: Rifampin and pyrazinamide are recommended for treatment of latent tuberculosis infection in adults without HIV infection, but reports of severe hepatotoxicity have raised concerns about its safety. Clinical trials have not compared this treatment with isoniazid in adults without HIV infection. OBJECTIVE: To compare the safety and tolerance of a 2-month regimen of rifampin and pyrazinamide with that of a 6-month regimen of isoniazid for treatment of latent tuberculosis infection. DESIGN: Multicenter, prospective, open-label trial. SETTING: Three urban public health tuberculosis clinics in the United States. PATIENTS: 589 adults with latent tuberculosis infection who met U.S. criteria for treatment. INTERVENTION: Patients were assigned in alternate weeks to receive rifampin and pyrazinamide daily for 2 months (n = 307) or isoniazid daily for 6 months (n = 282). MEASUREMENTS: Primary end points were hepatotoxicity, other adverse events, and percentage of patients who completed treatment. RESULTS: Sixteen of 207 (7.7%) patients assigned to rifampin and pyrazinamide developed grade 3 or 4 hepatotoxicity compared with 2 of 204 (1%) patients assigned to isoniazid (odds ratio, 8.46 [95% CI, 1.9 to 76.5]; P = 0.001). The rifampin plus pyrazinamide regimen was more likely than the isoniazid regimen to be discontinued because of hepatotoxicity (odds ratio, 5.19; P = 0.033). The overall percentage of nonhepatotoxic adverse events was 20% in the rifampin-pyrazinamide group and 16% in the isoniazid group. The proportion of patients who completed the study treatment was 61% and 57%, respectively. CONCLUSIONS: A 2-month regimen of rifampin and pyrazinamide was associated with an increased risk for grade 3 or 4 hepatotoxicity compared with a 6-month regimen of isoniazid. Liver enzymes should be measured routinely during treatment to screen for liver injury and prevent progression to severe toxicity.""",1
10177,12381969,Beta interferons for multiple sclerosis,,1
10178,12387696,Meloxicam,"Meloxicam (Mobic trade mark, Boehringer Ingelheim) is a relatively new oral non-steroidal anti-inflammatory drug (NSAID) approved for the treatment of osteoarthritis in the US. It has also been evaluated for the treatment of rheumatoid arthritis, ankylosing spondylitis and acute 'rheumatic' pain. Meloxicam has been shown to be COX-2 preferential, particularly at its lowest therapeutic dose, and is anti-inflammatory by inhibiting prostanoid synthesis in inflammatory cells. Since it is COX-2 preferential, it would be expected to have less gastrointestinal toxicity than non-selective NSAIDs. In clinical trials of meloxicam in osteoarthritis, it was found to be as effective as piroxicam, diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations, obstructions and bleeds by meta-analysis. Adverse events, including peripheral oedema and hypertension, occurred at a similar rate as with traditional NSAIDs.",1
10179,12393437,Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome,"Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.",1
10180,12396323,"The pharmacokinetics, safety and tolerability of the co-administration of diethylcarbamazine and albendazole","""The pharmacokinetics, safety and tolerability of single, oral doses of diethylcarbamazine (DEC) and albendazole, given alone or in combination, were investigated in a double-blind, randomized and placebo-controlled trial involving 42 amicrofilaraemic subjects living in an area of India where lymphatic filariasis is endemic. The subjects (34 males and eight females, aged 18-52 years and weighing 46-66.5 kg) were randomly allocated to one of the three drug groups. Fourteen were given just DEC (6 mg/kg), another 14 were given just albendazole (400 mg) and the remaining 14 were given both DEC (6 mg/kg) and albendazole (400 mg). Blood samples for pharmacokinetic study were collected at specified intervals before and after drug administration. Plasma concentrations of DEC and albendazole/albendazole sulphoxide were estimated using gas chromatography and HPLC, respectively. The safety and tolerability of the treatments were evaluated through clinical and laboratory assessments. Both the DEC and albendazole were well tolerated when given alone or in combination, no adverse events being observed. In all three treatment groups, the drugs were rapidly absorbed from the gastro-intestinal tract although there was marked inter-individual#10; variation. The pharmacokinetics of DEC, albendazole and albendazole sulphoxide were similar, whether each drug was given alone or in combination. These results indicate that there is no adverse pharmacokinetic or pharmacodynamic reason why DEC and albendazole should not be co-administered to control lymphatic filariasis.""",1
10181,12399158,Mechanisms of idiosyncratic drug reactions: the case of felbamate,"""Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and often result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate. To date there exists no pre-clinical model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, we have studied the IDR associated with a model compound, felbamate. Our studies with felbamate are consistent with the theory that compounds which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In additon, our data suggest that under normal physiological conditions glutathione plays a protective role in preventing IDR during felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clinical studies with felbamate have been able to demonstrate an association between reactive metabolite formation and a clinically relevant toxicity; however, additional research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.""",1
10182,12399240,Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn's disease,"Ciprofloxacin, a fluorinated quinolone, is a powerful antibiotic widely used for its broad spectrum of activity in ambulatory and long-term care setting. Until now, ciprofloxacin administration has been associated with a few cases of acute, sometimes cholestatic jaundice or fulminant hepatic failure believed mainly related to idiosyncratic hypersensitivity. We report a case of delayed and prolonged cholestatic hepatitis with ductopenia occurring after 6 months of treatment in a patient with Crohn's disease. This observation suggests the potential for the drug to induce long-term likely dose-related severe hepatotoxicity.",1
10183,12404034,"[Sodium gold thiosulfate therapy: an open, viewed, multicenter trial in rheumatoid arthritis patients followed for two years]","OBJECTIVE: To evaluate if parenteral gold-therapy with Sodium gold thiosulfate is effective and safe for the treatment of rheumatoid arthritis we began an open, multicenter trial. METHODS: 126 rheumatoid arthritis patients were treated with Sodium gold thiosulfate for two years. Efficacy, quality of life, progression of joint damage, inflammatory parameters and side effects were evaluated. RESULTS: Gold salts reduced joint inflammation and improved subjective and objective symptoms, quality of life and activity of illness within 6 months. Side effects appeared in 13,8% of all cases and regressed, promptly, when gold therapy stopped. The poor efficacy caused the interruption and the change from the gold therapy to others disease-modifying anti-rheumatic drugs (DMRDs) in 17,8 % of the patients. CONCLUSIONS: The follow-up showed Sodium gold thiosulfate was effective in Rheumatoid Arthritis and the survival in therapy was of 77,8% to one year and of 68,4% to two years.",1
10184,12404619,Efficacy and safety of novel antipsychotics: a critical review,"Efficacy and safety of novel antipsychotic (AP) drugs (amisulpride, olanzapine, quetiapine, ziprasidone and zotepine) have been reviewed. Data on their antipsychotic efficacy and side effects profile have been evaluated only on the basis of controlled trials so far published. Overall, all these drugs have shown an antipsychotic efficacy on positive symptoms of schizophrenia similar to that of the conventional AP drugs. On negative symptoms, all novel AP drugs, except quetiapine and ziprasidone, demonstrated a better efficacy than haloperidol. Long-term efficacy of these AP drugs in the maintenance treatment of schizophrenia needs to be explored by further, better-designed, epidemiological studies. The safety profile shows that the novel AP drugs are generally well-tolerated and induce significantly less acute extrapyramidal side effects in comparison with haloperidol. Some methodological flaws in the experimental design of the clinical trials analysed are discussed. Although these novel AP drugs have potential clinical advantages, a number of relevant questions still remain to be addressed, in order to establish the impact of these drugs in the overall treatment of schizophrenia. Copyright 2000 John Wiley & Sons, Ltd.",1
10185,12407142,Fulminant hepatic failure after the start of an efavirenz-based HAART regimen in a treatment-naive female AIDS patient without hepatitis virus co-infection,,1
10186,12408730,Tolerabilities of antiretrovirals in paediatric HIV infection,"Data on the efficacy and tolerability of antiretrovirals in children are limited as, in contrast to adult studies, large paediatric cohort studies are lacking. Thus, data pertaining to adults are often extrapolated to children despite the acknowledgement that children are not little adults. This review summarises information gathered from existing reports and focuses on the tolerabilities of antiretrovirals in children infected with HIV-1. The efficacy of antiretrovirals is not included in the scope of the discussion. Taste of antiretrovirals should be an important factor when considering the tolerability of antiretrovirals in children. However, antiretroviral options are often limited in young children as only some of the antiretrovirals are available as paediatric formulations. All antiretrovirals have been associated with toxicities in children, but in general, they are relatively well tolerated. The gastrointestinal system including hepatic system is most prone to being affected by these drugs. Skin rashes and hypersensitivity reactions are also associated with antiretroviral use, particularly with the non-nucleoside reverse transcriptase inhibitors. Mitochondrial toxicities that lead to impairment of liver function, pancreatic function and lactic acidosis are associated with most of the nucleoside analogues. Haematological toxicity is often a dose limiting adverse effect especially of the nucleoside analogues, in particular zidovudine. The protease inhibitors are associated with gastrointestinal intolerance (diarrhoea) and metabolic derangements that can lead to hypercholesterolaemia and hypertriglyceridaemia, which in turn and can lead to changes in body habitus. The renal system is also affected by several drugs, the most important of which is indinavir, which has been associated with renal stones and damage to the renal tubules. Fortunately, with lower incidence of major toxicity and with the range of drugs now available for paediatric use, toxicities are usually not a barrier to effect antiretroviral therapy in children.",1
10187,12414243,Safety concerns about kava not unique,,1
10188,12422250,Naltrexone in the treatment of alcohol dependence: a Canadian trial,"OBJECTIVES: Alcohol dependence is a prevalent psychiatric disorder affecting approximately 12% of the adult population at some point in their lifetime. Psychosocial treatments are associated with only modest success rates. The first Canadian clinical trial with naltrexone, an opiate antagonist, was conducted to evaluate its safety and usefulness as an adjunctive treatment in the management of alcohol dependence. METHODS: One hundred twenty alcohol-dependent individuals were assessed to receive treatment with 50 mg of naltrexone orally for 12 weeks in an open-label trial. Patients were seen biweekly and received a concurrent psychosocial intervention. Treatment was conducted at multiple sites in Canada. RESULTS: Fifty-four per cent of subjects completed the entire 12 weeks of treatment. During the study, 39% of patients abstained, while of the individuals reporting drinking at baseline, 86% were consuming less alcohol by their final visit. These reductions were accompanied by a significant decrease in craving for alcohol at week 12, as measured by the Obsessive Compulsive Drinking Scale (P<0.01). Naltrexone was well tolerated and no serious adverse events were experienced. CONCLUSIONS: The data lend support to the hypothesis that endogenous opioid activity is involved in the regulation of alcohol intake, and that antagonists of endogenous opioids decrease craving and drinking. Opiate antagonists such as naltrexone are a new strategy in the treatment of alcohol dependence. Naltrexone can be safely given to female and male alcoholics, is acceptable to patients, and plays a role in reducing alcohol consumption and preventing relapse to heavy drinking.",1
10189,12428223,"Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial","OBJECTIVE: To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses. METHODS: The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebo-controlled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebo-controlled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure). RESULTS: A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy. CONCLUSION: The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.",1
10190,12434090,[Acute cytolytic hepatitis after taking venlafaxine],,1
10191,12435222,Pharmacologic management of acute attacks of migraine and prevention of migraine headache,,1
10192,12437496,Fluvastatin,"Fluvastatin was the first wholly synthetic statin to the market and is effective in reducing total and low density lipoprotein cholesterol, which translates into reductions in coronary heart disease events. The Lescol Intervention Prevention Study has established the effectiveness of the early use of statins in reducing recurrent events in high-risk patients with coronary heart disease post percutaneous coronary interventions. Fluvastatin is well-tolerated with few side effects. The occurrence of significant abnormalities in liver enzymes is infrequent, and the risk of myositis and rhabdomyolysis seems to be less than with other statins. There have been no reports of fatal rhabdomyolysis to date. The potential for drug interactions with fluvastatin is low. It seems safe in combination with cyclosporin and there have been few reports of rhabdomyolysis when using fluvastatin in combination with other lipid-lowering agents. It is nevertheless important to be vigilant for this potentially important side effect and, as with other statins, inform patients of the potential risk and suggestive symptoms. Fluvastatin provides a useful option in treating hypercholesterolaemia in patients at high risk of coronary heart disease.",1
10193,12439126,Vanishing bile duct syndrome associated with elevated pancreatic enzymes after short-term administration of amoxicillin,"Amoxicillin is a widely used antibiotic, rarely being considered a cause of hepatic injury. We report the case of a 45-year-old woman who developed a vanishing bile duct syndrome 8 weeks after initiation of amoxicillin therapy. Liver biopsy showed destruction and loss of preformed bile ducts together with an inflammatory infiltrate involving eosinophilic leucocytes. Cholestasis was progressive despite prednisolone treatment and was accompanied by elevation of pancreatic enzymes. The patient died after 18 months from progressive liver failure. This case illustrates that amoxicillin alone can be a cause of progressive and ultimately fatal vanishing bile duct syndrome.",1
10194,12440344,[Clinical case of the month. Cholestatic hepatitis after administration of piperacillin],"We describe a patient suffering from infection of the upper respiratory tract, who was treated with a dose of 4 x 4 g of piperacillin over 10 days. Two days after the end of the treatment, she developed jaundice and had elevated alkaline phosphatase, gammaglutamyltransferase and transaminases. After exclusion of viral hepatitis, a vascular problem, and gall stone disease, the possibility of piperacillin-induced hepatitis was discussed. Lymphocyte transformation test for piperacillin was positive, suggesting an immunological mechanism for the observed hepatopathy. The patient was discharged a few days after in good clinical condition and with reduced liver values. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 2 months. We conclude that short-term therapy with piperacillin can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Positive lymphocyte transformation is compatible with an immunological mechanism.",1
10195,12446275,Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis,"""An alternative regimen for the treatment of latent tuberculosis infection is 2 months of rifampin and pyrazinamide, but some patients have died of hepatitis associated with this therapy. One hundred fourteen patients received rifampin/pyrazinamide in Wake County, North Carolina, between December 1999 and May 2002; 60.5% of these patients were homeless, and at least 17% drank alcohol to excess. Seventy-seven patients (67.5%) completed a full 2-month course. Nine patients had a history of viral hepatitis or chronic liver disease. Four of 114 (3.5%; 95% confidence interval, 1.0-8.7%) patients developed hepatitis on therapy, and another two had symptoms consistent with hepatitis but did not report for laboratory testing (total confirmed plus suspected hepatitis rate 5.3%; 95% confidence interval, 2.0-11.1%). No patient who developed hepatitis had a history of viral hepatitis or liver disease, and none had been previously treated with isoniazid. No patients died or were hospitalized due to drug side effects. Rifampin/pyrazinamide was associated with a significantly higher rate of hepatitis than previously described with isoniazid therapy for latent tuberculosis but resulted in a high completion rate. The rifampin/pyrazinamide regimen for latent tuberculosis infection may be useful for high-risk, traditionally nonadherent patient groups, but careful monitoring for toxicity is required.""",1
10196,12451188,"Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial","""BACKGROUND: Interferon beta (IFNbeta) reduces relapses and MRI activity in relapsing-remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial. METHODS: This randomized, controlled, multicenter trial compared the efficacy and safety of IFNbeta-1a (Rebif) 44 micro g subcutaneously three times weekly (tiw), and IFNbeta-1a (Avonex) 30 micro g IM once weekly (qw) in 677 patients with RRMS. Assessors blinded to treatment performed neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks. RESULTS: After 24 weeks, 74.9% (254/339) of patients receiving IFNbeta-1a 44 micro g tiw remained relapse free compared with 63.3% (214/338) of those given 30 micro g qw. The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks, favoring 44 micro g tiw. Patients receiving 44 micro g tiw had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks) compared with those receiving 30 micro g qw. Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage. Neutralizing antibodies developed in 25% of 44 micro g tiw patients and in 2% of patients receiving 30 micro g qw. CONCLUSIONS: IFNbeta-1a 44 micro g subcutaneously tiw was more effective than IFNbeta-1a 30 micro g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.""",1
10197,12452750,Acute cholestatic hepatitis associated with celecoxib,"OBJECTIVE: To report a case of acute cholestatic hepatitis associated with the selective cyclooxygenase-2 inhibitor celecoxib. CASE SUMMARY: A 41-year-old white man was hospitalized for jaundice after 2 doses of celecoxib 200 mg for pain associated with right-knee trauma. Laboratory workup showed hyperbilirubinemia, mildly elevated serum transaminase concentrations, and cholestasis. Abdominal imaging showed no dilation of the biliary tree. Histology showed cholestasis, with bile plugs in dilated bile canaliculi and a mild portal infiltrate that are highly suggestive of drug-induced cholestasis. DISCUSSION: This is the fourth report in the English-language literature describing cholestatic hepatitis temporally related to celecoxib use, the second supported by histologic findings typical of drug-induced cholestasis, and the first in a patient who denied use of alcoholic beverages and was taking no other drugs or herbal products at the time of the reaction. The Naranjo probability scale indicated that celecoxib was a probable cause of acute cholestatic hepatitis in this patient. CONCLUSIONS: Cholestatic hepatitis is a well-recognized adverse effect of several drugs. Although celecoxib is considered to have a very low potential for hepatic toxicity, well-documented reports of adverse reactions can contribute significantly to the definition of more accurate safety profiles for new drugs introduced into clinical practice.",1
10198,12454559,Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a German multicenter study,"In a placebo-controlled, double-blind German multicenter study (seven sites) the efficacy of naltrexone as an adjunctive treatment in alcoholism to maintain abstinence was assessed for 12 weeks. A total of 171 detoxified patients (97.7% met the DSM-III-R criteria for alcohol dependence) were included. Patients had been abstinent for a mean of 19.5 +/- 9.4 days at study entry. Eighty-four and 87 patients were randomized to receive naltrexone (50 mg/day) and placebo, respectively. Each site was instructed to provide its usual psychosocial alcohol treatment program. The primary effectiveness measure was the time to first heavy drinking as derived from self-reports of drinking (timeline-follow-back method). Secondary effectiveness measures included time to first drink, amount of alcohol consumption, intensity of craving, severity of alcoholism problems, and liver enzymes. Thirty-three (38%) placebo patients and 28 (33%) naltrexone patients discontinued the study. At endpoint, 62% of the patients in each group did not have an episode of heavy drinking. Also, there were no significant differences between the study groups concerning secondary effectiveness measures as well as compliance and adverse clinical events--with the exception of the gamma-GT, which was significantly greater reduced in the naltrexone group throughout the study. Based upon an intention-to-treat population, this study confirms the safety but not the efficacy of naltrexone in prevention of alcohol relapse. Nevertheless, the question arises whether self-reports of drinking are more reliable than gamma-GT as a measure of recent alcohol consumption.",1
10199,12456539,Surveillance for fatal suspected adverse drug reactions in the UK,"AIM: To determine the nature and number of suspected adverse drug reactions (ADRs) associated with fatal outcomes in children reported through the yellow card scheme. METHODS: All reports of suspected ADRs with a fatal outcome in children received by the UK Committee on Safety of Medicines through its Yellow Card Scheme from 1964 until December 2000 were reviewed. Reports associated with vaccines and overdose were excluded. The medicine, date of the report, diagnosis, ADR, and the age of the child were analysed. No formal causality assessment was performed. RESULTS: There were 331 deaths with 390 suspected medicines reported for children aged 16 years or less. Medicines most frequently mentioned were anticonvulsants (65 deaths), cytotoxics (34 deaths), anaesthetic agents (30 deaths), and antibiotics (29 deaths). The individual drug most frequently mentioned was sodium valproate (31 deaths). The nature of the reported ADRs were diverse, with hepatic failure the most frequent. In the past decade, there has been an increase in both the total number of suspected ADRs reported in children and the number of reports with a fatal outcome. CONCLUSIONS: A wide range of suspected ADRs are associated with fatalities in children. Anticonvulsants were associated with the greatest number of reports of fatalities and hepatotoxicity in particular.",1
10200,12461586,Mortality due to liver failure and impact on survival of hepatitis virus infections in HIV-infected patients receiving potent antiretroviral therapy,"The aim of the present study was to examine the causes of death, the mortality attributable to liver failure, and the impact of hepatitis virus infections on the survival of a cohort of HIV-infected patients before and after the extensive use of highly active antiretroviral therapy (HAART). Liver disease associated with hepatitis C virus (HCV) seems to be accelerated in patients infected with the human immunodeficiency virus (HIV). On the other hand, the effect of HCV on HIV progression was controversial before the introduction of HAART. However, the last study to report changes in mortality due to liver failure was published in 1997, and the impact of HCV carriage on the survival of HIV-infected patients receiving HAART needs to be clarified. In this investigation, 492 patients who were prescribed antiretroviral drugs between April 1989 and September 2000 were included in the study cohort. The median duration of follow-up of the cohort was 1,392 days. HCV infection was present in 323 (68%). Mortality attributable to AIDS decreased from 4.5 to 1.8 per 100 persons per year. Mortality due to liver failure increased from 0.3 to 0.5 per 100 persons per year ( P<0.01). The survival of patients with and without HCV infection was similar ( P=0.8). Although liver failure is an increasing cause of death among HIV-infected patients receiving HAART, HCV infection has still no impact on the survival of HIV-infected patients.",1
10201,12465084,Entacapone-induced hepatotoxicity and hepatic dysfunction,"We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports.",1
10202,12466051,Morinda citrifolia (Noni): a literature review and recent advances in Noni research,"Morinda citrifolia L (Noni) has been used in folk remedies by Polynesians for over 2000 years, and is reported to have a broad range of therapeutic effects, including antibacterial, antiviral, antifungal, antitumor, antihelmin, analgesic, hypotensive, anti-inflammatory, and immune enhancing effects. In order to reveal the nutritional and medicinal value of the Noni plant, and to summarize scientific evidence that supports the Polynesians' claim, a literature review and recent advances in Noni research is given below.",1
10203,12469151,Tamoxifen-induced non-alcoholic steatohepatitis in patients with breast cancer: determination of a suitable biopsy site for diagnosis,"We have evaluated the distribution of fatty infiltration in the liver for determination of a suitable biopsy site for diagnosis of tamoxifen-induced non-alcoholic steatohepatitis (NASH) in patients with breast cancer. Thirty-eight consecutive breast cancer patients undergoing tamoxifen treatment were analyzed by CT to identify hepatic steatosis (HS) via calculation of the liver/spleen CT ratio in Couinaud's 8 areas. We defined hepatic fatty infiltration as a liver/spleen ratio of less than 0.9. The extent and distribution of the fatty infiltration was assessed using the liver/spleen ratio of the patients who had the lowest CT ratio below 0.9 in the 8 areas. Thirteen (34.2%) of the 38 patients had hepatic fatty infiltration. The liver/spleen ratios of each area differed significantly in all patients (p<0.0001). The CT ratio of these 13 patients was significantly lower in the right lobe than the left lobe (p<0.0001), although the ratios did not differ significantly among the 4 areas of the right lobe (p=0.52). Needle biopsy for diagnosis of NASH should be performed at the right lobe, which contains significantly more infiltrated fat than the left lobe in the liver.",1
10204,12473959,Gamma hydroxybutyrate (Xyrem) for narcolepsy,,1
10205,12477481,Isolated liver perfusion for non-resectable liver tumours: a review,"Many treatments have been proposed for non-resectable primary or secondary hepatic cancer but the results have generally been disappointing. Isolated Hepatic Perfusion (IHP) was first attempted four decades ago but it gained acceptance only recently, after spectacular tumour responses were obtained by isolated limb perfusion with melphalan and tumour necrosis factor (TNF) for melanomas and sarcomas. Surgical isolation of the liver is a technically demanding operation that allows the safe administration of high doses of chemotherapeutics and TNF. Percutaneous techniques using balloon occlusion catheters are simpler but result in higher leakage rates from the perfusion circuit into the systemic circulation. Several phase I-II trials indicate that IHP can yield high tumour response rates, even when there is resistance to systemic chemotherapy. However, no significant advantage in overall survival has been demonstrated so far. IHP offers unique pharmacokinetic advantages for locoregional chemotherapy and biotherapy. It might also allow gene therapy with limited systemic exposure and toxicity. At present, IHP nevertheless remains an experimental treatment modality which should therefore be used in controlled trials only.",1
10206,12490491,Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy,"""OBJECTIVE: A study was conducted on hepatic fat content to investigate the frequency and clinical course of hepatic steatosis induced by tamoxifen. MATERIALS AND METHODS: Sixty-seven patients with breast cancer treated with adjuvant tamoxifen were included. The patients underwent postoperative annual abdominal CT, both with and without contrast enhancement, for 5 years. We retrospectively reviewed unenhanced CT images and obtained hepatic and splenic CT attenuation values to calculate the liver-spleen ratio. Hepatic steatosis was defined as a liver-spleen ratio of less than 0:9, and its degree was classified as mild (liver-spleen ratio, 0:5-0:9), moderate (0-0:5), or severe (<0). The pattern of steatosis was classified as generalized, lobar, segmental, or focal. RESULTS: In the study population, hepatic CT values decreased during therapy (p < 0.0001, t test) and increased after therapy (p < 0.0001, paired t test). Twenty-nine patients (43.2%) developed hepatic steatosis within the first 2 years; its degree was mild in 16, moderate in nine, and severe in four. Seventeen patients showed a generalized pattern of steatosis, and the other 12 showed a lobar pattern. Twenty-three of these patients showed an increase in the liver-spleen ratio after therapy to within the normal range, with a mean recovery time of 1.2 years after therapy ended. None progressed to steatohepatitis or cirrhosis. CONCLUSION: Tamoxifen had a statistically significant influence on hepatic fat content and was associated with frequent development of hepatic steatosis. Radiologists should be aware of this phenomenon and the possible occurrence of hepatic dysfunction and should differentiate steatosis from metastasis in postoperative patients with breast cancer.""",1
10207,12490687,Herbal remedies,,1
10208,12492247,Light and electron microscopic analysis of liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy,"""OBJECTIVE: We study liver damage in forty-two patients with rheumatoid arthritis (RA) using light (LM) and electron microscopy (EM) and assess histological changes after four years of treatment with methotrexate (MTX). PATIENTS AND METHODS: liver biopsies (LB) were taken before and after four years of treatment. Patients received weekly doses of between 7.5-15 mg of MTX. RESULTS: Fourteen per cent of the baseline LB presented mild perisinusoidal fibrosis (Roenigk IIIA) and the rest a lower Roenigk grade; EM identified an increase in collagen fibers in the Disse spaces in 50% of baseline LB. Neither microscopy technique revealed histological progression in any of the sequential LB. Variables that correlated with histological abnormalities were patient's age, length of evolution of the disease, alcohol consumption and biochemical data (gammaglutamate transferase and albumin); the cumulative dose of MTX was not correlated with worse histological findings. Correlation between the two microscopy techniques was good, though EM was more sensitive than LM for the detection of fibrosis. CONCLUSIONS: RA patients present with liver damage before treatment with MTX. The alterations are mild. At low doses MTX treatment is safe. In addition to the recommendations of the American College of Rheumatology, other factors associated with liver impairment are patient's age and length of evolution of the RA.""",1
10209,12497002,Caffeine test in predicting flutamide-induced hepatic injury in patients with prostate cancer,"""The caffeine test measures the activity of cytochrome p450 (CYP1A2) which is a major enzyme involved in the activation of flutamide. The usefulness of this test in predicting flutamide-induced hepatic injury in patients with prostate cancer was examined. The subjects were: (1). five patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level rose to 100 IU/l or higher following the start of flutamide (moderately injured group); (2). four patients whose AST and ALT levels were higher than normal but less than 100 IU/l (mildly injured group); and (3). two patients whose hepatic function remained normal (normal group). The subjects were each given canned coffee to drink. Urinary caffeine (137X), paraxanthine (17X) and 1, 7-dimethyluric acid (17U) levels were measured 4-5 h later. The metabolite ratio, (17U+17X)/137X, was calculated to serve as an indicator of CYP1A2 activity. The metabolite ratio for the moderately injured group (3.98+/-1.56) and the mildly injured group (5.55+/-1.42) were lower than that for the normal group (9.56). The results suggest that a decrease in CYP1A2 activity is involved in the onset of flutamide-induced hepatic injury, and that the caffeine test seems to provide a useful means of its prediction.""",1
10210,12500154,Dutasteride (Avodart) for benign prostatic hyperplasia,,1
10211,12501883,"Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of patients hospitalized with community-acquired pneumonia: a randomized, open-label, multicenter study of clinical efficacy and tolerability","""OBJECTIVE: This study aimed to compare the efficacy and safety of oral gemifloxacin, an enhanced-affinity quinolone, with sequential therapy with IV ceftriaxone followed by oral cefuroxime (with or without a macrolide) in patients hospitalized for community-acquired pneumonia (CAP). METHODS: A randomized, open-label, multicenter study comprised adults hospitalized with a clinical and radiologic diagnosis of CAP. Patients were randomized 1:1 to receive either (1) oral gemifloxacin 320 mg once daily (7-14 days); or (2) IV ceftriaxone 2 g once daily (1-7 days) followed by oral cefuroxime 500 mg twice daily (1-13 days) for a total of < or = 14 days. Patients receiving ceftriaxone/cefuroxime were allowed concomitant macrolide treatment. RESULTS: A total of 345 patients were randomized, of whom 341 received at least 1 dose of study medication (gemifloxacin, 169/172; ceftriaxone/cefuroxime, 172/173). Clinical success rates in the clinically evaluable (CE) population at follow-up (day 21-28 post-therapy), the primary end point, were 92.2% (107/116) for gemifloxacin and 93.4% (113/121) for ceftriaxone/cefuroxime (treatment difference, -1.15; 95% CI, -7.73 to 5.43). In patients in Fine risk classes IV and V, the clinical success rate was 87.0% (20/23) for gemifloxacin versus 83.3% (20/24) for ceftriaxone/cefuroxime. No difference in clinical response at follow-up was noted based on macrolide use. Bacteriologic success rates at follow-up in the bacteriologically evaluable (BE) population were 90.6% (58/64) for gemifloxacin and 87.3% (55/63) for ceftriaxone/cefuroxime (treatment difference 3.32; 95% CI, -7.57 to 14.21). The clinical success rate in bacteremic patients at follow-up (BE population) was 100.0%. Both treatments were generally well tolerated. The frequency and types of adverse events were similar between the 2 groups. The most common treatment-related adverse events with gemifloxacin were diarrhea, liver-function adverse events, and rash; with ceftriaxone/cefuroxime, they were diarrhea, elevated hepatic-enzyme activity, and moniliasis. CONCLUSION: The clinical efficacy and tolerability of oral gemifloxacin 320 mg once daily were similar to those of IV ceftriaxone followed by oral cefuroxime (with or without a macrolide) in the treatment of adult patients hospitalized with moderate to severe CAP. Both treatments were effective in bacteremic patients and those at increased risk of mortality.""",1
10212,12503933,Fulminant liver failure associated with clarithromycin,"OBJECTIVE: To report a patient developing fulminant liver failure while being treated with clarithromycin for pneumonia. CASE SUMMARY: A 58-year-old white woman developed fulminant liver failure while being treated with the macrolide antibiotic clarithromycin for pneumonia. Comedication included N-acetylcysteine, atenolol, and isradipine. Other causes of liver failure, such as viral hepatitis, autoimmune hepatitis, toxins, and heart failure, were excluded by appropriate diagnostic means. All drugs were stopped, and the patient was transferred to another hospital for liver transplantation. She recovered spontaneously within several days, making transplantation unnecessary. A liver biopsy obtained 10 days after the initial presentation revealed centroacinar necrosis and beginning fibrous reorganization, compatible with recent centroacinar damage. DISCUSSION: Since no other cause could be identified, liver injury was considered to be drug related. Fulminant liver failure has not previously been described with concomitant use of atenolol and N-acetylcysteine. Although isradipine has been associated with hepatocellular injury, there are no reports of fulminant liver failure with this agent, and our patient had been treated for >2 years without signs of toxicity. The most likely cause of liver failure in this patient was, therefore, clarithromycin, which undergoes hepatic metabolism and has been reported to cause fulminant hepatic failure. A second possibility is an interaction between clarithromycin and isradipine, potentially increasing the hepatic toxicity of isradipine. CONCLUSIONS: Clarithromycin may be a cause of fulminant liver failure either alone or by inhibiting the metabolism of other drugs.",1
10213,12504397,"Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial","""BACKGROUND: Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients. METHODS: 194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy. FINDINGS: Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268). INTERPRETATION: Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.""",1
10214,12506529,Acute hepatitis complicating intravenous amiodarone treatment,"We describe a case of acute hepatitis after a loading dose of intravenous amiodarone. An 83-year-old woman was admitted in emergency for recent-onset atrial fibrillation associated with left ventricular failure. Twenty-four hours after having started parenteral amiodarone, she developed biochemical alterations indicative of severe hepatic cytolysis associated with impairment of the synthetic capacity which rapidly reverted after suspension of the drug. No clinical sign or symptom of hepatopathy was noted except for mild icterus. A review of the literature regarding amiodarone-related hepatotoxicity is reported.",1
10215,12510038,A controlled trial of natalizumab for relapsing multiple sclerosis,"BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.",1
10216,12520208,[Microvacuolar steatosis following low doses of doxycycline],,1
10217,12525716,"Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial","""BACKGROUND: Patients with primary progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to primary progressive MS. METHODS: Fifty subjects were randomized to weekly IM interferon beta-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability. Secondary outcomes included the timed 10-meter walk, nine-hole peg test, and on MRI, T2 and T1 brain lesion loads and brain and spinal cord atrophy. RESULTS: The 30- microg dose of interferon beta-1a was well tolerated, but the 60- microg dose caused severe flulike reactions and raised liver enzymes. No treatment effect was seen on the primary endpoint. Subjects on interferon beta-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of ventricular enlargement than controls (p = 0.025). CONCLUSIONS: This study has demonstrated that interferon beta-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.""",1
10218,12527609,Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity,"CONTEXT: American Thoracic Society guidelines recommend a 9-month course of therapy with isoniazid for treatment of persons with latent tuberculosis infection who are at high risk for reactivation of disease. Major liver injury has been reported with the alternative regimen, a 2-month course of pyrazinamide and rifampin. OBJECTIVE: To evaluate the rate of completion and incidence of hepatotoxicity of a short regimen of pyrazinamide and rifampin for latent tuberculosis as compared with standard isoniazid therapy before and after instituting an intensive monitoring program. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 224 patients in a community setting between 1999 and 2001. INTERVENTIONS: Daily pyrazinamide and rifampin for 2 months or daily isoniazid for 6 months. MAIN OUTCOME MEASURES: Treatment completion, hepatotoxicity (fourfold increase of alanine transaminase [ALT]), severe hepatotoxicity (40-fold increase in ALT). RESULTS: Treatment was completed by 71% (78 of 110 patients) in the pyrazinamide/rifampin group and by 59% (67 of 114 patients) in the isoniazid group (p = 0.07). Hepatotoxicity (ALT > 160 U/L) was documented in 13% (14 of 110 patients) in the pyrazinamide/rifampin group and in 4% (5 of 114 patients) in the isoniazid group (p = 0.03). Severe hepatotoxicity (ALT > 1,600 U/L) occurred in 2 of 43 patients (5%) receiving pyrazinamide/rifampin prior to instituting intensive monitoring. Once more intensive monitoring of liver enzymes was implemented, severe hepatotoxicity occurred in none of 67 patients. CONCLUSION: The risk of hepatitis in patients receiving pyrazinamide/rifampin for prevention of latent tuberculosis is increased threefold as compared to patients receiving isoniazid. When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance (p = 0.15).",1
10219,12529096,Linezolid: the first oxazolidinone antimicrobial,"""Linezolid is the first of a new class of antimicrobial agents, the oxazolidinones, to be approved for clinical use in the United States and elsewhere. The drug is a totally synthetic compound, which lessens the likelihood of naturally occurring resistance mechanisms. It has excellent activity against virtually all important gram-positive pathogens, including methicillin-resistant staphylococci, penicillin-resistant pneumococci, macrolide-resistant streptococci, and vancomycin-resistant enterococci. Development of resistance to the compound has been infrequent thus far. Linezolid is 100% bioavailable, so it can be given in equal doses orally or parenterally. Its elimination half-life allows dosing twice per day, and alteration of drug dosage is not required in patients with impaired renal or hepatic function. Linezolid has approved indications for skin and soft tissue infections; lower respiratory tract infections; and vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia. The drug has an acceptable profile of adverse events, but reversible myelosuppression has occurred in patients receiving high doses for more than 2 weeks.""",1
10220,12531167,Efficacy and safety of herbal stimulants and sedatives in sleep disorders,"""World-wide use of herbal medicines is increasing, following regulatory and manufacturing developments. Herbs are attractive alternative medications to many patients with sleep disorders, who may be averse to using conventional drugs. We review here the most common herbal stimulants and sedatives. Caffeine, in herbal teas, black tea, coffee, soft drinks and pharmaceuticals, is used widely to control sleepiness, but more research is needed on its use in sleep disorders. Ephedra, and its constituent ephedrine, are used in both stimulant and weight loss preparations, sometimes with caffeine; safety concerns have arisen with this practice. Yohimbe is another herb used in stimulant and body-building preparations which has safety concerns. Asian and Siberian ginseng have been traditionally used for fatigue, and have some supportive experimental evidence for this use. Herbal sedatives also have some evidence for efficacy; the observations that certain plant flavonoid compounds bind to benzodiazepine receptors adds interest to their use. Valerian and kava have received the most research attention; both have decreased sleep onset time and promoted deeper sleep in small studies, and kava also shows anxiolytic effects. German chamomile, lavender, hops, lemon balm and passionflower are reputed to be mild sedatives but need much more experimental examination.""",1
10221,12534328,The pharmacovigilance of pantoprazole: the results of postmarketing surveillance on 11 541 patients in England,"OBJECTIVE: To conduct a postmarketing surveillance study involving patients treated with pantoprazole in general practice in the 6-month period following the launch of this drug in November 1996. Prescription-event monitoring (PEM) provides data on a large cohort of patients in 'real life' settings. The aim was to monitor the safety of pantoprazole as used in general practice. It was the third proton pump inhibitor launched in the UK. METHODS: Patients were identified by data from dispensed prescriptions (FP10s) written by general practitioners (GPs) in England for pantoprazole. Green forms were posted to GPs approximately 6 months following the first prescription identified. GPs were asked to list events that occurred during and after treatment. The incidence density of each event was calculated, ranked and the difference between the incidence of each event in the first and subsequent months of exposure was tested by constructing confidence intervals. RESULTS: Data were collected for 11 541 patients. The major indications for treatment were oesophageal reflux (22.7%) and dyspepsia (16.9%). Of GPs expressing an opinion, 81.9% reported pantoprazole to be effective. GPs reported 107 events as adverse drug reactions. The most frequent reason given for stopping was diarrhoea (106 patients), which corresponded with the adverse event with the highest incidence density. CONCLUSION: This PEM study has defined the reported safety profile of pantoprazole as used in general practice in England. The commonest adverse events found in this study have already been reported in the Summary of Product Characteristics.",1
10222,12535476,Amantadine in Parkinson's disease,"BACKGROUND: Although levodopa is the most common drug prescribed to relieve the symptoms of Parkinson's disease it is associated with motor and psychiatric side-effects. Consequently, interest has turned to alternative drugs with improved side-effect profiles to replace or augment levodopa. Amantadine, originally used as an antiviral drug, has been shown to improve the symptoms of Parkinson's disease. OBJECTIVES: To compare the efficacy and safety of amantadine therapy (monotherapy or adjuvant therapy) versus placebo in treating people with Parkinson's disease. SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted. SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of patients with a clinical diagnosis of idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion. MAIN RESULTS: Six randomised controlled trials were found comparing amantadine monotherapy or adjuvant therapy with placebo in the treatment of idiopathic Parkinson's disease. Five examined amantadine as adjuvant therapy with optimal levels of levodopa or anticholinergics and one examined amantadine as an adjuvant therapy with minimum tolerated levels of anticholinergics or as a monotherapy. Five were double-blind cross-over studies and one was a double-blind parallel group study. In total they examined 215 patients. The parallel group study allowed the randomisation codes to be broken and allowed patients in the placebo group to then receive amantadine. This could have led to bias. One study did not present the results of the placebo arm of the trial, hence we could not determine the difference between the two treatment groups. Two cross-over studies presented the results of the combined data from both treatment and placebo arms. The risk of carry-over effect into the second arm meant that these results could not be analysed. The final two studies presented at least some of their data from the end of the first arm of the trials. However only means were given, without standard deviations, so we could not determine the statistical significance of any difference between the amantadine and placebo groups. Although the authors did report on the side-effects from amantadine (such as livido recticularis, dry mouth and blurred vision), they state that none of them were severe. REVIEWER'S CONCLUSIONS: A considerable amount of evidence on the effectiveness of amantadine has accrued from non-controlled trials, often in patients with Parkinsonian conditions other than idiopathic Parkinson's disease. However, rigorous analysis of the six randomised controlled trials of amantadine reveals insufficient evidence of its efficacy and safety in the treatment of idiopathic Parkinson's disease.",1
10223,12542566,Paracetamol-induced hepatotoxicity at recommended dosage,"In patients who develop liver damage following moderate paracetamol overdose in the order of 5-10 g daily, recent fasting and nutritional impairment have been identified as key precipitants. Hepatotoxicity caused by paracetamol at recommended dosage, in the absence of exposure to enzyme-inducing drugs, has recently been described as an idiosyncratic phenomenon. The possible importance of fasting and malnutrition in this setting is uncertain. We report a severely malnourished 53-year-old woman who developed severe hepatotoxicity whilst receiving paracetamol at recommended dosage (4 g daily) following a period of fasting, in the absence of enzyme-inducing agents. Subsequent paracetamol exposure up to 2.6 g daily thrice weekly, in the setting of ongoing malnutrition and fasting as before, did not lead to recurrent liver damage. These findings indicate that paracetamol-related liver damage occurring within recommended dosage guidelines can be a dose-dependent rather than necessarily idiosyncratic phenomenon, at least in the setting of recent fasting and severe malnutrition.",1
10224,12544730,Idraparinux and liver enzymes: observations from the PERSIST trial,"A potential influence of idraparinux--a synthetic analogue of the pentasaccharide sequence in heparins--on plasma liver enzyme levels was analysed in 37 patients suffering from deep vein thrombosis and participating in the PERSIST trial. Plasma gamma-glutamyl-transferase, aspartate aminotransferase and alanine aminotransferase were determined prior to enoxaparin treatment (screening), prior to randomization (baseline) and once weekly during the 12-week treatment period. Patients were initially treated with weight-adjusted enoxaparin for 4-7 days and then randomized to either idraparinux (2.5, 5, 7.5 or 10 mg) or warfarin. Gamma-glutamyl-transferase was significantly increased after administration of enoxaparin at the baseline visit (P = 0.004) and in week 2 (P = 0.009) to return to screening levels in week 3 for the remaining study period (all P > 0.05). Aspartate aminotransferase (P = 0.001) and alanine aminotransferase (P < 0.001) were significantly increased at the baseline visit and returned to screening values at week 2 for the remaining study period (all P > 0.05). There was no significant difference between the mean values of plasma liver enzymes of the four idraparinux groups and the warfarin group in all 13 measurements. We concluded that idraparinux in contrast to enoxaparin does not increase plasma liver enzymes significantly.",1
10225,12549952,Acute liver failure with concurrent bupropion and carbimazole therapy,"OBJECTIVE: To report a case of fatal liver failure possibly associated with concurrent use of bupropion and carbimazole. CASE SUMMARY: A 41-year-old Chinese man with a history of hyperthyroidism had been treated with carbimazole and propranolol for the past 5 years. He received a 10-day course of bupropion as an aid for smoking cessation 10 weeks prior to presentation. He developed acute liver failure with rapid deterioration of renal function. Liver biopsy showed evidence of nonspecific drug-induced acute liver injury. His condition was further complicated by sepsis and coagulopathy. Death resulted 19 days after the onset of symptoms. The likelihood that bupropion induced hepatotoxicity in our patient was possible, based on the Naranjo probability scale. DISCUSSION: Although there is increasing evidence of hepatotoxicity induced by bupropion, this is the first case of fatality that could have resulted from acute liver failure in a patient receiving bupropion while on concomitant treatment with carbimazole. CONCLUSIONS: Clinicians should be aware of the possibility of acute liver insult induced by bupropion given concurrently with other hepatotoxic drugs.",1
10226,12556218,Sjogren's syndrome: evolving therapies,"Sjogren's syndrome (keratoconjunctivis sicca) is a relatively common disorder with incidence of approximately 0.5% of adult women. It has both local (ocular and oral) features as well as systemic manifestations. There has been recent FDA approval of agents to stimulate salivation (pilocarpine and cevimeline) and studies are in progress to determine their role in the treatment of dry eye. New therapies are in clinical trials for ocular manifestations with the most interest focused on topical cyclosporin A and purinogenic receptor agonists. In oral therapy, topical human interferon has reported encouraging results in short-term studies. However, the high placebo response (probably reflecting the beneficial response of mechanical stimulation of the buccal mucosa by the lozenge) and the response to much cheaper therapies (such as acid maltose lozenges) may offer safer and cheaper alternatives. For systemic disease, there is interest in tumour necrosis factor inhibitors. However, the cost-effectiveness and safety of biological agents needs longer term follow up, as they appear much less dramatic in their effect on systemic lupus erythematosus or Sjogren's syndrome than in rheumatoid arthritis.",1
10227,12562142,"Efficacy, safety, and tolerability of quetiapine in patients with schizophrenia","Schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population, with its economic cost in the United States alone estimated to exceed that of all cancers combined. The new generation of atypical antipsychotics introduced over the past decade have comparable or greater efficacy than traditional antipsychotics in treating the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. Quetiapine, the fourth atypical antipsychotic marketed in the United States, was approved by the U.S. Food and Drug Administration in September 1997 and is also currently approved in over 70 countries worldwide for the treatment of psychosis associated with schizophrenia. This article will review the clinical trials examining the efficacy, safety, and tolerability of quetiapine in the treatment of patients with schizophrenia.",1
10228,12569078,Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis,"""Major adverse reactions to antituberculosis drugs can cause significant morbidity, and compromise treatment regimens for tuberculosis (TB). Among patients treated for active TB we estimated the incidence, and risk factors, of major side effects from first-line anti-TB drugs. Side effects, resulting in modification or discontinuation of therapy, or hospitalization, were attributed on the basis of resolution after withdrawal, and/or recurrence with rechallenge. Among 430 patients treated between 1990 and 1999, the incidence of all major adverse effects was 1.48 per 100 person-months of exposure (95% confidence interval [95% CI], 1.31 to 1.61) for pyrazinamide, compared with 0.49 (95% CI, 0.42 to 0.55) for isoniazid, 0.43 (95% CI, 0.37 to 0.49) for rifampin, and 0.07 (95% CI, 0.04 to 0.10) for ethambutol. Occurrence of any major side effect was associated with female sex (adjusted hazard ratio, 2.5; 95% CI, 1.3 to 4.7), age over 60 years (adjusted hazard ratio, 2.9; 95% CI, 1.3 to 6.3), birthplace in Asia (adjusted hazard ratio, 2.5; 95% CI, 1.3 to 5.0), and human immunodeficiency virus-positive status (adjusted hazard ratio, 3.8; 95% CI, 1.05 to 13.4). Pyrazinamide-associated adverse events were associated with age over 60 years (adjusted hazard ratio, 2.6; 95% CI, 1.01 to 6.6) and birthplace in Asia (adjusted hazard ratio, 3.4; 95% CI, 1.4 to 8.3), whereas rifampin-associated adverse events were associated with age over 60 years (adjusted hazard ratio, 3.9; 95% CI, 1.02 to 14.9) and human immunodeficiency virus-positive status (adjusted hazard ratio, 8.0; 95% CI, 1.5 to 43). The incidence of pyrazinamide-induced hepatotoxicity and rash during treatment for active TB was substantially higher than with the other first-line anti-TB drugs, and higher than previously recognized.""",1
10229,12583521,Zafirlukast-induced acute hepatitis,"Zafirlukast, a competitive cysteinyl leukotriene receptor antagonist, is a new class of asthma medications. It has shown an adverse event profile similar to that of placebo. Herein, we present a 69-year-old female patient who suffered from general malaise, poor appetite, nausea and jaundice after 3 months of zafirlukast therapy for asthma. She had no past history of liver disease, nor history of alcoholism, herb medication, blood transfusion, acupuncture, tattoo or recent traveling history. Liver biochemistries revealed elevated serum alanine aminotransferase and aspartase aminotransferase levels up to 481 U/L and 212 U/L, respectively. Moreover, peak serum total bilirubin level was elevated to 34.8 mg/dL during admission. Serum viral hepatitis marker, antinuclear antibody, anti-mitochondrial antibody and anti-smooth muscle antibody were all negative. Her general condition and liver biochemistries improved gradually after zafirlukast was discontinued. Roussel Uclaf causality assessment for adverse drug reaction confirmed the diagnosis of drug-induced liver injury. This case reminds us that zafirlukast is a potentially hepato-toxic drug. If clinical manifestations of hepatitis develop, patients should be managed cautiously and closely monitored for liver biochemistries. If drug-induced hepatitis is suspected, medication should be discontinued immediately to prevent further liver injury.",1
10230,12585842,Acute hepatocellular-cholestatic liver injury after olanzapine therapy,,1
10231,12587804,Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy,"""STUDY OBJECTIVE: To evaluate risk factors for the development of arthralgias or myalgias associated with quinupristin-dalfopristin. DESIGN: Retrospective chart review and case-control analysis. SETTING: An 850-bed tertiary care medical center. PATIENTS: All adult and pediatric patients who had received quinupristin-dalfopristin through either a compassionate-use protocol (February 1996-October 1999) or in the year after quinupristin-dalfopristin was added to the hospital formulary (November 1999-October 2000) were included in this study. Case patients were those who developed arthralgias or myalgias while receiving quinupristin-dalfopristin therapy; control patients were those who received quinupristin-dalfopristin but did not develop arthralgias or myalgias. INTERVENTION: Medical records, pharmacy dispensing information, and microbiology data were reviewed by a physician and a pharmacist, both of whom specialized in infectious diseases. Presence or absence of arthralgias or myalgias was the primary outcome assessed. MEASUREMENTS AND MAIN RESULTS: Quinupristin-dalfopristin was administered to 68 patients during the period defined by the study. Arthralgias and myalgias could not be assessed in 18 of the 68 patients because they were sedated and paralyzed, or they were young children who could not communicate the presence of pain. Univariate analysis demonstrated that significant risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin were female sex, chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, major surgery, and receipt of either mycophenolate or cyclosporine. Multivariate analysis demonstrated a strong association with chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate. Of 50 evaluable patients receiving quinupristin-dalfopristin, 25 had pain that may have been associated with this antimicrobial agent. CONCLUSION: The mechanism for development of arthralgias or myalgias associated with quinupristin-dalfopristin remains unknown, but these adverse events are more likely to occur in patients with chronic liver disease and those who have received a liver transplant or are receiving cyclosporine or mycophenolate.""",1
10232,12590235,Hepatotoxicity associated with 6-thioguanine therapy for Crohn's disease,"6-Thioguanine (6-TG) is a thiopurine analogue that is closely related to 6-mercaptopurine (6-MP) and azathioprine (AZA). These agents have potent cytotoxic and immunomodulatory effects and are useful in the treatment of a variety of conditions, including inflammatory bowel disease. Both 6-MP and AZA are widely used and are known to cause hepatotoxicity in a proportion of patients. 6-Thioguanine is being increasingly used in the treatment of inflammatory bowel disease but has not been reported to cause liver injury in this context. We describe a case of significant elevation of serum transaminases in a patient treated with 6-TG for a flare of Crohn's disease. We believe the temporal association of the abnormal liver enzymes in this patient, in the absence of other offending agents, argues strongly in favor of 6-TG as a cause of liver enzyme abnormalities. This case highlights the need to monitor liver enzymes in patients treated with 6-TG and identifies the need for additional research focused on the mechanism of thiopurine-induced hepatic injury.",1
10233,12591083,Valsartan-induced hepatotoxicity in a HBs-Ag-Positive patient,,1
10234,12594381,[Montelukast induced cytolytic acute hepatitis],,1
10235,12598775,A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk,"OBJECTIVE: To evaluate the safety, tolerability, and trough levels of three pre-exposure prophylaxis regimens of nevirapine among HIV-1-uninfected subjects at high risk for HIV-1 infection. METHODS: A phase I/II trial (HIVHOP 101) in which 33 such uninfected subjects received a 200 mg tablet of nevirapine once weekly (cohort A, n = 12), twice weekly (cohort B, n = 12), or every other day (cohort C, n = 9) for 12 weeks. Clinical signs/symptoms, laboratory parameters, and nevirapine trough levels were assessed at entry and at 1, 2, 4, 6, 9, and 12 weeks, with a follow-up sample at 16 weeks. RESULTS: No subject experienced clinical symptoms attributed to nevirapine, including rash. There were no significant changes in liver enzyme levels from baseline to week 12 in the three cohorts, except for glutamyl transpeptidase in cohort B. Median nevirapine trough levels at weeks 1 and 12 were 119 ng/ml (range, < 25-205) and 135 ng/ml (range, < 25-1065), respectively, for cohort A, 569 ng/ml (range, 135-2641) and 431 ng/ml (range, 42-2454) for cohort B, and 1942 ng/ml (range, 1214-2482) and 943 ng/ml (range, 262-5281) for cohort C. No subject became HIV-1 antibody positive by week 16. CONCLUSIONS: A single dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was safely tolerated by the subjects in this small study, and resulted in nevirapine levels well above the IC (inhibitory concentration of 50%: 10 ng/ml) over the 12-week period in nearly all evaluable subjects. (50)",1
10236,12602731,Treatment of acute isoniazid toxicity of unknown dose,,1
10237,12603798,Acute liver failure in children: A regional experience,"OBJECTIVE: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. METHODOLOGY: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. RESULTS: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long-term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. CONCLUSIONS: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.",1
10238,12605205,British anti-Lewisite (dimercaprol): an amazing history,"Emergency physicians are familiar with British anti-Lewisite (BAL) because it is a heavy metal-chelating agent that is recommended in some cases of metal poisoning, especially arsenic. Although there are more modern chelating agents, the fact that BAL is still recommended and stocked by hospital pharmacies more than 60 years after its initial synthesis is itself remarkable. During World War II, BAL minimized the risk to the Allied infantry of injury or death from Lewisite, a very potent arsenic-based chemical warfare agent. Once developed, BAL revolutionized the treatment of heavy metal poisonings, both accidental and iatrogenic (eg, toxicity from treatment of arthritis with gold salts). In 1951, BAL was used to treat Wilson's disease with striking success. Today, BAL might again become prominent should terrorists or governments use Lewisite against civilians or military forces.",1
10239,12605820,[Acute hepatitis due to montelukast],,1
10240,12606734,Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B,"BACKGROUND: Adefovir dipivoxil, a nucleotide analogue, demonstrated clinically significant antiviral activity in patients with chronic hepatitis B in phase 1 and 2 clinical trials. METHODS: We randomly assigned 185 patients with chronic hepatitis B who were negative for hepatitis B e antigen (HBeAg) to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks in a 2:1 ratio and a double-blind manner. The primary end point was histologic improvement. RESULTS: At week 48, 64 percent of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities (77 of 121), as compared with 33 percent of patients in the placebo group (19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levels were reduced to fewer than 400 copies per milliliter in 51 percent of patients in the adefovir dipivoxil group (63 of 123) and in 0 percent of those in the placebo group (0 of 61, P<0.001). The median decrease in log-transformed HBV DNA levels was greater with adefovir dipivoxil treatment than with placebo (3.91 vs. 1.35 log copies per milliliter, P<0.001). Alanine aminotransferase levels had normalized at week 48 in 72 percent of patients receiving adefovir dipivoxil (84 of 116), as compared with 29 percent of those receiving placebo (17 of 59, P<0.001). No HBV polymerase mutations associated with resistance to adefovir were identified. The safety profile of adefovir dipivoxil was similar to that of placebo. CONCLUSIONS: In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo. There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations.",1
10241,12608888,"New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon","Insomnia affects 30-35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects. In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named omega(1) and omega(2), which are located in different areas of the CNS. The sedative action of benzodiazepines is related to omega(1) receptors, whereas omega(2) receptors are responsible for their effects on memory and cognitive functioning. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (<3 hours), medium half-life (8-24 hours) and long half-life (>24 hours). The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three 'Z' agents all share a short plasma half-life and limited duration of action. In addition, these agents are selective compounds that interact preferentially with omega(1) receptors (sedative effect), whereas benzodiazepines also interact with omega(2) receptors (adverse effects on cognitive performance and memory). Zaleplon is characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7-8 hours later (i.e. in the morning) generally show no relevant alterations. As with benzodiazepines, the three 'Z' non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.",1
10242,12610038,Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial,"OBJECTIVE: Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population. RESEARCH DESIGN AND METHODS: In a 52-week, double-blind, placebo-controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 +/- 10 years, diabetes duration 12 +/- 7 years, BMI 34.0 +/- 7.0 kg/m(2), HbA(1c) 9.1 +/- 1.2%, mean +/- SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 micro g TID, 90 microg BID, or 120 microg BID). RESULTS: Treatment with pramlintide 120 micro g BID led to a sustained reduction from baseline in HbA(1c) (-0.68 and -0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P < 0.05). The proportion of patients achieving an HbA(1c) <8% was approximately twofold greater with pramlintide (120 microg BID) than with placebo (46 vs. 28%, P < 0.05). The glycemic improvement with pramlintide 120 micro g BID was accompanied by a mean weight loss (-1.4 kg vs. +0.7 kg with placebo at week 52, P < 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea. CONCLUSIONS: Mealtime amylin replacement with pramlintide 120 microg BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes.",1
10243,12611558,Therapeutic applications of fenugreek,"Fenugreek has a long history of medical uses in Ayurvedic and Chinese medicine, and has been used for numerous indications, including labor induction, aiding digestion, and as a general tonic to improve metabolism and health. Preliminary animal and human trials suggest possible hypoglycemic and antihyperlipidemic properties of oral fenugreek seed powder.",1
10244,12614468,Time on antiretroviral therapy is a protective factor for liver fibrosis in HIV and hepatitis C virus (HCV) co-infected patients,"""To assess the factors associated with liver fibrosis in human immunodeficiency virus and hepatitis C virus (HIV/HCV) co-infected patients eligible for anti-HCV therapy, we performed an observational, single-centred, cross-sectional study of 180 HIV/HCV co-infected patients who underwent liver biopsy between May 1998 and November 2001. A total of 126 patients with a known date of HCV infection were evaluated. Liver fibrosis was defined as a Knodell stage of fibrosis 1-4. The mean age was 36.7 (3.8) years, 81% were male and had a mean age of 20.5 (3.8) years at HCV infection. Mean CD4 cell count and plasma HIV-1 RNA load at the time of biopsy were 552 cell/mm3 (239) and 2.5 log10 (0.9), respectively; 118 patients had been on antiretroviral therapy (ART) for a median of 45 months (Q1-Q3: 21-75) and 84 on protease inhibitor for a median of 12.0 months (Q1-Q3: 0-29.5); 55 had an AIDS event or a CD4 cell count nadir < 200 cells/mm3 prior to biopsy. Median histological activity index was 6 and 27% had a Knodell stage of fibrosis 0. On the multivariate analysis time on ART (OR for 6 months extra: 0.954, 95% CI: 0.859-0.994), CD4 cell count at the time of liver biopsy (OR for 100 cells/mL increase: 0.740, 95% CI: 0.670-0.905), age at HCV infection acquisition (OR for 5 years extra: 2.594, 95% CI: 1.326-5.133) and alcohol intake (> 50 g/day) (OR: 2.73, 95% CI: 1.108-6.731) were associated with liver fibrosis. Hence ART should be a priority in HIV/HCV co-infected patients eligible for anti-HCV treatment as it is a protective factor for liver fibrosis.""",1
10245,12622609,Role of liver function tests in detecting methotrexate-induced liver damage in sarcoidosis,"BACKGROUND: Methotrexate has become a standard second-line agent for the treatment of sarcoidosis. Because sarcoidosis has a high frequency of liver involvement, we routinely perform a liver biopsy after each cumulative gram of methotrexate therapy in patients with sarcoidosis in whom we plan to continue therapy. METHODS: Following a previously described protocol for methotrexate therapy, we have performed 100 liver biopsies on 68 patients with chronic sarcoidosis at our institution. On the basis of the liver biopsy results, we identified the following 4 groups: sarcoidosis (47 cases), toxic effects of methotrexate (14 cases), hepatitis C (2 cases), and normal liver tissue (37 cases). RESULTS: We found no difference among the groups in terms of age, weight at time of biopsy, the number of patients receiving corticosteroids at the time of biopsy, cumulative dose of methotrexate, race, or sex. The 14 cases of toxic reactions to methotrexate included 5 patients who had undergone 1 or more previous liver biopsies in which the results did not show toxic effects. We found a significant difference between groups for levels of alkaline phosphatase and asparate aminotransferase at the time of starting (or restarting) methotrexate therapy (analysis of variance, P<.05). This finding was also true for the liver function tests performed at the time of the biopsy (analysis of variance, P<.05). The highest values were for those whose biopsy findings showed sarcoidosis. CONCLUSIONS: Toxic reactions to methotrexate eventually occurred in more than 10% of patients with sarcoidosis treated for more than 2 years with methotrexate. Because of hepatic involvement owing to sarcoidosis, results of serial liver function tests were not useful in determining which patients would have this reaction to methotrexate.",1
10246,12627729,"A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy","""OBJECTIVES: To evaluate the long-term safety and efficacy of nightly sodium oxybate for the treatment of narcolepsy. DESIGN: A multicenter, 12-month, open-label trial. PARTICIPANTS: 118 narcolepsy patients previously enrolled in a 4-week double-blind sodium oxybate trial. INTERVENTIONS: Patients were administered 6 g sodium oxybate nightly, taken in equally divided doses at bedtime and 2.5 to 4 hours later. The study protocol permitted the dose to be increased or decreased in 1.5-g increments at 2-week intervals based on efficacy response or adverse experiences but staying within the range of 3 to 9 g nightly. MEASURES: Narcolepsy symptoms and adverse events were recorded in daily diaries. Safety measures included physical and laboratory examinations repeated at 6 and 12 months. The primary efficacy measure was the change in weekly cataplexy attacks from baseline. Secondary measures included daytime sleepiness using the Epworth Sleepiness Scale (ESS), inadvertent naps/sleep attacks, nighttime awakenings, and the overall change in disease severity as rated by the investigators (Clinical Global Impression of Change; CGI-c). RESULTS: Sodium oxybate, in doses of 3 to 9 g nightly, produced overall improvements in narcolepsy symptoms, which were significant at 4 weeks and maximal after 8 weeks. Reported improvements included a significant decrease in frequency of cataplexy attacks (p < 0.001); diminished daytime sleepiness (p < 0.001); and patient descriptions of nocturnal sleep quality, level of alertness, and ability to concentrate (for each p < 0.001). Adverse events were generally mild and patients showed no evidence of tolerance. CONCLUSION: Sodium oxybate is an effective and well-tolerated treatment for narcolepsy.""",1
10247,12630021,"Retrospective monocentric study of 17 patients with adult Still's disease, with special focus on liver abnormalities","BACKGROUND/AIMS: Adult Still's disease is one of the febrile disorders of unknown etiology, characterized by high fever, transient cutaneous rash and leukocytosis. Liver dysfunction in adult Still's disease has been described in some case reports. The objective of this study was to analyze the pattern and the frequency of liver abnormalities in a monocenter series of adult Still's disease patients. METHODOLOGY: Data of 17 patients with adult Still's disease (fulfilling Yamaguchi's diagnostic criteria) were retrospectively reviewed. These patients were followed in an Internal Medicine Department over a period of 7 years. RESULTS: The median age was 27 years with a sex ratio M/F of 1.4. Fever was present in 100% of the cases and hepatomegaly occurred in 47% of the cases. Abnormalities in liver biochemistry, apparent in 76% of the subjects were characterized from moderate (elevation of transaminases between 2 and 5 N) (65%) to severe cytolysis (level of transaminases > 5 N) (12%), cholestasis (elevation of gamma GT and/or PAL) (65%), and increase in the level of LDH (35%). All of these symptoms disappeared either spontaneously or under treatment (83%), within a median period of 18 days. CONCLUSIONS: This study confirms the high frequency of liver dysfunction in adult Still's disease patients. Although it is moderate and asymptomatic in most cases, severe cytolytic hepatitis has been described. This study especially puts forward the need for exploring the possibility of adult Still's disease in the presence of a fever and hepatic cytolysis.",1
10248,12633134,Acute liver failure after administration of herbal tranquilizer kava-kava (Piper methysticum),,1
10249,12635752,Successful treatment with carbimazole of a hyperthyroid pregnancy with hepatic impairment after propylthiouracil administration: a case report,"We report the case of a 27-year-old woman with hyperthyroidism during pregnancy. Antithyroid treatment with propylthiouracil (PTU) resulted in elevated hepatic enzymes and after the 12th week of pregnancy treatment was changed to carbimazole (CBZ). The remaining pregnancy, delivery and follow-up period were uneventful for the mother and her offspring. Antithyroid treatment during pregnancy should allow the use not only of PTU but also of CBZ and methimazole.",1
10250,12637463,Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer,"""PURPOSE: Bexarotene is a retinoid X receptor-selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer. PATIENTS AND METHODS: The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m(2)/d. RESULTS: One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m(2)/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis. CONCLUSION: The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.""",1
10251,12638783,Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS),"The ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation occurring during the luteal phase or during early pregnancy. This complication is unusual as it is not the consequence of a treatment which is vital or mandatory for the patient's health. Nevertheless, it can be accompanied by severe morbidity and may even be fatal. Data pertaining to the clinical course and consequences of OHSS in women and its treatment were searched using Medline, Current Contents and PubMed. To date, only a few studies have collected a large number of cases of OHSS. The clinical course of OHSS may involve, according to its severity and the occurrence of pregnancy, electrolytic imbalance, neurohormonal and haemodynamic changes, pulmonary manifestations, liver dysfunction, hypoglobulinaemia, febrile morbidity, thromboembolic phenomena, neurological manifestations and adnexal torsion. Treatment of the acute phase relies only on an empirical and symptomatic approach. The general approach will be adapted to the levels of severity. Specific approaches such as paracentesis, pleural puncture, surgical approach of OHSS and specific medication during OHSS were evaluated sporadically. More adequate treatment methods would require a better understanding of the underlying pathophysiological mechanisms, to promote an aetiological therapeutic approach. Properly conducted studies, including large numbers of patients are required in order to determine the best method of prevention and management.",1
10252,12639171,Recurrent cholestasis due to ampicillin,"OBJECTIVE: To present a single case of ampicillin-induced recurrent cholestasis and a literature review. CASE SUMMARY: A 23-year-old man was hospitalized due to recurrent and self-limited cholestatic symptoms. He had used ampicillin before each cholestatic attack. He became well clinically and biochemically each time after cessation of the drug. One year after his recovery and discontinuance of ampicillin, the patient has had no recurrence of cholestasis. An objective causality assessment revealed that the adverse drug reaction was probable. DISCUSSION: Ampicillin-related hepatotoxicity is very rare, with injury being mainly hepatocellular. To our knowledge, there is only 1 case report in the literature referring to chronic cholestatic-type hepatotoxicity related to ampicillin. CONCLUSIONS: Ampicillin, which is one of the most widely used antibiotics, may cause recurrent cholestatic hepatitis. Clinicians should be aware of this adverse effect, and it should be kept in mind during diagnostic workup of liver injury.",1
10253,12645809,Liver transplantation for propylthiouracil-induced acute hepatic failure,,1
10254,12649798,[Pantoprazole-induced hepatitis],"HISTORY: A 46-year-old woman presented for an emergency admission because of colic-like upper abdominal pain and markedly impaired general condition. Eight days before admission she had started and continued to take pantoprazole because of symptoms of gastroesophageal reflux. INVESTIGATIONS: Clinical examination and laboratory tests indicated abnormal liver functions suggesting hepatitis. Serology largely excluded an infectious, autoimmunological or metabolic cause. Duplex sonography gave no evidence of bile obstruction or Budd-Chiari syndrome. DIAGNOSIS AND COURSE: The patient's condition and laboratory tests after the drug had been discontinued gradually improved on symptomatic treatment, indicating pantoprazole-induced hepatitis. CONCLUSION: Intake of proton pump inhibitors is a rare cause but should be considered in the differential diagnosis of hepatitis of uncertain etiology.",1
10255,12653814,Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients,"AIMS: To assess the efficacy of buprenorphine compared with methadone maintenance therapy for opioid dependence in a large sample using a flexible dosing regime and the marketed buprenorphine tablet. DESIGN: Patients were randomized to receive buprenorphine or methadone over a 13-week treatment period in a double-blind, double-dummy trial. SETTING: Three methadone clinics in Australia. PARTICIPANTS: Four hundred and five opioid-dependent patients seeking treatment. INTERVENTION: Patients received buprenorphine or methadone as indicated clinically using a flexible dosage regime. During weeks 1-6, patients were dosed daily. From weeks 7-13, buprenorphine patients received double their week 6 dose on alternate days. MEASUREMENTS: Retention in treatment, and illicit opioid use as determined by urinalysis. Self-reported drug use, psychological functioning, HIV-risk behaviour, general health and subjective ratings were secondary outcomes. FINDINGS: Intention-to-treat analyses revealed no significant difference in completion rates at 13 weeks. Methadone was superior to buprenorphine in time to termination over the 13-week period (Wald chi 2 = 4.371, df = 1, P = 0.037), but not separately for the single-day or alternate-day dosing phases. There were no significant between-group differences in morphine-positive urines, or in self-reported heroin or other illicit drug use. The majority (85%) of the buprenorphine patients transferred to alternate-day dosing were maintained in alternate-day dosing. CONCLUSIONS: Buprenorphine did not differ from methadone in its ability to suppress heroin use, but retained approximately 10% fewer patients. This poorer retention was due possibly to too-slow induction onto buprenorphine. For the majority of patients, buprenorphine can be administered on alternate days.",1
10256,12655157,"Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients","The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin.",1
10257,12659378,Severe hepatitis associated with oxacillin therapy,,1
10258,12666126,Quinacrine-induced cytolytic hepatitis in sporadic Creutzfeldt-Jakob disease,,1
10259,12668542,Acute hepatitis associated with oral levofloxacin therapy in a hemodialysis patient,"Levofloxacin is a fluoroquinolone antibiotic commonly used to treat respiratory, urinary tract, skin and soft-tissue infections. Levofloxacin is generally well tolerated and has fewer reported side effects than other fluoroquinolones. We present a case of levofloxacin-associated severe hepatocellular injury. The hepatitis resolved soon after discontinuation of levofloxacin.",1
10260,12669734,Preclinical safety profile of alendronate,"""Acute toxicity studies showed that the LD50 values of oral alendronate in female animals corresponded to human oral doses of 27,800 mg in rats and 48,300 mg in mice; LD50 values in male animals were even higher. Chronic toxicity studies showed clinically nonrelevant retention of primary spongiosa of bone in areas of endochondral bone formation, serum biochemical changes (reductions in serum concentrations of calcium, phosphate and alkaline phosphatase) and nephrotoxicity. Of the 5 genotoxicity studies performed, 4 showed no evidence of mutagenicity, including those most relevant to human carcinogenic potential. Carcinogenicity studies in rats and mice at maximum tolerated doses showed no increased tumour incidence associated with alendronate treatment. Alendronate had no effect on fertility or reproductive performance in male or female rats receiving oral doses up to 5 mg/kg/day. No adverse developmental effects were noted at doses up to 25 mg/kg/day in rats and 35 mg/kg/day in rabbits. Alendronate had no deleterious effect on bone strength or morphology. The evidence presented in these studies supports the conclusion that alendronate administered to humans at therapeutic doses is a safe drug for the treatment of postmenopausal osteoporosis.""",1
10261,12670127,Interactions between the cytochrome P450 system and the second-generation antipsychotics,"Awareness of the metabolism of second-generation antipsychotics by the cytochrome P450 (CYP) system can inform the clinician about how to avoid and manage drug-drug interactions involving these enzymes. Clozapine is metabolized primarily by CYP1A2, with additional contributions by CYP2C19, CYP2D6 and CYP3A4. Risperidone is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Olanzapine is metabolized primarily by CYP1A2 and to a lesser extent by CYP2D6. Quetiapine and ziprasidone are metabolized by CYP3A4. At the usual clinical doses, these drugs appear not to significantly affect the metabolism of other medications. There is, however, a lack of in vivo metabolic data, especially for the 3 newest second-generation antipsychotics: olanzapine, quetiapine and ziprasidone.",1
10262,12672274,Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis,"Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.",1
10263,12672860,Memantine in moderate-to-severe Alzheimer's disease,"""BACKGROUND: Overstimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate is implicated in neurodegenerative disorders. Accordingly, we investigated memantine, an NMDA antagonist, for the treatment of Alzheimer's disease. METHODS: Patients with moderate-to-severe Alzheimer's disease were randomly assigned to receive placebo or 20 mg of memantine daily for 28 weeks. The primary efficacy variables were the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev). The secondary efficacy end points included the Severe Impairment Battery and other measures of cognition, function, and behavior. Treatment differences between base line and the end point were assessed. Missing observations were imputed by using the most recent previous observation (the last observation carried forward). The results were also analyzed with only the observed values included, without replacing the missing values (observed-cases analysis). RESULTS: Two hundred fifty-two patients (67 percent women; mean age, 76 years) from 32 U.S. centers were enrolled. Of these, 181 (72 percent) completed the study and were evaluated at week 28. Seventy-one patients discontinued treatment prematurely (42 taking placebo and 29 taking memantine). Patients receiving memantine had a better outcome than those receiving placebo, according to the results of the CIBIC-Plus (P=0.06 with the last observation carried forward, P=0.03 for observed cases), the ADCS-ADLsev (P=0.02 with the last observation carried forward, P=0.003 for observed cases), and the Severe Impairment Battery (P<0.001 with the last observation carried forward, P=0.002 for observed cases). Memantine was not associated with a significant frequency of adverse events. CONCLUSIONS: Antiglutamatergic treatment reduced clinical deterioration in moderate-to-severe Alzheimer's disease, a phase associated with distress for patients and burden on caregivers, for which other treatments are not available.""",1
10264,12676781,Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells,"A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 +/- 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.",1
10265,12680749,The pharmacovigilance of mirtazapine: results of a prescription event monitoring study on 13554 patients in England,"Mirtazpine is the first noradrenaline and serotonin specific antidepressant. We monitored the safety of mirtazapine as reported in primary practice in England. The exposure data were provided by monitoring the dispensed prescriptions issued between September 1997 and February 1999. Questionnaires sent to GPs provided outcome data. Drowsiness/sedation and malaise/lassitude were the most frequent ADRs (116, 71 respectively) and had the highest incidence density (per 1000 patient-months) in the first month of treatment (58.1, 27.8 respectively). Agitation (73), aggression (70), rash (20), hallucinations (13) and abnormal dreams (31 were unlabelled AES while abnormal liver function tests (12), syncope (8), abnormal behaviour (4) and visual disturbance (3) were labelled AES possibly due to mirtazapine use. Serious suspected ADRs reported were facial oedema (5), allergy (3), bone marrow toxicity (2) and myelodysplasia (1).",1
10266,12681025,Latin-American trial of orlistat for weight loss and improvement in glycaemic profile in obese diabetic patients,"AIM: To determine if obese non-insulin-dependent diabetic patients lose more weight when treated for 24 weeks (6 months) with orlistat (120 mg t.i.d.), in conjunction with a hypocaloric diet plus behavioural counselling, than when treated by placebo (t.i.d.) plus similar instructions. The secondary objectives were to evaluate the effects on glucose profile and to determine the tolerability and safety of orlistat. DESIGN: Double-blind, parallel, randomized, placebo-controlled, multicentre study. SUBJECTS: Obese, non-insulin-dependent diabetic patients, aged 18-70 years old, with BMI > 27 kg/m2, evaluated at 10 Latin-American centres, in five countries. EFFICACY AND TOLERABILITY MEASUREMENTS: After screened, eligible patients passed by a 2-week placebo run-in period receiving a hypocaloric diet. On day 0, patients were randomized to orlistat or placebo for 24 weeks. At each visit, body weight, blood pressure and waist circumference were measured. At the screening visit, baseline visit (week 0), and at weeks 8, 16 and 24, a central laboratory was in charge of measuring fasting glucose and insulin, HbA1c, postprandial glucose and insulin, fasting total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and postprandial triglycerides. Other safety laboratory assessments were measured locally at the screening visit, baseline visit and at the end of the study. Adverse events were assessed at each visit from baseline. RESULTS: After 24 weeks of treatment, the orlistat group lost an average of 4.7% of initial body weight vs. 3.0% in the placebo group (p = 0.0003). A greater weight loss was achieved in the orlistat compared with the placebo group (4.24 +/- 0.23 vs. 2.58 +/- 1.46 kg, p = 0.0003). Almost twice as many patients receiving orlistat (30% vs. 17%) lost > or = 5% of initial body weight (p = 0.003). Orlistat treatment plus diet compared to placebo plus diet was associated with significant improvement in glycaemic control, as reflected in decreases in HbA1c (p = 0.04), fasting plasma glucose (p = 0.036) and postprandial glucose (p = 0.05). Orlistat-treated patients had a mean decrease in glucose levels of 1.00 +/- 0.34 mmol/l [3.7%] vs. 0.01 +/- 0.30 mmol/l for placebo group, at week 24 and an absolute decrease of HbA1c of 0.61 +/- 0.15 vs. a decrease of 0.22 +/- 0.14% in the placebo group. Orlistat therapy also resulted in significantly greater improvements than placebo in lipid profile, with reductions in total cholesterol (p = 0.0001) and LDL-cholesterol (p = 0.002). Mild to moderate transient gastrointestinal events were reported, mainly with orlistat treatment, but their association with withdrawal from the study was low. CONCLUSION: Orlistat is a useful and an effective therapy in obese diabetic patients, promoting clinically significant weight loss and improved glycaemic control and lipid profile.",1
10267,12684925,Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine,"We describe a 49-year-old man with human immunodeficiency virus infection and stable chronic renal insufficiency who developed acute oliguric renal failure and severe lactic acidosis and who died several weeks after tenofovir was added to an antiretroviral regimen that included didanosine. Although the role of tenofovir in precipitating acute renal failure is unclear, progressive accumulation of the drug and pharmacologic interaction that caused increased levels of didanosine were the likely antecedents of increased mitochondrial toxicity that led to lactic acidosis.",1
10268,12686075,Questions about the antimalarial amodiaquine,,1
10269,12688327,Hepatosplenic T-gammadelta lymphoma in a patient with Crohn's disease treated with azathioprine,"Hepatosplenic gammadelta T-cell lymphoma (HS-gammadeltaTCL) is an uncommon type of peripheral T-cell lymphoma, which has been associated in some cases with immunosuppression, mainly after solid organ transplants. We describe a case of HSgammadeltaTCL with a leukaemic course in a patient with Crohn's disease who had received azathioprine during the previous 5.5 years. Sinusoidal infiltration by atypical lymphocytes was observed in the liver, spleen and bone marrow and the typical cytogenetic abnormalities (isochromosome 7 and trisomy 8) were found. The patient did not respond to intensive chemotherapy. This case shows the importance of ruling out HSgammadeltaTCL in patients with hepatosplenomegaly, B-symptoms and any immunosuppressive condition.",1
10270,12691611,Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion,"Herpes simplex virus thymidine kinase (HSV-tk) converts ganciclovir (GCV) into an active compound, which can be incorporated into DNA molecules and terminate DNA synthesis. Gene transfer of HSV-tk followed by GCV administration has been used with success to treat experimental cancer and this strategy has entered into clinical trials. Although it is thought that the cytotoxic effect occurs mainly in tumoral dividing cells, where mitotic activity favors integration of the genotoxic compound into nuclear DNA, there are concerns of potential damage to normal nondividing cells. In the present work we have explored the mechanisms of HSV-tk/GCV toxicity and in particular whether this therapy may cause lesions of mitochondrial DNA (mtDNA) and mitochondrial dysfunction. We found that the administration of GCV to rats injected with adenovirus encoding HSV-tk induced hepatocellular damage characterized by the presence of apoptotic bodies, ballooning of hepatocytes, and severe hepatic steatosis with mitochondria enlargement and cristae dissolution at the ultrastructural level. Remarkably, Southern blot analysis showed substantial reduction in the amount of mtDNA in the liver. Using radiolabeled GCV we could demonstrate incorporation of this compound into both nuclear and mtDNA in HSV-tk-transduced rat hepatocytic cell line MCA-RH7777 and subsequent alteration of mitochondrial function. Our observations confirm that GCV can damage both nuclear and mtDNA in cells transduced with HSV-tk and that this effect could be responsible for severe mitochondrial dysfunction and toxicity in normal nondividing cells. These data are relevant for the design of clinical trials using adenoviral vectors encoding HSV-tk.",1
10271,12695153,"Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis","OBJECTIVE: To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Data were used from a randomised clinical 48 week trial on 411 patients with RA all treated with MTX, comparing folates and placebo. Logistic regression was used to study the relation between baseline variables and various dependent factors, including hepatotoxicity (alanine aminotransferase >/=3 x upper limit of normal), MTX withdrawal, final MTX dose >/=15 mg/week, and MTX efficacy. RESULTS: Addition of folates to MTX treatment was strongly related to the lack of hepatotoxicity. Next to this, high body mass index was related to the occurrence of hepatotoxicity. Prior gastrointestinal (GI) events and younger age were related to the adverse event, diarrhoea. Hepatotoxicity and GI adverse events were the main reason for MTX withdrawal, which in turn was associated with the absence of folate supplementation, body mass index, prior GI events, and female sex. Renal function (creatinine clearance >/=50 ml/min) was not associated with toxicity. Reaching a final dose of MTX of >/=15 mg/week was related to folate supplementation and the absence of prior GI events. Efficacy of MTX treatment was associated with low disease activity at baseline, male sex, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lower creatinine clearance. CONCLUSIONS: MTX toxicity, final dose, and efficacy are influenced by folate supplementation. Baseline characteristics predicting the outcome of MTX treatment are mainly prior GI events, body mass index, sex, use of NSAIDs, and creatinine clearance.",1
10272,12697018,Black cohosh and other herbal remedies associated with acute hepatitis,,1
10273,12702895,Hepatic injury and pancreatitis during treatment with serotonin reuptake inhibitors: data from the World Health Organization (WHO) database of adverse drug reactions,"Severe hepatic adverse drug reactions have been occasionally reported in the literature for the selective serotonin reuptake inhibitors (SSRIs), venlafaxine and nefazodone. In addition, a few case reports have suggested a possible association between SSRI treatment and pancreatitis. To further investigate this issue, a Bayesian confidence propagation neural network (BCPNN) method was applied on the World Health Organization database of adverse drug reactions. This method identifies whether a drug/adverse drug reaction combination is reported more frequently to the database than expected on the basis of chance alone compared to general reporting in the database. A statistically significant unexpected high number of reports were found for nefazodone and hepatic injury, relative to the generality of the dataset but, for the other drug/adverse drug reaction combinations, no such association was found. The nefazodone finding is in accordance with data from other publications, suggesting that the risk of hepatic injury is increased. However, because of the nature of the BCPNN, the negative findings do not necessarily prove that there is no excess risk for hepatic injury/pancreatitis during treatment with drugs other than nefazodone. Further studies are required using alternative methodologies to demonstrate whether the selective serotonin reuptake inhibitors or venlafaxine may cause hepatic injury or pancreatitis.",1
10274,12715317,Serotonin syndrome after concomitant treatment with linezolid and citalopram,"Linezolid, a new synthetic antimicrobial, is an important weapon against methicillin-resistant Staphylococcus aureus (MRSA). Although there are reports of serotonin syndrome developing after concomitant use of linezolid and the selective serotonin reuptake inhibitor paroxitene, this report concerns a patient receiving citalopram who developed thrombocytopenia, serotonin syndrome, and lactic acidosis and died following long-term linezolid therapy.",1
10275,12717339,Alefacept (Amevive) for treatment of psoriasis,,1
10276,12720503,Kava hepatotoxicity with Western herbal products: does it occur with traditional kava use?,,1
10277,12721703,Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. A comparative study of 270 cases,"102 rheumatoid arthritis (RA) and 104 psoriatic arthritis (PsA) patients' records were analysed according to a standardised protocol. Using Cox regression, life-table analysis and log rank test, the effectiveness and toxicity of, and duration of disease modifying antirheumatic drug (DMARD) treatment were compared in RA and PsA. RA patients were treated with gold sodium thiomalate (GST), methotrexate (MTX) and sulphasalazine (SSZ) for a median duration of 35, 72 and 12 months respectively, whereas PsA patients were treated for 12, 12 and 17 months. The differences for GST and MTX were statistically significant (p=0.0043 and 0.0447). Drug toxicity was more frequently seen among patients with PsA (p=0.0023). No difference in efficacy could be proved. Results suggest that there is a significant difference between RA and PsA patients in terms of toxicity of these agents. Therefore, separate treatment strategies are needed, and earlier results with RA may not be directly applicable to PsA.",1
10278,12725583,Kava-kava: a lesson for the phytomedicine community,,1
10279,12730142,Safety and tolerability of linezolid,"""Clinical trials have shown that linezolid (600 mg twice daily in adults) is safe and generally well tolerated for up to 28 days. Drug-related adverse events, which are typically mild to moderate in intensity and of limited duration, include diarrhoea, nausea and headache in adults, and diarrhoea, loose stools and vomiting in children. Clostridium difficile-related complications with linezolid are uncommon. Linezolid is a weak, reversible monoamine oxidase inhibitor: foods containing high concentrations of tyramine should be avoided, and linezolid should be used with caution in patients taking adrenergic or serotonergic agents or in those with uncontrolled hypertension. In the majority of patients, linezolid has minimal adverse effects on blood chemistry or haematology. There have been case reports of reversible thrombocytopenia, anaemia and neutropenia associated with linezolid therapy. In Phase III studies, 2.4% of patients treated with linezolid and 1.5% of patients treated with comparator drugs developed reversible thrombocytopenia (P = 0.066), but there was no evidence of an increased risk of agranulocytosis, aplastic anaemia or other irreversible blood dyscrasias. Reduced platelet counts were associated with linezolid treatment for >/=2 weeks; complete blood counts should be monitored weekly in patients receiving linezolid for more than 14 days and treatment should be discontinued if there is evidence of myelosuppression.""",1
10280,12733846,Acute hepatitis induced by kava kava,"BACKGROUND: Herbal preparations are available widely and regarded generally by the public as harmless remedies for a variety of medical ailments. We report a case of acute hepatitis associated with the use of kava kava, derived from the root of the pepper plant, Piper methysticum. It is used in the United States as an antianxiety and sedative agent. CASE REPORT: A previously healthy 14-year-old female was admitted to the hospital with hepatic failure. Initial therapy, including plasmapheresis, was unsuccessful and she deteriorated. She ultimately required a liver transplant and now remains well. The liver biopsy showed hepatocellular necrosis consistent with chemical hepatitis. A work-up for alternative causes of liver failure was negative. The patient gave a history of taking a kava kava-containing product for four months. The use of kava kava and liver failure, is supported by kava kava use, a negative work-up for alternative causes of liver failure, and histological changes in the liver. CONCLUSIONS: Health care professionals need to be aware of the possibility of kava kava-induced hepatotoxicity. The toxicity of these alternative remedies emphasizes the importance of surveillance programs and quality control in the manufacture of these products. Clinicians must remain aware of the toxic potential of herbal products and always inquire about their intake in cases of unexplained liver injury.",1
10281,12734908,The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia,"""OBJECTIVE: Fibromyalgia (FM) is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate has been shown to increase both slow-wave sleep and growth hormone levels. This double blind, randomized, placebo controlled crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSG) sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM. METHODS: Patients received either 6.0 g/day sodium oxybate or placebo for 1 month, with an intervening 2 week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events. RESULTS: Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p = 0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p < 0.005). Alpha intrusion, sleep latency, and rapid-eye-movement sleep were significantly decreased, while slow-wave (stage 3/4) sleep was significantly increased, compared with placebo (p < 0.005). Two of the 5 subjective sleep related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p = 0.0033) and quality of sleep (improved by 33% and 10%, respectively; p = 0.0003). CONCLUSION: Sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the nonrestorative sleep characteristic of this disorder.""",1
10282,12737123,HIV treatment-associated hepatitis,"Combination antiretroviral therapy, as well as a variety of other medications prescribed, places patients with HIV disease at high risk for adverse drug reactions and interactions. Sever hepatitis has been reported with all of the currently available classes of antiretroviral agents. Physicians should be aware of the risk of hepatocellular injury in patients receiving antiretroviral therapy and monitor transaminase levels in those at risk. This article reviews the incidence, clinical features, risk factors, and etiology of drug-induced hepatitis with various combinations used in clinical practice.",1
10283,12739107,Non-fatal acute liver injury possibly related to high-dose ciprofloxacin,Fulminant hepatic failure is an uncommon but life-threatening adverse reaction to antibiotic therapy. Reported here is a case of severe liver injury associated with ciprofloxacin administered for treatment of a gram-negative infection in a 79-year-old female. The patient presented with metabolic acidosis 48 hours after the first ciprofloxacin intake. Symptoms resolved after cessation of ciprofloxacin therapy. This report highlights an uncommon side effect of a commonly used antimicrobial agent.,1
10284,12740787,Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications,"Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13.9% in historic controls (P = not significant [NS]). The prevalence of hepatic artery complications was 5.3% in sirolimus-treated patients compared with 8.3% in historic controls (P = NS). The prevalence of obesity and OKT3 administration was significantly lower in sirolimus-treated patients. Multivariate analysis failed to show an association between sirolimus therapy and hepatic artery or wound complications. The prevalence of wound and hepatic artery complications is not different in liver transplant recipients administered sirolimus as part of a primary immunosuppressive regimen compared with historic controls.",1
10285,12744550,Clopidogrel-induced systemic inflammatory response syndrome,"Clopidogrel bisulfate, a widely used inhibitor of platelet aggregation, is considered at least as safe as aspirin. We describe a patient who developed a systemic inflammatory response syndrome consisting of high fever, tachycardia, cellulitis-like rash, impaired liver function, and mild leukopenia after receiving clopidogrel before coronary angiography and stent implantation. The reaction resolved promptly after withdrawal of the drug and recurred shortly after a rechallenge dose was administered, thus making the diagnosis of a clopidogrel-induced reaction highly probable. Recognition of this clopidogrel-induced syndrome is extremely important, both for rapid discontinuation of the offending drug and for avoidance of unnecessary drug therapy or invasive procedures.",1
10286,12747823,[Acute hepatitis due to bentazepam],,1
10287,12750575,[Disulfiram-induced hepatitis],"""Overt disulfiram-induced hepatitis is rare; it has a high mortality rate, especially when the etiology is non suspected and when the treatment is not promptly discontinued. The Authors describe a case of disulfiram-induced acute hepatitis and emphasize close clinical and biochemical monitoring.""",1
10288,12750737,Safety of rituximab in lymphoma patients with hepatitis B or hepatitis C virus infection,,1
10289,12755473,Liver death and regeneration in paracetamol toxicity,"""Paracetamol overdose (POD) is a major clinical problem as the commonest cause of fulminant hepatic failure (FHF) in the UK and the USA. While the main loss of liver mass occurs following hepatocyte necrosis, hepatocyte apoptosis has also been reported to occur during paracetamol toxicity in murine liver. Hepatocyte apoptosis has not previously been identified in human liver and the significance of apoptosis in paracetamol toxicity is not known. In this study of paracetamol toxicity in human liver after POD, hepatocyte apoptosis was identified at time of liver transplantation or death and was associated with striking regenerative activity. The biological significance of apoptosis is unclear but the rates of apoptosis found (0.6%) could account for a significant loss of hepatic parenchyma. The stimulus for apoptosis is not known but it is unlikely to be induced directly by paracetamol since it is absent from serum at this time. The possibility that apoptosis may be induced by Kupffer cell activation with cytokine production is raised. Patients who develop FHF after POD have a poor prognosis, with few therapeutic options apart from liver transplantation; an understanding of the dynamics of liver regeneration and ongoing cell loss by apoptosis may allow the development of new therapies in these patients.""",1
10290,12763939,Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone,"The identification of a safe, orally active iron chelator is critically important for the prevention of morbidity and early death in patients receiving regular red cell transfusions. Based on our findings in a 1-year multicenter, prospective study of the safety and efficacy of deferiprone in patients with thalassemia major, we have extended the treatment period to 4 years. The mean dose of the chelator was 73 mg/kg per day during 531 patient-years. The rates of agranulocytosis (absolute neutrophil count [ANC] < 500 x 10(9)/L) and milder forms of neutropenia (ANC, 500-1500 x 10(9)/L) were 0.2 and 2.8 per 100 patient-years, respectively. Neutropenia occurred significantly more commonly in patients with intact spleens. Gastrointestinal and joint symptoms decreased significantly after the first year of therapy, and led to discontinuation of deferiprone in only one patient in years 2 to 4. The mean alanine aminotransferase (ALT) value of 71 U/L after 4 years of therapy was significantly higher than the baseline value of 61 U/L. Trend analysis showed no increase in the ALT levels or the percentage of patients with ALT levels greater than twice the upper limit of the reference range. Ferritin levels did not change significantly from the values at the time of change from deferoxamine to deferiprone in either the intention-to-treat analysis or in the 84 patients who completed 4 years of therapy. Because of concerns regarding the effectiveness of the studied dose of deferiprone, 47 patients discontinued therapy, whereas 15 patients interrupted therapy because of concerns regarding low iron levels. The results of this study help to define the safety and effectiveness of long-term therapy with deferiprone.",1
10291,12766341,Anticonvulsant hypersensitivity syndrome: report of 2 cases from Kuwait,"OBJECTIVE: To illustrate the clinical features, laboratory findings, and management of anticonvulsant hypersensitivity syndrome (AHS), emphasizing the importance of recognizing its multiple clinical components and raising awareness of the cross-sensitivity among different anticonvulsants. CLINICAL PRESENTATION AND INTERVENTION: Two cases of AHS due to carbamazepine and a combination of sodium valproate and lamotrigene are reported. Both patients presented within the first month of starting the new antiepileptic medication with fever, skin rashes, hematological abnormalities, and hepatitis. The offending antiepileptic drugs were immediately stopped in both cases. Skin rashes responded to intravenous immunoglobulin in case 1 and to intravenous hydrocortisone in case 2. CONCLUSION: AHS is a serious, life-threatening condition. This report demonstrates that the most important steps in the management of AHS are to recognize the disorder, discontinue the offending antiepileptic drug, and provide supportive care in an inpatient setting and treat with benzodiazepines if seizures occur.",1
10292,12772052,"[Kava, kavapyrones and toxic liver injury]","Kava extracts are obtained from the rhizoma of the kava shrub (Piper methysticum) and contain various pyrones which are used as herbal anxiolytic remedies for generalized anxiety syndromes of low and intermediate grades. The commonly recommended daily dose of 60-120 mg kavapyrones and the duration of the therapy of up to 3 months should not be increased without consultation of a physician and were not followed by most patients, since herbal drugs are considered by the population not only as effective but also as safe. Whereas kava extracts are well tolerated by most patients and rare side effects are rapidly reversible upon drug discontinuation, there are suspected hepatotoxic reactions reported during the last years in temporal and not necessarily causal association with a therapy with kava extracts. Almost 80 % of the patients took kavapyrones in overdose (maximally 480 mg/d) and/or for a prolonged time of more than 3 months up to 2 years. Additional risks factors include co-medication with up to 5 other chemically defined or herbal drugs with in part potentially hepatotoxic properties as well as a genetic deficiency of the hepatic microsomal cytochrome P450 2D6. Severe clinical courses with liver transplantation and possible fatal outcome occurred in 7 patients with overdose and/or long duration of the therapy with kavapyrones. Preventive measures should therefore include a dose of 120, maximally 210 mg kavapyrones per day for 1 month, maximally 2 months, as well as a prescription by a physician. Laboratory test (ALT and gamma-GT) should be done before and during the therapy, and co-medication and alcohol consumption should be avoided. With these measures the hepatotoxic risks under the treatment with kavapyrones might be minimized which are also available via internet and from abroad with possible severe consequences when taken without medical supervision.",1
10293,12773645,Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia,"BACKGROUND: The T-20 vs. Optimized Regimen Only Study 2 (TORO 2) compared the efficacy and safety of 24 weeks of treatment with the fusion inhibitor enfuvirtide in combination with an optimized background antiretroviral regimen with the efficacy and safety of the optimized background regimen alone. METHODS: The patients had previous treatment with each of the three classes of antiretroviral drugs, documented resistance to each class, or both and a plasma level of human immunodeficiency virus type 1 (HIV-1) RNA of at least 5000 copies per milliliter. They were randomly assigned in a 2:1 ratio to receive either enfuvirtide (90 mg twice daily) plus a background regimen optimized with the aid of resistance testing (enfuvirtide group) or the background regimen alone (control group). RESULTS: Of the 512 patients who underwent randomization, 335 in the enfuvirtide group and 169 in the control group received at least one dose of study medication and had at least one follow-up measurement of plasma HIV-1 RNA. The median base-line plasma HIV-1 RNA level was 5.1 log10 copies per milliliter in both groups. The median CD4+ cell count was 98.0 cells per cubic millimeter in the enfuvirtide group and 101.5 cells per cubic millimeter in the control group. Patients had a median of seven years of previous treatment and had received a median of 12 antiretroviral drugs. The background regimen comprised a mean of four antiretroviral drugs in both groups. At 24 weeks, the least-squares mean change from base line in the plasma viral load (intention-to-treat, last observation carried forward) was a decrease of 1.429 log10 copies per milliliter in the enfuvirtide group and a decrease of 0.648 log10 copies per milliliter in the control group, a difference of 0.781 log10 copies per milliliter (P<0.001). The mean increase in the CD4+ cell count was greater in the enfuvirtide group (65.5 cells per cubic millimeter) than in the control group (38.0 cells per cubic millimeter, P=0.02). CONCLUSIONS: The addition of enfuvirtide to an optimized background regimen provided significant viral suppression and immunologic benefit over a 24-week period in HIV-1-infected patients who had previously received multiple antiretroviral drugs.",1
10294,12781504,Hyperlactataemia syndromes associated with HIV therapy,"Hyperlactataemia is seen in 8-18.3% of HIV-infected patients taking nucleoside-analogue reverse transcriptase inhibitors (NRTIs). Recent epidemiological studies suggest that most episodes are transient and subclinical. However, symptomatic and occasionally life-threatening cases accompanied by metabolic acidosis and hepatic steatosis (ie, lactic acidosis syndrome) have also been described. Though yet to be fully elucidated, the proposed mechanism is NRTI-induced inhibition of mitochondrial DNA polymerase culminating in derangements in oxidative phosphorylation and lactate homeostasis. Signs and symptoms range from mild hyperlactataemia accompanied by nausea, abdominal discomfort, and weight loss to severe, intractable lactic acidosis complicated by coma and multi-organ failure. Significant progress has recently been made with regard to the natural history of NRTI-related hyperlactataemia. However, other important aspects of the disorder, such as its pathogenesis, predisposing conditions, and management, remain poorly understood. This article reviews the current published work on these issues, identifies areas of controversy, and addresses directions for future research.",1
10295,12784346,"Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America","""BACKGROUND: Aprepitant is a novel neurokinin 1 (NK(1)) antagonist that has been shown to improve control of chemotherapy-induced nausea and vomiting (CINV) when added to a standard antiemetic regimen of a 5-hydroxytriptamine-3 antagonist plus a corticosteroid. The authors sought to evaluate further the efficacy and tolerability of aprepitant plus standard therapy in a large clinical trial. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-groups, Phase III study. Patients with cancer who were scheduled to receive treatment with high-dose cisplatin chemotherapy were randomized to receive 1 of 2 treatment regimens; the standard therapy group received intravenous ondansetron 32 mg and oral dexamethasone 20 mg on Day 1, and oral dexamethasone 8 mg twice daily on Days 2-4. The aprepitant group received oral aprepitant 125 mg, intravenous ondansetron 32 mg, and oral dexamethasone 12 mg on Day 1; oral aprepitant 80 mg and oral dexamethasone 8 mg once daily on Days 2-3; and oral dexamethasone 8 mg on Day 4. Patients recorded episodes of emesis, use of rescue therapy, and severity of nausea in a diary. A modified intent-to-treat approach was used to analyze the efficacy data. The primary endpoint was complete response (no emesis and no rescue therapy) during the 5-day period postcisplatin. Treatment comparisons were made using logistic regression models, and reported adverse events and physical and laboratory assessments were used to assess tolerability. RESULTS: A total of 523 patients were evaluated for efficacy, and 568 patients were evaluated for safety. During the 5 days after chemotherapy, the percentages of patients who achieved a complete response were 62.7% in the aprepitant group (163 of 260 patients) versus 43.3% in the standard therapy group (114 of 263 patients; P < 0.001). For Day 1, the complete response rates were 82.8% for the aprepitant group and 68.4% for the standard therapy group (P < 0.001); for Days 2-5, the complete response rates were 67.7% in the aprepitant group and 46.8% in the standard therapy group (P < 0.001). The overall incidence of adverse events was similar between the 2 treatment groups (72.8% in the aprepitant group [206 of 283 patients] and 72.6% in the standard therapy group [207 of 285 patients]) as were rates of serious adverse events, discontinuations due to adverse events, and deaths. CONCLUSIONS: In patients with cancer who are receiving high-dose cisplatin-based chemotherapy, therapy consisting of aprepitant (125 mg on Day 1 and 80 mg on Days 2-3) plus a standard regimen of ondansetron and dexamethasone provided superior antiemetic protection compared with standard therapy alone and was generally well tolerated.""",1
10296,12787946,The toxicological potential of khat,,1
10297,12789790,[Drug-induced severe jaundice],,1
10298,12791479,Erythema multiforme-type drug eruption due to ethambutol with eosinophilia and liver dysfunction,,1
10299,12792250,Terbinafine-associated hepatotoxicity,"Terbinafine, an orally and topically active agent licensed for treatment of dermatophytic infection, has gained rapid worldwide acceptance in medical practice. Despite its fairly benign profile of adverse reactions, liver toxicity has occasionally been linked to terbinafine. This report describes a patient with severe cholestatic hepatitis associated with use of terbinafine. The patient was treated successfully with corticosteroids after partial response to ursodeoxycholic acid and cholestyramine. We attempt to identify risk factors for terbinafine-induced hepatotoxicity by an analytical review of all relevant literature. The mechanism underlying terbinafine hepatotoxicity could be more than just an idiosyncratic reaction. 7,7-dimethylhept-2-ene-4-ynal (TBF-A), the allylic aldehyde metabolite of terbinafine, may play a role in the pathogenesis of its hepatotoxicity. Our analysis supports monitoring patients clinically and measuring liver biochemistry through periodic blood tests, after confirming normal liver function at the onset of therapy with terbinafine. Early detection of abnormal hepatic function should prompt immediate discontinuation of this drug along with further evaluation.",1
10300,12794546,Pretreatment of chronic active hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy,"""Chronic hepatitis C virus (HCV) is an independent risk factor for antiretroviral-related hepatotoxicity, but little is known about the frequency of severe liver toxicity in patients with HIV-HCV coinfection first treated for HCV (pretreated). The aim of this prospective study of 105 patients was to compare the incidence of progression to severe antiretroviral-related liver toxicity in 66 patients pretreated (36 with interferon-alpha [IFNalpha], 30 with IFNalpha plus ribavirin), and 39 patients not pretreated. The subjects could choose whether to receive anti-HCV therapy. Severe liver toxicity was defined as alanine aminotransferase (ALT) level > or =5-times the upper limit of normal in patients with normal baseline levels and > or =3.5-times in those with increased baseline levels. The authors also estimated the hepatotoxicity-related risk of discontinuing antiretroviral therapy. During antiretroviral therapy, 10 subjects (9.5%) experienced severe hepatotoxicity: 4 of 66 pretreated patients and 6 of 39 untreated patients (24-month survival: 94% +/- 2.9% vs. 85% +/- 5.8%). After adjusting for baseline CD4 cell counts, ALT levels, histologic scores, HCV and HIV viremia, HCV genotype (genotype 1 in 29% of pretreated patients and 20% of patients not pretreated), and previous anti-HCV therapy, the risk of discontinuing anti-HIV treatment was significantly higher in the anti-HCV untreated patients (RR = 10.4; 95% CI: 1.6-66; p =.0127) and in those with increased baseline ALT levels (RR = 1.014; 95% CI: 1.006-1.021; p =.0005). The authors' data suggest that previous treatment of chronic active HCV is an independent factor associated with a decrease of severe liver toxicity as the result of a subsequent antiretroviral regimen. The authors also confirm that the baseline level of ALT is an important prognostic factor for increased liver damage during antiretroviral therapy.""",1
10301,12795770,Clinical response to alefacept: results of a phase 3 study of intramuscular administration of alefacept in patients with chronic plaque psoriasis,"""BACKGROUND: Recognition of psoriasis as a T-cell-mediated immune disease has led to the development of various therapeutic approaches directed against the pathogenic T cells. Alefacept, a novel and selective biological recombinant protein, binds CD2 on T cells to block T-cell activation and proliferation and interacts with FcgammaRIII receptors on accessory cells to produce selective T-cell apoptosis. OBJECTIVE: To demonstrate the efficacy and safety of once-weekly alefacept IM compared with placebo given for 12 weeks to patients with chronic plaque psoriasis. METHODS: Multicentre (63 sites in Europe, the USA, and Canada), randomized, double-blind, parallel-group study comparing 10 mg and 15 mg of alefacept and placebo administered IM once weekly for 12 weeks. Patients were followed for an additional 12 weeks after cessation of therapy. Patients were eligible for enrollment if they were > or = 18 years of age, had chronic plaque psoriasis for > or = 12 months involving > or = 10% body surface area, and had CD4+ T-cell counts at or above the lower limit of normal. RESULTS: 507 patients were enrolled into three treatment groups, which were well balanced for demographic, baseline disease characteristics, and treatment history. A significantly greater percentage of patients treated with alefacept 15 mg IM achieved > or = 75% PASI reduction from baseline 2 weeks after the last dose compared with placebo (21% vs. 5%, P < 0.001); 12% of patients treated with alefacept 10 mg IM reached this level of improvement (P = NS vs. placebo). Alefacept was well tolerated, with adverse events similar to that of placebo. CONCLUSIONS: Treatment with alefacept 15 mg IM provided highly significant improvements in all measures of psoriasis disease activity compared with placebo. Pharmacodynamic data confirmed that alefacept is a selective biological agent that reduces memory-effector T cells (CD4+CD45RO+ and CD8+CD45RO+), the source of the pathogenic mediators of psoriasis, while having relatively no effect on naive T-cell populations.""",1
10302,12800071,Hepatotoxicity associated with antiretroviral therapy containing HIV-1 protease inhibitors,"""Human immunodeficiency virus 1 (HIV-1) protease inhibitors are important components of highly active antiretroviral therapy and have had a profound impact on the natural history of HIV and AIDS. However, in the era of highly active antiretroviral therapy (HAART), drug-induced hepatotoxicity or liver injury has emerged as an important potential complication of combination antiretroviral therapy, particularly those regimens containing protease inhibitors (PIs). Liver injury has been associated each of the six PIs currently approved by the U. S. Food and Drug Administration (FDA), most commonly with administration of full dose ritonavir (600 mg bid or 400 mg bid with saquinavir). However, this regimen has been largely replaced by the use of low-dose ritonavir (</= 200 mg bid) to pharmacologically """"boost"""" other PI, such as lopinavir or indinavir, which has not been associated with an increased risk of hepatotoxicity compared with other PIs. Coinfection with hepatitis C virus (HCV) and B virus (HBV) remains an important risk factor for the development of HAART-associated liver injury. Although studies indicate that coinfected patients can be safely treated with PIs, such patients should be closely monitored. In addition, although unsubstantiated, some experts recommend evaluation or treatment, or both, of underlying chronic viral hepatitis prior to the initiation of antiretroviral therapy. Further research is needed to understand the etiopathogenesis of PI-associated liver injury, particularly among patients with hepatitis B or C infection.""",1
10303,12801963,Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients,"OBJECTIVES: To compare the rate of hepatic fibrosis progression in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients, and to identify factors that may influence fibrosis progression. PATIENTS AND METHODS: A total of 153 HCV infected and 55 HCV-HIV coinfected patients were identified from two London hospitals. Eligible patients had known dates of HCV acquisition, were HCV-RNA positive, and had undergone a liver biopsy, which was graded using the Ishak score. Univariate and multivariate logistic regression analyses were used to identify factors associated with fibrosis progression rate and the development of advanced fibrosis (stages 3 and 4). RESULTS: The estimated median fibrosis progression rate was 0.17 units/year (interquartile range (IQR) 0.10-0.25) in HIV-HCV coinfected and 0.13 (IQR 0.07-0.17) in HCV monoinfected patients (p=0.01), equating to an estimated time from HCV infection to cirrhosis of 23 and 32 years, respectively. Older age at infection (p<0.001), HIV positivity (p=0.019), higher alanine aminotransferase (ALT) level (p=0.039), and higher inflammatory activity (p<0.001) on first biopsy were all independently associated with more rapid fibrosis progression. ALT was correlated with histological index (r=0.35, p<0.001). A CD4 cell count < or =250 x 10(6)/l was independently associated with advanced liver fibrosis (odds ratio 5.36 (95% confidence interval 1.26-22.79)) and was also correlated with a higher histological index (r=-0.42, p=0.002). CONCLUSION: HIV infection modifies the natural history of HCV by accelerating the rate of fibrosis progression by 1.4 fold, and the development of advanced fibrosis threefold. A low CD4 cell count was independently associated with advanced disease and correlated with higher histological index, which suggests that early antiretroviral therapy may be of benefit in slowing HCV progression in coinfected patients.",1
10304,12804070,Are kavalactones the hepatotoxic principle of kava extracts? The pitfalls of the glutathione theory,,1
10305,12809593,[Cholestatic hepatitis due to amoxicillin-clavulanic acid with positive re-exposure],,1
10306,12815153,Interleukin-1-receptor antagonist in the Muckle-Wells syndrome,,1
10307,12821054,Prolonged cholestasis and ductopenia associated with tenoxicam,"""Cholestatic liver diseases leading to progressive destruction of intra-hepatic bile ducts and ductopenia encompass multiple etiologies. Pathophysiology and natural history of drug-induced cholangiopathies remain unclear. We report a case of prolonged ductopenia attributed to Tenoxicam (Tilcotil o--a non-steroidal anti-inflammatory drug of the oxicam family) ingested at therapeutic dose. A 36 year-old male patient was admitted for jaundice and Lyell syndrome starting 1 week after the ingestion of Tenoxicam. Liver biopsy showed cholestasis, non-suppurative cholangitis and polymorphous inflammatory infiltrate of the portal tracts (round cells, macrophages an eosinophils). Treatment with ursodesoxycholic acid and cholestyramine was instituted and the patient was asymptomatic 1 year after. Three years later mild biological cholestasis persisted and ductopenia was evidenced on liver biopsy. In this report we found that: (1) The toxicity of tenoxicam was probably mediated by an immunoallergic mechanism (Lyell syndrome and eosinophils on histology); (2) ductopenia was secondary to inflammatory cholangitis. Factors responsible for this chronic evolution are still unknown (genetic predisposition, vascular factors, etc.); and (3) the presence of ductopenia contrasted with the """"clinical recovery"""" of the disease suggesting accessory bile drainage by cholangioles or partial reconstruction of the biliary tree.""",1
10308,12826635,"A phase 2 study of bortezomib in relapsed, refractory myeloma","BACKGROUND: Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS: In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS: Of 193 patients who could be evaluated, 92 percent had been treated with three or more of the major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immunofixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.",1
10309,12830336,Ceftriaxone-associated nephrolithiasis and biliary pseudolithiasis in a child,"""Ceftriaxone is a widely used third-generation cephalosporin. It is generally very safe, but complications of biliary pseudolithiasis and, rarely, nephrolithiasis have been reported in children. These complications generally resolve spontaneously with cessation of the ceftriaxone therapy; however, they may symptomatically mimic more serious clinical problems, such as cholecystitis. We report a case of both ceftriaxone-induced biliary pseudolithiasis and nephrolithiasis.""",1
10310,12834011,Kava extracts: safety and risks including rare hepatotoxicity,"Kava is a perennial shrub native to some islands of the South Pacific and has been cultivated for centuries to prepare a psychoactive beverage from its rhizoma by means of extraction. Subsequently, kava extracts are commonly used as herbal anxiolytic drugs also in many other countries all over the world including European ones and the USA. Toxicological and clinical studies have shown that kava extracts are virtually devoid of toxic effects with the exception of rare hepatotoxic side effects reported in few patients. When assessed primarily by the British regulatory authority MCA but also by us, a critical analysis of the suspected cases (n = 19) in Germany reveals that only in 1 single patient a very probable causal relationship could be established between kava treatment and the development of toxic liver disease due to a positive result of an unscheduled reexposure test, whereas in another patient there might be a possible association. Out of the remaining 17 cases 12 patients were not yet assessable due to insufficient data and in 5 other cases a causal relationship was unlikely or could be excluded. The German regulatory authority might therefore well be advised to provide now additional information for those 12 patients with so far unsatisfactory data, facilitating a more appropriate assessment of causality. Nevertheless, in the meantime physicians and patients should continue to keep an eye on possible hepatotoxic side effects in the course of kava treatment, to stop the treatment alredy at first suspicion and to start with a careful diagnostic work up ruling out all other causes.",1
10311,12839296,Reversibility of cirrhotic regenerative liver nodules upon NTBC treatment in a child with tyrosinaemia type I,"UNLABELLED: In a male patient with hereditary tyrosinaemia type I (HTI), NTBC [2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion] treatment and a diet low in phenylalanine and tyrosine were started at the age of 4 wk. At the recommended average dosage (1 mg kg(-1)), liver failure improved transiently. After 4 mo of treatment, with increased body weight, the dose had decreased to 0.7 mg kg(-1), and diffuse cirrhotic changes in liver parenchyma and multiple nodules were visualized by ultrasonography. Multiple nodules in the liver parenchyma were differentiated from hepatocellular carcinoma by magnetic resonance imaging (MRI) using mangafodipir trisodium as a paramagnetic liver-specific contrast agent. Augmentation of NTBC dosage resulted in a decrease in serum alpha-fetoprotein levels and in significant regression of liver nodules on MRI. CONCLUSION: In HTI patients with a poor response to NTBC treatment and/or development of cirrhotic changes of liver parenchyma, augmentation of the recommended NTBC dosage may result in significant improvement of symptoms.",1
10312,12842950,Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs,"OBJECTIVE: To estimate the risk of acute hepatotoxicity associated with nimesulide compared with other non-steroidal anti-inflammatory drugs. DESIGN: Retrospective cohort and nested case-control study. SETTING: Umbria region, Italy. PARTICIPANTS: 400 000 current, recent, and past users (almost 2 million prescriptions) of non-steroidal anti-inflammatory drugs between 1 January 1997 and 31 December 2001. MAIN OUTCOME MEASURES: Admissions to hospital for acute non-viral hepatitis and incidence of all hepatopathies and liver injury among users of nimesulide and other non-steroidal anti-inflammatory drugs. RESULTS: Current use of non-steroidal anti-inflammatory drugs was associated with a 1.4 (95% confidence interval 1.0 to 2.1) increased risk of hepatopathy compared with past use. In current users of nimesulide the rate ratio for all hepatopathies and more severe liver injury was 1.3 (0.7 to 2.3) and 1.9 (1.1 to 3.8), respectively. CONCLUSION: The risk of liver injury in patients taking nimesulide and other non-steroidal anti-inflammatory drugs is small.",1
10313,12848097,Acute hepatitis after parenteral amiodarone,,1
10314,12850405,"""Mixed drug intoxication involving zaleplon (""""Sonata"""")""","""Zaleplon (""""Sonata"""") is a pyrazolopyrimidine derivative approved for use in the United States for the treatment of insomnia. To date, there has been little data in the toxicological literature where zaleplon has been implicated as causing a fatal intoxication, either alone or in combination with other drugs. This report documents a case where zaleplon was identified in a suicide by multiple drug ingestion. The following zaleplon concentrations were found: heart blood 2.2mg/l; bile 8.6mg/l and urine 1.4mg/l. Zaleplon was also detected but not quantitated in the kidney and liver.""",1
10315,12853193,Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial,"BACKGROUND: Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. METHODS: In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. FINDINGS: The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. INTERPRETATION: Our results suggest that carvedilol extends survival compared with metoprolol.",1
10316,12858469,Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still's disease,"Infliximab, a chimeric anti-tumor necrosis factor-alpha monoclonal antibody, has been demonstrated to be efficient and safe in patients with active rheumatoid arthritis and in the management of severe bouts of Crohn's disease. However, the safety of infliximab has not been evaluated in patients infected with hepatitis B virus. We report the case of a 28-year-old woman, with a positive hepatitis B virus surface antigen, who developed fulminant hepatitis 2 weeks after receiving a second infliximab infusion for a refractory adult onset Still's disease.",1
10317,12860159,"Pancreatitis in an HIV-infected person on a tenofovir, didanosine and stavudine containing highly active antiretroviral treatment",,1
10318,12865865,Bortezomib (velcade) for multiple myeloma,,1
10319,12868201,[Coxibs: highly selective cyclooxygenase-2 inhibitors. Part II. Side effects],"Slow, time-dependent, irreversible, highly selective inhibitors of COX-2 such as celecoxib, etoricoxib, rofecoxib and valdecoxib, so-called coxibs, are a new group of drugs widely used in rheumatology as well as in other fields of medicine. The tolerability of these drugs is at least equivalent to that of commonly used non-selective COX inhibitors (e.g. diclofenac, ibuprofen, naproxen). The unquestionable superiority of selective COX-2 blockade includes a low risk of gastrointestinal side effects. However, similarly to the other COX inhibitors, coxibs must be carefully administered to patients with coexistent liver and renal disease, generalised atherosclerosis, ischaemic heart disease, and to the elderly and children. Pregnancy and lactation require precise monitoring of adverse effects on the fetus, neonate and infant, or discontinuation of therapy with the drug.",1
10320,12873607,"Early onset, nefazodone-induced fulminant hepatic failure",,1
10321,12877312,Fatal cyclobenzaprine overdose with postmortem values,"There are only two published cases of overdose with postmortem blood cyclobenzaprine concentrations, both with confounding factors. We report two additional cases of fatal cyclobenzaprine overdose with postmortem values. Case 1: a 56-year-old female was found in full cardiopulmonary arrest after a verbal suicide threat to a friend. Postmortem blood concentrations were cyclobenzaprine 0.96 mg/L and diazepam 0.3 mg/L. Case 2: a 37-year-old male was found in full arrest by a family member after an intentional ingestion of cyclobenzaprine. Postmortem blood concentrations were cyclobenzaprine 0.8 mg/L and ethanol 0.174 gm/dL. The concentrations of diazepam and ethanol reported in these two patients were not found in quantities usually associated with a fatal outcome, suggesting that the cyclobenzaprine was the primary cause of the fatality. Additionally, the blood was drawn from a femoral site, so that postmortem redistribution is not a likely factor. Blood concentration of > or = 0.8 mg/L cyclobenzaprine may be associated with a fatal outcome.",1
10322,12879680,Propofol infusion syndrome--report of an adult fatality,"This report describes a fatal case of the propofol infusion syndrome in an adult patient being sedated for a closed head injury using high doses of propofol. The features of circulatory collapse, metabolic acidosis, mild rhabdomyolysis and renal impairment are consistent with the syndrome and not readily attributable to alternative aetiologies. Potential mechanisms for the syndrome may relate to antagonism of beta-receptors, impaired myocardial oxygen utilization and a specific disruption to fatty-acid oxidation. This is the first published Australian case of the propofol infusion syndrome in an adult and should serve as an additional case report to the existing literature highlighting this potentially fatal syndrome in adults.",1
10323,12879990,Hepatotoxicity of antibiotics and antifungals,"Hepatotoxicity associated with any antibiotic is rare. With the wide-spread use of antimicrobial agents, however, hepatic injury is not an infrequent occurrence. Penicillins remain a widely used class of antimicrobials with a well defined record of low hepatotoxicity. The combination of clavulanate with amoxicillin may be associated with the greatest risk for liver injury from any antimicrobial agent. Significant hepatotoxicity also may occur with sulfamethoxazole/ trimethoprim and combination regimens used to treat tuberculosis. An autoimmune-like hepatitis may result from minocycline or nitrofurantoin exposure and most often resolves with cessation of therapy. Treatment with high doses of tetracycline and oxacillin may be associated with severe hepatotoxicity. Early suspicion of hepatocellular injury in the setting of antimicrobial exposure should prompt cessation of therapy and avoidance of rechallenge.",1
10324,12879992,Hepatotoxicity of hypolipidemic drugs,"Dyslipidemic conditions and their cardiovascular related complications are common. Effective primary and secondary prevention strategies include therapies to lower LDL and total cholesterol and to increase HDL. Further, it seems that there is a need for therapeutic reduction in triglycerides as it emerges as an independent risk factor for CVD. Many clinical trials have been designed to evaluate pharmacologic compounds in the treatment of the dyslipidemias and they seem to have shown a safe profile, both in the experiment phases and in post-marketing observation studies. Nevertheless, sporadic reports of hepatotoxicity with statins and niacin still arise (Table 2). Although routine hepatic biochemical test monitoring is recommended, the cost-effectiveness is questionable because often these reactions are idiosyncratic and may not be identified by this routine screening. The risk/benefit ratio is in favor of using these medications in individuals at risk. There is no evidence to suggest intrinsic hepatotoxic activity as such. Drugs that lower triglycerides such as fibrates, have been observed to improve hepatic biochemical tests, although in small series. This leads to speculation whether treatment with fibrates would be beneficial for non-alcoholic fatty liver disease (NAFLD), a condition that is emerging as one of enormous magnitude.",1
10325,12879994,Hepatotoxicity and complementary and alternative medicines,"Though some herbal medicines have been shown to protect against or treat experimental liver injury in vitro, and many may possess one or a combination of antioxidant, antifibrotic, immunomodulatory, or antiviral activities, they have not been shown effective in human trials. It has been extremely difficult to construct randomized, controlled trials using complementary and alternative medicines because of an incomplete understanding of their modes of action, the lack of standardization in their manufacture, and the complexity of ingredients in any herbal extract. This may become easier once more standardized and broad-based regulatory oversight of marketing and manufacture of these products is achieved. Despite this, the use of complementary and alternative medicines is ever increasing, especially in patients having chronic liver disease. With this growing popularity, it is becoming more apparent that many of these treatments possess the potential for appreciable hepatotoxicity, in some instances resulting in significant morbidity and mortality. Until these products are more closely regulated and their advertising better scrutinized, all physicians and patients should become more familiar with the natural and alternative products that are commonly used, and recognize which can be harmful (Table 4). Better public awareness should be maintained with regard herb and prescription drug interactions.",1
10326,12879996,Leukotriene antagonists,"Hepatotoxicity is the most common cause of fulminant hepatic failure in the United States and the main indication for market withdrawal of drugs. This condition has been increasingly recognized as a problem of enormous medical, financial legal, and regulatory importance. It is in context of this heightened awareness of hepatotoxicity, particularly associated with new high profile drugs, that the authors reviews the published data regarding liver injury related to a novel group of asthma drugs.",1
10327,12885805,Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for resected intermediate- and high-risk primary melanoma without clinically detectable node metastasis,"""PURPOSE: Low-dose interferon alfa (IFNalpha) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients. PATIENTS AND METHODS: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose IFNalpha2b (3 million international units [MU]/m2/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m2/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval. RESULTS: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFNalpha2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFNalpha2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P =.93). CONCLUSION: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFNalpha2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival.""",1
10328,12891528,6-thioguanine can cause serious liver injury in inflammatory bowel disease patients,"""BACKGROUND & AIMS: Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD. METHODS: Liver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities. RESULTS: Laboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (<200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1-7.3; P < 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2-7.4; P < 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P < 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2. CONCLUSIONS: NRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.""",1
10329,12895162,Health effects of kava use in an eastern Arnhem Land Aboriginal community,"BACKGROUND: Heavy kava use in Aboriginal communities has been linked to various health effects, including anecdotes of sudden cardiac deaths. AIMS: To examine associations between kava use and potential health effects. METHODS: A cross-sectional study was carried out within a kava-using east Arnhem Land Aboriginal community in tropical northern Australia. One-hundred-and-one adults who were current, recent or non-users of kava were enrolled in March 2000. Main outcome measures were physical, anthropometric, biochemical, haematological, immunological and neurocognitive assessments. RESULTS: Kava users more frequently showed a characteristic dermopathy (P<0.001). They had increased levels of gamma-glutamyl transferase and alkaline phosphatase (P<0.001). Lymphocyte counts were significantly lower in kava users (P<0.001). Fibrinogen, plasminogen activator inhibitor-1 and neurocognitive tests were not different between kava use categories. IgE and IgG antibodies were elevated across the whole group, as were C-reactive protein and homocysteine. CONCLUSIONS: Kava use was associated with dermopathy, liver function abnormalities and decreased lymphocytes. If kava continues to be used by Aboriginal populations, monitoring should focus on the health consequences of these findings, including a possible increase in serious infections. The interaction between kava, alcohol and other substances requires further study. Although markers of cardiovascular risk are increased across the population, these were not higher in kava users, and this increase may be linked to the large infectious pathogen burden reflective of the socioeconomic disadvantage seen in many remote Aboriginal communities.",1
10330,12902594,Lactic acidosis in HIV infected patients: a systematic review of published cases,"OBJECTIVE: To describe the clinical, epidemiological, and biochemical characteristics of published cases of lactic acidosis (LA) and to generate hypotheses concerning risk factors associated with this complication. METHODS: Systematic review of cases reported in the medical literature. RESULTS: 217 published cases were identified, 90 of which fulfilled the study definition and had sufficient individual data on potential risk factors to be included. The 90 patients had a mean age of 40.1 years (range 16-69) and 53% were female. All 90 patients were taking nucleoside reverse transcriptase inhibitors (NRTI) at the time of the episode. Among the 83 patients with details of their antiretroviral therapy (ART) regimen 51 patients were taking stavudine, 29 zidovudine, 27 didanosine, and 25 lamivudine. Around 50% of the patients had abdominal pain, nausea, or vomiting. Hepatic steatosis was consistently reported (53/90) and in 36 (68%) there was histological evidence. The case fatality rate was 48%. Six cases were rechallenged with NRTI and three developed a further LA episode. Using data on the numbers of HIV infected individuals receiving care in the United States, we estimate that the risk of LA could be 2.5 times higher for women than men. CONCLUSIONS: NRTI use and female sex appear to be risk factors for the development of LA. What other factors are involved is still not clear but might include duration of NRTI therapy, specific drug use, and genetic predisposition. A case-control study is needed to better define risk factors for severe LA.",1
10331,12903579,[Acute liver toxicity of antiretroviral therapy (HAART) after liver transplantation in a patient with HIV-HCV coinfection and associated hepatocarcinoma (HCC)],"OLT in HIV infected patients still remains a challenging option requiring a careful monitoring of patients for HCV reinfection, drug interactions and antiretroviral toxicity. Severe adverse events due to HAART have been already reported for post exposure prophylaxis in HIV infected patients. Here we report a case of liver graft toxicity related to HAART in a HIV-HCV co-infected patient (46 yrs-male) with associated a small HCC transplanted with a marginal liver graft. The patient had pre-OLT plasma HIV 1-RNA levels undetectable and CD4+ T-cell count of > 200 cells/microL for 6 months. At day 2 a severe graft dysfunction was observed (AST 1570 U/L, ALT 2180 U/L, BIL tot 8.3 mg/dL, BIL Dir 6.6 mg/dL and PT 35%--INR 2.5). Doppler scan showed hepatic artery always patient. Later the postoperative in-hospital course was complicated by tense ascites and severe cholestasis. Serum bilirubin reached 42 mg/dL in day 12. Hypertransaminasemia ended at day 15 while cholestasis ended after 46 days. Tacrolimus was reintroduced at day 7. A liver biopsy 10 after OLT showed severe intrahepatic cholestasis, centrolobular necrosis and macrovesicular steatosis (30%). The patient was discharged 48 days after OLT with good liver function. After seven months HIV-RNA is still undetectable and HAART has not been restarted. We believe that the early complications we observed may be attributed to a sudden increase in plasma concentration of antiretroviral drugs secondary to drug redistribution from peripheral tissues and hepatic clearance deficiency after OLT. Although a pre-OLT withdrawal of HAART seems unjustified a delayed re-introduction of HAART or the use of less hepatotoxic drugs may be advisable.",1
10332,12904105,Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson's disease,"""Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson's disease (PD). They extend the duration of action of levodopa. As a result, they increase 'on' time, decrease 'off' time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.""",1
10333,12904741,"Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003","CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month regimen of rifampin with pyrazinamide (RZ). On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring. To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003. This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI. The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI. Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease.",1
10334,12908848,Safety and pharmacology of oseltamivir in clinical use,"Oseltamivir is a novel agent approved for the treatment and prevention of influenza infection and illnesses in adults and children. Assessment of data from the clinical trial programme, a US health insurance database study and postmarketing surveillance allowed a comprehensive review of the safety of oseltamivir in clinical use in subjects >1 year of age. Oseltamivir has been studied over the course of a 5-year development programme in >11000 subjects from North America, Europe and the Southern Hemisphere, including otherwise healthy adults, approximately 500 elderly/high-risk subjects, and children (>1000) aged 1-12 years. Safety evaluations included treatment-emergent adverse events, hospitalisations and deaths, as well as haematological and biochemical laboratory safety tests. The data reveals that oseltamivir has simple, uncomplicated pharmacology and lacks potential for drug-drug interactions. Electrocardiogram parameters, including corrected QT interval, were unaffected by oseltamivir even at high doses. Postmarketing studies confirmed that transient gastrointestinal disturbance is the major adverse effect of oseltamivir and that this can be reduced by taking oseltamivir after a light snack. On treatment serious adverse events were reported in 1.3% of oseltamivir 75mg twice daily, 0.7% of oseltamivir 150 mg twice daily and 1.2% of placebo recipients, respectively, in the clinical trial programme. Postmarketing, it is estimated that, to date, over 4 million oseltamivir prescriptions have been dispensed worldwide. Approximately 2300 spontaneous reports were received by the manufacturer over the three winter seasons of use. As these events are reported infrequently and from an unknown number of users, it is not possible to definitively assess causality or frequency of reported events. Most reports were of gastrointestinal and skin reactions. However, a clear association between the skin reactions and oseltamivir has not been established. A large study of insurance records, which permitted the assessment of the relative risk of medical events treated in the month following prescription of oseltamivir in general use, showed no evidence of increased risk of cardiac, neuropsychiatric or respiratory events for those receiving oseltamivir compared with those who did not. To conclude, no important safety concerns have evolved which might limit the suitability of oseltamivir for the treatment and prevention of influenza in all patient populations.",1
10335,12908948,Fatal acute topiramate toxicity,"A 44-year-old Caucasian female was found dead in bed. Qualitative screening detected ethanol, phenobarbital, and methotrimeprazine. However, none were sufficient to attribute as the cause of death. Additionally, high concentrations of topiramate, an antiepilieptic agent, were found. Analysis of available biological fluids and tissues was carried out with the following results: blood (central) 170 mg/L, liver 140 mg/kg, stomach contents greater than 300 mg, and vitreous fluid 65 mg/L. The cause of death was ascribed to topiramate overdose.",1
10336,12912743,High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure,"""HYPOTHESIS: The use of potentially hepatotoxic herbal and dietary supplements is highly prevalent in the fulminant hepatic failure (FHF) patient population at our institution, and this subgroup of patients has a worse prognosis. DESIGN: Retrospective case series. Settings An adult tertiary care university hospital and a Veterans Affairs hospital in Oregon. PATIENTS: All patients referred to the liver transplantation service for FHF from January 2001 through October 2002 (N = 20). We defined FHF as onset of encephalopathy within 8 weeks of onset of jaundice in the absence of preexisting liver disease. All patients underwent investigation for potential causes of liver injury. Potentially hepatotoxic supplements were defined as those with previously published reports of hepatic injury related to their use. RESULTS: Ten patients (50%) were recent or active users of potentially hepatotoxic supplements or herbs; 10 had no history of supplement use. In the supplement group, 7 patients (35%) had no other identified cause for hepatic failure. Six patients in the supplement group and 2 patients in the nonsupplement group underwent orthotopic liver transplantation. Five patients in each group died. There were no significant differences in transplantation rate (P =.07) or survival (P>.99) between groups. Supplement use alone accounted for the most cases of FHF during this period, exceeding acetaminophen toxicity and viral hepatitis. CONCLUSIONS: Herbal and dietary supplements were potential hepatotoxins in a high proportion of patients with FHF at our institution. Enhanced public awareness of the potential hepatotoxicity of these commonly used agents and increased regulatory oversight of their use is strongly urged.""",1
10337,12915604,Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer,"""PURPOSE: This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens. PATIENTS AND METHODS: Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned. RESULTS: A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04). CONCLUSION: Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated.""",1
10338,12916063,Ephedra in perspective--a current review,"""Although the traditional use of Ephedra 'ma huang' has been established for thousands of years, its resurgence in the US as a herbal dietary supplement is currently a matter of national controversy. At the heart of the debate are three important questions: (1) the identity and composition of Ephedra products with regard to ephedrine and related alkaloids; (2) the potential therapeutic utility of Ephedra supplements for weight loss or performance enhancement; and (3) potential health risks associated with such uses of Ephedra, particularly in sensitive individuals or in cases of intentional abuse for its stimulant properties. This review surveys the literature on Ephedra with regard to traditional uses, botany, chemistry, analytics, pharmacological effects and health risks. A brief discussion of the central issues in the current debate on the regulation of Ephedra in the United States is included as this is where most of the problems have occurred to date.""",1
10339,12917302,Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis,"""BACKGROUND: Methotrexate and cyclosporine are well-known systemic therapies for moderate-to-severe chronic plaque psoriasis. We conducted a randomized, controlled trial comparing methotrexate and cyclosporine in terms of effectiveness, side effects, and the quality of life. METHODS: A total of 88 patients with moderate-to-severe psoriasis were randomly assigned to treatment for 16 weeks with either methotrexate (44 patients; initial dose, 15 mg per week) or cyclosporine (44 patients; initial dose, 3 mg per kilogram of body weight per day) and were followed for another 36 weeks. The primary outcome was the difference between groups in the psoriasis area-and-severity index after 16 weeks of treatment, after adjustment for base-line values; scores were determined in a blinded fashion by trained observers. RESULTS: Two patients were excluded from the analysis after randomization because they were found to be ineligible, and one patient withdrew his consent. Twelve patients in the methotrexate group had to discontinue treatment because of reversible elevations in liver-enzyme levels, and 1 patient in the cyclosporine group had to do so because of an elevation in the bilirubin level, but all 13 were included in the analysis. After 16 weeks of treatment, the mean (+/-SE) score for the psoriasis area-and-severity index decreased from 13.4+/-3.6 at base line to 5.0+/-0.7 among 43 patients treated with methotrexate, whereas the score decreased from 14.0+/-6.6 to 3.8+/-0.5 among 42 patients treated with cyclosporine. After adjustment for base-line values, the mean absolute difference in values at 16 weeks was 1.3 (95 percent confidence interval, -0.2 to 2.8; P=0.09). The physician's global assessment of the extent of psoriasis, the time to and the rates of remission, and the quality of life were similar in the two groups. CONCLUSIONS: No significant differences in efficacy were found between methotrexate and cyclosporine for the treatment of moderate-to-severe psoriasis.""",1
10340,12921251,Acetaminophen intoxication and length of treatment: how long is long enough?,"The currently recommended dosing scheme for treating acetaminophen overdose in the United States consists of a loading dose of oral N-acetylcysteine 140 mg/kg, followed by 70 mg/kg every 4 hours for 17 doses, for a total of 72 hours of oral N-acetylcysteine therapy. This protocol has been both effective and safe. We critically evaluated the evidence that supports reducing the course of N-acetylcysteine therapy from 72 hours to 24 or 36 hours. This shorter regimen offers important benefits for both the patient and the patient's family, such as increased drug tolerability and reduced hospital stay. Patients who intentionally ingested acetaminophen with harmful intent could receive appropriate psychosocial treatment more quickly. In addition, shorter courses of N-acetylcysteine therapy have positive financial ramifications by reducing the hospital stay by 1 or 2 days. Clearly, a shorter treatment regimen would not be appropriate for all patients, particularly those who seek treatment late (> 24 hrs after ingestion) and those with evidence of organ toxicity. In order to provide the necessary evidence to support a change in accepted clinical practice, further investigation on the safety and efficacy of a shorter N-acetylcysteine regimen should be conducted by clinical researchers in a controlled manner.",1
10341,12926190,Anticonvulsant drug hypersensitivity,"""BACKGROUND: Cutaneous adverse reactions are frequently described with anticonvulsant drugs, especially with aromatic drugs such as carbamazepine, phenytoin, and phenobarbital. Patch tests could be useful for diagnosing this clinical picture. Hypersensitivity to several anticonvulsant drugs is common but unpredictable. MATERIAL AND METHODS: 15 patients from our allergy section, suffering from anticonvulsant skin allergy, were included. We describe their analitic alterations, responsible drugs, and anticonvulsants tolerated, the results of patch tests with anticonvulsant drugs (5% pet. and aq.), and skin biopsies wherever carried out. RESULTS: 23 adverse skin reactions with different anticonvulsant drugs occurred in the 15 patients: 13 resulted in fever and generalized cutaneous rash, 7 patients suffered only from cutaneous rash. There was one case of palpable purpura, one of erythema multiforme (target lesions), and another one suffered only cutaneous pruritus. Eosinophilia was found in 5 cases. Liver enzymes were elevated in 9 (7 of whom suffered fever and cutaneous rash). The responsible drugs were carbamazepine (8 adverse reactions), phenytoin (5), lamotrigine (4), phenobarbital (4), sodium valproate (1), and felbamate (1). The drugs tolerated were sodium valproate (6 patients), topiramate (4), vigabatrin (2), lamotrigine (1), clonazepam (1), and gabapentin (1). We found 12 positive patch tests: 6 with carbamazepine, 3 with phenytoin and, 1 each with lamotrigine, sodium valproate and phenobarbital. Skin biopsies were carried out in 5 patients, 4 of whom showed some characteristic findings of erythema multiforme (lymphocytic exocytosis, dyskeratotic cells, vacuolation of basal cells and pigmentary incontinence) and the other one showed a typical leucocytoclastic angitis. CONCLUSIONS: The cutaneous adverse reactions more frequently seen in our allergy section because of anticonvulsant drugs are rashes with fever. Eosinophilia and elevated levels of liver enzymes are frequently associated. This clinical picture is called """"anticonvulsant hypersensitivity syndrome."""" The drugs implicated most frequently are carbamazepine and phenytoin. Hypersensitivity to more than one drug was variable and unpredictable. The best-tolerated drug was sodium valproate, but it was not tolerated by a patient with phenytoin and carbamazepine hypersensitivity. Patch tests are useful for diagnosing anticonvulsant hypersensitivity. The most frequently findings in the skin biopsies were typical of erythema multiforme.""",1
10342,12932244,Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis,"BACKGROUND: Therapy with fumaric acid esters (FAE) has been shown to be safe and effective in patients with severe psoriasis in several clinical studies with limited follow-up periods. In view of the chronic character of psoriasis, long-term safety aspects are of major importance in determining the suitability of a drug during prolonged periods of treatment. OBJECTIVES: To investigate adverse events of therapy with systemic FAE with follow-up periods of up to 14 years, in order to determine safety aspects of their long-term use in patients with severe psoriasis. METHODS: Current and/or past therapeutic use of FAE was reviewed in 66 patients with severe psoriasis. RESULTS: Forty-one of 66 patients had received FAE for at least 1 year, and 12 of these 41 patients had received FAE for between 10 and 14 years. Adverse events were reported in 73% of the patients. These were usually mild and mainly consisting of flushing (55%), diarrhoea (42%), nausea (14%), tiredness (14%) and stomach complaints (12%). A relative lymphocytopenia was observed in 76% of patients during therapy with FAE, resulting in a permanent discontinuation of therapy with FAE in four patients. A transient eosinophilia and moderate liver enzyme elevations were observed in 14% and 25% of patients, respectively. CONCLUSIONS: The present study indicates that FAE can be considered as a safe long-term treatment in patients with severe psoriasis.",1
10343,12942419,Pancreatitis with didanosine and tenofovir disoproxil fumarate [corrected],"Pancreatitis occurs in up to 7% of patients infected with human immunodeficiency virus who are treated with standard doses of didanosine. Tenofovir disoproxil fumarate increases the plasma levels of didanosine and, thus, the combination of these agents may increase the risk of pancreatitis. Four cases of pancreatitis that occurred during administration of this drug combination are examined, including 1 that resulted in death.",1
10344,12948873,Benefit-risk assessment of Rosuvastatin 10 to 40 milligrams,"The aim of this article is to examine the benefit-risk profile of rosuvastatin at doses of 10 to 40 mg. In dyslipidemic patients, rosuvastatin produced markedly greater reductions in low-density lipoprotein (LDL) cholesterol and equivalent or greater improvements in various lipid measures, including high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and triglycerides when compared with atorvastatin, simvastatin, and pravastatin. In addition, rosuvastatin is more effective than these statins in allowing patients to reach National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and Joint European Societies LDL cholesterol goals. The safety profile of rosuvastatin was reviewed (as of April 2003) in 12,569 patients, representing 14,231 patient-years of treatment at doses up to 80 mg. In controlled trials, rosuvastatin 10 to 40 mg demonstrated a similar adverse event profile to those for atorvastatin 10 to 80 mg, simvastatin 10 to 80 mg, and pravastatin 10 to 40 mg. Myopathy (defined as muscle symptoms plus serum creatine kinase levels >10 times the upper limit of normal) attributed to rosuvastatin occurred in < or = 0.03% of patients receiving rosuvastatin 10 to 40 mg. No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg. Clinically significant alanine aminotransferase elevations occurred in 0.2% of patients receiving rosuvastatin and those receiving atorvastatin, simvastatin, and pravastatin. Compared with other widely used statins, the benefit-risk profile of rosuvastatin 10 to 40 mg appears to be very favorable.",1
10345,12950418,Systematic review: hepatotoxic events associated with herbal medicinal products,"BACKGROUND: Large proportions of patients use herbal medicinal products, and encouraging data in terms of effectiveness exist for some of these. One aspect, however, which is still largely under-investigated is the question of potential harm. AIM: To review the recent evidence on hepatotoxic events associated with the use of herbal medicinal products. METHODS: Systematic literature searches were performed on Medline, Embase, The Cochrane Library, Amed and Ciscom. To identify additional data, searches were conducted by hand in relevant medical journals and in our own files. The screening and selection of articles and the extraction of data were performed independently by the two authors. There were no restrictions regarding the language of publication. In order to be included articles were required to report data on hepatotoxic events associated with the therapeutic use of herbal medicinal products. RESULTS: Single medicinal herbs and combination preparations are associated with hepatotoxic events. Clinically, the spectrum ranges from transient elevations of liver enzyme levels to fulminant liver failure and death. In most instances hepatotoxic herbal constituents are believed to be the cause, while others may be due to herb-drug interactions, contamination and/or adulteration. CONCLUSIONS: A number of herbal medicinal products are associated with serious hepatotoxic events. Incidence figures are largely unknown, and in most cases a causal attribution is not established. The challenge for the future is to systematically research this area, educate all parties involved, and minimize patient risk.",1
10346,12952113,"Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma","OBJECTIVE: To evaluate the long-term effects of the anti-IgE antibody omalizumab in children with asthma. METHODS: This was a 28-week, double-blind, randomized, placebo-controlled trial with a 24-week open-label extension. In the core trial 225 children (ages 6 to 12 years) with moderate-to-severe allergic asthma requiring inhaled beclomethasone dipropionate (BDP) received omalizumab every 2 or 4 weeks, and 109 received placebo. BDP dosage was stable for weeks 1 to 16, then reduced during weeks 17 to 24 using strict safety criteria. The lowest dose for optimal asthma control was maintained for 4 more weeks. During the 24-week extension, all patients (n = 309) received open-label omalizumab in addition to other asthma medications. One-year safety data were analyzed. RESULTS: The incidence of adverse events in patients treated with omalizumab for 52 weeks was similar to those treated for 28 weeks in the core trial, which was generally comparable with placebo. In the 52-week omalizumab group, upper respiratory tract infection and headache were the most frequently reported adverse events (47.1% and 42.7%, respectively). Eleven patients (4.9%) reported urticaria, which resolved spontaneously or with antihistamine, except for 1 patient who was discontinued because of severe urticaria. No anaphylactic reactions or adverse events suggestive of serum sickness or immune complex formation occurred. No anti-omalizumab antibodies were detected in any of the children. There is no evidence that new or more serious adverse events occur with long-term omalizumab treatment. CONCLUSIONS: Long-term treatment with omalizumab is safe and well tolerated in children with allergic asthma.",1
10347,12954743,Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone,"""BACKGROUND: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial. RESULTS: The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated. CONCLUSIONS: Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting.""",1
10348,12960733,"Yondelis (trabectedin, ET-743): the development of an anticancer agent of marine origin","Yondelis (trabectedin, ET-743) is a novel antitumor agent derived from a marine source, the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies demonstrated activity at low concentrations against a variety of tumors. The mechanism by which ET-743 exerts its antitumor activity has not been completely elucidated yet. Binding to the minor groove of DNA which causes a bend towards the major groove has been demonstrated. Furthermore, ET-743 interferes with DNA binding proteins and transcription factors. Clinical studies have been initiated as phase I dose-finding studies at four different treatment regimens. Dose-limiting toxicities were hematological, including neutropenia and thrombocytopenia. Furthermore, significant liver toxicity was observed, especially as a rise in transaminase levels. Antitumor activity in phase I and phase II trials was studied in multiple tumor types, including soft tissue sarcomas, melanomas and breast cancer. ET-743 is currently being extensively investigated in advanced soft tissue sarcomas. The present review describes the development of ET-743, highlighting chemical properties, mode of action, metabolism and preclinical and clinical studies.",1
10349,12969980,Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients,"""Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.""",1
10350,12974198,Hypersensitivity to aldesleukin (interleukin-2 and proleukin) presenting as facial angioedema and erythema,"Aldesleukin is a human recombinant interleukin-2 product. It also is known as interlukin-2 and Proleukin in the United States. It is indicated for the treatment of adults with metastatic renal cell carcinoma as well as for adults with metastatic melanoma. However, its use has been limited because of severe systemic toxicity. There have been no reports of aldesleukin producing a hypersensitivity reaction. This is the first reported case of an immediate systemic hypersensitivity reaction occurring after aldesleukin administration confirmed by enzyme-linked immunosorbent assay for specific immunoglobulin E against aldesleukin.",1
10351,12997743,Testosterone therapy for the pruritus of obstructive jaundice,,1
10352,13003416,"""Ferrous sulfate poisoning; report of a fatal case""",,1
10353,13012048,"""Toxipathic hepatitis due to Fowler's solution; a case treated with dimercaprol""",,1
10354,13040367,The phenobarbital sensitivity syndrome,,1
10355,13065995,Hypervitaminosis A: report of a case in an adult male,,1
10356,13105180,Hepatomegaly and diabetes mellitus,,1
10357,13114814,Jaundice due to methyl testosterone therapy,,1
10358,13129873,Mycophenolate mofetil for the treatment of scleritis,"PURPOSE: To evaluate the usefulness of mycophenolate mofetil (MMF) (CellCept, Roche, Nutley, NJ), an antimetabolite immunosuppressant with a selective antiproliferative effect on T and B lymphocytes, for the treatment of scleritis. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Eight patients with scleritis treated with MMF in a tertiary referral center. METHODS: Review of the clinical records of patients evaluated at the National Eye Institute and prescribed MMF for the treatment of scleritis. MAIN OUTCOME MEASURES: Control of scleral inflammation, the ability to taper prednisone or other immunosuppressive medications, and adverse events were recorded for each patient. Mycophenolate mofetil was determined to be an effective steroid-sparing agent if the daily prednisone dosage could be reduced by 50% or more and was determined to be an effective adjunctive immunosuppressive agent if the scleral inflammation was controlled in patients with active scleritis. RESULTS: Four patients with diffuse anterior scleritis, two with necrotizing scleritis with inflammation, one with nodular anterior scleritis, and one with nodular anterior and posterior scleritis, were identified. Mycophenolate mofetil administration was initiated as a steroid-sparing agent in 4 patients with controlled scleritis and as an additional immunosuppressive agent in 4 patients with active scleritis receiving concomitant treatment with prednisone and cyclosporine or methotrexate. In 3 of the 4 patients started on MMF as a steroid-sparing agent, the scleritis remained controlled while the prednisone dosage was tapered by more than 50%. One of the patients started on MMF as a steroid-sparing agent had recurrent scleritis, and each of the patients with active scleritis continued to have persistent scleral inflammation requiring additional immunosuppressive therapy. Adverse effects recorded in 4 of the 8 patients included a rash, gastrointestinal symptoms, paresthesias, and laboratory evidence of hepatotoxicity and renal toxicity. CONCLUSIONS: Although MMF maybe be useful as a steroid-sparing agent, it was not effective as an adjunctive immunosuppressive agent in patients with active scleritis in our small, tertiary referral series. The adverse effects encountered with the use of MMF in this study cannot be attributed conclusively to MMF and are more likely complications of the multiagent systemic immunosuppressive therapy required for the treatment of recalcitrant scleritis.",1
10359,13131080,Dimercaprol in the pre-neurological stage of Wilson's disease (hepatolenticular degeneration),,1
10360,13131842,Blood dyscrasias associated with chloramphenicol. an investigation into the cases in the British Isles,,1
10361,13151835,Investigation of use of aurothioglycanide (Lauron) in rheumatoid arthritis: preliminary report of toxicity and therapeutic effects of a fine suspension,,1
10362,13182288,Fatal case of toxic hepatitis implicating chlorpromazine,,1
10363,13188454,"""Ferrous sulfate poisoning; a nonfatal case""",,1
10364,13211245,Fatal case of iron intoxication in a child,,1
10365,13214378,Jaundice during chlorpromazine therapy,,1
10366,13221416,"""Obstructive-type jaundice due to chlorpromazine (thorazine); report of three cases""",,1
10367,13240579,The mechanism of acute ferrous sulphate poisoning,,1
10368,13261870,Hepatitis following isoniazid,,1
10369,13362281,"Penicillamine, a new oral therapy for Wilson's disease",,1
10370,13366645,Adverse reactions to meprobamate,,1
10371,13388017,Serial liver-function and blood studies in patients receiving chlorpromazine,,1
10372,13401997,"[Chronic arsenic poisoning of Moselle vineyard-workers, with special reference to arsenic cancer]",,1
10373,13413258,Fatal agranulocytosis during treatment with a amodiaquine,,1
10374,13419432,Celontin (PM-396) in the treatment of epilepsy,,1
10375,13452049,Addiction to meprobamate,,1
10376,13483950,Jaundice and aplastic anaemia following chloramphenicol therapy,,1
10377,13487604,Allergy to chlorpromazine manifested by jaundice,,1
10378,13491691,Jaundice during administration of methylestrenolone,,1
10379,13538708,"""Hepatotoxicity due to chlorambucil; report of a case""",,1
10380,13552940,Meprobamate habituation: a controlled clinical study,,1
10381,13578100,Jaundice occurring in a patient treated with chlorothiazide,,1
10382,13590448,"""Chlorpromazine-type cholangitis; report of a case occurring after the administration of prochlorperazine""",,1
10383,13617281,"A six-month evaluation of an anabolic drug, norethandrolone, in underweight persons. II. Bromsulphalein (BSP) retention and liver function",,1
10384,13618612,Oral methyltestosterone and jaundice,,1
10385,13629130,Late prognosis of chlorpromazine jaundice,,1
10386,13637600,Studies with chlorpropamide in diabetic patients,,1
10387,13647410,"[Experiences with a new phenothiazine derivative, melleril Sandoz]",,1
10388,13672072,Isoniazid and para-aminosalicylic acid toxicity in 513 cases: a study including high doses of INH and gastrointestinal intolerance to PAS,,1
10389,13672808,Jaundice occurring during nicotinic acid therapy for hypercholesteremia,,1
10390,13678762,A case of valproate-associated hepatotoxicity treated with L-carnitine,"Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures and that is usually well tolerated. Nevertheless, serious side effects can occur, including hepatotoxicity. This side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia. These factors suggest that L-carnitine supplementation may play a role in preventing hepatotoxicity. We report a case of valproate-induced acute liver injury with a favorable evolution after L-carnitine therapy.",1
10391,13679326,Hepatic injury in 12 patients taking the herbal weight loss AIDS Chaso or Onshido,"BACKGROUND: The Chinese herbal dietary supplements Chaso and Onshido are marketed for weight loss in Japan. The safety of these weight loss aids is unknown. OBJECTIVE: To describe patients who developed liver injury while taking Chaso or Onshido. DESIGN: Case series. SETTING: Keio University Hospital, Tokyo, Japan, and other hospitals in Japan. PATIENTS: 6 patients who took Chaso and 6 patients who took Onshido before presenting with liver injury. MEASUREMENTS: Pathologic, clinical, and laboratory evaluations and chemical analysis of the herbal weight loss aids. RESULTS: All 12 patients developed acute liver injury characterized by a marked increase in serum liver chemistry values (mean alanine aminotransferase level, 1978 U/L [range, 283 to 4074 U/L]) after ingesting these products. Two patients developed fulminant hepatic failure: 1 patient required liver transplantation, and the other patient died. N-nitroso-fenfluramine, a variant of the appetite-depressant drug fenfluramine, was present in these products. CONCLUSIONS: The use of the weight loss aids Chaso and Onshido may be associated with acute liver injury. N-nitroso-fenfluramine is a possible hepatotoxic ingredient.",1
10392,13689710,Chlordiazepoxide hydrochloride (Librium) and jaundice: report of a case,,1
10393,13693318,Acute copper sulphate poisoning,,1
10394,13693888,Chronic pulmonary tuberculosis treatment with ethionamide combined with cycloserine or oxytetracycline,,1
10395,13696480,"""Three amine-oxidase inhibitor drugs in the treatment of depression; relative value and toxic effects""",,1
10396,13715243,Hepatitis caused by the newer amine-oxidase-inhibiting drugs,,1
10397,13733026,"Studies of nicotinic acid use in hypercholesteremia. Changes in hepatic function, carbohydrate tolerance, and uric acid metabolism",,1
10398,13745578,[Prochlorperazine in chronic psychoses],,1
10399,13750037,Acute copper poisoning. An outbreak traced to contaminated water from a corroded geyser,,1
10400,13757117,Drug-induced hepatic injury: Marplan hepatitis,,1
10401,13766606,Acute hepatitis due to intoxication with atabrine,,1
10402,13771657,"""[Cholostatic hepatosis caused by gold; analogy to chlorpromazine and androgen icterus]""",,1
10403,13784491,[Clinical research on the problem of liver damage by certain androgenic and anabolic steroids],,1
10404,13795916,Cholestatic jaundice from tolbutamide,,1
10405,13803875,Clinical evaluation of the effectiveness and safety of trimethobenzamide (tigan),,1
10406,13812634,Jaundice precipitated by prochlorperazine (compazine) in the treatment of alcoholic psychiatric disturbance,,1
10407,13832654,Jaundice due to prochiorperazine (compazine),,1
10408,13847249,Liver cell necrosis in chlorpromazine jaundice (allergic cholangiolitis). A serial study of twenty-six needle biopsy specimens in nine patients,,1
10409,13861044,Liver damage after chemotherapy for leukemia and lymphoma,,1
10410,13870055,Jaundice following thioridazine administration,,1
10411,13874077,Chloramphenicol and aplastic anemia: report of four cases,,1
10412,13881235,"Trimethobenzamide antiemetic in immediate postoperative period. Double-blind study in 2,000 cases",,1
10413,13898638,Clinical and chemical studies with alpha-methyl-dopa in patients with hypertension,,1
10414,13903000,Acute copper sulphate poisoning with special reference to its management with corticosteroid therapy,,1
10415,13911166,Portal hypertension in the myeloproliferative syndrome and the reticuloses,,1
10416,13917277,[Contribution to the study of jaundice caused by intrahepatic cholestasis of drug origin: forms of chlorpropamide and sulfamethoxypyridazine],,1
10417,13930795,Hepatic necrosis associated with halothane anesthesia,,1
10418,13942996,"Successful treatment of advanced isonizid- and streptomycin-resistant pulmonary tuberculosis with ethionamide, pyrazinamide, and isoniazid",,1
10419,13947807,Intrahepatic cholestasis with fatal termination following norethandrolone therapy,,1
10420,13948619,"""Liver """"autoantibodies"""" in a case of drug-induced jaundice""",,1
10421,13968454,Vincristine in the treatment of lymphomas and leukemias,,1
10422,13991599,Studies of hepatic excretory function. The effect of 17alpha-ethyl-19-nortestosterone on sulfobromophthalein sodium (BSP) metabolism in man,,1
10423,13998698,Jaundice following administration of fluphenazine dihydrochloride,,1
10424,14004438,Prolonged hepatic dysfunction after clinical recovery from chlorpromazine jaundice,,1
10425,14015698,Halothane anesthesia as a possible cause of massive hepatic necrosis,,1
10426,14028076,Upper abdominal pain and intrahepatic cholestasis as manifestations of sensitivity to ilosone,,1
10427,14038696,Hepatitis following administration of Ilosome. Case report,,1
10428,14046304,Generalized Hypersensitivity with Hepatitis and Jaundice after the Use of Penicillin and Streptomycin,,1
10429,14051363,CHRONIC HYPERVITAMINOSIS A. REPORT OF A CASE IN AN ADULT,,1
10430,14055046,Encephalopathy and Fatty Degeneration of the Viscera. A Disease Entity in Childhood,,1
10431,14059734,Fatal Liver Disease after Intravenous Administration of Tetracycline in High Dosage,,1
10432,14067683,"""TWO CASES OF UNTOWARD REACTION AFTER """"ILOSONE""""""",,1
10433,14086226,"Cholestatic Jaundice, Liver Decompensation, and Shock Resulting from Tolbutamide: Report of a Case",,1
10434,14090383,METHOTREXATE-INDUCED HEPATIC INJURY IN AN ADULT. A CASE REPORT,,1
10435,14109504,ACUTE IRON INTOXICATION. TREATMENT WITH DESFERRIOXAMINE (BA-29837),,1
10436,14114004,HEPATIC REACTIONS TO TETRACYCLINE,,1
10437,14117143,[Jaundice during Oral Antidiabetic Therapy],,1
10438,14120343,Production of Fatty Liver in the Rat by Cortisone,,1
10439,14122794,POSTOPERATIVE HEPATIC NECROSIS. ITS INCIDENCE AND DIAGNOSTIC VALUE IN ASSOCIATION WITH THE ADMINISTRATION OF HALOTHANE,,1
10440,14125225,Effect of Griseofluvin in Acute Intermittent Porphyria,,1
10441,14130886,Meprobamate: A Decade of Experience,,1
10442,14140236,[CONTRIBUTION TO THE STUDY OF THE TOXIC EFFECTS DUE TO HYPOGLYCEMIC SULFONYLUREAS],,1
10443,14160244,Hepatic Impairment during the Intake of Contraceptive Pills: Clinical Trial with Postmenopausal Women,,1
10444,14161411,PORPHYRIA CUTANEA TARDA ASSOCIATED WITH CHRONIC GRANULOCYTIC LEUKEMIA TREATED WITH BUSULFAN (MYLERAN),,1
10445,14164294,"""[Action of Mitomycin C in 65 Cases of Malignant Tumor. Comparison of Repeated Small Doses and """"Massive"""" Doses]""",,1
10446,14171108,Oral Contraceptives and Liver Damage,,1
10447,14172046,Oral Contraceptives and Liver Damage,,1
10448,14179556,MITHRAMYCIN IN THE TREATMENT OF EMBRYONAL CANCER,,1
10449,14185627,Oral Contraceptives and Liver Damage,,1
10450,14198736,Oral Contraceptives and Liver Damage,,1
10451,14208075,[HEPATIC FUNCTION IN PATIENTS TREATED WITH CHLORPROPAMIDE FOR PROLONGED PERIODS],,1
10452,14211383,CLINICAL OBSERVATIONS OF THE SIDE-EFFECTS OF HALOPERIDOL,,1
10453,14213591,Oral Contraceptives and Acute Intermittent Porphyria,,1
10454,14221666,Ethionamide-Induced Hepatitis. A Review with a Report of an Additional Case,,1
10455,14224214,MITHRAMYCIN IN THE TREATMENT OF DISSEMINATED TESTICULAR NEOPLASMS,,1
10456,14226570,ACUTE IRON POISONING: ITS EFFECTS AND TREATMENT,,1
10457,14227802,REACTIONS TO ANTITUBERCULOSIS DRUGS AMONG CHINESE IN HONG KONG,,1
10458,14231833,[a Fatal Case of Prolonged Chlorpromazine Jaundice],,1
10459,14234213,Contraindications of Biological-Oxidation Inhibitors in the Treatment of Porphyria,,1
10460,14238106,Jaundice and Its Relation to Therapeutic Agents,,1
10461,14242178,THE TREATMENT OF PSORIASIS WITH FOLIC ACID ANTAGONISTS,,1
10462,14243179,FAILURE OF NON-17-ALKYLATED ANABOLIC STEROIDS TO PRODUCE ABNORMAL LIVER FUNCTION TESTS,,1
10463,14245190,MANAGEMENT OF ACUTE IRON POISONING,,1
10464,14245215,ORAL CONTRACEPTIVES AND LIVER DAMAGE,,1
10465,14253900,Hypervitaminosis A: Report of a Case,,1
10466,14260636,Oral Contraceptives and Liver Damage,,1
10467,14262279,HEPATOTOXICITY PRODUCED BY TETRACYCLINE OVERDOSAGE,,1
10468,14266828,Fatty Liver of Pregnancy and Its Relationship to Tetracycline Therapy,,1
10469,14278818,"""Effects of Chloroquine on Patients with Cutaneous Porphyria of the """"Symptomatic"""" Type""",,1
10470,14279496,SURVIVAL IN A CASE OF ACUTE ORAL CHROMIC ACID POISONING WITH ACUTE RENAL FAILURE TREATED BY HAEMODIALYSIS,,1
10471,14286994,Oral Contraceptives and Liver Injury,,1
10472,14291456,HEPATIC AND RENAL LESIONS IN A CASE OF TETRACYCLINE TOXICITY DURING LONG-TERM ESTROGEN THERAPY AFTER ORCHIECTOMY,,1
10473,14295333,Oral Contraceptives and Liver Injury,,1
10474,14315662,"METHYLTESTOSTERONE, RELATED STEROIDS, AND LIVER FUNCTION",,1
10475,14318470,Intrahepatic Cholestatic Jaundice of Pregnancy Followed by Enovid-Induced Cholestatic Jaundice: Report of a Case,,1
10476,14326711,JAUNDICE DURING TREATMENT WITH ORAL CONTRACEPTIVE AGENTS: REPORT OF TWO CASES,,1
10477,14328478,Acute Anaphylactoid Reaction to Probenecid,,1
10478,14350490,Jaundice during methimazole (tapazole) administration,,1
10479,14350545,Summary of experience with 6-mercaptopurine,,1
10480,14367012,"""Clinical study of a new tranquilizing drug; use of miltown (2-methyl-2-n-propyl-1,3-propanediol dicarbamate)""",,1
10481,14378593,"""Liver damage and eosinophilia following chlorpromazine therapy; report of a case""",,1
10482,14405648,Hepatic fibrosis in children with acute leukemia: a complication of therapy,,1
10483,14433954,The effect of amodiaquin (camoquin) on the course of rheumatoid arthritis,,1
10484,14438978,Hepatocellular jaundice as a complication of iproniazid therapy,,1
10485,14467350,[Icterus in imipramine therapy],,1
10486,14470759,Erythromycin hepato-sensitivity: a preliminary report of two cases,,1
10487,14477414,"Shock, liver necrosis, and death after penicillin injection",,1
10488,14486256,Serum glutamic oxaloacetic transaminase elevation and possible hepatotoxicity accompanying the administration of ethionamide,,1
10489,14492926,Hepatic dysfunction associated with triacetyloleandomycin and propionyl erythromycin ester lauryl sulfate,,1
10490,14495139,"[Chlorpromazine icterus, a form of cholostatic hepatosis. Clinical-pathological report on 14 observations]",,1
10491,14500805,"The effects of parathyroid hormone, alendronate, or both in men with osteoporosis","""BACKGROUND: Because parathyroid hormone increases both bone formation and bone resorption, it is possible that combining parathyroid hormone with an antiresorptive agent will enhance its effect on bone mineral density. METHODS: We randomly assigned 83 men who were 46 to 85 years of age and had low bone density to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 microg subcutaneously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months; parathyroid hormone therapy was begun at month 6. The bone mineral density of the lumbar spine, proximal femur, radial shaft, and total body was measured every six months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured at base line and month 30 by means of quantitative computed tomography. Serum alkaline phosphatase levels were measured every six months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine. RESULTS: The bone mineral density at the lumbar spine increased significantly more in men treated with parathyroid hormone alone than in those in the other groups (P<0.001 for both comparisons). The bone mineral density at the femoral neck increased significantly more in the parathyroid hormone group than in the alendronate group (P<0.001) or the combination-therapy group (P=0.01). The bone mineral density of the lumbar spine increased significantly more in the combination-therapy group than in the alendronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase level were significantly greater in the parathyroid hormone group than in the alendronate group or the combination-therapy group (P<0.001 for both comparisons). CONCLUSIONS: Alendronate impairs the ability of parathyroid hormone to increase the bone mineral density at the lumbar spine and the femoral neck in men. This effect may be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate.""",1
10492,14502318,"The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis","""OBJECTIVE: Non-alcoholic steatohepatitis (NASH) is frequent in obese subjects and has a relatively benign course; however, it may progress to cirrhosis. Weight loss in these patients may alleviate the findings of NASH. The aim of this study was to investigate the effects of pharmacological anti-obesity therapies on the findings of NASH. SUBJECTS: There were thirteen patients (9 women, 4 men) in sibutramine group and 12 patients (8 women, 4 men) in orlistat group. The mean ages and body-mass indexes of the two groups were 42.5 years, 37.3 kg/m2 and 43.2 years, 36.1 kg/m2, respectively. METHOD: The obese subjects with NASH were given sibutramine or orlistat for six months. Additionally, all patients were given a low caloric diet. Liver enzymes (AST, ALT, GGT and ALP), insulin resistance (analysed by HOMA) and hepatic ultrasound (US) findings were assessed at baseline and after 6 months. RESULTS: Both sibutramine and orlistat significantly reduced body weight (10.2 and 8.4%, respectively), insulin resistance (47 and 40%, respectively), AST (41 and 39%, respectively), ALT (59 and 58%, respectively), and GGT serum levels (27 and 25%, respectively). The ultrasonographic regression in steatosis was observed in 11 patients who received sibutramine and 8 patients who received orlistat. During the treatment, unexpectedly significant increases in total alkaline phosphatase levels were found in both sibutramine and orlistat groups (9 and 14%, respectively). CONCLUSION: The present study shows that both sibutramine-induced and orlistat-induced weight losses result in reduction of insulin resistance, and improvements in biochemical markers and US findings of NASH. Because the GGT levels decreased in both groups, the increased ALP levels might have another source.""",1
10493,14508682,Efficacy and safety of intravenous amiodarone for incessant tachycardias in infants,"UNLABELLED: Amiodarone is an effective anti-arrhythmic agent for the treatment of supraventricular and ventricular tachycardias. The safety and efficacy of intravenous amiodarone has been described in adults and children but only to a limited extent in infants. The purpose of this study was to evaluate the safety and efficacy of intravenous amiodarone in infants. Between February 1994 and June 2001, 23 infants with a median age of 8 days (range 1-300 days) with life-threatening incessant tachycardias (17 supraventricular, 6 ventricular) were treated with intravenous amiodarone as single anti-arrhythmic agent. At presentation, 22 infants were haemodynamically unstable. Amiodarone was given as an intravenous loading dose of 5 mg/kg over 1 h followed by an intravenous maintenance dose of 5 micro g/kg per min with stepwise increase up to 25 micro g/kg per min until arrhythmia control or side-effects occurred. Amiodarone was effective in 19 infants, partially effective in three and ineffective in one infant. The median time until arrhythmia control was 24 h (range 1-96 h) and the median maintenance dosage 15 micro g/kg per min (range 5-26 micro g/kg per min). Electrophysiological side-effects necessitating dose reduction comprised of sinus bradycardia in two patients. Hypotension in one patient resolved after dose diminution. Neurological side-effects consisted of choreatic movements in one infant, which resolved over time. Amiodarone administration was stopped in one patient with elevated liver enzymes. CONCLUSION: intravenous amiodarone is a safe and effective therapy for life-threatening incessant tachycardias in infants.",1
10494,14512477,Drug points: Fatal lactic acidosis associated with tenofovir,,1
10495,14519954,Metabolite profiles of flutamide in serum from patients with flutamide-induced hepatic dysfunction,"Hepatic dysfunction due to flutamide administration has been reported and this side effect often limits the use of the agent. The prediction of flutamide-induced hepatotoxicity is attributed to the proper use of the antiandrogen. In this study, we investigated whether hepatic dysfunction could be assessed by the metabolite profile in serum from patients receiving this drug. Serum samples were obtained from 15 patients with prostate cancer, 12 patients with no sign of hepatotoxicity and 3 patients with slight hepatic dysfunction during long-term flutamide treatment. We analyzed the metabolite profiles by LC/MS in selected ion monitoring mode and detected a new metabolite (M3) that was an oxidation product of flutamide. However, there were no consistent differences in the serum flutamide metabolites between patients with normal function and those suffering hepatic dysfunction. The metabolite profiles in the beta-glucuronidase-treated serum showed a similar pattern between normal functioning and dysfunctional groups. Thus, the profile of flutamide metabolites determined in serum may not contribute to the risk prediction of flutamide-related hepatotoxicity.",1
10496,14523278,Case series of acute hepatitis in a non-selected group of HIV-infected patients on nevirapine-containing antiretroviral treatment,"OBJECTIVE: To evaluate the characteristics of patients who developed acute clinical hepatitis in an unselected outpatient population. METHODS: Patients who started a nevirapine-containing regimen in the period January 1999-February 2001 and presented with clinical symptoms in accordance with increased transaminase values within 12 weeks of initiation of nevirapine were considered possible cases of clinical hepatotoxicity. Patient characteristics, co-medicated drugs, HIV-1 RNA levels and clinical chemistry parameters were collected from outpatient medical records and clinical medical records. RESULTS: At the defined period, 306 patients started a nevirapine-containing regimen, of whom eight developed an acute hepatitis (2.6%) in a median of 24 days [interquartile range (IQR) 20-25 days]. Transaminases peaked at 28 days (IQR, 27-32 days). Injury pattern was in general mixed-hepatocellular. Withdrawal of the antiretroviral agent led to rapid restoration of transaminase levels and resolution of clinical symptoms. The reason for developing this hepatic reaction was not clear in every case as no specific risk factor(s) covering all patients in this case series could be identified. CONCLUSIONS: It is very important to monitor closely transaminase levels of all patients starting a nevirapine-containing regimen, including patients with no specific characteristics that put them at risk. The rapid onset of the clinical symptoms pleads for transaminase monitoring at a very early stage (i.e., within 2 weeks of initiation) of the nevirapine-containing regimen.",1
10497,14524163,Hepatocellular carcinoma associated with precocious puberty and oral contraceptives. A case report,"A 36-year-old woman presented with sudden abdominal pain and vomiting. Computed tomography showed a tumour of the right hepatic lobe with possible signs of acute haemorrhage. Her medical history revealed precocious puberty when she was a 5-year-old and the use of oral contraceptives for 18 years. Bisegmentectomy was performed and histological examination revealed hepatocellular carcinoma. The role of male and female sex hormones in the development of hepatic tumours has been well documented but, to our knowledge, association with precocious puberty has not yet been described.",1
10498,14531175,Successful treatment of refractory cerebral oedema in ecstasy/cocaine-induced fulminant hepatic failure using a new high-efficacy liver detoxification device (FPSA-Prometheus),"Ecstasy-induced fulminant hepatic failure is associated with high mortality. If complicated by cerebral oedema, orthotopic liver transplantation is the only established treatment. We report a case of combined ecstasy/cocaine-induced fulminant hepatic failure presenting with severe rhabdomyolysis, myocardial infarction and multiorgan failure. Transplantation was declined by the transplant surgeons because of a history of intravenous drug abuse. As excessive hyperammonaemia (318 mumol/l) and refractory transtentorial herniation developed, treatment with a new liver detoxification device combining high-flux haemodialysis and adsorption (FPSA-Prometheus) was initiated. Within a few hours of treatment, ammonia levels normalised. Cerebral oedema was greatly reduced by day 4 and hepatic function gradually recovered. Following neurologic rehabilitation for ischaemic sequelae of herniation, the patient was discharged from hospital with only minimal deficits. In conclusion, efficient extracorporeal detoxification may be an option for reversal of hyperammonaemia and refractory cerebral oedema in ecstasy/cocaine-induced acute liver failure.",1
10499,14559139,Rapidly fatal acute amiodarone hepatitis occurring in the context of multiple organ failure,,1
10500,14561005,Fatal cholestatic liver failure associated with gemcitabine therapy,"Drug-induced hepatotoxicity accounts for more than a third of the cases of acute liver failure in the United States. In complex medical conditions, the diagnosis of drug-induced liver injury may be confounding and, specifically, the potential hepatotoxicity of chemotherapeutic agents may be easily overlooked. Two fatal cases of cholestatic hepatotoxicity have been previously reported, clearly implicating gemcitabine therapy. We report a third fatal case of cholestatic liver failure that we think is strongly linked to the use of gemcitabine. This chemotherapeutic agent is a fluorine analog with broad-spectrum antitumor activity commonly used in the treatment of breast, lung, prostate, and cervical cancer. The case we report is of a 45-year-old woman with a history of metastatic breast cancer to her spine. The patient was in remission for two years before she presented with a compensated mixed hepatitis of mild to moderate severity. Inpatient work-up found metastases to the right humerus and inferior pubic ramus, but none in the liver. Gemcitabine and carboplatin therapy was initiated for relapse of breast cancer. The patient's liver enzyme elevation diminished, but did not normalize before the start of chemotherapy. She received four courses of gemcitabine/carboplatin and subsequently presented with decompensated, severe cholestatic hepatitis. Transjugular liver biopsy displayed marked cholestasis and hepatocellular injury consistent with drug-induced hepatoxicity. Gemcitabine has been extensively studied in the oncology literature and at this time is thought to be a low-risk hepatotoxin causing hepatic adaptation and transient, reversible liver enzyme elevation, rarely leading to termination of gemcitabine therapy for solid tumors. We believe that gemcitabine therapy, particularly in the setting of preexisting liver injury or metastases to the liver, increases the relative risk of severe and potentially fatal hepatic injury possibly by idiosyncratic and dose-dependent mechanisms. We recommend careful monitoring and dose adjustment of gemcitabine in patients with abnormal liver function tests or evidence of hepatic metastases until further study clarifies this issue.",1
10501,14562419,Liver cell adenoma with malignant transformation: a case report,"A 57-year-old woman was referred to our hospital because of a liver mass detected by computed tomography. She had taken oral contraceptives for only one month at the age of thirty. Physical examination revealed no abnormalities, and laboratory data, including hepatic function tests, were within the normal range, with the exception of elevated levels of those serum proteins induced by the absence of vitamin K or by raised levels of the antagonist (PIVKA)-II (3,502 AU/ml). Abdominal ultrasonography revealed a hyperechoic mass measuring 10 X 10 cm in the left posterior segment of the liver. Because hepatocellular carcinoma could not be completely excluded, this mass was resected. The tumor consisted of sheets of uniform cells with clear cytoplasm, perinuclear eosinophilic granules and round nuclei. These histological findings were consistent with liver cell adenoma. Background hepatic tissue appeared normal. After resection of the tumor, serum PIVKA-II fell to within the normal range. An area of hepatocellular carcinoma (HCC) with a mid-trabecular pattern was immunohistochemically found, which was positive for PIVKA-II. Sinusoidal endothelial cells were CD34-positive, containing scattered PIVKA-II positive cells. This tumor was therefore finally diagnosed as liver cell adenoma with focal malignant transformation to HCC.",1
10502,14566034,Hepatocellular damage from non-steroidal anti-inflammatory drugs,"Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of rheumatological disorders, and as analgesics and antipyretics. Hepatotoxicity is an uncommon, but potentially lethal complication, which usually occurs within 12 weeks of starting therapy. It can occur with all NSAIDs, but appears to be more common with diclofenac and particularly sulindac. Female patients aged >50 years, with autoimmune disease, and those on other potentially hepatotoxic drugs, appear to be particularly susceptible. Liver function test abnormalities generally settle within 4-6 weeks of stopping the causative drug. However, some patients may develop acute liver failure and successful orthotopic liver transplantation may be undertaken in such patients. Recent in vitro animal studies have shown that the mechanism of diclofenac toxicity relates both to impairment of ATP synthesis by mitochondria, and to production of active metabolites, particularly n,5-dihydroxydiclofenac, which causes direct cytotoxicity. Mitochondrial permeability transition (MPT) has also been shown to be important in diclofenac-induced liver injury, resulting in generation of reactive oxygen species, mitochondrial swelling and oxidation of NADP and protein thiols. Physicians and hepatologists must be vigilant to the hepatotoxic potential of any NSAID, as increased awareness, surveillance and reporting of these events will lead to a better understanding of the risk factors and the pathophysiology of NSAID-related hepatotoxicity.",1
10503,14568893,Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension,"""BACKGROUND: The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown. METHODS AND RESULTS: We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by > or =1 class in all patients. Pretreatment versus posttreatment values (mean+/-SEM) were as follows: 6-minute walk, 376+/-30 versus 504+/-27 m, P<0.0001; mean PA pressure, 70+/-3 versus 52+/-3 mm Hg, P<0.007; pulmonary vascular resistance index 1702+/-151 versus 996+/-92 dyne x s x cm(-5) x m(-2), P<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels. CONCLUSIONS: This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of 492 dollars Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.""",1
10504,14570950,"Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial","CONTEXT: More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. OBJECTIVE: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. INTERVENTION: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). MAIN OUTCOME MEASURES: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). RESULTS: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006). CONCLUSIONS: Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.",1
10505,14571732,Prochlorperazine-induced cholestasis in a patient with alpha-1 antitrypsin deficiency,"""A case of a 58-year-old woman with history of bilateral lung transplant secondary to alpha-1 antitrypsin deficiency (PIZZ), who presented with a severe drug-induced cholestasis secondary to prochlorperazine is reported. After 27 months of prochlorperazine use, she developed liver failure consisting of jaundice with ascites. Computed tomography of the abdomen, abdominal ultrasonography as well as an endoscopic retrograde cholangiopancreatography showed no evidence for biliary obstruction. Liver biopsy demonstrated diffuse ongoing advanced chronic cholestasis, moderate portal and periportal inflammation as well as bridging fibrosis. During her hospitalization, her total bilirubin increased to 38.6 mg/dL; alkaline phosphatase to 362 IU/L, alanine aminotransferase to 71 IU/L and aspartate aminotransferase to 88 IU/L. After several weeks of ursodiol therapy without clinical improvement the prochlorperazine was discontinued and was followed by a rapid improvement in her measures of liver injury. An immediate decline of her serum total bilirubin and alkaline phosphatase to 21.4 mg/dL and 258 IU/L, respectively, occurred strongly suggesting the idea of a prochlorperazine-induced injury.""",1
10506,14575648,Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity,"The nonsteroidal antiinflammatory drug diclofenac causes rare but significant cases of serious hepatotoxicity, typically with a delayed onset (>1-3 months). Because there is no simple dose relationship and because liver injury cannot be reproduced in current animal models, individual patient-specific susceptibility factors have been evoked to account for the increased risk. While these patient factors have remained undefined, a number of molecular hazards have been characterized. Among these are metabolic factors (bioactivation by hCYP2C9 or hCYP3A4 to thiol-reactive quinone imines, activation by hUGT2B7 to protein-reactive acyl glucuronides and iso-glucuronides, and 4'-hydroxylation secondary to diclofenac glucuronidation), as well as kinetic factors (Mrp2-mediated concentrative transport of diclofenac metabolites into bile). From the toxicodynamic view, both oxidative stress (caused by putative diclofenac cation radicals or nitroxide and quinone imine-related redox cycling) and mitochondrial injury (protonophoretic activity and opening of the permeability transition pore) alone or in combination have been implicated in diclofenac toxicity. In some cases, immune-mediated liver injury is involved, inferred from inadvertent rechallenge data and from a number of experiments demonstrating T cell sensitization. Why certain underlying diseases (e.g., osteoarthritis) also increase the susceptibility to diclofenac hepatotoxicity is not clear. To date, cumulative damage to mitochondrial targets seems a plausible putative mechanism to explain the delayed onset of liver failure, perhaps even superimposed on an underlying silent mitochondrial abnormality. Increased efforts to identify both patient-specific risk factors and disease-related factors will help to define patient subsets at risk as well as increase the predictability of unexpected hepatotoxicity in drug development.",1
10507,14576622,Lowering plasma homocysteine,,1
10508,14577588,Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites,"""The frequency, severity, and outcome of flutamide-induced hepatic injury were prospectively evaluated in 55 patients with prostate cancer who received 125 mg of flutamide 3 times a day (daily dose: 375 mg) combined with an agonistic analogue of luteinizing hormone-releasing hormone. In addition, we examined plasma and urine concentrations of flutamide and its major metabolites 4 weeks after the beginning of flutamide therapy, and evaluated their significance in predicting flutamide-induced hepatic dysfunction. Hepatic function could be assessed in 50 patients and hepatic dysfunction during therapy was observed in 9 patients (18%); 3 patients (6%) were classified as having moderate liver dysfunction and 6 (12%) were classified as having mild liver dysfunction. The steady-state plasma levels of flutamide and its biologic active metabolite, hydroxyflutamide (OH-Flu), were not related to hepatic dysfunction. However, the concentration of another major metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) was considerably higher in 2 patients who developed clinically significant hepatic dysfunction. These findings suggest that clinically significant hepatic dysfunction could be induced in patients with compromised flutamide metabolism, which leads to a high concentration of FLU-1. Based on results of this study, we propose that plasma FLU-1 levels are one of the predictive factors for flutamide-induced hepatic dysfunction. This hypothesis will be confirmed in a large-scale study.""",1
10509,14583571,Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection,"BACKGROUND: Tumour necrosis factor alpha (TNF alpha) antagonists are effective for the treatment of rheumatoid arthritis (RA), but concerns remain about the safety of these agents in the presence of chronic infections, including hepatitis C virus (HCV) infection. OBJECTIVE: To examine the influence of treatment with TNF alpha antagonists on levels of HCV viraemia and serum transaminases in patients with RA and HCV. METHODS: In a retrospective survey the course of 16 HCV infected patients with RA who had received the TNF alpha antagonists etanercept or infliximab was analysed. Eight additional patients with RA and HCV were also enrolled into a three month prospective trial of etanercept. Serum concentrations of albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and HCV were followed. RESULTS: Viraemia was measured in 22 patients receiving a TNF alpha antagonist at the start of treatment and after 1-34 months (median 9 months follow up). Twenty four patients had serial tests of liver related enzymes and albumin. None of the differences between liver related tests at baseline and at follow up achieved significance (p>0.05). Similarly, the mean HCV measurement at 1-3, 4-6, 7-12, and 13-34 months did not differ significantly from baseline (p>0.05). CONCLUSION: In this study, liver related blood tests and HCV viral load measurements did not change substantially. These findings suggest that TNF alpha antagonists merit further study for the treatment of RA in HCV infected patients. Larger and longer term studies are still needed.",1
10510,14588070,[Acute hepatitis and minocycline],,1
10511,14600521,Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis,"OBJECTIVE: To evaluate the safety and efficacy of rechallenging patients who have recovered from nucleoside reverse transcriptase inhibitor (NRTI)-induced symptomatic hyperlactatemia or lactic acidosis with alternative NRTI-containing regimens. METHODS: Data in this case series was collected from patients followed at the UCSD Owen Clinic from July 1998 through September 2002. Cases of symptomatic hyperlactatemia were HIV-infected adults receiving NRTI who had symptoms compatible with hyperlactatemia and two lactates > 2 times the upper normal limit. Lactic acidosis was defined as lactate > 5 mmol/l with bicarbonate < 20 mmol/l. The suspected offending NRTI in the prior regimen were replaced with other NRTI thought to have equivalent antiviral potency but less mitochondrial toxicity. RESULTS: Ten patients diagnosed with symptomatic hyperlactatemia and two with lactic acidosis were later restarted on antiretrovirals that included new NRTI. The NRTI that patients were receiving when symptomatic hyperlactatemia or lactic acidosis was diagnosed included stavudine and lamivudine (n = 6), stavudine and didanosine (n = 4), and stavudine and abacavir (n = 2). The median (range) peak lactate was 5.4 (4.7-19.1) mmol/l. Five patients were rechallenged with abacavir and lamivudine, five with zidovudine, abacavir and lamivudine, and two with zidovudine and lamivudine. Among the 12 patients contributing over 22 years of cumulative reexposure to NRTI-containing therapy, one developed symptomatic hyperlactatemia again yielding a recurrence rate of 45.5 cases/1000 patient-years. Virologic control was maintained in all patients. CONCLUSIONS: This data supports the strategy that in cases of symptomatic hyperlactatemia or lactic acidosis in which the toxicity is associated with stavudine, didanosine or both, it is safe and efficacious to reintroduce NRTI that are less potent inhibitors of mitochondria.",1
10512,14607759,Hepatitis B virus reactivation after fludarabine-based regimens for indolent non-Hodgkin's lymphomas: high prevalence of acquired viral genomic mutations,"""BACKGROUND AND OBJECTIVES: Chemotherapy can cause hepatitis flare-up through viral reactivation in patients who have had contact with hepatitis viruses. Few data are available on the genotype of the reactivated viruses. DESIGN AND METHODS: In 40 consecutive adult patients with indolent non-Hodgkin's lymphoma (NHL) receiving fludarabine-based front-line chemotherapy, we performed a prospective study on viral hepatitis reactivation and analyzed the genotype of the reactivated viruses. Before chemotherapy, 4 patients were healthy carriers of hepatitis B surface antigen (HBsAg), 2 had HB core antigen antibodies (anti-HBc), 6 anti-HBs and 6 anti-HCV; 22 were seronegative. RESULTS: Hepatitis flare-up occurred in the 4 HBsAg-positive patients and in 1 anti-HBc-positive patient at a median of 1 month (range 1-4) after chemotherapy, when the CD4/CD8 ratio was still inverted. HBV reactivation was documented in all 5 instances (HBV-DNA 2-8 x 10(6) copies/mL). Two of the 5 patients responded to lamivudine, whereas 1 died of acute liver failure and 2 had persistent severe hepatitis. HBV genome sequencing at hepatitis flare-up showed that deviation from the closest related published sequences was 1.0% and 1.1% in the 2 lamivudine-responsive patients, and 1.5%, 1.8% and 1.7% in the 3 lamivudine-resistant patients. The polymerase open reading frame (ORF) and the HBs ORF of lamivudine-resistant strains contained several novel amino acid substitutions. INTERPRETATION AND CONCLUSIONS: These results suggest that fludarabine treatment of HBV-infected patients is frequently associated with acute hepatitis due to viral reactivation, and that lamivudine may be less effective in this situation than in other settings of immunocompromised hosts because of the emergence of resistant mutant strains.""",1
10513,14616149,Acute hepatitis and rash to fluconazole,,1
10514,14622530,[Liver toxicity of Camellia sinensis dried etanolic extract],,1
10515,14625346,Acetaminophen-induced hepatotoxicity,"""The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1beta is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.""",1
10516,14627335,The irony of herbal hepatitis: Ma-Huang-induced hepatotoxicity associated with compound heterozygosity for hereditary hemochromatosis,,1
10517,14628283,Acute liver enzyme elevations in HIV-1-infected patients,"BACKGROUND: Acute liver enzyme elevations (ALEE) have been associated with a first-line highly active antiretroviral therapy (HAART) and/or viral hepatitis coinfections in HIV-infected patients. By comparison, the frequency and the risk factors of ALEE in untreated patients and in patients treated with several antiretroviral regimens need to be assessed. PURPOSE: To describe the long-term frequency and the characteristics of ALEE in antiretroviral treated and untreated patients and to define risk factors for ALEE in a retrospective cohort of HIV-1-infected patients. METHOD: An HIV-infected cohort was retrospectively examined. ALEE was defined as levels of alanine amino transferase and/or alkaline phosphatase rising to at least 2.5 times above baseline values. Hazard ratios (HR) for ALEE were estimated using an extension of the Cox proportional model taking into account recurrent events. RESULTS: Out of 239 assessable patients, 12 (5%) were coinfected with hepatitis B virus (HBV) and 34 (14.2%) with hepatitis C virus (HCV). The incidence rate of ALEE was 9.9/100 patients-year and the cumulative incidence was 20.9%. HCV genotype 3 tended to give a higher risk of ALEE. Independent factors for developing ALEE in multivariate logistic regression were HBV (HR = 4.0) and HCV (HR = 3.4) coinfections, antiretroviral therapy (HR = 2.6), CDC stage C (HR = 2.5), and high alkaline phosphatase baseline values (HR = 1.7). CONCLUSION: The occurrence of ALEE is influenced more by the past medical history and the clinical background of the patients than by antiretroviral therapy. These patient-linked variables must be taken into account to avoid unwarranted treatment withdrawal.",1
10518,14631314,[Acute cytolytic and cholestatic hepatitis induced by fenofibrate],,1
10519,14636963,Acamprosate and naltrexone treatment for alcohol dependence: an evidence-based risk-benefits assessment,"This paper provides an evidence-based risk-benefit assessment of acamprosate and naltrexone in the treatment of alcohol dependence. A risk-benefit assessment is based on the premise that the choice of treatment depends on a number of factors, notably the adverse event profile and efficacy. An evidence-based approach attempts to operationalize how such risk-benefit assessments are made to inform physician choices. This approach involves a systematic assessment of all published double-blind, placebo-controlled trials. Based on this review, we conclude acamprosate and naltrexone are both useful in the treatment of alcohol dependence. However, the two drugs act in different ways in the brain, and their clinical profiles are different. Treatment effects seem to be more reliable for acamprosate, and this drug is better tolerated. The safety of the two drugs in combination has been supported by two independent double-blind studies, and combination treatment may offer an advantage for some patients.",1
10520,14642633,Ductopenic hepatitis related to Enalapril,,1
10521,14643119,Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection,"""BACKGROUND: Highly active antiretroviral therapy (HAART) has improved the prognosis of HIV infection. However, replication of hepatitis C virus (HCV) is not inhibited by HAART, and treatment-related hepatotoxicity is common. To clarify the effect of HAART in HIV/HCV-coinfected patients, we studied liver-related mortality and overall mortality in 285 patients who were regularly treated during the period 1990-2002 at our department. METHODS: Survival was analysed retrospectively by Kaplan-Meier and Cox's regression analyses after patients (81% haemophiliacs) had been stratified into three groups according to their antiretroviral therapy (HAART n=93, available after 1995; treatment exclusively with nucleoside analogues n=55, available after 1992; or no treatment, n=137). FINDINGS: Liver-related mortality rates were 0.45, 0.69, and 1.70 per 100 person-years in the HAART, antiretroviral-treatment, and untreated groups. Kaplan-Meier analysis of liver-related mortality confirmed the significant survival benefit in patients with antiretroviral therapy (p=0.018), and regression analysis identified HAART (odds ratio 0.106 [95% CI 0.020-0.564]), antiretroviral treatment (0.283 [0.103-0.780]), CD4-positive T-cell count (0.746 [0.641-0.868] per 0.05x10(9) cells/L), serum cholinesterase (0.962 [0.938-0.986] per 100 U/L), and age (1.065 [1.027-1.105] per year) as independent predictors of liver-related survival. Severe drug-related hepatotoxicity was seen in five patients treated with nucleoside analogues alone and 13 treated with HAART. No patient died from drug-related hepatotoxicity. INTERPRETATION: In addition to improved overall survival, antiretroviral therapy significantly reduced long-term liver-related mortality in our patients. This survival benefit seems to outweigh by far the associated risks of severe hepatotoxicity.""",1
10522,14644871,High incidence of hepatotoxicity of isoniazid treatment for tuberculosis chemoprophylaxis in patients with rheumatoid arthritis treated with methotrexate or sulfasalazine and anti-tumour necrosis factor inhibitors,,1
10523,14651558,Toxic hepatitis due to enalapril in childhood,,1
10524,14656650,[Hepatitis related to amoxicillin or levofloxacin: a case report],,1
10525,14662583,Reassessing Reye syndrome,,1
10526,14671507,Antiretroviral therapy-related hepatotoxicity: predictors and clinical management,"Severe hepatotoxicity develops in 5-10% of people with HIV infection in the first 12 months following initiation of highly-active antiretroviral therapy (HAART), with continuing risk in subsequent years. The major risk factors for severe hepatotoxicity are underlying chronic viral hepatitis, abnormal baseline levels of serum hepatic transaminases, and nevirapine or high-dose ritonavir-containing antiretroviral therapy regimens. The vast majority of severe hepatotoxicity cases are not associated with development of symptoms of acute hepatitis or other adverse hepatic outcomes and resolve within a few months. Antiretroviral therapy should be discontinued in association with grade 4 elevations in serum hepatic transaminase measurements, hyperlactataemia, symptoms of acute hepatitis, or features of drug hypersensitivity.",1
10527,14677172,Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis,"OBJECTIVE: To study which factors are associated with longterm methotrexate (MTX) use in rheumatoid arthritis (RA). METHODS: All patients with RA who had started MTX after January 1, 1993, were selected from a regional hospital based registration system. Data on demographic and clinical features were retrieved through chart review. By means of life table analysis and Cox regression analysis, MTX survival and the relation between demographic variables, clinical features, and MTX survival were studied. RESULTS: A total of 1072 MTX treatment episodes in 1022 patients were analyzed. The cumulative MTX survival probability after 5 years was 64%, and after 9 years was 50%. Univariate analysis showed a significant relation between MTX survival probability and folic acid supplementation, attending rheumatologist, concurrent prednisolone use, concurrent sulfasalazine use, and the number of previous disease modifying drugs. In the multivariate analysis folic acid supplementation, attending rheumatologist, and concurrent prednisolone use remained significantly related to MTX survival. Age, disease duration, and creatinine clearance were not. CONCLUSION: In this retrospective study of 1022 patients with RA the cumulative MTX survival probability was 64% after 5 years and 50% after 9 years. Folic acid supplementation and to a lesser extent prednisolone were associated with a longer MTX survival. In addition, treatment strategies of individual rheumatologists influenced MTX survival.",1
10528,14678056,"""Disulfiram: cautions on liver function; how to supervise""",,1
10529,14679270,Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial,"""CONTEXT: Because T-cell interactions are involved in the pathophysiology of psoriasis, therapy with a T-cell modulator may have beneficial effects on psoriasis severity and health-related quality of life (HRQL). OBJECTIVE: To assess the efficacy and safety of efalizumab, a T-cell modulator, in patients with plaque psoriasis. DESIGN, SETTING, AND PATIENTS: Phase 3 randomized, double-blind, parallel-group, placebo-controlled trial involving 556 adult patients with stable, moderate to severe plaque psoriasis and conducted at 30 study centers in the United States and Canada between January and July 2002. INTERVENTIONS: Patients were randomly assigned in a 2:1 ratio to receive 12 weekly doses of subcutaneous efalizumab, 1 mg/kg (n = 369), or placebo equivalent (n = 187). MAIN OUTCOME MEASURES: At least 75% improvement on the Psoriasis Area and Severity Index (PASI-75); improvement on the overall Dermatology Life Quality Index (DLQI), Itching Visual Analog Scale (VAS), and Psoriasis Symptom Assessment (PSA) at week 12 vs baseline. RESULTS: Efalizumab-treated patients experienced significantly greater improvement on all end points than placebo-treated patients. Twenty-seven percent of efalizumab-treated patients achieved PASI-75 vs 4% of the placebo group ( P<.001). Efalizumab-treated patients exhibited significantly greater mean percentage improvement than placebo-treated patients on the overall DLQI (47% vs 14%; P<.001), Itching VAS (38% vs -0.2%; P<.001), and PSA frequency and severity subscales (48% vs 18% and 47% vs 17%, respectively; P<.001 for both) at the first assessment point. Efalizumab was safe and well tolerated, with primarily mild to moderate adverse events. CONCLUSION: In this 12-week study, efalizumab resulted in significant improvements in clinical end points, including physician-assessed and dermatology-specific patient-reported HRQL measures, in patients with moderate to severe plaque psoriasis.""",1
10530,14682193,Protective effect of Sesbania grandiflora against erythromycin estolate-induced hepatotoxicity,"Sesbania grandiflora, commonly known as 'sesbania', is widely used in Indian folk medicine for the treatment of liver disorders. Oral administration of an ethanolic extract of S. grandiflora leaves (200 mg/kg/day) for 15 days produced significant hepatoprotection against erythromycin estolate (800 mg/kg/day)-induced hepatotoxicity in rats. The increased level of serum enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), bilirubin, cholesterol, triglycerides, phospholipids, free fatty acids, plasma thiobarbituric acid reactive substances and hydroperoxides observed in rats treated with erythromycin estolate were significantly decreased in rats treated concomitantly with sesbania extract and erythromycin estolate. The sesbania extract also restored the depressed levels of antioxidants to near normal. The results of the study reveal that sesbania could afford a significant protective effect against erythromycin estolate-induced hepatotoxicity. The effect of sesbania was compared with that of silymarin, a reference hepatoprotective drug.",1
10531,14685664,Lactic acidosis: an early marker of propofol infusion syndrome?,,1
10532,14691408,Alfuzosin (uroxatral)--another alpha1-blocker for benign prostatic hyperplasia,,1
10533,14693494,Drug Hypersensitivity Syndrome in a West-Indian population,"Some studies have suggested an ethnic susceptibility to Hypersensitivity Syndrome. We did a 7-year-prospective study in Guadeloupe whose population is mainly of African ancestry, and has free access to modern care facilities. Most patients included were Afro-Caribbeans (26/28), and females (20/28). However, ethnic distribution did not reach significant conclusions. Annual incidence rate was estimated at 0.9/100,000. Medium incubation and duration were 33 and 66 days respectively. Two patients with grade 4 hepatitis died from the syndrome. Two thirds of the patients were given prednisone, which usually alleviated the systemic symptoms, but did not prevent their development (in 5 patients) nor death. Carbamazepine, allopurinol, and minocycline accounted for 2/3 of the cases. Sixty four percent of the causative prescriptions were judged inappropriate. DHS appeared as the most frequent type of severe systemic drug reaction in this population, and may largely be prevented by rational prescribing.",1
10534,14702291,Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload: an update,,1
10535,14703931,Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure,"Trimethoprim-sulfamethoxazole (TMP-SMZ) is one of the most commonly used antibiotics. Although many of its adverse effects are well recognized, TMP-SMZ related hepatotoxicity is considered rare and is usually characterized by cholestasis or mixed hepatocellular-holestatic reactions. In this study, we describe the case of a previously healthy young man with acute fulminant liver failure caused by TMP-SMZ. The patient presented with complaints of 'flu-like' symptoms with myalgia and fever after taking TMP-SMZ for 7 d for otitis externa. The patient subsequently developed fever, worsening jaundice, and a rash on his neck and chest. Liver enzymes peaked on day 3 with alanine aminotransferase (ALT) 11,549, aspartate aminotransferase (AST) 23,289, alkaline phosphatase 245, and total bilirubin 10.3 mg/dL, with a conjugated bilirubin of 8.3 mg/dL, prothrombin time (PT) 60.5 s, partial normalized ratio (PTT) 49 s, and international normalized ratio (INR) 7.5. Of note, acetaminophen level on admission was undetectable. Serology for hepatitis A, B, C, cytomegalovirus, HIV, toxoplasmosis, and blood cultures were all negative. The patient developed hepatic encephalopathy with hallucination on day 4. Laboratory tests revealed a serum ammonia level of 190 U, serum creatinine kinase (CK) 10,466 (42 on admission), serum creatinine 8.2 mg/dL (1.2 on admission), and significant metabolic acidosis. Renal ultrasound was unremarkable. The patient was started on hemodialysis for acute renal failure. Meanwhile, liver transplantation assessment was also initiated. On day 8 post-admission (15 d after taking TMP-SMZ), the patient received a successful orthotopic liver transplant.",1
10536,14706991,Gatifloxacin-induced hepatotoxicity and acute pancreatitis,,1
10537,14711911,A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis,"BACKGROUND: Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy. METHODS: In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo. RESULTS: Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported among patients in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups. CONCLUSIONS: In a well-defined population of patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or the quality of life. Owing to the size and duration of the trial, a clinically significant survival benefit could not be ruled out.",1
10538,14716035,Probable veno-occlusive disease after treatment with gemtuzumab ozogamicin in a patient with acute myeloid leukemia and a history of liver transplantation for familial hemochromatosis,"A 69-yr-old male with a history of familial hemochromatosis and status after liver transplantation was found to have severe thrombocytopenia (platelet count of 8000/microL). He was also anemic and was diagnosed with acute myeloid leukemia (AML) after a bone marrow biopsy. He was started on gemtuzumab ozogamicin (Mylotarg) and developed hepatic and multiorgan failure consistent with veno-occlusive disease within 2 wk. He did not have a history of hematopoietic stem cell transplantation, which is usually the case in AML patients who develop veno-occlusive disease of the liver after treatment with Mylotarg.",1
10539,14716770,Phase II study of pentostatin in advanced T-cell lymphoid malignancies: update of an M.D. Anderson Cancer Center series,"""BACKGROUND: The goal of the current study was to assess the toxicity, safety, and efficacy of pentostatin in patients with T-cell lymphoid malignancies. METHODS: Patients were eligible if they had biopsy-proven T-cell lymphoma or leukemia and failure to respond to previous therapy or an expected complete response rate to conventional therapy of < 20%. Pentostatin was administered at an initial dose of 3.75 or 5.0 mg/m(2) by intravenous bolus daily over a consecutive 3-day period every 3 weeks. RESULTS: Forty-two of 44 patients enrolled in the study were evaluable. The median age of the patients was 62 years (range, 38-86 years). Patients received a median of 3 previous therapies (range, 0-10 previous therapies). Of these patients, 32 (76%) had mycosis fungoides/S?zary syndrome and 10 patients (24%) had other T-cell leukemias or lymphomas. The overall response rate was 54.8% (complete remission, 6 patients [14.3%]; partial remission, 17 patients [40.5%]). Durable responses were observed mainly in patients with S?zary syndrome or peripheral T-cell lymphoma. The median follow-up period for surviving patients was 20 months (range, 1-83+ months). The median duration of response was 4.3 months (range, 1-61 months). The most common toxicities were neutropenia, nausea, and CD4 suppression. A transient early """"flare"""" of disease was observed in some responders. CONCLUSIONS: At these doses, pentostatin was reasonably well tolerated and is an effective drug for the treatment of T-cell lymphomas.""",1
10540,14717619,Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder,"""Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor and nonstimulant that has shown greater efficacy than placebo in attention deficit hyperactivity disorder (ADHD) in adults. In two large, well controlled, 10-week trials in adults with ADHD, improvements in ADHD symptoms, as assessed by investigator- and patient-rated scores, were greater with oral atomoxetine (60, 90 or 120 mg/day) than with placebo. Mean reductions in the total ADHD symptom score on the investigator-rated Conners' Adult ADHD Rating Scale (CAARS) in atomoxetine versus placebo recipients were 28.3% versus 18.1% and 30.1% versus 19.6%, respectively. Mean reductions in the scores on the Clinician Global Impression of Severity Scale, patient-rated CAARS and Wender-Reimherr Adult Attention Deficit Disorder Scale were also significantly greater with atomoxetine than with placebo. Continued efficacy was demonstrated in a noncomparative, 34-week extension phase. Atomoxetine was generally well tolerated in clinical trials; withdrawal rates due to adverse events in atomoxetine-treated versus placebo-treated patients participating in the two major trials were 7.8% versus 4.3% and 9.3% versus 2.4% (p<0.05 for the latter trial). Adverse events reported significantly more frequently with atomoxetine than placebo included dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems and palpitations. Modest increases in heart rate and blood pressure were well tolerated and gradually decreased on cessation of treatment. Atomoxetine was not associated with QT interval prolongation. Atomoxetine can be administered once or twice daily. Its subjective-effects profile is different to that of methylphenidate and atomoxetine is not associated with abuse or diversion; it is therefore not a controlled substance in the US. This also means repeat prescriptions during long-term treatment can be more conveniently processed. CONCLUSION: Atomoxetine is an effective and generally well tolerated treatment for adults with ADHD. It is a nonstimulant and is the first ADHD treatment to be approved specifically for adult use based on its efficacy in well controlled adult trials. It can be administered as a single daily dose or split into two evenly divided doses. It carries negligible risk of abuse or diversion and is not a controlled substance. Atomoxetine is a valuable new treatment option for adults with ADHD and is particularly useful in patients who are at risk for substance abuse or who do not wish to take a controlled substance.""",1
10541,14719195,"Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis)","OBJECTIVE: This study, known as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), evaluated the safety and efficacy of adalimumab (Humira), a fully human monoclonal tumor necrosis factor-alpha (TNF-a) antibody, when given with standard antirheumatic therapy in patients with active rheumatoid arthritis (RA) not adequately responding to such therapies. Standard antirheumatic therapy included traditional disease modifying antirheumatic drugs (DMARD), low dose corticosteroids, nonsteroidal antiinflammatory drugs (NSAID), and/or analgesics. METHODS: In this 24-week, double-blind, placebo-controlled study, 636 patients with RA were randomly assigned to receive adalimumab 40 mg subcutaneously (sc) every other week (n = 318) or placebo (n = 318) while continuing standard antirheumatic therapy. The frequencies of adverse events, serious adverse events, severe or life-threatening adverse events, adverse events leading to withdrawal, infection, or serious infection were the primary endpoints. Secondary endpoints were determined by American College of Rheumatology (ACR) response criteria. RESULTS: During the study, the majority of patients received concomitant traditional DMARD (83.5%) and/or corticosteroids, NSAID, and/or analgesics (97.3%). Overall, 56.0% of patients continued treatment with one, 23.6% with 2, and 3.9% with > or = 3 traditional DMARD. At 24 weeks, there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events (86.5% vs 82.7%), serious adverse events (5.3% vs 6.9%), severe or life-threatening adverse events (11.9% vs 15.4%), or those leading to withdrawal (2.8% vs 2.2%). There were also no statistically significant differences in the rates of infections (52.2% vs 49.4%) or serious infections (1.3% vs 1.9%) between the groups. The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD (0, 1, or 2). Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 (52.8% vs 34.9%), ACR50 (28.9% vs 11.3%), and ACR70 (14.8% vs 3.5%) response rates at Week 24 (p < or = 0.001). CONCLUSION: This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.",1
10542,14722204,Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study of 16 patients,"""OBJECTIVE: To evaluate the effectiveness and toxicity of infliximab in patients with recalcitrant psoriatic arthritis (PsA). METHODS: Patients with treatment resistant PsA and at least six actively inflamed joints, who had failed to respond to at least two disease modifying agents, were included. Infliximab (5 mg/kg) was given at weeks 0, 2, 6, and every 6-8 weeks pending response. Clinical and laboratory measures included actively inflamed joint count (AJC), swollen joint count (SJC), psoriasis severity (PASI), HAQ, and SF-36. Response was defined as at least a 30% reduction in AJC and PASI. Differences from baseline were analysed using the signed rank test. RESULTS: Sixteen patients (12 male, 4 female), mean age 48 and disease duration 14 years, were included. At baseline the mean AJC was 22.5 and mean PASI 4.5. Eleven patients continued receiving methotrexate. The AJC did not show a statistically significant response. SJC improved significantly at week 54 (p = 0.01). The PASI improved significantly at weeks 14 (p = 0.001) and 30 (p = 0.002) and CRP was reduced significantly at week 30 (p = 0.02). The HAQ score improved at week 30 (p = 0.02). Six patients became positive for dsDNA without clinical features of a connective tissue disease. Six patients discontinued treatment owing to lack of efficacy (1) and toxicity (5). Other serious adverse events included: urticaria (3); thrombocytopenia (1); lower gastrointestinal bleeding (2); severe diarrhoea (2); serious infections (6). Raised transaminases, at least 1.5x normal, occurred in four patients. CONCLUSION: In refractory PsA, infliximab led to a marked improvement in psoriasis but modest response in joint disease. Toxicity and rate of treatment termination was high.""",1
10543,14724824,Long-term safety of lamivudine treatment in patients with chronic hepatitis B,"BACKGROUND & AIMS: Data on the long-term safety of lamivudine are limited. The aim of this analysis was to determine the incidence of hepatitis flares, hepatic decompensation, and liver-disease-related (LDR) serious adverse events (SAE) during long-term lamivudine treatment. METHODS: We reviewed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years (median, 4 years) and 200 patients who received placebo for 1 year. RESULTS: Hepatitis flares occurred in 10% of the lamivudine-treated patients in year 1 and in 18%-21% in years 2-5. A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43% in year 1 to >80% in year 3. Ten hepatic decompensation events occurred in 8 (<1%) lamivudine-treated patients. Fifty-three (5%) lamivudine-treated patients experienced a total of 60 LDR SAEs. Four patients died, 2 from liver-related causes. The proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5. During each year of the study, patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations (P < 0.005). The occurrence of hepatic decompensation (0%-2%) and LDR SAEs (1%-10%) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6% (P = 0.03) and 20% (P = 0.009), respectively. CONCLUSIONS: This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivudine-resistant mutations may experience worsening liver disease.",1
10544,14727939,Cilostazol: a review of its use in intermittent claudication,"Cilostazol (Pletal) is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.Randomized, double-blind, placebo-controlled 12- to 24-week trials in >2000 patients with moderate to severe intermittent claudication demonstrated that cilostazol generally significantly increased walking distances and improved quality of life compared with placebo. Additionally, a large comparative 24-week trial showed that cilostazol 100 mg twice daily was significantly more effective than pentoxifylline 400mg three times daily (pentoxifylline was not significantly different from placebo). Cilostazol was generally well tolerated. Adverse events reported significantly more often with cilostazol than with placebo included headache, diarrhea, abnormal stools, infection, rhinitis and peripheral edema and in comparison with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal. Significant drug interactions are observed when cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e.g. erythromycin or diltiazem) or CYP2C19 (e.g. omeprazole). As a result, in Europe cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors and in the US it is recommended that dosage reduction for cilostazol be considered during coadministration of cilostazol and CYP3A4 or CYP2C19 inhibitors. Conversely, cilostazol itself does not appear to inhibit CYP3A4. Coadministration of cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation. CONCLUSION: In six of eight well designed clinical trials, cilostazol was significantly more effective than placebo in increasing walking distances and improving the quality of life of patients with moderate to severe intermittent claudication. In addition, limited comparative data have shown that cilostazol has superior efficacy compared with pentoxifylline. Cilostazol is also generally well tolerated. Additional comparative trials are required to confirm these results, to determine the place of cilostazol in relation to other agents or exercise therapy and risk factor reduction alone, and to establish the effects of long-term treatment with cilostazol in patients with intermittent claudication. Cilostazol is contraindicated in several subpopulations of patients, particularly those with congestive heart failure and severe hepatic or renal impairment. Nonetheless, current data support the choice of cilostazol as a promising therapy amongst the limited options available for patients with intermittent claudication.",1
10545,14733885,[Irbesartan-induced acute hepatitis],,1
10546,14734594,Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial,"""CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed. OBJECTIVE: To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial. INTERVENTIONS: Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks. MAIN OUTCOME MEASURES: Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale). RESULTS: The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively. CONCLUSIONS: In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.""",1
10547,14740794,Liver function test abnormalities and pruritus in a patient treated with atorvastatin: case report and review of the literature,"The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (also known as statins) are associated with elevated transaminase levels in 1-3% of patients. Therapy with these drugs requires monitoring of alanine aminotransferase (ALT) levels because animal studies and premarketing clinical trials showed signs of hepatotoxicity that were primarily minor elevations of ALT. Nevertheless, postmarketing experience suggests that hepatotoxicity is rare, and that elevated ALT levels are reversible with continued therapy and probably are related to cholesterol lowering. Based on the low occurrence of ALT elevations and the lack of clinical evidence of hepatotoxicity, some clinicians are calling for a change in the current practice of monitoring liver function tests. We report, however, the case of a 71-year-old woman who was receiving atorvastatin and experienced elevated transaminase levels on two occasions, and developed pruritus on rechallenge with the drug. Thus, clinicians should be aware of asymptomatic elevations in liver function tests in patients receiving atorvastatin who do not have known risk factors for liver damage.",1
10548,14745453,Diclofenac residues as the cause of vulture population decline in Pakistan,"""The Oriental white-backed vulture (OWBV; Gyps bengalensis) was once one of the most common raptors in the Indian subcontinent. A population decline of >95%, starting in the 1990s, was first noted at Keoladeo National Park, India. Since then, catastrophic declines, also involving Gyps indicus and Gyps tenuirostris, have continued to be reported across the subcontinent. Consequently these vultures are now listed as critically endangered by BirdLife International. In 2000, the Peregrine Fund initiated its Asian Vulture Crisis Project with the Ornithological Society of Pakistan, establishing study sites at 16 OWBV colonies in the Kasur, Khanewal and Muzaffargarh-Layyah Districts of Pakistan to measure mortality at over 2,400 active nest sites. Between 2000 and 2003, high annual adult and subadult mortality (5-86%) and resulting population declines (34-95%) (ref. 5 and M.G., manuscript in preparation) were associated with renal failure and visceral gout. Here, we provide results that directly correlate residues of the anti-inflammatory drug diclofenac with renal failure. Diclofenac residues and renal disease were reproduced experimentally in OWBVs by direct oral exposure and through feeding vultures diclofenac-treated livestock. We propose that residues of veterinary diclofenac are responsible for the OWBV decline.""",1
10549,14749610,Emergency contraception OTC,,1
10550,14754466,Single-agent gemcitabine in the treatment of advanced breast cancer,"Despite the availability of a number of active cytotoxic agents and combination regimens derived from them, the median survival of patients with metastatic breast cancer (MBC) has not been dramatically prolonged and it remains largely an incurable disease. As such, common goals of treatment in this setting are to ameliorate cancer-related symptoms and maintain or improve patient quality of life for as long as possible. Achieving optimal palliation, however, requires balancing the toxicities of therapy with the cancer-controlling benefits, and, to this end, the development of effective and well-tolerated regimens is a priority. Gemcitabine, a novel nucleoside analogue with demonstrated antitumor activity and a favorable safety profile, has been evaluated in a number of recent clinical trials as single-agent therapy for MBC, including studies of first- and second-line therapy, as well as the salvage setting for patients with taxane- and anthracycline-refractory advanced disease.",1
10551,14762182,Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria,"BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH. METHODS: Eleven transfusion-dependent patients with PNH received infusions of eculizumab (600 mg) every week for four weeks, followed one week later by a 900-mg dose and then by 900 mg every other week through week 12. Clinical and biochemical indicators of hemolysis were measured throughout the trial. RESULTS: Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment (P=0.002). The mean percentage of PNH type III erythrocytes increased from 36.7 percent of the total erythrocyte population to 59.2 percent (P=0.005). The mean and median transfusion rates decreased from 2.1 and 1.8 units per patient per month to 0.6 and 0.0 units per patient per month, respectively (P=0.003 for the comparison of the median rates). Episodes of hemoglobinuria were reduced by 96 percent (P<0.001), and measurements of the quality of life improved significantly. CONCLUSIONS: Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.",1
10552,14767983,"Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine","""The """"D drug"""" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the """"non-D drugs"""" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation.""",1
10553,14770125,[Gabapentine-induced acute hepatitis],,1
10554,14780348,"""Ferrous sulfate toxicity; report of a fatal case""",,1
10555,14832059,"""Hypervitaminosis A; report of a case in an adult""",,1
10556,14857918,Acute iron poisoning. Report of a case and review of the literature,,1
10557,14871278,Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified?,"BACKGROUND: Reports that up to 26% of subjects with psoriasis develop cirrhosis have led to a recommendation of serial liver biopsies after each cumulative dose of 1500 mg of methotrexate. AIM: To evaluate the progression of liver injury in patients with psoriasis and the impact of monitoring by liver biopsy on their management. METHODS: One hundred and twenty-one liver biopsies from 66 subjects (aged 11-79 years) with psoriasis, receiving a median cumulative dose of 3206 mg of methotrexate over a period of 280.5 weeks, were evaluated. RESULTS: The assessment of advanced fibrosis according to the Ishak system (>or= 4) correlated perfectly with that of the Scheuer system (>or= 3) and poorly with that of the Roenigk scale (>or= 3b) (r2 = 1.0 and 0.31, respectively). Two of 24 pre-treatment biopsies showed advanced fibrosis and both subjects were heavy drinkers. The cumulative probabilities of advanced fibrosis (Ishak >or= 4) were 0%, 2.6%, 2.6%, 8.2% and 8.2% at cumulative doses of 1500, 3000, 4500, 5000 and 6000 mg, respectively. None of the subjects developed cirrhosis during follow-up or discontinued therapy on the basis of liver biopsy findings. CONCLUSIONS: Advanced hepatic fibrosis with low-dose methotrexate therapy is much less frequent than previously reported. Pre-treatment or monitoring liver biopsies in accordance with the current guidelines have little impact on patient management.",1
10558,14882450,"The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson's disease)",,1
10559,14889814,DIMERCAPROL for hepatolenticular degeneration,,1
10560,14898410,"""Ferrous sulfate poisoning; report of three cases""",,1
10561,14923834,"Myocarditis, arteritis, and focal hepatic, splenic, and renal granulomas apparently due to penicillin sensitivity",,1
10562,14937220,Hepatomegaly with fatty infiltration secondary to cortisone therapy: case report,,1
10563,14938068,Fatal aplastic anemia following chloramphenicol (chloromycetin) administration,,1
10564,14938165,Aplastic anemia associated with administration of chloramphenicol,,1
10565,14941256,"""Vitamin A intoxication; report of a case""",,1
10566,14944846,Fatal aplastic anaemia after chloramphenicol treatment,,1
10567,14960147,Fatal fulminant hepatic failure induced by a natural therapy containing kava,,1
10568,14963199,Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review,"""OBJECTIVES: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effects. Adverse effects are thought to be mediated via folate antagonism. In this paper we summarize the current data on the use of folates as a supplement to MTX use in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and propose guidelines for standard practice. METHODS: A Medline search was performed using the search terms """"methotrexate"""", """"folic acid"""", """"folinic acid"""", """"folate"""" and """"homocysteine"""". Literature relevant to the use of folates as a supplement to MTX in the treatment of RA was reviewed and other papers referred to as references were explored. RESULTS: The use of supplemental folates, including folic and folinic acid, in RA patients treated with MTX has been shown to improve continuation rates by reducing the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to significantly reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid offsets the elevation in plasma homocysteine associated with the use of MTX. This may in turn reduce the risk of cardiovascular disease, which is over-represented amongst patients with RA, and for which hyperhomocysteinaemia is now recognized as an independent risk factor. CONCLUSIONS: We propose that folic acid supplements be prescribed routinely to all patients receiving MTX for the treatment of RA. We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of MTX administration.""",1
10569,14966256,Pulmonary and hepatic toxicity due to nitrofurantoin and fluconazole treatment,"OBJECTIVE: To reemphasize potential risks associated with chronic nitrofurantoin use and to report a case of combined pulmonary and hepatic toxicity precipitated from acute use of fluconazole concomitantly with chronic nitrofurantoin. CASE SUMMARY: A 73-year-old white man taking nitrofurantoin 50 mg/day for 5 years developed combined hepatic and pulmonary toxicity after taking fluconazole acutely for onychomycosis. Two months after starting fluconazole, the patient's hepatic enzymes showed elevation 5 times the upper limits of normal. In addition, the patient reported fatigue, dyspnea on exertion, pleuritic pain, burning trachea pain, and a cough. Chest X-rays showed bilateral pulmonary disease consistent with nitrofurantoin toxicity. Both drugs were determined to be the cause of the patient's pulmonary and hepatic toxicity, so they were discontinued. Pulmonary function tests measured after discontinuation were abnormal and also consistent with nitrofurantoin toxicity. The patient's hepatic and pulmonary toxicity resolved upon discontinuation of both drugs and use of inhaled corticosteroids. DISCUSSION: Changes in hepatic enzyme measurement, pulmonary function measurements, and chest X-rays indicate that our patient developed hepatic and pulmonary toxicity due to his drug therapy. An objective causality assessment revealed that these adverse events were probably due to fluconazole given with nitrofurantoin. Either drug may have caused the hepatic toxicity. However, it is possible that pharmacokinetic changes induced by an interaction with fluconazole precipitated the nitrofurantoin-induced pulmonary toxicity. CONCLUSIONS: Our patient developed pulmonary and hepatic toxicity after starting fluconazole in combination with chronic nitrofurantoin. A potential drug interaction of unknown mechanism may have been the cause of the toxicities.",1
10570,14971714,Flutamide-associated acute liver failure,"The nonsteroidal antiandrogenic drug flutamide [4'-nitro-3'-(trifluoromethyl)isobutyranilide] is a safe and generally well-tolerated drug used for the treatment of prostate cancer. We describe the case of a 74-year-old male who developed life-threatening acute liver failure during flutamide therapy. Other causes of acute liver failure were appropriately ruled out and there was no evidence of active prostate cancer or liver metastases. The use of the Naranjo probability scale indicated a highly probable relationship between the development of acute liver failure and flutamide therapy. Severe liver dysfunction has been rarely documented in patients treated with flutamide, even though cases of fulminant liver failure have been described. A few cases have been reported also among patients with hirsutism being treated with flutamide. The mechanisms responsible for the occurrence of hepatotoxicity during treatment with flutamide are unknown. Mitochondrial dysfunction seems to be implicated. The potential of flutamide to act as a potent hepatotoxin should be borne in mind when treatment with this drug is being planned.",1
10571,14971821,Leflunomide-induced acute hepatitis,"Leflunomide, a new immunomodulatory agent, was prescribed to a 67-year-old female patient with rheumatoid arthritis. Fifteen days later she developed diarrhoea and elevated liver enzymes. A liver biopsy showed a pattern of acute hepatitis. The patient was homozygous for the rare CYP2C9*3 allele, which determines the slowest metabolic rate for CYP2C9 enzymatic activity, that is probably involved in the metabolism of leflunomide. Liver damage subsided in few weeks. This case illustrates the risk of hepatotoxicity by leflunomide and suggests that it is possibly related to CYP2C9 polymorphism.",1
10572,14973403,Drugs for intermittent claudication,,1
10573,14976355,Workshop overview: Hepatotoxicity assessment for botanical dietary supplements,"Botanical dietary supplements (herbal products) have flooded the market in the United States over the past decade, and studies show a significant percentage of Americans use them. With increasing frequency and duration of exposure, some serious adverse effects, though relatively uncommon, have been reported. Among the most troublesome is the association of some botanicals with serious hepatotoxicity. In some cases, hepatotoxicity has been linked to the consumption of botanicals with recognized hepatotoxic components (e.g., pyrrolizidine alkaloids). However, in other cases, the causative agent(s) is less clear and, overall, the mechanisms of hepatotoxicity are poorly understood. To help create a scientific basis for understanding botanical-induced hepatotoxicity and better tools for hepatotoxicity assessment and prediction, the National Center for Natural Product Research (NCNPR) hosted a workshop (September 8 and 9, 2003) in cooperation with the Center for Food Safety and Applied Nutrition (CFSAN) of the Food and Drug Administration (FDA). The workshop featured presentations by 22 experts and was attended by 65 individuals. The agenda can be found in the supplementary data at www.toxsci.oupjournals.org.",1
10574,14982164,Health and aesthetic impacts of copper corrosion on drinking water,"Traditional research has focused on the visible effects of corrosion--failures, leaks, and financial debits--and often overlooked the more hidden health and aesthetic aspects. Clearly, corrosion of copper pipe can lead to levels of copper in the drinking water that exceed health guidelines and cause bitter or metallic tasting water. Because water will continue to be conveyed to consumers worldwide through metal pipes, the water industry has to consider both the effects of water quality on corrosion and the effects of corrosion on water quality. Integrating four key factors--chemical/biological causes, economics, health and aesthetics--is critical for managing the distribution system to produce safe water that consumers will use with confidence. As technological developments improve copper pipes to minimize scaling and corrosion, it is essential to consider the health and aesthetic effects on an equal plane with chemical/biological causes and economics to produce water that is acceptable for public consumption.",1
10575,14983979,Pregabalin (Pfizer),"Pregabalin is a gamma-aminobutyric acid analog that is under development by Pfizer for the potential treatment of central nervous system disorders, including epilepsy, neuropathic pain, fibromyalgia and generalized anxiety disorder. By April 2003, Pfizer had filed for approval of pregabalin in Europe for neuropathic pain and as an adjunctive therapy for epilepsy, and in October 2003 an NDA was filed for these indications and generalized anxiety disorder. At this time, phase III trials in fibromyalgia were ongoing.",1
10576,14986278,Nucleoside-related mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy: insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA,"Nucleoside analogues inhibit human DNA polymerase gamma. As a result, they can produce mitochondrial toxicity. We evaluated the possible role of random venous lactic-acid determinations as a screening tool for mitochondrial toxicity among patients receiving nucleoside therapy. More recently, we have developed an assay that can detect changes in mitochondrial DNA (mtDNA) levels in peripheral blood cells. Using this assay, we have characterized changes in mtDNA relative to nuclear DNA (nDNA) in peripheral blood cells from patients with symptomatic nucleoside-induced hyperlactatemia. Our results demonstrated that symptomatic hyperlactatemia was associated with markedly low mtDNA : nDNA ratios. A statistically significant increase in the mtDNA : nDNA ratio was observed after the discontinuation of antiretroviral therapy. Full validation of monitoring the mtDNA : nDNA ratio is currently under way.",1
10577,14986280,Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors,"Since their introduction, hepatotoxicity has been associated with the use of human immunodeficiency virus (HIV)-1 protease inhibitors (PIs). However, the complexity of the HIV-infected patient and the combinations of medications used to treat HIV complicate the understanding of the independent effects of PIs in the development of drug-induced liver injury (DILI). I discuss the current understanding of PI-associated hepatotoxicity. Of the PI regimens studied, the greatest risk of DILI has been observed among patients receiving full-dose ritonavir. Similarly, hepatitis B and/or C virus coinfection has been associated with a greater risk of DILI, compared with those with no hepatitis. Although the specific mechanism by which viral hepatitis increases this risk is not known, patients with cirrhosis may have decreased cytochrome P450 activity, leading to increased PI exposure. Clearly, further research is needed to define the interaction of PIs and chronic viral hepatitis in the development of DILI.",1
10578,14988826,Cholic acid supplementation enhances cholesterol absorption in humans,"BACKGROUND & AIMS: Qualitative and quantitative changes in intralumenal bile acid composition may alter cholesterol absorption and synthesis and low-density lipoprotein (LDL) receptor expression. The role of cholic acid (CA) in cholesterol absorption in humans remains unclear and, thus, was examined in the current study. METHODS: In a crossover design outpatient study, 12 adults aged 24-36 years took 15 mg/kg/day (CA) or no bile acid supplement (control) while being fed a controlled diet (AHA heart-healthy diet). A liquid meal of defined composition was given on day 14 of the diet, and lumenal samples were collected. Thereafter, cholesterol absorption and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic methods from days 16 to 20. RESULTS: With CA treatment, bile was enriched significantly with CA (P < 0.0004) to 60.2% +/- 2.4% (mean +/- SEM) compared with 43.3% +/- 2.4% for controls. CA plus diet treatment significantly increased (P = 0.013) cholesterol absorption (72.6% +/- 2.9%) compared with diet treatment alone (60.4% +/- 2.9%). Percentage micellar cholesterol was increased by CA plus diet treatment vs. diet alone after meal ingestion (P = 0.004). Plasma total and high-density lipoprotein (HDL) and LDL cholesterol was unchanged with CA treatment. CONCLUSIONS: Thus, enrichment in lumenal bile with CA results in an increase in cholesterol absorption, an effect potentially mediated by enhanced cholesterol solubilization in micelles.",1
10579,14990645,Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients,"""PURPOSE: A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients. PATIENTS AND METHODS: Patients received ET-743 1,500 microg/m(2) (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies). Results Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease (> or = 6 months). Three patients were rendered tumor free after surgery. Median progression-free survival was 1.9 months (range, 0.69 to 17.90 months); 24% of patients were progression free at 6 months. Median survival was 12.8 months, with 30% of patients alive at 2 years. Four patients withdrew because of treatment-related toxicity. Two treatment-related deaths occurred (renal failure and febrile neutropenia, and rhabdomyolysis and decompensated cirrhosis, respectively) that were probably related to protocol eligibility violations. Reversible grade 3 to 4 AST or ALT occurred in 50% of patients and grade 3 to 4 neutropenia occurred in 61% of patients, with six episodes of febrile neutropenia. Nausea, vomiting, and asthenia were prevalent but mild and manageable. CONCLUSION: With a 4% overall response rate (95% CI, 0.5 to 12.8) and an 11% rate of third-party-verified tumor regression (overall response rate + minor response), ET-743 has a 24% 6-month disease progression control rate, confirming evidence of antitumoral activity and a manageable safety profile in patients experiencing disease progression with pretreated soft tissue sarcoma.""",1
10580,14993230,Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor,"""PURPOSE: To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. PATIENTS AND METHODS: Phase II, open-label clinical trial. Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation. Patients were required to have received irinotecan, either alone or in a combination regimen, and to have demonstrated clinical failure on this regimen before study entry. Cetuximab was administered weekly by intravenous infusion. The first dose of 400 mg/m(2) was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m(2) during the course of 1 hour. RESULTS: Fifty-seven eligible patients were treated. All were assessable for toxicity and response. The most commonly encountered grade 3 to 4 adverse events, regardless of relationship to study drug, were an acne-like skin rash, predominantly on the face and upper torso (86% with any grade; 18% with grade 3), and a composite of asthenia, fatigue, malaise, or lethargy (56% with any grade, 9% with grade 3). Two patients (3.5%) experienced grade 3 allergic reactions requiring discontinuation of study treatment. A third patient experienced a grade 3 allergic reaction that resolved, and the patient continued on the study. Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months. CONCLUSION: Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease.""",1
10581,14994731,Ciprofloxacin-induced acute liver injury: case report and review of literature,"Ciprofloxacin is a fluorinated quinolone antibiotic with relatively low occurrence of adverse side effects. However, increasing evidence suggests that ciprofloxacin may cause severe liver damage. Until now, 14 cases of ciprofloxacin-associated liver injuries have been reported. We describe a case of a 22-year-old male who developed hepatic failure after intake of ciprofloxacin. The patient had been treated with 2 x 250 mg ciprofloxacin per day. He presented with symptoms of acute liver failure 14 days later. Liver biopsy revealed extensive hepatocellular necrosis involving zones 3 and 2 of hepatic acini and a mixed inflammatory infiltration containing abundant eosinophils. Symptoms resolved after corticoidsteroid therapy. In the present paper, we report the clinico-pathological characteristics of a case of ciprofloxacin-associated acute hepatic failure and discuss the current literature.",1
10582,14996697,Metformin hepatotoxicity,,1
10583,14998068,Naratriptan for the treatment of acute migraine: meta-analysis of randomised controlled trials,"""OBJECTIVE: To evaluate the comparative efficacy and tolerability of naratriptan in the treatment of acute attacks of migraine. DESIGN: Meta-analysis of randomised controlled trials using a random effects model. SUBJECTS: A total of 4499 patients suffering from moderate or severe attacks of acute migraine reported in ten trials. MAIN OUTCOME MEASURES: Response rate ratios for headache relief, pain-free response and sustained relief (4-24 hours). Adverse events were estimated with the rate ratio (RR), risk difference and number needed to harm. RESULTS: Pooled RRs relative to placebo for pain-free response at 2 and 4 hours for naratriptan 2.5 mg were 2.52 (95% CI: 1.78-3.57) and 2.58 (1.99-3.35). Naratriptan 2.5 mg was more effective than naratriptan 1 mg; the corresponding RRs for pain-free response at 2 and 4 hours were 1.54 (95% CI: 1.28-1.86) and 1.35 (1.20-1.51). In contrast, naratriptan 2.5 mg was less effective in pain-free response than either rizatriptan 10 mg at 4 hours (RR: 0.68; 95% CI: 0.55-0.85) or sumatriptan 100 mg at 4 hours (RR: 0.79; 95% CI: 0.67-0.93). However, significantly fewer patients experienced adverse effects with naratriptan 2.5 mg than with rizatriptan 10 mg (RR: 0.73; 95% CI: 0.56-0.97) or sumatriptan 100 mg (RR: 0.68; 95% CI: 0.55-0.86). CONCLUSIONS: Naratriptan is an effective and well-tolerated treatment for acute attacks of migraine. Head-to-head comparisons suggest that naratriptan 2.5 mg is significantly more effective than the 1 mg dose. Rizatriptan 10 mg and sumatriptan 100 mg were superior to naratriptan in terms of headache relief, while zolmitriptan 2.5 mg seemed to have comparable efficacy. Randomised controlled trials have shown that at licensed doses (1 and 2.5 mg), naratriptan is associated with a lower incidence of adverse effects than rizatriptan, sumatriptan and zolmitriptan. The incidence rates of adverse effects were similar to placebo.""",1
10584,14998559,Protective role of tetrahydrocurcumin against erythromycin estolate-induced hepatotoxicity,"Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, was investigated for its possible hepatoprotective effect in Wistar rats against erythromycin estolate-induced toxicity. Oral administration of THC significantly prevented the occurrence of erythromycin estolate-induced liver damage. The increased level of serum enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP)), bilirubin, cholesterol, triglycerides, phospholipids, free fatty acids and plasma thiobarbituric acid reactive substances (TBARS) and hydroperoxides observed in rats treated with erythromycin estolate were very much reduced in rats treated with THC and erythromycin estolate. This biochemical observation were supplemented by histopathological examination of liver section. Results of this study revealed that THC could afford a significant protection against erthromycin estolate-induced hepatocellular damage. Tetrahydrocurcumin had a better protective effect when compared with Silymarin, a reference drug.",1
10585,14998986,"Prospective, randomized study comparing quinupristin-dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections","""OBJECTIVES: Quinupristin-dalfopristin and linezolid have been shown to be efficacious in the treatment of vancomycin-resistant Enterococcus faecium (VREF) infections. However, the two antibiotics have not been compared in terms of safety and efficacy in a prospective randomized study. The objective of this study was to compare the safety and efficacy of the two drugs in the treatment of VREF infections in cancer patients. PATIENTS AND METHODS: Forty cancer patients with VREF infection were randomized to receive linezolid 600 mg every 12 h or quinupristin-dalfopristin 7.5 mg/kg every 8 h. All patients were followed up for 30 days after discontinuation of study drugs. RESULTS: Linezolid and quinupristin-dalfopristin had comparable clinical responses (58% and 43%, respectively, P = 0.6). Myalgias and/or arthralgias occurred at a frequency of 33% in patients who received quinupristin-dalfopristin, but were not observed in the linezolid group (P = 0.03). In contrast, drug-related thrombocytopenia occurred in 11% of patients who received linezolid, but was not observed in the quinupristin-dalfopristin group (P = 0.2). CONCLUSION: In cancer patients, quinupristin-dalfopristin treatment is associated with a relatively high frequency of myalgias/arthralgias; however, profound thrombocytopenia might limit the choice of linezolid in a subpopulation of cancer patients.""",1
10586,15005637,"Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone","Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics. The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon. The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night's sleep. Only the patient's symptoms and response to treatment will dictate the best course of treatment.",1
10587,15006718,"Safety and side effects of the acne drug, oral isotretinoin","Isotretinoin is a very effective medication for the treatment of severe recalcitrant acne. However, its use is associated with many side effects, some of which can be very serious. The most important issue is its teratogenicity, which has resulted in new pregnancy prevention policies and programmes implemented by the manufacturer. Recently, the association of isotretinoin with depression has been recognised and new guidelines have been adopted for this possible side effect. The most common adverse events, observed during treatment, are mucocutaneous and ophthalmological. In addition, laboratory abnormalities and effects in the nervous, musculoskeletal, gastrointestinal, pulmonary and other systems have been described.",1
10588,15015823,Antiandrogen-associated hepatotoxicity in the management of advanced prostate cancer,"BACKGROUND: Antiandrogens available for patients with advanced prostate cancer are reported to cause hepatotoxicity. The aim of this study is to investigate the antiandrogen-associated hepatotoxicity in patients with advanced prostate cancer. METHODS: By retrospective charts review, 229 patients (47-89 years old) with advanced prostate cancer treated by total androgen blockade (TAB) with bilateral orchiectomy or LHRH (luteinizing hormone-releasing hormone) analogues plus antiandrogen, or antiandrogen-radiotherapy were enrolled in this study. There were 124 patients taking flutamide 750 mg daily and 105 patients taking cyproterone acetate (CPA) 150 mg daily. Hepatotoxicity defined by the International Consensus Meeting in 1990 and Food and Drug Administration, USA was used to evaluate the hepatotoxicity (including serious hepatotoxicity). RESULTS: There was a higher occurrence of hepatotoxicity in patients taking flutamide (15.3%) than taking CPA (9.5%) (p = 0.034). The occurrence of serious hepatotoxicity of flutamide and CPA was 4.8% (6/124) and 3.8% (4/105), respectively. The mean latency period of hepatotoxicity for CPA was 4.8 +/- 2.0 months for flutamide and 5.8 +/- 1.9 months for CPA, respectively. The 2 groups made no significant difference of liver enzyme (mean maximal alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) = 284.2 +/- 99.3/300.6 +/- 58.5 U/L versus 341.8 +/- 67.1/301.6 +/- 80.5 U/L). All of the 19 patients (100%) and 9 of 10 patients (90%) with flutamide and CPA-induced hepatotoxicity got self-resolution after discontinuation of the antiandrogens. The average time of self-resolution is 4.5 +/- 3.1 months and 6.3 +/- 4.7 months for flutamide and CPA, respectively. Five patients of flutamide-induced and 2 patients of CPA-induced hepatotoxicity got resolution after changing to other antiandrogen. CONCLUSIONS: Flutamide and CPA appear to cause hepatotoxic effects in some patients. Discontinuation of the antiandrogens seems to be the resolution of hepatotoxicity. A change to other antiandrogen may be the alternative strategy to the antiandrogen-induced hepatotoxicity. The results of this study suggest that all patients received flutamide and CPA should be monitored carefully for signs and symptoms referable to hepatic injury to prevent the development of serious hepatic dysfunction.",1
10589,15021314,"Efavirenz versus nevirapine in current clinical practice: a prospective, open-label observational study","An open-label, observational, prospective 18-month survey was conducted to compare the efficacy and tolerability of the 2 available nonnucleoside reverse transcriptase inhibitors (NNRTIs) in all possible indications of current clinical practice. A broad range of clinical and laboratory variables accounting for drug efficacy and tolerability (with special emphasis on metabolic and hepatic toxicity) were measured in 287 evaluable patients treated with efavirenz, compared with 258 subjects taking nevirapine for 18 months. A separate efficacy analysis was performed in 154 antiretroviral-naive subjects, 298 patients experienced with 2-7 prior anti-HIV lines who abandoned protease inhibitors (PIs), and 103 subjects entering a salvage regimen containing at least 4 drugs, including PIs. Antiretroviral-naive patients experienced greater efavirenz activity at 3-12 months (maximum HIV RNA drop =-2.4 log(10) copies/mL), associated with a significantly higher rate of complete viral suppression, while immunologic results proved significant only after 6-9 months. When assessing experienced patients and those on rescue regimens, a similar and progressively blunted laboratory response was achieved, on the ground of a worse baseline virologic and immunologic profile, and duration of prior anti-HIV therapy. Both first-month (4.2 and 4.3% for efavirenz and nevirapine, respectively) and overall discontinuation rates (11.5 and 12%, respectively) proved similar, but a profound difference emerged as to the different spectrum of untoward events: central nervous system (CNS) disturbances, persisting metabolic abnormalities, and possibly gynecomastia and laboratory pancreatic abnormalities for efavirenz vs. immediate allergy and increased hepatotoxicity (regardless of chronic infection with hepatitis B or C virus and methadone use) for nevirapine. A limited virologic and immunologic advantage of efavirenz was observed in the first 12-month assessment of antiretroviral-naive patients, whereas all other examined situations did not disclose relevant efficacy differences between efavirenz and nevirapine throughout the 18-month comparison. Although the short- and long-term toxicity and withdrawal rates of the 2 drugs were comparable, the different pathways prompting allergic, metabolic, liver, and CNS disturbances observed with NNRTIs deserve careful investigation, to prevent toxicity of these relevant antiretroviral compounds.",1
10590,15023035,The canals of hering might represent a target of methotrexate hepatic toxicity,"""Methotrexate treatment for psoriasis is known to cause hepatic fibrosis in some patients, which might progress to cirrhosis. The fine, radiating, fibrous septa developing in this setting have a distribution that is reminiscent of the location of the canals of Hering (coH). To assess the possibility of fibrous obliteration of the coH in patients receiving methotrexate, we developed a staining technique by combining an immunohistochemical stain for cytokeratin 7 with a modified Masson trichrome. Sixteen biopsy specimens from 7 patients were evaluated. The biopsies had a variety of histologic changes, including steatosis, anisonucleosis, multinucleation, chronic inflammation, bile duct damage, and ductular reaction. Fibrosis was present in 13 biopsy specimens (81%) and was mild in 7, moderate in 3, and severe in 3 specimens. Compared with normal (control) liver specimens, biopsy specimensfrom patients receiving methotrexate had decreased numbers of coH (1.9 +/- 0.8 vs 5.2 +/- 1.7; P < .025). In specimens with moderate or severe fibrosis, fibrous septa sometimes extended along the coH. These findings suggest that scarring of the coH might be a consequence of the toxic effects of methotrexate.""",1
10591,15026563,Tibolone: a unique version of hormone replacement therapy,"OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of tibolone in the treatment of menopausal symptoms and the prevention of osteoporosis. DATA SOURCES: Information was obtained from a MEDLINE search (1966-July 2003) and from Organon International. The bibliographies of reviewed literature were searched for additional studies. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles evaluating tibolone were evaluated. Since tibolone has been available for many years in Europe and has an extensive literature base, this review emphasizes information from studies published after 1995. DATA SYNTHESIS: Tibolone possesses estrogenic activity and is effective for treating the symptoms and osteoporosis associated with menopause. While the impact of tibolone on the risk of breast cancer or cardiovascular and thromboembolic events is not well defined, its unique pharmacologic profile may provide a safer alternative to traditional hormone replacement therapy. Although widely used for many years in other countries, tibolone has not been approved for use in the US. CONCLUSIONS: Results of recent trials have led to questions regarding the safety of established hormone replacement therapies in peri- and postmenopausal women. Tibolone appears to be an attractive alternative to these traditional regimens. Additional studies will determine whether the promise of increased safety with tibolone will be realized.",1
10592,15030049,Nimesulide-induced acute hepatotoxicity,,1
10593,15030994,Atorvastatin as a trigger of autoimmune hepatitis,,1
10594,15037196,Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress,"""Usnic acid, a lichen acid, is a compound found in crude medicines and dietary supplements, including Lipokinetix, a supplement marketed as a weight loss agent that caused hepatotoxicity and acute liver failure in patients. In this study, we examined the toxicity of usnic acid and assessed whether usnic acid may be contributing to hepatotoxicity caused by Lipokinetix. In primary cultured murine hepatocytes, usnic acid treatment (5 microM) resulted in 98% necrosis within 16 hr (no apoptosis was detected). Usnic acid treatment was associated with early inhibition and uncoupling of the electron transport chain in mitochondria of cultured hepatocytes. This inhibition of mitochondria by usnic acid corresponded with a fall in ATP levels in hepatocytes. In isolated liver mitochondria, usnic acid was observed to directly inhibit and uncouple oxidative phosphorylation. Oxidative stress appears to be central in usnic acid-induced hepatotoxicity based on the following findings: (1) pretreatment with antioxidants (butylated hydroxytoluene+Vitamin E) decreased usnic acid-induced necrosis by nearly 70%; (2) depletion of mitochondrial GSH with diethylmaleate increased susceptibility of hepatocytes to usnic acid; (3) usnic acid treatment was associated with increase free radical generation, measured using the fluorescent probe, dichlorodihydrofluorescin. The source of reactive oxygen species after usnic acid treatment include autoxidation of usnic acid and increased hydrogen peroxide generation by mitochondria caused by usnic acid inhibition of the respiratory chain, with the latter playing a more prominent role. Taken together, our results suggest that usnic acid is a strong hepatotoxic agent that triggers oxidative stress and disrupts the normal metabolic processes of cells. Usnic acid therefore may contribute to the hepatotoxic effects of Lipokinetix and its use in any supplement must come into question.""",1
10595,15043514,"Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis","""BACKGROUND: The herbal preparation, aloe vera, has been claimed to have anti-inflammatory effects and, despite a lack of evidence of its therapeutic efficacy, is widely used by patients with inflammatory bowel disease. AIM: To perform a double-blind, randomized, placebo-controlled trial of the efficacy and safety of aloe vera gel for the treatment of mildly to moderately active ulcerative colitis. METHODS: Forty-four evaluable hospital out-patients were randomly given oral aloe vera gel or placebo, 100 mL twice daily for 4 weeks, in a 2 : 1 ratio. The primary outcome measures were clinical remission (Simple Clinical Colitis Activity Index </= 2), sigmoidoscopic remission (Baron score </= 1) and histological remission (Saverymuttu score </= 1). Secondary outcome measures included changes in the Simple Clinical Colitis Activity Index (improvement was defined as a decrease of >/= 3 points; response was defined as remission or improvement), Baron score, histology score, haemoglobin, platelet count, erythrocyte sedimentation rate, C-reactive protein and albumin. RESULTS: Clinical remission, improvement and response occurred in nine (30%), 11 (37%) and 14 (47%), respectively, of 30 patients given aloe vera, compared with one (7%) [P = 0.09; odds ratio, 5.6 (0.6-49)], one (7%) [P = 0.06; odds ratio, 7.5 (0.9-66)] and two (14%) [P < 0.05; odds ratio, 5.3 (1.0-27)], respectively, of 14 patients taking placebo. The Simple Clinical Colitis Activity Index and histological scores decreased significantly during treatment with aloe vera (P = 0.01 and P = 0.03, respectively), but not with placebo. Sigmoidoscopic scores and laboratory variables showed no significant differences between aloe vera and placebo. Adverse events were minor and similar in both groups of patients. CONCLUSION: Oral aloe vera taken for 4 weeks produced a clinical response more often than placebo; it also reduced the histological disease activity and appeared to be safe. Further evaluation of the therapeutic potential of aloe vera gel in inflammatory bowel disease is needed.""",1
10596,15047046,Factitious granulomatous hepatitis?,,1
10597,15052514,Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics,"""Numerous studies compare side effects or adverse drug reactions (ADRs) of the various typical and newer atypical neuroleptics in patients with schizophrenia. However, these studies, as controlled randomized trials, represent an artificial setting of drug administration and do not easily relate to the """"real-life"""" setting of psychiatric treatment. In contrast, the AMSP drug safety program allows the monitoring of ADRs of all types of psychopharmacological agents in the naturalistic setting of routine clinical practice. In the present study, the data on neuroleptics acquired in the AMSP program from 1993 to 2000 are analyzed. In this period, 86,439 patients treated with at least one neuroleptic agent were monitored. In 1.1 % of the patients severe ADRs occurred. In contrast to the results from controlled trials, atypical neuroleptics caused more severe ADRs than did typical neuroleptics. This result was mainly caused by the high number of severe ADRs in patients treated with clozapine and concerned delirium and non-EPS neurological, gastrointestinal, hepatic, dermatological, hematological, and endocrinological ADRs. Atypical neuroleptics were found to be superior in EPS and urological ADRs. Excluding the data on clozapine, we found typical and atypical neuroleptics to be similar in the occurrence of severe ADRs, although the profiles differ between these two groups as well as between the single substances. Our findings provide valuable information on the type and frequency of ADRs in psychiatric practice, thus enabling differential indication of neuroleptics based not only on the efficacy and tolerability data of controlled trials but also on their differential ADR profile occurring in the """"real-life"""" setting of routine clinical treatment.""",1
10598,15055165,ART and liver-related mortality in HIV/HCV,,1
10599,15060467,[Acute hepatitis associated with milnacipran treatment],,1
10600,15061685,Safety of tumour necrosis factor-alpha antagonists,"Tumour necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFalpha plays an adaptive role in immune protection and wound healing at 'physiological' levels, excess TNFalpha production can lead to adverse consequences. TNFalpha is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFalpha antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFalpha antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn's disease). Worldwide, over half a million patients have been treated with TNFalpha antagonists and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin's lymphoma and treatment with TNFalpha antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin's lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFalpha antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFalpha antagonists and continued vigilance is warranted in patients on TNFalpha antagonists for the development of these diseases. At present there is no evidence implicating TNFalpha antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.",1
10601,15062202,Cholestasis in HIV-infected patients,"Cholestasis is frequently observed in the HIV-infected population and can be caused by drugs, such as highly active antiretroviral therapy (HAART) and antimicrobial agents, and by opportunistic infections of the liver. Less common causes such as HIV-related malignancies or biliary tract disease are also encountered. Most disorders respond to medical management, but patient outcome was often dictated by the stage of the HIV infection and concomitant illnesses in the pre-HAART era. Prompt recognition and specific treatment may improve the outcome for these patients in the HAART era.",1
10602,15068826,Kava kava: examining new reports of toxicity,"""Before 1998, extracts of kava kava, Piper methysticum, were considered to be very safe alternatives to anxiolytic drugs and to possibly exert a wide range of other benefits. Major reviews published through the end of 2002 continued to confirm kava's safety and efficacy. Nevertheless, by January 2003 kava extracts had been banned in the entire European Union and Canada, and were subject to cautions and advisories by the US FDA as a result of 11 cases of hepatic failure leading to liver transplants, including four deaths. A total of 78 cases of hepatotoxicity reputedly linked to kava ingestion are available for review from various databases. Of these adverse events, four probably are linked to kavalactones taken alone and another 23 are potentially linked to kava intake, but also involve the concomitant ingestion of other compounds with potential hepatotoxicity. Three possible mechanisms for kavalactone hepatotoxicity are known: inhibition of cytochrome P450, reduction in liver glutathione content and, more remotely, inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava extracts is quite small under any analysis, yet the potential for drug interactions and/or the potentiation of the toxicity of other compounds is large. Presently, kava toxicity appears to be """"idiosyncratic."""" The risk-to-benefit ratio of kava extracts, nevertheless, remains good in comparison with that of other drugs used to treat anxiety.""",1
10603,15069011,"New case of acute hepatitis following the consumption of Shou Wu Pian, a Chinese herbal product derived from Polygonum multiflorum",,1
10604,15072604,An evaluation of bicalutamide in the treatment of prostate cancer,"""Although prostate cancer is traditionally considered a disease of old age, improved diagnostic techniques have resulted in early diagnosis, and many men are now treated while still physically and sexually active. Current therapies for prostate cancer often include medical or surgical castration, which cause adverse effects on physical and sexual function; therefore, greater attention has been focused on quality of life. The nonsteroidal antiandrogen bicalutamide is an effective agent with a favorable tolerability profile and, in some settings, represents an alternative to castration. Mature survival data reveal that bicalutamide monotherapy provides survival benefits for untreated locally advanced disease that do not differ significantly from those of castration and maintains better physical capacity and sexual interest. Recent data from a prospective randomized trial demonstrate that bicalutamide given as immediate therapy, either alone or as adjuvant to therapy of curative intent, significantly reduces the risk of objective disease progression in patients with localized or locally advanced prostate cancer. Antiandrogens are also used in combination with castration, a treatment known as combined androgen blockade (CAB), for advanced disease. A randomized trial demonstrated that CAB with bicalutamide is associated with similar survival outcome to CAB with flutamide and is better tolerated. Current evidence demonstrates that bicalutamide currently has a favorable risk-benefit ratio in several stages of prostate cancer and that the role of bicalutamide will be further defined by ongoing studies.""",1
10605,15073958,Omeprazole-induced hepatotoxicity? A case report,"CASE REPORT: We observed a serious symptomatic hepatocellular liver injury in an 85-year-old man treated with omeprazole for many years. Peak values for AST, ALT and AP were 1542 U/l (normal range 14-50), 1236 U/l (11-60) and 154 U/l (30-125) respectively. Abdominal CT scan was normal and viral serologic testing was negative. Omeprazole was discontinued and liver enzymes normalized in 12 days. The patient was known to suffer from ischemic heart disease and had had a myocardial infarction 6 months previously. He was reexposed to omeprazole and the level of liver enzymes rose again and normalized after stopping omeprazole. Despite the improvement of his liver function, the patient died 5 days later due to chronic congestive heart failure. DISCUSSION: Five cases of omeprazole-induced liver injury have been reported to the Swiss Drug Regulatory Agency since 1990, among them two of cholestatic hepatitis and one of hepatic failure. The WHO Data Base has collected 13,630 ADRs related to omeprazole, with more than 80 cases of hepatitis, 60 of jaundice and about 40 of cholestatic hepatitis. In contrast, only one case of severe symptomatic hepatotoxicity is described in the literature. Clinical studies reported minimal increase of liver enzymes only, in 1-5% of cases. CONCLUSION: This case with reexposure, together with those reported internationally, suggests that hepatitis is a possible but obviously rare complication of omeprazole treatment.",1
10606,15075511,Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine,"""BACKGROUND: The hepatotoxicity of highly active antiretroviral therapy (HAART) could enhance liver fibrosis in HIV/Hepatitis C virus (HCV)-coinfected patients. Moreover, HAART-related immune restoration could lessen HCV-associated liver damage. The data on the effect of protease inhibitors (PI) on liver fibrosis are scant and contradictory. No information is available on the relationship between non-nucleoside analogue therapy and liver fibrosis in co-infected patients. OBJECTIVE: To investigate the associations between the use of different antiretroviral drugs and the liver fibrosis in patients with HIV and HCV infections. DESIGN: Cross-sectional study. METHODS: All HIV/HCV co-infected patients with an available liver biopsy and known or estimated duration of HCV infection seen at a Infectious Diseases Unit were included in the study. The fibrosis stage and the fibrosis progression rate were evaluated. RESULTS: The inclusion criteria were fulfilled by 152 patients. Age at HCV infection < 20 years [adjusted odds ratio (AOR), 0.39; 95% confidence interval (CI), 0.19-0.82], PI-based HAART (AOR, 0.39; 95% CI, 0.19-0.78) and nevirapine-based HAART (AOR, 2.56; 95% CI, 1.02-6.58) were associated with fibrosis stage >or= F3. The variables associated with fibrosis progression rate > 0.2 units/year were age at HCV infection < 20 years (AOR, 0.23; 95% CI, 0.1-0.52), CD4 cell counts < or = 250 x 10/l at liver biopsy (AOR, 2.8; 95% CI, 1.1-7.1), PI-based HAART (AOR, 0.39; 95% CI, 0.2-0.8) and nevirapine-based HAART (AOR, 3.82; 95% CI, 1.9-7.6). CONCLUSIONS: HAART regimens including nevirapine are associated with faster liver fibrosis progression in HIV-infected patients with chronic hepatitis C. In contrast, patients on PI as the backbone of potent antiretroviral therapy are more likely to show less liver fibrosis.""",1
10607,15076252,Ultrastructural liver mitochondrial abnormalities in HIV/HCV-coinfected patients receiving antiretroviral therapy,,1
10608,15079851,"Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects",,1
10609,15086428,Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukaemia,,1
10610,15088997,Acute poisoning with autumn crocus (Colchicum autumnale L.),"""INTRODUCTION: Colchicum autumnale, commonly known as the autumn crocus or meadow saffron, contains the antimitotic colchicine, which binds to tubulin and prevents it forming microtubules that are part of the cytoskeleton in all cells. CASE REPORT: A 71-year-old woman ate a plant she thought to be wild garlic (Allium ursinum). Ten hours later she arrived at the emergency department complaining of nausea, vomiting and watery diarrhea. Ingestion of a poisonous plant was suspected and she was treated with gastric lavage, oral activated charcoal and an infusion of normal saline. Toxicology analysis with gas chromatography and mass spectrometry revealed colchicine in the patient's gastric lavage, blood (5 microg/l) and urine (30 microg/l). She developed arrhythmias, liver failure, pancreatitis, ileus, and bone marrow suppression with pancytopenia. Alopecia began in the third week. Treatment was supportive only. Five months later she had no clinical or laboratory signs of poisoning. DISCUSSION: The patient mistakenly ingested autumn crocus instead of wild garlic because of their great similarity. Colchicine primarily blocks mitosis in tissues with rapid cell turnover; this results in gastroenterocolitis in the first phase of colchicine poisoning, bone marrow hypoplasia with pancytopenia in the second and alopecia in the third, all of which were present in our patient. Colchicine toxicity in tissues without rapid cell turnover caused arrhythmias, acute liver failure and pancreatitis. CONCLUSION: Colchicine poisoning can result in gastroenterocolitis followed by multi-organ dysfunction syndrome. In unexplained gastroenterocolitis after ingestion of wild plants as a salad or spice, especially when wild garlic is mentioned, we should always consider autumn crocus. Diagnosis could be confirmed only by toxicology analyses. Management of colchicine poisoning is restricted to supportive therapy.""",1
10611,15095236,Nucleoside analogues and mitochondrial toxicity,"An evaluation of the US Food and Drug Administration's Adverse Event Reporting System identified that patients coinfected with human immunodeficiency virus and chronic hepatitis C virus who were treated with a regimen of ribavirin and didanosine, with or without stavudine, were at increased risk for events associated with mitochondrial toxicity, including fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis. In response, the US product labels for didanosine and ribavirin have been revised to caution clinicians against coadministration of these drugs.",1
10612,15096981,Transient absence of hepatic uptake on gallium-67 scintigraphy following fludarabine therapy,,1
10613,15106034,Hepatotoxicity induced by celecoxib and amlodipine,,1
10614,15114087,Preliminary experience with alemtuzumab (Campath-1H) and low-dose tacrolimus immunosuppression in adult liver transplantation,"""BACKGROUND: The administration of alemtuzumab (Campath-1H [C1H]; Berlex Laboratories, Montville, NJ) at transplantation prevents a vigorous immune response and is believed to allow a gradual engagement of the host immune system. We report our preliminary experience with C1H and tacrolimus (Tac) immunosuppression in adult liver transplantation. METHODS: We administered C1H and low-dose Tac to 40 adult recipients of cadaveric liver allografts between December 2001 and April 2003. A control group who met the same eligibility criteria consisted of 50 liver transplant recipients treated with our standard Tac and steroids protocol. RESULTS: Baseline characteristics and patient and graft survival were similar (P >0.15). The incidence of acute rejection was significantly lower during the first 2 months posttransplantation (P =0.002) and slightly lower overall in the study group versus the control group at 12 months (46% vs. 55%, P =0.12, log-rank test). Median time to rejection among those experiencing rejection was significantly longer in the study group versus control group (2.76 vs. 0.34 months, P =0.0007). The mean Tac dose, 12-hr trough level, and percentage of patients receiving maintenance steroids were significantly lower in the group receiving C1H and Tac (P <0.0001 during the first 3 months, P <0.05 thereafter), as were the mean creatinine levels (P <0.05) and incidence of nephrotoxicity (P =0.004, conversion from Tac to other agents). Finally, in the group receiving C1H/Tac, patients with an average Tac trough level less than 6.5 ng/mL during the first 2 months post-transplantation demonstrated a significantly higher rejection rate beyond that time (P =0.02). CONCLUSION: C1H and low-dose Tac seems to be at least as effective as our standard Tac and steroids regimen in preventing acute rejection in adult liver allotransplantation with less renal toxicity and less use of maintenance steroids.""",1
10615,15114493,Kava Hepatotoxicity: Are we any closer to the truth?,"In recent years, kava kava ( Piper methysticum, Forst. f., Piperaceae) has been implicated in a number of liver failure cases. Ever since this has kept the scientific world busy. Even though, on closer inspection, the majority of the case reports are probably not connected to kava intake, hepatotoxic effects of kava cannot generally be ruled out. In this article the major theories as to the mechanism of kava hepatotoxicity are summarized. But in spite of all these hypotheses, there is still no satisfactory answer. In any case, further studies, that might hopefully restore the reputation of kava, are required.",1
10616,15118496,Nefazodone-induced liver failure,,1
10617,15120718,"A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context","Gemifloxacin is a broad-spectrum quinolone antibacterial with enhanced potency against Gram-positive bacteria, including multi-drug resistant Streptococcus pneumoniae, and retained potency against Gram-negative bacilli and bacterial strains resistant to other antibiotics. It has proven particularly effective in respiratory and urinary tract infection. This review presents safety data from 6775 patients included in clinical trials, receiving either the recommended 320 mg once daily oral dose of gemifloxacin, or standard dose of other quinolones, macrolides or beta-lactams (n = 5248). Studies in healthy volunteer and special populations are also reported. Adverse experiences (AEs) were observed in 44.7% of gemifloxacin-treated patients and 47.5% of those who received comparator drugs. Mild gastro-intestinal adverse drug reactions (ADRs) (diarrhoea 5.1%, nausea 3.9%) predominated. Rash, usually maculo-papular and in no case proceeding to more severe eruptions, was observed in 3.6% of those receiving gemifloxacin. A higher incidence of rash (>20%) was observed in young women and was the subject of further study. Adverse drug reactions suspected or probably related to treatment occurred in 17.4% of patients receiving gemifloxacin and in 20% of those receiving comparator antibiotics. Diarrhoea and nausea were experienced by 3.6 and 2.7%, respectively, of gemifloxacin-treated patients (4.6 and 3.2% of comparators), rash by 2.8% (0.6% of comparators) and headache by 1.2% (1.5% of comparators). Gemifloxacin-related vomiting (0.9%), dizziness (0.8%) and taste perversion (0.3%) were uncommon. Treatment discontinuation followed one or more adverse drug reactions in 2.2% of gemifloxacin-treated patients (0.9% due to rash) and 2.1% of comparator-treated patients. A total of 63 deaths (33 receiving gemifloxacin) occurred in the trial population: none were considered related to treatment. A slight prolongation in QT interval (2.56 ms (S.D. +/-24.5)) was observed in gemifloxacin-treated patients: no cardiac arrhythmias were reported. There was a low incidence of liver function tests (LFTs) classified as of potential clinical concern: gemifloxacin (0.4-1.2%), comparators (0.2-1.3%). Serious adverse events (SAEs), occurring during but not necessarily related to therapy, occurred in 3.6% of gemifloxacin-treated patients (4.3% of comparators). SAEs related to treatment agents were rare (0.4% in each group) and included rash (0.1%) and elevated liver enzymes (<0.1%). Gemifloxacin was well tolerated by the elderly, those with renal or hepatic impairment and when co-administered with omeprazole, digoxin, theophylline, warfarin (with which there were no significant interactions) and Maalox. In conclusion, gemifloxacin 320 mg once daily demonstrated a favourable safety and tolerability profile similar to that of comparator antibiotics, including other quinolones.",1
10618,15122714,Valproate therapy and nonalcoholic fatty liver disease,"Nonalcoholic fatty liver disease was defined recently as another symptom of insulin resistance. Continuous therapy with valproate can result in increased body weight and insulin resistance, but no data are yet available on a possible relationship between valproate and nonalcoholic fatty liver disease. We here demonstrate in abdominal ultrasound investigations that characteristics of fatty liver disease were present in 61% of valproate-treated patients as compared with 23% receiving carbamazepine therapy.",1
10619,15122773,"Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity","""Diclofenac is a nonsteroidal anti-inflammatory drug that causes rare but serious hepatotoxicity, the mechanism of which is unclear. The purpose of the present study was to explore the potential role played by the immune processes. Antibodies to diclofenac metabolite-modified liver protein adducts were detected in the sera of seven out of seven patients with diclofenac-induced hepatotoxicity, 12 of 20 subjects on diclofenac without hepatotoxicity, and none of four healthy controls. The antibodies recognized adducts expressed in livers from rats treated with multiple doses of diclofenac, but not in those given single doses. In addition, several potential diclofenac adducts were identified in the liver of a patient with diclofenac-induced hepatic failure, but not from a normal human donor liver, by immunoblotting with an adduct-selective rabbit antiserum. To determine whether or not polymorphisms in genes encoding cytokine-related proteins influence susceptibility to hepatotoxicity, genotyping for the polymorphisms -627 in the interleukin (IL)-10 gene, -590 in the IL-4 gene, and codon 551 in the IL-4 receptor (IL-4R) were performed on DNA from 24 patients on diclofenac with hepatotoxicity, 48 subjects on diclofenac without hepatotoxicity, and healthy controls. The frequencies of the variant alleles for IL-10 and IL-4 were higher in patients (OR [odds ratio]: 2.8 for IL-10; 2.6 for IL-4; 5.3 for IL-10 + IL-4) compared with healthy controls and subjects on diclofenac without hepatotoxicity (OR: 2.8 for IL-10; 1.2 for IL-4; 5.0 for IL-10 + IL-4). In conclusion, the observed polymorphisms, resulting in low IL-10 and high IL-4 gene transcription, could favor a T helper (Th)-2 mediated antibody response to neoantigenic stimulation associated with disease susceptibility.""",1
10620,15128079,Liver transplantation for disulfiram-induced fulminant hepatic failure,"Disulfiram has been used as a popular adjunct in programs for alcohol rehabilitation. However, in rare cases, disulfiram has been reported to cause fulminant hepatitis. Disulfiram use and its associated complications in adolescents have received minimal attention in the literature. We report the first pediatric case of successful orthotopic liver transplantation for disulfiram-induced fulminant hepatic failure in a 16-year-old girl, who developed an idiosyncratic reaction associated with short-term, low-dose disulfiram use, as evidenced by her liver biopsy and explanted liver. This case report indicates that a high index of suspicion, and aggressive therapeutic interventions are necessary to recognize and manage disulfiram-induced fulminant hepatic failure in adolescents. Success of this case suggests that transplant centers should consider liver transplantation of an adolescent alcoholic patient with fulminant hepatic failure due to non-alcohol-related causes such as disulfiram. Orthotopic liver transplantation should be considered early in the management of disulfiram-induced fulminant hepatic failure.",1
10621,15131789,Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity,"""BACKGROUND & AIMS: Studies that evaluate the risk of hepatotoxicity from statins in hyperlipidemic subjects with elevated baseline serum transaminases are lacking. We conducted a study to test the hypothesis that patients with elevated baseline liver enzymes have higher risk of statin hepatotoxicity. METHODS: Our study consisted of the following 3 cohorts of patients seen between January 1, 1998 and June 31, 2002: Cohort 1: 342 hyperlipidemic patients with elevated baseline enzymes (AST >40 IU/L or ALT >35 IU/L) who were prescribed a statin; cohort 2: 1437 hyperlipidemic patients with normal transaminases who were prescribed a statin; and cohort 3: 2245 patients with elevated liver enzymes but who were not prescribed a statin. The effect of statins on liver biochemistries was assessed over a 6-month period after statins were prescribed. Elevations in liver biochemistries during follow-up were categorized into mild-moderate or severe based on predefined criteria. RESULTS: The incidence of mild-moderate elevations and severe elevations in liver biochemistries in cohort 1 were 4.7% and 0.6%, respectively. Compared with cohort 1, individuals in cohort 2 had lower incidence of mild-moderate elevations (1.9%, P = 0.002) but not severe elevations (0.2%, P = 0.2). However, between cohorts 1 and 3, there were no differences in the incidence of mild-moderate elevations (4.7% vs. 6.4%, respectively, P = 0.2) or severe elevations (0.6% vs. 0.4%, respectively, P = 0.6). Statin discontinuation during the follow-up was similar between cohorts 1 and 2 (11.1% vs. 10.7%, respectively, P = 0.8). CONCLUSIONS: These data suggest that individuals with elevated baseline liver enzymes do not have higher risk for hepatotoxicity from statins.""",1
10622,15135271,Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study,,1
10623,15139498,Acute cholestatic hepatitis associated with long-term use of rofecoxib,,1
10624,15140336,"Upper gastrointestinal and overall tolerability of alendronate once weekly in patients with osteoporosis: results of a randomized, double-blind, placebo-controlled study","""OBJECTIVE: To compare the upper gastrointestinal (GI) and overall tolerability profiles of alendronate 70 mg once weekly with placebo. RESEARCH DESIGN AND METHODS: This 12-week international, multi-center, randomized, double-blind, placebo-controlled trial included 449 postmenopausal women and men with osteoporosis at 44 sites in 19 countries in Europe, the Americas, Africa, and Asia-Pacific. Subjects were randomized to alendronate 70 mg once weekly or matching placebo in a 1:1 ratio. MAIN OUTCOME MEASURES: The safety and tolerability of weekly alendronate and placebo were captured as clinical and laboratory adverse events. The primary endpoint was upper GI tolerability based on the incidence of upper GI tract adverse events. Secondary endpoints included the percentage of subjects who discontinued therapy due to a drug-related upper GI adverse event. Change from baseline in bone turnover as measured by the urinary N-telopeptide-collagen crosslinks corrected for creatinine (NTx/Cr) was assessed at 12 weeks as an indicator of efficacy. RESULTS: The percentages of subjects reporting an upper GI tract adverse event in the alendronate 70 mg once weekly group (9.8%) and the placebo group (9.4%) were similar. The risk difference between the two treatment groups (alendronate minus placebo) was 0.4% [95% confidence interval (CI), -5.1%, 5.9%]. Percentages of subjects who discontinued due to a drug-related upper GI adverse event were also similar (alendronate 2.7%; placebo 2.2%; risk difference 0.4%, 95% CI, -2.4, 3.3). The overall tolerability profile of alendronate 70 mg once weekly, as measured by the percentage 8.0% (95% CI, 1.4%, 15.0%) increase in the of subjects reporting any adverse event, was similar to that of placebo (risk difference 2.1%, 95% CI -6.9, 11.0). There was a significant 43.3% (95% CI, -47.9%, -38.3%) decrease from baseline in urinary NTx/Cr in the alendronate group compared with an placebo group at Week 12. CONCLUSION: Alendronate 70 mg administered once weekly to women and men with osteoporosis has an upper GI and overall tolerability profile similar to that of placebo.""",1
10625,15143929,Resection and radiofrequency ablation of multiple liver adenomas secondary to anti-conceptive pills,"A case of multiple hepatic adenomas associated with birth control pills in a 25-year-old female is presented. Her only complaint was abdominal pain, and an elevated alkaline phosphatase was the only laboratory abnormality. The largest adenoma was located in the caudate lobe and was resected. The other two were small, located deep in the right lobe, and treated with radiofrequency ablation. Currently, the patient is asymptomatic and her alkaline phosphatase has returned to normal levels.",1
10626,15146159,[Probable hepatoxicity from epigallocatecol gallate used for phytotherapy],,1
10627,15150081,Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors,"Nonmyeloablative regimens for allogeneic hematopoietic cell transplantation (HCT) have been developed for patients ineligible for myeloablative conditioning. We compared regimen-related toxicities (RRTs) and nonrelapse mortality (NRM) in 73 nonmyeloablative and 73 myeloablative recipients of HLA-matched related donor HCT, using the National Cancer Institute (NCI) Common Toxicity Criteria. Nonmyeloablative regimens were 2 Gy total body irradiation (TBI), either alone (n = 40) or combined with fludarabine, 30 mg/m(2)/d for 3 days (n = 33). Posttransplantation immunosuppression included mycophenolate mofetil and cyclosporine. Myeloablative regimens consisted mostly of cyclophosphamide + TBI or busulfan + cyclophosphamide, followed by posttransplantation methotrexate and cyclosporine. Nonmyeloablative patients were at higher risk than ablative patients because of greater age, longer time from diagnosis to HCT, more frequent preceding high-dose HCT, and higher pretransplantation Charlson comorbidity scores. Nevertheless, they experienced significantly less severe toxicities in 7 organs/systems: hematologic, gastrointestinal, hepatic, hemorrhage, infection, metabolic, and pulmonary. This translated into less NRM at day 100 (3% versus 23%, P = 10(-4)) and 1 year (16% versus 30%, P =.04). In multivariate analysis, the strongest factor predicting lessened RRT and NRM was nonmyeloablative conditioning, whereas high pretransplantation comorbidity scores predicted higher NRM. In conclusion, nonmyeloablative regimens had lower RRT and NRM and could be considered for comparative studies, including younger patients with more favorable Charlson comorbidity scores.",1
10628,15151550,Ceftriaxone-associated biliary sludge and pseudocholelithiasis during childhood: a prospective study,"BACKGROUND: Cholelithiasis is a rare condition seen during childhood. The aim of this study was to determine frequency of biliary sludge and cholelithiasis with ceftriaxone therapy. METHODS: Thirty-eight children aged between 1 month and 17 years were evaluated with ultrasonographic examination at the initiation of the ceftriaxone therapy and 10th day of therapy, consecutively. If biliary sludge or cholelithiasis were demonstrated, scans were repeated monthly until pathology disappeared. RESULTS: Abnormal gallbladder sonograms were demonstrated in 36.8% (n = 14) of patients at the 10th day of therapy. Cholelithiasis was detected in 28.9% (n = 11) of patients and biliary sludge was detected in 7.9% (n = 3). Two children still had cholelithiasis at the 30th day after therapy and one had cholelithiasis after the 60th day. The 9-year-old girl who still had cholelithiasis after 60 days of therapy also had nausea, vomiting and abdominal pain at 7 days after cessation of therapy. Her 90th day sonographic examination was normal. CONCLUSION: Reversible biliary sludge or pseudocholelithiasis due to ceftriaxone treatment is not a rare condition. Therefore it is benign, spontaneously resolved and clinical signs are usually absent.",1
10629,15153351,[Hepatotoxicity due to Camelia sinensis],,1
10630,15156449,Atazanavir: new option for treatment of HIV infection,"Atazanavir is a recently approved human immunodeficiency virus (HIV) protease inhibitor that has an important role in the treatment of both antiretroviral-naive and antiretroviral-experienced individuals. Atazanavir (400 mg) can be administered once per day and requires only 2 capsules. Drug exposure can be safely increased with coadministration of a once-daily regimen of atazanavir (300 mg) and ritonavir (100 mg). Atazanavir is not associated with elevations in serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides, potentially reducing the need for lipid-lowering agents. Atazanavir is associated with elevations in unconjugated bilirubin levels, which are usually not dose limiting. For treatment-naive patients receiving atazanavir who experience virologic rebound, the I50L mutation in HIV protease arises, which does not confer cross-resistance to other protease inhibitors. In treatment-experienced patients with high-level resistance to other protease inhibitors, susceptibility to atazanavir is usually reduced, and optimal effects of atazanavir are seen when it is administered with ritonavir. Similar to other protease inhibitors, careful attention must be paid to drug interactions when administering atazanavir with concomitant medications.",1
10631,15158349,Genetic alterations in hepatocellular adenomas: recent findings and new challenges,,1
10632,15160930,Hepatitis B virus reactivation in a case of non-Hodgkin's lymphoma treated with chemotherapy and rituximab: necessity of prophylaxis for hepatitis B virus reactivation in rituximab therapy,"A patient with Non-Hodgkin's lymphoma is reported, in which reactivation of the hepatitis B virus was achieved from treatment with rituximab. The patient's HBs antigens were positive on admission, and she tested positive for HBs, HBe, and HBc antibodies, and negative for the HBe antigens. She was treated with a regimen of three courses of rituximab-containing anti-cancer drugs and one course of combined anti-cancer drugs. Throughout these chemotherapy courses, prednisolone was not given. After the fourth course of chemotherapy with the third rituximab she developed hepatic dysfunction, and the serum titers of HBs and HBc antibodies suddenly decreased. After administration of lamivudine, however, she gradually recovered from liver failure.",1
10633,15161945,Phase IV trial evaluating the effectiveness and safety of dofetilide,"""BACKGROUND: Dofetilide gained Food and Drug Administration approval for persistent atrial fibrillation/flutter (AFF) based on 2 randomized, placebo-controlled, dose-ranging studies. Concerns of proarrhythmia have prompted the manufacturer to develop specific treatment guidelines. OBJECTIVE: To determine the effectiveness and safety of dofetilide in clinical practice as well as to ascertain whether clinicians are following established dosing guidelines. METHODS: This retrospective analysis evaluated guideline adherence and safety in patients who received dofetilide at a tertiary care medical center. Safety assessment included monitoring for the occurrence of excessive QTc interval prolongation and torsade de pointes. Excessive QTc interval prolongation was defined as >15% above baseline after the first dose or >500 msec following any dose (>550 msec in patients with ventricular conduction abnormalities). Patients were included in the effectiveness assessment if they received at least 36 hours of dofetilide for persistent AFF, received an appropriate dose per guidelines, and did not receive direct current cardioversion during the evaluation period. We compared the 36-hour conversion rate with dofetilide in this study with that observed in the EMERALD and SAFIRE-D trials using the Z test, and we evaluated the incidence of excessive QTc interval prolongation in high-risk subgroups by chi(2) analysis. RESULTS: Investigators identified 107 patients. The primary indication for dofetilide was AFF, with 58.9% receiving the drug for paroxysmal disease. Prescribing followed established guidelines, except that it was used intermittently by nonconfirmed prescribers (5.6%) and/or at inconsistent doses (14%). Excessive prolongation of the QTc interval occurred in 17.8% of patients after the first dose and 26.2% during subsequent doses; prolongation was more common in those with structural heart disease (p < 0.01). No patients developed torsade de pointes. In the effectiveness assessment (n = 25), the conversion of persistent AFF at 36 hours was higher than in previous studies (48% vs 27.2%; p = 0.05). CONCLUSIONS: In clinical practice, the conversion of persistent AFF with dofetilide is at least comparable to premarketing studies, with a similar safety profile. Institutions should continue to emphasize adherence with established treatment guidelines.""",1
10634,15165202,Acetaminophen-induced toxic epidermal necrolysis in a child,"Toxic epidermal necrolysis (TEN) is a severe, life-threatening disorder that usually affects adults. It is often drug induced. We report an instance of a severe case of TEN in a 6-year-old boy, probably induced by acetaminophen, and less likely by codeine. A lymphocyte stimulation test could not identify the culprit drug. Treatment with intravenous immunoglobulin seemed to halt the disease progression.",1
10635,15168958,Management of hyponatremia,"Hyponatremia is an important electrolyte abnormality with the potential for significant morbidity and mortality. Common causes include medications and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Hyponatremia can be classified according to the volume status of the patient as hypovolemic, hypervolemic, or euvolemic. Hypervolemic hyponatremia may be caused by congestive heart failure, liver cirrhosis, and renal disease. Differentiating between euvolemia and hypovolemia can be clinically difficult, but a useful investigative aid is measurement of plasma osmolality. Hyponatremia with a high plasma osmolality is caused by hyperglycemia, while a normal plasma osmolality indicates pseudohyponatremia or the post-transurethral prostatic resection syndrome. The urinary sodium concentration helps in diagnosing patients with low plasma osmolality. High urinary sodium concentration in the presence of low plasma osmolality can be caused by renal disorders, endocrine deficiencies, reset osmostat syndrome, SIADH, and medications. Low urinary sodium concentration is caused by severe burns, gastrointestinal losses, and acute water overload. Management includes instituting immediate treatment in patients with acute severe hyponatremia because of the risk of cerebral edema and hyponatremic encephalopathy. In patients with chronic hyponatremia, fluid restriction is the mainstay of treatment, with demeclocycline therapy reserved for use in persistent cases. Rapid correction should be avoided to reduce the risk of central pontine myelinolysis. Loop diuretics are useful in managing edematous hyponatremic states and chronic SIADH. In all instances, identifying the cause of hyponatremia remains an integral part of the treatment plan.",1
10636,15172900,Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial,"BACKGROUND: The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin). OBJECTIVE: To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis. DESIGN: Randomized, double-blind study. SETTING: 154 centers worldwide. PATIENTS: 2205 patients with acute symptomatic deep venous thrombosis. INTERVENTION: Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0. MEASUREMENTS: The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes. RESULTS: 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, -0.15 percentage point [95% CI, -1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively. LIMITATIONS: Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients. CONCLUSIONS: Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight-adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis.",1
10637,15175000,Acute liver failure associated with the use of herbal preparations containing black cohosh,,1
10638,15176650,Epidemiological assessment of 160 cases of insulin overdose recorded in a regional poisons unit,"OBJECTIVE: Overdoses with insulin are common, and cases of hypoglycemic coma can be fatal and cause cerebral defects. However, data published on this topic are rare, consisting mostly of case reports or reports in a small number of patients. The present investigation analyzes inquiries made to a regional poisons unit involving overdoses with insulin. PATIENTS AND METHODS: A total of 175,890 inquiries for the years 1995-2003 (until September) were evaluated. 160 inquiries were received by telephone concerning insulin overdoses, and a standardized questionnaire was sent to the physicians asking for follow-up information. The cases were analyzed in regard to etiology, type of insulin used, concomitant substances being taken by the patient, symptoms and clinical outcome. RESULTS: Of the 160 inquiries investigated, 53.1% of the patients were female, 43.1% male and in 3.8% the sex of the patient was unknown. The average age was 44.7 years. 89.4% involved suicidal or parasuicidal cases, 5.0% were accidental overdoses and 1.9% involved cases of criminal overdose (3.7% were for other reasons). Rapidly acting insulins (57.8%) were used more commonly than long-acting formulations (42.8%). Benzodiazepines were the most frequently ingested concomitant medication (37.5%) with ethanol 15.6%, antihypertensive drugs 12.5% and antidepressants 10.0%. Most patients presented with a delay of 2-3 hours after insulin administration (15.0%). Almost 50% of the patients presented within the first 6 hours. According to the Poisoning Severity Score, no symptoms were observed in 16.8% of the patients, minor symptoms in 36.8%, major symptoms in 25.2% and serious symptoms in 21.3%. Information concerning the clinical outcome (75 cases) showed that a full recovery occurred in most patients (94.7%), but in 2.7% there were cerebral defects and 2.7% of the patients died. CONCLUSIONS: The etiology of overdoses with insulin was mainly deliberate self-poisoning. Physicians should take into account that long-acting insulin formulations and concomitant substances were frequently used. For overdoses with insulin, relatively high rates of serious symptoms and deaths were observed.",1
10639,15185301,HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease,"""Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequence-specific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P =.002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P =.001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P =.003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P =.0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage.""",1
10640,15189743,Leflunomide in the treatment of rheumatoid arthritis,"""BACKGROUND: Current drug therapies for rheumatoid arthritis (RA), including nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs, help control inflammation but can cause significant toxicity. Drugs are needed that are able to suppress inflammation and modify the underlying immune response with improved tolerability. Leflunomide is an agent that affects the inflammatory process, particularly in RA. OBJECTIVE: This paper reviews the pharmacology of leflunomide, its approved use in RA, and the results of major clinical trials, including adverse events. METHODS: Relevant trials were identified through a search of the English-language literature indexed on EMBASE, MEDLINE, Current Contents, and the Cochrane Controlled Trials Register from January 1980 to November 2003. Search terms were limited to leflunomide. RESULTS: In 3 large Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent clinical efficacy and tolerability to methotrexate and sulfasalazine and superior efficacy and tolerability compared with placebo. In US301 (N = 482), the ACR (American College of Rheumatology) 20 response rate (proportion of patients with > or =20% improvement from baseline in tender and swollen joint counts, patient's assessment of pain, patient's and physician's global assessment of disease activity, physical function, and acute-phase reactant value) at 1 year was similar with leflunomide and methotrexate and significantly greater with both active treatments than with placebo (52%, 46%, and 26%, respectively; both, P < 0.001). The efficacy of leflunomide was seen early (after 4 weeks of treatment) and was sustained throughout the study. There was less radiographic damage in both active-treatment groups compared with placebo (leflunomide, P < or = 0.001; methotrexate, P = 0.02). In MN301 (N = 358), the ACR20 response rate at 6 months was similar with leflunomide and sulfasalazine and significantly greater with both active treatments compared with placebo (55%, 56%, and 29%, respectively; both, P < 0.001). Radiographic progression was also similar with leflunomide and sulfasalazine, both of which were significantly superior to placebo (Larsen score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study revealed maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat population, N = 999), 50.5% of patients in the leflunomide group were ACR20 responders at the end of 1 year, compared with 64.8% in the methotrexate group (P < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of leflunomide appears promising, although monitoring for elevations in liver enzymes and bone marrow suppression is recommended. The most common drug-related adverse events associated with leflunomide in these clinical trials were diarrhea, abnormalities in liver enzymes, rash, and hypertension.""",1
10641,15199528,Gemcitabine plus docetaxel administered every other week as first-line treatment of metastatic breast cancer: preliminary results from a phase II trial,"The purpose of this study was to assess the toxicity and efficacy of gemcitabine and docetaxel administered every other week as first-line therapy in metastatic breast cancer. Fifty-one patients with histologically confirmed metastatic breast cancer were enrolled. Patients received docetaxel 65 mg/m(2) followed by gemcitabine 2,500 mg/m(2), both on day 1 of a 14-day cycle, for 10 cycles without granulocyte-colony stimulating factor support. Thirty-five patients were evaluable for toxicity and 32 for efficacy. Median age was 65 years (range, 37 to 72 years), and median performance status was 90 (range, 60 to 100). The number of disease sites was 2 or > or =3 in 39% and 44% of patients, respectively, with visceral involvement in the liver and/or lung in 44% of patients. A total of 45% had received prior adjuvant chemotherapy. So far, 267 cycles have been administered. Twenty-five percent of the docetaxel and gemcitabine doses were reduced or delayed due primarily to neutropenia, giving a median dose intensity of 90% of the planned dose for both drugs. Grade 3/4 toxicities were mainly hematologic, with neutropenia in 46% of patients (two patients experienced neutropenic fever). Other toxicities were asthenia, diarrhea, transaminase elevation, and nausea. Overall response rate was 66% (four complete responses, 17 partial responses), with 22% of patients achieving stable disease. Responses were observed in all disease sites, including lung (60%) as well as liver (37.5%). In conclusion, preliminary evaluation from our phase II study shows that the combination of docetaxel and gemcitabine given every 2 weeks is a tolerable and highly active combination in patients with metastatic breast cancer. These data compare favorably with those obtained with other docetaxel schedules.",1
10642,15201414,Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis,"""BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.""",1
10643,15206996,Acute and clinically relevant drug-induced liver injury: a population based case-control study,"""AIMS: To provide quantitative information about the absolute and relative risks of acute and clinically relevant drug-induced liver injury. METHODS: We performed a population-based case-control study using the UK-based General Practice Research Database as the source of information. A total of 1,636,792 persons subjects aged 5-75 years old registered in the database from 1 January, 1994 to 31 December, 1999 were followed-up for a total of 5,404,705 person-years. Cases were identified by an exhaustive computer search, then reviewed manually and finally validated against the clinical records. Only idiopathic cases serious enough to be referred to hospital or a consultant were selected. A total of 5000 controls were randomly sampled from the person-time of study cohort. Current users were defined if a prescription ended within 15 days of the index date, and nonusers if there was no prescription before the index date. RESULTS: One hundred and twenty-eight patients were considered as valid cases, being the crude incidence rate of 2.4 (95% confidence interval: 2.0, 2.8) per 100 000 person-years. The strongest associations were found with chlorpromazine (adjusted odds ratio (AOR); 95% CI = 416; 45, 3840), amoxicillin/clavulanic acid (AOR = 94.8; 27.8, 323), flucloxacillin (AOR = 17.7; 4.4, 71.0), macrolides (AOR = 6.9; 2.3, 21.0), tetracyclines (AOR = 6.2; 2.4, 15.8); metoclopramide (AOR = 6.2; 1.8, 21.3); chlorpheniramine (AOR = 9.6; 1.9, 49.7); betahistine (AOR = 15.3; 2.9, 80.7); sulphasalazine (AOR = 25.5; 6.0, 109); azathioprine (AOR = 10.5; 1.4, 76.4), diclofenac (AOR = 4.1; 1.9, 8.8) and antiepileptics (AOR = 5.1; 1.9, 13.7). A dose-effect was apparent for diclofenac, amoxicillin/clavulanic acid and flucloxacillin. The combination of two or more hepatotoxic drugs increased the risk by a factor of 6. The highest crude incidence rates were found for chlorpromazine, azathioprine, and sulfasalazine (about 1 per 1000 users). CONCLUSIONS: Idiopathic, acute and clinically relevant liver injury, which has the use of drugs as the most probable aetiology, is a rare event in the general population. The relative risks of 40 drugs/therapeutic classes are provided, along with the crude incidence rates for 15 of them where a statistical association was found.""",1
10644,15210739,"Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer","PURPOSE: To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. RESULTS: Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. CONCLUSION: ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.",1
10645,15216400,Efficacy and tolerability of linezolid in treating severe skin and soft tissue infections caused by Gram-positive pathogens,"""BACKGROUND AND PURPOSE: Linezolid, an oxazolidinone, has shown efficacy in the treatment of adults with nosocomial or community-acquired pneumonia; skin and soft tissue infections; and infections due to methicillin-resistant Staphylococcus aureus. The purpose of this open-label, single-arm, multicenter study was to evaluate the efficacy and tolerability of linezolid in patients from the Asia-Pacific Region with severe Gram-positive skin and soft tissue infections. METHODS: 166 patients at 27 sites in 7 countries from the Asia-Pacific region were enrolled. The patients had severe skin infection involving the deeper layers or extensive surface area. Patients received 7 to 28 days of treatment with linezolid by clinical judgment. All patients received intravenous linezolid 600 mg twice a day initially and were switched over to an equivalent oral dose (600 mg twice a day) when the investigator discerned clinical improvement. The primary efficacy endpoint in this study was clinical outcome at the follow-up visit, 14 to 21 days after completion of treatment (test of cure), and the secondary efficacy variable was microbiologic response at test-of-cure. RESULTS: 166 patients received the study medication and were included in the intent-to-treat analysis. The clinical success rate was approximately 93% in both the intent-to-treat and clinically evaluable populations at the end of treatment and test-of-cure visits. In the modified intent-to-treat and microbiologically evaluable populations, the microbiologic success rates at the test-of-cure visit were 88.9% and 93.8%, respectively. The most frequent treatment-emergent adverse events were nausea (13%), dizziness (8%), anemia (7%), and vomiting (5%). CONCLUSIONS: Linezolid was effective and well tolerated in patients with severe skin and soft tissue infections caused by Gram-positive pathogens.""",1
10646,15220700,Lack of recurrence of hyperlactatemia in HIV-infected patients switched from stavudine to abacavir or zidovudine,"""Stavudine (d4T) has been observed in clinical trials and cohort studies to be more often implicated in cases of hyperlactatemia than other nucleoside reverse transcriptase inhibitors, possibly because of its relatively greater propensity to induce mitochondrial toxicity. The ESS40010 study was a 48-week, open-label, switch study that assessed changes in serum lactate levels and signs/symptoms of hyperlactatemia after substitution of abacavir (n = 86) or zidovudine (n = 32) for d4T in 118 virologically suppressed HIV-infected patients (HIV-1 RNA <400 copies/mL) who had developed serum lactate concentrations > or =2.2 mmol/L (n = 16) or had remained normolactatemic (n = 102) after receiving > or =6 months of d4T-based treatment. Median serum lactate decreased significantly below baseline at week 24 (-0.15 mmol/L, P = 0.0002) and week 48 (-0.15 mmol/L, P = 0.0015). In 10 hyperlactatemic patients in whom d4T was discontinued, serum HIV-1 RNA levels rebounded over the ensuing 31 days, but virologic suppression (HIV-1 RNA <400 copies/mL) was regained when treatment using abacavir or zidovudine was subsequently instituted. In the group with elevated lactate at baseline, symptoms of hyperlactatemia improved in 8% to 23% of patients, did not change in 69%, and worsened in 8%. Serum transaminases, which had been elevated while patients received d4T, normalized after d4T discontinuation and remained in the normal range after the switch to abacavir or zidovudine. Overall, in patients with d4T-associated hyperlactatemia, stopping d4T results in normalization of lactate and a rebound in viral load; restarting treatment using abacavir or zidovudine subsequently maintains normal lactate levels and rapidly leads to a return of virologic suppression.""",1
10647,15220797,Lactic acidosis during propofol-remifentanil anesthesia in an adult,,1
10648,15225535,[Hepatotoxicity due to trazodone],,1
10649,15229826,[Anticonvulsant hypersensitivity syndrome with severe repercussions in the skin and kidneys due to carbamazepine],"INTRODUCTION: Anticonvulsant hypersensitivity syndrome (AHS) is characterised by fever, skin rashes and involvement of the internal organs. Owing to the low frequency with which it appears and its high clinical heterogeneity, it is not always suspected. Moreover, the symptoms often overlap with those of a vasculitis or of an infection. The most commonly associated antiepileptic drugs (AED) are the aromatic agents. We report the case of a female patient who developed AHS with several different AED and presented an especially severe kidney and skin disorder due to carbamazepine (CBZ). CASE REPORT: We describe the case of a 26-year-old woman who, after being diagnosed as suffering from secondarily generalised partial seizures, began treatment with 200 mg/12 hours CBZ. A few weeks later, she developed itchy skins lesions compatible with exanthematic pustulosis, together with acute kidney failure requiring haemodialysis. A biopsy study of the kidney revealed immunoallergic tubulointerstitial nephropathy, which is a lesion that has only very occasionally been reported in relation to CBZ therapy. The patient also presented a moderate rise in the level of transaminases and leukocytosis with eosinophilia. She was discharged from hospital without AED but suffered new seizures and was treated with phenytoin and, later, with valproic acid, both as monotherapy. With these drugs she developed AHS consisting in fever, rashes, eosinophilia and subclinical hepatitis. In epicutaneous tests with anticonvulsants, the three AED presented a positive reading, as well as others. The patient was treated with tiagabine, and there were no further hypersensitivity phenomena and a good control of seizures was achieved. CONCLUSIONS: AHS is an infrequent, but potentially serious, clinical entity and must therefore be suspected in patients taking AED who develop fever, rashes or disorders affecting the internal organs.",1
10650,15231010,Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis,"""Oral daily (2.5 mg) and intermittent ibandronate (between-dose interval of >2 months), delivering a similar cumulative exposure, were evaluated in 2946 osteoporotic women with prevalent vertebral fracture. Significant reduction in incident vertebral fracture risk by 62% and 50%, respectively, was shown after 3 years. This is the first study to prospectively show antifracture efficacy for the intermittent administration of a bisphosphonate. INTRODUCTION: Bisphosphonates are important therapeutics in postmenopausal osteoporosis. However, they are currently associated with stringent dosing instructions that may impair patient compliance and hence therapeutic efficacy. Less frequent, intermittent administration may help to overcome these deficiencies. This study assessed the efficacy and safety of oral ibandronate administered either daily or intermittently with a dose-free interval of >2 months. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled, parallel-group study enrolled 2946 postmenopausal women with a BMD T score < or = -2.0 at the lumbar spine in at least one vertebra (L1-L4) and one to four prevalent vertebral fractures (T4-L4). Patients received placebo or oral ibandronate administered either daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months). RESULTS AND CONCLUSIONS: After 3 years, the rate of new vertebral fractures was significantly reduced in patients receiving oral daily (4.7%) and intermittent ibandronate (4.9%), relative to placebo (9.6%). Thus, daily and intermittent oral ibandronate significantly reduced the risk of new morphometric vertebral fractures by 62% (p = 0.0001) and 50% (p = 0.0006), respectively, versus placebo. Both treatment groups also produced a statistically significant relative risk reduction in clinical vertebral fractures (49% and 48% for daily and intermittent ibandronate, respectively). Significant and progressive increases in lumbar spine (6.5%, 5.7%, and 1.3% for daily ibandronate, intermittent ibandronate, and placebo, respectively, at 3 years) and hip BMD, normalization of bone turnover, and significantly less height loss than in the placebo group were also observed for both ibandronate regimens. The overall population was at low risk for osteoporotic fractures. Consequently, the incidence of nonvertebral fractures was similar between the ibandronate and placebo groups after 3 years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo groups, respectively; difference between arms not significant). However, findings from a posthoc analysis showed that the daily regimen reduces the risk of nonvertebral fractures (69%; p = 0.012) in a higher-risk subgroup (femoral neck BMD T score < -3.0). In addition, oral ibandronate was well tolerated. Oral ibandronate, whether administered daily or intermittently with an extended between-dose interval of >2 months, is highly effective in reducing the incidence of osteoporotic fractures in postmenopausal women. This is the first time that significant fracture efficacy has been prospectively shown with an intermittently administered bisphosphonate in the overall study population of a randomized, controlled clinical trial. Thus, oral ibandronate holds promise as an effective and convenient alternative to current bisphosphonate therapies.""",1
10651,15232664,Hepatotoxicity due to a possible interaction between cytosine arabinoside and dipyridamole: a case report,,1
10652,15234643,Newer disease-modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis,"""BACKGROUND: Spontaneous cases of hepatic adverse events have been reported in patients with rheumatoid arthritis who were being treated with leflunomide, one of the newer disease-modifying antirheumatic drugs (DMARDs). We assessed the risk of hepatic events associated with the use of leflunomide and other DMARDs. METHODS: Two cohorts comprising 41,885 patients with rheumatoid arthritis who had been dispensed a DMARD between September 1, 1998, and December 31, 2001, were formed using claims databases. Follow-up was from the first dispensing date to the occurrence of a serious or nonserious hepatic event. A nested case-control approach was used to estimate adjusted rate ratios of hepatic events associated with DMARDs dispensed during the prior year, as compared with methotrexate monotherapy. RESULTS: There were 25 cases of serious hepatic events (rate, 4.9 per 10,000 per year) and 411 nonserious hepatic events (rate, 80.0 per 10,000 per year). There was no increase in the rate of serious hepatic events with either leflunomide (rate ratio [RR] = 0.9; 95% confidence interval [CI]: 0.2 to 4.9) or traditional DMARDs (RR = 2.3; 95% CI: 0.8 to 6.5). However, the rate was increased with biologic DMARDs (RR = 5.5; 95% CI: 1.2 to 24.6). The rate of nonserious hepatic events was also increased with biologic DMARDs (RR = 1.5; 95% CI: 1.0 to 2.3), but not with leflunomide (RR = 0.9; 95% CI: 0.7 to 1.3) and traditional DMARDs (RR = 1.1; 95% CI: 0.8 to 1.4). CONCLUSIONS: We found no evidence of an excess risk of serious or nonserious hepatic events with the use of leflunomide as compared with methotrexate. Still, the increased risk observed with the new biologic DMARDs should be investigated further.""",1
10653,15238771,SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients,"""OBJECTIVE: To compare the magnitude and durability of the antiviral response to fosamprenavir (FPV) plus ritonavir (RTV) once-daily (FPV/r QD) with nelfinavir twice-daily (NFV BID), each administered with abacavir and lamivudine twice-daily. METHODS: An international, phase III, randomized, open-label study in antiretroviral therapy-naive, HIV-infected adults. RESULTS: Patients with advanced HIV disease received FPV/r QD (n = 322) or NFV BID (n = 327). At week 48, 69% of patients in the FPV/r QD group and 68% in the NFV BID group had plasma HIV-1 RNA (vRNA) < 400 copies/ml, whereas 55% of patients in the FPV/r QD group and 53% in the NFV BID group had vRNA < 50 copies/ml (intent to treat, rebound/discontinuation = failure). More patients in the NFV BID group (17%) experienced virological failure than in the FPV/r QD group (7%). Efficacy of FPV/r QD was maintained in patients with CD4+ cell counts < 50 x 10 cells/l or vRNA >/= 100 000 copies/ml at entry. At week 48, median CD4+ cell counts were increased to 203 x 10 cells/l (FPV/r QD group) and 207 x 10 cells/l (NFV BID group). Both regimens were generally well tolerated. Diarrhea was more common on NFV BID than on FPV/r QD (16 versus 9%; P = 0.008). Fasting lipid profile results were generally favorable in both treatment arms. FPV/r QD maintained plasma amprenavir (APV) trough concentrations above the mean phenotypic drug-susceptibility (IC50) for wild-type virus for APV. CONCLUSION: As a first choice protease inhibitor with a low daily pill burden, FPV/r QD was well tolerated and provided potent, durable antiviral suppression.""",1
10654,15239078,Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure,"Acetaminophen overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year. Data from the U.S. Acute Liver Failure Study Group registry of more than 700 patients with acute liver failure across the United States implicates acetaminophen poisoning in nearly 50% of all acute liver failure in this country. Available in many single or combination products, acetaminophen produces more than 1 billion US dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self-diagnosis and treatment of minor aches and pains, its benefits are said by the Food and Drug Administration to outweigh its risks. It still must be asked: Is this amount of injury and death really acceptable for an over-the-counter pain reliever?",1
10655,15242144,Management of marked liver enzyme increase during clozapine treatment: a case report and review of the literature,"""OBJECTIVE: Clozapine-induced hepatotoxicity is not infrequent and usually transient. It mostly causes asymptomatic elevation of liver transaminases. """"Elevation in liver enzymes to what extent should preclude further treatment?"""" or """"Is only a dose-reduction sufficient?"""" are questions yet to be answered. The present article uses a case report to discuss the treatment alternatives when liver enzymes reach three times the upper normal limits during the clozapine therapy. METHODS: In the following case report, the authors describe a 27-year-old male patient diagnosed with schizophrenia, resistant to different atypical and typical antipsychotics. Based on the pathological findings of our patient and a review of the literature, the author summarizes the reasons for the liver enzymes increase and treatment alternatives during clozapine treatment. RESULTS: Substantial improvement was achieved with clozapine therapy. Increase in liver enzymes at the beginning of the clozapine treatment was successfully managed with a multidisciplinary approach: the treatment was initially withdrawn, afterwards restarted, and carefully continued. CONCLUSION: The authors demonstrate that clozapine may be cautiously continued in selected patients who showed marked psychiatric improvement with clozapine in the face of liver enzyme elevation.""",1
10656,15243334,[Amoxicillin induced acute hepatitis],,1
10657,15246210,Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure,"BACKGROUND/AIMS: Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. METHODS: A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity. RESULTS: The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed. A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure. CONCLUSIONS: Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure.",1
10658,15247878,[Glimepiride-induced cute cholestatic hepatitis],,1
10659,15249568,Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial,"CONTEXT: Tenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue reverse transcriptase inhibitor. OBJECTIVE: To evaluate the efficacy and safety of tenofovir DF compared with stavudine in antiretroviral-naive patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, double-blind study conducted at 81 centers in the United States, South America, and Europe from June 9, 2000, to January 30, 2004. A total of 753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study. INTERVENTION: Patients were randomized to receive either tenofovir DF (n = 299) or stavudine (n = 303), with placebo, in combination with lamivudine and efavirenz. MAIN OUTCOME MEASURE: Proportion of patients with HIV RNA levels of less than 400 copies/mL at week 48. RESULTS: In the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, -10.4% to 1.5%), exceeding the predefined -10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA <50 copies/mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P =.06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n = 170] vs +134 mg/dL for stavudine [n = 162], P<.001), total cholesterol (+30 mg/dL [n = 170] vs +58 mg/dL [n = 162], P<.001), direct low-density lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], P<.001), and high-density lipoprotein cholesterol (+9 mg/dL [n = 168] vs +6 mg/dL [n = 154], P =.003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, P<.001). The number of bone fractures and the renal safety profile were similar between the 2 groups. CONCLUSIONS: Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.",1
10660,15251538,Chlorpropamide-induced cholestatic liver failure resulting in death,"OBJECTIVE: To describe the first reported case of a death that occurred as a result of chlorpropamide-induced cholestatic liver disease. METHODS: We review the clinical and laboratory details of an 81-year-old man with type II diabetes mellitus, who was hospitalized because of nausea, vomiting, and jaundice. RESULTS: The patient had been taking a sulfonylurea (chlorpropamide, 250 mg orally three times a day) for 2 months. On initial assessment, the patient was noted to have cutaneous and scleral icterus and an erythematous maculopapular rash on the torso. The alkaline phosphatase level was substantially increased, and the transaminases were mildly increased. Use of all medications was discontinued. In the hospital, the patient's status rapidly deteriorated, and death ensued after cardiopulmonary arrest on day 6. CONCLUSION: The findings were consistent with a hypersensitivity reaction to chlorpropamide that ultimately resulted in fulminant cholestatic liver disease and death.",1
10661,15259896,"Safety and efficacy of once-daily didanosine, tenofovir and nevirapine as a simplification antiretroviral approach","OBJECTIVE: To assess the efficacy and safety of a once-daily antiretroviral regimen in HAART-experienced subjects with long-lasting viral suppression. METHODS: One-hundred-and-sixty-nine patients with chronically suppressed viral load (limit of detection <50 copies/ml) were recruited. Based on patient willingness to simplify treatment, 84 of them continued receiving their usual treatment (BID Group) and 85 switched to once-daily didanosine/tenofovir/nevirapine (QD Group) in a non-randomized fashion. RESULTS: At week 48, the proportion of patients with viral suppression in the QD and in the BID Group, respectively, was 97 vs 100% in the per-protocol analysis (P = 0.497), and 76 vs 86% for the intention-to-treat analysis (P = 0.176). Nevertheless, CD4 count decreased in the QD Group, with a mean decline of 95 cells/mm3 (95% CI: 45-145). Twelve subjects in the QD Group (14%) discontinued treatment due to adverse events, mainly nevirapine-related hepatitis (6%). No significant differences regarding the rate of acute pancreatitis or peripheral neuropathy were observed between both groups. A significant improvement in the lipid profile was only seen in the QD Group. High levels of adherence were observed in both groups during follow-up, as well as a good quality of life. At week 48, a reduction in effort to take medication (P < or = 0.001) and an increment in the satisfaction with the treatment (P < 0.001) was only seen in the QD group. No differences were observed in median nevirapine trough levels between patients on twice-daily nevirapine at baseline (4820 ng/ml) and subjects in the QD Group (6090 ng/ml, P = 0.30). CONCLUSION: Treatment simplification to a once-daily antiretroviral regimen based on didanosine, tenofovir and nevirapine may be a valid approach in HIV-infected subjects with long-lasting viral suppression. Combination of standard doses of didanosine and tenofovir may have contributed to the CD4 cell decline observed with this QD regimen.",1
10662,15264122,Dydrogesterone-induced hepatitis and autoimmune hemolytic anemia,"Dydrogesterone, similar to women's natural progesterone, has been used in a wide range of gynecological conditions. Despite its widespread use, dydrogesterone-induced hepatotoxicity and dydrogesterone-induced hemolytic anemia have, to the best of our knowledge, never been reported previously. We describe a case of hepatitis and warm antibody hemolytic anemia due to dydrogesterone.",1
10663,15266040,Cholestatic attack due to ampicillin and cross-reactivity to cefuroxime,,1
10664,15266186,Valproate-induced hyperammonemic encephalopathy,,1
10665,15269191,Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia,"""OBJECTIVES: This study was conducted to investigate the potential equivalence in clinical efficacy and assess safety of a 5 or 7 day regimen of oral telithromycin (800 mg once daily) and a 10 day regimen of oral clarithromycin (500 mg twice daily) in treating community-acquired pneumonia (CAP). Bacteriological efficacy was also compared. METHODS: This was a multicentre, randomized, double-blind, active-controlled study. Patients with mild to moderate CAP received telithromycin 800 mg once a day for 5 (n=193) or 7 (n=195) days or clarithromycin 500 mg twice a day for 10 days (n=187). In these groups, 159, 161 and 146 patients, respectively, completed the study. RESULTS: At the post-therapy/test-of-cure evaluation, clinical cure rates (per-protocol clinical population) were 89.3% (5 days) and 88.8% (7 days) for telithromycin, and 91.8% for clarithromycin 10 days. Satisfactory bacteriological outcome rates (per-protocol bacteriological population) were 87.7% and 80.0% for 5 and 7 days of telithromycin, respectively, and 83.3% for 10 days of clarithromycin. Bacteriological eradication rates in the respective treatment groups were, for Streptococcus pneumoniae, 95.8% (23/24), 96.7% (29/30) and 88.5% (23/26); for Haemophilus influenzae, 88.0% (22/25), 84.0% (21/25) and 88.2% (15/17) and for Moraxella catarrhalis, 1/1, 4/5 and 3/4. Both telithromycin regimens demonstrated clinical efficacy against pneumococcal bacteraemia (19/19), atypical pathogens (9/9) and erythromycin-resistant S. pneumoniae isolates (5/5). Most treatment-emergent adverse events were mild to moderate in intensity with most commonly reported adverse events involving the gastrointestinal system. CONCLUSIONS: Telithromycin 800 mg administered once a day for 5 or 7 days was as effective and safe as clarithromycin 500 mg administered twice a day for 10 days in treating patients with CAP caused by common respiratory pathogens, including macrolide-resistant isolates, and pneumococcal bacteraemia.""",1
10666,15271182,Hepatotoxicity possibly due to paracetamol with carbamazepine,,1
10667,15271707,Hepatitis after sevoflurane exposure in an infant suffering from primary hyperoxaluria type 1,"An 11-mo-old child with primary hyperoxaluria was scheduled for a nephroureteromia procedure. Anesthesia was induced and maintained with sevoflurane. Two days after the operation, a hepatomegaly was diagnosed, and a considerable increase in liver enzymes was observed. These pathologic findings disappeared without treatment within 7 days. In a subsequent operation 2 wk later, general anesthesia was performed (sevoflurane was avoided). After the second operation, no pathologic findings could be detected. Nothing in this patient's disease or the conduct of the anesthesia suggested a cause for the injury other than an idiosyncratic response to sevoflurane.",1
10668,15276195,Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review,"Skeletal muscle relaxants are a heterogeneous group of medications used to treat two different types of underlying conditions: spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Although widely used for these indications, there appear to be gaps in our understanding of the comparative efficacy and safety of different skeletal muscle relaxants. This systematic review summarizes and assesses the evidence for the comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. Randomized trials (for comparative efficacy and adverse events) and observational studies (for adverse events only) that included oral medications classified as skeletal muscle relaxants by the FDA were sought using electronic databases, reference lists, and pharmaceutical company submissions. Searches were performed through January 2003. The validity of each included study was assessed using a data abstraction form and predefined criteria. An overall grade was allocated for the body of evidence for each key question. A total of 101 randomized trials were included in this review. No randomized trial was rated good quality, and there was little evidence of rigorous adverse event assessment in included trials or observational studies. There is fair evidence that baclofen, tizanidine, and dantrolene are effective compared to placebo in patients with spasticity (primarily multiple sclerosis). There is fair evidence that baclofen and tizanidine are roughly equivalent for efficacy in patients with spasticity, but insufficient evidence to determine the efficacy of dantrolene compared to baclofen or tizanidine. There is fair evidence that although the overall rate of adverse effects between tizanidine and baclofen is similar, tizanidine is associated with more dry mouth and baclofen with more weakness. There is fair evidence that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared to placebo in patients with musculoskeletal conditions (primarily acute back or neck pain). Cyclobenzaprine has been evaluated in the most clinical trials and has consistently been found to be effective. There is very limited or inconsistent data regarding the effectiveness of metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene compared to placebo in patients with musculoskeletal conditions. There is insufficient evidence to determine the relative efficacy or safety of cyclobenzaprine, carisoprodol, orphenadrine, tizanidine, metaxalone, methocarbamol, and chlorzoxazone. Dantrolene, and to a lesser degree chlorzoxazone, have been associated with rare serious hepatotoxicity.",1
10669,15277263,Gemtuzumab ozogamicin (MylotargTM) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease,"BACKGROUND: Gemtuzumab ozogamicin (GO) is approved for the treatment of older adults with acute myeloid leukemia in first relapse. Several reports have suggested an association between GO administration and hepatic veno-occlusive disease (VOD), which has recently been termed sinusoidal obstructive syndrome (SOS). However, the majority of these studies were done in patients who had undergone high-dose therapy with stem cell transplantation or when GO was administered in combination with other cytotoxic chemotherapy. PATIENTS AND METHODS: We performed a retrospective review of all patients treated at our institution with single-agent GO, either as initial therapy or in the relapsed and refractory setting. All patients were planned to receive GO 9 mg/m2 in two doses, 14 days apart. We reviewed liver function tests before and after administration and analyzed hepatic injuries in the context of patients' other comorbid conditions. Patients were classified as experiencing liver toxicity if their liver function(s) abnormality lasted for > 7 days, as documented by repeated serum studies. RESULTS: Forty-seven patients were analyzed. Response rate (27.2%) and median duration of response (6 months) were comparable to other reports. All patients were assessable for liver toxicity, of which 23 (48%) had elevation of at least one of their liver function tests (alanine aminotransferase, aspartate aminotransferase, total bilirubin or alkaline phosphatase). Elevations in liver function test(s) were noted at a median of 14 days (range 7-175 days). Eight patients had other comorbid conditions that could explain their liver abnormality, making the incidence of direct GO-induced liver injury 31%. However, only one patient had radiographic and clinical evidence suggesting SOSVOD. CONCLUSIONS: When administered using the recommended dose and schedule, GO has little association with VODSOS if given as a single agent. In this retrospective review, the incidence of GO-related SOSVOD is as low as 2%.",1
10670,15280688,A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications,"BACKGROUND: Sirolimus (SRL) is a powerful immunosuppressant used primarily in calcineurin inhibitors (CNI)-related nephrotoxicity. However, reports of drug-related side effects are increasing. The aim of our report is to review the frequency and timing of these complications within our transplant patient population. METHODS: We retrospectively reviewed the medical records of liver-transplanted patients treated with sirolimus between November 1998 and April 2002. The data collected included SRL serum levels, frequency of reported and documented SRL-related side effects, and survival outcomes. Statistical evaluation included Pearson chi-square and the Fisher's exact tests. RESULTS: Overall, 205 patients were identified, with 30 patients removed from the analysis for different reasons. Of the remaining 175 patients, 91 (52%) patients developed a complication other than an increase in serum triglycerides and/or cholesterol. The most frequent complications were: bilateral lower extremity edema (57.1%), dermatitis (25.3%), oral ulcers (24.2%), joint pain (23.0%), pleural effusion (16.5%) and increase in abdominal girth (9.9%). Other complications included: generalized edema (5.5%), pericardial effusion (5.5%), facial edema (2.2%), and upper extremity edema (1.3%). In addition, we reported two cases of hepatic artery thrombosis, one case of wound dehiscence with evisceration that required surgical repair, and one case of skin cancer. Interestingly, we found that a previous history of myocardial ischemia correlates with the development of SRL side effects. CONCLUSIONS: SRL is a powerful immunosuppressant but not devoid of side effects. These results have elevated our level of suspicion when instituting SRL and may help with early recognition and prevention of drug related complications.",1
10671,15282233,Which agents should we use for the treatment of multidrug-resistant Mycobacterium tuberculosis?,"The inappropriate treatment of drug-susceptible tuberculosis can lead to the selection and transmission of multidrug-resistant tuberculosis (MDR-TB), indicating resistance to at least isoniazid and rifampicin. In the treatment of MDR-TB, residual first-line drugs, such as ethambutol, pyrazinamide and streptomycin must be appropriately combined with additional second-line drugs, guided by individual susceptibility patterns. The clinical pharmacology of these second-line antituberculous drugs is reviewed. Fluoroquinolones represent the only substantial therapeutic advance in the last 20 years. Many factors potentially affect the outcome of MDR-TB. Treatment adherence, prior exposure to antituberculous drugs, the number of drugs to which the infection is still susceptible and the time since the first diagnosis of tuberculosis are the most relevant. The management of MDR-TB requires considerable expertise. When initiating or revising therapy for MDR-TB, the process of selecting drugs should rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence. In making drug selection, we propose to follow a hierarchy based on the intrinsic activity against Mycobacterium tuberculosis and the clinical evidence of efficacy of the available active compounds.",1
10672,15283649,[Liver toxicity associated with flutamide],,1
10673,15286086,Pharmacological and clinical profile of moexipril: a concise review,"Angiotensin-converting enzyme (ACE) inhibitors are effective and safe antihypertensive drugs, with the exception of the rare occasion of angioedema. These drugs have demonstrated additional cardiovascular protective effects to their blood pressure lowering, and their combination with the diuretic hydrochlorothiazide potentiates their antihypertensive effectiveness. Moexipril is a long-acting ACE inhibitor suitable for once-daily administration, and like some ACE inhibitors, moexipril is a prodrug and needs to be hydrolyzed in the liver into its active carboxylic metabolite, moexiprilat, to become effective. Moexipril alone and in combination with low-dose hydrochlorothiazide has been shown in clinical trials to be effective in lowering blood pressure and be well tolerated and safe given in single daily doses. In this review, the pharmacological profile of this drug and its clinical usefulness are discussed.",1
10674,15289784,Acute vanishing bile duct syndrome after ibuprofen therapy in a child,"We report the case of a 10 year-old girl who had Stevens-Johnson syndrome and cholestasis after ibuprofen therapy. Liver histology was compatible with vanishing bile duct syndrome. She received ursodeoxycholic acid, and liver tests normalized within 7 months. This report confirms that ibuprofen may induce acute vanishing bile duct syndrome.",1
10675,15297281,Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha,"BACKGROUND: Research on autoantibody formation in patients treated with TNF alpha inhibitors has produced contradictory results. OBJECTIVE: To study the prevalence of autoantibodies in patients with rheumatoid arthritis treated with the TNF alpha inhibitor infliximab. METHODS: 53 patients (48 female, 11 male) treated with infliximab for rheumatoid arthritis were followed for autoantibody production before treatment and after 14, 30, and 54 weeks. Six patients treated with etanercept were studied for comparison. The analyses included antibodies against nuclear antigens (ANA), extractable nuclear antigens, double stranded (ds)DNA (by ELISA, IIF on Crithidia luciliae for IgM and IgG, and Farr assay), nucleosomes, cardiolipin, smooth muscle, mitochondria, proteinase 3, and myeloperoxidase antigens. RESULTS: The number of patients treated with infliximab who developed antibodies against dsDNA of both IgG and IgM class (tested by IIF) increased significantly. The prevalence of patients positive for IgG class increased to 66% at 30 weeks and 45% at 54 weeks, and of IgM class to 85% and 70%, respectively. The titre and number of patients expressing antibodies against nucleosomes and ANA also increased significantly. The number of rheumatoid factor or anticardiolipin positive patients was stable and there was no increase in antibodies against the other antigens. A lupus-like syndrome was seen in one patient. No patient treated with etanercept developed any of these autoantibodies. CONCLUSIONS: Patients treated with infliximab may develop anti-dsDNA antibodies of both IgM and IgG class, anti-nucleosome antibodies, and ANA, with a gradual increase until 30 weeks.",1
10676,15301575,Clinical pharmacokinetics of levetiracetam,"""Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.""",1
10677,15307009,Longitudinal effect of antiretroviral therapy on markers of hepatic toxicity: impact of hepatitis C coinfection,"""To characterize longitudinal hepatic toxicity of antiretroviral therapy in HIV-infected women with and without hepatitis C virus (HCV) infection, we measured alanine and aspartate aminotransferase values among women initiating highly active antiretroviral therapy (HAART). For 312 HIV/HCV coinfected women who received HAART for a mean of 1.8 years, the prevalence of elevated aminotransferase levels >3 times and >5 times the upper limit of normal (ULN) was low (<12% and <4%, respectively), and the prevalence of elevated aminotransferase levels declined over time. When we analyzed trends in aminotransferase levels according to type of HAART received among HCV-infected and uninfected women, we found that mean aminotransferase levels declined among 539 women receiving therapy with protease inhibitors (decreases of 5.34%-4.23% of the ULN per year; P values for trend of.007-.06), but mean values among 128 women receiving therapy with nonnucleoside reverse-transcriptase inhibitors remained stable (from decreases of 1.65% to increases of 7.57% of the ULN per year; P values of.19-.71). Our findings lend support to assertions that antiretroviral therapy is safe for women with HCV infection.""",1
10678,15307844,Diagnosis of 6 mercaptopurine hepatotoxicity post liver transplantation utilizing metabolite assays,"Azathioprine and 6-mercaptopurine (6 MP) are commonly used as immunosuppression postsolid organ transplantation. Recently, a better understanding of the metabolism of these drugs has developed. 6 Mercaptopurine is metabolized by thiopurine methyl transferase (TPMT) which is under the control of a common genetic polymorphism. Genetic testing and measurement of levels of 6 MP metabolites allow identification of patients at risk of toxicity. We report two cases of cholestatic hepatocellular injury associated with 6 MP toxicity occurring after orthotopic liver transplantation. Cholestasis developed after the introduction of 6 MP. Patients underwent extensive investigation and 6 MP toxicity was considered only after all other causes had been excluded. Thiopurine methyl transferase alleles identified on genetic testing were normal as were the 6 thioguanine levels. However, 6-methyl mercaptopurine levels were significantly elevated into the toxic range. Cholestasis resolved within a few weeks of drug withdrawal. 6 Mercaptopurine hepatotoxicity can present with a variety of clinical, biochemical and histological manifestations post OLT and should be considered as a cause of liver enzyme elevation. Monitoring of 6 MP metabolite levels in addition to TPMT allele testing is useful to prevent 6 MP toxicity and to help guide therapy.",1
10679,15307912,Short communication: liver toxicity of lopinavir-containing regimens in HIV-infected patients with or without hepatitis C coinfection,"Liver toxicity is a common side effect of antiretroviral therapy, particularly in subjects coinfected with the hepatitis C virus (HCV). The incidence of severe liver toxicity after initiation of treatment with lopinavir (LPV) as well as its possible association with LPV plasma levels were assessed in 120 HIV-infected patients (52% coinfected by HCV). The incidence of severe liver toxicity at 3 months was 1.7% and the cumulative incidence at 12 months was 4%. The development of severe liver toxicity was associated with HCV coinfection but not with LPV plasma levels.",1
10680,15310155,Moxifloxacin--a new fluoroquinolone antibacterial,"""Moxifloxacin (Avelox - Bayer plc), the latest fluoroquinolone antibacterial to be launched in the UK, is licensed for the oral treatment of adults with community-acquired pneumonia, acute exacerbation of chronic bronchitis or acute sinusitis. The company claims that the drug provides """"rapid relief from chest infections"""". Here we review the place of moxifloxacin in treating patients with respiratory tract infections.""",1
10681,15312442,[The clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism],"OBJECTIVE: To study the clinical characteristics and factors of symptomatic propylthiouracil (PTU)-induced hepatic injury in patients with hyperthyroidism. METHODS: A retrospective study of the patients diagnosed with symptomatic PTU-induced hepatic injury, admitted to Peking Union Medical College (PUMC) Hospital from January 1993 to December 2002, were carried out with regard to clinical characteristics, laboratory findings and management. In addition, a comparative study was carried out in hyperthyroidism with symptomatic, asymptomatic and without PTU-induced hepatic injury at the same time. Symptomatic PTU induced hepatic injury was defined as the development of hepatitis symptoms or jaundice with at least 3-times elevation of liver function test without other causes. RESULTS: Nine hundred fourteen patients were admitted to PUMC Hospital from January 1993 to December 2002. Clinically overt symptomatic hepatic injury developed in twelve patients [1.3%, age (30 +/- 9) yr, male:female ratio, 1:11] between 7 and 77days after PTU administration. Abdominal distention and fatigue developed in all patients. Serum level of ALT and total bilirubin (TBil) increased to (531.7 +/- 352.0) 113 - 1425 U/L and 67.6 (17.1 - 567.7) micro mol/L, respectively. Prothrombin time prolonged in three cases and plasma ammonia elevated in one case. The types of hepatic injury were hepatocellular in eight, cholestatic in one and mixed in two. None resulted from viral hepatitis and autoimmune hepatitis. There was significant difference in history of side effects of antithyroid agents, PTU dose and abnormal ratio of serum ALT among patients with symptomatic, asymptomatic and without hepatic injury (P < 0.05). However, there were no statistic differences in age, sex, serum levels of T(4), T(3), and increased thyroglobulin antibody, thyroid peroxidase antibody and thyrotrophin receptor antibody at initial diagnosis. The liver function test normalized in all patients from 14 to 140 days after the PTU withdrawal. CONCLUSIONS: Symptomatic hepatic injury usually develops with PTU administration in the first few months, though it is unusual. It may be difficult to predict its development and the patient should be monitored for the liver function in the early stage of PTU administration.",1
10682,15316320,Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease,"BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.",1
10683,15320978,Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto's thyroiditis: case report,"A 43-year-old woman with Hashimoto's thyroiditis (HT), euthyroid on levothyroxine since 1999, developed thyroid-associated ophthalmopathy (TAO) in February 2002. She had involvement of the eye muscles, as shown by computed tomography (CT) scan. She was started on methylprednisolone pulse therapy 7.5 mg/kg of body weight, (one cycle every 2 weeks, each cycle comprising two infusions on alternate days), with rapid improvement of soft tissue inflammation and of eye motility, as confirmed by the reduction of clinical activity score (CAS) and eye muscles size on CT scan. At the end of treatment the patient showed a marked and rapid increase of serum aminotransferases (up to 1200 U/L). She had negative hepatitis A, B, and C viruses serology, but circulating antinuclear antibodies. A liver biopsy, performed at 4 weeks after the discontinuation of intravenous steroids, led to the diagnosis of autoimmune hepatitis (AIH). The patient was treated with oral steroids with a rapid reduction of serum aminotransferases concentrations. To our knowledge, there have been only two reports of liver dysfunction after intravenous steroids for TAO, but the etiology of such hepatitis had not been established. AIH may develop in patients with multiple autoimmunity and may not become overt until immune rebound occurs (i.e. after cessation of or between immunosuppressive treatment cycles). Steroids are the first line of treatment for AIH, hence their use would not be contraindicated when patients with TAO have chronic hepatitis, provided that the modalities of treatment are appropriate.",1
10684,15324623,[Acarbose-induced acute hepatitis. Report of two events in the same patient],"A 57-year-old woman with non-insulin-dependent diabetes mellitus and inadequate glycemic control was prescribed acarbose (100 mg 3 times daily). Two months later she presented with acute hepatitis (ALT 2,300 IU/l). Other causes of liver damage were excluded. Three months after acarbose had been discontinued, all results of laboratory tests returned to normal values. Three years later the patient was given acarbose again. Acarbose (100 mg three times daily) had been added to glibenclamide (15 mg daily) 2 weeks before she presented with acute hepatitis (ALT 2,778 IU/l). Acarbose was stopped and the results of liver tests returned to normal within 2 months. Of the eight cases of acarbose-associated hepatotoxicity previously reported, five (as well as the two presented herein) were Spanish. The latency period, from the start of drug therapy to the onset of liver injury, was relatively long (> 2 months). We suggest that acarbose be included in the list of drugs which may induce acute hepatitis.",1
10685,15332488,"Antituberculosis drug-induced hepatitis: risk factors, prevention and management","Apart from infectious or viral hepatitis, other most common non-infectious causes of hepatitis are alcohol, cholestatic, drugs and toxic materials. The most common mode that leads to liver injuries is antituberculosis drug-induced hepatitis. The severity of drug-induced liver injury varies from minor nonspecific changes in hepatic structure to fulminant hepatic failure, cirrhosis and liver cancer. Patients receiving antitubercular drug frequently develop acute or chronic hepatitis. The time required for the metabolites to reach hepatotoxic levels is much earlier with isoniazid plus rifampicin treatment than isoniazid alone and this has been shown to be synergistic rather than additive. Antituberculosis drug (ATT)-inducible cytochrome P-4502E1 (CYP2E1) is constitutively expressed in the liver. Recent studies show that polymorphism of the N-acetyltransferase 2 (NAT2) genes and glutathione-S-transferase (GST) are the major susceptibility risk factors for ATT-induced hepatitis. The hepatic NAT and GST are involved in the metabolism of several carcinogenic arylamines and drugs. The NAT2 enzyme has a genetic polymorphism in human. N-acetyltransferase 2 genes (NAT2) have been identified to be responsible for genetic polymorphism of slow and rapid acetylation in humans. Slow acetylators of NAT2 prove to develop more severe hepatotoxicity than rapid acetylators making it a significant risk factor. Deficiency of GST activity, because of homozygous null mutations at GSTM1 and GSTT1 loci, may modulate susceptibility to drug and xenobiotic-induced hepatotoxicity. Polymorphisms at GSTM1, GSTT1 and NAT2 loci had been linked to various forms of liver injury, including hepatocellular carcinoma.",1
10686,15334875,Management of thalidomide toxicity,"Thalidomide has re-emerged as a novel antineoplastic agent with immunomodulatory and antiangiogenic activities. In the early sixties, it was withdrawn from the market after its infamous association with congenital abnormalities that left about 10,000 children affected world-wide. With strict regulations and precautions, thalidomide is now approved by the FDA for the treatment of erythema nodosum leprosum. Its role in cancer therapy is promising, with clinical trials in the past 5 years showing significant activity in multiple myeloma. Several trials are ongoing in other malignancies, such as myelodysplastic syndrome, agnogenic myeloid metaplasia, renal cell carcinoma, and prostate cancer. The major toxicities of thalidomide are birth defects, sensorimotor peripheral neuropathy, somnolence, rash, fatigue, and constipation. Less common side effects include deep venous thrombosis, Stevens-Johnson syndrome, elevated liver enzymes, malaise, and peripheral edema. The incidence and severity of adverse events are related to dose and duration of therapy. Doses of the drug of 200 mg/day or less are usually well tolerated. In this review, we will discuss the incidence and management of the side effects of thalidomide and the precautions and interventions needed to minimize the toxicities of this drug.",1
10687,15337804,Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma,"""PURPOSE: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed stage 4 neuroblastoma patients older than 1 year who underwent consolidation treatment with the chimeric monoclonal anti-GD2-antibody ch14.18. PATIENTS AND METHODS: Stage 4 patients older than 1 year who completed initial treatment without event were eligible. ch14.18 was scheduled in a dose of 20 mg/m2/d during 5 days in six cycles every 2 months. Patients who did not receive ch14.18 served as controls. RESULTS: Of 334 assessable patients, 166 received ch14.18, 99 received a 12-month low-dose maintenance chemotherapy (MT) instead, and 69 had no additional treatment. During 695 ch14.18 cycles, fever (55% of cycles), abnormal C-reactive protein without infection (35%), cough (24%), rash (22%), and pain (16%) were the main side effects. Univariate analysis found similar event-free survival (EFS) for the three groups (3-year EFS, 46.5% +/- 4.1%, 44.4% +/- 4.9%, 37.1% +/- 5.9% for patients treated with antibody ch14.18, MT, and no additional therapy, respectively; log-rank test, P =.314). For overall survival (OS), ch14.18 treatment (3-year OS, 68.5% +/- 3.9%) was superior to MT (3-year OS, 56.6% +/- 5.0%) or no additional therapy (3-year OS, 46.8% +/- 6.2%; log-rank test, P =.018). Separate univariate analysis of patients with autologous stem-cell transplantation revealed no difference between patients with ch14.18 treatment and no additional consolidation. Multivariate analysis failed to demonstrate an advantage of antibody treatment for EFS and OS. CONCLUSION: Consolidation treatment of stage 4 neuroblastoma with ch14.18 was associated with considerable but manageable side effects. Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients.""",1
10688,15338857,Fatal lactic acidosis associated with coadministration of didanosine and tenofovir disoproxil fumarate,"Lactic acidosis is an uncommon but potentially life-threatening adverse effect of didanosine. When given concomitantly with tenofovir disoproxil fumarate (DF), the area under the concentration-time curve of didanosine is increased by 48-60%. A 63-year-old man with human immunodeficiency virus (HIV) infection tolerated several didanosine-containing antiretroviral regimens. He developed generalized weakness, loss of appetite, weight loss, nausea, and vomiting 1.5 years after tenofovir DF was added to his didanosine-containing regimen. He was diagnosed with lactic acidosis and died after a 13-day hospital stay, when his lactate level increased to 189.7 mg/dl and his arterial blood gas pH value fell to 6.75. Health care providers should maintain a high index of suspicion for lactic acidosis in patients with HIV infection who receive didanosine and tenofovir DF concurrently. For patients receiving antiretroviral regimens containing this drug combination, it would be prudent to monitor lactate levels periodically. This is especially important when patients experience symptoms suggestive of lactic acidosis, such as weakness, abdominal pain, weight loss, nausea and vomiting, and shortness of breath.",1
10689,15345904,Reported case of severe hepatotoxicity likely due to fluconazole and not desloratadine,,1
10690,15350998,[Oxcarbazepine and DRESS syndrome: a paediatric cause of acute liver failure],"Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, also called hypersensitivity reaction, is a severe idiosyncratic reaction to drugs, especially to anti-epileptic drugs. Clinical features associate cutaneous eruption, fever, multiple peripheral ganglions, and potentially life-threatening damage of one or more organs. DRESS syndrome is well described in adults treated with aromatic anti-epileptic drugs, such as phenytoin, phenobarbital, and carbamazepine, but also with other drugs. The new anti-epileptic drugs, such as oxcarbazepine also induce various cutaneous eruptions, but with less report of DRESS syndrome. In children, DRESS syndrome is rare and probably underdiagnosed. We report on the case of a 11-year-old girl hospitalised with an acute severe hepatitis revealing an oxcarbazepine-induced DRESS syndrome.",1
10691,15356412,Autoimmune hepatitis associated with the use of black cohosh: a case study,"Herbal remedies generate more than 1.8 billion dollars in annual sales in the United States. Herbal products have been associated with a wide spectrum of hepatic toxicities. With the recent Women's Health Initiative Study demonstrating increased risk of breast cancer and cardiovascular events associated with hormone therapy, many women may resort to herbal remedies for persistent menopause symptoms. We report a case of autoimmune hepatitis likely triggered by the use of black cohosh (Actaea racemosa), an agent marketed to treat menopause symptoms. Given this case report, we recommend close monitoring of women using this herbal preparation.",1
10692,15356822,Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons?,"""BACKGROUND: In 2000, results of a multinational trial demonstrated that a 2-month course of rifampin and pyrazinamide (RZ) was as effective as isoniazid (INH) in reducing tuberculosis in human immunodeficiency virus (HIV)-infected individuals with latent tuberculosis infection (LTBI). After the release of new guidelines, the Centers for Disease Control and Prevention received reports of severe hepatotoxicity associated with the use of the RZ regimen for the treatment of LTBI in the general population. To better understand the occurrence of hepatotoxicity in an HIV-infected population, we conducted a more detailed analysis of the liver function test results obtained in the multinational trial of RZ. METHODS: At study entry, patients were required to have a bilirubin level of < or =2.5 mg/dL and both an aspartate aminotransferase (AST) level and an alkaline phosphatase level of < or =5 times the upper limit of normal. Patients with acute hepatitis were excluded. At months 1 and 2 of the study, all patients had bilirubin and AST levels measured. RESULTS: There was no difference between the RZ and INH groups with regard to AST level or bilirubin level at baseline. An increase in the AST level of > or =40 U/L was associated with the use of INH and older age; and an increase in the bilirubin level of > or =0.5 mg/dL was associated with the use of RZ, male sex, and nonwhite race (P<.05). An absolute AST level of >250 U/L occurred in 12 of 745 INH recipients and in 15 of 721 RZ recipients (P=.56), and an absolute bilirubin level of >2.5 mg/dL occurred in 5 of 743 INH recipients and 13 of 718 RZ recipients (P=.06). CONCLUSIONS: These data demonstrate very little liver injury associated with either INH or RZ in the HIV-infected subjects, leaving unclear the reasons for serious RZ-related liver damage in the general population.""",1
10693,15365421,Cephalexin-induced cholestatic hepatitis,,1
10694,15367725,Muscle pain associated with daptomycin,"""OBJECTIVE: To report a case of muscle pain without pronounced creatine kinase (CK) elevation in a patient receiving daptomycin. CASE SUMMARY: A 26-year-old African American woman had antibiotic intolerance to vancomycin and quinupristin/dalfopristin. She presented with methicillin-resistant Staphylococcus aureus endocarditis that was treated with intravenous daptomycin 6 mg/kg daily for 14 days. The patient developed muscle aches and pains with only a minor elevation (492 U/L) of CK; both resolved after daptomycin was discontinued. DISCUSSION: Daptomycin is a newly approved lipopeptide antibiotic derived from Streptomyces roseosporus with rapid bactericidal activity. Daptomycin has excellent coverage against gram-positive bacteria. The adverse effect profile has included rare reports of myopathy and elevated CK levels. Daptomycin is a promising agent with many potential applications. Once-daily dosing has diminished the preclinical incidence of myopathy. The current package labeling recommends discontinuation of daptomycin with significant myopathy symptoms in association with a CK elevation >1000 U/L or in patients without muscle pain and a CK >10 times normal. CONCLUSIONS: An objective causality assessment revealed that the myopathy was possibly related to daptomycin. Clinicians should recognize that significant myopathy with daptomycin can occur without pronounced CK elevation.""",1
10695,15371928,Acute hepatitis due to buprenorphine administration,"BACKGROUND: Buprenorphine, a synthetic molecule derived from thebaine, has been commercialized in France since 1987 as a substitute treatment for pharmacodependence on opiates. Hepatotoxicity is poorly documented, since only few cases of hepatic injury have been reported. METHODS: We report seven cases of acute cytolytic hepatitis due to buprenorphine. All patients were former drug addicts by the parenteral route and had been receiving withdrawal therapy with buprenorphine for an average of 91 days at a daily dosage ranging from 2 to 12 mg. Liver tests, complete viral screening and an abdominal computerized tomography scan were performed in each patient. RESULTS: Five out of seven subjects presented with acute icteric hepatitis without abdominal pain or fever. Average alanine aminotransferase levels were 39 times the normal rate. There was no sign of liver failure. All patients had anti-hepatitis C virus-positive serology and two had positive hepatitis C virus-RNA. Although no specific treatment was administered, buprenorphine doses were reduced whenever possible. Cytolysis and jaundice resolved rapidly in all cases, although treatment was continued at the same doses in four cases and the dosage was reduced by 50% in three other cases. CONCLUSIONS: Although buprenorphine hepatitis is uncommon and has spontaneously good evolution, we suggest better monitoring of hepatic profiles in patients whose mitochondrial function is already impaired by viral infections or other toxic factors.",1
10696,15378131,Efficacy and safety of a metabolic modulator drug in chronic stable angina: review of evidence from clinical trials,"A number of newer antianginal agents, including nicorandil, trimetazidine, and ivabradine, have been synthesized in recent years, but ranolazine, a piperazine derivative that partially inhibits fatty acid oxidation and the late INa current in animal models, is of particular interest mechanistically. Earlier clinical trials with immediate-release ranolazine led to the current sustained-release version tested in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) (n = 193) and Combination Assessment of Ranolazine In Stable Angina (CARISA) trials (n = 823) of patients with chronic angina and severe limitation of exercise capacity (ie, < 5 metabolic equivalents). MARISA was a placebo-controlled, randomized trial that compared ranolazine monotherapy (500 mg, 1000 mg, and 1500 mg, twice daily) to placebo. CARISA was a placebo-controlled trial that randomized patients on background beta-blocker or calcium antagonist therapy to placebo or ranolazine (750 mg or 1000 mg, twice daily). Both studies showed a significant increase in total exercise duration, time to angina onset, and time to 1 mm ST segment depression. The average magnitude of increase in exercise duration over placebo was 29 to 56 seconds at peak and 24 to 46 seconds at trough with the 3 doses tested in MARISA, and 24 to 34 seconds greater than placebo with the 2 doses used in CARISA. The beneficial effect was achieved without clinically important changes in rest or exercise heart rate or blood pressure. Weekly angina attack frequency and nitroglycerin usage were significantly reduced in a dose-dependent manner in the 12-week CARISA trial. Reported adverse effects were similar in MARISA and CARISA and consisted of asthenia, nausea, constipation, and dizziness. Syncope, reported in 8 patients at doses of 1000 mg twice daily or more may be related to attenuation of alpha-1 receptor activity. The mean QTc interval increased with dose and was less than 10 msec on ranolazine at 1000 mg twice daily. The mortality rates at 1 and 2 years in MARISA and CARISA open-label run-on studies were 2% and less than 5%, acceptable for this high-risk population with limited exercise capacity. In conclusion, clinical trial evidence with ranolazine to date is consistent with its proposed mechanism of action and demonstrates an effective antianginal profile that may benefit patients with severe chronic angina.",1
10697,15383643,Recurrent acute hepatitis associated with use of cetirizine,"""OBJECTIVE: To describe a case of recurrent acute hepatitis related to the use of cetirizine, a selective histamine(1)-receptor antagonist approved for the treatment of common allergic diseases. CASE SUMMARY: A 26-year-old man was hospitalized with a week-long history of weakness, nausea, anorexia, and hyperchromic urine, which had developed after 6 days of therapy with oral cetirizine 10 mg/day for allergic rhinitis. Admission laboratory testing revealed evidence of acute hepatitis and seropositivity for liver-kidney microsome antibodies. Liver biopsy findings of diffuse portal tract and lobular inflammation with a prominent eosinophilic infiltrate were consistent with drug-related hepatitis. The patient was discharged after one week of treatment with tocopherol and glutathione. Three months after discharge, transaminase levels were normal. At 6 months, seropositivity for liver-kidney microsome antibodies was still present, but considerably less intense. The patient had suffered 2 previous episodes of """"acute hepatitis of unknown origin,"""" and both had occurred after cetirizine use. DISCUSSION: Use of the Naranjo probability scale indicated cetirizine as the probable cause of acute hepatitis, and the positivity for liver-kidney microsome antibodies is suggestive of an autoimmune mechanism for liver damage. As of September 13, 2004, ours is the fourth reported case of acute hepatitis associated with cetirizine and the second in which liver-kidney microsome antibodies have been documented. CONCLUSIONS: Although cetirizine is considered to have low potential for severe hepatic toxicity, the possibility that it can provoke autoimmune-mediated hepatotoxicity should be considered.""",1
10698,15384252,Hepatic changes in the acute phase of streptozotocin (SZ)-induced diabetes in mice,"We have reported the streptozotocin (SZ)-induced hepatic lesions in the subacute phase (4 to 12 weeks after the treatment), which are characterized by appearance of oncocytic hepatocytes, cytomegalic hepatocytes and bile duct hyperplasia. In this study, we focused on the acute phase (6 to 48 hours after the treatment) of the SZ-induced hepatic lesions of mice to clarify the onset of the hepatic alterations, especially before the induction of hyperglycemia. Livers were taken from 8-week-old Crj:CD-1 (ICR) male mice at 6, 12, 24, 36 and 48 hours after the 200 mg/kg b.w. of SZ-injection. SZ-induced hyperglycemia was noted at 36 and 48 hours after the treatment, but the hepatic changes including lipid peroxidation, mitochondrial swelling, peroxisome proliferation and inhibition of hepatocyte proliferation occurred before the elevation of the serum glucose levels. The present findings indicate the direct effects of SZ on hepatocytes rather than the secondary effects of diabetes, and certain correlations between the hepatocytic changes in the acute phase and those in the subacute one. In addition, ulcer and submucosal edema of the gallbladder were observed at 36 or 48 hours after the SZ-treatment, which can be a novel finding in SZ-treated animal.",1
10699,15386721,Risks of herbal medicinal products,"PURPOSE: Herbal medicinal products (HMPs) are again highly popular. Their current popularity renders the assessment of their safety an urgent necessity. METHOD: Narrative review using examples only. RESULTS: Constituents of HMPs can be toxic and numerous examples of liver, kidney or other organ damage are on record. All HMPs contain a range of pharmacologically active constituents, and users of HMPs often combine HMPs with prescribed drugs. Thus herb-drug interactions are a real possibility. In most countries, HMPs are not submitted to stringent regulation and control. Thus unreliable quality can be a problem. In particular, this poses a risk when HMPs are contaminated (e.g. with heavy metals) or adulterated (e.g. with prescription drugs). The medical literature holds numerous examples for all of these scenarios and some are used in this article to illustrate the above points. As this area is grossly under-researched, it is rarely possible to define the size of the problem. CONCLUSIONS: It is concluded that the widespread notion of HMPs being inherently safe is naive at best and dangerous at worst. More research is required to minimise the risk HMPs may pose to consumers' health.",1
10700,15389228,A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: lack of effect,"BACKGROUND: Contrast-induced nephropathy (CIN) after cardiac catheterization is common in patients with preexisting renal dysfunction. Studies of oral acetylcysteine to prevent CIN have produced conflicting results. Intravenous N-acetylcysteine (NAC) has logistic advantages in this setting. The objective of this study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency. METHODS: Patients with renal dysfunction undergoing cardiac catheterization were randomly assigned to intravenous NAC 500 mg immediately before the procedure or placebo. All patients received isotonic saline (200 mL) beforehand, followed by 1.5 mL/kg per hour for 6 hours, unless contraindicated. Exclusion criteria included acute renal failure, creatinine >400 micromol/L, concurrent dialysis, unstable clinical status, and prior NAC use. Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later. The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of >5 mL/min (Cockcroft-Gault formula). RESULTS: The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients. The median baseline creatinine clearance was 44 mL/min (interquartile range, 33, 55). Median contrast received was 120 mL (interquartile range, 80, 175). Baseline characteristics were similar in the two groups. Altogether, 98 (22.0%) subjects had the primary end point: 23.3% in the NAC group and 20.7% in the placebo arm (P =.57). CONCLUSIONS: In this large, randomized trial, enrolling a high-risk group of patients with impaired renal function, intravenous NAC was ineffective in preventing CIN.",1
10701,15404975,Jaundice during methyl testosterone therapy,,1
10702,15411312,Unusual case of apparent malingering,,1
10703,15415251,Exfoliative dermatitis and hepatitis due to phenobarbital,,1
10704,15419170,Fowler's solution as an etiologic agent in cirrhosis,,1
10705,15452330,Liver injury associated with the beta-interferons for MS,,1
10706,15456599,[Erythroderma and hepatitis],,1
10707,15462159,Iron bezoar retained in colon despite 3 days of whole bowel irrigation,"""Concretion formation is a documented complication of large iron ingestions. The generally accepted treatment is supportive care, whole bowel irrigation, and intravenous deferoxamine for systemic toxicity. Laparotomy and gastrotomy have also been used in patients with a high iron burden and bezoar formation. Though experiments suggest that iron is poorly absorbed in the colon, there are no case reports of iron overdose without systemic toxicity, despite a retained colonic bezoar. We report the case of a 16-month-old who presented to an Emergency Department 19 h after an iron ingestion. Initial laboratory studies revealed an anion gap of 14 mEq/L, and a 20 h serum iron concentration of 429 mcg/dL. An abdominal radiograph revealed multiple pills throughout the stomach and small bowel; whole bowel irrigation was initiated. Deferoxamine was administered at 10 mg/kg/h and then stopped when the serum iron level reached 27 mcg/dL, 36 h later. At this time, the abdominal radiograph showed an iron bezoar remaining in the ascending colon despite a clear rectal effluent from whole bowel irrigation. Despite whole bowel irrigation over the next 36 h, the iron bezoar was not removed and actually migrated proximally in the colon. Treatment was stopped on the third day and a normal diet was instituted with prompt passage of the bezoar.""",1
10708,15464682,Risk of adverse events with fibrates,"An increased risk for adverse events was observed with gemfibrozil relative to fenofibrate, predominantly driven by an increased rate of rhabdomyolysis. This difference was especially noticeable in patients taking the combination of gemfibrozil and a statin, particularly cerivastatin.",1
10709,15468367,Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial,"""OBJECTIVE: . To compare the safety and efficacy of a topical diclofenac solution versus oral diclofenac in relieving the symptoms of primary osteoarthritis (OA) of the knee, in a randomized, double-blind, double-dummy equivalence trial. METHODS: A total of 622 men and women with radiological evidence of primary knee OA and mild to severe symptoms were randomly assigned to treatment with a topical diclofenac solution plus placebo oral capsules, or placebo topical solution plus oral diclofenac (50 mg) capsules. Patients applied 50 drops of study solution and took 1 study capsule 3 times daily for 12 weeks. Efficacy variables were pain and physical function, measured by the Western Ontario and McMaster Universities (WOMAC) VA 3.1 OA Index, and patient global assessment (PGA). Equivalence in the per-protocol group was based on previously defined ranges of clinically significant difference. Safety was assessed by evaluation of adverse events, vital signs, and laboratory data. RESULTS: The difference in mean (95% CI) change scores (final minus baseline) between treatments was 13.3 mm (-8.6 to 35.2) for pain (total scale 500 mm), 71.0 mm (-2.4 to 144.5) for physical function (total scale 1700 mm), and 4.3 mm (-1.2 to 9.8) for PGA (total scale 100 mm). The CI for each efficacy variable fell within the predefined equivalence ranges (pain, +/- 75 mm; physical function, +/- 255 mm; PGA, +/- 20 mm), indicating that no clinically relevant difference was found between the 2 treatment arms. Safety analyses of patients applying topical diclofenac solution revealed some minor skin irritation at the application site--mostly skin dryness in 83/311 (27%) patients--but a significantly reduced incidence, relative to oral diclofenac, of total and severe gastrointestinal (GI) adverse events, including dyspepsia, abdominal pain, diarrhea, and nausea. The number of patients developing abnormal liver function tests (including clinically significant elevation), hemoglobin, and creatinine clearance was significantly higher in the oral diclofenac group. CONCLUSION: Application of this topical diclofenac solution to the knee of patients with OA produced relief of symptoms equivalent to oral diclofenac, with minor local skin irritation, but significantly reduced incidence of diclofenac-related GI complaints and abnormal laboratory values.""",1
10710,15477437,"Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial","""BACKGROUND: Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve the symptoms of osteoarthritis (OA) but can produce harmful systemic effects and end-organ damage. A topical NSAID formulation may provide symptom relief with fewer adverse effects. A new topical diclofenac sodium solution-containing the absorption enhancer dimethyl sulfoxide-was evaluated for the relief of the symptoms of primary OA of the knee. METHODS: A total of 326 patients met entry criteria (including abnormal radiographic findings and flare of pain) and were randomized to receive 40 drops of topical diclofenac solution or a vehicle-control solution, 4 times daily, for 12 weeks. We evaluated 3 primary outcome measures, the Western Ontario McMaster Universities LK3.1 OA Index (WOMAC) pain and physical function subscales and a patient global assessment, and 2 other measures, stiffness and pain on walking, at baseline and after final application. We assessed safety by evaluation of adverse events, vital signs, and irritation at the application site. RESULTS: Topical diclofenac solution was significantly more effective than the vehicle-control solution for all outcome measures; pain, P = .001; physical function, P = .002; patient global assessment, P = .003; stiffness, P = .005; and pain on walking, P = .004. Among patients receiving topical diclofenac, self-limiting minor skin irritation occurred in 68 (41.5%) of 164 patients, including dryness in 60 (36.6%), rash in 18 (11.0%), and paresthesia, pruritus, and vesiculobullous rash in 1 (0.6%) each. There was no significant difference between groups in NSAID-related gastrointestinal tract complaints or in dropouts due to study-related adverse effects. CONCLUSION: Topical diclofenac is effective in the treatment of the symptoms of primary OA of the knee, with only minor local irritation and no significant systemic adverse events.""",1
10711,15478165,Anti-tumor necrosis factor agents for rheumatoid arthritis in the setting of chronic hepatitis C infection,"OBJECTIVE: To examine the safety of using anti-tumor necrosis factor (TNF) therapy in patients with rheumatoid arthritis (RA) in the setting of hepatitis C virus (HCV) infection. METHODS: The charts of 5 patients known to have RA requiring anti-TNF therapy as well as established HCV infection were reviewed retrospectively for laboratory data of hepatic parenchymal inflammation and viral proliferation while taking these agents. RESULTS: In a mean +/- SD followup period of 41 months (+/- 28.2 months), no patient displayed evidence of sustained elevation of serum aminotransferases during therapy with anti-TNF. Additionally, 1 patient was observed to have a decreased HCV viral load after extended treatment with only anti-TNF (no therapy for HCV). CONCLUSION: Anti-TNF therapy for RA in the setting of HCV appears to be safe and well tolerated without apparent influence on the underlying HCV infection. Therefore, this approach should be further evaluated prospectively for longterm safety.",1
10712,15479865,"Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection","Tumour necrosis factor alpha (TNFalpha) is a pivotal cytokine in host defences with broad ranging effects on the innate and adaptive immune systems. Clinically, TNFalpha inhibitors have demonstrated remarkable efficacy in a wide range of autoimmune and inflammatory disorders but clearly at the cost of heightened susceptibility to a variety of infections in those treated with these agents. Most reports to date have described increased susceptibility to intracellular pathogens in patients with underlying chronic viral infections, but little in the way of adverse event reporting in these patients has occurred. While the reported experience to date is rather limited, TNFalpha inhibitors have displayed a reasonable safety profile in the setting of some chronic viral infections and in certain circumstances have demonstrated adjunctive activity in the treatment of these infections. Given the high prevalence of chronic viral infections in patients who are candidates for anti-TNF therapy and the potential for these agents in the treatment of chronic viral illness, additional studies are urgently needed to assess the risks and benefits of such therapy in these populations.",1
10713,15480385,Long-term follow-up of well-treated nephropathic cystinosis patients,"We report the excellent clinical outcomes of siblings with nephropathic cystinosis treated diligently with cysteamine starting at 20 months and 2 months of age. Now 15 and 8 years old, they have glomerular filtration rates of 78 and 105 mL/min/1.73m 2 , respectively. These cases illustrate the critical importance of early diagnosis and treatment.",1
10714,15485308,Aprepitant: a neurokinin-1 receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting,"Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life, and although the use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, delayed nausea and vomiting remain a significant clinical problem. Aprepitant (Emend), Merck) is the first agent available in the new drug class of neurokinin-1 receptor antagonists. When added to a standard regimen of a 5-HT3 receptor antagonist and dexamethasone in patients receiving highly emetogenic chemotherapy, it improves the complete response rate of acute CINV. Aprepitant also improves the complete response of delayed CINV when used in combination with dexamethasone compared with dexamethasone alone. Based on these studies, new guidelines for the prevention of CINV have been developed for patients receiving highly emetogenic chemotherapy. The use of aprepitant in patients receiving moderately emetogenic chemotherapy will await the review and analysis of recently completed Phase III trials. Aprepitant is a substrate, a moderate inhibitor and an inducer of cytochrome P450 (CYP)3A4 and CYP2C9. Drug interactions should be monitored when aprepitant is coadministered with agents affected by CYP3A4 and CYP2C9 isoenzymes. The safety and efficacy of aprepitant has not been established in pediatric or adolescent patients, and aprepitant has not been evaluated in the treatment of patients with established nausea and vomiting. Future studies may consider the use of aprepitant with current and other new agents in moderately and highly emetogenic chemotherapy, as well in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.",1
10715,15492205,Analysis of risk factors in psoriatic patients with methotrexate-induced increases in transaminase levels,,1
10716,15493119,[Life-threatening adverse effects of pharmacologic antihyperuricemic therapy],"Minor hypersensitivity reactions to allopurinol presenting as skin rash occur in approximately 2% of patients. A more severe, albeit rare, hypersensitivity reaction with fever, eosinophilia, dermatitis, renal failure, vasculitis and hepatic dysfunction carries a mortality of up to 20%. The incidence of this severe reaction can probably be reduced by adjusting the dose of allopurinol in patients with impaired renal function. Azathioprine and mercaptopurine are metabolised by xanthine oxidase, the enzyme that is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by approximately 75%. The uricosuric agent benzbromarone has recently been withdrawn from the market because of several cases of fulminant hepatic failure with subsequent death of the patient or liver transplantation.",1
10717,15494716,Phase I/II study of DHA-paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours,"DHA-paclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHA-paclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHA-paclitaxel 660 mg m(-2) and carboplatin AUC 5 with DHA-paclitaxel 880 mg m(-2). Both drugs were given on day 1 every 21 days. A total of 15 patients were enrolled with a median age of 59 years (range 33-71). All patients had advanced cancer refractory to standard treatment, performance status 0-2 and were without major organ dysfunction. A total of 54 cycles of treatment were delivered. No dose-limiting toxicity (DLT) was seen in the first cohort of three patients. In an expanded second cohort, neutropenia was the main DLT, occurring in the first cycle of treatment in five of 12 patients: three of these patients and one additional patient also experienced dose-limiting grade 3 transient rises in liver transaminases. No alopecia was seen and one patient developed clinically significant neuropathy. One partial response was seen in a patient with advanced adenocarcinoma of the oesophago-gastric junction and 12 patients had stable disease with a median time to progression of 184 days (range 60-506 days). The recommended phase II dose in pretreated patients is Carboplatin AUC 5 and DHA-paclitaxel 660 mg m(-2) given every 21 days. Further studies with Carboplatin AUC 5 and DHA-paclitaxel 880 mg m(-2), given every 28 days, are warranted in chemo-naive patients.",1
10718,15495253,Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions,"""The association between anabolic androgenic steroids and liver tumors was first noted in patients with Fanconi's anemia (FA). The hypotheses which led to this review were as follows: (1) androgen-treated individuals who do not have FA are also at risk of liver tumors; (2) parenteral as well as oral androgens may be responsible for liver tumors; (3) FA patients develop liver tumors after smaller and briefer androgen exposure than non-FA individuals; (4) the risk of hepatic neoplasms may depend on the specific androgen. Medline and Web of Science were searched for all cases of liver tumors associated with androgens. Information from individual cases was entered into a spreadsheet and descriptive statistical analyses were performed. Thirty-six FA cases and 97 non-FA cases with both nonhematologic disorders and acquired aplastic anemia (non-FA AA) were identified. The most common androgens were oxymetholone, methyltestosterone, and danazol. Hepatocellular carcinomas (HCC) were more often associated with oxymetholone and methyltestosterone, while adenomas were associated with danazol. Tumors were reported in six patients who received only parenteral and not oral androgens. FA patients were younger than non-FA patients when androgen use was initiated, and the FA patients developed tumors at younger ages. Non-AA patients were treated with androgens for longer periods of time, compared with FA and non-FA AA patients. All patients on anabolic androgenic steroids are at risk of liver tumors, regardless of underlying diagnosis. The magnitude of the risk cannot be determined from currently available data, because the number of patients receiving androgens is unknown.""",1
10719,15499067,Nephrolithiasis associated with ceftriaxone therapy: a prospective study in 51 children,"BACKGROUND: Ceftriaxone, a third generation cephalosporin, is widely used for treating infection during childhood. The kidneys eliminate approximately 33-67% of this agent, and the remainder is eliminated via the biliary system. Ceftriaxone may bind with calcium ions and form insoluble precipitate leading to biliary pseudolithiasis. The aim of this study was to assess whether ceftriaxone associated nephrolithiasis develops by the same mechanism, and whether this condition is dose related. METHODS: The study involved 51 children with various infections. Of these, 24 were hospitalized with severe infection and received 100 mg/kg/day ceftriaxone divided into two equal intravenous doses. The other 27 patients received a single daily intramuscular injection of 50 mg/kg/day. Serum and urine parameters were evaluated before and after treatment, and abdominal ultrasonographic examinations were also carried out before and after treatment. RESULTS: Serum urea, creatinine, and calcium levels were normal in all patients before and after treatment. Post-treatment ultrasound identified nephrolithiasis in four (7.8%) of the 51 subjects. The stones were all of small size (2 mm). Comparison of the groups with and without nephrolithiasis revealed no significant differences with respect to age, sex distribution, duration of treatment, or dose/route of administration of ceftriaxone. The renal stones disappeared spontaneously in three of the four cases, but were still present in one patient 7 months after ceftriaxone treatment. CONCLUSIONS: Conclusions: The study showed that children taking a 7 day course of normal or high dose ceftriaxone may develop small sized asymptomatic renal stones. The overall incidence of nephrolithiasis in this study was 7.8%.",1
10720,15500411,Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity,"The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.",1
10721,15500418,Risks of testosterone replacement therapy in ageing men,"Testosterone has been available to practitioners for several decades. However, testosterone prescriptions have increased in recent years partly because of the introduction of newer delivery systems that are topical and have good bioavailability. In the US alone, approximately 2 million prescriptions for testosterone were written in 2002. This represents a 30% increase from 2001 and a 170% increase from 1999. There has also been a 500% increase in prescription sales in the past 10 years. The rise in prescriptions may be in part due to the increasing recognition of hypogonadism in ageing males or andropause. Treatment relating to hypogonadism has relieved symptoms and improved the quality of life of many individuals. Epidemiological studies point toward an association with increased morbidity and mortality, with low testosterone states in ageing males. For example, there is a higher prevalence of depression, coronary heart disease, osteoporosis, fracture rates, frailty and even dementia with low testosterone states. Recently, there have been some concerns raised regarding the long-term safety of testosterone replacement therapy (TRT) from the Institute of Medicine. Current evidence suggests no causal relationship between prostate cancer and physiological dosing of testosterone, especially with careful selection and monitoring of patients. Cardiovascular risks have, overall, been neutral, although suggestions have been made that there are positive vasodilatory properties with testosterone. Mild eythrocytosis can be a common side effect of TRT, but thromboembolic events have rarely been reported in the literature. This paper addresses the evidence to date regarding the safety aspects of TRT. The medical-legal implications of TRT for men at this point in time is also discussed.",1
10722,15502722,Two-dose daclizumab induction therapy in 209 liver transplants: a single-center analysis,"""BACKGROUND: Patient and graft survival after liver transplantation are adversely affected by early posttransplant renal dysfunction. Therefore, our immunosuppressive strategies should be as """"renal sparing"""" as possible. This is the largest published series to date using daclizumab induction therapy in a renal-sparing regimen. METHODS: This is a retrospective, nonrandomized study comparing 209 adult liver transplants with daclizumab induction to 115 transplants with no induction. RESULTS: Patient and graft survival were similar, despite higher pretransplant acuity of illness and older age in the induction group. Acute rejection within the first 6 months occurred less commonly in the induction group (25.4% vs. 39.1%, P=0.01), despite significantly delayed initiation and lower doses of a calcineurin inhibitor. Mycophenolate mofetil was used more commonly in induction patients, but the efficacy of daclizumab in preventing rejection was independent of this. Patients with a pretransplant creatinine concentration 1.5 mg/dL or less had less rejection if they received induction. Renal function worsened in noninduction patients but showed sustained improvement throughout follow-up in induction patients with a pretransplant creatinine concentration greater than 1.5 mg/dL. Induction therapy provided better rejection prophylaxis among those requiring temporary calcineurin inhibitor cessation because of renal dysfunction. The incidences of histologic hepatitis C recurrence and cytomegalovirus infection were similar in each group. CONCLUSIONS: Liver recipients with and without pretransplant renal dysfunction have less acute rejection with daclizumab induction therapy. This is not associated with an increased risk of over-immunosuppression. Sustained renal improvement in recipients with pretransplant renal dysfunction is possible with daclizumab induction.""",1
10723,15508106,Environmental factors and risk for hepatocellular carcinoma,"Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important risk factors for the development of hepatocellular carcinoma (HCC) in humans. HBV is the primary cause of HCC in high-risk areas including China and Africa, whereas in developed countries such as the United States, HCV plays a more prominent role and is at least partially responsible for the increase in HCC incidence in this country. Humans are exposed to hepatocarcinogenic aflatoxins through ingestion of moldy foods, a consequence of poor storage of susceptible grains. Highly exposed populations are primarily in sub-Sahara Africa and Asia, where dietary aflatoxins significantly enhance the carcinogenic effects of viral hepatitis. Heavy, long-term alcohol use is a risk factor for HCC, whereas moderate use (1-3 drinks/day) is not. Constituents of cigarette smoke are hepatic carcinogens in animals, and there is mounting evidence that the liver is an organ susceptible to tobacco carcinogenicity. Diabetic patients are at risk for HCC probably as a result of the hepatic injury, fibrosis, and eventual cirrhosis resulting from fatty liver disease. Given the current epidemic of obesity and diabetes in the United States, this risk factor will be increasingly important. Increased risk for HCC is evident in young noncirrhotic users of oral contraceptives in the United States and Europe. In summary, risk factors for HCC are identifiable in most patients and primarily are associated with chronic hepatic injury.",1
10724,15510325,Liver injury induced by the non-steroidal anti-inflammatory drug mefenamic acid,"INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat musculoskeletal disorders, inflammation and to control pain. Virtually all NSAIDs are capable of producing liver injury ranging from mild reversible elevation of liver enzymes to severe hepatic necrosis. METHODS: Mice were dosed intraperitoneally with mefenamic acid either one day at 100mg/kg and 200mg/kg, or 14 days dosing at 50mg/kg/day and 100mg/kg/day. Plasma was taken for alanine aminotransferase activity. Mice were sacrificed at the end of the study. Livers were removed and weighed. Liver samples were taken for histology. results: One-day doses of mefenamic acid revealed dose-dependent hepatocyte degeneration in the liver parenchyma. There were no significant changes in plasma alanine aminotransferase activity. Interestingly, 14-day daily doses induced hepatocellular necrosis, massive degeneration and inflammation. This was accompanied by a significant increase in plasma alanine aminotransferase activity and significant increase in the liver weight in the 100mg/kg/day mefenamic acid-dosed mice. CONCLUSION: Results from this study suggest that mefenamic acid is capable of producing hepatotoxicity and care should be taken when prescribing or using this drug.",1
10725,15511691,"Zonisamide: chemistry, mechanism of action, and pharmacokinetics","Zonisamide is a synthetic 1,2-benzisoxazole-3-methanesulfonamide with anticonvulsant properties. The sulfamoyl group on zonisamide was expected to suppress seizures in a manner similar to another sulfonamide analogue, acetazolamide, through inhibition of carbonic anhydrase. However, this does not appear to be the primary mechanism of action since zonisamide requires much higher doses than acetazolamide to achieve equivalent titration in vivo. Studies with cultured neurons indicate that zonisamide blocks repetitive firing of voltage-sensitive sodium channels and reduces voltage-sensitive T-type calcium currents without affecting L-type calcium currents. Its dual mechanism of action may explain its efficacy in patients resistant to other antiepileptic drugs (AEDs). Zonisamide has a pharmacokinetic profile favorable for clinical use. It is rapidly and completely absorbed and has a long half-life (63-69h in healthy volunteers) which allows twice-daily, or even once-daily, dosing. Zonisamide is not highly bound to plasma proteins. Consequently, it does not affect protein binding of other highly protein-bound AEDs. Furthermore, zonisamide does not induce its own metabolism and does not induce liver enzymes. However, since zonisamide is metabolized by cytochrome P450, liver enzyme-inducing AEDs will increase zonisamide clearance, and dosage adjustments may be necessary when it is used in combination with certain AEDs.",1
10726,15516308,Fatal overdoses associated with quetiapine,"Quetiapine (Seroquel) is an atypical antipsychotic drug belonging to a new chemical class, the benzothiazepine derivatives. We present three cases from the Provincial Toxicology Center of British Columbia, Canada in which suicidal overdose deaths were associated with quetiapine. The blood specimens were initially subjected to a thorough qualitative analysis. Basic drugs were screened for by liquid-liquid extraction followed by gas chromatography-nitrogen-phosphorus (GC-NPD) and gas chromatography-mass spectrometry-electron impact detection utilizing both in-house and commercial search libraries. Acidic and neutral drugs were screened for by liquid-liquid extraction followed by high-performance liquid chromatography-diode-array detection. Volatiles were assayed by gas chromatography-flame-ionization detection. Quetiapine was assayed in biological specimens by basic extraction with n-butyl chloride and derivatized with 50 microL of MTBSTFA and separation by GC-NPD. Linearity was observed up to 2.0 mg/L. Samples with concentrations exceeding the linearity were diluted. These cases were chosen for study because they were all deaths as a result of suicidal ingestion of drugs in which quetiapine was considered a significant factor. The concentrations of quetiapine in these cases are 6-16 times greater than the upper reported therapeutic range (0.1-1.0 mg/L). In case #1, the concentrations of quetiapine found were 7.20 mg/L (19 micromol/L) in blood and 0.93 mg/L (2.4 micromol/L) in vitreous fluid. In case #2, the concentrations of quetiapine found were 16 mg/L in blood (42 micromol/L), 120 mg/kg (310 micromol/kg) in liver, and 1.8 mg/L (4.6 micromol/L) in vitreous fluid. In case #3, the concentrations of quetiapine found in femoral blood was 5.90 mg/L (15 micromol/L). In all cases, drugs in addition to quetiapine were detected, but in cases #1 and #2, the cause of death was considered to be a quetiapine overdose and the other drugs were not considered to be contributory. Case #3 was considered a mixed drug overdose.",1
10727,15518608,"Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors","Three-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are first-line treatments for hypercholesterolemia. Although exceedingly well tolerated, treatment with statins incurs a small risk of myopathy or potentially fatal rhabdomyolysis, particularly when coadministered with medications that increase their systemic exposure. Studies compared the multiple-dose pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with 4 inhibitors of cytochrome P450-3A4 isoenzymes in healthy subjects. Compared with pravastatin alone, coadministration of verapamil, mibefradil, or itraconazole with pravastatin was associated with no significant changes in pravastatin pharmacokinetics. However, concomitant verapamil increased the simvastatin area under the concentration:time curve (AUC) approximately fourfold, the maximum serum concentration (C(max)) fivefold, and the active metabolite simvastatin acid AUC and C(max) approximately four- and threefold, respectively (all comparisons p <0.001). Similar (greater than fourfold) important increases in these parameters and a >60% increase in the serum half-life (p = 0.03) of atorvastatin were observed when coadministered with mibefradil. The half-life of atorvastatin also increased by approximately 60% (p = 0.052) when coadministered with itraconazole, which elicited a 2.4-fold increase in the C(max) of atorvastatin and a 47% increase in the AUC (p <0.001 for C(max) and AUC). Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). Pravastatin has a neutral drug interaction profile relative to cytochrome P450-3A4 inhibitors, but these substrates markedly increase systemic exposure to simvastatin and atorvastatin.",1
10728,15523233,[Imatinib mesylate-induced acute cytolytic hepatitis],,1
10729,15525294,Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer's disease: multicenter trial,"In clinical trials, short-term galantamine treatment produces consistent positive effects on global ratings, cognitive tests, and assessments of activities of daily living and behavior in patients with mild-to-moderate Alzheimer's disease (AD), providing the rationale for longer-term, open-label treatment. In this continuation trial following enrollment in previous 12-month trials, patients received galantamine 24 mg/day for a total of 24 months (total exposure up to 36 months). Primary efficacy measures were the ADAS-cog/11 and DAD. Adverse events (AEs) were coded to WHO preferred terms, including AEs begun in previous trials. Initial improvement in cognitive function was followed by a gradual decline, as measured by increased ADAS-cog/11 scores. At 36 months, ADAS-cog/11 scores increased by a mean (SEM) of 12.4 (0.80) points (P < 0.001) versus a projected 22-point increase for untreated patients. Functional abilities, as measured by the DAD, had decreased significantly at each time point versus baseline (P < 0.001). The most common treatment-emergent AEs were agitation (16.1%), insomnia (12.4%), fall (11.2%), and urinary tract infection (10.2%). AEs were mainly mild to moderate, appropriate for an elderly population, with few judged treatment related. Galantamine 24 mg/day is safe and effective for long-term treatment of mild-to-moderate AD. Potential exists for prolonged benefit with galantamine therapy versus lack of treatment for the long-term.",1
10730,15544745,[Acute hepatitis associated with Camellia thea and Orthosiphon stamineus ingestion],,1
10731,15545689,Acute hepatotoxicity caused by repaglinide,,1
10732,15548156,Oral contraceptives and liver hemangioma: a case-control study,"""OBJECTIVE: To study whether there is an epidemiological association between liver hemangiomas and oral contraception use, as may be suggested by clinical observations of liver hemangioma growth during pregnancy and under estrogen administration. METHODS: A case-control study of 40 women with liver hemangiomas, as diagnosed by imaging studies [ultrasonography (US) or computed tomography (CT) and nuclear scan], and 109 age-matched control with normal studies. The women were interviewed with respect to their menstrual, reproductive and oral contraception use history. RESULTS: The liver hemangioma and control groups did not differ significantly with regard to their menstrual or reproductive history. Ever oral contraception use was reported by 30% of the cases and 27% of controls. The odds ratio (OR) was 1.1 [95% confidence interval (CI) 0.52-2.60] for ever use, 1.64 (95% CI 0.37-7.13) for initiation before the age of 20, and 0.62 (95% CI 0.16-2.42) for use duration of less than 1 year. On the multivariate analysis only the women's age emerged as a predictor for liver hemangiomas (OR 3.1; 95% CI 1.16-8.96). CONCLUSIONS: In this study liver hemangiomas were not associated with menstrual, reproductive and oral contraception use history.""",1
10733,15554758,Adverse effects of St. John's Wort: a systematic review,"""OBJECTIVE: To obtain an overview of the available clinical evidence on safety and tolerability of hypericum extracts, we reviewed (1) dropout rates and adverse effects in double-blind randomized trials comparing hypericum extracts and placebo or synthetic standard antidepressants; (2) dropout rates and adverse effects in large-scale observational studies; and (3) adverse effects reported in published cases and to public drug surveillance agencies. METHOD: Data on dropout rates and adverse effects were extracted from double-blind randomized trials of hypericum monopreparations collected for a Cochrane review (last search July 2003) and from a PubMed search (text word hypericum; search dates 1998-January 2003). Similar data were extracted from uncontrolled observational studies including at least 100 patients identified through a PubMed search (search term hypericum NOT animal, last update May 2003), contacts with manufacturers, and screening of review articles. Case reports and case series on adverse events associated with hypericum products were identified through a MEDLINE search (1966-November 2002; search term: hypericum AND [adverse effects OR interaction]) and a PubMed search (February 2003) and were collected from 5 public drug surveillance agencies (data through May 2001). All database searches were conducted as English and non-English language searches. RESULTS: Data from 35 double-blind randomized trials showed that dropout and adverse effects rates in patients receiving hypericum extracts were similar to placebo, lower than with older antidepressants, and slightly lower than with selective serotonin reuptake inhibitors. Dropout rates due to adverse effects in 17 observational studies including 35,562 patients ranged from 0% to 5.7%; interactions or serious adverse effects were not reported in any study. Published cases and cases reported to drug surveillance agencies suggest that interactions with a variety of drugs (particularly cyclosporine in transplant patients) are the most relevant adverse effects of hypericum extracts. CONCLUSIONS: The available evidence suggests that hypericum extracts are well tolerated and safe if taken under control of a physician who is aware of potentially relevant risks in specific circumstances.""",1
10734,15569226,Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A,"BACKGROUND: Mild, transient alanine aminotransferase (ALT) elevations were seen in Phase I studies of caspofungin and cyclosporin A (CsA). METHODS: We conducted a retrospective chart review at four sites to characterize the hepatic safety in patients receiving > or =1 day of both drugs over a 20-month period. Investigators assessed reasons for discontinuing concomitant therapy and the presence/etiology of any hepatotoxicity. RESULTS: Forty patients receiving concomitant therapy for 1-290 days (median 17.5 days) were identified. Although common, liver enzyme abnormalities were frequently attributed to other comorbidities or medications. ALT and/or aspartate aminotransferase (AST) elevations occurred in 14 patients (35%). Five had AST elevations at least possibly related to caspofungin/CsA, but none were >3.6 times the normal upper limit. No ALT elevations were related to caspofungin/CsA. Two of 4 patients had discontinuation of therapy because of hepatotoxicity possibly related to caspofungin/CsA. No serious adverse events occurred because of caspofungin. CONCLUSIONS: These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin/CsA.",1
10735,15571584,A pilot trial of pentoxifylline in nonalcoholic steatohepatitis,"OBJECTIVES: Tumor necrosis factor alpha (TNF alpha) contributes to liver damage and insulin resistance among patients with nonalcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF alpha production. We therefore conducted a 12-month pilot trial to assess the efficacy and safety of pentoxifylline (1,600 mg/day) among 20 patients with NASH. METHODS: Patients had biopsy-confirmed NASH with other causes of liver disease and secondary causes of NASH excluded. Patients who drank more than 40 gm of ethanol weekly were also excluded. Pentoxifylline (400 mg q.i.d.) was given for 12 months. Liver enzymes and adverse events were monitored every 3 months until completion. RESULTS: The 20 patients had a mean age of 50 +/- 11 yr. Eleven (55%) were female, 14 were obese (body mass index > or =30 kg/m(2)), and 7 (35%) were diabetic. At baseline, median steatosis grade was 2 (range 1-3), median necroinflammatory grade was 1 (1-2), and median fibrosis stage was 2 (0-4). Nine patients withdrew from the study, primarily because of nausea. No serious adverse events occurred. Alanine and aspartate aminotransferase levels were significantly lower at 12 months compared to baseline (84 +/- 64 vs 138 +/- 76, p= 0.002 and 58 +/- 37 vs 102 +/- 62, p= 0.003, respectively). Bilirubin did not change significantly from baseline (0.8 +/- 0.4 vs 0.8 +/- 0.3, p= 0.95), nor did alkaline phosphatase (193 +/- 68 vs 180 +/- 53, p= 0.62) or albumin (4.0 +/- 0.2 vs 4.2 +/- 0.3, p= 0.41). CONCLUSIONS: Aminotransferase levels among patients with NASH improve with administration of pentoxifylline. Strategies to overcome side effects will be needed for future trials.",1
10736,15577409,Effectiveness of generic fixed-dose combinations of highly active antiretroviral therapy for treatment of HIV infection in India,"OBJECTIVE: To assess clinical and immunologic effectiveness and acute toxicity to nevirapine (NVP)-based fixed-dose combinations (FDCs) in antiretroviral-naive HIV-1-infected patients in India. DESIGN: Observational study of patients initiated on NVP-based combination therapy delivered as FDCs. METHODS: Antiretroviral-naive HIV-1-infected patients initiated on FDCs (zidovudine/lamivudine [3TC]/NVP or stavudine/3TC/NVP) were assessed clinically and with CD4 counts periodically. Adverse events to NVP were assessed clinically and by laboratory markers. Frequency and risk factors for development of adverse events and clinical outcomes were determined. RESULTS: Of the 1291 patients started on therapy, 1253 completed a minimum of 3 months of follow-up. Rash and hepatitis were documented in 6.6% (95% confidence interval [CI]: 5.5-8.3) and 3.2% (95% CI: 2.3-4.8) of patients initiating therapy, respectively. There was significant improvement in CD4 counts over 2 years. Fourty-eight patients died, and 186 clinical events were documented in these patients. Tuberculosis was the most common cause of morbidity and mortality. Self-reported adherence was high. CONCLUSION: Fixed-dose formulations of NVP-based combination therapy are safe and produced durable clinical and immunologic benefit.",1
10737,15578352,Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy,"BACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. RESULTS: Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received >or=1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. CONCLUSION: Caspofungin demonstrated usefulness in the salvage treatment of IA.",1
10738,15586905,"Would Sacaca, Croton cajucara Benth (Euphorbiaceae) be an hepatotoxic plant like Germander, Teucrium chamaedrys L. (Labiatae)?","Clinical and experimental studies have consistently incriminated the medicinal plant germander (Teucrium chamaedrys L.) in epidemic and sporadic cases of liver diseases. The sacaca (Croton cajucara Benth), a common plant in Brazilian Amazon region also comes being incriminated in similar clinical cases. Of both plants were isolated diterpenoid compounds with similar chemical structures.",1
10739,15591419,The erythropoietin receptor and its expression in tumor cells and other tissues,"Erythropoietin (EPO) is the primary regulator of erythropoiesis, stimulating growth, preventing apoptosis, and promoting differentiation of red blood cell progenitors. The EPO receptor belongs to the cytokine receptor superfamily. Although the primary role of EPO is the regulation of red blood cell production, EPO and its receptor have been localized to several nonhematopoietic tissues and cells, including the central nervous system (CNS), endothelial cells, solid tumors, the liver, and the uterus. The presence of EPO receptors and the possibility of EPO signaling in these tissues and cells have led to numerous studies of the effects of EPO at these sites. In particular, expression of EPO and the EPO receptor in cancer cells has generated much interest because of concern that administration of recombinant human erythropoietin (rHuEPO) to patients with breast and other cancer cells expressing the EPO receptor may promote tumor growth via the induction of cell proliferation or angiogenesis. However, evidence supporting a growth-promoting effect has been inconclusive. Moreover, several preclinical studies have shown a beneficial effect of EPO on delaying tumor growth. Further, it is conceivable that increased expression of EPO could reduce tumor hypoxia and ameliorate the deleterious effects of hypoxia on tumor growth, metastasis, and treatment resistance. On the other hand, EPO has also been shown to produce an angiogenic effect in vascular endothelial cells in vitro. However, there is no evidence that these effects occur in vivo to promote tumor growth. EPO and EPO receptors are expressed in neural tissue, and they are upregulated there by hypoxia. Animal studies have shown that administration of epoetin alfa (an rHuEPO) reduces tissue injury due to ischemic stroke, blunt trauma, and experimental autoimmune encephalomyelitis. These findings suggest that epoetin alfa may provide a therapeutic benefit in patients with stroke, trauma, epilepsy, and other CNS-related disorders. Clearly, further study of EPO and the EPO receptor in nonhematopoietic tissue is warranted to determine the potential therapeutic usefulness of rHuEPO as well as to determine the signaling pathway responsible for its effect in vivo.",1
10740,15599214,The burden of acute nonfulminant drug-induced hepatitis in a United States tertiary referral center [corrected],"""BACKGROUND/GOALS: There are limited data regarding the frequency and proportionality of drug-induced hepatotoxicity in the United States. We sought to determine the scope of nonfulminant drug-induced hepatitis as seen in a community-based hepatology referral service. STUDY: From a population of 4,039 outpatients referred for evaluation of acute (n = 96) and chronic (n = 3,943) liver disease over a 10-year period, we reviewed the records of those patients diagnosed with acute bona fide drug-induced hepatitis. RESULTS: Thirty-two patients presented with self-limited acute drug-induced hepatitis, representing 0.8% of all hepatology patients and 33% of those patients presenting with acute liver injury. Antibiotics (amoxicillin/clavulanic acid, minocycline, nitrofurantoin, an investigational ketolide antibiotic, trimethoprim-sulfamethoxazole, and trovafloxacin) were the class of drugs most frequently implicated (14 of 32; 44%), while amiodarone was the single agent most commonly associated with liver injury (7 of 32; 22%). The mean age of affected patients was 52.2 years, and we found a male predominance (18 of 32; 56%). The mean time to biochemical resolution after discontinuation of the offending agent was 14.1 weeks. CONCLUSIONS: Drug-induced hepatitis is an uncommon entity in clinical hepatology but does represent a significant proportion of acute self-limited liver disease in the United States. Antibiotics and amiodarone were the most common drug culprits in our population. Time to resolution following the discontinuation of the offending agent may be protracted. Prospective studies are needed to further assess the burden of drug-induced liver injury.""",1
10741,15602119,Valproic acid-associated hyperammonemic encephalopathy: a case report from the psychiatric setting,"Valproic acid-associated hyperammonemic encephalopathy (VHE) has been described in the neurology and emergency medicine literature, but the case reports identified therein are rarely derived from the psychiatric use of this medication. Valproic acid is widely used as a mood stabilizer in bipolar affective disorder and schizoaffective disorder. Patients with normal blood levels, liver function and metabolic tests may present with markedly elevated ammonia and a variety of neurological symptoms. We report the case of a patient on long-term valproic acid therapy, with stable dosing, who presented with an elevated ammonia level, new-onset tremor, confusion, and loss of consciousness. This case illustrates the need to check ammonia levels in psychiatric patients who are taking valproic acid and who present with new neurological symptoms.",1
10742,15604569,Hepatotoxicity induced by antiandrogens: a review of the literature,"INTRODUCTION: Hepatotoxicity is a serious adverse reaction potentially induced by all antiandrogens. We have reviewed here the published cases of hepatotoxicity induced by steroidal and nonsteroidal antiandrogens, and compared the type and characteristics of liver damage. METHODS: Using two different databases: MEDLINE and IDIS (Iowa Drug Information Service), we searched for published cases of liver injury induced by antiandrogens. Analysis was made of the type of hepatotoxicity, therapeutic indication, other pharmacological treatments and evolution. Mean values of latency and recovery periods of the adverse reactions and liver function tests were also evaluated. RESULTS: Hepatitis was the most common type of hepatotoxicity reported, and was associated with all antiandrogens. This adverse reaction does not seem to be dependent on the patients age, therapeutic indication or the dose prescribed. Hepatitis showed a longer latency period for cyproterone acetate than for flutamide. Some transaminase levels were significantly higher for flutamide than for cyproterone acetate, although the evolution was no worse in the cases reported for flutamide. We also found occasional reports of hepatocellular carcinoma and hepatic cirrhosis suspected of being induced by cyproterone acetate. CONCLUSION: Although there are differences in the clinical features of hepatotoxicity induced by steroidal and nonsteroidal antiandrogens, these do not predict which patients will develop hepatotoxicity during treatment or evolution. Serial liver function tests are required for early detection of liver damage.",1
10743,15610717,Gefitinib therapy for non-small cell lung cancer,"Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.",1
10744,15611441,Moxifloxacin-associated drug hypersensitivity syndrome with toxic epidermal necrolysis and fulminant hepatic failure,,1
10745,15614306,[Colestasic toxic hepatitis caused by terbinafine: case report],"Trichophytic onychomycosis of the feet represents an important and serious medical problem. Until recent years, there was not cure for this unpleasant pathology. It is only at the beginning of the 50s, especially at the onset of the antimycotic systemic therapy that a cure is available offering high rate of clinical and mycological therapy. The purpose of this report is to better inform on the undesirable side-effects of antimycotic agents which are currently so largely disseminated. The case of a young patient is presented who was enjoying good health and who after 6 weeks of starting therapy with terbinafine on a doses of 1 pill of 250 mg a day, to treat a trichophytic onychomycosis in both feet, developed severe symptoms of toxic colostatic hepatitis duly corroborated after pertinent testing. Patient had a full recovery after a few months of having interrupted her therapy, apparently without any sequel. The literature in this regard has been revised and a close monitoring of the hepatic function is recommended prior and during treatment with this drug. The need to continue research to find an ideal antimycotic still not found is also recommended.",1
10746,15617171,[Ecstasy-induced toxic hepatitis],"INTRODUCTION: The use of ecstasy (MDMA) has developed in the young since the eighties, particularly in festive settings. Among the severe adverse events induced by this synthetic drug, the hepatotoxicity related to MDMA and to its physiopathological mechanism warrant attention. OBSERVATION: A 21 year-old man consulted for anaemia that had persisted over the past months with abnormality in hepatic profile. The imputability of ecstasy in perturbations in his hepatic profile was highly probable in view of the fact that his transaminase level returned to normal one month after he stopped taking the drug, all the viral markers of hepatitis became negative and in the absence of concomitant consumption of any psycho-active drugs other than cannabis. DISCUSSION: A review of the literature showed the great variability in clinical pictures related to the hepato-toxicity of ecstasy, ranging from acute to lethal, fulminating hepatitis. The physiopathological mechanism of this phenomenon is little known. Various hypotheses are evoked with, among others, immuno-allergic-type hypersensitivity, phenomenon of apoptosis, vitamin E deficiency, and the role of occasionally concomitant malignant hyperthermia. The part played by the metabolites of the synthetic drug has also been suggested as well as individual variations in genetic origin with regards to the risk of developing acute hepatitis after ingestion of ecstasy. The hepato-toxicity of this drug does not appear to be dose-dependant nor related to the cumulated duration of exposure.",1
10747,15618854,Subfulminant liver failure associated with quetiapine,"We report the clinical history of a patient with drug induced liver injury due to quetiapine who ultimately developed subfulminant hepatic failure and died. The clinical presentation, laboratory data, as well as liver histopathology were supportive of the putative diagnosis of drug induced liver injury. To our knowledge, this is the first report of the important association between quetiapine and drug induced liver injury.",1
10748,15621343,Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture,"Recent reports on sporadic cases of liver disorders (acute hepatitis, icterus, hepatocellular necrosis) after ingestion of dietary supplements based on hydro-alcoholic extracts from green tea leaves led to restrictions of the marketing of such products in certain countries of the EU. Since green tea is considered to exert a number of beneficial health effects, and, therefore, green tea products are widely used as dietary supplements, we were interested in the possible mechanism of hepatotoxicity of green tea extracts and in the components involved in such effects. Seven hours after seeding on collagen, rat hepatocytes in primary culture were treated with various hydro-alcoholic green tea extracts (two different native 80% ethanolic dry extracts and an 80% ethanolic dry extract cleared from lipophilic compounds). Cells were washed, and reduction of resazurin, used as a viability parameter monitoring intact mitochondrial function, was determined. It was found that all seven green tea extracts examined enhanced resazurin reduction significantly at a concentration range of 100-500 microg/ml medium, while a significant decrease was observed at 1-3mg/ml medium. Decreased levels were concomitant with abundant necrosis as observed by microscopic inspection of the cultures and with increased leakage of lactate dehydrogenase activity from the cells. In a separate series of experiments, the green tea constituents (-)-epicatechin, (-)-epigallocatechin-3-gallate, caffeine and theanine were tested at concentrations reflecting their levels in a typical green tea extract. Synthetic (+)-epigallocatechin (200 microM) was used for comparison. Cytotoxicity was found with (-)-epigallocatechin-3-gallate only. The concomitant addition of 0.25 mM ascorbate/0.05 mM alpha-tocopherol had no influence on cytotoxicity. In conclusion, our results suggest that high concentrations of green tea extract can exert acute toxicity in rat liver cells. (-)-Epigallocatechin-3-gallate seems to be a key constituent responsible for this effect. The relatively low bioavailability of catechins reported after oral exposure to green tea argues, however, against a causal role of these constituents in the reported liver disorders.",1
10749,15625224,Fatal hepatic failure and valproate,,1
10750,15627041,Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts,"Genetic (human leukocyte antigen), disease-related and demographic risk factors for nevirapine reactions were examined in a nevirapine-exposed cohort. Cases involving combinations of hepatitis, fever or rash were associated with an interaction between HLA-DRB1*0101 and the percentage of CD4, whereas no associations were detected for isolated rash. These data suggest that HLA-DRB1*0101 and the CD4 status may determine susceptibility to nevirapine hypersensitivity, consistent with a CD4 T-cell-dependent immune response to nevirapine-specific antigens.",1
10751,15633581,[Hepatotoxicity of nimesulide],,1
10752,15639300,Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease,"""Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive """"designer"""" theophylline, the archetypal non-selective phosphodiesterase inhibitor.""",1
10753,15644659,Hepatotoxicity during rapid intravenous loading with amiodarone: Description of three cases and review of the literature,"OBJECTIVE: Atrial fibrillation is the most common arrhythmia after cardiac surgery. Amiodarone can effectively prevent and control postoperative atrial and ventricular fibrillation. Acute hepatic damage after intravenous amiodarone, which can be fatal, is not well recognized. We describe three cases of acute hepatocellular injury after intravenous amiodarone administration in critically ill patients. Another 25 published cases and six cases reported to the Swiss Pharmacovigilance Center (Swissmedic) are discussed. DESIGN: This study consisted of a series of three case reports and review of the literature. SETTING: : This study was conducted at an operative critical care unit at the University Hospital Basel, Switzerland. PATIENTS: Three hemodynamically compromised patients after open heart surgery developed significant increases of transaminases (up to more than 100-fold of the upper limit of normal) shortly after the introduction of intravenous amiodarone. INTERVENTIONS AND MEASUREMENT: Cessation of intravenous amiodarone and of other potentially hepatotoxic drugs. RESULTS: Liver parameters significantly improved or returned to normal in all three patients, even after start of oral amiodarone in two patients. CONCLUSIONS: Amiodarone is a highly effective antiarrhythmic agent for the treatment and prevention of atrial and ventricular arrhythmias. Acute liver damage after intravenous amiodarone, possibly induced by the solubilizer polysorbate 80, is rare but potentially harmful. Amiodarone loading should therefore be adapted to the necessity of an immediate effect of the drug, and liver function should be monitored closely in critically ill patients. Oral maintenance therapy with amiodarone is possible, even in patients who developed liver disease during intravenous loading.",1
10754,15647411,"Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease","""Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.""",1
10755,15650005,Pharmacokinetics and hepatotoxicity of lopinavir/ritonavir in non-cirrhotic HIV and hepatitis C virus (HCV) co-infected patients,,1
10756,15655751,Tolerability of postexposure prophylaxis with the combination of zidovudine-lamivudine and lopinavir-ritonavir for HIV infection,"""Tolerability of the combination of zidovudine-lamivudine and lopinavir-ritonavir as postexposure prophylaxis (PEP) for human immunodeficiency virus infection was prospectively assessed. A total of 121 patients were enrolled in the study; 23 patients discontinued PEP prematurely for reasons other than adverse events. Of the other 98 patients, 58 (59%) experienced adverse effects, which led to premature PEP discontinuation in 20 cases (20%).""",1
10757,15657914,Troglitazone and liver injury: in search of answers,,1
10758,15663284,Peliosis hepatis revealed by biliary colic in a patient with oral contraceptive use,"Peliosis hepatis is a rare condition associated with a variety of diseases and drugs. We report a patient who developed peliosis hepatis while taking oral contraceptives. Three months after withdrawal of this oral contraceptive, reduction in size of these lesions was observed.",1
10759,15665326,"Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis","""Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without an effective therapy to date. In a double-blind, randomized, placebo-controlled trial, 107 patients were prospectively evaluated for efficacy of a novel compound, pirfenidone. The difference in the change in the lowest oxygen saturation by pulse oximetry (SpO2) during a 6-minute exercise test, the primary endpoint, from baseline to 6 months was not significant between the two groups (p = 0.0722). In a prespecified subset of patients who maintained a SpO2 greater than 80% during a 6-minute exercise test at baseline, the lowest SpO2 improved during a 6-minute exercise test in the pirfenidone group at 6 and 9 months (p = 0.0069 and 0.0305, respectively). Positive treatment effect was demonstrated in secondary endpoints: (1) change in VC measurements at 9 months (p = 0.0366) and (2) episodes of acute exacerbation of IPF occurring exclusively in the placebo group during the 9 months (p = 0.0031). Significant adverse events were associated with pirfenidone; however, adherence to treatment regimen was similar between pirfenidone and placebo groups. In conclusion, treatment with pirfenidone improved VC and prevented acute exacerbation of IPF during the 9 months of follow-up. Future long-term studies are needed to clarify the overall safety and efficacy of pirfenidone in IPF.""",1
10760,15671137,Clozapine-induced toxic hepatitis with skin rash,,1
10761,15674105,Could irbesartan trigger autoimmune cholestatic hepatitis?,,1
10762,15680290,An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults,"""BACKGROUND AND PURPOSE: This randomized, double-blind, placebo-controlled study assessed the efficacy and safety of eszopiclone, a non-benzodiazepine hypnotic agent, in healthy adults using the first-night effect model of transient insomnia. PATIENTS AND METHODS: A total of 436 healthy, normal sleeping participants were randomized to receive either eszopiclone 1, 2, 3, or 3.5mg, or placebo. Efficacy and next-morning effects were evaluated via polysomnography (PSG), Digit Symbol Substitution Test (DSST), and self-report. RESULTS: Patients treated with eszopiclone had significantly less PSG latency to persistent sleep (all doses except 1mg; P< or =0.0001), wake time after sleep onset (all doses; P< or =0.05) and number of awakenings (3 and 3.5mg doses; P<0.005), and greater sleep efficiency (all doses; P< or =0.02) compared with placebo. Self-reported efficacy results were similar to PSG. Self-reported morning sleepiness scores were significantly better for eszopiclone 3 and 3.5mg compared with placebo (P<0.05). Treatment was well tolerated by patients, and the most common treatment-related adverse event was unpleasant taste. CONCLUSIONS: In this model of transient insomnia, all doses of eszopiclone were more effective than placebo and were well tolerated by patients.""",1
10763,15684251,Severe desflurane hepatotoxicity after colon surgery in an elderly patient,"PURPOSE: To report a case of desflurane hepatotoxicity. CLINICAL FEATURES: An 81-yr-old woman with a remote history of abdominal surgery developed severe acute liver injury after general anesthesia with desflurane for resection of colonic cancer. Serum alanine aminotransferase and aspartate aminotransferase peaked at postoperative day six (2188 and 425 U*L(-1) respectively), with the development of coagulopathy with an international normalized ratio of 2.29 on postoperative day eight, progressive jaundice with a peak serum total bilirubin of 214 mumol*L(-1) on postoperative day 12 and hepatic encephalopathy on postoperative day ten. Other causes for liver disease were excluded. Treatment with corticosteroids was started. The liver biochemistry normalized completely by postoperative day 30 and the patient was discharged from hospital on postoperative day 21. CONCLUSIONS: To our knowledge, this represents only the third report of desflurane hepatotoxicity and the first with reversible fulminant liver failure. Our experience suggests that all fluorinated anesthetics may cause acute hepatic damage.",1
10764,15689582,131I-tositumomab therapy as initial treatment for follicular lymphoma,"BACKGROUND: Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients. METHODS: Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body. RESULTS: Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed. CONCLUSIONS: A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.",1
10765,15701215,Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia,"""OBJECTIVE: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia. RESEARCH DESIGN AND METHODS: Patients (n = 308) were randomized to receive placebo or eszopiclone (2 mg or 3 mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST). RESULTS: Eszopiclone 3 mg had significantly less time to sleep onset (p < or = 0.0001), more total sleep time and sleep efficiency (p < or = 0.0001), better sleep maintenance (p < or = 0.01), and enhanced quality and depth of sleep (p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2 mg had significantly less time to sleep onset (p < or = 0.001), more total sleep time (p < or = 0.01) and sleep efficiency (p < or = 0.001), and enhanced quality and depth of sleep (p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste. CONCLUSIONS: Patients treated with nightly eszopiclone 3 mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.""",1
10766,15701910,Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial,"""CONTEXT: In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use. OBJECTIVE: To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors. INTERVENTIONS: Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. MAIN OUTCOME MEASURES: The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model. RESULTS: During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, -0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, -0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, -14% to -6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred. CONCLUSIONS: The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.""",1
10767,15706460,Fluoxetine versus trimipramine in the treatment of depression in geriatric patients,"INTRODUCTION: Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), and trimipramine, a tricyclic antidepressant (TCA), were compared in terms of efficacy and tolerability in a six-week, parallel group, double-blind pilot study in 41 geriatric patients with major depression (61 - 85 years old). METHOD: The Hamilton Rating Scale for Depression (HAMD-17), the Montgomery-Asberg Rating Scale (MADRS), the Adjective Mood Scale (Bf-S), the Clinical Global Impression (CGI), and the Patients Global Impression (PGI) were used to measure changes in depressive symptoms. RESULTS: Improvement with treatment was found on all scales. Efficacy and tolerability were similar in both groups. No statistically significant differences were found. CONCLUSION: These findings suggest that fluoxetine and trimipramine are comparable in terms of efficacy and tolerability in the treatment of major depression in geriatric patients.",1
10768,15709899,Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy,"Parkinson's disease patients treated with a combination of levodopa and an aromatic L-amino acid decarboxylase inhibitor usually develop motor complications after some years. To minimise this problem, selective catechol-O-methyltransferase (COMT) inhibitors were developed in order to improve the poor pharmacokinetic profile of levodopa. Tolcapone and entacapone are the two marketed drugs in this class, and both increase the half-life of levodopa and improve clinical parameters, such as the increase in the duration of 'on' and decrease of 'off' time. Soon after its release, tolcapone was suspended in the EU due to it's implication in the deaths of three Parkinsonian patients. The cause of death in these patients was fulminant hepatitis. The mechanism by which tolcapone induces liver damage has been studied. Results show that this drug induces uncoupling of oxidative phosphorylation in mitochondria, thus significantly reducing the cell's capacity to generate ATP. This toxic effect was demonstrated both in vitro and in vivo in several models but the concentrations required to induce it are significantly higher than those needed to inhibit COMT. Inter-individual differences in the capacity to metabolise tolcapone may yield higher plasma levels and may explain its toxic effects in a small sample of patients. Recently, the suspension on tolcapone was lifted, based on new clinical data and ongoing monitoring of its use in other countries. The European Agency for the Evaluation of Medicinal Products concluded that, in some situations, tolcapone has a clinical efficacy that is superior to entacapone and that an adequate level of safety could be achieved with appropriate liver function monitoring and other measures. It is concluded that tolcapone can be safely used in Parkinsonian patients who do not respond or cannot, for other reasons, be prescribed with other COMT inhibitors.",1
10769,15710213,Hepatitis C coinfection increases the risk of fulminant hepatic failure in patients with HIV in the HAART era,"BACKGROUND/AIMS: It is uncertain if patients coinfected with hepatitis C and HIV are more likely to suffer fulminant hepatic failure (FHF) when compared to patients with HIV-only. METHODS: We conducted a retrospective cohort study using national administrative databases from the Department of Veterans Affairs in patients hospitalized for the first time with HIV and/or hepatitis C between 10/1991 and 9/2000. Fulminant hepatic failure was defined as occurring after the index hospitalization through 9/2001 in the absence of pre-existing liver disease. We calculated incidence rates, Kaplan Meier cumulative incidence curves, and Cox proportional hazards ratios while adjusting for demographics and other potential confounders. RESULTS: We identified 11,678 patients with HIV-only and 4761 patients with coinfection. There were 92 cases of fulminant hepatic failure yielding an incidence rate of 1.1/1000 person-years and 2.5/1000 person-years in the HIV-only and coinfected groups. The cumulative incidence of fulminant hepatic failure in the coinfected group was higher than in the HIV-only group (P<0.0001). The risk of fulminant hepatic failure in patients with coinfection compared to HIV-only during the HAART era was several folds higher than that during the pre-HAART era. CONCLUSIONS: HAART and hepatitis C coinfection appeared to act synergistically in HIV-infected patients to increase the risk of fulminant hepatic failure, a rare but often fatal disease.",1
10770,15711498,Natalizumab (Tysabri) for relapsing multiple sclerosis,"Natalizumab (Tysabri), a selective adhesion molecule inhibitor, decreases the number of relapses and new brain lesions in patients with MS. Administered IV every 4 weeks, it is usually well tolerated, but anaphylaxis can occur and persistent neutralizing antibodies were reported in 6% of patients. No comparisons to other MS treatments and no data concerning its effect on progression of disability are currently available.",1
10771,15712655,Infliximab therapy for Crohn's disease in a patient with chronic hepatitis B,,1
10772,15715889,Comparison of pioglitazone with other antidiabetic drugs for associated incidence of liver failure: no evidence of increased risk of liver failure with pioglitazone,"AIM: The aim of this study was to assess the incidence of liver failure in association with antidiabetic treatment using pioglitazone vs. other oral antidiabetic medications. METHODS: The study was a retrospective analysis of claim data from the PharMetrics Patient-Centric Database that had over 1.12 million enrollees with type 2 diabetes. All patients, > or =18 years of age with type 2 diabetes, who had initiated treatment either with a thiazolidinedione (pioglitazone and rosiglitazone), sulfonylurea or metformin were identified and matched on the basis of propensity scores, which served as a proxy for severity of disease. The primary measure of interest was the incidence of liver failure or hepatitis post-index date. In addition to unadjusted comparisons, Cox proportional hazard models were employed to estimate the risk of developing liver failure or hepatitis. RESULTS: There was no significant difference in the 1- and 2-year incidence rates of liver failure or hepatitis (primary and secondary diagnoses) between the pioglitazone monotherapy group and the respective comparator groups. In Cox proportional hazard models controlling for age, pre-index total healthcare costs, Charlson comorbidity index, procedures and a hospitalization or Emergency room (ER) visit for pre-index hyperglycaemia, and pioglitazone were not associated with an increased risk of liver failure or hepatitis, compared to all other defined groups. Furthermore, no primary or secondary diagnosis of liver failure was reported in the pioglitazone group during the follow-up period. CONCLUSIONS: Results of retrospective data analysis demonstrate no evidence of increased risk of liver failure or hepatitis for patients initiating therapy on pioglitazone, compared to other oral antidiabetic agents. Pioglitazone therapy was not associated with an increased risk of liver failure at 2 years relative to other oral antidiabetic therapies.",1
10773,15723979,"Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients","""BACKGROUND: Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. METHODS AND RESULTS: The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] > or =95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3+/-0.8, 11.8+/-0.8, and 11.5+/-0.8 mm Hg, respectively, versus 6.3+/-0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4+/-1.3, 15.8+/-1.2, and 15.7+/-1.2 mm Hg, respectively, versus 5.3+/-1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9+/-0.7 and 12.5+/-1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. CONCLUSIONS: Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.""",1
10774,15729487,A side effect of neuraminidase inhibitor in a patient with liver cirrhosis,"Neuraminidase inhibitors have been widely used in Japan since 2001, and several side-effects of their use have been reported. However, erythema toxicum has rarely been described as a side-effect of these drugs in patients with liver function disorder. Here, we report a case of generalized rash after treatment with the neuraminidase inhibitors zanamivir and oseltamivir administered prophylactically to prevent influenza infection in two patients with hepatoma associated with liver cirrhosis.",1
10775,15731621,Metabolic acidosis due to propofol infusion,,1
10776,15735221,Cholestatic hepatitis associated with repaglinide,,1
10777,15738379,Bortezomib-induced severe hepatitis in multiple myeloma: a case report,"Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its toxicity is manageable, and the most frequent adverse effects mainly consist of gastrointestinal symptoms, peripheral neuropathy, neuropatic pain, and thrombocytopenia. Severe liver toxicity has not been previously recognized. A patient with relapsed multiple myeloma who developed bortezomib-induced severe recurrent hepatitis is described. The importance of recognizing this rare potential toxicity is highlighted in order to discontinue this agent if liver adverse reaction is suspected.",1
10778,15738907,[Probable sildenafil (Viagra) induced acute hepatitis in a patient with no other risk factors],,1
10779,15743917,HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol,"""Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) (P < 10(-7)). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value = 4.7 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 10(-18)]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.""",1
10780,15746106,Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial,"""OBJECTIVE: To assess the incidence, cofactors, and excess risk of development of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis, attributable to tamoxifen in women. DESIGN: Prospective, randomised, double blind, placebo controlled trial. SETTING AND PARTICIPANTS: 5408 healthy women who had had hysterectomies, recruited into the Italian tamoxifen chemoprevention trial from 58 centres in Italy. INTERVENTION: Women were randomly assigned to receive tamoxifen (20 mg daily) or placebo for five years. MAIN OUTCOME MEASURE: Development of non-alcoholic fatty liver disease in all women with normal baseline liver function who showed at least two elevations of alanine aminotransferase (> or = 1.5 times upper limit of normal) over a six month period. RESULTS: During follow up, 64 women met the predefined criteria: 12 tested positive for hepatitis C virus, and the remaining 52 were suspected of having developed non-alcoholic fatty liver disease (34 tamoxifen, 18 placebo)--hazard ratio = 2.0 (95% confidence interval 1.1 to 3.5; P = 0.04). In all 52 women ultrasonography confirmed the presence of fatty liver. Other factors associated with the development of non-alcoholic fatty liver disease included overweight (2.4, 1.2 to 4.8), obesity (3.6, 1.7 to 7.6), hypercholesterolaemia (3.4, 1.4 to 7.8), and arterial hypertension (2.0, 1.0 to 3.8). Twenty women had liver biopsies: 15 were diagnosed as having mild to moderate steatohepatitis (12 tamoxifen, 3 placebo), and five had fatty liver alone (1 tamoxifen, 4 placebo). No clinical, biochemical, ultrasonic, or histological signs suggestive of progression to cirrhosis were observed after a median follow up of 8.7 years. CONCLUSIONS: Tamoxifen was associated with higher risk of development of non-alcoholic steatohepatitis only in overweight and obese women with features of metabolic syndrome, but the disease, in both the tamoxifen and the placebo group, after 10 years of follow up seems to be indolent.""",1
10781,15747161,"First NIH/Office of Rare Diseases Conference on Cystinosis: past, present, and future",,1
10782,15751090,"Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout","""OBJECTIVE: Gout affects approximately 1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>or=8.0 mg/dl). METHODS: We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28. RESULTS: Greater proportions of febuxostat-treated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups. CONCLUSION: Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.""",1
10783,15752290,Methotrexate for psoriasis: current European practice. A postal survey,"The aim of this survey was to determine current practice throughout Europe regarding use and monitoring of methotrexate therapy for psoriasis. A structured questionnaire with questions on methotrexate prescribing and monitoring was mailed to 150 dermatologists in 32 European countries in June 2002. Dermatologists' names were chosen at random from the 2001 European Academy of Dermatology and Venereology membership directory. A reply was received from 69 dermatologists of whom 59 prescribed methotrexate regularly. In those patients receiving systemic treatment for psoriasis, methotrexate was the most widely used drug (4.4 patients of every 10) followed by acitretin (3.2) and cyclosporin (1.6). Myelosuppression was the commonest reported fatal side-effect of methotrexate (eight of a total of 10 cases). None of the respondents routinely requested a baseline liver biopsy before starting methotrexate treatment and of every 10 of their patients on long-term methotrexate it was estimated that less than two had had a liver biopsy some time during treatment. Serum measurement of the amino-terminal peptide of type III procollagen (PIIINP) was used routinely to detect liver fibrosis by 12 (20%) of the 59 respondents who regularly prescribed methotrexate. This survey demonstrates that, despite the advent of new therapies, methotrexate retains a central role in the treatment of severe psoriasis in Europe. The responses demonstrated variation in, among others, the methotrexate dose regimen utilized and the use of folate supplementation, confirming the need for randomized controlled studies to address these issues.",1
10784,15753430,Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a,The authors studied the tolerability of subcutaneous interferon beta-1a (IFNbeta-1a) in 51 patients with early-onset multiple sclerosis. The most frequent systemic adverse effects were flu-like symptoms in 65%. Laboratory abnormalities included asymptomatic leukopenia (27%) and elevated hepatic transaminases (35%). Treatment with IFNbeta-1a was safe and well tolerated in the majority of children and adolescents.,1
10785,15754377,Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial,"Ursodeoxycholic acid (UDCA) is a safe medical therapy for primary biliary cirrhosis (PBC), but its effect on liver histology remains uncertain. Budesonide is a glucocorticoid with high receptor activity and high first-pass metabolism in liver. We evaluated the combination of budesonide and UDCA on liver histology and compared this with UDCA alone in a 3-year prospective, randomized, open multicenter study. Patients with PBC (n = 77), at stages I to III, were randomized into 2 treatment arms, A (n = 41): budesonide 6 mg/d and UDCA 15 mg/kg/d and B (n = 36): UDCA 15 mg/kg/d. Liver histology was assessed at the beginning and at the end of the study. Liver function tests and glucose and cortisol values were determined every 4 months. Paired liver biopsy specimens were available from 69 patients (A = 37 and B = 32). Stage improved 22% in group A but deteriorated 20% in group B (P = .009). Fibrosis decreased 25% in group A but increased 70% in group B (P = .0009). S-PIIINP decreased significantly in group A. Inflammation decreased in both groups, 34% in group A (P = .02), but only 10% in group B (P = NS). Serum liver enzymes decreased significantly in both treatment arms. Bilirubin values rose in group B but stayed stable in group A (A/B P = .002). A mild systemic glucocorticoid effect from budesonide was evident after 2 years. In conclusion, budesonide combined with UDCA improved liver histology, whereas the effect of UDCA alone was mainly on laboratory values. Studies with longer follow-up using a combination of budesonide and UDCA are warranted to confirm safety and effects.",1
10786,15755765,Intensive lipid lowering with atorvastatin in patients with stable coronary disease,"""BACKGROUND: Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD). METHODS: A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. RESULTS: The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001). There was no difference between the two treatment groups in overall mortality. CONCLUSIONS: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.""",1
10787,15757455,Ertapenem: review of a new carbapenem,"The carbapenems are beta-lactam-type antibiotics with an exceptionally broad spectrum of activity. Ertapenem is a new carbapenem developed to address the pharmacokinetic shortcomings (short half-life) of imipenem and meropenem. Ertapenem shares similar structural features with meropenem, including its stability to dehydropeptidase-1, allowing it to be administered without a dehydropeptidase-1 inhibitor. Ertapenem, like imipenem and meropenem, demonstrates broad-spectrum antimicrobial activity against many Gram-positive and -negative aerobes and anaerobes and is resistant to nearly all beta-lactamases, including extended-spectrum beta-lactamases and AmpCs. However, it differs from both imipenem and meropenem in demonstrating limited activity against Enterococcusspp., Pseudomonasaeruginosa and other nonfermentative Gram-negative bacteria commonly associated with nosocomial infections. The extensive protein binding of ertapenem extends the half-life and allows for once-daily dosing. Prospective, multicenter, randomized, double-blind, comparative clinical studies demonstrate similar clinical efficacy of ertapenem compared with other agents. Clinical trials of complicated intra-abdominal infection, acute pelvic infection, complicated skin and soft-structure infection, community-acquired pneumonia and complicated urinary tract infections demonstrated that ertapenem has equivalent efficacy and safety compared with ceftriaxone and piperacillin/tazobactam. Ertapenem is a promising new carbapenem with excellent efficacy and safety for the treatment of a variety of community-acquired infections. It also appears to be of great value as an outpatient parenteral antimicrobial therapy.",1
10788,15759960,Acute liver failure due to iron overdose in an adult,"The vast majority of acute iron toxicity cases occur in children less than 5 years of age. Moreover, clinical hepatic injury is uncommon with most symptoms stemming from the intestinal tract (eg, nausea, vomiting, diarrhea). Therefore, physicians, particularly those who do not routinely treat pediatric patients, are often unfamiliar with hepatotoxicity related to iron overdose. Nevertheless, hepatotoxicity caused by acute iron poisoning is associated with a high mortality rate. We report a case of severe hepatic injury in an adult who overdosed on iron tablets with suicidal intent. Tests for other hepatotoxins (eg, acetaminophen), hepatatrophic viruses, and other causes of acute liver injury were negative. Although peak serum iron level (340 microg/dL) was significantly lower than that reported to cause hepatotoxicity (>1,700 microg/dL), rapid and significant elevations in aminotransferases (>4,000 U/L), total bilirubin (5 mg/dL), and prothrombin time (50 seconds) occurred within 48 hours. Treatment with deferoxamine was prompt and followed by empiric N-acetylcysteine once liver injury was apparent. The patient was minimally symptomatic and she eventually had a full recovery.",1
10789,15763603,Tigecycline: an investigational glycylcycline antimicrobial with activity against resistant gram-positive organisms,"""BACKGROUND: Bacterial resistance to currently available antimicrobials is an increasing concern, particularly among various gram-positive organisms such as drug-resistant pneumococci, methicillin-resistant staphylococci, and drug-resistant enterococci. Tigecycline is an investigational glycylcycline antibiotic that shows promising activity against these resistant gram-positive organisms. OBJECTIVE: : This paper reviews the pharmacology, pharmacokinetic and pharmacodynamic properties, in vitro and in vivo activity, safety profile, and potential role of tigecycline in the management of gram-positive infections involving resistant microbes. METHODS: Articles included in this review were identified through a search of MEDLINE from 1998 through 2004 using the terms tigecycline and GAR-936. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy from 1998 to 2003 were searched using the same terms. The reference lists of identified articles were also reviewed for pertinent publications. RESULTS: Whereas resistance has developed with many of the earlier tetracycline derivatives, tigecycline appears to have a reduced potential for resistance. Several reports have evaluated the in vitro activity of this agent against a number of organisms. It has exhibited pronounced activity against most gram-positive microbes, including resistant strains (eg, drug-resistant pneumococci, methicillin-resistant staphylococci, resistant enterococci). Tigecycline has also shown useful activity against many clinically important gram-negative microbes. In vivo studies of tigecycline are limited. Only 2 clinical trials have been reported to date, one in patients with complicated skin and skin-structure infections and the other in patients with complicated intra-abdominal infections. In these studies, tigecycline therapy resulted in clinical cures in more than two thirds of evaluable patients. Tigecycline was well tolerated in both studies; nausea and vomiting were the most common adverse events. CONCLUSIONS: Although published clinical trials involving tigecycline are limited and additional trials are needed, preliminary reports on its use in the treatment of gram-positive infections are encouraging. Tigecycline has favorable pharmacokinetic properties and, apart from gastrointestinal adverse events, appears to be well tolerated.""",1
10790,15764207,Linezolid use associated with lactic acidosis,Linezolid is a new synthetic antibiotic with a broad spectrum of activity against virtually all important Gram-positive infections. Lactic acidosis is a well known side-effect of metformin and nucleoside reverse-transcriptase inhibitors. We report a case in which lactic acidosis developed as an adverse effect of linezolid treatment.,1
10791,15766996,"Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial","""BACKGROUND: Rasagiline mesylate is a novel drug for Parkinson's disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson's disease and motor fluctuations. METHODS: In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson's disease rating scale (UPDRS) scores. Analysis was by intention to treat. FINDINGS: 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001). Frequency of adverse events was similar for all treatments. INTERPRETATION: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.""",1
10792,15767636,Two patients with acute liver injury associated with use of the herbal weight-loss supplement hydroxycut,,1
10793,15771859,[Autoimmune hepatitis after risperidone-induced cholestatic hepatitis],,1
10794,15773037,Rifampin plus pyrazinamide-induced hepatitis requiring hospitalization in a 30-y-old male with latent tuberculosis,The case of a 30-y-old male with latent tuberculosis who developed chemical hepatitis requiring hospitalization after 50 d of treatment with rifampin and pyrazinamide is reported. This case justifies the CDC guidelines that were updated on 31 August 2003 advising against the use of this brief regimen for patients with latent tuberculosis due to its risk for hepatotoxicity.,1
10795,15777222,Medicinal properties of neem leaves: a review,"Azadirachta indica, commonly known as neem, has attracted worldwide prominence in recent years, owing to its wide range of medicinal properties. Neem has been extensively used in Ayurveda, Unani and Homoeopathic medicine and has become a cynosure of modern medicine. Neem elaborates a vast array of biologically active compounds that are chemically diverse and structurally complex. More than 140 compounds have been isolated from different parts of neem. All parts of the neem tree- leaves, flowers, seeds, fruits, roots and bark have been used traditionally for the treatment of inflammation, infections, fever, skin diseases and dental disorders. The medicinal utilities have been described especially for neem leaf. Neem leaf and its constituents have been demonstrated to exhibit immunomodulatory, anti-inflammatory, antihyperglycaemic, antiulcer, antimalarial, antifungal, antibacterial, antiviral, antioxidant, antimutagenic and anticarcinogenic properties. This review summarises the wide range of pharmacological activities of neem leaf.",1
10796,15780424,Chronic hepatotoxicity after long-term antiretroviral treatment including nevirapine,,1
10797,15783243,Hepatic findings in long-term clinical trials of ximelagatran,"OBJECTIVE: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. PATIENTS AND METHODS: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). RESULTS: An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. CONCLUSION: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.",1
10798,15786619,[DRESS syndrome to allopurinol: a case in Dakar],"We report a case of DRESS syndrome also called drug hypersensitivity reaction occurring a 47 years old Senegalese man who has been taking allopurinol for 3 months. That drug was prescribed for peripheric arthralgias associated to a hyperuricemia. He presented a generalised pruritus, cutaneous lesions, fever and facial oedema. On the biological examens, hyperleucocytosis with hypereosinophilia and hyperlymphocytosis associated to the presence of segmented basophiles. In addition, a hepatic cytolysis and cholestasis were documented. Liver ultrasound was normal. The hemocults were negative. These following serologies have been performed and were negative: hepatitis B and C, Epstein Barr-virus, cytomegalovirus, syphilis, toxoplasma and parvovirus B19. The anti-nuclear and anti-DNA antibodies were negative. A favourable clinical evolution was remarked after allopurinol treatment withdrawal. A desquamation occurred after 6 days and hemogram turned out to the normal as well as the hepatic tests after 2 weeks. The virologic examens performed 2 months later were unremarkable. This case point out the importance of the early diagnosis and quick withdrawal of the drug in order to prevent serious forms leading to the 10% of death.",1
10799,15787813,Monitoring patients on methotrexate: hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen,"BACKGROUND: The aminoterminal peptide of type III procollagen (PIIINP) is formed during the synthesis of type III collagen and can be measured in the serum. It has been used as a marker for hepatic fibrosis in patients on long-term methotrexate and it has been suggested that serial assay of PIIINP could reduce or eliminate the need for liver biopsies in these patients. OBJECTIVES: To determine whether routine use of the PIIINP assay in a cohort of patients on methotrexate would reliably identify those who were developing hepatic fibrosis and exclude those who were not, thereby reducing or eliminating the need for liver biopsies in this latter group. METHODS: Data were available from a clinical series of 38 patients on methotrexate, who had undergone a total of 70 liver biopsies and 306 PIIINP assays. Liver biopsies were graded using the Roenigk classification. RESULTS: In 34 patients, the findings on 46 liver biopsies could be compared with the results of contemporaneous PIIINP assays. Apart from two biopsies from two patients where fibrosis was no longer detected on a subsequent biopsy, all four biopsies showing fibrosis had abnormal results on over half of the associated PIIINP assays. There were no biopsies showing fibrosis where all associated PIIINP assays were normal. However, 50% of biopsies without fibrosis had at least one abnormal associated assay. In 23 patients, the results of serial PIIINP assays performed between two sequential liver biopsies were correlated with changes in the biopsy in terms of fibrosis. Data were available for 32 pairs of liver biopsies. Apart from a biopsy pair in one patient where fibrosis on the second biopsy was not detected on a third biopsy, all four biopsy pairs defined as showing deterioration had abnormal results on over half of the intervening PIIINP assays. There were no biopsy pairs showing deterioration where all intervening assay results were normal. However, 63% of stable biopsy pairs had at least one abnormal intervening assay. Two patients with nonalcoholic steatohepatitis, which manifests a pattern of fibrosis not scored under the Roenigk classification, had persistently and substantially elevated PIIINP levels. CONCLUSIONS: The data presented support the view that follow-up liver biopsies, as recommended by published guidelines, for patients on long-term low-dose methotrexate can be avoided if PIIINP levels are consistently normal. This approach would have reduced the number of patients requiring biopsy in our series by 45%. The PIIINP assay will also be helpful in the management of patients on methotrexate in whom liver biopsy is contraindicated, and in patients with nonalcoholic steatohepatitis.",1
10800,15791519,Nitazoxanide: a new thiazolide antiparasitic agent,"Nitazoxanide is a new thiazolide antiparasitic agent that shows excellent in vitro activity against a wide variety of protozoa and helminths. It is given by the oral route with good bioavailability and is well tolerated, with primarily mild gastrointestinal side effects. At present, there are no documented drug-drug interactions. Nitazoxanide has been licensed for the treatment of Giardia intestinalis-induced diarrhea in patients >or=1 year of age and Cryptosporidum-induced diarrhea in children aged 1-11 years. At present, it is pending licensure for treatment of infection due to Cryptosporidium species in adults and for use in treating immunocompromised hosts. It represents an important addition to the antiparasitic arsenal.",1
10801,15792824,Thiopurine methyltransferase (TPMT) heterozygosity and enzyme activity as predictive tests for the development of azathioprine-related adverse events,"""Thiopurine methyltransferase (TPMT) is a key enzyme in azathioprine metabolism mediating both immunosuppression and cytotoxicity. TPMT activity may be influenced by a mutation in the TPMT gene resulting in individual differences in azathioprine metabolism. Individuals heterozygous for TPMT mutations or with low TPMT activity may be susceptible to azathioprine toxicity. We evaluate TPMT genotyping and TPMT enzyme activity as predictive tests for developing azathioprine-related adverse events. Neurological patients (n=129) observed whilst taking azathioprine therapy were genotyped for the TPMT*2, *3A and *3C mutations; TPMT enzyme activity was analysed in 92 of these patients. Ethnic appropriate controls (Black, Mixed-Ancestry and White) were genotyped (n=465) and of these controls TPMT activity was also measured in 115. Azathioprine-related adverse events developed in 21.7% of the patients; early (within 1 week) events included gastrointestinal symptoms (n=8/28). Haematological toxicity, hepatotoxicity, arthralgia, rashes and pancreatitis developing between 4 and 240 weeks. Genotyping showed that only four of 28 cases who developed adverse events, were heterozygous for TPMT*3A or *3C. Heterozygous patients developed either haematological or hepatic toxicity. In an ethnically heterogeneous society TPMT enzyme activity proved difficult to interpret as measurements amongst controls showed significant ethnic variation (p=1 x 10(-6)); cut-points between """"low"""" and """"normal"""" TPMT activity correlated with indigenous African genetic ancestry. Ethnic appropriate cut-points were determined but due to the ambiguity in interpreting TPMT enzyme results in heterogeneous societies, we favour genotyping as a predictive test. The positive predictive value of genotyping was low, but the likelihood ratio for developing either haematological or hepatotoxicity by identifying TPMT heterozygosity, was 9.75. In our patient population this translates into an improvement from a pre-test probability of developing haematological or hepatotoxicity of 11%, to a post-test level of 50%. Heterozygous patients may then be targeted for a more """"tailored"""" increase in dosing and regular laboratory monitoring.""",1
10802,15799034,Mechanisms of benzarone and benzbromarone-induced hepatic toxicity,"""Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 micromol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 micromol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [micromol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial beta-oxidation was decreased by 71%, 87%, and 58% with 100 micromol/L amiodarone or benzarone and 50 micromol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and beta-oxidation only at 100 micromol/L. In the presence of 100 micromol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.""",1
10803,15802212,The life-threatening complications of dermatologic therapies,"""Dermatologists use a variety of systemic drugs, some of which can cause severe adverse reactions and even fatalities. Ivermectin, a well-tolerated drug, can cause severe neurological side effects, whereas metronidazole, in high cumulative doses, has been associated with convulsions and rarely with hepatotoxicity. Dapsone is associated with frequent hematologic side effects, such as methemoglobinemia, hemolysis, and anemia. Although hepatotoxicity is rare and usually mild and reversible with the new antifungal agents, severe cutaneous reactions (such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylaxis) have been reported. Even a relatively safe drug such as acyclovir has been reported to be the cause of renal failure and neurotoxicity. Retinoids can cause not so benign """"benign"""" intracranial hypertension. Methotrexate can cause not only liver toxicity, but also myelosuppression and pancytopenia, which may be acute and life threatening. Nephrotoxicity is a well-recognized side effect of cyclosporine, whereas thrombotic thrombocytopenic purpura, which is associated with high morbidity and mortality, is less well known. Dermatologists should be familiar with these and other severe adverse reactions of the most popular and most used systemic medications of our trade.""",1
10804,15802977,Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus,"""OBJECTIVE: To ascertain the prevalence and severity of hepatic steatosis among patients coinfected with HIV and hepatitis C virus (HCV) who had been taking antiretroviral therapy (ART); to investigate if steatosis is associated with more advanced liver disease, and to identify factors that might contribute to the process. METHODS: Steatosis was assessed among a randomly selected subset of HIV-HCV-coinfected patients who had received at least 2 years of ART in a cohort study at the Johns Hopkins University HIV clinic. Liver histology was evaluated by a single pathologist. The primary outcome measure was the hepatic steatosis grade, which was classified on a 5 point scale: 0, none; 1, steatosis involving < 5% of hepatocytes; 2, 5-29%; 3, 30-60%; 4 > 60%. RESULTS: Liver histology was assessed in 112 patients, 74% of whom were taking ART at the time of biopsy. The median cumulative exposure to nucleoside reverse transcriptase inhibitors and protease inhibitors was 5.8 and 3.7 years, respectively. No steatosis was detected in 60%; grades 2-4 steatosis was recognized in 18%. In multivariate analysis, steatosis was independently associated with Caucasian race, weight > 86 kg, hyperglycemia, and stavudine use. Patients with steatosis also were more likely to have greater hepatic fibrosis (P = 0.02) and necroinflammatory activity (P = 0.005). CONCLUSIONS: Steatosis was observed in 40% of HIV-HCV-coinfected patients with extensive ART exposure and was associated with more severe HCV-related liver disease. Metabolic abnormalities (excess weight and hyperglycemia) and stavudine use were modifiable risk factors for steatosis in this population.""",1
10805,15805066,Do preclinical testing strategies help predict human hepatotoxic potentials?,"""Overt hepatotoxicity due to drug administration is a real and present issue in drug development and regulatory circles. Preclinical drug development is intended to identify potential risks and target tissues prior to introduction of new molecular entities into the human population. The standard regimen is testing at various multiples of the intended human therapeutic dose in at least 2 species of animals, one rodent (rats or mice), one non-rodent (dogs,nonhuman primates, minipigs, and rabbits, as examples) for at least two weeks of repeated dosing. Experience has shown that this regimen """"works""""most of the time. However, preclinical models are not infallible and are not always predictive. Whether the lack of predictivity is due to individual human genetic sensitivities, immunologically mediated phenomena, disease mediation or idiosyncratic reactions, the animal models are limited in detecting these characteristics and other low incidence phenomena. While it is uncommon for drug developers to continue development with products that elicit overt hepatic toxicity early in the animal testing, some products have made it through the approval process and then shown significant adverse effects. Some of the drugs (acetaminophen, isoniazid, trovafloxacin, troglitazone, bromfenac, clarithromycin, telithromycin) that have shown this propensity will be discussed in detail from early preclinical development to marketing and, in some instances, to limitations to usage or removal from the U.S. marketplace.""",1
10806,15810638,Fulminant liver failure associated with the use of black cohosh,,1
10807,15811480,"Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study","""BACKGROUND: Ezetimibe (EZE) is a cholesterol-lowering drug that inhibits absorption of dietary and biliary cholesterol across the intestinal wall without affecting absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. It has a complementary mechanism of action to the statins, which inhibit cholesterol synthesis in the liver. Coadministration of EZE and statins provides inhibition of 2 sources of cholesterol, leading to greater reductions in low-density lipoprotein cholesterol (LDL-C) than with either agent alone. OBJECTIVES: This study evaluated the long-term safety and tolerability profiles and lipid-modifying efficacy of treatment with EZE 10 mg/d plus simvastatin (SIMVA) 10, 20, 40, or 80 mg/d for 48 weeks in patients with primary hypercholesterolemia. METHODS: This was an extension of a multicenter, double-blind, placebo (PBO)-controlled base study in which hypercholesterolemic patients were randomized to receive EZE 10 mg/d or PBO in addition to their current statin for 8 weeks. Patients who successfully completed the base study could enter the extension study if they were willing to switch from their current statin to an approximately equipotent dose of SIMVA for the 54-week study period. After a 6-week open-label SIMVA run-in phase, patients were rerandomized to receive EZE 10 mg/d or PBO in a 4:1 ratio, respectively, for 48 weeks. At each clinic visit, beginning at week 12, the dose of SIMVA was titrated upward until patients reached their National Cholesterol Education Program Adult Treatment Panel II LDL-C goal or the maximum SIMVA dose of 80 mg/d. Safety/tolerability and lipid efficacy parameters were assessed at 12-week intervals. RESULTS: Of 433 patients entering the extension study, 355 were randomized to receive EZE and 78 were randomized to receive PBO. Baseline demographic characteristics and lipid levels were similar between treatment groups. Overall, coadministration of EZE + SIMVA was well tolerated. There were no clinically meaningful differences between the EZE and PBO groups with regard to the incidence of treatment-related adverse events (AEs) (19% vs 17%, respectively), discontinuations due to AEs (7% vs 10%), serious AEs (12% vs 17%), consecutive elevations in liver function tests > or =3 times the upper limit of normal (ULN) (0.3% vs 0%), or elevations in creatine kinase > or =10 times the ULN (both, 0%). As in the base study, LDL-C levels were significantly lower with the addition of EZE to SIMVA compared with the addition of PBO (-24% vs 3%; P < 0.001). CONCLUSION: In these patients with primary hypercholesterolemia, EZE 10 mg/d added to ongoing SIMVA treatment for 48 weeks had a favorable safety and tolerability profile and was more efficacious than SIMVA monotherapy.""",1
10808,15817846,Vitamins E and C are safe across a broad range of intakes,"A robust database shows that dietary supplements of vitamins E and C are safe for the general population. Because these nutrients supply antioxidant and other functions for homeostasis and protection against free radical damage, supplementation has been intensively studied. Because of perceived benefits, many persons consume quantities of vitamins E and C well above the recommended dietary allowances. As safety guidance, tolerable upper intake levels have been established by the Food and Nutrition Board, Institute of Medicine, at 1000 mg for vitamin E and 2000 mg for vitamin C in adults. Many clinical trials with these vitamins have involved subjects with various diseases, and no consistent pattern of adverse effects has occurred at any intake. Numerous studies of vitamin C supplementation have provided no pattern of evidence to support concerns about safety other than occasional gastrointestinal upset or mild diarrhea resulting from the osmotic effects of unabsorbed quantities of vitamin C. Evidence of bleeding effects and other potential adverse effects of high vitamin E intakes in humans is not convincing. Evidence of adverse effects of vitamin C that result from its effects on iron absorption and metabolism has not been confirmed in clinical trials. Thus, we conclude from clinical trial evidence that vitamin E supplements appear safe for most adults in amounts </=1600 IU (1073 mg RRR-alpha-tocopherol or the molar equivalent of its esters) and that vitamin C supplements of </=2000 mg/d are safe for most adults.",1
10809,15821208,Adverse events and treatment completion for latent tuberculosis in jail inmates and homeless persons,"""BACKGROUND: Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI). STUDY OBJECTIVES: To determine the acceptability, tolerability, and completion of treatment. DESIGN: Observational cohort study. SETTING: Five county jails and TB outreach clinics for homeless populations in three cities. PATIENTS: Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons). INTERVENTIONS: Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI. MEASUREMENTS: Types and frequency of drug-related adverse events and outcomes of treatment. RESULTS: Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%). CONCLUSIONS: This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority.""",1
10810,15823761,Anakinra: review of recombinant human interleukin-I receptor antagonist in the treatment of rheumatoid arthritis,"BACKGROUND: Interleukin-1 (IL-1) plays an important role in the pathophysiology and progression of rheumatoid arthritis (RA) by contributing to destruction of cartilage, bone, and periarticular tissues. Inhibiting IL-1 synthesis or activity with the use of recombinant human IL-1 receptor antagonist (anakinra) may prove to be an effective approach to the treatment of RA. OBJECTIVE: The purpose of this article is to review the effects of anakinra in the treatment of RA. METHODS: A MEDLINE search from 1982 to 2003 was used to identify animal studies and randomized clinical trials of anakinra and other therapies that target IL-1. RESULTS: Clinical trials of anakinra have shown that it reduces the signs and symptoms of active disease and slows the rate of radiographic destruction in adults with RA. With anakinra 150 mg/d, 43% of patients achieved an American College of Rheumatology (ACR) 20% response, compared with 27% with placebo (P = 0.014). The ACR20 score indicates at least 20% improvement in the ACR composite score, which includes assessment of tender and swollen joint count, and other clinical end points such as pain and disability assessment. Patients treated with anakinra also experienced a 59% reduction in new bony erosion compared with controls (P < 0.001) and a 65% reduction in joint space narrowing as measured by the modified Sharp score (P = 0.020). Injection-site reactions were the most commonly reported adverse event, occurring in 50%, 73%, and 81% of patients receiving anakinra 30, 75, and 150 mg/d, respectively, compared with 25% of patients receiving placebo. Few serious adverse events were reported, and they typically occurred in patients receiving the highest daily dosage. CONCLUSIONS: IL-1 is an important cytokine in promoting the damage associated with RA. Anakinra is mildly to moderately effective and well tolerated in patients with active RA when used as monotherapy or in combination with methotrexate.",1
10811,15825012,Cytomegalovirus hepatitis associated with use of anti-tumor necrosis factor-alpha antibody,,1
10812,15827451,Ma huang associated acute liver failure requiring liver transplantation,"An ever increasing number of herbal remedies are recognized as potentially hepatotoxic. We report a case of fulminant hepatic failure requiring liver transplantation associated with the use of Ma huang, a traditional Chinese remedy containing ephedrine-type alkaloids. The literature surrounding the potential liver toxicities of Ma huang is reviewed and the proposed pathogenetic mechanisms are critically examined.",1
10813,15828118,Drug-induced hepatitis with saquinavir/ritonavir + rifampin,,1
10814,15834064,Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment for severe spondyloarthropathy,,1
10815,15839319,Amiodarone toxicity and surveillance,,1
10816,15841003,Lactic acidosis following short-term propofol infusion may be an early warning of propofol infusion syndrome,,1
10817,15846537,Ceftriaxone-induced symptomatic pseudolithiasis mimicking ICP elevation,"""In neurosurgery, ceftriaxone is a widely used, third generation cephalosporin for the treatment of CNS infections and perioperational prophylaxis. Recent studies have demonstrated that ceftriaxone induces reversible precipitates in the gallbladder. This complication is referred to as """"biliary pseudolithiasis"""", and it has symptoms similar to the raised intracranial pressure (ICP) symptoms of the perioperative period. Symptomatic biliary pseudolithiasis should be kept in mind in all pediatric neurosurgery cases under ceftriaxone therapy in order to prevent unnecessary postoperative investigations and surgery.""",1
10818,15849435,Efficacy of colestimide coadministered with atorvastatin in japanese patients with heterozygous familial hypercholesterolemia (FH),"BACKGROUND: Colestimide, a 2-methylimidazole-epichlorohydrin polymer, is a new bile-acid-sequestering resin, that is 4-fold as powerful at lowering low-density lipoprotein cholesterol (LDL-C) as the conventional resin (cholestyramine). Moreover, colestimide has excellent patient compliance because it is available in tablet form. METHODS AND RESULTS: The clinical efficacy of colestimide coadministered with atorvastatin on lipid and apolipoprotein concentrations was examined in 15 patients (M/F=10/5, mean+/-SE age=54+/-9 years) with heterozygous familial hypercholesterolemia (FH). After a period of wash-out of any lipid-lowering drugs, atorvastatin (20-40 mg) was administered to patients for at least 8 weeks, and then 3 g of colestimide was administered for a further 8 weeks. Total and LDL-C significantly (<0.0001) decreased by 35% from 361 to 233 mg/dl and 41% from 274 to 161 mg/dl, respectively. Addition of colestimide caused a further significant 12% and 20% reduction, respectively, from the initial values to 205 and 129 mg/dl, respectively. Colestimide was also effective in reducing serum LDL-C concentrations in heterozygous FH patients with hypertriglyceridemia (triglycerides>or=150 mg/dl). CONCLUSIONS: When monotherapy with atorvastatin is insufficient to treat severely hypercholesterolemic patients, such as those with heterozygous FH, colestimide acts to reinforce the action of statins.",1
10819,15855748,"Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential","Rifaximin (4-deoxy-4'-methylpyrido[1',2'-1,2]imidazo- [5,4-c]-rifamycin SV) is a synthetic antibiotic designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a nonsystemic antibiotic with a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually nonabsorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents, therefore, the primary therapeutic target and GI infections the main indication. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, inflammatory bowel disease and colonic diverticular disease. Potential indications include the irritable bowel syndrome and chronic constipation, Clostridium difficile infection and bowel preparation before colorectal surgery. Because of its antibacterial activity against the microorganism and the lack of strains with primary resistance, some preliminary studies have explored the rifaximin potential for Helicobacter pylori eradication. Oral administration of this drug, by getting rid of enteric bacteria, could also be employed to achieve selective bowel decontamination in acute pancreatitis, liver cirrhosis (thus preventing spontaneous bacterial peritonitis) and nonsteroidal anti-inflammatory drug (NSAID) use (lessening in that way NSAID enteropathy). This antibiotic has, therefore, little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children. Although rifaximin has stood the test of time, it still attracts the attention of both basic scientists and clinicians. As a matter of fact, with the advancement of the knowledge on microbial-gut interactions in health and disease novel indications and new drug regimens are being explored. Besides widening the clinical use, the research on rifaximin is also focused on the synthesis of new derivatives and on the development of original formulations designed to expand the spectrum of its clinical use.",1
10820,15857541,Ceftriaxone-induced hemolytic anemia and hepatitis in an adolescent with hemoglobin SC disease,"OBJECTIVES: To describe a case of a ceftriaxone-induced hemolytic anemia and hepatitis leading to multiple organ failure and death in an adolescent with hemoglobin SC disease and to review the previous cases of this rare and potentially fatal disorder in children. DESIGN: Case report and literature review. SETTING: Intensive care unit. PATIENT: Adolescent with hemoglobin SC. INTERVENTIONS: Emergency treatment. MEASUREMENTS AND MAIN RESULTS: After 4 days of ceftriaxone therapy, the adolescent experienced an acute hemolytic reaction (hemoglobin decreased to 5 g/dL with hemoglobinuria) and severe hepatitis (all enzymes increasing dramatically including aminoaspartate transferase >20,000 IU/L). Renal failure and ultimately multiple organ failure ensued, and the patient died on hospital day 19. Direct antiglobulin tests on red cells obtained from the patient on hospital day 2 showed microscopic agglutination with polyspecific and anticomplement (C3) antiglobulin reagents. Plasma samples showed macroscopic agglutination reactions when incubated in the presence of ceftriaxone, many days after cessation of ceftriaxone, indicating the continued presence of ceftriaxone-dependent antibodies. CONCLUSIONS: Drug reactions leading to hemolysis are relatively uncommon, and a total of ten cases of ceftriaxone-induced hemolytic anemia have been reported in children. The present case describes an adolescent who ultimately died on hospital day 19 from multiple organ failure, although the presentation of this case seems atypical in several respects. Children with clinical syndromes that place them at risk for hemolysis and children who frequently require broad spectrum antibiotics present unique diagnostic challenges, and the possibility that hemolytic syndromes may be due to ceftriaxone must be considered.",1
10821,15863816,Anticonvulsant hypersensitivity syndrome from addition of lamotrigine to divalproex,,1
10822,15864235,Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study,"BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. METHODS: This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg). Patients were stratified by prerandomization LDL-C level. RESULTS: At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of <100 mg/dL and the optional LDL-C target of <70 mg/dL. C-reactive protein reductions were similar between treatment groups. Consecutive elevations in alanine aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/simvastatin patients. No myopathy or liver-related adverse events led to study discontinuation with either drug. CONCLUSIONS: Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolemic patients.",1
10823,15868813,Ceftriaxone-associated gallbladder pseudolithiasis: report of one case,"Ceftriaxone is known to induce reversible precipitates in the gallbladders of adults and children. However, ceftriaxone-associated gallbladder pseudolithiasis in children is rarely reported in Taiwan. We report a case of 5-year-old boy with Salmonella gastroenteritis, who was treated with ceftriaxone due to multidrug resistance and severe course. Cholelithiasis developed five days after initiation of ceftriaxone therapy and completely resolved one month after the end of treatment. Pediatricians and radiologists must be aware of this complication to prevent anxiety and unnecessary cholecystectomy.",1
10824,15871634,"Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions","Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.",1
10825,15875340,Levodopa + carbidopa + entacapone. Entacapone: a second look: new preparations. Parkinson's disease: a modest effect,"""(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in """"on"""" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.""",1
10826,15879659,Cholestatic liver injury due to ibuprofen,Ibuprofen is a member of the propionic acid class of NSAID. We report a 35-year-old man with ibuprofen-induced acute severe cholestatic liver injury. He recovered after seven months.,1
10827,15880319,Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients,"""BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) might cause hepatic side effects, but the frequency of these laboratory and clinical side effects is uncertain. METHODS: Searches of bibliographic databases MEDLINE and EMBASE and of public archives of the Food and Drug Administration were conducted to identify randomized controlled trials of diclofenac, naproxen, ibuprofen, celecoxib, rofecoxib, valdecoxib, or meloxicam in adults with osteoarthritis or rheumatoid arthritis that provided information on aminotransferase elevations >3 x upper limit of normal, liver-related discontinuations, hepatic serious adverse events, liver-related hospitalizations, or liver-related deaths. The proportion of patients with each of the hepatic toxicity outcomes was calculated separately by using sample size weighted pooling for each NSAID. RESULTS: Sixty-seven articles from the bibliographic database and 65 studies from the Food and Drug Administration archives met inclusion criteria. Diclofenac (3.55%; 95% confidence interval [CI], 3.12%-4.03%) and rofecoxib (1.80%; 95% CI, 1.52%-2.13%) had higher rates of aminotransferase >3 x upper limit of normal than placebo (0.29; 95% CI, 0.17-0.51) and the other NSAIDs (all < or = 0.43%). The 95% CIs for liver-related discontinuations of all NSAIDs except diclofenac (2.17%; 95% CI, 1.78%-2.64%) overlapped with placebo. Only 1 liver-related hospitalization (among 37,671 patients) and 1 liver-related death (among 51,942 patients) occurred, with naproxen. CONCLUSIONS: Diclofenac and rofecoxib had higher rates of aminotransferase elevations than placebo and other NSAIDs studied. No NSAID studied had increased rates of liver-related serious adverse events, hospitalizations, or deaths.""",1
10828,15881625,[Disorder of liver functions in a schizophrenic patient after long-term risperidone treatment--case report],We present a 51-year old man with an 18-year history of chronic paranoid schizophrenia. The last four years he was treated only with risperidone at a dose of 3 mg per day. He was admitted to hospital due to a psychotic decompensation. Jaundice and skin pruritus were also observed at admission. Laboratory tests revealed elevated liver enzymes. Cholestatic and viral hepatitis were excluded. Risperidone was changed to other antipsychotic drugs. After 7 weeks of treatment the patient was discharged with significant improvement of his mental condition. The liver function test results returned to normal values except for the slightly increased total bilirubin level. Regular liver monitoring was suggested. In this case liver dysfunction was possibly correlated with long-term risperidone therapy.,1
10829,15886082,Focal nodular hyperplasia after busulfan treatment,"The case of a 48-year-old woman in whom focal nodular hyperplasia of the liver developed after busulfan therapy was administered for essential thrombocytosis is described. Focal nodular hyperplasia is a reactive disorder related to a circulation disorder. The close temporal relation between the haematological disease, busulfan treatment and the appearance of hyperplastic diseases of the liver in our patient supports the possibility that the association of the events might not be casual.",1
10830,15888169,Treatment of psoriasis with alefacept in patients with hepatitis C infection: a report of two cases,"Alefacept is a fully human fusion protein for use in adult patients with moderate to severe chronic plaque psoriasis. Its dual mechanism of action involves inhibition of T-cell activation and selective reduction of memory T cells. We report the clinical course of two patients with hepatitis C virus (HCV) infection who have received alefacept for psoriasis. Consistent with its mechanism of action, administration of alefacept led to transient decreases in CD4+ and CD8+ T-cell counts. However, these reductions were not associated with an increase in HCV viral load or exacerbation of infection. Liver enzymes remained stable throughout the treatment and follow-up periods. Alefacept has a selective mechanism of action that specifically targets memory T cells and this selectivity may account for its safety and tolerability in patients with hepatitis.",1
10831,15892770,Simultaneous presentation of rofecoxib-induced acute hepatitis and acute interstitial nephritis,,1
10832,15897550,"Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer","PURPOSE: To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. PATIENTS AND METHODS: Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. RESULTS: Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. CONCLUSIONS: Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.",1
10833,15899737,"Dilated cardiomyopathy and acute liver injury associated with combined use of ephedra, gamma-hydroxybutyrate, and anabolic steroids","Anabolic-androgenic steroids are synthetic derivatives of testosterone that some athletes have used to enhance muscle mass and improve their athletic performance. Ephedrine is a potent sympathomimetic agent that can lead to cardiomyopathy similar to that seen with catecholamine excess. Adverse cardiovascular events attributed to anabolic steroid and ephedra use, such as arrhythmias, myocardial infarction, cardiomyopathy, and sudden death, are rarely reported. Bodybuilders have used gamma-hydroxybutyrate, a potent secretagogue of growth hormone, to promote muscle development. Although dilated cardiomyopathy is a known complication of excess growth hormone levels, it has not been associated with use of gamma-hydroxybutyrate. A healthy 40-year-old man was admitted to our hospital for new-onset congestive heart failure and severe acute hepatitis that developed several months after he began using anabolic-androgenic steroids, ephedra, and gamma-hydroxybutyrate supplements. Analysis with an objective causality assessment scale revealed a probable adverse drug reaction between the patient's use of anabolic steroids, ephedra, and gamma-hydroxybutyrate and the development of his cardiomyopathy and acute liver injury.",1
10834,15902772,Clofarabine,,1
10835,15912124,Pramlintide (symlin) for diabetes,An injected analog of human amylin used as an adjunct to insulin.,1
10836,15916912,Fatal lactic acidosis associated with tenofovir and abacavir,,1
10837,15920217,Propofol infusion syndrome associated with short-term large-dose infusion during surgical anesthesia in an adult,In this case report we describe a case of propofol infusion syndrome in an adult after a short-term infusion of large-dose propofol during a neurosurgical procedure. Large-dose propofol (9 mg.kg(-1).h(-1)) was given for only 3 h during surgery and was followed by a small-dose infusion (2.3 mg.kg(-1).h(-1)) for 20 h postoperatively. The patient had also received large doses of methylprednisolone. He developed a marked lactic acidosis with mild biological signs of renal impairment and rhabdomyolysis but no cardiocirculatory failure. There were no other evident causes of lactic acidosis as documented by laboratory data. We believe this is the first report of reversible lactic acidosis associated with a short duration of large-dose propofol anesthesia.,1
10838,15922478,Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study,"BACKGROUND/AIMS: The aim of this study was to evaluate long term safety and antiviral activity of different doses of emtricitabine given once daily to patients chronically infected with hepatitis B. METHODS: Eligible patients were randomized in a double-blind, parallel study to evaluate 25, 100 or 200 mg once daily doses of emtricitabine for 48 weeks. Patients were then followed for an additional 48 weeks on open-label 200 mg emtricitabine. Serum HBV DNA, ALT, and hepatitis B serology were measured at regular intervals over the 2 years. Resistance surveillance was performed after 1 and 2 years on viremic samples, i.e. > 4700 copies/mL. RESULTS: Emtricitabine was well tolerated and produced a dose proportional antiviral response. After 2 years, 53% of the patients had serum HBV DNA < or = 4700 copies/mL, 33% seroconverted to anti-HBe and 85% had normal ALT. Eighteen percent of the patients who had received 200 mg emtricitabine for 2 years developed resistance mutations. CONCLUSIONS: Emtricitabine was well tolerated and demonstrated a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection. Based on these data, 200 mg emtricitabine once daily was chosen as the optimal dose for future hepatitis B studies.",1
10839,15930079,Toxicity with selective serotonin reuptake inhibitors,,1
10840,15934837,CDP-870 (certolizumab) in rheumatoid arthritis,"The development of biological anti-TNF-alpha therapy has revolutionised the treatment of rheumatoid arthritis and other inflammatory diseases, and has identified a worldwide market for expensive yet effective therapies for chronic diseases. Certolizumab (CDP-870) is a new agent that employs a novel strategy to neutralise TNF-alpha--namely the prokaryotic expression of TNF-alpha-specific Fab antibody fragments, coupled to polyethylene glycol--to produce a drug that is potentially less expensive to manufacture than other anti-TNF-alpha agents and which may be administered by subcutaneous injection once a month. The background to the ongoing development of this new agent and its clinical effects are discussed in this article.",1
10841,15938595,The real-life safety and efficacy of vardenafil: an international post-marketing surveillance study--results from 29 358 German patients,"We assessed the safety, efficacy and patient acceptability of vardenafil (Levitra, Bayer HealthCare, Leverkusen, Germany) under real-life conditions in patients with erectile dysfunction (ED) in a multinational post-marketing surveillance study. An initial and up to two follow-up visits were documented for 29 358 German ED patients receiving vardenafil. Patients were interviewed about overall treatment success, and individual sexual attempts were evaluated in a patient questionnaire. Overall erectile improvement was reported by 93.9% of physicians, and similar improvement rates were reported for both 10 mg and 20 mg vardenafil dosages. Most patients experienced improved erections after the first (73.6%) or second (88.5%) tablet. Sexual attempts were successful with respect to partner penetration in 94.9% of patients and with respect to maintenance of erection during intercourse in 87.7% of patients. Adverse drug reactions were very rare (1.3% of patients). Vardenafil was highly effective, reliable and well tolerated in ED patients treated under real-life conditions.",1
10842,15941798,Cocaine-induced acute hepatitis and thrombotic microangiopathy,,1
10843,15942881,Antimicrobial safety: focus on fluoroquinolones,"""BACKGROUND/PURPOSE: Infrequent toxicities associated with certain drugs and drug classes have recently gained much attention from different health-care perspectives. To protect the patient, continued surveillance of safety and tolerability data is essential. Data from preclinical testing, phase 1-3 trials, and postmarketing surveillance may be used to objectively assess the risks associated with a specific drug or family of compounds. This review summarizes safety and tolerability data for the quinolones. MAIN FINDINGS: The most common adverse events associated with the quinolone class involve the gastrointestinal tract (nausea and diarrhea) and central nervous system (CNS) (headache and dizziness). These adverse events are usually mild and do not require discontinuation of therapy. Uncommon and potentially serious quinolone-related adverse events involve the cardiovascular system (rate-corrected electrocardiographic QT interval prolongation), musculoskeletal system (tendinitis and tendon rupture), endocrine system (glucose homeostasis dysregulation), renal system (crystalluria, interstitial nephritis, and acute renal failure), and the CNS (seizures). Severe idiosyncratic adverse events are specific to individual agents that may share some structural congruity, such as the 1-(2,4)-difluorophenyl group shared by trovafloxacin (associated with hepatitis), temafloxacin (associated with hemolytic-uremic syndrome), and tosufloxacin (associated with eosinophilic pneumonitis). Overall, discontinuation rates from clinical trials were <4% for the currently marketed quinolones. Quinolones with higher discontinuation rates, such as trovafloxacin (7.0%) and grepafloxacin (6.4%), are no longer available for general use. CONCLUSIONS: The currently marketed quinolones are well tolerated, with safety profiles similar to those of other antimicrobial classes. Although adverse effects are unusual, some, including tendinitis and CNS-related effects, are more common with quinolones than with other antimicrobial classes. Rare adverse effects attributed to some members of the quinolone family (e.g., Torsades de Pointes, hepatotoxicity, and dysglycemias) are more likely to occur in select """"susceptible"""" populations. These adverse events can often be circumvented by avoiding exposure to the specific quinolone. In some cases, the therapeutic value offered by a quinolone may outweigh its potential risks.""",1
10844,15953335,Reye's syndrome developing in an infant on treatment of Kawasaki syndrome,"Aspirin is commonly used as an anti-inflammatory therapy for Kawasaki syndrome. Early initiation with high dose aspirin (80 to > 100 mg/kg per day), followed by low-dose therapy at the afebrile stage, has been often used to reduce morbidity and mortality in coronary complications. We report a 10-month-old infant who was diagnosed with Kawasaki syndrome. Sudden onset of poor activity, poor appetite, lethargy, tachycardia, tachypnea, hepatomegaly, increased AST/ALT, coagulopathy and hyperammonemia developed 3 days after the high-dose aspirin therapy. His histopathological and ultrastructural findings from the liver biopsy were compatible with Reye's syndrome. He recovered completely, and there was no recurrence.",1
10845,15956233,Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides,"OBJECTIVE: To report a case of chronic ingestion of very large amounts of senna fruits as an herbal tea, possibly leading to severe hepatotoxicity. CASE SUMMARY: A 52-year-old woman who had ingested, for >3 years, one liter of an herbal tea each day made from a bag containing 70 g of dry senna fruits, developed acute hepatic failure and renal impairment requiring intensive care therapy. The severity of the hepatic failure was reflected by the increase in prothrombin time (international normalized ratio >7) and the development of encephalopathy. Liver transplantation was discussed, but the patient ultimately recovered with supportive therapy. Renal impairment was consistent with proximal tubular acidosis, also with marked polyuria refractory to vasopressin administration. Suprisingly, large amounts of cadmium were transiently recovered in the urine. DISCUSSION: Cassia acutifolia and angustifolia plants are widely used as laxatives. Their chronic abuse may be associated with serious manifestations, including fluid and electrolyte loss, with chronic diarrhea. Severe hepatotoxicity is unusual, but could be explained by the exposure of the liver to unusual amounts of toxic metabolites of anthraquinone glycosides (sennosides). An objective causality assessment suggests that hepatotoxicity was possibly related to senna laxative abuse. Regarding nephrotoxicity, there are no available human data on sennosides, while experimental models suggest that anthraquinone derivatives may also accumulate in the kidneys. The finding of high urinary concentrations of cadmium would suggest contamination of the herbal tea by metals, but this hypothesis could not be verified. CONCLUSIONS: Ingestion of large doses of senna laxatives may expose people to the risk of hepatotoxicity.",1
10846,15963219,Toxic hepatitis associated with paroxetine,"Hepatotoxicity is a rare complication of paroxetine, a selective serotonin reuptake inhibitor. Regarded as safe in therapeutic use, there have been reports of cases of severe hepatic dysfunction with gross elevations of transaminase levels that may be related to this drug. We report here severe adverse cholestatic and hepatocellular injury in a patient taking paroxetine probably due to an immune-mediated hypersensitivity reaction.",1
10847,15967829,FDA drug approval summary: pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer,"""On August 19, 2004, pemetrexed for injection (Alimta); Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) received accelerated approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received prior chemotherapy. Approval was primarily based on a single, controlled, unblinded trial. Five hundred seventy-one protocol-eligible patients were randomized to receive either pemetrexed or docetaxel (Taxotere); Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com). The primary efficacy end point was overall survival. The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm. Neither superiority nor noninferiority for overall survival could be demonstrated, the latter because a reliable and consistent survival effect of docetaxel could not be estimated and because of significant crossover of pemetrexed-treated patients to docetaxel after tumor progression. Comparable response rates, 9.1% for pemetrexed and 8.8% for docetaxel, times to progressive disease, and progression-free survival times supported the conclusion that an effect of pemetrexed on survival was reasonably likely, however. In addition, pemetrexed was felt to have a more favorable safety profile than docetaxel. Of greatest importance, pemetrexed caused significantly less neutropenia, febrile neutropenia, neutropenic infections, and need for granulocyte/macrophage colony-stimulating factors.""",1
10848,15973669,"Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials","""BACKGROUND: The tendency of chemotherapeutic regimens to cause vomiting is dependent on the individual drugs in the regimen. The authors analyzed data combined from 2 Phase III trials to assess the effect of the neurokinin-1 (NK(1)) antagonist aprepitant combined with a 5HT(3) antagonist plus a corticosteroid in a subpopulation receiving > 1 emetogenic chemotherapeutic agent. METHODS: In the current study, 1043 cisplatin-naive patients (42% were women) receiving cisplatin-based (> or = 70 mg/m(2)) chemotherapy were assigned randomly to a control regimen (ondansetron [O] 32 mg intravenously and dexamethasone [D] 20 mg orally on Day 1; D 8 mg twice daily on Days 2-4) or an aprepitant (A) regimen (A 125 mg orally plus O 32 mg and D 12 mg on Day 1; A 80 mg and D 8 mg once daily on Days 2-3; and D 8 mg on Day 4). Randomization was stratified for use of concomitant chemotherapy and female gender. The primary end point was complete response (no vomiting and no rescue therapy) on Days 1-5 (0-120 hours). Data were analyzed by a modified intent-to-treat approach, and logistic regression was used to make treatment comparisons among patients receiving the most frequently coadministered emetogenic concomitant chemotherapy (Hesketh level > or = 3). RESULTS: Among the approximately 13% of patients (n = 81 for A; n = 80 for control) who received additional emetogenic chemotherapy (doxorubicin or cyclophosphamide), the aprepitant regimen provided a 33 percentage-point improvement in the complete response rate compared with the control regimen. Among the general population, the advantage with aprepitant was 20 percentage points. CONCLUSIONS: The current analysis of > 1000 patients from 2 large randomized trials showed that in the subpopulation at increased risk of chemotherapy-induced nausea and vomiting due to concomitant emetogenic chemotherapy, the addition of aprepitant to standard antiemetics improved protection to an even greater extent than in the general study population.""",1
10849,15977966,Tigecycline: a novel glycylcycline,"""Antibacterials have been in clinical use for almost 60 years; however, the effectiveness of these valuable agents has been diminished by widespread emergence of bacterial resistance. Tigecycline is the first in a new class of glycylcyclines with activity against a wide range of clinically important pathogens. Tigecycline has demonstrated potent microbiological activity and excellent therapeutic response in animal infection models and in recently reported phase III human clinical trials. It is effective against intra-abdominal and skin and soft tissue infections caused by susceptible or multidrug-resistant staphylococci, enterococci or streptococci as well as most Enterobacteriaceae and anaerobic pathogens. In clinical trials nausea and vomiting were the most common adverse events and were of a magnitude typical of those observed with tetracyclines in general. Additionally, tigecycline has proven to be efficacious in animal models of infection, including pneumonia, endocarditis and peritonitis. Tigecycline is only available as an intravenous agent and distributes extensively in tissues. Administration of a 100mg loading dose of tigecycline followed by twice-daily doses of 50mg yielded an apparent volume of distribution of 7-10 L/kg. Systemic clearance ranged from 0.2 to 0.3 L/h/kg and its half-life varied from 37 to 67 hours. The pharmacokinetics of tigecycline appear unaffected by sex, age, renal disease or the presence of food. Data from animal studies would suggest that time above the minimum inhibitory concentration is the pharmacodynamic factor that best correlates with bacterial eradication. The efficacy, safety profile and pharmacodynamic attributes of tigecycline support its continuing clinical development as empirical parenteral treatment of challenging nosocomial and community-acquired infections, including those caused by proven or suspected resistant pathogens.""",1
10850,15982998,"Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability","A number of medicinal plants are traditionally endowed with anxiolytic or sedative properties and, in the context of this revue, both indications are considered since the former may induce a mood conducive to the latter. For any sleep-inducing drug to be effective, a tranquil ambience needs to be established a priori. Thus, physical ailments (i.e. pain), factors interfering with sleep (i.e. noise), psychological conditions causing stress, psychiatric illnesses (i.e. depression) and other drugs that interfere with sleep (i.e. caffeine) need to be controlled, if possible. Kava-kava is a well-established hypnotic drug, with a rapid onset of effect, adequate duration of action and minimal morning after-effects. However, reports of serious hepatotoxicity with this preparation have led to it being banned in most countries worldwide. On the other hand, side-effects with valerian would appear to be bland indeed. However, it's slow onset of effect (2-3 weeks) renders it unsuitable for short-term use (i.e. 'jet-lag'), but it does have profound beneficial effects on sleep architecture (augments deep sleep) that may make it particularly suitable for long-term use and for the elderly. In a personal trial (not double-blind) in stress-induced insomnia, both kava and valerian improved sleep and the ill-effects of stress, and the combination of the two was even more effective for the control of insomnia. Aromatherapy (lavender, chamomile, Ylang-Ylang) would appear to improve sleep, but how practical a form of treatment this may be remains to be determined. The only other plant drug that may have some effect on sleep is melissa, but reports are too scanty to form any opinion about this. Based on animal experiments, passion flower (passiflora) may have a sedative action, but the sedative action of hops has not been investigated in any detail. In conclusion, there is a need for longer-term controlled studies with some of these compounds (particularly valerian). Aromatherapy constitutes a tantalising possibility. In the interpretation of this review, it should be borne in mind that the evidence on which it is based is often incomplete or missing, but that is all that is available. Consequently some conjecture on the part of the author is inevitable and should be appreciated as such.",1
10851,15988400,Pegaptanib sodium (Macugen) for macular degeneration,,1
10852,15989835,[Toxic hepatitis after flutamide treatment],,1
10853,15998891,Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial,"""CONTEXT: Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons. OBJECTIVE: To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. DESIGN, SETTING, AND PARTICIPANTS: In the Women's Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years. INTERVENTION: Administration of 600 IU of natural-source vitamin E on alternate days. MAIN OUTCOME MEASURES: Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer. RESULTS: During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR, 1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53). CONCLUSIONS: The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.""",1
10854,16000935,Hepatic injury in a patient taking rosiglitazone,"We describe a 52-year-old man with type 2 diabetes mellitus who developed cholestatic hepatitis in association with rosiglitazone use. Liver biopsy findings included dilated canaliculi, inspissated bile, intrahepatocellular bile pigment deposits, and enlarged xanthomatous Kupffer cells. The form of liver injury reported in this case differs markedly from those reported previously for rosiglitazone.",1
10855,16004028,Case reports: treatment of nevirapine-associated dress syndrome with intravenous immune globulin (IVIG),"Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse drug reaction most commonly associated with aromatic antiepileptic agents. It is characterized by the triad of skin eruption, fever, and systemic involvement, with the latter usually manifesting as hepatitis and lymphadenopathy. Mortality is primarily due to hepatic failure and can be as high as 10%. Formerly referred to by names such as Dilantin hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome, DRESS syndrome is a more precise term since this reaction pattern can be seen with other agents. DRESS syndrome has also been reported in association with sulfonamides, allopurinol, terbinafine, minocycline, azathioprine, and dapsone as well as with several antiretroviral agents such as abacavir and nevirapine. We describe a patient with HIV who developed nevirapine hypersensitivity syndrome who was successfully treated with intravenous immune globulin (IVIG).",1
10856,16005168,Adverse effects of anabolic steroids in athletes. A constant threat,"Anabolic-androgenic steroids (AAS) are used as ergogenic aids by athletes and non-athletes to enhance performance by augmenting muscular development and strength. AAS administration is often associated with various adverse effects that are generally dose related. High and multi-doses of AAS used for athletic enhancement can lead to serious and irreversible organ damage. Among the most common adverse effects of AAS are some degree of reduced fertility and gynecomastia in males and masculinization in women and children. Other adverse effects include hypertension and atherosclerosis, blood clotting, jaundice, hepatic neoplasms and carcinoma, tendon damage, psychiatric and behavioral disorders. More specifically, this article reviews the reproductive, hepatic, cardiovascular, hematological, cerebrovascular, musculoskeletal, endocrine, renal, immunologic and psychologic effects. Drug-prevention counseling to athletes is highlighted and the use of anabolic steroids is must be avoided, emphasizing that sports goals may be met within the framework of honest competition, free of doping substances.",1
10857,16007524,The hepatotoxicity of antifungal medications in bone marrow transplant recipients,"""BACKGROUND: Systemic antifungal medications can be lifesaving but can also have important toxicities. With a number of new antifungal drugs being introduced, there is a compelling need to define the toxicities associated with existing therapies. METHODS: We identified cases of hepatotoxicity among patients who underwent bone marrow transplantation and selected matched control subjects from the same population. Multivariable logistic regression modeling was used to control for patient characteristics in evaluating the relationship between hepatotoxicity and exposure to antifungal medications. Follow-up analyses were performed for patients who continued receiving antifungal medications after developing hepatotoxicity. RESULTS: The unadjusted incidence of hepatotoxicity was 0.78 cases per 100 patient-days of exposure to amphotericin deoxycholate, 0.98 for fluconazole, and 1.50 for liposomal amphotericin B. Case-control analyses found that liposomal amphotericin B was associated with a substantial increase in the risk of hepatotoxicity in these patients (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.61-6.88); a smaller increase in risk was found for fluconazole (OR, 1.99; 95% CI, 1.21-3.26). There was no statistically significant association between amphotericin B deoxycholate and the development of hepatotoxicity. Patients had greater elevations of serum transaminase values associated with exposure to larger cumulative doses of liposomal amphotericin B. In the follow-up analysis of patients who developed hepatotoxicity and who continued receiving antifungal medication, one-third of those receiving liposomal amphotericin B had marked increases in bilirubin levels, as opposed to 8% of patients treated with fluconazole. CONCLUSIONS: In these bone marrow transplant recipients, liposomal amphotericin B and fluconazole were both associated with increased risk of hepatotoxicity, independent of other treatments received or patient characteristics; the magnitude of the risk was larger for liposomal amphotericin B. Patients who develop hepatotoxicity appear to tolerate continued therapy with fluconazole, but a large fraction of those who received liposomal amphotericin B have worsening conditions with continued treatment.""",1
10858,16009537,Hepatotoxicity associated with the use of a fixed combination of chloroquine and proguanil,"Here we report on a case of hepatotoxicity associated with the use of a fixed combination of chloroquine and proguanil. Alternative causes of liver injury were excluded. The pathophysiological mechanism remains unclear, with a possibility of allergic reaction. In view of the widespread use of both drugs, clinicians should be aware of this drug-induced liver injury.",1
10859,16011443,Adalimumab: a review of side effects,"Adalimumab (Humira) is a human monoclonal TNF-alpha antibody that blocks the effects of TNF-alpha. It is administered by subcutaneous injection. It has been approved alone or in combination with methotrexate for the treatment of rheumatoid arthritis in the EU and US. Approval for its use for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis is expected in the near future. Its side effect profile is favourable when compared with traditional systemic treatments for these diseases. It does not require laboratory monitoring. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. There is a two-fold risk of serious infections with the use of adalimumab, as reported in the Premier trial. This risk should not be minimised in this way. It should not be used during periods of active infection. Its most notable infectious complication is the reactivation of tuberculosis. Tuberculosis screening should be according to country standards and may or may not include purified protein derivative test or chest X-ray. Deep fungal and other serious and atypical infection can also be promoted by adalimumab. It has been associated infrequently with skin rashes. Rare side effects include: worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis/neurological disease. There has been reported pancytopenia and elevated transamines with the use of adalimumab, which suggest that laboratory monitoring blood counts and liver functions, at least intermittently, are useful. In patients with any of the foregoing problems, its use should be extremely carefully considered. Adalimumab is a useful medication which can be safely used if its side effects are recognised.",1
10860,16011454,Safety review of kava (Piper methysticum) by the Natural Standard Research Collaboration,"This systematic review discusses the proposed uses, dosing parameters, adverse effects, toxicology, interactions and mechanism of action of kava. The widespread concern regarding the potential hepatotoxicity of kava is discussed. A recommendation is made to consolidate and analyse available reports and to continue postmarket surveillance in an international repository to prevent duplicates and promote collection of thorough details at the time of each report so that any association with kava is clearly defined.",1
10861,16014882,Erlotinib in previously treated non-small-cell lung cancer,"""BACKGROUND: We conducted a randomized, placebo-controlled, double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non-small-cell lung cancer after the failure of first-line or second-line chemotherapy. METHODS: Patients with stage IIIB or IV non-small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo. RESULTS: The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects. CONCLUSIONS: Erlotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy.""",1
10862,16019563,"Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibody-positive patient: potential implications for future prophylaxis recommendations","In the absence of prophylaxis, the reactivation of hepatitis B in oncology patients who are hepatitis B carriers is a well-known and often fatal complication of chemotherapy. The current recommendations in Canada and the USA are that patients who are positive for hepatitis B surface antigen (HBsAg) receive antiviral prophylaxis prior to chemotherapy. We report a 67-year-old man with B-cell lymphoma who developed hepatitis B reactivation following chemotherapy with cyclophosphamide, adriamycin, vincristine, prednisone and rituximab. Pre-chemotherapy, the patient was negative for HBsAg, positive for hepatitis B core antibody (anti-HBc) and weakly positive for hepatitis B surface antibody. Despite treatment with lamivudine, the patient died of fulminant hepatic failure. Our experience indicates that patients who are negative for HBsAg but positive for anti-HBc are still at risk for reactivation of latent hepatitis B during and after chemotherapy and may be considered for prophylaxis.",1
10863,16025496,Outcome and prognostic markers in severe drug-induced liver disease,"""The combination of high aminotransferases (hepatocellular injury) and jaundice has been reported to lead to a mortality rate of 10% to 50% for different drugs, a phenomenon known as """"Hy's rule."""" However, Hy's rule has never been validated, and limited data exist on predictors for outcome in hepatocellular and other forms of drug-induced liver disease. All reports of suspected hepatic adverse drug reactions received by the Swedish Adverse Drug Reactions Advisory Committee (1970-2004) were reviewed. Cases with bilirubin levels 2 or more times the upper limit of normal (ULN) were analyzed. A total of 784 cases were retrieved-409 with hepatocellular injury, 206 with cholestatic injury, and 169 with mixed liver injury. The mortality/transplantation rate was 9.2%, and bilirubin (median 18.7 x ULN [IQR 12.6-25]; range 4.5-42) was higher (P < .0001) in the deceased/transplant recipients compared with the surviving patients (median 5.5 x ULN [IQR 3.3-9.5]; range 2.0-38). A total of 7.8% with cholestatic and 2.4% with a mixed pattern died. The mortality rate in hepatocellular injury for different drugs varied from 40% (6 of 15) for halothane to 0% (0 of 32) for erythromycin, in total 12.7%. Using logistic regression analysis, age, aspartate aminotransferase (AST) and bilirubin were found to independently predict death or liver transplantation in the hepatocellular group, whereas among patients with cholestatic/mixed liver injury, bilirubin was the only independent predictor. In conclusion, hepatocellular jaundice has a high but variable mortality rate, depending on the drug involved. The AST and bilirubin levels are the most important predictors of death or liver transplantation.""",1
10864,16035110,Ziprasidone-induced hypersensitivity syndrome in an aged schizophrenia patient,,1
10865,16038474,Are adverse events of nevirapine and efavirenz related to plasma concentrations?,"OBJECTIVE: The relationships between adverse events (AEs) and plasma concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part of the large, international, randomized 2NN study. METHODS: Treatment-naive, HIV-1-infected patients received NVP (once or twice daily), EFV or their combination, each in combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian estimates of the area under the plasma concentration-time curve over 24 h (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as measures for drug exposure of NVP and EFV, were generated using a previously developed population pharmacokinetic model. Pharmacokinetic parameters were compared for patients with and without central nervous system (CNS) and psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic parameter could be identified above which the incidence of AEs was clearly increased. AEs were also related to demographic parameters and baseline characteristics. RESULTS: In total, from 1077 patients, NVP (3024 samples) and EFV (1694 samples) plasma concentrations and AE data (825 observations) were available. For all patients Cmin, Cmax and AUC24h were determined. When corrected for known covariates of gender, CD4 cell count at baseline, region, hepatitis coinfection and possible interactions between these factors, no significant associations between AEs and any tested exposure parameter of NVP was observed. Also, no target Cmin value, above which patients were at increased risk for AEs, could be established. On the other hand, geographical region, hepatitis coinfection, CD4 cell count and gender were found to be significantly related with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash during the treatment with NVP. The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk for elevated liver enzymes. No other correlations between AEs and EFV pharmacokinetics or patient characteristics could be identified. CONCLUSIONS: Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN trial when corrected for known covariates. The value of periodical drug monitoring of NVP as a way to prevent toxicity is therefore limited. Treating physicians should instead focus on factors that are more predictive of AEs (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in elevated liver enzyme values during the first 6 weeks of treatment. Regular measurement of EFV levels and liver enzymes at the start of therapy may therefore be advised.",1
10866,16044093,Hepatocellular damage following therapeutic intravenous iron sucrose infusion in a child,"The maximum tolerated single dose of intravenous iron infusion and iron pharmacokinetics are not known in children and not clear in adults. The case reported here is of a child given a large dose of intravenous iron sucrose (16 mg/kg) over 3 hours, who subsequently developed features of systemic iron toxicity. A TDM consultant discusses the case in the context of toxicokinetic analysis. Because the maximum tolerated dose and pharmacokinetics of intravenous iron preparations are not known, their use in both adults and children should still be undertaken with caution.",1
10867,16048430,[Hepatic fibrosis after antidepressant treatment],,1
10868,16051732,Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro,"Root extracts from kava-kava (Piper methysticum G. Forst) are clinically used for the treatment of anxiety and restlessness. Due to reported cases of liver toxicity, kava-kava extracts were withdrawn from the market in several countries in 2002. Because the efflux transporter P-glycoprotein (P-gp) is involved in the absorption, distribution, and excretion of many drugs and often participates in drug-drug interactions, we studied the effect of a crude kava extract and the main kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin on the P-gp-mediated efflux of calcein-acetoxymethylester in the P-gp-overexpressing cell line P388/dx and the corresponding cell line P388. The crude extract and the kavalactones showed a moderate to potent inhibitory activity with f2) (concentration needed to double baseline fluorescence) values of 170 microg/ml and 17 to 90 microM, respectively. The f2 value of yangonin could not be determined due to its higher lipophilicity. In conclusion, our results for the first time demonstrate P-gp-inhibitory activity of kava-kava and its components in vitro.",1
10869,16053424,Riluzole: a glimmer of hope in the treatment of motor neurone disease,,1
10870,16053970,Ambrisentan therapy for pulmonary arterial hypertension,"""OBJECTIVES: The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan, an oral endothelin type A receptor-selective antagonist, in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options. Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH. METHODS: In this double-blind, dose-ranging study, 64 patients with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use, or human immunodeficiency virus infection were randomized to receive 1, 2.5, 5, or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan. The primary end point was an improvement from baseline in 6-min walk distance (6MWD); secondary end points included Borg dyspnea index, World Health Organization (WHO) functional class, a subject global assessment, and cardiopulmonary hemodynamics. RESULTS: At 12 weeks, ambrisentan increased 6MWD (+36.1 m, p < 0.0001) with similar and statistically significant increases for each dose group (range, +33.9 to +38.1 m). Improvements were also observed in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (-5.2 mm Hg, p < 0.0001), and cardiac index (+0.33 l/min/m2, p < 0.0008). Adverse events were mild and unrelated to dose, including the incidence of elevated serum aminotransferase concentrations >3 times the upper limit of normal (3.1%). CONCLUSIONS: Ambrisentan appears to improve exercise capacity, symptoms, and hemodynamics in patients with PAH. The incidence and severity of liver enzyme abnormalities appear to be low.""",1
10871,16056110,"Recurrent toxic hepatitis in a Caucasian girl related to the use of Shou-Wu-Pian, a Chinese herbal preparation",,1
10872,16080072,The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam,"""Two phase 3, double-blind studies in hospitalized adults with complicated skin and skin-structure infections (cSSSI) determined the safety and efficacy of tigecycline versus that of vancomycin-aztreonam. Patients received tigecycline (100 mg, followed by 50 mg intravenously twice daily) or vancomycin (1 g intravenously twice daily) plus aztreonam (2 g intravenously twice daily) for up to 14 days. Populations were as follows: 1116 patients (566 treated with tigecycline, and 550 treated with vancomycin-aztreonam) constituted the modified intent-to-treat (mITT) population, 1057 patients (538 treated with tigecycline, and 519 treated with vancomycin-aztreonam) constituted the clinical mITT (c-mITT) population, and 833 patients (422 treated with tigecycline, and 411 treated with vancomycin-aztreonam) constituted the clinically evaluable population. Clinical responses to tigecycline and vancomycin-aztreonam at test-of-cure were similar: c-mITT, 79.7% (95% confidence interval [CI], 76.1%-83.1%) versus 81.9% (95% CI, 78.3%-85.1%) (P = .4183); and clinically evaluable, 86.5% (95% CI, 82.9%-89.6%) versus 88.6% (95% CI, 85.1%-91.5%) (P = .4233). Adverse events were similar, with increased nausea and vomiting in the tigecycline group and increased rash and elevated hepatic aminotransferase levels in the vancomycin-aztreonam group. Tigecycline monotherapy is as safe and efficacious as the vancomycin-aztreonam combination in treating patients with cSSSI.""",1
10873,16082288,Erythromycin-associated cholestatic hepatitis and liver dysfunction in children: the British experience,,1
10874,16083708,Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period,"""BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.""",1
10875,16085447,Fulminant hepatic failure following halothane anaesthesia,"The forensic pathologist is responsible for determining the cause, manner and approximate time of death and injury. After recording the detailed description of the external and internal appearances, a short summary should be offered of the major positive findings and their relationship to the cause of death. In many cases this will be obvious, however when the findings are less clear-cut, or are multiple, then the alternatives should be discussed detailing the possible sequence of events and interpreting the findings in concluding the cause of death. It is essential to causally connect the autopsy findings to the cause of death. We present a case report wherein a person who sustained avulsion injury to his left hand in an industrial accident, died due to, fulminant hepatitis, hepatic encephalopathy and acute renal failure, having undergone six operations under general anesthesia with halothane during his stay in the hospital.",1
10876,16086731,Sildenafil-associated hepatotoxicity,,1
10877,16094725,Hepatotoxicity of NONI juice: report of two cases,NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice. A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acute hepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice.,1
10878,16096600,Omeprazole-induced hepatitis,"""Omeprazole; the first proton pump inhibitor (PPI) showing an effective acid inhibitory ability, provides the satisfactory therapy either in gastro-esophageal reflux symptom relief or in healing of erosive esophagitis. It's also effective in peptic ulcer disease. Up to date, omeprazole efficacy and safety are well established in many trials. Omeprazole-related hepatotoxicity is not very well recognized especially in pediatric population. We report a child who developed hepatitis following omeprazole intake. We believe that this is the first case report of omeprazole-induced hepatitis in pediatric population.""",1
10879,16097177,[Acute hepatitis in a woman after intake of slimming pills bought via Internet],,1
10880,16103779,Low incidence of hepatotoxicity in a cohort of HIV patients treated with lopinavir/ritonavir,"We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrollment.",1
10881,16110850,Vanishing bile duct syndrome and inflammatory pseudotumor associated with a case of anabolic steroid abuse,,1
10882,16116598,Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence,"""BACKGROUND: In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg), an antibody-targeted chemotherapy for CD33-positive acute myeloid leukemia (AML). METHODS: Patients with CD33-positive AML in first recurrence were entered in 3 open-label, single-arm, Phase II studies. Patients received monotherapy with GO 9 mg/m(2) as a 2-hour intravenous infusion in 2 doses separated by 2 weeks. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Two hundred seventy-seven patients (median age, 61 yrs) were treated with GO, and 71 patients (26%) achieved remission, which was defined as < or = 5% blasts in the bone marrow without leukemic blasts in the peripheral blood, neutrophil recovery to > or = 1500/microL, hemoglobin > or = 9 g/dL, and independence from red blood cell and platelet transfusions. Complete remission (CR) with platelet recovery (> or = 100,000/microL) or without full platelet recovery (< 100,000/microL) (CRp) was observed in 35 patients (13%) and 36 patients (13%), respectively. The median recurrence-free survival was 6.4 months for patients who achieved CR and 4.5 months for patients who achieved CRp. Although expected incidences of Grade 3 or 4 neutropenia (98%) and thrombocytopenia (99%) were observed, the incidence of Grade 3 or 4 sepsis (17%) and pneumonia (8%) was relatively low. Grade 3 or 4 hyperbilirubinemia and hepatic aspartate aminotransferase and alanine aminotransferase elevations were reported in 29%, 18%, and 9% of patients, respectively; 0.9% of patients who did not undergo prior or subsequent hematopoietic stem cell transplantation developed hepatic venoocclusive disease after GO treatment. CONCLUSIONS: When it was administered to patients with CD33-positive AML in first recurrence, single-agent GO induced a 26% remission rate with a generally acceptable safety profile.""",1
10883,16120141,Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases,"BACKGROUND: Fumaric acid esters (FAE) have been used to treat severe psoriasis in northern Europe for over 20 years. A recent systematic review has shown FAE to be an effective systemic treatment for severe psoriasis. However, FAE remain unlicensed in the U.K. OBJECTIVES: To present data relating to the efficacy and tolerability of FAE in severe psoriasis and report our experiences of FAE therapy at one U.K. centre. METHODS: Patients who had received FAE for severe psoriasis at one U.K. regional referral centre between June 1999 and October 2003 were identified from pharmacy records. Their records were analysed retrospectively. RESULTS: Fifty-eight patients (25 women, 33 men) were identified. Fifty-five (95%) of the 58 patients had previously used other systemic antipsoriatic therapies with over 70% previously using two or more agents. Thirty-two patients (55%) showed improvement in their psoriasis with 10 (17%) being rated as 'clear' or 'virtually clear' by the attending physician. No improvement was seen in 28% patients and 16% showed worsening of their disease. Adverse events were common and were reported in 66% patients. These mainly consisted of abdominal pain (61%), diarrhoea (55%), flushing (45%), nausea (21%) and malaise (15%). They led to discontinuation of treatment in 15 patients after a mean period of 4.7 months. Lymphocytopenia developed during treatment in 57% of patients, all of whom had had a baseline value within the normal range. In only one patient was this considered severe enough to warrant withdrawal of treatment. CONCLUSIONS: Our study has shown that FAE are an effective therapy in selected patients with severe psoriasis, even in those who have previously been intolerant of systemic therapy or where it has failed.",1
10884,16122280,"Clinical pharmacokinetics of telithromycin, the first ketolide antibacterial","Telithromycin is the first ketolide, which is a new class of antibacterial agents related to the macrolides that have structural modifications permitting dual binding to bacterial ribosomal RNA so that activity is retained against Streptococcus pneumoniae with macrolide-lincosamide-streptogramin(B) resistance. Clinical experience in infectious patients has shown that oral telithromycin 800mg once daily for 5-10 days is effective for the treatment of community-acquired upper and lower respiratory tract infections. Absorption of telithromycin in humans is estimated to be > or = 90%. Prior to entering the systemic circulation, telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg. Telithromycin is 60-70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation, telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism). Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent drug. In healthy subjects receiving telithromycin 800 mg once daily, the peak plasma concentration achieved is 2.27 microg/mL. Plasma concentrations of telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2-3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of CYP3A4 by potent inhibitors such as itraconazole and ketoconazole results in a 54% and 95% increase in telithromycin area under the plasma concentration-time curve, respectively. The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin. The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia. In conclusion, telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800 mg once daily.",1
10885,16123721,Induction therapy for pediatric and adult heart transplantation: comparison between OKT3 and daclizumab,"""BACKGROUND: Induction therapy can reduce morbidity and early mortality in pediatric and adult heart transplant recipients. Monoclonal and polyclonal agents are most widely used; they nonspecifically deplete the T-cell pool and are thus associated with drug-induced side effects. The cytokine release syndrome is one of the most problematic events associated with induction. Daclizumab, a highly humanized, specific interleukin-2 receptor blocker, may be efficacious to the monoclonal agent, OKT3. Due to its specific action and properties, the safety profile of this agent may be superior to OKT3. METHODS: Forty subjects received daclizumab and their clinical outcomes were compared against a historical group of 40 subjects who received OKT3. Three- and six-month outcome measures included survival, rejection history, steroid burden, and complications. RESULTS: Mortality was low between the groups with equivalent 6-month survival. No differences in rejection profile or time to the first significant rejection event were detected; no subject had severe acute rejection within the first 180 days. Steroid requirement for maintenance immunosuppression and treatment of rejection was also similar between the groups. Six-month prevalence for complications were significantly different; 55% of OKT3-treated subjects having at least one event compared to 33% of daclizumab-treated subjects (P=0.04). The likelihood of complications occurred within the first month after transplantation. CONCLUSIONS: Daclizumab induction therapy is as efficacious as OKT3 in the prevention of early acute rejection after heart transplantation among pediatric and adult subjects. Complications related to the induction agent are significantly lower in the humanized product.""",1
10886,16128682,Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine,"BACKGROUND: Many non-responders to azathioprine or mercaptopurine (6-mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6-methylmercaptopurine instead of the active 6-tioguanine (6-tioguanine) metabolites. AIM: To describe the use of allopurinol in mercaptopurine/azathioprine non-responders to deliberately shunt metabolism of mercaptopurine towards 6-tioguanine. METHODS: Fifteen thiopurine non-responders whose metabolites demonstrated preferential metabolism towards 6-methylmercaptopurine are described. Subjects were commenced on allopurinol 100 mg po daily and mercaptopurine/azathioprine was reduced to 25-50% of the original dose. Patients were followed clinically and with serial 6-tioguanine and 6-methylmercaptopurine metabolite measurements. RESULTS: After initiating allopurinol, 6-tioguanine levels increased from a mean of 185.73 +/- 17.7 to 385.4 +/- 41.5 pmol/8 x 10(8) red blood cells (P < 0.001), while 6-methylmercaptopurine decreased from a mean of 10 380 +/- 1245 to 1732 +/- 502 pmol/8 x 10(8) RBCs (P < 0.001). Allopurinol led to a decrease in white blood cell from a mean of 8.28 +/- 0.95 to 6.1 +/- 0.82 x 10(8)/L (P = 0.01). CONCLUSIONS: The addition of allopurinol to thiopurine non-responders with preferential shunting to 6-methylmercaptopurine metabolites appears to be an effective means to shift metabolism towards 6-tioguanine.",1
10887,16133366,Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid,"We report a case of hepatocellular carcinoma (HCC) arising in nonalcoholic steatohepatitis (NASH). The patient, a 64-year-old man, was incidentally found to have multiple tumors in the liver when admitted for pneumonia. He had been obese, had been receiving a standard dose of valproic acid since clipping surgery for subarachnoid hemorrhage 17 years previously, and had not consumed any alcohol since the surgery. Laboratory data revealed moderate hyperlipidemia and no evidence of diabetes mellitus, hepatitis B or C infection. The patient died of hepatic insufficiency, and an autopsy was performed. A tumor, a maximum of 13 cm in diameter, grossly occupied the entire left lobe and one third of the right lobe of the liver. Histologically, moderately differentiated HCC was found with foci of poorly differentiated HCC. The non-tumorous area showed NASH with moderate bridging fibrosis, without interface hepatitis, hemochromatosis, or copper accumulation. In this patient, obesity, hyperlipidemia, and long-term treatment with valproic acid could have all been associated with induction of NASH. The present case suggests that HCC could develop in non-cirrhotic NASH liver, and that chronic inflammation in itself could be an important risk factor in the development of HCC.",1
10888,16137480,[Severe acute hepatitis due to flutamide and elevated CA 19.9],,1
10889,16138357,Rituximab-induced acute liver failure after an allogeneic transplantation for chronic myeloid leukemia,"Autoimmune hemolytic anemia (AIHA) is a well-recognized complication of allogeneic bone marrow transplantation (BMT) and can affect up to 5% patients. Several recent case reports suggested the efficacy of anti-CD20 monoclonal antibody, rituximab, in treating this condition. We report our experience with a 21-year-old female with accelerated-phase chronic myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation from a matched, unrelated donor. The patient developed autoimmune hemolytic anemia that failed to respond to steroids, intravenous immunoglobulins, and plasma exchange. She was then treated with rituximab that resulted in fatal acute liver toxicity.",1
10890,16143120,"A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease","""BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.""",1
10891,16144190,Proton-pump-inhibitor-induced hepatitis,,1
10892,16146335,Properties of thalidomide and its analogues: implications for anticancer therapy,"""Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.""",1
10893,16149155,Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: a case report,"The anti-arrhythmic agent amiodarone (AD) is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless, asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD (200 mg/d) daily for 84 mo. The patient was a 85-year-old male with a history of ischemic heart disease. Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure. Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore, periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.",1
10894,16152998,Uncommon side effect of MMF in renal transplant recipients,"Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used in renal transplantation. Gastrointestinal and hematological side effects are commonly observed, but hepatotoxicity has not been reported. In this study, we assessed MMF-related hepatotoxicity in renal transplant recipients. A total of 124 renal transplantation recipients (RTRs) were evaluated for elevated liver enzymes associated with MMF, and 79 patients were enrolled to the study. Patients used MMF 2 g/day. The patients who had progressive increase in liver enzymes after renal transplantation and their AST, ALT, GGT, ALP, bilirubin levels, hepatitis, cytomegalovirus (CMV), abdominal ultrasonography, duration of hepatotoxicity, and decreased dosage or withdrawal of MMF were recorded. Also, we evaluated their liver enzymes while the patients were on the waiting list. Of the 79 patients, 11 patients (13.9%) had a progressive increase in liver enzymes. The median (min-max) age of the patients with MMF-hepatotoxicity was 29 (19-54) and 72.7% of them were male. None of the patients had hepatitis B or C, CMV infection, or other possible causes for elevated liver enzymes and their abdominal ultrasonography were normal. High liver enzyme levels regressed after the withdrawal (n=6) or reduce dosage (n=5) of MMF. The median time of the increase in liver enzymes was 28 (4-70) days and after 50% reduction or withdrawal of MMF, returned to normal values in 16 (4-210) days. The median levels of ALT in waiting list (I), before (II), and after (III) reduction dosage or withdrawal of MMF were 22.0 (3-22), 222.0 (51-508), and 33.0 (21-64) U/L, respectively (p I-II=0.004,p I-II=0.013, andp II-III=0.005). There were no differences for ALP, GGT, total bilirubin, and direct bilirubin levels. Also, the correlation between recovery time of ALT and persistence time of ALT elevation before adjustment of MMF was significant (r=0.739, p=0.009). Consequently, after renal transplantation, hepatotoxicity can occur due to a lot of reason including MMF usage. If hepatotoxicity related to MMF is not considered, especially in the early period of renal transplantation, resolution of hepatotoxicity can be required long term.",1
10895,16154196,"A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema","""OBJECTIVE: To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). DESIGN: Randomized, double-masked, multicenter, dose-ranging, controlled trial. PARTICIPANTS: Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. INTERVENTION: Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. MAIN OUTCOME MEASURES: Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. RESULTS: One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. CONCLUSIONS: In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.""",1
10896,16162908,Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis,,1
10897,16163639,Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir,"""BACKGROUND: Highly active antiretroviral therapy (HAART) initiation in patients coinfected with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) has been associated with transaminase and HCV viral load flares. Previous studies have included highly variable antiretroviral regimens. We compared effects of 2 protease inhibitor-based regimens on alanine aminotransferase (ALT) levels and HCV loads in HCV-HIV-coinfected patients initiating HAART. METHODS: Seventy HIV-infected patients with positive baseline results of HCV enzyme-linked immunosorbant assay from a treatment trial comparing lopinavir-ritonavir with nelfinavir were evaluated during a 48-week period. HCV and HIV titers were analyzed at baseline, at weeks 24 and 48 of treatment, and during flares in the ALT level of >5 times the upper limit of normal. RESULTS: A total of 57 of 70 patients tested positive for HCV RNA at baseline. HCV titers for patients in lopinavir-ritonavir and nelfinavir groups, respectively, were as follows: baseline, 6.07 and 6.22 log IU/mL; week 24 of treatment, 6.68 and 6.48 log IU/mL; and week 48 of treatment, 6.32 and 6.44 log IU/mL. Of patients with a CD4+ cell count of <100 cells/mm3 at baseline, 5 of 11 in the nelfinavir group and 0 of 10 in the lopinavir-ritonavir group had an increase in the HCV load of >0.5 log IU/mL from baseline to week 48. The mean ALT level increased by 45 U/L at 24 weeks and 18 U/L at 48 weeks in the nelfinavir group but decreased by 18 U/L at 24 weeks and 7 U/L at 48 weeks in the lopinavir-ritonavir group. Eight patients in the nelfinavir group and 2 patients in the lopinavir-ritonavir group had grade 3 or 4 flares in the ALT level. CONCLUSIONS: HAART initiation is associated with increased HCV loads and ALT levels. A low baseline CD4+ cell count is associated with persistent increases in the HCV RNA load in nelfinavir-treated patients. These results warrant careful interpretation of abnormalities in the ALT load after HAART initiation in HCV-HIV-coinfected patients to prevent premature discontinuation of treatment.""",1
10898,16166134,Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia,,1
10899,16168995,Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients,,1
10900,16171893,Herbal hepatotoxicity,,1
10901,16175516,Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery,"BACKGROUND: The aim of this study was to assess whether the synthetic factor Xa inhibitor fondaparinux reduced the risk of venous thromboembolism more efficiently than the low molecular weight heparin dalteparin in patients undergoing major abdominal surgery. METHODS: In a double-blind double-dummy randomized study, patients scheduled for major abdominal surgery under general anaesthesia received once-daily subcutaneous injections of fondaparinux 2.5 mg or dalteparin 5000 units for 5-9 days. Fondaparinux was started 6 h after surgery. The first two doses of dalteparin, 2500 units each, were given 2 h before surgery and 12 h after the preoperative administration. The primary outcome measure was a composite of deep vein thrombosis detected by bilateral venography and symptomatic, confirmed deep vein thrombosis or pulmonary embolism up until day 10. The main safety outcome measure was major bleeding during treatment. RESULTS: Among 2048 patients evaluable for efficacy, the rate of venous thromboembolism was 4.6 per cent (47 of 1027) with fondaparinux compared with 6.1 per cent (62 of 1021) with dalteparin, a relative risk reduction of 24.6 (95 per cent confidence interval -9.0 to 47.9) per cent (P = 0.144), which met the predetermined criterion for non-inferiority of fondaparinux. Major bleeding was observed in 49 (3.4 per cent) of 1433 patients given fondaparinux and 34 (2.4 per cent) of 1425 given dalteparin (P = 0.122). CONCLUSION: Postoperative fondaparinux was at least as effective as perioperative dalteparin in patients undergoing high-risk abdominal surgery.",1
10902,16180681,[A case of acute severe hepatitis induced by fosfomycin],,1
10903,16185184,Biliary sludge and hyperbilirubinemia associated with ceftriaxone in an adult: case report and review of the literature,"""Ceftriaxone is a commonly used third-generation cephalosporin that has antimicrobial activity against many gram-positive and gram-negative organisms. Generally, ceftriaxone is a safe antibiotic; however, symptomatic biliary sludge has been reported in rare instances, most of which have involved children. It is uncommon for ceftriaxone to cause increases in laboratory indexes, such as bilirubin levels. We describe the case of a 53-year-old man who was treated with intravenous ceftriaxone 2 g every 12 hours. After 7 days of therapy, the patient's liver function test results, including total, direct, and indirect bilirubin levels, increased significantly from baseline, and the patient became jaundiced. A right upper quadrant ultrasound examination revealed biliary sludge and cholelithiasis without sonographic evidence of cholecystitis. Ceftriaxone was thought to be the responsible agent, and it was discontinued. The patient's jaundice subsided, and his liver function test results improved, returning to baseline within 14 days. Clinicians need to be aware of the association of ceftriaxone and biliary pseudolithiasis and hyperbilirubinemia, and monitor accordingly.""",1
10904,16187174,Acute liver failure due to amoxicillin and amoxicillin/clavulanate,"""The aim of our study is to report upon the presentation of two patients with life-threatening acute liver failure (ALF) due to amoxicillin and amoxicillin/clavulanate. A 59-year-old, Caucasian male presented with ALF 34 days after receiving amoxicillin/clavulanate. Despite aggressive supportive care, he died on hospital day 10. A 42-year-old, Caucasian female presented with ALF 21 days after receiving amoxicillin. She underwent successful liver transplantation on hospital day 19. In both cases, all competing causes of ALF had been excluded, liver pathology was consistent with drug-induced hepatitis, and cases were deemed """"definite/highly probable"""" using causality assessment. Amongst 14 prior ALF/death cases due to amoxicillin/clavulanate, the mean age (62 years), male predominance (57%), and mean delay from drug cessation to presentation (17 days) is similar to what has been reported in patients with self-limited cholestatic hepatitis. Acute liver failure is a rare manifestation of amoxicillin and amoxicillin/clavulanate hepatotoxicity with no obvious clinical features at presentation portending a poor prognosis. Early transfer of patients with severe drug-induced hepatotoxicity (i.e., encephalopathy or coagulopathy) to a transplant center is recommended due to their poor likelihood of recovery.""",1
10905,16190944,Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (Mars),,1
10906,16197300,Betaine: a key modulator of one-carbon metabolism and homocysteine status,"""Betaine serves as a methyl donor in a reaction converting homocysteine to methionine, catalysed by the enzyme betaine-homocysteine methyltransferase. It has been used for years to lower the concentration of plasma total homocysteine (tHcy) in patients with homocystinuria, and has recently been shown to reduce fasting and in particular post-methionine load (PML) tHcy in healthy subjects. Betaine exists in plasma at concentrations of about 30 micromol/L; it varies 10-fold (from 9 to 90 micromol/L) between individuals, but the intra-individual variability is small. Major determinants are choline, dimethylglycine and folate in plasma, folic acid intake and gender. Recent studies have demonstrated that plasma betaine is a stronger determinant of PML tHcy than are vitamin B6 and folate. The betaine-PML tHcy relationship is attenuated after supplementation with B-vitamins, and is most pronounced in subjects with low folate. Betaine shows a weaker association with fasting tHcy (than with PML tHcy), and also this association is most pronounced in subjects with low folate. In pregnancy, plasma betaine declines until gestational week 20, and thereafter remains constant. From gestational week 20 onwards, fasting tHcy shows a strong inverse association with plasma betaine, and betaine becomes a stronger predictor than folate of fasting tHcy. To conclude, betaine status is a component of an individual's biochemical make-up with ramifications to one-carbon metabolism. Betaine status should be investigated in pathologies related to altered metabolism of homocysteine and folate, including cardiovascular disease, cancer and neural tube defects.""",1
10907,16199856,Risperidone-induced immunoallergic hepatitis,,1
10908,16204016,Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who had previously responded to I-131 tositumomab,"""PURPOSE: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab. PATIENTS AND METHODS: A prior response > or = 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm(3) or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days. RESULTS: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses > or = 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia. CONCLUSION: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.""",1
10909,16206173,Fulminant hepatic failure associated with propylthiouracil: a case report with treatment emphasis on the use of plasmapheresis,"Propylthiouracil is a commonly used medication for hyperthyroidism. Though propylthiouracil-induced hepatotoxicity is a rarely encountered problem, death due to fulminant hepatic failure may occur. In the English literature, only 34 cases have been described with severe hepatotoxicity secondary to this drug. Here we report a case of fulminant hepatic failure due to propylthiouracil and review the issues of treatment and management with special emphasis on the use of plasmapheresis in such situations.",1
10910,16211594,Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study,"""Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing """"rescue"""" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa """"rescue"""" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.""",1
10911,16219898,Natalizumab for the treatment of multiple sclerosis and Crohn's disease,"OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and pivotal clinical trials for natalizumab in the treatment of multiple sclerosis (MS) and inflammatory bowel disease. DATA SOURCES: A PubMed/MEDLINE search was conducted (1966-June 2005), and information was obtained from Iowa Drug Information Services. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles examining natalizumab were evaluated. All published, randomized clinical trials evaluating natalizumab in MS and IBD were included in this review. DATA SYNTHESIS: Natalizumab is the first drug in a new class of agents called selective adhesion molecule inhibitors. It has shown promising results in MS and inflammatory bowel disease and appears superior compared with current therapies in reducing relapse rates. However, 3 recent, confirmed case reports of progressive multifocal leukoencephalopathy (PML) create concern about natalizumab's use in combination with existing therapies or in undefined patient subgroups. Natalizumab was voluntarily withdrawn from the market in March 2005 while the drug's safety is further evaluated. CONCLUSIONS: Although long-term efficacy and safety of natalizumab have not been established, available data indicate that it is a novel drug for patients with MS or inflammatory bowel disease. Analysis of its possible association with PML will determine the risk-benefit evaluation and eventual place in therapy for natalizumab.",1
10912,16221163,Sirolimus-associated hepatotoxicity in the kidney graft recipient,"The aim of our paper was to describe hepatotoxicity of sirolimus (SRL) in a kidney graft recipient. We report the case of a 30-year-old male after kidney transplantation, treated with steroids, cyclosporin A and SRL, with steroid-resistant acute rejection in anamnesis. At 16th month after transplantation, elevation of serum aminotransfereases was observed. After exclusion of common reasons of this condition, liver biopsy was performed. Nonspecific changes were observed, with probability of drug-induced injury. SRL was changed to mycophenolate mofetil, which was followed by quick normalization of serum aminotransferase levels. Hepatoxicity is a rare complication of SRL therapy and may be connected with some diagnostic and/or therapeutic problems. Conversion to another immunosuppressant seems to be an appropriate procedure in this condition.",1
10913,16226335,Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia,"BACKGROUND/AIMS: The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm. METHODS: We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6-22) months. All these children were treated in the 6TG-arm. RESULTS: The median (range) age at presentation was 6.6 (3.2-11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80 IU/l, normal range 10-50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4-36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children. CONCLUSIONS: 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.",1
10914,16230048,An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia,"""BACKGROUND AND PURPOSE: A double-blind placebo-controlled study of eszopiclone found significant, sustained improvement in sleep and daytime function. The 6-month open-label extension phase is described herein. PATIENTS AND METHODS: Adults (21-64) with primary insomnia who reported sleep duration <6.5 h/night or sleep latency >30 min/night were included. Patient-reported endpoints included sleep and daytime function. Safety and compliance were assessed at monthly clinic visits. The final double-blind month was used as the baseline for efficacy analyses of the open-label period. RESULTS: Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone (n=111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (P<or=0.0001 all monthly endpoints). There was no evidence of tolerance on any measure in either group. These subjects (n=360) sustained the double-blind treatment gains for all sleep and daytime parameters, with further significant improvement in a number of measures. Eszopiclone was well tolerated in both groups; unpleasant taste was the only undesirable effect reported by >5% of patients. CONCLUSIONS: The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double-blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3mg was well tolerated; tolerance was not observed.""",1
10915,16230965,[Cytolytic hepatitis and esomeprazole during chemotherapy],"INTRODUCTION: Esomeprazole, the pure S isomer form of omeprazole, is indicated for the treatment of peptic esophagitis. We report here a major episode of cytolytic hepatitis following a single administration. CASE: A 41-year-old woman with infiltrating ductal carcinoma of the breast was undergoing chemotherapy with paclitaxel and trastuzumab. On the fourth day of the second course, she took 1 tablet of esomeprazole 20 mg for epigastric pain. Liver pain and asthenia followed, and liver function tests showed substantial cytolysis. These tests returned to normal levels despite continuation of the chemotherapy. DISCUSSION: This cytolytic hepatitis is very probably imputable to esomeprazole, but a synergistic hepatic toxicity of the chemotherapy with esomeprazole cannot be ruled out.",1
10916,16231956,The safety profile of sustained release paracetamol during therapeutic use and following overdose,"""Sustained release (SR) formulations of paracetamol (acetaminophen) have been introduced in several countries to provide lasting pain relief and reduced risk of rebound pain. However, few studies have evaluated the safety of paracetamol SR formulations. To assess the available published safety data regarding SR formulations of paracetamol, the EMBASE and MEDLINE databases were searched from 1980 to June 2003 for published worldwide human experience with paracetamol SR formulations. All publications that included any information about ingestion of any paracetamol SR formulation were systematically reviewed and abstracted by trained staff. The literature searches returned a total of 14 references containing safety data on paracetamol SR. In addition, the Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers (AAPCC) database was searched for human exposure cases. The TESS database yielded 3003 cases from 1994 to 2002 that involved a paracetamol SR product. The available information indicates that the adverse event and safety profile of paracetamol SR is very similar to immediate release (IR) formulations of paracetamol. During therapeutic use, minor effects such as gastrointestinal upset and headache may occur. The rate of these effects varies substantially among studies but overall does not appear to be different between the SR and IR formulations of paracetamol. Overdose with paracetamol SR is expected to cause liver injury similar to overdose with IR formulations. The number of human exposure cases has increased since introduction of the SR formulation; however, sales of the SR formulation amounted to 7.5% of all paracetamol sales but accounted for 2.5% of the cases reported to poison centres. There were two deaths recorded in the TESS database: both were the result of multiple drug ingestion. No cases of death or unusual types of toxicity have been described from an overdose of paracetamol SR alone.""",1
10917,16236737,Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer,"""BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)""",1
10918,16236892,The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis,"""BACKGROUND: Cystic fibrosis (CF) is characterized by chronic pulmonary infection with acute pulmonary exacerbations (APEs) requiring IV antibiotic treatment. We report on a blinded comparative trial of IV meropenem (40 mg/kg to 2 g q8h) or ceftazidime (5 mg/kg to 2 g q8h), each of which was administered with IV tobramycin (at a serum peak of > or = 8 microg/mL and a trough of < 2 microg/mL), as treatment for CF patients with APEs. METHODS: Patients who were > or = 5 years of age who were infected with ceftazidime-susceptible Pseudomonas aeruginosa were stratified by lung function and randomized to treatment with meropenem/tobramycin or ceftazidime/tobramycin. Patients infected with Burkholderia cepacia complex or ceftazidime-resistant P aeruginosa were assigned to receive open-label meropenem/tobramycin. Clinical response was assessed by spirometry to determine the change in percent predicted FEV1 and by a clinical acute change score (ACS). RESULTS: One hundred two patients were randomized to meropenem/tobramycin (n = 50) or ceftazidime/tobramycin (n = 52). Nineteen patients received open-label meropenem/tobramycin. FEV1 was improved at the end of treatment (EOT) with meropenem/tobramycin (mean [+/- SD] increase, 38.8 +/- 52.3%) and with ceftazidime/tobramycin (mean increase, 29.4 +/- 35.1%; p < 0.0001 vs baseline values). The proportion of patients with > or = 15% relative increase from baseline FEV1 (satisfactory response) at day 7 was 62% for the meropenem/tobramycin group and 44% for the ceftazidime/tobramycin group (p = 0.04). The median time to FEV1 response was 4 days for meropenem/tobramycin therapy vs 6 days for ceftazidime/tobramycin therapy. Similarly, FEV1 improved in the open-label group (mean increase, 12.5 +/- 25.7%; p = 0.05). ACS improved in all three groups at EOT (p < 0.0001 vs baseline values). CONCLUSIONS: Therapy with both meropenem/tobramycin and ceftazidime/tobramycin improved pulmonary and clinical status and reduced sputum bacterial burden in CF patients with APEs. A larger proportion of patients receiving meropenem/tobramycin therapy demonstrated a satisfactory FEV1 response at day 7. Resistant P aeruginosa emerged infrequently during treatment with both regimens.""",1
10919,16238904,Pharmacokinetics of telithromycin: application to dosing in the treatment of community-acquired respiratory tract infections,"INTRODUCTION: Telithromycin is the first ketolide anti bacterial approved for treating community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis in adults. The purpose of this article is to review the main pharmacokinetic properties of telithromycin and their application to the treatment of these infections. METHODS: Sources of information were identified through a Medline search (up to March 2005). MAIN FINDINGS: The absolute oral bioavailability of telithromycin is approximately 57%, which is unaffected by food intake. At the recommended 800 mg once-daily oral dosing regimen, telithromycin reaches a steady-state concentration of approximately 2 microg/mL in plasma and has an elimination half-life of approximately 10 hours. Telithromycin shows extensive tissue distribution and penetrates effectively into bronchopulmonary tissue and epithelial lining fluid. Since elimination of telithromycin occurs via multiple pathways--the highest proportion (70%) through metabolism--impairment of a single pathway has a limited impact on telithromycin exposure. Dose adjustments are unnecessary in elderly patients or in individuals with hepatic impairment or mild to moderate renal impairment. A reduced dose could be recommended in patients with severe renal impairment. Telithromycin is metabolized primarily in the liver, approximately half of which is via the cytochrome P450 (CYP) 3A4 system. Telithromycin AUC(0-24 h) increased by 1.5- to 2.0-fold in the presence of itraconazole and ketoconazole. Administration of telithromycin with drugs metabolized via CYP3A4 may result in increased exposure to the co-administered drug, as shown for simvastatin (5.3-fold) and midazolam (6-fold). Co-administration of telithromycin minimally increases (1.2- to 1.4-fold) exposure to theophylline, digoxin, and metoprolol. Although telithromycin does not affect the pharmacokinetics of warfarin, consideration should be given to monitoring prothrombin times/INR in patients receiving telithromycin and oral anticoagulants simultaneously. CONCLUSION: Overall, the pharmacokinetic/pharmaco dynamic properties of telithromycin indicate that this ketolide antibacterial is a valuable and convenient treatment option for community-acquired respiratory tract infections.",1
10920,16245328,Long remissions in hairy cell leukemia with purine analogs: a report of 219 patients with a median follow-up of 12.5 years,"""BACKGROUND: Both pentostatin and cladribine have efficacy in hairy cell leukemia (HCL), but it is not known which agent achieves better results. METHODS: We reviewed a series of 219 patients with HCL, with median follow-up from diagnosis of 12.5 years (range 1.0 -34.6 yrs), treated with either pentostatin (n = 185) or cladribine (n = 34), to compare these agents and assess the potential for cure. RESULTS: Overall response to pentostatin was 96% with a complete response (CR) in 81% and a median disease-free survival (DFS) of 15 years. Response to first-line cladribine was 100% with a CR in 82% and DFS of 11+ years. The relapse rates at 5 years and 10 years were 24% and 42%, respectively, with pentostatin, and 33% and 48% with cladribine. Survival at 10 years was respectively 96% and 100%. CR rates decreased with each sequential relapse through 69% to 45% (P < or = 0.001). Patients achieving CR after first-line treatment had a significantly longer DFS (P = 0.00007) than those achieving a partial response; a similar result was seen after second-line therapy (P = 0.00001). DFS also declined with sequential treatment (P = 0.00005). CONCLUSION: We have shown equivalent efficacies for both agents in the treatment of HCL, with DFS showing no plateau. True cure in HCL remains elusive, but the addition of monoclonal antibodies may be beneficial. Our results suggest that achieving CR should remain the main goal of treatment.""",1
10921,16250039,Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis,"""This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.""",1
10922,16251482,Cisplatin-induced hepatotoxicity is enhanced by elevated expression of cytochrome P450 2E1,"In this study, the possible potentiation of cisplatin-induced hepatotoxicity by cytochrome P450 2E1 (CYP2E1) was examined both in vitro and in vivo. Transfected HepG2 cells expressing CYP2E1 (E47 cells) and not expressing CYP2E1 (C34 cells) were used as an in vitro model, and mice drinking 2% acetone for 7 days to induce CYP2E1 were used as an in vivo model. Exposure of E47 cells to cisplatin caused a much greater loss of cell viability, more striking depletion of reduced glutathione (GSH), and higher reactive oxygen species (ROS) production as compared with C34 cells. The prooxidant L-buthionine-[R,S]-sulfoximine (BSO), which depletes GSH, enhanced cisplatin-induced loss of cell viability, whereas the antioxidant glutathione ethyl ester, or the iron chelator deferoxamine mesylate (DFO) protected against the cisplatin-induced loss of E47 cell viability. Diallyl sulfide (DAS), an inhibitor of CYP2E1, also protected against the cisplatin toxicity in the E47 cells. After being injected with cisplatin (ip, 45 mg/kg), mice drinking 2% acetone with increased CYP2E1 levels exhibited elevated levels of serum ALT and AST, liver caspase-3 activity and positive staining of TUNEL increased, and histopathology indicated the presence of necrotic foci in livers of acetone plus cisplatin-treated mice. Lipid peroxidation and protein oxidation as indicated by carbonyl formation, staining of 3-nitrotyrosine (3-NT) and iron were higher in the cisplatin plus acetone group, compared with cisplatin alone group. Both in vitro and in vivo results indicate that elevated CYP2E1 enhances cisplatin-induced hepatotoxicity, and the mechanism may involve increased production of ROS and oxidative stress.",1
10923,16255657,Alefacept: a safety profile,"Alefacept is a selective immunomodulating, antipsoriatic drug that blocks the LFA-3/CD2 interaction necessary for the activation and proliferation of memory effector T cells by binding to CD2 expressed on the T cell surface. Because the CD4+ count is reduced by alefacept, it is recommended that this count be monitored on a regular basis to ensure that it does not drop below 250 cells/mul. Few side effects have been related to the use of alefacept that differ from placebo even when CD4+ counts drop below 250 cells/microl. The side effects that have been reported are minor and include: headache, nasopharyngitis, rhinitis, influenza, upper respiratory tract infections, pruritus, arthralgias, fatigue, nausea, accidental injury and increases in liver enzymes. Serious infections and malignancies do not appear linked to the use of alefacept. The percentage of patients who developed antibodies against alefacept is very low. Alefacept is a very safe biological therapy for moderate-to-severe chronic plaque psoriasis with few side effects reported. The utility of checking CD4 counts while administering alefacept for 12 weeks appears minimal.",1
10924,16256055,Acute hepatitis and atovaquone/proguanil,"A 31-year-old healthy man developed acute hepatitis after receiving atovaquone (250 mg) and proguanil (100 mg) for malaria prophylaxis daily for 25 days. Although atovaquone/proguanil is generally well-tolerated, this case highlights the hepatotoxic potential with considerable morbidity and should alert physicians to this harmful side effect.",1
10925,16260522,Third-trimester maternal toxicity with nevirapine use in pregnancy,"""OBJECTIVE: Nevirapine-based therapy is associated with increased frequency of adverse events among women with CD4+ cell count of 250 cells/microL or greater. We evaluated the safety of nevirapine-based antiretroviral therapy in human immunodeficiency virus (HIV)-1-infected pregnant women. METHODS: We retrospectively evaluated 23 pregnancies managed with nevirapine-based regimens from July 2001 to April 2005. The incidence of adverse events was determined and analyzed by CD4+ cell count of either less than or greater than or equal to 250 cells/microL, and gestational age when nevirapine was initiated. Liver function abnormality was graded according to the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity guidelines. RESULTS: Five of 23 patients (21.7%) started nevirapine-based therapy after 27 weeks of gestation. All 3 cases of adverse events occurred in this group within 6 weeks of initiating therapy and with CD4+ cell count greater than 250 cells/microL. A significant difference was noted in the proportion of patients who developed toxicity while starting nevirapine in the third trimester (3/5, 60%; 95% confidence interval 14.66-94.73) compared with those starting nevirapine earlier in pregnancy (0/18, 0%; 95% confidence interval 0.0-18.53; P < .006). Two patients developed rash, eosinophilia, and liver function abnormality, with one developing clinical hepatitis and renal failure. A third patient had abnormal elevation of liver enzymes but was asymptomatic. CONCLUSION: The incidence of adverse events with nevirapine may be lower than previously reported (13% versus 29%) and may be primarily noted with initiating the drug late in pregnancy. Further study of nevirapine in larger cohorts of HIV-infected pregnant women is warranted to determine the relationship between nevirapine hepatotoxicity and trimester use. LEVEL OF EVIDENCE: II-3.""",1
10926,16265126,Drug Insight: appetite suppressants,"""The term 'appetite suppressant' is used to denote drugs that act primarily on the neurochemical transmitters of the central nervous system to reduce food intake. In addition to drugs that release or mimic the effect of norepinephrine (noradrenaline), this could include drugs that inhibit: reuptake of norepinephrine or 5-hydroxytryptamine (also known as serotonin); bind to the gamma-aminobutyric acid receptors or the cannabinoid receptors; and some peptides that reduce food intake. The sympathomimetic drugs phentermine, diethylpropion, benzphetamine, and phendimetrazine--so named because they mimic many effects of norepinephrine--are only approved in a few countries, and then only for short-term use. Sibutramine, a norepinephrine-5-hydroxytryptamine reuptake inhibitor, is approved for long-term use. Several new mechanisms for drug action are under investigation. Appetite suppressants should be viewed as useful adjuncts to diet and physical activity and might help selected patients to achieve and maintain weight loss.""",1
10927,16267494,Ramelteon (Rozerem) for insomnia,,1
10928,16268429,Subacute cholestatic hepatitis likely related to the use of senna for chronic constipation,"We report a case of senna-induced cholestatic hepatitis which was not diagnosed at presentation. A 77 year old male was referred with abdominal pain, jaundice and elevated transaminase levels. A diagnosis of extrahepatic cholestasis was first suspected, due to the observation of a duodenal diverticulum and dilated proximal choledocus. However, the sphincterotomy did not improve cholestasis. At further evaluation, HBsAg was positive but serological work up was compatible with a healthy-carrier status. Further interrogation of the patient revealed a history of chronic senna intake to treat a chronic constipation. Liver biopsy showed bridging hepatocellular necrosis as well as canalicular cholestasis. Drug withdrawal resulted in a slow and progressive reduction in bilirubin levels and liver enzymes. In this case senna was likely the cause of a subacute cholestatic hepatitis exemplifying again the potential role of herbal related liver injury.",1
10929,16276709,The efficacy and toleration of celecoxib (Celebrex) in the treatment of osteoarthritis in Nigeria: a multicentre study,"BACKGROUND: Non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) are effective in terms of pain relief and improving function in osteoarthritis. The advent of cyclooxygenase-2 (Cox-2) specific inhibitor, celecoxib, in the treatment of osteoarthritis has shown similar efficacy in relieving pain in osteoarthritis with low incidence of GI (Gastrointestinal) symptoms. OBJECTIVE: To determine the efficacy and toleration of celecoxib in treatment of osteoarthritis in Nigerian population. METHODS: Eighty patients were recruited from six tertiary health institutions scattered over Nigeria. A fixed dose of 200 mg celecoxib was administered daily with patient seen on the second and six weeks after commencement of study. Efficacy of the drug and safety were assessed during the study. RESULTS: The patients had a mean age of 57.8 years with a standard deviation of 13.3 year. The mean weight was 74.7 +/- 14.9kg while the female sex constituted the majority (73.8%) of the patients. Using the physician global assessment of osteoarthritis instrument, 36.3% of the patients were rated as having poor arthritis score at baseline. This value reduced to 2.6% at second visit and 0.00% at end of the study respectively. There was no significant difference between the vital signs, haematological indices, renal and hepatic function at baseline and the final visit. There was no case of serious adverse effect. CONCLUSION: The study showed statistically significant improvements in the symptoms of osteoarthristis following the administration of Celecoxib 200mg daily for six weeks.",1
10930,16278718,"Quinine allergy causing acute severe systemic illness: report of 4 patients manifesting multiple hematologic, renal, and hepatic abnormalities","Quinine is widely used for the common symptom of leg cramps. Quinine tablets require a prescription, but quinine and the product from which it is derived, cinchona, are also available without prescription. They are components of over-the-counter remedies for many common symptoms, of nutrition products, and of beverages such as tonic water and bitter lemon. Although quinine has been used for centuries, initially as an extract from the bark of the cinchona tree, allergic reactions to quinine can be severe and can affect multiple organs. These allergic reactions can cause thrombocytopenia, neutropenia, anemia, disseminated intravascular coagulation, acute renal failure, liver toxicity, and neurological abnormalities. Because quinine use is often intermittent, defining quinine as a cause of an acute disorder may be difficult. Moreover, since quinine use is often self-regulated, patients may not mention it in response to direct questions about medication use, adding to diagnostic difficulty. The diversity and severity of quinine-associated disorders and the difficulties of diagnosis are illustrated by the presentation of 4 case histories. Awareness of the variety of potential quinine-associated reactions is important for accurate diagnosis and critical for prevention of recurrent illness.",1
10931,16280073,"Subcutaneously administered Menopur, a new highly purified human menopausal gonadotropin, causes significantly fewer injection site reactions than Repronex in subjects undergoing in vitro fertilization","BACKGROUND: The safety and tolerability of a new highly purified, urine-derived human menopausal gonadotropin (hMG) preparation [Menopur] was compared with a currently available hMG [Repronex] in women undergoing in vitro fertilization (IVF). METHODS: This was a randomized, open-label, parallel-group, multicenter study conducted in subjects undergoing IVF. Women (N = 125), 18-39 years of age, underwent pituitary down-regulation with leuprolide acetate beginning 7 days prior to onset of menses and continuing up to the day before hCG administration. Subjects were randomized to receive subcutaneous (SC) Menopur (n = 61) or Repronex SC (n = 64) for a maximum of 12 days. All adverse events (AEs) were recorded and subject self-assessments of injection site reactions were recorded in a daily diary. RESULTS: Significantly fewer subjects in the Menopur group reported injection site reactions (P < 0.001) compared to the Repronex group. Overall, there was no statistically significant difference in the incidence of AEs between the two treatment groups. CONCLUSION: Menopur SC offers a greater safety and tolerability profile compared to Repronex SC.",1
10932,16282728,Changes in hepatic parenchymal ultrasound images in tamoxifen medication patients,"We experienced changes in ultrasonographic features of hepatic parenchyma in 156 patients treated with Tamoxifen (TAM) as an adjuvant hormonal therapy for breast cancer. After the treatment with TAM subsequent to the surgery for breast cancer, 36% of patients showed changes in ultrasonographic features of the liver more than Grade 2, despite no obvious hepatic involvement at the start of the medication. Forty-five percent of affected patients showed Grade 2 or 3 changes in hepatic parenchymal images within the first 6 months of TAM medication, while the average interval of change was 11.3 months. Abdominal ultrasound inspection should be undertaken within 6 months of surgery to aid the early detection of liver metastasis and fatty liver changes, which may play an important role in determining postoperative follow-up care for breast cancer patients.",1
10933,16284461,Is there evidence for an increase in the death rate from liver-related disease in patients with HIV?,"BACKGROUND: Increases in deaths due to liver-related disease (LRD) among HIV-infected individuals have been reported although the influence of combination antiretroviral therapy (cART) on LRD is controversial. AIMS: To determine changes over time in the death rate from LRD and if longer exposure to cART was associated with an increased death rate from LRD in 10 937 patients from EuroSIDA, an observational longitudinal cohort study. RESULTS: A total of 184 (1.7%) died from LRD during 52 236 person-years of follow-up (PYFU). The death rate from LRD declined from 6.9 per 1000 PYFU before 1995 [95% confidence interval (CI), 3.9-9.9] to 2.6 at/after 2004 (95% CI, 1.6-4.0). When the current CD4 cell count and other factors were taken into account, there was a 13% increase in the death rate from LRD per year (95% CI, 5-20%, P = 0.0008). In patients who had started cART, there was a 12% increase in the death rate from LRD per additional year exposure to cART (95% CI, 4-20%, P = 0.022) after adjustment for current CD4 cell count and other factors. CONCLUSIONS: Death rates from LRD appeared to decrease across Europe. However after adjustment for the current CD4 cell count, and therefore increases in CD4 cell counts in patients taking cART, there was a significant increase over time in death rates from LRD. In patients with similar CD4 cell counts, longer exposure to cART was associated with an increased death rate from LRD. This may be due to direct liver toxicity of antiretrovirals, progression of liver disease due to hepatitis B virus or hepatitis C virus over time as patients survive longer, or some other factor.",1
10934,16285074,Infliximab: lymphomas and severe hepatitis,,1
10935,16286736,Have methotrexate-induced liver fibrosis and cirrhosis become rare? A matter for reappraisal of routine liver biopsies,,1
10936,16288075,Acute hyperammonemic coma with chronic valproic acid therapy,"OBJECTIVE: To report a case of dose-related hyperammonemic coma without liver failure in a patient receiving chronic valproate therapy. CASE SUMMARY: A 56-year-old woman with poorly controlled epilepsy, receiving valproate at subtherapeutic levels for 6 years, developed a life-threatening hyperammonemic coma following a moderate dosage increase. DISCUSSION: Hyperammonemic coma without associated liver failure is an extremely rare complication of valproate therapy, described primarily in patients with inborn errors of metabolism and occurring idiosyncratically during initial stages of therapy. In our case, family history was suggestive of an X-linked disorder, raising the possibility that our patient may have been an asymptomatic carrier of a urea cycle enzyme deficiency unmasked by valproate therapy. To our knowledge, as of October 24, 2005, only one prior case of hyperammonemic coma in the context of chronic valproate monotherapy has been described. Application of the Naranjo probability scale score suggests that a causal relationship between valproic acid and hyperammonemic coma was probable. CONCLUSIONS: The widespread use of valproic acid emphasizes the need to maintain a high degree of suspicion with respect to this rare but potentially fatal adverse effect at all times, regardless of therapy duration.",1
10937,16291042,PDE-5 inhibitors: current status and future trends,"Phosphodiesterase-5 (PDE-5) inhibitors are a well-established, first-line therapy for erectile dysfunction (ED). Extensive clinical trials and clinical experience established the highly significant efficacy and the safety of this class of drugs in the treatment of ED.Furthermore, the efficacy of PDE-5 inhibitors has been established in men with ED with a broad range of etiologies and comorbidities. The future of PDE-5 inhibitors includes the expansion of indications such as the treatment of pulmonary hypertension and the potential of treatment of symptomatic BPH.",1
10938,16292105,Orlistat (Xenical)-induced subacute liver failure,,1
10939,16294367,Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system,"PURPOSE: To analyse the type and main features of the hepatotoxicity induced by steroidal and non-steroidal antiandrogens spontaneously reported by physicians, pharmacists and nurses. This analysis could increase the information related to these adverse reactions mainly available from the published isolated cases. METHODS: Using the Spanish Pharmacovigilance database we searched for spontaneous reports recorded since the date of approval of each antiandrogen up to the present time. We analysed the frequency of liver disorders, the preferred terms coded, the presence of other hepatotoxic drugs, and the characteristics of cases of hepatitis. RESULTS: Liver disorders were the most common adverse reactions associated with flutamide and bicalutamide, but not with cyproterone acetate. 'Hepatitis' and 'cholestatic hepatitis' were the most frequent terms coded. In 38% of the reports related to cyproterone acetate, 18% of those related to flutamide and 33% of those related to bicalutamide the patient had simultaneously received other hepatotoxic drugs. The disproportionality analysis of hepatitis showed a strong association with flutamide and a weak association with bicalutamide and cyproterone acetate. Mean doses of flutamide and bicalutamide were very close to their defined daily dose (DDD) to treat prostate cancer, although in the case of cyproterone acetate it was slightly higher. The latency period of hepatitis was between 3 and 10 months for the three antiandrogens, and the recovery period was shorter (0.5-3 months). The majority of the reported cases of hepatitis evolved favourably. CONCLUSION: Our results highlight the hepatotoxic potential of flutamide compared to cyproterone acetate. The data related to bicalutamide should be cautiously considered due to the smaller number of reports.",1
10940,16300170,Statin toxicity: a situation that mimics viral hepatitis,A case is presented involving a female patient who experienced rhabdomyolysis following high-dose therapy with a statin. Acute renal failure was a complicating factor necessitating the use of hemodialysis. The patient recovered fully within about 6 weeks.,1
10941,16306522,Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis,"""BACKGROUND: Nonselective beta-adrenergic blockers decrease portal pressure and prevent variceal hemorrhage. Their effectiveness in preventing varices is unknown. METHODS: We randomly assigned 213 patients with cirrhosis and portal hypertension (minimal hepatic venous pressure gradient [HVPG] of 6 mm Hg) to receive timolol, a nonselective beta-blocker (108 patients), or placebo (105 patients). The primary end point was the development of gastroesophageal varices or variceal hemorrhage. Endoscopy and HVPG measurements were repeated yearly. RESULTS: During a median follow-up of 54.9 months, the rate of the primary end point did not differ significantly between the timolol group and the placebo group (39 percent and 40 percent, respectively; P=0.89), nor were there significant differences in the rates of ascites, encephalopathy, liver transplantation, or death. Serious adverse events were more common among patients in the timolol group than among those in the placebo group (18 percent vs. 6 percent, P=0.006). Varices developed less frequently among patients with a baseline HVPG of less than 10 mm Hg and among those in whom the HVPG decreased by more than 10 percent at one year and more frequently among those in whom the HVPG increased by more than 10 percent at one year. CONCLUSIONS: Nonselective beta-blockers are ineffective in preventing varices in unselected patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events. (ClinicalTrials.gov number, NCT00006398.)""",1
10942,16307333,Microscopic polyangiitis complicated by the development of prostate cancer and flutamide-induced hepatitis,"We report a case of a 65-year-old man with microscopic polyangiitis who developed prostate cancer and gastric adenocarcinoma after prolonged oral use of cyclophosphamide. Acute hepatitis with jaundice and marked increase in aminotranferases occurred after 6 months of flutamide treatment for metastatic prostate carcinoma. It is suggested that patients with vasculitis or other autoimmune disorders should avoid prolonged use of cyclophosphamide and other cytotoxic drugs in order to minimize long-term adverse effects, of which the risk of cancer is by far the most important. In patients on flutamide treatment, careful monitoring of flutamide administration with repeated liver function tests should be undertaken, and the drug must be immediately discontinued in patients with abnormal results to avoid progression of liver injury.",1
10943,16309958,"An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia","BACKGROUND AND PURPOSE: To evaluate the efficacy, safety, and dose response of Ramelteon, a novel highly selective MT1/MT2 receptor agonist, in patients with chronic primary insomnia. PATIENTS AND METHODS: A randomized, multicenter, double-blind, placebo-controlled, five-period crossover study design was performed. A total of 107 patients, aged 18-64 years, were randomized into a dosing sequence that included 4, 8, 16, and 32 mg of Ramelteon and placebo. Patients received all five treatments, with a 5- to 12-day washout period between treatments, and served as their own controls. Medication was administered 30 min before habitual bedtime and polysomnographic monitoring. Next-day residual effects were assessed with two visual analog scales (mood and feeling), digit symbol substitution test (DSST), word-list memory tests (immediate recall and delayed recall), and a post-sleep questionnaire that ascertained patients' alertness and ability to concentrate. RESULTS: All tested doses of Ramelteon resulted in statistically significant reductions in latency to persistent sleep (LPS) and increases in total sleep time (TST). No next-day residual effects were apparent at any dose, as compared with placebo. There were no differences in the number or type of adverse events between any active treatment and placebo group. The most commonly reported adverse events were headache, somnolence, and sore throat. CONCLUSIONS: Ramelteon demonstrated a statistically significant reduction in LPS and a statistically significant increase in TST, with no apparent next-day residual effects, in patients with chronic primary insomnia.",1
10944,16316778,Adefovir added to lamivudine for hepatitis B recurrent infection in refractory B-cell chronic lymphocytic leukemia on prolonged therapy with Campath-1H,"We describe a case of severe reactivation of occult hepatitis B virus infection in a 49-year-old man, who was treated with high doses of chlorambucil for a Binet stage A B-cell chronic lymphocytic leukemia (B-CLL). The patient was initially treated with lamivudine and subsequently with lamivudine and adefovir dipivoxil combination therapy to control viral replication and allow for long-term anti-cancer chemotherapy with alemtuzumab (Campath-1H), which was introduced to rescue for a B-CLL relapse. During 20 months of anti-HBV therapy, ALT and HBV-DNA levels progressively declined and B-CLL was successfully kept under control by long-term alemtuzumab administration.",1
10945,16317692,"Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study","""Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.""",1
10946,16321842,Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment,"Reactivation of chronic hepatitis B virus (HBV) infection in patients undergoing chemotherapy is well-documented, but reactivation during imatinib mesylate treatment has not been reported. This study reports a 54-year-old man, without prior liver dysfunction but with chronic HBV infection, in whom fatal HBV reactivation occurred during treatment of chronic myeloid leukemia (CML) with imatinib mesylate. He developed fulminant hepatitis followed by marked elevation of HBV DNA polymerase, probably from the lymphocytopenic and immunosuppressive status induced by imatinib mesylate. Imatinib mesylate is widely used to treat CML patients. Although therapy with imatinib mesylate is generally well tolerated, the case presented here suggests that viral reactivation should be considered, even when using imatinib mesylate to treat CML.",1
10947,16323571,Hepatotoxicity in acute iron poisoning,"Although liver injury is a recognized consequence of acute iron poisoning, its description is limited to several case reports. It appears to be dose-related, however, there are published reports of severe iron poisoning without liver injury. The purpose of this study is to examine the hypothesis that this is a dose-related phenomenon and to identify the serum iron concentration of risk for this outcome. The design of this study is a retrospective review of our hospital's experience over 20 years. Extracted data included demographics, time of ingestion, highest serum iron concentration and highest hepatic transaminase activity. Iron poisoning was defined as a serum iron concentration >300 microg/dL (55 micromol/L) within 12 hours of ingestion. Hepatotoxicity was defined as a serum transaminase (either ALT or AST) >150 U/L. Severe hepatotoxicity was defined >1000U/L. Seventy-three patients (1-48 years old) participated in the study and of these patients 60 (47 female) did not have hepatotoxicity. Their serum iron concentrations were 300-704 microg/dL (55-128 micromol/L). Thirteen patients had hepatotoxicity and of these patients, nine had severe liver injury. Severe injury was associated with serum iron concentrations well in excess of 1000 microg/dL (182 micromol/L). Our data support hepatotoxicity due to iron poisoning as a dose-related phenomenon with clinically important cases unlikely with a serum iron concentration of < 700 microg/dL (128 micromol/L) within the first 12 hours. Clinically important hepatotoxicity occurs with values in excess of 1000 microg/dL (182 micromol/L).",1
10948,16333209,Anaphylaxis and hypersensitivity syndrome reactions in increasing severity following repeated exposure to tinidazole,,1
10949,16335333,Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial,"""CONTEXT: Insomnia is a prevalent health complaint associated with daytime impairments, reduced quality of life, and increased health-care costs. Although it is often self-treated with herbal and dietary supplements or with over-the-counter sleep aids, there is still little evidence on the efficacy and safety of those products. OBJECTIVE: To evaluate the efficacy and safety of a valerian-hops combination and diphenhydramine for the treatment of mild insomnia. DESIGN AND SETTING: Multicenter, randomized, placebo-controlled, parallel-group study conducted in 9 sleep disorders centers throughout the United States. PATIENTS: A total of 184 adults (110 women, 74 men; mean age of 44.3 years) with mild insomnia. INTERVENTIONS: (1) Two nightly tablets of standardized extracts of a valerian (187-mg native extracts; 5-8:1, methanol 45% m/m) and hops (41.9-mg native extracts; 7-10:1, methanol 45% m/m) combination for 28 days (n = 59), (2) placebo for 28 days (n = 65), or (3) 2 tablets of diphenhydramine (25 mg) for 14 days followed by placebo for 14 days (n = 60). OUTCOME MEASURES: Sleep parameters measured by daily diaries and polysomnography, clinical outcome ratings from patients and physicians, and quality of life measures. RESULTS: Modest improvements of subjective sleep parameters were obtained with both the valerian-hops combination and diphenhydramine, but few group comparisons with placebo reached statistical significance. Valerian produced slightly greater, though nonsignificant, reductions of sleep latency relative to placebo and diphenhydramine at the end of 14 days of treatment and greater reductions than placebo at the end of 28 days of treatment. Diphenhydramine produced significantly greater increases in sleep efficiency and a trend for increased total sleep time relative to placebo during the first 14 days of treatment. There was no significant group difference on any of the sleep continuity variables measured by polysomnography. In addition, there was no alteration of sleep stages 3-4 and rapid eye movement sleep with any of the treatments. Patients in the valerian and diphenhydramine groups rated their insomnia severity lower relative to placebo at the end of 14 days of treatment. Quality of life (Physical component) was significantly more improved in the valerian-hops group relative to the placebo group at the end of 28 days. There were no significant residual effects and no serious adverse events with either valerian or diphenhydramine and no rebound insomnia following their discontinuation. CONCLUSIONS: The findings show a modest hypnotic effect for a valerian-hops combination and diphenhydramine relative to placebo. Sleep improvements with a valerian-hops combination are associated with improved quality of life. Both treatments appear safe and did not produce rebound insomnia upon discontinuation during this study. Overall, these findings indicate that a valerian-hops combination and diphenhydramine might be useful adjuncts in the treatment of mild insomnia.""",1
10950,16340060,Nitazoxanide,,1
10951,16344532,Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism,"The authors report two cases of catechol-O-methyltransferase (COMT) inhibitor-induced asymptomatic hepatic dysfunction in women with Parkinson disease. The patients were genotyped for the UDP-glucuronosyltransferase (UGT) 1A9 gene (which encodes the main COMT inhibitor-metabolizing enzyme), and found to carry mutations leading to defective glucuronidation activity. This suggests that UGT1A9 poor metabolizer genotype(s) may be a predisposing factor for COMT inhibitor-induced hepatotoxicity.",1
10952,16352812,"A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia","""Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.""",1
10953,16364504,[Nitrofurantoin-induced lupus-like syndrome associated with hepatitis],,1
10954,16370086,Tipranavir,,1
10955,16371728,Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases,"OBJECTIVE: : To assess the effects of preoperative systemic chemotherapy on remnant liver parenchyma, liver function, and morbidity after major liver resection for colorectal liver metastases. BACKGROUND: : Many patients operated upon for colorectal cancer liver metastases receive previous chemotherapy. Whether systemic chemotherapy alters liver parenchyma in such way that it increases the risks of liver resection remains unclear. PATIENTS AND METHODS: : Among 214 patients who received a liver resection for colorectal liver metastases between 1998 and 2002 in a single institution, 67 who underwent a major liver resection under total hepatic vascular exclusion form the basis of this report. Forty-five patients operated upon after systemic chemotherapy were compared with 22 who did not receive any chemotherapy in the 6 months prior to resection. Postoperative mortality, morbidity, liver function tests, and pathology of the resected liver in the two groups were compared. RESULTS: : There was no postoperative mortality. Values of liver function tests on days 1, 3, 5, and 10 were similar in both groups. Morbidity rate was higher in the chemotherapy group (38% versus 13.5%, P = 0.03). Postoperative morbidity was correlated with the number of cycles of chemotherapy administered before surgery but not to the type of chemotherapy. Preoperative chemotherapy was significantly associated with sinusoidal dilatation, atrophy of hepatocytes, and/or hepatocytic necrosis (49% versus 25%, P = 0.005). CONCLUSION: : Prolonged neoadjuvant systemic chemotherapy alters liver parenchyma and increases morbidity after major resection under total hepatic vascular exclusion, but it does not increase operative mortality. This should be taken into consideration before deciding a major liver resection in patients who have received preoperative chemotherapy.",1
10956,16373019,[Hepatitis due to Chinese herbs],,1
10957,16377516,Sinusoidal obstruction syndrome is a major feature of hepatic lesions associated with oxaliplatin neoadjuvant chemotherapy for liver colorectal metastases,,1
10958,16378897,Angiotensin converting enzyme inhibitor toxicity causing interstitial pneumonitis and cholestatic hepatitis,,1
10959,16380589,"Prophylactic Oral Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement, or Repair: PAPABEAR: a randomized controlled trial","""CONTEXT: Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. OBJECTIVE: To determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. DESIGN, SETTING, AND PATIENTS: Double-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft (CABG) surgery and/or valve replacement/repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year. INTERVENTION: Oral amiodarone (10 mg/kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery (13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative beta-blockers. MAIN OUTCOME MEASURE: Incidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day. RESULTS: Atrial tachyarrhythmias occurred in fewer amiodarone patients (48/299; 16.1%) than in placebo patients (89/302; 29.5%) overall (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34-0.69; P<.001); in patients younger than 65 years (19 [11.2%] vs 36 [21.1%]; HR, 0.51 [95% CI, 0.28-0.94]; P = .02); in patients aged 65 years or older (28 [21.7%] vs 54 [41.2%]; HR, 0.45 [95% CI, 0.27-0.75]; P<.001); in patients who had CABG surgery only (22 [11.3%] vs 46 [23.6%]; HR, 0.45 [95% CI, 0.26-0.79]; P = .002); in patients who had valve replacement/repair surgery with or without CABG surgery (25 [23.8%] vs 44 [44.1%]; HR, 0.51 [95% CI, 0.31-0.84; P = .008); in patients who received preoperative beta-blocker therapy (27 [15.3%] vs 42 [25.0%]; HR, 0.58 [95% CI, 0.34-0.99]; P = .03); and in patients who did not receive preoperative beta-blocker therapy (20 [16.3%] vs 48 [35.8%]; HR, 0.40 [95% CI, 0.22-0.71]; P<.001), respectively. Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients (1/299; 0.3%) than in placebo patients (8/302; 2.6%) (P = .04). Dosage reductions of blinded therapy were more common in amiodarone patients (34/299; 11.4%) than in placebo patients (16/302; 5.3%) (P = .008). There were no differences in serious postoperative complications, in-hospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality. CONCLUSION: Oral amiodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and may be safe overall and in important patient subgroups. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00251706.""",1
10960,16389032,Nevirapine toxicity in a cohort of HIV-1-infected pregnant women,"OBJECTIVE: The purpose of this study was to complete an evaluation of nevirapine (NVP) toxicity in a cohort of HIV+ pregnant women. STUDY DESIGN: This was a retrospective study of 611 women followed from January 1996 to December 2003. All women who used NVP for > 7 days were included. Multivariate logistic regression was used to test independent association of CD4 and hepatitis C virus (HCV) infection related to the outcome of toxic effects of NVP. RESULTS: One hundred ninety-seven women were exposed to NVP for > 7 days, and toxicity occurred in 11 (5.6%), leading to drug discontinuation in 7 patients. One case of Stevens-Johnson syndrome occurred. No serious liver toxicity occurred except for 1 grade 4 cholestasis. Median CD4 was 344 in women without toxicities and 298 in women with toxicities. HCV was the only significant factor associated to toxicity by logistic regression (odds ratio [OR] 15.61, P = .001). CONCLUSION: NVP toxicities occurred in a very small fraction of patients and were not associated with fatalities.",1
10961,16392079,Severe or fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent tuberculosis infection,"""BACKGROUND: Severe liver injuries were attributed to the rifampin and pyrazinamide (RZ) regimen after it was recommended for treating latent tuberculosis infection. Implicating RZ as the likeliest cause required excluding alternative causes. METHODS: US health departments reported data on patients who died or were hospitalized for liver disease within 1 month after taking RZ for latent tuberculosis infection from October 1998 through March 2004. The circumstances were investigated on site for each case. Illness characteristics, reasons for RZ treatment, doses and frequency of administration of pyrazinamide, monitoring during treatment, and causes of liver injury were determined. RESULTS: Liver injury was attributable to RZ use for all 50 patients reported, 12 of whom died. For 47 patients, RZ was the likeliest cause of liver injury. The median patient age was 44 years (range, 17-73 years). Thirty-two patients (64%) were male. Seven (16%) of 43 patients tested had hepatitis C virus antibodies, 1 (2%) of 45 had chronic hepatitis B, 3 (14%) of 22 had positive results of HIV serologic tests, 34 (71%) of 48 had alcohol use noted, and 33 (66%) of 50 were taking additional hepatotoxic medications. Six patients, 2 of whom died, had no predictors for liver disease. Patients who died were older (median age, 52 vs. 42 years; P=.08) and took a greater number of other medications (median number of medications, 4 vs. 2; P=.05) than did those who recovered, but these 2 factors were correlated (P<.01). Thirty-one patients (62%) were monitored according to guidelines, 9 of whom died. CONCLUSIONS: RZ was the likeliest cause of most of these liver injuries, some of which were fatal in spite of monitoring. Fatality was predicted by age or use of other medications, but none of the cofactors showed promise as a reliable clinical predictor of severe liver injury.""",1
10962,16393447,Assessment of age-related isoniazid hepatotoxicity during treatment of latent tuberculosis infection,"BACKGROUND: Since the introduction of new recommendations for the treatment of latent tuberculosis infection (LTB1) disregarding age as a limitation, increasing numbers of older individuals are expected to undergo treatment with isoniazid for the prevention of tuberculosis, raising the potential for an increase in isoniazid hepatotoxicity. OBJECTIVE: To compare the frequency of hepatotoxicity requiring withdrawal of isoniazid therapy for LTB1 in patients under and over 35 years of age, managed according to current practice guidelines. DESIGN: A retrospective analysis of 300 patients who underwent isoniazid therapy for LTB1 according to a protocol based on the current practice guidelines. SETTING: Public health clinic of Passaic County, NJMain outcome measures: The frequency of symptomatic isoniazid hepatitis in various age groups. RESULTS: Of 165 patients < 35 years of age, 3(2%) patients developed hepatitis (AST > 3 times the upper limit of normal). Of 135 patients > or = 35 years of age, 4(3%) patients developed hepatitis. Statistical comparison between the two groups failed to show a significant difference (p = 0.705). CONCLUSIONS: No difference was detected in the frequency of isoniazid hepatotoxicity between patients < 35 and > or = 35 years of age. Clinically monitored isoniazid therapy of LTB1 patients > or = 35 years of age may not predispose subjects to an increased risk of hepatotoxicity. Limitations of this work include the small sample size and the retrospective nature of the study.",1
10963,16394850,Influence of genotype 3 hepatitis C coinfection on liver enzyme elevation in HIV-1-positive patients after commencement of a new highly active antiretroviral regimen: results from the EPOKA-MASTER Cohort,"""BACKGROUND: The independent role of hepatitis C virus (HCV) genotype 3 in liver transaminase elevation following highly active antiretroviral regimens is still controversial. METHODS: Analysis of data from a cohort of 492 HIV/HCV-coinfected patients was conducted using an intention-to-treat approach. Incidence of grade > or = III liver transaminase elevation was estimated per 100 patient-years of follow-up. Univariate and multiple proportional hazards regression analysis of factors that may predict liver enzyme elevation was performed. RESULTS: The incidence of grade > or = III hepatotoxicity was 25 per 100 patient-years among patients coinfected with HCV genotype 3 and 11 per 100 patient-years among those with other genotypes. On multiple proportional hazard regression analysis, time-to-grade > or = III liver enzyme elevation was directly correlated with HCV genotype 3 (hazards ratio [HR]: 2.0, 95% CI: 1.3 to 2.9; P = 0.001), male gender (HR: 2.7; 95% CI: 1.3 to 5.7; P = 0.007), chronic hepatitis B virus infection (HR: 2.9, 95% CI: 1.5 to 5.9; P = 0.002), and alanine aminotransferase level at baseline (per 10 IU/L HR: 1.10; 95% CI: 1.06 to 1.15; P < 0.001). In the same model, higher CD4 T-cell counts at baseline were inversely correlated with risk of hepatotoxicity (HR: 0.998; 95% CI: 0.997 to 0.999; P = 0.036). Moreover, among patients experienced to antiretroviral drugs, previous grade > or = III hepatotoxicity (HR: 2.8; 95% CI: 1.8 to 4.3; P < 0.001) was an adjunctive independent risk factor. CONCLUSIONS: HIV-positive patients coinfected with HCV genotype 3 displayed a higher risk of relevant hepatotoxicity, independently from other clinical variables. The impact of HCV genotype outweighed the role of drugs in determining hepatotoxicity.""",1
10964,16397313,Myelotoxicity and hepatotoxicity during azathioprine therapy,"Azathioprine is a frequently used immunosuppressant for managing inflammatory bowel disease (IBD). In recent years the hepatotoxic profile of thiopurines has been recognised. We report the case of a 40-year-old man with Crohn's disease treated with azathioprine. After taking azathioprine (2.2 mg/kg daily) for two years, his liver function tests were found to be elevated. Moreover, a myelodepression was established as platelet and leucocytes counts were lowered. The 6-thioguaninenucleotide level was 738 picomoles/8 x 10(8) per red blood cell, which is well above the proposed upper limit of efficacy and associated with an increased risk of developing a myelodepression. Genotyping of the enzyme thiopurine methyltransferase revealed no mutant alleles. The ultrasonography and CT scan showed signs of portal hypertension (spleen 17 cm and widened splenic vein). A liver biopsy was performed and an incomplete septal liver cirrhosis was found. An upper endoscopy revealed oesophageal varices (grade 2 to 3). Autoimmune and viral liver diseases were ruled out by laboratory parameters. After cessation of therapy, all laboratory parameters normalised. Therefore, azathioprine is believed to be the causative factor for inducing the liver cirrhosis. Continuous monitoring of patients taking thiopurines is mandatory. The role of 6-thioguaninenucleotide levels in inducing myelotoxicity and hepatotoxicity is discussed.",1
10965,16403928,"Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial","""CONTEXT: Implantable cardioverter defibrillator (ICD) therapy is effective but is associated with high-voltage shocks that are painful. OBJECTIVE: To determine whether amiodarone plus beta-blocker or sotalol are better than beta-blocker alone for prevention of ICD shocks. DESIGN, SETTING, AND PATIENTS: A randomized controlled trial with blinded adjudication of events of 412 patients from 39 outpatient ICD clinical centers located in Canada, Germany, United States, England, Sweden, and Austria, conducted from January 13, 2001, to September 28, 2004. Patients were eligible if they had received an ICD within 21 days for inducible or spontaneously occurring ventricular tachycardia or fibrillation. INTERVENTION: Patients were randomized to treatment for 1 year with amiodarone plus beta-blocker, sotalol alone, or beta-blocker alone. MAIN OUTCOME MEASURE: Primary outcome was ICD shock for any reason. RESULTS: Shocks occurred in 41 patients (38.5%) assigned to beta-blocker alone, 26 (24.3%) assigned to sotalol, and 12 (10.3%) assigned to amiodarone plus beta-blocker. A reduction in the risk of shock was observed with use of either amiodarone plus beta-blocker or sotalol vs beta-blocker alone (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.28-0.68; P<.001). Amiodarone plus beta-blocker significantly reduced the risk of shock compared with beta-blocker alone (HR, 0.27; 95% CI, 0.14-0.52; P<.001) and sotalol (HR, 0.43; 95% CI, 0.22-0.85; P = .02). There was a trend for sotalol to reduce shocks compared with beta-blocker alone (HR, 0.61; 95% CI, 0.37-1.01; P = .055). The rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for beta-blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomized to amiodarone. CONCLUSIONS: Despite use of advanced ICD technology and treatment with a beta-blocker, shocks occur commonly in the first year after ICD implant. Amiodarone plus beta-blocker is effective for preventing these shocks and is more effective than sotalol but has an increased risk of drug-related adverse effects.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00257959.""",1
10966,16410201,Riluzole therapy for motor neurone disease: an early Australian experience (1996-2002),"""Riluzole is the only therapy proven in clinical trials to prolong survival in patients with motor neurone disease (MND). Prior to its listing by the Australian Pharmaceutical Benefits Advisory Scheme in June 2003, the aim of the present study was to provide Australian patients with MND early access to riluzole and to expand the safety profile data of this therapy. Patients with MND were referred to the programme by neurologists covering the Sydney metropolitan region. To be eligible to receive riluzole, patients had to be aged between 18 and 75 years and have probable or definite MND based on El Escorial criteria, with a disease duration of less than 5 years and a vital capacity greater than 60% before study entry. Patients were prescribed riluzole 50 mg twice daily. Safety data were collected through documentation of adverse events by clinical history in combination with regular laboratory screening. Full blood count, haematocrit, differential white cell counts and serum liver transaminase levels were obtained monthly for 3 months, and then at each 3-monthly visit for 1 year. In total, 25 patients with MND (17 male, 8 female; age range 40-74 years; mean age 59 years) were commenced on riluzole. Of these, 28% had definite MND and the remaining 72% were diagnosed as probable MND, with the majority (84%) having limb-onset MND. At 12 months, 68% of patients continued on riluzole, 16% had died from their disease and 16% ceased riluzole because of side-effects or other reasons, largely disenchantment owing to a perceived lack of efficacy. Haematological and biochemical assays showed no significant alteration during the initial 12-month period. Long-term survival data for patients in the present series suggest a greater benefit for patients who commenced riluzole early in the course of their illness. In conclusion, riluzole was generally tolerated well by Australian patients with MND. Of the few patients who experienced side-effects attributed to riluzole, all were reversible. Issues related to patient perceptions of efficacy highlight the need for patients and treating physicians to maintain realistic expectations of riluzole therapy.""",1
10967,16410371,Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone,"Treatment with the antidepressant nefazodone has been associated with clinical idiosyncratic hepatotoxicty. Using membranes expressing human bile salt export pump (BSEP), human sandwich hepatocytes, and intact rats, we compared nefazodone and its marketed analogs, buspirone and trazodone. We found that nefazodone caused a strong inhibition of BSEP (IC(50) = 9 microM), inhibition of taurocholate efflux in human hepatocytes (IC(50) = 14 microM), and a transient increase in rat serum bile acids 1 h after oral drug administration. Buspirone or trazodone had no effect on biliary transport system. Nefazodone produced time- and concentration-dependent toxicity in human hepatocytes with IC(50) = 18 microM and 30 microM measured by inhibition of protein synthesis after 6 h and 24 h incubation, respectively. Toxicity was correlated with the amount of unmetabolized nefazodone. Partial recovery in toxicity by 24 h has been associated with metabolism of nefazodone to sulfate and glucuronide conjugates. The saturation of nefazodone metabolism resulted in sustained decrease in protein synthesis and cell death at 50 microM. The toxicity was not observed with buspirone or trazodone. Addition of 1-aminobenzotriazole (ABT), an inhibitor of CYP450, resulted in enhancement of nefazodone toxicity at 10 microM and was associated with accumulation of unmetabolized nefazodone. In human liver microsomes, ABT also prevented metabolism of nefazodone and formation of glutathione conjugates. We suggest that inhibition of bile acid transport by nefazodone is an indicator of potential hepatotoxicity. Our findings are consistent with the clinical experience and suggest that described methodology can be applied in the selection of nonhepatotoxic drug candidates.",1
10968,16414334,Menopause: a review of botanical dietary supplements,"""Since the release of the Women's Health Initiative (WHI) findings, an increasing number of dietary supplement products specifically targeting women in menopause have appeared in the American marketplace. This growth highlights the need for a critical evaluation of the tolerability and effectiveness of these products. The purpose of this article is to assess the evidence for safety and benefit of botanical monopreparations used for relief of menopause-related symptoms. The Cochrane Library and Medline databases were searched from January 1966 to October 2004, using a detailed list of terms related to botanicals and menopausal symptoms. Studies were considered eligible (1) if they were controlled trials of a botanical monopreparation administered orally for a minimum of 6 weeks to perimenopausal or postmenopausal women with hot flashes and (2) if they included a placebo or comparative treatment arm. Topical preparations, botanical combinations, and dietary interventions, such as soy food or protein, were not included. No language restrictions were imposed on the search. A total of 19 studies met the inclusion criteria. The majority of studies indicate that extract of black cohosh (Actaea racemosa L.) improves menopause-related symptoms; however, methodologic shortcomings in the trials were identified. To date, 4 case reports of possible hepatotoxicity have been published, although previous safety reviews suggest that black cohosh is well tolerated and that adverse events are rare when it is used appropriately. The results of 6 clinical studies on soy (Glycine max L.) isoflavone extracts are mixed. Moreover, the composition and dose of soy supplements varies widely across studies, making comparisons and definitive conclusions difficult. One study challenged the long-term safety of high-dose soy isoflavone extract (150 mg/day for 5 years) on the uterine endometrium. Clinical data from 5 controlled trials assessing the efficacy of semipurified isoflavone red clover (Trifolium pratense L.) leaf extracts to reduce hot flash frequency and severity or to relieve symptoms associated with the domains of the Greene Menopausal Symptom Scale are contradictory. The largest study showed no benefit for reducing symptoms associated with menopause for 2 different red clover isoflavone products compared with placebo. No significant adverse events have been reported in the literature. Single clinical trials do not support the use of dong quai (Angelica sinensis L.), ginseng (Panax ginseng C.A. Mey), or evening primrose seed oil (Oenothera biennis L.) for improving menopausal symptoms. We conclude that black cohosh extracts appear to ease menopausal symptoms; ongoing studies funded by the National Institutes of Health (NIH) will provide more definitive safety and efficacy data. Soy isoflavone extracts appear to have minimal to no effect, although definitive conclusions are difficult given the wide variation in product composition and dose. Long-term safety of higher dosage (150 mg/day) soy isoflavone extracts is uncertain. Semipurified isoflavone red clover leaf extracts have minimal to no effect in reducing menopausal symptoms. Dong quai, ginseng extract, and evening primrose seed oil appear to be ineffective in ameliorating menopausal symptoms at the dosages and in the preparations used in these studies.""",1
10969,16416192,Acute icteric hepatitis induced by a short course of low-dose cyclophosphamide in a patient with lupus nephritis,,1
10970,16427718,Acute hepatitis associated with the use of green tea infusions,,1
10971,16436463,Intermediate dose 5-fluorouracil-induced encephalopathy,"As an acute neurotoxicity, high dose 5-fluorouracil (5-FU)-induced encephalopathy is well-known, but encephalopathy associated with lower dose is rarely reported. Here, we report a case of a male with anal cancer who was treated with 5-FU 1000 mg/m(2), continuous infusion for 5 days q4 weeks. At the second and the fourth cycles of chemotherapy, sudden confusion, cognitive dysfunction and disorientation occurred during 5-FU infusion. They were accompanied by hyperammonemia in the absence of focal neurological deficits or structural abnormalities. These symptoms completely disappeared and the serum ammonia level returned to normal after discontinuation of 5-FU and conservative care. In order to investigate a possible deficit of dihydropyrimidine dehydrogenase (DPD), we checked its mRNA level before and after treatment using real-time PCR. The patient's pre-treatment level was 80% compared with reference group, and it was elevated up to 187% of initial after 5-FU treatment, implying that that his encephalopathy may be 5-FU catabolite type rather than DPD deficiency. In conclusion, we report that encephalopathy can develop even with the dose of 5-FU lower than ever reported, and it should be considered as a differential diagnosis for proper management.",1
10972,16438629,[Methyldopa-induced acute toxic hepatitis],,1
10973,16442685,Lamotrigine-associated anticonvulsant hypersensitivity syndrome in bipolar disorder,"Anticonvulsant hypersensitivity syndrome (AHS) is a rare but life-threatening adverse effect of aromatic anticonvulsants such as phenytoin, phenobarbital and carbamazepine, although there is extensive experience with AHS related to these anticonvulsants. Very few cases of lamotrigine-associated AHS have been reported in bipolar patients and most reported cases were published in non-psychiatric journals. The authors describe here the occurrence of an AHS in a 48-year-old bipolar woman who was treated with lamotrigine, valproic acid and venlafaxine for her depressive symptoms. She developed a high fever, generalized maculopapular rash, pancytopenia, pneumonitis and hepatitis after we added lamotrigine to valproate and venlafaxine. These adverse drug reactions resolved after the discontinuation of lamotrigine and valproate, and the administration of oral antihistamine and corticosteroid. Our case demonstrates that the most important steps in the management of lamotrigine-associated AHS are to recognize the disorder, discontinue the offending anticonvulsants, provide supportive care in an inpatient setting, and treat with antihistamine and steroids when appropriate.",1
10974,16443079,"Etanercept monotherapy for a patient with psoriasis, psoriatic arthritis, and concomitant hepatitis C infection",,1
10975,16444584,Protective effects of ginkgo biloba against acetaminophen-induced toxicity in mice,"""BACKGROUND: The analgesic acetaminophen (AAP) causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. It was reported that these toxic effects of AAP are due to oxidative reactions that take place during its metabolism. OBJECTIVE: In this study, we aimed to investigate the possible beneficial effect of Ginkgo biloba (EGb), an antioxidant agent, against AAP toxicity in mice. METHODS: Balb/c mice were injected i.p. with: (1) vehicle, control (C) group; (2) a single dose of 50 mg/kg Ginkgo biloba extract, EGb group; (3) a single dose of 900 mg/kg i.p. acetaminophen, AAP group, and (4) EGb, in a dose of 50 mg/kg after AAP injection, AAP + EGb group. Serum ALT, AST, and tumor necrosis factor-alpha (TNF-alpha) levels in blood and glutathione (GSH), malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity, and collagen contents in liver tissues were measured. Formation of reactive oxygen species in hepatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lusigenin probe. Tissues were also examined microscopically. RESULTS: ALT, AST levels, and TNF-alpha were increased significantly (p < 0.001) after AAP treatment, and reduced with EGb. Acetaminophen caused a significant (p < 0.05-0.001) decrease in GSH levels while MDA levels and MPO activity were increased (p < 0.001) in liver tissues. These changes were reversed by EGb treatment. Furthermore, luminol and lusigenin CL levels in the AAP group increased dramatically compared to control and reduced by EGb treatment (p < 0.01). CONCLUSION: Our results implicate that AAP causes oxidative damage in hepatic tissues and Ginkgo biloba extract, by its antioxidant effects protects the tissues. Therefore, its therapeutic role as a """"tissue injury-limiting agent"""" must be further elucidated in drug-induced oxidative damage.""",1
10976,16447103,"Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer","""BACKGROUND: Gram-positive pathogens can cause serious infections in neutropenic patients with cancer, and vancomycin therapy is often initiated empirically. Linezolid may offer an option for these patients. METHODS: To compare the safety and efficacy of linezolid and vancomycin in febrile, neutropenic patients with cancer, we conducted a double-blind, multicenter equivalence study. Eligible patients with proven or suspected infection due to a gram-positive pathogen were randomized to receive linezolid or vancomycin. RESULTS: Clinical success rates 7 days after completion of therapy (primary end point) were equivalent between groups in the intent-to-treat (ITT) analysis (linezolid, 219 [87.3%] of 251 patients; vancomycin, 202 [85.2%] of 237 patients; 95% CI, -4.1 to 8.1; P=.52), modified ITT analysis, clinically evaluable analysis, and microbiologically evaluable analysis, as well as between subsets analyzed by malignancy and infection type. Mean time to defervescence was shorter for linezolid than vancomycin in the modified ITT (6.6 vs. 8.5 days; P=.04) and microbiologically evaluable subsets (5.9 vs. 9.1 days; P=.01), although post hoc analyses revealed delayed recovery of absolute neutrophil counts for linezolid in these subsets (P<.05). There were no between-group differences in microbiologic success rates in the modified ITT subset (41 [57.7%] of 71 patients vs. 29 [50.0%] of 58 patients; P=.38) and microbiologically evaluable subsets, as well as in mortality rates in the ITT subset (17 [5.6%] of 304 patients vs. 23 [7.6%] of 301 patients; P=.31) and all subsets. Distribution of adverse events, including reported hematologic events, was similar between groups, except that linezolid was associated with fewer drug-related adverse events (52 [17.2%] of 303 patients vs. 72 [24.0%] of 300 patients; P=.04) and fewer cases of drug-related renal failure (1 [0.3%] of 303 patients vs. 7 [2.3%] of patients; P=.04). CONCLUSIONS: Linezolid demonstrated efficacy and similar safety outcomes equivalent to those for vancomycin in febrile neutropenic patients with cancer.""",1
10977,16456421,Minocycline-induced autoimmune hepatitis with subsequent cirrhosis,,1
10978,16458968,Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration,"PURPOSE: To report the short-term safety, biologic effect, and a possible mechanism of action of intravitreal bevacizumab in patients with neovascular age-related macular degeneration (AMD). DESIGN: Interventional, consecutive, retrospective case series. PARTICIPANTS: Eighty-one eyes of 79 patients with subfoveal neovascular AMD. METHODS: Patients received intravitreal bevacizumab (1.25 mg) on a monthly basis until macular edema, subretinal fluid (SRF), and/or pigment epithelial detachment (PED) resolved. Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography (OCT). MAIN OUTCOME MEASURES: Assessments of safety, changes in Snellen VA, OCT retinal thickness, and angiographic lesion characteristics were performed. RESULTS: No significant ocular or systemic side effects were observed. Most patients (55%) had a reduction of >10% of baseline retinal thickness at 1 week after the injection. At 4 weeks after injection, 30 of 81 eyes demonstrated complete resolution of retinal edema, SRF, and PEDs. Of the 51 eyes with 8 weeks' follow-up, 25 had complete resolution of retinal thickening, SRF, and PEDs. At 1, 4, 8,and 12 weeks, the mean retinal thickness of the central 1 mm was decreased by 61, 92, 89, and 67 mum, respectively (P<0.0001 for 1, 4, and 8 weeks and P<0.01 for 12 weeks). At 4 and 8 weeks, mean VA improved from 20/200 to 20/125 (P<0.0001). Median vision improved from 20/200 to 20/80(-) at 4 weeks and from 20/200 to 20/80 at 8 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab (1.25 mg) is well tolerated and associated with improvement in VA, decreased retinal thickness by OCT, and reduction in angiographic leakage in most patients, the majority of whom had previous treatment with photodynamic therapy and/or pegaptanib. Further evaluation of intravitreal bevacizumab for the treatment of choroidal neovascularization is warranted.",1
10979,16461865,"Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial","CONTEXT: Oral naltrexone can completely antagonize the effects produced by opioid agonists. However, poor compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence. OBJECTIVE: To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, 8-week trial conducted at 2 medical centers. PARTICIPANTS: Sixty heroin-dependent adults. INTERVENTIONS: Participants were stratified by sex and years of heroin use (> or = 5 vs < 5) and then were randomized to receive placebo or 192 or 384 mg of depot naltrexone. Doses were administered at the beginning of weeks 1 and 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit. MAIN OUTCOME MEASURES: Retention in treatment and percentage of opioid-negative urine samples. RESULTS: Retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Time to dropout had a significant main effect of dose, with mean time to dropout of 27, 36, and 48 days for the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively. The percentage of urine samples negative for opioids, methadone, cocaine, benzodiazepines, and amphetamine varied significantly as a function of dose. When the data were recalculated without the assumption that missing urine samples were positive, a main effect of group was not found for any drugs tested except cocaine, where the percentage of cocaine-negative urine samples was lower in the placebo group. Adverse events were minimal and generally mild. This formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention. CONCLUSION: These data provide new evidence of the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence.",1
10980,16467543,Saw palmetto for benign prostatic hyperplasia,"""BACKGROUND: Saw palmetto is used by over 2 million men in the United States for the treatment of benign prostatic hyperplasia and is commonly recommended as an alternative to drugs approved by the Food and Drug Administration. METHODS: In this double-blind trial, we randomly assigned 225 men over the age of 49 years who had moderate-to-severe symptoms of benign prostatic hyperplasia to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo. The primary outcome measures were changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate. Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects. RESULTS: There was no significant difference between the saw palmetto and placebo groups in the change in AUASI scores (mean difference, 0.04 point; 95 percent confidence interval, -0.93 to 1.01), maximal urinary flow rate (mean difference, 0.43 ml per minute; 95 percent confidence interval, -0.52 to 1.38), prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen levels during the one-year study. The incidence of side effects was similar in the two groups. CONCLUSIONS: In this study, saw palmetto did not improve symptoms or objective measures of benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00037154.).""",1
10981,16473858,Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis,"""OBJECTIVE: To conduct a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. DATA SOURCES: 13 electronic databases and reference lists of relevant reviews and included studies; Associated Professional Sleep Society abstracts (1999 to 2003). STUDY SELECTION: The efficacy review included randomised controlled trials; the safety review included randomised and non-randomised controlled trials. QUALITY ASSESSMENT: Randomised controlled trials were assessed by using the Jadad Scale and criteria by Schulz et al, and non-randomised controlled trials by the Downs and Black checklist. DATA EXTRACTION AND SYNTHESIS: One reviewer extracted data and another reviewer verified the data extracted. The inverse variance method was used to weight studies and the random effects model was used to analyse data. MAIN RESULTS: Six randomised controlled trials with 97 participants showed no evidence that melatonin had an effect on sleep onset latency in people with secondary sleep disorders (weighted mean difference -13.2 (95% confidence interval -27.3 to 0.9) min). Nine randomised controlled trials with 427 participants showed no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (-1.0 (-2.3 to 0.3) min). 17 randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use (three months or less). CONCLUSIONS: There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.""",1
10982,16476694,"Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin","AIMS: This double-blind, parallel-group study was conducted to assess the pharmacodynamics, pharmacokinetics, and safety of AZD6140, the first oral, reversible adenosine diphosphate (ADP) receptor antagonist. METHODS AND RESULTS: Patients (n = 200) with atherosclerosis were randomized to receive AZD6140 50, 100, or 200 mg twice daily (bid) or 400 mg daily (qd) or clopidogrel 75 mg qd for 28 days. All groups received aspirin 75-100 mg qd. AZD6140 (100 and 200 mg bid, 400 mg qd) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at day 28. On day 1, peak final-extent inhibition of platelet aggregation (IPA) was observed 2-4 h post-dose with AZD6140, whereas clopidogrel minimally inhibited platelet aggregation (mean percentage IPA < 20%, all time points). Four hour post-dose at steady state, the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA (approximately 90-95%), which exceeded that with AZD6140 50 mg bid or clopidogrel (approximately 60%). AZD6140 was generally well tolerated. All bleeding events, except one in a patient receiving 400 mg qd, were minor and of mild-to-moderate severity. CONCLUSION: AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.",1
10983,16477242,Induction of autoimmune hepatitis by pegylated interferon in a liver transplant patient with recurrent hepatitis C virus,,1
10984,16478395,Liver enzyme elevation in hepatitis C virus (HCV)-HIV-coinfected patients prior to and after initiating HAART: role of HCV genotypes,"Transaminase elevation is frequently seen in hepatitis C virus (HCV)-HIV-coinfected patients receiving antiretroviral therapy (ART), representing an increase in the immune response against HCV and being one of the mechanisms proposed to be involved. There is a report claiming that HCV genotype 3 is an independent risk factor. Our objectives were to assess the incidence of liver toxicity in an HIV-HCV-coinfected population with relatively preserved cellular immunity, and the role of HCV genotypes in the elevation of liver enzymes, both at baseline and after initiating ART. All HIV(+) patients with positive anti-HCV serology and CD4(+) cell counts above 100/mm(3) who began triple ART were identified, and their HCV-RNA levels and HCV genotype were determined. Liver enzymes were determined at baseline and bimonthly during follow-up. Of anti-HCV patients 147 were included, 128 (87.1%) of whom had detectable plasma HCV-RNA. HCV-1 and HCV-4 genotypes were found to confer an increased probability of having at baseline transaminases within normal limits over the other genotypes. Severe transaminase elevations (grades 3 and 4) occurred in 5/124 patients (4.0%), all with high pre-HAART ALT and positive HCV-RNA levels. Multivariate analysis showed that patients with genotype HCV-3 had a 3.27 times higher risk of developing HAART-related transaminase elevations of any grade. In conclusion, subjects with the HCV-1 genotype more often had transaminases within normal limits at baseline. The incidence of severe transaminase elevation after initiating ART was very low (4%) in this HIV(+) population with relatively preserved cellular immunity. HCV genotype 3 was identified as a risk factor for the development of transaminase elevation of any grade.",1
10985,16481450,Summaries for patients. Telithromycin: a possible cause of severe liver damage?,,1
10986,16487618,Clinical characteristics and prognostic markers in disulfiram-induced liver injury,"BACKGROUND/AIMS: Limited systematic data exists on the incidence of drug-induced hepatotoxicity due to disulfiram and the most important prognostic markers. We aimed to determine the nature and frequency of suspected disulfiram hepatotoxicity in Sweden. METHODS: All reports of suspected hepatic adverse drug reactions (ADR) associated with disulfiram received by the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) 1966-2002 were reviewed. Causality assessment was based on the International Consensus Criteria. RESULTS: A total of 82 reports of disulfiram suspected ADRs had at least a possible causal relationship. Eight patients died or underwent liver transplantation (Tx). Mortality or Tx was 16% in patients with jaundice. The median age of the patients (65% males) was 45 years with a median duration of treatment of 42 days. Bilirubin was higher (P<0.0001) in the deceased/transplanted patients compared to surviving patients. No difference was observed in age or duration of therapy between deceased and transplanted and those who recovered. Eosinophilic infiltration in liver biopsies was associated with a favourable outcome, hepatocyte drop-out with a poor outcome. CONCLUSIONS: Disulfiram associated hepatitis has a considerable mortality risk. Histological signs of immunoallergy seem to be common. Bilirubin and hepatocyte drop-out were the only predictors for death or transplantation.",1
10987,16487623,6-Thioguanine-related hepatotoxicity in patients with inflammatory bowel disease: dose or level dependent?,,1
10988,16493232,Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date,"Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist, is currently the only agent approved for moderately severe to severe Alzheimer disease (AD) in Europe and for moderate-to-severe Alzheimer disease in the United States. In clinical trials, memantine has consistently demonstrated a reduced rate of deterioration on global, cognitive, functional, and behavioral measures, across a range of outcome measures compared with usual care. Notably, improvements versus placebo were seen in individual activities of daily living and behavior, particularly agitation. Efficacy was demonstrated in patients with newly diagnosed Alzheimer disease, patients previously or currently receiving acetylcholinesterase inhibitors, and both institutionalized and community-dwelling Alzheimer disease patients. Memantine has a tolerability profile similar to placebo. This review presents the results of key clinical trials, and includes clinically relevant analyses, such as numbers-needed-to-treat and effect sizes. Increased dependency and institutionalization are significant cost drivers in Alzheimer disease. Memantine is able to reduce dependency, caregiver time required, and mean monthly caregiver and societal costs. Recent studies of the relationship between Alzheimer disease progression, caregiver burden, and healthcare costs emphasize the need for treatments such as memantine that can slow the rate of decline in Alzheimer disease.",1
10989,16495253,Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir,"High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval (tau) at steady state [AUC(0-tau)], maximum concentration of drug in plasma (C(max)), and plasma concentration at the end of tau at steady state (C(tau)) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC(0-tau), C(max), and C(tau) were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC(0-tau), C(max), and C(tau) increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.",1
10990,16498306,Abatacept (Orencia) for rheumatoid arthritis,,1
10991,16503324,Possible metformin-induced hepatotoxicity,"BACKGROUND: Metformin hydrochloride is widely used for the treatment of type 2 diabetes mellitus (DM-2). To date, only 2 cases of possible metformin-induced hepatotoxicity (acute hepatitis) have been reported worldwide. OBJECTIVE: The aim of this article was to report a case of serious hepatotoxicity possibly associated with metformin use in an elderly patient with DM-2. METHODS: After receiving metformin 500 mg/d for 3 weeks, a 73-year-old Japanese woman weighing 33.5 kg with poorly controlled DM-2 presented with fatigue, jaundice, nausea, vomiting, anorexia, and abdominal pain. Laboratory analysis showed severe hepatotoxicity (elevated aspartate and alanine aminotransferases [AST and ALT, respectively], alkaline phosphatase [ALP], and total bilirubin concentrations). The history, clinical findings, laboratory features, and clinical course of this case, as well as the pharmacologic profile of metformin, are presented. RESULTS: Immediate hospitalization and discontinuation of metformin treatment led to improvements in liver function (decreased AST, ALT, ALP, and total bilirubin concentrations) and resolution of the presented symptoms within 3 weeks. The probability of an adverse drug reaction (ADR), as assessed using the Naranjo ADR probability scale, in this case was 4 (probable). CONCLUSIONS: In this case of an elderly woman with DM-2 who presented with symptoms of hepatotoxicity after 3 weeks of metformin treatment, metformin appeared to have caused a mixed-type (hepatocellular and cholestatic) hepatic damage. Although rare, severe hepatotoxicity might be associated with metformin use in some cases.",1
10992,16503749,The safety of bevacizumab,"Despite the significant gains made in the treatment of many cancers over the last few decades, further improvements in survival using traditional chemotherapeutic agents have now begun to plateau. The development of bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, has provided promise for continued gains in survival in the therapy of a variety of cancers, including some previously refractory to traditional chemotherapeutic agents. Although its toxicity profile differs from traditional chemotherapeutic drugs, bevacizumab is not completely without side effects. The mechanisms of its unique toxicities have not yet been fully characterised, and at this time it is not possible to predict which toxicities will be experienced by each individual patient or which population.",1
10993,16507377,An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy,"""BACKGROUND: Information on longer-term safety and tolerability is needed to confidently prescribe alefacept therapy for chronic plaque psoriasis beyond 1 or 2 courses. OBJECTIVE: The aim of this work was to further examine the safety profile of alefacept by integrating data from clinical trials involving patients with chronic plaque psoriasis who received up to 9 courses of therapy over a 5-year period. METHODS: Data from 13 clinical trials conducted in patients with plaque psoriasis were integrated because they had similar inclusion/exclusion criteria and assessments. Patients who enrolled in the analyzed trials were aged > or =15 years with chronic plaque psoriasis for > or =12 months that involved > or =10% of body surface area, and CD4+ T lymphocyte counts above the lower limit of normal (>404 cells/microL). The incidences of adverse events (AEs), serious AEs, discontinuations for AEs, infections, serious infections, malignancies, and anti-alefacept antibodies were summarized for each course of alefacept. The incidence of infections was stratified according to CD4+ T lymphocyte counts (<250 cells/microL vs > or =250 cells/microL). RESULTS: Data from 13 clinical trials of alefacept were integrated and summarized (multicenter, randomized, double-blind studies, n = 6; multicenter, open-label studies, n = 5; other, n = 2). The analyzed population (n = 1869) included 1291 (69.1%) men and 578 (30.9%) women, between the ages of 15 and 84 years (mean, 44.8 years), of whom 1648 (88.2%) were white. Weights ranged from 40 kg to 206 kg (mean, 90.0 kg). A total of 1369 of these patients had been included in a previous analysis. Among the most commonly reported AEs in each treatment course were headache (0%-14.2%), nasopharyngitis (7.7%-25.0%), influenza (0%-8.1%), upper respiratory tract infection (0%-12.5%), and pruritus (0%-7.5%). The rates of discontinuations due to AEs (0%-4.8%), serious AEs (0%-4.8%), serious infections (0%-0.9%), or malignancies (0%-4.8%) did not appear to increase with repeated exposure. Fewer than 1 % of patients in each course developed a serious infection. No opportunistic infections or infection-related deaths were reported. The incidence of infections appeared to be unrelated to CD4+ T lymphocyte counts. Fewer than 2.5% of patients tested positive for anti-alefacept antibodies during any course of therapy. CONCLUSIONS: This integrated analysis of data from 13 trials with 1869 patients supports the safety and tolerability of alefacept for longer-term treatment of psoriasis.""",1
10994,16510744,"A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis","""BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).""",1
10995,16511441,"Deaths associated with hypocalcemia from chelation therapy--Texas, Pennsylvania, and Oregon, 2003-2005","Chelating agents bind lead in soft tissues and are used in the treatment of lead poisoning to enhance urinary and biliary excretion of lead, thus decreasing total lead levels in the body. During the past 30 years, environmental and dietary exposures to lead have decreased substantially, resulting in a considerable decrease in population blood lead levels (BLLs) and a corresponding decrease in the number of patients requiring chelation therapy. Chelating agents also increase excretion of other heavy metals and minerals, such as zinc and, in certain cases, calcium. This report describes three deaths associated with chelation-therapy--related hypocalcemia that resulted in cardiac arrest. Several drugs are used in the treatment of lead poisoning, including edetate disodium calcium (CaEDTA), dimercaperol (British anti-Lewisite), D-penicillamine, and meso-2,3-dimercaptosuccinic acid (succimer). Health-care providers who are unfamiliar with chelating agents and are considering this treatment for lead poisoning should consult an expert in the chemotherapy of lead poisoning. Hospital pharmacies should evaluate whether continued stocking of Na2EDTA is necessary, given the established risk for hypocalcemia, the availability of less toxic alternatives, and an ongoing safety review by the Food and Drug Administration (FDA). Health-care providers and pharmacists should ensure that Na2EDTA is not administered to children during chelation therapy.",1
10996,16515487,Understanding and avoiding antiretroviral adverse events,"""UNLABELLED: To discuss prevention and management of adverse drug reactions which result from antiretroviral use in patients infected with HIV. There are four classes of antiretroviral agents used in the treatment of HIV/AIDS. Side effects to medications are common place and often difficult to avoid. In many cases, research is not able to identify the exact cause of an event. The severity of adverse reactions varies greatly, and some may be difficult to manage; typically, prevention is more desirable than treatment. However, this is not always true. This paper will review class-wide and individual side effects from antiretrovirals and, in some cases, the mechanism of action that results in the event. Class-wide side effects for nucleoside/tide reverse transcriptase inhibitors (NRTIs) include lactic acidosis, peripheral neuropathy and lipoatrophy. Adverse reactions from individual NRTIs, such as abacavir-induced hypersensitivity reactions, will also be discussed. Class-wide side effects to non-nucleoside reverse transcriptase inhibitors include rash and hepatotoxicity, while efavirenz has its own unique CNS reactions. Protease inhibitor side effects include hyperglycemia, lipoaccumulation, dyslipidemia, and gastrointestinal (GI) intolerance. We will also review specific side effects caused by indinavir, ritonavir, and atazanavir. Finally, adverse reactions from the fusion inhibitor, enfuvirtide, will be mentioned. CONCLUSION: Antiretrovirals are an important break-through in the treatment of HIV/AIDS. However, adverse reactions from these drugs can range from mild to life-threatening, and determining which agent is the cause is frequently difficult to discern. Fortunately, side effects can be monitored, treated and in many cases, prevented.""",1
10997,16518561,Sulphasalazine-induced DRESS,"Drug rash with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity syndrome. It presents with severe cutaneous eruption, fever, lymphadenopathy, hepatitis, haematological abnormalities with eosinophilia, atypical lymphocytes and may also involve other organs. The multi-organ involvement differentiates this entity from other common drug eruptions. DRESS has been associated with higher morbidity and mortality compared to other adverse drug reactions. Sulphasalazine hypersensitivity is rarely reported and we wish to highlight a case of sulfasalazine-induced DRESS presenting as leukocytoclastic vasculitis, hepatitis and haematological abnormalities in a 49-year-old Indian woman.",1
10998,16525107,A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy,"In 1982-1984 we conducted a six-month clinical trial in 50 previously untreated lepromatous leprosy patients randomly assigned to directly observed monotherapy with one of two thioamides, ethionamide or prothionamide, each given six times a week at doses of either 250 mg or 500 mg. The findings of this study have only recently been analyzed, and the potential for the use of these thioamides in leprosy patients placed in perspective. However, because of the small number of patients included in this study, the results must be interpreted with some caution. Clinical improvement was noted in 74% of the patients treated with ethionamide and in 83% of those treated with prothionamide. Therapy was well tolerated and drug-related hepatotoxicity did not require discontinuation of therapy. The 500-mg dose of both ethionamide and prothionamide resulted in loss in Mycobacterium leprae viability more rapidly than did the 250-mg dose, and prothionamide at both dose levels was superior to the equivalent dose of ethionamide. Overall killing of M. leprae in this study was found to be similar to that obtained previously with dapsone and clofazimine, but less than was obtained with rifampin, minocycline, clarithromycin, pefloxacin, and ofloxacin.",1
10999,16525138,Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B,"BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P=0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).",1
11000,16527695,Effect of nitazoxanide in diarrhea and enteritis caused by Cryptosporidium species,"""BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy of nitazoxanide for the treatment of diarrhea and enteritis caused by Cryptosporidium species in patients 12 years of age and older. METHODS: A multicenter, randomized, double-blind, placebo-controlled study was conducted in 90 outpatients 12 years of age and older from the Nile Delta region of Egypt. Patients were randomized to receive either one 500 mg tablet or one matching placebo tablet, or 25 mL of nitazoxanide oral suspension (500 mg nitazoxanide), each given twice daily for 3 days. Clinical and microbiologic response rates were evaluated 4 days after completion of treatment. RESULTS: Twenty-seven (96%) of the 28 patients receiving nitazoxanide tablets responded clinically compared with 11 (41%) of 27 patients who received placebo (P < .0001). Twenty-six (93%) of the 28 patients who received nitazoxanide were free of Cryptosporidium oocysts in each of 2 posttreatment stool samples compared with only 10 (37%) of 27 patients who received placebo (P < .0001). Response rates in patients receiving the tablets and the suspension were comparable (clinical response rate for suspension, 27 of 31 [87%]; microbiologic response rate for suspension, 28 of 31 [90%]). CONCLUSIONS: These findings show that a 3-day course of nitazoxanide is effective in treating diarrhea and enteritis caused by Cryptosporidium in nonimmunodeficient patients 12 years of age and older.""",1
11001,16529526,Ketamine : from medicine to misuse,"""This review describes the medical, research and recreational uses of ketamine, an anaesthetic derivative of phencyclidine that has dissociative, analgesic and psychedelic properties. Ketamine has a complex mechanism of action that is further complicated by stereoselectivity; however, antagonism of glutamate NDMA receptors is thought to underlie its analgesic, dissociative and neuroprotective effects. While ketamine use in medical and veterinary settings is well documented and has a good safety record, the increase in its unregulated use outside of such controlled environments is a cause for concern. The impact on higher centres in the brain, particularly altered perception of auditory, visual and painful stimuli, results in a general lack of responsive awareness that puts the recreational user at (often unrecognised) risk of personal harm. The perceptual and mood changes observed in those who have consumed ketamine are highly sensitive to age, dose, route of administration, previous experience and setting. At low doses, stimulant effects predominate and the effect of environmental conditions are significant; with higher doses, psychedelic effects predominate and the effect of the environment diminishes. The potential of ketamine as a novel clinical and research tool is matched by its abuse potential outside medical settings.""",1
11002,16531613,Homocysteine lowering with folic acid and B vitamins in vascular disease,"""BACKGROUND: In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. METHODS: We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS: Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). CONCLUSIONS: Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).""",1
11003,16532500,Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study,"""BACKGROUND: Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. METHODS: A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. RESULTS: Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). CONCLUSIONS: Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further.""",1
11004,16537868,"Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial","""BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening disease for which both continuous IV epoprostenol and continuous subcutaneous treprostinil have proven effective. With continuous IV treprostinil having potential advantages over both of the above therapies, we investigated the safety and efficacy of this regimen in patients with PAH. METHODS: We conducted a 12-week, prospective, open-label, uncontrolled, multicenter study of continuous IV treprostinil in 16 patients with PAH that was idiopathic (n = 8), related to connective tissue disease (n = 6), or related to congenital heart disease (n = 2). The primary end point was change from baseline to week 12 in exercise capacity assessed by the 6-min walk (6MW) test. RESULTS: Continuous IV treprostinil increased 6MW distance (mean +/- SE) by 82 m from baseline (319 +/- 22 m) to week 12 (400 +/- 26 m) [n = 14; p = 0.001]. There were also significant improvements in the secondary end points of Naughton-Balke treadmill time (p = 0.007), Borg dyspnea score (p = 0.008), and hemodynamics (mean pulmonary artery pressure, p = 0.03; cardiac index, p = 0.002; pulmonary vascular resistance, p = 0.001) at week 12 compared with baseline. Side effects were mild and consistent with those reported with prostacyclin treatment. One death, unrelated to study drug, occurred during the 12-week study in a patient who received 3 days of treprostinil and died 2 weeks later. CONCLUSIONS: Long-term IV infusion of treprostinil is safe and appears to be effective for the treatment of patients with PAH.""",1
11005,16547087,Paracetamol induced hepatotoxicity,"""AIM: To identify the clinical and biochemical risk factors associated with outcome of paracetamol induced significant hepatotoxicity in children. METHODS: Retrospective case notes review of those with paracetamol overdose admitted from 1992 to 2002. Patients were analysed in two groups: group I recovered after conservative treatment and group II developed progressive liver dysfunction and were listed for liver transplantation. RESULTS: Of 51 patients (6 males, 45 females, aged 0.8-16.1 years), 6 (aged <7 years) received cumulative multiple doses, and 45 a single large overdose (median 345 mg/kg, range 91-645). The median (range) interval to hospital at presentation post-ingestion was 24 hours (4-65) and 44 hours (24-96) respectively in groups I and II. Patients received standard supportive treatment including N-acetylcysteine. All children in group I survived. In group II, 6/11 underwent orthotopic liver transplantation (OLT) and 2/6 survived; 5/11 died awaiting OLT. Cerebral oedema was the main cause of death. Children who presented late to hospital for treatment and those with progressive hepatotoxicity with prothrombin time >100 seconds, hypoglycaemia, serum creatinine >200 micromol/l, acidosis (pH <7.3), and who developed encephalopathy grade III, had a poor prognosis or died. Although hepatic transaminase levels were markedly raised in both groups, there was no correlation with necessity for liver transplantation or death. CONCLUSION: Accidental or incidental paracetamol overdose in children may be associated with toxic liver damage leading to fulminant liver failure. Delayed presentation and/or delay in treatment, and hepatic encephalopathy > or =grade III were significant risk factors, implying poor prognosis and need for OLT. Prompt identification of high risk patients, referral to a specialised unit for management, and consideration for liver transplantation is essential.""",1
11006,16549859,Telithromycin,,1
11007,16550301,Successful treatment with etanercept in a patient with hepatotoxicity closely related to infliximab,"To date, hepatotoxicity with anti-TNF therapy has been associated with concomitant liver-toxicity drugs, infection or malignant diseases. We report the case of one patient with spondyloarthropathty who presented severe liver dysfunction related to infliximab. After the second infusion serum controls showed an slightly increase of transaminases. Before the administration of fifth infusion, infliximab therapy was stopped due to severe liver damage (AST 327 mU/ml, ALT 656 mU/mL, GGT 140 mU/mL, alkaline phosphate 227 mU/mL). Ten weeks after infliximab discontinuation serum concentrations of liver blood tests were normal but ankylosing spondylitis symptoms had relapsed. Therefore, he was treated with etanercept with a rapid and sustained improvement. Serum concentrations of albumin, AST, ALT, GGT and alkaline phosphate were followed and did not change for five months.",1
11008,16556632,Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections,"OBJECTIVES: Absorption of oral voriconazole is good and in contrast to the intravenous (iv) formulation it can be given in patients with renal insufficiency. Furthermore, the acquisition costs are significantly lower. The aim of this study was to compare the incidence of hepatotoxicity in patients treated with the oral formulation of voriconazole with that in patients treated with the iv formulation. METHODS: This was a retrospective observational study. A total of 35 patients with haematological disease and an invasive fungal infection were treated with oral voriconazole during the entire regimen. We compared the incidence of hepatotoxicity with that in 11 patients treated intravenously during the first week. RESULTS: The incidence of increased liver enzymes was comparable between both groups. Voriconazole was discontinued in two patients in the oral group and one patient in the iv group because of hepatotoxicity. The incidence of liver enzyme elevations in the entire study cohort of 46 patients was higher than that previously reported in a comparable study population (P < 0.001). However, clinically significant hepatotoxicity was infrequently observed (3/46 or 6.5%). CONCLUSIONS: In 35 patients with invasive fungal infections we instituted oral voriconazole therapy from day 1 and found an incidence of hepatotoxicity comparable to 11 controls treated intravenously.",1
11009,16565588,Stevens-Johnson syndrome associated with intravenous acetazolamide administration for evaluation of cerebrovascular reactivity. Case report,"A 62-year-old man with left middle cerebral artery stenosis manifesting as transient ischemic attack underwent evaluation of regional cerebrovascular reactivity to acetazolamide using single photon emission computed tomography. Three days after intravenous administration of acetazolamide, erythematous eruptions of various sizes appeared on his back and spread over almost his entire body. Subsequently, painful ulcerations developed on his lips, and oral and nasal mucosa, and the conjunctiva became hyperemic, indicating Stevens-Johnson syndrome. The results of the lymphocyte transformation test were positive to only acetazolamide. Stevens-Johnson syndrome, also known as erythema multiforme major, can be life-threatening, and may be induced by intravenous administration of acetazolamide.",1
11010,16567254,An unusual case of 4-aminopyridine toxicity,"""4-aminopyridine (4-AP) is an orphan drug in the United States. It enhances neuronal conduction at synapses and is indicated in the treatment of selected neuromuscular disorders, including multiple sclerosis and myasthenia gravis, among others. Its documented toxicity generally has been limited to central nervous system (CNS) hyperexcitation and gastrointestinal upset. In this case, a 56-year-old man accidentally overdosed on an unknown amount of generic 4-AP. This history was unknown by his family and unavailable to initial providers. Approximately 1 h after ingestion, his son found him diaphoretic, vomiting, and having unintelligible speech. In the ensuing 2-3 h, the patient became moderately hypothermic (32.8 degrees C; 91 degrees F), developed atrial fibrillation with a rapid ventricular response, and had neurological changes that were confused with an acute cerebrovascular accident. After a 36-h stay in the intensive care unit that included mechanical ventilation, cardioversion, passive rewarming, and an extensive medical workup, the patient recovered without sequelae. After extubation he stated that he thought he may have ingested too much 4-AP after rubbing a large amount of it against a sore tooth to take advantage of its local analgesic properties. This case of 4-AP overdose resulting in atrial fibrillation with rapid ventricular response, hypothermia, and acute neurological changes mistaken for an acute cerebrovascular accident is an unusual one. This case shows that overdose of 4-AP can cause or mimic several serious medical conditions, and that a detailed history and physical examination are essential for uncovering unusual diagnoses.""",1
11011,16569079,Safety of drug therapies used for weight loss and treatment of obesity,"Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.",1
11012,16570576,"Acute hepatitis induced by Chinese hepatoprotective herb, xiao-chai-hu-tang","Xiao-chai-hu-tang (syo-saiko-to in Japanese) is a herbal remedy that has been widely used in China for treatment of respiratory, hepatobiliary, and gastrointestinal diseases, particularly among patients with chronic liver disease. However, its safety has recently been challenged. We, herein, report a Chinese patient with acute hepatitis induced by this herb. A 52-year-old woman presented with weakness, fatigue, and tea-colored urine after continual consumption of the decoction of xiao-chai-hu-tang for 1.5 months. Laboratory studies disclosed acute hepatitis even though all of the viral hepatitis markers were negative. Liver biopsy also revealed a picture of acute hepatocellular hepatitis. The symptoms improved after discontinuing the drug, and liver biochemical tests normalized 2 months later. The case report reminds us of the probable adverse drug reaction of herbs, even in some that are claimed to have hepatoprotective effects.",1
11013,16575495,Severe acute hepatitis related to hydroxychloroquine in a woman with mixed connective tissue disease,"Antimalarial drugs are used for the control of mild manifestations of autoimmune diseases due to their low toxicity. Hydroxychloroquine (HCQ), a alpha-hydroxylated derivative of chloroquine, is usually preferred because of its higher tolerability. Mild and unspecific gastrointestinal symptoms are the main secondary effects related to HCQ use. Less than 1% of subjects show liver enzyme increase, although the percentage can be as high as 50% in subjects with chronic liver disease. A woman with mixed connective tissue disease who developed a reversible acute hepatitis shortly after the initiation of low-dose HCQ is presented. Two previous cases of patients with acute liver failure have previously been published. All three cases have been reported in the absence of previous liver disease. It seems to be a dose-dependent, idiosyncratic, and molecule-specific toxic effect and must be considered, taking into account the potential bad prognosis.",1
11014,16581329,Statin safety: a systematic review,"A systematic review of cohort studies, randomized trials, voluntary notifications to national regulatory authorities, and published case reports was undertaken to assess the incidence and characteristics of adverse effects in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins. For statins other than cerivastatin, the incidence of rhabdomyolysis in 2 cohort studies was 3.4 (1.6 to 6.5) per 100,000 person-years, an estimate supported by data from 20 randomized controlled trials. Case fatality was 10%. Incidence was about 10 times greater when gemfibrozil was used in combination with statins. Incidence was higher (4.2 per 100,000 person-years) with lovastatin, simvastatin, or atorvastatin (which are oxidized by cytochrome P450 3A4 [CYP3A4], which is inhibited by many drugs) than pravastatin or fluvastatin (which are not oxidized by CYP3A4). In persons taking simvastatin, lovastatin, or atorvastatin, 60% of cases involved drugs known to inhibit CYP3A4 (especially erythromycin and azole antifungals), and 19% involved fibrates, principally gemfibrozil. The incidence of myopathy in patients treated with statins, estimated from cohort studies supported by randomized trials, was 11 per 100,000 person-years. For liver disease, randomized trials reported fewer hepatobiliary disorders in patients allocated statins than in those allocated placebo. The notification rate of liver failure to regulatory authorities was about 1 per million person-years of statin use. Randomized trials show no excess of renal disease or proteinuria in statin-allocated participants, and the decline in glomerular filtration rate was smaller with statins than with placebo. Evidence from 4 cohort studies and case reports suggests that statins cause peripheral neuropathy, but the attributable risk is small (12 per 100,000 person-years). No change in cognitive function was found in randomized trials of statins in elderly patients.",1
11015,16581404,"Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study","""BACKGROUND: The cholinesterase inhibitor donepezil is used to treat mild-to-moderate Alzheimer's disease. Its efficacy in severe dementia has not been assessed and is controversial. Our aim was to ascertain the effectiveness of donepezil in patients with severe Alzheimer's disease, by focusing primarily on cognition and activities of daily living. METHODS: We did a 6-month, double-blind, parallel-group, placebo-controlled study in 248 patients with severe Alzheimer's disease (mini mental state examination score 1-10) who were living in assisted care nursing homes ran by trained staff in Sweden. We assigned patients oral donepezil (5 mg per day for 30 days then up to 10 mg per day thereafter, n=128) or matched placebo (n=120). Our primary endpoints were change from baseline to month 6 in the severe impairment battery (SIB) and modified Alzheimer's Disease Cooperative Study activities of daily living inventory for severe Alzheimer's disease (ADCS-ADL-severe). We analysed outcomes for patients with data at baseline and at one or more other timepoints (modified intent-to-treat population) with last observation carried forward used to replace missing data. FINDINGS: 95 patients assigned donepezil and 99 patients assigned placebo completed the study. Patients treated with donepezil improved more in SIB scores and declined less in ADCS-ADL-severe scores at 6 months after initiation of treatment compared with baseline than did controls (least squares [LS] mean difference, 5.7, 95% CI 1.5-9.8; p=0.008, and 1.7, 0.2-3.2; p=0.03, respectively). The incidence of adverse events was comparable between groups (donepezil 82% [n=105] vs placebo 76% [n=91]), with most being transient and mild or moderate in severity. More patients discontinued treatment because of adverse events in the donepezil group (n=20) than in the placebo group (n=8). INTERPRETATION: Donepezil improves cognition and preserves function in individuals with severe Alzheimer's disease who live in nursing homes.""",1
11016,16584299,"Defibrotide, a polydisperse mixture of single-stranded phosphodiester oligonucleotides with lifesaving activity in severe hepatic veno-occlusive disease: clinical outcomes and potential mechanisms of action","Veno-occlusive disease of the liver (VOD) remains a troubling and potentially fatal complication of high-dose chemotherapy and hematopoietic stem cell transplantation conditioning regimens. No effective therapy has been available for these patients to date, and the best supportive care measures remain woefully inadequate. Defibrotide (DF) (Gentium, S.p.A., Como, Italy), a polydisperse mixture of all the single-stranded phosphodiester oligodeoxyribonucleotides that can be obtained from the controlled depolymerization of porcine intestinal mucosal genomic DNA, seems to offer a safe and effective treatment for some patients suffering from severe VOD, a condition for which no accepted standard therapy currently exists. Early clinical studies evaluating the efficacy of DF for the treatment of severe VOD in patients undergoing hematopoietic stem cell transplantation have been very encouraging. Approximately 45% of the patients treated in multiple initial phase II clinical trials achieved a complete response at day +100, demonstrating normalization of serum bilirubin and resolution of the clinical syndrome. However, although multi-institutional, these represented single arm studies. A large, FDA-approved, pivotal, prospective, multi-institutional, global phase III trial of DF vs. historical controls (best available therapy) commenced in the first quarter of 2006 and should provide further validation of DF's efficacy. The drug seems to have few significant side effects, and almost all test subjects who have received this treatment have tolerated it well. Although the mechanism of action remains unclear, the drug exerts minimal systemic anticoagulant effects yet appears to induce numerous antithrombotic and profibrinolytic effects both in vitro and in vivo. It may function as an adenosine receptor agonist and causes increased concentrations of endogenous prostaglandins, which modulate thrombomodulin, platelets, and fibrinolysis. It also appears to block lipopolysaccharide (LPS)-induced tissue factor (TF) expression. However, despite the fact the DF is composed of oligonucleotides, its mechanism of action, which at the present time is unclear, is not related to Watson-Crick base pair-dependent downregulation of gene expression but is rather likely a result of its polyanionic nature.",1
11017,16598777,"Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results","""Everolimus is a macrolide immunosuppressive agent with known consistent absorption. In this double-blind study, we examined the safety and tolerability of everolimus vs. placebo in de novo liver transplant recipients. One hundred and nineteen liver allograft recipients were randomized to 1 of 4 groups: everolimus 0.5 mg bid, everolimus 1.0 mg bid, everolimus 2 mg bid, or placebo. Patients received oral cyclosporine to achieve a target trough level of 150-400 ng/mL in combination with prednisone. Primary and secondary endpoints of safety, tolerability, and efficacy were determined at 12 months, and patients were followed through 36 months. There was a trend toward fewer treated acute rejections in the everolimus group than in the placebo group: everolimus 0.5 mg: 39.3%; everolimus 1.0 mg: 30.0%; everolimus 2 mg: 29.0%; placebo: 40.0% (P = not significant). Adverse events were higher in everolimus-treated patients especially at the 4-mg/day dose, but there was no difference in the incidence of thrombocytopenia or leukopenia between all groups and renal function as determined by serum creatinine, and creatinine clearance remained stable to 36 months in everolimus-treated patients. Mean cholesterol and triglycerides increased from baseline in all treatment groups, and maximum levels were seen at 6 months. In conclusion, this study demonstrates that everolimus in combination with oral cyclosporine had an acceptable safety and tolerability profile, paving the way for additional studies in this transplant indication.""",1
11018,16603583,Safety of anti-TNF-alpha therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis,"""OBJECTIVE: To assess the safety of anti-tumour necrosis factor (TNF)-alpha therapy in patients with rheumatoid arthritis (RA) or spondylarthropathies (SA) and concurrent chronic hepatitis B or C. METHODS: Records concerning 480 outpatients attending the Rheumatology Department of the University Hospital of Nice (France) for RA or SA were retrospectively reviewed for the duration of disease, treatment, serological status and biological data. RESULTS: Six relevant cases were identified: two of RA with chronic hepatitis B; one of SA with chronic hepatitis B and three of RA with chronic hepatitis C. Five patients had received etanercept and one infliximab; two had been given adalimumab after an unsuccessful trial of etanercept. Patients with concurrent chronic hepatitis B were also given lamivudine. In none of the cases had changes in serum aminotransferases or viral load been reported. CONCLUSION: The use of anti-TNF-alpha therapy (plus lamivudine in the presence of concurrent underlying hepatitis B viral infection) appeared to be safe in that it had no effect on serum aminotransferases and/or viral load. However, repeated monitoring is necessary throughout the treatment period.""",1
11019,16607155,Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy,"""Azathioprine represents an effective and widely used immunosuppressant; however, there are increasing concerns about the hepatotoxicity of thiopurines because of an entity called """"nodular regenerative hyperplasia"""" (NRH) observed in patients treated with 6-thioguanine. In line with this hypothesis, we report and comment on a patient with inflammatory bowel disease (IBD) diagnosed with NRH as a reversible but potentially serious hepatotoxic side-effect of azathioprine. Our report strengthens the importance of further safety studies to evaluate the aetiology and prevalence of NRH in IBD patients before general conclusions on the use of thiopurines can be drawn. Physicians caring for IBD patients need to be alert to this rare but serious complication.""",1
11020,16610575,Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid,"""Dietary supplements containing usnic acid are marketed for weight loss and have been associated with hepatotoxicity. The specific ingredient responsible for the hepatotoxicity is currently unknown. We describe 2 patients who developed severe hepatotoxicity within 3 months of taking a dietary supplement containing usnic acid. One patient developed fulminant hepatic failure requiring emergency liver transplantation; the other developed submassive hepatic necrosis but did not require transplantation. Thorough investigation, including histopathological examination of the liver, revealed no other cause of acute liver injury. Usnic acid hepatotoxicity should be considered as a possible etiologic factor in patients presenting with fulminant hepatic failure, especially if they have been taking dietary supplements for weight reduction.""",1
11021,16614539,Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients,"OBJECTIVES: This study was carried out to test the hypothesis that the hepatic safety profile of prolonged high-dose oral naltrexone (150 mg/d) is acceptable if over-the-counter analgesic use is restricted. METHODS: Data from 41 consecutive outpatients with impulse-control disorder receiving naltrexone therapy were analyzed. RESULTS: The mean treatment duration was 328 days and the mean naltrexone dose was 142 mg/d. Pretherapy/posttherapy mean aspartate transaminase and alanine transaminase levels in the naltrexone-alone group were 21.79/22.54 and 21.74/21.49 U, respectively (all within reference range). CONCLUSIONS: Although limited in scope, these findings support the hypothesis that long-term use of high-dose oral naltrexone is safe in otherwise healthy patients with impulse-control disorders who restrict their intake of acetaminophen, aspirin, or nonaspirin nonsteroidal anti-inflammatory drugs (NSAID). However, confirming studies are needed.",1
11022,16621917,Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene,"Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.",1
11023,16622909,Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis,"""Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungal-related adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.""",1
11024,16625144,Deferasirox (Exjade): a new iron chelator,,1
11025,16625578,Interventions for paracetamol (acetaminophen) overdose,"BACKGROUND: Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdose. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies until December 2005. SELECTION CRITERIA: Randomised clinical trials and observational studies were included. DATA COLLECTION AND ANALYSIS: The primary outcome measure was all-cause mortality plus liver transplantation. Secondary outcome measures were clinical symptoms, (eg, hepatic encephalopathy, fulminant hepatic failure), hepatotoxicity, adverse events, and plasma paracetamol concentration. We used Peto odds ratios and odds ratios with 95% confidence intervals (CI) for analysis of outcomes. Random- and fixed-effects meta-analyses were performed. MAIN RESULTS: Ten small and low-methodological quality randomised trials, one quasi-randomised study, and 48 observational studies were identified. It was not possible to perform relevant meta-analyses of randomised trials that have addressed our outcome measures. Activated charcoal, gastric lavage, and ipecacuanha are able to reduce the absorption of paracetamol, but the clinical benefit is unclear. Of these, activated charcoal seems to have the best risk-benefit ratio. N-acetylcysteine seems preferable to placebo/supportive treatment, dimercaprol, and cysteamine, but N-acetylcysteine's superiority to methionine is unproven. It is not clear which N-acetylcysteine treatment protocol offers the best efficacy. No strong evidence supports other interventions for paracetamol overdose. N-acetylcysteine may reduce mortality in patients with fulminant hepatic failure (Peto OR 0.26, 95% CI 0.09 to 0.94, one trial). Liver transplantation has the potential to be life saving in fulminant hepatic failure, but refinement of selection criteria for transplantation and long-term outcome reporting are required. AUTHORS' CONCLUSIONS: Our results highlight a paucity of randomised trials on interventions for paracetamol overdose. Activated charcoal seems the best choice to reduce absorption. N-acetylcysteine should be given to patients with overdose but the selection criteria are not clear. No N-acetylcysteine regime has been shown to be more effective than any other. It is a delicate balance when to proceed to liver transplantation, which may be life-saving for patients with poor prognosis.",1
11026,16627542,Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies,"""Understanding of the natural history and basic biology of hepatitis B virus (HBV) has increased greatly in recent years. In view of this, the following are reviewed here: (a) recent advances in HBV biology pertinent to the rheumatic disease population; (b) the risks of HBV reactivation in patients with rheumatic disease undergoing immunosuppression; and (c) potential strategies to manage these risks.""",1
11027,16628699,Pegylated interferon-induced immune-mediated hepatitis post-liver transplantation,A 55-year-old Caucasian male developed a well characterized autoimmune hepatitis after completing treatment with pegylated interferon and ribavirin for recurrent hepatitis C. We hypothesize that pegylated interferon triggered a severe form of immune-mediated hepatitis.,1
11028,16632162,Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity,"Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Among these atypical antipsychotics, mostly transient, asymptomatic increase in hepatic enzymes has been reported with olanzapine, however olanzapine rarely may induce a clinical and/or biological hepatic toxicity. The pathogenesis of olanzapine-associated hepatotoxicity is not well known and is mostly a transient phenomenon. However, substantial and lasting changes may occur and result in symptomatic hepatitis. In the following case report, we report on a 44-year-old female patient diagnosed as Bipolar Disorder Type I, whose liver enzyme levels increased ten fold of normal ranges during the third year of the olanzapine treatment and returned to the normal levels within three weeks after olanzapine discontinuation. Although significant liver enzyme elevations are uncommon during olanzapine treatment, based on reports of serious hepatotoxicity, controlled and longitudinal research are needed to learn side effects of this drug on liver. Clinicians should be aware of possible hepatotoxic effects of atypical antipsychotics and should monitor the liver enzyme levels whenever they feel necessary.",1
11029,16634717,"Nitazoxanide, a broad-spectrum thiazolide anti-infective agent for the treatment of gastrointestinal infections","Colonisation of the gastrointestinal tract by anaerobic bacteria, protozoa, trematodes, cestodes and/or nematodes and other infectious pathogens, including viruses, represents a major cause of morbidity and mortality in Africa, South America and southeast Asia, as well as other parts of the world. Nitazoxanide is a member of the thiazolide class of drugs with a documented broad spectrum of activity against parasites and anaerobic bacteria. Moreover, the drug has recently been reported to have a profound activity against hepatitis C virus infection. In addition, nitazoxanide exhibits anti-inflammatory properties, which have prompted clinical investigations for its use in Crohn's disease. Studies with nitazoxanide derivatives have determined that there must be significantly different mechanisms of action acting on intracellular versus extracellular pathogens. An impressive number of clinical studies have shown that the drug has an excellent bioavailability in the gastrointestinal tract, is fast acting and highly effective against gastrointestinal bacteria, protozoa and helminthes. A recent Phase II study has demonstrated viral response (hepatitis C) to monotherapy, with a low toxicity and an excellent safety profile over 24 weeks of treatment. Pre-clinical studies have indicated that there is a potential for application of this drug against other diseases, not primarily affecting the liver or the gastrointestinal tract.",1
11030,16638794,The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases,"We studied 26 patients belonging to 20 families with a disorder caused by mutations in the POLG gene. The patients were homozygous for 1399 G/A or 2243 G/C (giving the amino acid changes A467T and W748S, respectively) or compound heterozygotes for these two mutations. Irrespective of genotype, the patients exhibited a progressive neurological disorder usually starting in their teens and characterized by epilepsy, headache, ataxia, neuropathy, myoclonus and late onset ophthalmoplegia. However, major differences in survival were seen depending on genotype, with compound heterozygotes having a significantly shorter survival time than patients homozygous either for the A467T or W748S (P = 0.006). Epilepsy occurred in 22 of the 26 patients and in the majority of these there was an occipital EEG focus. Episodes of both generalized and focal motor status epilepticus were common and highly resistant to treatment, even with generalized anaesthesia. Status epilepticus was the recorded cause of death in 9 of 11 patients. Liver failure was the sole cause of death in two patients and evolved terminally in six others, all but one of whom were being treated with sodium valproate. Two patients underwent liver transplantation, but only one survived. Delayed psychomotor development and subsequent cognitive decline also occurs. This study demonstrates the clinical spectrum of a disorder that combines features of Alpers' syndrome and a later onset mitochondrial spinocerebellar ataxia with epilepsy and headache. Patients with this disorder are at high risk of death from status epilepticus and from liver failure, if exposed to sodium valproate. Each mutation appears capable of producing a disorder that is recessively inherited, although we also find evidence in one patient suggesting that heterozygotes may manifest. Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect.",1
11031,16641430,"Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B","""Emtricitabine (FTC) is approved for the treatment of human immunodeficiency virus. FTC and clevudine (CLV) have activity against hepatitis B virus (HBV). This report summarizes the results of a double-blind, multicenter study of patients with chronic hepatitis B who had completed a phase 3 study of FTC and were randomized 1:1 to 200 mg FTC once daily (QD) plus 10 mg CLV QD or 200 mg FTC QD plus placebo for 24 weeks with 24 weeks of follow-up. One hundred sixty-three patients were treated (82 with FTC plus CLV [FTC+CLV] and 81 with FTC); 72% were men, 53% were Asian, 47% were Caucasian, and 52% were hepatitis B e antigen positive, and the median baseline HBV DNA level was 6 log(10) copies/ml. After 24 weeks of treatment, 74% (FTC+CLV) versus 65% (FTC alone) had serum HBV DNA levels of <4,700 copies/ml (P = 0.114) (Digene HBV Hybrid Capture II assay). Twenty-four weeks posttreatment, the mean change in serum HBV DNA levels from baseline was -1.25 log(10) copies/ml (FTC+CLV), 40% had undetectable viremia (versus 23% for FTC alone), and 63% had normal alanine aminotransferase levels (versus 42% for FTC alone) (P < or = 0.025 for all endpoints). The safety profile was similar between arms during treatment, with less posttreatment exacerbation of hepatitis B in the combination arm. In summary, after 24 weeks of treatment, no significant difference between arms was observed, but there was a significantly greater virologic and biochemical response 24 weeks posttreatment in the FTC+CLV arm.""",1
11032,16643206,Hepatotoxicity of antiretroviral drugs in HIV HCV patients with congenital coagulopathies followed at an Haemophilia Unit during a decade,"""The aim of the study was to assess the incidence and the cumulative probability of cytolytic and cholestatic hepatotoxicity during antiretroviral treatment in a group of HIV HCV haemophiliacs. We evaluated 47 patients that received 246 courses of antiretroviral treatment [98 courses of pre-highly active antiretroviral therapy (pre-HAART) and 148 HAART treatments]. Liver function tests were assessed at baseline of each treatment, after 1 month and at least every 4 months thereafter. Cytolytic and cholestatic hepatotoxicity was recorded. Of the 246 treatments, 28 (12.45%) were followed by cytolytic hepatotoxicity and 32 (13%) by cholestatic hepatotoxicity. Cytolytic hepatotoxicity was similar in HAART (16/148; 10.8%) and in pre-HAART treatment (12/98; 12.2%) and cholestatic hepatotoxicity was more frequent in HAART (29/148; 19.6%) than in pre-HAART treatment (3/98; 3.1%) (P < 0.001). The actuarial probability of developing cytolytic and cholestatic hepatotoxicity at 10 years of onset of antiretroviral treatments was 39% and 56%, respectively. Most enzyme elevations were asymptomatic, but in eight cases therapy was discontinued or changed and in one case a cirrhotic patient died of progressive liver failure. In HIV HCV haemophiliacs, the cumulative probability of developing hepatotoxicity during follow-up is high and although in the most cases the toxicity is mild, fatal cases can occur.""",1
11033,16645871,[Severe drug hepatitis caused by Chelidonium],"We report the case of a 58-year-old male patient who was admitted with severe acute cholestatic hepatitis. Liver biopsy showed signs of drug-induced hepatitis. Other causes of acute hepatitis were excluded. Therefore, the ingestion of a Chelidonium-containing preparation (celandine) was thought to be responsible for the hepatitis. Shortly after stopping the administration of Chelidonium, the highly pathological levels of several liver parameters began to normalise. As no autoantibodies were detectable, an idiosyncratic reaction as the cause of drug-induced hepatitis is probable. In cases of unknown hepatitis, herbal medications should be taken into account as a possible cause.",1
11034,16647134,"Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials","""OBJECTIVE: To evaluate the safety of pegaptanib sodium injection, a specific vascular endothelial growth factor (VEGF) antagonist, in the treatment of neovascular age-related macular degeneration (AMD) during 2 years of therapy. DESIGN: Two concurrent, prospective, randomized, multicenter, double-masked, sham-controlled studies. METHODS: Patients with all angiographic choroidal neovascularization lesion compositions of AMD received either intravitreous pegaptanib sodium (0.3 mg, 1 mg, 3 mg) or sham injections every 6 weeks for 54 weeks. Those initially assigned to pegaptanib were re-randomized (1:1) to continue or discontinue therapy for 48 more weeks; sham-treated patients were re-randomized (1:1:1:1:1) to continue sham, discontinue, or receive one of the pegaptanib doses. MAIN OUTCOME MEASURES: All reported adverse events, serious adverse events, and deaths. PARTICIPANTS: In year 1, 1190 subjects received at least one study treatment (0.3 mg, n = 295; 1 mg, n = 301; 3 mg, n = 296; sham, n = 298); 7545 intravitreous injections of pegaptanib were administered. In year 2, 425 subjects (0.3 mg, n = 128; 1 mg, n = 126; 3 mg, n = 120; sham, n = 51) continued the same masked treatment as in year 1 and received at least one study treatment in year 2; 2663 intravitreous injections of pegaptanib were administered in these subjects. RESULTS: All doses of pegaptanib were well tolerated. The most common ocular adverse events were transient, mild to moderate in intensity, and attributed to the injection preparation and procedure. There was no evidence of an increase in deaths, in events associated with systemic VEGF inhibition (e.g., hypertension, thromboembolic events, serious hemorrhagic events), or in severe ocular inflammation, cataract progression, or glaucoma in pegaptanib-treated patients relative to sham-treated patients. In year 1, serious injection-related complications included endophthalmitis (12 events, 0.16%/injection), retinal detachment (RD) (6 events [4 rhegmatogenous, 2 exudative], 0.08%/injection), and traumatic cataract (5 events, 0.07%/injection). Most cases of endophthalmitis followed violations of the injection preparation protocol. In patients receiving pegaptanib for >1 year, there were no reports of endophthalmitis or traumatic cataract in year 2; RD was reported in 4 patients (all rhegmatogenous, 0.15%/injection). CONCLUSION: The 2-year safety profile of pegaptanib sodium is favorable in patients with exudative AMD.""",1
11035,16669963,"Efficacy and safety of bisacodyl in the acute treatment of constipation: a double-blind, randomized, placebo-controlled study","""BACKGROUND: Although laxatives are a first-line treatment for constipation, there are few randomized placebo-controlled trials assessing their efficacy. AIM: To determine the effect and safety of oral bisacodyl on stool frequency and consistency in patients with idiopathic constipation. METHODS: 55 patients (age 19-89 years) with idiopathic constipation were recruited from eight primary care practices and randomized to receive bisacodyl, 10 mg once daily, or placebo, on three successive days following a 3-day run-in period. Patients recorded stool frequency and consistency and adverse events. RESULTS; In each treatment group, 27 patients were evaluable for efficacy. The mean number of stools per day was significantly greater in the bisacodyl-treated group (1.8/day) compared with placebo (0.95/day) over the treatment phase (P=0.0061). Mean stool consistency score improved from 'hard' (run-in) to between 'soft' and 'well-formed' during bisacodyl treatment, remaining between 'moderately hard' and 'hard' for placebo treatment (P<0.0001). The investigator's global efficacy score was superior for the bisacodyl group compared with placebo. Both treatments were well tolerated. Serum electrolyte levels and incidence of adverse events were comparable between treatment groups. CONCLUSIONS: Bisacodyl is effective and safe in improving stool frequency and consistency in acute treatment of idiopathic constipation.""",1
11036,16673364,Ceftriaxone-associated biliary pseudolithiasis in children,"""PURPOSE: Ceftriaxone is known to induce reversible precipitations, known as pseudolithiasis, in the gallbladder and urinary tract. The aim of this study was to investigate the incidence and predisposing factors that contribute to this side effect. METHODS: A prospective study was conducted in 156 children admitted for the treatment of various infections with different daily ceftriaxone doses (50 mg/kg, 75 mg/kg, and 100 mg/kg). Sonographic examinations of the gallbladder and urinary tract were performed before treatment on the third and seventh day of therapy, and at the first and second month after the end of treatment. Patients with positive findings were followed with weekly sonographic examinations until the abnormality resolved. RESULTS: Abnormal gallbladder sonograms were demonstrated in 27 children (17%); 16 of them (10%) had gallbladder lithiasis, 11 had gallbladder sludge (7%) (n = 4 on the third day, n = 23 on the seventh day), and 1 developed urolithiasis (0.6%). Five children (19%) were symptomatic. The abnormalities resolved after a mean of 16 days (range 10-30 days). Patients with pseudolithiasis were older and treated with higher drug doses than those with normal sonographic findings (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: Biliary pseudolithiasis (and infrequently nephrolithiasis) usually occurs in children receiving high doses of ceftriaxone. It is generally asymptomatic. When this reversible complication becomes symptomatic, unnecessary cholecystectomy should be avoided.""",1
11037,16678076,Safety and tolerability of tegaserod in patients with chronic constipation: pooled data from two phase III studies,"""BACKGROUND & AIMS: Studies show that tegaserod effectively relieves the symptoms of chronic constipation/idiopathic constipation (CC). This pooled analysis assessed the safety and tolerability of tegaserod in a large dataset of CC patients. METHODS: Adverse event (AE) data were pooled from 2 double-blind, placebo-controlled phase III trials of 12 weeks' duration. Post hoc analysis was conducted for the most frequent AEs (incidence, >or=3%). RESULTS: Eight hundred eighty-one, 861, and 861 patients received tegaserod 6 mg twice a day, 2 mg twice a day, or placebo, respectively. Most AEs were mild/moderately severe. AE incidence was similar for the tegaserod 6 mg and 2 mg twice a day (57.1% and 56.3%, respectively) and placebo groups (59.6%) and most frequent in the gastrointestinal system (tegaserod 6 mg twice a day, 25.8%; 2 mg twice a day, 22.5%; placebo, 24.6%). Headache, the most common AE, was slightly more frequent in the placebo group (tegaserod 6 mg twice a day, 11.0%; 2 mg twice a day, 10.1%; placebo, 13.2%). Diarrhea (generally transient and resolved with continued treatment) was the only AE with a statistically significant difference between groups (tegaserod 6 mg twice a day 6.6% vs placebo 3.0%, P=.0005). Serious AE incidence (1.4% overall) was comparable across treatment groups, although abdominal surgery was less common in the combined tegaserod (0.5%) than the placebo group (1.0%). Discontinuation as a result of AEs was slightly higher in tegaserod 6 mg twice a day patients (5.7%; 2 mg twice a day, 3.3%; placebo, 3.7%), mainly because of diarrhea. Laboratory and electrocardiogram parameters were comparable across groups. CONCLUSIONS: Tegaserod is well tolerated by patients with CC during 12 weeks of treatment.""",1
11038,16679704,Rapid onset of glycogen storage hepatomegaly in a type-2 diabetic patient after a massive dose of long-acting insulin and large doses of glucose,"We present a case of rapid onset of glycogen storage hepatomegaly, caused by a massive dose of long-acting insulin and large doses of glucose, in a type-2 diabetic patient. A 41-year-old man was admitted to our hospital because of hypoglycemia and unconsciousness following subcutaneous administration of 180 units of insulin glargine in a suicide attempt. Despite continuous hypercaloric infusion with additional intravenous glucose injections, hypoglycemia persisted for 36 hours. Although the hepatic function was normal and no hepatomegaly was detected on admission, the liver function tests became abnormal and hepatomegaly was detected on hospitalization day 3. Plain abdominal computed tomography (CT) scanning confirmed liver enlargement, with hepatic CT attenuation markedly elevated at 83.7 HU. Liver biopsy revealed hepatocytic glycogen deposition with edematous degeneration. Based on these findings, the diagnosis was made as rapid onset glycogen storage hepatomegaly caused by administration of a massive dose of long-acting insulin and supplementation with large doses of glucose. With improved glycemic control, the liver function improved, the CT findings of hepatomegaly improved, and the hepatic CT attenuation decreased. Repeat liver biopsy also confirmed almost complete disappearance of glycogen deposits. When hepatic dysfunction or hepatomegaly is detected during treatment with insulin, the possibility of hepatic glycogen deposition should be considered. CT scanning and liver biopsy were useful in diagnosing this case.",1
11039,16682062,First case of ivermectin-induced severe hepatitis,"Loiasis, caused by the filarial parasite Loa loa, is endemic in West and Central Africa. Ivermectin has been shown to be an effective treatment of loiasis. We report the case of a 20-year-old woman originally from Cameroon who was infected by the L. loa parasite and developed severe hepatitis, identified 1 month after a single dose of ivermectin. Liver biopsy showed intralobular inflammatory infiltrates, confluent necrosis and apoptosis, compatible with drug-induced liver disease. To our knowledge, this is the first case of ivermectin-induced severe liver disease published in the literature.",1
11040,16688096,Severe liver disease associated with prolonged exposure to antiretroviral drugs,"BACKGROUND: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. METHODS: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. RESULTS: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. CONCLUSIONS: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.",1
11041,16691302,Rofecoxib-induced hepatotoxicity: a forgotten complication of the coxibs,"Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively inhibit cyclooxygenase-2. Although the coxibs are generally well-tolerated, rofecoxib was recently withdrawn from the market due to concerns regarding cardiovascular safety. Rare cases of hepatic injury attributable to the coxibs have been reported. In the present study, two additional cases of severe hepatotoxicity are described in patients with cholestatic symptoms and abnormal liver biochemistry, shortly following the initiation of rofecoxib for arthritic complaints. In both cases, liver histology was compatible with drug-induced hepatotoxicity, and rapid clinical and biochemical improvements were observed following rofecoxib discontinuation. With new coxibs and expanding indications on the horizon, physicians in all areas of practice must be aware of this disorder and consider it in any patient who develops hepatic dysfunction after taking a coxib.",1
11042,16696815,"A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients","""BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver injury. Currently, there are no proven effective therapies available. Atorvastatin is a new 3-hydroxy-3-metylglutaryl coenzyme A reductase inhibitor that reduces lipid serum levels. AIM: To evaluate the effectiveness and safety of atorvastatin in dyslipemid, non-alcoholic fatty liver patients. PATIENTS AND METHODS: We prospectively enrolled 25 patients with NAFLD; 22 of them completed the study. Body mass index, serum lipids, liver function tests and liver density assessed by echography were measured at baseline and after 1, 3, 6, 9 and 12 months of treatment. Normalization of transaminases and/or improvement in liver density were treatment end points. Patients received atorvastatin (10-80 mg/daily) according to basal serum choleresterol levels; additionally, they were given standard weight-loss counselling and encouraged to follow a low fat diet. RESULTS: All 22 patients (14 men, mean age 47 +/- 10 years) had high cholesterol levels at baseline and 11 (44%) also presented high trygliceride levels. After 6 months of treatment, eight patients (36.3%) presented normal transaminase levels. The remaining patients continued treatment for 12 months when 20% of patients presented with normal transaminase levels, while the other patients showed a 10% reduction in basal levels. Mean cholesterol levels were 268.5 +/- 44.2 and 186.8 +/- 14.4 mg/dL before and after treatment, respectively (P < 0.05). The mean body mass index was 27.4 +/- 3.1 at baseline and 26.3 +/- 2.8 kg/cm2 at the end of treatment (P > 0.05). No side effects were reported. CONCLUSIONS: Serum aminotransferase and lipid levels were reduced significantly in all patients with atorvastatin treatment. Therapy with atorvastatin in NAFLD patients with hyperlipidemia was found to be both effective and safe.""",1
11043,16697324,Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan,"""OBJECTIVES: We sought to determine the optimal dose of the selective endothelin A (ET(A)) receptor antagonist sitaxsentan for the treatment of pulmonary arterial hypertension (PAH); for observation only, an open-label (OL) bosentan arm was included. BACKGROUND: Endothelin is a mediator of PAH. In a preliminary PAH study, the selective ET(A) receptor antagonist sitaxsentan improved six-min walk (6MW) distance, World Health Organization (WHO) functional class (FC), and hemodynamics. METHODS: In this double-blind, placebo-controlled 18-week study, 247 PAH patients (idiopathic, or associated with connective tissue disease or congenital heart disease) were randomized; 245 patients were treated: placebo (n = 62), sitaxsentan 50 mg (n = 62) or 100 mg (n = 61), or OL (6MW tests, Borg dyspnea scores, and WHO FC assessments third-party blind) bosentan (n = 60). The primary end point was change in 6MW distance from baseline to week 18. Secondary end points included change in WHO FC, time to clinical worsening, and change in Borg dyspnea score. RESULTS: At week 18, patients treated with sitaxsentan 100 mg had an increased 6MW distance compared with the placebo group (31.4 m, p = 0.03), and an improved WHO FC (p = 0.04). The placebo-subtracted treatment effect for sitaxsentan 50 mg was 24.2 m (p = 0.07) and for OL bosentan, 29.5 m (p = 0.05). The incidence of elevated hepatic transaminases (>3x the upper limit of normal) was 6% for placebo, 5% for sitaxsentan 50 mg, 3% for sitaxsentan 100 mg, and 11% for bosentan. CONCLUSIONS: Treatment with the selective ET(A) receptor antagonist sitaxsentan, orally once daily at a dose of 100 mg, improves exercise capacity and WHO FC in PAH patients, with a low incidence of hepatic toxicity.""",1
11044,16699635,Treatment of chronic hepatitis C in non-responsive patients with pegylated interferon associated with ribavirin and thalidomide: report of six cases of total remission,"Hepatitis C virus (HCV) infection is an important public health issue worldwide. It is estimated that over 170 million people are infected with the virus. The present study reports six cases in which patients did not respond to combination therapy with pegylated interferon and ribavirin. However, after the addition of thalidomide to the therapy, the patients presented negative RNA PCR. The use of thalidomide combined with pegylated interferon and ribavirin for the treatment of hepatitis C is described here for the first time in the related literature.",1
11045,16702859,Hepatitis caused by the herbal remedy Teucrium polium L,"Herbal remedies have become increasingly popular throughout the globe as a result of disappointment with conventional medicines and also of the alleged belief that herbal preparations are basically harmless. On the other hand, their effects can be exceedingly potent or even lethal if used improperly. Drugs and other chemicals account for less than 5% of cases of jaundice or acute hepatitis and smaller number of cases of chronic liver disease. Drug reactions can mimic any hepatobiliary disease, posing a diagnostic challenge for physicians and pathologists. Hepatotoxicity generally occurs after approximately 2 months of ingestion and consists of a non-specific hepatitis, which usually runs a benign course. Typical features include anorexia, nausea, abdominal pain, and jaundice associated with a marked elevation in serum aminotransferases. We present a case of acute hepatitis in a 70-year-old farmer, using Teucrium polium (golden germander) as hypoglycaemic aid. The patient presented only with jaundice, after 1 month's consumption of large quantities of this herb in a tea form.",1
11046,16705566,Rhabdomyolysis during therapy with daptomycin,"""The use of daptomycin has been associated with an elevation in creatine phosphokinase level, with a reported incidence of 2.8% in phase III clinical trials. Published case reports have documented the presence of myopathy in patients who received daptomycin; however, there have been no previously reported cases of rhabdomyolysis in animals or humans to date. We describe a case of rhabdomyolysis during therapy with daptomycin.""",1
11047,16707401,Hepatic veno-occlusive disease due to tacrolimus in a single-lung transplant patient,"""Hepatic veno-occlusive disease is defined as nonthrombotic fibrous obliterative endophlebitis of small centrilobular hepatic venules. Clinically, patients present with elevated liver enzymes and a triad of jaundice, hepatomegaly and ascites. Although reported as a complication of other solid organ and stem cell transplantation, there have been no reported cases to date of veno-occlusive disease following lung transplantation. The present authors report a case of veno-occlusive disease following single-lung transplantation in a patient on a triple-drug immunosuppressive regimen composed of tacrolimus, mycophenolate mofetil and prednisone. The diagnosis was established by transjugular liver biopsy and by discontinuing tacrolimus; there was clinical regression of symptoms and serological return to baseline.""",1
11048,16710026,Randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: the 20030125 Study Group Trial,"""PURPOSE: Chemotherapy-induced anemia is widely treated in the United States with darbepoetin alfa (DA) or epoetin alfa (EA). This noninferiority study systematically compares efficacy and safety of DA and EA using common doses and schedules used in clinical practice. METHODS: Patients had a diagnosis of nonmyeloid malignancy with > or = 8 weeks of planned chemotherapy, age >or = 18 years, and anemia (hemoglobin < or = 11 g/dL). Patients were randomly assigned 1:1 to DA 200 microg every two weeks (Q2W) or EA 40,000 units every week (QW) for up to 16 weeks with identical dose adjustment rules. Efficacy was assessed by the incidence of RBC transfusion (Kaplan-Meier estimate). The definition of noninferiority was that the upper 95% CI limit of the observed difference in RBC transfusions between groups was less than 11.5%; this noninferiority margin was based on the treatment effect observed in placebo-controlled EA studies. RESULTS: Of 1,220 patients randomly assigned, 1,209 received > or = one dose of the study drug. Common tumor types were lung (26%), breast (21%), and gastrointestinal (18%). Transfusion incidence from week 5 to the end of the treatment phase (the primary end point) was 21% in the DA group and 16% in the EA group; noninferiority was concluded because the upper 95% CI limit of the difference between groups (10.8%) was below the prespecified noninferiority margin. Sensitivity analyses using alternate statistical methods and analysis sets yielded similar results. Hemoglobin, quality of life, and safety end points further support equivalency of the erythropoietic therapies. CONCLUSION: This large, phase III study demonstrates comparable efficacy of DA Q2W and EA QW. Less frequent dosing offers potential benefits for patients, caregivers and health care providers.""",1
11049,16710914,Drug-related hepatotoxicity,,1
11050,16713365,Does rapid dose titration affect the hepatic safety profile of Bosentan?,"RATIONALE: Bosentan, a dual endothelin receptor antagonist, has proven efficacy in pulmonary hypertension. Due to an association with hepatic dysfunction, it is typically initiated at a sub-therapeutic dose for 4 weeks before titration to a therapeutic dose. At our institution some patients have undergone rapid titration, to potentially benefit from therapy earlier. This study assesses the impact of this practice on hepatic safety. METHOD: All patients initiated on bosentan therapy before April 2005 were included. Rapidly titrated patients achieved a therapeutic dose by 3 days, whereas standard titration patients were titrated at 4 weeks. All patients were monitored with monthly liver function tests. RESULTS: 149 patients commenced bosentan, of which 55 were rapidly titrated. At baseline, the two groups were similar in age, BMI, diagnosis, 6-min walking distance, alanine aminotransferase (ALT), cardiac index and pulmonary artery pressures. The rapid group had elevated right atrial pressures (9.7 mm Hg versus 7.4 mm Hg, p = 0.016) and worse WHO functional class (p = 0.008) and included less females (31% versus 69%, p = 0.024). The incidence of hepatic dysfunction in all patients was 12.8% at 12 months. There was no statistical difference in incidence between the rapid and standard groups (4% versus 11% at 3 months, p = 0.211 and 6% versus 15% at 12 months, p = 0.219). Of all patients on bosentan, hepatic dysfunction was most significantly associated with a higher baseline ALT (p = 0.021), female sex (p = 0.003) and underlying connective tissue disease (p = 0.025). Subgroup analysis suggested these factors were not confounders when comparing rapid and standard titration. CONCLUSIONS: Rapid and standard titration of bosentan resulted in similar hepatic safety profiles. Baseline ALT, female sex and the presence of connective tissue disease increased the risk of hepatic dysfunction independent of the titration method used.",1
11051,16714039,Scedosporium apiospermum mycetoma with bone involvement successfully treated with voriconazole,"""Treatment of Scedosporium apiospermum mycetoma usually requires limb amputation. A 49-year-old woman, from Ivory Coast, was diagnosed with Madura foot in 1995. She failed to respond to several treatments including itraconazole, fluconazole and co-trimoxazole, and refused limb amputation. In December 2002 she was admitted to hospital in France with a painful, swollen right leg and foot. She had no fever and C-reactive protein was 120 mg/l. Magnetic resonance imaging (MRI) confirmed the destruction of tarsus bones with a tibia extension. Voriconazole (400 mg/day) treatment was initiated in March 2003; a significant clinical improvement was observed within 4 months as confirmed by C-reactive protein (16 mg/l) and MRI. Voriconazole was maintained for 18 months with good tolerance. Cholestasis appeared after the first month and remained stable. In October 2004 voriconazole was discontinued due to side effects on the liver (alanine aminotransferase 17 times the normal level); MRI showed impressive regression of bone lesions. As of July 2005, the patient remains clinically well. Voriconazole appears to be a promising drug for the treatment of S. apiospermum mycetomas.""",1
11052,16720565,Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C,"""OBJECTIVES: To determine the incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients with known stage of liver fibrosis. METHODS: All HIV/HCV-coinfected patients were monitored for a period of 12 months after starting nelfinavir-containing regimens and, with an available liver biopsy, were included in a retrospective study. RESULTS: A total of 82 patients were included in the study. Nine (10.9%) HIV/HCV-coinfected patients showed an episode of severe hepatotoxicity during the study period. Eight (9.8%) individuals showed grade 3 or 4 change in levels of serum alanine aminotransferase and one subject presented with an event of decompensated liver cirrhosis. Six (18.2%) of 33 patients with advanced liver fibrosis and three (6%) of 49 individuals without advanced liver fibrosis showed an episode of severe hepatotoxicity (P = 0.1). In the multivariate analysis, only nevirapine use during nelfinavir therapy [adjusted odds ratio (AOR) 8.9; 95% confidence interval (CI), 1.4-54.1; P = 0.01] was independently associated with risk of development of severe liver toxicity. CONCLUSIONS: The incidence of severe hepatotoxicity of nelfinavir-containing regimens is low among HIV/HCV-coinfected patients with known stage of liver fibrosis. In addition, our findings show that concomitant nevirapine use is associated with an increased risk of severe hepatotoxicity in these subjects. Likewise, the proportion of severe liver toxicity tended to be higher in individuals with advanced liver fibrosis.""",1
11053,16720708,Vancomycin-induced elevation of liver enzyme levels,"OBJECTIVE: To report a case of oral vancomycin-induced elevation of liver enzyme levels. CASE SUMMARY: A 57-year-old man with multiple medical conditions requiring systemic antibiotic therapy developed numerous Clostridium difficile-associated enterocolitis episodes. The patient did not respond adequately to oral metronidazole, as evidenced by his continuing diarrhea. He was treated with oral vancomycin on 5 separate occasions (with doses from 125 to 500 mg/day), each of which resulted in significant elevations in alanine aminotransferase (to 371 U/L) and aspartate aminotransferase (to 203 U/L) levels. The elevations resolved on each occasion with discontinuation of vancomycin. DISCUSSION: Vancomycin, a glycopeptide antibiotic, has primary activity against gram-positive bacteria. Oral vancomycin can be used for the treatment of C. difficile-associated enterocolitis in patients who fail to respond to or are intolerant to metronidazole therapy. Oral vancomycin has very poor bioavailability and, as of May 4, 2006, has not been associated with hepatic toxicity. Inflammatory bowel disease processes can result in increased absorption of oral vancomycin. CONCLUSIONS: This is the first reported case of oral vancomycin-induced elevation of hepatic enzyme levels. Use of the Naranjo probability scale indicated that this was a probable adverse drug-associated event.",1
11054,16721710,[Acute hepatitis due to kava-kava and St John's Wort: an immune-mediated mechanism?],"HISTORY AND CLINICAL FINDINGS: In an otherwise healthy 48-year-old female patient, acute hepatitis with transaminase increase (GOT up to 613 U/l, GPT up to 752 U/l), inconspicuous hepatitis serology findings, negative autoantibody status and negative virus serology was observed after a 10-week long intake of kava-kava (1-3 x 200 mg/day) and St John's Wort (1 x 425 mg/day). Biopsy of the liver showed lobular and portal necroinflammatory activity without indication of cirrhosis. DIAGNOSIS: Due to these findings with proven T-cell activity (lymphocyte typing, neopterin determination) as well as the aetiopathology, this form of hepatitis with histological characteristics of a nutritive/medicinal toxic origin was classified as induced immunologic idiosyncratic hepatitis, possibly in terms of an antibody-negative autoimmune hepatitis. TREATMENT AND CLINICAL COURSE: Discontinuation of the existing medication and simultaneous onset of immunosuppressive combination therapy of cortisone, azathioprine and ursodeoxycholic acid resulted in normalisation of the liver parameters within a period of two months. CONCLUSION: On the one hand, it appears that simultaneous intake of St John's Wort possibly potentiates the toxicity of kavapyrones. On the other hand, an immune-mediated mechanism, induced by kava-kava, cannot be completely excluded in the present case. It must be stressed that in patients with autoimmune hepatitis, precise history of medication intake should also be available.",1
11055,16722929,Iron-induced mucosal injury to the upper gastrointestinal tract,"""AIMS: To define the causes and associations of mucosal iron deposition in upper gastrointestinal biopsy specimens and to describe the morphological features of iron-related injury. METHODS: The histological pattern, intensity and distribution of iron in biopsies obtained from 1991 to 2005 were recorded and correlated with endoscopic and clinical findings. RESULTS: Twenty-five biopsies (16 gastric, four duodenal, five oesophageal) were accrued. Iron deposition was seen in two groups: 10 cases showed erosive injury, with brown-black crystalline material overlying eroded epithelium. These patients were taking oral iron tablets. The remaining 15 cases showed variable iron deposition in the surface epithelium, lamina propria and glands. In nine patients, there was a history of oral iron intake and at least eight had had blood transfusions. The most intense iron deposition was noted in patients with end-stage liver disease. The mean age of patients with erosive injury was 43% higher than in the iron overload group (76 versus 53 years). Iron stains were also performed on 15 normal gastric biopsies and five biopsies with chronic, non-specific gastritis; all were negative for haemosiderin deposition. CONCLUSIONS: Iron-related erosive injury is related to oral iron pill ingestion and occurs in older patients. Mucosal iron deposition is also associated with iron overload disorders.""",1
11056,16728538,Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant,"We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.",1
11057,16730038,Oral miltefosine for the treatment of Indian visceral leishmaniasis,"""Large-scale antimony resistance in the treatment of visceral leishmaniasis (VL) in north Bihar, India, has led to the development of miltefosine as an alternative therapy. In a pilot study and later in three Phase II studies involving 249 patients, oral miltefosine, 100-150 mg/day for 28 days, was shown to cure approximately 90% patients with reasonable safety. In the pivotal Phase III trial, 299 patients were treated at three centres with amphotericin B as the comparator drug (99 patients). In this trial 38% and 20% patients had mild to moderate vomiting and diarrhoea respectively, similar to previous studies. Asymptomatic transient elevation of hepatic transaminases and mild renal dysfunction were observed in 15% and 10% patients respectively. The final cure rate was 94% with miltefosine and 97% with amphotericin B; based on these results, the drug was approved in India. Subsequently in two paediatric studies involving 119 patients in the age group of 2-11 years, the safety and efficacy of miltefosine (2.5 mg/kg daily for 28 days) was established with a cure rate (94%) similar to that seen in adults. Miltefosine is the first oral antileishmanial drug with a high degree of safety and efficacy for the treatment of VL.""",1
11058,16737808,Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma,"""Trabectedin is a marine-derived cytoxic alkaloid which has shown promising antitumour activity in a variety of human malignancies including sarcoma. Fifty-four patients with advanced sarcoma (age 43 yrs, range 18-70), all pretreated with prior chemotherapy, were enrolled on a named individual basis for treatment with trabectedin. Diagnosis was adult soft tissue sarcoma (STS) in 46 patients, Ewing's family tumour (EFT) in 4, and osteosarcoma (OS) in 4. The initial 23 patients (total number of courses administered: 68) did not receive premedication prior to trabectedin, while the other 31 patients (total number of courses administered: 134) received premedication with dexamethasone 4 mg po bid 24 hours before therapy. Incidence of toxicity (grade 3-4), expressed as percentage of courses, was as follows: in patients without dexamethasone, elevation of transaminases 34%, neutropenia 24% and thrombocytopenia 25%; in patients with prior dexamethasone, elevation of transaminases 2%, neutropenia 2% and no thrombocytopenia. The median received dose intensity of trabectedin was superimposable in the two groups (404 microg and 400 microg per week, respectively), as well as progression-free survival (19% at 6 months). Among STS patients, 9% had objective responses. In this unselected patient series, premedication with dexamethasone strongly reduced drug-induced hepatotoxicity and myelosuppression.""",1
11059,16747610,The vitamin A content and toxicity of bear and seal liver,,1
11060,16750972,Voriconazole treatment for subacute invasive and chronic pulmonary aspergillosis,"BACKGROUND: Voriconazole is a novel triazole antifungal with a broad spectrum including Aspergillus species. We conducted an open, noncomparative multicenter study to evaluate the efficacy and safety of voriconazole in subacute invasive and chronic pulmonary aspergillosis (CPA). METHODS: Patients without profound neutropenia and a proven or probable diagnosis of subacute invasive aspergillosis (IA) or CPA received voriconazole 200 mg twice daily for a period of 4-24 weeks as primary or salvage therapy. Dose escalation was allowed if efficacy was suboptimal, and toleration and safety were satisfactory. Response was assessed by clinical, radiological and mycological changes. A complete or partial response in subacute IA and improved or stable in CPA were assessed as favorable responses. RESULTS: Of 39 patients treated, 36 were assessable. The majority of patients had subacute IA (n = 21), proven in all 11 extra-pulmonary and in 23/25 (92%) of the pulmonary cases. Voriconazole was given as primary therapy in 22 (61%). All patients receiving salvage therapy (n = 14) had refractory IA, having failed itraconazole or amphotericin B (AmB) or both. Overall, a complete or partial response was seen in 9/21(43%) of subacute IA and improved or stable in 12/15 (80%) of those with CPA. Adverse events, mainly liver function test abnormalities, skin reactions, and visual disturbances were mild and transient, leading to early discontinuation of treatment in 5 cases. CONCLUSIONS: In patients with subacute IA and CPA, voriconazole was efficacious as salvage or primary therapy.",1
11061,16753757,Invasive and non-invasive investigations for tamoxifen-induced non-alcoholic steatohepatitis (NASH): the benefit of computed tomography scan guided liver biopsy,,1
11062,16759058,Drug-specific T cells in an HIV-positive patient with nevirapine-induced hepatitis,"BACKGROUND: Nevirapine is associated with idiosyncratic reactions such as skin rash, hepatitis and hypersensitivity syndrome, which have the hallmarks of being immune mediated. However, there is little laboratory evidence to support an immune pathogenesis. METHODS: A HIV-positive individual who developed hepatitis within 6 weeks of starting nevirapine, in the absence of any cutaneous manifestations, is described. Other causes of hepatitis were excluded, and the patients liver function normalized on withdrawal of nevirapine. Lymphocytes from the patient, and six individuals with HIV who were on nevirapine without adverse effects, were exposed to nevirapine and its metabolites, and lymphocyte proliferation assessed by 3H-thymidine incorporation on day 5. RESULTS: The T cells taken from the nevirapine-hypersensitive patient proliferated in the presence of nevirapine with a stimulation index of greater than 2. There was no proliferation with nevirapine metabolites. T cells taken from HIV-positive control individuals showed no proliferation with either nevirapine or its metabolites. CONCLUSION: The results from our patient suggest that T cells may be involved in the pathogenesis of nevirapine-induced hepatitis. Larger numbers of patients need to be studied to fully evaluate the role of T cells in nevirapine-induced hepatitis and nevirapine hypersensitivity syndrome.",1
11063,16761304,"Results from a rosuvastatin historical cohort study in more than 45,000 Dutch statin users, a PHARMO study","PURPOSE: Clinical benefits of statin therapy are accepted, but their safety profiles have been under scrutiny, particularly for the recently introduced statin, rosuvastatin, relating to serious adverse events involving muscle, kidney and liver. Therefore, a historical cohort study was performed to evaluate the association between rosuvastatin versus other statin use and the incidence of rhabdomyolysis, myopathy, acute renal failure and hepatic impairment. METHODS: Incident users of rosuvastatin or other statins in 2003-2004 and a cohort of patients not prescribed statins were included from the PHARMO database of >2 million Dutch residents. Cases of hospitalisations for myopathy, rhabdomyolysis, acute renal failure or hepatic impairment were identified for these cohorts. Potential cases were validated through a multi-step process using data obtained from hospital records. Additionally, cases of all cause deaths were identified from certification alone. RESULTS: In 2003 and 2004, 10,147 incident rosuvastatin users, 37,396 incident other statin users and 99,935 patients without statin prescriptions were included. There were 26 validated outcome events in the three cohorts including one case each of myopathy (other statin group) and rhabdomyolysis (non-treated group). There were no significant differences in the incidence of outcome events between rosuvastatin and other statin users. CONCLUSION: This study indicated that the number of outcome events is less than 1 per 3000 person years. This study in more than 45,000 Dutch statin users suggests that rosuvastatin does not lead to an increased incidence of rhabdomyolysis, myopathy, acute renal failure or hepatic impairment compared to other statins.",1
11064,16762627,"Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B","BACKGROUND & AIMS: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. METHODS: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). RESULTS: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was -5.11 log(10) copies/mL for entecavir-treated patients and -0.48 log(10) copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. CONCLUSIONS: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile.",1
11065,16765457,Antiviral drugs for cytomegalovirus diseases,"""Cytomegalovirus infections are associated with severe morbidity and mortality is patients at risk for disease because of immune system disabilities; in particular, recipients of stem cell (HSCT) or solid organ (SOT) transplants. There are three systemic drugs approved for CMV treatment: ganciclovir, or its prodrug valganciclovir, foscarnet, and cidofovir. An anti-sense therapeutic, ISIS 2922, is also approved specifically as in intravitreal treatment for CMV retinitis. Ganciclovir, and more recently, valganciclovir, have been useful in proactive approaches of CMV disease management; in both prophylactic and preemptive regimens in HSCT and SOT populations. The major anti-herpes agent valacyclovir has also been approved for prophylaxis of renal transplant recipients, or SOTs outside of the US. These drugs have provided major advances in CMV disease management, although they are limited by intolerable toxicities, oral bioavailability and efficacy, and risk of drug resistance with extended use. Several drugs are in early clinical development which may address these limitations; this review will provide an overview of our current arsenal of available drugs, and of those in the early clinical development pipeline.""",1
11066,16770243,A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study,"""BACKGROUND: Antilymphocytic antibodies have been long used for the prevention of acute rejection early after heart transplantation (HTx), but their adverse effects have limited their widespread use. Our aim was to evaluate the safety, tolerability, and efficacy of the novel anti-CD25 antibody basiliximab (BAS) compared with muromonab (OKT3). PATIENTS AND METHODS: In this multicenter study, 99 patients were randomly assigned to receive either BAS or OKT3 in the early post-HTx period. The primary endpoint was safety and tolerability. Specific safety variables were predefined for a better comparison of adverse effects. Secondary endpoints concerning anti-rejection efficacy were also evaluated. RESULTS: No adverse events related to study medication were found in the BAS group, whereas 23 were observed among patients receiving OKT3 (P<0.0001). The proportion of patients with predefined adverse events day 4 post-HTx was much higher with OKT3 than with BAS (43% vs. 4%; P<0.0001). Fever, acute pulmonary edema, hypotension, and other complications accounted for most of the difference. At 1-year follow-up, biopsy-proven rejection episodes grade>or=3A had occurred in 39.6% of BAS patients versus 40.4% of OKT3 patients (P=0.87). There were no differences in terms of severity and timing of acute rejection episodes. The number of infectious episodes, complications not related to study medication, and actuarial survival were similar in both groups. CONCLUSION: In this HTx study, induction therapy with BAS was safer and better tolerated than OKT3, without significant differences in efficacy outcomes.""",1
11067,16770646,CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis,"""OBJECTIVE: To determine whether pharmacogenetic tests such as N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genotyping are useful in identifying patients prone to antituberculosis drug-induced hepatotoxicity in a cosmopolite population. METHODS: In a prospective study we genotyped 89 patients treated with isoniazid (INH) for latent tuberculosis. INH-induced hepatitis (INH-H) or elevated liver enzymes including hepatitis (INH-ELE) was diagnosed based on the clinical diagnostic scale (CDS) designed for routine clinical practice. NAT2 genotypes were assessed by fluorescence resonance energy transfer probe after PCR analysis, and CYP2E1 genotypes were determined by PCR with restriction fragment length polymorphism analysis. RESULTS: Twenty-six patients (29%) had INH-ELE, while eight (9%) presented with INH-H leading to INH treatment interruption. We report no significant influence of NAT2 polymorphism, but we did find a significant association between the CYP2E1 *1A/*1A genotype and INH-ELE (OR: 3.4; 95% CI:1.1-12; p = 0.02) and a non significant trend for INH-H (OR: 5.9; 95% CI: 0.69-270; p = 0.13) compared with other CYP2E1 genotypes. This test for predicting INH-ELE had a positive predictive value (PPV) of 39% (95% CI: 26-54%) and a negative predictive value (NPV) of 84% (95% CI: 69-94%). CONCLUSION: The genotyping of CYP2E1 polymorphisms may be a useful predictive tool in the common setting of a highly heterogeneous population for predicting isoniazid-induced hepatic toxicity. Larger prospective randomized trials are needed to confirm these results.""",1
11068,16772759,Nationwide efficacy-safety study of nebivolol in mildly hypertensive patients,"""Nebivolol has been adequately tested in clinical efficacy trials of patients with mild hypertension. Clinical efficacy trials or their meta-analyses did not accurately predict the outcome of subsequent large studies. The primary objective was to assess the efficacy/safety of nebivolol 5-10 mg daily in a nationwide study of patients with mild hypertension. Secondary objectives were (1) to compare efficacy/safety as monotherapy versus add-on therapy and (2) to assess the effect of nebivolol on ISH. This was an open-label, 6-week follow-up study of 6,356 patients with mild hypertension or ISH, as defined by the 1999 World Health Organization guidelines, recruited from 2,700 facilities. Previous monotherapies were continued except for beta-blockers. Results are reported as means+/-SDs. Intention-to-treat analysis is given. A total of 5,740 patients completed the study; of the withdrawals, 90% were lost for follow-up or were noncompliant, 38% were untreated before, 23% had beta-blockers. In the accumulated data, mean systolic and diastolic blood pressures fell by 24+/-14 and 13+/-9 mm Hg (both P<0.001). The differences between the blood pressure-reducing effects of nebivolol monotherapy and add-on therapy were not statistically significant: 28+/-16 and 22+/-14 mm Hg for systolic and 15+/-11 and 11+/-8 mm Hg for diastolic blood pressures. Adverse events were limited to 0.5% of the patients, no serious adverse events were observed. In the ISH patients, diastolic blood pressure fell by 4+/-6 mm Hg compared with 15+/-10 mm Hg in the no-ISH patients (P<0.01). Efficacy-safety effects of nebivolol in patients with mild hypertension can be generalized in a nationwide assessment. The efficacy of nebivolol as monotherapy and as the efficacy as add-on therapy are very similar. Nebivolol is highly efficacious in patients with ISH.""",1
11069,16773722,Noni juice is not hepatotoxic,"Noni juice (Morinda citrifolia) has been approved for use as a safe food within the European Union, following a review of safety. Since approval, three cases of acute hepatitis in Austrian noni juice consumers have been published, where a causal link is suggested between the liver dysfunction and ingestion of anthraquinones from the plant. Measurements of liver function in a human clinical safety study of TAHITIAN NONI Juice, as well as subacute and subchronic animal toxicity tests revealed no evidence of adverse liver effects at doses many times higher than those reported in the case studies. Additionally, M. citrifolia anthraquinones occur in the fruit in quantities too small to be of any toxicological significance. Further, these do not have chemical structures capable of being reduced to reactive anthrone radicals, which were implicated in previous cases of herbal hepototoxicity. The available data reveals no evidence of liver toxicity.",1
11070,16775235,Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL,"""BACKGROUND: Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. METHODS: In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily. RESULTS: Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission. CONCLUSIONS: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov].).""",1
11071,16778286,Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension,"STUDY OBJECTIVES: The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter. DESIGN: Multicenter retrospective study. SETTING: Three European university hospitals. METHODS: Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 +/- 17.2 months (+/- SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival. RESULTS: At 3 years, significant improvements from baseline were observed in mean SMWD (305 +/- 11 to 445 +/- 12 m, p = 0.0001), Borg dyspnea score (5.7 +/- 0.2 to 4.5 +/- 1, p = 0.0006), and NYHA class (3.20 +/- 0.04 to 2.1 +/- 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 +/- 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively. CONCLUSIONS: Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.",1
11072,16790701,Omalizumab for asthma,,1
11073,16793166,Hepatotoxicity due to extracts of Chinese green tea (Camellia sinensis): a growing concern,,1
11074,16797241,Severe hepatic side effects of ezetimibe,"BACKGROUND AND AIMS: Ezetimibe was introduced recently as a new class of cholesterol-lowering drugs. Until now only limited increases of transaminase levels were reported. METHODS: We studied 2 patients with severe hepatic side effects of ezetimibe in a general community hospital. RESULTS: Ezetimibe may lead to 2 distinct types of severe hepatic side effects. CONCLUSIONS: Ezetimibe may rarely cause hepatotoxicity, severe cholestatic hepatitis, or acute autoimmune hepatitis.",1
11075,16798646,Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients,"""Deferiprone (L1) is an orally active iron-chelation agent that is being evaluated as a treatment for iron overload in thalassemia major. Although some reports have concluded that LI may exacerbate hepatic fibrosis and the deterioration of liver function in thalassemia patients, other studies have reported no detrimental effects. In view of these serious concerns regarding the hepatic toxicity of LI, a Taiwanese group of beta-thalassemia (thal) patients with the longest known duration of LI therapy and who had provided liver biopsies, were enrolled in this study. From April 1999 to July 2004, the 17 enrolled thalassemia major patients had been on L1 therapy for as long as 19 to 60 months. Two liver biopsies from each of the 17 patients were received at the China Medical University Hospital, Taichung, Taiwan. Serum alanine aminotransferase (ALT), viral serological studies for hepatitis B and hepatitis C, iron scores and fibrosis scores were available at the beginning of the study and at the time of the second biopsy. Overall, the 17 patients received L1 therapy continuously for a mean period of 3.3 years. With the exception of two patients, fibrosis scores decreased in all patients after LI therapy. Three patients had increased iron scores after therapy of L1 and 11 patients had increased ALT levels; increased ALT levels occurred more frequently in hepatitis C positive patients. In this study, most thalassemia major patients had no progression of hepatic fibrosis or increased liver iron stores during long-term LI therapy.""",1
11076,16798778,High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?,"""BACKGROUND: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. METHODS: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. RESULTS: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a """"probable autoimmune hepatitis"""" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). CONCLUSIONS: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.""",1
11077,16800967,Gefitinib monotherapy in chemotherapy-naive patients with inoperable stage III/IV non-small-cell lung cancer,"""BACKGROUND: Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor with activity in previously treated patients with advanced-stage non-small-cell lung cancer (NSCLC). However, little is known of its activity as monotherapy in chemotherapy-naive patients. This phase II study (1839IL/0456) evaluated first-line gefitinib in patients with advanced-stage NSCLC. PATIENTS AND METHODS: Eligible patients with proven inoperable stage III/IV NSCLC, no previous chemotherapy, and a performance status of 0-2 received gefitinib 250 mg per day until disease progression. Patient reevaluation was performed by radiography and computed tomography at regular intervals. RESULTS: Fifty-eight of 59 patients were available for analysis. Response rate (complete plus partial responses) was 5% (3 of 58 patients); 40% (23 of 58 patients) exhibited stable disease (overall disease control rate, 45% [26 of 58 patients]). Median progression-free survival was 7 weeks, and median overall survival was 29 weeks. All responders were women and/or nonsmokers with adenocarcinoma or bronchoalveolar carcinoma. Gefitinib treatment was well tolerated; skin toxicities occurred in 71% of patients, including severe skin toxicities in 2 patients, and mild to moderate diarrhea occurred in 50% of patients. CONCLUSION: Gefitinib monotherapy has some efficacy in chemotherapy-naive patients with advanced-stage or metastatic NSCLC. However, activity seems to be limited to particular patient groups.""",1
11078,16801674,Unmasking of autoimmune hepatitis in a patient with MS following interferon beta therapy,,1
11079,16804838,Safety and completion rate of short-course therapy for treatment of latent tuberculosis infection,"BACKGROUND: Nine months of isoniazid therapy is the recommended regimen for treatment of latent tuberculosis infection, but low completion rates are a serious problem. The search for shorter regimens, compared with the standard isoniazid regimen, is of vital importance. We describe our experience using short-course regimens for the treatment of latent tuberculosis infection. METHODS: We conducted a nonrandomized, observational study of 459 patients in a county health department from June 2000 to January 2006. Short-course therapy was defined as pyrazinamide and rifampin taken daily or twice weekly for 2 months or rifampin taken daily for 4-6 months. Conventional therapy consisted of a 9-month regimen of isoniazid. Liver function testing was performed for both groups in accordance with clinical guidelines. Treatment completion and hepatotoxicity (according to the World Health Organization classification) were determined for the short-course and conventional therapy groups. RESULTS: Treatment was completed by 241 (77.7%) of 310 patients in the short-course group and by 98 (65.8%) of 149 patients in the isoniazid group (P = .009). Moderate to severe hepatotoxicity (grades 3 and 4) occurred in 6.1% of patients receiving short-course therapy and in 2.0% of patients receiving isoniazid (P=.09). The hepatotoxicity observed in the short-course group was confined to patients receiving pyrazinamide and rifampin daily and was self limited in all cases after the medications were discontinued. CONCLUSIONS: The rate of treatment completion was significantly higher with short-course regimens, compared with the isoniazid regimen. Although the overall risk of hepatotoxicity in patients receiving pyrazinamide and rifampin daily for the treatment of latent tuberculosis infection was higher, liver functions returned to normal after the medications were discontinued.",1
11080,16815744,"Efficacy and safety of zolpidem-MR: a double-blind, placebo-controlled study in adults with primary insomnia","""BACKGROUND AND PURPOSE: To evaluate the clinical efficacy and safety of modified-release zolpidem (zolpidem-MR 12.5mg) for the treatment of primary insomnia in adults. PATIENTS AND METHODS: Two hundred and twelve (123 women, 89 men; mean age 44.3+/-SD 3.0 years), Diagnostic and Statistical Manual of Mental Disorders--4th Edition (DSM-IV)-defined primary insomnia patients were randomized in a double-blind, placebo-controlled, parallel-group study. The study was completed by 192 patients. Patients received 3 weeks of nightly treatment with either zolpidem-MR 12.5mg or placebo, preceded and followed by two nights of single-blind placebo. The main outcome measures were mean polysomnographic (PSG) sleep parameters of nights 1/2 and nights 15/16 of double-blind treatment and daily subjective sleep estimates from sleep questionnaires to assess efficacy, and PSG parameters of nights 22 and 23 of single-blind placebo substitution to assess the effect of drug discontinuation. RESULTS: Relative to placebo, zolpidem-MR 12.5mg improved sleep maintenance by significantly reducing PSG wake time after sleep onset (WASO) during the first 6h of sleep as well as the number of awakenings. Consistent with the effects of standard zolpidem, zolpidem-MR also significantly reduced latency to persistent sleep, and significantly increased sleep efficiency, both at the beginning and after 2 weeks of double-blind treatment. There was no evidence of next-day residual effects as measured objectively by psychometric tests. Rebound insomnia on the first night after abrupt discontinuation resolved the following night. Overall, zolpidem-MR was well tolerated. CONCLUSIONS: Zolpidem-MR 12.5mg is effective and safe in treating primary insomnia in adults and improves sleep maintenance, induction and duration of sleep.""",1
11081,16819252,Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab,"A 59-year-old man developed acute hepatitis with reactivated hepatitis B virus (HBV) following administration of rituximab (anti-CD20 monoclonal antibody). The patient was diagnosed with malignant lymphoma in 1998, and virus marker testing indicated HBV surface antigen (HBsAg)-negative and anti-HBs antibody (anti-HBs)-positive results when chemotherapy including rituximab was started. Levels of aminotransferases were elevated, and HBsAg results turned positive. Despite therapy for late-onset hepatic failure, the patient died. Rituximab appears likely to have induced HBV reactivation in this case. Anti-viral agents should be administered for both HBsAg-positive and anti-HBs-positive patients who are scheduled to receive rituximab.",1
11082,16820547,"Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial","""CONTEXT: Varenicline, a partial agonist at the alpha4beta2 nicotinic acetylcholine receptor, has the potential to aid smoking cessation by relieving nicotine withdrawal symptoms and reducing the rewarding properties of nicotine. OBJECTIVE: To determine the efficacy and safety of varenicline for smoking cessation compared with placebo or sustained-release bupropion (bupropion SR). DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial conducted between June 2003 and March 2005 at 14 research centers with a 12-week treatment period and follow-up of smoking status to week 52. Of 1413 adult smokers who volunteered for the study, 1027 were enrolled; 65% of randomized participants completed the study. INTERVENTION: Varenicline titrated to 1 mg twice daily (n = 344) or bupropion SR titrated to 150 mg twice daily (n = 342) or placebo (n = 341) for 12 weeks, plus weekly brief smoking cessation counseling. MAIN OUTCOME MEASURES: Continuous abstinence from smoking during the last 4 weeks of treatment (weeks 9-12; primary end point) and through the follow-up period (weeks 9-24 and 9-52). RESULTS: During the last 4 weeks of treatment (weeks 9-12), 43.9% of participants in the varenicline group were continuously abstinent from smoking compared with 17.6% in the placebo group (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.69-5.50; P<.001) and 29.8% in the bupropion SR group (OR, 1.90; 95% CI, 1.38-2.62; P<.001). For weeks 9 through 24, 29.7% of participants in the varenicline group were continuously abstinent compared with 13.2% in the placebo group (OR, 2.83; 95% CI, 1.91-4.19; P<.001) and 20.2% in the bupropion group (OR, 1.69; 95% CI, 1.19-2.42; P = .003). For weeks 9 through 52, 23% of participants in the varenicline group were continuously abstinent compared with 10.3% in the placebo group (OR, 2.66; 95% CI, 1.72-4.11; P<.001) and 14.6% in the bupropion SR group (OR, 1.77; 95% CI, 1.19-2.63; P = .004). Treatment was discontinued due to adverse events by 10.5% of participants in the varenicline group, 12.6% in the bupropion SR group, and 7.3% in the placebo group. The most common adverse event with varenicline was nausea, which occurred in 101 participants (29.4%). CONCLUSIONS: Varenicline is an efficacious, safe, and well-tolerated smoking cessation pharmacotherapy. Varenicline's short-term and long-term efficacy exceeded that of both placebo and bupropion SR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00143364.""",1
11083,16820551,Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial,"""CONTEXT: During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed. OBJECTIVE: To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo. DESIGN, SETTING, AND PARTICIPANTS: A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units. INTERVENTION: Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter. RESULTS: None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. CONCLUSIONS: Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.""",1
11084,16825915,Clinico-histopathological characteristics of clopidogrel-induced hepatic injury: case report and review of literature,"Clopidogrel is a thienopyridine derivative with a relatively low occurrence of adverse side effects. Increasing evidence, however, suggests that clopidogrel may cause severe liver injury. Until now, five cases of clopidogrel-induced acute hepatitis have been reported. We describe the case of an 80-year-old man who developed symptomatic liver disease 6 weeks after 1x75 mg/day clopidogrel intake as adjunctive antiplatelet therapy for a renal artery stent implantation. Histological examination revealed severe acute hepatitis with extensive hepatocanalicular cholestasis and focal cell necrosis with a preferential zone-3 distribution of hepatic damage. In the present paper, we describe the clinico-histopathological characteristics of a case of clopidogrel-induced acute hepatitis and discuss the current literature.",1
11085,16829296,Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial,"BACKGROUND: Rotavirus is a leading cause of morbidity and mortality in children younger than 5 years, but there is no effective treatment. We assessed the activity of nitazoxanide, a broad-spectrum anti-infective drug, against rotavirus in cell culture and in a clinical trial in paediatric patients hospitalised with severe rotavirus diarrhoea. METHODS: We did a randomised double-blind placebo-controlled trial in 50 children admitted to the Cairo University Children's Hospital between June 15 and Aug 23, 2005, with severe rotavirus diarrhoea. 38 children aged 5 months to 7 years (median age 11 months) with rotavirus as the sole identified cause of gastroenteritis were enrolled in the clinical study. Patients were randomly assigned either 7.5 mg/kg nitazoxanide as an oral suspension or placebo twice a day for 3 days, and all remained in hospital for 7 days after start of treatment. The primary endpoint was time from first dose to resolution of illness, and analysis was by modified intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00302640. FINDINGS: Survival analysis showed that the median time to resolution of illness was 31 h (IQR 22-73) for the nitazoxanide-treated group compared with 75 h (51-124) for the placebo group (p=0.0137). No significant adverse events were reported. INTERPRETATION: A 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalised paediatric patients. These results are encouraging, and might lead us to think about new approaches to managing rotavirus disease in children.",1
11086,16837676,Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women,"""BACKGROUND: The effect of raloxifene, a selective estrogen-receptor modulator, on coronary heart disease (CHD) and breast cancer is not established. METHODS: We randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for CHD to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer. RESULTS: As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor-positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman-years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman-years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000). CONCLUSIONS: Raloxifene did not significantly affect the risk of CHD. The benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke. (ClinicalTrials.gov number, NCT00190593 [ClinicalTrials.gov].).""",1
11087,16839858,Study of hepatotoxicity of naltrexone in the treatment of alcoholism,"Since a black box warning was issued by the Food and Drug Administration regarding the use of the opiate antagonist naltrexone (NTX), many clinicians have been concerned about current labeling of the potential hepatotoxicity risk of NTX in the treatment of opiate dependence and alcoholism. Despite many reports that demonstrated that the use of NTX did not cause elevation of liver enzymes, controversy concerning whether NTX is hepatotoxic continues. The current study monitored 74 alcoholic patients who received 25mg of NTX daily in the first week and then 50mg of NTX daily for the rest of the 12-week period. After the 12-week treatment, levels of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) did not show any elevation, except in one subject, and the results strongly support that NTX did not induce abnormalities in liver function tests or elevate the liver enzymes. Instead, a statistical significance of decreasing levels of ALT and AST in the liver was shown throughout the study. These findings provide further support that NTX is not hepatotoxic at the recommended daily dose and may be beneficial for patients with elevated liver enzymes.",1
11088,16847416,Severe hepatotoxicity associated with the combination of enfuvirtide and tipranavir/ritonavir: case report,,1
11089,16854576,Hepatotoxicity potential of saw palmetto (Serenoa repens) in rats,"""Saw palmetto (Serenoa repens L.) is an herbal drug used to treat symptoms of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). There has been a report that a preparation containing this herb has caused cholestatic hepatitis in one person and some indications exist that it may have the potential to produce liver toxicity. The purpose of this study was to evaluate the effect of saw palmetto on rat liver function by measuring its effects on several enzymes and formation of malondialdehyde (MDA), a byproduct of lipid peroxidation. A significant increase in these parameters is considered an indication of liver toxicity. Thirty-six rats were divided into 6 groups of 6 animals each. They were treated for 2 or 4 weeks with a placebo or saw palmetto at doses of 9.14 or 22.86 mg/kg/body wt./day; that is, 2 x and 5 x the maximum recommended daily human dosages. After 2 or 4 weeks, the animals were sacrificed and blood was collected to prepare serum for enzyme assays, which were performed using commercially available kits. A portion of the liver was removed, and a homogenate prepared for the lipid peroxidation assay. Results showed no significant difference in animal body weight, enzyme activity, or MDA formation at either time or dosage level, as compared to controls. The data indicate that at the doses and time periods tested, saw palmetto did not produce any significant effect on the normal biological markers of liver toxicity.""",1
11090,16861097,Severe hepatotoxicity after therapeutic doses of acetaminophen,"""BACKGROUND: Acetaminophen overdose is a frequent cause of acute liver failure. Controversy exists over the rare association of severe hepatotoxicity or acute liver failure with therapeutic doses of acetaminophen. CASE SUMMARY: A 45-year-old white man weighing 85 kg with asymptomatic HIV, hepatitis B virus, and hepatitis C virus (HCV) infection presented with signs of severe hepatotoxicity: aspartate aminotransferase (AST), 8,581 IU/L; alanine aminotransferase (ALT), 5,433 IU/L; L-lactate dehydrogenase, 13,641 IU/L; and prothrombin international normalized ratio, 2.15. He reported taking acetaminophen 1,000 mg QID for the previous 4 days and 1,000 mg that morning because of a febrile illness. Immediate administration of continuous IV N-acetylcysteine 150 mg/kg for the first 90 minutes and then 50 mg/kg q4h for the next 3 days was followed by clinical improvement and a rapid decrease in AST and ALT. AST levels decreased from 8,581 to 42 IU/L within 11 days. Several potential risk factors for acetaminophen hepatotoxicity (ie, chronic alcohol, tobacco, and opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection) were present in this patient. CONCLUSIONS: This patient with multiple risk factors and severe hepatotoxicity after therapeutic dosage of acetaminophen was successfully treated with N-acetylcysteine.""",1
11091,16864918,Efficacy and safety of leflunomide alone and in combination with methotrexate in the treatment of refractory rheumatoid arthritis,"BACKGROUND: Rheumatoid arthritis patients who develop refractoriness are left with no alternatives other than leflunomide and costly biological response modifiers. Leflunomide, though effective, was associated with adverse events and has not been extensively studied in the Indian population. AIMS: Determination of safety and efficacy of leflunomide alone and if not useful, in combination with methotrexate in patients refractory to conventional disease-modifying agents. SETTING AND DESIGN: Open labeled clinical trial with leflunomide [100 mg, OD x 3 days followed by 20 mg, OD x 6 months], if no improvement at three months, combined with methotrexate [5-7.5 mg, OD x 3 months] at a tertiary care hospital. MATERIALS AND METHODS: The primary endpoint in the improvement in EULAR criteria and secondary endpoints were patient and physician global evaluation, incidence of remission and biochemical and clinical adverse events. STATISTICAL ANALYSIS: Chi square test or Fisher's exact test and parametric and non-parametric repeat measure ANOVA were used for analysis. RESULTS: Among 84 patients who were included in the study, leflunomide showed improvement and remission in 52 [62%] and 6 [7%] in six months, by intention to treat analysis. Adverse events were observed in 15, discontinuation in 5 and 24 dropped out. With combination in 11 patients, there was improvement and remission in nine [91%] and one [9%] after three months. Adverse events were observed in six and one discontinued. CONCLUSIONS: If regular monitoring of hepatic function and hematological parameters are performed, leflunomide is an effective and safe drug in the Indian population in resistant rheumatoid arthritis patients, especially if used alone.",1
11092,16867024,Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems,"Several non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with liver damage. The aim of this study was to compare proportions of hepatic adverse drug reaction reports associated with NSAIDs in France and Spain. Information from the Spanish and French pharmacovigilance databases were used from 1982 to 2001. To assess the risk of liver injury, the case/non-case methodology was applied, 'cases' being reports of liver damage and 'non-cases' or controls, all other reports. Exposure was considered as the presence of at least one NSAID. Liver injury risk was estimated for each drug in the two databases by calculation of reporting odds ratio in cases and non-cases, with its 95% confidence interval. Out of 62 456 reports from the Spanish database, 2114 (3.38%) were identified as liver injuries, whereas there were 27 372 liver injuries out of 200 046 (13.68%) in the French database. In Spain, there was a significant association between liver injuries and droxicam, sulindac, and nimesulide. The risk was also slightly above 1 for aceclofenac. In France, the risk was very high with clometacin, followed by sulindac, and was slightly above 1 for naproxen, diclofenac, piroxicam, and tenoxicam. This study shows that some NSAIDs are associated with reports of hepatic injuries when compared with other drugs, and most of those have been withdrawn from the market for this reason. However, the frequency of drug-related hepatic injuries reported differed in the French and Spanish databases, and some drugs did not show the same risk level in the two countries. These discrepancies could be explained in part not only by reporting rates, but also by difference in drug use patterns and/or by genetic or environmental factors.",1
11093,16873803,"Safety of type 2 diabetes treatment with repaglinide compared with glibenclamide in elderly people: A randomized, open-label, two-period, cross-over trial",,1
11094,16875457,"A fine pile of pate: the cautionary tale of telithromycin, hepatic failure, and study 3014",,1
11095,16878370,Amphotericin B-associated hyperbilirubinemia: case report and review of the literature,"A 53-year-old woman with an intraabdominal infection secondary to Candida albicans experienced hyperbilirubinemia after receiving amphotericin B in two different formulations--amphotericin B deoxycholate and amphotericin B lipid complex. Only a few case reports of amphotericin B-induced hyperbilirubinemia have been documented in the literature, each with different patterns of corresponding abnormalities in liver function tests. The unpredictable nature of this adverse effect warrants monitoring of bilirubin levels and liver function at baseline and potentially during therapy with amphotericin B, regardless of formulation, dosage, or duration of therapy.",1
11096,16881537,Prevalence of amiodarone-related hepatotoxicity in 720 Chinese patients with or without baseline liver dysfunction,"BACKGROUND: The prevalence of hepatotoxicity after longterm oral amiodarone therapy in Chinese patients with or without elevated liver enzymes at baseline is unknown. HYPOTHESIS: Amiodarone may still be safely prescribed for Chinese patients who have baseline liver dysfunction. METHODS: This is a retrospective cross-sectional study. Significant liver dysfunction (SLD) was defined as alanine aminotransferase (ALT) > 2 times upper limit of normal range. RESULTS: Baseline liver function was checked in 628 of the 720 Chinese patients identified. The mean duration of amiodarone use was 615.9 +/- 703.1 days. Ninety patients (14.3%) had elevated baseline ALT. The prevalence of SLD was 3.7% (confidence interval [CI] 2.1-5.3%) and 4.4% (CI 0.2-8.6%) in patients with normal (n = 538) and elevated (n = 90) baseline ALT, respectively (p = 0.765). Therapy was continued in 42 patients with elevated baseline ALT until final follow-up. Eight of these (19.0%) had elevated ALT upon final follow-up, but the derangement was mild (mean ALT 134.8 +/- 145.9 IU/l, median 76 IU/l). During follow up, 24 patients developed SLD and half of these subsequently withdrew from therapy. The ALT levels at final follow-up had improved over time in both groups, but the mean difference was not significant (255.1 +/- 706.4 vs. 131.0 +/- 207.5 IU/l, p = 0.312). CONCLUSION: The prevalence of SLD in Chinese patients taking oral amiodarone with or without elevated baseline ALT was similar (4.4 vs. 3.7%). It seems that amiodarone may be safely prescribed in patients with elevated baseline ALT.",1
11097,16882708,Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia,"""Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.""",1
11098,16887334,Olanzapine and haloperidol in first episode psychosis: two-year data,"Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.",1
11099,16887497,Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans,"Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. To test this hypothesis, 2 cross-over outpatient studies were conducted in adults with apo-A IV 1/1 or apo-E 3/3 genotypes. Study 1 included 11 subjects 24 to 37 years of age, taking 15 mg/kg/day chenodeoxycholic acid (CDCA) or no bile acid for 20 days while being fed a controlled diet. Study 2 included 9 adults 25 to 38 years of age, taking 15 mg/kg/day deoxycholic acid (DCA) or no bile acid, following the same experimental design and procedures as study 1. CDCA had no effect on plasma lipid concentrations, whereas DCA decreased (P < 0.05) plasma high-density lipoprotein (HDL)-cholesterol and tended to decrease (P = 0.15) low-density lipoprotein (LDL)-cholesterol. CDCA treatment enriched (P < 0.0001) bile with CDCA and increased cholesterol concentration in micelles, whereas meal-stimulated bile acid concentrations were decreased. DCA treatment enriched (P < 0.0001) bile with DCA and tended to increase intralumenal cholesterol solubilized in micelles (P = 0.06). No changes were found in cholesterol absorption, free cholesterol fractional synthetic rate (FSR), or 3-hydroxy-3 methylglutaryl (HMG) CoA reductase and LDL receptor messenger ribonucleic acid (mRNA) levels after CDCA treatment. DCA supplementation tended to decrease cholesterol absorption and reciprocally increase FSR and HMG CoA reductase and LDL receptor mRNA levels. Results of these 2 studies suggest that the solubilization of cholesterol in the intestinal micelles is not a rate-limiting step for its absorption.",1
11100,16890833,Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials,"""BACKGROUND: Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS: We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS: 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION: Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.""",1
11101,16891869,Phase II evaluation of docetaxel plus exisulind in patients with androgen independent prostate carcinoma,"""OBJECTIVES: In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind. METHODS: Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously. RESULTS: All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added. CONCLUSIONS: : Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.""",1
11102,16899281,"Arsenic groundwater contamination and its health effects in the state of Uttar Pradesh (UP) in upper and middle Ganga plain, India: a severe danger","This communication presents results of our 2-year survey on groundwater arsenic contamination in three districts Ballia, Varanasi and Gazipur of Uttar Pradesh (UP) in the upper and middle Ganga plain, India. Analyses of 4,780 tubewell water samples revealed that arsenic concentrations in 46.5% exceeded 10 microg/L, in 26.7%, 50 microg/L and in 10% 300 microg/L limits. Arsenic concentrations up to 3,192 microg//L were observed. The age of tubewells (n=1,881) ranged from less than a year to 32 years, with an average of 6.5 years. Our study shows that older tubewells had a greater chance of contamination. Depth of tubewells (n=3,810) varied from 6 to 60.5 m with a mean of 25.75 m. A detailed study in three administrative units within Ballia district, i.e. block, Gram Panchayet, and village was carried out to assess the magnitude of the contamination. Before our survey the affected villagers were not aware that they were suffering from arsenical toxicity through contaminated drinking water. A preliminary clinical examination in 11 affected villages (10 from Ballia and 1 from Gazipur district) revealed typical arsenical skin lesions ranging from melanosis, keratosis to Bowens (suspected). Out of 989 villagers (691 adults, and 298 children) screened, 137 (19.8%) of the adults and 17 (5.7%) of the children were diagnosed to have typical arsenical skin lesions. Arsenical neuropathy and adverse obstetric outcome were also observed, indicating severity of exposure. The range of arsenic concentrations in hair, nail and urine was 137-10,900, 764-19,700 microg/kg, and 23-4,030 microg/L, respectively. The urine, hair and nail concentrations of arsenic correlated significantly (r=0.76, 0.61, and 0.55, respectively) with drinking water arsenic concentrations. The similarity to previous studies on arsenic contamination in West Bengal, Bihar and Bangladesh indicates that people from a significant part of the surveyed areas in UP are suffering and this will spread unless drives to raise awareness of arsenic toxicity are undertaken and an arsenic safe water supply is immediately introduced.",1
11103,16899775,High-dose atorvastatin after stroke or transient ischemic attack,"""BACKGROUND: Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack (TIA) remains to be established. METHODS: We randomly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry, had low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), and had no known coronary heart disease to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke. RESULTS: The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. CONCLUSIONS: In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke. (ClinicalTrials.gov number, NCT00147602 [ClinicalTrials.gov].).""",1
11104,16908788,"Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up","""BACKGROUND: Currently available smoking cessation therapies have limited success rates. Varenicline tartrate is a novel, selective nicotinic receptor partial agonist developed specifically for smoking cessation. This study evaluated the efficacy, tolerability, and safety of 3 varenicline doses for smoking cessation. Bupropion hydrochloride was included as an active control. METHODS: A phase 2, multicenter, randomized, double-blind, placebo-controlled study of healthy smokers (18-65 years old). Subjects were randomized to varenicline tartrate, 0.3 mg once daily (n = 128), 1.0 mg once daily (n = 128), or 1.0 mg twice daily (n = 127), for 6 weeks plus placebo for 1 week; to 150-mg sustained-release bupropion hydrochloride twice daily (n = 128) for 7 weeks; or to placebo (n = 127) for 7 weeks. RESULTS: During the treatment phase, the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate, 1.0 mg twice daily (48.0%; P<.001) and 1.0 mg once daily (37.3%; P<.001), than for placebo (17.1%). The bupropion rate was 33.3% (P = .002 vs placebo). The carbon monoxide-confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate, 1.0 mg twice daily, group compared with the placebo group (14.4% vs 4.9%; P = .002). The bupropion rate was 6.3% (P = .60 vs placebo). Discontinuation owing to treatment-emergent adverse events was 15.9% for bupropion, 11.2% to 14.3% for varenicline, and 9.8% for placebo. No dose-related increases occurred in adverse events for varenicline. CONCLUSIONS: Varenicline tartrate demonstrated both short-term (1 mg twice daily and 1 mg once daily) and long-term efficacy (1 mg twice daily) vs placebo. Varenicline was well tolerated and may provide a novel therapy to aid smoking cessation.""",1
11105,16908797,Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study,"""BACKGROUND: An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons with access to combination antiretroviral therapy (cART) are due to complications of liver diseases. METHODS: We investigated the frequency of and risk factors associated with liver-related deaths in the Data Collection on Adverse Events of Anti-HIV Drugs study, which prospectively evaluated 76 893 person-years of follow-up in 23 441 HIV-infected persons. Multivariable Poisson regression analyses identified factors associated with liver-related, AIDS-related, and other causes of death. RESULTS: There were 1246 deaths (5.3%; 1.6 per 100 person-years); 14.5% were from liver-related causes. Of these, 16.9% had active hepatitis B virus (HBV), 66.1% had hepatitis C virus (HCV), and 7.1% had dual viral hepatitis co-infections. Predictors of liver-related deaths were latest CD4 cell count (adjusted relative rate [RR], 16.1; 95% confidence interval [CI], 8.1-31.7 for <50 vs > or =500/microL), age (RR, 1.3; 95% CI, 1.2-1.4 per 5 years older), intravenous drug use (RR, 2.0; 95% CI, 1.2-3.4), HCV infection (RR, 6.7; 95% CI, 4.0-11.2), and active HBV infection (RR, 3.7; 95% CI, 2.4-5.9). Univariable analyses showed no relationship between cumulative years patients were receiving cART and liver-related death (RR, 1.00; 95% CI, 0.93-1.07). Adjustment for the most recent CD4 cell count and patient characteristics resulted in an increased risk of liver-related mortality per year of mono or dual antiretroviral therapy before cART (RR, 1.09; 95% CI, 1.02-1.16; P = .008) and per year of cART (RR, 1.11; 95% CI, 1.02-1.21; P = .02). CONCLUSIONS: Liver-related death was the most frequent cause of non-AIDS-related death. We found a strong association between immunodeficiency and risk of liver-related death. Longer follow-up is required to investigate whether clinically significant treatment-associated liver-related mortality will develop.""",1
11106,16911678,Hepatitis B and C virus infections and anti-tumor necrosis factor-alpha therapy: guidelines for clinical approach,"Anti-tumor necrosis factor-alpha (TNF) therapy has recently been recognized to be associated with activation of hepatitis B virus (HBV) infection, with a potentially fatal outcome, mirroring experience in the setting of immune suppression and subsequent reconstitution in cancer chemotherapy and transplantation. Although there is no current evidence that anti-TNF therapy influences the natural history of hepatitis C virus (HCV) infection, the involvement of TNF in the pathogenesis of hepatic injury and extrapolation from other clinical situations heighten awareness of a potential conflict. Preventive strategies should be mandatory. These include screening of all patients for HBV and HCV infection prior to commencement of anti-TNF therapy, and active monitoring of aminotransferases and, for HBV, viral load during and for 3 months after therapy has terminated. Prophylactic or early intervention strategies with nucleoside analogs are recommended for patients with evidence of HBV infection.",1
11107,16912957,Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration,"""Associations have been reported between an MDR1 variant and responses to nonnucleoside reverse-transcriptase inhibitors. We explored associations between MDR1, CYP2B6, and CYP3A polymorphisms and nevirapine hepatotoxicity. Among participants in a randomized study in South Africa (FTC-302), MDR1 3435C-->T was significantly associated with decreased risk of hepatotoxicity (risk ratio, 0.30; P=.016).""",1
11108,16915552,[Acute hepatitis due to kava-kava and St John's Wort: an immune-mediated mechanism?],,1
11109,16915554,[Acute hepatitis due to kava-kava and St John's Wort: an immune-mediated mechanism?],,1
11110,16917217,Fatty liver and transaminase changes with adjuvant tamoxifen therapy,"We investigated the time it took to develop fatty liver and changes in serum aspartate aminotransferase and alanine aminotransferase levels in patients with breast cancer treated with adjuvant tamoxifen. Liver sonography to detect fatty liver and measurement of serum aspartate and alanine aminotransferase levels were performed regularly for patients with early breast cancer. The results were compared in groups of patients with and without adjuvant tamoxifen as well as those on chemotherapy. Eighty-two of 156 patients treated with tamoxifen developed fatty liver, compared with eight of 62 patients not taking it. Fatty liver appeared as early as 3 months after beginning tamoxifen and was detected within 2 years in most cases. It persisted for 48 months after discontinuing tamoxifen in 17 of the 82 patients who developed it. The incidence of fatty liver in patients receiving both chemotherapy and tamoxifen was the same as that in patients receiving tamoxifen alone. While 115 patients had elevations of aspartate aminotransferase, alanine aminotransferase or both, the magnitude of the elevation was clinically significant in only 32 patients. Patients on both chemotherapy and tamoxifen had a higher incidence of elevated transaminases than those on tamoxifen alone. Adjuvant tamoxifen increases the incidence of fatty liver, but has only a minimal effect on aspartate aminotransferase and alanine aminotransferase. Fatty liver may appear as early as 3 months after beginning tamoxifen and may persist for more than 4 years after discontinuing it. Therefore, long-term follow-up is warranted. Chemotherapy is not clearly associated with fatty liver, but may cause a greater degree of hepatocellular damage than does tamoxifen.",1
11111,16918530,The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation,"Alemtuzumab is a monoclonal anti-CD52 antibody, which has been used extensively off label in solid organ transplantation. Its primary use has been as an induction agent at the time of organ transplantation, although there is limited experience using it to treat steroid-resistant rejection. Prolonged lymphocyte depletion can be expected following alemtuzumab treatment even with one dose of 30 mg intravenously. The nature and kinetics of lymphocyte repopulation depend on the maintenance immunosuppression being administered. In comparison with Thymoglobulin, a polyclonal depleting antibody preparation, alemtuzumab offers significant practical benefits with lower cost, fewer side effects in administration, and no specific issues with i.v. access. The risks and benefits of depleting induction agents, such as alemtuzumab, are compared with nondepleting agents, such as anti-CD25 induction therapy. While the majority of experience in solid organ transplantation has been in kidney transplantation, there is more limited experience in liver, pancreas, islet, small bowel, and lung transplantation. We herein review some of the lessons learned from clinical experience to date in solid organ transplantation using alemtuzumab as an immunosuppressant.",1
11112,16924392,Inhibition of TNFalpha does not induce viral reactivation in patients with chronic hepatitis C infection: two cases,"Chronic infections, such as hepatitis C, in the setting of rheumatic disorders pose a potential hindrance to optimal management because of possible complications linked to the institution of immune suppression, as well as the high incidence of hepatotoxicity associated with many of the disease-modifying antirheumatic drugs included in the conventional therapeutic regimens. In the setting of hepatitis C, however, the effect of TNFalpha blockade may be potentially beneficial because TNFalpha appears to be involved in the pathogenesis of liver fibrosis through the stimulation of apoptotic pathways. Data related to this subject are, unfortunately, still limited and without detailed information regarding the clinical progression of the rheumatic disorder. We report the cases of two patients, one with ankylosing spondylitis and one with psoriatic arthritis, who were efficiently treated long-term with anti-TNF agents for their rheumatic disease without any evidence of reactivation or flaring of their hepatitis C infection or deterioration of their liver function. Our results indicate that TNFalpha blockade is a highly efficient and uncompromising therapy in hepatitis C-affected individuals with connective tissue disorders. However, systematic, large-scale studies addressing the issue of safety of these new efficient drugs, i.e., monoclonal antibodies targeted against TNFalpha, in patients with chronic hepatitis C will be needed to properly assess the risks and benefits of this treatment in analogous cases.",1
11113,16926609,Mycophenolate sodium-induced hepatotoxicity: first report,,1
11114,16932279,"Long-term, low-dose flutamide does not cause hepatotoxicity in hyperandrogenic women",,1
11115,16937512,Adverse hepatic reactions associated with calcium carbimide and disulfiram therapy: is there still a role for these drugs?,"Disulfiram and calcium carbimide are two alcohol deterrants widely used in alcoholism treatment, however, there exist great concerns over their safety. Reports on hepatotoxicity, mainly related to disulfiram therapy, have been published. The hepatotoxic potential of calcium carbimide is less well characterized. Here, we describe four cases of liver damage related to this therapeutic group that were submitted to a Registry of hepatotoxicity and point out the limitations that we face when prescribing these compounds. A reassessment of the role of these compounds in the management of alcohol dependence is clearly needed.",1
11116,16940892,Autoimmune hepatitis triggered by statins,"Although the cause of autoimmune hepatitis (AIH) is unknown, drugs are believed to be potential triggers in some patients. In isolated case reports, statins have been considered such triggers. Here we describe 3 patients in whom it is probable that statins initiated the development of AIH. Two men (aged 47 and 51) and one woman (aged 57) developed AIH after the initiation of statin therapy. They developed positive titers of antinuclear antibodies, antismooth muscle antibodies (1/40 to 1/160), and hypergammaglobulinemia. Features of all 3 patients met the criteria for AIH according to the International Autoimmune Hepatitis Panel. Liver biopsies in all 3 showed varying stages of fibrosis and plasma cell infiltration, compatible with AIH. The woman developed hepatitis due to statins on 2 separate occasions: the first in 1999, due to simvastatin, and the second in 2001 to 2002, due to atorvastatin, which was severe and persisted even after discontinuing medication. Similarly, in the 2 other cases, exposure to statins preceded development of AIH, which persisted despite discontinuing medications. All 3 patients responded well to prednisone and azathioprine or mycophenolate therapy. 3 similar previously reported cases are reviewed. We conclude that the 3 cases reported here and 3 similar previously reported cases, indicate that severe, ongoing AIH on rare occasions can be triggered by statins.",1
11117,16941266,Severe liver enzyme elevation due to single-dose ranitidine in a pregnant woman,,1
11118,16947782,"Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate","OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.",1
11119,16950959,Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause,"OBJECTIVE: Acetaminophen cysteine protein adducts are a widely recognized correlate of acetaminophen-mediated hepatic injury in laboratory animals. The objective of this study was to use a new assay for the detection of acetaminophen cysteine protein adducts in children with acute liver failure to determine the role of acetaminophen toxicity in acute liver failure of unknown cause. METHODS: Serum samples from children with acute liver failure were measured for acetaminophen cysteine protein adducts using high-performance liquid chromatography with electrochemical detection. For comparison, samples from children with well-characterized acetaminophen toxicity and children with known other causes of acute liver failure also were measured for acetaminophen cysteine protein adducts. The analytical laboratory was blinded to patient diagnoses. RESULTS: Acetaminophen cysteine protein adduct was detected in 90% of samples from children with acute liver failure that was attributed to acetaminophen toxicity, 12.5% of samples from children with acute liver failure of indeterminate cause, and 9.6% of samples from children with acute liver failure that was attributed to other causes. Adduct-positive patients from the indeterminate cause subgroup had higher levels of serum aspartate aminotransferase and alanine aminotransferase and lower levels of bilirubin. Adduct-positive patients also had lower rates of transplantation and higher rates of spontaneous remission. CONCLUSIONS: A small but significant percentage of children with acute liver failure of indeterminate cause tested positive for acetaminophen cysteine protein adducts, strongly suggesting acetaminophen toxicity as the cause of acute liver failure. An assay for the detection of acetaminophen cysteine protein adducts can aid the diagnosis of acetaminophen-related liver injury in children.",1
11120,16952291,Identification of a novel 974C-->G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids,"Rifampicin (RIF) and ursodeoxycholic acid (UDCA) therapies have beneficial effects in chronic cholestatic diseases. These may result in part from the induction of multidrug-resistance protein 2 (MRP2/ABCC2) expression in the liver and kidney. However, the precise mechanisms by which RIF and UDCA act in cholestasis remain unclear. In the present study, we report the effects of chronic administration of both drugs in a patient with Dubin-Johnson syndrome (DJS), an inherited autosomal recessive disorder characterized by the absence of functional MRP2 protein at the canalicular hepatocyte membrane. A novel 974C-->G nonsense mutation was identified in the MRP2 gene sequence from this patient. RIF induced further increase in conjugated bilirubinemia, whereas concomitant administration of RIF and UDCA led to a dramatic rise in serum bile acid concentrations. These biochemical effects, which are in marked contrast to those observed in cholestatic settings, were concomitant with an increased MRP3, but not MRP4, expression on basolateral hepatocyte membrane. Such findings highlight the key role of MRP2 in the pharmacological properties of RIF and UDCA and suggest that both drugs should be used with caution in pathologic settings in which MRP2 expression may be downregulated, as in advanced stage of cholestatic diseases.",1
11121,16959316,Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project,"Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration's Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses < or =6 mg/m(2) if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9 mg/m(2). Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure.",1
11122,16960145,"Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)","The activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) were evaluated in patients with refractory cutaneous T-cell lymphoma (CTCL). Group 1 received vorinostat 400 mg daily, group 2 received vorinostat 300 mg twice daily for 3 days with 4 days rest, and group 3 received vorinostat 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily. Treatment continued until disease progression or intolerable toxicity. The primary objective was to determine the complete and partial response (PR) rate. Time to response (TTR), time to progressive disease (TTP), response duration (DOR), pruritus relief, and safety were determined. Thirty-three patients who had received a median of 5 prior therapies were enrolled. Eight patients achieved a PR, including 7 with advanced disease and 4 with S?zary syndrome. The median TTR, DOR, and TTP for responders were 11.9, 15.1, and 30.2 weeks, respectively. Fourteen of 31 evaluable patients had pruritus relief. The most common drug-related AEs were fatigue, thrombocytopenia, diarrhea, and nausea. The most common grade 3 or 4 drug-related AEs were thrombocytopenia and dehydration. Vorinostat demonstrated activity in heavily pretreated patients with CTCL. The 400 mg daily regimen had the most favorable safety profile and is being further evaluated.",1
11123,16967041,Predictors of antiretroviral-related hepatotoxicity in the adult AIDS Clinical Trial Group (1989-1999),"""HIV antiretroviral therapy (ART)-related hepatotoxicity is a significant clinical problem, resulting in severe elevations of liver enzymes and, potentially, liver failure and death. We retrospectively determined baseline clinical predictors of severe hepatotoxicity (SH; serum aminotransferases or total bilirubin >5 times and >2.5 times the upper limit of normal [ULN], respectively) among 8,851 subjects enrolled in 16 Adult AIDS Clinical Trial Group studies from October 1989 to June 1999. Subjects were divided into the following treatment categories: single nucleoside reverse transcriptase inhibitors (NRTIs), multiple NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs) combined with NRTIs, and the protease inhibitor (PI) indinavir (IDV) combined with NRTIs. SH occurred in 824 (9.3%) subjects, in 613 (6.92%) in the first 6 months and in another 211(2.38%) in the subsequent 6 months of study ART. Consistent with other reports, baseline elevation in serum aminotransferases was a significant risk factor for SH for all regimens. Risk factors not previously identified included concomitant hepatotoxic medications, thrombocytopenia, and renal insufficiency. Hepatitis C virus coinfection was associated with an increased risk of SH (odds ratio [OR] = 2.7; P < 0.003). In conclusion, this study identified known and previously unreported risk factors for severe hepatotoxicity that should be considered before the initiation of ART.""",1
11124,16970133,"Migraine prophylaxis: who, why, and how","""If a patient has frequent, severely debilitating migraine headaches, prophylactic treatment may help. Beta-blockers, tricyclic antidepressants, and anticonvulsants have the best evidence of efficacy; calcium channel blockers and nonsteroidal anti-inflammatory drugs are also popular because they are well tolerated and inexpensive. We review migraine treatment with emphasis on prophylaxis.""",1
11125,16971721,Echinocandins for candidemia in adults without neutropenia,,1
11126,16979537,Problems encountered during anti-tumour necrosis factor therapy,"Worldwide, over 400,000 patients have been treated with tumour necrosis factor (TNF)-alpha antagonists for indications that include rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis and ankylosing spondylitis. Since their approval, concerns regarding safety have been raised. There is a risk of re-activation of granulomatous diseases, especially tuberculosis, and measures should be taken for detection and treatment of latent tuberculosis infections. Preliminary data suggest that anti-TNF therapy may be safe in chronic hepatitis C. However, TNF-alpha antagonists have resulted in re-activation of chronic hepatitis B if not given concurrently with antiviral therapy. Solid tumours do not appear to be increased with anti-TNF therapy. Variable rates of increased lymphoma risk have been described with anti-TNF therapy compared with the general population, although no increased risk was found compared with a rheumatoid arthritis population. Large phase II and III trials with TNF-alpha antagonists in advanced heart failure have shown trends towards a worse prognosis, and should therefore be avoided in this population. Both etanercept and infliximab are associated with the formation of autoantibodies, and these autoantibodies are rarely associated with any specific clinical syndrome. Rare cases of aplastic anaemia, pancytopenia, vasculitis and demyelination have been described with anti-TNF therapy. This chapter will discuss the safety profile and adverse events of the three commercially available TNF-alpha antagonists: etanercept, infliximab and adalimumab. The data presented in this review have been collected from published data, individual case reports or series, package inserts, the Food and Drug Administration postmarketing adverse events surveillance system, and abstracts from the American College of Rheumatology and European Congress of Rheumatology meetings for 2005.",1
11127,16982484,Repeated supratherapeutic doses of paracetamol in children--a literature review and suggested clinical approach,"The safety of paracetamol when given in the recommended dosage is well documented. However, in recent years there have been many reports of liver failure associated with repeated exposure to supratherapeutic doses of paracetamol. This paper reviews the literature on chronic supratherapeutic paracetamol exposure in children and the different dosing guidelines. Based on which, we suggest the following approach: liver injury secondary to repeated dosing of paracetamol should be considered when a child has received more than 75 mg/kg/d for at least 2 d, or if risk factors for paracetamol toxicity have been identified. Liver transaminases, coagulation factors, and paracetamol serum concentrations should be measured in these children and in symptomatic children with vomiting, right upper quadrant abdominal pain, and jaundice who have taken paracetamol. Treatment with N-acetyl cysteine should be started regardless of paracetamol concentrations if transaminases or INR are elevated. CONCLUSION: Liver injury secondary to repeated dosing of paracetamol is rare but may result in severe morbidity and mortality. The cumulative dose of paracetamol should not exceed 75 mg/kg/d. Children treated with higher doses for more than 2 d should be evaluated for possible liver injury and treated with N-acetyl cysteine if evidence of liver injury is found.",1
11128,16984566,"Experience of the treatment with gemcitabine, docetaxel, and carboplatin (GDC) chemotherapy for patients with small-cell carcinoma of the prostate","""Small-cell carcinoma of the prostate (SCCP) is a rare entity. Many treatment modalities have been done, but thus far no uniform treatment has been clearly established. We carried out combination chemotherapy with gemcitabine, docetaxel, and carboplatin (GDC) regimen (for two patients with refractory SCCP. Case 1 involved a 53-year-old man diagnosed with SCCP after receiving hormone therapy for prostate cancer (stage D1). Six cycles of GDC chemotherapy was applied. Initially the primary site reduced according with a decline of neuro-specific enolase and with relief of the symptoms; however, bone disease occurred and he died of cancer 13 months after diagnosis of SCCP. Case 2 involved a 69-year-old man complaining of severe anal pain. He underwent a biopsy and a huge prostate tumor showing SCCP was showed. He had pelvic node metastases but no distant lesions, and received four cycles of GDC chemotherapy. He was discharged after receiving subsequent radiotherapy and remained stable for a while; however, he died of possible drug-induced hepatitis. This is the first report of chemotherapy with GDC against patients with SCCP. This regimen raised the possibility that it would intensify the outcome, which had been poorly achieved.""",1
11129,16988579,Clofarabine and nelarabine: two new purine nucleoside analogs,"PURPOSE OF REVIEW: Both clofarabine and nelarabine recently received an accelerated approval by the US Food and Drug Administration for use in refractory or relapsed pediatric acute lymphoblastic leukemia and in refractory-relapsed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Both drugs have been studied for their metabolism and mechanisms of action in preclinical investigations and for their efficacy in clinical trials. This review will summarize these investigations and will suggest future plans with these nucleoside analogs. RECENT FINDINGS: Clofarabine and nelarabine were designed based on preclinical and clinical findings with other nucleoside analogs or normal deoxynucleotides such as dGTP. Studies in cell lines have demonstrated that triphosphate is the active metabolite for both these purine nucleoside analogs. Pharmacokinetic and pharmacodynamic investigations during clinical trials have verified the importance of triphosphate levels in achieving clinical responses. Several phase I and II clinical explorations have suggested the utility of clofarabine in acute leukemias and nelarabine in T-cell diseases. Dose-limiting toxicities were nonhematologic: hepatotoxicity for clofarabine and neurotoxicity for nelarabine. SUMMARY: Clofarabine is the first deoxyadenosine analog that shows promise in adult and pediatric acute leukemias without untoward toxicity. Nelarabine, as expected from its design, is a drug that may be directed to T-cell diseases.",1
11130,16990386,The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria,"""BACKGROUND: We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed. RESULTS: Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae. CONCLUSIONS: Eculizumab is an effective therapy for PNH.""",1
11131,17000452,"Pilocarpine hydrochloride for the treatment of xerostomia in patients with Sj�gren's syndrome in Taiwan--a double-blind, placebo-controlled trial","BACKGROUND/PURPOSE: Sj�gren's syndrome (SS) is characterized by diminished exocrine secretions with the resultant symptoms of dry mouth and dry eye. As genetic predisposition and ethnicity may alter the effectiveness of drug treatment, evaluation of the efficacy and safety of the secretagogue pilocarpine hydrochloride in the treatment of xerostomia in patients with SS in different populations is needed. METHODS: Forty-four patients with SS were enrolled in this double-blind, placebo-controlled trial. Patients were randomized to receive 5 mg pilocarpine (Salagen) or placebo tablet four times daily for 12 weeks. Global evaluation and subjective responses of patients were assessed by questionnaires with visual analog scales and categorical checkboxes. Saliva production was also measured by modified Saxon's test. RESULTS: Pilocarpine treatment significantly improved global assessment of dry mouth, symptoms associated with dry mouth (mouth comfort, ability to sleep and ability to speak), and saliva production compared to placebo. The drug was well tolerated and the most common adverse effect was sweating (5/23, 21.7%) resulting from the muscarinic agonist action of the drug. No serious drug-related adverse effect was found in this study. CONCLUSION: The results of this study suggest that therapy with 5 mg pilocarpine four times daily is effective, safe and well tolerated for the relief of oral symptoms in patients with SS in Taiwan.",1
11132,17005575,Standard anti-tuberculosis treatment and hepatotoxicity: do dosing schedules matter?,"A nested case-control study was conducted in order to examine whether dosing schedules of standard pyrazinamide-containing anti-tuberculosis (TB) treatment (standard treatment) might affect hepatotoxicity. The present authors retrospectively identified all patients with hepatitis using biochemical criteria from a cohort of 3,007 clinic patients who commenced anti-TB treatment from January 1 to June 30, 2001. Each case with hepatitis between 1-9 weeks post-TB treatment was compared using conditional logistic regression analysis with two controls selected randomly from patients without hepatitis in the same period and matched by sex, age and standard treatment. Impacts of sex and age were examined by logistic regression analysis of cases and patients without hepatitis. Hepatitis occurred in 167 patients, of whom 96 qualified as cases. A conditional logistic risk model identified hepatitis B surface antigen carriage as the only risk factor (odds ratio (95% confidence interval (CI)) 1.8 (1.1-3.1)). Logistic regression analysis showed that sex was nonsignificant but ageing increased the odds of hepatitis. The risk of hepatitis increased from 2.6% (1.9-3.5%) to 4.1% (3.2-5.3%) as age exceeded 49 yrs. Dosing schedules in the first 9 weeks have little impact on hepatotoxicity. If patients at risk of both hepatitis and relapse receive standard treatment, daily dosing is preferable.",1
11133,17014576,Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study,"BACKGROUND: Safety of traditional Chinese medicine in patients with chronic hepatitis B is unknown. AIM: To study the clinical outcome of traditional Chinese medicine-induced hepatotoxicity in chronic hepatitis B patients. PATIENTS AND METHODS: All chronic hepatitis B patients in 2004 with liver dysfunction requiring hospitalization were screened prospectively for traditional Chinese medicine intake. The hepatotoxicity of individual traditional Chinese medicine elements was determined by extensive search of both English and Chinese publications. RESULTS: Of 45 chronic hepatitis B patients, the liver dysfunction in seven (15.6%) was attributable to traditional Chinese medicine. All had liver dysfunction pattern resembling those of acute exacerbation of chronic hepatitis B. Three patients had adverse outcomes (two deaths, one liver transplantation). One patient had accelerated course of cirrhosis now awaiting liver transplantation. The identified hepatotoxic components were Polygonum multiflorum Thunb, Cassia obtusifolia L, Melia toosendan Sieb., Rheum palmatum L., Scolopendra subspinipes mutilans L, Alisma orientale Juzepe, Glycyrrhiza uralensis Fisch. and Mentha haplocalyx Briq. One traditional Chinese medicine formula was adulterated with a highly hepatotoxic agent, N-nitrosofenfluramine. CONCLUSIONS: Traditional Chinese medicine-related hepatotoxicity resulted in high mortality in chronic hepatitis B patients. Prospective randomized-controlled trials with the same stringent criteria as western medicine clinical trials are required for Chinese medicines, to document their efficacies and safety before they can be advocated for the treatment of patients.",1
11134,17018383,"Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major","BACKGROUND AND OBJECTIVES: Deferasirox (ICL670) is a novel once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. This study evaluated the safety and tolerability of deferasirox in pediatric patients with transfusion-dependent beta-thalassemia major. Efficacy and pharmacokinetic assessments were secondary objectives. DESIGN AND METHODS: Forty patients equally stratified into two age groups--children (2 to <12 years) and adolescents (12-17 years)--were treated with deferasirox for 48 weeks. All received once-daily deferasirox 10 mg/kg/day with modifications allowed after 12 weeks' treatment. Safety, liver iron concentration (LIC), serum ferritin and pharmacokinetics were assessed. RESULTS: Thirty-nine patients completed the study. One withdrew due to a skin rash. Adverse events were typical of this population, but only four were considered related to the study drug: mild nausea (two adolescents) and moderate skin rash (two children). There were no serious adverse events related to the study drug. Five patients briefly interrupted treatment due to elevated transaminases with no recurrences when treatment resumed. The mean deferasirox dose was 11.3 mg/kg/day. Overall LIC increased gradually from week 12 as mean daily iron intake was higher than excretion. Steady-state plasma levels of deferasirox and its iron complex, Fe-[deferasirox]2, were comparable between children and adolescents. INTERPRETATION AND CONCLUSIONS: Deferasirox was well tolerated by this pediatric population. Toxicities known to be associated with other commercially available iron chelators were not observed. The dose employed was too low to induce a net negative iron balance in this regularly transfused population. Pharmacokinetic data support a once-daily dosing regimen based on body weight.",1
11135,17021318,Ranibizumab for neovascular age-related macular degeneration,"BACKGROUND: Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration. METHODS: In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. RESULTS: We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab. CONCLUSIONS: Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].).",1
11136,17021358,An official ATS statement: hepatotoxicity of antituberculosis therapy,"Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.",1
11137,17030680,"Results from the Loire-Ardeche-Drome-Isere-Puy-de-Dome (LADIP) trial on atrial flutter, a multicentric prospective randomized study comparing amiodarone and radiofrequency ablation after the first episode of symptomatic atrial flutter","""BACKGROUND: There is no published randomized study comparing amiodarone therapy and radiofrequency catheter ablation (RFA) after only 1 episode of symptomatic atrial flutter (AFL). The aim of the Loire-Ardeche-Drome-Isere-Puy-de-Dome (LADIP) Trial of Atrial Flutter was 2-fold: (1) to prospectively compare first-line RFA (group I) versus cardioversion and amiodarone therapy (group II) after only 1 AFL episode; and (2) to determine the impact of both treatments on the long-term risk of subsequent atrial fibrillation (AF). METHODS AND RESULTS: From October 2002 to February 2006, 104 patients (aged 78+/-5 years; 20 women) with AFL were included, with 52 patients in group I and 52 patients in group II. The cumulative risk of AFL or AF was interpreted with the use of Kaplan-Meier curves and compared by the log-rank test. Clinical presentation, echocardiographic data, and follow-up were as follows: age (78.5+/-5 versus 78+/-5 years), history of AF (27% versus 21.6%); structural heart disease (58% versus 65%), left ventricular ejection fraction (56+/-14% versus 54.5+/-14%), left atrial size (43+/-7 versus 43+/-6 mm), mean follow-up (13+/-6 versus 13+/-6 months; P=NS), recurrence of AFL (3.8% versus 29.5%; P<0.0001), and occurrence of significant AF beyond 10 minutes (25% versus 18%; P=0.3). Five complications (10%) were noted in group II (sick sinus syndrome in 2, hyperthyroidism in 1, and hypothyroidism in 2) and none in group I (0%) (P=0.03). CONCLUSIONS: RFA should be considered a first-line therapy even after the first episode of symptomatic AFL. There is a better long-term success rate, the same risk of subsequent AF, and fewer secondary effects.""",1
11138,17033446,Anastrozole-induced hepatotoxicity,We present a case of hepatotoxicity induced by an aromatase-inhibiting hormonal antineoplastic drug (anastrazol) in an elderly woman. This is the first reported case in the literature.,1
11139,17036403,Propylthiouracyl-induced severe liver toxicity: an indication for alanine aminotransferase monitoring?,"Propylthiouracyl (PTU)-related liver toxicity is likely to occur in about 1% of treated patients. In case of acute or subacute hepatitis, liver failure may occur in about one third. We report two further cases of PTU-induced subacute hepatitis, in whom the delay between occurrence of liver damage after the initiation of treatment, the underestimation of its severity and the delayed withdrawal of the drug were all likely responsible for liver failure. The high incidence of liver toxicity related to PTU, its potential severity and delayed occurrence after initiation of treatment are in favor of monthly alanine aminotransferase monitoring, at least during the first six months of therapy.",1
11140,17042673,An assessment of statin safety,"Recently, statin safety and potential drug interactions have received close attention in the consumer and medical press. In particular, rosuvastatin, the most recent statin introduced into the US market, has been the object of much speculation. Many of these reports have lost sight of the proven efficacy of statins in coronary disease prevention at a time when coronary heart disease is the number one killer of adults, and have failed to frame the potential drug toxicity in the context of this benefit. Summarized here are the conclusions of the National Lipid Association's Statin Safety Assessment Task Force, which reviewed extensive new drug application (NDA) and postmarketing data for all the currently marketed statins regarding their effect on the liver, muscle, renal, and neurologic systems. The task force found that, overall, hepatic, renal, or neurologic function does not appear to be compromised by statin use. They do not recommend routine monitoring of these systems but do recommend ongoing surveillance of symptomatic patients. With respect to muscle toxicity, the task force's Muscle Expert Panel concluded that the incidence of myopathy and rhabdomyolysis is low and appears to be dose-related, rather than associated with the degree of low-density lipoprotein cholesterol lowering and also appears to be related to the individual statin used. For example, from the rosuvastatin NDA database and additional postmarketing data, the overall incidence of myopathy was found to be lower than that observed with other statins. Administrative claims data of hospitalization rates for adverse events in statin patients confirm the task force conclusion that, overall, statins are safe and well tolerated when used as monotherapy.",1
11141,17043506,"Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sj�gren's Syndrome Patients With Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study","BACKGROUND: : Sj�gren's syndrome is characterized by the presence of xerostomia and/or xerophthalmia. Pilocarpine, a muscarinic cholinergic agonist, has been proven to be efficacious in treating radiation-induced xerostomia (up to 30 mg/day) and symptoms of dry mouth in Sj�gren's patients (up to 20 mg/day). OBJECTIVE: : To compare the safety and efficacy of oral pilocarpine (dose-adjusted) versus placebo in the treatment of dry eye and dry mouth symptoms in Sj�gren's syndrome at 6 and 12 weeks. METHODS: : In this 11-center, 256-patient placebo-controlled study, the safety and efficacy of oral pilocarpine (20 mg to 30 mg daily) for relief of Sj�gren's-related dry mouth and dry eye symptoms was assessed. Changes in symptoms and salivary flow were measured over 12 weeks. RESULTS: : Compared with placebo, salivary flow was significantly increased in the pilocarpine group (P</= 0.0001) after the first dose and throughout the study. Significant improvement in patients' global assessment of dry mouth (P</= 0.0001) with relief in 5 of 7 separate oral symptoms (P</= 0.02) was reported by the treated patients throughout study. Minimal differences in 3 of 8 ocular symptoms were noted at 6 weeks (5-mg dose), but at 12 weeks (5- to 7.5-mg dose), the pilocarpine group demonstrated both significant improvement in global assessment of dry eyes (P</= 0.0001) and relief in 6 of 8 related symptoms (P</= 0.04). The drug was well tolerated at both doses. The most common pilocarpine-related side effects were sweating, urinary frequency, flushing, and chills. CONCLUSIONS: : Significant relief in dry mouth symptoms was noted at 20 mg/day, and significant relief in ocular symptoms, including lower artificial tear requirement, was noted after the dose was increased to 30 mg/day.",1
11142,17047115,A pilot study in patients with established advanced liver fibrosis using pirfenidone,,1
11143,17051134,Ranibizumab (Lucentis) for macular degeneration,,1
11144,17054106,Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia: a nation-wide retrospective study in Austria,"BACKGROUND: In previous studies, alemtuzumab demonstrated considerable activity in patients with previously treated B-cell chronic lymphocytic leukemia (CLL), including fludarabine-refractory disease. In this retrospective study, the authors evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced, previously treated CLL who received treatment in the routine clinical setting. METHODS: Data were collected from 115 consecutive patients who received alemtuzumab therapy at 25 participating centers in Austria. Patients received a median of 3 prior lines of therapy (range, 1-11 prior lines of therapy), and 59% had fludarabine-refractory disease. Alemtuzumab was administered intravenously or subcutaneously with a planned schedule of 30 mg 3 times per week for up to 12 weeks. Patients received valacyclovir and trimethoprim/sulfamethoxazole for antiinfective prophylaxis. RESULTS: The overall response rate was 23%, with complete responses achieved in 5% of patients. Stable disease (SD) was achieved in 36% of patients. After a median follow-up of 17.5 months, the median overall survival (OS) was 20.2 months for all patients. A multivariate Cox regression analysis that included pretreatment baseline characteristics, response to therapy, and cumulative dose of alemtuzumab indicated that bulky lymphadenopathy, the administration of > r =3 previous therapies, and lack of response to alemtuzumab remained significant independent risk factors for inferior OS. The median OS had not been reached for responding patients. The median OS was 29.5 months for patients with SD and 10.8 months for patients with progressive disease. CONCLUSIONS: The broad use of alemtuzumab in the routine clinical practice setting is feasible and active in unselected patients with pretreated CLL, and the current results confirmed the activity and safety of this agent, as reported in previously published clinical studies.",1
11145,17057609,"Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis","""BACKGROUND: In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented. METHODS: In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance. RESULTS: Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001). CONCLUSION: Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells.""",1
11146,17061643,Short-term low-dose propofol anaesthesia associated with severe metabolic acidosis,"Propofol-induced metabolic acidosis is well recognised in the paediatric literature, but the existence of such a syndrome in adults remains contentious. In most reported cases, metabolic acidosis complicated prolonged administration of propofol in critically ill patients. We present a case of severe non-fatal reversible metabolic acidosis, without ventilatory depression or hypoxia, related to short-term propofol infusion in an adult during and after coronary artery bypass grafting. We suggest that lactic acidosis occurred in a genetically susceptible patient with an abnormality of mitochondrial function. This report discusses an unusual adverse effect of propofol anaesthesia and sedation and highlights the need for further investigation to define propofol toxicity.",1
11147,17063522,Lamivudine prophylaxis and treatment of hepatitis B Virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab,"Individuals with past exposure to hepatitis B virus (HBV) may reactivate HBV following bone marrow transplantation. Alemtuzumab (CAMPATH)-based reduced intensity conditioning bone marrow transplantation has been associated with a high incidence of viral infections. Lamivudine prophylaxis for HBV should be instituted in this setting. The management of 240 CAMPATH-based reduced intensity conditioning bone marrow transplantation, carried out over an 8-year period at Kings College Hospital, was reviewed. Hepatitis B core total antibody (anti-HBc) testing identified recipients and donors with previous HBV exposure. Fifteen donor-recipient pairs were identified as being at risk of HBV reactivation. Eight recipients of anti-HBc negative donors were HBsAg negative, anti-HBc positive pre-transplantation. Five anti-HBc negative recipients received transplants from HBsAg negative, anti-HBc positive donors. Two HBV carrier recipients had one anti-HBc negative and one positive donor, respectively. Pre-transplant lamivudine prophylaxis was given to 8/10 (80%) anti-HBc positive recipients. Although HBsAg and HBV DNA were detected 4 months after bone marrow transplantation in one patient who did not receive prophylaxis, a good antiviral response was documented on starting lamivudine. The two HBV carrier recipients had stopped lamivudine at 8 and 31 months post-bone marrow transplantation, respectively, and died of liver failure with a sharp rise in HBV DNA levels. The five anti-HBc negative recipients with anti-HBc positive donors remained HBsAg and HBV DNA negative. Although lamivudine prophylaxis prevented HBV reactivation, it is unclear at what stage post-transplantation prophylaxis can be discontinued. Close monitoring of liver function tests (LFTs), HBsAg, and HBV DNA must be undertaken even after stopping antiviral prophylaxis.",1
11148,17068398,"Hepatotoxicity from interferon-beta, not noni juice",,1
11149,17072088,Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review,"Troglitazone (TGZ), a thiazolidinedione class of antidiabetic agent, causes serious idiosyncratic hepatotoxicity. TGZ is metabolized into reactive metabolites that covalently bind to cellular macromolecules, one of which is oxidation at the chromane ring, a unique structure of TGZ, and another involves oxidative cleavage of the thiazolidinedione ring, a structure common to less hepatotoxic antidiabetics, rosiglitazone and pioglitazone. TGZ is cytotoxic to HepG2 cells and rat and human hepatocytes. However, the role of the reactive metabolite on the TGZ toxicity is controversial, because there was no correlation of the generation of the reactive metabolites with susceptibility to the TGZ cytotoxicity, and chemical inhibitors of drug metabolizing enzymes could not protect the cells against the toxicity. Mitochondrial dysfunction, especially mitochondrial permeability transition, may be a pathophysiological event, which is mediated by TGZ itself and is a major non-metabolic factor. Other events such as apoptosis and PPARgamma-dependent steatosis could be also mediated by TGZ, while inhibition of bile salt export pump, a cause of TGZ-induced cholestasis, may be caused by the TGZ sulfate. In conclusion, although the TGZ is biotransformed into chemically reactive metabolites, there is currently no potential evidence for involvement of the reactive metabolite in the TGZ-induced liver injury.",1
11150,17072991,Portal thrombosis and steatosis after preoperative chemotherapy with FOLFIRI-bevacizumab for colorectal liver metastases,"In order to discuss the role of preoperative chemotherapy for colorectal liver metastases, which is used frequently before hepatic resection, even in patients with resectable disease at presentation, we herein report the development of two complications, partial portal vein thrombosis and hepatic steatosis with lobular inflammation, during the course of preoperative chemotherapy with FOLFIRI plus bevacizumab for colorectal liver metastases, which recognition led to timely discontinuation of chemotherapy as well as a change in the surgical strategy to resect the tumors and the damaged liver through advanced techniques. We conclude that duration of treatment and drug doses and combinations may impact the development of chemotherapy-induced liver injury. Surgeons and medical oncologists must work together to devise safe, rational, and oncologically appropriate treatments for patients with multiple colorectal liver metastases, and to improve the understanding of the pathogenesis of chemotherapy-induced liver injury.",1
11151,17073989,Combination of pulse therapy with terbinafine tablets and topical terbinafine cream for the treatment of dermatophyte onychomycosis: a pilot study,"We performed a pilot study to assess the safety and efficacy of pulse therapy with terbinafine tablets in 66 patients with dermatophyte onychomycosis. One pulse consisted of oral terbinafine tablets (500 mg/day) given for 1 week followed by a 3-week interval. Topical 1% terbinafine cream was applied daily. The number of pulses was determined by the extent of improvement in the affected nails and by the patient's requests, up to a maximum of six pulses. Efficacy was assessed based on both clinical and mycological examinations 1 year after treatment initiation. We observed a complete cure in 51 patients (77.3%), marked improvement in five patients (7.6%), improvement in five patients (7.6%) and slight improvement in one patient (1.5%). Four patients (6.0%) showed no change. In the patients who were completely cured, the average number of pulses used was 3.7 +/- 1.4 pulses and the treatment duration was 3.3 +/- 1.6 months. Nine patients experienced adverse effects, consisting of gastrointestinal disturbance (eight patients) and drug-induced eruption (one patient). There were no abnormal findings in the laboratory tests, including liver function tests. In summary, terbinafine pulse therapy in combination with topical application of terbinafine cream appeared safe and effective in this pilot study.",1
11152,17075352,Infliximab single administration followed by acute liver injury,,1
11153,17076974,Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials,"""BACKGROUND: In two recent osteoarthritis trials, alanine aminotransferase (ALT) elevations were observed more frequently in patients receiving acetaminophen 3.9 g daily than in patients receiving placebo, and the rates were higher than aminotransferase values observed in some previous osteoarthritis studies with acetaminophen. OBJECTIVE: To retrospectively analyze ALT data from McNeil osteoarthritis clinical studies involving acetaminophen in order to assess the frequency and magnitude of ALT elevations and rate of ALT resolution while patients remained on acetaminophen treatment. A review of the literature revealed a few reports of isolated aminotransferase elevations occurring during acetaminophen therapy, but these reports were not included in the analysis because they did not include enough information to evaluate the frequency, magnitude, and rate of ALT elevations while patients remained on acetaminophen treatment. RESEARCH DESIGN AND METHODS: Nine controlled clinical trials were identified in which at least one of the treatments was acetaminophen alone. Studies were included if patients had ALT and aspartate aminotransferase (AST) values obtained at baseline and an ALT value at an additional visit after initiating therapy. Seven studies met these criteria and were included in this analysis. In these studies, patients received acetaminophen 1950-4000 mg/day for 4 weeks up to 12 months. Laboratory testing was performed at weeks 0 and 4 in the three 4-week studies; at weeks 0, 2, 4, 8, and 12 in the two 12-week studies; at weeks 0, 1, 2, 4, 6, 8, and 13 in the 13-week study; and at months 0, 1, 3, 6, 9, and 12 in the 12-month study. The pooled data set consisted of patient demographics, dosing records, aminotransferase and bilirubin laboratory values, and adverse events. RESULTS: There were no reports of hepatotoxicity or hepatic failure in any acetaminophen-treated patient (n = 1530). In the seven studies, 1039 patients had both baseline AST and ALT activity < or = upper limit of the reference range and an on-treatment ALT measurement. While on long-term acetaminophen treatment, 181 of 1039 (17.4%) patients had an ALT value that exceeded the upper limit of the reference range. None of the 1039 patients had an on-treatment ALT level > 3 times upper limit of the reference range in conjunction with a serum bilirubin > upper limit of the reference range, and no patient had an ALT level > 10 times upper limit of the reference range. Of the 1039 patients, 44 (4.2%) had an on-treatment ALT level > 1.5 times upper limit of the reference range, and 31 of the 44 patients had a subsequent measurement of ALT. Of these 31 patients, 29 (93.5%) had documented resolution or decreasing ALT while on treatment. An ALT level > 1.5 times upper limit of the reference range was not associated with a higher frequency of symptoms potentially related to hepatic origin. LIMITATIONS: The studies included in this analysis were limited to McNeil studies, none of which were designed to specifically evaluate the patterns of ALT activity. Thus, the incidence of ALT elevations after any specific duration of dosing, and the temporal pattern of ALT elevations, cannot be accurately determined. In addition, methodological differences existed across the studies. CONCLUSION: This analysis involving > 1000 acetaminophen-treated patients shows that low-level, transient ALT elevations usually resolve or decrease with continued acetaminophen treatment, are unaccompanied by signs or symptoms of liver injury, and, as such, appear to be clinically insignificant. Maximum recommended daily doses of acetaminophen did not cause liver failure or dysfunction.""",1
11154,17083024,Rifapentine for the treatment of pulmonary tuberculosis,"Rifapentine is a recently approved antituberculosis drug that has not yet been widely used in clinical settings. Clinical data support intermittent use of rifapentine with isoniazid during the continuation phase of tuberculosis treatment. Patients with culture-positive, noncavitary, pulmonary tuberculosis whose sputum smear is negative for acid-fast bacilli at the end of the 2-month intensive treatment phase are eligible for rifapentine therapy. Rifapentine should not be used in human immunodeficiency virus-infected patients, given their increased risk of developing rifampin resistance with currently recommended dosages. Rifapentine is not currently recommended for children aged <12 years, pregnant or lactating women, or individuals with culture-negative or extrapulmonary tuberculosis. Rifapentine (600 mg) is administered once weekly with isoniazid (900 mg) during the continuation phase of treatment. This combination should only be given under direct observation. As with rifampin, drug-drug interactions are common, and regular patient monitoring is required. Ease of administration makes this regimen attractive both for tuberculosis-control programs and for patients.",1
11155,17085773,Safety and efficacy of black cohosh (Cimicifuga racemosa) during pregnancy and lactation,"""BACKGROUND: There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbal medicines in pregnancy and lactation. This is one article in a series that systematically reviews the evidence for commonly used herbs during pregnancy and lactation. OBJECTIVES: To systematically review the literature for evidence on the use, safety, and pharmacology of black cohosh focusing on issues pertaining to pregnancy and lactation. METHODS: We searched 7 electronic databases and compiled data according to the grade of evidence found. RESULTS: Black cohosh, alone or in combination with other medicinal herbs as """"mother's cordial"""", has a long traditional use and is frequently used by midwives as a uterine stimulant and labour-inducing aid. Low-level evidence based on theory and expert opinion shows the following concerns with respect to black cohosh use during pregnancy: 1) labour-inducing effects, 2) hormonal effects, 3) emmenagogue properties and, 4) anovulatory effects. During lactation, there is low-level evidence from theoretical and expert opinion of black cohosh having hormonal properties. CONCLUSIONS: Black cohosh should be used with caution during pregnancy, particularly during the first trimester where its purported labour-inducing effects could be of concern, and during lactation. Black cohosh should undergo rigorous high quality human studies to determine its safety in pregnancy and lactation.""",1
11156,17086563,Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile,"BACKGROUND: COX-2 and NSAIDS differ in their gastrointestinal (GI) and cardiovascular (CV) toxicity from pharmacological, clinical and epidemiologic point of views. OBJECTIVE: Describe the patterns of use of NSAIDS and COX-2 in The Health Improvement Network (THIN) database in UK and the PharMetrics database in USA. METHODS: We examined the experience of 10 distinct cohorts of new users of diclofenac, naproxen, ibuprofen, piroxicam, other NSAIDS, meloxicam, celecoxib, etoricoxib, rofecoxib and valdecoxib. The study period was 1 January 1995 through 2004 (31 March in UK and 28 February in USA). We collected information on covariates including history of upper GI disease, CV disease, hepatic disease, dosage, concomitant medication, and visits to a rheumatologist. RESULTS: We identified 486 076 unique patient-drug pairs in UK and 1 533 239 in USA. In UK population 78 201 (16%) were COX-2 users and in PharMetrics 324 206 (21%) were COX-2 users. Diclofenac and ibuprofen (NSAIDS), and celecoxib and rofecoxib (COX-2) were the agents prescribed most frequently. The duration of therapy was longer among celecoxib and rofecoxib users than among other users. More COX-2 users than NSAIDS users received concomitant gastroprotective agents (GPA), corticosteroids and anti-platelet therapy, and had a history of thromboembolic events and hypertension. PharMetrics patients were prescribed higher doses of NSAIDS and COX-2. The use of any single agent for more than 90 days was uncommon, but more frequent in PharMetrics. Switching was uncommon and was generally to a NSAID. DISCUSSION: Our results confirm some previous findings from other authors such as the presence of both GI and CV channelling to COX-2 agents but refute others, such as the frequency of drug switching between these agents. The typical use of COX-2 agents in practice is for shorter duration, and at lower doses, than was employed in randomized clinical trials. This difference may help clarify the apparent discrepancy with respect to CV toxicity between the results from clinical trials, which showed a higher CV risk with these drugs, and non-experimental epidemiologic studies, which showed lower or no increase in risk.",1
11157,17089403,"Entacapone to tolcapone switch: Multicenter double-blind, randomized, active-controlled trial in advanced Parkinson's disease","This double-blind study examined the efficacy and safety of replacing entacapone with tolcapone in fluctuating Parkinson's disease (PD) patients. Patients receiving entacapone for > or =15 days were randomly assigned to continue entacapone (n = 75) or switch to tolcapone (n = 75) and were followed up for 3 weeks. Efficacy measures included changes in on time (without disabling dyskinesia) and an investigator's global assessment (IGA). The on time increased by > or =1 hour/day (primary efficacy measure) in 43% of entacapone-treated patients and 53% of tolcapone-treated patients, and by > or =3 hours/day in 13% and 25%, respectively. The IGA indicated moderate/marked improvements in 25% of entacapone patients and 39% receiving tolcapone. Response rates (the proportion of patients with > or =1 hour/day increase in on time and improvements on IGA) were 17% with entacapone and 32% with tolcapone. Dyskinesia was the most common adverse event affecting 29% of entacapone and 31% of tolcapone recipients. One patient in each group had elevated liver enzymes, resulting in treatment withdrawal (levels returned to normal thereafter in both cases). In conclusion, within the limits of the protocol, there was a tendency for tolcapone to offer enhanced efficacy in patients with fluctuating PD, despite optimized entacapone therapy. Tolcapone can be considered, therefore, for patients whose motor fluctuations are inadequately controlled by their existing regimen.",1
11158,17090282,"Safety, tolerability, and efficacy of tegaserod over 13 months in patients with chronic constipation","""OBJECTIVE: To assess the long-term safety and tolerability of tegaserod in patients with chronic constipation (CC). METHODS: This 13-month, uncontrolled extension study enrolled CC patients who completed a 12-wk randomized, double-blind, placebo-controlled core study. Patients receiving tegaserod 6 or 2 mg b.i.d. during the core study continued on the same dose; those receiving placebo were switched to tegaserod 6 mg b.i.d (placebo-to-tegaserod). Safety and tolerability were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs, and electrocardiograms. Symptom evaluations included patient satisfaction with bowel habit and bothersomeness of constipation, abdominal distension/bloating, and abdominal discomfort/pain. RESULTS: A total of 842 patients entered the extension study; 451 (54%) completed. AEs typically occurred within the first month of tegaserod treatment. Long-term treatment neither increased AE incidence nor revealed new safety risks. Headache (11.3%, 14.5%, and 16.1% in the tegaserod 6 mg b.i.d., 2 mg b.i.d., and placebo-to-tegaserod groups, respectively) and abdominal pain (8.8%, 8.8%, 10.9%) were the most common AEs. Diarrhea, the most common drug-related AE (4.9%, 2.5%, 8.0%), rarely led to discontinuation (0.7%, 0.0%, 2.2%). Diarrhea was transient, resolved without treatment interruption or rescue medication, and had no clinically significant consequences. Of 27 serious AEs, none were considered treatment related. No deaths or reports of ischemic colitis occurred in tegaserod-treated patients. No clinically relevant changes occurred in other safety parameters. Safety findings were similar in patients switched from placebo to tegaserod and those maintained on tegaserod. CONCLUSIONS: Tegaserod has a favorable safety profile and is well tolerated during continuous long-term treatment in patients with CC.""",1
11159,17092772,A brief history of inhaled asthma therapy over the last fifty years,"This year is the 50th anniversary of the introduction into clinical use of the first modern inhaler for the management of asthma--the pressurised metered-dose inhaler (pMDI). The pMDI was initially used for the administration of the non-selective beta-agonists adrenaline and isoprenaline. However, the epidemic of asthma deaths which occurred in the 1960s led to these drugs being superseded by the selective short-acting beta-agonist salbutamol, and the first inhaled corticosteroid (ICS) beclomethasone. At the same time, sodium cromoglycate was introduced, to be administered via the first dry-powder inhaler--the Spinhaler--but owing to its relatively weak anti-inflammatory action its use is now very limited. Over the last 10 years, the long-acting beta-agonists (LABAs) have become an important add-on therapy for the management of asthma, and they are now often used with ICS in a single ICS/LABA combination inhaler.",1
11160,17098089,The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes,"Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.",1
11161,17098601,Spleen rupture secondary to anticonvulsant hypersensitivity syndrome,"Anticonvulsant hypersensitivity syndrome (AHS) is a rare complication associated with the use of anti-epileptic medications. The syndrome's main symptoms are cutaneous eruptions, fever, hepatitis, and lymphadenopathy. We describe a 23-year-old woman who developed AHS 2 months after starting phenytoin therapy. She presented with fever, orofacial edema, skin rash, and lymphadenopathy. Four days after admission, she developed agonizing epigastric pain with diffuse epigastric tenderness. An abdominal CT scan demonstrated splenomegaly with a large, hypodense area involving the upper half of the spleen, consistent with splenic rupture. She was managed medically in an effort to avoid splenectomy. There are no other documented cases of spleen rupture linked to AHS. A possible mechanism is the alteration of lymphocytic function due to the accumulation of cytotoxic metabolites and infiltration of the spleen with lymphocytic cells, distending the capsule and predisposing it for rupture. We believe that the case presented here should increase awareness of the potentially life-threatening complications associated with AHS.",1
11162,17099317,Highly active antiretroviral treatment containing efavirenz or nevirapine and related toxicity in the TREAT Asia HIV Observational Database,,1
11163,17103263,Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease,"BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement <or=50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). RESULTS: Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3-4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1-6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). CONCLUSIONS: Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.",1
11164,17109986,"Hepatic safety profile and glycemic control of pioglitazone in more than 20,000 patients with type 2 diabetes mellitus: postmarketing surveillance study in Japan","""The prospective observational study was designed to identify factors affecting glycemic control with pioglitazone and to confirm the hepatic safety of the drug in patients with type 2 diabetes. Baseline patient characteristics, changes in serum hemoglobin A1c (A1c) and alanine aminotransferase (ALT), other treatments for diabetes mellitus, and hepatobiliary adverse reactions were examined. In total, 24,993 patients, representing 28,008 patient-years, were included in the safety evaluation and 20,447 patients in the efficacy evaluation. No case of hepatic failure was reported, and neither temporal nor dose relations were found between pioglitazone and ALT abnormalities. Serum A1c was clearly reduced in patients with baseline body mass index <25 kg/m(2) or baseline fasting immunoreactive insulin <5.0 microU/mL. Among the patients treated for more than 6 months, the change in A1c was -1.0% at 6 months with both monotherapy and combination therapy and remained stable up to 18 months. The overall rate of achievement of A1c<7% in patients with baseline A1c above 7% was 34.1%; notably, the achievement rate of A1c<7% was approximately 30% even in patients with high baseline A1c (mean 8.8%) taking multiple antidiabetic medications, including sulfonylurea, for whom insulin therapy is usually indicated in Japan.""",1
11165,17122520,Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide,"""Prolonged drug-induced cholestasis may be due to destruction and disappearance of bile ducts, sometimes referred to as vanishing bile duct syndrome. Although some of these cases progress to fibrosis, cirrhosis, and liver failure, others improve with time. We report a case of a 35-year-old man who developed vanishing bile duct syndrome after ingestion of zonisamide, an antiepileptic drug that is also prescribed for weight loss. His liver biopsy showed complete absence of bile ducts 3 weeks after starting treatment. There was no ductular reaction. The drug was stopped and a follow-up biopsy 3 months later showed strands of intermediate hepatobiliary cells at the periphery of the portal tracts that extended into lobules; these structures lacked lumina and expressed biliary cytokeratins, CK7 and CK19. A third biopsy, 7 months later, showed the presence of ductules with lumina located within portal tracts. Intermediate hepatobiliary cells were rare; although sparse clusters of hepatocytes with membrane staining for CK7 were present. Cholestasis and levels of bilirubin improved over time. The histologic features in this case document the sequence of events in restoration of the biliary tree after loss of bile ducts, which seems to be a process of maturation of intermediate hepatobiliary cells that arise from a proliferative compartment at the porto-hepatic interface.""",1
11166,17124639,[Gabapentin treatment in a female patient with panic disorder and adverse effects under carbamazepine during benzodiazepine withdrawal],"Despite their addictive potential, benzodiazepines belong to the most often prescribed drugs. We report on a patient with alprazolam dependence, who initially was treated with carbamazepine because of severe withdrawal symptoms. Due to liver enzyme elevation related to carbamazepine, we had to stop this treatment and instead of that started gabapentin treatment. Under this new therapy, the patient showed a dramatic relief of withdrawal symptoms and of the panic attacks recurring during withdrawal. Hence, due to their effectiveness and tolerability, newer anticonvulsants could be considered as medication for benzodiazepine withdrawal and as an alternative for benzodiazepine treatment in panic disorders.",1
11167,17127556,An evaluation of phencyclidine (PCP) psychosis: a retrospective analysis at a state facility,"It has been reported in the literature that phencyclidine (PCP) psychosis recovery may take up to 4-6 weeks. This retrospective review sought to determine whether patients with a new onset of PCP psychosis have a longer hospitalization than those patients with new onset functional psychosis. The PCP arm (N = 20) was found to have a significantly shorter hospitalization than those with a new onset functional psychosis (N = 20)-mean 4.8 days (range 1-9) versus 13.6 days (range 3-41), p < .05. In addition, patients with psychosis related to PCP use were treated more aggressively with conventional antipsychotics than patients with a new onset functional psychosis at this facility.",1
11168,17132810,Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout,"OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, safety profile, precautions, and place in therapy of febuxostat, a novel nonpurine xanthine oxidase inhibitor in development for the treatment of hyperuricemia and gout. DATA SOURCES: Available studies and abstracts were identified through MEDLINE (1990-November 2006), Science Citation Index, International Pharmaceutical Abstracts, Cochrane Databases, and the American College of Rheumatology and European League Against Rheumatism Web sites. Key search terms were febuxostat, TMX-67, TEI-6720, hyperuricemia, and gout. STUDY SELECTION AND DATA EXTRACTION: All available studies describing the pharmacology of febuxostat were included. Human studies formed the basis for discussion of clinical parameters, including pharmacokinetics, pharmacodynamics, efficacy, and safety of febuxostat. DATA SYNTHESIS: Febuxostat significantly reduces uric acid levels within 2 weeks after initiation of therapy and up to 48% by the end of 104 weeks of therapy. Approximately 60% of patients achieved the primary goal of serum uric acid less than 6 mg/dL during the last 3 months following once-daily administration of febuxostat 80 mg or 120 mg for at least 52 weeks. The most common adverse reactions to febuxostat were abnormal results from liver function tests, diarrhea, headache, arthralgias, and musculoskeletal symptoms. Due to its potency, patients are at an increased risk of experiencing gout flares for at least the first year of therapy. Up to 70% of patients in clinical trials experienced gout flares despite concomitant prophylactic treatment with colchicine or naproxen. Additional clinical trial evidence supports the efficacy and safety of febuxostat in the treatment of hyperuricemia and gout. CONCLUSIONS: Febuxostat is a promising alternative to allopurinol for the treatment of gout and hyperuricemia. The optimal length of prophylactic therapy, clinical significance of abnormal liver function tests results during therapy, and safety in patients with moderate or severe renal insufficiency warrant further investigation.",1
11169,17133470,Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry,"""A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin-clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage.""",1
11170,17133573,Acute liver failure induced by green tea extracts: case report and review of the literature,"In industrialized countries, over-the-counter dietary supplements have become popular in preventing and treating an expanding list of medical conditions. Although most commercially available supplements have not been rigorously tested for safety and efficacy, they have found an enlarging market because they are considered natural. Oral supplements containing green tea extract have been marketed as effective for weight loss and to prevent and cure some solid tumors. Although there is little scientific evidence of the effectiveness of green tea extracts to improve the quality of health of regular consumers, there is an increasing body of medical literature supporting the hypothesis that they can cause serious side effects. Our experience adds to previous reports of acute liver toxicity observed in individuals consuming supplements containing green tea extract. We highlight the importance of obtaining a detailed history of dietary supplement consumption when evaluating a patient presenting with acute liver dysfunction.",1
11171,17137406,Sunitinib,"""Sunitinib and its active metabolite (SU012662) are selective inhibitors of multiple receptor tyrosine kinases associated with tumour growth and angiogenesis. The clinical efficacy of oral sunitinib has been demonstrated in patients with advanced gastrointestinal stromal tumours (GIST). In a phase III, randomised, double-blind, placebo-controlled, multicentre trial in patients with metastatic and/or unresectable GIST following unsuccessful imatinib therapy, the median time to tumour progression and median progression-free survival time were > or =4-fold longer in patients receiving sunitinib 50 mg/day than in those receiving placebo, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week rest period. Sunitinib also exhibited antitumour activity in patients with advanced renal cell carcinoma (RCC) following unsuccessful cytokine therapy. In two multicentre, single-arm, phase II clinical trials in patients with cytokine-refractory metastatic RCC, partial responses were reported in 40% and 43% of patients receiving sunitinib 50 mg/day for 4 weeks followed by 2 weeks without treatment in 6-week cycles; 27% and 22% of patients achieved stable disease for > or =3 months. Sunitinib was more effective than interferon-alpha as a first-line therapy in patients with metastatic RCC. In a large, well designed, phase III trial in previously untreated patients, progression-free survival was significantly longer in patients receiving sunitinib 50 mg/day in 6-week cycles (4 weeks of treatment followed by a 2-week rest period) compared with those receiving interferon-alpha 9MU three times weekly (47.3 vs 24.9 weeks). In general, sunitinib was well tolerated in patients with GIST and RCC, with adverse events usually being of mild or moderate severity.""",1
11172,17147458,Reye's syndrome: the case for a causal link with aspirin,"Reye's syndrome is a serious, acute encephalopathy that has been linked with aspirin (acetylsalicylic acid) use in children and teenagers <18 years of age. Although others may disagree, it is my belief that any objective analysis of published material in the last 20 years must conclude that there is a close link between the devastating encephalopathy Reye's syndrome and ingestion of aspirin during the febrile prodrome. The drug appears to act as a co-factor in susceptible individuals. Although some of the epidemiological data indicate an association between the two, the burden of evidence suggests actual causality and is both consistent and specific as well as strong and time related. Some of the evidence points to illness severity being dose related although it seems that in the presence of a viral infection, no dose of aspirin can be considered safe. No published work, using methodology that can be critically evaluated, has shown evidence to contradict these conclusions and they have been widely accepted. Since government health warnings were appended to aspirin-containing formulations, the decline in case numbers on both sides of the Atlantic has been nothing short of remarkable. Recent in vitro findings have pinpointed the site of action of the drug on the long chain hydroxyacyl-CoA dehydrogenase enzyme (a component of the mitochondrial trifunctional enzyme) and, even at therapeutic concentrations, oxidation is impaired in cultured fibroblasts from patients who have recovered from the disorder. This is quite unlike that seen in cells from normal controls. Even when major influenza outbreaks occur in the future, Reye's syndrome is preventable provided government health warnings are heeded and the cogent evidence set forth here is acted upon by the parents of feverish children and self-medicating teenagers.",1
11173,17148651,Combined organ failure with combination antihyperlipidemic treatment: a case of hepatic injury and acute renal failure,"OBJECTIVE: To report a case of acute hepatic injury and acute renal failure secondary to rhabdomyolysis associated with fluvastatin-gemfibrozil combination therapy for hyperlipidemia. CASE SUMMARY: A 56-year-old woman with a history of hyperlipidemia presented with fatigue, weakness in her lower extremities, and red-colored urine. One month prior, she had started combination therapy of fluvastatin 80 mg/day and gemfibrozil 1200 mg/day. On physical examination, she had a serious loss of motor function in the upper and lower extremities. Her laboratory tests revealed severe liver enzyme elevation and abnormal renal function. Abdominal ultrasound did not show hepatic cholestasis, renal parenchymal abnormality, or obstruction. DISCUSSION: Statins and fibric acid derivatives have complementary effects on mixed hyperlipidemia. However, such combination therapy increases the risk of myopathy, which may result in life-threatening rhabdomyolysis. Several reports have suggested that combination fluvastatin-gemfibrozil therapy is both effective and safe in mixed lipid disorders. In our patient, severe rhabdomyolysis with serious hepatocellular injury was observed one month after the combination antihyperlipidemic therapy was started. Assessment with the Naranjo probability scale determined that an adverse drug reaction was probable. The mechanism of this combined toxicity is difficult to clarify, although in vivo and in vitro studies to date have reported considerable data concerning antihyperlipidemic drug interactions. CONCLUSIONS: Clinicians should carefully consider the risks and benefits of treating dyslipidemia with fluvastatin-gemfibrozil combination therapy.",1
11174,17150972,Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities,"Troglitazone, a first-generation thiazolidinedione antidiabetic drug, was withdrawn from the market due to an unacceptable risk of idiosyncratic hepatotoxicity. Troglitazone does not cause hepatotoxicity in normal healthy rodents, but it produces mitochondrial injury in vitro at high concentrations. The aim of this study was to explore whether genetic mitochondrial abnormalities might sensitize mice to hepatic adverse effects of troglitazone. We used heterozygous superoxide dismutase 2 (Sod2(+/-)) mice as a model of clinically silent mitochondrial stress. Troglitazone was daily administered for 4 weeks (0, 10 or 30 mg/kg/day, ip). We found that troglitazone caused overt liver injury in the high-dose group, manifested by increased serum alanine aminotransferase activity (> twofold) and midzonal areas of hepatic necrosis, in Sod2(+/-) but not in wild-type mice. No signs of hepatotoxicity were apparent at 2 weeks of treatment. Hepatic mitochondria isolated from troglitazone-treated mice exhibited decreased activities of aconitase (by 45%) and complex I (by 46%) and increased (by 58%) protein carbonyls, indicative of enhanced mitochondrial oxidant stress. This was paralleled by compensatory increases in mitochondrial glutathione levels. Finally, in hepatocytes isolated from untreated Sod2(+/-), but not wild-type mice, troglitazone caused a concentration-dependent increase in superoxide anion levels as demonstrated with a selective mitochondria-targeting fluorescent probe. In conclusion, prolonged administration of troglitazone can superimpose oxidant stress, potentiate mitochondrial damage, and induce delayed hepatic necrosis in mice with genetically compromised mitochondrial function. These data are consistent with our hypothesis that inherited or acquired mitochondrial abnormalities may be one of the contributing determinants of susceptibility to troglitazone-induced idiosyncratic liver injury.",1
11175,17154043,[Liver damage in treatment of latent tuberculous infection by isoniazid],"PURPOSE: To study the frequency and degree of liver damage as adverse effect of isoniazid (INH) preventive therapy in Japanese people. OBJECT AND METHOD: Chart review of Japanese persons who started isoniazid preventive chemotherapy in the two clinics in Tokyo, from 2003/1/1 to 2004/12/31. RESULT: There were 779 cases who did not transiently or completely stop INH preventive therapy because of adverse effect, and 26 cases who stopped INH transiently or completely because of liver damage as adverse effect (total 805 cases). In 371 cases, of those 779 cases, AST (asparate aminotransferase) and ALT (alanine aminotransferase) was measured after starting INH at least once. In 14.9% (59/397) of these 391 cases (= 371 + 26), liver damage as adverse effect was found. In 1.51% (6/397), liver damage with AST and/or ALT higher than 400 IU/L was found. Clinical hepatitis, associated with clinical symptom of hepatitis, was seen in 0.37% (3/805). Hepatitis with liver failure was seen in 0.12%. There was no death due to liver damage. CONCLUSION: Liver damage as adverse effect of isoniazid (INH) preventive therapy in Japanese people is not rare.",1
11176,17157086,Fatal liver failure following food supplements during chronic treatment with montelukast,"""High aminotransferases and prolonged prothrombin time on entering our liver unit were revealing parenchymal collapse for this 45-year-old obese woman; treatment failure led her to death. Autoimmunity, paracetamol use, alcoholism, and Wilson's disease were all excluded as causes. Because of chronic asthma, she had been receiving a leukotriene receptor antagonist (montelukast) for 5 years before the current presentation; 1 week before onset she had had 1 week of treatment with two dietary supplements for weight control; one of these included Garcinia Cambogia, a possible cause of two recent cases of hepatitis in the USA; in addition, both formulas contained a citrus derivative that interferes cytochrome functions. We speculate on a causal relationship between the assumption of the additives and the fatal hepatitis and envisage a synergy between the additives and montelukast, which per se has well been studied as a hepatotoxic drug. Despite the speculative nature of this presentation, we believe the warning may serve to focus attention on the uncontrolled escalation of food additives going on in these days.""",1
11177,17162212,Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases,"""Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.""",1
11178,17163303,Onset of liver damage after a single administration of infliximab in a patient with refractory ulcerative colitis,"We report the case of a patient with refractory ulcerative colitis who developed cholestatic acute liver damage after a single infusion of infliximab. Unusual aspects of this case were the early onset (after the first administration) of liver damage and the absence of antinuclear antibodies, alcohol intake, hepatotoxic drugs and all known viral and metabolic causes of hepatic injury. Moreover, no serological or morphological findings of primary sclerosing cholangitis were observed. The patient's liver damage resolved spontaneously within 6 weeks. Although a direct relationship between administration of infliximab and onset of acute liver damage could not be definitely established, our case suggests that infliximab may induce direct liver damage, the course of which is similar to acute cholestatic hepatitis and resolves following withdrawal of the drug.",1
11179,17165637,Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study,"""OBJECTIVE: To compare the efficacy and safety of the recommended usual starting and next highest doses of ezetimibe/ simvastatin and atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia. PATIENTS AND METHODS: This double-blind, multicenter study (June 22 to December 7, 2005) consisted of adult patients randomized to the recommended usual starting (ezetimibe/simvastatin, 10/20 mg/d, vs atorvastatin, 10 or 20 mg/d) or next highest (ezetimibe/simvastatin, 10/40 mg/d, vs atorvastatin, 40 mg/d) doses. Efficacy end points included percent changes from baseline in low-density lipoprotein cholesterol (LDL-C) levels (primary) and proportion of patients attaining LDL-C levels less than 70 mg/dL (secondary). RESULTS: A total of 1229 patients participated in the study. Significantly greater mean reductions were found in LDL-C levels with ezetimibe/simvastatin, 10/20 mg/d (-53.6%; 95% confidence interval [CI], -55.4% to -51.8%), than with atorvastatin, 10 mg/d (-38.3%; 95% CI, -40.1% to -36.5%; P < .001) or 20 mg/d (-44.6%; 95% CI, -46.4% to -42.8%; P < .001), and with ezetimibe/simvastatin, 10/40 mg/d (-57.6%; 95% CI, -59.4% to -55.8%), vs atorvastatin, 40 mg/d (-50.9%; 95% CI, -52.7% to -49.1%; P < .001). Ezetimibe/simvastatin was also superior to atorvastatin in attainment of LDL-C levels less than 70 mg/dL (P < .001 for all dose comparisons). Significantly better improvements with ezetimibe/simvastatin than with atorvastatin (P < or = .001) were observed for total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol. Ezetimibe/ simvastatin, 10/20 mg/d, reduced high-sensitivity C-reactive protein and triglyceride levels significantly more than atorvastatin, 10 mg/d (P = .02), with comparable reductions at other doses. Incidences of clinical adverse events, including serious drug-related and prespecified gastrointestinal-, gallbladder-, and hepatitis-related allergic reactions or rash events, and laboratory adverse events, including repeated elevation of hepatic transaminases or creatine kinase levels, were similar for both treatments. CONCLUSION: Ezetimibe/simvastatin provided additional lipid-modifying benefits over atorvastatin monotherapy at the recommended usual starting and next highest doses in patients with type 2 diabetes. Both treatments were generally well tolerated.""",1
11180,17167851,Hepatotoxicity induced by cyproterone acetate: a report of three cases,"Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.",1
11181,17168987,Valproate hepatotoxicity in a 5-year-old boy with cerebral palsy due to neonatal asphyxia,,1
11182,17176621,Safety profile of proton pump inhibitors according to the spontaneous reports of suspected adverse reactions,"OBJECTIVE: [corrected] To evaluate similarities and differences in safety among proton pump inhibitors (PPIs) under the usual conditions of prescription. METHODS: A search of spontaneous reports on adverse reactions associated with these drugs and registered between January 1, 2004 and December 31, 2004 was undertaken in the Spanish Pharmacovigilance System Database. We compared the frequency of reports with the consumption of PPIs, and analyzed the organ and system distribution for each PPI. Of the organ and system groups more commonly affected, diarrhea, myalgia, abnormal vision and hepatitis were selected for further analysis. RESULTS: Nearly 8 times more reports for omeprazole compared to other drugs were found but a similar difference was observed in their consumption. Skin and appendage disorders were more frequently reported for omeprazole and rabeprazole, the urinary, female reproductive and endocrine systems for lansoprazole, musculoskeletal for omeprazole and esomeprazole, vision for pantoprazole, rabeprazole and esomeprazole, gastrointestinal tract for omeprazole and lansoprazole and liver and biliary systems for omeprazole, lansoprazole and pantoprazole. Myalgia appears more often in younger patients than diarrhea, abnormal vision or hepatitis and shows longer periods of latency and recovery. The four adverse reactions analyzed were mainly reversible. CONCLUSION: A direct relationship was found between consumption and the number of reports. Some organ and system groups were affected by more than one PPI and this showed a specific pattern of group toxicity to these pharmacological agents. Some reports involved only lansoprazole and these require further analysis.",1
11183,17179451,Acetaminophen and aminotransferase elevations,,1
11184,17181445,Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going?,"Tamoxifen is a cheap and effective estrogen-receptor antagonist, used as the adjuvant hormonal treatment of choice in women with estrogen-receptor-positive breast cancer. Tamoxifen-induced non-alcoholic steatohepatitis (NASH) may increase the demand on oncologists, not only with regard to screening for diabetes, but also for the suggested link of NASH with high incidence of coronary heart disease. At present, there is no guideline for treatment of hyperlipidaemia associated with tamoxifen-induced NASH. However, exemstane (and other aromatase inhibitors) has been shown to lower triglyceride and have a neutral effect on low-denisty lipoprotein and cholesterol levels. These may be alternative agents if severe progressive liver disease or hyperlipidaemia were encountered with tamoxifen administration. Other lipid-lowering medications may have potential benefits in the treatment of tamoxifen-induced NASH and is discussed in this article.",1
11185,17184550,Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia--Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR),"""BACKGROUND: Many patients at high risk of cardiovascular disease do not achieve recommended low-density lipoprotein cholesterol (LDL-C) goals. This study compared the efficacy and safety of low doses of rosuvastatin (10 mg) and atorvastatin (20 mg) in high-risk patients with hypercholesterolemia. METHODS: A total of 996 patients with hypercholesterolemia (LDL-C > or = 3.4 and < 5.7 mmol/L [130 and 220 mg/dL]) and coronary heart disease (CHD), atherosclerosis, or a CHD-risk equivalent were randomized to once-daily rosuvastatin 10 mg or atorvastatin 20 mg. The primary endpoint was the percentage change from baseline in LDL-C levels at 6 weeks. Secondary endpoints included LDL-C goal achievement (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] goal < 100 mg/dL; 2003 European goal < 2.5 mmol/L for patients with atherosclerotic disease, type 2 diabetes, or at high risk of cardiovascular events, as assessed by a Systematic COronary Risk Evaluation (SCORE) risk > or = 5% or 3.0 mmol/L for all other patients), changes in other lipids and lipoproteins, cost-effectiveness, and safety. RESULTS: Rosuvastatin 10 mg reduced LDL-C levels significantly more than atorvastatin 20 mg at week 6 (44.6% vs. 42.7%, p < 0.05). Significantly more patients achieved NCEP ATP III and 2003 European LDL-C goals with rosuvastatin 10 mg compared with atorvastatin 20 mg (68.8% vs. 62.5%, p < 0.05; 68.0% vs. 63.3%, p < 0.05, respectively). High-density lipoprotein cholesterol was increased significantly with rosuvastatin 10 mg versus atorvastatin 20 mg (6.4% vs. 3.1%, p < 0.001). Lipid ratios and levels of apolipoprotein A-I also improved more with rosuvastatin 10 mg than with atorvastatin 20 mg. The use of rosuvastatin 10 mg was also cost-effective compared with atorvastatin 20 mg in both a US and a UK setting. Both treatments were well tolerated, with a similar incidence of adverse events (rosuvastatin 10 mg, 27.5%; atorvastatin 20 mg, 26.1%). No cases of rhabdomyolysis, liver, or renal insufficiency were recorded. CONCLUSION: In high-risk patients with hypercholesterolemia, rosuvastatin 10 mg was more efficacious than atorvastatin 20 mg at reducing LDL-C, enabling LDL-C goal achievement and improving other lipid parameters. Both treatments were well tolerated.""",1
11186,17188950,"Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?","BACKGROUND: 6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology. AIMS: Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients. PATIENTS AND METHODS: Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging. RESULTS: Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia. DISCUSSION: Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine. CONCLUSION: 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.",1
11187,17192538,Lapatinib plus capecitabine for HER2-positive advanced breast cancer,"""BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).""",1
11188,17195556,Arsenic contamination in groundwater: a global perspective with emphasis on the Asian scenario,"The incidence of high concentrations of arsenic in drinking-water has emerged as a major public-health problem. With newer-affected sites discovered during the last decade, a significant change has been observed in the global scenario of arsenic contamination, especially in Asian countries. This communication presents an overview of the current scenario of arsenic contamination in countries across the globe with an emphasis on Asia. Along with the present situation in severely-affected countries in Asia, such as Bangladesh, India, and China, recent instances from Pakistan, Myanmar, Afghanistan, Cambodia, etc. are presented.",1
11189,17197379,Low incidence of severe liver events in HIV patients with and without hepatitis C or B coinfection receiving lopinavir/ritonavir,"OBJECTIVES: To analyze the incidence of severe liver events in HIV patients treated with lopinavir/ritonavir and the role of coinfection in the development of this toxicity. METHOD: This was a retrospective, multicenter, cohort study of all HIV-positive patients who started a regimen of HAART that included lopinavir/ritonavir (LPV/r). The main outcome variable was the emergence of a severe liver event, defined as decompensation of pre-existing chronic liver disease and grade 3-4 hypertransaminasemia (HT), that is, plasma AST or ALT values >5 times above the upper limit of normality, if baseline levels were normal, or >3.5 times the baseline values when they were abnormal. RESULTS: 388 HIV-infected patients were included, with a median follow-up of 25.6 months. Coinfection with HCV was present in 61% of the patients and with HBV in 6.7%. There were 6 cases of severe liver events, all involving patients who were coinfected with HCV and all within the first 6 months. This represents 0.72 events per 100 patient-years (95% confidence interval [CI] 0.36-2.98) and 1.21 events per 100 patient-years (95% CI 0.60-5.86) in coinfected patients. The only factors associated with severe liver events at 6 months were baseline HT and HCV coinfection. CONCLUSION: The incidence of severe hepatic events in HIV-positive patients receiving a HAART regimen including LPV/r was very low, even in coinfected patients. HCV coinfection and baseline HT were the only factors associated with severe liver events. LPV/r can be considered a safe and well-tolerated option in HIV patients with hepatotropic virus coinfections.",1
11190,17197833,"Severe liver toxicity in postexposure prophylaxis for HIV infection with a zidovudine, lamivudine and fosamprenavir/ritonavir regimen",,1
11191,17201699,Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003,"PURPOSE: Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. We provide an update on hepatotoxic side effects in Germany between 1994 and 2003. METHODS: We mailed a questionnaire to all members of the German Section of the International League Against Epilepsy, asking for VPA-induced side effects, especially severe side effects such as hepatopathy. RESULTS: As a result of our questionnaire, we found 31 cases of reversible hepatotoxicity and nine cases of lethal hepatopathies in Germany from 1994 to 2003. CONCLUSIONS: The outcome of patients with severe hepatotoxicity is better than that in the past. The risk of a VPA-induced hepatopathy is not limited to patients younger than 2 years, receiving polytherapy, or patients with congenital or acquired metabolic diseases.",1
11192,17202605,Miltefosine in children with visceral leishmaniasis,"""Sixty four children (38 boys and 26 girls), aged 1 yr to 14 yr, presenting with fever, splenomegaly and positive LD body in splenic smear examination, admitted to pediatric ward of Nalanda Medical college and Child care center between 1st July 03 to 30th June 04 were taken for study. Patients were categorized into two groups: 44 were in Group I (Patients who had not received prior antileishmanial drug) and 20 in Group II (Patients who had received 30 days course of SAG; 20 mg per kg per day). All patients were given Miltefosine in dose of 2.5 per kg per day od or bid per orally to a maximum of 100 mg and were followed at completion of therapy, 1 month and 6 months for clinical response, splenic size and parasite density. 63 patients had parasitological cure with relapse in one patient of Group I during follow up. One patient in Group II had no response with first course but became parasitologically negative with 2nd course of Miltefosine. In Group I, one patient had persistent splenomegaly and found to have associated portal hypertension. GI side effects i.e. diarrhea and vomiting were observed in 26 and 23 patients respectively. Majority of patients had pancytopenia. Elevated ALT (> 3 times of normal) were seen in 28 and 11 patients of Group I and Group II respectively which returned to normal in subsequent follow up. The final cure rates were 93.2 percent and 95 percent in Groups I and II respectively.""",1
11193,17206072,Antibiotic therapy: a major cause of drug-induced jaundice in southwest England,"OBJECTIVE: To determine the incidence and causes of drug-induced jaundice in a rural community. METHODS: A retrospective analysis of 800 patients presenting to a single-centre jaundice referral system serving a community of 400 000 over a period of 66 months (1998-2004). Standard criteria for drug-induced liver injury were applied to patients with a putative diagnosis of drug-induced jaundice. The incidence rates per prescription of drug-induced jaundice caused by co-amoxiclav and flucloxacillin were derived from local and national annual prescription rates. RESULTS: The incidence of drug-induced jaundice was 1.27 (confidence limits 0.85-1.8) per 100 000 per annum in a total of 28 patients (17 men, mean age 69 years). Antibiotics were the commonest cause of jaundice (n=21). Of these, co-amoxiclav (n=9) and flucloxacillin (n=7) caused the majority with an incidence rate per 100 000 prescriptions of 9.91 (4.6-18.0) and 3.60 (1.5-7.2), respectively. Co-amoxiclav-induced jaundice was observed more commonly in elderly males (age 65 years, M : F 7 : 2). In those patients with flucloxacillin or co-amoxiclav-induced jaundice, bilirubin ranged from 54 to 599 mumol/l (267 mumol/l) with a resolution of jaundice between 30 and 90 days. Counselling with regard to potential drug-induced liver injury and reporting of the adverse reaction had been performed in 1/28 patients. CONCLUSIONS: 8.1% patients with no biliary obstruction and jaundice had a drug-induced and predominantly antibiotic-related aetiology particularly affecting an elderly population. We recommend that all patients receiving co-amoxiclav and flucloxacillin should be counselled before the therapy regarding the potential risk of jaundice and that an alternative antibiotic to co-amoxiclav is used if possible in men over the age of 60 years.",1
11194,17206687,Occult hepatitis B and infliximab-induced HBV reactivation,,1
11195,17208628,Severe acute hepatitis in a patient treated with anastrozole,,1
11196,17215532,Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia,"BACKGROUND: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients. METHODS: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study. RESULTS: All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%. CONCLUSIONS: Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.",1
11197,17216557,Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy,,1
11198,17219067,Drug-induced liver injury associated with ezetimibe therapy,,1
11199,17219444,"Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia","BACKGROUND: Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML. METHODS: Nineteen adults with a diagnosis of CMML treated on decitabine studies were analyzed. Decitabine was given at 100 mg/m(2) per course every 4 weeks. The median number of courses given was 9 (range, 1-18). RESULTS: Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3-4) extramedullary side effects were rare. CONCLUSIONS: Decitabine is active in CMML. Studies of combinations of decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated.",1
11200,17223307,The prevalence and risk of hepatitis flares in a Serbian cohort of HIV and HCV co-infected patients treated with HAART,"Despite substantial benefits of HAART treatment of HIV-infected patients, cumulative long-term toxicity, including drug-induced hepatotoxicity, has emerged as an important complication. Thus, to examine the prevalence and risk of developing severe hepatic injury during HAART, we conducted a retrospective study in a cohort of 364 HIV-infected patients treated with HAART between January 1998 and May 2006, for whom data on alanine aminotransferase activity were available both before and during HAART. HCV co-infection was recorded in 35.4% of the series, but was found not to influence either the efficacy of HAART or survival (P>0.05). Severe hepatotoxicity occurred in a total of 24 patients (6.6%). Multivariate logistic regression defined HCV co-infection (OR 16.6, 95% CI 3.8-46.0, P<0.0001), and the use of SQV/RTV and d4T (OR 3.1, 95% CI 1.2-8.16, P=0.02, and OR 7.1, 95% CI 1.0-54.5, P=0.05, respectively) as independent risk factors for aggravation of hepatitis. In addition, there was a significant increase in the probability of developing liver damage over years of treatment (Log rank, P<0.01). Conversely, the probability of developing hepatotoxicity was not associated with an increase in the CD4 cell count to values greater than 350/microL (Log rank, P=0.59). In conclusion, in the setting of chronic viral hepatitis, hepatotoxicity during HAART may be attributed to the cumulative toxicity of drugs that induce mitochondrial toxicity, along with particular PIs and/or NNRTIs. Furthermore, our data suggest prudent use of D-drugs, still common in resource-limited countries, in HCV co-infected patients.",1
11201,17226065,Hepatotoxicity induced by alendronate therapy,"Here we describe a 47-year-old postmenopausal woman who had been taking alendronate 70 mg/week for osteoporosis. After two months of alendronate therapy, she developed hepatotoxicity, and no other etiological factors for this besides the alendronate were apparent. After the alendronate therapy was discontinued, the patient's hepatic enzyme levels slowly returned to normal. Hepatotoxicity due to alendronate therapy is a rare but possible adverse effect.",1
11202,17233202,Hepatotoxicity after low-dose cyclophosphamide therapy,,1
11203,17234519,Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan,"BACKGROUND: Bosentan, an oral ET(A)/ET(B) receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ET(A)-selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing bosentan. METHODS: Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organization (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12. RESULTS: With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued bosentan because inadequate efficacy improved, demonstrating a >15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a >15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated. CONCLUSIONS: Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan.",1
11204,17244643,Mirtazapine-associated dose-dependent and asymptomatic elevation of hepatic enzymes,,1
11205,17253473,Molindone for schizophrenia and severe mental illness,"""BACKGROUND: Antipsychotic therapy is the mainstay of treatment for people with schizophrenia. In recent years new or atypical antipsychotics have been introduced. These are less likely to produce movement disorders and raise serum prolactin. Researchers have suggested that molindone should be classified as an atypical antipsychotic. OBJECTIVES: To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: For the original search we searched the following databases: Biological Abstracts (1980-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999). We also searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog and the references of all identified studies for further trials. Finally, we contacted the manufacturer of molindone and the authors of any relevant trials. For the update of this review, we searched The Cochrane Schizophrenia Group's Trials Register (August 2005). SELECTION CRITERIA: We included all randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently and analysed on an intention to treat basis calculating, for binary data, the fixed effect relative risk (RR), their 95% confidence intervals (CI), and the number needed to treat or harm (NNT or NNH). We excluded data if loss to follow up was greater than 50%. MAIN RESULTS: We included fourteen studies. Duration ranged from very short (10 days) studies of the intramuscular preparation, to trials lasting over three months. For measures of global assessment, available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics we found no evidence of a difference in effectiveness (doctors' 4 RCTs n=150, RR 1.13, CI 0.69 to 1.86; nurses 4RCTs n=146, RR 1.23, CI 0.82 to 1.86). Molindone is no more or less likely than typical drugs to cause movement disorders, but it does cause significantly more weight loss (2RCTs n=60 RR 2.78, CI 1.10 to 6.99, NNH 5 CI 2 to 77). AUTHORS' CONCLUSIONS: The strength of the evidence relating to this compound is limited, owing to small sample size, poor study design, limited outcomes and incomplete reporting. Molindone may be an effective antipsychotic but its adverse effect profile does not differ significantly from that of typical antipsychotics (apart from the event of weight loss). Data from this review suggest, at present, there is no evidence to suggest that it may have an atypical profile.""",1
11206,17253880,"Safety profile of rosuvastatin: results of a prescription-event monitoring study of 11,680 patients","""BACKGROUND AND OBJECTIVE: Rosuvastatin is a lipid-lowering drug, the newest of a class of drugs called HMG-CoA reductase inhibitors, or 'statins', launched in the UK in March 2003. Our objective was to monitor the post-marketing safety of this drug, prescribed in primary care in England, using prescription-event monitoring. METHODS: An observational cohort study in which patients were identified from dispensed prescriptions issued by primary care physicians/general practitioners (GPs) between August and December 2003. Demographic and clinical-event data were collected from questionnaires posted to GPs at least 6 months after the date of first prescription for each patient. Stratified analysis of specific events by starting dose of rosuvastatin was conducted. Follow-up and causality assessment of medically significant events was undertaken. RESULTS: The cohort comprised 11,680 patients (median age 64 years); 50.3% were males (5880 of 11,680). The median period of treatment was 9.8 months. Of these patients, 72.7% (n = 8494) were started on rosuvastatin 10 mg/day. A total of 17.5% (n = 2047) of the patients were reported to have stopped treatment with rosuvastatin. Myalgia was the most frequent reason for stopping rosuvastatin and the most frequently reported clinical event. A 2.5-fold increase in the rate of abnormal liver-function tests (LFTs) was observed for patients started on rosuvastatin 40 mg/day compared with those started on 10 mg/day (2.71; 95% CI 1.53, 4.53). No case of rhabdomyolysis was reported in this cohort. CONCLUSION: Rosuvastatin was considered to be a reasonably well tolerated drug. In the majority of patients, rosuvastatin was prescribed in line with recommendations. Abnormality of LFTs was found to be more frequent with the 40 mg/day dosage of rosuvastatin. Results from this study should be taken into account together with those of other clinical and pharmacoepidemiological studies of rosuvastatin.""",1
11207,17255142,Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors,"Liver toxicity is one of the most relevant adverse effects of antiretroviral therapy. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz can be considered a safer drug for the liver than nevirapine. In fact, the frequency of severe increased liver enzymes in patients on efavirenz ranges from 1 to 8%, whereas in patients treated with nevirapine, it ranges from 4 to 18%. Likewise, nevirapine is more commonly associated than efavirenz with early acute hepatitis, which is produced by a hypersensitivity mechanism and has a defined risk profile that often makes it avoidable. Despite the fact that most cases of NNRTI-induced liver toxicity are asymptomatic, the rates of symptomatic events in patients treated with nevirapine are greater than in subjects on efavirenz. In any case, it is unusual for an NNRTI to be suspended due to liver toxicity.",1
11208,17261402,"Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system)","Recent national guidelines support combination drug therapy targeting multiple lipid abnormalities. Current drug labeling warns of an increased risk of adverse events with statin and niacin combinations. These recommendations have been based solely on case reports. We compared the rates of adverse event reports (AERs) received by the United States Food and Drug Administration (1999 to March 2005) associated with the combination of lovastatin/niacin-extended release (ER) with those of lovastatin or niacin-ER alone, and other commonly used statins. The following AERs were considered: events that were fatal, life-threatening, or resulted in hospitalization (serious AERs), hepatotoxicity (liver AERs), and rhabdomyolysis (rhabdomyolysis AERs). We also calculated the prevalence of concomitant niacin-ER therapy in statin-associated AERs. The rate of serious AERs associated with the combination lovastatin/niacin-ER was similar to that of lovastatin or niacin-ER alone, and significantly less than that of atorvastatin or simvastatin. Likewise, the rates of liver and rhabdomyolysis AERs associated with lovastatin/niacin-ER were similar to those of the other statins or niacin-ER alone and lower than those of simvastatin-associated rhabdomyolysis reports (p <0.01). Concomitant niacin-ER use in statin-associated AERs was rare (<or=1%). In conclusion, these findings do not support a clinically significant adverse drug interaction between niacin-ER and statins and should encourage the safe use of this combination in appropriate high-risk patients, as recommended by the national guidelines.",1
11209,17262050,Acetaminophen-induced hepatic failure with encephalopathy in a newborn,We report a case of oral acetaminophen toxicity in a term newborn infant successfully treated with a 20 h intravenous N-acetylcysteine infusion protocol without any adverse effects. This case report supports the use of N-acetylcysteine to treat neonatal acetaminophen toxicity and highlights the need for better education of parents regarding the appropriate use and dosage of acetaminophen in newborns.,1
11210,17264438,Recurrent acute hepatitis in patient receiving pulsed methylprednisolone for multiple sclerosis,"We report clinically significant, recurrent acute hepatitis in a 48-year-old woman receiving pulsed treatment with methylprednisolone for multiple sclerosis. No other cause was found for the episodes and the temporal and histological correlations were consistent with immune-allergic type drug-induced hepatitis.",1
11211,17266883,[Omeprazole-induced acute cholestatic hepatitis],,1
11212,17272503,Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens,"The addition of antithymocyte globulin (ATG) to a regimen of high-dose cyclophosphamide has been advocated to enhance engraftment after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA). In a prospective clinical trial, 134 patients were randomly assigned to receive cyclophosphamide alone or in combination with ATG. All patients received T-cell-replete bone marrow from an HLA-matched sibling. With a median follow-up of 6 years, the 5-year probabilities of survival were 74% for the cyclophosphamide alone group and 80% for the cyclophosphamide plus ATG group (P = .44). Graft failure and graft-versus-host disease (GVHD) rates were similar in both groups. With the survival rates achieved, this study is not adequately powered to detect significant differences between the 2 treatment groups. In conclusion, the results of allogeneic BMT for SAA have improved over time related to advances in supportive care. The addition of ATG to the preparative regimen did not significantly improve the outcome.",1
11213,17279048,Clinical toxicity of highly active antiretroviral therapy in a home-based AIDS care program in rural Uganda,"""BACKGROUND: We evaluated clinical toxicity in HIV-infected persons receiving antiretroviral therapy (ART) in Uganda. METHODS: From May 2003 through December 2004, adults with a CD4 cell count < or =250 cells/microL or World Health Organization stage 3/4 HIV disease were prescribed ART. We calculated probabilities for time to toxicity and single-drug substitution as well as multivariate-adjusted hazard ratios for development of toxicity. RESULTS: ART (stavudine plus lamivudine with nevirapine [96%] or efavirenz [4%]) was prescribed for 1029 adults, contributing 11,268 person-months of observation. Toxicities developed in 543 instances in 411 (40%) patients (incidence rate = 4.47/100 person-months): 36% peripheral neuropathy (9% severe); 6% rash (2% severe); 2% hypersensitivity reaction; < or =0.5% acute hepatitis, anemia, acute pancreatitis, or lactic acidosis; and 13% other. Probabilities of remaining free from any toxicity at 6, 12, and 18 months were 0.76, 0.59, and 0.47 and from any severe toxicity at 6, 12, and 18 months were 0.92, 0.86, and 0.85, respectively. For 217 patients (21%), 222 single-drug substitutions were made, mostly because of peripheral neuropathy or rash. CONCLUSIONS: Clinical toxicities were common, but no patients discontinued ART because of toxicity. The most common toxicities, peripheral neuropathy and rash, were managed with single-drug substitutions. In resource-limited settings, toxicity from ART regimens containing stavudine or nevirapine is manageable but more tolerable regimens are needed.""",1
11214,17286240,"Morinda citrifolia (Noni) fruit--phytochemistry, pharmacology, safety","Products derived from Noni fruit (Morinda citrifolia) have been commercialised in the USA since the 1990s and are increasingly distributed all over the world. A large number of beneficial effects have been claimed for Noni. Fruit juice of Noni has been approved as a Novel Food by the European Commission in 2003. This article reviews current knowledge on the phytochemistry, pharmacology, safety aspects of Noni fruit and Noni-derived products, and health-related claims and benefits. The knowledge on the chemical composition of Noni fruit has considerably increased over recent years. A number of in vitro and, to a certain extent, in vivo studies demonstrate a range of potentially beneficial effects. However, clinical data are essentially lacking. To what extent the findings from experimental pharmacological studies are of potential clinical relevance is not clear at present. Based on a toxicological assessment, Noni juice was considered as safe. Due to recent reports of cases of hepatotoxicity, the safety issue has been re-examined in Europe. While the European Food Safety Authority sees no link between adverse effects on liver and consumption of Noni juice, a continuing monitoring of the situation is desirable and some vigilance advised.",1
11215,17292769,Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial,"""BACKGROUND: Artemisinin-based combination regimens are widely advocated for malarial treatment, but other effective regimens might be cheaper and more readily available. Our aim was to compare the risk of recurrent parasitaemia in patients given artemether-lumefantrine with that in those given amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated malaria. METHODS: We enrolled 521 patients aged 6 months or older with uncomplicated falciparum malaria in Bobo-Dioulasso, Burkina Faso. Patients were randomly assigned to receive standard doses of either artemether-lumefantrine (261) or amodiaquine plus sulfadoxine-pyrimethamine (260) for 3 days. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. The study is registered at controlled-trials.gov with the identifier ISRCTN54261005. FINDINGS: Of enrolled patients, 478 (92%) completed the 28-day study. The risk of recurrent symptomatic malaria was lowest in the group given amodiaquine plus sulfadoxine-pyrimethamine (1.7%vs 10.2%; risk difference 8.5%; 95% CI 4.3-12.6; p=0.0001); as was the risk of recurrent parasitaemia (4.7%vs 15.1%; 10.4%; 5.1-15.6; p=0.0002). Nearly all recurrences were due to new infections. Recrudescences were four late treatment failures with artemether-lumefantrine and one early treatment failure with amodiaquine plus sulfadoxine-pyrimethamine. Both regimens were safe and well tolerated, with pruritus more common with amodiaquine plus sulfadoxine-pyrimethamine than with artemether-lumefantrine. Each regimen selected for new isolates with mutations that have been associated with decreased drug susceptibility. INTERPRETATION: Amodiaquine plus sulfadoxine-pyrimethamine was more effective than was artemether-lumefantrine for the treatment of uncomplicated malaria. For regions of Africa where amodiaquine plus sulfadoxine-pyrimethamine continues to be effective, this less expensive and more available regimen should be considered as an alternative to blanket recommendations for artemisinin-based combination treatment for malaria.""",1
11216,17297432,Cholestatic hepatitis with severe systemic reactions induced by trimethoprim-sulfamethoxazole,"Trimethoprim-Sulfomethoxazole (TMP-SMX) related hepatotoxicity and associated severe systemic reaction are not frequent and documented only in case reports. We report a case of a 30-year-old man, who underwent a 15-day therapy with TMP-SMX for urinary tract infection and two weeks later developed acute cholestatic hepatitis, fever and a skin rash followed by severe systemic reaction. He was admitted in Intensive Care unit and with supportive therapy and prednisolone administration, he showed subsequent improvement over a period of few days. He had fully recovered months later. All tests for other causes of liver disease were negative and his liver biopsy showed evidence of drug-induced hepatic injury.",1
11217,17298197,[Finasteride-induced hepatitis],,1
11218,17305884,Liver-related mortality in human-immunodeficiency-virus-infected patients between 1995 and 2003 in the French GERMIVIC Joint Study Group Network (MORTAVIC 2003 Study),"The objective of the present study was to determine mortality because of end-stage liver disease (ESLD) in a nationwide population of HIV-infected patients, 7 years following the introduction of highly active antiretroviral therapy (HAART). All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV-infected patients during 2003. Fifty-nine departments, following a total of 20 940 HIV-infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995, 1997 and 2001. Among 215 deaths observed during 2003, 101 (46.9%) were related to AIDS, 27 (12.6%) to ESLD and 87 (40.5%) to other causes. Mortality because of ESLD represented 23.7% of non-AIDS-related deaths. Patients dying from ESLD had chronic hepatitis because of hepatitis C virus (HCV) in 92.6% of cases and moderate (30-60 g) or high (>60 g) alcohol consumption (43.5% and 26.0%, respectively). In this population, deaths because of ESLD were 1.5% in 1995, 6.6% in 1997, 14.3% in 2001 and 12.6% in 2003. The prevalence of hepatocellular carcinoma as a cause of death remained high in 2003 but stable when compared with 2001 (25%vs 14.8%). Treatment of hepatitis C in patients who died from ESLD was more frequent in 2003 (44.4%) than in 2001 (26.3%). Seven years after the introduction of HAART, ESLD associated with HCV infections is a leading cause of mortality in HIV-infected patients, which did not increase between the years 2001 and 2003.",1
11219,17307102,Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial,"""BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.""",1
11220,17314522,Is the increased risk of liver enzyme elevation in patients co-infected with HIV and hepatitis virus greater in those taking antiretroviral therapy?,"""OBJECTIVES: To investigate if the risk of liver enzyme elevation (LEE) in HIV/hepatitis B or C (HBV, HCV) co-infection is altered by HAART (two or more drugs). METHODS: Analysis comprised HIV-positive patients in the ICoNA study without acute hepatitis who had >or= 1 positive HCV antibody test and > 1 positive HBV surface antigen test. LEE was defined as > 5x baseline alanine aminotransferase (ALT) or > 3.5x baseline if the baseline was > 40 IU/l. Analysis used Poisson regression with generalized estimating equation correction to examine HBV or HCV co-infection, use of HAART, baseline ALT and demographics as LEE predictors. RESULTS: Of the 5272 patients, 47.6% were co-infected with HCV/HBV; 29.9% were female and 39% were intravenous drug users. There were 275 episodes of LEE during 18 259 person-years follow up. Taking HAART did not significantly increase risk of LEE [adjusted relative risk (RR), 1.19; 95% confidence interval (CI), 0.81-1.75; P = 0.37]. Co-infection increased the risk of LEE (adjusted RR, 5.07; 95% CI, 3.47-7.48; P < 0.001), with no significant differences if taking HAART (adjusted RR, 4.99; 95% CI, 3.38-7.37) or not (adjusted RR, 6.02; 95% CI, 2.02-17.98) (P = 0.74 for interaction). Females were at lower risk of LEE than males (adjusted RR, 0.59; 95% CI, 0.42-0.83; P = 0.02). CONCLUSIONS: HIV and HBV/HCV co-infection per se is associated with increased risk of LEE that is not modified by HAART. The recommendation for caution in HAART use in co-infected patients, simply based on a high rate of LEE in people on therapy, may be questionable.""",1
11221,17316149,The echinocandins,"""The changing pattern in fungal infections has driven the need to expand the targets of antifungal activity. The echinocandins are the newest addition to the arsenal against fungal infections. Three echinocandins have been approved by the United States Food and Drug Administration: caspofungin, micafungin, and anidulafungin. These agents have a broad spectrum of activity and are similar to each other with respect to in vitro activity against Candida sp, with micafungin and anidulafungin having similar minimum inhibitory concentrations (MICs) that are generally lower than the MIC of capsofungin. The MICs of the echinocandins are highest against Candida parapsilosis; however, whether this will affect clinical outcomes is unknown. Several case reports have identified clinical failure due to elevated MICs with caspofungin or micafungin against Candida albicans, Candida krusei, and C. parapsilosis. Resistance to the echinocandin class was present in some but not all of the isolates. Empiric therapy with one of the echinocandins for candidemia or invasive candidiasis in patients with neutropenia and those without neutropenia appears to be appropriate when one factors in mortality rate, the increasing frequency of non-albicans Candida infections, and the broad spectrum, safety, and fungicidal effect of the echinocandins. After speciation of the organism, continued therapy with an echinocandin can and should be reevaluated. The echinocandins demonstrate similar in vitro and in vivo activity against Aspergillus sp, but only caspofungin is approved for treatment in patients who are intolerant of or refractory to other therapies. Voriconazole and amphotericin B have demonstrated synergy with the echinocandins. The clinical response to combination therapy has been variable; however, the mortality rate appears to be lower with combination therapy than monotherapy. Large controlled trials are needed to determine the role of combination therapy for invasive aspergillosis. Micafungin and anidulafungin generally have a lower frequency of adverse reactions compared with caspofungin. Phlebitis (3.5-25% of patients) and elevated liver enzyme levels (1-15%) occur more often with caspofungin compared with micafungin and anidulafungin (< 8%). Overall, the three echinocandins are relatively safe and effective agents for the treatment of Candida infections.""",1
11222,17325565,Re: Minocycline-induced autoimmune hepatitis with subsequent cirrhosis,,1
11223,17325912,Fulminant B hepatitis in a surface antigen and hepatitis B DNA-negative patient with diffuse large B-cell lymphoma after CHOP chemotherapy plus rituximab,,1
11224,17326221,Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results,"Wait-listed (n = 226) or post-liver transplantation (n = 241) chronic hepatitis B (CHB) patients with lamivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (<1,000 copies/mL) in 59% and 65% at weeks 48 and 96, respectively. After 48 weeks, alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 77%, 76%, 60%, and 84% of wait-listed patients, respectively. Among posttransplantation patients, serum HBV DNA levels became undetectable in 40% and 65% at weeks 48 and 96, respectively. After 48 weeks, ALT, albumin, bilirubin, and prothrombin time normalized in 51%, 81%, 76%, and 56% of posttransplantation patients, respectively. Among wait-listed patients who underwent on-study liver transplantation, protection from graft reinfection over a median of 35 weeks was similar among patients who did (n = 34) or did not (n = 23) receive hepatitis B immunoglobulin (HBIg). Hepatitis B surface antigen was detected on the first measurement only in 6% and 9% of patients who did or did not receive HBIg, respectively. Serum HBV DNA was detected on consecutive visits in 6% and 0% of patients who did or did not receive HBIg, respectively. Treatment-related adverse events led to discontinuation of adefovir dipivoxil in 4% of patients. Cumulative probabilities of resistance were 0%, 2%, and 2% at weeks 48, 96, and 144, respectively. In conclusion, adefovir dipivoxil is effective and safe in wait-listed or posttransplantation CHB patients with lamivudine-resistant HBV and prevents graft reinfection with or without HBIg.",1
11225,17329700,Amiodarone for atrial fibrillation,,1
11226,17332278,Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma,"PURPOSE: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. EXPERIMENTAL DESIGN: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokine-refractory metastatic renal cell carcinoma. RESULTS: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1 and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. CONCLUSIONS: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.",1
11227,17334017,Nevirapine-induced fulminant hepatitis,"Nevirapine induced hepatotoxicity is known but fatality is rare. We report a case of a young individual who developed nevirapine (NVP) induced fatal hepatitis without apparent risk factors or preceding rash. Exacerbation of underlying silent chronic liver dysfunction possibly contributed to the fatal outcome. This case stresses the need for careful evaluation, regular monitoring and prompt omission of drug on suspicion of hepatotoxicity.",1
11228,17335680,Epidemiology of acute liver failure,"Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure. Its definition is based on the timing from onset of jaundice to encephalopathy. In 2005, ALF accounted for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the United States. Several classification systems have been developed for ALF, with the King's College criteria most widely used for prediction of OLT. Specific diagnostic tests should be implemented to identify the cause of ALF, which will help to determine its treatment and prognosis. Viral hepatitis was previously reported to be the most common cause of ALF in the United States, but acetaminophen overdose and idiosyncratic drug reactions have emerged as the most frequent causes in recent studies. Malignancy is an uncommon cause of ALF, and thus imaging studies may not be useful in this setting, but liver biopsy may be beneficial in selected cases. An overall strategy for ALF should start with identifying the cause, assessing the prognosis, and early transfer to a transplantation center for suitable candidates. OLT has emerged as a life-saving procedure leading to marked improvement in survival rates. Improved surgical techniques, immunosuppression, and comprehensive care have led to an overall survival rate of approximately 65% with OLT. N-acetylcysteine is effective in ALF caused by acetaminophen overdose, with results strongly related to how soon it is given rather than the route of administration. Liver support systems show potential for the treatment of ALF, but their role needs validation in large multicenter randomized trials.",1
11229,17335720,[Acute hepatitis associated with mefloquine therapy],,1
11230,17335732,[Hepatotoxicity associated with the consumption of herbal slimming products],,1
11231,17339877,Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study,"""Genetic risk factors for ticlopidine-induced hepatotoxicity were determined in 22 Japanese patients with ticlopidine-induced hepatotoxicity and 85 Japanese patients who tolerated ticlopidine therapy without experiencing adverse reactions. There was a significant correlation between ticlopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles: HLA-A*3303, HLA-B*4403, HLA-Cw*1403, HLA-DRB1*1302 and HLA-DQB1*0604 (corrected probability (P)-value (Pc)<0.01). In particular HLA-A*3303 was present in 15 (68%) of the 22 patients with ticlopidine-induced hepatotoxicity and in 12 (14%) of the 85 ticlopidine-tolerant patients (odds ratio, 13.04; 95% confidence interval (CI), 4.40-38.59; the corrected P-value (Pc)=1.24 x 10(-5)). HLA-A*3303 was present in 12 (86%) of the 14 patients with ticlopidine-induced cholestatic hepatotoxicity (odds ratio, 36.50; 95% CI, 7.25-183.82, Pc=7.32 x 10(-7)). Ticlopidine-induced severe cholestatic hepatotoxicity occurred more frequently in subjects with HLA-A*3303 and its haplotype in Japanese patients. These findings may explain the high incidence of ticlopidine-induced hepatotoxicity in Japanese patients mediated via an immune-mediated mechanism.""",1
11232,17347554,Pseudolithiasis due to ceftriaxone treatment for meningitis in children: report of 8 cases,"Cholelithiasis rarely occurs in childhood. Ceftriaxone is a widely used antimicrobial agent in pediatrics due to the broad spectrum. Reversible biliary sludge and/or lithiasis, named as pseudolithiasis, have been reported in patients treated with ceftriaxone. We observed ceftriaxone-associated pseudolithiasis in 8 patients with meningitis. The aim of this study was to report the clinical characteristics of these patients and to evaluate the related factors for the development of ceftriaxone-associated pseudolithiasis in children. The study group consisted of 7 boys and 1 girl. All patients received ceftriaxone 100 mg/kg/day for meningitis. The ultrasonographic evaluation was performed on 5th-10th days after the initiation of the therapy. Biliary sludge was detected in one patient, and gallstone was detected in three patients, while biliary sludge with gallstone was detected in four patients. Six of the cases were diagnosed during summer time. Thus, high temperature may cause loss of fluid, leading to easier formation of sludge. Ceftriaxone treatment was discontinued after sonographic demonstration of pseudolithiasis. Gallbladder sonograms were found to be normal in all patients at the follow-up sonographic examinations performed after 30 days of the diagnosis without specific treatment. Clinicians should screen all pediatric patients living in areas with high temperature and receiving ceftriaxone treatment (over 100 mg/kg) by ultrasonography for biliary sludge or gallstone formation even if they are asymptomatic.",1
11233,17347980,Stevens-Johnson syndrome associated with oral minoxidil: a case report,"Minoxidil is frequently used in patients with advanced renal disease who have been unresponsive to other antihypertensive agents. We describe a case of a 50-year-old man with chronic renal failure who was hospitalized complaining of a 2-week history of sore throat that had progressed to severe oral lesions and multiple pustular blisters on many sites of his body. The patient had been placed on oral minoxidil for uncontrolled hypertension one week prior to the onset of symptoms. The diagnosis of minoxidil-induced Stevens-Johnson syndrome (SJS) was established, minoxidil was discontinued and the patient subsequently improved. Although minoxidil-induced SJS is extremely rare, clinicians should be aware of this potentially severe adverse effect. This report emphasizes the importance of monitoring patients who are taking oral minoxidil for any signs or symptoms associated with SJS.",1
11234,17349881,Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE),"OBJECTIVES: This report describes safety and tolerability data from 746 chronic angina patients treated in the ROLE (Ranolazine Open Label Experience) program. BACKGROUND: Ranolazine treats angina without depressing hemodynamic status. The long-term safety and tolerability of ranolazine have not been previously reported. METHODS: Patients with severe functional impairment from angina (mean Duke Treadmill Score [DTS] of -14.4) who completed 1 of 2 randomized treadmill trials entered the ROLE program. Ranolazine was titrated to optimal dosages between 500 and 1,000 mg twice daily. Physical examination, laboratory tests, and adverse event reporting were performed periodically. We conducted analyses to evaluate possible predictors of ranolazine intolerance, such as advanced age, diabetes, poor exercise tolerance, or history of myocardial infarctions or congestive heart failure (CHF). The ROLE program's mortality was compared against the DTS predictive model and other contemporary cohorts of high-risk CHD patients. RESULTS: Mean follow-up was 2.82 years. Two years after initial dosing, 571 patients (76.7%) remained on therapy and 72 patients (9.7%) discontinued ranolazine due to adverse events. Among 6 factors evaluated, only age > or =64 years predicted for higher withdrawal rates. Patients with a history of CHF had lower withdrawal rates. Mean QTc interval was prolonged by 2.4 ms. No treatment discontinuations occurred due to QTc prolongation, and no Torsades de Pointes was reported. Sixty-four deaths occurred during a total of 2,102 patient-years (3.0% annually) during the ROLE program. When extending observations to all patients exposed to ranolazine during the double-blind trials (n = 972) preceding the ROLE program, annual mortality was 2.8% compared with >5% as predicted by DTS. CONCLUSIONS: Long-term therapy with ranolazine seems well tolerated in high-risk CHD patients. Survival analyses suggest that symptomatic improvements attributable to ranolazine are not offset by increased mortality.",1
11235,17351559,Vorinostat (Zolinza) for cutaneous T-Cell lymphoma,,1
11236,17352036,Acute pancreatitis and amiodarone: a case report,"Amiodarone, a class III antiarrhythmic drug, is one of the most effective drugs used in the treatment of ventricular and paroxysmal supraventricular tachyarrhythmia. Adverse effects of amiodarone including pulmonary toxicity, hepatotoxicity, aggravation of arrhythmia, and thyroid diseases are well understood. A 66-year old woman with acute pancreatitis was admitted to our hospital with the complaint of epigastralgia radiating to both flanks for two months. Her symptoms and elevation of pancreatic enzymes did not respond to conventional medical treatment of pancreatitis for 18 d. No known causal factors for pancreatitis such as biliary tract stone, hypertriglyceridemia and alcohol consumption could be identified. Under the suspicion of amiodarone-induced acute pancreatitis, amiodarone was substituted by propafenone. Her symptoms soon alleviated and serum lipase level declined. Three months after hospital discharge, the abdominal pain did not recur. Amiodarone was approved to treat recurrent ventricular fibrillation or sustained ventricular tachyarrhythmia that has been resistant to other medications since 1986. Pancreatitis is a very rare adverse effect associated with the use of amiodarone, and only four cases of amiodarone-induced pancreatitis have been reported in literature. We report a patient who developed acute pancreatitis during amiodarone therapy.",1
11237,17355464,Black pigments in the liver related to gold and titanium deposits. A report of four cases,Black pigments are rarely described in the liver. We report four patients with chronic cholestasis and black pigments described on liver histological examination. Energy-dispersive X-ray analysis identified these black pigments as gold particles in the first three patients and titanium particles in the fourth. The origin of the gold deposits was unknown in this first patient and related to gold salts therapy in the two others. Titanium deposits was associated with hepatic granulomas and related to total knee replacement.,1
11238,17357382,Atomoxetine-induced hepatitis in a child,"""OBJECTIVE: To report a case of hepatitis associated with atomoxetine hydrochloride use and to describe the previously-unpublished severe cases of this syndrome. CASE SUMMARY: An eight-year-old female with attention deficient hyperactive disorder (ADHD) was treated with atomoxetine hydrochloride. She complained of increased abdominal pain and occasional emesis; her transaminases and bilirubin were markedly elevated. She was admitted to a tertiary-care pediatric hospital and treated for drug-induced hepatitis. Atomoxetine was discontinued and supportive care was instituted. A liver biopsy showed hepatitis with moderate piecemeal necrosis. Clinical status and liver function tests improved over 13 days of hospitalization. DISCUSSION: To our knowledge this is the first published severe case of atomoxetine-induced hepatitis. The International Organization of Medical Science Diagnostic Scale and the Adverse Drug Reaction Probability Scale by Naranjo et al. were applied to assess causality. Both scales indicated the association of atomoxetine and hepatitis as """"probable;"""" a positive rechallenge would have made this association """"definitive."""" This potential serious adverse reaction should be considered in children receiving atomoxetine therapy.""",1
11239,17364993,Imatinib-induced immune hepatitis: case report and literature review,"Imatinib is one of the most recent medications used for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). It is an orally administered protein-tyrosine kinase inhibitor, an enzyme which is produced by BCR-ABL fusion which results from translocation of 9:22 chromosome (Philadelphia chromosome). Imatinib blocks proliferation and induces apoptosis of BCR-ABL-expression in CML. Many side effects produced by imatinib have been documented but its induction of hepatotoxcity has been rarely reported. Only a few cases so far have been reported in the literature and almost all were in females. We describe another case of hepatotoxicity due to imatinib in a 17-year old female with clinical, laboratory and histopathological changes. The case described here suggests that imatinib may also induce immune hepatitis, in some patients.",1
11240,17368274,Safety considerations with niacin therapy,"Niacin has beneficial effects on plasma lipoproteins and has demonstrated clinical benefits in reducing cardiovascular events and atherosclerosis progression. The side effects of niacin, however, have limited its use in general clinical practice. An understanding of cutaneous flushing based on the best available evidence should enhance patient education efforts and improve adherence. Although serious hepatic toxicity from niacin administration has been reported, it is largely confined to the use of slow-release formulations given as unregulated nutritional supplements. Niacin has been shown to induce insulin resistance in short-term trials, but the glycemic response in subjects with and without diabetes is usually minor. Niacin can be used safely in patients with diabetes. Despite a few case reports of myopathy associated with niacin-statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) combination therapy, 2 decades of clinical evidence since the introduction of statins do not support a general myopathic effect of niacin either alone or in combination with statins. Rare, less well-defined side effects of niacin include blurred vision due to cystoid macular edema, nausea and vomiting, and the exacerbation of peptic ulcers. Laboratory abnormalities that are usually small (< or =10%) and clinically unimportant include increased prothrombin time, increased uric acid, and decreases in platelet count and serum phosphorus. Overall, the perception of niacin side effects is often greater than the reality. As a result, a valuable medication for cardiovascular risk is underused.",1
11241,17369076,The thalidomide saga,"""Over the past 50 years, thalidomide has been a target of active investigation in both malignant and inflammatory conditions. Although initially developed for its sedative properties, decades of investigation have identified a multitude of biological effects that led to its classification as an immunomodulatory drug (IMiD). In addition to suppression of tumor necrosis factor-alpha (TNF-alpha), thalidomide effects the generation and elaboration of a cascade of pro-inflammatory cytokines that activate cytotoxic T-cells even in the absence of co-stimulatory signals. Furthermore, vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF) secretion and cellular response are suppressed by thalidomide, thus antagonizing neoangiogenesis and altering the bone marrow stromal microenvironment in hematologic malignancies. The thalidomide analogs, lenalidomide (CC-5013; Revlimid) and CC-4047 (Actimid), have enhanced potency as inhibitors of TNF-alpha and other inflammatory cytokines, as well as greater capacity to promote T-cell activation and suppress angiogenesis. Both thalidomide and lenalidomide are effective in the treatment of multiple myeloma and myelodysplastic syndromes for which the Food and Drug Administration granted recent approval. Nonetheless, each of these IMiDs remains the subject of active investigation in solid tumors, hematologic malignancies, and other inflammatory conditions. This review will explore the pharmacokinetic and biologic effects of thalidomide and its progeny compounds.""",1
11242,17372135,Hepatitis B reactivation during glioblastoma treatment with temozolomide: a cautionary note,,1
11243,17375980,The clinical pharmacokinetics of escitalopram,"""Escitalopram is the (S)-enantiomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram. Clinical studies have shown that escitalopram is effective and well tolerated in the treatment of depression and anxiety disorders. Following oral administration, escitalopram is rapidly absorbed and reaches maximum plasma concentrations in approximately 3-4 hours after either single- or multiple-dose administration. The absorption of escitalopram is not affected by food. The elimination half-life of escitalopram is about 27-33 hours and is consistent with once-daily administration. Steady-state concentrations are achieved within 7-10 days of administration. Escitalopram has low protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs. It is widely distributed throughout tissues, with an apparent volume of distribution during the terminal phase after oral administration (V(z)/F) of about 1100L. Unmetabolised escitalopram is the major compound in plasma. S-demethylcitalopram (S-DCT), the principal metabolite, is present at approximately one-third the level of escitalopram; however, S-DCT is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram. The didemethyl metabolite of escitalopram (S-DDCT) is typically present at or below quantifiable concentrations. Escitalopram and S-DCT exhibit linear and dose-proportional pharmacokinetics following single or multiple doses in the 10-30 mg/day dose range. Adolescents, elderly individuals and patients with hepatic impairment do not have clinically relevant differences in pharmacokinetics compared with healthy young adults, implying that adjustment of the dosage is not necessary in these patient groups. Escitalopram is metabolised by the cytochrome P450 (CYP) isoenzymes CYP2C19, CYP2D6 and CYP3A4. However, ritonavir, a potent inhibitor of CYP3A4, does not affect the pharmacokinetics of escitalopram. Coadministration of escitalopram 20mg following steady-state administration of cimetidine or omeprazole led to a 72% and 51% increase, respectively, in escitalopram exposure compared with administration alone. These changes were not considered clinically relevant. In vitro studies have shown that escitalopram has negligible inhibitory effects on CYP isoenzymes and P-glycoprotein, suggesting that escitalopram is unlikely to cause clinically significant drug-drug interactions. The favourable pharmacokinetic profile of escitalopram suggests clinical utility in a broad range of patients.""",1
11244,17378926,A retrospective nationwide case study on the use of a new antifungal agent: patients treated with caspofungin during 2001-2004 in Finland,"""The aim of this study was to evaluate the efficacy and safety of caspofungin in patients treated in Finland during the period 2001-2004. The medical records of 78 adult patients treated with caspofungin in five major hospitals were reviewed retrospectively. Fifty-nine (76%) patients had proven invasive fungal infection, of whom 22 (28%) had aspergillosis and 37 (47%) had candidiasis. Nineteen (24%) patients were treated empirically; only 13 (17%) patients received caspofungin as primary therapy. A favourable response was achieved in 52 (67%) patients. The response rate was 78% in patients with candidiasis, and 50% in patients with aspergillosis. At the end of the study period, 40 (51%) patients remained alive; of the 38 deaths, nine (24%) were caused by fungal infection. The response rates were lower, although not significantly, for patients with high (>20) vs. low (< or =20) Acute Physiology and Chronic Health Evaluation (APACHE II) scores (response rate 50% vs. 68%, p 0.48, respectively), and were also lower in patients with long-term (>20 days) vs. shorter duration (< or =20 days) neutropenia (55% vs. 73%, p 0.32, respectively), and in those with an underlying haematological malignancy vs. patients with other diseases (59% vs. 73%, p 0.2, respectively). In five (6%) patients, caspofungin therapy was discontinued prematurely because of adverse drug reactions (ADRs) (elevated liver enzyme values in three patients, neuropathic pain in one, and skin rash in one). Serious ADRs occurred in two (3%) patients (severe hepatic insufficiency with consequent death, and eosinophilia with elevated alkaline phosphatase levels), and laboratory abnormalities, mostly mild and reversible, in 24 (31%) patients. In this unselected patient population, caspofungin was safe, well-tolerated, and had an efficacy comparable to that in previous reports from prospective trials.""",1
11245,17379045,"Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders","""BACKGROUND: The US Food and Drug Administration (FDA) approved pregabalin in December 2004 for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is the first drug approved in the United States and in Europe for both conditions. In June 2005, pregabalin was approved as an adjunctive treatment in adults with partial-onset seizures. The FDA currently is considering the approval of pregabalin as adjunctive therapy in adults with generalized anxiety disorder (GAD) or social anxiety disorder (SAD). OBJECTIVES: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of pregabalin; review its approved uses in the management of neuropathic pain and refractory partial-onset seizures; and investigate its potential use in patients with GAD or SAD. METHODS: Relevant English-language literature was identified through a search of MEDLINE (1993-June 2006) and International Pharmaceutical Abstracts (2000-June 2006). The search terms included pregabalin, Lyrica, S-(+)-3 isobutyl-gaba, PN, DPN, diabetic peripheral neuropathy, PHN, postherpetic neuralgia, partial seizures, epilepsy, generalized anxiety disorder, and CI-1008. RESULTS: In 4 clinical trials in a total of 1068 patients with diabetic peripheral neuropathy, the patients receiving pregabalin 300 to 600 mg/d had significantly greater improvement in mean pain scores than placebo recipients (P < or = 0.01). Patients with postherpetic neuralgia receiving pregabalin 450 to 600 mg/d had significantly greater improvement in relief of pain and pain-related sleep interference than placebo recipients (P < or = 0.002). Patients with refractory partial-onset seizures who received pregabalin 150 to 600 mg/d (divided into 2 or 3 doses) concomitantly with antiepileptic drugs had significantly fewer seizures than placebo recipients (P < or = 0.001). In the 3 studies that evaluated the efficacy of pregabalin in patients with GAD or SAD, the patients receiving pregabalin 200 to 600 mg/d (divided into 2 or 3 daily doses) had a significantly greater reduction in mean pain scores on the Hamilton Anxiety Scale than placebo recipients (P < or = 0.01). Across all the reviewed clinical trials, the most commonly reported adverse effects (AEs) were those affecting the central nervous system, including somnolence (< or =50%), dizziness (< or =49%), and headache (< or =29%). AEs resulted in withdrawal from the study in < or =32% of patients. CONCLUSIONS: Pregabalin appears to be an effective therapy in patients with diabetic peripheral neuropathy, postherpetic neuralgia, and adults with refractory partial-onset seizures. The available data suggest that pregabalin may be beneficial as an adjunctive therapy in adult patients with GAD or SAD.""",1
11246,17384437,Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial,"""CONTEXT: Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure. OBJECTIVE: To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure. DESIGN, SETTING, AND PARTICIPANTS: The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment. INTERVENTION: Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy. MAIN OUTCOME MEASURES: Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema. RESULTS: During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups. CONCLUSION: Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00071331""",1
11247,17389704,Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease,"""CONTEXT: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat hyperthyroidism caused by Graves' disease (GD), there is still no clear conclusion about the choice of drug or appropriate initial doses. OBJECTIVE: The aim of the study was to compare the MMI 30 mg/d treatment with the PTU 300 mg/d and MMI 15 mg/d treatment in terms of efficacy and adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Patients newly diagnosed with GD were randomly assigned to one of the three treatment regimens in a prospective study at four Japanese hospitals. MAIN OUTCOME MEASURES: Percentages of patients with normal serum free T(4) (FT4) or free T(3) (FT3) and frequency of adverse effects were measured at 4, 8, and 12 wk. RESULTS: MMI 30 mg/d normalized FT4 in more patients than PTU 300 mg/d and MMI 15 mg/d for the whole group (240 patients) at 12 wk (96.5 vs. 78.3%; P = 0.001; and 86.2%, P = 0.023, respectively). When patients were divided into two groups by initial FT4, in the group of the patients with severe hyperthyroidism (FT4, 7 ng/dl or more, 64 patients) MMI 30 mg/d normalized FT4 more effectively than PTU 300 mg/d at 8 and 12 wk and MMI 15 mg/d at 8 wk, respectively (P < 0.05). No remarkable difference between the treatments was observed in patients with initial FT4 less than 7 ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with PTU and significantly lower with MMI 15 mg/d compared with MMI 30 mg/d. CONCLUSIONS: MMI 15 mg/d is suitable for mild and moderate GD, whereas MMI 30 mg/d is advisable for severe cases. PTU is not recommended for initial use.""",1
11248,17391318,Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review,"""The mean prevalence of azathioprine (AZA) or 6-mercaptopurine (MP)-induced liver injury in patients with inflammatory bowel disease was approximately 3%, and the mean annual drug-induced liver disorder rate was only 1.4%. However, this low figure calculated from retrospective studies contrasts with a much higher incidence (>10%) reported by a prospective study. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis). A small percentage of patients present with a slight elevation of liver tests (LTs) that do not have clinical implications and LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of the immunomodulator. However, when abnormalities in LTs are more marked, the dose of AZA/MP may be reduced 50%, with posterior clinical and analytical controls. With this strategy, LTs frequently normalize spontaneously, and the initial AZA/MP dose may be cautiously prescribed again. Thiopurines may induce an unusual severe cholestatic jaundice that may not regress but even progress despite thiopurine withdrawal. Therefore, these drugs should be completely withdrawn, and not only tapered, in those patients presenting clinically significant jaundice. Despite a lack of evidence that monitoring of LTs is necessary in patients receiving AZA/MP, routinely performed laboratory controls including LTs seem recommendable. However, the optimal monitoring schedule remains to be established. As long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction of 6-thioguanine, this drug should not be administered outside a clinical trial setting. (Am J Gastroenterol 2007;102:1518-527).""",1
11249,17395120,Hypertension in pregnancy,"""Hypertensive disorders of pregnancy are the most common medical disorders of pregnancy and are associated with increased maternal and perinatal risks. The pathophysiology, diagnosis, and treatment are herein reviewed for chronic hypertension, preeclampsia, gestational hypertension, and severe hypertension. The benefits and risks of treating mild, moderate, and severe hypertension are discussed. A variety of oral and parenteral therapies are approved for the treatment of hypertension in pregnancy; methyldopa, labetalol, and nifedipine have been used safely in pregnancy, as has hydrochlorothiazide in those already taking this medication before conception. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in pregnancy because of adverse fetal effects, and atenolol should be avoided due to concerns with fetal growth. Severe hypertension >160/110 mmHg may require parenteral therapy, and treatment with intravenous labetalol now supplants the use of hydralazine. Women may remain hypertensive for a period postpartum and require treatment for a short interval. Early or severe preeclampsia warrants workup postpartum for secondary causes. Pregnancy induced hypertension or preeclampsia are emerging as risk factors for future cardiovascular risk.""",1
11250,17400422,Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: a clinical and pharmacologic evaluation,"Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery-portal vein perfusion, HI-HPP). Between December 2001 and December 2004, 30 patients with colorectal cancer liver metastases underwent HI-HPP with 200mg melphalan. Samples of the perfusate were taken for pharmacokinetic analysis. Patients were monitored for response, toxicity and survival. Perfusion was aborted prematurely in 2 patients due to leakage. During melphalan administration in the hepatic inflow cannula a mean flow rate of 121.3 mL/min and mean pressure of 62.5mm Hg were achieved. One patient died within 30 days after HI-HPP. Four patients developed veno-occlusive disease (VOD), while 2 patients showed signs of VOD. Twelve patients showed hepatic response, with a median duration of response of 11.5 months, according to WHO criteria. Although HI-HPP results in high perfusate melphalan concentration levels, it is associated with a relatively high level of hepatotoxicity and a limited response rate. We believe that the low flow and pressure rates found in this study can result in reduced drug penetration of the tumour and thus limited tumour response.",1
11251,17403186,Drug-induced liver injury at an Asian center: a prospective study,"BACKGROUND/AIMS: The aetiology of drug-induced liver injuries (DILI) in Asia is different from that in the West, as anecdotal studies have shown that traditional complementary and alternative medicines (CAM) accounted for a major proportion of offending drugs in DILI in Asia. We aimed to study DILI in Asia prospectively, and to test whether DILI caused by traditional CAM was related to adulterants. METHODS: A collaborative group consisting of a tertiary-hospital hepatology department, a pharmaceutical laboratory, and a pharmacovigilance unit was formed to study patients with DILI at a tertiary hospital over a 26-month period prospectively. Traditional medicines that were implicated were tested for the presence of adulterants. RESULTS: Thirty-one patients with DILI were enrolled: age 51+/-3 (18-79) years, 17 (55%) male. Twenty-three (74%) had hepatocellular, six (19%) had cholestatic, and two (7%) had a mixed pattern of injury. Chinese traditional CAM was the most common medication type implicated, accounting for 17 (55%) patients, followed by Malay CAM in five (16%). Thirty-one traditional medicines from 17 patients were available for chemical analysis. Adulterants were found in nine (29%) of them. CONCLUSIONS: DILI in Asia has a different aetiology as compared with the West, and could be related to presence of adulterants in traditional CAM.",1
11252,17404860,Development of hepatocellular carcinoma in a patient with Crohn's disease treated with azathioprine,,1
11253,17407625,Comparison of bisacodyl and sodium picosulphate in the treatment of chronic constipation,"""BACKGROUND: Chronic constipation is a widespread condition. Although laxatives are generally accepted as being effective treatments, few studies have made formal comparisons of their efficacy and safety in chronic use. OBJECTIVE: To compare the safety and efficacy of bisacodyl and sodium picosulphate in the treatment of chronic constipation over a 4-week period. METHODS: Patients with chronic constipation (N = 144), recruited from out-patient clinics, were analysed for safety and efficacy in this open-label, randomised, parallel-group study. Patients were treated daily for 4 weeks (bisacodyl, 5-10 mg daily: 70 patients; sodium picosulphate, 5-10 mg daily: 74 patients). Primary efficacy criteria consisted of the number of bowel movements and stool consistency. Secondary efficacy criteria were straining at stool and physicians' global efficacy assessment. Safety assessments included adverse event monitoring, tolerability and changes in laboratory parameters. RESULTS: Both treatments were equally effective in treating chronic constipation, providing sustained improvement in symptoms. Compared to baseline, there were significant (p < 0.001) improvements in stool frequency and consistency and in the occurrence of straining at 14 and 28 days for both treatment groups. Based on the physicians' global assessment, a significant improvement was observed in 74.6% (bisacodyl) and 79.2% (sodium picosulphate) of patients. Neither treatment had significant effects on serum electrolytes. There was a trend for better tolerability in patients receiving bisacodyl treatment based on the number of drug-related adverse events (bisacodyl: 7; sodium picosulphate: 14, two patients withdrawn). CONCLUSIONS: Bisacodyl and sodium picosulphate are equally well tolerated and effective in the treatment of chronic constipation over a 4-week period.""",1
11254,17416261,Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials,"""BACKGROUND: The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). METHODS: After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097). FINDINGS: At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. INTERPRETATION: Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.""",1
11255,17420403,"Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures","OBJECTIVE: To evaluate the efficacy and safety of retigabine 600, 900, and 1,200 mg/day administered three times daily as adjunctive therapy in patients with partial-onset seizures. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was performed. After an 8-week baseline phase, patients were randomized to a 16-week double-blind treatment period (8-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. Primary efficacy was the percentage change from baseline in monthly seizure frequency and compared across treatment arms. Secondary efficacy comparisons included the proportion of patients experiencing >/=50% reduction in seizure frequency (responder rate), emergence of new seizure types, and physician assessment of global clinical improvement. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population. RESULTS: Of the 399 randomized patients, 279 (69.9%) completed the double-blind treatment period. The median percent change in monthly total partial seizure frequency from baseline was -23% for 600 mg/day, -29% for 900 mg/day, and -35% for 1,200 mg/day vs -13% for placebo (p < 0.001 for overall difference across all treatment arms). Responder rates for retigabine were 23% for 600 mg/day, 32% for 900 mg/day (p = 0.021), and 33% for 1,200 mg/day (p = 0.016), vs 16% for placebo. The most common treatment-emergent AEs were somnolence, dizziness, confusion, speech disorder, vertigo, tremor, amnesia, abnormal thinking, abnormal gait, paresthesia, and diplopia. CONCLUSION: Adjunctive therapy with retigabine is well tolerated and reduces the frequency of partial-onset seizures in a dose-dependent manner.",1
11256,17426078,Terbinafine-induced acute autoimmune hepatitis in the setting of hepatitis B virus infection,"""OBJECTIVE: To report a case of terbinafine-induced autoimmune hepatitis in a patient with chronic hepatitis B infection. CASE SUMMARY: A 57-year-old Taiwanese male with chronic hepatitis B virus (HBV) began an oral regimen of terbinafine 250 mg once daily for dermatophyte toenail onychomycosis, despite the manufacturer's recommendation not to use the drug in patients with liver dysfunction. The patient's liver enzyme levels were within normal limits at initiation of therapy. Immediately prior to concluding the 12 week treatment course, he became anorexic with malaise and subsequently developed ascites and jaundice. After a visit to an outside emergency department and positively trending liver function test levels, he was referred to our liver clinic. The patient was taking no other medications or herbal supplements, did not drink alcohol, and did not appear to suffer a flare of HBV infection. The diagnosis was supported by the presence of transient autoantibodies and a liver biopsy consistent with acute autoimmune drug injury. Three weeks after terbinafine was discontinued, peak levels of aspartate aminotransferase (1282 IU/L), alanine aminotransferase (1044 IU/L), and bilirubin (5.9 mg/dL) were noted; his platelet level had decreased to 77 x 10(3)/mm3. He was treated with supportive care that included vitamin K for coagulopathy, diuretics for ascites, and adefovir to prevent hepatitis B exacerbation. The patient's liver function studies began to normalize 6 weeks after terbinafine was discontinued. DISCUSSION: Terbinafine-induced hepatobiliary dysfunction, due to hepatocellular injury, cholestasis, or mixed form, has been reported, but this is the first case of autoimmune hepatitis supported by serologic, biochemical, and biopsy results. Use of the Naranjo probability scale revealed a probable relationship between the patient's hepatitis and terbinafine. Furthermore, the Roussel Uclaf Causality Assessment Method, a scoring system that specifically assesses the likelihood of drug-induced elevated levels of liver-associated enzymes, also supported a probable relationship. The pathogenesis of most drug-induced autoimmune hepatitis remains speculative, likely involving hapten-carrier complex and the cytochrome P450 isoenzymes. In this patient, his chronic HBV carrier state may have predisposed him to this autoimmune reaction. CONCLUSIONS: Healthcare practitioners should heed the manufacturer's warning that terbinafine not be used in patients with underlying hepatic disease.""",1
11257,17434401,Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial,"""BACKGROUND: Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients. METHODS: HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per muL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00105157. FINDINGS: 179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9.9 years (range 0.4-17.3 years) and the mean baseline viral load was 4.7 (SD 0.5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was -1.80 (95% CI -2.10 to -1.50) log10 copies per mL in the 200 mg group, -1.87 (-2.16 to -1.58) log10 copies per mL in the 400 mg group, -1.84 (-2.10 to -1.58) log10 copies per mL in the 600 mg group, and -0.35 (-0.61 to -0.09) log(10) copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities. INTERPRETATION: In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.""",1
11258,17438216,Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study,"""BACKGROUND: In patients experiencing motor fluctuations, a major treatment challenge is the reduction of """"off"""" time, particularly upon awakening. Rotigotine (Neupro) is a novel dopaminergic agonist with 24-hour transdermal delivery. METHODS: A randomized, double-blind, placebo-controlled trial (PREFER Study) was performed to assess efficacy and safety with two targeted transdermal doses of rotigotine in subjects with advanced Parkinson disease with > or =2.5 hours of daily """"off"""" time. Subjects were randomized to receive placebo patches (n = 120) or rotigotine up to either 8 mg/24 hours (n = 120) or 12 mg/24 hours (n = 111). The primary efficacy measures compared changes from baseline to the end of week 24 in the number of daily hours """"off"""" and responder rates for subjects achieving > or =30% reduction in """"off"""" time. RESULTS: Compared to placebo, there were significant decreases in mean """"off"""" time of 1.8 hours/day for the rotigotine 8 mg/24 hours group and 1.2 hours/day for the 12 mg/24 hours group. For rotigotine 8 and 12 mg/24 hours groups, > or =30% responder rates were 56.6% and 55.1% compared to the 34.5% placebo response. """"On"""" time without dyskinesia after awakening was more than doubled in both rotigotine treatment groups vs placebo. Drug-related adverse effects included typical dopaminergic side effects, which were generally mild/moderate in intensity. Patch application site reactions including erythema and pruritus were mild to moderate and transient in the majority of instances. CONCLUSIONS: Transdermal rotigotine significantly improved """"off"""" time in subjects with Parkinson disease not optimally controlled with levodopa and was safe and well tolerated, with typical dopaminergic side effects and occasional application site reactions.""",1
11259,17442902,The FDA and the case of Ketek,,1
11260,17445935,Vaptans: a promising therapy in the management of advanced cirrhosis,"""BACKGROUND/AIMS: Hyponatremia (serum sodium concentration, <135 mmol/L) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis--excretion of electrolyte-free water--might be of benefit in hyponatremia. METHODS: In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. RESULTS: Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. CONCLUSIONS: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. [Abstract reproduced by permission of N Engl J Med 2006;355:2099-2112].""",1
11261,17450113,Panitumumab (Vectibix) for metastatic colorectal cancer,,1
11262,17451560,Review article: drug hepatotoxicity,"BACKGROUND: Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. AIMS: (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre-existing liver disease and in the post-liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. METHODS: A Medline search was performed to identify relevant literature using search terms including 'drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics'. RESULTS: Amoxicillin-clavulanic acid is one of the most frequently implicated causes of drug-induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co-infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. CONCLUSIONS: Drug-induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.",1
11263,17452935,ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: one-year safety and efficacy evaluation,"""OBJECTIVE: To demonstrate that drotrecogin alfa (activated) has an acceptable safety profile 1 yr from randomization. DESIGN: One-year follow-up of patients participating in a placebo-controlled clinical study of drotrecogin alfa (activated) in severe sepsis patients at low risk of death (the ADDRESS study). SETTING: The study was conducted at 516 hospitals in 34 countries. PATIENTS: The study included 2,640 patients. INTERVENTIONS: One-year follow-up was performed as an addendum to the placebo-controlled ADDRESS study. Treatment groups were compared using the chi-square test and Kaplan-Meier estimates. MEASUREMENTS AND MAIN RESULTS: Survival status at 1 yr was obtained for 90% of patients enrolled in the study (n = 2,376). The difference in mortality rate between drotrecogin alfa (activated) and placebo patients was numerically smaller at 1 yr (34.2% and 34.0%, respectively, p = .94) than at 28 days (18.5% and 17.0%, respectively, p = .34). In the subgroups defined by organ dysfunction class (single or multiple) and Acute Physiology and Chronic Health Evaluation II score (<25 or >or=25), the differences in mortality rate between treatment groups at 1 yr were consistent with those observed at 28 days; no significant differences in mortality rates between treatment groups were observed. No additional serious adverse events were reported during the period between hospital discharge and 1 yr. CONCLUSIONS: No increased risk of death or evidence of harm at 1 yr was associated with drotrecogin alfa (activated) administration in patients with severe sepsis at lower risk of death.""",1
11264,17455203,Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients,"""BACKGROUND: The aim of the study was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA)/mercaptopurine (MP)-induced liver injury in a long-term follow-up study. METHODS: All consecutive IBD patients followed for at least 5 years were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin were periodically monitored. """"Abnormality-of-LTs"""" was defined as LTs between N (upper limit of the normal range) and 2 N, and """"liver injury/hepatotoxicity"""" as LTs>2 N. RESULTS: A total of 786 patients were included, and 138 received AZA/MP; 120 patients (15%) and 39 (5%) presented abnormality of LTs or hepatotoxicity, respectively, during follow-up. The most frequent explanations were AZA/MP treatment and fatty liver disease. Among AZA/MP-treated patients (690 patient-years follow-up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% and 2.6% per patient-year. Most patients spontaneously normalized LTs despite maintaining AZA/MP. These drugs were withdrawn due to hepatotoxicity (LTs>5 N and lack of decrease despite 50% dose reduction) in 3.6% of the patients and all of them normalized LTs. CONCLUSIONS: In IBD patients, AZA or MP treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only approximately 4% of the patients.""",1
11265,17456819,Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial,"""CONTEXT: Ranolazine is a novel antianginal agent that reduces ischemia in patients with chronic angina but has not been studied in patients with acute coronary syndromes (ACS). OBJECTIVE: To determine the efficacy and safety of ranolazine during long-term treatment of patients with non-ST-elevation ACS. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled, multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, n = 3279) or matching placebo (n = 3281), and followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial between October 8, 2004, and February 14, 2007. MAIN OUTCOME MEASURES: The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end of study. The major safety end points were death from any cause and symptomatic documented arrhythmia. RESULTS: The primary end point occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P = .11). The major secondary end point (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86-1.08; P = .50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P = .87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P = .03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P = .84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80-1.22; P = .91). CONCLUSIONS: The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00099788.""",1
11266,17459290,Psoriasis and hepatitis C treated with anti-TNF alpha therapy (etanercept),"The treatment of severe psoriasis in patients with concomitant hepatitis-C virus infection is quite difficult because several systemic anti-psoriatic drugs are contraindicated owing to their liver toxicity. Recent observations in the literature suggest that etanercept is an effective and safe therapy for this setting of patients. We present a 45-year-old man with extensive plaque psoriasis and concurrent hepatitis C, successfully treated with 12-month etanercept monotherapy. Regular controls of hepatic enzymes and viral load during the treatment disclosed no worsening of baseline values. This case confirms that etanercept may be a safe option for the therapy of patients with psoriasis and hepatitis-C virus infection.",1
11267,17462781,Oral contraception and the risk of hepatocellular carcinoma,"""BACKGROUNDS/AIMS: We performed a meta-analysis of observational epidemiological studies to examine the association between oral contraceptives (OC) and hepatocellular carcinoma (HCC). METHODS: Two independent researchers conducted PubMed searches followed by systematic abstraction of studies that compared OC use between patients with HCC and a group of controls. Pooling of ORs was conducted using a random effects model. Heterogeneity and publication bias among studies were examined. RESULTS: Twelve case-control studies that included 739 cases and 5223 controls met the inclusion and exclusion criteria. The pooled estimate of ORs (age- and sex-matched only) from all 12 studies was 1.57 (95% CI=0.96-2.54, p=0.07) with a heterogeneity of I(2)=39.9. Exclusion of one large multi-national European study decreased the heterogeneity to I(2)=16.9 and increased the pooled OR to 1.70 (95% CI=1.12-2.59, p=0.01). Eight studies reported adjusted ORs (in addition to age and sex); the pooled estimate was 1.45 (95% CI=0.93-2.27, p=0.11) with a heterogeneity of I(2)=20.4. Only few studies identified or adjusted for other HCC risk factors. Six studies showed a significant 2- to 20-fold increase in HCC risk with longer durations of OC use; however, the reporting was too inconsistent to allow meta-analysis. CONCLUSIONS: The evidence is inconclusive to establish a relation between oral contraceptives and the risk of hepatocellular carcinoma. Future studies should focus on the duration, intermittency, and recency of OC use.""",1
11268,17464162,Is black cohosh a hepatotoxic medicinal herb?,,1
11269,17465867,Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy,"""BACKGROUND: Intravenous methylprednisolone pulses (IVMP) are more efficacious and better tolerated than oral prednisone in Graves' ophthalmopathy (GO) patients. However, acute and severe liver damage has been reported in sporadic cases during IVMP, resulting in fatal acute liver failure in four patients so far. The mechanism causing the liver damage is incompletely understood. DESIGN: We performed a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe GO (group B) who were treated with high-dose (group A) or low-dose (group B) IVMP; cumulative steroid doses were 8.45 g in group A and 4.5 g in group B, and follow-up time was 24 weeks. MAIN OUTCOME: Slight increases in serum aminotransferases (in alanine aminotransferase [ALAT] more than in aspartate aminotransferase [ASAT]) were observed, in seven patients exceeding the upper normal limit of 40 U/L. These changes were more prominent in group A than in group B as was also evident from a decrease in ASAT/ALAT ratio in group A but not in group B. Changes in serum aminotransferases occurred especially in the first 6 weeks of IVMP, becoming smaller thereafter with the decrease in steroid dosage. Pretreatment liver steatosis or diabetes were not related to liver damage, but preexistent viral hepatitis was. CONCLUSION: IVMP in GO patients causes dose-dependent liver damage by a direct toxic effect of glucocorticoids on hepatocytes. Nevertheless, IVMP seems to be pretty safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during pulse therapy.""",1
11270,17470858,Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer,"""PURPOSE: Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy. PATIENTS AND METHODS: We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study. RESULTS: Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions. CONCLUSION: Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.""",1
11271,17472546,Donepezil: an update,"""Donepezil hydrochloride is the most widely prescribed drug for Alzheimer's disease (AD). The main mechanism of action through which it influences cognition and function is presumed to be the inhibition of acetylcholinesterase enzyme in the brain; however, donepezil may also impact the pathophysiology of AD at several other points. Officially approved for mild-to-moderate and severe AD, donepezil has also been shown to be effective in early-stage AD, vascular dementia, Parkinson's disease dementia/Lewy body disease and cognitive symptoms associated with multiple sclerosis. In addition, one study suggested that donepezil may delay the onset of AD in subjects with mild cognitive impairment, a prodrome to AD. The pharmacokinetics, pharmacodynamics, safety/tolerability profile and drug interaction properties of donepezil make it an easy and safe agent to use. However, in general, the efficacy of donepezil is limited, and ongoing studies are investigating other agents that may ultimately overtake its present position as the mainstay of anti-AD therapy.""",1
11272,17473493,Selective estrogen receptor modulator raloxifene-associated aggravation of nonalcoholic steatohepatitis,"A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, was diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BMI) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene.",1
11273,17481633,"Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EP-EMA) regimen","OBJECTIVE: To evaluate the effectiveness of the etoposide and cisplatin/etoposide, methotrexate and actinomycin D (EP-EMA) regimen in patients with gestational trophoblastic neoplasia who had been successfully treated with the etoposide, methotrexate, and actinomycin D/cyclophosphamide and vincristine (EMA-CO) regimen but experienced a relapse, or who became refractory to EMA-CO treatment. METHODS: From January 1999 to December 2005, 18 patients with gestational trophoblastic neoplasia who had been successfully treated with the EMA-CO regimen but sustained a relapse (n=7) or who became refractory to it (n=11) were treated with the EP-EMA regimen. The effectiveness, adverse effects, and tolerated dose intensity of the EP-EMA regimen were retrospectively analyzed. RESULTS: The 18 patients received a total of 74 cycles of the EP-EMA regimen and 12 (66.7%) achieved complete remission. Nine of the 11 patients (81.8%) apparently resistant to the EMA-CO regimen achieved complete remission. However, only 3 of the 7 patients (42.9%) who experienced a relapse after treatment with the EMA-CO regimen achieved complete remission. The main adverse effects of the EP-EMA regimen were myelosuppression and gastrointestinal problems. Because of myelosuppression and hepatotoxicity, only 56.8% of the patients could be treated with the planned dose intensity. CONCLUSION: EP-EMA may be an effective option for the treatment of gestational trophoblastic neoplasia in patients resistant to treatment with the EMA-CO regimen. However, it does not seem to benefit all the patients who experienced a relapse after treatment with the EMA-CO regimen.",1
11274,17483788,[Acute cholestatic hepatitis due to glucosamine forte],,1
11275,17488146,Comparative review of the carbapenems,"""The carbapenems are beta-lactam antimicrobial agents with an exceptionally broad spectrum of activity. Older carbapenems, such as imipenem, were often susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) located in renal tubules and required co-administration with a DHP-1 inhibitor such as cilastatin. Later additions to the class such as meropenem, ertapenem and doripenem demonstrated increased stability to DHP-1 and are administered without a DHP-1 inhibitor. Like all beta-lactam antimicrobial agents, carbapenems act by inhibiting bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs). Carbapenems are stable to most beta-lactamases including AmpC beta-lactamases and extended-spectrum beta-lactamases. Resistance to carbapenems develops when bacteria acquire or develop structural changes within their PBPs, when they acquire metallo-beta-lactamases that are capable of rapidly degrading carbapenems, or when changes in membrane permeability arise as a result of loss of specific outer membrane porins. Carbapenems (imipenem, meropenem, doripenem) possess broad-spectrum in vitro activity, which includes activity against many Gram-positive, Gram-negative and anaerobic bacteria; carbapenems lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Compared with imipenem, meropenem and doripenem, the spectrum of activity of ertapenem is more limited primarily because it lacks activity against Pseudomonas aeruginosa and Enterococcus spp. Imipenem, meropenem and doripenem have in vivo half lives of approximately 1 hour, while ertapenem has a half-life of approximately 4 hours making it suitable for once-daily administration. As with other beta-lactam antimicrobial agents, the most important pharmacodynamic parameter predicting in vivo efficacy is the time that the plasma drug concentration is maintained above the minimum inhibitory concentration (T>MIC). Imipenem/cilastatin and meropenem have been studied in comparative clinical trials establishing their efficacy in the treatment of a variety of infections including complicated intra-abdominal infections, skin and skin structure infections, community-acquired pneumonia, nosocomial pneumonia, complicated urinary tract infections, meningitis (meropenem only) and febrile neutropenia. The current role for imipenem/cilastatin and meropenem in therapy remains for use in moderate to severe nosocomial and polymicrobial infections. The unique antimicrobial spectrum and pharmacokinetic properties of ertapenem make it more suited to treatment of community-acquired infections and outpatient intravenous antimicrobial therapy than for the treatment of nosocomial infections. Doripenem is a promising new carbapenem with similar properties to those of meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than meropenem. Clinical trials are required to establish the efficacy and safety of doripenem in moderate to severe infections, including nosocomial infections.""",1
11276,17489062,Herb-induced hepatitis by Teucrium polium L.: report of two cases and review of the literature,"Herbal medicinal products are being increasingly used throughout the world. Herbal 'remedies' are, however, not risk free and many cases of hepatotoxicity have been reported. Teucrium polium grows mostly in the Mediterranean basin and is popular, because of hypoglycemic and hypolipidemic properties. We report two cases of T. polium-induced hepatitis in Greek female patients, who used the plant's extract to control the cholesterol levels. Both patients presented with very high aminotransferases after consuming herbal tea for 2 or 3 months. One patient also developed jaundice. Histologic examination of liver biopsies showed hepatitis with moderate or severe necroinflammatory activity. Discontinuation of the herbal remedy resulted in normalization of the liver enzymes in both patients. Our findings, and those of other authors, suggest that T. polium may not be safer than T. chamaedrys and T. capitatum, which have also been reported to occasionally cause hepatotoxicity.",1
11277,17493431,Thalidomide-induced fulminant hepatic failure,,1
11278,17493839,"Reversible hepatotoxicity, pancreatitis, coagulation disorder and simultaneous bone marrow suppression with valproate in a 2-year-old girl","""Valproic acid (VPA) is considered to be a drug of first choice for the therapy of generalized and focal epilepsies, including special epileptic syndromes like the WEST-syndrome. The drug is usually well tolerated; rare serious complications may occur in some patients, including haemorrhagic pancreatitis, coagulapathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy. We report a case of combined appearance of several severe VPA-associated side effects in a two- and a half-year-old girl with lissencephaly.""",1
11279,17496767,Carnitine as an antidote for acute valproate toxicity in children,"PURPOSE OF REVIEW: Valproic acid is a widely used anticonvulsant that has recently been approved for stabilization of manic episodes in patients with bipolar disorder. As the use of valproic acid increases, the number of both accidental and intentional exposures increases. This is paralleled by more reports of valproic-acid-induced toxicity. The purpose of this article is to review the pathophysiology and toxicology of valproic acid and determine whether the literature supports the use of carnitine as a treatment for acute valproic-acid-induced toxicity. RECENT FINDINGS: Recent literature documents no cases of allergic reactions or serious side effects associated with the administration of carnitine when given patients with acute ingestions of valproic acid. Other findings suggest that carnitine increases the survival rate of patients who develop valproic-acid-induced hepatotoxicity. Early intervention with intravenous rather than enteral L-carnitine was associated with the greatest hepatic survival. Isolated pediatric case reports show that carnitine administration may reverse toxic metabolic pathways but may not hasten clinical improvement. SUMMARY: Based on this recent literature, it seems reasonable to use carnitine for documented severe valproic acid toxicity, particularly in cases where patients present with coma, rising ammonia level, or valproic acid levels greater than 450 mg/l.",1
11280,17503656,Identifying safety concerns from genetic data: lessons from the development of CCR5 inhibitors,,1
11281,17504674,[Hepatic lesions and prolonged use of oral contraceptive],,1
11282,17504894,"Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study","""CONTEXT: In previous 1-yr trials, treatment with pramlintide (120 microg), an analog of the beta-cell hormone amylin, induced sustained reductions in A1C and body weight in insulin-using subjects with type 2 diabetes. OBJECTIVE: To assess the potential of pramlintide as an antiobesity agent, we assessed the weight effect, safety, and tolerability of pramlintide in non-insulin-treated obese subjects with and without type 2 diabetes at doses greater than previously studied. DESIGN/SETTING: We performed a randomized, double-blind, placebo-controlled, multicenter study. PATIENTS: A total of 204 obese subjects [80/20% female/male, age 48 +/- 10 yr, and body mass index 37.8 +/- 5.6 kg/m(2) (mean +/- SD)] participated in the study. INTERVENTION: For 16 wk, without concomitant lifestyle intervention, subjects self-administered pramlintide (nonforced dose escalation < or = 240 microg) or placebo via sc injection three times a day before meals. MAIN OUTCOME MEASURES: Weight, waist circumference, tolerability, and safety were the main outcome measures. RESULTS: Pramlintide was generally well tolerated, with 88% of subjects able to escalate to the maximum dose of 240 microg. Withdrawal rates were similar between placebo (25%) and pramlintide-treated subjects (29%). Subjects completing 16 wk of pramlintide treatment experienced placebo-corrected reductions in body weight of 3.7 +/- 0.5% (3.6 +/- 0.6 kg; P < 0.001) and waist circumference (3.6 +/- 1.1 cm; P < 0.01). Approximately 31% of pramlintide-treated subjects achieved > or =5% weight loss (vs. 2% placebo; P < 0.001). More pramlintide than placebo-treated subjects reported improvements in appetite control (72% vs. 31%), weight control (63% vs. 24%), and overall well-being (52% vs. 17%). No unexpected safety signals were observed. The most common adverse event reported was mild, transient nausea. Pramlintide-treated subjects not reporting nausea experienced weight loss similar to those who did (3.6 +/- 0.5% and 3.9 +/- 0.5%, respectively). CONCLUSION: These results support continued evaluation of pramlintide as a potential treatment for obesity.""",1
11283,17505501,Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis,"One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.",1
11284,17509004,Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese,"A previous study conducted in Taiwan found a 100% association between HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals.",1
11285,17509162,"Efficacy and safety of ixabepilone, a novel epothilone analogue","The epothilones and their analogues are a new class of anticancer agents derived from the fermentation of myxobacterium Sorangium cellulosum. These compounds have some similarities to taxanes in targeting and stabilizing microtubules, but they also have important differences. Among the epothilone family, ixabepilone has emerged to be a semisynthetic epothilone analogue of interest. Ixabepilone has demonstrated consistent preclinical activity and seems active against various taxane-sensible and taxane-resistant cell lines, including those with overexpression of multidrug resistance and with mutations in the beta-tubulin gene. The interest of this ixabepilone has been confirmed clinically. Phase II clinical studies have demonstrated high activity in patients with taxane-resistant metastatic breast cancer and in patients with other chemotherapy-resistant tumor types.",1
11286,17509920,A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease,"An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher disease (D409V/null). Biochemical characterization of Genz-112638 showed good potency (IC(50) approximately 24nM) and specificity against the target enzyme. Mice that received drug prior to significant accumulation of substrate (10 weeks of age) showed reduced levels of glucosylceramide and number of Gaucher cells in the spleen, lung and liver when compared to age-matched control animals. Treatment of older mice that already displayed significant amounts of tissue glucosylceramide (7 months old) resulted in arrest of further accumulation of the substrate and appearance of additional Gaucher cells in affected organs. These data indicate that substrate inhibition therapy with Genz-112638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher disease.",1
11287,17510207,Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors,"PURPOSE: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor. EXPERIMENTAL DESIGN: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/wk) over 1 h starting 30 min after completion of paclitaxel. RESULTS: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion. CONCLUSIONS: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.",1
11288,17516833,[Hepatotoxicity induced by amoxicillin],,1
11289,17517076,Clinical and pathological features of a prolonged type of acute intrahepatic cholestasis,"AIM: We examined the clinical and pathological features of drug-induced acute intrahepatic cholestasis (AIC) to elucidate the pathogenesis of prolonged cases. METHODS: Twenty-six cases of drug-induced AIC were divided into prolonged and non-prolonged groups. Serum bilirubin levels and other biochemical data were compared between the two groups. Biopsy liver specimens were examined by light and electron microscopy. The localization of multidrug resistance protein 2 (MRP2) was immunohistochemically assessed by the Envision technique. RESULTS: The causative drugs of four prolonged cases were found to be tiopronin, chlorpromazine and diclofenac. Two of the patients either died or underwent liver transplantation. The maximal total bilirubin levels (35.2 +/-> 13.8 mg/dL) were significantly higher and a half-life of total bilirubin (78.8 +/-> 69.6 days) was markedly longer in the prolonged cases, in comparison to the non-prolonged cases (16.8 +/-> 8.1 mg/dL, 22.1 +/-> 12.7 days, respectively). The liverbiopsy specimens revealed canalicular cholestasis and a slight degree of lobular inflammation. In the prolonged cases, liver cell injury and cholestasis was marked, and the interlobular bile ducts disappeared in the portal triads. The reaction products of MRP2, recognized on the bile canaliculi in a control liver, were weakened and found in the pericanalicular vesicles in AIC. CONCLUSION: These results indicated disturbances in the canalicular bilirubin transport through MRP2 in the prolonged cases, resulting from severe cholestasis, liver cell injury and vanishing bile ducts. The histological findings of the liver at the acute icteric phase may be important to understand the pathogenesis and to predict the prognosis in AIC.",1
11290,17523700,Aspirin and Reye syndrome: a review of the evidence,"Reye syndrome is an extremely rare but severe and often fatal disease. Death occurs in about 30-40% of cases from brainstem dysfunction. The disease typically is preceded by a viral infection with an intermediate disease-free interval of 3-5 days. The biochemical explanation for Reye-like symptoms is a generalized disturbance in mitochondrial metabolism, eventually resulting in metabolic failure in the liver and other tissues. The etiology of 'classical' Reye syndrome is unknown. Hypothetically, the syndrome may result from an unusual response to the preceding viral infection, which is determined by host genetic factors but can be modified by a variety of exogenous agents. Thus, several infections and diseases might present clinically with Reye-like symptoms. Exogenous agents involve a number of toxins, drugs (including aspirin [acetylsalicylic acid]), and other chemicals. The 'rise and fall' in the incidence of Reye syndrome is still poorly understood and unexplained. With a few exceptions, there were probably no new Reye-like diseases reported during the last 10 years that could not be explained by an inherited disorder of metabolism or a misdiagnosis. This may reflect scientific progress in the better understanding of cellular and molecular dysfunctions as disease-determining factors. Alternatively, the immune response to and the virulence of a virus might have changed by alteration of its genetic code. The suggestion of a defined cause-effect relationship between aspirin intake and Reye syndrome in children is not supported by sufficient facts. Clearly, no drug treatment is without side effects. Thus, a balanced view of whether treatment with a certain drug is justified in terms of the benefit/risk ratio is always necessary. Aspirin is no exception.",1
11291,17524919,Pediatric liver transplantation for acute liver failure,"""The only proven therapy for patients unlikely to recover from acute liver failure (ALF) is liver transplantation. Correct diagnosis of these individuals and rapid referral to a transplant center are crucial. We evaluated 12 pediatric patients with ALF who underwent liver transplantation (LT) at our institution during a 3-year period. The reasons for transplantation were hepatitis A (3 patients); non-A, non-E hepatitis (3); autoimmune hepatitis (1); fulminant Wilson's disease (3); Amanita phalloides (mushroom) poisoning (1); and hepatitis B and toxic hepatitis with leflunomide treatment (1). Seven of the participants were female and five were male (mean age, 9.1 +/- 4.2 years). Three received right liver-lobe grafts, one received a whole liver graft, and the remainder received left or left-lateral liver lobe grafts. All patients recovered from hepatic coma the second postoperative day. Two patients died at postoperative days 57 and 71 due to adult respiratory distress syndrome and sepsis with multiorgan failure, respectively. One patient required retransplantation because of chronic rejection 7 months after the initial transplantation. That patient died 10 days after retransplantation because of sepsis. Nine patients were healthy at follow-up (range, 2-46 months). LT is the only treatment option for ALF in patients in countries with low organ-donation rates. In this scenario, donor preparation in a limited time frame is difficult. We have been able to decrease the duration of donor preparation to approximately 4 hours (including biopsy of the donated liver tissue).""",1
11292,17532683,Nimesulide-induced hepatotoxicity in a previously healthy woman,,1
11293,17536874,Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature,"""Paracetamol (acetaminophen) is the most common drug taken in overdose in the UK, accounting for 48% of poisoning admissions to hospital and being involved in an estimated 100-200 deaths per year. In 1998, the UK government introduced legislation that reduced the maximum pack size of all non-effervescent tablets and capsules containing aspirin (acetylsalicylic acid) or paracetamol that can be sold or supplied from outlets other than registered pharmacies from 25 to 16 tablets or capsules. This article reviews the literature to determine the effectiveness of the legislation, focusing specifically on paracetamol poisoning. Seventeen studies on this subject were identified. Three studies found reductions in mortality rates; one study found an increase in mortality rates, while one found an initial reduction followed by an eventual increase; three found no significant difference in mortality rates before and after introduction of the legislation. Five studies found reductions in admissions to liver units, three of these finding a reduction in liver transplantation rates; two further studies found no change in liver function tests and rates of paracetamol-induced acute liver injury or failure. Four studies found a sustained decrease in hospital admissions, while two found an initial decrease followed by an eventual increase. One study found a decline in admissions for paracetamol poisoning and an increase in admissions for non-paracetamol poisoning. Sales data are conflicting, with two studies finding no significant difference in paracetamol sales before and after the introduction of the legislation and one reporting a decline. The severity of overdose appears to have decreased since the maximum permitted packet size was reduced, with five studies reporting a reduction in the number of severe overdoses (measured by numbers of tablets ingested, serum paracetamol concentrations and usage of antidotes). Only two studies reported an increase in the number of severe overdoses.Paracetamol-associated mortality rates, admissions to liver units/liver transplants, hospital admissions and the severity of paracetamol overdose appear to have been decreasing since 1998. However, one study showed that the reductions in mortality and hospital admissions began in 1997; therefore, the contribution of the 1998 legislation to the observed changes is unclear. Most of the studies are based on short-term follow-up so it is difficult to draw any conclusions regarding long-term trends. Many of the studies were also restricted to relatively small areas of the UK; this, combined with a variety of outcome measures, makes it difficult to distinguish any conclusive trends. The studies also suffer from a lack of comparison and control groups. Some studies do not clearly differentiate between the paracetamol preparations covered by the legislation and those not. The limited number of studies to date, combined with a variety of outcome measures, make it difficult to determine with accuracy whether or not the legislation has been a success. More long-term studies are needed to fully assess the impact of the legislation.""",1
11294,17537866,"Gemifloxacin once daily for 5 days versus 7 days for the treatment of community-acquired pneumonia: a randomized, multicentre, double-blind study","OBJECTIVES: Short-course therapy has been advocated for the treatment of community-acquired pneumonia (CAP). We compared the efficacy and safety of 5 and 7 day courses of gemifloxacin for outpatient treatment of mild-moderate CAP. PATIENTS AND METHODS: In a multicentre, double-blind, parallel group study, patients were randomized to receive 320 mg of oral gemifloxacin once daily for 5 or 7 days. Over 95% of all patients in each cohort had a Fine score of <or=III. The primary efficacy endpoint was clinical cure at follow-up (days 24-30). Secondary outcomes were clinical and bacteriological responses at the end of therapy (days 7-9) and bacteriological and radiological responses at follow-up. Adverse events (AEs) were also monitored. RESULTS: In a total of 469 per protocol (PP) patients, clinical resolution at follow-up was 95% and 92% for 5 and 7 day treatments, respectively [95% confidence interval (CI) -1.48, 7.42], indicating non-inferiority of 5 day treatment. Clinical resolution at the end of therapy was 96% for both regimens (95% CI -3.85, 3.42). Bacteriological response rates in PP patients at the end of therapy were 94% and 96% for 5 and 7 day groups, respectively (95% CI -8.27, 3.25) and 91% for both groups at follow-up (95% CI -6.89, 7.93). Radiological success in PP patients at follow-up was 98% and 93% in 5 and 7 day groups, respectively (95% CI 0.35, 7.91). Pre-therapy pathogens were identified in 242 (47.3%) patients, most commonly Streptococcus pneumoniae. Frequency of treatment-related AEs was 21% in both cohorts with discontinuation rates of 1.2% and 2% in the 5 and 7 day groups, respectively. A lower incidence of rash was observed in the 5 day cohort (0.4%) versus the 7 day cohort (2.8%) (P=0.04). CONCLUSIONS: Gemifloxacin once daily for 5 days is not inferior to 7 days in the PP population with respect to clinical, bacteriological and radiological efficacy. Further work is needed, however, to explore whether fewer treatment days would improve patient compliance and reduce the incidence of AEs.",1
11295,17538086,"Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma","""BACKGROUND: Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. METHODS: In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. RESULTS: Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02). CONCLUSIONS: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).""",1
11296,17538762,Nimesulide-induced hepatotoxicity and fatal hepatic failure,"Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (cox-2) inhibitors are structurally heterogeneous drugs that share similar therapeutic actions and adverse effects. Hepatotoxicity, although a relatively rare adverse effect of this class of drugs, can be severe. This has led to the withdrawal of some NSAIDs from the market. Nimesulide is an NSAID, with cox-2 preference, which has been reported to cause death from hepatic failure. However, most reports have been from European countries. Asian reports include that from Israel and India. We report three patients who presented with acute hepatitis after being prescribed nimesulide, one of whom died from fulminant hepatic failure.",1
11297,17539979,Risk of acute liver injury associated with the use of drugs: a multicentre population survey,"BACKGROUND: Acute liver injury of uncertain aetiology is often drug related and quantitative information about the associated risk is scarce. AIM: To estimate the risk of acute liver injury associated with the use of drugs. METHODS: In a population survey study, 126 cases of acute liver injury were prospectively assembled from January 1993 to December 1999, in patients over 15 years of age, in 12 hospitals in Barcelona (Spain). We estimated the relative risk for each drug as the ratio between the incidence of acute liver injury among the exposed population to the drug and the incidence of acute liver injury among those not exposed to it. Drug consumption data were used to estimate the exposed population. RESULTS: Isoniazid, pyrazinamide, rifampicin, amoxicillin with clavulanic acid, erythromicin, chlorpromazine, nimesulide, and ticlopidine presented the highest risk (point relative risk > 25). Amoxicillin, metoclopramide, captopril and enalapril, furosemide, hydrochlorothiazide, fluoxetine, paroxetine, diazepam, alprazolam, lorazepam, metamizole, low-dose acetylsalicylic acid and salbutamol showed the lowest risk (point relative risk < 5). CONCLUSIONS: This study provides a risk estimation of serious liver disease for various drugs that will be useful in its diagnosis and management, and when comparing with the drug therapeutic benefit in each indication. Some observed associations would be worth specific studies.",1
11298,17542767,Effectiveness and hepatotoxicity of statins in men seropositive for hepatitis C virus,"""STUDY OBJECTIVE: To evaluate the effectiveness and hepatotoxicity of statins in patients who are seropositive for hepatitis C virus (HCV). DESIGN: Retrospective review of a registry of patients with HCV. SETTING: Veterans Affairs Medical Center. PATIENTS: One hundred forty-six male patients who were seropositive for HCV and had received statin therapy between January 1, 1995, and September 9, 2003. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data were collected for each patient; lipid and alanine aminotransferase (ALT) levels at baseline (within 6 mo of starting a statin), at 3 and 6 months after starting a statin, and at long-term follow-up (mean 22 mo) were also recorded. The primary efficacy end point was a significant decrease from baseline to long-term follow-up low-density lipoprotein cholesterol (LDL) level; the primary safety end point was a significant increase from baseline in ALT level. The mean change in LDL level was a reduction of 22% (p<0.01). No significant increases in ALT levels were observed; only one patient discontinued therapy due to ALT level elevations greater than 3 times the upper limit of normal. CONCLUSION: In men seropositive for HCV, statins were effective in reducing LDL levels and did not result in significant increases in ALT levels from baseline. Thus, statin therapy should be considered for patients with HCV who are at risk for coronary heart disease and do not have significantly elevated serum transaminase levels at baseline.""",1
11299,17545749,Transient decrease in serum albumin concentrations in epileptic children treated with sodium valproate monotherapy,"""OBJECTIVE: Hypoalbuminemia has been reported in patients with severe disability and epilepsy and in patients with epilepsy treated with short-term sodium valproate (VPA) therapy; however, serum albumin concentrations have not previously been determined in otherwise healthy patients with epilepsy and receiving long-term VPA monotherapy. METHODS: Serum albumin concentrations were determined in 26 ambulatory children with epilepsy before and at 6, 12, and 24 months of VPA monotherapy. Serum total protein concentrations and serum concentrations of other biochemical markers of liver and renal function such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and creatinine concentration were also measured in the study participants before and at 6, 12, and 24 months of treatment. RESULTS: Serum albumin concentrations were reduced at 6 months of treatment (P = 0.007). Serum alanine aminotransferase concentrations were significantly increased at 6 (P = 0.034) and 12 months of treatment (P = 0.046), whereas serum aspartate aminotransferase concentrations were significantly increased at 6 (P = 0.002) and 12 months of treatment (P = 0.002). There were no significant correlations between serum albumin and the other parameters at 6 months of treatment. CONCLUSIONS: Ambulatory children who receive VPA monotherapy may have early but transient decrease in serum albumin concentrations. Further studies are needed to address this issue and to determine the possible clinical implications and the mechanisms involved in VPA-mediated decrease in serum albumin concentrations.""",1
11300,17550572,"DRESS syndrome caused by teicoplanin and vancomycin, associated with reactivation of human herpesvirus-6",,1
11301,17552060,Effective etanercept treatment for psoriatic arthritis complicating concomitant human immunodeficiency virus and hepatitis C virus infection,High levels of tumor necrosis factor-alpha (TNF-alpha) are associated with hepatitis C virus (HCV) infection and all stages of human immunodeficiency virus (HIV) infection. TNF-alpha may have a role in both the pathogenesis and the response to treatment of these chronic viral diseases. We describe a 42-year-old HIV/HCV coinfected hemophiliac man who developed psoriasis and severe psoriatic arthritis not responding to combination treatment with methotrexate and cyclosporin A. Treatment with etanercept 25 mg twice weekly was followed by remission of the joint inflammation and improvement of the exanthem. This is the first report of anti-TNF-alpha treatment for rheumatic complications in a patient with both HIV and HCV infection.,1
11302,17554118,Adjuvant mitotane treatment for adrenocortical carcinoma,"""BACKGROUND: Adrenocortical carcinoma is a rare neoplasm characterized by a high risk of recurrence after radical resection. Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial. Our aim was to evaluate the efficacy of adjuvant mitotane in prolonging recurrence-free survival. METHODS: We performed a retrospective analysis involving 177 patients with adrenocortical cancer who had undergone radical surgery at 8 centers in Italy and 47 centers in Germany between 1985 and 2005. Adjuvant mitotane was administered to 47 Italian patients after radical surgery (mitotane group), whereas 55 Italian patients and 75 German patients (control groups 1 and 2, respectively) did not receive adjuvant treatment after surgery. RESULTS: Baseline features in the mitotane group and the control group from Italy were similar; the German patients were significantly older (P=0.03) and had more stage I or II adrenocortical carcinomas (P=0.02) than did patients in the mitotane group. Recurrence-free survival was significantly prolonged in the mitotane group, as compared with the two control groups (median recurrence-free survival, 42 months, as compared with 10 months in control group 1 and 25 months in control group 2). Hazard ratios for recurrence were 2.91 (95% confidence interval [CI], 1.77 to 4.78; P<0.001) and 1.97 (95% CI, 1.21 to 3.20; P=0.005), respectively. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival. Adverse events associated with mitotane were mainly of grade 1 or 2, but temporary dose reduction was needed in 13% of patients. CONCLUSIONS: Adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma.""",1
11303,17559736,The safety profile of moxifloxacin and other fluoroquinolones in special patient populations,"""BACKGROUND: Fluoroquinolones, including ciprofloxacin, levofloxacin, gemifloxacin, and moxifloxacin, represent a major advance in the development of antimicrobial agents. They offer significant activity against Gram-negative pathogens, while more advanced generation fluoroquinolones including levofloxacin, gemifloxacin, and moxifloxacin are significantly active against Gram-positive (e.g., Streptococcus pneumoniae for some members of the class), typical, atypical, and anaerobic pathogens. Fluoroquinolones have a pharmacokinetic/pharmacodynamic profile that exhibits concentration-dependent killing and good oral absorption, allowing for once-daily dosing. OBJECTIVE: Review of data from fluoroquinolone studies, with an emphasis on the associated rare, but potentially clinically important, adverse events in specific patient populations. Review of clinical efficacy is included where relevant to the topic under discussion. METHODS: A literature search was conducted using terms including fluoroquinolones, moxifloxacin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, safety, adverse events, drug interactions, and pharmacokinetic parameters to identify literature providing information regarding the safety profile of specified fluoroquinolones in special patient populations (i.e., the elderly, patients with liver disease, kidney disease, glycemic disorder, those at risk for cardiovascular events). Although specific date criteria were not applied to the search, preference was given to more recent publications. Online databases searched include MEDLINE and EMBASE and relevant textbooks were utilized as well. FINDINGS: Fluoroquinolones, when used either as monotherapy or as combination therapy depending on their individual indications, attain adequate concentrations for treating infections in different target sites, including epithelial lining fluid, alveolar macrophages, skin, and gastrointestinal tissues. Overall, fluoroquinolones have predictable and mild-to-moderate adverse-event profiles and are generally well tolerated. Findings of this review are limited by the availability of publications and case reports. CONCLUSIONS: Fluoroquinolones, are associated with rare, but clinically important, adverse events in special patient populations (including the elderly; those with hepatic, renal, or glycemic disorders; and those at risk for cardiovascular events). Recognition of differences in the clinical efficacy and safety profiles of fluoroquinolones in special patient populations should lead to better antimicrobial agent selection.""",1
11304,17561634,Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence,"PURPOSE: To evaluate the level of evidence regarding the safety and efficacy of nonprescription therapies used for insomnia. REVIEWERS: Members of the American Academy of Sleep Medicine's Clinical Practice Review Committee. METHODS: A search of the World Wide Web was conducted using the terms insomnia, herbal remedies, and alternative treatments to develop a list of therapies. Therapies in this review include passionflower, valerian, Jamaican dogwood, hops, California poppy, chamomile, lemon balm, St. John's wort, kava kava, wild lettuce, scullcap, Patrinia root, first-generation histamine-1-receptor antagonists, alcohol, calcium, vitamin A, nicotinamide, magnesium, vitamin B12, I-tryptophan, 5-hydroxytryptophan, dietary changes, Natrum muriaticum, and Yoku-kan-san-ka-chimpi-hange. A search of the PubMed database was conducted in October 2002 using MeSH terms insomnia and each product listed in this paper, including only articles published in English between 1980 and 2002. Additional relevant articles from reference lists were also reviewed. Given the paucity of pediatric publications, this age group was excluded from this review. RESULTS AND CONCLUSIONS: Although randomized, placebo-controlled studies were available for a few compounds, rigorous scientific data supporting a beneficial effect were not found for the majority of herbal supplements, dietary changes, and other nutritional supplements popularly used for treating insomnia symptoms. Nevertheless, such treatments are described as alternative remedies for insomnia. Studies are limited by small numbers of participants and, in some instances, inadequate design, lack of statistical analysis, and sparse use of objective measurements. Sparse or no scientific data were found to support the efficacy of most products as hypnotics, including chamomile and St. John's wort. There is preliminary but conflicting evidence suggesting Valerian officinalis L. and first-generation histamine-1-receptor antagonists have efficacy as mild hypnotics over short-term use. There are significant potential risks associated with the use of Jamaican dogwood, kava kava, alcohol, and I-tryptophan. Physicians may find this information useful in counseling their patients.",1
11305,17563866,[Lethal course after chemotherapy with docetaxel. Acute liver failure with accompanying erythema multiforme major],"We report on the lethal course of a patient receiving low-dose, weekly docetaxel who developed acute liver failure accompanied by a Stevens-Johnson syndrome. After receiving the fifth application of his chemotherapy, the patient was admitted to hospital because of neutropenia and severe erythema. The course worsened towards an acute liver failure and an erythema multiforme major. Despite an interdisciplinary approach, the further course could not be influenced and the patient died 6 weeks after admission due the toxicity of docetaxel. This case report underlines the spectrum of toxicity of docetaxel even in the low-dose weekly schedule.",1
11306,17564408,"A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy","STUDY OBJECTIVE: Assess the efficacy of sodium oxybate for the treatment of narcolepsy with an emphasis on excessive daytime sleepiness. DESIGN: Eight-week, multicenter, double-blind, placebo-controlled trial. SETTING: Forty-two sleep clinics in the United States, Canada, and Europe. PARTICIPANTS: Two hundred twenty-eight adults with narcolepsy with cataplexy. INTERVENTIONS: Patients were withdrawn from antidepressant treatment and then randomly assigned to receive 4.5 g, 6 g, or 9 g of sodium oxybate nightly or placebo for 8 weeks. Six-gram and 9-g doses were titrated in weekly 1.5-g increments. Patients who were receiving placebo underwent a mock dose-titration schedule. Stimulant use continued unchanged. Excessive daytime sleepiness was measured using the Epworth Sleepiness Scale and Maintenance of Wakefulness Test. The Clinical Global Impression of Change was used to measure changes in disease severity. Changes in narcolepsy symptoms and adverse events were recorded in daily diaries. RESULTS: After 8 weeks, patients treated with 9 g of sodium oxybate nightly displayed a significant median increase of > 10 minutes in the Maintenance of Wakefulness Test (p < .001). Patients displayed dose-related decreases in median Epworth Sleepiness Scale scores and frequency of weekly inadvertent naps, which were significant at the 6-g and 9-g doses (for each, p < .001). The improvements in excessive daytime sleepiness were incremental to those achieved by concomitant stimulants alone. Significant improvements in the Clinical Global Impression of Change were noted for each group treated with sodium oxybate (p < or = .001). Adverse events were consistent with the known safety profile of sodium oxybate. CONCLUSIONS: When combined with its previously demonstrated anticataplectic effects, the results of the current study indicate sodium oxybate is the first drug to demonstrate efficacy for the 2 major symptoms of narcolepsy.",1
11307,17567345,Propofol infusion syndrome,"The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l(-1)), rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver. There is an association between PRIS and propofol infusions at doses higher than 4 mg.kg(-1).h(-1) for greater than 48 h duration. Sixty-one patients with PRIS have been recorded in the literature, with deaths in 20 paediatric and 18 adult patients. Seven of these patients (four paediatric and three adult patients) developed PRIS during anaesthesia. It is proposed that the syndrome may be caused by either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. An early sign of cardiac instability associated with the syndrome is the development of right bundle branch block with convex-curved ('coved type') ST elevation in the right praecordial leads (V1 to V3) of the electrocardiogram. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease. Treatment options are limited. Haemodialysis or haemoperfusion with cardiorespiratory support has been the most successful treatment.",1
11308,17574447,Hepatonecrosis and cholangitis related to long-term phenobarbital therapy: an autopsy report of two patients,"Phenobarbital (PB) has a reputation for safety, and it is commonly believed that PB-related increases in serum aminotransferase levels do not indicate or predict the development of significant chronic liver disease. Here we report of two adult patients with a long history of epilepsy treated with PB who died suddenly: one as consequence of cardiac arrest, the other of acute bronchopneumonia. At autopsy, analysis of liver parenchyma revealed rich portal inflammatory infiltrate, which consisted of mixed eosinophil and monocyte cells, associated with several foci of necrosis surrounded by a hard ring of non-specific granulomatous tissue. Inflammatory reactions of internal and external hepatic biliary ducts were also seen. Our findings illustrate that PB may be associated with chronic liver damage, which may lead to more serious and deleterious consequences. For this reason, each clinician should recognize this entity in the differential diagnosis of PB-related asymptomatic chronic hepatic enzyme dysfunction.",1
11309,17575588,Troglitazone hepatotoxicity: are we getting closer to understanding idiosyncratic liver injury?,,1
11310,17578360,Comparison of the efficacy and safety of a new recombinant human follicle-stimulating hormone (DA-3801) with follitropin-alpha (Gonal-F) in women undergoing controlled ovarian hyperstimulation for assisted reproductive technology,"""AIM: To compare the efficacy and safety of a new recombinant human follicle-stimulating hormone (FSH; DA-3801) with follitropin-alpha (Gonal-F) in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproductive technology (ART). METHODS: This was a phase III, multicenter, randomized, non-inferiority study. A total of 97 women were randomized to receive COH using DA-3801 (DA-3801 group, n = 49) or Gonal-F (Gonal-F group, n = 48). All subjects underwent COH using a gonadotropin-releasing hormone (GnRH) antagonist protocol. The primary efficacy endpoint was the number of oocytes retrieved, and the secondary efficacy endpoints included the total dose of FSH, the duration of stimulation, the serum estradiol levels on the day of human chorionic gonadotropin (hCG) administration, and the fertilization, implantation and pregnancy rates. Safety was evaluated using pre- and post-treatment laboratory tests and all adverse events were recorded. RESULTS: The number of oocytes retrieved was 13.0 +/- 6.2 (DA-3801) versus 10.6 +/- 6.7 (Gonal-F) in the intention-to-treat (ITT) population, and 12.7 +/- 6.4 (DA-3801) versus 11.0 +/- 7.1 (Gonal-F) in the per-protocol (PP) population. The non-inferiority of DA-3801 was demonstrated with differences of 2.3 +/- 6.5 (95% confidence interval [CI] = 0.13, infinity) and 1.7 +/- 6.7 (95% CI = -0.74, infinity), respectively, in the ITT and PP populations. The total dose of FSH used (1789.8 +/- 465.5 vs 2055.6 +/- 646.7 pg/mL, P = 0.027) and duration of stimulation (8.3 +/- 1.4 vs 9.1 +/- 1.9 days, P = 0.036) in the ITT population were significantly lower in the DA-3801 group. Other secondary efficacy endpoints, including pregnancy and implantation rates and the incidence and severity of adverse events, were comparable between the two groups. CONCLUSIONS: The results of this study demonstrate that DA-3801 is not inferior to follitropin-alpha in terms of its efficacy and safety in women undergoing COH for ART.""",1
11311,17580264,"Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality","""The pharmacokinetics of cyclophosphamide (CY) and its metabolites hydroxycyclophosphamide and carboxyethylphosphoramide mustard were determined in 75 patients receiving targeted oral busulfan followed by i.v. CY ((T)BU/CY) and in 147 patients receiving i.v. CY followed by total body irradiation (CY/TBI) in preparation for hematopoietic cell transplantation (HCT). In the (T)BU/CY patients only, the association of the pharmacokinetic data with liver toxicity, relapse, and survival was evaluated. CY was infused at 60 mg/kg/day over 1 or 2 hours on 2 consecutive days; the majority of patients had BU levels targeted to a steady state plasma concentration (Css) of 800-900 ng/mL. Systemic exposure (i.e., area under the concentration-time curve [AUC]) of CY, hydroxycyclophosphamide, and carboxyethylphosphoramide mustard was measured. Liver toxicity was assessed as the development of hepatic sinusoidal obstruction syndrome (SOS). CY metabolism was highly variable and age dependent. (T)BU/CY-treated patients had lower AUC(CY) (P < .0001), higher AUC(HCY) (P < .0001), and higher AUC(CEPM) (P = .15) than CY/TBI-conditioned patients. Among patients receiving (T)BU/CY, 17 (23%) developed SOS, and there were no statistically significant associations between the AUC of CY or its metabolites and SOS, nonrelapse mortality, relapse, or survival (all P >.15). In conclusion, CY exhibits conditioning-regimen dependent pharmacokinetics and pharmacodynamics, suggesting that lowering CY doses is unlikely to improve outcomes to (T)BU/CY. Alternative strategies, such as administering i.v. busulfan or CY before BU, should be explored.""",1
11312,17583775,Anakinra in patients with treatment-resistant adult-onset Still's disease: four case reports with serial cytokine measurements and a review of the literature,"""OBJECTIVE: To determine the efficacy of the interleukin (IL)-1-receptor antagonist (IL-1RA) anakinra in patients with adult-onset Still's disease (AOSD) refractory to standard treatments such as glucocorticosteroids (GC), immunosuppressive drugs, and tumor necrosis factor (TNF)-antagonists; to verify disease remission objectively by serial cytokine measurements; and to review the current literature on anakinra for this indication. METHODS: Four patients with AOSD--2 with acute flares of the chronic form of the disease and 2 with intermittent disease--were treated with prednisolone and methotrexate. One was also treated with several other immunosuppressive drugs including etanercept and infliximab. One patient had life-threatening symptoms (toxic megacolon, pneumonitis, disseminated intravascular coagulation) despite high-dose prednisolone. Treatment with anakinra 100 mg/d subcutaneously was initiated. White blood cells (WBC), C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), liver enzymes, ferritin levels, and serum cytokines were analyzed. The current literature on the efficacy of anakinra for AOSD is reviewed. RESULTS: Patients with chronic AOSD quickly responded to anakinra treatment (1 day to 3 days). GC could be tapered. ESR, CRP, WBC, ferritin, and liver enzymes returned to normal. Serum cytokine measurements revealed moderately elevated IL-1beta levels and highly elevated IL-18 levels in active disease, which normalized with anakinra. TNF-alpha and IL-6 were moderately elevated only in the 2 patients with chronic AOSD. In the literature, 17 similar cases have been reported to date. CONCLUSIONS: Anakinra is effective in treatment-resistant and in life-threatening AOSD. IL-18 serum levels, in addition to CRP, ESR, liver enzymes, ferritin, and WBC, may be helpful in assessing disease activity and response to treatment.""",1
11313,17588301,Safety and tolerability of prolonged-release nicotinic acid in statin-treated patients,"OBJECTIVE: To evaluate the safety and tolerability of prolonged-release nicotinic acid (Niaspan) added to statin therapy in patients at increased cardiovascular risk. METHODS: This was a 6-month, prospective, observational, multicentre, open-label evaluation of prolonged-release nicotinic acid (maximum dose 2000 mg/day) in statin-treated patients with cardiovascular disease and/or type 2 diabetes. The primary endpoint was the safety and tolerability of prolonged-release nicotinic acid, with special regard to treatment-related adverse drug reactions (ADRs). Secondary endpoints were changes in lipids and 10-year cardiovascular risk (Prospective Cardiovascular Munster (PROCAM) score). RESULTS: The study population included 1053 patients: 50% had hypertension, diabetes and/or metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria) and 80% had cardiovascular disease. Flushing (mostly mild or moderate) occurred in 430 patients (40.8%). Other ADRs occurred in 125 patients (12.5%), most commonly pruritus (2.7%), gastro-intestinal symptoms (3.8%) and nervous system-related complaints (3.8%). Serious ADRs were uncommon (0.6%). All patients recovered completely from these ADRs after treatment discontinuation. In total, 11.1% of the patients discontinued study medication for flushing and 8.4% for other ADRs. There was no evidence of hepatotoxicity or myopathy. New-onset hyperglycaemia was negligible. Overall tolerability of prolonged-release nicotinic acid treatment (n = 734 patients at closeout) was 'very good' in 130 (17.7%), 'good' in 262 (35.7%), and 'acceptable' in 144 (19.6%) patients. High-density lipoprotein (HDL) cholesterol increased by 23%, triglycerides decreased by 15% and LDL-C decreased by 4%. CONCLUSIONS: Prolonged-release nicotinic acid was safe and generally well tolerated and effective in combination with statin therapy in patients at high risk of cardiovascular events, with a side-effect profile consistent with previous clinical experience.",1
11314,17589205,Nodular regenerative hyperplasia: a new serious antiretroviral drugs side effect?,,1
11315,17589805,Stevens-Johnson syndrome in children receiving phenobarbital therapy and cranial radiotherapy,"Stevens-Johnson syndrome (SJS) is a severe cutaneous eruption that most often appears as an adverse reaction to medication. In this report, we present two children with brain tumour who developed SJS while receiving cranial irradiation and anticonvulsant therapy with phenobarbital. Concomitant application of these two therapies may play an important role in the occurrence of the disease.",1
11316,17592340,Safety issues about nevirapine administration in HIV-infected pregnant women,,1
11317,17596147,Association or lack of association between tetracycline class antibiotics used for acne vulgaris and lupus erythematosus,"BACKGROUND: Previous studies have associated tetracyclines and, perhaps more specifically, minocycline use for the treatment of acne with onset of drug-induced lupus erythematosus (LE). OBJECTIVES: To determine the frequency of LE among those with acne who used antibiotics from the tetracycline class of antibiotics. METHODS: A retrospective cohort study of individuals aged 15-35 years with acne within the practices of the general practice physicians in the U.K. who participate in The Health Information Network (THIN). Our outcome measure was physician reports of LE. RESULTS: We identified 97 694 subjects with acne who were followed for about 520 000 person-years. They were on average about 22 years old and 57.5% were female. Minocycline exposure was noted in 24.8% of our subjects, doxycycline exposure in 15.6%, other tetracyclines in 42.3%, and 17.3% had not received a tetracycline antibiotic. The overall hazard ratio for the association of minocycline to LE was 2.64 (95% confidence interval 1.51-4.66) and when adjusted for age and gender was 3.11 (1.77-5.48). Those affected were often treated for LE. No association was noted for doxycycline and the other tetracyclines. CONCLUSIONS: The use of minocycline and not the other tetracyclines is associated with LE. LE as reported in THIN often required systemic therapy. Overall, the event is uncommon but the risk and benefit of minocycline therapy must be carefully considered.",1
11318,17600380,"Fulminant hepatic failure in chronic hepatitis B on withdrawal of corticosteroids, azathioprine and infliximab for Crohn's disease",,1
11319,17602085,Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women,"""PURPOSE: To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. PATIENTS AND METHODS: This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. RESULTS: CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. CONCLUSION: The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.""",1
11320,17602963,A case of hepatotoxicity caused by green tea,,1
11321,17605513,Telithromycin: the perils of hasty adoption and persistence of off-label prescribing,"BACKGROUND: Telithromycin (Ketek) was approved in April 2004 for the treatment of acute bacterial exacerbations of chronic bronchitis (ABECB), bacterial sinusitis, and community-acquired pneumonia. The approval of telithromycin was controversial due to trial irregularities, noninferiority study designs, and use of foreign safety data. Safety concerns involving hepatotoxicity, myasthenia gravis exacerbation, and visual disturbances were increasingly documented in the literature after approval. On February 12, 2007, the U.S. Food and Drug Administration (FDA) removed the bacterial sinusitis and ABECB indications and strengthened safety warnings for telithromycin. OBJECTIVE: To (1) assess the prevalence and distribution of on-label telithromycin utilization before and after the revisions of the product label and (2) assess the association of pivotal events in the life cycle of telithromycin with its use as reflected in pharmacy and medical claims. METHODS: Using retrospective administrative medical and pharmacy claims from a large midwestern commercial insurer with an eligible membership of 1.8 million members, individuals with a telithromycin claim during January 1, 2007, through April 13, 2007, were identified. Their medical claims within 30 days prior to or on the initial telithromycin claim were analyzed for the presence of an on-label diagnosis code. Monthly telithromycin and clarithromycin claim totals per million members from January 2004 through March 2007 were calculated. Claim totals were plotted to identify utilization trends in relation to the FDA health advisory for telithromycin on January 20, 2006, and the telithromycin label changes on February 12, 2007. RESULTS: The medical diagnosis analysis consisted of 507 members with 1 or more medical claims with dates of service within 30 days of at least 1 pharmacy claim for telithromycin. Using the original approved telithromycin indications, 52.3% (256 of 507) of telithromycin use was on-label. The most common on-label diagnoses were sinusitis (33.9%) and bronchitis (14.4%). A diagnosis of pneumonia was present for 3.9% of telithromycin utilizers. After the February 12, 2007, label change limiting telithromycin to community-acquired pneumonia, on-label use was 6.7% (12 of 179) of utilizers. Telithromycin claims were first detected in August 2004 and overtook the clarithromycin rate of 729 claims per million members in January 2005, reaching a peak rate of 940 claims per million members in January 2006. Telithromycin monthly claims remained higher than clarithromycin until April 2006, 3 months after the liver toxicity health advisory. In comparison with January 2006, the January 2007 telithromycin claims were 186 claims per million members, a decrease of 80%. CONCLUSION: Despite revised FDA indications and safety warnings, fewer than 1 in 15 active telithromycin users have a medical claim consistent with the only currently approved indication (pneumonia). Pharmacy claims for telithromycin dropped substantially following reports of severe hepatotoxicity and strengthened safety warnings. The high prevalence of telithromycin off-label use despite hepatotoxicity and other safety risks is cause for continued concern.",1
11322,17606652,Hyperammonemia due to valproic acid in the psychiatric setting,,1
11323,17606972,"Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy","PURPOSE: There is a need for new agents to treat metastatic breast cancer (MBC) in patients for whom anthracycline therapy has failed or is contraindicated. This study was conducted to assess the efficacy and safety of the novel antineoplastic, the epothilone B analog ixabepilone, in patients with MBC previously treated with an adjuvant anthracycline. PATIENTS AND METHODS: Patients were age >or= 18 years and had received a prior anthracycline-based regimen as adjuvant treatment. Ixabepilone as first-line metastatic chemotherapy was administered as a 40 mg/m(2) intravenous infusion during 3 hours every 3 weeks. The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression, and survival. RESULTS: All 65 patients were assessable for response. Their median age was 52 years (range, 33 to 80 years). ORR was 41.5% (95% CI, 29.4% to 54.4%), median duration of response was 8.2 months (95% CI, 5.7 to 10.2 months), and median time to response was 6 weeks (range, 5 to 17 weeks). Median survival was 22.0 months (95% CI, 15.6 to 27.0 months). Treatment-related adverse events were manageable and mostly grades 1/2: the most common of these (other than alopecia) was mild to moderate neuropathy, which was primarily sensory and mostly reversible in nature. CONCLUSION: Ixabepilone is efficacious and has a predictable and manageable safety profile in women with MBC previously treated with an adjuvant anthracycline.",1
11324,17606974,"Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine","""PURPOSE: To evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study. PATIENTS AND METHODS: Patients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m(2) monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF). RESULTS: A total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD >or= 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received >or= eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks. CONCLUSION: Ixabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.""",1
11325,17607296,Drug-induced acute cholestatic liver damage in a patient with mutation of UGT1A1,"""BACKGROUND: A 54-year-old woman presented with a 3-week history of fatigue and with jaundice that began 2 days before admission. She had been undergoing treatment with flavoxate for urinary incontinence (for 2 months before admission) and with tibolone for climacteric syndrome (for 6 months before admission). Laboratory tests revealed elevated concentrations of aminotransferases, bilirubin, gamma-glutamyltransferase and alkaline phosphatase. Liver biopsy revealed histological evidence of subacute, drug-induced liver damage. INVESTIGATIONS: Physical examination, liver function tests, serology tests, autoantibody tests, genetic analysis of the TATA box of the UGT1A1 gene, ultrasonography and CT scan; MRI cholangiography; liver biopsy. DIAGNOSIS: Drug-related hepatitis in a patient with Gilbert's syndrome. MANAGEMENT: Flavoxate and tibolone were discontinued. Liver function test results improved progressively and normalized after almost 2 months.""",1
11326,17617270,"Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial","""BACKGROUND: Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). METHODS: DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. FINDINGS: 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9-25; p=0.005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). INTERPRETATION: In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.""",1
11327,17617272,"Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial","""BACKGROUND: The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients. METHODS: Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877. FINDINGS: Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients. INTERPRETATION: In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population.""",1
11328,17621237,Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients: 24-week results of POWER 3,"""OBJECTIVE: In POWER 1 and POWER 2, darunavir (TMC114) with low-dose ritonavir (darunavir/r) demonstrated greater efficacy versus control protease inhibitors (PIs). To examine the efficacy and safety of the selected darunavir/r dose further, additional patients were analyzed. METHODS: Treatment-experienced HIV-1-infected patients received darunavir/r at a dose of 600/100 mg twice daily plus an optimized background regimen. The primary intent-to-treat analysis was the proportion of patients with an HIV-1 RNA reduction >or=1 log10 at week 24. RESULTS: Three hundred twenty-seven patients were treated; the baseline mean HIV-1 RNA was 4.6 log10 copies/mL, and the median CD4 count was 115 cells/mm3 (median primary PI mutations = 3, PI resistance-associated mutations = 9). Two hundred forty-six patients reached week 24 by the cutoff date and were included in the efficacy analysis: 65% and 40% achieved HIV-1 RNA reductions of >or=1 log10 and <50 copies/mL, respectively, at week 24. The mean CD4 count increase was 80 cells/mm3. The most common adverse events (AEs) were diarrhea (14%), nasopharyngitis (11%), and nausea (10%). Nine (3%) patients discontinued treatment because of AEs or HIV-1-related events. Six treatment-unrelated deaths (2%) were reported. CONCLUSIONS: These results corroborate POWER 1 and POWER 2. In this larger set of treatment-experienced patients, darunavir/r at a dose of 600/100 mg twice daily provided substantial virologic and immunologic responses and was generally safe and well tolerated.""",1
11329,17623837,Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma,"""BACKGROUND: Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. METHODS: Patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. Tumor response was assessed every 2 cycles by using Response Evaluation Criteria in Solid Tumors (RECIST; National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Md) criteria. Patients accrued to either """"low"""" or """"high"""" EGFR expression cohorts; each cohort had stopping rules applied when there was a lack of efficacy. RESULTS: Forty HCC patients were enrolled. Median age was 64 years (range, 33-83 years), sex distribution was 32 males and 8 females, performance scores were 40% PS 0, 55% PS 1, Childs-Pugh distribution was 75% A and 20% B. There were no complete or partial responses; however, 17 of 40 patients achieved stable disease at 16 weeks of continuous therapy. The PFS at 16 weeks was 43%, and the median overall survival (OS) was 43 weeks (10.75 months). No patients required dose reductions of erlotinib. No correlation between EGFR expression and outcome was found. CONCLUSIONS: Results of this study indicated that single-agent erlotinib is well tolerated and has modest disease-control benefit in HCC, manifested as modestly prolonged PFS and OS when compared with historical controls.""",1
11330,17624846,Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis,"BACKGROUND: Visceral leishmaniasis (VL) is a major public health problem in Bihar, accounting for 90% of all cases in India. Development of high levels of resistance to various existing drugs necessitated the search for alternative orally administered drugs. Hospital-based studies have shown that oral miltefosine is a highly effective treatment for VL both in adults and in children. METHODS: An open, single-arm trial was designed to investigate the feasibility of treatment of VL patients with miltefosine in field conditions in 13 centers in Bihar. RESULTS: The phase 4 study was conducted among 1132 adult and pediatric VL patients. Compliance was good, with 1084 (95.5%) patients completing the full 28-day treatment course. Nine hundred and seventy-one (85.8%) patients returned for the final cure assessment at 6 months after treatment. The final cure rate was 82% by intention to treat analysis and 95% by per protocol analysis (similar to the 94% cure rate in hospitalized patients). Treatment-related adverse events of common toxicity criteria grade 3 occurred in ~3% of patients, including gastrointestinal toxicity and rise in aspertate amino transferase, alanine amino transferase, or serum creatinine levels, similar to previous clinical experience. CONCLUSION: This study supports the use of miltefosine in an outpatient setting in an area where VL is endemic.",1
11331,17629631,"A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence","BACKGROUND: The potential efficacy of tiagabine for treating cocaine dependence is suggested by both pre-clinical research and two small clinical trials. METHOD: One hundred and forty one participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double blind, placebo controlled outpatient trial. Participants received either tiagabine (20 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine (BE) results, and qualitative and quantitative urine toxicology measures. Safety measures included adverse events, EKGs, vital signs, and laboratory tests. RESULTS: Seventy-nine participants (i.e., 56%) completed the 12-week trial. The safety results suggest that tiagabine was safe and generally well tolerated by the participants. Participants in both groups improved significantly on cocaine craving and global functioning, with no significant differences between the groups. There were no significant changes in cocaine use as measured by self-report confirmed by urine BE or by quantitative urine toxicology results. Qualitative urine toxicology results suggest a possible weak effect for tiagabine in reducing cocaine use. CONCLUSION: These results suggest that tiagabine, at a dose of 20 mg/day, did not have a robust effect in decreasing cocaine use.",1
11332,17630819,Medical management of levodopa-associated motor complications in patients with Parkinson's disease,"""Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity. Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with levodopa. Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease 'off' time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility. All medications used to manage levodopa-associated motor complications in patients with Parkinson's disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.""",1
11333,17634458,Certolizumab pegol for the treatment of Crohn's disease,"""BACKGROUND: Certolizumab pegol is a pegylated humanized Fab' fragment that binds tumor necrosis factor alpha. METHODS: In a randomized, double-blind, placebo-controlled trial, we evaluated the efficacy of certolizumab pegol in 662 adults with moderate-to-severe Crohn's disease. Patients were stratified according to baseline levels of C-reactive protein (CRP) and were randomly assigned to receive either 400 mg of certolizumab pegol or placebo subcutaneously at weeks 0, 2, and 4 and then every 4 weeks. Primary end points were the induction of a response at week 6 and a response at both weeks 6 and 26. RESULTS: Among patients with a baseline CRP level of at least 10 mg per liter, 37% of patients in the certolizumab group had a response at week 6, as compared with 26% in the placebo group (P=0.04). At both weeks 6 and 26, the corresponding values were 22% and 12%, respectively (P=0.05). In the overall population, response rates at week 6 were 35% in the certolizumab group and 27% in the placebo group (P=0.02); at both weeks 6 and 26, the response rates were 23% and 16%, respectively (P=0.02). At weeks 6 and 26, the rates of remission in the two groups did not differ significantly (P=0.17). Serious adverse events were reported in 10% of patients in the certolizumab group and 7% of those in the placebo group; serious infections were reported in 2% and less than 1%, respectively. In the certolizumab group, antibodies to the drug developed in 8% of patients, and antinuclear antibodies developed in 2%. CONCLUSIONS: In patients with moderate-to-severe Crohn's disease, induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates, as compared with placebo, but with no significant improvement in remission rates. (ClinicalTrials.gov number, NCT00152490 [ClinicalTrials.gov].).""",1
11334,17635557,Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures,"""PURPOSE: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions. METHODS: During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. RESULTS: Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p=0.0023) and 600 mg/day (p=0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p=0.0038) and 600 mg/day (p=0.0141). Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs. CONCLUSIONS: In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.""",1
11335,17638715,Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus,"BACKGROUND: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy. PURPOSE: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus. DATA SOURCES: The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched. STUDY SELECTION: 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States. DATA EXTRACTION: Using standardized protocols, 2 reviewers serially abstracted data for each article. DATA SYNTHESIS: Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A1c level of about 1 percentage point). Nateglinide and alpha-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents. LIMITATIONS: Data on major clinical end points were limited. Studies inconsistently reported adverse events other than hypoglycemia, and definitions of adverse events varied across studies. Some harms not assessed in trials or observational studies may have been overlooked. CONCLUSIONS: Compared with newer, more expensive agents (thiazolidinediones, alpha-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.",1
11336,17639967,[Painless jaundice after ecstasy and alcohol consumption],,1
11337,17644554,Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis,"""OBJECTIVES: A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA). METHODS: The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly. RESULTS: Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. """"Infections"""" or """"respiratory disorders"""" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab. CONCLUSION: This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.""",1
11338,17646919,Hepatitis C virus RNA in serum as a risk factor for isoniazid hepatotoxicity,,1
11339,17655517,"Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome","Linezolid is an oxazolidinone antibacterial agent indicated for serious gram-positive infections. Only minor adverse effects were seen in phase III trials. However, more serious adverse effects were reported after commercial release, including cases of lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome. Peripheral and optic neuropathy was usually seen after several months of linezolid therapy (median 5 mo), lactic acidosis after several weeks (median 6 wks), and serotonin syndrome after several days (median 4 days). Death occurred in two of seven reported cases of lactic acidosis, and three of 15 reported cases of serotonin syndrome. Improvement or complete recovery occurred in all cases of optic neuropathy, whereas complete recovery failed to occur in any patient with peripheral neuropathy. Linezolid should be discontinued immediately in patients experiencing these adverse effects. Patients receiving linezolid for more than 28 days should be monitored for signs of peripheral and optic neuropathy.",1
11340,17657620,"An analysis from clinico-epidemiological data of the principal adverse events from the COX-2 selective NSAID, nimesulide, with particular reference to hepatic injury","The safety of the cyclo-oxygenase-2 (COX-2) selective NSAID, nimesulide, has been evaluated from information (a) in clinical trials in osteoarthritis that have been performed in Europe as well as in earlier pilot studies that were performed in patients with rheumatoid arthritis in the USA, and (b) in post-marketing studies (PMS) that have been performed by the manufacturer since the introduction of the drug in Europe and some South American countries. Upon analysis there have been clear indications of elevation of liver enzymes being related to the drug in 3/753 patients who were investigated in clinical trials in osteoarthritis. The results of the analysis of adverse drug reactions (ADRs) in patients with osteoarthritis (which is the principal indication for the drug) in PMS showed that the greatest number of these were in the skin and appendages, digestive system and organs wherein metabolic effects were manifest. There was a relatively low number of reports of gastrointestinal ulceration and haemorrhage, and these observations are in agreement with published experimental studies in humans and laboratory animals. Recent reports of ADRs in the liver in 25 patients were analysed in detail. In many of the cases there was evidence of confounding disease (e.g. cancer, prior liver damage) or prior or concurrent intake of known hepatotoxic NSAIDs (diclofenac, aspirin). Often elevations of liver enzymes above the laboratory norms are the only indication of liver injury and this in many cases is variable. The major cases of elevated liver enzymes and other liver changes have been in elderly patients.This first extensive analysis of ADRs from a COX-2 selective NSAID, nimesulide, indicates that there is a relatively low incidence of ADRs especially in the gastrointestinal tract, while those in the liver are within or below the general incidence with other NSAIDs.",1
11341,17661800,Non-convulsive status epilepticus secondary to valproic acid-induced hyperammonemic encephalopathy,"BACKGROUND: Valproic acid (VPA) may induce hyperammonemic encephalopathy. On the other hand, seizure-inducing effects of antiepileptic drugs (AEDs) may be a paradoxical reaction or a result of AED-induced encephalopathy (commonly induced by VPA). METHODS: We present the case of a 19-year-old male who developed acute mental status changes consistent with encephalopathy evolving into repetitive seizures with oral automatisms induced by relatively small doses of VPA. RESULTS: Although serum hepatic enzymes, such as AST and ALT, were normal, serum ammonia concentration was high, i.e. 70 micromol/l (normal range 9-33 micromol/l). Administration of VPA was discontinued immediately after admission. The patient's condition improved during the second week of hospitalization and ammonium levels returned to normal. CONCLUSION: In conclusion, although uncommon, a possible induction of non-convulsive status epilepticus by valproate-induced hyperammonemic encephalopathy should be taken into account and properly managed by discontinuation of the drug.",1
11342,17662392,"Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials","OBJECTIVES: We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer. BACKGROUND: Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated. METHODS: Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression. RESULTS: In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 <0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23). CONCLUSIONS: Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.",1
11343,17663974,[A new case: pioglitazone hepatotoxicity],,1
11344,17666604,Effectiveness of two tinidazole regimens in treatment of bacterial vaginosis: a randomized controlled trial,"""OBJECTIVE: To assess the effectiveness at 21-30 days after treatment of tinidazole administered orally at 1 g once daily for 5 days and 2 g once daily for 2 days, compared with placebo, in the treatment of bacterial vaginosis, using rigorous U.S. Food and Drug Administration (FDA)-recommended criteria to define cure. METHODS: A total of 235 women at 10 U.S. centers participated in this prospective, randomized, double-blinded, placebo-controlled trial. Presence or absence of all five following criteria was required to define diagnosis or cure of bacterial vaginosis: 1) clue cells were at least 20% of squamous cells in microscopic examination of vaginal fluid; 2) positive potassium hydroxide whiff test; 3) a homogeneous, thin, white-gray vaginal discharge; 4) vaginal pH greater than 4.5; and 5) Nugent score greater than or equal to 4 on Gram-stained vaginal fluid. Compliance, tolerability, and safety were assessed using patient diaries and interviews at 8-10 days and 21-30 days after treatment. Cochran-Mantel-Haenszel statistical analysis with Bonferroni adjustment was used to compare outcomes. RESULTS: Superior efficacy was demonstrated by tinidazole for the 1 g once daily for 5 days regimen (36.8% cured, P<.001, number needed to treat 3.2) and for the 2 g once daily for 2 days regimen (27.4% cured, P<.001, number needed to treat 4.5), when compared with placebo (5.1% cured) in the primary endpoint analysis. Using more traditional criteria for cure, efficacy was greater. Compliance with study therapy and tolerability were comparable in the three treatment groups. CONCLUSION: Both tinidazole regimens studied provided effective treatment for bacterial vaginosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00229216 LEVEL OF EVIDENCE: I.""",1
11345,17668247,Intravenous delivery of cysteamine for the treatment of cystinosis: association with hepatotoxicity,"Nephropathic cystinosis is a lysosomal storage disorder, which, if untreated, results in renal failure by age 10 years. Oral cysteamine has been shown to preserve renal function in these patients. In this study, a 2-year-old girl with nephropathic cystinosis and severe gastrointestinal dysmotility was treated with intravenous (i.v.) administration of cysteamine hydrochloride (HCl). This is only the second report of long-term i.v. cysteamine therapy for nephropathic cystinosis. Unlike the treatment in the previous case, however, treatment in our patient was limited by liver toxicity.",1
11346,17668878,"Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial","""UNLABELLED: The hepatotoxic potential of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in patients with underlying chronic liver disease remains controversial. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that compared pravastatin (80 mg) to a placebo administered once daily to hypercholesterolemic subjects greater than 18 years of age with at least a 6-month history of compensated chronic liver disease and with a low-density lipoprotein cholesterol (LDL-C) level greater than or equal to 100 mg/dL and a triglyceride (TG) level lower than 400 mg/dL. The efficacy was determined by the percentage change in LDL-C [along with the total cholesterol (TC), high-density lipoprotein cholesterol, and TG] from the baseline to week 12. The safety was analyzed by the proportion of subjects who developed at least 1 alanine aminotransferase (ALT) value greater than or equal to 2 times the upper limit of normal for those with normal ALT at the baseline or a doubling of the baseline ALT for those with elevated ALT at the baseline during 36 weeks of treatment. A total of 630 subjects were screened, and 326 subjects were randomized; nonalcoholic fatty liver disease was present in 64%, and chronic hepatitis C was present in 23%. In the intent-to-treat population, pravastatin (80 mg/day) significantly lowered the mean LDL-C, TC, and TG values at week 12 and at other times (weeks 4, 8, 24, and 36) in comparison with the placebo. The incidence of subjects who met the primary prespecified ALT event definition was lower in the pravastatin group at all times over the 36 weeks of therapy in comparison with the placebo group, although the difference was not statistically significant. No differences were seen on the basis of the baseline ALT values or among the different liver disease groups. CONCLUSION: High-dose pravastatin (80 mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL-C, TC, and TGs in comparison with the placebo and was safe and well tolerated. The concern over an increased potential for statin-induced hepatotoxicity in patients with chronic liver disease appears to be lessened on the basis of these results.""",1
11347,17674307,Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients,"""BACKGROUND: The risk of liver toxicity during antiretroviral drug use in human immunodeficiency virus (HIV)-positive patients increases in the presence of chronic hepatitis C virus (HCV) infection. It is unknown whether sustained HCV clearance after interferon (IFN)-based therapy might reduce this complication. METHODS: The incidence of severe elevations in liver enzyme levels during antiretroviral therapy was retrospectively analyzed in a group of HIV/HCV-coinfected patients after completion of a full course of IFN-based therapy. Hepatic events were recorded according to the achievement of a sustained virological response (SVR), and the presence of advanced liver fibrosis was assessed by transient elastometry. RESULTS: A total of 132 HIV/HCV-coinfected patients were analyzed (66% men; mean age, 38 years). Overall, 33% achieved an SVR and 40% had advanced liver fibrosis after IFN therapy. A total of 49 episodes of liver toxicity occurred during a mean of 35 months of follow-up (9.7% per year) after IFN therapy. The yearly incidence of hepatic events was greater in patients who did not achieve an SVR than in those who did (12.9% vs. 3.1%; P<.001) and in patients with advanced liver fibrosis than in those without it (14.4% vs. 7.6%; P=.003). Drugs involved in hepatic events were dydeoxynucleoside analogues (namely, didanosine and stavudine; 40%) nevirapine (30%), efavirenz (11%), and protease inhibitors (PIs; 8%). In logistic regression analysis, lack of an SVR (odds ratio [OR], 6.13 [95% confidence interval {CI}, 1.83-37.45]; P=.003) and the use of dydeoxynucleosides (OR, 3.59 [95% CI, 1.23-10.42]; P=.02) were independent predictors of hepatotoxicity after IFN therapy. Conversely, regimens containing PIs (OR, 0.07 [95% CI, 0.02-0.30]; P<.01) or efavirenz (OR, 0.13 [95% CI, 0.04-0.44]; P=.001) were associated with a diminished risk of hepatic events. CONCLUSION: Sustained HCV clearance after IFN-based therapy reduces the risk of liver toxicity during antiretroviral therapy, which should further encourage the treatment of chronic hepatitis C in HIV-coinfected patients. In this population, prescription of PIs or efavirenz decreases and use of dydeoxynucleoside analogues increases the risk of hepatotoxicity.""",1
11348,17682975,Inborn errors of bile acid metabolism,"""Bile acids are synthesized by the liver from cholesterol through a complex series of reactions involving at least 14 enzymatic steps. A failure to perform any of these reactions will block bile acid production with failure to produce """"normal bile acids"""" and, instead, result in the accumulation of unusual bile acids and intermediary metabolites. Failure to synthesize bile acids leads to reduced bile flow and decreased intraluminal solubilization of fat and fat-soluble vitamins. In some circumstances, the intermediates created because of blockade in the bile acid biosynthetic pathway may be toxic to hepatocytes. Nine recognized inborn errors of bile acid metabolism have been identified that lead to enzyme deficiencies and impaired bile acid synthesis in infants, children, and adults. Patients may present with neonatal cholestasis, neurologic disease, or fat and fat-soluble vitamin malabsorption. If untreated, progressive liver disease may develop or reduced intestinal bile acid concentrations may lead to serious morbidity or mortality. This review focuses on a description of the disorders of bile acid synthesis that are directly related to single defects in the metabolic pathway, their proposed pathogenesis, treatment, and prognosis.""",1
11349,17689147,Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study,"""BACKGROUND: Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. METHODS: Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. FINDINGS: At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. INTERPRETATION: Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.""",1
11350,17692110,"Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women","""OBJECTIVE: To provide evidence of efficacy and safety for use of lutropin alfa in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency. DESIGN: An open-label, noncomparative extension of a randomized, double-blind, placebo-controlled study PATIENTS: A total of 31 hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in 23 medical centres in four countries were studied. INTERVENTIONS: Lutropin alfa 75 IU and follitropin alfa (75-225 IU), individually based on each patient's response as is consistent with usual medical practice. MEASUREMENTS: Follicular development as defined by (i) at least one follicle >or= 17 mm; (ii) preovulatory serum oestradiol level >or= 109 pg/ml on the day of hCG administration; and (iii) midluteal phase P(4) level >or= 7.9 ng/ml. Pregnancy and over-response leading to cycle cancellation were considered treatment successes. Pregnancy rates were assessed. RESULTS: In a total of 54 cycles, 27 of 31 (87.1%) profoundly gonadotrophin-deficient patients achieved follicular development within three cycles. Twenty of 27 patients (74.1%) who achieved follicular development and received hCG became pregnant; 16 (59.3%) continued to clinical pregnancy. One patient was hospitalized for severe ovarian hyperstimulation syndrome. Lutropin alfa was well tolerated. CONCLUSIONS: Coadministration of lutropin alfa 75 IU and follitropin alfa is safe and effective in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in a setting consistent with established medical practice.""",1
11351,17692207,Acute hepatitis associated to leflunomide in a patient with rheumatoid arthritis,,1
11352,17692765,Impact of activated charcoal after acute acetaminophen overdoses treated with N-acetylcysteine,"Previous studies have suggested that patients receiving both activated charcoal (AC) and N-acetylcysteine (NAC) after acute acetaminophen (APAP) overdoses may have improved outcomes. We evaluated all acute acetaminophen overdoses that received NAC therapy reported to US poison centers for the years 1993 through 2004. Groups were separated based on therapy received: 1) both AC and NAC and 2) NAC alone. There were 97,960 acetaminophen overdoses reported, with 49,427 patients (50%) receiving NAC and AC. Reports of AST/ALT > 1000, a major effect, and death were 1301 (2.9%), 2957 (6.6%), and 232 (0.5%), respectively, for patients receiving NAC plus AC, vs. 5273 (12%), 4534 (10.3%), and 369 (0.8%), respectively, for patients receiving NAC alone (p < 0.01). Use of Toxic Exposure Surveillance System data in the present study has a number of limitations, including its retrospective nature and no documentation of when NAC therapy was initiated. It is possible that those patients who did not receive AC presented to the Emergency Department later in their overdose and had NAC therapy initiated later, and therefore they were predisposed to a greater risk of hepatic injury. Evaluation of 12 years of acute APAP overdoses suggests that the use of AC, in addition to NAC therapy, may provide improved patient outcomes.",1
11353,17692989,Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products,"""BACKGROUND/AIMS: Herbal agents are popular and perceived as safe because they are supposedly 'natural'. We report 10 cases of toxic hepatitis implicating Herbalife products. METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis. Sinusoidal obstruction syndrome was observed in one case. Three patients without liver biopsy presented with hepatocellular (2) or mixed (1) liver injury. Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.""",1
11354,17696578,"Safety profile of meropenem: an updated review of over 6,000 patients treated with meropenem","Meropenem is a broad-spectrum carbapenem antibacterial with potent antimicrobial activity against a broad range of Gram-negative, Gram-positive and anaerobic bacteria. The second parenteral carbapenem to be introduced worldwide, meropenem has been in clinical use since 1994. Two previous safety reviews have established that meropenem has a favourable and acceptable safety profile. This new review was conducted after the approval of meropenem in the US in 2005 for the treatment of patients with complicated skin and skin-structure infections, in addition to the previously approved indications of intra-abdominal infections and paediatric bacterial meningitis. The analysis includes the clinical trial data from the previous safety reviews, updated with expanded experience across a number of serious bacterial infections, including a large international study in patients with skin or skin-structure infections and further experience in patients with intra-abdominal infections and bacterial meningitis. A total of 6154 patients with 6308 meropenem exposures were compared with 4483 patients treated with comparator agents (4593 exposures), and the paediatric population base for which safety data are available has doubled to over 1000 patients. The data presented reinforce the favourable safety profile of meropenem. In general, the incidence and pattern of adverse events occurring with meropenem were similar to those of the first carbapenem, imipenem/cilastatin, and to those of the cephalosporin- and clindamycin-based regimens to which it had been compared. The most common adverse events reported for meropenem were diarrhoea (2.5%), rash (1.4%) and nausea/vomiting (1.2%). No adverse event occurred in more than 3% of patient exposures to meropenem, indicating a low overall frequency of adverse events as well as excellent gastrointestinal tolerability. Furthermore, no unexpected adverse events were identified, and the very low incidence of seizures in patients with meningitis was not considered to be drug related. In infections other than meningitis, the incidence of seizures considered by investigators to be related to meropenem treatment was 0.07%. In the new studies that updated the earlier safety data, no new cases of drug-related seizure were reported for any treatment or patient group (meningitis/non-meningitis infections). In conclusion, meropenem is well tolerated and has good CNS and gastrointestinal tolerability when used for the treatment of serious bacterial infections in a wide range of adult and paediatric patient populations.",1
11355,17696943,"Black cohosh, safety, and public awareness",,1
11356,17697789,"Acute hepatic injury in four children with Dravet syndrome: valproic acid, topiramate or acetaminophen?","We describe four children with Dravet syndrome treated with the combination of valproic acid (VPA) and topiramate (TPM) who developed transient liver toxicity. The time-interval between fever, administration of acetaminophen, epileptic status and liver enzyme disturbances in our four cases suggests that accumulation of toxic acetaminophen-metabolites is possibly responsible for liver toxicity. If acetaminophen and its metabolites cause those liver problems in children treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma.",1
11357,17704426,Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma,"""PURPOSE: To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had <or= one line of chemotherapy for recurrent and/or metastatic disease, Eastern Cooperative Oncology Group performance status of <or= 2, and adequate organ function. At the end of stage 1, efficacy criteria for further accrual were not met, but the study was amended to enroll an additional five patients for paired tumor biopsies. RESULTS: Twenty-seven and 26 patients were eligible for toxicity and efficacy evaluations, respectively. One patient (3.7%; 95% CI, 0.1% to 19.0%) achieved a partial response. Disease stabilization was maintained in 10 patients (37.0%; 95% CI, 22.4% to 61.2%). The median time to progression was 1.8 months (95% CI, 1.6 to 3.4 months), and median overall survival time was 4.2 months (95% CI, 3.6 to 8.7 months). Sorafenib was well tolerated with few grade 3 and no grade 4 toxicities. Biomarker analysis of paired tumor samples before and after treatment with sorafenib revealed a decrease of pERK in all five patients, with a decrease in Ki67 in four patients, consistent with a disruption of ERK signaling. The antiapoptotic protein Mcl-1 was downregulated in four patients, and there was also evidence of antiangiogenic activity. CONCLUSION: Sorafenib was well tolerated and had modest anticancer activity comparable to monotherapy with other targeted agents in this group of patients. Further development in combination with radiation or other agents may be warranted.""",1
11358,17708618,Fulminant hepatic failure in a case of autoimmune hepatitis in hepatitis C during peg-interferon-alpha 2b plus ribavirin treatment,"A 27-year-old Caucasian female with hepatitis C virus (HCV) infection treated with interferon (IFN) who developed severe autoimmune hepatitis (AIH) is described. The infecting viral strain was of genotype Ib and the pre-treatment HCV viral load was at a high level. The patient was treated with pegylated IFN-alpha 2b and ribavirin, and her HCV-RNA became negative at wk 12, but after that she developed fulminant hepatic failure. The patient recovered after steroid pulse therapy consisting of methylprednisolone 1000 mg/d for three days which was administered twice. A needle liver biopsy revealed the typical pathological findings of AIH.",1
11359,17709758,Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy,"""BACKGROUND: The full burden of nephropathic cystinosis in adulthood and the effects of long-term oral cysteamine therapy on its nonrenal complications have not been elucidated. OBJECTIVE: To assess the severity of cystinosis in adults receiving and not receiving oral cysteamine therapy. DESIGN: Case series. SETTING: National Institutes of Health Clinical Center. PATIENTS: 100 persons (58 men and 42 women) age 18 to 45 years with nephropathic cystinosis examined between January 1985 and May 2006. MEASUREMENTS: Historical data were collected on renal transplantation, administration of oral cysteamine, and time and cause of death. Patients were evaluated for height and weight; thyroid, pulmonary, and swallowing function; muscle atrophy; hypogonadism (in men); retinopathy; vascular and cerebral calcifications; diabetes mellitus; and homozygosity for the common 57-kb deletion in CTNS. Laboratory studies were also performed. RESULTS: Of 100 adults with nephropathic cystinosis, 92 had received a renal allograft and 33 had died. At least half of the patients had hypothyroidism, hypergonadotropic hypogonadism (in men), pulmonary insufficiency, swallowing abnormalities, or myopathy. One third of the patients had retinopathy or vascular calcifications, and 24% had diabetes. Homozygosity for the 57-kb CTNS deletion was associated with an increased risk for death and morbidity. The 39 patients who received long-term (> or =8 years) oral cysteamine therapy were taller and heavier, had a renal allograft later in life, had lower cholesterol levels, and experienced fewer complications and deaths than patients who received cysteamine for fewer than 8 years. The frequency of diabetes mellitus, myopathy, pulmonary dysfunction, hypothyroidism, and death increased as time off cysteamine treatment increased, and it decreased as time on cysteamine therapy increased. LIMITATIONS: The study was retrospective and not randomized. The criteria used to measure adequacy of treatment were arbitrary. CONCLUSIONS: Untreated nephropathic cystinosis causes extensive morbidity and death in adulthood. Long-term oral cysteamine therapy mitigates these effects.""",1
11360,17712291,Transdermal rotigotine (Neupro) for Parkinson's disease,,1
11361,17715646,Idiosyncratic toxic hepatitis secondary to single dose of naproxen,,1
11362,17721109,Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST,"In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.",1
11363,17721646,Porphyria cutanea tarda: effects and risk factors for hepatotoxicity from high-dose chloroquine treatment,"High-dose chloroquine therapy for porphyria cutanea tarda is rarely used now because of its hepatic side-effects. The mechanisms of the effects and side-effects are poorly understood. We describe here effects, side-effects and long-term follow-up in 57 patients with a first-time diagnosis of porphyria cutanea tarda treated with 1-3 phlebotomies followed by 250 mg chloroquine phosphate daily for 7 days. A hepatotoxic reaction with high serum aminotransferases occurred in almost all patients. Within 3 months, clinical remission was obtained in all patients, and biochemical remission in almost all patients. Relapse occurred in 27 patients after 0.5-12 years. Subjective side-effects occurred more frequently in women, who also had higher maximum ALAT, ferritin and uroporphyrin values during treatment. Both subjective side-effects and ALAT during treatment correlated with pre-treatment uroporphyrin excretion and maximum uroporphyrin during treatment, but not with markers of hereditary haemochromatosis.",1
11364,17723075,Does therapeutic use of acetaminophen cause acute liver failure?,"STUDY OBJECTIVE: To compare the reported occurrence of liver failure in subjects in prospective trials with that in patients in retrospective reports after repeated use of therapeutic dosages of acetaminophen. DESIGN: Systematic review of the medical literature. DATA SOURCE: MEDLINE and EMBASE biomedical and pharmacologic databases. SUBJECTS: Adults who received repeated dosing of acetaminophen 4 g/day or lower for at least 24 hours. MEASUREMENTS AND MAIN RESULTS: Articles written in several languages were abstracted by trained personnel using a structured abstraction form. Data were categorized by methodology (prospective vs retrospective), acetaminophen dosage, and type of liver effect. A total of 791 articles were identified, which included 30,865 subjects in prospective studies and 9337 patients in retrospective reports. The prospective studies reported no cases of fulminant hepatic injury, liver transplantation, or death due to acetaminophen. Of the 30,865 subjects in these studies, 129 (0.4%) were identified who had a serum aminotransferase level that exceeded the upper limit of normal, including 61 subjects in randomized trials in which the proportion of serum aminotransferase level increase was the same as or less than that in the placebo group and 68 subjects in trials without a placebo group. In addition, 4263 (13.8%) received the maximum recommended therapeutic dosage (3.9-4 g/day). In the retrospective reports, 96 patients (1.0%) had a serum alanine aminotransferase level that exceeded the upper limit of normal, one (0.01%) underwent liver transplantation, and six (0.06%) died. Causality relationship of acetaminophen for each retrospective case was assessed with the Naranjo adverse drug reaction probability scale. The mean +/- SD Naranjo score for all 103 retrospective cases was 3.2 +/- 1.9, indicating a possible relationship between the increased aminotransferase levels and acetaminophen use. Some retrospective reports contained information suggesting that the patient had ingested an overdose despite a history of therapeutic use. CONCLUSION: Prospective studies indicated that repeated use of a true therapeutic acetaminophen dosage may slightly increase the level of serum aminotransferase activity, but hepatic failure or death was not reported. Retrospective reports indicated a higher rate of increased serum aminotransferase levels, and several reported associated liver injury and death. The differing results and presence of evidence indicating inaccurate acetaminophen dosage information in some case reports suggests that these cases may be inadvertent overdoses, rather than true therapeutic dosages.",1
11365,17723918,Acetaminophen hepatotoxicity,"""Acetaminophen is a commonly used antipyretic and analgesic agent. It is safe when taken at therapeutic doses; however, overdose can lead to serious and even fatal hepatotoxicity. The initial metabolic and biochemical events leading to toxicity have been well described, but the precise mechanism of cell injury and death is unknown. Prompt recognition of overdose, aggressive management, and administration of N-acetylcysteine can minimize hepatotoxicity and prevent liver failure and death. Liver transplantation can be lifesaving for those who develop acute liver failure.""",1
11366,17723921,Herbal hepatotoxicity,"There is appropriate concern about the potential risk for hepatotoxicity from herbal products because they are unregulated and therefore not standardized with regard to their contents. This is particularly the case for the crude herbals that are commonly formulated as a mixture, so that their ingredients may be ambiguous and even contain harmful contaminants. Presented here is an overview of the more commonly recognized herbal products that have been reported to be associated with liver injury. Although many of them are clearly implicated, there are some, particularly those identified solely through an occasional case report, for which the relationship is uncertain.",1
11367,17723923,Drug-induced liver injury associated with HIV medications,"Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.",1
11368,17724898,[Carbamazepine hepatoxicity--a case report],"An acute liver damage with jaun. dice and biochemical abnormalities developed in 16-year-old adolescent, affected by chronic hepatitis B, after 3 years of carbamazepine therapy. The maximum bilirubin concentration in the blood was 445 micromol/L and the highest activity of AST, ALT, PA, GTP were noted, 648 U/L, 1497 U/L, 312 U/L, 85 U/L respectively. INR was 1.59. The blood ammonia level was elevated to 60.9 micromol/L. The carbamazepine treatment was stopped and laboratory parameters improved.",1
11369,17760894,Side effects of HIV therapy,"The use of highly active effective antiretroviral therapies (ART) has dramatically decreased the morbidity and mortality of the HIV infection. Over 20 anti-retroviral substances are available in four different classes. Side effects of HIV therapy are common and may influence the prognosis, as the medications are required lifelong for the still incurable infection. ART-associated allergic reactions, lipodystrophy syndrome and immune reconstitution syndrome are side effects frequently seen by dermatologists. Exanthems are challenging as drug reactions must be separated from immune reconstitution, syphilis and viral exanthems and then the causative agent must be identified from a long list of medications. Non-nucleoside reverse transcriptase inhibitors typically cause allergic exanthems. Mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitors is responsible for lipoatrophy and fatty changes in the liver. Protease inhibitors cause diarrhea, abnormalities of glucose and fat metabolism and lipohypertrophy. Before other medications or surgical measures are undertaken to address side effects of ART, the regimen should be adjusted to include alternative but equally effective agents.",1
11370,17764540,Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial,"""BACKGROUND: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. METHODS: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Patients were followed-up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. RESULTS: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group (absolute difference, -1.3%; 95% CI, -7.3 to 4.6) and 40.5% (213 of 526) of the 150 mg group (2.8%; 95% CI, -3.1 to 8.7). Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% versus 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. CONCLUSIONS: Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.""",1
11371,17765049,The safety of oral antifungal treatments for superficial dermatophytosis and onychomycosis: a meta-analysis,"""PURPOSE: We estimated the absolute risks of treatment termination and incidence of adverse liver outcomes among all commonly used oral antifungal treatments for superficial dermatophytosis and onychomycosis. METHODS: MEDLINE, EMBASE, and Cochrane Library were searched to identify randomized and nonrandomized controlled trials, case series, and cohort studies published before December 31, 2005. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. Treatment arms with the same regimen in terms of drug, type (continuous or intermittent), and dosage were combined to estimate the risk of an outcome of interest. RESULTS: We identified 122 studies with approximately 20,000 enrolled patients for planned comparison. The pooled risks (95% confidence intervals) of treatment discontinuation resulting from adverse reactions for continuous therapy were 3.44% (95% confidence interval [CI], 2.28%-4.61%) for terbinafine 250 mg/day; 1.96% (95% CI, 0.35%-3.57%) for itraconazole 100 mg/day; 4.21% (95% CI, 2.33%-6.09%) for itraconazole 200 mg/day; and 1.51% (95% CI, 0%-4.01%) for fluconazole 50 mg/day. For intermittent therapy, the pooled risks were as follows: pulse terbinafine: 2.09% (95% CI, 0%-4.42%); pulse itraconazole: 2.58% (95% CI, 1.15%-4.01%); intermittent fluconazole 150 mg/week: 1.98% (95% CI, 0.05%-3.92%); and intermittent fluconazole 300 to 450 mg/week: 5.76% (95% CI, 2.42%-9.10%). The risk of liver injury requiring termination of treatment ranged from 0.11% (continuous itraconazole 100 mg/day) to 1.22% (continuous fluconazole 50 mg/day). The risk of having asymptomatic elevation of serum transaminase but not requiring treatment discontinuation was less than 2.0% for all treatment regimens evaluated. CONCLUSION: Oral antifungal therapy against superficial dermatophytosis and onychomycosis, including intermittent and continuous terbinafine, itraconazole, and fluconazole, was associated with a low incidence of adverse events in an immunocompetent population.""",1
11372,17786067,"A randomized, double-blind, placebo-controlled parallel-group study to assess the efficacy and safety of nebivolol, a novel beta-blocker, in patients with mild to moderate hypertension","""This double-blind, multicenter, randomized placebo-controlled study evaluated the antihypertensive efficacy and safety of nebivolol, a selective beta1-adrenoreceptor blocker with vasodilating effects, in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] > or =95 mm Hg and < or =109 mm Hg). A total of 909 patients were randomized to receive placebo or nebivolol 1.25, 2.5, 5, 10, 20, or 40 mg once daily for up to 84 days. The primary end point was the change in trough SiDBP from baseline to study end. Nebivolol significantly reduced trough SiDBP (8.0-11.2 mm Hg compared with 2.9 mm Hg with placebo; P<.001) and trough sitting systolic blood pressure (a 4.4-9.5-mm Hg decrease compared with a 2.2-mm Hg increase [corrected] with placebo; P< or =.002). The overall adverse event experience was similar in the nebivolol (46.1%) and placebo (40.7%) groups (P=.273). Once-daily nebivolol is an effective antihypertensive in mild to moderate hypertensive patients.""",1
11373,17804204,Early-onset rhabdomyolysis related to daptomycin use,,1
11374,17806197,[Acute cholestatic hepatitis caused by simvastatine in a 67-year-old patient],"The following work presents the case of undesired during side effect (toxic hepatocellular damage ) by Simvastatine (Cardin). The main syptoms were jaundice and pruritus. Conclusions draw the attention to the role of history taking in the diagnosis of the described disease, as well as the importance of regular patient checkups whoin those use statines.",1
11375,17825686,Sunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors,"""BACKGROUND: Sunitinib was approved by the US Food and Drug Administration (FDA) on January 26, 2006, for the treatment of metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST) in patients who have failed to respond to imatinib or were unable to tolerate it. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of sunitinib; potential drug interactions; and the results of clinical trials evaluating its efficacy and tolerability. METHODS: Pertinent literature was identified by searches of MEDLINE (1966-January 31, 2007), the American Society of Clinical Oncology abstracts database (2000-2007 annual meetings/symposia and previous meetings), and the FDA Web site (October 2006). Search terms included, but were not limited to, sunitinib, SUl1248, renal cell carcinoma, gastrointestinal stromal tumor, pharmacology, pharmacokinetic, adverse events, and clinical trial. Additional publications were found by scanning the reference lists of the identified articles. RESULTS: Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors. Its Tmax is reached within 6 to 12 hours, and food does not appear to affect its bioavailability. Sunitinib is metabolized by cytochrome P450 (CYP) 3A4 to an active metabolite, SU12662, which is further metabolized by CYP3A4 to an inactive moiety. The parent compound and active metabolite have similar biochemical activity and potency and reach similar plasma concentrations. Sunitinib and SU12662 have a tl/2 of 40 to 60 hours and 80 to 110 hours, respectively. Steady-state concentrations of both active entities are reached after 10 to 14 days of therapy. In a Phase III trial comparing sunitinib with interferon-alfa (IFN-00 as first-line therapy for mRCC, sunitinib was associated with a median progression-free survival of 11 months, compared with 5 months with IFN-cz (P < 0.001). A randomized, double-blind, placebo-controlled trial evaluating sunitinib as second-line therapy for GIST found a median time to progression of 28.9 weeks in the sunitinib arm, compared with 7 weeks in the placebo arm (hazard ratio = 0.28; P < 0.001). In Phase II trials, sunitinib also had anti-tumor activity in patients with breast cancer, neuroendocrine tumors, and non-small cell lung cancer. Further evaluation in these tumors, as well as in patients with acute myelogenous leukemia, may lead to expanded indications. The approved dose of sunitinib is 50 mg/d PO for 4 weeks, followed by a 2-week rest; this pattern is repeated until tumor progression or the occurrence of intolerable adverse effects. The most common clinical toxicities attributable to sunitinib include diarrhea, mucositis/stomatitis, hypertension, rash, skin discoloration, and altered taste, whereas commonly occurring laboratory abnormalities have been seen in association with gastrointestinal toxicity, renal toxicity, and hematologic toxicity. Of grade 3/4 toxicities occurring with sunitinib (which are relatively uncommon [<10%]), those that are clinically important include hypertension, diarrhea, fatigue, and hand-foot syndrome. CONCLUSIONS: Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of mRCC and GIST. Evidence for long-term clinical benefit in renal cell cancer and other tumors awaits the results of ongoing trials.""",1
11376,17845269,Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials,"""OBJECTIVES: We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials in acute bipolar mania to summarize available data on drug treatment of mania. METHODS: We included trials of medications licensed in the USA or UK for the treatment of any phase of bipolar disorder. Outcomes investigated were changes in mania scores, attrition, extrapyramidal effects and weight change. Data were combined through meta-analyses. RESULTS: We included 13 studies (involving 3,089 subjects) and identified 2 studies for each of the following medications: carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate semisodium and aripiprazole. All drugs showed significant benefit compared with placebo for reduction in mania scores. Compared with placebo, for all antipsychotics pooled, response to treatment (> or =50% reduction in Young Mania Rating Scale scores) was increased more than 1.7 times [relative risk (RR) = 1.74, 95% confidence interval (CI) = 1.54, 1.96]; for all mood stabilizers pooled, response to treatment was doubled (RR 2.01, 95% CI = 1.66, 2.43). Overall withdrawals were 34% fewer (24-43%) with antipsychotics, and 26% fewer (10-39%) with mood stabilizers. However, for carbamazepine, aripiprazole and lithium an increase in risk of withdrawal could not be excluded. Small but significant increases in extrapyramidal side effects occurred with risperidone and aripiprazole. CONCLUSIONS: Antipsychotics and mood stabilizers are significantly more effective than placebo for the treatment of acute mania. Their effect sizes are similar. Small differences between effect sizes may be due to differences in the patients included in the studies or to chance. Carbamazepine and lithium may be more poorly tolerated, and antipsychotics cause more extrapyramidal side effects.""",1
11377,17845866,The measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist?,"""Hyperammonemia (HA) commonly occurs with the use of valproic acid (VPA); while it has no clinical significance in most cases, the Physician Desk Reference recommends its discontinuation in the presence of HA. The purpose of this study is to review the literature in order to estimate the prevalence and magnitude of HA in VPA treated patients, to establish any association with hepatotoxicity and encephalopathy and to identify any factors associated with its occurrence. A search of MEDLINE and Cochrane Database of Systematic Reviews, between 1980 and 2005 was performed. Out of 183 studies, 24 met our inclusion criteria. The prevalence of HA in the prospective studies ranged between 70% and 100%, while in cross-sectional studies it varied between 16% and 100%. Ammonia (NH(3)) blood levels increased by a two-fold average relative to the baseline levels. There was no association between HA and clinical symptoms. Concomitant administration of other antiepileptic drugs (AEDs) was the factor most frequently associated with HA.""",1
11378,17846778,Etanercept and adalimumab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons leading to discontinuation of the treatment,"In the present study, we determined from a single-center data the treatment continuation, discontinuation and reasons for discontinuation in the patients with active rheumatoid arthritis (RA) or spondyloarthropathies (SpA) who were treated with etanercept or adalimumab. All RA and SpA patients, who were treated with etanercept (n = 53) or adalimumab (n = 43) as their first biological treatment according to national guidelines in the Center for Rheumatic Diseases, Tampere University Hospital during the years 1999-2005, were analyzed at baseline and after 1-year treatment. The treatment was regarded ineffective if the clinical response was lower than ACR50 in RA or the reduction of BASDAI was lower than 50% or 2 cm in SpA. After 1 year, the continuation rate was 74% with etanercept and 60% with adalimumab. Mean prednisolone dose among continuers was diminished by 52% in etanercept-treated patients and by 44% in adalimumab-treated patients. During 1-year follow-up, 14 (26%) of the etanercept-treated patients and 17 (40%) of the adalimumab-treated patients discontinued the medication. Eleven patients were regarded as poor responders, seven in etanercept group and four in adalimumab group. Adverse events (mainly infections and injection reactions) caused six discontinuations in etanercept-treated group and 11 discontinuations in adalimumab-treated group. Etanercept was discontinued due to other adverse event in two patients: in one patient due to adenocarcinoma of ovary and in one patient due to drug-related leukopenia. One patient treated with adalimumab developed clinical and immunological features of systemic lupus erythematosus (SLE). In the present study, etanercept and adalimumab treatments were started in patients who had active RA or SpA despite ongoing treatment with combinations of traditional disease modifying antirheumatic drugs (DMARDs). Thirty-nine (74%) patients and twenty-six (60%) patients achieved at least 50% response when etanercept or adalimumab was added to their earlier DMARD treatment. Adverse events (mainly infections and injection reactions) were in line with previous reports. Three rare adverse events were reported: one patient with ovarial carcinoma, one with leukopenia and one with features of drug-induced SLE.",1
11379,17854362,Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome,"BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is an adverse reaction with clinical signs of fever, rash and internal organ involvement. In the vast majority of patients in Japan, the causative drugs for DIHS are limited to the following eight: carbamazepine, phenytoin, phenobarbital, zonisamide, mexiletine, dapsone, salazosulfapyridine and allopurinol. The association of human herpesvirus (HHV)-6 reactivation with DIHS has been reported by various groups. OBJECTIVES: To confirm the relationship between the flaring and severity of DIHS and HHV-6 reactivation. METHODS: We evaluated 100 patients with drug rash and systemic symptom(s) caused by the drugs associated with DIHS. HHV-6 reactivation was examined by serological antibody assay and quantitative real-time polymerase chain reaction assay of serial serum samples. RESULTS: Anti-HHV-6 IgG titres increased in 62 of 100 patients, 14-28 days after the onset of symptoms. These patients suffered from severe organ involvement and a prolonged course compared with 38 patients showing no reactivation of HHV-6. Significant amounts of HHV-6 DNA were detected in serum samples from 18 of the 62 patients. Flaring of symptoms such as fever and hepatitis was closely related to HHV-6 reactivation in these 18 patients. It should be emphasized that all five patients with fatal outcome and 10 patients with renal failure were in the HHV-6 reactivation group. CONCLUSIONS: A combination of immunological reaction to a drug and HHV-6 reactivation results in the severe course of DIHS. The demonstration of HHV-6 reactivation is a useful marker of diagnosis as well as prognosis in DIHS.",1
11380,17869635,"Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial","""BACKGROUND: After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS: In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS: Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION: Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.""",1
11381,17875115,Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study,"""BACKGROUND AND OBJECTIVE: An FDA Working Group, along with representatives of PhRMA and the American Association for the Study of Liver Diseases, as well as the Institute of Medicine Report 'To Err is Human: Building a Safer Health Care System' have suggested that post-marketing drug surveillance is a important method to decrease adverse drug events. While tetracyclines are known to cause hepatotoxicity, no post-marketing drug surveillance studies have examined the risk of developing hepatotoxicity with tetracyclines. Therefore, the objective of this study is to determine the difference in risk of hepatotoxicity in patients receiving doxycycline or tetracycline using California Medicaid claims. METHODS: This study used a retrospective, matched case-control study using California Medicaid claims data. The cases were defined as recipients who had at least one diagnosis of hepatotoxicity any time from 1 July 1999 to 31 December 2001. One control was identified for each case, matched on age, gender and race. Logistic regression was used to determine the adjusted odds ratio (OR) and 95% confidence intervals for current users and past users of tetracycline and doxycycline. Covariates controlled for in the analysis were age, use of other hepatotoxic drugs, renal dysfunction, pregnancy, and alcohol or illicit drug use. RESULTS: A total of 3377 cases of hepatotoxicity were identified. Current users and past users of tetracycline had a statistically significant increased risk of developing hepatotoxicity (current use OR 3.70, 95% CI 1.19-11.45; past use OR 2.72, 95% CI 1.26-5.85). Current users or past users of doxycycline did not have an increased risk of developing hepatotoxicity (current use OR 1.49, 95% CI 0.61-3.62; past use OR 1.74, 95% CI 0.99-3.06). Tetracycline was commonly used for acne, acute bronchitis and upper respiratory infections. Doxycycline was commonly used for acute bronchitis, vaginitis and acne. DISCUSSION AND CONCLUSION: Doxycycline was potentially less hepatotoxic than tetracycline. Doxycycline could potentially be a safe substitute for tetracycline, when appropriate.""",1
11382,17876158,[Reactivation of hepatitis B virus due to rituximab plus CHOP after preemptive lamivudine administration in a patient with diffuse large B-cell lymphoma],"A 59-year-old woman received eight cycles of R-CHOP for diffuse large B-cell lymphoma from July, 2004. Pretreatment HBV serological tests were positive, however, the transaminases were within normal limits, and she remained asymptomatic. Lamivudine (LAM) was administered orally from the start of R-CHOP. HBV-DNA levels gradually decreased and were not detected until December, 2004. LAM was administered until 3 months after the end of chemotherapy, with the entire treatment lasting less than 1 year. Two months after the cessation of treatment, she was re-admitted for general malaise. A liver function test revealed severe abnormalities, and HBVDNA levels were increased. Clinically, she was experiencing acute hepatitis due to HBV reactivation. She was then treated with LAM and interferon-beta immediately. Her HBV-DNA levels soon decreased, and liver function improved.",1
11383,17877444,The safety of rosuvastatin: effects on renal and hepatic function,"Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to reduce elevated serum cholesterol resulting in a reduced risk of coronary artery disease and its complications. Rosuvastatin is the latest of the class of HMG-CoA reductase inhibitors and has the most potent reduction of low-density lipoprotein and elevation of high-density lipoprotein in the class. Questions have been raised about its safety. In a careful examination of the data, rosuvastatin has the same rate of elevations of hepatic enzymes as the other statins. Whether any of the statins actually cause significant liver injury is doubtful, and this raises questions about the usefulness of routine monitoring of liver enzymes in statin patients. Rosuvastatin has been noted to produce low levels of transient proteinuria. However, transient proteinuria is seen with other comparable statins. Long-term administration of rosuvastatin and other statins have been shown not to be associated with any decline in renal function, but instead have been shown to produce modest but clear improvement in glomerular filtration rate. Therefore, it is clear that rosuvastatin, and other statins, are very safe and useful agents and do not appear to present significant risks to hepatic or renal safety.",1
11384,17878423,Prescribing amiodarone: an evidence-based review of clinical indications,"""CONTEXT: Although amiodarone is approved by the US Food and Drug Administration only for refractory ventricular arrhythmias, it is one of the most frequently prescribed antiarrhythmic medications in the United States. OBJECTIVE: To evaluate and synthesize evidence regarding optimal use of amiodarone for various arrhythmias. EVIDENCE ACQUISITION: Systematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other studies with clinical pertinence. The search was limited to human-participant, English-language reports published between 1970 and 2007. Amiodarone was searched using the terms adverse effects, atrial fibrillation, atrial flutter, congestive heart failure, electrical storm, hypertrophic cardiomyopathy, implantable cardioverter-defibrillator, surgery, ventricular arrhythmia, ventricular fibrillation, and Wolff-Parkinson-White. Bibliographies of identified articles and guidelines from official societies were reviewed for additional references. Ninety-two identified studies met inclusion criteria and were included in the review. EVIDENCE SYNTHESIS: Amiodarone may have clinical value in patients with left ventricular dysfunction and heart failure as first-line treatment for atrial fibrillation, though other agents are available. Amiodarone is useful in acute management of sustained ventricular tachyarrythmias, regardless of hemodynamic stability. The only role for prophylactic amiodarone is in the perioperative period of cardiac surgery. Amiodarone may be effective as an adjunct to implantable cardioverter-defibrillator therapy to reduce number of shocks. However, amiodarone has a number of serious adverse effects, including corneal microdeposits (>90%), optic neuropathy/neuritis (< or =1%-2%), blue-gray skin discoloration (4%-9%), photosensitivity (25%-75%), hypothyroidism (6%), hyperthyroidism (0.9%-2%), pulmonary toxicity (1%-17%), peripheral neuropathy (0.3% annually), and hepatotoxicity (elevated enzyme levels, 15%-30%; hepatitis and cirrhosis, <3% [0.6% annually]). CONCLUSION: Amiodarone should be used with close follow-up in patients who are likely to derive the most benefit, namely those with atrial fibrillation and left ventricular dysfunction, those with acute sustained ventricular arrhythmias, those about to undergo cardiac surgery, and those with implantable cardioverter-defibrillators and symptomatic shocks.""",1
11385,17883521,Meta-analysis examining the efficacy and safety of almotriptan in the acute treatment of migraine,"""OBJECTIVE: To evaluate the comparative efficacy and safety of oral almotriptan in treating acute migraine attacks. BACKGROUND: Almotriptan is an oral selective sertonin(1B/1D) receptor agonist (triptan) with a high bioavailability and short half-life, developed for the treatment of migraine. In recent years, a number of randomized controlled trials have been published examining the efficacy and safety of almotriptan in the acute treatment of migraine. METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs) using a random-effects model to estimate the pooled rate ratios (RRs) and 95% confidence intervals (95%CI) for the proportions of patients achieving headache relief and pain-free responses at 1 or 2 hours post-dose, sustained pain-free response at 2-24 hours post-dose, and safety outcomes (proportions of patients experiencing any adverse events, dizziness, somnolence, asthenia, and chest tightness) comparing almotriptan against placebo, other triptans, and different dosages of almotriptan. Absolute rate differences (ARDs) for 2-hour headache relief, pain free, and sustained pain free responses between almotriptan and placebo were also calculated. RESULTS: Eight RCTs involving 4995 patients were included in the analysis. Almotriptan 12.5 mg was significantly more effective than placebo for all efficacy outcomes (RRs ranged from 1.47 to 2.15; ARDs ranged from 0.01 to 0.28) and there were no significant differences in any of the safety outcomes. There were also no significant differences in efficacy outcomes comparing almotriptan 12.5 mg against sumatriptan 100 mg and zolmitriptan 2.5 mg, but almotriptan 12.5 mg was associated with significantly fewer adverse events than sumatriptan 100 mg (RR: 0.39, 95%CI: 0.23, 0.67). However, there was no significant difference between almotriptan and sumatriptan in terms of clinically important adverse effects, such as dizziness, somnolence, asthenia, and chest tightness. Almotriptan 12.5 mg was significantly less effective than almotriptan 25 mg for 1-hour pain-free response (RR: 0.45, 95%CI: 0.21, 0.95), but associated with significantly fewer patients experiencing adverse events (RR: 0.61, 95%CI: 0.41, 0.91) than almotriptan 25 mg. CONCLUSIONS: Almotriptan 12.5 mg is an effective treatment for acute attacks of migraine, in particular, it has been found to be as effective as sumatriptan 100 mg and zolmitriptan 2.5 mg. The risk of adverse events associated with almotriptan 12.5 mg was similar to placebo and significantly lower than sumatriptan 100 mg. Further research is required to assess the comparative efficacy of almotriptan against other triptans.""",1
11386,17892995,"Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial","BACKGROUND: Fibrinolytic therapy for acute myocardial infarction (AMI) results in normal flow in only about half of patients. Adjunctive treatment with potent antiplatelet and antithrombin agents increases arterial patency but is associated with excessive bleeding. Cangrelor (formerly AR-C69931MX) is a rapidly acting, specific antagonist of platelet aggregation via binding to the adenosine diphosphate P2Y12 receptor subtype. The aim of this study was to assess the safety and coronary artery patency of cangrelor as an adjunct to alteplase (tissue plasminogen activator [t-PA]). METHODS: Patients with AMI received aspirin, heparin, and an intravenous infusion of either cangrelor alone, full-dose t-PA alone, or 1 of 3 doses of cangrelor along with half-dose t-PA. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 60 minutes. Secondary end points included TIMI frame count, TIMI myocardial perfusion grade, extent of ST-segment resolution, composite clinical events, and bleeding. RESULTS: Ninety-two of planned 180 patients were enrolled. The combination of cangrelor and half-dose t-PA resulted in similar 60-minute patency as full-dose t-PA alone (55% vs 50%, P = not significant) and greater patency than with cangrelor alone (55% vs 18%, P < .05). The percentage of patients achieving >70% ST-segment resolution at 60 minutes tended to be greater with combination therapy than with either cangrelor or t-PA alone (28% vs 13%, P = .13 and 28% vs 14%, P = .30, respectively). Bleeding and adverse clinical events were comparable among the groups. CONCLUSION: This first experience with the intravenous P2Y12 receptor inhibitor, cangrelor, suggests the potential of this compound as an adjunct to fibrinolysis during treatment of AMI.",1
11387,17898558,Alfuzosin-induced acute liver injury,"We describe a 56-year-old man who developed an acute liver injury after taking alfuzosin for 1 month to control his newly diagnosed benign prostatic hypertrophy (BPH). There was no history of alcohol consumption or the taking herbal or traditional remedies. Viral causes, autoimmune hepatitis, and biliary tree obstruction were excluded. Other rare causes of hepatitis such as hemochromatosis, primary biliary cirrhosis and Wilson's disease were also absent in this patient. His liver test results began to improve after discontinuing the alfuzosin. Two weeks later, alfuzosin was administered again because the patient complained of dysuria. After 10 days of alfuzosin reuse, his liver test results worsened. Five months later after the complete discontinuation of the drug, his liver test results had returned to normal. This clinical sequence suggests that alfuzosin caused his acute liver injury.",1
11388,17900246,Anabolic-androgenic steroids and liver injury,"Athletes and nonathletes have been using anabolic-androgenic steroids (AAS) for a long time, in an inadequate and unsurveilled manner, with the aim of improving sports performance or for cosmetic purposes. AAS consumption is becoming more widespread and involving younger people, and there is a trend for self-administration of higher doses and for combining AAS with other potentially harmful drugs. Almost any subject abusing AAS will experience adverse effects. Therefore, adverse effects from these exposures, including liver toxicity, are expected to increase in the years to come. The present manuscript describes a representative case of intrahepatic cholestasis with the intention to discuss AAS-related liver toxicity (including the potential therapeutic role of ursodeoxycholic acid) and to comment on several aspects of the clinical scenario the gastroenterologist should be aware of.",1
11389,17909306,Results from a 2-year centralized tolcapone liver enzyme monitoring program,"""OBJECTIVES: Tolcapone, administered with levodopa/carbidopa to patients with Parkinson disease, is an effective and generally well-tolerated adjunctive therapy. However, 4 early cases of hepatotoxicity causing 3 deaths in patients not properly monitored gave rise to more rigorous liver function test monitoring guidelines and a liver function test monitoring program in which blood samples from tolcapone-treated patients were tested and results were collected in a central database. We analyzed these results to determine the percentages of patients with at least 1 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation above the upper limit of normal (ULN) and at least 1 elevation greater than 2 times the ULN. METHODS: This retrospective, observational analysis included all AST and ALT values recorded in the database from 11,883 samples from patients who received tolcapone for up to 2 years or longer (January 1999-January 2001). RESULTS: Of 1725 patients who had at least 1 AST or ALT measurement, 3.9% (n = 67) had elevations above the ULN. Less than 1% (15/1725) of patients had AST or ALT elevations greater than 2 times the ULN. Most values returned to normal during continued tolcapone treatment. In 472 patients monitored biweekly while receiving tolcapone for 20 to 114 consecutive weeks, only 0.6% (n = 3) had an AST or ALT value greater than 2 times the ULN; no significant elevations occurred in the remaining 469 (99.4%). CONCLUSIONS: This analysis of results from the central monitoring program suggests that significant transaminase elevations are rare, typically transient, and may return to normal in the face of continued tolcapone therapy in most patients.""",1
11390,17910522,Atorvastatin: a safety and tolerability profile,"Extensive data are available on the safety of atorvastatin from randomised clinical trials, postmarketing analyses and reports to regulatory agencies. Atorvastatin is generally well tolerated across the range of therapeutic dosages, with the exception of a slightly higher rate of liver enzyme elevations with atorvastatin 80 mg/day which does not appear to confer an increased risk of clinically important adverse events. Unlike simvastatin, atorvastatin is associated with a low incidence of muscular toxicity. It is not associated with neurological, cognitive or renal adverse effects and does not require dosage adjustment in patients with renal dysfunction, due to its favourable pharmacokinetic profile, which is unique among the statins. In patients aged > or =65 years, atorvastatin is well tolerated with no dose-dependent increase in adverse events up to the maximum daily dosage of 80 mg/day. Thus, atorvastatin is a safe and well tolerated statin for use in a wide range of patients.",1
11391,17916050,Daclizumab,"Daclizumab is a humanized monoclonal antibody which binds to the IL-2 receptor on activated lymphocytes and blocks the production of IL-2. Its use is well established in solid organ transplantation as induction therapy, especially in high-risk patients where reduction or delayed dose of standard immunosuppression would be beneficial. It has been used effectively in both 2-dose and 5-dose regimens in conjunction with other standard immunosuppressive agents. The incidence of acute rejection appears reduced without increasing the rates of infection or post-transplant lympho-proliferative disorders. The agent is generally well tolerated in adults and children and there is no need for additional monitoring. Daclizumab has also been used outside the transplant arena in a variety of immune-mediated diseases with limited success.",1
11392,17917083,A case-control study of non-alcoholic fatty liver disease in breast cancer,"""BACKGROUND: Patients with breast cancer sometimes present with increased liver enzymes during follow-up period that may be consistent with hepatic steatosis. This effect known as non-alcoholic fatty liver disease may be associated with the malignancy itself, drugs or some other well-known risk factors that may induce steatosis. We studied the influences of primary disease and treatment on steatosis in patients with breast cancer. MATERIALS AND METHODS: There were four groups of patients in our study. Group 1: 40 newly diagnosed, previously untreated breast cancer; Group 2: 45 cases of breast cancer treated with systemic therapy; Group 3: 40 cases of ovarian cancer; Group 4: 40 healthy women. Hepatic steatosis was evaluated by sonography by two radiologist, independently. We also evaluated major risk factors, biochemical findings, and influences of treatment on hepatic steatosis. RESULTS: We detected steatosis in 63%, 72%, 77%, and 48% of patients in groups 1, 2, 3, and 4, respectively. There was a statistically significant difference only between groups 3 and 4 (P = 0.045). However, grade 2 and 3 steatosis were more frequent in breast cancer patients (group 1 and 2), compared with mild steatosis in ovarian cancer patients and healthy women. Although a good correlation was found between tamoxifen use and chemotherapy on development of non-alcoholic fatty liver disease, no association of hepatic steatosis with transaminase levels was found, which might be of help for earlier detection of steatosis. AST/ALT ratio was found to have no impact on the rate of hepatic steatosis, contrary to the literature. CONCLUSION: Hepatic steatosis, excluding patients with grade 1 steatosis, which may be a normal variant, were more readily detected in patients with breast cancer. This effect was aggravated by use of tamoxifen, but not the chemotherapy. Non-alcoholic fatty liver disease in patients with breast cancer may be associated with the primary tumor itself or some well-known risk factors such as obesity, hyperlipidemia, and diabetes mellitus, which needs to be explored.""",1
11393,17919553,Acute hepatitis attack after exposure to telithromycin,"""INTRODUCTION: Antibiotic-associated hepatotoxicity is rare. With widespread use of antimicrobial agents, however, hepatic injury occurs frequently, and among adverse drug reactions, idiosyncratic reactions are the most serious. CASE SUMMARY: A 25-year-old male patient, with a height of 175 cm and weight of 72 kg presented to Marmara University Hospital Emergency Department, Istanbul, Turkey, with 5 days' history of jaundice, malaise, nausea, and vomiting. He had been prescribed telithromycin 400 mg/d PO to treat an upper respiratory tract infection 7 days prior. Admission laboratory tests were as follows: alanine aminotransferase, 67 U/L (reference range, 10-37 U/L); aspartate aminotransferase, 98 U/L (10-40 U/L); alkaline phosphatase, 513 U/L (0-270 U/L); gamma-glutamyltransferase, 32 U/L (7-49 U/L); amylase, 46 U/L (0-220 U/L); total bilirubin, 20.1 mg/dL (0.2-1.0 mg/dL); direct bilirubin, 14.8 mg/dL (0-0.3 mg/dL); and albumin, 4.7 mg/dL (3.5-5.4 mg/dL). No toxin, alcohol, or other drugs were reported. The patient had suffered a previous episode of """"acute hepatitis of unknown origin,"""" that occurred after telithromycin usage. Both incidents occurred within a year. DISCUSSION: Telithromycin is the first of the ketolide antibacterials to receive US Food and Drug Administration approval for clinical use. It has been associated with infrequent and usually reversible severe hepatic dysfunction. Based on a score of 8 on the Naranjo adverse drug reaction probability scale, telithromycin was the probable cause of acute hepatitis in this patient, and pathological findings suggested drug-induced toxic hepatitis. Recurrence of hepatitis attack might have been avoided if the initial incident had been communicated to the attending physician who prescribed telithromycin the second time. CONCLUSION: Here we report a case of acute hepatitis probably associated with the administration of telithromycin.""",1
11394,17922899,"Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell)","""BACKGROUND: The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihydrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. METHODS: Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. RESULTS: The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum. The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges on week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05-2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18-6.97]. Nicotinell lozenges were found to be safe with mainly mild and reversible adverse events. The safety of the 1 mg lozenge formulation, even when misused was also demonstrated. CONCLUSION: The data presented in this review demonstrate high nicotine bioavailability, excellent safety profile and proven short-term efficacy of Nicotinell lozenges. At nominal equivalent doses 1 and 2 mg Nicotinell lozenges were shown to deliver larger amounts of bioavailable nicotine compared to the nicotine polacrilex gum. According to the data developed here, the systemic exposure to nicotine could be ranked: 4 mg polacrilex gum > 2 mg Nicotinell lozenge > 1 mg Nicotinell lozenge = 2 mg polacrilex gum.Adverse events observed during the clinical trials were mild or moderate in severity, transient and completely reversible. With respect to efficacy in smoking cessation, significantly higher continuous abstinence rates were achieved with lozenge compared to placebo. In conclusion, Nicotinell lozenges offer a valuable addition to the therapeutic armamentarium available for smoking cessation.""",1
11395,17927491,Linezolid: effectiveness and safety for approved and off-label indications,"Multi-drug resistant Gram-positive cocci have emerged as significant pathogens of community- and hospital-acquired infections. Several antimicrobial agents that can be used for the treatment of these infections are presently available. However, the most appropriate treatment for each infection has not been established. Linezolid seems to be a promising choice. Linezolid is bactericidal against Streptococci and bacteriostatic against Enterococci and Staphylococci. It has excellent pharmacokinetic and pharmacodynamic profiles, which allow early change from intravenous to oral administration. In addition, its effectiveness for the treatment of Gram-positive infections in immunocompetent and immunodeficient patients have been studied in several randomized controlled trials. In this review, the authors summarize all the available evidence regarding the effectiveness and safety of linezolid compared with other antimicrobial agents for its approved and off-label indications.",1
11396,17931091,The use of colesevelam hydrochloride in the treatment of dyslipidemia: a review,"Bile-acid sequestrants augment cholesterol excretion via enhanced conversion to bile acids, and act to lower low-density lipoprotein cholesterol (LDL-C), especially when combined with other cholesterol-lowering drugs. Colesevelam hydrochloride (HCL) has become the preferred drug of this class due to fewer gastrointestinal adverse effects. This article reviews the use of colesevelam in the treatment of dyslipidemia. Bile-acid sequestrants are a class of drugs developed to lower LDL-C levels. Two of the bile-acid sequestrants, colestyramine resin and colestipol, have been used since the 1980s, and have proven effective and safe as nonsystemic approaches to cholesterol reduction. However, tolerability and compliance issues related to palatability and gastrointestinal side effects have limited the use of these sequestrants. Colesevelam HCL (Daiichi Sankyo, Inc., Parsippany, NJ) is a nonabsorbed lipid-lowering agent that can be used in monotherapy or in combination with an HMG-CoA reductase inhibitor to reduce LDL-C in patients with primary hypercholesterolemia (Fredrickson type IIa). This article reviews the clinical efficacy and use of colesevelam HCL for the management of dyslipidemia.",1
11397,17935234,"Rotigotine transdermal patch in early Parkinson's disease: a randomized, double-blind, controlled study versus placebo and ropinirole","Rotigotine is a new, non-ergot dopamine agonist formulated in a transdermal delivery system. The present study was to investigate the efficacy and safety of the rotigotine transdermal patch in the treatment of early Parkinson's disease. Patients (n = 561) were randomized to rotigotine, ropinirole, or placebo. The titration period was up to 13 weeks, and there was a minimum dose-maintenance period of 24 weeks for ropinirole and 33 weeks for rotigotine. The primary endpoint was the proportion of patients with a minimum of 20% decrease in the combined Unified Parkinson's Disease Rating Scale Part II and Part III scores. The responder rate in the rotigotine group was significantly higher than in the placebo group (52% vs. 30%, P < 0.0001). Transdermal rotigotine at doses < or =8 mg/24 h did not show noninferiority to ropinirole at doses < or =24 mg/day. In a post-hoc subgroup analysis, rotigotine < or =8 mg/24 hours had a similar efficacy to ropinirole at doses < or =12 mg/day. The rotigotine transdermal patch was well tolerated. The most common adverse events were application-site reactions, nausea, and somnolence. Application-site reactions were predominantly mild or moderate in intensity. In conclusion, the rotigotine transdermal patch represents an effective and safe option for the treatment of patients with early Parkinson's disease.",1
11398,17936403,Predictors of toxicity of weekly docetaxel in chemotherapy-treated non-small cell lung cancers,"""Weekly docetaxel seems to be safe and effective compared with traditional tri-weekly docetaxel as a second-line treatment for non-small cell lung cancer. However, the risk factors for severe toxicity of weekly docetaxel in this group of patients are not well-described. Patients with advanced non-small cell lung cancer receiving weekly docetaxel as second- or third-line treatment at a medical center between 1999 and 2003 were identified from cancer registry and pharmacy records. The clinical characteristics, prior chemotherapy regimens, docetaxel administration schedules, and treatment efficacy were collected. Logistic regression was performed to identify risk factors for adverse outcomes and Cox's proportional hazards model was used to analyze cumulative-dose related adverse events. A total of 155 patients were analyzed for treatment effect and toxicity. The overall response rate of weekly docetaxel was 5.2% and the median survival was 8.1 months. The incidence of treatment withdrawal due to adverse events was 43.2% and was significantly related to previous anthracycline use (odds ratio, 4.582; p=0.0144) and chronic hepatitis B or C virus infection (odds ratio, 3.928; p=0.0058). The incidence of grade 3 or 4 neutropenia was 23.2% and was significantly associated with old age (odds ratio, 7.232; p<0.001), lower baseline white blood cell counts (odds ratio, 5.57; p<0.05), and chronic hepatitis B or C virus infection (odds ratio, 3.25; p<0.05). The incidence of fluid retention was 41.3% and the median cumulative dose of docetaxel at onset was 327 mg/m(2). Abnormal liver function status significantly increased the risk for fluid retention (odds ratio, 2.368; p<0.05); while pre-medication with steroids (odds ratio, 0.184; p<0.01), elevated albumin (odds ratio, 0.237; p<0.01), and previous surgical resection (odds ratio, 0.341; p<0.05) decreased the risk. Weekly docetaxel given as second- or third-line chemotherapy to patients with advanced non-small cell lung cancer harbors significant side effects. It should be given cautiously in elderly patients and in patients with chronic viral hepatitis or low white blood cell counts.""",1
11399,17938425,Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group,"""BACKGROUND: This phase III study was designed to compare the combination paclitaxel (Taxol)-gemcitabine (PG) versus carboplatin-gemcitabine (CG) in patients with advanced inoperable non-small-cell lung cancer. METHODS: Chemotherapy-naive patients with performance status of zero or one were randomized to gemcitabine 1 gm/m(2) on days 1 and 8 plus either paclitaxel 200 mg/m(2) on day 1 (arm A) or carboplatin at an area under the concentration-time curve of 6 mg on day 1 (arm B) every 3 weeks. Primary end point was overall survival (OS). Secondary end points included objective response (OR), time to progression and toxicity. RESULTS: A total of 512 patients were enrolled and 452 eligible (arm A, 225; arm B, 227) were analyzed. All characteristics were well balanced with the exception of vena cava obstruction symptoms and lymph node involvement. Median survival was 9.97 months [95% confidence interval (CI) 8.74-12.0] for group A and 10.49 (95% CI 9.04-11.94) for group B. There was no difference in the OS, 1-year survival, OR and TtP. However, statistically significant differences were seen in toxicity. CONCLUSION: The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group.""",1
11400,17939344,Amiodarone-induced hepatitis and polyneuropathy,"Amiodarone chlorhydrate is a diiodated benzofuran derivative, and it is used to treat cardiac rhythm abnormalities. Hepatotoxicity is a relatively uncommon side effect of amiodarone, and symptomatic hepatic dysfunction occurs in fewer than 1% of the patients taking amiodarone. Cirrhosis is a rare complication that's been confirmed in 12 cases. Peripheral neuropathy occurs in 10% of patients taking aminodarone. We report here on an unusual case of amiodarone-induced hepatotoxicity and peripheral neurotoxicity. A 75 year old man with normal liver function was given amiodarone for treating his atrial fibrillation and heart failure. He developed nausea, vomiting, muscle weakness and wasting after 17.8 months therapy with amiodarone (400 mg orally once per day). Liver biopsy showed the presence of foam cells in the hepatic sinusoids and Mallory bodies in the periportal hepatocytes on light microscopy. Sural nerve biopsy showed demyelination, and nerve conduction studies showed mixed sensorimotor polyneuropathy. These observations show the necessity of monitoring the hepatic function and conducting neurologic examination of the patients treated with amiodarone.",1
11401,17943403,A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease,"""OBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.""",1
11402,17943763,Loxapine for schizophrenia,"""BACKGROUND: Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical. OBJECTIVES: To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: For this 2007 update, we searched the Cochrane Schizophrenia Group's Register (January 2007). SELECTION CRITERIA: We included all randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments. DATA COLLECTION AND ANALYSIS: We independently inspected abstracts ordered papers, re-inspected and quality assessed these. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a fixed effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed effects model. MAIN RESULTS: We were able to include 41 studies in this review. Compared with placebo, loxapine has an antipsychotic effect (Global effect - not improved at six weeks: n=78, 2 RCTs, RR 0.30 CI 0.1 to 0.6 NNT 3 CI 3 to 5). It is as effective as typical drugs in the short term (4 -12 weeks) (Global effect: n=580, 13 RCTs, RR 0.86 CI 0.7 to 1.1; mental state: n=915, 6 RCTs, RR 0.89 CI 0.8 to 1.1). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. Loxapine is also as effective as atypicals (risperidone, quetiapine) (n=468, 6 RCTs, RR mental state not improved 1.07 CI 0.8 to 1.5). Adverse effect profile is similar to typicals but loxapine may cause more extrapyramidal adverse effects when compared with atypicals (n=340, 4 RCTs, RR 2.18 CI 1.6 to 3.1). AUTHORS' CONCLUSIONS: Loxapine is an antipsychotic which is not clearly distinct from typical or atypical drugs in terms of its effects on global or mental state. Loxapines profile of adverse effects is similar to that of the older generation of antipsychotic drugs.""",1
11403,17947726,Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer,"""PURPOSE: The addition of either capecitabine or erlotinib to gemcitabine in the first-line treatment of advanced pancreatic cancer is associated with modest improvements in overall survival. We evaluated an oral regimen of capecitabine and erlotinib in patients with advanced pancreatic cancer who had experienced treatment failure with standard first-line therapy with gemcitabine. PATIENTS AND METHODS: Thirty patients with gemcitabine-refractory metastatic pancreatic cancer were treated with capecitabine, administered at a dose of 1,000 mg/m2 twice daily for 2 weeks, followed by a 1-week break. All patients also received erlotinib 150 mg daily. Patients were observed for evidence of response, toxicity, and survival. EGFR mutational status was assessed in available tumor blocks. RESULTS: Treatment with capecitabine and erlotinib in gemcitabine-refractory patients was associated with an overall objective radiologic response rate of 10% and a median survival duration of 6.5 months. In addition, 17% of the treated patients experienced decreases in tumor marker (CA 19-9) levels of more than 50% from baseline. Common toxicities included diarrhea, skin rash, fatigue, and hand-foot syndrome. EGFR mutations were detected in two of five available tumors; no association between treatment response and EGFR mutational status was evident. CONCLUSION: The combination of capecitabine and erlotinib is active in patients with gemcitabine-refractory pancreatic cancer. This regimen may represent an acceptable treatment option in patients who experience treatment failure with standard first-line therapy with gemcitabine or for whom gemcitabine may not be an appropriate first-line treatment option.""",1
11404,17950795,Long-term efficacy and safety of rosuvastatin 40 mg in patients with severe hypercholesterolemia,"Patients with elevated low-density lipoprotein (LDL) cholesteral levels are at high risk of cardiovascular events but are often undertreated and fail to achieve lipid goals. This open-label, noncomparative, multicenter study assessed efficacy and safety of rosuvastatin 40 mg for < or =96 weeks in 1,380 patients with severe hypercholesterolemia, including heterozygous familial hypercholesterolemia. Patients > or =18 years old with fasting LDL cholesterol > or =190 and < or =260 mg/dl and triglycerides <400 mg/dl entered a 6-week dietary lead-in, before receiving rosuvastatin 40 mg for 48 weeks. An optional additional 48-week treatment period followed. The initial period had 2 primary end points: percentage of patients achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL cholesterol goals at 12 weeks, and long-term safety, assessed during 48 weeks by incidence and severity of adverse events (AEs) and abnormal laboratory values. Safety was the primary end point in the extension period. At 12 weeks, 83% of patients achieved NCEP ATP III LDL cholesterol goals, which were maintained during 48 and 96 weeks (81% and 84%, respectively). At 48 weeks, rosuvastatin 40 mg reduced LDL cholesterol from baseline by 52% and increased high-density lipoprotein (HDL) cholesterol by 11% (both p <0.0001). At 96 weeks, LDL cholesterol was reduced by 54% and HDL cholesterol increased by 13%. Rosuvastatin 40 mg was well tolerated during 96 weeks. The overall pattern and incidence of AEs and abnormal laboratory values were consistent with the published safety profile of rosuvastatin and higher doses of other statins. In conclusion, long-term treatment with rosuvastatin 40 mg is safe and effective in patients with severe hypercholesterolemia.",1
11405,17956959,Tobramycin-induced hepatotoxicity,"""OBJECTIVE: To report a case of tobramycin-induced hepatotoxicity. CASE SUMMARY: A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3-6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values. DISCUSSION: This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive timeline present, lack of specific symptoms, and unnecessary risk to the patient. CONCLUSIONS: Although no other case reports on this interaction have been published through October 9, 2007, historical data from tertiary sources reveal the possibility of aminoglycoside-induced hepatotoxicity; therefore, tobramycin-induced hepatotoxicity cannot be ruled out in this patient. Clinicians should be aware of this adverse event.""",1
11406,17959415,Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study,"""BACKGROUND: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment. METHODS: Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011. FINDINGS: In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44.2% (95% CI 30.5-58.7). Median response duration was 23.0 months (20.9-not estimable; range 4.2-29.8). However, 12 of 23 initial responders progressed with response duration ranging from 4.2 months to 26.5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15.7 months (8.4-23.4, range 0.03-31.5) and median overall survival was 29.9 months (20.3-not estimable; range 2.4-35.8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline. INTERPRETATION: Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.""",1
11407,17960962,Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial,"OBJECTIVE: This 6-week trial assessed the efficacy, tolerability, and safety of the investigational psychopharmacologic agent asenapine versus placebo and risperidone in patients with acute schizophrenia (DSM-IV criteria). METHOD: In a study conducted from August 2001 to May 2002, patients were randomly assigned to receive sublingual asenapine 5 mg b.i.d., placebo b.i.d., or oral risperidone 3 mg b.i.d. The primary outcome measure was improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included changes in Clinical Global Impressions-Severity of Illness (CGI-S) score and scores on PANSS positive, negative, and general psychopathology subscales. RESULTS: The intent-to-treat population comprised 174 patients who received >or= 1 dose of study drug and >or= 1 postbaseline assessment. At study end or last observation, mean improvements on PANSS total, negative subscale, and general psychopathology subscale scores were all significantly greater with asenapine than with placebo (p < .005, p = .01, and p < .005, respectively). Compared with placebo, improvements on CGI-S and PANSS positive subscale scores were significantly greater with both asenapine (p < .01 and p = .01) and risperidone (p < .005 and p < .05). Overall incidence rates of adverse events were comparable for asenapine and placebo, whereas risperidone was associated with substantial weight gain and prolactin elevation. CONCLUSION: Asenapine was effective and well tolerated in patients with acute schizophrenia and may provide a new option for control of negative symptoms.",1
11408,17966956,Marked elevation of liver transaminases after high-dose fluvastatin unmasks chronic hepatitis C: safety and re-challenge,"""The statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have emerged as the drugs of choice for patients with dyslipidemia and have been shown to reduce major cardiovascular adverse events in large-scale clinical trials for both primary and secondary prevention. Statins are generally safe; however, the results of clinical trials do demonstrate possibilities of significant adverse effects in liver and muscle. Moreover, the numbers from the trials may not reflect the real situation in daily practice because individuals at increased risk for hepatotoxicity are usually deliberately and carefully excluded in clinical trials. We presented an 85-year-old woman who had a marked elevation of ALT (up to 409 U/L) after treatment with fluvastatin 80 mg/day for 6 weeks. Hepatitis C was identified after this episode. The elevation of ALT resolved 10 weeks after discontinuation of fluvastatin. Re-institution of fluvastatin from 40 to 80 mg/day for 2 months only cause mild elevation of ALT. This case suggests that elevation of transaminases during statin therapy may not be solely ascribed to statins. Re-challenge with the same statin at lower doses or with other statins may help to identify the patients who can still be treated with drugs of this category.""",1
11409,17979620,Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis,"Autoimmune hepatitis is a rare but increasingly recognised serious complication of treatment with the tumour necrosis factor-alpha (TNF-alpha) blocking agent, infliximab. This report adds to the small but growing number of articles describing this significant adverse effect. Baseline liver function should be routinely tested in all patients receiving anti-TNF-alpha agents, and periodic monitoring for the development of hepatitis is important.",1
11410,17980139,[Patient with autoimmune hepatitis and idiopathic thrombocytopenic purpura after minocycline therapy],,1
11411,17982182,Prasugrel versus clopidogrel in patients with acute coronary syndromes,"""BACKGROUND: Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention. METHODS: To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. RESULTS: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002). CONCLUSIONS: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591 [ClinicalTrials.gov].)""",1
11412,17984315,Lenalidomide-induced severe hepatotoxicity,,1
11413,17987884,Update on ovarian hyperstimulation syndrome: Part 1--Incidence and pathogenesis,"Ovarian hyperstimulation syndrome (OHSS) is a rare and potentially life-threatening complication during controlled ovarian stimulation. It can be associated with severe morbidity and may even be fatal. The etiology of the condition and predisposing factors are still not fully understood. Data concerning pathophysiology in patients with OHSS were searched using PubMed and other medical data bases. The incidence of severe OHSS, as calculated by World Health Organization (WHO), is 0.2-1% of all stimulation cycles in assisted reproduction. Considerations on OHSS classifications and forms of manifestations are discussed in detail. New insights concerning genetics and altered FSH receptor are given. OHSS may involve, according to its grade of severity, elevated or decreased levels of growth factors, cytokines, mediators, changes in hormones, renin-angiotensin and kinin-kallikrein system. There are massive electrolytic imbalances and changes in hemodynamic and fluid metabolism. Furthermore, liver and pulmonary dysfunction is observed as well as increased coagulation with subsequent thromboembolism. The influence of OHSS on the pregnancy rate and outcome of pregnancy is a matter of controversy. Patients with OHSS have high pregnancy rates with a tendency to an increased incidence of abortion.",1
11414,17989857,[Serum liver tests in patients treated with methotrexate. A retrospective analysis],"BACKGROUND: Methotrexate is one of the best systemic treatments for psoriasis. However it has significant adverse effects such as myelotoxicity and hepatotoxicity. AIM: To evaluate serum liver test in psoriatic patients treated with methotrexate. MATERIAL AND METHODS: Retrospective review of medical records of psoriatic patients treated with methotrexate between the years 2000 and 2005. All patients received a minimum of 7.5 mg weekly of methotrexate, for at least 4 weeks. RESULTS: Sixty three patients were included. Mean cumulative dose of methotrexate was 576 mg. Thirty two percent had alterations in liver tests, but only 9% had values that duplicated the upper limit of normal range of aminotransferases or alkaline phosphatases or a serum bilirubin over 2 mg/dl. We did not find a direct relationship between the dose of methotrexate and the magnitude of liver test alterations. Only one patient exceeded 1.5 g as cumulative dose. A liver biopsy performed to him, did not show signs of fibrosis. CONCLUSIONS: This retrospective study does not show a direct relationship between weekly doses, cumulated dose and length of treatment with methotrexate, and the degree of alteration of serum liver tests.",1
11415,17993041,Evaluation of the safety of modafinil for treatment of excessive sleepiness,"""STUDY OBJECTIVES: Modafinil is a wake-promoting agent shown to improve wakefulness in patients with excessive sleepiness (hypersomnolence) associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from 6 randomized, double-blind, placebo-controlled studies were combined to evaluate modafinil across these different patient populations. METHODS: One thousand five hundred twenty-nine outpatients received modafinil 200, 300, or 400 mg or placebo once daily for up to 12 weeks. Assessments included recording of adverse events and effects of modafinil on blood pressure/heart rate, electrocardiogram intervals, polysomnography, and clinical laboratory parameters. RESULTS: Two hundred seventy-three patients with shift work sleep disorder, 292 with obstructive sleep apnea, and 369 with narcolepsy received modafinil; 567 received placebo. Modafinil was well tolerated versus placebo, with headache (34% vs 23%, respectively), nausea (11% vs 3%), and infection (10% vs 12%) the most common adverse events. Adverse events were similar across all patient groups. Twenty-seven serious adverse events were reported (modafinil, n = 18; placebo, n = 9). In modafinil-treated patients, clinically significant increases in diastolic or systolic blood pressure were infrequent (n = 9 and n = 1, respectively, < 1% of patients). In the studies, 1 patient in the modafinil group and 1 in the placebo group had a clinically significant increase in heart rate. New clinically meaningful electrocardiogram abnormalities were rare with modafinil (n = 2) and placebo (n = 4). Clinically significant abnormalities in mean laboratory parameters were observed in fewer than 1% of modafinil-treated patients at final visit. Modafinil did not affect sleep architecture in any patient population according to polysomnography. CONCLUSIONS: Modafinil is well tolerated in the treatment of excessive sleepiness associated with disorders of sleep and wakefulness and does not affect cardiovascular or sleep parameters.""",1
11416,17996663,Methimazole-induced cholestatic jaundice in an elderly hyperthyroid patient,"BACKGROUND: Hyperthyroidism is a common disease in the elderly. Antithyroid medications such as methimazole are one of the few treatment options. CASE SUMMARY: A 76-year-old white woman presented to the clinic with a 1-week history of fatigue, sleepiness, 7-pound weight loss, and tachycardia. Her blood work showed low levels of thyroid-stimulating hormone and high levels of free thyroxine. Due to persistence of her symptoms, she was hospitalized and started on methimazole 10 mg TID. Six weeks after receiving methimazole for the treatment of hyperthyroidism, she had severe jaundice and itching. Results of her liver function tests showed elevation of her alkaline phosphatase and liver transaminase levels, as well as hyperbilirubinemia, formed mainly of the conjugated fraction. Methimazole-induced cholestatic jaundice was diagnosed. Her symptoms gradually improved after discontinuation of the medication, and plasma bilirubin levels were near normal after 8 weeks without methimazole. CONCLUSIONS: We report here a probable association between methimazole use and severe cholestatic jaundice in an elderly hyperthyroid patient. The patient's jaundice was reversed after drug discontinuation.",1
11417,17997502,Alefacept revisited: Our 3-year clinical experience in 200 patients with chronic plaque psoriasis,"BACKGROUND: Alefacept was the first biologic agent approved in the United States for the treatment of moderate to severe chronic plaque psoriasis (January 2003). Standard prescription is 12 weekly intramuscular doses. The mechanism of action involves the inhibition of T-cell activation and the selective induction of apoptosis of memory T cells. A proportion of patients responding to therapy have been reported to experience remissions of approximately 7 to 8 months, characterized by disease-free and treatment-free intervals. OBJECTIVE: We sought to evaluate the efficacy and safety of alefacept treatment in patients with psoriasis during routine clinical practice. METHODS: We conducted a retrospective chart analysis of data involving 201 patients and 296 courses of alefacept from February 2003 to January 2006. Standard informed consent was obtained. RESULTS: Of the 62 patients (32.6%) who achieved an excellent response, 45% received dosage regimens defined as alternative and 73% had concomitant therapy in at least one of the treatment courses that they received. The average remission time of these patients who achieved an excellent response was approximately 7 months, with a maximum of up to 25 months. Adverse events were generally manageable and rarely led to treatment discontinuation. LIMITATIONS: Study data rely on retrospective analysis of chart-documented clinical examination findings, and patient compliance with visit schedules. CONCLUSION: Alefacept is a long-term treatment option for psoriasis with long-term remissions noted in a proportion of patients.",1
11418,18003886,"Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study","""Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.""",1
11419,18004066,Severe ticlopidine-induced cholestatic syndrome,"A patient with chronic renal insufficiency undergoing dialysis treatment presented with a clinical picture of acute intrahepatic cholestasis and alterations in liver function indices. Liver biopsy showed a histological picture of hepatitis with cholestatic signs. A causal correlation with the recent administration of ticlopidine was hypothesized, which led to the drug being discontinued. Four months after drug withdrawal no improvement in the biochemical parameters had yet occurred and the patient's clinical conditions were indeed worsening so we proceeded with extracorporeal selective plasmapheresis treatments to reduce the bilirubin. As the cholestatic syndrome was unresolved and owing to the progressive worsening in the clinical picture, the patient was submitted to combined liver and kidney transplant followed by a rapid functional recovery in both organs. Regular monitoring of the hepatic function indices during the therapy with ticlopidine is therefore indispensable for the early detection of unpredictably severe hepatotoxicity.",1
11420,18018770,Risk factors for acute liver enzyme abnormalities in HIV-hepatitis B virus-coinfected patients on antiretroviral therapy,"BACKGROUND: Little is known about the prognostic factors of acute liver enzyme variations in HIV-hepatitis B virus (HBV)-coinfected patients. OBJECTIVES: To identify prognostic factors of acute liver enzyme abnormalities in HIV-HBV-coinfected patients with a focus on the putative role of antiretroviral drugs. DESIGN: Data from a 3-year, prospective, multicentre cohort study involving HIV-HBV patients were used. METHODS: A Markov model was used to identify prognostic factors of acute episodes of cytolysis and cholestasis in 300 HIV-HBV-coinfected patients. The effect of antiretroviral therapy was analysed according to the classes of drugs, duration of treatment and treatment modifications. RESULTS: The incidence rates of acute episodes of cytolysis and cholestasis were 13.4 per 100 patient-years (95% confidence interval [CI] 9.5-17.3) and 7.1 per 100 patient-years (95% CI 4.2-10.0), respectively (median follow up 34.1 months). Independent risk factors for cytolysis were a high level of HBV or HIV replication, as well as a low of CD4+ T-cell count. No antiretroviral drug was associated with cytolysis, whereas protease inhibitors seemed to be independently associated with cholestasis, along with treatment modifications and the duration of HIV infection. CONCLUSION: Acute and reversible episodes of cytolysis or cholestasis were common and associated with virus- and host-related determinants. The choice of the optimal antiretroviral combination in HIV-HBV-coinfected patients must take into account the necessity of exerting an efficient control of HIV and HBV replication (associated with transient cytolysis) and the risk of inducing cholestasis (associated with the use of protease inhibitors and treatment modifications).",1
11421,18022508,Acute toxic hepatitis after amiodarone intravenous loading,,1
11422,18023105,Mycophenolate mofetil for drug-induced vanishing bile duct syndrome,"Amoxicillin/clavulanate is associated with liver injury, mostly of a cholestatic pattern. While outcomes are usually benign, progression to cirrhosis and death has been reported. The role of immunosuppressive therapy for patients with a protracted course is unclear. We report the case of an elderly patient who developed prolonged cholestasis secondary to amoxicillin/clavulanate. Vanishing bile duct syndrome was confirmed by sequential liver biopsies. The patient responded to prednisone treatment, but could not be weaned off corticosteroids, even when azathioprine was added. Complete withdrawal of both prednisone and azathioprine was possible by using mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor. Sustained remission has been maintained for more than 3 years with low-dose mycophenolate mofetil.",1
11423,18025891,Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience,"Suspected hypersensitivity is the main reason for the early discontinuation of abacavir. After the observation that the risk of hypersensitivity correlated with ethnicity, the presence of the HLA allele B5701 was found to be the strongest retrospective predictor of hypersensitivity. Two prospective cohorts have since demonstrated a significant reduction in abacavir hypersensitivity rates with the use of prospective human leukocyte antigen screening. We describe our experience of prospective HLA-B5701 testing and the impact on rates of abacavir hypersensitivity.",1
11424,18031103,Aldesleukin (recombinant interleukin-2),"Aldesleukin [recombinant interleukin-2 (IL-2)] is a biological response modifier which, like endogenous IL-2, has a range of immunomodulatory properties. Although aldesleukin is currently approved only for treatment of renal cell carcinoma, it has been widely used in patients with metastatic melanoma and has been assessed in numerous noncomparative trials in this indication. Durable complete responses have been reported in a small proportion of patients with good performance status who received immunotherapy or chemoimmunotherapy involving aldesleukin in several clinical trials. Overall median survival times of about 10 or 11 months are typical. Combination chemoimmunotherapy involving aldesleukin has produced relatively high response rates (up to 56%), but these are not predictive of increased survival time. Aldesleukin has not been directly compared with standard chemotherapy in randomised studies. The use of continuous intravenous infusion and subcutaneous administration of aldesleukin, together with improved patient selection, has successfully reduced the severity of adverse events produced by the drug (the original intravenous bolus regimen is particularly toxic and often necessitates admission to an intensive care unit). However, the risk/benefit profile of aldesleukin in the treatment of melanoma requires further study, particularly after subcutaneous administration. Thus, aldesleukin has shown modest efficacy in the treatment of metastatic melanoma. Although aldesleukin-containing regimens have produced promising results in many noncomparative trials, their clinical value in comparison with standard chemotherapy remains to be determined in phase III studies. Until results from such trials are available, clinicians will need to carefully balance the potential benefits of the drug against the risks and likely quality-of-life implications associated with its toxicity in each patient. Current investigations centre on the use of aldesleukin as part of complex biochemotherapy regimens, and results from these trials are awaited with interest.",1
11425,18032762,Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma,"""BACKGROUND: Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus dexamethasone in the treatment of relapsed or refractory multiple myeloma. METHODS: Of 351 patients who had received at least one previous antimyeloma therapy, 176 were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive placebo on days 1 to 21 of a 28-day cycle. In addition, all patients received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles and subsequently, after the fourth cycle, only on days 1 to 4. Patients continued in the study until the occurrence of disease progression or unacceptable toxic effects. The primary end point was time to progression. RESULTS: The time to progression was significantly longer in the patients who received lenalidomide plus dexamethasone (lenalidomide group) than in those who received placebo plus dexamethasone (placebo group) (median, 11.3 months vs. 4.7 months; P<0.001). A complete or partial response occurred in 106 patients in the lenalidomide group (60.2%) and in 42 patients in the placebo group (24.0%, P<0.001), with a complete response in 15.9% and 3.4% of patients, respectively (P<0.001). Overall survival was significantly improved in the lenalidomide group (hazard ratio for death, 0.66; P=0.03). Grade 3 or 4 adverse events that occurred in more than 10% of patients in the lenalidomide group were neutropenia (29.5%, vs. 2.3% in the placebo group), thrombocytopenia (11.4% vs. 5.7%), and venous thromboembolism (11.4% vs. 4.6%). CONCLUSIONS: Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00424047 [ClinicalTrials.gov].).""",1
11426,18035187,Ranibizumab for the treatment of neovascular age-related macular degeneration: a review,"""BACKGROUND: Choroidal neovascular (wet) age-related macular degeneration (ARMD) is becoming more prevalent worldwide as life expectancy continues to increase. Ranibizumab for intravitreal injection is an inhibitor of human vascular endothelial growth factor A approved by the US Food and Drug Administration for the treatment of ARMD in June 2006. The actions of ranibizumab result in reduced cell proliferation, reduced formation of new blood vessels, and minimization of vascular leakage. OBJECTIVE: This paper reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of ranibizumab, and pharmacoeconomic considerations associated with its use. METHODS: MEDLINE (1966-December 2006) and International Pharmaceutical Abstracts (1970-December 2007) were searched for original research studies (Phase I, II, III, and IIIb), abstracts, and review articles concerning ranibizumab. The search terms were choroidal neovascularization, macular degeneration, Lucentis, ranibizumab, retinal degeneration, and vascular endothelial growth factor. Preference was given to Phase IlfllI studies. Selected information from the manufacturer of ranibizumab was also included. RESULTS: The efficacy of ranibizumab has been studied in 3 large clinical trials having the same primary efficacy end point, the proportion of patients losing <15 letters from baseline at 12 months (Early Treatment of Diabetic Retinopathy Study chart). A multicenter, Phase III, randomized, double-blind, sham-controlled, 24-month clinical trial evaluated ranibizumab 0.3 and 0.5 mg in 716 patients with minimally classic or occult choroidal neovascularization (CNV) associated with ARMD. The results for the primary efficacy end point were 94.5% and 94.6% in the ranibizumab 0.3- and 0.5-mg groups, respectively, compared with 62.2% in the sham-injection group (P < 0.001, both ranibizumab groups vs sham injection); at 24 months, the corresponding proportions were 92.0%, 90.0%, and 52.9% (P < 0.001, both ranibizumab groups vs sham injection). A 2-year, Phase I/II, single-masked (masked patient and visual acuity examiner, unmasked investigator), multicenter trial evaluated the tolerability and efficacy of the combination of ranibizumab 0.5 mg and verteporfin photodynamic therapy (PDT) compared with verteporfin PDT alone in 162 patients with predominantly classic CNV. For the primary efficacy end point, the results were 90.5% for ranibizumab + PDT and 67.9% for PDT alone (P < 0.001). Receipt of ranibizumab + PDT was also associated with improved visual acuity, with 23.8% of patients gaining >15 letters from baseline, compared with 5.4% of those who received PDT alone (P = 0.003). Finally, an international Phase III, double-blind, active-controlled study compared ranibizumab 0.3 and 0.5 mg with verteporfin PDT in 423 patients with predominantly classic lesions associated with CNV secondary to ARMD. For the primary efficacy end point, the results were 35.7% for ranibizumab 0.3 mg, 40.3% for ranibizumab 0.5 mg, and 5.6% for verteporfin PDT (P < 0.001). Serious adverse ocular events, which occurred in association with < 0.1% of intravitreal injections in these trials, included retinal detachment and endophthalmitis. Less serious adverse ocular reactions occurring in < 2% of patients included intraocular inflammation and increased intraocular pressure. CONCLUSION: The findings of these 3 large clinical trials suggest that ranibizumab was effective and well tolerated in patient.""",1
11427,18035189,Nelarabine: a novel purine antimetabolite antineoplastic agent,"""BACKGROUND: Nelarabine was approved by the US Food and Drug Administration (FDA) in October 2005 for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. OBJECTIVES: This article reviews the pharmacology, mechanism of action, and pharmacokinetic and pharmacodynamic properties of nelarabine. Also reviewed are nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies; its toxicity profile, dosage, and administration; and areas of ongoing and future research. METHODS: Relevant literature was identified through searches of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and the American Society of Hematology database (2003-2006) using the terms nelarabine, Arranon, 506U78, and 2-amino-6-methoxypurine arabinoside. The reference lists of the identified articles were searched for additional sources. Product information obtained from the manufacturer of nelarabine was consulted, as were the FDA reviews of nelarabine. All identified publications were considered, and those meeting the objectives of this review were included. RESULTS: Nelarabine, a soluble prodrug of 9-beta-D- arabinofuranosylguanine (ara-G), is a novel purine antimetabolite antineoplastic that preferentially accumulates in T-cells. Ara-G is rapidly phosphorylated in T-cells to ara-G triphosphate (ara-GTP), which exerts cytotoxic effects. Renal elimination of ara-G is decreased in patients with mild to moderate renal impairment; however, no dose adjustment is recommended. Accumulation of ara-GTP occurs in T-cells in a dose-dependent manner, leading to preferential cytotoxicity. Nelarabine has activity in T-cell malignancies, as evaluated in 2 Phase I and 5 Phase II studies. It received accelerated approval from the FDA based on the resuits of 2 Phase II trials, one in pediatric patients (PGAA 2001) and the other in adults (CALGB 19801). In PGAA 2001, patients with T-ALL in first relapse (n = 33) had an objective response rate of 55% (16 with a complete response [CR] and 2 with a partial response [PR]), and those with T-ALL in second relapse (n = 30) had an objective response rate of 27% (7 CR and 1 PR). Among patients with central nervous system-positive T-ALL or T-cell non-Hodgkins lymphoma (T-NHL) (n = 21), 33% had an objective response (5 CR and 2 PR); among patients with T-ALL or T-NHL with extramedullary relapse (n = 22), 14% had a PR. CALGB 19801 included 39 adult patients with T-cell malignancies, of whom 7 (18%) had a CR and an additional 2 (5%) had a CR without full hematologic recovery. The recommended dose of nelarabine in adults is 1500 mg/m(2) IV given over 2 hours on days 1, 3, and 5, repeated every 21 days; the recommended dose in pediatric patients is 650 mg/m(2) IV given over 1 hour for 5 consecutive days, repeated every 21 days. Dose-limiting toxicities observed in the Phase I and II trials included central and peripheral neurotoxicity. Symptoms of central neurotoxicity included somnolence, seizures, dizziness, confusion, and ataxia; symptoms of peripheral neurotoxicity included paresthesias, pain in the extremities, and peripheral neuropathy. CONCLUSIONS: Nelarabine is indicated for the treatment of T-ALL and T-LBL that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Objective response rates in Phase II clinical trials of nelarabine have ranged from 11% to 60%. Use of nelarabine is limited by potentially severe neurotoxicity.""",1
11428,18035802,Predisposing factors for nevirapine toxicity among AIDS patients with low baseline CD4 count,"The objective of the study was to determine the predisposing factors and incidence of toxicity among AIDS patients treated with a nevirapine (NVP)-based regimen in clinical practice. A retrospective cohort study of representative samples of AIDS patients treated with a NVP-based regimen was performed. A total of 206 adult HIV/AIDS cases with median age (IQR) 33 years (range, 29-38 years), 51% male, treated between January 2004-December 2005, were included. Most (92.2%) of the patients were na?ve to antiretroviral drug. The incidence of NVP toxicity was 1.09/100 person-months. The median onset time was 4 weeks post NVP initiation (2.57 weeks for skin toxicity and 12.43 weeks for hepatic toxicity). History of drug allergy and NVP toxicity were significantly associated (p = 0.006), as were sulfamethoxazole allergy and toxicity (p = 0.015). Regarding concomitant medication, concurrent anti-tuberculosis drugs significantly increased the risk of NVP associated liver toxicity (p = 0.001). Therefore, it is important to monitor adverse events from NVP, including liver function tests among HIV/AIDS patients with history of drug allergy, especially against sulfamethoxazole, and those concurrently treated with antituberculosis drugs.",1
11429,18042504,Case-control exploration of relationships between early rash or liver toxicity and plasma concentrations of nevirapine and primary metabolites,"OBJECTIVE: This investigation measured trough nevirapine and five oxidative metabolite concentrations in plasma specimens collected from patients who exhibited a rash or liver function abnormality during the first 6 weeks of treatment. METHOD: Patient selection came from three clinical trials, totaling 1,357 patients, from which frozen specimens had been stored and were available for assay. The control patients were matched according to trial, steroid use, CD4 cell count, gender, race, and hepatitis B/C status. Observed plasma metabolite concentrations were compared using signed rank tests. RESULTS: A total of 49 case-control pairs were studied. Women had significantly greater exposure than men to nevirapine and four of the five metabolites at week 2, but the plasma concentrations were comparable by week 4. Steroid (prednisone) co-medication produced significantly different plasma nevirapine and metabolite concentrations for the majority of case-control comparisons at week 3, a week after cessation of steroid treatment, but only occasionally produced a measurable difference at other weeks. CONCLUSION: During the first 6 weeks of nevirapine therapy, the rashes and liver enzyme elevations that occurred appear to be idiosyncratic. There were no strong relationships observed between the plasma concentrations of nevirapine or any of its five metabolites to a casedefining event. The systemic exposure of the metabolite 12-hydroxynevirapine and its successor 4-carboxynevirapine, hypothesized in the skin rash female Brown Norway rat model as reactive intermediates for idiosyncratic immune-mediated adverse reactions, were comparable between case and control samples and were comparable in proportion to the precursor nevirapine exposure.",1
11430,18046910,Utility of tolcapone in fluctuating Parkinson's disease,"""Fluctuating Parkinson's disease (PD) represents a clinical management challenge. The primary utility of levodopa in patients with PD is moderated by the """"wearing off"""" phenomena seen with long-term use. COMT inhibitors slow down the rapid metabolism of levodopa, resulting in a more-sustained response to dopaminergic therapy. Tolcapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor, shown to have both peripheral and central effects. In clinical trials, tolcapone has been shown to reduce """"off"""" time, increase """"on"""" time, improve patient and clinician assessments of disease severity, and improve patient quality of life. In a SWITCH study, tolcapone was associated with greater duration of """"on"""" time than remaining on entacapone. Adverse effects of tolcapone are related to the class, with the exception of rare cases of hepatotoxicity. Tolcapone has been recently reintroduced on the European market and recent guidance from the US Food and Drug Administration has reduced the hepatic monitoring requirements for patients initiating tolcapone therapy. With proper monitoring, tolcapone is an effective, well-tolerated drug useful in the management of patients with fluctuating PD.""",1
11431,18052761,Role of tolcapone in the treatment of Parkinson's disease,"For decades, the cornerstone of treatment for Parkinson's disease (PD) has been levodopa, which provides a smooth clinical response early in the course of disease. However, many PD patients develop motor complications on long-term levodopa therapy. Catechol-O-methyltransferase (COMT) is a selective and widely distributed enzyme involved in the catabolism of levodopa. Tolcapone and entacapone are selective and potent COMT inhibitors that slow the metabolism of levodopa, thus prolonging its effects. While both drugs act peripherally, tolcapone also inhibits COMT in the CNS. Tolcapone has been shown to be an effective adjunct in the treatment of PD in Phase II and III clinical trials, improving motor fluctuations and reducing levodopa requirements. Rare reports of severe hepatotoxicity, however, limited tolcapone's implementation in the treatment of PD. A reappraisal of the data for tolcapone treatment in PD has found that this risk is very small if proper hepatic monitoring guidelines are followed. This article reviews the pharmacology and clinical data on tolcapone, with particular focus on drug safety and the future role of tolcapone therapy in the treatment of PD.",1
11432,18055189,Hepatocellular toxicity of kava leaf and root extracts,"Kava extracts are used widely for different purposes and were thought to be safe. Recently, several cases of hepatotoxicity have been published. To explore possible mechanisms of kava hepatotoxicity, we prepared and analyzed three different kava extracts (a methanolic and an acetonic root and a methanolic leaf extract), and investigated their toxicity on HepG2 cells and isolated rat liver mitochondria. All three extracts showed cytotoxicity starting at a concentration of 50 microg/ml (lactate dehydrogenase leakage) or 1 microg/ml (MTT test). The mitochondrial membrane potential was decreased (root extracts starting at 50 microg/ml) and the respiratory chain inhibited and uncoupled (root extracts) or only uncoupled (leaf extract) at 150 microg/ml, and mitochondrial beta-oxidation was inhibited by all extracts starting at 100 microg/ml. The ratio oxidized to reduced glutathione was increased in HepG2 cells, whereas the cellular ATP content was maintained. Induction of apoptosis was demonstrated by all extracts at a concentration of 150 microg/ml. These results indicate that the kava extracts are toxic to mitochondria, leading to inhibition of the respiratory chain, increased ROS production, a decrease in the mitochondrial membrane potential and eventually to apoptosis of exposed cells. In predisposed patients, mitochondrial toxicity of kava extract may explain hepatic adverse reactions of this drug.",1
11433,18056280,Entecavir for treatment of hepatitis B virus displays no in vitro mitochondrial toxicity or DNA polymerase gamma inhibition,"Therapy with nucleoside reverse transcriptase inhibitors (NRTIs) can be associated with mitochondrial toxicity. In vitro studies have been used to predict the predisposition for and characterize the mechanisms causing mitochondrial toxicity. Entecavir (ETV) is an approved deoxyguanosine nucleoside for the treatment of chronic hepatitis B virus (HBV) infection that exhibits potent activity against viral reverse transcriptase. We assessed the potential for mitochondrial toxicity of ETV in long-term cultures of HepG2 hepatoma cells by measuring mitochondrial function (through lactate secretion), levels of mitochondrial DNA (mtDNA), and levels of mitochondrial proteins COX II and COX IV. Furthermore, we tested the activity of ETV-triphosphate (ETV-TP) against mitochondrial DNA polymerase gamma (Pol gamma) in vitro. ETV concentrations as high as 100 times the maximal clinical exposure (C(max)) did not affect cell proliferation, levels of lactate, mitochondrial DNA, or mitochondrial proteins throughout the 15-day culture. The lack of mitochondrial toxicity was consistent with the finding that ETV-TP was not recognized by mitochondrial DNA Pol gamma and failed to be incorporated into DNA or inhibit the polymerase assay at the highest levels tested, 300 microM. Combinations of ETV with each of the other HBV NRTI antivirals, adefovir, tenofovir, and lamivudine at 10 times their respective C(max) levels also failed to result in cellular or mitochondrial toxicity. In summary, cell culture and enzymatic studies yielded no evidence that would predict mitochondrial toxicity of ETV at exposure levels in excess of those expected to be achieved clinically.",1
11434,18060778,Severe sensorimotor neuropathy after intake of highest dosages of vitamin B6,"We illustrate a white caucasian patient with a severe sensorimotor neuropathy due to vitamin B6 hypervitaminosis. The patient used the pendulum to calculate his daily metabolic demands and ingested 9.6g pyridoxine/day. To our knowledge, this is the highest dosage of vitamin B6 administered to humans over prolonged periods of time ever reported in the medical literature. The unique aspect of this case is the muscle weakness and motor findings on electrophysiological testing in what is suggested by the literature to be a pure sensory neuronopathy.",1
11435,18072160,A report of two deaths from massive ibuprofen ingestion,"""INTRODUCTION: Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion. CASE 1: A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 microg/mL: the therapeutic range is 10-50 microg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired. CASE 2: A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 microg/mL and serum valproate concentration was 560 microg/mL: the therapeutic range is 50-100 microg/mL. In spite of supportive care and hemodialysis, he expired. DISCUSSION: We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.""",1
11436,18072873,"Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study","""Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2-yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. INTRODUCTION: Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24-mo, randomized, double-blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. MATERIALS AND METHODS: Healthy postmenopausal women with a BMD T-score at the lumbar spine or femoral neck between -1.0 and -2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. RESULTS: The intent-to-treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 +/- 0.28%, 1.41 +/- 0.28%, 1.49 +/- 0.28%, and 1.49 +/- 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. CONCLUSIONS: Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.""",1
11437,18080055,Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial,"""BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease. PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline. RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated. CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.""",1
11438,18081377,Raltegravir,"* Raltegravir, the first in a new class of orally administered HIV type-1 (HIV-1) integrase inhibitors, selectively inhibits the strand transfer activity of HIV-1 and its integration into human DNA, a key stage in retroviral propagation, thereby limiting viral replication and the infection of new cells. * In two randomized, double-blind (with in-house blinding), placebo-controlled, multicentre, ongoing phase III trials, the proportion of patients achieving HIV-1 RNA loads of <400 copies/mL (primary endpoint) was significantly greater in raltegravir plus optimized background therapy (OBT) recipients than in placebo plus OBT recipients (preliminary 24-week results). * The proportion of patients achieving viral loads of <50 copies/mL was significantly greater with raltegravir plus OBT than with placebo plus OBT in the two studies. * In addition, mean CD4+ cell counts (secondary endpoint) were significantly increased from baseline in patients receiving raltegravir plus OBT relative to those receiving placebo plus OBT. * Raltegravir therapy was well tolerated overall. The incidence of mild to moderate adverse events was similar in the raltegravir and placebo arms of the two randomized trials.",1
11439,18084695,Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis,"Application of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-alpha agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-alpha blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-alpha blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-alpha blocking agents and be alert to any adverse events for a better management of RA patients.",1
11440,18086586,Safety of pegylated interferon-alpha-2a in adjuvant therapy of intermediate and high-risk melanomas,"Pegylated (PEG)-IFN-alpha-2a is a modified form of recombinant human IFN-alpha-2a with sustained absorption and prolonged half-life. Our aim was to evaluate its safety profile in adjuvant treatment of high-risk melanoma patients in a single centre setting and to compare this safety profile with data obtained from the literature for a) low dose IFN-alpha and b) high dose IFN. Eighteen consecutive melanoma patients (AJCC 2002 stages IIa-IIIc) were retrospectively analyzed for toxicities associated with adjuvant PEG-IFN-alpha-2a (180 microg/week s.c.). The most frequently reported adverse events were constitutional side effects (78%), myelosuppression (83%) and hepatotoxicity (78%). The proportion of patients receiving PEG-IFN-alpha-2a and suffering from myelosuppression and liver toxicity was significantly higher than for patients reported in the literature undergoing low-dose IFN-alpha treatment (P = 0.008, P = 0.001 respectively), while fatigue and depression were seen less frequently with PEG-IFN-alpha-2a. By contrast, compared to patients treated with high-dose IFN-alpha, PEG-IFN-alpha-2a treated patients less frequently experienced fatigue (P < 0.001), neutropenia (P < 0.068) and neuropsychiatric (statistically not significant) adverse events. In conclusion, subcutaneously delivered PEG-IFN-alpha-2a is well tolerated in a once-weekly dose of 180 mug by most patients with high risk malignant melanoma. The frequency of side effects is increased compared to low dose, but reduced compared to high dose standard IFN-alpha. Due to its pharmacokinetic properties, pegylated IFN-alpha has, as in the treatment of hepatitis C, potential for increased efficacy in adjuvant therapy of melanoma.",1
11441,18090299,Higher-than-expected rates of lactic acidosis among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial,"""BACKGROUND: The ability of nucleoside reverse transcriptase inhibitors (NRTIs) to inhibit human mitochondrial polymerase-gamma results in impaired synthesis of mitochondrial enzymes that generate adenosine triphosphate (ATP) by oxidative phosphorylation. This has been associated with several long-term mitochondrial toxicities, which include lactic acidosis and pancreatitis, peripheral neuropathy, and lipoatrophy. METHODS: Enrolled highly active antiretroviral therapy (HAART)-treated adults have completed nearly 2 years of follow-up as part of the ongoing randomized clinical trial Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study. All patients were intensively screened for the presence of ARV-related toxicities. RESULTS: Six hundred fifty adults (69% female) were initiated on NRTI-based HAART. Overall, 2.0% of patients developed moderate to severe symptomatic hyperlactatemia, with 7 (1.0%), all female, diagnosed with lactic acidosis. Female gender (P = 0.008) and being overweight, namely having a body mass index (BMI) of greater than 25 (P = 0.001), were predictive for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis. Older age (age >40 years) showed a statistical trend (P = 0.053) as a predictor for the development of toxicity, whereas exposure to d4T and/or ddI for 6 or more months was not predictive (P = 0.102). Those diagnosed with lactic acidosis had a mean BMI of 32.38 (interquartile range [IQR] = 29.4 to 35) at the time of toxicity and had been receiving HAART for a mean of 12.1 months (IQR = 7 to 20.8). Four of the 7 (57%) died of lactic acidosis and/or hemorrhagic pancreatitis; these 4 patients also had a comorbid diagnosis of severe clinical pancreatitis with grade 3/4 lipase elevations and abdominal symptoms at the time of their demise. CONCLUSIONS: Rates of lactic acidosis appear to be higher in southern Africa when compared with rates previously described elsewhere. Risk factors for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis appear to be multifactorial but include female gender and having a BMI of greater than 25. Additional studies are ongoing to evaluate for other possible risk factors, such as host genetic differences.""",1
11442,18090405,Interruptions of tenofovir/emtricitabine-based antiretroviral therapy in patients with HIV/hepatitis B virus co-infection,"""Thai patients enrolled in STACCATO with HIV/hepatitis B virus (HBV) co-infection and tenofovir/emtricitabine-based antiretroviral therapy (ART) were randomly assigned to continuous treatment or CD4 cell count-guided interruptions. HBV replication was suppressed below detection in 15/16 patients. Structured treatment interruption increased transaminases and HBV viraemia in five of six patients; one flare was severe. Conversion to anti-hepatitis Be occurred with continuous treatment only. Tenofovir/emtricitabine-containing ART is highly effective in controlling chronic HIV/HBV co-infection but treatment should not be interrupted.""",1
11443,18094741,Acute liver failure caused by hepatitis E virus and paracetamol,"Acute liver failure is characterized by severe and sudden liver cell dysfunction leading to hepatic encephalopathy and hepatic coagulopathy in a person without history of liver disease in the past. This catastrophic illness can rapidly progress to coma and death from cerebral edema and multi organ dysfunction. It carries a high mortality rate if liver transplantation is not carried out. In West, paracetamol is the main cause of hepatotoxicity whereas in the East viral hepatitis tops the list. This report describes a case of acute liver failure in which probably both the agents were involved. The patient recovered with antidote therapy and maximum supportive care.",1
11444,18095015,Acute hepatitis in adult Still's disease during corticosteroid treatment successfully treated with anakinra,"Adult onset Still's disease (AOSD) is a well-recognized clinical disorder characterized by involvement of various organs, including liver. However, acute hepatitis or hepatic failure is extremely rare, and most of the reported cases occurred during treatment with hepatotoxic drugs. Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Experimental and clinical data support a central role for IL-1Ra in fulminant hepatic failure. We report the case of a patient with AOSD complicated with acute hepatitis during treatment with corticosteroids, which was dramatically improved with anakinra.",1
11445,18103475,A drug sensitizing the organism to ethyl alcohol,,1
11446,18116112,"""Nitrogen mustard therapy in Hodgkin's disease; analysis of 50 consecutive cases""",,1
11447,18133760,"""Fatality associated with benzedrine ingestion; a case report""",,1
11448,18155871,Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects),"BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, is indicated to treat the symptoms of intermittent claudication and increase walking distance in patients with peripheral arterial disease (PAD). At the time of approval, the United States Food and Drug Administration required an additional long-term safety study to evaluate the effect cilostazol on mortality. METHODS: A total of 1899 subjects with a clinical diagnosis of PAD and symptoms of claudication were screened for participation in a randomized, double-blinded, placebo-controlled safety study of cilostazol. The intent-to-treat (ITT) population, which was the primary analysis (n = 1435), was defined as all randomized patients who received at least one dose of study medication and included patients who were followed up >30 days after discontinuation of study drug. A total of 717 patients received cilostazol and 718 received placebo. Cilostazol was administered at a primary dose of 100 mg twice daily. The dose could be reduced to 50 mg twice daily if patients experienced an adverse event that might have been drug related. RESULTS: Long-term adherence to study medication was poor, with >60% of participants discontinuing therapy by 36 months. The mortality analysis therefore focused on deaths during the period on-treatment, defined as the period during which the study drug was taken plus a 30-day follow-up period after dosing. Total patient-years of exposure were 1046 on-treatment for cilostazol and 1090 for placebo. On-treatment, there were 18 deaths on cilostazol and 19 deaths on placebo for a hazard ratio of 0.99 (95% confidence interval [CI], 0.52-1.88). Cardiovascular deaths on-treatment occurred in 14 patients on cilostazol and 14 on placebo. In the full ITT population at 36 months, there were 101 deaths, 49 on cilostazol and 52 on placebo, with hazard ratio of 0.94 (95% CI, 0.64-1.39). Thus, most deaths occurred >30 days after study drug discontinuation. Serious bleeding events affected 18 patients taking cilostazol in the on-treatment population and 22 taking placebo. The rates of bleeding events were similar in patients who used aspirin, aspirin plus clopidogrel, or anticoagulants at anytime during the course of the study CONCLUSIONS: This long-term study demonstrated no safety signal for cilostazol on all-cause or cardiovascular mortality. The study, however, was underpowered to detect a small adverse impact of cilostazol on mortality (hazard ratio upper bound of the 95% CI was 1.88 in the on-treatment population). Serious bleeding events appeared not to be increased by cilostazol.",1
11449,18161828,Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure,"""Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminophen-induced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) > 2 and abnormal liver function or INR >1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989-1994), standard care (n = 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995-2004), standard care and NAC administration (n = 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR < 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P = not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P = ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P = 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P = 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P = 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P = ns; and LT was performed in 32 (54%) vs. 42 (38%), P = ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P = 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation.""",1
11450,18166520,Pattern of adverse drug reactions experienced by tuberculosis patients in a tertiary care teaching hospital in Western Nepal,"Tuberculosis is a common problem in developing countries including Nepal. Data regarding the safety profile of anti tubercular drugs is lacking in Nepal. The present study analyzed the pattern of ADRs caused by the antitubercular drugs. Inpatient files of all the TB patients who received treatment at the Manipal Teaching Hospital, Pokhara, Nepal during the period from 1st January 2001 till 31st December 2006 were taken. Altogether 326 patients were identified among which 40 (females 24, males 16) experienced at least one ADR (incidence 12.27%). The mean+/-SD age of the patients was 42.12+/-20.41 years. The most common ADR was elevated liver enzymes [24 (57.14%)] and hepatobiliary system was the most common system affected [24 (58.5%)]. More than half the ADRs [21 (52.55%)] developed with in 20 days of initiation of therapy. Isoniazid and pyrazinamide were the suspected drugs responsible for 32.32% each of the total ADRs. The mean+/-SD of the total number of drugs used in the patients were 4.77+/-1.46. The most common laboratory abnormality observed was elevated SGOT level [21 patients (52.5%)]. Seven (17.5%) patients needed specific drug treatment for managing the ADRs and 10 (25%) needed symptomatic management. Thirty five (87.5%) patients recovered following the ADR. Multiple drug therapy was the reason behind the development of 30 (75%) ADRs. It was found that 29 (72.5%) ADRs were 'probably' due to the suspected drugs. Majority [19 (47.5%)] of the ADRs were mild [level (1)]. This study shows that ADRs to anti tubercular drugs are common. Since TB is a common problem in Nepal, special efforts are needed to tackle the drug related complications associated with ATT drugs.",1
11451,18166906,[Severe cholestatic hepatitis associated with Stevens-Johnson syndrome after taking ibuprofen],,1
11452,18173814,Ezetimibe-associated adverse effects: what the clinician needs to know,"OBJECTIVE: Ezetimibe is a relatively new lipid lowering agent, which is indicated for the treatment of primary hypercholesterolaemia, either as monotherapy or in combination with other hypolipidaemic drugs. The objective of the present article was to review the side effects attributed to ezetimibe administration and discuss their possible underlying mechanisms. Moreover, we aimed to comment on the possible drug interactions of ezetimibe and present current guidelines regarding its safe use. METHODS: Relevant articles were identified through a PubMed search (up to June 2007). RESULTS: Compelling evidence from the majority of the data reviewed here showed that adverse effects associated with ezetimibe use are few and mild without having been associated with serious clinical outcomes. In most studies ezetimibe has not been associated with increased rates of myopathy or rhabdomyolysis, whether used alone or in combination with statins, although there have been some case reports of myopathy attributed to this agent. Moreover, ezetimibe has been associated with mild elevations of liver transaminases, mainly in combination with a statin. Other side effects are extremely rare. It should be noted, however, there are no long-term safety data or outcome studies for ezetimibe yet. CONCLUSIONS: Ezetimibe is a safe alternative option for hyperlipidaemic patients intolerant to other lipid lowering drugs as well as a beneficial supplementary agent for patients who do not reach the recommended serum cholesterol level with their current hypolipidaemic treatment. However, as is the case with all new medications, physicians should be alert to recognise adverse effects associated with ezetimibe and report them to regulatory authorities.",1
11453,18173932,Methotrexate/naproxen-associated severe hepatitis in a child with juvenile idiopathic arthritis,"""Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). Although associated with many mild adverse effects, the short and long-term safety of MTX in JIA has been excellent. While many JIA children treated with MTX develop liver enzyme abnormalities, no cases of irreversible liver damage or of severe non-infectious hepatitis with Reye-like features have been reported in non-systemic JIA. We report a 2-year-old girl with oligoarthritis whose liver enzyme increased to greater than 45 times the upper limit of normal, and developed hypoglycemia and hyperammonemia after 10 months of MTX and naproxen therapy. An infectious and metabolic work-up for other causes was unremarkable. She recovered completely after folinic acid therapy; MTX and naproxen was not restarted. While very rare in JIA, MTX in synergism with naproxen can induce severe liver toxicity and it is important to screen children for liver enzyme abnormalities.""",1
11454,18176959,Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump,"""AIM: To study the association of three common ABCB11 and ABCC2 polymorphisms (ABCB11: 1331T>C --> V444A; ABCC2: 3563T>A --> V1188E and 4544G>A --> C1515Y) with intrahepatic cholestasis of pregnancy (ICP) and contraceptive-induced cholestasis (CIC). METHODS: ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS: The ABCB11 1331T>C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls: C allele 76.2% (CI, 58.0-94.4) vs 51.3% (CI 35.8-66.7), respectively (P = 0.0007); and CC allele 57.1% (CI 36.0-78.3) vs 20% (CI 7.6-32.4), respectively (P = 0.0065). All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION: Our data support a role for the ABCB11 1331T>C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and gamma-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.""",1
11455,18178686,Hepatocellular carcinoma associated with recreational anabolic steroid use,"A 35-year-old male bodybuilder was found to have a hepatocellular carcinoma (HCC) arising in a pre-existing hepatic adenoma following recreational anabolic steroid use. Given the widespread use of recreational anabolic steroids, another potentially life-threatening complication is highlighted in addition to the more commonly recognised hepatic adenoma. Malignant transformation to HCC from a pre-existing hepatic adenoma confirmed by immunohistochemical study has previously not been reported in athletes taking anabolic steroids. Further studies using screening programmes to identify high-risk individuals are recommended.",1
11456,18180256,Does the patient history predict hepatotoxicity after acute paracetamol overdose?,"BACKGROUND: Initial management of patients who were presented to hospital after acute paracetamol overdose depends on the suspected amount ingested and more than 12 g is potentially fatal. However, the validity of this approach has received comparatively little attention. METHODS: The present study is sought to establish whether the stated paracetamol dose might predict systemic exposure and risk of hepatotoxicity. A prospective observational study of consecutive patients presenting to the Emergency Department due to acute paracetamol overdose was performed. Serum paracetamol concentrations between 4 and 15 h post-ingestion were compared with the Rumack-Matthew '200-line' nomogram, and hepatotoxicity was defined by prothrombin time ratio >1.3 or alanine transaminase > or =1000 U/l. RESULTS: There were 987 patients, and the stated quantity of paracetamol ingested was 0-12 g in 475 (48.1%), >12 g in 349 (35.4%) and unknown in 163 (16.5%). Ingestion of >12 g was associated with paracetamol concentration above the '200-line' in 31.8% (95% CI 27.1-36.9%) vs. 3.2% (1.9-5.2%), P < 0.0001 by chi2 proportional test, and associated with hepatotoxicity in 6.9% (4.6-10.1%) vs. 1.3% (0.5-2.8%), P = 0.0001. CONCLUSION: Therefore, ingestion of >12 g predicted higher paracetamol exposure and increased risk of hepatotoxicity and supports the validity of patient history in this context.",1
11457,18182663,"Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study","""PURPOSE: Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell non-Hodgkin's lymphoma (NHL) refractory to rituximab. PATIENTS AND METHODS: Patients received bendamustine 120 mg/m(2) intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety. RESULTS: Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%). CONCLUSION: Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.""",1
11458,18187367,Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases,"""BACKGROUND & AIMS: Methasteron is a nutritional supplement used to increase weight or accelerate the build-up of muscle mass. The aim of this study was to describe 5 cases of hepatotoxicity in patients using methasteron seen at tertiary-care medical centers. METHODS: A case report design was used. RESULTS: Five previously healthy patients who used methasteron developed jaundice 2 weeks after discontinuation; they presented to a tertiary-care medical center 2 weeks later. Within another 2 to 3 weeks, bilirubin levels peaked. About 12 weeks after initial presentation, all cases resolved with no identifiable residual hepatic dysfunction. CONCLUSIONS: Methasteron use can result in severe hepatotoxicity. Liver failure can worsen after initial presentation, especially within 2 weeks. With close observation and supportive care, acute hepatic injury should resolve.""",1
11459,18192896,A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs,"BACKGROUND: Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B*1502 and HLA-B*5801 in a Han Chinese population from Taiwan and other Asian countries. OBJECTIVE: The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population. METHODS: HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam. RESULTS: Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B*5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P<10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B*38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam. CONCLUSION: At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.",1
11460,18197163,Two new drugs for HIV infection,,1
11461,18199168,"Risk of side effects associated with the use of nevirapine in treatment-na?ve patients, with respect to gender and CD4 cell count","""OBJECTIVES: A warning about the use of nevirapine (NVP) by its pharmaceutical manufacturer has been issued in which it has been recommended that NVP should not be prescribed in patients with increased risk of toxicity based on CD4 cut-offs and gender. The aim of this study was to determine whether these recommendations are of use in preventing side effects. METHODS: This retrospective study included antiretroviral drug-na?ve patients who started treatment with NVP. Patients were divided into two groups: those with high CD4 counts (H; women: CD4 count >250 cells/microL; men: CD4 count >400 cells/microL) and those with low CD4 counts (L; women: CD4 count <250 cells/microL; men: CD4 count <400 cells/microL). RESULTS: A total of 142 patients were included in the study, 61 in the H group and 81 in the L group. Skin rash developed in 6.56% of patients [95% confidence interval (CI) 2.67-15.70%] in the H group and in 14.81% of patients (95% CI 8.72-24.17%) in the L group (P=0.18). Hepatotoxicity developed in 4.92% (95% CI 1.79-13.50%) and 6.17% (95% CI 2.73-13.66%) of patients with high and low CD4 cell counts, respectively (P=1.0). CONCLUSION: The recommendations not to use NVP in drug-na?ve patients at increased risk of toxicity on the basis of gender and CD4 cell count do not seem to be of use in preventing the occurrence of side effects. However, a small number of patients were included in this study, and hence the possibility cannot be excluded that the recommendations are appropriate in another clinical practice setting.""",1
11462,18203324,Treatment of psoriatic arthritis and rheumatoid arthritis with disease modifying drugs -- comparison of drugs and adverse reactions,"OBJECTIVE: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory diseases of the musculoskeletal system. Although it seems likely that these conditions have a different pathogenesis, the drugs used to treat them are the same. Our study used a cross-sectional clinical database to compare drug use and side-effect profile in these 2 diseases. METHODS: The CASPAR study collected data on 588 patients with PsA and 536 controls, 70% of whom had RA. Data on disease modifying drug treatments used over the whole illness were recorded, together with their outcomes, including adverse events, for RA and PsA. RESULTS: For both diseases methotrexate (MTX) was the most frequently used disease modifying drug (39% of patients with PsA, 30% with RA), with over 70% of patients in both diseases still taking the drug. Other drugs were used with the following frequencies in PsA and RA, respectively: sulfasalazine 22%/13%, gold salts 7%/11%, antimalarial drugs 5%/14%, corticosteroids 10%/17%, and anti-tumor necrosis factor (TNF) drugs 6%/5%. Compared to RA, cyclosporine and anti-TNF agents were less likely to be ineffective in PsA. Compared to RA, subjects with PsA were less likely to be taking MTX and more likely to be taking anti-TNF agents. Hepatotoxicity with MTX was more common in PsA and pulmonary toxicity with MTX was found more often in RA. CONCLUSION: These data provide insight into prescribing patterns of disease modifying drugs in RA and PsA in a large international cohort, together with the differential adverse events of these drugs between these diseases.",1
11463,18203607,Black cohosh-induced hepatitis,"Herbal products are widely used by American consumers. Herbal remedies are not regulated by the Food and Drug Administration, but they are not immune from serious medication side-effects. We report the case of a 50-year-old woman who presented with fatigue and right upper quadrant pain. The patient had begun the popular postmenopausal herbal remedy black cohosh two weeks prior to presentation. Laboratory results revealed acute hepatitis. After other causes of liver failure were ruled out, the patient was diagnosed with black cohosh-induced hepatitis. She recovered uneventfully following withdrawal of the herb. There are five prior reports of hepatitis or hepatic failure likely caused by the herbal remedy black cohosh in the English literature. This case illustrates the importance of a broad differential diagnosis for abdominal pain and highlights the importance of a complete medication list, including herbs.",1
11464,18209599,Epstein Barr virus-induced hepatitis associated with methotrexate treatment,,1
11465,18214047,Pharmacogenetic analysis of liver toxicity after busulfan/cyclophosphamide-based allogeneic hematopoietic stem cell transplantation,"THE AIM of this study was to evaluate the impact of genomic polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR-C677T, MTHFR-A1298C) and various glutathione S-transferases (GSTP1-Ilel05Val, GSTA1*a/b, GSTM1, GSTT1) on the occurrence of liver toxicity in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: Eighty-four adult patients were enrolled in this retrospective study. All patients were treated with busulfan/cyclophosphamide as a conditioning regimen and received cyclosporine and short-course MTX for GvHD prophylaxis. Genotyping was performed using PCR based restriction-fragment-length-polymorphism (RFLP) techniques. RESULTS: Multivariate analysis identified the MTHFR-A1298C polymorphism as an independent predictor for maximum levels of bilirubin (p=0.0025) and duration of hyperbilirubinaemia (p=0.013). Furthermore, there was an association between this polymorphism and the occurrence of the sinusoidal obstruction syndrome (SOS) (p=0.048). No significant associations between the MTHFR-C677T or the various GST polymorphisms and liver toxicity were observed. CONCLUSION: The MTHFR-A1298C polymorphism might be associated with liver toxicity in patients receiving allogeneic HSCT.",1
11466,18214726,Acamprosate efficacy in alcohol-dependent patients: summary of results from three pivotal trials,"""In 2004, the United States Food and Drug Administration (FDA) approved acamprosate for use in conjunction with psychosocial support in the maintenance of abstinence in alcohol-dependent patients who are abstinent at treatment initiation. That approval was based primarily on a re-analysis of three European double-blind, placebo-controlled trials in which complete abstinence was the primary outcome measure. The current report presents data from the re-analysis of the pivotal trials, which were 13-, 48-, and 52-week studies. A total of 998 DSM-III-R alcohol-dependent patients were included in the studies, with the majority abstinent at randomization. Using a more stringent definition of abstinence, re-analysis of the rate of complete abstinence, percent days abstinent, and the time to first drink confirmed the original findings for the efficacy of acamprosate in the treatment of alcohol dependence. Rate of complete abstinence was significantly higher with acamprosate than placebo (p < .05); both percent days abstinent and time to first drink were also significantly greater among acamprosate-treated than placebo-treated patients (p < .01). These findings support the use of acamprosate in the treatment of alcohol dependence and illustrate some of the issues that can arise in the FDA process for approval of medications to treat the disorder.""",1
11467,18217912,Incidence of adverse events with HMG-CoA reductase inhibitors in liver transplant patients,"UNLABELLED: Transplant patients are at increased risk of developing dyslipidemia, which contributes to coronary artery disease and cardiovascular events. The purpose of this study was to explore documented adverse effects of liver transplant recipients receiving lipid-lowering therapies. METHODS: A retrospective chart review of 69 liver transplant patients was conducted to evaluate the incidence of adverse effects, especially rhabdomyolysis and liver function abnormalities, in liver transplant patients treated with a lipid lowering agent (LLA). Data were collected from the time of initiation of LLA to 12 months later, looking at the type, dose, and duration of LLA, concurrent cytochrome P450 inhibitors, immunosuppression used, and laboratory parameters. RESULTS: For HMG-CoA reductase inhibitor therapy, simvistatin was used in five (7.8%) patients, pravastatin in 40 (62.5%), fluvastatin in one (1.6%), atorvastatin in five (7.8%), and lovastatin in three (4.7%). Gemfibrozil, a fibric acid derivative, was employed as monotherapy in 10 (15.6%) of patients. There were five patients who received combination therapy with a fibric acid derivative, four (80%) with gemfibrozil + pravastatin, and one (20%) with gemfibrozil + simvastatin. Six patients studied had adverse effects, five (7.2%) with myalgia and one (1.4%) with myopathy. LLA monotherapy with either pravastatin or atorvastatin was used in these patients. The five patients with myalgia were on concurrent therapy with cyclosporin, and the patient with myopathy was on concurrent cyclosporin + diltiazem therapy, both of which are P450 inhibitors. One out of 23 patients on a non-immunosuppressant P450 inhibitor developed adverse effects. No significant elevation of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase was noted in any patient. CONCLUSIONS: Overall, there was a general tolerability with a low incidence of adverse events, no incidence of severe complications, and no alterations in liver function tests in the study population with the use of LLA.",1
11468,18218290,Fatal amiodarone-induced hepatotoxicity: a case report and literature review,"""OBJECTIVE: To report a fatal case of amiodarone-induced acute hepatotoxicity after intravenous amiodarone administration and similar fatal cases review. CASE SUMMARY: A 72-year-old woman with a history of hypertension, prior cardiovascular disease, atrial fibrillation and diabetes mellitus was admitted to the hospital with acute pyelonephritis and transferred to the intensive care unit due to cerebral infarction. An antidiabetic drug, a low dose of aspirin and intravenous amiodarone therapy was started. After receiving a second dose of amiodarone (1,200 mg; injection rate 1 mg/min), the woman developed ascites, jaundice, high levels of serum transaminases, decreased prothrombin time, and finally became unconscious. Immediately after treatment was discontinued, her extremely high hepatic parameters returned to normal. According to the Naranjo probability scale, this adverse reaction was highly probable. DISCUSSION: The occurrence of acute liver damage after intravenous amiodarone is rare but harmful. It can be induced by polysorbate 80, a solubilizer, by immunomediated centrilobular necrosis, or by the presence of a functional PPAR-I+/- gene. CONCLUSION: Amiodarone is an effective antiarrhythmic agent for preventing and treating atrial and ventricular arrhythmias. The molecular mechanism causing acute hepatic damage after amiodarone treatment is not clear. Therefore, amiodarone must be administered with care, and liver function should be monitored closely in patients treated with this drug.""",1
11469,18220081,"Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study","""STUDY OBJECTIVES: To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic primary insomnia. DESIGN: Multicenter, 25-week, phase IIIb, randomized, double-blind, placebo-controlled, parallel-group. SETTING: Outpatient; visits every 4 weeks. PATIENTS: Aged 18 to 64 years; DSM-IV criteria for chronic primary insomnia; > or =3 months of difficulty initiating or maintaining sleep or experiencing nonrestorative sleep. INTERVENTIONS: Single-dose zolpidem extended-release 12.5 mg (n = 669) or placebo (n = 349), self-administered from a minimum of 3 nights/week to a maximum of 7 nights/week. MEASUREMENTS AND RESULTS: Patient's Global Impression (PGI) and Clinical Global Impression-Improvement (CGI-I) were assessed every 4 weeks up to week 24. Patient Morning Questionnaire (PMQ), recorded daily, assessed subjective sleep measures-sleep onset latency (SOL), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and quality of sleep (QOS)-and next-day functioning. At week 12, PGI, Item 1 (aid to sleep), the primary endpoint, was scored as favorable (i.e., """"helped me sleep"""") by 89.8% of zolpidem patients vs. 51.4% of placebo patients (P < 0.0001, based on rank score) and at week 24 by 92.3% of zolpidem extended-release patients vs. 59.7% of placebo patients. Zolpidem extended-release also was statistically significantly superior to placebo at every time point for PGI (Items 1-4) and CGI-I (P < 0.0001, rank score), TST, WASO, QOS (P < 0.0001), and SOL (P < or = 0.0014); NAW (Months 2-6; P < 0.0001). Sustained improvement (P < 0.0001, all time points) was observed in morning sleepiness and ability to concentrate (P = 0.0014, month 6) with zolpidem extended-release compared with placebo. Most frequent adverse events for zolpidem extended-release were headache, anxiety and somnolence. No rebound effect was observed during the first 3 nights of discontinuation. CONCLUSIONS: These findings establish the efficacy of 3 to 7 nights per week dosing of zolpidem extended-release 12.5 mg for up to 6 months. Treatment provided sustained and significant improvements in sleep onset and maintenance and also improved next-day concentration and morning sleepiness.""",1
11470,18222155,Telithromycin and the FDA: implications for the future,,1
11471,18234091,Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia?,"BACKGROUND: Hyperammonemia in patients with methylmalonic aciduria (MMA) and propionic aciduria (PA) is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises. CASE PRESENTATION: We described two patients (one with MMA and one with PA) with hyperammonemia at diagnosis. Carglumic acid, when associated with standard treatment of organic acidurias, may be helpful in normalizing the ammonia level. CONCLUSION: Even though the usual treatment which decreases toxic metabolites remains the standard, carglumic acid could be helpful in lowering plasma ammonia levels over 400 micromol/L more rapidly.",1
11472,18241321,Hepatic safety of once-monthly injectable extended-release naltrexone administered to actively drinking alcoholics,"""BACKGROUND: Hepatoxicity has been reported with oral naltrexone. Hepatic safety data were examined from a 6-month study evaluating the efficacy and safety of a now available extended-release formulation of naltrexone (XR-NTX) in patients with alcohol dependence. METHODS: In all, 624 patients (68% male; median age of 44 years) were randomly assigned to XR-NTX 380 mg (n = 205), XR-NTX 190 mg (n = 210), or placebo (n = 209). RESULTS: There were no significant differences in alanine aminotransferase, aspartate aminotransferase, or bilirubin levels between the study groups at study initiation or at subsequent assessments. Gamma-glutamyltransferase in the XR-NTX 380 mg group was lower compared with placebo at weeks 4, 8, 12, and 20. Both high (>3 times the upper limit of normal) liver chemistry tests (LCTs) and hepatic-related adverse events were infrequent in all study groups. In patients who were drinking heavily throughout the study, obese subjects, or those taking nonsteroidal anti-inflammatory drugs, there was no increase in frequency of high LCTs or hepatic-related adverse events in patients receiving XR-NTX (either dose) compared with placebo. CONCLUSION: Extended-release formulation of naltrexone does not appear to be hepatotoxic when taken at the recommended clinical doses in actively drinking alcohol-dependent patients.""",1
11473,18243011,A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian Trial in Ovarian cancer (MITO-5) study,"""BACKGROUND: Carboplatin/paclitaxel every 3 weeks is the standard for patients with ovarian cancer, but elderly patients frequently receive modified schedules or single agent chemotherapy to avoid toxicity. A phase II study was conducted to describe tolerability of a weekly schedule of both drugs in elderly patients. METHODS: Patients aged>or=70 years with stage IC-IV ovarian cancer, performance status<or=2, were eligible. Treatment was carboplatin (AUC 2)+paclitaxel (60 mg/m2) on days 1, 8, 15 every 4 weeks, up to six cycles. A two-stage design was applied with lack of unacceptable toxicity as primary endpoint; 26 patients were required at the final stage, with at least 23 of them without unacceptable toxicity to conclude for a positive result. Geriatric assessment was performed by activity daily living (ADL) and instrumental ADL (IADL) scales. RESULTS: Twenty-six patients were analysed (median age 77 years, range 70-84). Performance status was 0 in 10 and 1 in 16 patients; 14 patients had two or more comorbidities; 8 and 18 patients had some dependency in ADL or IADL. Twenty-three patients (88.5%) were treated without suffering unacceptable toxicity. Unacceptable toxic events were grade 3 heart rhythm, grade 3 increase of liver transaminases and prolonged haematological toxicity. Grade 1 neuropathy was reported in four cases. Out of 13 patients evaluable by RECIST, 5 partial responses were observed (response rate 38.5%). Two complete responses were observed among six patients with non-target lesions. Eight patients eligible for CA-125 response assessment had a response after six cycles. Median estimated progression-free survival was 13.6 months, and median overall survival was 32.0 months. CONCLUSIONS: In a series of elderly ovarian cancer patients, characterized by a high incidence of comorbidities and functional impairment, weekly carboplatin and paclitaxel demonstrated a favourable toxicity profile.""",1
11474,18256392,HLA-B*5701 screening for hypersensitivity to abacavir,"BACKGROUND: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. METHODS: This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. RESULTS: The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). CONCLUSIONS: HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)",1
11475,18259682,Five-year efficacy and safety of levodopa/DDCI and entacapone in patients with Parkinson's disease,"This was a retrospective pooled analysis of data from four comparably designed, double-blind, placebo-controlled, Phase III studies and their long-term open-label extensions. Patients on levodopa and a dopa decarboxylase inhibitor (DDCI) were randomized to entacapone or to placebo in the 6-month, double-blind phase, with all patients subsequently receiving entacapone in the extension phase. UPDRS III motor scores improved by -2.1 points during the first 6 months of levodopa/DDCI and entacapone therapy, and remained below baseline for up to 2 years. Increased daily 'ON' time, together with response duration to a single morning dose of levodopa and clinical global evaluation, also supported the long-term efficacy of levodopa/DDCI and entacapone. The mean daily dose of levodopa did not increase over the 5-year follow-up period. Long-term therapy with levodopa/DDCI and entacapone was well-tolerated.",1
11476,18264031,Budesonide/formoterol (Symbicort) for asthma,,1
11477,18265937,Acute hepatitis associated with use of paroxetine,,1
11478,18274956,Metabolism and related human risk factors for hepatic damage by usnic acid containing nutritional supplements,"Usnic acid is a component of nutritional supplements promoted for weight loss that have been associated with liver-related adverse events including mild hepatic toxicity, chemical hepatitis, and liver failure requiring transplant. To determine if metabolism factors might have had a role in defining individual susceptibility to hepatotoxicity, in vitro metabolism studies were undertaken using human plasma, hepatocytes, and liver subcellular fractions. Usnic acid was metabolized to form three monohydroxylated metabolites and two regio-isomeric glucuronide conjugates of the parent drug. Oxidative metabolism was mainly by cytochrome P450 (CYP) 1A2 and glucuronidation was carried out by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A3. In human hepatocytes, usnic acid at 20 microM was not an inducer of CYP1A2, CYP2B6, or CYP3A4 relative to positive controls omeprazole, phenobarbital, and rifampicin, respectively. Usnic acid was a relatively weak inhibitor of CYP2D6 and a potent inhibitor of CYP2C19 (the concentration eliciting 50% inhibition (IC(50)) = 9 nM) and CYP2C9 (IC(50) = 94 nM), with less potent inhibition of CYP2C8 (IC(50) = 1.9 microM) and CYP2C18 (IC(50) = 6.3 microM). Pre-incubation of microsomes with usnic acid did not afford any evidence of time-dependent inhibition of CYP2C19, although evidence of slight time-dependent inhibition of CYP2C9 (K(I) = 2.79 microM and K(inact) = 0.022 min(-1)) was obtained. In vitro data were used with SimCYP(R)to model potential drug interactions. Based on usnic acid doses in case reports of 450 mg to >1 g day(-1), these in vitro data indicate that usnic acid has significant potential to interact with other medications. Individual characteristics such as CYP1A induction status, co-administration of CYP1A2 inhibitors, UGT1A1 polymorphisms, and related hyperbilirubinaemias, or co-administration of low therapeutic index CYP2C substrates could work alone or in consort with other idiosyncrasy risk factors to increase the risk of adverse events and/or hepatotoxicity. Thus, usnic acid in nutritional supplements might be involved as both victim and/or perpetrator in clinically significant drug-drug interactions.",1
11479,18277899,Long-term methotrexate for Crohn's disease: safety and efficacy in clinical practice,"GOALS: To assess the efficacy and safety profile of methotrexate (MTX) for the treatment of Crohn's disease (CD) in clinical practice. BACKGROUND: MTX is widely used for some chronic immunologic diseases. Although some randomized controlled trials suggest its efficacy in CD, this drug remains a second-line, underused, immunomodulator. STUDY: Medical records of all patients treated with MTX for CD in our center (n=44) were reviewed. Clinical and epidemiologic parameters, including risk factors for hepatotoxicity, were registered. RESULTS: MTX was prescribed mainly for steroid-dependency (n=22) and as concomitant treatment to infliximab (n=18). Mean duration of treatment was 22.9+/-19 months, with a mean cumulative dose of MTX of 1169+/-784 mg. Thirty-nine percent of patients developed drug-related side effects, hepatotoxicity being the most frequent [13 patients (30%)]. However, only 5 patients (11%) had to discontinue MTX. In steroid-dependent CD patients, disease remission and complete steroid withdrawal was achieved in 77% of cases. Seven patients lost their initial response to MTX during follow-up, leading to a cumulative probability of remission of 39% after 3 years of treatment. CONCLUSIONS: MTX is well tolerated in most CD patients. Although a great proportion of steroid-dependent CD patients achieve disease remission and steroid withdrawal, there is a trend to a loss of efficacy with time. Larger, long-term studies are necessary to establish the role of MTX in the management of CD.",1
11480,18279672,False positive acetaminophen concentrations in patients with liver injury,"BACKGROUND: Acetaminophen toxicity is the most common form of acute liver failure in the U.S. After acetaminophen overdoses, quantitation of plasma acetaminophen can aid in predicting severity of injury. However, recent case reports have suggested that acetaminophen concentrations may be falsely increased in the presence of hyperbilirubinemia. METHODS: We tested sera obtained from 43 patients with acute liver failure, mostly unrelated to acetaminophen, utilizing 6 different acetaminophen quantitation systems to determine the significance of this effect. In 36 of the 43 samples with bilirubin concentrations ranging from 1.0-61.5 mg/dl no acetaminophen was detectable by gas chromatography-mass spectroscopy. These 36 samples were then utilized to test the performance characteristics of 2 immunoassay and 4 enzymatic-colorimetric methods. RESULTS: Three of four colorimetric methods demonstrated 'detectable' values for acetaminophen in from 4 to 27 of the 36 negative samples, low concentration positive values being observed when serum bilirubin concentrations exceeded 10 mg/dl. By contrast, the 2 immunoassay methods (EMIT, FPIA) were virtually unaffected. The false positive values obtained were, in general, proportional to the quantity of bilirubin in the sample. However, prepared samples of normal human serum with added bilirubin showed a dose-response curve for only one of the 4 colorimetric assays. CONCLUSIONS: False positive acetaminophen tests may result when enzymatic-colorimetric assays are used, most commonly with bilirubin concentrations >10 mg/dl, leading to potential clinical errors in this setting. Bilirubin (or possibly other substances in acute liver failure sera) appears to affect the reliable measurement of acetaminophen, particularly with enzymatic-colorimetric assays.",1
11481,18282716,Selection of agents for prevention of cisplatin-induced hepatotoxicity,"""The objective of this study was to explore the optimal combination of agents used along with cisplatin for protection of hepatotoxicity. Animal experiment was carried out based on the orthogonal design L(8) (2(7)) setting seven factors with two different levels of each, and eight groups of mice were needed. The agents tested in this study were zinc, selenium, fosfomycin, sodium thiosulfate (STS), N-acetyl-cysteine (NAC), methionine and taurine. Mice were supplemented by gavage with various combinations of agents as designed in the orthogonal table once a day for nine days beginning two days before cisplatin administration. 3.5mg/kg body weight of cisplatin was given intraperitoneally once a day for five days simultaneously. After cessation of cisplatin administration, the agents were supplemented continuously for two days. Activities of alanine aminotransferase (ALT) in serum, levels of glutathione (GSH) and malondialdehyde (MDA) in liver were analyzed after cessation of supplementation. Results showed zinc, fosfomycin and methionine were the effective factors for protection of weight loss; fosfomycin and methionine were the effective factors for prevention of decreased liver ratio; selenium, fosfomycin and STS were the effective factors for prevention of increased ALT activities in serum. On the other hand, methionine was the only effective factor for prevention of decreased GSH levels in liver; zinc, selenium and fosfomycin were the effective factors for prevention of increased MDA levels in liver. Based on the data observed in this study, the optimum combinations of agents were selenium, fosfomycin, methionine and taurine, and zinc, selenium, STS and methionine. In conclusion, each agent used in this study could play a beneficial role for prevention of cisplatin hepatotoxicity, however, none could play the crucial role. The potentiated actions for prevention of cisplatin hepatotoxicity could be achieved via combined use of these agents.""",1
11482,18283910,[Drug-induced hepatotoxicity caused by anti-tuberculosis drugs in tuberculosis patients complicated with chronic hepatitis],"""OBJECTIVES: To investigate retrospectively the incidence of drug-induced hepatitis (DIH) caused by antituberculosis drugs including isoniazid (INH), rifampicin (RFP), with and without pyrazinamide (PZA), and to evaluate risk factors for DIH in tuberculosis patients complicated with chronic hepatitis (CH). MATERIALS: One hundred and seven tuberculosis patients with CH (M/F= 96/11, mean age +/- SE, 60.8 +/- 1.4 yr) admitted to our hospital during 1998-2006, whose laboratory data had been followed before and at least 2 months after starting antituberculosis chemotherapy, were enrolled in this study. Of these, 58 were being treated with anti-tuberculosis chemotherapy consisting of INH, RFP and PZA (HRZ group) and the remaining 49 with INH and RFP (HR group). For a case-control study, patients admitted to the hospital during the same period and without CH were selected to each CH patient (n=107) of the same gender, the same treatment regimens, and the same age. Clinical diagnosis of CH was based on laboratory data and in some cases pathological findings; etiology of CH was C-CH (CH caused by hepatitis C virus) in 68 patients, B-CH (CH caused by hepatitis B virus) in 23, and alcoholic CH in 16. METHODS: DIH was defined by elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at 1 or 2 months after starting anti-tuberculosis chemotherapy. For patients with serum levels of AST or ALT already abnormally high before starting chemotherapy, an increase of > 1.5 times from the initial serum level was defined to indicate DIH, whereas for patients with AST and ALT within the normal range, and increase of > 3X the normal upper limit was defined to indicate DIH. The incidence of DIH was calculated separately in the groups HRZ and HR for patients with and patients without CH (control). In the HRZ group, the severity of DIH was defined by the maximum serum levels of AST and ALT, and their mean values were compared between CH patients and the control. Risk factors for DIH were examined by comparing patients with and without CH. The clinical course after development of DIH was also followed. [Results] The incidence of DIH in the HRZ group was 13/ 58 (22.4%) for CH patients and 10/36 (27.8%), 2/13 (15.4%) and 1/9 (11.1%) for C-CH, B-CH and alcoholic hepatitis patients, respectively, which was significantly (p < 0.05) higher than that in the control [4/58 (6.9%)]. Confining to the C-CH patients, the incidence of DIH was 10/36 (27.8%) compared with the control 2/36 (5.6%) (p < 0.05). In contrast, the incidence of DIH in the HR group was not significantly different between CH patients and the control, [2/49 (4.1%) vs 2/49 (4.1%)], respectively. The severity of DIH in the HRZ group estimated by the maximum level of serum AST and ALT was not significantly different in CH patients and the control (176.6 +/- 28.1 vs. 311.0 +/- 154.5 IU/L for AST and 187.8 +/- 19.1 vs. 277.8 +/- 72.4 IU/L for ALT). Of the 13 CH patients suffering from DIH caused by antituberculosis chemotherapy containing INH, RFP and PZA, 3 were continued treatment without altering the regimen, and 9 were continued treatment after changing the regimen to INH and RFP, omitting PZA. The one remaining patient was re-treated using INH, RFP and ethambutol (EB), but this again resulted in development of DIH, and he was ultimately treated with INH, EB and levofloxacin, with a successful outcome. Thus, at least 12 out of the 13 CH patients who developed DIH in the HRZ group could be treated by an anti-tuberculosis chemotherapy regimen containing INH and RFP excluding PZA. In C-CH patients who were treated with INH, RFP and PZA, the incidence of DIH was significantly higher when the daily alcohol intake was >20 g [8/18 (44.4%)] compared with those <20 g [0/10 (0%)] (p < 0.05), indicating that alcohol is a risk factor for DIH in C-CH patients treated with INH, RFP and PZA. CONCLUSIONS: In CH patients, anti-tuberculosis chemotherapy containing INH and RFP without PZA can be used safely. The inclusion of PZA in the regimen does substantially increase the incidence of DIH but nonetheless it can be used with caution, especially bearing in mind that daily alcohol intake of >20 g is a significant risk factor for C-CH patients.""",1
11483,18290705,[Tahitian Noni juice is not hepatotoxic],,1
11484,18293747,[Several cases of liver affected by aloe vera],,1
11485,18296419,Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma,"""BACKGROUND: Vorinostat has demonstrated activity in refractory cutaneous T-cell lymphoma. In a phase I trial, an encouraging activity in diffuse large-B-cell lymphoma (DLBCL) was noted. PATIENTS AND METHODS: We carried out a phase II trial (NCT00097929) of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week) in patients with measurable, relapsed DLBCL who had received two or more systemic therapies. Response rate and duration (DOR), time to progression (TTP) and safety were assessed. RESULTS: Eighteen patients were enrolled (median age: 66 years; median prior therapies: 2). Seven received 300 mg b.i.d. 14 days/3 weeks, but four had grade 3 or 4 toxicity (dose-limiting toxicity, DLT). The schedule was amended to 300 mg b.i.d. 3 days/week), and none had DLT. One achieved a complete response (TtR = 85 days; DOR =or >468 days) and one had stable disease (301 days). Sixteen discontinued for progressive disease; median TTP was 44 days. Median number of cycles was 2 (1 to >19). Common drug-related adverse experiences (AEs; mostly grade 1/2) were diarrhea, fatigue, nausea, anemia and vomiting. Three patients had dose reduction; none discontinued for drug-related AEs. Drug-related AE >or=grade 3 included thrombocytopenia (16.7%) and asthenia (11.1%). CONCLUSION: Vorinostat was well tolerated at 300 mg b.i.d. 3 days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activity against relapsed DLBCL.""",1
11486,18300198,Propofol-induced acute toxic hepatitis after brief sedation for endoscopic retrograde cholangiopancreatography,,1
11487,18303141,Abacavir hypersensitivity reaction: an update,"OBJECTIVE: To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR). DATA SOURCES: A MEDLINE (1950-October 2007) and EMBASE (1980-October 2007) search using key words abacavir, HIV, human immunodeficiency virus, hypersensitivity reaction, HLA-B(*)5701, and patch tests was conducted. Conference abstracts and article bibliographies were reviewed to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Studies that investigated the clinical and immunogenetic risk factors for abacavir hypersensitivity and the benefit of genetic screening, as well as articles that focused on the clinical presentation, assessment, and management of abacavir HSR, were considered for this review. DATA SYNTHESIS: Abacavir hypersensitivity is an immune-mediated reaction that typically occurs within the first 6 weeks of therapy. Signs and symptoms of abacavir HSR are nonspecific, which makes the diagnosis challenging, particularly in medically complex patients. Patch testing may improve the diagnosis and confirmation of abacavir HSR, but it remains experimental. Clinical management is aimed at supportive therapy and discontinuation of abacavir. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction. Appropriate patient education and a clear communication plan are essential for the safe use of this medication. Identification of patients at risk of developing abacavir hypersensitivity through routine genetic screening for human leukocyte antigen (HLA) HLA-B(*)5701 represents a significant advance in the field of pharmacogenomics, with an apparent 100% negative predictive value when used to screen for abacavir HSR. Preliminary data suggest that pharmacogenetic testing for HLA-B(*)5701 is cost effective. However, until routine testing is available, pharmacovigilance is necessary for the safe and effective use of abacavir. CONCLUSIONS: Serious adverse events associated with the use of abacavir can be avoided by appropriate recognition and management of the HSR. Screening patients for HLA-B(*)5701 prior to initiation of abacavir represents a tool to further decrease the risk of HSRs as well as unnecessary discontinuation of this drug.",1
11488,18305062,FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia,"""On September 19, 2007, the U.S. Food and Drug Administration granted regular approval and expanded labeling for alemtuzumab (Campath); Genzyme Corporation, Cambridge, MA) as single-agent treatment for B-cell chronic lymphocytic leukemia (B-CLL). Alemtuzumab was initially approved in 2001 under accelerated approval regulations. Conversion to regular approval was based on a single study submitted to verify clinical benefit. Efficacy and safety were demonstrated in an open-label, international, multicenter, randomized trial of 297 patients with previously untreated, Rai stage I-IV B-CLL experiencing progression of their disease. Patients were randomized to either alemtuzumab, 30 mg i.v. over 2 hours three times per week on alternate days for a maximum of 12 weeks, or chlorambucil, 40 mg/m(2) orally every 28 days for a maximum of 12 months. The progression-free survival time, the primary study endpoint, was significantly longer in the alemtuzumab arm than in the chlorambucil arm. Both the overall and complete response rates were also significantly higher in the alemtuzumab arm. No differences in survival were observed. There were no new safety signals identified in patients receiving alemtuzumab. The most serious, and sometimes fatal, toxicities of alemtuzumab are cytopenias, infusion reactions, and infections.""",1
11489,18309471,[A 42-year-old farmer with nonspecific leucocytosis and elevated transaminases. Acute septic reaction in Coxiella burnetii infection],"""We report about a 42-year-old farmer with leucocytosis, elevation of transaminases and liver cirrhosis as an underlying condition. The diagnosis of Q fever hepatitis was made through liver biopsy and serology. Under therapy with doxycycline, transaminases initially increased again; after switching to ciprofloxacin, the patient could be discharged 3 weeks after admission. Q fever is caused by Coxiella burnetii. The most frequent acute manifestation is a self-limiting flu-like illness. Chronic Q fever mostly presents as endocarditis. The diagnosis is made through histology (""""doughnut"""" granulomas), PCR, serology (acute: anti-phase II antibodies, chronic: anti-phase I antibodies) and culture. Standard therapy is doxycycline.""",1
11490,18318440,Acute liver failure: Summary of a workshop,"""Acute liver failure (ALF) is a rare but challenging clinical syndrome with multiple causes; a specific etiology cannot be identified in 15% of adult and 50% of pediatric cases. The course of ALF is variable and the mortality rate is high. Liver transplantation is the only therapy of proven benefit, but the rapidity of progression and the variable course of ALF limit its use. Currently in the United States, spontaneous survival occurs in approximately 45%, liver transplantation in 25%, and death without transplantation in 30% of adults with ALF. Higher rates of spontaneous recovery (56%) and transplantation (31%) with lower rates of death (13%) occur in children. The outcome of ALF varies by etiology, favorable prognoses being found with acetaminophen overdose, hepatitis A, and ischemia (approximately 60% spontaneous survival), and poor prognoses with drug-induced ALF, hepatitis B, and indeterminate cases (approximately 25% spontaneous survival). Excellent intensive care is critical in management of patients with ALF. Nonspecific therapies are of unproven benefit. Future possible therapeutic approaches include N-acetylcysteine, hypothermia, liver assist devices, and hepatocyte transplantation. Advances in stem cell research may allow provision of cells for bioartificial liver support. ALF presents many challenging opportunities in both clinical and basic research.""",1
11491,18318821,Hepatotoxic slimming aids and other herbal hepatotoxins,"Perceptions of safety and/or cultural mores prompt individuals to seek herbal slimming aids in preference to conventional dietary, physical activity and medication-based protocols. In recent years, terpenoid-containing dietary supplements have been implicated in causing severe and sometimes fatal hepatotoxicity. Teucrium polium (germander) was the first of these herbal products to be clearly linked to cases of acute liver failure. Subsequently, similar hepatotoxicity has been observed with other members of the Teucrium genus. While diterpenoid-derived reactive metabolites are central to germander hepatotoxicity, it may also be that the hepatic effects of compounds such as Sho-saiko-to, Centella asiatica and Black cohosh are linked to their triterpenoid content. Other non-terpenoid-containing herbal remedies marketed for weight reduction have been causally associated with significant liver injury. Important among these are preparations containing N-nitrosofenfluramine, usnic acid and ephedra alkaloids. Finally, we review recent data on known and emerging hepatotoxins such as Boh-Gol-Zhee, Kava, pyrrolizidine alkaloids and Shou-Wu-Pian. Better public and physician awareness through health education, early recognition and management of herbal toxicity and tighter regulation of complementary/alternative medicine systems are required to minimize the dangers of herbal product use.",1
11492,18322868,Toxicity of kava kava,"Kava is a traditional beverage of various Pacific Basin countries. Kava has been introduced into the mainstream U.S. market principally as an anti-anxiety preparation. The effects of the long-term consumption of kava have not been documented adequately. Preliminary studies suggest possible serious organ system effects. The potential carcinogenicity of kava and its principal constituents are unknown. As such, kava extract was nominated for the chronic tumorigenicity bioassay conducted by the National Toxicology Program (NTP). At present toxicological evaluation of kava extract is being conducted by the NTP. The present review focuses on the recent findings on kava toxicity and the mechanisms by which kava induces hepatotoxicity.",1
11493,18325075,Late-onset celecoxib-induced combined hepato-nephrotoxicity,,1
11494,18328291,The Janus faces of allopurinol-allopurinol hypersensitivity syndrome,,1
11495,18333861,"Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers","AIMS: To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. METHODS: Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. RESULTS: Maraviroc is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5-4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3-1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10-12 l h(-1) and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. CONCLUSIONS: Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.",1
11496,18334761,"Memantine treatment in patients with mild to moderate Alzheimer's disease: results of a randomised, double-blind, placebo-controlled 6-month study","""Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist currently approved for the treatment of moderate to severe Alzheimer's disease (AD). A 24-week, double-blind, placebo-controlled, study (Study 99679) conducted in Europe evaluated the efficacy and tolerability of 20 mg/day memantine in patients with mild to moderate AD. Patients were randomised to either memantine or placebo in a 2:1 ratio. Efficacy was primarily assessed as change from baseline in ADAS-cog and CIBIC-plus score. Of 470 patients randomised and treated (memantine, n=318; placebo, n=152), 85% and 91% completed the study. Memantine-treated patients showed statistically significant improvement relative to placebo at weeks 12 and 18, and numerical superiority at week 24 on both efficacy scales. The lack of significance at week 24 was attributed to an unexpectedly high placebo response. Memantine was well tolerated with an adverse event profile similar to placebo. The data presented support the efficacy of memantine in mild to moderate AD.""",1
11497,18334909,"Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia","""Iloperidone is a mixed D2/5-HT2 antagonist in development for treatment of schizophrenia. This trial aimed to evaluate the efficacy and safety of a fixed dose of iloperidone in patients with acute exacerbations of schizophrenia. This randomized, placebo-controlled, multicenter study comprised a 1-week titration period and a 3-week double-blind maintenance period. Eligible patients (n = 593) were randomized to iloperidone 24 mg/d, ziprasidone 160 mg/d as an active control, or placebo. Primary efficacy variable was change from baseline in the Positive and Negative Syndrome Scale Total (PANSS-T) score, using a mixed-effects model repeated measures analysis. Iloperidone demonstrated significant reduction versus placebo on the PANSS-T score (P< 0.01). Significant improvement versus placebo was also demonstrated with ziprasidone (P < 0.05). Compared with ziprasidone, iloperidone was associated with lower rates of many adverse events (AEs) that are particularly troublesome with antipsychotics, including sedation, somnolence, extrapyramidal symptoms, akathisia, agitation, and restlessness; iloperidone was associated with higher rates of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal congestion as reported as an AE. Most AEs were mild to moderate. A similar amount of QT prolongation was observed with both active treatments, although no patient had a treatment-emergent postbaseline corrected QT interval of 500 msec or greater. The incidence of clinically relevant changes in laboratory parameters was comparable between iloperidone and ziprasidone. Iloperidone was associated with a low incidence of extrapyramidal symptoms. Overall, there was improvement in akathisia with iloperidone treatment. Iloperidone treatment was effective, safe, and well tolerated in patients with acute exacerbation of schizophrenia.""",1
11498,18334911,Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies,"""Iloperidone is an atypical antipsychotic in development for the treatment of schizophrenia. This report examines efficacy results from three 6-week, randomized, double-blind, placebo- and active comparator-controlled studies in patients with schizophrenia or schizoaffective disorder. Multiple doses of iloperidone were studied. Active comparators (haloperidol 15 mg/d, or risperidone 4-8 mg/d) were included to confirm trial validity. The primary protocol-defined efficacy variable in Study 1 was change from baseline to end point in Positive and Negative Syndrome Scale total scores; in Studies 2 and 3, it was change in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale scores. Results were assessed through analysis of covariance using last observation carried forward in the intent-to-treat population. In total, 1943 patients were randomized. At least 1 iloperidone dosing group in each study demonstrated significantly better efficacy than placebo (Study 1, iloperidone 12 mg/d [P = 0.047]; Study 2, 4-8 mg/d [P = 0.012] and 10-16 mg/d [P = 0.001]; and Study 3, 20-24 mg/d [P = 0.010]). Active controls were also significantly more effective than placebo in each trial, thus validating the trials. Additional analysis in patients who received active treatment for at least 2 weeks indicated comparable efficacy score reductions at 6 weeks for patients receiving iloperidone 20 to 24 mg/d versus those receiving haloperidol or risperidone. Risk for motor-related adverse events (eg, akathisia and extrapyramidal symptoms) was lower with iloperidone than with risperidone and haloperidol and was generally similar to placebo. These trials indicate that iloperidone is effective for the treatment of schizophrenia.""",1
11499,18337443,Hydroxyurea induced acute elevations in liver function tests,"Hydroxyurea (HU) is a ribonucleotide reductase inhibitor used to treat myeloproliferative diseases including polycythemia vera (PV) and essential thrombocythemia (ET). We describe an 82-year-old male who was started on HU 500 mg three times weekly for the treatment of PV. Eight days after initiation of HU he experienced anorexia, nausea, vomiting, fever, fatigue, dizziness, and shaking chills. Discontinuation of the HU resulted in resolution of his symptoms within 2 days, and HU was re-started. Ten days after re-starting HU, the patient re-presented with nausea and anorexia. Lab tests revealed elevations in liver enzyme function tests, which resolved promptly after cessation of HU. Patients being initiated on HU should be advised that rarely, fevers, chills, nausea, and elevations in liver function tests may occur.",1
11500,18341684,Hepatotoxicity associated with antiepileptic drugs,"BACKGROUND: Drug-induced liver injury associated with antiepileptic drugs (AED) is well recognized. The frequency of the most common AED is rare but the consequences can be very serious leading to death or liver transplantation due to acute liver failure induced by these drugs. CLINICAL FEATURES: Hypersensitivity features are found in more than 70% of patients with phenytoin-induced liver injury, whereas this is only observed in 30% of carbamazepine-associated hepatotoxicity and very rarely with valproate (VPA)-induced liver injury. PATHOPHYSIOLOGY: The underlying mechanisms behind hepatotoxicity induced by AED are not clear. Reactive metabolites from AED can, in some cases, lead to direct cytotoxicity and liver cell necrosis, whereas in other cases this may lead to neoantigen formation inducing immunoallergic mechanisms. TREATMENT: No specific therapy is of proved value in severe hepatotoxicity due to AED. However, N-acetylcystein is an appropriate treatment in patients with clinically significant liver injury due to phenytoin and carbamazepine. In patients with VPA-associated liver injury, carnitine that is an important co-factor in the mitochondrial beta-oxidation of fatty acids is the recommended treatment. Early referral of patients with severe liver reactions and coagulopathy to liver transplant centers before encephalopathy can be the difference between liver transplantation and death.",1
11501,18343240,Panitumumab: human monoclonal antibody against epidermal growth factor receptors for the treatment of metastatic colorectal cancer,"""BACKGROUND: Panitumumab, formerly known as ABX-EGF, was the first recombinant human immunoglobulin G2 monoclonal antibody approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. OBJECTIVE: The purpose of this review was to evaluate the pharmacokinetic and pharmacodynamic properties, clinical efficacy, and safety profile of panitumumab in the treatment of metastatic colorectal cancer. METHODS: Computerized searches of MEDLINE and International Pharmaceutical Abstracts from 1985 to August 15, 2007, were performed with the search terms panitumumab, ABX-EGF, EGFr, and colorectal cancer. All available clinical trials and ongoing trials were included in this review. Relevant abstracts presented at the annual meetings of the American Society of Clinical Oncology, American Association for Cancer Research, and Gastrointestinal Cancer Symposium (1999-2007) also were reviewed and included. RESULTS: Preclinical and clinical studies have established a role for panitumumab in mCRC refractory to multiple chemotherapeutic regimens. In a Phase III trial of panitumumab plus best supportive care (BSC) versus BSC alone in patients with refractory mCRC, panitumumab was found to have efficacy in time-related end points, such as progression-free survival. In the panitumumab group, a significant (46%) reduction in tumor progression rate was reported compared with BSC (hazard ratio, 0.54; 95% CI, 0.44-0.66; P < 0.001). At the present time, the use of panitumumab as first-line treatment for mCRC with standard chemotherapy and bevacizumab is not indicated due to increased toxicity with no advantage in efficacy. The efficacy of panitumumab is being evaluated in other solid tumors, such as lung, breast, ovarian, bladder, and head and neck cancers. CONCLUSION: Panitumumab appears to have relatively acceptable tolerability and is now available as an additional option for patients with mCRC refractory to multiple chemotherapeutic regimens.""",1
11502,18344107,Are recommended doses of acetaminophen hepatotoxic for recently abstinent alcoholics? A randomized trial,"""Although acetaminophen overdose is a leading cause of fulminant hepatic failure, it is controversial whether therapeutic doses of acetaminophen can cause hepatotoxicity in alcoholics, especially those rendered most vulnerable by recent abstinence. We performed a randomized, triple-blind, parallel-group trial comparing sustained-release acetaminophen, 1300 mg orally q8h for 11 doses, against placebo. We enrolled chronic alcohol abusers (defined as >or= 6 drinks daily for >or= 6 weeks) who had discontinued alcohol consumption 12 to 72 hours prior to enrollment. Individuals with self-reported viral hepatitis, HIV or intravenous drug use, baseline AST or ALT >120 IU/L, or INR >1.5 were excluded. Hepatic function tests were drawn daily for 5 days. The primary outcome was change in serum alpha-GST, a sensitive experimental biomarker of hepatocellular injury; secondary outcomes were changes in serum AST, ALT, INR, and study withdrawal for a doubling of aminotransferases to >120 IU/L. Of 52 subjects randomized, 40 completed at least four days of intervention. Subjects receiving acetaminophen had 32% [95% CI 7%, 50%] and 29% [6%, 46%] lower serum alpha-GST concentrations on days 2 and 3, respectively, compared to placebo, but these differences disappeared by day 4. No subjects were withdrawn for safety reasons. In conclusion, therapeutic doses of sustained-release acetaminophen cause a measurable decrease in serum alpha-GST during the first days of abstinence from chronic alcohol use. While the mechanism is unclear, these observations do provide some reassurance that short courses of acetaminophen are unlikely to cause subclinical hepatocellular injury in recently abstinent alcoholics.""",1
11503,18344747,Drug-induced liver disease related to citalopram,,1
11504,18348774,The treatment of giardiasis in children: single-dose tinidazole compared with 3 days of nitazoxanide,"""Giardia lamblia is among the commonest intestinal protozoa world-wide and may cause significant morbidity, especially in children. Although 5-nitroimidazole compounds have formed the mainstay of giardiasis treatment for several years, the increasing number of reports of refractory cases given these and other antigiardial agents has raised concern and led to a search for other compounds. The aim of the present study was to compare the efficacy and safety, in the treatment of children infected with G. lamblia, of nitazoxanide, given at a dose of 7.5 mg/kg twice a day for 3 days, with those of tinidazole, given as a single dose of 50 mg/kg. Overall, 166 children, each proven to be infected with G. lamblia by the microscopical examination of a faecal sample, were included in the open and randomized trial, each being allocated to receive nitazoxanide or tinidazole. The parents of each treated child were asked to collect two faecal samples from the child between 5 and 10 days after the completion of treatment, for the parasitological follow-up. Only if no G. lamblia were found in both post-treatment samples from a child was that child considered cured. Among the 137 children who completed the study (74 given nitazoxanide and 63 given tinidazole), the frequency of parasitological cure following a single dose of tinidazole was significantly higher than that following six doses of nitazoxanide (90.5% v. 78.4%; P<0.05). Both treatment schedules were well accepted and well tolerated, with only mild, transient and self-limited side-effects reported. The commonest symptom on enrolment, diarrhoea, generally cleared 2-6 days after the initiation of treatment. Although apparently less efficacious than tinidazole, nitazoxanide remains a good candidate for the treatment of children with G. lamblia infection.""",1
11505,18350206,Incidence of nevirapine-associated hepatitis in an antenatal clinic,"""OBJECTIVE: To describe the incidence, clinical presentation and management of nevirapine-associated hepatitis among antiretroviral-naive pregnant women treated with nevirapine-based antiretroviral therapy at a dedicated antenatal antiretroviral clinic. METHODS: Retrospective analysis of pregnant women initiated on nevirapine-based highly active antiretroviral therapy at a dedicated antenatal antiretroviral clinic between July 2004 and December 2006. RESULTS: Three hundred and ninety women were included in the analysis. Median age was 29 (interquartile range (IQR) 26-32) years and median pre-treatment CD4 cell counts was 157 (IQR 104-193) cells/microl. Baseline alanine transaminase (ALT) was elevated in 2.8% of women (11/390). After initiation of nevirapine-based ART 8% (31/390) experienced an ALT elevation. Three of these patients developed clinical hepatitis with jaundice (0.8%, 3/390). The mean and median time to clinical presentation was 5 weeks. Hepatitis resolved following discontinuation of ART. Non-nevirapine regimens were initiated following biochemical and symptomatic improvement; symptoms did not recur. CONCLUSIONS: Among pregnant women, nevirapine-containing ART has a favourable safety profile, with a low incidence of serious hepatic events.""",1
11506,18355433,[Cocaine-induced hepatotoxicity],,1
11507,18358677,Estimated risk of hepatotoxicity after an acute acetaminophen overdose in alcoholics,"""A published logistic regression model based on the Canadian Acetaminophen Overdose Study registry was used to calculate the risk of hepatotoxicity after an acute acetaminophen overdose and to estimate a treatment threshold line for alcoholic patients who did not co-ingest alcohol (i.e., abstinent alcoholics) on the Rumack-Matthew nomogram. The risk of hepatotoxicity in nonalcoholic and abstinent alcoholic patients was calculated at the acetaminophen concentration of 150 microg/ml at 4h (37.5 microg/ml at 12h) treatment threshold line. This corresponds to the """"possible risk"""" line on the Rumack-Matthew nomogram and represents a 1.6% risk of hepatotoxicity for nonalcoholic patients at or below this line. At or below this same 150 microg/ml at 4-h line, abstinent alcoholic patients have a hepatotoxicity risk of 10.7%. The risk of hepatotoxicity in abstinent alcoholics' equivalent to that of nonalcoholics (i.e., 1.6%) occurs at a lower acetaminophen concentrations treatment threshold line, that is, 104 microg/ml at 4h (26 microg/ml at 12h). Because of difficulties plotting this new line on the familiar Rumack-Matthew semilogarithmic scale, a line connecting 100 microg/ml at 4h (25 microg/ml at 12h) is proposed. This line equates to a 1.1% risk of hepatotoxicity in abstinent alcoholic patients. The analysis supports the observation that based on the published model abstinent alcoholics might have a greater risk of hepatotoxicity after an acute acetaminophen overdose. This proposed new risk line can be used in hypothesis generation for future clinical studies in this alcohol related problem.""",1
11508,18360262,"Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness","""BACKGROUND: Clinical data are lacking concerning concomitant administration of everolimus and tacrolimus in renal transplant recipients. METHODS: In a prospective, multicenter, open-label, exploratory, randomized, 6-month study, 92 de novo renal transplant patients received everolimus, steroids, and basiliximab with low or standard tacrolimus exposure. The primary objective was to compare renal function at 6 months after transplant. RESULTS: Mean 6-month serum creatinine (primary safety variable) was 112+/-31 micromol/L (1.26+/-0.35 mg/dL) and 127+/-50 micromol/L (1.44+/-0.57 mg/dL) in the low and standard tacrolimus groups, respectively, (n.s.); mean estimated GFR (Nankivell) was 75.3+/-16.6 mL/min and 72.5+/-15.2 mL/min (n.s.). Biopsy-proven acute rejection occurred in 13 patients: seven (14%) in the low tacrolimus group and six (14%) in the standard tacrolimus group, n.s. One graft was lost in the standard tacrolimus group. No patients died. CONCLUSIONS: Tacrolimus exposure reduction in the presence of everolimus, steroids and basiliximab induction results in good efficacy in de novo renal transplant recipients with very well-preserved renal function. Additional studies are warranted because between-group comparisons were limited by the relatively small differences in tacrolimus exposure in the 2 arms; trough levels were toward the upper end of the low-exposure ranges and toward the bottom of the standard-exposure ranges.""",1
11509,18360803,Varicella-zoster virus hepatitis in polymyositis,"A 31-year-old woman had recurrent mild flare-ups of polymyositis for years. Fourteen days after low-dose methotrexate was added in an attempt to taper the corticosteroid, she began to feel abdominal and lower back pain, followed by generalized pustulosis, severe liver dysfunction, and disseminated intravascular coagulation. On the diagnosis of varicella-zoster virus (VZV) hepatitis, acyclovir, immune globulin and plasmapheresis were given with a favorable outcome. Physicians should be aware that VZV infection could complicate severe hepatitis in immuno-suppressed patients.",1
11510,18363520,Armodafinil: a new treatment for excessive sleepiness,"BACKGROUND: Armodafinil is a wake-promoting agent developed by Cephalon that was approved in mid-2007 for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder. It is the R-enantiomer of the compound modafinil. Like modafinil, the mechanism of action for armodafinil is not fully characterized. OBJECTIVE: To determine what data are available to support the potential use of armodafinil in clinical settings. METHODS: There are limited data on armodafinil available in the public domain, particularly in regard to chemistry and pharmacokinetics/dynamics. Data were reviewed from refereed journals, scientific presentations, and published labeling. RESULTS/CONCLUSION: Clinical trials demonstrated efficacy and safety profiles that were similar to those of the parent compound with wake promotion sustained throughout the day. The longer duration of effect has the potential for improved patient response and compliance but this will require further study. The primary commercial challenge may be the future availability of generic modafinil.",1
11511,18366240,Propofol infusion syndrome: an overview of a perplexing disease,"Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent that is widely used in adults and children for sedation and the induction and maintenance of anaesthesia. Propofol has gained popularity for its rapid onset and rapid recovery even after prolonged use, and for the neuroprotection conferred. However, a review of the literature reveals multiple instances in which prolonged propofol administration (>48 hours) at high doses (>4 mg/kg/h) may cause a rare, but frequently fatal complication known as propofol infusion syndrome (PRIS). PRIS is characterized by metabolic acidosis, rhabdomyolysis of both skeletal and cardiac muscle, arrhythmias (bradycardia, atrial fibrillation, ventricular and supraventricular tachycardia, bundle branch block and asystole), myocardial failure, renal failure, hepatomegaly and death. PRIS has been described as an 'all or none' syndrome with sudden onset and probable death. The literature does not provide evidence of degrees of symptoms, nor of mildness or severity of signs in the clinical course of the syndrome. Recently, a fatal case of PRIS at a low infusion rate (1.9-2.6 mg/kg/h) has been reported. Common laboratory and instrumental findings in PRIS are myoglobinuria, downsloping ST-segment elevation, an increase in plasma creatine kinase, troponin I, potassium, creatinine, azotaemia, malonylcarnitine and C5-acylcarnitine, whereas in the mitochondrial respiratory electron transport chain, the activity of complex IV and cytochrome oxidase ratio is reduced. Propofol should be used with caution for sedation in critically ill children and adults, as well as for long-term anesthesia in otherwise healthy patients, and doses exceeding 4-5 mg/kg/h for long periods (>48 h) should be avoided. If PRIS is suspected, propofol must be stopped immediately and cardiocirculatory stabilization and correction of metabolic acidosis initiated. So, PRIS must be kept in mind as a rare, but highly lethal, complication of propofol use, not necessarily confined to its prolonged use. Furthermore, the safe dosage of propofol may need re-evaluation, and new studies are needed.",1
11512,18366245,Hepatic events associated with atomoxetine treatment for attention-deficit hyperactivity disorder,"OBJECTIVE: This study describes and assesses potential hepatobiliary events related to atomoxetine therapy, as reported in clinical trials and as spontaneous adverse event reports post-launch in 2002. METHODS: Case reports that contained potential hepatobiliary events were identified by a computerized search of the Eli Lilly and Company atomoxetine spontaneous adverse events and clinical trials databases. All cases were reviewed by at least two company physicians, one with expertise in hepatology, to determine the relevance of the information in respect of potential liver toxicity. RESULTS: Of 7961 paediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as having hepatobiliary events requiring additional analysis. Most of these events were mild increases in ALT and AST levels. None of these cases met Hy's rule criteria or progressed to liver failure. During the 4 years after market launch, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the remaining 282 cases, 133 contained possible confounding factors (and were deemed to be possibly related), 146 presented too little information to assess, and three suggested atomoxetine as a probable cause of liver injuries. One of the three had a positive rechallenge. All three patients recovered after discontinuation of the drug. CONCLUSIONS: Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.",1
11513,18367739,Hydroxyurea for the treatment of sickle cell anemia,,1
11514,18367863,[A case of ticlopidine induced acute cholestatic hepatitis and pure red cell aplasia],"Ticlopidine inhibits platelet aggregation and provides beneficial secondary prevention of cerebrovascular and coronary artery disease. Frequently reported adverse effects of ticlopidine include diarrhea, nausea, and rash. However, to our knowledge, there are only a few published reports of the simultaneous occurrence of cholestatic hepatitis and pure red cell aplasia. Here we report a patient with simultaneous severe cholestatic hepatitis and pure red cell aplasia associated with ticlopidine. Although these adverse effects are rare, periodic hematological and liver function tests are recommended after starting ticlopidine.",1
11515,18375237,Mechanism of action of niacin,"Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.",1
11516,18376233,Phase II study of imatinib in unresectable hepatocellular carcinoma,"""BACKGROUND: The expression of platelet-derived growth factor, a potent mitogen, and its receptor both in tissue and serum correlate with the severity of liver cirrhosis. Over-expression of platelet-derived growth factor has been demonstrated in human hepatocellular carcinoma (HCC) tumors and cell lines. Imatinib, a potent inhibitor of BCR-ABL and c-kit, also inhibits the platelet-derived growth factor receptor tyrosine kinase. The trial was designed to assess the efficacy and safety of imatinib in patients with unresectable HCC. METHODS: Eligibility criteria consisted of HCC patient over the age of 18 with reasonable organ function, unresectable but measurable disease, not candidates for chemoinfusion, and a performance status of 0 to 2. Imatinib was started at 300 mg/d orally with 100 mg/wk dose escalation up to 800 mg/d if toxicity permitted. RESULTS: Fifteen patients, median age 58 years, were enrolled and treated with imatinib. Most, or 7, patients had hepatitis B virus as a risk factor for HCC, followed by hepatitis C virus in 3 patients. Metastatic disease (American Joint Committee on Cancer stage IV) was noted in 13 patients and locally advanced (stage III) in the remainder. The median dose-level of imatinib was 500 mg/d. Two patients had stable disease lasting more than 2 months. The remainder progressed within 2 months of initiation of imatinib. No grade 3 or 4 hematologic toxicity was observed. Two patients had grade 3 elevated liver function tests during treatment; otherwise, there was no other grade 3 or 4 nonhematologic toxicity noted. CONCLUSION: Although toxicities were tolerable, imatinib as a monotherapy for the treatment of unresectable HCC has little, if any, significant efficacy.""",1
11517,18379232,"Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study","""OBJECTIVE: Doripenem is an investigational carbapenem with broad-spectrum activity against gram-negative and gram-positive pathogens, including multidrug-resistant strains, commonly responsible for ventilator-associated pneumonia (VAP). This large, phase III study compared doripenem with imipenem for the treatment of ventilator-associated pneumonia. DESIGN: Prospective, multicenter, parallel randomized, active-controlled, open-label study. SETTING: Intensive care units. PATIENTS: Adults (N = 531) who met clinical and radiologic criteria for ventilator-associated pneumonia. INTERVENTIONS: Patients were stratified by duration of mechanical ventilation (< 5 vs. > or = 5 days), severity of illness (Acute Physiology and Chronic Health Evaluation II score < or = 15 vs. > 15), and geographic region and then randomly assigned to doripenem 500 mg every 8 hrs via a 4-hr intravenous infusion or imipenem 500 mg every 6 hrs or 1000 mg every 8 hrs via 30- or 60-min intravenous infusions, respectively, for 7-14 days. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end points were the clinical cure rates in the clinical modified intent-to-treat (cMITT) and clinically evaluable populations. Doripenem was noninferior to imipenem (lower boundary of 95% confidence interval around the difference between treatments > or = -20%). Clinical cure rates were 68.3% (doripenem) and 64.2% (imipenem) in the clinically evaluable and 59.0% (doripenem) and 57.8% (imipenem) in the cMITT populations. In patients with Pseudomonas aeruginosa, clinical cure was 80.0% (doripenem) and 42.9% (imipenem) (p not significant); microbiological cure was 65.0% (doripenem) and 37.5% (imipenem). Only 18% (5 of 28) of P. aeruginosa isolates had minimum inhibitory concentration > or = 8 microg/mL at baseline or following therapy in the doripenem arm compared with 64% (16 of 25) in the imipenem treatment group (p = .001). Clinical cure rate was higher with doripenem than imipenem at higher Acute Physiology and Chronic Health Evaluation II scores and older ages. Doripenem was generally well tolerated. CONCLUSIONS: In this large, phase III study of patients with ventilator-associated pneumonia, a 4-hr intravenous infusion of doripenem was clinically efficacious and therapeutically noninferior to imipenem.""",1
11518,18381923,Acute hepatotoxicity associated with lamotrigine,,1
11519,18383539,"Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study","OBJECTIVE: To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX). METHODS: Patients were randomly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo. RESULTS: The primary end point was attained. Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P=0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P<0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group. CONCLUSION: Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.",1
11520,18385198,Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features,"BACKGROUND: Temsirolimus, a novel inhibitor of mammalian target of rapamycin, has demonstrated prolonged overall survival and progression-free survival compared with interferon alfa (IFN) in patients with advanced renal cell carcinoma (RCC) and poor prognostic features. Adverse events (AEs) of any causality were previously reported, but AEs that were deemed temsirolimus related are of particular relevance for poor-risk patients and for defining mammalian target of rapamycin inhibitor-specific side-effects. PATIENTS AND METHODS: Patients with advanced RCC, no prior systemic therapy, and three or more of six poor-risk factors were randomly assigned to one of three groups: (i) IFN s.c. up to 18 MU thrice weekly, (ii) temsirolimus i.v. 25 mg weekly, or (iii) temsirolimus i.v. 15 mg weekly plus interferon s.c. 6 MU thrice weekly. RESULTS: Among 208 patients, the most common temsirolimus-related grades 3-4 AEs were anemia (13%), hyperglycemia (9%), and asthenia (8%). Grades 3-4 hypercholesterolemia (1%), hypertriglyceridemia (3%), and hypophosphatemia (4%) were also seen. Although pneumonitis occurred infrequently, vigilance for its development is needed. Guidelines for management of toxic effects are presented on the basis of available clinical experience. CONCLUSIONS: Temsirolimus-related grades 3-4 AEs were primarily metabolic in nature and easily controlled medically. In general, these did not negatively impact patient quality of life.",1
11521,18389904,"Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome","""BACKGROUND: Cases of severe unexplained liver disease in HIV-infected individuals have recently been reported and are often associated with exposure to didanosine (ddl) and nodular regenerative hyperplasia. Herein, we examine the clinical outcome following ddl removal. METHODS: From 3,300 HIV-infected patients attending three clinics since 2004, all who exhibited persistently elevated aminotransferases and/or significant liver fibrosis in the absence of any known cause of liver damage were identified. RESULTS: Thirty-two individuals (prevalence approximately 1%) met the inclusion criteria - all were on antiretroviral therapy. Of these, 84% were male and 68% had acquired HIV through homosexual contact. Liver biopsy was performed in 12, of whom three showed nonspecific advanced liver fibrosis, two nodular regenerative hyperplasia and three showed only periportal fibrosis. On follow up, nine patients developed episodes of hepatic decompensation, mainly as a consequence of portal hypertension; in eight cases (25%) portal thrombosis was diagnosed. No association was found with plasma HIV RNA or CD4+ T-cell count. All patients but three had been exposed to ddl for a median of 44 months; removal of ddl in 27 was followed 12 months later by improvement in clinical and laboratory parameters in 13 (48%) patients. Finally, a trend towards liver fibrosis improvement was recognised using FibroScan. CONCLUSIONS: Idiopathic persistent liver enzyme elevations in HIV-infected individuals are often associated with cirrhotic and non-cirrhotic portal hypertension. Although this is a relatively rare condition, prolonged exposure to ddl seems to play a pathogenic role and removal of the drug is associated with clinical and laboratory improvements.""",1
11522,18390837,"First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial","""Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.""",1
11523,18391918,Erlotinib-induced acute hepatitis in a patient with pancreatic cancer,,1
11524,18392678,Inpatient admissions for drug-induced liver injury: results from a single center,"""Objective To review all cases of drug-induced liver injury (DILI) requiring hospitalization at a single tertiary care center. Methods Patient records were identified by ICD-9 codes for inpatient visits from November 1998 through March 2006. Results Of a total 83,265 hospital admissions during the study period, 40 were for DILI (0.048%). Thirteen patients had non-acetaminophen DILI (NA-DILI); 27 had acetaminophen-related DILI (A-DILI). In the NA-DILI group, mean age was 59 +/- 17.9 years and liver injury was classified as hepatocellular (7), cholestatic (5), or mixed (1). A variety of medications were implicated with antimicrobials being the most common class. Resolution occurred in seven, two died of complications related to hepatotoxicity, one underwent liver transplantation, and the outcome was undetermined in three who were lost to follow-up. In the A-DILI group, mean age was 35 +/- 11.0 years. Eighteen involved intentional overdose of acetaminophen; nine were associated with chronic use. The pattern of injury was hepatocellular in all. Resolution occurred in 4 patients, death in 8, and improvement in 15. Conclusions DILI is a rare cause of inpatient admission but is associated with significant mortality. Spontaneous resolution occurs in most patients but return to normal liver function may take months. Antimicrobial agents account for the largest proportion of NA-DILI.""",1
11525,18396749,Acute hepatitis with prolonged cholestasis and disappearance of interlobular bile ducts following tibolone and Hypericum perforatum (St. John's wort). Case of drug interaction?,"The case of a patient under tibolone therapy for two years who developed a mixed-type liver injury with prolonged cholestasis and features of the vanishing bile duct syndrome following a ten weeks treatment with St. John wort (Hypericum Perforatum) infusions is reported. In the absence of evidence of a potential role for concomitant medication i.e. hydroxychloroquine sulfate to play a role in the clinical, biochemical and morphological picture, an interaction between the herbal preparation and tibolone was suspected as the likely cause of liver damage.",1
11526,18397566,Fulminant autoimmune hepatitis after successful interferon treatment in an HIV-HCV co-infected patient,"Hepatitis C (HCV) treatment using interferon-alpha (IFN-alpha) and ribavirin is recommended in HIV/HCV co-infected patients to prevent liver cirrhosis and liver-related death. However, in addition to its antiviral activity, IFN is a pleiotropic cytokine able to synergistically amplify T-cell autoreactivity. Here, we report for the first time the induction of a subfulminant autoimmune hepatitis (AIH) after four months of a successful treatment of HCV-1b infection using peg-IFN and ribavirin, in a 48-year-old woman co-infected with HIV. Diagnosis was assessed according to the international AIH scoring system, including liver biopsy and confirmed by positive response to steroid challenge.",1
11527,18398081,Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials,"""CONTEXT: Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE: To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS: Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS: Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE: Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS: For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION: In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.""",1
11528,18398832,"Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies","Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses, decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at 'optimal biologic' doses that modulate hypomethylation). In these dose schedules of decitabine (100 to 150 mg/m(2) per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies.",1
11529,18401994,[Sevoflurane and liver dysfunction],,1
11530,18403950,Lycopodium similiaplex-induced acute hepatitis: a case report,"""A 46-year-old woman was admitted to our department with symptoms of nausea, anorexia and asthenia. Serum alanine aminotransferase and aspartate aminotransferase levels were increased; all serological tests for viral hepatitis and autoimmune disorders were negative. She had taken Lycopodium similiaplex solution as sedative for the previous 8 weeks, whose two constituents, Lycopodium serratum and Chelidonium majus, are found to be potentially toxic. After discontinuing L. similiaplex use, liver values returned to normal and she was asymptomatic. The diagnosis was definitively confirmed by liver biopsy; on the basis of the histological specimen, a hypersensitivity reaction was hypothesized as a possible pathogenic mechanism. Hepatotoxicity of phytotherapy has already been described, although so far, the true incidence and the pathogenic mechanisms are largely unknown. It is important to increase awareness of both clinicians and patients about the potential dangers of herbal remedies; surveillance systems and quality control of these products are necessary.""",1
11531,18410471,Fluvastatin inhibits hepatitis C replication in humans,"""UNLABELLED: BACKGROUND Hepatitis C viral (HCV) infection is the leading cause of death due to liver disease in the United States. Currently, pegylated interferon and ribavirin produce sustained viral remission in only 50% of patients. Additional agents are needed to increase the cure rate. In vitro experiments show strong antiviral effects of fluvastatin against HCV. OBJECTIVES: To assess the safety and antiviral effects of fluvastatin in chronic HCV carriers. METHODS: 31 veterans with chronic HCV were prospectively given oral doses of fluvastatin, 20 to 320 mg/day, for 2-12 weeks with weekly monitoring of HCV RNA and liver tests. Reductions of viral load (P < 0.01) versus a control group were considered suppressive. RESULTS: With 80 mg a day or less, 11/22 (50%) patients responded by lowering HCV RNA. The first lowering occurred within 4 weeks (9/11, 82%). The greatest weekly change in HCV RNA level was a 1.75 log(10) reduction. When lowered in responders, the viral load remained relatively constant for 2-5 weeks (7/9, 78%), or on the next test rebounded immediately to a non-significant change from, baseline (n = 2). Continued lowering of virus was seen in 2/19 (22 %) patients when the study ended. We found no evidence of liver tests worsening. CONCLUSIONS: FLV used as monotherapy in vivo showed suppressive effects of HCV clinically that are modest, variable, and often short-lived. These findings support """"proof-of-concept"""" for pilot trials combining fluvastatin with standard therapy. Statins and fluvastatin, in particular, appear to be safe for use in hepatitis C.""",1
11532,18413635,Memantine-induced hepatitis with cholestasis in a very elderly patient,,1
11533,18419635,"Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer","Oral mucositis is a major toxicity associated with high-dose methotrexate (HD-MTX) therapy in the treatment of children with acute lymphoblastic leukaemia and osteosarcoma. This pilot matched case-control study investigated the associations between plasma concentration of MTX at 42 (p-MTX(42h)) and 66 (p-MTX(66h)) h, absolute neutrophil count (ANC) < or = or >1.0 x 10(9)/l, serum transaminases (ASAT/ALAT) < or > or =58 U/l, WHO < or > or =grade 2 nausea/vomiting and WHO < or > or =grade 2 oral mucositis. In this study, 11 children with WHO > or =grade 2 oral mucositis were compared with 17 control children matched for age, diagnosis and MTX-dosage. The results indicated that children with p-MTX(42h) > or = 1.0 micromol/l had an odds ratio (OR) of 4.3 of developing oral mucositis when compared with the referent group of children who had p-MTX(42h) < 1.0 micromol/l. Children with p-MTX(66h) >= 0.2 micromol/l had an OR of 8.2 of developing oral mucositis when compared with the referent group of children who had p-MTX(66h) < 0.2 micromol/l. Children with ANC < or = 1.0 x 10(9)/l had an OR of 1.2 of developing oral mucositis when compared with the referent group of children who had ANC > 1.0 x 10(9)/l. In comparison with the referent group of children, who had <58 U/l ASAT/ALAT, those with ASAT/ALAT > or = 58 U/l had an OR of 1.2 of developing oral mucositis. Finally, children with WHO grade > or =2 nausea/vomiting had an elevated risk of developing oral mucositis when compared with the referent group of children who had WHO grade <2 nausea/vomiting (OR = 8.7). In conclusion, the results in this preliminary study provide support for the hypothesis that the risk of oral mucositis is associated with the plasma MTX concentration at 66 h and the level of nausea/vomiting.",1
11534,18421452,Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil,"PURPOSE: To determine the frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions (ADRs), anti-tuberculosis (TB) drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity in a population from Brazil. METHODS: Two hundred and fifty-four Brazilian TB patients using isoniazid (INH), rifampicin (RMP), and pirazinamide (PZA) were tested in a prospective cohort study. NAT2 genotyping was performed by direct PCR sequencing. The association between gastrointestinal ADRs/hepatotoxicity and the NAT2 profile genotype was evaluated by univariate analysis and multiple logistic regression. RESULTS: Of the 254 patients analyzed, 69 (27.2%) were slow acetylators and 185 (72.8%) were fast acetylators. Sixty-five (25.6%) patients were human immunodeficiency virus (HIV)-positive. Thirty-three (13%) and 14 (5.5%) patients developed gastrointestinal ADR and hepatotoxicity, respectively. Of the 14 hepatotoxicity patients, nine (64.3%) were slow acetylators and five (35.7%) were fast acetylators. Sex, age, presence of hepatitis C virus, alcohol abuse, and baseline aminotransferases were not found to be risk factors for hepatotoxicity. However, logistic regression analysis revealed that slow acetylator status and the presence of HIV (p < 0.05) were independent risk factors for hepatotoxicity. CONCLUSIONS: Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs.",1
11535,18424383,Severe liver dysfunction due to bosentan in a patient with mixed connective tissue disease,,1
11536,18425987,"The safety of rosuvastatin in comparison with other statins in over 25,000 statin users in the Saskatchewan Health Databases","PURPOSE: To compare mortality and the incidence of hospitalization for myopathy, rhabdomyolysis, acute renal failure and acute liver injury in patients receiving rosuvastatin and those taking other statins. METHODS: Patients prescribed a statin that they had not used before were selected from the Saskatchewan Health Databases (SHD) and followed up from 1 July 2003 until 31 March 2005. RESULTS: We studied 10,384 patients on rosuvastatin and 14,854 taking other statins. Two cases of myopathy were identified (one on rosuvastatin, one on another statin). The relative risk (RR) of myopathy in patients currently taking rosuvastatin compared with other statins was 1.31 (95% confidence interval [CI]: 0.13-13.41). Two cases of rhabdomyolysis were detected among current rosuvastatin users (incidence: 2.9 [95% CI: 0.8-10.7] per 10 000 person-years). No cases of acute liver injury occurred among rosuvastatin patients. Seventeen cases of acute renal failure were identified (five among rosuvastatin users, 12 taking other statins). The RR of acute renal failure in current rosuvastatin users compared with other statins was 0.49 (95% CI: 0.16-1.50). We identified 285 deaths during the study period (87 among rosuvastatin users, 198 taking other statins). The RR of death in current rosuvastatin users compared with other statins was 0.42 (95% CI: 0.32-0.57). CONCLUSIONS: We found no evidence that patients prescribed rosuvastatin were at greater risk of the study outcomes than patients prescribed other statins. There was no evidence of increased mortality among patients taking rosuvastatin, even after allowing for age, sex and prior statin use.",1
11537,18430913,Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis,"""CONTEXT: More than a quarter of the human population is likely infected with soil-transmitted helminths (Ascaris lumbricoides, hookworm, and Trichuris trichiura) in highly endemic areas. Preventive chemotherapy is the mainstay of control, but only 4 drugs are available: albendazole, mebendazole, levamisole, and pyrantel pamoate. OBJECTIVE: To assess the efficacy of single-dose oral albendazole, mebendazole, levamisole, and pyrantel pamoate against A lumbricoides, hookworm, and T trichiura infections. DATA SOURCES: A systematic search of PubMed, ISI Web of Science, ScienceDirect, the World Health Organization library database, and the Cochrane Central Register of Controlled Trials (1960 to August 2007). STUDY SELECTION: From 168 studies, 20 randomized controlled trials were included. DATA EXTRACTION AND DATA SYNTHESIS: Information on study year and country, sample size, age of study population, mean infection intensity before treatment, diagnostic method used, time between evaluations before and after treatment, cure rate (the percentage of individuals who became helminth egg negative following treatment with an anthelminthic drug), egg reduction rate, adverse events, and trial quality was extracted. Relative risk, including a 95% confidence interval (CI), was used to measure the effect of the drugs on the risk of infection prevalence with a random-effects model. RESULTS: Single-dose oral albendazole, mebendazole, and pyrantel pamoate for infection with A lumbricoides resulted in cure rates of 88% (95% CI, 79%-93%; 557 patients), 95% (95% CI, 91%-97%; 309 patients), and 88% (95% CI, 79%-93%; 131 patients), respectively. Cure rates for infection with T trichiura following treatment with single-dose oral albendazole and mebendazole were 28% (95% CI, 13%-39%; 735 patients) and 36% (95% CI, 16%-51%; 685 patients), respectively. The efficacy of single-dose oral albendazole, mebendazole, and pyrantel pamoate against hookworm infections was 72% (95% CI, 59%-81%; 742 patients), 15% (95% CI, 1%-27%; 853 patients), and 31% (95% CI, 19%-42%; 152 patients), respectively. No pooled relative risks could be calculated for pyrantel pamoate against T trichiura and levamisole for any of the parasites investigated. CONCLUSIONS: Single-dose oral albendazole, mebendazole, and pyrantel pamoate show high cure rates against A lumbricoides. For hookworm infection, albendazole was more efficacious than mebendazole and pyrantel pamoate. Treatment of T trichiura with single oral doses of current anthelminthics is unsatisfactory. New anthelminthics are urgently needed.""",1
11538,18431703,[Portal vein hypertension during azathioprine therapy in patients with Crohn's disease--a frequent phenomenon?],"HISTORY AND FINDINGS ON ADMISSION: A 45-year-old man with 18 years history of Crohn's disease who was on treatment with azathioprine (AZA) for the past 48 months was admitted because of haematemesis and melaena. INVESTIGATIONS AND DIAGNOSIS: Tests showed a slight elevation of bilirubin and a low platelet count. Endoscopy revealed esophageal and gastric fundus varices. Magnetic resonance imaging (MRI) revealed severe portal vein hypertension with a spleen-kidney convolute of varices. Liver biopsy showed hyperplasia of hepatocytes and a reticular fibrosis, consistent with the diagnosis of nodular regenerative hyperplasia (NRH). TREATMENT AND COURSE: AZA treatment was stopped. The fundal varices were treated with endoscopic histoacryl injection. The patient is at present in good health and is followed up in our outpatient department. CONCLUSION: AZA as a widely used immunosuppressive drug has side effects in about 5 - 10 % of the cases. The risk of hepatotoxicity in patients treated with AZA is often underestimated. Therefore, physicians treating patients with inflammatory bowel disease have to be precocious regarding the increase of hepatic enzymes and pathologic signs in liver imaging in relation of AZA treatment. The latter might refer to NRH which would lead to severe portal vein hypertension.",1
11539,18432322,Prophylaxis and therapy of HBV infection in 20 patients treated with disease modifying antirheumatic drugs or with biological agents for rheumatic diseases,"""OBJECT: To evaluate the safety and tolerability of lamivudine in patients with HBV infection needing immunosuppressive treatment for rheumatic diseases. PATIENTS AND METHODS: Twenty patients with rheumatic diseases planned to receive immunosuppressive DMARDs or biological agents were screened for HBV markers. In all active carriers antiviral treatment was recommended. Inactive carriers (HBsAg positive, aminotrasferase and viremia persistently normal) were divided into two risk categories according to the type and the degree of immunosuppression, and antiviral prophylaxis was started only in patients of the high risk category. Antiviral treatment was recommended also in potential occult carriers (HBsAg negative, HBcAb positive) treated with rituximab. In twenty patients antiviral treatment was started: 1 was a potential occult carrier planned to receive rituximab; 9 were inactive carriers, in which prophylactic therapy was needed for a high risk of HBV reactivation (in 3, for the use of TNF blocking agents); 10 were treated for active viral replication. Prophylaxis and therapy were performed with lamivudine. In three patients adefovir was associated. RESULTS: Antiviral drugs were well tolerated. In all cases, immunosuppressive treatment was given for the planned duration of therapy, with good results on the rheumatic diseases. Median duration of antiviral treatment was 19 months (for a total of 386 month/person). No cases of viral reactivation were observed. CONCLUSION: Our experience demonstrates the feasibility of a prophylaxis and therapy of HBV infection in patients with rheumatic diseases. This approach reduces the risk of viral reactivation and allows the choice of the optimal immunosuppressive treatment in rheumatic patients.""",1
11540,18436195,"N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial","""BACKGROUND: Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period. METHODS: A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment. RESULTS: Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [-5.97 (-10.44, -1.51), p = .009], PANSS negative [mean difference -1.83 (95% confidence interval: -3.33, -.32), p = .018], and PANSS general [-2.79 (-5.38, -.20), p = .035], CGI-Severity (CGI-S) [-.26 (-.44, -.08), p = .004], and CGI-Improvement (CGI-I) [-.22 (-.41, -.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits. CONCLUSIONS: These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.""",1
11541,18444791,Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms,"BACKGROUND: Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. METHODS: We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged > or = 18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). RESULTS: A total of 1867 patients were randomized and received > or = 1 dose of study medication. In the clinically evaluable population, at 7-14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, -2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, -1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, -0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. CONCLUSIONS: Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.",1
11542,18444971,Treatment of dermatophyte onychomycosis with three pulses of terbinafine (500 mg day for a week),"We assessed the safety and efficacy of pulse therapy with terbinafine tablets in 55 patients with dermatophytic onychomycosis. One pulse consisted of oral terbinafine tablets (500 mg day(-1)) given for 1 week usually followed by a 3-week interval. This regimen was repeated twice. Topical 1% terbinafine cream was applied daily. Efficacy was assessed based on both clinical and mycological examinations 1 year after treatment initiation. We observed a complete cure in 41 patients (74.5%), marked improved in three patients (5.6%), slight improvement in three patients (5.6%) and drop out in six patients (10.7%). Two patients (3.6%) discontinued terbinafine because of gastrointestinal disturbance (one patient) and drug-induced eruption (one patient). No patient had abnormal laboratory findings, including liver function tests. In summary, a regimen of three pulses of terbinafine therapy given daily for 1 week in combination with topical application of terbinafine cream appears to be safe and effective in treating dermatophytic onychomycosis and offers advantages in convenience and cost-effectiveness compared with continuous dosing.",1
11543,18447614,Management of hepatic complications in HIV-infected persons,"In the era of effective antiretroviral therapy (ART), liver disease is the second most common cause of death among persons with human immunodeficiency virus (HIV) infection. Liver disease-related deaths mostly result from chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). In addition, recent reports suggest that HCV infection may be transmitted sexually between HIV-infected men who have sex with men. Management of these conditions in HIV-infected persons requires careful consideration, balancing the potential benefits of therapy with the potential for significant treatment-related adverse effects (HCV infection) and viral resistance and/or hepatitis flares (HBV infection). Furthermore, several antiretroviral agents are active against HBV infection, including lamivudine, emtricitabine, tenofovir, and, more recently, entecavir. Despite the complexity and potential for antiretroviral-associated hepatotoxicity, ART usually is safe for patients with viral hepatitis coinfection, and, in some cases, treatment for HIV infection may be beneficial for the liver.",1
11544,18452419,Mild hepatitis at recommended doses of acetaminophen in patients with evidence of constitutionally enhanced cytochrome P450 system activity,"Acetaminophen (paracetamol) is used throughout the world for pain relief and antipyresis in both children and adults. In many countries, it can be purchased without a medical prescription and it is also a common component of a number of over-the-counter remedies for colds, influenza and the like. Fasting, malnutrition and use of alcohol and/or other drugs are thought to play causal roles in hepatotoxicity associated with recommended doses of acetaminophen although liver injury provoked by therapeutic doses has also been observed in the absence of these factors. We describe two patients who experienced subclinical hepatotoxic reactions after taking acetaminophen at therapeutic doses. The results of an antipyrine metabolism test suggest the presence of constitutional hyperactivity of the cytochrome P450-dependent mixed function oxidative system in both patients. We hypothesize that the latter contributed to the hepatotoxicity and that it may play a role in idiosyncratic reactions to this drug.",1
11545,18453862,Does tenofovir increase efavirenz hepatotoxicity?,,1
11546,18458271,National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease,,1
11547,18458669,Natalizumab (Tysabri) for Crohn's disease,,1
11548,18460663,Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial,"""CONTEXT: Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials. OBJECTIVE: To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD. DESIGN, SETTING, AND PARTICIPANTS: Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005. INTERVENTION: Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12. MAIN OUTCOME MEASURES: A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality. RESULTS: Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years vs 39.5/10,000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10,000 person-years vs 36.8/10,000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10,000 person-years vs 49.6/10,000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95% CI, 1.54-2.96 micromol/L). CONCLUSION: After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000541.""",1
11549,18466043,"Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebo-controlled studies","""OBJECTIVE: To evaluate the efficacy and safety of an extended-release (ER) formulation of paliperidone in patients with an acute episode of schizophrenia, in the dosage range of 3 to 15 mg daily. METHOD: A pooled analysis of 3 similarly designed 6-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled studies in 1326 patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score of 70-120) was performed. Patients were randomly assigned to receive 3, 6, 9, 12, or 15 mg daily of paliperidone ER or placebo. Efficacy and safety assessments were performed. The primary endpoint was change in PANSS total score from baseline to endpoint. RESULTS: PANSS total, PANSS subscale factor, and Personal and Social Performance scale scores significantly improved at endpoint for all doses of paliperidone ER relative to placebo (p <or= .001). A significantly greater proportion of paliperidone ER-treated patients at all doses achieved a clinical response compared with placebo (p <or= .001). Treatment-emergent adverse events (TEAEs) occurred in 66% to 77% of patients in the paliperidone ER groups and 66% of patients in the placebo group; serious TEAEs occurred in 6% of patients who received placebo and 5% to 6% of paliperidone ER-treated patients. Regardless of treatment group, median Simpson-Angus Rating Scale global, Abnormal Involuntary Movement Scale total, and Barnes Akathisia Rating Scale scores were 0 at both baseline and endpoint. There were no clinically relevant differences in measures of body weight gain, glucose handling, lipid metabolism, or proportion of patients with abnormal corrected QT intervals on electrocardiography and no important differences between the proportion of patients who received paliperidone ER or placebo who reported potentially glucose- or prolactin-related events. CONCLUSIONS: Paliperidone ER given once daily for 6 weeks appears to be a safe, well-tolerated, and effective treatment for patients with acute schizophrenia.""",1
11550,18467918,Severe jaundice following treatment with ezetimibe,"Ezetimibe is a cholesterol-lowering agent that modulates intestinal absorption of sterols. It is well tolerated but hepatic toxicity has been reported when ezetimibe is used in conjunction with a statin medication. In this case report, we report severe isolated hyperbilirubinaemia occurring in a patient with occult cirrhosis, probably owing to nonalcoholic steatohepatitis, who was treated with ezetimibe alone. The adverse event started after ezetimibe therapy was initiated and resolved when the drug was stopped. We propose a mechanism for this reaction and believe that liver function should be monitored in patients with abnormal liver tests who are treated with ezetimibe, even if they are not on concomitant treatment with a statin.",1
11551,18472735,[Terbinafine induced hepatitis with persistent cholestasis],,1
11552,18473409,"N-acetyl-L-cysteine combined with mesalamine in the treatment of ulcerative colitis: randomized, placebo-controlled pilot study","""AIM: To evaluate the effectiveness and safety of oral N-acetyl-L-cysteine (NAC) co-administration with mesalamine in ulcerative colitis (UC) patients. METHODS: Thirty seven patients with mild to moderate UC were randomized to receive a four-wk course of oral mesalamine (2.4 g/d) plus N-acetyl-L-cysteine (0.8 g/d) (group A) or mesalamine plus placebo (group B). Patients were monitored using the Modified Truelove-Witts Severity Index (MTWSI). The primary endpoint was clinical remission (MTWSI < or = 2) at 4 wk. Secondary endpoints were clinical response (defined as a reduction from baseline in the MTWSI of > or = 2 points) and drug safety. The serum TNF-alpha, interleukin-6, interleukin-8 and MCP-1 were evaluated at baseline and at 4 wk of treatment. RESULTS: Analysis per-protocol criteria showed clinical remission rates of 63% and 50% after 4 wk treatment with mesalamine plus N-acetyl-L-cysteine (group A) and mesalamine plus placebo (group B) respectively (OR = 1.71; 95% CI: 0.46 to 6.36; P = 0.19; NNT = 7.7). Analysis of variance (ANOVA) of data indicated a significant reduction of MTWSI in group A (P = 0.046) with respect to basal condition without significant changes in the group B (P = 0.735) during treatment. Clinical responses were 66% (group A) vs 44% (group B) after 4 wk of treatment (OR = 2.5; 95% CI: 0.64 to 9.65; P = 0.11; NNT = 4.5). Clinical improvement in group A correlated with a decrease of IL-8 and MCP-1. Rates of adverse events did not differ significantly between both groups. CONCLUSION: In group A (oral NAC combined with mesalamine) contrarily to group B (mesalamine alone), the clinical improvement correlates with a decrease of chemokines such as MCP-1 and IL-8. NAC addition not produced any side effects.""",1
11553,18474531,Unintended consequences: mandatory tuberculin skin testing and severe isoniazid hepatotoxicity,"After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.",1
11554,18479386,Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile,"PURPOSE: To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies. METHODS: Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB. RESULTS: Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p < 0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency >50%) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p < 0.027) and longer total time on VGB (p < 0.045) was associated with better IQ-developmental quotient (DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52%. VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings. CONCLUSION: We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.",1
11555,18480537,Clopidogrel-induced hepatotoxicity,,1
11556,18482790,Acute copper sulphate poisoning: a case report and literature review,"Voluntary copper poisoning is a rare mode of suicide. We report a case of copper sulphate poisoning in a patient presenting delusions with mystic demands for purification. The initial gastrointestinal symptoms were followed by intravascular haemolysis and renal failure. The course was favourable after symptomatic treatment and specific copper chelation therapy. However, the pathogenesis is not fully understood and with the present state of knowledge, no one treatment can be said to be superior to another. The authors discuss the various treatments of this rare poisoning through a review of the available literature.",1
11557,18484783,Safety of the nonselective NSAID nabumetone : focus on gastrointestinal tolerability,"""Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased cardiovascular risk. Finally, there is no particular concern about the nephrotoxic and hepatotoxic potential of nabumetone. Nonetheless, the potential for adverse drug reactions remains, and hence nabumetone, as with any NSAID, should be used at the lowest dose, which is effective for each patient, and for the shortest time necessary to control symptoms.""",1
11558,18486043,Ethionamide,,1
11559,18486739,"Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)","""BACKGROUND: Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis. METHODS: In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969. FINDINGS: All randomised patients were included in the efficacy analysis. 171 (67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab 90 mg, and eight (3.1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 mg and 63.3%, 57.1-69.4, p<0.0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0.0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54.5%) of the 510 patients receiving ustekinumab and 123 (48.2%) of the 255 receiving placebo. Serious adverse events occurred in six (1.2%) of 510 patients receiving ustekinumab and in two (0.8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase. INTERPRETATION: Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients.""",1
11560,18486984,"Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients","""BACKGROUND/AIMS: This study assessed the safety and antiviral effects of telaprevir (VX-950) in combination with peginterferon alfa-2a and ribavirin. METHODS: Twelve treatment-na?ve patients with chronic genotype 1 hepatitis C virus infection received telaprevir (750 mg q8h), peginterferon alfa-2a (180 microg/week), and ribavirin (1000 or 1200 mg/day) for 28 days. Patients could then start off-study treatment with peginterferon alfa-2a and ribavirin for up to 44 weeks, at the discretion of the investigator and patient. RESULTS: The combination of telaprevir, peginterferon alfa-2a, and ribavirin was well tolerated, with no serious adverse events or treatment discontinuations. Rash or pruritus occurred in 5 of the 12 patients; all cases resolved either during or after the end of telaprevir treatment. All 12 patients had undetectable HCV RNA levels by day 28 (rapid viral response, RVR). Eight patients completed 44 weeks of off-study peginterferon alfa-2a and ribavirin treatment. Eight patients achieved a sustained viral response (SVR), including one patient who received only 22 weeks of treatment. CONCLUSIONS: The combination of telaprevir, peginterferon alfa-2a, and ribavirin was generally well tolerated. Events of pruritus and rash resolved during or after end of telaprevir dosing. All 12 patients achieved an RVR.""",1
11561,18496387,Hormonal therapy for the treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectasia,,1
11562,18498432,Weight gain in bipolar disorder: pharmacological treatment as a contributing factor,"OBJECTIVE: The aim of this paper was to review the association of most commonly used psychopharmacological drugs with weight gain in bipolar disorder. METHOD: Information was retrieved from a PubMed/Medline literature search reviewing weight gain in pharmacological studies in bipolar disorder. RESULTS: Obesity and overweight in bipolar disorder are partly related to prescribed drugs with a strong effect of clozapine and olanzapine. Lesser but still relevant weight gain is caused by quetiapine, risperidone, lithium, valproate, gabapentin and by some antidepressants. Ziprasidone, aripiprazole, carbamazepine and lamotrigine do not seem to cause significant overweight. CONCLUSION: Careful monitoring of weight changes in patients before and after drug prescription should be implemented in the clinical routine and drugs which potentially cause weight gain should be avoided in overweight patients with bipolar disorder. Furthermore, eating habits and daily activities should be targeted as they may also have a significant impact on overall health and weight-related issues.",1
11563,18506008,"Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2","""BACKGROUND: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. METHODS AND RESULTS: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. CONCLUSIONS: Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.""",1
11564,18508226,Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia,"""Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], -2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI -4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.""",1
11565,18512708,American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis,,1
11566,18515881,Hepatitis B virus-related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemo-immune therapy,,1
11567,18520609,Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs: overview of 26 cases,"""There is discussion concerning the cardiac safety of citalopram in an overdose. The aim of this study was to investigate the toxic effects and toxicokinetic parameters of citalopram in an overdose as a single drug and in combination with other drugs. Cases observed between 1997 and 2006 were evaluated. Patient demographics, ingested doses, serum concentrations of citalopram, coingested drugs, and clinical parameters were acquired. Outcomes were observed symptoms of the gastrointestinal tract, respiratory tract, central nervous system, and cardiovascular system. Poisoning Severity Score was used to evaluate severity of every intoxicated patient. Individual toxicokinetic parameter values were calculated. Twenty-nine cases of citalopram overdose were observed; three cases had incomplete data so that 26 cases were evaluable. The ingested amount ranged from 200 to 4960 mg. Blood concentrations ranged from 0.21 to 7.5 mg/L with 20 minutes to 8 hours between suggested time of ingestion and blood sampling. Most frequently reported symptoms were drowsiness (seven cases), tachycardia (15 cases), QTc prolongation (eight cases), decrease of consciousness (eight cases), and seizures (four cases). Median length of hospital stay was 3 days (range, 1-8 days). Of the 26 evaluated cases, two fatalities occurred, one because of a cardiac arrest and one as a result of a respiratory arrest. According to Poisoning Severity Score, severity of intoxication was minor in three patients (11%), moderate in nine patients (35%), and severe in 14 patients (54%). Severity was mainly caused by neurologic and respiratory effects. Elimination half-life was prolonged but did not correlate with the amount of ingestion. Citalopram intoxications seem to proceed more severely than is known for other selective serotonin reuptake inhibitor intoxications, causing drowsiness, coma, and seizures in overdose. Cardiac toxicity is generally mild. Therefore, we recommend seizure precautions and intensive care unit admission with cardiac monitoring for citalopram-intoxicated patients. Because elimination half-life is prolonged, normal pharmacokinetics do not apply.""",1
11568,18521913,Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease,"BACKGROUND: Thiopurines are a mainstay of immunomodulator therapy in inflammatory bowel disease (IBD). Despite their efficacy, some patients may have a poor response due to inability to achieve adequate levels of the active metabolite, 6-thioguanine (6-TGN). Others experience hepatotoxicity, which correlates with excessive 6-methylmercaptopurine (6-MMP) levels. Two adult studies have demonstrated successful manipulation of thiopurine metabolism with allopurinol, a xanthine oxidase inhibitor, to achieve more optimal thiopurine levels. The aim was to retrospectively characterize the utility of allopurinol to optimize thiopurine metabolite levels in pediatric IBD patients. METHODS: Thirteen patients received allopurinol daily (100 mg in patients >or=30 kg and 50 mg <30 kg), and their thiopurine dose was simultaneously reduced to 25%-50% of the previous maintenance dose. Metabolite levels and other screening labs were checked 2-4 weeks later. RESULTS: The mean azathioprine dose was decreased from 148.1 to 59.6 mg daily (60% of the mean original dose). The mean 6-TGN level increased from 173 to 303 pmol/8 x 10(8) red blood cell count (RBC) (P = 0.03), and the mean 6-MMP level decreased from 7888 to 2315 pmol/8 x 10(8) RBC (P < 0.001). Elevated transaminase levels improved or resolved in all patients. Two patients experienced reversible neutropenia. At the conclusion of the study 9 patients (69%) remained on combination therapy with a mean duration of follow-up of 162.8 +/- 119.2 days. CONCLUSIONS: Combination therapy successfully shunted thiopurine metabolites to a more favorable pattern. Reversible neutropenia was the most common side effect (2 patients). Long-term prospective studies are needed in this patient population.",1
11569,18528824,Late reactivation of resolved hepatitis B virus infection: an increasing complication post rituximab-based regimens treatment?,"Reactivation of hepatitis B infection is an increasing problem for patients with lymphoma, even in resolved infections, who were treated with rituximab-based regimens. Our cases point out the need of prolonged prophylaxis in HBsAg-negative patients due to the high risk of developing fatal reactivation.",1
11570,18537189,"Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks","UNLABELLED: In hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who were refractory to current lamivudine therapy, switching to entecavir was superior to continued lamivudine at week 48 for histologic improvement, viral load reduction by polymerase chain reaction and alanine aminotransferase normalization. We assessed the efficacy, safety, and resistance profile of entecavir through 96 weeks of treatment. A total of 286 patients were randomized and treated with entecavir 1 mg (n = 141) or continued lamivudine 100 mg (n = 145). At week 52, 77 entecavir-treated patients who had a protocol-defined virologic response (HBV branched DNA [bDNA] < 0.7 MEq/mL but HBeAg-positive) continued blinded therapy for up to 96 weeks. Patients were assessed for efficacy, safety, and emerging resistance. Cumulative proportions of all treated patients who achieved confirmed efficacy endpoints were also analyzed. Between week 48 and the end of dosing, the proportions of patients with HBV DNA <300 copies/mL by polymerase chain reaction increased from 21% to 40%, and alanine aminotransferase normalization (< or =1x upper limit of normal) increased from 65% to 81%. In the second year, HBeAg seroconversion was achieved by 10% of patients. Of the 77 patients in the second year treatment cohort, entecavir resistance emerged in six patients, and seven experienced virologic breakthrough (five with genotypic resistance acquired before year 2). The safety profile of entecavir in the second year of therapy was consistent with that reported during year 1. CONCLUSION: Through 96 weeks of treatment, 1 mg entecavir resulted in continued clinical benefit in lamivudine-refractory HBeAg-positive chronic hepatitis B patients with a safety profile comparable to lamivudine.",1
11571,18538469,"Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer","BACKGROUND: Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. OBJECTIVE: To determine the efficacy and safety of initial doses of 200 mg or 240 mg of degarelix and thereafter monthly subcutaneous maintenance doses of 80 mg, 120 mg, or 160 mg of degarelix for the treatment of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: The 1-yr study was of open-label, randomised design and involved 187 patients (range: 52-93 yr, median: 72 yr) with histologically confirmed adenocarcinoma of the prostate and a baseline PSA >2 ng/ml. RESULTS AND LIMITATIONS: At baseline, median serum testosterone was 4.13 ng/ml (range: P25-P75, 3.37-5.19 ng/ml) and PSA was 27.6 ng/ml (range: P25-P75, 11.9-55.0 ng/ml). On day 3, 88% and 92% of patients in the groups to whom 200-mg and 240-mg initial doses of degarelix were administered, respectively, had testosterone levels < or =0.5 ng/ml. For patients with testosterone levels < or =0.5 ng/ml at 1 mo, the testosterone levels remained < or =0.5 ng/ml until the end of the study in 100% of the patients treated with a monthly maintenance dosage of 160 mg of degarelix. No evidence of testosterone surge was detected. PSA decreased by 97-98% after 1 yr and the median time to 90% reduction in PSA was 8 wk in all but one patient (from the 80-mg dosage treatment group at the initial 200-mg dose of degarelix). Thirteen patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation. CONCLUSIONS: Degarelix treatment for 1 yr resulted in a fast, profound, and sustained suppression of testosterone and PSA, with no evidence of testosterone surge. Degarelix was well tolerated.",1
11572,18541827,Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial,"""BACKGROUND: Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system. We sought to determine whether topiramate's antidrinking effects are bolstered by improvements in physical and psychosocial well-being. METHODS: In a 17-site, 14-week, double-blind, randomized controlled trial, we compared the effects of topiramate (up to 300 mg/d) vs placebo on physical health, obsessional thoughts and compulsions about using alcohol, and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy. RESULTS: Topiramate was more efficacious than placebo in reducing body mass index (calculated as weight in kilograms divided by height in meters squared) (mean difference, 1.08; 95% confidence interval [CI], 0.81-1.34; P < .001), all liver enzyme levels (P < .01 for all comparisons), plasma cholesterol level (mean difference, 13.30 mg/dL; 95% CI, 5.09-21.44 mg/dL; P = .002), and systolic (mean difference, 9.70 mm Hg; 95% CI, 6.81-12.60 mm Hg; P < .001) and diastolic (mean difference, 6.74 mm Hg; 95% CI, 4.57-8.90 mm Hg; P < .001) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease. Topiramate compared with placebo significantly (P < .05 for all comparisons) decreased obsessional thoughts and compulsions about using alcohol, increased subjects' psychosocial well-being, and improved some aspects of quality of life, thereby diminishing the risk of relapse and longer-term negative outcomes. Paresthesia, taste perversion, anorexia, and difficulty with concentration were reported more frequently for topiramate than for placebo. CONCLUSION: Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects.""",1
11573,18547415,Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children,"""BACKGROUND: Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. METHODS: A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. RESULTS: Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings. CONCLUSION: This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential. TRIAL REGISTRATION: Current Controlled Trials Identifier ISRCTN37517549.""",1
11574,18549664,"Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study","""OBJECTIVE: Doripenem is a new carbapenem that has broad-spectrum activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP). It has several advantages over currently available carbapenems and other classes of drugs used in this indication. This prospective, randomized, open-label, multicenter study was designed to establish whether doripenem was noninferior to piperacillin/tazobactam in NP. METHODS: Adults (n=448) with signs and symptoms of NP, including non-ventilated patients and those ventilated for <5 days, were stratified by ventilation mode, illness severity (Acute Physiology and Chronic Health Evaluation II score), and geographic region and then randomly allocated to treatment with doripenem 500 mg every 8 h by a 1-h intravenous (IV) infusion or piperacillin/tazobactam 4.5 g every 6 h by 30-min IV infusion. After receiving IV study drug for at least 72 h, eligible patients could be switched to oral levofloxacin 750 mg once daily. Antibiotic therapy was continued for a total of 7-14 days. The primary endpoint was the clinical cure rate, assessed 7-14 days after treatment completion, in clinically evaluable patients and in the clinical modified intent-to-treat population (cMITT). TRIAL REGISTRATION: ClinicalTrials.gov, NCT00211003. RESULTS: Doripenem was noninferior to piperacillin/tazobactam. Clinical cure rates in clinically evaluable patients (n=253) were 81.3% in the doripenem arm and 79.8% in the piperacillin/tazobactam arm (between-treatment difference: 1.5%; 95% confidence interval [CI], -9.1 to 12.1%) and in the cMITT population 69.5% and 64.1%, respectively, (between-treatment difference: 5.4%; 95% CI, -4.1 to 14.8%). Baseline resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa to piperacillin/tazobactam was 44% and 26.9%, respectively; a doripenem minimum inhibitory concentration (MIC) >8 mug/mL occurred in 0% and 7.7%, respectively. Favorable microbiological outcome rates against Gram-negative pathogens were numerically higher with doripenem than with piperacillin/tazobactam, but the difference was not statistically significant. Both study drugs were generally well tolerated, as only 16.1% and 17.6% of patients receiving doripenem and piperacillin/tazobactam, respectively, had a drug-related adverse event. Study limitations included the open-label design, the low rate of monotherapy (adjunctive use of aminoglycoside was required when P. aeruginosa was suspected), and the exclusion of the most critically ill and immunocompromized patients. CONCLUSIONS: Doripenem was clinically and microbiologically effective in patents with NP, including those with early-onset ventilator-associated pneumonia, and was therapeutically noninferior to piperacillin/tazobactam.""",1
11575,18552890,Reye syndrome: a case report with review of literature,"Here we describe a case of Reye syndrome diagnosed at postmortem liver biopsy of a three-year old girl who presented with vomiting, low grade fever for three days and loss of consciousness for 18 hours. Clinically, the differential diagnoses were meningitis, encephalitis and septicemia. No history of past illness or any drug ingestion including aspirin were present. Laboratory investigations indicated a diagnosis of Reye syndrome. The child was given supportive treatment but died after two days of admission and postmortem needle-biopsy of the liver showed microvesicular steatosis consistent with Reye syndrome.",1
11576,18558790,Benefit-risk assessment of telithromycin in the treatment of community-acquired pneumonia,"""The purpose of this review is to assess the benefits and risks associated with the use of the ketolide antibacterial telithromycin, currently licensed for the treatment of adults with mild to moderate community-acquired pneumonia (CAP). Telithromycin is active against both the major (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) and atypical/intracellular (Chlamydophila pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae) CAP pathogens. It is associated with a low potential to select for resistance and has maintained its in vitro activity against isolates of respiratory pathogens in countries where it has been in clinical use for several years. In randomized clinical trials, telithromycin has demonstrated efficacy comparable to the established antibacterial classes (macrolides, fluoroquinolones and beta-lactams) in the treatment of CAP.The safety profile of telithromycin is broadly similar to that of other antibacterials used to treat CAP. The most common adverse events are gastrointestinal adverse effects and headache; these are generally mild to moderate in severity and reversible. Telithromycin appears to be well tolerated by adult patients in all age groups, including those with co-morbid conditions. In common with other antibacterials, telithromycin has the potential to affect the corrected QT interval; the concomitant use of cisapride or pimozide with telithromycin is contraindicated, while telithromycin should be avoided in patients receiving Class IA or Class III antiarrhythmic drugs. Visual disturbances (usually transient) have occurred in a small proportion of patients treated with telithromycin; it is recommended that activities such as driving are minimized during treatment. Telithromycin is contraindicated in patients with myasthenia gravis. Hepatic dysfunction may occur in some patients taking telithromycin; rare cases of acute hepatic failure and severe liver injury, including deaths, have been reported. As telithromycin is an inhibitor of the cytochrome P450 (CYP) 3A4 system, coadministration of telithromycin with drugs metabolized by this pathway may require dose adjustments (e.g. with benzodiazepines) or a temporary hiatus in the use of the coadministered drug (e.g. HMG-CoA reductase inhibitors) metabolized by CYP3A4. Telithromycin may potentiate the effects of oral anticoagulants; careful monitoring is recommended in patients receiving telithromycin and oral anticoagulants simultaneously.Although serious and sometimes fatal events have occurred in patients receiving telithromycin therapy, current data indicate that telithromycin offers an acceptable benefit risk ratio in the treatment of mild to moderate CAP.""",1
11577,18562231,Cross-sectional multicenter study of patients with urea cycle disorders in the United States,"Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the proteins that is essential for ureagenesis. We report on a cross-sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study. The study has been conducted by the Urea Cycle Disorders Consortium within the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institutes of Health. One-hundred eighty-three patients were enrolled into the study. Ornithine transcarbamylase (OTC) deficiency was the most frequent disorder (55%), followed by argininosuccinic aciduria (16%) and citrullinemia (14%). Seventy-nine percent of the participants were white (16% Latinos), and 6% were African American. Intellectual and developmental disabilities were reported in 39% with learning disabilities (35%) and half had abnormal neurological examination. Sixty-three percent were on a protein restricted diet, 37% were on Na-phenylbutyrate and 5% were on Na-benzoate. Forty-five percent of OTC deficient patients were on L-citrulline, while most patients with citrullinemia (58%) and argininosuccinic aciduria (79%) were on L-arginine. Plasma levels of branched-chain amino acids were reduced in patients treated with ammonia scavenger drugs. Plasma glutamine levels were higher in proximal UCD and in neonatal type disease. The RDCRN allows comprehensive analyses of rare inherited UCD, their frequencies and current medical practices.",1
11578,18563955,"Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin","HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T>C (p.Val174Ala) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gemfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription status. On the pharmacokinetic basis, fluvastatin and pravastatin can be better choices than simvastatin or lovastatin for an OTC statin.",1
11579,18570167,Dietary supplement adverse events: report of a one-year poison center surveillance project,"""BACKGROUND: The safety and efficacy of dietary supplements is of growing concern to regulators, health-care providers and consumers. Few scientific data exist on clinical effects and potential toxicities of marketed products. Harmful supplements may not be identified for months or years with existing adverse event monitoring mechanisms. Retrospective review of poison center statistics to capture supplement-associated toxicity also has limitations. METHODS: We collaborated with the FDA Center for Food Safety and Nutrition (CFSAN) to conduct a 1-year prospective surveillance study of dietary supplement-related poison control center calls in 2006. Prompt follow-up of symptomatic cases, laboratory analysis of implicated dietary supplements, and causality assessment by a case review expert panel were performed. RESULTS: Of 275 dietary supplements calls, 41% involved symptomatic exposures; and two-thirds were rated as probably or possibly related to supplement use. Eight adverse events required hospital admission. Sympathomimetic toxicity was most common, with caffeine products accounting for 47%, and yohimbe products accounting for 18% of supplement-related symptomatic cases. Suspected drug-herb interactions occurred in 6 cases, including yohimbe co-ingested with buproprion (1) and methamphetamine (3), and additive anticoagulant/antiplatelet effects of NSAIDs taken with fish oils (1) and ginkgo (1). Laboratory analysis identified a pharmacologically active substance in 4 cases; supplement toxicity was ruled unlikely when analytical testing was negative in 5 cases. CONCLUSION: Most supplement-related adverse events were minor. Clinically significant toxic effects were most frequently reported with caffeine and yohimbe-containing products. Active surveillance of poison control center reports of dietary supplement adverse events enables rapid detection of potentially harmful products, which may facilitate regulatory oversight.""",1
11580,18572079,"Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial","""BACKGROUND: Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease (WHO functional class [FC] III and IV). This study was designed to assess the effect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension. METHODS: Patients with WHO FC II pulmonary arterial hypertension aged 12 years or over with 6-min walk distance of less than 80% of the normal predicted value or less than 500 m associated with a Borg dyspnoea index of 2 or greater were enrolled in this double-blind, placebo-controlled, multicentre trial. 185 patients were randomly assigned to receive bosentan (n=93) or placebo (n=92) for the 6-month double-blind treatment period via a centralised integrated voice recognition system. Primary endpoints were pulmonary vascular resistance at month 6 expressed as percentage of baseline and change from baseline to month 6 in 6-min walk distance. Analyses of the primary endpoints were done with all randomised patients who had a valid baseline assessment and an assessment or an imputed value for month 6. This trial was registered with ClinicalTrials.gov, number NCT00091715. FINDINGS: Analyses were done with 168 patients (80 in the bosentan group, 88 in the placebo group) for pulmonary vascular resistance and with 177 (86 and 91) for 6-min walking distance. At month 6, geometric mean pulmonary vascular resistance was 83.2% (95% CI 73.8-93.7) of the baseline value in the bosentan group and 107.5% (97.6-118.4) of the baseline value in the placebo group (treatment effect -22.6%, 95% CI -33.5 to -10.0; p<0.0001). Mean 6-min walk distance increased from baseline in the bosentan group (11.2 m, 95% CI -4.6 to 27.0) and decreased in the placebo group (-7.9 m, -24.3 to 8.5), with a mean treatment effect of 19.1 m (95% CI 3.6-41.8; p=0.0758). 12 (13%) patients in the bosentan group and eight (9%) in the placebo group reported serious adverse events, the most common of which were syncope in the bosentan group and right ventricular failure in the placebo group. INTERPRETATION: Bosentan treatment could be beneficial for patients with WHO FC II pulmonary arterial hypertension.""",1
11581,18579812,Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty,"""BACKGROUND: We investigated the efficacy of rivaroxaban, an orally active direct factor Xa inhibitor, in preventing venous thrombosis after total knee arthroplasty. METHODS: In this randomized, double-blind trial, 2531 patients who were to undergo total knee arthroplasty received either oral rivaroxaban, 10 mg once daily, beginning 6 to 8 hours after surgery, or subcutaneous enoxaparin, 40 mg once daily, beginning 12 hours before surgery. The primary efficacy outcome was the composite of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause within 13 to 17 days after surgery. Secondary efficacy outcomes included major venous thromboembolism (i.e., proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death related to venous thromboembolism) and symptomatic venous thromboembolism. The primary safety outcome was major bleeding. RESULTS: The primary efficacy outcome occurred in 79 of 824 patients (9.6%) who received rivaroxaban and in 166 of 878 (18.9%) who received enoxaparin (absolute risk reduction, 9.2%; 95% confidence interval [CI], 5.9 to 12.4; P<0.001). Major venous thromboembolism occurred in 9 of 908 patients (1.0%) given rivaroxaban and 24 of 925 (2.6%) given enoxaparin (absolute risk reduction, 1.6%; 95% CI, 0.4 to 2.8; P=0.01). Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin (P=0.005). Major bleeding occurred in 0.6% of patients in the rivaroxaban group and 0.5% of patients in the enoxaparin group. The incidence of drug-related adverse events, mainly gastrointestinal, was 12.0% in the rivaroxaban group and 13.0% in the enoxaparin group. CONCLUSIONS: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding. (ClinicalTrials.gov number, NCT00361894.)""",1
11582,18580619,Fanconi syndrome and lactic acidosis associated with stavudine and lamivudine therapy,"We report a case of the nucleoside reverse transcriptase inhibitors, stavudine and lamivudine inducing Fanconi syndrome in a patient. The presence of simultaneous lactic acidosis suggests mitochondrial toxicity within the proximal renal tubular cells as the likely pathogenesis. We recommend that both the above nucleosides be added to the list of antiretroviral drugs that can induce Fanconi syndrome and that patients on stavudine and lamivudine be monitored carefully for early signs of Fanconi syndrome.",1
11583,18585461,Black cohosh (Cimicifuga racemosa) for menopausal symptoms: a systematic review of its efficacy,"""Since conventional hormone replacement therapy has fallen out of favour, alternatives are being sought by many women. These therapies include herbal preparations such as black cohosh (Cimicifuga racemosa). The purpose of this update of a previous systematic review is to evaluate the clinical evidence for or against the efficacy of black cohosh in alleviating menopausal symptoms. Five computerized databases (Medline, Embase, Amed, Phytobase and Cochrane Library) were searched to identify all clinical data that provided evidence on the efficacy of C. racemosa. Bibliographies of the articles thus located were scanned for further relevant publications. Only double blind, randomized, clinical trials (RCTs) were included in the evaluation of efficacy. No language restrictions were imposed. Trials were excluded if they did not focus on menopausal problems, they included women suffering medically induced menopause, they did not use black cohosh monopreparations, or they did not use placebo or a standard drug treatment for the control group. Six studies with a total of 1112 peri- and post-menopausal women met our inclusion criteria. The evidence from these RCTs does not consistently demonstrate an effect of black cohosh on menopausal symptoms; a beneficial effect of black cohosh on peri-menopausal women cannot be excluded. The efficacy of black cohosh as a treatment for menopausal symptoms is uncertain and further rigorous trials seem warranted.""",1
11584,18590343,Use of second-generation antiepileptic drugs in the pediatric population,"Epilepsy is common in the pediatric population. Nine second-generation antiepileptic drugs have been approved in the US for use in epilepsy over the past 15 years: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Their use in pediatric patients is fairly widespread, despite most of these agents not having US FDA indications for use. Felbamate and gabapentin were the first two second-generation antiepileptic drugs to be approved in the US. Felbamate use has been limited because of the occurrence of hepatotoxicity and aplastic anemia. Although gabapentin is a fairly well tolerated antiepileptic drug, its use has also been limited as a result of inconsistent efficacy and concern about seizure exacerbation. Lamotrigine and topiramate are broad-spectrum antiepileptic drugs with efficacy in a wide variety of seizure types. Both agents have some tolerability concerns: rash with lamotrigine and neuropsychiatric events with topiramate. There are very little data on tiagabine use in children, but this agent appears to be effective and to have a good tolerability profile. Levetiracetam is a second-generation antiepileptic agent that is available intravenously. Considering its good efficacy, fast onset of action, and low incidence of serious adverse effects, its use in the acute setting could potentially increase. Oxcarbazepine and zonisamide have been relatively well studied in pediatric seizure patients, including use as monotherapy. Both agents have demonstrated good efficacy and tolerability for patients as young as 1 month old. Vigabatrin and rufinamide are currently not available in the US, but have been shown to have some success in other countries. Pregabalin is the newest antiepileptic agent, but lacks pediatric data currently.",1
11585,18593678,Aliskiren,"""PURPOSE: The pharmacology, bioavailability and pharmacokinetics, clinical efficacy, adverse effects and toxicity, drug interactions, and dosage and administration of aliskiren as well as safety and economic issues related to its use are reviewed. SUMMARY: Aliskiren is the first of a new class of antihypertensive agents, direct renin inhibitors, that act by blocking the rate- limiting step of the renin-angiotensin- aldosterone system (RAAS). It was approved by the Food and Drug Administration in 2007 for use as monotherapy or in combination with other antihypertensives. Clinical studies comparing aliskiren monotherapy with placebo indicated a dose-dependent reduction in both systolic and diastolic blood pressure (BP). Greater reductions in BP have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as a RAAS-acting drug, it should be prescribed for such patients only with caution. CONCLUSION: Aliskiren at a dosage of 150 or 300 mg daily may be a good option for control of mild-to-moderate hypertension in patients with or without diabetes in whom first-line antihypertensives have failed to adequately control BP; comparative studies with other antihypertensives are needed to determine which patients can most benefit from aliskiren therapy.""",1
11586,18595895,Fatal reactivation of hepatitis B after chemotherapy for lymphoma,,1
11587,18599449,Sirt1 protects against high-fat diet-induced metabolic damage,"The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat diet-induced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1alpha, and lower activation of proinflammatory cytokines, such as TNFalpha and IL-6, via down-modulation of NFkappaB activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.",1
11588,18607115,Vancomycin-induced DRESS syndrome in a female patient,"BACKGROUND: DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a hypersensitivity reaction with skin rashes, eosinophilia, fever, lymph node enlargement and internal organ involvement. CASE REPORT: A 60-year-old diabetic woman was hospitalized at the University Hospitals of Geneva for mid-leg amputation due to peripheral arterial occlusive disease. No drug allergy was reported. Because of a wound infection by methicillin-resistant Staphylococcus aureus, treatment with vancomycin (2 g/day) in continuous perfusion was initiated. Approximately 2 weeks later, she developed a toxidermia with fever, a progressive maculopapular skin rash, eosinophilia and acute renal insufficiency. The skin biopsy revealed a necrosis with lymphocytic and eosinophilic infiltrations, supporting the suspicion of DRESS syndrome. A cure was achieved by the withdrawal of vancomycin and the administration of methylprednisolone (1 g/day), antihistaminics and topical mometasone, without the introduction of other antibiotics. CONCLUSION: Vancomycin can be a cause of DRESS syndrome. A high index of suspicion is warranted in order not to miss this potentially lethal disease.",1
11589,18608283,Endoscopic removal of iron bezoar following acute overdose,,1
11590,18608866,Dasatinib-induced acute hepatitis,,1
11591,18615121,Risk for immune-mediated liver reactions by nevirapine revisited,"Implementation of combination antiretroviral therapies has transformed the prognosis of HIV infection during the past decade. Because of its low-pill burden, convenient administration once or twice daily without food restrictions and, in the case of nevirapine, favorable metabolic profile and proven safety in pregnant women and newborns, nonnucleoside reverse transcriptase inhibitors have been shown to be often superior to protease inhibitors as third agents in combination with a backbone of two nucleoside reverse transcriptase inhibitors. Therefore, two nucleoside reverse transcriptase inhibitors plus one nonnucleoside reverse transcriptase inhibitor are currently the most popular used first-line therapies. Hepatotoxicity during the first weeks of therapy with nevirapine, particularly when initiated in women with CD4 counts > 250 cells/mm3, has prompted changes in guidelines and led to a modification in the product label. Recent data, however, suggest that virologically suppressed patients under any other antiretroviral drug combination may safely switch to nevirapine as a part of a simplification strategy, regardless of their current CD4 count. This subset of patients does not show an increased risk of hepatotoxicity or rash with elevated CD4 counts, as has been reported in drug-naive HIV persons. This information is important and may expand the number of candidates who could benefit from nevirapine use, since a substantial proportion of HIV patients show metabolic abnormalities (dyslipidemia, insulin resistance, liver steatosis) and are at increased cardiovascular risk. Fortunately, many of these conditions may ameliorate or improve using nevirapine.",1
11592,18617872,Lubiprostone (Amitiza) for irritable bowel syndrome with constipation,,1
11593,18620577,Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up,"BACKGROUND: Artesunate-amodiaquine (AS+AQ) and artemether-lumefantrine (AM-L) are efficacious artemisinin combination therapy (ACT) regimens that have been widely adopted in sub-Saharan Africa. However, there is little information on the efficacy of these regimens on subsequent episodes beyond 28 days, or on the safety of repeated treatments. METHODS: Children aged six months to 14 years with uncomplicated malaria were randomly assigned to treatment with AS+AQ (n = 116), or AM-L (n = 111). Recruited subjects were followed-up, initially for 28 days, and then monthly for up to one year. All subsequent attacks of uncomplicated malaria after 28 days were treated with the same regimen as at randomization. Investigations aimed at determining efficacy and side effects were conducted. RESULTS: Adequate clinical and parasitological response in subjects with evaluable end-points were, 97.1% (100/103) and 98.2% (107/109) on day 14, and 94.2% (97/103) and 95.3% (102/107) on day 28 in the AM-L and AS+AQ groups, respectively. Similar results were obtained after PCR correction. The incidence of malaria attacks in the year following recruitment was similar between the two treatment groups (p = 0.93). There was a high incidence of potentially AQ-resistant parasites in the study area. The incidence of adverse events, such as pruritus, fatigue and neutropaenia were similar in the two treatment groups. No patient showed signs of hearing impairment, and no abnormal neurological signs were observed during one year of follow-up. Other adverse events were mild in intensity and overlapped with known malaria symptomatology. No adverse event exacerbation was observed in any of the subjects who received multiple treatment courses with these ACT regimens during one year follow-up. CONCLUSION: AS+AQ and AM-L were efficacious for treatment of children with uncomplicated malaria in Ghana and drug-related adverse events were rare in treated subjects during one year of follow-up. The high prevalence of potentially AQ resistant parasites raises questions about the utility of AQ as a partner drug for ACT in Ghana. The efficacy of AS+AQ in Ghana requires, therefore, continuous monitoring and evaluation. TRIAL REGISTRATION: NCT 00406146 http://www.clinicaltrials.gov.",1
11594,18626108,Ibuprofen-induced liver injury in an adolescent athlete,,1
11595,18628444,Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy,"OBJECTIVE: To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose. CASE SUMMARY: A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 microg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 microg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 microg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 microg/mL approximately 48 hours postingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely. DISCUSSION: Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy. CONCLUSIONS: In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21-hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need for prolonged treatment.",1
11596,18628990,Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes,"Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs). Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports.",1
11597,18630824,[Acute acetaminophen overdose],"""Acute ingestion of acetaminophen can induce a dose-dependent hepatotoxicity and lead to death. The management of acute acetaminophen poisoning at the early stage is well codified. A reported amount of ingestion > 200 mg/kg in a child, > 150 mg/kg in an adult (125 mg/kg if risk factors are present) require hospitalisation. Activated charcoal is administered within 1-2 hours of ingestion. AST/ALT levels are measured on admission, 12 hours after, and according to outcome every 12-24 h. N-acetylcysteine (NAC) administration within 8-10 hours protects against acetaminophen-induced hepatotoxicity. The two protocols of NAC administration, intravenous and oral, have a comparable effectiveness. NAC is indicated if the serum acetaminophen level drawn 4 hours after ingestion and plotted on the nomograme falls above the """"200 mg/L-4 hours"""" line. Nomograme is not usable with repeated acute ingestion or repeated supratherapeutic doses; presence of risk factors (enzymatic induction, malnutrition, chronic alcoholism) must be taken into account (""""100 mg/L - 4 hours"""" line). Outcome is favorable with respect to these conditions.""",1
11598,18636784,A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients?,"""Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthelabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available.The overall aim of this paper is to determine if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To determine this, we examined (i) the clinical benefits associated with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone.Large reductions in plasma urate concentrations in patients with hyperuricaemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 hours); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 hours) and is the major species responsible for the uricosuric activity of benzbromarone, although its metabolism by cytochrome P450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/day).Adverse effects associated with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthelabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estimated risk of hepatotoxicity in Europe was approximately 1 in 17 000 patients but may be higher in Japan.Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is associated with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approximately 1 in 56 000. Rash occurs in approximately 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been associated with life-threatening reactions in a very small number of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clinical trials, but abnormal liver function is the most commonly reported adverse reaction.Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Determination of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity.We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout.""",1
11599,18637831,Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population,"""PURPOSE: Previous studies found a strong association between HLA-B*1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA-B*1502 was not associated with CBZ-induced maculopapular eruptions (MPE). This study seeks to identify whether HLA-B*1502 is associated with CBZ- or phenytoin (PHT)-induced SJS or MPE in a Thai population. METHODS: Eighty-one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty-one subjects had antiepileptic drug (AED)-induced SJS or MPE (6 CBZ-SJS, 4 PHT-SJS, 9 CBZ-MPE, 12 PHT-MPE), and 50 were AED-tolerant controls. RESULTS: For the first time, a strong association between HLA-B*1502 and PHT-induced SJS was found (p = 0.005). A strong association was also found between the HLA-B*1502 and CBZ-induced SJS (p = 0.0005), making Thai the first non-Chinese population demonstrating such an association. Some patients, who were HLA-B*1502 and suffered from CBZ-induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA-B*1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA-B alleles and CBZ- or PHT-induced MPE was found. CONCLUSIONS: CBZ- and PHT-induced SJS, but not MPE, is associated with HLA-B*1502 allele in Thai population.""",1
11600,18642110,Early linezolid-associated lactic acidosis in a patient treated for tuberculous spondylodiscitis,,1
11601,18647279,"Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes","AIM: A large longitudinal interventional study of patients with a urea cycle disorder (UCD) in hyperammonaemic crisis was undertaken to amass a significant body of data on their presenting symptoms and survival. METHODS: Between 1982 and 2003, as part of the FDA approval process, data were collected on patients receiving an intravenous combination of nitrogen scavenging drugs (Ammonul sodium phenylacetate and sodium benzoate (10%, 10%)) for the treatment of hyperammonaemic crises caused by urea cycle disorders. RESULTS: A final diagnosis of a UCD was made for 260 patients, representing 975 episodes of hospitalization. Only 34% of these patients presented within the first 30 days of life and had a mortality rate of 32%. The most common presenting symptoms were neurological (80%), or gastrointestinal (33%). This cohort is the largest collection of patients reported for these diseases and the first large cohort in the United States. CONCLUSION: Surprisingly, the majority (66%) of patients with heritable causes of hyperammonaemia present beyond the neonatal period (>30 days). Patients with late-onset presenting disorders exhibited prolonged survival compared to the neonatal-presenting group.",1
11602,18650153,Phase I/II study of ixabepilone plus capecitabine in anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer,"""PURPOSE: The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle). RESULTS: No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption. CONCLUSION: Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.""",1
11603,18650514,Sorafenib in advanced hepatocellular carcinoma,"""BACKGROUND: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. RESULTS: At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. CONCLUSIONS: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)""",1
11604,18657023,Bicalutamide-associated fulminant hepatotoxicity,"Abstract Bicalutamide is a nonsteroidal antiandrogen used extensively during the start of androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist to reduce occurrence of the symptoms of tumor flare in patients with metastatic prostate carcinoma. The most common adverse effects of bicalutamide are induced by its pharmacologic property of competitive androgen receptor blockade and include gynecomastia, hot flashes, fatigue, and decreased libido. Although not as common, increases in liver function test results are also seen with bicalutamide therapy. These elevations are typically transient, and patients remain asymptomatic. We describe a 59-year-old man with metastatic prostate carcinoma treated with bicalutamide as part of androgen deprivation therapy before starting chemotherapy. At baseline, his liver function test results and serum creatinine concentration were within normal limits, and an abdominal computed tomographic scan did not demonstrate liver metastasis. After 4 days of bicalutamide therapy, the patient came to the emergency department with complaints of abdominal pain, distension, and tenderness. His liver function tests were abnormal, and bicalutamide was discontinued. After 2 days of increasing liver function tests and symptoms of hepatotoxicity, the patient developed tachycardia and hypotension that was resistant to fluid resuscitation. Multiorgan damage was manifested by an alanine aminotransferase level greater than 40 times the upper limit of normal, serum creatinine concentration of 4.2 mg/dl, and troponin I level of 18 ng/ml. The patient died 8 days after bicalutamide therapy was begun secondary to multiorgan failure, most likely as a result of fulminant hepatotoxicity. The Naranjo adverse drug reaction probability scale showed a probable (score of 5) causal relationship between bicalutamide and fulminant hepatotoxicity. Fulminant hepatotoxicity is a rare but potentially fatal adverse effect of bicalutamide. Liver function tests should be monitored before and during bicalutamide therapy, even for patients who have previously completed a course of this therapy with no signs or symptoms of toxicity.",1
11605,18661913,[Accidental acetaminophen overdose],"Acetaminophen is an OTC medication and amongst the most used pain relievers. It is the analgesic of first choice in pregnancy. Because of its low therapeutic index, accidental and suicidal acetaminophen intoxication is one of the most common causes of acute liver failure. Thus, face-to-face counselling of patients on the proper use of acetaminophen is essential for drug safety.",1
11606,18665787,"Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial","""In this 3-yr, randomized, double-blind, placebo- and active-controlled study, healthy postmenopausal women with osteoporosis (55-85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent-to-treat population, the incidence of new vertebral fractures was significantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T-score <or= -3.0 and/or >or=1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p < 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.""",1
11607,18668535,Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies,"""OBJECTIVE: To assess the efficacy and safety of rilonacept (Interleukin-1 [IL-1] Trap), a long-acting and potent inhibitor of IL-1, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). METHODS: Forty-seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score. RESULTS: Forty-four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single-symptom disease flare days, single-symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C-reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions. CONCLUSION: Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.""",1
11608,18668652,A new indication for liver transplantation: nodular regenerative hyperplasia in human immunodeficiency virus-infected patients,"Nodular regenerative hyperplasia is one of the causes of noncirrhotic portal hypertension and has recently been described in human immunodeficiency virus-infected patients, and the potential role of a prothrombotic state and hepatotoxic antiretroviral medication has been suggested. Moreover, it is now established that liver transplantation is feasible in HIV-infected patients. We describe here our experience concerning 3 HIV-infected patients with severe complications of nodular regenerative hyperplasia treated with liver transplantation.",1
11609,18670224,Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants,"""OBJECTIVE: To assess hematologic and hepatic toxicities associated with in utero and breastfeeding exposure to maternal highly active antiretroviral therapy (HAART) among infants in Botswana. DESIGN: A nested cohort study within a randomized clinical trial (the Mashi Study). Laboratory toxicities among infants born to women who initiated HAART before delivery were compared with toxicities among those born to women who received zidovudine and a single dose of nevirapine or placebo in labor. Infants were randomized to breastfeed with extended zidovudine or to formula-feed. METHODS: Hemoglobin concentrations, absolute neutrophil and platelet counts, and alanine aminotransferase and aspartate aminotransferase levels were recorded from birth to 7 months of age in infants. Grade 3 and 4 toxicities were compared by infant antiretroviral exposure status. RESULTS: In-utero exposure to maternal HAART was associated with increased risk for neutropenia in infants up to 1 month of age; 21.7% of HAART-exposed infants were neutropenic, compared with 5.5% of the infants exposed to zidovudine (P < 0.01). However, neutropenia was no longer associated with antenatal exposure to HAART after 1 month of age. Postnatal exposure to HAART was not associated with hematologic or hepatic toxicities. Laboratory toxicities were clinically asymptomatic in all but one infant. CONCLUSION: Exposure to maternal HAART in utero may increase the risk for infant neutropenia, particularly among breastfed infants, but the clinical significance of this finding is uncertain. The lack of association between exposure to HAART through breastfeeding and long-term toxicities in infants is reassuring but deserves study in larger cohorts.""",1
11610,18671816,"A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn's disease","OBJECTIVES: A prospective study was undertaken to compare the efficacy of everolimus versus azathioprine or placebo in maintaining steroid-induced remission in active Crohn's disease (CD) and assess the safety and pharmacokinetics of everolimus. METHODS: This was a randomized, double-blind, placebo-controlled, proof-of-concept study in adults with moderate-to-severe active CD. The patients received oral steroids for a rapid induction of remission plus everolimus 6 mg/day, azathioprine 2.5 mg/kg/day, or placebo as maintenance treatment. The main outcome measure was the treatment success, defined as a steroid-free remission by the end of month 3 and maintained until study cutoff without the use of prohibited efficacy treatments. RESULTS: Following an interim analysis, the study was terminated before enrollment was completed due to the lack of efficacy. The full intent-to-treat population comprised 138 patients. Only 96 patients who entered the study > or =7 months prior to data cutoff were included in the primary efficacy population. The treatment success was achieved in 13 of 38 everolimus patients, 22 of 36 azathioprine patients, and 8 of 22 placebo patients. Using the Kaplan-Meier estimates at month 7, the incidence of treatment success was 22.0% with everolimus group (95% confidence interval [CI] 6.7-37.3%, P= 0.610 vs placebo), 38.3% with azathioprine group (95% CI 20.6-55.9%, P= 0.500 vs placebo), and 28.8% with placebo group (95% CI 7.7-49.9%). The type and incidence of adverse events in the everolimus cohort were similar to those reported in the approved transplantation indications. CONCLUSIONS: The safety and tolerability of everolimus (6 mg/day) in patients with active CD were comparable to azathioprine. At this dose, everolimus is not more efficacious in achieving a steroid-free remission in active CD than the comparators.",1
11611,18673162,Amiodarone hepatotoxicity,"Potential hepatotoxicity related to amiodarone therapy is often a concern when deciding whether to initiate or continue treatment with this medication. While mostly associated with long-term oral administration of the drug, toxicity has also been reported early during intravenous administration and months after discontinuation of therapy. In the majority of patients, it is discovered incidentally during routine testing of liver biochemistry and rarely do the hepatic effects develop into symptomatic liver injury or failure. Despite the widespread use of amiodarone, prospective clinical studies have been sparse and there has been little consensus among experts in the field regarding optimum monitoring for adverse effects in patients receiving this drug. In order to examine the current state of knowledge surrounding the incidence, pathogenesis and mechanism of liver effects associated with amiodarone, the existing literature was reviewed, with particular emphasis on clinical recommendations for monitoring.",1
11612,18679077,Initially obscure hepatotoxicity attributed to sildenafil,"We describe a patient with a hepatotoxic reaction, presenting with general malaise, severe jaundice, and pruritus. This turned out to be caused by the, at first unrevealed, use of sildenafil. The injury seems to be hepatocanalicular, characterized by a hepatocellular liver test pattern, combined with extensive cholestasis on liver biopsy. One should bare in mind that the use of sildenafil may not be readily disclosed by the patient nor his doctor.",1
11613,18683044,Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review,"A systematic review was undertaken to examine all available evidence to develop and support clinical recommendations regarding the use of fulvestrant (Faslodex((R))) as systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women. MEDLINE, EMBASE, American Society of Clinical Oncology Annual Meeting proceedings, San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library were searched through to April of 2008 for reports of randomized controlled trials that met established inclusion criteria. Four relevant Phase III trials were available for inclusion based on established criteria. Three of four Phase III superiority trials found no significant difference between fulvestrant and control, either anastrozole or exemestane, across efficacy and safety endpoints following prior endocrine therapy failure, with two trials further confirming non-inferiority of fulvestrant to anastrozole retrospectively. Fulvestrant can therefore be considered as alternative therapy to anastrozole or exemestane in postmenopausal women with locally advanced or metastatic breast cancer that has recurred on prior adjuvant endocrine therapy or progressed on prior endocrine therapy for advanced disease. There are, however, important methodological concerns across reviewed trials that should be taken under consideration as they may limit the strength of such a conclusion.",1
11614,18688917,Safety of anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection,"""OBJECTIVE: The prevalence of concurrent rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection is probably underestimated because of the increasing spread of this virus worldwide, especially in developing countries. In these patients, anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy may aggravate hepatitis and increase viremia. We evaluated the safety of these treatments, which remain controversial. METHODS: Thirty-one HCV-positive patients (23 women, 8 men, mean age 59+/-13 yrs, mean disease duration 13+/-11.5 SD yrs) with active RA [Disease Activity Score 28 (DAS28)>3.2] unresponsive to conventional therapies were treated with TNF-alpha blockers (infliximab 11, etanercept 17, adalimumab 3) at standard dosages. Safety and efficacy were evaluated at the third month of treatment and at the patient's last observation. RESULTS: A significant clinical-serological improvement was recorded at the 3-month reevaluation. Mean values of patients assessment of general health on visual analog scale (range 0.100) decreased from 69+/-29 (SD) to 35+/-27 (p<0.0001), Ritchie index from 21.6+/-13.9 to 10.1+/-3.7 (p<0.0001), erythrocyte sedimentation rate from 36+/-25 to 28+/-22 mm/h (p=0.04), and DAS28 from 5.2+/-1.6 to 2.78+/-1.3 (p<0.0001); a DAS28<2.6 was recorded in 15/31 (48%) patients. At the last observation 19 patients (61%) continued TNF-alpha blockers, and the observed benefits persisted after 22+/-11 months of followup. Mean values of transaminases (ALT) and HCV viral load showed no significant variations; TNF-alpha blockers were discontinued in only one patient because of persistently elevated ALT not correlated to the variations of HCV viremia; this latter increased significantly (>or=2 log10) in 4 cases. CONCLUSION: Previous observations had suggested the safety of TNF-alpha blockers for treatment of RA in patients with concurrent HCV infection. Given the clinical-therapeutic implications, our results support the safety of TNF-alpha blockers in patients with HCV, provided there is close monitoring of clinical and virological data (mainly ALT and HCV viremia).""",1
11615,18690931,The safety of the temozolomide in patients with malignant glioma,"The temozolomide is a promising orally cytotoxic agent used in malignant glioma. The survival curve improvement after drug administration appears to be statistically significant. The review of temozolomide side effects is carried out by search on literature data found on web and is divided on the 4 grades of toxicity according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The adverse effects related with TMZ administration are divided in three categories: myelosuppression, non haematologic toxicity, and infections. The main adverse effect is the myelosuppression that appears to be rather low and reversible as well as the vomiting or nausea. The different schedules of administration are analysed. The frequency of concomitant infections is underlined. In particular, if available, the relationship between temozolomide and other cytotoxic agents or anticonvulsivant drugs is analysed to clarify the possibility of increase of toxicity. The temozolomide is used also in children but the toxicity could be more frequent.",1
11616,18690989,Side effects of clozapine and some other psychoactive drugs,"The recognition, management, and if possible prevention, of major cardiovascular, central nervous system, haematological, and metabolic adverse effects, including diabetes mellitus and weight gain, of antipsychotics and some other drugs used to treat mental illness is a topic of much debate. However, a wide range of other adverse effects, some of which may be life-threatening, may also be encountered. Side-effects reviewed here include: gastrointestinal-associated effects (constipation, hypersalivation, oropharyngeal lesions, nasal congestion, nausea, nocturnal enuresis, and urinary retention), metabolic effects (obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, and hypertension), neuromuscular effects (extrapyramidal side effects, myoclonus, and neuroleptic malignant syndrome, and pleurothotonus), thermoregulatory effects, effects on the liver, pancreas, and kidney, sexual side effects, and effects on skin and bone. Metabolic factors affecting the incidence of adverse effects to clozapine especially are also discussed. The increasing use of atypical (second generation) antipsychotics and indeed of selective serotonin reuptake inhibitors has led to a greater appreciation of not only the benefits of these drugs, but also of the spectrum of toxicity that may occur in clinical practice. The adverse effects of antipsychotics are a major factor in promoting poor adherence to, and even discontinuation of, antipsychotic treatment on the one hand, and increasing the risk of cardiovascular and metabolic disease on the other. As such they merit recognition and either harm minimization strategies (use of the minimum effective dose, or use of lower doses of combinations of antipsychotics), or in extreme cases discontinuation of the offending drug(s).",1
11617,18690992,Hepatic effects of duloxetine-II: spontaneous reports and epidemiology of hepatic events,"OBJECTIVE: Review spontaneous reports and epidemiology of hepatic events associated with duloxetine. METHODS: Spontaneous reports of adverse events potentially associated with hepatic injury were identified. Classification schemes were Clinical Significance and Etiologic Category relative to likelihood of being related to duloxetine. RESULTS: Duloxetine has been taken by an estimated 5,083,000 patients, representing approximately 1,551,000 person-years (PY) of worldwide exposure. In the Etiologic categorization of the 406 cases containing event terms potentially related to the liver that have been reported to the manufacturer, 26 were deemed Probable and 127 Possible. Because of scantly-reported information, 182 cases were considered Indeterminate. For Severe Hepatic Injury, the observed spontaneous reporting rate was 0.7/100,000 persons exposed. Of the 406 cases, 225 experienced enzyme elevations to values <500 U/L, most with concentrations well below this level. The calculated cumulative spontaneous reporting rate of all duloxetine hepatic-related events combined was 0.00799%, in the context of other drug-induced hepatic injury rates reported in the literature of 0.7 to 40.6 per 100,000 PY of observation. CONCLUSIONS: There were few cases of true hepatic injury possibly or probably related to duloxetine. The calculated cumulative reporting rate is consistent with very rarely reported per the Council for International Organizations of Medical Sciences.",1
11618,18690994,Laboratory monitoring of hematological and hepatic parameters in ambulatory patients receiving alpha-methyldopa in a Nigerian tertiary care setting,"""The objective of the study is to assess the frequency and comprehensiveness of laboratory monitoring of hematological and hepatic parameters in ambulatory Nigerian hypertensive patients on methyldopa therapy. A retrospective cross sectional study was conducted between 1(st) February and 31(st) March 2007 at the Medical Outpatient Clinic of a 900-bed premier teaching hospital located in Ibadan, Nigeria. 260 case notes of hypertensive patients, out of the 1178 case notes of patients who had been prescribed at least 250 mg of methyldopa for at least 2 months, were reviewed. 22.1% of the hypertensive patients were on methyldopa alone or in combination with other anti-hypertensives for a mean period of 26.8+/-2.3 months (Range: 2-36 months). Overall, red cell count was prescribed and conducted in only 15.4% (40) of cohort. Only 4.2% (11) of patients had follow-up red cell count done after one month of methyldopa therapy; 9 out of these patients had marked reduction of red blood cells. Only 2.3% of cohort had baseline Liver Function Test (LFT) before start of methyldopa therapy and Alanine Transaminases and Aspartate transaminases levels were elevated in all patients. No patient had subsequent LFT prescribed and conducted particularly within 6-12 weeks of use of methyldopa. Direct Anti-Globulin Test was neither prescribed nor conducted in any of the cohort before and after commencement of methyldopa therapy. In conclusion, laboratory monitoring of ambulatory hypertensive patients on methyldopa therapy particularly for possible hematological and hepatic toxicities is less than optimal. The consequent therapeutic benefit of continuing considerable prescription and use of methyldopa in Nigeria is less likely to be realized without proper monitoring to preclude possible methyldopa-use related harms.""",1
11619,18693206,Rivaroxaban: an oral direct inhibitor of factor Xa,"""PURPOSE: The mechanism of action, pharmacodynamics, pharmacokinetics, efficacy in clinical trials, interactions, adverse effects and toxicity, and place in therapy of rivaroxaban are reviewed. SUMMARY: Rivaroxaban, the first oral, direct factor Xa (FXa) inhibitor to reach Phase III trials, inhibits thrombin generation by both the intrinsic and the tissue factor pathways. It has shown predictable, reversible inhibition of FXa activity, and it may have the ability to inhibit clot-bound FXa. Rivaroxaban is being evaluated for prevention of venous thrombosis in patients undergoing hip or knee arthroplasty, treatment of venous thrombosis, long-term use for secondary prevention of venous thrombosis, and prevention of stroke in atrial fibrillation. To date, only short-term trials have been reported, but rivaroxaban's safety and efficacy appear to be at least equivalent to those of traditional anticoagulants. The results of four studies of primary prevention of venous thrombosis in patients undergoing orthopedic surgery suggest that rivaroxaban 10 mg daily is a promising alternative to low-molecular-weight heparins. Rivaroxaban appears to have a low potential for drug-drug or drug-food interactions. It offers the advantages of a fixed oral dose, rapid onset of action, and predictable and consistent anticoagulation effect, precluding the need for routine monitoring of anticoagulation. CONCLUSION: Rivaroxaban is a promising alternative to traditional anticoagulants for the prevention and treatment of venous thromboembolism and for stroke prevention in atrial fibrillation; it offers once-daily oral administration without the need for routine monitoring.""",1
11620,18700192,Hepatotoxicity in patients prescribed efavirenz or nevirapine,"AIM: For several years Nonnucleoside reverse transciptase inhibitors (NNRTIs) in antiretroviral therapy have been associated with hepatic side effects. Particularly the hepatotoxic potential of Nevirapine is well analysed today. We performed a prospective, multicenter study to compare the hepatotoxicity of Efavirenz (EFV) with that of Nevirapine (NVP) and to investigate further risk factors. MATERIAL AND METHODS: The study included HIV-1-infected patients from five clinics and private medical practices in southwestern Germany who initiated an antiretroviral therapy with NVP or EFV between July 1998 and December 2001. Among 296 patients in total, 151 received EFV and 145 received NVP. Laboratory tests during the course of treatment included liver enzymes, HIV-RNA and CD4 cell-count. Additionally, signs of clinical hepatitis were recorded. Hepatotoxicity was graded in the manner of Sulkowsky et al. (2000), who used a scale modified from that of the AIDS Clinical Trials Group. RESULTS: Hepatitis C virus and hepatitis B virus were detected in 10.1% and 4.1% of patients, respectively. The overall rate of severe hepatotoxicity (grade 3 to 4 elevations in aspartate aminotransferase and/or alanine aminotransferase) was 2 of 151 (1.3%) in patients prescribed EFV and 3 of 145 (2.1%) in patients prescribed NVP. Mild-to-moderate hepatotoxicity (grade 2 elevation) was observed in 6.0% (EFV) and 3.4% (NVP) of patients. Incidence of mild-to-moderate and severe hepatotoxicity did not differ significantly between the study groups. 3 of 14 patients (2.1%) with grade 2 elevation of liver enzymes (LEE) and 4 of 5 patients (80%) with grade 3 to 4 LEE were symptomatic. Only risk factor for the development of mild-to-moderate hepatotoxicity was hepatitis C coinfection. CONCLUSION: Increases of liver enzymes during therapy with NVP or EFV are not unusual, but are mostly mild-to-moderate and asymptomatic. LEE occurs just as frequent in patients prescribed EFV as in patients prescribed NVP.",1
11621,18703472,The effects of tibolone in older postmenopausal women,"""BACKGROUND: Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS: During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS: Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)""",1
11622,18711704,Reye's and Reye's-like syndromes,"The review reports various questions about Reye's syndrome and Reye's-like syndromes. Although there is a significant decrease in the classic Reye's syndrome cases, because of the reduced employment of salicylates in children (salicylate seems to be the most important inducing factor of the syndrome in paediatric subjects affected by viral infection), the problem is still of interest considering the presence of different Reye's-like forms. All these pathological situations are associated with various aetiologic or predisposing causes that are examined in the text. Particular attention is placed on metabolic disorders, especially of fatty acid metabolism, and also of one amino acid. In fact, a latent form can also be the basis of possible biochemical disturbances induced by various exogenous factors such as viral infections, particularly of the respiratory tract (more rarely of bacterial aetiology), or produced by microbial toxins, or by chemical substances, including some therapeutic drugs. A full discussion of biochemical mechanisms of salicylate-induced Reye's syndrome is reported. Finally a possible diagnostic differentiation from classic Reye's syndrome and Reye's-like syndromes plus therapeutic prospects are briefly examined.",1
11623,18714667,Questions regarding causality in presumed black cohosh hepatotoxicity,,1
11624,18717872,Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review,"""Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but severe drug reaction, most commonly to aromatic anticonvulsants with a delayed onset, variable clinical presentation and protracted course. The exact incidence of DRESS syndrome is not known because of the variability in clinical presentation, lack of strict diagnostic criteria and universally accepted nomenclature. We report four cases of DRESS syndrome associated with the use of carbamazepine. The clinical manifestation was similar: a maculopapular eruption progressing to exfoliative erythroderma, fever, and lymphadenopathy. Leukocytosis, atypical lymphocytes and liver injury (in 2 patients) were also observed. Assessment of causality using the Naranjo algorithm established a """"probable"""" relationship with carbamazepine in three of the cases and a """"possible"""" relationship in one case. Detection of DRESS syndrome is dependent on the exclusion of a variety of diseases with similar manifestations and may be delayed in time. DRESS syndrome is a potentially life-threatening multisystem adverse drug reaction, and accidental reexposure or drug provocation tests must be avoided.""",1
11625,18718731,"A rapid method for chemical fingerprint analysis of Hoodia species, related genera, and dietary supplements using UPLC-UV-MS","Recently, ultra-performance liquid chromatography (UPLC) has proven to be one of the most promising developments in the area of high-speed chromatographic separations with increased sensitivity and resolution. In this work, a reverse phase chromatographic method was developed using UPLC for the chemical fingerprint analysis of 12 hoodigosides, related genera and dietary supplements. The method is also used for the quantification of P57 in Hoodia species and dietary supplements that claim to contain Hoodia. The analysis was performed on a Waters Acquity UPLC system with an Acquity UPLC BEH C18 column (100 mm x 2.1mm I.D., 1.7 microm) and a gradient elution of water and acetonitrile, both containing 0.05% formic acid with a run time of 15 min. The calibration curve of P57 showed good linearity (r(2)>0.999) within the established range (1-100 microg/mL). The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.3 and 0.9 microg/mL, respectively. The RSD for intra- and inter-day were less than 3.0%, and the recovery efficiency as 97-103%. LC-mass spectrometry coupled with electrospray ionization (ESI) interface method is described for the identification of P57. The developed method was successfully applied to the identification of 12 oxypregnane glycosides in four different species of Hoodia, 23 related genera and 35 dietary supplements that claim to contain H. gordonii. The UPLC profiles of various plant samples were compared for the presence of oxypregnane glycosides. Different sample matrices were successfully analyzed, providing the wide range of applicability of this method, including gels, capsules, tablets, sprays, tea bags, snack bars, powders and juices.",1
11626,18720005,Severe cholestasis and renal failure associated with the use of the designer steroid Superdrol (methasteron): a case report and literature review,,1
11627,18721215,"Immediate allergy, drug-induced eruption, by entecavir",,1
11628,18722869,"Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study","""BACKGROUND: Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients. METHODS: In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779. FINDINGS: At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1.7%, 95% CI -3.8 to 7.1). Mean increases from baseline in CD4 cell count were similar (203 cells per muL in the atazanavir/ritonavir group vs 219 cells per muL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2-4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2-4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3-4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir. INTERPRETATION: In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia.""",1
11629,18725594,Levetiracetam as a possible cause of fulminant liver failure,,1
11630,18729332,Demonstration of the metabolic pathway responsible for nevirapine-induced skin rash,"""The reverse transcriptase inhibitor, nevirapine (NVP), causes skin rashes and hepatotoxicity. We used a rat model to determine if the rash is caused by the parent drug or a reactive metabolite. By manipulation of metabolic pathways and testing analogues, we eliminated all but one pathway, 12-hydroxylation, which involves the oxidation of an exocyclic methyl group, as being responsible for the rash. Treatment with 12-OH-NVP caused a rash, and an analogue in which the methyl hydrogens were replaced by deuterium to inhibit the 12-OH pathway did not cause a rash; however, quite unexpectedly, blood levels of the deuterated analogue were very low. This is due to partitioning of the benzylic free radial intermediate between oxygen rebound to form 12-OH-NVP and loss of another hydrogen atom to form a reactive quinone methide, which inactivates P450. Cotreatment with the P450 inhibitor, 1-aminobenzotriazole, led to comparable levels of NVP and the deuterated analogue, and the deuterated analogue still caused a lower rash incidence. These data clearly point to the 12-hydroxy pathway being responsible for NVP skin rash. We propose that the hepatotoxicity of NVP in humans is due to the quinone methide formed by P450 in the liver, while the skin rash may be due to the quinone methide formed in the skin by sulfation of 12-OH metabolite followed by loss of sulfate. This is the first example in which a valid animal model of an idiosyncratic drug reaction was used to determine the metabolic pathway responsible for the reaction.""",1
11631,18729537,Febuxostat,"*Febuxostat is an orally administered, non-purine, selective inhibitor of xanthine oxidase approved for the management of chronic hyperuricaemia in patients with gout. *In a randomized, double-blind, dose-ranging study in patients with gout and hyperuricaemia, significantly more recipients of febuxostat 40-120 mg/day than placebo had serum urate levels of < 6.0 mg/dL after 4 weeks of treatment. *Serum urate levels were reduced below 6.0 mg/dL at the last three monthly observations in a significantly greater proportion of patients with gout and hyperuricaemia receiving febuxostat 80 or 120 mg once daily than in those receiving allopurinol 300 mg once daily in a 52-week, randomized, double-blind trial (FACT). *Similarly, febuxostat 80, 120 or 240 mg once daily showed significantly greater urate-lowering efficacy than allopurinol 100 or 300 mg once daily in a 28-week, randomized, double-blind, placebo-controlled trial (APEX) in patients with gout and hyperuricaemia. *Long-term treatment with febuxostat for up to 4 years or more reduced the incidence of gout flares to (or close to) zero. *Febuxostat was generally well tolerated in clinical trials, including extension studies lasting > or = 4 years, with most treatment-related adverse events being mild to moderate in severity.",1
11632,18748245,Internal medicine-epitomes of progress: hepatotoxicity caused by acetaminophen or salicylates,,1
11633,18752330,Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B,"""Treatment of 171 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long-term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty-five patients given ADV 10 mg in year 1 elected to continue in a long-term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log(10) copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 x upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log(10) copies/mL and -50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow-up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV. CONCLUSION: Treatment with ADV beyond 48 weeks was well tolerated and produced long-term virological, biochemical, serological, and histological improvement.""",1
11634,18753638,Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke,"""BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)""",1
11635,18757088,"Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial","BACKGROUND: Ivabradine specifically inhibits the I(f) current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction. METHODS: Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7.5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507. FINDINGS: Mean heart rate at baseline was 71.6 (SD 9.9) beats per minute (bpm). Median follow-up was 19 months (IQR 16-24). Ivabradine reduced heart rate by 6 bpm (SE 0.2) at 12 months, corrected for placebo. Most (87%) patients were receiving beta blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1.00, 95% CI 0.91-1.1, p=0.94). 1233 (22.5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22.8%) controls (p=0.70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0.91, 95% CI 0.81-1.04, p=0.17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49-0.84, p=0.001) and coronary revascularisation (0.70, 95% CI 0.52-0.93, p=0.016). INTERPRETATION: Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.",1
11636,18759308,Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study,"OBJECTIVE: To assess the efficacy of pegloticase in achieving and maintaining plasma urate levels of <6 mg/dl in gout patients in whom other treatments have failed, and to assess the pharmacokinetics and safety of pegloticase. METHODS: Forty-one patients were randomized to undergo 12-14 weeks of treatment with pegloticase at 1 of 4 dosage levels: 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks. Plasma uricase activity, plasma urate, and antipegloticase antibodies were measured, pharmacokinetic parameters were assessed, and adverse events were recorded. RESULTS: The mean plasma urate level was reduced to <or=6 mg/dl within 6 hours in all dosage groups, and this was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups. The most effective dosage was 8 mg every 2 weeks. Twenty-six patients received all protocol doses. The percentage of the patients in whom the primary efficacy end point (plasma urate <6 mg/dl for 80% of the study period) was achieved ranged from 50% to 88%. Gout flares occurred in 88% of the patients. The majority of adverse events (excluding gout flare) were unrelated to treatment and were mild or moderate in severity. Infusion-day adverse events were the most common reason for study withdrawal (12 of 15 withdrawals). There were no anaphylactic reactions. Antipegloticase antibody, present in 31 of 41 patients, was associated with reduced circulating half-life of pegloticase in some patients. CONCLUSION: Pegloticase, administered in multiple doses, was effective in rapidly reducing and maintaining plasma urate levels at <or=6 mg/dl in most patients in whom conventional therapy had been unsuccessful due to lack of response, intolerability, or contraindication.",1
11637,18759708,"Maraviroc, risks and benefits: a review of the clinical literature","BACKGROUND: Maraviroc represents the first licensed CCR5 co-receptor antagonist from the new antiretroviral (ARV) drug-class of entry inhibitors. RESULTS: Results of Phase III clinical trials in three-drug-class experienced patients have presented maraviroc as a promising new agent for treatment of HIV-1-infection. Maraviroc (b.i.d./q.d.) + optimised background therapy (OBT) provided significantly superior virological control and CD4+ increases compared with placebo + OBT at 48 weeks, with no clinically relevant differences in the safety profile between the maraviroc and the placebo groups. CONCLUSION: Its proven efficacy in cases of virological failure and three-class ARV-drug resistance is a major benefit of maraviroc compared to the so far commercially available drugs from existing (non-) nucleoside reverse transcriptase inhibitors ([N]NRTI) and protease inhibitors drug-classes, particularly in times of increasing ARV drug resistance. Moreover, the tolerability profile of the drug makes maraviroc particularly appealing as a combination partner in ARV therapy. As maraviroc however is only effective against CCR5-tropic HIV-1, tropism testing is required before initiation of treatment. Tropism-testing possibilities are still limited, and presently only possible at high costs. The main constraints to be considered in the clinical use of maraviroc are the declining number of CCR5-tropic patients with advanced HIV-1 disease owing to tropism-shifting and the occurrence of drug-drug interactions, requiring regular dose adaptations. The true clinical value of this new substance and its future role in the treatment of HIV-1-infection remains to be defined by further data from clinical studies and by future experiences of practitioners.",1
11638,18760136,Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study,"""BACKGROUND: Dronedarone is a new multichannel blocker for atrial fibrillation (AF) previously demonstrated to have both rhythm and rate control properties in paroxysmal and persistent AF. The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) trial assessed the efficacy of dronedarone in the control of ventricular rate in patients with permanent AF, when added to standard therapy. METHODS: In this randomized, double-blind, multinational trial, dronedarone, 400 mg twice a day (n = 85), or matching placebo (n = 89) was administered for 6 months to adult patients with permanent AF, in addition to standard therapy. The primary end point was the change in mean ventricular rate between baseline and day 14, as assessed by 24-hour Holter. Ventricular rate was also assessed during submaximal and maximal exercise. RESULTS: Dronedarone significantly decreased mean 24-hour ventricular rate. Compared with placebo, the mean treatment effect at day 14 was a reduction of 11.7 beats per minute (beat/min; P < .0001). Comparable reductions were sustained throughout the 6-month trial. During maximal exercise and compared to placebo, there was a mean reduction of 24.5 beat/min (P < .0001), without any reduction in exercise tolerance as measured by maximal exercise duration. The effects of dronedarone were additive to those of other rate-control agents, including beta-blockers, calcium antagonists, and digoxin. Dronedarone was well tolerated, with no organ toxicities or proarrhythmia. CONCLUSION: In addition to its reported rhythm-targeting and rate-targeting therapeutic actions in paroxysmal and persistent AF, dronedarone improves ventricular rate control in patients with permanent AF. Dronedarone was well tolerated with no evidence of organ toxicities or proarrhythmias in this short-term study.""",1
11639,18763297,Serious drug-induced liver disease secondary to ezetimibe,"Ezetimibe is the first member of a new family of lipid-lowering drugs that inhibits uptake of dietary and biliary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with ezetimibe.",1
11640,18770032,Serum concentration-dependent hepatotoxicity in individuals receiving oral salsalate,,1
11641,18774664,Agranulocytosis following phenytoin-induced hypersensitivity syndrome,"Phenytoin, one of the most common antiepileptic drugs, is a major cause of antiepileptic drug hypersensitivity syndrome (AHS), which is a rare but potentially fatal complication. We herein report a 5-year-old boy who developed unexpected agranulocytosis with fever approximately one week after recovering from the typical symptoms of AHS, characterized by fever, rash, lymphadenopathy, and hepatitis, but lacking eosinophilia or lymphocytosis. High-dose steroid therapy for the former symptoms of AHS, and immunoglobulin, granulocyte colony-stimulating factor, and cefepime for the latter agranulocytosis were successfully performed. This unexpected progression from AHS to agranulocytosis shortly after recovering from the former should be recognized as another risk of AHS, possibly leading to a life-threatening condition.",1
11642,18778975,Severe hemolytic anemia and fatal hepatic failure associated with nimesulide,,1
11643,18782308,The risks of long-term nitrofurantoin prophylaxis in patients with recurrent urinary tract infection: a recent medico-legal case,,1
11644,18782642,Exenatide once weekly in type 2 diabetes,,1
11645,18783691,[Hepatotoxicity induced by herbs and medicines used to induce weight loss],"In the last few years, a considerable number of reports have been published on hepatotoxicity associated with herbal products attributed with weight-reducing properties. Clinical expression of hepatotoxicity has ranged from symptoms of self-limiting hepatitis, indistinguishable from those caused by the hepatitis viruses, to forms of fulminant hepatitis causing death or requiring liver transplantation. These products, which are sold as dietary products or supplements, do not undergo the safety tests required of drugs before their release on to the market. To prevent the toxic effects of herbal products, the general public should be made aware of their harmful effects and since the benefits of these products have not been demonstrated avoid their use, while physicians should strongly discourage patients from taking these products. Authorization of the commercialization of all these natural products should be strictly regulated to minimize the harm they can cause.",1
11646,18785286,Halothane hepatitis in Iran: a review of 59 cases,"AIM: To study halothane hepatitis (HH) in Iran and its associated risk factors. METHODS: We retrospectively studied files of all cases diagnosed with HH referred to three referral hospitals and four private centers in Iran from April 1994 to September 2006. Information on age at surgery, gender, medications history, obesity, history of previous exposure, previous reaction to halothane, familial history, type of surgery, perioperative hypoxia or sepsis, morbidity and mortality were recorded and analyzed. RESULTS: A total of 59 cases were identified. Forty-eight (81%) were women. The median age at the time of surgery was 44 years (range, 18 to 80 years). Sixty percent of patients were above 40-year-old. Obesity was observed in 22.2%. Previous history of exposures to halothane was noted in 61% of which 50% had history of post-exposure reaction. Coronary artery bypass graft (CABG), cholecystectomy, and cosmetic surgeries (mainly weight reduction) were the most frequent surgeries. The mortality rate was 12.2%. In patients developing encephalopathy, it was as high as 50%. CONCLUSION: HH remains an important cause of morbidity and mortality in centers still using this anesthetic. However, a large percentage of these cases could have been avoided. To lessen occurrence of further cases of HH, the authors suggest that in female patients having a history of surgery (or delivery) with general anesthesia, the use of halothane should be absolutely avoided. Utilization of proper substitutes in adults' anesthesia is advocated.",1
11647,18787478,Pregabalin as a probable cause of acute liver injury,,1
11648,18791959,Valproate-induced hyperammonemic encephalopathy treated by hemodialysis,"Valproate-induced hyperammonemic encephalopathy is an unusual but serious complication that may occur in people with normal liver-associated enzyme levels, despite normal therapeutic doses and serum levels of valproate. Here, we describe an adolescent girl who had absence seizure and complained about progressive dizziness and general malaise several days after restarting valproate. Then, she presented vomiting and decreased consciousness three weeks after valproate use. Notably, her serum ammonia level was five times the upper limit of normal (184 micrommol/L), with normal liver-associated enzyme and supra-therapeutic valproate level. EEG showed continuous generalized slowing. The tandem mass analysis revealed carnitine deficiency. Consciousness improved after emergent hemodialysis. Ammonia level and EEG also returned to normal. Possible mechanisms, risk factors and the treatments of valproate-induced hyperammonemic encephalopathy are described. Physicians should consider this possibility when consciousness disturbance occurs in patients treated with valproate.",1
11649,18794551,Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group,"""PURPOSE: This phase III randomized open-label clinical trial was designed to evaluate the efficacy and safety of the steroidal aromatase inactivator exemestane versus the antiestrogen tamoxifen as first-line treatment for metastatic breast cancer (MBC) in postmenopausal women. PATIENTS AND METHODS: The study was conducted at 81 centers and enrolled postmenopausal patients with measurable hormone-sensitive metastatic or locally advanced breast cancer. Prior adjuvant chemotherapy and/or tamoxifen were allowed. One previous chemotherapy regimen and no prior hormone therapy for advanced disease were permitted. Patients were randomly assigned to receive exemestane 25 mg or tamoxifen 20 mg orally once daily until disease progression or unacceptable toxicity occurred. RESULTS: A total of 371 patients enrolled at 79 sites (182 exemestane, 189 tamoxifen) were included in the analysis. Both treatments were generally well tolerated without major toxicity. Overall response rate was greater for exemestane than for tamoxifen treatment (46% v 31%; odds ratio = 1.85; 95% CI, 1.21 to 2.82; P = .005). Median progression-free survival (PFS) was longer with exemestane (9.9 months; 95% CI, 8.7 to 11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3 to 8.1 months). However, these early differences (Wilcoxon P = .028) did not translate to a longer-term benefit in PFS, the primary study end point (log-rank P = .121). There was also no difference in survival between both study arms. CONCLUSION: Exemestane is an effective and well-tolerated first-line hormonal treatment for postmenopausal women with MBC and offers significant early improvement in time to tumor progression when compared with tamoxifen.""",1
11650,18795397,Etanercept tolerance in a patient with previous infliximab-induced hepatitis,,1
11651,18796127,Sorafenib-induced liver failure,,1
11652,18798068,Hairy cell leukemia: current concepts,"""Hairy cell Leukemia (HCL) is a chronic lymphoproliferative disorder that was characterized in the late 1950s. HCL is defined, according to the WHO classification, as a mature (peripheral) B-cell neoplasm (1). HCL accounts for between 2-3% of all leukemia cases, with about 600 new cases diagnosed in the U.S. each year (1). HCL occurs more commonly in males, with an overall male to female ratio of approximately 4:1. The median age of onset is 52 years. This disease is seen more commonly in Caucasians and appears to be especially frequent in Ashkenazi Jewish males, with rare occurrence in persons of Asian and African descents (1). Hairy cells are distinct, clonal B cells arrested at a late stage of maturation. They are small B lymphoid cells that possess oval nuclei and abundant cytoplasm with characteristic micro-filamentous (""""hairy"""") projections. They strongly express CD103, CD22, and CD11c (2). These cells typically infiltrate the bone marrow, the spleen, and to a lesser extent the liver, lymph nodes, and skin. Many patients present with splenomegaly and pancytopenia. Other clinical manifestations include recurrent opportunistic infections and vasculitis. Historically, HCL was considered uniformly fatal (2). However, recent treatment advances, using purine analogues such as Cladribine and Pentostatin, led to a significant improvement in prognosis with achievement of high response rates and durable remissions (2).""",1
11653,18798702,Systemic pilocarpine for treatment of xerostomia,"BACKGROUND: Xerostomia is the feeling of dryness in the mouth, usually owing to hypofunctioning of the salivary glands. Causes of xerostomia include medications, the effects of radiation therapy on the salivary glands during the treatment of head and neck cancer or thyroid cancer, and autoimmune diseases such as Sj�gren's syndrome. The primary treatment to reduce xerostomia is oral pilocarpine. OBJECTIVE: This review discusses the randomized trials available on the efficacy and tolerability of oral pilocarpine for the treatment of xerostomia. METHODS: The randomized trials of pilocarpine for xerostomia available in the medical literature are reviewed. RESULTS/CONCLUSION: Pilocarpine has some efficacy in the treatment of xerostomia from radiation therapy, graft-versus-host disease and Sj�gren's syndrome. It has limited activity for the prevention of xerostomia during radiation therapy. It may have increased efficacy in combination with newer forms of radiation therapy.",1
11654,18801077,Focal nodular hyperplasia-like lesion of the liver in a child previously treated for nephroblastoma,Described herein is the case of an 8-year-old boy who developed a hepatic nodular lesion after having received anti-neoplastic therapy for nephroblastoma. Histological examination of the excised specimen indicated a disordered arrangement of hepatic components with hemangioma-like features. This case was diagnosed as a variant of focal nodular hyperplasia. It is speculated that this hepatic lesion is a late complication of treatment for nephroblastoma and might develop from congenital malformative area of the liver.,1
11655,18801505,"A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America","PURPOSE: Degarelix is a gonadotropin-releasing hormone receptor antagonist (blocker) with rapid onset of action suppressing gonadotropins, testosterone and prostate specific antigen in prostate cancer. In the present open label, randomized study in North America we evaluated the efficacy and safety of a starting dose of 200 mg degarelix followed by monthly injections of 60 or 80 mg during 1 year of prostate cancer treatment. MATERIALS AND METHODS: A total of 127 patients (median age 76 years, range 47 to 93) with histologically confirmed prostate cancer were enrolled in the study. Efficacy was assessed by measuring serum testosterone and prostate specific antigen. RESULTS: Median baseline testosterone and prostate specific antigen levels were 4.13 ng/ml (P25-P75 3.03-5.11) and 13.4 ng/ml (P25-P75 6.80-25.7), respectively. The starting dose induced a rapid suppression of testosterone in that 88% of the patients had testosterone levels of 0.5 ng/ml or less 1 month after the injection. For patients who had testosterone levels of 0.5 ng/ml or less after 1 month, 93% and 98% of those receiving maintenance doses of 60 and 80 mg, respectively, had testosterone levels that were consistently 0.5 ng/ml or less at all monthly measurements from 1 month to 1 year. No evidence of testosterone surge was detected. In both groups prostate specific antigen decreased by 96% after 1 year and median time to 90% reduction in prostate specific antigen was 56 days. Six patients (5%) withdrew from the study due to adverse events. CONCLUSIONS: Degarelix treatment for 1 year resulted in a fast, profound and sustained suppression of testosterone and prostate specific antigen with no evidence of testosterone surge. Degarelix was well tolerated.",1
11656,18803986,Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases,"""BACKGROUND: Lapatinib, the first dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, was approved by the US Food and Drug Administration (FDA) in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and trastuzumab. OBJECTIVE: This review summarizes the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of lapatinib, and its current and potential role in the treatment of breast cancer and other malignancies. METHODS: Relevant English-language publications were identified through searches of MEDLINE (1966-May 2008),the American Society of Clinical Oncology abstracts database (2000-2007), abstracts from the San Antonio Breast Cancer Symposium (2005-2007), and the FDA Web site (January 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clinical trials. RESULTS: The T(max) of lapatinib after oral administration is 3 to 4 hours. Dividing the dose or administering it with food, particularly a high-fat meal, increases the AUC >2-fold. Lapatinib is metabolized primarily by the cytochrome P450 3A4 isozyme, with 1 metabolite remaining active against EGFR but not HER2. Due to drug accumulation, the t(1/2) of lapatinib is 24 hours with continuous dosing. In a Phase III trial comparing lapatinib and capecitabine with capecitabine alone in women with HER2-positive, locally advanced breast cancer or MBC that had progressed after treatment with an anthracycline, a taxane, and trastuzumab, the combination of lapatinib and capecitabine was associated with a numeric improvement in response rate compared with capecitabine alone (22% vs 14%, respectively; P = NS) and a significant increase in time to progression (6.2 vs 4.3 months; hazard ratio = 0.57; 95% CI, 0.43-0.77; P < 0.001). Lapatinib has been reported to have antitumor activity in Phase II trials when used as first-line therapy for MBC, in patients with inflammatory breast cancer, and in patients with central nervous system metastases. Phase II trials in other solid tumor types found modest activity. The approved dosing of lapatinib is 1,250 mg PO QD given continuously in combination with capecitabine 2,000 mg/m(2) daily administered in 2 divided doses on days 1 to 14 of a 21-day cycle. The most common clinical toxicities of all grades associated with lapatinib used in combination with capecitabine in the pivotal clinical trial were diarrhea (65%), hand-foot syndrome (53%), nausea (44%), rash (29%), and fatigue (24%). Cardiac toxicity appears to be less frequent with lapatinib than with trastuzumab. CONCLUSIONS: Lapatinib is a dual inhibitor of the EGFR and HER2 tyrosine kinases. It is approved by the FDA for use in combination with capecitabine for the treatment of HER2-positive MBC that has progressed with standard treatment. In clinical trials, this combination was associated with a significant improvement in the time to progression in patients with MBC. Lapatinib's efficacy in other malignancies that overexpress EGFR and/or HER2 is under evaluation.""",1
11657,18809940,Safety and efficacy of enfuvirtide in combination with darunavir-ritonavir and an optimized background regimen in treatment-experienced human immunodeficiency virus-infected patients: the below the level of quantification study,"""Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treatment. This prospective, open-label, 24-week, single-arm trial assessed the efficacy and safety of enfuvirtide (90 mg injected subcutaneously twice daily) in combination with darunavir-ritonavir (600/100 mg administered orally twice daily) in triple-antiretroviral-class-experienced adults failing their current regimen. The primary efficacy endpoint was the proportion of participants with plasma HIV RNA loads of <50 copies/ml. Other virological and immunological measures were also evaluated, as were the effects of the baseline viral coreceptor tropism and darunavir phenotype sensitivity scores on the outcomes. At week 24, 60.3%, 72.5%, and 84.0% of 131 participants achieved viral loads of <50 copies/ml and <400 copies/ml and a change from the baseline load of > or =1 log(10) copies/ml, respectively. A baseline viral load of < or =5 log(10) copies/ml was a significant predictor of achieving a viral load of <50 copies/ml at 24 weeks; however, neither background genotype sensitivity nor darunavir phenotype sensitivity was a significant predictor of the achievement of viral loads of <50 copies/ml. Although these findings are limited by the relatively small numbers of participants with darunavir susceptibility changes of > or =10-fold, they suggest that combining enfuvirtide and darunavir-ritonavir with an optimized background regimen in triple-class experienced participants na?ve to these agents can result in positive virological and immunological responses regardless of most baseline parameters.""",1
11658,18813027,Severe hepatotoxicity caused by a methasteron-containing performance-enhancing supplement,,1
11659,18814084,"Hepatic vascular involvement related to pregnancy, oral contraceptives, and estrogen replacement therapy","Both pregnancy and oral contraception (mainly when estrogen is included) may precipitate the development of Budd-Chiari syndrome in patients with underlying thrombophilia. By contrast, there is little evidence for such a role of pregnancy and oral contraception in women with portal vein thrombosis. In pregnant women, special modalities for anticoagulation are required, whereas the management of portal hypertension can be similar to that recommended in other diseases and settings. Hereditary hemorrhagic telangiectasia may deteriorate during pregnancy and improve after delivery. Hepatic sinusoidal dilatation and hepatic peliosis are classic complications of long-term use of oral contraceptives. The impact of pregnancy or oral contraceptives on the natural history on hemangioma and focal nodular hyperplasia appears to be limited. Preeclampsia, a liver disease unique to pregnancy, may be complicated by life-threatening liver vascular involvement, especially when the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) is present.",1
11660,18818219,"The management of prolonged, isolated hyperbilirubinemia following cytarabine-based chemotherapy for acute myeloid leukaemia","BACKGROUND: Patients diagnosed with Acute Myeloid Leukaemia (AML) often receive cytarabine-based chemotherapy as standard treatment. Cytarabine is usually given in combination with other agents such as idarubicin. Such treatments are known to cause hepatic dysfunction characterized by a combination of jaundice, hyperbilirubinemia and increases in liver enzymes. Isolated hyperbilirubinemia is rarely reported. It is often difficult to identify a causative agent for the hepatic dysfunction, as there are often complicating factors such as sepsis. AIM: To report a case of isolated hyperbilirubinemia in a patient treated with cytarabine-based chemotherapy for AML. CLINICAL DETAILS: After a diagnosis of AML the patient was admitted to hospital to receive induction chemotherapy consisting of high-dose cytarabine, idarubicin, and etoposide. All baseline laboratory results were normal, except the full blood evaluation that was consistent with AML. The chemotherapy was delivered over 7 days, and on the eighth day the patient had a bilirubin (BL) level of 27 micromol/L(normal range 522 micromol/L). All other liver function tests (LFT) were normal. This isolated hyperbilirubinemia remained for the rest of the patient's admission, peaking on day 26, with a level of 255 micromol/L. After a stay in the intensive care unit, the patient was discharged on day 45 with a bilirubin level of 33 micromol/L. All other LFT remained unremarkable. OUTCOME: The isolated hyperbilirubinemia resolved slowly and on day 68, when the patient was re-admitted for further dose-reduced cytarabine, the BL level was 21 micromol/L. The patient was successfully retreated with this lower dose regimen. CONCLUSION: Isolated hyperbilirubinemia is an uncommon presentation of cytarabine induced liver dysfunction. Resolution does occur but over a prolonged period. A lower dose of cytarabine for future treatment should be considered.",1
11661,18823729,[Doxycycline induced hepatitis],,1
11662,18827903,Relative safety profiles of high dose statin regimens,"Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.",1
11663,18830435,Levetiracetam in the treatment of epilepsy,"Epilepsy is a common chronic disorder that requires long-term antiepileptic drug therapy. Approximately one half of patients fail the initial antiepileptic drug and about 35% are refractory to medical therapy, highlighting the continued need for more effective and better tolerated drugs. Levetiracetam is an antiepileptic drug marketed since 2000. Its novel mechanism of action is modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain. Its pharmacokinetic advantages include rapid and almost complete absorption, minimal insignificant binding to plasma protein, absence of enzyme induction, absence of interactions with other drugs, and partial metabolism outside the liver. The availability of an intravenous preparation is yet another advantage. It has been demonstrated effective as adjunctive therapy for refractory partial-onset seizures, primary generalized tonic-clonic seizures, and myoclonic seizures of juvenile myoclonic epilepsy. In addition, it was found equivalent to controlled release carbamazepine as first-line therapy for partial-onset seizures, both in efficacy and tolerability. Its main adverse effects in randomized adjunctive trials in adults have been somnolence, asthenia, infection, and dizziness. In children, the behavioral adverse effects of hostility and nervousness were also noted. Levetiracetam is an important addition to the treatment of epilepsy.",1
11664,18831033,Levetiracetam for seizures in children with brain tumors and other cancers,"""Children with brain tumors and other cancers can suffer from seizures. Unfortunately, most antiepileptic therapies are metabolized by the hepatic cytochrome P450 (CYP) system. Levetiracetam, a newer anticonvulsant, does not undergo CYP metabolism and does not alter the pharmacokinetics of chemotherapy, antiemetics, and corticosteroids, which are metabolized by the liver. We studied 23 patients with cancer and seizures treated with levetiracetam. Over 95% of patients had fewer seizures, with 65.2% becoming seizure free; only one patient experienced an adverse reaction. Levetiracetam is effective and well tolerated in children with brain tumors and other cancers, who are often on multiple enzyme-inducing drugs.""",1
11665,18835049,Tolcapone in elderly patients with Parkinson's disease: a prospective open-label multicenter non-interventional trial,"""Safety and efficacy of tolcapone was studied in 237 patients with advanced Parkinson's disease (PD) in a prospective, open-label, multicenter, non-interventional trial. Main outcome measures were tolerability (adverse events=AE) and safety parameters (liver enzymes). A subgroup analysis was performed for patients at < 70 years and > or = 70 years of age. Improvement of symptoms based on investigator global assessment was reported in 84% of all patients: 14.8% greatly improved, 42.6% improved, and 27% slightly improved. Slight worsening was reported in only 2.6% of subjects. There were no significant differences concerning the treatment efficacy between the age subgroups (p=0.74). The incidence of AE was slightly higher in the subgroup of patients > or = 70 years than in the subgroup of patients < 70 years (relative risk, RR=3.03; 95% confidence interval, CI=1.04-8.96; p=0.03), but AE judged as potentially related to tolcapone were equally distributed among both groups (8.5% vs. 2.9%, RR: 2.91; CI=0.82-10.27; p=0.08). Diarrhea was the most common potentially tolcapone-related AE in both groups. Elevations of liver enzymes (aspartate aminotransferase=AST, and alanine aminotransferase=ALT) above the upper limit of normal were observed in 19% (CI=8.3-23.4) of all patients with slightly but not statistically significant higher percentages in the young patients group compared to older patient group (RR=0.54; CI=0.28-1.04; p=0.06). This observational study provides evidence that tolcapone can be effectively and safely used for the treatment of response fluctuations in elderly patients with PD.""",1
11666,18838736,Symptomatic hepatitis associated with the use of herbal red yeast rice,,1
11667,18843630,Inhaled sodium cromoglycate for asthma in children,"BACKGROUND: Sodium cromoglycate has been recommended as maintenance treatment for childhood asthma for many years. Its use has decreased since 1990, when inhaled corticosteroids became popular, but it is still used in many countries. OBJECTIVES: To determine the efficacy of sodium cromoglycate compared to placebo in the prophylactic treatment of children with asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Trials Register (October 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2007), MEDLINE (January 1966 to November 2007), EMBASE (January 1985 to November 2007) and reference lists of articles. We also contacted the pharmaceutical company manufacturing sodium cromoglycate. In 2007 we updated the review. SELECTION CRITERIA: All double-blind, placebo-controlled randomised trials, which addressed the effectiveness of inhaled sodium cromoglycate as maintenance therapy, studying children aged 0 up to 18 years with asthma. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We pooled study results. MAIN RESULTS: Of 3500 titles retrieved from the literature, 24 papers reporting on 23 studies could be included in the review. The studies were published between 1970 and 1997 and together included 1026 participants. Most were cross-over studies. Few studies provided sufficient information to judge the concealment of allocation. Four studies provided results for the percentage of symptom-free days. Pooling the results did not reveal a statistically significant difference between sodium cromoglycate and placebo. For the other pooled outcomes, most of the symptom-related outcomes and bronchodilator use showed statistically significant results, but treatment effects were small. Considering the confidence intervals of the outcome measures, a clinically relevant effect of sodium cromoglycate cannot be excluded. The funnel plot showed an under-representation of small studies with negative results, suggesting publication bias. AUTHORS' CONCLUSIONS: There is insufficient evidence to be sure about the efficacy of sodium cromoglycate over placebo. Publication bias is likely to have overestimated the beneficial effects of sodium cromoglycate as maintenance therapy in childhood asthma.",1
11668,18848937,"A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis","""BACKGROUND & AIMS: Alcoholic hepatitis is a cause of major morbidity and mortality that lacks effective therapies. Both experimental and clinical evidence indicate that the multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) contributes to pathogenesis and clinical sequelae of alcoholic hepatitis. A pilot study demonstrated that the TNF-alpha-neutralizing molecule etanercept could be an effective treatment for patients with alcoholic hepatitis. METHODS: Forty-eight patients with moderate to severe alcoholic hepatitis (Model for End-Stage Liver Disease score > or = 15) were enrolled and randomized to groups that were given up to 6 subcutaneous injections of either etanercept or placebo for 3 weeks. Primary study end points included mortality at 1- and 6-month time points. RESULTS: There were no significant baseline differences between the placebo and etanercept groups in demographics or disease severity parameters including age, gender, and Model for End-Stage Liver Disease score. The 1-month mortality rates of patients receiving placebo and etanercept were similar on an intention-to-treat basis (22.7% vs 36.4%, respectively; OR, 1.8; 95% CI, 0.5-6.5). The 6-month mortality rate was significantly higher in the etanercept group compared with the placebo group (57.7% vs 22.7%, respectively; OR, 4.6; 95% CI, 1.3-16.4; P = .017). Rates of infectious serious adverse events were significantly higher in the etanercept group compared with the placebo group (34.6% vs 9.1%, respectively, P = .04). CONCLUSIONS: In patients with moderate to severe alcoholic hepatitis, etanercept was associated with a significantly higher mortality rate after 6 months, indicating that etanercept is not effective for the treatment of patients with alcoholic hepatitis.""",1
11669,18852631,Drug-related hepatotoxicity and acute liver failure,"Drug-induced acute liver failure (ALF) accounts for approximately 20% of ALF in children and a higher percentage of ALF in adults. Although most patients experience milder drug hepatotoxic reactions such as hepatitis, cholestasis, or asymptomatic enzyme elevation, it is important to recognize the potential for progression to ALF. The most common cause of drug-induced ALF in children is acetaminophen (15% of all ALF in children in the United Kingdom and the United States), whereas other drugs such as antituberculous and antiepileptic therapy account for 5%. The pathogenesis of liver injury includes direct hepatotoxicity and idiosyncratic reactions for most drugs, although for others the mechanism of injury is assumed on the basis of clinical presentation and hepatic histological findings. We review the adult and pediatric literature of drug-induced hepatotoxicity and ALF, with special attention to commonly used or offending medications, mechanism of the toxicity, clinical presentation, diagnosis, treatment, and prognosis. Although most of the available information is based on experience in adult patients, we have included that which is applicable to children, or we have cited pediatric examples. Enhanced awareness of the potential hepatotoxicity of commonly prescribed medications may minimize the frequency of serious hepatotoxicity and ALF in pediatric patients.",1
11670,18884886,Acute exfoliative dermatitis and death following penicillin therapy,,1
11671,18906096,The toxicity of mepacrine in man,,1
11672,18926826,"Oral budesonide for maintenance treatment of collagenous colitis: a randomized, double-blind, placebo-controlled trial","""BACKGROUND & AIMS: Oral budesonide effectively induces clinical remission in patients with collagenous colitis, a debilitating illness characterized by chronic watery/loose diarrhea, but there is a high rate of relapse after treatment cessation. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of long-term therapy with oral budesonide (Entocort CIR capsules) for maintenance of clinical remission of collagenous colitis. Patients were aged >18 years with histologically proven collagenous colitis and >3 watery/loose stools per day on >or=4 of the prior 7 days. Open-label oral budesonide 9 mg/d was administered to all patients for 6 weeks. Patients in clinical remission (<or=3 stools per day) at week 6 were subsequently randomized to double-blind oral treatment with budesonide 6 mg/d or matching placebo for 6 months. Relapse was defined as >3 stools per day on >or=4 consecutive days (and included patients withdrawn because of adverse events). RESULTS: Of 48 enrolled patients, 46 (96%) achieved clinical remission at week 6 and were randomized to maintenance budesonide or placebo. There were 21 relapses during maintenance therapy, and almost all occurred during the first 2 months. Budesonide therapy was associated with a significantly lower cumulative rate of relapse compared with placebo (6/23 [26%] and 15/23 [65%], respectively; P = .022), and high correlation between clinical remission and histologic improvement was observed. Budesonide was well tolerated with no serious adverse events. CONCLUSIONS: Oral budesonide 6 mg/d is efficacious and well tolerated for long-term maintenance of clinical remission in patients with collagenous colitis.""",1
11673,18928762,[Acute hepatitis secondary to bupropion],,1
11674,18939305,"FDA notifications. Abacavir package insert changes approved. Hypersensitivity, other issues addressed",,1
11675,18945310,The impact of treatment with tumour necrosis factor-alpha antagonists on the course of chronic viral infections: a review of the literature,"Biologics that antagonize the biological activity of tumour necrosis factor (TNF)-alpha, namely infliximab, etanercept and adalimumab, are increasingly used for treatment of immune-mediated inflammatory diseases, including psoriasis, worldwide. TNF-alpha antagonists are known to increase the risk of reactivation and infection, particularly of infections with intracellular bacteria such as Mycobacterium tuberculosis. More frequently these agents are given to patients with viral infections. Viral hepatitis and human immunodeficiency virus infections are often present in these patients, with a considerable geographical variation. Other concomitant viral infections such as herpes, cytomegalovirus and varicella zoster virus may occur much more frequently than tuberculosis or leprosy. General recommendations about the management related to possible problems associated with anti-TNF-alpha treatment and these viral infections are lacking. This short review will give an overview of the most recent data available on the effects of anti-TNF-alpha therapy on viral infections with a particular focus on patient management and screening recommendations.",1
11676,18952478,Liver toxicity of TNFalpha antagonists,,1
11677,18955056,"Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States","""BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled. METHODS: Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded. RESULTS: DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%. CONCLUSIONS: DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.""",1
11678,18957621,Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis,"OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, and safety profile of tocilizumab, a new biologic agent targeting the interleukin-6 cytokine receptor. DATA SOURCES: A systematic search of MEDLINE (1998-June 2008) and International Pharmaceutical Abstracts (1970-June 2008) was performed to identify published clinical trials and review articles. Key search terms were tocilizumab, MRA, interleukin-6/receptors, interleukin-6/immunology, and rheumatoid arthritis. The search was limited to studies in humans that were published in the English language. References from articles located during this search were evaluated for other relevant citations. Abstracts from national and international rheumatology meetings (American College of Rheumatology and European League Against Rheumatism) and from unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov) were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All available human studies describing the pharmacology, pharmacokinetics, efficacy, safety, and adverse effects of tocilizumab were included. DATA SYNTHESIS: At doses greater than 4 mg/kg, tocilizumab use has resulted in significant improvement in clinical outcomes, including the American College of Rheumatology parameters indicating a patient's level of improvements and disease remission. Improvements were noted when tocilizumab was used as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs. The most effective dose of tocilizumab appears to be 8 mg/kg, which has shown significant improvements in radiographic measures of joint damage. The most common adverse effects have included abnormal results of liver function tests, hyperlipidemia, neutropenia, infections, nasopharyngitis, gastrointestinal complaints, musculoskeletal disorders, headache, rash, and pruritus. CONCLUSIONS: Tocilizumab represents a promising new treatment for rheumatoid arthritis. Additional research is warranted to confirm its radiographic benefits, clarify its safely profile, and identify its place in rheumatoid arthritis treatment relative to current biologic agents.",1
11679,18958618,Sertraline hepatotoxicity: report of a case and review of the literature,"Sertraline is a commonly prescribed selective serotonin reuptake inhibitor drug. Hepatotoxicity caused by sertraline is rare. Asymptomatic elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels have been rarely reported and shortly normalize after discontinuation of the agent. We present a case of severe drug-induced hepatitis in a patient receiving sertraline. To our knowledge, this is the seventh case in the medical literature as being associated with severe hepatotoxicity. Since it is extremely rare, we do not suggest a strict laboratory monitoring. However, sertraline should be discontinued in cases with symptoms implying hepatotoxicity and the patients should be informed of the potential of this side effect.",1
11680,18975305,"Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial","OBJECTIVE: To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis (AS) in the GO-RAISE study. METHODS: Patients with active AS, a Bath AS Disease Activity Index (BASDAI) score > or =4, and a back pain score of > or =4 were randomly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab (50 mg or 100 mg) or placebo every 4 weeks. The primary end point was the proportion of patients with at least 20% improvement in the ASsessment in AS (ASAS20) criteria at week 14. RESULTS: At randomization, 138, 140, and 78 patients were assigned to the 50-mg, 100-mg, and placebo groups, respectively. After 14 weeks, 59.4%, 60.0%, and 21.8% of patients, respectively, were ASAS20 responders (P < 0.001). A 40% improvement in the ASAS criteria at week 24 occurred in 43.5%, 54.3%, and 15.4% of patients, respectively. Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey, the Jenkins Sleep Evaluation Questionnaire score, the BASDAI score, and the Bath AS Functional Index score, but not the Bath AS Metrology Index score. Through week 24, 85.6% of golimumab-treated patients and 76.6% of patients in the placebo group had > or =1 adverse event, and 5.4% and 6.5% of patients, respectively, had > or =1 serious adverse event. Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values (> or =100% increase from baseline and a value >150 IU/liter), which were transient. CONCLUSION: Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period.",1
11681,18977719,Low rate of adverse hepatic events associated with fosamprenavir/ritonavir-based antiretroviral regimens,"PURPOSE: To appraise the incidence of liver toxicity in a population of patients receiving fosamprenavir/ritonavir (FPV/r) with a high frequency of viral hepatitis co-infection. METHOD: 636 patients, 341 (54%) with HCV antibodies and 38 (5.6%) bearing serum HBsAg, were recruited. All of them received FPV/r 700/100 twice every day. 93 (27%) patients who tested positive for HCV antibodies showed an AST to platelet ratio index (APRI) higher than 1.5, consistent with significant liver fibrosis. RESULTS: After a median (range) follow-up time of 6.91 (0.46-20.66) months, 3 (0.47%) patients developed grade 3 ALT elevation. All the former patients were hepatitis virus co-infected, 2 with hepatitis C virus and 1 with hepatitis B virus. The frequency of grade 3 ALT elevation in patients with HCV antibodies was 0.58% and in those harbouring HBsAg it was 2.63%. 4 (0.62%) patients suffered from a liver decompensation and 1 died due to a hepatic cause while on follow-up. No patients with APRI equal to or higher than 1.5 showed grade 3 ALT elevation. CONCLUSION: The incidence of adverse hepatic events in patients receiving FPV/r including combinations seems to be low, even in subjects co-infected with hepatitis virus and in those with significant liver fibrosis.",1
11682,18981291,Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP,"""Chronic immune thrombocytopenic purpura (ITP) is characterized by low platelet counts and mucocutaneous bleeding. In previous studies romiplostim (AMG531), a thrombopoiesis-stimulating protein, increased platelet counts in most patients with chronic ITP. This ongoing, long-term open-label, single-arm study investigated safety and efficacy in patients who completed a previous romiplostim study and had platelet counts less than or equal to 50 [corrected] x 10(9)/L. One hundred forty-two patients were treated for up to 156 weeks (mean, 69 weeks). Platelet responses (platelet count > or = 50 x 10(9)/L and double baseline) were observed in 87% of all patients and occurred on average 67% of the time in responding patients. In 77% of patients, the romiplostim dose remained within 2 microg/kg of their most frequent dose at least 90% of the time. Ninety patients (63%) received treatment by self-administration. Treatment-related serious adverse events were reported in 13 patients (9%). Bone marrow reticulin was observed in 8 patients; marrows were not routinely performed in this study, so the true incidence of this event cannot be determined. Severe bleeding events were reported in 12 patients (9%). Thrombotic events occurred in 7 patients (5%). In conclusion, romiplostim increased platelet counts in most patients for up to 156 weeks without tachyphylaxis and had an acceptable safety profile. (ClinicalTrials.gov Identifier NCT00116688).""",1
11683,18981785,Elevated alkaline phosphatase with raltegravir in a treatment experienced HIV patient,,1
11684,18983224,Paroxetine: safety and tolerability issues,"Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) available in immediate release and controlled release (CR) formulations. Paroxetine is the most potent inhibitor of serotonin re-uptake among the now available SSRIs. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. The overall efficacy of paroxetine seems to be comparable to other SSRIs in the treatment of approved indications, although paroxetine treatment induces more sedation, constipation, sexual dysfunction, discontinuation syndrome and weight gain than other SSRIs. Recent data suggest that paroxetine treatment leads to increased rates of congenital malformations, although this evidence is not conclusive. Paroxetine and paroxetine CR are not indicated for use in the paediatric population and are categorised as Pregnancy Class D. In conclusion, whether the tolerability profile of paroxetine differs substantially from other new antidepressants (including other SSRIs) needs to be determined in adequately powered well-designed randomised controlled comparative clinical trials.",1
11685,18986457,Anticonvulsant hypersensitivity syndrome: clinical and laboratory features,"BACKGROUND: Anticonvulsant hypersensitivity syndrome (AHS) is a severe adverse drug reaction with multiorgan involvement. Aromatic anticonvulsants are the most frequently involved drugs. This study was aimed to highlight the clinical and laboratory findings of AHS. METHODS: The medical records of 31 patients diagnosed as AHS in a 12-year period were evaluated retrospectively. RESULTS: The syndrome was related to carbamazepine in 48.38%, phenytoin in 35.48%, lamotrigine in 9.6% and cotreatment with lamotrigine and valproic acid in 6.45% of cases. Symptoms appeared 2-86 (mean: 35.96) days after ingestion of the offending agent. The type of skin rash was maculopapular and/or erythrodermic in 77.42% of patients, bullous in 19.35%, and erythematopustular in 3.22%. Fever and peripheral lymphadenopathy were detected in 61.29% and 54.82% of cases, respectively. Laboratory investigations revealed elevation of hepatic enzymes in 70.96%, leucocytosis in 43.3%, and peripheral eosinophilia in 64.3% of patients. CONCLUSIONS: Our analysis showed that carbamazepine and phenytoin are still the major causes of AHS, with lamotrigine being the third etiologic agent. Valproic acid and benzodiazepines are safe alternatives of the causative anticonvulsants. As there are yet no strict diagnostic criteria, the constellation of clinical and laboratory features that occur within 3 months of the associated anticonvulsant agents helps to recognize the disorder. The risk of seizure due to withdrawal or changing of the anticonvulsant drug and the potentially serious clinical features often necessitates providing care and treatment in an inpatient setting.",1
11686,18989142,Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases,"BACKGROUND/AIMS: Hepatotoxicity has been previously suspected by national regulatory agencies in 26 patients in causal relationship with the treatment by kava extracts commonly used as herbal anxiolytic drugs. METHODS: A quantitative causality assessment was undertaken using the system of the Council for International Organizations of Medical Sciences, scale of objective probability scoring. RESULTS: Causality was unassessable, unrelated, or excluded in 16 patients owing to lack of temporal association and causes independent of kava or comedicated drugs. Low Council for International Organizations of Medical Sciences scores additionally resulted in excluded or unlikely causality assessments (n=2), leaving a total of eight patients with various degrees of causality for kava +/- comedicated drugs. Only one out of these eight patients adhered to the regulatory recommendations regarding both daily dose (<or=120 mg kavapyrones) and duration of therapy (<or=3 months) and experienced toxic liver injury with a probable causality for kava. In six cases with kava overdose and/or increased duration of kava treatment causality for kava was possible (n=3) and for kava together with the comedicated drug(s) possible (n=2) or probable (n=1). CONCLUSION: Kava taken as recommended is associated with rare hepatotoxicity, whereas overdose, prolonged treatment, and comedication may carry an increased risk.",1
11687,18989148,Severe hepatotoxicity with high 6-methylmercaptopurine nucleotide concentrations after thiopurine dose escalation due to low 6-thioguanine nucleotides,"Azathioprine and its initial metabolite, 6-mercaptopurine (6-MP), are associated with high rates of treatment cessation due to toxicity or inadequate response. Individualization of thiopurine dose based on concentrations of the active 6-thioguanine nucleotide (6-TGN) metabolites can help improve outcomes with this class. Some individuals, however, preferentially metabolize thiopurine drugs to the potentially hepatotoxic 6-methylmercaptopurine nucleotide (6-MMPN) metabolites rather than the 6-TGNs. For these patients, escalation in thiopurine dose is not likely to increase 6-TGN concentrations sufficiently but may lead to a disproportionate increase in exposure to the 6-MMPNs. We present three cases in whom thiopurine dose escalation based on clinical status and low 6-TGN concentrations (100-262 pmol/8 x 10 RBC) resulted in severe hepatotoxicity (liver failure in two cases) associated with unrecognized extremely high 6-MMPN concentrations of 26,000-40,000 pmol/8 x 10 RBC. These cases illustrate a risk with thiopurine dose adjustment based on monitoring of 6-TGN metabolites without also monitoring 6-MMPN.",1
11688,19000014,Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children,"""BACKGROUND: Human immunodeficiency virus (HIV) therapy includes a backbone of nucleoside reverse-transcriptase inhibitors (NRTIs). Toxicities associated with NRTIs are not fully defined in children. METHODS: We studied 2233 children < or =13 years of age who were perinatally infected with HIV and were receiving > or =2 NRTIs, to determine the relative toxicities of the 5 most common NRTI pairs: zidovudine (ZDV)/lamivudine (3TC), ZDV/didanosine (ddI), stavudine (d4T)/3TC, d4T/ddI, and ddI/3TC. Incidence rates for clinical and laboratory toxicities were estimated, and NRTI pairs were compared with regard to the time to the first toxicity. RESULTS: The most common clinical toxicities noted were hepatitis, peripheral neuropathy, lipodystrophy/lipoatrophy, and pancreatitis, whereas the most common laboratory toxicities were an elevated anion gap, an increased total amylase level, neutropenia, and thrombocytopenia. Overall, regimens containing ZDV were associated with a significantly lower rate of clinical toxicities than were those containing d4T (adjusted hazard ratio [HR], 0.49; P = .02) ); regimens containing ddI were associated with a significantly lower rate of laboratory toxicities than were those containing 3TC (adjusted HR, 0.78; P = .04). ZDV/3TC was associated with a lower rate of clinical toxicities than were d4T/ddI and ddI/3TC and with a higher rate of laboratory toxicities than was ZDV/ddI. ZDV/ddI was associated with a lower rate of clinical toxicities than was d4T/3TC. CONCLUSIONS: In children, regimens containing ZDV have less toxicity than do those containing d4T, thereby supporting their use in first-line regimens. D4T/3TC, d4T/ddI, and ddI/3TC have similar toxicity rates and are appropriate for second-line therapy.""",1
11689,19004919,Early stages of propofol infusion syndrome in paediatric cardiac surgery: two cases in adolescent girls,,1
11690,19005287,Abacavir-induced hepatotoxicity: a report of two cases,,1
11691,19008178,Fatal acute liver failure due to reactivation of hepatitis B following treatment with fludarabine/cyclophosphamide/rituximab for low grade non-Hodgkin's lymphoma,"BACKGROUND: Reactivation of chronic hepatitis B in HBsAg carriers is a well known complication of chemo?therapy. The clinical spectrum ranges from asymptomatic hepatitis to fatal hepatic failure. Although it impairs the prognosis of cancer treatment, it may be overlooked due to other possible causes of liver damage. CASE REPORT: The patient presented with acute liver failure after 6 cycles of rituximab, fludarabine, and cyclophosphamide for low grade non-hodgkin's lymphoma. Differential diagnoses were chemotherapy-induced liver failure, autoimmune hepatitis, phenprocoumon-induced liver failure and infiltration of the liver by lymphoma. Finally, reactivation of hepatitis B with a fibrosing cholestatic pattern was identified. CONCLUSION: This case reminds clinicians that patients receiving high-intensive chemotherapy or immunosuppressive therapy should be screened for HBsAg. HbsAg positive patients should obtain prophylactic antiviral therapy with lamivudine or another substance active against HBV.",1
11692,19010650,"Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh, root): critical analysis and structured causality assessment","Severe hepatotoxicity has been described as spontaneous or case reports in 42 patients in assumed causal relationship with the treatment by Cimicifugae racemosae rhizoma corresponding to the root of black cohosh (BC) for postmenopausal symptoms. However, an assessment by EMEA (European Medicines Agency) has shown a possible or probable causality in only 4 out of 42 patients. A diagnostic algorithm was now applied in the 4 patients with suspected BC hepatotoxicity, which included the qualitative and quantitative causality assessment of the updated system of the Council for International Organizations of Medical Sciences (CIOMS), allowing the study to objectively assess, score and scale the probability in each case. Due to incomplete data, the case of 1 patient was not assessable. In the remaining 3 patients, a severe course of liver disease was apparent, and steroid therapy was initiated under the provisional diagnosis of drug-induced hepatic injury. The analysis shows, however, that the observed liver diseases were unrelated to drugs. Only 1 patient had a favourable course under continued steroid therapy, and the final diagnosis was autoimmune hepatitis. The 2 other patients required liver transplantation under the final diagnosis of herpetic hepatitis established now. Quantitative evaluation showed no causality for BC in all 3 patients regarding the observed severe liver disease. Using a thorough causality assessment in the form of a diagnostic algorithm we have shown that there is no evidence for a causal relationship between treatment by black cohosh and the observed liver disease in the 4 patients.",1
11693,19013295,Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia,"""Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of the metabolic syndrome. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the efficacy of atorvastatin in the treatment of NASH associated with hyperlipidemia. This prospective study included 31 patients with biopsy-proven NASH with hyperlipidemia. Body mass index, serum lipids, liver function tests, fibrosis markers, and adipocytokines (adiponectin, leptin, tumor necrosis factor-alpha) were measured periodically during an open-label study of atorvastatin (10 mg daily) for 24 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance test and liver density assessed by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 17 patients. All 31 patients had high cholesterol levels at baseline, and 20 also presented high triglyceride levels. The body mass index and serum glucose levels did not change during the treatment. After treatment, 23 patients (74.2%) presented normal transaminase levels. Adiponectin levels were significantly increased, and the levels of tumor necrosis factor-alpha were significantly decreased. However, leptin levels were not changed significantly. The concentration of long-chain fatty acids was decreased; and significant decreases were observed in C18:2,n-6 (linoleic acid, -21%) and C20:4,n-6 (arachidonic acid, -22%). Liver steatosis and nonalcoholic fatty liver disease activity score were significantly improved, whereas 4 patients had increased fibrosis stage. The NASH-related metabolic parameters improved with therapy, including fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period, with 3 of them progressing to stage 3. It is unclear whether this divergent response represents sampling error, heterogeneity in the population, or untreated postprandial hyperglyceridemia. Controlled trials are needed to further investigate and resolve this.""",1
11694,19014870,Treatment with etanercept in six patients with chronic hepatitis C infection and systemic autoimmune diseases,"OBJECTIVE: To describe the clinical and immunologic features of 6 patients with rheumatic disease and Hepatitis C Virus (HCV) chronic infection, treated with anti-TNF alpha drugs. PATIENTS AND METHODS: Six patients, with repeated positive serology for HCV infection, were affected by Rheumatoid arthritis (RA) (4 cases), Psoriatic Arthritis (PsA) and Polymyositis in one case each. They started anti-TNFalpha treatment (Etanercept), due to a previous failure of combination of different immunosuppressants (Methotrexate, Sulfasalazine, Cyclosporine, Hydroxychloroquine). RESULTS: Patients (3 female and 3 males) showed a mean age at disease onset of 50.6 years (SD 14.5) and a mean disease duration of 12.5 years (SD: 8.8). Etanercept (dosage of 50 mg weekly) was continued for a median period of 14 months. Patients affected by RA and PsA achieved a good clinical response, with a significant reduction of DAS28 during treatment (p: 0.0001). No patient received any specific therapy for HCV infection. Elevated HCV-RNA titres were recorded in 5 cases at start of Etanercept. No significant increase was observed during anti-TNF alpha treatment. No cases of hepatic failure were recorded. CONCLUSION: Anti-TNF alpha therapy showed to be effective, safe and well tolerated in the setting of HCV infection.",1
11695,19016373,Evaluation of the efficacy of the combination of oral bexarotene and methotrexate for the treatment of early stage treatment-refractory cutaneous T-cell lymphoma,"BACKGROUND: Various combination therapies are used in refractory cutaneous T-cell lymphoma (CTCL). Although bexarotene has been studied in combination with psoralen photochemotherapy (PUVA), IFN-alpha and denileukin difitox, there have been no published data assessing the efficacy of the combination of bexarotene and methotrexate. OBJECTIVE: To evaluate the efficacy and safety of an oral bexarotene and methotrexate combination for the treatment of refractory CTCL. METHOD: A retrospective study was carried out of 12 patients with refractory stage CTCL treated with an oral combination of bexarotene and methotrexate from 2000 to 2007. RESULTS: Twelve patients with CTCL stage IA-IIB disease who received a combination of bexarotene and methotrexate were identified. The median dose of bexarotene was 150 mg/day (range 75-300 mg/day) and methotrexate 15 mg/week (range 5-30 mg/week). The duration of time to achieve an overall response was 6.5 months (range 3-11 months). The overall response occurred in 66% (8/12). One patient had complete response (CR = 8%) and seven had partial response (PR = 58%). Six of 12 patients progressed at some point during treatment and needed additional intervention. Tolerance to the treatment was good and commonly observed side effects were hyperlipidemia, elevated liver transaminases and a decreased white blood cell count. Limitations of the study included a restricted number of patients, relatively short evaluation times and retrospective analysis. CONCLUSION: An oral bexarotene and methotrexate combination may be a promising future alternative to monotherapy for the treatment of CTCL, but further studies are required.",1
11696,19017830,Clinical application of voriconazole concentrations in the treatment of invasive aspergillosis,"""OBJECTIVE: To review the current literature to determine the clinical application of therapeutic drug monitoring of voriconazole in the treatment of invasive aspergillosis (IA). DATA SOURCE: A MEDLINE search (1966-June 2008) was performed using the search terms voriconazole, aspergillosis, levels, monitoring, and serum concentration. STUDY SELECTION AND DATA EXTRACTION: All pertinent English-language literature on voriconazole use in adults was included for evaluation. DATA SYNTHESIS: IA is a serious fungal infection with a mortality rate of nearly 100% without adequate treatment; current therapeutic options are limited. A clinical trial comparing amphotericin B deoxycholate with voriconazole in treatment of IA found voriconazole to be superior. The use of voriconazole, however, is complicated due to its saturable metabolism, nonlinear kinetic profile, and drug interactions, which result in considerable interpatient variability in concentrations. Therefore, therapeutic monitoring of voriconazole trough concentrations may lead to improved patient outcomes. A recent prospective study on the use of voriconazole for treatment of invasive mycoses demonstrated that 46% of the patients had a lack of response when trough plasma concentrations were less than or equal to 1 microg/mL, compared with 12% of patients with trough concentrations greater than 1 microg/mL (p = 0.02). All patients with low trough concentrations who did not respond to voriconazole improved upon dose escalation. The upper limit of a therapeutic range is based on the presence of adverse events. The most common adverse effects associated with voriconazole are visual disturbances (21%) and elevations in liver transaminase levels (12.4%). Current literature suggests that a greater incidence of adverse effects may be associated with trough concentrations greater than 6 microg/mL. CONCLUSIONS: A standardized therapeutic range for voriconazole has not been defined. Most available studies recommend trough concentrations of approximately 1-6 microg/mL. Prospective, randomized trials are needed to confirm the correlation between plasma voriconazole concentrations and clinical outcomes.""",1
11697,19018717,HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis,"INTRODUCTION: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 and HLA-B*5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B*1502 and HLA-B*5801 in Japanese SJS/TEN patients. METHODS: HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan. RESULTS: There were no HLA-B*1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B*5801 carriers, which included four allopurinol-related SJS/TEN patients. CONCLUSION: While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.",1
11698,19019888,"Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study","OBJECTIVES: To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. METHODS: In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. RESULTS: 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. CONCLUSION: In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.",1
11699,19022608,Safety and effectiveness of acetadote for acetaminophen toxicity,"BACKGROUND: Acetaminophen (APAP) toxicity is commonly encountered in the Emergency Department. Until 2004, treatment consisted of either oral N-acetylcysteine (NAC) or filtered oral NAC administered intravenously (i.v.). Intravenous acetylcysteine (Acetadote) is a new Food and Drug Administration-approved i.v. formulation of acetylcysteine manufactured by Cumberland Pharmaceuticals in Nashville, Tennessee. Little post-marketing data exists on the effectiveness and safety of i.v. acetylcysteine. OBJECTIVES: We evaluated the clinical presentations and outcomes of patients treated with i.v. acetylcysteine for APAP toxicity. METHODS: We performed a retrospective chart review of patients treated with i.v. acetylcysteine for APAP ingestion. The primary outcome measures were: adverse reactions to and effectiveness of i.v. acetylcysteine, as defined by elevation of transaminases, liver failure, renal failure, death, and hospital length of stay (LOS). Data collected included: comorbidities, allergies, intentionality, timing and dosing of i.v. acetylcysteine, hospital LOS, transaminases > 1000 IU/L, development of liver failure requiring transplant, development of renal failure requiring hemodialysis, death, and anaphylactoid reactions. RESULTS: Sixty-four patients met our study criteria. Overall, 16 (25%) patients developed transaminases > 1000 IU/L, 4 (6%) of them died and 2 (3%) received liver transplants. Of the 15 patients (23%) treated within 8 h, none died or developed liver or renal failure, and only 1 developed transient transaminase elevation > 1000 IU/L. In the patients treated outside of 8 h, the median LOS was 3 days, whereas the group treated within 8 h had a median LOS of only 1 day. Six (9%) patients developed anaphylactoid reactions, 2 of whom received the i.v. acetylcysteine bolus over 15 min. Five of these patients were treated pharmacologically and completed treatment, and one had treatment discontinued for undocumented reasons. CONCLUSION: Intravenous acetylcysteine seemed to be a safe and effective formulation of N-acetylcysteine.",1
11700,19025848,Treatment with potentially hepatotoxic drugs and the risk of hepatocellular carcinoma: results of a european case - control study,"Some toxicological data and case reports have suggested that patients taking potentially hepatotoxic drugs may have an increased risk of benign and malignant liver tumours. Pharmacoepidemiological studies on this issue are sparse, most of them focusing on the association between hepatocellular carcinoma (HCC) and the use of oral contraceptives (OC). The objectives of our study were to examine the risk of HCC in patients taking the drugs mentioned in these case reports and toxicological studies. We used data from an international case - control study which had investigated the risk of HCC in women taking OC including 317 cases of HCC and 1060 frequency age-matched hospital controls. We investigated the risk for oral antidiabetic and immunosuppressive drugs, methyldopa, nitrofurantoin and clofibrate using unconditional logistic regression analysis. The analysis was adjusted for age, hepatitis B, hepatitis C, alcohol abuse and other risk factors of HCC. The adjusted odds ratios for ever-use of the investigated drugs varied between 0.67 and 1.64, none of them being statistically significant. There was equally no significantly increased risk for long-term use of these drugs. Altogether there is no evidence for an increased risk of HCC in patients taking the drugs investigated, however, the relatively small statistical power for certain drugs with a low exposure prevalence has to be taken into account. Copyright (c) 2000 John Wiley & Sons, Ltd.",1
11701,19027013,2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B,"""BACKGROUND & AIMS: The GLOBE trial has compared the efficacy and safety of telbivudine versus lamivudine treatment over 2 years in patients with chronic hepatitis B. METHODS: Hepatitis B e antigen (HBeAg)-positive (n = 921) and HBeAg-negative (n = 446) patients received telbivudine or lamivudine once daily for 104 weeks. The primary outcome, assessed in the intent-to-treat population, was therapeutic response (hepatitis B virus DNA <5 log(10) copies/mL and either HBeAg loss or normalization of alanine aminotransferase [ALT] level). RESULTS: The therapeutic response to telbivudine was superior to that of lamivudine in HBeAg-positive (63% vs 48%; P < .001) and HBeAg-negative (78% vs 66%; P = .007) patients. HBeAg-positive patients given telbivudine also had better outcomes compared with lamivudine in terms of nondetectable viremia (< 300 copies/mL) at 55.6% versus 38.5% (P < .001), HBeAg loss at 35.2% versus 29.2% (P = .056), and viral resistance at 25.1% versus 39.5% (P < .001). Hepatitis B e antigen seroconversion was 29.6% versus 24.7% (P = .095) in all patients and 36% versus 27% (P = .022) in patients with baseline ALT level > or = 2 times normal. Telbivudine-treated HBeAg-negative patients showed higher rates of nondetectable viremia compared with lamivudine at 82.0% versus 56.7% (P < .001) and less resistance at 10.8% versus 25.9% (P < .001). Adverse events occurred with similar frequency, whereas grade 3/4 increases in creatine kinase levels were more common in patients given telbivudine (12.9% vs 4.1%, P < .001). Multivariate logistic regression analyses identified telbivudine treatment, among other variables, as an independent predictor of better week 104 outcomes. CONCLUSIONS: Telbivudine is superior to lamivudine in treating patients with chronic hepatitis B over a 2-year period.""",1
11702,19029525,4-aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis,,1
11703,19033479,Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms,"BACKGROUND: With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin. OBJECTIVE: To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs). METHODS: Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin. RESULTS: A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS. CONCLUSIONS: A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.",1
11704,19035858,"The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer","""OBJECTIVE: To evaluate the efficacy and safety of degarelix, a new gonadotrophin-releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer. PATIENTS AND METHODS: In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent-to-treat (ITT) and per protocol populations were analysed. RESULTS: The primary endpoint of the trial was suppression of testosterone to <or=0.5 ng/mL at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were <or=0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (P < 0.001). The hormonal side-effect profiles of the three treatment groups were similar to previously reported effects for androgen-deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injection-site reactions than with the i.m. leuprolide injection (40% vs <1%; P < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3% vs 9%. P < 0.01, respectively), arthralgia (4% vs 9%, P < 0.05, respectively) and chills (4% vs 0%, P < 0.01, respectively). There were no systemic allergic reactions. CONCLUSIONS: Degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1-year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for antiandrogen supplements to prevent the possibility of clinical 'flare'.""",1
11705,19043517,Tiagabine: efficacy and safety in partial seizures - current status,"""Tiagabine hydrochloride (TGB) is a selective gamma-aminobutyric acid (GABA) reuptake inhibitor. TGB is effective as an add-on medication in adults and children 12 years and older in the treatment of partial seizures. Results of nonrandomized add-on trials with TGB show treatment success with seizure reduction of at least 50% in 33% to 46% of patients. In newly diagnosed patients with partial epilepsy, TGB monotherapy was as effective as carbamazepine. Comedication with TGB elevates the risk of nonconvulsive status (7.8% vs 2.7% without TGB). The most common side effects include dizziness/lightheadedness, asthenia/lack of energy and somnolence. TGB has no negative effects on cognition; it does not increase the risk of fractures or rash. TGB may interfere with color perception. TGB presents an intermediate risk for depression in patients with epilepsy (approximately 4%). Regarding the risk of overdose, 96-680 mg TGB (mean 224 mg) caused seizures or coma. TGB is an antiepileptic drug exhibiting a specific anticonvulsive mechanism of action, the efficacy of which is relatively low when used in comedication. Critical side effects, such as the induction of nonconvulsive status epilepticus, further limit its use.""",1
11706,19047275,Erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis in lenalidomide-treated patients,,1
11707,19047848,"""Negrin Dastis S. et al.: Liver transplantation for nonsteroidal anti-inflammatory drug-induced liver failure: nimesulide as the first implicated compound. Eur J Gastroenterol Hepatol 2007; 19:919-922""",,1
11708,19048536,[Reye's syndrome. Description of a case focused on the patient's epileptic seizures],"INTRODUCTION: Reye's syndrome is an acute disease characterised by encephalopathy and fatty degeneration of the liver that occurs almost exclusively in children. It can cause the death of the patient in up to a third of all cases, generally due to severe cerebral oedema. The aetiopathogenesis of this condition is uncertain and is usually preceded by a viral infection, generally from the influenza or varicella virus. Some studies have shown a strong epidemiological association between the ingestion of acetylsalicylic acid (ASA) during the viral infection and development of Reye's syndrome. CASE REPORT: We describe the case of a 20-month-old female who developed Reye's syndrome within the context of a viral infection and the ingestion of ASA. A hepatic biopsy study is appropriate in this syndrome. The patient presented a non-convulsive status during the acute phase and at one year developed Lennox-Gastaut syndrome. She died from pneumonia at the age of 18 years. CONCLUSIONS: In all patients with clinical features that suggest Reye's syndrome, inborn errors of metabolism that can mimic it must be precluded. Although the incidence of this syndrome has gone down considerably in recent years, it is important to keep it in mind as an early and aggressive diagnosis and treatment of cerebral hypertension will reduce the mortality rate and the sequelae.",1
11709,19051503,Phase I study of 5-azacytidine (NSC-102816),"Thirty patients with various solid tumors were treated with 5-azacytidine. Total doses ranged from 1.0 to 24.0 mg/kg and were given over a minimal period of 8 days. The major toxic effect was hematologic with significant leukopenia and thrombocytopenia usually occurring 20-30 days after the start of therapy, especially at higher dose levels. The marrow depression lasted 1-5 weeks and was fully reversible. Nausea and mild diarrhea were common following injection of the drug. Serum glutamic oxaloacetic transaminase levels rose in several patients. No other evidence of hepatic toxicity was seen. Objective remissions were noted in seven of 11 patients with cancer of the breast, two of five with melanoma, and two of six with cancer of the colon.",1
11710,19054552,Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials,"""BACKGROUND: Circadian rhythm sleep disorders are common causes of insomnia for millions of individuals. We did a phase II study to establish efficacy and physiological mechanism, and a phase III study to confirm efficacy of the melatonin agonist tasimelteon (VEC-162) for treatment of transient insomnia associated with shifted sleep and wake time. METHODS: We undertook phase II and phase III randomised, double-blind, placebo-controlled, parallel-group studies. In a phase II study, 39 healthy individuals from two US sites were randomly assigned to tasimelteon (10 [n=9], 20 [n=8], 50 [n=7], or 100 mg [n=7]) or placebo (n=8). We monitored individuals for 7 nights: 3 at baseline, 3 after a 5-h advance of sleep-wake schedule with treatment before sleep, and 1 after treatment; we measured plasma melatonin concentration for circadian phase assessment. In a phase III study, 411 healthy individuals from 19 US sites, who had transient insomnia induced in a sleep clinic by a 5-h advance of the sleep-wake schedule and a first-night effect in a sleep clinic, were given tasimelteon (20 [n=100], 50 [n=102], or 100 mg [n=106]) or placebo (n=103) 30 min before bedtime. Prespecified primary efficacy outcomes were polysomnographic sleep efficiency (phase II study), latency to persistent sleep (phase III study), and circadian phase shifting (phase II study). Analysis was by intention to treat. Safety was assessed in both studies. These trials are registered with ClinicalTrials.gov, numbers NCT00490945 and NCT00291187. FINDINGS: In the phase II study, tasimelteon reduced sleep latency and increased sleep efficiency compared with placebo. The shift in plasma melatonin rhythm to an earlier hour was dose dependent. In the phase III study, tasimelteon improved sleep latency, sleep efficiency, and wake after sleep onset (ie, sleep maintenance). The frequency of adverse events was similar between tasimelteon and placebo. INTERPRETATION: After an abrupt advance in sleep time, tasimelteon improved sleep initiation and maintenance concurrently with a shift in endogenous circadian rhythms. Tasimelteon may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.""",1
11711,19057523,"Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women","Lorcaserin (APD356) is a potent, selective 5-HT(2C) agonist with ~15-fold and 100-fold selectivity vs. 5-HT(2A) and 5-HT(2B) receptors, respectively. This study evaluated the safety and efficacy of lorcaserin for weight reduction in obese patients during a 12-week period. The randomized, double-blind, placebo-controlled, parallel-arm study enrolled 469 men and women between ages 18 and 65 and with BMI 30-45 kg/m(2). Patients received placebo, lorcaserin 10 mg q.d., lorcaserin 15 mg q.d., or lorcaserin 10 mg b.i.d. for 12 weeks, and were counseled to maintain their usual diet and activity. The primary end point was change in weight from baseline to day 85 by completer analysis. Safety analyses included echocardiograms at Screening and day 85/study exit. Lorcaserin was associated with progressive weight loss of 1.8 kg, 2.6 kg, and 3.6 kg at 10 mg q.d., 15 mg q.d., and 10 mg b.i.d., respectively, compared to placebo weight loss of 0.3 kg (P < 0.001 for each group). Similar results were seen by intent-to-treat last observation-carried forward (ITT-LOCF) analysis. The proportions of completers achieving > or =5% of initial body weight were 12.8, 19.5, 31.2, and 2.3% in the 10 mg q.d., 15 mg q.d., 10 mg b.i.d., and placebo groups, respectively. The most frequent adverse events (AEs) were transient headache, nausea, and dizziness. Echocardiograms showed no apparent drug-related effects on heart valves or pulmonary artery pressure (PAP). Lorcaserin was well tolerated and efficacious for weight reduction in this 12-week study. Longer-term trials employing behavior modification will be needed to more fully assess its safety and efficacy.",1
11712,19058842,Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis,"BACKGROUND: Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia. METHODS: We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation. FINDINGS: We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication. INTERPRETATION: Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.",1
11713,19060002,Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research,"""OBJECTIVE: To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA). METHODS: A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied. RESULTS: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a-2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b-4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b-4). CONCLUSION: This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.""",1
11714,19066002,New compounds in the management of venous thromboembolism after orthopedic surgery: focus on rivaroxaban,"Rivaroxaban (Xarelto) is a member of a new class of oral, direct (antithrombin-independent) factor Xa inhibitors, which restrict thrombin generation both in vitro and in vivo. After oral administration the absorption is near 100%, the bioavailability is near 80%, and the elimination half-life is 5-9 hours with mixed excretion via the renal and fecal/biliary routes. The pharmacokinetics of rivaroxaban are predictable and consistent with a rapid onset of antithrombotic action within 2 hours after administration. Phase II clinical studies have been carried out in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) and a dose of 10 mg once daily for thromboprophylaxis was selected for further clinical development. The results of the phase III studies showed a significantly better antithrombotic efficacy of rivaroxaban compared with enoxaparin both in the short term (10-14 days) in TKA patients and long term (35 +/- 4 days) in THA patients with a comparable safety. Symptomatic thromboembolic events were also significantly reduced with rivaroxaban. Liver enzyme elevation was seen in patients treated with rivaroxaban, but there was no indication of an increased risk of liver toxicity compared with enoxaparin. In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopedic surgery.",1
11715,19067373,"Randomized, controlled trial of miglustat in Gaucher's disease type 3","""OBJECTIVE: To evaluate the efficacy and safety of miglustat, concomitant with enzyme replacement therapy (ERT), in patients with Gaucher's disease type 3 (GD3). METHODS: This 24-month, phase II, open-label clinical trial of miglustat in GD3 was conducted in two phases. During the initial 12 months, patients were randomized 2:1 to receive miglustat or """"no miglustat treatment."""" The randomized phase was followed by an optional 12-month extension phase in which all patients received miglustat. All patients received ERT during the 24-month period. The primary efficacy end points were change from baseline to months 12 and 24 in vertical saccadic eye movement velocity as determined by the peak amplitude versus amplitude regression line slope. Secondary end points included changes in neurological and neuropsychological assessments, pulmonary function tests, liver and spleen organ volumes, hematological and clinical laboratory assessments, and safety evaluations. RESULTS: Thirty patients were enrolled, of whom 21 were randomized to miglustat and 9 to """"no miglustat treatment."""" Twenty-eight patients entered the 12-month extension phase. No significant between-group differences in vertical saccadic eye movement velocity or in the other neurological or neuropsychological evaluations were observed. Organ volumes and hematological parameters remained stable in both treatment groups, but improvement in pulmonary function and decrease of chitotriosidase levels were observed with miglustat compared with patients receiving ERT alone. INTERPRETATION: Miglustat does not appear to have significant benefits on the neurological manifestations of GD3. However, miglustat may have positive effects on systemic disease (pulmonary function and chitotriosidase activity) in addition to ERT in patients with GD3.""",1
11716,19069362,Etanercept therapy for psoriasis in a patient with concomitant hepatitis C and liver transplant,"We report a case of a 49 year-old male who had undergone liver transplant due to hepatitis C, Laennec's cirrhosis, and hepatocellular carcinoma, and was treated with etanercept for recalcitrant generalized psoriasis. Clearance of psoriasis was achieved without any adverse effects or complications of his current conditions.",1
11717,19075968,Febuxostat: a novel non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in gout,"""Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase being developed for the management of hyperuricaemia in patients with gout. To critically review the clinical trial data, safety profile, pharmacology, and role of febuxostat for the treatment of hyperuricemia and gout. A review of the literatures on febuxostat was performed. All available human studies describing the pharmacology of febuxostat were included; including pharmacodynamics, efficacy, and safety of febuxostat. Available studies, patents and abstracts were identified through PubMed (1990-December 2006), Delphion, Cochrane Databases, and the American College of Rheumatology and European League Against Rheumatism Web sites. Key search terms were febuxostat, TMX-67, and TEI-6720. Febuxostat has been used at a dose of 80 to 120 mg for the management of hyperuricemia in gout. The drug is mainly metabolized by the liver and therefore mild-moderate renal impairment does not appear to impede its effect. However, given the limited long-term liver function safety data, failure of a large percentage of patients taking febuxostat to achieve the primary end point of serum urate levels less than 6.0 mg/dL, and higher drop out rate in the Febuxostat group in the clinical trials, the exact role of febuxostat as a urate-lowering therapy remains uncertain. Febuxostat is a promising alternative to allopurinol for the treatment of gout and hyperuricemia. The optimal length of colchicines prophylactic therapy for chronic gout, clinical significance of abnormal liver function tests results during therapy, and safety in patients with moderate or severe hepatic and renal insufficiency warrant further investigation. A post-market surveillance is also needed to address the safety issue of long-term febuxostat treatment.""",1
11718,19077780,Fulminant hepatitis induced by lamotrigine,"Anticonvulsant hypersensitivity syndrome (AHS) is a potentially life-threatening adverse drug reaction presenting with fever, skin eruptions, and internal organ involvement. We describe a case of AHS with fulminant hepatitis that occurred two weeks after introduction of lamotrigine in a 40-year-old female patient with a recently diagnosed bipolar disorder, no pre-existent systemic organ involvement, and no other medication. Lamotrigine was introduced at a dosage of 25 mg daily and increased to 50 mg daily 12 days later. The patient had favorable evolution with cessation of lamotrigine and supportive treatment. This report suggests that AHS with fulminant hepatitis may occur idiosyncratically, independent of dosage, titration and comedication with other potentially hepatotoxic drugs.",1
11719,19083237,Thalidomide-induced severe hepatotoxicity,,1
11720,19085967,Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy,"UNLABELLED: Liver damage associated with chronic unexplained high serum transaminases in human immunodeficiency virus (HIV)-infected patients under combined antiretroviral therapy is unknown. Liver histology was prospectively investigated in patients presenting serum transaminase elevation for more than 6 months, after exclusion of alcohol abuse, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, autoimmune, and genetic liver diseases. In a subgroup of patients, liver mitochondrial activities were measured by spectrophotometry and mitochondrial DNA (mtDNA) by real-time polymerase chain reaction (PCR). Thirty patients were included with median values of alanine aminotransferase (ALT) levels: 80 U/L, age: 46 years, body mass index: 23 kg/m(2), HIV RNA: 200 copies/mL, CD4 count: 365/mm(3), duration of HIV infection: 13 years, and duration of treatment exposure: 118, 41, and 53 months for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Histological anomalies were found in 22 of 30 patients. Steatosis was present in 18 patients, severe in nine patients, and associated with inflammation in 16 patients with a diagnosis of non-alcoholic steatohepatitis (NASH). Fibrosis was found in 18 patients, severe in six patients and associated with steatosis in 13 patients. Significant liver respiratory complex I defect, contrasting with high complex IV activity and normal mitochondrial DNA content, was observed in the group of patients compared with controls. The presence of NASH was correlated with high fasting glycemia and insulin levels, not with liver mitochondrial function or mitochondrial DNA content. CONCLUSIONS: HIV-infected patients on combined antiretroviral therapy with chronic transaminase elevation of unknown origin have a high rate of liver lesions, mostly consistent with NASH related to insulin resistance.",1
11721,19092641,Hydralazine-induced cholestatic hepatitis,"Hydralazine has been widely used for treating hypertension, particularly in patients with renal failure. We report a case on a patient in whom we believe the drug was implicated in an otherwise unexplained disturbance of liver function. A 63-year-old African-American female with medical history of hypertension and end-stage renal disease (on hemodialysis) was admitted to the hospital with epigastric pain and jaundice. The symptoms started about 1 week ago. Initial laboratory tests showed abnormal liver enzymes with elevated conjugated bilirubin and alkaline phosphatase suggestive of cholestatic jaundice. Amylase and lipase were normal. Abdominal ultrasound showed normal caliber common bile duct without evidence of obstruction. Abdominal CT scan does not show any evidence of intra- or extrahepatic biliary ductal dilatation, and no mass lesions were seen in the pancreas. Further blood chemistry showed worsening of liver enzymes and increased bilirubin over the next 2-3 days. Magnetic resonance cholangiopancreatography failed to show any evidence of intra- or extrahepatic biliary ductal dilatation. No other laboratory evidence of cholestatic jaundice was found. Before proceeding for invasive diagnostic procedure, that is, endoscopic retrograde cholangiopancreatography, the patient's drug history was reviewed. She was on hydralazine 75 mg 3 times per day, started 5 months ago. At that time, her liver function tests were normal. As we could not find any other cause of cholestatic jaundice, we attributed this as a side effect of hydralazine. A trial was given by stopping the hydralazine. It was seen that there was significant improvement in the liver function enzymes over the next week. Complete clinical and biochemical recovery occurred over the next 4 weeks. Liver injury after long-term therapy with hydralazine and after short-term therapy with hydralazine (2-10 days) has been described. Hydralazine-induced hepatotoxicity may manifest as hypersensitivity-type injury, mixed hepatocellular injury, acute hepatitis, cholestatic jaundice, or centrilobular necrosis. The Hydralazine-induced cholestatic liver injury seems to be fully reversible. Complete clinical and biochemical recovery occurs after discontinuation of the drug. Also, the differential diagnosis of any patient with hepatocellular injury should include medications. This will prevent unnecessary diagnostic tests.",1
11722,19092674,Fulminant hepatic failure following overdose of the vitamin A metabolite acitretin,"Hepatotoxicity associated with the therapeutic ingestion of the vitamin A metabolite acitretin is well recognized. No reported cases of hepatic dysfunction as a consequence of acitretin overdose are, however, present. Here for the first time we report a case of fulminant hepatic failure following an intentional overdose of 600 mg of acitretin. The patient fulfilled the King's College Hospital poor prognostic criteria by 66 h after overdose, but demonstrated a rapid improvement thereafter and did not require liver transplantation. Given the known association between psoriasis and depression, and the possible association of acitretin with psychiatric illness, this is an important potential adverse event.",1
11723,19094887,[Hepatotoxicity related to escitalopram],,1
11724,19095497,"Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial","""BACKGROUND: Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. METHODS: Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. FINDINGS: 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. INTERPRETATION: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.""",1
11725,19098880,Prolonged cholestasis associated with benazepril therapy,,1
11726,19098892,Acute hepatitis in a patient with cirrhosis and hepatocellular carcinoma treated with sorafenib,,1
11727,19105705,Anagrelide: 20 years later,"Thrombocytosis is a common feature of chronic myeloproliferative disorders (MPD) and may be asymptomatic or associated with transient microvascular vaso-occlusive symptoms or large vessel arterial or venous thrombosis. Failure of either the hematocrit or the platelet count to correlate with thrombotic events is a peculiar conundrum of the MPDs. Asymptomatic thrombocytosis in young MPD patients with no cardiovascular risk factors does not require treatment. It is also undisputed that lowering the platelet count reduces the incidence of microvascular events in MPD patients. At the same time, no study to date has demonstrated that platelet count reduction prolongs survival in MPD patients. Agents such as hydroxyurea, busulfan, IFN-alpha and anagrelide, have been used to reduce an elevated platelet count and decrease thrombohemorrhagic events in at-risk patients with thrombocytosis associated with an MPD. When treatment is required, it makes sense to use drugs that are not myelotoxic or mutagenic. Based on the Primary Thrombocythaemia 1 study, hydroxyurea is the treatment of choice for thrombocytosis-associated transient ischemic attacks. However, hydroxyurea does not prevent venous thrombosis, is not more effective in preventing arterial thrombosis than anagrelide and its long-term safety is not established. Therefore, unless curative therapy is planned, one should use the least myelotoxic agent when platelet count reduction is required. In this regard, anagrelide can be considered a first-line drug. With regard to long-term safety of anagrelide, the EMEA has required close monitoring of the safety points identified in future Periodic Safety Update Reports and in a Post Authorisation Safety Study in the EU, which will focus especially on cardiovascular events and acute leukemia. In this article, we review anagrelide pharmacology, the physiology of thrombopoiesis, the differential diagnosis of thrombocytosis and the management of patients with an elevated platelet count.",1
11728,19107482,"L-asparaginase in the treatment of refractory and relapsed extranodal NK/T-cell lymphoma, nasal type","There is no standard salvage regimen for patients with refractory and relapsed extranodal NK/T-cell lymphoma (NKTCL), nasal type. This study was conduced to evaluate the efficacy of L-asparaginase-based regimen as a salvage regimen, on refractory and relapsed extranodal NKTCL, nasal type. Between March 1996 and March 2008, 45 patients with refractory and relapsed extranodal NKTCL, nasal type, were studied retrospectively. All patients were treated with L-asparaginase-based salvage regimen. Thirty-nine patients also received primary involved-field radiation after L-asparaginase-based chemotherapy. The complete response rate, partial response rate, and overall response rate for the whole group were 55.6%, 26.7%, and 82.2%, respectively. Both of 3-year and 5-year overall survival (OS) rates were 66.9%. The major adverse effects of L-asparaginase were myelosuppression, liver dysfunction, hyperglycemia, and allergic reaction. In general, the side effects could be tolerated. On univariate analysis, age, the stage of disease, and performance status were found to be prognostic factors influencing OS. On multivariate analysis, the stage of disease and age were independent prognostic factors for OS. L-Asparaginase-based regimen was obviously effective for the patients with refractory and relapsed extranodal NKTCL, nasal type.",1
11729,19108787,"Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial","""BACKGROUND: Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM). OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM. METHODS: This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18-70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (> or = 30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a > or = 6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial. RESULTS: Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m(2). Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P<0.001 for both doses), physical function (SF-36 physical functioning domain-100 mg/d: P < 0.001; 200 mg/d: P = 0.02), and fatigue (Multidimensional Fatigue Inventory- 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients. CONCLUSION: In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124.""",1
11730,19115757,Symptomatic hyperlactataemia in adults on antiretroviral therapy: a single-centre experience,"OBJECTIVE: There are limited data on symptomatic hyperlactataemia caused by antiretroviral therapy (ART) in resource-limited settings. We assessed individuals who developed symptomatic hyperlactataemia on ART in an outpatient clinic in South Africa. DESIGN: A retrospective record review was performed on patients attending the clinic from January 2004 to December 2005. RESULTS: Thirty-five patients, all on stavudine-containing regimens, developed symptomatic hyperlactataemia. The incidence in this population was 20.5 cases per 1 000 person-years of ART with an associated mortality of 21%. The major risk factor was being female (risk ratio (RR) 3.27). Significant clinical symptoms preceding symptomatic hyperlactataemia include nonspecific gastrointestinal symptoms, weight loss, and development of symptomatic neuropathy. CONCLUSIONS: The incidence of symptomatic hyperlactataemia in our population was high. Simple clinical measures, such as neuropathy symptoms and monitoring of weight, may alert the clinician to impending symptomatic hyperlactataemia. Early diagnosis expedites safe outpatient care and switching of ART regimens without interruption, in many cases.",1
11731,19117595,The risk of infections with biologic therapies for rheumatoid arthritis,"OBJECTIVES: To assess the risk of serious and nonserious bacterial and viral infections associated with the use of biologic therapy (abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab) in patients with rheumatoid arthritis (RA). METHODS: Information was derived from PubMed, EMBASE, and the Cochrane clinical trials register and database of systematic reviews and relevant congress abstracts up to and including February 2008. RESULTS: Compared with the general population, patients with RA have a heightened risk of infection, including tuberculosis. Long-term clinical trials and postmarketing studies indicate that anakinra and the tumor necrosis factor (TNF) inhibitors are associated with an increased risk of infections versus conventional disease-modifying antirheumatic drugs (DMARDs), especially early in the course of treatment. The most common sites of infection are the respiratory tract (including pneumonia), skin and soft tissue, and the urinary tract. The risk of tuberculosis also appears higher with TNF inhibitors (in particular, infliximab) versus DMARDs, although this can be reduced by screening and prophylaxis. TNF inhibitors do not appear to significantly increase the risk of reactivating chronic viral infections. Influenza and pneumococcal vaccinations are generally effective in the face of TNF inhibitors or abatacept. Available data suggest that the risk of infections and serious infections with abatacept and rituximab may be similar to that of the TNF inhibitors. To date, there have been no reports from clinical trials of increased tuberculosis or opportunistic infections with abatacept or rituximab. CONCLUSIONS: All marketed TNF inhibitors for compared to control RA appear to increase the risk of serious and nonserious infections compared with DMARDs. Although suggestive, data for abatacept and rituximab are less definitive and longer periods of patient exposure to these agents are needed before an assessment of their risks can be made.",1
11732,19127256,Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours,"""Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.""",1
11733,19128733,[Hepatic cytolysis from infliximab],,1
11734,19129081,Early development of lactic acidosis with short term linezolid treatment in a renal recipient,,1
11735,19132781,"The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial","""OBJECTIVE: To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM). METHODS: A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient's individual response to therapy. """"FM responders"""" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while """"FM pain responders"""" concurrently satisfied response criteria for improvements in pain and PGIC. RESULTS: At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (realtime, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events. CONCLUSION: Milnacipran is safe and effective for the treatment of multiple symptoms of FM.""",1
11736,19133574,Valproate-induced hyperammonemic encephalopathy,"Valproate-induced hyperammonemic encephalopathy is an unusual but serious complication that can occur in people with normal liver-associated enzyme levels, and despite normal therapeutic doses and serum levels of valproate. Here, we describe an adolescent girl suffering from absence seizures, who complained of progressive dizziness and general malaise several days after restarting valproate. She developed vomiting and decreased consciousness after 3 weeks of valproate use. She had a serum ammonia level five times higher than the upper normal limit, normal liver-associated enzymes, and a supra-therapeutic valproate level. Electroencephalography (EEG) showed continuous generalized slowing. Tandem mass spectrometry analysis revealed carnitine deficiency. Her consciousness improved after emergent hemodialysis. Her ammonia level and EEG also became normal. Possible mechanisms, risk factors and treatments of valproate-induced hyperammonemic encephalopathy are described. Physicians should consider this possibility when consciousness disturbance occurs in patients treated with valproate.",1
11737,19135998,"Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin","""BACKGROUND & AIMS: Sustained virologic response (SVR) rates of 50%-60% have been achieved in patients with chronic hepatitis C genotype 4 treated with peginterferon plus ribavirin. The safety and efficacy of nitazoxanide plus peginterferon alfa-2a, with or without ribavirin, were evaluated in a randomized controlled trial at 2 centers in Egypt. METHODS: Previously untreated patients with chronic hepatitis C and genotype 4 infection were assigned randomly to groups that were given standard of care (peginterferon alfa-2a and ribavirin for 48 weeks, n = 40), nitazoxanide monotherapy for 12 weeks followed by nitazoxanide plus peginterferon alfa-2a for 36 weeks (n = 28), or nitazoxanide monotherapy for 12 weeks followed by nitazoxanide plus peginterferon alfa-2a and ribavirin for 36 weeks (n = 28). Therapeutics included nitazoxanide (500 mg) twice daily, peginterferon alfa-2a (180 microg) once weekly, and weight-based ribavirin (1000-1200 mg/day). RESULTS: The percentages of rapid virologic response (RVR), defined as undetectable HCV RNA at week 4 of combination therapy, and SVR were significantly higher in patients given the triple therapy compared with the standard of care (64% vs 38%, P = .048; and 79% vs 50%, P = .023; respectively). Patients given nitazoxanide plus peginterferon alfa-2a had intermediate rates of RVR (54%) and SVR (61%). Adverse events were similar across treatment groups except for higher rates of anemia in the groups receiving ribavirin. CONCLUSIONS: The combination of nitazoxanide, peginterferon alfa-2a, and ribavirin increased the percentages of patients with RVR and SVR, compared with patients given peginterferon plus ribavirin, without an increase in adverse events.""",1
11738,19139391,"Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide","""BACKGROUND: Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension. METHODS AND RESULTS: After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (-20.3/-14.2 versus -18.6/-13.0 mm Hg; P<0.05) and were also greater at week 52 (-22.1/-16.0 versus -21.2/-15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (-17.4/-12.2 versus -14.7/-10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001). CONCLUSIONS: Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension.""",1
11739,19145729,Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease,"""BACKGROUND: Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP), in up to 10% of patients with inflammatory bowel disease. Our group previously demonstrated that allopurinol with AZA/ciclosporin/steroid 'triple therapy' improved renal graft survival. AIM: To confirm the hypothesis that allopurinol may alleviate thiopurine hepatotoxicity by similar mechanisms as proposed in our renal study. METHODS: Unselected patients with acute thiopurine hepatotoxicity were offered allopurinol co-therapy with low-dose AZA or MP. The starting AZA/MP dose was determined by thiopurine methyltransferase (TPMT) activity (two patients were intermediate TPMT); then this dose was reduced to 25% for allopurinol co-therapy. Response to treatment was assessed by clinical severity indices, endoscopy and blood tests. RESULTS: Of 11 patients (three Crohn's disease, eight ulcerative colitis) treated, nine (82%) remain in long-term remission (median 42 months) with normal liver tests. One patient also successfully bypassed flu-like symptoms. Two stopped: one nausea, one abnormal liver function (stealosis on biopsy). Leucopenia occurred in two cases and resolved with minor dose reductions. CONCLUSIONS: Allopurinol co-therapy with low-dose AZA/MP can alleviate thiopurine hepatotoxicity. It appears safe and effective for long-term use, but requires monitoring for myelotoxicity. Assessing the TPMT activity helps tailor the AZA/MP doses.""",1
11740,19147616,Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide,"""INTRODUCTION: Potential hepatotoxicity associated with disease-modifying antirheumatic drugs (DMARDs) requires laboratory monitoring. In patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA), the incidence of elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF) and MTX+LEF versus other DMARDs was examined. METHODS: Patients with RA and PsA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1- or 2-fold times above the upper limits of normal (ULN). Odds ratios (OR) between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalised estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared with each individually. RESULTS: Elevated ALT/AST levels (>1x ULN) occurred in 22%, 17%, 31% and 14% of patients with RA receiving MTX, LEF, MTX+LEF or neither, respectively; elevations were 2.76-fold (95% CI 1.84 to 4.15) more likely in patients with PsA. Elevations >2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared with 5% with the combination. After multivariable adjustment and compared with either monotherapy, the combination of MTX and LEF was associated with a greater risk according to MTX dose used as part of the combination: MTX 10-17.5 mg/week, OR 2.91 (95% CI 1.23 to 6.90); MTX > or =20 mg/week, OR 3.98 (95% CI 1.72 to 9.24). CONCLUSIONS: Abnormal ALT/AST levels developed in 14-35% of patients with RA or PsA initiating DMARD therapy. The risks were incrementally greater in those with PsA and in those receiving MTX (> or =10 mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.""",1
11741,19149521,"Reyes's syndrome, encephalopathy, hyperammonemia and acetyl salicylic acid ingestion in a city hospital of Buenos Aires, Argentina","""Twelve cases of Reye's syndrome are presented with different degrees of encephalopathy, hyperammonemia and hypoglycemia; associated to acetyl salicylic acid (ASA) ingestion. The aim of the present retrospective study was to describe our experience in selected patients with Reye's syndrome associated to the ASA ingestion and to underline the influence of hyperammonemia on Reye's encephalopathy. All the cases presented moderate hyperbilirubinemia, elevated alanine aminotransferase, aspartate aminotransferase with an average of 302+/-205 UI/L and 285+/-149 UI/L respectively. Arterial blood ammonia averaged 172.4+/-71.3 micromol/L and glycaemia averaged 35.2+/-17.0 mg/dl. A high mortality was found in our series (41.7%). Considering that encephalopathy is the leading syndrome in these cases, the influence of ammonia on brain tissue was described. Glutamate is an excitotoxic neurotransmitter, capable to produce neuron and astrocyte damage and apoptosis. The presence of ASA could cause the onset of the mitochondrial permeability transition and the mitochondrial swelling in the astrocyte, leading to hyperammonemia. In Reye's syndrome, hyperammonemia and perhaps the increase of glutamate are the leading factors in the mechanism of brain damage and encephalopathy. Aspirin must be carefully administrated and controlled by professionals. Furthermore, parents must be informed about the risks in the use of this drug in children.""",1
11742,19153164,Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis,"OBJECTIVE: The aim of this study was to determine the relation of medications to the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in children <15 years of age. METHODS: We conducted a pooled analysis by using data from 2 multicenter international case-control studies: the severe cutaneous adverse reaction (SCAR) study and the multinational severe cutaneous adverse reaction (EuroSCAR) study conducted in France, Germany, Italy, Portugal, the Netherlands, Austria, and Israel. We selected case subjects aged <15 years, hospitalized for Stevens-Johnson syndrome, Stevens-Johnson syndrome/toxic epidermal necrolysis-overlap, or toxic epidermal necrolysis, and age-, gender-, and country-matched hospital controls. Pooled crude odds ratios were estimated and adjusted for confounding by multivariate methods when numbers permitted. RESULTS: Our study included 80 cases and 216 matched controls. Antiinfective sulfonamides, phenobarbital, carbamazepine, and lamotrigine were strongly associated with the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. Significant associations were highlighted in univariate analysis for valproic acid and nonsteroidal antiinflammatory drugs as a group and for acetaminophen (paracetamol) in multivariate analysis. CONCLUSIONS: We confirmed 4 previously highly suspected drug risk factors for Stevens-Johnson syndrome/toxic epidermal necrolysis in children: antiinfective sulfonamides, phenobarbital, carbamazepine, and lamotrigine. Among more unexpected risk factors, we suspect that acetaminophen (paracetamol) use increases the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.",1
11743,19154213,"Long-term efficacy and safety of aripiprazole in patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder: 26-week prospective study","AIMS: To date there have been no reports of long-term efficacy of aripiprazole in Asian populations. The aim of the present study was therefore to investigate the long-term efficacy, safety and tolerability of aripiprazole in a large number of patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder in Korea. METHODS: This study was a prospective, multicenter, single-group, 26-week open study of patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. A total of 300 Korean patients participated in the study. The primary efficacy measure was the Positive and Negative Syndrome Scale (PANSS) total score, and secondary efficacy measures included the PANSS positive and negative subscales, Clinical Global Impression-Severity of Illness (CGI-S). Tolerability and safety were assessed by monitoring the frequency and severity of treatment-emergent adverse events, extrapyramidal symptoms (EPS), vital signs, weight, and laboratory tests. RESULTS: Aripiprazole produced rapid and significant improvements on all efficacy measures. As evidenced by PANSS total score, PANSS positive subscales and the CGI-S scores, first-episode drug-naive patients demonstrated significantly greater efficacy relative to patients who had previously experienced one or more episodes of relapse. Aripiprazole was associated with significant decrease of serum prolactin level. The subjects showed mild weight gain. CONCLUSION: Aripiprazole is an effective antipsychotic in the long-term treatment of both positive and negative symptoms. This study extends the findings of previous long-term studies, and has found that there is no significant difference with regard to ethnicity in response to aripiprazole.",1
11744,19157382,[Toxic hepatitis by consumption Herbalife products a case report],"Toxic hepatitis by consumption Herbalife products is an affection poorly documented and with a great impact in the population due to their massive consumption. We present the case of a 63-years-old woman with probable diagnosis of toxic hepatitis secondary to the consumption of nutritional supplements Herbalife. The nutritional supplements based on natural ingredients are of massive consumption worldwide. Because they are recognized like innocuous and of non-controlled comercialization, they lack suitable controls. Although there are reported cases of hepatotoxicity and other side effects induced by these products, there is still not strong evidence to generate a positive reaction of the control organisms. We report a case of acute toxic hepatitis potencially due to the consumption of Herbalife.",1
11745,19159178,[Recurrent acute liver toxicity from intravenous methylprednisolone],"""Adverse drug reactions (hepatotoxicity) are a frequent cause of acute liver injury with a wide clinical and histological spectrum. An early recognition of drug-related liver disease has been considered essential in clinical practice due to potential risks. In most cases exposure discontinuation improves the clinical picture.Steroids are used in a variety of clinical settings. However, intravenous steroids have rarely been associated with hepatotoxicity. We report the case of a middle-aged woman with multiple sclerosis who received a bolus of methylprednisolone on three occasions for the management of relapsing disease, with the development of repeated episodes of elevated liver enzymes after corticoid administration. In the third episode a liver biopsy was performed, which showed acute hepatitis with bridging necrosis; such histological picture has not been described before in patients treated with intravenous steroids.""",1
11746,19169683,A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer,"PURPOSE: To evaluate the response to lapatinib, an inhibitor of epidermal growth factor receptors 1 and 2, in patients with advanced bilary tree cancer (BTC) and hepatocellular cancer (HCC). METHODS: Lapatinib was dosed at 1,500 mg/day orally continuously. RESULTS: Fifty-seven patients were accrued (BTC 17, HCC 40). Therapy was well tolerated. The response in BTC was 0% and in HCC was 5%. The progression free survival (PFS) for BTC and HCC patients was 1.8 (95% CI: 1.7-5.2) months and 2.3 (95% CI: 1.7-5.6) months. The median survival for BTC and HCC patients was 5.2 (95% CI 3.3-infinity) months and 6.2 (95% CI: 5.1-infinity) months. EGFR genotyping indicated HCC patients with <20 repeats have the lowest PFS. The occurrence of any skin rash significantly prolonged PFS and survival. CONCLUSIONS: Lapatinib was well-tolerated. There was evidence of activity in HCC, but therapy with lapatinib did not meet the predefined efficacy rate.",1
11747,19171931,The liver toxicity biomarker study: phase I design and preliminary results,"Drug-induced liver injury (DILI) is the primary adverse event that results in withdrawal of drugs from the market and a frequent reason for the failure of drug candidates in development. The Liver Toxicity Biomarker Study (LTBS) is an innovative approach to investigate DILI because it compares molecular events produced in vivo by compound pairs that (a) are similar in structure and mechanism of action, (b) are associated with few or no signs of liver toxicity in preclinical studies, and (c) show marked differences in hepatotoxic potential. The LTBS is a collaborative preclinical research effort in molecular systems toxicology between the National Center for Toxicological Research and BG Medicine, Inc., and is supported by seven pharmaceutical companies and three technology providers. In phase I of the LTBS, entacapone and tolcapone were studied in rats to provide results and information that will form the foundation for the design and implementation of phase II. Molecular analysis of the rat liver and plasma samples combined with statistical analyses of the resulting datasets yielded marker analytes, illustrating the value of the broad-spectrum, molecular systems analysis approach to studying pharmacological or toxicological effects.",1
11748,19172239,Temsirolimus in patients with advanced renal cell carcinoma: an overview,"Treatment of patients with advanced renal cell carcinoma (RCC) has changed dramatically with the advent of targeted therapeutics. Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has proven beneficial in the treatment of advanced RCC with poor prognosis. The rationale for mTOR inhibitors in treatment of RCC, the pharmacokinetics and toxicities of temsirolimus, landmark clinical trials of temsirolimus in advanced RCC, and the indications for its use in the treatment of RCC are reviewed here. The status of temsirolimus in the rapidly evolving therapeutic landscape of advanced RCC is also discussed.",1
11749,19174081,[Constitutional syndrome associated to metformin induced hepatotoxicity],"Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.",1
11750,19174109,[Toxic hepatitis associated with the use of medroxyprogesterone],,1
11751,19174782,"How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial","""OBJECTIVES: Few data are available from prospective trials to define the hepatotoxicity of diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world. We determined the rate of laboratory and clinical adverse hepatic effects in a large double-blind trial of diclofenac. METHODS: Patients > or = 50 years with rheumatoid arthritis or osteoarthritis were randomly assigned to diclofenac (150 mg daily) or etoricoxib (60 or 90 mg daily). Patients with hepatic disease or who reported > or = 14 alcoholic drinks weekly were excluded. Patients had visits (with liver tests) every 4 months and were contacted by phone between visits and every 6 months after discontinuation until the end of the study. Causality assessment was performed for liver-related hospitalizations, Hy's cases (serious adverse events with AST or ALT >3 x upper limit of normal (ULN) and bilirubin >2 xULN), and liver failure/transplant/death. RESULTS: A total of 17,289 patients received diclofenac for a mean of 18 months. Liver end points with diclofenac were ALT/AST>3 xULN: 527(3.1%); ALT/AST >10 xULN: 86(0.5%); liver-related hospitalizations: 4(0.023%); Hy's cases: 2(0.012%); liver failure/death/transplant: 0. Aminotransferase elevations occurred primarily within the first 4-6 months of therapy, whereas liver-related hospitalizations occurred between 9 days and 21 months. CONCLUSIONS: Diclofenac is commonly associated with aminotransferase elevations, generally in the first 4-6 months of therapy. Clinical liver events requiring hospitalization are relatively rare (23/100,000 patients), but may develop early or late in therapy. The markedly increased rate of aminotransferase elevation with diclofenac may not be paralleled by a proportional marked increase in clinical liver events, although clinical events potentially also may be decreased with regular monitoring in a clinical trial setting.""",1
11752,19175782,Methotrexate treatment in 13 children with severe plaque psoriasis,"BACKGROUND: Severe plaque psoriasis in childhood has a significant morbidity and can warrant the use of systemic agents, although there are no published clinical trials in this group. OBJECTIVES: We report a series of 13 children with severe plaque psoriasis treated with low-dose once-weekly methotrexate. METHODS: We reviewed the notes of all 13 children treated with low-dose methotrexate at Birmingham Children's Hospital. RESULTS: Of the 13 patients reviewed, 11 responded with clearance of psoriasis, leaving small residual plaques. Five patients are currently maintained on methotrexate. Three patients needed two courses of methotrexate and one needed three courses, with treatment-free intervals of between 9 and 22 months. One patient stopped treatment due to rises in the results of liver function tests (LFTs) at 6 weeks, and one patient stopped the second course of methotrexate after two doses because of slightly raised baseline LFT results. There were no other adverse events. CONCLUSIONS: We propose that when carefully monitored, methotrexate can be a safe and efficacious treatment option for severe psoriasis in children as well as in adults. Obesity may be a relative contraindication, as associated nonalcoholic fatty liver disease is likely to increase hepatotoxicity.",1
11753,19179636,Posaconazole: a new oral antifungal agent with an expanded spectrum of activity,"PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, spectrum of activity and resistance, clinical utility, adverse effects, dosage and administration, and recommended monitoring of posaconazole are reviewed. SUMMARY: Posaconazole is a member of the azole class of antifungals recently approved for the prophylaxis and treatment of invasive fungal infections. Posaconazole has a large volume of distribution and distributes well into tissues. Posaconazole-induced fungal killing is optimal when peak drug concentrations achieved are 2-10 times the organism's minimum inhibitory concentration. Posaconazole demonstrates fungistatic activity against most species of Candida, Cryptococcus, and Trichosporon. In a direct comparison, posaconazole appeared 2-4 times more active than itraconazole against most pathogenic yeast species. Posaconazole also showed activity against Candida and Aspergillus isolates resistant to the other azoles and amphotericin B. Posaconazole has superior activity to the other azoles against Zygomycetes isolates. It has demonstrated activity equal or superior to other antifungal agents against almost all varieties of yeast and mold. The most common treatment-related adverse events associated with posaconazole are nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and abnormal liver function test values. Significant drug interactions include cimetidine, rifabutin, and phenytoin, for which concomitant use should be avoided, as well as cyclosporine, tacrolimus, and midazolam, for which dosage reductions are recommended. CONCLUSION: Posaconazole is an oral anti-fungal agent with a broader spectrum of activity and better clinical efficacy than other available antifungals. It is less nephrotoxic than the polyenes and probably less likely to be involved in drug-drug interactions than the mold-active azoles.",1
11754,19180340,"Adverse effects of tuberculosis treatment: experience at an outpatient clinic of a teaching hospital in the city of S?o Paulo, Brazil","OBJECTIVES: To determine the frequency of adverse effects related to the use of the tuberculosis treatment regimen designated Regimen I and the need for regimen alterations due to these effects. METHODS: A retrospective analysis of 329 medical charts of patients who were treated with Regimen I and discharged after cure between March 2000 and April 2006 was carried out at the Tuberculosis Outpatient Clinic, Department of Pulmonology of the Santa Casa de Miseric?rdia de S?o Paulo Hospital in the city of S?o Paulo, Brazil. Adverse effects and the timing of their appearance, as well as subsequent modifications in the treatment regimen, were investigated. RESULTS: We included 297 patients, 146 (49.1%) of whom presented one or more adverse effects related to antituberculosis medications. The frequency of minor side effects was 41.1%, and that of major side effects was 12.8%. The most common reactions were those involving the gastrointestinal tract (40.3%) and the skin (22.1%). Adverse effects were more common in the first and second months of treatment (58.4%). Modification of the treatment regimen was necessary in 11 cases (3.7% of the total sample). Drug-induced hepatitis was the adverse effect that demanded the most regimen changes. CONCLUSIONS: In this group of patients, the frequency of adverse effects related to treatment with Regimen I was 49.1%. However, in most of the cases, it was not necessary to modify the treatment regimen due to side effects.",1
11755,19183142,Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease,"""BACKGROUND: Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance. AIM: To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance. METHODS: We identified 135 patients (74 women; median age 40 years) with Crohn's disease (n = 88) or ulcerative colitis (n = 47) and reviewed their medical records. RESULTS: A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362-1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8-92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4-15.3) vs. 11.8 (9.6-14.2) U/mL red blood cells; P = 0.04; n = 81]. CONCLUSIONS: A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.""",1
11756,19183227,Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial,"PURPOSE: To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. METHODS: This multicenter, double-blind, placebo-controlled trial randomized patients (age 16-70 years) with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period. RESULTS: Four hundred eighty-five patients were randomized and received trial medication. Among these, 87% were taking two or more concomitant AEDs. Median percent reduction in seizure frequency per 28 days from baseline to maintenance period (intent-to-treat, ITT) was 20.5% for placebo, 35.3% for lacosamide 200 mg/day (p = 0.02), and 36.4% for 400 mg/day (p = 0.03). In the per protocol population, the reductions were 35.3% for lacosamide 200 mg/day (p = 0.04) and 44.9% for 400 mg/day (p = 0.01) compared to placebo (25.4%). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant (p = 0.01) over placebo (25.8%), but was not for 200 mg/day (35.0%). In the per protocol population, the 50% responder rate for lacosamide 400 mg/day (46.3%) was significant (p < 0.01) compared with the placebo responder rate (27.5%). Dose-related adverse events (AEs) included dizziness, nausea, and vomiting. Clinically relevant changes in the mean plasma concentrations of commonly used AEDs were not observed. DISCUSSION: Results of this trial demonstrated the efficacy and tolerability of adjunctive lacosamide 200 and 400 mg/day and support that lacosamide may be an advantageous option for the treatment of partial-onset seizures in patients with epilepsy.",1
11757,19186568,Donepezil-related toxic hepatitis,"Alzheimer's disease (AD) is the leading cause of dementia. It is characterized by the presence of senile plaques and neurofibrillary tangles in the brain, and impairment of the central cholinergic system, which contribute to memory loss and cognitive dysfunction. Cholinesterase inhibitors prevent the hydrolysis of acetylcholine and are currently approved for the symptomatic treatment of Alzheimer's disease. Donepezil, a piperidine-based, reversible and specific inhibitor of acetylcholinesterase, has been demonstrated to be clinically effective in the treatment of patients with mild to moderate AD. To date, clinical trials have not reported an association between treatment with donepezil and hepatotoxicity. We describe a case of toxic hepatitis, documented by liver biopsy, in a patient treated with donepezil.",1
11758,19192130,Toxic hepatitis after consumption of traditional kava preparation,"Liver toxicity from the use of kava dietary supplements has been reported, but little is known about the side effects of traditional kava preparations. We present a case study of a tourist who developed serious toxic liver disease after consumption of kava beverages in traditional Samoan kava ceremonies.",1
11759,19194314,Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir,"BACKGROUND: Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P4503A by rifampin markedly lowers HIV protease inhibitor plasma concentrations. METHODS: This phase 1, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included 3 sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours. RESULTS: Upon adding atazanavir and ritonavir, the first 3 subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated. CONCLUSIONS: Coadministration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies, which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.",1
11760,19195818,[Acute liver failure due to a treatment by nimesulide],,1
11761,19197097,Dilated common bile ducts mimicking choledochal cysts in ketamine abusers,"Substance abuse is a major health and social problem among Hong Kong youth and ketamine is the drug most commonly abused. Ketamine abuse is associated with a series of side-effects that include hallucination, nausea, vomiting, elevation of blood pressure, and urinary bladder dysfunction. Here we report three cases of ketamine abuse in which the abusers presented with recurrent epigastric pain and dilated common bile ducts that mimicked choledochal cysts on imaging. The dilated biliary tree may occur more frequently than was once assumed.",1
11762,19198578,Severe acute cholestatic hepatitis with prolonged cholestasis and bile-duct injury following atorvastatin therapy: a case report,"We report the case of a patient who exhibited severe acute hepatitis with symptomatic cholestasis for more than 3 months and bile duct injury following the prescription of atorvastatin. After withdrawal the drug, the patient's wellbeing slowly improves and biological features normalize in 4 months. Therapy aimed at treating severe liver steatosis and hypercholesterolemia. Atorvastatin is a highly effective 3-hydroxy-3 methylglutamyl- coenzyme A reductase (statin) used to lower low-density lipoprotein. Reported frequent adverse events of the medication include nausea, depression, myalgia, abdominal pain and abnormal liver function tests. Although abnormal liver function tests is not an uncommon side effect of the medication, more serious liver injury is rare. In a recent literature review, about ten cases of serious hepatotoxicity have been documented. In the typical presentation, the duration of exposure prior to hepatic toxicity is variable. Liver injury is generally of the mixed type. A prolonged cholestasis for more than 3 months has been seldom reported. Morphological changes includes canalicular cholestasis, feathery degeneration but no cholangiolitis nor cholangitis under the form of cytological and inflammatory changes at the level of interlobular bile ducts. This case report provides further evidence that among statins, atorvastatin may be implicated in drug-induced liver injury and indicates for the first time that such liver injury may be followed by prolonged cholestasis and interlobular bile duct injury. Atorvastatin has thus to be added to the list of medication potentially responsible for bile duct injury.",1
11763,19200687,Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases,"AIM: In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited. METHODS: Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone. CONCLUSIONS: This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.",1
11764,19203894,An open-label clinical trial evaluating safety and pharmacokinetics of two dosing schedules of panitumumab in patients with solid tumors,"""PURPOSE: This study evaluated safety, pharmacokinetics, and efficacy of 2 dose schedules and 2 infusion times of panitumumab in patients with advanced solid malignancies. PATIENTS AND METHODS: This phase I multicenter, open-label study sequentially enrolled patients with advanced solid tumors refractory to standard therapy, or for which no standard therapy exists, to receive panitumumab 6 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. Patients receiving panitumumab every 2 weeks received either all infusions over 60 minutes or a 60-minute infusion for the first dose followed by 30-minute infusions if the first infusion was well tolerated. Patients in the every-3-week cohort received 60-minute infusions. Safety outcomes included the incidence of adverse events and antipanitumumab antibody formation. Pharmacokinetic properties were determined. Efficacy endpoints included response rate and duration of response. RESULTS: Eighty-six patients were enrolled; 84 (98%) received panitumumab. Treatment-related adverse events occurred in 90% of patients. Safety profiles were similar between patients receiving 30-minute (n = 20) and 60-minute (n = 43) infusions every 2 weeks and patients receiving panitumumab every 3 weeks (n = 21). Panitumumab exposure at steady state increased dose proportionally, and peak serum concentrations were similar in patients receiving either 30- or 60-minute infusions every 2 weeks. Objective responses were seen in 4 patients (5%) with colon, rectal, esophageal, and bladder cancers. CONCLUSION: Similar drug exposures and safety profiles were observed in patients receiving panitumumab 6 mg/kg every 2 weeks with either 30- or 60-minute infusions and antitumor activity was seen in some patients. Exposure increased approximately dose proportionally at steady state.""",1
11765,19203910,Upper gastrointestinal bleeding may unmask didanosine-associated portal hepatopathy in HIV/HCV co-infected patients,Three HIV individuals with chronic hepatitis C presented with esophageal variceal bleeding. They had mild liver fibrosis and normal liver function tests. All had received didanosine for long periods. Noncirrhotic portal hypertension associated with didanosine may appear in HIV patients without any liver disease or added to chronic hepatitis C.,1
11766,19208320,Alpha-methyldopa hepatotoxicity in pregnancy,"A 12-week pregnant, 33-year-old African American female, presented with jaundice and change in urine colour. Liver function tests revealed raised transamines and normal alkaline phosphatase. She was started on methyldopa 6 weeks prior to presentation. After initial negative investigations including viral and autoimmune hepatitis, she was given prednisone for methyldopa induced hepatitis. Two weeks later, repeat enzymes revealed normal values. Important clinical and management points related to methyldopa induced hepatotoxicity are discussed.",1
11767,19209117,Reversible acute hepatitis induced by rosuvastatin,,1
11768,19214031,"Acute kidney injury, hepatitis, and CPK elevation associated with nitrofurantoin therapy",,1
11769,19221540,Dress syndrome and fulminant hepatic failure induced by lamotrigine,"Lamotrigine is a non-aromatic antiepileptic drug. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe idiosyncratic reaction to drugs, especially anti-epileptic drugs. Associated clinical features include cutaneous eruption, fever, multiple peripheral lymphadenopathies, and potentially life-threatening damage of one or more organs. We report a case of DRESS syndrome induced by lamotrigine presenting with a hypersensitivity syndrome and fulminant hepatic failure requiring liver transplant. A 21-year old female patient presented an episode of seizure with loss of conscience. CT and EEG studies performed were normal. Treatment with lamotrigine was prescribed. In the course of 30 days, the patient developed skin lesions, pruritus, cholestatic hepatitis, and systemic symptoms -fever, lymphadenopathies, extensive exfoliative erythematous maculopapular rash, and jaundice. Serologic and laboratory tests showed no other causes responsible for the clinical spectrum. Hematologic tests revealed peripheral eosinophilia. Fulminant hepatic failure was diagnosed and an orthotopic liver transplant was performed. Histologic sections of the explanted liver demonstrated submassive hepatic necrosis, with the remnant portal spaces and lobules showing a mixed inflammatory infiltrate with lymphocytes and eosinophils. Lamotrigine treatment has been associated with multiorgan failure, DRESS syndrome, acute hepatic failure, and disseminated intravascular coagulation. In conclusion, we suggest that these potentially fatal side effects should be considered in any patient with clinical deterioration following administration of this drug.",1
11770,19223285,Anti-TNF-alpha therapy for rheumatoid arthritis among patients with chronic hepatitis B infection,,1
11771,19224957,Life threatening liver disease during treatment with monoclonal antibodies,,1
11772,19230981,"The efficacy, safety, and tolerability of aripiprazole for the treatment of schizoaffective disorder: results from a pooled analysis of a sub-population of subjects from two randomized, double-blind, placebo-controlled, pivotal trials","""BACKGROUND: Schizoaffective disorder shares clinical characteristics with schizophrenia and affective disorders, with patients experiencing concurrent manic, mixed, or depressive episodes during psychosis. Because efficacy may be better in schizoaffective disorder than schizophrenia, this post-hoc analysis examines the efficacy, safety, and tolerability of aripiprazole in patients with schizoaffective disorder. METHOD: Data were obtained from a sub-sample of subjects with schizoaffective disorder (randomized: aripiprazole n=123, placebo n=56) who participated in two 4-week, multicenter, double-blind trials of subjects with schizophrenia or schizoaffective disorder. Aripiprazole was administered at fixed doses of 15 mg/day, 20 mg/day, or 30 mg/day. Efficacy assessments included the Positive and Negative Syndrome Scale (PANSS) Total score, and the Positive, Negative, and General Psychopathology subscale scores. Safety and tolerability evaluations included incidence of treatment-emergent adverse events and extrapyramidal symptom assessments (SAS, BARS, and AIMS), and metabolic profile changes including weight and BMI. RESULTS: A significantly greater improvement from baseline to endpoint was observed with aripiprazole compared with placebo on the PANSS Total (-15.9 vs. -3.4; p=0.038) and PANSS Positive subscale (-4.6 vs. -1.0; p=0.027). Differences between treatments were not significant for the PANSS Negative subscale score (-3.7 vs. -1.2; p=0.15) or PANSS General Psychopathology subscale score (-8.3 vs. -3.1; p=0.06). There were no statistically significant differences at endpoint between groups in the mean change from baseline to endpoint in weight, glucose, or total cholesterol, or on SAS, BARS, or AIMS scores. There was a statistically significant decrease in prolactin in subjects treated with aripiprazole compared with placebo (-5.6 vs. -1.3, p<0.001). CONCLUSION: Aripiprazole was efficacious and well tolerated in patients with schizoaffective disorder.""",1
11773,19238093,Prolonged intrahepatic cholestasis and renal failure secondary to anabolic androgenic steroid-enriched dietary supplements,"The illegal enrichment of anabolic androgenic steroids in over-the-counter dietary supplements is well documented, but the health consequences have not been widely recognized. Three recent reports document cholestatic jaundice and nephropathy due to these compounds. We present 3 additional cases of anabolic androgenic steroid-enriched dietary supplement-induced hepatotoxicity and 1 case of renal failure, and we review the literature and the relevant features of this growing health concern. Recognition of this entity could obviate the need for invasive diagnostic testing and hospitalization and facilitate diagnosis and appropriate counseling.",1
11774,19239041,Valproic acid related idiosyncratic drug induced hepatotoxicity in a glioblastoma patient treated with temozolomide,"Glioblastoma patients undergoing treatment with surgery followed by radiation and temozolomide chemotherapy often develop a state of immunosuppression and are at risk for opportunistic infections and reactivation of hepatitis and herpes viruses. We report the case of a 48-year-old glioblastoma patient who developed acute cholestatic hepatitis with hepatic failure during adjuvant treatment with temozolomide and the integrin inhibitor cilengitide. A viral hepatitis was excluded and valproic acid treatment was stopped. Upon normalisation of the liver tests, temozolomide treatment was resumed without perturbation of the liver tests. Valproic acid related idiosyncratic drug induced hepatotoxicity should be considered as a differential diagnosis in glioblastoma patients undergoing adjuvant therapy.",1
11775,19247029,"Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases","OBJECTIVE/BACKGROUND: The GONO-FOLFOXIRI regimen improved the rate of R0 secondary resection of metastases in initially unresectable metastatic colorectal cancer. The objective of this study was to evaluate the long-term outcome of resected patients and the impact of FOLFOXIRI on perioperative morbidities, mortality, and chemotherapy induced hepatotoxicity. PATIENTS AND METHODS: Overall, 196 patients with initially unresectable metastatic colorectal cancer were treated with FOLFOXIRI in 2 phase II and 1 phase III trial. This regimen was associated with an elevated response rate (70.4%) and 37 patients (19%) could undergo a secondary R0 surgery on metastases. This study was registered with the Australian New Zealand Clinical Trials Registry Database at http://www.anzctr.org.au/Statistics.aspx and has ID number ACTRN12608000615381. RESULTS: Main characteristics of the 37 radically resected patients were: median age 64 years (45-73), Eastern Cooperative Oncology Group Performance Status (ECOG) PS > or = 1 in 30%, synchronous metastases in 65%, multiple sites of disease in 22%, and metastases confined to the liver in 68%. Preoperative FOLFOXIRI was administered for a median of 5.5 months. There was no perioperative mortality and all morbidities (27% of patients) resolved without sequelae. After a median follow up of 67 months, 5-year and 8-year survival are 42% and 33% respectively. At 5 years, 29% of patients are free of disease. The analysis of treatment-induced liver injury showed neither G3 vascular toxicity nor G4 steatosis, and steato-hepatitis in only 5% of patients. CONCLUSIONS: The GONO-FOLFOXIRI regimen allow an R0 surgery in approximately 1 out of 5 unselected patients with initially unresectable metastatic colorectal cancer, and the long-term survival of resected patients is considerable. Neoadjuvant FOLFOXIRI for 3-6 months is safe and not associated with severe liver injury.",1
11776,19247302,Febuxostat,,1
11777,19249634,"Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial","""BACKGROUND: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. METHODS: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. FINDINGS: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. INTERPRETATION: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.""",1
11778,19255017,"A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients","""OBJECTIVE: We evaluated the safety, tolerability, and efficacy of caspofungin in pediatric patients with invasive aspergillosis, invasive candidiasis, or esophageal candidiasis. METHODS: This was a multicenter, prospective, open-label study in children 3 months to 17 years of age with proven or probable invasive aspergillosis, proven invasive candidiasis, or proven esophageal candidiasis. All of the patients received caspofungin 70 mg/m(2) on day 1, followed by 50 mg/m(2) per day (maximum: 70 mg/day), as primary or salvage monotherapy. Favorable response was defined as complete resolution of clinical findings and microbiologic (or radiographic/endoscopic) eradication (complete response) or significant improvement in these parameters (partial response). Efficacy was assessed at the end of caspofungin therapy in patients with a confirmed diagnosis who received >/=1 dose of caspofungin. The primary safety evaluation was the proportion of patients with clinical or laboratory drug-related adverse events. RESULTS: Of the 49 patients enrolled, 3 were <2 years of age, 30 were 2 to 11 years of age, and 16 were 12 to 17 years of age. Forty-eight patients had confirmed disease: invasive aspergillosis (10), invasive candidiasis (37), and esophageal candidiasis (1). Eight of 10 patients with invasive aspergillosis had pulmonary involvement; 34 of 37 patients with invasive candidiasis had candidemia. Caspofungin was given for 2 to 87 days. Success at end of therapy was achieved in 5 of 10 patients with invasive aspergillosis, 30 of 37 with invasive candidiasis, and 1 of 1 with esophageal candidiasis. One patient (invasive candidiasis) relapsed during the 28-day follow-up period. Drug-related clinical or laboratory adverse events occurred in 27% and 35% of patients, respectively. There were no serious drug-related adverse events or discontinuations of caspofungin because of toxicity. CONCLUSIONS: Caspofungin was generally well tolerated in pediatric patients aged 6 months through 17 years. Efficacy outcomes in patients with invasive aspergillosis or invasive candidiasis were consistent with previous adult studies in these indications.""",1
11779,19258191,Acute and long-term gastrointestinal consequences of chemotherapy,"There are many anti-neoplastic agents in cancer treatment. Combination regimens are often the main standard treatment, particularly for gastrointestinal malignancies. The introduction of new regimens that combine fluoropyrimidines with irinotecan or oxaliplatin and recently also with antibodies against the Epidermal Growth Factor Receptor (EGFR) (cetuximab and panitumumab) and against the Vascular Endothelial Growth Factor (VEGF) (bevacizumab) pathways, has dramatically improved the progression free survival and survival of patients with metastatic colorectal cancer. This rapid extension of available anti-neoplastic drugs has, however, also highlighted the urgent need for clinicians to better understand and identify the spectrum of acute and late toxicities of these drugs. Acute and long-term adverse effects are inherent to non-surgical cancer treatment using chemotherapy and/or radiation therapy, which can profoundly affect the gastrointestinal tract leading to a wide spectrum of acute and late toxicities. An improved knowledge of the aetiology, incidence, supportive measures and of the prevention of these toxicities is warranted to improve patient care. We herein review and discuss the main acute and late gastrointestinal toxicities of chemotherapy and/or radiotherapy for patients with gastrointestinal malignancies.",1
11780,19261446,Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes,"""Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n=10; non-wild-type, n=19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration > or = 3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild-type and 4.4-6.5mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses.""",1
11781,19262358,Cyclophosphamide therapy in granulomatous hepatitis: cure or culprit?,"Three months after diagnosis of Wegener granulomatosis, an 84-year-old woman who was treated with cyclophosphamide (CPY) and prednisone developed deranged liver function tests (LFTs). Treatment with CPY was held, which led to normalization of LFTs, but after reinitiating of CPY, LFTs started increasing. Liver biopsy showed noncaseating epithelioid granulomas within liver lobules consistent with granulomatous hepatitis. Patient died within 2 months secondary to liver failure. This elevation of transaminases was considered to be secondary to CPY-induced hepatotoxicity. Involvement of liver in patients with Wegener granulomatosis is seen but it presents with necrotizing granulomatous vasculitis. CPY-induced hepatitis is an extremely rare phenomenon with only 1 case reported in literature. Clinicians and hepatologists should be aware of this potentially serious complication when CPY therapy is initiated. Baseline LFTs and periodic assessment are recommended before and during treatment with CPY.",1
11782,19262406,Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis,"Over the years, a variety of abnormal immune reactions to minocycline have been reported including arthritis, systemic lupus erythematosus, and hepatitis. The current report describes the detailed clinical and pathologic features of 3 patients who presented with chronic/autoimmune hepatitis alone while on minocycline at our hospital over a 2-year period. Minocycline use in these patients was temporally related to onset of severe hepatitis. Adolescents with such a reaction to minocycline have been included in previous reports but have not been well described as a distinct entity. We have compared our cases with similar cases previously reported with a review of the literature and a discussion of the implications for prescribing physicians.",1
11783,19264768,Multi-center phase II trial of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric and gastro-esophageal cancer,"OBJECTIVE: This study is performed to evaluate the response rate, time to progression and safety of the combination chemotherapy with weekly paclitaxel plus cisplatin in advanced gastric and gastro-esophageal cancer. METHODS: The paclitaxel 100 mg/m(2) was administered through a 1 h intravenous infusion on Days 1 and 8. The cisplatin 30 mg/m(2) was also administered along with a program of forced diuresis that included at least 2000 ml of fluids after the paclitaxel infusion over 30 min on Days 1 and 8. The chemotherapy was given every 21 days and continued until disease progression, patient refusal or an unacceptable toxicity up to nine cycles. RESULTS: Forty-seven (95.9%) of the 49 patients were assessable for response. Two cases of complete response and 19 cases of partial response were confirmed, giving an overall response rate of 42.9% (95% CI, 29.0-56.8%). The median time to progression and overall survival for all patients were 5.9 months (95% CI, 1.6-9.1 months) and 11.2 months (95% CI, 6.1-21.3 months). The most severe hematologic adverse event was neutropenia, which occurred with a Grade 3 intensity in 17.0% and Grade 4 in 4.3%. Grade 3 vomiting, peripheral neuropathy and elevated transaminase were observed in 4.3%, 4.3% and 2.1% of patients. CONCLUSIONS: Combination of weekly paclitaxel plus cisplatin is an active regimen with excellent tolerability as a first-line treatment of advanced gastric and gastro-esophageal cancer.",1
11784,19265776,Alemtuzumab (Compath) off-label for relapsing multiple sclerosis,,1
11785,19269791,Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study,"This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.",1
11786,19274931,Nine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors,"Although rare, anaphylactic reactions induced by proton pump inhibitors have been reported. The presence of cross-reactivity between different members of the group is not clear. We studied 9 patients with adverse reactions to omeprazole. Clinical symptoms appeared immediately in 8 patients and after 4 hours in 1. Symptoms ranged from urticaria/angioedema in 7 cases to anaphylaxis in 2 cases. Skin prick tests and oral controlled challenge tests with omeprazole, lansoprazole, and pantoprazole were performed. Skin prick or intradermal tests with omeprazole were positive in 8 patients. Four were also positive to pantoprazole. Prick tests with lansoprazole were always negative. Lansoprazole was administered to all 9 patients, with good tolerance in 8. Only 3 patients were challenged with pantoprazole and developed widespread urticaria. We present 9 patients with immunoglobulin E-mediated allergy to omeprazole. In most of our cases, lansoprazole proved to be a good alternative treatment.",1
11787,19278034,Liver failure associated with the use of black cohosh for menopausal symptoms,,1
11788,19285625,A pediatric case study of treprostinil overdose,"This case study reports the effects of a treprostinil accidental overdose in a patient with pulmonary hypertension. Treprostinil is labeled for treatment of pulmonary hypertension with New York Heart Association (NYHA) Class II, III and IV symptoms. It is characterized as a long-acting prostacyclin analog that can be delivered by intravenous or subcutaneous continuous infusions. This pediatric case report describes a massive overdose without significant side effects, thus suggesting a beneficial therapeutic index in pediatric patients.",1
11789,19286847,Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout,"OBJECTIVE: To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout. METHODS: Subjects (n=1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and <6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance. RESULTS: After 1 month initial treatment, >80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA<6.0 mg/dl. After ULT reassignment, >80% of all remaining subjects maintained the primary efficacy endpoint of SUA<6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA<6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA<6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups. CONCLUSION: Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time. Registered as NCT00175019.",1
11790,19291301,The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum,"BACKGROUND: Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested. METHODS: A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety. RESULTS: Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients. CONCLUSION: Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07576538.",1
11791,19292023,Hepatotoxicity in an infant following supratherapeutic dosing of acetaminophen for twenty-four hours,"Severe hepatotoxicity in acute acetaminophen overdose in children is uncommon. This apparent protection does not extend to chronic or repeated high dose acetaminophen administration. The Illinois Poison Center (IPC) was consulted on a case involving a 7 month old 17 lb infant, who had presented the day prior to an emergency department with complaint of febrile illness. Patient had been prescribed acetaminophen for symptoms, and the mother called IPC when she realized that she had been incorrectly giving the patient concentrated infant acetaminophen (80 mg per 0.8 mL) totalling 42.3 mg/kg/dose or 234 mg/kg/24 hours instead of children's acetaminophen (160 mg/5 ml). Per recently published national triage guidelines, the patient was referred to an acute care facility for evaluation. The patient presented with significantly elevated aspartate aminotransferrase (AST) and alanine aminotransferrase (ALT) levels of 1339 and 907 U/L respectively, and was initiated on i.v. n-acetylcysteine therapy. The patient responded well to therapy, with AST and ALT declining to 145 and 479 U/L respectively over the next 48 hours. This case represents one of the shortest durations of chronic acetaminophen therapy to cause hepatic injury in an infant. Further, while the level was only slightly above the national triage guideline recommended referral dose per 24 hours, significant hepatotoxicity was observed.",1
11792,19296759,Efficacy and safety of olmesartan medoxomil alone and in combination with hydrochlorothiazide,"In at least 50% of patients with hypertension, particularly those with stage 2 hypertension, combination drug therapy is required to achieve the currently recommended blood pressure (BP) goals. It is likely that future hypertension guidelines will recommend lowering BP beyond the currently recommended systolic/diastolic BP goals of lower than 140/90 mmHg for all patients with hypertension and lower than 130/80 mmHg for patients with diabetes or chronic kidney disease. In a series of clinical trials, the combination of olmesartan medoxomil, a well-established angiotensin receptor blocker, and hydrochlorothiazide, a thiazide diuretic, has produced greater reductions in systolic BP and diastolic BP and greater proportions of patients achieving BP goals than monotherapy with either component. Additionally, the increased efficacy resulting from the combination with hydrochlorothiazide does not appear to significantly affect the tolerability profile of olmesartan medoxomil. This article provides a comprehensive evaluation of the chemistry, clinical efficacy, safety and tolerability of this combination and discusses its role in the management of hypertension.",1
11793,19299495,Costs and cost-effectiveness of four treatment regimens for latent tuberculosis infection,"RATIONALE: Isoniazid given daily for 9 months is the standard treatment for latent tuberculosis infection (LTBI), but its effectiveness is limited by poor completion rates. Shorter course regimens and regimens using directly observed therapy result in improved adherence but have higher upfront costs. OBJECTIVES: To evaluate the costs and cost-effectiveness of regimens for the treatment of LTBI. METHODS: We used a computerized Markov model to estimate total societal costs and benefits associated with four regimens for the treatment of LTBI: self-administered isoniazid daily for 9 months, directly observed isoniazid twice-weekly for 9 months, directly observed isoniazid plus rifapentine once weekly for 3 months, and self-administered rifampin daily for 4 months. In the base-case analysis, subjects were assumed to have newly positive tuberculin skin tests after recent exposure to infectious tuberculosis. MEASUREMENTS AND MAIN RESULTS: We determined the costs of treatment, quality-adjusted life-years gained, and cases of active tuberculosis prevented. In the base-case analysis, rifampin dominated (less costly with increased benefits) all other regimens except isoniazid plus rifapentine, which was more effective at a cost $48,997 per quality-adjusted life year gained. Isoniazid plus rifapentine dominated all regimens at a relative risk of disease 5.2 times the baseline estimate, or with completion rates less than 34% for isoniazid or 37% for rifampin. Rifampin could be 17% less efficacious than self-administered isoniazid and still be cost-saving compared with this regimen. CONCLUSIONS: In our model, rifampin is cost-saving compared with the standard therapy of self-administered isoniazid. Isoniazid plus rifapentine is cost-saving for extremely high-risk patients and is cost-effective for lower-risk patients.",1
11794,19302249,Safety and tolerability of omalizumab,"BACKGROUND: Omalizumab (Xolair) is a recombinant humanized monoclonal anti-IgE antibody with proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. OBJECTIVE: To review clinical study data to assess the safety profile of omalizumab. METHODS: We analysed the safety of omalizumab using data from completed clinical studies (up to 1 year) involving more than 7500 patients with asthma, rhinitis or related conditions and up to 4 years in one study of patients with severe allergic asthma, as well as post-marketing safety data. Analysis focuses on the risk of immune-system effects, hypersensitivity reactions, malignant neoplasia, parasitic infections and thrombocytopenia. RESULTS: Omalizumab exhibited a good safety and tolerability profile that was maintained up to 4 years in one study. The incidence of anaphylaxis was 0.14% in omalizumab-treated patients and 0.07% in control patients. No omalizumab-treated patient developed measurable anti-omalizumab antibodies. Post-marketing, based on estimated exposure of 57,300 patients (June 2003-December 2006), the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients. Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab. CONCLUSION: Data indicate that the proven efficacy of add-on omalizumab in patients with moderate-to-severe or severe allergic asthma is accompanied by a favourable safety and tolerability profile.",1
11795,19303984,Risk factors for chemotherapy-associated liver injuries: A multivariate analysis of a group of 146 patients with colorectal metastases,"BACKGROUND: Chemotherapy for colorectal liver metastases (CLM) may be associated with pathologic changes to the liver parenchyma, possibly increasing the risk of surgery. The aim of this study was to determine the risk factors for chemotherapy-associated liver injuries (CALI). METHODS: From 1998 to 2006, 146 patients underwent a liver resection for CLM within 3 months of preoperative chemotherapy. CALI were defined as follows: steatosis > or =30%, or steatohepatitis, or moderate or severe sinusoidal lesions. Univariate and multivariate analysis were used to examine the relationship between CALI and 36 other preoperative factors. RESULTS: Pathologic examination showed CALI in 74/146 patients (51%), including sinusoidal lesions (n = 50), steatosis > or = 30% (n = 32), and steatohepatitis (n = 15). Twenty-three patients had overlapping CALI. In multivariate analysis, BMI > 27 (P = .002), hyperglycemia > 7 mmol/l (P = .006), and an interval between chemotherapy and surgery < 4 weeks (P = .011) were independent risk factors for CALI, whereas aspirin intake was associated with reduced risk of CALI (P = .002). In multivariate analysis, synchronous metastases (P = .015), unresectable liver metastases at diagnosis (P = .034), GGT plasma level > 1.5N (P = .028), and oxaliplatin-based chemotherapy (P < .01) were risk factors for sinusoidal lesions. Aspirin intake was associated with reduced risk for sinusoidal lesions (P = .03). In multivariate analysis, BMI > 27 (P = .026) was the only risk factor for steatosis or steatohepatitis. CONCLUSION: In patients with CLM, there are few preoperative risk factors for CALI. In patients treated by oxaliplatin-based chemotherapy, aspirin intake appears to be associated with a reduced risk of sinusoidal lesions and should be tested in a randomized phase II study.",1
11796,19312340,The Treatment of Rheumatoid Arthritis Including Gold Salts Therapy,,1
11797,19318348,Extensively drug-resistant tuberculosis in the UK: 1995 to 2007,"BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDRTB) and extensively drug-resistant tuberculosis (XDRTB) is a threat to global tuberculosis control. Limited information is, however, available on the outcome of XDRTB cases. This study describes the susceptibility to second- and third-line antituberculosis drugs among MDRTB cases and treatment outcome of identified XDRTB cases. METHOD: The results of second-line antituberculosis drug susceptibility tests in the UK between January 1995 and December 2007 were retrospectively reviewed and clinicians contacted for treatment outcome of XDRTB cases. Participants included all 678 patients with culture-confirmed MDRTB in the UK. The main outcome measures were the proportion of isolates resistant to second-line antituberculosis drugs and treatment outcome for XDRTB cases. RESULTS: Among MDRTB isolates, levels of resistance to amikacin, capreomycin, ciprofloxacin, cycloserine, ethionamide and p-aminosalicylic acid (PAS) were 5.5, 3.4, 5.6, 5.1, 14.0 and 16.7%, respectively. Six XDRTB cases (0.9% of MDR cases) were identified during this period. Two further cases of XDRTB were reported in 2008. Five individuals with XDRTB died of tuberculosis within 3 years of diagnosis and three are still on treatment. CONCLUSION: Levels of MDRTB remain low, and those of XDRTB very low, in this high income country. The case fatality ratio among XDRTB cases was high despite low levels of HIV co-infection.",1
11798,19323621,Fatal toxic epidermal necrolysis associated with minoxidil,"""Minoxidil is a direct-acting peripheral vasodilator for the treatment of symptomatic hypertension, or refractory hypertension associated with target organ damage, that is not manageable with a diuretic and two other antihypertensive drugs. The most frequent adverse events associated with minoxidil include hypertrichosis and cardiovascular events related to its powerful antihypertensive effect, and less frequently, rashes, bullous eruptions, and Stevens-Johnson syndrome (SJS). Evidence suggests that SJS and toxic epidermal necrolysis (TEN) are variants of a single disease with common causes and mechanisms, but differing severities. Epidermal detachment is mild in SJS, moderate in overlap SJS-TEN, and severe (> 30% of body surface area) in TEN. We describe a case of minoxidil-associated SJS that evolved into fatal TEN. A 69-year-old African-American woman with a history of chronic kidney disease was admitted to the hospital for a cerebrovascular accident and uncontrolled hypertension. On hospital day 12, oral minoxidil was added to her drug regimen. On day 23, she developed a maculopapular rash on her face that gradually diffused to her chest and back. Vesicles and papular lesions extended to her extremities and mucosal membranes; results of a skin biopsy revealed SJS. A positive Nikolsky's sign (blisters spread on application of pressure) was detected. On days 27-31, diffuse bullae developed with rash exacerbation. Skin detachment exceeded 30% and was consistent with TEN. The patient died on day 39. An evaluation of the causality and time course suggested that minoxidil was the most likely culpable drug, with a Naranjo adverse drug reaction probability scale score indicating that the likelihood of the association was possible (score of 3). The mechanism of this reaction has not been well elucidated. It may be related to an impaired clearance of the minoxidil metabolite, or an immune stimulation resulting in apoptosis and epidermis destruction. To our knowledge, this is the first case report of fatal TEN associated with minoxidil. This case report emphasizes the importance of monitoring for serious dermatologic reactions in patients receiving minoxidil therapy.""",1
11799,19325134,Adverse effects with use of nicotine replacement therapy among quitline clients,"INTRODUCTION: Nicotine replacement therapy (NRT) increases quit rates and is increasingly distributed through quitlines, but no systematic data are available on adverse effects and safety among quitline NRT users. METHODS: Smokers who contacted the New York State Smokers' Quitline and were sent free NRT were followed by phone at 2 weeks (n = 33,690), and a randomly selected subsample was followed at 3 months (n = 1,187). All were asked about their use of NRT and adverse effects. Prevalence and perceived severity (rated mild, moderate, or severe) of selected adverse side effects were assessed. Subjects also were asked about their smoking behavior while using NRT and reasons for discontinuation of NRT. RESULTS: Among those who reported having used NRT at the 2-week contact, about one in four reported an adverse effect. This rate increased to about 42% among those surveyed at 3 months. The prevalence and specific types of adverse effects reported were consistent with findings from clinical trials of NRT and varied in relationship to the type of NRT used (patch, gum, lozenge). The majority of adverse effects reported were rated as mild, and only 4.4%-5.4% of subjects (across the 2-week and 3-month follow-ups) reported discontinuation of NRT as a result of adverse effects. DISCUSSION: The prevalence and types of adverse effects observed among smokers receiving NRT were as expected with product labeling and support the conclusion that the distribution of over-the-counter NRT through quitlines is safe as long as clients are screened adequately per the labeling instructions.",1
11800,19330871,"Hepatitis C, alcohol abuse, and unintentional overdoses are risk factors for acetaminophen-related hepatotoxicity",,1
11801,19336648,Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine,"OBJECTIVE: To report the occurrence of fatal acute liver failure following addition of levothyroxine to a regimen of sunitinib and acetaminophen. CASE SUMMARY: A 57-year-old woman who started sunitinib treatment for relapsed metastatic gastrointestinal stromal tumor after imatinib failure had disease stabilization and normal liver function through 8 cycles of sunitinib 50 mg/day for 4 weeks, followed by 2 weeks off treatment. Her continuing medications included acetaminophen approximately 4.5 g/wk, as well as standard medications for asthma. In cycle 8, she received oral levothyroxine 50-150 microg/day for approximately 30 days to control hypothyroidism before beginning cycle 9 of sunitinib. On day 4 of cycle 9, she was hospitalized with progressively rising circulating liver enzyme levels. She died 4 days postadmission despite discontinuation of sunitinib and initiation of intensive supportive treatment. At autopsy, her liver showed severe centrilobular necrosis with moderate-to-severe steatosis and minimal parenchymal invasion by the neoplasm. Viral stains were negative. DISCUSSION: Hepatic failure has been reported rarely in patients receiving sunitinib. Autopsy results excluded neoplastic disease progression and viral infection in the etiology of the event, and the patient may have died of the combined interaction of sunitinib, acetaminophen, and levothyroxine. Although sunitinib was not more than a possible hepatotoxin (Roussel Uclaf Causality Assessment Method) and may even have been hepatoprotective over a 48-week period against chronic intake of acetaminophen (probable hepatotoxin) by producing regional hypothyroidism within the liver, it is hypothesized that correction of the putative hepatic hypothyroidism with oral levothyroxine (possible hepatotoxin) and reinitiation of sunitinib treatment may have triggered hepatic necrosis. CONCLUSIONS: Acetaminophen should be used with particular caution in patients receiving sunitinib. In sunitinib-treated patients who also require levothyroxine therapy, increased caution in restarting subsequent sunitinib treatment and discontinuation of acetaminophen, if possible, is advisable. Further evaluation of this potential interaction is warranted.",1
11802,19340528,Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders,"""We investigated the role of therapeutic dose monitoring (TDM) in the treatment of fungal infections with voriconazole through 49 analyses of 34 patients who received treatment for hematologic diseases. Voriconazole concentration was highly variable among patients regardless of renal, liver functions, or age, and the effect of dose enhancement was not constant. This indicates the difficulty of predicting voriconazole concentration without TDM. We evaluated the outcome with the composite assessment system where patients were assumed non-responders when they failed to show improvement in at least 2 of the following 3 criteria: clinical, radiologic, and mycologic. We showed that concentration-response relationship depended on the status of underlying hematologic diseases; this relationship was observed only in cases without refractory hematologic diseases, but not in those with refractory diseases. In the former group, cases with >2 mg/L of concentration were associated with good response to voriconazole. On the other hand, elevation of hepatic enzyme was frequently observed when voriconazole concentration was >6 mg/L. From these results, we concluded that TDM should be executed and targeted to 2-6 mg/L to improve efficacy and to avoid side effects.""",1
11803,19341754,Historical perspectives on cadmium toxicology,"The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.",1
11804,19346146,Spondyloarthropathy and chronic B hepatitis. Effect of anti-TNF therapy,"UNLABELLED: Several cases of TNF antagonist-related reactivation of hepatitis B have been reported. Here, we describe 4 cases in patients with spondyloarthropathies. Long-term monitoring of the hepatitis B virus (HBV) load is in order in HBV-positive patients treated with TNF antagonists. CASE REPORTS: There were 3 men and 1 woman, aged 30-40 years. Follow-up ranged from 1 to 5 years. In 2 patients, the HBV infection was not discovered until the pre-TNF antagonist therapy workup. A viral load increase was noted after a TNF antagonist was added to methotrexate in 2 patients, whose viral load values returned to baseline after the introduction of the antiviral agent lamivudine. Lamivudine was started at the same time as the TNF antagonist in the other 2 patients, whose viral loads remained undetectable. Escape phenomenon requiring a switch to another antiviral agent was required in 1 patient after more than 4 years of treatment with 3 TNF antagonists. CONCLUSION: These 4 case reports illustrate the challenges raised by latent HBV infection in patients who require TNF antagonist therapy. They support routine HBV testing before treatment initiation, followed in HBV-positive patients by viral load monitoring. Antiviral therapy can be used preventively and should be given if the viral load increases under TNF antagonist therapy. In patients on antiviral therapy, viral load monitoring should be continued, given the risk of escape phenomenon after several years.",1
11805,19346518,Rhabdomyolysis and acute renal failure associated with the co-administration of daptomycin and an HMG-CoA reductase inhibitor,,1
11806,19347984,Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study,"""INTRODUCTION: Vorinostat is a small molecule inhibitor of histone deacetylase, and has shown preclinical activity in non-small cell lung cancer (NSCLC). METHODS: Patients with relapsed NSCLC were eligible. Patients received oral vorinostat, 400 mg daily. The primary objective was response rate, with the goal of at least one responder in the first 14 evaluable patients, according to the two-stage minimax design. Secondary objectives included time to progression (TTP), overall survival (OS), and safety. RESULTS: Sixteen patients enrolled from January 2006 to April 2007. The median age was 59.5 years. Thirteen patients were female. Two patients were not evaluable for response due to progressive disease within Cycle 1. No objective antitumor responses were seen in the 14 evaluable patients. Eight patients experienced stable disease (median 3.7 months, range 1.4-19.4). Median TTP was 2.3 months (range 0.9-19.4 months), median OS was 7.1 months (range 1.4-30.0+ months), and estimated 1 year OS rate was 19% (SE 10%). One patient died on study from an acute ischemic stroke; this event was deemed possibly related to treatment. Grade 3/4 adverse events possibly related to vorinostat included neutropenia, lymphopenia, fatigue, pulmonary embolus/deep vein thrombosis, dehydration, elevated alkaline phosphatase, and hypokalemia. CONCLUSIONS: No objective antitumor activity was detected with single agent vorinostat in this setting; however, it yields TTP in relapsed NSCLC similar to that of other targeted agents. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.""",1
11807,19357418,Ending propylthiouracil-induced liver failure in children,,1
11808,19357926,In search of the black sheep: is it bevacizumab or extended chemotherapy?,,1
11809,19359544,Development of a second-generation antiandrogen for treatment of advanced prostate cancer,"Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.",1
11810,19362607,Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury,"""BACKGROUND & AIMS: Acetaminophen-induced liver injury is the most common cause of acute liver failure in the United States; it occurs inadvertently in approximately half of all cases. Concomitant use of other medications might impact susceptibility to acetaminophen hepatotoxicity. We investigated its association with administration of drugs that have been shown to modulate liver injury and/or repair in preclinical studies. METHODS: We analyzed data from 6386 cases of acetaminophen-associated liver injury that were defined in the FDA database of reported adverse events. Data reported in the severe adverse event categories of """"died"""" or """"life-threatening"""" (defined as """"fatal"""" cases, n = 2512) were compared with those of """"non-fatal"""" cases (n = 3874). Potential associations between fatality and concomitant use of 9 drug classes were assessed using multiple logistic regression analyses after adjusting for other variables. RESULTS: Among female subjects, concomitant use of statins, fibrates or nonsteroidal anti-inflammatory drugs was associated with decreased likelihood of fatality, whereas ethanol use was associated with increased likelihood. Among male subjects, concomitant use of statins was associated with decreased likelihood of fatality, whereas concomitant use of sympathetic stimulants or ethanol was associated with increased likelihood. Concomitant use of angiotensin converting enzyme inhibitors or angiotensin receptor II antagonists was associated with decreased likelihood of fatality among younger subjects. CONCLUSIONS: Concomitant use of medications that have been shown in preclinical studies to modulate liver injury and/or repair influenced acetaminophen hepatotoxicity. Drugs that reduce injury or increase repair are protective, whereas those that exacerbate injury or reduce repair are detrimental.""",1
11811,19364299,Two recent updates for psychiatric conditions,,1
11812,19368419,Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence,"Buprenorphine/naloxone (Suboxone) comprises the partial mu-opioid receptor agonist buprenorphine in combination with the opioid antagonist naloxone in a 4 : 1 ratio. When buprenorphine/naloxone is taken sublingually as prescribed, the naloxone exerts no clinically significant effect, leaving the opioid agonist effects of buprenorphine to predominate. However, when buprenorphine/naloxone is parenterally administered in patients physically dependent on full agonist opioids, the opioid antagonism of naloxone causes withdrawal effects, thus reducing the abuse potential of the drug combination. Buprenorphine/naloxone is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone, although more data are needed. Less frequent dispensing of buprenorphine/naloxone (e.g. thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Buprenorphine/naloxone is more effective than clonidine as a medically-supervised withdrawal therapy. Moreover, buprenorphine/naloxone is a generally well tolerated medically-supervised withdrawal and maintenance treatment. Thus, sublingual buprenorphine/naloxone is a valuable pharmacotherapy for the treatment of opioid dependence.",1
11813,19370307,Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept,"We present a case of toxic hepatitis related to infliximab treatment in a 38-year-old woman with rheumatoid arthritis (RA). The patient had previously been treated with different disease-modifying drugs (DMARDs) alone or in combination but had never revealed signs of liver dysfunction. Due to high disease activity, treatment with infliximab (3 mg/kg i.v.) was initiated in combination with methotrexate (MTX) (25 mg/week) and folic acid (5 mg/week). The patient stopped MTX and folic acid on her own initiative after 3 weeks due to improvement of joint symptoms. After seven infusions, progressive elevations of the transaminases up to five times the upper normal limit were noted and treatment with infliximab was terminated. Serological tests for viral and autoimmune hepatitis and for ANA and anti-dsDNA were all negative. Specific infliximab antibodies could not be detected. Ultrasound of the liver was normal. Liver biopsy showed late signs of acute toxic hepatitis without MTX-related fibrosis. This is one the first cases that convincingly demonstrates that infliximab treatment may cause toxic hepatitis. Moreover, the case suggests a lack of hepatic cross-toxicity between infliximab and etanercept as the patient continued with etanercept without new episodes of liver dysfunction.",1
11814,19371619,"Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh","The contamination of groundwater by arsenic in Bangladesh is a major public health concern affecting 35-75 million people. Although it is evident that high levels (>300 microg/L) of arsenic exposure from drinking water are related to adverse health outcomes, health effects of arsenic exposure at low-to-moderate levels (10-300 microg/L) are not well understood. We established the Health Effects of Arsenic Longitudinal Study (HEALS) with more than 20,000 men and women in Araihazar, Bangladesh, to prospectively investigate the health effects of arsenic predominantly at low-to-moderate levels (0.1 to 864 microg/L, mean 99 microg/L) of arsenic exposure. Findings to date suggest adverse effects of low-to-moderate levels of arsenic exposure on the risk of pre-malignant skin lesions, high blood pressure, neurological dysfunctions, and all-cause and chronic disease mortality. In addition, the data also indicate that the risk of skin lesion due to arsenic exposure is modifiable by nutritional factors, such as folate and selenium status, lifestyle factors, including cigarette smoking and body mass index, and genetic polymorphisms in genes related to arsenic metabolism. The analyses of biomarkers for respiratory and cardiovascular functions support that there may be adverse effects of arsenic on these outcomes and call for confirmation in large studies. A unique strength of the HEALS is the availability of outcome data collected prospectively and data on detailed individual-level arsenic exposure estimated using water, blood and repeated urine samples. Future prospective analyses of clinical endpoints and related host susceptibility will enhance our knowledge on the health effects of low-to-moderate levels of arsenic exposure, elucidate disease mechanisms, and give directions for prevention.",1
11815,19378876,Green tea: potential health benefits,"Green tea has been used widely and in high doses for centuries as a health tonic in many societies. Evidence suggests that green tea is effective for treating genital warts. There is some supportive evidence for the use of green tea in cancer prevention. Drinking green tea is associated with a decrease in all-cause mortality, but not in cancer-related mortality. Small clinical studies have found that green tea may also be helpful in losing and managing weight, and lowering cholesterol. Epidemiologic evidence suggests that green tea may prevent stroke and cardiovascular disease. Green tea appears to be safe, although there have been case reports of hepatotoxicity possibly related to a specific extract in pill or beverage form. Green tea seems to be a low-risk complementary therapy for a number of conditions, but more studies are needed.",1
11816,19381336,Unexpected Hepatotoxicity of Rifampin and Saquinavir/Ritonavir in Healthy Male Volunteers,"""OBJECTIVES: Rifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers. METHODS: In an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIV-negative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured. RESULTS: In arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (>/= grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations. CONCLUSIONS: Although not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.""",1
11817,19381768,Clinical experience of tolcapone in advanced Parkinson's disease,"""We are reporting our clinical experience in 66 patients with advanced Parkinson's disease (PD) who were switched to tolcapone because of persisting off periods despite treatment with entacapone (according to the European Agency for the Evaluation of Medicinal products: EMEA). We used UPDRS II-III-IV in """"on"""" state to monitor tolcapone effectiveness at 6 and 12 months. We found significant reductions in mean off-time duration (UPDRS item 39) and levodopa dose at follow up. Eleven patients dropped out (17%) during the first month of treatment, 2 (3%) because liver enzymes exceeded normal limit. Amongst patients who continued tolcapone, 30/55 (54%) reported """"off-time"""" reduction > or =25% (UPDRS-39 decrement > or =1 point). Our findings indicate that tolcapone widens the levodopa therapeutic window, even in patients who have not benefited from entacapone. We suggest that tolcapone is indicated before patients are referred for more invasive procedures.""",1
11818,19393838,Nebivolol: a third-generation beta-blocker for hypertension,"""BACKGROUND: Nebivolol is a third-generation beta(1)-selective beta-blocker that is approved for the treatment of hypertension. OBJECTIVE: This article reviews the clinical pharmacology of nebivolol and its efficacy and safety profile in clinical studies of hypertension (the US Food and Drug Administration-approved indication) and heart failure (off-label use). METHODS: Pertinent articles were identified through searches of MEDLINE and Current Contents from 1966 through December 15, 2008, using the terms nebivolol, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. Abstracts presented at meetings of the American Heart Association and the American Society of Hypertension from 2006 through 2008 were also reviewed. All human clinical trials were included, regardless of design. RESULTS: Twelve published clinical trials were identified that evaluated the use of nebivolol in the management of hypertension; 1 was placebo controlled, 1 was placebo and active controlled, and 10 involved direct comparisons with other antihypertensive agents. Nebivolol was reported to be as effective in lowering blood pressure (BP) as other beta-blockers (atenolol and bisoprolol), angiotensin-converting enzyme inhibitors (lisinopril and enalapril), the angiotensin-receptor blocker telmisartan, and calcium channel blockers (nifedipine and amlodipine). No published studies were identified that evaluated the effect of nebivolol on long-term cardiovascular outcomes. In data from a study in heart failure, nebivolol was associated with a 14% reduction in all-cause mortality and cardiovascular hospitalization at 12 months (P < 0.05). In comparative clinical studies, nebivolol appeared to be well tolerated relative to the other antihypertensive agents studied. The most commonly reported adverse events with nebivolol were fatigue (4%-79%), headache (2%-24%), paresthesia (7%-13%), bradycardia (6%-11%), rhinitis (1%-7%), and dizziness (2%-5%). Because of differences in its pharmacologic properties, nebivolol may have potential advantages in patients who are unable to tolerate traditional beta-blockers (eg, patients with asthma or chronic obstructive pulmonary disease, or men who experience erectile dysfunction while taking antihypertensive therapy). CONCLUSIONS: Nebivolol is a cardioselective beta-blocker that has been reported to be efficacious and well tolerated for achieving BP control in patients with hypertension. Preliminary evidence suggests a potential for reduced mortality in patients with heart failure.""",1
11819,19395155,Isolated fatty liver from prolonged propofol use in a pediatric patient with refractory status epilepticus,"Propofol is a widely used rapidly acting sedating or hypnotic agent in the intensive care setting. It is generally considered safe in both pediatric and adult patients and has been used frequently in cases of refractory status epilepticus. The formulation of propofol is highly lipophilic to facilitate central nervous system penetration and has a high fat content, and prolonged infusions have been known to cause both extrahepatic complications and hepatomegaly secondary to fatty liver. Whereas extrahepatic manifestations of prolonged propofol infusions have been well reported in non-neurologic intensive care patients, cases of pathologically confirmed fatty liver in patients with status epilepticus are relatively few. Furthermore, these cases of hepatomegaly and fatty liver have been also in the context of concomitant extrahepatic side effects. We report on a pediatric patient with refractory status epilepticus treated with a prolonged propofol infusion who developed isolated pathologically confirmed fatty liver without the usually reported extrahepatic manifestations.",1
11820,19397968,Hepatitis from Greater celandine (Chelidonium majus L.): review of literature and report of a new case,"ETHNOPHARMACOLOGICAL RELEVANCE: Folk medicine is a rich source of useful therapeutic tools. Nevertheless, use of medicinal plants can have unwanted, negative effects. By means of the description of an adverse reaction to a herbal remedy, we highlight the need for better efficacy-toxicity studies on these products. AIM OF THE STUDY: To report a case of possible Chelidonium majus L. (Greater celandine)-induced hepatitis and evaluate the past published cases. MATERIALS AND METHODS: We outlined the main features of hepatitis associated with use of Chelidonium majus by providing a review of cases reported and analysing in detail a new one. RESULTS: Several cases of acute hepatitis related to Greater celandine consumption were found in the literature. The assessment for causality using Naranjo probability scale showed a probable relationship between the liver injury and the consumption of Chelidonium majus in the case we described. CONCLUSIONS: Our case, along with the other ones reported in the literature, increases the concern about the safety of oral use of Chelidonium majus. Plants used in traditional medicine are not necessarily harmless. Customers and prescribers should be aware of this, especially when a herbal drug is used with therapeutic purposes in absence of reliable studies of clinical efficacy and benefit-risk assessment.",1
11821,19399620,Meloxicam as a cause of drug-induced autoimmune hepatitis,,1
11822,19400686,Safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens,"""BACKGROUND: Fluoroquinolones are frequently used to replace agents in first-line anti-tuberculosis (anti-TB) regimens in patients with TB who have drug-induced hepatic dysfunction. We investigated the safety of using fluoroquinolone in an area where TB is endemic and where there is a high incidence of drug-induced liver injury. METHODS: From September 2003 through August 2006, patients who had aspartate aminotransferase and/or alanine aminotransferase levels >3 times the upper limit of normal in the presence of hepatitis symptoms or who had aspartate aminotransferase and/or alanine aminotransferase levels >5 times the upper limit of normal after receipt of anti-TB treatment were enrolled. The control group received ethambutol, with or without streptomycin; study groups received either (1) ethambutol plus levofloxacin, with or without streptomycin; or (2) ethambutol plus moxifloxacin, with or without streptomycin. The outcome measurement was the time from onset of hepatitis to normalization of liver functions. RESULTS: One hundred thirty-four (11.3%) of 1191 patients received a diagnosis of hepatotoxicity and needed to stop anti-TB treatment. The risk factor was abnormal baseline transaminase levels. Twenty-two of the 134 patients received the control medication, 40 received levofloxacin, and 45 received moxifloxacin; the remaining patients were excluded from the study. There were no significant prestudy differences between groups. Time to liver function normalization was almost the same for all groups (mean +/- standard deviation, 29.1+/-21.4, 25.5+/-17.6, and 29.7+/-14.3 days, respectively). CONCLUSIONS: Abnormal baseline transaminase levels are the independent risk factors for anti-TB therapy-induced hepatitis. Levofloxacin and moxifloxacin caused no additional hepatotoxicity when they were used by patients with hepatitis induced by first-line anti-TB drugs.""",1
11823,19401368,Effects of teriparatide retreatment in osteoporotic men and women,"CONTEXT: The stimulatory effect of teriparatide on bone mineral density (BMD) and bone turnover is initially exuberant, but then diminishes. OBJECTIVE: Our objective was to determine whether retreating with teriparatide after a drug-free period can restore the initial exuberant response to teriparatide. DESIGN AND SETTING: This was a planned extension of a randomized controlled trial conducted in a single university hospital. PATIENTS AND INTERVENTION: Subjects previously participated in a 30-month randomized trial comparing the effects of alendronate (group 1), teriparatide (group 2), or both (group 3) on BMD and bone turnover in men and women with low BMD (phase 1). Subjects who completed phase 1 on their assigned therapy entered phase 2 (months 30-42), during which teriparatide was stopped in groups 2 and 3. Teriparatide was administered to all subjects during months 42 to 54 (phase 3). MAIN OUTCOME MEASURES: We compared changes in BMD and markers of bone turnover (serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide) between phase 1 and 3 in subjects receiving teriparatide alone. RESULTS: Posterior-anterior and lateral spine BMD increased 12.5 +/- 1.5 and 16.9 +/- 1.7%, respectively, during the first 12 months of teriparatide administration and 5.2 +/- 0.8 and 6.2 +/- 1.8%, respectively, during teriparatide retreatment (P < 0.001 and P = 0.001). Increases in osteocalcin (P < 0.001), N-terminal propeptide of type 1 collagen (P < 0.001), and N-telopeptide (P < 0.001) were greater during the first period of teriparatide administration. CONCLUSION: The response to teriparatide is attenuated when readministered after a 12-month hiatus.",1
11824,19402188,"Comparison of the phenolic component profiles of skullcap (Scutellaria lateriflora) and germander (Teucrium canadense and T. chamaedrys), a potentially hepatotoxic adulterant","INTRODUCTION: Scutellaria lateriflora, commonly known as skullcap, is used as an ingredient in numerous herbal products. Unfortunately, it has occasionally been adulterated with Teucrium canadense or T. chamaedrys, commonly known as germander, which contains potentially hepatotoxic diterpenes. Chromatographic profiles of the phenolic components provide a means of distinguishing between these plants and enhancing public safety. OBJECTIVE: To develop a chromatographic method for the identification of Scutellaria lateriflora and two Teucrium species and to quantify the latter as adulterants. METHODOLOGY: Samples were extracted with aqueous methanol and the extracts were analysed using a standardised LC-DAD-ESI/MS profiling method to obtain their phenolic profiles. RESULTS: Skullcap contained primarily flavonoids, while the major phenolic components of the two Teucrium species were the phenylethanoids, verbascoside and teucrioside. Using the phenylethanoids as markers, it was possible to clearly distinguish between the two genus and to determine 5% Teucrium mixed with Scutellaria using either ultraviolet absorption spectrometry or mass spectrometry in the total ion count mode. Using MS in the selective ion monitoring (SIM) mode, 1% Teucrium could be measured. CONCLUSIONS: This study showed that chromatographic profiling was able to identify Scutellaria and Teucrium, separately and when mixed together.",1
11825,19403902,Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection,"BACKGROUND: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies. METHODS: We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy). RESULTS: The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation. CONCLUSIONS: Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.)",1
11826,19404202,Severe hepatitis associated with the use of black cohosh: a report of two cases and an advice for caution,"In spite of the fact that severe side effects have been reported, black cohosh [Actaea racemosa (syn. Cimifuga racemosa)] is likely to be one of the most popular herbs used in the treatment of postmenopausal symptoms and menstrual dysfunction. We report the cases of two patients, one with submassive liver necrosis and the other with chronic hepatitis most likely related to the use of two different preparations containing black cohosh. This represents another advice for caution concerning this popular preparation of inconsistent therapeutic value.",1
11827,19413662,Hepatitis caused by Lotus-f3?,"We present a case of hepatitis and jaundice are associated with ingestion of Lotus-f3 submitted to our regional pharmacovigilance centre. A 56-year-old woman with psoriatic arthritis developed increased liver enzymes and jaundice 3 weeks after having started to take the product. The woman had been treated with etanercept for more than a year. She was hospitalized with hepatitis, and viral causes were ruled out. Liver biopsy suggested autoimmune or toxic hepatitis. Both etanercept and Lotus-f3 were withdrawn, and 6 weeks later the liver enzymes were normalized without any treatment. Etanercept was subsequently successfully reintroduced, and based on the rapid resolution of the hepatitis, a toxic effect of Lotus-f3 was suggested. This was the first report in the national adverse drug reaction database for this product, but three similar cases have now been reported. Lotus-f3 contains an extract of green tea, which has been associated with hepatotoxicity. The Norwegian adverse drug reaction database contains nine reports of hepatitis or jaundice associated with natural products. Four different natural products containing extracts of green tea have been suspected in eight out of these nine reports.",1
11828,19418576,Intrahepatic cholestasis of pregnancy,"Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus in the third trimester, raised serum bile acids and increased rates of adverse fetal outcomes. The etiology of ICP is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites in genetically susceptible women. Equally unclear are the mechanisms by which the fetal complications occur. This article reviews the epidemiology, clinical features, diagnosis, etiology and management of ICP.",1
11829,19420309,Propofol infusion syndrome: case report and literature review,"PURPOSE: A case of propofol infusion syndrome in a patient with respiratory failure and sepsis is reported. SUMMARY: A 36-year-old Hispanic woman was admitted to the medical intensive care unit for treatment of respiratory failure and sepsis, likely secondary to pneumonia. Her medical history included human immunodeficiency virus infection and chronic hepatitis C virus infection. She was intubated and placed on mechanical ventilation. Empirical i.v. antimicrobial therapy was initiated with vancomycin, moxifloxacin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and micafungin, along with corticosteroids and vasopressors. Propofol 1.5 mg/kg per hour i.v. and midazolam i.v. were initiated for sedation, but the dosages of both propofol and midazolam needed to be increased due to persistent agitation. On hospital day 7, the patient developed a morbilliform rash on her neck, shoulders, and chest and multiple abnormal laboratory test values, including elevated levels of alanine transaminase, aspartate transaminase, amylase, lipase, creatine kinase, and triglycerides. Serial electrocardiograms revealed sinus tachycardia. Computed tomography of the abdomen showed hepatomegaly with fatty infiltration of the liver, no gallstones, and a normal pancreas. I.V. phenobarbital was added for sedation, and propofol was tapered and discontinued on the same day. The patient responded adequately to phenobarbital maintenance therapy and was eventually weaned off all other sedatives. The patient's laboratory test values returned to normal within 72 hours after discontinuation of the propofol infusion, and the rash and tachycardia resolved. CONCLUSION: Propofol infusion syndrome developed in a patient with respiratory failure and sepsis after a prolonged infusion of high-dose propofol.",1
11830,19426297,Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose,,1
11831,19433964,A Phase II trial of Denileukin Diftitox in patients with previously treated advanced non-small cell lung cancer,"""INTRODUCTION: Denileukin diftitox, a chimeric protein, uses the cytocidal properties of diphtheria toxin to cells expressing interleukin-2 receptors. The aim of this study was to evaluate the efficacy and safety of denileukin diftitox in the treatment of advanced relapsed nonsmall cell lung cancer (NSCLC). PATIENTS AND METHODS: Multicenter phase II trial in patients with NSCLC with Eastern Cooperative Oncology Group PS 0-2, stage IIIB/IV at diagnosis, who had failed at least 1 previous chemotherapy regimen. Denileukin diftitox was infused at 18 microg/kg/d x 5 days, every 21 days for 6 cycles. RESULTS: For the 41 patients enrolled, the median age was 56 years (range, 21-80), 25 were men, and the median number of previous chemotherapy regimens was 2 (range, 1-5). The median number of treatment cycles was 2 (range, 1-6). By RECIST criteria, 18 (44%) had stable disease, 10 (24%) progressive disease, and 13 (32%) were not evaluable for response as they received less than 2 treatment cycles. The median time to disease progression was 1.8 months [range, 0.3-11.3; 95% confidence interval (CI) 1.3-2.6]. Median survival was 5.8 months (range, 0.3-33.6; 95% CI 3.4-11.4). The median follow-up time was 16.1 month. One death from myocarditis verified at autopsy was attributed to treatment. One grade 4 toxicity (vascular leak syndrome) was encountered, and 18 grade 3 toxicities, primarily gastro-intestinal, vascular leak syndrome, and constitutional symptoms. CONCLUSION: Denileukin diftitox at current dose schedule has limited activity in patients with previously treated NSCLC, manifested by disease control without impact on survival.""",1
11832,19438818,The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis,"""OBJECTIVE: To compare the efficacy and safety of intermittent terbinafine with standard courses of terbinafine and itraconazole for dermatophyte toenail onychomycosis. DESIGN: Data from a Canadian study of continuous terbinafine (CTERB) and intermittent itraconazole (III) was compared to an intermittent terbinafine regimen (TOT) using similar protocol to the randomized study. INTERVENTIONS: Terbinafine 250 mg/day for 4 weeks followed by 4 weeks of no terbinafine and then an additional 4 weeks of terbinafine 250 mg/day (TOT); terbinafine 250 mg/day for 12 weeks (CTERB); itraconazole pulse of 200 mg twice daily for 7 days on, 21 days off, three pulses given (III). RESULTS: At 72 weeks, mycological cure rates (negative KOH and culture) were 36 of 43 (83.7%), 25 of 32 (78.1%), and 17 of 30 (56.7%), for the TOT, CTERB, and III groups, respectively (P = 0.01 for TOT vs. III). Effective cure rates (simultaneous mycological cure and < or =10% nail plate involvement) were 34 of 43 (79.1%), 21 of 32 (65.6%), and 11 of 30 (36.7%), respectively (P < 0.001 for TOT vs. III; P = 0.02 for CTERB vs. III). No significant differences in effective and mycological cure rates were noted between the two terbinafine groups. Adverse events reported were similar to those reported in the respective package inserts. Most adverse events were mild to moderate, transient, and did not require interruption of the drug regimens. No serious adverse events were reported. CONCLUSIONS: A TOT intermittent terbinafine regimen provided similar efficacy and safety to the gold standard continuous terbinafine regimen and better effective cure rates than pulse itraconazole therapy.""",1
11833,19442259,"Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people","BACKGROUND: Simvastatin reduces cardiovascular mortality and morbidity but, as with other HMG-CoA reductase inhibitors, can cause significant muscle toxicity and has been associated with elevations of liver transaminases. METHODS: Muscle and liver adverse effects of simvastatin 40 mg daily were evaluated in a randomized placebo-controlled trial involving 20,536 UK patients with vascular disease or diabetes (in which a substantial reduction of cardiovascular mortality and morbidity has previously been demonstrated). RESULTS: The excess incidence of myopathy in the simvastatin group was < 0.1% over the 5 years of the trial, and there were no significant differences between the treatment groups in the incidence of serious hepatobiliary disease. CONCLUSION: Among the many different types of high-risk patient studied (including women, older individuals and those with low cholesterol levels), there was a very low incidence (< 0.1%) of myopathy during 5 years treatment with simvastatin 40 mg daily. The risk of hepatitis, if any, was undetectable even in this very large long-term trial. Routine monitoring of liver function tests during treatment with simvastatin 40 mg is not useful.",1
11834,19444259,Incretin-based therapies for type 2 diabetes mellitus,"Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.",1
11835,19447449,[Fatal acute hepatitis and cholestasis associated with liver disease],,1
11836,19447938,Anakinra for rheumatoid arthritis: a systematic review,"OBJECTIVE: To perform a systematic review of clinical effectiveness and safety of anakinra in rheumatoid arthritis (RA). METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and the reference lists of included articles for randomized controlled trials comparing anakinra to placebo in adults with RA. RESULTS: Five trials involving 2846 patients, 781 randomized to placebo and 2065 to anakinra, were included. There was a significant improvement in the number of participants achieving American College of Rheumatology (ACR)20 (38% vs 23%) treated with anakinra 50-150 mg daily versus placebo after 24 weeks. ACR50 (18% vs 7%), ACR70 (7% vs 2%), Health Assessment Questionnaire, visual analog scale for pain, Larsen radiographic scores, and erythrocyte sedimentation rate all demonstrated significant improvement with anakinra versus placebo as well. There were no statistically significant differences noted in the number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). An increase in incidence of serious infections in anakinra versus the placebo group (1.8% vs 0.6%) was noted that may be clinically significant. Injection site reactions were significantly increased, occurring in 71% of anakinra versus 28% of placebo group. CONCLUSION: Anakinra is a relatively safe and modestly efficacious biologic therapy for RA. More studies are needed to evaluate safety and efficacy, especially in comparison to other therapies, and adverse event data for the longterm use of anakinra have yet to be assessed.",1
11837,19449473,[The network of methotrexate toxicity],"""INTRODUCTION: Methotrexate is a folic acid antagonist recognised as one of the most important DMARD's in the rheumatoid arthritis treatment. Although the indisputable efficacy and the good tolerance profile, the broad toxicity spectrum is very variable with respect both to symptoms and intensity. The side effects vary from malaise and asthenia to pneumonitis or pancytopenia, which can be fatal. OBJECTIVES: To review the adverse effects of methotrexate in the treatment of rheumatoid arthritis. MATERIALS AND METHODS: Literature review, using Medline as a starting point, searching with the keywords """"methotrexate"""", """"toxic effects"""", """"adverse effects"""", """"rheumatoid arthritis"""". The relevant papers and selected references found therein were used. RESULTS: The gastrointestinal symptoms are the most frequent, but myelossupression and pneumonitis are the most feared ones. Elevation of transaminases could indicate hepatic toxicity, placing the risk of cirrhosis. Cutaneous lesions, neurologic symptoms, changes in the bone metabolism, teratogenecity and hyperhomocysteinemia are other examples of the adverse effects of methotrexate. The post-dosing reactions are still not well known. The folate supplementation is important in the prevention of folate metabolism dependent symptoms. The farmacogenomics may help to identify patients in greater risk for multiple side effects. CONCLUSIONS: Knowing and monitoring the methotrexate side effects is extremely important and should be carefully considered in order to prevent both therapeutic withdrawals due to toxicity as well as fatal outcomes.""",1
11838,19451427,"Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043)","""PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.""",1
11839,19452483,Impact of high-dose atorvastatin in coronary heart disease patients age 65 to 78 years,"""BACKGROUND: High-dose statin therapy may be underutilized in aged patients due to doubts about efficacy and safety. HYPOTHESIS: To investigate outcomes and safety in patients aged 65-78 years compared with patients aged < 65 years in the ALLIANCE study. METHODS: A total of 2,442 stable coronary heart disease (CHD) patients with dyslipidemia were randomized to either aggressive treatment (low-density lipoprotein cholesterol titration goal of < 80 mg/dL or maximum 80 mg/d of atorvastatin) or usual care (continuation of baseline lipid-lowering therapy, with changes and laboratory analyses directed by treating physicians). RESULTS: A total of 1,001 patients aged 65-78 years were followed for a median period of 53.9 mo. Older, aggressively treated atorvastatin patients experienced a 27% relative risk reduction for the primary composite endpoint of adverse cardiovascular outcomes (hazard ratio [HR]: 0.73; 95% confidence intervals [CI]: 0.57-0.94; p = 0.016). In addition, significant risk reductions were observed for nonfatal myocardial infarction (MI; HR: 0.43; 95% CI: 0.23-0.79; p = 0.006), cardiac revascularization (HR: 0.67; 95% CI: 0.48-0.93; p = 0.017), and the combined endpoint of cardiac death and nonfatal MI (HR: 0.48; 95% CI: 0.32-0.72; p = 0.001). The rate of significant liver transaminase elevations in atorvastatin patients was low and not age related. There were no cases of rhabdomyolysis. The rate of study discontinuations due to serious adverse events was higher in patients aged 65-78 years than in those younger than 65 years, but was similar between the treatment groups. CONCLUSIONS: Our data support the efficacy and safety of aggressive lipid management with atorvastatin in older CHD patients.""",1
11840,19454870,Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens,"OBJECTIVES: The aims of this multicenter, randomized, placebo-controlled, double-blind trial were to confirm the efficacy of lacosamide at a daily dose of 400 mg/d and to explore the efficacy, safety, and tolerability of lacosamide 200 mg/d and 600 mg/d in the treatment of painful diabetic neuropathy. METHODS: The trial consisted of a 2-week run-in period, a 6-week titration phase, and a 12-week maintenance phase, during which patients received placebo or fixed doses of lacosamide 200, 400, or 600 mg/d. No back titration was allowed during the trial. The primary efficacy criterion was the change in Likert pain score from baseline to the average over the last 4 weeks of the maintenance phase in the intent-to-treat population. RESULTS: The lacosamide 400 mg/d group demonstrated statistically significant improvement in Likert pain score over placebo for the primary efficacy measure. At the end of treatment, 58% of patients in the lacosamide 400 mg/d treatment group achieved at least a 2-point or 30% reduction in Likert pain score, compared with 46% of placebo-treated patients. The lacosamide 200 mg/d group separated from placebo, but failed to show statistical significance for any of the primary or secondary outcome measures. The lacosamide 600 mg/d group was significantly more efficacious than placebo in the observed cases but not in the intent-to-treat population. This was probably secondary to a relatively high-premature withdrawal rate due to adverse events that occurred during the titration phase in that group. Overall lacosamide at daily doses of 200 to 400 mg was well tolerated, with 8% of patients discontinuing due to an adverse event from the 200 mg/d group and 23% from the 400 mg/d group compared with 9% in the placebo group. Discontinuations due to adverse events were highest in the 600 mg/d group (40%). The most common adverse events consisted of dizziness, nausea, tremor, headache, and fatigue. Somnolence, cognitive and behavioral side effects, weight change, and edema were notably low. DISCUSSION: Safety and efficacy analyses indicated that lacosamide 400 mg/d provided an optimal balance between efficacy and side effects in patients with painful diabetic neuropathy.",1
11841,19457587,[Severe intrahepatic cholestasis associated with cetirizine],,1
11842,19460762,"Efficacy and safety of comfrey root extract ointment in the treatment of acute upper or lower back pain: results of a double-blind, randomised, placebo controlled, multicentre trial","""OBJECTIVE: The objective was to show the superiority of comfrey root extract ointment to placebo ointment in patients with acute upper or lower back pain. DESIGN: The study was conducted as a double-blind, multicentre, randomised clinical trial with parallel group design over a period of 5 days (SD 1). The patients (n = 120, mean age 36.9 years) were treated with verum or placebo ointment three times a day, 4 g ointment per application. The trial included four visits. MAIN OUTCOME MEASURES: The primary efficacy variable was the area under the curve (AUC) of the visual analogue scale (VAS) on active standardised movement values at visits 1 to 4. The secondary efficacy variables were back pain at rest using assessment by the patient on VAS, pressure algometry (pain-time curve; AUC over 5 days), global assessment of efficacy by the patient and the investigator, consumption of analgesic medication and functional impairment measured using the Oswestry disability index. RESULTS: There was a significant treatment difference between comfrey extract and placebo regarding the primary variable. In the course of the trial the pain intensity on active standardised movement decreased on average (median) approximately 95.2% in the verum group and 37.8% in the placebo group. CONCLUSIONS: The results of this clinical trial were clear-cut and consistent across all primary and secondary efficacy variables. Comfrey root extract showed a remarkably potent and clinically relevant effect in reducing acute back pain. For the first time a fast-acting effect of the ointment (1 h) was also witnessed.""",1
11843,19467387,Infliximab treatment for severe psoriasis in a patient with active hepatitis B virus infection,,1
11844,19471856,"Hyperbilirubinemia during atazanavir treatment in 2,404 patients in the Italian atazanavir expanded access program and MASTER Cohorts","""BACKGROUND: Although the mechanism of atazanavir (ATV)-related hyperbilirubinemia is well identified, its prevalence, risk factors, and association with transaminase flares have rarely been assessed in a large population from the """"real life"""" setting. METHODS: Prospectively collected data on 2,404 patients from the Italian MASTER Cohort and the Italian ATV expanded access program database were examined. Uni- and multivariable Cox proportional hazards regression models were conducted to identify risk factors for grade >or= III hyperbilirubinemia during the administration of ATV. The risk of increased levels of serum alanine aminotransferase (ALT) was compared between patients with or without grade >or= III hyperbilirubinemia in a Cox regression analysis stratified by hepatitis C virus (HCV) serostatus. RESULTS: Grade III and IV hyperbilirubinemia were observed in 1,072 (44.6%) and 174 (7.2%) of the patients, respectively. Higher CD4+ T-cell counts, abnormal bilirubinemia at baseline, and ritonavir co-administration were associated with a higher risk of developing grade >or= III hyperbilirubinemia. In contrast, female gender, clinical class C, and non-nucleoside reverse transcriptase co-administration appeared to be protective. Higher bilirubinemia at baseline and the use of ritonavir were associated with a higher risk of grade IV hyperbilirubinemia. The occurrence of grade >or= III hyperbilirubinemia was not associated with severe hepatotoxicity (hazard ratio 1.00, 95% confidence interval 0.64-1.57; p = 0.997). CONCLUSIONS: Hyperbilirubinemia is a common side effect of an ATV pharmacotherapeutic regimen. However, grade IV increase in bilirubin was rarely found. In most cases, ATV hyperbilirubinemia appeared to be an innocent phenomenon as far as the risk of a subsequent increase in liver enzyme level is concerned.""",1
11845,19474352,Histological patterns in drug-induced liver disease,"The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. Acute hepatitis, with or without cholestasis, is the most common histological pattern of DILI, and drugs such as acetaminophen are the leading causes of acute liver failure. Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate can lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimmune hepatitis. Prolonged cholestasis and ductopenia resembling primary chronic biliary disease can occur. Drug-induced steatohepatitis is also an uncommon pattern, but is well described with drugs such as amiodarone and irinotecan. In the presence of risk factors such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine can precipitate or exacerbate steatohepatitis. Other observed patterns include granulomatous hepatitis, vascular injury (eg, sinusoidal obstruction syndrome), Ito cell lipidosis and neoplasms (eg, adenomas).",1
11846,19479138,Prolonged course of acute generalized exanthematous pustulosis with liver involvement due to sensitization to amoxicillin and paracetamol,,1
11847,19480805,[Stevens-Johnson syndrome and toxic hepatitis due to esomeprazole],,1
11848,19483646,"Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) administered for 3 years as adjuvant therapy of stages II(T4), III, and IV melanoma","""A hypothesis generating study was conducted to evaluate the safety and efficacy of prolonged (3 y) administration of granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) as surgical adjuvant therapy in patients with melanoma at high risk of recurrence. Ninety-eight evaluable patients with stages II(T4), III, or IV melanoma were given prolonged treatment with GM-CSF after surgical resection of disease. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m2 was delivered daily for 14 days followed by 14 days rest. Treatment cycles continued for 3 years or until disease recurrence, which could not be surgically excised. Patients were evaluated for toxicity, disease-free survival, and melanoma-specific survival. Prolonged administration of GM-CSF was well tolerated; grade 1 or 2 side effects occurred in 82% of the patients. There were no grade 3 or 4 treatment-related side effects. Two patients developed acute myelogenous leukemia after completion of 3 years of GM-CSF administration. With a median follow-up of 5.3 years, the median melanoma-specific survival has not yet been reached. The 5-year melanoma-specific survival rate was 60%. The current study has expanded the preliminary evidence on GM-CSF as adjuvant therapy of patients with melanoma who are at high risk for recurrence.""",1
11849,19484789,The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer,"""BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a form of liver damage that can progress to cirrhosis. NASH is associated with obesity and diabetes. The condition also may be associated with some medications, including tamoxifen. Early case reports and small series have documented NASH in patients who received tamoxifen. METHODS: The records of patients registered in the St. Vincent Hospital Cancer Registry of Green Bay Wisconsin from January 1, 1992 to December 31, 2000 were reviewed. RESULTS: In total, 1105 patients with breast cancer were evaluated for NASH, and 24 cases of NASH were documented (2.2%). Seven patients had NASH before their diagnosis of breast cancer, and 17 patients developed NASH after their diagnosis of breast cancer. In multivariate analysis, the factors associated with NASH were tamoxifen use (odds ratio [OR], 8.2; 95% confidence interval [CI], 1.06-63.72), body mass index (BMI) (OR, 1.13; 95% CI, 1.06-1.20), and age (OR, 95% CI, 0.91-0.99). NASH improved after tamoxifen was stopped. After discontinuation of tamoxifen, transaminase levels returned to normal in 14 of 16 patients. CONCLUSIONS: NASH was present in 24 of 1105 patients with breast cancer (2.2%). Seven patients had NASH before they were diagnosed with breast cancer, and 17 patients developed NASH after their diagnosis. NASH was associated with the use of tamoxifen and improved when tamoxifen was stopped.""",1
11850,19487945,Metformin-associated lactic acidosis: a prognostic and therapeutic study,"""OBJECTIVES: Metformin-associated lactic acidosis is a rare and serious complication of biguanide treatment. It usually occurs when a precipitating disease induces an acute renal failure and an incidental overdose. Voluntary intoxication is rare. Bicarbonate hemodialysis (HD) is recommended to decrease metformin levels and correct acidosis but its optimal duration has not been determined. This study was designed to document the characteristics and prognostic factors of intentional and incidental metformin overdose and to determine the optimal duration of HD. DESIGN: Ten years retrospective analysis of patients admitted in intensive care unit for metformin-associated lactic acidosis. SETTING: Two intensive care units (50 beds) in a university hospital. MEASUREMENTS AND MAIN RESULTS: Clinical and biological characteristics, organ failures, and sequential metformin levels during HD were recorded. Forty-two patients were included (13 voluntary intoxications and 29 incidental overdoses); 74% of patients were in acute renal failure and needed HD. No death was observed in intentional overdose patients compared with 48.3% mortality in incidental overdose patients. The factors significantly associated with mortality were logistic organ dysfunction system score, pH, plasma lactate, and prothrombin activity. By multivariate analysis, a prothrombin activity <50% was the only independent predictive factor of mortality (relative risk: 59.8; confidence limits: 6.3-568; p < 0.0001). Sequential measurements of metformin levels during HD were consistent with a bicompartmental elimination pattern. A cumulative HD duration of 15 hours was associated with the return of metformin level to the therapeutic normal range. CONCLUSIONS: In our study, the outcome of MALA was uniformly favorable after intentional metformin overdose. The vital prognosis was mainly influenced by the occurrence of multiple organ dysfunctions, the best predictive factor of death being an acute liver dysfunction as assessed by PT activity. Prolonged HD was needed to correct metformin overdose.""",1
11851,19491826,"A randomized, double-blind, placebo-controlled trial of rifaximin, a nonabsorbable antibiotic, in the treatment of tropical enteropathy","OBJECTIVES: Tropical enteropathy is characterized by an increased urinary lactulose-to-mannitol (L:M) ratio on a site-specific sugar absorption test and is associated with increased intestinal permeability and decreased nutrient absorptive capacity. The etiology of tropical enteropathy is postulated to be intestinal bacterial overgrowth. This study tested the hypothesis that treatment with a nonabsorbable, broad-spectrum antibiotic, rifaximin, reduces the L:M ratio in rural Malawian children, among whom tropical enteropathy is common. METHODS: All children aged 3-5 years from one village were enrolled in a randomized, double-blind, placebo-controlled trial of treatment with rifaximin for 7 days. The L:M ratio was measured before and after treatment, and the change in the L:M ratio was the primary outcome. Secondary outcomes were changes in the urinary sucrose-to-lactulose (SUC:L) and sucralose-to-lactulose (SCL:L) ratios, as well as changes in the fractions of each test sugar recovered in the urine. RESULTS: A total of 144 children participated in this study, of whom 76% had an elevated L:M ratio on enrollment (L:M > or = 0.10). Children who received rifaximin did not show an improvement in their L:M ratio compared with those who received placebo (-0.01+/-0.12 vs. 0.02+/-0.16, respectively, P=0.51, mean+/-s.d.), nor were there significant differences between the two groups in excretion of lactulose, mannitol, sucralose, or sucrose, or in the SUC:L and SCL:L ratios. CONCLUSIONS: Rifaximin had no effect on the tropical enteropathy of 3-5-year-old Malawian children, suggesting that small-bowel bacterial overgrowth is not an important etiological factor in this condition.",1
11852,19494217,Use of canakinumab in the cryopyrin-associated periodic syndrome,"BACKGROUND: The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab is a human anti-interleukin-1beta monoclonal antibody. METHODS: We performed a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS. In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab. We evaluated therapeutic responses using disease-activity scores and analysis of levels of C-reactive protein (CRP) and serum amyloid A protein (SAA). RESULTS: In part 1 of the study, 34 of the 35 patients (97%) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81%) receiving placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg per liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Of the 31 patients, 28 (90%) completed part 3 in remission. In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P=0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo. CONCLUSIONS: Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS. (ClinicalTrials.gov number, NCT00465985.)",1
11853,19497249,"Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial","""OBJECTIVE: Lurasidone is a novel psychotropic agent with high affinity for D(2) and 5-HT(2A) receptors, as well as for receptors implicated in the enhancement of cognition and mood and the reduction of negative symptoms (5-HT(7), 5-HT(1A), and alpha(2c)). The objective of the study was to evaluate the safety and efficacy of lurasidone in patients hospitalized for an acute exacerbation of DSM-IV-defined schizophrenia. METHOD: Patients were randomly assigned to 6 weeks of double-blind treatment with a fixed dose of lurasidone 80 mg (N = 90, 75.6% male, mean age = 39.7 years, mean baseline score on the Brief Psychiatric Rating Scale derived from the Positive and Negative Syndrome Scale [BPRSd] = 55.1) or placebo (N = 90, 77.8% male, mean age = 41.9 years, mean BPRSd score = 56.1). The primary efficacy measure was the BPRSd. The study was conducted from May to December 2004. RESULTS: At day 42, last-observation-carried-forward endpoint, treatment with lurasidone was associated with significant improvement compared to placebo on the BPRSd (least squares mean +/- SE = -8.9 +/- 1.3 vs. -4.2 +/- 1.4; p = .012), as well as on all secondary efficacy measures, including the PANSS total score (-14.1 +/- 2.1 vs. -5.5 +/- 2.2; p = .004) and the PANSS positive (-4.3 +/- 0.7 vs. -1.7 +/- 0.7; p = .006), negative (-2.9 +/- 0.5 vs. -1.3 +/- 0.5; p = .025), and general psychopathology (-7.0 +/- 1.1 vs. -2.7 +/- 1.2; p = .0061) subscales. Significant improvement was seen as early as day 3, based on BPRSd, PANSS, and Clinical Global Impressions-Severity of Illness assessments. Treatment with lurasidone was generally well tolerated and was not associated with adverse changes in metabolic or electrocardiogram parameters. There were no clinically significant differences between lurasidone and placebo in objective measures of extrapyramidal symptoms. CONCLUSIONS: The results of this study suggest that the novel psychotropic agent lurasidone is a safe and effective treatment for patients with an acute exacerbation of schizophrenia. TRIAL REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00088634.""",1
11854,19501269,"Kava hepatotoxicity: comparison of aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures","ETHNOPHARMACOLOGICAL RELEVANCE: Ethanolic and acetonic kava extracts have previously been causally related to rare hepatotoxicity observed in patients from Germany and Switzerland, but causality assessment was not performed in cases of patients having taken the traditional aqueous kava extracts of South Pacific islands or kava-herbs mixtures. AIM OF THE STUDY: To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands. MATERIALS AND METHODS: Causality of hepatotoxicity by aqueous kava extracts and kava-herbs mixtures was assessed, using the updated score of the quantitative CIOMS (Council for the International Organizations of Medical Sciences). RESULTS: Causality was established in five patients from New Caledonia, Australia, the United States and Germany for aqueous kava extracts and kava-herbs mixtures. A comparison with 9 patients from Germany and Switzerland with established causality of hepatotoxicity by ethanolic and acetonic kava extracts reveals that the clinical picture in all 14 patients is similar, independently whether aqueous, ethanolic and acetonic kava extracts or kava-herbs mixtures were used. CONCLUSIONS: Kava hepatotoxicity occurs also with traditional aqueous kava extracts of the South Pacific islands and thereby independently from ethanol or acetone as chemical solvents, suggesting that the toxicity is linked to the kava plant itself with a possibly low quality of the used kava cultivar or kava plant part rather than to chemical solvents.",1
11855,19505304,"Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria","BACKGROUND: The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. METHODS: A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. RESULTS: Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events. CONCLUSION: The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. TRIAL REGISTRATION: The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.",1
11856,19505409,Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity,"Inhibitors of tumor necrosis factor (TNF) alpha (infliximab, etanercept, adalimumab) are nowadays widely used for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), not responding to conventional therapies. Anti-TNF alpha drugs have demonstrated great efficacy in slowing the disease, however, to date, concern still remains regarding acute and long-term toxicity related to TNF block. Increase in liver tests may be observed during treatment with anti-TNF agents, more often related to concomitant drugs (i.e. NSAIDS, methotrexate) or to reactivation of chronic HBV or HCV infections. However, liver damage directly induced by the drug has been described in patients treated with infliximab or adalimumab. To our knowledge, no cases of liver injury closely related to etanercept have been reported so far. We report the case of a patient with PsA who presented liver dysfunction during adalimumab, subsequently successfully treated with etanercept.",1
11857,19513631,The role of eszopiclone in the treatment of insomnia,"INTRODUCTION: Insomnia is a common and underdiagnosed condition that can result in significant economic and clinical consequences. Despite numerous behavioral and pharmacotherapeutic treatment options available for insomnia, few receive adequate treatment, and sleep maintenance (staying asleep) remains a significant problem. To date, available sedative-hypnotic agents have limitations that have lead to inadequate treatment of insomnia. This review provides an overview of eszopiclone and its role in the treatment of insomnia. METHODS: Electronic databases (MEDLINE, EMBASE, International Pharmaceutical Abstracts) were searched for applicable primary literature and review articles. RESULTS: Mechanisms of action at the gamma-amino butyric acid (GABA) receptor sites and pharmacologic and pharmacokinetic characteristics are presented. Eszopiclone, a nonbenzodiazepine S-enantiomer of racemic zopiclone, is highlighted as the first sedative-hypnotic agent to be approved by the United States Food and Drug Administration for the treatment of sleep onset latency and sleep maintenance insomnia with no short-term restrictions. Recently, the European Medicines Agency recommended marketing authorization of eszopiclone. CONCLUSION: Eszopiclone has been shown to be an efficacious and cost-effective option for the treatment of transient and chronic insomnia in adults.",1
11858,19519355,Nilotinib therapy in chronic myelogenous leukemia: the strength of high selectivity on BCR/ABL,"""Imatinib mesylate is currently the standard therapy for chronic myeloid leukemia (CML) patients. Despite the remarkable results achieved with imatinib, the emergence of resistance to this drug has become a significant problem. Several strategies have been developed to overcome imatinib resistance, including dose escalation of the drug, combination treatments or novel targeted agents. Nilotinib is a second-generation tyrosine kinase inhibitor 30-50 fold more potent than imatinib with high affinity and selectivity on BCR/ABL, active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients; front-line treatment of chronic phase Ph+ CML demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials.""",1
11859,19523718,[Jaundice in a patient treated with etanercept],,1
11860,19525305,Topical administration of chloramphenicol can induce acute hepatitis,,1
11861,19528562,Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial,"""BACKGROUND: Red yeast rice is an herbal supplement that decreases low-density lipoprotein (LDL) cholesterol level. OBJECTIVE: To evaluate the effectiveness and tolerability of red yeast rice and therapeutic lifestyle change to treat dyslipidemia in patients who cannot tolerate statin therapy. DESIGN: Randomized, controlled trial. SETTING: Community-based cardiology practice. PATIENTS: 62 patients with dyslipidemia and history of discontinuation of statin therapy due to myalgias. INTERVENTION: Patients were assigned by random allocation software to receive red yeast rice, 1800 mg (31 patients), or placebo (31 patients) twice daily for 24 weeks. All patients were concomitantly enrolled in a 12-week therapeutic lifestyle change program. MEASUREMENTS: Primary outcome was LDL cholesterol level, measured at baseline, week 12, and week 24. Secondary outcomes included total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, liver enzyme, and creatinine phosphokinase (CPK) levels; weight; and Brief Pain Inventory score. RESULTS: In the red yeast rice group, LDL cholesterol decreased by 1.11 mmol/L (43 mg/dL) from baseline at week 12 and by 0.90 mmol/L (35 mg/dL) at week 24. In the placebo group, LDL cholesterol decreased by 0.28 mmol/L (11 mg/dL) at week 12 and by 0.39 mmol/L (15 mg/dL) at week 24. Low-density lipoprotein cholesterol level was significantly lower in the red yeast rice group than in the placebo group at both weeks 12 (P < 0.001) and 24 (P = 0.011). Significant treatment effects were also observed for total cholesterol level at weeks 12 (P < 0.001) and 24 (P = 0.016). Levels of HDL cholesterol, triglyceride, liver enzyme, or CPK; weight loss; and pain severity scores did not significantly differ between groups at either week 12 or week 24. LIMITATION: The study was small, was single-site, was of short duration, and focused on laboratory measures. CONCLUSION: Red yeast rice and therapeutic lifestyle change decrease LDL cholesterol level without increasing CPK or pain levels and may be a treatment option for dyslipidemic patients who cannot tolerate statin therapy.""",1
11862,19530981,The hepatic safety and tolerability of the cyclooxygenase-2 selective NSAID celecoxib: pooled analysis of 41 randomized controlled trials,"""OBJECTIVE: To assess the hepatic safety and tolerability of celecoxib versus placebo and three commonly prescribed nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). RESEARCH DESIGN AND METHODS: This was a retrospective, pooled analysis of a 41-study dataset involving patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, and Alzheimer's disease. Criteria for selection of studies were: (1) Randomized, parallel-group design and planned treatment duration of > or =2 weeks (2) > or =1 placebo or NSAID comparator (3) > or =1 arm with celecoxib at total daily dose of > or =200 mg (4) Data available as of October 31, 2004 Data were pooled by treatment and subject from the safety analysis population of included studies. Treatment-emergent hepatobiliary adverse events (AEs) were compared for celecoxib <200 mg/day (943 patients), 200 mg/day (12 008 patients), 400 mg/day (7380 patients), and 800 mg/day (4602 patients); placebo (4057 patients); diclofenac 100-150 mg/day (7639 patients); naproxen 1000 mg/day (2953 patients); and ibuprofen 2400 mg/day (2484 patients). Hepatobiliary laboratory abnormalities were also analyzed. RESULTS: There were no cases of liver failure, treatment-related liver transplant, or treatment-related hepatobiliary death. Incidence of serious hepatic AEs was low, with 13 (0.05%) serious hepatic AEs among 24 933 celecoxib-treated patients, and 16 (0.21%) among 7639 diclofenac-treated patients. No patients receiving celecoxib or any nonselective NSAID met criteria for Hy's rule (alanine aminotransferase [ALT] > or =3 x upper limit of normal [ULN] with bilirubin > or =2 x ULN). The incidence of notable (> or =5 x ULN) and severe (> or =10 x ULN) ALT elevations was similar for all treatment groups except diclofenac. Significantly fewer hepatobiliary AEs were reported for celecoxib (any dose; 1.11%) than for diclofenac (vs. 4.24%, p < 0.0001); for ibuprofen (vs. 1.53%, p = 0.06) and placebo (vs. 0.89%, p = 0.21) the incidence of AEs was comparable to celecoxib. LIMITATIONS: A number of limitations should be considered when evaluating the results: findings were limited by the quality and reporting of the studies selected; difficulty in estimating the incidence of AEs due to the low frequency of events; acetaminophen not included as an active comparator. CONCLUSIONS: In this pooled analysis, the incidence of hepatic AEs in patients treated with celecoxib was similar to that for both placebo-treated patients and patients treated with ibuprofen or naproxen, but lower than for diclofenac.""",1
11863,19534646,Hepatotoxicity induced by methimazole in a previously healthy patient,"We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.",1
11864,19538488,Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil,"""Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF.""",1
11865,19539102,"Fatal acute hepatitis after sequential treatment with levofloxacin, doxycycline, and naproxen in a patient presenting with acute Mycoplasma pneumoniae infection","""BACKGROUND: The diagnosis of drug-induced liver injury relies on comprehensive clinical assessments due to the absence of an established biomarker or pathognomonic features of liver histology. However, prompt recognition of a culprit drug as the cause of liver injury is the most important aspect in the management of hepatotoxicity. CASE SUMMARY: A 63-year-old white male (85 kg) was admitted because of community-acquired pneumonia with associated pericarditis and subclinical hepatitis, subsequently related to acute Mycoplasma pneumoniae infection (diagnostic positive immuno-globulin M enzyme immunoassay, on hospital days 5 and 20). The patient had received cisplatin and radiotherapy from March to May 2006, as treatment for pharyngolaryngeal squamous cell carcinoma T3N0M0 without subsequent evidence of localized or meta-static recurrent disease (last oncologic consultation, May 17, 2007). He reported alcohol ingestion until March 2006 but no known liver disease, blood transfusion, or exposure to mushrooms or industrial cleaning solvents. Results of serologic tests for viral and nonviral infectious hepatitis, iron and copper studies, and tests for autoantibodies were normal or negative. The patient became initially asymptomatic and fever disappeared following sequential treatment with levo-floxacin (500 mg BID), doxycycline (100 mg BID), and naproxen (500 mg TID). However, on hospital day 10 jaundice and a significant elevation (alanine aminotransferase, 1577 U/L; aspartate amino-transferase, 1754 U/L; alkaline phosphatase, 189 U/L) of serum transaminases appeared. Despite the discontinuation of all medication, the patient gradually deteriorated and died 27 days after admission due to acute fulminant hepatic failure. Autopsy revealed massive hepatic necrosis, inflammatory changes with presence of eosinophils, and cholestasis. An objective causality assessment scale (Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method scale) suggested that each of the 3 drugs could """"probably"""" (score = 6) be related to the patient's fulminant hepatitis. The Naranjo Adverse Drug Reactions Probability Scale assessment for the same drugs indicated a """"possible"""" causal relation (score = 2). CONCLUSION: We report a case of lethal hepatitis possibly/probably associated with levofloxacin, doxy-cycline, and naproxen in a patient with acute M pneumoniae infection.""",1
11866,19546826,"Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial","""OBJECTIVE: The aim of this study was to assess the safety and efficacy of bazedoxifene (BZA)/conjugated estrogens (CE) treating moderate to severe vasomotor symptoms in the Selective Estrogen Menopause and Response to Therapy 2 trial. METHODS: This was an outpatient, multicenter, double-blind, randomized, placebo-controlled, phase 3 study conducted in the United States. Healthy postmenopausal women (N = 332; aged 40-65 y) with moderate to severe hot flushes (>or=7/d or 50/wk) were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo once daily for 12 weeks. Changes from baseline in the average daily number of moderate and severe hot flushes and daily severity score were assessed at weeks 4 and 12; adverse events were recorded. RESULTS: BZA/CE significantly reduced the number and severity of hot flushes at weeks 4 and 12 (P < 0.001). At week 12, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg reduced hot flushes from baseline by 74% (10.3 hot flushes [baseline] vs 2.8 [week 12]) and 80% (10.4 vs 2.4), respectively, compared with 51% (10.5 vs 5.4) for placebo. More participants at week 12 had at least a 75% decrease in hot flushes with BZA 20 mg/CE 0.45 mg (61%) and BZA 20 mg/CE 0.625 mg (73%) versus placebo (27%; P < 0.001). The safety profile was similar between BZA/CE and placebo, and no unexpected safety findings were reported. CONCLUSIONS: BZA 20 mg paired with CE 0.45 or 0.625 mg is effective, with short-term safety, for treating vasomotor symptoms in postmenopausal women.""",1
11867,19550064,Montelukast induced acute hepatocellular liver injury,"A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast induced hepatocellular liver injury. Liver tests began to improve and returned to normal 55 days after drug cessation. Causality of this adverse drug reaction by the Council for International Organizations of Medical Sciences or Roussel Uclaf Causality Assessment Method (CIOMS or RUCAM) and Naranjo's algorithm was 'probable'. Liver tests should be monitored in patients receiving montelukast and any early signs of liver injury should be investigated with a high index of suspicion for drug induced liver injury.",1
11868,19555529,Rifapentine vs. rifampicin for the treatment of pulmonary tuberculosis: a systematic review,"""OBJECTIVE: To evaluate the efficacy and safety of rifapentine (RPT) vs. rifampicin (RMP) for the treatment of pulmonary tuberculosis (PTB). DESIGN: Systematic review of randomised controlled trials (RCTs) that compared combination drug regimens containing RPT with those containing RMP for the treatment of drug-susceptible or previously untreated PTB. RESULTS: Nine RCTs were identified. Statistically significant differences were not found in the cure rates, severe adverse effects, severe hepatotoxicity or bacteriological relapse rates between the regimens containing once- or twice-weekly RPT and those containing daily RMP for human immunodeficiency virus (HIV) negative patients, but were found in the bacteriological relapse rates between regimens containing once-weekly or less frequent RPT and those containing twice- or thrice-weekly RMP: the pooled relative risks in the two subgroups were respectively 1.71 (95%CI 1.13-2.58, P = 0.01) and 2.44 (95%CI 1.15-5.18, P = 0.02). The trial for HIV-positive patients did not show significant differences in the sputum conversion rate, severe adverse effects or bacteriological relapse rate between the RPT- and RMP-containing regimens; four of the five relapses were associated with the RPT-containing regimen, but none of the three relapses with the RMP-containing regimen produced monoresistance to rifamycin (RIF). CONCLUSION: Once- or twice-weekly RPT and daily RMP have similar efficacy and safety for the treatment of HIV-negative PTB, but once-weekly or less frequent use of RPT, in comparison with twice- or thrice-weekly RMP, increases the risk of bacteriological relapse. RPT might increase the risk of resistance to RIF in HIV-positive patients.""",1
11869,19560810,"Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial","BACKGROUND: Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors. METHODS: 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546. FINDINGS: Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0-22.0) swollen and 26.0 (16.0-41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% CI 1.5-4.2], p=0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6-4.7], p=0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1-16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1-24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab. INTERPRETATION: Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors. FUNDING: Centocor Research and Development and Schering-Plough Research Institute.",1
11870,19563414,Hepatocellular carcinoma occurring in a young Crohn's disease patient,"""Reported herein is a case of hepatocellular carcinoma (HCC) occurring in a 25-year-old Japanese man who was diagnosed with Crohn's disease (CD) at 14 years of age; treatment included predonisolone, azathioprine, and infliximab. The tumor was located in right upper lobe and the size was 8 cm in diameter; histology was poorly differentiated HCC with pleomorphic cellular changes. Adjacent normal liver showed no evidence of cirrhosis or viral hepatitis. Until now, only six cases of HCC arising in patients with CD have been reported in the English-language literature. Most of these patients had early onset of CD and HCC: none had cirrhosis or virus hepatitis. Most patients had a long disease history of CD and were being medicated with several immunosuppressive agents. Some factors associated with CD might indirectly or directly be related to the development of HCC in CD patients, although the possibility that these HCC occurred coincidentally in CD patients, including the present patient, cannot be ruled out. Accumulation of cases is necessary to evaluate the relationship between CD and HCC precisely.""",1
11871,19565475,"The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo","OBJECTIVE: To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. METHODS: Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. RESULTS: By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms. CONCLUSION: Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.",1
11872,19570573,"Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial","BACKGROUND: Idiopathic pulmonary fibrosis is a fatal disease for which no effective treatment exists. We assessed whether treatment with interferon gamma-1b improved survival compared with placebo in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function. METHODS: 826 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries, the USA, and Canada. Patients were randomly assigned (double-blind) in a 2:1 ratio to receive 200 microg interferon gamma-1b (n=551) or equivalent placebo (n=275) subcutaneously, three times per week. Eligible patients were aged 40-79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55-90% of the predicted value, and a haemoglobin-corrected carbon monoxide diffusing capacity of 35-90% of the predicted value. The primary endpoint was overall survival time from randomisation measured at the second interim analysis, when the proportion of deaths had reached 75% of those expected by the study conclusion. This study is registered with ClinicalTrials.gov, number NCT00075998. FINDINGS: At the second interim analysis, the hazard ratio for mortality in patients on interferon gamma-1b showed absence of minimum benefit compared with placebo (1.15, 95% CI 0.77-1.71, p=0.497), and indicated that the study should be stopped. After a median duration of 64 weeks (IQR 41-84) on treatment, 80 (15%) patients on interferon gamma-1b and 35 (13%) on placebo had died. Almost all patients reported at least one adverse event, and more patients on interferon gamma-1b group had constitutional signs and symptoms (influenza-like illness, fatigue, fever, and chills) than did those on placebo. Occurrence of serious adverse events (eg, pneumonia, respiratory failure) was similar for both treatment groups. Treatment adherence was good and few patients discontinued treatment prematurely in either group. INTERPRETATION: We cannot recommend treatment with interferon gamma-1b since the drug did not improve survival for patients with idiopathic pulmonary fibrosis, which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function. FUNDING: InterMune.",1
11873,19575026,Hepatosplenic T-cell lymphoma in a patient with Crohn's disease,"BACKGROUND: A 58-year-old man who had a 35-year history of Crohn's disease presented to our IBD center with a disease flare, pararectal fistulas and abscess formation. The patient had previously undergone ileocolic resection for a stenosis and his abscesses had been treated by surgical drainage. He had been taking azathioprine therapy for approximately 5.5 years and had received high-dose steroids. He had also previously taken metronidazole and antihypertensive medications. INVESTIGATIONS: Physical examination, laboratory investigations including hemoglobin levels and white blood cell counts, genetic testing, CT, bone-marrow biopsy, immunophenotyping by fluorescence-activated cell sorting, polymerase chain reaction analyses, fluorescence in situ hybridization, sputum culture and diagnostic splenectomy. DIAGNOSIS: Hepatosplenic T-cell lymphoma. MANAGEMENT: Splenectomy, antibiotic therapy and chemotherapy with cyclophosphamide.",1
11874,19578136,Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate,"""OBJECTIVE: MTX hepatotoxicity is considered to occur more frequently in patients with psoriasis than in patients with RA. However, toxicity guidelines are based on reports from studies with small sample sizes and limited follow-up periods. The current study's objective was to examine the long-term risk of MTX hepatotoxicity based on a database review of patients with RA or psoriasis, and to examine whether the two populations differed. METHODS: We conducted a retrospective cohort review among members of a large health maintenance organization (HMO) in Israel who were diagnosed with either RA (n = 119) or psoriasis (n = 690) and who had purchased at least one dose of MTX. Liver function analyses were performed serially in these patients during the follow-up. All abnormal assays were recorded in the computerized database of the HMO. RESULTS: Both groups had hepatic enzyme elevation; the pre-disposing factors predictive of liver damage were female gender and a higher cumulative dose of MTX (hazard ratios, 1.46 and 1.07, respectively, P < 0.001). Age, concurrent diseases and type of disease had no influence on susceptibility to liver damage. No statistically significant difference was detected in any abnormal liver function test among patients with either RA or psoriasis. CONCLUSION: Our study did not corroborate previous findings of significant differences between psoriasis patients and RA patients concerning susceptibility to hepatotoxicity from MTX therapy. The only significant factor predicting a higher risk of hepatic damage was female gender.""",1
11875,19583451,Varenicline: a novel pharmacotherapy for smoking cessation,"Varenicline is an orally administered small molecule with partial agonist activity at the alpha4beta2 nicotinic acetylcholine receptor. Varenicline was approved by both the US FDA and the European Medicines Agency of the EU in 2006 as an aid to smoking cessation. Subsequently, varenicline has been approved in over 80 other countries. Varenicline is almost entirely absorbed following oral administration, and absorption is unaffected by food, smoking or the time of day. Varenicline undergoes only minimal metabolism and approximately 90% of the drug is excreted in the urine unchanged. Varenicline has a mean elimination half-life after repeated administration of approximately 24 hours in smokers. The area under the plasma concentration-time curve is increased in patients with moderate or severe renal failure. No clinically relevant varenicline-drug interactions have been identified. In two identical, randomized, double-blind, phase III clinical trials in healthy, motivated-to-quit, mainly Caucasian smokers aged 18-75 years in the US, 12 weeks of treatment with varenicline 1 mg twice daily was associated with significantly higher abstinence rates over weeks 9-12 than sustained-release bupropion 150 mg twice daily or placebo. In a separate phase III trial, an additional 12 weeks of treatment in smokers achieving abstinence in the first 12 weeks was associated with greater abstinence through to week 52 than placebo treatment. Varenicline treatment was also associated with significantly higher rates of abstinence than placebo treatment in randomized, double-blind, clinical trials in smokers in China, Japan, Korea, Singapore, Taiwan and Thailand. In a randomized, open-label, multi-national, phase III trial, varenicline treatment was associated with a significantly higher rate of abstinence than transdermal nicotine-replacement therapy. In these trials, varenicline treatment was associated with lower urge to smoke and satisfaction from smoking in relapsers than placebo or active comparators. In the two US phase III trials, 12 weeks of treatment with varenicline 1 mg twice daily had an acceptable safety and tolerability profile. Nausea and abnormal dreams were the most common adverse events that occurred in more varenicline than placebo recipients. The incidence and prevalence of nausea were greatest in weeks 1 and 2 of treatment, and declined thereafter. The prevalence of early adverse effects can be reduced by individual dose titration. Adverse events associated with varenicline therapy have been reported in post-marketing surveillance, including neuropsychiatric events such as depressed mood, agitation, changes in behaviour, suicidal ideation and suicide. Currently, it is unclear whether the association of varenicline therapy with these adverse events is causal, coincidental or related to smoking cessation. Given the greater efficacy of varenicline compared with other pharmacotherapies, and the high risk of morbidity and mortality associated with continued smoking, varenicline is a valuable pharmacological aid to smoking cessation.",1
11876,19584064,ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy,"""AIM: To evaluate the nature and frequency of ATP-binding cassette subfamily B member 4 (ABCB4) gene variants in a series of French patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: In this prospective study, the entire ABCB4 gene coding sequence was analysed by DNA sequencing in 50 unrelated women with ICP defined by pruritus and raised serum alanine aminotransferase activity or bile acid concentration, with recovery after delivery. Genomic variants detected in patients with ICP were sought in 107 control pregnant women. Patients with ICP and controls were of Caucasian origin. RESULTS: Eight genomic variants were observed. One nonsense mutation (p.Arg144Stop) and two missense mutations (p.Ser320Phe and p.Thr775Met) were revealed each in one heterozygous patient. A third missense mutation (p.Arg590Gln) was detected in three heterozygous patients and in two homozygous patients also homozygous for a particular haplotype of three single-nucleotide polymorphisms (c.175C>T, c.504T>C, c.711A>T). The chromosomal frequency of the p.Arg590Gln variant was significantly different between the ICP and control group (7.0% vs 0.5%; p = 0.0017; OR 16.03, 95% CI 1.94 to 132.16). An association was also found between allele T of the c.504T>C silent nucleotide polymorphism and ICP (68.0% vs 53.7%; p = 0.017; OR 1.83, 95% CI 1.08 to 3.11). The chromosomal frequency of the p.Arg652Gly variant did not differ between the ICP and control group (p = 0.40). CONCLUSIONS: This study shows that 16% of Caucasian patients with ICP bear ABCB4 gene mutations, and confirms the significant involvement of this gene in the pathogenesis of this complex disorder.""",1
11877,19585548,High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis,"Previous controlled trials are inconclusive regarding the efficacy of ursodeoxycholic acid (UDCA) for treating primary sclerosing cholangitis (PSC). One hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose UDCA (28-30 mg/kg/day) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. At enrollment, the UDCA (n = 76) and placebo (n = 74) groups were similar with respect to sex, age, duration of disease, serum aspartate aminotransferase and alkaline phosphatase levels, liver histology, and Mayo risk score. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the UDCA group than the placebo group (P < 0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the UDCA group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. After adjustment for baseline stratification characteristics, the risk of a primary endpoint was 2.3 times greater for patients on UDCA than for those on placebo (P < 0.01) and 2.1 times greater for death, transplantation, or minimal listing criteria (P = 0.038). Serious adverse events were more common in the UDCA group than the placebo group (63% versus 37% [P < 0.01]). CONCLUSION: Long-term, high-dose UDCA therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.",1
11878,19588433,Artemisinin-based combination therapy for treating uncomplicated malaria,"""BACKGROUND: The World Health Organization recommends uncomplicated P. falciparum malaria is treated using Artemisinin-based Combination Therapy (ACT). This review aims to assist the decision making of malaria control programmes by providing an overview of the relative benefits and harms of the available options. OBJECTIVES: To compare the effects of ACTs with other available ACT and non-ACT combinations for treating uncomplicated P. falciparum malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) to March 2009. SELECTION CRITERIA: Randomized head to head trials of ACTs in uncomplicated P. falciparum malaria.This review is limited to: dihydroartemisinin-piperaquine; artesunate plus mefloquine; artemether-lumefantrine (six doses); artesunate plus amodiaquine; artesunate plus sulfadoxine-pyrimethamine and amodiaquine plus sulfadoxine-pyrimethamine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on P. vivax, gametocytes, haemoglobin, and adverse events. MAIN RESULTS: Fifty studies met the inclusion criteria. All five ACTs achieved PCR adjusted failure rates of < 10%, in line with WHO recommendations, at most study sites.Dihydroartemisinin-piperaquine performed well compared to the ACTs in current use (PCR adjusted treatment failure versus artesunate plus mefloquine in Asia; RR 0.39, 95% CI 0.19 to 0.79; three trials, 1062 participants; versus artemether-lumefantrine in Africa; RR 0.39, 95% CI 0.24 to 0.64; three trials, 1136 participants).ACTs were superior to amodiaquine plus sulfadoxine-pyrimethamine in East Africa (PCR adjusted treatment failure versus artemether-lumefantrine; RR 0.12, 95% CI 0.06 to 0.24; two trials, 618 participants; versus AS+AQ; RR 0.44, 95% CI 0.22 to 0.89; three trials, 1515 participants).Dihydroartemisinin-piperaquine (RR 0.32, 95% CI 0.24 to 0.43; four trials, 1442 participants) and artesunate plus mefloquine (RR 0.30, 95% CI 0.21 to 0.41; four trials, 1003 participants) were more effective than artemether-lumefantrine at reducing the incidence of P.vivax over 42 days follow up. AUTHORS' CONCLUSIONS: Dihydroartemisinin-piperaquine is another effective first-line treatment for P. falciparum malaria.The performance of the non-ACT (amodiaquine plus sulfadoxine-pyrimethamine) falls below WHO recommendations for first-line therapy in parts of Africa.In areas where primaquine is not being used for radical cure of P. vivax, ACTs with long half-lives may provide some benefit.""",1
11879,19590488,Acetaminophen safety - deja vu,,1
11880,19592625,"Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing","OBJECTIVE: To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy. RESEARCH DESIGN AND METHODS: In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m(2), A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16. RESULTS: Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (-0.87, -0.79, and -0.87%, respectively) versus placebo (-0.17%, P < 0.004) and exenatide (-0.54%). Weight loss (-1.1 to -1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide. CONCLUSIONS: Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.",1
11881,19596747,The conquest of Wilson's disease,,1
11882,19608677,Reactivation of DNA viruses in association with histone deacetylase inhibitor therapy: a case series report,"Histone deacetylase inhibitors are a class of anti-neoplastic agents that induce growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. A phase II study exploring the efficacy of romidepsin, an histone deacetylase inhibitor, in patients with cutaneous or peripheral T-cell lymphomas was initiated at the National Cancer Institute. To date, over 120 patients with T-cell lymphoma have been treated on a multi-institutional phase II trial of romidepsin. Reactivation of latent DNA viruses including EBV, HBV, and VZV is well described as a consequence of the immune suppression associated with systemic chemotherapy. The incidence of viral reactivation in patients treated with histone deacetylase inhibitors is not yet known. We report the observation of EBV-associated illnesses in 2 patients and the reactivation of HBV in an additional patient treated with romidepsin. These cases may represent reactivation of DNA viruses due to histone deacetylase inhibitor induced immunosuppression, or direct promotion of viral replication via histone deacetylase inhibitor induced chromatin remodeling, or, alternatively, may be related to the underlying disease process. These observations suggest that vigilance for DNA virus reactivation is needed to quantify the risk in patients treated with histone deacetylase inhibitors.",1
11883,19622360,Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy,"BACKGROUND & AIMS: Oral bile acid replacement has been shown to be an effective therapy in primary bile acid synthesis defects, but to date there have been no reports of the long-term effects of this therapy. The aim of the study was to evaluate the long-term effectiveness and safety of cholic acid (CA) therapy. METHODS: Fifteen patients with either 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase (3beta-HSD) (n = 13) or Delta(4)-3-oxosteroid 5beta-reductase (Delta(4)-3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed up prospectively. RESULTS: CA therapy was started at a median age of 3.9 years (range, 0.3-13.1 years). The median follow-up with treatment was 12.4 years (range, 5.6-15 years). The mean daily dose of CA was initially 13 mg/kg and was 6 mg/kg at last evaluation. During CA therapy, physical examination findings, laboratory test results, and findings on sonography normalized. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites was reduced by 500-fold and 30-fold in 3beta-HSD and Delta(4)-3-oxo-R deficiency, respectively, and total urinary bile acid excretion decreased dramatically. Liver biopsies performed in 14 patients after at least 5 years of CA therapy showed marked improvement, especially in patients with the 3beta-HSD deficiency. CA was well tolerated with all children developing normally, including 2 women having 4 normal pregnancies during treatment. CONCLUSIONS: Oral CA therapy is a safe and effective long-term treatment of the most common primary bile acid synthesis defects.",1
11884,19622807,FDA focuses on drugs and liver damage: labeling and other changes for acetaminophen,,1
11885,19624990,[Stevens-Johnson syndrome plus intrahepatic cholestasis caused by clindamycin or chlorpheniramine],"A 48-year-old woman was hospitalized with the diagnosis of hepatitis. She presented with symptoms of jaundice, headache, elevated bilirubin, and elevated hepatic enzymes. She related a recent episode of a bronchial infection that was treated during the previous eight days with paracetamol (500mg, 2 doses only), chlorpheniramine, betamethasone and clindamycin. After an initial clinical and laboratorial improvement, she began to complain of pruritus of the palms and soles. Thereafter, vesicles evolving to blisters developed and a deterioration of her general health ensued. Serologies for hepatitis A, B, and C viruses were negative. Intrahepatic cholestasis and Stevens Johnson Syndrome (SJS) were the final diagnosis. The association of the Stevens Johnson Syndrome and intrahepatic cholestasis simultaneously, related to adverse drug reactions, is very rare. The drugs reportedly involved are mainly antibiotics, such as ampicillin, vancomycin, amoxicillin/clavulinic acid and erythromycin. Other drugs involved are non-steroidal anti-inflamatory drugs, such as mefenamic acid, ibuprofen, and sulindac. The reactions can be minor or severe and can even cause death, an outcome that has been reported in patients of all races and ethnic groups, but appears to be more rare in patients of Latin origin. We present a discussion of this case and review the main characteristics of the Stevens Johnson Syndrome.",1
11886,19632720,Nilotinib post-liver transplantation for acute hepatic failure related to imatinib,"This is the case report of a 47-year-old woman referred to our institution due to acute liver failure related to imatinib, who was submitted to a successful liver transplantation. Nilotinib was safely used post-transplant.",1
11887,19637786,Acute hepatitis after treatment for hair loss with oral green tea extracts (Camellia Sinensis),"Nutritional additives based on green tea have been claiming various beneficial health effects. However, several case reports on hepatotoxicity after the intake of green tea derivatives containing Camellia Sinensis have been published. We report a patient with an acute hepatitis after intake of an oral green tea derivative claiming protection against hair loss, showing a histological image compatible with drug induced hepatitis. Other important causes of hepatitis were excluded. After cessation of this nutritional additive there was a rapid and sustained recovery. We raise concern about the safety of nutritional additives with few proven beneficial effects and want to emphasize the importance of accurate and thorough history taking, with attention for over the counter drugs and herbal products.",1
11888,19640235,Acute neurotoxicity after yohimbine ingestion by a body builder,"""Yohimbine is an alkaloid obtained from the Corynanthe yohimbe tree and other biological sources. Yohimbine is currently approved in the United States for erectile dysfunction and has undergone resurgence in street use as an aphrodisiac and mild hallucinogen. In recent years yohimbine use has become common in body-building communities for its presumed lipolytic and sympathomimetic effects. We describe a 37-year-old bodybuilder in which severe acute neurotoxic effects occurred in 2 h after yohimbine ingestion. The patient presented with malaise, vomiting, loss of consciousness, and repeated seizures after ingestion of 5 g of yohimbine during a body-building competition in a gymnasium. His Glasgow Coma Score was 3, requiring orotracheal intubation. Two hours after admission, vital signs were blood pressure 259/107 mmHg and heart rate 140 beats/min. Treatment with furosemide, labetalol, clonidine, and urapidil and gastrointestinal decontamination were performed. Twelve hours later the patient was extubated with normal hemodynamic parameters and neurological examination. The yohimbine blood levels at 3, 6, 14, and 22 h after ingestion were 5,240; 2,250; 1,530; and 865 ng/mL, respectively, with a mean half-life of 2 h. Few data are available about yohimbine toxicity and the related blood levels. This is a case of a large ingestion of yohimbine in which severe hemodynamic and neurological manifestations occurred and elevated blood levels of yohimbine were detected.""",1
11889,19641858,Chronic myeloid leukemia patient manifesting fatal hepatitis B virus reactivation during treatment with imatinib rescued by liver transplantation: case report and literature review,"Imatinib mesylate (imatinib) is now a standard treatment for patients with chronic myeloid leukemia (CML). Although imatinib is known to have a potential impact on various infectious organisms by altering the T-cell mediated immune response, only two cases of hepatitis B virus (HBV) reactivation during imatinib treatment have actually been reported. The role of liver transplantation (LT) after fatal HBV reactivation in patients with potentially treatable or curable hematologic malignancy is also unknown. Therefore, this report presents a case of fatal HBV reactivation during imatinib treatment for CML, where the patient is rescued by LT. Following a successful living donor LT, the liver function improves rapidly and the patient remains in complete cytogenetic remission after retreatment with imatinib for 6 months. The present report also covers the role of tyrosine kinase inhibitor in triggering HBV reactivation and a literature review of fulminant hepatic failure in CML patients taking imatinib.",1
11890,19645709,Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness,"Invasive fungal infections (IFI) are common after lung transplantation and there are limited data for the use of antifungal prophylaxis in these patients. Our aim was to compare the safety and describe the effectiveness of universal prophylaxis with two azole regimens in lung transplant recipients. This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality. Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole.",1
11891,19646443,"Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial","BACKGROUND & AIMS: Therapy for polycystic liver is invasive, expensive, and has disappointing long-term results. Treatment with somatostatin analogues slowed kidney growth in patients with polycystic kidney disease (PKD) and reduced liver and kidney volume in a PKD rodent model. We evaluated the effects of lanreotide, a somatostatin analogue, in patients with polycystic liver because of autosomal-dominant (AD) PKD or autosomal-dominant polycystic liver disease (PCLD). METHODS: We performed a randomized, double-blind, placebo-controlled trial in 2 tertiary referral centers. Patients with polycystic liver (n = 54) were randomly assigned to groups given lanreotide (120 mg) or placebo, administered every 28 days for 24 weeks. The primary end point was the difference in total liver volume, measured by computerized tomography at weeks 0 and 24. Analyses were performed on an intention-to-treat basis. RESULTS: Baseline characteristics were comparable for both groups, except that more patients with ADPKD were assigned to the placebo group (P = .03). The mean liver volume decreased 2.9%, from 4606 mL (95% confidence interval (CI): 547-8665) to 4471 mL (95% CI: 542-8401 mL), in patients given lanreotide. In the placebo group, the mean liver volume increased 1.6%, from 4689 mL (95% CI: 613-8765 mL) to 4895 mL (95% CI: 739-9053 mL) (P < .01). Post hoc stratification for patients with ADPKD or PCLD revealed similar changes in liver volume, with statistically significant differences in patients given lanreotide (P < .01 for both diseases). CONCLUSIONS: In patients with polycystic liver, 6 months of treatment with lanreotide reduces liver volume.",1
11892,19648163,Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival,"BACKGROUND: The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. DESIGN AND METHODS: The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. RESULTS: Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13-21.95 and odds ratio 4.57, 95% confidence interval 1.01-20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38-33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00-36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46-8.45). CONCLUSIONS: Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival.",1
11893,19648225,Can ketamine prescribed for pain cause damage to the urinary tract?,"Presentation of three palliative care patients who were given ketamine as an analgesic and subsequently developed significant and debilitating urological symptoms. In one patient there was resolution of symptoms following cessation of ketamine, but some symptoms persisted until death in the other two. Possible mechanisms for damage to the urothelium by ketamine are suggested.",1
11894,19652053,Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer,"""PURPOSE: No previous prospective trials have been reported with sorafenib in patients with sunitinib-refractory metastatic renal cell cancer (MRCC). We conducted a multicenter study to determine the activity and tolerability of sorafenib as second-line therapy after sunitinib progression in MRCC. PATIENTS AND METHODS: Between January 2006 and September 2008, 52 patients were enrolled onto this single-arm phase II study. All patients received sorafenib 400 mg orally twice a day until disease progression or intolerable toxicity. The primary end point was objective response rate (complete or partial response) evaluated every 8 weeks by use of the Response Evaluation Criteria in Solid Tumors; secondary end points were toxicity, time to progression (TTP), and overall survival (OS). RESULTS: All patients were included in response and safety analyses. Partial responses were observed in 9.6% of patients (five of 52 patients; 95% CI, 5% to 17%) after two cycles. Grade 1 to 2 fatigue, diarrhea, nausea/vomiting, rash, and neutropenia were the most common side effects, noted in 16 (30.8%), 19 (36.5%), 20 (38.5%), 19 (36.5%), and 20 patients (38.5%), respectively. The most common grade 3 toxicity was diarrhea, noted in six patients (11.5%). Median TTP was 16 weeks (range, 8 to 40 weeks), and median OS was 32 weeks (range, 16 to 64 weeks). CONCLUSION: Although well tolerated, sorafenib shows limited efficacy in sunitinib-refractory MRCC. Further randomized trials comparing sorafenib with other drugs that target different biologic pathways are needed to define the best second-line treatment option in these patients.""",1
11895,19652065,Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules,"""PURPOSE: To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide. PATIENTS AND METHODS: Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m(2) 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m(2) 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images. RESULTS: Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted. CONCLUSION: Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.""",1
11896,19652076,Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia,"PURPOSE: To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML). PATIENTS AND METHODS: A phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m(2) daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel. RESULTS: The 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to >or= 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to >or= 160 weeks. Five patients (12%) remain alive post-transplantation at >or= 63, >or= 71, >or= 86, >or= 114, and >or= 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event. CONCLUSION: Clofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.",1
11897,19657276,Fatal subacute liver failure after repeated administration of sevoflurane anaesthesia,"Sevoflurane is a widely used halogenated inhalation anaesthetic. In comparison with other similar anaesthetics, it is not metabolized to potentially hepatotoxic trifluoroacetylated proteins. In this case report, we present a 66-year-old woman with breast carcinoma, who underwent sevoflurane general anaesthesia twice in 25 days. Soon after the second elective surgical procedure, jaundice and marked elevations in serum transaminases developed. The patient died 66 days thereafter. Autopsy results denied evidence of major cardiovascular abnormality, and histological examination confirmed massive liver cell necrosis with no feature of chronic liver injury. Sevoflurane anaesthesia was imputed as the cause after exclusion of other possible aetiological agents. Besides, coexistent malignant tumours found in the patient could have modulated the immunological response to the applied anaesthetic followed by fatal consequences.",1
11898,19660012,Overdose of meprobamate: plasma concentration and Glasgow Coma Scale,,1
11899,19664854,[Moxifloxacin and hepatic toxicity],,1
11900,19666995,"FDA's acetaminophen meeting sparks confusion, uncertainty",,1
11901,19669260,Hepatocellular adenoma: what is new in 2008,"Patients (85%) with hepatocellular adenoma (HCA) are women taking oral contraceptives. They can be divided into four subgroups according to their genotype/phenotype features. (1) Hepatocyte nuclear factor 1alpha (HNF1alpha) biallelic somatic mutations are observed in 35% of the HCA cases. It occurs in almost all cases in women. HNF1alpha-mutated HCA are most of the time, highly steatotic, with a lack of expression of liver fatty acid binding protein (LFABP) in immunohistochemistry analyses. Adenomatosis is frequently detected in this context. An HNF1alpha germline mutation is observed in less than 5% of HCA cases and can be associated with MODY 3 diabetes. (2) An activating beta-catenin mutation was found in 10% of HCA. These beta-catenin activated HCAs are observed in men and women, and specific risk factors, such as male hormone administration or glycogenosis, are associated with their development. Immunohistochemistry studies show that these HCAs overexpress beta-catenin (nuclear and cytoplasmic) and glutamine synthetase. This group of tumours has a higher risk of malignant transformation into hepatocellular carcinoma. (3) Inflammatory HCAs are observed in 40% of the cases, and they are most frequent in women but are also found in men. Lesions are characterised by inflammatory infiltrates, dystrophic arteries, sinusoidal dilatation and ductular reaction. They express serum amyloid A and C-reactive protein. In this group, GGT is frequently elevated, with a biological inflammatory syndrome present. Also, there are more overweight patients in this group. An additional 10% of inflammatory HCAs express beta-catenin, and are also at risk of malignant transformation. (4) Currently, less than 10% of HCAs are unclassified. It is hoped that in the near future it will be possible with clinical, biological and imaging data to predict in which of the 2 major groups (HNF1alpha-mutated HCA and inflammatory HCA) the patient belongs and to propose better guidelines in terms of surveillance and treatment.",1
11902,19669304,A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH),"PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is implicated in non-alcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF-alpha. We wanted to evaluate the efficacy of Pentoxifylline on NASH patients. METHODS: Patients with biopsy proven NASH and persistently elevated alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal were randomized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo. Liver function tests, serum lipids and TNF-alpha, Interleukin 6 (IL-6), and plasma hyaluronic acid were measured at baseline, at weeks 6 and 12. Categorical data were analyzed by Fisher's exact test while independent sample t-test and Mann-Whitney test were used for continuous data. RESULTS: Eleven patients were randomized into the Pentoxifylline and nine to the placebo group. After 3 months of treatment body mass index (BMI), ALT and aspartate aminotransferase (AST) decreased significantly in both groups. There was no difference between the two groups in reduction of BMI (P = 0.897). There was significantly greater reduction in AST in the Pentoxifylline group (P = 0.038). There was a trend toward lower ALT level (P = 0.065) in the Pentoxifylline group. TNF-alpha and IL-6 decreased significantly in both groups after treatment, but there was no significant difference between the two groups. CONCLUSION: Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls.",1
11903,19669383,A case of lamivudine-sensitive de novo acute hepatitis B induced by rituximab with the CHOP regimen for diffuse large B cell lymphoma,"A case of de novo acute hepatitis B that showed symptoms of general malaise and anorexia during rituximab therapy with the CHOP regimen for diffuse large B cell lymphoma is reported. Lamivudine was strikingly effective, showing a rapid recovery from liver damage with jaundice. Hepatitis B virus (HBV) DNA in serum became and stayed undetectable even after the withdrawal of lamivudine, although HBsAg remained positive over 42 months from the onset. Liver biopsy showed a picture suggestive of acute viral hepatitis with multinucleated giant hepatocytes and CD38-positive plasma cell infiltration into liver parenchyma. Immunohistochemically, CD3-positive T-cells were predominant cells that infiltrated in liver parenchyma, whereas CD20-positive B cells were essentially null. Hence, it is suggested from these findings that B lymphocytes might be crucial for the continuous latency in HBV infection and may give rise to de novo acute hepatitis B if totally deleted. Moreover, the CHOP regimen might have some additive effects with the repeated on-off use of corticosteroids to the onset of the disease. In addition, significance of plasma cell infiltration in this setting is discussed.",1
11904,19670918,"Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US","""BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD), the major hepatic manifestation of type 2 diabetes mellitus, is the most common liver disease in the US. Thiazolidinediones, a commonly used drug class for the treatment of type 2 diabetes, have emerged as a potentially useful treatment for NAFLD. There are, however, lingering concerns about their potential toxicity as well as emerging concerns about how to monitor for and assess hepatotoxicity. We conducted a randomized, long-term, double-blind, hepatic safety study at 171 centres in the US in which 2097 patients with type 2 diabetes received either pioglitazone or glibenclamide (glyburide). METHODS: Patients were randomized to receive either pioglitazone (15-45 mg once daily) or glibenclamide (5-15 mg once daily) for 3 years. The primary objective was to evaluate drug-induced liver injury manifested by liver enzyme elevations, measured every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint was a confirmed ALT greater than three times the upper limit of normal (>3 x ULN) with a secondary endpoint of 8 x ULN. MAIN RESULTS: The intent-to-treat population included 1051 pioglitazone-treated and 1046 glibenclamide-treated patients; of these, 411 pioglitazone patients and 413 glibenclamide patients completed the study. The incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617). Analyses of the secondary endpoints revealed no ALT >8 x ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 x ULN + total bilirubin 2 x ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 x ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p < or = 0.05) fewer cases of ALT >1.5 x ULN, aspartate aminotransferase >1.5 x ULN and gamma-glutamyl transpeptidase >1.5 x ULN were seen with pioglitazone compared with glibenclamide. No case of hepatic dysfunction or hepatic failure was reported in either treatment group; two cases of hepatic cirrhosis with glibenclamide were reported. CONCLUSION: This study demonstrates an hepatic safety profile of pioglitazone similar to that of glibenclamide in long-term use in patients with poorly controlled type 2 diabetes. Trial registration number (clinicaltrials.gov): NCT00494312.""",1
11905,19671697,"Comment on: Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy",,1
11906,19680221,"Hepatitis temporally associated with an herbal supplement containing artemisinin - Washington, 2008","""Artemisinins are a class of compounds that include artesunate, artemether, and artemisinin and have potent antimalarial activity. In combination with other drugs (artemisinin combination therapy), these compounds are the first-line treatment recommended by the World Health Organization for Plasmodium falciparum infections. Artemisinins have been available in the United States without a prescription as herbal supplements for at least 10 years; these supplements are marketed for general health maintenance and for treatment of parasitic infections and cancers. On August 27, 2008, CDC was notified of a patient who developed hepatitis after a 1-week course of an herbal supplement containing artemisinin. The patient had abdominal pain, dark urine, and laboratory results consistent with hepatitis (e.g., serum alanine aminotransferase of 898 IU/L [normal: 10-55 IU/L]). Samples of the supplement were sent to CDC and the Georgia Institute of Technology for analysis to determine the amount of artemisinin and to identify any contaminants. Analysis indicated that the supplement contained 94%-97% of the 100 mg of artemisinin stated on the packaging and the supplement contained no other common pharmaceutical active ingredients. Given the patient's clinical course and laboratory evaluation, CDC investigators concluded that the hepatitis might have been associated with ingestion of the herbal supplement containing artemisinin. More data are needed to establish any causal connection between artemisinin and hepatitis. Health-care providers should be aware of the possibility of hepatic toxicity in patients taking herbal supplements containing artemisinin.""",1
11907,19682195,Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease,"BACKGROUND AND AIMS: Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA. METHODS: The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA). RESULTS: Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < or = 3000/microL) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment (P = 0.0033). CONCLUSION: The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.",1
11908,19685452,Veto on vedolizumab (MLN0002) for Crohn's disease,,1
11909,19687370,Dronedarone,"Amiodarone is the most effective antiarrhythmic drug for maintaining sinus rhythm for patients with atrial fibrillation. Extra-cardiac side effects have been a limiting factor, especially during chronic use, and may offset its benefits. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been developed for the treatment of atrial fibrillation and atrial flutter. Similar to amiodarone, dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, the acetylcholine activated potassium current, peak sodium current, and L-type calcium current, and exhibits antiadrenergic effects. It has been studied for maintenance of sinus rhythm and control of ventricular response during episodes of atrial fibrillation. Dronedarone reduces mortality and morbidity in patients with high-risk atrial fibrillation, but may be unsafe in those with severe heart failure. This article will review evidence of safety and effectiveness of dronedarone in patients with atrial fibrillation.",1
11910,19694603,Hypersensitivity reaction to ranitidine: description of a case and review of the literature,"Ranitidine is an H2-receptor antagonist which is usually well tolerated. Hypersensitivity reactions to ranitidine, as well as other H2 antihistamines, have been rarely described. We report the case of a 47-year-old woman who developed an anaphylactic reaction to ranitidine used as intravenous premedication before anesthesia induction. The patient's history revealed that previous use of oral ranitidine for a peptic ulcer disease did not cause any adverse reaction. Intradermal test with ranitidine at a dilution of 1:100 gave an intense positive reaction. The protective role of H2-receptor antagonists as premedication is still unclear and should be carefully reconsidered on the basis of the available controversial evidence and the possible risk of hypersensitivity reactions.",1
11911,19695740,Is the oral acetylcysteine protocol the best treatment for late-presenting acetaminophen poisoning?,,1
11912,19697151,Insidious peripheral neuropathy occurring under treatment in infantile MTHFR deficiency,"5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency was diagnosed in a 1-month-old baby with signs of cerebral distress. Under a classic treatment using methionine supplementation, methyl donor (betaine) folinic acid, vitamin B(6) and vitamin B(12), the neuromotor development was satisfactory. At 15 years of age, however, despite no clear modification of the biochemical markers in body fluids, she developed a clinically overt peripheral axonal neuropathy. Only partial clinical improvement was obtained after reinforcement of betaine doses. Surveillance of the peripheral nerve is indicated in MTHFR deficiency, including in the infantile form with a good therapeutic compliance.",1
11913,19699593,A placebo-controlled trial of buspirone for the treatment of marijuana dependence,"""The present study investigated the potential efficacy of buspirone for treating marijuana dependence. Participants received either buspirone (maximum 60mg/day) (n=23) or matching placebo (n=27) for 12 weeks, each in conjunction with motivational interviewing. In the modified intention-to-treat analysis, the percentage of negative UDS results in the buspirone-treatment group was 18 percentage points higher than the placebo-treatment group (95% CI: -2% to 37%, p=0.071). On self-report, participants receiving buspirone reported not using marijuana 45.2% of days and participants receiving placebo reported not using 51.4% of days (p=0.55). An analysis of participants that completed the 12-week trial showed a significant difference in the percentage negative UDS (95% CI: 7-63%, p=0.014) and a trend for participants randomized to the buspirone-treatment group who completed treatment to achieve the first negative UDS result sooner than those participants treated with placebo (p=0.054). Further study with buspirone in this population may be warranted; however, strategies to enhance study retention and improve outcome measurement should be considered in future trials.""",1
11914,19701976,Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation,"Selective cyclooxygenase-2 (COX-2) inhibitors are widely used due to their efficacy and good safety profile. However, recent case reports have described varying degrees of liver injuries associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.",1
11915,19703814,Exenatide-induced acute pancreatitis,"OBJECTIVE: To report acute pancreatitis in a patient with non-insulin-dependent diabetes mellitus (NIDDM) receiving exenatide and critically review previous reports. METHODS: We describe clinical and laboratory data of a woman with probable exenatide-induced pancreatitis and apply the same criteria to previously published cases. RESULTS: A 64-year-old, nonalcoholic woman with NIDDM presented with a 1-month history of epigastric pain beginning 2 days after starting exenatide. Serum lipase concentration was 2700 U/L (reference range, 114-320 U/L), and serum amylase concentration was 131 U/L (reference range, 30-110 U/L). Liver function test results, lipid profile, and serum creatinine concentration were normal. Abdominal computed tomography (CT) showed changes consistent with pancreatitis, and the gallbladder was absent. Exenatide was discontinued. Conservative therapy resulted in rapid resolution of symptoms, normal lipase concentration (151 U/L), and normal findings from CT of the pancreas 90 days later. The US Food and Drug Administration has reported 36 cases of presumed pancreatitis associated with exenatide. However, none of the selection criteria were specified, two-thirds of the patients did not have CT, and 90% had at least 1 other risk factor for acute pancreatitis. A single published case report of exenatide-induced pancreatitis contains no description of the pancreas on abdominal CT, does not mention alcohol use, and does not report normal lipase values. CONCLUSIONS: This is the most thoroughly documented example of probable exenatide-induced pancreatitis. In any diabetic patient with acute pancreatitis, exenatide must be ruled out as the cause and its use discontinued.",1
11916,19706026,Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation,"DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a rare drug hypersensitivity reaction with a significant mortality. We describe a 60-year-old man with polyarthritis treated with sulfasalazine who developed DRESS and fulminant liver failure after additional vancomycin treatment. Liver histology revealed infiltration of granzymeB+ CD3+ lymphocytes in close proximity to apoptotic hepatocytes. After a superurgent liver transplantation and initial recovery, the patient developed recurrent generalized exanthema and eosinophilia, but only moderate hepatitis. Histology showed infiltration of FasL+ lymphocytes and eosinophils in the transplanted liver. Treatment with high-dose methylprednisolone was unsuccessful. Postmortem examination revealed extensive necrosis of the liver transplant. This case report illustrates that patients with DRESS may develop fulminant liver failure and that DRESS recurrence can recur in the transplanted liver. Histological and immunological investigations suggest an important role of granzymeB and FasL mediated cell death in DRESS associated hepatitis.",1
11917,19710593,"Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials","""OBJECTIVE: To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced adults infected with HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor and other antiretrovirals. DESIGN: DUET-1 (NCT00254046) and DUET-2 (NCT00255099) are two identically designed, randomized, double-blind phase III trials. METHODS: Patients received twice-daily etravirine 200 mg or placebo, each plus a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. Eligible patients had documented nonnucleoside reverse transcriptase inhibitor resistance, at least three primary protease inhibitor mutations at screening and were on a stable but virologically failing regimen for at least 8 weeks, with plasma viral load more than 5000 copies/ml. Pooled 48-week data from the two trials are presented. RESULTS: Patients (1203) were randomized and treated (n = 599, etravirine; n = 604, placebo). Significantly more patients in the etravirine than in the placebo group achieved viral load less than 50 copies/ml at week 48 (61 vs. 40%, respectively; P < 0.0001). Significantly fewer patients in the etravirine group experienced at least one confirmed or probable AIDS-defining illness/death (6 vs. 10%; P = 0.0408). Safety and tolerability in the etravirine group was comparable to the placebo group. Rash was the only adverse event to occur at a significantly higher incidence in the etravirine group (19 vs. 11%, respectively, P < 0.0001), occurring primarily in the second week of treatment. CONCLUSION: At 48 weeks, treatment-experienced patients receiving etravirine plus background regimen had statistically superior and durable virologic responses (viral load less than 50 copies/ml) than those receiving placebo plus background regimen, with comparable tolerability and no new safety signals reported since week 24.""",1
11918,19713003,[Candesartan-induced cholestatic hepatitis: a case report],,1
11919,19716960,Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials,"""BACKGROUND: The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. METHODS: In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 microg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. FINDINGS: Patients were assigned to treatment, stratified according to smoking status and treatment with longacting beta(2) agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV(1) increased by 48 mL with roflumilast compared with placebo (p<0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8-25], p<0.0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg. INTERPRETATION: Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. FUNDING: Nycomed.""",1
11920,19717844,Dabigatran versus warfarin in patients with atrial fibrillation,"""BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)""",1
11921,19719703,Exenatide efficacy and safety: a systematic review,"OBJECTIVE: To examine the efficacy, effectiveness and side effects of exenatide when compared with oral glucose-lowering agents or insulin therapy. RESEARCH DESIGN AND METHODS: Relevant citations were identified from searches of multiple bibliographic databases supplemented with searches of the US Food and Drug Administration website and other sources. A qualitative synthesis was performed, with a random effects meta-analysis when appropriate. RESULTS: We identified 17 studies. In placebo-controlled trials of subjects with poorly controlled diabetes (with both groups receiving various oral glucose-lowering agents), exenatide 10 microg twice daily improved glycated haemoglobin (HbA(1c)) by approximately 1.0% over 30 weeks [pooled estimate -0.97%, 95% confidence interval (CI), -1.16 to -0.79%, P < 0.0001] and exenatide treatment over 16-30 weeks was associated with weight loss of 1.0-2.5 kg. Exenatide appeared to confer a similar benefit to various insulin regimes for glycaemic control at follow-up between 16 and 52 weeks (pooled estimate HbA(1c)-0.04%, 95% CI, -0.14 to 0.06%, P = 0.41), but was advantageous over insulin with respect to weight loss (3-6 kg loss at up to 52 weeks of follow-up). Nausea was the most common adverse event in placebo- and active-controlled trials. Rates of hypoglycaemia were similar in exenatide and insulin groups, but were higher with exenatide 10 microg twice daily compared with placebo and hypoglycaemia was most frequent when a sulphonylurea was administered. CONCLUSIONS: In subjects with poorly controlled diabetes, exenatide was associated with a reduction in HbA(1c) that was similar to introducing another oral agent or insulin. Weight loss may be an advantage with exenatide. Long-term studies in diverse and unselected populations are needed to clarify the benefit vs. harm profile of this drug.",1
11922,19720812,Sitaxentan-induced hepatic failure in two patients with pulmonary arterial hypertension,,1
11923,19723392,The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection,"BACKGROUND: To examine chronic viral hepatitis (CVH) as a risk factor for hepatotoxicity during isoniazid (INH) treatment for latent tuberculosis infection (LTBI). METHODS: A search of MEDLINE (1966-May 2008) was conducted using the terms 'tuberculosis', 'antitubercular', 'therapeutics', 'treatment', 'prevention', 'prophylaxis', 'hepatitis', 'toxic hepatitis', 'hepatotoxic', 'liver' and 'injury'. Peer-reviewed, English-language articles describing the relationship between a history of CVH and occurrence of hepatotoxicity during LTBI treatment were selected. We limited CVH diagnoses to reports with positive serological test or biopsy for hepatitis B or C. Risk ratios and 95% confidence intervals were abstracted or derived. RESULTS: We reviewed 486 abstracts, and 11 studies met the selection criteria. Populations included in the studies were the general population (n = 6) and transplant recipients (n = 5). The variability in study designs and case finding practices precluded performing a quantitative meta-analysis. Two studies of former or current drug users reported a consistent, positive association between chronic hepatitis C infection and INH hepatotoxicity. Other risk ratios did not significantly or consistently show any association between CVH in patients treated for LTBI and the development of INH hepatotoxicity. CONCLUSION: Owing to the limited number of published papers, CVH was not established as a risk factor for INH hepatotoxicity during LTBI treatment. Controlled studies are needed to define the safety and tolerability of LTBI treatment in those with CVH and to provide an evidence base for recommendations for LTBI treatment in persons with CVH.",1
11924,19723821,Histologically proven isoniazid hepatoxicity in complicated tuberculous salpingitis,"Isoniazid (INH) hepatic injury is histologically indistinguishable from viral hepatitis and is related to individual susceptibility of patients who hydrolyze the drug to isonicotinic acid at different rates. We here present a case initially involving a complaint of lower abdominal pain, which was diagnosed after a long diagnostic work-up as tuberculous salpingitis and which is rare in women in developed countries. A lack of pulmonary effects further delayed correct diagnosis of the underlying tuberculosis infection. Based on the clinical follow up and liver histology, INH-induced severe hepatoxicity, which further contributed to the abdominal symptoms, could be confirmed. After adaptation of the standard therapeutic regimen no further complications occurred.",1
11925,19729225,[Benign recurrent intrahepatic cholestasis simulating cetirizine-induced toxic hepatitis],,1
11926,19731558,Elevated liver enzymes in HIV monoinfected patients on HIV therapy: what are the implications?,,1
11927,19732994,[Anticonvulsant hypersensitivity syndrome: an entity to be remembered],"Anticonvulsant hypersensitivity syndrome is an unpredictable, potentially fatal drug reaction to aromatic anticonvulsants such as carbamazepine, phenytoin and phenobarbital. The hallmark features include fever, eosinophilia, rash and involvement of one or more internal organs. Clearly established diagnostic criteria and treatment guidelines are lacking. A high index of suspicion is required to identify this syndrome, allowing early withdrawal of the drug and avoiding re-exposure. We report an illustrative case of anticonvulsant hypersensitivity syndrome and review the published literature.",1
11928,19734642,Gemcitabine-induced hepatitis in a pancreatic cancer patient receiving adjuvant therapy following metastasectomy,,1
11929,19737952,A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas,"BACKGROUND: Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC. METHODS: A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of <10% and detect a true response rate of > or =30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins. RESULTS: Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting >120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival. CONCLUSIONS: Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.",1
11930,19740406,Three cases of severe hepatic impairment caused by erlotinib,,1
11931,19743890,Balsalazide: a novel 5-aminosalicylate prodrug for the treatment of active ulcerative colitis,"BACKGROUND: 5-Aminosalicylate (5-ASA) agents are the mainstay of oral therapy for ulcerative colitis (UC). Balsalazide, a prodrug of 5-ASA, has recently been approved for the treatment of UC. OBJECTIVE: To summarize current data on balsalazide and to discuss its impact on management of UC. METHODS: A systematic review of published literature was performed on PubMed using the search terms 'Balsalazide' and 'Colazal(TM)'. The Cochrane database was also reviewed. RESULTS: Balsalzide, a 5-ASA prodrug, ulilizes azoreduction by colonic bacteria to achieve a sustained release of active 5-ASA throughout the colon. A recent clinical trial has demonstrated balsalazide 6.7 g/day to be superior to placebo in inducing remission in symptomatic UC. The drug is well tolerated with a safety profile comparable to other oral 5-ASA agents. The current data suggests that symptomatic remission occurs with both greater swiftness and greater frequency when compared with mesalamine. CONCLUSION: Balsalazide is approved for the treatment of mild-to-moderate active UC. It is efficacious for the induction of remission in mild to moderate UC and has a favorable safety profile, with the added advantages of greater efficacy of remission induction and rapidity of onset.",1
11932,19744017,Tumor lysis syndrome after starting treatment with Gleevec in a patient with chronic myelogenous leukemia,"Chronic myelogenous leukemia (CML) is one of the myeloproliferative disorders. It accounts for 15-20% of all leukemias in adults. The mainstay of diagnosis is the detection of Philadelphia chromosome or one of its products. Tyrosine kinase inhibitors changed the paradigm of treating such disease with the good responses. However, they do have side effects. In our case we will report tumor lysis syndrome happening after starting Imatinib myselate. We did a literature review and looked all the cases that documented this complication.",1
11933,19747360,"Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia","""The safety and efficacy of the combination clofarabine/cyclophosphamide/etoposide were evaluated in children with advanced acute lymphoblastic leukaemia (ALL). The study enrolled 25 paediatric patients (median age 12.5 years) with either refractory (n = 17; 68%) or multiple relapsed (n = 8; 32%) ALL to receive clofarabine 40 mg/m(2), cyclophosphamide 400 mg/m(2) and etoposide 150 mg/m(2), daily for 5 consecutive days. No patient died from treatment-related complications. The most common adverse events were febrile neutropenia, mucositis and reversible liver toxicity; no case of liver veno-occlusive disease was reported. The overall remission rate was 56%: 13 patients (52%) achieved complete remission (CR) and one (4%) CR without platelet recovery (CRp). In seven of the 13 (54%) patients achieving CR, remissions were of sufficient duration to allow patients to receive allogeneic haematopoietic stem cell transplantation. The probability of CR/CRp was greater in the 17 patients with B cell precursor ALL than in the eight with T-ALL (76% vs. 12%, respectively, P < 0.01). The 18-month overall survival probability was 39% and 0% in patients who did or did not respond to the treatment, respectively (P < 0.01). These data suggest that the clofarabine/cyclophosphamide/etoposide regimen is well tolerated and can induce clinical response in a relevant proportion of children with refractory/multiple relapsed ALL.""",1
11934,19751861,The effects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver: a systematic review,"BACKGROUND: This report evaluates the effects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver. METHODS: PubMed and Cochrane databases were searched from inception to June 2008 for publications that examined the use of hormonal contraceptives among women with viral hepatitis or cirrhosis of the liver. RESULTS: Six studies met the inclusion criteria. In one study of acute hepatitis, combined oral contraceptive (COC) use did not affect duration of hospitalization or successful disease resolution. The remainder of the studies examined chronic hepatitis or its sequelae. Women recovered from hepatitis experienced transaminase elevation with COC use which resolved after 4 weeks in one study or increased slightly over 6 months in another study. Hepatitis B virus carriers using COCs had similar transaminase levels as nonusing carriers over 6 months. Studies of chronic hepatitis C infection demonstrated no influence of COC use on progression or severity of liver fibrosis or development of hepatocellular carcinoma. CONCLUSION: Data from one study suggest that COCs do not affect the course of acute hepatitis. Limited data from studies on chronic hepatitis or its sequelae suggest that COC use does not affect the rate of progression or severity of cirrhotic fibrosis, the risk of hepatocellular carcinoma in women with chronic hepatitis, or the risk of liver dysfunction in hepatitis B virus carriers.",1
11935,19766640,Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis,"""BACKGROUND AND AIMS: It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. METHODS: A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. RESULTS: The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events. CONCLUSIONS: Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.""",1
11936,19770681,Acute pancreatitis in children with acute lymphoblastic leukemia treated with L-asparaginase,"BACKGROUND: L-asparaginase (L-asp) is used as part of the initial treatment in children with acute lymphoblastic leukemia (ALL), inducing remission in 83% to 95% of the treated patients. Major toxicity effects reported are hypersensitivity reactions and dysfunctions of the liver and pancreas. Acute pancreatitis (AP) induced by L-asp has been noted in 2.5% to 16% of the treated patients. The purpose of this study was to determine the frequency and outcome of AP in children with ALL treated with L-asp in a tertiary care pediatric hospital. METHODS: From January 1999 to June 2005, the charts of children with ALL admitted for L-asp treatment were reviewed. Data from children who developed AP were analyzed retrospectively. AP was defined as the presence of clinical data (nausea, vomiting, and abdominal pain), elevated pancreatic enzymes, and changes in the abdominal ultrasound and/or computed tomography (CT) scan. Clinical and biochemical data, abdominal ultrasound, and CT scan findings, complications, treatment, and outcome were analyzed retrospectively. RESULTS: During the last 6 years, 266 ALL new cases were started on chemotherapy including L-asp, of which 18 of 266 (6.7%) developed AP. Pancreatic necrosis by CT scan was found in 10 patients, peripancreatic collections and pseudocyst formation were detected in 5 and 3 cases, respectively, and resolved by cystogastrostomy or drainage. Two patients developed chronic pancreatitis and 3 diabetes. There was no relationship between number of doses and pancreatic toxicity. None of the patient died due to pancreatic toxicity. CONCLUSIONS: L-asp is an effective drug to treat ALL, the administration of L-asp requires the monitoring of pancreatic toxicity to detect AP and have treatment initiated as early as possible. Chronic complications after AP occur in almost one third of cases.",1
11937,19774214,Long-term efficacy and safety of letrozole for the adjuvant treatment of early breast cancer in postmenopausal women: a review,"Aromatase inhibitors (AIs) are becoming more widely used than tamoxifen as adjuvant hormonal therapy for postmenopausal women (PMW) with early breast cancer (EBC). It is clear that these drugs offer important efficacy benefits over tamoxifen and differ from tamoxifen in their safety profile. The accepted strategies for adjuvant AI therapy include initial adjuvant treatment following surgery, switching and/or sequencing from prior tamoxifen, and extended adjuvant therapy following the full 5 years of tamoxifen treatment. Among the available AIs, letrozole has been evaluated in large, well-controlled, double-blind clinical trials in the initial adjuvant, extended adjuvant, and more recently, the sequential adjuvant settings. Letrozole is the most potent of the AIs and provides near complete suppression of plasma estrogens in PMW. Letrozole also significantly reduces the occurrence of early distant metastases, the most lethal type of recurrence event, which can lead to improved survival. Clinical comparisons of letrozole with both tamoxifen and placebo have also provided important long-term safety data on the use of AIs as adjuvant therapy in PMW with EBC. The weight of clinical evidence indicates that letrozole is a safe and effective option for adjuvant hormonal therapy across all three AI treatment settings.",1
11938,19776295,Atenolol hepatotoxicity: report of a complicated case,"OBJECTIVE: To report a case of acute hepatitis related to atenolol administration in a liver transplant (LT) recipient. CASE SUMMARY: A 57-year-old woman was evaluated for LT because of liver failure due to cirrhosis of unknown origin. LT was performed in November 2006. In March 2007, results of liver function tests (LFTs) were within the reference ranges. She had received atenolol for hypertension for 3 years prior to surgery and it was reintroduced at a dose of 100 mg/day because of recurrence of hypertension. One month later, she presented with acute hepatitis. The first post-LT liver biopsy was performed. Histologic examination disclosed a combination of portal and centrilobular inflammatory lesions. The diagnosis of acute rejection was accepted and 3 bolus doses of prednisone 500 mg/day were administered. Evolution was not favorable and a second liver biopsy was obtained. Histologic examination showed the complete disappearance of portal inflammatory lesions but an increase of centrilobular lesions. Toxic hepatitis was suspected and atenolol was stopped. No other therapeutic modification was done and resolution of the toxicity was good. An objective causality assessment revealed that the adverse drug event was probable. DISCUSSION: This case report represents a very rare severe hepatotoxicity due to atenolol and illustrates the diagnostic difficulties raised by such clinical situations in the context of LT. It is noteworthy that the initial diagnosis considered in this patient was acute rejection. This diagnosis had to be reconsidered because of the unfavorable outcome, despite specific treatment of rejection. Moreover, the patient had been treated with atenolol for 3 years before LT: in the absence of any other etiology, the possibility that she had drug-induced cirrhosis may therefore be considered. The mechanism of beta-blocker-related hepatotoxicity is debatable. In our case, the composition of the inflammatory infiltrates observed in the liver biopsy specimens suggests an immune-mediated mechanism. CONCLUSIONS: Despite the fact that beta-blocker-induced hepatotoxicity is probably extremely rare, it must be suspected and the drug therefore discontinued.",1
11939,19781876,Suspected black cohosh hepatotoxicity--causality assessment versus safety signal,,1
11940,19783064,Emerging profile of cetuximab in non-small cell lung cancer,"This paper summarizes the phase II and III clinical trial experience with cetuximab in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Single-arm and randomized phase II studies show that adding cetuximab to platinum-based doublets has favorable efficacy compared to chemotherapy alone or historical control groups that did not receive cetuximab. Two phase III studies have been conducted with different primary endpoints: overall survival in the pivotal FLEX trial, and progression-free survival (PFS) as assessed by an independent radiologic review committee in the supportive BMS 099 trial. FLEX shows that adding cetuximab significantly prolongs survival compared to chemotherapy alone. BMS 099 did not meet its primary objective, but did show that adding cetuximab significantly prolongs PFS as assessed by investigators. Across all studies, the safety and tolerability of adding cetuximab was predictable and manageable, and did not exacerbate the toxicity associated with chemotherapy. These trials enrolled a broad population of NSCLC patients regardless of histological subtype or comorbid cardiovascular disease, populations that have been underrepresented in clinical trials of other biologics. Cetuximab does not carry restrictions in use due to safety, and therefore it may be a particularly valuable option for patients who are not eligible for other biologics.",1
11941,19783845,Capture compound mass spectrometry sheds light on the molecular mechanisms of liver toxicity of two Parkinson drugs,"Capture compound mass spectrometry (CCMS) is a novel technology that helps understand the molecular mechanism of the mode of action of small molecules. The Capture Compounds are trifunctional probes: A selectivity function (the drug) interacts with the proteins in a biological sample, a reactivity function (phenylazide) irreversibly forms a covalent bond, and a sorting function (biotin) allows the captured protein(s) to be isolated for mass spectrometric analysis. Tolcapone and entacapone are potent inhibitors of catechol-O-methyltransferase (COMT) for the treatment of Parkinson's disease. We aimed to understand the molecular basis of the difference of both drugs with respect to side effects. Using Capture Compounds with these drugs as selectivity functions, we were able to unambiguously and reproducibly isolate and identify their known target COMT. Tolcapone Capture Compounds captured five times more proteins than entacapone Capture Compounds. Moreover, tolcapone Capture Compounds isolated mitochondrial and peroxisomal proteins. The major tolcapone-protein interactions occurred with components of the respiratory chain and of the fatty acid beta-oxidation. Previously reported symptoms in tolcapone-treated rats suggested that tolcapone might act as decoupling reagent of the respiratory chain (Haasio et al., 2002b). Our results demonstrate that CCMS is an effective tool for the identification of a drug's potential off targets. It fills a gap in currently used in vitro screens for drug profiling that do not contain all the toxicologically relevant proteins. Thereby, CCMS has the potential to fill a technological need in drug safety assessment and helps reengineer or to reject drugs at an early preclinical stage.",1
11942,19786849,Phase II study of paclitaxel and irinotecan with intercalated gefitinib in patients with advanced non-small-cell lung cancer,"OBJECTIVES: We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) alternating with gefitinib (Gef) to determine the qualitative and quantitative toxicities and efficacy of this combination against advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with CPT at 60 mg/m2 and Pac at 160 mg/m2 on day 1 followed by Gef at 250 mg per day on days 8 to 14 every 3 weeks. RESULTS: Between April 2005 and March 2006, 16 patients received the chemotherapy with Pac and CPT alternating with Gef. Eleven patients received 4 to 6 cycles, except for 5 patients who discontinued treatment in the second or third cycles because of disease progression in 2, grade 3 pneumonitis with pulmonary infiltration in 2, and decreased performance status in 1. Grade 3 toxicities were neutropenia, an increased glutamic pyruvic transaminase level, allergy, pneumonitis, anorexia, and fatigue. Elevation of the serum glutamic oxaloacetic transaminase level after 1 cycle was the only grade 4 toxicity. Seven of 16 patients achieved a partial response and the overall response rate in the prospective study was 43.8%. The median survival time was 18.1 months. The 1- and 2-year survival rates were 56.3% and 43.8%, respectively. CONCLUSION: Pac and CPT combined with Gef was not effective enough for NSCLC.",1
11943,19789166,Nitrofurantoin-induced acute liver damage in pregnancy,"This article presents a rare case of acute toxic hepatitis in thirty-one-year old primigravida. In the 36th week of gestation, the patient was introduced nitrofurantoin 100 mg a day due to symptoms of dysuria and enterococcus isolated from urine culture. After induced delivery at term because of hypertension, repeated laboratory findings showed increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and negative hepatitis C and B markers. The patient was subicteric at the time. Coagulation and complete blood count values were within the normal range. Nitrofurantoin therapy was discontinued. Abdominal ultrasound was normal with the exception of a slight hepatomegaly without any lesions, focal or diffuse. Given that discontinuation of nitrofurantoin and introduction of methylprednisolon therapy significantly lowered liver enzyme levels, restoring most of them to normal, we concluded that this was probably the case of toxic liver damage caused by nitrofurantoin.",1
11944,19795041,Severe acute cholestasis caused by Teucrium polium,,1
11945,19797868,Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit,"Morinda citrifolia (noni) fruit juice has been approved as a safe food in many nations. A few cases of hepatitis in people who had been drinking noni juice have been reported, even though no causal link could be established between the liver injury and ingestion of the juice. To more fully evaluate the hepatotoxic potential of noni fruit juice, in vitro hepatotoxicity tests were conducted in human liver cells, HepG2 cell line. A subchronic oral toxicity test of noni fruit was also performed in Sprague-Dawley (SD) rats to provide benchmark data for understanding the safety of noni juice, without the potential confounding variables associated with many commercial noni juice products. Freeze-dried filtered noni fruit puree did not decrease HepG2 cell viability or induce neutral lipid accumulation and phospholipidosis. There were no histopathological changes or evidence of dose-responses in hematological and clinical chemistry measurements, including liver function tests. The no-observed-adverse-effect level (NOAEL) for freeze-dried noni fruit puree is greater than 6.86 g/kg body weight, equivalent to approximately 90 ml of noni fruit juice/kg. These findings corroborate previous conclusions that consumption of noni fruit juice is unlikely to induce adverse liver effects.",1
11946,19800146,[Topiramate-induced acute hepatitis],,1
11947,19801042,"Propofol infusion syndrome with arrhythmia, myocardial fat accumulation and cardiac failure","Propofol is a potent and widely used central-acting sedative drug. It has been implicated in the development of a usually fatal syndrome characterized by metabolic acidosis, rhabdomyolysis, ventricular arrhythmia, and Brugada-like cardiac rhythm disturbances, all leading to cardiac and renal failure. The investigators describe a 12-year-old male patient with a fatal case of this so-called propofol infusion syndrome. Postmortem investigation showed not only the well-known myocytolysis in skeletal and cardiac muscle but also not previously demonstrated widespread fat accumulation in the myocardium. In conclusion, this cardiac fat accumulation illustrates the proposed underlying pathophysiology of impaired (muscular) free fatty acid utilization.",1
11948,19807633,"An unusual case of recurrent fever, jaundice and right upper quadrant pain",,1
11949,19811848,Treatment of psoriasis in patients with hepatitis C: from the Medical Board of the National Psoriasis Foundation,"BACKGROUND: Treating psoriasis in patients with concomitant hepatitis C virus (HCV) infection presents a special challenge. Not only is psoriasis exacerbated by interferon therapy, the standard of care for HCV, but many psoriasis therapies are potentially hepatotoxic, immunosuppressive, or both, which has been generally thought to be a contraindication in chronic infections such as HCV. OBJECTIVE: Our aim was to arrive at a consensus on treating psoriasis in patients with concomitant HCV infection. METHODS: Reports in the literature were reviewed regarding common psoriasis therapies and liver toxicity. RESULTS: Topical therapies are first-line therapy for patients with limited psoriasis and HCV. Ultraviolet B phototherapy may be considered as a second-line treatment when needed. Ultraviolet B phototherapies in combination with topical therapies are first line for patients with moderate to severe psoriasis, and are considered safe in those patients with concomitant HCV infection. Other systemic therapies, such as acitretin, etanercept, and, possibly, other tumor necrosis factor inhibitors, are considered second line. Psoralen plus ultraviolet A should also be considered a second-line therapy. LIMITATIONS: There are few evidence-based studies on treating psoriasis with systemic therapy in patients with pre-existing liver disease. CONCLUSIONS: There are no large double-blind clinical trials addressing the treatment of psoriasis in patients with HCV infection and more studies are needed.",1
11950,19819595,[Linezolid-induced lactic acidosis],,1
11951,19822772,Long-term miglustat therapy in children with Niemann-Pick disease type C,"Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months' treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.",1
11952,19826128,Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma,"""PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or S?zary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.""",1
11953,19826974,Genetic association studies in drug-induced liver injury,"""Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the """"slow acetylator"""" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.""",1
11954,19826976,Drug-induced steatohepatitis leading to cirrhosis: long-term toxicity of amiodarone use,"Nonalcoholic steatosis/steatohepatitis is the most common cause for abnormal liver chemistries. Apart from metabolic syndrome, drugs may also lead to development of steatohepatitis that may, rarely, progress to cirrhosis and portal hypertension. We discuss a case of amiodarone-induced steatohepatitis with advanced fibrosis, presenting with hepatic decompensation and portal hypertension manifesting as ascites and recurrent esophageal variceal hemorrhage. Amiodarone is a lipophilic drug that concentrates in the liver and usually, over a period of time, leads to toxicity related to drug accumulation. There is marked histological similarity between amiodarone-induced liver disease and alcoholic and nonalcoholic steatohepatitis. The clinical manifestations of amiodarone-induced hepatotoxicity and the mechanism of toxicity are also discussed.",1
11955,19828470,"Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial","OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.",1
11956,19830433,Reactivation of chronic hepatitis B virus infection following rituximab administration for rheumatoid arthritis,,1
11957,19836097,Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximab,"BACKGROUNDS/AIMS: Hepatitis B virus (HBV) reactivation following treatment with rituximab has been reported in patients with either HBsAg-positive, or HBsAg-negative and anti-HBc positive infection. Patients with severe reactivation often have a fatal outcome despite treatment with lamivudine. The use of entecavir has not been reported in patients with severe HBV reactivation. METHODS: We present a case of a HBsAg-negative patient diagnosed with chronic lymphocytic leukemia who received a chemotherapeutic regimen that included rituximab, who subsequently presented with severe HBV reactivation with ascites, jaundice and coagulopathy and was treated with entecavir. A review of the literature and underlying HBV associated mutations are discussed. RESULTS: Entecavir produced a rapid and sustained suppression of HBV that was associated with rapid clinical improvement without any side effects. CONCLUSION: Entecavir is an efficacious and safe treatment for severe HBV reactivation.",1
11958,19839402,[Acute hepatitis as a side effect of albendazole: a pediatric case],"""We describe a case of acute hepatitis with jaundice in a patient of seven years of age in oral treatment with albendazole; a mild increase of liver function tests is a well-known side effect after prolonged administration but acute hepatitis has never been described in childhood.""",1
11959,19840307,Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS),"""OBJECTIVE: To review 32 pediatric patients with anticonvulsant hypersensitivity syndrome. DESIGN: Retrospectively, data and photographs were collected on 32 patients who had been diagnosed with anticonvulsant hypersensitivity syndrome. SETTING: The sections of dermatology at Children's Memorial Hospital in Chicago, Illinois, and Children's Mercy Hospitals and Clinics in Kansas City, Missouri. MAIN OUTCOME MEASURES: Presentation, implicated medications, laboratory evaluations, complications, treatment and outcome. RESULTS: The mean age of all patients with anticonvulsant hypersensitivity syndrome (ACHSS) was 8.9 years. The mean duration of anticonvulsant therapy before onset of symptoms was 3 weeks. Phenytoin, carbamazepine, and phenobarbital were the most commonly implicated medications. Lamotrigine, oxcarbamazepine, and primidone were implicated in some of our patients. Fever and rash were seen in all patients, while lymphadenopathy was found in 84.4% of patients. Hematologic abnormalities were seen in 93.8% and hepatic involvement was seen in 90.4% of cases, representing the two most commonly involved systems. Atypical lymphocytosis and eosinophilia was seen in 72% and 56% of patients, respectively. Renal and pulmonary involvement were each seen in 15.6% of cases. Systemic steroids were used in 59.4% of ACHSS patients; 16% of patients received intravenous immunoglobulin. No deaths were reported in our group of pediatric patients. CONCLUSIONS: The ACHSS is a distinct clinical entity which may occur in pediatric patients treated with anticonvulsants, and may have potentially life-threatening consequences. Involvement of multiple organ systems, including the hematologic, hepatic, renal, and pulmonary systems was common. Treatment varied widely, but ranged from supportive care to systemic corticosteroids.""",1
11960,19842040,Apoplexy in non functioning pituitary adenoma after one dose of leuprolide as treatment for prostate cancer,"We report the case of a 60 year old male who complained of headache and blurry vision--that progressed to left ophthalmoplegia and ptosis--after receiving a dose of leuprolide for Prostate cancer therapy. Imaging showed a hemorrhagic sellar mass. The patient underwent transsphenoidal debulking, and the tissue obtained demonstrated immunohistochemical staining for LH. A literature review revealed nine previously reported cases of pituitary apoplexy after GnRH agonist therapy for prostate cancer. In most cases, the sellar tissues stained for LH, consistent with a gonadotropinoma. The pathophysiology of these events is unclear, but recent animal models suggest possible explanations. The predominance of gonadotropinomas is important because they do not usually present with hypersecretory symptoms. Particular attention to clinical findings suggestive of a non functioning pituitary tumor in patients receiving GnRH agonist therapy is critical as routine screening with MRI is not practical.",1
11961,19843838,A comprehensive review of the loop diuretics: should furosemide be first line?,"""OBJECTIVE: To review the literature regarding the pharmacokinetic profiles, comparative safety and efficacy, and comparative costs of loop diuretics to evaluate the current clinical usefulness of furosemide. DATA SOURCES: A search of MEDLINE (1966-June 2009) was conducted using the terms furosemide, torsemide, bumetanide, ethacrynic acid, and loop diuretics. Articles were limited to those written in English. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. Studies were eligible if they encompassed pharmacokinetics, comparative safety and efficacy, or comparative costs of the loop diuretics. DATA SYNTHESIS: In patients with heart failure (HF), torsemide demonstrated decreased mortality compared with furosemide in 1 study (2.2% vs 4.5% in the furosemide group; p < 0.05), decreased hospitalizations in 1 study (23 in the torsemide group vs 61 in the furosemide group; p < 0.01), and improved New York Heart Association functional classifications in 2 studies. In the first, 45.8% with torsemide versus 37.2% with furosemide demonstrated improvement in at least one functional class (p = 0.00017). In the second, 40.2% with torsemide and 30.7% with furosemide demonstrated improvement in at least one functional class (p = 0.014). In 2 of 3 studies of patients with cirrhosis, torsemide increased natriuresis and total volume diuresed compared with furosemide in patients with cirrhosis; however, no significant difference between the agents with respect to plasma renin and aldosterone concentrations was demonstrated. In patients with pulmonary hypertension, central venous pressure, capillary wedge pressure, and stroke volume significantly improved from baseline among patients who received torsemide, but not in those who received furosemide, although the intergroup analysis failed to reach statistical significance. Among patients with chronic kidney disease, no significant differences were noted with respect to natriuresis and blood pressure control between the 2 agents; however, in patients with acute kidney injury, patients who received furosemide had a significant improvement in urine output versus the torsemide group. Additionally, 2 trials comparing bumetanide with furosemide were identified, although the results were conflicting. In patients with nephrotic syndrome, bumetanide significantly improved weight loss in the first 4 weeks and in week 20, compared with furosemide. In patients with HF, significant improvement in dyspnea at rest and on exertion was exhibited in the bumetanide group, but not in the furosemide group; no significant difference was noted between the 2 groups when evaluating global assessment. CONCLUSIONS: Growing evidence demonstrates more favorable pharmacokinetic profiles of torsemide and bumetanide compared with furosemide. Furthermore, torsemide may be more efficacious and safer than furosemide in patients with HF. A trial comparing all 3 drugs would be required to confirm torsemide as the primary loop diuretic in patients with HF, but based upon limited current evidence, we recommend torsemide over furosemide. Currently, little evidence exists to support either torsemide or bumetanide as first-line treatment over furosemide in patients with other edematous disease states.""",1
11962,19848345,[Hepatic adverse effects of allopurinol],,1
11963,19852530,Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer,"""Gefitinib (Iressa) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that offers treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in particular in those who are harbouring EGFR mutations. In a large phase III trial (IPASS) in chemotherapy-naive Asian patients with adenocarcinoma who were never smokers or former light smokers, oral gefitinib was more effective than carboplatin plus paclitaxel in prolonging progression-free survival (PFS). In a prespecified subgroup analysis, EGFR-mutation-positive status was associated with a positive response to gefitinib treatment. Furthermore, a trial in chemotherapy-naive patients with NSCLC that was restricted to those with EGFR mutations found that gefitinib recipients had significantly longer PFS than carboplatin plus paclitaxel recipients. In large phase III trials (INTEREST, V-15-32) in unselected, previously treated patients, the overall survival (OS) in gefitinib recipients was noninferior to, or not significantly different from, that of docetaxel recipients. In a placebo-controlled trial in previously treated patients (ISEL), pre-planned subgroup analyses in Asian patients and non-smokers showed that in these subgroups gefitinib prolonged OS, and that EGFR biomarkers predicted a positive response to gefitinib. Gefitinib was also associated with greater improvements in quality of life (QOL) in both chemotherapy-naive and previously treated patients. A head-to-head trial of gefitinib versus erlotinib in EGFR-mutation-positive patients would help position gefitinib relative to erlotinib in this population. Further research is also required to identify factors associated with non-response to EGFR-tyrosine-kinase inhibitors in EGFR-mutation-positive patients. Gefitinib was a generally well tolerated treatment, with rash and diarrhoea being the most common treatment-emergent adverse events. Interstitial lung disease (ILD) is a serious co-morbidity of NSCLC associated with gefitinib and other cancer treatments; ILD-type events occurred with an overall incidence of approximately 1% in gefitinib recipients participating in clinical trials, and were more common in Asian patients. Notably, gefitinib was associated with significantly fewer haematological and neurological adverse effects than comparator chemotherapy regimens. Gefitinib as monotherapy is an effective treatment for patients with locally advanced or metastatic NSCLC with EGFR mutations.""",1
11964,19857081,"The safety of flavocoxid, a medical food, in the dietary management of knee osteoarthritis","""This study was designed to determine the safety of a medical food, flavocoxid, a proprietary blend of free-B ring flavonoids and flavans from the root of Scutellaria baicalensis (Chinese skullcap) and the bark of Acacia catechu in the dietary management of knee osteoarthritis. The 12-week, randomized, double-blind, placebo-controlled trial in an academic medical center enrolled 59 patients with moderate osteoarthritis of at least one knee who were recruited who were classified as having """"below average"""" to """"a moderately above average cardiovascular risk"""" with a Framingham-based scoring tool. Subjects were randomized to flavocoxid 250 mg twice a day versus identical placebo. Safety measures, including recording of adverse events, incidence of serious adverse events, and results of routine laboratory values, were compared between the two groups. There were no major differences in the baseline demographic characteristics of the placebo and flavocoxid groups. With one exception no significant differences were found between the two groups with respect to adverse events by body system, blood pressure, or laboratory values. There was a significantly higher incidence of upper respiratory adverse events in the placebo group (35.4% vs. 5.8%, P = .0003). There were no intra- or inter-group differences in any of the laboratory parameters from study baseline to completion. Thus, flavocoxid is safe when used in a population with """"below average"""" to """"moderately above average cardiovascular risk"""" compared to placebo.""",1
11965,19858119,Comment on: Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate,,1
11966,19862667,Long-term Safety and Tolerability of Colesevelam HCl in Subjects with Type 2 Diabetes,"""The bile acid sequestrant, colesevelam hydrochloride, is approved for glycemic control in adults with type 2 diabetes. In three double-masked, placebo-controlled studies, colesevelam hydrochloride 3.75 g/day demonstrated its glycemic-lowering properties when added to existing metformin-, insulin-, or sulfonylurea-based therapy in adults with inadequately controlled type 2 diabetes. This was a 52-week open-label extension study conducted at 63 sites in the United States and one site in Mexico to further evaluate the safety and tolerability of colesevelam hydrochloride in subjects with type 2 diabetes. All subjects who completed the three double-masked, placebo-controlled studies were eligible to enroll in this open-label extension. In total, 509 subjects enrolled and received open-label colesevelam hydrochloride 3.75 g/day for 52 weeks. Safety and tolerability of colesevelam hydrochloride was evaluated by the incidence and severity of adverse events. In total, 360 subjects (70.7%) completed the extension. Of the safety population, 361 subjects (70.9%) experienced an adverse event, most (88.1%) being mild or moderate in severity. Fifty-six adverse events (11.0%) were drug-related; the most frequent drug-related adverse events were constipation and dyspepsia. Thirty-five subjects (6.9%) discontinued due to an adverse event. Fifty-four subjects (10.6%) experienced a serious adverse event; only one was considered drug-related (diverticulitis). Seventeen subjects (3.3%) experienced hypoglycemia; most episodes were mild or moderate in severity. Glycemic improvements with colesevelam hydrochloride were seen without change in weight over 52 weeks (0.2 kg mean reduction from baseline). Colesevelam hydrochloride was safe and well-tolerated as long-term therapy for patients with type 2 diabetes.""",1
11967,19874308,Severe liver dysfunction from hepatitis C virus reactivation following alemtuzumab treatment for chronic lymphocytic leukaemia,,1
11968,19874950,"Micronutrients in parenteral nutrition: boron, silicon, and fluoride","Boron may be beneficial for bone growth and maintenance, central nervous system function, and the inflammatory response, and silicon may be beneficial for bone maintenance and wound healing. Fluoride is not an essential element but amounts provided by contamination may be beneficial for bone strength. Fluoride toxicity may be a concern in parenteral nutrition. Further studies are warranted to determine whether there are optimal amounts of boron and silicon that should be delivered to typical and special population patients receiving parenteral nutrition. In addition, further studies are needed to determine whether providing the dietary guideline of adequate intake amounts of fluoride parenterally would prevent or treat parenteral nutrition osteopenia.",1
11969,19876849,A retrospective evaluation of shortened-duration oral N-acetylcysteine for the treatment of acetaminophen poisoning,"""INTRODUCTION: The use of less than the traditional 72-hour course of oral N-acetylcysteine has been an alternative treatment option following potentially toxic acute and chronic acetaminophen ingestions felt to be at low risk of developing hepatotoxicity. While clinical experience with shortened treatment duration is extensive, there are few studies evaluating the effectiveness and extent to which these regimens may be used. METHODS: A large statewide poison center database was reviewed for all acetaminophen exposures involving potentially toxic acute and chronic ingestions, in addition to those taking place at unknown times. Patients were identified who met laboratory criteria for early N-acetylcysteine (NAC) discontinuation (APAP>10 micro/mL, INR<or=1.3, and AST/ALT<or=60 IU) after a minimum of a 140-mg/kg oral NAC loading dose and 5 additional 70-mg/kg doses over 20 hours. A further search of the poison center database was conducted for individuals who received shortened-course (20-48 hours) oral NAC treatment who developed subsequent hepatotoxicity or death. RESULTS: Of 3303 individuals with potentially toxic acetaminophen ingestions, 1932 met criteria for early NAC discontinuation. Mean treatment duration was 36.4+/-7.7 hours (acute=37.3+/-7.6 hours; chronic=34.8+/-7.4 hours; unknown=35.2+/-7.6 hours). The poison center database search identified no short-course eligible subjects who developed subsequent hepatotoxicity or death following<or=48 hours of oral NAC. CONCLUSION: Treatment with shortened-course oral NAC in patients meeting criteria for early discontinuation may be an effective treatment option in a sizeable proportion of individuals with potentially toxic acetaminophen ingestions.""",1
11970,19877219,"A prospective randomized open study in liver transplant recipients: daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids","This open-label, randomized study compared the efficacy of a regimen of corticosteroids and tacrolimus (standard therapy group, n = 79) with a regimen of daclizumab induction therapy in combination with mycophenolate mofetil and tacrolimus (modified therapy group, n = 78) in primary liver transplant recipients. The primary endpoint was biopsy-proven acute rejection (BPAR) at 24 weeks. Secondary endpoints included time to rejection and patient and graft survival. The incidence of BPAR was significantly reduced in the modified therapy group compared to the standard therapy group (11.5% versus 26.6%, respectively, P = 0.017). The time to rejection was significantly shorter in the standard therapy group compared with the modified therapy group (P = 0.044). There was no significant difference between groups in patient or graft survival. Hepatitis C virus-positive patients exhibited no differences from hepatitis C virus-negative patients with respect to the incidence of BPAR. A steroid-sparing regimen of daclizumab, mycophenolate mofetil, and tacrolimus was effective and well tolerated in the prevention of BPAR in adult liver transplant recipients in comparison with a standard regimen of tacrolimus and steroids.",1
11971,19877725,Pediatric safety of tizanidine: clinical adverse event database and retrospective chart assessment,"""BACKGROUND: Tizanidine is an imidazoline with central alpha(2)-adrenoceptor agonist activity at both spinal and supraspinal levels, which is indicated as a short-acting drug for the management of spasticity. Despite being used in pediatric populations, there is no adequate information or well controlled studies to document the safety and efficacy of tizanidine in this group. OBJECTIVE: To evaluate the safety of tizanidine in the pediatric population. We compared spontaneous adverse event reports in the Acorda Therapeutics worldwide clinical adverse event database for children (< or = 16 years; n = 99) and adults (>16 years; n = 1153) who had received tizanidine and for whom at least one adverse event was reported, and performed a retrospective chart review of the safety of tizanidine in children (< or = 16 years; n = 76) at a large US pediatric neurology practice. Causality of adverse events in our worldwide clinical adverse event database were neither assessed nor assigned by the company. RESULTS: When adverse events from the clinical adverse event database were collapsed into the 25 Medical Dictionary for Regulatory Activities (MedDRA; version 9.0) organ system classes, five classes were more frequent in adults (general disorders and administration site conditions [p = 0.0006], hepatobiliary disorders [p = 0.0031], nervous system disorders [p = 0.0108], skin and subcutaneous disorders [p = 0.0063], and vascular disorders [p = 0.0029]), while one class was more frequent in children (psychiatric disorders [p < 0.0001]). The most common adverse event classes in children were psychiatric disorders (52.5%) followed by nervous system disorders (29.3%), and gastrointestinal disorders (16.2%), whereas the most common adverse event classes in adults were nervous system disorders (42.4%), general disorders and administration site conditions (28.6%), and gastrointestinal disorders (21.3%). Serious adverse events were substantially less frequent in children than adults (19.2% vs 45.9%) in the clinical adverse event database. In the pediatric practice chart review, the incidence of adverse events in the MedDRA psychiatric disorders class was very similar (52.6%) to that for children in the clinical adverse event database, while the next most common classes were gastrointestinal disorders (14.5%), and nervous system disorders (13.2%). There were three deaths in children across the databases, including one from accidental exposure and two from cardiac events; the relationship of cardiac events in relation to tizanidine or other causes was difficult to assess with the limited available information.The major causes of death in adults were related to suicide or overdose. Minor, transient liver transaminase increases were occasionally reported; the effect of tizanidine could not be ruled out. CONCLUSION: The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.""",1
11972,19879596,Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia,"""OBJECTIVE: Evaluate the efficacy and safety of colesevelam hydrochloride in children with heterozygous familial hypercholesterolemia (heFH). STUDY DESIGN: This was a randomized, double-blind, 41-site study in 194 children aged 10 to 17 years (inclusive) with heFH (statin-na?ve or on a stable statin regimen). After a 4-week stabilization period (period I), subjects were randomized 1:1:1 to placebo, colesevelam 1.875 g/d, or colesevelam 3.75 g/d for 8 weeks (period II). All then received open-label colesevelam 3.75 g/d for 18 weeks (period III), with follow-up 2 weeks later. The primary endpoint was percent change in low-density lipoprotein (LDL)-cholesterol from baseline to week 8. Secondary endpoints included percent change in other lipoprotein variables, including non-high-density lipoprotein (non-HDL)-cholesterol. Adverse events were also evaluated. RESULTS: At week 8, a significant difference from baseline in LDL-cholesterol was reported with colesevelam 1.875 g/d (-6.3%; P = .031) and colesevelam 3.75 g/d (-12.5%; P < .001) compared with placebo. Significant treatment effects were also reported for total cholesterol (-7.4%), non-HDL-cholesterol (-10.9%), HDL-cholesterol (+6.1%), apolipoprotein A-I (+6.9%), and apolipoprotein B (-8.3%) and a nonsignificant effect for triglycerides (+5.1%) with colesevelam 3.75 g/d compared with placebo at week 8. These treatment effects were maintained during period III. CONCLUSIONS: Colesevelam significantly lowered LDL-cholesterol levels in children with heFH.""",1
11973,19880688,Lupus-like syndrome attributable to anti-tumor necrosis factor alpha therapy in 14 patients during an 8-year period at Mayo Clinic,"""OBJECTIVE: To examine clinical characteristics, laboratory features, and outcomes of patients with lupus-like syndrome attributable to anti-tumor necrosis factor alpha (TNF-alpha) therapy. PATIENTS AND METHODS: We performed a retrospective review of patients with lupus-like syndrome attributable to anti-TNF-alpha therapy at Mayo Clinic's site in Rochester, MN, between July 1, 2000, and June 30, 2008. RESULTS: Of 14 patients (mean age at disease onset, 46.2 years), 12 (86%) were female. Ten patients (71%) had Crohn disease, and 4 (29%) had rheumatoid arthritis. Thirteen patients (93%) originally were treated with infliximab, and 1 (7%) was treated with adalimumab. A lupus-ike syndrome occurred after a mean treatment duration of 16.2 months. Features of lupus included presence of antinuclear antibodies (14 patients [100%]), arthritis (13 patients [93%]), anti-double-stranded-DNA antibodies (10 patients [71%]), cutaneous findings (malar rash, discoid rash, or photosensitivity, 4 patients [29%]), serositis (4 patients [29%]), hematologic abnormalities (4 patients [29%]), oral ulcers (4 patients [29%]), and lupus anticoagulant (1 patient [7%]). No patient had renal or neurologic abnormalities. All patients improved after stopping anti-TNF-alpha therapy (mean time to improvement, 2.9 months). Four (80%) of 5 patients tolerated an alternative TNF-alpha inhibitor (adalimumab, 3 patients; etanercept, 1 patient) without recurrence of lupus-like syndrome. CONCLUSION: Compared with previous studies, cutaneous findings were less frequent and arthritis was more frequent in our cohort of patients. Some patients were able to tolerate an alternative TNF-alpha inhibitor without recurrence of lupus-like syndrome.""",1
11974,19883714,Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice,"The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been studied for chronic disease preventive effects, and is marketed as part of many dietary supplements. However, case-reports have associated the use of green tea-based supplements with liver toxicity. We studied the hepatotoxic effects of high dose EGCG in male CF-1 mice. A single dose of EGCG (1500 mg/kg, i.g.) increased plasma alanine aminotransferase (ALT) by 138-fold and reduced survival by 85%. Once-daily dosing with EGCG increased hepatotoxic response. Plasma ALT levels were increased 184-fold following two once-daily doses of 750 mg/kg, i.g. EGCG. Moderate to severe hepatic necrosis was observed following treatment with EGCG. EGCG hepatotoxicity was associated with oxidative stress including increased hepatic lipid peroxidation (5-fold increase), plasma 8-isoprostane (9.5-fold increase) and increased hepatic metallothionein and gamma-histone 2AX protein expression. EGCG also increased plasma interleukin-6 and monocyte chemoattractant protein-1. Our results indicate that higher bolus doses of EGCG are hepatotoxic to mice. Further studies on the dose-dependent hepatotoxic effects of EGCG and the underlying mechanisms are important given the increasing use of green tea dietary supplements, which may deliver much higher plasma and tissue concentrations of EGCG than tea beverages.",1
11975,19885811,[Two cases of serious hepatic injury caused by antithyroid drugs],We present two cases of severe hepatotoxicity caused by antithyroid drugs in women with Graves disease. The first medication in both cases was methimazole replaced by propylhiouracil due to intolerance. The main symptom was jaundice lasting about 2 months. As a first step in the treatment we terminated the antithyroid drug administration and introduced prednisone and ursodesoksycholic acid therapy. The termination of thyrotoxicosis by means of 131 I administration had also positive influence on the course of disease. In summary we emphasise the significance of prompt discontinuation of antithyroid drug once toxic symptoms appeared and avoid replacement one thyrostatic drug for another in fovour of radioiodine treatment.,1
11976,19888250,Hepatitis with cholestasis caused by rivastigmine transdermal patch,,1
11977,19889479,[Hepatotoxicity induced by new immunosuppressants],"Immunosuppressants are among the pharmacological agents with the greatest potential to cause adverse reactions, although induction of hepatotoxicity is paradoxical from the pathogenic point of view, since the response of the innate and acquired immune system is a key element in the chain of events leading to chemical liver damage. Hepatotoxicity induced by immunosuppressants is difficult to evaluate since these drugs are sometimes used to treat liver diseases, or in combination with other drugs that can also cause hepatotoxicity, or in the context of liver transplantation, in which rejection or biliary complications can act as confounding factors. In addition, immunosuppressant therapy can favor the development of infections, which by themselves can cause liver damage, or reactivate latent chronic viral hepatitis. Corticosteroids and calcineurin inhibitors only exceptionally cause hepatotoxicity. Methotrexate at high doses and in patients with risk factors can induce advanced fibrosis and cirrhosis. Thiopurine agents can cause a spectrum of hepatic lesions, including hepatocellular of cholestatic lesions, and hepatic vascular alterations. Leflunomide has high hepatotoxic potential, especially when combined with methotrexate. Anti-tumor necrosis factor-alpha agents have rarely been associated with hepatotoxicity, often with detectable autoantibodies, and most of the reactions - some severe - have been linked to infliximab, especially when used in patients with rheumatological diseases.",1
11978,19895648,Fatal liver injury associated with clopidogrel,"Clopidogrel, an adenosine diphosphate receptor blocker, is widely used as an adjunctive antiplatelet therapy in acute coronary syndrome and percutaneous coronary stenting. It appears to be a safe drug with few occurrences of liver side-effects that usually resolved after drug withdrawal. We report a serious liver injury with fatal outcome in a 63-year-old man developed 19 days after starting clopidogrel for percutaneous coronary stenting.",1
11979,19906050,Vanishing bile duct syndrome associated with azithromycin in a 62-year-old man,"Vanishing bile duct syndrome is a severe cholestatic disease associated with toxic effects of medications. Stevens-Johnson syndrome is a hypersensitivity disorder that may also be caused by medications. We present a case of a 62-year-old male patient who developed vanishing bile duct syndrome a month after Stevens-Johnson syndrome. These adverse drug reactions were associated with the use of azithromycin (500 mg daily for 3 days). The patient was initially treated for Stevens-Johnson syndrome with steroids, antihistamines and proton pump inhibitors and fully recovered. However, a month after the beginning of Stevens-Johnson syndrome, he developed vanishing bile duct syndrome and was treated with steroids, ursodeoxycholic acid, antihistamines and tacrolimus. Unfortunately, the treatment was unsuccessful and he was listed for liver transplantation which was performed 7 months after the beginning of jaundice. This is the first case of vanishing bile duct syndrome associated with the use of azithromycin and one of few that reports vanishing bile duct syndrome and Stevens-Johnson syndrome co-occurrence.",1
11980,19906627,Didanosine withdrawal is associated with improved liver function tests,,1
11981,19910731,Management of clozapine-related hepatotoxicity,,1
11982,19911936,4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity,"""BACKGROUND: One-third of the world's population is infected with tuberculosis, and 9 months of isoniazid monotherapy is the treatment of choice for latent tuberculosis infection. However, this approach has been associated with hepatotoxicity and poor compliance. A shorter (4-month) rifampin regimen has been evaluated in recent clinical trials. METHODS: We performed a meta-analysis of the published studies to compare compliance, toxicity, and cost-effectiveness between the 2 strategies. Pooled effects were calculated as risk ratios (RRs) by means of random-effects and fixed-effects models. RESULTS: Pooled data from 3586 patients suggested that 4-month rifampin therapy was associated with a significant reduction in the risk of noncompletion (RR for random-effects model, 0.53; 95% confidence interval [CI], 0.44-0.63). Noncompletion rates were lower among patients who received 4-month rifampin therapy (range, 8.6%-28.4%), compared with noncompletion rates among patients who received 9-month isoniazid therapy (range, 24.1%-47.4%). Also, rates of hepatotoxicity (defined as grade 3 or 4 liver failure leading to drug discontinuation) were lower for patients who received 4-month rifampin therapy (range, 0%-0.7%), compared with the corresponding rates for patients who received 9-month isoniazid therapy (range, 1.4%-5.2%), and rifampin was associated with significant reduction in the risk of hepatotoxicity (RR for fixed-effects model, 0.12; 95% CI, 0.05-0.30). Notably, with the data from our meta-analysis, we calculated that the 4-month rifampin strategy is also cost-effective and results in $213 savings per patient treated ($90/patient when doctor fees are not included). CONCLUSIONS: The improved compliance, safety, and cost associated with the 4-month rifampin therapy suggest that the efficacy of this approach needs to be evaluated in detail. An extended posttreatment follow-up in future studies will clarify the unresolved issue of tuberculosis reactivation rates.""",1
11983,19916579,Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing,"Evidence is accumulating for the early sustained usage of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis. Leflunomide was licensed for the treatment of rheumatoid arthritis in 1998. Postmarketing surveillance, case reports and observational studies have highlighted less common or unexpected adverse events. Therefore, it is appropriate that we review the benefit-risk profile of leflunomide after 10 years of widespread usage. A wide-based search of relevant literature was performed to formulate this assessment. The improvements in rheumatoid arthritis shown by double-blind, randomized controlled trials (RCTs) of leflunomide have now been shown to be maintained beyond 4 years in open-label extension studies. Leflunomide is comparable to methotrexate, but better than sulfasalazine at 24 months in only one study. However, tolerance in clinical practice research shows higher than expected withdrawal rates due to both toxicity and lack of efficacy when compared with methotrexate and placebo. Adverse events reported include gastrointestinal upset, hypertension, headache, hepatotoxicity and hair loss, as well as predisposition to infection and peripheral neuropathy. The incidence of gastrointestinal adverse effects for leflunomide is similar to sulfasalazine but higher than those seen with methotrexate. Serious drug-induced hepatotoxicity leading to hospitalization is rare (0.02%), but isolated fatalities from liver failure have been documented. It is considered likely, but not yet proven, that there may be an increased incidence of weight loss and interstitial lung disease with leflunomide. Leflunomide in combination with methotrexate or sulfasalazine is an effective regimen in RCTs utilizing placebo controls, but more research is needed to confirm its effectiveness in combination with other DMARDs, particularly biologicals. The active metabolite of leflunomide is teratogenic in animal studies and is also found in breast milk. Therefore, contraception is advised in both males and females of child-bearing potential. There are genetic, pharmacokinetic and biochemical reasons to explain variation in both patient response and adverse event profile. Hence, blood and blood pressure monitoring are recommended and therapeutic drug monitoring should be considered in clinical nonresponders. Leflunomide is an effective DMARD that sustains a clinical and radiological response comparable to sulfasalazine and methotrexate. However, adverse effects necessitate frequent monitoring. It should be used with caution in those of child-bearing potential and with pre-existing lung and liver disease.",1
11984,19920916,Experience with the once-yearly histrelin (GnRHa) subcutaneous implant in the treatment of central precocious puberty,"In 2007, a hydrogel histrelin implant was approved for the treatment of children with central precocious puberty (CPP). Children with CPP commonly have reduced height potential due to premature closure of the epiphyseal growth plates from exposure to sex steroids. Gonadotropin-releasing hormone analog (GnRHa) treatment halts puberty and allows for improvement of adult height. A hydrogel implant delivery system utilizing the potent GnRHa, histrelin, was first developed for use in men with prostate cancer. A once yearly histrelin subcutaneous implant was subsequently developed for the treatment of children with CPP. Studies to date have demonstrated safety, tolerability, and effectiveness of this treatment option in patients treated up to 2 years. The most common adverse effects of the implant relate to implant site pain or bruising. Cost of this treatment seems comparable to somewhat higher than the commonly used GnRHa treatment option, depot leuprolide. While long term studies are needed to establish continued efficacy and safety beyond 2 years of treatment, the histrelin implant appears to be an attractive option for GnRHa treatment in patients with CPP.",1
11985,19924579,Mortality and drug exposure in a 5-year cohort of patients with chronic liver disease,"""BACKGROUND: Chronic liver diseases are common in the general population. Drug treatment in this group may be challenging, as many drugs are hepatically metabolised and hepatotoxic. OBJECTIVES: We aimed to assess the mortality of patients with chronic liver disease according to specific drug exposures and the three laboratory parameters creatinine, bilirubin and International Normalised Ratio (INR). METHODS: We conducted a multicentre, 5-year retrospective cohort study in two tertiary university referral hospitals and a secondary referral hospital, using a research database to evaluate the crude and adjusted mortality. RESULTS: Of 1159362 individual patients 1.7% (n = 20158) had chronic liver disease and in this group 36.8% had unspecified chronic non-alcoholic liver disease, 30.1% chronic hepatitis C and 11.9% cirrhosis of the liver. 8.4% of patients presented a diagnosis associated with alcohol. The 4-year survival rates were significantly higher in the group with the most normal laboratory values (94.3%) versus 34.5% in the group with elevated parameters (p <0.001). Overall, drug exposure was not associated with higher mortality; in adjusted multivariate analysis the hazard ratio for anti-cancer drugs was 2.69 (95% CI 1.32-5.46). Of individual drugs, mortality hazard ratios for amiodarone, morphine oral, acetazolamide, sirolimus and lamivudine were 2.46 (95% CI 1.68-3.61), 2.26 (95% CI 1.78-2.86), 2.10 (95% CI 1.19-3.70), 1.81 (95% CI 1.02-3.21) and 1.72 (95% CI 1.17-2.53) respectively. CONCLUSIONS: Drug exposure in general was not associated with higher mortality except for a few categories. Mortality in patients with chronic liver disease was high and is associated with simple laboratory values.""",1
11986,19935411,Hepatotoxicity after high-dose methylprednisolone for demyelinating disease,"Liver toxicity, although not mentioned among the possible adverse effects of corticosteroids, has been occasionally reported in literature. We observed 2 cases of hepatotoxicity after a high-dose methylprednisolone treatment of a demyelinating disease and evaluated the potential relationship in the light of available evidence. The first patient developed a histologically documented acute hepatitis and recovered after 3 weeks. In the second patient, a mild augmentation of liver enzymes occurred, followed by normalization in a few days. The causal relationship between hepatotoxicity and methylprednisolone treatment was deemed probable in both cases. Careful review of the literature suggests that corticosteroid-induced liver damage may be more frequent than commonly believed.",1
11987,19940816,Antifungal drugs,,1
11988,19941696,"Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study","We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [-5.2 (21.5)] and PP 100 mg eq. [-7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56-71%), mild (24-39%), moderate (2-12%), or severe (0-2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.",1
11989,19944093,Hypervitaminosis A inducing intra-hepatic cholestasis--a rare case report,"The use of over-the-counter supplements is commonplace in today's health conscious society. We present an unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one Herbalife shake with two multivitamin tablets of the same brand for 12 years. When calculated this equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care providers documenting non-prescribed dietary supplements and considering them in the etiology of cholestatic liver disease.",1
11990,19949017,Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen,"""PURPOSE: To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2). MATERIALS AND METHODS: Data submitted to the Early Breast Cancer Trialists' Collaborative Group were used in separate meta-analyses of two cohorts. Primary analyses involve postmenopausal women with tumors reported to be estrogen receptor positive. Log-rank P values are two-sided. RESULTS: Cohort 1 comprised 9,856 patients with a mean of 5.8 years of follow-up. At 5 years, AI therapy was associated with an absolute 2.9% (SE = 0.7%) decrease in recurrence (9.6% for AI v 12.6% for tamoxifen; 2P < .00001) and a nonsignificant absolute 1.1% (SE = 0.5%) decrease in breast cancer mortality (4.8% for AI v 5.9% for tamoxifen; 2P = .1). Cohort 2 comprised 9,015 patients with a mean of 3.9 years of follow-up. At 3 years from treatment divergence (ie, approximately 5 years after starting hormonal treatment), AI therapy was associated with an absolute 3.1% (SE = 0.6%) decrease in recurrence (5.0% for AI v 8.1% for tamoxifen since divergence; 2P < .00001) and an absolute 0.7% (SE = 0.3%) decrease in breast cancer mortality (1.7% for AI v 2.4% for tamoxifen since divergence; 2P = .02). There was no convincing heterogeneity in the proportional recurrence reduction with respect to age, nodal status, tumor grade, or progesterone receptor status and no indication of an increase in nonbreast deaths with AIs in either cohort. CONCLUSION AIs produce significantly lower recurrence rates compared with tamoxifen, either as initial monotherapy or after 2 to 3 years of tamoxifen. Additional follow-up will provide clearer information on long-term survival.""",1
11991,19951112,Voriconazole pharmacokinetics and pharmacodynamics in children,"""BACKGROUND: Voriconazole pharmacokinetic and pharmacodynamic data are lacking in children. METHODS: Records at the Childrens Hospital Los Angeles were reviewed for children with > or =1 serum voriconazole concentration measured from 1 May 2006 through 1 June 2007. Information on demographic characteristics, dosing histories, serum concentrations, toxicity and survival, and outcomes was obtained. RESULTS: A total of 207 voriconazole measurements were obtained from 46 patients (age, 0.8-20.5 years). A 2-compartment Michaelis-Menten pharmacokinetic model fit the data best but explained only 80% of the observed variability. The crude mortality rate was 28%, and each trough serum voriconazole concentration <1000 ng/mL was associated with a 2.6-fold increased odds of death (95% confidence interval, 1.6-4.8; P=.002). Serum voriconazole concentrations were not associated with hepatotoxicity. Simulations predicted an intravenous dose of 7 mg/kg or an oral dose of 200 mg twice daily would achieve a trough >1000 ng/mL in most patients, but with a wide range of possible concentrations. CONCLUSIONS: We found a pharmacodynamic association between a voriconazole trough >1000 ng/mL and survival and marked pharmacokinetic variability, particularly after enteral dosing, justifying the measurement of serum concentrations.""",1
11992,19955344,Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies,"Rufinamide is a novel antiepileptic agent recently approved in the United States for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. To help inform clinical decision making, the authors analyzed safety and tolerability data from the entire pediatric population in the rufinamide epilepsy clinical development program. The analysis population comprised 212 rufinamide-treated (age range 3-16 years) and 197 placebo patients (age range 4-17 years) in the double-blind studies, and 391 patients receiving rufinamide in the double-blind and/or open-label extensions. The most common adverse effects observed in rufinamide-treated patients in the double-blind studies were somnolence, vomiting, and headache. Changes in laboratory values, vital signs, and weight were generally clinically insignificant. This pooled analysis of data from pediatric patients in clinical studies of rufinamide for the treatment of seizures, mainly as adjunctive therapy, suggests a favorable safety and tolerability profile in this patient population.",1
11993,19957035,Long-term tegaserod treatment for dysmotility-like functional dyspepsia: results of two identical 1-year cohort studies,"BACKGROUND: Functional dyspepsia (FD) is a chronic disorder that adversely affects health-related quality of life (HRQoL). Published information on its long-term management is minimal and treatment options are limited. AIM: The aim of this study was to evaluate safety, efficacy and HRQoL with tegaserod 6 mg twice daily over 1 year in women with FD who completed one of two 6-week, randomized, placebo-controlled, double-blind studies. METHODS: About 780 patients received tegaserod 6 mg twice daily in two identical 1-year extension studies. Scheduled assessments included adverse events, the Short-Form Nepean Dyspepsia Index (SF-NDI), Work Productivity and Activity Impairment-Dyspepsia (WPAI-Dyspepsia) questionnaire, and patient perceptions of treatment efficacy. RESULTS: Mean tegaserod treatment duration in the two studies was 236 and 222 days. Most adverse events occurred in the first 6 months, were similar to previous reports (commonly diarrhea), and were transient and well tolerated. SF-NDI, WPAI-Dyspepsia scores and perceived symptom relief improved from baseline over the 1-year evaluation. CONCLUSIONS: The long-term safety profile of tegaserod in women with FD was consistent with that of short-term treatment and accompanied by improvements in HRQoL, work productivity and symptom relief. These long-term results add to the clinical experience with FD and support the potential value of a 5-HT(4) agonist in the management of FD.",1
11994,19963097,Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma,"""Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.""",1
11995,19966341,Dabigatran versus warfarin in the treatment of acute venous thromboembolism,"""BACKGROUND: The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. METHODS: In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. RESULTS: A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). CONCLUSIONS: For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.)""",1
11996,19995399,Salvage treatment for children with refractory first or second relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study,"The prognosis of children with relapsed/refractory acute myeloid leukaemia (AML) is poor, and new therapies are needed. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to the antitumor antibiotic calicheamicin. We conducted an investigator-initiated phase II study with GO to assess its efficacy and safety, administering two dosages of 7.5 mg/m(2) with a 14 d-interval. Thirty children who were refractory to re-induction at first relapse or suffered from second relapse of AML received a total of 64 infusions of GO. The response rate [complete remission (CR) and CR with insufficient platelet recovery] was 37%. Nine patients were subsequently transplanted (median time to transplant, 4 weeks, range 3-21 weeks), and three of these patients are currently in continuous CR with a median follow-up of >3 years, and can considered to be cured. This resulted in a statistically significant survival advantage for children who responded to GO versus those who did not [27% (standard error 13%) vs. 0%, respectively, P = 0.001]. All other children died, mainly from progressive disease. The treatment was generally well tolerated by most patients. The frequency of transient transaminatis was low. All but one patient received defibrotide prophylaxis during the transplant procedure, and no cases of veno-occlusive disease were noted. This study showed a favourable safety/efficacy profile of single-agent GO in children with refractory first or second relapse of AML.",1
11997,19996196,Pirfenidone in idiopathic pulmonary fibrosis,"""Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.""",1
11998,20000310,FPIN's Clinical Inquiries. Aspirin use in children for fever or viral syndromes,"Aspirin should not be used to treat acute febrile viral illness in children. (Strength of Recommendation [SOR]: C, based on case-control studies). Although no causal link has been proven, data from case-control and historic cohort studies demonstrate an association between aspirin use and Reye syndrome. The risk of Reye syndrome decreases with age, becoming extremely rare by the late teenage years. Other nonsteroidal anti-inflammatory drugs are effective antipyretics and are not associated with the constellation of symptoms seen in Reye syndrome, which includes nausea, vomiting, headache, excitability, delirium, combativeness, and coma. Aspirin use in children younger than 19 years should be limited to diseases in which aspirin has a proven benefit, such as Kawasaki disease and the juvenile arthritides. (SOR: C, based on expert opinion).",1
11999,20006208,Bajiaolian poisoning-a poisoning with high misdiagnostic rate,"BACKGROUND: One of the oldest Chinese herbal medicine, bajiaolian is widely used in traditional therapy. In Taiwan, bajiaolian is the fifth highest cause of poisoning among herbal medicines. The diagnosis is difficult because physicians are unfamiliar with this medicine's multiple presentations in different stages of intoxication. PROCEDURES: The records of 4 major poison centers in Taiwan were searched for all bajiaolian intoxication from July 1985 (the opening of first poison center) to March 2003. Two emergency physicians with toxicologic training reviewed the admission charts and visited case patients for follow-up. FINDINGS: Seventeen patients were identified, of which 15 (88.2%) had been misdiagnosed initially. In the beginning of their medical care, 14 cases were diagnosed as acute gastroenteritis. CONCLUSION: Bajiaolian intoxication is probably misdiagnosed because of early gastrointestinal symptoms followed by neurologic symptoms. A detailed patient history should be taken, and symptoms should be reviewed systemically to improve diagnostic accuracy.",1
12000,20009116,Glycogenic hepatopathy: a rare cause of elevated serum transaminases in diabetes mellitus,"Glycogenic hepatopathy (GH) is a rare cause of serum transaminase elevations in type 1 diabetes mellitus (DM). We describe a 29-year-old woman with a history of poorly controlled type 1 DM who presented with hepatomegaly and severe transaminase flares. Liver histology confirmed GH, with glycogen accumulation due to severe fluctuations in both glucose and insulin. GH can be regarded as an adult variant of Mauriac's syndrome. Despite severe laboratory abnormalities, it does not cause liver cirrhosis. Treatment consists of improving glycaemic control.",1
12001,20009146,Ciprofloxacin-induced acute cholestatic hepatitis,,1
12002,20012484,Efficacy and safety of lubiprostone in patients with chronic constipation,"""AIMS: The aim of this study is to assess the efficacy and safety of lubiprostone in adults with chronic constipation. METHODS: This multicenter, parallel-group trial enrolled 237 patients with chronic constipation and randomized them to 4 weeks of double-blind treatment with oral lubiprostone 24 mcg or placebo twice daily. The primary efficacy endpoint was the number of spontaneous bowel movements (SBMs) after 1 week of treatment. Secondary evaluations included SBMs at weeks 2, 3, and 4; percentage of patients with a SBM within 24 h of first study dose; stool consistency; degree of straining; constipation severity; abdominal bloating and discomfort; global treatment effectiveness; and safety assessments. RESULTS: Lubiprostone-treated patients experienced greater mean numbers of SBMs at week 1 compared with placebo (5.89 versus 3.99, P = 0.0001), with significantly greater percentages having SBMs within 24 h of the first dose (61.3% versus 31.4%, P < 0.0001). At each assessment, SBM frequency and percentages of full responders (> or =4 SBM per week) were significantly greater among lubiprostone-treated patients compared with placebo (P < or = 0.0171). Lubiprostone-treated patients reported significant improvements in stool consistency, straining, and constipation severity at all weeks, and in abdominal bloating at week 1. Patient assessments of treatment effectiveness were significantly greater with lubiprostone compared with placebo at all weeks (P < 0.0004). Gastrointestinal-related disorders were the most common adverse events in both treatment groups. CONCLUSIONS: In patients with chronic constipation, lubiprostone produced a bowel movement in the majority of individuals within 24 h of initial dosing, with sustained improvement in frequency as well as other constipation symptoms over 4 weeks of treatment.""",1
12003,20014183,"A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL)","BACKGROUND: Despite limited preclinical and clinical investigations, milk thistle (MT) is often used for the treatment of chemotherapy-associated hepatotoxicity. Limited treatment options exist for chemotherapy-related hepatoxicity. Given the wide use of MT, the authors investigated MT in both the laboratory and a clinical setting. METHODS: In a double-blind study, children with acute lymphoblastic leukemia (ALL) and hepatic toxicity were randomized to MT or placebo orally for 28 days. Liver function tests were evaluated during the study period. To assess MT in vitro, the authors evaluated supratherapeutic concentrations in an ALL cell line. RESULTS: Fifty children were enrolled. No significant differences in frequency of side effects, incidence and severity of toxicities, or infections were observed between groups. There were no significant changes in mean amino alanine transferase (ALT), aspartate amino transferase (AST), or total bilirubin (TB) at Day 28. At Day 56, the MT group had a significantly lower AST (P = .05) and a trend toward a significantly lower ALT (P = .07). Although not significantly different, chemotherapy doses were reduced in 61% of the MT group compared with 72% of the placebo group. In vitro experiments revealed no antagonistic interactions between MT and vincristine or L-asparaginase in CCRF-CEM cells. A modest synergistic effect with vincristine was observed. CONCLUSIONS: In children with ALL and liver toxicity, MT was associated with a trend toward significant reductions in liver toxicity. MT did not antagonize the effects of chemotherapy agents used for the treatment of ALL. Future study is needed to determine the most effective dose and duration of MT and its effect on hepatotoxicity and leukemia-free survival.",1
12004,20017669,Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique,"""AIMS: Nevirapine is widely used to treat HIV-1 infection to prevent mother-to-child transmission; unfortunately adverse drug reactions have been reported. Our aim was to identify genes/variants involved in nevirapine-induced hepatotoxicity. MATERIALS & METHODS: Patients from Mozambique, 78 with nevirapine-induced hepatotoxicity and 78 without adverse events, were genotyped for ABCB1, CYP2B6, CYP3A4 and CYP3A5 gene variants. We conducted a case-control association study and a genotype/phenotype correlation analysis. RESULTS: The ABCB1 c.3435C>T SNP was associated with hepatotoxicity (p = 0.038), with the variant T allele showing a protective effect (odds ratio: 0.42). Moreover, four SNPs in the CYP2B6 and CYP3A5 genes resulted significantly correlated with transaminase values. In particular, for the CYP2B6 c.983T>C SNP, the difference in the alanine aminotransferase mean values were highly significant between TT and TC genotypes (p < 0.001). CONCLUSION: Our preliminary results confirm the contribution of the ABCB1 c.3435C>T SNP in nevirapine-induced hepatotoxicity risk and, at the same time, suggest the necessity for further studies.""",1
12005,20021666,Tetrabenazine as anti-chorea therapy in Huntington disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators,"""BACKGROUND: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (Neurology 2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD. METHODS: Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale. RESULTS: Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysarthria [corrected] scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg). CONCLUSIONS: TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia. TRIAL REGISTRATION: Clinicaltrials.gov registration number (initial study): NCT00219804.""",1
12006,20028520,Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist,"PURPOSE: We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA). METHODS: Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction. RESULTS: In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month. CONCLUSIONS: Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.",1
12007,20032006,Hepatic safety profile of raltegravir in HIV-infected patients with chronic hepatitis C,"""BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection experience antiretroviral-associated liver toxicity more frequently than HIV mono-infected persons. Herein, we report the hepatic safety profile of raltegravir in a relatively large group of HIV/HCV co-infected patients, a population that was poorly represented in the registrational studies. METHODS: Prospective, observational study of all antiretroviral-experienced HIV-infected patients who initiated raltegravir from January 2006 to January 2009 at a reference HIV clinic. Clinical data, laboratory parameters and liver stiffness measured at baseline, week 4 and every 3 months thereafter were collected. Chronic hepatitis C was defined as positive serum HCV-RNA. Grade 1-4 hepatotoxicity was defined following the AIDS Clinical Trials Group definition for liver enzyme elevations (LEEs). A control group of patients who initiated protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) was examined similarly. RESULTS: Data from 218 HIV-infected patients on raltegravir were analysed, 126 HIV mono-infected and 92 HIV/HCV co-infected patients. Any degree of LEEs occurred in 10 (7.9%) HIV mono-infected and 23 (25%) co-infected patients (relative risk 3.1; 95% confidence interval 2.9-3.4; P = 0.002). Severe hepatotoxicity (grade 3-4), however, was only seen in 3 (1.4%) patients, all co-infected with HCV. It occurred at months 1, 15 and 15, respectively. In all three subjects other reasons than raltegravir exposure most likely explained LEEs. Multivariate analysis revealed HCV co-infection as the only independent variable associated with any degree of hepatotoxicity on raltegravir (P = 0.03). Finally, the rate of LEEs in patients on raltegravir was lower than in those who were treated with PIs or NNRTIs. CONCLUSIONS: LEEs are less frequent in patients treated with raltegravir than with other antiretroviral drug classes. However, HIV/HCV co-infected patients treated with raltegravir experienced LEEs more frequently than HIV mono-infected persons. In this series, LEEs in patients treated with raltegravir were uniformly mild and no cases of grade 3-4 hepatotoxicity could be directly attributed to the drug. These results reinforce the overall hepatic safety profile of raltegravir.""",1
12008,20037312,[Predictive factors for histopathological liver injury in the patients who received preoperative systemic chemotherapy for colorectal liver metastases],"The operation for liver metastases from colorectal cancer is increasing due to a progress of chemotherapy. On the other hand, the live damage induced by chemotherapy affects on post operative course. We studied histopathological liver injury on the patients who received preoperative chemotherapy. Between January 2004 and May 2009, forty seven patients underwent hepatectomy for colorectal liver metastases after systemic chemotherapy, and the remnant liver was histopathologically investigated about sinusoidal dilatation and non-alcoholic steatohepatitis. As a result, chemotherapy including irinotecan or oxaliplatin was significantly associated with sinusoidal dilatation, and female gender or higher body mass index was correlated with non-alcoholic steatohepatitis. These results should be taken into consideration before liver resection in patients who have received preoperative chemotherapy.",1
12009,20043026,Pazopanib,"""In October 2009, pazopanib (Votrient; GlaxoSmithKline)--a multikinase inhibitor with targets that include vascular endothelial growth factor receptors--was approved by the US FDA for the treatment of advanced renal cell carcinoma.""",1
12010,20052860,Margosa (Kohomba) oil induced toxic encephalopathy following home remedy for intestinal worms,,1
12011,20057324,Clofarabine-induced capillary leak syndrome in a child with refractory acute lymphoblastic leukemia,"Clofarabine has significant efficiency in children with relapsed or refractory leukemia. In previous pediatric trials, various adverse effects have been described. In this case, we report a child with refractory acute lymphoblastic leukemia who developed fatal capillary leak syndrome during clofarabine therapy.",1
12012,20062998,Effect of etanercept and entecavil in a patient with rheumatoid arthritis who is a hepatitis B carrier: a review of the literature,"In this report, we describe a case of a 48-year-old Japanese woman who is a hepatitis B (HB) carrier with rheumatoid arthritis (RA). She had the following antibody profile: HBs Ag(+), HBs Ab(-), HBe Ag(-), HBe Ab (+), HBc Ab(-) and undetectable HBV-DNA level. She was treated with auranofin, salazosulfapyridine, and bucillamine. Finally, she was treated with D: -penicillamine, but her disease activity remained elevated. Prophylactic treatment of entecavir 0.5 mg daily was started in March 2008 and all disease-modifying anti-rheumatic drugs were stopped. After 2 weeks, etanercept monotherapy was started at 25 mg subcutaneously once a week. Significant improvement in clinical parameters of disease activity and well being was observed. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and HB virus viral load did not change significantly. Serum ALT, AST, and HB virus viral load were followed-up at every 3-month intervals, from initiation of therapy up to 24 months after the start of treatment with etanercept. We have also summarized the course of nine RA patients who received etanercept and were HB carriers or had chronic HB according to our literature search. Based on the results of our study, treatment of these patients with etanercept co-administered with lamivudine or entecavir appears to be safe.",1
12013,20065189,Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer,"""PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.""",1
12014,20067958,Efficacy and safety of lacosamide in painful diabetic neuropathy,"""OBJECTIVE: To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy. RESEARCH DESIGN AND METHODS: Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks. RESULTS: For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar. CONCLUSIONS: Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.""",1
12015,20071701,Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis,"""BACKGROUND: Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit-risk profiles of such therapies are not well known. We compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor necrosis factor alpha), for the treatment of psoriasis. METHODS: We randomly assigned 903 patients with moderate-to-severe psoriasis to receive subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). The primary end point was the proportion of patients with at least 75% improvement in the psoriasis area-and-severity index (PASI) at week 12; a secondary end point was the proportion with cleared or minimal disease on the basis of the physician's global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a crossover from etanercept to ustekinumab were evaluated after week 12. RESULTS: There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, respectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physician's global assessment, as compared with 49.0% of those who received etanercept (P<0.001 for both comparisons). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab. One or more adverse events occurred through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab. CONCLUSIONS: The efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of high-dose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov number, NCT00454584.)""",1
12016,20074411,Outcomes and safety of concomitant nevirapine and rifampicin treatment under programme conditions in Malawi,"SETTING: Thyolo District Hospital, rural Malawi. OBJECTIVES: To report on 1) clinical, immunological and virological outcomes and 2) safety among human immunodeficiency virus (HIV) infected patients with tuberculosis (TB) who received concurrent nevirapine (NVP) and rifampicin (RMP) based treatment. DESIGN: Retrospective cohort study. METHODS: Analysis of programme data, June-December 2007. RESULTS: Of a total of 156 HIV-infected TB patients who started NVP-based antiretroviral treatment, 136 (87%) completed TB treatment successfully, 16 (10%) died and 5 (4%) were transferred out. Mean body weight and CD4 gain (adults) were respectively 4.4 kg (95%CI 3.3-5.4) and 140 cells/mm(3) (95%CI 117-162). Seventy-four per cent of patients who completed TB treatment and had a viral load performed (n = 74) had undetectable levels (<50 copies/ml), while 17 (22%) had a viral load of 50-1000 copies/ml. Hepatotoxicity was present in 2 (1.3%) patients at baseline. Two patients developed Grade 2 and one developed Grade 3 alanine transaminase enzyme elevations during TB treatment (incidence rate per 10 years of follow-up 4.2, 95%CI 1.4-13.1). There were no reported deaths linked to hepatotoxicity. CONCLUSIONS: In a rural district in Malawi, concomitant NVP and RMP treatment is associated with good TB treatment outcomes and appears safe. Further follow-up of patients would be useful to ascertain the longer-term effects of this concurrent treatment.",1
12017,20076813,Amiodarone hepatotoxicity in the context of the metabolic syndrome and right-sided heart failure,"BACKGROUND: Amiodarone is associated with varying degrees of hepatotoxicity. AIMS: to study the association between the presence of the metabolic syndrome or right-sided heart failure and the prevalence of amiodarone induced liver disease. METHODS: Retrospective chart review of patients who received amiodarone for > or =60 days at a university affiliated community hospital. We collected information about clinical progression and liver chemistries on 409 included patients. Subgroup analysis was based on the presence or absence of right-sided heart failure and the metabolic syndrome. RESULTS: The 409 patients (58% male, 55% Caucasian) had a mean age of 62 years, mean follow up of 37.6 months and mean cumulative amiodarone dose of 295+/-404 grams. No subjects developed clinical hepatitis, cirrhosis or death related to amiodarone. Eight patients developed amiodarone hepatotoxicity, 5 required discontinuation and 3 required dose reduction of the medication with resolution of the transaminitis in all. No differences in liver chemistries at follow up between patients with or without the metabolic syndrome and with or without right cardiac dysfunction were noted. CONCLUSION: Administration of amiodarone was associated with a low incidence of hepatotoxicity without relationship to cumulative dose. The presence of the metabolic syndrome or right-sided heart failure does not increase the incidence of amiodarone hepatotoxicity.",1
12018,20082451,Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America,"""BACKGROUND: The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. METHODS: In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. RESULTS: The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. CONCLUSIONS: Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).""",1
12019,20087691,Successful treatment of gefitinib-induced acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review,"Cytotoxic chemotherapy offers a modest benefit for patients with advanced non-small cell lung cancer (NSCLC), with response rates of 20-35% and median survival of 10-12 months. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib are active against lung cancer. In retrospective studies, EGFR-TKI therapy among patients harboring EGFR mutations showed response rates higher than 65% and a median survival of 20-30 months. Gefitinib is well tolerated and less toxic compared to conventional cytotoxic drugs, but gefitinib-related interstitial lung disease (ILD) has been reported as a serious adverse effect. Although the mechanism remains unknown, multivariate analysis revealed male sex, history of smoking, and the coexistence of interstitial pneumonia or pre-existence of pulmonary fibrosis and poor performance status were all significant risk factors. Here, we reported a case of gefitinib pneumonitis with severe hypoxemia and impending respiratory failure who showed poor response to intermediate dose of systemic steroids but good recovery with high-dose pulse therapy.",1
12020,20089952,A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis,"""BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. METHODS: In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). RESULTS: A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. CONCLUSIONS: As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)""",1
12021,20095792,Letrozole,"IMPORTANCE OF THE FIELD: Aromatase is an enzyme which converts adrenal androgens to estrogens in postmenopausal women. Given the importance of estrogens in breast cancer growth, aromatase inhibitors are used to treat breast cancer in different settings. This review focuses on letrozole, a third generation aromatase inhibitor, encompassing pharmacodynamic and pharmacokinetic aspects as well as its clinical efficacy and safety. AREAS COVERED IN THIS REVIEW: A literature search and review of the studies published on letrozole were carried out using the MEDLINE database up to November 2009. WHAT THE READER WILL GAIN: The paper provides the reader with information about pharmacodynamic and pharmacokinetic aspects of letrozole, its preclinical and clinical efficacy and its safety. TAKE HOME MESSAGE: Letrozole is a well-tolerated and effective drug in metastatic breast cancer in postmenopausal women. Two clinical trials conducted in early breast cancer have confirmed its role in the adjuvant setting in postmenopausal women. More recently, data have confirmed its efficacy as neoadjuvant treatment in breast cancer. Future developments include the combination of letrozole with new biologic agents and tailoring of treatment with gene expression profiling studies.",1
12022,20097592,Frequency and tolerance of antituberculosis treatment according to national guidelines for prevention of risk of tuberculosis due to tumor necrosis factor blocker treatment,"PURPOSE: Tumor necrosis factor (TNF) blockers increase the risk of tuberculosis infection. National recommendations in France for prevention of latent tuberculosis recommend treatment by rifampicin (RIF) 600 mg/day and isoniazid (INH) 300 mg/day for 3 months. However, its toxicity is unknown in this context and is a subject of debate. OBJECTIVE: To assess (a) frequency of prescription, (b) reasons for prescription, (c) tolerance of INH/RIF for prevention of tuberculosis. METHODS: Systematic retrospective study of medical records of one tertiary rheumatology unit, from 2002 to 2007, of all patients who were prescribed INH/RIF before receiving TNF blockers. DATA COLLECTION: patients'demographic characteristics, reasons of prescription, tolerance and levels of aminotransferase before and during INH/RIF treatment. ANALYSIS: Descriptive and determination of risk factors of hepatotoxicity by multivariate logistic regression. RESULTS: Of 1028 patients treated by TNF blockers between 2002 and 2007, 216 (21.1%) received INH/RIF treatment. Of 93 patients with complete data, 17 (18.2%) presented hepatotoxicity of which only one above 10 times the upper limit of the norm. Fourteen (15.0%) had other side effects. Ten (10.7%) patients had to interrupt INH/RIF for intolerance. Factors predicting intolerance were male sex, aminotransferases before treatment, a higher body mass index and leflunomide comedication. CONCLUSION: This systematic case review indicates a high rate of necessity for preventive treatment by INH/RIF, and in particular for positive skin tests. This association had a high rate of hepatotoxicity without severe consequences. A better screening of patients before preventive therapy is needed.",1
12023,20101750,Tolvaptan and hyponatremia in a patient with cirrhosis,,1
12024,20102918,"Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance","Currently, no consensus has been reached regarding the management of hyperlipidemia in patients who develop statin-associated myalgia (SAM). Many statin-intolerant patients use alternative lipid-lowering therapies, including red yeast rice. The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia. The study was conducted in a community-based setting in Philadelphia, Pennsylvania. A total of 43 adults with dyslipidemia and a history of statin discontinuation because of myalgia were randomly assigned to red yeast rice 2,400 mg twice daily or pravastatin 20 mg twice daily for 12 weeks. All subjects were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcomes included the incidence of treatment discontinuation because of myalgia and a daily pain severity score. The secondary outcomes were muscle strength and plasma lipids. The incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.",1
12025,20103782,Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study,"In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m(2) every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 x 10(9)/L and neutrophils 0.5 x 10(9)/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.",1
12026,20107858,Hepatotoxicity of antibacterials: Pathomechanisms and clinical,"Drug-induced hepatotoxicity is a frequent cause of liver disease and acute liver failure, particularly in patients treated with multiple drugs. Several antibacterial drugs have the potential to cause severe liver injury and failure. This article aims to increase the awareness and understanding of drug induced liver injury (DILI) due to antibacterial drugs. It reviews the pattern of antibacterial DILI and provides details on molecular mechanisms and toxicogenomics, as well as clinical data based on epidemiology studies. Certain antibacterial drugs are more frequently linked to hepatotoxicity than others. Therefore, the hepatotoxic potential of tetracyclines,sulfonamides, tuberculostatic agents, macrolides, quinolones,and beta-lactams are discussed in more detail. Efforts to improve the early detection of DILI and the acquisition of high-quality epidemiological data are pivotal for increased patient safety.",1
12027,20110044,Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer,"""BACKGROUND: Lapatinib is an oral, small-molecule, reversible inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases. In March 2007, the US Food and Drug Administration approved lapatinib for use in combination with capecitabine in the treatment of advanced breast cancer overexpressing HER2 (HER2+). OBJECTIVES: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of lapatinib, and to review studies of the approved and investigational uses of lapatinib. METHODS: English-language reports of clinical trials of lapatinib in patients with cancer were identified through searches of PubMed/MEDLINE (1990-October 2009) and the American Society of Clinical Oncology abstracts database (2003-2008). Search terms included lapatinib, Tykerb, HER2, EGFR, breast cancer, dual tyrosine kinase inhibitor, and GW572016. RESULTS: Lapatinib was well tolerated in a Phase II monotherapy trial in patients with advanced breast cancer; however, the response was minimal in HER2+ patients, and no HER2- patients achieved an objective tumor response. A Phase II trial of lapatinib monotherapy in 39 HER2+ patients with breast cancer and brain metastases yielded 1 partial response, although 15.4% of patients had stable disease for > or =16 weeks. In a Phase III trial comparing lapatinib plus capecitabine with capecitabine alone in HER2+ patients with advanced breast cancer that had progressed after trastuzumab therapy, the median time to progression was 8.4 months with combination therapy, compared with 4.4 months with capecitabine alone (P < 0.001). There were no significant differences between combination therapy and capecitabine alone in terms of the overall response rate (22% and 14%, respectively) or overall survival. CONCLUSIONS: Lapatinib monotherapy was well tolerated, although the response rate was low in patients with advanced breast cancer. Lapatinib combined with capecitabine was associated with significant improvements in the time to progression and response rate compared with capecitabine alone. The available evidence suggests that clinical efficacy in breast cancer is limited to HER2+ disease.""",1
12028,20116624,[Safety and tolerability of etravirine],"Etravirine (ETR) is the first representative of a new generation of non-nucleoside reverse transcriptase inhibitors (NNRTI) and is indicated in patients with HIV infection and virological failure. The recommended dose is 200 mg (two tablets) every 12 hours after a meal. ETR has good tolerability and the tablets can be dissolved in water, which can aid swallowing in some patients. This drug has a plasma half-life of 30-40 hours and consequently is a candidate for once-daily regimens. The most frequent adverse effect is rash (affecting 19% of patients), which is usually mild (grades 1 or 2) and does not lead to drug withdrawal. The DUET 1 and 2 studies, which compared ETR versus placebo, with both groups receiving boosted darunavir and an optimized background regimen, did not demonstrate a higher incidence of liver toxicity, neuropsychiatric symptoms, gastrointestinal disturbances or atherogenic dyslipidemia in patients receiving ETR. The safety profile of ETR suggests that it could be used as a substitute drug in patients with toxicity induced by first-generation NNRTIs or other antiretroviral drugs.",1
12029,20117244,Continuous therapy with certolizumab pegol maintains remission of patients with Crohn's disease for up to 18 months,"""BACKGROUND & AIMS: The safety and efficacy of maintenance therapy with the anti-tumor necrosis factor certolizumab pegol has not been reported beyond 6 months. We assessed the long-term efficacy, safety, and immunogenicity of continuous versus interrupted maintenance therapy with subcutaneous certolizumab pegol in patients with Crohn's disease. METHODS: Patients who responded to induction therapy at week 6 of the PEGylated Antibody Fragment Evaluation in Crohn's Disease: Safety and Efficacy (PRECiSE) 2 trial were assigned randomly to groups given certolizumab pegol (continuous) or placebo (drug-interruption) during weeks 6 to 26. Patients who completed PRECiSE 2 were eligible to enter PRECiSE 3, an ongoing, prospective, open-label extension trial in which patients have received certolizumab pegol (400 mg) every 4 weeks for 54 weeks to date, and were not offered the option to increase their dose. Disease activity was measured by the Harvey-Bradshaw Index. RESULTS: Harvey-Bradshaw Index responses at week 26 for the continuous and drug-interruption groups were 56.3% and 37.6%, respectively; corresponding remission rates were 47.9% and 32.4%, respectively. Of patients responding at week 26, response rates at week 80 after the start of PRECiSE 2 in the continuous and drug-interruption groups were 66.1% and 63.3%, respectively; among patients in remission at week 26, week 80 remission rates were 62.1% and 63.2%, respectively. More patients in the drug-interruption group developed antibodies against certolizumab pegol (and had lower plasma concentrations of certolizumab pegol) than the continuously treated group. CONCLUSIONS: Certolizumab pegol effectively maintains remission of Crohn's disease for up to 18 months. Continuous therapy is more effective than interrupted therapy.""",1
12030,20118145,Golimumab: a tumor necrosis factor alpha inhibitor for the treatment of rheumatoid arthritis,"OBJECTIVE: To review the pharmacologic, pharmacokinetic, efficacy, and safety data of golimumab, an anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody. DATA SOURCES: A search of MEDLINE (1950-September 2009) was performed to identify any published clinical trials or review articles pertaining to golimumab. Key search terms included golimumab, rheumatoid arthritis, CNTO 148, and anti-TNF-alpha inhibitors. Bibliographies of selected articles were reviewed to identify other relevant citations. Abstracts from national and international meetings and information from the manufacturer were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All available published articles and abstracts describing golimumab's pharmacologic or pharmacokinetic profile, efficacy, and safety were included. DATA SYNTHESIS: Golimumab is a fully humanized TNF-alpha monoclonal antibody that is specific for human TNF-alpha. Trials have investigated the use of golimumab in patients who have rheumatoid arthritis (RA) and are on methotrexate, are methotrexate-na?ve, and have previously tried TNF-alpha inhibition therapy. When used in combination with methotrexate or another disease-modifying antirheumatic drug, golimumab therapy results in improvements of clinical outcomes including the American College of Rheumatology parameters in all of the aforementioned populations. Although multiple doses and dosing regimens have been studied, the Food and Drug Administration-approved dose is 50 mg subcutaneously every 4 weeks. The most common adverse effects include injection site erythema, headaches, and nausea. There were a limited number of incidences of serious infection or malignancy. CONCLUSIONS: With 4 TNF-alpha monoclonal antibodies currently on the market, it is unclear what golimumab's place in therapy for RA will be. Some benefits include monthly injections, proven efficacy after previous TNF-alpha inhibitor therapy, and limited antibody development during therapy. However, with a lack of longer-term trials assessing efficacy and safety compared with other TNF-alpha inhibitors, golimumab should be reserved for use after other therapies fail.",1
12031,20124183,"Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer","PURPOSE: Pertuzumab is a humanized monoclonal antibody inhibiting human epidermal growth factor receptor 2 (HER2) dimerization. The aim of this phase II trial was to assess the antitumor activity and safety profile of pertuzumab monotherapy in patients with HER2-negative metastatic breast cancer. The utility of biomarkers detected in paraffin-embedded tissue as predictors of response was also explored. PATIENTS AND METHODS: This was an international, multicenter, open-label, randomized phase II study. Patients (n = 79) with centrally confirmed HER2-negative metastatic breast cancer were randomly assigned to receive pertuzumab once every 3 weeks with a loading dose of 840 mg followed thereafter by either 420 mg (arm A) or 1,050 mg (arm B). Patients were stratified by country and prior taxane therapy. RESULTS: Of 79 patients who were randomly assigned, 78 were included in the intent-to-treat population. In arm A (n = 41), two patients had partial responses, and 18 patients (44%) experienced stable disease (SD) lasting > or = 12 weeks. In arm B (n = 37), SD was observed in 14 patients (38%). Overall, six of 78 patients responded or had SD > or = 6 months. Pertuzumab was generally well tolerated, and most adverse events were mild to moderate. Decline in left ventricular ejection fraction of > or = 10% and/or to less than 50% was observed in eight patients, with one case of congestive heart failure in arm A. Pharmacokinetic data supported a fixed dose of pertuzumab once every 3 weeks. CONCLUSION: The limited efficacy observed in this study, generally SD of relatively short duration, suggested little benefit of further investigation of single-agent pertuzumab in unselected patients with HER2-negative disease.",1
12032,20127601,Fulminant hepatic failure due to chemotherapy-induced hepatitis B reactivation: role of rituximab,"Hepatitis B virus reactivation during immunosuppressive therapies can lead to liver failure with very limited treatment options available. We report here on two cases of severe hepatitis B reactivation during chemotherapy including rituximab for B cell lymphoma which were treated with liver or liver-cell transplantation. Liver function was normal and HBV infection was unknown in both patients before chemotherapy was started. Impaired liver function became apparent after 4 and 6 courses of chemotherapy, respectively, and both patients experienced fulminant hepatic failure despite antiviral treatment with lamivudine or entecavir. Patient A underwent liver transplantation after documentation of complete remission of the lymphoma and survived without any evidence for hepatitis B recurrence. Patient B received 4 courses of hepatocyte transplantation but did not survive. These cases underline the importance of anti-HBc screening in patients receiving immunosuppressive treatments in particular when rituximab is given. Pre-emptive antiviral treatments should be administered since delayed antiviral treatment is frequently unable to prevent liver failure.",1
12033,20131276,"Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study","OBJECTIVE: To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). METHODS: Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15-25 mg/week for > or = 4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. RESULTS: The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). CONCLUSION: The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns.",1
12034,20132298,Safety profile of oxcarbazepine: results from a prescription-event monitoring study,"""PURPOSE: To monitor safety of oxcarbazepine, prescribed in primary care in England, using prescription-event monitoring (PEM). METHODS: Postmarketing surveillance using observational cohort technique of PEM. Exposure data were obtained from dispensed British National Health Service prescriptions issued by general practitioners (GPs) March 2000-July 2003. Demographic, drug utilization, and clinical event data were collected from questionnaires posted to GPs at least 6 months after first prescription date for each patient. Incidence densities (IDs) (number of first reports per 1,000 patient-months of treatment) were calculated and differences for events reported in month 1 (ID(1)) and months 2-6 (ID(2-6)) (99% confidence intervals) were examined for changes in event rates. Follow-up and causality assessment of medically significant events were undertaken. RESULTS: The cohort comprised 2,243 patients [mean age 40.4 years; range 2-99 years; standard deviation (SD) 18.8; 46.3% (n = 1,038) male]. Most frequently reported primary indications were epilepsy, convulsion (n = 1,111; 49.5%, n = 209; 9.3%, respectively). GPs recorded 932 reasons for stopping medication in 698 (31.1%) patients; most frequent clinical reason """"drowsiness/sedation"""" (n = 57; 2.5% of cohort). Clinical events (excluding indication) associated with starting treatment (lower 99% CI > 0) included: """"drowsiness/sedation"""" (ID(1)-ID(2-6) = 14.2), """"nausea/vomiting"""" (ID(1)-ID(2-6) = 13.0), and dizziness (ID(1)-ID(2-6) = 11.6). Events followed up and assessed as probably related to oxcarbazepine use included rash (7 of 11) and hyponatremia (15 of 38). DISCUSSION: There were no serious adverse drug reactions reported during this study. Results of the study should be taken in context with other epidemiologic studies.""",1
12035,20145262,"Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial","The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.",1
12036,20147568,Aqueous extract of Trigonella foenum graecum (fenugreek) prevents cypermethrin-induced hepatotoxicity and nephrotoxicity,"Cypermethrin (CM) is an important type II pyrethroid pesticide used extensively in pest control and is reported to cause hepatic and renal toxicity. Oxidative stress and lipid peroxidation (LPO) has been implicated in the toxicology of pyrethroids. Fenugreek is known for its antitoxic and antioxidant potential. We have investigated the protective effect of aqueous extract of germinated fenugreek seeds in CM-induced hepatic and renal toxicity. Male Wistar rats were treated with 1/10 LD(50) (25 mg/kg body weight) of CM and 10% aqueous extract of fenugreek (GFaq) for 60 days. CM treatment caused increased thiobarbituric acid reactive substances (TBARS), depletion in glutathione (GSH) and reduction in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) in liver and kidneys. There was a significant reduction in total phospholipids and increased activities of phospholipases A (PLA) and C (PLC) in liver and kidneys and increased activities of serum marker enzymes, aspartate transaminase (AST), alanine tansaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT). Treatment with 10% GFaq showed replenishment of antioxidant status and brought all the values to near normal, indicating the protective effect of fenugreek. Phytochemicals present in fenugreek could play an important role in ameliorating the pesticide-induced toxicity.",1
12037,20151997,"Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus, metabolic syndrome or neither","AIM: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid-altering drugs in these patient populations. METHODS: A double-blind, parallel group trial of adult patients with hypercholesterolaemia at high-CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL-C, total cholesterol, HDL-C , non-HDL-C , Apo A-I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). RESULTS: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL-C, triglycerides, Apo B, non-HDL-C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL-C , Apo A-I and high sensitivity C-reactive protein (hs-CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. CONCLUSIONS: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high-CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).",1
12038,20155993,Atorvastatin-induced prolonged cholestasis with bile duct damage,"""We report a case of acute-onset, long-lasting cholestasis induced by atorvastatin. This antihyperlipidaemic drug was taken for 40 days by a 72-year-old male as a treatment for his mixed dyslipidaemia. At that point, the patient presented with asthenia, nausea, painless icterus, acholic stools and hyperchromic urine with biochemical analyses showing a dramatic increase in bilirubin (total bilirubin 22 mg/dL; direct bilirubin 21 mg/dL) and alkaline phosphatase (up to 4-fold over the normal level) with less marked increases in transaminases. Liver histology showed a pattern of cholestasis with evident signs of cholangiolitis and damage of the interlobular bile ducts. Serum transaminase and bilirubin levels returned to normal within 5 months after atorvastatin withdrawal while alkaline phosphatase normalized after only 8 months. Scores on both the Maria and Victorino clinical scale for the diagnosis of drug-induced hepatitis and the Naranjo Adverse Drug Reaction Probability Scale indicated that atorvastatin was the probable cause of prolonged cholestasis in this patient. This is a rare case of cholestasis probably caused by atorvastatin and unusually characterized by bile duct damage.""",1
12039,20156056,Challenges in reintroducing tuberculosis medications after hepatotoxicity,,1
12040,20159814,Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer,"PURPOSE: Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy. PATIENTS AND METHODS: Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated. RESULTS: A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-na?ve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen. CONCLUSION: AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.",1
12041,20160715,Changes in liver biochemistry during methotrexate use for inflammatory bowel disease,"""OBJECTIVES: We aimed to characterize the spectrum of liver enzyme test (LET) abnormalities that occur while using methotrexate for inflammatory bowel disease (IBD). METHODS: A retrospective review was undertaken of subjects using methotrexate for IBD at a single center. The clinical and epidemiological parameters, and hepatotoxicity risk factors, were recorded. Subjects were excluded if cumulative methotrexate doses could not be ascertained, if they had a diagnosis of rheumatoid arthritis or psoriasis, or if baseline and follow-up LETs were not available. Also noted were the cumulative methotrexate dose during the peak LET increase, severity of LET increase, and whether normalization occurred. RESULTS: Eighty-seven subjects were included (Crohn's disease, n=67; UC, n=17; indeterminate colitis n=3). The mean therapy duration was 81 weeks (3- to 364-week range), and the cumulative average dose was 1,813 mg (25-8,255-mg range). Thirty-seven (43%) subjects received a cumulative dose >1,500 mg. Sixty-seven (77%) had normal LETs, and in 51 (76%) LETs remained normal throughout methotrexate therapy. In the 16 (24%) who developed LET abnormalities, seven (44%) had underlying risk factor(s) for liver disease. Normalization (without dose reduction) occurred in 14 (88%) while continuing methotrexate. Of 20 subjects with abnormal LETs at baseline, nine (45%) subsequently normalized while continuing methotrexate, whereas nine (45%) worsened. Seventeen liver biopsies were performed in 11 and were classified as Roenigk's grade I in 15 (88%) subjects. Roenigk IIIb or IV was not seen. CONCLUSIONS: Methotrexate is commonly associated with LET abnormalities, but these frequently normalize while still on therapy, and in only 5% will drug discontinuation be necessary. Liver biopsies rarely have substantive abnormalities.""",1
12042,20163278,Role of ribavirin in HCV treatment response: now and in the future,"IMPORTANCE OF THE FIELD: Ribavirin is a broad spectrum antiviral agent that is used with pegylated IFN (Peg-IFN) for HCV treatment. Ribavirin does not significantly reduce HCV viral load when used alone but increases rates of sustained virologic response (SVR) when combined with Peg-IFN. HCV genotype 1 infected patients require higher doses of ribavirin administered for a longer duration of time versus HCV genotypes 2 and 3 patients who respond effectively to Peg-IFN with lower doses of ribavirin and shorter duration of therapy. Higher serum concentrations of ribavirin are associated with higher response rates but also higher rates of hemolytic anemia which is a dose limiting side effect. Alternatives to current therapy are under clinical evaluation. AREAS COVERED IN THIS REVIEW: Systematic literature review of ribavirin use in HCV patients from 1995 to 2009 was conducted. WHAT THE READER WILL GAIN: To review the efficacy and safety of ribavirin in current HCV treatment and in new therapies in Phase III clinical trials. TAKE HOME MESSAGE: Ribavirin is a drug which is essential to produce higher SVR rates both with Peg-IFN and HCV protease inhibitors currently in Phase III clinical trials. Thus, ribavirin is and will remain an important drug to achieving higher SVR rates in HCV infected persons.",1
12043,20163378,Clinically significant liver injury in patients treated with natalizumab,"BACKGROUND: Natalizumab is a recombinant monoclonal antibody approved for the treatment of patients with multiple sclerosis and patients with Crohn's disease. Because of its immunosuppressive effects, natalizumab has been associated with a number of atypical and opportunistic infections. AIM: To describe and summarize six spontaneously reported post-marketing cases of clinically significant drug induced-liver injury associated with natalizumab use. METHODS: The FDA maintains a database of adverse event reports (AERS). We searched the AERS database for reports of serious liver injury associated with natalizumab use from November 2004, when the drug was approved, through 30 June 2008. RESULTS: The search resulted in six spontaneously reported post-marketing cases of severe drug-induced liver injury. Four of six patients developed liver injury with elevations of serum transaminases and hyperbilirubinemia after only a single infusion of natalizumab. One of these patients experienced repeated increases of aminotransferases and bilirubin when natalizumab was re-administered. CONCLUSIONS: Serious hepatic injury may occur in association with natalizumab use. Health professionals should be alerted to possible serious liver injury in patients receiving natalizumab.",1
12044,20167278,"Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial","""Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.""",1
12045,20170750,Important elements for the diagnosis of drug-induced liver injury,"""BACKGROUND & AIMS: Drug-induced liver disease is the leading cause of acute liver failure in the United States. Accurate reporting of drug-induced liver injury is essential for early detection of hepatotoxicity and for developing reliable, interpretable literature. We assessed the extent to which published case reports of drug-induced liver disease include sufficient clinical data for interpreting the cause of toxicity. METHODS: We developed a list of 42 predetermined, specific minimal elements necessary in evaluating causality of drug-induced liver injury. We then analyzed 97 published case reports or series studies of hepatotoxicity from 6 drugs (from 3 classes): amoxicillin/clavulanic acid (n = 35), troglitazone (n = 32), rosiglitazone (n = 10), pioglitazone (n = 8), zafirlukast (n = 8), and montelukast (n = 4). RESULTS: Patient age, sex, primary disease, and drug name were reported in most, if not all, published case reports. However, many elements were underreported; some publications did not mention initial bilirubin levels (12%), many did not provide initial alkaline phosphatase levels (58%), and others provided vague descriptions of how certain diagnoses were excluded, that is, tests for hepatitis A, B, and C were negative. Data on abnormal results from serial liver tests frequently were absent. Exclusions of competing viral etiologies were reported in less than 50% of the studies. CONCLUSIONS: Reports of drug-induced liver diseases often do not provide the data needed to determine the causes of the adverse effects. Efforts to promote and include a list of essential diagnostic elements in research articles could increase the quality and clinical utility of published case reports of drug toxicity.""",1
12046,20172201,[Does bevacizumab have a protective effect on hepatotoxicity induced by chemotherapy?],"Although the prognosis of patients with colorectal liver metastases (CLM) has improved dramatically with oxaliplatin and irinotecan, the enthusiasm for the preoperative use of these cytotoxic agents is being tempered by concerns about their impact on the nontumoral liver parenchyma. Bevacizumab, an anti-angiogenic agent that specifically targets the vascular endothelial growth factor, exerts an antitumor effect by inhibiting the development of the vascular network that is promoted by the tumor and mandatory for its growth. Yet angiogenesis is also a physiologic event contributing to wound healing and tissue regeneration. To date, it is well documented that the use of bevacizumab in combination with cytotoxic agents greatly improves pathologic response. Also well described is the protective effect of bevacizumab against sinusoidal injuries induced by oxaliplatin-based chemotherapy. Up to now, no side effects related to the perioperative use of bevacizumab have been reported in the setting of liver resection for CLM, and bevacizumab was shown not to impair liver regeneration following portal vein embolization. The clinical consequences of the protective effect of bevacizumab against sinusoidal injuries are hard to evaluate as patient selection and preparation have improved and these improvements contribute greatly to the favorable outcomes following liver resection for CLM. Indeed, patient safety in the setting of hepatic resection for CLM mainly depends on a careful preoperative evaluation of liver volumes and a limited use of cytotoxic agents followed by a delay of at least 5 weeks before the surgery.",1
12047,20173735,ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C,"Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.",1
12048,20175701,Pioglitazone: side effect and safety profile,"IMPORTANCE OF THE FIELD: Thiazolidinediones (TZDs) are useful glucose-lowering agents for patients with Type 2 diabetes. Through PPAR-gamma-mediated effects, these drugs not only improve insulin sensitivity and glycemia, they also have beneficial effects on lipid metabolism and the vascular endothelium, with potential to improve cardiovascular risk. However, this promise has not been entirely fulfilled. The first TZD, troglitazone, was withdrawn after reports of severe liver damage. The second TZD, rosiglitazone, has been reported in meta-analyses to be associated with possible increased risk of cardiovascular disease (CVD) events. The third TZD approved for clinical use in the US, pioglitazone, appears to be associated with decreased CVD events in most studies/meta-analyses. AREAS COVERED IN THIS REVIEW: We undertook a literature search in Pubmed from the year 2000 onwards to review the side effect/safety profile of pioglitazone. WHAT THE READER WILL GAIN: A comprehensive summary of the currently available data on the side effect/safety profile of pioglitazone. TAKE HOME MESSAGE: The main adverse effects reported with pioglitazone are those common to the TZD class: weight gain, pedal edema, bone loss and precipitation of congestive heart failure in at-risk individuals, without any increase in CVD/all-cause mortality. Overall, the safety profile of pioglitazone is favorable and remains a useful option for the treatment of insulin-resistant patients with Type 2 diabetes. Further studies are needed to confirm/clarify its cardiovascular benefits.",1
12049,20177126,Serotonin syndrome after administration of milnacipran for fibromyalgia,,1
12050,20179258,Pitavastatin: a new HMG-CoA reductase inhibitor,"OBJECTIVE: To review pitavastatin, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and determine its place in the treatment of hypercholesterolemia. DATA SOURCES: Literature was accessed through PubMed (1948-December 2009). Pitavastatin, itavastatin, nisvastatin, NK 104, and NKS 104 were used as search terms. Results were limited to articles written in the English language. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data source were reviewed for inclusion. Articles included were those pertaining to the pharmacology and pharmacokinetic properties of pitavastatin, in addition to original research evaluating the clinical efficacy of pitavastatin for hypercholesterolemia. DATA SYNTHESIS: Pitavastatin is an oral HMG-CoA reductase inhibitor recently approved by the Food and Drug Administration for the treatment of primary hyperlipidemia and mixed dyslipidemia. Pitavastatin 2 mg has been shown to be noninferior to atorvastatin 10 mg and simvastatin 20 mg with respect to low-density lipoprotein cholesterol (LDL-C)-lowering ability. Additionally, pitavastatin 2 mg was shown in one study to lower LDL-C significantly more than pravastatin 10 mg. As with other HMG-CoA reductase inhibitors, primary safety concerns are related to myopathies and alterations in liver enzyme levels. While efficacy regarding beneficial effects on lipid parameters is comparable to that of other agents, a potential advantage of pitavastatin is its cytochrome P450 (CYP450) independent elimination, thereby reducing the likelihood of clinically significant drug-drug interactions. However, this is not a unique property, as pravastatin and rosuvastatin also possess this property. CONCLUSIONS: In light of the lack of outcome data, pitavastatin offers no clear advantage over other drugs in this class.",1
12051,20182423,Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans,"""Achieving the ability to identify individuals who are susceptible to drug-induced liver injury (DILI) would represent a major advance in personalized medicine. Clayton et al. demonstrated that the pattern of endogenous metabolites in urine could predict susceptibility to acetaminophen-induced liver injury in rats. We designed a clinical study to test this approach in healthy adults who received 4 g of acetaminophen per day for 7 days. Urine metabolite profiles obtained before the start of treatment were not sufficient to distinguish which of the subjects would develop mild liver injury, as indicated by a rise in alanine aminotransferase (ALT) to a level more than twice the baseline value (responders). However, profiles obtained shortly after the start of treatment, but prior to ALT elevation, could distinguish responders from nonresponders. Statistical analyses revealed that predictive metabolites included those derived from the toxic metabolite N-acetyl paraquinone imine (NAPQI), but that the inclusion of endogenous metabolites was required for significant prediction. This """"early-intervention pharmaco-metabonomics"""" approach should now be tested in clinical trials of other potentially hepatotoxic drugs.""",1
12052,20186247,Severe hepatitis in a primary sclerosing cholangitis patient receiving recent cetirizine therapy,,1
12053,20189775,Safety and pharmacokinetics of oseltamivir at standard and high dosages,"Although clinical evidence is currently lacking, opinion in the literature on avian influenza A/H5N1 suggests that increased doses of the oral neuraminidase inhibitor oseltamivir may offer clinical benefits against highly pathogenic influenza where high levels of viral replication and disseminated infection cause severe disease. We assessed the pharmacokinetics and safety/tolerability of oseltamivir at dosages up to 450 mg twice daily. Healthy adult volunteers were randomised to receive placebo or oseltamivir 75, 225 or 450 mg every 12h for 5 days. Volunteers were followed up to Day 7 for pharmacokinetic parameters, vital signs, adverse events and cardiac safety. In total, 391 volunteers were randomised and evaluated. Pharmacokinetics were linear and dose-proportional, with no evidence of accumulation of oseltamivir or its active metabolite at any dosage. Headache was the most common adverse event (16.8-23.7% across groups), but its incidence was unrelated to dosage. Dosage-related events with oseltamivir included nausea (up to 31.3% of volunteers) and vomiting (up to 16.2%), which generally occurred on Day 1 and lasted <1 day, and possibly dizziness (up to 11.3%). Oseltamivir had no relevant effects on vital signs, laboratory parameters or cardiac function. In conclusion, oseltamivir was well tolerated, with dose-proportional pharmacokinetics and no accumulation. Possible clinical benefit in severe influenza infections could be investigated at dosages higher than those currently recommended.",1
12054,20191055,Aloe-induced toxic hepatitis,"Aloe has been widely used in phytomedicine. Phytomedicine describes aloe as a herb which has anti-inflammatory, anti-proliferative, anti-aging effects. In recent years several cases of aloe-induced hepatotoxicity were reported. But its pharmacokinetics and toxicity are poorly described in the literature. Here we report three cases with aloe-induced toxic hepatitis. A 57-yr-old woman, a 62-yr-old woman and a 55-yr-old woman were admitted to the hospital for acute hepatitis. They had taken aloe preparation for months. Their clinical manifestation, laboratory findings and histologic findings met diagnostic criteria (RUCAM scale) of toxic hepatitis. Upon discontinuation of the oral aloe preparations, liver enzymes returned to normal level. Aloe should be considered as a causative agent in hepatotoxicity.",1
12055,20194492,Remission of drug-induced hepatitis after switching from risperidone to paliperidone,,1
12056,20197595,[Hepatotoxicity associated with the use of Herbalife],"""OBJECTIVE: Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. METHODS: The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. RESULTS: Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. CONCLUSIONS: Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.""",1
12057,20200196,Full recovery from a potentially lethal dose of orphenadrine ingestion using conservative treatment: a case report,"Intoxication by orphenadrine is uncommon. The clinical features consist of both central and peripheral anticholinergic effects. Ingestion of 2 to 3 g orphenadrine in an adult has been associated with fatality. A 46-year-old female was brought to our emergency department 1.5 hours after ingesting 40 tablets of 100 mg orphenadrine. She became stuporous 3 hours post-ingestion and developed generalized convulsions 1 hour later. Fifty-five hours post-ingestion, she had recovered and was found to have anterior shoulder dislocation. In addition, severe rhabdomyolysis and persistent nausea were observed. All of the above-noted toxic effects resolved with conservative treatment. Although orphenadrine intoxication can cause convulsions and hemodynamic instability, there is no available antidote and treatment remains supportive.",1
12058,20203555,"Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection - United States, 2004-2008","Since the 1960s, 6 to 9 months of isoniazid (INH) has been the mainstay of treatment for latent tuberculosis infection (LTBI), but its application has been limited by concerns about the toxicity of INH and the long duration of treatment. To quantify the frequency of severe adverse events (SAEs) associated with LTBI treatment and to characterize the clinical features of affected patients, in January 2004 CDC began a national project to monitor SAEs associated with treatment for LTBI. State health departments were encouraged to report SAEs associated with any LTBI treatment regimen to a passive surveillance system. This report summarizes the results for 2004-2008, when 17 SAEs in 15 adults and two children (aged 11 and 14 years) were reported. All patients had received INH therapy and had experienced severe liver injury. Five patients, including one child, underwent liver transplantation. Five adults died, including one liver transplant recipient. These findings underscore the risk for an idiosyncratic drug-induced reaction in patients of any age treated with INH, including those with or without a putative predictor for INH-associated liver injury. Patients receiving INH for LTBI therapy should be monitored according to American Thoracic Society (ATS)/CDC recommendations because of the risk for drug-induced hepatoxicity. Providers should counsel patients to terminate INH therapy promptly and seek medical attention if they experience signs and symptoms of illness.",1
12059,20208468,Telavancin (Vibativ) for gram-positive skin infections,,1
12060,20208474,Iloperidone (Fanapt)--another second-generation antipsychotic,,1
12061,20210729,"Antibiotic-induced liver toxicity: mechanisms, clinical features and causality assessment","Antibiotics are the therapeutic agents most often associated with hepatotoxicity. However, this is mainly due to the widespread prescription of these drugs. The relative risk of antibiotic-related hepatotoxicity is low. Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult, particularly because some cases occur long after the drug has been stopped. Among the penicillins, amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations. Flucloxacillin ranks as the second highest cause of DILI in many countries. The severity of antibiotic-induced DILI varies widely, with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestatic/mixed type. The pattern is strongly influenced by age. Recently telithromycin (a new generation macrolide) has been linked with DILI, with a typical pattern, which includes abrupt commencement of fever, abdominal pain, jaundice and, in some cases, ascites. Antibiotic-induced DILI appears, in most instances, to be idiosyncratic. Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity.",1
12062,20213329,FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable?,"Hepatotoxicity from paracetamol is of great concern because of the considerable number of patients who develop severe toxicity from this drug. A group of senior medical practitioners, academics and scientists were brought together on June 29 and 30, 2009 by the Food and Drug Administration of USA (FDA) with the aim of providing advice on how to limit the number of cases of hepatotoxicity due to paracetamol in USA. The most contentious recommendations were the reduction in the dose of paracetamol to 650 mg and the elimination of prescription combination products of paracetamol and opiates. The first recommendation indicates that many members of the committee consider, despite much evidence to the contrary, that therapeutic doses of paracetamol (up to 4 g daily) are associated with a significant incidence of hepatotoxicity. The second recommendation, if accepted by FDA, will require major changes in the therapeutic use of paracetamol and opiates. Adoption of these two recommendations may lead to the increased use of NSAIDs with the potential of increasing incidence of NSAIDs-related adverse reactions.",1
12063,20216203,"A long-term, open-label study to confirm the safety of topical diclofenac solution containing dimethyl sulfoxide in the treatment of the osteoarthritic knee","To assess the long-term safety of a topical solution of diclofenac sodium in a vehicle containing dimethyl sulfoxide (TDiclo), subjects with radiologically confirmed, symptomatic osteoarthritis of the knee(s) applied the clinical dose of TDiclo (40 drops, four times daily) to each painful knee for up to 52 weeks. Safety assessment included adverse events, skin irritation scores of the treated knee(s), ocular examinations, and routine laboratory tests. There were 793 subjects (mean age, 62.5 years) who applied TDiclo to one or both (72%) knees for an average of 204 days, including 463 subjects for 6 months and 144 for 1 year. The most frequent adverse events were at the application site with no increase in incidence with prolonged exposure: dry skin (25.3%), contact dermatitis without vesicles (13.0%) or with vesicles (9.5%). Skin irritation score was 0 (normal) in 61.0% of subjects, 0.5 (dryness or flaking) in 23.9%, 1 or 2 (erythema without or with induration) in 6.9%, and 3 or 4 (erythema with induration and vesicles/bullae) in 8.2%. Subject dropouts included 114 (14.4%) with an application site skin adverse event. Individual subject laboratory test shift to abnormal occurred for hemoglobin (3.2%), aspartate aminotransferase (6.4%), alanine aminotransferase (7.3%), and creatinine (4.2%), but few shifts (less than 0.3% per variable) were clinically significant. No increased risk of cardiovascular or cataract events was noted. This long-term study of TDiclo revealed a safety profile comparable to that shown in multiple, shorter, well-controlled, double-blind trials with the predominant adverse effect noted being an application site reaction.",1
12064,20216301,Frequent hepatitis B virus rebound among HIV-hepatitis B virus-coinfected patients following antiretroviral therapy interruption,"""BACKGROUND: The impact of antiretroviral therapy (ART) interruption in HIV-hepatitis B virus (HBV)-coinfected patients was examined in the Strategic Management of AntiRetroviral Therapy (SMART) study. METHODS: Plasma HBV DNA was measured in all hepatitis B surface antigen-positive (HBV-positive) participants at baseline, and at months 1, 2, 4, 6, 8, 10, and 12. RESULTS: Among HBV-positive participants in the ART interruption (drug conservation) (n = 72) and ART continuation (virological suppression) (n = 62) arms, HBV DNA rebound of more than 1 log from baseline at months 1-4 was seen in 31-33% (P = 0.003) and 3-4% (P = 0.017), respectively. Thirteen HBV-positive participants had HBV DNA rebound of more than 3 log, including 12 in the drug conservation arm, of which eight were on tenofovir-containing regimens. Factors independently associated with a HBV DNA rebound were drug conservation arm (P = 0.0002), nondetectable HBV DNA at baseline (P = 0.007), and black race (P = 0.03). Time to ART reinitiation was shorter (7.5, 15.6, and 17.8 months; P < 0.0001) and proportion reinitiating greater (62.5, 46.5, and 39.7%; P = 0.0002) among HBV-positive participants as compared with hepatitis C virus-positive and non-HBV/hepatitis C virus participants in the drug conservation arm. No hepatic decompensation events occurred among HBV-positive participants in either arm. CONCLUSION: HBV DNA rebound following ART interruption is common and may be associated with accelerated immune deficiency in HIV-HBV-coinfected patients.""",1
12065,20220738,Antiviral drugs for influenza,,1
12066,20225990,"GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin","""OBJECTIVES: GOAL (Gauging Osteoarthritis [OA] with Limbrel*), an open-label, post-marketing study was performed to determine the overall efficacy and gastrointestinal (GI) tolerability of flavocoxid, a novel, plant-based, anti-inflammatory medication, in a 'real world' clinical practice setting. To this end, the study enrolled several unique patient types including nonsteroidal anti-inflammatory drug (NSAID) na?ve patients, those who had used NSAIDs in the past, regardless of outcome (positive or negative), and those who had previously taken a gastroprotective medication to improve GI tolerability or continued to take it as a precautionary measure to prevent NSAID-associated GI damage. METHODS: A total of 1067 individuals at 41 rheumatology practices were enrolled and prescribed flavocoxid, 500 mg b.i.d., for 60 days. The Physician Global Assessment of Disease (PGAD) visual analog scale (VAS) was used as a global measure to assess the signs and symptoms of OA, including joint discomfort, functional stiffness, functional mobility and quality of life. In addition, overall tolerability and upper GI tolerability were assessed by individual questions scored on a 5-part Likert scale. The physicians also monitored any interruption in, or cessation of use of flavocoxid due to a GI issue as well as changes in the use of gastroprotective medications. Adverse event (AE) monitoring was also conducted. RESULTS: Of the 1005 patients who completed all follow-up visits, physicians recorded an average improvement in VAS scores from 60.1 +/- 18.8 at baseline to 42.5 +/- 21.9 at 8 weeks (p < 0.001) in 65.8% of patients. The PGAD VAS noted the most significant improvement in those patients with moderate to severe OA (baseline VAS [0 = least severe, 100 = most severe]: 0-25 mm, -3.5 +/- 6.9; 26-50 mm, -10.1 +/- 17.0; 51-75 mm, -19.3 +/- 19.5; 76-100 mm, -29.6 +/- 23.6; p < 0.001) and in those patients who were historically non-responders to NSAIDs (40.3 +/- 21.1 vs. 66.3 +/- 17.7 at baseline; p < 0.001). Patients who had previously responded well to NSAIDs had VAS scores of 42.6 +/- 19.8 vs. 58.0 +/- 18.0 (p < 0.001) and NSAID na?ve subjects showed improvement in VAS scores from 60.5 +/- 18.0 at baseline to 46.3 +/- 23.7 (p < 0.001). The study recorded a low incidence ( approximately 10%) of AEs reported to physicians and good overall tolerability to flavocoxid. Flavocoxid showed improved upper GI tolerability in almost 50% of previous NSAID users (p < 0.001) and reduced therapy interruption in approximately 90% of previous NSAID users with a history of GI-related therapy interruptions (p < 0.0001). Finally, the use of flavocoxid resulted in a >30% reduction in or cessation of the use of gastroprotective medications such as proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2s) in subjects (p < 0.001). CONCLUSIONS: Within a 'real world' clinical rheumatology practice setting, flavocoxid demonstrated significant efficacy in the management of OA in multiple patient types and displayed significant potential for reducing the possibility of adverse GI side-effects and use of gastroprotective agents associated with more traditional OA medications. A limitation of this study was that it was open-label and not rigorously controlled. The large population may compensate for this lack of control.""",1
12067,20227033,Gastrointestinal and liver side effects of drugs in elderly patients,"It is expected that the percentage of people >60 years of age will be 22% worldwide by the year 2050. Multi-morbidity and poly-pharmacy are common in individuals during old age, while adverse drug reactions are at least twice as common in the elderly compared to younger adults. Publications related to drug side effects are rather rare in this age group since most clinical trials exclude patients >75-80 years of age. Gastrointestinal adverse drug reactions studied in the elderly include non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulant-induced gastrointestinal tract mucosal injuries. Malabsorption, diarrhoea and constipation are common side effects of laxatives, antibiotics, anticholinergics and calcium channel blockers. Drug (amoxycilin/clavulanic acid, isoniazide, nitrofurantoin, diclifenac and methotrexate)-induced hepatotoxicity in the elderly is four times more common than in younger adults and may simulate almost all known liver disorders. Further clinical studies are needed to investigate gastrointestinal and hepatic side effects of drugs in elderly patients.",1
12068,20233236,Suicide attempt of a physician with 3600 units of insulin and rapid onset acute hepatitis,,1
12069,20237968,Corticosteroid therapy in a case of severe cholestasic hepatitis associated with amoxicillin-clavulanate,"Amoxicillin-clavulanate is the most common drug involved in drug-induced liver injury and the single most frequently prescribed product leading to hospitalization for drug-induced liver disease in Spain. The liver damage most frequently associated with amoxicillin-clavulanate is cholestasic type. The latency period between first intake and onset of symptoms is 3-4�weeks on average. A 76-year-old man developed fever, pruritus, and jaundice 3�weeks after having completed treatment with amoxicillin-clavulanate. Liver function tests showed cholestasic hepatitis (up to 50.75�mg/dL of total serum bilirubin level). The ultrasound-guided liver biopsy revealed severe canalicular cholestasis and portal and lobular eosinophilic infiltrates. Prednisone and ursodeoxycholic acid therapy were then prescribed. The patient became symptom-free with normal liver function tests. Amoxicillin-clavulanate can cause hepatocellular, cholestasic, or mixed liver injury. The presence of eosinophilic infiltrates in the liver biopsy and the clinical signs of hypersensitivity in some of the cholestasic cases suggest a pathophysiological immunoallergic mechanism. For this reason, corticosteroid treatment should be considered for patients with severe cholestasic liver injury.",1
12070,20248077,Two cases of ferrous sulphate poisoning,,1
12071,20289621,"Poisoning with a preparation of iron, copper, and manganese",,1
12072,20299955,Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings,"BACKGROUND: Liver disease of unknown cause in HIV-infected persons is rare but increasingly being reported. Noncirrhotic portal hypertension is the main feature in a subset of these patients, in whom gastrointestinal bleeding is the most frequent and potentially life-threatening clinical presentation. METHODS: We describe the epidemiological, clinical and histological features of 12 HIV-positive individuals presenting with noncirrhotic portal hypertension. RESULTS: An interpretable liver biopsy was available in 11, and cirrhosis was absent in all patients. Three patients had nodular regenerative hyperplasia of the liver, whereas eight showed morphological features previously described as 'hepatoportal sclerosis'. In four of the later group, a distinctive lesion was noted characterized by massive absence of portal veins along with focal fibrous obliteration of small portal veins. All patients had been treated with didanosine for long periods and inflammatory and thrombotic processes hypothetically triggered by this purine analogue in the hepatic microvasculature might result in this form of obliterative portal venopathy. CONCLUSION: Noncirrhotic portal hypertension is a rare but unique entity presenting in HIV-positive individuals generally with prior prolonged exposure to didanosine, which shows an obliteration of portal veins as the most distinctive histological finding in the liver.",1
12073,20304628,Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours,"AIM: Micropapillary/borderline (LMP) ovarian tumours are rarely included in clinical trials and are intrinsically resistant to radiation and chemotherapy. Platinum resistant epithelial ovarian cancer (EOC) has a poor prognosis. The histone deacetylase inhibitor belinostat demonstrated antitumour activity in pre-clinical ovarian cancer models. METHODS: A phase II study was performed to evaluate the activity of belinostat in two patient populations: women with metastatic or recurrent platinum resistant (progression within 6 months) EOC and LMP ovarian tumours, both groups had received no more than 3 prior lines of chemotherapy. Belinostat 1000 mg/m(2)/d was administered iv days 1-5 of a 21 d cycle. Peripheral blood mononuclear cells (PBMCs) and tumour biopsies, where possible, for correlative studies were obtained prior to and following treatment. RESULTS: Eighteen patients with EOC and 14 patients with LMP tumours were enrolled on study. Belinostat was well tolerated with no grade four toxicity (179 cycles). Grade 3 toxicity consisted of thrombosis (3 patients), hypersensitivity (1) and elevated ALP (1). One patient with LMP tumour had a partial response (unconfirmed) and 10 had stable disease (SD), 3 were non-evaluable. Median progression-free survival (PFS) was 13.4 months (95% confidence interval (CI), 5.6--not reached). Best response in patients with EOC was SD (nine patients) and median PFS was 2.3 months (95% CI, 1.2-5.7 months). An accumulation of acetylated histones H3 and H4 was noted in PBMCs and in tumour tissue. CONCLUSIONS: Belinostat is well tolerated in both patient groups and shows some activity in patients with micropapillary (LMP) disease.",1
12074,20307226,Bosentan,"""IMPORTANCE TO THE FIELD: Pulmonary arterial hypertension (PAH) is a morbid condition with high mortality if left untreated. Bosentan is an effective treatment option for group 1 pulmonary arterial hypertension. Bosentan improves exercise tolerance and functional class and delays the time to clinical worsening in these patients. Investigation is ongoing to determine its efficacy in other groups of pulmonary hypertension. AREAS COVERED IN THIS REVIEW: This review provides a background on endothelin activity in PAH, as a rationale for the use of bosentan in this disease. It also presents evidence from key clinical trials of bosentan and discusses future directions in the study of bosentan to help the clinician better understand the role of bosentan in PAH management. WHAT THE READER WILL GAIN: i) An understanding of the rationale for using endothelin receptor antagonists in treating PAH; ii) an understanding of the clinical evidence to support bosentan for the treatment of PAH; and iii) an understanding of how to use bosentan optimally in the treatment of PAH. TAKE HOME MESSAGE: Bosentan is an effective and safe treatment for patients with PAH. Patients with suspected PAH should be evaluated carefully as the use of bosentan in non-group 1 pulmonary hypertension is still being investigated. Patients on bosentan should be monitored with monthly liver transaminase testing. Coadministration with other drugs should be reviewed carefully as drug-drug interactions may be important.""",1
12075,20308724,"Hepatotoxicity due to rifampicin, isoniazid and pyrazinamide in patients with tuberculosis: is anti-HCV a risk factor?","""BACKGROUND AND RATIONALE: Among the adverse events related to tuberculosis treatment, hepatotoxicity is the most serious, and recognition of risk factors for it is essential to achieve successful therapy. The aim of the study is to evaluate the role of anti-HCV as a risk factor for hepatotoxicity in hospitalized patients under tuberculosis treatment with rifampicin, isoniazid and pyrazinamide (RHZ). METHODS: Historical cohort study carried out at Hospital Sanatorio Partenon, from 1998 to 2006. Patients aged 18 years or older, tested for anti-HCV, who presented normal pre-treatment aminotransferases (AST, ALT) and bilirrubin and who used RHZ during hospitalization were included in the study. Individuals who used anti-tuberculosis drugs six months prior to hospitalization, had clinical evidence of chronic liver disease or showed previous history of hepatotoxicity to RHZ were excluded. RESULTS: A sample of 534 patients was studied. The incidence of hepatotoxicity was 8.8% (n = 47). After univariate analysis, the following variables were associated to hepatotoxicity: anti-HIV positive, anti-HCV positive, use of antiretroviral therapy and high doses of rifampicin and isoniazid per kg of body weight (p < 0.05). When Cox regression was performed, anti-HIV positive [RR = 2.3 (IC(95% )1.2-4.1); p = 0.008] and high doses of isoniazid per kg of body weight [RR = 1.3 (IC(95%) 1.1-1.7); p = 0.016] remained independently associated to development of hepatotoxicity. CONCLUSIONS: In conclusion, the anti-HIV positive and high doses of isoniazid were considered independent risk factors for hepatotoxicity due to RHZ esqueme in the present study. Though univariate analysis showed that anti-HCV was associated to the outcome, it was not identified as an independent risk factor for hepatotoxicity related to the use of RHZ when the analysis was controlled to HIV.""",1
12076,20331580,"Review article: rifaximin, a minimally absorbed oral antibacterial, for the treatment of travellers' diarrhoea","""BACKGROUND: Travellers' diarrhoea, a common problem worldwide with significant medical impact, is generally treated with anti-diarrhoeal agents and fluid replacement. Systemic antibiotics are also used in selected cases, but these may be associated with adverse effects, bacterial resistance and drug-drug interactions. AIM: To review the clinical evidence supporting the efficacy and safety of the minimally absorbed oral antibiotic rifaximin in travellers' diarrhoea. METHODS: PubMed and the Cochrane Register of Controlled Clinical Trials (to January 2010) and International Society of Travel Medicine congress abstracts (2003-2009) were searched to identify relevant publications. RESULTS: A total of 10 publications were included in the analysis. When administered three times daily for 3 days, rifaximin is superior to placebo or loperamide; it is at least as effective as ciprofloxacin in reducing duration of illness and restoring wellbeing in patients with travellers' diarrhoea, both with and without identification of a pathogen, as well as in diarrhoea caused by Escherichia coli infection. Rifaximin demonstrates only minimal potential for development of bacterial resistance and for cytochrome P450-mediated drug-drug interactions, and its tolerability profile is similar to that of placebo. CONCLUSION: When antibiotic therapy is warranted in uncomplicated travellers' diarrhoea, rifaximin may be considered as a first-line treatment option because of its favourable efficacy, tolerability and safety profiles.""",1
12077,20332334,Imatinib and Panax ginseng: a potential interaction resulting in liver toxicity,"OBJECTIVE: To report a case of imatinib-induced hepatotoxicity after concurrent ginseng ingestion in a patient with chronic myelogenous leukemia (CML). CASE SUMMARY: A 26-year-old man with CML who had taken imatinib 400 mg daily for 7 years with no complications presented with right upper quadrant pain. Laboratory test results included alanine aminotransferase 1069 U/L, aspartate aminotransferase 481 U/L, alkaline phosphatase 124 IU/L, total bilirubin 1.4 mg/dL, albumin 4.0 g/dL, and international normalized ratio 1.08. Liver biopsy showed acute lobular hepatitis favoring a drug-induced etiology, and a diagnosis of imatinib-induced hepatotoxicity was made. The patient's only lifestyle modification prior to the diagnosis of hepatotoxicity was daily ingestion of Panax ginseng via energy drinks for the past 3 months. Both imatinib and ginseng were discontinued, and the patient was treated with a short course of corticosteroids. Imatinib was later restarted at the same dose with no recurrent elevations in his liver enzyme levels. DISCUSSION: Imatinib-associated hepatotoxicity usually presents within 1-2 years of therapy initiation, with the median time to hepatotoxicity being 100 days. Ginseng is an herb that is not known to be hepatotoxic. In vivo, ginseng is known to inhibit CYP3A4, the primary enzyme involved in the metabolism of imatinib. We propose that our patient's late-onset imatinib-associated hepatotoxicity was due to an interaction between ginseng and imatinib through CYP3A4. Based on the Naranjo probability scale, it is probable that imatinib caused this patient's hepatotoxicity, and the Horn drug interaction probability scale also indicates a probable interaction between imatinib and ginseng. CONCLUSIONS: This case emphasizes the importance of continuous monitoring of liver function tests even after several years of imatinib therapy and the importance of advising patients to avoid ginseng and any other over-the-counter herbal supplements that may interact with imatinib.",1
12078,20333776,Association between gastrointestinal manifestations following acetaminophen poisoning and outcome in 291 acetaminophen poisoning patients,"""BACKGROUND: Acetaminophen poisoning is a common clinical problem, and early identification of patients with more severe poisoning is key to improving outcomes. PURPOSES: This study intends to document prevalence, clinical characteristics, and predictors of gastrointestinal (GI) manifestations and to assess the impact of these manifestations on outcome in patients with acetaminophen poisoning. METHODS: This is a retrospective cohort study of hospital admissions for acute acetaminophen poisoning conducted over a period of 5 years from 1 January 2004 to 31 December 2008. Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. Statistical Package for Social Sciences (SPSS) 15 was used for data analysis. RESULTS: Two hundred and ninety-one patients were studied; their mean age was 23.01 +/- 7.4 years and 76.6% had GI manifestations. Multiple logistic regression showed that significant risk factors for GI manifestations were present among patients who reported acetaminophen dose ingested >or=10 g (p < 0.001), and latency time more than 8 hours (p = 0.030). GI manifestations at first admission predicted poorer outcomes in terms of estimated acetaminophen levels to be a possible toxic (p < 0.001), elevated bilirubin levels (p = 0.002), prolonged prothrombin time (PT; p = 0.002), elevated creatinine level (p = 0.028), declination of potassium level (p < 0.001), and prolonged hospital stay (p < 0.001). CONCLUSIONS: GI manifestations were common among patients with acetaminophen poisoning. This study suggests that the presence of GI manifestations at first presentation appears to be an important risk marker of subsequent hepatotoxicity and nephrotoxicity.""",1
12079,20335583,Rifaximin treatment in hepatic encephalopathy,"""BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)""",1
12080,20338127,Drug-induced hepatitis and lupus during infliximab treatment for psoriasis: case report and literature review,"BACKGROUND: Infliximab (IFX) can induce elevation of hepatic aminotransferase levels. Hepatitis has been reported in patients treated with IFX and with risk factors such as viral hepatitis, alcohol intake, or concomitant use of hepatotoxic drugs. Liver disorders occurring in a patient without risk factors have rarely been reported, and liver biopsies to substantiate the liver changes have very rarely been described. The presence of lupus-like symptoms with newly positive antinuclear antibodies (ANAs), sometimes with double-stranded deoxyribonucleic acid (DNA) antibodies, has also been reported with IFX. Only a few articles have reported in detail these types of adverse events in patients with psoriasis. To our knowledge, the combination of lupus-like symptoms with simultaneous occurrence of a biopsy-proven hepatitis has not been reported with the use of IFX for psoriasis. OBJECTIVE: Description of a case of drug-induced hepatitis in a patient with concurrent clinical and serologic features of lupus induced by IFX. METHODS: We present the case of a 40-year-old woman with psoriasis who developed a biopsy-proven drug-induced hepatitis and concurrent lupus symptoms with positive ANAs while under IFX treatment. A review of related publications is presented. CONCLUSION: The clinician must be aware of uncommon side effects of IFX, such as liver anomalies and development of autoantibodies. Liver enzymes should be monitored regularly, and ANAs should be checked if liver enzymes are increasing and in the presence of lupus symptoms.",1
12081,20348931,A case of lactic acidosis induced by linezolid,"BACKGROUND: A 36-year-old African American man with end-stage renal disease on chronic maintenance hemodialysis was transferred first from a hospital to a long-term acute care facility for advanced care then to the intensive care unit of our university hospital with unexplained abdominal pain, nausea, hypotension, altered mental status and anion gap metabolic acidosis. Subsequent review of the patient's medication list revealed that the he had been on linezolid for 6 weeks for the treatment of vancomycin-resistant Enterococcus fecalis bacteremia. INVESTIGATIONS: Medical history, physical examination, laboratory tests, CT imaging of the thorax, abdomen and pelvis and PCR-based tests to determine the presence of polymorphisms in the 16S ribosomal RNA gene. DIAGNOSIS: Lactic acidosis associated with prolonged exposure to linezolid. MANAGEMENT: Discontinuation of linezolid.",1
12082,20352584,Acute treatment of migraine headaches,"Optimum acute treatment of migraine requires prevention of headache as a top priority. Recognition of the multitude of migraine presentations, the frequency of total headache attacks, and number of days of headache disability are critical. Successful treatment requires excellent patient-clinician communication enhancing confidence and mutual trust based on patient needs and preferences. Optimum management of acute migraine nearly always requires pharmacologic treatment for rapid resolution. Migraine-specific triptans, dihydroergotamine, and several antiinflammatories have substantial empirical clinical efficacy. Older nonspecific drugs, particularly butalbital and opioids, contribute to medication overuse headache and are to be avoided. Clinicians should utilize evidence-based acute migraine-specific therapy stressing the imperative acute treatment goal of early intervention, but not too often with the correct drug, formulation, and dose. This therapy needs to provide cost-effective fast results, meaningful to the patient while minimizing the need for additional drugs. Migraine-ACT evaluates 2-hour pain freedom with return to normal function, comfort with treatment, and consistency of response. Employ a thoroughly educated patient, formulary, testimonials, stratification, and rational cotherapy against the race to central sensitization for optimum outcomes.",1
12083,20360293,Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma,"The beneficial role of statins in primary and secondary prevention of coronary heart disease has resulted in their frequent use in clinical practice. However, safety concerns, especially regarding hepatotoxicity, have driven multiple trials, which have demonstrated the low incidence of statin-related hepatic adverse effects. The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis, in which liver enzyme levels are elevated in the absence of proven hepatotoxicity. This class effect is usually asymptomatic, reversible, and dose-related. However, the increasing incidence of chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis C, has created a new challenge when initiating statin treatment in patients with high cardiovascular risk. These diseases result in abnormally high liver biochemistry values, discouraging statin use by clinicians, fostering treatment discontinuation, and leaving a large number of at-risk patients untreated. A PubMed/MEDLINE search of the literature regarding statin safety (January 1, 1994-December 31, 2008) was performed, using the following search terms: statin safety, statin-related hepatotoxicity, and chronic liver disease and statin use, as well as the specific names of different statins and different liver diseases. Relevant clinical trials, review articles, panel discussions, and guideline recommendations were selected. This review supports the use of statin treatment in patients with high cardiovascular risk whose elevated aminotransferase levels have no clinical relevance or are attributable to known stable chronic liver conditions. For each patient, the decision should be based on an individual assessment of risks and benefits.",1
12084,20363054,[Hepatitis B reactivation in an HbsAg-negative/anti-HBc-positive patient with B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab],Reactivation of hepatitis B virus infection in patients with resolved infection is rare and is usually associated with immunosuppressive therapy. Morbidity and mortality are high. Some cases of hepatitis B reactivation associated with the use of rituximab have previously been published. We present the case of a patient with B-cell non-Hodgkin lymphoma receiving combination chemotherapy with rituximab who showed hepatitis B reactivation followed by liver failure. The most recent literature on this topic is reviewed and discussed.,1
12085,20369908,Olanzapine: in adolescents with schizophrenia or bipolar I disorder,"Olanzapine is an atypical antipsychotic that, in addition to its use in adults, is now indicated for the treatment of schizophrenia, and manic or mixed episodes associated with bipolar I disorder in adolescents aged 13-17 years. In a randomized, double-blind, multicentre, 6-week trial in adolescents aged 13-17 years with schizophrenia, the least squares mean reduction from baseline to 6 weeks in the Brief Psychiatric Rating Scale for Children (BPRS-C) total score (primary endpoint) was significantly greater with olanzapine than with placebo. In a randomized, double-blind, multicentre, 3-week trial in adolescents, aged 13-17 years, with manic or mixed episodes associated with bipolar I disorder, the mean reduction from baseline to 3 weeks in the Adolescent Structured Young Mania Rating Scale (YMRS) total score (primary endpoint) was significantly greater with olanzapine than with placebo. In extensions of each of the pivotal placebo-controlled trials in schizophrenia and bipolar mania, open-label treatment with olanzapine for up to 26 weeks produced significant reductions from baseline to endpoint in BPRS-C and YMRS total scores, respectively. Oral olanzapine was generally well tolerated in adolescents with schizophrenia or bipolar mania. Sedation and weight gain were the most common adverse events in placebo-controlled trials. Extrapyramidal symptoms were reported by 10% of olanzapine recipients compared with 6% of placebo recipients. Olanzapine-treated adolescents were likely to experience greater increases in bodyweight, sedation, blood lipids, serum prolactin and liver transaminase levels than olanzapine-treated adults. Therefore, careful consideration of risk-benefit is recommended before using olanzapine in adolescents.",1
12086,20371655,Retrospective observational study on the effects and tolerability of flutamide in a large population of patients with various kinds of hirsutism over a 15-year period,"OBJECTIVE: The aim of the study was to evaluate the long-term effects and tolerability of flutamide (Flu) in hirsute women. To the best of our knowledge, this study represents the largest report, concerning the population studied and the duration of treatment, to evaluate Flu use in hirsutism treatment. DESIGN, PATIENTS AND METHODS: Over a 15-year period spanning from January 1991 to January 2006, a total of 414 premenopausal women with hirsutism of different aetiopathogeneses received yearly reducing doses (250, 125 and 62.5 mg/day) of Flu alone or in combination with oral contraceptives for a period varying from at least 3 to 8 years and more. Clinical and endocrine evaluations were assessed half-yearly and yearly respectively in the first 3 years of the study, and yearly in the following years. Liver function evaluations were assessed quarterly. RESULTS: Both the groups of patients under Flu therapy showed a marked decrease in hirsutism scores after 12 months compared with basal values. The maximum drug effect was observed after 2 years, and it was maintained during the following years of treatment. Androgens were strongly suppressed during treatment. During the first year of treatment, 6.0% of patients abandoned the study due to hepatic disorders related to the drug. During the following years with the lowest treatment regimen, none of the patients abandoned the study due to hepatic discomfort. CONCLUSIONS: Flu is a satisfactory therapeutic regimen for any form of hirsutism in the long run. Moreover, the use of very low doses of Flu is associated with minimal side-effects and high compliance.",1
12087,20373370,"Hepatobiliary complications of hematopoietic cell transplantation, 40 years on","Liver problems caused by infection, cholestasis and sinusoidal liver injury in the months following HCT have become less frequent because of preventive and pre-emptive strategies. When patients develop jaundice after transplant, the time to search for treatable causes is early in the course of jaundice, as the risk of mortality rises steeply with small increments of serum bilirubin above normal. Chronic hepatitis C, persistent GVHD, cirrhosis and hepatocellular carcinoma are significant liver problems in the longest-lived survivors of HCT.",1
12088,20377116,"Efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis: a randomized, placebo-controlled study","""BACKGROUND: Levocetirizine, a second-generation antihistamine for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria, has not been previously studied in US patients. OBJECTIVE: To assess the efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis (SAR). METHODS: This multicenter, double-blind trial randomized adults with SAR, sensitized to at least 1 grass allergen, to receive levocetirizine, 5 mg, or placebo once daily in the evening for 2 weeks. The primary end point was the 24-hour reflective Total 5-Symptom Score (T5SS; sum of rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) during the entire treatment period. Secondary assessments included the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS), each assessed at week 1, week 2, and the end of treatment. RESULTS: The intent-to-treat population comprised 287 patients taking levocetirizine and 290 taking placebo, with no significant between-group differences at baseline. Levocetirizine resulted in significantly greater improvement from baseline vs placebo in the T5SS (P < .001), overall RQLQ score (P < .001), general and work-related WPAI-AS subscores (P < .05), and ESS score (P < .001). Overall incidence of treatment-emergent adverse events was 14.4% for levocetirizine and 18.4% for placebo. The incidence of somnolence and fatigue was 0.7% and 1.8% with levocetirizine and 1.0% and 0% with placebo, respectively. CONCLUSIONS: Levocetirizine was well tolerated and was significantly more effective than placebo in improving the naso-ocular symptoms and health-related quality of life in US patients with SAR.""",1
12089,20382058,"Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control","""Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-h blood ammonia. METHODS: An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA). RESULTS: Ten subjects completed the study. Adverse events were comparable for the two drugs; 2 subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were approximately 30% lower than on NaPBA (time-normalized AUC=26.2 vs. 38.4 micromol/L; Cmax=56.3 vs. 79.1 micromol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC(0-24)) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 microgh/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 microg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 microg h/mL) were similar. Urinary PAGN excretion accounted for approximately 54% of PBA administered for both NaPBA and GPB; other metabolites accounted for <1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=-0.82; p<0.0001) but weakly or not at all with blood metabolite levels. CONCLUSIONS: Safety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.""",1
12090,20385853,Intravenous voriconazole after toxic oral administration,"In a male patient with rhinocerebral invasive aspergillosis, prolonged high-dosage oral administration of voriconazole led to hepatotoxicity combined with a severe cutaneous reaction while intravenous administration in the same patient did not. High concentrations in the portal blood precipitate liver enzyme abnormalities, and therefore, oral administration of voriconazole may have a hepatotoxicity profile different from that of intravenous (i.v.) administration. Intravenously administered voriconazole might still be an option after oral-voriconazole-induced toxicity has resolved.",1
12091,20387081,"A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose-response of tolvaptan in patients with decompensated liver cirrhosis","OBJECTIVES: We examined the efficacy of tolvaptan, an orally effective nonpeptide vasopressin V(2) receptor antagonist, in a Japanese clinical study in patients with intractable ascites and/or lower limb edema associated with decompensated liver cirrhosis. METHODS: Tolvaptan was orally administrated at titrated doses of 15, 30, and 60 mg once daily after breakfast for 3 days at each dose to 18 liver cirrhosis patients with persistent ascites and/or lower limb edema despite receiving oral furosemide at 40 mg/day or higher. RESULTS: Decreased body weight and abdominal circumference and improvement of ascites and edema were observed following tolvaptan administration beginning from 15 mg. Composite ascites/edema improvement rate was 88.2% at individual maximum doses and 64.7, 80.0, and 90.9%, respectively, after 3-day administration at 15, 30, and 60 mg. Changes in body weight after 3-day administration at 15, 30, and 60 mg were -1.6 ? 0.9, -2.6 ? 1.2, and -3.4 ? 2.1 kg (mean ? SD), respectively, and decreases of 1 kg or more were seen from day 2 (24 h after first dosing). Changes in abdominal circumference ranged from -2.8 to -6.0 cm. Cumulative 24-h urine volumes after 3-day administration at 15, 30, and 60 mg were, respectively, 3240.3 ? 1014.5, 3943.3 ? 1060.6, and 4537.4 ? 1621.3 mL/day (mean ? SD). Urine osmolarity was markedly decreased and remained decreased until the end of treatment. CONCLUSION: Tolvaptan dose-dependently decreased body weight and abdominal circumference and improved ascites and edema beginning from 15 mg, demonstrating a potent aquaretic effect.",1
12092,20389182,[Fulminant hepatic failure with hepatitis B virus reactivation after rituximab treatment in a patient with resolved hepatitis B],"It is well known that the reactivation of hepatitis B virus (HBV) may occur as an acute hepatitis after chemotherapy or immunosuppressive therapy. Although most of these cases have been reported in HBsAg-positive patients, there have been a few reports of HBV reactivation in HBsAg-negative patients. There have been concerns for the need to screen the reactivation as well as anti-viral prophylaxis in HBsAg-negative patients with possible HBV occult infection who are planning to undergo chemotherapy or immunosuppressive therapy. Rituximab, an anti-CD20 monoclonal antibody, is effective in the treatment of non-Hodgkins lymphoma. However, rituximab can affect the immunity against HBV, consequently increasing viral replication. In fact, there have been reports of HBV reactivation after treatment with rituximab. Here, we report a case of HBV reactivation following rituximab plus systemic chemotherapy in diffuse large B cell lymphoma patient who was HBsAg negative, anti-HBs positive, and anti-HBc positive, ultimately leading to treatment-unresponsive fulminant hepatic failure.",1
12093,20389299,Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism,"""BACKGROUND: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. METHODS: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. RESULTS: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3-32.2) compared with other genotypes. CONCLUSIONS: The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.""",1
12094,20392657,Hepatic coma culminating in severe brain damage in a child with a SCN1A mutation,"An 11 months old boy, developed liver failure after febrile status epilepticus while being treated with valproic acid for myoclonic epilepsy and recurrent partial and generalized seizures. The diagnosis of Alpers-Huttenlocher disease was considered. A muscle biopsy showed mitochondrial dysfunction. Mitochondrial DNA depletion was ruled out. Sequencing of the polymerase gamma gene (POLG1) did not detect any mutations. Sequencing of the alpha-1 subunit gene of the voltage-gated neuronal sodium channel (SCN1A) revealed a novel, de novo amino acid change p.Val 1637 Glu. This case expands the spectrum of clinical presentations related to mutations in SCN1A. We warn that children with SCN1A mutations may be at risk for developing liver failure following status epilepticus, due to mitochondrial dysfunction.",1
12095,20407399,"Drug rash, eosinophilia, and systemic symptoms syndrome: Two pediatric cases demonstrating the range of severity in presentation--A case of vancomycin-induced drug hypersensitivity mimicking toxic shock syndrome and a milder case induced by minocycline","BACKGROUND: Drug rash, eosinophilia, and systemic symptoms syndrome is a type of drug hypersensitivity reaction characterized by the clinical triad of skin eruption, fever, and internal organ involvement. Drug rash, eosinophilia, and systemic symptoms syndrome has rarely been reported in association with vancomycin or in the pediatric population. There have only been four pediatric case reports of drug rash, eosinophilia, and systemic symptoms syndrome and three cases of drug rash, eosinophilia, and systemic symptoms syndrome involving vancomycin published in the English literature to date. CASE REPORTS: We describe two pediatric cases of drug rash, eosinophilia, and systemic symptoms syndrome to illustrate the range in severity of presentation. The first case illustrates drug rash, eosinophilia, and systemic symptoms syndrome associated with vancomycin exposure in a 14-yr-old boy with Duchenne muscular dystrophy after posterior spinal fusion, whose clinical presentation was indistinguishable from toxic shock syndrome. The second case illustrates a milder and more typical presentation of drug rash, eosinophilia, and systemic symptoms syndrome in a 14-yr-old boy being treated with minocycline for acne. We also present a review of the literature relevant to this syndrome. CONCLUSIONS: : Drug rash, eosinophilia, and systemic symptoms syndrome is relatively unknown among general pediatricians and pediatric intensivists and may potentially become more common with the increasing use of long-term medications in the pediatric population. Our cases demonstrate the importance of an awareness of drug rash, eosinophilia, and systemic symptoms syndrome among general pediatricians and pediatric intensivists because drug rash, eosinophilia, and systemic symptoms syndrome may present in any range of severity, from indolent illness to frank and refractory shock.",1
12096,20408947,Medical and psychiatric outcomes for patients transplanted for acetaminophen-induced acute liver failure: a case-control study,"""BACKGROUND: Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure (ALF) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence. AIMS AND METHODS: We compared the severity of pretransplant illness, psychiatric co-morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999-2004 for acetaminophen-induced ALF (n=36) with age- and sex-matched patients undergoing emergent LT for non-acetaminophen-induced ALF (n=35) and elective LT for chronic liver disease (CLD, n=34). RESULTS: Acetaminophen-induced ALF patients undergoing LT had a greater severity of pre-LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) acetaminophen-induced ALF patients had a formal psychiatric diagnosis before LT (non-acetaminophen-induced ALF=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow-up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (acetaminophen-induced ALF 1 year 87%, 5 years 75%; non-acetaminophen-induced ALF 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two acetaminophen-induced ALF patients reattempted suicide post-LT (one died 8 years post-LT). CONCLUSIONS: Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for acetaminophen-induced ALF were comparable to those transplanted for non-acetaminophen-induced ALF and electively for CLD. Multidisciplinary approaches with long-term psychiatric follow-up may contribute to low post-transplant suicide rates seen and low rates of graft loss because of non-compliance.""",1
12097,20409026,Treatment of latent tuberculosis infection: An update,"""Isoniazid (INH) has been the mainstay of treatment of latent tuberculosis infection for almost 50 years. The currently recommended preferred regimen is 9 months daily self-administered INH (9H); this has efficacy of more than 90% if completed properly. Unfortunately, INH is associated with serious adverse events, including hepatotoxicity. Although risk factors for this complication are well established, allowing for better selection of candidates for therapy, this complication still occurs, and is occasionally fatal. Hence close follow up of patients is necessary, increasing the cost and complexity of treatment. This problem, plus the lengthy duration, results in poor acceptance by patients and providers, and poor adherence by patients. As a result, many preventable cases of tuberculosis continue to occur, and the public health impact of latent tuberculosis infection treatment is suboptimal. These problems have spurred interest in finding shorter, safer and cheaper alternative regimens, with similar efficacy. Of the many regimens that have been examined, 2 months of rifampin and pyrazinamide has excellent efficacy-in experimental studies in mice and randomized trials, largely in HIV-infected persons. However, while the safety of 2 months of rifampin and pyrazinamide appears acceptable in HIV-infected persons and children, in non-HIV-infected adults this regimen is associated with an unacceptably high rate of severe liver toxicity. Three to four months of INH and rifampin has had equivalent effectiveness as 6 months INH in several randomized trials. However, completion of therapy and toxicity has been the same as with INH-possibly because two drugs are taken rather than one. The fourth commonly studied regimen is 4 months rifampin. This has been found to have significantly better completion than 9H, with significantly less toxicity, especially hepatotoxicity. However, only one trial has evaluated efficacy and effectiveness of mono-rifampin therapy. In this trial, 3 months rifampin had somewhat better efficacy than either 3 months of isoniazid and rifampin (3HR) or 6 months isoniazid. Two large scale trials are ongoing; one is comparing efficacy and effectiveness of 9H with 4 months rifampin (both daily and self-administered), while the second, which is nearing completion, compares daily self-administered 9H with 3 months directly observed once weekly INH combined with rifapentine. The results of these two trials will likely shape future recommendations substantially.""",1
12098,20410233,"Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, phase II trial","""CONTEXT: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide. OBJECTIVE: Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly. DESIGN: We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study. PATIENTS: Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment. INTERVENTION: After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d. MAIN OUTCOME MEASURE: A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls. RESULTS: After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated. CONCLUSIONS: Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.""",1
12099,20411370,Seizure and coma following Kratom (Mitragynina speciosa Korth) exposure,"Reports of toxicity secondary to Kratom are rare and lack of diagnostic testing in human specimens has prevented confirmatory explanation of observed clinical effects. We present a novel case of serious human toxicity following Kratom use confirmed via quantitative analysis of urine by high performance liquid chromatography coupled to electrospray tandem mass spectrometry. A 64�year-old male was witnessed to have a seizure at home following kratom consumption. Upon arrival to the emergency department (ED), the patient was unresponsive. While in the ED, the patient sustained a second seizure. He was intubated to protect his airway. The remainder of his hospital course was uneventful. A urine specimen was collected shortly after admission and sent for analysis. The mitragynine concentration in the urine was 167???15�ng/ml. We report a rare case of Kratom toxicity characterized by a seizure and coma confirmed by urinary analysis of mitragynine by high performance liquid chromatography coupled to electrospray tandem mass spectrometry. The proposed mechanism for this reaction is unclear but suggested mechanisms include adenosine binding or stimulation of adrenergic and/or serotonergic receptors similar to tramadol.",1
12100,20411998,Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus,"Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and beta-cell dysfunction, leading to hyperglycemia and eventual micro- and macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP-4 inhibitors-sitagliptin, vildagliptin, saxagliptin, and alogliptin-in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966-July 2009) for pertinent English-language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005-2009 were also searched. As a drug class, the DPP-4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse-effect profile, and once-daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease beta-cell apoptosis and increase beta-cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP-4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP-4 inhibition versus inhibition of other isoenzymes associated with toxicity, comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.",1
12101,20412573,"Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes","""BACKGROUND: In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies. METHODS: The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea +/- metformin, insulin +/- metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea +/- metformin, insulin +/- metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events. RESULTS: Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events. CONCLUSIONS: In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.""",1
12102,20419362,"Polyuria, acidosis, and coma following massive ibuprofen ingestion","Ibuprofen was the first over-the-counter nonsteroidal anti-inflammatory drug available in the United States. Despite being a common agent of ingestion, significant toxicity in overdose is rare. We report a case of a massive ibuprofen ingestion who developed polyuria, acidosis, and coma but survived, despite having a serum ibuprofen concentration greater than previous fatal cases. A 19-year-old man ingested 90 g (1,200 mg/kg) ibuprofen. He was initially awake and alert, but his level of consciousness deteriorated over several hours. Seven hours following the ingestion, he was intubated and mechanically ventilated secondary to loss of airway reflexes. He developed a lactic acidosis and polyuria, which lasted for nearly 24 h. His serum creatinine peaked at 1.12 mg/dL. An ibuprofen level drawn 7 h postingestion was 739.2 mg/L (therapeutic 5-49 mg/L). We describe a case of a massive ibuprofen overdose characterized by metabolic acidosis, coma, and a state of high urine output who survived with aggressive supportive care. This case is unique in several ways. First, ibuprofen levels this high have only rarely been described. Second, polyuria is very poorly described following ibuprofen ingestions.",1
12103,20422497,Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy,"Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 ( ABCB4) and BSEP ( ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis.",1
12104,20425345,Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate,"""Imatinib (imatinib mesylate, Gleevec(R) [formerly known as STI571], Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for patients with all phases of chronic myeloid leukemia (CML). Imatinib is remarkably effective as treatment for CML in the chronic phase (at a dosage of 400 mg/d) and the accelerated phase (at 600 mg/d). At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently in some patients so that they are functionally """"cured,"""" and also whether the increased rate of major molecular response induced by doses of imatinib higher than 400 mg/d will further improve overall survival of patients with CML in the chronic phase. The value of molecular monitoring of response in patients with CML in the chronic phase is examined. Although imatinib 800 mg/d can induce dramatic responses in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the responses are usually incomplete and of short duration. We discuss the role of imatinib in relation to allogeneic stem cell transplantation (particularly in younger patients), recognizing that the data upon which any decisions can be made are relatively immature. Finally, recent data on new tyrosine kinase inhibitors capable of overcoming primary or acquired resistance to imatinib are reviewed.""",1
12105,20426712,Gefitinib for the treatment of non-small-cell lung cancer,"IMPORTANCE OF THE FIELD: The epidermal growth factor receptor (EGFR) is a leading target for treatment of non-small-cell lung cancer (NSCLC). Recent trials of the small-molecule EGFR inhibitor gefitinib have now more clearly defined indications for usage, and clinical and molecular factors predictive of benefit. AREAS COVERED IN THIS REVIEW: A systematic search of the literature (Medline, ASCO, WCLC meeting abstracts) was performed from January 2000 to January 2010. The Phase III INTEREST study found gefitinib in unselected, pretreated patients was not inferior to docetaxel chemotherapy in overall survival, offering improved quality of life and superior toxicity profile. The Phase III IPASS study demonstrated improved progression-free survival with gefitinib compared with paclitaxel-carboplatin chemotherapy in chemotherapy-naive, never/light ex-smokers with adenocarcinoma histology. Stratifying for EGFR mutation revealed mutation-positive patients had superior outcomes with gefitinib compared with chemotherapy. Subsequent studies (WJOG4305, NEJ002), selecting only EGFR mutation-positive patients prospectively confirm this finding. WHAT THE READER WILL GAIN: The profile of gefitinib and landmark trials in NSCLC are summarized. How biomarkers may further optimize therapeutic benefit is highlighted. TAKE HOME MESSAGE: Gefitinib is expected to have an important impact on management of pretreated and selected chemotherapy-naive patients with advanced NSCLC. In addition, activating EGFR mutations are proven to be of value for prediction of those who will derive most benefit.",1
12106,20427778,"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis","""BACKGROUND: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. METHODS: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. RESULTS: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. CONCLUSIONS: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)""",1
12107,20429777,Famciclovir: a focus on efficacy and safety,"IMPORTANCE OF THE FIELD: Famciclovir is the prodrug of penciclovir, a guanosine analogue that inhibits viruses of the alpha sub-family of the Herpesviridae, as well as hepatitis B virus. It is indicated for management of mucocutaneous herpes simplex virus disease and acute herpes zoster, and has been investigated for management of hepatitis B virus infection. AREAS COVERED IN THIS REVIEW: Data for this review were identified by searches of papers published in English on Medline and Scopus, spanning the years 1975 through 1 February 2010 with the key words: 'famciclovir', 'famvir', 'penciclovir', 'herpes', 'oral', 'genital', 'varicella', 'zoster' and 'virus' in association with 'safety', 'toxicity', 'tolerability', 'efficacy' and 'indications'. Relevant references were also obtained from articles acquired through the search strategy. WHAT THE READER WILL GAIN: Readers are also provided with up-to-date information on the use of famciclovir for infections due to herpes simplex, varicella zoster and hepatitis B viruses. Clinical data pertaining to the safety and tolerability of famciclovir are also reviewed. TAKE HOME MESSAGE: Famciclovir is a safe, convenient, and well-tolerated drug when used for its approved indications. The most common side effects indicated in the majority of studies were headache and nausea. Data for its use in childhood and pregnancy are limited.",1
12108,20430649,Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey,"""BACKGROUND: Epoprostenol and treprostinil are intravenous prostacyclin medications used to treat pulmonary arterial hypertension (PAH). This survey explored hospital policies regarding prostacyclin infusions, and investigated the type and frequency of errors that occurred in the inpatient setting. METHODS: Information on prostacyclin infusion policies and inpatient errors was obtained through detailed interviews with 18 PAH nurses, and through an electronic survey completed by 97 PAH clinicians. RESULTS: The electronic survey respondents reported wide variability in prostacyclin infusion policies, including variability in the use of home vs hospital infusion pumps, and variability in the use and storage of back-up epoprostenol and treprostinil. Serious or potentially serious errors in medication administration were reported by 68% of survey respondents. The most common error types (reported by >or=25%), included: incorrect cassette placed in the pump; inaccurate pump programming; errant drug dosing; and inadvertent cessation of the pump. Nine errors, all at different centers, were believed to have contributed to patient death. In the separate interviews with the PAH nurses, 94% reported serious errors. These errors prompted many of the centers to implement policy changes in an attempt to reduce future errors, improve safety and optimize patient outcomes. CONCLUSIONS: These findings suggest that prostacyclin infusion therapy is problematic and that an opportunity exists to improve safety. The development of standardized treatment guidelines should be considered.""",1
12109,20434759,Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials,"BACKGROUND: Three randomized, double-blind trials compared dabigatran, an oral direct thrombin inhibitor, with enoxaparin for the primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee arthroplasty. OBJECTIVES AND METHODS: We conducted a pre-specified pooled analysis of these trials. 8,210 patients were randomized, of whom 8,135 were treated (evaluable for safety) with dabigatran 220 mg or 150 mg once-daily, or subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Efficacy analyses were based on the modified intention-to-treat population of 6,200 patients with an evaluable outcome. The common risk difference (RD) of treatment effect between each dabigatran dose and enoxaparin was estimated using fixed-effects models, and statistical heterogeneity was estimated using the I2 statistic. RESULTS: The composite outcome of major VTE (proximal deep vein thrombosis and/or pulmonary embolism) and VTE-related mortality occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, 95% CI -1.3% to 0.9%, I2=37%) and 3.8% of the 150 mg group (RD vs. enoxaparin 0.5%, -0.6% to 1.6%, I2=0%). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, -0.8% to 0.5%, I2=40%) and 1.1% of the 150 mg group (RD vs. enoxaparin -0.4%, -1.0% to 0.2%, I2=0%). CONCLUSIONS: Oral dabigatran was as effective as subcutaneous enoxaparin in reducing the risk of major VTE and VTE-related mortality after hip or knee arthroplasty and has a similar bleeding profile.",1
12110,20435378,[Acute toxic hepatitis secondary to a single dose of bupropion],,1
12111,20436075,Golimumab for rheumatoid arthritis: a systematic review,"""OBJECTIVE: To perform a Cochrane systematic review of benefit (American College of Rheumatology 50% improvement criteria; ACR50) and safety (adverse events and withdrawals) of golimumab in patients with rheumatoid arthritis (RA). METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), OVID Medline, CINAHL, Embase, Science Citation Index (Web of Science), and Current Controlled Trials databases for randomized or controlled clinical trials of golimumab compared to placebo or disease-modifying antirheumatic drug in adults with RA. Two authors independently selected appropriate studies and abstracted study characteristics and safety and efficacy data and performed risk-of-bias assessment. We calculated mean differences for continuous measures, and relative risks for categorical measures. RESULTS: Four randomized controlled trials with 1231 golimumab-treated and 483 placebo-treated patients were included. Of these, 436 were treated with golimumab at 50 mg every 4 weeks [a dosage approved by the US Food and Drug Administration (FDA)]. At an average of 4-6 months, compared to patients treated with placebo and methotrexate (MTX), patients treated with the FDA-approved dosage of golimumab and MTX were 2.6 times more likely to reach ACR50 (p = 0.005, 95% CI 1.3, 4.9; absolute percentage, 38% vs 15%) and 0.5 times as likely to have overall withdrawals (p = 0.005, 95% CI 0.3, 0.8; absolute percentage, 5% vs 10%). Golimumab-treated patients were significantly more likely than those taking placebo to achieve remission (22% vs 4%; p < 0.00001), and to have improvement in functional ability on the Health Assessment questionnaire [0.2 points lower (p < 0.00001, 95% CI 0.25, 0.15); absolute risk difference, -20% (95% CI -25% to -15%); relative percentage difference, -11% (95% CI -14% to -8.3%)]. The studies were too small and short to be powered sufficiently for safety outcomes, but no substantive statistically significant differences were noted between golimumab and placebo regarding adverse events, serious adverse events, infections, serious infections, lung infections, tuberculosis, cancer, withdrawals due to adverse events, and withdrawals due to inefficacy and deaths. CONCLUSION: At the approved dosage, in patients with active RA taking background MTX, golimumab is significantly more beneficial than placebo. The short-term safety profile is reasonable. Longterm surveillance studies are needed for safety assessment.""",1
12112,20440256,Clopidogrel treatment in a patient with ticlopidine-induced hepatitis following percutaneous coronary stenting,"Thienopyridines are commonly prescribed antiplatelets drugs, extremely useful for the acute and chronic management of patients with cerebrovascular and cardiovascular diseases. The occurrence of their side effects is fortunately uncommon, although unpredictable. We thereby describe a case of prescription of clopidogrel in a patient with ticlopidine-induced hepatitis confirmed by liver biopsy that had undergone multiple percutaneous coronary stenting procedures necessitating subsequent compulsory antiplatelets treatment. The description of this exceptional clinical case is of relevant knowledge to orientate a physician treating a patient with absolute need of antiplatelets and history of previous drug-induced reactions.",1
12113,20443662,Azathioprine-induced liver injury in a patient with multiple autoimmune syndrome,"Extraintestinal manifestations are frequent in patients with ulcerative colitis. They are most commonly associated with active bowel disease but can also occur prior to bowel disease or during a period of remission. The disease often requires long-term therapy. The tolerability of drugs is essential for the comprehensive management of patients. Azathioprine is considered an indispensable drug for the treatment of severe ulcerative colitis patients. It is used to prevent relapse or to treat patients who are refractory to corticosteroids. We report a patient who had alopecia areata, vitiligo, recurrent episcleritis, ulcerative colitis and azathioprine-induced liver injury, and review the related literature.",1
12114,20446076,"""Bactrian (""""double hump"""") acetaminophen pharmacokinetics: a case series and review of the literature""","""After acute ingestion, acetaminophen (APAP) is generally absorbed within 4 h and the APAP concentration ([APAP]) slowly decreases with a predictable half-life. Alterations in these pharmacokinetic principles have been rarely reported. We report here three cases of an unusual double hump, or Bactrian, pattern of [APAP]. We review the literature to describe the case characteristics of these rare cases. A 38-year-old woman ingested 2 g hydrocodone/65 g acetaminophen. Her [APAP] peaked at 289 mcg/mL (8 h), decreased to 167 mcg/mL (31 h), then increased to 240 mcg/mL (39 h). She developed liver injury (peak AST 1603 IU/L; INR1.6). A 25-year-old man ingested 2 g diphenhydramine/26 g APAP. His [APAP] peaked at 211 mcg/mL (15 h), decreased to 185 mcg/mL (20 h), and increased again to 313 mcg/mL (37 h). He developed liver injury (peak AST 1153; INR 2.1). A 16-year-old boy ingested 5 g diphenhydramine and 100 g APAP. His [APAP] peaked at 470 mcg/mL (25 h), decreased to 313 mcg/mL (36 h), then increased to 354 mcg/mL (42 h). He developed liver injury (peak AST 8,686 IU/L; peak INR 5.9). We report three cases of Bactrian (""""double hump"""") pharmacokinetics after massive APAP overdoses. Cases with double hump pharmacokinetics may be associated with large ingestions (26-100 g APAP) and are often coingested with antimuscarinics or opioids. Several factors may contribute to these altered kinetics including the insolubility of acetaminophen, APAP-induced delays in gastric emptying, opioid or antimuscarinic effects, or enterohepatic circulation. Patients with double hump APAP concentrations may be at risk for liver injury, with AST elevations and peaks occurring later than what is typical for acute APAP overdoses.""",1
12115,20448284,Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis,"""OBJECTIVE: Liver function test (LFT) elevations are reported with the use of tumour necrosis factor inhibitors (TNF-Is). The aim of this study was to compare LFT elevations in patients with rheumatoid arthritis receiving adalimumab (ADA), etanercept (ETN) or infliximab (INF) enrolled in the Consortium of Rheumatology Researchers of North America from October 2001 to March 2007. METHODS: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >1x upper limit of normal (ULN) were considered elevations and ALT/AST levels >2x ULN were considered abnormalities. Treatments included TNF-Is, methotrexate (MTX), leflunomide and other disease-modifying antirheumatic agents (DMARDs). Patients were censored after their first LFT elevation. Three analytical models were evaluated: (1) individual TNF-I vs non-biological DMARDs (primary model); (2) individual TNF-I plus MTX vs MTX monotherapy; and (3) limited to new users of individual TNF-I vs non-biological DMARDs. ORs for LFT elevations were estimated using generalised estimating equation logistic regression. RESULTS: 6861 patients (ADA: 849; ETN: 1383; INF: 1449) with 22 522 determinations were analysed. LFT elevations >1x ULN with TNF-I use were seen in 5.9% of AST/ALT determinations and abnormalities >2x ULN in 0.77%. In the primary model the adjusted ORs for LFT elevations >1x ULN were ADA 1.35 (95% CI 1.09 to 1.66), ETN 1.00 (95% CI 0.83 to 1.21) and INF 1.58 (95% CI 1.35 to 1.86). For 2x ULN, adjusted ORs were ADA 1.72 (95% CI 0.99 to 3.01), ETN 1.10 (95% CI 0.64 to 1.88) and INF 2.40 (95% CI 1.53 to 3.76). Similar results were obtained in other models. CONCLUSION: The overall incidence of LFT elevations >1x ULN with TNF-I use was uncommon and abnormalities >2x ULN were rarely observed. Significant differences were most consistently observed with INF, less commonly with ADA and were not observed with ETN compared with comparator DMARDs.""",1
12116,20451251,Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study,"""The prospective 1-year EPIC study enrolled 341 patients with myelodysplastic syndromes (MDS); although baseline iron burden was >2500ng/mL, approximately 50% were chelation-na?ve. Overall median serum ferritin decreased significantly at 1 year (p=0.002). Decreases occurred irrespective of whether patients were chelation-na?ve or previously chelated; changes were dependent on dose adjustments and ongoing iron intake. Sustained reductions in labile plasma iron were observed. Discontinuation rate (48.7%) and adverse event profile were consistent with previously reported deferasirox data in MDS. Alanine aminotransferase levels decreased significantly; change correlated significantly with reduction in serum ferritin (p<0.0001). This large dataset prospectively confirms the efficacy and well characterizes the safety profile of deferasirox in MDS.""",1
12117,20452889,"Raltegravir, tenofovir, and emtricitabine in an HIV-infected patient with HCV chronic hepatitis, NNRTI intolerance and protease inhibitors-induced severe liver toxicity","BACKGROUND: In HIV-infected patients with HCV-related chronic hepatitis, liver impairment and drug toxicity may substantially reduce the number of possible therapeutic options. CASE DESCRIPTION: we here describe the case of an HCV-HIV coinfected woman who had repeated severe episodes of drug-related liver toxicity with indinavir, saquinavir, fosamprenavir, and darunavir, with minimal further therapeutic options left in this class. Previous treatment-limiting side effects with efavirenz and nevirapine also precluded use of non-nucleoside reverse transcriptase inhibitors. Introduction of an integrase-inhibitor regimen based on raltegravir, tenofovir, and emtricitabine allowed a prompt achievement of undetectable viral load and a substantial rise of CD4 count to high levels, with no subsequent episodes of hepatic toxicity, and no other side effects. CONCLUSIONS: given the relatively common prevalence of HCV-related chronic hepatitis among people with HIV, raltegravir might represent an important alternative option for a substantial number of patients who cannot be treated with protease inhibitors or NNRTI because of drug-related hepatic toxicity.",1
12118,20457690,Eosinophilic hepatitis in an adolescent during lisdexamfetamine dimesylate treatment for ADHD,"We describe here the case of an adolescent who developed eosinophilic hepatitis during treatment for attention-deficit/hyperactivity disorder with lisdexamfetamine dimesylate (Vyvanse [Shire US Inc, Wayne, PA]). A 14-year-old boy presented to his primary care provider with abdominal pain and worsening jaundice. A diagnosis of hepatitis was made with biochemical markers, but evaluation failed to provide an etiology. Worsening hepatitis prompted hospitalization and initiation of steroids for presumed autoimmune hepatitis. A subsequent liver biopsy showed evidence of eosinophilic hepatitis. Known causes of eosinophilic hepatitis were ruled out, and a presumptive diagnosis of reaction to lisdexamfetamine dimesylate was made. Discontinuation of the medication led to resolution of the hepatitis and normalization of the liver biopsy. To our knowledge, this is the first report of hepatic injury attributed to lisdexamfetamine dimesylate.",1
12119,20461008,Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity,"INTRODUCTION: Isoniazid, rifampicin, and pyrazinamide, the first-line antituberculosis (anti-TB) drugs, are associated with hepatotoxicity. AIMS AND OBJECTIVES: To study the hepatoprotective effect of N-acetylcysteine (NAC) on liver injury induced by anti-TB drugs. METHODS: A randomized clinical trial was conducted on 60 new TB patients who were aged 60 years or more. Patients were randomized into two groups. In group I (n=32), drug regimen included daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients in group II (n=28) were treated with the same regimen and NAC. The patients were followed up for 2 weeks. Liver enzymes and bilirubins were measured at baseline, after 1 and 2 weeks of treatment, and whenever the patients presented with clinical symptoms of hepatotoxicity. RESULTS: The mean+/-SD values of aspartate aminotransferase and alanine aminotransferase were significantly higher in group I than in group II after 1 and 2 weeks of treatment. Hepatotoxicity occurred in 12 patients with (37.5%) group I and none in group II. The mean duration of treatment before the onset of hepatotoxicity was 4.67+/-4.58 days. CONCLUSION: NAC protects against anti-TB drug-induced hepatotoxicity.",1
12120,20466184,Safety of etanercept in patients with psoriasis and hepatitis C virus assessed by liver histopathology: preliminary data,,1
12121,20471573,"[Toxic hepatitis following sequential treatment with cotrimoxazol, levofloxacin, doxycycline and sertraline in a patient with a respiratory infection]",,1
12122,20473057,"A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia","This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P < or = 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (> or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.",1
12123,20478543,Ibuprofen-induced hypersensitivity syndrome,"Ibuprofen is a widely used antipyretic and analgesic nonsteroidal antiinflammatory drug (NSAID). With the aging of the population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions. This increase likely will lead to a parallel increase in the use of NSAIDs, including ibuprofen. The primary effect of the NSAIDs is to inhibit cyclooxygenase (prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Although in the majority of cases it is safe, this NSAID, ibuprofen, can produce an unpredictable, idiosyncratic, type B reaction that may pose a major concern in clinical practice. Type B reactions are known to occur in susceptible individuals. The true hypersensitivity reaction (HSR) is a systemic disease defined by the triad of fever, rash, and internal organ involvement that starts 1 day to 12 weeks after the initiation of therapy. HSR has limited the therapeutic use of many drugs, including ibuprofen. Hypersensitivity syndrome associated with ibuprofen is a host-dependent drug reaction that is idiosyncratic in nature. This reaction likely is caused by a combination of metabolic and immunologic factors. Immune mediated components, such as T-cell and their products cytokines and chemokines, can exacerbate cellular responses and create complex pathways that lead to a variety of clinical manifestations. Our review presents an ibuprofen-induced clinical manifestation of hypersensitivity syndrome and the necessity of wisely monitoring the patients clinically and by laboratory investigations when prescribing this drug.",1
12124,20479902,Reactivation of Pulmonary Tuberculosis in a Patient with Polygonum multiflorum Thunb-Induced Hepatitis,"Several cases of Polygonum multiflorum Thunb-induced hepatitis have been reported worldwide. Anthraquinone is an active ingredient of P. multiflorum Thunb. that has been thought to play a role in its hepatotoxicity. Here we report the case of a 34-year-old Korean man who had P. multiflorum Thunb-induced hepatitis and reactivation of pulmonary tuberculosis caused by bone marrow suppression, which developed simultaneously. He was admitted to our hospital with recently developed fatigue and aggravated jaundice. He was a previously healthy man except for the sequelae of pulmonary tuberculosis seen on chest X-ray. He had a 30-day history of ingesting the root of P. multiflorum as a form of liquor and tea. The patient was diagnosed with P. multiflorum Thunb-induced hepatitis after excluding all other potential causes of acute hepatitis. Liver function gradually improved following the total cessation of the consumption of the material. However, he suffered from spiking fever with progressive pancytopenia during the hospital stay. A bone marrow biopsy showed markedly hypocellular marrow, suggesting transient bone marrow suppression, which was probably caused by extrinsic factors such as drugs, toxins, and viral infection. Although he began to complain of a dry cough, repeated sputum investigations revealed positive acid-fast bacillus staining. The fever subsided and pancytopenia improved after treatment for pulmonary tuberculosis. These observations suggest that P. multiflorum Thunb induces both bone marrow suppression and hepatotoxicity.",1
12125,20482507,Safety and efficacy of baclofen in the treatment of alcohol-dependent patients,"Preclinical studies show that antagonism of the GABA(B) receptor may represent an effective neuropharmacological approach to treat alcohol dependence. Consistent with preclinical evidence, the majority of the human studies have demonstrated that the prototype GABA(B) receptor antagonist baclofen may represent an effective mediation to treat alcohol-dependent individuals. Specifically, baclofen has shown to reduce alcohol withdrawal symptoms, as well as to reduce alcohol craving and intake, and to promote alcohol abstinence. Notably, baclofen has shown a safe profile when administered to alcoholics, including those with liver cirrhosis. In summary, baclofen represents a safe and effective medication to treat alcohol dependence, thus holding promise as a new pharmacotherapy. However, large studies are needed to confirm the present findings.",1
12126,20484019,"Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer","""PURPOSE: Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer. EXPERIMENTAL DESIGN: Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex. RESULTS: Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8%; 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 >12.5 pg/mL had worse survival than those with levels <12.5 pg/mL (53% versus 94%; P = 0.02). After treatment, IL-6 levels were >250-fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks. CONCLUSIONS: CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis.""",1
12127,20486755,[Cholestatic sindrome due to labetalol],,1
12128,20491750,The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol - a randomized study,"BACKGROUND: Retrospective accounts suggest that therapeutic doses of paracetamol can produce severe hepatic injury in patients with putative high-risk conditions, including alcoholism and infectious hepatitis. Metabolism of paracetamol to its hepatotoxic metabolite is enhanced in patients who abuse alcohol, who also have compromised liver defences from depressed hepatic glutathione. AIM: To determine the effect of paracetamol on serum liver tests of newly abstinent subjects who abuse alcohol, including subjects with hepatitis C infection. METHODS: A randomized, double-blind, placebo-controlled study. Adult alcohol abusers with a current drinking episode longer than 7 days received either placebo or paracetamol 4 g/day for 5 days. RESULTS: Of 142 subjects enrolled, 74 received paracetamol and 68 received placebo. Mean ALT activity during treatment increased from 48 to 62 IU/L in the paracetamol group and from 47 to 49 IU/L in the placebo group. Maximum ALT was 238 and 249 IU/L in the paracetamol and control groups respectively. The INR remained unchanged and serum bilirubin decreased in both groups. Subgroup analyses for subjects with alcoholic hepatitis, hepatitis C virus antibody and other subgroups showed no statistical difference between groups. CONCLUSION: Administration of paracetamol 4 g/day appears safe in newly abstinent patients who abuse alcohol.",1
12129,20492853,"A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder","""OBJECTIVE: This study was designed to assess efficacy and safety of paliperidone extended-release (ER) in patients with schizoaffective disorder. METHOD: A randomized, 6-week, double-blind, placebo-controlled study was conducted. Subjects with a Structured Clinical Interview for DSM-IV diagnosis of schizoaffective disorder, Positive and Negative Syndrome Scale (PANSS) total score >or= 60, score >or= 4 on >or= 2 PANSS items (hostility, excitement, tension, uncooperativeness, poor impulse control), and Young Mania Rating Scale and/or Hamilton Depression Rating Scale, 21-item version scores >or= 16 were eligible. Subjects received higher-dose (12 mg/d) or lower-dose (6 mg/d) paliperidone ER. Dose adjustments by 3-mg increments were allowed until day 15. The study was conducted from October 2006 through February 2008. RESULTS: A total of 316 subjects were randomly assigned to paliperidone ER lower dose (n = 109), higher dose (n = 100), or placebo (n = 107). Mean +/- SD modal dose in lower- and higher-dose groups: 5.7 +/- 0.9 and 11.6 +/- 1.0 mg/d, respectively. Mean +/- SE PANSS total score (primary outcome) improved significantly with higher-dose paliperidone ER versus placebo (-32.4 +/- 2.1 versus -24.1 +/- 2.1; P = .003). Change with lower-dose paliperidone ER (-27.7 +/- 2.1) was not significantly different from placebo (P = .187). No new safety issues were identified; common adverse events were headache (placebo: 16.8%; paliperidone ER: lower dose, 13.9%, higher dose, 13.3%) and tremor (3.7%, 12.0%, 11.2%, respectively). Mean prolactin and weight changes were greater with active treatment than placebo. CONCLUSIONS: Higher-dose paliperidone ER was effective and well tolerated in patients with acute schizoaffective disorder. These findings and those from a companion study constitute the first registration program for antipsychotic treatment in schizoaffective disorder. TRIAL REGISTRATION: clincaltrials.gov Identifier: NCT00397033.""",1
12130,20494268,Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study,"""OBJECTIVE: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. METHOD: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. RESULTS: Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. CONCLUSIONS: Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.""",1
12131,20495643,Perioperative chemotherapy with bevacizumab and liver resection for colorectal cancer liver metastasis,"BACKGROUND: Surgery remains the only curative option for patients with colorectal cancer liver metastases (CRLM). Perioperative chemotherapeutic strategies have become increasingly popular in the treatment of CRLM. Although the role of bevacizumab (Bev) in this setting remains unclear, its widespread use has raised concerns about the use of Bev as part of perioperative chemotherapy. METHODS: We retrospectively reviewed all patients who received Bev and underwent liver resection between July 2004 and July 2008 at the McGill University Health Center. Chemotherapy-related toxicity, response to chemotherapy, surgical morbidity and mortality, liver function and survival data were assessed. RESULTS: A total of 35 patients were identified. Of these, 26 (74.3%) patients received oxaliplatin-based cytotoxic chemotherapy, six (17.1%) received irinotecan-based therapy and the remainder received both agents. A total of 17 patients (48.6%) underwent portal vein embolization prior to resection and 12 (34.3%) underwent staged resection for extensive bilobar disease. A median of six cycles of preoperative Bev were administered. Nine patients (25.7%) experienced grade 3 or higher chemotherapy-related toxicities. Four events were deemed to be related to Bev. The overall response rate was 65.7% (complete and partial response). One patient progressed on therapy, but this did not prevent R0 resection. The incidence of postoperative morbidity was 42.3%. A total of 21.7% of complications were Clavien grade 3 or higher. There were no perioperative mortalities. There were no cases of severe sinusoidal injury or steatohepatitis. The Kaplan-Meier estimate of 4-year survival was 52.5%. CONCLUSIONS: These data confirm the safety of chemotherapy regimens which include Bev in the perioperative setting and demonstrate that such perioperative chemotherapy in patients with CRLM does not adversely affect patient outcome. There was no increase in perioperative morbidity compared with published rates. The addition of Bev to standard chemotherapy may improve response rates, which may, in turn, impact favourably on patient survival.",1
12132,20502130,Effectiveness of switching from aripiprazole to ziprasidone in patients with schizophrenia,"OBJECTIVES: Aripiprazole and ziprasidone are 2 antipsychotic medications that are relatively devoid of the metabolic adverse effects associated with the second-generation antipsychotics. This study aimed to evaluate the effectiveness of switching to ziprasidone in patients who had insufficient response or intolerance to aripiprazole for the treatment of schizophrenia. METHODS: Nineteen patients receiving aripiprazole treatment for schizophrenia participated in this open-label 12-week study. Outcome measures included the Positive and Negative Syndrome Scale, Social and Occupational Functioning Assessment Scale, Calgary Depression Scale for Schizophrenia, Beck Depression Inventory, and Subjective Well-being under Neuroleptics Scale. Safety measures included metabolic parameters and scales to evaluate extrapyramidal adverse effects. RESULTS: After switching to ziprasidone from aripiprazole, significant improvement of scores on the negative symptom subscale of the Positive and Negative Syndrome Scale, the Social and Occupational Functioning Assessment Scale, the Calgary Depression Scale for Schizophrenia, and the Beck Depression Inventory were observed at the study end point evaluation. Metabolic parameters including body weight, waist and hip circumferences, fasting blood glucose, and alanine aminotransferase showed statistically significant decreases. However, serum prolactin levels were significantly increased, and sedation was the most common adverse event. CONCLUSIONS: Switching to ziprasidone in patients with schizophrenia who showed insufficient response or intolerance to aripiprazole improved depression, negative symptoms, and metabolic disturbances. However, sedation and hyperprolactinemia were commonly associated with the switch to ziprasidone.",1
12133,20506254,"Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study","OBJECTIVE: To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to > or = 1 disease-modifying antirheumatic drug. METHODS: This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (i.v.) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. RESULTS: AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. CONCLUSION: Our findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.",1
12134,20508578,Velaglucerase (Vpriv) for Gaucher's disease,,1
12135,20508581,Romidepsin (Istodax) for cutaneous T-cell lymphoma,,1
12136,20512985,Multiple effects of silymarin on the hepatitis C virus lifecycle,"Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. CONCLUSION: Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell.",1
12137,20512995,Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis,"""UNLABELLED: Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. CONCLUSION: GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.""",1
12138,20515399,Life-threatening complications of vitamin D intoxication due to over-the-counter supplements,"INTRODUCTION: Ninety percent of hypercalcemic cases are caused by primary hyperparathyroidism or malignancy. Less frequent causes are granulomatous diseases, drug-induced diseases, and intoxications. CASE REPORT: We present two women with life-threatening hypercalcemia due to the intake of vitamin D-concentrated supplements, which turned out to be 100-1,000 times higher than stated on the label of over-the-counter dietary supplements. Laboratory analysis revealed ionized calcium levels of 4.00 (16.00) and 4.56 mmol/L (18.24 mg/dL) with vitamin D(25) concentrations of 1,372 and 644 nmol/L, respectively. Apart from a patient with general symptoms of hypercalcemia, a case of refractory status epilepticus after correction of serum calcium levels, and in need of prolonged ICU treatment, is described. CONCLUSION: Initial drug-taking history in the presented cases did not reveal the use of over-the-counter supplements, which underlines the importance of a thorough evaluation of (non-)prescribed medication. Moreover, these supplements may contain higher levels of vitamin D than the label states. As a result, hypercalcemia may be an underlying cause for life-threatening complications, including a well-documented refractory status epilepticus.",1
12139,20518811,Safety of pramlintide added to mealtime insulin in patients with type 1 or type 2 diabetes: a large observational study,"The objective of this Phase 4, open-label, multicentre, observational study was to fulfil food and drug administration (FDA) postapproval requirement to evaluate in healthcare practices the risk of insulin-induced severe hypoglycaemia following initiation of pramlintide therapy in N = 1297 patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) with inadequate glycaemic control. The duration of the study was approximately 6 months. During the adjustment period (0-3 months), the incidence and event rate of patient-ascertained severe hypoglycaemia (PASH) were 4.8% and 0.33 events/patient-year in patients with T1DM and 2.8% and 0.19 events/patient-year in patients with T2DM. During the maintenance period (>3-6 months), the incidence and event rate of PASH declined in patients with T1DM or T2DM. This study confirms that in healthcare practices, the risk of insulin-induced severe hypoglycaemia following the initiation of pramlintide is low in patients with T1DM or T2DM.",1
12140,20525992,Improved survival with ipilimumab in patients with metastatic melanoma,"""BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)""",1
12141,20525995,Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia,"BACKGROUND: Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. METHODS: In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. RESULTS: After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. CONCLUSIONS: Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)",1
12142,20528871,"Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma","A combination of 5 d of nelarabine (AraG) with 5 d of etoposide (VP) and cyclophosphamide (CPM) and prophylactic intrathecal chemotherapy was used as salvage therapy in seven children with refractory or relapsed T-cell leukaemia or lymphoma. The most common side effects attributable to the AraG included Grade 2 and 3 sensory and motor neuropathy and musculoskeletal pain. Haematological toxicity was greater for the combination than AraG alone, although median time to neutrophil and platelet recovery was consistent with other salvage therapies. All patients had some response to the combined therapy and five of the seven went into complete remission after one or two courses of AraG/VP/CPM. Our experience supports the safety of giving AraG as salvage therapy in synchrony with etoposide and cyclophosphamide, although neurological toxicity must be closely monitored.",1
12143,20533546,"Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study","""OBJECTIVE: To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1? monoclonal antibody, for the treatment of acute gouty arthritis. METHODS: In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS: Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ? 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION: Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.""",1
12144,20538634,Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study,"""OBJECTIVES: To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration. DESIGN: Prospective, double masked, multicentre, randomised controlled trial. SETTING: Three ophthalmology centres in the United Kingdom. PARTICIPANTS: 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control. INTERVENTIONS: Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration). PRIMARY OUTCOME: proportion of patients gaining >or=15 letters of visual acuity at one year (54 weeks). SECONDARY OUTCOMES: proportion of patients with stable vision and mean change in visual acuity. RESULTS: Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care. CONCLUSIONS: Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks. Trial registration number Current controlled trials ISRCTN83325075.""",1
12145,20542184,Ingestion of a dietary supplement resulting in selenium toxicity,,1
12146,20546320,"Long-term, open-label safety study of oral almotriptan 12.5 mg for the acute treatment of migraine in adolescents","""OBJECTIVES: This study evaluated the long-term safety of oral almotriptan 12.5 mg for the treatment of multiple migraine episodes in adolescents over a 12-month period. Efficacy outcomes were assessed as a secondary objective. METHODS: Adolescent migraineurs aged 12-17 years were enrolled in this 12-month, open-label study (Study ID CR002827). Patients were instructed to record their assessments on paper headache records whenever they experienced a migraine headache that they treated with study medication. Safety was assessed descriptively and assessments included adverse event (AE) recording, change in laboratory values, vital signs, and electrocardiogram parameters. Efficacy outcomes were assessed descriptively and outcomes included rates for 2- and 24-hour pain relief and sustained pain relief, 2- and 24-hour pain-free and sustained pain-free, and presence of migraine-associated symptoms of photophobia, phonophobia, nausea and vomiting. RESULTS: Overall, 67.1% of patients reported >or=1 AE over the course of the trial, 7.6% had an AE judged by the study investigator to be related to treatment with almotriptan, 2.4% discontinued because of an AE, and 1.9% reported serious AEs. The most commonly reported treatment-related AEs (occurring in >or=1% of patients) were nausea (1.4%) and somnolence (1.4%). Pain relief responses for treated migraines of moderate or severe intensity at baseline were 61.7% and 68.6%, at 2 and 24 hours, respectively; the sustained pain relief rate was 55.5%. Pain-free responses were reported for 40.5% of all treated migraines at 2 hours and 65.9% of treated migraines at 24 hours; the sustained pain-free rate was 38.4%. The proportion of migraines that achieved the pain relief, sustained pain relief, pain-free and sustained pain-free endpoints were similar in the 12- to 14-year and 15- to 17-year age groups. Treating with almotriptan 12.5 mg when headache pain was mild was associated with higher rates of pain relief and pain-free at 2 and 24 hours, and sustained pain relief and sustained pain-free, compared with treatment initiated when pain was severe. CONCLUSIONS: Almotriptan 12.5 mg was well tolerated in this adolescent population over a 12-month period. No unexpected safety or tolerability concerns were revealed over the course of this study. The results are consistent with almotriptan 12.5 mg being effective for the acute treatment of pain and symptoms associated with migraine in both younger and older adolescents.""",1
12147,20551297,A population study of the frequency of high-dose acetaminophen prescribing and dispensing,"BACKGROUND: Recurrent intake of 4 g/day or more of acetaminophen has been associated with elevation of serum alanine aminotransferase (ALT) levels in 30-40% of the exposed population and may result in hepatotoxicity. OBJECTIVE: To describe the frequency that patients are prescribed acetaminophen doses that exceed 4 g/day across a large population. METHODS: Using California's Medicaid (Medi-Cal) fee-for-service population, pharmacy claims including over-the-counter (OTC) medications were examined for prescriptions that could result in acetaminophen doses of 4 g/day or more. The period studied, October 2004 through September 2005, was before the Part D pharmacy benefit was available to dually eligible Medicare patients when all prescriptions were covered by the Medi-Cal claims process. RESULTS: During the pre-Part D evaluation period, approximately 3.27 million beneficiaries were enrolled in the fee-for-service Medi-Cal program. A total of 192,716 (5.9%) were potentially exposed to at least 1 day of 4 g/day or more of acetaminophen. Of those, 769 patients were potentially exposed to at least 1 day of 16 g/day or more. A total of 2664 beneficiaries were dispensed prescriptions and OTC products that, if taken as directed, would have resulted in more than 100 days of acetaminophen doses of 4 g/day or more during the study year. CONCLUSIONS: Despite electronic systems designed to warn dispensing pharmacists of duplications of drug class and cumulative excessive doses, potentially toxic amounts of acetaminophen are commonly prescribed and dispensed to this population. Better systems, increased awareness, and education of patients, prescribers, and pharmacists are needed to reduce this potential toxic exposure.",1
12148,20553090,Atorvastatin: safety and tolerability,"IMPORTANCE OF THE FIELD: Atorvastatin is the most widely used statin administered in a variety of settings, including primary and secondary prevention of cardiovascular events, in the elderly, in patients with chronic kidney disease and in diabetic patients. Therefore, the safety and tolerability of atorvastatin is of paramount importance. AREAS COVERED IN THIS REVIEW: We searched MEDLINE for literature published between 1997 and 2010 on the safety and tolerability of atorvastatin. We retrieved data from randomized controlled trials, meta-analyses, post-marketing studies, reports to regulatory bodies and case reports of rare adverse events. WHAT THE READER WILL GAIN: The reader will gain insight into the incidence, severity, prevention and management of the major adverse effects of atorvastatin (i.e., liver function abnormalities and muscle-related side effects) overall and in special populations. TAKE HOME MESSAGE: The existing data suggest that atorvastatin is generally well tolerated across the range of its therapeutic dosage (10 - 80 mg/day).",1
12149,20557453,Resveratrol and liver disease: from bench to bedside and community,"Liver diseases incorporate several maladies, which can range from benign histological changes to serious life-threatening conditions. These may include inborn metabolic disease, primary and metastatic cancers, alcoholic cirrhosis, viral hepatitis and drug-induced hepatotoxicity. Liver disease remains a major cause of morbidity and mortality with significant economic and social costs. Several novel approaches are currently being studied which may provide a better therapeutic outcome. The use of naturally occurring phytochemicals, some of them obtained from dietary sources, in the amelioration of illness have recently gained considerable popularity. These agents, having anti-oxidant and anti-inflammatory properties, provide a safe and effective means of ameliorating chronic disease. Resveratrol, a grape polyphenol, has shown considerable promise as a therapeutic agent in the treatment of the aforementioned liver ailments. Several studies have highlighted the hepatoprotective properties of resveratrol. Resveratrol has been shown to prevent hepatic damage because of free radicals and inflammatory cytokines, induce anti-oxidant enzymes and elevate glutathione content. Resveratrol has also been shown to modulate varied signal transduction pathways implicated in liver diseases. This review critically examines the current preclinical in vitro and in vivo studies on the preventive and therapeutic effects of resveratrol in liver diseases. The review highlights the pharmacological mechanisms involved in mediating the aforementioned effects. Toxicity, pharmacokinetics and clinical bioavailability of resveratrol are also reviewed in this article. The challenges involved, future directions and novel approaches such as site-specific drug delivery in the use of resveratrol for the prevention and treatment of liver disease are also discussed.",1
12150,20561122,Safety of anti-tumour necrosis factor-alpha agents in psoriasis patients who were chronic hepatitis B carriers: a retrospective report of seven patients and brief review of the literature,"BACKGROUND: Issues concerning the potential risks of reactivating chronic hepatitis B virus arise when the use of anti-Tumour Necrosis Factor-alpha (TNFalpha) agents is imperative in patients with concurrent psoriasis and hepatitis B virus infection. OBJECTIVE: The aim of this study was to report the experience regarding safety in the management of patients with coexisting psoriasis and chronic hepatitis B with the anti-TNFalpha agents: infliximab, etanercept and adalimumab. METHODS: The psoriasis outpatient database of our dermatological department was searched for psoriasis and hepatitis B diagnoses and the medical records of these patients were reviewed for use of anti-TNFalpha agents. RESULTS: Seven cases (four women and three men) were identified, with mean age of 51years (34-65years). Three patients received adalimumab, three patients were given etanercept and one infliximab. All patients received lamivudin, 100mg/day, which started 2weeks before the initiation of anti-TNFalpha medication and went on during the whole treatment period. Follow-up period extended from 6-24months. All patients were inactive HbsAg (+) carriers. Liver function tests - at baseline and at the end of follow-up period - were within the normal range. There was no considerable rise in the viral load in any case, from baseline until the last available measurement, although a patient receiving infliximab showed an increase that reached 600 IU/mL. CONCLUSION: Successful treatment of psoriasis with anti-TNFalpha agents in patients who are inactive HBsAg carriers is possible and could be safe under the conditions of concomitant lamivudin administration and intensive monitoring. Larger randomized controlled studies are needed to confirm these findings.",1
12151,20564545,"Milk thistle in liver diseases: past, present, future","Silybum marianum or milk thistle (MT) is the most well-researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin-induced liver diseases.",1
12152,20568836,"Tinzaparin sodium: a review of its use in the prevention and treatment of deep vein thrombosis and pulmonary embolism, and in the prevention of clotting in the extracorporeal circuit during haemodialysis","Tinzaparin sodium (Innohep) is a low molecular weight heparin (LMWH) that is effective in the prevention and treatment of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and in maintaining the patency of haemodialysis circuits in adult patients. In terms of preventing DVT and/or PE, therapy with subcutaneous tinzaparin sodium was more effective than oral warfarin and equivalent to subcutaneous enoxaparin sodium in patients undergoing orthopaedic surgery, and did not significantly differ from that of subcutaneous unfractionated heparin (UFH) in patients undergoing general surgery. In the initial therapy of adult patients with DVT and/or PE, subcutaneous tinzaparin sodium was at least as effective as intravenous UFH and did not significantly differ from subcutaneous dalteparin sodium. Various other studies have demonstrated that the long-term efficacy of subcutaneous tinzaparin sodium in the treatment of patients with DVT and/or PE was sustained for a total period of up to 12 months. Tinzaparin sodium was also demonstrated to be effective in maintaining the patency of haemodialysis circuits in adult patients with end-stage renal failure. In clinical studies, tinzaparin sodium was generally well tolerated in the prevention and treatment of DVT and/or PE in adult patients, including in elderly patients, and in patients undergoing haemodialysis. As expected, bleeding complications were the most frequently occurring adverse event. Thus, available data indicate that tinzaparin sodium is a useful option in the prevention and treatment of DVT and/or PE, and in maintaining the patency of haemodialysis circuits in adult patients.",1
12153,20572041,Activity and tolerability of nilotinib: a retrospective multicenter analysis of chronic myeloid leukemia patients who are imatinib resistant or intolerant,"""BACKGROUND: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications. METHODS: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT). RESULTS: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P=.0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting. CONCLUSIONS: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib.""",1
12154,20574538,"A randomised trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children","BACKGROUND: Results from trials of intermittent preventive treatment (IPT) in infants and children have shown that IPT provides significant protection against clinical malaria. Sulfadoxine-pyrimethamine (SP) given alone or in combination with other drugs has been used for most IPT programmes. However, SP resistance is increasing in many parts of Africa. Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ) and dihydroartemisinin (DHA) plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission. METHODS: During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ), SP plus piperaquine (PQ) or dihydroartemisinin (DHA) plus PQ at monthly intervals on three occasions during the peak malaria transmission season. To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed. To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages. Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season. RESULTS: All three treatment regimens showed good safety profiles. No severe adverse event related to IPT was reported. The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite. Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group. The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22), 0.06 (95% CI: 0.022, 0.16) and 0.06 (95% CI: 0.02, 0.15) respectively. The incidence of malaria in the control group was 0.79 cases per child year (0.58, 1.08). CONCLUSION: All the three regimens of IPT in children were safe and highly efficacious TRIAL REGISTRATION: ClinicalTrials.gov NCT00561899.",1
12155,20577158,"Malaria surveillance - United States, 2008","""PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to areas with ongoing malaria transmission. In the United States, cases can occur through exposure to infected blood products, congenital transmission, or local mosquitoborne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. PERIOD COVERED: This report summarizes cases in patients with onset of illness in 2008 and summarizes trends during previous years. DESCRIPTION OF SYSTEM: Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by health-care providers or laboratory staff members. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), National Notifiable Diseases Surveillance System (NNDSS), and direct CDC consultations. Data from these reporting systems are the basis for this report. RESULTS: CDC received reports of 1,298 cases of malaria with an onset of symptoms in 2008 among patients in the United States, a decrease of 13.8% from the 1,505 cases reported for 2007 (p<0.001). These cases included one cryptic [corrected] case, one congenital case, and two fatal cases. Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were identified in 40.6%, 14.6%, 1.5%, and 1.4% of cases, respectively. The first documented case of simian malaria, P. knowlesi, was reported in a U.S. traveler. Eight (0.6%) of the 1,298 patients were infected by two or more species. The infecting species was unreported or undetermined in 41.2% of cases. Based on estimated volume of travel from the World Tourism Organization, the highest estimated relative case rates of malaria among travelers occurred among those returning from countries in West Africa. A total of 508 U.S. civilians acquired malaria abroad; among the 480 civilians for whom chemoprophylaxis information was known, 344 (71.7%) reported that they had not followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. Fourteen cases were reported in pregnant women, among whom none adhered to a complete prevention drug regimen. INTERPRETATION: A significant decrease in the number of malaria cases occurred from 2007 to 2008. No change occurred in the proportions of cases caused by the various Plasmodium species. U.S. civilians traveling to countries in West Africa had the highest estimated relative case rates. In the majority of reported cases, U.S. civilians who acquired malaria abroad had not adhered to a chemoprophylaxis regimen that was appropriate for the country in which they acquired the infection. PUBLIC HEALTH ACTIONS: Persons traveling to an area in which malaria is endemic should take steps to prevent malaria, which might include taking one of the recommended chemoprophylaxis regimens appropriate for the region of travel and using personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and who subsequently develops a fever or influenza-like symptoms should seek medical care immediately and report their travel history to the clinician; investigation should always include blood-film tests for malaria with results available immediately. Malaria infections can be fatal if not diagnosed and treated promptly. Malaria prevention recommendations are available from CDC online (http://wwwn.cdc.gov/travel/contentDiseases.aspx#malaria) or by calling the Malaria Hotline (telephone 770-488-7788). Malaria treatment recommendations can be obtained from CDC online (http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm) or by calling the Malaria Hotline.""",1
12156,20581898,Nodular regenerative hyperplasia of the liver secondary to azathioprine in a patient with inflammatory bowel disease,A case of dramatic portal hypertension with massive ascites and splenomegaly is described in a patient with inflammatory bowel disease receiving azathioprine therapy. Liver biopsy confirmed the subtle changes of nodular regenerative hyperplasia and the patient recovered following withdrawal of the azathioprine and commencement of spironolactone. Thrombocytopaenia is an early clue to azathioprine-induced nodular regenerative hyperplasia of the liver.,1
12157,20585286,Ofatumumab (Arzerra) for CLL,,1
12158,20586514,Etanercept in a patient with severe psoriasis and latent viral hepatic disease and latent tuberculosis,"This case report describes the effective use of etanercept in a 63-year-old male patient with moderate to severe psoriasis and vitiligo unresponsive to local and systemic therapies. Latent tuberculosis was diagnosed at baseline and the patient was treated with isoniazid for 9 months. One month after starting isoniazid, etanercept therapy (12 weeks) for psoriasis was initiated. One month later, hepatitis B virus (HBV) markers were detected, but virological tests for active HBV were negative. Isoniazid and etanercept treatments were completed without incidence. Further clinical investigations are required to confirm the potential effects of anti-tumour necrosis factor alpha agents in such patients.",1
12159,20589317,Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study,"Edoxaban is a new oral direct factor Xa inhibitor. The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement. A total of 903 patients were randomised to oral edoxaban 15, 30, 60 or 90 mg once daily or subcutaneous dalteparin once daily (initial dose 2,500 IU, subsequent doses 5,000 IU). Both drugs were begun 6-8 hours postoperatively and continued for 7-10 days, when bilateral venography was performed. The primary efficacy endpoint was the incidence of total VTE, which included proximal and/or distal deep-vein thrombosis (DVT) by venography or symptomatic, objectively confirmed DVT or pulmonary embolism during the treatment period. The primary safety outcome was the incidence of the composite of major and clinically relevant non-major bleeding. All venograms and bleeding events were reviewed by a central independent adjudication committee blinded as to treatment allocation. Of the 903 patients randomised, 776 were evaluable for the primary efficacy analysis. The incidences of VTE were 28.2%, 21.2%, 15.2%, and 10.6% in patients receiving edoxaban 15, 30, 60 and 90 mg, respectively, compared with 43.8% in the dalteparin group (p<0.005 ). There was a statistically significant (p<0.001) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE. The incidence of clinically relevant bleeding was low and similar across the groups. Oral edoxaban once daily is effective for preventing VTE after total hip replacement.",1
12160,20592253,"Adjunctive brivaracetam for refractory partial-onset seizures: a randomized, controlled trial","""OBJECTIVE: To explore efficacy and safety/tolerability of adjunctive brivaracetam (BRV), a novel, high-affinity synaptic vesicle protein 2A ligand, which also inhibits neuronal voltage-dependent sodium channels, in patients with refractory partial-onset seizures (POS). METHODS: This was an exploratory, phase IIb, double-blind, randomized, parallel-group, placebo-controlled, dose-ranging study in patients 16-65 years with epilepsy experiencing > or =4 POS during 4-week baseline despite 1-2 concomitant antiepileptic drugs. Patients were randomized (1:1:1:1) to placebo, BRV 5 mg/day (BRV5), BRV 20 mg/day (BRV20), or BRV 50 mg/day (BRV50), administered BID without uptitration during a 7-week treatment period. Primary efficacy endpoint was POS frequency/week during the treatment period relative to placebo. RESULTS: A total of 208 patients constituted the intention-to-treat population; 197 completed the study. Estimated percentage reductions over placebo in POS frequency/week were 9.8% (BRV5; p = 0.240), 14.9% (BRV20; p = 0.062), and 22.1% (BRV50; p = 0.004). Median percent reductions from baseline in POS frequency/week were 21.7% (placebo), 29.9% (BRV5; p = 0.086), 42.6% (BRV20; p = 0.014), and 53.1% (BRV50; p < 0.001); > or =50% responder rates were 16.7% (placebo), 32.0% (BRV5; p = 0.047), 44.2% (BRV20; p = 0.002), and 55.8% (BRV50; p < 0.001); seizure freedom rates (POS) during the 7-week treatment period were 1.9% (placebo), 8.0% (BRV5; p = 0.193), 7.7% (BRV20; p = 0.193), and 7.7% (BRV50; p = 0.201). BRV was well-tolerated. Most adverse events were mild to moderate and occurred with similar incidence in placebo and BRV groups, and discontinuations due to treatment-emergent adverse events were infrequent (placebo 3.7%; BRV 2.6%). CONCLUSIONS: This interventional study provides preliminary Class I evidence that adjunctive BRV was efficacious and well-tolerated in patients aged 16-65 years with POS.""",1
12161,20593510,Hepatocellular carcinoma occurring in a Crohn's disease patient,"We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn's disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the non-neoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.",1
12162,20600032,Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis,"""BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine. METHODS: We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, open-label phase during which all patients received budesonide in addition to azathioprine. The primary end point was complete biochemical remission, defined as normal serum levels of aspartate aminotransferase and alanine aminotransferase, without predefined steroid-specific side effects, at 6 months. RESULTS: The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%) (P < .001; 97.5% 1-side confidence interval [CI] = 16.2). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone (P = .001; CI: 7.7); 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone group (P < .001; CI = 12.3). Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12 (P < .002). CONCLUSIONS: Oral budesonide, in combination with azathioprine, induces and maintains remission in patients with noncirrhotic AIH, with a low rate of steroid-specific side effects.""",1
12163,20605103,Possible fulminant toxicity by all-trans-retinoic acid in a patient with acute promyelocytic leukemia,,1
12164,20606503,[Toxic hepatitis associated with Polygoni multiflori],"Toxic hepatitis has been reported as a major cause of acute hepatitis, but its potential induction by herbal remedies and/or health foods is usually neglected. We experienced a case of toxic hepatitis associated with Polygoni multiflori, a Chinese herb commonly known as Ho-Shou-Wu. A 54-year-old woman consumed Ho-Shou-Wu for 1 month, after which she experienced fatigue and overall weakness. A diagnosis of toxic hepatitis was made based on her clinical history, the findings for viral markers and other laboratory data, and ultrasonography. Her condition improved considerably after she stopped taking Ho-Shou-Wu. However, she resumed taking Ho-Shou-Wu immediately after discharge from hospital, which aggravated her symptoms and liver function. She was immediately readmitted and stopped taking Ho-Shou-Wu. Her relapse into hepatitis immediate after resuming consumption of the herb is strongly indicative of the validity of Koch's postulate in this case.",1
12165,20609467,Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial,"""BACKGROUND: Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. METHODS: Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. FINDINGS: Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). INTERPRETATION: The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. FUNDING: AstraZeneca.""",1
12166,20610515,"Drug for low sexual desire carries significant harms, FDA advisers find",,1
12167,20613460,Salsalate is poorly tolerated and fails to improve endothelial function in virologically suppressed HIV-infected adults,"In this 13-week, open-label, randomized study of the anti-inflammatory salsalate versus usual care, there were no significant improvements in flow-mediated dilation of the brachial artery, endothelial activation, inflammation or coagulation markers, homeostasis model assessment of insulin resistance or lipoproteins with salsalate or between groups in virologically suppressed, HIV-infected adults on antiretrovirals. Tinnitus and transaminitis occurred frequently in the salsalate group. Dose reduction due to toxicities encountered and low level of inflammation may explain these results.",1
12168,20616953,An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes,"Myelodysplastic syndromes (MDS) are clonal bone marrow malignancies characterized by peripheral cytopenias and dysplastic changes in the bone marrow with various clinical features. Patients with MDS, in particular those with intermediate-2 (Int-2) and high-risk disease, have a poor prognosis. The mainstay of treatment includes cytoxic chemotherapy and supportive care. Over the last decade, promising results from studies focusing on hypomethylating agents, such as decitabine (5-aza-deoxycytidine) and 5-azacitidine, have led to the expansion of the therapeutic arsenal for MDS. This review presents the current data available on the clinical efficacy and safety profile for decitabine as a treatment for MDS. Although not fully understood, decitabine's antitumor activity may involve its ability to induce hypomethylation and reactivation of genes responsible for cellular differentiation, stimulate an immune response, induce DNA damage/apoptotic response pathways, and/or augment stem cell renewal. Future studies that use epigenetic therapies that combine hypomethylating agents with histone deacetylase inhibitors (HDACi) and head-to-head comparison studies of decitabine and 5-azacitidine will provide valuable pre-clinical and clinical data, enhancing our understanding of these drugs.",1
12169,20626402,Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared to rosuvastatin 10 mg in high-risk patients with and without type 2 diabetes mellitus inadequately controlled despite prior statin monotherapy,"AIMS: This post hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) or rosuvastatin 10 mg (ROSUVA) in uncontrolled high-risk hypercholesterolemic patients with/without type 2 diabetes mellitus (T2DM) despite statin monotherapy. METHODS: Patients (n = 618) at high risk for coronary vascular disease with elevated LDL-C >/=100 and </=190 mg/dL despite use of statins were randomized 1:1 to double-blind EZE/SIMVA 10/20 mg or ROSUVA 10 mg for 6 weeks. Patients were classified as having T2DM based on >/=1 of the following: diagnosis of T2DM, antidiabetic medication, or FPG >/=126 mg/dL. This analysis evaluated percent changes from baseline in lipids among patients with (n = 182) and without T2DM (n = 434). RESULTS: EZE/SIMVA was more effective than ROSUVA at lowering LDL-C, TC, non-HDL-C, and apo B in the overall study population and within both subgroups. Numerically, greater between-treatment reductions in LDL-C, TC, non-HDL-C, and apo B were seen in patients with T2DM versus those without T2DM. A significant interaction (P= 0.015) was seen for LDL-C indicating that patients with T2DM achieved larger between-group reductions versus those without T2DM. CONCLUSIONS: Switching to EZE/SIMVA 10/20 mg versus ROSUVA 10 mg provided superior lipid reductions in patients with/without T2DM.",1
12170,20630022,Kava hepatotoxicity: pathogenetic aspects and prospective considerations,"""Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ? comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.""",1
12171,20633172,Zolpidem poisoning in a cat,"Zolpidem (Stilnox) is a non-benzodiazepine hypnotic drug of the imidazopyridine class intended for treatment of insomnia in humans. A 16-year-old neutered cat, weighing 3.8 kg, was presented with sudden onset of stupor, disorientation, severe ataxia, vomiting and hypersalivation. Symptomatic treatment was given when ingestion of 1.25 mg/kg zolpidem (half of a 10-mg tablet) was confirmed, because no information on the efficacy and safety of the use of flumazenil in the treatment of zolpidem poisoning in cats has been published to date. As zolpidem is prescribed with increasing frequency in humans, the occurrence of accidental poisonings of pets is likely to increase.",1
12172,20635058,Adverse reactions to antituberculosis drugs in in-hospital patients: Severity and risk factors,"""INTRODUCTION: Given Mycobacterium tuberculosis's characteristics, the treatment of tuberculosis (TB) infection is administered over a long period of time (for six months or more) with a combination of several drugs which could cause adverse reactions (AR). These can cause significant morbidity and compromise tuberculosis treatment regimens. AIM: To determine the incidence and severity of and risk factors for major adverse reactions to antituberculosis drugs in in-hospital patients treated for active tuberculosis. METHODS: Retrospective analysis of clinical records of patients admitted to Pulido Valente Hospital (Pulmonology Unit III) with active TB treated with anti-tuberculosis agents April 1999 to July 2007. Adverse reactions resulting in modification or discontinuation of treatment or hospital admission were recorded. Patients' demographic characteristics and clinical data were used as independent variables. The relationship between independent variables and the frequency and severity of AR was studied using multivariate analysis using a logistic regression model. The data were analysed using the Student t test, one-way ANOVA and logistic regression. Statistical analysis was performed using the SPSS (Statistical Package for the Social Sciences) version 15.0. RESULTS: We recorded 1400 in-hospital patients treated for active TB 1999 to 2007, of which 175 patients (12.5%), 118 male and 57 female, had at least one AR induced by antituberculosis agents, to a total of 192 events. Hepatotoxicity was the most prevalent AR (83/47.4%), followed by skin reactions (55/31.4%) and gastrointestinal intolerance (24/13.7%). In 76 patients (43.4%) AR caused prolonged hospital stay. Statistically significant differences (p < 0.001) were observed in the average hospital stay (58.4 days for patients with AR and 26 days for patients without AR). Isoniazid (62.2%) and rifampicin (51.9%) were the most frequently implicated drugs. It was possible to characterise the AR severity in 134 cases. In 106 cases (79%) AR resulted in discontinuation of the drug. The relationship between drug and AR was definitive in 23 cases (17%). Of the 13 patients (9.6%) who died, AR was directly implicated in the cause of death in six (4.4%). AR were associated with alcoholism (relative risk [RR] 3.0; 95% confidence interval [CI] 1.1-7.9) and CD4 levels < 350 cells/mm(3) (RR 2.6; CI 1.4-5). In the predictive model, hepatic reactions were associated with viral hepatitis B and/or C (RR 2.5, CI; 1.2-5.1) and that CD4 levels < 350 cells/mm(3) (RR5.5; CI 1.6-18.6). CONCLUSIONS: Antituberculosis drugs are associated with a significant number of AR that can cause significant morbidity, prolonged hospital stay and even death. Our results show that alcoholism and levels of CD4 < 350 cells/mm(3) were significantly associated with a high risk of AR and hepatitis B and C and levels of CD4 < 350 cells/mm3 were also significantly associated with hepatotoxicity.""",1
12173,20638564,Acute liver failure,"""Acute liver failure is a rare disorder with high mortality and resource cost. In the developing world, viral causes predominate, with hepatitis E infection recognised as a common cause in many countries. In the USA and much of western Europe, the incidence of virally induced disease has declined substantially in the past few years, with most cases now arising from drug-induced liver injury, often from paracetamol. However, a large proportion of cases are of unknown origin. Acute liver failure can be associated with rapidly progressive multiorgan failure and devastating complications; however, outcomes have been improved by use of emergency liver transplantation. An evidence base for practice is emerging for supportive care, and a better understanding of the pathophysiology of the disorder, especially in relation to hepatic encephalopathy, will probably soon lead to further improvements in survival rates.""",1
12174,20642956,"Copper sulphate toxicity in a young male complicated by methemoglobinemia, rhabdomyolysis and renal failure","Copper sulphate is a compound prepared by the action of sulphuric acid on copper II. Copper sulphate is widely used asfungicide, herbicide and for photography. In a human being, it can lead to anemia. Medical literature is lacking regarding accidental or suicidal poisoning cases of copper sulphate in Pakistan. We present a case of accidental ingestion of copper sulphate resulting in severe acute toxicity, which was successfully managed by intensive supportive measures and Dimercaprol (BAL).",1
12175,20647205,Drug management of obesity--efficacy versus safety,,1
12176,20647715,[Safety analysis of eight patients treated with erlotinib after severe gefitinib-induced liver injury],"""Gefitinib and erlotinib are commercially available epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) that are widely used for the treatment of non-small-cell lung cancer (NSCLC). Acute severe liver injury, although rare, has been observed in patients receiving these EGFR-TKIs. Some studies have reported that erlotinib treatment does not cause severe liver toxicity in patients with NSCLC who previously presented with severe liver injury during the course of gefitinib treatment. We retrospectively assessed the occurrence of liver toxicity in patients with NSCLC who were receiving erlotinib and had previously presented with severe gefitinib-induced liver injury.Severe liver injury occurred in only 1 of the 8 patients receiving erlotinib treatment. In this case, erlotinib was discontinued because of the onset of grade 3 skin rash and liver injury. After liver function was restored, erlotinib (100 mg) was administered at a lower dose; nonetheless, grade 4 liver injury occurred. Our findings suggest that it is necessary not only to explain the early symptoms of liver toxicity to patients who are receiving erlotinib treatment and have previously experienced gefitinib-induced severe liver injury but also to more closely monitor liver function.""",1
12177,20650576,"Legal highs on the net-Evaluation of UK-based Websites, products and product information","""BACKGROUND: A vast array of substances are marketed as """"legal highs"""" in the UK. These products are mainly marketed online and are packaged and produced to mimic illicit drugs. Little is known about the full range of products available at present and no studies have evaluated the product information provided to consumers. AIMS & HYPOTHESIS: To describe the available legal high products marketed by UK-based Internet retailers and evaluate the product information provided to consumers. METHODS: Websites were identified using the terms """"buy legal highs+UK"""" and two search engines. The first 100 hits and a random sample of 5% of the remaining results were screened. Websites based in the UK were included and all products were entered on a database. Information on product name, list price, claimed effects, side effects, contraindications and interactions was extracted. A descriptive analysis was conducted using SPSS v14. RESULTS: 115 Websites met the inclusion criteria but due to duplicate listings this was reduced to 39 unique Websites. 1308 products were found and evaluated. The average product price was 9.69 British pounds. Products took the form of pills (46.6%), smoking material (29.7%) and single plant material/extract (18.1%). Most products claimed to be stimulants (41.7%), sedatives (32.3%), or hallucinogens (12.9%). 40.1% of products failed to list ingredients, 91.9% failed to list side effects, 81.9% failed to list contraindications and 86.3% failed to list drug interactions. Top 5 products (with active ingredients in brackets) by frequency were Salvia divinorum (Salivinorin A), Kratom (Mitragynine), Hawaiian Baby Woodrose Seeds (Lysergic Acid Amide), Fly Agaric (Ibotenic Acid, Muscimol) and Genie (JWH018, CP47497). CONCLUSIONS: Products marketed as """"legal highs"""" are easily available from UK-based Internet retailers and are reasonably affordable. Safety information provided to consumers is poor. Uninformed users risk serious adverse effects.""",1
12178,20652697,Histological and immediate postoperative outcome after preoperative cetuximab: case-matched control study,"BACKGROUND: The aim of this study was to analyze the effects of preoperative cetuximab (cetu) on nontumorous liver parenchyma and the clinical and biological outcomes after liver resection for colorectal liver metastases (CLM). METHODS: Between January 2005 and June 2009, 26 patients who received preoperative cetu were matched to a control group of 26 patients who did not receive cetu. They were matched on the basis of age, gender, body mass index, extent of hepatectomy, and type and number of cycles of neoadjuvant chemotherapy. RESULTS: Liver function tests, postoperative outcome, and histopathology of the resected liver were compared. There was no mortality. Postoperative morbidity and perioperative bleeding rates were similar in both groups. Serum aspartate aminotransferase and serum alanine aminotransferase were higher on postoperative day 5 in the control group (p�=�0.02 and p�=�0.04, respectively). In the cetu group, the postoperative peaks of ?-glutamyl transpeptidase and alkaline phosphatase were statistically higher than in the control group. Interestingly, pathological review of the nontumorous liver parenchyma revealed no significant difference between patients who received cetu and those treated without cetu with respect to prevalence of steatosis, steatohepatitis, sinusoidal obstructive syndrome, and fibrosis. CONCLUSIONS: The addition of cetu to the neoadjuvant chemotherapy regimens does not appear to increase the morbidity rate after hepatectomy for CLM, and also in cases of major hepatectomy. The pathological examination did not show additional injury to the nontumorous liver parenchyma.",1
12179,20656473,Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET,"""BACKGROUND: The phase III Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) indicated that sorafenib is effective and well tolerated in advanced renal cell carcinoma patients. However, few data have been published on the safety of long-term sorafenib treatment. A retrospective subgroup analysis was performed to evaluate the efficacy and safety of sorafenib in patients in TARGET who received treatment for >1 year. METHODS: The present subgroup analysis (based on the September 2006 database with updated safety analysis) evaluated the efficacy and safety of sorafenib in all patients in the sorafenib arm of TARGET who were treated for >1 year. The assessments included the overall survival, progression-free survival (PFS), disease control rate (DCR), and safety. The patients remained on therapy post-progression at the discretion of the investigator. RESULTS: In TARGET, 169 patients received treatment with sorafenib for >1 year. The median PFS of patients in this subpopulation was 10.9 months from the date of randomisation, with a DCR of 92%. The most commonly reported treatment-related adverse events of any grade were diarrhoea (74%), rash/desquamation (51%), hand-foot skin reaction (49%), alopecia (39%), and fatigue (38%). Adverse events were mild to moderate, and presented early in the course of the treatment; there were no unexpected toxicities associated with the long-term administration of sorafenib. CONCLUSIONS: Results of this subgroup analysis of patients enrolled in TARGET who received treatment for >1 year indicate that long-term treatment with sorafenib is associated with continued efficacy and a well-tolerated safety profile.""",1
12180,20662881,"A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality, acute cellular rejection, infections, and changes in the liver function tests while on caspofungin","""This study is a retrospective analysis of death, adverse events (AE), fungal infections, and hepatic function among recipients of liver transplantation at high risk of fungal infection who received prophylactic treatment with caspofungin. After reviewing data of 105 patients who had received isolated liver transplant between January 2003 and April 2007, we identified and analyzed 82 high-risk patients. Post-transplant patients at high risk for fungal infection are commonly defined by the presence of at least one of the following: (i) re-transplantation; (ii) re-operation; (iii) renal dysfunction. However, in our practice, patients are also considered at high risk for developing fungal infections if they present with the following: (iv) fever of unknown origin; (v) hypothermia; (vi) positive random culture for fungus at the time of transplant (bile and/or ascites); (vii) sepsis; (viii) use of vasopressors; (ix) re-intubation, during the first hospitalization after liver transplant; (x) prolonged intubation (>24 h), and (xi) acute respiratory distress syndrome, until negative fungal cultures are obtained. Exact conditional logistic regression was used to compare the risk of death, AEs, and fungal infections between patients who received caspofungin, other antifungal drugs, and no antifungal drugs. Analyses were then performed with SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Patients were between 27 and 72 yr old (mean = 55), with two-thirds male and three-quarters Caucasian. Sixteen patients received caspofungin (11 preventively), and 32 received other antifungal (26 preventively). There were no proven fungal infections among the patients who received caspofungin, three infections among patients who received other antifungal (3/26 = 12%), and 14 infections among patients who were not preventively treated (14/45 = 31%). These infection rates were significantly different across the three groups (p = 0.029), with caspofungin and other antifungal preventive treatment comparable (p = 0.540), and both better than no preventive treatment at all (OR = 0.15, p = 0.049, for caspofungin versus no preventive treatment; OR = 0.29, p = 0.085, for other antifungal versus no preventive treatment). Caspofungin appears to be an effective preventive agent against fungal infections when used in recipients of liver transplant designated as high risk for fungal infection. Usage of caspofungin in these patients does not carry an apparent increase in risk of death or acute cellular rejection, although we observed a significantly higher risk of AEs, especially acute renal failure (p = 0.001), in patients who received this agent.""",1
12181,20664046,Treatment of primary Sj�gren syndrome: a systematic review,"""CONTEXT: A variety of topical and systemic drugs are available to treat primary Sj�gren syndrome, although no evidence-based therapeutic guidelines are currently available. OBJECTIVE: To summarize evidence on primary Sj�gren syndrome drug therapy from randomized controlled trials. DATA SOURCES: We searched MEDLINE and EMBASE for articles on drug therapy for primary Sj�gren syndrome published between January 1, 1986, and April 30, 2010. STUDY SELECTION: Controlled trials of topical and systemic drugs including adult patients with primary Sj�gren syndrome were selected as the primary information source. RESULTS: The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. CONCLUSIONS: In primary Sj�gren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab.""",1
12182,20667290,The pharmacologic treatment of anxiety disorders: a review of progress,"Anxiety disorders, as a group, are among the most common mental health conditions and frequently cause significant functional impairment. Both psychotherapeutic and pharmacologic techniques are recognized to be effective management strategies. This review provides a discussion of the major classes of psychotropic medications investigated in clinical trials of the following anxiety disorders: panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Findings suggest that both selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are useful first-line agents for most of the anxiety disorders, particularly given the frequent comorbidity with mood disorders. Highly serotonergic agents are preferred for obsessive-compulsive disorder. Other antidepressants, such as tricyclic antidepressants or monoamine oxidase inhibitors, are generally reserved as second- and third-line strategies due to tolerability issues. Evidence for other agents, including anticonvulsants and atypical antipsychotics, suggests that they may have an adjunctive role to antidepressants in cases of treatment resistance, while azapirones have been used effectively for generalized anxiety disorder, and a substantial body of evidence supports benzodiazepine use in panic disorder and generalized anxiety disorder. Despite notable advances, many patients with anxiety disorders fail to adequately respond to existing pharmacologic treatments. Increased research attention should be focused on systematizing pharmacologic and combined pharmacologic-psychosocial strategies to address treatment resistance and developing novel treatments for anxiety disorders.",1
12183,20675204,[Acute toxic hepatitis induced by methimazole: two cases],,1
12184,20680104,Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer,"The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.",1
12185,20683930,"The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial","Colesevelam is an anion-exchange resin with a 7-fold higher bile acid-binding capacity and fewer side effects than cholestyramine, the current first-line treatment option for cholestatic pruritus. The aim of this trial was to compare the effects of colesevelam and a placebo in patients with cholestatic pruritus. In a randomized, double-blind, investigator-initiated, multicenter trial, patients with cholestatic pruritus, both treatment-naive and previously treated, received 1875 mg of colesevelam or an identical placebo twice daily for 3 weeks. The effect on pruritus was assessed with daily visual analogue scales, quality-of-life scores, and evaluations of cutaneous scratch lesions. The predefined primary endpoint was the proportion of patients with at least a 40% reduction in pruritus visual analogue scale scores. Thirty-eight patients were included, and 35 were evaluable: 17 took colesevelam, 18 took the placebo, 22 were female, 8 were treatment-naive, 14 had primary biliary cirrhosis, and 14 had primary sclerosing cholangitis. The mean serum bile acid levels were comparable between the groups before treatment (P = 0.74), but they were significantly different after treatment (P = 0.01) in favor of patients treated with colesevelam. Thirty-six percent of patients in the colesevelam group reached the primary endpoint versus 35% in the placebo group (P = 1.0). There were no significant differences between the groups with respect to pruritus scores, quality-of-life scores, and severity of cutaneous scratch lesions. Mild side effects occurred in one colesevelam-treated patient and four placebo-treated patients. CONCLUSION: Although colesevelam significantly decreased serum bile acid levels, this trial was unable to demonstrate that it was more effective than a placebo in alleviating the severity of pruritus of cholestasis.",1
12186,20686286,"Toxic hepatitis induced by show-wu-pian, a Chinese herbal preparation","Herbal preparations are widely available and often regarded by the public as harmless remedies for a variety of medical ailments. However, some of these products or their metabolites can cause adverse effects such as liver damage. In this case report a 53-year-old female taking shou-wu-pian for 8 months presented with acute hepatitis. Histopathological assessment of liver tissue obtained by biopsy was consistent with a toxic reaction. Clinical and biochemical resolution was brought about following cessation of the drug. It is important for clinicians to consider Chinese herbal preparations as a potential cause of abnormal liver function test results.",1
12187,20688025,Deferasirox induced liver injury in haemochromatosis,Durg-induced liver injury is a common side-effect of many medicines. It is particularly problem when the original condition under treatment is already causing liver damage. This report describes the hepatotoxicity induced by Deferasirox in a patient with haemochromatosis with a discussion of possible pathogenetic mechanism.,1
12188,20693257,Treatment of latent infection with Mycobacterium tuberculosis: update 2010,"Much remains unknown about latent infection with Mycobacterium tuberculosis. Existing immunodiagnostic tools for this condition have various limitations, most importantly in their ability to predict disease. Randomised controlled trials have established protective efficacy of isoniazid therapy for 6-12 months among non-HIV-infected and HIV-infected subjects. While efficacy may reach 90%, acceptance and adherence to prolonged therapy are less than desired. Rifampicin plus pyrazinamide for 2 months, though efficacious, has been associated with excess hepatotoxicity in non-HIV-infected persons. Isoniazid plus rifampicin for 3 months has proven efficacy, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy. Rifampicin monotherapy for 3-4 months is well tolerated, but efficacy data are currently limited, and concerns remain over possible selection of rifampicin-resistant mutants. For contacts of patients with multidrug-resistant tuberculosis, expert opinions differ on whether to treat with at least two drugs or just a fluoroquinolone, and for how long. With the existing diagnostic and treatment tools, efficacy of preventive therapy does not necessarily translate into field effectiveness. A targeted approach is required to maximise cost-effectiveness. Each geographic region needs to set its own priority after taking into account available scientific data and local circumstances.",1
12189,20695801,"Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection","BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. METHODS: Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days. RESULTS: Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. CONCLUSIONS: Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.",1
12190,20703158,Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2,"""BACKGROUND: Maraviroc, the first approved CCR5 antagonist, demonstrated 48-week safety and virologic efficacy in CCR5-tropic HIV-infected, treatment-experienced patients; however, critical longer-term safety and durability of responses are unknown. METHODS: Two-year follow-up of 2 prospective, randomized, blinded studies of maraviroc once daily or twice daily, or placebo in treatment-experienced patients with R5-tropic HIV-1 receiving an optimized background regimen. Unblinding occurred after the week-48 visit of the last enrolled patient. Safety and virologic parameters were assessed through week 96. RESULTS: One thousand forty-nine patients were randomized and received study drugs. HIV-1 RNA was <50 copies per milliliter at week 96 in 39% and 41% of patients receiving maraviroc every day or twice a day, respectively. Among patients with HIV-1 RNA <50 copies per milliliter at week 48, 81% and 87% of patients receiving maraviroc every day or twice a day, respectively, maintained this response at week 96. At week 96, median CD4+ T-cell counts increased from baseline by 89 and 113 cells per cubic millimeter with maraviroc every day and twice a day, respectively. Exposure-adjusted rates of adverse events were similar with maraviroc or placebo. No new or unexpected events were observed after week 48. CONCLUSIONS: Maraviroc-containing antiretroviral regimens maintained durable responses in treatment-experienced patients with R5 HIV-1 through 96 weeks of treatment with a safety profile similar to placebo.""",1
12191,20705798,Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension,"""BACKGROUND: Ambrisentan is a selective endothelin-receptor antagonist that is approved by the US Food and Drug Administration for the treatment of pulmonary arterial hypertension. We describe hemodynamic responses and clinical outcomes of patients with portopulmonary hypertension (POPH) treated with ambrisentan. METHODS: In this observational study, we prospectively identified and followed consecutive adult patients with POPH who received monotherapy with ambrisentan </= 10 mg daily from January 2007 until December 2009. Liver enzymes were assessed monthly. Pulmonary hemodynamic responses were assessed using echocardiograms and right-sided heart catheterizations. RESULTS: We identified 13 patients (seven men) with POPH and began monotherapy with ambrisentan. The median age was 57 (interquartile range [IQR], 52-60). Patients were followed for a median of 613 days (IQR, 385-1,011). The median model for end-stage liver disease score was 10 (IQR, 8.5-15); eight patients had Child-Turcotte-Pugh A classification. Median time on ambrisentan therapy was 390 days (IQR, 363-611). Two patients died, one of advanced hepatocellular carcinoma and one of septic shock following pneumonia. The mean pulmonary artery pressure decreased from a baseline median of 58 mm Hg (IQR, 37-63) to 41 mm Hg (IQR, 27-48) (P = .004). The pulmonary vascular resistance median was reduced from 445 dynes/s/cm(5) (IQR, 329-834) to 174 dynes/s/cm(5) (IQR, 121-361) (P = .008). There was no difference in the longitudinal analysis of liver function tests (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and international normalized ratio) after 12 months of therapy. One patient underwent successful liver transplantation and normalized pulmonary hemodynamic responses after transplantation. CONCLUSIONS: In this small cohort of patients with moderate to severe pulmonary hypertension in the setting of POPH, we have shown that ambrisentan monotherapy can significantly improve pulmonary hemodynamic responses without adverse effect on hepatic function.""",1
12192,20707932,Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report,"BACKGROUND: Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. CASE PRESENTATION: We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. CONCLUSIONS: This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important.",1
12193,20709051,The effect of UGT1A1 promoter polymorphism on bilirubin response to hydroxyurea therapy in hemoglobinopathies,"OBJECTIVES: Hydroxyurea is known to reduce ineffective erythropoiesis and thereby hemolysis leading to a reduction in bilirubin levels in patients with hemoglobinopathies. However, the effect of hydroxyurea on hyperbilirubinemia in relation to the UGT1A1 gene promoter polymorphism is not known in Indian patients with different hemoglobinopathies. DESIGN AND METHODS: We studied 112 patients (77 sickle cell anemia, 22 beta-thalassemia intermedia and 13 HbE-beta-thalassemia) who were on hydroxyurea therapy for 2 years for their response towards hyperbilirubinemia associated with UGT1A1 promoter polymorphism. RESULTS: The patients with (TA)(7)/(TA)(7) repeats had significantly higher serum bilirubin levels than those with (TA)(6)/(TA)(6) repeats in all the groups and the reduction in serum bilirubin after hydroxyurea therapy was still higher among patients with (TA)(7)/(TA)(7) repeats when compared with (TA)(6)/(TA)(6) repeats. CONCLUSIONS: Higher bilirubin levels were associated with the (TA)(7)/(TA)(7) sequence however they did not come down to normal levels after hydroxyurea therapy.",1
12194,20710057,Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine,"""BACKGROUND: Unexpected cases of severe liver disease in HIV-infected patients have been reported and an association with didanosine (ddI) has been suggested. Transient elastography (TE) might detect patients harbouring such a condition. Our objective was to search for the presence of abnormal liver stiffness (LS) in a cohort of HIV-infected patients without HBV or HCV coinfection and to assess the related factors. METHODS: A cross-sectional prospective study was conducted. LS was assessed by TE in 258 HIV-infected patients without HBV or HCV coinfection and with no evidence of acute hepatotoxicity or other origins of liver disease. LS values > or =7.2 kPa were considered abnormal. Multivariate analyses were performed to identify factors associated with abnormal LS. RESULTS: Abnormal LS was observed in 29 (11.2%) patients. A total of 18 (16.4%) patients previously treated with ddI and 11 (7.4%) of those who never received ddI had LS values > or =7.2 kPa (P=0.02). The prevalence of abnormal LS was higher in patients previously treated with abacavir than in those who had never received abacavir (15 [21.7%] versus 14 [7.4%]; P=0.001). After multivariate analyses, age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.002-1.1; P=0.004) alcohol intake >50 g/day (AOR 7.2, 95% CI 2.6-19.7; P<0.0001), CD4(+) T-cell count <200 cells/ml (AOR 3.4, 95% CI 1.06-11.007; P=0.03), time on ddI treatment (AOR 1.31, 95% CI 1.12-1.52; P=0.001) and previous abacavir exposure (AOR 3.01, 95% CI 1.18-7.67; P=0.02) were independently associated with abnormal LS. CONCLUSIONS: The prevalence of abnormal LS in HIV-infected patients without HBV or HCV coinfection is substantial. Long-term exposure to ddI is a major cause of liver damage in these patients.""",1
12195,20713668,Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection,"""Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.""",1
12196,20713865,Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study,"""PURPOSE: Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid. PATIENTS AND METHODS: Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid ? 7.5 mg/dL during days 3 to 7. RESULTS: Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol. CONCLUSION: In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol.""",1
12197,20714691,Adverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-based study,"OBJECTIVE: To evaluate the side effects of methotrexate (MTX) in rheumatoid arthritis (RA) patients and to evaluate the possible predisposing variables. METHODS: A retrospective analysis conducted for all patients diagnosed with RA and treated with MTX over 3-years (January 2006 to December 2008) at King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia. Frequency of MTX side effects and the predictive variables were recorded and analyzed statistically. RESULTS: Out of 116 RA patients, 71 patients used MTX. The most frequent side effect was gastrointestinal (GIT) disturbance in 31%, followed by central nervous system symptoms in 18%, hepatotoxicity in 14%, stomatitis and alopecia in 10% each, macrocytosis 7%, fever, malar rash and pancytopenia in 4%, and MTX-induced lung injury with increase in the size of rheumatoid nodule in 1% of patients. By Logistic regression analysis, renal impairment was the most significant variable increasing the risk of the side effects (OR=7.14, p<0.05). Other associated variables were male-gender, non-Saudi nationality, smoking, steroids use, hypoalbuminemia, and the presence of extra-articular manifestations. CONCLUSION: Methotrexate is the most commonly drug used in the treatment of RA. Gastrointestinal disturbances were the most common side effect while lung involvement was the least. The impact of each clinical variable on MTX side effects requires paying more attention on the disease management as not all variables can be considered as risk factors.",1
12198,20720265,Kava hepatotoxicity--a clinical review,"""This review critically analyzes the clinical data of patients with suspected kava hepatotoxicity and suggests recommendations for minimizing risk. Kava is a plant (Piper methysticum) of the pepper family Piperaceae, and its rhizome is used for traditional aqueous extracts in the South Pacific Islands and for commercial ethanolic and acetonic medicinal products as anxiolytic herbs in Western countries. A regulatory ban for ethanolic and acetonic kava extracts was issued in 2002 for Germany on the basis of reports connecting liver disease with the use of kava, but the regulatory causality assessment was a matter of international discussions. Based on one positive reexposure test with the kava drug, it was indeed confirmed that kava is potentially hepatotoxic. In subsequent studies using a structured, quantitative and hepatotoxicity specific causality assessment method in 14 patients with liver disease described worldwide, causality for kava +/- comedicated drugs and dietary supplements including herbal ones was highly probable (n = 1), probable (n = 4) or possible (n = 9) regarding aqueous extracts (n = 3), ethanolic extracts (n = 5), acetonic extracts (n = 4), and mixtures containing kava (n = 2). Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements comprizing herbal ones in most of the 14 patients. Hepatotoxicity occurred independently of the used solvent, suggesting poor kava raw material quality as additional causative factor. In conclusion, in a few individuals kava may be hepatotoxic due to overdose, prolonged treatment, comedication, and probably triggered by an unacceptable quality of the kava raw material; standardization is now required, minimizing thereby hepatotoxic risks.""",1
12199,20724951,Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia,"L-asparaginase (L-ASNase) has been an essential component of multiagent chemotherapy for acute lymphoblastic leukemia in childhood for over 3 decades. There are currently 2 Food and Drug Administration (FDA)-approved formulations of L-ASNase derived from Escherichia coli and 1 non-FDA approved formulation derived from Erwinia chrysanthemi. Modifications in L-ASNase have included pegylation, which decreases drug immunogenicity and increases the half-life, allowing less frequent administration. Although L-ASNase is well-tolerated in most patients and causes little myelosuppression, significant toxicities occur in up to 30% of patients. Hypersensitivity is the most common toxicity of L-ASNase therapy and limits the further use of the drug. Other significant toxicities relate to a reduction in protein synthesis and include pancreatitis, thrombosis, central nervous system complications, and liver dysfunction. The spectrum of common toxicities and the efficacy of different formulations of L-ASNase are presented in this review.",1
12200,20726808,Nodular regenerative liver hyperplasia as a complication of azathioprine-containing immunosuppressive treatment for Crohn's disease,"Nodular regenerative liver hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for autoimmune disorders, organ transplantation, and/or oncological treatment. Here we report a case of a 40-year-old female patient with Crohn's disease and genetic hypercoagulability disorder-factor V Leiden, who in the course of azathioprine immunosuppressive treatment for inflammatory bowel disease developed NRH, which was clinically manifested by thrombocytopenia and delicate hepato-splenomegaly. Moreover, her endoscopic examination of upper gastrointestinal tract demonstrated esophageal varices. Genetic analysis revealed heterozygous genotype (*1/*3A) of thiopurine S-methyltransferase (TPMT), a key enzyme of thiopurines' metabolism, which results in lower activity of TPMT enzyme, thereby making our patient more susceptible to azathioprine-related hepato and myelotoxicity development. Treatment was started with the immediate cessation of azathioprine therapy, and administration of propranolol as primary prophylaxis for bleeding from esophageal varices. Currently (3 years after diagnosis) remission of Crohn's disease is achieved, however, progression of features of portal hypertension is observed. Propranolol administration is continued and the patient is constantly monitored in our Department. Our Case Study highlights the clinical difficulties and challenges associated with diagnosing of azathioprine-induced NRH, as well as, supports previous observations that hypercoagulability disorders and abnormal TPMT activity may contribute to NRH development.",1
12201,20733547,Treatment of atrial fibrillation,,1
12202,20736149,"Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study","BACKGROUND: The MERIT study evaluated maraviroc versus efavirenz, both with zidovudine/lamivudine, in treatment-naive patients with CCR5-tropic (R5) HIV-1. Post hoc analyses previously assessed week 48 outcomes in patients rescreened with R5 virus by a more sensitive tropism assay. METHODS: Week 96 efficacy (post hoc, n = 614) and safety (n = 721) were assessed. RESULTS: Proportions of subjects <50 copies/mL (58.8% maraviroc, 62.7% efavirenz) and time to loss of virologic response (TLOVR) responders (<50 copies/mL: 60.5% vs 60.7%) were similar. Maraviroc recipients had greater CD4 increases (+ 212 vs + 171 cells/mm(3)) and fewer adverse event discontinuations (6.1% vs 15.5%), malignancies, and category C events. CONCLUSION: Week 96 data confirm week 48 observations in MERIT.",1
12203,20739231,Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis,"""BACKGROUND: Thioguanine has been used for the treatment of inflammatory bowel disease, in particular for patients who failed conventional thiopurine therapy. To date, thioguanine has been infrequently studied in ulcerative colitis. AIM: To evaluate the tolerability, safety and efficacy of thioguanine in the treatment of ulcerative colitis. METHODS: A database analysis was performed on inflammatory bowel disease patients who had failed conventional thiopurine therapy and were treated with thioguanine. Rates and reasons for treatment failure were assessed. Laboratory values, abdominal ultrasonography, liver biopsy and endoscopic remission rates were evaluated. RESULTS: Forty-six patients were included and median treatment duration was 22 months (range 0.3-72.0). Nine patients failed thioguanine therapy: six due to adverse events, three due to therapy resistance. Concomitant treatment with aminosalicylates protected against thioguanine failure (hazard ratio (HR) 0.11, 95% CI 0.03-0.48). When performed, ultrasonography (n = 21) revealed no suspected therapy-related pathology in all but one patient, in whom hepatomegaly was observed. Liver histology (n = 12) predominantly revealed no abnormalities (n = 4) or non-specific regeneration (n = 4); none showed nodular regenerative hyperplasia. At follow-up, 40% of colonoscopies revealed endoscopic remission as compared with 10% at baseline (P = 0.180). CONCLUSIONS: Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy.""",1
12204,20740194,Acute Fatal Liver Toxicity under Erlotinib,"""We describe the case of a never-smoker who received second-line erlotinib as a treatment for his non-small cell lung cancer. Within one month, acute hepatic failure developed as well as a thrombotic-thrombocytopenic microangiopathy, with fatal outcome. In patients with non-small cell lung cancer, hepatic toxicity of erlotinib is a rare but severe complication; so far three fatal cases have been reported. Patients' liver function should be assessed before starting erlotinib and special care is recommended if pretreatment bilirubin is elevated.""",1
12205,20798484,Drug rash with eosinophilia and systemic symptoms due to telaprevir,"We report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to telaprevir (VX-950), a specific inhibitor of the hepatitis C virus (HCV) serine protease. A 57-year-old woman with chronic hepatitis C was included in a phase 2 rollover study of VX-950. She received VX-950 in combination with pegylated interferon alfa-2a and ribavirin. Six weeks later, she developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnoea and lymph node swelling. She had an eosinophilia (up to 2.7 x 109 cells/l), large activated lymphocytes and increased concentrations of aminotransferases. Histological examination of a cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped, and she was treated with topical and oral steroids. Cutaneous and systemic symptoms disappeared within 1 month. Telaprevir was considered the culprit drug. We report to our knowledge the first case of DRESS syndrome due to telaprevir. The safety data of telaprevir is derived mainly from the PROVE1, PROVE2 and PROVE3 studies. They showed a high frequency of cutaneous side effects reported under the imprecise terms of pruritus and rash, leading to an increased rate of treatment discontinuation. Telaprevir, due to its efficacy, is probably on the way to obtaining regulatory approval in the near future. It is therefore important to be aware of the high incidence of cutaneous side effects and better describe them. Our observation suggests that potentially severe hypersensitivity reactions may belong to the spectrum of rashes induced by this drug.",1
12206,20800921,Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury,"BACKGROUND & AIMS: Co-amoxiclav is one of the most common causes of drug-induced liver injury (DILI). Although there are previous reports of genetic associations between HLA class II and co-amoxiclav-related DILI, studies to date have been based on very small numbers from single centres only. In order to address this problem we have investigated the role of HLA class II DRB1 and DQB1 in 61 cases of co-amoxiclav DILI as part of a UK-wide multicentre study. METHODS: HLA alleles and genotypes were compared with those of 40 individuals exposed to co-amoxiclav without toxicity (treated controls) and 191 population controls. RESULTS: There were two significant findings from the study. First, HLA-DRB1*15 was increased in patients (53%) versus both treated (33%: OR=2.29: 95% CI: 1.00-5.26) and population controls (30%: OR=2.59:95% CI: 1.44-4.68: p=0.002). Second, DRB1*07 was found to be reduced in patients (9.8%) compared to both treated (35%: OR=0.18: 95% CI: 0.06-0.52: p=0.0011, pc=0.0154) and population controls (29%: OR=0.266: 95% CI: 0.11-0.65: p=0.0019, pc=0.0266). CONCLUSIONS: These results confirm the previously reported significant genetic risk for HLA-DRB1*15 and also provide evidence of a protective effect of the HLA-DRB1*07 family of alleles. HLA alleles and haplotypes may be particularly important in susceptibility and resistance to co-amoxiclav-DILI, but it remains to be seen whether this effect is due to the identified alleles or others in close linkage disequilibrium elsewhere on the MHC.",1
12207,20807095,Prognostic analysis of acute exacerbations of hepatitis-B after chemotherapy in combination with rituximab in 19 patients with lymphoma,"The prognosis and management of acute exacerbations of hepatitis-B in patients with lymphoma after chemotherapy in combination with rituximab remain unclear. Here, we describe 19 Chinese patients with lymphoma who suffered this complication, in order to analyze their clinical characteristics. Receiver operating characteristic analysis and Kaplan-Meier survival analysis were utilized to determine potential prognostic factors. We found that key prognostic factors included the peak prothrombin time (PT), international normalized ratio (INR), and total bilirubin (TB), as well as the PT and INR on admission and the interval between acute exacerbation of hepatitis-B and the last cycle of chemotherapy. Moreover, our data suggested that shorter interval between the last cycle of rituximab and acute exacerbation of hepatitis-B might be another prognostic indicator of inferior survival. Our results revealed that the severity of hepatic damage and the interval between the last cycle of chemotherapy and hepatitis flare were the major prognostic factors of an acute exacerbation of hepatitis-B induced by immunochemotherapy. Prophylactic antiviral and rescue antiviral therapy remain to be further characterized.",1
12208,20814315,"A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia","Monotherapy is recommended for schizophrenia treatment, but the risk-benefit issue of antipsychotic drug combination (except for clozapine) remains unclear. Risperidone, an atypical antipsychotic drug, has a lower incidence of extrapyramidal syndrome but higher risks of prolactinemia and metabolic syndrome than haloperidol, a typical agent. This study compared efficacy and safety of risperidone monotherapy versus low-dose risperidone plus low-dose haloperidol in schizophrenia. In this 6-week, double-blind study, patients were randomized to the combination group (2-mg/d risperidone plus 2-mg/d haloperidol, n = 46) or the monotherapy group (4-mg/d risperidone, n = 42). Efficacy assessments included Clinical Global Impression-Severity, Positive and Negative Syndrome Scale and subscales, Calgary Depression Scale, Global Assessment of Functioning, and Medical Outcomes Study Short-Form 36. Safety was rigorously monitored. Response was defined as 30% reduction in the Positive and Negative Syndrome Scale total score. The 2 treatment groups were similar in (1) demographic and clinical characteristics at baseline, (2) response rate, and (3) improvement in various psychopathological measures and quality of life at end point. The monotherapy group had a higher increase in prolactin levels (P = 0.04) and Simpson-Angus Scale scores (P = 0.04) and a higher percentage of biperiden use (P = 0.045). There were no significant between-group difference in changes in weight, vital signs, corrected QT interval, liver/renal function, fasting glucose level, and lipid profiles. The findings suggest that risperidone monotherapy may yield higher prolactin levels than a combination of low-dose risperidone plus low-dose haloperidol. The 2 treatment groups are similar in efficacy, life quality, and other safety profiles. Future long-term studies are warranted.",1
12209,20814850,Re-introduction of kava (Piper methysticum) to the EU: is there a way forward?,"""Kava (Piper methysticum) is an effective anxiolytic that has been withdrawn from various consumer markets in European countries due to concerns over its hepatotoxicity. It is plausible that the reported hepatotoxicity may be due in part to plant substitution, or an incorrect cultivar, or plant parts being used (such as leaves or bark); thus both the plant chemotype and the plant part used may be critical factors. If re-institution of kava in the EU is to occur, more evidence is required to determine its safety and efficacy. Furthermore, according to current evidence, the study of traditional water soluble rhizome extracts using a noble cultivar of kava may be advised. The Kava Anxiety-Lowering Medication (KALM) project is due to start in late 2010 to address these considerations. The KALM project uses an aqueous rhizome extract of a noble cultivar of kava in participants with generalised anxiety and Generalised Anxiety Disorder (GAD). The project comprises of 1) an acute RCT, kava (180 mg of kavalactones) versus oxazepam and placebo in 20 anxious people, testing effects on cognition, mood, anxiety, and driving; 2) an 8-week RCT comparing kava (120 mg kavalactones) versus placebo in 100 patients with GAD. To assess differences between dosages, non-responders at 3 weeks will be titrated to 240 mg of kavalactones. The project will also assess the effects of kava on liver function tests and its side effects profile. A novel component of the project is the pharmacogenomic exploration of phenotypical responses (GABA system and cytochrome P450 markers). The results of the study may be of benefit to sufferers of anxiety and the future economy of the Pacific islands, potentially providing an important step in the way forward with kava.""",1
12210,20814896,"A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis","""Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ? 45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase > 3 ? baseline and greater than the upper limit of normal range, and eight patients had serum creatinine > 33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to < 250 ng/mL. CONCLUSION: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population.""",1
12211,20817384,The SUMMIT trial: a field comparison of buprenorphine versus methadone maintenance treatment,"""This prospective patient-preference study examined the effectiveness in practice of methadone versus buprenorphine maintenance treatment and the beliefs of subjects regarding these drugs. A total of 361 opiate-dependent individuals (89% of those eligible, presenting for treatment over 2 years at a drug service in England) received rapid titration then flexible dosing with methadone or buprenorphine; 227 patients chose methadone (63%) and 134 buprenorphine (37%). Participants choosing methadone had more severe substance abuse and psychiatric and physical problems but were more likely to remain in treatment. Survival analysis indicated those prescribed methadone were over twice as likely to be retained (hazard ratio for retention was 2.08 and 95% confidence interval [CI] = 1.49-2.94 for methadone vs. buprenorphine), However, those retained on buprenorphine were more likely to suppress illicit opiate use (odds ratio = 2.136, 95% CI = 1.509-3.027, p < .001) and achieve detoxification. Buprenorphine may also recruit more individuals to treatment because 28% of those choosing buprenorphine (10% of the total sample) stated they would not have accessed treatment with methadone.""",1
12212,20818844,"Inhibition of mutated, activated BRAF in metastatic melanoma","BACKGROUND: The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. METHODS: We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. RESULTS: A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. CONCLUSIONS: Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)",1
12213,20819434,Genetic polymorphisms of cytochrome P450 and glutathione S-transferase associated with antituberculosis drug-induced hepatotoxicity in Chinese tuberculosis patients,"This study was designed to investigate the association of genetic polymorphisms of cytochrome P450 subtype 2E1 (CYP2E1) and glutathione S-transferase mu 1 (GSTM1) with susceptibility to antituberculosis drug-induced hepatotoxicity (ADIH) in Chinese tuberculosis patients. All patients were treated with a combination of isoniazid, rifampicin, pyrazinamide and ethambutol. Genomic DNA from 104 patients with ADIH and 111 without ADIH was analysed for the frequency of CYP2E1 RsaI and GSTM1 RsaI genotypes by polymerase chain reaction and restriction fragment length polymorphism. The association of polymorphisms with susceptibility to ADIH was calculated using the chi(2)-test and logistic regression analysis. The CYP2E1 RsaI polymorphisms were significantly associated with ADIH and the c1/c1 genotype was an independent risk factor for ADIH. Compared with the GSTM1 RsaI present genotype, the GSTM1 RsaI null genotype tended to increase susceptibility to ADIH, but the association with ADIH was not significant. The results indicate that CYP2E1 RsaI genotype c1/c1 is a potential risk factor for ADIH in the Chinese population. The tendency of the GSTM1 RsaI null genotype to increase susceptibility to ADIH needs further study.",1
12214,20825558,Hepatotoxicity of khat chewing,,1
12215,20831537,Hepatotoxicity of alpha-methyldopa in pregnancy,"Alpha-methyldopa is one of the most widely prescribed antihypertensive agents used during pregnancy. Despite its known potential hepatotoxicity, there have been only a few reports describing hepatotoxicity with the use of this drug during pregnancy. We report here a new case of acute hepatitis in a pregnant woman related to the use of alpha-methyldopa, and briefly review the literature on alpha-methyldopa-induced hepatotoxicity in pregnancy.",1
12216,20831685,Case report. Efficacy of Hoodia for weight loss: is there evidence to support the efficacy claims?,"Increasing rates of adult obesity and its negative health consequences are likely to become an increasing burden to the Canadian health care system. Consumers are looking for treatment options and often try the natural health products that are heavily promoted as safe, fast and effective. In this case report, MH, a 57-year-old overweight female wanted advice regarding whether she should use the natural product Hoodia to help her attain her weight loss goals. A literature search was conducted using Medline, EMBASE, the Cochrane Library, Natural Medicines Comprehensive Database and IPA from inception to March 2009. The internet, files of the authors and bibliographies of articles were searched for additional references. No published, peer-reviewed randomized controlled trials examining efficacy of Hoodia were found. Unpublished data from two small trials reported promising results with no adverse events. However, this leaves many unanswered questions regarding the use of Hoodia for weight loss such as the appropriate dose and duration, short and long term safety and use in patients with concomitant diseases. Literature suggests that some commercial products may not actually contain Hoodia at all. Additionally, Hoodia is not yet listed in the Canadian Licensed Natural Health Products Database meaning products sold in Canada may not meet Canadian regulatory standards. Upon discussing this information, MH decided not to use Hoodia, and other evidence-based recommendations were discussed.",1
12217,20838387,"The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (high-dose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): efficacy and safety of a triple antiemetic combination","Complete protection from nausea/vomiting is currently achieved in a minority of patients receiving high-dose chemotherapy (HDC). Currently the use of 5-HT3-antagonists and dexamethasone (DEX) represents the standard of care. The role of the NK-1-antagonist aprepitant in HDC remains to be better defined. A total of 64 patients undergoing multiple days of HDC received granisetron, DEX plus aprepitant during chemotherapy. After the end of chemotherapy aprepitant plus DEX was given for a further 2 days. Primary end point was CR defined as no vomiting and no use of rescue medication in the overall phase (day 1 until 5 days after end of chemotherapy). Acute/delayed and overall CR were achieved in 83%/70% and 63%, respectively. Acute and delayed nausea were observed in 20 and 38% of the patients. The tolerability of the aprepitant regimen over 4-5 days was comparable with the 3-day antiemetic regimen. In our study, aprepitant demonstrated good tolerability. Taking into account the methodological constraints of comparing our results with those from the available literature, the addition of aprepitant to the antiemetic treatment regimen may provide improved prevention of chemotherapy-induced nausea and vomiting during HDC.",1
12218,20840530,Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder,"INTRODUCTION: Flibanserin is a novel pharmacologic agent in late-stage clinical testing for hypoactive sexual desire disorder (HSDD) in premenopausal women. AIM: The aim of this article is to review the hypothetical mechanism of action of flibanserin in HSDD. METHODS: A literature review was conducted of all published works on flibanserin and on related studies of serotonin (5-HT)(1A) receptors and 5-HT(2A) receptors, including their actions on monoamines and on sexual function. MAIN OUTCOME MEASURES: The main outcome measures are preclinical pharmacologic actions, especially changes in regional monoamines following treatment with flibanserin. RESULTS: At clinically relevant doses, flibanserin acts predominantly at 5-HT(1A) receptors as an agonist and secondarily at 5-HT(2A) receptors as an antagonist. Additional binding actions within an order of magnitude of its 5-HT(1A) affinity, which are not likely to be clinically relevant, include weaker antagonist actions at 5-HT(2C) and 5-HT(2B) receptors, and less defined activity at dopamine (DA) D4 receptors. The 5-HT(1A) actions of flibanserin are only seen postsynaptically, which is unlike other agents such as buspirone that act at presynaptic 5-HT(1A) receptors. Furthermore, the postsynaptic actions of chronic flibanserin administration appear to demonstrate a preference for some populations of postsynaptic 5-HT receptors, particularly those that are located on the prefrontal cortex (PFC) pyramidal neurons, which regulate monoamine release in certain selective brain regions. CONCLUSIONS: The regional selectivity of flibanserin results in a unique pattern of monoamine modulation. Sustained increases in baseline of DA and norepinephrine (NE) are observed in the PFC, and flibanserin dosing increases DA and NE levels above the basal changes. Conversely, flibanserin induces transient decreases in 5-HT levels in some brain areas such as the PFC, nucleus accumbens, and hypothalamus, but not in other brain areas such as the hippocampus. Therefore, since DA and NE are excitatory and 5-HT is inhibitory to sexual desire and arousal, it is tempting to postulate that the actions of flibanserin on serotonin receptors at the PFC pyramidal neurons, resulting in increased DA and NE yet reduced 5-HT in the PFC, are the mechanistic underpinnings of enhancing sexual desire in HSDD.",1
12219,20842109,Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial,"OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis. Its prevalence has been found to be as high as 39%. It is estimated that up to 15% of those affected will go on to have progressive liver disease. Currently, there is no proven therapy for NAFLD. In this study, we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD. METHODS: In all, 1,005 men and women, aged 50-70 years were randomized to receive either a daily combination of atorvastatin 20 mg, vitamin C 1 g, and vitamin E 1,000 IU vs. matching placebo, as part of the St Francis Heart Study randomized clinical trial. Liver to spleen (LS) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence. Baseline and final LS ratios were compared within treatment groups, and results were compared between the treatment and placebo groups using univariate and multivariate analyses. Mean duration of follow-up was 3.6 years. RESULTS: There were 80 patients with NAFLD at baseline. We identified baseline triglyceride levels (odds ratio (OR)=1.003, P<0.001) and body mass index (OR=0.10, P<0.001) as independent correlates of NAFLD. Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up, 70 vs. 34% (OR=0.29, P<0.001). CONCLUSIONS: In conclusion, atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy.",1
12220,20843324,First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer,"BACKGROUND: Lung cancer is a malignant carcinoma which has the highest morbidity and mortality in Chinese population. Gefitinib, a tyrosine kinase (TK) inhibitor of epidermal growth factor receptor (EGFR), displays anti-tumor activity. The present data regarding first-line treatment with single agent gefitinib against non-small-cell lung cancer (NSCLC) in Chinese population are not sufficient. PURPOSE: To assess the efficacy and toxicity of gefitinib in Chinese patients with advanced non-small-cell lung cancer (NSCLC), a study of single agent treatment with gefitinib in Chinese patients was conducted. METHODS: 45 patients with advanced NSCLC were treated with gefitinib (250 mg daily) until the disease progression or intolerable toxicity. RESULTS: Among the 45 patients, 15 patients achieved partial response (PR), 17 patients experienced stable disease (SD), and 13 patients developed progression disease (PD). None of the patients achieved complete response (CR). The tumor response rate and disease control rate was 33% and 71.1%, respectively. Symptom remission rate was 72.5%, and median remission time was 8 days. Median overall survival and median progression-free survival was 15.3 months and 6.0 months, respectively. The main induced toxicities by gefitinib were skin rash and diarrhea (53.3% and 33.3%, respectively). The minor induced toxicities included dehydration and pruritus of skin (26.7% and 22.2%, respectively). In addition, hepatic toxicity and oral ulceration occurred in few patients (6.7% and 4.4%2, respectively). CONCLUSIONS: Single agent treatment with gefitinib is effective and well tolerated in Chinese patients with advanced NSCLC.",1
12221,20845002,"Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee","""INTRODUCTION: Flavocoxid is a novel flavonoid-based """"dual inhibitor"""" of the 5-lipoxygenase (5-LOX) enzyme and the cyclooxygenase (COX) enzymes. This study was designed to compare the effectiveness and safety of flavocoxid to naproxen in subjects with moderate to severe osteoarthritis (OA) of the knee. METHODS: In this randomized, multicenter, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. The trial was structured to show noninferiority of flavocoxid to naproxen. Primary outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and subscales and a timed walk. RESULTS: More than 90% of the subjects in both groups noted significant reduction in the signs and symptoms of knee OA. There were no statistically significant differences in efficacy between the flavocoxid and naproxen groups when the entire intent-to-treat population was analyzed. The flavocoxid group had significantly fewer upper gastrointestinal (UGI) and renal (edema) adverse events (AEs) as well as a strong trend toward fewer respiratory AEs. CONCLUSION: Flavocoxid, a first-in-class flavonoid-based therapeutic that inhibits COX-1 and COX-2 as well as 5-LOX, was as effective as naproxen in managing the signs and symptoms of OA of the knee. Flavocoxid demonstrated better UGI, renal (edema), and respiratory safety profiles than naproxen.""",1
12222,20847716,Dalfampridine (Ampyra) for MS,,1
12223,20848612,Drug-induced autoimmune hepatitis: an easily reversible type of liver fibrosis?,,1
12224,20851491,Drug-induced liver injury: is it time for genetics to change our clinical practice?,,1
12225,20854865,Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate?,"Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.",1
12226,20857257,The clinical management of acetaminophen poisoning in a community hospital system: factors associated with hospital length of stay,"""Acetaminophen (APAP) overdose is the most common pharmaceutical poisoning. The objective of this study was to examine the management of patients admitted for treatment of APAP overdose. Factors impacting hospital length of stay (LOS) were of particular interest. This was a retrospective cohort study of patients admitted to Kaiser Permanente Northern California hospitals for APAP overdose from July 2003 through December 2007. Medical records were abstracted for patient demographic data, key factors of overdose, California Poison Control System (CPCS) contact, data regarding hospital course, transfer for liver transplantation, and death. Four hundred thirty-five patients were included. The mean hospital LOS was 66.5 h (95% CI 62.1, 71.0). Four patients (0.9%) died. Eight patients (1.8%) were transferred for liver transplantation, but all of these patients later recovered without transplant. Of 289 cases eligible for placement on the Rumack-Matthew nomogram (acute ingestion with known time of ingestion <24 h and normal liver enzymes), 161 (55.7%) had APAP levels above the """"200"""" line and 77 (26.6%) fell below the """"150"""" line. CPCS was contacted in 295 cases (67.8%). Mean LOS in cases with CPCS consultation was 61.9 h (95% CI 57.2, 66.5 h) versus 76.3 h (95% CI 66.6, 86.0 h) in those without. LOS in cases treated with IV NAC was 67.1 h (95% CI 57.7, 76.5 h) versus 66.4 h (95% CI 61.2, 71.5 h) in cases treated with oral NAC. Many patients admitted for APAP overdose had serum APAP levels below the minimum toxicity level. Use of IV NAC did not impact hospital LOS. CPCS consultation appeared to decrease mean hospital LOS.""",1
12227,20858619,Clinical efficacy and safety of sunitinib after imatinib failure in Japanese patients with gastrointestinal stromal tumor,"BACKGROUND: Imatinib used to be the only effective treatment for advanced gastrointestinal stromal tumor. However, early clinical reports have shown that sunitinib has substantial anticancer activity in patients with advanced gastrointestinal stromal tumor after failure of imatinib. METHODS: Eighteen Japanese patients with advanced gastrointestinal stromal tumor who were resistant or intolerant to previous treatment with imatinib were entered into this study. These patients were given sunitinib orally, once daily at a 50-mg starting dose, in 6-week cycles with 4 weeks on and 2 weeks off treatment. Tumor response and drug safety were then evaluated. RESULTS: Median time-to-treatment failure was 207 days. Overall, 5.6% (1/18) of patients achieved partial response, 38.9% (7/18) had stable disease and 44.4% (8/18) had progressive disease. The common adverse events were hand-foot syndrome, liver dysfunction, fatigue, anorexia and hypertension. Mild anemia, leukocytopenia and neutropenia were also noted. Nine patients required dose reduction or cessation because of adverse events. CONCLUSIONS: This study demonstrates that sunitinib may be an effective agent for advanced gastrointestinal stromal tumor after failure of imatinib in clinical practice.",1
12228,20863377,Autoimmune hepatitis triggered by nitrofurantoin: a case series,"INTRODUCTION: Drugs can occasionally trigger the onset of autoimmune liver disease. CASE PRESENTATION: Three Caucasian women (aged 65, 42 and 74 years old) who were receiving long-term nitrofurantoin as prophylaxis against recurrent urinary tract infections developed hepatitic liver disease. Serological auto-antibody profiles and liver histology appearances were consistent with autoimmune hepatitis. Two of the patients presented with jaundice, and one required a prolonged hospital admission for liver failure. In all three patients nitrofurantoin was withdrawn, and long-term immunosuppressive therapy with prednisolone and azathioprine or mycophenolate was given. The patients responded well, with liver biochemistry returning to normal within a few months. CONCLUSIONS: Although nitrofurantoin rarely causes autoimmune hepatitis, this antimicrobial is increasingly used as long-term prophylaxis against recurrent urinary tract infection. General practitioners and urologists who prescribe long-term nitrofurantoin therapy should be aware of this adverse effect.",1
12229,20864900,"Dasatinib, a multikinase inhibitor: therapy, safety, and appropriate management of adverse events","Tyrosine kinase inhibitors are the standard of care for the treatment of chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Dasatinib is a second-generation tyrosine kinase inhibitor that has been shown to be efficacious in treatment of patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to frontline imatinib. In clinical trials of dasatinib, the adverse events that arise during therapy are mostly mild to moderate in severity and are usually reversible and manageable with appropriate intervention. Cytopenias can be treated with dose modification or interruption. Pleural effusions can be effectively managed with prompt delivery of supportive care and dose modification. Patients at risk of cardiac abnormalities or bleeding-related events require careful monitoring. Pharmacokinetic analysis of dasatinib indicates interactions with a number of other agents and a complete treatment history should be taken before initiating therapy because mitigating drug-drug interactions are critical for patient safety.",1
12230,20874042,"Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology","Everolimus, a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) drug class, has many clinical applications, including in organ transplantation, oncology, and cardiology. It currently has United States Food and Drug Administration (FDA) approval for prophylaxis against rejection in de novo renal transplant recipients, treatment of renal cell carcinoma, and use as a drug-eluting stent. To review the pharmacology, pharmacokinetics, efficacy, and safety of everolimus, we performed a search of the MEDLINE database (January 1997-April 2010) for all English-language articles of in vitro and in vivo studies that evaluated everolimus, as well as abstracts from recent scientific meetings and the manufacturer. In transplantation, everolimus demonstrates immunosuppressive properties and has been used to prevent acute rejection in cardiac, liver, lung, and renal transplant recipients. It appears that this agent may be potent enough to allow for the minimization or removal of calcineurin inhibitors in the long-term management of renal transplant recipients. In oncology, everolimus has been proven effective for the management of treatment-resistant renal cell carcinoma. In cardiology, everolimus is available as a drug-coated stent and is used in percutaneous coronary interventions for prevention of restenosis. In transplant recipients and patients with renal cell carcinoma, everolimus appears to have an extensive adverse-event profile. The pharmacologic properties of everolimus differentiate this agent from other drugs used in these clinical areas, and its pharmacokinetic properties differentiate it from sirolimus.",1
12231,20879012,Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation,"""The standard antitubercular treatment (ATT), which consists of isoniazid (INH), rifampicin (RIF), ethambutol, and pyrazinamide (PZA), is the best available treatment for tuberculosis (TB). However, the hepatotoxicity of INH and PZA can be severe, and even after drug withdrawal, patients may require liver transplantation (LT). In these cases, the strategy for the treatment of TB is poorly defined. Between 1986 and 2008, 14 patients presented at our department with severe hepatitis secondary to INH and PZA treatment. Four of these patients were immunosuppressed: 2 after renal transplantation and 2 because of human immunodeficiency virus infection. In seven of the 14 patients an alternative ATT was begun on admission, which was well tolerated. Hepatitis improved spontaneously in 5 patients, and alternative ATT was continued for 9.3 +/- 4.2 months; 1 patient deteriorated and underwent LT, and 1 patient died. ATT was stopped definitively in 2 patients. Six patients required urgent LT, and alternative ATT was started after transplantation and was successful. Five patients receiving RIF had an episode of acute rejection. In conclusion, hepatitis secondary to ATT can be successfully treated with alternative anti-TB regimens. The use of RIF in LT patients may lead to acute rejection. RIF should therefore be avoided in these patients.""",1
12232,20882524,Efficacy and safety of micafungin for treating febrile neutropenia in hematological malignancies,"Less toxic antifungal drugs are required for empirical antifungal therapy. Micafungin is an echinocandin drug that is effective against both Candida and Aspergillus, and preliminary clinical studies have shown good antifungal activity. We prospectively examined the effect and safety of micafungin against febrile neutropenia with suspected fungal infection in 53 patients (median age, 56 years) who had undergone chemotherapy. The administered dose of micafungin was 150 mg/day, and its effect was evaluated as fever resolution as well as the results of chest imaging and serum fungal tests. Micafungin levels were measured on day 4 after the first administration using high-performance liquid chromatography. We also measured trough levels of micafungin. Underlying diseases comprised acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 20), multiple myeloma (n = 3), and non-Hodgkin's lymphoma (n = 26). The overall efficacy of micafungin was 70%. Breakthrough fungal infections were documented in two (3.8%) patients, both of whom died of invasive mycosis. None of the patients were switched to other antifungal drugs due to events unrelated to adverse effects. Plasma levels of micafungin and the degree of hepatic or renal dysfunction did not correlate. Micafungin is safe and effective for the empirical antifungal therapy of febrile neutropenia in patients with hematological malignancies.",1
12233,20888974,Cabazitaxel in prostate cancer: stretching a string,,1
12234,20919852,Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease,"Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 micromol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 micromol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 micromol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.",1
12235,20920530,Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data,"For many years, warfarin was the only effective oral anticoagulant to prevent and treat thromboembolism. Nevertheless, its clinical use is limited by a narrow therapeutic window, extensive drug interactions, need of strict dietary control and frequent monitoring. The pharmacological response is also unpredictable and highly variable among patients. Suboptimal anticoagulation can lead to detrimental thromboembolic events or life-threatening bleeding. Direct thrombin inhibitor (DTI) activity represents a new class of anticoagulant activity that was intended to replace warfarin. Ximelagatran was the first DTI shown to have similar efficacy to warfarin, but failed to replace it because of a high incidence of liver toxicity. Dabigatran etexilate is another novel DTI with a more predictable pharmacokinetic profile and fewer drug interactions compared with warfarin. Recent large-scaled, randomized studies have shown that it does not share ximelagatran's hepatotoxicity, and is as effective as conventional anticoagulants for venous thromboembolism (VTE) and prophylaxis in atrial fibrillation (AF). These findings led to the approval of dabigatran etexilate for thromboprophylaxis following hip or knee replacement surgery in Europe, Canada and the United Kingdom. Here we summarize the latest evidence concerning the use of dabigatran etexilate in VTE (BISTRO, RE-MODEL, RE-NOVATE, RE-MOBILIZE and RECOVER) and AF (PETRO and RELY). Potential problems related to dabigatran use are also discussed to examine whether it can truly replace warfarin as the gold standard.",1
12236,20922203,Ranitidine induced hepatitis,,1
12237,20926753,"Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment","""Ticagrelor, a P2Y(1)(2) receptor antagonist that inhibits ADP-induced platelet aggregation (IPA), has demonstrated improved outcomes in patients with acute coronary syndromes compared with clopidogrel. Because ticagrelor undergoes extensive hepatic elimination, this study evaluated the effect of mild hepatic impairment on its pharmacokinetics, pharmacodynamics, and safety. A single oral 90-mg ticagrelor dose was administered to volunteers with and without hepatic impairment (10 with Child-Pugh class A; 10 with normal liver function). Absorption of ticagrelor and formation of its active metabolite, AR-C124910XX, were rapid in both groups. Ticagrelor exposure was higher in hepatically impaired volunteers (maximum concentration [C(max)] 12%; area under the plasma concentration-time curve from time 0 to infinity [AUC] 23%) compared with controls. AR-C124910XX exposure was also higher in hepatic impairment (C(max) 17%; AUC 66%). Ticagrelor is highly protein bound (>99.8%); the unbound fraction in plasma was comparable in volunteers with hepatic impairment and controls. Overall, IPA parameters were not significantly different between groups, and similar IPA-concentration profiles were observed. Ticagrelor was well tolerated in both groups, and no adverse events were reported. In conclusion, mild hepatic impairment resulted in modestly higher exposure to ticagrelor and AR-C124910XX, without subsequent effects on pharmacodynamics or tolerability. Based on these data, no ticagrelor dosage adjustment is needed in patients with mild hepatic impairment.""",1
12238,20926902,Fatal reactivation of occult hepatitis B virus infection after rituximab and chemotherapy in lymphoma: necessity of antiviral prophylaxis,"The anti-CD20 monoclonal antibody rituximab has been used extensively in the treatment of B-cell lymphoma. However, several studies reported hepatitis B virus (HBV) reactivation after rituximab administration. The majority of these cases have been described in chronic carriers of HBV, whereas reactivation in occult hepatitis B carriers is relatively rare. We report a fatal case of fulminant hepatitis B that occurred in a B-cell lymphoma patient with occult hepatitis B after rituximab-containing chemotherapy, which raised the necessity of antiviral prophylaxis in this setting.",1
12239,20930099,Hepatitis B reactivation and rituximab in the oncology practice,"Rituximab use in hematology and oncology practice has significantly and positively improved the clinical outcomes in patients with a wide variety of B-cell lymphoproliferative disorders. However, emerging data reveal that there is a risk of viral hepatitis B reactivation in some patients treated with rituximab. Many of these cases result in treatment delays, inferior oncologic outcomes, increased morbidity, and more rarely fulminant hepatic decompensation and death. Indeed, the rituximab package insert and many clinical practice guidelines have been modified to reflect these concerns. The true incidence and mechanism of reactivation are still being elucidated. This article focuses on the current evidence that supports these recently revised clinical recommendations along with a review of the risk factors for reactivation, suggested monitoring, and preventative interventions.",1
12240,20935227,"Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis","Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.",1
12241,20937175,Age-related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review,"OBJECTIVE: To determine the age-related risk of hepatotoxicity under currently recommended treatment regimens for latent tuberculosis (TB) infection (LTBI). METHODS: A systematic review of the MEDLINE and EMBASE databases (from database inception to 2008) was performed to determine the risk of isoniazid (INH) and/or rifampicin hepatotoxicity in LTBI treatment stratified by patient age. Study selection, study quality assessment and data extraction were performed using piloted proformas. Rate data were meta-analysed to generate summary rates with 95%CI within age-related subgroups using a random effects model. RESULTS: Seven relevant studies (18,610 participants, including 115 cases of hepatotoxicity) met the selection criteria. The median rate of hepatotoxicity was 1.8% (range 0.07-11.9). On average, rates were higher among those aged >/= 35 years (1.7%, 95%CI 1.4-2.2) than those aged <35 years (0.2%, 95%CI 0.1-0.3). CONCLUSION: The rates of hepatotoxicity were low. Summary estimates of risks generated in this review can be used for counselling individuals for whom chemoprophylaxis is recommended. The use of INH for the treatment of LTBI is safe in older patients with clinical or biochemical monitoring.",1
12242,20943071,Etanercept therapy in patients with psoriasis and concomitant HCV infection,"Treatment of patients with psoriasis and/or psoriatic arthritis and concomitant hepatitis C infection remains difficult. Except for cyclosporine, other drugs have proved unacceptable because of hepatotoxicity in patients with HCV. With the advent of anti-TNF-alpha drugs, including etanercept, new therapeutic options have become available. Our study population was five patients with psoriasis and/or psoriatic arthritis and concomitant chronic HCV infection undergoing etanercept therapy. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and viral load were used as markers for liver damage and disease progression, respectively. The Psoriasis Area Severity Index (PASI) was used as a reference parameter for evaluating the therapeutic efficacy of etanercept therapy in improving the clinical skin picture. AST, ALT, viral load and PASI were monitored at 3-month intervals starting from the beginning of therapy up to two years after initiation of etanercept therapy. In four out of five patients, liver enzyme levels and viral load remained substantially unchanged during the course of therapy. In the one remaining patient, viral load and liver enzyme levels increased during etanercept therapy, and then decreased following the initiation of Peg-IFN/ribavirin in combination with anti-TNF-alpha therapy. PASI scores decreased in all five patients. Our data suggest that etanercept therapy is safe and provides an efficacious therapeutic alternative in patients with psoriasis and concomitant HCV infection.",1
12243,20944674,Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia,,1
12244,20949522,Discordance for Schimmelpenning-Feuerstein-Mims syndrome in monochorionic twins supports the concept of a postzygotic mutation,"The Schimmelpenning-Feuerstein-Mims (SFM) syndrome comprises a craniofacial nevus sebaceus, seizures, developmental delay, ocular and skeletal abnormalities. It is a sporadic condition and hypothesized to result from mosaicism involving a lethal autosomal dominant gene. We report a second occurrence of discordant monozygotic (MZ) twins with severe SFM, supporting the concept of a postzygotic mutation.",1
12245,20952452,Fulminant hepatic failure in woman with iron and non-steroidal anti-inflammatory drug intoxication,"A 17-year-old, previously healthy female ingested 16,000 mg iron sulphate (96.15 mg of iron ions per kg of b.wt.) with a suicidal intent. The patient was admitted to a toxicology unit 10 hours after the drug ingestion. Serum iron concentration at admission was 2351 ?g% (421.0 ?mol/L). In the course of the intoxication, hemorrhagic gastritis, renal insufficiency and increasing signs of fulminant hepatic failure complicated with coagulopathy and encephalopathy were observed. Treatment with deferoxamine was started immediately after admission to the hospital and continued for 15 hours until the serum concentration of iron decreased to 145 ?g% (25.9 ?mol/L). Patient was qualified for liver transplant, therefore albumin dialysis as a bridge to liver transplantation was performed. In spite of two procedures of albumin dialysis using the Prometheus system, deep coma, shock and respiratory insufficiency developed. The patient died 80 hours after iron ingestion. In the presented case, the ingestion of a very high dose of iron and late introduction of deferoxamine treatment contributed to fulminant liver failure and fatal outcome of the intoxication.",1
12246,20956624,Nilotinib in a patient with postnecrotic liver cirrhosis related to imatinib,,1
12247,20956650,Is etanercept safe for treating plaque psoriasis in a patient with chronic hepatitis C virus infection?,,1
12248,20957213,Safety and efficacy of azacitidine in myelodysplastic syndromes,"PURPOSE: The clinical efficacy, different dosages, treatment schedules, and safety of azacitidine are reviewed. SUMMARY: Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival and delaying time to progression to acute myelogenous leukemia. The recommended dosage of azacitidine is 75 mg/m(2) daily for 7 days, with different treatment schedules validated. It appears to be well tolerated, with the most common adverse effects being myelosuppression. Several other off-label recommendations were also analyzed. CONCLUSION: Azacitidine is the first DNA hypomethylating agent approved by FDA for the treatment of myelodysplastic syndromes with demonstrated efficacy.",1
12249,20959504,Comment: a population study of the frequency of high-dose acetaminophen prescribing and dispensing,,1
12250,20960257,Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes,"Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.",1
12251,20969501,When do the aminotransferases rise after acute acetaminophen overdose?,"CONTEXT: Rising aminotransferases (ATs) [either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are one of the first signs of hepatotoxicity following acetaminophen (APAP)] overdose (OD). However, the timing and speed of such rises are not well characterized, hampering early risk prediction. OBJECTIVE: To describe the kinetics of AT release in acute APAP OD patients who develop hepatotoxicity despite treatment. METHODS: A descriptive study of acute APAP OD patients with peak AT > 1,000 IU/L taken from the derivation subset of the Canadian Acetaminophen Overdose Study (CAOS), a large, multicenter retrospective cohort of patients hospitalized for APAP poisoning. RESULTS: Of 2,488 hospital admissions for acute APAP OD, 94 met inclusion criteria. Treatment with acetylcysteine, mostly intravenously, was begun in all cases within 24 h of ingestion. The initial AT concentration was already elevated in most patients at presentation [median 211 (IQR 77-511) IU/L obtained at 15.3 (12.1-19.2) h postingestion], and exceeded 100 IU/L in almost all patients within 24 h of ingestion. Serum AT concentrations rose rapidly [doubling time 9.5 h (95% CI: 8.7-10.4 h)], especially in patients who developed AT > 1,000 IU/L within 48 h of ingestion. Coagulopathy was worse in these patients and in those with an AT > 250 IU/L during the first 12 h of treatment with acetylcysteine. DISCUSSION AND CONCLUSIONS: An abnormal and rapidly doubling AT at presentation is more typical in severely poisoned patients, as judged by the effects on clotting. These data suggest that risk prediction instruments may be improved by incorporating both the serum AT concentration at initiation of antidotal therapy and its rate of change. Further studies using such an approach are warranted.",1
12252,20972845,Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis,"OBJECTIVE: twice-daily flavocoxid, a cyclooxygenase and 5-lipoxygenase inhibitor with potent antioxidant activity of botanical origin, was evaluated for 12 weeks in a randomized, double-blind, active-comparator study against naproxen in 220 subjects with moderate-severe osteoarthritis (OA) of the knee. As previously reported, both groups noted a significant reduction in the signs and symptoms of OA with no detectable differences in efficacy between the groups when the entire intent-to-treat population was considered. This post-hoc analysis compares the efficacy of flavocoxid to naproxen in different subsets of patients, specifically those related to age, gender, and disease severity as reported at baseline for individual response parameters. METHODS: in the original randomized, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. In this subgroup analysis, primary outcome measures including the Western Ontario and McMaster Universities OA index and subscales, timed walk, and secondary efficacy variables, including investigator global assessment for disease and global response to treatment, subject visual analog scale for discomfort, overall disease activity, global response to treatment, index joint tenderness and mobility, were evaluated for differing trends between the study groups. RESULTS: subset analyses revealed some statistically significant differences and some notable trends in favor of the flavocoxid group. These trends became stronger the longer the subjects continued on therapy. These observations were specifically noted in older subjects (>60 years), males and in subjects with milder disease, particularly those with lower subject global assessment of disease activity and investigator global assessment for disease and faster walking times at baseline. CONCLUSIONS: initial analysis of the entire intent-to-treat population revealed that flavocoxid was as effective as naproxen in managing the signs and symptoms of OA of the knee. Detailed analyses of subject subsets demonstrated distinct trends in favor of flavocoxid for specific groups of subjects.",1
12253,20974867,Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections,"""The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for ?7 days was completed. Patients receiving a fixed dose (i.e., labeled dose) were frequency matched and compared to those receiving a weight-based dose (i.e., high dose). The primary endpoint of hepatotoxicity was evaluated by using NCI Common Terminology Criteria (CTC) and components of liver enzymes measuring >3? the upper limit of normal (ULN) and >5? baseline measurements. Secondary endpoints included an incidence of other adverse drug events. Twenty-five labeled-dose and 84 high-dose voriconazole patients were studied. Liver enzyme abnormalities were similar between groups, with the exception of labeled-dose patients experiencing more alkaline phosphatase (ALP) CTC >2? the baseline (P = 0.02) and ALP levels >3? the ULN (P = 0.02). Treatment with high dose was associated with the discontinuation of voriconazole for practitioner attribution of adverse drug events (P = 0.03), although reasons varied and no commonality of biomarker abnormality was identified. Multivariate analysis revealed that the duration of therapy and higher mg/kg total daily doses as interval variables were predictive of some hepatotoxicity outcomes. No difference existed in liver abnormalities for high-dose voriconazole; however, higher mg/kg doses and a longer duration of therapy may be associated with hepatotoxicity.""",1
12254,20976768,A phase 3 trial of extended release oral dalfampridine in multiple sclerosis,"""OBJECTIVE: A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended-release dalfampridine (4-aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics. METHODS: This was a 39-center, double-blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25-Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on-treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect. RESULTS: One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine-treated TWRs during the 8-week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0-28.4%); the mean improvement at the last on-treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings. INTERPRETATION: This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.""",1
12255,20979469,Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer,"""BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).""",1
12256,21001532,Atabrine dermatitis and associated aplastic anemia,,1
12257,21029821,Safety and efficacy of ezetimibe/simvastatin combination versus atorvastatin alone in adults >/=65 years of age with hypercholesterolemia and with or at moderately high/high risk for coronary heart disease (the VYTELD study),"""Higher than 80% of coronary heart disease-related mortality occurs in patients >/=65 years of age. Guidelines recommend low-density lipoprotein (LDL) cholesterol targets for these at-risk patients; however, few clinical studies have evaluated lipid-lowering strategies specifically in older adults. This multicenter, 12-week, randomized, double-blind, parallel-group trial evaluated the efficacy and safety of the usual starting dose of ezetimibe/simvastatin (10/20 mg) versus atorvastatin 10 or 20 mg and the next higher dose of ezetimibe/simvastatin (10/40 mg) versus atorvastatin 40 mg in 1,289 hypercholesterolemic patients >/=65 years of age with or without cardiovascular disease. Patients randomized to ezetimibe/simvastatin had greater percent decreases in LDL cholesterol (-54.2% for 10/20 mg vs -39.5% and -46.6% for atorvastatin 10 and 20 mg, respectively; -59.1% for 10/40 mg vs -50.8% for atorvastatin 40 mg; p <0.001 for all comparisons) and the number attaining LDL cholesterol <70 mg/dl (51.3% for 10/20 mg, 68.2% for 10/40 mg) and <100 mg/dl (83.6% for 10/20 mg; 90.3% for 10/40 mg) was significantly larger compared to those receiving atorvastatin for all prespecified dose comparisons (p <0.05 to <0.001). A significantly larger percentage of high-risk patients achieved LDL cholesterol <70 mg/dl on ezetimibe/simvastatin 10/20 mg (54.3%) versus atorvastatin 10 mg (10.9%, p <0.001) or 20 mg (28.9%, p <0.001) and ezetimibe/simvastatin 10/40 mg (69.2%) versus atorvastatin 40 mg (38.2%, p <0.001), and a significantly larger percentage of intermediate-risk patients achieved LDL cholesterol <100 mg/dl on ezetimibe/simvastatin 10/20 mg (82.1%) versus atorvastatin 10 mg (59.3%, p <0.05). Improvements in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and lipoprotein ratios were significantly greater with ezetimibe/simvastatin than atorvastatin for all comparisons (p <0.01 to <0.001). High-density lipoprotein cholesterol and triglyceride results were variable. All treatments were generally well tolerated. In conclusion, ezetimibe/simvastatin provided significantly greater improvements in key lipid parameters and higher attainment of LDL cholesterol targets than atorvastatin, with comparable tolerability.""",1
12258,21039766,Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase,"AIM: To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. METHODS: Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. RESULTS: Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. CONCLUSIONS: Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.",1
12259,21045756,Denosumab (prolia) for postmenopausal osteoporosis,,1
12260,21045760,Interferon beta-1b (Extavia) for multiple sclerosis,,1
12261,21045763,Sibutramine (Meridia) withdrawn,,1
12262,21052089,A phase-2 trial of low-dose pomalidomide in myelofibrosis,"""In a previous study, we reported on the safety and efficacy of low-dose (0.5?mg) pomalidomide and prednisone and pomalidomide alone (2?mg/day), for the treatment of anemia associated with myelofibrosis (MF). The current study examined the value of low-dose pomalidomide alone. The main eligibility criterion was transfusion-dependency or hemoglobin <10?gm per 100?ml. Anemia response was assessed by International Working Group criteria. Pomalidomide (0.5?mg/day) was given to 58 patients (median age 68 years); 46 (79%) were transfusion-dependent and 42 were JAK2V617F positive. Anemia response was documented only in the presence of JAK2V617F (24 vs 0%; P=0.03) but was not further affected by mutant allele burden (P=0.39); 9 of the 10 anemia responders became transfusion independent. Anemia response in JAK2V617F-positive patients was predicted by the presence of pomalidomide-induced basophilia in the first month of therapy (38 vs 6%; P=0.02) or absence of marked splenomegaly (38 vs 11%; P=0.05). A total of 14 (58%) of 24 patients with a platelet count of ? 100 ? 10(9) cells/l experienced a >50% increment in platelet count. There were no spleen responses. Grade 3 or 4 thrombocytopenia/neutropenia occurred in 2%/0% of patients. Low-dose pomalidomide is effective in the treatment of anemia associated with JAK2V617F-positive MF; response is predicted by early drug-induced basophilia.""",1
12263,21057388,Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of United Network for Organ Sharing registry data,"""BACKGROUND: Induction agents have been shown to reduce the rate of acute rejection. They have not been clearly shown to improve graft and patient survival. METHODS: United Network for Organ Sharing registry data were analyzed to show the status of induction therapy in the United States and to determine the effect of induction therapy on long-term graft and patient survival. RESULTS: Since establishment of the United Network for Organ Sharing renal transplant registry, there have been three distinct eras of induction regimen: (1) the low-induction, old antibody era, 1987 to 1993, when antilymphocyte globulin and muromonab-CD3 were the major agents; (2) a high-induction, transitional era, 1994 to 2002, when basiliximab (1998), daclizumab (1998), and rabbit antithymocyte globulin (rATG; 1999) replaced antilymphocyte globulin and muromonab-CD3, with maintenance agents also used; (3) the high-induction, modern antibody era, 2003 to present, with most patients receiving rATG, basiliximab, daclizumab, or alemtuzumab (2003). Induction recipients had higher graft and patient survival rates than nonrecipients in all categories of organ transplant. The improvement was statistically significant in kidney, liver, and lung transplants, although liver and lung recipients had a lower percentage of patients receiving induction than did kidney patients. Kidney transplant recipients on alemtuzumab with steroids had the lowest risk of graft failure, followed by those on alemtuzumab alone, rATG with steroids, rATG alone, and then basiliximab with steroids. Improvement was not statistically significant with daclizumab (alone or with steroids), basiliximab alone, or steroids alone. CONCLUSION: Induction immunosuppression improved graft and patient outcome for most organ transplants. Depleting agents (alemtuzumab and rATG)--especially in combination with steroids--seem to be more efficient in preventing renal graft failure than nondepleting agents (basiliximab and daclizumab).""",1
12264,21061183,"Chemotherapy, liver injury, and postoperative complications in colorectal liver metastases","""BACKGROUND: Systemic chemotherapy (CTx) is increasingly used before surgery for colorectal liver metastases (CRC-LM). However, CTx may cause liver injury like steatosis, steatohepatitis, and sinusoidal injury which may be associated with postoperative morbidity. Some recent data have even shown an increased mortality in patients with CTx-associated steatohepatitis. We, therefore, analyzed our recent experience with potential hepatic injury and its association with CTx and morbidity in patients undergoing surgery for CRC-LM. METHODS: From 2001 to 2007, 179 patients underwent primary liver resection for CRC-LM. Sufficient non-tumorous liver parenchyma could be re-evaluated for this study in 102 patients. In these 102 patients (66% male, median age 62 years, median BMI 26, 8% diabetics (IDDM)), liver injury was classified using established criteria for steatosis and sinusoidal dilatation (SD) and then compared with preoperative CTx and postoperative outcome. Fifty-eight percent of the operations were (extended) hemihepatectomies (ExtRes), 42% segmental or wedge resections (LimRes). Before resection, 66% had received CTx (33% FU-based (FU), 19% oxaliplatin-based (Oxa), 12% irinotecan-based (Iri), and 3% Oxa+Iri). The interval between CTx and surgery was always ?4 weeks. RESULTS: Mortality was 3/102 (2.9%). Any complication occurred in 48%, hepatic insufficiency in 5.9%, and liver-related complications in 24%. Hepatic steatosis >20% was found in 37% (half of them with steatosis >50%). BMI correlated with the frequency of steatosis. Steatosis >20% was more frequent in patients with preoperative chemotherapy but did not depend on the chemotherapy regimen. No relevant risk factor for grades 2 and 3 SD was found. The specific use of Oxa or Iri did not significantly correlate with hepatic injury. Neither a CTx per se nor the different CTx regimens nor the extent of hepatic injury showed any negative influence on mortality, complication rates, or hepatic insufficiency. Patients with IDDM had a higher mortality (25% vs 1% without IDDM; p<0.02), increased complication rate (75% vs 46%; p=0.11), a higher rate of hepatic insufficiency (25% vs 4%; p<0.02), and more liver related complications (50% vs 21%; p=0.06). Patients undergoing ExtRes had a higher overall (p<0.01) and liver-related (p=0.05) complication rate compared to LimRes. None of the 34 patients with preoperative Oxa or Iri died or developed hepatic insufficiency. CONCLUSIONS: In our experience, hepatic injury (steatosis) was influenced by BMI and by preoperative CTx. Neither preoperative CTx nor liver injury increased perioperative morbidity. Patients with IDDM were at a rather high perioperative risk.""",1
12265,21067381,Romiplostim or standard of care in patients with immune thrombocytopenia,"""BACKGROUND: Romiplostim, a thrombopoietin mimetic, increases platelet counts in patients with immune thrombocytopenia, with few adverse effects. METHODS: In this open-label, 52-week study, we randomly assigned 234 adult patients with immune thrombocytopenia, who had not undergone splenectomy, to receive the standard of care (77 patients) or weekly subcutaneous injections of romiplostim (157 patients). Primary end points were incidences of treatment failure and splenectomy. Secondary end points included the rate of a platelet response (a platelet count >50?10(9) per liter at any scheduled visit), safety outcomes, and the quality of life. RESULTS: The rate of a platelet response in the romiplostim group was 2.3 times that in the standard-of-care group (95% confidence interval [CI], 2.0 to 2.6; P<0.001). Patients receiving romiplostim had a significantly lower incidence of treatment failure (18 of 157 patients [11%]) than those receiving the standard of care (23 of 77 patients [30%], P<0.001) (odds ratio with romiplostim, 0.31; 95% CI, 0.15 to 0.61). Splenectomy also was performed less frequently in patients receiving romiplostim (14 of 157 patients [9%]) than in those receiving the standard of care (28 of 77 patients [36%], P<0.001) (odds ratio, 0.17; 95% CI, 0.08 to 0.35). The romiplostim group had a lower rate of bleeding events, fewer blood transfusions, and greater improvements in the quality of life than the standard-of-care group. Serious adverse events occurred in 23% of patients (35 of 154) receiving romiplostim and 37% of patients (28 of 75) receiving the standard of care. CONCLUSIONS: Patients treated with romiplostim had a higher rate of a platelet response, lower incidence of treatment failure and splenectomy, less bleeding and fewer blood transfusions, and a higher quality of life than patients treated with the standard of care. ( ClinicalTrials.gov number, NCT00415532.).""",1
12266,21071176,Association study of lamotrigine-induced cutaneous adverse reactions and HLA-B*1502 in a Han Chinese population,"""Antiepileptic drugs including lamotrigine (LTG) and carbamazepine (CBZ) are among the most common causes of cutaneous adverse reactions (cADRs). Human leukocyte antigen (HLA)-B*1502 has been strongly associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). To investigate this relationship, we performed high-resolution HLA genotyping on LTG-tolerant controls, healthy volunteers, and patients affected by LTG-induced cADRs, ranging from maculopapular exanthema (MPE) to SJS/TEN. Patients with LTG-induced cADRs (n=25, including three with SJS/TEN and 22 with MPE), 21 LTG-tolerant controls, and 71 healthy volunteers were enrolled. The differences in the starting dosage of LTG among the SJS/TEN, MPE, and LTG-tolerant control groups were not statistically significant. HLA-B*1502 frequency was 33.3% (1/3; LTG-induced SJS/TEN group), 9.1% (2/22; LTG-induced MPE group), 4.8% (1/21; LTG-tolerant group), and 8.5% (6/71; healthy volunteers). There was no significant difference in the frequency of subjects with the HLA-B*1502 allele between the SJS/TEN group and LTG-tolerant group (p=0.239, OR=10.0, 95% CI 0.44-228.7), and healthy volunteers (p=0.26, OR=5.42, 95% CI 0.43-68.8), MPE and LTG-tolerant groups (p=1.0, OR=1.08, 95% CI 0.20-5.8), and healthy volunteers (p=1.0, OR=2.0, 95% CI 0.17-23.9). None of the HLA alleles detected were associated with LTG-induced cADRs. In conclusion, HLA-B*1502 and other HLA alleles are not directly associated with LTG-induced MPE. The possibility that HLA-B*1502 is associated with an increased risk of LTG-induced SJS/TEN could not be excluded.""",1
12267,21074222,[Fulminating hepatitis for imatinib in a patient with chronic myeloid leukaemia],,1
12268,21081732,Risk of kava hepatotoxicity and the FDA consumer advisory,,1
12269,21084035,Atorvastatin-induced acute elevation of hepatic enzymes and the absence of cross-toxicity of pravastatin,"Atorvastatin has been associated with liver injury. We reported here two cases of aminotransferases elevation within 12 h of low-dose atorvastatin therapy. Liver functions were fully recovered to the baseline level 11 days after discontinuation of atorvastatin treatment. The possible relative risk factors included advanced age, chronic and systemic diseases, and co-administration of cytochrome P450 3A (CYP3A) enzyme-dependent metabolic drugs or its inhibitors such as clopidogrel and diltiazem. No significant transaminase elevation was observed after switching to pravastatin. Thus, pravastatin might be safer than atorvastain in patients with chronic or systemic diseases, or with co-administration of CYP3A enzyme-dependent drugs.",1
12270,21091041,Lapatinib for breast cancer: a review of the current literature,"IMPORTANCE OF THE FIELD: The identification of HER-2 expression as a predictive and prognostic marker revolutionized breast cancer. Trastuzumab, a humanized mAb, improves survival in both early and advanced HER-2 overexpressing breast cancer. However, many cancers either do not respond or develop resistance to this agent. Lapatinib is an oral tyrosine kinase inhibitor which has both HER-1 and -2 activities and has been licensed for use in recurrent breast cancer that overexpresses HER-2. Studies of lapatinib in early breast cancer are ongoing. AREAS COVERED IN THIS REVIEW: A PubMed search was conducted using 'lapatinib' and 'breast cancer' as the key words. All published works up to July 2010 were reviewed. A manual review of abstracts presented at the ASCO Annual meeting and the San Antonio Breast Cancer Symposium was conducted for the last 2 years. In this review, we summarize the current knowledge of lapatinib and pose questions which need to be addressed as we further expand our knowledge of the HER-2 subtypes of breast cancer. WHAT THE READER WILL GAIN: The reader will gain an up-to-date and comprehensive review of the current literature as it pertains to the safety and efficacy of lapatinib in the treatment of breast cancer. TAKE HOME MESSAGE: Lapatinib has provided an alternative for the treatment of advanced HER-2 overexpressing breast cancer and is currently being assessed in early disease.",1
12271,21095462,Toxicology and safety of COMT inhibitors,"The development of catechol-O-methyltransferase (COMT) inhibitors for the adjunct treatment to levodopa and aromatic L-amino acid decarboxylase (AADC) inhibitors in Parkinson's disease started in the late 1950s. The first-generation inhibitors were associated with toxic properties: they induced convulsions, or they were toxic to the liver. None of them was taken into clinical use. The second-generation inhibitors entacapone and tolcapone have now been in clinical use for over a decade, and some new inhibitors are under development. The main adverse events in the use of entacapone and tolcapone are dopaminergic and dependent of the concomitant use of levodopa, but the symptoms are generally moderate or mild. Among the non-dopaminergic adverse events, diarrhea is the most prominent one induced by both entacapone and tolcapone. In clinical use, entacapone has been safe, but tolcapone is under strict regulations on liver enzyme monitoring, since in the early years, a few hepatotoxicity cases appeared, three of them with fatal outcome. The mechanism behind tolcapone-induced liver toxicity has been evaluated both in vitro and in vivo, but no clear answer exists at the moment. In the regulatory animal studies, both inhibitors have been safe with no reported toxicity. Also nebicapone, the latest of the second-generation inhibitors in clinical trials has shown some liver enzyme elevations in human subjects. New inhibitors with a structure differing from nitrocatechols are under development. No safety concerns have been reported connected to COMT inhibiton as such. COMT knockout mice are fertile without any pathologies due to the total COMT inhibition.",1
12272,21098156,Therapeutic acetaminophen is not associated with liver injury in children: a systematic review,"""BACKGROUND: Concern exists about the potential for liver injury with therapeutic dosing of acetaminophen in children. OBJECTIVE: We systematically reviewed the medical literature to determine the rate at which liver injury has been reported for children prescribed therapeutic doses of acetaminophen (?75 mg/kg per day orally or intravenously or ?100 mg/kg per day rectally). METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials to locate all studies in which acetaminophen was administered to a defined pediatric population for ?24 hours and for all case reports of liver injury after therapeutic acetaminophen dosing. Trained reviewers extracted data from each report. Major and minor hepatic adverse events (AEs) were defined prospectively. Causality was assessed by using the Naranjo algorithm. RESULTS: A total of 62 studies that enrolled 32,414 children were included. No child (0% [95% confidence interval: 0.000-0.009]) was reported to have exhibited signs or symptoms of liver disease, to have received an antidote or transplantation, or to have died. Major or minor hepatic AEs were reported for 10 children (0.031% [95% confidence interval: 0.015-0.057]). The highest transaminase value reported was 600 IU/L. Naranjo scores (2-3) suggested """"possible"""" causation. Twenty-two case reports were identified. In 9 cases, the Naranjo score suggested """"probable"""" causation (5-6). CONCLUSIONS: Hepatoxicity after therapeutic dosing of acetaminophen in children is rarely reported in defined-population studies. Case reports suggest that this phenomenon may occur, but few reports contain sufficient data to support a probable causal relationship.""",1
12273,21103229,A Rare Case of Propofol-Induced Acute Liver Failure and Literature Review,"The incidence of drug-induced acute liver failure is increasing. A number of drugs can inhibit mitochondrial functions, alter ?-oxidation and cause accumulation of free fatty acids within the hepatocytes. This may result in hepatic steatosis, cell death and liver injury. In our case, propofol, an anesthetic drug commonly used in adults and children, is suspected to have induced disturbance of the mitochondrial respiratory chain, which in consequence led to insufficient energy supply and finally liver failure. We report the case of a 35-year-old Caucasian woman with acute liver failure after anesthesia for stripping of varicose veins. Liver histology, imaging and laboratory data indicate drug-induced acute liver failure, presumably due to propofol. Hepatocyte death and microvesicular fatty degeneration of 90% of the liver parenchyma were observed before treatment with steroids. Six months later, a second biopsy was performed, which revealed only minimal steatosis and minimal periportal hepatitis. We suggest that propofol led to impaired fatty acid oxidation possibly due to a genetic susceptibility. This caused free fatty acid accumulation within hepatocytes, which presented as hepatocellular fatty degeneration and cell death. Large scale hepatocyte death was followed by impaired liver function and, consecutively, progressed to acute liver failure.",1
12274,21109302,Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis,"""BACKGROUND: Long-term statin treatment reduces the frequency of cardiovascular events, but safety and efficacy in patients with abnormal liver tests is unclear. We assessed whether statin therapy is safe and effective for these patients through post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study population. METHODS: GREACE was a prospective, intention-to-treat study that randomly assigned by a computer-generated randomisation list 1600 patients with coronary heart disease (aged <75 years, with serum concentrations of LDL cholesterol >2?6 mmol/L and triglycerides <4?5 mmol/L) at the Hippokration University Hospital, Thessaloniki, Greece to receive statin or usual care, which could include statins. The primary outcome of our post-hoc analysis was risk reduction for first recurrent cardiovascular event in patients treated with a statin who had moderately abnormal liver tests (defined as serum alanine aminotransferase or aspartate aminotransferase concentrations of less than three times the upper limit of normal) compared with patients with abnormal liver tests who did not receive a statin. This risk reduction was compared with that for patients treated (or not) with statin and normal liver tests. FINDINGS: Of 437 patients with moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease, 227 who were treated with a statin (mainly atorvastatin 24 mg per day) had substantial improvement in liver tests (p<0?0001) whereas 210 not treated with a statin had further increases of liver enzyme concentrations. Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3?2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (10?0 events per 100 patient-years; 68% relative risk reduction, p<0?0001). This cardiovascular disease benefit was greater (p=0?0074) than it was in patients with normal liver tests (90 [14%] events in 653 patients receiving a statin [4?6 per 100 patient-years] vs 117 [23%] in 510 patients not receiving a statin [7?6 per 100 patient-years]; 39% relative risk reduction, p<0?0001). Seven (<1%) of 880 participants who received a statin discontinued statin treatment because of liver-related adverse effects (transaminase concentrations more than three-times the upper limit of normal). INTERPRETATION: Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease. FUNDING: None.""",1
12275,21113977,Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia,"""Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty-seven patients were treated. The median age was 41 years, 44% of patients were either in ?2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing.""",1
12276,21117864,"Retrospective, observational study on the effects and tolerability of flutamide in a large population of patients with acne and seborrhea over a 15-year period","The long-term effects and tolerability of flutamide (Flu) in women with acne and seborrhea were evaluated. Over the 15-year period, which spans from January 1991 to January 2006, a total of 230 Caucasian women with acne, 211 of which also with seborrhea, received yearly reducing doses (250, 125, and 62.5 mg/day) of Flu alone or combined with oral contraceptive for a period varying from 3 to 6 years and more. Clinical and endocrine evaluations were performed half-yearly and yearly, respectively, in the first 3 years of the study, and yearly in the following years. Liver function evaluations were performed quarterly. Both the groups of patients under Flu therapy showed a similar, marked decrease in acne and seborrhea scores after 6 months of treatment compared with basal values. The maximum drug effect was observed after 1 year, and it was maintained during the following years of treatment. Androgens were strongly suppressed during treatment. During the first year of treatment with 250 mg/day, 4.8% of patients interrupted the study due to hepatic disorders. During the following years on the 125 and 62.5 mg/day doses, no transaminase elevation was observed. The study supports very low-dose Flu as a first-line therapy for women with acne and seborrhea.",1
12277,21119102,Cytolytic hepatitis possibly related to levonorgestrel/ethinylestradiol oral contraceptive use: 2 case reports,,1
12278,21121872,Clinical safety of tocilizumab in rheumatoid arthritis,"IMPORTANCE OF THE FIELD: Tocilizumab is a new biologic disease-modifying antirheumatic drug directed against the activity of IL-6, a key pro-inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). This drug has proved highly effective in RA patients, including those who had previously not responded to anti-TNFs. As side effects are a major cause for discontinuing biologic therapy, the present article focuses on the tolerability profile of tocilizumab. AREAS COVERED IN THIS REVIEW: This review describes the adverse events (AEs) reported in RA patients treated with tocilizumab. Most data are derived from controlled clinical trials and their open-label extensions. WHAT THE READER WILL GAIN: The reader will gain a comprehensive review of treatment-emergent AEs associated with tocilizumab therapy. These AEs include infections, including opportunistic infections, infusion and hyper-sensitivity reactions, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia. TAKE HOME MESSAGE: Based on current data, tocilizumab appears to have an acceptable safety profile inasmuch as most AEs were manageable or controllable. However, results from large scale pharmacoepidemiological investigations and appropriate post-marketing surveillance are awaited to identify the full spectrum of AEs and define the true benefit:risk ratio of tocilizumab.",1
12279,21122554,Hepatosplenic T-cell lymphoma and inflammatory bowel disease,"""OBJECTIVE: This article reviews the current literature and knowledge about hepatosplenic T-cell lymphoma (HSTCL), providing an overview of the clinical features, a description of its pathology and immunophenotypic traits in relation to other lymphomas. In addition, we explore the history of reported cases of hepatosplenic T-cell lymphoma in relation to the possible existence of a causal relationship between infliximab use and HSTCL. The treatments for HSTCL will be briefly addressed. METHODS: A comprehensive literature search using multiple databases was performed. Keyword search phrases including """"lymphoma,"""" """"hepatosplenic T-cell lymphoma,"""" """"Inflammatory bowel disease,"""" """"6-mercaptopurine,"""" and """"infliximab"""" were used in various combinations. In addition references from published papers were reviewed as well. RESULTS: There are over 200 reported cases of HSTCL. Only 22 cases of hepatosplenic T-cell lymphoma are associated with IBD treatment. Clinicians usually reserve immunomodulators and biologics for moderate to severe IBD cases. The ultimate goal of therapy is to control inflammation and therefore allow mucosal healing. IBD patients demonstrating mucosal healing are less likely to undergo surgery and experience complications related to their disease. We manipulate the immune system with corticosteroids, immunomodulators, and biologics, therefore causing bone marrow suppression. With bone marrow suppression, malignant degeneration may begin through selective uncontrolled cell proliferation, initiating HSTCL development in the genetically susceptible. CONCLUSION: Hepatosplenic T-cell lymphoma is a rare disease, often with a poor outcome. With the increasing number of reported cases of HSTCL linked to the use of infliximab, adalimumab, and AZA/6-MP, there appears to be an undeniable association of HSTCL development with the use of these agents. This risk is unquantifiable. When considering the rarity of cases and the multiple complications with uncontrolled disease, however, the benefit of treatment far outweighs the risk.""",1
12280,21122697,An evaluation of alanine transaminase and creatine kinase elevations with the use of ezetimibe in an ambulatory care setting,"""BACKGROUND: Authors evaluating the safety and efficacy of ezetimibe have demonstrated a low occurrence of serious adverse reactions, such as elevations in alanine transaminase (ALT) and/or creatine kinase (CK). This study describes the incidence of ALT and CK elevations among those patients who were prescribed ezetimibe in a large ambulatory care population to further elucidate the safety of ezetimibe in a diverse """"real-world"""" population. METHODS: Adults (?18 years) with at least one prescription for ezetimibe between January 1, 2002, and December 31, 2007, were eligible. All patients with an ALT greater than 3 times the upper limit of normal (3X ULN) and/or CK greater than 3X ULN any time after the first sold date of ezetimibe were identified. Medical records were reviewed by the use of predetermined assessment criteria to further classify patients and determine whether the elevation was possibly related, related, or not related to ezetimibe treatment. RESULTS: There were 4958 patients with a prescription for ezetimibe within the study period. Of these patients, 4332 (87%) had either an ALT or CK drawn. There were 82 patients identified with ALT greater than 3X ULN (n = 44) or with a CK greater than 3X ULN (n = 38). Of 82 patients, 17 (21%) were deemed possibly related to ezetimibe, of which only 5 (0.1%) had no other reasons noted for the elevation. In all cases the ezetimibe was prescribed in combination with a statin. CONCLUSIONS: The incidence of ALT or CK elevations greater than 3X ULN in a large diverse population of patients was rare and similar to placebo rates in other published trials.""",1
12281,21126198,Intravenous acetylcysteine for the treatment of acetaminophen overdose,"IMPORTANCE OF THE FIELD: Acetaminophen is a leading cause of overdose-related hepatotoxicity. Although acetylcysteine prevents or minimizes acetaminophen-induced hepatotoxicity and reduces mortality, some patients presenting with complicated overdose scenarios (massive ingestions or combination or modified-release formulations) may develop toxicity despite administration of recommended dosage regimen. AREAS COVERED IN THIS REVIEW: The article evaluates evidence regarding intravenous acetylcysteine's effectiveness in patients with acute overdoses who receive treatment within 10 h or > 10 h, patients with chronic supratherapeutic ingestions, and those with acetaminophen-induced fulminant hepatic failure. Intravenous and oral acetylcysteine are compared. WHAT THE READER WILL GAIN: A one-size-fits-all approach towards acetylcysteine therapy provides suboptimal care in some patients. High-risk patients are identified. Specific discontinuation criteria are presented. TAKE HOME MESSAGE: The standard intravenous regimen will effectively treat most early-presenting uncomplicated overdoses. Acetylcysteine dosing should be individualized in patients with complicated presentations and in particular situations in which plasma acetaminophen concentrations may be persistently elevated at the end of the infusion or in late presenters. More studies are needed to evaluate the optimal intravenous dosage regimen and the role of oral acetylcysteine in these high-risk patients. Treatment decisions may be aided by consultation with a poison center and/or clinical toxicologist.",1
12282,21127120,Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults,,1
12283,21128314,Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage?,"""Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with anti-infectious agents, list on the top for causes of Drug-Induced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the controversy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data.""",1
12284,21131035,Sickle-cell disease,"""Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.""",1
12285,21134110,Re-appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection,"BACKGROUND AND AIM: De novo hepatitis B virus (HBV)-related hepatitis is a well-known fatal complication following chemo-immunosuppressive therapy in patients with past HBV infection (HB surface antigen and serum HBV DNA negative, but HB core antibody and/or HB surface antibody positive). This research was conducted to evaluate the incidence of and clinical features associated with re-appearance of serum HBV DNA following chemo-immunosuppressive therapy in Japanese patients with past HBV infection. METHODS: This is a retrospective review. Forty-five patients with past HBV infection who had received chemo-immunosuppressive therapy for haematological disease were followed up for >6 months, to determine whether the serum test for HBV changed from negative to positive (i.e. re-appearance of serum HBV DNA following chemo-immunosuppressive therapy). RESULTS: Re-appearance of serum HBV DNA was confirmed in five (20.8%) of the 24 patients who had received treatment regimens containing rituximab, but in none of the 21 patients who had not received treatment regimens containing rituximab (P=0.035). The HBV genotype could be determined in four of the five aforementioned patients, and in all four, HBV genotype C, which is the most prevalent genotype in Japan, was identified. CONCLUSION: This research showed that re-appearance of serum HBV DNA is not rare in Japanese patients treated with chemotherapy regimens containing rituximab, and no other factors related to such re-appearance of serum HBV DNA could be identified. Well-designed clinical studies, including immunological and genetic analyses of the host and of the HBV, are required for further elucidation.",1
12286,21136019,Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies,"""Four phase III studies compared oral rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty (THA or TKA). A pooled analysis of these studies compared the effect of rivaroxaban with enoxaparin on symptomatic VTE plus all-cause mortality and bleeding events, and determined whether these effects were consistent in patient subgroups. Patients (N=12,729) aged >/=18 years and scheduled for elective THA or TKA received rivaroxaban 10 mg once daily or enoxaparin 40 mg once daily or 30 mg every 12 hours. The composite of symptomatic VTE and all-cause mortality, the prespecified primary efficacy endpoint and adjudicated bleeding events were analysed in the day 12+/- 2 active treatment pool. Subgroup analyses of these outcomes were performed over the total treatment period. In the day 12+/- 2 pool, the primary efficacy endpoint occurred in 29/6,183 patients receiving rivaroxaban (0.5%) versus 60/6,200 patients receiving enoxaparin (1.0%; p=0.001). Major bleeding occurred in 21 (0.3%) versus 13(0.2%) patients, p=0.23; major plus non-major clinically relevant bleeding in 176(2.8%) versus 152 (2.5%) patients, p=0.19; and any bleeding in 409 (6.6%) versus 384 (6.2%) patients, p=0.38, respectively. The reduction of symptomatic VTE plus all-cause mortality was consistent across prespecified subgroups (age, gender, body weight, creatinine clearance) in the total treatment period. Compared with enoxaparin regimens, rivaroxaban reduces the composite of symptomatic VTE and all-cause mortality after elective THA or TKA, with a small increase in bleeding, no signs of compromised liver safety and fewer serious adverse events.""",1
12287,21142272,Risk of hepatic events in patients treated with vancomycin in clinical studies: a systematic review and meta-analysis,"""BACKGROUND: Routine surveillance of spontaneous reporting data and subsequent disproportionality analyses have indicated that the use of vancomycin might be associated with an increased risk of hepatic events. OBJECTIVE: To conduct a meta-analysis of published randomized controlled clinical trials (RCTs) to better understand if the use of vancomycin is potentially associated with an increased risk of hepatic events. DATA SOURCES: A comprehensive search and review of published clinical studies indexed in MEDLINE, PubMed, International Pharmaceutical Abstracts and the Cochrane Library from 1950 to June 2010 was conducted. STUDY SELECTION: The inclusion criteria consisted of (i) published RCTs comparing vancomycin with/without other additional treatments to other comparators; and (ii) studies that reported hepatic events. DATA EXTRACTION: The data related to any hepatic events reported in RCTs were extracted and examined. The quality of selected studies was assessed based on the Jadad scale. The effect size was presented as a risk ratio (RR) with a 95% CI and number needed to harm. The pooled RRs were calculated by using both fixed-effects and random-effects models. The impact of publication bias was assessed by funnel plot and the Egger's test. DATA SYNTHESIS: A total of 20 RCTs, including 7419 patients, met the study inclusion criteria and were selected. An increased incidence of hepatic events, specifically elevated serum aminotransferase levels, was observed in patients receiving vancomycin, when compared with other comparators (pooled RR=1.95; 95% CI 1.62, 2.36; p<0.001), but the majority of the events were mild to moderate in nature. No evidence is currently available suggesting that the use of vancomcycin confers a risk of progressive or severe drug-induced liver injury. CONCLUSIONS: Continuous monitoring of hepatic events on a routine basis among patients with the use of vancomycin is suggested.""",1
12288,21143497,Understanding lactic acidosis in paracetamol (acetaminophen) poisoning,"""Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure.""",1
12289,21145803,Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma,"BACKGROUND & AIMS: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. METHODS: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. RESULTS: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)xULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT>/=3xULN. The odds ratio (95% CI) for ALT>/=3xULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT>/=3xULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. CONCLUSIONS: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.",1
12290,21148263,Drug-induced Sweet's syndrome after mitoxantrone therapy in a patient with multiple sclerosis,"We report a 55-year-old male patient with secondary progressive multiple sclerosis who developed an acute febrile syndrome with fever, neutrophilia and tender erythematous plaques and papules on his upper extremities after his fifth mitoxantrone infusion. Infectious, haematological and rheumatological diseases were ruled out, but skin biopsy showed neutrophilic infiltrations in the dermis consistent with Sweet's syndrome. Treatment with oral corticosteroids led to prompt improvement of systemic and cutaneous symptoms. To our knowledge, this is the first report of a patient with Sweet's syndrome after mitoxantrone therapy. Clinicians should be aware of Sweet's syndrome in patients with otherwise unexplained acute febrile illness and erythematous skin rash in association with mitoxantrone therapy. Skin biopsy helped to exclude other diseases and confirmed Sweet's syndrome.",1
12291,21148537,Noncirrhotic portal hypertension and didanosine: a re-analysis,,1
12292,21150835,Drugs for female sexual dysfunction,,1
12293,21165382,Re: Recent case report of clozapine-induced acute hepatic failure,,1
12294,21167499,Valproic acid-associated acute liver failure in children: case report and analysis of liver transplantation outcomes in the United States,"""OBJECTIVE: To determine whether valproic acid (VPA)-associated acute liver failure (ALF; VPA-ALF) explains the poor outcomes after liver transplantation (LT) in children. STUDY DESIGN: Organ Procurement and Transplantation Network data of pediatric patients who underwent LT for VPA-ALF and ALF caused by other drugs (non-VPA-drug-induced acute liver failure [DIALF]) were analyzed. Pre- and post-transplant variables and post-LT survival were compared between VPA-ALF and non-VPA-DIALF. RESULTS: Seventeen children were transplanted for VPA-ALF. Of the 17 children, 82% died within 1 year of LT. Pre- and post-transplant parameters of VPA versus non-VPA-DIALF were comparable with two exceptions. The median alanine aminotransferase level at transplant was remarkably lower in VPA-ALF compared with non-VPA-DIALF (45 versus 1179 IU/L, P = .004). One-year survival probability was worse in VPA-ALF than non-VPA-DIALF (20% versus 69%, P < .0001). Median post-LT survival time for VPA-ALF was 2.8 months. CONCLUSION: Children who underwent LT for VPA-ALF had a significantly lower survival probability than children with non-VPA-DIALF. Current data suggest that VPA-ALF in children represents an """"unmasking"""" of mitochondrial disease. VPA-ALF should be a contraindication for LT, even in the absence of a documented mitochondrial disease.""",1
12295,21168244,[Nodular regenerative hyperplasia: azathioprine-induced hepatotoxicity in a patient with Crohn's disease],"We report the case of a 53-year-old man with Crohn's disease who developed azathioprine-induced nodular regenerative hyperplasia of the liver. The diagnosis was suspected when abnormalities in liver function tests were observed and transabdominal ultrasonography and upper gastrointestinal endoscopy showed signs of portal hypertension. The final diagnosis was established by liver biopsy, showing the characteristic alterations in liver architecture. Outcome was favorable after treatment discontinuation, with complete normalization of liver function tests within a year. The present article describes the incidence and the main clinical characteristics of this adverse effect to thiopurines.",1
12296,21170695,"Efficacy and safety of silexan, a new, orally administered lavender oil preparation, in subthreshold anxiety disorder - evidence from clinical trials","""We review the data on the efficacy and tolerability of silexan, a novel preparation from lavender oil for oral use, in the treatment of anxiety disorders and related condition with particular attention to subthreshold generalized anxiety disorder (GAD). Three randomized, double-blind clinical trials were identified which investigated the efficacy of silexan in subsynromal anxiety disorder (vs. placebo; 10 weeks' treatment), in GAD (vs. lorazepam; 6 weeks), and in restlessness and agitation (vs. placebo; 10 weeks) according to DSM-IV and ICD-10 criteria. All trials assessed the participants' anxiety levels using the Hamilton Anxiety Scale (HAMA). Across all trials 280 patients were exposed to silexan 80 mg/day, 37 were treated with lorazepam 0.5 mg/day and 192 received placebo. Average within group HAMA total scores at baseline ranged between 24.7 and 27.1 points. Patients treated with silexan showed average HAMA total score decreases by between 10.4 ? 7.1 and 12.0 ? 7.2 points at week 6 and by between 11.8 ? 7.7 and 16.0 ? 8.3 points at week 10. In GAD silexan and lorazepam showed comparable HAMA total score reductions (90% CI for mean value difference: -2.3; 2.8 points).""",1
12297,21172265,Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease,"BACKGROUND AND AIMS: We previously reported that IBD patients who are non-responders to thiopurines with preferential shunting of metabolites to hepatotoxic 6-methylmercaptopurine ribonucleotides compared to 6-thioguanine nucleotides can reverse the ratio of 6-MMP/6-TGN and respond to thiopurines with the addition of allopurinol. The objective of this study is to report long term efficacy and safety, along with results for an additional 11 patients. METHODS: Retrospective chart review of patients at the University of Chicago IBD Center treated with allopurinol in addition to thiopurines. RESULTS: Twenty five patients with Crohn's disease or ulcerative colitis were enrolled. Within the first month of therapy 6-TGN metabolite levels increased from a mean of 186.5?17.4 (SE) to 352.8?37.8�pmol/8?10(8) (p=0.0001). Over the same period 6-MMP levels decreased from a mean of 11,966?1697 to 2004?536�pmol/8?10(8) (p<0.0001). The mean daily dosage of prednisone decreased from 19.8?3.8�mg to 5.3?2.7�mg (p=0.03). Thirteen patients have a minimum of one year follow-up. Nine of these thirteen patients have continued on therapy for at least 2�years. All thirteen of these patients continue to be in clinical remission at the last follow-up visit. No patients have had evidence of sustained thrombocytopenia or abnormal liver enzymes. CONCLUSIONS: In AZA/6-MP non-responders with increased 6-MMP/6-TGN ratios, addition of allopurinol continues to demonstrate safety and efficacy for long-term maintenance and steroid-sparing in IBD.",1
12298,21173910,Acute liver injury induced by weight-loss herbal supplements,"We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.",1
12299,21175232,Autoimmune hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab,"Infliximab and adalimumab are anti-tumor necrosis factor (TNF) alpha agents used for treating Crohn's disease. Autoimmune hepatitis (AIH) is a rare complication of treatment with these drugs. We report on a case of AIH in a patient with Crohn's disease treated with infliximab who fully recovered after drug withdrawal. More interestingly, because there were no other treatment options, the patient was then treated with adalimumab without recurrence of the liver disease and with control of the intestinal disease.",1
12300,21177421,Everolimus: a new mammalian target of rapamycin inhibitor for the treatment of advanced renal cell carcinoma,"OBJECTIVE: To review clinical trials and main characteristics of everolimus, with focus on treatment of advanced renal cell carcinoma. DATA SOURCES: Pertinent data were identified primarily through a search of MEDLINE and PubMed (1966-November 2010) using the primary search terms everolimus, RAD001, renal cell carcinoma, and mTOR inhibitors. STUDY SELECTION AND DATA EXTRACTION: Studies evaluating the safety and efficacy of everolimus in patients with cancer were evaluated, including Phase 1, 2, and 3 trials. Preference was given to Phase 2 and 3 studies evaluating use of everolimus in patients with renal cell carcinoma. DATA SYNTHESIS: Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor approved for the management of patients with advanced renal cell carcinoma who progressed on tyrosine kinase inhibitor therapy. Actions of everolimus within the mTOR pathway result in decreased protein synthesis and cell cycle arrest, as well as decreased angiogenesis. A usual starting dose for patients with renal cell carcinoma is 10 mg daily. Everolimus undergoes extensive hepatic metabolism, primarily through the CYP3A4 isoenzyme, which predisposes it to drug interactions with inducers and inhibitors of this enzyme. Most commonly reported adverse events associated with everolimus include anemia, hyperglycemia, hypercholesterolemia, mucositis, fatigue, and rash. Approval of everolimus was based on the results of a Phase 3 trial that demonstrated an increase in median progression-free survival by 2.1 months in patients receiving everolimus therapy as compared to placebo. The drug was recently added to the National Comprehensive Cancer Network guidelines as a treatment option for patients with advanced renal cell carcinoma who have progressed on tyrosine kinase therapy. CONCLUSIONS: Based on a review of the currently available literature, everolimus provides a safe and efficacious treatment option for patients with renal cell carcinoma who have progressed on treatment with sunitinib and/or sorafenib.",1
12301,21181011,Antituberculosis drug-induced hepatotoxicity: a comparison between patients with and without human immunodeficiency virus seropositivity,"""INTRODUCTION: The prevalence and risk factors for rifampin, isoniazid and pyrazinamide hepatotoxicity were evaluated in HIV-infected subjects and controls. METHODS: Patients with tuberculosis (30 HIV positive and 132 HIV negative), aged between 18 and 80 years-old, admitted to hospital in Brazil, from 2005 to 2007, were selected for this investigation. Three definitions of hepatotoxicity were used: I) a 3-fold increase in the lower limit of normal for alanine-aminotransferase (ALT); II) a 3-fold increase in the upper limit of normal (ULN) for ALT, and III) a 3-fold increase in the ULN for ALT plus a 2-fold increase in the ULN of total bilirubin. RESULTS: In groups with and without HIV infection the frequency of hepatotoxicity I was 77% and 46%, respectively (p < 0.01). Using hepatotoxicity II and III definitions no difference was observed in the occurrence of antituberculosis drug-induced hepatitis. Of the 17 patients with hepatotoxicity by definition III, 3 presented no side effects and treatment was well tolerated. In 8 (36.4%) out of 22, symptoms emerged and treatment was suspended. Alcohol abuse was related to hepatotoxicity only for definition I. CONCLUSIONS: Depending on the definition of drug-induced hepatitis, HIV infection may or may not be associated with hepatotoxicity. The impact that minor alterations in the definition had on the results was impressive. No death was related to drug-induced hepatotoxicity. The emergence of new symptoms after initiating antituberculosis therapy could not be attributed to hepatotoxicity in over one third of the cases.""",1
12302,21186976,Buprenorphine-induced elevated liver enzymes in an adolescent patient,,1
12303,21189918,Therapeutic misadventure with paracetamol in children,"""Paracetamol (acetaminophen), though considered a safe, """"over the counter"""" analgesic and antipyretic, can cause liver injury with overdose. Therapeutic misadventure is a unique problem where the existing nomogram used for acute poisoning is not applicable. In this context, early initiation of N-acetylcysteine even before a biochemical evidence of liver injury may be beneficial. A series of 6 children with this type of paracetamol overdose are presented here to increase the awareness and understanding of this problem since no such data is available from India.""",1
12304,21194596,Acute hepatitis associated with the use of levofloxacin,"""BACKGROUND: Levofloxacin is a fluoroquinolone used globally to treat respiratory, skin, and genitourinary tract infections. It is generally well tolerated and there is a very low risk for liver injury in patients taking this antibiotic. OBJECTIVE: We report an acute case of hepatitis following treatment with levofloxacin for pneumonia. CASE SUMMARY: A 77-year-old white male (height, 162 cm; weight, 58 kg) with chronic bronchitis presented to the emergency department of the Hospital Curry Cabral, Lisbon, Portugal, with respiratory difficulty and productive cough. The patient had a history of chronic bronchitis, arterial hypertension, hypercholesterolemia, and benign prostatic hyperplasia, and was being treated with salmeterol 50 ?g plus fluticasone 250 ?g BID, and amlodipine 5 mg, simvastatin 20 mg, alfuzosin 10 mg, and finasteride 5 mg once daily. Initially, the patient refused admission and was sent home, medicated with levofloxacin 500 mg once daily (single dose) for pneumonia and acetaminophen 1 g (as needed, maximum TID) if axillary temperature exceeded 38.0?C (100.4?F). Three days later, the patient returned for a follow-up visit, and despite clinical and radiologic improvement, blood tests revealed a slight aggravation of anemia. On the seventh day of treatment with levofloxacin, the patient showed an elevation of transaminases. The temporal relation between the use of levofloxacin and the liver injury, the exclusion of other causes of hepatitis, and a compatible liver biopsy (conducted 14 days after identification of hepatitis) was consistent with the diagnosis of levofloxacin-associated hepatotoxicity. Levofloxacin treatment was stopped and the patient made a full recovery. The Naranjo Adverse Drug Reaction Probability Scale score for this association was """"probable"""" (score 7) and the Roussel Uclaf Causality Assessment Method Scale score was """"highly probable"""" (score 9). Unlike the 5 reported cases in the literature, this is the only case in which both a liver biopsy was performed in the course of the disease and the patient survived. CONCLUSION: The acute hepatitis observed in this elderly patient was probably associated with the administration of levofloxacin.""",1
12305,21198946,Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic,"Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost-effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long-term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non-invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.",1
12306,21199516,Changing etiologies and outcomes of acute liver failure: A perspective from Japan,"Acute liver failure in Japan usually consists of fulminant hepatitis (FH) due to viral infection, autoimmune hepatitis and drug-allergy-induced liver injury. The annual incidence of FH was estimated at 429 cases in 2004. FH is classified into acute or subacute type, and the prognosis of the latter is poor. Hepatitis B virus (HBV) is the most frequently identifiable agent that causes FH in Japan. Transient HBV infection is more prevalent in the acute than subacute type, whereas the frequency of HBV carriers is greater in the subacute type. FH due to HBV reactivation from resolved hepatitis B has been increasingly observed in patients with malignant lymphoma treated with rituximab and corticosteroid combination therapy. The prognosis is poor in HBV carriers with acute exacerbation, especially in patients with HBV reactivation from resolved hepatitis B. Despite careful investigation, the etiology is still unknown in 16% and 39% of the acute and subacute type of FH, respectively. Autoimmune hepatitis and drug-allergy-induced liver injury are found in 7% and 10%, respectively, and are more frequently observed in the subacute type of FH. Living donor liver transplantation is now the standard care for individuals with poor prognosis. Artificial liver support with plasmapheresis and hemodiafiltration plays a central role while waiting for a donor liver or for the native liver to regenerate. Further research is necessary to identify the causes of unknown origin. In addition, to improve the prognosis of FH, it is necessary to establish treatment modalities that are effective for liver regeneration.",1
12307,21200420,Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial,"""BACKGROUND: Cutaneous leishmaniasis (CL) is treated with parenteral drugs for decades with decreasing rate cures. Miltefosine is an oral medication with anti-leishmania activity and may increase the cure rates and improve compliance. METHODOLOGY/PRINCIPAL FINDINGS: This study is a randomized, open-label, controlled clinical trial aimed to evaluate the efficacy and safety of miltefosine versus pentavalent antimony (Sb(v)) in the treatment of patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients were enrolled in the trial; 60 were assigned to receive miltefosine and 30 to receive Sb(v). Six months after treatment, in the intention-to-treat analyses, the definitive cure rate was 53.3% in the Sb(v) group and 75% in the miltefosine group (difference of 21.7%, 95% CI 0.08% to 42.7%, p?=?0.04). Miltefosine was more effective than Sb(v) in the age group of 13-65 years-old compared to 2-12 years-old group (78.9% versus 45% p?=?0.02; 68.2% versus 70% p?=?1.0, respectively). The incidence of adverse events was similar in the Sb(v) and miltefosine groups (76.7% vs. 78.3%). Vomiting (41.7%), nausea (40%), and abdominal pain (23.3%) were significantly more frequent in the miltefosine group while arthralgias (20.7%), mialgias (20.7%) and fever (23.3%) were significantly more frequent in the Sb(v) group. CONCLUSIONS: This study demonstrates that miltefosine therapy is more effective than standard Sb(v) and safe for the treatment of CL caused by Leishmania braziliensis in Bahia, Brazil. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT00600548.""",1
12308,21204807,HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients,"Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 with carbamazepine-induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA-B*1508, HLA-B*1511, or HLA-B*1521, which are members of the HLA-B75 type along with HLA-B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA-B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA-B*1502 carriers, four patients had HLA-B*1511. Our data suggest that HLA-B*1511, a member of HLA-B75, is a risk factor for carbamazepine-induced SJS/TEN in Japanese.",1
12309,21207059,N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia,"Hyperammonemia occurs mainly in patients with branched-chain organic acidemias such as propionic, methylmalonic, and isovaleric acidemias. Its pathophysiological process is mainly via the competitive inhibition of N-acetylglutamate synthetase. Oral carglumic acid (N-carbamylglutamate) administration can correct hyperammonemia in neonates with propionic and methylmalonic acidemias, thus avoiding dialysis therapy. Isovaleric acidemia is an autosomal recessive disease of leucine metabolism due to deficiency of isovaleryl-CoA dehydrogenase. For the first time, we report a neonate with isovaleric acidemia, whose plasma ammonia concentration dropped dramatically after one oral load of carglumic acid. This experience suggests that carglumic acid could be considered for acute hyperammonemia resulting from isovaleric acidemia. However, trials with more patients are needed.",1
12310,21212744,Ella: a new emergency contraceptive,,1
12311,21219501,The health and social effects of drinking water-based infusions of kava: a review of the evidence,"""ISSUES: To review the evidence on the health and social effects of drinking kava; a water-based infusion of the roots of the kava plant. APPROACH: Included all empirical studies of the effects of kava published 1987-2008 reporting health and social outcomes. Evidence appraised on study design (level of evidence) and standard epidemiological criteria for causality. KEY FINDINGS: Causality indicated: scaly skin rash, weight loss, raised Gamma Glutamyl Transpeptidase liver enzyme levels, nausea, loss of appetite or indigestion; Association indicated but causality unclear: red sore eyes, impotence or loss of sexual drive, self-reported poor health, raised cholesterol, and loss of time and money, low motivation and 'slow/lazy' days following use, reduced alcohol consumption and related violence; Association hypothesised: fits or seizures, Melioidosis, Ischaemic Heart Disease, protective effects for cancer; No association indicated: cognitive performance; No association suggested: cognitive impairment, liver toxicity or permanent liver damage, other pneumonia; No association hypothesised: hallucinations. IMPLICATIONS: The health and social implications of chronic kava drinking can be significant for individuals and communities, although most effects of even heavy consumption appear to be reversible when consumption is stopped. CONCLUSION: An Australia-wide ban on commercial importation of kava has been in place since mid-2007, but there is no published literature to date on the impact of the ban.""",1
12312,21220090,Glucosamine and chondroitin sulfate,"Glucosamine and chondroitin sulfate, components of normal cartilage that are marketed as dietary supplements in the United States, have been evaluated for their potential role in the treatment of osteoarthritis. Due to claims of efficacy, increased prevalence of osteoarthritis, and a lack of other effective therapies, there has been substantial interest in using these dietary supplements as therapeutic agents for osteoarthritis. Though pharmacokinetic and bioavailability data are limited, use of these supplements has been evaluated for management of osteoarthritis symptoms and modification of disease progression. Relevant clinical trial efficacy and safety data are reviewed and summarized.",1
12313,21220617,Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy,,1
12314,21225098,"Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial","""This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.""",1
12315,21234410,Propylthiouracil-induced acute liver failure: role of liver transplantation,"Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death.",1
12316,21242741,A 52-week study of gabapentin enacarbil in restless legs syndrome,"""OBJECTIVES: This open-label, multicenter, 52-week extension study (NCT00333359) assessed the long-term safety and efficacy of gabapentin enacarbil in subjects with moderate-to-severe primary restless legs syndrome (RLS). METHODS: Subjects had completed one of 4 randomized, double-blind parent studies (XP052/XP053/XP081/XP083). Gabapentin enacarbil 1200 mg was administered once daily at 5 pm; dose adjustments to 600 or 1800 mg were permitted based on investigator judgment. Safety assessments included adverse events (AEs), vital signs, clinical laboratory tests, and electrocardiograms. Efficacy evaluations included the International Restless Legs Scale total score and the investigator-rated Clinical Global Impression-Improvement scale, at week 52 last observation carried forward. RESULTS: The safety population comprised 573 subjects; 386 (67.4%) completed the study. Treatment-emergent AEs were reported by 80.1% of subjects and led to withdrawal in 10.3% of subjects; most (67.7%) were mild or moderate in intensity. The most common AEs were somnolence and dizziness (19.7% and 11.5% of subjects). Twenty subjects (3.5%) reported serious AEs; one subject died (fall, 25 days after stopping gabapentin enacarbil, judged not treatment related). No serious AE occurred in more than 1 subject. No clinically relevant changes were reported in vital signs, laboratory parameters, or electrocardiograms. At week 52 last observation carried forward, the mean (SD) change from parent study baseline in International Restless Legs Scale total score was -15.2 (8.85 [parent study baseline score, 23.2 (5.03)]), and 84.8% of subjects were Clinical Global Impression-Improvement responders (""""much improved"""" or """"very much improved""""). CONCLUSIONS: Gabapentin enacarbil was generally safe and well tolerated and improved RLS symptoms in subjects with moderate-to-severe primary RLS for up to 64 weeks of treatment.""",1
12317,21244693,Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy,"BACKGROUND: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. METHODS: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. RESULTS: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 +/- 4%, 31 +/- 5%, and 32 +/- 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 +/- 4%) compared to NB90 MT (34 +/- 5%, p = 0.026) and to no consolidation (35 +/- 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. CONCLUSIONS: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.",1
12318,21245435,Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study,"PURPOSE: Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity. PATIENTS AND METHODS: Patients with independently confirmed PTCL who progressed following ? 1 line of prior therapy received pralatrexate intravenously at 30 mg/m(2)/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%). CONCLUSION: To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.",1
12319,21248613,Thinking beyond the obvious: hepatotoxicity secondary to idiosyncratic depakote toxicity,"""Depakote-induced hepatotoxicity has been well established as an adverse effect, and periodic monitoring of drug level is often required. Depakote-induced hepatotoxicity mostly occurs at supratherapeutic drug level. Rarely, an idiosyncratic response is triggered, and hepatotoxicity can occur at the therapeutic drug level mostly in chronic users. Here, we describe a rare case of idiosyncratic depakote-induced hepatotoxicity. A 25-year-old female with non-insulin-dependent diabetes mellitus, hypothyroidism, seizure disorder, and Dandy Walker Syndrome presented with an unwitnessed seizure and altered mental status. The patient's medication list included zonisamide, depakote, and synthroid. She was noted to be lethargic, disoriented, nonverbal, but awake. An arterial blood gas examination showed severe anion gap metabolic acidosis. Blood work was consistent with hepatitis, hyperammonemia, thrombocytopenia, and coagulopathy. The Depakote level was therapeutic. Head computed tomography and liver ultrasound results were not significant. After ruling out all other causes and seeing improvement of parameters after the drug was discontinued, idiosyncratic depakote toxicity was diagnosed. Based on the patient's rapid improvement; idiosyncratic valproate toxicity was confirmed. This case signifies the importance of recognizing, diagnosing, and treating depakote toxicity in chronic users who have no other explanation for their symptomatology.""",1
12320,21252843,Denosumab for bone metastases,,1
12321,21256454,Treatment of patients with essential tremor,"Essential tremor is a common movement disorder. Tremor severity and handicap vary widely, but most patients with essential tremor do not receive a diagnosis and hence are never treated. Furthermore, many patients abandon treatment because of side-effects or poor efficacy. A newly developed algorithm, based on the logarithmic relation between tremor amplitude and clinical tremor ratings, can be used to compare the magnitude of effect of available treatments. Drugs with established efficacy (propranolol and primidone) produce a mean tremor reduction of about 50%. Deep brain stimulation (DBS) in the thalamic nucleus ventrointermedius or neighbouring subthalamic structures reduces tremor by about 90%. However, no controlled trials of DBS have been done, and the best target is still uncertain. Better drugs are needed, and controlled trials are required to determine the safety and efficacy of DBS in the nucleus ventrointermedius and neighbouring subthalamic structures.",1
12322,21261721,Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis,"""BACKGROUND AND AIM: Antituberculosis drugs, isoniazid and rifampicin, in combination, are known to develop drug-induced hepatotoxicity (DIH). A higher risk of DIH during antituberculosis treatment (ATT) has been reported in the Indian subcontinent compared to its Western counterparts. The role of genetic factors in a higher incidence of ATT hepatotoxicity in the Indian population is still unclear. The present study was aimed at investigating the role of the N-acetyltransferase2 (NAT2) and cytochrome P4502E1 (CYP2E1) gene polymorphisms in ATT hepatotoxicity. METHODS: The study population included 218 pulmonary tuberculosis patients who were started on ATT and followed up for the occurrence of ATT-induced hepatitis. The genetic polymorphisms of the NAT2 and CYP2E1 genes were studied by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The occurrence of DIH was 18.8% (41/218). There was a higher prevalence of NAT2 slow-acetylator genotypes in DIH (70.73%) compared to non-DIH (44.63%; P < 0.05). The frequency of the NAT2*5/*7 and NAT2*6/*7 genotypes was significantly higher in DIH than non-DIH (19.51% vs 6.78%, and 19.51% vs 5.08%). No association of the CYP2E1 RsaI polymorphism could be demonstrated with DIH. However, the DraI C/D genotype of the CYP2E1 gene was mostly prevalent in DIH (85.37%), compared to non-DIH (64.41%) (P < 0.05). Slow-acetylator status and the CYP2E1 C/D or C/C genotype together showed a higher frequency in DIH (65.85%) compared to non-DIH (28.81%) (P < 0.0001). CONCLUSION: The study demonstrates for the first time a possible association between the DraI polymorphism of the CYP2E1 gene and the risk of ATT hepatotoxicity. The genotyping of the NAT2 and CYP2E1 genes could possibly identify the groups at highest risk of developing ATT-induced hepatitis prior to medication.""",1
12323,21263458,Hepatotoxicity related to antirheumatic drugs,"Antirheumatic agents are among commonly used drugs associated with adverse hepatic reactions. Sulfasalazine and azathioprine are among the most important causes of acute hepatotoxicity. Because such a large number of people take NSAIDs, even the rare occurrence of hepatotoxicity from these agents might contribute substantially to the total burden of drug-induced liver disease. A wide spectrum of hepatotoxic effects is described with antirheumatic drugs. Studies investigating genetic susceptibility to diclofenac hepatotoxicity have expanded our understanding of the potential drug-specific, class-specific and general factors involved in its pathogenesis, and methotrexate-associated liver disease demonstrates the interaction between drug, host and environmental factors that determines the likelihood and magnitude of liver disease. Infliximab therapy is associated with typical drug-induced autoimmune hepatitis. Although validated causality assessment methods have been used to objectively assess the strength of the association between a drug and a clinical event, in practice the diagnosis of drug-induced liver injury (DILI) involves a clinical index of suspicion, pattern recognition, the establishment of a temporal relationship between drug exposure and the adverse event, and the exclusion of alternative explanations for the clinical presentation. Detailed understanding of genetic and environmental factors underlying an individual's susceptibility would enable risk reduction and potentially primary prevention of hepatotoxicity.",1
12324,21269234,The impact of biologic response modifiers on hepatitis B virus infection,"INTRODUCTION: The biologic response modifiers are a diverse group of medications that have emerged over the last decade. They target pro-inflammatory cytokines or cell surface molecules that drive illnesses such as rheumatoid arthritis. Despite the greater control afforded they have also ushered in a new spectrum of side effects. As the same immunologic machinery that helps control infections such as HBV contributes to the pathogenesis of rheumatologic diseases, persistence or reactivation of the virus remains an evolving concern. AREAS COVERED: A systemic literature review was performed using the PubMed and Medline databases (1996 to January 2010) searching for the index term 'Hepatitis B' combined with the terms 'tumor necrosis factor', 'B cell', 'rituximab', 'IL-1', 'anakinra', 'IL-6', 'tocilizumab', 'CTLA-4', and 'abatacept'. All relevant articles in English were reviewed and secondary references of interest were also retrieved. This paper addresses the role of the various cytokines and cluster of differentiation molecules in controlling HBVinfection and the currently known effect that the biologic response modifiers have on viral control by the host immune response. EXPERT OPINION: The risk of HBV reactivation is greatest in HBsAg positive patients. These patients should start antiviral therapy one week before receiving a biologic response modifier. The risk of HBV reactivation in HBsAg negative patients appears very low but when HBsAb titers are low use of rituximab or TNF-? antagonists may increase the risk of reactivation.",1
12325,21272804,Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease,"Thiopurines represent an effective and widely used immunosuppressant in the therapeutic armamentarium of inflammatory bowel disease. However up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32%. Veno-occlusive disease, peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia have all been described with thiopurines. Recent trials of 6-tioguanine, although successful in patients with allergies to azathioprine or mercaptopurine, have been compromised by increased hepatotoxicity, either veno-occlusive disease or nodular regenerative hyperplasia. We describe a report of nodular regenerative hyperplasia in a Crohn's disease patient associated with 6-mercaptopurine therapy and have reviewed the management and the literature regarding this complication. Our report strengthens the importance of further safety studies to evaluate the etiology, prevalence, risk factors and screening modalities for hepatotoxicity, in particular of nodular regenerative hyperplasia, in patients treated with thiopurines for inflammatory bowel disease.",1
12326,21280009,Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series,"""OBJECTIVE: To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS: Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS: Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION: Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.""",1
12327,21281438,Chewing khat and chronic liver disease,,1
12328,21283930,[Ferrous sulfate: acute poisoning with a frequent use drug],"The iron is the main component of hemoglobin and is also part of myoglobin and enzymes. Its deficit is the most common cause of nutritional anemia in humans. The use of iron salts is very common in children, because they are indicated for prophylaxis and treatment of iron deficiency anemia. The availability in households and the emergence of flavored formulations that promote adherence to treatment, greatly assist in this type of poisoning. Usually, the overdose is considered a low hazard, because it is a mineral supplement added in many of the baby food. Iron in free state is able of producing toxicity, disrupting multiple cellular processes by catalyzing redox reactions with lipid peroxidation and free radical formation. We report a case of serious toxicity by iron salts, in which early intervention and management with specific chelator, allowed a favorable evolution.",1
12329,21288078,Fidaxomicin versus vancomycin for Clostridium difficile infection,"""BACKGROUND: Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection. METHODS: Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence). RESULTS: A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non?North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. CONCLUSIONS: The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non?North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)""",1
12330,21291469,Phencyclidine: a 5-year retrospective review from the New York City Medical Examiner's Office,"We report here a 5-year retrospective review of autopsy cases from the New York City Medical Examiner's Office that demonstrated phencyclidine (PCP) in the blood. There were a total of 138 cases. There were 52 deaths because of mixed drug intoxication: the blood PCP concentrations in these cases ranged from <1 to 598 ng/mL. There were 80 violent deaths in which PCP was quantified in the blood but was unrelated to the cause of death. There were five nonviolent deaths in which PCP exclusively was detected. In four of these, there were preexisting medical conditions that could also have contributed to death. In these, the highest PCP concentration was 361.3 ng/mL, a concentration lower than seven of the individuals in our violent death category. This suggests that lower concentrations may be fatal with comorbid conditions.",1
12331,21294203,"A double-blind, placebo-controlled investigation of the effects of Passiflora incarnata (passionflower) herbal tea on subjective sleep quality","Passiflora incarnata is a traditional herbal sedative, anxiolytic and a popular sleep aid used for the treatment of sleep disturbance. Several controlled experiments have demonstrated enhanced sleep in laboratory animals, but clinical trials in humans are lacking. The aim of the present study was to investigate the efficacy of Passiflora incarnata herbal tea on human sleep, as measured using sleep diaries validated by polysomnography (PSG). This study featured a double-blind, placebo-controlled, repeated-measures design with a counterbalanced order of treatments (passionflower vs placebo tea), separated by a 1?week 'washout' period. Forty-one participants (18-35 years) were exposed to each treatment for a week, whereby they consumed a cup of the tea and filled out a sleep diary for 7?days, and completed Spielberger's state-trait anxiety inventory on the seventh morning. Ten participants also underwent overnight PSG on the last night of each treatment period. Of six sleep-diary measures analysed, sleep quality showed a significantly better rating for passionflower compared with placebo (t(40)?=?2.70, p?<?0.01). These initial findings suggest that the consumption of a low dose of Passiflora incarnata, in the form of tea, yields short-term subjective sleep benefits for healthy adults with mild fluctuations in sleep quality.",1
12332,21296403,"Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial","""BACKGROUND: Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. METHODS: Patients (aged >/=18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction >/=4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0.3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. FINDINGS: 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1.55 [95% CI 1.10-2.19]; p=0.0129) and 10 mg/kg (167 [58%], 1.83 [1.30-2.59]; p=0.0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1.51 [1.07-2.14]; p=0.0189) and 10 mg/kg (169 [58%], 1.71 [1.21-2.41]; p=0.0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1.38 [0.93-2.04]; p=0.1064) and 10 mg/kg (236 [81%], 1.62 [1.09-2.42]; p=0.0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1.68 [1.15-2.47]; p=0.0078) and 10 mg/kg (231 [80%], 1.74 [1.18-2.55]; p=0.0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. INTERPRETATION: Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. FUNDING: Human Genome Sciences and GlaxoSmithKline.""",1
12333,21298607,Pantoprazole induces severe acute hepatitis,"A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole.",1
12334,21300924,Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma,"PURPOSE: We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma. PATIENTS AND METHODS: In this open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with ? 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability. RESULTS: All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses [CR] and five partial responses [PR]). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue. CONCLUSION: Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted.",1
12335,21303383,Baclofen effect related to liver damage,,1
12336,21304237,Steroid and ursodesoxycholic Acid combination therapy in severe drug-induced liver injury,"""BACKGROUND: Drug-induced liver injury (DILI) is the leading cause of acute severe liver disease in Western countries. Treatment strategies for DILI are still not well defined. AIM: We studied the safety and outcomes of steroid/ursodesoxycholic acid (UDCA) combination therapy in DILI patients. PATIENTS, MATERIALS AND METHODS: 15 consecutive patients with severe DILI were analyzed for clinical, biochemical and histological data. Nine patients were treated with a steroid step-down therapy with reduction of the daily dose over several weeks; 6 patients received a steroid pulse therapy for 3 days. UDCA was administered for several weeks in both groups. RESULTS: Patients without histological signs of preexistent liver damage (n = 10) showed the most favorable clinical course. Bilirubin and serum transaminases dropped to <50% of peak values within 2 weeks, and normalized within 4-8 weeks. In contrast, patients with positive autoimmune antibodies (anti-nuclear antibodies and/or soluble liver antigen) and/or histological features of chronic hepatitis (n = 3) exhibited a slower reduction in bilirubin and serum transaminase levels. These patients were given immunosuppressants (steroids, azathioprine) for a further 6 months. CONCLUSION: Treatment of severe DILI with corticosteroids (both pulse and step-down therapy) and UDCA appears to be safe, and leads to a more rapid reduction in bilirubin and transaminases after DILI.""",1
12337,21304447,Drugs for migraine,,1
12338,21306565,Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population,"Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA-B*1502 and carbamazepine-induced SJS/TEN has been identified in Chinese and Thai. Although three of seven cases with HLA-B*1502 have been reported in LTG-induced SJS/TEN so far, the relationship between HLA-B*1502 and LTG-induced SJS/TEN needs further investigation. It is also unclear whether there is a specific genetic marker associated with LTG-induced MPE in Chinese. In this study, we genotyped 43 Han Chinese patients treated with LTG (14 cases with LTG-induced cADRs and 29 LTG-tolerant controls), using PCR-SSP for HLA-B*1502 testing and low-resolution genotyping, as well as sequencing for four-digit genotyping. The two cases with SJS were negative for HLA-B*1502, with B1301/1301 and 4601/5610, respectively. Combining the data with previous studies, there was no significant difference in the frequency of subjects with HLA-B*1502 between the LTG-induced SJS/TEN group and the LTG-tolerant group (p = 0.08, OR 4.23, 95% CI 0.94-18.97). In the MPE group, only one was positive for HLA-B*1502. There was no significant difference in the frequency of a specific HLA-B allele between the MPE group and the LTG-tolerant group either. In this study, no significant association between HLA-B*1502 and LTG-induced SJS or MPE was found. Given the small sample size and only HLA-B locus genotyping, further large-scale studies are required to explore genetic associations with LTG-induced cADRs.",1
12339,21310551,"Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial","""Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double-blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow back method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P=.02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P=.02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.""",1
12340,21314468,Unexpected severe hepatotoxicity of ciprofloxacine: two case reports,"Ciprofloxacin is a fluoroquinolone antibiotic that has a relatively low rate of occurence of adverse side effects. However, increasing evidences suggest that ciprofloxacin may cause unexpected severe liver damage. Especially, the risk of hepatotoxicity is significantly higher in elderly men receiving drug for a long time. In this article, 2 cases of unexpected severe hepatoxicity of ciprofloxacin are presented.",1
12341,21315714,Correcting a misrepresentation of hypervitaminosis A attributed to Herbalife product consumption,,1
12342,21320923,Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1,"""BACKGROUND: Limited data compare once-daily options for initial therapy for HIV-1. OBJECTIVE: To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN: A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING: 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS: Antiretroviral-naive patients. INTERVENTION: Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine. MEASUREMENTS: Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS: 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF-emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine. LIMITATIONS: Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION: Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine. PRIMARY FUNDING SOURCE: National Institutes of Health.""",1
12343,21327704,Drug-induced autoimmune-like hepatitis,"The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.",1
12344,21330679,Febuxostat for treatment of chronic gout,"PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, and safety of febuxostat are reviewed. SUMMARY: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase for the management of hyperuricemia in patients with gout. The ability of febuxostat to decrease serum uric acid production through selective inhibition of enzyme xanthine oxidase has been established in short-term Phase II and III clinical trials and long-term open-label studies. Clinical studies have revealed that febuxostat lowers serum uric acid levels more potently than allopurinol while having minimal effects on other enzymes associated with purine and pyrimide metabolism. The most frequent adverse events reported in clinical trials with febuxostat were liver function abnormalities, nausea, arthralgias, and rash. More cardiovascular thromboembolic events occurred in randomized trials in patients treated with febuxostat. Although a causal relationship has not been established, patients should be monitored for signs and symptoms of myocardial infarction and stroke. Febuxostat is available as 40- and 80-mg tablets. The recommended starting dosage is 40 mg orally once daily. If serum uric acid concentrations are not less than 6 mg/dL after two weeks, the dosage can be increased to 80 mg orally once daily. Dosage adjustments are not needed in elderly patients or patients with mild or moderate renal or hepatic impairment. CONCLUSION: Febuxostat is efficacious as a second-line therapy in lowering serum uric acid levels in patients with gout. Febuxostat may be an alternative for patients with gout who are unable to take allopurinol due to hypersensitivity, intolerance, or lack of efficacy.",1
12345,21333390,[Recurrent hepatocellular lesion due to alfuzosin],,1
12346,21337649,Phytochemical fingerprinting to thwart black cohosh adulteration: a 15 Actaea species analysis,"""INTRODUCTION: The popular use of black cohosh products (Actaea racemosa L., syn. Cimicifuga racemosa L.) is growing as the demand for alternatives to estrogen therapy has increased. Critical to safe use is the assurance of unadulterated, high-quality products. Questions have been raised about the safety of black cohosh due to cases of liver toxicity in patients who reported taking it; subsequent evaluation found some products to be adulterated with other related herbal species. Correct plant species identification is a key first step for good manufacturing practices of safe black cohosh products. OBJECTIVES: To develop analytical methods which distinguish black cohosh from other species (American and Asian) of Actaea increasingly found as adulterants in commercially available black cohosh products. MATERIAL AND METHODS: Fifteen species of Actaea were collected from North America and Asia, and the phytochemical fingerprints of these samples were established using HPLC-PDA and LC-MS techniques. RESULTS: The HPLC and LC-MS fingerprints for polyphenols and triterpene glycosides revealed distinct patterns that make black cohosh clearly distinguishable from most other species of Actaea. Two marker compounds, cimifugin and cimiracemoside F, were found to be important to distinguish black cohosh from most Asian species of Actaea. Formononetin was not found from either Asian or American species of Actaea. CONCLUSIONS: Phytochemical fingerprinting is a practical, reliable method for authenticating black cohosh and distinguishing it from other species of Actaea increasingly found as adulterants in commercially available black cohosh products. This should facilitate the continued development of high-quality, unadulterated black cohosh products.""",1
12347,21349718,Progressive encephalopathy with cerebral oedema and infarctions associated with valproate and diazepam overdose,"Valproic Acid (VPA) in overdose is known to cause encephalopathy with or without cerebral odema, hyperammonaemia, hepatotoxicity, bone marrow suppression and non gap acidosis. Most of these conditions are reversible. We report a 45-year-old man who suffered permanent disability from the non reversible effects of cerebral odema and infarctions associated with Valproate overdose which would have been aggravated by Diazepam. This patient's presentation emphasizes the role of early detection and therapy of cerebral odema in Valproate and Diazepam overdose.",1
12348,21353271,"A randomised controlled clinical trial on the safety of co-administration of albendazole, ivermectin and praziquantel in infected schoolchildren in Uganda","Integrated chemotherapy of neglected tropical diseases (NTD) through mass drug administration given as a single dose would increase treatment coverage and cost-effectiveness. This study reports on the safety of a combination of albendazole, ivermectin and praziquantel in the treatment of lymphatic filariasis (LF), schistosomiasis and soil-transmitted helminthiasis (STH) in infected children. In this randomised, controlled, single-blinded clinical trial conducted in 235 primary school children aged 5-18 years in Yumbe District in Northern Uganda, the triple combination therapy was compared with the current NTD programme regimen. Liver function testing was performed for all children who received combined therapy. The study included 48 children with LF alone, 60 children with schistosomiasis (Schistosoma mansoni), 41 children with STH, 49 children with schistosomiasis + LF and 37 children with all three types of infection. Children were closely monitored by a paediatrician for any adverse reactions for 7 days. No serious adverse events were experienced. However, 4 of 18 children in the test group and 2 of 3 children in the control group who did not report any ill conditions before treatment developed adverse drug reactions. The combined and conventional therapies were found to be equally safe. The efficacies of both therapies were comparable and satisfactory. [ClinicalTrials.gov identifier: NCT01050517].",1
12349,21358399,Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review,"OBJECTIVES: The aims of this review are to summarize the definitions, causes, and clinical course as well as the current understanding of the genetic background, mechanism of disease, and therapy of toxic epidermal necrolysis and Stevens-Johnson syndrome. DATA SOURCES: PubMed was searched using the terms toxic epidermal necrolysis, Stevens-Johnson syndrome, drug toxicity, drug interaction, and skin diseases. DATA SYNTHESIS: Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute inflammatory skin reactions. The onset is usually triggered by infections of the upper respiratory tract or by preceding medication, among which nonsteroidal anti-inflammatory agents, antibiotics, and anticonvulsants are the most common triggers. Initially the diseases present with unspecific symptoms, followed by more or less extensive blistering and shedding of the skin. Complete death of the epidermis leads to sloughing similar to that seen in large burns. Toxic epidermal necrolysis is the most severe form of drug-induced skin reaction and includes denudation of >30% of total body surface area. Stevens-Johnson syndrome affects <10%, whereas involvement of 10%-30% of body surface area is called Stevens-Johnson syndrome/toxic epidermal necrolysis overlap. Besides the skin, mucous membranes such as oral, genital, anal, nasal, and conjunctival mucosa are frequently involved in toxic epidermal necrolysis and Stevens-Johnson syndrome. Toxic epidermal necrolysis is associated with a significant mortality of 30%-50% and long-term sequelae. Treatment includes early admission to a burn unit, where treatment with precise fluid, electrolyte, protein, and energy supplementation, moderate mechanical ventilation, and expert wound care can be provided. Specific treatment with immunosuppressive drugs or immunoglobulins did not show an improved outcome in most studies and remains controversial. The mechanism of disease is not completely understood, but immunologic mechanisms, cytotoxic reactions, and delayed hypersensitivity seem to be involved. CONCLUSION: Profound knowledge of exfoliative skin diseases is needed to improve therapy and outcome of these life-threatening illnesses.",1
12350,21360569,Detection of acetaminophen-cysteine adducts in cases of indeterminate liver failure is not diagnostic of intentional overdose,,1
12351,21364038,Probable ketoprofen-associated nonalcoholic fatty liver disease and steatohepatitis,,1
12352,21370308,Drug induced hepatotoxicity: data from the Serbian pharmacovigilance database,"PURPOSE: The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. METHODS: Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. RESULTS: Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). CONCLUSIONS: Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals.",1
12353,21370947,Clinical course of repeated supratherapeutic ingestion of acetaminophen,"""BACKGROUND: Repeated supratherapeutic ingestion (RSTI) of acetaminophen (APAP) is recognized as an important cause of APAP-related morbidity and mortality. This study describes the characteristics and clinical course of patients with RSTI, and identifies the risk factors for developing hepatotoxicity and death. METHODS: This secondary analysis of a multicenter retrospective chart review studied patients treated with IV and/or oral N-acetylcysteine for acetaminophen poisoning. For this analysis, we included all subjects coded as RSTIs, defined as ingestions of greater than 4 g of APAP per 24 h over a period longer than 8 h. Data collected include demographics, coingestants, comorbidities, presenting laboratory data, and outcomes. The analysis includes descriptive statistics and associations of demographic and clinical factors with patient outcome. RESULTS: Of the 503 patients enrolled, 119 (23.7%) were RSTI. The mean age was 39.6 years (SD ? 15); 63.9% of the patients were females, 60.5% Caucasians, 27.7% alcoholics, 5% malnourished, 10.9% had viral hepatitis, and 3.4% had other liver diseases. Coingestants included ethanol, opioids, and antihistamines (17.6, 48.7, and 19.3%, respectively). Among this group, 44 patients developed hepatotoxicity, two received liver transplants, and four died (37.0, 1.7, and 3.4%, respectively). The risk for hepatotoxicity increased with a history of alcoholism, viral hepatitis, and other liver diseases. A history of alcoholism and an elevated presenting serum creatinine were associated with increased risk for death/transplant. The lowest presenting ALT levels in a subject who developed hepatotoxicity and who died were 252 and 426 IU/l, respectively. CONCLUSION: RSTI-induced hepatotoxicity and poor outcomes can be predicted at the patient's presentation. All patients with RSTI who developed hepatotoxicity presented with an abnormal ALT. A history of alcoholism and an elevated creatinine at presentation are markers of increased risk for hepatotoxicity and death.""",1
12354,21375570,Rilonacept and canakinumab,,1
12355,21377431,"Herbal hepatotoxicity by kava: update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits","Herbal hepatotoxicity by the anxiolytic kava (Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.",1
12356,21385988,"Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial","""BACKGROUND: Postoperative nausea and vomiting (PONV) are common complications after surgery. Neurokinin-1 (NK(1)) receptor antagonists have been shown to be safe and effective for the prevention and treatment of PONV in humans. Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions. We evaluated the dose response for rolapitant for the prevention of PONV in subjects at high risk for this condition, and rolapitant's effects on preventing delayed PONV were explored up to 5 days after surgery. METHODS: A randomized, multicenter, double-blind, dose-ranging study of rolapitant was conducted with placebo and active control groups. Six hundred nineteen adult women undergoing open abdominal surgery were randomly assigned in equal ratios to 1 of 6 study arms: oral rolapitant in 5-mg, 20-mg, 70-mg, or 200-mg doses; IV ondansetron 4 mg; or placebo, stratified by history of PONV or motion sickness. The primary study endpoint was absence of emetic episodes, regardless of use of rescue medication, at 24 hours after extubation. RESULTS: Groups assigned to rolapitant 20-mg, 70-mg, and 200-mg had a higher incidence of no emesis in comparison with placebo at 24 hours after surgery. A linear relationship between rolapitant dose and primary outcome was seen. The probability of an emetic episode was significantly lower in the rolapitant 70-mg and 200-mg groups in comparison with placebo (P ? 0.001 based on the log-rank test). No significant differences were noted between rolapitant and the active control (ondansetron) at 24 hours after surgery, but there was a higher incidence of no emesis (regardless of rescue medication use) in the rolapitant 200- and 70-mg groups at 72 and 120 hours, respectively. CONCLUSION: Rolapitant is superior to placebo in reducing emetic episodes after surgery and reduces the incidence of vomiting in a dose-dependent manner. No differences in side effect profile were observed between rolapitant and placebo.""",1
12357,21393205,Clinical experience with daptomycin in Europe: the first 2.5 years,"""OBJECTIVES: To describe the patient populations and infections being treated with daptomycin, as well as the efficacy and safety outcomes. PATIENTS AND METHODS: Data from the European Cubicin Outcomes Registry and Experience (EU-CORESM), retrospectively collected at 118 institutions between January 2006 and August 2008, were analysed. RESULTS: Daptomycin treatment was documented in 1127 patients with diverse infections, including complicated skin and soft tissue infections (33%), bacteraemia (22%), endocarditis (12%) and osteomyelitis (6%). It was used empirically, before microbiological results became available, in 53% of patients. Staphylococcus aureus was the most common pathogen (34%), with 52% of isolates resistant to methicillin; coagulase-negative staphylococci and enterococci were also frequent, with 22% of Enterococcus faecium isolates resistant to vancomycin. Daptomycin was used as first-line therapy in 302 (27%) patients. When used second line, the most common reasons for discontinuation of previous antibiotic were treatment failure and toxicity or intolerance. The use of concomitant antibiotics was reported in 65% of patients. Most frequent doses were 6 mg/kg (47%) and 4 mg/kg (32%). The median duration of daptomycin therapy was 10 days (range 1-246 days) in the inpatient setting and 13 days (range 2-189 days) in the outpatient setting. The overall clinical success rate was 79%, with a clinical failure rate of <10% for all infection types. Low failure rates were observed in first- and second-line therapy (6% and 8%, respectively). Daptomycin demonstrated a favourable safety and tolerability profile regardless of treatment duration. CONCLUSIONS: Daptomycin has a relevant role in the treatment of Gram-positive infections.""",1
12358,21395357,Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma,"Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC. The primary mechanism of action of pazopanib in RCC is through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of vascular endothelial growth factor receptor and platelet-derived growth factor receptor. A placebo-controlled phase III study demonstrated that pazopanib significantly improved response rates and progression-free survival (PFS) in both treatment-na?ve and cytokine-pretreated patients. Among treatment-na?ve patients, the response rate was 32% and PFS was 11.1 months. In cytokine-pretreated patients, the response rate and PFS were 29% and 7.4 months, respectively. Common adverse effects of pazopanib include diarrhoea, hypertension and elevation of liver enzymes. Overall, the adverse effect profile of pazopanib is similar to that of other TKIs used for the treatment of RCC, but variation in the incidence and severity may exist. Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. Hepatic function must be monitored closely with dose interruption and/or reduction if elevation of hepatic function tests occurs. Pazopanib is administered on an empty stomach at a dose of 800 mg daily until disease progression, but dose reduction may be required in patients with baseline elevation of hepatic function tests, particularly total bilirubin. The minimum dose recommended for baseline hepatic dysfunction or toxicity is 200 mg daily. The potential for drug interactions exists for pazopanib. It is a substrate of cytochrome P450 (CYP) 3A4, P-glycoprotein and breast cancer resistance protein, and it weakly inhibits CYP3A4, CYP2C8 and CYP2D6, and potently inhibits UGT1A1 and OATP1B1. Currently, no study has directly compared pazopanib with other first- or second-line therapies in RCC. However, published clinical trials of pazopanib show similar efficacy outcomes to those of other targeted therapies. Therefore, pazopanib may be considered a first-line treatment option among other therapies including sunitinib, temsirolimus, and bevacizumab plus interferon-?. After failure of cytokine therapy, pazopanib is a treatment option as well as sorafenib or bevacizumab. No study has evaluated pazopanib treatment after failure of another targeted therapy. Future studies will further clarify the comparative efficacy of pazopanib with other agents as well as optimal sequencing with other agents. If similar efficacy is seen among the TKIs, it is likely that varying incidences of adverse effects may be analysed to tailor therapy according to the patient's individual co-morbidities and preferences.",1
12359,21395650,Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy,"AIMS: 6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response. METHODS: Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. RESULTS: During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 x 10(8) RBC) than in older children (600 pmol/8 x 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 x 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 x 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 x 10(8) RBC was associated with an increased risk of hepatotoxicity. CONCLUSION: In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.",1
12360,21401949,Acetaminophen-cysteine adducts during therapeutic dosing and following overdose,"""BACKGROUND: Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. METHODS: Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. RESULTS: Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin. CONCLUSIONS: Lower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.""",1
12361,21412057,"Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection","""OBJECTIVE: To assess the safety and efficacy of two, single-tablet regimens for the initial treatment of HIV infection. DESIGN: Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. METHODS: Antiretroviral treatment-naive adults with a screening HIV-1 RNA at least 5000 copies/ml and a CD4 cell count more than 50 cells/?l were randomized 2: 1 to receive fixed-dose combination tablets of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; N = 48) or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF; n = 23) for 48 weeks. The primary endpoint was proportion of participants with HIV-1 RNA less than 50 copies/ml at week 24. RESULTS: Participants receiving EVG/COBI/FTC/TDF exhibited a more rapid decline in HIV-1 RNA and a greater proportion suppressed viral load to less than 50 copies/ml than participants receiving EFV/FTC/TDF. Both EVG/COBI/FTC/TDF and EFV/FTC/TDF resulted in high rates of viral suppression and increases in CD4 cell count. Ninety and 83% of participants suppressed HIV-1 RNA to less than 50 copies/ml both at the 24-week and 48-week visits for EVG/COBI/FTC/TDF and EFV/FTC/TDF, respectively. Once-daily administration of EVG/COBI/FTC/TDF provided a mean EVG trough concentration 10-fold over its protein binding-adjusted IC(95) across study visits. EVG/FTC/TDF/GS-9350 was generally well tolerated with a lower rate of drug-related central nervous system (17%) and psychiatric (10%) adverse events versus EFV/FTC/TDF (26 and 44%, respectively). Decreases in estimated glomerular filtration rate occurred within the first few weeks of dosing in participants receiving EVG/COBI/FTC/TDF, remained within the normal range and did not progress at week 24 or 48; no participant experienced a clinical adverse event or discontinued study drug due to changes in serum creatinine or renal function. CONCLUSION: Once-daily EVG/COBI/FTC/TDF achieved and maintained a high rate of virologic suppression with fewer central nervous system and psychiatric adverse events compared to a current standard-of-care regimen of EFV/FTC/TDF.""",1
12362,21416695,Liver toxicity of sitaxentan in pulmonary arterial hypertension,,1
12363,21418672,Constipation in adults,"INTRODUCTION: Although there are defined criteria for the diagnosis of constipation, in practice, diagnostic criteria are less rigid, and depend in part on the perception of normal bowel habit. Constipation is highly prevalent, with approximately 12 million general practitioner prescriptions for laxatives in England in 2001. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug interventions, bulk-forming laxatives, faecal softeners, stimulant laxatives, osmotic laxatives, prostaglandin derivatives, and 5-HT4 agonists in adults with idiopathic chronic constipation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 51systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: arachis oil, biofeedback, bisacodyl, cascara, docusate, exercise, glycerol/glycerine suppositories, high-fibre diet, increasing fluids, ispaghula husk, lactitol, lactulose, lubiprostone, macrogols (polyethylene glycols), magnesium salts, methylcellulose, paraffin, phosphate enemas, seed oils, senna, sodium citrate enemas, prucalopride, and sterculia.",1
12364,21420888,Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis,"""Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism, platelet dysfunction, and in some subtypes, fatal pulmonary fibrosis. There is no effective treatment for the pulmonary fibrosis except lung transplantation, but an initial trial using pirfenidone, an anti-fibrotic agent, showed promising results. The current, randomized, placebo-controlled, prospective, double-blind trial investigated the safety and efficacy of pirfenidone for mild to moderate HPS-1 and 4 pulmonary fibrosis. Subjects were evaluated every 4 months at the National Institutes of Health Clinical Center, and the primary outcome parameter was change in forced vital capacity using repeated measures analysis with random coefficients. Thirty-five subjects with HPS-1 pulmonary fibrosis were enrolled during a 4-year interval; 23 subjects received pirfenidone and 12 received placebo. Four subjects withdrew from the trial, 3 subjects died, and 10 serious adverse events were reported. Both groups experienced similar side effects, especially gastroesophageal reflux. Interim analysis of the primary outcome parameter, performed 12 months after 30 patients were enrolled, showed no statistical difference between the placebo and pirfenidone groups, and the study was stopped due to futility. There were no significant safety concerns. Other clinical trials are indicated to identify single or multiple drug regimens that may be effective in treatment for progressive HPS-1 pulmonary fibrosis.""",1
12365,21426451,"Clinical efficacy of i.v. doripenem, a new class of carbapenem, in patients with biliary tract infection: A multicenter trial","""AIM: ? We conducted a multicenter trial to evaluate the efficacy and safety of i.v. doripenem (DRPM), a new class of carbapenem, in patients with moderate to severe biliary tract infection based on severity assessment using the Guidelines for the Management of Acute Cholangitis and Cholecystitis (1st Edition). METHODS: ? One hundred and nineteen patients with moderate to severe acute cholangitis and/or cholecystitis were subjected to this study. After the initial collection of bile, patients were administrated DRPM 0.5?g three times daily by i.v. drip infusion. RESULTS: ? The characteristics of the 119 patients were well balanced, including 60 with cholangitis, 44 with cholecystitis and 15 with cholangitis complicated by cholecystitis; there were 88.2% (105/119) moderate cases and 11.8% (14/119) severe. Based upon the assumption of the use of bile drainage, the rate of response to DRPM was 92.4% (110/119) in the group of all patients. The clinical response rates were 95.0% (57/60) for cholangitis, 93.2% (41/44) for cholecystitis and 80% (12/15) for cholangitis complicated by cholecystitis. Also, the clinical response rate was 80% (8/10) in 10 patients without drainage. In contrast, bacteriological efficacy was assessed in 50 patients, and the response rates were 87.0% (20/23) in patients with cholangitis, 100% (20/20) in patients with cholecystitis and 85.7% (6/7) in patients with cholangitis complicated by cholecystitis. Adverse events were found in six patients (5.0%), but were not serious and disappeared after treatment. CONCLUSION: ? These findings suggest that DPRM is useful as a new option for moderate to severe biliary tract infection.""",1
12366,21428768,Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan,"""BACKGROUND: Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS-TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS-TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition. METHODS: From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them for symptoms. We used the estimated historical incidence of SJS-TEN as a control. RESULTS: Mild, transient rash developed in 4.3% of subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS-TEN did not develop in any of the HLA-B*1502-negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001). CONCLUSIONS: The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. (Funded by the National Science Council of Taiwan and the Taiwan Drug Relief Foundation.).""",1
12367,21428848,Drug safety evaluation of exemestane,"INTRODUCTION: Hormone-dependent breast cancer can be successfully treated by either blocking the estrogen receptor, as with tamoxifen, or reducing the production of estrogens, as with aromatase inhibitors. Exemestane is a third-generation aromatase inhibitor used in the treatment of estrogen-receptor-positive breast cancer in postmenopausal women. In various trials, exemestane has shown superiority over tamoxifen in both efficacy and safety. Furthermore, aromatase inhibitors are gaining territory in the metastatic, as well as the early, setting for treating patients with breast cancer. AREAS COVERED: The authors describe the mechanism of action and pharmacokinetic/pharmacodynamic characteristics of exemestane and discuss its efficacy and safety within the framework of currently approved and potential new indications. The reader can expect a full update on the characteristics of exemestane, including its efficacy and safety profile compared with tamoxifen and other third-generation aromatase inhibitors. EXPERT OPINION: Exemestane is a safe drug due to its steroidal structure, which blocks aromatase at a different site to nonsteroidal AIs (eg., anastrozole and letrozole). Noncross-resistance with nonsteroidal aromatase inhibitors makes it an attractive alternative for all clinical indications of aromatase inhibitors in patients with breast cancer.",1
12368,21434942,"Linezolid, the first oxazolidinone antibacterial agent","""Linezolid (Zyvox) is the first member of an entirely new class of antibiotics to reach the market in over 35 years; it was approved for use in 2000. A member of the oxazolidinone class of antibiotics, linezolid is highly effective for the treatment of serious Gram-positive infections and has activity that compares favorably with vancomycin for most clinically relevant pathogens. Zyvox is approved for use against serious Gram-positive infections, including those caused by Streptococcus pneumoniae, and the very challenging methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium organisms. Zyvox inhibits bacterial protein synthesis by binding to 23S rRNA in the catalytic site of the 50S ribosome. It can be administered both orally and intravenously and has good tissue distribution. Recent results have demonstrated that oxazolidinone analogs related to linezolid are effective in treating pulmonary tuberculosis caused by resistant Mycobacterium tuberculosis in animal infection models and suggest additional new therapeutic applications for these antibiotics.""",1
12369,21435130,Efficacy and safety in sitagliptin therapy for diabetes complicated by chronic liver disease caused by hepatitis C virus,"AIM: ? Diabetes is present in patients with chronic liver disease caused by hepatitis C virus (HCV). The aim of this case-control study is to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with chronic liver disease caused by HCV. METHODS: ? Sixteen HCV positive patients with T2DM treated by sitagliptin were retrospectively enrolled. These patients were given sitagliptin between December 2009 and January 2010. Another 16 HCV patients with T2DM treated only with diet and excise for 48?weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48?weeks after the initiation of treatment. RESULTS: ? In the sitagliptin group, the average HbA1C level decreased approximately 0.8% at 48?weeks after the initiation of sitagliptin. Next, the average FPG level decreased approximately 20?mg/dL during follow up after the initiation of sitagliptin. All the patients were able to take sitagliptin of 50?mg/day without reduction because of sitagliptin-related side-effects. On the other hand, in the control group, the average HbA1C and FPG level did not change with statistical significance during follow up of 48?weeks. Regarding aminotransferase, there were no significant changes of average AST and ALT level during follow up of 48?weeks in both the sitagliptin group and control group. CONCLUSION: ? Our results indicate that sitagliptin is effective and safe for the treatment of T2DM complicated with HCV positive chronic liver disease.",1
12370,21440672,Oral bisacodyl is effective and well-tolerated in patients with chronic constipation,"BACKGROUND & AIMS: Although stimulant laxatives have been used for many years to treat patients with constipation, their clinical value has been questioned, and there have been few high-quality trials to assess their efficacy. We tested the efficacy and safety of 4 weeks of treatment with oral bisacodyl tablets in patients with chronic constipation, defined by Rome III criteria. METHODS: This randomized, double-blind, placebo-controlled, parallel-group study was conducted in 27 centers in the United Kingdom. After a 2-week baseline period without study medication, patients were randomly assigned, in a 2:1 ratio, to groups that were given 10 mg bisacodyl (n = 247) or placebo (n = 121), once daily, for 4 weeks. Patients used an electronic diary each day to record information relating to their constipation. RESULTS: The mean (? standard error of the mean [SEM]) number of complete spontaneous bowel movements (CSBMs) per week during the treatment period increased from 1.1 ? 0.1 in both groups to 5.2 ? 0.3 in the bisacodyl group and 1.9 ? 0.3 in the placebo group (P < .0001). All secondary end points (number of complete spontaneous bowel movements for each single week, number of spontaneous bowel movement (SBMs), and constipation-associated symptoms) differed significantly between groups, demonstrating efficacy for bisacodyl (P < .0001). Compared with baseline, there was a statistically significant improvement in the overall Patient Assessment of Constipation quality of life (PAC-QOL) score and all subscales (satisfaction, physical discomfort, psychosocial discomfort, worries and concerns) in the bisacodyl-treated patients, compared with those that received placebo (P ? .0070). Treatment with bisacodyl was well-tolerated. CONCLUSIONS: Oral bisacodyl is an effective and well-tolerated treatment for patients with chronic constipation. It improves bowel function, constipation-related symptoms, and disease-related QOL.",1
12371,21443284,Linagliptin: in type 2 diabetes mellitus,"Linagliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, has a favourable pharmacokinetic profile in terms of its predominantly non-renal elimination. It shows highly selective, potent, dose-dependent inhibition of DPP-4, with >/= 80% inhibition of DPP-4 throughout the 24-hour dosing interval. In two double-blind, multicentre trials (n >350 evaluable patients/trial) in adult patients with inadequately controlled type 2 diabetes mellitus, oral linagliptin monotherapy (5 or 10 mg once daily) was significantly more effective than placebo in improving glycaemic control and several parameters of pancreatic function, with placebo-corrected adjusted mean changes in glycosylated haemoglobin (HbA(1c)) levels of -0.69% to -0.88% after 12 or 24 weeks. Linagliptin 5 or 10 mg once daily was also significantly more efficacious than voglibose 0.2 mg three times daily in terms of improving glycaemic control in a 26-week, double-blind, multicentre trial (n >450 evaluable patients). In several similarly designed trials (n >250 evaluable patients/trial) of 12-24 weeks' duration in adult patients with inadequately controlled type 2 diabetes, oral linagliptin (5 mg once daily) as add-on therapy to metformin, a sulfonylurea drug or metformin plus a sulfonylurea drug, or in combination with pioglitazone, improved glycaemic control significantly more than placebo plus the respective oral antihyperglycaemic therapy, with improvements in adjusted mean HbA(1c) levels considered clinically relevant. Linagliptin, as monotherapy or in combination with other oral antihyperglycaemic drugs, was generally well tolerated in clinical trials, having neutral or minimal effects on bodyweight and generally being associated with a very low incidence of hypoglycaemia.",1
12372,21449784,Boceprevir for previously treated chronic HCV genotype 1 infection,"""BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).""",1
12373,21451802,Hepatotoxicity by bosentan in a patient with portopulmonary hypertension: a case-report and review of the literature,"Bosentan is an endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension. Mild liver reactions occur in about 10% of treated patients but severe hepatotoxicity is rare. We present clinical data and treatment outcome of a severe drug induced liver injury due to bosentan in a patient with non-cirrhotic portopulmonary hypertension. After 18 months of uncomplicated therapy with bosentan 125 mg b.i.d., the patient developed a severe mixed hepatic injury. Serum levels of bilirubin were 316 ?mol/l (ref. value <20 micromol/l), AST 14 ?kat/l (ref. value < 0.9 ?kat/l), ALT 10 ?kat/l (ref. value < 0.9 ?kat/l), ALP 8 ?kat/l (ref. value <1.8 ?kat/l) and INR 1.8 (ref. value 0.9-1.1). Complete diagnostic work-up disclosed no other cause of hepatotoxicity. Treatment with prednisolone 40 mg/day in tapering doses was ultimately added and the patient made a full recovery. Subsequent treatment with sildenafil and ambrisentan for pulmonary arterial hypertension was well tolerated and liver function tests have remained normal during 12 months' follow-up. A review of the literature revealed three other women with severe hepatotoxicity due to bosentan. Bosentan may cause severe liver injury, even after long uneventful therapy, and current recommendations on regular monitoring of liver function tests are reinforced. Ambrisentan may be a therapeutic alternative in patients with pulmonary arterial hypertension and hepatotoxicity by bosentan.",1
12374,21453541,Anastrozole-related acute hepatitis with autoimmune features: a case report,"""BACKGROUND: Two cases of acute hepatitis occurring during treatment with anastrozole have previously been reported, but the underlying mechanisms of liver injury are still uncertain. We report the case of anastrozole-related acute hepatitis with some autoimmune features. CASE PRESENTATION: A 70-year-old woman developed acute hepatitis associated with serum antinuclear antibodies during anastrozole treatment; after drug withdrawal, liver function parameters rapidly improved and serum auto-antibodies were no longer detectable. CONCLUSIONS: Anastrozole-induced hepatotoxicity is a very rare event. Drug-drug interactions or metabolically-mediated damage might be involved, with a possible role of individual susceptibility. Our report suggests that an immune-mediated mechanism may also be considered in anastrozole-related liver injury.""",1
12375,21455106,Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene,"BACKGROUND: POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion. MATERIAL/METHODS: A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations. RESULTS: The p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion). CONCLUSIONS: Our results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.",1
12376,21457433,Review of liver injury associated with dietary supplements,"""Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms 'dietary/nutritional supplements', 'adverse hepatic reactions', 'liver injury'; 'hepatitis', 'liver failure', 'vitamin A' and 'retinoids', and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.""",1
12377,21464059,Dabigatran etexilate: a new oral thrombin inhibitor,,1
12378,21464643,Dabigatran etexilate: the first oral anticoagulant available in the United States since warfarin,"For more than 5 decades, warfarin has been the mainstay of therapy when oral anticoagulation is required. It has been shown to be effective in the prevention as well as treatment of various thromboembolic disorders. However, drawbacks of warfarin, such as time-consuming requirements for frequent international normalized ratio monitoring, as well as drug and food interactions, have encouraged the development of alternative oral agents. One such agent, dabigatran, has risen up to the challenge. Due to its predictable anticoagulation response, dabigatran does not require routine anticoagulation monitoring. Another advantage dabigatran has over warfarin is its more favorable drug and food interaction profiles. Dabigatran was shown to be noninferior to warfarin in studies evaluating the prevention of stroke and systemic embolism in patients with atrial fibrillation, thus leading to the US Food and Drug Administration approval for this indication. Dabigatran has also demonstrated efficacy in the prevention of venous thromboembolism in patients undergoing total hip or knee replacement surgery as well as the prevention of recurrent venous thromboembolism, although these are not current Food and Drug Administration-approved indications. The safety profile appears to be similar to warfarin with regards to overall bleeding risk, though the risk for gastrointestinal bleeds was higher in patients on dabigatran 150 mg twice daily. Disadvantages of dabigatran may include a higher frequency of dyspepsia compared with warfarin, lack of dosing information in severe renal impairment, possible missed opportunities for periodic health examinations and interventions due to elimination of regular physician's visit for international normalized ratio monitoring, and drug costs. This article provides an overview of the clinical studies, pharmacokinetic profile, adverse effects, drug interactions as well as advantages and disadvantages associated with dabigatran.",1
12379,21475067,Acute amiodarone hepatotoxicity after liver transplantation,,1
12380,21477892,[Acute cholestatic hepatitis associated with levofloxacin],,1
12381,21481053,Spontaneous adverse event reports associated with zolpidem in Australia 2001-2008,"A prominent media publicity cluster during 2007-2008 in Australia linked the common hypnotic zolpidem to adverse drug reaction reports of parasomnias, amnesia, hallucinations and suicidality. The collection of adverse drug reaction data through spontaneous reporting systems is a mainstay of drug safety monitoring, but a stimulated reporting event such as this often renders such data uninterpretable. As such, we aimed to investigate whether these associations were present before the media cluster and then to quantify the effect of stimulated reporting on those four specific outcomes. Using disproportionality analyses we compared zolpidem to all other drugs in the database, and then separately to each of all hypnotics, then all benzodiazepines, and then temazepam alone, and did so in every year from 2001 to 2008. Year-by-year analyses of Reporting odds ratios for zolpidem exposure and adverse events of interest, adjusted for a number of covariates, revealed an association between zolpidem exposure and parasomnias, amnesia and hallucination both before and after the cluster of media publicity beginning in early 2007. The odds ratios increased significantly after the media publicity for only parasomnias and amnesia. Suicidality was increased in some analyses, but limited data make this outcome difficult to interpret. We conclude that zolpidem adverse drug reaction reports have higher odds for parasomnia, amnesia, hallucination and perhaps suicidality compared to either all other drugs or hypnotics, even before the media publicity cluster. However, the extant literature and the limitations of these spontaneously reported adverse drug reaction data do not allow us to conclude that these events are related causally to zolpidem.",1
12382,21482079,Early life-threatening lactic acidosis following a single infusion of linezolid,,1
12383,21487083,Prospective cohort study on the effects and tolerability of flutamide in patients with female pattern hair loss,"BACKGROUND: Flutamide has been rarely used for the treatment of female pattern hair loss (FPHL). Flutamide treatment for FPHL has not been evaluated in long-term studies with sufficiently large numbers of women. OBJECTIVE: To evaluate long-term effects, safety, and tolerability of flutamide in women with FPHL. METHODS: A prospective cohort study was conducted in our tertiary care university hospital. The cohort included 101 women diagnosed with FPHL from January 1991 to January 2006. These women received yearly reducing doses (250, 125, and 62.5 mg/day) of flutamide for 4 years. The cohort included 33 patients treated with flutamide alone and 68 treated with flutamide combined with an oral contraceptive. Clinical and endocrine evaluations were assessed semiannually and annually, respectively, in the first 3 years of the study, and once in the following year. Liver function was evaluated quarterly. RESULTS: Both groups showed a marked decrease in alopecia scores after 12 months of flutamide therapy, compared with baseline values. The maximum drug effect occurred after 2 years and was maintained during the following 2 years of treatment. Androgens were strongly suppressed. During the first year of treatment, 4% of patients abandoned the study due to hepatic disorders related to the drug. During the following years, with the lower treatment regimen, no patient abandoned the study because of hepatic alterations. CONCLUSIONS: Flutamide is a satisfactory therapeutic regimen for treatment of FPHL in the long run. Moreover, the use of very low doses (62.5 mg/day) of flutamide is associated with complete hepatic tolerability and high adherence.",1
12384,21490889,Hemorrhagic cholecystitis in an elderly patient taking aspirin and cilostazol,"Hemorrhage is a rare complication of acute cholecystitis. Patients who develop this complication often are receiving anticoagulation therapy or have a pathologic coagulopathy. We present a case of an elderly patient who developed hemorrhagic cholecystitis while taking aspirin and cilostazol, a phosphodiesterase inhibitor. The patient underwent an emergent abdominal exploration. A large, blood-filled gallbladder was found along with a large hematoma between the liver and gallbladder. We also briefly review the literature regarding hemorrhagic cholecystitis, hemorrhage into the biliary tree, and hemorrhage as a complication of aspirin and phosphodiesterase inhibitor therapy.",1
12385,21492891,[Relationship between plasma concentrations of valproic acid and hepatotoxicity in patients receiving high doses],"INTRODUCTION: Valproic acid (VPA) is an anticonvulsivant drug widely prescribed in the treatment of many forms of generalized epilepsy. In literature, the incidence of liver damage induced by AVP is 0.01%. It is potentialized by the combination therapy (phenobarbital, carbamazepine). Severe hepatotoxicity is rare and appears to be independent of dose and to cause a high mortality. METHODS: The aim of our study was to evaluate the relationship between plasma concentrations of AVP and the occurrence of side effects especially hepatotoxicity in patients receiving high doses of AVP. RESULTS: In this period, 425 plasmatic AVP monitoring were carried out in our laboratory. From 128 patients treated by high doses of AVP, only 73 were included in this study. Our work showed that adverse effects in epileptics under high doses of AVP was related to the association of the AVP with other antiepileptic in particular carbamaz?pine, phenobarbital and benzodiazepines rather than supra-therapeutic plasmatic concentrations of AVP. The association of AVP to major antiepileptics (carbamaz?pine and or phenobarbital) does not seem to generate an increase in the plasmatic concentration of AVP, which was not associated with a greater risque of adverse effects. CONCLUSION: Consequently, clinical signs of liver toxicity may be present in AVP concentrations generally considered in the therapeutic range especially when used in high doses and or combined with antiepileptic drugs like phenobarbital or carbamazepine.",1
12386,21499580,Acute liver failure caused by 'fat burners' and dietary supplements: a case report and literature review,"Globally, people are struggling with obesity. Many effective, nonconventional methods of weight reduction, such as herbal and natural dietary supplements, are increasingly being sought. Fat burners are believed to raise metabolism, burn more calories and hasten fat loss. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. The present report describes a young healthy woman who presented with fulminant hepatic failure requiring emergent liver transplantation caused by a dietary supplement and fat burner containing usnic acid, green tea and guggul tree extracts. Thorough investigation, including histopathological examination, revealed no other cause of hepatotoxicity. The present case adds to the increasing number of reports of hepatotoxicity associated with dietary supplements containing usnic acid, and highlights that herbal extracts from green tea or guggul tree may not be free of adverse effects. Until these products are more closely regulated and their advertising better scrutinized, physicians and patients should become more familiar with herbal products that are commonly used as weight loss supplements and recognize those that are potentially harmful.",1
12387,21502555,Safe and successful treatment with erlotinib after gefitinib-induced hepatotoxicity: difference in metabolism as a possible mechanism,,1
12388,21502935,Eribulin mesylate (Halaven) for breast cancer,"Eribulin mesylate (Halaven-Eisai) has been approved by the FDA for treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapy regimens for metastatic cancer. Prior therapy should have included an anthracycline and a taxane in either an adjuvant or metastatic setting. Other drugs used to treat anthracycline- and taxane-refractory metastatic breast cancer include capecitabine (Xeloda), gemcitabine (Gemzar, and others) and vinorelbine (Navelbine, and others).",1
12389,21506562,Constituents in kava extracts potentially involved in hepatotoxicity: a review,"Aqueous kava root preparations have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava extracts in Western countries, where mainly ethanolic or acetonic extracts are used. The mechanism of toxicity has not been established, although several theories have been put forward. The composition of the major constituents, the kava lactones, varies according to preparation method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain composition of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chemical structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones have been identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addition of GSH to kava extracts has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava extract, such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.",1
12390,21513619,Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton,"The leaves of Kratom, a medicinal plant in Southeast Asia, have been used as an herbal drug for a long time. At least one of the alkaloids present in Kratom, mitragynine, is a mu-receptor agonist. Both Kratom and an additional preparation called Krypton are available via the internet. It seems to consist of powdered Kratom leaves with another mu-receptor agonist, O-desmethyltramadol, added. O-Desmethyltramadol is an active metabolite of tramadol, a commonly prescribed analgesic. We present nine cases of intoxication, occurring in a period of less than one year, where both mitragynine and O-desmethyltramadol were detected in the postmortem blood samples. Neither tramadol nor N-desmethyltramadol was present in these samples, which implies that the ingested drug was O-desmethyltramadol. The blood concentrations of mitragynine, determined by ultra-performance liquid chromatography-tandem mass spectrometry, ranged from 0.02 to 0.18 ?g/g, and O-desmethyltramadol concentrations, determined by gas chromatography with nitrogen-specific detection, ranged from 0.4 to 4.3 ?g/g. We believe that the addition of the potent mu-receptor agonist O-desmethyltramadol to powdered leaves from Kratom contributed to the unintentional death of the nine cases presented and conclude that intake of Krypton is not as harmless as it often is described on internet websites.",1
12391,21514865,[Survival following liver transplant due to imatinib-induced acute liver failure: a case study],,1
12392,21521704,Clinical experience with linezolid in infants and children,"The worldwide spread of multidrug-resistant organisms has required the development of new antimicrobials. Linezolid, the first oxazolidinone, has a broad spectrum of activity against Gram-positive bacteria, including resistant strains. Although approved by the Food and Drug Administration in 2002, the clinical experience with linezolid in the paediatric population is still limited, also given the fact that in most European countries the paediatric use of linezolid is off-label. In this paper we summarize the actual evidence on both licensed and off-label clinical uses of linezolid in children, including efficacy, safety and tolerability issues. Taking into account the potential bias in comparing heterogeneous clinical trials and reports, the available literature data suggest that linezolid is a safe and effective agent for the treatment of serious Gram-positive bacterial infections in neonates and children. At present, linezolid is reserved for those children who are intolerant to or fail conventional agents. A linezolid-containing regimen can be a valuable option for treating multidrug-resistant and extensively drug-resistant tuberculosis in children as well as disseminated non-tuberculous mycobacterial infections. Given the rare occurrence of serious side effects, careful monitoring of haematological parameters, possible drug interactions and neurological manifestations is recommended in linezolid-treated children, especially in case of prolonged treatments. Appropriate linezolid dosage and hospital infection control measures are essential to avoid the spread of linezolid resistance. Further studies are needed to establish novel paediatric indications for linezolid use and to assess the tolerability of long-term treatments.",1
12393,21521847,Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial,"""CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established. OBJECTIVE: To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. MAIN OUTCOME MEASURES: The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. RESULTS: Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. CONCLUSION: Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063635.""",1
12394,21527335,A single arm phase II study of a Far-Eastern traditional herbal formulation (sho-sai-ko-to or xiao-chai-hu-tang) in chronic hepatitis C patients,"""ETHNOPHARMACOLOGICAL RELEVANCE: Hepatitis C is a major public health problem internationally. Many patients cannot benefit from the current treatment regimen (interferon/ribavirin combinations) due to its side effects or ineffectiveness. Xiao-Chai-Hu-Tang or Sho-sai-ko-to (SST), a compound of seven botanical extracts used for liver diseases traditionally in East Asia, was shown to reduce transaminases and the incidence of hepatocellular carcinoma in hepatitis B patients. We conducted a phase II trial of SST in hepatitis C patients who were not candidates for interferon-based therapy to determine whether this agent is worthy of further study. MATERIALS AND METHODS: Twenty four chronic hepatitis C patients received SST at 2.5 g per os (p.o.) three times daily (t.i.d.) for 12 months. Liver function, hepatitis C virus (HCV) viral load and liver biopsy histology were assessed before and after the intervention. RESULTS: Improvement of aspartate aminotransferase (AST) was observed in 16 (67%) of study participants. Improvement of alanine aminotransferase (ALT) was seen in 18 (75%) patients. Viral load response was mixed, with 7 patients showing reductions, 10 increases and 7 indeterminate due to assay limitations. Among the 9 (38%) subjects who showed improvement per Knodell's histology activity index (HAI) scores in paired comparison of pre- and post-treatment liver biopsy (the primary endpoints of the study), 5 (21%) showed an improvement of 2 points or greater, meeting the pre-defined criteria for """"response. CONCLUSIONS: Sho-sai-ko-to (SST or Xiao Chai Hu Tang) may improve liver pathology in selected hepatitis C patients who are not candidates for interferon based treatment. Larger, controlled studies of this botanical formulation may be warranted.""",1
12395,21528385,Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa),"INTRODUCTION: Kratom (Mitragyna speciosa) is a common medical plant in Thailand and is known to contain mitragynine as the main alkaloid. According to an increase in published reports and calls at German poison control centers, it has been used more frequently as a drug of abuse in the western hemisphere during the last couple of years. Despite this increase, reports of severe toxicity are rare within the literature. CASE REPORT: We describe a case of a young man who presented with jaundice and pruritus after intake of kratom for 2 weeks in the absence of any other causative agent. Alkaloids of M. speciosa were detected in the urine. CONCLUSION: While M. speciosa is gaining in popularity among illicit drug users, its adverse effects remain poorly understood. This is the first published case of intrahepatic cholestasis after kratom abuse.",1
12396,21532224,A case of drug-induced hepatic injury associated with sitagliptin,"A 58-year-old man with a 10-year history of type II diabetes mellitus presented with progressive jaundice that began three days before admission. Thorough history-taking revealed that the patient had started on a new medication, sitagliptin, one month previously for the treatment of diabetes mellitus. Laboratory investigations showed severe liver dysfunction. Ultrasonography detected no extrahepatic biliary duct dilatation or gallstones. Abdominal computed tomography excluded pancreatic and hepatic focal lesions. Liver function improved upon discontinuation of sitagliptin. Drugs are an important, often unrecognized, cause of acute liver injury. This report presents a rare case in which sitagliptin was responsible for acute hepatic damage. As demonstrated, a thorough drug history is helpful in any case of unexplained liver injury.",1
12397,21535985,Status and trends in poisonings in Denmark 2007-2009,"INTRODUCTION: The Danish Poison Information Centre (DPIC) provides information to the public and health care professionals on acute poisonings. The DPIC received 41,000 enquiries during the first three years of its existence as an open 24h telephone service. The aim of this data register study was to classify all substance exposures, to gain knowledge of the status and trends in poisonings (toxico-surveillance) and to evaluate the development in the number of contacts. MATERIAL AND METHODS: Information and inquiries were continuously entered into a poison-centre database. A new classification system was established during the study to ensure that all agents were properly classified. A total of 41,139 calls were divided into 18 substance categories, each consisting of 3-11 subgroups. RESULTS: The number of contacts per year increased by 70% from 2007 to 2009. Three contacts per thousand individuals in the Danish population were registered in 2009. For all groups, except drugs of abuse, the data showed an increase in the actual number of exposures from 2008 to 2009. Pharmaceuticals represent one third of substance exposures, and analgesics constitute a third of these poisonings. A relative increase in contacts concerning household substances, plants and vitamins was observed. CONCLUSION: The classification gave detailed knowledge of the current poisoning status. Evaluation of subgroups showed a need for a larger number of subgroups to ensure a sufficient level of toxico-surveillance. Compared to other national poison centres, we predict a doubling in enquiries during the next ten years, mainly from the public.",1
12398,21538061,Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS),"The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and ?2 prior therapies were treated with belinostat 1,000 mg/m(2) IV on days 1-5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n?=?7) and chemotherapy (n?=?8). The patients were treated with a median of four cycles (range, 1-8) of belinostat. There was one confirmed response-hematologic improvement in neutrophils-for an overall response rate of 5% (95% CI, 0.2-23). Median overall survival was 17.9 months. Grades 3-4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n?=?10), thrombocytopenia (n?=?9), anemia (n?=?5), fatigue (n?=?2), febrile neutropenia (n?=?1), headache (n?=?1), and QTc prolongation (n?=?1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.",1
12399,21543290,Etanercept in the treatment of psoriasis and psoriatic arthritis with concomitant hepatitis C virus infection: clinical and virological study in three patients,"Treatment of patients with psoriasis and concomitant hepatitis-C virus (HCV) infection poses a therapeutic challenge because most systemic drugs are associated with potential hepatotoxicity, either due to direct liver damage or to immunosuppression. Among newly available drugs for the treatment of psoriasis and psoriatic arthritis, studies investigating the effect of anti-tumour necrosis factor-alpha in such patients are still limited. We describe three psoriatic patients with HCV, one with concomitant alcoholic hepatitis, who were treated with etanercept monotherapy for six months. We obtained good clinical responses for both psoriasis and arthritis in all three patients. While no significant changes in viral load and transaminases were observed in two patients, alanine aminotrasferase and gamma-glutamyltransferase levels were raised during treatment in the patient with concomitant alcoholic hepatitis. At baseline, one patient was negative and two were positive for mixed-type cryoglobulins. During treatment, none of the patients developed cryoglobulinemia-related clinical symptoms, and one of the two patients positive at baseline was negative for cryoglobulins at the end of follow-up. Our results add to accumulating data suggesting that etanercept represents a valuable therapeutic option for treatment of HCV-positive psoriatic patients, with an acceptable safety profile in the short-term. However, etanercept treatment of HCV cases with concomitant alcoholic hepatitis must be undertaken with caution.",1
12400,21546160,Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases,"Studies on the efficacy of ketamine in the treatment of chronic pain indicate that prolonged or repetitive infusions are required to ensure prolonged pain relief. Few studies address ketamine-induced toxicity. Here we present data on the occurrence of ketamine-induced liver injury during repeated administrations of S(+)-ketamine for treatment of chronic pain in patients with complex regional pain syndrome type 1 as part of a larger study exploring possible time frames for ketamine re-administration. Six patients were scheduled to receive 2 continuous intravenous 100-hour S(+)-ketamine infusions (infusion rate 10-20mg/h) separated by 16 days. Three of these patients developed hepatotoxicity. Patient A, a 65-year-old woman, developed an itching rash and fever during her second exposure. Blood tests revealed elevated liver enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and gamma-glutamyl transferase, all >/= 3 times the upper limit of normal) and modestly increased eosinophilic leukocytes. Patient E, a 48-year-old woman, developed elevated liver enzymes of similar pattern as Patient A during her second ketamine administration and a weakly positive response to antinuclear antibodies. In a third patient, Patient F, a 46-year-old man, elevated liver enzymes (alanine transaminase and gamma-glutamyl transferase) were detected on the first day of his second exposure. In all patients, the ketamine infusion was promptly terminated and the liver enzymes slowly returned to reference values within 2 months. Our data suggest an increased risk for development of ketamine-induced liver injury when the infusion is prolonged and/or repeated within a short time frame. Regular measurements of liver function are therefore required during such treatments.",1
12401,21552449,A Case of Drug-Induced Hepatitis due to Lenalidomide,"Lenalidomide is a recent thalidomide analog used for the treatment of refractory multiple myeloma. The main toxicity of this drug consists in severe neutropenia and thrombocytopenia. Lenalidomide-associated liver injury is rare, manifesting itself as elevated liver enzymes and hyperbilirubinemia reversible upon weeks after drug withdrawal. We report here in detail the clinical course as well as the biological and histological alterations of an acute lenalidomide-induced liver injury. Findings on liver biopsy allowed us to discriminate acute inflammatory changes due to the drug and minor associated lesions of graft-versus-host disease in this patient with recurrent myeloma after allogeneic bone marrow transplantation.",1
12402,21555686,"Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer","""PURPOSE: This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with MBC were randomly assigned 2:1 to receive docetaxel 80 mg/m2 once every 3 weeks plus axitinib 5 mg twice per day (combination arm) or placebo (placebo arm), following a lead-in phase I trial. The primary end point was time to progression (TTP). RESULTS: In all, 168 patients were enrolled; 112 were randomly assigned to axitinib and 56 to placebo. Median TTP was numerically longer in the combination arm than in the placebo arm (8.1 v 7.1 months), but this difference was not statistically significant (hazard ratio, 1.24; 95% CI, 0.82 to 1.87; one-sided P = .156). The difference in median TTP was greatest among patients who had received prior adjuvant chemotherapy (9.2 v 7.0 months; P = .043, prespecified subgroup analysis). Objective response rate was higher in the combination arm (41.1% v 23.6%; P = .011). The most common grades 3 to 4 treatment-related adverse events (combination/placebo) included diarrhea (10.8%/0%), fatigue (10.8%/5.4%), stomatitis (12.6%/1.8%), mucositis (9.0%/0%), asthenia (7.2%/0%), and hypertension (4.5%/0%). Three patients in the combination arm experienced serious thromboembolic events (one death). Febrile neutropenia was more frequent in the combination arm (15.3% v 7.1%); rates of other hematologic toxicities were comparable. Increased toxicity with axitinib was generally managed by dose reduction and/or growth factor support. CONCLUSION: The addition of axitinib to docetaxel did not improve TTP in first-line MBC treatment. Combination therapy may be more effective in patients previously exposed to adjuvant chemotherapy.""",1
12403,21561828,Baclofen-induced acute hepatitis in alcohol-dependent patient,,1
12404,21565649,"Developing consumer-centered, nonprescription drug labeling a study in acetaminophen","BACKGROUND: In the U.S., acetaminophen overdose has surpassed viral hepatitis as the leading cause of acute liver failure, and misuse contributes to more than 30,000 hospitalizations annually. Half to two thirds of acetaminophen overdoses are unintentional, suggesting the root cause is likely poor understanding of medication labeling or failure to recognize the consequences of exceeding the recommended maximum daily dosage. PURPOSE: Elicit subject feedback about active ingredient and dosing information on over-the-counter (OTC) acetaminophen and elicit feedback on proposed plain-language text and icons. METHODS: Six focus groups, preceded by individual interviews, were conducted in April 2010 among 45 adults in two cities from two clinics and an adult basic education center. The individual interviews evaluated knowledge of OTC pain relievers, attention to product label information and literacy level while the group discussion elicited preference for label messages and icons. Analyses were conducted from April to June 2010. RESULTS: Forty-four percent read at or below the 6th-grade level. Individual interviews revealed that <50% of participants routinely examine product label information. Only 31% know acetaminophen is in Tylenol(R). The groups achieved consensus on a preferred icon for acetaminophen, desired explicit statement of potential liver damage in the warning against simultaneous use of acetaminophen products, and indicated preference for an icon and wording for maximum dose. CONCLUSIONS: With the high prevalence of OTC use, a consumer-centered approach to developing icons and messages to promote awareness and safe use of acetaminophen could benefit consumers.",1
12405,21570397,Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles,"BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8?10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1?10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8?10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2?10(-6)) and HLA-DQB1*0602 (P=5?10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3?10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.",1
12406,21572852,Hepatotoxicity from first line antiretroviral therapy: an experience from a resource limited setting,"""BACKGROUND: Highly active antiretroviral therapy (HAART) has been associated with liver toxicity. The role of monitoring for liver toxicity has not been well studied in resource-limited settings (RLS). OBJECTIVES: To determine the background prevalence and incidence of liver injury and describe the associated signs and symptoms of acute hepatitis after initiating HAART; and to determine the role of liver enzyme tests in monitoring hepatotoxicity. METHODS: In this prospective study, in Mulago Hospital AIDS Clinics, we consecutively enrolled adult patients initiated on one of three first line HAART regimens [Stavudine (d4T)-Lamivudine (3TC) and nevirapine (NVP); Zidovudine (AZT)-3TC and Efavirenz (EFV) or d4T-3TC-EFV]. We monitored ALT (alanine aminotransferase) and clinical evidence of acute hepatitis at baseline, 2(nd), 6(th), 10(th) and 14(th) week of therapy. RESULTS: Two hundred and forty HIV-positive HAART- na?ve patients were enrolled in the study. The baseline prevalence of transaminitis was 1.7% with an incidence of 4.2% at 14 weeks. Grade 3-4 hepatotoxicity was documented in 1.3%. Jaundice was seen in grade 2-4 ALT elevations. Being on concurrent HAART and antituberculous drugs was associated with grade 2-4 toxicity compared to those who were only on HAART [OR; 16.0 (95% CI; 2.4-104.2)]. CONCLUSIONS: Incidence of severe hepatotoxicity within three months of first-line antiretroviral therapy was low, suggesting that routine measurement of transaminases may not be necessary in all patients initiating HAART in RLS. Routine measurement may be important in following patients on HAART and concurrent TB treatment as well as those with jaundice to avoid missing hepatotoxicity.""",1
12407,21575891,Autoimmune hepatitis during infliximab therapy for Crohn's disease: a case report,"We present the case of a 60-year-old Caucasian male with Crohn's disease treated with infliximab. Within 14 weeks of treatment induction, an asymptomatic acute hepatitis was detected. Elevated autoantibodies and liver biopsy findings supported the diagnosis of autoimmune hepatitis. No competing aetiologies were present. The hepatitis completely responded to infliximab cessation and administration of corticosteroids. This case is the most compelling to date of an infliximab-induced autoimmune hepatitis. Although the role of liver enzyme monitoring is unclear, an awareness of this adverse effect is important, given the potential for a rapid and complete response to specific treatment.",1
12408,21576633,Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival,"PURPOSE: Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. PATIENTS AND METHODS: Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 ?g/m2/24 hours. RESULTS: Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. CONCLUSION: Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.",1
12409,21584420,Liver toxicity is rare in rheumatoid arthritis patients using combination therapy with leflunomide and methotrexate,"OBJECTIVE: Some studies have reported that adding leflunomide (LEF) to the treatment of rheumatoid arthritis (RA) in patients who do not respond to methotrexate (MTX) improved efficacy but increased the risk of liver toxicity. This study aimed at assessing the incidence of liver toxicity in patients with active RA using the LEF and MTX combination therapy in comparison with that of patients on MTX monotherapy. METHODS: Between February and September 2009, 97 consecutive patients followed up at the University Hospital of the Universidade Federal de Santa Catarina, Brazil, were enrolled. RA patients on MTX alone or using the LEF and MTX combination had their medical records systematically reviewed. The alanine/aspartate aminotransferase enzymes were retrospectively analyzed since the beginning of treatment with MTX or MTX plus LEF. Hepatotoxicity was defined as an increase of at least two-fold the upper limits of normal of the liver enzymes. RESULTS: 71 RA patients were included in the study: 36.6% were using 20-25 mg/week of MTX alone and 63.4% were using 20-25 mg/week of MTX plus 20 mg/day of LEF. Of the patients on the combination therapy, 11.1% had abnormal levels of liver enzymes versus 11.5% of the patients on monotherapy (P = 1.0). Abnormal aminotransferase levels have been seen with both MTX and LEF monotherapies in patients with RA. In our study, no difference was found between the percentages of aminotransferase elevations of patients being treated with MTX alone or in combination with LEF. CONCLUSION: The combination of MTX and LEF in RA patients is generally safe and well tolerated.",1
12410,21586591,Hepatic safety of antibiotics used in primary care,"Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre-clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co-trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome-wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity.",1
12411,21591943,Alemtuzumab induction in renal transplantation,"""BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).""",1
12412,21592453,The DRESS syndrome: a literature review,"""The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. We used the RegiSCAR scoring system that grades DRESS cases as """"no,"""" """"possible,"""" """"probable,"""" or """"definite"""" to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as """"probable/definite"""" DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with """"probable/definite"""" DRESS cases, whereas skin rash was described in almost all of the cases, including """"possible cases."""" Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice.""",1
12413,21596364,Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study),"""The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk.""",1
12414,21599576,Treatment recommendations for radioimmunotherapy in follicular lymphoma: a consensus conference report,"Radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab combines a radiation-emitting radionuclide with an antibody targeting CD20 to treat B-cell non-Hodgkin lymphoma. Multiple studies demonstrate favorable RIT efficacy and safety profiles in follicular lymphoma (FL). The primary toxicity is reversible myelosuppression. Various FL treatment options include single-agent immunotherapy, radiation, chemoimmunotherapy, and RIT. Examining RIT clinical effects and position within treatment algorithms is important to optimal patient benefit. Clinical studies support using single-agent RIT in relapsed/refractory FL, in selected patients with new, untreated FL, and as consolidation after induction chemotherapy or chemoimmunotherapy. RIT as consolidation enhances response rates (with conversion of partial to complete responses following induction therapy) and prolongs disease control versus observation. The overall response rate is 60-80% in the relapsed setting. Time to progression is longer with low-bulk disease, fewer prior therapies, and retained rituximab sensitivity. RIT apparently does not preclude subsequent therapies or increase risk of secondary malignancies compared with chemotherapy's known risk. This article summarizes consensus recommendations for RIT and presents RIT treatment algorithms developed by hematologists/oncologists who regularly treat patients with FL. Maximizing RIT benefit requires healthcare providers to utilize algorithms assisting with treatment decisions.",1
12415,21601431,"Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence","""Research in the area of herbal psychopharmacology has increased markedly over the past decades. To date however, a comprehensive review of herbal antidepressant, anxiolytic and hypnotic psychopharmacology and applications in depression, anxiety and insomnia has been absent. A search of MEDLINE (PubMed), CINAHL, PsycINFO, and the Cochrane Library databases was conducted (up to February 21st 2011) on commonly used psychotropic herbal medicines. A review of the literature was conducted to ascertain mechanisms of action of these botanicals, in addition to a systematic review of controlled clinical trials for treatment of mood, anxiety and sleep disorders, which are common comorbid psychiatric disorders. Specific emphasis was given to emerging phytomedicines. Analysis of evidence levels was conducted, as were effect sizes (Cohen's d) where data were available. Results provided evidence of a range of neurochemical, endocrinological, and epigenetic effects for 21 individual phytomedicines, which are detailed in this paper. Sixty six controlled studies were located involving eleven phytomedicines. Several of these provide a high level of evidence, such as Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. Several human clinical trials provide preliminary positive evidence of antidepressant effects (Echium amoenum, Crocus sativus, and Rhodiola rosea) and anxiolytic activity (Matricaria recutita, Ginkgo biloba, Passiflora incanata, E. amoenum, and Scutellaria lateriflora). Caution should however be taken when interpreting the results as many studies have not been replicated. Several herbal medicines with in vitro and in vivo evidence are currently unexplored in human studies, and along with use of emerging genetic technologies """"herbomics"""", are areas of potential future research.""",1
12416,21611719,"Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena","The terminal complement inhibitor eculizumab has become the standard of treatment in patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). In this retrospective study, 19 PNH patients received chronic therapy with eculizumab with a median duration of 16 months (range 6-46 months). Parameters of hemolysis, transfusion requirements, and serum iron parameters were analyzed. Lactate dehydrogenase levels were significantly decreased by 85% from a median of 1897 U/l (range 293-3360) to 283 U/l (range 143-667), with an 86% reduction of transfusion requirements, whereas other parameters of hemolysis remained abnormal. Six patients (31.6%) became completely transfusion independent. A significant increase in ferritin levels from a median of 104 ?g/l before to a median of 528 ?g/l (p = 0.011) during treatment with eculizumab was observed. This was more pronounced in patients with low reticulocyte production index and/or requiring blood transfusions. Monospecific direct Coombs test was positive in most PNH patients, indicating a shift to extravascular hemolysis. Positive immunofixation for IgG kappa was observed, due to the presence of eculizumab in the serum. Eculizumab was safe and well tolerated long term in our study population. Iron should not be routinely supplemented in PNH patients treated with eculizumab without close monitoring of iron parameters, and iron depletion therapy should be considered in the case of overload.",1
12417,21612962,"""Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate""","""Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). STUDY DESIGN: Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. RESULTS: Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 ?mol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p?0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. CONCLUSIONS: These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.""",1
12418,21618201,Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate,"OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [?10 mg/kg] on day 1) or IV abatacept (?10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.",1
12419,21621876,[Ibuprofen-induced cholestatic hepatitis],,1
12420,21628399,Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up,"""Patients with ?-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ? 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ? 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ? 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ? 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ? 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ? 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with ?-thalassemia suggests treatment for ? 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.""",1
12421,21631324,gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma,"""BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).""",1
12422,21632851,Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response,"""PURPOSE: Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response. EXPERIMENTAL DESIGN: Thirty-three patients received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating """"disease progression"""" in context of a 50% or more decline in PSA level, with scan improvement or stability 3 months later. RESULTS: A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients. Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (?0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was indicated in radiologist's report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11 of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports. CONCLUSION: Clinical responses to abiraterone plus prednisone were frequent and durable in men with metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on patient management and interpretation of results. Clin Cancer Res; 17(14); 4854-61. ?2011 AACR.""",1
12423,21633602,Lapatinib-induced hepatitis: a case report,"Lapatinib is an inhibitor of the tyrosine kinases of human epidermal growth factor receptor type 2 (HER2) and epidermal growth factor receptor type 1, with clinical activity in HER2-positive metastatic breast cancer. We present here a 60 year-old patient with metastatic breast cancer who presented with jaundice and increased serum aminotransferase levels and who had been treated with lapatinib for the previous 14 days. Laboratory tests excluded other causes of acute liver injury. Liver biopsy revealed lesions compatible with drug-induced hepatotoxicity. Bilirubin and liver enzymes returned to normal within three months of lapatinib discontinuation. Lapatinib should be included among the causes of drug-induced hepatitis.",1
12424,21639808,Improved survival with vemurafenib in melanoma with BRAF V600E mutation,"""BACKGROUND: Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS: We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS: At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).""",1
12425,21639816,Pharmacokinetic evaluation of levocetirizine,"INTRODUCTION: There have recently been guidelines developed for the diagnosis and treatment of rhinitis and urticaria. For both conditions, second-generation antihistamines remain as the first-line therapy. AREAS COVERED: The article presents the current pharmacology, chemical properties, pharmacokinetics and metabolism of levocetirizine. The article also reviews the clinical efficacy of levocetirizine for seasonal allergic and perennial rhinitis, as well as chronic urticaria. The article is formed through the review of all the published literature in English retrieved from the PubMed/MEDLINE database between 1966 and March 2011 using the search terms: levocetirizine, allergic rhinitis, chronic urticaria and antihistamine. Furthermore, the article also reviews data provided by the manufacturer in addition to reports from governmental agencies. EXPERT OPINION: Levocetirizine has several pharmacokinetic properties that are desirable for an antihistamine providing a combination of both potency and safety. Its clinical advantages are derived from its rapid and extensive absorption, limited distribution and its very low degree of metabolism. Furthermore, levocetirizine scores very highly in terms of clinical efficacy as well as in patient/physician satisfaction studies. Given the lack of large multi-center studies that compare the treatment options for urticaria, clinicians must rely on potency studies when choosing treatment and levocetirizine does score very highly. However, other potent skin antihistamines, such as desloratadine or fexofenadine, should be preferred for patients who have a strict contraindication to the sedative effects of the drug.",1
12426,21644468,"Adverse effects of multi-drug therapy in leprosy, a two years' experience (2006-2008) in tertiary health care centre in the tribal region of Chhattisgarh State (Bastar, Jagdalpur)","""OBJECTIVE: To assess the adverse effects of multi drug therapy (MDT) in leprosy patients. METHODS: A prospective and descriptive study carried out in Department of Dermatology, Government Medical College, Jagdalpur. The adverse effects were recorded on the personal record of every individual patient, filled during the course of treatment. RESULTS: 176 patient's records were analysed, looking for adverse effects. Among the 176 patients, 79 had adverse effects due to one or more components of MDT, 73 had adverse effects due to dapsone, eight due to rifampicin and 16 due to clofazimine. Mean (+/- SD) duration for the development of adverse effects from the start of therapy was 1.99 (+/- 0.69) months for dapsone, 36 (+/- 0.68) months for rifampicin and 7.13 (+/- 0.79) months for clofazimine. There was a significant (P < 0.05) correlation between adverse effects and low Body Mass Index (BMI). The suspected drug was stopped and an alternative regime started in nine patients; six had dapsone stopped, two had rifampicin stopped and one had clofazimine stopped. CONCLUSION: Adverse effects attributed to MDT are comparable to previous studies and we found that ADR due to Dapsone was very high but most of the ADR were managed by supportive treatment without replacing the suspected drug.""",1
12427,21654262,Pregabalin-induced hepatotoxicity,,1
12428,21659968,Belimumab (Benlysta) for systemic lupus eruthematosus,,1
12429,21660145,Black Cohosh Hepatic Safety: Follow-Up of 107 Patients Consuming a Special Cimicifuga racemosa rhizome Herbal Extract and Review of Literature,"European Medicines Agency (EMEA) and the Committee on Herbal Medicinal Products (HMPC) on July 2006 have released an alert to get European sanitary authorities aware of 42 cases of suspected hepatotoxic reactions in patients consuming Cimicifuga racemosa rhizome. In the public statement EMEA itself considered reliable as hepatotoxic reactions only four cases, on the base of RUCAM score: two were considered possible and two probable. Lacking in almost all of them a precise description of cases, especially a botanical-chemical analysis of the suspected substance, we think there is no real proof of supposed C. racemosa rhizome hepatotoxicity. In our department we administer from about 10 years C. racemosa as special herbal dry extract as single substance or mixed with other medicinal plants at the dose of 500-1000?mg daily, for treatment of menopause related disorders without any reported adverse effect. After EMEA's official signal we have contacted all our patients using a C. racemosa rhizome herbal extract continuously from more than 12 months to verify possible hepatotoxic effects. We followed-up 107 women, and asked them by telephone (33/107) and/or after anamnesis and clinical examination (74/107) to undergo a blood sample examination. In all the patients there was no sign of hepatic disease, or worsening of already altered but stable parameters. We think on the base of these data and current literature C. racemosa rhizome extract should not be considered a potential hepatotoxic substance.",1
12430,21666089,Ulipristal acetate for emergency contraception,"OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of data of ulipristal acetate, a new emergency contraceptive approved for use up to 120 hours after unprotected intercourse. DATA SOURCES: Articles pertaining to the topic were identified and reviewed through searches of PubMed (1994-March 2011) and clinicaltrials.gov, using the key terms ulipristal and CDB-2914. Ella approval documents were obtained and reviewed from Drugs@FDA on the Food and Drug Administration (FDA) Web site. STUDY SELECTION AND DATA EXTRACTION: All published data and FDA approval documents examining pharmacologic, pharmacokinetic, and clinical studies related to ulipristal acetate as an emergency contraceptive were evaluated. Selected studies included 3 randomized trials and 1 meta-analysis. DATA SYNTHESIS: Ulipristal acetate is a progesterone agonist/antagonist emergency contraceptive approved for the prevention of pregnancy to be taken as soon as possible, within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. Based upon results of the Phase 3 clinical trials used to obtain approval, ulipristal acetate administration was at least as effective as levonorgestrel in the reduction of pregnancy rate when studied alone after unprotected intercourse and when taken up to 120 hours after unprotected intercourse. Commonly reported adverse effects associated with ulipristal acetate in trials included headache, breast tenderness, nausea, and abdominal pain. CONCLUSIONS: Ulipristal acetate is effective as an emergency contraceptive for up to 120 hours after unprotected intercourse. Because ulipristal is available only via prescription, it may be covered by insurance. However, the additional factors of travel expenses and time to make and attend a physician appointment must be taken into account when considering use of ulipristal as an emergency contraceptive. Due to the similarity of its structure to mifepristone, controversy regarding ulipristal's mechanism of action has arisen.",1
12431,21672924,Efficacy and safety of a levonorgestrel enteric-coated tablet as an over-the-counter drug for emergency contraception: a Phase IV clinical trial,"BACKGROUND: An enteric-coated levonorgestrel emergency contraceptive pill (E-LNG-ECP) is an improved formulation, in terms of side effects, which both dissolves and is absorbed in the intestine. Our aim was to evaluate the efficacy and safety of E-LNG-ECP as an over-the-counter (OTC) drug for emergency contraception (EC) in Chinese women. METHODS: A Phase IV clinical trial was conducted in five family planning clinics in China. Women seeking EC within 72 h after unprotected sexual intercourse or contraceptive failure who met the inclusion criteria were recruited. The efficacy of contraception (primary end-point was pregnancy rate), side effects (i.e. safety) and the value of E-LNG-ECP for EC were investigated. RESULTS: Of 2445 women (aged 15-48 years) who took E-LNG-ECP with follow-up to determine pregnancy, only five pregnancies (0.2%) occurred. The efficacy of contraception was 95.3%. In total, 6.5% of women reported at least one adverse event after taking E-LNG-ECP, and no serious adverse events were reported. Only four subjects (0.16%) reported vomiting. The incidence of menstrual cycle disturbance was 20.1% after taking E-LNG-ECP. Subjects who had previously taken ECPs (54.4% of these women) rated the acceptability of E-LNG-ECP at 9.36 (on a 10-point scale) higher (P<0.05) than the rating of other LNG-EC pills taken previously. CONCLUSIONS: The study found that E-LNG-ECP was effective, safe and well tolerated as an OTC drug. However, an randomized controlled trial should be performed to compare standard LNG tablets with E-LNG-ECP.",1
12432,21677326,Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications,"Herb induced liver injury (HILI) is a particular challenge that also applies to purported cases presumably caused by black cohosh (BC), an herb commonly used to treat menopausal symptoms. We analyzed and reviewed all published case reports and spontaneous reports of initially alleged BC hepatotoxicity regarding quality of case details and causality assessments. Shortcomings of data quality were more evident in spontaneous reports of regulatory agencies compared to published case reports, but assessments with the scale of CIOMS (Council for the International Organizations of Sciences) or its updated version revealed lack of causality for BC in all cases. The applied causality methods are structured, quantitative, and liver specific with clear preference over an ad hoc causality method or the liver unspecific Naranjo scale. Reviewing the case data and the reports dealing with quality specifications of herbal BC products, there is general lack of analysis with respect to authentication of BC in the BC products used by the patients. However, in one single regulatory study, there was a problem of BC authentication in the analysed BC products, and other reports addressed the question of impurities and adulterants in a few BC products. It is concluded that the use of BC may not exert an overt hepatotoxicity risk, but quality problems in a few BC products were evident that require additional regulatory quality specifications.",1
12433,21677899,"A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome","""STUDY OBJECTIVE: To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS). METHODS: This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as """"very much"""" or """"much"""" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events. RESULTS: 325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: -3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo-treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg). CONCLUSIONS: GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated.""",1
12434,21680702,"Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases--safety, pharmacokinetics, and pharmacodynamics","The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ? 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility.",1
12435,21683321,"Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial)","""AMR101 is an omega-3 fatty acid agent containing ?96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (?500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG ?500 mg/dl and ?2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo-corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (-2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A(2), very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels.""",1
12436,21685549,Lactic acidosis and symptomatic hyperlactataemia in a randomized trial of first-line therapy in HIV-infected adults in South Africa,"""BACKGROUND: Lactic acidosis (LA) is a potentially life-threatening complication of antiretroviral (ARV) therapy. Few randomized prospective studies have compared LA between different ARV regimens. METHODS: Characterization of cases of LA (serum lactate >5 mmol/l and arterial pH<7.35 or bicarbonate <20 mmol/l) and symptomatic hyperlactataemia (SH; serum lactate >2.2 mmol/l and symptoms) was made in a randomized open-label 2x2 factorial study of stavudine/lamivudine (d4T/3TC)-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz (EFV)-based therapy in 1,771 HIV-infected adults initiating therapy between 2004 and 2008. RESULTS: The LA incident rate was 3.5/1,000 person-years (95% CI 1.8-5.9), and for combined LA/SH was 11.0/1,000 person-years (95% CI 7.9-14.9). There were two deaths (15% mortality) among 13 LA cases; all 11 survivors experienced symptom resolution and started new ARV regimens. LA cases were more likely to be female (OR 7.19, 95% CI 1.84-40.75; P=0.001) and had a higher body mass index (BMI; P<0.0001) compared with non-cases. There was no increase in LA according to ARV regimen, age or CD4(+) T-cell count at randomization. When combined, LA/SH cases (n=41) were more often female (OR 4.76, 95% CI 2.36-10.08; P<0.0001), had increased BMI (P<0.0001), were more likely to be assigned d4T/3TC (OR 3.17, 95% CI 1.50-7.28; P=0.001) and were more likely to be assigned EFV (OR 2.18, 95% CI 1.08-4.61; P=0.026). CONCLUSIONS: Female sex and increased BMI were associated with severe LA in this large randomized trial of first-line ARV in South Africa. While female sex, increased BMI and d4T are previously described risk factors for the development of clinically significant lactate elevations, the independent risk associated with EFV is a novel observation warranting further investigation.""",1
12437,21686945,Acute liver impairment after sodium valproate overdose,"Liver impairment is a recognised adverse effect of long-term sodium valproate treatment, but there are few reports concerning its occurrence after acute overdose. This report describes a 36-year-old woman who deliberately ingested 32 g of sodium valproate (Epilim). Serum valproate concentration was 4370 ?mol/l (630 mg/l) at 4.3 h post-ingestion (therapeutic reference range: 300-600 ?mol/l), and the elimination half-life was 14.1 h. Liver biochemistry tests were initially normal but gradually became impaired, and highest alanine aminotransferase (761 U/l) occurred 2.3 days after ingestion. Supportive measures alone were sufficient to allow recovery of liver function. This case indicates that sodium valproate overdose may cause acute hepatocellular injury, even in the absence of pre-existing liver disease.",1
12438,21688986,Liver toxicity of antiretroviral combinations including fosamprenavir plus ritonavir 1400/100?mg once daily in HIV/hepatitis C virus-coinfected patients,"Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV-coinfected patients, including those with cirrhosis.",1
12439,21693205,Posttransplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving thymoglobulin: a systematic review,"""Posttransplantation lymphoproliferative disorder (PTLD) is an important complication of transplantation. Risk factors include increased overall immunosuppression exposure and inadequate antiviral prophylaxis; however, the effects of T-cell-depleting agents on PTLD are unclear. A systematic literature review was conducted to assess PTLD in clinical studies published 1999-2009 in transplant patients with ? 3 years follow-up who received Thymoglobulin for induction. Twenty studies were identified (12 kidney, 7 heart, and 1 liver), of which 3 were excluded for insufficient PTLD reporting. The final study group comprised 2,246 kidney and heart transplant recipients (liver study excluded) who received Thymoglobulin. At a median follow-up of 5 years, the incidence of PTLD was 0.98% (kidney, 0.93%; heart, 1.05%) among Thymoglobulin-treated patients. The cumulative Thymoglobulin dose reported in these studies was not associated with the development of PTLD (P = NS). However, incidence of PTLD was significantly lower with antiviral prophylaxis (0.63%) than without (1.87%; P = .013). Heart transplant recipients not receiving antiviral prophylaxis had the highest PTLD incidence, possibly attributable to a greater overall immunosuppressive burden. This analysis revealed that PTLD incidences in kidney and heart transplant recipients receiving Thymoglobulin were low overall and perhaps related more to concomitant anti-viral prophylaxis use.""",1
12440,21695388,"Efficacy and safety of micafungin as an empirical therapy for invasive fungal infections in patients with hematologic disorders: a multicenter, prospective study","This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of ?-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150�mg/day and 13�days, respectively. The overall response rate for suspected IFIs (n?=?119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n?=?81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.",1
12441,21696307,Telaprevir for previously untreated chronic hepatitis C virus infection,"""BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).""",1
12442,21696520,Evaluation of the physicians' approach to the diagnosis and treatment of patients with antituberculosis drug-induced hepatotoxicity,"""OBJECTIVES: To describe the practices of physicians on the diagnosis and treatment of antituberculosis drug-induced hepatotoxicity (ATH), and to evaluate the concordance between these practices and the American Thoracic Society (ATS) 2006 guidelines. METHODS: Information was reviewed on 670 new cases of tuberculosis patients aged not less than 15 years and registered at the outpatient clinics of a large hospital in southern Thailand during October 2006 to September 2009. The patient was identified as having ATH if: (1) he/she was diagnosed as transaminitis, hepatitis or hepatotoxicity from antituberculosis (anti-TB) drugs; (2) their treatment regimen was subsequently modified by their attending physicians; and (3) their liver enzyme decreased after withdrawal of the suspected anti-TB drugs. Compliance with the ATS guidelines was considered on diagnosis, initial management, selection of alternative regimens, and a reintroduction strategy. RESULTS: The prevalence of ATH was 6.7%. The proportion of patients diagnosed as ATH in accordance with the ATS 2006 guidelines was 73.8%. For the initial management, isoniazid, rifampicin and pyrazinamide were concurrently stopped in 55.0% of patients. While waiting for normalization of liver enzymes, 28 patients (70.0%) were treated with alternative regimens and 12 patients (30.0%) took no drug. Only 47.5% of the ATH patients received a regimen in accordance with ATS guidelines, including three less hepatotoxic drugs (ethambutol, ofloxacin and streptomycin). Of 34 patients who discontinued the treatment, anti-TB drugs were reintroduced sequentially in 30 patients (88.2%). Of these, only 23.4% were firstly rechallenged with rifampicin as suggested by the ATS guidelines. CONCLUSIONS: The practice of physicians on the diagnosis and management of ATH varied. The practices of physicians on the diagnosis and rechallenged method were in high compliance with the ATS guidelines. For the initial management and selection of alternative regimens, the physicians' compliance was not good.""",1
12443,21701192,Acute toxicity of ingested fluoride,"This chapter discusses the characteristics and treatment of acute fluoride toxicity as well as the most common sources of overexposure, the doses that cause acute toxicity, and factors that can influence the clinical outcome. Cases of serious systemic toxicity and fatalities due to acute exposures are now rare, but overexposures causing toxic signs and symptoms are not. The clinical course of systemic toxicity from ingested fluoride begins with gastric signs and symptoms, and can develop with alarming rapidity. Treatment involves minimizing absorption by administering a solution containing calcium, monitoring and managing plasma calcium and potassium concentrations, acid-base status, and supporting vital functions. Approximately 30,000 calls to US poison control centers concerning acute exposures in children are made each year, most of which involve temporary gastrointestinal effects, but others require medical treatment. The most common sources of acute overexposures today are dental products - particularly dentifrices because of their relatively high fluoride concentrations, pleasant flavors, and their presence in non-secure locations in most homes. For example, ingestion of only 1.8 ounces of a standard fluoridated dentifrice (900-1,100 mg/kg) by a 10-kg child delivers enough fluoride to reach the 'probably toxic dose' (5 mg/kg body weight). Factors that may influence the clinical course of an overexposure include the chemical compound (e.g. NaF, MFP, etc.), the age and acid-base status of the individual, and the elapsed time between exposure and the initiation of treatment. While fluoride has well-established beneficial dental effects and cases of serious toxicity are now rare, the potential for toxicity requires that fluoride-containing materials be handled and stored with the respect they deserve.",1
12444,21701442,Ipilimumab (Yervoy) for metastatic melanoma,,1
12445,21702069,Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality?,"""PURPOSE: Causality assessment of cases with herbal hepatotoxicity represents a major regulatory challenge and included, in the past, the application of a diagnostic algorithm consisting of causality evaluation methods with either liver-specific or liver-unspecific characteristics. To evaluate various causality assessing methods in cases with suspected herbal hepatotoxicity, two different scales were now used for reasons of comparison. METHODS: We used the liver-specific scale of the updated Council for International Organizations of Medical Sciences (CIOMS) as well as the Naranjo scale that is not organ specific and therefore not liver specific. Both scales were applied to 22 cases of spontaneous reports with initially assumed herbal hepatotoxicity caused by black cohosh, used for menopausal symptoms. RESULTS: The analysis shows that causality was either unlikely (n = 6) or excluded (n = 16), using the updated CIOMS scale. There were various confounding variables: pre-existing liver diseases (n = 6) including genuine autoimmune hepatitis or alcoholic or cardiac hepatopathy; hepatotoxicity induced by interferon or fluoxetine (n = 2); marginally increased serum activities of alanine aminotransferase (n = 2) or gamma-glutamyltranspeptidase (n = 2) of unassessable causality; a mixed group consisting of unassessable cases (n = 6) and cases with questionable, poorly documented hepato-biliary diseases (n = 3); and rosuvastin-induced rhabdomyolysis (n = 1). These confounding factors were not recognized by the Naranjo scale. CONCLUSIONS: Structured hepatotoxicity-specific causality assessment methods such as the updated CIOMS scale are the preferred tools for causality assessment of assumed herbal hepatotoxicity and should replace the liver-unspecific Naranjo scale. Applying the updated CIOMS scale to cases with initially assumed hepatotoxicity by BC, causality was now found either unlikely or excluded.""",1
12446,21705899,Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy,"""OBJECTIVE: Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen. DESIGN: Case report. SETTING: Johns Hopkins Hospital. PATIENT: A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated. INTERVENTIONS: She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter. MEASUREMENTS AND MAIN RESULTS: Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began to return to normal. CONCLUSIONS: We suggest that the biochemical data are consistent with the osmotic gliopathy theory--high plasma ammonia leads to high plasma glutamine--an indicator of excess glutamine in astrocytes (the site of brain glutamine synthesis). This excess glutamine leads to osmotic stress in these cells. The lag in recovery of brain function presumably reflects time taken for the astrocyte glutamine concentration to return to normal. We hypothesize that an inhibitor of brain glutamine synthesis may be an effective treatment modality for acute liver failure.""",1
12447,21708411,Antiarrhythmic drugs for the maintenance of sinus rhythm: risks and benefits,"Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice, and its complications impose a significant economic burden. The development of more effective agents to manage patients with AF is essential. While clinical trials show no major differences in outcomes between rate and rhythm control strategies, some patients with AF require treatment with antiarrhythmic drugs (AADs) to maintain sinus rhythm, reduce symptoms, improve exercise tolerance, and improve quality of life. Currently available AADs, while effective, have limitations including limited efficacy, adverse events, toxicity, and proarrhythmic potential. The 6 most commonly used AADs (amiodarone, disopyramide, dofetilide [USA but not Europe], flecainide, propafenone, sotalol) have proarrhythmic effects (fewer with amiodarone). Amiodarone is the most effective AAD, but its safety profile limits its usefulness. Recent advances in AAD therapy include dronedarone and vernakalant. Dronedarone, approved by the United States Food and Drug Administration and the European Medicines Authority and others, has been proven efficacious in maintaining sinus rhythm and reducing the incidence of hospitalization due to cardiovascular events or death in patients with AF. The intravenous formulation of vernakalant is approved in the European Union, Iceland, and Norway. Oral vernakalant is currently undergoing evaluation for preventing AF recurrence and appears to be effective with an acceptable safety profile. Treatment should be individualized to the patient with consideration of pharmacologic risks and benefits according to AF management guidelines. Accumulating efficacy and safety data for new and emerging AADs holds promise for improved AF management and outcomes.",1
12448,21710108,Profile and pattern of Stevens-Johnson syndrome and toxic epidermal necrolysis in a general hospital in Singapore: treatment outcomes,"""Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life-threatening, reactions to medications. Both conditions have significant morbidity and mortality. The aim of this study was to document the epidemiological features, aetiologies, treatment and clinical outcomes of retrospectively reviewed data of all patients with SJS or TEN treated from January 2004 to November 2010 in a general hospital. There were 18 cases of SJS, seven cases of SJS/TEN overlap and three cases of TEN. Mean age was 50.6 years, with a range of 13-85 years. The male/female ratio was 1. Drugs accounted for 26 cases; one case was caused by Neisseria gonorrhoea infection. Anti-convulsants (35.7%) were the most common implicated drugs followed by antibiotics (28.5%), non-steroidal anti-inflammatory drugs (NSAIDS) (14.3%), allopurinol (7.1%) and traditional Chinese medication (7.1%). In seven cases, multiple drugs were implicated. Most SJS cases (88%) were treated with corticosteroids, of which 61% were given high-dose systemic corticosteroids. No infective complications were observed. Six out of the seven SJS/TEN overlap syndrome and all three TEN cases were given intravenous immunoglobulins. One patient with TEN died. In conclusion, anti-convulsants, especially carbamazepine, were the most frequently implicated drugs, followed by antibiotics and NSAIDS. High-dose corticosteroids were effective in SJS, whereas intra-venous immunoglobulin were useful in TEN and SJS/TEN overlap syndrome.""",1
12449,21714770,Cholestatic hepatitis related to amoxicillin,"While it is well recognized that the combination of amoxicillin and clavulanic acid has been associated with hepatic adverse events, there are only a few reports about amoxicillin alone causing hepatic toxicity. We describe a 34-year-old woman who developed severe cholestatic hepatitis following amoxicillin treatment.",1
12450,21719588,Efficacy and safety of sustained-release niacins,,1
12451,21723455,Prolonged-release melatonin for children with neurodevelopmental disorders,"""Previous studies demonstrated the efficacy and safety of prolonged-release melatonin in children and adolescents with neurodevelopmental and behavioral disorders. The long-term effectiveness and safety of prolonged-release melatonin treatment were assessed in 88 children (42 girls and 46 boys) with neurodevelopmental disorders. These patients participated in a compassionate-use program with the drug Circadin (2 mg; Neurim Pharmaceuticals, Tel Aviv, Israel) in France, and received treatment in the context of regular care by a specialized physician. The study involved a structured questionnaire for the�parents, comprising a combination of multiple-choice and numeric questions addressing sleep onset/offset, sleep quality problems, and mood. The dose of melatonin ranged from 4-6 mg, and treatment duration ranged from 6-72 months. Within 3 months, sleep latency with prolonged-release melatonin decreased by 44.0% (P < 0.001), sleep duration increased by 10.1% (P < 0.001), the number of awakenings decreased by 75% (P < 0.001), and sleep quality improved by 75%, compared with baseline (P < 0.001). No serious adverse events or treatment-related comorbidities were reported. Prolonged-release melatonin remains a safe, effective therapy for the long-term treatment of sleep disorders in children with neurodevelopmental disorders.""",1
12452,21726014,Misuse of acetaminophen in the management of dental pain,"PURPOSE: We highlight the risk associated with acetaminophen misuse in patients having dental pain in France based on a series of cases of unintentional acetaminophen overdose reported by the Emergency Dental Service of Nancy over a 9-month period. METHODS: Data were collected by querying the French Pharmacovigilance database. Each retrieved clinical data were reviewed by a clinician. RESULTS: Thirteen cases of acetaminophen overdose were reported to the Regional Pharmacovigilance Center of Lorraine, Nancy, France. Most cases (10/13) concerned men aged 20-40 years old. Mild, unspecific clinical symptoms were observed in seven of 13 patients. The median value of the supposed ingested dose was 137 mg/kg/24 h. Liver enzyme activity was tested in 10 patients and was abnormal in four patients. N-acetylcysteine treatment was administered to four patients. CONCLUSIONS: We propose that even patients with mild clinical symptoms with a supposed ingested dose of acetaminophen greater than 150 mg/kg/24 h should be referred to an emergency department and that liver enzyme activity should be analyzed. No case of liver failure was observed during our short survey. However, hepatotoxicity of repeated supratherapeutic ingestion of acetaminophen was suspected in four patients. Patients and practitioners should thus be better informed about the risk of unintentional acetaminophen overdose following supratherapeutic acetaminophen ingestion.",1
12453,21726841,Comparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting,"""Atrial fibrillation (AF) is common after coronary artery bypass grafting (CABG) and increases the morbidity and cost. Amiodarone reduces AF after CABG. Ranolazine, an antianginal agent, also prolongs atrial refractoriness and inhibits after depolarizations and triggered activity; effects that could decrease AF after CABG. The present study compared amiodarone versus ranolazine for the prevention of AF after CABG. A retrospective cohort study of patients undergoing CABG at Aspirus Hospital from June 2008 to April 2010. The patients received either amiodarone (400 mg preoperatively followed by 200 mg twice daily for 10 to 14 days) or ranolazine (1,500 mg preoperatively followed by 1,000 mg twice daily for 10 to 14 days). The primary end point was any identified AF after CABG. A total of 393 consecutive patients undergoing CABG (mean age 65 ? 10 years, 72% men) received either amiodarone (n = 211 [53.7%]) or ranolazine (n = 182 [46.3%]). AF occurred in 26.5% of the amiodarone-treated patients compared to 17.5% of the ranolazine-treated patient (p = 0.035). The univariate predictors of AF included amiodarone use, age, chronic lung disease, and congestive heart failure. The multivariate predictors of AF included amiodarone use (odds ratio 1.7, 95% confidence interval 1.01 to 2.91, p = 0.045 vs ranolazine), age (odds ratio 2.2 per 10 years, 95% confidence interval 1.63 to 2.95, p <0.001), and chronic lung disease (odds ratio 1.86, 95% confidence interval 1.00 to 3.43, p = 0.049). No difference was found in the risk of adverse events between the 2 therapies. In conclusion, ranolazine was independently associated with a significant reduction of AF compared to amiodarone after CABG, with no difference in the incidence of adverse events. Randomized studies should be conducted to confirm these results.""",1
12454,21729690,Hepatitis C reactivation in patients who have diffuse large B-cell lymphoma treated with rituximab: a case report and review of literature,"""BACKGROUND: Whether to interrupt or to continue induction therapy for lymphoma when hepatitis C virus (HCV) reactivation occurs during therapy with rituximab and chemotherapy remains a controversial question. There is limited evidence-based literature to help guide the management of patients with lymphoma in the setting of HCV reactivation. To address this issue we report an illustrative case and review the prevalence of non-Hodgkin lymphoma (NHL) in HCV-infected patients; the role of HCV in lymphomagenesis; the role of antiviral therapy in the management of HCV-associated lymphomas; as well as comparing the outcomes for NHL patients with and without HCV infection. CASE REPORT: A patient diagnosed with diffuse large B-cell lymphoma was treated with rituximab and chemotherapy with the patient achieving a complete remission, but treatment was complicated by asymptomatic HCV reactivation. Because conflicting data exist regarding management of such cases, the criteria for discontinuing chemotherapy, in the event of escalation in HCV replication in an asymptomatic patient, remain unclear. CONCLUSION: Patients with HCV have increased prevalence of marginal zone lymphoma, diffuse large B-cell lymphoma, and lymphoplasmacytic lymphoma. Whether HCV has a role in the lymphomagenesis is still uncertain, and limited to conjecture. The question whether to treat HCV-related lymphomas with antiviral therapy is debatable and not well-supported. Without initial liver dysfunction, HCV-infected patients can experience a similar outcome compared to their HCV-negative counterparts when treated with standard chemotherapy/immunotherapy despite differences in the presentation of the disease.""",1
12455,21735310,Cardiotoxicity and serotonin syndrome complicating a milnacipran overdose,"Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor, recently approved for use in the USA for treatment of fibromyalgia. This case report describes a 59-year-old woman who ingested 3,000 mg of milnacipran in a suicide attempt. Following the ingestion, she became obtunded and developed autonomic instability. She required mechanical ventilation, treatment for hypertension, and then ultimately vasopressor support for refractory hypotension. In addition, she developed a transient, acute cardiac dysfunction with global hypokinesis and an ejection fraction of 30%. Resolution of the cardiac dysfunction was documented on repeat echocardiogram 2 days after the initial study. This was confirmed by cardiac catheterization performed 4 days after the acute ingestion in which coronary arteriogram was normal and left ventricular ejection fraction was 70%. Acute overdose was confirmed by quantification of plasma milnacipran concentration of 8,400 ng/mL obtained 5 h post-ingestion. To our knowledge, this represents the first case of cardiac toxicity complicating a milnacipran overdose in the medical literature.",1
12456,21737904,Acute pancreatitis in the course of meprobamate poisoning,"CONTEXT: We report a case of massive poisoning with meprobamate leading to acute pancreatitis. CASE REPORT: A 43-year-old patient with a history of schizophrenia and multiple suicide attempts was admitted to the intensive care unit for severe poisoning with meprobamate (voluntary ingestion of 60 g). On admission, the patient was deeply comatose with low blood pressure and hypothermia. Laboratory analysis revealed leukocytosis and high lipase and amylase serum levels. There was no eosinophilia. Abdominal computed tomography showed pancreatitis grade A. The patient was intubated and ventilated, and intravenous dopamine was infused. The patient regained consciousness and was extubated five days later. Improvement in pancreatic tests was noted several days later. The outcome was favorable. DISCUSSION: According to the Naranjo probability scale, meprobamate-induced acute pancreatitis was probable. Acute pancreatitis in meprobamate poisoning is exceptional. The pathogenesis of pancreatitis-induced meprobamate poisoning may be explained by two mechanisms: stimulation of pancreatic secretion secondary to cholinergic activation and pancreatic ductal hypertension. CONCLUSIONS: The signs of severe meprobamate toxicity are numerous including cardiovascular and central nervous symptoms. Acute pancreatitis should also be added as a possible manifestation of meprobamate poisoning.",1
12457,21738109,Levofloxacin revisited,,1
12458,21740555,Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh,"BACKGROUND: Chronic arsenic exposure has been shown to cause liver damage. However, serum hepatic enzyme activity as recognized on liver function tests (LFTs) showing a dose-response relationship with arsenic exposure has not yet been clearly documented. The aim of our study was to investigate the dose-response relationship between arsenic exposure and major serum enzyme marker activity associated with LFTs in the population living in arsenic-endemic areas in Bangladesh. METHODS: A total of 200 residents living in arsenic-endemic areas in Bangladesh were selected as study subjects. Arsenic concentrations in the drinking water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The study subjects were stratified into quartile groups as follows, based on concentrations of arsenic in the drinking water, as well as in subjects' hair and nails: lowest, low, medium and high. The serum hepatic enzyme activities of alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) were then assayed. RESULTS: Arsenic concentrations in the subjects' hair and nails were positively correlated with arsenic levels in the drinking water. As regards the exposure-response relationship with arsenic in the drinking water, the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates. With internal exposure markers (arsenic in hair and nails), the ALP, AST and ALT activity profiles assumed a similar shape of dose-response relationship, with very few differences seen in the higher groups compared to the lowest group, most likely due to the temporalities of exposure metrics. CONCLUSIONS: The present study demonstrated that arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails. Further, this study revealed a novel exposure- and dose- response relationship between arsenic exposure metrics and serum hepatic enzyme activity. Elevated serum hepatic enzyme activities in the higher exposure gradients provided new insights into arsenic-induced liver toxicity that might be helpful for the early prognosis of arsenic-induced liver diseases.",1
12459,21744485,Massive accidental overdose of hydroxyurea in a young child with sickle cell anemia,"""The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) confirmed safety and efficacy of hydroxyurea therapy for infants with sickle cell anemia. Treatment was associated with reduction in rates of pain, acute chest syndrome, hospitalizations, and blood transfusions; improved hematologic values; and, perhaps, preservation of organ function. During the study, a 2-year-old ingested at one time an entire 35-day supply of hydroxyurea (612 mg/kg body weight). Despite a serum level of 7,756 microM 4 hours post-ingestion, the only toxicity was transient mild myelosuppression. With wider usage of hydroxyurea anticipated, conservative management of future overdoses seems reasonable (ClinicalTrials.gov NCT00006400).""",1
12460,21747115,Dose-response of five bile acids on serum and liver bile Acid concentrations and hepatotoxicty in mice,"""Feeding bile acids (BAs) to rodents has been used to study BA signaling and toxicity in vivo. However, little is known about the effect of feeding BAs on the concentrations of BAs in serum and liver as well as the dose of the fed BAs that causes liver toxicity. The present study was designed to investigate the relative hepatotoxicity of individual BAs by feeding mice cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), or ursodeoxycholic acid (UDCA) at concentrations of 0.01, 0.03, 0.1, 0.3, 1.0, or 3% in their diet for 7 days. The data demonstrate that (1) the ability of the fed BAs to produce hepatotoxicity is UDCA<CA<CDCA<DCA<LCA; (2) the lowest concentration of each BA in the feed that causes hepatotoxicity in mice is CA and CDCA at 0.3%, DCA at 0.1%, and LCA at 0.03%; (3) BA feeding results in a dose-dependent increase in the total serum BA concentrations but had little effect on liver total BA concentrations; (4) hepatotoxicity of the fed BAs does not simply depend on the concentration or hydrophobicity of total BAs in the liver; and (5) liver BA-conjugation enzymes are saturated by feeding UDCA at concentrations higher than 0.3%. In conclusion, the findings of the present study provide guidance for choosing the feeding concentrations of BAs in mice and will aid in interpreting BA hepatotoxicity as well as BA-mediated gene regulation.""",1
12461,21748765,Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial,"The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ? 2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention-to-treat analysis showed a decrease of ? 2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ? 2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was -1.6 in the PTX group, versus -0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score -0.9 versus -0.04 with placebo, P < 0.001) and lobular inflammation (median change -1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was -0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. CONCLUSION: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH.",1
12462,21749526,"A prospective, randomized, multicenter acceptability and safety study of direct buprenorphine/naloxone induction in heroin-dependent individuals","""AIMS: To provide controlled data on direct induction with buprenorphine/naloxone (BNX) versus indirect buprenorphine (BPN)-to-BNX induction. DESIGN: Phase 4, prospective, randomized, active-drug controlled, parallel-group trial consisting of a 2-day, double-blind, double-dummy induction phase followed by 26 days of open-label treatment with BNX. SETTING: Nineteen sites in 10 European countries from March 2008 to December 2009. PARTICIPANTS: A total of 187 opioid-dependent men and women ? 15 years of age. MEASUREMENTS: The primary objective was assessment of patient response to direct and indirect BNX induction [proportion of patients receiving the scheduled 16-mg BNX dose on day 3 (i.e. first day post-induction)]. Secondary assessments included illicit drug use, treatment retention and compliance, withdrawal scale scores, and safety. FINDINGS: Patient response to direct- versus indirect-BNX induction was similar [direct 91.4% (85/93) versus indirect 90.4% (85/94); 95% confidence interval (CI): -7.3%, 9.2%]. Rapid dose induction (16 mg of BPN equivalent on day 2) was acceptable and 72% of patients completed treatment (day 28). There were no significant differences in secondary measures across groups. An average BNX maintenance dose of 15.3 mg across groups was associated with substantial reductions in illicit opioid use and no self-reported intravenous misuse. Treatment compliance and retention rates were similar (98.5% and 81.3%, respectively). Treatment-emergent adverse event rates were comparable: 75% versus 74% for direct- versus indirect-induction groups, respectively. CONCLUSIONS: Direct buprenorphine/naloxone induction was a safe and effective strategy for maintenance treatment of opioid dependence. Response to high-dose direct buprenorphine/naloxone induction appears to be similar to indirect buprenorphine-to-buprenorphine/naloxone induction and was not associated with reports of intravenous buprenorphine/naloxone misuse.""",1
12463,21751292,Continuous reporting of new cases in Spain supports the relationship between Herbalife� products and liver injury,"""PURPOSE: Previous publications have linked Herbalife� products to hepatotoxicity. The identification of earlier cases in which the culprit agent could not be established raised the hypothesis of a possible contamination of some specific batches of Herbalife products. METHODS: We searched the Spanish Pharmacovigilance Centres' database of adverse reactions for reports of liver injury associated with the use of Herbalife products from 2003, when the first case was submitted, through September 2010. RESULTS: The search resulted in 20 reports of liver damage (mean age, 49 years; 16 women), with 12 patients (60%) requiring hospitalization. Hepatocellular damage predominated, and nine (53%) of the hepatocellular cases with bilirubin values were jaundiced, fulfilling the Hy's law criteria, which increases the risk for serious outcomes. Two patients experienced a positive rechallenge. One patient developed cirrhosis, whereas all the others recovered. Causality assessment by the Karch and Lasagna modified algorithm showed a category of definite in 1 case, probable in 14, and possible in 5. Analysis of the different Herbalife products that each patient had taken did not enable us to identify any commonly known hepatotoxic ingredient. CONCLUSIONS: Our results support the relationship between the consumption of Herbalife products and hepatotoxicity, underscore the concern regarding the liver-related safety of this dietary supplement, and emphasize the need to establish further regulatory measures.""",1
12464,21752152,"Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome","""BACKGROUND: Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long-term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype-phenotype correlation. METHODS: A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1. RESULTS: The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of ?-fetoprotein and coagulopathy. The most common mutation was IVS6-1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 ?mol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma. CONCLUSIONS: Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6-1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6-1(G > T) mutation was observed.""",1
12465,21755815,Risk of hepatotoxicity with add-on leflunomide in rheumatoid arthritis patients,"""Combination of disease-modifying antirheumatic drugs (DMARDs) is increasingly used in the treatment of rheumatoid arthritis (RA) patients. Hepatotoxicity has been an important safety concern with DMARDs therapy. Though leflunomide (CAS 75706-12-6) has emerged as an effective oral DMARD, its use is associated with hepatotoxicity. Limited data is available regarding hepatotoxic risk when leflunomide is used in combination therapy in RA patients. An open-label, prospective study was conducted to evaluate the hepatotoxic risk after addition of leflunomide with other DMARDs in RA patients, who did not respond to their ongoing DMARD therapy. A total of 46 patients were enrolled and leflunomide was given as add-on therapy with earlier DMARDs. Biochemical parameters of serum aminotransferase levels (AST and ALT) were estimated at the baseline and then every month after addition of leflunomide. Study results showed that 13.0% patients developed > 1.5 to < 2 times upper limit of normal (ULN) elevation; 6.5% patients developed > 2 to < 3 times the ULN elevation and 2.2% patients developed > 3 times the ULN elevation. In 20% of the patients with hepatic enzyme elevations, enzyme levels returned to normal within 4-6 weeks after discontinuation of leflunomide therapy, whereas in 50% of patients the dose of leflunomide was reduced from 20 mg/day to 10 mg/day for normalization of enzymes levels. 30% of patients were continued with leflunomide without dose reduction. None of the patients showed clinical signs and symptoms of hepatotoxicity. Leflunomide therapy with other DMARDs requires strict monitoring of serum aminotransferases.""",1
12466,21760875,Non-cirrhotic portal hypertension in human immunodeficiency virus-infected patients: a new challenge in antiretroviral therapy era,"Non-cirrhotic portal hypertension (NCPH) has been recently reported as a liver disease in Human Immunodeficiency Virus (HIV)-infected patients under antiretroviral therapy (ART). Combination of non-exclusive mechanisms has been described: primary endothelial damage of terminal portal veins induced by HIV or immunologic disorders, mitochondrial toxicity by didanosine and prothrombotic state. It is characterized by heterogeneous liver histological findings, frequently identified as nodular regenerative hyperplasia and clinical manifestations of portal hypertension with well-preserved liver function. We describe herein two HIV-infected patients with clinical picture suggestive of NCPH. Besides the case reports, we briefly address questions to apply to patient care in clinical practice.",1
12467,21763935,"Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial","""BACKGROUND: The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). METHODS: We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (?18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725. FINDINGS: From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI -1.7 to 8.8]; p(non-inferiority)<0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0.0001), as were rash and dizziness (p<0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0.0001). INTERPRETATION: Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1. FUNDING: Tibotec.""",1
12468,21764828,Use of linezolid in infants and children: a retrospective multicentre study of the Italian Society for Paediatric Infectious Diseases,"OBJECTIVES: Because of the spread of drug-resistant Gram-positive bacteria, the use of linezolid for treating severe infections is increasing. However, clinical experience in the paediatric population is still limited. We undertook a multicentre study to analyse the use of linezolid in children. METHODS: Hospitalized children treated with linezolid for a suspected or proven Gram-positive or mycobacterial infection were analysed retrospectively. Side effects were investigated, focusing on younger children and long-term treatments. RESULTS: Seventy-five patients (mean age 6.8 years, range 7 days to 17 years) were studied. Mean +/- SD linezolid treatment duration was 26.13 +/- 17 days. Clinical cure was achieved in 74.7% of patients. The most frequent adverse events were diarrhoea and vomiting. Two patients had severe anaemia, two neutropenia and one thrombocytopenia. Two cases of grade 3 liver function test elevation and one case of pancreatitis were reported. The overall frequency of adverse events was similar between patients treated for >28 days and those receiving shorter treatments (30.8% versus 28.6%, P = 0.84). Children aged <2 years received linezolid for a shorter duration than older children (21.2 days versus 28.4 days, P = 0.05), whereas the frequency of adverse events was similar in the two age groups. CONCLUSIONS: In our paediatric population, linezolid appeared safe and effective for the treatment of selected Gram-positive and mycobacterial infections. The adverse reactions encountered were reversible and appeared comparable to those reported in paediatric clinical trials. Nevertheless, the potential for haematological toxicity of linezolid in children means that careful monitoring is required during treatment.",1
12469,21772953,Antituberculosis drug-induced hepatotoxicity in children,"Recent increases in the dosages of the essential antituberculosis agents isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) for use in children recommended by World Health Organization have raised concerns regarding the risk of hepatotoxicity. Published data relating to the incidence and pathogenesis of antituberculosis drug-induced hepatotoxicity (ADIH), particularly in children, is reviewed. Amongst 12,708 children receiving chemoprophylaxis, mainly with INH, but also other combinations of INH, RMP and PZA only 1 case (0.06%) of jaundice was recorded and abnormal liver functions documented in 110 (8%) of the 1225 children studied. Excluding tuberculous meningitis (TBM) 8984 were children treated for tuberculosis disease and jaundice documented in 75 (0.83%) and abnormal liver function tests in 380 (9.9%) of the 3855 children evaluated. Amongst 717 children treated for TBM, however, jaundice occurred in 72 (10.8%) and abnormal LFT were recorded in 174 (52.9%) of those studied. Case reports document the occurrence of ADIH in at least 63 children. Signs and symptoms of ADIH were frequently ignored in the recorded cases. ADIH can occur in children at any age or at any dosage of INH, RMP or PZA, but the incidence of.ADIH is is considerably lower in children than in adults. Children with disseminated forms of disease are at greater risk of ADIH. The use of the higher dosages of INH, RMP and PZA recently recommended by WHO is unlikely to result in a greater risk of ADIH in children.",1
12470,21778965,Roflumilast (Daliresp) for COPD,,1
12471,21779819,"Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study","""UNLABELLED: In this 2-year extension of a 3-year study, bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated. INTRODUCTION: This study evaluated the efficacy and safety of bazedoxifene for the treatment of postmenopausal osteoporosis over 5 years. METHODS: A total of 4,216 postmenopausal women with osteoporosis were enrolled in this 2-year extension of a 3-year, randomized, double-blind, placebo-controlled, phase 3 trial. In the core study (N = 7,492), subjects received bazedoxifene 20 or 40 mg/day, raloxifene 60 mg/day, or placebo. The raloxifene arm was discontinued after 3 years; subjects receiving bazedoxifene 40 mg were transitioned to bazedoxifene 20 mg after 4 years. Five-year findings are reported for bazedoxifene 20 and 40/20 mg and placebo. Endpoints included incidence of new vertebral fractures (primary) and non-vertebral fractures, and changes in bone mineral density (BMD) and bone turnover markers. RESULTS: At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was significantly lower with bazedoxifene 20 mg (4.5%) and 40/20 mg (3.9%) versus placebo (6.8%; P < 0.05), with relative risk reductions of 35% and 40%, respectively. Non-vertebral fracture incidence was similar among groups. In a subgroup of higher-risk women (n = 1,324; femoral neck T-score </=-3.0 and/or >/= 1 moderate or severe or >/= 2 mild vertebral fracture[s]), bazedoxifene 20 mg reduced non-vertebral fracture risk versus placebo (37%; P = 0.06); combined data for bazedoxifene 20 and 40/20 mg reached statistical significance (34% reduction; P < 0.05). Bazedoxifene significantly increased BMD and reduced bone turnover versus placebo (P < 0.05) and was generally safe and well tolerated. CONCLUSIONS: The findings support a sustained anti-fracture effect of bazedoxifene on new vertebral fractures in postmenopausal osteoporotic women and on non-vertebral fractures in the higher-risk subgroup of women.""",1
12472,21782760,Herbal medicine hepatotoxicity revisited,,1
12473,21784456,Cysteamine toxicity in patients with cystinosis,"OBJECTIVE: To report new adverse effects of cysteamine. STUDY DESIGN: Detailed clinical information was obtained from the patients' physicians. RESULTS: New adverse events were reported in 8 of 550 patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m(2)/day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration. CONCLUSION: Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m(2)/day should be prescribed with great caution, but underdosing is not advocated.",1
12474,21785953,Unchanged serum viral load and liver function during tocilizumab treatment in a patient with rheumatoid arthritis and hepatitis C virus infection,,1
12475,21790926,Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status?,"AIMS: Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients. METHODS: We examined 23 patients referred with AH. RESULTS: Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian. CONCLUSIONS: Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.",1
12476,21792808,[Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults],,1
12477,21796717,Trends in emergency department visits attributable to acetaminophen overdoses in the United States: 1993-2007,"PURPOSE: With the heightened concern over acetaminophen overdose induced liver toxicity, it is important to track the overdose incidences over time. We estimated the trends in emergency department (ED) visits attributable to acetaminophen overdoses and compared the risk across sociodemographic groups and geographic regions. METHODS: ED visits attributable to acetaminophen overdoses were identified using physician diagnosis codes and cause of injury codes from the National Hospital Ambulatory Medical Care Survey (1993-2007). Annual rates of ED visits for acetaminophen overdoses per 100,000 persons in the U.S. population and by subgroups (age, gender, race, insurance coverage, geographic region, and presence of alcohol abuse and dependence) were calculated. Bivariate analysis and logistic regressions were used to examine the associations of patient demographic characteristics with ED visits for acetaminophen overdoses. Data were analyzed using STATA 9.2 accounting for complex survey design. RESULTS: From 1993 through 2007, an estimated 751,552 ED visits (0.05% of all ED visits) were attributable to acetaminophen overdoses. The annual rate per 100,000 persons was significantly higher prior to 2000 (21.0 visits in 1993-1999 vs. 15.2 visits in 2000-2007, p = 0.017). Rates were particularly high in young children under 5 years (72.4 visits, 95% confidence interval (CI): 49.1-95.8) and for adolescents between 15-17 years (61.8 visits, 95%CI: 35.4-88.3). Rates also varied cross gender, insurance coverage, and geographic regions. CONCLUSIONS: ED visits attributable to acetaminophen overdose decreased in recent years. Children less than 5 years of age, adolescents and young adults account for the overwhelming majority of these visits.",1
12478,21801394,Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe,"""BACKGROUND: Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but extremely severe cutaneous adverse drug reactions in which drug-specific associations with HLA-B alleles were described. OBJECTIVES: To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients. METHODS: We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel. RESULTS: Six SNPs located in the HLA region showed significant evidence for association (OR range: 1.53-1.74). The haplotype formed by their risk allele was more associated with the disease than any of the single SNPs and was even much stronger in patients exposed to allopurinol (OR(allopurinol) = 7.77, 95%CI = [4.66; 12.98]). The associated haplotype is in linkage disequilibrium with the HLA-B*5801 allele known to be associated with allopurinol induced SJS/TEN in Asian populations. CONCLUSION: The involvement of genetic variants located in the HLA region in SJS/TEN is confirmed in European samples, but no other locus reaches genome-wide statistical significance in this sample that is also the largest one collected so far. If some loci outside HLA play a role in SJS/TEN, their effect is thus likely to be very small.""",1
12479,21809177,Hepatitis B virus reactivation associated with temozolomide for malignant glioma: a case report and recommendation for prophylaxis,"Hepatitis B virus (HBV) reactivation during anticancer chemotherapy or immunosuppressive therapy in chronic carriers can lead to fatal liver failure. We report a rare case of severe HBV reactivation during postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ) for malignant glioma. A 49-year-old Japanese woman with a history of HBV carrier status with positive results for hepatitis B surface antigen presented with persistent headache due to a tumor in the left frontal lobe. The tumor was partially resected and anaplastic astrocytoma was diagnosed. Postoperative liver function was normal and radiotherapy plus concomitant and adjuvant TMZ was started. Impaired liver function became apparent just before administration of adjuvant TMZ, and acute liver failure developed. Antiviral therapy including entecavir, a nucleoside analog, led to a successful outcome and the patient survived. This case underlines the possibility of HBV reactivation due to TMZ and suggests the utility of HBV screening and antiviral prophylaxis before administration of TMZ to patients with malignant glioma.",1
12480,21811391,Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis,"""BACKGROUND: Topical nonsteroidal anti-inflammatory drug (NSAID) formulations, which produce less systemic exposure compared with oral formulations, are an option for the management of osteoarthritis (OA). However, the overall safety and efficacy of these agents compared with oral or systemic therapy remains controversial. METHODS: Two 12-week, double-blind, double-dummy, randomized, controlled, multicenter studies compared the safety and efficacy profiles of diclofenac topical solution (TDiclo) with oral diclofenac (ODiclo). Each study independently showed that TDiclo had similar efficacy to ODiclo. To compare the safety profiles of TDiclo and ODiclo, a pooled safety analysis was performed for 927 total patients who had radiologically confirmed symptomatic OA of the knee. This pooled analysis included patients treated with TDiclo, containing 45.5% dimethyl sulfoxide (DMSO), and those treated with ODiclo. Safety assessments included monitoring of adverse events (AEs), recording of vital signs, dermatologic evaluation of the study knee, and clinical laboratory evaluation. RESULTS: AEs occurred in 312 (67.1%) patients using TDiclo versus 298 (64.5%) of those taking ODiclo. The most common AE with TDiclo was dry skin at the application site (24.1% vs 1.9% with ODiclo; P < 0.0001). Fewer gastrointestinal (25.4% vs 39.0%; P < 0.0001) and cardiovascular (1.5% vs 3.5%; P = 0.055) AEs occurred with TDiclo compared with ODiclo. ODiclo was associated with significantly greater increases in liver enzymes and creatinine, and greater decreases in creatinine clearance and hemoglobin (P < 0.001 for all). CONCLUSIONS: These findings suggest that TDiclo represents a useful alternative to oral NSAID therapy in the management of OA, with a more favorable safety profile.""",1
12481,21812068,Reliability of the reported ingested dose of acetaminophen for predicting the risk of toxicity in acetaminophen overdose patients,"PURPOSE: The present study examines the relationship between the dose of acetaminophen reported to have been ingested by patients and the occurrence of serum acetaminophen levels above the 'possible toxicity' line in patients presenting at the hospital after acetaminophen overdose. The prognostic value of patient-reported dosage cut-offs of 8, 10 and 12?g was determined. METHODS: This retrospective cohort study included patients admitted to the emergency department or hospital within 24 hours of acetaminophen ingestion. Serum acetaminophen concentrations were considered to be the gold standard, and specificity, sensitivity and positive/negative predictive values were calculated from the reported ingested dose, to predict toxicity using the Rumack-Matthew nomogram (i.e. the 'possible toxicity' treatment line) and standard equations. RESULTS: Of 305 patients identified, 291 met the study inclusion criteria, and 121 (41.6%) had serum acetaminophen concentrations above the 'possible toxicity' treatment line. The range of patient-reported acetaminophen ingested was 1-75?g, with 185 patients (63.6%) reporting ?8?g. One hundred eighteen patients (97.5%) who reported ingesting ?8?g had serum acetaminophen concentrations above the '150-line', compared with only three patients (2.5%) who reported ingesting <8?g (p?<?0.001). The positive predictive value of a patient-reported dose ?8?g for predicting serum acetaminophen concentrations above the 'possible toxicity' treatment line was 63.78%, with a negative predictive value of 97.17%. The sensitivity of patient-reported doses ?8?g was high (97.52%) but with low specificity (60.59%). The sensitivity of patient-reported doses ?10?g also was high (89.26%) with low specificity (65.29%), whereas the sensitivity of ?12?g dose was low (61.16%) with high specificity (86.47%). CONCLUSIONS: Patient-reported doses of acetaminophen are good risk indicators for acetaminophen overdose patients in Malaysia. Patient-reported ingestion of ?8?g (as a cut-off dose) had a higher sensitivity than ?10?g or ?12?g. The results of this study have important implications for toxicity risk evaluations in areas with poor serum acetaminophen assay availability.",1
12482,21814588,Randomized clinical trial on ivermectin versus thiabendazole for the treatment of strongyloidiasis,"BACKGROUND: Strongyloidiasis may cause a life-threatening disease in immunosuppressed patients. This can only be prevented by effective cure of chronic infections. Direct parasitologic exams are not sensitive enough to prove cure if negative. We used an indirect immune fluorescent antibody test (IFAT) along with direct methods for patient inclusion and efficacy assessment. METHODOLOGY/PRINCIPAL FINDINGS: Prospective, randomized, open label, phase III trial conducted at the Centre for Tropical Diseases (Verona, Italy) to compare efficacy and safety of ivermectin (single dose, 200 microg/kg) and thiabendazole (two daily doses of 25 mg/Kg for two days) to cure strongyloidiasis. The first patient was recruited on 6(th) December, 2004. Follow-up visit of the last patient was on 11(th) January, 2007. Consenting patients responding to inclusion criteria were randomly assigned to one of the treatment arms. Primary outcome was: negative direct and indirect (IFAT) tests at follow-up (4 to 6 months after treatment) or subjects with negative direct test and drop of two or more IFAT titers. Considering 198 patients who concluded follow-up, efficacy was 56.6% for ivermectin and 52.2% for thiabendazole (p = 0.53). If the analysis is restricted to 92 patients with IFAT titer 80 or more before treatment (virtually 100% specific), efficacy would be 68.1% for ivermectin and 68.9% for thiabendazole (p = 0.93). Considering direct parasitological diagnosis only, efficacy would be 85.7% for ivermectin and 94.6% for thiabendazole (p = 0.21). In ivermectin arm, mild to moderate side effects were observed in 24/115 patients (20.9%), versus 79/108 (73.1%) in thiabendazole arm (p = 0.00). CONCLUSION: No significant difference in efficacy was observed, while side effects were far more frequent in thiabendazole arm. Ivermectin is the drug of choice, but efficacy of single dose is suboptimal. Different dose schedules should be assessed by future, larger studies. TRIAL REGISTRATION: Portal of Clinical Research with Medicines in Italy 2004-004693-87",1
12483,21819286,Acetaminophen psi parameter: a useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose,"""CONTEXT: The risk of hepatotoxicity secondary to acute acetaminophen overdose is related to serum acetaminophen concentration and lag time from ingestion to N-acetylcysteine (NAC) therapy. Psi (Greek letter psi) is a toxicokinetic parameter that takes the acetaminophen level at 4 h post-ingestion ([APAP](4 h)) and the time-to-initiation of NAC (tNAC) into account and was found to be significantly predictive of hepatotoxicity in Canadian patients with acetaminophen overdose treated with intravenous NAC. OBJECTIVE: We report the relationship of psi and hepatotoxicity in a Thai population with acute acetaminophen overdose. METHODS: This is a retrospective study of patients with acute paracetamol overdose during January 2004 to June 2009 at Siriraj Hospital. Patients were treated with the standard 21-h intravenous NAC regimen. Univariate analyses were performed with logistic regression to assess the relationships of psi, [APAP](4 h), and tNAC, and hepatotoxicity. RESULTS: A total of 127 patients were enrolled. The median (interquartile range; IQR) of [APAP](4 h) was 267.8 (196.0-380.0) mg/L. The median (IQR) of tNAC was 8.5 (6.2-12.0) h. Thirteen patients (10.2%) developed hepatotoxicity. Univariate analysis revealed [APAP](4 h), tNAC, and psi as statistically significant predictors of hepatotoxicity. DISCUSSION AND CONCLUSION: The psi parameter is a reliable prognostic tool to predict hepatotoxicity secondary to acute acetaminophen overdose treated with intravenous NAC. Our evidence shows that psi may be a more superior tool than either acetaminophen level or time-to-initiation of NAC at predicting hepatotoxicity.""",1
12484,21823520,Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome,"""OBJECTIVE: The aim of this study was to compare the efficacy and adverse reactions during initial treatment and long-term outcome between children and adolescents with Graves' disease (GD) treated with propylthiouracil (PTU) and those treated with methimazole (MMI). DESIGN, SETTING AND PARTICIPANTS: Retrospective and collaborative study. Children and adolescents with GD were divided into group M (MMI: n=64) and group P (PTU: n=69) and into four subgroups by initial dose: group M1 (<0.75 mg/kg of MMI, n=34), group M2 (> or = 0.75 mg/kg, n=30), group P1 (<7.5 mg/kg of PTU, n=24) and group P2 (> or = 7.5 mg/kg, n=45). MAIN OUTCOME MEASURES: The duration for normalization of serum T4 on initial treatment, the incidence of adverse effects for one year and outcomes at 10 years after were compared. RESULTS: Mean durations for normalization of T4 (+/- SD) were 1.7 +/- 1.0 months in group M and 2.3 +/- 2.4 in group P [not significant (NS)], while the mean duration in group P1 (3.1 +/- 3.3) was significantly longer than those in the other subgroups (M1: 1.9 +/- 1.2; M2: 1.4 +/- 0.7; P2; 1.7 +/- 1.3). No major adverse reaction was observed. Minor adverse effects occurred in 25.0% of cases in group M and 31.9% in group P (NS). The incidence in group P2 (44.4%) was significantly higher than those in group M1 (20.6%) and group P1 (8.3%). Remission rates did not differ between the MMI-treated group (35.0%, n=20) and PTU-treated group (50.0%, n=40). CONCLUSIONS: PTU may not be suitable for initial use in children and adolescents with GD, even with the risk of major adverse reactions such as liver failure excluded.""",1
12485,21830967,Two randomized trials of linaclotide for chronic constipation,"""BACKGROUND: Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation. METHODS: We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 ?g or 290 ?g, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored. RESULTS: For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 ?g of linaclotide and by 19.4% and 21.3% of the patients who received 290 ?g of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups. CONCLUSIONS: In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).""",1
12486,21841501,"Pralatrexate with vitamin supplementation in patients with previously treated, advanced non-small cell lung cancer: safety and efficacy in a phase 1 trial","INTRODUCTION: Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities. METHODS: Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response. RESULTS: Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (?190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ?190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2). CONCLUSIONS: Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.",1
12487,21842452,Adverse effects and adherence to treatment of rifampicin 4 months vs isoniazid 6 months for latent tuberculosis: a retrospective analysis,"""AIM OF STUDY: To compare rates of treatment interruption because of side effects and completion rates between subjects treated for latent tuberculosis infection (LTBI) by isoniazid (INH) for 6 months and subjects treated with rifampicin (RIF) for 4 months. METHODS: Retrospective analysis of all patients treated for LTBI by INH (1993-2002) or RIF (2004-2007) based on a database including age, gender, prior liver diseases, alcohol consumption, completion rates, time and cause of interruption and monthly analysis of ASAT and ALAT. RESULTS: 624 subjects were included, 426 treated by INH and 198 by RIF. Gender, origin, history of prior hepatic disease and alcohol excess did not differ between groups. Treatment interruption because of hepatotoxicity was significantly higher in the INH group than in the RIF group (6.1% vs 2.0%; p = 0.03). Completion of treatment was significantly higher in the RIF group compared to the INH group (83% vs 74%; p = 0.02). CONCLUSION: A 4-month RIF treatment was associated with significantly less interruption of treatment because of hepatotoxicity and higher completion rates compared to a 6-month INH regimen. These results support the RIF regimen as an alternative to the presently recommended 9 months of INH in clinical practice.""",1
12488,21845011,Cholestatic hepatitis with intravenous ceftriaxone,"Drug-induced liver injury is a major health problem. Its predominant forms include acute hepatitis, cholestasis, and a mixed pattern. Ceftriaxone is a third-generation cephalosporin and is widely used in the postoperative period due to its wider spectrum, longer half-life, and better tissue penetrability. Earlier cases of high aminotransferase levels and hepatitis have also been reported with the use of ceftriaxone. Here we report a case of cholestatic hepatitis with intravenous ceftriaxone.",1
12489,21846890,Acute liver failure associated with dronedarone,,1
12490,21848806,Two contemporary cases of hepatitis associated with Teucrium chamaedrys L. decoction use: case reports and review of literature,"Teucrium chamaedrys L. is a herbaceous plant common in European woods that has been used for many purposes for centuries. Recently, T.�chamaedrys L. has become popular as a slimming decoction without any scientific proof of efficacy notwithstanding its well-known hepatotoxicity. Hydroalcoholic extracts are currently used as flavourings in the preparation of wines, bitters and liqueurs. Teucrin A and teuchamaedryn A are the major toxic components of the diterpenoid fraction of T.�chamaedrys L.",1
12491,21851539,Long-term efficacy and tolerability of once-yearly histrelin acetate subcutaneous implant in patients with advanced prostate cancer,"OBJECTIVE: To evaluate the efficacy and tolerability of a once-yearly histrelin implant during an open-label extension of a pivotal study. PATIENTS AND METHODS: Men with advanced prostate cancer and a clinical response to 52 weeks of treatment with the histrelin implant. Implants were placed annually. The primary efficacy variable was achievement of serum testosterone levels of ?50 ng/dL. Secondary efficacy variables were disease progression, analgesia use, performance status and tolerability of therapy. RESULTS: Of 104 patients enrolled, over 70% received three consecutive histrelin implants, and the longest, single treatment period was greater than 4 years. Serum testosterone was consistently suppressed below 50 ng/dL in all patients and mean testosterone levels were 13.1, 14.8 and 10.8 ng/dL after 104 weeks (year 2), 156 weeks (year 3) and 208 weeks (year 4) of treatment, respectively. Most patients showed no clinical worsening of their disease, were able to continue normal daily activities, and did not require analgesic medication during the extension period. Mean (SD) time to place the histrelin implant was 4.5 (6.2) min, with only three patients having insertions that were considered difficult. Adverse events were reported in 100 (96.2%) patients. The eight deaths and 28 (26.9%) serious adverse events were judged as unrelated to the study drug. The most commonly reported drug-related adverse events was hot flashes in 67 (64.4%) patients. Most of these cases was judged as mild or moderate. CONCLUSIONS: The once-yearly histrelin implant maintained testosterone suppression for repeated treatment cycles and was generally well tolerated. The histrelin implant provides a clinically attractive option for long-term androgen deprivation therapy in patients with advanced prostate cancer seeking fewer office visits and repeated injections.",1
12492,21852542,"Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study","RATIONALE: Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways. IL-5 is involved in the activation and survival of eosinophils. OBJECTIVES: To evaluate the effect of the antibody to IL-5, reslizumab, in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid. METHODS: Patients were randomly assigned to receive infusions of reslizumab at 3.0 mg/kg (n = 53) or placebo (n = 53) at baseline and at Weeks 4, 8, and 12, with stratification by baseline Asthma Control Questionnaire (ACQ) score less than or equal to 2 or greater than 2. The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy (Week 15 or early withdrawal). MEASUREMENTS AND MAIN RESULTS: Mean changes from baseline to end of therapy in ACQ score were -0.7 in the reslizumab group and -0.3 in the placebo group (P = 0.054) and in FEV(1) were 0.18 and -0.08 L, respectively (P = 0.002). In those patients with nasal polyps, the changes in ACQ score were -1.0 and -0.1, respectively (P = 0.012). Median percentage reductions from baseline in sputum eosinophils were 95.4 and 38.7%, respectively (P = 0.007). Eight percent of patients in the reslizumab group and 19% of patients in the placebo group had an asthma exacerbation (P = 0.083). The most common adverse events with reslizumab were nasopharyngitis, fatigue, and pharyngolaryngeal pain. CONCLUSIONS: Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control than those receiving placebo. Reslizumab was generally well tolerated.",1
12493,21856096,Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis,"""SETTING: Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins. AIM: To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients. METHODS: A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. RESULTS: Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01). CONCLUSION: Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.""",1
12494,21859685,"Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial","""OBJECTIVES: To evaluate the efficacy and safety of intravenous ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, active rheumatoid arthritis (RA) patients despite methotrexate treatment. METHODS: In this double-blind, placebo-controlled, phase III study, active RA patients on stable methotrexate were randomly assigned to one course of two infusions of ofatumumab 700 mg (n=130) or placebo (n=130), 2 weeks apart. The primary endpoint was the ACR20 response at week 24. Secondary endpoints included ACR50/70, EULAR response, disease activity score based on 28 joints using C-reactive protein, adverse events (AE) and immunogenicity. RESULTS: At week 24, a greater proportion of patients on ofatumumab compared with placebo achieved an ACR20 response (50% vs 27%, p<0.001) and a good or moderate EULAR response (67% vs 41%, p<0.001). All other key secondary efficacy endpoints were significantly improved on ofatumumab. Efficacy observed by 8 weeks was sustained throughout the study. The most common AE for ofatumumab versus placebo were rash (21% vs <1%) and urticaria (12% vs <1%), mostly occurring on the first infusion day. Overall, first-dose infusion reactions were 68% for ofatumumab and 6% for placebo, mostly mild to moderate; second-dose infusion reactions markedly declined (<1% and 0%). Serious AE were reported in 5% of ofatumumab versus 3% of placebo patients. Infection rates were 32% and 26% (serious infections <1% and 2%), respectively. One death (interstitial lung disease), unrelated to study drug, was reported on ofatumumab. No antidrug antibodies were detected in ofatumumab patients. CONCLUSIONS: Ofatumumab significantly improved all clinical outcomes in biological-naive, active RA patients with no detectable immunogenicity at week 24. No unexpected safety findings were identified. Trial Registry clinical trials.gov registration number NCT00611455.""",1
12495,21860151,Monitoring methotrexate hepatotoxicity in psoriasis,,1
12496,21860366,Rivaroxaban (Xarelto)--a new oral anticoagulant,,1
12497,21865319,Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C,"Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.",1
12498,21869687,"A 1-year, open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder","""Vilazodone, a selective serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, was efficacious in two 8-week placebo-controlled studies in adults with major depressive disorder. This open-label, multicenter study assessed the long-term safety of vilazodone. Adult patients with a 17-item Hamilton Rating Scale for Depression score of 18 or greater received vilazodone according to a fixed-titration schedule to reach a dose of 40 mg/d continued up to 1 year. Safety assessments included adverse events (AEs), physical examinations, clinical chemistry, electrocardiograms, and the Changes in Sexual Functioning Questionnaire. Effectiveness was assessed with the Montgomery-?sberg Depression Rating Scale and Clinical Global Impressions scales. The safety population comprised 599 patients; 254 patients completed 1 year of treatment. The most frequent AEs were diarrhea (35.7%), nausea (31.6%), and headache (20.0%); greater than 90% of these AEs were mild or moderate. Adverse events resulting in discontinuation in more than 1% of patients were nausea (1.3%) and diarrhea (1.2%). There were no clinically important changes in physical examinations, electrocardiograms, or clinical chemistries. Mean weight increased by 1.7 kg (observed cases). Changes in Sexual Functioning Questionnaire mean scores (observed cases) improved throughout treatment for both males and females. Montgomery-?sberg Depression Rating Scale mean scores were 29.9 at baseline, 11.4 at week 8, and 7.1 at week 52 (observed cases). Vilazodone 40 mg/d for 1 year was safe and well tolerated by adults with major depressive disorder.""",1
12499,21878205,Safety of low-dose oral dantrolene sodium on hepatic function,"""OBJECTIVE: To investigate the incidence of hepatobiliary dysfunction after administration of low-dose dantrolene sodium. DESIGN: A retrospective survey of medical records. SETTING: One secondary and 2 tertiary hospitals. PARTICIPANTS: Patients (N=243; 144 men, 27 children; mean age +/- SD, 47.8 +/- 19.7y) who were administered dantrolene at a daily dose of 12.5 to 400mg for more than 4 weeks. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Liver function test (LFT) results, including serum total bilirubin, aspartate transaminase, alanine transaminase, and alkaline phosphatase, were recorded before and at least 1 month after the initial dose of dantrolene. In cases of treatment cessation, the reason was investigated. Significantly elevated LFT levels were defined as >/= to 2 times the upper limit of the normal range. RESULTS: Treatment duration was 268.0 +/- 428.5 days with a daily dose of 65.2 +/- 44.7 mg. At the end of the investigation, 95 patients (39.1%) had been lost to follow-up, and 105 (43.2%) had stopped treatment. The reasons for cessation were improved spasticity (42.9%), no effect of the medication (27.6%), weakness (6.7%), and other medical problems (5.7%). Patients with weaknesses did not have elevated LFT values. A 32-year-old man with head injuries and multiple trauma developed hepatic dysfunction 82 days after the initial dose and 43 days after a dose increment to 400mg/d. Other patients did not experience significant LFT abnormalities. CONCLUSIONS: One case of hepatic dysfunction was recorded in 243 cases after at least 4 weeks of low-dose oral dantrolene administration. Low-dose dantrolene can be used safely with meticulous clinical and laboratory monitoring.""",1
12500,21880696,"Normal in the blood, abnormal in the urine",,1
12501,21881934,Gemfibrozil hepatotoxicity: a case report,"CASE DESCRIPTION: A 55-year-old woman was admitted to our hospital for management of thoracic trauma and bone fractures. One month after admission she started to receive gemfibrozil for hypertriglyceridemia. In the second month of admission, the patient complained of nausea and malaise. Laboratory value showed an acute hepatitis with raised AST, ALT. The abdominal ultrasound scan was normal, and viral serologic tests were negative. Gemfibrozil was discontinued and in a few days AST and ALT levels returned to normal. CONCLUSION: Gemfibrozil-induced hepatitis is a rare event but should be considered in the differential diagnoses of hepatitis in which no other obvious alternative cause is found.",1
12502,21883506,Iron and acetaminophen a fatal combination?,"Intentional iron overdose in adults is uncommon. Clinical consequences are variable and depend on the quantity of iron ingested and the delay to treatment. Severe iron overdose can lead to multi-organ failure and acute hepatic necrosis. Here, we report three cases of polypharmacy overdose including iron resulting in acute liver failure. Despite maximum supportive care including liver transplantation in two cases, all patients died. Iron poisoning may have an additive toxic effect in drug-induced acute liver failure and worsen outcome.",1
12503,21884601,Integrated safety in tocilizumab clinical trials,"""INTRODUCTION: The efficacy and safety of tocilizumab in patients with rheumatoid arthritis have been evaluated in a comprehensive phase 3 program. Patients from these randomized trials could receive tocilizumab treatment in open-label extension trials. Here, the long-term safety profile of tocilizumab, using pooled data from all of these trials, is reported. METHODS: Cumulative safety data (as of February 6, 2009) from five core phase 3 trials, two ongoing extension trials, and one clinical pharmacology study were analyzed. Two patient populations were evaluated: an all-control population (n = 4,199), which included all patients randomly assigned in the placebo-controlled portions of the five core studies, and an all-exposed population (n = 4,009), which included patients from any of the eight studies who received at least one dose of tocilizumab. RESULTS: Total exposure to tocilizumab was 8,580 patient years (PY), and total duration of observation was 9,414 PY. Overall adverse event (AE) and serious AE (SAE) rates were 278.2/100 PY and 14.4/100 PY, respectively. These events included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), gastrointestinal perforations (0.28/100 PY), malignancy (1.1/100 PY), myocardial infarction (0.25/100 PY), and stroke (0.19/100 PY). The rates of SAEs and serious infections were stable over time; no increase with prolonged exposure was noted. CONCLUSIONS: The longer-term safety profile of tocilizumab (mean treatment duration, 2.4 years) is consistent with that observed in the phase 3 studies (duration up to 1 year).""",1
12504,21887162,Acute liver injury associated with the use of herbal preparations containing glucosamine: three case studies,"""The use of complementary and alternative medicines is becoming increasingly popular in Western society. As a result the number of reported adverse reactions is increasing. Glucosamine is a herbal remedy commonly used to ease joint pain in osteoarthritis, and only two previous reports of hepatotoxicity have been published in the scientific literature. The present report describes three patients who developed acute liver injury following exposure to glucosamine; one patient made a complete recovery on cessation of ingestion, the second developed chronic hepatitis and the third died following progression to fulminant hepatic failure. A diagnosis of glucosamine-induced hepatotoxicity was made based on the temporal relationship between onset of liver injury and glucosamine ingestion, exclusion of all other potential aetiologies and, in the two surviving cases, improvement in condition on withdrawal of the supplement.""",1
12505,21889878,Double-blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder,"""BACKGROUND: Lurasidone is a new atypical antipsychotic agent with high affinity for D(2), 5-HT(2A) and 5-HT(7) receptors. The current study evaluated the safety and efficacy of lurasidone and ziprasidone in stable outpatients diagnosed with schizophrenia or schizoaffective disorder. METHODS: Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder that was chronic (?6 months duration) and stable were randomized to 21 days of double-blind treatment with a fixed dose of lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). Changes from baseline in efficacy measures were evaluated using mixed model for repeated measures (MMRM) analyses. RESULTS: The proportion of patients who discontinued from the study was similar for lurasidone and ziprasidone (32.5% vs. 30.7%); the proportion who discontinued due to adverse events was similar (10.4% vs. 11.1%). Treatment with lurasidone and ziprasidone was associated with a small endpoint reduction in median weight (-0.65 kg vs. -0.35 kg) and median total cholesterol (-6.4 vs. -4.4 mg/dL); no endpoint change was observed in median triglycerides (0.0 vs. 0.0 mg/dL). There were no clinically significant changes in other laboratory or ECG parameters. Improvement was observed on an MMRM analysis of the PANSS total score for lurasidone and ziprasidone at Week 1 (-4.1 vs. -1.6; P=0.020), Week 2, (-6.1 vs. -3.6; P=0.074), and Week 3 (-6.3 vs. -4.5; P=0.229). CONCLUSION: In this double-blind, fixed-dose comparison of lurasidone 120 mg and ziprasidone 160 mg, treatment with lurasidone was well-tolerated and safe, and was not associated with clinically significant changes from baseline in weight, metabolic parameters, or QTc interval. Study limitations include the relatively short trial duration and lack of placebo control.""",1
12506,21890228,Safety and effectiveness of pemetrexed in patients with malignant pleural mesothelioma based on all-case drug-registry study,"""BACKGROUND: Pemetrexed in combination with cisplatin (Pem/Cis) is the only approved chemotherapeutic regimen for malignant pleural mesothelioma (MPM). At the time of launch, limited safety information was available. The purpose of this postmarketing all-case registry study was to investigate the safety and effectiveness of pemetrexed in patients with MPM. METHODS: From January 2007 to May 2008, MPM patients to be treated with pemetrexed in Japan were registered to this study to monitor its safety and effectiveness. Supply of pemetrexed was restricted to institutions with experienced medical oncologists based on predetermined criteria. RESULTS: Of 953 patients registered, data from 903 patients were eligible for analysis. Most patients were male, with median age of 65 years and 68.5% had a history of asbestos exposure. More than 90% of patients received the first cycle of Pem/Cis treatment; median number of treatment cycles was 4.0. Treatment-associated death was reported in 0.8% of patients. The incidence of Interstitial lung disease (ILD) associated with Pem/Cis during the observation period was 0.9%. The frequency of ILD in patients with pre-existing asbestosis was higher than that in patients without it. For tumor response, the overall response rate was 25.0% (95% confidence interval (CI): 22.2-28.0%). The six-month survival rate estimated by the Kaplan-Meier method was 75.9%. CONCLUSIONS: This large scale all case registry study appeared to have enrolled a major portion of Japanese MPM patients. Treatment with pemetrexed was generally well tolerated and showed safety and effectiveness comparable to prior clinical trials.""",1
12507,21893153,Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports,"Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n=2), probable (n=6), possible (n=10), unlikely (n=1), and excluded (n=3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.",1
12508,21896097,"A randomized, double-blind, pilot study of rifaximin 550 mg versus placebo in the prevention of travelers' diarrhea in Mexico during the dry season","BACKGROUND: Rifaximin has been shown to be effective in treating and preventing travelers' diarrhea (TD) during the summer season. METHODS: The goal of this double-blinded multicenter trial was to assess the efficacy and safety of rifaximin 550 mg administered once daily for 14 days compared with placebo in the prevention of TD during the dry season in Mexico. RESULTS: There were 101 participants randomized. Overall, 25 participants developed TD during the 3 weeks of the study: 22% from the rifaximin group and 29% from the placebo group (p = 0.4). Mild diarrhea (defined as only one or two unformed stools during a 24-h period plus at least one abdominal symptoms) developed in only 3 (6%) participants taking rifaximin compared with 10 (21%) taking placebo during the first week of study (p = 0.03). No clinically significant or serious adverse events were reported. CONCLUSIONS: Antibiotic prophylaxis of TD in Mexico during the dry season needs to be further studied and its benefits weighed against the benefits of self-treatment.",1
12509,21896924,Ofatumumab: a novel anti-CD20 monoclonal antibody for treatment of refractory chronic lymphocytic leukemia,"OBJECTIVE: To present the current clinical evidence on ofatumumab for use in refractory chronic lymphocytic leukemia (CLL). DATA SOURCES: A literature search was performed using MEDLINE and PubMed (both 1966-May 2011), as well as the American Society of Hematology abstracts (2000-May 2011), using the primary search terms ofatumumab and HuMax-CD20. STUDY SELECTION AND DATA EXTRACTION: Clinical studies and abstracts available in the English language, describing the pharmacology, pharmacokinetics, clinical activity, and safety of ofatumumab in CLL were included in this review. DATA SYNTHESIS: Ofatumumab is a human immunoglobulin monoclonal antibody that binds to B-lymphocytes expressing CD-20 cell surface antigens. Ofatumumab was granted accelerated approval by the Food and Drug Administration in October 2009 for the treatment of CLL refractory to fludarabine and alemtuzumab. A Phase 1/2 trial has established the safety and tolerability of single-agent ofatumumab at an initial dose of 300 mg intravenously on week 1, followed by 2000 mg once weekly for 7 doses (weeks 2-8), followed by 2000 mg once every 4 weeks for 4 doses (weeks 9-12), for a total of 12 doses. The final analysis of a pivotal international multicenter trial has shown promising activity in patients with CLL refractory to fludarabine and alemtuzumab, demonstrating overall response rates of 44-51%, with prolonged progression-free and overall survival. Ofatumumab activity has also been shown in a variety of other malignant and nonmalignant conditions, including non-Hodgkin lymphoma, rheumatoid arthritis, and multiple sclerosis. The most common adverse effect is grade 1 and 2 infusion reactions. Other adverse effects include infection, neutropenia, anemia, rash, fever, and diarrhea. CONCLUSIONS: Clinical evidence suggests that ofatumumab is an effective agent in patients with CLL refractory to fludarabine and alemtuzumab. Data are awaited comparing ofatumumab to other salvage regimens. Until results of head-to-head trials are conducted comparing ofatumumab to existing regimens, it cannot be said whether ofatumumab is more efficacious or tolerable than currently available therapies.",1
12510,21897349,Gabapentin encarbil (Horizant) for restless leg syndrome,"Gabapentin enacarbil (Horizant-GlaxoSmithKline), a new extended-release (ER) tablet formulation of gabapentin, has been approved by the FDA for treatment of moderate-to-severe restless legs syndrome (RLS). The immediate-release (IR) formulation of gabapentin (Neurontin,and others), which is approved for treatment of epilepsy and postherpetic neuralgia, has been used for many years to treat RLS. Another ER tablet formulation of gabapentin (Gralise) has been approved by the FDA for treatment of postherpetic neuralgia.",1
12511,21900728,The value of screening HIV-infected individuals for didanosine-related liver disease?,,1
12512,21902621,"Long-term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV type 1-infected antiretroviral-naive patients: week 192 results from a phase IIb randomized trial","TMC278-C204 (NCT00110305), a 96-week trial of the nonnucleoside reverse transcription inhibitor (NNRTI) rilpivirine (RPV, TMC278) in 368 HIV-1-infected, treatment-naive patients, was extended to investigate long-term safety and efficacy. Week 192 analysis results are presented. This was a long-term follow-up of a Phase IIb, randomized trial. No significant RPV dose-response relationships with respect to the primary endpoint (composite ITT-TLOVR algorithm) were observed at week 48 or 96. All RPV-treated patients were switched to open-label 75 mg qd at week 96 and then to 25 mg qd, the Phase III dose, at approximately week 144 as it gave the best benefit-risk balance. All control patients continued receiving open-label efavirenz (EFV) 600 mg qd. At week 192, 59% of RPV- and 61% of EFV-treated patients maintained confirmed viral load <50 copies/ml (ITT-TLOVR algorithm). The mean changes from baseline in CD4 cell count were similar in both groups (RPV: 210 cells/mm(3) vs. EFV: 225 cells/mm(3)). No new safety concerns were noted between week 48 and 192. In the week 192 analysis, RPV compared with EFV was associated with a lower overall incidence of grade 2-4 adverse events (AEs) at least possibly related to treatment, including rash (p<0.001) and neurologic AEs (p<0.05 Fisher's exact test, post hoc analyses) Incidences of serious AEs, grade 3 or 4 AEs, and discontinuations due to AEs were similar across groups. Increases in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were significantly lower with RPV than with EFV. RPV continued to show sustained efficacy similar to EFV at week 192 with a generally more favorable safety profile.",1
12513,21903660,Liver toxicity associated with antiretroviral therapy including efavirenz or ritonavir-boosted protease inhibitors in a cohort of HIV/hepatitis C virus co-infected patients,"OBJECTIVES: To compare the frequency of grade 3 or 4 transaminase elevations (TEs) in HIV/hepatitis C virus (HCV) co-infected patients who started a three-antiretroviral drug regimen including efavirenz or a ritonavir-boosted protease inhibitor (PI/r) and the influence of pre-existing significant hepatic fibrosis or cirrhosis. PATIENTS AND METHODS: All pre-treated or treatment-naive HIV/HCV co-infected patients who started an antiretroviral regimen including two nucleos(t)ide reverse transcriptase inhibitors along with efavirenz or a PI/r in seven Spanish centres from January 2007 to December 2009 were included in this prospective study. RESULTS: Of 262 patients included in this study, 76 (29%) individuals began antiretroviral therapy (ART) including efavirenz and 186 (71%) a PI/r-based combination. The median (interquartile) follow-up was 14.0 (6.2-23.7) months. A total of 20 (7.6%) patients presented grade 3-4 TEs. Four (1.5%) subjects discontinued ART due to this adverse event. Grade 3-4 TEs were observed in 5 (6.6%) subjects receiving efavirenz and 15 (8.1%) treated with PI/r (P?=?0.681). Three (6.5%) patients in the efavirenz group with significant fibrosis developed grade 3-4 TEs versus 2 (8.7%) without pre-existing significant fibrosis (P?=?0.743). In the PI/r group, the corresponding figures were 10 (8.8%) and 5 (9.3%), respectively (P?=?0.931). CONCLUSIONS: The frequency of grade 3-4 TEs associated with efavirenz-based ART combinations under clinical practice conditions is low and similar to that found in patients receiving PI/r currently used in HIV/HCV co-infected patients. The baseline fibrosis stage does not have an impact on the development of TEs caused by these antiretroviral drugs in this population.",1
12514,21904569,An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer,"Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostate-specific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.",1
12515,21907311,"Rapid-onset, linezolid-induced lactic acidosis in MELAS","Due to their prokaryotic origins, mitochondria are susceptible to a number of antibiotics that target the bacterial ribosome, and this vulnerability is exacerbated by certain mutations of the mitochondrial genome. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome is characterised by biochemical and structural abnormalities of the muscle mitochondria, in which episodes of lactic acidosis stem from dysfunction of assembled respiratory complex I. Linezolid is an oxazolidinone antibiotic that has been reported to induce lactic acidosis, especially after prolonged administration, through inhibition of the mitochondrially synthesised components of oxidative phosphorylation. We report a patient with longstanding MELAS who suffered a severe lactic acidosis of rapid onset, with associated features of mitochondrial failure, shortly after the commencement of linezolid therapy and in the context of an otherwise improving clinical picture. This case emphasises the importance of circumspection when utilising drugs known to be toxic to the mitochondrion in patients with mitochondrial disease. In particular, given the biochemically plausible interaction, it would seem prudent to avoid the use of linezolid in patients with MELAS whenever possible.",1
12516,21913872,Genetic association studies in drug-induced liver injury,"A large number of case-control association studies on genetic susceptibility to drug-induced liver injury, involving both candidate gene and genome-wide association approaches, have now been reported. The strongest associations have been observed for human leukocyte antigen (HLA) class I and II genes and N-acetyltransferase 2 (NAT2). The associations with HLA class I and II genes are drug specific, though some apparently unrelated compounds show genetic associations with the same alleles. The underlying mechanism for the HLA association is likely to involve T-cell responses to either drug-protein adducts or to drug alone, but needs further investigation. The NAT2 association relates to liver injury induced by isoniazid, with most published studies finding an increased risk of injury in slow acetylators lacking NAT2 enzyme activity, presumably because of the accumulation of toxic metabolites. Other associations with genes relevant to drug disposition, innate immunity, oxidative stress, and mitochondrial function have also been reported, though these still need to be confirmed by replication in independent cohorts.",1
12517,21915865,Reactivation of overt and occult hepatitis B infection in various immunosuppressive settings,"""The aim of the study was to evaluate clinical and virological differences in HBV reactivation between patients with overt and occult HBV infection. Twenty-three consecutive patients with symptomatic HBV reactivation occurring during or after immunosuppressive therapy were enrolled in a retrospective study: 10 with reactivation of overt HBV infection (overt group) and 13 of occult HBV infection (occult group). Twenty-one patients were treated with nucleot(s)ide analogues after HBV reactivation. Regimens including rituximab or fludarabine were administered more frequently in the occult group (61% vs. 31%, respectively). HBV reactivation was severe frequently in the overt (40%) and occult groups (38.4%). Patients in the overt group showed higher HBV-DNA titers (1.1 ? 10(8) ? 1.4 ? 10(8) vs. 5.1 ? 10(5) ? 6.8 ? 10(5) IU; P < 0.005). Seven patients died during HBV reactivation, two in the overt and five in the occult group. Of these seven patients, two remained untreated and five had been treated with Lamivudine; of the 16 patients showing remission of HBV reactivation, four had been treated with Lamivudine, four with Entecavir, two with Telbivudine, and six with Lamivudine plus Adefovir. It is concluded that HBV reactivation is life-threatening in patients with diseases inhibiting the immune response and/or receiving immunosuppressive drugs. Supportive therapy without antiviral drugs or Lamivudine monotherapy may not be effective for treating patients with HBV reactivation.""",1
12518,21916639,Response-guided telaprevir combination treatment for hepatitis C virus infection,"""BACKGROUND: Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS: We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 ?g per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS: Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS: In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).""",1
12519,21917864,Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States,"CONTEXT: More than 50% of Americans use dietary supplements, and 60-70% fail to report this use to their physicians. Intoxication from vitamin D supplements has been rarely reported but may now occur more frequently. This may be attributable to an increase in vitamin D supplement intake due to the findings that deficiency is common and has been associated with a number of disease states. OBJECTIVE: We report two cases of vitamin D intoxication with dietary supplements made in the United States caused by manufacturing and labeling errors. METHODS: Case histories were obtained, and serial laboratory data (calcium and vitamin D metabolites) were measured. Each dietary supplement was analyzed by UV spectrophotometry followed by HPLC. RESULTS: In both cases, repetitive inquiries were required to elicit the use of dietary supplements. Because of significant manufacturer errors and a labeling error, patients had been consuming more than 1000 times the recommended daily dose of vitamin D(3). Hypercalcemia is directly proportional to serum 25-hydroxyvitamin D [25(OH)D] but not 1,25-dihydroxyvitamin D levels. It took approximately 1 yr to normalize 25(OH)D levels. However, once 25(OH)D levels decreased below 400 ng/ml, both patients became normocalcemic and asymptomatic without long-term sequelae. CONCLUSIONS: Although rare, vitamin D intoxication should be considered in the differential diagnosis of hypercalcemia. Patients should be asked whether they are using dietary supplements, and serial questioning may be required because patients may not consider these supplements to be potential health risks. Errors in the manufacturing and labeling of dietary supplements made in the United States may place individuals at increased risks for side effects.",1
12520,21921356,Tamoxifen-induced hepatotoxicity,,1
12521,21923436,"High-dose daptomycin for treatment of complicated gram-positive infections: a large, multicenter, retrospective study","STUDY OBJECTIVE: To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections. DESIGN: Multicenter, retrospective, observational, case series analysis. SETTING: Five academic medical centers in four major United States cities. PATIENTS: Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (? 8 mg/kg/day) for at least 72 hours for complicated gram-positive infections between January 1, 2005, and March 1, 2010. MEASUREMENTS AND MAIN RESULTS: Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0-10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5-16 days) and 13 days (IQR 6-18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy CPK level was 39 U/L (IQR 26-67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level. CONCLUSION: Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted.",1
12522,21928702,A case of autoimmune hepatitis with Graves' disease treated by propylthiouracil,"A 58-year-old woman was referred to our hospital because of liver dysfunction. Her serum levels of AST (619 IU/l) and ALT (603 IU/l) had increased. Histological findings in the liver biopsy were compatible to autoimmune hepatitis (AIH), and the diagnosis of AIH was confirmed by the diagnostic criteria. She was admitted to a nearby hospital 3 years ago, and diagnosed with Graves' disease. She received methimazole (MMI) at first, which was discontinued due to liver injury in one month, then propylthiouracil (PTU) was administered. One year later, transaminase increased and was decreased by stopping PTU administration. PTU was restarted after her transaminase decreased, but a recurrence of hepatotoxicity was observed, and she was referred to our hospital. Oral prednisolone decreased liver function immediately. In this case, PTU-induced liver injury was suspected as a possible trigger of AIH. While PTU remains a commonly used drug in the treatment of hyperthyroidism, severe liver injury is reported in some cases. If liver injury is observed in patients treated with PTU, rechallenge is not recommended in order to avoid severe hepatotoxicity.",1
12523,21929775,Severe propylthiouracil-induced hepatotoxicity in pregnancy managed successfully by liver transplantation: A case report,"INTRODUCTION: Propylthiouracil-induced severe hepatotoxicity is a relatively rare occurrence, with very few cases reported in the literature. The management of this complication in pregnancy can be a challenge because of the effects of the various treatment options on the fetus. CASE PRESENTATION: We report a rare case of fulminant hepatic failure in a 36-year-old gravida 2 black woman of African descent that occurred at 17 weeks gestation following propylthiouracil treatment for Graves' disease. Her liver failure was managed by liver transplantation and thyroidectomy. Her pregnancy was continued to term, though with not so favorable early childhood sequelae. CONCLUSION: This case illustrates a very rare complication of treatment with a presumed safe drug during pregnancy followed by adverse neonatal outcomes due to the extensive treatment.",1
12524,21930633,Care needed with i.v. acetaminophen,,1
12525,21937501,The combination of phentermine and topiramate is an effective adjunct to diet and lifestyle modification for weight loss and measures of comorbidity in overweight or obese adults with additional metabolic risk factors,,1
12526,21941157,Evaluation of multi-drug therapy for leprosy in the United States using daily rifampin,"OBJECTIVES: To evaluate the occurrence of relapse of multibacillary leprosy after multi-drug treatment including daily rifampin. METHODS: A retrospective review was performed utilizing data from the National Hansen's Disease Program (NHDP) on patients with leprosy treated and followed from 1988-1997 who received multi-drug therapy including daily rifampin. The occurrence of relapse in this cohort was measured, and demographic data and various clinical variables were also gathered. RESULTS: Ultimately, 158 cases fulfilled the eligibility criteria. 77% of cases were multibacillary patients and were treated with 2 or 3 drug protocols at rates of 36% and 35% before and after 1992, respectively. Only one case of relapse was found, and this patient underwent 2-drug therapy versus 3-drug therapy. CONCLUSION: These data are remarkable for the absence of relapse with daily rifampin, as contrasted with the published experience using the WHO protocol with monthly rifampin.",1
12527,21941228,Antithrombotic drugs,,1
12528,21943863,Hepatotoxicity in the treatment of tuberculosis using moxifloxacin-containing regimens,,1
12529,21947732,Naproxen-induced liver injury,"""BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the-counter medication since 1994, but has rarely been reported to cause liver injury. METHODS: We treated a 30-year-old woman with jaundice and intractable pruritus that developed shortly after taking naproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. RESULTS: The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. CONCLUSIONS: Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.""",1
12530,21950420,Pharmacological treatment of generalized anxiety disorder,"INTRODUCTION: Generalized anxiety disorder (GAD) is a chronic, relapsing, debilitating disorder, associated with markedly impaired social and occupational functioning. Pharmacological treatment is considered standard care and several drug classes are now FDA approved for the treatment of GAD. While there are clear data for the efficacy of short-term acute treatment, long-term treatment and treatment-resistant GAD remain challenging. AREAS COVERED: This article describes current pharmacological treatment options for GAD, with focus on benzodiazepines, azapirones, antidepressants and anticonvulsant and antipsychotic drugs. Recent findings from placebo-controlled clinical trials are reviewed and evidence-based clinical implications are discussed. A PubMed search was completed using the terms: 'generalized anxiety disorder AND treatment' and 'generalized anxiety disorder AND therapy'. Additional pivotal trials were included for a historical perspective (older landmark trials that established efficacy and safety for older drug classes in the treatment of GAD). EXPERT OPINION: Efficacy for treatment of GAD has been established for several different drug classes. At present, based on clear efficacy and good tolerability, first-line treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated. If an initial, at least moderate, clinical response is achieved under antidepressant therapy, treatment should be at least continued for 12 months.",1
12531,21951984,Vilazodone: clinical basis for the US Food and Drug Administration's approval of a new antidepressant,"OBJECTIVE: Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions. DATA SOURCES: The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data. STUDY SELECTION: Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug. DATA EXTRACTION: The FDA had access to original raw data sets for these trials. RESULTS: Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates. CONCLUSIONS: Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.",1
12532,21952978,"Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs","""OBJECTIVE: To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. METHODS: In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Treatment with tofacitinib at a dose of ?3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ? 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). CONCLUSION: Tofacitinib monotherapy at ?3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.""",1
12533,21956725,"Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome","OBJECTIVE: To evaluate efficacy and safety of clobazam, a 1,5-benzodiazepine, as adjunctive therapy for Lennox-Gastaut syndrome (LGS). METHODS: Patients aged 2-60 years were randomized to placebo or clobazam 0.25, 0.5, or 1.0 mg/kg/day. Study consisted of 4-week baseline, 3-week titration, and 12-week maintenance phases, followed by a 2- or 3-week taper or continuation in an open-label extension. Primary endpoint was percentage decrease in mean weekly drop seizure rates during maintenance vs baseline phases for modified intention-to-treat (mITT) population. Secondary outcomes included other seizure types, responder rates, and physicians' and caregivers' global assessments. RESULTS: A total of 305 patients were screened, 238 were randomized, and 217 composed the mITT population. Of patients enrolled after a protocol amendment, 125/157 (79.6%) completed. Average weekly drop seizure rates decreased 12.1% for placebo vs 41.2% (p = 0.0120), 49.4% (p = 0.0015), and 68.3% (p < 0.0001) for the clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Responder rates (?50%) were 31.6% (placebo) vs 43.4% (p = 0.3383), 58.6% (p = 0.0159), and 77.6% (p < 0.0001) for clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Physicians' and caregivers' assessments indicated clobazam significantly improved symptoms. Somnolence, pyrexia, upper respiratory infections, and lethargy were the most frequent adverse events reported for clobazam. CONCLUSIONS: Clobazam significantly decreased weekly drop seizure rates in LGS. No new safety signals were identified. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that clobazam as adjunctive therapy is efficacious, in a dosage-dependent manner, in reducing mean weekly drop seizure rates of patients with LGS over 12 weeks.",1
12534,21959356,Vemurafenib (Zelboraf) for metastatic melanoma,,1
12535,21965434,Rhabdomyolysis associated with the co-administration of daptomycin and pegylated interferon alpha-2b and ribavirin in a patient with hepatitis C,,1
12536,21967976,Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia,"""The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; >/= 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.""",1
12537,21969990,"Systematic review on the efficacy of fexofenadine in seasonal allergic rhinitis: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials","""RATIONALE: Evidence-based medicine represents the effort to highlight the best intervention for patients, clinicians, and policy makers, each from their respective viewpoint, to solve a particular health condition. According to a recently diffused grading system of evidence and recommendations for medical interventions, efficacy and safety represent 2 of the most important features to consider, and data from meta-analyses of randomized controlled clinical trials (RCTs) is the strongest supporting demonstration. Fexofenadine has been used for its efficacy and safety in the treatment of allergic rhinitis (AR) for many years although no meta-analyses supporting its use currently exist. The aim of this study is to assess for the first time the efficacy and safety of fexofenadine in the treatment of AR by means of a meta-analytic analysis of existing RCTs. Since specific evidence should be provided to address recommendations in a pediatric population, the quality of the estimates of this subgroup analysis is assessed. METHODS: All double-blind, placebo-controlled randomized trials assessing the efficacy of fexofenadine in AR were searched for in OVID, Medline, and Embase databases up to December 2007. Outcomes were extracted from original articles; when this information was not available, the authors of each trial were contacted. Some graphics were digitalized. The RevMan 5 program was used to perform the analysis. GradePro 3.2.2 was used to assess the quality of the evidence for a pediatric population. RESULTS: Of 2,152 identified articles, 20 were potentially relevant trials. Eight studies satisfied the inclusion criteria and were included in the meta-analysis. The main reasons for exclusion were: unnatural exposure, strong study limitations, an atypical outcome measurement, a design for other outcomes, and not being a placebo-controlled, single-blind study. Seven trials investigated a mixed population of adults and children, 1 trial investigated only children, and 1 trial only adults. In 1,833 patients receiving fexofenadine (1,699 placebo), a significant reduction of the daily reflective total symptom scores (TSS) (SMD ?0.42; 95% CI ?0.49 to ?0.35, p < 0.00001) was found. Positive results were also found for morning instantaneous TSS and individual nasal symptom scores (sneezing, rhinorrhea, itching, and congestion). The safety analysis did not show a significant difference in reported adverse events (AE) between the active and placebo treatment groups (OR = 1.03; 95% CI 0.87?1.22, p = 0.75). A very low heterogeneity between the studies was detected, so a fixed-effects model was used. The mean quality level of the included trials was medium. Specific information for a pediatric population may be assumed with a moderate quality of evidence from only 1 study and with a low quality of evidence, mainly due to indirectness, from the others. CONCLUSIONS: This study has 5 major strengths: it represents the first attempt to evaluate the efficacy and safety of fexofenadine in the treatment of AR by means of a meta-analysis of RCTs; there was consistency between positive results in terms of efficacy in TSS and in individual symptoms; a large population was studied; there was an irrelevant interstudy heterogeneity, and the AE frequency was similar in both groups. All of these values encourage the recommendation of fexofenadine for AR. Further research focused on the benefits and disadvantages for a pediatric population is needed.""",1
12538,21975503,"Iron poisoning: a literature-based review of epidemiology, diagnosis, and management","Although seen less frequently than acetaminophen or salicylate poisoning, acute iron poisoning remains a dangerous threat, particularly to pediatric patients. Multiple factors-including legal and manufacturing practices-have changed the landscape of iron poisoning over the decades. Despite these changes, diagnosis and management of iron poisoning have minimally evolved, and the current evidence for iron poisoning is yet based principally on case series, expert consensus, animal studies, and adult volunteer studies. This review article describes in detail the epidemiology of acute iron poisoning as it relates to the pediatric patient, as well as the historical and current array of literature on diagnosis and management.",1
12539,21978572,Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials,"""BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. OBJECTIVE: We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. METHODS: Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. RESULTS: During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. LIMITATIONS: Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. CONCLUSIONS: The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.""",1
12540,21979474,Prospective evaluation of seropositive occult hepatitis B viral infection in lymphoma patients receiving chemotherapy,"OBJECTIVE. To serially evaluate the viral kinetics of occult hepatitis B virus infection in lymphoma patients and perform a correlation with clinical outcomes. DESIGN. Case series with 1-year follow-up. SETTING. Regional hospital, Hong Kong. PATIENTS. Consecutive patients who were newly diagnosed to have lymphoma in the hospital between 1 April 2007 and 31 March 2008 were tested for hepatitis B (HB) surface (s) antigen (Ag), anti-HBs antibody (Ab) and anti-HB core (c) Ab. Seropositive occult hepatitis B patients as defined by being negative for HBsAg but positive anti-HBsAb and/or anti-HBcAb without a hepatitis B vaccination history were recruited. Serum HBsAg, anti-HBsAb, anti-HBcAb, hepatitis B virus deoxyribonucleic acid (DNA) level, and liver biochemistry were checked at baseline and every 4 weeks during and after chemotherapy until 12 months after the completion of chemotherapy or death. Entecavir was started if patients developed biochemical flare-up of hepatitis B associated with virological rebound. The prevalence and course of hepatitis B virus-related hepatitis, as well as any temporal relationship to viral kinetics and clinical hepatitis, were assessed. RESULTS. Of 47 patients tested, 10 (21%) with lymphoma were seropositive occult hepatitis carriers. Their median baseline hepatitis B virus DNA level was 89 IU/mL (range, <34-807 IU/mL). Virological rebound (as defined by a 10-fold increase in serum hepatitis B virus DNA level from pre-chemotherapy level persisted for 4 weeks) occurred in one of the 10 patients, followed by biochemical reactivation. Whereupon entecavir treatment was started and no liver failure ensued. Regarding the other seropositive occult patients, their serum hepatitis B virus DNA levels fluctuated, but there was no associated biochemical reactivation. CONCLUSION. Detectable baseline serum hepatitis B virus DNA is not uncommon in patients with occult hepatitis B who receive chemotherapy. Transient elevation in serum hepatitis B virus DNA levels does not predict biochemical reactivation, but antiviral treatment might be considered if virological rebound persists.",1
12541,21981435,Opioid-paracetamol prescription patterns and liver dysfunction: a retrospective cohort study in a population served by a US health benefits organization,"""BACKGROUND: Paracetamol (acetaminophen) is the most common cause of acute liver failure (ALF). ALF attributed to paracetamol is most often associated with the following features: an unintentional overdose, a single product, an opioid-paracetamol combination, duration of <7 days, and a median dose of 7.5 g/day. Currently, the recommended maximum daily dose of paracetamol is 4 g. OBJECTIVES: The aims of the study were to determine opioid-paracetamol prescription patterns, including prescriptions exceeding the recommended dose of paracetamol (4 g/day) [prescriptions and beneficiaries]; examine factors associated with receiving opioid-paracetamol prescriptions in excess of paracetamol 4 g/day; and evaluate opioid-paracetamol prescription patterns for beneficiaries with liver dysfunction. METHODS: A retrospective cohort study examining prescription data of 4.8 million beneficiaries from a US health benefits organization from 1 January 2009 through 31 December 2009. The main outcomes examined were daily paracetamol dose and liver dysfunction. RESULTS: A large proportion (8.1%) of the 5.3 million prescriptions for opioid-paracetamol exceeded the recommended maximum daily dose of paracetamol (4 g/day), putting over one-quarter of a million (255 123 [18.9%]) of the 1.35 million beneficiaries receiving an opioid-paracetamol prescription at risk of toxicity. The most frequently prescribed products that exceeded paracetamol dose guidelines contained dextropropoxyphene and hydrocodone. Multiple factors, including type of product (i.e. dextropropoxyphene or oxycodone-containing), geographical location (Midwest), strength of the paracetamol in the opioid-paracetamol product (>325 mg) and prescriber specialty (dentist, physician assistant), were associated with high-dose paracetamol prescriptions. Liver dysfunction was diagnosed in 3818 cases, and 23.4% of these beneficiaries received an opioid-paracetamol prescription in the 90 days prior to the liver dysfunction diagnosis. CONCLUSIONS: Although most opioid-paracetamol prescriptions are written and dispensed for <4 g/day of paracetamol, a significant portion of beneficiaries are being prescribed and dispensed excessive doses of paracetamol. Efforts to curtail this practice may involve provision of prescriber and pharmacist education, utilization of benefit manager systems to flag excessive dosing or that require confirmation of dosing, and implementation of US FDA recommendations supported by these data.""",1
12542,21985145,Apparent acute idiosyncratic hepatic necrosis associated with zonisamide administration in a dog,,1
12543,21989327,A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer,"""BACKGROUND: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that recently gained Food and Drug Administration approval for late-line metastatic breast cancer (MBC). PATIENTS AND METHODS: In this single-arm, multicentre open-label phase II trial Japanese patients pretreated with an anthracycline and a taxane received 1.4 mg/m(2) eribulin mesylate (2- to 5-min i.v. infusion on days 1 and 8 of a 21-day cycle). The primary efficacy end point was overall response rate (ORR) by independent review. RESULTS: Patients (N = 80) had received a median of three prior chemotherapy regimens (range 1-5). ORR was 21.3% [95% confidence interval (CI) 12.9-31.8; all partial responses (PRs)], stable disease (SD) occurred in 30 patients (37.5%) and the clinical benefit rate (complete response + PR + SD ?6 months) was 27.5% (95% CI 18.1-38.6). Median duration of response was 3.9 months (95% CI 2.8-4.9), progression-free survival was 3.7 months (95% CI 2.0-4.4) and overall survival was 11.1 months (95% CI 7.9-15.8). The most frequent treatment-related grade 3/4 adverse events were neutropenia (95.1%), leukopenia (74.1%) and febrile neutropenia (13.6%). Grade 3 peripheral neuropathy occurred in 3.7% of patients (no grade 4). CONCLUSIONS: Eribulin exhibited efficacy and tolerability in Japanese patients with heavily pretreated MBC.""",1
12544,21989920,Amiodarone-induced acute hepatotoxicity,,1
12545,21991951,Randomized trial of oral teriflunomide for relapsing multiple sclerosis,"""BACKGROUND: Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis. METHODS: We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks. RESULTS: Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI). Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels (?1 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred. CONCLUSIONS: Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo. (Funded by Sanofi-Aventis; TEMSO ClinicalTrials.gov number, NCT00134563.).""",1
12546,21993434,"Effects of 15-d repeated consumption of Hoodia gordonii purified extract on safety, ad libitum energy intake, and body weight in healthy, overweight women: a randomized controlled trial","BACKGROUND: Extracts from Hoodia gordonii have been shown to decrease food intakes and body weights in animals and were proposed as a food supplement or ingredient for weight management. OBJECTIVE: We assessed the safety and efficacy of a 15-d repeated consumption of H. gordonii purified extract (HgPE) relative to a placebo in humans. DESIGN: Healthy, overweight women, who were stratified by percentage body fat, received either HgPE (n = 25) or a placebo (n = 24) for 15 d. Subjects were resident in a clinic for a 4-d run-in period and a 15-d treatment period in which they received 2 servings/d of 1110 mg HgPE or a placebo formulated in a yogurt drink 1 h before breakfast and dinner. Subjects were otherwise allowed to eat ad libitum from standardized menus. RESULTS: There were no serious adverse events, but HgPE was less well tolerated than was the placebo because of episodes of nausea, emesis, and disturbances of skin sensation. Blood pressure, pulse, heart rate, bilirubin, and alkaline phosphatase showed significant (P < 0.05) increases in the HgPE group. Mean effects on ad libitum energy intakes and body weights did not differ significantly between the HgPE- and placebo-treatment groups (P > 0.05). CONCLUSIONS: In comparison with a matched placebo, the consumption of HgPE for 15 d appeared to be associated with significant adverse changes in some vital signs and laboratory parameters. HgPE was less well tolerated than was the placebo and did not show any significant effects on energy intakes or body weights relative to the placebo. This trial was registered at clinicaltrials.gov as NCT01306422.",1
12547,21999163,Drug safety evaluation of rosuvastatin,"INTRODUCTION: Rosuvastatin is a highly efficacious statin approved for use throughout the world. Rosuvastatin has been exhaustively evaluated in the setting of a broad variety of dyslipidemias and cardiovascular disease states in clinical trials encompassed within the GALAXY program. AREAS COVERED: The efficacy and adverse event profile of rosuvastatin are evaluated based on the results of randomized, controlled clinical trials and observational studies available in the Medline database. EXPERT OPINION: Rosuvastatin is a safe and efficacious lipid modifying drug in a broad variety of patient populations (men and women, irrespective of race) for treating multiple forms of dyslipidemia. Rosuvastatin reduces atherogenic lipoproteins and triglycerides and increases high-density lipoprotein cholesterol better than other statins. Compared to other statins, it has no excess signal for liver, skeletal muscle or renal toxicity. This is supported by evidence from both an extensive clinical trial program as well as post-marketing surveillance. The incidence of myalgia with this drug is comparable to that observed with other statins. Rosuvastatin does not depend on cytochrome P450 3A4-dependent metabolism and has a favorable drug interaction profile. Care must be taken to reduce the dose of rosuvastatin in patients of Asian ancestry or with stage IV chronic kidney disease (severe renal insufficiency), as well as patients being treated with protease inhibitors or cyclosporine.",1
12548,22000311,Alpers syndrome with mutations in POLG: clinical and investigative features,"Alpers syndrome is a rare autosomal recessive hepatocerebral degenerative disorder. Seventeen patients with Alpers syndrome or polymerase-? gene mutations were identified. Case records of 12 patients with Alpers syndrome and polymerase-? mutations in both alleles were reviewed. All patients manifested developmental delay or regression, refractory epilepsy, and biochemical liver dysfunction. Liver failure occurred in three patients previously treated with valproate. Other signs included ataxia, visual disturbance, motor paresis, and tremor. Myoclonic and focal motor seizures were common, often manifesting as status epilepticus. Electroencephalograms demonstrated absent/slow posterior dominant rhythms. Interictal discharges were common, usually involving the occipital lobes. Rhythmic high-amplitude delta with (poly)spikes was evident in four patients. Magnetic resonance imaging showed migratory, cortical, and subcortical T(2) hyperintensities in four children most often affected the parietal and occipital lobes. Developmental regression and refractory focal motor or myoclonic seizures are consistent clinical features of Alpers syndrome with polymerase-? mutations. Liver dysfunction constitutes a late manifestation. Migratory T(2)/fluid attenuated inversion recovery signal abnormalities involving metabolically active occipital and sensorimotor cortical regions comprise characteristic imaging findings. Interictal and ictal electroencephalogram patterns are more variable than previously reported. Three common polymerase-? mutations, in patients of European descent, can assist with rapid diagnosis, circumventing the need for liver biopsy.",1
12549,22006202,"A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone","""OBJECTIVE: To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. METHODS: In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ?3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ? 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. CONCLUSION: In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ?3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.""",1
12550,22008955,Lamotrigine-induced vanishing bile duct syndrome in a child,,1
12551,22011982,Lorcaserin: an investigational serotonin 2C agonist for weight loss,"""PURPOSE: The pharmacology, pharmacokinetics, and adverse effects of the selective serotonin (5-HT) agonist lorcaserin are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. SUMMARY: Lorcaserin is highly selective for a subtype of 5-HT receptors important in appetite regulation, with low affinity for other 5-HT-receptor subtypes whose activation is thought to underlie serious cardiovascular adverse effects; such effects have been seen with nonselective serotonergic agents for weight loss (e.g., fenfluramine). In two Phase III trials of lorcaserin, the cumulative proportion of patients who achieved weight loss of ?5% over 12 months was about 47% with lorcaserin use versus 20-25% among placebo users (p < 0.0001 for both trials). Lorcaserin was generally well tolerated in the clinical trials to date; nausea and vomiting, headache, and dizziness were the most commonly reported adverse effects. In two of the three Phase III trials to date, lorcaserin use was not found to increase the risk of cardiac valvulopathy; however, in the other Phase III trial, which focused on patients with diabetes, lorcaserin use was associated with an increased rate of new valvulopathy. In a carcinogenicity evaluation involving laboratory rats, lorcaserin was linked to the development of various malignancies, a finding with uncertain implications for its potential future use in humans. CONCLUSION: Lorcaserin, a 5-HT(2C) agonist, has demonstrated efficacy in patients who are obese or are overweight with associated comorbidities. Phase III trials have found that more than 35% of patients lost greater than 5% of their baseline weight. The maker of lorcaserin has indicated it will continue to seek U.S. marketing approval of the drug for the indications of long-term weight loss and weight-loss maintenance in specific patient populations.""",1
12552,22012970,Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study,"""OBJECTIVE: To assess the efficacy and safety of golimumab over 104 weeks in patients with active ankylosing spondylitis. METHODS: At baseline, patients with active ankylosing spondylitis (n=356) were randomly assigned (1:1.8:1.8) to subcutaneous injections of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3) every 4 weeks. At week 16, patients in groups 1 and 2 with <20% improvement in total back pain and morning stiffness entered early escape to 50 or 100 mg, respectively. At week 24, patients still receiving placebo crossed over to golimumab 50 mg. Findings through week 24 were previously reported; those through week 104 are presented herein. RESULTS: At week 104, 38.5%, 60.1% and 71.4% of patients in groups 1, 2 and 3, respectively, had at least 20% improvement in the Assessment in SpondyloArthritis international Society response criteria (ASAS20); 38.5%, 55.8% and 54.3% had an ASAS40 response and 21.8%, 31.9% and 30.7% were in ASAS partial remission. Mean Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores were <3 at week 104 for all the treatment regimens. Golimumab safety through week 104 was similar to that through week 24. CONCLUSION: Clinical response that was achieved by patients receiving golimumab through 24 weeks was sustained through 52 and 104 weeks. The golimumab safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.""",1
12553,22015077,"Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study","""BACKGROUND: Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed. METHODS: We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT00708162. FINDINGS: Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1?1%, 95% CI -6?0 to 8?2), meeting the criterion for non-inferiority (p=0?001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0?023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0?020) or aspartate aminotransferase (p=0?009). INTERPRETATION: Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence. FUNDING: Gilead Sciences.""",1
12554,22017800,Toxicity after radiochemotherapy for glioblastoma using temozolomide--a retrospective evaluation,"PURPOSE: Retrospective evaluation of toxicity and results after radiochemotherapy for glioblastoma. METHODS: 46 patients with histopathologically proven glioblastoma received simultaneous radiochemotherapy (RCT). The mean age at the beginning of therapy was 59 years, the mean Karnofsky performance index 80%. 44 patients had been operated on before radiotherapy, two had not. A total dose of 60 Gy was applied in daily single fractions of 2.0 Gy within six weeks, 75 mg/m2/day Temozolomide were given orally during the whole radiotherapy period. RESULTS: A local progression could be diagnosed in 34/46 patients (70%). The median survival time amounted to 13.6 months resulting in one-year and two-year survival probabilities of 48% and 8%, respectively. Radiotherapy could be applied completely in 89% of the patients. Chemotherapy could be completed according to schedule only in 56.5%, the main reason being blood toxicity (50% of the interruptions). Most of those patients suffered from leucopenia and/or thrombopenia grade III and IV CTC (Common toxicity criteria). Further reasons were an unfavourable general health status or a rise of liver enzymes. The mean duration of thrombopenia and leucopenia amounted to 64 and 20 days. In two patients, blood cell counts remained abnormal until death. In two patients we noticed a rise of liver enzymes. In one of these in the healing phase of hepatitis a rise of ASAT and ALAT CTC grade IV was diagnosed. These values normalized after termination of temozolomide medication. One patient died of pneumonia during therapy. CONCLUSION: Our survival data were well within the range taken from the literature. However, we noticed a considerable frequency and intensity of side effects to bone marrow and liver. These lead to the recommendations that regular examinations of blood cell count and liver enzymes should be performed during therapy and temozolomide should not be applied or application should be terminated according to the criteria given by the manufacturer.",1
12555,22020137,Clofazimine: current status and future prospects,"Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.",1
12556,22023530,"Expanding Nilotinib Access in Clinical Trials (ENACT), an open-label multicenter study of oral nilotinib in adult patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase or blast crisis","""Nilotinib has shown favorable safety in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic (CML-CP) or accelerated phase (CML-AP) who failed prior imatinib, and superior efficacy over imatinib in newly diagnosed Ph+ patients with CML-CP. Reported here are the efficacy and safety data for patients in CML-AP (n = 181) or blast crisis (CML-BC) (n = 190; myeloid BC, 133; lymphoid BC, 50; unknown, seven) enrolled in an expanded access phase IIIb study. Non-hematologic adverse events were mostly mild to moderate. Drug-related myelosuppression was generally manageable with dose reductions or interruptions and infrequently led to discontinuation of nilotinib. Drug-related grade 3/4 elevations in serum bilirubin and lipase were infrequent. While an analysis of efficacy was not the primary objective of this study, significant hematologic and cytogenetic responses were observed. These results support the safety and efficacy of nilotinib in patients with advanced CML in AP and BC.""",1
12557,22023901,The RANKL pathway and denosumab,"Denosumab (Prolia) is a fully human monoclonal antibody directed against receptor activator of nuclear factor-?B ligand (RANKL), which interferes with the formation, activation, and survival of osteoclasts. It was approved by the Food and Drug Administration in June 2010 as a new treatment for postmenopausal osteoporosis in women who are at high risk for fracture. Given its mechanism of action, it is an antiresorptive therapy that is administered as a 60-mg subcutaneous injection every 6 months. It is the first biologic antiresorptive therapy for osteoporosis, and the first osteoporosis therapy to show efficacy and safety in patients with renal impairment.",1
12558,22025146,"Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial","""PURPOSE: There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. PATIENTS AND METHODS: Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. RESULTS: Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). CONCLUSION: Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).""",1
12559,22027252,Reactivation of hepatitis B virus after glioblastoma treatment with temozolomide--case report,"A 61-year-old man with glioblastoma and positive for hepatitis B surface antigen (HBsAg) developed acute hepatitis due to hepatitis B virus (HBV) reactivation after concomitant postoperative treatment with temozolomide (75 mg/m(2)/day) and radiation therapy (60 Gy in 30 fractions). Corticosteroids were not used during chemo-radiation therapy, and grade 4 lymphocytopenia was observed. The levels of liver function tests (LFTs), including levels of aspartate aminotransferase and alanine aminotransferase, increased 5 weeks after the completion of chemo-radiation therapy, and reached the maximum levels of 1,549 IU/l (normal 13 to 33 IU/l) and 1,653 IU/l (normal 8 to 42 IU/l), respectively, after 2 weeks. At this point, serum HBV-deoxyribonucleic acid (DNA) level had increased to 630-fold over the baseline, and therapy with the antivirus agent entecavir (0.5 mg daily) was started. Over the next 2 weeks, the levels of LFTs and HBV-DNA improved. The present and previous cases suggest that grade 3/4 lymphocytopenia or grade 2 lymphocytopenia with corticosteroid use might have a significant effect on HBV reactivation. To avoid this complication, HBsAg-positive patients with glioblastoma should consult a hepatologist for initiating antivirus therapy before temozolomide treatment.",1
12560,22027579,"Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis","""BACKGROUND & AIMS: Tolvaptan is a vasopressin V2-receptor antagonist that improves serum sodium concentration by increasing renal solute-free water excretion. Specific data on the safety and efficacy of tolvaptan in patients with cirrhosis and hyponatremia has not been exclusively evaluated. METHODS: This sub-analysis of the Study of Ascending Levels of Tolvaptan trials examined cirrhotic patients with hyponatremia who received 15 mg oral tolvaptan (n=63; increased to 30 or 60 mg if needed) or placebo (n=57) once-daily for 30 days. At baseline, 44% had mild hyponatremia (serum sodium 130-134 mmol/L), 56% had marked hyponatremia (serum sodium <130 mmol/L), 85% had cirrhosis due to alcohol and/or hepatitis B/C, and 80% were Child-Pugh class B/C. RESULTS: Tolvaptan was effective in raising serum sodium. Average daily area under the curve for serum sodium was significantly greater in the tolvaptan group from baseline to day 4 (p<0.0001) and day 30 (p<0.0001). This superiority was maintained after stratification by baseline hyponatremia (mild and marked), estimated glomerular filtration rate (</= 60 ml/min and >60 ml/min), or serum creatinine levels (<1.5mg/dl and >/= 1.5mg/dl). Hyponatremia recurred 7 days after discontinuation of tolvaptan. Mean mental component summary scores of the SF-12 health survey improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, p=0.02). Major side effects due to tolvaptan were dry mouth and thirst. Gastrointestinal bleeding occurred in 10% and 2% of patients in the tolvaptan and placebo group, respectively (p=0.11). Adverse event rates, withdrawals, and deaths were similar in both groups. CONCLUSIONS: One month of tolvaptan therapy improved serum sodium levels and patient-reported health status in cirrhotic patients with hyponatremia. Hyponatremia recurred in tolvaptan-treated patients after discontinuation.""",1
12561,22030947,"Effects of 1,3-dimethylamylamine and caffeine alone or in combination on heart rate and blood pressure in healthy men and women","BACKGROUND: The use of 1,3-dimethylamylamine (geranamine), alone and in combination with caffeine, is becoming widespread within the dietary supplement industry. To our knowledge, no data are available concerning the effects of oral geranamine intake on heart rate (HR) and blood pressure in individuals. METHODS: Ten young healthy men and women ingested 1 of 5 conditions on different days using a double-blind, randomized, crossover design. The following were ingested after a 10-hour overnight fast: 250 mg caffeine (C), 50 mg geranamine (G 50 mg), 75 mg geranamine (G 75 mg), 250 mg caffeine + 50 mg geranamine (C + G 50 mg), and 250 mg caffeine + 75 mg geranamine (C + G 75 mg). Heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), and rate pressure product (RPP) were measured pre-ingestion and at 30, 60, 90, and 120 minutes post-ingestion. Plasma norepinephrine (NE) and epinephrine (EPI) were measured pre-ingestion and at 60 and 120 minutes post-ingestion. RESULTS: Heart rate was unaffected by treatment, but blood pressure and RPP were higher with geranamine, generally in a dose-dependent manner. The peak percent change from pre-ingestion in SBP (~20%), DBP (~17%), and RPP (~9%) was noted with C + G 75 mg at 60 minutes post-ingestion. Plasma NE and EPI were relatively unaffected by treatment. CONCLUSION: We report for the first time that acute ingestion of 1,3-dimethylamylamine alone and in combination with caffeine results in an increase in SBP, DBP, and RPP without an increase in HR. The largest increase is observed at 60 minutes post-ingestion of C + G 75 mg. These changes cannot be explained by circulating NE and EPI.",1
12562,22033451,Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases,"""The emergence of tumor necrosis factor-? (TNF-?)-targeted therapies as a key therapeutic option for patients with rheumatic, digestive, and dermatologic autoimmune diseases has been associated with increasing reports of liver damage in patients with hepatitis B virus (HBV) infection. We studied the current evidence on the use of anti-TNF agents in patients with HBV through a systematic analysis of cases reported in the MEDLINE and EMBASE databases using the MeSH term """"hepatitis B virus"""" combined with the terms """"infliximab,"""" """"etanercept,"""" """"adalimumab,"""" """"certolizumab,"""" """"golimumab,"""" and """"anti-TNF agents,"""" and summarize the results here. We analyzed 257 patients with positive HBV markers who received anti-TNF therapy (255 identified in the search strategy and 2 new cases), 89 HBsAg+ carriers, and 168 anti-HBc+ persons. HBV reactivation was reported in 35 (39%) HBsAg+ carriers. The percentage of reactivation was higher in patients previously treated with immunosuppressive agents (96% vs. 70%, p=0.033) and lower in those who received antiviral prophylaxis (23% vs. 62%, p=0.003). Acute liver failure was reported in 5 patients, 4 of whom died. Infliximab was associated with a higher rate of induced liver disease (raised transaminase levels, clinical signs, viral reactivation, and acute liver failure) compared with etanercept. In anti-HBc+ persons, reactivation was reported in 9 (5%) cases, including 1 patient who died due to fulminant liver failure.In summary, our search of the current evidence identified 257 reported HBV+ patients treated with anti-TNF agents, with a significant percentage of liver damage in HBsAg+ carriers, including raised transaminase levels (42%), signs and symptoms of liver disease (16%), reappearance of serum HBV-DNA (39%), and death related to liver failure (5%). The rate of reactivation in anti-HBc+ persons was 7-fold lower than in HBsAg+ carriers. The increasing number of reported cases of HBV reactivation following TNF-targeted therapies and the associated morbidity and mortality demand specific preventive strategies.""",1
12563,22034658,Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis,"""Ruxolitinib (INCB018424) is a JAK1 and JAK2 inhibitor recently evaluated for the treatment of myelofibrosis (MF) in early- and advanced-phase clinical trials. In 2 recent communications that focused on short-term and long-term ruxolitinib treatment outcome, respectively, the drug was shown to be effective in controlling constitutional symptoms and splenomegaly but was also associated with important adverse effects, including moderate to severe thrombocytopenia and anemia. The most recent of the 2 communications focused on 51 Mayo Clinic patients who participated in the original phase 1/2 ruxolitinib clinical trial and highlighted a high treatment discontinuation rate (92% after a median time of 9.2 months), primarily for loss of treatment benefit but also because of drug-associated adverse effects. The report also discussed the occurrence of sometimes severe withdrawal symptoms during ruxolitinib treatment discontinuation. This """"ruxolitinib withdrawal syndrome"""" was characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation, including a septic shocklike syndrome. In the current sponsor-independent analysis, we describe the details of these events in 5 severely affected cases (11%) among 47 Mayo Clinic patients with MF in whom ruxolitinib therapy had been discontinued. Our experience calls for full disclosure of the ruxolitinib withdrawal syndrome to patients with MF before initiating ruxolitinib therapy, and treatment discontinuation must be done under close physician supervision and preferably in a tapering schedule.""",1
12564,22041509,Chemotherapy before liver resection of colorectal metastases: friend or foe?,"OBJECTIVE: We conducted a systematic review of the published literature to critically assess benefits and risks of the use of preoperative chemotherapy in patients presenting with colorectal liver metastases. BACKGROUND: In many centers, chemotherapy is used before hepatic resection of colorectal metastases, even in the presence of a single lesion. Application of chemotherapy requires clear conceptual distinction between patients presenting with resectable lesions (neoadjuvant) versus patients presenting with unresectable lesions, for which chemotherapy is used to reach a resectable situation (downsizing). METHODS: The literature (PubMed) was systematically reviewed for publications related to liver surgery and chemotherapy according to the methodology recommended by the Cochrane Collaboration. RESULTS: For unresectable liver metastases, combination regimens result in enhanced tumor response and resectability rates up to 30%, although the additional benefit from targeted agents such as bevacizumab or cetuximab is marginal. For resectable lesions, studies on neoadjuvant chemotherapy failed to convincingly demonstrate a survival benefit. Most reports described increased postoperative complications in a subset of patients due to parenchymal alterations such as chemotherapy-associated steatohepatitis or sinusoidal obstruction syndrome. CONCLUSION: Preoperative standard chemotherapy can be recommended for downsizing unresectable liver metastases, but not for resectable lesions, for which adjuvant chemotherapy is preferred.",1
12565,22045675,Circulating microRNAs as potential markers of human drug-induced liver injury,"""UNLABELLED: New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median DeltaDeltaCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). CONCLUSION: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury.""",1
12566,22047565,Therapy for cystic fibrosis--the end of the beginning?,,1
12567,22048844,Use of linezolid in neonatal and pediatric inpatient facilities--results of a retrospective multicenter survey,"""The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8 years (interquartile range 0.6-15.5 years; range 0.1-21.2 years; ten patients were older than 18 years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14 days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12 years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved.""",1
12568,22054632,Severe INR elevation related to duloxetine use: a case report,,1
12569,22059112,Revisiting acute liver injury associated with herbalife products,"In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.",1
12570,22062945,"Herbs in epilepsy: evidence for efficacy, toxicity, and interactions","Herbs and dietary supplements enjoy widespread use in the treatment of epilepsy although supportive data yielding efficacy and safety are lacking. Ten specific products, American hellebore, betony, blue cohosh, kava, mistletoe, mugwort, pipsissiwa, skullcap, valerian, and melatonin, have either multiple-cited recommendations for use in epilepsy or a rationale for antiepileptic action and are discussed in detail. These items paradoxically often have a proconvulsant effect in addition to potentially serious adverse effects. Herb-drug interactions also occur at the level of the P450 hepatic enzyme system of drug catabolism and the P-glycoprotein transport system regulating the entry of exogenous compounds into the vasculature or blood-brain barrier. Thus, significant pharmacokinetic interactions may occur, in addition to pharmacodynamic interactions and proconvulsant effects of alternative medications themselves. Patients should be inquired as to the nature of any alternative medicine products they are using, with the view that these products may be reasonable if traditional antiepileptic drug therapy is continued, potential adverse effects of the alternative agents are monitored, and the alternative and traditional agents do not conflict.",1
12571,22067384,"Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia","""Antithymocyte globulin (ATG) + cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatment-naive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG + cyclosporine (n = 27) and alemtuzumab (n = 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P = .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% CI, 43%-85%) for rabbit ATG (P = .16). For relapsed disease (n = 25), alemtuzumab was administered in a single-arm study; the response rate was 56% (95% CI, 35%-77%) and the 3-year survival was 86% (95% CI, 72%-100%). In treatment-naive patients (n = 16), alemtuzumab was compared with horse and rabbit ATG in a 3-arm randomized study; the response rate was 19% (95% CI 0%-40%), and the alemtuzumab arm was discontinued early. We conclude that alemtuzumab is effective in SAA, but best results are obtained in the relapsed and refractory settings. The present trials were registered at www.clinicaltrials.gov as NCT00195624, NCT00260689, and NCT00065260.""",1
12572,22069142,Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC,"OBJECTIVE: The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations. METHODS: We here assess the neurocognitive development using standardized psychometric test batteries with respect to cognition, motor abilities and speech in nine early-treated patients with HT I under long-term NTBC treatment. RESULTS: High plasma tyrosine concentrations were frequently documented resulting in elevated 12-month median plasma tyrosine concentrations in seven out of nine patients. Plasma NTBC concentrations were generally in the lower therapeutic range. Five out of seven patients (71%) above 3 years of age had a total IQ score below the average. In addition, five out of seven patients above 3 years showed an inhomogenous test profile with significant differences between the different testing scales. Motor abilities were subnormal in four out of seven patients(57%). Cerebral MRI revealed no abnormalities. Logopedic evaluation in children at school age documented dysfunction or retardation in language development in all but one of the tested patients (80%), however, all but one patients had a migration background. CONCLUSIONS: A high number of patients performed below normal in the assessment of development, motor function and speech. We propose intellectual impairment as long-term complication in HT type I with elevated plasma tyrosine under NTBC treatment as observed in other hypertyrosinemias. These findings remain to be reproduced in greater patient numbers.",1
12573,22075044,Massive aquaresis after tolvaptan administration and albumin infusion in a patient with alcoholic cirrhosis,,1
12574,22077677,Use of anti-tumor necrosis factor-? therapy in hepatitis B virus carriers with psoriasis or psoriatic arthritis: a case series in Taiwan,"The use of anti-tumor necrosis factor (TNF)-? therapy in patients with psoriasis who are hepatitis B virus (HBV) carriers is usually not recommended, and routine antiviral prophylaxis is suggested for those who need the treatment. We report our experience on the safety of anti-TNF-? therapy in patients with psoriasis who are HBV carriers in our clinic using HBV viral load as a guide for HBV treatment. Between 2007 and 2011, seven HBV carriers receiving TNF-? inhibitors for psoriasis in our clinic were collected retrospectively. The HBV viral load and aminotransferase levels were regularly monitored. Two of the seven patients were inactive HBV carriers, and the other five patients had chronic hepatitis B. Only one patient received antiviral agents before the anti-TNF-? treatment. The mean duration of the anti-TNF-? treatment was 26.6 months (range, 14-45 months). These patients were followed up from the start of the anti-TNF-? therapy for a mean duration of 28.9 months (range, 14-45 months). HBV reactivation was observed in three patients, one of whom required antiviral treatment. No HBV reactivation-related hepatitis was observed. In conclusion, prevention of HBV reactivation by monitoring of HBV viral load is cost-effective and may decrease the risk of developing drug resistance from routine anti-HBV prophylaxis treatment. It can be considered as an alternative in psoriasis patients treated by TNF-? inhibitors, especially in areas with a high HBV burden and in hepatitis B e-antigen-negative patients who have a lower risk of viral reactivation.",1
12575,22078360,Deferasirox induced liver injury in haemochromatosis,,1
12576,22082652,Association of ABCC10 polymorphisms with nevirapine plasma concentrations in the German Competence Network for HIV/AIDS,"""BACKGROUND: Nevirapine exhibits marked interpatient variability in pharmacokinetics. CYP2B6 activity and demographic factors are important, but there are a few data on drug transporters for nevirapine. ABCC10 (MRP7) is an efflux transporter highly expressed in liver, intestine, and peripheral blood cells. We investigated whether nevirapine is a substrate for ABCC10 and whether genetic variants contribute to variability in nevirapine plasma concentrations. METHODS: Accumulation of nevirapine was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4+ cells, and monocyte-derived macrophages from healthy volunteers (n=8). ABCC10 small interfering RNA studies were also conducted. DNA samples with paired plasma drug concentrations were available from 163 HIV-infected patients receiving nevirapine-containing regimens. Sequenom was used to screen 14 single nucleotide polymorphisms in ABCC10. Linear regression models were used to identify factors independently associated with nevirapine plasma concentration. RESULTS: Nevirapine accumulation was 37% lower in HEK293-ABCC10 cells compared with parental HEK293 cells (P=0.02), and this was reversed by cepharanthine (an ABCC10 inhibitor). After small interfering RNA knockdown of ABCC10, there was an increase in accumulation of nevirapine in CD4 cells (32%; P=0.03) and monocyte-derived macrophages (38%; P=0.04). Marked differences in the haplotype structure of ABCC10 was observed between White and Black patients in the cohort. In Whites, an exonic single nucleotide polymorphism (rs2125739) was significantly associated with nevirapine plasma concentration (P=0.02). Multivariate regression analysis identified carriage of a composite genotype of ABCC10 rs2125739 and CYP2B6 516G>T (P=0.001), time post dose (P=0.01) and BMI (P=0.07) to be independently associated with nevirapine plasma concentrations. CONCLUSION: Nevirapine is a substrate for ABCC10 and genetic variants influence its plasma concentrations. ABCC10 in lymphocytes and macrophages may also contribute to variability in intracellular permeation of nevirapine. Further studies are required to determine the clinical implications of these findings.""",1
12577,22085343,Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy,"""BACKGROUND: In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk. METHODS: We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. RESULTS: A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test). CONCLUSIONS: Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; AIM-HIGH ClinicalTrials.gov number, NCT00120289.).""",1
12578,22088484,"A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group","""PURPOSE: To determine the toxicity, efficacy and pharmacokinetics of trabectedin given over 24h every 3 weeks to children with recurrent rhabdomyosarcoma, Ewing sarcoma, or non-rhabdomyosarcoma soft tissue sarcomas. PATIENTS AND METHODS: Trabectedin was administered as a 24-h intravenous infusion every 21 days. Two dose levels were evaluated (1.3 and 1.5mg/m(2)) for safety; efficacy was then evaluated using a traditional 2-stage design (10+10) at the 1.5mg/m(2) dose level. Pharmacokinetics (day 1 and steady state) were performed during cycle 1. RESULTS: Fifty patients were enrolled, eight patients at 1.3mg/m(2) and 42 at 1.5mg/m(2). Dose limiting toxicities (DLTs) in the dose finding component included fatigue and reversible GGT elevation in 1/6 evaluable patients at 1.3mg/m(2) and 0/5 at 1.5mg/m(2). Efficacy was evaluated in 42 patients enrolled at the 1.5mg/m(2) dose of whom 22% experienced reversible grade 3 or 4 toxicities that included AST, ALT, or GGT elevations, myelosuppression and deep venous thrombosis. One patient with rhabdomyosarcoma had a partial response and one patient each with rhabdomyosarcoma, spindle cell sarcoma and Ewing sarcoma had stable disease for 2, 3 and 15 cycles, respectively. CONCLUSION: Trabectedin is safe when administered over 24h at 1.5mg/m(2). Trabectedin did not demonstrate sufficient activity as a single agent for children with relapsed paediatric sarcomas.""",1
12579,22089354,Dermatologists' awareness of and screening practices for hepatitis B virus infection before initiating tumor necrosis factor-alpha inhibitor therapy,"OBJECTIVE: The aim of the study was to assess dermatologists' awareness of available guidelines and drug package insert information on the screening for and management of hepatitis B (HBV) infection in patients receiving tumor necrosis factor-alpha inhibitor (TNF-alphaI) drug therapies for dermatological disorders. MATERIALS AND METHODS: An electronic descriptive cross-sectional questionnaire was administered to a random, nationwide sample of physician members of the American Academy of Dermatology. Each participating physician answered 8 questions regarding his or her awareness of the risk of HBV reactivation. RESULTS: More than half of the dermatologists surveyed (52%) were aware of guidelines regarding TNF-alphaI use in dermatological disorders. Dermatologists who were aware of the guidelines performed universal screening 81% of the time versus 3% of those who were unaware. Approximately 30% of the dermatologists were aware of drug manufacturers' package insert warnings for risk of HBV reactivation with TNF-alphaIs. Screening in their high-risk patients was highly variable because >90% performed screening in patients with a history of hepatitis or with elevated liver-associated enzymes. Most (73%) screened appropriately with HB surface antigen. One case of HBV reactivation was observed with infliximab use for psoriasis treatment. CONCLUSIONS: Based on this survey, improving education among dermatologists regarding the risks of HBV reactivation and its prevention for patients receiving TNF-alphaI seems warranted. More specific consensus guidelines are recommended to achieve universal screening as the standard of care in these patients.",1
12580,22094954,Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial,"""BACKGROUND: Cytomegalovirus (CMV) prevention can be achieved by prophylaxis or preemptive therapy. We performed a prospective randomized trial to determine whether renal transplant recipients with a positive CMV serostatus (R+) had a higher rate of CMV infection and disease after transplantation when treated preemptively for CMV infection, compared with primary valganciclovir prophylaxis. METHODS: Prophylaxis was 2 x 450 mg oral valganciclovir/day for 100 days; preemptive patients were monitored by CMV-polymerase chain reaction (PCR), and after a positive PCR test received 2 x 900 mg valganciclovir/day for at least 14 days followed by secondary prophylaxis. Valganciclovir dosage was adjusted according to renal function. Patients are followed up for 5 years and initial 12-month data are presented. Two hundred and ninety-six recipients were analyzed (168 donor/recipient seropositive [D+/R+], 128 donor seronegative/recipient seropositive [D-/R+]; 146 receiving prophylaxis and 150 preemptive therapy). RESULTS: Overall, CMV infection (asymptomatic CMV viral load >/= 400 CMV DNA copies/mL proven by CMV-PCR) was significantly higher in recipients under preemptive therapy (38.7% vs. 11.0%, P<0.0001), with the highest incidence in D+/R+ preemptive patients (53.8% vs. 15.6%, P<0.0001). D+/R+ recipients with preemptive therapy also had the highest rate of CMV disease (CMV syndrome and tissue-invasive disease that was clinically diagnosed and biopsy proven) (19.2% vs. 4.4%, P=0.003). Renal function assessed by creatinine clearance was similar for both groups. Graft loss occurred in 7 vs. 4 patients on preemptive versus prophylactic therapy (P>0.05). Tolerability was similar for both treatment groups. CONCLUSIONS: Oral valganciclovir prophylaxis significantly reduces CMV infection and disease, particularly for D+/R+ patients. Hence, our study supports routine prophylaxis for all D+/R+ recipients.""",1
12581,22102391,A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage,"""Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range.""",1
12582,22106978,Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials,"""OBJECTIVE: Dipeptidyl peptidase-4 inhibitors (DPP4i) have been recently associated with increased risk of pancreatitis and cancer. The aim of the present meta-analysis of randomized clinical trials is the assessment of the effect of DPP4i on the incidence of major cardiovascular events (MACE), cancer, and pancreatitis. RESEARCH DESIGN AND METHODS: An extensive Medline and Embase search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin' was performed, collecting all randomized clinical trials on humans up to March 1, 2011. The present meta-analysis was therefore performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP4i with either placebo or active drugs. Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov, Food and Drug Administration, and European Medicines Agency website. RESULTS: Fifty-three trials enrolling 20,312 and 13,569 patients for DPP4i and comparators, respectively, were included, reporting 176 malignancies, 257 MACE, and 22 pancreatitis. DPP4i, compared with placebo or other treatment, were associated with a similar risk of cancer (MH-OR 1.020 [0.742-1.402]; p = 0.90) and pancreatitis (0.786 [0.357-1.734], p = 0.55), and with a reduced risk of MACE (MH-OR 0.689 [0.528-0.899], p = 0.006). CONCLUSIONS: The present meta-analysis seems to exclude any relevant short term effect of DPP4i on the incidence of cancer and suggest a possible protection from cardiovascular events. This result should be interpreted with caution, as those events were not the principal endpoint, the trial duration was short, and the characteristics of patients included could be different from routine clinical practice.""",1
12583,22111942,The long-term outcome of patients with polycystic liver disease treated with lanreotide,"BACKGROUND: Polycystic liver disease (PLD) is a phenotypical expression of autosomal dominant polycystic kidney disease and isolated polycystic liver disease. Somatostatin analogues, such as lanreotide, reduce polycystic liver volume. AIM: To establish long-term outcome and safety of lanreotide. METHODS: This was an open-label, observational extension study of a 6-month, randomised, placebo-controlled trial with lanreotide (120 mg/month) in PLD. The length of total treatment was 12 months. Primary endpoint was relative change in liver volume, as determined by CT-volumetry after 12 months of treatment. We offered patients a CT scan 6 months after stopping lanreotide. RESULTS: A total of 41/54 (76%) patients participated in the extension study. Liver volume decreased by 4% (IQR -8% to -1%) after 12 months of treatment. The greatest effect was observed during the first 6 months of treatment (decrease of 4% (IQR -6% to -1%)). Liver volume remained unchanged during the following 6 months. We found that liver volume increased by 4% (IQR 0-6%) 6 months after end of treatment (n = 22). CONCLUSIONS: Lanreotide reduces liver volume within the first 6 months of treatment and the beneficial effect is maintained in the following 6 months. Stopping results in recurrence of polycystic liver growth. This suggests that continuous use of lanreotide is needed to maintain its effect.",1
12584,22118500,Drug safety evaluation of maraviroc for the treatment of HIV infection,"INTRODUCTION: Maraviroc is the only C-chemokine receptor 5 (CCR5) antagonist approved for the treatment of infection with HIV. This article reviews the safety and efficacy of maraviroc in the treatment of HIV infection. AREAS COVERED: The PubMed database was searched using the keywords 'maraviroc' and 'HIV'. In addition, conference proceedings from CROI, IAS and EACS meetings were searched for maraviroc clinical trials. The PubMed search revealed one Phase IIb - III clinical trial in treatment-naive HIV(+) patients (MERIT) and three Phase IIb - III randomized clinical trials (RCTs) in treatment-experienced patients (MOTIVATE 1 and 2, A4001029). All RCTs showed an excellent safety profile for maraviroc in the treatment of HIV-1 infection. However, long-term (> 3 years) safety data generated on maraviroc therapy are still scarce. Based on the findings from RCTs so far, no relevant toxicities and co-morbidities such as coronary heart disease or hepatotoxicity have been described. The overall CD4(+) cell count increase resulting from a maraviroc-containing regimen appears to be higher than those seen with other antiretroviral regimens. However, the significance remains controversial. To date, maraviroc has shown a potent and durable virological efficacy profile for the treatment of HIV-1 infection. The only use of maraviroc depends on pretreatment testing for CCR5 tropism. EXPERT OPINION: Maraviroc is a generally safe and well-tolerated medication for the treatment of HIV-1 infection with a unique mechanism of action. Long-term (i.e., > 5 years) risks are not known and have to be carefully monitored.",1
12585,22120092,"Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study)","PURPOSE: Diuretics are recommended to treat volume overload with heart failure (HF), however, they may cause serum electrolyte imbalance, limiting their use. Moreover, patients with advanced HF could poorly respond to these diuretics. In this study, we evaluated the efficacy and safety of Tolvaptan, a competitive vasopressin V2-receptor antagonist developed as a new drug to treat volume overload in HF patients. METHODS: A phase III, multicenter, randomized, double-blind, placebo-controlled parallel study was performed to assess the efficacy and safety of tolvaptan in treating HF patients with volume overload despite the use of conventional diuretics. One hundred and ten patients were randomly assigned to receive either placebo or 15 mg/day tolvaptan for 7 consecutive days. RESULTS: Compared with placebo, tolvaptan administered for 7 days significantly reduced body weight and improved symptoms associated with volume overload. The safety profile of tolvaptan was considered acceptable for clinical use with minimal adverse effects. CONCLUSION: Tolvaptan reduced volume overload and improved congestive symptoms associated with HF by a potent water diuresis (aquaresis).",1
12586,22121930,"Liver function tests in children and adolescents receiving risperidone treatment for a year: a longitudinal, observational study from Turkey","OBJECTIVE: To determine the changes in liver function tests after long-term risperidone treatment in a child and adolescent population. METHODS: Weight, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase and serum bilirubin of the patients were assessed in pre-treatment period, and at the sixth and 12th months of treatment. One hundred children and adolescents (aged between 3 and 18 years) were enrolled to the study. RESULTS: Liver enzyme and bilirubin levels are higher than normal in 21.0% of the patients without clinical symptoms. No cases of hepatic failure or jaundice were seen. Only in an 8-year-old boy were there ALT level increases up to three-fold and AST level increases up to two-fold. After discontinuation of the risperidone treatment, enzyme levels were normalized in this patient. Alkaline phosphatase, alanine and aspartate aminotransferases were the most frequently increased enzymes. CONCLUSION: In this study, after long-term risperidone treatment of children and adolescents there was no evidence of clinically significant increases of liver enzymes and bilirubin levels. These results indicate that risperidone treatment may rarely cause serious liver enzyme increases, and may commonly cause clinically insignificant changes in liver function tests.",1
12587,22123416,Phototherapy in the age of biologics,"Dermatologists are presented with a diversity of therapeutic modalities for the treatment of inflammatory, sclerosing, and neoplastic conditions, but with the development of various new irradiation devices that utilize specific parts of the electromagnetic spectrum, phototherapy has become a more viable, accessible, and efficacious option in the treatment of these conditions. The ultraviolet (UV) range (10-400 nm) is further subdivided into UVA and UVB, each of which has been particularly useful in a number of skin conditions. The most commonly used forms of UV irradiation are UVA1, psoralen plus UVA (PUVA), and narrowband (NB) UVB. Each of these modalities differ in their mechanism of action, indications, and side effect profiles, and it is important that clinicians be familiar with these differences. Today, phototherapy is a valuable option in the treatment of many nonpsoriatic conditions including atopic dermatitis, sclerosing skin conditions such as morphea, vitiligo, and mycosis fungoides. Due to its relative safety, phototherapy may be used in most populations, including children and pregnant women. However, contraindications and side effects are known and should be considered before patients begin a phototherapeutic regimen.",1
12588,22129890,"Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer","""PURPOSE: This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy. METHODS: Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ? 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression. RESULTS: Siltuximab plus M/P was well tolerated in Part 1 (n=9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P=0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P=0.0003). CONCLUSION: While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated.""",1
12589,22132422,Surrogate decision making: a woman in fulminant liver failure after an acetaminophen overdose,,1
12590,22133323,Herbal medicines for the management of opioid addiction: safe and effective alternatives to conventional pharmacotherapy?,"Striking increases in the abuse of opioids have expanded the need for pharmacotherapeutic interventions. The obstacles that confront effective treatment of opioid addiction - shortage of treatment professionals, stigma associated with treatment and the ability to maintain abstinence - have led to increased interest in alternative treatment strategies among both treatment providers and patients alike. Herbal products for opioid addiction and withdrawal, such as kratom and specific Chinese herbal medications such as WeiniCom, can complement existing treatments. Unfortunately, herbal treatments, while offering some advantages over existing evidence-based pharmacotherapies, have poorly described pharmacokinetics, a lack of supportive data derived from well controlled clinical trials, and severe toxicity, the cause for which remains poorly defined. Herbal products, therefore, require greater additional testing in rigorous clinical trials before they can expect widespread acceptance in the management of opioid addiction.",1
12591,22136512,HLA alleles and drug hypersensitivity reactions,"The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions.",1
12592,22138369,Late hepatitis B virus reactivation after lamivudine prophylaxis interruption in an anti-HBs-positive and anti-HBc-negative patient treated with rituximab-containing therapy,"We describe a case of an anti-HBs-positive patient who experienced hepatitis B reactivation 18 months after the discontinuation of rituximab and after 12 months of lamivudine prophylaxis. The patient carried a hepatitis B genotype D virus harbouring a single immune escape mutation, sT118K. No consensus guidelines regarding the optimal length of treatment or the best elective drug have been defined for antiviral prophylaxis for HBsAg-negative, anti-HBc- and/or anti-HBs-positive patients undergoing immunosuppressive treatment. Screening based on HBV serological markers and HBV DNA testing is a critical issue to recognise hepatitis B reactivation as early as possible. Furthermore, it is of outstanding importance to identify alternative markers (e.g. cccDNA, HBV core related antigen, etc.), that could be predictive of HBV reactivation.",1
12593,22138553,Hepatic safety of efavirenz in HIV/hepatitis C virus-coinfected patients with advanced liver fibrosis,"OBJECTIVE: To assess the frequency of severe liver toxicity in HIV/hepatitis C (HCV)-coinfected patients with advanced liver fibrosis receiving efavirenz (EFV)-based antiretroviral combinations. METHODS: One hundred and eighty-nine previously antiretroviral na?ve, HIV/HCV-coinfected patients, who started a regimen including two nucleoside analogues plus EFV, and in whom the presence or absence of advanced liver fibrosis could be established, were retrospectively analyzed. Liver fibrosis was evaluated according to a stepwise algorithm including liver biopsy, transient elastography and FIB-4 index. RESULTS: Fifty-six patients had advanced fibrosis - 25 with cirrhosis - and 133 did not. Three (5.4%) subjects with and 9 (6.8%) (p=0.717) without advanced fibrosis developed grade 3-4 transaminase elevation (TE). Grade 4 total bilirubin elevation was seen in 5 (8.9%) patients with advanced fibrosis and in 1 (0.8%) without it (p=0.003). Liver events led to EFV discontinuation in 10 (5.3%) patients, 6 (10.7%) with and 4 (3%) without advanced fibrosis (p=0.031). CONCLUSIONS: The hepatic tolerability of EFV was good in HIV/HCV-coinfected patients with advanced liver fibrosis. The frequency of grade 3-4 TE was similar to that observed in patients without advanced fibrosis, there was no death attributable to liver failure caused by drug toxicity and the rate of EFV discontinuations due to liver events was low.",1
12594,22139685,Herb-drug interactions: focus on metabolic enzymes and transporters,"As the uses of herbal medicines from traditional natural products are increased, the need for pharmacokinetic studies and relevant data are also increased for safe pharmacotherapy. The market entry for the traditional herbal medicine is easier compared with that for synthetic drugs because of a lower regulatory barrier. Thus, the exact mechanisms for the absorption, distribution, metabolism and excretion of active components in herbal medicines and the potential herb-drug interactions are not always fully understood. Recently, there has been an increasing interest in pharmacokinetic studies of herbal remedies and relevant data of commonly used herbal remedies are accumulating in this field. In this review, the effects of nine botanicals (ginkgo, green tea, grapes, licorice, saw palmetto, garlic milk thistle, ginseng and St. John's wort) on metabolic enzymes and transporters affecting absorption and disposition of herbal products are summarized. The source of samples (extracts and individual components), the species (human and animal) and in vivo and in vitro systems were separately reviewed for a better understanding of herb-drug interactions.",1
12595,22141295,Temozolomide induced liver injury,"A 62-year female received radiotherapy over six weeks with daily 75 mg/m2 Temozolomide (TMZ) for Glioblastoma (GB). At the last week of radiotherapy, her liver enzymes and serum bilirubin started deteriorating. TMZ was discontinued. The histopathology demonstrated the features of acute cholestasis and focal parenchymal inflammation. A range of investigations failed to show any other contributory cause of hepatitis. She required in-hospital care for a prolonged period for a grade three hepatic failure. The liver functions very slowly recovered over 40 weeks, but her general condition continues to deteriorate. TMZ may cause a mild temporary rise in the liver enzymes and has been reported to reactivate hepatitis B. In few other cases concomitant medications were the possible causes of hepatitis. However, searching the Medline and other bibliographic database, we have not come across any case of TMZ-induced liver injury (TMZ-DILI). Histopathology and pattern of liver enzyme elevation suggest that unlike Dacarbazine, which causes veno-occlusive type liver damage, TMZ in this patient caused mainly cholestasis type liver injury. On Naranjo Adverse Drug Reaction (ADR) probability scale, this case falls in probable grade (Scale 7).",1
12596,22144789,Azithromycin induced hepatocellular toxicity and hepatic encephalopathy in asymptomatic dilated cardiomyopathy,"Azithromycin is a widely used macrolide derivative and has generally been considered to be a very safe medication. Though gastrointestinal symptoms and reversible hearing loss are common, potentially serious side effects including angioedema and cholestatic jaundice occurred in less than one percent of patients. We report a case of asymptomatic dilated cardiomyopathy with Azithromycin induced severe hepatocellular toxicity and hepatic encephalopathy.",1
12597,22147460,Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study,"BACKGROUND: Vedolizumab is a gut-selective biologic that has shown efficacy in ulcerative colitis (UC) and Crohn's disease (CD). We studied the pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy of a new formulation of vedolizumab produced by an improved manufacturing process. METHODS: UC patients were randomized to receive vedolizumab (2, 6, or 10 mg/kg) or placebo on days 1, 15, 29, and 85. Safety, pharmacokinetics, pharmacodynamics, and immunogenicity evaluations were performed at multiple timepoints through day 253. Partial Mayo Scores and fecal calprotectin levels were used to assess efficacy. RESULTS: In all, 46 patients (9 placebo, 37 vedolizumab) received at least one dose of study medication. The vedolizumab serum concentration declined monoexponentially until concentrations reached 1-10 ?g/mL, and then fell nonlinearly. Vedolizumab maximum serum concentration (C(max) ) and area under the curve (AUC) increased approximately proportionally as a function of dose. Vedolizumab maximally saturated ?(4) ?(7) receptors on peripheral serum lymphocytes at all measurable serum concentrations. Vedolizumab was well tolerated, with no deaths and no adverse events leading to discontinuation. At every assessment from day 29 through day 253, over 50% of vedolizumab-treated patients were in clinical response, while placebo response rates generally ranged between 22% and 33%. Vedolizumab treatment reduced fecal calprotectin levels compared with placebo. CONCLUSIONS: Vedolizumab demonstrated dose-proportional pharmacokinetics and maximally saturated ?(4) ?(7) receptors over the tested dose range. Multiple dosing up to 10 mg/kg was well tolerated. Over the course of follow-up a greater proportion of patients treated with vedolizumab were in clinical response than those who were assigned to placebo.",1
12598,22149736,Generic atorvastatin and health care costs,,1
12599,22150035,Three months of rifapentine and isoniazid for latent tuberculosis infection,"""BACKGROUND: Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. METHODS: We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%. RESULTS: In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). CONCLUSIONS: The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).""",1
12600,22150950,Risk of hepatitis B reactivation in patients treated with tumor necrosis factor-? inhibitors,"The use of tumor necrosis factor-? (TNF-?) inhibitors has been increasing especially in patients with rheumatoid arthritis (RA). As TNF-? inhibitors are strongly immunosuppressive, the occurrence of hepatitis B virus (HBV) reactivation has recently been observed. Reports suggest a higher risk of complicating HBV reactivation in carriers who are treated with TNF-? inhibitors. Therefore, HBV carriers are recommended to undergo prophylactic administration of nucleos(t)ide analogs (NAs). Our literary analysis uncovered several characteristics of de novo hepatitis B due to TNF-? inhibitors. First, the time between the start of TNF-? inhibitors and the occurrence of de novo hepatitis was longer than one year. Second, patients were usually treated with additional non-biologic agents, which also had immunosuppressive effects. Third, the disease could be fatal. Fourth, several types of TNF-? inhibitors exhibited a risk of developing de novo hepatitis. Although the incidence of de novo hepatitis B varied among reports (0-5%/year), it is suggested that patients with prior HBV infection are at risk of developing de novo hepatitis due to TNF-? inhibitors. Many reports maintain that regular measurement of HBV DNA is effective in preventing de novo hepatitis. Prophylactic administration of NAs is also considered useful to avoid de novo hepatitis, although the issue of cost-effectiveness needs to be addressed. Lastly, whereas maintenance of circulating anti-HBs titer using HB vaccines may be effective in responders to prevent de novo hepatitis, further studies are required to clarify the utility of HB vaccination.",1
12601,22152281,Pitavastatin: an overview,"""Compared to other statins, pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient hepatocyte low-density lipoprotein-cholesterol (LDL-C) receptor inducer. Its characteristic structure (heptenoate as the basic structure, a core quinoline ring and side chains that include fluorophenyl and cyclopropyl moieties) provides improved pharmacokinetics and significant LDL-C-lowering efficacy at low doses. Unlike other statins, the cyclopropyl group on the pitavastatin molecule appears to divert the drug away from metabolism by cytochrome P450 (CYP) 3 A4 and allows only a small degree of clinically insignificant metabolism by CYP2C9. As a result, pitavastatin is minimally metabolized; most of the bioavailable fraction of an oral dose is excreted unchanged in the bile and is reabsorbed by the small intestine ready for enterohepatic recirculation. This process probably accounts for pitavastatin's increased bioavailability relative to most other statins and contributes to its prolonged duration of action. In addition to its potent LDL-C-lowering efficacy, a number of pleiotropic benefits that might lead to a reduction in residual risk have been suggested in vitro. These include beneficial effects on endothelial function, stabilisation of the coronary plaque, anti-inflammatory effects and anti-oxidation. With regard to the clinical safety and efficacy of pitavastatin, the Phase IV Collaborative study of Hypercholesterolemia drug Intervention and their Benefits for Atherosclerosis prevention (CHIBA study) showed similar changes in lipid profile with pitavastatin and atorvastatin in Japanese patients with hypercholesterolemia. However, a subgroup analysis of the CHIBA study showed that pitavastatin produced more significant changes from baseline in LDL-C, TG, and HDL-C in patients with hypercholesterolemia and metabolic syndrome. The clinical usefulness of pitavastatin has been further demonstrated in a number of Japanese patient groups with hypercholesterolemia, including those with insulin resistance, low levels of high-density lipoprotein-cholesterol (HDL-C), high levels of C-reactive protein, and chronic kidney disease. Finally, the Japan Assessment of Pitavastatin and AtorvastatiN in Acute Coronary Syndrome (JAPAN-ACS) study showed that pitavastatin induces plaque regression in patients with ACS, which suggests potential benefits for pitavastatin in reducing CV risk.""",1
12602,22153759,Safety and efficacy of daptomycin for the treatment of hospitalized adult patients in Taiwan with severe staphylococcal infections,"""BACKGROUND AND PURPOSE: The safety and efficacy of treating serious infections caused by Staphylococcus aureus with daptomycin in a Taiwanese population were studied. METHODS: A retrospective, multicenter study was performed in Taiwan between December 2007 and June 2009. This study included adult hospitalized patients who had received intravenous daptomycin therapy for infections caused by S aureus. All patients were followed until discharge from the hospital or death. RESULTS: A total of 52 patients (males, n=44; median age: 62 years) were evaluated. Infections included complicated skin and soft-tissue infections (n=14), catheter-related bacteremia (n=14), osteomyelitis and septic arthritis (n=12), endovascular infections and endocarditis (n=11), and urinary tract infections (n=1). Overall, 47 (90.4%) patients were successfully treated and their clinical symptoms were resolved. Adverse effects related to daptomycin were detected in nine patients, but none were required to discontinue daptomycin. CONCLUSION: The results support daptomycin as an effective and safe treatment for staphylococcal infections in Taiwanese populations.""",1
12603,22154199,Ulipristal acetate: review of the efficacy and safety of a newly approved agent for emergency contraception,"""BACKGROUND: Emergency contraception (EC) is used to prevent unintended pregnancies. The current gold standard for oral EC is levonorgestrel (LNG) administered as a single 1.5-mg dose or in 2 doses of 0.75 mg separated by 12 hours. LNG has shown to be effective up to 72 hours after coitus. Ulipristal acetate (UPA) is a selective progesterone receptor modulator approved for EC use in the United States in August 2010. UPA is administered as a one-time, 30-mg dose within 120 hours of intercourse. OBJECTIVE: The goal of this review was to provide a summary of the available literature on the use of UPA for EC. METHODS: PubMed, Cochrane Library, ClinicalTrials.gov, International Pharmaceutical Abstracts, EBSCO, and Iowa Drug Information Service were searched from February 2011 through September 2011 to identify relevant articles. Search terms included ulipristal acetate, CDB-2914, VA 2914, and emergency contraception. RESULTS: In an open-label study, UPA was effective in preventing pregnancy in 1241 women who presented for EC up to 120 hours (5 days) after unprotected intercourse, with an observed pregnancy rate of 2.1% (95% CI, 1.4%-3.1%) versus 5.5% (ie, the expected pregnancy rate without EC). The efficacy of UPA did not decrease significantly (P = 0.44) over time, with pregnancy rates at intervals between >48 and 72 hours at 2.3% (95% CI, 1.4%-3.8%), >72 and 96 hours at 2.1% (95% CI, 1.0%-4.1%), and >96 and 120 hours at 1.3% (95% CI, 0.1%-4.8%). In a single-blind, comparative noninferiority study of 1696 women, UPA was at least as effective as LNG when used within 72 hours for EC, with 15 pregnancies in the UPA group and 22 pregnancies in the LNG group (odds ratio = 0.68 [95% CI, 0.35-1.31]). In addition, UPA prevented significantly (P = 0.037) more pregnancies than LNG when used between 72 and 120 hours after unprotected intercourse, with 0 pregnancies in the UPA group and 3 pregnancies in the LNG group. In a meta-analysis, UPA prevented a greater percentage of pregnancies than LNG at intervals up to 24 hours (0.9% UPA vs 2.5% LNG; P = 0.035), up to 72 hours (1.4% UPA vs 2.2% LNG; P = 0.046), and up to 120 hours (1.3% UPA vs 2.2% LNG; P = 0.025). The most commonly (>10%) reported adverse events included headache, nausea, and abdominal pain. In addition, UPA delayed onset of menstruation by a mean of 2.1 to 2.8 days. CONCLUSIONS: Based on clinical trials, UPA seems to be a reasonably tolerable and effective method of EC when used within 120 hours of intercourse. UPA is at least as effective as LNG when used within the first 72 hours after unprotected intercourse. However, UPA may be more effective than LNG when used between 72 to 120 hours after unprotected intercourse, extending the window of opportunity for EC. UPA may provide a new option for women who require EC up to 5 days after unprotected intercourse.""",1
12604,22154408,Literature review and practical aspects on the management of oxaliplatin-associated toxicity,"Colorectal cancer is currently a public health priority because it is the second leading cause of cancer deaths in Western countries. Combination regimes of oxaliplatin and infusional fluorouracil/leucovorin or capecitabine have emerged as important options in the palliative and adjuvant treatment of colorectal cancer. Although better tolerated than cisplatin, oxaliplatin displays a characteristic profile of adverse events whose recognition and management are essential for physicians who treat patients with colorectal cancer and other malignancies that benefit from the use of oxaliplatin. Peripheral neuropathy is probably the most frequent and clinically relevant adverse event associated with the use of oxaliplatin, and several measures have been proposed to mitigate this toxicity. Temporary interruption of oxaliplatin before limiting neurotoxicity develops during therapy is a potential approach to avoid the problem of oxaliplatin-associated neuropathy in patients with metastatic colorectal cancer. Calcium and magnesium infusions have no effect on chemotherapy efficacy and also constitute a useful approach in clinical practice. Finally, the incidence and severity of chronic peripheral neuropathy in patients treated with oxaliplatin may be reduced by the use of neuroprotective agents, for example, venlafaxine. Other adverse events, such as gastrointestinal and liver toxicity, thrombocytopenia, and hypersensitivity reactions, are also reviewed in this article, and suggestions are made for their management.",1
12605,22158731,"Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study","""BACKGROUND: Obesity is a serious chronic disease. Controlled-release phentermine/topiramate (PHEN/TPM CR), as an adjunct to lifestyle modification, has previously shown significant weight loss compared with placebo in a 56-wk study in overweight and obese subjects with ?2 weight-related comorbidities. OBJECTIVE: This study evaluated the long-term efficacy and safety of PHEN/TPM CR in overweight and obese subjects with cardiometabolic disease. DESIGN: This was a placebo-controlled, double-blind, 52-wk extension study; volunteers at selected sites continued with original randomly assigned treatment [placebo, 7.5 mg phentermine/46 mg controlled-release topiramate (7.5/46), or 15 mg phentermine/92 mg controlled-release topiramate (15/92)] to complete a total of 108 wk. All subjects participated in a lifestyle-modification program. RESULTS: Of 866 eligible subjects, 676 (78%) elected to continue in the extension. Overall, 84.0% of subjects completed the study, with similar completion rates between treatment groups. At week 108, PHEN/TPM CR was associated with significant, sustained weight loss (intent-to-treat with last observation carried forward; P < 0.0001 compared with placebo); least-squares mean percentage changes from baseline in body weight were -1.8%, -9.3%, and -10.5% for placebo, 7.5/46, and 15/92, respectively. Significantly more PHEN/TPM CR-treated subjects at each dose achieved ?5%, ?10%, ?15%, and ?20% weight loss compared with placebo (P < 0.001). PHEN/TPM CR improved cardiovascular and metabolic variables and decreased rates of incident diabetes in comparison with placebo. PHEN/TPM CR was well tolerated over 108 wk, with reduced rates of adverse events occurring between weeks 56 and 108 compared with rates between weeks 0 and 56. CONCLUSION: PHEN/TPM CR in conjunction with lifestyle modification may provide a well-tolerated and effective option for the sustained treatment of obesity complicated by cardiometabolic disease. This trial was registered at clinicaltrials.gov as NCT00796367.""",1
12606,22162992,Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients,"BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment na?ve TB-HIV co-infected patients (n?=?353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p?=?0.001), higher plasma efavirenz level (p?=?0.009), efavirenz/8-hydroxyefavirenz ratio (p?=?0.036), baseline AST (p?=?0.022), ALT (p?=?0.014), lower hemoglobin (p?=?0.008), and serum albumin (p?=?0.007), NAT2 slow-acetylator genotype (p?=?0.039) and ABCB1 3435TT genotype (p?=?0.001). CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.",1
12607,22166636,Liver injury in HIV-1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy,"""BACKGROUND: Liver injury is one of the most important adverse effects of antiretroviral therapy, leading to therapy changing or discontinuation. Data on liver injury in human immunodeficiency virus-1-infected patients receiving antiretroviral therapy are limited in China. The purpose of this study was to investigate the features of liver injury in human immunodeficiency virus type 1-infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy in China. METHODS: Seventy-five patients on antiretroviral therapy containing non-nucleosides reverse transcriptase inhibitors were retrospectively studied. The patients were divided into 2 groups: group 1 (with liver injury, n = 45) and group 2 (without liver injury, n = 30). The features of liver injury were analyzed. The sex, age, baseline CD4 counts, hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection, hepatotoxic drug use and nevirapine or efavirenz use were compared between two groups. RESULTS: Forty-five patients (60.0%), 31 (68.9%) males and 14 (31.1%) females, aged 12 to 52 years (averaged (39 ? 9) years), experienced at least one episode of liver injury. Forty (53.3%) patients were co-infected with HBV and/or HCV, 42 (56%) patients had concomitant use of antituberculosis drugs or cotrimoxazole, 46 (61.3%) and 29 (38.7%) patients received regimen containing nevirapine and efavirenz, respectively. Grade 1 liver injuries were observed in 26 (57.8%) patients, grade 2 in 16 (35.6%), grade 3 in 2 (4.0%) and grade 4 in 1 (2.2%). Three (6.7%) patients discontinued highly active antiretroviral therapy (HAART) due to liver injury. In group 1, there were 29 (64.4%) patients co-infected with HBV and/or HCV, 32 (71.1%) patients received regimen containing nevirapine, and 30 (66.7%) patients had concomitant use of anti-tuberculosis drugs or cotrimoxazole, respectively, significantly higher than those in group 2 (11 (36.7%), 14 (46.7%) and 12 (40%), respectively; P = 0.018, 0.033, 0.023, respectively). The sex, age, baseline CD4 counts and disease stage were not factors associated with liver injury. CONCLUSIONS: Liver injury associated with HAART containing non-nucleosides reverse transcriptase inhibitors was mild to moderate and those who were co-infected with HBV and/or HCV, had concomitant use of antituberculosis drugs or cotrimoxazole and received a regimen containing nevirapine were prone to liver injury while receiving HAART.""",1
12608,22168538,"Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single-centre study","""BACKGROUND AND OBJECTIVES: Ticagrelor (Brilinta) is an antithrombotic agent that reversibly binds to P2Y(12) receptors and inhibits adenosine diphosphate-induced platelet aggregation. Ticagrelor has undergone evaluation in the phase III PLATO trial, which enrolled 18 624 patients with acute coronary syndromes (ACS) from 43 countries, and 6% of patients were Asian. Subsequently, ticagrelor has now been approved in more than 40 countries for the prevention of atherothrombotic events in adult patients with ACS. Gene polymorphisms in drug-metabolizing enzymes may vary with ethnicity, and can alter drug exposure, potentially impacting drug efficacy and/or tolerability. The objectives of this study were to assess the pharmacokinetic parameters of ticagrelor and its active metabolite AR-C124910XX, and the safety and tolerability of ticagrelor in healthy Chinese subjects, following single and multiple oral doses of ticagrelor. METHODS: This trial was an open-label, sequential, two-cohort, single-centre study investigating 90 mg and 180 mg doses of ticagrelor in healthy Chinese subjects. On day 1, 12 subjects received a single oral dose of ticagrelor 90 mg. Following a 2-day washout period, ticagrelor was administered twice daily (90 mg twice daily) on days 4-9 and as a single dose on day 10. After completion of this phase, additional subjects (n = 14) were recruited into the ticagrelor 180 mg group, and received ticagrelor 180 mg under the same dosing schedule. On days 1 and 10 of both dosing schedules, blood samples for pharmacokinetic analyses were collected for 72 hours. RESULTS: Following single and multiple doses at both dose levels, ticagrelor was rapidly absorbed (median time [t(max)] to reach maximum plasma concentration [C(max)] 2 hours) with a mean elimination half-life (t(1/2;)) of 10.9-14.9 hours. AR-C124910XX was rapidly formed (median t(max) 2.0-3.0 hours; mean t(1/2;) 9.1-11.9 hours). Steady-state concentrations of ticagrelor and AR-C124910XX were rapidly established with both dosing regimens. Both parent and metabolite exhibited linear and predictable pharmacokinetics with single and multiple dosing as mean minimum plasma concentration (C(min)), C(max) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) were approximately 2-fold higher with ticagrelor 180 mg (e.g. multiple-dosing, geometric mean [% coefficient of variation]: C(max) 1973 [27] and AUC(infinity) 18 035 [46]) versus 90 mg (e.g. multiple dosing: C(max) 915 [32] and AUC(infinity) 7168 [35]) dosing regimens. Overall, ticagrelor was generally well tolerated in healthy Chinese subjects. Two subjects discontinued in the ticagrelor 90 mg group due to elevated serum levels of ALT and AST. Mild ticagrelor-associated adverse events were seen: bleeding events (90 mg: epistaxis n = 1; 180 mg: gingival bleeding n = 1) and dyspnoea (180 mg: n = 3). CONCLUSION: In healthy Chinese subjects, ticagrelor and AR-C124910XX pharmacokinetics were linear and predictable. Although ticagrelor and AR-C124910XX exposure at steady state were found to be slightly higher in Chinese subjects, these results were broadly similar to previous data in Caucasian subjects. Overall, ticagrelor was well tolerated in healthy Chinese subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00721448.""",1
12609,22171861,The health impacts of khat: a qualitative study among Somali-Australians,"OBJECTIVES: To identify patterns of khat use among Somali-Australians in Australia and to explore their views about the links between khat use and personal health. DESIGN, SETTING AND PARTICIPANTS: Qualitative study using semistructured focus groups among adult members of Somali communities in Brisbane, Sydney, Melbourne and Perth who volunteered to attend focus groups in January and December 2010. MAIN OUTCOME MEASURES: Emergent themes related to Somali-Australians' understanding of the links between khat use and personal health. RESULTS: Nineteen focus groups included 114�participants. Khat use was reported to be common among the Somali community, and more common among men than women. Khat was usually chewed in prolonged sessions, producing mild psychostimulant effects such as increased energy, enhanced mood, reduced appetite and reduced sleep. Khat was widely perceived to be a food, not a drug, and as harmless, or even beneficial, to the user's health. Many users reported discontinuation effects such as lethargy, sleep disturbances and mood problems after sessions of heavy khat use, and some reported self-medicating with alcohol to cope with such problems. Problems of addiction to khat were identified by some participants, but not all believed it is addictive. Many khat users reported visiting their health professionals for treatment of adverse effects and failing to disclose their khat use. CONCLUSIONS: Health professionals require greater awareness of khat use and related health problems. Health promotion activities targeting communities with high levels of khat use are required to increase understanding of the potential risks of regular khat use, to promote harm-reduction strategies, and to increase awareness of services available for those experiencing harm. Health professionals should consider targeted screening for khat use among individuals from Horn of Africa communities who present to health services.",1
12610,22180279,[Hepatitis-B reactivation during treatment with tumor necrosis factor-alpha blocker adalimumab in a patient with psoriasis arthritis],"HISTORY AND ADMISSION FINDINGS: A 66-year-old man with acute fever, myalgia, arthralgia, restricted movement and neck stiffness was admitted to our emergency unit. Three weeks earlier treatment with adalimumab, a tumor necrosis factor(TNF)-alpha antagonist was started by the patient's dermatologist because of a psoriasis vulgaris with associated psoriasis arthritis. All previous laboratory tests where without pathological findings. INVESTIGATIONS: The imaging procedures showed no pathological findings. Transaminase and CRP levels were markedly elevated. Hepatitis serology revealed reactivation of a chronic hepatitis B infection, while a combined viral and toxic hepatitis was detected by liver biopsy. TREATMENT AND COURSE: On the day of admittance acute neurological symptoms developed including muscular cramps and dyskinesia. Hypotonia and tachyarrhythmia were treated with parenteral infusions and digitoxin. Reactivation of a chronic hepatitis B infection with subfulminant liver failure was diagnosed, caused by immunosuppressive therapy with adalimumab. The patient was transferred to be treated with the antiviral drug entecavir. CONCLUSION: The exclusion of acute and/or chronic hepatitis before using TNF-alpha antagonists is recommended but in daily routine often ignored. The presented case demonstrates the risk of reactivating a chronic hepatitis B during therapy with a TNF-alpha antagonist.",1
12611,22188392,Anti-TNF drugs in patients with hepatitis B or C virus infection: safety and clinical management,"INTRODUCTION: Drugs targeting TNF-? biological activity are increasingly used for the treatment of immune-mediated diseases, like rheumatoid arthritis, inflammatory bowel diseases and psoriasis. Since TNF-? is a mediator of the immune response against viral infections, use of TNF-? inhibitors in patients with concurrent HBV or HCV infection can promote viral reactivation and potentially fatal liver failure. AREAS COVERED: This paper reviews TNF mechanisms of action in viral hepatitis B and C, recommendations for managing HBV and HCV-infected patients receiving treatment with anti-TNF drugs, safety and anti-TNF hepatotoxicity. EXPERT OPINION: In hepatitis B surface antigen (HBsAg) carriers undergoing anti-TNF therapy, either anti-HBV treatment or prophylaxis is mandatory to prevent hepatitis reactivation, whereas HBsAg-negative antibody to hepatitis B core antigen (anti-HBc) seropositive patients require watchful monitoring, only. Conversely, in HCV-infected patients, TNF-? inhibition by specific drugs is safe and could be even beneficial, as TNF-? pathways are involved in perpetuating liver inflammation and fibrosis progression in HCV. HBV- or HCV-infected patients should be referred to a hepatologist for expert clinical management whenever antiviral therapy is deemed necessary or hepatitis reactivation occurs.",1
12612,22189691,Suspected Greater Celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe,"BACKGROUND AND OBJECTIVES: In 21 published case reports, the use of the herb Greater Celandine (GC) (Chelidonium majus L.) has been causally related to liver injury, but a variety of confounding variables were evident that might have offset causality. This study reanalyses causality levels in these cases with a liver-specific causality evaluation method. METHODS: All 21 cases were submitted to the liver-specific, standardized, structured, quantitative and updated scale of the Council for International Organizations of Medical Sciences. This scale considers, among other items, latency period, course of alanine aminotransferase after treatment discontinuation, risk factors, comedication and alternative causes. RESULTS: Using this method for assessment, causality for GC was highly probable in two and probable in six cases, with lower causality grading in the remaining 13 cases. In these patients, causality for GC was possible in 10 cases and excluded in three cases. On the basis of the eight cases with highly probable and probable causality gradings, GC hepatotoxicity represents an idiosyncratic reaction of the metabolic type, whereas immunologic or obligatory hepatotoxic features are lacking. In some cases, alternative diagnoses and poor data quality were confounding variables that reduced causality levels. CONCLUSION: Confounding variables reduced causality levels for GC in reported cases of liver injury, but there is still striking evidence for herb-induced liver injury by GC with high causality gradings. GC hepatotoxicity is caused by an idiosyncratic reaction of the metabolic form, but there is uncertainty with respect to its culprit(s).",1
12613,22192729,"Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study","""BACKGROUND: Targeting of VEGF is a potential therapeutic option in patients with malignant ovarian ascites. We present the final results of a multicentre study of the efficacy and safety of aflibercept, a potent inhibitor of both VEGF and placental growth factor, in the treatment of malignant ascites. METHODS: In this double-blind, placebo-controlled, parallel-group, phase 2 study, patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly assigned (1:1) via an interactive voice response system to either intravenous aflibercept (4 mg/kg every 2 weeks) or placebo, stratified by interval of time (? 2 weeks vs > 2 weeks) between the two most recent paracenteses before randomisation. Patients participated in the double-blind period (during which patients, investigators, and sponsor personnel were masked to treatment assignment) until they had a repeat paracentesis and for at least 60 days, and could also participate in an optional open-label period during which all patients received aflibercept. The primary efficacy endpoint was time to repeat paracentesis based on response during the double-blind period alone, and was analysed in the intention-to-treat population with censoring of patients who did not have a repeat paracentesis as of the last day of the double-blind period. Safety analyses included both double-blind and open-label periods. This study is registered at ClinicalTrials.gov, number NCT00327444. FINDINGS: 55 patients with a median of four (range two to 11) previous lines of chemotherapy were randomly assigned to receive placebo (n=26) or aflibercept (n=29). Mean time to repeat paracentesis was significantly longer with aflibercept than with placebo (55?1 [SE 7?3] vs 23?3 [7?7] days; difference 31?8 days, 95% CI 10?6-53?1; p=0?0019). In the aflibercept group, two patients did not need a repeat paracentesis during 6 months of double-blind treatment. The most common grade 3 or 4 treatment-emergent adverse events were dyspnoea (six [20%] aflibercept vs two [8%] placebo), fatigue or asthenia (four [13%] vs 11 [44%]), and dehydration (three [10%] vs three [12%]). The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis). INTERPRETATION: This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit-risk balance should be thoroughly discussed for each patient. FUNDING: Sanofi Oncology.""",1
12614,22198540,Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation,"Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 muM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status >/=70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 muM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 muM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 muM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 muM-min x 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 muM-min x 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.",1
12615,22200551,Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation,"BACKGROUND & AIMS: Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can result in vascular liver lesions such as sinusoidal dilatations. Physiopathology remains unclear and variability between patients suggests that there is individual susceptibility. A better understanding of the molecular mechanisms of oxaliplatin liver toxicity may allow the identification of biomarkers and adaptation of chemotherapy delivery. METHODS: Between 1998 and 2009, 83 non-tumor frozen liver samples were obtained from patients operated on for CRLM after an exclusive oxaliplatin-based chemotherapy. Gene-expression profiles were first analyzed by microarray on a selected population of 19 patients: 9 patients with severe sinusoidal dilatation after a short period of chemotherapy and 10 patients without any sinusoidal dilatation after a long period of chemotherapy. These were compared with a control group of 5 patients without any chemotherapy and lesions. Twenty-two differentially-expressed (at least 1.5-fold difference in expression) genes were selected. These were validated using microfluidic quantitative RT-PCR in an independent set of 58 patients (28 with sinusoidal dilatation and 30 without sinusoidal dilatation). RESULTS: Among the 22 selected genes, 12 were validated as being up-regulated in samples from patients with sinusoidal dilatation compared to patients without sinusoidal dilatation. Genes involved in angiogenesis (VEGFD, THY-1, GPNMB) and cellular adhesion (VWF, CDH13, THBS2), and extracellular matrix components (COL1A1, COL4A1, SLCO1A2) were over-represented in patients with sinusoidal dilatation. CONCLUSIONS: This molecular signature confirms the involvement of angiogenesis and coagulation in sinusoidal injuries induced by oxaliplatin and reinforces a potential protective role of bevacizumab and aspirin, as suggested in retrospective clinical studies.",1
12616,22205272,Autoimmune hepatitis induced by adalimumab with successful switch to abatacept,,1
12617,22211087,"Adverse event profiles of 5-fluorouracil and capecitabine: data mining of the public version of the FDA Adverse Event Reporting System, AERS, and reproducibility of clinical observations","OBJECTIVE: The safety profiles of oral fluoropyrimidines were compared with 5-fluorouracil (5-FU) using adverse event reports (AERs) submitted to the Adverse Event Reporting System, AERS, of the US Food and Drug Administration (FDA). METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving 5-FU and oral fluoropyrimidines were analyzed. Standardized official pharmacovigilance tools were used for the quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. RESULTS: Based on 22,017,956 co-occurrences, i.e., drug-adverse event pairs, found in 1,644,220 AERs from 2004 to 2009, it was suggested that leukopenia, neutropenia, and thrombocytopenia were more frequently accompanied by the use of 5-FU than capecitabine, whereas diarrhea, nausea, vomiting, and hand-foot syndrome were more frequently associated with capecitabine. The total number of co-occurrences was not large enough to compare tegafur, tegafur-uracil (UFT), tegafur-gimeracil-oteracil potassium (S-1), or doxifluridine to 5-FU. CONCLUSION: The results obtained herein were consistent with clinical observations, suggesting the usefulness of the FDA's AERS database and data mining methods used, but the number of co-occurrences is an important factor in signal detection.",1
12618,22217947,Valproic Acid-related anticonvulsant hypersensitivity syndrome and subsequent olanzapine-related neutropenia and thrombocytopenia: a case report,,1
12619,22224084,Hepatic failure related to itraconazole use successfully treated by corticosteroids,"BACKGROUND: Itraconazole is believed to carry a low risk of hepatic toxicity owing to its low affinity for the human P-450 enzyme. Therefore, hepatic failure caused by itraconazole is exceedingly rare. OBJECTIVES: We report the case of a 46-year-old woman who developed hepatic failure related to itraconazole that was administered for the treatment of onychomycosis. Her condition deteriorated after withdrawal of the drug, followed solely by supportive care initially. CASE REPORT: Treatment with corticosteroids was started 10 days after her admission, and her condition gradually improved. Unfortunately, her condition worsened when the dosage of corticosteroids was abruptly decreased. Ultimately, her condition improved with appropriate adjustments of corticosteroid dosage. DISCUSSION: We conclude that corticosteroid therapy may be effective for itraconazole-induced hepatitis, especially in those patients who do not respond to conservative treatment. Notably, any decrease in the dosage should be performed with caution. We also recommend that close monitoring of liver function is mandatory during the use of itraconazole.",1
12620,22226471,Latent tuberculosis seems not to reactivate in multiple sclerosis patients on natalizumab,"Current safety recommendations for multiple sclerosis (MS) patients who are considered for natalizumab do not specify how to screen for latent tuberculosis (LTB). Only chest X-ray is recommended as a routine, and follow-up depends on its results. The incidence of TB in Spain is high and the risk of a LTB reactivation due to natalizumab is unknown. Our objective is to describe in our clinical practice if following the current recommendations for the MS population on natalizumab allows identifying patients with a LTB, as well as the risk for TB reactivation. Our study demonstrated that, in our environment, current recommendations are not sensitive enough to identify cases of LTB, though no cases of active TB were observed. Considering the lack of documented active TB cases worldwide among natalizumab patients, we suggest that these safety measures are probably unnecessary, even in countries with a high TB incidence.",1
12621,22227465,"Hcv coinfection, an important risk factor for hepatotoxicity in pregnant women starting antiretroviral therapy","OBJECTIVES: This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART. METHODS: Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naive, pregnant and non-pregnant women, followed between January 1997 and February 2008. Demographic, treatment and pregnancy related data were collected. Risk of hepatotoxicity was determined using univariate and multivariate logistic regression. Analyses were adjusted for age, region of origin, baseline HIV-RNA levels and CD4 cell counts, cART regimen and hepatitis B and C coinfection. ALT and AST values of more than 5 times ULN were considered as hepatotoxicity. RESULTS: Four-hundred and twenty-five pregnant and 1121 non-pregnant women were included. Independent risk factors of hepatotoxicity in all women were the presence of detectable HCV RNA (OR 5.48, 95% CI 2.25-13.38, p<0.001) and NVP use (OR 2.63, 95% CI 1.54-4.55, p<0.001). Stratified for pregnancy, the adjusted risk of hepatotoxicity was significantly associated with HCV coinfection only during pregnancy (OR 23.53, 95% CI 4.69-118.01, p<0.001). NVP use is related to hepatotoxicity in pregnant (OR 5.26, 95% CI 1.61-16.67, p<0.005) as well as in non-pregnant women (OR 2.13, 95% CI 1.11-4.00, p=0.02). CONCLUSION: HCV coinfection and NVP use are associated with a higher risk of cART induced hepatotoxicity in pregnant women.",1
12622,22233588,Vandetanib (Caprelsa) for medullary thyroid cancer,,1
12623,22237953,Immunosuppression induction with rabbit anti-thymocyte globulin with or without rituximab in 1000 liver transplant patients with long-term follow-up,"""Rabbit anti-thymocyte globulin (rATG)-based immunosuppression induction is being increasingly used in liver transplantation (LT) in conjunction with steroid-free protocols to delay the initiation of calcineurin inhibitors. This study reports a single-center comparison of transplant outcomes and complications in 3 immunosuppression eras. Data were obtained retrospectively from a center research database, and the analysis included LT patients from 2001 to 2008. The immunosuppression consisted of rATG induction in 3 doses (6 mg/kg in all): (1) the first dose was administered perioperatively [the rabbit anti-thymocyte globulin in the operating room (rATG-OR) era]; (2) the first dose was delayed until 48 hours after transplantation [the rabbit anti-thymocyte globulin after a delay (rATG-D) era]; or (3) the first dose was delayed until 48 hours after transplantation, and a single dose of rituximab was added 72 hours after transplantation [the rabbit anti-thymocyte globulin after a delay plus rituximab (rATG-D-Ritux) era]. The initial maintenance immunosuppression was tacrolimus monotherapy, which was started on postoperative day 2. There were 166 patients (16%) in the rATG-OR era, 259 patients (26%) in the rATG-D era, and 588 patients (58%) in the rATG-D-Ritux era (1013 patients in all). Demographically, the latter eras were characterized by higher recipient and donor ages; greater percentages of liver-kidney transplants, hepatocellular carcinoma (HCC), donation after cardiac death (DCD), and imported organs; and shorter graft ischemia times. There were no significant differences between the 3 immunosuppression groups in unadjusted patient survival 3 and 5 years after transplantation (80% and 75% for the rATG-OR era, 75% and 67% for the rATG-D era, and 79% and 71% for the rATG-D-Ritux era, P = 0.15). The 5-year survival rates for patients with hepatitis C virus (HCV) and HCC were 65% and 68%, respectively. The factors included in the Cox regression model for patient death included the Model for End-Stage Liver Disease score [hazard ratio (HR) = 1.03, P = 0.001], HCV (HR = 1.28, P = 0.04), donor age (HR = 1.01, P = 0.001), recipient age (HR = 1.01, P = 0.05), and DCD (HR = 1.55, P = 0.11). rATG-based induction immunosuppression can be safely used in adult LT recipients with excellent survival and low rejection rates and without increases in immunosuppression-related side effects.""",1
12624,22239529,Inhibition of IkappaB kinase by thalidomide increases hepatitis C virus RNA replication,"Hepatic fibrosis is an integral element in the progression of chronic liver disease. Elevated hepatic interleukin (IL)-8 is an important contributor to fibrosis in patients chronically infected with the hepatitis C virus (HCV). Thalidomide has been used to reduce liver inflammation and fibrosis in HCV-infected patients, but its impact on HCV replication remains unclear. This study examined the effect of thalidomide on HCV replication in vitro. Results revealed that while thalidomide reduced IL-8 and nuclear factor kappa B (NF-kappaB) activity by 95% and 46% in Huh-7 cells, increasing concentrations of thalidomide correlated with a linear rise in HCV replication (17-fold at 200 mum). The NF-kappaB inhibitors, wedelolactone and NF-kappaB activation inhibitor-1, which mimic the actions of thalidomide by preventing phosphorylation and activation of IkappaB kinase (IKK) and hence block NF-kappaB activity, increased HCV RNA by 18- and 19-fold, respectively. During in vitro HCV replication in Huh-7 cells, we observed a 30% increase in IKKalpha protein and 55% decrease in NF-kappaB(p65)/RelA protein relative to cellular beta-actin. Ectopic expression of IKKalpha to enhance the inactive form of IKK in cells undergoing virus replication led to a 13-fold increase in HCV RNA. Conversely, enhanced expression of NF-kappaB(p65)/RelA in infected cells resulted in a 17-fold reduction in HCV RNA. In conclusion, HCV RNA replication was significantly augmented by the inhibition of IKK activation and subsequent NF-kappaB signalling, whereas a restoration of NF-kappaB activity by the addition of NF-kappaB/RelA markedly reduced HCV replication. This study lends added importance to the role of the NF-kappaB signalling pathway in controlling HCV replication.",1
12625,22241104,Argininosuccinate lyase deficiency,"The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of argininosuccinic acid to arginine and fumarate. ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with hyperammonemia within the first few days after birth or as a late-onset form with episodic hyperammonemia and/or long-term complications that include liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen-scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation (OLT) is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.",1
12626,22248038,Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study,"INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is the most common form of female sexual dysfunction and is characterized by low sexual desire that causes distress. AIM: The aim of this study was to assess the efficacy and safety of flibanserin, a postsynaptic 5-HT(1A) agonist/5-HT(2A) antagonist, in premenopausal women with HSDD. METHODS: North American premenopausal women with HSDD were randomized to 24 weeks' treatment with placebo (N?=?295), flibanserin 50?mg (N?=?295), or flibanserin 100?mg (N?=?290), once daily at bedtime. MAIN OUTCOME MEASURES: Coprimary endpoints were change from baseline to study end in number of satisfying sexual events (SSE) and sexual desire score measured daily using an electronic diary (eDiary). Secondary endpoints included change from baseline to study end in female sexual function index (FSFI) desire domain and total scores, female sexual distress scale-revised (FSDS-R) Item 13 and total scores, and patient's global impression of improvement. RESULTS: Flibanserin 50?mg and 100?mg led to increases in SSE (P?<?0.05 and P?<?0.01 vs. placebo, respectively). There was a numerical trend toward improvement in eDiary desire score on flibanserin 100?mg, but statistical significance was not reached (P?=?0.07 vs. placebo). FSFI desire domain and total scores increased with both flibanserin regimens (P?<?0.05). FSDS-R total and Item 13 scores decreased with flibanserin 100 mg (P?<?0.001), indicating reduced sexual distress. More women receiving flibanserin 50?mg and 100?mg considered their HSDD to have improved than women receiving placebo (39.6% and 50.0% vs. 30.3%, respectively) (P?<?0.05). CONCLUSION: In premenopausal women with HSDD, flibanserin 50?mg and 100?mg once daily at bedtime were well tolerated and associated with statistically significant improvements in SSE, sexual desire (FSFI desire domain score but not eDiary desire score) and overall sexual function, and reduction of sexual distress, vs. placebo.",1
12627,22251066,Rifaximin for the treatment of irritable bowel syndrome,"INTRODUCTION: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS. AREAS COVERED: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed. EXPERT OPINION: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.",1
12628,22253086,"Predicting death in patients with acetaminophen-induced acute liver failure: the King's College Hospital model is on the SOFA, not the mat",,1
12629,22253554,Safety and efficacy of everolimus in adult patients with neuroendocrine tumors,"Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors.",1
12630,22257673,"Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial","""BACKGROUND: The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. METHODS: In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg [DOSAGE ERROR CORRECTED], subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. FINDINGS: 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51?3%; 95% CI 43?1-59?5]) than in the group given trastuzumab alone (44 of 149 patients [29?5%; 22?4-37?5]; difference 21?1%, 9?1-34?2, p=0?0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24?7%, 18?1-32?3]) and the trastuzumab (difference -4?8%, -17?6 to 8?2, p=0?34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23?4%]) and lapatinib plus trastuzumab (32 [21?1%]) than with trastuzumab (three [2?0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17?5%]) and lapatinib plus trastuzumab (15 [9?9%]) than with trastuzumab (11 [7?4%]). INTERPRETATION: Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. FUNDING: GlaxoSmithKline.""",1
12631,22261533,Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment,"""BACKGROUND AND AIMS: High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. METHODS: A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events. RESULTS: Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21 mg (9-24)) was 23 weeks (6-96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p<0.001). Median aspartate aminotransferase and alanine aminotransferase concentrations decreased from 34 U/l (20-59) and 64 U/l (15-175) to 23 U/l (18-40; p=0.003) and 20 U/l (14-48; p=0.019), respectively. CONCLUSION: Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients.""",1
12632,22265699,Lithium toxicity profile: a systematic review and meta-analysis,"""BACKGROUND: Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium. METHODS: We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity. FINDINGS: We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6.22 mL/min (95% CI -14.65 to 2.20, p=0.148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158.43 mOsm/kg, 95% CI -229.78 to -87.07, p<0.0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0.5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5.78, 95% CI 2.00-16.67; p=0.001), and thyroid stimulating hormone was increased on average by 4.00 iU/mL (95% CI 3.90-4.10, p<0.0001). Lithium treatment was associated with increased blood calcium (+0.09 mmol/L, 95% CI 0.02-0.17, p=0.009), and parathyroid hormone (+7.32 pg/mL, 3.42-11.23, p<0.0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1.89, 1.27-2.82, p=0.002), but not those receiving olanzapine (0.32, 0.21-0.49, p<0.0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders. INTERPRETATION: Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment. FUNDING: National Institute for Health Research Programme Grant for Applied Research.""",1
12633,22271566,"Here today, gone tomorrow?and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines","""Despite their widespread Internet availability and use, many of the new drugs of abuse remain unfamiliar to health care providers. The herbal marijuana alternatives, like K2 or Spice, are a group of herbal blends that contain a mixture of plant matter in addition to chemical grade synthetic cannabinoids. The synthetic cathinones, commonly called """"bath salts,"""" have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. Kratom, a plant product derived from Mitragyna speciosa Korth, has opioid-like effects, and has been used for the treatment of chronic pain and amelioration of opioid-withdrawal symptoms. Salvia divinorum is a hallucinogen with unique pharmacology that has therapeutic potential but has been banned in many states due to concerns regarding its psychiatric effects. Methoxetamine has recently become available via the Internet and is marked as """"legal ketamine."""" Moreover, the piperazine derivatives, a class of amphetamine-like compounds that includes BZP and TMFPP, are making a resurgence as """"legal Ecstasy."""" These psychoactives are available via the Internet, frequently legal, and often perceived as safe by the public. Unfortunately, these drugs often have adverse effects, which range from minimal to life-threatening. Health care providers must be familiar with these important new classes of drugs. This paper discusses the background, pharmacology, clinical effects, detection, and management of synthetic cannabinoid, synthetic cathinone, methoxetamine, and piperazine exposures.""",1
12634,22271879,CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma,"PURPOSE: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. EXPERIMENTAL DESIGN: Patients with metastatic melanoma were treated in three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab with gp100 peptides. In protocol 2, 36 patients received ipilimumab with interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. RESULTS: With median follow-up for protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively. Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in protocol 1 and 6% in protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became complete responders had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. CONCLUSIONS: This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial.",1
12635,22273250,Non-bacterial infections in Asian patients treated with alemtuzumab: a retrospective study of the Asian Lymphoma Study Group,"This retrospective study concerns non-bacterial infections in Asian patients receiving alemtuzumab. The clinical data of 182 patients treated with alemtuzumab alone or alemtuzumab-containing chemotherapy between the years 2003 and 2009 was collected from six Asian countries. Alemtuzumab was used in the setting of frontline (n =48) or salvage (n =90) treatment, and as a part of the conditioning regimen for allogeneic stem cell transplant (n =44). Reactivation of cytomegalovirus (66/182) and varicella zoster virus (25/182), and fungal infection (31/182) including invasive pulmonary aspergillosis, were the most common infectious complications in this retrospective analysis. Thus, we recommend routine prophylaxis with valganciclovir and itraconazole, especially when alemtuzumab is used in the conditioning regimen for allogeneic stem cell transplant. Pneumocystis jirovecii pneumonia (PJP) was found in four patients (3%, 4/122) receiving alemtuzumab as conditioning for stem cell transplant or salvage treatment. Three cases of hepatitis B virus reactivation were found in antigen-negative patients, and 16 cases of tuberculosis were observed. Infection is the major complication of alemtuzumab therapy, and these infectious complications are potentially severe and life-threatening. Based on our retrospective analysis, we have constructed a guideline for antimicrobial prophylaxis in Asian patients receiving alemtuzumab therapy.",1
12636,22274160,Noncirrhotic portal hypertension associated with didanosine: a case report and literature review,"Noncirrhotic portal hypertension (NCPH) has recently been reported as a liver complication in human immunodeficiency virus (HIV)-infected patients and has been found to be associated with exposure to didanosine. Here, we describe the case of an HIV-infected patient with portal hypertension who initially presented with massive ascites and portal vein thrombosis. The patient's HIV-1 infection was well-controlled with highly active antiretroviral therapy (lamivudine/didanosine plus nevirapine) for 3 years since its diagnosis in 2007. He had no history of alcoholism, drug abuse, or liver diseases. An extensive work-up for other possible causes of liver disease was performed, but the results were inconclusive. In addition to reporting this case, we have reviewed the literature on didanosine-related NCPH and analyzed the findings of 61 similar previously reported cases.",1
12637,22280517,Clinicopathologic features of late-onset veno-occlusive disease/sinusoidal obstruction syndrome after high dose intravenous busulfan and hematopoietic cell transplant,"Most cases of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occur <21 days after allogeneic hematopoietic stem cell transplant (HCT). Rarely, however, VOD/SOS can occur later, and can be confused with other causes. We report the clinicopathologic features of eight patients with advanced hematologic malignancies developing VOD/SOS >30 days after dose-escalated busulfan/fludarabine/alemtuzumab and HCT. Median time to diagnosis was 52 days (range: 33-77). For seven patients, VOD/SOS was confirmed by liver biopsies showing classical features including reticulin deposition within sinusoids, central vein occlusions, hepatocyte atrophy/necrosis, sinusoidal/perivenular hemorrhage and sparing of portal tracts. VOD/SOS risk was directly related to higher busulfan plasma exposures. Two patients died from VOD/SOS, and in another two patients VOD/SOS was contributory to death. Late-onset VOD/SOS may be underrecognized and should be considered in the differential diagnosis of patients undergoing HCT, particularly after high dose busulfan. Liver biopsy should be entertained even late in the course if appropriate signs/symptoms exist.",1
12638,22283902,N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians,"""OBJECTIVE: To analyse slow-acetylation N-acetyltransferase 2 (NAT2) polymorphisms for their association with the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH). DESIGN: A case-control study including Caucasian patients with tuberculosis (TB) treated with isoniazid, rifampicin and pyrazinamide. NAT2 genotype results were compared between ATDH cases and controls and with a healthy Spanish control population of Caucasian origin. RESULTS: Fifty cases and 67 controls were included in the study. Slow, intermediate and rapid NAT2 genotypes were found in respectively 72%, 18% and 10% of cases compared with 65.7%, 25.4% and 9% of controls (P> 0.05). On comparing NAT2 genotypes among cases with those among healthy controls (n = 1312), we found more slow NAT2 genotypes and fewer intermediate genotypes among cases (respectively 72% and 18% in cases vs. 54.8% and 38.1% in controls; OR 2.07, 95%CI 1.12-2.79, P = 0.016 and OR 0.37, 95%CI 0.18-0.75, P = 0.003). CONCLUSIONS: We could not demonstrate an increased risk of ATDH related to the presence of slow NAT2 polymorphisms among this Caucasian TB cohort. However, we found a significantly greater frequency of slow and a significantly lower frequency of intermediate NAT2 genotypes among the ATDH cases compared with the healthy control population.""",1
12639,22287855,Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions,"BACKGROUND: Elevation of liver enzymes in rheumatoid arthritis patients treated with tocilizumab (Actemra((R))) or anakinra (Kineret((R))) is a well-documented phenomenon. However, characterization of liver histology has not been defined in most cases. Similarly, the factors involved in decisions regarding discontinuation of treatment and outcome have not been discussed in the literature to any significant extent. CASES: Two women with rheumatoid arthritis refractory to standard therapies are reported here. One was treated with tocilizumab and the other with anakinra, and both developed toxic liver effects. Liver biopsy in both cases showed focal necrosis of hepatocytes - a hallmark of drug toxicity - with steatosis and early fibrosis. Inflammatory infiltrates were prominent in the patient treated with anakinra but not in the tocilizumab-treated patient. However, FibroTest (Assistance publique - Hopitaux de Paris, Paris, France) in the latter patient showed an inflammatory activity of A2 and was staged as F2, and the histology also showed hemorrhagic areas. Although both patients were overweight and both had been exposed to steroids, the steatosis and steatohepatitis were considered to be related to drug hepatotoxicity. Other possible etiologies for liver injury were excluded. Discontinuation of anakinra led to rapid normalization of liver enzymes. The patient receiving tocilizumab developed hepatosplenomegaly but had normal liver enzymes. In spite of the hepatosplenomegaly, the tocilizumab treatment was continued since the patient had not responded to other drugs. There was a good response to the tocilizumab treatment and the liver biopsy showed only insignificant, reversible liver injury. At follow-up at 6-months the patient remains stable. CONCLUSION: As cases showing tocilizumab or anakinra liver toxicity are appearing more frequently to the authors, a full assessment for liver injury is recommended in patients given those drugs, with careful consideration of the decision to continue or discontinue treatment. Further studies with long-term follow-up analysis are mandatory to guide appropriate management strategies.",1
12640,22292789,Herb-drug interactions and mechanistic and clinical considerations,"Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.",1
12641,22295178,"Efficacy and Safety of Low-Dose Cyclosporine with Everolimus and Steroids in de novo Heart Transplant Patients: A Multicentre, Randomized Trial","""A six-month, multicenter, randomized, open-label study was undertaken to determine whether renal function is improved using reduced-exposure cyclosporine (CsA) versus standard-exposure CsA in 199 de novo heart transplant patients receiving everolimus and steroids +/- induction therapy. Mean C(2) levels were at the low end of the target range in standard-exposure patients (n = 100) and exceeded target range in reduced-exposure patients (n = 99) throughout the study. Mean serum creatinine at Month 6 (the primary endpoint) was 141.0 +/- 53.1 mumol/L in standard-exposure patients versus 130.1 +/- 53.7 mumol/L in reduced-exposure patients (P = 0.093). The incidence of biopsy-proven acute rejection >/=3A at Month 6 was 21.0% (21/100) in the standard-exposure group and 16.2% (16/99) in the reduced-exposure group (n.s.). Adverse events and infections were similar between treatment groups. Thus, everolimus with reduced-exposure CsA resulted in comparable efficacy compared to standard-exposure CsA. No renal function benefits were demonstrated; that is possibly related to poor adherence to reduced CsA exposure.""",1
12642,22298601,Gabapentin enacarbil for treatment of restless legs syndrome in adults,"OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling for gabapentin enacarbil for the treatment of restless legs syndrome (RLS) in adults. DATA SOURCES: A literature search was conducted using the terms gabapentin enacarbil, XP13512/GSK1838262, and restless legs syndrome. MEDLINE, Books@Ovid, Journals@Ovid Full Text, BIOSIS Previews, and EMED databases were the primary search sites (2004-October 2011). All English-based articles and abstracts obtained from the literature searches were reviewed. Additional information was obtained from references cited in the articles. STUDY SELECTION AND DATA EXTRACTION: All gabapentin enacarbil information related to RLS was considered. Study selection included human trials evaluating safety and efficacy of gabapentin enacarbil for the treatment of RLS. DATA SYNTHESIS: Gabapentin enacarbil is a prodrug of gabapentin that is Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe primary RLS in adults. In placebo-controlled trials, gabapentin enacarbil demonstrated efficacy in reducing the symptoms of RLS. Most clinical trials assessed gabapentin enacarbil at dosages greater than the FDA-approved 600-mg dosage. For the approved dose of 600 mg, the most commonly reported adverse effects are somnolence and dizziness. CONCLUSIONS: Clinical trials have evaluated gabapentin enacarbil for safety and efficacy in treating moderate-to-severe RLS symptoms for up to 64 weeks. It offers a pharmacokinetic advantage over gabapentin by having improved absorption and a longer duration of action, but clinically significant differences are yet to be determined. Potential disadvantages of gabapentin enacarbil include cost, concerns of suicide risk and pancreatic cancer, and a lack of data for the FDA-approved 600-mg dosage. Overall, gabapentin enacarbil is a viable therapeutic option for adults with moderate-to-severe RLS for whom more conventional therapies have failed.",1
12643,22301417,Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women,"""OBJECTIVES: To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa. DESIGN: In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/mul randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity. METHODS: NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations. RESULTS: Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h in women without 3+ rash (P = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (P = 0.046). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/mul (P = 0.003). CONCLUSION: In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4 cell count at least 250 cells/mul was significantly associated with NVP toxicity.""",1
12644,22304375,Hepatitis: a herbal remedy Germander,,1
12645,22307384,Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years,"""BACKGROUND: Teriflunomide, an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis (RMS), was well tolerated and effective in reducing magnetic resonance imaging (MRI) lesions in 179 RMS patients in a phase 2 36-week, placebo-controlled study. METHODS: A total of 147 patients who completed the core study entered an open-label extension. Teriflunomide patients continued their assigned dose, and placebo patients were re-allocated to teriflunomide, 7 mg/day or 14 mg/day. An interim analysis was performed at a cut-off on January 8 2010. RESULTS: The mean and median duration of study treatment, including both the core and extension phase, from baseline to the interim cut-off, was 5.6 years (standard deviation: 2.7 years) and 7.1 years (range: 0.05-8.5 years), respectively. Of 147 patients, 62 (42.2%) discontinued (19% due to treatment-emergent adverse events (TEAEs)). The most common TEAEs were mild infections, fatigue, sensory disturbances and diarrhoea. No serious opportunistic infections occurred, with no discontinuations due to infection. Asymptomatic alanine aminotransferase increases (?3? upper limit of normal (ULN)) were common (7 mg, 64.2%; 14 mg, 62.1%); increases >3?ULN were similar across groups (7 mg, 12.3%; 14 mg, 12.1%). Mild decreases in neutrophil counts occurred; none led to discontinuation. The incidence of malignancies was comparable to that of the general population, and cases were not reminiscent of those observed in immunocompromised patients. Annualised relapse rates remained low, minimal disability progression was observed, with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters. CONCLUSION: Teriflunomide had a favourable safety profile for up to 8.5 years.""",1
12646,22313089,Acute renal failure and liver necrosis associated to allopurinol therapy,,1
12647,22318932,"Pharmacology, efficacy, and safety of linagliptin for the treatment of type 2 diabetes mellitus","OBJECTIVE: To review the pharmacology, pharmacokinetics, and clinical efficacy and safety of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor recently approved in the US for use as a treatment for type 2 diabetes mellitus. DATA SOURCES: English-language articles in the PubMed database to October 2011 (selected using the search terms linagliptin, alogliptin, sitagliptin, saxagliptin, vildagliptin, and pharmacokinetics, pharmacodynamics, or diabetes) were identified for review. Reference lists from identified articles were reviewed for additional references of interest. Abstracts published at relevant meetings were also evaluated, and information was obtained from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Publications reporting the pharmacology, pharmacokinetics, and clinical efficacy and safety of linagliptin were reviewed. DATA SYNTHESIS: Linagliptin therapy results in clinically meaningful reductions in hemoglobin A(1c), as well as fasting and postprandial plasma glucose levels in patients with type 2 diabetes mellitus. It contrasts with other agents in its class by not requiring dosage adjustment in patients with renal or hepatic impairment. Oral doses of linagliptin 5 mg once daily have been shown to be clinically effective, well tolerated, and weight-neutral. An increased rate of hypoglycemia when linagliptin was used in combination with an insulin secretagogue compared to placebo was noted in clinical trials. CONCLUSIONS: Linagliptin provides an additional therapeutic option for type 2 diabetes mellitus and, in contrast to other agents in the DPP-4 class, can be used without dose adjustment in patients with any degree of declining renal function.",1
12648,22321026,Elvitegravir: a once-daily inhibitor of HIV-1 integrase,"INTRODUCTION: Elvitegravir (EVG) is a potent inhibitor of HIV-1 integrase (IN) undergoing Phase III clinical trials. It blocks the strand-transfer step in a multi-step process that allows double-stranded cDNA to be irreversibly incorporated within the host DNA. It is the second member of the HIV-1 IN inhibitor class, following raltegravir. Co-administration with a CYP3A inhibitor, such as ritonavir or cobicistat, substantially increases EVG plasma exposure and prolongs elimination half-life. AREAS COVERED: A Medline review of Phase II and III trials involving EVG as well as a review of abstracts from major HIV and infectious disease conferences from 2010 to 2011 was conducted. EVG produces rapid and durable virologic suppression when combined with active background therapy. Trials investigating the efficacy of once-daily co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) demonstrate a high rate of virologic suppression with fewer CNS and psychiatric adverse events compared with co-formulated efavirenz/emtricitabine/tenofovir. The resistance profile for EVG is similar to raltegravir. EXPERT OPINION: Co-formulated EVG/COBI/FTC/TDF is an option for the treatment of antiretroviral na?ve and experienced patients. Once-daily dosing offers an advantage over raltegravir, but the requirement for pharmacologic boosting increases regimen complexity. Dolutegravir in development offers a favorable resistance profile and no requirement for pharmacologic boosting.",1
12649,22322005,Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome,"""BACKGROUND: Increasing studies have revealed that HLA alleles are the major genetic determinants of drug hypersensitivity; however, the underlying molecular mechanism remains unclear. OBJECTIVE: We adopted the HLA-B *1502 genetic predisposition to carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) as a model to study the pathologic role of HLA in delayed-type drug hypersensitivity. METHODS: We in vitro expanded CBZ-specific cytotoxic T lymphocytes (CTLs) from patients with CBZ-induced SJS/TEN and analyzed the interaction between HLA-B and CBZ analogs based on CTL response, surface plasmon resonance, peptide-binding assay, site-directed mutagenesis, and computer modeling. RESULTS: The endogenous peptide-loaded HLA-B *1502 molecule presented CBZ to CTLs without the involvement of intracellular drug metabolism or antigen processing. The HLA-B *1502/peptide/beta(2)-microglobulin protein complex showed binding affinity toward chemicals sharing 5-carboxamide on the tricyclic ring, as with CBZ. However, modifications of the ring structure of CBZ altered HLA-B *1502 binding and CTL response. In addition to HLA-B *1502, other HLA-B75 family members could also present CBZ to activate CTLs, whereas members of the HLA-B62 and HLA-B72 families could not. Three residues (Asn63, Ile95, and Leu156) in the peptide-binding groove of HLA-B *1502 were involved in CBZ presentation and CTL activation. In particular, Asn63 shared by members of the B75 family was the key residue. Computer simulations revealed a preferred molecular conformation of the 5-carboxamide group of CBZ and the side chain of Arg62 on the B pocket of HLA-B *1502. CONCLUSIONS: This study demonstrates a direct interaction of HLA with drugs, provides a detailed molecular mechanism of HLA-associated drug hypersensitivity, and has clinical correlations for CBZ-related drug-induced SJS/TEN.""",1
12650,22330924,"Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity","Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 ?g/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ? 60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ? 2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ? 1.5 ?g/ml or >1.5 ?g/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 ?g/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ? 1.5 ?g/ml (P = 0.01) and among patients with no trough of >1.5 ?g/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 ?g/ml. A cutoff for toxicity was not identified, but troughs of >4 ?g/ml were rare. The data support a target range of >1.5 to 4 ?g/ml.",1
12651,22332331,Antituberculous drug-induced liver injury: current perspective,"Drug-induced liver injury (DILI) is a minor but significant cause of liver injury across all regions. Antituberculosis drug-induced liver injury (TB DILI) is a leading cause of DILI and drug-induced acute liver failure (DIALF) in India and much of the developing world. Single center registries of DILI continue to highlight the high incidence of DILI and DIALF, much of it due to diagnostic errors and inappropriate prescriptions. The clinical spectrum includes asymptomatic elevation in liver tests to acute hepatitis and acute liver failure. TB DILI can occur across all age groups including children with significant morbidity and mortality. Although TB DILI develops more commonly in males, ALF is noted to be commoner in females with a worse prognosis. Contrasting reports on the role of genetic and environmental factors continue to be published. Since DILI is a diagnosis of exclusion, acute viral hepatitis particularly hepatitis E needs to be excluded in such cases. The presence of jaundice, hypoalbuminemia, ascites, encephalopathy and high prothrombin time are poor prognostic markers. Recent reports of the beneficial role of N-acetylcysteine in DIALF and in preventing TB DILI in elderly individuals needs further investigation. Reintroduction of antitubercular therapy must be balanced with the knowledge of adaptation a common occurrence with antituberculosis drugs. Although monitoring and rechallenge practices vary greatly, the importance of early clinical symptoms cannot be underestimated. Simultaneous rechallenge with combination drugs or sequential treatment have similar incidence of DILI, although increasing reports about the role of pyrazinamide in DILI and on rechallenge warrants its careful use. The combined affliction of HIV or chronic hepatitis B or C and tuberculosis poses multiple challenges including the greatly increased risks of DILI.",1
12652,22333382,Successful treatment of non-small cell lung cancer with gefitinib after severe erlotinib-related hepatotoxicity,"Gefitinib and erlotinib are first-generation small molecular inhibitors of EGFR tyrosine kinase activity. To the best of our knowledge, to date, two reports have stated that patients with NSCLC who develop severe hepatotoxicity secondary to gefitinib treatment can be safely switched to erlotinib. However, the reverse situation has not been reported. Here, we present the first case with non-small cell lung cancer harboring EGFR mutation who developed grade 3/4 hepatotoxicity after initiation of erlotinib, which resolved when therapy was changed to gefitinib. As far as we know, this is the first report showing the efficacy of gefitinib for a non-small cell lung cancer patient who developed severe hepatotoxicity while under erlotinib therapy.",1
12653,22335455,Cryopyrin-associated periodic syndromes: diagnosis and management,"""Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory disorders; many cases of CAPS are caused by mutations in the NLRP3 gene. In these conditions, interleukin (IL)-1 is overproduced, and this overproduction plays a major role in disease onset and progression. CAPS include three variants, ranging in order of increasing severity from familial cold autoinflammatory syndrome, previously termed familial cold urticaria, through Muckle-Wells syndrome, to chronic infantile neurologic cutaneous articular syndrome, also known as neonatal onset multisystemic inflammatory disease. Diagnosis of CAPS is initially based on clinical manifestations and medical history, and later confirmed genetically. CAPS should be suspected when characteristic skin lesions, typical periodic fever episodes, bone/joint manifestations, and CNS involvement are recognized. CAPS are life-long diseases, and early diagnosis and early treatment with IL-1-targeted therapies may improve prognosis.""",1
12654,22340890,What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review,"""BACKGROUND: Obesity [defined as a body mass index (BMI) >/= 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients. DATA SOURCES: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature. REVIEW METHODS: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin. RESULTS: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > pound2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of pound20,000 per QALY. LIMITATIONS: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses. CONCLUSION: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of pound20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously. FUNDING: The National Institute for Health Research Health Technology Assessment programme.""",1
12655,22343174,Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials,"""BACKGROUND: Pooled analysis of phase 3, double-blind, double-dummy ECHO and THRIVE trials comparing rilpivirine (TMC278) and efavirenz. METHODS: Treatment-naive HIV-1-infected adults were randomized 1:1 to rilpivirine 25 mg once daily or efavirenz 600 mg once daily, with background tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (ECHO) or TDF/FTC, zidovudine/lamivudine, or abacavir/lamivudine (THRIVE). The primary endpoint was confirmed response [viral load <50 copies per milliliter; intent-to-treat time-to-loss-of-virologic-response (ITT-TLOVR) algorithm] at week 48. The pooled data set enabled analyses of subgroups and predictors of response/virologic failure. RESULTS: Confirmed responses were 84% (rilpivirine) and 82% (efavirenz). The difference in response rates (95% confidence interval) was 2.0% (-2.0% to 6.0%). The incidence of virologic failure was 9% (rilpivirine) versus 5% (efavirenz). Responses in ITT-TLOVR and ITT-snapshot analyses were consistent. Responses were similar for rilpivirine and efavirenz by background regimen, gender, race and clade. Suboptimal adherence and higher baseline viral load resulted in lower responses, higher virologic failure, and development of resistance in both groups; the effects on virologic failure were more apparent with rilpivirine. CD4 cell count increased over time in both groups. Rilpivirine compared with efavirenz gave smaller incidences of adverse events leading to discontinuation (3% vs. 8%, respectively), treatment-related grade 2-4 adverse events (16% vs. 31%), rash (3% vs. 14%), dizziness (8% vs. 26%), abnormal dreams/nightmares (8% vs. 13%), and grade 2-4 lipid abnormalities. CONCLUSIONS: At week 48, rilpivirine 25 mg once daily and efavirenz 600 mg once daily had comparable response rates. Rilpivirine had more virologic failures and improved tolerability versus efavirenz.""",1
12656,22346357,"Acamprosate for treatment of alcohol dependence: mechanisms, efficacy, and clinical utility","Acamprosate, or N-acetyl homotaurine, is an N-methyl-D-aspartate receptor modulator approved by the Food and Drug Administration (FDA) as a pharmacological treatment for alcohol dependence. The exact mechanism of action of acamprosate is still under investigation, but the drug appears to work by promoting a balance between the excitatory and inhibitory neurotransmitters, glutamate and gamma-aminobutyric acid, respectively, and it may help individuals with alcohol dependence by reducing withdrawal-associated distress. Acamprosate has low bioavailability, but also has an excellent tolerability and safety profile. In comparison with naltrexone and disulfiram, which are the other FDA-approved treatments for alcohol dependence, acamprosate is unique in that it is not metabolized by the liver and is also not impacted by alcohol use, so can be administered to patients with hepatitis or liver disease (a common comorbid condition among individuals with alcohol dependence) and to patients who continue drinking alcohol. Acamprosate has demonstrated its efficacy in more than 25 placebo-controlled, double-blind trials for individuals with alcohol dependence, and has generally been found to be more efficacious than placebo in significantly reducing the risk of returning to any drinking and increasing the cumulative duration of abstinence. However, acamprosate appears to be no more efficacious than placebo in reducing heavy drinking days. Numerous trials have found that acamprosate is not significantly more efficacious than naltrexone or disulfiram, and the efficacy of acamprosate does not appear to be improved by combining acamprosate with other active medications (eg, naltrexone) or with psychosocial treatment (eg, cognitive-behavioral therapy). In this review, we present the data on acamprosate, including its pharmacology, efficacy, safety, and tolerability in the treatment of alcohol dependence.",1
12657,22347828,Still disease and the liver-an underappreciated association,,1
12658,22350498,Safety of a fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg in patients with mixed hyperlipidaemia: a pooled analysis from a database of clinical trials,"""BACKGROUND: Fenofibrate can be prescribed concomitantly with an HMG-CoA reductase inhibitor (statin) to improve achievement of lipid goals in patients with atherogenic mixed hyperlipidaemia. However, some safety concerns, particularly an increased risk of myopathy, have been reported when these drugs are taken together. OBJECTIVE: The aim of this analysis was to assess the general safety and tolerability of a fenofibrate/pravastatin (FF/PRA) 160 mg/40 mg fixed-dose combination (FDC) capsule based on a pooled database of phase III clinical trials in patients with mixed hyperlipidaemia. METHODS: Safety data were pooled from five phase III studies (four double-blind with an uncontrolled extension and one open) of >/=12 to 64 weeks' duration. Adverse event (AE) profiles of FF/PRA 160 mg/40 mg (n=645 in the double-blind cohort) were evaluated relative to comparators (statins, n=519 or fenofibrate, n=122). Absolute incidence rates were calculated in both the double-blind cohort and the all-studies cohort (FF/PRA 160 mg/40 mg, n=1566) for all AEs, drug-related AEs, serious AEs, discontinuations due to AEs, AEs of specific interest including abnormal laboratory data, and deaths. RESULTS: The frequency and/or intensity of overall AEs, drug-related AEs, serious AEs and discontinuations due to AEs were not significantly increased for the FDC (36.0%, 12.3%, 1.7% and 5.1%, respectively) versus the statin (28.7%, 8.9%, 0.8% and 2.7%, respectively) and fenofibrate (59.0%, 21.3%, 0% and 4.9%, respectively) monotherapies. No deaths were reported during the course of treatment in clinical trials. Nevertheless, three deaths were reported more than 30 days after the patients completed the study; none of these deaths were assessed as being related to FF/PRA 160 mg/40 mg treatment. Among the AEs of special interest, no myopathy or rhabdomyolysis were reported; no patients were considered to have experienced a drug-induced liver injury; no case of pancreatitis occurred in the double-blind cohort and four patients reported pancreatitis in the all-studies cohort, two of them being study-treatment related; no case of pulmonary embolism was reported in the double-blind cohort and two patients presented with pulmonary embolism, unrelated to the study drug, in the all-studies cohort; there were more cases of decreased creatinine clearance in the FF/PRA 160 mg/40 mg group (1.7%) than in the statin group (0.6%). CONCLUSION: Within the limitations of this database (notably low percentage of very elderly patients, limited sample size of patients with mild renal insufficiency, and mode of selection in the clinical trials), no particular safety concern was raised with FF/PRA 160 mg/40 mg in the double-blind cohort as compared with statin and fenofibrate monotherapies. The acceptable long-term safety profile of FF/PRA 160 mg/40 mg was confirmed with a low frequency of AEs of interest, comparable to that observed in the 12-week double-blind cohort. Emergent effects possibly related to FF/PRA 160 mg/40 mg were mainly those attributable to fenofibrate (decrease in creatinine clearance and pancreatitis).""",1
12659,22352734,Acetylcysteine therapy for acetaminophen poisoning,"Acetylcysteine has been used to treat acetaminophen overdose for nearly 50 years. While no placebo controlled trials have been conducted, the efficacy of acetylcysteine is accepted for the prevention of hepatic injury when administered early after acetaminophen overdose. Acetylcysteine can be administered as an infusion or oral solution. The duration of treatment varies from 21 to 72 hours, depending on the protocol. Acetylcysteine also prevents death when administered to patients with hepatic failure from acetaminophen.",1
12660,22354219,Aflibercept (eylea) for age-related macular degeneration,,1
12661,22355024,Metformin-induced hepatotoxicity,,1
12662,22356324,Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib,"""BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).""",1
12663,22357577,Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial,"AIMS: Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization. METHODS AND RESULTS: A post-hoc analysis was carried out of the placebo group of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial, which enrolled patients hospitalized for HF with an ejection fraction (EF) </=40% and no history of primary significant liver disease or acute hepatic failure. LFTs (abbreviation, cut-offs for abnormal values) including serum albumin (ALB, <3.3 g/dL), aspartate transaminase (AST, >34 IU/L), alanine transaminase (ALT, >34 IU/L), alkaline phosphatase (AP, >123 IU/L),gamma-glutamyl transferase (GGT, >50 IU/L), and total bilirubin (T Bili, >1.2 mg/dL) were measured at baseline, discharge/day 7, and post-discharge. Co-primary endpoints were all-cause mortality (ACM) and cardiovascular mortality or first HF hospitalization (CVM + HFH). Study participants had a mean age of 65.6 +/-12.0 years, were mostly male, reported high prevalences of medical co-morbidities, and were well treated with evidence-based therapies. Baseline LFT abnormalities were common (ALB 17%, AST 21%, ALT 21%, AP 23%, GGT 62%, and T Bili 26%). Abnormal T Bili was the only marker to decrease substantially from baseline (26%) to discharge/day 7 (19%). All LFTs, except AP, improved post-discharge. Lower baseline ALB and elevated T Bili were associated with higher rates of ACM, and in-hospital decreases in ALB and increases in T Bili were associated with higher rates of both ACM and CVM + HFH. CONCLUSION: LFT abnormalities are common during hospitalization for HF in patients with reduced EF and were persistent at discharge. Baseline and in-hospital changes in ALB and T Bili provide additional prognostic value.",1
12664,22359388,Comfrey: a clinical overview,"Comfrey has a centuries-old tradition as a medicinal plant. Today, multiple randomized controlled trials have demonstrated the efficacy and safety of comfrey preparations for the topical treatment of pain, inflammation and swelling of muscles and joints in degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 or 4 and over. This paper provides information on clinical trials and non-interventional studies published on comfrey to date and further literature, substantiating the fact that topical comfrey preparations are a valuable therapy option for the treatment of painful muscle and joint complaints.",1
12665,22361569,Drugs for inflammatory bowel disease,,1
12666,22364685,"Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial","""BACKGROUND: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. METHODS: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. FINDINGS: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7?7%, 95% CI -15?3 to -0?1; Z test for competing risk analysis p=0?0488; log-rank test p=0?0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. INTERPRETATION: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. FUNDING: Gentium SpA, European Group for Blood and Marrow Transplantation.""",1
12667,22372628,Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial,"PURPOSE: To evaluate the long-term (up to 5 years exposure) safety and efficacy of lacosamide as adjunctive therapy in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs) in open-label extension trial SP756 (NCT00522275). METHODS: Patients who completed the double-blind trial SP754 (NCT00136019) were eligible to participate in this open-label extension trial (SP756). At the conclusion of trial SP754, patients had transitioned to lacosamide 200 mg/day. Subsequent dosage adjustments of lacosamide (100-800 mg/day) and/or concomitant AEDs were allowed to optimize tolerability and seizure reduction. Treatment-emergent adverse events (TEAEs), vital signs, body weight, clinical laboratory data, electrocardiography studies, and seizure frequency were evaluated. KEY FINDINGS: A total of 308 patients received open-label lacosamide and 138 patients (44.8%) completed the long-term trial. The median modal dose (defined as the daily lacosamide dose a patient received for the longest duration during the treatment period) was 500 mg/day. The percentages of patients with lacosamide exposure >1, >2, >3, or >4 years were 75%, 63%, 54%, and 29%, respectively. Primary reasons for discontinuation were lack of efficacy (26%) and adverse events (11%). Common TEAEs (>/=15%) were dizziness, headache, contusion, nausea, convulsion, nasopharyngitis, fall, vomiting, and diplopia. TEAEs that led to discontinuation in >/=1.0% of patients were dizziness (1.6%) and convulsion (1.0%). The median percent reductions from baseline of trial SP754 in 28-day seizure frequency were 53.4%, 55.2%, 58.1%, and 62.5%, respectively, for 1-, 2-, 3-, and 4-year completers. The >/=50% responder rates were 52.8%, 56.5%, 58.7%, and 62.5% for 1-, 2-, 3-, and 4-year completers, respectively. Seven of eight patients on lacosamide monotherapy for >/=12 months were deemed 50% responders. Of patients exposed to lacosamide >/=2 years, 3.1% remained seizure-free for a period >/=2 years. SIGNIFICANCE: Long-term (up to 5 years) lacosamide treatment was generally well tolerated. The safety profile of lacosamide observed in this trial is consistent with that established in previous double-blind, placebo-controlled trials. Although the open-label trial design limits the analysis of efficacy, long-term reduction in seizure frequency and maintenance of efficacy was observed.",1
12668,22374707,Drug-induced Stevens-Johnson syndrome: case series from tertiary care centre in Gujarat,"PURPOSE: The aims of the present article were to study clinical features and to analyse them in different drug class associated with Stevens-Johnson syndrome (SJS) in a tertiary care hospital in Gujarat, India. MATERIALS AND METHODS: A prospective hospital-based study was carried out over a period of 3 years (June 2007 to September 2009) at Sheth Vadilal Hospital, Ahmedabad, India. The diagnosis of SJS was made mainly on the basis of the clinical findings, which included extensive erythema multiforme, purpuric lesions with bullae and detachment of skin involving at least two mucous membranes. Further, in each patient suspected with SJS, various laboratory tests such as complete blood count, liver function tests, metabolic panel, chest X-ray and other serological test were carried out. SJS was confirmed on the basis of most widely accepted Bastuji-Garin definition. Causality assessment was performed using the Naranjo scale. Only 'probable' and 'definite' reactions were included. RESULTS: Antibacterials for systemic use, anti-inflammatory and antirheumatic products and antiepileptics were the drug classes most commonly associated (8 of 29 cases, each) with SJS. Individually, ibuprofen was involved in the highest number of cases (five cases, 17.2%), followed by carbamazepine (four cases, 13.8%) . The mean duration of developing SJS symptoms was 15.9 days (SD = 8.7 days) and improvement after treatment was 14.2 days (SD = 4.6 days). The duration of appearing SJS symptoms varied significantly between different classes of drugs (p < 0.001). The appearance of SJS symptom started within 10 days for anti-inflammatory and antibacterial compared with 24 days of antiepileptic agents. All the patients with antiepileptic agent-induced SJS had 7% to 9% of detached body surface area. In two patients, SJS progressed to toxic epidermal necrolysis and of which one led to death and the other developed long-term complication of conjunctival xerosis. A total of six patients developed long-term complications: four patients had conjunctival synechia, one patient had conjunctival xerosis and one patient had urethral stricture. CONCLUSION: More than 80% of the SJS events were induced by antibacterial, anti-inflammatory and antiepileptic agents with same frequency. The duration of the appearance of SJS symptoms significantly varied between different drug classes and started within 10 days for anti-inflammatory and antibacterial compared with 24 days of antiepileptic agents.",1
12669,22375971,"A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis","""BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis. METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival. RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group. CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).""",1
12670,22377512,"A randomized, placebo- and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode","""BACKGROUND: Paliperidone ER monotherapy was efficacious in treating acute mania in two 3-week studies in patients with bipolar I disorder. We assessed its efficacy in a study investigating maintenance treatment of clinically stable patients with this disorder. METHODS: Patients (n=766), aged 18 to 65 years inclusive, with current manic or mixed episodes were initially randomized (4:1) to flexibly-dosed paliperidone ER (3-12 mg/day) or olanzapine (5-20 mg/day; 3-week acute treatment phase); responders continued the same treatment (12-week continuation phase). Patients on paliperidone ER who achieved remission during this phase were randomized (1:1) to fixed-dose paliperidone ER (n=152) or placebo (n=148); those on olanzapine continued to receive that at fixed dose (n=83) (maintenance phase). RESULTS: Median time to recurrence of any mood symptoms (primary endpoint) was: 558 days (paliperidone ER), 283 days (placebo) and not observed with olanzapine (<50% of patients experienced recurrence). Time to recurrence of any mood symptoms was significantly longer with paliperidone ER than placebo (p=0.017; based on weighted Z-test at 0.0198 significance level; hazard ratio [placebo: paliperidone ER; unweighted 95% confidence interval]: 1.43 [1.03; 1.98]); the difference was significant for preventing recurrence of manic, but not depressive, symptoms. Treatment-emergent adverse events (maintenance phase) occurred more often in olanzapine group (64%) than placebo (59%) or paliperidone ER groups (55%). LIMITATIONS: Responder-enriched design prevents extrapolation of data to patients not previously stabilized on paliperidone ER. CONCLUSIONS: Paliperidone ER significantly delayed the time to recurrence of any mood symptoms, versus placebo, in patients with bipolar I disorder. No new safety concerns emerged.""",1
12671,22379337,Spontaneously reported hepatic adverse drug events in Korea: multicenter study,"Hepatic adverse drug reactions (ADRs) to certain drugs may differ within each country, reflecting different patterns of prescription, socioeconomic status, and culture. The purpose of this study was to assess the suspected cause of hepatic ADRs using the spontaneously reported pharmacovigilance data from Korea. A total of 9,360 spontaneously reported adverse drug events (ADEs) from nine Pharmacovigilance Centers were analyzed. Risk of hepatic ADEs was assessed by calculating the reporting odds ratio (ROR). Of the 9,360 cases, 567 hepatic ADEs were reported. The most frequently prescribed drug classes inducing hepatic ADEs were anti-tuberculotics, cephalosporins, valproic acids, penicillins, quinolones, non-steroidal anti-inflammatory drugs (NSAIDs), anti-viral agents, and statins. ROR values were especially high in anti-tuberculosis drugs, systemic antifungal drugs for systemic use, anti-epileptics, propylthiouracil, and herbal medicines. Underlying diseases such as tuberculosis (6.9% vs 0.9%), pneumonia (4.9% vs 1.7%), intracranial injury including skull fracture (4.5% vs 0.9%), HIV (3.4% vs 0.4%), subarachnoid hemorrhage (2.8% vs 0.5%), and osteoporosis (2.4% vs 1.4%) were significantly more common in hepatic ADE group. In conclusion, anti-infective drugs, anti-epileptics, NSAIDs and statins are the most common suspects of the spontaneously reported hepatic ADEs, in Korea. Careful monitoring for such reactions is needed for the prescription of these drugs.",1
12672,22382580,Clobazam (Onfi) for Lennox-Gastaut syndrome,,1
12673,22386736,Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol,"BACKGROUND AND AIMS: Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25-33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort. METHOD: Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought. RESULTS: 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting. CONCLUSION: This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.",1
12674,22388910,[Severe recurrent intrahepatic cholestasis in systemic AL amyloidosis without obvious liver involvement: unexplained hepatic toxicity or a case of misdiagnosed liver amyloidosis?],"We report the case of a 50-year-old woman who was admitted to the hospital for acute abdominal pain with nephrotic proteinuria, rapidly progressive renal failure, and moderate anemia. Laboratory tests showed mild Bence Jones (lambda) proteinuria with negative serum immunofixation and a mild increase in lambda free light chains. A bone marrow biopsy and a fat tissue aspirate showed multiple myeloma and amyloidosis. Because of the end-stage renal disease, the patient began regular dialysis treatment and was started on bortezomib 1.3 mg/m2 plus dexamethasone 40 mg on days 1, 4, 8 and 11 of 21-day cycles. Ten days later she complained of a new episode of abdominal pain with jaundice. A CT scan and an MRI scan ruled out all secondary causes of cholangitis including cancer. Acute intrahepatic cholestasis due to amyloid deposition was then hypothesized. After 4 well tolerated cycles of bortezomib and dexamethasone, blood tests showed a complete hematological response with full reversal of cholestasis. After three months, a new episode of abdominal pain occurred and this time the patient was operated on and found to have an intestinal volvulus. Because of the jaundice, a transjugular liver biopsy was performed showing no evidence of amyloid deposits. Two months later the patient died of septic shock. Although no autopsy was performed and the ultimate cause of the cholestasis could not be ascertained, amyloidosis remains the major culprit in this unfortunate case.",1
12675,22391540,"Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance","""The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P = 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P = 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.""",1
12676,22395527,"Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study","""The aim of this study is to evaluate the long-term safety and tolerability of lurasidone in the treatment of schizophrenia. Clinically stable adult outpatients with schizophrenia were randomized in a 2 : 1 ratio to 12 months of double-blind treatment with once-daily, flexibly-dosed lurasidone (40-120 mg) or risperidone (2-6 mg). Outcome measures included adverse events (AEs), vital signs, ECG, and laboratory tests. Secondary assessments included measures of psychopathology. A total of 427 patients were randomized to treatment with lurasidone and 202 with risperidone. The three most frequent AEs in the lurasidone group (vs. risperidone) were nausea (16.7 vs. 10.9%), insomnia (15.8 vs. 13.4%), and sedation (14.6 vs. 13.9%); the three most frequent AEs in the risperidone group (vs. lurasidone) were increased weight (19.8 vs. 9.3%), somnolence (17.8 vs. 13.6%), and headache (14.9 vs. 10.0%). A higher proportion of patients receiving risperidone had at least a 7% endpoint increase in weight (14 vs. 7%). The median endpoint change in prolactin was significantly higher for risperidone (P<0.001). A comparable improvement in efficacy measures was observed with both agents and the rates of relapse were similar. All-cause discontinuation rates were higher for lurasidone versus risperidone. Long-term treatment with lurasidone was generally well tolerated in this study, with minimal effects on weight and metabolic outcomes.""",1
12677,22398069,"A case report: ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis","In recent years, the use of antibodies against tumor necrosis factor ? (TNF?) has expanded in rheumatology, gastroenterology, and dermatology. In addition to the more common side effects such as infections and hypersensitivity reactions, elevations of liver enzymes have been reported during anti-TNF? therapy, although severe liver failure has been extremely uncommon. This report describes a patient with severe liver failure after induction therapy with the TNF? antibody infliximab (Remicade�). A 46-year old female patient received two infusions of infliximab at a dose of 400 mg on weeks 0 and 8 for steroid-dependent ulcerative colitis. Eight weeks after the second infusion, she suffered acute liver failure with necrosis, requiring liver transplantation.",1
12678,22404426,Clinical significance of hyperbilirubinemia among HIV-1-infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study,"""CASTLE was a randomized 96-week study that demonstrated that atazanavir/ritonavir (ATV/r) was noninferior to lopinavir/ritonavir (LPV/r) in treatment-na?ve HIV-infected patients. Analyses were carried out among patients who received ATV/r in the CASTLE study to better understand the clinical significance of unconjugated hyperbilirubinemia associated with administration of boosted ATV. Hyperbilirubinemia was defined as total bilirubin (conjugated and unconjugated) elevation greater than 2.5 times the upper limit of normal (grade 3-4). Patients in the ATV/r arm were assessed based on the presence or absence of hyperbilirubinemia through week 96. Analyses included number of confirmed virologic responders (CVR; HIV RNA<50 copies per milliliter), impact of hyperbilirubinemia on symptoms, elevations in liver enzymes, patient quality of life, and medication adherence. Through 96 weeks in the CASTLE study, 44% of patients who received ATV/r had hyperbilirubinemia at any time point, and between 12.5% and 21.6% had hyperbilirubinemia at any single study visit. At 96 weeks, 74% of patients overall and 84% and 69% of patients with and without hyperbilirubinemia, respectively, achieved CVR. Symptoms of jaundice or scleral icterus occurred in 5% of patients overall and in 11% with hyperbilirubinemia and 0% without hyperbilirubinemia. Four percent of patients with and 3% of patients without hyperbilirubinemia had grade 3-4 elevations in liver transaminases. Less than 1% of patients discontinued treatment due to hyperbilirubinemia. There were no differences in quality of life or adherence between patients with or without hyperbilirubinemia. In the CASTLE study, hyperbilirubinemia observed in the ATV/r group did not negatively impact clinical outcomes in HIV-infected patients.""",1
12679,22407198,Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases,"Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (?75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.",1
12680,22407603,Response to Teschke et al,,1
12681,22410137,Latent tuberculosis infection treatment for prison inmates: a randomised controlled trial,"""SETTING: A prison in northern Taiwan. OBJECTIVE: To compare safety and the completion rate of the 4-month daily rifampicin regimen (4R) vs. the standard 6-month daily isoniazid regimen (6H) for latent tuberculosis infection (LTBI) in prison inmates. DESIGN: This was an open-label randomised trial among human immunodeficiency virus negative male inmates. Inmates without active tuberculosis (TB) who tested positive for both the tuberculin skin test and QuantiFERON(R)-TB Gold In-Tube were eligible, but those with baseline glutamic pyruvic transaminase (GPT) levels >/= 120 U/l, bilirubin levels >/= 2.4 U/l or a platelet count < 150 k/mm(3) were excluded. The primary endpoint was any adverse event that resulted in discontinuation of LTBI treatment. RESULTS: Participants (n = 373; 14% hepatitis B surface antigen positive, 21% anti-hepatitis C virus [HCV] positive) were randomised (stratified by hepatitis B virus, HCV status and 2-year prison term) to receive either 4R or 6H under directly observed treatment. The 4R group (n = 190) was less likely to experience an adverse event leading to discontinuation of treatment (2% vs. 12%, P < 0.001 for all adverse events; 0% vs. 8%, P < 0.001 for hepatotoxicity), and more likely to complete LTBI treatment (86% vs. 78%, P = 0.041), compared with the 6H group (n = 183). CONCLUSIONS: 4R is safer and has a higher completion rate than 6H as treatment for LTBI among male prison inmates.""",1
12682,22413822,Rheumatology meets hepatology in 2012: a clinician's guideline for TNF inhibitors in hepatitis B/C virus carriers,"Effective and less toxic biologics have revolutionized rheumatology as well as hepatology over the last decennia resulting in higher therapeutic goals. Traditional disease modifying anti-rheumatic drugs (tDMARDs) failing to achieve a quiescent chronic rheumatoid arthritis (RA) or spondylarthropathic arthritis (SA) inflammatory disease, nowadays are to be switched into a more potent strategy with ultimately a combination of tDMARD plus TNF inhibitors (TNFi) early in disease. Patients with previous microbiological infections however present a challenge for a modern rheumatologist aiming at complete remission, particularly in carriers of viral infections. Hepatologists nowadays, can treat chronic hepatitis B and C virus infections effectively with potent antivirals. In the current issue an overview is given regarding patients in whom TNFi may be indicated, but also have been infected with viral hepatitis.",1
12683,22415886,Unintentional chronic acetaminophen poisoning during pregnancy resulting in liver transplantation,"INTRODUCTION: Acetaminophen (APAP) is a widely used medication in pregnancy and is considered safe. Unfortunately, APAP is also among the most commonly reported agents implicated in overdoses during pregnancy. We present a unique case of a pregnant patient with fulminant hepatic failure resulting in a liver transplant from repeated supratherapeutic ingestions of APAP. CASE REPORT: A 22 year pregnant female presented with abdominal pain and hepatotoxicity after taking supratherapeutic amounts of APAP to treat dental pain. The patient denied intentional or acute ingestion of APAP but did admit to taking approximately 8-9 grams of APAP per day for 10-14 days for dental pain. Other cause of hepatotoxicity, including acute fatty liver of pregnancy, were evaluated for and ruled out. She developed fulminant hepatic failure and required liver transplantation which was successful. The pregnancy remained viable through the operation but intrauterine fetal demise occurred 2 weeks later. An MRI of the fetus showed extensive peri-cerebral and intraventricular hemorrhage with extensive periventricular leukomalacia. DISCUSSION: The degree of morbidity from repeated supratherapeutic ingestions of APAP seen in this case is rare and poorly described in a pregnant patient. There are no prior reports describing the need for liver transplant after repeated supratherapeutic ingestions of APAP during pregnancy. Along with the typical cause of hepatotoxicy several unique pregnancy-related causes also had to be evaluated for. This case highlights the significant morbidity that can occur with even unintentional APAP toxicity and the need to educate patients, especially pregnant patients, of the risk of excessive APAP use.",1
12684,22418569,Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer,"The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2-negative MBC.",1
12685,22419135,[Diclofenac induced liver injuries],"We report the case of an 83-year-old female patient who developed diclofenac-associated liver injury nine days after therapy had started. Diclofenac was used to treat back pain associated with an acute exacerbation of a chronic lumbovertebral symptoms reversed. We discuss the adverse reaction profile of diclofenac, particularly diclofenac-induced liver injury. We also discuss the epidemiology, clinical presentation and mechanisms of NSAID-induced liver injury, as well as risk factors and preventive measures.",1
12686,22421001,Oxaliplatin in combination with infusional 5-fluorouracil as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumors,"BACKGROUND: We previously reported a 35% overall response rate (ORR) with biweekly 5-fluorouracil (5-FU) continuous infusion (TTD [Spanish Cooperative Group for Digestive Tumour Therapy] schedule) plus irinotecan as first-line therapy in elderly patients with metastatic colorectal cancer (mCRC). The present study also was carried out in elderly patients to determine the efficacy and safety of the same 5-FU schedule plus oxaliplatin. PATIENTS AND METHODS: Patients (aged ?72 years old) with mCRC, measurable disease, ECOG (Eastern Cooperative Oncology Group) ?2, and no prior treatment were treated with oxaliplatin 85 mg/m(2) plus 5-FU 3000 mg/m(2) as a 48-hour infusion every 2 weeks. RESULTS: The study included 134 patients, of whom, 129 were eligible. The main comorbidities were hypertension (44%), diabetes (17%), and chronic obstructive pulmonary disease (11%). The ORR and disease control rate (ORR plus stable disease) were 52% and 80%, respectively. With a median follow-up of 14 months, the median progression-free survival and overall survival were 9.1 and 16.3 months, respectively. The most frequent grade 3/4 adverse events included neutropenia (16%), diarrhea (11%), and grade 3 neurotoxicity (18%). No correlation was found between efficacy or safety and comorbidities. CONCLUSIONS: To our knowledge, this is the largest phase II prospective study in elderly patients with mCRC. The observed efficacy and safety of this schedule compared favorably with those reported in this population, including regimens with monoclonal antibodies.",1
12687,22422493,Hepatic steatosis and disease activity in subjects with psoriatic arthritis receiving tumor necrosis factor-alpha blockers,"""OBJECTIVE: Little is known about tumor necrosis factor-alpha (TNF-alpha) blockers, disease activity, and liver steatosis (hepatic steatosis; HS) in subjects with psoriatic arthritis (PsA). We prospectively evaluated changes in HS during treatment with TNF-alpha blockers. METHODS: In 48 patients with PsA who had evidence of HS before the beginning of TNF-alpha blocker treatment, an ultrasound followup examination was performed after a 12-month treatment period with TNF-alpha blockers. All subjects were stratified according to minimal disease activity (MDA) or not (n-MDA), during treatment with TNF-alpha blockers. Changes in grade of HS were evaluated in parallel in 42 controls with HS and without PsA. RESULTS: At baseline, no significant difference in HS score was found between PsA subjects and controls (HS scores 1.46 +/- 0.65 vs 1.62 +/- 0.66, respectively; p = 0.249). At 12-month followup, a worsening HS score was found in 20 (41.7%) patients with PsA and in 6 (14.3%) controls (p = 0.005). Overall, the grade of HS worsening was higher in patients with PsA (0.37 +/- 0.70) than in controls (0.09 +/- 0.43; p = 0.028). A significantly lower prevalence of worsening HS was found among patients with PsA with MDA, compared with n-MDA subjects (16.7% vs 66.7%, respectively; p = 0.001). Laboratory measures of liver function behaved similarly. The risk of worsening HS in patients with PsA who had MDA was similar to that in controls (HR 1.20, 95% CI 0.34-4.33, p = 0.77), and higher in patients who did not have MDA (HR 4.46, 95% CI 1.73-11.47, p = 0.001, regression analysis). CONCLUSION: Compared with patients with MDA, those with active disease after 12-month treatment with TNF-alpha blockers exhibited significantly higher incidence of worsening liver steatosis.""",1
12688,22429105,Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia,"INTRODUCTION: Insomnia is common among the elderly. The use of hypnotic drugs in elderly patients is frequently criticized owing to dependency, cognitive impairments, falls and withdrawal effects. The production of melatonin, a physiological sleep and circadian rhythm regulator, declines with age. Prolonged-release melatonin (Circadin�), designed to mimic the endogenous pattern of melatonin production, is licensed for insomnia in patients aged ? 55 years. AREAS COVERED: This review summarizes published studies on Circadin's efficacy and safety (Summary of Product Characteristics and Medline search on 'Circadin' and 'insomnia'). EXPERT OPINION: The main significant and clinically relevant benefits are improvements in sleep quality and latency, next-day morning alertness and quality of life. The responses may develop over several days. An oral 2-mg dose once daily, for 3 months, has generally been well tolerated with no rebound, withdrawal or 'hangover' effects and no safety concerns on concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs. Untoward effects of hypnotics on cognition, memory, postural stability and sleep structure are not seen with Circadin. Given as a first-line prescription, with 13 weeks' posology and the lack of rebound effects, Circadin has the potential to improve quality of life in insomnia patients aged 55 years and older and avoid long-term use of hypnotics.",1
12689,22431230,"Rabbit anti-thymocyte globulin in liver transplantation: all that glitters is not gold, but 1000 patients are so many to dazzle",,1
12690,22431778,A randomized controlled trial of belimumab for the treatment of active systemic lupus erythematosus,,1
12691,22431927,Case report: safety and efficacy of tocilizumab in a patient with rheumatoid arthritis and chronic hepatitis C,"Tocilizumab is a monoclonal humanized anti-IL-6-receptor antibody used for the treatment of rheumatoid arthritis. The safety of tocilizumab in HCV patients is an open question. We report on safety and efficacy of tocilizumab in a 71-year-old female with rheumatoid arthritis and chronic hepatitis C. Monotherapy with tocilizumab (8 mg/kg every 4 weeks, i.v.) was prescribed after the discontinuation, determined by clinical inefficacy, of anti-TNF-alfa agents (adalimumab and, subsequently, etanercept). We have registered an optimal and rapid clinical response to tocilizumab with early remission (SDAI <3.3 since 4 weeks). The safety was good with no adverse events and maintenance, during a six-month followup, of normal liver enzymes. These data suggest a good safety profile of tocilizumab in patients with rheumatoid arthritis and chronic hepatitis C virus pathology.",1
12692,22432938,Non-genetic risk factors and predicting efficacy for docetaxel--drug-induced liver injury among metastatic breast cancer patients,"BACKGROUND AND AIM: Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel-drug-induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear. METHODS: We conducted a retrospective cohort study to identify non-genetic risk factors for docetaxel-DILI among 647 metastasis breast cancer patients treated with docetaxel-containing regimens. RESULTS: Sixty-seven (10.36%) patients were diagnosed as docetaxel-DILI. By logistic regression analysis, premenopausal status (odds ratio [OR][95% confidence interval {CI}] = 2.24 [1.30-3.87]), past hepatitis B virus (HBV) infections (OR [95% CI] = 4.23 [1.57-11.42]), liver metastasis (OR [95% CI] = 3.70 [2.16-6.34]). The predominant occurrence of DILI was seen in groups with docetaxel combination regimens. (OR [95% CI] = 2.66 [1.59-4.55]). The potential increasing occurrence of docetaxel-DILI was associated with multiple risk factors in an exposure-response manner (P < 0.001), and patients with more than three risk factors would be exposed to a 36.61-fold risk of DILI (95% CI = 10.18-131.62). Further analysis by the risk score and area under the receiver-operator characteristic curve (AUC) showed that those four factors contributed to an AUC of 0.7536 (95% CI = 0.70-0.81), with a predictive sensitivity of 74.63% and specificity of 65.17%. CONCLUSIONS: Docetaxel-DILI with a relatively higher incidence should be addressed among metastatic breast cancer patients. Four predominant risk factors, including premenopausal status, past HBV infection, liver metastasis, and docetaxel combination regimens, were potential predicators for DILI.",1
12693,22439841,Anti-obesity drugs: a review about their effects and their safety,"""INTRODUCTION: Amphetamines, rimonabant and sibutramine licenses as anti-obesity drugs have been withdrawn because of their adverse effects. In fact, orlistat is the only available long-term treatment for obesity. AREAS COVERED: The efficacy and safety of long-term drug therapy is very important in the management obesity; for this reason, the authors decided to conduct a review on the efficacy and safety of current, past and future pharmacotherapies for weight loss. EXPERT OPINION: Orlistat is a good choice for the treatment of obesity, because of its safety on cardiovascular events and its positive effects on diabetic control, even if it is not as effective as rimonabant or sibutramine in reducing body weight. Regarding emerging anti-obesity therapies in diabetic people, we currently have drugs that have already been marketed including the glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide; other than improving glycemic control, they also suppress appetite reducing body weight. Moreover, some other drugs are currently in study such as tesofensine, phentermine + topiramate, bupropion + naltrexone and bupropion + zonisamide. Furthermore, several additional gut hormone-based treatments for obesity are under investigation in Phase II and III clinical trials, with particular focus on ghrelin, peptide YY, pancreatic polypeptide, amylin and oxyntomodulin.""",1
12694,22444104,Evaluation of harm in the pharmacotherapy of irritable bowel syndrome,"""OBJECTIVE: Current treatment options for irritable bowel syndrome are limited and often poorly studied. A select few drugs have been studied in irritable bowel syndrome, and the number needed to treat is frequently used to assess the relative efficacy of these treatments. However, side effects are an important consideration in the clinical decision on which particular treatment to use. This study examines trials of subjects with irritable bowel syndrome with diarrhea and constipation who are receiving a drug intervention deemed of merit by the American College of Gastroenterology task force and compares these therapies to examine the number needed to harm using a systematic review and meta-analysis approach. METHODS: Potential studies of irritable bowel syndrome treatments were identified through a search of MEDLINE (1950 to April 2011), EMBASE (1980 to April 2011), the Cochrane central register of controlled trials, and the bibliography of recent meta-analyses. Clinical trials of pharmacotherapy for irritable bowel syndrome were eligible for inclusion only if a description of adverse events and the number of patients who discontinued treatment because of adverse events were reported. The relative risk of experiencing an adverse event requiring discontinuation of treatment was used to determine the number needed to harm. In addition, the number and severity of adverse events were summarized. RESULTS: Twenty-six clinical trials (4 with selective serotonin reuptake inhibitors, 3 with lubiprostone, 6 with tricyclic antidepressants, 8 with alosetron, and 5 with rifaximin) were included. Lubiprostone was safe with insignificant harm in one combined phase III trial. Selective serotonin reuptake inhibitors did not have enough data for a reliable meta-analysis of harm but seemed to be safe. More rigorous data were available for tricyclic antidepressants, alosetron, and rifaximin; the numbers needed to harm were 18.3, 19.4, and 8971, respectively, and the numbers needed to treat were 8, 7.5, and 10.6, respectively. For tricyclic antidepressant and alosetron, an adverse event resulting in discontinuation of the study medication occurred for every 2.3 and 2.6 patients who benefited from a drug, respectively. For rifaximin, this number was 846 patients. In addition, adverse events were more common with tricyclic antidepressants and alosetron. CONCLUSION: In irritable bowel syndrome with diarrhea, tricyclic antidepressants and alosetron are associated with a significant number needed to harm compared with rifaximin. Apart from lubiprostone, treatment of irritable bowel syndrome with constipation is limited to small studies (with poor descriptions of side effects), although lubiprostone and selective serotonin reuptake inhibitors appear safe.""",1
12695,22449251,Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B,"BACKGROUND: Combination antiviral therapy holds the promise of increasing response rates while decreasing antiviral resistance, but has yet to be shown to be beneficial or necessary in chronic hepatitis B. AIM: To evaluate the benefit of combination therapy with adefovir and lamivudine versus adefovir alone in maintaining virological, biochemical and histological responses. METHODS: Patients with chronic hepatitis B with and without previous lamivudine therapy were randomised to receive adefovir alone (10 mg/daily) or adefovir and lamivudine (100 mg/daily) for up to 192 weeks. Study endpoints were (i) maintained virological (HBV DNA <500 copies/mL), biochemical and histological response, (ii) loss of HBeAg and (iii) loss of HBsAg. RESULTS: A total of 41 patients were enrolled, including 31 HBeAg -positive and 31 treatment-naive subjects. 30 patients remained on assigned therapy at 192 weeks. The percentage of patients achieving a combined maintained response was higher in the combination than the monotherapy arm, both at week 48 (59% vs. 26%, P = 0.06) and 192 (68% vs. 31%, P = 0.03). At week 192, 76% of the combination vs. 36% of the monotherapy group had loss of HBeAg (P = 0.03). One patient receiving adefovir cleared HBsAg. Adefovir resistance developed in 6 of 19 (32%) monotherapy but none of 22 combination treated patients (P = 0.03). CONCLUSIONS: Extended combination therapy with lamivudine and adefovir is associated with a high rate of long-term virological and biochemical response. Adefovir monotherapy appears to be less effective mainly because of poor initial response and the ultimate development of antiviral resistance (www.Clinical. Trials.gov NCT00023309).",1
12696,22449514,"Human cystic echinococcosis: epidemiologic, zoonotic, clinical, diagnostic and therapeutic aspects","""This review represents an updated scenario on the transmission cycle, epidemiology, clinical features and pathogenicity, diagnosis and treatment, and prevention and control measures of a cestode parasite Echincoccus granulosus (E. granulosus) infection causing cystic echinococcosis (CE) in humans. Human CE is a serious life-threatening neglected zoonotic disease that occurs in both developing and developed countries, and is recognized as a major public health problem. The life cycle of E. granulosus involves a definitive host (dogs and other canids) for the adult E. granulosus that resides in the intestine, and an intermediate host (sheep and other herbivores) for the tissue-invading metacestode (larval) stage. Humans are only incidentally infected; since the completion of the life cycle of E. granulosus depends on carnivores feeding on herbivores bearing hydatid cysts with viable protoscoleces, humans represent usually the dead end for the parasite. On ingestion of E. granulosus eggs, hydatid cysts are formed mostly in liver and lungs, and occasionally in other organs of human body, which are considered as uncommon sites of localization of hydatid cysts. The diagnosis of extrahepatic echinococcal disease is more accurate today because of the availability of new imaging techniques, and the current treatments include surgery and percutaneous drainage, and chemotherapy (albendazole and mebendazole). But, the wild animals that involve in sylvatic cycle may overlap and interact with the domestic sheep-dog cycle, and thus complicating the control efforts. The updated facts and phenomena regarding human and animal CE presented herein are due to the web search of SCI and non-SCI journals.""",1
12697,22452896,"Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial","""BACKGROUND: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. METHODS: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. FINDINGS: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10?8 months (95% CI 10?0-12?0) in the afatinib group and 12?0 months (10?2-14?3) in the placebo group (hazard ratio 1?08, 95% CI 0?86-1?35; p=0?74). Median progression-free survival was longer in the afatinib group (3?3 months, 95% CI 2?79-4?40) than it was in the placebo group (1?1 months, 0?95-1?68; hazard ratio 0?38, 95% CI 0?31-0?48; p<0?0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. INTERPRETATION: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. FUNDING: Boehringer Ingelheim Inc.""",1
12698,22454421,Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma,"PURPOSE: Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. PATIENTS AND METHODS: In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. RESULTS: The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. CONCLUSION: The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.",1
12699,22455413,Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis,"""BACKGROUND: Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17A (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY2439821), a humanized anti-interleukin-17 monoclonal antibody, for psoriasis treatment. METHODS: In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 90% or by 100%. RESULTS: At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose)--150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%)--than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. CONCLUSIONS: Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.).""",1
12700,22459264,"Ginkgo biloba extract EGb 761� in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg","A multi-centre, double-blind, randomised, placebo-controlled, 24-week trial with 410 outpatients was conducted to demonstrate efficacy and safety of a 240 mg once-daily formulation of Ginkgo biloba extract EGb 761(�) in patients with mild to moderate dementia (Alzheimer's disease or vascular dementia) associated with neuropsychiatric symptoms. Patients scored 9 to 23 on the SKT cognitive battery, at least 6 on the Neuropsychiatric Inventory (NPI), with at least one of four key items rated at least 4. Primary outcomes were the changes from baseline to week 24 in the SKT and NPI total scores. The ADCS Clinical Global Impression of Change (ADCS-CGIC), Verbal Fluency Test, Activities of Daily Living International Scale (ADL-IS), DEMQOL-Proxy quality-of-life scale and 11-point box scales for tinnitus and dizziness were secondary outcome measures. Patients treated with EGb 761(�) (n = 200) improved by 2.2 ? 3.5 points (mean ? sd) on the SKT total score, whereas those receiving placebo (n = 202) changed only slightly by 0.3 ? 3.7 points. The NPI composite score improved by 4.6 ? 7.1 in the EGb 761(�)-treated group and by 2.1 ? 6.5 in the placebo group. Both drug-placebo comparisons were significant at p < 0.001. Patients treated with EGb 761(�) also showed a more favourable course in most of the secondary efficacy variables. In conclusion, treatment with EGb 761(�) at a once-daily dose of 240 mg was safe and resulted in a significant and clinically relevant improvement in cognition, psychopathology, functional measures and quality of life of patients and caregivers.",1
12701,22460902,Systematic identification of genomic markers of drug sensitivity in cancer cells,"Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.",1
12702,22463890,Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy,"""BACKGROUND: Oxandrolone, an anabolic agent, has been administered for 1 year post burn with beneficial effects in pediatric patients. However, the long-lasting effects of this treatment have not been studied. This single-center prospective trial determined the long-term effects of 1 year of oxandrolone administration in severely burned children; assessments were continued for up to 4 years post therapy. STUDY DESIGN: Patients 0 to 18 years old with burns covering >30% of the total body surface area were randomized to receive placebo (n = 152) or oxandrolone, 0.1 mg/kg twice daily for 12 months (n = 70). At hospital discharge, patients were randomized to a 12-week exercise program or to standard of care. Resting energy expenditure, standing height, weight, lean body mass, muscle strength, bone mineral content (BMC), cardiac work, rate pressure product, sexual maturation, and concentrations of serum inflammatory cytokines, hormones, and liver enzymes were monitored. RESULTS: Oxandrolone substantially decreased resting energy expenditure and rate pressure product, increased insulin-like growth factor-1 secretion during the first year after burn injury, and, in combination with exercise, increased lean body mass and muscle strength considerably. Oxandrolone-treated children exhibited improved height percentile and BMC content compared with controls. The maximal effect of oxandrolone was found in children aged 7 to 18 years. No deleterious side effects were attributed to long-term administration. CONCLUSIONS: Administration of oxandrolone improves long-term recovery of severely burned children in height, BMC, cardiac work, and muscle strength; the increase in BMC is likely to occur by means of insulin-like growth factor-1. These benefits persist for up to 5 years post burn.""",1
12703,22464087,Efficacy and safety of human chorionic gonadotropin for follicular phase stimulation in assisted reproduction: a systematic review and meta-analysis,"OBJECTIVE: To assess the efficacy and safety of hCG to induce follicular stimulation. DESIGN: Systematic literature searches of PubMed, EMBASE, CENTRAL, and SciSearch databases. Randomized controlled trials (RCTs) using hCG in early or late follicular phases were included. SETTING: Three reproductive medicine services of gynecology in Spain and two universities. PATIENT(S): A total of 1,068 women treated in 11 RCTs were included. INTERVENTION(S): Use of hCG versus other hormone treatments, no administration, or placebo during the period of follicular stimulation. MAIN OUTCOME MEASURE(S): Live birth, clinical pregnancy, mature oocytes, miscarriage, ovarian hyperstimulation syndrome (OHSS), and FSH doses. RESULT(S): No differences in live birth, miscarriage, and OHSS rates between hCG (given at either the early or late follicular phases) and different control regimens were found. Pooled analysis for clinical pregnancy showed significant differences in favor of hCG at the late follicular phase. The doses of FSH were lower in women treated with hCG at either the early or late follicular phase than in those treated with FSH alone. CONCLUSION(S): The use of hCG in the early and late follicular phase in controlled ovarian stimulation has the advantage of decreasing the doses of FSH.",1
12704,22466137,Prescription acetaminophen ingestions associated with hepatic injury and death,"The U.S. Food and Drug Administration has formally requested that pharmaceutical manufacturers limit the amount of acetaminophen (APAP) in prescription products. The goal of this study was to describe a state-wide poison control system's experience with prescription APAP ingestions that resulted in hepatic injury or death. Retrospective analysis of statewide California Poison Control System electronic database for cases from the years 2000 through 2009. INCLUSION CRITERIA: adults ?18 years of age following therapeutic use of an acetaminophen-containing prescription with laboratory evidence of liver injury. Forty cases met the inclusion criteria. All cases involved at least two concurrent acetaminophen-containing products. Prescription APAP strengths of 500 mg per tablet or greater were involved in 32 of 40 cases (80 %). Thirty patients survived, three died, one underwent liver transplantation and seven cases were lost to follow up. The ingestion of concentrated prescription APAP-containing medications in combination with other sources of APAP can result in severe liver injury and death. Limiting the amount of APAP from prescription medications in conjunction with enhanced prescriber and patient education regarding the hazards of ingesting multiple APAP-containing products may assist in decreasing the overall incidence of unintentional APAP poisonings in the United States. Future prospective studies are required to determine if these measures will have a significant impact on both the morbidity and mortality associated with APAP administration.",1
12705,22466919,Amoxicillin/clavulanic acid-induced cholestatic liver injury after pediatric liver transplantation,"""BACKGROUND: Amoxicillin/clavulanic acid-induced liver injury is a well recognized complication. Presentation and outcome may vary, which is related to individual liver maturity, genetic predisposition, enzyme heterogeneity, intensity of treatment, and drug interactions. In most cases withdrawing the drug is sufficient treatment; however, cases of progressive liver damage leading to liver transplantation have been reported. CASE REPORT: We present the case of an 8-year-old patient after liver transplantation who developed drug induced liver injury (DILI) after amoxicillin/clavulanic acid treatment for upper respiratory tract infection. Jaundice appeared 2 days after cessation of treatment. Clinical presentation and liver biopsy were consistent with DILI. Because of rapidly increasing bilirubin levels, we used 3 boluses of methylprednisolone and ursodeoxycholic acid. The treatment reversed progression of the cholestasis and full recovery was achieved in 3 months. CONCLUSIONS: In most cases of DILI, withdrawing the toxic drug is sufficient treatment, but we must be aware of a possible fatal outcome in case of progressive cholestasis. Corticosteroids may have beneficial effects in these patients.<br />""",1
12706,22467668,Excess deaths associated with tigecycline after approval based on noninferiority trials,"""BACKGROUND: On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death. METHODS: PubMed, EMBASE, Scopus, and ClinicalTrials.gov were searched using the terms """"tigecycline"""" and """"randomized controlled trial (RCT)"""" through April 2011. Excess deaths and noncure rates for both approved and nonapproved indications were examined using meta-analysis. RESULTS: Ten published and 3 unpublished studies met inclusion criteria (N = 7434). No significant heterogeneity was seen for mortality (I(2 )= 0%; P = .99) or noncure rates (I(2 )= 25%; P = .19). Across randomized controlled trials, tigecycline was associated with increased mortality (risk difference [RD], 0.7%; 95% confidence interval [CI], 0.1%-1.2%; P = .01) and noncure rates (RD, 2.9%; 95% CI, 0.6%-5.2%; P = .01). Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (I(2 )= 0%; RD, 0.6%; P = .04). A pooled analysis of the 5 trials completed by early 2005 before tigecycline was approved would have demonstrated a similar harmful effect of tigecycline on survival (I(2 )= 0%; RD, 0.7%; P = .06). CONCLUSIONS: Pooling noninferiority studies to examine survival may help ensure the safety and efficacy of new antibiotics. The association of tigecycline with excess deaths and noncure includes indications for which it is approved and marketed. Tigecycline cannot be relied on in serious infections.""",1
12707,22468635,Drug safety evaluation of pregabalin,"INTRODUCTION: Pregabalin is an anticonvulsant with one known mechanism of action which is used most specifically in the management of neuropathic pain. AREAS COVERED: The adverse effect profile of this medication from controlled, randomized studies as well as open and long-term studies is described with consideration of the evidence-based results for pregabalin's clinical use. EXPERT OPINION: Pregabalin is a mostly well tolerated medication for the management of neuropathic pain and other conditions. Pregabalin use is associated with benign central nervous system and systemic adverse effects with very limited metabolic, idiosyncratic, or teratogenic adverse effects. Understanding of these adverse effects is essential for the clinician treating the patient and for the patient receiving treatment. Sedation, dizziness, peripheral edema, and dry mouth are the most prevalent adverse events experienced in all clinical populations. Other adverse effects are rare, but are discussed.",1
12708,22469651,Ruxolitinib (Jakafi) for myelofibrosis,,1
12709,22473827,"Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN","""Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of """"intolerance"""" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.""",1
12710,22474138,Probable celecoxib-induced hepatorenal syndrome,,1
12711,22476655,Long-term efficacy of miglustat in paediatric patients with Niemann-Pick disease type C,"Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease characterized by progressive neurological manifestations. Oral miglustat was first approved for the treatment of children and adults with NP-C in Europe in 2009. There are still relatively few published data on the long-term efficacy and safety of miglustat in patients with NP-C in clinical practice. We report the effects of up to 6 years of treatment with miglustat 100 mg t.i.d. in five children. Overall, 3/5 patients displayed progressive dysphagia before starting miglustat, and 4/5 showed marked cognitive and/or motor impairment. The mean age at treatment start was 11.6 years, and the median (range) duration of therapy so far is 4 (4.1 to 6.1) years. No treatment dose alterations were required, but therapy was interrupted for 1-3 months at least once in all patients due to supply issues. Swallowing function was stabilised during miglustat therapy, with no significant increase in Han dysphagia scale or aspiration-penetration index scores among four evaluable patients (p > 0.05). Scores on the mini-mental state examination indicated an improvement in cognitive function during the first 3-6 months of miglustat therapy, followed by stabilisation up to 5 years. Ambulatory function remained stable for at least the first 2 years of treatment in most patients, but there was a trend towards deterioration thereafter, possibly related to treatment interruptions. The safety/tolerability profile of miglustat was similar to previous clinical studies, although reports of gastrointestinal disturbances were rare. Overall, miglustat appeared to stabilise key parameters of neurological disease progression.",1
12712,22480725,"Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension","""BACKGROUND: Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension. METHODS: Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ? 10 mmHg, and/or cardiac index ? 2.2 liters/min/m(2)). Treprostinil dose adjustments were driven by clinical symptoms and side effects. RESULTS: The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years. CONCLUSION: First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.""",1
12713,22484597,Efficacy and safety of atovaquone-proguanil in treating imported malaria in Japan: the second report from the research group,"""Malaria remains an important health risk among travelers to tropical/subtropical regions. However, in Japan, only 2 antimalarials are licensed for clinical use - oral quinine and mefloquine. The Research Group on Chemotherapy of Tropical Diseases introduced atovaquone-proguanil in 1999, and reported on its excellent antimalarial efficacy and safety for treating non-immune patients with uncomplicated Plasmodium falciparum malaria (20 adult and 3 pediatric cases) in 2006. In the present study, additional cases of malaria were analyzed to confirm the efficacy and safety of this antimalarial drug. Fourteen adult and 2 pediatric cases of P. falciparum malaria and 13 adult cases and 1 pediatric case of P. vivax/ovale malaria were successfully treated with atovaquone-proguanil, including 3 P. falciparum cases in which the antecedent treatment failed. Two patients with P. vivax malaria were treated twice due to primaquine treatment failure as opposed to atovaquone-proguanil treatment failure. Except for 1 patient with P. falciparum malaria who developed a moderate liver function disturbance, no significant adverse effects were observed. Despite the intrinsic limitations of this study, which was not a formal clinical trial, the data showed that atovaquone-proguanil was an effective and well-tolerated therapeutic option; licensure of this drug in Japan could greatly contribute to individually appropriate treatment options.""",1
12714,22488501,Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol,"OBJECTIVE: Allopurinol is the most commonly used urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. Dosing guidelines based on creatinine clearance have been proposed based on the recognition that dosages of >/=300 mg/day may be associated with AHS, particularly in patients with renal impairment. However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol dosing and AHS. METHODS: A retrospective case-control study of patients with gout who developed AHS between January 1998 and September 2010 was undertaken. For each case, 3 controls with gout who were receiving allopurinol but did not develop AHS were identified. Controls were matched with cases for sex, diuretic use at the time of initiating allopurinol, age (+/-10 years), and estimated glomerular filtration rate (estimated GFR). Starting dose and dose at the time of the reaction in cases were compared between cases and controls. RESULTS: Fifty-four AHS cases and 157 controls were identified. There was an increase in the risk of AHS as the starting dose of allopurinol corrected for the estimated GFR increased. For the highest quintile of starting dose per estimated GFR, the odds ratio was 23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of controls received a starting dose of allopurinol of >/=1.5 mg per unit of estimated GFR (mg/ml/minute). CONCLUSION: Our findings indicate that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS. In patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level.",1
12715,22490456,Unusually high alanine aminotransferase to aspartate aminotransferase ratio in a patient with cyproterone-induced icteric hepatitis,"A 70-year-old man with prostatic adenocarcinoma received cyproterone acetate 200 mg per day. Three months later, mild fatigue and anorexia with elevation of the alanine aminotransferase (ALT) level to 1311 U/L, total bilirubin level to 14 mg/dL and prothrombin time of 15/11.9 seconds developed. At that time the aspartate aminotransferase (AST) level was only 82 U/L. Viral hepatitis and autoimmune markers were all negative. This hepatitis resolved quickly after cyproterone therapy was discontinued. One and a half years later, the patient was prescribed cyproterone 100 mg daily at another hospital where staff were unaware of his previous history. General malaise, upper abdominal pain and jaundice developed two months later. Laboratory studies at emergency room revealed an AST of 245 U/L, ALT of 255 U/L, total bilirubin of 8.2 mg/dL, amylase of 6055 U/L, prothrombin time of 15.2/11.1 seconds and platelet count of 68000 cells/mL. Although cyproterone was discontinued, the patient died of multiple organ failure 20 days after admission. This case report presents a rare situation with marked elevation of the ALT level without AST level elevation. This finding suggests that cyproterone may induce specific damage to the plasma membrane, and the mitochondria are not involved in the initial stage.",1
12716,22491501,Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus,"""BACKGROUND: On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA. METHODS: An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases. RESULTS: The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports. CONCLUSIONS: Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information.""",1
12717,22497693,The safety profile of dalfampridine extended release in multiple sclerosis clinical trials,"""BACKGROUND: Dalfampridine (fampridine outside the United States) is a broad-spectrum potassium channel blocker. Dalfampridine extended-release tablets have been approved by the US Food and Drug Administration to improve walking in patients with multiple sclerosis (MS). OBJECTIVE: The objective of this article is to review the safety profile of dalfampridine extended-release tablets with respect to its expected use in patients with MS. METHODS: We reviewed published data relevant to patient safety profiles based on searches of articles in PubMed published up to December 31, 2010, using the search terms fampridine OR dalfampridine OR 4-aminopyridine AND (multiple sclerosis) in combination with toxicity, safety, clinical trial, pharmacokinetics, and seizures. These searches were supplemented with data derived from the approved package insert and relevant sections of the New Drug Application (22-250) as submitted to the US Food and Drug Administration. RESULTS: The literature searches returned 58 unique citations, of which 26 were considered relevant for characterizing the safety profile of dalfampridine; excluded citations were as follows: reviews (19), evaluation of 3,4-diaminopyridine (4), intravenous dosing (2), inadequate information on patient doses (2), preclinical models (2), and """"other"""" (3). Dalfampridine is nearly completely (approximately 96%) eliminated unchanged in urine, with limited transformation to 2 inactive metabolites and low risk for interaction with drugs metabolized by hepatic P450 cytochromes. However, in patients with renal impairment (creatinine clearance [CrCl], ?80 mL/min), mean peak plasma concentrations were 68%-101% higher and apparent clearance was 43%-73% lower relative to those without impairment, precluding dalfampridine use in patients with moderate (CrCl, 30-50 mL/min) or severe renal impairment (CrCl, <30 mL/min). Dalfampridine has a narrow therapeutic range. At the therapeutic dose of 10 mg twice daily, adverse events were generally mild to moderate and, consistent with the mechanism of action of dalfampridine, were primarily related to stimulatory effects on the nervous system. A thorough QT study suggested a low risk of induction of QT prolongation and associated cardiac arrhythmias in healthy individuals at therapeutic (10 mg, twice daily) or supratherapeutic (30 mg, twice daily) doses. Although the incidence of seizures was dose related, data from the clinical trials of dalfampridine extended-release tablets suggest that the risk of seizure at the therapeutic dose, in patients with no history of seizure, is not likely to be higher than background rates in MS. CONCLUSION: In patients with MS, dalfampridine has a narrow therapeutic range but an acceptable safety profile when used at the therapeutic dose of 10 mg twice daily.""",1
12718,22504093,Abatacept for Crohn's disease and ulcerative colitis,"""BACKGROUND & AIMS: The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown. METHODS: Four placebo-controlled trials evaluated the efficacy and safety of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe CD (CD-IP; CD-MP) and UC (UC-IP1; UC-MP). In CD-IP and UC-IP1, 451 patients with CD and 490 patients with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo, and dosed at weeks 0, 2, 4, and 8. In MP, 90 patients with CD and 131 patients with UC who responded to abatacept at week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through week 52. RESULTS: In CD-IP, 17.2%, 10.2%, and 15.5% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at weeks 8 and 12, vs 14.4% receiving placebo (P = .611, P = .311, and P = .812, respectively). In UC-IP1, 21.4%, 19.0%, and 20.3% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at week 12, vs 29.5% receiving placebo (P = .124, P = .043, and P = .158, respectively). In CD-MP, 23.8% vs 11.1% of abatacept vs placebo patients were in remission at week 52. In UC-MP, 12.5% vs 14.1% of patients receiving abatacept vs placebo were in remission at week 52. Safety generally was comparable between groups. CONCLUSIONS: The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.""",1
12719,22506503,Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B,"""BACKGROUND: Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD). AIM: To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B. METHODS: A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria. RESULTS: Among 51 patients treated for 1-10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0-3.0 mg/dL), creatinine (1.6-1.1 mg/dL), uric acid (2.7-3.8 mg/dL) and proteinuria. CONCLUSIONS: Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2-9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy.""",1
12720,22507491,The developing clinical problem of chemotherapy-induced hepatic injury,"Chemotherapy is being administered to an increasing number of patients with colorectal liver metastases (CRLM), whether they have resectable disease or not. Although this may be appropriate to downstage patients with unresectable disease, and offers theoretical advantages to those who have resectable disease, there is a price to be paid in the development of chemotherapy-induced hepatic injuries (CIHI). These include chemotherapy-associated fatty liver diseases and sinusoidal injuries. The main chemotherapeutic agents currently used in the adjuvant setting for colorectal carcinoma, and the neoadjuvant treatment of CRLM include 5-flurouracil, oxaliplatin and irinotecan, and while there are non-specific and overlapping injury profiles, oxaliplatin does appear to be primarily associated with sinusoidal injury and irinotecan with steatohepatitis. In this review, the rationale for administering chemotherapy to patients with CRLM is presented, and the problems this brings are outlined. The specific injury patterns will be detailed, as well as the data correlating specific chemotherapy regimens to these injury patterns. Finally, the clinical outcomes of patients with CRLM who undergo neoadjuvant chemotherapy followed by hepatic resection will be considered. The need for methods to identify patients at risk of CIHI and to recognize established CIHI prior to surgery will be emphasized.",1
12721,22510353,Liver toxicity of initial antiretroviral drug regimens including two nucleoside analogs plus one non-nucleoside analog or one ritonavir-boosted protease inhibitor in HIV/HCV-coinfected patients,"OBJECTIVE: To evaluate the incidence and risk factors for grade 3 or 4 ALT or AST elevations (TE) and grade 4 total bilirubin elevations (TBE) among HIV/HCV- coinfected treatment-naive patients with an initial regimen including 2 nucleoside analogs plus efavirenz (EFV), nevirapine (NVP), or a ritonavir-boosted protease inhibitor (PI/r). PATIENTS AND METHODS: This was a retrospective multicenter observational cohort study that recruited 745 HIV-infected drug-naive patients with detectable plasma HCV RNA who started a regimen including EFV, NVP, or PI/r. RESULTS: EFV was prescribed in 323 (43%), NVP in 126 (17%), and a PI/r in 296 (40%) patients. Grade 3 or 4 TE were observed in 19 (5.9%) individuals receiving EFV compared with 14 (11%) on NVP (P = .056) and 31 (10.5%) on PI/r (P = .036). Grade 4 TBE were identified in 7 (2.2%) patients on EFV, 1 (0.8%) on NVP, and 11 (3.7%) on PI/r (P = .19). Therapy was discontinued due to liver toxicity in 13 (4%) patients on EFV, 16 (13%) on NVP, and 17 (6%) on PI/r (P = .003). CONCLUSIONS: Regimens including EFV, NVP, or PI/r are generally safe in treatment-naive HIV/HCV-coinfected patients. Grade 3-4 TE are less commonly seen with EFV than with PI/r. Discontinuations due to hepatotoxicity were less frequent for patients receiving EFV than for those treated with NVP.",1
12722,22510871,Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation,"""Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ? grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT.""",1
12723,22516469,CASE 6--2012: suspected amiodarone hepatotoxicity after cardiac surgery,,1
12724,22516948,"A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours","""BACKGROUND: The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy. METHODS: E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles. RESULTS: Eighty-two patients received E7080 in dose cohorts from 0.2 to 32?mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32?mg, and the MTD was defined as 25?mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks' administration. CONCLUSION: E7080 is well tolerated at doses up to 25?mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma.""",1
12725,22524173,Role of genetic factors in statins side-effects,"Statins are relevant drugs involved in the reduction of cardiovascular events both in primary and secondary prevention. Related muscular side-effects are the most common cause of withdrawal and statins discontinuation could induce a negative rebound effect in terms of vascular events. Among factors in association with statins side-effects the combination with other drugs and the female sex are established conditions. However recent data suggest a specific genetic influence in intolerance development, at least for some statins. Indeed a genome-wide study in patients treated with simvastatin found an impressive association between single-nucleotide polymorphisms (SNPs) located within SLCO1B1 gene on chromosome 12 and established myopathy. Furthermore, the association between the SLCO1B1*5 variant and side-effects was found also in patients treated with atorvastatin but not, apparently, with pravastatin and categorized as carriers of mild-myopathy. Recently a similar evidence has been suggested in type 2 diabetic patients treated mainly with simvastatin. However another relevant issue is that, apart from genetic influence in liver transporters influencing drug levels, the complexity of mechanisms involved in the muscular side effects of statins has been addressed by the evidence of other influencing pathways such as the variant within the COQ2 gene involved in Coenzyme Q(10) mild-asymptomatic deficiency and skeletal muscle drug transporters expression. In conclusion, the picture of putative pharmacogenetic modulation of statins safety is reaching a growing body of evidence for translation into clinical practice but more specific studies for each single statin, in different clinical settings, both from genome-wide or competitive candidate genes evaluation, are needed before describing a definitive class-risk profile.",1
12726,22525393,The importance of vancomycin in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome,"Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome characterized by fever, rash, eosinophilia, atypical lymphocytes, and multiorgan involvement has a significant mortality. Inpatient vancomycin use is increasing and appears to be emerging as an important etiology of DRESS syndrome. This study highlights the importance of vancomycin as a cause of DRESS syndrome. We reviewed all cases of DRESS syndrome among inpatients consulted by the Allergy & Immunology service at Massachusetts General Hospital (MGH) from July 2009 through December 2010. We also reviewed the use of inpatient parenteral vancomycin over the past 4 years at MGH. Six patients fulfilled clinical criteria for DRESS syndrome, including rash, fever, eosinophilia, and hepatitis, with five (83%) having vancomycin as the attributable cause. Onset of symptoms varied from 12 days to 4 weeks after start of vancomycin treatment. Systemic findings included atypical lymphocytes, lymphadenopathy, nephritis, hypotension, tachycardia, and pharyngitis. Treatment with corticosteroids was required in three cases. Recurrence of peripheral eosinophilia was a marker of disease relapse. In three of the five patients (60%), elevated human herpesvirus 6 (HHV6) IgG titers correlated with greater systemic involvement and prolonged time to resolution. MGH pharmacy records indicate a progressive increase in the number of patients treated with parenteral vancomycin over the last 4 years. Causative agents for DRESS syndrome in an inpatient setting is likely different from that seen in the general population. With increasing use of vancomycin, we are likely to see more cases of DRESS syndrome caused by vancomycin. Recognition of vancomycin as a common cause of inpatient DRESS syndrome is important.",1
12727,22527349,Paracetamol toxicity: What would be the implications of a change in UK treatment guidelines?,"""BACKGROUND: Treatment of single-time-point ingestion acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is guided by plotting a timed plasma paracetamol concentration on established nomograms. Guidelines in the UK differ from those in the U.S. and Australasia by having two treatment lines on the nomogram. Patients deemed to be at 'normal' risk of hepatotoxicity are treated using the treatment line starting at 200 mg/L at 4 h post-ingestion; those at higher risk are treated using the 'high risk' treatment line starting at 100 mg/L at 4 h post-ingestion. AIM: To examine the effect on treatment numbers if UK guidelines were to adopt a single treatment line nomogram or lower, risk-stratified treatment lines. METHODS: We undertook a retrospective analysis of a series of acute single-time-point paracetamol poisonings presenting to our inner city emergency department. Treatment numbers and effect on treatment costs were modelled for three alternative scenarios: a 150 line-a combined single treatment line starting at a 4 h concentration of 150 mg/L, a 100 line-a combined single treatment line starting at a 4 h concentration of 100 mg/L, and a 150/75 line-a double treatment line at the lower concentrations of 150 mg/L for normal risk and 75 mg/L for high risk patients. RESULTS: A total of 1,214 cases were identified. Under current UK guidance, 133 (11.0%) high risk cases and 98 (8.1%) normal risk cases needed treatment (total 231, 19.0%). A 150 line would result in 87 (7.2%) high risk cases and 155 (12.8%) normal risk cases needing treatment (total 242, 19.9%). A 100 line would result in 133 (11.0%) high risk and 251 (20.7%) normal risk cases needing treatment (total 384, 31.6%). A 150/75 line would result in 153 (12.6%) high risk and 155 (12.8%) normal risk cases needing treatment (total 308, 25.4%). CONCLUSIONS: Both a 100 line and a 150/75 line would result in a large increase in the number of patients being treated and an associated increase in the costs of treatment. A single 150 mg/L treatment line would simplify treatment algorithms and lead to a similar number of patients being treated with NAC overall. A potential concern however is whether any of the high risk cases that would no longer be treated might develop significant hepatotoxicity. After consideration of the evidence for dual treatment lines, we feel that these risks are small and that it is worth reconsidering a change of treatment recommendations to a single 150 line.""",1
12728,22532465,"Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials","""OBJECTIVES: The efficacy and hepatic safety of the non-nucleoside reverse transcriptase inhibitors rilpivirine (TMC278) and efavirenz were compared in treatment-naive, HIV-infected adults with concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in the pooled week 48 analysis of the Phase III, double-blind, randomized ECHO (NCT00540449) and THRIVE (NCT00543725) trials. METHODS: Patients received 25 mg of rilpivirine once daily or 600 mg of efavirenz once daily, plus two nucleoside/nucleotide reverse transcriptase inhibitors. At screening, patients had alanine aminotransferase/aspartate aminotransferase levels </=5x the upper limit of normal. HBV and HCV status was determined at baseline by HBV surface antigen, HCV antibody and HCV RNA testing. RESULTS: HBV/HCV coinfection status was known for 670 patients in the rilpivirine group and 665 in the efavirenz group. At baseline, 49 rilpivirine and 63 efavirenz patients [112/1335 (8.4%)] were coinfected with either HBV [55/1357 (4.1%)] or HCV [57/1333 (4.3%)]. The safety analysis included all available data, including beyond week 48. Eight patients seroconverted during the study (rilpivirine: five; efavirenz: three). A higher proportion of patients achieved viral load <50 copies/mL (intent to treat, time to loss of virological response) in the subgroup without HBV/HCV coinfection (rilpivirine: 85.0%; efavirenz: 82.6%) than in the coinfected subgroup (rilpivirine: 73.5%; efavirenz: 79.4%) (rilpivirine, P = 0.04 and efavirenz, P = 0.49, Fisher's exact test). The incidence of hepatic adverse events (AEs) was low in both groups in the overall population (rilpivirine: 5.5% versus efavirenz: 6.6%) and was higher in HBV/HCV-coinfected patients than in those not coinfected (26.7% versus 4.1%, respectively). CONCLUSIONS: Hepatic AEs were more common and response rates lower in HBV/HCV-coinfected patients treated with rilpivirine or efavirenz than in those who were not coinfected.""",1
12729,22534814,Randomized phase 2b study of pralatrexate versus erlotinib in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) after failure of prior platinum-based therapy,"""INTRODUCTION: Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. METHODS: In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ?1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. RESULTS: A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. CONCLUSIONS: Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.""",1
12730,22538522,Drugs for rheumatoid arthritis,,1
12731,22541332,Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis,"Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65-75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future.",1
12732,22544734,Drug-induced cholestatic hepatitis: how late can it occur even after the cessation of the culpable drug?,,1
12733,22547422,Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation,"""BACKGROUND: Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy. OBJECTIVES: We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women. METHODS: We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations. RESULTS: The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation. CONCLUSIONS: In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.""",1
12734,22550315,"Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials","OBJECTIVE: To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. METHODS: Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) organ domain scores. RESULTS: At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA-SLEDAI, and immunological by SELENA-SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA-SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (</=16%) at baseline, including the SELENA-SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA-SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. CONCLUSIONS: Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.",1
12735,22554152,Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension,"BACKGROUND AND AIM: To evaluate hepatic hemodynamics in patients with nodular regenerative hyperplasia of the liver (NRH) with portal hypertension (PHT). METHODS: We retrospectively reviewed the charts of 24 patients referred for PHT related to biopsy-proven NRH. Hemodynamic measurements included wedged hepatic vein (WHVP) and inferior vena cava (IVCP), and, in 12 patients, portal vein pressure (PVP). Hepatic vein pressure gradient (HVPG: WHVP-IVCP) and portal vein pressure gradient (PVPG: PVP-IVCP) were calculated. RESULTS: Nodular regenerative hyperplasia was associated in 24 patients with various diseases (oxaliplatin chemotherapy, treatment with purine antagonists, post liver transplantation, hematologic and rheumatologic conditions and HIV infection). Liver function parameters were either completely normal or slightly impaired. Patients were referred for gastroesophageal varices (n = 18), and/or ascites (n = 11), and/or splenomegaly (n = 20). In patients with varices or ascites, HVPG was lower than 10 mmHg (a cut-off point for the presence of varices and/or ascites) in 15/21, suggesting a pre-sinusoidal component to their PHT confirmed by a PVP higher than 12 mmHg in 12/12 patients. The mean difference between HVPG and PVPG was 8.7 mmHg in these patients. Ten patients were treated by transjugular intrahepatic portosystemic shunt. None of them re-bled, and one presented transient hepatic encephalopathy. CONCLUSIONS: Presinusoidal PHT associated with NRH is probably related to compression of portal venules by the regenerative nodules. In patients with HTP and a HVPG < 10 mmHg, the diagnosis of NRH must be suspected and PVP measured, which is important in the management of these patients.",1
12736,22555080,Rilpivirine: a second-generation nonnucleoside reverse transcriptase inhibitor,"PURPOSE: The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of rilpivirine are reviewed. SUMMARY: Rilpivirine is a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in adult patients not previously treated with antiretroviral therapy. Rilpivirine is primarily metabolized by the cytochrome P-450 (CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP 3A inhibitors may lead to increased concentrations of rilpivirine, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric pH may lead to decreased concentrations of rilpivirine, thus promoting virological failure or resistance to rilpivirine. Two Phase III, randomized, double-blind, double-dummy, active-controlled trials compared rilpivirine with efavirenz in HIV-infected adults not previously treated with an antiretroviral. The investigators concluded that rilpivirine, when combined with two nucleoside or nucleotide reverse transcriptase inhibitors, was noninferior to efavirenz for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/mL) in adults with HIV infection not previously treated with antiretroviral therapy. The most commonly reported adverse effects included depression, insomnia, headache, and rash. Rilpivirine is administered as a single 25-mg tablet given once daily in combination with other antiretroviral drugs in order to optimize efficacy and reduce resistance. CONCLUSION: Rilpivirine is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy.",1
12737,22564299,Hepatic injury to the newborn liver due to drugs,"The result of the use of drugs in the newborn may be strongly influenced by the peculiar state of the neonate, characterized by the immaturity, at birth, of the processes controlling the absorption, distribution, metabolism and excretion of drugs. Additional important factors that may affect drugs' bioavailability and toxicity are gestational age, birth weight, intrauterine growth restriction, gender and, especially, liver function immaturity. Because of the high susceptibility to infections, antibiotics, in particular ampicillin and gentamicin, are the most widely used drugs in newborns. Erythromycin is often used for the therapy of gastrointestinal dismotility, while azithromycin has been proposed for the prevention of bronchopulmonary dysplasia. Prostaglandin synthesis inhibitors, like indomethacin, are administered on the first days of life to close the patent ductus arteriosus. All these drugs have been proved to can give rise to hepatotoxicity. The acute and chronic liver toxicity due to the most widely used drugs in the neonates will be here reviewed.",1
12738,22565557,[Cholestasis in young men after taking anabolic steroids],,1
12739,22567755,Sulbactam/ampicillin associated hepatocellular type liver injury,,1
12740,22571348,Hepatic sinusoidal obstruction syndrome (SOS) reduces the effect of oxaliplatin in colorectal liver metastases,"""AIMS: Oxaliplatin is an important chemotherapeutic agent used to reduce hepatic colorectal metastases, resulting in tumour reduction and permitting surgical resection. This treatment has significant side effects, as oxaliplatin can induce sinusoidal obstruction syndrome (SOS) in the non-tumour-bearing liver, resulting in increased morbidity. We hypothesized that SOS might impede hepatic perfusion, thereby interfering with the tumour environment and attenuate the response to the chemotherapy. METHODS AND RESULTS: From the prospective database of the Maastricht University Medical Centre we collected 50 patients with hepatic colorectal carcinoma metastases. All patients received neo-adjuvant oxaliplatin followed by partial hepatectomy. Metastases and non-tumour-bearing liver were studied histopathologically. Thirty-two of 50 (64%) patients showed SOS lesions, classified as mild (26%) and moderate-severe (38%). The response to treatment, as expressed in the tumour regression grade (TRG), was grade 1 (10%); grade 2 (14%); grade 3 (28%); grade 4 (32%) and grade 5 (16%). Statistical analysis showed that a higher grade of SOS was associated with a higher grade of TRG (P = 0.016). CONCLUSION: Developing SOS is associated with a lower tumour response to neo-adjuvant oxaliplatin treatment. Hepatic hypoperfusion due to sinusoidal obstruction syndrome might induce hepatic hypoxia, diminishing the response to chemotherapy.""",1
12741,22573522,The liver toxicity biomarker study phase I: markers for the effects of tolcapone or entacapone,"""The Liver Toxicity Biomarker Study is a systems toxicology approach to discover biomarkers that are indicative of a drug's potential to cause human idiosyncratic drug-induced liver injury. In phase I, the molecular effects in rat liver and blood plasma induced by tolcapone (a """"toxic"""" drug) were compared with the molecular effects in the same tissues by dosing with entacapone (a """"clean"""" drug, similar to tolcapone in chemical structure and primary pharmacological mechanism). Two durations of drug exposure, 3 and 28 days, were employed. Comprehensive molecular analysis of rat liver and plasma samples yielded marker analytes for various drug-vehicle or drug-drug comparisons. An important finding was that the marker analytes associated with tolcapone only partially overlapped with marker analytes associated with entacapone, despite the fact that both drugs have similar chemical structures and the same primary pharmacological mechanism of action. This result indicates that the molecular analyses employed in the study are detecting substantial """"off-target"""" markers for the two drugs. An additional interesting finding was the modest overlap of the marker data sets for 3-day exposure and 28-day exposure, indicating that the molecular changes in liver and plasma caused by short- and long-term drug treatments do not share common characteristics.""",1
12742,22578793,"Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial","""BACKGROUND: Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. METHODS: Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m(2) temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60.0 Gy, administered over 6-7 weeks in 30 fractions of 1.8-2.0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. FINDINGS: Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8.6 months (95% CI 7.3-10.2) in the temozolomide group versus 9.6 months (8.2-10.8) in the radiotherapy group (hazard ratio [HR] 1.09, 95% CI 0.84-1.42, p(non-inferiority)=0.033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3.3 months [95% CI 3.2-4.1] vs 4.7 [4.2-5.2]; HR 1.15, 95% CI 0.92-1.43, p(non-inferiority)=0.043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11.9 months [95% CI 9.0 to not reached] vs 8.2 months [7.0-10.0]; HR 0.62, 95% CI 0.42-0.91, p=0.014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8.4 months [95e% CI 5.5-11.7] vs 4.6 [4.2-5.0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3.3 months [3.0-3.5] vs 4.6 months [3.7-6.3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). INTERPRETATION: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. FUNDING: Merck Sharp & Dohme.""",1
12743,22583335,Efficacy and safety of the interleukin-1 antagonist rilonacept in Schnitzler syndrome: an open-label study,"BACKGROUND: Schnitzler syndrome (SchS) is a rare disease with suspected autoinflammatory background that shares several clinical symptoms, including urticarial rash, fever episodes, arthralgia, and bone and muscle pain with cryopyrin-associated periodic syndromes (CAPS). Cryopyrin-associated periodic syndromes respond to treatment with interleukin-1 antagonists, and single case reports of Schnitzler syndrome have shown improvement following treatment with the interleukin-1 blocker anakinra. This study evaluated the effects of the interleukin-1 antagonist rilonacept on the clinical signs and symptoms of SchS. METHODS: Eight patients with SchS were included in this prospective, single-center, open-label study. After a 3-week baseline, patients received a subcutaneous loading dose of rilonacept 320 mg followed by weekly subcutaneous doses of 160 mg for up to 1 year. Efficacy was determined by patient-based daily health assessment forms, physician's global assessment (PGA), and measurement of inflammatory markers including C-reactive protein (CRP), serum amyloid A (SAA), and S100 calcium-binding protein A12 (S100A12). RESULTS: Treatment with rilonacept resulted in a rapid clinical response as demonstrated by significant reductions in daily health assessment scores and PGA scores compared with baseline levels (P < 0.05). These effects, which were accompanied by reductions in CRP and SAA, continued over the treatment duration. Rilonacept treatment was well tolerated. There were no treatment-related severe adverse events and no clinically significant changes in laboratory safety parameters. CONCLUSION: Rilonacept was effective and well tolerated in patients with SchS and may represent a promising potential therapeutic option.",1
12744,22584460,"Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin","""Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine-Cytarabine-Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen.""",1
12745,22586173,"Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions","""OBJECTIVES: Gouty arthritis patients for whom non-steroidal anti-inflammatory drugs and colchicine are inappropriate have limited treatment options. Canakinumab, an anti-interleukin-1beta monoclonal antibody, may be an option for such patients. The authors assessed the efficacy/safety of one dose of canakinumab 150 mg (n=230) or triamcinolone acetonide (TA) 40 mg (n=226) at baseline and upon a new flare in frequently flaring patients contraindicated for, intolerant of, or unresponsive to non-steroidal anti-inflammatory drugs and/or colchicine. Core study co-primary endpoints were pain intensity 72 h postdose (0-100 mm visual analogue scale and time to first new flare. METHODS: Two 12-week randomised, multicentre, active-controlled, double-blind, parallel-group core studies with double-blind 12-week extensions (response in acute flare and in prevention of episodes of re-flare in gout (beta-RELIEVED and beta-RELIEVED-II)). RESULTS: 82.6% patients had comorbidities. Mean 72-h visual analogue scale pain score was lower with canakinumab (25.0 mm vs 35.7 mm; difference, -10.7 mm; 95% CI -15.4 to -6.0; p<0.0001), with significantly less physician-assessed tenderness and swelling (ORs=2.16 and 2.74; both p</=0.01) versus TA. Canakinumab significantly delayed time to first new flare, reduced the risk of new flares by 62% versus TA (HR: 0.38; 95% CI 0.26 to 0.57) in the core studies and by 56% (HR: 0.44; 95% CI 0.32 to 0.60; both p</=0.0001) over the entire 24-week period, and decreased median C-reactive protein levels (p</=0.0001 at 72 h and 7 days). Over the 24-week period, adverse events were reported in 66.2% (canakinumab) and 52.8% (TA) and serious adverse events were reported in 8.0% (canakinumab) and 3.5% (TA) of patients. Adverse events reported more frequently with canakinumab included infections, low neutrophil count and low platelet count. CONCLUSION: Canakinumab provided significant pain and inflammation relief and reduced the risk of new flares in these patients with acute gouty arthritis.""",1
12746,22592097,Hepatic safety profile of fosamprenavir-containing regimens in HIV-1-infected patients with or without hepatitis B or C coinfection,"""PURPOSE: This post hoc analysis investigated the hepatic safety profile of fosampre-navir (FPV) in patients monoinfected with HIV or coinfected with HIV and hepatitis B (HbsAg positive) and/or hepatitis C (anti-HCV antibody positive). METHODS: Data were pooled from 7 prospective, randomized clinical trials of FPV. RESULTS: Baseline demographics were generally well-matched between the 205 coinfected (72% HCV, 24% HBV, 3% both) and 1,114 monoinfected patients in this analysis. At baseline, most regimens included ritonavir 100 mg (58%) or 200 mg (38%), and 73% of subjects were ART-na?ve. Over 48 weeks, the rate of treatment-related serious adverse events was similar between the coinfected (8%; 16/205) and monoinfected (6%; 62/1114) groups, and the rate of treatment-related grade 2-4 adverse events was higher in the coinfected (38%; 77/205) compared with the monoinfected (29%; 320/1114) group. The percentage of patients with grade 3/4 liver enzyme elevations at any time through week 48 was 14% (ALT) and 12% (AST) in the coinfected group and 1% (both ALT and AST) in the monoinfected group. Median AST to platelet ratio index (APRI) scores decreased by 29% in both groups. CONCLUSION: Liver enzyme elevations in coinfected patients treated with FPV with or without ritonavir appear generally similar to those reported for other second-generation protease inhibitors.""",1
12747,22595892,Cardiac rehabilitation participant with sickle cell trait and statin-related hepatotoxicity: a case report,"PURPOSE: Exercise recommendations for patients with sickle cell trait (SCT) and myocardial infarction (MI) are limited. This case report describes such a patient, who subsequently participated in cardiac rehabilitation (CR). CASE: Patient experienced sudden intense chest pressure and shortness of breath while singing in church. Electrocardiogram and cardiac enzymes confirmed acute ST elevation MI. Laboratory tests indicated hyperlipidemia and elevated liver enzyme levels >4 times the upper normal limit (UNL). Day 40 post-MI, the patient returned to the hospital complaining of daily chest discomfort, atypical for angina pectoris. Following an unremarkable stress test result, the patient was encouraged to proceed with CR. Patient made regular progress through CR, although continued to experience paroxysmal chest discomfort away from CR, which he denied having during exercise. On day 75, his lipid profile met recommended targets while taking atorvastatin, but with liver enzymes >38 times UNL. Atorvastatin was discontinued at day 85, to which his enzymes responded appropriately, but by day 165, hyperlipidemia had returned. Rosuvastatin was started but was discontinued (day 197), with liver enzymes 6 times UNL. He continued CR without lipid therapy but at CR completion, the lipid panel did not meet targets. However, fitness and social indices improved significantly, although he occasionally still experienced chest pain, but with lesser frequency and intensity, and never with exercise. CONCLUSIONS: CR in a patient with SCT, MI, and statin-related hepatotoxicity requires several specific considerations. Although SCT-exercise associated deaths are described in the literature, this case suggests that such patients can benefit from CR and can exercise safely.",1
12748,22605661,Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease,"BACKGROUND: Thiopurines are the mainstay of conventional maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to 50% of patients discontinue immunosuppressive therapy within 2 years due to intolerance or lack of efficacy. Allopurinol with low-dose thiopurine can optimize thiopurine metabolism for IBD patients with preferential shunting toward 6-methyl mercaptopurine (6-MMP) formation. The aim of this study was to assess long-term maintenance effectiveness and tolerability of allopurinol-thiopurine therapy in a larger multicenter cohort of IBD patients. METHODS: Enrolled patients who failed monotherapy with thiopurines due to a skewed metabolism were subsequently treated with a combination therapy of allopurinol and low-dose thiopurine. Adverse events were monitored and therapeutic adherence was assessed. Seventy-seven IBD patients were enrolled with a mean follow-up of 19 months. RESULTS: The median 6-thioguanine nucleotide concentration increased from 145 during monotherapy to 271 pmol/8 ? 10(8) red blood cell (RBC) after at least 8 weeks of combination therapy while reducing the thiopurine dosage (P < 0.001). In contrast, median 6-MMP concentrations decreased from 10,110 to 265 pmol/8 ? 10(8) RBC (P < 0.001). Leukopenia occurred in 12 patients (16%), requiring dose adaptation. Liver test abnormalities normalized in 81% of patients after the addition of allopurinol. Sixteen (21%) patients had to discontinue combination therapy. The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 87%, 85%, 76%, and 65%, respectively. CONCLUSIONS: Long-term combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in IBD patients with a skewed thiopurine metabolism.",1
12749,22608068,Buspirone: what is it all about?,"""Buspirone is an anxiolytic drug and is a partial agonist for the serotonin 5-HT(1A) receptors as well as possessing low affinity and is an antagonist for the dopamine D(2) autoreceptors, with some evidence of a weak affinity to 5-HT(2) receptors. The underlying mechanism of action of buspirone is not clear; however it is thought that its main pharmacology is mediated via the 5-HT(1A) receptors. Initially developed for use in the treatment of generalised anxiety disorder, it appears that buspirone may be useful in various other neurological and psychiatric disorders, such as attenuating side effects of Parkinson's disease therapy, ataxia, depression, social phobia, and behaviour disturbances following brain injury, and those accompanying Alzheimer's disease, dementia and attention deficit disorder. Considering the potential of this drug to be included in the management of many conditions, thorough and controlled studies are required to elucidate the exact mechanism of action. This review will consider the evidence so far for both the potential underlying mechanisms and its use in various conditions.""",1
12750,22611746,Drug rash with eosinophilia and systemic symptoms (DRESS syndrome),,1
12751,22613860,Stevens-Johnson syndrome and toxic epidermal necrolysis,"Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare but severe adverse cutaneous drug reactions that are to be considered medical emergencies. The average reported mortality rate for SJS is 1-5%, and up to 25-35% for TEN. TEN and SJS are characterized by more or less extensive painful erythematous and erosive lesions of the skin, conjunctiva and mucous membranes resulting from massive apoptosis of epithelial cells, and are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs including allopurinol, antibiotics, anticonvulsants and NSAIDs of the oxicam type are the main cause of SJS/TEN in most cases. Recent evidence supports a genetic susceptibility to SJS and TEN as exemplified by the strong association observed in Han Chinese between the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnoses include autoimmune bullous dermatoses, acute generalized exanthematous pustulosis, disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome. Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, rapid identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and the consideration of immunomodulatory agents such as high-dose intravenous immunoglobulin.",1
12752,22614989,Management of immune-related adverse events and kinetics of response with ipilimumab,"""Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)-ipilimumab and tremelimumab-have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.""",1
12753,22616830,Drotrecogin alfa (activated) in adults with septic shock,"""BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 ?g per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).""",1
12754,22616981,The safety and efficacy of antitumour necrosis factor-alpha therapy for inflammatory bowel disease in patients post liver transplantation: a case series,"BACKGROUND: The role of antitumour necrosis factor-alpha (anti-TNF) therapy for inflammatory bowel disease (IBD) among liver transplant recipients is largely unknown given the rarity of this population and the paucity of literature on the subject. AIM: To investigate the safety and efficacy of anti-TNF therapy for refractory IBD in the post liver transplant population. METHODS: The liver transplant database at London Health Sciences Centre was searched to identify adult patients with IBD treated with anti-TNF therapy post transplantation. RESULTS: Six patients (five men, one woman) were identified, aged 28-65. All patients had cadaveric orthotopic liver transplants. Four patients required transplantation due to primary sclerosing cholangitis, one due to autoimmune hepatitis, and one due to biliary atresia. Five patients suffered from Crohn's disease and the remaining patient from indeterminate colitis. All patients were treated with infliximab 5 mg/kg every 8 weeks after undergoing induction at weeks 0, 2 and 6, with the exception of one patient. The duration of infliximab therapy ranged from 8 weeks to 4 years. Four patients treated with infliximab experienced sustained improvement of their IBD symptoms post transplantation, as documented by Harvey-Bradshaw Index scores demonstrating clinical remission. Of the remaining two patients, neither had sustained improvement of their IBD with infliximab or subsequent adalimumab. One patient was diagnosed with systemic lupus erythematosus and another with colorectal adenocarcinoma following anti-TNF therapy. Otherwise, no side effects were attributed to anti-TNF therapy. CONCLUSIONS: Based on this case series, anti-TNF therapy appears to be safe and effective for treating refractory IBD in patients post liver transplantation. These patients respond to anti-TNF therapy similar to those who have not been previously transplanted.",1
12755,22632481,"Oral paliperidone extended-release: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability","INTRODUCTION: Paliperidone is a second-generation (atypical) antipsychotic approved for the treatment of schizophrenia in adults and in adolescents aged 12 - 17 years. It is also approved for the treatment of adults with schizoaffective disorder, both as a monotherapy and as adjunctive therapy to mood stabilizers and/or antidepressants. Paliperidone is the active metabolite of risperidone. AREAS COVERED: The purpose of this review is to describe the pharmacokinetic profile of paliperidone and its clinical implications in the treatment of schizophrenia and schizoaffective disorder. Background information is also provided regarding chemistry, pharmacodynamics, clinical efficacy and safety/tolerability data. EXPERT OPINION: The recommended dose of paliperidone extended-release (ER) in adults is 6 mg/day and no initial dose titration is required. Higher doses may provide additional benefit as well as dose-related increases in some adverse reactions. The maximum recommended dose is 12 mg/day. Peak plasma concentrations are reached approximately 24 h after dosing. Pharmacokinetics are dose-proportional. Terminal half-life is approximately 23 h. Renal excretion is the major route of elimination. Although paliperidone is the active metabolite of risperidone, paliperidone's route of metabolism and elimination is quite different from that for risperidone and paliperidone ER may be preferred over risperidone when liver disease, drug-drug interactions or other alterations in metabolism render the appropriate dosing of risperidone difficult to determine for an individual patient. The use of paliperidone ER will need to be considered within the context of its cost and availability as risperidone is now a generic product.",1
12756,22635416,Adherence to hepatitis B screening and prophylactic lamivudine for prevention of rituximab-associated hepatitis B reactivation,"""PURPOSE: Treatment with rituximab can be associated with hepatitis B reactivation leading to fulminant hepatitis and sometimes fatal hepatitis. The manufacturer has recommended screening the high-risk patients and monitoring hepatitis B virus carriers during and several months after the therapy. Prophylaxis with lamivudine has been recommended to prevent reactivation in hepatitis B virus carriers receiving rituximab. An institutional guideline was developed and implemented. This study evaluated the adherence to these clinical guidelines of hepatitis B screening in patients receiving rituximab-based treatment, the use of lamivudine prophylaxis, and the prevalence of positive hepatitis B virus surface antigen in this patient population in southeast Michigan. METHODS: A retrospective chart review of patients begun on rituximab therapy from January 2009 through June 2010 was conducted. RESULTS: Two hundred and eighty patients who received rituximab were identified. Approximately 70% of patients had hepatitis B virus surface antigen screening test prior to rituximab therapy. Antibody to hepatitis B virus core antigen was detected in 11.1% of patients, although the hepatitis B virus surface antigen positive rate was only 0.6%. One patient had hepatitis B virus reactivation despite lamivudine prophylaxis, but fully recovered after antiviral therapy was changed to tenofovir. CONCLUSION: The prevalence of hepatitis B virus surface antigen positivity is low in this study; however, antibody to hepatitis B virus core antigen positivity is high. Education to clinicians is warranted to increase awareness and further improve adherence to the clinical guidelines.""",1
12757,22640653,Thiabendazole-induced acute liver failure requiring transplantation and subsequent diagnosis of polyarteritis nodosa,"""Polyarteritis nodosa (PAN), a systemic necrotising vasculitis that affects medium- and small-sized arteries, has visceral involvement in 40-60% of the patients. According to the Five-Factor Score (FFS), it is associated with poor outcome. We describe a patient who underwent orthotopic liver transplantation (OLT) for severe ductopenia induced by thiabendazole that was empirically prescribed for chronic hypereosinophilia. Eleven years later, despite immunosuppressive treatment to prevent graft rejection, he developed mononeuritis multiplex; PAN was diagnosed. He also had severe recurrent ischaemic cholangitides because of post-OLT hepatic artery ligation to treat a postoperative severe haematemesis. His outcome was favourable after second OLT, under steroids, cyclophosphamide pulses and tacrolimus. In retrospect, his initial symptoms and hypereosinophilia were probably attributable to PAN.""",1
12758,22643350,Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-na?ve patients with chronic hepatitis B,"""BACKGROUND & AIMS: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are potent antiviral agents that might have additive or synergistic antiviral activity in treatment of patients with chronic hepatitis B (CHB). We compared the efficacy and safety of ETV monotherapy with those of a combination of ETV and TDF. METHODS: We performed a randomized, open-label, multicenter, superiority study of 379 nucleos(t)ide-na?ve patients with hepatitis B e antigen (HBeAg)-positive (n = 264) or HBeAg-negative (n = 115) CHB. Subjects were given ETV 0.5 mg (n = 182) or a combination of ETV 0.5 mg and TDF 300 mg (n = 197) for 100 weeks. RESULTS: At week 96, comparable proportions of patients in each study arm achieved the primary end point of a level of hepatitis B virus (HBV) DNA <50 IU/mL (83.2% vs 76.4%; P = .088). Among HBeAg-positive patients, a greater proportion given combination therapy achieved levels of HBV DNA <50 IU/mL than those given ETV alone (80.4% vs 69.8%; P = .046). However, this difference was observed only in patients with baseline levels of HBV DNA ? 10(8) IU/mL (79% vs 62%) and not in those with baseline levels of HBV DNA <10(8) IU/mL (83% in both arms). Rates of HBeAg loss and HBeAg seroconversion were comparable between groups, whereas the rate of alanine aminotransferase normalization was greater in the ETV monotherapy group. No HBV variants associated with ETV or TDF resistance were detected. Safety profiles were consistent with previous reports of ETV or TDF monotherapy. CONCLUSIONS: The antiviral efficacy of ETV monotherapy is comparable to that of ETV plus TDF in a mixed population of nucleos(t)ide-na?ve patients with CHB (70% HBeAg positive). The combination therapy could provide an incremental benefit to HBeAg-positive patients with baseline levels of HBV DNA ? 10(8) IU/mL.""",1
12759,22646133,Tioguanine in the treatment of refractory coeliac disease--a single centre experience,"BACKGROUND: Refractory coeliac disease type I is a complicated form of coeliac disease characterised by primary or secondary resistance to a gluten-free diet with persisting or reoccurring intestinal villous atrophy and symptoms of malabsorption. Besides corticosteroids, azathioprine has been advocated for the treatment of refractory coeliac disease type I. However, tioguanine (TG) might be better tolerated and more efficacious owing to a simpler metabolism towards bioactivation. AIM: To evaluate tolerability and effectiveness of the nonconventional thiopurine derivative TG in refractory coeliac disease type I. METHODS: Refractory coeliac disease type I patients treated with TG between June 2001 and November 2010 with a follow-up period of at least 1�year were included. Adverse events, laboratory values, 6-thioguanine nucleotide concentrations and rates of both clinical and histological response were evaluated at baseline and during follow-up. RESULTS: Twelve adult refractory coeliac disease type I patients were included. The median TG treatment duration was 14�months. Ten patients tolerated TG treatment on the long term, whereas two patients withdrew treatment due to adverse events. No nodular regenerative hyperplasia of the liver was observed. During follow-up clinical and histological response was observed in 83% and 78%, respectively. Corticosteroid dependency decreased by 50%. CONCLUSION: Tioguanine appears to be a convenient drug for the treatment of refractory coeliac disease type I based on higher histological and similar clinical response rates as compared with historical conventional therapies.",1
12760,22648560,Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19,"Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC(5)(0) values were greater than 40 muM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC(5)(0) = approximately 8 muM) and esomeprazole with CYP2C8 (IC(5)(0) = 31 muM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC(5)(0) ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC(5)(0) (IC(5)(0) ratio, </= 2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC(5)(0) = 0.73 muM) and esomeprazole (IC(5)(0) = 3.7 muM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC(5)(0) = approximately 7.0 muM). Rabeprazole and pantoprazole (IC(5)(0) = >/= 25 muM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC(5)(0) ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 muM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.",1
12761,22653773,"Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension","""Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short- and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics. All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and event-free status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients. Significant improvements from baseline were observed in NYHA FC, 6 MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after mean ? SD 5 ? 2 months. Mean follow-up time was 43 ? 19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH. These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.""",1
12762,22658127,"Safety, activity, and immune correlates of anti-PD-1 antibody in cancer","""BACKGROUND: Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. METHODS: We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. RESULTS: A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006). CONCLUSIONS: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).""",1
12763,22662786,Recurrent hepatotoxicity associated with etanercept and adalimumab but not with infliximab in a patient with rheumatoid arthritis,,1
12764,22664749,"A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome","""OBJECTIVE: The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). METHODS: Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography-mass spectrometry/mass spectrometry method at weeks 4 and 12. RESULTS: Exposure to gabapentin was proportional to GEn dose. Time to maximum plasma concentration was 7 to 9 hours, and elimination half-life was ~6 hours. The mean reduction from baseline to week 12 in International Restless Legs Syndrome Rating Scale total score and proportions of subjects with """"much improved""""/""""very much improved"""" Clinical Global Impression-Improvement scores (investigator and patient ratings) ranged from -12.9 to -13.9 for GEn treatment groups versus -9.3 for placebo. The 2 most commonly reported adverse events were somnolence and dizziness. CONCLUSIONS: Gabapentin exposure was approximately proportional to GEn dose. Efficacy data showed that a once-daily dose of GEn 600 to 2400 mg provides greater relief of RLS symptoms than placebo; GEn was generally well tolerated with an adverse event profile consistent with gabapentin.""",1
12765,22665938,A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma,"""This phase 1/2 study in patients with newly diagnosed multiple myeloma (N = 53) assessed CRd--carfilzomib (20, 27, or 36 mg/m2, days 1, 2, 8, 9, 15, 16 and 1, 2, 15, 16 after cycle 8), lenalidomide (25 mg/d, days 1-21), and weekly dexamethasone (40/20 mg cycles 1-4/5+)--in 28-day cycles. After cycle 4, transplantation-eligible candidates underwent stem cell collection (SCC) then continued CRd with the option of transplantation. The maximum planned dose level (carfilzomib 36 mg/m2) was expanded in phase 2 (n = 36). Thirty-five patients underwent SCC, 7 proceeded to transplantation, and the remainder resumed CRd. Grade 3/4 toxicities included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); peripheral neuropathy was limited to grade 1/2 (23%). Most patients did not require dose modifications. After a median of 12 cycles (range, 1-25), 62% (N = 53) achieved at least near-complete response (CR) and 42% stringent CR. Responses were rapid and improved during treatment. In 36 patients completing 8 or more cycles, 78% reached at least near CR and 61% stringent CR. With median follow-up of 13 months (range, 4-25 months), 24-month progression-free survival estimate was 92%. CRd was well tolerated with exceptional response rates. This study is registered at http://www.clinicaltrials.gov as NCT01029054.""",1
12766,22670903,Efficacy and safety of vismodegib in advanced basal-cell carcinoma,"""BACKGROUND: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS: In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS: Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).""",1
12767,22674457,Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus,"OBJECTIVE: To evaluate the safety profile of long-term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. METHODS: Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. RESULTS: Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with belimumab in the long-term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. CONCLUSION: Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.",1
12768,22677988,Reactivation of hepatitis B virus replication due to cytotoxic therapy: a five-year prospective study,"""BACKGROUND AND AIMS: In hepatitis B virus (HBV) carriers receiving chemotherapy, the risk of reactivation is high, particularly if rituximab is given alone or in combination with steroids. The aim of this study was to assess the incidence, prevalence, and clinical course of HBV infection in a cohort of patients with hematological malignancies receiving cytotoxic therapy as well as to propose a strategy for managing HBV reactivation. METHODS: This is a prospective observational study. All consecutive patients with hematological malignancies receiving intravenous cytotoxic chemotherapy between October 2005 and June 2010 and followed up for at least six months were enrolled in the study. Viral hepatitis markers and liver function indexes were monitored prospectively. RESULTS: We enrolled 478 patients, including 263 males (55%) and 465 (97.3%) Italians. Non-Hodgkin's lymphoma was the most frequent diagnosis (66%). At least one HBV marker was positive in 96 patients (20%): 21 (4.4%) patients were HBsAg positive, 17 (3.5%) were anti-HBc positive, and 58 (12.1%) were anti-HBc/anti-HBs positive. All but one HBsAg-positive patient received therapy with nucleoside/nucleotide analogs prior to chemotherapy. All but three reached complete virological suppression at six months from the start of treatment. Of the 17 HBsAg-negative/anti-HBc-positive patients, three (18%) had reactivation with seroreversion. All three obtained viral suppression with adefovir. Regarding the 58 anti-HBc/anti-HBs-positive patients, two (3.4%) experienced seroreversion and were treated successfully with nucleoside analogs; both were taking rituximab. No severe ALT flares were observed during or after antiviral therapy. CONCLUSION: Our data suggest that pre-treatment screening of patients at risk of viral reactivation yields benefit and therefore should be practiced by clinicians treating patients with malignancies.""",1
12769,22679188,An unusual case of DRESS syndrome due to leflunomide,"The DRESS (drug rash, eosinophilia and systemic symptoms) syndrome, is a type of drug hypersensitivity syndrome, is a severe idiosyncratic reaction to several drugs, mainly antiepileptics and antibiotics, which can occasionally produce acute hepatic failure. In this article, the authors report a case of DRESS syndrome with severe exfoliative dermatitis with acute hepatitis associated with intake of leflunomide. Rapid diagnosis with withdrawal of offending agent is crucial for survival of these cases.",1
12770,22681723,Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer's disease,"""BACKGROUND: Donepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD. METHODS: Patients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs. RESULTS: 915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ? 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study. CONCLUSION: This study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.""",1
12771,22683926,Peginesatide (Omontys) for anemia in chronic kidney failure,,1
12772,22683928,Axitinib (Inlyta) for advanced renal cell carcinoma,,1
12773,22689417,Effects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally-tolerated background therapy: analysis from the Combination Assessment of Ranolazine In Stable Angina (CARISA) randomized trial,"""BACKGROUND: Ranolazine has been previously shown to improve exercise capacity and symptoms in patients with severe chronic angina treated with standard doses of beta-blockers and calcium-channel blockers, without a significant effect on heart rate or blood pressure. OBJECTIVE: The purpose of this study was to assess whether the benefit of ranolazine extends to the subgroup of angina patients treated with maximally-tolerated doses of beta-blockers or calcium blockers. METHODS AND RESULTS: In this post-hoc analysis, 258 patients from the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial were considered as treated with maximally-tolerated doses of beta-blockers or calcium-channel blockers (systolic blood pressure (SBP) </= 100 mm Hg, and/or a resting heart rate </= 60 beats per minute, and/or an ECG PR interval >/= 200 msec). Change from baseline in total exercise duration after 12 weeks compared to placebo were 34.5 (95% CI 0.8; 68.1) sec (p = 0.045) with ranolazine (750/1000 mg bid) at trough drug levels and 46.3 (13.5; 79.1) (p = 0.006) at peak drug levels. The number of angina attacks per week compared to baseline were reduced compared to placebo (-2.3 +/- 0.3 vs -0.9 +/- 0.6 (p < 0.001)). The effects of ranolazine 750 mg bid and 1000 mg bid were similar and the beneficial effects of ranolazine in this subgroup of maximally-treated patients were consistent with those not on maximally-tolerated doses of the background therapy. CONCLUSION: Ranolazine is effective for the symptomatic treatment of patients with stable angina on background therapy with maximally-tolerated doses of first line anti-anginal therapies.""",1
12774,22691153,Topiramate increases the risk of valproic acid-induced encephalopathy,"Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA-induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA-induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA-induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA-induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA-induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment.",1
12775,22696691,Nodular regenerative hyperplasia of the liver associated with didanosine persists for years even after its interruption,"The authors describe an HIV-positive patient with nodular regenerative hyperplasia of the liver with non-cirrhotic portal hypertension. Despite stopping the culprit drug, didanosine, the radiologic changes persisted for years. When evaluating liver pathologies, antiretroviral drugs must be included in the differential diagnosis, even when they have been stopped years ago.",1
12776,22699418,Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up,"""Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients compares nilotinib and imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). With a minimum follow-up of 3 years, major molecular response, molecular response of BCR-ABL? 0.01% expressed on the international scale (BCR-ABL(IS); MR(4)) and BCR-ABL(IS)? 0.0032% (MR(4.5)) rates were significantly higher with nilotinib compared with imatinib, and differences in the depth of molecular response between nilotinib and imatinib have increased over time. No new progressions occurred on treatment since the 2-year analysis. Nilotinib was associated with a significantly lower probability of progression to accelerated phase/blast crisis vs imatinib (two (0.7%) progressions on nilotinib 300 mg twice daily, three (1.1%) on nilotinib 400 mg twice daily and 12 (4.2%) on imatinib). When considering progressions occurring after study treatment discontinuation, the advantage of nilotinib over imatinib in preventing progression remained significant (nine (3.2%) progressions on nilotinib 300 mg twice daily, six (2.1%) on nilotinib 400 mg twice daily and 19 (6.7%) on imatinib). Both nilotinib and imatinib were well tolerated, with minimal changes in safety over time. Nilotinib continues to demonstrate superior efficacy in all key response and outcome parameters compared with imatinib for the treatment of patients with newly diagnosed CML-CP.""",1
12777,22701258,Allopurinol-induced DRESS syndrome,"A 70-year-old man was admitted to our clinic with complaints of fever, jaundice, dyspnea, and generalized rash after 3 months of allopurinol treatment for gout. On physical examination, he was found to have fever (38.5 degrees C), jaundice, and generalized maculopapular rash. Leukocytosis, eosinophilia, elevation of liver enzymes, and hyperbilirubinemia were detected in his blood analysis. Skin biopsy was consistent with drug-induced hypersensitivity. He was diagnosed as Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Allopurinol treatment was stopped and steroid treatment was launched. At day 24 of admission, the patient died because of multiple organ failure.",1
12778,22707550,Recurrent imatinib-induced hepatotoxicity in a chronic myeloid leukaemia patient successfully managed with prednisone,"Imatinib, the frontline tyrosine kinase inhibitor (TKI), has revolutionised the management of chronic myeloid leukaemia (CML). Severe hepatotoxicity, although uncommon, can occur with this drug. This tends to subside with dose reduction or cessation, but can recur with reintroduction of the drug. Recurrent severe hepatotoxicity mandates permanent discontinuation of imatinib. This can cause difficulties in the management of CML, more so if the patient cannot afford or get access to alternate therapy. Furthermore, alternate therapy, for example, second-line TKIs, can impose a huge economic burden on a healthcare system. Here, the authors report the case of 20-year-old CML patient who developed recurrent hepatotoxicity with the use of imatinib. Introduction of corticosteroids enabled successful reintroduction of imatinib therapy.",1
12779,22710999,Amoxicillin-clavulanic acid hepatotoxicity in children,"OBJECTIVES: The objectives of the present study were to determine the importance of amoxicillin-clavulanic acid (AC) hepatotoxicity in the paediatric population and to characterise the episodes identified and potential host-specific factors. This was addressed via a prospective observational study in which 8 Spanish hospitals participated. METHODS: A total of 11 cases were examined. For each patient included in the study, a structured and codified data-collection protocol was complied with, taking note of patient demographics, characteristics of the treatment assumed to provoke the reaction, concomitant medication, course and outcome of the episode, and laboratory variables during the reaction. The latter were determined every 6 months from the outset to the eventual resolution of the case. RESULTS: A total of 11 cases of AC hepatotoxicity were detected, affecting 9 boys and 2 girls, ages 1 to 11 years. Causality criteria were assessed using the Council for International Organizations of Medical Sciences scale. CONCLUSIONS: We conclude that the introduction of hepatotoxicity record systems in paediatric care, together with the continuing study and development of existing systems, would contribute to improving our epidemiological knowledge about the harmful effects of drugs on the liver.",1
12780,22711083,Medical food and food supplements: not always as safe as generally assumed,,1
12781,22714001,"Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial","""BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 ?g per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb.""",1
12782,22718926,Assessing the safety of biologic agents in patients with rheumatoid arthritis,"Biologic treatments--including five TNF-alpha inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy.",1
12783,22723310,"A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density","CONTEXT: Men with low bone mineral density (BMD) were treated with denosumab. OBJECTIVE: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. DESIGN, SUBJECTS, AND INTERVENTION: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. MAIN OUTCOME MEASURE: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. RESULTS: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ? 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. CONCLUSIONS: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.",1
12784,22727462,"Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management","BACKGROUND: Tumor necrosis factor inhibitory agents are currently considered to be contraindicated in psoriatic patients with hepatitis B. OBJECTIVE: We aim to provide guidance to dermatologists on the use of tumor necrosis factor inhibitor therapy in these patients. METHODS: The current literature was reviewed regarding the use of tumor necrosis factor-alpha inhibitory agents (etanercept, adalimumab, and infliximab) in psoriatic patients with particular reference to hepatitis B infection. RESULTS: Tumor necrosis factor-alpha inhibitor therapy may result in reactivated hepatitis B in hepatitis B surface antigen-positive patients with psoriasis. This also occurs, although less frequently in patients with an isolated positive hepatitis B core antibody. Thus, all psoriasis patients should be screened for hepatitis B surface antigen plus hepatitis B core antibody prior to the initiation of tumor necrosis factor-alpha inhibitor therapy. Infliximab has been associated with more reactivation cases than the other 2 agents and fatalities have been reported with this agent. Evidence is presented that the risk of reactivation can be greatly minimized or eliminated by early or pre-emptive antiviral therapy. LIMITATIONS: The data is largely based on small case series that are retrospective in nature. CONCLUSIONS: Hepatitis B screening is essential prior to the initiation of tumor necrosis factor-alpha inhibitor therapy. Psoriatic patients found to be hepatitis B surface antigen or hepatitis B core antibody-positive should be referred to an appropriate specialist for evaluation and therapy. This would allow for the safe use of tumor necrosis factor-alpha inhibitors in psoriatic patients despite recently published guidelines to the contrary.",1
12785,22728692,Lamivudine plus adefovir or telbivudine plus adefovir for chronic hepatitis B patients with suboptimal response to adefovir,"""BACKGROUND: There is no standard management of chronic hepatitis B (CHB) patients with suboptimal response to nucleoside/nucleotide analogues (NAs). This study aimed to evaluate two different NA combination therapies in patients with suboptimal response to adefovir (ADV). METHODS: In this study, 72 CHB patients with suboptimal response to ADV were assessed, with 37 patients receiving lamivudine plus ADV (group A) and 35 patients receiving telbivudine plus ADV (group B). RESULTS: Baseline characteristics between two groups were similar. At month 12, rates of biochemical response (BR) and virological response (VR) were similar between groups A and B (17/19 versus 18/20 for BR, [P=0.269] and 30/37 versus 31/35 for VR [P=0.377]), and cumulative rates of serological response were greater in group B than in group A (10/26 versus 2/28 in hepatitis B e antigen [HBeAg] loss [P=0.006] and 7/26 versus 1/28 in HBeAg/hepatitis B e antibody seroconversion [P=0.022]). After 12-month treatment, 8.1% (3/37) of patients in group A and 5.7% (2/35) of patients in group B had VR; among patients in group A, two had rtM204V/I and rtL180M and one had rtN236T, whereas the two patients in group B had rtM204I+rtL180M. CONCLUSIONS: Both combination therapies led to a significant decrease in HBV DNA. HBeAg serological outcomes were higher with telbivudine plus ADV combination therapy.""",1
12786,22733303,A prospective nationwide study of drug-induced liver injury in Korea,"""OBJECTIVES: To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea. METHODS: From May 2005 to May 2007, cases of DILI (alanine transferase > 3 ? upper normal limit or total bilirubin > 2 ? upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used. RESULTS: A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included """"herbal medications"""" (102, 27.5%), """"prescription or non-prescription medications"""" (101, 27.3%), """"health foods or dietary supplements"""" (51, 13.7%), """"medicinal herbs or plants"""" (35, 9.4%), """"folk remedies"""" (32, 8.6%), """"combined"""" (30, 8.2%), """"herbal preparations"""" (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hy's law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM. CONCLUSIONS: DILI appears to be a highly relevant health problem in Korea. """"Herbal medications"""" are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.""",1
12787,22734293,Vitamin D intoxication,"Vitamin D intoxication (VDI) may result from supplementation rarely, but it has been reported more frequently in recent years. This may be attributable to an increase in vitamin D supplement intake due to an understanding of the role of vitamin D (25OHD) in the pathogenesis of several diseases. The symptoms and findings associated with VDI are closely related to serum calcium concentration and duration of hypercalcemia. In patients with VDI, hypercalcemia, normal or high serum phosphorus levels, normal or low levels of alkaline phosphatase (ALP), high levels of serum 25OHD, low serum parathyroid hormone (PTH), and high urine calcium/creatinine are usually present. Serum 25OHD levels above 150 ng/ml are considered as VDI. The main goal of treatment for VDI is correction of the hypercalcemia. When the calcium concentration exceeds 14 mg/dl, emergency intervention is necessary because of the adverse effects of hypercalcemia on cardiac, central nervous system, renal, and gastrointestinal functions. However, since vitamin D is stored in fat tissues, effects of toxicity may last for months despite the removal of the exogenous source of vitamin D. Treatment for VDI includes: discontinuation of intake, a diet with low calcium and phosphorus content, intravenous hydration with saline, loop diuretics, glucocorticoids, calcitonin, and bisphosphonates. In conclusion, the diagnosis of vitamin D deficiency rickets (VDDR) without checking serum 25OHD level may cause redundant treatment that leads to VDI. All patients who are clinically suspected of VDDR should be checked for serum vitamin D status and questioned for previous vitamin D administration before starting vitamin D therapy. On the other hand, parents of all infants should be asked whether they are using dietary or oral supplements, and serial questioning may be required during supplementation to avoid excessive intake.",1
12788,22741618,The efficacy and tolerability of artemisinin-piperaquine (Artequick�) versus artesunate-amodiaquine (Coarsucam�) for the treatment of uncomplicated Plasmodium falciparum malaria in south-central Vietnam,"BACKGROUND: In Vietnam, the artemisinin-based combination therapy (ACT) of dihydroartemisinin-piperaquine is currently used for first-line treatment of uncomplicated Plasmodium falciparum malaria. However, limited efficacy and tolerability data are available on alternative forms of ACT in Vietnam in case there is a reduction in the susceptibility of dihydroartemisinin-piperaquine. A study was conducted to compare the efficacy and tolerability of two fixed-dose formulations of ACT, artemisinin-piperaquine (Artequick�, ARPQ) and artesunate-amodiaquine (Coarsucam�, ASAQ) for the treatment of P. falciparum malaria in south-central Vietnam. METHODS: A randomized, open-label trial was conducted comparing the efficacy of a two-day regimen of ARPQ (~2.8 mg/kg artemisinin plus ~17.1 mg/kg of piperaquine per day) and a three-day regimen of ASAQ (~4.7 mg/kg of artesunate plus ~12.6 mg/kg of amodiaquine per day) for the treatment of children and adults with uncomplicated falciparum malaria. Primary efficacy endpoint was day 42, PCR-corrected, parasitological cure rate. Secondary endpoints were parasite and fever clearance times and tolerability. RESULTS: Of 128 patients enrolled, 63 were administered ARPQ and 65 ASAQ. Of the patients who completed the 42 days follow-up period or had a recurrence of malaria, 55 were on ARPQ (30 children, 25 adults) and 59 were on ASAQ (31 children, 28 adults). Recrudescent parasitaemia was PCR-confirmed for one patient in each treatment group, with cure rates at day 42 of 98% (95% CI: 88-100) for both forms of ACT. The median parasite clearance time was significantly slower in the ARPQ group compared with the ASAQ group (48 h vs. 36 h, P<0.001) and fever clearance times were shorter in the ASAQ group (12 h vs. 24 h, P=0.07). The two forms of ACT were well tolerated with no serious adverse events. CONCLUSION: Both forms of ACT were highly efficacious in the treatment of uncomplicated P. falciparum malaria. Although the two-day course of ARPQ was equally as effective as the three-day course of ASAQ, parasite and fever clearance times were shorter with ASAQ. Further studies are warranted in different regions of Vietnam to determine the nationwide efficacy of ASAQ. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number, ACTRN12609000816257.",1
12789,22748590,"Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial","""BACKGROUND: The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection. METHODS: This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586. FINDINGS: 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89?5%] vs 308 patients [86?8%], adjusted difference 3?0%, 95% CI -1?9% to 7?8%). Both regimens had favourable safety and tolerability; 13 (3?7%) versus 18 (5?1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 ?mol/L vs 260 ?mol/L, p=0?006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 ?mol/L vs 7 ?mol/L). INTERPRETATION: If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment. FUNDING: Gilead Sciences.""",1
12790,22748702,Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial,"""BACKGROUND: Apremilast, a small-molecule inhibitor of phosphodiesterase 4, works intracellularly to modulate proinflammatory and anti-inflammatory mediator production, and doses of 20 mg twice daily have shown efficacy in the treatment of moderate to severe plaque psoriasis in a 12-week phase 2 study. We assessed the clinical efficacy and safety of different doses of apremilast in the treatment of patients with moderate to severe plaque psoriasis. METHODS: In this phase 2b, multicentre, randomised, placebo-controlled, dose-ranging study, patients (aged ?18 years) with moderate to severe psoriasis were randomly assigned (in a 1:1:1:1 ratio) to receive oral placebo or apremilast 10, 20, or 30 mg twice daily at 35 US and Canadian sites between Sept 24, 2008, and Oct 21, 2009. At week 16, patients in the placebo group were assigned apremilast 20 or 30 mg twice daily until week 24. Randomisation was generated with a permuted-block randomisation list via interactive voice response system. For the first 16 weeks, treatment assignment was concealed from both investigators and participants. During weeks 16-24, investigators and participants all knew that treatment was active, but the dose was concealed. The primary endpoint was the proportion of patients achieving at least 75% reduction from baseline psoriasis area and severity index (PASI-75) at week 16. Analyses were by intention to treat; missing values were imputed by last-observation-carried-forward. This trial is registered with ClinicalTrials.gov, number NCT00773734. FINDINGS: 89 patients were randomly assigned apremilast 10 mg, 87 apremilast 20 mg, and 88 apremilast 30 mg twice daily; 88 were assigned placebo. At week 16, PASI-75 was achieved in five patients (6%) assigned placebo, ten (11%) assigned apremilast 10 mg, 25 (29%) assigned 20 mg, and 36 (41%) assigned 30 mg. Apremilast 10 mg did not differ significantly from placebo in achievement of the endpoint (odds ratio 2?10; 95% CI 0?69-6?42); for both apremilast 20 mg (6?69; 2?43-18?5; p<0?0001) and apremilast 30 mg (11?5; 4?24-31?2; p<0?0001), the differences from placebo were significant. Most adverse events (96%) were mild or moderate; at least 5% of patients had nausea, upper respiratory tract infection, diarrhoea, nasopharyngitis, headache, arthralgia (placebo), gastroenteritis, or dyspepsia. Eight serious adverse events occurred (three each, placebo and apremilast 20 mg; two, apremilast 30 mg); none were judged to be related to apremilast. Apremilast had no apparent effect on the results of haematological, urinalysis, immunological or inflammation, serum chemistry, or electrocardiographic tests. INTERPRETATION: Apremilast, given orally at 20 or 30 mg twice daily, seems to be efficacious, safe, and tolerable for patients with moderate to severe plaque psoriasis. Our results support continuing, longer-term studies. FUNDING: Celgene Corporation.""",1
12791,22752858,Safety analysis of fidaxomicin in comparison with oral vancomycin for Clostridium difficile infections,"Fidaxomicin is a novel macrocyclic antibiotic recently approved by the US Food and Drug Administration for the treatment of Clostridium difficile-associated diarrhea in adults. We reviewed safety data from nonclinical studies and clinical trials (phases 1, 2A, and 3) with fidaxomicin. In nonclinical studies, fidaxomicin was administered orally at approximately 1 g/kg/d to dogs for up to 3 months with no significant target-organ toxicities observed. A total of 728 adults have received oral fidaxomicin in clinical trials to date: 116 healthy volunteers and 612 patients with C. difficile infection. In phase 3 clinical trials, fidaxomicin was well tolerated, with a safety profile comparable with oral vancomycin. There were no differences in the incidence of death or serious adverse events between the 2 drugs. Fidaxomicin appears to be well tolerated. Continued monitoring of adverse events in the postmarketing setting will provide additional information about the full safety profile of fidaxomicin.",1
12792,22760756,[Fulminant hepatic failure due to tuberculostatic drugs: case report],"Hepatoxicity of isoniazid, mainly in association with rifampin, is a rare secondary effect of tuberculostatic treatment. In the United States, it accounts for 0.2% of all pediatric orthotropic liver transplant, and 14% of transplants for drug hepatotoxicity. We report the case of a 10 year-old patient who presented with acute liver failure requiring orthotropic liver transplant after forty days of tuberculostatic treatment with isoniazid, rifampin and pyrazinamide.",1
12793,22763150,"Efficacy of leflunomide 100mg weekly compared to low dose methotrexate in patients with active rheumatoid arthritis. Double blind, randomized clinical trial","""OBJECTIVE: To determine the clinical efficacy and safety of Leflunomide (LFN) 100 mg/week compared to low dose Methotrexate (MTX) 10 mg/week in a double-blind, randomized, controlled trial with 52 weeks of follow up in Rheumatoid Arthritis (RA) patients. PATIENTS AND METHODS: Patients who met ARC1987 criteria for RA were included. All patients had medical records, including laboratory tests and hand X-rays. Clinical evaluations for improvement and ACR and EULAR response criteria were performed. Statistical analysis for independent's samples between both groups defined a P value of </=.05. Safety was evaluated by comparing the proportion of adverse events (AE) registered. RESULTS: Of 90 patients screened; five were withdrawn; the remaining 85 patients were randomised: 43 LFN and 42 MTX. Sixty-three patients completed the study; 72% in the LFN group and 74.4% in the MTX group. ACR20 improvement criteria were achieved by LFN group in 90.3%, and in MTX 78.1% (P=.14) at week 52. EULAR improvement criteria applied at the end point showed a DAS28 score for the LFN group of 3.45, and for the MTX group was 3.67(P=.43). Total withdrawals, including loss during follow up, AE and lack of efficacy for each group was 12 patients in the LFN group, and 10 patients in the MTX group. Regarding safety, no serious AE of a life threatening nature were reported. CONCLUSIONS: These outcomes confirm that LFN 100 mg/week offers an adequate and sustained improvement effect on the clinical manifestations of RA, similar to low dose treatment with MTX 10 mg/every week after 52 weeks of follow up; it may be a good therapeutic option alone or in combination with others anti-rheumatic drugs.""",1
12794,22763953,Safety of saxagliptin: rationale for and design of a series of postmarketing observational studies,"PURPOSE: To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. METHODS: We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. RESULTS: Forthcoming. CONCLUSIONS: This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.",1
12795,22766517,An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer,"BACKGROUND: Both sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib. METHODS: Two sequential prospective single arm phase II studies investigated either 12 weeks of sunitinib (n=43) or pazopanib (n=34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800 mg once daily (OD)) and sunitinib (50 mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12 weeks of therapy. RESULTS: There was no significant difference in the overall number of toxic events (grade 1-4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p>0.05). Increased grade 2-4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11-2.56] p<0.03). Sunitinib was associated with an increased grade 2-4 mucositis (16% versus 0% p=0.02) and fatigue (42% versus 15% p=0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p=0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p<0.05). There was no difference in the occurrence of asymptomatic toxicity. CONCLUSION: This indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient's choice. Further comparative data from randomised trials are awaited.",1
12796,22768265,Use of intravenous peramivir for treatment of severe influenza A(H1N1)pdm09,"""Oral antiviral agents to treat influenza are challenging to administer in the intensive care unit (ICU). We describe 57 critically ill patients treated with the investigational intravenous neuraminidase inhibitor drug peramivir for influenza A (H1N1)pdm09 [pH1N1]. Most received late peramivir treatment following clinical deterioration in the ICU on enterically-administered oseltamivir therapy. The median age was 40 years (range 5 months-81 years). Common clinical complications included pneumonia or acute respiratory distress syndrome requiring mechanical ventilation (54; 95%), sepsis requiring vasopressor support (34/53; 64%), acute renal failure requiring hemodialysis (19/53; 36%) and secondary bacterial infection (14; 25%). Over half (29; 51%) died. When comparing the 57 peramivir-treated cases with 1627 critically ill cases who did not receive peramivir, peramivir recipients were more likely to be diagnosed with pneumonia/acute respiratory distress syndrome (p = 0.0002) or sepsis (p = <0.0001), require mechanical ventilation (p = <0.0001) or die (p = <0.0001). The high mortality could be due to the pre-existing clinical severity of cases prior to request for peramivir, but also raises questions about peramivir safety and effectiveness in hospitalized and critically ill patients. The use of peramivir merits further study in randomized controlled trials, or by use of methods such as propensity scoring and matching, to assess clinical effectiveness and safety.""",1
12797,22771137,Safety and efficacy of ezogabine (retigabine) in adults with refractory partial-onset seizures: Interim results from two ongoing open-label studies,"Interim results of two open-label extension studies assessed ezogabine/retigabine safety and tolerability for partial-onset seizures. At data cutoff, 336 (60%) patients received ? 12 months' open-label ezogabine/retigabine. The most common TEAEs included dizziness (22%), somnolence (19%), headache (14%), and fatigue (10%). Change in seizure frequency from baseline (median reduction, 53%) and responder rate (52.5%) was maintained in patients remaining on ezogabine/retigabine. Continuous 6-month and 12-month seizure-free rates for ezogabine/retigabine exposures ? 12 months were 13.1% and 7.1%, respectively.",1
12798,22772698,Angioedema occurring in patient prescribed iloperidone and haloperidol: a cross-sensitivity reaction to antipsychotics from different chemical classes,,1
12799,22777212,Advice for travelers,,1
12800,22777303,Vismodegib (Erivedge) for basal cell carcinoma,,1
12801,22782458,4-aminopyridine toxicity: a case report and review of the literature,"INTRODUCTION: 4-Aminopyridine (4-AP) selectively blocks voltage-gated potassium channels, prolongs the action potential, increases calcium influx, and subsequently, enhances interneuronal and neuromuscular synaptic transmission. This medication has been studied and used in many disease processes hallmarked by poor neuronal transmission in both the central and peripheral nervous systems including: multiple sclerosis (MS), spinal cord injuries (SCI), botulism, Lambert-Eaton syndrome, and myasthenia gravis. It has also been postulated as a potential treatment of verapamil toxicity and reversal agent for anesthesia-induced neuromuscular blockade. To date, there have been limited reports of either intentional or accidental 4-AP toxicity in humans. Both a case of a patient with 4-AP toxicity and review of the literature are discussed, highlighting commonalities observed in overdose. CASE REPORT: A 37-year-old man with progressive MS presented with diaphoresis, delirium, agitation, and choreathetoid movements after a presumed 4-AP overdose. 4-AP concentration at 6 h was 140 ng/mL. With aggressive benzodiazepine administration and intubation, he recovered uneventfully. DISCUSSION: The commonalities associated with 4-AP toxicity conforms to what is known about its mechanism of action combining cholinergic features including diaphoresis, altered mental status, and seizures with dopamine-related movement abnormalities including tremor, choreoathetosis, and dystonia. Management of patients poisoned by 4-AP centers around good supportive care with definitive airway management and controlling CNS hyperexcitability aggressively with gamma-aminobutyric acid agonist agents. Adjunctive use of dopamine antagonists for extrapyramidal effects after sedation is a treatment possibility. As 4-aminopyridine recently received Federal Drug Administration approval for the treatment of ambulation in patients with MS, physicians should be keenly aware of its presentation, mechanism of action, and management in overdose.",1
12802,22789729,Thalidomide-induced acute cholestatic hepatitis: case report and review of the literature,Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.,1
12803,22795685,Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females,"""OBJECTIVE: To investigate the impact of low- and ultralow-dose regimens of flutamide on liver function of young hyperandrogenic females. DESIGN: A 10-year surveillance study. SETTING: University teaching hospital. PATIENT(S): Two hundred three hyperandrogenic young females (mean age: 20.9 +/- 4.9 years). INTERVENTION(S): Inclusion criterion was receiving low- or ultralow-dose of flutamide as antiandrogenic treatment. Patients were categorized into Groups A and B, according to the administered dose (Group A = 62.5 mg/daily, Group B = 125 mg/daily). The two groups were further subdivided into subgroups (A1, A2, B1, B2) depending on the coadministration of estroprogestagen oral contraceptives (OCs) (A2, B2). MAIN OUTCOME MEASURE(S): Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were periodically evaluated and used as markers of hepatotoxicity. RESULT(S): Mild-to-severe increase of circulating AST/ALT was detected in 19 (9.4%; 95% CI = 5.9%-14.4%) patients during the first year of treatment (mild = 16 [7.9%, 95% CI = 4.7%-12.7%], moderate = 2 [0.9%, 95% CI = 0.1%-3.9%], severe = 1 [0.5%, 95% CI = 0.0%-3.1%]). No statistical differences were observed in relation to flutamide dose regimens and coadministration of OC. The median time to hypertransaminasemia was 12 weeks (range: 2-48) with no difference between Group A and Group B. A significant correlation was observed between hepatotoxicity and pretreatment BMI, ALT basal level, and AST basal level. CONCLUSION(S): Hepatotoxicity is a rare but possible event using low- and ultralow-dose regimens of flutamide. We need larger study populations in order to identify risk patterns for hepatotoxicity development.""",1
12804,22801677,Lemons for obesity,,1
12805,22802554,Multicenter trial of desirudin for the prophylaxis of thrombosis: an alternative to heparin-based anticoagulation (DESIR-ABLE),"Desirudin, a subcutaneously (SC) administered direct thrombin inhibitor, is indicated for prevention of venous thromboembolic events (VTEs) after total joint replacement surgery. DESIR-ABLE (multicenter trial of desirudin for the prophylaxis of thrombosis: an alternative to heparin-based anticoagulation) was a multicenter, open-label, single-arm study of hospitalized patients requiring VTE protection designed to extend the safety profile for desirudin to include a broad population of perioperative/critically ill patients. The primary end point was major bleeding. A total of 516 patients undergoing major surgery (378, 73%) or who were medically ill with prolonged immobility (138, 27%) were enrolled at 19 centers and received desirudin 15 mg Q12H. Many patients had high-risk features for bleeding and thrombosis such as thrombocytopenia (<100 x 10(9)/mL, n = 50), severe obesity (body mass index >35, n = 145), and renal impairment (creatinine clearance <60 mL/min, n = 292). There were no major bleeds and no VTE-related deaths in this study. The DESIR-ABLE demonstrated the safety of desirudin in critically ill perioperative and medical patients. Trials in specific surgical or medically ill patients are needed to confirm these findings.",1
12806,22804484,Fatal fulminant hepatitis following administration of clarithromycin in a patient chronically treated with antipsycotic drugs,"BACKGROUND: Clarithromycin is a widely used antibiotic, especially prescribed for the treatment of respiratory tract infections, The drug is generally well tolerated. It is described as a very rare cause of fulminant liver failure. CASE PRESENTATION: Herein we report a case of fatal fulminant hepatitis in a young patient. In his past history the patient presented documented episodes of hypertransaminasemia. CONCLUSIONS: This case confirms that clarithromycin although very rarely, can be a cause of fulminant hepatitis, especially in patients with pre-existing liver damage. Although the presumption that clarithromycin hepatotoxicity is dose related is reasonable, an immune-toxicologic hypothesis cannot be excluded.",1
12807,22805291,"Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial","""BACKGROUND: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. METHODS: We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. FINDINGS: We enrolled 206 patients (median age 58?5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1?81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. INTERPRETATION: The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. FUNDING: GlaxoSmithKline.""",1
12808,22806399,"Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study","""OBJECTIVE: To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA). METHODS: This phase II, multicenter, randomized, double-blind, placebo-controlled study included the following: a 12-week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12-week treatment-extension phase, with patients in the placebo group re-randomized to receive apremilast; and a 4-week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms. RESULTS: Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment-extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re-randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment-extension phase (68.3%) reported ? 1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported. CONCLUSION: Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.""",1
12809,22808112,Liver enzyme abnormalities and associated risk factors in HIV patients on efavirenz-based HAART with or without tuberculosis co-infection in Tanzania,"OBJECTIVES: To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. METHODS AND FINDINGS: A total of 473 treatment naive HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. CONCLUSIONS: Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians.",1
12810,22809883,Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression,"""BACKGROUND: Drotrecogin alfa (activated) was approved for use in severe sepsis in 2001 on the basis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, but controversies about its effectiveness remain. We aimed to assess effectiveness and safety of use of this drug in the past 10 years and compare them with the original PROWESS results. METHODS: We searched PubMed, Embase, Ovid, Cochrane Library, Evidence-Based Medicine, and the American College of Physicians Journal Club databases for experimental and analytical studies of drotrecogin alfa (activated) in adults with severe sepsis until Jan 31, 2012. We calculated adjusted risk ratios for effectiveness and safety outcomes with random-effects models. We did a metaregression to assess the effect of severity of illness on the risk of death and the risk of bleeding associated with drotrecogin alfa (activated). FINDINGS: We included nine controlled trials (41,401 patients) and 16 single-group studies (5822 patients) in effectiveness analyses and 20 studies (8245 patients) in safety analyses. Hospital mortality was reduced by 18% with drotrecogin alfa (activated) compared with controls (relative risk 0?822, 95% CI 0?779-0?867; p<0?0001; I(2)=40%). This mortality reduction was much the same as was noted in PROWESS (0?851, 0?740-0?979), but smaller than that of patients in PROWESS with high disease severity (0?708, 0?590-0?849). Propensity-adjusted studies also showed a significant mortality reduction with lower heterogeneity (0?844, 0?800-0?891; p<0?0001, I(2)=18%). These findings were not changed by the addition of PROWESS-SHOCK results. Metaregression showed greater benefits of drotrecogin alfa (activated) with increasing control mortality (p=0?01) and more severe disease (p=0?04). Hospital mortality for single-group studies of drotrecogin alfa (activated) was 41% (95% CI 35-48), and was higher than that noted in PROWESS at 31% (27-36; p<0?0001). The serious bleeding rate with drotrecogin alfa (activated) was 5?6% (4?5-6?9), which was higher than the 3?5% (2?5-5?0) noted in PROWESS (p=0?003), but similar to that reported in PROWESS high disease severity (p=0?073). INTERPRETATION: Real-life use of drotrecrogin alfa (activated) was associated with significant reduction in hospital mortality and increased rates of bleeding in patients with severe sepsis. Our effectiveness findings were in line with the PROWESS trial but not with the PROWESS-SHOCK trial. FUNDING: None.""",1
12811,22818365,Symptoms and course of intoxication with mesuximide--a case report,"We report on a 31-year-old, female patient who presented with somnolence due to an intoxication by the antiepileptic drug, mesuximide (MSM). The serum concentration of its metabolite n-desmethyl-mesuximide (85.7 mg/L) was above the so-called therapeutic range (10-40 mg/L) but below the concentration range that led to an impairment of consciousness in previous cases according to the German SPC (>150 mg/L). The symptoms remitted quickly under hemodialysis. In somnolent patients treated with MSM, the treating physicians should be aware of drug intoxication as a possible etiology. Therefore, the serum concentration should be measured early. Due to the, often, long latency until the results are available, treatment initiation may be necessary based on suspicion.",1
12812,22820213,The propylthiouracil dilemma,"""PURPOSE OF REVIEW: To bring to the attention of healthcare professionals the additional information on propylthiouracil (PTU)-related hepatotoxicity, based on a reanalysis of medical files reported to the Food and Drug Administration (1982-2008) for acute liver failure in PTU-treated hyperthyroid patients, and propose recommendations for the clinical use of PTU. Thirteen files of PTU-related severe liver adverse effects were analyzed for the pediatric population, seventeen for nonpregnant adults and two for pregnant women. RECENT FINDINGS: The recent findings showed that the daily PTU dose administered was high in the children, with a mean of 300 mg/day for an average 10-year-old individual. With regard to treatment duration, PTU administration lasted for at least 4 months in 75% of pediatric cases. Similarly, in a majority of adult cases (64%), PTU-induced liver injury occurred after a relatively long treatment period (4 months to >1 year). SUMMARY: PTU should not be used in children, in whom methimazole (MMI) represents the logical alternative. In adults, PTU should be restricted to those rare patients with Graves' disease for whom no better alternative can be offered and in patients with thyroid storm. For the special circumstance of pregnancy, PTU is the preferred choice during early gestation; switching back to MMI during later gestational stages remains a matter of clinical judgment. It is unknown whether liver function tests monitoring is worthwhile to prevent life-threatening, PTU-related hepatotoxicity.""",1
12813,22824772,Fatal hepatitis B reactivation treated with entecavir in an isolated anti-HBs positive lymphoma patient: a case report and literature review,"Hepatitis B virus (HBV) reactivation is a well-recognized complication that occurs in lymphoma patients who undergo chemotherapy. Only very few cases of HBV reactivation in patients with isolated antibody against hepatitis B surface antigen (anti-HBs) have been reported. We present a case of a 78-year-old woman diagnosed with diffuse large B cell non-Hodgkin's lymphoma who only displayed a positive anti-HBs, as the single possible marker of occult HBV infection, before starting therapy. She was treated with several chemotherapeutic regimens (including rituximab) for disease relapses during 3 years. Forty days after the last cycle of chemotherapy, she presented with jaundice, markedly elevated serum aminotransferase levels, and coagulopathy. HBV serology showed positivity for HBsAg, anti-HBc and anti-HBs. HBV DNA was positive. Antiviral treatment with entecavir was promptly initiated, but the patient died from liver failure. A review of the literature of HBV reactivation in patients with detectable anti-HBs levels is discussed.",1
12814,22825690,Pertuzumab (Perjecta) for HER2-positive metastatic breast cancer,,1
12815,22827594,Paracetamol intoxications: a retrospective population-based study in Iceland,"OBJECTIVE: Paracetamol is the most common cause of acute liver failure (ALF) in many countries. Much data on paracetamol toxicity originate from liver transplant centers and tertiary referral institutions. The authors analyzed the population-based annual incidence of paracetamol overdoses and ALF, and described the risk factors for hepatotoxicity. METHODS: A search was undertaken for the diagnosis of paracetamol overdoses in the diagnoses registry of the National University Hospital of Iceland from 2004 to 2009 serving a population of 219,249 inhabitants. Relevant information was collected from medical records. RESULTS: A total of 1913 drug-related poisoning episodes were identified and reviewed, 352 (18%) involved paracetamol overdoses. The annual incidence of paracetamol overdoses declined from 30.0 (2004) to 16.0/100,000 per year (2009) (p < 0.05). The female/male ratio was 3.0 and the largest age group was 16-25 years. After the initial examination, 26% were discharged home. Hospitalized index visits were 182 with accidental overdoses constituting 16 (9%) with no gender difference. Compared with intentional overdose the accidental group had higher aminotransferases (p < 0.005). ALF occurred in 3.8% (7/182) of the index visits and the incidence was 0.7/100,000 per year. In the intentional group, 1.2% (2/163) developed ALF versus 25% (4/16) of the accidental group (p = 0.001). Only one patient died from ALF and none underwent liver transplantation. CONCLUSION: The annual incidence of paracetamol overdoses was high in this population-based study but declined. Young females with intentional overdose accounted for most of the cases, whereas accidental overdoses were more common in older patients. The occurrence of ALF was low and mostly associated with accidental overdose.",1
12816,22830672,Acute liver failure resulting from discontinuation of nucleoside analogues in chronic hepatitis B patients: a report of two cases,"Lamivudine, adefovir, telbivudine, and entecavir are nucleoside analogues that can inhibit hepatitis B virus replication and are licensed in China by the Food and Drug Administration. This study presents the cases of 2 patients who were chronically infected with HBV and suffered hepatic failure resulting from withdrawal of telbivudine and adefovir, respectively.",1
12817,22833576,HLA-B*1502 screening in carbamazepine and lamotrigine candidates of Asian background,,1
12818,22834474,Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome,"INTRODUCTION: Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction. AREAS COVERED: This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages. EXPERT OPINION: Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.",1
12819,22835967,Acute Ibuprofen intoxication: report on a case and review of the literature,"""A fatality following the ingestion of ibuprofen is reported. Ibuprofen is a prototypical nonsteroidal anti-inflammatory drug widely prescribed as an analgesic, anti-inflammatory, and antipyretic agent. To date, there are few case reports of fatal overdose with ibuprofen, following ibuprofen self-poisoning or accidental overdose. We report the case of a 51-year-old man with medical history of psychiatric disease, who was brought to the emergency department by ambulance with a chief complaint of having taken large amounts of drugs in a suicide attempt.Multiple empty containers of medications (ibuprofen, meloxicam, celecoxib, risperidone, citalopram, ketorolac, bromazepam) were found at the scene. He died 4 hours after admission to the emergency department, despite vigorous supportive care. Toxicological analyses were performed using a gas chromatography/mass spectrometry technique. The estimated ibuprofen concentration in the plasma was 600 mug/mL; gastric content was 200 mug/mL for this compound. Our report describes results of the forensic investigation and discuss the review of the literature.""",1
12820,22836071,Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage),"""BACKGROUND: We evaluated the safety and efficacy of the 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pitavastatin in patients with mild-to-moderate increased levels of hepatic enzymes. METHODS AND RESULTS: In this 12-week, prospective, randomized, open-label, active drug-controlled, and dose-titration study, 189 subjects with elevated low-density lipoprotein cholesterol (>/=3.36 mmol/L) and alanine transaminase (ALT; x1.25>/= and </=x2.5 ULN; 50-100 IU/L) concentrations, but nonalcoholic and serologically negative for viral hepatitis markers at screening, were randomized to 12 weeks of treatment with pitavastatin 2-4 mg/day (PITA, n = 97) or atorvastatin 10-20 mg/day (ATOR, n = 92). Pitavastatin and atorvastatin equally reduced low-density lipoprotein cholesterol concentrations (-34.6 +/- 16.0% and -38.1 +/- 16.2%, respectively, P < .0001 each by analysis of variance). Seven (n = 4 PITA, n = 3 ATOR) and 10 (n = 5 PITA, n = 5 ATOR) patients experienced episodes of ALT >100 IU/L at weeks 4 and 12, respectively, with one patient in each group excluded because of severe ALT elevation >3x ULN (>120 IU/L) at week 4. The 135 patients with persistently increased ALT concentrations at screening and randomization showed significant reductions in ALT after 12 weeks of treatment with PITA (n = 68, -8.4%) or ATOR (n = 67, -8.9%; P < .05, analysis of variance). Serial nonenhanced computed tomography in 38 subjects (n = 18 PITA, n = 20 ATOR) showed that both statins reduced the severity of hepatic steatosis, especially in subjects with clear hepatic steatosis at baseline (n = 9 PITA, n = 10 ATOR). Statin treatment of another 38 subjects with spontaneous normalization of ALT at randomization had little effect on ALT levels but did not induce severe ALT elevation (>100 IU/L). CONCLUSIONS: Conventional doses of pitavastatin and atorvastatin effectively and safely reduce elevated hepatic enzyme concentrations.""",1
12821,22841133,Mercaptopurine-induced hepatoportal sclerosis in a patient with Crohn's disease,"""Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.""",1
12822,22841985,Drug induced autoimmune hepatitis and TNF-alpha blocking agents: is there a real relationship?,"Hepatotoxicity is an expected side effect of tumour necrosis factor-alpha (anti-TNF-alpha) blocking agents including, infliximab, etanercept and adalimumab. Although mild to moderate elevations of liver enzymes have been recognised after the use of these agents, severe hepatitis is rarely reported. Reactivation of viral hepatitis and drug induced liver injury is two main causes of liver dysfunction in these patients. A broad spectrum, ranging from minor immunological alterations to systemic autoimmune disease, has been reported during treatment with anti-TNF-alpha. Therefore, in recent studies TNF-alpha blocking agents have been considered a potential cause of drug induced autoimmune hepatitis. Taking into account the advances in the field of hepatology, this review summarizes the general characteristics of anti-TNF-alpha induced liver injury and autoimmune hepatitis.",1
12823,22844299,A fatal case of nafcillin-induced hepatotoxicity: a case report and the literature review,"Background. Drug-induced hepatotoxicity (DIH) is quite common, and there are several recommendations for its treatment based upon its etiology. DIH may range from mild and subclinical to fulminant liver failure and death. Even though there is extensive list of drugs causing DIH, antibiotics, as a class of drugs, are the most common cause of DIH. Here, we present a fatal case of nafcillin-induced hepatotoxicity confirmed by liver biopsy, with total bilirubin peaking to 21.8?mg/dl and subsequent further extensive evaluation for hepatic injury turning out to be negative.",1
12824,22850321,Temozolomide-related idiosyncratic and other uncommon toxicities: a systematic review,"Temozolomide (TMZ)-related idiosyncratic and other uncommon toxicities have been reported. To better characterize these toxicities and to identify any associated risk factors, we performed a systematic review. We searched the PubMed database, limited to the English language, published between 1999 and December 2011. We selected only those articles in which TMZ was temporally related and was the sole or main contributing chemotherapeutic drug to idiosyncratic drug reactions (IDRs) and other uncommon toxicities. Hematological IDRs are biopsy-proven aplastic anemia or grade V toxicity or grade IV toxicity with slow and incomplete hematological recovery. Seventy-three cases were identified, including 21 hematological IDRs, 31 nonhematological IDRs and uncommon infections, and 21 second primary cancers. With a caveat of publication and reporting bias, the following observations could be made. The hematological IDRs predominantly occurred in female patients (exact binomial two-tailed, P=0.0041) and most patients were receiving TMZ concomitantly with radiotherapy for glioma. The median duration of exposure to TMZ was 30 days and the median cumulative TMZ exposure was 2250 mg/m (range, 500-6900 mg/m). The sex predilection was not evident in nonhematological IDRs and other uncommon toxicities. TMZ-induced pneumonitis and cholestatic hepatitis are emerging as a nonhematological hypersensitive reaction and IDR, respectively. For TMZ-related myelodysplasia or leukemia, the cumulative dose of TMZ ranged from 1400 to 30 000 mg/m. The cumulative dose of TMZ was lower and latency was shorter with a previous exposure to other leukemogenic drugs, suggesting that TMZ may have augmented the leukemogenic potential of other drugs. Early appearance of profound myelosuppression during the course of TMZ and concurrent radiotherapy could be a hematological IDR, which warrants prompt investigations to exclude aplastic anemia. Myelodysplasia or leukemia developed after a median TMZ exposure of 15 g/m.",1
12825,22850787,Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases,"Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1? antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1? antibody are in clinical trials.",1
12826,22853986,Safety and efficacy of transition from systemic prostanoids to inhaled treprostinil in pulmonary arterial hypertension,"Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ? 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.",1
12827,22855434,Transient reactivation of occult hepatitis B virus infection despite lamivudine prophylaxis in a patient treated for non-Hodgkin lymphoma,A female patient with non-Hodgkin lymphoma who tested positive for surface antigen of the hepatitis B virus and negative for hepatitis B core antibody experienced a reactivation of occult HBV infection 20 months after rituximab discontinuation despite lamivudine prophylaxis covering the 4 months of rituximab administration and the subsequent 12 months.,1
12828,22856423,[Levofloxacin hepatotoxicity. Higher risk in diabetics?],"Levofloxacin, commonly used in medical practice, is prescribed to treat pneumonia in patients with comorbidities. Although generally well tolerated and safe, it has a well-known, but rarely reported, undercharacterized and ill-identified hepatotoxicity, with an unknown signature. With cases of fulminant hepatitis, cholestasis episodes reveal an apparently benign progression. Its capability of interference with the glucidic metabolism is also well-known, and the susceptibility factors to these events include age, presence of multiple pathologies and polymedication. The link between Diabetes Mellitus and hepatotoxicity has not yet been identified. Nonetheless, reports of several cases in literature along with the identification of two cases in insulin-treated diabetics, lead to believe that this is a higher-risk group.",1
12829,22857866,[Methimazole-induced liver injury],,1
12830,22861496,Safety and efficacy evaluation of ambrisentan in pulmonary hypertension,"INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, which can lead to right heart failure and death. Endothelin-1 binding ETA and ETB receptors seem to play a critical role in the pathogenesis and progression of the disease, and oral endothelin receptor antagonists (ERAs) have been shown to be an effective treatment. Bosentan and ETA-selective ambrisentan are the ERAs currently available for PAH treatment. AREAS COVERED: On the basis of the analysis of the literature, this paper addresses the efficacy and safety of ambrisentan in the treatment for PAH. EXPERT OPINION: Ambrisentan has shown an efficacy comparable with other ERAs. Compared with bosentan, ambrisentan seems to have a better safety profile with regards to hepatic safety and drug-drug interactions. On the other hand, ambrisentan shows a higher rate of other adverse events, such as nasal congestion and peripheral edema. Ambrisentan is a viable option for PAH treatment. However, there is still a need for more robust data about long-term mortality, treatment in non-PAH pulmonary hypertension (PH) (such as PH due to left heart disease and PH due to chronic hypoxic lung diseases) and combination therapy.",1
12831,22863840,"Prevention of nausea and vomiting associated with stem cell transplant: results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens","Uncontrolled delayed nausea and vomiting remains a problem after high-dose preparative regimens used for autologous and allogeneic hematopoietic stem cell transplants. Recently, aprepitant was approved for highly and moderately emetogenic chemotherapy, and, in particular, is effective for decreasing delayed emesis. To evaluate its safety and efficacy in the transplantation setting, we performed a randomized, placebo-controlled, phase 3 trial of aprepitant in combination with ondansetron and dexamethasone in patients treated with ablative preparative regimens. Patients were randomized to receive oral aprepitant or placebo daily with oral ondansetron and dexamethasone during and for 3 days after the completion of the preparative regimen in this prospective randomized, double-blind study. The primary objective was complete response (CR) rate, defined as no emesis with no or mild nausea. Other endpoints included number of emetic episodes, nausea severity assessed using a 100-mm visual analog scale (VAS), the need for rescue antiemetics, and transplantation outcome, including regimen-related toxicity. One hundred eighty-one patients were randomized and 179 patients were eligible for analysis. Overall, CR rates were 81.9% for the aprepitant and 65.8% for the placebo arms (P < .001). Percentages of patients with no emesis all days were 73.3% for aprepitant and 22.5% placebo (P < .001). Mean VAS scores were 16.6 mm aprepitant and 16.9 mm placebo (NS), and there were no differences in the amount of rescue antiemetics used, regimen related toxicity, engraftment, or transplantation outcome. Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, whereas not increasing RRT or affecting short-term survival but had no significant impact on the use of PRN antiemetics, or overall VAS nausea scores.",1
12832,22871500,Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients,"""BACKGROUND & AIMS: Data on acute exacerbation and reactivation of chronic hepatitis C virus (HCV) infection following chemotherapy are very limited. We sought to characterize the episodes of acute exacerbation and viral reactivation of HCV infection in cancer patients. METHODS: The medical records of HCV-infected patients seen at our institution (2008-2009) were analyzed retrospectively. Acute exacerbation was defined as greater than 3-fold increase in serum level of alanine aminotransferase, and viral reactivation as ? 1 log(10) IU/ml increase of HCV viral load following chemotherapy. RESULTS: Acute exacerbation occurred in 33 (11%) of 308 patients with proven HCV infection. Patients with acute exacerbation more often had underlying hematological malignancies (73% vs. 29%; p<0.001) and lymphopenia (6% vs. 0%; p=0.01) than patients without it. In multivariate analysis, underlying hematological malignancies (p=0.02; odds ratio, 3.2; 95% confidence interval, 1.2-8.7) and use of rituximab (p=0.004; odds ratio, 4.2; 95% confidence interval, 1.6-10.9) were associated with acute exacerbation. Patients with acute exacerbation received higher median cumulative dose of rituximab than those without exacerbation. Discontinuation of chemotherapy due to liver dysfunction was more common in patients with acute exacerbation than in patients without it (45% vs. 11%; p<0.001). Eight (36%) of 22 patients with known pre- and post-chemotherapy viral load had viral reactivation. CONCLUSIONS: Acute exacerbation and reactivation of chronic HCV infection occur often after chemotherapy. Liver dysfunction can lead to discontinuation of potentially life-saving chemotherapy in nearly one-half of the patients with exacerbation of HCV infection.""",1
12833,22873505,Glatiramer acetate induced hepatotoxicity,"INTRODUCTION: Glatiramer acetate (Copaxone), a polypeptide has been approved for treating patients with active relapsing-remitting multiple sclerosis. CASE PRESENTATION: We report the first case of severe acute hepatitis after commencing treatment for multiple sclerosis with glatiramer acetate. A 31-year-old female with multiple sclerosis presented with anorexia, lethargy and jaundice five weeks after commencing glatiramer acetate. She had never received beta-interferon treatment. Investigations revealed a bilirubin of 0.109 mmol/L (0.002-0.02 mmoL/L) and prothrombin time of 21 secs (9-15 secs). Her liver function tests were normal before commencing glatiramer acetate. A liver biopsy performed approximately 6 weeks after commencement of glatiramer acetate showed predominantly centrilobular hepatocyte necrosis with portal-venous bridging, along with mild portal and interface hepatitis. The necrosis was not accompanied by an acute inflammatory or chronic inflammatory infiltrate. The features were not suggestive of autoimmune hepatitis but consistent with drug toxicity. The liver tests returned to normal within 2 months after cessation of glatiramer acetate. CONCLUSION: Physicians should be aware that glatiramer acetate can be associated with uncommon but yet significantly severe liver toxicity.",1
12834,22873531,Tofacitinib or adalimumab versus placebo in rheumatoid arthritis,"""BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. METHODS: In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). RESULTS: At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. CONCLUSIONS: In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).""",1
12835,22882018,Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies,"PURPOSE: To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures. METHODS: Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks. KEY FINDINGS: Seizure frequency was significantly reduced with ESL 800 mg (p < 0.0001) and 1,200 mg (p < 0.0001) compared to placebo. Median relative reduction in seizure frequency was, respectively, 35% and 39% (placebo 15%) and responder rate was 36% and 44% (placebo 22%). ESL was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant antiepileptic drugs (AEDs). Incidence of adverse events (AEs) and AEs leading to discontinuation were dose dependent. AEs occurred mainly during the first weeks of treatment, with no difference between groups after 6 weeks. Most common AEs (>10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. SIGNIFICANCE: Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.",1
12836,22883023,"Arsenic exposure through drinking water increases the risk of liver and cardiovascular diseases in the population of West Bengal, India","BACKGROUND: Arsenic is a natural drinking water contaminant affecting 26 million people in West Bengal, India. Chronic arsenic exposure causes cancer, cardiovascular disease, liver disease, neuropathies and ocular diseases. The aims of the present study were to assess bioindicators of hepatocellular injury as indicated by the levels of liver enzymes, to determine the auto immune status, as indicated by the amounts of anti-nuclear antibodies (ANA) and anti-dsDNA antibodies in their serum, and to predict cardiovascular risk in the arsenic exposed population. METHODS: Effect of chronic arsenic exposure on liver was determined by liver function tests. Autoimmune status was measured by measuring ANA and anti-dsDNA in serum. Inflammatory cytokines associated with increased cardiovascular disease risk, IL6, IL8 and MCP-1 were determined. RESULTS: Our results indicated that serum levels of bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase and ANA were increased in the arsenic exposed population. Serum levels of IL6 and IL8 also increased in the arsenic exposed group. CONCLUSIONS: Chronic arsenic exposure causes liver injury, increases the serum levels of autoimmune markers and imparts increased cardiovascular risk.",1
12837,22884162,Hepatic safety of caspofungin during treatment of invasive fungal diseases in elderly patients,,1
12838,22885033,Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Qu?bec,"BACKGROUND: Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Qu?bec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin �) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Qu?bec since 1994. METHODS: We recorded the clinical course of 78 Qu?bec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1 month of age (26 patients) and those treated before 1 month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter. FINDINGS: No hospitalizations for acute complications of HT1 occurred during 5731 months of nitisinone treatment, versus 184 during 1312 months without treatment (p<0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26 months, versus 7 late-treated patients (26%, p<0.001), and no early-treated patient (p<0.001). No early-treated patient has developed detectable liver disease after more than 5 years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p<0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia. INTERPRETATION: Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1 month had no detectable liver disease after more than 5 years.",1
12839,22886031,Tolerability of HIV integrase inhibitors,"PURPOSE OF REVIEW: This review discusses the available safety data for three integrase strand transfer inhibitors (INSTIs)--raltegravir, elvitegravir and dolutegravir--derived from studies in both HIV-infected and HIV-uninfected cohorts. RECENT FINDINGS: Phase 2 and 3 clinical trials show that all three INSTIs are well tolerated in treatment-naive and treatment-experienced patients with headache and gastrointestinal effects being the most commonly reported adverse events. Other nervous system (including neuropsychiatric) effects are often reported with INSTIs but are milder and less frequent than with efavirenz. Limited data suggest that effects upon lipid metabolism with raltegravir and dolutegravir are favourable compared with efavirenz and protease inhibitors, with more variable findings for elvitegravir because of coadministration with the boosting agent cobicistat. Cobicistat and dolutegravir have effects upon proximal renal tubular function causing mild-to-moderate creatinine elevation. Rare and severe events possibly related to INSTIs include systemic hypersensitivity reactions and rhabdomyolysis. SUMMARY: INSTIs are an important recent addition to the antiretroviral armamentarium, with good short-term and medium-term safety. Long-term data from ongoing clinical studies are needed for a definitive assessment of their safety profile.",1
12840,22891208,Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study,"BACKGROUND: Although fluoroquinolones are sometimes associated with mild, transient elevations in aminotransferase levels, serious acute liver injury is uncommon. Regulatory warnings have identified moxifloxacin as presenting a particular risk of hepatotoxicity. Thus, we examined the risk of idiosyncratic acute liver injury associated with the use of moxifloxacin relative to other selected antibiotic agents. METHODS: We conducted a population-based, nested, case-control study using health care data from Ontario for the period April 2002 to March 2011. We identified cases as outpatients aged 66 years or older with no history of liver disease, and who were admitted to hospital for acute liver injury within 30 days of receiving a prescription for 1 of 5 broad-spectrum antibiotic agents: moxifloxacin, levofloxacin, ciprofloxacin, cefuroxime axetil or clarithromycin. For each case, we selected up to 10 age- and sex-matched controls from among patients who had received a study antibiotic, but who were not admitted to hospital for acute liver injury. We calculated odds ratios (ORs) to determine the association between admission to hospital and previous exposure to an antibiotic agent, using clarithromycin as the reference. RESULTS: A total of 144 patients were admitted to hospital for acute liver injury within 30 days of receiving a prescription for one of the identified drugs. Of these patients, 88 (61.1%) died while in hospital. After multivariable adjustment, use of either moxifloxacin (adjusted OR 2.20, 95% confidence interval [CI] 1.21-3.98) or levofloxacin (adjusted OR 1.85, 95% CI 1.01-3.39) was associated with an increase in risk of acute liver injury relative to the use of clarithromycin. We saw no such risk associated with the use of either ciprofloxacin or cefuroxime axetil. INTERPRETATION: Among older outpatients with no evidence of liver disease, moxifloxacin and levofloxacin were associated with an increased risk of acute liver injury relative to clarithromycin.",1
12841,22892501,Sudden onset agranulocytosis and hepatotoxicity after taking methimazole,"Agranulocytosis is a rare adverse effect of methimazole. The usual duration of treatment prior to the onset of agranulocytosis is approximately 1 to 4 months, and can be as long as 1 year. Agranulocytosis together with hepatotoxicity is an extremely rare idiosyncratic side effect of methimazole treatment. We present an unprecedented case of a Grave's disease patient who showed a strong reaction to methimazole with obvious agranulocytosis and hepatotoxicity which developed only six days after administration. This case, along with a literature review, is offered with the aim to increase the awareness of physicians of sudden onset agranulocytosis and hepatotoxicity from methimazole.",1
12842,22895139,First-line gefitinib in patients aged 75 or older with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations: NEJ 003 study,"""INTRODUCTION: Recent studies have demonstrated that first-line treatment with gefitinib, an epidermal growth factor receptor (EFGR)-targeted tyrosine kinase inhibitor, is significantly superior to standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Meanwhile, the efficacy of gefitinib therapy among elderly populations diagnosed with EGFR-mutated NSCLC has not yet been elucidated. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations; generally, these patients have no indication for treatment with platinum doublets. METHODS: Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations, as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, were enrolled. The enrolled patients received 250 mg/day of gefitinib orally. RESULTS: Between January 2008 and May 2009, 31 patients were enrolled, all of whom were eligible. The median age was 80 (range, 75-87) years. Twenty-five patients (81%) were women, and 30 patients (97%) had adenocarcinoma. The overall response rate was 74% (95% confidence interval, 58%-91%), and the disease control rate was 90%. The median progression-free survival was 12.3 months. The common adverse events were rash, diarrhea, and liver dysfunction. One treatment-related death because of interstitial lung disease occurred. CONCLUSIONS: This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation. Considering its strong antitumor activity and mild toxicity, first-line gefitinib may be preferable to standard chemotherapy for this population.""",1
12843,22896000,Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation,"""Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m(2) twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.""",1
12844,22897075,"Probable hypersensitivity reaction to vancomycin associating rash, fever and neutropenia","We describe the case of a 54-year old woman with breast cancer who was treated by vancomycin for febrile neutropenia due to a methicillin-resistant Staphyloccocus epidermidis infection of a surgically implanted catheter. She developed an hypersensitivity reaction to vancomycin associating neutropenia, fever, skin rash and elevated liver enzymes following re-challenge with vancomycin after having been misdiagnosed with septic thrombophlebitis. Following this re-challenge, neutrophils count fell dramatically but promptly resolved after cessation of vancomycin.",1
12845,22898678,"Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial","""BACKGROUND: No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS: In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ?18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS: Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0?63, 60% CI 0?54-0?74; one-sided p=0?008): median PFS was 11?1 months (95% CI 7?7-14?0) for patients in the vandetanib group and 5?9 months (4?0-8?9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION: Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING: AstraZeneca.""",1
12846,22900786,Primaquine radical cure of Plasmodium vivax: a critical review of the literature,"""BACKGROUND: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax. METHODS: Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (?2.5 mg/kg), low (>2.5 mg/kg-?<?5.0 mg/kg) and high (? 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. RESULTS: Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n?=?44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n?=?82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR?=?0.60, 95%CI 0.33-1.09, p?=?0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR?=?0.14, 95%CI: 0.06-0.35, p?<?0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR?=?0.03 (95%CI: 0.01-0.13); p?<?0.0001). CONCLUSIONS: Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.""",1
12847,22901886,"Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial","""BACKGROUND: Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. METHODS: We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0?9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. FINDINGS: 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2?40 per patient per year in the placebo group, 1?24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0?0001), 1?46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0?0005), and 1?15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0?0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. INTERPRETATION: Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. FUNDING: GlaxoSmithKline.""",1
12848,22907181,In brief: transdermal rotigotine (Neupro),,1
12849,22908905,"Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia","BACKGROUND: Vaptans may correct hyponatraemia and mobilise ascites through an increased excretion of water. The effect on clinical outcomes is debated. AIM: To determine the effects of vaptans (tolvaptan, satavaptan and lixivaptan) on patients with cirrhosis and hyponatraemia or ascites. METHODS: Systematic review of randomised controlled trials. The primary outcome measure was mortality. Electronic and manual searches were combined (April 2012). Data were extracted from published reports, online information from the Food and Drug Administration website or obtained through correspondence with authors and pharmaceutical companies. The primary meta-analyses were performed using random effects models due to an expected clinical diversity. RESULTS: Twelve trials with a total of 2266 patients were included. Randomisation was adequate in all trials. Eight trials were double-blind. Random effects meta-analyses found no clear differences between vaptans and control groups regarding mortality (RR = 1.06, 95% CI = 0.90-1.26, I(2) = 0%), variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, or renal failure. Vaptans increased serum sodium levels (WMD = 1.8 mmol/L, 95% CI = 0.79-2.96) and lead to reductions in weight and the time to the first paracentesis. Vaptans increased the risk of adverse events (RR = 3.97, 95% CI = 1.78-8.83), including an excessive urine volume (RR = 9.96, 95% CI = 1.38-71.68). CONCLUSIONS: Vaptans have a small beneficial effect on hyponatraemia and ascites, but do not affect mortality, complications to cirrhosis or renal failure. The data do not support the routine use of vaptans in cirrhosis.",1
12850,22910896,Prospective evaluation of accuracy of liver biopsy findings in the identification of chemotherapy-associated liver injuries,"""OBJECTIVE To evaluate the accuracy of liver biopsy findings in preoperative assessment of chemotherapy-associated liver injuries (CALIs). DESIGN Prospective study. SETTING Tertiary care referral hospital. PATIENTS From July 1, 2007, to January 31, 2011, all patients with colorectal metastases receiving preoperative oxaliplatin- and/or irinotecan-based chemotherapy (?4 cycles) were considered for the present study. Patients underwent parenchymal biopsy before liver resection. Blinded CALI evaluation was performed on biopsy and resection specimens. INTERVENTION Liver resection. MAIN OUTCOME MEASURES Sensitivity, specificity, and accuracy of liver biopsy in CALI evaluation. RESULTS We included 100 patients. At specimen analysis, grade 2�or 3 steatosis was diagnosed in 30 patients; grade 2 or 3 sinusoidal dilatation, in 28; grade 2 hepatocellular ballooning, in 3; grade 2 or 3 lobular inflammation, in 25; and steatohepatitis in 19. Obesity was associated with grade 3 steatosis (20.8% vs 5.3%; odds ratio [OR], 4.74 [P�=�.03]) and steatohepatitis (33.3% vs 14.5%; OR, 2.96 [P�=�.04]). Oxaliplatin administration was associated with higher sinusoidal dilatation grade (P�=�.049). Mortality (2 cases) was increased among patients with steatohepatitis (10.5% vs 0; OR, 13.67 [P�=�.04]). Biopsy findings correctly predicted steatosis (sensitivity, 88.9%; accuracy, 93.0%) but had low sensitivity and accuracy for sinusoidal dilatation (21.4% and 63.0%, respectively), hepatocellular ballooning (16.0% and 69.0%, respectively), lobular inflammation (20.0% and 78.0%, respectively), and steatohepatitis (21.1% and 79.0%, respectively). Biopsy accuracy did not improve regarding specific chemotherapy regimens or prolonged treatments. CONCLUSIONS Liver biopsy cannot be considered a reliable tool in assessing CALIs except for steatosis. The procedure should not be recommended during preoperative workup.""",1
12851,22915447,"Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study","""Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS-cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model (difference from placebo: -1.45, P = .050, for 5 mg; -1.45, P = .076, for 10 mg). Alternative ADAS-cog analysis, removing the treatment-by-country interaction term from the model, revealed significant, dose-dependent benefit with donepezil (difference from placebo: -2.08, P = .002, for 5 mg; -3.31, P < .001, for 10 mg). The 10-mg group, but not the 5-mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points-Mini-Mental State Exam; Delis-Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD-showed significant benefit for both donepezil doses (P ? .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. ? 2012 Movement Disorder Society.""",1
12852,22917890,Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology,"OBJECTIVE: To review the evidence regarding the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches last were conducted in September 2011, in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Library without a language limitation. The combined searches yielded 532 citations, of which 45 were deemed clinically relevant for the authors to review in full text and to assign ratings of level of evidence to each of the selected studies with the guidance of the panel methodologists. RESULTS: At this time, there are 5 studies that provide level I evidence for intravitreal ranibizumab, alone or in combination with other treatments for DME. There is also 1 study that provides level I evidence for intravitreal pegaptanib sodium for DME. Nine studies reviewed were rated as level II, and 2 additional studies reviewed were graded as level III. Most studies do not provide information about long-term results (i.e., more than 2 years of follow-up) or the comparative efficacy of anti-VEGF pharmacotherapies. CONCLUSIONS: Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment over 2 years for DME. Further evidence is required to support the long-term safety of these pharmacotherapies and their comparative efficacy.",1
12853,22919164,Efficacy and safety of oral gemifloxacin for the empirical treatment of pneumonia,"""CONTEXT: Respiratory tract infections (RTI) are common causes of morbidity and mortality worldwide. Initial antibiotic therapy in upper and lower respiratory tract infections is usually empirical. The increasing evidence of antibacterial resistance in the pathogens commonly associated with pneumonia has raised concerns about the efficacy of currently available therapies and poses a challenge to clinicians. Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most Gram negative and Gram positive organisms. Hence, this study was planned to evaluate the efficacy of gemifloxacin as an empirical therapy in pneumonia. MATERIALS AND METHODS: This was an open labelled, single-arm study. Patients with clinical features of community acquired pneumonia (CAP) who fulfilled the inclusion criteria received treatment with oral gemifloxacin 320 mg once daily for 5-7 days. Once enrolled in the study, patients were treated as outpatient or as inpatient depending on clinical need. The primary efficacy was to evaluate the clinical response at the end of therapy, i.e., day 9-11 for CAP. Secondary efficacy parameters included radiological and bacteriological response at the end of therapy. Patients were evaluated three times during the entire course of treatment (Visit 1, Day 0; Visit 2, Day 2-4; Visit 3, Day 9-11) for their clinical, radiological and/or bacteriological response, as well as for safety assessment. RESULTS: A total of 105 patients received the study medication (gemifloxacin 320 mg orally). Two patients were """"lost to follow-up"""" and one patient had to discontinue medication due to insufficient therapeutic effects. Clinical response at the end of therapy was successful in 99 (96.1%) while clinical failure was reported in 4 (3.9%) patient. As per the radiological response, 77.1% of the total cases showed improvement, 8.6% had no change, and 2.9% cases had deterioration in radiological findings. Gemifloxacin is an effective drug in the management of CAP. CONCLUSIONS: Gemifloxacin with coverage against both Gram positive and Gram negative organisms as well as atypical pathogens, with once daily oral dosing and minimum side effect is a very effective and economical choice for treating CAP empirically.""",1
12854,22920341,[Could gosereline acetate induce autoimmune-like hepatitis?],"We report a case of acute icteric hepatitis attributed to goserelin acetate, occurred during prostate cancer treatment. Gosereline acetate could induce acute hepatitis, which characteristics are close to autoimmune hepatitis type I and may require hepatic monitoring.",1
12855,22920930,Prasugrel versus clopidogrel for acute coronary syndromes without revascularization,"""BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).""",1
12856,22924949,"Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study","""BACKGROUND: Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis. OBJECTIVES: This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. METHODS: One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ??75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12. RESULTS: At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25?0% (2?mg; P?<?0?001), 40?8% (5 mg; P < 0?0001) and 66?7% (15 mg; P?<?0?0001), compared with placebo (2?0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22?4% (2 mg twice daily), 20?4% (5 mg twice daily), 36?7% (15 mg twice daily) and 32?0% (placebo). Discontinuations due to AEs were 6?0%, 2?0%, 4?1% and 6?1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed. CONCLUSION: Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.""",1
12857,22928719,"Randomized, double-blind, placebo-controlled study of safety and efficacy of miltefosine in antihistamine-resistant chronic spontaneous urticaria","""BACKGROUND: Chronic spontaneous urticaria (CSU), a mast cell-driven condition, is debilitating, common, and hard to treat. Miltefosine, a lipid raft modulator, can inhibit mast cell responses in vivo. OBJECTIVE: To study the safety and efficacy of systemic miltefosine treatment in CSU patients resistant to standard-dosed antihistamines. METHODS: In this investigator-initiated multicentre, randomized, double-blind, placebo-controlled study, CSU patients were treated for 4 weeks with daily doses of up to 150-mg miltefosine (n = 47) or placebo (n = 26). Disease activity was assessed using the urticaria activity score. Safety and tolerability of miltefosine were also assessed. RESULTS: After 4 weeks of treatment, Urticaria Activity Score (UAS7) levels were substantially more reduced in miltefosine-treated patients (-6.3 vs. -3.5 in placebo-treated patients; P = 0.05). Also, the number of weals, but not the intensity of pruritus, was significantly reduced in miltefosine-treated patients vs. placebo-treated patients (P = 0.02). In general, adverse events were frequent in both groups (miltefosine: 88%, placebo: 65% of patients) but mostly mild to moderate in severity. We did not observe any serious adverse events. CONCLUSIONS: The results of this study indicate that miltefosine is an effective and safe treatment option for CSU patients who do not respond to standard-dosed antihistamines.""",1
12858,22930597,Long-term safety of rituximab in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection,,1
12859,22933131,Hepatitis B virus management to prevent reactivation after chemotherapy: a review,"""PURPOSE: Reactivation of hepatitis B virus (HBV) infection after chemotherapy can lead to liver failure and death. Conflicting recommendations regarding HBV screening in cancer patients awaiting chemotherapy mean that some patients at risk for HBV reactivation are not being identified and treated with prophylactic antiviral therapy. METHODS: We performed a narrative review of the existing evidence regarding screening for and management of HBV infection among patients with cancer using Ovid Medline, PubMed, and the Cochrane Library. RESULTS: Our review showed inconsistencies in the definition and management strategies for HBV reactivation. The timeframe of reactivation is variable, and its molecular mechanisms are not clear. There are five effective antiviral agents that can be used as prophylaxis to prevent reactivation of HBV infection in cancer patients; however, the optimal drug and duration of therapy are unknown. Reactivation is more commonly reported in patients with hematologic malignancies receiving rituximab treatment, but reactivation can occur after other chemotherapies and in patients with solid tumors. Screening with all three screening tests-HBsAg, anti-HBc, and anti-HBs-allows the most thorough interpretation of a patient's serologic profile and assessment of reactivation risk; however, decision-making and cost-effectiveness studies are needed to determine optimal screening strategies. CONCLUSIONS: Prevention of reactivation of HBV infection depends on identification of patients at risk and initiation of antiviral prophylaxis, but data to guide screening and treatment strategies are lacking. Additional research is necessary to accurately define and predict reactivation, identify best antiviral treatment strategies, and identify cost-effective HBV screening strategies.""",1
12860,22937760,Acute liver failure following cleft palate repair: a case of therapeutic acetaminophen toxicity,"Background : Acetaminophen is a widely used analgesic and antipyretic agent in the pediatric population. While the hepatotoxic effects of the drug have been well recognized in cases of acute overdose and chronic supratherapeutic doses, the toxic effects of acetaminophen are rarely documented in cases where therapeutic guidelines are followed. Case : An 8-month-old boy underwent cleft palate repair and placement of bilateral myringotomy tubes. His anesthetic course was uneventful, consisting of maintenance with desflurane and fentanyl. He received acetaminophen for routine postoperative pain management and was tolerating liquids and discharged home on postoperative day 1. On day 3, the child was profoundly lethargic with multiple episodes of emesis and was taken to the emergency department. He suffered a 45-second tonic-clonic seizure in transport to the regional children's medical center, and initial laboratory results demonstrated acute hepatitis with AST 24,424 U/L, ALT 12,885 U/L, total bilirubin 3.1 mg/dL, and a serum acetaminophen level of 83 ?g/mL. Aggressive supportive measures including blood products and periprocedural fresh frozen plasma, piperacillin/tazobactam, and intravenous infusions of N-acetylcysteine, sodium phenylacetate and sodium benzoate, carnitine, and citrulline were administered. His metabolic acidosis and acute hepatitis began to correct by day 4, and he was discharged home without further surgical intervention on day 15. Conclusion : Although acetaminophen is an effective and commonly used analgesic in pediatric practice, hepatotoxicity is a potentially devastating complication. This report challenges the appropriateness of existing guidelines for acetaminophen administration and emphasizes the importance of close follow-up and hydration after even relatively minor surgery.",1
12861,22941860,Developing a new formulation of sodium phenylbutyrate,"BACKGROUND: Sodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control. OBJECTIVES: A new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers. RESULTS: The in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of approximately 10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (C(max)) or for area under the plasma concentration-time curve (AUC). CI for C(max) and AUC(0-inf) of NaPB were included in the bioequivalence range of 0.80-1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements. CONCLUSIONS: In vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.",1
12862,22945360,GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus,"""In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of ?-cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient.""",1
12863,22950592,Characteristics of older and younger patients with suspected paracetamol toxicity,"AIM: The aim of this study was to compare the characteristics of older and younger patients with suspected paracetamol toxicity. METHODS: A retrospective audit of the medical records of older (?65 years, n = 25) and younger (20-30 years, n = 50) patients with a detectable paracetamol level at a Sydney hospital. RESULTS: Older patients showed a different clinical pattern of suspected paracetamol toxicity and were more likely than younger patients to have multifactorial elevation of liver function tests. Additionally, older age was more likely to be associated with chronic therapeutic paracetamol dosing (71% older, 6% younger, P < 0.001), or with accidental toxic exposure (90% older, 29% younger, P < 0.001), while younger patients were more likely to have a deliberate high-dose exposure (10% older, 71% younger, P < 0.001). CONCLUSIONS: The age-related differences in paracetamol exposure, paracetamol levels and liver function tests described in this population should be considered when ordering and interpreting paracetamol levels.",1
12864,22954349,A drug safety evaluation of everolimus in kidney transplantation,"INTRODUCTION: Calcineurin inhibitors (CNI) have greatly reduced the rate of acute rejection and improved short-term graft survival after organ transplantation, however, long-term survival has hardly changed since their introduction. CNIs are believed to contribute to graft fibrosis, have side effects that adversely affect cardiovascular risk, and are associated with an increased rate of post-transplant malignancies. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is not associated with graft fibrosis, has a superior cardiovascular risk profile to CNI therapy and has shown potential for the prevention and treatment of diverse forms of cancer. AREAS COVERED: This review summarizes key aspects of everolimus, including its mechanism of action, pharmacokinetics, pharmacodynamics, drug-drug interactions and pivotal clinical studies with a focus on safety and efficacy. EXPERT OPINION: Everolimus is effective in improving graft function in selected kidney transplant patients. Most adverse events are present for a short time after the introduction of everolimus, and are manageable. Everolimus has the potential to become an important agent in de novo and maintenance immunotherapy in kidney transplant recipients.",1
12865,22954507,Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study,"BACKGROUND: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. METHODS: In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195. FINDINGS: Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60?8%, 95% CI 52?3-68?9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7?9 weeks (range 2?1-39?6) and median duration of response was 49?1 weeks (95% CI 39?3-75?4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9?7 months (95% CI 7?7-12?8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87?9% (95% CI 81?3-92?3) and 74?8% (66?4-81?5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). INTERPRETATION: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.",1
12866,22956473,Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan,"BACKGROUND: Though various clinical conditions of aspergillosis can occur, depending essentially on the host's immunological status, the focus of research in North American and European countries has mainly been on invasive pulmonary aspergillosis in immunocompromised patients. There are, however, also many problems to overcome in chronic forms of aspergillosis. One of those problems is that there are no codified treatment guidelines for chronic pulmonary aspergillosis (CPA). Especially in Japan, this issue is more serious, because there are more cases with CPA due to the many aged people with past history of tuberculosis. Several clinical cases and case series have reported the usefulness of the various antifungal agents that are available. The new triazole, voriconazole, in particular, seems to be effective in the treatment of CPA. The aim of the present study is to evaluate the efficacy and safety of voriconazole in the treatment of CPA in non-immunocompromised patients. PATIENTS AND METHODS: We conducted a prospective, open-label, non-comparative, multicenter study over a 2-year period. For inclusion in the study, patients with confirmed or probable CPA were recruited in 11 hospitals of the National Hospital Organization in Japan. Clinical, radiological, serological, and mycological data were collected at baseline and 12 weeks after treatment or at the end of treatment. RESULTS: Among 77 patients enrolled in the study, 71 patients (mean age 65.9 years, 56 males and 15 females) were eligible for the study. All of the eligible patients presented with underlying lung diseases, including sequelae of tuberculosis (n = 35), non-tuberculous mycobacterial lung disease (n = 8), chronic obstructive pulmonary disease (COPD) (n = 8), interstitial pneumonia (n = 7), cystic lung disease (n = 4), pneumothorax (n = 3), bronchial cancer (n = 1), and others (n = 5). Voriconazole was indicated in 48 cases (68 %) as the first-line treatment for CPA and 23 patients previously received other antifungal therapies. Based on a composite of clinical, radiologic, serological, and mycologic criteria, good response was seen in 43 patients (60.6 %), no response was observed in 19 patients (26.8 %), and 4 cases (5.6 %) got worse. Five patients (7.0 %) were unassessable for efficacy. The common adverse events were visual disturbances (17 patients, 23.9 %), abnormal liver function test results (12 patients, 16.9 %), adverse psychological effects (3 patients, 4.2 %), and others (10 patients, 14.0 %). Treatment with voriconazole had to be stopped in 2 cases (2.8 %) because of serious adverse events (abnormal liver function test results). There was no association between adverse effects and trough voriconazole levels in serum. CONCLUSIONS: In Japan, voriconazole provides effective therapy of CPA in non-immunocompromised patients with an acceptable level of toxicity.",1
12867,22959186,Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial,"BACKGROUND: Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. METHODS: Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. FINDINGS: The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7?1 months (range 0?7-34?4, IQR 2?5-18?0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39?6%, 90% CI 27?7-52?5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. INTERPRETATION: Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring.",1
12868,22962308,Dabigatran-induced acute hepatitis,,1
12869,22967105,Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naive patients with HBV-related decompensated cirrhosis,"Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double-blind trial randomized 232 treatment-naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once-daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child-Turcotte-Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent-to-treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol-defined composite endpoint in intent-to-treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.",1
12870,22968522,Romidepsin: a histone deacetylase inhibitor for refractory cutaneous T-cell lymphoma,"OBJECTIVE: To evaluate the efficacy and safety of romidepsin in refractory cutaneous T-cell lymphoma (CTCL). DATA SOURCES: An English-language literature search of PubMed and MEDLINE (Nov 2011-April 2012) was performed using the terms romidepsin, CTCL, and depsipeptide (FK228). The National Comprehensive Cancer Network guidelines, American Society of Clinical Oncology abstracts, American Society of Hematology abstracts, clinical trial registry, and prescribing information from the manufacturer were reviewed for additional information. STUDY SELECTION AND DATA EXTRACTION: Phase 1 and 2 trials evaluating the efficacy and safety of romidepsin were reviewed with a specific focus on its use in cutaneous T-cell lymphoma. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. DATA SYNTHESIS: In advanced stage CTCL, single or combination chemotherapy regimen responses are variable and lack durability. Romidepsin is a histone deacetylase inhibitor approved for refractory cutaneous T-cell lymphoma. Romidepsin has shown an improvement in duration of response and pruritus over traditional therapy. In 2 independent Phase 2 trials, romidepsin showed an overall response rate of 34% and durable response of 13-15 months in patients with refractory CTCL. The most frequent toxicities of romidepsin include nausea, vomiting, fatigue, or myelosuppression. Clinically insignificant QT interval changes have been observed but did not correlate with a decrease in left ventricular ejection fraction, or elevated laboratory markers of myocardial damage. CONCLUSIONS: Romidepsin is an effective, durable, and well-tolerated single-agent therapy in patients with refractory CTCL and should be considered for formulary addition in this population.",1
12871,22971242,Drug safety evaluation of dronedarone in atrial fibrillation,"""INTRODUCTION: Dronedarone was developed with the intent of replicating the antiarrhythmic effects of amiodarone, while minimizing its side effects. AREAS COVERED: Side effects reported in eight randomized clinical trials are discussed, comparing dronedarone and placebo (DAFNE, EURIDIS, ADONIS, ERATO, ANDROMEDA, ATHENA, PALLAS, total number of patients treated with dronedarone 5347), or dronedarone and amiodarone (DIONYSOS, total number of patients treated with dronedarone 249). EXPERT OPINION: The results of the first trials, including ATHENA, set high expectations by suggesting that dronedarone may decrease the risk of hospitalization (and even cardiovascular mortality) among patients with paroxysmal and persistent atrial fibrillation (AF), and that it could be regarded as an easy-to-use drug that could be prescribed by general practitioners; unfortunately, dronedarone has not met these expectations. Dronedarone may increase mortality and heart failure hospitalization in patients with advanced NYHA class and in patients with permanent AF, preventing its use in these settings. In addition to gastrointestinal side effects that may lead to discontinuation in 5 - 10% of patients, dronedarone may induce very rare but severe liver and lung toxicity. Despite these limitations and its relatively limited antiarrhythmic potency, dronedarone may still be a useful drug for well-selected patients.""",1
12872,22973106,Avanafil for treatment of erectile dysfunction: review of its potential,"Avanafil is a medication that was recently approved by the US Food and Drug Administration for the management of erectile dysfunction. Avanafil is a new phosphodiesterase type 5 inhibitor similar to sildenafil and tadalafil. Avanafil was studied in over 1300 patients during clinical trials, including patients with diabetes mellitus and those who had undergone radical prostatectomy, and was found to be more effective than placebo in all men who were randomized to the drug. The medication was studied with on-demand dosing that may occur after food and/or alcohol. Avanafil is dosed as 50 mg, 100 mg, or 200 mg tablets. Avanafil may differentiate itself from the other phosphodiesterase type 5 inhibitors with its quicker onset and higher specificity for phosphodiesterase type 5 versus other phosphodiesterase subtypes, but may lead to complications of therapy.",1
12873,22977061,Comment on: Tocilizumab treatment in a patient suffering from rheumatoid arthritis and concomitant chronic hepatitis C infection,,1
12874,22981498,Panobinostat activity in both bexarotene-exposed and -na?ve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial,"BACKGROUND: Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in bexarotene-exposed and -na?ve patients with refractory cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Patients with CTCL subtypes mycosis fungoides and S?zary syndrome who received ?2 prior systemic therapy regimens received panobinostat (20mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ?25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir. RESULTS: Seventy-nine bexarotene-exposed and 60 bexarotene-na?ve patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the bexarotene-exposed and -na?ve groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the bexarotene-exposed and -na?ve groups, respectively. The median duration of response was 5.6 months in the bexarotene-exposed patients and was not reached at data cutoff in the bexarotene-na?ve patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable. CONCLUSION: Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in bexarotene-exposed and -na?ve CTCL patients. ClinicalTrials.gov Identifier: NCT00425555.",1
12875,22984206,Response to raltegravir-based salvage therapy in HIV-infected patients with hepatitis C virus or hepatitis B virus coinfection,"OBJECTIVES: To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine. METHODS: We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection. RESULTS: Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred. CONCLUSIONS: Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.",1
12876,22985451,"Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: a retrospective, multicentre study in a clinical setting","""BACKGROUND: Both the safety and efficacy of biologic therapy may be affected in the presence of highly prevalent chronic viral hepatitis. OBJECTIVE: To evaluate the safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and concomitant chronic viral hepatitis. METHODS: This was a retrospective, multicentre study. Twenty-five patients with psoriasis and concurrent hepatitis C virus (HCV) (20 patients) or hepatitis B virus (HBV) (five patients) infection who had received at least one biologic agent (etanercept, 21 treatments; adalimumab, four; ustekinumab, four; infliximab, two) were included. Clinical, imaging and laboratory data were recorded. RESULTS: In the case of HCV infection, the majority of the patients did not exhibit increases in their viral load or serum liver tests. Aspartate aminotransferase, alanine aminotransferase and gamma glutamyl transpeptidase were doubled from the baseline measurement in only one patient treated with etanercept. Two other cases exhibited viral load increases during the follow-up period. In total, 18 of the 26 treatments achieved a 75% improvement in their Psoriasis Area and Severity Index (PASI 75) score during the follow-up period. Two patients treated with etanercept were diagnosed with hepatocellular carcinoma. In the case of HBV infection, all of the patients were being treated with antiviral therapy, and none presented significant variations in viral load or serum liver enzymes. All patients achieved a PASI 75 during follow-up. CONCLUSIONS: Biologic therapy was effective and safe for the majority of our patients with HCV and HBV infection, although there may be a risk of reactivation or aggravation. We describe the first cases to receive ustekinumab. The use of biologics should be limited to those cases in which the risk-benefit ratio is justified.""",1
12877,22985946,Hepatotoxicity with flutamide,,1
12878,22986440,"A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation","""OBJECTIVES: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 ? g oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration ? s (FDA ? s) primary end point for IBS-C (responder: improvement of ? 30 % in average daily worst abdominal pain score and increase by ? 1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50 % of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9 / 12 weeks. Adverse events (AEs) were monitored. RESULTS: The trial evaluated 800 patients (mean age = 43.5 years, female = 90.5 % , white = 76.9 % ). The FDA end point was met by 136 / 405 linaclotide-treated patients (33.6 % ), compared with 83 / 395 placebo-treated patients (21.0 % ) ( P < 0.0001) (number needed to treat: 8.0, 95 % confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6 / 12 treatment period weeks, a reduction of ? 30 % in abdominal pain (50.1 vs. 37.5 % , P = 0.0003) and an increase of ? 1 CSBM from baseline (48.6 vs. 29.6 % , P < 0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points ( P < 0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points ( P < 0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7 % of linaclotide and 0.3 % of placebo patients. CONCLUSIONS: Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.""",1
12879,22987284,Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury,"UNLABELLED: The role of the adaptive immune system in adverse drug reactions that target the liver has not been defined. For flucloxacillin, a delay in the reaction onset and identification of human leukocyte antigen (HLA)-B*57:01 as a susceptibility factor are indicative of an immune pathogenesis. Thus, we characterize flucloxacillin-responsive CD4+ and CD8+ T cells from patients with liver injury and show that naive CD45RA+CD8+ T cells from volunteers expressing HLA-B*57:01 are activated with flucloxacillin when dendritic cells present the drug antigen. T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL 25, and secreted interferon-gamma (IFN-gamma), T helper (Th)2 cytokines, perforin, granzyme B, and FasL following drug stimulation. Flucloxacillin bound covalently to selective lysine residues on albumin in a time-dependent manner and the level of binding correlated directly with the stimulation of clones. Activation of CD8+ clones with flucloxacillin was processing-dependent and restricted by HLA-B*57:01 and the closely related HLA-B*58:01. Clones displayed additional reactivity against beta-lactam antibiotics including oxacillin, cloxacillin, and dicloxacillin, but not abacavir or nitroso sulfamethoxazole. CONCLUSION: This work defines the immune basis for flucloxacillin-induced liver injury and links the genetic association to the iatrogenic disease.",1
12880,22992072,Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis,"""BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).""",1
12881,22992487,2 new drugs for weight loss,,1
12882,22993667,A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione,"""The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients.""",1
12883,22995653,"Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study","""BACKGROUND: Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). METHODS: Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. FINDINGS: Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20?2 months (IQR 18?4-22?1), median overall survival for the abiraterone group was longer than in the placebo group (15?8 months [95% CI 14?8-17?0] vs 11?2 months [10?4-13?1]; hazard ratio [HR] 0?74, 95% CI 0?64-0?86; p<0?0001). Median time to PSA progression (8?5 months, 95% CI 8?3-11?1, in the abiraterone group vs 6?6 months, 5?6-8?3, in the placebo group; HR 0?63, 0?52-0?78; p<0?0001), median radiologic progression-free survival (5?6 months, 5?6-6?5, vs 3?6 months, 2?9-5?5; HR 0?66, 0?58-0?76; p<0?0001), and proportion of patients who had a PSA response (235 [29?5%] of 797 patients vs 22 [5?5%] of 398; p<0?0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). INTERPRETATION: This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up.""",1
12884,22998988,Cocaine intoxication,"Cocaine, a natural alkaloid derived from the coca plant, is one of the most commonly abused illicit drugs. Cocaine is commonly abused by inhalation, nasal insufflation, and intravenous injection, resulting in many adverse effects that ensue from local anesthetic, vasoconstrictive, sympathomimetic, psychoactive, and prothrombotic mechanisms. Cocaine can affect all body systems and the clinical presentation may primarily result from organ toxicity. Among the most severe complications are seizures, hemorrhagic and ischemic strokes, myocardial infarction, aortic dissection, rhabdomyolysis, mesenteric ischemia, acute renal injury and multiple organ failure.",1
12885,23007149,Gefitinib-induced hepatotoxicity in patients treated for non-small cell lung cancer,"BACKGROUND: Although epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) are widely used in the management of advanced non-small cell lung cancer (NSCLC), gefitinib-induced hepatotoxicity has been underappreciated and rarely reported. CASE REPORT: The medical records of 92 NSCLC patients, who were admitted to our cancer center in the past 5 years, were reviewed retrospectively. All patients received treatment with gefitinib (250 mg/day), during which liver function was monitored. Of the 92 NSCLC patients, 6 (6.5%) developed mild to moderate hepatotoxicity during gefitinib treatment. The time of onset of hepatotoxicity ranged from 7 days to 6 months after gefitinib administration. 1 patient (1.1%) suffered from grade 2 hepatotoxicity, and gradually recovered her normal liver function after reduction of the gefitinib dose. The other 5 patients with grade 1 hepatic impairment tolerated gefitinib well without requiring dose reductions or drug cessation. CONCLUSION: Gefitinib-induced hepatotoxicity is not uncommon. Although the extent of this toxicity is generally mild in nature and most patients tolerate gefitinib well, meticulous monitoring is mandatory to avoid severe hepatic impairment.",1
12886,23011167,Acetylcysteine for acetaminophen overdose in patients who weigh >100 kg,"N-Acetylcysteine (NAC) dosing for acetaminophen (APAP) overdose is weight based (150 mg/kg intravenous or 140-mg/kg oral loading dose) and, in the United States, the dosing protocol recommends using a maximum patient weight of 100 and 110 kg, respectively. Little clinical data describe the use of NAC for APAP poisoning in patients weighing >100 kg. The aim of this study was to describe the demographics, outcomes, and adverse event (AE) rates of patients weighing >100 kg treated with oral or IV NAC for APAP poisoning. Patients were identified from a multicenter retrospective NAC safety study for APAP overdose. We included patients with a recorded weight. Trained chart abstractors used a standardized form. Selected data included age, gender, weight, serum alanine transaminase, and aspartate transaminases, coingestants, NAC administration route, ingestion type, AEs, and outcome [hepatotoxicity (alanine transaminase > 1000 U/L), liver transplant, or death]. Descriptive statistics were used. Of 503 study patients, 37 (7.4%) had recorded weights >100 kg. The median (range) weight was 110 kg (101-160). The median (range) dosing for patients treated with oral NAC was 140 mg/kg (127-143 mg/kg) and 150 (108-168) mg/kg for IV NAC. Hepatotoxicity occurred in 12/36 (33.3%) patients. Death occurred in 4/36 (11.1%) patients. Thirteen NAC-related AEs occurred in 8 patients (1.6 per person). All AEs were related to NAC and were rated nonserious by the reviewer. Clinicians use an actual weight-based NAC dose rather than a maximum weight cutoff dose. Hepatotoxicity was common in our cohort. AEs were relatively common but not serious.",1
12887,23013963,Dress syndrome and acute tubulointerstitial nephritis after treatment with vancomycin and beta-lactams. Case report and literature review,,1
12888,23018574,Treatment of acquired aplastic anemia in patients with acute liver failure occurring concurrently: a case series,"The association between acquired aplastic anemia (AA) and hepatitis/acute liver failure has been well characterized as AA temporally after the presentation of acute hepatitis. In this case series we report 2 cases of patients who present with AA occurring simultaneously with the development of acute liver failure. This is among only a few reported cases known to date in which AA occurs simultaneously with impending liver failure. More importantly, this is the first report that demonstrates the feasibility of administering immunosuppressive therapy before complete resolution of the hepatic dysfunction and with excellent results. Both of our cases avoided orthotopic liver transplantation through the use of timely immunosuppressive therapy, demonstrating the potential role of medical management to avoid transplantation in these patients. Previous studies have suggested a link between an unidentified viral process and immune dysregulation that may lead to the development of AA after acute hepatitis. These 2 cases support the rationale that in our patients the 2 disease processes may share a common etiology and encourage further research into the complex pathogenic mechanism affecting these 2 different organ systems at varying points in time.",1
12889,23020162,Trastuzumab emtansine for HER2-positive advanced breast cancer,"""BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. METHODS: We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).""",1
12890,23021126,Perioperative chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer undergoing liver resection,"The impact of adding bevacizumab to perioperative chemotherapy in patients with colorectal cancer (CRC) undergoing liver resection is yet to be defined. A retrospective review of our patient records showed that the addition of bevacizumab did not increase morbidity or mortality related to liver resection. Pathologic complete response (CR) is associated with prolonged survival. BACKGROUND: Patients with colorectal cancer (CRC) and liver metastases benefit from perioperative chemotherapy and liver resection. The potential benefit of adding bevacizumab is yet to be defined. The impact of bevacizumab on liver resection complications has been explored in a small number of retrospective studies. METHODS: The records of patients with CRC and liver metastases who underwent liver resection and had received perioperative chemotherapy were reviewed. Complications were reported separately for 2 groups (chemotherapy alone vs chemotherapy and bevacizumab). Survival outcomes (progression-free survival [PFS] and overall survival [OS]) for responders and nonresponders were estimated using the Kaplan-Meier method. RESULTS: Fifty-two patients received chemotherapy alone and 42 patients received chemotherapy and bevacizumab. The median time from the end of systemic treatment to liver resection was 59 days (33-181 days) for the chemotherapy group and 62 days (44-127 days) for the chemotherapy and bevacizumab group. Postoperative complications developed in 54% of the chemotherapy group and in 48% of the chemotherapy and bevacizumab group. Severe complications (grade III-V) occurred in only 13% and 12%, respectively (P = .822). Pathologic complete response (CR) was seen in 11/94 patients. Poor performance status (PS) before starting chemotherapy was associated with higher rates of complications (P = .002), and severe complications led to prolonged hospital admission (P = .001). Patients with pathologic CR had longer OS (P = .0275), but there was no difference in OS between responders and nonresponders (P = .778). CONCLUSION: The addition of bevacizumab to chemotherapy does not increase liver resection complication rates. Pathologic CR is associated with prolonged survival.",1
12891,23024237,Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL,"Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell-engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.",1
12892,23029716,"Pentoxifylline in severe alcoholic hepatitis: a prospective, randomised trial","""BACKGROUND: Role of corticosteroids in treatment of severe alcoholic hepatitis (SAH) is controversial. Pentoxifylline (PTX), an inhibitor of TNF, has also been shown to decrease short term mortality in SAH. Aim of this study was to evaluate the effect of PTX on short term mortality, renal and hepatic functions in patients with SAH. METHODS: Fifty patients with SAH {Maddrey's Discriminant Function (DF) > or = 32} were prospectively enrolled. Twenty five patients received PTX (400 mg orally, three times a day), and 25 received placebo for 4 weeks. Serum tumor necrosis factor (TNF) was measured in both groups. RESULTS: Baseline characteristics of the two groups were similar. At 4 weeks, mortality in PTX group was lower than that in controls {20% (5/25) versus 40% (10/25) respectively; p = 0.216; RR 0.5; 95% CI 0.19-1.25}. Renal failure was the cause of mortality in 20% (1/5) patients in PTX group, and 70% (7/10) in controls (p = 0.11). Significant reduction in urea, creatinine, DF and TNF was noted in PTX group. Reduction in TNF did not correlate with reduction in creatinine or DF. CONCLUSIONS: In patients with SAH, PTX leads to a significant improvement in renal and hepatic functions, and a trend towards decreased short term mortality.""",1
12893,23031624,Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study,"BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are rare, inherited autoinflammatory disorders associated with considerable hardship to patients. The interleukin-1 inhibitor rilonacept has been shown to be well-tolerated and effective in preventing CAPS symptoms in 2 pivotal studies. OBJECTIVE: In this study, the long-term effects of rilonacept for improvement in CAPS symptoms and its safety and tolerability were evaluated during extended treatment. METHODS: Patients with CAPS entered a 72-week open-label extension (OLE) following 2 sequential placebo-controlled Phase III studies (n = 44), or entered directly into the OLE (n = 57). Adults received weekly subcutaneous rilonacept 160 mg, and pediatric patients received subcutaneous rilonacept 2.2 mg/kg, up to 160 mg/week. Safety was evaluated in all patients, and efficacy was evaluated using a validated composite key symptom score in 56 patients. RESULTS: After rilonacept treatment for 72 to 96 weeks mean key symptom score at OLE Week 72 was reduced from 2.6 to 0, and the mean number of multisymptom flare days was reduced from 7.3 (34.8% of days) at baseline to 0.6 (2.9% of days) at end point. Elevated levels of inflammatory markers (eg, high sensitivity-C reactive protein and serum amyloid A, were normalized. Adverse events were generally mild to moderate, the most common being injection site reactions and upper respiratory tract infections. The incidence of these events was similar to or lower than the rate reported in the pivotal studies. CONCLUSIONS: Long-term treatment with rilonacept of up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation. Rilonacept exhibited a generally favorable safety and tolerability profile in adult and pediatric patients with CAPS throughout the extended treatment period. ClinicalTrials.gov identifier: NCT 00288704.",1
12894,23032409,The safety of flucloxacillin in HIV-infected patients with positive HLA-B*5701 genotype,"Positive HLA-B*5701 genotype has recently been identified as the main genetic risk factor for flucloxacillin drug-induced liver injury (DILI). Testing for HLA-B*5701 is routine in many HIV clinics to identify those at risk of hypersensitivity reaction (HSR) to abacavir. Considering the high prevalence of soft-tissue infections in HIV patients, we conducted a retrospective study to investigate whether flucloxacillin use was associated with adverse events in HIV patients known to be HLA-B*5701 positive.",1
12895,23034060,Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases,"BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a heterogeneous group of severe adverse reactions to medications. The cutaneous phenotype has a number of guises, accompanied by a variety of systemic features including fever, haematological abnormalities and visceral involvement, most commonly the liver. Clinical markers of prognosis have not been identified. OBJECTIVES: To assess the cutaneous signs and dermatopathological features of DRESS in order to identify potential prognostic markers. METHODS: We reviewed the clinical features, dermatopathology and outcomes of 27 consecutive cases of DRESS presenting to a single unit. RESULTS: Four distinct patterns of cutaneous involvement were identified: an urticated papular exanthem (13/27 patients), a morbilliform erythema (three of 27), an exfoliative erythroderma (three of 27) and an erythema multiforme-like (EM-like) reaction consisting of atypical targets (eight of 27). All patients mounted a fever, most developed lymphadenopathy (24/27) and peripheral eosinophilia (25/27) and the most common organ involved was the liver (27/27). Review of the dermatopathic features of patients with DRESS demonstrated a superficial spongiotic dermatitis in the majority of cases (16/27). A smaller number of cases showed basal cell vacuolar degeneration and necrotic keratinocytes (nine of 27). The patients with these biopsy findings more commonly had an EM-like cutaneous phenotype, and more severe hepatic involvement. Three patients died, two following failed liver transplants. CONCLUSIONS: Our series is the first in which a detailed dermatological assessment has been made of consecutive patients presenting with DRESS, and the largest U.K. series to date. Our results suggest a possible prognostic role of the cutaneous and dermatopathic findings in DRESS in predicting the severity of visceral involvement in this syndrome. What's already known about this topic? * Drug reaction with eosinophilia and systemic symptoms (DRESS) has a heterogeneous clinical presentation, with a skin eruption of variable morphology. * DRESS carries considerable morbidity and mortality, usually hepatic in origin, although renal, pulmonary and pericardial involvement can be seen. What does this study add? * The cutaneous phenotype in DRESS can be categorized as an urticated papular exanthem, a morbilliform erythema, exfoliative erythroderma or erythema multiforme-like (EM-like). * An EM-like eruption DRESS may be prognostic of more severe hepatic involvement.",1
12896,23034699,"Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication","""BACKGROUND: A systematic review and network meta-analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD). METHODS: MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings, BIOSIS, National Research Register and MetaRegister databases were searched. Eligible studies were randomized controlled trials (RCTs) and published systematic reviews of patients with intermittent claudication due to PAD and whose symptoms persisted despite a period of conservative management. Study selection was conducted by one reviewer with involvement from a clinician. Data were extracted by one reviewer with no blinding to authors or journal, and checked by a second reviewer. Outcome measures were maximum walking distance (MWD) and pain-free walking distance (PFWD). RESULTS: The review identified 1876 citations; 26 RCTs met the inclusion criteria for the systematic review. Eleven trials provided data relevant for the meta-analysis. Naftidrofuryl oxalate was ranked first for both MWD and PFWD (probability of 0?947 and 0?987, respectively, of being the best treatment) followed by cilostazol and pentoxifylline. For naftidrofuryl oxalate, cilostazol and pentoxifylline, MWD increased by 60 (95 per cent credible interval 20 to 114) per cent, 25 (11 to 40) per cent and 11 (-1 to 24) per cent respectively relative to placebo, and PFWD increased by 49, 13 and 9 per cent. CONCLUSION: Naftidrofuryl oxalate and cilostazol are both effective treatments for claudication; naftidrofuryl oxalate is likely to be the most effective, with minimal serious adverse events.""",1
12897,23037652,Hyperammonemia associated with valproic acid use in elderly psychiatric patients,"""Valproic acid (VPA) is associated with hyperammonemia; however, little is known about this phenomenon in the geriatric psychiatric population. Of 12 such patients prescribed VPA, 83.3% had elevated ammonia. This occurred in the absence of elevated liver enzymes, and there was no association of VPA serum-level to hyperammonemia.""",1
12898,23040887,Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes,"BACKGROUND: Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HESs. OBJECTIVE: We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES. METHODS: MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored. RESULTS: Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ? 12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons. CONCLUSION: Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES.",1
12899,23041049,Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience,"BACKGROUND: Patients undergoing liver resection for colorectal cancer liver metastasis (CRCLM) are often treated with chemotherapy before surgery. However, the associations between chemotherapy, liver injury, perioperative outcomes, and other confounding factors remain unclear. This study investigates the effect of preoperative chemotherapy for CRCLM on nontumoral liver histology and perioperative outcomes in a contemporary cohort. STUDY DESIGN: Five hundred six patients underwent hepatic resection for CRCLM between April 2003 and March 2007. Histologic evaluation of nontumoral liver parenchyma for sinusoidal dilatation, steatosis, and steatohepatitis was performed in 384 cases for which tissue was available. Patient factors, tumor characteristics, chemotherapy regimens, histology of nontumoral liver, and perioperative morbidity were analyzed. RESULTS: Two hundred fifty patients (65%) received preoperative chemotherapy for a median duration of 24 weeks. Irinotecan, increased body mass index (BMI), and diabetes mellitus (DM) were associated with hepatic steatosis and steatohepatitis. Sinusoidal dilatation was not associated with chemotherapy or any clinicopathologic factors. Perioperative blood transfusion was independently associated with an increased risk of any complication. Major postoperative complications were independently associated with major (? 3 segments) resections (57%) and perioperative blood transfusion. The use of any preoperative chemotherapy decreased the odds of major complications. Liver-related complications were independently associated with major resection and blood transfusion, but not with chemotherapy. Three postoperative deaths (0.8%) occurred, all in patients who were not treated with chemotherapy and had no evidence of liver injury. CONCLUSIONS: With appropriate patient selection, liver resection for CRCLM can be safely performed in patients treated with preoperative chemotherapy.",1
12900,23043422,Hepatic sinusoidal obstruction syndrome reduces the effect of oxaliplatin in colorectal liver metastases,,1
12901,23044657,Quantification of mitochondrial toxicity in HIV-infected individuals by quantitative PCR compared to flow cytometry,"""BACKGROUND: Non-invasive diagnostic assays to evaluate mitochondrial toxicity could have significant clinical utility for HIV-infected individuals on antiretroviral therapy (ART). METHODS: This study compared the ratio of mitochondrial to nuclear DNA determined by quantitative polymerase chain reaction (qPCR) to the ratio of mitochondrial to nuclear-encoded proteins by flow cytometry, in peripheral blood mononuclear cells from 73 HIV-infected individuals with and without risk factors for mitochondrial toxicity. RESULTS: PCR detected similar mitochondrial/nuclear DNA in HIV-infected individuals without a history of ART, and those receiving ART with lipodystrophy, lipoatrophy, or a history of suspected lactic acidosis. However, the ratio was significantly greater in ART-untreated compared to those receiving either stavudine or didanosine. In contrast, flow cytometry did not detect any differences in mitochondrial/nuclear protein (Lin et al., Cytometry B 2009;76B:181-190). There was no correlation between the assays (rho = -0.05, P = 0.65). CONCLUSIONS: Assessment of the mitochondrial/nuclear DNA ratio by qPCR performed better than the mitochondrial/nuclear-encoded protein ratio by flow cytometry to detect adverse effects of nucleoside analogs on mitochondria.""",1
12902,23049275,Liposomal bupivacaine: a review of a new bupivacaine formulation,"Many attempts have been made to increase the duration of local anesthetic action. One avenue of investigation has focused on encapsulating local anesthetics within carrier molecules to increase their residence time at the site of action. This article aims to review the literature surrounding the recently approved formulation of bupivacaine, which consists of bupivacaine loaded in multivesicular liposomes. This preparation increases the duration of local anesthetic action by slow release from the liposome and delays the peak plasma concentration when compared to plain bupivacaine administration. Liposomal bupivacaine has been approved by the US Food and Drug Administration for local infiltration for pain relief after bunionectomy and hemorrhoidectomy. Studies have shown it to be an effective tool for postoperative pain relief with opioid sparing effects and it has also been found to have an acceptable adverse effect profile. Its kinetics are favorable even in patients with moderate hepatic impairment, and it has been found not to delay wound healing after orthopedic surgery. More studies are needed to establish its safety and efficacy for use via intrathecal, epidural, or perineural routes. In conclusion, liposomal bupivacaine is effective for treating postoperative pain when used via local infiltration when compared to placebo with a prolonged duration of action, predictable kinetics, and an acceptable side effect profile. However, more adequately powered trials are needed to establish its superiority over plain bupivacaine.",1
12903,23052187,"Therapy of 1,025 severely ill patients with complicated infections in a German multicenter study: safety profile and efficacy of tigecycline in different treatment modalities","""This large prospective non-interventional study investigated the effects of tigecycline either as single agent or in combination with other antimicrobial agents in 1,025 patients treated in clinical routine at German hospitals. Sixty-five percent of the patients had APACHE II scores > 15, indicating high overall disease severity. Complicated intra-abdominal infections (cIAI) or complicated skin and skin tissue infections (cSSTI) were the most common indications, with Staphylococcus aureus, Enterococcus faecium and Escherichia coli being the most frequently isolated pathogens. Clinical success was reported at the end of tigecycline therapy in 74.2% of the total population, in 75.4% of the cIAI and in 82.2% of the cSSTI patients. The subpopulation (28.0% of the patients) infected with multidrug-resistant pathogens (methicillin-resistant S. aureus, extended-spectrum ?-lactamase producers and vancomycin-resistant enterococci) were treated with similar success rates as the overall population. Tigecycline was generally well tolerated. Drug-related adverse events (AEs) were reported in 7.7% of the total population; 2.5% had serious AEs mostly attributable to inefficacy of therapy or deterioration of the disease. Mortality rates were consistent with the types of infection and severity of illness. There was no indication of excessive mortality associated with tigecycline as had been suggested in previously performed meta-analyses. In this large non-interventional study performed in the clinical routine setting, tigecycline achieved favorable clinical success rates in a patient population with high severity of illness and a high prevalence of multidrug-resistant pathogens and showed a good safety and tolerability profile.""",1
12904,23052987,A double-blind comparative study of the safety and efficacy of caspofungin versus micafungin in the treatment of candidiasis and aspergillosis,"""The safety and efficacy profile of caspofungin and micafungin in Japanese patients with fungal infections were directly compared in this prospective, randomized, double-blind study. The proportion of patients who developed significant drug-related adverse event(s) (defined as a serious drug-related adverse event or a drug-related adverse event leading to study therapy discontinuation) was compared in 120 patients [caspofungin 50 mg, or 50 mg following a 70-mg loading dose on Day 1 (hereinafter, 70/50 mg) group: 60 patients; micafungin 150 mg: 60 patients]. The overall response rate was primarily evaluated in the per-protocol set (PPS) population. The proportion of patients who developed significant drug-related adverse events was 5.0 % (3/60) in the caspofungin group and 10.0 % (6/60) in the micafungin group [95 % confidence interval (CI) for the difference: -15.9 %, 5.2 %]. The favorable overall response in the PPS population for patients with esophageal candidiasis, invasive candidiasis, and chronic pulmonary aspergillosis including aspergilloma was 100.0 % (6/6), 100.0 % (3/3), and 46.7 % (14/30) in the caspofungin group, and 83.3 % (5/6), 100.0 % (1/1), and 42.4 % (14/33) in the micafungin group, respectively. In Japanese patients with Candida or Aspergillus infections, there was no statistical difference in the safety between caspofungin and micafungin. Consistent with other data on these two agents, the efficacy of caspofungin and micafungin was similar.""",1
12905,23059146,CYP2D6 genotype information to guide pimozide treatment in adult and pediatric patients: basis for the U.S. Food and Drug Administration's new dosing recommendations,"OBJECTIVE: The occurrence of pimozide-induced arrhythmias is concentration dependent. Hence, it is important for prescribers to consider causes of increased pimozide exposure. This article summarizes the U.S. Food and Drug Administration's (FDA's) review of drug interaction and pharmacogenomic studies and discusses pharmacokinetic simulations we performed to develop new cytochrome P450 2D6 (CYP2D6) genotype-guided dosing recommendations for pimozide. METHOD: Pharmacokinetic parameters by CYP2D6 genotype were derived from a published single-dose pharmacogenomic study of pimozide. We simulated what pimozide exposures would result from a multiple-dose scenario in different CYP2D6 genotype groups: extensive, intermediate, and poor metabolizers. The maximum dose for poor metabolizers was defined as the dose that would not exceed pimozide concentrations following 10 mg daily in extensive metabolizers and intermediate metabolizers (the current maximum dose in an unselected population). RESULTS: Dose-ranging analyses revealed that 4 mg daily in CYP2D6 poor metabolizers was the maximum dose that would not result in plasma concentrations in excess of those observed in extensive metabolizer and intermediate metabolizer patients receiving 10 mg daily. CYP2D6 genotyping is now consequently recommended in the pimozide product label before exceeding 4 mg of pimozide daily in adults or 0.05 mg/kg/d in children. Previously, dose adjustment was recommended every 3 days to achieve the desired clinical response for all patients. The label was modified to subsequently reflect that pimozide doses should not be increased earlier than 14 days in patients who are known CYP2D6 poor metabolizers. CONCLUSIONS: Given the risk of increased pimozide concentrations and longer time to steady state in CYP2D6 poor metabolizers, the FDA has revised the pimozide label to provide clinicians with clearer dosing, titration, and genotype testing recommendations. The new information is intended to enhance therapeutic individualization of pimozide in pediatric and adult patients.",1
12906,23059776,"Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer","""INTRODUCTION: In a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non-small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results. METHODS: After four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D). RESULTS: Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p <0.001), anti-infectives (25.3% versus 16.7%; p = 0.028), and hospitalizations because of study drug (8.4% versus 3.3%, p = 0.028) than placebo-treated patients did. No significant treatment-by-time interactions, overall treatment differences, or clinically relevant changes from baseline were observed in EQ-5D scores during treatment. CONCLUSIONS: Long-term use of continuation maintenance pemetrexed was well tolerated; resource use was low, corresponding with known pemetrexed toxicities. The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening QoL.""",1
12907,23063577,Fatal liver failure in a patient treated with sunitinib for renal cell carcinoma,,1
12908,23065000,Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized 'FIRST' study,"""Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. At data cut-off, only 36 % of patients had progressed and the median time to progression (TTP) had not been reached for fulvestrant. Here, we report follow-up data for TTP for fulvestrant 500 mg versus anastrozole 1 mg. Key inclusion criteria were postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy. Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug. Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1; anastrozole was administered 1 mg/day. TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis, and investigator opinion after data cut-off. Best overall response to subsequent therapy and serious adverse events are also reported. In total, 205 patients received fulvestrant 500 mg (n = 102) or anastrozole (n = 103). Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment. Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole; a 34 % reduction in risk of progression (hazard ratio 0.66; 95 % confidence interval: 0.47, 0.92; P = 0.01). Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups. No new safety concerns for fulvestrant 500 mg were documented. These longer-term, follow-up results confirm efficacy benefit for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP, and, importantly, show similar best overall response rates to subsequent endocrine therapy.""",1
12909,23066948,"Detection of HLA-B*58:01, the susceptible allele for allopurinol-induced hypersensitivity, by loop-mediated isothermal amplification","BACKGROUND: Allopurinol, a common medication for gout treatment, can cause rare but life-threatening severe cutaneous adverse reactions. A strong pharmacogenetic association of human leucocyte antigen (HLA)-B*58:01 with allopurinol-induced drug hypersensitivity has been reported, especially in the Han Chinese population. OBJECTIVES: To develop a rapid and simple loop-mediated isothermal amplification (LAMP) assay of HLA-B*58:01 and evaluate its feasibility in predicting allopurinol-induced drug hypersensitivity. METHODS: Two sets of LAMP primers targeting exons 2 and 3 of HLA-B*58:01 were designed. DNA extracted from 20 clinical blood samples of patients with gout was used to evaluate the effectiveness of the two LAMP primer sets for the detection of HLA-B*58:01. RESULTS: The results were compared with routine clinical genotyping methods. All extracted DNA samples tested with the HLA-B*58:01 LAMP assay showed agreement with the routine genotyping results. No amplifications were observed when unextracted blood samples were tested. CONCLUSIONS: The HLA-B*58:01 LAMP assay was confirmed to be simple, rapid and specific for the detection of HLA-B*58:01, and therefore of potential value in the diagnosis of allopurinol-induced hypersensitivity.",1
12910,23069874,Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients,"BACKGROUND: Cognitive decline has been recognised as a frequent symptom in multiple sclerosis (MS). Cholinesterase inhibitors (ChEIs) are employed for the treatment of Alzheimer's disease, but there is some evidence that ChEIs might also be effective in MS patients with cognitive deficits, particularly deficits of memory function. OBJECTIVE: The aim of this study was to evaluate efficacy on memory function and safety of the ChEI rivastigmine in MS patients with cognitive deficits as measured by the change from baseline of the total recall score of the selective reminding test (SRT) after 16 weeks of treatment. METHODS: Efficacy and safety of rivastigmine were analysed in a 16-week, multicentre, double-blind, randomised, placebo-controlled study, followed by an optional one-year open-label treatment phase. Effects of rivastigmine and placebo were compared by an analysis of covariance. RESULTS: In total, 86 patients were enrolled. Patients who received rivastigmine (n = 43) showed a non-significant increase in total recall score (sum of all words immediately recalled over all six trials) over placebo (n = 38) after 16 weeks of treatment (p = 0.2576). Other outcome measures provided no evidence supporting benefits of rivastigmine. Treatment with rivastigmine was well tolerated. CONCLUSIONS: With the results of this study, the need for an effective therapy in cognitively impaired MS patients is still required. Thus, intensive and continued clinical research is required to explore therapeutic options for cognitive deficits in MS patients.",1
12911,23073329,Venlafaxine-induced cholestatic hepatitis: case report and review of literature,"""Venlafaxine is a widely used antidepressant with relatively low occurrence of adverse side effects. Increasing evidence suggests that venlafaxine may cause severe liver damage. Until now, 10 cases of venlafaxine-related liver injuries have been reported. We describe a case of a 39-year-old woman who developed cholestatic hepatitis after intake of venlafaxine. The patient had taken low-dose venlafaxine (75 mg/d) for 2.5 years. Three months before admission to the hospital, the venlafaxine dosage had been increased to 300 mg/d because of severe depression. Laboratory findings revealed elevated serum transaminases (aspartate aminotransferase 1033 U/L; alanine aminotransferase 2063 U/L), alkaline phosphatase (274 U/L), ?-glutamyltransferase (284 U/L), and serum bilirubin (4.6 mg/dL). Liver biopsy showed cholestatic hepatitis predominantly involving zone 3 of hepatic acini and a mixed portal inflammatory infiltrate along with eosinophils. Symptoms rapidly resolved after cessation of venlafaxine and administration of corticosteroid. The present paper describes detailed clinicohistopathologic characteristics of venlafaxine-associated cholestatic hepatitis and provides a comprehensive summary of prior case reports.""",1
12912,23075178,Ustekinumab induction and maintenance therapy in refractory Crohn's disease,"""BACKGROUND: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).""",1
12913,23077853,Physicians' practices regarding management of antituberculosis drug-induced hepatotoxicity,"To investigate the practices of physicians regarding the diagnosis and management of antituberculosis drug-induced hepatotoxicity (ATH), a cross sectional descriptive survey using a self-administered questionnaire with multiple choice questions was conducted among physicians who treated adult tuberculosis (TB) patients at 74 public hospitals in southern Thailand. Of the 272 questionnaires mailed, 204 (75%) were returned. Sixty-two physicians (31.0%) said they used alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin concurrently to diagnose ATH. Only 9.0% of physicians adhered to the American Thoracic Society (ATS) guidelines of using either an ALT or AST level. Nearly all physicians (96.6%) withheld suspected antituberculosis (anti-TB) drugs in their management of ATH patients. While waiting for normalization of liver enzyme, the alternative combination regimen of ethambutol, ofloxacin, and streptomycin (EOS) was used by most physicians (99/197). Of the 197 physicians who withheld anti-TB drugs, 175 (88.8%) decided to reintroduce them. Among these, 169 (96.6%) used a sequential rechallenge method (16.6% prescribed a full dosage, 71.4% prescribed an increasing dosage) and 1 (0.6%) used a simultaneous rechallenge method. Isoniazid was prescribed as the first drug for rechallenge in 77.5% of physicians. Only 6.5% of physicians complied with the ATS guidelines by prescribing rifampicin as the first agent. The reported practices of physicians in the diagnosis and management of ATH noticeably diverged from ATS guidelines. However, alternative regimen selection and rechallenge method complied with ATS guidelines.",1
12914,23082173,Long-term effects of intermittent IL-2 in HIV infection: extended follow-up of the INSIGHT STALWART Study,"""BACKGROUND: The Study of Aldesleukin with and without Antiretroviral Therapy (STALWART) was designed to evaluate whether intermittent IL-2 alone or with peri-cycle ART increased CD4+ cell counts (and so delayed initiation of ART) in HIV infected individuals having >/= 300 CD4+ cells/mm(3) compared to untreated controls. When the results of two large clinical trials, ESPRIT and SILCAAT, showed no clinical benefit from IL-2 therapy, IL-2 administration was halted in STALWART. Because IL-2 recipients in STALWART experienced a greater number of opportunistic disease (OD) or death and adverse events (AEs), participants were asked to consent to an extended follow-up phase in order to assess persistence of IL-2 effects. METHODOLOGY: Participants in this study were followed for clinical events and AEs every 4 months for 24 months. Unadjusted Cox proportional hazards models were used to summarize death, death or first OD event, and first grade 3 or 4 AE. PRINCIPAL FINDINGS: A total of 267 persons were enrolled in STALWART (176 randomized to the IL-2 arms and 91 to the no therapy arm); 142 individuals in the IL-2 group and 80 controls agreed to enter the extended follow-up study. Initiation of continuous ART was delayed in the IL-2 groups, but once started, resulted in similar CD4+ cell and viral load responses compared to controls. The hazard ratios (95% CI) for IL-2 versus control during the extension phase for death or OD, grade 3 or 4 AE, and grade 4 AE were 1.45 (0.38, 5.45), 0.43 (0.24, 1.63) and 0.20 (0.04, 1.03), respectively. The hazard ratios for the AE outcomes were significantly lower during the extension than during the main study. CONCLUSIONS: Adverse events associated with IL-2 cycling did not persist upon discontinuation of IL-2. The use of IL-2 did not impact the subsequent response to initiation of cART.""",1
12915,23082895,A drug fatality involving Kratom,"""A 17-year-old white man who showed no obvious signs of trauma was found unresponsive in bed and was pronounced dead at the scene. The decedent had a documented history of heroin abuse and chronic back pain and reportedly self-medicated with Kratom (mitragynine). The autopsy was remarkable only for pulmonary congestion and edema and a distended bladder, both of which are consistent with, though not diagnostic of, opiate use. A laboratory work-up revealed therapeutic levels of over-the-counter cold medications and benzodiazepines. However, of interest was a level of mitragynine at 0.60 mg/L. Given the facts of the case, the Medical Examiner certified the cause of death as """"possible Kratom toxicity"""" and the manner of death was classified as """"accident.""""""",1
12916,23084240,Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration,"""OBJECTIVE: Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab. DESIGN: Double-masked, multicenter, parallel-group, active-controlled, randomized trials. PARTICIPANTS: Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD. INTERVENTION: Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4). MAIN OUTCOME MEASURES: The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures. RESULTS: All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups. CONCLUSIONS: Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.""",1
12917,23085354,Hepatic failure during anabolic steroid therapy,,1
12918,23087723,Excess gooD can be Dangerous. A case series of iatrogenic symptomatic hypercalcemia due to hypervitaminosis D,"Vitamin D is increasingly recognized to have several beneficial effects. Its toxicity, causing hypercalcemia, is considered as extremely rare. We report case series of 15 patients (most of them being elderly subjects) with iatrogenic symptomatic hypercalcemia in whom toxicity occurred due to empirical excessive administration of vitamin D by oral and parenteral route.",1
12919,23096251,One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus,"""OBJECTIVE: The aim of this study was to assess the safety of ospemifene, a novel selective estrogen receptor modulator, for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, long-term safety extension study, nonhysterectomized women aged 40 to 80 years (n = 180) received daily oral doses of placebo, ospemifene 30 mg/day, or ospemifene 60 mg/day for 40 weeks (continued as blinded treatments from the initial 12-week pivotal efficacy study of ospemifene). The total treatment period was 52 weeks. Safety assessments included adverse events, cervical Papanicolaou tests, endometrial histology, endometrial thickness, gynecological examination, breast palpation, mammography, physical examination, and clinical safety laboratory assessments. RESULTS: No clinically significant adverse changes in safety assessments were observed in any treatment group. Most treatment-emergent adverse events were mild or moderate in severity. Hot flushes, the most frequently occurring treatment-emergent adverse event related to the study drug, had a low discontinuation rate (1.6%). No study participants discontinued because of endometrial or cervical pathology; no endometrial findings were clinically meaningful. On week 52, more than 95% of endometrial biopsy samples either were classified as atrophic or inactive or had insufficient tissue for diagnosis. There were no treatment-emergent adverse events of pelvic organ prolapse or venous thromboembolism. No cases of endometrial hyperplasia or carcinoma were observed. Only three participants (1.7%) taking ospemifene experienced vaginal bleeding or spotting, which was self-limiting. CONCLUSIONS: Daily doses of ospemifene 30 mg and ospemifene 60 mg yielded few treatment-emergent adverse events and demonstrated no significant endometrial changes during the 1-year treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus.""",1
12920,23099850,Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor,"Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St John's wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (<50 cells/mm(3)). Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N. Resistance to rilpivirine largely excludes future use of the NNRTI class.",1
12921,23103084,Visceral varicella in a patient with chronic lymphocytic leukemia treated with fludarabine: a case report,,1
12922,23106107,"Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study","""BACKGROUND: Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long-term safety. Interleukin (IL)-17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. OBJECTIVES: To assess the efficacy and safety of different doses of secukinumab, a fully human anti-IL-17A IgG1? monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 ? 25 mg (n = 29), 3 ? 25 mg (n = 26), 3 ? 75 mg (n = 21) or 3 ? 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12-week treatment period, patients entered a follow-up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator's Global Assessment (IGA) and PASI 90 and 50 response rates. RESULTS: After 12 weeks of treatment, secukinumab 3 ? 150 mg and 3 ? 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0?001 and P = 0?002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow-up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 ? 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0?005) and were consistently higher for the 3 ? 150 mg and 3 ? 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 ? 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow-up period. Secukinumab was well tolerated. Two cases of neutropenia (? grade 2) were reported in the 3 ? 150 mg cohort. CONCLUSIONS: Treatment with subcutaneous secukinumab 3 ? 75 mg and 3 ? 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate-to-severe psoriasis.""",1
12923,23109446,Greater Celandine hepatotoxicity: a clinical review,"Herbal hepatotoxicity is a rare and poorly described disease because reported cases are mostly scattered and lack an appropriate causality assessment. We now describe in detail the clinical picture of herbal hepatotoxicity by extracts of Greater Celandine (GC), syn. Chelidonium majus L. from the Papaveraceae family, which contain more than 20 ingredients including various biologically active isoquinoline alkaloids. For this purpose, we analyzed and reviewed published cases of 16 patients from various European countries. In all patients, herbal hepatotoxicity was of probable and highly probable causality for GC, using the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences). GC associated hepatotoxicity usually has an acute clinical course exhibiting a hepatocellular pattern of injury and is correlated to an idiosyncratic reaction with its metabolic subtype. Jaundice combined with high values of serum aminotransferases was present in virtually all cases with favourable outcome despite severe clinical course. In conclusion, GC hepatotoxicity is a typical herbal hepatotoxicity with a sound causality track for GC, but there is uncertainty regarding the respective causative compound(s). The present detailed review of GC hepatotoxicity may serve as an example for clinical causality assessments of future cases of liver injury due to other herbs.",1
12924,23112237,Clobazam: a newly approved but well-established drug for the treatment of intractable epilepsy syndromes,"Clobazam, a 1,5-benzodiazepine, was introduced in the 1970s as an anxiolytic and antiepileptic drug. Despite worldwide usage, it was only recently approved in the United States (seizures associated with Lennox-Gastaut syndrome). This article reviews historical and recent data to help practitioners better understand clobazam's clinical properties and usage. In many clinical trials, open-label studies, and retrospective reviews, clobazam was generally associated with ?50% seizure reduction for more than half of Lennox-Gastaut syndrome patients, with approximately 10% achieving freedom from drop attacks. Efficacy is persistent, with little evidence for development of tolerance. Clobazam's safety profile appears to be similar to that of other benzodiazepines, but with substantially decreased sedation and increased psychomotor performance. Studies suggest clobazam acts through potentiation of gamma-aminobutyric acid type A receptors in a manner similar to other benzodiazepines. However, clobazam appears to display greater selectivity for receptors responsible for anticonvulsant activity than for those involved in sedation.",1
12925,23114284,Difficult clinical management of anti-tuberculosis DRESS syndrome,"We describe 11 cases of anti-tuberculosis DRESS (drug-related rash with eosinophilia and systemic symptoms) syndrome, a potentially serious complication of treatment that led to interruption of treatment for prolonged periods, systemic corticosteroid use and the resumption of treatment with less effective regimens. All patients had rash and toxic hepatitis, one died of multi-organ failure and, contrary to expectations, the evolution of tuberculosis (advanced in most cases) did not progress under corticosteroid treatment. The drug most frequently involved was rifampicin, while retreatment schemes included, in most cases, levofloxacin, ethambutol, streptomycin and cycloserine.",1
12926,23115404,Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study,"""STUDY OBJECTIVES: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Sleep disorders and research center. PARTICIPANTS: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. INTERVENTIONS: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. MEASUREMENTS AND RESULTS: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. CONCLUSIONS: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525.""",1
12927,23116325,Randomized controlled trial comparing highly purified (HP-hCG) and recombinant hCG (r-hCG) for triggering ovulation in ART,"BACKGROUND: A randomized controlled trial (RCT) comparing highly purified human Choriogonadotrophin (HP-hCG) and recombinant hCG (r-hCG) both administered subcutaneously for triggering ovulation in controlled ovarian stimulation (COS) for Assisted Reproductive Technology (ART). METHODS: Multi-centre (n = 4), prospective, controlled, randomized, non-inferiority, parallel group, investigator blind design, including 147 patients. The trial was registered with www.clinicaltrials.gov, using the identifier: NCT00335569. The primary endpoint is the number of oocytes retrieved, while the secondary endpoints include embryo implantation, pregnancy and delivery rates as well as safety parameters. RESULTS: The number of retrieved oocytes was not inferior when HP-hCG was used as compared to r-hCG: the mean number was 13.3 (6.8) in HP-hCG and 12.5 (5.8) in the r-hCG group (p = 0.49) with a 95% CI (-1.34, 2.77). Regarding the secondary outcomes, there were also no differences in fertilization rate at 57.3% (467/815) vs. 61.3% (482/787) (p = 0.11), the number of embryos available for transfer and cryopreservation (2PN stage) and implantation, pregnancy and delivery rates. Furthermore, there were no differences in the number and type of adverse events reported. HP-hCG was therefore not inferior to r-hCG. CONCLUSIONS: HP-hCG and r-hCG are equally efficient and safe for triggering ovulation in ART and, both being administered subcutaneously, equally practical and well tolerated by patients.",1
12928,23117073,"Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial","BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (?70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 ?g/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.",1
12929,23121117,Review article: herbal and dietary supplement hepatotoxicity,"BACKGROUND: Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. AIMS: To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. METHODS: A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. RESULTS: The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. CONCLUSIONS: A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety.",1
12930,23121377,Tolvaptan in patients with autosomal dominant polycystic kidney disease,"""BACKGROUND: The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. RESULTS: Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). CONCLUSIONS: Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).""",1
12931,23122767,Lomitapide for homozygous familial hypercholesterolaemia,,1
12932,23124649,Phase II study of nedaplatin and irinotecan in patients with extensive small-cell lung cancer,"BACKGROUND: The standard chemotherapy for Japanese patients with extensive disease of small-cell lung cancer (ED-SCLC) is cisplatin and irinotecan. METHODS: Patients with untreated ED-SCLC were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan (CPT) at 50 mg/m(2) on days 1 and 8 every 4 weeks for four cycles. RESULTS: Twenty-five patients were registered. Nineteen patients were male and six female, with a median age of 64 years (50-79 years). Two patients had a performance status of 2. Nineteen of them were able to receive 4 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 8.0, 68.0, and 36.0 % of patients, respectively. Other grade 3 toxicities were SGOT, hyponatremia, fatigue, vomiting, diarrhea, hypotension, febrile neutropenia, oral hemorrhage, and pneumonia. Grade 4 fatigue occurred in one patient. There was no treatment-related death. The overall response rate was 100 %. The median progression-free and overall survivals were 6.6 and 16.0 months, respectively, and the 2-year survival rate was 28 %. CONCLUSION: NP with CPT is effective and safe for patients with ED-SCLC.",1
12933,23128910,Old and new antirheumatic drugs and the risk of hepatotoxicity,"Given the high prevalence of the use of medications in daily practice and the large number of people taking antirheumatic agents, the risk of drug-drug interactions and of hepatotoxicity is of concern. Both old and new compounds show such a risk. Nonsteroidal antinflammatory drugs are widely used drugs with potential adverse hepatic reactions. Nonsteroidal antinflammatory drugs are responsible for an important aliquot of transaminase elevation in the general population. Genetic susceptibility to diclofenac hepatotoxicity has promoted the knowledge about drug-specific, class-specific reactions. Some drugs (sulfasalazine, azathioprine, and leflunomide) may cause acute liver injury, whereas other compounds (methotrexate) may cause chronic liver damage as the result of the interaction among drug, host and environmental factors. The tumor necrosis factor-alpha inhibitor, infliximab, is associated with typical drug-induced autoimmune hepatitis. Also, the other biological disease-modifying antirheumatic drugs are not free of potential hepatotoxicity. The diagnosis of drug-induced liver injury follows the exclusion of other causes, involves a temporal relationship between drug exposure and adverse event, and should consider the potential participation of the underlying rheumatic disease to event occurrence. This article also includes data regarding hepatotoxicity from our outclinic patients receiving biological disease-modifying antirheumatic drugs.",1
12934,23131606,Repeated exposure to modern volatile anaesthetics may cause chronic hepatitis as well as acute liver injury,"""Volatile anaesthetic agents are known to cause acute hepatitis and fulminant hepatic failure in susceptible individuals. Four patients were identified with prolonged liver injury due to volatile anaesthetic-induced hepatitis. Three had liver biopsy confirmation and all gave blood for specific diagnostic tests (TFA and CYP 2E1 IgG4 antibodies). The Roussel Uclaf Causality Assessment Method (RUCAM) drug causality scale was used to determine the likelihood of volatile anaesthetics causing the chronic liver injury. We describe four cases of volatile anaesthetic hepatitis in which three evolved into chronic hepatitis. The fourth followed a more typical pattern of acute hepatitis; however, resolution took a few months. These cases all occurred with modern volatile anaesthetics, predominantly sevoflurane, and all cases were proven with specific antibody tests, liver histology and a drug causality scale. This is the first report of chronic liver injury due to volatile anaesthetic exposure.""",1
12935,23133319,Efficacy and tolerability of pharmacotherapy options for the treatment of medullary thyroid cancer,Metastatic and unresectable medullary thyroid carcinoma (MTC) is often difficult to treat as it is relatively unresponsive to radiation and conventional chemotherapy. This emphasizes the importance of the development of targeted therapies for advanced MTC. Vandetanib was approved by the US Food and Drug Administration for the treatment of symptomatic or progressive MTC in patients with advanced disease in April 2011. This therapy proved to be a breakthrough in the management of MTC. We review the efficacy and safety of this novel treatment and other treatments that are being evaluated in this disease.,1
12936,23136242,Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients,"""OBJECTIVES: Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). METHODS: Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. RESULTS: As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years' follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ?4 months after ?1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. CONCLUSIONS: This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.""",1
12937,23136357,Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet for HIV-1 infection treatment,"OBJECTIVE: To review the clinical trials, pharmacologic characteristics, safety, and efficacy of the elvitegravir/cobicistat/emtricitabine/tenofovir single tablet formulation (Stribild). DATA SOURCES: Literature searches were performed in MEDLINE (1948-September 2012) and PubMed (1966-September 2012) using the search terms GS-9137, elvitegravir, GS 9350, cobicistat, quad pill, Stribild, and integrase inhibitors. Abstracts from HIV/AIDS conferences were reviewed. STUDY SELECTION AND DATA EXTRACTION: Phase 3 studies evaluating the safety and efficacy of Stribild were preferentially evaluated, as well as relevant references from the published studies. DATA SYNTHESIS: Stribild contains complete antiretroviral therapy for HIV-1 infection in a single tablet. It is the first once-daily therapy option available with an integrase inhibitor and a novel pharmacokinetic boosting agent. Stribild has shown noninferiority in viral load suppression at 48 weeks when compared with dual nucleoside/nucleotide reverse transcriptase inhibitor and either a ritonavir-boosted protease inhibitor or nonnucleoside reverse transcriptase inhibitor regimen. Stribild was well tolerated, but some patients experienced increases in serum creatinine early in treatment that stabilized over time. CONCLUSIONS: Stribild is the first single-tablet regimen for HIV-1 infection treatment containing an integrase inhibitor. It is expected to have a prominent place in the formularies of health plans providing care for individuals with HIV-1 infection.",1
12938,23138449,Efficacy and safety of taspoglutide versus sitagliptin for type 2 diabetes mellitus (T-emerge 4 trial),"""INTRODUCTION: The efficacy and safety of taspoglutide, a long-acting human glucagon-like peptide-1 analog, were compared with sitagliptin or placebo, as adjunct to metformin, in patients with inadequately controlled type 2 diabetes. METHODS: In this randomized, double-blind, double-dummy, parallel-group trial, patients were randomized to taspoglutide 10�mg once weekly (QW), 20�mg QW, 100�mg sitagliptin once daily (QD), or placebo for 24�weeks, followed by 28-week short-term and 104-week long-term extension periods. The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) after 24�weeks. RESULTS: In this study, 666 patients (baseline HbA(1c), 7.96% [SD, 0.87]; fasting plasma glucose, 9.61�mmol/L [2.56]; body weight, 92.4�kg [19.3]) were randomized to taspoglutide 10�mg QW (n�=�190), 20�mg QW (n�=�198), 100�mg�sitagliptin QD (n�=�185), or placebo (n�=�93) for 24�weeks. After 24�weeks, least squares mean (SE) HbA(1c) reductions were greater with taspoglutide 10�mg (-1.23% [0.06]) and 20�mg (-1.30% [0.06]) versus sitagliptin (-0.89% [0.06]) or placebo (-0.10% [0.08]). Mean treatment differences with taspoglutide 10�mg and 20�mg were -0.34 (95% confidence intervals [CI]: -0.49, -0.19) and -0.41 (-0.56, -0.26) versus sitagliptin; and -1.13 (-1.31, -0.95) and -1.20 (-1.38, -1.02) versus placebo. Weight loss was greater with taspoglutide 10�mg (-1.8�kg [0.3]) and 20�mg (-2.6�kg [0.3]) than sitagliptin (-0.9�kg [0.3]) or placebo (-0.5�kg [0.4]). Effects on HbA(1c) and weight loss continued through 52�weeks of treatment. No cases of severe hypoglycemia occurred with any active treatment. Gastrointestinal adverse events, and allergic and injection-site reactions were higher in the taspoglutide groups, causing higher discontinuation rates. Anti-taspoglutide antibodies were confirmed in 46% of patients. CONCLUSION: Taspoglutide demonstrated better efficacy on glycemic control and weight loss than sitagliptin, but a high incidence of adverse events led to high discontinuation rates. The safety profile of taspoglutide in this trial was similar to other trials in the clinical program, and led to the discontinuation of dosing.""",1
12939,23141566,Human leukocyte antigen-associated drug hypersensitivity,"A growing number of associations between adverse drug reactions and alleles of the human leukocyte antigen (HLA) genes are now known. Although several models have been proposed to explain these associations, an underlying molecular basis has only recently been described. The associations between HLA-B*57:01 and abacavir hypersensitivity syndrome, and HLA-B*15:02 and carbamazepine-induced bullous skin disease have provided new insights into the mechanism associated with hypersensitivity reactions to these drugs. Here we discuss recent evidence that small molecules can interact with specific HLA to distort self-peptide presentation leading to autoimmune-like drug hypersensitivities that potentially provide clues to the mechanisms underlying other immunopathologies.",1
12940,23143207,Dose-finding study of hepatic arterial infusion of oxaliplatin-based treatment in patients with advanced solid tumors metastatic to the liver,"""BACKGROUND: Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients. PATIENTS AND METHODS: Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab. Patients were divided into two treatment arms according to KRAS mutational status and physician choice. A """"3 + 3"""" design was used. RESULTS: Among 76 patients (median age 61 years; 34 women; median number of prior therapies 4), the most common cancer was colorectal (CRC) (n = 58). Overall, the only dose-limiting toxicity was Grade 3 diarrhea (n = 2). The most common treatment-related toxicities were hypertension (n = 40), nausea (n = 29), fatigue (n = 28), and transaminitis (n = 26). Of 76 patients, one (1 %) had a complete response (CR), 12 (16 %) had a partial response (PR), and 12 (16 %) had SD for ? 6 months (total CR/PR/SD ? 6 months 25/76 = 33 %). In CRC (n = 58), total CR/PR/SD ? 6 months was 31 % (n = 18). Both patients with pancreatic neuroendocrine tumors achieved a PR (24+ months) and a CR (6+ months). Time to treatment failure (TTF) on the current regimen was 3.5 versus 2.8 months on patients' prior systemic treatment (p = 0.37). CONCLUSIONS: HAI oxaliplatin combination therapy with 5-fluorouracil, leucovorin, bevacizumab, and/or cetuximab was well tolerated and had antitumor activity in selected heavily pretreated patients with predominant liver disease.""",1
12941,23144450,Long-term safety of pegloticase in chronic gout refractory to conventional treatment,"""OBJECTIVE: To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout. METHODS: This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy. RESULTS: Patients (n=149) received a mean?SD of 28?18 pegloticase infusions and were followed for a mean of 25?11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained <6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence. CONCLUSIONS: The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.""",1
12942,23146476,Transplantation for acute liver failure: report of results in the region of Castilla y Leon (Spain) after 10 years of activity,"""Acute liver failure is an uncommon disease but its overall mortality rate is still high without liver transplantation, which is the treatment of choice for patients achieving certain criteria. We have reported herein the experience and retrospectively analyzed results of liver transplantation for acute liver failure since the beginning of activity of our group, which is the only one in the region of """"Castilla y Leon"""" (Spain). In 10 years, 14 patients underwent emergency transplantation among an overall series of 325 subjects. The patients were generally young men and women; the average wait list time was 2.14 days. The most common etiology was toxic exposure (no cases were related to acetaminophen overdose), followed by viral infection (all because of acute hepatitis B). Our posttransplant outcomes were: perioperative mortality, 0%; posttransplant in-hospital mortality, 14%; and 1-y, 3-y, and 5-year survival rates of 77.1%, 64.3%, and 64.3% respectively. Retransplantation rate was 7%. A major morbidity occurred in four patients: one primary dysfunction, one hyperacute rejection due to ABO blood group-incompatibility requiring retransplantation, two arterial complications, and two biliary leakages. Our outcomes of emergency transplantation were similar to those reported by both the European and Spanish Liver Transplantation Registries, despite the small number of patients.""",1
12943,23148576,Acute portal vein thrombosis precipitated by indomethacin in a HCV-positive elderly patient,"""BACKGROUND: An increased risk of venous thromboembolism has been reported in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). We describe a case of acute portal vein thrombosis (PVT) in a hepatitis C virus (HCV)-positive elderly patient following administration of indomethacin. CASE PRESENTATION: A 79-year-old HCV-positive man was hospitalized for severe abdominal pain, nausea and vomiting, 15 days after starting indomethacin for back pain. Clinical signs and imaging evaluations disclosed a picture of PVT. Indomethacin was discontinued, and the patient was started on fondaparinux and antithrombin. He was discharged 15 days later due to improvement of his clinical conditions. Thirty days later, a follow-up ultrasound did not show appreciable signs of PVT. The time elapsing between the start of analgesic therapy and PVT onset suggests a role of indomethacin as the triggering agent. Indomethacin could have precipitated PVT by a combination of at least two detrimental mechanisms: 1) direct action on liver vascular endothelium by inhibition of prostacyclin biosynthesis; 2) damage to the intestinal mucosa, followed by inflammatory and pro-coagulant activation of portal endothelium upon exposure to bacterial endotoxins. CONCLUSIONS: This case can be of interest to physicians, who should exert caution when prescribing NSAIDs for inflammatory pain in patients with background inflammatory dysfunctions of the portal vein endothelium.""",1
12944,23151650,Efficacy of prophylactic lamivudine to prevent hepatitis B virus reactivation in B-cell lymphoma treated with rituximab-containing chemotherapy,"PURPOSE: Reactivation of hepatitis B virus (HBV) is a common complication in patients with HBV infection who receive cytotoxic chemotherapy. In rituximab-containing chemotherapy for B-cell lymphoma, severe hepatitis due to HBV reactivation occurred. The aim of this study is to estimate the effect of prophylactic lamivudine on the risk of HBV reactivation in patients with HBV infection who receive rituximab-containing chemotherapy. METHODS: In this study, HBV markers and liver function tests were monitored in 268 consecutive patients with B-cell lymphoma, who received rituximab-containing chemotherapy between January 2008 and November 2011. Sixty-nine patients (25.7 %) with either chronic HBV infection or past HBV infection received prophylaxis with lamivudine 100 mg daily by oral intake. RESULTS: In the HBsAg-positive group, six (6/38) patients developed hepatitis, only one of which was attributed to HBV reactivation. In the HBsAg-negative and HBcAb-positive group, two (2/31) patients developed hepatitis, none of which was attributed to HBV reactivation. CONCLUSIONS: These results support that prophylactic lamivudine can prevent HBV reactivation for B-cell lymphoma with HBV infection who was receiving rituximab-containing chemotherapy.",1
12945,23155684,Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts,"Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are the most common drugs used today in cases of adolescent thyrotoxicosis. Skepticism has been growing regarding the use of PTU in childhood and its association with severe liver failure. The aim of this review is to present all the recent data regarding pathogenesis of PTU hepatotoxicity in children and adolescents. Specifically, reactive drug metabolites and increased oxidative stress can directly activate inflammatory and immunological pathways. Drugs are not only immunogenic because of their chemical reactivity but also because they may bind through electrostatic forces to available T-cell receptors. Redox modulation is also a key regulatory strategy in the adaptive immune system. Subtle changes in the extracellular redox status may cause profound functional changes in redox-sensitive proteins. Genetic factors that affect drug biotransformation could also be implicated in this mechanistic model of PTU-related hepatotoxicity. Further studies are needed to fully understand the pathophysiology of PTU-induced liver damage.",1
12946,23161902,"Clinical efficacy, radiographic and safety findings through 2 years of golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of the randomised, placebo-controlled GO-REVEAL study","OBJECTIVES: To assess long-term golimumab efficacy/safety in patients with active psoriatic arthritis (PsA). METHODS: Adult PsA patients (>/=3 swollen, >/=3 tender joints, active psoriasis) were randomly assigned to subcutaneous injections of placebo, golimumab 50 mg or 100 mg every 4 weeks (q4wks) through week 20. All patients received golimumab 50 or 100 mg beginning week 24. Findings through 2 years are reported. Efficacy evaluations included >/=20% improvement in American College of Rheumatology (ACR20) response, good/moderate response in Disease Activity Scores incorporating 28 joints and C-reactive protein (DAS28-CRP), >/=75% improvement in Psoriasis Area and Severity Index (PASI75) and changes in PsA-modified Sharp/van der Heijde scores (SHS). RESULTS: Golimumab treatment through 2 years was effective in maintaining clinical response (response rates: ACR20 63%-70%, DAS28-CRP 77%-86%, PASI75 56%-72%) and inhibiting radiographic progression (mean change in PsA-modified SHS in golimumab-treated patients: -0.36), with no clear difference between doses. No new safety signals were identified through 2 years. With the study's tuberculosis screening and prophylactic measures, no patient developed active tuberculosis through 2 years. CONCLUSIONS: Golimumab 50 and 100 mg for up to 2 years yielded sustained clinical and radiographic efficacy when administered to patients with active PsA. Increasing the golimumab dose from 50 to 100 mg q4wks added limited benefit. Golimumab safety through up to 2 years was consistent with other antitumour necrosis factor alpha agents used to treat PsA. Treatment of patients with latent tuberculosis identified at baseline appeared to be effective in inhibiting the development of active tuberculosis.",1
12947,23165696,"Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis","OBJECTIVE: The objective of this article is to evaluate the efficacy and safety of gabapentin enacarbil (GEn) for migraine prophylaxis. METHODS: In this randomized, double-blind, parallel-group study, patients with International Headache Society-defined migraine who met criteria suggesting the need for prophylactic therapy were randomized 2:1:2:2:1 to one of the following five groups, designated according to target daily dose of study medication during the 20-week treatment period: placebo, GEn 1200 mg, GEn 1800 mg, GEn 2400 mg, or GEn 3000 mg. RESULTS: The intent-to-treat population included 523 patients (n = 128 placebo, n = 66 GEn 1200 mg, n = 134 GEn 1800 mg, n = 133 GEn 2400 mg, n = 62 GEn 3000 mg). No statistically significant difference between active treatment (the average of 1800 mg and 2400 mg treatment groups) and placebo was found for change from baseline in the number of migraine headache days during the last four weeks of treatment prior to taper (the primary endpoint). Results of analyses of the primary endpoint using the per protocol population, analyses using imputation methods different from those of the primary analysis, and nonparametric analyses were consistent with the primary analysis in showing no difference between active treatment and placebo. The pattern of results was similar for the secondary efficacy endpoints. Pharmacokinetic data demonstrate that patients had adequate estimated exposure to GEn. The adverse event profile of GEn was consistent with that in previous studies. CONCLUSION: GEn did not significantly differ from placebo for migraine headache prophylaxis. A high placebo effect should be considered when interpreting these results.",1
12948,23168376,A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol,"BACKGROUND AND AIMS: A skewed thiopurine metabolism is a phenomenon associated with both poor treatment response and toxicity. Our aim was to evaluate the frequency of this phenomenon and the relationship to thiopurine methyltransferase (TPMT) function. METHODS: All thiopurine metabolite measurements in adult patients (n=4033) between January 2006 and April 2012 were assessed to evaluate the occurrence of a skewed metabolism and the relationship to TPMT genotype and activity. RESULTS: A skewed metabolism was observed in 14% of all patients. It only developed in patients with a normal TPMT genotype, but was observed at all TPMT activity levels within the normal range (9.1-24.2 U/ml RBC). Two cases that illustrate typical clinical scenarios of a skewed metabolism and the effect of combination treatment with low-dose azathioprine and allopurinol are presented. CONCLUSIONS: A skewed metabolism is a common clinical phenomenon in patients with a normal TPMT function, which can develop at all TPMT activity levels within the normal range. We suggest that metabolite measurements should be considered in patients not responding to treatment and in those with hepatotoxicity or myelotoxicity in order to detect a skewed metabolism, since this phenomenon can be successfully managed by a combination of low-dose azathioprine and allopurinol.",1
12949,23177514,"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial","""BACKGROUND: No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. METHODS: We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. FINDINGS: Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6?4 months in the regorafenib group versus 5?0 months in the placebo group (hazard ratio 0?77; 95% CI 0?64-0?94; one-sided p=0?0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). INTERPRETATION: Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. FUNDING: Bayer HealthCare Pharmaceuticals.""",1
12950,23177516,Evaluation of regorafenib in colorectal cancer and GIST,,1
12951,23178933,Analysis of anonymous pooled urine from portable urinals in central London confirms the significant use of novel psychoactive substances,"AIM: Analysis of urine samples collected across a city centre, for the detection of novel psychoactive substances (NPS). DESIGN: Cross-sectional study of anonymized urine samples used for the analysis of classical recreational drugs, NPS and metabolites. METHODS: Pooled urine samples collected from portable stand-alone four-person urinals across a city centre were analysed using full-scan accurate-mass high-resolution liquid chromatography coupled to tandem mass spectrometry. Data were processed against compound databases containing >1700 drug compounds and metabolites. RESULTS: Seven established recreational drugs (3,4-methylenedioxyamphetamine, cocaine, cannabis, ketamine, 3,4-methylenedioxy-N-methylamphetamine, methamphetamine and amphetamine) and six potential NPS [hordenine (all 12 urinals), cathine (11), methylhexaneamine (9), 4-methylmethcathinone (6), methiopropamine and metabolites (2) and methoxetamine and metabolites (1)] were detected. Methylhexaneamine, methiopropamine and hordenine are currently uncontrolled in the UK, whereas methoxetamine is currently subject to a Temporary Class Drug Order. Metabolites of the anabolic steroid nandrolone were found in two urinals and trenbolone metabolites and clenbuterol in one urinal. CONCLUSION: Analysis of pooled urine samples collected anonymously from stand-alone urinals in a large inner city can detect the use of recreational drugs, NPS and anabolic steroids. Metabolite detection indicates actual drug use, metabolism and elimination rather than simply discarded drugs in the urinals. This technique by confirming the actual drug(s) used has the potential to be additive to currently used datasets/key indicators providing more robust information for healthcare authorities, legislative and law enforcement on the drugs actually being used.",1
12952,23179639,Sunitinib adverse events in metastatic renal cell carcinoma: a meta-analysis,"""BACKGROUND: Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated survival benefit in patients with metastatic renal cell carcinoma (mRCC); however, significant adverse events (AEs) have been associated with its use. The significant variation in the reported incidences of AEs has prompted this meta-analysis to quantify the risk and explore associated predictors. METHODS: According to predefined selection criteria, a literature search identified 12 studies that were included in the analyses. RESULTS: The meta-analysis included 5,658 patients; 66�% patients had prior systemic therapy whereas the remaining patients (34�%) received sunitinib in the first-line setting. For any grade toxicity, skin rash, fatigue, diarrhea, and mucositis were the most frequently encountered events (81, 52, 45, and 33�%, respectively). Anemia, neutropenia, or thrombocytopenia of any grade occurred in more than one-third of patients, although grades 3 or 4 were less common. Any grade raised by liver enzymes or serum creatinine occurred in 40 and 44�% of patients, respectively. Meta-regression analyses showed that study size was inversely related to the risk of experiencing fatigue, diarrhea, mucositis, anemia, and thrombocytopenia. In particular, the incidence of AEs was higher when sunitinib was used in pretreated versus naive patients; however, there was no significant difference between the two groups concerning the incidence of laboratory abnormalities. We addressed the limitations of reporting AEs in clinical studies. CONCLUSIONS: The present meta-analysis quantified sunitinib-associated AEs. The derived estimates would be similar to that to be expected from the use of sunitinib in community practice in unselected patients with metastatic renal cell carcinoma (mRCC).""",1
12953,23182291,[Severe hepatitis in a patient with adult-onset Still's disease treated with anakinra],"INTRODUCTION: Adult-onset Still's disease is characterized by non-specific polymorphic features. The efficacy of anakinra, an IL-1 receptor antagonist, has been shown in several studies. This medication is well-tolerated, and only one case of severe hepatitis has been previously reported. CASE REPORT: A 22-year-old woman presented with fever, rash, arthritis, and pericarditis, associated with systemic inflammatory response syndrome and elevated ferritin serum level with low glycosylated ferritin. Adult-onset Still's disease was diagnosed, but treatment with steroids did not achieve remission. The patient was then treated with anakinra, which resulted in spectacular improvement, but 3 weeks after the initiation of the treatment she experienced severe hepatitis that resolved after the discontinuation of anakinra. CONCLUSION: Hepatitis is a rare side effect of anakinra and the monitoring of liver tests should be recommended during anakinra therapy.",1
12954,23182850,Hyperthermic isolated liver perfusion with melphalan and bevacizumab,"Whereas surgical resection is the only curative treatment for liver tumors, effective treatment for isolated unresectable lesions when there is tumor progression in spite of several lines of chemotherapy remains to be found. We report herein two cases of patients treated by a 1-hour Hyperthermic Isolated Liver Perfusion (HILP) with a combination of melphalan and bevacizumab leading to complete response. The first patient had liver metastases secondary to previously resected malignant glucagonoma and the second, recurrent hepatocellular carcinoma. We used bevacizumab in association with melphalan for HILP because of the additional effect of an anti-VEGF antibody in these highly vascularized tumors and its locally restricted delivery to the isolated hepatic vascular compartment despite of its classic contraindication in association with surgery. The protocol was approved by the Ethics Committee. Enhanced CT scans during follow-up showed complete tumor necrosis as early as the second postoperative day. Patients had 27 and 7 months disease-free survival and 48 and 41 months overall survival after HILP, for neuroendocrine liver metastases and HILP plus liver transplantation for HCC respectively. Under very specific conditions, bevacizumab in HILP can provide excellent tumor response in hopeless clinical cases of liver tumors.",1
12955,23183319,Linaclotide (Linzess) for constipation,,1
12956,23183526,Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options,"""BACKGROUND & AIMS: Improved therapeutic options for chronic hepatitis C virus (HCV) infection are needed for patients who are poor candidates for treatment with current regimens due to anticipated intolerability or low likelihood of response. METHODS: In this open-label, phase 2a study of Japanese patients with chronic HCV genotype 1b infection, 21 null responders (<2 log?? HCV RNA reduction after 12 weeks of peginterferon/ribavirin) and 22 patients intolerant to or medically ineligible for peginterferon/ribavirin therapy received dual oral treatment for 24 weeks with the NS5A replication complex inhibitor daclatasvir (DCV) and the NS3 protease inhibitor asunaprevir (ASV). The primary efficacy end point was sustained virologic response at 12 weeks post-treatment (SVR??). RESULTS: Thirty-six of 43 enrolled patients completed 24 weeks of therapy. Serum HCV RNA levels declined rapidly, becoming undetectable in all patients on therapy by week 8. Overall, 76.7% of patients achieved SVR?? and SVR??, including 90.5% of null responders and 63.6% of ineligible/intolerant patients. There were no virologic failures among null responders. Three ineligible/intolerant patients experienced viral breakthrough and four relapsed post-treatment. Diarrhea, nasopharyngitis, headache, and ALT/AST increases, generally mild, were the most common adverse events; three discontinuations before week 24 were due to adverse events that included hyperbilirubinemia and transaminase elevations (two patients). CONCLUSIONS: Dual therapy with daclatasvir and asunaprevir, without peginterferon/ribavirin, was well tolerated and achieved high SVR rates in two groups of difficult-to-treat patients with hepatitis C virus genotype 1b infection.""",1
12957,23185842,"Asenapine: a less effective, yet, more dangerous neuroleptic!","""The preferred treatment for manic episodes in patients with bipolar disorder is lithium, a """"mood stabiliser"""". A well-documented neuroleptic such as haloperidol may be added when severe psychotic symptoms are also present. Asenapine, an """"atypical"""" neuroleptic, is authorised in the European Union solely for the treatment of manic episodes in patients with bipolar disorder. It is administered sublingually, because oral absorption is virtually zero. Clinical evaluation of asenapine includes no trials versus lithium or versus another neuroleptic in patients also receiving lithium. Two double-blind randomised trials versus both placebo and olanzapine included a total of 976 patients. Another double-blind randomised placebo-controlled trial included 323 patients who were also receiving a mood stabiliser. In two of these three trials, the clinical relevance of the differences found between the asenapine and placebo groups was questionable. A comparison between asenapine and olanzapine, not planned in the protocol, favoured olanzapine. Serious adverse events were more common in the asenapine groups than in the groups receiving other neuroleptics. The adverse effect profile of asenapine largely overlaps that of other atypical neuroleptics. However, asenapine can also cause oral hypoaesthesia and severe hypersensitivity reactions (angioedema, hypotension, skin reactions, etc).Tardive dyskinesia has also been reported with asenapine. Sublingual administration may be impractical during a manic episode. Other neuroleptics are available for patients who have difficulty swallowing, such as oral solutions and orodispersible tablets. In practice, clinical trials of asenapine were not designed to answer questions posed by healthcare professionals and patients. Asenapine is no more effective or convenient to use than other neuroleptics, while it carries a risk of additional, sometimes severe, adverse effects. Patients with manic episodes should continue to receive lithium first, combined with a well-documented neuroleptic such as haloperidol if they have severe psychotic symptoms.""",1
12958,23190221,Ponatinib in refractory Philadelphia chromosome-positive leukemias,"""BACKGROUND: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. METHODS: In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). RESULTS: Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. CONCLUSIONS: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).""",1
12959,23190413,"Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs","""BACKGROUND AND AIM: Treatment with antituberculosis (TB) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N-acetyltransferase 2 (NAT-2) and cytochrome P450 2E1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT-2 and CYP2E1 polymorphisms with the development of anti-TB drug-induced hepatotoxicity (ATDH). METHODS: One hundred and seventy-five TB patients who had been treated with anti-TB drugs were studied. The allelic and genotypic frequency distributions of the NAT-2 and CYP2E1 enzymes were studied using polymerase chain reaction-restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity. RESULTS: Having a slow acetylator status (odds ratio [OR] = 2.615; confidence interval [CI] = 1.264-5.411; P = 0.01), being female (OR = 2.734; CI = 1.325-5.639, P = 0.006), and having Bolivian ethnicity (OR = 2.711; CI = 1.307-6.625, P = 0.007) were found to be independent predictor variables for ATDH. CONCLUSIONS: This study showed that a patient's NAT-2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP2E1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients' acetylator status prior to or at the beginning of the TB treatment regimen.""",1
12960,23194469,"Prevalence of thyrotoxicosis, antithyroid medication use, and complications among pregnant women in the United States","BACKGROUND: Population-based estimates of the prevalence of thyrotoxicosis (TTX), the frequency of antithyroid drug (ATD) use, and risk of adverse events in pregnant women and their infants are lacking. Therefore, our objective was to obtain epidemiologic estimates of these parameters within a large population-based sample of pregnant women with TTX. METHODS: A retrospective claims analysis was performed from the MarketScan Commercial Claims and Encounters health insurance database for the period 2005-2009. Women aged 15-44 years, enrolled for at least 2 years, and who had a pregnancy during the study period were included. Diagnosis of TTX was based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes using narrow (TTX-1=ICD 242.0) and broad (TTX-2=ICD 242.0 or 242.9) definitions. ATD use was based on prescriptions filled for propylthiouracil (PTU) or methimazole (MMI). Adverse events in mothers and infants were determined from the ICD-9-CM diagnosis codes recorded on submitted claims. RESULTS: The database contained 904,497 eligible women. The average yearly prevalence per 1000 pregnant women was 2.46 for TTX-1 and 5.88 for TTX-2. Thirty-nine percent used ATD at any time during the study period. Compared to women without a TTX diagnosis, there was more than a twofold increase for liver disease among women with TTX (odds ratio [OR]=2.08, p<0.001) and a 13% increased risk for congenital anomalies (OR=1.13, p=0.014), but no association was observed with ATD use. The rates of congenital defects (per 1000 infants) associated with ATD use were 55.6 for MMI, 72.1 for PTU, and 65.8 for untreated women with TTX, compared to 58.8 among women without TTX. CONCLUSIONS: There was some indication of an elevated risk of liver disease and congenital anomalies in women with TTX, but the risk did not appear to be related to the ATD use. There seems to be a higher pregnancy termination rate for women with TTX on MMI, which likely reflects elective pregnancy terminations.",1
12961,23196726,Benzbromarone: a double-edged sword that cuts the liver?,,1
12962,23197951,Massive colchicine overdose with recovery,"Colchicine is an active alkaloid that is commonly used for treatment of multiple diseases including gout, primary biliary cirrhosis and familial Mediterranean fever. Less commonly, it has been implicated in several fatal overdoses. Deaths from colchicine overdoses are usually due to multi-organ failure, whether directly from colchicine toxicity or due to ensuing sepsis. We report an extreme case of colchicine ingestion (1.38 mg/kg), which is the largest reported non-fatal colchicine overdose. The patient was a 47-year-old First Nations woman with a history of depression and no other comorbidities. Ingestion was intentional and initial presentation was within 2 h of ingestion, at which point she had normal clinical and laboratory parameters. Early implementation of a targeted therapeutic strategy directed at the predicted multi-organ failure which included aggressive use of a GI decontamination protocol, timely supportive measures including ventilator support and renal replacement therapy, as well as the utilization of broad-spectrum antibiotics and G-CSF for sepsis and leucopenia management, resulted in successful support and discharge of this patient off dialysis.",1
12963,23203167,Corneal depositions in tyrosinaemia type I during treatment with Nitisinone,"We present a 17-year-old boy, diagnosed with tyrosinaemia type I at an age of 7 months, with new complaints of severe intermittent photophobia and burning eyes. His tyrosinaemia type I is treated with nitisinone and a protein-restricted diet. Dietary compliance is low since he entered puberty. His ocular complaints are attributable to subepithelial corneal deposits, resembling the common corneal phenotype of tyrosinaemia type II. Serum tyrosine levels were markedly elevated. Tyrosinaemia is a metabolic disease of tyrosine metabolism, subdivided into two types. Corneal deposits and photophobia are cardinal features of untreated tyrosinaemia type II, but not of type I. Novel treatment strategies (with nitisinone) for type I tyrosinaemia lead to a phenotype comparable with type II, including these corneal deposits. At follow-up visits his ocular complaints unfortunately remained unchanged, though he states his dietary compliance improved through the years.",1
12964,23212147,?3-Adrenoceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men,"PURPOSE: To investigate the safety and efficacy of mirabegron for patients with overactive bladder (OAB) that is unresponsive to antimuscarinic agents or is related to benign prostatic hyperplasia (BPH). METHODS: Fifty-two newly diagnosed OAB patients (M group) and 45 patients with OAB that was unresponsive to antimuscarinics (S group) received mirabegron 50 mg once daily and were evaluated by OAB symptom score (OABSS), IPSS-QOL index, and IPSS at the time of baseline, 4 and 8 weeks. Newly diagnosed OAB patients treated with antimuscarinic agents were compared as controls. RESULTS: Mirabegron was effective for 85.2 % in M group. Significant improvements were seen in each domain of OABSS, and there was no significant difference with antimuscarinic therapy. Mirabegron was efficacious for 61.6 % of S group, and significant decreases of OABSS and IPSS-QOL index were observed. Significant improvements were also seen in voiding symptoms in men. Post-void residual urine volumes before and after treatment were 32.1 and 34.8 ml, and 26.2 and 31.3 ml in M and S group, respectively, and there was no significant difference. The incidence of adverse events was 8.4 %, although none were serious, and the patients recovered spontaneously after mirabegron was discontinued. CONCLUSION: The present study suggests mirabegron is as effective as antimuscarinics for OAB. It improves OAB symptoms in patients with OAB for which antimuscarinic agents are insufficient. This study revealed that mirabegron improves not only OAB symptoms related to BPH, but also voiding symptoms in men. Low and mild incidences of side effects support the safe utility of mirabegron.",1
12965,23212430,"Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects","""Kratom (Mitragyna speciosa) is a plant indigenous to Thailand and Southeast Asia. Kratom leaves produce complex stimulant and opioid-like analgesic effects. In Asia, kratom has been used to stave off fatigue and to manage pain, diarrhea, cough, and opioid withdrawal. Recently, kratom has become widely available in the United States and Europe by means of smoke shops and the Internet. Analyses of the medical literature and select Internet sites indicate that individuals in the United States are increasingly using kratom for the self-management of pain and opioid withdrawal. Kratom contains pharmacologically active constituents, most notably mitragynine and 7-hydroxymitragynine. Kratom is illegal in many countries. Although it is still legal in the United States, the US Drug Enforcement Administration has placed kratom on its """"Drugs and Chemicals of Concern"""" list. Physicians should be aware of the availability, user habits, and health effects of kratom. Further research on the therapeutic uses, toxic effects, and abuse potential of kratom and its constituent compounds are needed.""",1
12966,23214106,"""[Case report; a case of biliary pseudolithiasis associated with ceftriaxone]""",,1
12967,23216982,Anti-malarial drug safety information obtained through routine monitoring in a rural district of South-Western Senegal,"""BACKGROUND: Knowing the safety profile of anti-malarial treatments in routine use is essential; millions of patients receive now artemisinin combination therapy (ACT) annually, but the return on information through current systems is as yet inadequate. Cohort event monitoring (CEM) is a WHO (World Health Organization)-recommended practice; testing its performance and feasibility in routine practice in malaria-endemic is important. METHODS: A nine-year CEM-based study of the safety of artesunate-amodiaquine (ASAQ) at five peripheral health facilities in a rural district of South-western Senegal. Staff (nurses, health workers) were trained to collect actively and systematically information on the patient, treatment and events on a purposely designed questionnaire. The occurrence and severity of events was collected before, during and after treatment up to 28 days in order to generate information on all adverse events (AEs) as well as treatment-emerging signs/symptoms (TESS). Laboratory tests (haematology, liver and renal) was planned for at least 10% of cases. RESULTS: During 2001-2009, 3,708 parasitologically-confirmed malaria cases (mean age = 16.0 +/- 12.7 years) were enrolled (26% and 52% of all and parasitologically-confirmed ASAQ treatments, respectively). Treatment was supervised in 96% of cases. Products changed over time: 49% were a loose combination of individually-packaged products (available 2001-03), 42% co-blistered products (2004-09) and 9% a fixed-dose co-formulation (2006-09); dosing was age-based for 42%, weight-based for 58%. AS and AQ were correctly dosed in 97% and 82% of cases with the loose and 93% and 86% with the fixed combination, but only 50% and 42% with the co-blistered product.Thirty-three per cent (33%) of patients had at least one sign/symptom pre-treatment, 12% had at least one AE and 9% a TESS (total events 3,914, 1,144 and 693, respectively). AEs overestimated TESS by 1.2-2 fold (average 1.7). Changes in laboratory value were insignificant. Over-dosing more than doubled the risk of TESS, though statistical significance was reached only during 2003-2007. The incidence of serious events (including death) was five per thousand. CONCLUSIONS: The study was successful in quantifying and characterizing known reactions and has benchmarking value. Health staff performance varied. Investments in training, motivating and providing a quality control system would be needed. The study proved that a CEM-based system is feasible in this setting but more research is needed to assess whether it is sustainable and what conditions would make it cost-effective, including the amount and quality of data generated, and the use thereof for decision-making.""",1
12968,23225901,Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study,"""BACKGROUND: Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance. METHODS: Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ?0.7 log(10) copies/mL from baseline or was <400 copies/mL. RESULTS: A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. CONCLUSION: Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.""",1
12969,23231846,The safety of methimazole and propylthiouracil in pregnancy: a systematic review,"""BACKGROUND: Hyperthyroidism is one of the most common endocrine disorders in pregnant women, and it can severely complicate the course and outcome of pregnancy. Methimazole (MMI) and propylthiouracil (PTU) are the standard anti-thyroid drugs used in the treatment of hyperthyroidism in pregnancy. Traditionally, MMI has been considered to have clearer evidence of teratogenicity than PTU. Recent studies suggest that PTU can be hepatotoxic, leading to a United States Food and Drug Administration """"black box alert."""" We wished to systematically review the effects of PTU and MMI during pregnancy, and to compare maternal and fetal safety. METHODS: We conducted a systematic search of PubMed, EMBASE, TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google. Both English and non-English publications were included. We excluded studies using anti-thyroid therapies other than PTU and MMI, studies not allowing interpretation of results, and abstracts of meetings. RESULTS: Overall, insufficient statistical power precluded determination of accurate rates of either MMI teratogenicity or PTU hepatotoxicity in cohort studies. However, a case-control study helped identify the relative risk of MMI-induced choanal atresia. A second case-control study failed to show that aplasia cutis congenita is associated with MMI. PTU has been associated with a rare but serious form of hepatic failure. CONCLUSION: MMI causes a specific pattern of rare teratogenic effects after first trimester exposure, while PTU therapy may be followed by rare but severe hepatotoxic sequelae. It is therefore appropriate to use PTU to treat maternal hyperthyroidism during the first trimester of pregnancy, and to switch to MMI for the remainder of the pregnancy.""",1
12970,23234465,Fulminant hepatic failure in association with quetiapine: a case report,"INTRODUCTION: Fulminant hepatic failure is a serious disease with significant mortality and morbidity. Identifying the exact cause of hepatic failure and predicting prognosis is of paramount importance in managing such patients. Drug-induced liver injury is a common but challenging entity to treat. The use of newer drugs and medications with previously unknown hepatotoxicity add to the challenges faced by treating physicians. Quetiapine is an antipsychotic that has rarely been linked to acute liver injury. In the present work we describe a case of fulminant hepatic failure secondary to use of quetiapine. CASE PRESENTATION: A 59-year-old Caucasian woman with known Parkinson's disease was being treated with quetiapine for hallucinations. She was referred to our hospital with yellow discoloration of the sclera and later on developed clinical features suggestive of hepatic encephalopathy. A diagnosis of fulminant hepatic failure was made following her admission to the intensive care unit. Her condition improved after discontinuing the drug and providing the standard supportive treatment. CONCLUSIONS: Our findings in the present report emphasize the importance of keeping an open mind in cases of fulminant hepatic failure. As drug-induced hepatotoxicity is the most common cause of fulminant hepatic failure in many parts of the world, consideration should be given to the medication(s) patients receive as the potential cause and a review of this list should be part of the clinical care given.",1
12971,23234725,Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study,"BACKGROUND: Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. METHODS: After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (>/=2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (>/=1 unit decrease by Ishak scoring system). FINDINGS: Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0.0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (>/=1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0.0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. INTERPRETATION: In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. FUNDING: Gilead Sciences.",1
12972,23239775,Acute liver injury associated with glucosamine dietary supplement,"A 55-year-old woman taking �over-the-counter (OTC) glucosamine developed symptomatic hepatotoxicity. Several of her liver enzymes were elevated to 10 times the upper limit of normal. One week after discontinuing glucosamine, serum transaminases fell dramatically, with some returning to normal limits. Four weeks after glucosamine was discontinued, all her liver tests were normal. Rechallenge was not attempted. The potential causes of hepatocellular injury were evaluated. Glucosamine is a dietary supplement available in a wide variety of commercial preparations, primarily used for joint relief in osteoarthritis. Despite the extensive use of glucosamine supplements, significant elevations of transaminases are rare. The mechanism of hepatotoxicity in many OTC herbal preparations is unknown. It is vital for physicians to elicit a careful history of OTC medications and educate their patients on their potential adverse effects.",1
12973,23248257,Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor,"""PURPOSE: BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. PATIENTS AND METHODS: This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. RESULTS: In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. CONCLUSION: Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.""",1
12974,23250120,Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults,"""N-acetyl-glutamate synthase (NAGS) deficiency is a rare autosomal recessive urea cycle disorder (UCD) that uncommonly presents in adulthood. Adult presentations of UCDs include; confusional episodes, neuropsychiatric symptoms and encephalopathy. To date, there have been no detailed neurological descriptions of an adult onset presentation of NAGS deficiency. In this review we examine the clinical presentation and management of UCDs with an emphasis on NAGS deficiency. An illustrative case is provided. Plasma ammonia levels should be measured in all adult patients with unexplained encephalopathy, as treatment can be potentially life-saving. Availability of N-carbamylglutamate (NCG; carglumic acid) has made protein restriction largely unnecessary in treatment regimens currently employed. Genetic counselling remains an essential component of management of NAGS.""",1
12975,23250699,Drug-induced liver injury in the elderly,"""Historically, the elderly have been considered to be at increased risk for drug-induced liver injury (DILI). Animal studies have demonstrated changes in hepatic physiology that affect drug metabolism in the aging liver; however, there is no evidence that this leads to any appreciable deterioration of liver function in healthy older humans. Updated data from international DILI registries give us pause to consider whether the elderly are truly at increased risk to develop hepatic injury. Instead, hepatotoxicity in the elderly appears to be more a function of drug exposure, polypharmacy and drug-drug interactions. Isoniazid and benoxaprofen are the only two agents with a well-studied correlation between increasing age and risk of DILI. Nevertheless, given the increasing proportion of patients over age 65 in the U.S. and abroad, the influence of age on the risk of DILI is the focus of this review.""",1
12976,23252526,Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis,"""BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1? monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ?2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ?1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).""",1
12977,23252566,Triptorelin in the management of prostate cancer,"Among the therapies to achieve medical castration, gonadotropin-releasing hormone (GnRH) agonists have better safety profiles than estrogens and anti-androgens. In addition, slow-release formulations of GnRH agonists offer patients flexibility, improve quality of life and eventually reduce cost. To illustrate the role of medical castration in prostate cancer, this paper reviews data on the GnRH agonist triptorelin long-duration and shorter-duration formulations. A similar proportion of patients achieved and maintained castration levels of serum testosterone (?50 ng/dl) with all triptorelin formulations. Moreover, using a stricter definition of medical castration (serum testosterone <20 ng/dl), castration was maintained in >90% of patients with the 6-month triptorelin formulation. The new formulation was also well-tolerated, whilst being more convenient for patients. This short review assesses the role of this GnRH agonist in the treatment of prostate cancer.",1
12978,23252949,Genetic risk factors for drug-induced liver injury in rheumatoid arthritis patients using low-dose methotrexate,"Low-dose methotrexate (MTX) is part of the mainstay of rheumatoid arthritis treatment. Hepatotoxicity is among the most feared side effects of low-dose MTX and is associated with increased morbidity. At present, histological evaluation of liver biopsies is the gold standard to retrospectively diagnose MTX-induced liver damage. Genetic markers present an interesting opportunity to preemptively identify patients at risk for MTX-induced hepatotoxicity. Here, we will review the literature on candidate genetic markers for the risk of MTX-induced hepatotoxicity. These candidate genetic markers include polymorphisms in the gene encoding the enzyme MTHFR.",1
12979,23254437,"Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia","Radical cure of Plasmodium vivax infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by P. vivax acquired in Papua, Indonesia.",1
12980,23257938,Euforia-induced acute hepatitis in a patient with scleroderma,"Euforia, a supplement containing a variety of natural ingredients, is widely used as an antioxidant and anti-inflammatory formula. It is not approved by the US Food and Drug Administration and its side effects are unknown. We report a 45-year-old woman with limited systemic sclerosis who presented with jaundice and marked elevation of serum transaminases. One month before, she started taking Euforia juice. A liver biopsy disclosed submassive hepatocellular necrosis with histopathological changes consistent with toxic hepatitis. The patient's symptoms resolved with cessation of Euforia. Six months later, she persisted with abnormal liver function tests, but these resolved 18 months after discontinuation of Euforia. The mechanism by which Euforia causes liver injury is unknown. Some ingredients contained in this supplement (green tea, Aloe vera, noni and goji) are linked to hepatic injury. To our knowledge, this is the first report of hepatotoxicity associated with Euforia.",1
12981,23263831,Comparison of adverse events and efficacy between gefitinib and erlotinib in patients with non-small-cell lung cancer: a retrospective analysis,"""Previous studies have demonstrated that both gefitinib and erlotinib are markedly effective for the treatment of non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR-mt). These agents are considered to act on EGFR through the same mechanism. However, the efficacy of these agents against EGFR wild-type (-wt) NSCLC remains unclear, and the frequency of adverse events (AEs) appears to differ between them at each approved dose. Here, we conducted a retrospective analysis of AEs and drug efficacy in patients with NSCLC whose EGFR mutation status had been confirmed and who all received 250 mg gefitinib or 150 mg erlotinib once daily. The erlotinib group (n = 35) had more AEs, including rash, fatigue, stomatitis, anorexia and constipation. On the other hand, liver dysfunction and nail change were more frequent in the gefitinib group (n = 107). AEs of >/=grade 2, including rash, fatigue and nausea, were more frequent in the erlotinib group. The erlotinib group also showed more of a tendency to require dose reduction due to AEs. With regard to treatment efficacy for patients with EGFR-wt, there was no significant difference in progression-free survival between the two drug groups. However, this study has several limitations as of the nature of retrospective design; our data suggest that gefitinib and erlotinib might have almost equal efficacy for patients with EGFR-wt NSCLC, as is the case for patients with EGFR-mt tumors, although erlotinib appears to have higher toxicity than gefitinib at each approved dose.""",1
12982,23268703,Ticagrelor: the first novel reversible P2Y(12) inhibitor,"INTRODUCTION: Dual antiplatelet therapy is a standard of care for treating patients with acute coronary syndrome (ACS). Combination therapy with aspirin and one of the P2Y(12) inhibitors (clopidogrel, prasugrel, or most recently, ticagrelor ) has been recommended by both ACC/AHA and ESC guidelines for ACS patients. AREAS COVERED: Ticagrelor is the first generation of a new class of reversible P2Y(12) inhibitors, recently added to updated ACC and ESC guidelines for use in patients with ACS. The authors review the studies that evaluate the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of ticagrelor in comparison to currently available antiplatelet agents. EXPERT OPINION: Ticagrelor 180 mg loading dose followed by 90 mg b.i.d. is significantly more efficacious and, in general, as safe as clopidogrel in the treatment of all patients with an ACS regardless of treatment strategy. In addition, besides aspirin compared to placebo, it is the only pharmaceutical intervention shown to have a cardiovascular mortality benefit within 1 year in a broad ACS population. Whether this surprising benefit is realized in other populations is currently being tested.",1
12983,23270487,"Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study","""BACKGROUND: Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy. METHODS: Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count. RESULTS: Forty-two patients were enrolled (mean?SD age, 45.1?12.7 years; previous enzyme therapy duration 9.5?4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3-765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (-1.1%; 95%CI -6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, -0.95 (-1.38, -0.53) g/dL and -44.1 (-57.6, -30.7) ?109/L, respectively. CONCLUSIONS: The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00319046.""",1
12984,23274324,Safety and efficacy of everolimus after kidney and hematopoietic stem cell transplantation,"""BACKGROUND: The aim of this retrospective study was to investigate the efficacy of everolimus at our institution and to report incidence and type of side effects in patients who underwent kidney transplantation or hematopoietic stem cell transplantation (HSCT). MATERIAL/METHODS: Electronic medical records were evaluated for 122 patients (76 men and 46 women) treated with everolimus between January 2000 and January 2009. Of these patients, 81 had undergone kidney transplantation (mean age: 56?12 years) and 41 patients were treated with HSCT (mean age: 47?11 years). RESULTS: Everolimus was discontinued in a total of 53% of patients (n=64) with no difference observed in kidney transplant recipients vs. stem cell transplanted patients (p=0.85). In one half of the patients, cessation of the drug was due to a lack of long-term efficacy (n=32). In the other half, everolimus was discontinued due to side effects (n=32). However, patients with side effects had no elevated everolimus concentrations (5.5?2.3 vs. 5.2?1.7 ng/ml; p=0.39). Pneumonitis (n=5) or proteinuria over 1.5 g per day (n=13) were only observed in kidney transplant patients, while polyomavirus-induced cystitis (n=3) and thrombotic thrombocytopenic purpura (n=7) were only observed in stem cell transplanted patients. CONCLUSIONS: Everolimus was an effective immunosuppressive agent in half of the patients. A quarter of all patients developed side effects resulting in discontinuation of the drug. The profile of side effects in kidney recipients clearly differs from hematopoietic stem cell transplanted patients.""",1
12985,23276893,Efficacy and safety of biologic treatments in Familial Mediterranean Fever,"OBJECTIVE: Colchicine is the mainstay treatment for Familial Mediterranean Fever (FMF). However 5% to 10% of the patients with FMF are unresponsive or intolerant to colchicine. Biologics are efficient in many rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, cryopyrin-associated periodic syndromes. We performed a systematic review to analyze patients with FMF, including juvenile patients who received treatment with biologics. METHODS: A MEDLINE search, including articles published in English language between 1990 and May 2012, was performed. Patients who had Mediterranean fever variants but could not be classified as FMF according to Tel-Hashomer criteria were excluded. RESULTS: There is no controlled trial on the efficacy and safety of biologics in FMF. Fifty-nine (32 female and 27 male) patients with FMF who had been treated with biologics (infliximab, etanercept, adalimumab, anakinra, and canakinumab) were reported in 24 single reports and 7 case series. There were 16 children and 43 adults (7- to 68-year olds). Five patients were reported to have colchicine intolerance or had adverse events related to colchicine use, and the rest 54 were unresponsive to colchicine treatment. CONCLUSIONS: The current data are limited to case reports, and it is difficult to obtain a quantitative evaluation of response to biologic treatments. However, on the basis of reported cases, biologic agents seem to be an alternative treatment for patients with FMF who are unresponsive or intolerant to colchicine therapy and seem to be safe. Controlled studies are needed to better evaluate the safety and efficacy of biologics in the treatment of patients with FMF.",1
12986,23279307,Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise,"""AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise. METHODS: In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N?=?584) received canagliflozin 100 or 300?mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c?<?7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study. RESULTS: At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300?mg compared with placebo (-0.77, -1.03 and 0.14%, respectively; p?<?0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p?<?0.001 for all), and increased HDL-C compared with placebo (p?<?0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups. CONCLUSION: Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.""",1
12987,23281974,Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C,"""BACKGROUND: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection. METHODS: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks after therapy. RESULTS: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. CONCLUSIONS: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; ClinicalTrials.gov number, NCT01260350.).""",1
12988,23282792,Carfilzomib (Kryprolis) for multiple myeloma,,1
12989,23287989,Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer,"BACKGROUND: Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin. METHODS: In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR. RESULTS: Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate-severe) SOS (P=0.026). CONCLUSION: The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment.",1
12990,23288133,Tofacitinib (Xeljanz) for rheumatoid arthritis,,1
12991,23291545,HLA-B*5701 and flucloxacillin associated drug-induced liver disease,,1
12992,23293208,Severe hepatitis induced by cyproterone acetate: role of corticosteroids. A case report,"Cyproterone acetate (CPA) is an oral anti-androgen commonly used to treat advanced prostate cancer. A variety of hepatotoxic reactions has been reported with CPA. Here we describe a case of a male patient who developed severe drug-induced hepatotoxicity during the treatment with CPA. The case, presenting sub-acute hepatitis, was characterized by a rapid evolution of cirrhosis and a protracted activity during the period of a few months despite the treatment withdrawal and an apparent benefits of corticosteroids, suggesting their indication in life threatening cases.",1
12993,23297121,Tolvaptan as an alternative treatment for refractory fluid retention associated with sinusoidal obstruction syndrome after allogeneic stem cell transplantation,"Tolvaptan is an oral vasopressin V2-receptor antagonist recognized as effective for fluid retention associated with congestive heart failure and liver cirrhosis. However, there have been no reports concerning clinical experience with tolvaptan for sinusoidal obstruction syndrome (SOS). A 42-year-old male with primarily refractory T-lymphoblastic lymphoma underwent allogeneic peripheral blood stem cell transplantation from an HLA-matched sibling donor. The myeloablative conditioning regimen consisted of busulfan and cyclophosphamide. On day 20, the total bilirubin level was elevated to 2.0 mg/dL, and body weight increased from 76 to 85 kg, allowing a diagnosis of SOS to be made. Treatments with thrombomodulin, furosemide, carperitide, and low-dose dopamine were ineffective. By day 27, the patient's body weight had increased to 90 kg, and he subsequently developed cardiopulmonary failure. Therefore, we administered low-dose tolvaptan for 2 days (3.75 mg on day 27 and 7.5 mg on day 28). Consequently, his ascites and edema were significantly reduced, and body weight returned to 77 kg by day 34. However, he died of lymphoma progression on day 55. Tolvaptan may be an alternative and promising treatment for refractory fluid retention associated with SOS, although it is unclear whether tolvaptan administration leads to improvement in clinical outcome.",1
12994,23298605,Lacosamide in pediatric and adult patients: comparison of efficacy and safety,"""PURPOSE: This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy. METHOD: This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months. RESULTS: A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean?SD age was 15.9?6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B. CONCLUSION: Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.""",1
12995,23301632,Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up,"BACKGROUND: Long-term safety evaluations of biologics are needed to inform patient management decisions. OBJECTIVES: To evaluate the safety of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years. METHODS: Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest [infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE)] per 100 patient-years (PY) of follow-up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow-up (years 1-5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population. RESULTS: Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for >/=4 years (including 838 patients >/=5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242.6, 225.3), SAEs (7.0, 7.2), serious infections (0.98, 1.19), NMSCs (0.64, 0.44), other malignancies (0.59, 0.61) and MACE (0.56, 0.36) were comparable between dose groups. Year-to-year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population. CONCLUSIONS: No dose-related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate-to-severe psoriasis.",1
12996,23303260,Efficacy and safety of caspofungin in critically ill patients. ProCAS Study,"INTRODUCTION: Caspofungin is an echinocandin with proven efficacy in invasive candidiasis (IC) and invasive aspergillosis (IA). ProCAS is a study sponsored by the Working Group of the Infectious Diseases of the Spanish Society of Intensive Care Medicine, which analyzes the effectiveness and safety of caspofungin in routine clinical practice conditions in the critically ill. METHODS: A prospective, multicenter, observational study designed to estimate the clinical effectiveness and safety of caspofungin acetate in the treatment of IC and IA in patients refractory to or intolerant of conventional antifungal therapy. The assessment of effectiveness both clinic and the microbiological was carried out at the end of the treatment with caspofungin. RESULTS: We included 98 patients, 62 IC proven, 25 probable and 11 IA probable, from 24 centers during 2005 and 2006. Treatment with caspofungin monotherapy was performed in 89.8% of cases and as first line therapy in 54.1%. The favorable clinical response obtained for IC, probable IC, and probable IA was 91.9, 84, and 81.8%, respectively. The microbiological response was favorable in 74.6, 68, and 54.6% for proven cases of IC, probable IC, and probable IA, respectively. No serious adverse effects were observed. CONCLUSIONS: In routine clinical practice conditions, caspofungin is effective and safe for the treatment of invasive fungal infections (IC/IA). The efficacy and safety profile was similar to that observed in published clinical trials.",1
12997,23306923,[Efficacy of low-dose erlotinib against gefitinib-induced hepatotoxicity in a patient with lung adenocarcinoma harboring EGFR mutations],"We report a case of a female in her 80s who was diagnosed with recurrent lung adenocarcinoma after primary surgery. She was treated with a systemic chemotherapy regimen consisting of carboplatin plus paclitaxel until the disease showed progression. On detection of epidermal growth factor receptor(EGFR)mutations, we administered gefitinib, an EGFR tyrosine kinase inhibitor, at a dosage of 250 mg daily. After 6 months of gefitinib therapy, laboratory findings revealed elevated serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels(grade 2), indicative of hepatotoxicity. Gefitinib was discontinued and erlotinib was initiated at a dosage of 50 mg daily. She continued the therapy for 3 years, during which her disease stabilized without any further complications or hepatotoxicity. Thus, low-dose erlotinib may be effective and well tolerated by patients with non-small cell lung cancer harboring EGFR mutations who are intolerant to gefitinib.",1
12998,23307827,"Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial","""BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. METHODS AND RESULTS: Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). CONCLUSIONS: Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.""",1
12999,23312567,"Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial","""INTRODUCTION/OBJECTIVE: Long-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone. METHODS: Patients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion. RESULTS: A total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total. DISCUSSION/CONCLUSION: This study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.""",1
13000,23315296,Adverse drug reactions to gabapentin and pregabalin: a review of the French pharmacovigilance database,"BACKGROUND: Gabapentin and pregabalin are widely used as antineuropathic pain drugs. Their use is also associated with the development of adverse drug reactions (ADRs), mainly neuropsychiatric. OBJECTIVE: The aim of this work was to study 'serious' and/or 'unexpected' adverse reactions associated with pregabalin and gabapentin. STUDY DESIGN: We studied ADRs reported to the French Pharmacovigilance System occurring between 1995 and 2009. MAIN OUTCOME MEASURE: For each ADR associated with gabapentin or pregabalin, we noted year, patient age and sex, type of adverse reaction, as well as the imputability score. Reporting rate of serious ADRs for gabapentin and pregabalin was estimated with regard to data of use (obtained from the French National Health Insurance Fund) using the defined daily dose. A global and descriptive analysis of the adverse reactions for each drug is presented. Secondly, details of deaths and ADRs with an imputability score of at least 'probable' or 'likely' were presented. RESULTS: Overall, 1333 cases were recorded (725 related to gabapentin, 608 related to pregabalin), mainly neuropsychiatric ADRs. Among the 22 deaths recorded, 8 were related to gabapentin in obstetrical situations. Other less well-documented ADRs were identified, such as hepatitis associated with gabapentin and haematological ADRs associated with pregabalin. CONCLUSION: This study confirmed the prevalence of neuropsychiatric ADRs associated with gabapentin or pregabalin. A high rate of death occurred with gabapentin in an obstetrical context. New adverse reactions have been noted, such as haematological or hepatic adverse reactions associated with pregabalin and gabapentin, respectively.",1
13001,23315786,Severe hepatitis associated with tocilizumab in a patient with rheumatoid arthritis,,1
13002,23319574,Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du My?lome 2009-02,"The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).",1
13003,23322457,The SMILE study -- safety of methotrexate in combination with leflunomide in rheumatoid arthritis,"OBJECTIVE: To assess the safety of treating patients with rheumatoid arthritis with a combination of methotrexate (MTX) and leflunomide (LEF) in comparison to MTX monotherapy, in clinical practice. METHODS: The Safety of Methotrexate in Combination with Leflunomide in Rheumatoid Arthritis (SMILE) study was a multicenter, observational, cross-sectional, retrospective safety study. The study was conducted by the Optimising Patient Outcomes in Australian Rheumatology-Quality Use of Medicines Initiative (OPAL QUMI). Data were deidentified for patient, clinic, and clinician prior to collection from 13 participating rheumatology practices (25 rheumatologists). Comparative analysis of safety for the different treatments, primarily with regard to neutropenia and liver abnormalities, was performed. RESULTS: In total, 2975 patients were included in the study: 74% female, 26% male, mean age 62 years (SD 13.6). Distribution of therapy: MTX monotherapy 52.2%, LEF monotherapy 7.3%, MTX plus LEF 13.9%, and neither MTX nor LEF 26.6%. Comorbid liver disease was reported in 8.1% of patients. Liver function abnormalities were reported in 12% of the MTX monotherapy group, 16% of the LEF monotherapy group, 19% of the MTX-LEF combination group, and 14% of the group not taking either drug. Neutropenia was reported in 2.3% of the MTX monotherapy group, 5.5% of the LEF monotherapy group, 3.9% of the MTX-LEF combination group, and 4.2% of the group not taking either drug. CONCLUSION: The combination of MTX and LEF was well tolerated, with adverse events comparable to those of monotherapy and the other nonbiologic disease-modifying antirheumatic drug treatment group.",1
13004,23324122,Adverse events following statin-fenofibrate therapy versus statin alone: a meta-analysis of randomized controlled trials,"""The combination of fenofibrate with statins is a beneficial therapeutic option for patients with mixed dyslipidaemia, but concerns about adverse events (AEs) make physicians reluctant to use this combination therapy. Medline, Embase and the Cochrane Library were searched to identify 13 randomized controlled trials, involving 7712 patients, of statin-fenofibrate therapy versus statin alone for review. There were significant decreases in low-density lipoprotein-cholesterol, triglycerides and total cholesterol and increases in high-density lipoprotein-cholesterol in patients receiving combination therapy compared with statin therapy alone. The incidence of aminotransferase elevations in the fenofibrate-statin therapy group was significantly higher than in the statin monotherapy group (odds ratio (OR), 1.66; 95% confidence interval (CI) 1.17-2.37; P < 0.05). The incidence of elevated creatine kinase levels (OR 0.88; 95% CI 0.63-1.23; P > 0.05), muscle-associated AEs (OR 0.98; 95% CI 0.88-1.09; P > 0.05) and withdrawals attributed to liver and muscle dysfunction did not differ significantly between the two groups. The efficacy of fenofibrate + standard-dose statin and incidence of AEs in the fenofibrate + standard-dose statin group were almost identical to those in the fenofibrate-statin group. In conclusion, combination therapy improves the blood lipid profile of patients. Fenofibrate-statin combination therapy appears to be as well tolerated as statin monotherapy. Physicians should consider fenofibrate-statin combination therapy in patients but monitor aminotransferase levels to avoid hepatic complications.""",1
13005,23325533,Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study,"BACKGROUND: Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. OBJECTIVES: The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). RESULTS: In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. CONCLUSIONS: ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.",1
13006,23326172,Vanishing bile duct syndrome in human immunodeficiency virus infected adults: a report of two cases,"""Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.""",1
13007,23327817,Hepatitis in an infant treated with octreotide for congenital hyperinsulinism,"Congenital hyperinsulinism is characterized by hypoglycemia caused by several genetic disorders of inappropriate insulin secretion. Octreotide, an analogue of somatostatin, plays a major role in the pharmaceutical treatment of this condition. A 9-month-old infant treated with octreotide developed anicteric hepatitis with no other proven cause. After the discontinuation of this drug, the liver enzymes declined rapidly. Liver function tests should be followed in patients receiving octreotide.",1
13008,23328091,"Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of nevirapine-containing regimens in South Africa",,1
13009,23329527,Inflammatory bowel diseases and primary sclerosing cholangitis: hepatic and pancreatic side effects due to azathioprine,"BACKGROUND AND OBJECTIVES: In up to 80% of cases primary sclerosing cholangitis (PSC) is associated with inflammatory bowel diseases (IBD). The efficacy of azathioprine (AZA), in the maintenance of remission of IBD has been suggested by several studies. However, AZA tends to exter varied well-known toxicity. Since the rate of hepato-pancreatic side-effects in patients with IBD and PSC is still unclear, we investigated this issue. MATERIALS AND METHODS: Consecutive subjects who underwent Outpatient Clinic admission for both IBD and PSC were included. Both conditions were diagnosed according to International Guidelines. RESULTS: Data of 43 patients were elaborated. Twelve of them underwent therapy with AZA. Five (41.7%) presented hepatic (n=4) or pancreatic toxicity. Eighty percent of the patients with hepato-pancreatic reactions versus 28.6% of those without (p < 0.001) were males, with 60% affected by ulcerative colitis and 40% by Crohn's disease versus 57% and 43%, respectively. Forty percent of patients with reactions versus 43% of those without needed an operation for IBD, and the same percentage underwent orthotopic liver transplantation, with a 100% versus 66.7% (p < 0.001) need of second transplantation. Colonic neoplasia (20%) was detected only in the former group while cholangiocarcinoma (28.6%) only in the latter. CONCLUSIONS: The occurrence of hepato-pancreatic reactions from AZA in our caseload is higher (41.7%) compared to that reported in literature (4%). Therefore, the presence of PSC, in association to IBD, may strongly affect AZA tolerability compared to presence of IBD only. �",1
13010,23330262,[Thiopurine-induced hyperammonaemic encephalopathy in a patient with Crohn's disease],"Thiopurine drugs, azathioprine (Imuran) and 6-mercaptopurine (6-MP), are immunomodulators that have been shown to be effective at inducing and maintaining remission in inflammatory bowel disease. Although usually well-tolerated, the occurrence of side effects, typically myelotoxicity and hepatotoxicity, is a major drawback. The side effects can be classified as dose-dependent and independent. Both cholestatic hepatitis and endothelial injury, leading to vascular congestion and nodular regenerative hyperplasia, have been described during therapy with thiopurines, which can end up with portal hypertension. These injuries are potentially mediated by different metabolites. In this article we present a case of hyperammonaemic encephalopathy during therapy with 6-MP, possibly the first recorded in the literature, which probably resulted from the combination of thiopurine-induced liver injury with portal hypertension and the presence of spontaneous portosystemic venous shunts.",1
13011,23333219,Liver injury from tumor necrosis factor-? antagonists: analysis of thirty-four cases,"""BACKGROUND & AIMS: Tumor necrosis factor (TNF)-? antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-? antagonists. METHODS: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-? antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-? antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-? antagonists, identifying 28 additional cases suitable for analysis. RESULTS: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-? agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. CONCLUSIONS: Acute liver injury caused by TNF-? antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.""",1
13012,23339116,Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase,"""Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ?2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa phase 3 clinical trial program.""",1
13013,23343061,Peginesatide in patients with anemia undergoing hemodialysis,"""BACKGROUND: Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).""",1
13014,23344102,Safety of desirudin in thrombosis prevention after total knee arthroplasty: the DESIR-ABLE study,"""Desirudin, administered 30 minutes before total hip arthroplasty is superior to enoxaparin in preventing proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) with similar bleeding. The purpose of this study was to determine the safety of desirudin in patients undergoing elective total knee arthroplasty (TKA) when the first dose of desirudin was administered the evening after surgery. This is a case series of patients undergoing TKA who received desirudin 15 mg every 12 hours subcutaneously for an average of 5 days with the first dose administered postoperatively. The primary endpoint was major bleeding; secondary endpoints included wound outcomes (oozing and infection) and new symptomatic DVT or PE. Desirudin has a favorable safety profile when administered postoperatively in patients undergoing TKA with no reports of major bleeding, wound ooze, or infection. No patients experienced symptomatic DVT, but 2 patients had PE detected by computed tomography after experiencing atypical symptoms. The safety profile of desirudin is improved when administered postoperatively. Bleeding and wound outcomes seem to occur less frequently than historical desirudin and enoxaparin controls.""",1
13015,23348233,Drugs for epilepsy,,1
13016,23348842,"Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects","""Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n?=?75) involving chronic administration of kava (one tablet of kava twice per day; 120?mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240?mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p?=?0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample.""",1
13017,23352552,"Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals","BACKGROUND: Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS: During a weighted average scheduled treatment duration of 5?2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57?3 nmol/L for the folic acid groups vs 13?5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1?06, 95% CI 0?99?1?13, p=0?10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0?23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0?13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. FUNDING: British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.",1
13018,23353547,Toxicological evaluation of neem (Azadirachta indica) oil: acute and subacute toxicity,"Neem (Azadirachta indica), popularly known as traditional medicine is a native plant in India. Neem oil is a vegetable oil derived from seeds or fruits of the neem tree through pressing or solvent extraction, and largely used in popular medicine to have antifungal, antibacterial, antimalarial, antiparasitic, anti-inflammatory, as well as immunemodulatory properties in different animal species. In the present study, acute and 28-day subacute toxicity tests were carried out. In the acute toxicity test, the LD50 values of neem oil were found to be 31.95g/kg. The subacute treatment with neem oil failed to change body weight gain, food and water consumption. Serum biochemistry analysis showed no significant differences in any of the parameters examined under the dose of 1600mg/kg/day. Histopathological exams showed that the target organs of neem oil were testicle, liver and kidneys up to the dose of 1600mg/kg/day.",1
13019,23358971,Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial,"""PURPOSE: In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS: We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS: In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION: This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.""",1
13020,23361084,"Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial","""OBJECTIVE: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). METHODS: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). RESULTS: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p=?0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. CONCLUSIONS: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.""",1
13021,23362969,"Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study","""BACKGROUND: Interleukin (IL)-17A has major proinflammatory activity in psoriatic lesional skin. OBJECTIVES: To assess the efficacy and safety of secukinumab, a fully human IgG1? monoclonal anti-IL-17A antibody, in moderate-to-severe plaque psoriasis in a phase II regimen-finding study. METHODS: A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was ? 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). RESULTS: At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54?5% and 42?0% vs. 1?5%; P < 0?001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed-interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start-of-relapse regimen [67% (n = 45), P = 0?020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed-interval and start-of-relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection-site reactions were reported. Reported cases of neutropenia were mild-to-moderate (? grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long-term safety. CONCLUSIONS: Secukinumab shows efficacy for induction and maintenance treatment of moderate-to-severe plaque psoriasis.""",1
13022,23368661,Liver toxicity due to olanzapine,,1
13023,23371016,Letter in response to the recently published review: hyponatremia in cirrhosis and end-stage liver disease--treatment with the vasopressin v2-receptor antagonist tolvaptan,,1
13024,23373554,Combination therapy efavirenz/emtricitabine/tenofovir disoproxil fumarate associated with hepatic failure,"A single pill daily fixed dose combination of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) provides a potent and convenient treatment option for HIV/AIDS. The components have been shown to be well tolerated and are effective in randomized controlled trials. A literature search revealed no case of hepatic failure reported with this drug combination. We here in describe the 1st case of acute hepatic failure developing after 3 months of treatment with EFV/FTC/TDF in a 41 year old African American male without pre-existing liver disease or risk factors.",1
13025,23376661,Near fatal iron intoxication managed conservatively,"We report here the case of an infant who presented to the emergency department after unintentional ingestion of almost 130 mg/kg of elemental iron. The infant had evidence of serious toxicity in the form of hypotension, metabolic acidosis and excessive irritability. Her serum iron levels were 360 ?g/dl, which was well above the normal range for her age. Despite such high serum levels, the infant made an uneventful recovery with medical management alone and did not require exchange transfusion. We chose to report this case to highlight her uneventful recovery with conservative therapy alone.",1
13026,23377389,Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS),"""BACKGROUND: Available biologic agents for the treatment of psoriasis in China are limited. OBJECTIVES: The LOTUS study is a phase 3, double-blind, placebo-controlled study that evaluated the efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis. PATIENTS AND METHODS: Patients (n=322) were randomized to receive ustekinumab 45 mg or placebo at weeks 0 and 4, with placebo crossover to ustekinumab at week 12; all patients were followed up to week 36. The primary end point was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) at week 12. Other end points at week 12 included the proportion of patients with a Physician's Global Assessment (PGA) score of 0 or 1 and the change in Dermatology Life Quality Index (DLQI) score from baseline. RESULTS: At week 12, 82.5% of ustekinumab-treated patients achieved PASI 75 responses compared with 11.1% of placebo-treated patients (P<.001). Clinical responses were maintained through week 28, with maximum responses observed at week 24. Significant improvements in PGA and DLQI were observed at week 12 and were generally maintained through week 28. At week 12, adverse events rates were similar between groups (45 mg: 42.5% vs placebo: 38.5%), and serious adverse events were reported in 0.6% of patients in each group. Through week 36, no cases of active tuberculosis, serious infections, malignancies, or major adverse cardiovascular events were reported. CONCLUSIONS: Consistent with results previously reported in global phase 3 studies, ustekinumab was highly effective and generally well tolerated in Chinese patients with moderate to severe psoriasis through 36 weeks.""",1
13027,23377559,Presentation and outcomes with clinically apparent interferon beta hepatotoxicity,"AIMS: The aim of this study was to describe the presenting features and outcomes of consecutive patients with liver injury attributed to interferon beta. METHODS: The presenting features of eight subjects with clinically apparent liver injury attributed to interferon beta enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) prospective registry between 2004 and 2010 were reviewed and compared to 11 published reports of symptomatic hepatotoxicity. RESULTS: All eight of the DILIN patients were women, 75 % were Caucasian and the mean age was 49 years. Most subjects presented with an acute hepatocellular injury pattern and mean serum alanine aminotransferase (ALT) levels were 725 ? 593 U/L. The median duration of interferon beta use before injury onset was 462 days, and four patients had been treated for more than a year. No patient had detectable antinuclear or smooth muscle antibodies. One patient died of acute liver failure and the remaining patients usually recovered within 2-3 months. Causality assessment scored three cases as definite, three highly likely, one probable and one possible. Eleven additional published cases were all women, mean age was 40 years, mean ALT at onset 840 U/L, and 7 (63 %) had autoantibodies. Liver histology in three cases from DILIN and nine from the literature commented upon centrilobular (zone 3) necrosis and infiltrates with lymphocytes and plasma cells. CONCLUSIONS: Interferon beta hepatotoxicity occurs mostly in women and has a variable, but often prolonged time to onset. Most patients have self-limited acute hepatocellular liver injury but several have required liver transplantation or died of acute liver failure. Liver histology available in three cases demonstrated zone 3 necrosis and autoimmune features suggestive of an immunologic basis to this adverse drug reaction.",1
13028,23379510,Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients,"BACKGROUND: Increasing the dosage of daptomycin may be advantageous in severe infection by enhancing bactericidal activity and pharmacodynamics. However, clinical data on using daptomycin at doses above 6 mg/kg in Asian population are limited. METHODS: A retrospective observational cohort study of all hospitalized adult patients treated with daptomycin (> 6 mg/kg) for at least 72 hours was performed in Taiwan. RESULTS: A total of 67 patients (40 males) with a median age of 57 years received a median dose of 7.61 mg/kg (range, 6.03-11.53 mg/kg) of daptomycin for a median duration of 14 days (range, 3-53 days). Forty-one patients (61.2%) were in intensive care units (ICU). Sites of infections included complicated skin and soft tissue infections (n = 16), catheter-related bacteremia (n = 16), endocarditis (n = 11), primary bacteremia (n = 10), osteomyelitis and septic arthritis (n = 9), and miscellaneous (n = 5). The median Pitt bacteremia score among the 54 (80.6%) patients with bacteremia was 4. The most common pathogen was methicillin-resistant Staphylococcus aureus (n = 38). Fifty-nine patients (88.1%) were treated with daptomycin after glycopepetide use. Overall, 52 (77.6%) patients achieved clinical success. The all-cause mortality rate at 28 day was 35.8%. In multivariate analysis, the significant predictors of in-hospital mortality in 54 bacteremic patients were malignancies (P = 0.01) and ICU stay (P = 0.02). Adverse effects of daptomycin were generally well-tolerated, leading to discontinuation in 3 patients. Daptomycin-related creatine phosphokinase (CPK) elevations were observed in 4 patients, and all received doses > 8 mg/kg. CONCLUSIONS: Treatment with high dose daptomycin as salvage therapy was generally effective and safe in Taiwan. CPK level elevations were more frequent in patients with dose > 8 mg/kg.",1
13029,23383366,Hepatitis B reactivation related to everolimus,"""Reactivation of hepatitis B virus (HBV) during chemotherapy is a well known complication in patients with chronic hepatitis B and cancer. The clinical manifestations range from subclinical elevation of liver enzymes to severe, potentially fatal fulminant hepatitis. Reactivation can occur in a patient with previous inactive HBV infection; either an inactive carrier or a patient with resolved hepatitis. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved in renal cell carcinoma, neuroendocrine tumours and breast cancer. mTOR inhibitors are a new generation of drugs for targeted treatment; therefore, little about their side effects is known. Here, we report a patient with renal cell carcinoma who experienced a flare of hepatitis B infection during treatment with everolimus. Clinicians should be aware of HBV reactivation in patients who are undergoing treatment with everolimus, and screening for hepatitis B infection and prophylactic antiviral treatment should be considered.""",1
13030,23386328,"Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study","""Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment-na?ve, anemic patients with GD1 (4-62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 ? 10(9) /L (P=0.002); 45 U/kg: +66.4%; +40.9 ? 10(9) /L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: -50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: -39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug-related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease-specific parameters measured demonstrated clinically meaningful improvements after 12 months.""",1
13031,23387536,"Hyponatremia: clinical associations, prognosis, and treatment in cirrhosis","""Hyponatremia has long been associated with worsened clinical outcomes in patients with cirrhosis and those awaiting liver transplant. However, in the last several years, new modalities of therapy, particularly aquaretics known as """"vaptans,"""" and comprehensive prognostic models have been increasingly studied in the hopes of bolstering serum sodium levels and altering liver transplant candidate status. To examine the most recent, comprehensive, and pertinent data, a systematic review of both prospective and retrospective studies available on MEDLINE was completed, which provided information detailing clinical associations, treatment, and prognoses seen in those with hyponatremia in cirrhosis. Clinical associations with hyponatremia in cirrhosis including hepatorenal syndrome and hepatic encephalopathy were identified. For hyponatremia in those awaiting liver transplant, tolvaptan is an effective agent in temporarily normalizing serum sodium levels with minimal risk of osmotic demyelination. Prognostic models incorporating serum sodium levels were better able to predict urgency and need for transplant; yet the benefits and posttransplant effects of redefining a liver allocation score have yet to be established.""",1
13032,23388845,Drug-induced liver injury caused by intravenously administered medications: the Drug-induced Liver Injury Network experience,"BACKGROUND AND AIMS: Idiosyncratic drug-induced liver injury (DILI) can be caused by intravenous (IV) medications, but the characteristics of DILI caused by these agents are not known. The aim of this study is to characterize the clinical features of subjects with suspected DILI associated with IV agents enrolled into the Drug Induced Liver Injury Network Prospective Study. METHODS: Subjects with suspected DILI due to IV medications with probable, highly likely, or definite casuality scores were eligible. RESULTS: Between 2004 and October 2010, 542 cases of DILI were adjudicated for causality, of which 32 were eligible for inclusion in this study. DILI was ascribed to a single IV agent in 27 subjects, and to multiple IV agents in 5 subjects. Antimicrobial agents (62%), antineoplastic agents (16%), and phenytoin (9%) were most commonly implicated. The pattern of liver injury was hepatocellular in 30%, mixed in 33%, and cholestatic in 37%. The peak alanine aminotransferase (ALT), alkaline phosphatase (AlkP), and total bilirubin were 686 ? 915 U/L, 623 ? 563 U/L, and 8.7 ? 10.3 mg/dL, respectively. The duration for ? 50% improvement from peak ALT, AlkP, and total bilirubin were 25 ? 37, 59 ? 69, and 20 ? 28 days, respectively. DILI severity was mild in 37%, moderate in 47%, severe in 13%, and fatal in 3%, with no liver transplantation. Their causality was adjudicated as definite in 5, very likely in 17, and probable in 10 subjects. The frequency of chronic DILI was 13%. CONCLUSIONS: Antimicrobial and antineoplastic agents are the most common IV agents to cause DILI. DILI ascribed to IV agents is relatively infrequent, but its outcomes are similar to those of the overall Drug Induced Liver Injury Network cohort.",1
13033,23390034,Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital,"""Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. CONCLUSION: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.""",1
13034,23391805,An analysis of drug induced Stevens-Johnson syndrome,,1
13035,23393020,Carfilzomib,"This spotlight review focuses on the second-generation proteasome inhibitor carfilzomib, which was recently approved by the U.S. Food and Drug Administration for treatment of relapsed and refractory multiple myeloma patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. This review focuses on clinical trial data leading to drug approval and provides advice for treating physicians who are now accessing this drug for patients.",1
13036,23394127,N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients,"""SETTING: Isoniazid (INH) is related to the development of hepatotoxicity in some patients. OBJECTIVE: To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population. DESIGN: Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods. RESULTS: Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008). CONCLUSIONS: Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.""",1
13037,23399877,Safety and efficacy of acamprosate for the treatment of alcohol dependence,"Acamprosate (calcium acetylhomotaurine) is an amino acid modulator that has displayed efficacy in some clinical trials in reducing craving and promoting abstinence in alcohol dependent patients following detoxification. While acamprosate is safe and generally well-tolerated, not all studies have demonstrated clinical efficacy that is superior to placebo. In addition, the precise neurochemical mechanisms of action of acamprosate have still not yet been identified. In this review, we summarize current clinical data on the safety, efficacy, and pharmacokinetic properties of acamprosate, as well theories on its potential mechanism of action. We also discuss tolerability and patient preference issues and conclude with a discussion of the place of acamprosate in addiction medicine and therapy.",1
13038,23401436,"ALK in lung cancer: past, present, and future","In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positive cancers are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011. Although crizotinib induces remissions and extends the lives of patients, cures are not achieved as resistance to therapy develops. In this review, we will discuss the history of this field, current diagnostic and treatment practices, and future challenges and opportunities to advance outcomes for patients with ALK-positive lung cancers.",1
13039,23402094,A new cause of acute hepatitis: gemifloxacin,,1
13040,23407048,The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity,"""BACKGROUND: Earlier studies have demonstrated an association between N-acetyltransferase 2 (NAT2) catalytic activity and the genotype of a recently published tag single nucleotide polymorphism (SNP), rs1495741. There have been no reports on the relationship between the rs1495741 genotype and antituberculosis drug-induced hepatotoxicity (ATDIH) to date. OBJECTIVE: The aim of the present study was to determine the frequency of the NAT2 tag SNP (rs1495741) in the Taiwanese and its relation to the incidence of ATDIH. MATERIALS AND METHODS: A total of 348 tuberculosis patients were enrolled to determine the frequency of NAT2 tag SNP rs1495741 and its relation to the incidence of ATDIH. The conventional NAT2 variants alleles have also been investigated. Furthermore, to evaluate the correlation of NAT2 activity and rs1495741 genotypes, a pharmacokinetic study of isoniazid was also conducted in healthy volunteers. RESULTS: Among the 348 tuberculosis patients, 20 (5.7%) were diagnosed with ATDIH. The frequencies of the three rs1495741 genotypes, viz., AA, AG, and GG, were 24.7, 52.3, and 23.0%, respectively. Signi&filig;cant differences among rs1495741 genotypes and susceptibility to hepatotoxicity were noted (odds ratio=14.068, P<0.05). Moreover, the rs1495741 genotypes showed an association with the isoniazid dosage required for induction of hepatotoxicity. In the pharmacokinetic study, NAT2 activity was strongly associated with genotype categories (P<0.001). CONCLUSION: The present study demonstrated that the three genotypes according to rs1495741 were in good accordance with conventional NAT2 alleles-inferred phenotypes and the tag SNP could be used as a proxy to determine the susceptibility to ATDIH.""",1
13041,23408116,"The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure","Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3'UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3'UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, ?(2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual's risk for acetaminophen-induced liver injury.",1
13042,23411809,Giant hepatic adenoma associated with anabolic-androgenic steroid abuse: case report,,1
13043,23414168,Psoriasis treated with ustekinumab in a patient with hepatitis C,,1
13044,23419281,Erythema nodosum in a patient undergoing vemurafenib therapy for metastatic melanoma,,1
13045,23420283,Asymptomatic elevation of liver enzymes due to levetiracetam: a case report,"Levetiracetam is a commonly used broad-spectrum anticonvulsant efficacious in both partial and generalized seizures. It has an extremely favorable side effect profile with few drug-drug interactions, low potential for hematological and hepatic toxicity, and thus has rapidly become the preferred drug in patients with traumatic brain injuries who need seizure prophylaxis. We report, here, a patient who was started on levetiracetam for seizure prophylaxis after developing large bifrontal-parietal traumatic subdural hematomas (SDH) following a fall from a horse necessitating bifrontal craniotomies for evacuation. The patient developed an asymptomatic elevation of the liver enzymes. The liver enzymes trended back to normal after levetiracetam was stopped, and topiramate was initiated in its place.",1
13046,23423489,"A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation","PURPOSE: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. METHODS: Patients with chemotherapy na?ve measurable metastatic melanoma, performance status ?2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. RESULTS: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. CONCLUSIONS: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.",1
13047,23425050,Pharmacokinetic and pharmacodynamic considerations for the current chronic constipation treatments,"INTRODUCTION: Chronic constipation is a frequent condition often treated pharmacologically. The laxatives available belong to very different pharmacologic groups. AREAS COVERED: This is a short but comprehensive review of the pharmacology, efficacy and safety of currently available laxatives for chronic constipation. Pertinent publications were retrieved from reference lists of publications and by literature searches via PubMed, lastly performed in November 2012. EXPERT OPINION: The most relevant laxative groups are the older representatives osmotic salts, sugars and sugar alcohols, macrogol, anthraquinones, diphenolic laxatives or diphenyl methanes (bisacodyl and sodium picosulfate) and the newer compounds prucalopride, lubiprostone and linaclotide. For all of these laxatives efficacy has been shown in controlled trials. Electrolyte losses do not occur when laxatives are given in therapeutic doses (rare exceptions with phosphate salts and salinic laxatives). The older laxatives are also safe regarding teratogenicity, abortion and lactation. For the newer compounds no respective data are available as yet. It is questionable whether the newer compounds offer advantages over the older ones. Unfortunately, comparative trials are lacking.",1
13048,23432142,Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria,"""BACKGROUND: Many patients with chronic idiopathic urticaria (also called chronic spontaneous urticaria) do not have a response to therapy with H-antihistamines, even at high doses. In phase 2 trials, omalizumab, an anti-IgE monoclonal antibody [corrected] that targets IgE and affects mast-cell and basophil function, has shown efficacy in such patients. METHODS: In this phase 3, multicenter, randomized, double-blind study, we evaluated the efficacy and safety of omalizumab in patients with moderate-to-severe chronic idiopathic urticaria who remained symptomatic despite H-antihistamine therapy (licensed doses). We randomly assigned 323 patients to receive three subcutaneous injections, spaced 4 weeks apart, of omalizumab at doses of 75 mg, 150 mg, or 300 mg or placebo, followed by a 16-week observation period. The primary efficacy outcome was the change from baseline in a weekly itch-severity score (ranging from 0 to 21, with higher scores indicating more severe itching). RESULTS: The baseline weekly itch-severity score was approximately 14 in all four study groups. At week 12, the mean (?SD) change from baseline in the weekly itch-severity score was -5.1?5.6 in the placebo group, -5.9?6.5 in the 75-mg group (P=0.46), -8.1?6.4 in the 150-mg group (P=0.001), and -9.8?6.0 in the 300-mg group (P<0.001). Most prespecified secondary outcomes at week 12 showed similar dose-dependent effects. The frequency of adverse events was similar across groups. The frequency of serious adverse events was low, although the rate was higher in the 300-mg group (6%) than in the placebo group (3%) or in either the 75-mg or 150-mg group (1% for each). CONCLUSIONS: Omalizumab diminished clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H-antihistamines. (Funded by Genentech and Novartis Pharma; ClinicalTrials.gov number, NCT01292473.).""",1
13049,23432528,Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy,"""Romiplostim was effective, safe, and well-tolerated over 6-12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia (ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long-term, single-arm, open-label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50 ? 10(9) per litre), and the proportion of patients requiring rescue treatments. Treatment-related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6.5% of patients and were not associated with platelet count. Median platelet counts of 50-200 ? 10(9) per litre were maintained with stable doses of romiplostim (mean 5-8 ?g/kg; generally self-administered at home) throughout the study. A platelet response was achieved at least once by 95% of patients, with a platelet response maintained by all patients on a median 92% of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and well-tolerated over 614 patient-years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment.""",1
13050,23432640,"A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma","""Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ? 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ? grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.""",1
13051,23433739,"Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial","""BACKGROUND: Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas. METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ?3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024). INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects. FUNDING: Roche Pharma AG, Ribosepharm/Mundipharma GmbH.""",1
13052,23436544,Vemurafenib-associated pancreatitis: case report,"Vemurafenib is a novel BRAF kinase inhibitor indicated in metastatic melanoma patients with V600E mutation. We report the first case of vemurafenib-associated pancreatitis. Two weeks after initiation of vemurafenib, a patient presented to the emergency department with severe epigastric pain and a serum lipase of 1544 units/L. Drug-induced pancreatitis was diagnosed on exclusion of all other potential causes. Vemurafenib was rechallenged at half the daily dose and the patient subsequently developed exacerbated symptoms of pancreatitis after two doses. The strong temporal relationship between drug exposure and toxicity, along with the positive results from a rechallenge study, strongly support a conclusion of causality. To our knowledge, this is the first report of vemurafenib-induced pancreatitis.",1
13053,23439908,Chronic acetaminophen exposure in pediatric acute liver failure,"""BACKGROUND: Acetaminophen (N-acetyl-p-aminophenol [APAP]) is a widely used medication that can cause hepatotoxicity. We examined characteristics and outcomes of children with chronic exposure (CE) to APAP in the multinational Pediatric Acute Liver Failure (PALF) Study. METHODS: A total of 895 children enrolled from 2002 to 2009 were grouped by APAP exposure history as: CE (received multiple doses \x{2265}2 days; n = 83), single dose exposure (SE; n = 85), and no exposure (NE; n = 498). CE was the reference group for pairwise comparisons. Median values are shown. RESULTS: Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008). CONCLUSIONS: Children in the PALF study with CE had lower bilirubin and higher alanine aminotransferase than those with NE. Outcomes with CE were worse than with SE but better than with NE. Potential reasons for this outcomes advantage over non-APAP-exposed subjects should be explored.""",1
13054,23444397,"HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment","""AIMS: Niacin has potentially favourable effects on lipids, but its effect on cardiovascular outcomes is uncertain. HPS2-THRIVE is a large randomized trial assessing the effects of extended release (ER) niacin in patients at high risk of vascular events. METHODS AND RESULTS: Prior to randomization, 42 424 patients with occlusive arterial disease were given simvastatin 40 mg plus, if required, ezetimibe 10 mg daily to standardize their low-density lipoprotein (LDL)-lowering therapy. The ability to remain compliant with ER niacin 2 g plus laropiprant 40 mg daily (ERN/LRPT) for ~1 month was then assessed in 38 369 patients and about one-third were excluded (mainly due to niacin side effects). A total of 25 673 patients were randomized between ERN/LRPT daily vs. placebo and were followed for a median of 3.9 years. By the end of the study, 25% of participants allocated ERN/LRPT vs. 17% allocated placebo had stopped their study treatment. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetes, and musculoskeletal side effects. When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy [75 (0.16%/year) vs. 17 (0.04%/year): risk ratio 4.4; 95% CI 2.6-7.5; P < 0.0001]; 7 vs. 5 were rhabdomyolysis. Any myopathy (definite or incipient) was more common among participants in China [138 (0.66%/year) vs. 27 (0.13%/year)] than among those in Europe [17 (0.07%/year) vs. 11 (0.04%/year)]. Consecutive alanine transaminase >3x upper limit of normal, in the absence of muscle damage, was seen in 48 (0.10%/year) ERN/LRPT vs. 30 (0.06%/year) placebo allocated participants. CONCLUSION: The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ~1 month, three-quarters continued to take it for ~4 years.""",1
13055,23458313,Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis,"""OBJECTIVES: Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics. METHODS: Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of ?3. RESULTS: All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non-SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of ?14.35?cm/s together with a cross-section area of ?1.55?cm(2) was found to predict SI with sensitivity of 100% and specificity of 78%. CONCLUSIONS: Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively.""",1
13056,23458534,Letter: retrospective reviews of liver-related case reports allegedly associated with Herbalife present insufficient and inaccurate data--authors' reply,,1
13057,23459414,Antiviral drugs,,1
13058,23460018,Incidence of sinusoidal obstruction syndrome following Mylotarg (gemtuzumab ozogamicin): a prospective observational study of 482 patients in routine clinical practice,"""The purpose of this prospective observational study was to determine the incidence of hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab ozogamicin (GO) therapy in routine clinical practice. Patients receiving GO for acute myeloid leukemia (AML) were eligible. Assessments were requested to be performed weekly for 6�weeks after the start of GO therapy or 4�weeks after the last dose (whichever was later), and after 6�months. The primary outcome variable was the incidence of SOS as judged by a panel of independent experts. A total of 512 patients were enrolled at 54 US centers and 482 were evaluable. The incidence of SOS in this study population was 9.1�% (44/482; 95�% confidence interval 6.9-12.0�%). Of the 44 patients classified as having SOS, 8 were mild, 17 moderate, and 19 severe; 33 died within 6�months (20 of disease progression and 13 of SOS and multiorgan failure). Most (68�%) patients in the study died within 6�months; most of these deaths (73�%) were due to progression of AML. Serious adverse events occurred in 85�% of patients, most (81�%) due to AML, febrile neutropenia, pyrexia, and sepsis. GO administered in routine clinical practice carries an overall 9.1�% risk of SOS and a 2.7�% risk of death from SOS and multiorgan failure. No risk factors were identified for the development of SOS.""",1
13059,23461450,[Dronedarone-associated hepatotoxicity. A propos of a case],,1
13060,23463087,Hyaluronic acid as a marker of sinusoidal obstruction syndrome after oxaliplatin-based chemotherapy for colorectal liver metastases: don't forget the tumor,,1
13061,23466649,Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States,"""OBJECTIVES: To evaluate the clinical safety of daily tenofovir disoproxil fumarate (TDF) among HIV-negative men who have sex with men. DESIGN: Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to immediate or delayed study drug (TDF, 300 mg orally per day, or placebo). METHODS: Four hundred healthy HIV-uninfected men who have sex with men reporting anal sex with another man within the previous 12 months enrolled in Atlanta, Boston, and San Francisco. HIV serostatus, clinical and laboratory adverse events (AEs), adherence (pill count, Medication Event Monitoring System, and self-report), and sexual and other sociobehavioral data were assessed at 3-month intervals for 24 months. Primary outcomes were clinical safety, assessed by incidence of AEs and laboratory abnormalities. RESULTS: Study drug was initiated by 373 (93%) participants (186 TDF and 187 placebo), of whom 325 (87%) completed the final study visit. Of 2428 AEs reported among 334 (90%) participants, 2366 (97%) were mild or moderate in severity. Frequencies of commonly reported AEs did not differ significantly between TDF and placebo arms. In multivariable analyses, back pain was more likely among TDF recipients (P = 0.04); these reports were not associated with documented fractures or other objective findings. There were no grade >/=3 creatinine elevations; grades 1 and 2 creatinine increases were not associated with TDF receipt. Estimated percentage of study drug doses taken was 92% by pill count and 77% by Medication Event Monitoring System. Seven seroconversions occurred: 4 on placebo and 3 among delayed arm participants not yet on study drug. CONCLUSIONS: Daily oral TDF was well tolerated, with reasonable adherence. No significant renal concerns were identified.""",1
13062,23467121,Enzalutamide (Xtandi) for prostate cancer,,1
13063,23468307,Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors,"""Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m? twice daily days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.""",1
13064,23471546,A phase II dose-ranging study of mirabegron in patients with overactive bladder,"""INTRODUCTION AND HYPOTHESIS: Mirabegron is a potent and selective ?3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder. METHODS: Patients completed a single-blinded, 2-week placebo run-in period followed by 12 weeks of randomized (n?=?928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200 mg once-daily (QD), placebo or tolterodine extended release (ER) 4 mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24 h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24 h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume. RESULTS: Mirabegron 25, 50, 100, and 200 mg resulted in dose-dependent reductions (improvements) from baseline to end-of-treatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24 h respectively, versus 1.4 micturitions/24 h with placebo (p???0.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (p?<?0.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events. CONCLUSIONS: The favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program.""",1
13065,23472089,Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis,"BACKGROUND: This study aims to comprehensively summarize the currently available evidences on the efficacy and safety of gemcitabine plus erlotinib for treating advanced pancreatic cancer. METHODOLOGY/PRINCIPAL FINDINGS: PubMed, EMBASE, The Cochrane Library and abstracts of recent major conferences were systematically searched to identify relevant publications. Studies that were conducted in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib (with or without comparison with gemcitabine alone) and reporting objective response rate, disease control rate, progression-free survival, time-to-progression, overall survival, 1-year survival rate and/or adverse events were included. Data on objective response rate, disease control rate, 1-year survival rate and adverse events rate, respectively, were combined mainly by using Meta-Analyst software with a random-effects model. Data on progression-free survival, time-to-progression and overall survival were summarized descriptively. Sixteen studies containing 1,308 advanced pancreatic cancer patients treated with gemcitabine plus erlotinib were included. The reported median progression-free survival (or time-to-progression), median overall survival, 1-year survival rates, objective response rates and disease control rates were 2-9.6 months, 5-12.5 months, 20%-51%, 0%-28.6% and 25.0%-83.3%, respectively. The weighted 1-year survival rate, objective response rate and disease control rate based on studies reporting robust results were 27.9%, 9.1% and 57.0%, respectively. According to the studies with relevant data, the incidences of total and severe adverse events were 96.3% and 62.9%, respectively. The most frequently reported adverse events were leucopenia, rash, diarrhea, vomitting, neutropenia, thrombocytopenia, anaemia, stomatitis, drug-induced liver injury, fatigue and fever. Compared with gemcitabine alone, the progression-free survival and overall survival with gemcitabine plus erlotinib were significantly longer, but there were also more deaths and interstitial lung disease-like syndrome related to this treatment. CONCLUSIONS/SIGNIFICANCE: Gemcitabine plus erlotinib represent a new option for the treatment of advanced pancreatic cancer, with mild but clinically meaningful additive efficacy compared with gemcitabine alone. Its safety profile is generally acceptable, although careful management is needed for some specific adverse events.",1
13066,23473369,Effect of platelet inhibition with cangrelor during PCI on ischemic events,"""BACKGROUND: The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. RESULTS: The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. CONCLUSIONS: Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).""",1
13067,23481513,The European Medicines Agency review of vemurafenib (Zelboraf(R)) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use,"""The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).""",1
13068,23483799,Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor,"Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy. Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors, which are now widely used in the treatment of patients with chronic myeloid leukemia. Although HBV reactivation induced by imatinib mesylate has been reported, nilotinib-related HBV reactivation has not been reported in the English literature. We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.",1
13069,23485521,Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease,"""Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM(-1G>A)), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM(-1G>A) homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy.""",1
13070,23493664,Effects of repeat exposure to inhalation anesthetics on liver and renal function,"BACKGROUND: Cross hypersensitivity to inhalation anesthetics has not been studied. The aim of this study was to investigate it by comparing liver and renal function after repeated anesthesia with sevoflurane and isoflurane retrospectively. MATERIALS AND METHODS: The adult patients who received general anesthesia twice within the interval of 14 days to 1 year were retrospectively analyzed. Those who received sevoflurane anesthesia twice (SS group, 53 cases), isoflurane anesthesia twice (II group, 31 cases), sevoflurane followed by isoflurane anesthesia (SI group, 29 cases), isoflurane followed by sevoflurane anesthesia (IS group, 35 cases), and propofol-fentanyl anesthesia twice (PP group, 58 cases) were enrolled. Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (Bil), gamma-glutamyl transpeptidase (gamma-GTP), blood urea nitrogen (BUN), and creatinine (Cr) measured 1-3, 5-8, and 12-16 days after surgery were investigated. RESULTS: In the IS group, the number of the patients with abnormal values of ALT and gamma-GTP 5-8 days after surgery were significantly smaller at second anesthesia compared to the first anesthesia. The number of the patients with abnormal values of AST, ALT, and gamma-GTP were significantly larger in the II group than the SS and PP groups. The number of patients who had higher values in each parameter at second anesthesia compared to the first anesthesia was not different among the groups. CONCLUSIONS: Sevoflurane and isoflurane might have no cross hypersensitivity. Both anesthetics might not have any additional risks to increase liver and renal damage by second anesthesia.",1
13071,23499440,"Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial","""BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ?800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0?94), or in cohort C (p=0?78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.""",1
13072,23507873,Budesonide (Uceris) for ulcerative colitis,,1
13073,23510965,"Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21,789 patients","BACKGROUND: The epidemiology of drug-induced liver injury (DILI) in China has rarely been studied before. The aim of the present study was to determine the etiology of DILI in a Chinese population by reporting a systematic analysis of the Chinese literature published from 1994 to 2011. METHODS: A comprehensive database search of the Chinese literature was performed to obtain all the relevant studies. The data, including the drug names and patients' sex, age, clinical classification, and prognosis, were collected and analyzed. RESULTS: In this research, we found 279 studies including 24 112 patients. There were 265 studies that reported the sex of 21 789 patients, 11 787 men and 10 002 women. The therapeutics included (but were not limited to) tuberculostatics, complementary and alternative medicines (CAMs), antibiotics, NSAIDs, antineoplastics, central nervous system agents, antithyroid drugs, and immunomodulators. Of these drugs, tuberculostatics and CAMs were the most common etiologies of DILI in China. CONCLUSION: DILI in China has a different etiology from that in Europe and USA. NSAIDs, which are the most common causes of DILI in western populations, are uncommon in China. Therefore, government, physicians, and patients should pay more attention to these drugs in DILI.",1
13074,23512705,Efficacy and safety of standardized extract of Trigonella foenum-graecum L seeds as an adjuvant to L-Dopa in the management of patients with Parkinson's disease,"The objective of this study is to evaluate disease modifying efficacy and safety of a standardized extract of Trigonella foenum-graecum L, Fenugreek (IBHB) (family Fabaceae) as a nutritional adjuvant to Levo-dopa (L-Dopa) in Parkinson's disease (PD) patients. We conducted double-blind placebo-controlled proof of concept clinical study of IBHB capsules (300 mg, twice daily) with matching placebo for 6 months of period in 50 patients of PD stabilized on L-Dopa therapy. The efficacy outcome measures were the scores of Unified Parkinson's Disease Rating Scale (UPDRS - total and its subsections), and Hoehn and Yahr (H&Y) staging at baseline and end of 6-months treatment duration. Safety evaluation included haematology, biochemistry, urinalysis parameters and adverse event monitoring. Total UPDRS scores in IBHB treatment (0.098%) showed slower rise as opposed to steep rise (13.36%) shown by placebo. Further, Clinically Important Difference for total UPDRS scores and scores of motor subsection of UPDRS was found to be 5.3 and 4.8, respectively, in favour of IBHB treatment. Similar improvement was shown by IBHB in terms of H&Y staging as compared with placebo. IBHB was found to have excellent safety and tolerability profile. In conclusion, IBHB can be useful adjuvant treatment with L-Dopa in management of PD patients.",1
13075,23515511,Brentuximab vedotin: an anti-CD30 antibody-drug conjugate,"""PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, and safety and tolerability of brentuximab vedotin are reviewed. SUMMARY: Brentuximab vedotin is a potent antibody-drug conjugate composed of the monoclonal antibody cAC10, which targets the CD30 antigen on Hodgkin lymphoma and systemic anaplastic large-cell lymphoma (sALCL) cells; a highly stable valine-citrulline linker; and a potent chemotherapeutic agent monomethyl auristatin E, which inhibits microtubule polymerization. Brentuximab is indicated for patients with relapsed Hodgkin lymphoma after autologous stem-cell transplantation (ASCT), for patients who are not candidates for ASCT who have not responded to at least two multiagent chemotherapy regimens, and for patients with ALCL who have not responded to at least one multiagent chemotherapy regimen. In a Phase II, single-group, multicenter study, brentuximab produced an overall response rate of 75% in relapsed or refractory Hodgkin lymphoma. In another Phase II study, brentuximab demonstrated clinical benefit in sALCL, with 86% of patients achieving a response and 57% of patients achieving complete remission. Adverse events most commonly reported included nausea, fatigue, diarrhea, neutropenia, and peripheral sensory neuropathy. A Phase III study is currently ongoing in patients at high risk for residual Hodgkin lymphoma after ASCT. CONCLUSION: Brentuximab vedotin, a novel antibody-drug conjugate combining a cytotoxic agent with a selective monoclonal antibody, is a therapeutic option for patients with relapsed or refractory Hodgkin lymphoma and sALCL. Phase I and II studies have shown brentuximab to have a manageable toxicity profile.""",1
13076,23522569,Hepatoxicity of new antiretrovirals: a systematic review,"There has been a major paradigm shift in the management of HIV infected patients, with earlier initiation of antiretroviral treatment and lifelong exposure to drugs for which long-term safety issues must be faced by clinicians. Within the past 5 years, new drugs from both previously established and novel therapeutic classes have been released that tend to be safer and more efficient than their former combinations. Although hepatotoxicity was one of the most common side effects from initial antiretrovirals, phase II/III safety data regarding liver tolerance from more recent drugs are reassuring. However, data on the long-term exposure to these therapeutic options are needed, and a handful of case reports are emerging, reporting rare but potentially life-threatening adverse hepatic events in patients with hepatitis co-infection or taking other hepatotoxic drugs.",1
13077,23525934,Recombinant human activated protein C for adults with septic shock: a randomized controlled trial,"RATIONALE: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. OBJECTIVES: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. METHODS: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 ? 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 ?g/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. MEASUREMENTS AND MAIN RESULTS: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. CONCLUSIONS: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).",1
13078,23532097,Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results,"""BACKGROUND: ?Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity in vitro. METHODS: ?An international, randomized, double-blind, double-dummy, active-controlled trial was conducted to evaluate the efficacy and safety of COBI versus ritonavir (RTV) as a pharmacoenhancer of atazanavir (ATV) in combination with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in treatment-naive patients. The primary end point was a human immunodeficiency virus type 1 (HIV-1) RNA load of <50 copies/mL at week 48 by the Food and Drug Administration snapshot algorithm; the noninferiority margin was 12%. RESULTS: ?A total of 692 patients were randomly assigned to a treatment arm and received study drug (344 in the COBI group vs 348 in the RTV group). At week 48, virologic success was achieved in 85% of COBI recipients and 87% of RTV recipients (difference, -2.2% [95% confidence interval, -7.4% to 3.0%]); among patients with a baseline HIV-1 RNA load of >100 000 copies/mL, rates were similar (86% vs 86%). Similar percentages of patients in both groups had serious adverse events (10% of COBI recipients vs 7% of RTV recipients) and adverse events leading to discontinuation of treatment with the study drug (7% vs 7%). Median increases in the serum creatinine level were 0.13 and 0.09 mg/dL, respectively, for COBI and RTV recipients. CONCLUSIONS: ?COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.""",1
13079,23535099,Optimal management of DRESS syndrome in course of infectious endocarditis,,1
13080,23538078,"Ginkgo biloba: indications, mechanisms, and safety","Ginkgo biloba special extract (EGb761) is used in most randomized control trials. Indications include cognition and memory in Alzheimer disease, age-associated dementia, cerebral insufficiency, intermittent claudication, schizophrenia, and multi-infarct dementia. Dosages range from 80 to 720 mg/d for durations of 2 weeks to 2 years. Mechanisms of action include increasing cerebral blood flow, antioxidant and antiinflammatory effects, with antiplatelet effects attributed to flavone and terpene lactones. Possible interactions with monoamine oxidase inhibitors, alprazolam, haloperidol, warfarin, and nifedipine have been reported. Optimal dosage/duration, dose-response characteristics, drug interactions, bioavailability, long-term effects, and optimal intervention timing should be the focus of future work.",1
13081,23539016,Toxic epidermal necrolysis induced by lansoprazole,"Toxic epidermal necrolysis is a rare, severe cutaneous reaction, mostly caused by drugs. It affects the skin and mucous membranes, with involvement of more than 30% of body surface. We describe the case of a young woman, previously healthy, who developed skin detachment of more than 90% of the body surface 15 days after being administered lansoprazole for peptic disease. The treatment consisted in discontinuation of the drug involved and early administration of intravenous human immunoglobulin, which led to a satisfactory outcome of the case, substantiating the impact of early diagnosis and treatment on the morbidity and mortality of these patients.",1
13082,23540612,Mauriac syndrome still exists,"""BACKGROUND/OBJECTIVE: Mauriac syndrome (MS) is a rare complication of type 1 diabetes mellitus (DM1). It is related to low insulin concentrations and is less common since longer-acting insulins became available. It is characterized by hepatomegaly, growth and puberty delay, and the presence of elevated transaminases and serum lipids. The aim of this study was to describe the patients from a pediatric diabetic population that fulfill the criteria of MS. MATERIALS AND METHODS: A retrospective analysis of the pediatric diabetic population with diagnostic criteria of MS currently followed at Hospital de Braga, was performed. RESULTS: From a population of 91 patients with DM1 18 years, 6 patients with the criteria for MS were identified: 5 girls, and 1 boy. The age at presentation was 13-17 years, with a minimum interval between DM1 diagnosis and MS criteria of 4 years. All the patients were prescribed intensive insulin therapy (median daily insulin dose: 0.88 U/kg). All had a previous history of poor glycemic control before the diagnosis of MS with glycated hemoglobin (HbA1c) between 8.8 and 12.9%. Increase of hepatic enzymes was present in all the patients; 4 of them had associated hepatomegaly. All the girls presented puberty delay and cushingoid features. None of the patients presented short stature and 5 of them presented mixed dyslipidemia. CONCLUSIONS: Although MS is an ancient entity described in DM1, it still exists, particularly in adolescent females. Being aware of MS is of extreme importance since most of the clinical features are reversible with better glycemic control.""",1
13083,23542331,Efficacy and safety of oral chelators in treatment of patients with Wilson disease,"""BACKGROUND & AIMS: Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. METHODS: We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). RESULTS: Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). CONCLUSIONS: Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.""",1
13084,23545581,Two new drugs for homozygous familial hyperchelesterolemia,,1
13085,23545671,A rare case of propofol-induced liver injury during modified electroconvulsive therapy in an elderly woman,"A 75-year-old woman developed depression in 2010 and was treated with oral medications at our Department of Psychiatry. Since she showed no tendency toward improvement, she underwent modified electroconvulsive therapy (mECT). Later, she developed severe liver injury that was presumably induced by the propofol used for mECT. Propofol is an intravenous anesthetic agent that reportedly can be used relatively safely in the presence of liver dysfunction. We herein report the first case of propofol-induced liver injury definitively diagnosed based on positive drug lympocyte stimulation testing (DLST).",1
13086,23548536,Stevens-Johnson syndrome: a review of 14 adult cases with one fatal outcome,,1
13087,23550685,Hepatotoxicity with combination of vemurafenib and ipilimumab,,1
13088,23551330,Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis,"""Patients with colorectal liver metastasis (CRLM) can be cured with surgical resection. Recent advances in systemic chemotherapy, including molecular target agents, can be used to introduce """"conversion surgery"""" and achieve R0 resection even in patients with initially unresectable CRLM. Furthermore, neoadjuvant chemotherapy also tries to be applied in patients with resectable CRLM to maximize the remnant liver and reduce the residual micrometastasis before surgery. The development of chemotherapy-induced hepatic injuries is increasingly being recognized, including sinusoidal obstructive syndrome (SOS), steatosis, steatohepatitis and biliary sclerosis. Especially, oxaliplatin (L-OHP)-based chemotherapy in clinical settings appears to be primarily associated with SOS. Various reports have tried to demonstrate the rationale of the correlation between L-OHP-based chemotherapy and SOS for the following hepatic surgery. While we can recognize that this pathophysiological disadvantage leads to hepatic dysfunction and the increasing postoperative morbidity, the essential part of this problem including clinical disadvantage, onset mechanism, evaluation systems, and targeted agents for prevention and treatment of SOS continue to be unclear. In this review, we summarize the current experience with hepatic injury induced by L-OHP-based chemotherapy, focusing on SOS-based on clinical and experimental data, in order to assist in the resolution of these identified factors. Finally, the need for reliable methods to identify the risk of SOS, to evaluate SOS status and to predict the safety of surgical treatment in patients with chemotherapy prior to surgery will be emphasized.""",1
13089,23556046,Mastabol induced acute cholestasis: A case report,"A 26-year-old male presented with three weeks of jaundice after the self-initiation of the injectable anabolic steroid, Mastabol [Dromastanolone Di-Propionate (17 beta-Hydroxy-2alpha-methyl-5alpha-androstan-3-one propionate)]. He reported dark urine, light stools, and pruritus. He denied abdominal pain, intravenous drug use, intranasal cocaine, blood transfusions, newly placed tattoos, or sexually transmitted diseases. He used alcohol sparingly. Physical exam revealed jaundice with deep scleral icterus. The liver was palpable 2 cm below the right costal margin with no ascites. The peak bilirubin was 23.6 mg/dL, alkaline phosphatase was 441 units/L, and aspartate aminotransferase/alanine aminotransferase were 70 units/L and 117 units/L respectively. A working diagnosis of acute intrahepatic cholestasis was made. Liver biopsy revealed a centrilobular insult with neutrophilic infiltrates and Ito cell hyperplasia consistent with acute drug induced cholestasis. The patient's clinical symptoms resolved and his liver enzymes, bilirubin, and alkaline phosphatase normalized. Anabolic steroids with 17 alpha carbon substitutions have been associated with a bland variety of cholestatic injury with little hepatocellular injury. Cholestasis, under these circumstances, may be secondary to the binding of drugs to canalicular membrane transporters, accumulation of toxic bile acids from canalicular pump failure, or genetic defects in canalicular transport proteins. Mastabol is an injectable, 17 beta hydroxyl compound with no alpha alkyl groups at the 17 carbon position. As such, it has been reported to have little potential toxic effects on the liver. This is the first known reported case of Mastabol-induced cholestatic liver injury. It highlights the need for physicians to consider such widely available substances when faced with hepatic injury of unclear etiology.",1
13090,23556122,"Eltrombopag, a thrombopoietin- receptor agonist in the treatment of adult chronic immune thrombocytopenia: a review of the efficacy and safety profile","Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count that has persisted for more than 12 months. Patients may be asymptomatic but those with severe disease may have significant morbidity and require treatment. Corticosteroids and intravenous immunoglobulin are recommended as first-line treatments. Recently, two thrombopoietin-receptor agonists, romiplostim and eltrombopag have been licensed for the treatment of chronic ITP. The current indications for thrombopoietin-receptor agonists are for splenectomized adult patients with chronic ITP who are refractory to other treatments and adult nonsplenectomized patients in whom splenectomy is contraindicated. This article reviews data on the pharmacology, clinical efficacy and safety profile of eltrombopag in the treatment of ITP.",1
13091,23558578,The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression,"""Cadmium (Cd) is a highly hepatotoxic heavy metal, which is widely dispersed in the environment. Acute Cd hepatotoxicity has been well studied in experimental animals; however, effects of prolonged exposure to Cd doses on the liver remain unclear. In the present study, to evaluate chronic Cd hepatotoxicity, we examined specimens from cases of itai-itai disease, the most severe form of chronic Cd poisoning. We compared 89 cases of itai-itai disease with 27 control cases to assess Cd concentration in organs. We also examined 80 cases of itai-itai disease and 70 control cases for histopathological evaluation. In addition, we performed immunohistochemistry for metallothionein, which binds and detoxifies Cd. Hepatic Cd concentration was higher than Cd concentration in all other organs measured in the itai-itai disease group, whereas it was second highest following renal concentration in the control group. In the liver in the itai-itai disease group, fibrosis was observed at a significantly higher rate than that in the control group. Metallothionein expression was significantly higher in the itai-itai disease group than that in the control group. Prolonged exposure to low doses of Cd leads to high hepatic accumulation, which can then cause fibrosis; however, it also causes high expression of metallothionein, which is thought to reduce Cd hepatotoxicity.""",1
13092,23561229,"Efficacy and safety of levomilnacipran sustained release 40 mg, 80 mg, or 120 mg in major depressive disorder: a phase 3, randomized, double-blind, placebo-controlled study","""OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of fixed-dose levomilnacipran sustained release (SR) compared with placebo in patients with major depressive disorder (MDD); the study was conducted from September 2009-May 2011. METHOD: Outpatients met DSM-IV-TR criteria for MDD with an ongoing major depressive episode ? 8 weeks' duration. After a 1-week placebo lead-in, patients were randomly assigned to receive placebo (n = 179) or levomilnacipran SR 40 mg (n = 181), 80 mg (n = 181), or 120 mg (n = 183) once daily for 8 weeks of double-blind treatment, followed by a 2-week double-blind down-taper. The primary efficacy parameter was change from baseline on the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS) total score. The prespecified secondary efficacy parameter was change from baseline in Sheehan Disability Scale (SDS) total score. Additional efficacy measures included the 17-item Hamilton Depression Rating Scale (HDRS(17)) and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I). Safety and tolerability were also evaluated. RESULTS: The least squares mean difference (LSMD) for change from baseline in MADRS total score was significantly superior to placebo for all dose groups: -3.23 (P = .0186), -3.99 (P = .0038), and -4.86 (P = .0005) for levomilnacipran SR 40, 80, and 120 mg, respectively. The LSMD was significantly different for levomilnacipran SR 80 mg and 120 mg versus placebo on the SDS (-2.51 and -2.57, respectively, P < .05 for both doses), HDRS(17) (-2.09 and -2.34, respectively, P < .05 for both doses), CGI-S (-0.43 [P < .01] and -0.35 [P < .05], respectively), and CGI-I (-0.34 and -0.32, respectively, P < .05 for both doses) assessments. The most common treatment-emergent adverse events (? 10% of any treatment group) were headache, nausea, constipation, dry mouth, increased heart rate, and hyperhidrosis. CONCLUSIONS: Levomilnacipran SR demonstrated significant improvement in depressive symptoms and functioning relative to placebo. In this study, levomilnacipran SR was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00969709.""",1
13093,23562041,Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis,"BACKGROUND: The addition of Rituximab to standard chemotherapy (C) has been reported to improve the end of treatment outcome in non-Hodgkin lymphoma (NHL) patients. Nevertheless, rituximab has been associated with hepatitis B virus reactivation (HBV-R). OBJECTIVES: The aim of this systematic review and meta-analysis is to research the relationship between rituximab and HBV-R. STUDY DESIGN: We searched the commonly used databases both in English and Chinese from November 1997 to June 30, 2012. Meta-analysis was performed in fixed/random-effects models using Review Manager 5.1 and STATA 10.0. Publication bias was examined through Egger's test and Begg's funnel plot. RESULTS: Nine eligible articles were selected in this review (8 studies in English and 1 studies in Chinese), which included 971 adult patients and met all inclusion and exclusion criteria. Of rituximab-associated HBV-R cases reported through case series (n=387), 304 were HBcAb (+)/HBsAg (-) and 83 HBsAg (+). The pooled effect of rituximab-based therapy on HBV-R significantly increased under fixed-effects model [Relative risk (RR) 2.14, 95%CI 1.42-3.22, P=0.0003]. In subgroup analysis, rituximab-associated HBV-R in isolated HBcAb (+) patients remained high, and the RR was 5.52 (95%CI 2.05-14.85, P=0.0007). The RR of HBV-R in NHL patients with HBsAg (+) treated with R-based therapy when compared with the control population was 1.63 by the random-effects model. CONCLUSIONS: Rituximab therapy may increase the risk of developing HBV-R in NHL patients with HBcAb(+).",1
13094,23563410,Urea cycle disorder drug approved,,1
13095,23567788,Early onset imatinib mesylate-induced hepatotoxicity in a patient with gastrointestinal stromal tumors,"""Imatinib mesylate is used for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs). It has been associated with severe hepatotoxicity, which may lead to liver failure and death. Few cases of imatinib mesylate-induced liver failure have been reported; most of them were observed in patients treated for chronic myeloid leukemia. To date, 2 cases were reported in patients treated for GISTs. Elevation of liver function tests is usually observed during the first 2-3 months after the initiation of therapy. We report a 46-year-old woman with advanced GISTs who developed hepatotoxicity 11 days after the initiation of imatinib therapy. Before therapy with imatinib, her liver function tests were normal. She had no known risk factors for viral or alcoholic liver disease. Imatinib was her only regular medication, and she had not used acetaminophen or over-the-counter medications. Her serologic studies for hepatitis were all negative. One week after imatinib discontinuation, liver function tests improved significantly. The present report confirms the possibility of early onset imatinib mesylate-induced liver failure in patients treated for GISTs. Surveillance of liver function tests should start early after the initiation of treatment and during all the duration of therapy.""",1
13096,23572293,Systematic review of UV-based therapy for psoriasis,"BACKGROUND: UV-based therapies, which include narrow-band (NB) UVB, broad-band (BB) UVB, and psoralen and UVA (PUVA), are well known treatment options for moderate to severe plaque psoriasis. However, there are limited evidence-based reviews on their efficacy, short-term safety, and tolerability. AIM: The aim of the study was to evaluate the efficacy, short-term safety, and tolerability of UV-based therapy in the treatment of adults with moderate to severe plaque psoriasis. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating NB-UVB, BB-UVB, and PUVA in adults with moderate to severe plaque-type psoriasis. Our efficacy outcomes were ? Psoriasis Area and Severity Index (PASI)-75 and clearance. We evaluated the short-term safety and tolerability from the percentage of adverse effects and withdrawal due to adverse effects, respectively. RESULTS: Forty-one RCTs, with a total of 2,416 patients, met the eligibility criteria and were included in the analysis. In regard to PASI-75 in monotherapy trials, PUVA (mean: 73 %, 95 % CI 56-88) was the most effective modality. Trials with BB-UVB also showed a high PASI-75 (73 %) but with a wide CI (18-98) due to heterogeneity of the total available three studies. This was followed by NB-UVB (mean: 62 %, 95 % CI 45-79) then bath PUVA (mean: 47 %, 95 % CI 30-65). In regard to clearance in the monotherapy trials, PUVA (mean: 79 %, 95 % CI 69-88) was superior to NB-UVB (mean: 68 %, 95 % CI 57-78), BB-UVB (mean: 59 %, 95 % CI 44-72), and bath PUVA (mean: 58 %, 95 % CI 44-72). The percentages of asymptomatic erythema development in monotherapy trials were 64 % for BB-UVB, 57 % for NB-UVB, 45 % for PUVA, and 34 % for bath PUVA. Symptomatic erythema or blistering percentages for the monotherapy trials were as follows: 7.8 % for NB-UVB, 2 % for BB-UVB, 17 % for PUVA, and 21 % for bath PUVA. The percentages of withdrawal due to adverse effects were 2 % for NB-UVB, 4.6 % for BB-UVB, 5 % for PUVA, and 0.7 % for bath PUVA monotherapy trials. CONCLUSIONS: As a monotherapy, PUVA was more effective than NB-UVB, and NB-UVB was more effective than BB-UVB and bath PUVA in the treatment of adults with moderate to severe plaque-type psoriasis, based on clearance as an end point. Based on PASI-75, the results were similar except for BB-UVB, which showed a high mean PASI-75 (73 %) that was similar to PUVA, but with a wide CI (18-98). The short-term adverse effects were mild as shown by the low rate of withdrawal due to adverse effects.",1
13097,23575622,HLA typing in Brazilian boys with aromatic antiepileptic drug-induced DRESS,"""CASES DESCRIPTION: We report two cases of drug rash with eosinophilia and systemic symptoms (DRESS) associated with the use of carbamazepine and phenytoin in Brazilian boys tested for human leukocyte antigen (HLA) class I and II alleles. The clinical manifestations were similar: a maculopapular eruption progressing to exfoliative erythroderma, fever, and lymphadenopathy. Leukocytosis, atypical lymphocytes, and liver injury were also observed. Assessment of causality using the Naranjo algorithm established a """"probable"""" relationship (score 6) in both cases. Case 1 patient presented the following results of HLA typing: HLA-A*02,29 B*44,50 C*06,16 DRB1*01,07 DQA1*01,02. Case 2 patient presented the following results of HLA typing: HLAA*23,24 B*39,53 C*04,07 DRB1*04,08 DQA1*03,05 DQB1*03,03. CONCLUSION: Neither of the cases reported here presented HLA typing similar to that strongly associated with the occurrence of DRESS in Asian or European patients.""",1
13098,23585064,Orlistat and the risk of acute liver injury: self controlled case series study in UK Clinical Practice Research Datalink,"OBJECTIVE: To measure the association between orlistat and acute liver injury. DESIGN: Self controlled case series study. SETTING: Population based primary care setting, United Kingdom. PARTICIPANTS: 94,695 patients receiving orlistat and registered in the UK Clinical Practice Research Datalink and linked with Hospital Episode Statistics data between 1999 and 2011. MAIN OUTCOME MEASURE: Relative incidence of acute liver injury comparing periods when patients were receiving orlistat with periods of non-usage. RESULTS: Among 94,695 patients who received orlistat, 988 cases of acute liver injury were identified, with 335 confirmed as definite cases and 653 as probable cases. For all cases an increased incidence of liver injury was detected during the 90 day period before orlistat was first started, with an incidence rate ratio of 1.50 (95% confidence interval 1.10 to 2.06). The incidence remained raised during the first 30 days of treatment (2.21, 1.43 to 3.42), before returning to baseline levels with prolonged treatment. When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of liver injury was not increased (1.02, 0.67 to 1.56). An analysis restricted to definite cases showed no evidence of an increased risk of liver injury during treatment. CONCLUSION: The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.",1
13099,23588946,Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the abatacept clinical trial program,"""OBJECTIVE: To assess the overall safety, including rare events, of intravenous (IV) abatacept treatment in rheumatoid arthritis (RA). METHODS: Data from 8 clinical trials of IV abatacept in RA were pooled. Safety events were assessed during the short-term (duration </= 12 months) and cumulative (short-term plus longterm extensions) abatacept treatment periods. Incidence rates per 100 patient-years were calculated. Standardized incidence ratios (SIR) for hospitalized infections and malignancies were compared with external RA cohorts and, for malignancies, with the US general population. RESULTS: There were 3173 IV abatacept-treated patients with 2331 patient-years of exposure in the short-term periods, and 4149 IV abatacept-treated patients with 12,132 patient-years of exposure in the cumulative period. Incidence rates for serious infections were low and consistent over time (3.68 for abatacept vs 2.60 for placebo during the short-term, and 2.87 for abatacept during the cumulative period). Hospitalized infections were generally similar to external RA patient cohorts and were consistent over time. Incidence rates of malignancies were similar for abatacept- and placebo-treated patients during the short-term period (0.73 vs 0.59) and remained low during the abatacept cumulative period (0.73). SIR of some tissue-specific malignancies (e.g., colorectal and breast) in the cumulative period tended to be lower, while others (lymphoma and lung) tended to be higher, compared with the general population; however, incidence rates were comparable with RA cohorts. Autoimmune events were rare and infusion reactions uncommon. CONCLUSION: Longterm safety of IV abatacept was consistent with the short-term, with no unexpected events and low incidence rates of serious infections, malignancies, and autoimmune events.""",1
13100,23591401,A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma,"""OBJECTIVES: Sorafenib, an oral multikinase inhibitor of the VEGFR/PDGFR/Raf/MEK/ERK pathway, has shown potential activity in patients with recurrent ovarian cancer (OC). One strategy to prolong disease control and survival in patients with OC is maintenance therapy after achieving a complete response. A double-blind, randomized, placebo-controlled, phase II study to assess the efficacy and safety of maintenance therapy with sorafenib in the treatment of OC is presented. METHODS: Patients with epithelial OC or primary peritoneal cancer in complete remission were randomized to sorafenib 400mg BID or matching placebo. The primary endpoint was progression-free survival (PFS). RESULTS: Of 246 randomized patients, 93% had OC; baseline characteristics were balanced between treatment arms. There was no significant difference between sorafenib and placebo arms for PFS (median 12.7 vs 15.7 months; hazard ratio 1.09; 95% CI 0.72-1.63), although there was a notable imbalance in early censoring. The most common ? grade 3 adverse events (AEs) were hand-foot skin reaction (39.0% vs 0.8%) and rash (14.6% vs 0%). More patients receiving sorafenib versus placebo required dose reductions (67.5% vs 30.1%), resulting in a lower than planned median daily dose (median 584.6 vs 800.0mg). Treatment with sorafenib was of shorter duration (median 17.6 vs 51.9 weeks) with more frequent discontinuations due to AEs (37.4% vs 6.5%). CONCLUSIONS: Sorafenib 400mg BID cannot be recommended as maintenance therapy for patients with OC in complete remission. Assessment of efficacy was limited by the high rate of dose reductions and early discontinuations.""",1
13101,23591830,Idiopathic acute liver injury in paediatric outpatients: incidence and signal detection in two European countries,"""BACKGROUND: Acute liver failure is idiopathic and drug-related in, respectively, around 50 and 15 % of children. Population-based, epidemiologic data about the pattern of disease manifestation and incidence of less severe acute liver injury, either idiopathic or potentially drug-attributed are limited in children and adolescents. OBJECTIVES: (i) To assess the incidence of idiopathic acute liver injury (ALI) and its clinical features in children and adolescent outpatients; and (ii) to investigate the role of the drug as a potential cause of ALI which is considered idiopathic. METHODS: A retrospective cohort study was performed during the years 2000-2008. Data were retrieved from three longitudinal electronic healthcare databases in two European countries: Pedianet and Health Search/CSD Longitudinal Patient Database from Italy and the Integrated Primary Care Information database from The Netherlands. Cases of idiopathic acute liver injury in population aged <18 years were identified by exclusion of all competing causes of liver injury (e.g. viral, autoimmune hepatitis), according to CIOMS criteria. The potential role of drug exposure as actual underlying cause of idiopathic ALI was detected through signal detection mining techniques. Both pooled and country-specific incidence rates [IR/100,000 person-years (PYs)] of idiopathic ALI and pooled adjusted rate ratios (RR) of drugs identified as a potential cause of idiopathic ALI, plus 95 % confidence intervals (CI) were estimated using the custom-built software Jerboa. RESULTS: Among 785 definite cases of idiopathic ALI, the pooled IR was 62.4/100,000 PYs (95 % CI 58.1-66.8). The country-specific IR was higher in Italy (73.0/100,000 PYs, 95 % CI 67.8-78.4) than in The Netherlands (21.0/100,000 PYs, 95 % CI 16.0-27.2) and increased with age in both countries. Isolated elevations of liver enzymes were reported in around two-thirds of cases in Italy, while in The Netherlands the cases were more often identified by a combination of signs/symptoms. Among drugs detected as potential underlying cause of idiopathic ALI, clarithromycin (RR 25.9, 95 % CI 13.4-50), amoxicillin/clavulanic acid (RR 18.6, 95 % CI 11.3-30.6), and amoxicillin (RR 7.5, 95 % CI 3.4-16.8) were associated with the highest risk compared to non-use. CONCLUSION: The incidence of idiopathic ALI in paediatrics is relatively low and comparable with adults. Clinical presentations differ between the two European countries. Signal detection in healthcare databases allowed identifying antibiotics as the drugs mostly associated with ALI with apparently unknown aetiology.""",1
13102,23593614,Two cases of telbivudine-induced myopathy in siblings with chronic hepatitis B,"Telbivudine is an L-nucleoside analogue with potent antiviral activity against hepatitis B virus (HBV). Clinical trials have shown that telbivudine has a more potent and sustained antiviral activity with a lower frequency of viral resistance than lamivudine. Although there are several reports concerning the safety profile of telbivudine, most adverse events are described as mild and transient in nature. Here we report two cases of telbivudine-induced myopathy in patients with chronic hepatitis B who were siblings.",1
13103,23594140,Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording,"OBJECTIVE: The sleep electroencephalogram (EEG) can reveal certain epileptiform activity patterns and facilitate localization of the focus. Sedation is often required for sleep EEG recording in pediatric patients, but there is no consensus on the optimal sedative. Hydroxyzine HCL (HH) and chloral hydrate (CH) are popular sedatives, but HH is rarely used for pediatric sleep EEG recording. The goal of this prospective study was to compare CH to HH for sleep induction efficacy, safety and effects on pediatric sleep EEG pattern. RESEARCH DESIGN AND METHODS: A total of 282 children (age 4-9 years) referred to our sleep EEG laboratory and requiring sedation were randomly assigned to two groups: the CH Group (n = 141) received 50 mg/kg CH and the HH group (n = 141) received 1 mg/kg HH. If sedation was unsatisfactory, a second equal dose of the same sedative was administered 30 min later. RESULTS: Sleep induction was less successful in the HH group compared to the CH group (p < 0.001). Sleep onset latency was significantly longer in the HH group (p < 0.01) and the proportion of HH group patients requiring a second sedative dose significantly higher (p < 0.01). There was no significant difference in the proportion of patients exhibiting epileptiform activity on the EEG or in adverse event rate between groups. CONCLUSION: CH was a superior sedative compared to HH owing to more rapid and successful sleep induction with no increase in adverse events.",1
13104,23596311,HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin,"Drug-induced liver injury (DILI) is a main cause of drug withdrawal. A particularly interesting example is flucloxacillin (FLUX)-DILI, which is associated with the HLA-B*57:01 allele. At present, the mechanism of FLUX-DILI is not understood, but the HLA association suggests a role for activated T cells in the pathomechanism of liver damage. To understand the interaction among FLUX, HLA molecules, and T cells, we generated FLUX-reacting T cells from FLUX-naive HLA-B*57:01(+) and HLA-B*57:01(-) healthy donors and investigated the mechanism of T cell stimulation. We found that FLUX stimulates CD8(+) T cells in two distinct manners. On one hand, FLUX was stably presented on various HLA molecules, resistant to extensive washing and dependent on proteasomal processing, suggesting a hapten mechanism. On the other hand, in HLA-B*57:01(+) individuals, we observed a pharmacological interaction with immune receptors (p-i)-based T cell reactivity. FLUX was presented in a labile manner that was further characterized by independence of proteasomal processing and immediate T cell clone activation upon stimulation with FLUX in solution. This p-i-based T cell stimulation was restricted to the HLA-B*57:01 allele. We conclude that the presence of HLA-B*57:01 drives CD8(+) T cell responses to the penicillin-derivative FLUX toward nonhapten mechanism.",1
13105,23598172,Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial,"""BACKGROUND: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. METHODS: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: Median overall survival was 20.1 months (95% CI 16.7-23.4) with axitinib and 19.2 months (17.5-22.3) with sorafenib (hazard ratio [HR] 0.969, 95% CI 0.800-1.174; one-sided p=0.3744). Median investigator-assessed PFS was 8.3 months (95% CI 6.7-9.2) with axitinib and 5?7 months (4.7-6.5) with sorafenib (HR 0.656, 95% CI 0.552-0.779; one-sided p<0.0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20.7 months (95% CI 18.4-24.6) versus 12.9 months (10.1-20.4) in the axitinib group (p=0.0116), and 20.2 months (17.1-32.0) versus 14.8 months (12.0-17.7) in the sorafenib group (one-sided p=0.0020). INTERPRETATION: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. FUNDING: Pfizer Inc.""",1
13106,23602345,"A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of gabapentin enacarbil in subjects with neuropathic pain associated with postherpetic neuralgia (PXN110748)","Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained, dose-proportional exposure to gabapentin. This randomized, double-blind, parallel-group, placebo-controlled study evaluated the safety and efficacy of 3 different maintenance doses of oral GEn in subjects with postherpetic neuralgia. Adults with a 24-hour average pain intensity score of ?4.0 received GEn 1,200 mg, 2,400 mg, 3,600 mg, or placebo for 14 weeks (including a 1-week up-titration, 12-week maintenance, and 1-week taper). The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. The intent-to-treat population consisted of 371 subjects (GEn 1,200 mg = 107, 2,400 mg = 82, 3,600 mg = 87, placebo�=�95). With regard to the primary endpoint, all 3 GEn treatment groups demonstrated a statistically significant difference relative to placebo. The adjusted mean change from baseline for the treatment groups ranged from -2.36 to -2.72 versus -1.66 for the placebo group. Exposure-response modeling suggested an ED50 around 1,200 mg/day, which was consistent with historical findings reported for gabapentin. The most commonly reported adverse events were dizziness and somnolence. All studied doses of GEn significantly improved pain associated with postherpetic neuralgia as compared to placebo and were well tolerated. PERSPECTIVE: GEn provides clinically important pain relief with doses from 1,200 mg to 3,600 mg and is generally well tolerated and efficacious. As an actively transported prodrug of gabapentin, it provides dose-proportional and extended exposure to gabapentin.",1
13107,23606919,Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier,"A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30�years ago. He was diagnosed with renal cell carcinoma when he was 57�years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers.",1
13108,23606935,Safety and efficacy of defibrotide for the treatment of severe hepatic veno-occlusive disease,"Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). VOD may occur in up to 62% of patients undergoing SCT, with onset generally within the first month after SCT. In severe cases, 100-day mortality is in excess of 80%. Current management consists of best supportive care, with no agents to date approved for treatment in the USA or the EU. Defibrotide, a polydisperse oligonucleotide, has been shown in phase II and III trials to improve complete response and survival in patients undergoing SCT with severe VOD. This article reviews our current understanding of VOD, and examines recent clinical findings on defibrotide for the treatment and prophylaxis of VOD.",1
13109,23607594,Sofosbuvir for previously untreated chronic hepatitis C infection,"""BACKGROUND: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. METHODS: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. CONCLUSIONS: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).""",1
13110,23616916,The efficacy and safety of romiplostim in adult patients with chronic immune thrombocytopenia,"Romiplostim is a thrombopoietin peptide mimetic agent recently approved for the treatment of adults with chronic immune thrombocytopenia (ITP). In randomized controlled studies, this agent has demonstrated an increase in the platelet count in the majority of patients with ITP, both in splenectomized and nonsplenectomized patients. In up to 5 years of follow up, its safety profile has been favorable, suggesting this could be a novel therapeutic agent in patients with ITP. This article summarizes the development of this new agent and explores its safety and efficacy in adults with chronic ITP.",1
13111,23617322,Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria,"Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66�months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97?6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86?9% at 36�months), reflecting inhibition of chronic haemolysis. TEs decreased by 81?8%, with 96?4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93?1% of patients exhibited improvement or stabilization in CKD score at 36�months. Transfusion independence increased by 90?0% from baseline, with the number of red blood cell units transfused decreasing by 54?7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.",1
13112,23620168,Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives,"The introduction of small-molecule tyrosine kinase inhibitors (TKIs) in clinical oncology has transformed the treatment of certain forms of cancers. As of 31 March 2013, 18 such agents have been approved by the US Food and Drug Administration (FDA), 15 of these also by the European Medicines Agency (EMA), and a large number of others are in development or under regulatory review. Unexpectedly, however, their use has been found to be associated with serious toxic effects on a number of vital organs including the liver. Drug-induced hepatotoxicity has resulted in withdrawal from the market of many widely used drugs and is a major public health issue that continues to concern all the stakeholders. This review focuses on hepatotoxic potential of TKIs. The majority of TKIs approved to date are reported to induce hepatic injury. Five of these (lapatinib, pazopanib, ponatinib, regorafenib and sunitinib) are sufficiently potent in this respect as to require a boxed label warning. Onset of TKI-induced hepatotoxicity is usually within the first 2�months of initiating treatment, but may be delayed, and is usually reversible. Fatality from TKI-induced hepatotoxicity is uncommon compared to hepatotoxic drugs in other classes but may lead to long-term consequences such as cirrhosis. Patients should be carefully monitored for TKI-induced hepatotoxicity, the management of which requires individually tailored reappraisal of the risk/benefit. The risk is usually manageable by dose adjustment or a switch to a suitable alternative TKI. Confirmation of TKI-induced hepatotoxicity can present challenges in the presence of hepatic metastasis and potential drug interactions. Its diagnosis in a patient with TKI-sensitive cancer requires great care if therapy with the TKI suspected to be causal is to be modified or interrupted as a result. Post-marketing experience with drugs such as imatinib, lapatinib and sorafenib suggests that the hepatotoxic safety of all the TKIs requires diligent surveillance.",1
13113,23625293,Catechins in dietary supplements and hepatotoxicity,"BACKGROUND: Many herbal dietary supplements (HDS) contain green tea extract (GTE) and its component catechins, although their presence may not always be indicated on the product label. PURPOSE: Because GTE and catechins have been implicated in human hepatotoxicity in several case reports, our objective was to determine whether catechins were present in HDS that were implicated in hepatotoxicity, even if not identified among the labeled ingredients, and whether these compounds could be associated with liver injury. METHODS: We assayed 97 HDS implicated in human hepatotoxicity for catechins. RESULTS: We found that 29 of 73 HDS (39.7%) that did not identify GTE or any of its component catechins on their label contained catechins. Among patients with confirmed hepatotoxicity, there was no statistically significant association between the presence of catechin or the dose consumed and liver injury causality score, severity, or pattern of liver injury. Catechin levels tended to be highest in products used for weight loss, although catechin concentrations were low in most products. CONCLUSIONS: Many HDS commonly contain catechins that are implicated in hepatotoxicity, although their presence may not be indicated on the product label. Although our results did not establish an association between GTE or catechins with hepatotoxicity, they highlight some of the many complexities and uncertainties that surround the attribution of drug-induced liver injury (DILI) to HDS.",1
13114,23632341,Characteristics of liver injury in drug-induced systemic hypersensitivity reactions,"BACKGROUND: The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury. METHODS: The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase >/=80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed. RESULTS: Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality. LIMITATIONS: This study was retrospective and the number of subjects was small. CONCLUSION: The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.",1
13115,23635030,"Successful treatment of severe iron intoxication with gastrointestinal decontamination, deferoxamine, and hemodialysis","Acute iron poisoning is a common and potentially serious problem in the pediatric population. Early recognition and treatment is crucial for a better outcome and to prevent morbidity and mortality. An 18-year-old female, who had accidental ingestion of 50 tablets of ferrous sulfate (100 mg of elemental iron per 335 mg tablet), 100 mg/kg of elemental iron, developed acute gastrointestinal and neurologic signs of toxicity and severe anion gap metabolic acidosis. The patient had received gastrointestinal decontamination, deferoxamine (DFO) infusion, and hemodialysis (HD) resulting in a decrease in serum iron concentration from 2150 to 160 mcg/dL at 24-h post-ingestion and improved mental status. Our cases demonstrate that HD may assist in decreasing serum iron concentration and improving clinical status in patients with massive overdose and life-threatening toxicity.",1
13116,23635947,Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury,"Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.",1
13117,23638621,"A prospective, randomised, investigator-blind, controlled, clinical study on the clinical efficacy and tolerability of two highly purified hMG preparations administered subcutaneously in women undergoing IVF","""The aim of this multicentre, prospective, randomised, investigator blind, controlled clinical trial was to evaluate the clinical efficacy and tolerability of a highly purified human menopausal gonadotrophin (hMG) preparation (Merional-HG) when administered to patients undergoing controlled ovarian stimulation (COS) for in-vitro fertilisation (IVF) procedure enrolled in hospital departments. One hundred fifty-seven patients were randomised in two parallel groups: 78 started COS with Merional-HG and 79 with Menopur. Results of the study showed that both highly purified hMG preparations were equivalent in terms of number of oocytes retrieved (primary endpoint: 8.8 ? 3.9 versus 8.4 ? 3.8, p = 0.54). In the patients treated with Merional-HG, we observed a higher occurrence of mature oocytes (78.3% versus 71.4%, p = 0.005) and a reduced quantity of gonadotrophins administered per cycle (2.556 ? 636 IU versus 2.969 ? 855 IU, p < 0.001). Fertilisation, cleavage, implantation rates and the number of positive ?-human chorionic gonadotrophin (hCG; pregnancy) tests and the clinical pregnancy rate were comparable in the two groups. Both treatments were well tolerated. In conclusion, the results of this study support the efficacy and safety of Merional-HG administered subcutaneously for assisted reproduction techniques. Efficiency of Merional-HG appears to be higher due to reduced quantity of drug used and the higher yield of mature oocytes retrieved.""",1
13118,23640345,Vandetanib: a novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer,"""PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety and tolerability, drug and food interactions, cost, and place in therapy of vandetanib are reviewed. SUMMARY: Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and receptor tyrosine kinase signaling pathways, which are involved in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Vandetanib was evaluated in a randomized, placebo-controlled, double-blind Phase III study comparing vandetanib with placebo in adult patients with unresectable locally advanced or metastatic hereditary or sporadic MTC. Vandetanib demonstrated a statistically significant longer progression-free survival (predicted median of 30.5 months) compared with placebo (median of 19.3 months) (hazard ratio, 0.46; 95% confidence interval, 0.31-0.69; p = 0.0001). The most commonly observed adverse effects of vandetanib include nausea, diarrhea, headache, rash, prolongation of the Q-T interval, and hypertension. Because it can prolong the Q-T interval, vandetanib is contraindicated for use in patients with serious cardiac complications, including congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, and a history of torsades de pointes. CONCLUSION: Vandetanib has been shown to be more effective than placebo in the treatment of advanced MTC; however, it has not been compared with radiation, resection, or embolization. Vandetanib also has significant and fairly common cardiac toxicities. The cost, benefits, and risks of vandetanib for patients with MTC should be weighed, as alternative treatments remain an option for most patients.""",1
13119,23645381,Infliximab-related hepatitis: a case study and literature review,,1
13120,23649869,Tumor lysis syndrome soon after treatment with hydroxyurea followed by nilotinib in two patients with chronic-phase chronic myelogenous leukemia,"Nilotinib, a second-generation tyrosine kinase inhibitor with 20- to 30-fold greater potency than imatinib, was developed to overcome imatinib intolerance or resistance. Recently, nilotinib has been approved as a first-line treatment for chronic myelogenous leukemia in the US and Japan. Tumor lysis syndrome (TLS) is an extremely rare adverse event that can occur during treatment with nilotinib, with only a few reported cases to date. Herein, we report two patients who developed TLS soon after the start of treatment with nilotinib. While in the first case, which co-presented with underlying mild-to-moderate renal insufficiency due to polycystic kidney disease, the TLS resolved on discontinuation of the drug, the second patient, who had an exceedingly high white blood cell count, presented with disseminated intravascular coagulation and severe liver injury triggered by TLS that developed after the start of nilotinib treatment, and died of multiple organ failure. Therefore, caution is necessary when this drug is used in the first-line setting in patients with renal insufficiency or a high tumor burden.",1
13121,23650408,Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma,"PURPOSE: Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population. PATIENTS AND METHODS: Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. RESULTS: Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients ? 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). CONCLUSION: BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation.",1
13122,23653147,Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study,"""PURPOSE: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. RESULTS: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. CONCLUSIONS: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.""",1
13123,23659772,Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands,"""BACKGROUND: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of the Dutch CUP, detailing the safety and efficacy of cabazitaxel in a routine clinical practice setting. PATIENTS AND METHODS: Safety and efficacy data of all 5 Dutch centers participating in the cabazitaxel CUP were collected. Safety data were collected prospectively using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Overall survival (OS) and progression-free survival (PFS), time to PSA progression (TTPP), and best clinical response were evaluated retrospectively. RESULTS: Fifty-one patients were registered in the CUP; 49 received cabazitaxel. Forty-two of 49 patients [85.7%], 42 patients had ? 2 metastatic sites. Patients received on average 6 cabazitaxel cycles (range, 1-21). A dose reduction or dose delay occurred in 13 and 20 patients [26.5% and 40.9%] respectively. Prophylactic granulocyte colony-stimulating factor (G-CSF) was used in 8 patients [16.3%]. Grade ? 3 adverse events were observed in 25 patients [51.0%]; 16 patients [32.7%] discontinued treatment because of treatment-emergent adverse events (TEAEs). Serious adverse events (SAEs) occurred in 16 (32.7%) patients; the most frequent SAEs were hematuria (4 patients [8.3%]) and urosepsis (3 patients [6.3%]). Febrile neutropenia occurred twice; no patient had grade ? 3 neuropathy. No toxicity-related mortality occurred. Median follow-up was 24.1 months. Median OS was 8.7 months (interquartile range [IQR], 6.0-15.9 months); median TTPP was 2.8 months (IQR, 1.7-5.9 months). CONCLUSION: In the Dutch CUP, patients with advanced mCRPC had delayed tumor progression with acceptable toxicities using cabazitaxel treatment.""",1
13124,23663001,Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies,"""PURPOSE: Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose. METHODS: Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving >/= 50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data. KEY FINDINGS: The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs. SIGNIFICANCE: Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile.""",1
13125,23664723,Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity,"INTRODUCTION: Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes--including CYP3A4/5, CYP1A1, and CYP2D6--in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. PATIENTS AND METHODS: Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade >/= 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. RESULTS: The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade >/= 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). CONCLUSION: Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.",1
13126,23665964,Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients,"BACKGROUND: To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. METHODS: Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. RESULTS: Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0-420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohn's disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohn's disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohn's disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. CONCLUSIONS: As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.",1
13127,23668332,Safety evaluation of leflunomide in rheumatoid arthritis,"INTRODUCTION: Leflunomide is a prodrug which is rapidly converted following oral administration and absorption to an active metabolite with anti-proliferative effects (A77 1726/teriflunomide). Leflunomide was developed as an immunomodulatory agent and subsequently developed as a disease-modifying anti-rheumatic drug (DMARD) for the management of rheumatoid arthritis (RA). AREAS COVERED: This review article covers the mechanism of action of the drug, clinical indications, including efficacy data from clinical trials, safety data from clinical trials, post marketing studies and surveillance databases and safety in special populations. Additionally, the review discusses the current place of leflunomide in the management of RA, and its likely future as an anti-rheumatic drug. EXPERT OPINION: Leflunomide is a relatively safe drug, with proven efficacy in RA management. Its clinical use is limited by the historic parallel development of other agents, including methotrexate, which has become the synthetic DMARD of choice and biological DMARDs that have superior efficacy.",1
13128,23669782,Canaglifozin (Invokana) for type 2 diabetes,,1
13129,23669799,Association between adverse reactions to allopurinol and exposures to high maintenance doses: implications for management of patients using allopurinol,"OBJECTIVE: The objective of this study was to estimate the association between adverse drug reactions (ADRs) and exposure to allopurinol maintenance doses higher than those in the 1984 suggested limits of Hande et al. adjusted for level of renal function. METHODS: We conducted a retrospective review of electronic health records of patients prescribed allopurinol from January 1, 2004, to June 30, 2011, to identify those who had a definite or possible ADR to allopurinol. The associations of ADRs with maintenance doses of allopurinol 1 to 1.5 times and more than 1.5 times the suggested limits of Hande et al. compared with doses within the suggested limits of Hande et al. were estimated using logistic regression models. RESULTS: Of 4755 patients prescribed allopurinol, 2946 had a serum creatinine measured within 6 months of starting allopurinol, and of these, 1268 patients' records were reviewed. Forty-eight patients had a definite ADR to allopurinol, 2 of which were allopurinol hypersensitivity syndrome. The odds ratios of definite ADRs with maintenance doses of allopurinol 1.0 to 1.5 times and more than 1.5 times suggested compared with doses within suggested limits were, respectively, 1.42 (95% confidence interval [CI], 0.66-3.04) and 2.04 (95% CI, 0.87-4.77). Among those with an allopurinol maintenance dose more than 1.5 times suggested limits, the proportion of patients with a definite ADR was 2.6% (95% CI, 1.0%-5.2%). CONCLUSIONS: There is no significant association of high maintenance doses of allopurinol with ADRs, and the absolute risk of ADRs at doses higher than 1.5 times the 1984 suggested limits of Hande et al. is low. Cautious, gradual increases in allopurinol maintenance doses above the suggested limits of Hande et al. are warranted if necessary to achieve a serum uric acid level less than 6 mg/dL.",1
13130,23671551,A rare coexistence: drug induced hepatitis and meningitis in association with Ibuprofen,"Ibuprofen, a commonly used NSAID is reported to be associated with drug induced liver injury. Ibuprofen is also known to be associated with drug-induced meningitis especially in patients with connective tissue disorders. However presentation of hepatitis and meningitis in association with Ibuprofen use in the same individual has never been reported. We present a case of young woman who developed abnormal liver chemistries and neurological symptoms while on Ibuprofen. Her liver biopsy findings were suggestive of drug induced liver injury and cerebrospinal fluid analysis was suggestive of aseptic meningitis. Clinical and biochemical improvement was noted on cessation of Ibuprofen.",1
13131,23672220,"Efficacy and safety of acarbose chewable tablet in patients with type 2 diabetes: a multicentre, randomized, double-blinded, double-dummy positive controlled trial","OBJECTIVE: To evaluate the effect and safety of HbA1c and glycemic control of acarbose chewable tablets in patients with type 2 diabetic. METHOD: A multicentre, randomized, double-blinded, double-dummy, positive controlled clinical trial was conducted. Two hundred thirty-four Chinese patients with type 2 diabetic were enrolled in eight clinical centres, who were divided randomly into the acarbose chewable tablet group (experimental group, n = 116) and the acarbose treatment group (control group, n = 118). RESULTS: Two hundred seven patients (88.5%) took part in the 12-week trial. At the beginning and end of the clinical trial, HbA1c and blood glucose as well as safety indexes were measured. After the treatment, the level of finger two-hour postprandial blood glucose (PPBG) was decreased 4.15 mmol/L (26.82%) and 3.54 mmol/L (22.77%), respectively, in the experiment group and the control group. The levels of venous two-hour PPBG in the experiment group and the control group were decreased 4.04 mmol/L (25.38%) and 2.75 mmol/L (17.26%), respectively, with the means of HbA1c lowering 11.67% and 12.44%, respectively. Fasting blood glucose (FBG) also was reduced significantly in both groups. Patients in both groups showed obvious weight reduction (P < 0.0001). There were no significant differences in the incidence of adverse events between the two groups. CONCLUSION: In summary, acarbose chewable tablets have a definite curative effect in treating type 2 diabetic patients as HbA1c and blood glucose levels decreased significantly after the 12-week treatment.",1
13132,23678006,Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy,"""Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor-activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. This trial was registered at www.clinicaltrials.gov as #NCT00103285.""",1
13133,23682110,Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial,"Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group.",1
13134,23683771,Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study,"""We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-na?ve ('na?ve') and 81 (70%) were enzyme pretreated ('pretreated'). Median (range) miglustat exposures in these groups were 15.1 (0.6-52.9)months and 15.2 (0.3-62.1)months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of miglustat therapy. The median (range) hemoglobin concentration at miglustat initiation was 12.8 (10.2-16.4)g/dl in na?ve patients and 13.6 (7.3-17.4)g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6)g/dl, respectively. The median (range) platelet counts at miglustat initiation were 101 (37-730)?10(9)/l in na?ve patients and 173 (43-382)?10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77-145)?10(9)/l and -10 (-144-434)?10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in na?ve but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in na?ve patients treated with miglustat, and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with miglustat in the current study is similar to previous studies.""",1
13135,23686600,Crizotinib for the treatment of non-small-cell lung cancer,"""PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, adverse effects, and dosage and administration of crizotinib in the management of non-small-cell lung cancer (NSCLC) are reviewed. SUMMARY: Crizotinib (Xalkori, Pfizer Inc.) is a novel tyrosine kinase inhibitor approved for the treatment of patients with locally advanced or metastatic NSCLC who exhibit assay-confirmed mutations of the gene coding for anaplastic lymphoma kinase (ALK). The primary biochemical mechanism of crizotinib is to inhibit ALK expression, leading to increased cell proliferation and decreased apoptosis. Crizotinib is metabolized and excreted after O-dealkylation by cytochrome P-450 (CYP) isoenzyme 3A4/5; as crizotinib is also an inhibitor of CYP3A4/5, its use entails a high potential for drug interactions, including confirmed interactions with ketoconazole and rifampin that can alter crizotinib pharmacokinetics. A Phase I trial involving patients with ALK gene mutation-positive NSCLC demonstrated significant disease control with oral crizotinib use, including an overall eight-week response rate of 87% and an estimated six-month survival of 72%. At the standard dosage of 250 mg twice daily, crizotinib is well tolerated. In clinical trials to date, the most common grade 1 or 2 adverse events were nausea, diarrhea, vomiting, and visual disturbances; more severe toxicities included transaminase elevations (less than 7% of patients) and pneumonitis (less than 2% of patients). Hypogonadism leading to low testosterone levels appears to be universal among male patients treated with crizotinib. CONCLUSION: Crizotinib appears to be efficacious and well tolerated in patients with NSCLC and may have future potential applications in treating lymphomas and other cancers driven by ALK or c-MET gene mutations.""",1
13136,23687539,Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis,"""INTRODUCTION: There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L) when treated with oral and IV acetylcysteine. METHODS: Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment. RESULTS: We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity. CONCLUSION: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration.""",1
13137,23691988,Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study,,1
13138,23692526,"Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies","""INTRODUCTION: To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results. METHODS: This prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, evaluated efficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co-primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end-points included patient-reported outcomes according to the Treatment Satisfaction-Visual Analogue Scale (TS-VAS) and responder analyses [dry rate (posttreatment), >/= 50% reduction in incontinence episodes/24 h, </= 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate). RESULTS: Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (>/= 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine. CONCLUSION: The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB.""",1
13139,23697284,Acute oxcarbazepine-induced hepatotoxicity in a patient susceptible to developing drug-induced liver injury,"Oxcarbazepine (OXC) is generally accepted as a drug without risk of severe drug-induced hepatotoxicity, but according to recently reported pharmacovigilance data this statement has been challenged. However, in the literature there have been no reports of acute OXC-induced hepatotoxicity without systemic manifestations of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome. We present a female with seizures one month after delivery who had borderline elevated liver enzymes prior to the initiation of OXC treatment. Two weeks after introducing OXC, highly elevated liver enzymes were found. After discontinuation of OXC the enzymes continued to rise for another week, and afterward gradually decreased. The causal relationship with OXC intake was determined to be highly probable. Two years later, the transitory elevation of liver enzymes was observed during the treatment of acute tonsilopharingitis with amoxicillin + clavulanic acid. The repeated elevation of liver enzymes related to use of different drugs might indicate patients susceptibility for drug induced liver injuries. We suggest that monitoring of liver function tests would be clinically rational for early detection of acute OXC-induced liver hepatotoxicity in the patients with clinical and/or laboratory features which might be interpreted as possible risk factors of the increased susceptibility to drug induced liver injuries.",1
13140,23701251,A phase II open-label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome,"Homoharringtonine is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. We report a phase II pilot study of homoharringtonine in myelodysplastic syndrome (MDS). Induction consisted of homoharringtonine at 2.5 mg/m(2) via continuous infusion for 7 days. Maintenance was given every 4 weeks. Nine patients were enrolled: five with refractory anaemia with excess blasts, two with refractory anaemia with excess blasts in transformation, one each with refractory anaemia and chronic myelomonocytic leukaemia respectively. Median age was 70 years (55-84) and 6 (66%) were male. Per International Prognostic Scoring System (IPSS) two patients were intermediate-1, five intermediate-2 and two high-risk. Median chemotherapy courses were one (1-3). One patient (11%) responded with complete haematological and cytogenetic remission after one course. Eight patients did not respond (four had stable disease, two progressed to acute leukaemia and two died during induction - from aspergillus pneumonia and intracerebral haemorrhage respectively). Grade 3/4 myelosuppression seen in 56% (5/9). Serious non-haematological toxicities included one case of grade 4 left bundle branch heart block and one grade 3 nephrotoxicity. Median time between courses was 42 days (35-72 days). In conclusion homoharringtonine might have clinical activity in some patients with MDS.",1
13141,23702916,L-Asparaginase-induced fulminating liver dysfunction,,1
13142,23715100,Drugs for psychiatric disorders,,1
13143,23716163,Successful extracorporeal liver dialysis for the treatment of trimethoprim-sulfamethoxazole-induced fulminant hepatic failure,"Trimethoprim-sulfamethoxazole (TMP-SMZ) is a commonly used antibiotic that has been associated with drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome is characterised by fever, rash, lymphadenopathy, eosinophilia and one or more major organ involvement. Although rare, TMP-SMZ is a recognised cause of fulminant hepatic failure. We report a 17-year-old Chinese male adolescent who presented with fever, myalgia, generalised maculopapular rash and lymphadenopathy after taking TMP-SMZ for acne vulgaris. He subsequently developed hepatic encephalopathy and was worked up for urgent liver transplantation. He responded well to extracorporeal liver dialysis (originally intended as a bridging therapy) and subsequently recovered without the need for liver transplantation. This case report highlights the importance of early recognition of TMP-SMZ-induced DRESS syndrome and the need for early discontinuation of the drug in the affected patient. Extracorporeal liver dialysis and transplantation should be considered in the management of TMP-SMZ-induced fulminant hepatic failure.",1
13144,23719881,Safety profile of antiviral medications: a pharmacovigilance study using the Italian spontaneous-reporting database,"""PURPOSE: The results of an analysis of suspected antiviral-associated adverse drug reactions (ADRs) in Italy over a 22-year period are presented. METHODS: A case/non-case analysis was conducted using ADR reports compiled in the nationwide spontaneous-reporting database through September 2010. All reported events included in the analysis were evaluated and coded by drug safety experts; causality assessments were performed according to the algorithm of Naranjo et al. The association between an adverse reaction and antiviral use was assessed by estimating the reporting odds ratio (ROR), with 95% confidence interval (CI), as a measure of disproportionality. RESULTS: Overall, 863 reports of suspected ADRs involving antivirals and 42,430 reports of adverse reactions to other drugs were identified; of those events, 3.3% and 64.3% were determined to be definite or probable ADRs, respectively, and an additional 32.4% were deemed possibly drug related. Several ADRs were disproportionately associated with antivirals relative to other drugs: renal colic (ROR, 25.5; 95% CI, 13.3-49.0), lactic acidosis (ROR, 18.6; 95% CI, 9.2-37.7), depression (ROR, 18.0; 95% CI, 11.6-27.9), anemia (ROR, 15.9; 95% CI, 12.3-20.4), hallucination (ROR, 4.3; 95% CI, 2.7-7.1), neutropenia (ROR, 4.1; 95% CI, 2.9-5.8), acute renal failure (ROR, 3.9; 95% CI, 2.3-6.4), fever (ROR, 3.8; 95% CI, 2.8-5.1), hyperpyrexia (ROR, 2.9; 95% CI, 1.7-4.9), and asthenia (ROR, 1.8; 95% CI, 1.2-2.8). CONCLUSION: Analysis of data from a large Italian database showed that, among antiviral agents, the ribavirin-interferon combination, acyclovir, valacyclovir, indinavir, and zidovudine accounted for the most serious hematologic, neuropsychiatric, and renal ADRs.""",1
13145,23724867,Nivolumab plus ipilimumab in advanced melanoma,"""BACKGROUND: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma. METHODS: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. RESULTS: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ?24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).""",1
13146,23725528,An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration,"An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.",1
13147,23726406,62-year-old man with painless jaundice and hyponatremia,,1
13148,23727264,Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease,"""BACKGROUND & AIMS: Obeticholic acid (OCA; INT-747, 6?-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. METHODS: We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7?-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. RESULTS: When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of ?-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7?-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. CONCLUSIONS: In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592.""",1
13149,23735025,Treatment with adalimumab in a patient with regenerative nodular hyperplasia secondary to azathioprine,"INTRODUCTION: regenerative nodular hyperplasia (RNH) is a rare liver disease with an etiology that is not well understood. Among the etiological factors are purine-analogue drugs such asazathioprine. CASE REPORT: we present a case of a 47-year-old patient diagnosed with Crohn?s disease in treatment with azathioprine due to corticosteroid dependency who developed RNH with clinical and laboratory signs of portal hypertension one year after starting treatment. After discontinuation of azathioprine, the patient started treatment and, given the poor disease progression, started treatment with adalimumab. This was continued with an excellent response and without deleterious effects on the liver. DISCUSSION: the relevance of this case is twofold: First, this is a rare and early side effect of azathioprine treatment and this is an irreversible disease with potentially serious complications. Second, because treatment was carried out with biological drugs (adalimumab) despite the patient having advance liver disease with portal hypertension without any evidence of it worsening, nor signs of deleterious effects or complications, given that there is scarce or no experience with adalimumab treatment in this type of situation.",1
13150,23738544,Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome,"""BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73?10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).""",1
13151,23740226,Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs: results of the GO-MORE study,"""OBJECTIVES: To evaluate the efficacy and safety of subcutaneous golimumab as add-on therapy in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6?months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28-ESR remission was measured. RESULTS: 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6?years and mean DAS28-ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (?25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. CONCLUSIONS: Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen.""",1
13152,23742015,The consequences of not having eosinophils,"Several lines of evidence suggest that deficiency of eosinophils is not associated with any characteristic abnormality. Patients lacking eosinophils, in the setting of immunodeficiency or as a consequence of IgG-mediated eosinophil precursor destruction, do not display any distinguishing abnormalities related to eosinophil reduction. The observation that eosinophil-deficient mice do not display any distinctive syndrome or failure of their health is evidence that, under ordinary laboratory conditions, the eosinophil does not play a critical role in the well-being of mammals. Observations that monoclonal antibodies to interleukin-5 (IL-5) are well tolerated appear unsurprising in light of these findings. For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6 years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL-5 receptor ?-chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated. Thus, data to the present suggest that reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil-associated diseases.",1
13153,23743692,Causality of Drugs Involved in Acute Liver Failure Leading to Transplantation: Results from the Study of Acute Liver Transplant (SALT),"BACKGROUND: Several methods have been proposed to assess causality in drug-induced liver injury but none have been tested in the specific context of acute liver failure leading to transplantation (ALFT). OBJECTIVE: We took advantage of the Study of Acute Liver Transplant (SALT), a European case-population study of ALFT, to test different causality scales. METHODS: Causality was assessed by experts in SALT, a 7-country case-population study from 2005 to 2007 of adult otherwise unexplained ALFT, for all drugs found within 30 days prior to the date of initial symptoms of liver disease (index date), using information content, causality scales, and data circuit determined from a pilot study, Salome. RESULTS: The consensus points from Salome were to provide full data on drugs including international non-proprietary name (INN) and doses except for non-steroidal anti-inflammatory drugs (NSAIDs) and to use the World Health Organization (WHO) causality scale. In SALT, among the 9,479 identified patients, 600 (6.3%) were cases of ALFT, of which 187 had been exposed to drugs within 30 days, without overdose. In 130 (69.5%) of these the causality score was possible, probable, or highly probable. CONCLUSION: In ALFT cases, once other clinical causes have been excluded and drug exposure established within 30 days, the main discriminant characteristic for causality will be previous knowledge of possible hepatotoxicity.",1
13154,23744424,Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions,"BACKGROUND: Epilepsy is a chronic neurological disease which affects about 1% of the human population. There are 50 million patients in the world suffering from this disease and 2 million new cases per year are observed. The necessary treatment with antiepileptic drugs (AEDs) increases the risk of adverse reactions. In case of 15% of people receiving AEDs, cutaneous reactions, like maculopapular or erythematous pruritic rash, may appear within four weeks of initiating therapy with AEDs. METHODS: This study involved 300 epileptic patients in the period between September 1989 and September 2009. A cutaneous adverse reaction was defined as a diffuse rash, which had no other obvious reason than a drug effect, and resulted in contacting a physician. RESULTS: Among 300 epileptic patients of Neurological Practice in Kielce (132 males and 168 females), a skin reaction to at least one AED was found in 30 patients. As much as 95% of the reactions occurred during therapies with carbamazepine, phenytoin, lamotrigine or oxcarbazepine. One of the patients developed Stevens-Johnson syndrome. CONCLUSION: Some hypersensitivity problems of epileptic patients were obviously related to antiepileptic treatment. Among AEDs, gabapentin, topiramate, levetiracetam, vigabatrin, and phenobarbital were not associated with skin lesions, although the number of patients in the case of the latter was small.",1
13155,23746170,The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C,"BACKGROUND: Ustekinumab, an interleukin (IL)-12 and IL-23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the use of ustekinumab in patients with viral hepatitis are limited. OBJECTIVE: To assess the safety profile of ustekinumab in the treatment of patients with psoriasis who have concomitant hepatitis B or hepatitis C. METHODS: This study included 18 patients with concurrent psoriasis and hepatitis B virus (HBV) infection (14 patients) or hepatitis C virus (HCV) infection (four patients) who were treated with at least two ustekinumab injections. Viral loads were measured at baseline and each time before the administration of ustekinumab. Relevant clinical data were recorded. RESULTS: Among 11 patients positive for hepatitis B surface antigen (HBsAg), two out of the seven (29%) patients who did not receive antiviral prophylaxis exhibited HBV reactivation during ustekinumab treatment. No viral reactivation was observed in the three occult HBV-infected patients (HBsAg-negative/hepatitis B core antibody-positive patients). One patient with HCV, liver cirrhosis and treated hepatocellular carcinoma (HCC) experienced HCV reactivation and recurrent HCC during the ustekinumab treatment. No significant increase in aminotransferase levels was observed in any patient. CONCLUSIONS: Antiviral prophylaxis appears to minimize the risk of viral reactivation in patients with concurrent psoriasis and HBV infection. Without effective anti-viral prophylaxis, the risk/benefit of ustekinumab treatment should be carefully assessed in patients with psoriasis and HBV or HCV infection and/or HCC. Close monitoring for HBV and HCV viral load is recommended, particularly for patients with high-risk factors. Serum aminotransferase determination may not be useful for early detection of viral reactivation.",1
13156,23747952,Ramipril-induced liver injury: case report and review of the literature,"""BACKGROUND: Ramipril, an inhibitor of the angiotensin-converting enzyme (ACEI), is a drug commonly used in the therapy of hypertension. ACEI-induced hepatotoxicity is rare, and most of the reported cases are associated with captopril. Here, we present the first case of ramipril-induced liver injury proven by positive rechallenge and a review of the literature including the data from the US Food and Drug Administration adverse event reporting system (FAERS). METHODS: Patient data were collected in the Berlin Case-Control Surveillance Study for adverse drug reactions. PubMed research on ACEI-induced hepatotoxicity included all ACEIs except captopril; analysis of the FAERS database focused on ramipril-induced hepatotoxicity in the period 2009-2011. RESULTS: A 40-year-old male patient presented with acute onset jaundice and highly (>20-fold increase of alanine aminotranferase (ALT)) elevated liver enzymes (LEs). Viral or autoimmune hepatitis and biliary etiology were ruled out. Withdrawal of several medications including ramipril resulted in an immediate decrease in LEs, whereas a subsequent re-exposure with ramipril resulted in a striking increase in LEs (>35-fold increase of ALT). After definitely discontinuing ramipril, a rapid decline in LEs was observed, suggesting a certain causal relationship between drug intake and hepatic damage. Analysis of the FAERS database retrieved 65 cases of ramipril-associated hepatotoxicity, with jaundice being the most frequent hepatic adverse event. PubMed research detected 23 relevant publications, with enalapril being the ACEI most commonly reported as being associated with liver injury. CONCLUSIONS: ACEI-induced hepatotoxicity is rare. Our case confirms a hepatotoxic potential of ramipril, highlighting the need for alertness among physicians regarding this matter.""",1
13157,23750489,Risk of oral antifungal agent-induced liver injury in Taiwanese,"AIM: Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations. METHODS: A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort. RESULTS: Of the 90,847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10,000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration >/= 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10,000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI. CONCLUSIONS: Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole.",1
13158,23751410,Reactive macrophage activation syndrome possibly triggered by canakinumab in a patient with adult-onset Still's disease,"""Macrophage activation syndrome (MAS) is a rare and serious complication of adult-onset Still's disease. We describe a case in a 49-year-old woman with Still's disease refractory to glucocorticoids, methotrexate, and infliximab. Anakinra provided satisfactory disease control for 1 year, after which escape phenomenon occurred. After four tocilizumab injections, cutaneous melanoma developed. The persistent systemic manifestations prompted treatment with two canakinumab injections. Ten days later, she had a spiking fever, dyspnea, low back pain, abdominal pain, odynophagia, and hepatomegaly. Laboratory tests showed liver cytolysis (180 IU/L; N: 10-35), acute renal failure (creatinine, 407 mumol/L; N:50-100), thrombocytopenia (60 G/L; N: 150-400), leukocytosis (12,200/mm(3); N: 4000-10,000), hypertriglyceridemia (5070 mmol/L; N: 0.4-1.6), lactate dehydrogenase elevation (4824 IU/L; N: 135-250), and hyperferritinemia (97 761 mug/L; N:15-150). Examination of a bone marrow biopsy showed phagocytosis. Tests were negative for viruses and other infectious agents. Glucocorticoid therapy (1.5 mg/Kg/d) and intravenous polyvalent immunoglobulins (0.5 g/Kg/d) were given. Her condition improved despite the many factors of adverse prognostic significance (thrombocytopenia, absence of lymphadenopathy, and glucocorticoid therapy at diagnosis). This is the first reported case of MAS after canakinumab therapy in a patient with adult-onset Still's disease.""",1
13159,23754188,Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis,"""OBJECTIVE: To determine the long-term safety and efficacy of rilonacept, an anti-interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4-week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open-label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated. RESULTS: Twenty-four patients entered the double-blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment-related adverse events were observed. CONCLUSION: Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in >50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated.""",1
13160,23757384,Cholestatic jaundice as a result of combination designer supplement ingestion,"""OBJECTIVE: To report a case of cholestatic jaundice as a result of combination herbal and designer supplement use. CASE SUMMARY: A 50-year-old Hispanic male presented to the hospital with a 1-week history of significant painless jaundice; total bilirubin on admission was 29.4 mg/dL. He reported use of both herbal (creatine and whey protein) and designer (Incredible Bulk and Spartan 45) supplements concurrently for approximately 2 months. Upon admission, all supplements were discontinued and multiple laboratory and diagnostic tests were ordered. On day 6 of his hospital admission, a liver biopsy was performed, the results of which indicated drug-induced hepa to toxicity. On day 9 he was discharged with prescriptions for ursodeoxycholic acid and hydroxyzine. Three months post hospital discharge, the patient continued to be supplement-free and bilirubin had decreased substantially. DISCUSSION: Anabolic-androgenic steroids are capable of causing hepatotoxicity, and multiple cases reported in the literature support this. A case report described hepato toxicity secondary to both creatine and whey protein consumption, and several reports have described liver damage secondary to designer supplement use. To our knowledge, this is the first case to describe hepatotoxicity as a result of combination herbal and designer supplement use. The Roussel Uclaf Causality Assess ment Method (RUCAM) score for drug-induced hepatotoxicity indicated a highly probable correlation between the use of combination supplements and cholestatic jaundice. CONCLUSIONS: Health care professionals need to be aware of complications associated with designer supplement use and should be able to identify patients who would benefit from education on herbal and designer supplement use.""",1
13161,23762711,Amiodarone hepatotoxicity with absent phospholipidosis and steatosis: a case report and review of amiodarone toxicity in various organs,"""We present the first description of amiodarone toxicity in the liver without phospholipidosis or steatosis. In doing so, we will review the various effects of amiodarone toxicity in various organs. The patient is a young adult who had cardiac reconstruction as a child for transposition of the great vessels. A needle biopsy was taken due to elevated liver enzymes. Her ALT was 188?U/L (5-50) and AST 162?U/L (5-50). Alkaline phosphatase, total bilirubin, protein, and albumin were within normal limits. A serologic panel for viral hepatitis was negative. Antinuclear antibodies were positive at 260; however, anti-smooth muscle antibody and anti-mitochondrial antibody were negative. A protein electrophoresis showed a slightly elevated beta globulin 2 level of 0.5. Quantitative immunoglobulin levels were within normal limits except for a slightly elevated IgA 409?mg/dL (60-350). Liver ultrasound was unremarkable. The clinical differential was broad and included hepatic congestion along with autoimmune hepatitis. Sections showed only ballooned hepatocytes with Mallory-Denk bodies and perisinusoidal fibrosis. Arrival to the diagnosis was possible only after careful review of the patient's medications. After discontinuation of amiodarone, the patient's liver enzymes returned to normal levels.""",1
13162,23764687,Clozapine toxicity and hepatitis,,1
13163,23769109,Accidental acetaminophen overdose results in liver transplant during second trimester of pregnancy: a case report,"Acetaminophen overdose is the most rapidly growing cause of fulminant hepatic failure in Western countries. Pregnant women are counseled that acetaminophen is safe during pregnancy and an alternative to nonsteroidal anti-inflammatory medications. This report describes a case of acetaminophen overdose during the second trimester of pregnancy with resultant fulminant hepatic failure requiring liver transplantation. The fetus was previable at the time of liver transplantation, and methods to preserve viability during and after transplantation are discussed. Despite the best attempts of the team, the fetus expired. The challenges and outcomes of fulminant hepatic failure in pregnancy are discussed in detail.",1
13164,23769296,"Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial","""BACKGROUND: Many patients with psoriasis develop psoriatic arthritis, a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures. The fully human monoclonal antibody ustekinumab is an efficacious treatment for moderate-to-severe plaque psoriasis. We did a randomised, placebo-controlled, phase 3 trial to assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis. METHODS: In this phase 3, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (?5 tender and ?5 swollen joints, C-reactive protein ?3?0 mg/L) were randomly assigned (1:1:1, by dynamic central randomisation based on an algorithm implemented by an interactive voice-web response system) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. Our primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24. This trial is registered with ClinicalTrials.gov (NCT01009086) and EudraCT (2009-012264-14). FINDINGS: Between Nov 30, 2009, and March 30, 2011, 615 patients were randomly assigned-206 to placebo, 205 to 45 mg ustekinumab, and 204 to 90 mg ustekinumab. More ustekinumab-treated (87 of 205 [42?4%] in the 45 mg group and 101 of 204 [49?5%] in the 90 mg group) than placebo-treated (47 of 206 [22?8%]) patients achieved ACR20 at week 24 (p<0?0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41?8%] vs 86 of 205 [42?0%]). INTERPRETATION: Ustekinumab significantly improved active psoriatic arthritis compared with placebo, and might offer an alternative therapeutic mechanism of action to approved biological treatments. FUNDING: Janssen Research & Development.""",1
13165,23770145,Severe immune-mediated drug-induced liver injury linked to ibandronate: a case report,"Ibandronate is a widely used bisphosphonate with no previously well documented hepatotoxicity. We report the first case of ibandronate-related hepatotoxicity and, to our knowledge, the first case of immune-mediated drug-induced liver injury (DILI) related to bisphosphonates.",1
13166,23772645,Very late onset hepatitis-B virus reactivation following rituximab despite lamivudine prophylaxis: the need for continued vigilance,,1
13167,23774827,Ipilimumab and its toxicities: a multidisciplinary approach,"The treatment for metastatic melanoma has evolved significantly in the past few years. Ipilimumab, an immunotherapy, is now in mainstream oncology practice given that it has shown improved overall survival in randomized clinical trials. Other immune modulating agents, such as programmed death receptor-1 and programmed death receptor ligand-1 antibodies, are showing promise in early clinical trials. This manuscript will review ipilimumab and its most common side effects. Immune-related adverse events (irAEs) are important to recognize early, and their presentation, timing of onset, and general recommendations for workup and management will be reviewed. Assembling a multidisciplinary team, as well as thorough education of the patient, is recommended to optimize patient care.",1
13168,23775837,Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure,"""UNLABELLED: Isoniazid (INH)-induced hepatotoxicity remains one of the most common causes of drug-induced idiosyncratic liver injury and liver failure. This form of liver injury is not believed to be immune-mediated because it is not usually associated with fever or rash, does not recur more rapidly on rechallenge, and previous studies have failed to identify anti-INH antibodies (Abs). In this study, we found Abs present in sera of 15 of 19 cases of INH-induced liver failure. Anti-INH Abs were present in 8 sera; 11 had anti-cytochrome P450 (CYP)2E1 Abs, 14 had Abs against CYP2E1 modified by INH, 14 had anti-CYP3A4 antibodies, and 10 had anti-CYP2C9 Abs. INH was found to form covalent adducts with CYP2E1, CYP3A4, and CYP2C9. None of these Abs were detected in sera from INH-treated controls without significant liver injury. The presence of a range of antidrug and autoAbs has been observed in other drug-induced liver injury that is presumed to be immune mediated. CONCLUSION: These data provide strong evidence that INH induces an immune response that causes INH-induced liver injury.""",1
13169,23776577,The efficacy and safety of Nucleos(t)ide analogues in patients with spontaneous acute exacerbation of chronic hepatitis B: a systematic review and meta-analysis,"""BACKGROUND: Spontaneous acute exacerbation (AE) of chronic hepatitis B (CHB) is often detrimental but sometimes leads to sustained immune control and disease remission. The efficacy and safety of nucleos(t)ide analogues (NAs) in patients with spontaneous AE of CHB remains unclear. METHODS: We performed a systematic review and meta-analysis of NAs in patients with spontaneous AE of CHB. We calculated pooled effects of NAs in these patients of each study and conducted quantitative meta-analysis, displaying results using Forest plots. RESULTS: 15 studies were included and substantial heterogeneity was noted in the inclusion/exclusion criteria and controls. Pooled data showed no benefit of lamivudine (LAM) vs. untreated controls for transplant-free survival in patients with spontaneous AE of CHB (OR = 0.98 (95% CI, 0.50-1.92; P = 0.956)), hepatic decompensation (OR = 0.94 (95% CI, 0.47-1.88; P = 0.862)) and liver failure owing to AE (OR = 2.30 (95% CI, 0.35-15.37; P = 0.387)) at 3 months. Entecavir achieved even higher short-term mortality than LAM. NAs led to rates of ALT normalization, undetectable HBV DNA, HBeAg loss, HBeAg seroconversion and drug resistance at 1 year in 88%, 61%, 46%, 35% and 5%. Pooled data also showed benefit favoring LAM vs. untreated controls for ALT normalization (OR = 1.98 (95% CI, 1.03-3.80; P = 0.039)) and undetectable HBV DNA (OR = 38.50 (95% CI, 7.68-192.99; P<0.001)) at 3 months. All NAs were relatively safe and well tolerated. CONCLUSION: NAs had no obvious impact on short-term survival in patients with AE of CHB, despite of possible better antiviral responses. We suggest additional studies to evaluate the efficacy of other NAs and early introduction of immunosuppressant in combination with NAs. We highlight developing prognostic models to identify predictors of mortality and disease progression for AE of CHB.""",1
13170,23781132,A survey of the FAERS database concerning the adverse event profiles of ?1-adrenoreceptor blockers for lower urinary tract symptoms,"""PURPOSE: Current guidelines recommend ?1-adrenoreceptor blockers (A1Bs) for treating lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but their adverse effects can be problematic. In this study, reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) between 1997 and 2011 were reviewed to assess the safety profiles of A1Bs. METHODS: After deleting duplicated submissions and revising arbitrary drug names, reports involving A1Bs for male patients were analyzed. Data mining algorisms were used for the quantitative detection of signals, where a signal represents an association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio, reporting odds ratio, information component given by a Bayesian confidence propagation neural network, and empirical Bayes geometric mean. RESULTS: The total number of reports used was 1,260,182. Signal scores suggested the associations of alfuzosin, doxazosin, tamsulosin, and terazosin with dizziness/vertigo, orthostatic hypotension, erectile dysfunction, ejaculation dysfunction (EjD), thirst/dry mouth, and constipation; however, reports on naftopidil, silodosin, and urapidil were not enough to compare with the other 4 A1Bs. Signal scores for EjD were higher for tamsulosin, and those for dizziness/vertigo were lower for doxazosin than for the other 3 drugs. CONCLUSIONS: Tamsulosin-associated EjD, which was found in clinical studies, was reproduced in this analysis with markedly higher signal scores, and these results strongly suggest the necessity of well-organized clinical studies on A1B-associated adverse events.""",1
13171,23782157,Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma,"""BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)""",1
13172,23787123,Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib,"""INTRODUCTION: Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: Data were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m(2) twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point. RESULTS: Eighty-one patients with CML-CP (median age, 59�years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months - not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%). CONCLUSION: Omacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.""",1
13173,23789833,Severe toxic hepatitis associated with dronedarone,"Dronedarone was introduced in 2009 as a new antiarrhythmic agent and since then has been increasingly prescribed in atrial fibrillation or flutter. To date, two cases of severe toxic hepatitis have been reported in patients treated with dronedarone, both requiring emergency liver transplantation, and the FDA as well as the EMA have issued warnings about possible severe hepatotoxicity of dronedarone. Here we report an additional case of toxic hepatitis associated with dronedarone presenting with acute liver failure, followed by spontaneous recovery, in a 69-year old woman.",1
13174,23791308,Use of carglumic acid in the treatment of hyperammonaemia during metabolic decompensation of patients with propionic acidaemia,"""Propionic acidaemia (PA) results from propionyl-CoA carboxylase deficiency. During metabolic decompensation, the accumulation of propionyl-CoA causes secondary hyperammonaemia through N-acetylglutamate synthetase inactivation. Carglumic acid, a structural analogue of N-acetylglutamate, was given to patients with PA (n=3) during episodes of metabolic decompensation (n=8; age range: birth to 4years), in addition to high energy/low protein intake and carnitine. Plasma ammonia concentrations normalised within 6-19h. Carglumic acid was well tolerated with no side effects noted.""",1
13175,23797799,Plan B One-Step OTC,,1
13176,23800008,Drug safety evaluation of vemurafenib in the treatment of melanoma,"INTRODUCTION: Nearly 50% of melanomas harbor a BRAF mutation, and vemurafenib has shown a clinical response rate of approximately 50% and a median progression-free survival duration of ? 6 - 7 months in patients with V600 BRAF-mutant advanced melanoma. Based on a Phase III study demonstrating a survival advantage over dacarbazine, vemurafenib was approved by the regulatory agencies for the treatment of V600 BRAF-mutant advanced melanoma in 2011. Although vemurafenib does not induce life-threatening toxicity frequently associated with conventional chemotherapy. It is associated with other adverse events, particularly skin toxicities. AREAS COVERED: We discuss the mechanism of action, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety profile of vemurafenib in patients with metastatic melanoma harboring a BRAF mutation. In particular, we describe in detail the skin toxicity of vemurafenib, including the development of keratoacanthoma and squamous cell carcinoma of the skin. EXPERT OPINION: Both preclinical and clinical investigations have shed light on our understanding of the skin toxicities associated with vemurafenib and have led to potential strategies for reducing the frequency of these adverse events. Further understanding of other associated toxicities could significantly improve the quality of life for patients undergoing treatment with vemurafenib or another BRAF inhibitor.",1
13177,23801528,"Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis","Treatment options for relapsing-remitting multiple sclerosis (RRMS) have been continuously expanding in recent years, and the emergence of a number of oral disease-modifying agents (DMAs) has significantly changed the landscape of therapeutic options for MS patients. Many of these oral DMAs have demonstrated satisfactory safety and tolerability profiles in clinical trial settings, but the long-term safety of these agents is an important concern. This review discusses salient points on the safety and clinical efficacy of the approved and emerging novel oral therapies in RRMS, including fingolimod, teriflunomide, dimethyl fumarate, laquinimod, and cladribine.",1
13178,23807722,Crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy,"""Crofelemer (Fulyzaq) is a botanical drug substance (oligomeric proanthocyanidin) extracted from the stem bark latex of the Croton lechleri tree. Crofelemer undergoes minimal systemic absorption following oral administration; it acts locally within the gastrointestinal (GI) tract by inhibiting the two principal chloride ion channels in the luminal membrane of enterocytes. Crofelemer is the first (and so far only) agent to be approved by the US FDA specifically for the symptomatic relief of non-infectious (i.e. secretory) diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy (ART). This approval was based on findings from the ADVENT study, a large (n = 376 randomized patients), multicentre, phase III trial in which the recommended dosage of oral crofelemer (125 mg twice daily) significantly reduced secretory diarrhoea in HIV-positive individuals on ART compared with placebo, as assessed over a 4-week period. Crofelemer was generally well tolerated in ADVENT (which included a 5-month placebo-free extension phase) and a 48-week, open-label, phase III safety study; infections and GI disorders were the most frequently reported treatment-emergent adverse events (TEAEs) in patients receiving the drug. Of note, the overall incidence of TEAEs was similar in the crofelemer and placebo groups during the 4-week placebo-controlled phase of ADVENT. Treatment with crofelemer had no appreciable effect on immune parameters, such as HIV viral load and CD4+ cell counts.""",1
13179,23809766,"Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study","""PURPOSE: We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first-line sorafenib. PATIENTS AND METHODS: Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival). RESULTS: The median treatment duration was 19.5 weeks (range 2-103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n=20), disease progression (n=10), consent withdrawal (n=2) and death (n=1). Seventeen patients required dose reductions (mostly for adverse events [n=15]); 35 patients had treatment interruption (mostly for adverse events [n=32] or patient error [n=11]). The most frequent treatment-related adverse events were hand-foot skin reaction (any grade n=19; grade ?3 n=5), diarrhoea (n=19; n=2), fatigue (n=19; n=6), hypothyroidism (n=15; n=0), anorexia (n=13; n=0), hypertension (n=13; n=1), nausea (n=12; n=0) and voice changes (n=10; n=0). Disease control was achieved in 26 patients (partial response n=1; stable disease n=25). Median time to progression was 4.3 months. Median overall survival was 13.8 months. CONCLUSION: Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib.""",1
13180,23810788,The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial,"""BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36?4 h (range 32?8-46?0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING: Merck Sharp and Dohme.""",1
13181,23812464,Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial,"""OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified.""",1
13182,23822543,Severe everolimus-induced steatohepatis: a case report,"The mammalian target of rapamycin inhibitors are normally favored as immunosuppressant agents for solid organ transplantation such as kidney, liver or heart. Only in recent years have they been increasingly administered for the treatment of neuroendocrine tumors. Even though mammalian target of rapamycin inhibitors are known to exhibit specific side effects, everolimus-related severe hepatic steatosis has not as yet been described in the literature. We report the case of a 76-year-old man who developed severe hepatic steatosis within four weeks of treatment with everolimus as concomitant tumor therapy for a progressively growing neuroendocrine carcinoma of the ileum. A diagnosis of hepatic steatosis was established using computer tomography and fibroscan(c). Other underlying causes for steatosis hepatis could be excluded. Further studies are warranted to explain the underlying mechanisms.",1
13183,23826928,Use of case reports and the Adverse Event Reporting System in systematic reviews: overcoming barriers to assess the link between Crohn's disease medications and hepatosplenic T-cell lymphoma,"BACKGROUND: To identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn's disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn's disease. METHODS: We identified cases of HSTCL in Crohn's disease in studies included in a comparative effectiveness review of Crohn's disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL. RESULTS: We found 37 unique cases of HSTCL in patients with Crohn's disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (<40 years of age) and male (86%). The most commonly reported medications were anti-metabolites (97%) and anti-tumor necrosis factor alpha (anti-TNFa) medications (76%). Dose and duration of therapy were not consistently reported. Use of aminosalicylates and corticosteroids were rarely reported, despite the high prevalence of these medications in routine treatment. Using the causality assessment tools, it could only be determined that anti-metabolite and anti-TNFa therapies were possible causes of HSTCL in Crohn's disease based on the data contained in the case reports. CONCLUSION: Systematic reviews that incorporate case reports of rare lethal events should search both published literature and AERS, but consideration should be given to the limitations of case reports. In this study, establishing a causative effect other than 'possible' between anti-metabolite or anti-TNFa therapies and HSTCL was not feasible because case reports lacked data required by the causality assessments, and because of the limited applicability of causality assessment tools for rare irreversible events. We recommend minimum reporting requirements for case reports to improve causality assessment and routine reporting of rare life-threatening events, including their absence, in clinical trials to help clinicians determine whether rare adverse events are causally related to a medication.",1
13184,23830355,"Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study","""BACKGROUND: Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. METHODS: ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. FINDINGS: Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7.4%, 95% CI 0.7 to 14.2); superiority of dolutegravir versus raltegravir was then concluded (p=0.03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3.7%, 95% CI -6.1 to -1.2; p=0.003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). INTERPRETATION: Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. FUNDING: ViiV Healthcare.""",1
13185,23833086,Subacute liver failure secondary to black cohosh leading to liver transplantation,"The use of herbal medications is increasing significantly in the UK and there is a perception that herbal preparations are without adverse effects. This case report highlights the potential risks of black cohosh, which is one of the most commonly used herbal products. This is a case report of a 60-year-old Caucasian lady who presented with subacute liver failure secondary to taking black cohosh. This was further confirmed by liver biopsy and she subsequently deteriorated and underwent liver transplantation. Available evidence supports an association between black cohosh and risk of hepatotoxicity. In current literature, there have only been four previously reported cases of hepatotoxicity associated with black cohosh, which required liver transplantation. We submit that our patient represents the fifth case. We recommend that patients taking this supplement should have close monitoring of their hepatic function, especially in the presence of other risk factors.",1
13186,23835707,PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer,"""PURPOSE: In the phase III PARAMOUNT trial, pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo (hazard ratio [HR], 0.62; 95% CI, 0.49 to 0.79; P < .001). Here we report final overall survival (OS) and updated safety data. PATIENTS AND METHODS: In all, 939 patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) received four cycles of pemetrexed-cisplatin induction therapy; then, 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were randomly assigned (2:1) to maintenance pemetrexed (500 mg/m(2) on day 1 of 21-day cycles; n = 359) or placebo (n = 180). Log-rank test compared OS between arms as measured from random assignment (? = .0498). RESULTS: The mean number of maintenance cycles was 7.9 (range, one to 44) for pemetrexed and 5.0 (range, one to 38) for placebo. After 397 deaths (pemetrexed, 71%; placebo, 78%) and a median follow-up of 24.3 months for alive patients (95% CI, 23.2 to 25.1 months), pemetrexed therapy resulted in a statistically significant 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64 to 0.96; P = .0195; median OS: pemetrexed, 13.9 months; placebo, 11.0 months). Survival on pemetrexed was consistently improved for all patient subgroups, including induction response: complete/partial responders (n = 234) OS HR, 0.81; 95% CI, 0.59 to 1.11 and stable disease (n = 285) OS HR, 0.76; 95% CI, 0.57 to 1.01). Postdiscontinuation therapy use was similar: pemetrexed, 64%; placebo, 72%. No new safety findings emerged. Drug-related grade 3 to 4 anemia, fatigue, and neutropenia were significantly higher in pemetrexed-treated patients. CONCLUSION: Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo, further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.""",1
13187,23836344,Long-acting injectable aripiprazole (Abilify Maintena) for schizophrenia,,1
13188,23836373,Ospemifene (Osphena) for dyspareunia,,1
13189,23838024,Safety issues with bisphosphonate therapy for osteoporosis,"Randomized controlled trials have demonstrated the efficacy of bisphosphonates (BP) in improving BMD and reducing fracture risk. Various safety issues that were not noted in clinical trials have, however, now emerged with post-marketing surveillance and increasing clinical experience. The risk of atypical femoral fracture could increase with long-term use of BP, although absolute risk is very small, particularly when balanced against benefits. A drug holiday should be considered after 5 years of treatment for patients at low risk of fracture, although there is no official recommendation regarding this to guide clinicians. Osteonecrosis of the jaw from low-dose BP used for osteoporosis is very rare, and mainly a complication with high-dose i.v. BP used in oncology. The risk of atrial fibrillation too is negligible, and a definite link cannot be established between BP and oesophageal cancer. BP should be avoided in patients with severe renal impairment and during pregnancy and lactation because of limited safety data. Further epidemiological and clinical data are required to establish safety of BP in long-term users (>5 years) and provide evidence-based management.",1
13190,23838819,Pregnancy in an NTBC-treated patient with hereditary tyrosinemia type I,,1
13191,23844038,"""Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions""","Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.",1
13192,23845191,Acute fulminant hepatatis in kidney transplant recipient after repeated sevoflurane anesthesia--a case report and literature review,"INTRODUCTION: A liver dysfunction induced by halogenated volatile anaesthetics is considered as a significant diagnostic problem. The aim of our report was to describe the first case of lethal hepatic failure in a female patient undergoing kidney transplantation (KTx) from a living donor after repeated sevoflurane anaesthesia. CASE PRESENTATION: A 47-year-old hypertensive and diabetic female patient received kidney from her 70-year-old mother. There was an immediate graft function and around 800 ml of blood loss on the abdominal drains, which gradually decreased after the erythrocyte and fresh frozen plasma (FFP) substitution. On the first postoperative (p.o.) day she gradually became anuric and overweighed at the next day undergoing dialysis. Because of prolonged hypotension and somnolence she required reintubation. The second day transaminases increased (AST&ALT>700, LDH>1200 U/L). On the third p.o. day she was urgently reoperated because of a sudden excessive bleeding. However, there was a rather slow flow of tears from the whole operative field that was even more excessive after the operation with signs of a consumptive coagulopathy. She was adequately substituted until the bleeding stopped more than 24 hrs after its onset. The new laboratory results showed further increase in transaminazes (3300 U/L-ALT, 5100-AST, 8900-LDH) and ultrasound investigation confirmed an extensive toxic hepatic lesion. On the fourth p.o. night the patient was stable, diuresis rate was at 100 ml/hour, but in the morning she became hyposaturated because of an increased bronchial secretion. The dialysis could not improve the cardio-respiratory insufficiency and she died 30min later. CONCLUSIONS: This case report suggests that sevoflurane can lead to a severe hepatotoxicity in at-risk individuals with repeated sevoflurane anaesthesia, having renal failure, in those with a preoperative known history of cardiovascular disorders, as well as in those with excessive extracellular volume. A particular precaution should be considered in cases of an elective surgery including organ transplantation.",1
13193,23846731,Trametinib: first global approval,"""Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.""",1
13194,23856559,"Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial","""BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Delta(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis. METHODS: In this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of >/=1 point from a baseline score of 4.0-5.0 or >/=0.5 points from a baseline score of >/=5.5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668). FINDINGS: Of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0.24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0.23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0.92 (95% CI 0.68-1.23; p=0.57). Mean yearly change in MSIS-29-PHYS score was 0.62 points (SD 3.29) in the dronabinol group versus 1.03 points (3.74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0.9 points (95% CI -2.0 to 0.2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group). INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change. FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.""",1
13195,23861303,"Golimumab, a human anti-tumor necrosis factor monoclonal antibody, injected subcutaneously every 4 weeks in patients with active rheumatoid arthritis who had never taken methotrexate: 1-year and 2-year clinical, radiologic, and physical function findings of a phase III, multicenter, randomized, double-blind, placebo-controlled study","""OBJECTIVE: To assess 2-year golimumab efficacy/safety in patients with active rheumatoid arthritis (RA) who had never taken methotrexate (MTX). METHODS: RA patients who had never taken MTX (n = 637) were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4) every 4 weeks. Nonresponders based on week 28 swollen/tender joint counts changed treatment as follows: group 1 added golimumab 50 mg, group 2 added MTX, group 3 increased golimumab to 100 mg, and group 4 had no change. Most group 1 patients (85%) initiated golimumab 50 mg + MTX at week 28 or subsequently at week 52. After the last patient completed week 52 and blinding was broken, the investigator could escalate golimumab to 100 mg and/or adjust MTX. The co-primary end points (week 24 American College of Rheumatology criteria for 50% improvement [ACR50] response and week 52 change in Sharp/van der Heijde score [SHS]) have been published previously. We now detail week 52 major secondary end points (Health Assessment Questionnaire [HAQ] disability index [DI] scores and SHS among patients with a baseline C-reactive protein [CRP] level >1.0 mg/dl) and week 104 findings. RESULTS: At week 52 for combined groups 3 and 4 versus group 1, the respective proportions of patients achieving ACR20 and ACR50 responses were 63.2% versus 51.9% (P = 0.017) and 45.3% versus 35.6% (P = 0.044). Respective week 52 mean HAQ DI improvements were 0.70 versus 0.58 (P = 0.053); mean SHS changes were 0.41 versus 1.37 (P = 0.006) among all patients and 0.74 versus 2.16 (P = 0.003) in patients with a CRP level >1.0 mg/dl. Improvements were maintained through week 104. Golimumab + MTX for 2 years yielded statistically less radiographic progression than initial MTX or golimumab 100 mg monotherapy. Golimumab safety profiles through weeks 24, 52, and 104 were generally consistent with those observed in other golimumab studies. CONCLUSION: In RA patients who had never taken MTX, up to 2 years of golimumab + MTX yielded sustained improvements in clinical signs/symptoms, physical function, and radiographic progression.""",1
13196,23862773,Safety and efficacy of romiplostim in patients with eltrombopag-resistant or -intolerant immune thrombocytopenia,,1
13197,23863919,Crofelemer (Fulyzaq) for antiretroviral-induced diarrhea,,1
13198,23865865,Pharmacokinetic drug interactions involving Ginkgo biloba,"Ginkgo biloba leaf extracts (GLEs) are popular herbal remedies for the treatment of Alzheimer's dementia, tinnitus, vertigo and peripheral arterial disease. As GLEs are taken regularly by older people who are likely to also use multiple other drugs for the treatment of, e.g. hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest. Preclinical studies of high doses/concentrations of GLEs of varying quality and standardization hinted at both an inhibition and induction of metabolic enzymes and transporters. However, in humans, positive in vitro-findings could not be replicated in vivo. At maximum recommended doses of 240 mg/day, a clinically relevant interaction potential of the standardized GLE EGb 761 could not be shown. GLE doses higher than the recommended ones led to a weak induction of the CYP2C19-mediated omeprazole 5-hydroxylation, and a weak inhibition of the CYP3A4-mediated midazolam 1'-hydroxylation, respectively. Also, the regular intake of a poorly characterized GLE at a dose of 360 mg/day slightly increased the bioavailability of talinolol, a substrate of P-glycoprotein and various organic anion-transporting polypeptides. Thus, regarding pharmacokinetic herb-drug interactions, the intake of the standardized GLE, EGb 761, together with synthetic drugs appears to be safe as long as daily doses up to 240 mg are consumed. If this applies to other extracts prepared according to the European Pharmacopoeia remains uncertain. Also, a relevant potential for drug interactions cannot be excluded for poorly standardized GLEs used in many food supplements.",1
13199,23866736,"Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia","BACKGROUND: Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal. METHODS: Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop(R)) or artemether-lumefantrine (AL, Coartem(R)), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28. RESULTS: Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis). CONCLUSION: Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT. TRIAL REGISTRATION: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).",1
13200,23869179,Clinical effectiveness of baclofen for the treatment of alcohol dependence: a review,"""Baclofen, an agonist at the B subunit of gaba-aminobutyric acid receptor, possesses pharmacologic properties that may confer utility for the treatment of alcohol dependence. Research suggests that not only can it be useful in promoting maintenance of alcohol abstinence but also it may play a key role in decreasing alcohol cravings and anxiety often associated with alcohol dependence. To assess the benefit of baclofen for alcohol dependence, a review of the literature was conducted to identify published data investigating this off-label treatment. Four randomized controlled trials to date have been published and were included in this review. Although primary outcomes differ between studies, patients randomized to baclofen experience higher rates of abstinence from alcohol than those taking placebo in two of the trials. Secondary analyses indicate that baclofen is safe in patients with alcohol dependence, including those with moderate to severe liver cirrhosis, and may provide beneficial anxiolytic effects. Despite some positive data, the largest available randomized controlled trial failed to find any differences between baclofen and placebo. In all studies, individuals with severe medical comorbidities, seizure disorders, and psychiatric disorders were excluded from trials, which may limit external validity. In summary, there may be beneficial effects from using baclofen for the treatment of alcohol dependence; however, limited conclusions can be drawn from the small number of studies currently available for review. Larger well-designed trials are needed to further define baclofen's role for the treatment of alcohol dependence.""",1
13201,23873481,"Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012","""BACKGROUND: Allopurinol is the primary therapy for the management of chronic gout. Utilization of allopurinol has increased in tandem with the growing prevalence of gout globally. This exposes more patients to the risk of allopurinol hypersensitivity (AH), a rare adverse reaction characterised by a spectrum of cutaneous reactions and systemic manifestations. Severe forms of AH have been associated with high mortality. The pathophysiology underlying this reaction remains unknown, but several risk factors have been proposed. OBJECTIVE: The aim of this study was to review all published cases of AH documented in the literature in order to better understand the constellation of factors predisposing to this reaction, building on previous reviews by Lupton and Odom, Singer and Wallace and Arellano and Sacristan. METHODS: A literature search was conducted in MEDLINE and EMBASE to identify relevant articles published between January 1950 and December 2012, with no language restrictions imposed. Articles that were included reported either allopurinol-induced cutaneous manifestations alone or satisfied the diagnostic criteria for AH as defined by Singer and Wallace. RESULTS: Nine hundred and one patients (overall AH cohort) were identified from 320 publications. Of these patients, 802 satisfied the Singer and Wallace criteria ('Singer and Wallace' cohort) while 99 patients had only mild cutaneous manifestations ('non-Singer and Wallace' cohort). Data were often incomplete; hence the results reported reflect the fractions of the subsets of the cohort where the data in question were available. In the overall AH cohort, 58 % (416/722) were male. The majority (73 %; 430/590) of patients were Asian. Renal impairment (48 %; 182/376) and hypertension (42 %; 160/376) were the most common chronic conditions; accordingly, diuretics (45 %; 114/252) and antihypertensives (39 %; 99/252) were the most prevalent concomitant medications. Allopurinol was prescribed for approved indications (chronic gout and chemoprophylaxis) in only 40 % (186/464) of patients. The median allopurinol dose was 300 mg/day (range 10-1,000 mg/day) and was taken by 50 % (168/338). There was no significant association between a higher dose (>300 mg/day) and an increased risk of severe cutaneous manifestations [odds ratio (OR) 1.76; 95 % CI 0.73-4.22; p = 0.23]. Approximately 90 % (489/538) of patients developed AH within 60 days of initiating allopurinol therapy. Serum oxypurinol (the active metabolite of allopurinol) concentration was only recorded in six patients, four of whom had levels within the putative therapeutic range of 30-100 mumol/L. The HLA-B*5801 allele was present in 99 % (166/167) of patients tested, with the majority (147/166) being of Asian ancestry. The all-cause mortality rate was 14 % (109/788) with 94 AH-related deaths, all of which occurred in the cohort meeting the Singer and Wallace criteria. LIMITATIONS: The publications included in this review utilized different laboratory reference ranges to classify the non-cutaneous manifestations of AH; this may have introduced some variation in the cases identified as AH. A majority of the articles included in this analysis consisted of case reports and series--publication types that are not recognized as best-quality evidence; this thus limited the conclusions we could draw about the many risk factors we were interested in evaluating. CONCLUSIONS: Risk factors associated with AH, such as concomitant diuretic use, pre-existing renal impairment and recent initiation of allopurinol, were commonly present in AH patients; however, their role in the mechanism of AH remains to be established. A clear risk factor was the HLA-B*5801 status; this was especially relevant in Asian populations where there is a higher carriage rate of the allele. High allopurinol dose, previously suggested to be a risk factor, was not confirmed as such. The paucity of well-documented case reports and studies of AH render it difficult to draw more concrete conclusions or construct a meticulous profile of patients at risk of AH. Future case reports of AH need to be better documented to contribute to understanding the risks for, and mechanisms of, AH.""",1
13202,23873972,Propofol-related infusion syndrome heralding a mitochondrial disease: case report,,1
13203,23876210,Efficacy and safety of entecavir treatment in a heterogeneous CHB population from a ?real-world? clinical practice setting in China,"Chronic hepatitis B infection is an important cause of liver-related mortality in China. This study assessed the efficacy and safety of entecavir in a heterogeneous patient population from a ?real-world? clinical practice setting in China. This prospective, observational cohort provides 48-week data on 2600 patients from 50 sites in China who received entecavir (0.5 or 1.0 mg) and were assessed for virologic, serologic and biochemical responses. Patients were nucleos(t)ide-na�?ve or -experienced and had compensated or decompensated liver function. At Week 48, 1545/2424 (64%) patients with compensated liver disease and 30/44 (68%) patients with decompensated liver disease achieved HBV DNA<50 IU/mL. Greater proportions of nucleos(t)ide-na�?ve than nucleos(t)ide-experienced (69% vs 53%), and adefovir-experienced than lamivudine/ telbivudine-experienced (62% vs 52%) patients achieved this endpoint. Most patients with HBV DNA<50 IU/mL also achieved HBV DNA<12 IU/L (60%, 45% and 61% of nucleos(t)ide-na�?ve, nucleos(t)ide-experienced and decompensated patients, respectively). In patients with compensated liver disease, ALT values normalized in 1532/1792 patients (85%), and HBeAg loss and HBeAg seroconversion were observed in 17% and 15% of treatment-na�?ve and 15% and 11% of treatment-experienced patients. Entecavir was generally well tolerated. Adverse event rates were comparable between treatment-na�?ve and treatment-experienced patients with compensated liver disease, but were higher in decompensated than in compensated patients, consistent with previous reports in these patients with more advanced disease. Four patients discontinued treatment due to adverse events. In a ?real-world? setting, entecavir was efficacious and well tolerated throughout 48 weeks in a heterogeneous Chinese CHB population.",1
13204,23881239,Safety and tolerability of tenofovir for preexposure prophylaxis among men who have sex with men,,1
13205,23882143,"Hemodynamic and hematologic profile of healthy adults ingesting dietary supplements containing 1,3-dimethylamylamine and caffeine","BACKGROUND: 1,3-dimethylamylamine (a constituent of geranium), alone and in combination with caffeine, is widely used within dietary supplements. We have recently determined the hemodynamic effects of 1,3-dimethylamylamine and caffeine alone and in combination, using a single ingestion study. However, no study has determined the hemodynamic effects of these ingredients following chronic use. Moreover, no study has determined the effects of these ingredients on bloodborne variables related to health and safety. Therefore, the purpose of this investigation was to assess the hemodynamic and hematologic profile of two different dietary supplements containing 1,3-dimethylamylamine and caffeine (in addition to other ingredients), before and after two weeks of daily intake. METHODS: 7 men (24.9 +/- 4.2 yrs) ingested the dietary supplement Jack3d, while 4 men and 2 women (22.5 +/- 1.8 yrs) ingested the dietary supplement OxyELITE Pro once per day for two weeks. On days 1 and 15, resting heart rate (HR), systolic (SBP), and diastolic (DBP) blood pressure were measured and rate pressure product (RPP) was calculated. Fasting blood samples were analyzed for complete blood counts, comprehensive metabolic panel, and lipid panel. These tests were done prior to ingestion of supplement. On days 1 and 15 following blood collection, subjects ingested the assigned supplement (2 servings) and HR, SBP, DBP, and RPP were recorded at 30, 60, 90, and 120 minutes post-ingestion. RESULTS: After 14 days of treatment, resting HR, SBP, DBP, and RPP were not increased (P > 0.05). No significant changes were noted in any measured bloodborne variable, with the exception of an increase in fasting blood glucose with ingestion of Jack3d (P = 0.02). In response to acute intake of the supplements, HR, DBP, and RPP were not increased statistically (P > 0.05). SBP was increased with OxyELITE Pro (P = 0.03), but not with Jack3d (P = 0.09). Compared to pre-ingestion and in general, both supplements resulted in an increase in SBP, DBP, and RPP from 5%-15%, with a peak occurring at the 60 or 90 minute post-ingestion time. CONCLUSION: Acute ingestion of OxyELITE Pro, but not Jack3d, results in an increase in SBP. Chronic intake of two servings per day of OxyELITE Pro or Jack3d over a 14 day period does not result in an elevation in resting HR, SBP, DBP, or RPP. No significant changes are noted in any measured bloodborne variable following 14 days of ingestion, with the exception of blood glucose with Jack3d. Longer term intervention studies inclusive of larger sample sizes are needed to extend these findings.",1
13206,23883377,Riociguat for the treatment of chronic thromboembolic pulmonary hypertension,"""BACKGROUND: Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. RESULTS: By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn?sec?cm(-5) in the riociguat group and increased by 23 dyn?sec?cm(-5) in the placebo group (least-squares mean difference, -246 dyn?sec?cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). CONCLUSIONS: Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)""",1
13207,23884038,Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS,"Glatiramer acetate (GA), a synthetic copolymer, is a frequently used first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Probable autoimmune hepatotoxicity during GA treatment has been reported,(1-4) but GA hepatotoxicity in the absence of positive autoimmune markers has not previously been described. Here, we report GA-induced hepatotoxicity in a pediatric patient with multiple sclerosis (MS).",1
13208,23889970,Albendazole-induced granulomatous hepatitis: a case report,"""INTRODUCTION: Drug-related hepatotoxicity is a common medical problem with implications for health systems. It constitutes a cause of acute liver failure and, in many cases, is responsible for the rejection of new pharmacological agents during efficacy and safety studies. Risk factors, as well as pathogenesis of drug-induced liver injury, are poorly understood. The diagnosis of drug-induced liver injury is challenging; it is difficult to define the cause of drug hepatotoxicity due to the heterogeneity of the clinical presentation and the absence of established criteria for accurate and reproducible identification of drug-associated liver toxicity. CASE PRESENTATION: We report the case of a 25-year-old Hispanic woman admitted to our Clinical Hepatology Unit with symptoms of acute hepatitis of unknown etiology. She was diagnosed with albendazole-induced granulomatous hepatitis after ruling out other possible causes, based on laboratory studies, liver biopsy, medical history, detailed drug history, and spontaneous improvement of her liver biochemical profile after medication withdrawal. This diagnosis was supported by the Council for International Organizations of Medical Sciences-Roussel Uclaf Causality Assessment Method, which showed a likely correlation between hepatocellular damage and drug toxicity as the etiology. CONCLUSIONS: Our patient's suspected diagnosis was albendazole-induced granulomatous hepatitis with confirmatory histologic pattern. This case deserves particular attention due to the wide use of albendazole in our country (Colombia) and the prevalent medical issue of drug-related hepatotoxicity.""",1
13209,23895707,Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis,"OBJECTIVE: To evaluate the incidence of Ketoconazole associated hepatotoxicity and related factor. METHODS: Literature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies. RESULTS: Totally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged >60 years was 1.4% (95% CI: 0.5%-4.2%) and 3.2% (95% CI: 1.1%-8.7%) respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% (95% CI: 4.5%-7.2%). CONCLUSION: Ketoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.",1
13210,23898368,Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests,"AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none. CONCLUSION: Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.",1
13211,23904473,"A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study)","""OBJECTIVES: This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. RESULTS: At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. CONCLUSIONS: Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.""",1
13212,23907700,Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-na?ve genotype 1 hepatitis C: the randomized PILLAR study,"""The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-?-2a and ribavirin (RBV) in treatment-na?ve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. CONCLUSION: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks.""",1
13213,23910494,Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group,"""BACKGROUND: Hepatitis B virus (HBV) reactivation is increasing, as rituximab has become widely used for B-cell lymphoma. Thus, prevention and management of HBV reactivation are important in HBV-endemic areas. METHODS: Hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-positive patients and HBsAg-negative/HBV core antibody (HBcAb)-positive patients who received rituximab-containing chemotherapy was investigated by the Asia Lymphoma Study Group via retrospective (n=340), and the results were compared to cross-sectional analysis with patients who were prospectively monitored in a single institute (n=127). The goal of the study was to define the frequency of HBV reactivation and the efficacy of antiviral prophylaxis. RESULTS: HBV reactivation was found in 27.8% of HBsAg-positive patients (45/162) in the retrospective analysis, being significantly less frequent in patients receiving antiviral prophylaxis than those not (22.9%, 32/140 versus 59.1%, 13/22; p<0.001). Lamivudine was most commonly used (96/162, 59.3%), but more than 20% of HBsAg-positive patients showed breakthrough HBV reactivation. In the cross-sectional analysis, a reduced rate of HBV reactivation occurred for entecavir as compared with lamivudine prophylaxis (6.3% versus 39.3%; p<0.05). HBV DNA monitoring of HBsAg-negative/HBcAb-positive patients in the cross-sectional analysis showed HBV reactivation in only 2.4% of cases. CONCLUSIONS: This is the largest study of HBV reactivation in patients receiving rituximab-containing chemotherapy to date, and we defined the probability of HBV reactivation in an HBV-endemic region.""",1
13214,23912008,[A case of ceftriaxone-associated pseudolithiasis in an adult patient that disappeared after the discontinuation of ceftriaxone],"We report a case of a 47-year-old female patient with ceftriaxone (CTRX)-associated pseudolithiasis. CTRX was administered at a dosage of 2g/day for 8 days because of colonic diverticulitis. A routine abdominal computed tomography (CT) scan was performed to investigate the diverticulitis. However, the CT scan demonstrated stones and sludge in the gallbladder, which had not been present before CTRX administration. Therefore, we diagnosed the patient with pseudolithiasis caused by CTRX and stopped CTRX administration. The stones and sludge disappeared 6 days after stopping CTRX administration. This underreported adverse effect of CTRX should be considered when treating both children and adult patients.",1
13215,23914755,Liver injury associated with antidepressants,"""Antidepressants are commonly prescribed and used in the management of depression, anxiety disorders, and other psychiatric illnesses. Antidepressants used in therapeutic dosing ranges are associated with causing several adverse drug reactions including hepatotoxicity. Paroxetine, fluoxetine, fluvoxamine, citalopram, mirtazapine and venlafaxine are associated with reversible liver injury upon discontinuation of the agent. Patient cases of hepatotoxicity involving the use of nefazodone, trazodone, duloxetine, bupropion, and sertraline are linked to causing death in its users. Due to the idiosyncratic nature of hepatotoxicity, monitoring of liver function tests and immediate discontinuation upon abnormal lab findings or signs and symptoms of liver dysfunction are crucial since most cases of hepatic damage are reversible when detected early. Onset of antidepressant-associated hepatotoxicity varies from 5 days to 3 years. Antidepressant-induced liver injury can occur in the absence of identifiable, underlying risk factors such as cirrhosis and hepatitis infection; only a few cases of hepatic injury involve patients with chronic hepatitis infection. Some of these cases involve possible drug interactions between antidepressants and concomitant agents that increase the risk for liver injury. Understanding druginduced liver injury associated with antidepressants and the importance of safety monitoring is essential to optimize outcomes for antidepressant treatment.""",1
13216,23918722,Systematic review and meta-analysis of the efficacy and safety of perampanel in the treatment of partial-onset epilepsy,"INTRODUCTION: Perampanel is a first-in-class antiepileptic drug approved for adjunctive treatment of partial-onset seizure in patients aged 12�years or older. Published randomised controlled trials (RCTs) had small sample sizes, and meta-analyses have included too few studies to draw conclusive results for the assessment of tolerability, efficacy and safety of perampanel. There is a need to conduct a meta-analysis with a larger dataset and an appropriate study design. OBJECTIVE: The aim of this study was to systematically review the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. METHODS: Electronic and clinical trials databases were searched for RCTs of perampanel published up to March 2013. Outcomes of interest were 50�% responder rates, seizure freedom, treatment-emergent adverse events (TEAEs) and incidence of withdrawal. Meta-analysis was performed to investigate the outcomes of interest. RESULTS: Five RCTs with a total of 1,678 subjects were included. The 50�% responder rates were significantly greater in patients receiving 4, 8 and 12�mg perampanel versus placebo, with risk ratios of 1.54 (95�% CI 1.11-2.13), 1.80 (95�% CI 1.38-2.35) and 1.72 (95�% CI 1.17-2.52), respectively. There was no statistical evidence of a difference in seizure freedom between 8 or 12�mg perampanel and placebo. Of the five commonly reported TEAEs included, both dizziness and somnolence were statistically associated with 8�mg perampanel, whilst dizziness was statistically associated with 12�mg perampanel. Incidences of withdrawal due to adverse events were significantly higher in the 8�mg and 12�mg perampanel groups versus placebo. CONCLUSION: The use of perampanel resulted in a statistically significant reduction of seizure frequency with respect to the 50�% responder rate in patients with partial-onset epilepsy. Perampanel is well tolerated at 4�mg and reasonably tolerated at 8 and 12�mg. Further clinical and pharmacovigilance studies are required to investigate the long-term efficacy and safety of perampanel in the management of other types of epilepsy.",1
13217,23922114,A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group,"BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.",1
13218,23923374,Recurrent acute hepatitis caused by albendazole,,1
13219,23926082,Reactivation of hepatitis B virus in patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma,"Despite increasing reports of hepatitis B virus (HBV) reactivation in hematological malignancies, its incidence, and risk factors are still obscure. The aim of this study was to clarify the frequency and risk factors of HBV reactivation in hepatitis B surface antigen (HBsAg) undetectable patients with malignant lymphoma or multiple myeloma, during or after chemotherapy. A total of 109 patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma were enrolled in this study. Anti-hepatitis B surface (anti-HBs) and anti-hepatitis B core (anti-HBc) were checked before treatment, and HBV DNA in sera was quantified monthly during and after chemotherapy. Out of 109 patients, 42 (38.5%) had anti-HBs and 59 (54.1%) had anti-HBc. Among the 59 anti-HBc positive patients, four patients (4/59, 6.8%) showed HBV reactivation during 20.5 median follow-up months. In all four patients with HBV reactivation, peripheral lymphocyte counts before chemotherapy were lower than those without HBV reactivation (P=0.033). HBV reactivation occurred during and after chemotherapy containing rituximab for non-Hodgkin lymphoma. Four patients, who had HBV reactivation, did not develop de novo hepatitis due to HBV reactivation and were able to undergo chemotherapy against malignant lymphoma as scheduled. Monitoring of HBV DNA in sera is useful for the early diagnosis of HBV reactivation, and preemptive therapy is an useful alternative to prevent hepatitis due to HBV reactivation. Patients must be monitored periodically for HBV-DNA levels during and after chemotherapy.",1
13220,23927437,Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials,"""BACKGROUND AND OBJECTIVES: Thrombopoietin receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow (BM) reticulin, neoplasms/haematological malignancies and fatal events. METHODS: Data from 13 romiplostim clinical trials in which 653 patients with ITP received romiplostim for up to 5 yr (921.5 patient-years) were pooled; subject incidence rates and exposure-adjusted event rates (per 100 patient-years) were calculated. RESULTS: The rate of thrombotic events (6% of patients, 7.5 events per 100 patient-years) did not appear to increase over time; 9 events were associated with platelet counts >400 x 10(9) /L and 10 with romiplostim doses exceeding current recommendations. Serious and grade >/=3 bleeding each occurred in approximately 8% of patients (~11 events per 100 patient-years). Adverse events of BM reticulin were recorded for 12 patients (1.8%, 1.3 events per 100 patient-years, confirmed by bone biopsy in ten patients) and BM collagen for one patient (0.2%, 0.1 event per 100 patient-years, confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events per 100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events per 100 patient-years, four events treatment-related). CONCLUSIONS: Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.""",1
13221,23931143,A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds?,,1
13222,23934275,Long-term efficacy and safety of eculizumab in Japanese patients with PNH: AEGIS trial,"""Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive hematopoietic stem cell disorder characterized by chronic complement-mediated hemolysis leading to life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal complement activation, reduces hemolysis, decreases the risk of thrombosis, and improves renal function and quality of life in PNH patients. The long-term efficacy and safety of eculizumab in Japanese patients were assessed in a 2-year extension to a 12-week, open-label study (AEGIS). Eculizumab treatment led to an immediate and sustained reduction in intravascular hemolysis (P < 0.001) and red blood cell transfusions (P = 0.0016) compared with baseline levels. There were no reports of thromboembolism during eculizumab treatment. The majority of patients had stable (56 %) or improved (41 %) renal function and an improved quality of life (P = 0.015), with sustained reductions in fatigue and dyspnea. Eculizumab was well tolerated; no deaths or serious hemolytic events were reported, and the rate of infections declined over time. There were no significant differences in the response to eculizumab in patients with or without bone marrow dysfunction. These results demonstrate that eculizumab is an effective, well-tolerated long-term treatment for Japanese PNH patients and leads to continued amelioration of some hemolytic complications.""",1
13223,23935355,Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab,"Hepatitis B virus (HBV) can still be found within the hepatocytes after its clearance and the control of viral replication depends on the immune response. However during immunosuppression, seroconversion of HBsAg has been described followed by disease reactivation. Hepatitis B virus reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents and in particular, by the use of rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profound and long-lasting immunosuppression. We describe a case of a 64-year old female patient with rheumatoid arthritis and resolved HBV infection, who experienced a severe hepatitis B reactivation after the administration of rituximab.",1
13224,23937548,EFV/FTC/TDF-associated hepatotoxicity: a case report and review,"""The fixed-dose combination efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF) is a first-line agent for the treatment of HIV. We report the case of a 40-year-old female with a history of HIV acquired through heterosexual contact who initiated EFV/FTC/TDF. Hepatitis B and C serologies were negative, CD4 cell count was 253 cells per cubic millimeter (15.8%), and HIV viral load was 67,373 copies per milliliter. Eight months later she developed transaminitis and severe right upper quadrant pain. Neither illicit drug abuse nor hepatotoxic medication such as acetaminophen was reported. After evaluation including negative acute viral hepatitis studies, EFV/FTC/TDF was discontinued; both her transaminitis and pain resolved. Hepatotoxicity is most often associated with efavirenz. Rarely, fulminant hepatic failure occurs. Efavirenz-related hepatotoxicity is thought to result from a cellular self-digestion process known as autophagy. This is the first report to our knowledge of EFV/FTC/TDF-related hepatotoxicity.""",1
13225,23944929,Drug-induced hepatotoxicity: incidence of abnormal liver function tests consistent with volatile anaesthetic hepatitis in trauma patients,"""BACKGROUND & AIMS: Volatile anaesthetic drug-induced liver injury can range from asymptomatic alanine transaminase elevations to fatal hepatic necrosis. There is very limited research regarding hepatotoxicity of modern volatile anaesthetic agents. The aim of this study was to determine how common liver injury consistent with volatile anaesthetic hepatitis is, following exposure to isoflurane, desflurane and sevoflurane; and to propose risk factors for its development. METHODS: Following ethics approval, we conducted a retrospective audit of adult trauma patients with abnormal liver biochemistry following volatile anaesthesia during January 1 to December 31, 2009. The data collected included patient demographics, volatile anaesthetic administration, concurrent medication, perioperative liver biochemistry results and comorbidities. The Council for International Organisations of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system was used to group cases according to the likelihood of volatile anaesthetic being the causative agent of drug-induced hepatotoxicity. RESULTS: Forty-seven (3%) of 1556 patients had abnormal post-operative liver biochemistry potentially attributable to volatile anaesthetic. Of the 47, 12 patients (26%) had peak alanine transaminase levels greater than 200 U/L. No significant predictors of volatile anaesthetic drug-induced liver injury following isoflurane, desflurane or sevoflurane anaesthesia could be identified. CONCLUSION: Volatile anaesthetic drug-induced liver injury in adult trauma patients may be significantly more common than previously noted. This study suggests that about a quarter of patients with volatile anaesthetic drug-induced liver injury develop significant liver injury. Further prospective studies are required to define risk factors and clinical outcomes.""",1
13226,23949147,"Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study","BACKGROUND/AIMS: To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB). METHODS: This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout. RESULTS: In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear. CONCLUSION: The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.",1
13227,23953514,Fatal acute liver failure after intravenous amiodarone administration,,1
13228,23958518,Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report,"Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.",1
13229,23962909,Severe toxicity and polymerase-? gene abnormalities in Malawian adults on stavudine-based antiretroviral therapy,"In a cohort study of Malawian adults who were followed up through their second year of stavudine-containing antiretroviral therapy, we sequenced the polymerase-? gene (POLG) of 10 of the 14 patients with the most severe stavudine side effects. No mutations were observed, suggesting that monogenic POLG mutations are not a common pathogenic determinant of severe stavudine-associated mitochondrial toxicity in Malawians.",1
13230,23964853,Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose,"""CONTEXT: There is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose. Objective. To determine if reported dose predicts the need for N-acetylcysteine (NAC). METHODS: Data were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line. RESULT: There were 1571 admissions in 1303 patients, with a median age of 27 years (12-96 years) and 1140 (73%) were females. The median dose was 10 g (1-100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4-7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6-9 g, a 10% chance of requiring NAC at a dose of 13-16 g, a 50% chance of requiring NAC at a dose of 30-34 g and a 90% chance for needing NAC at 48-50 g. CONCLUSION: Reported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be started on NAC immediately.""",1
13231,23964933,Vedolizumab as induction and maintenance therapy for Crohn's disease,"""BACKGROUND: The efficacy of vedolizumab, an ?4?7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ?150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (?100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).""",1
13232,23965889,[Ceftriaxone-associated biliary pseudolithiasis in a child with nephrotic syndrome],,1
13233,23970595,Liver transplantation for acute liver failure due to efavirenz hepatotoxicity: the importance of routine monitoring,"We present the first case report in the UK of acute liver failure caused by efavirenz therapy culminating in liver transplantation. A 26-year-old Zimbabwean woman commenced emtricitabine, tenofovir and efavirenz (Atripla) in December 2011. Her liver function tests at baseline and at 20 days after initiating antiretroviral therapy were normal. At three months of therapy her blood tests haemolysed and were not processed. She had previously missed follow-up appointments and on this occasion failed to return for repeat tests. She was not seen again until after six months of antiretroviral therapy when she presented to her general practitioner with acute liver failure. Her condition deteriorated and she required liver transplantation. She recovered well and re-started antiretroviral therapy to good effect. The case illustrates the value of routine monitoring after initiating antiretroviral therapy and the fundamental importance of engaging patients in long-term management to ensure safe treatment.",1
13234,23974193,Pomalidomide,"This spotlight review focuses on the second-generation immunomodulatory drug pomalidomide, which was recently approved by the US Food and Drug Administration. This drug was approved for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. This review focuses on the clinical trial data that led to approval and provides advice for treating physicians who are now prescribing this drug for patients.",1
13235,23978872,Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: a randomized controlled trial,"PURPOSE: To test the efficacy and safety of ursodeoxycholic acid (UDCA) in the treatment of patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: In the randomized (double-blind, placebo-controlled) study 20 pregnant women with ICP received (random allocation of) either 450 mg/day UDCA or placebo for 14 days during the third trimester of pregnancy. The severity of pruritus was registered and itching scores were assessed before the treatment and weekly thereafter. The effects of UDCA on liver function and fetoplacental hormone production were measured with covering laboratory testing: serum levels of alanine aminotransferase (ALAT), total bile acids (TBA), estradiol, progesterone, prolactin, cholesterol, HDL-cholesterol, triglycerides, activated partial thromboplastin time, fibrinogen D-dimers (FIDD) and platelet count were assessed before the treatment and weekly thereafter. Data on pregnancy and delivery outcome were recorded and analyzed. RESULTS: UDCA was well tolerated. A significant improvement in itching scores was detected in 2 weeks in the group receiving UDCA. Serum levels of ALAT and TBA fell after 2 weeks treatment. The other laboratory values were not modified by the treatment. CONCLUSIONS: UDCA improves maternal itching scores and liver function tests without interfering with the fetoplacental estrogen production in patients with ICP. UDCA is well tolerated by pregnant women. No fetal or neonatal side-effects could be detected.",1
13236,23979955,The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension,"CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.",1
13237,23980620,A randomized clinical trial comparing metabolic parameters after 48 weeks of standard- and low-dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV-infected South African patients,"OBJECTIVES: Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with tenofovir disoproxil fumarate (tenofovir DF) was performed to assess the effects on anthropometry, markers of inflammation, and lipid and glucose metabolism in Black South African patients. METHODS: Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or tenofovir DF (300 mg), each combined with lamivudine and efavirenz, for 48 weeks. Anthropometry, markers of inflammation, and lipid and glucose metabolism were assessed using standard techniques. RESULTS: In all three treatment arms, there was a significant increase in lipid levels over the study period. At 48 weeks, fasting glucose level (P < 0.005) and homeostasis model assessment (HOMA) score (P < 0.05) increased significantly in the standard-dose stavudine arm, as did insulin and C-peptide levels in both the standard- and low-dose stavudine arms. At week 48, a significant decrease (P < 0.05) in adiponectin was noted in the standard-dose stavudine arm, but there was an increase (P < 0.005) in the tenofovir DF arm. In both the stavudine arms, significant increases in anthropometric measures occurred at 24 weeks but these decreased by week 48. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms. CONCLUSIONS: This study highlights the occurrence of metabolic abnormalities with both stavudine and tenofovir DF treatment. Awareness of the potential increased cardiovascular risk should be of concern with the use of both these therapies.",1
13238,23982356,FDA: Acetaminophen may trigger serious skin problems,,1
13239,23983212,"Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study","""BACKGROUND: Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. METHODS: Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. RESULTS: One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1-11) a median of 4.5 days (range, 1-7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. CONCLUSIONS: Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. CLINICAL TRIALS REGISTRATION: NCT01014988.""",1
13240,23984728,Macitentan and morbidity and mortality in pulmonary arterial hypertension,"""BACKGROUND: Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. METHODS: We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. RESULTS: A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. CONCLUSIONS: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).""",1
13241,23986488,Vemurafenib-induced DRESS,,1
13242,23992260,Safety of infliximab therapy in rheumatoid arthritis patients with previous exposure to hepatitis B virus,"OBJECTIVE: To evaluate the safety of tumor necrosis factor-? (TNF-?) monoclonal antibody (infliximab) therapy in patients with rheumatoid arthritis (RA) and previous exposure to hepatitis B virus (HBV) who had normal liver function. METHODS: This is a retrospective study from a 26-week, prospective, multicenter trial in 234 patients with RA who received infusions of infliximab (3�mg/kg at week 0, 2, 6, 14 and 22). The medical records of these patients were reviewed, including the information on disease duration, laboratory tests and HBV markers. The data on liver function during the study was analyzed, as well as comparison between patients with previous exposure to HBV and patients without such exposure. RESULTS: Forty-one patients with previous exposure to HBV were HBsAg(-). Forty patients had normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and only one patient with positive anti-HBc showed an elevated ALT level before administration of infliximab, and had a further increase of ALT level at week 14, but decreased thereafter. The average ALT and AST levels rose slightly during the treatment but remained in normal range and the differences were insignificant compared with baseline. There was no statistically significant difference in the incidence of liver function abnormalities during the treatment of infliximab between the patients with previous exposure to HBV and those without such exposure. CONCLUSION: In patients with RA and previous exposure to HBV but with a negative HBsAg and normal liver function at baseline, liver function abnormalities were not observed during infliximab treatment.",1
13243,23993469,Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes,"""AIM: To compare the efficacy and safety of acarbose plus metformin fixed-dose combination (FDC) versus acarbose monotherapy for type 2 diabetes (T2D). METHODS: Eligible T2D patients undergoing treatment with diet control only or oral antidiabetic medications were run-in on acarbose 50mg thrice-daily for 4 weeks, then randomised either to continue this monotherapy, or to acarbose 50mg plus metformin hydrochloride 500mg FDC (acarbose/metformin FDC), each thrice-daily for 16 weeks. RESULTS: Acarbose/metformin FDC therapy significantly reduced HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) from baseline (all p<0.0001) with superior efficacy compared with acarbose monotherapy (between-group differences; HbA1c -1.35%; FPG -29.5mg/dl; PPG -41.6mg/dl; all p<0.0001). Proportionally more patients treated with acarbose/metformin FDC achieved HbA1c <7.0% (47.8% vs. 10.7%, p<0.0001). Both treatments reduced bodyweight (p<0.0001), with a significant between-group difference (-0.6kg, p<0.01) favouring acarbose/metformin FDC. Hypoglycaemia was not reported with either treatment, and the incidence of other adverse events did not differ significantly between the groups. CONCLUSIONS: Compared with acarbose monotherapy, acarbose/metformin FDC has superior antihyperglycaemic efficacy, brings proportionally more T2D patients to HbA1c goal, and further reduces bodyweight. Acarbose/metformin FDC is well-tolerated without significant risk of hypoglycaemia and is a potentially advantageous therapy for T2D.""",1
13244,23999912,"Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study","""BACKGROUND: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin (5-HT) and norepinephrine (noradrenaline) reuptake inhibitor approved for the treatment of major depressive disorder in adults. OBJECTIVE: The objective of this study was to evaluate the longer-term safety and tolerability of levomilnacipran extended-release (ER). METHODS: Patients who completed double-blind treatment/down-taper in one of three lead-in levomilnacipran ER studies were eligible for this 48-week open-label extension. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), physical examinations, laboratory and vital sign measures, and suicidality, summarized using descriptive statistics for the safety population. RESULTS: The completion rate was 47 %; median treatment duration was 280 days. The most frequent reasons for discontinuation were withdrawal of consent (14 %) and adverse events (AEs; 13 %). TEAEs were reported by 712 (86 %) patients; most were mild/moderate and occurred early in treatment. The most common TEAEs were headache (22 %) and nausea (16 %); 36 (4 %) patients had ?1 serious AEs. No clinically meaningful changes occurred in mean liver enzyme, metabolic, hematologic, urinalysis, or serum values; potentially clinically significant high AST or ALT values (?3 ? upper limit of normal) occurred in five patients. Vital sign changes occurred early and remained relatively stable. Mean increases for pulse rate (9.1 beats per minute [bpm]), and supine systolic (3.9 mmHg) and diastolic (3.3 mmHg) blood pressure were noted. The increase in the mean QT interval corrected using the Bazett formula (10.9 ms) was consistent with heart rate increase (12.8 bpm); there was no meaningful change in mean QT interval corrected using the Fridericia formula (-1.3 ms). Other than tachycardia and heart rate increases, ECG-related TEAEs were low (<0.5 %). CONCLUSION: No new or inconsistent safety/tolerability findings were discovered during longer-term evaluation.""",1
13245,24002197,Liver toxicity in HIV-infected patients receiving novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine,"There are few data on the hepatic safety profile of the novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine. Previous extensive studies including other drugs of the same class, nevirapine and efavirenz, have shown an incidence of liver toxicity of 3-20%, higher in the case of nevirapine. The pathogenic mechanisms involved are related to hypersensitivity, as described with nevirapine, impaired metabolism and therefore increased drug levels, and direct toxic effects with production of toxic metabolites. Hepatitis C coinfection seems to be the most important factor for toxicity, especially in the case of advanced liver fibrosis. Etravirine showed a similar rate of liver toxicity to placebo in regulatory studies, but this seems to be lower in the clinical setting, as has been observed in the Expanded Access Program and in cohort studies including HCV/HIV-coinfected patients with different degrees of fibrosis. Also, rilpivirine showed a low rate of liver toxicity, similar to the comparator efavirenz in development studies, even in coinfected patients. Both second-generation nonnucleoside reverse transcriptase inhibitors are rarely associated to hypersensitivity reactions, and drug metabolism is not severely altered in the case of HCV coinfection, at least in the absence of severe fibrosis. Also, both drugs are weak hepatic cell inducers. Therefore, clinical and pathogenic data suggest that both etravirine and rilpivirine are safe to be used in the clinical setting, including patients with liver abnormalities at baseline.",1
13246,24002736,Fatal hepatitis B reactivation due to everolimus in metastatic breast cancer: case report and review of literature,"Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.",1
13247,24005956,Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-na?ve hepatitis C genotype 1-infected patients in Japan: the DRAGON study,"BACKGROUND: Efficacy, safety and pharmacokinetics of simeprevir (TMC435), a once-daily, noncovalent, oral hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in combination with peginterferon ?-2a/ribavirin (PegIFN?-2a/RBV) for treatment-na?ve, HCV genotype�1-infected patients in Japan. METHODS: In a multicenter, randomized clinical trial in Japan, ninety-two patients received either simeprevir (50 or 100�mg QD) for 12 or 24�weeks with PegIFN?-2a/RBV for 24 or 48�weeks (according to response-guided therapy [RGT] criteria), or PegIFN?-2a/RBV for 48�weeks (PR48 group). RESULTS: Compared with the PR48 group, plasma HCV RNA reductions in the simeprevir groups were rapid and more substantial (Week 4: -5.2, -5.2 and -2.9 log10IU/mL for simeprevir 50�mg combined, 100�mg combined, and PR48 groups, respectively). High rapid virologic response rates (83, 90, and 8�% for simeprevir 50�mg combined, 100 mg combined, and PR48 groups, respectively) led to high sustained virologic response rates (77-92�%, compared with 46�% for PR48). All but one of the simeprevir-treated patients were eligible to complete treatment after 24�weeks (RGT). Relapse rates in simeprevir-treated patients were low (8-17�%, compared with 36�% for the PR48 group). There were no notable differences in the safety profile between the simeprevir and PR48 groups. CONCLUSIONS: The addition of simeprevir QD to PegIFN?-2a/RBV, as compared with PegIFN?-2a/RBV alone, demonstrated potent antiviral activity and significantly improved the rates of sustained virologic response, with a shortened 24-week treatment duration, in treatment-naive patients infected with HCV genotype 1 in Japan. Simeprevir was generally safe and well tolerated. (ClinicalTrials.gov number, NCT00996476).",1
13248,24008177,"Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability","INTRODUCTION: Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection. DISCUSSION: First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186. CONCLUSIONS: This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.",1
13249,24011271,Carbamazepine-induced DRESS syndrome in a child: rapid response to pulsed corticosteroids,"""DRESS syndrome is an idiosyncratic reaction to drugs, which can occur in both adults and children. To date there is no agreed upon criteria for its diagnosis; there is even less consensus on its management. We report the case of a 14- year-old boy with carbamazepine induced DRESS syndrome, predominantly involving the liver. He responded rapidly to high dose pulsed intravenous corticosteroids.""",1
13250,24019544,Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma,"PURPOSE: Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM. PATIENTS AND METHODS: In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria. RESULTS: The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ? minimal response. CONCLUSION: The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.",1
13251,24021246,Efficacy and safety of tocilizumab combined with cyclosporine A in a patient with rheumatoid arthritis and concomitant chronic hepatitis C virus infection,,1
13252,24023555,"Eosinophilia, pleural effusion, hepatitis, and jaundice occurring early in clozapine treatment","Clozapine use is associated with various adverse events, some of which have received little attention, including eosinophilia, pleural effusion, and hepatitis. Because of the fatality of jaundice with hepatitis, it is necessary to understand the course and management of clozapine-induced eosinophilia and hepatitis. We report on a case in which the eosinophil count began to increase shortly after clozapine use, and pleural effusion and fever then developed at the time eosinophilia was at its peak level. Jaundice with hepatitis consecutively developed when all the above symptoms subsided. The liver function recovered rapidly after clozapine was discontinued. We recommend that patients who develop rapid eosinophilia at the beginning of clozapine treatment should be monitored with LFTs, chest X-rays, and urine analysis tests.",1
13253,24026258,Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial,"""BACKGROUND: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN: 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING: 114 centers in 19 countries. PATIENTS: 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE: Pfizer.""",1
13254,24026598,Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial,"""IMPORTANCE: Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown. OBJECTIVE: To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome. INTERVENTION: Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days. MAIN OUTCOMES AND MEASURES: Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment. RESULTS: In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P?=?.91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P?=?.80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P?=?.91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P?=?.07). CONCLUSION AND RELEVANCE: In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01214226.""",1
13255,24030232,Liver complications in inflammatory bowel diseases,"Diseases of the liver and the biliary tract are commonly observed in patients with inflammatory bowel diseases (IBD). Besides primary sclerosing cholangitis (PSC), drug-induced hepatotoxicity and non-alcoholic fatty liver disease (NAFLD) are the most frequent liver complications in IBD. PSC is a chronic inflammatory and commonly progressive disorder of unknown etiology associated with fibrosis and stricture development in the intrahepatic and extrahepatic biliary tree. Interestingly, this form of liver disease is mainly associated with ulcerative colitis. Development of PSC is highly relevant for IBD patients as cholestasis-associated problems increase over time resulting in biliary strictures, cholangitis, cholangiocarcinoma and importantly these patients also have a higher risk to develop colon cancer. Another major aspect regarding IBD and liver disease refers to drug-induced hepatotoxicity. Clinically, most relevant is liver toxicity caused by immunosuppressants such as azathioprine. Azathioprine and its derivate 6-mercaptopurine can cause a spectrum of liver injuries ranging from asymptomatic elevated liver enzymes to cholestasis and nodular regenerative hyperplasia. The third common IBD-associated liver disease is NAFLD, and first studies suggest that NAFLD might appear in IBD patients independent of classical risk factors such as obesity or insulin resistance. Overall, liver complications are observed in 10-20% of IBD patients, and therefore physicians have to be familiar with these complications to improve and to optimize patient care.",1
13256,24033280,Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: a systematic review and meta-analysis,"Evidence regarding the efficacy of gemtuzumab ozogamicin (GO) addition to standard induction chemotherapy in newly diagnosed acute myeloid leukaemia (AML) is conflicting. This systematic review aimed to identify and summarize all evidence regarding the benefits and harms of adding GO to conventional chemotherapy for induction treatment of AML. A comprehensive literature search of two databases (PUBMED and Cochrane) from inception up to November 22, 2012, and 4 years of proceedings from four major haematology/oncology conferences was undertaken. Endpoints included benefits (complete remission, relapse-free, event-free, and overall survival), and harms (early mortality and incidence of hepatic veno-occlusive disease/sinusoidal obstructive syndrome). Seven trials (3942 patients) met all inclusion criteria. Addition of GO showed improved relapse-free [Hazard Ratio (HR) = 0.84 (95% confidence interval (CI) 0.71-0.99)] and event-free survival [HR = 0.59 (95%CI 0.48-0.74)] but not overall survival [HR = 0.95 (95%CI 0.83-1.08)]. Addition of GO resulted in higher rate of early mortality [Risk Ratio = 1.60 (95%CI 1.07-2.39)]. Improved overall survival was observed in studies using a lower cumulative GO dose (<6 mg/m(2) ) [HR = 0.89 (95%CI 0.81-0.99)]. Addition of GO to conventional chemotherapy as induction therapy may improve relapse-free and event-free survival, but does not impact overall survival and significantly increases early mortality in AML.",1
13257,24035250,"Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial","BACKGROUND: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2?10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99?8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING: Novartis.",1
13258,24037911,Isoniazid hepatotoxicity: progress in understanding the immunologic component,,1
13259,24041405,"Lethal cardiotoxicity, steatohepatitis, chronic pancreatitis, and acute enteritis induced by capecitabine and oxaliplatin in a 36-year-old woman","A 36-year-old female was hospitalized with symptoms suggesting intestinal occlusion. She was diagnosed with adenocarcinoma of the ampulla of Vater (pT4N0 stage) and underwent cephalic duodenopancreatectomy 8 months ago. Five cycles of postoperative chemotherapy were administrated using capecitabine and oxaliplatin (CAPOX or XELOX), the last one being completed 1 month ago. During the present hospitalization, because of normal computed tomography and ultrasound abdominal examination, rehydration and antibiotherapy were administrated. However, 4 days after hospital admission, the patient died. At autopsy and histological examination, we found a severe myocardial sclerosis with large scarring areas, severe steatohepatitis, chronic pancreatitis with large fibrotic areas, and acute enteritis. Alcohol consumption was denied. The patient died due to associated heart, liver and pancreatic failure. This multiorgan toxicity and death following CAPOX regimen had not yet been reported in the literature. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6472150549833105.",1
13260,24045857,Utilisation of an outpatient sedation unit in paediatric ophthalmology: safety and effectiveness of chloral hydrate in 1509 sedation episodes,"""OBJECTIVE: To report the largest study on the safety and effectiveness of sedation in paediatric ophthalmology in a nurse-led outpatient sedation unit. DESIGN: Retrospective cohort study reviewing all children who underwent sedation from January 2006 to December 2010. Patients were sedated with 80 mg/kg of chloral hydrate (CH) given orally with top up dose given at half dose as required. All demographic data, sedation and procedure duration, sedation success and adverse events were recorded. Univariate and multiple regression analyses were performed to assess factors associated with success and complications. RESULTS: Data was collected for 1509 sedation episodes. More boys were sedated compared with girls (56.3% vs 43.7% p=0.0003) with an average age of 23.86 months and weight of 11.76 kg. A higher proportion of patients had an American Society of Anaesthesiologists status of II than I (58.5%:41.5%, p=0.0001). Successful sedation was obtained in 96.69% of children with 4.77% requiring a top up dose to achieve this. The average sedation duration was 53.4 min (SD=21.5) with an average of 1.7 procedures performed; the most common being a detailed examination (93.5%) and electroretinogram (45.1%). Adverse events included paradoxical reaction (1.33%), oxygen desaturation (0.99%) and vomiting (0.53%). There were no serious complications or hospital admission. Multiple logistic regression analysis found weight greater than 15 kg and needing a top up dose to be significant risk factors for Failure (OR=2.49 and 8.69, respectively) and Adverse events (OR=2.1 and 3.97, respectively). Sex and American Society of Anesthesiologists Physical Status score did not significantly affect outcomes. CONCLUSIONS: CH sedation allows detailed examination and investigations in the majority of children with few side effects. Patients over 15 kg and need for a top up dose are risk factors for failure and adverse events. This is the largest study in the current literature looking at the use of CH sedation in ophthalmology and confirms its safety and effectiveness.""",1
13261,24050947,A brief review on experimental fluorosis,"Fluoride (F) is a naturally occurring contaminant in the water. F is essential for normal maintenance of teeth and bones. However, prolonged exposure to high concentration of F is found to be deleterious to teeth, bones and other organs. Besides drinking water, F can enter the body through food, dental products, drugs and industrial emission. People living in areas where F contamination is much higher than the expected level, are found to suffer from not only teeth and bone problem but also other systems, including brain and its functions. Since animals respond to the toxic effects of F like human beings, the deleterious effects of F have been produced experimentally in animals in order to determine the mechanism involved in the action of F. The reports indicating the chronic harmful effects of F in teeth, bones, heart, liver, kidneys, gastrointestinal tract, lungs, brain, blood, hormones and biochemical parameters of experimental animals and in in vitro studies have been reviewed in this article. The neurotoxic action of F that produces chiefly learning and memory impairment has also been included. The review also points out the harmful effects of F on reproduction, its teratogenic action and in inducing premature ageing. Finally, the reports indicating a reversal of certain toxicities of F in experimental animals after withdrawal of its exposure has been included.",1
13262,24057287,Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma,"CONTEXT: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head. OBJECTIVE: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. DESIGN/SETTING: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks. PATIENTS/INTERVENTIONS: Forty mitotane-na?ve patients with metastatic adrenocortical carcinoma were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail. MAIN OUTCOME MEASURE: The difference in median mitotane plasma levels between both treatment groups was measured. RESULTS: Despite a difference in mean cumulative dose (440 ? 142 g vs 272 ? 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients on the high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 ? 494 mg/L ? d vs 555 ? 168 mg/L ? d (P = .080). CONCLUSIONS: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.",1
13263,24074642,"Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial","""BACKGROUND: In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. METHODS: SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. FINDINGS: Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4?5%, 95% CI -1?1% to 10?0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per ?L for dolutegravir and 264 cells per ?L for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. INTERPRETATION: At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients.""",1
13264,24079055,Pancytopenia and lactic acidosis associated with linezolid use in a patient with empyema,"""OBJECTIVE: To describe a patient who developed pancytopenia and lactic acidosis after receiving linezolid therapy. CASE SUMMARY: A 32-year-old man with past medical history of heart failure, hypertension received a 14-day course of linezolid for treatment of empyema with broncho-pleural fistula. During his follow up visit, he was found to be septic and further evaluation showed pancytopenia, acidosis and elevated liver enzymes. With the exclusion of other possible etiologies, the time course to development of these laboratory abnormalities correlated with the use of linezolid. Antibiotics were switched subsequently and the labs improved after reaching a nadir on the fourth day after stopping linezolid. DISCUSSION: Linezolid was noted to cause time and dose-dependent reversible myelosuppression in preclinical studies. There are several case reports of throinbocytopenia occurring with linezolid use, but only few cases of pancytopenia and lactic acidosis are reported. Exact mechanism of toxicity is unknown, but many hypothesize it to be similar to chloramphenicol marrow toxicity because of the cross-reactivity to mitochondrial ribosomes. CONCLUSIONS: Clinicians should be aware of linezolid as a drug capable of causing pancytopenia, lactic acidosis and elevated liver enzymes. While recovery is usually complete following withdrawal of the drug, we need to still monitor for these rare but severe complications; and consider treating only for a shorter duration, if possible.""",1
13265,24081577,Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia,"Previous studies have shown that clofarabine plus low-dose cytarabine (LDAC) could induce roughly 60 % of complete remissions (CR) with acceptable toxicity and induction mortality in elderly acute myeloid leukemia (AML) patients not suitable for intensive chemotherapy. The Programa Espa�ol de Tratamientos en Hematolog?a group conducted a trial for patients diagnosed with untreated AML aged 60 years and older, using the combination of clofarabine (20 mg/m(2)???5 days) plus low-dose cytarabine (20 mg/m(2)???14 days). The protocol was flexible regarding the use of antifungal and antibacterial prophylaxis, and outpatient induction therapy was allowed. Although the planned recruitment goal was 75 patients, only 11 patients were enrolled (median age, 74 years) after observing high toxicity and unacceptable mortality (46 and 73 % at 4 and 8 weeks, respectively). The response assessment showed three CR (27 %), three resistant diseases (27 %), and five induction deaths (46 %). Induction was administered in an outpatient modality in five patients, while antifungal and antibacterial prophylaxis was not given in seven and five patients, respectively. In our context, induction therapy with the combination of clofarabine (20 mg/m(2)) plus LDAC was associated with high toxicity and unacceptable mortality in elderly AML patients, leading to the early interruption of the trial. Tight patients' clinical monitoring, follow-up, and intensive supportive care seem crucial to achieve at least acceptable clinical outcomes in elderly AML patients receiving clofarabine plus LDAC. This trial is registered at www.clinicaltrials.gov as no. NCT01193400.",1
13266,24082887,Autoimmune Hepatitis Triggered by Anti-TNF-alpha Therapy,"Autoimmune hepatitis (AIH) is occasionally triggered by drug treatments. Recently, as biological agents are becoming widely used for autoimmune disorders, there have been a growing number of reports of the development of autoimmune processes related to these agents. A 52-year-old Japanese woman with psoriasis developed liver damage two months after initiation of anti-TNF- alpha therapy with adalimumab. Liver histological findings were compatible with AIH, and positive conversions of ANAs were detected. The patient was treated with prednisolone and had a good response. While some cases of AIH triggered by anti-TNF- alpha therapies have been reported, the pathogenesis remains unspecified. When elevation of liver enzymes is observed with high IgG levels and seropositivity of ANA during the course of anti-TNF- alpha therapy, liver biopsy findings may be essential and important to make definitive diagnosis of AIH.",1
13267,24084500,Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies,"""PURPOSE: To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period. DESIGN: Two randomized, double-masked, active-controlled, phase 3 trials. PARTICIPANTS: Two thousand four hundred fifty-seven patients with neovascular AMD. METHODS: From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES: Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA. RESULTS: Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of�-0.64 [95% CI,�-0.89 to�-0.40] and�-0.55 [95% CI,�-0.79 to�-0.30]; P?<?0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week�96. CONCLUSIONS: All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96�weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.""",1
13268,24088753,Risk factors for liver injury with an elevated serum bilirubin concentration caused by antituberculous drugs,"""OBJECTIVE: No studies have so far sufficiently investigated the risk factors for drug-induced liver injury (DILI) with an elevated serum bilirubin concentration. METHODS: We conducted a historical cohort study observing inpatients admitted to two hospitals in Japan. A decreased level of activities of daily living (ADL) was defined as a Barthel Index score of <80. The patients were treated with standard regimens under a directly observed treatment short-course strategy. RESULTS: The cohort of 356 patients comprised 244 men (68.5%) and 112 women (31.5%), with a mean age of 63.8+/-20.2 years. Compared with the patients who did not experience DILI with a bilirubin level of >/=2.0 mg/dL, the patients who experienced DILI with a bilirubin level of >/=2.0 mg/dL more often had a decreased level of ADLs, were more likely to suffer from chronic cardiac disease, had lower serum albumin levels and were less often treated with four-drug regimens involving pyrazinamide (PZA). In a logistic regression analysis in which these five factors acted as independent variables, a decreased level of ADLs was the strongest predictor for DILI with a bilirubin level of >/=2.0 mg/dL, with an odds ratio of 16.5 (95%CI: 1.7-159; p=0.015), followed by chronic cardiac disease, with an odds ratio of 4.0 (95%CI: 1.2-12.6; p=0.020). CONCLUSION: A decreased level of ADLs and chronic cardiac disease are strong risk factors for DILI with a bilirubin level of >/=2.0 mg/dL resulting from the use of antituberculous drugs. Physicians should pay close attention to the possibility of DILI with a bilirubin level of >/=2.0 mg/dL when treating tuberculosis patients with a decreased level of ADLs and/or chronic heart disease.""",1
13269,24090944,Liver abnormalities in drug and substance abusers,"Drug and substance abuse remains a major medical problem. Alcohol use, abuse and dependence are highly prevalent conditions. Alcohol related liver disease can present as simple steatosis, steatohepatitis, alcoholic hepatitis or liver cirrhosis. Paracetamol hepatotoxicity secondary to accidental or deliberate overdose is another common problem. While the adverse cardiovascular, neurological, renal and psychiatric consequences of various illicit substance abuses are widely studied and publicized, less attention has been directed towards possible hepatotoxic effects. Illicit drug abuse can cause a range of liver abnormalities ranging from asymptomatic derangement of liver function tests to fulminant hepatic failure. This article reviews the epidemiology, risk factors, clinical manifestations, pathogenesis, investigations, management and prognostic factors of alcohol related liver disease and paracetamol hepatotoxicity as well as the current knowledge pertaining to hepatotoxicity of the more commonly used illicit substances including cannabis, amphetamine type stimulants, cocaine, khat chewing and complementary and alternate medicine.",1
13270,24094768,"Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial","""BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. METHODS: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. FINDINGS: 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5?2 months (IQR 2?3-9?9) in patients in the ramucirumab group and 3?8 months (1?7-7?1) in those in the placebo group (hazard ratio [HR] 0?776, 95% CI 0?603-0?998; p=0?047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0?774, 0?605-0?991; p=0?042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. INTERPRETATION: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. FUNDING: ImClone Systems.""",1
13271,24099020,Acetaminophen-related hepatotoxicity,"Acetaminophen (APAP) is the leading worldwide cause of drug overdose and acute liver failure (ALF). Single overdose ingestion and therapeutic misadventure may cause hepatotoxicity. Several factors, such as concomitant alcohol use or abuse, concurrent medications, genetic factors, and nutritional status, can influence the susceptibility and severity of APAP hepatotoxicity. Early manifestations of APAP hepatotoxicity are nonspecific, but require prompt recognition by physicians. Patients with repeated overdose tend to present late, and in such hepatotoxicity may have already evolved. N-acetylcysteine is a very effective antidote when giving within 8 hours, and is also recommended after a presentation of hepatotoxicity and ALF. The prognosis of patients with APAP-induced ALF is better than other causes of ALF. Liver transplantation should be offered to those who are unlikely to survive.",1
13272,24099027,Liver injury induced by herbal complementary and alternative medicine,"Herbal and dietary supplement use is common. Most marketed products consist of complex mixtures. Although they are perceived as safe, instances of hepatotoxicity attributable to these products underscore their potential for injury, but the exact component that is responsible for injury is difficult to discern. The lenient regulatory environment in the United States, which opens the possibility of adulteration and contamination, adds to the challenge of disease attribution. Although many different herbal and dietary supplements have been reported to cause liver injury, in the United States, products used for bodybuilding and weight loss are the most commonly implicated.",1
13273,24099468,"Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy","BACKGROUND: Nodular regenerative hyperplasia (NRH) is increasingly being recognised in patients with inflammatory bowel disease (IBD). However, the pathogenesis and incidence of NRH in IBD, and the putative roles played by azathioprine (AZA), mercaptopurine (MP), or tioguanine (TG) remain unclear. AIMS: To summarise the data on the association between NRH and thiopurine therapy in patients with IBD. METHODS: A literature search was performed in PubMed and MEDLINE databases using the keywords 'nodular regenerative hyperplasia AND (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (azathioprine OR mercaptopurine OR tioguanine OR thioguanine).' No time limit was placed on studies included. RESULTS: Inflammatory bowel disease patients treated with AZA have a cumulative incidence of NRH of approximately 0.6% and 1.28% at 5 and 10 years, respectively, whereas those treated with high-dose TG (>40 mg/day) have a frequency of NRH of up to 62%, which is higher in patients with elevated liver enzymes and/or thrombocytopaenia than those without these abnormalities (frequency 76% vs. 33%). Conversely, low-dose TG therapy (<20 mg/day) is relatively safe, with no cases of NRH observed. NRH has also been found in 6% of operated thiopurine-naive IBD patients. Male gender, older age, and stricturing disease/small bowel resection have been consistently identified as high-risk factors for NRH. CONCLUSIONS: The pathogenesis of nodular regenerative hyperplasia in patients with IBD is complex and multifactorial involving disease-specific, genetic and iatrogenic risk factors. Clinicians should maintain a high index of suspicion for diagnosing nodular regenerative hyperplasia, especially in IBD patients with high-risk factors on thiopurine therapy, regardless of the presence of laboratory abnormalities.",1
13274,24102928,"A phase 2a, randomized, crossover trial of gabapentin enacarbil for the treatment of postherpetic neuralgia in gabapentin inadequate responders","""OBJECTIVE: To compare the efficacy of high-dose (3,600?mg/day) vs low-dose (1,200?mg/day) oral gabapentin enacarbil (GEn) on pain intensity in adults with postherpetic neuralgia (PHN) and a history of inadequate response to ?1,800?mg/day gabapentin. DESIGN: Multicenter, randomized, double-blind, crossover study (NCT00617461). SETTING: Thirty-five outpatient centers in Germany and the United States. SUBJECTS: Subjects aged ?18 years with a diagnosis of PHN. METHODS: During a 2-week baseline period, subjects received open-label treatment with 1,800?mg/day gabapentin. Subjects who had a mean 24-hour average pain intensity score ?4 during the last 7 days of the baseline period were randomized to receive GEn (1,200 or 3,600?mg/day) for treatment period 1 (28 days), followed by GEn 2,400?mg/day (4 days), and the alternate GEn dose for treatment period 2 (28 days). RESULTS: There was a modest but significant improvement in pain intensity scores with GEn 3,600?mg vs 1,200?mg (adjusted mean [90% confidence interval] treatment difference, -0.29 [-0.48 to -0.10]; P?=?0.013). The difference in efficacy between doses was observed primarily in subjects who received the higher dose during treatment period 2; certain aspects of the study design may have contributed to this outcome. Plasma steady-state gabapentin exposure during GEn treatment was as expected and consistent between treatment periods. No new safety signals or adverse event trends relating to GEn exposure were identified. CONCLUSIONS: While the overall results demonstrated efficacy in a PHN population, the differences between treatment periods confound the interpretation. These findings could provide insight into future trial designs.""",1
13275,24107802,Hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ is associated with UGT1A1 polymorphisms,,1
13276,24109195,Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature,Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient's acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.,1
13277,24113901,Notes from the field: acute hepatitis and liver failure following the use of a dietary supplement intended for weight loss or muscle building--May-October 2013,"On September 9, 2013, the Hawaii Department of Health (HDOH) was notified of seven patients with severe acute hepatitis and fulminant liver failure of unknown etiology. Patients were previously healthy and sought medical care during May-September 2013. Clinicians reported that the seven patients had all used OxyELITE Pro, a dietary supplement marketed for weight loss and muscle gain, before illness onset.",1
13278,24116853,"Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial","""PURPOSE: To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. METHODS: This was a phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT00504881) in adults (16-70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16 weeks). KEY FINDINGS: A total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV- and 91.7% PBO-treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV- and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ?50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ?50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. SIGNIFICANCE: Adjunctive BRV given at individualized tailored doses (20-150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.""",1
13279,24117596,"A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis","BACKGROUND: Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals. AIMS: To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets. METHODS: A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies). RESULTS: Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine. CONCLUSIONS: This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.",1
13280,24118703,Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials,"""BACKGROUND & AIMS: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. METHODS: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. RESULTS: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. CONCLUSIONS: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.""",1
13281,24120216,Early changes in hepatic function among HIV-tuberculosis patients treated with nevirapine or efavirenz along with rifampin-based anti-tuberculosis therapy,"OBJECTIVES: To describe the longitudinal changes in hepatic function among HIV-infected tuberculosis (TB) patients receiving once-daily nevirapine (NVP)- or efavirenz (EFV)-based antiretroviral treatment (ART) along with rifampin-containing anti-TB treatment. METHODS: This was a nested study within a randomized clinical trial, taking place between May 2006 and June 2008 at the National Institute for Research in Tuberculosis, Chennai, India. Antiretroviral-naive HIV-infected TB patients were initiated on an intermittent short-course regimen and randomized to receive didanosine and lamivudine with either NVP (400 mg) or EFV (600 mg) once-daily. Blood was analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum alkaline phosphatase (SAP), and bilirubin at baseline, at ART initiation, fortnightly after ART initiation until 2 months, then monthly until 6 months and 6-monthly thereafter. RESULTS: Of the 168 patients included (79% men, median CD4 count 93 cells/mm3, median viral load 242,000 copies/ml), 104 were on EFV-based ART and 64 on NVP-based ART. There was a small but statistically significant elevation in ALT and SAP at 2 weeks and AST at 6 weeks after ART initiation. The proportion of patients with rate-limiting toxicity of liver enzymes was small. None had treatment terminated because of hepatotoxicity. CONCLUSION: Hepatotoxicity is not a major concern when HIV-infected TB patients, with normal baseline liver function initiate treatment for both infections simultaneously.",1
13282,24129835,A review of 29 incidents involving 4-aminopyridine in non-target species reported to the ASPCA Animal Poison Control Center,"""4-Aminopyridine (4-AP) is an avicide used in products that are approved by the Environmental Protection Agency (EPA) to control populations of various birds. Pharmaceutical 4-AP is also used in humans to treat neural and muscular dysfunctions associated with multiple sclerosis. Although strict restrictions for its use are in place, exposures to 4-AP bait by non-target species still occur. Twenty-nine exposures of 4-AP bait involving non-target species were identified and retrieved from the ASPCA Animal Poison Control Center medical record database. Canines were the most commonly exposed (86 %) species followed by felines (10 %). The highest frequency of exposures was reported from Colorado (22 %). Most commonly reported clinical signs in canines were tremors, hypersalivation, seizures, tachycardia, and ataxia. The onset time of signs ranged from 5 to 300 min with an average of 89 min. Clinical signs lasted from 15 to 84 h with an average of 37 h. Patient outcome was known in six cases; one dog died 4 h after the exposure and five made full recovery with supportive care. Treatment of five surviving patients included administration of activated charcoal, use of anticonvulsants and muscle relaxants like diazepam and methocarbamol, and intravenous fluids. Diagnosis of 4-AP toxicosis can be supported by testing the gastric contents of the exposed patient. Due to the rapid absorption, samples need to be collected and frozen/chilled promptly. For successful patient outcome, treatment must be implemented quickly after an exposure.""",1
13283,24133560,Pentoxifylline-induced drug rash with eosinophilia and systemic symptoms (DRESS) in a patient with caffeine intolerance,"BACKGROUND: Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction characterised by rash, eosinophilia and systemic involvement. MAIN OBSERVATIONS: We report a case of DRESS induced by pentoxifylline used for the treatment of severe alcoholic hepatitis, in a patient with longstanding caffeine intolerance. A history of intolerance to caffeine and other methylxanthines is listed as a contraindication to the use of pentoxifylline, yet this precaution is not mentioned in alcoholic hepatitis treatment guidelines. CONCLUSIONS: Prescribers should always seek a history of intolerance to caffeine and related compounds prior to use of pentoxifylline, as severe life threatening reactions can occur.",1
13284,24137699,A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Author's response,,1
13285,24140184,Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial,"BACKGROUND: Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. METHODS: In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. FINDINGS: Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0?019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). INTERPRETATION: The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease.",1
13286,24144196,"Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study","""BACKGROUND: Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults. METHODS: This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-?sberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings. RESULTS: The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%-83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (-3.3 [-5.5 to -1.1], p = 0.003) and 80 mg/day (-3.1, [-5.3 to -1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (-1.8, 95% [-3.6 to 0], p = 0.046) and 80 mg/day (-2.7 [-4.5 to -0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (? 5% and ? double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction. LIMITATIONS: Limitations to our study included short treatment duration and lack of an active control arm. CONCLUSION: Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population. CLINICAL TRIAL REGISTRATION: NCT01377194.""",1
13287,24145345,"Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma","PURPOSE: Nivolumab, a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma. PATIENTS AND METHODS: In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. RESULTS: Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1-specific CD8(+) T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab. CONCLUSION: In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.",1
13288,24150447,FDA: Increased HBV reactivation risk with ofatumumab or rituximab,,1
13289,24151371,Simultaneous intrahepatic and subgaleal hemorrhage in antiphospholipid syndrome following anticoagulation therapy,"Warfarin is a widely used anticoagulant. Interindividual differences in drug response, a narrow therapeutic range and the risk of bleeding render warfarin difficult to use clinically. An 18-year-old woman with antiphospholipid syndrome received long-term warfarin therapy for a recurrent deep vein thrombosis. Six years later, she developed right flank pain. We diagnosed intrahepatic and subgaleal hemorrhages secondary to anticoagulation therapy. After stopping oral anticoagulation, a follow-up computed tomography showed improvement in the hemorrhage. After restarting warfarin because of a recurrent thrombosis, the intrahepatic hemorrhage recurred. We decided to start clopidogrel and hydroxychloroquine instead of warfarin. The patient has not developed further recurrent thrombotic or bleeding episodes. Intrahepatic hemorrhage is a very rare complication of warfarin, and our patient experienced intrahepatic and subgaleal hemorrhage although she did not have any risk factors for bleeding or instability of the international normalized ratio control.",1
13290,24157994,Beware of paracetamol use in alcohol abusers: a potential cause of acute liver injury,"""There may be under-recognition of acute liver injury following reported therapeutic use of paracetamol in alcoholics. We present the case of an alcoholic patient who developed acute liver injury suspicious for chronic paracetamol toxicity on two occasions. The likely contribution of chronic paracetamol was not recognised at her second presentation, reflecting a need for increased awareness of this potential cause of acute liver injury. The biochemical hallmark of the syndrome is the 'towering' aspartate-aminotransferase (AST), often in the thousands; transaminases above 500 U/L should never be dismissed as secondary to alcoholic liver disease alone. Whether alcoholics are at increased risk of toxicity from therapeutic doses of paracetamol remains controversial, although many cases have been described for over 30 years. Randomised controlled trials to date have failed to show significant hepatic derangement in newly abstinent alcoholics exposed to short courses of paracetamol. We argue that these studies do not reflect the realities of paracetamol use in this population. In addition, alcoholics are at risk of accidental 'staggered overdoses', or repeated supra-therapeutic ingestions. In cases of suspected paracetamol toxicity, administration of the antidote n-acetyl cysteine (NAC) should be considered, even when the patient's serum paracetamol level is normal.""",1
13291,24162681,Apoptosis or necrosis in acetaminophen-induced acute liver failure? New insights from mechanistic biomarkers*,,1
13292,24166106,Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction,"PURPOSE: We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer. METHODS: We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m(2) day 1, 8 and oral capecitabine 650 mg/m(2) b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ?15 ?mol/L] and 3 cohorts with increasing TB (16-39, 40-80, >80 ?mol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography-tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis. RESULTS: Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10(-3)) and capecitabine (p = 10(-5)), and low intracellular gemcitabine triphosphate concentrations (p = 10(-3)). CONCLUSIONS: Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine's activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.",1
13293,24169027,"Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible-dose, 52-week extension study","""Patients with major depressive disorder often experience relapse after responding to treatment; therefore, maintenance therapy with antidepressants is recommended for maintaining response or remission. This multicenter, open-label, flexible-dose, 52-week extension study evaluated the long-term safety, tolerability, and maintenance of efficacy in study participants who had completed one of two randomized, double-blind, placebo-controlled, 8-week dose-ranging vortioxetine trials in study participants with major depressive disorder. At the open-label baseline, all study participants were switched to vortioxetine 5 mg/day for the first week, with subsequent dose adjustments from 2.5 to 10 mg/day on the basis of response and tolerability. Treatment with vortioxetine for 52 weeks was well tolerated, with no new safety signals identified. Among the 834 evaluable study participants, treatment-emergent adverse events were reported in 70.6%, with the most common in the combined (all doses) population of nausea (15.2%), headache (12.4%), nasopharyngitis (9.8%), diarrhea (7.2%), and dizziness (6.8%). The rate of adverse events related to sexual dysfunction was low and weight gain was minimal. Laboratory values, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale results showed no trends of clinical concern. The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 (from 17.6 at open-label baseline) in the observed case data set.""",1
13294,24170180,"Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study","""OBJECTIVE: The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder. METHOD: Patients were randomly assigned to receive double-blind treatment with lurasidone (20-60 mg/day [N=166] or 80-120 mg/day [N=169]) or placebo (N=170) for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-?sberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20-60 mg/day group (-15.4; effect size=0.51) and the 80-120 mg/day group (-15.4; effect size=0.51) compared with placebo (-10.7). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20-60 mg/day group (-1.8; effect size=0.61) and the 80-120 mg/day group (-1.7; effect size=0.50) compared with placebo (-1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20-60 mg/day (6.6%), 80-120 mg/day (5.9%), and placebo (6.5%) groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone. CONCLUSION: Monotherapy with lurasidone in the dosage range of 20-120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.""",1
13295,24173008,A review of tuberculosis: Focus on bedaquiline,"PURPOSE: The history and prevalence of tuberculosis and the role of bedaquiline in multidrug-resistant (MDR) tuberculosis are reviewed. SUMMARY: Tuberculosis continues to cause significant morbidity and mortality worldwide. Increasing rates of drug-resistant tuberculosis are a significant concern and pose serious implications for current and future treatment of the disease. In December 2012, the Food and Drug Administration approved bedaquiline as part of the treatment regimen for pulmonary MDR tuberculosis. Bedaquiline's unique mechanism of action presents an alternative approach to current antimycobacterial killing. By directly inhibiting adenosine triphosphate (ATP) synthase, bedaquiline is effective against both replicating and dormant mycobacteria. Pulmonary cavitary lesions can contain heterogeneous populations. This potential mix of semireplicating and hypometabolic mycobacteria is more difficult to eliminate with conventional antitubercular drugs, thus increasing the risk of resistance. No in vitro cross-resistance between bedaquiline and currently available antitubercular agents has been observed thus far. Because bedaquiline targets a completely different enzyme, cross-resistance with other conventional agents remains unlikely. Enhanced sterilizing capacity via synergistic depletion of ATP further exhibits the promising potential of bedaquiline with pyrazinamide. A course of bedaquiline requires 24 weeks of therapy in combination with other antitubercular drugs. CONCLUSION: The approval of bedaquiline represents a major milestone in MDR tuberculosis therapy. Bedaquiline should be considered in patients who have not responded to a regimen containing four second-line drugs and pyrazinamide and patients with documented evidence of MDR tuberculosis resistant to fluoroquinolones. The exact role of bedaquiline cannot be determined until further efficacy and safety data are obtained through ongoing Phase III trials.",1
13296,24174625,"Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis","""Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of >/=35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009).""",1
13297,24177317,"Using aggregated, de-identified electronic health record data for multivariate pharmacosurveillance: a case study of azathioprine","OBJECTIVE: To demonstrate the use of aggregated and de-identified electronic health record (EHR) data for multivariate post-marketing pharmacosurveillance in a case study of azathioprine (AZA). METHODS: Using aggregated, standardized, normalized, and de-identified, population-level data from the Explore platform (Explorys, Inc.) we searched over 10 million individuals, of which 14,580 were prescribed AZA based on RxNorm drug orders. Based on logical observation identifiers names and codes (LOINC) and vital sign data, we examined the following side effects: anemia, cell lysis, fever, hepatotoxicity, hypertension, nephrotoxicity, neutropenia, and neutrophilia. Patients prescribed AZA were compared to patients prescribed one of 11 other anti-rheumatologic drugs to determine the relative risk of side effect pairs. RESULTS: Compared to AZA case report trends, hepatotoxicity (marked by elevated transaminases or elevated bilirubin) did not occur as an isolated event more frequently in patients prescribed AZA than other anti-rheumatic agents. While neutropenia occurred in 24% of patients (RR 1.15, 95% CI 1.07-1.23), neutrophilia was also frequent (45%) and increased in patients prescribed AZA (RR 1.28, 95% CI 1.22-1.34). After constructing a pairwise side effect network, neutropenia had no dependencies. A reduced risk of neutropenia was found in patients with co-existing elevations in total bilirubin or liver transaminases, supporting classic clinical knowledge that agranulocytosis is a largely unpredictable phenomenon. Rounding errors propagated in the statistically de-identified datasets for cohorts as small as 40 patients only contributed marginally to the calculated risk. CONCLUSION: Our work demonstrates that aggregated, standardized, normalized and de-identified population level EHR data can provide both sufficient insight and statistical power to detect potential patterns of medication side effect associations, serving as a multivariate and generalizable approach to post-marketing drug surveillance.",1
13298,24180494,A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias,"""BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).""",1
13299,24183563,"Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial","""BACKGROUND: Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. METHODS: In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ?40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. FINDINGS: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5?79 decrease in SAPS-PD scores compared with -2?73 for placebo (difference -3?06, 95% CI -4?91 to -1?20; p=0?001; Cohen's d 0?50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. INTERPRETATION: Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. FUNDING: ACADIA Pharmaceuticals.""",1
13300,24184132,"Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection","""BACKGROUND & AIMS: The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. METHODS: We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). RESULTS: In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. CONCLUSIONS: In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.""",1
13301,24187513,Assessing the long-term clinical benefit of prolonged-release fampridine tablets in a real-world setting: a review of 67 cases,"""PURPOSE: To assess the long-term effects of prolonged-release (PR) fampridine tablets (dalfampridine extended release) in clinical practice in patients with multiple sclerosis (MS) with walking impairment. PATIENTS AND METHODS: MS patients with walking impairment deemed candidates for treatment with PR-fampridine tablets were included in this case series. Clinical assessments included the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 12-item Multiple Sclerosis Walking Scale (MSWS-12), EuroQoL-5D, and the Fatigue Severity Scale (FSS). The T25FW was videotaped at each visit. Assessments were performed at baseline and after 4 weeks of treatment with PR-fampridine tablets 10 mg twice daily. Clinical benefit of treatment was defined as any improvement in T25FW or MSWS-12 score at 4 weeks. Patients who demonstrated clinical benefit continued treatment and were assessed at 3 and 6 months. RESULTS: Among all patients (N = 67; mean MS duration, 16.5 years; mean EDSS score, 4.8; mean T25FW, 13.9 seconds), 65, 52, and 48 completed the 4-week, 3-month, and 6-month visits, respectively. After 4 weeks, 50.7% and 32.8% of patients walked ?10% and ?20% faster, respectively; and in 65.7% of patients, MSWS-12 scores improved. Three patients experienced adverse events (nausea, n = 2, insomnia, n = 1) that resulted in discontinuation of treatment. After 6 months, 38.8% and 16.4% of patients walked ?10% and ?20% faster versus baseline, respectively; and in 59.7% of patients, MSWS-12 scores improved. Among patients who demonstrated clinical benefit of treatment at 6 months, FSS scores improved on average by 1 point and MSWS-12 scores by 10 points. Three case studies showing different outcomes of PR-fampridine treatment are detailed with a visual depiction of the changes observed. CONCLUSION: In this case series, a proportion of patients demonstrated a clinical benefit of PR-fampridine treatment on walking. Determining which patients derive benefit from PR-fampridine is an important aspect of treatment. A range of clinical and patient-reported factors should be considered when assessing the clinical benefit of PR-fampridine treatment in MS patients.""",1
13302,24190702,A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC),"""PURPOSE: Lenvatinib is an oral multi-targeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFR?, RET, and KIT. Everolimus is an oral mammalian target of rapamycin inhibitor approved for advanced renal cell carcinoma (RCC). This phase 1b study assessed safety, maximum tolerated dose (MTD), and preliminary antitumor activity of lenvatinib plus everolimus in metastatic RCC (mRCC) patients. METHODS: Patients with advanced unresectable or mRCC and Eastern Cooperative Oncology Group performance status 0-1 were eligible (number of prior treatments not restricted). Starting dose was lenvatinib 12 mg once daily with everolimus 5 mg once daily administered continuously in 28-day cycles using a conventional 3 + 3 dose-escalation design. At the MTD, additional patients were enrolled in an expansion cohort. RESULTS: Twenty patients (mean 58.4 years) received lenvatinib [12 mg (n = 7); 18 mg (n = 11); 24 mg (n = 2)] plus everolimus 5 mg. MTD was established as once daily lenvatinib 18 mg plus everolimus 5 mg. The most common treatment-related treatment-emergent adverse events (all dosing cohorts) were fatigue 60 % (Grade ?3: 10 %), mucosal inflammation 50 %, proteinuria (Grade ?3: 15 %), diarrhea (Grade ?3: 10 %), vomiting (Grade ?3: 5 %), hypertension, and nausea, each 40 %. In MTD and lowest-dose cohorts (n = 18), best responses of partial response and stable disease were achieved in 6 (33?%) and 9 (50 %) patients, respectively. CONCLUSIONS: Lenvatinib 18 mg combined with everolimus 5 mg was associated with manageable toxicity consistent with individual agents and no new safety signals. Observed activity warrants further evaluation of the combination in advanced RCC patients.""",1
13303,24193402,Clinical features and prognostic factors in severe cutaneous drug reactions,"""BACKGROUND: Severe cutaneous adverse reactions (SCARs) include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). SJS and TEN (SJS/TEN) and DRESS are thought to be different diseases; however, they share some clinical and laboratory features. Although SCORTEN serves as an excellent prognostic marker for SJS/TEN, there is still a need for development of other prognostic markers for SCARs. METHODS: The study population consisted of 88 SCAR patients. Clinical characteristics and clinical manifestations were compared between SJS/TEN and DRESS. Risk factor analyses for prolonged hospitalization were performed. RESULTS: Of the 88 patients, 41 were SJS/TEN and 47 were DRESS. Mortality rates of TEN and DRESS were 9.8 and 2.1%, respectively. Allopurinol and carbamazepine were the most common causes of both SJS/TEN and DRESS (34.7 and 62.9%, respectively). Some of the systemic presentations, such as fever and laboratory abnormalities were common in both phenotypes. Thrombocytopenia tended to be related to prolonged hospitalization (longer than 3 weeks) in SJS/TEN (odds ratio, OR = 5.1, 95% confidence interval, CI 0.8-31.8, p = 0.076). In DRESS patients, leukocytosis at presentation (OR 4.8, 95% CI 1.1-20.3, p = 0.03) was related to prolonged hospitalization. CONCLUSIONS: Clinical features of SCARs in a tertiary hospital in Korea were similar to those reported previously. SJS/TEN and DRESS shared some clinical and laboratory features. Thrombocytopenia for SJS/TEN and leukocytosis at presentation for DRESS may be useful prognostic markers for prolonged hospitalization.""",1
13304,24195983,Vanishing bile duct syndrome in a Hodgkin's lymphoma patient with fatal outcome despite lymphoma remission,"Vanishing bile duct syndrome (VBDS) is a condition resulting from severe bile duct injury, progressive destruction, and disappearance of intrahepatic bile ducts (ductopenia) leading to cholestasis, biliary cirrhosis, and liver failure. VBDS can be associated with a variety of disorders, including Hodgkin's lymphoma (HL). We describe a 33-year-old male patient who presented with lymphadenopathy and jaundice, and was diagnosed to have HL. Serum bilirubin worsened progressively despite chemotherapy, with a cholestatic pattern of liver enzymes. Diagnosis of VBDS was established on liver biopsy. Although remission from HL was achieved, the patient died of liver failure. Presence of jaundice in HL patients should raise the possibility of VBDS. This report discusses the difficulties of delivering chemotherapy in patients with liver dysfunction. HL-associated VBDS carries a high mortality but lymphoma remission can be achieved in some patients. Therefore, liver transplantation should be considered early in these patients.",1
13305,24200190,Atovaquone-proguanil in the treatment of imported uncomplicated Plasmodium falciparum malaria: a prospective observational study of 553 cases,"""BACKGROUND: Each year, thousands of cases of uncomplicated malaria are imported into Europe by travellers. Atovaquone-proguanil (AP) has been one of the first-line regimens used in France for uncomplicated malaria for almost ten years. While AP's efficacy and tolerance were evaluated in several trials, its use in """"real life"""" conditions has never been described. This study aimed to describe outcome and tolerance after AP treatment in a large cohort of travellers returning from endemic areas. METHODS: Between September 2002 and January 2007, uncomplicated malaria treated in nine French travel clinics with AP were followed for 30 days after AP initiation. Clinical and biological data were collected at admission and during the follow-up. RESULTS: A total of 553 patients were included. Eighty-eight percent of them were born in Africa, and 61.8% were infected in West Africa, whereas 0.5% were infected in Asia. Migrants visiting friends and relatives (VFR) constituted 77.9% of the patients, the remainder (32.1%) were backpackers. Three-hundred and sixty-four patients (66%) fulfilled follow-up at day 7 and 265 (48%) completed the study at day 30. Three patients had treatment failure. One-hundred and seventy-seven adverse drug reactions (ADR) were reported during the follow-up; 115 (77%) of them were digestive ADR. Backpackers were more likely to experiment digestive ADR compared to VFR (OR = 3.8; CI 95% [1.8-8.2]). Twenty patients had to be switched to another regimen due to ADR. CONCLUSION: This study seems to be the largest in terms of number of imported uncomplicated malaria cases treated by AP. The high rate of reported digestive ADR is striking and should be taken into account in the follow-up of patients since it could affect their adherence to the treatment. Beside AP, artemisinin combination therapy (ACT) is now recommended as first-line regimen. A comparison of AP and ACT, in terms of efficacy and tolerance, would be useful.""",1
13306,24206391,Safety profile of iloperidone in the treatment of schizophrenia,"INTRODUCTION: Iloperidone is a novel antipsychotic medication approved for the treatment of schizophrenia in adults with efficacy similar to its class counterparts. The purpose of this article is to describe the safety profile of iloperidone and its clinical implications. AREAS COVERED: A PubMed search was undertaken on May 10, 2013, using the keyword iloperidone. Of the 121 articles that resulted, those with primary sources of information, along with secondary sources with an emphasis on drug safety, were included in this article. Iloperidone was found to have lower extrapyramidal symptom (EPS) and akathisia rates compared to haloperidol and risperidone. Twelve percent of patients experienced clinically significant weight gain, largely during initiation phase of treatment. No other clinically significant metabolic abnormalities were observed. QTc interval was increased by 10 ms, comparable to the effect observed with ziprasidone. QTc prolongation was heightened under inhibition of CYP2D6 and CYP3A4. Orthostatic hypotension was a common effect seen in the first week of treatment. EXPERT OPINION: The favorable EPS and akathisia profile of iloperidone makes it an attractive choice for patients whose compliance is limited by these effects. However, the slow titration schedule adapted to reduce orthostasis may limit the use of this agent in an acute setting.",1
13307,24206557,Aloe vera: Not always so beneficial in patients with chronic liver disease,,1
13308,24209977,"Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial","""BACKGROUND: Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen--a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen. METHODS: For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978. FINDINGS: In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75-100) in group 1, by 21 (100%) of 21 patients (84-100) in group 2, and by 18 (95%) of 19 patients (74-100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74-100) in group 4 and by all 21 (100%) of 21 patients (84-100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment. INTERPRETATION: These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin. FUNDING: Gilead Sciences.""",1
13309,24220561,Is antiviral prophylaxis necessary to prevent hepatitis B virus (HBV) reactivation in patients with HBV-resolved infection receiving rituximab-containing chemotherapy?,,1
13310,24224150,Adverse events associated with azathioprine treatment in korean pediatric inflammatory bowel disease patients,"PURPOSE: This study was aimed to evaluate the frequency and course of adverse events associated with azathioprine treatment in Korean pediatric patients with inflammatory bowel disease. METHODS: Total of 174 pediatric patients (age range, 1 to 19 years) with inflammatory bowel disease who received azathioprine in order to maintain remission at Samsung Medical Center (Seoul, Korea) from January 2002 through December 2012 were included in this study. Medical records of these subjects were retrospectively reviewed regarding the development of adverse events associated with azathioprine treatment. RESULTS: Ninety-eight patients (56.3%) of 174 patients experienced 136 episodes of adverse events, requiring dose reduction in 31 patients (17.8%), and discontinuation in 18 patients (10.3%). The mean dose of azathioprine that had been initially administered was 1.32?0.42 mg/kg/day. Among the adverse reactions, bone marrow suppression developed in 47 patients (27.0%), requiring dose reduction in 22 patients (12.6%) and discontinuation in 8 patients (4.6%). Other adverse events that occurred were gastrointestinal disturbance (15.5%), hair loss (12.1%), pancreatitis (7.5%), arthralgia (6.9%), hepatotoxicity (2.9%), skin rash/allergic reactions (2.9%), headache/dizziness (2.3%), sepsis (0.6%), and oral mucositis (0.6%). CONCLUSION: Bone marrow suppression, especially leukopenia was most commonly associated with azathioprine treatment in Korean pediatric inflammatory bowel disease patients. Close observation for possible adverse events is required in this population with inflammatory bowel diseases who are under treatment with azathioprine.",1
13311,24225327,Eslicarbazepine acetate: an update on efficacy and safety in epilepsy,"Epilepsy is a common neurological disorder. Despite a broad range of commonly used antiepileptic drugs, approximately 30% of patients with epilepsy have drug resistance or encounter significant adverse effects. Eslicarbazepine acetate is a new central nervous system-active compound with anticonvulsant activity whose mechanism of action is by blocking the voltage-gated sodium channel. Eslicarbazepine acetate was approved by the European Medicines Agency and launched onto the European market in 2009 for adjunctive treatment in adult subjects of partial-onset seizures, with or without secondary generalization. This article provides an overview on the recent studies on eslicarbazepine acetate in the treatment of drug-resistant partial epilepsy. Efficacy and safety of this drug for partial-onset seizures were assessed in four randomized clinical trials with responder rates ranged between 17% and 43%. Adverse events were usually mild to moderate in intensity and the most common were dizziness, somnolence, nausea, diplopia, headache, vomiting, abnormal coordination, blurred vision, vertigo and fatigue. Eslicarbazepine acetate is not recommended below 18 years, but a published phase II trial had the main goal to evaluate the pharmacokinetics, efficacy and safety of this drug in pediatric population. Eslicarbazepine acetate appears to be a safe and effective drug with a linear pharmacokinetics, very low potential for drug-drug interactions and therefore it can offer a valid alternative to current antiepileptic drugs. Additionally, it is undergoing investigation for monotherapy in subjects with partial epilepsy, and other neurological and psychiatric disorders.",1
13312,24236482,Specific HLA types are associated with antiepileptic drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese subjects,"AIM: This preliminary study investigated genomic biomarkers for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), related to three antiepileptic drugs, zonisamide, phenobarbital and phenytoin. PATIENTS & METHODS: HLA class I and HLA-DRB1 loci were genotyped for Japanese patients with zonisamide-, phenobarbital- or phenytoin-induced SJS/TEN (n = 12, 8 and 9, respectively) and for healthy Japanese volunteers (n = 2878). RESULTS: Carrier frequencies of HLA-A*02:07 in patients with zonisamide-induced SJS/TEN and in the general Japanese population were 41.7 and 6.81%, respectively. Carrier frequencies of HLA-B*51:01 in patients with phenobarbital- and phenytoin-induced SJS/TEN and in controls were 75.0, 55.6 and 15.2%, respectively. HLA-A*02:07 and HLA-B*51:01, in a dominant model, were significantly associated with zonisamide- and phenobarbital-induced SJS/TEN, respectively (Pc = 0.0176 and 0.0042, respectively). CONCLUSION: Our data suggest that HLA-A*02:07 and HLA-B*51:01 are potential biomarkers for zonisamide- and phenobarbital-induced SJS/TEN, respectively, in Japanese individuals.",1
13313,24238036,Ruxolitinib for myelofibrosis--an update of its clinical effects,"Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Clinical hallmarks include splenomegaly, anemia, and debilitating symptoms. In 2 randomized phase III studies, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib significantly improved splenomegaly and disease-related symptoms compared with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment [COMFORT-I]) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk MF. Although ruxolitinib therapy was associated with dose-dependent anemia and thrombocytopenia, these adverse events rarely led to treatment discontinuation. This update of the clinical effects of ruxolitinib in patients with MF was based on original articles and meeting abstracts published after the primary publication of the COMFORT trials in March 2012. Long-term follow-up data from the COMFORT trials and clinical experience with ruxolitinib in unselected patient populations suggest that improvement of splenomegaly and symptoms is durable. Patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. In COMFORT-I, platelet counts stabilized with dose adjustments, and hemoglobin levels gradually recovered to slightly below baseline after the first 8 to 12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to that found in the placebo group. The 2-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.",1
13314,24241638,Managing the risk of drug-induced liver injury,"In clinical trials, bosentan was shown to cause significant drug-induced liver injury (DILI) in some patients. Because it is not possible to identify those at higher risk for DILI, all patients to be treated with bosentan must enroll in a program requiring documentation of liver blood testing before they can receive the drug. Because this program is costly and is perceived as onerous, a genetic test capable of identifying susceptible individuals would probably be rapidly adopted by physicians.",1
13315,24255061,Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial,"""BACKGROUND: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. METHODS AND RESULTS: Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. CONCLUSION: Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.""",1
13316,24256083,"Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial","""PURPOSE: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16-70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. METHODS: This was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up-titration for 12 weeks, followed by down-titration or entry into a long-term follow-up study. The primary efficacy end point was percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ?50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment-emergent adverse events (TEAEs). KEY FINDINGS: Of 399 randomized patients, 398 were included in the intent-to-treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long-term follow-up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (?50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue. SIGNIFICANCE: In this study of adjunctive BRV (20-100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ?50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20-100 mg/day was well tolerated without up-titration, with a high completion rate.""",1
13317,24258498,"A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea","BACKGROUND: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial. METHODS: Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to <45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms. RESULTS: Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit <45% without phlebotomy was achieved in 97% of patients by week 24.Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification. CONCLUSIONS: Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.",1
13318,24259608,Ziv-aflibercept (Zaltrap) for the treatment of metastatic colorectal cancer,"""OBJECTIVE: Review pharmacology, pharmacokinetics, efficacy, and safety of ziv-aflibercept in combination with FOLFIRI for treatment of metastatic colorectal cancer (mCRC) resistant to or progressed following oxaliplatin-containing regimens. DATA SOURCES: Articles indexed in PubMed (1948-August 2013), TOXLINE (2001-August 2013), and Google Scholar as well as meeting abstracts were identified using the search terms ziv-aflibercept and colorectal cancer. STUDY SELECTION AND DATA EXTRACTION: Available English-language articles DATA SYNTHESIS: Ziv-aflibercept, a selective vascular endothelial growth factor antagonist, was evaluated as monotherapy for treatment of mCRC in a phase 2 study and added to FOLFIRI in a phase 3 trial. Patient response to ziv-aflibercept as monotherapy did not reach statistical significance. Results suggest that response to ziv-aflibercept treatment is not influenced by prior bevacizumab therapy. A phase 3 trial compared the safety and efficacy of ziv-aflibercept plus FOLFIRI with placebo plus FOLFIRI in patients with mCRC who experienced disease progression on an oxaliplatin-containing regimen. Patients in the ziv-aflibercept arm had a median overall survival of 13.5 months, versus 12.06 months for those receiving placebo (hazard ratio [HR] = 0.817, 95% CI = 0.713 to 0.937). Progression-free survival for patients receiving ziv-aflibercept was higher compared with placebo (HR = 0.758; 95% CI = 0.661 to 0.869). The most common adverse effects observed were anemia, diarrhea, and neutropenia. CONCLUSIONS: Ziv-aflibercept is a safe and effective option in combination with FOLFIRI for the treatment of mCRC in patients who progress on oxaliplatin-containing therapy. Superiority over other antiangiogenic treatment has not been established.""",1
13319,24261031,Azathioprine induced serious portal hypertension: a case series of three IBD patients and review of the literature,"We report 3 male IBD patients (2 Crohn's Disease, 1 Ulcerative Colitis) developing thrombocytopenia and splenomegaly on azathioprine treatment. All patients were diagnosed with significant portal hypertension due to histological proven nodular regenerative hyperplasia (NRH) of the liver. In two of three patients, liver function tests remained completely normal. In addition we provide a short literature review of azathioprine induced NRH covering etiology, imaging, pathology, prognosis and treatment.",1
13320,24263160,"Metformin as a Rare Cause of Drug-Induced Liver Injury, a Case Report and Literature Review","Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. Although metformin-associated gastrointestinal upset and metabolic acidosis is widely recognized side effect of this drug, metformin-induced liver injury has been rarely reported in the literature. In most cases reported, metformin-induced liver injury was associated with concomitant intake of other hepatotoxic drugs. Here, we report a case of a 70-year-old white woman who suffered metformin-induced liver injury 5 weeks after starting on this medication, and she was not on any other hepatotoxic agent. With increasing prescription of metformin, this case deserves particular attention for this rare but important side effect.",1
13321,24264834,Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity,"""Treatment with the tyrosine kinase inhibitor (TKI) imatinib for chronic myeloid leukemia in chronic phase (CML-CP) of disease may cause severe hepatotoxicity in rare cases. However, it remains unclear (1) how imatinib-induced hepatotoxicity should be treated; and (2) if and how TKI treatment can be resumed after recovery. We report a 32-year-old woman with CML-CP and histology confirmed imatinib-induced liver toxicity after 6 months of treatment. In this case, the early administration of corticosteroid therapy resulted in rapid and complete hepatic recovery, and treatment for CML-CP with the second generation TKI dasatinib was continued safely after recovery. Thus, dasatinib represents an option for maintaining therapeutic response in patients in whom continuation of imatinib is not possible due to its hepatic toxicity.""",1
13322,24276500,Ponatinib (Inclusig) marketing and sales suspended,,1
13323,24281236,Efficacy and safety of flibanserin in postmenopausal women with hypoactive sexual desire disorder: results of the SNOWDROP trial,"""OBJECTIVE: This study aimed to assess the efficacy and safety of flibanserin, a serotonin receptor 1A agonist/serotonin receptor 2A antagonist, in postmenopausal women with hypoactive sexual desire disorder (HSDD). METHODS: Naturally postmenopausal women with HSDD received flibanserin 100 mg once daily at bedtime (n = 468) or placebo (n = 481) for 24 weeks. Co-primary endpoints were changes from baseline to week 24 in the number of satisfying sexual events (SSEs) across 28 days and in the Female Sexual Function Index (FSFI) desire domain score. Secondary endpoints included change from baseline in Female Sexual Distress Scale-Revised (FSDS-R) Item 13 score (which assesses distress due to low sexual desire), FSDS-R total score, and FSFI total score. The Patient Benefit Evaluation was asked on treatment discontinuation. RESULTS: There were significant improvements with flibanserin versus placebo in the mean (SE) changes in the number of SSEs (1.0 [0.1] vs 0.6 [0.1]), FSFI desire domain score (0.7 [0.1] vs 0.4 [0.1]), FSDS-R Item 13 score (-0.8 [0.1] vs -0.6 [0.1]), FSDS-R total score (-8.3 [0.6] vs -6.3 [0.6]), and FSFI total score (4.2 [0.4] vs 2.7 [0.4]; all P < 0.01). More women on flibanserin (37.6%) than women on placebo (28.0%) reported experiencing meaningful benefits from the study medication on treatment discontinuation. The most frequent adverse events associated with flibanserin were dizziness, somnolence, nausea, and headache. CONCLUSIONS: In naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated.""",1
13324,24286114,Long-term tolerability and maintenance of therapeutic response to sodium oxybate in an open-label extension study in patients with fibromyalgia,"""INTRODUCTION: The long-term safety and therapeutic response of sodium oxybate (SXB) in fibromyalgia syndrome (FM) patients were assessed for a combined period of up to 1 year in a prospective, multicenter, open-label, extension study in patients completing 1 of 2 phase 3 randomized, double-blind, controlled, 14-week trials that examined the efficacy and safety of SXB 4.5 g, SXB 6 g, and placebo for treatment of FM. METHODS: This extension study comprised an additional 38 weeks of treatment and was carried out at 130 clinical sites in 7 countries. Initial entry criteria for the previous 2 double-blind clinical trials required that patients aged ? 18 years met the American College of Rheumatology 1990 criteria for FM, had a body mass index (BMI) < 40 kg/m2, and had a score ? 50 on a 100-mm pain visual analog scale (VAS) at baseline. All patients began treatment in the extension study with SXB 4.5 g/night (administered in 2 equally divided doses) for at least 1 week, followed by possible serial 1.5 g/night dose increases to 9 g/night (maximum) or reductions to 4.5 g/night (minimum). RESULTS: Of the 560 FM patients enrolled in this extension study, 319 (57.0%) completed the study. The main reason for early discontinuation was adverse events (AEs; 23.0% of patients). Patients were primarily middle-aged (mean 46.9???10.8 years), female (91.1%), white (91.4%), with a mean duration of FM symptoms of 9.9???8.7 years. Serious AEs were experienced by 3.6% of patients. The most frequently reported AEs (incidence ? 5% at any dose or overall) were nausea, headache, dizziness, nasopharyngitis, vomiting, sinusitis, diarrhea, anxiety, insomnia, influenza, somnolence, upper respiratory tract infection, muscle spasms, urinary tract infection, and gastroenteritis viral. Maintenance of SXB therapeutic response was demonstrated with continued improvement from controlled-study baseline in pain VAS, Fibromyalgia Impact Questionnaire (FIQ) total scores, and other measures. Responder analyses showed that 68.8% of patients achieved ? 30% reduction in pain VAS and 69.7% achieved ? 30% reduction in FIQ total score at study endpoint. CONCLUSIONS: The long-term safety profile of SXB in FM patients was similar to that in the previously reported controlled clinical trials. Improvement in pain and other FM clinical domains was maintained during long-term use. TRIAL REGISTRATION: ClinicalTrials.gov NCT00423605.""",1
13325,24287510,Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis,"We completed a network meta-analysis of published papers to compare bisphosphonate gastrointestinal safety. We found that zoledronic acid had the highest chance of causing gastrointestinal adverse events. Etidronate had the highest chance of discontinuation due to an adverse event. No difference was found for serious adverse events. INTRODUCTION: Bisphosphonates are first-line treatment for osteoporosis. Gastrointestinal (GI) adverse events (AE) are the primary reason for non-adherence. Little is known about the comparative GI safety of bisphosphonates. PURPOSE: Leverage published clinical trial data to examine the comparative GI safety of bisphosphonates. METHODS: We completed a systematic review of all English-language clinical trials that assessed bisphosphonate safety and/or efficacy in primary osteoporosis through to 2012. Randomized, blinded, and controlled studies were eligible. The primary outcome was any GI-related AE. Subanalyses were completed for upper GI symptoms, serious GI, nausea, esophageal-related events, and discontinuation due to AE. A Bayesian-based network meta-analysis was completed to allow for indirect comparisons. Results were reported as the probability that a specific drug had the highest number of events. RESULTS: We identified 50 studies: 32 alendronate, 12 risedronate, 5 etidronate, and 7 zoledronic acid. Zoledronic acid had the highest probability of having the highest number of any GI AE (91%) and nausea (70%). Etidronate (70%) and zoledronic acid (28%) had the highest probability of having the greatest attrition due to AE. Etidronate had the highest probability (56%) of having the greatest number of upper GI symptoms among oral bisphosphonates. CONCLUSION: Zoledronic acid had the highest probability of causing the greatest number of GI AE, possibly related to nausea. These results question the assumption that annual zoledronic acid will translate into better adherence. Little difference was found between alendronate and risedronate for serious AE. More research into real-world implications of the comparative safety of bisphosphonates is needed.",1
13326,24290498,Long-term effects of dalfampridine in patients with multiple sclerosis,"BACKGROUND/OBJECTIVE: Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9-12 months. METHODS: Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2 weeks and after 9-12 months later. RESULTS: Thirty out of fifty-two patients (~60%) were still on treatment after 9-12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9-12 months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9-12 months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients. CONCLUSION: Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS.",1
13327,24291473,Acute pancreatitis and elevated liver transaminases after rapid titration of oral levetiracetam,"We report a 25-year-old woman with new onset convulsive episodes. The patient initially failed to respond to phenytoin and was switched to levetiracetam (LEV) which was rapidly titrated to 3000 mg daily over 1 week. At initiation of LEV therapy, she developed mild nausea and decrease in appetite. This was rapidly followed by severe digestive symptoms consistent with acute pancreatitis. She was also found to have elevated liver transaminases. An extensive work-up failed to reveal an organic cause for her symptoms, suggesting a direct relationship to LEV. Clinical symptoms and laboratory abnormalities normalized after LEV discontinuation, along with supportive therapy.",1
13328,24295376,Real-world cabazitaxel safety: the Italian early-access program in metastatic castration-resistant prostate cancer,"AIM: Cabazitaxel is a novel taxane that is approved for use in metastatic castration-resistant prostate cancer based on the Phase III TROPIC study, which showed improved overall survival with cabazitaxel/prednisone versus mitoxantrone/prednisone. A global early-access program was initiated in order to provide early access to cabazitaxel in docetaxel-pretreated patients and to obtain real-world data. PATIENTS & METHODS: We report interim safety results from an Italian prospective, single-arm, multicenter, open-label trial of 218 patients receiving cabazitaxel 25 mg/m2 every 3 weeks plus prednisolone 10 mg/day, until disease progression, unacceptable toxicity, investigator's decision or death. RESULTS: Patients completing treatment received a median of six cabazitaxel cycles. The most common grade 3/4 adverse events were neutropenia (33.9%), leukopenia (15.6%), anemia (6%) and asthenia (6%). No peripheral neuropathy or nail disorders were observed. CONCLUSION: These results confirm that cabazitaxel has a manageable safety profile in daily clinical practice and support its use in patients with prostate cancer who progress during or after a docetaxel-based therapy.",1
13329,24298009,Vitamin D intoxication due to an erroneously manufactured dietary supplement in seven children,"Pediatric cases of vitamin D intoxication (VDI) with dietary supplements have not been previously reported. We report on 7 children with VDI caused by consumption of a fish oil supplement containing an excessively high dose of vitamin D due to a manufacturing error. Seven children aged between 0.7 and 4.2 years were admitted with symptoms of hypercalcemia. Initial median (range) serum concentrations of calcium and 25-hydroxyvitamin D were 16.5 (13.4-18.8) mg/dL and 620 (340-962) ng/mL, respectively. Repeated questioning of the parents revealed use of a fish oil that was produced recently by a local manufacturer. Analysis of the fish oil by gas chromatography/mass spectrometry revealed that the vitamin D3 content was ~4000 times the labeled concentration. Estimated daily amounts of vitamin D3 intake varied between 266,000 and 800,000 IU. Patients were successfully treated with intravenous hydration, furosemide, and pamidronate infusions. With treatment, serum calcium returned to the normal range within 3 days (range: 2-7 days). Serum 25-hydroxyvitamin D levels normalized within 2 to 3 months. Complications, including nephrocalcinosis, were not observed throughout the 1-year follow-up. In conclusion, errors in manufacturing of dietary supplements may be a cause of VDI in children. Physicians should be aware of this possibility in unexplained VDI cases and repeatedly question the families about dietary supplement use. To prevent the occurrence of such unintentional incidents, manufacturers must always monitor the levels of ingredients of their products and should be rigorously overseen by governmental regulatory agencies, as is done in the pharmaceutical industry.",1
13330,24300875,Genetics of drug-induced hepatotoxicity toxicity in Gilbert's syndrome,,1
13331,24305101,"[A case of portal hypertension after 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy]","A 46-year-old man with cancer of the sigmoid colon with hepatic metastasis underwent sigmoidectomy, partial hepatectomy, and cholecystectomy in May 2008. He subsequently received 10 cycles of a modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) regimen as adjuvant chemotherapy from June 2008 to December 2008, following which he developed thrombocytopenia and splenomegaly. In May 2011, upper gastrointestinal endoscopy was performed, which revealed esophageal and gastric varices. The varices were treated endoscopically with ligation and balloon-occluded retrograde transvenous obliteration. A liver biopsy was performed to determine the cause of the portal hypertension in the absence of severe hepatic dysfunction or liver cirrhosis. The biopsy revealed obliteration of the peripheral portal veins with sinusoidal dilatation without fibrosis or inflammatory cell infiltration in the hepatic lobules. Oxaliplatin-based chemotherapy has been associated with hepatovascular injury, such as sinusoidal dilatation and fibrosis, resulting in non-cirrhotic portal hypertension as seen in this case.",1
13332,24309172,"Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study","OBJECTIVE: To evaluate the clinical and microbiological efficacy and safety of three doses of 3 g fosfomycin tromethamine administered orally to treat lower urinary tract infections. DESIGN AND PARTICIPANTS: This prospective, uncontrolled, open-label study was conducted in 12 medical centres in China, between January and December 2011. According to the diagnosis criteria of Chinese Guidelines on Urological Infections, patients (18-70 years) with acute uncomplicated cystitis, recurrent lower urinary tract infection or complicated lower urinary tract infection received three doses of 3 g fosfomycin tromethamine orally, at days 1, 3 and 5. PRIMARY AND SECONDARY OUTCOME MEASURES: Efficacy endpoints (clinical efficacy, microbiological efficacy and overall efficacy) were evaluated on day 15. Clinical symptoms, physical signs, urinalysis, liver and kidney function, patient records and evaluation of adverse events (AEs) and serious AEs up to day 15 were evaluated for analysis of safety. RESULTS: 361 patients were included in the full analysis set, 356 in the safety analysis set and 335 in the per-protocol set (PPS). In the PPS, the clinical efficacy rates at day 15 for acute uncomplicated cystitis, recurrent lower urinary tract infection and complicated lower urinary tract infection were 94.71% (179/189), 77.22% (61/79) and 62.69% (42/67), respectively. The microbiological efficacy rates (day 15) were 97.65% (83/85), 94.44% (34/36) and 83.87% (26/31), respectively. The overall efficacy rates (day 15) were 95.29% (81/85), 77.78% (28/36) and 64.52% (20/31), respectively. 20/356 (5.6%) patients reported drug-related AEs, the most common being diarrhoea. No serious drug-related AEs were reported. CONCLUSIONS: This fosfomycin tromethamine dosing regimen showed clinical and microbiological efficacy with some AEs and good tolerability in patients with acute uncomplicated cystitis, recurrent lower urinary tract infection and complicated lower urinary tract infection.",1
13333,24309980,U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia,"""On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single-arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (>/=20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit-to-risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.""",1
13334,24315480,Herbal hepatotoxicity: analysis of cases with initially reported positive re-exposure tests,"BACKGROUND: Positive re-exposure tests are diagnostic hallmarks for hepatotoxicity. OBJECTIVE: To test validity of positive re-exposures in herb induced liver injury. METHODS: We searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ? 2? baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2? baseline alanine aminotransferase, or if baseline alanine aminotransferase? 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result. RESULTS: In 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb. CONCLUSIONS: Among 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs.",1
13335,24322664,Pertuzumab (Perjeta) for preoperative use in HER2-positive breast cancer,,1
13336,24326033,A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout,"""OBJECTIVE: To evaluate the safety and efficacy of febuxostat compared to allopurinol for the treatment of chronic gout. METHODS: We did a systematic review and meta-analysis of randomized and non-randomized controlled trials that compared oral febuxostat to oral allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios (RR) were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). RESULTS: From 1076 potentially relevant citations, 7 studies and 25 associated publications met inclusion criteria; 5 studies were ultimately included in the analysis. Febuxostat did not reduce the risk of gout flares compared with allopurinol (RR = 1.16, 95% CI = 1.03-1.30, I(2) = 44%). Overall, the risk of any adverse event was lower in febuxostat recipients compared to allopurinol (RR = 0.94, 95% CI = 0.90-0.99, I(2) = 13%). Patients receiving febuxostat were more likely to achieve a serum uric acid of <6 mg/dl than allopurinol recipients (RR = 1.56, 95% CI = 1.22-2.00, I(2) = 92%). Subgroup analysis did not indicate any significant difference between high- and low-dose febuxostat on the risk of gout flares. CONCLUSION: Although febuxostat was associated with higher likelihood of achieving a target serum uric acid level of <6 mg/dl, there was significant heterogeneity in the pooled results. There was no evidence that febuxostat is superior to allopurinol for clinically relevant outcomes. Given its higher cost, febuxostat should not be routinely used for chronic gout.""",1
13337,24332241,"Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial","""BACKGROUND: Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. METHODS: In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. FINDINGS: Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. INTERPRETATION: The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. FUNDING: Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.""",1
13338,24332433,Emergency contraception with a copper IUD or oral levonorgestrel: an observational study of 1-year pregnancy rates,"""OBJECTIVE: We investigated the 1-year pregnancy rates for emergency contraception (EC) users who selected the copper T380 intrauterine device (IUD) or oral levonorgestrel (LNG) for EC. STUDY DESIGN: This prospective study followed women for 1 year after choosing either the copper T380 IUD or oral LNG for EC. The study was powered to detect a 6% difference in pregnancy rates within the year after presenting for EC. RESULTS: Of the 542 women who presented for EC, agreed to participate in the trial and met the inclusion criteria, 215 (40%) chose the copper IUD and 327 (60%) chose oral LNG. In the IUD group, 127 (59%) were nulligravid. IUD insertion failed in 42 women (19%). The 1-year follow-up rate was 443/542 (82%); 64% of IUD users contacted at 1 year still had their IUDs in place. The 1-year cumulative pregnancy rate in women choosing the IUD was 6.5% vs. 12.2% in those choosing oral LNG [hazard ratio (HR) 0.53, 95% confidence interval (CI): 0.29-0.97, p=.041]. By type of EC method actually received, corresponding values were 5.2% for copper IUD users vs. 12.3% for oral LNG users (HR 0.42, 95% CI: 0.20-0.85, p=.017). A multivariable logistic regression model controlling for demographic variables demonstrates that women who chose the IUD for EC had fewer pregnancies in the following year than those who chose oral LNG (HR 0.50, 95% CI: 0.26-0.96, p=.037). CONCLUSION: One year after presenting for EC, women choosing the copper IUD for EC were half as likely to have a pregnancy compared to those choosing oral LNG. IMPLICATIONS: Compared to EC users who choose oral levonorgestrel, those who select the copper IUD have lower rates of pregnancy in the next year. Greater use of the copper IUD for EC may lower rates of unintended pregnancy in high-risk women.""",1
13339,24335449,Acute liver failure associated with traditional Chinese medicine: report of 30 cases from seven tertiary hospitals in China*,"OBJECTIVES: Up to now, limited cases with acute liver failure caused by traditional Chinese medicine have been reported, and thus this topic has been scarcely discussed. This study aims to report such cases from China. DESIGN: A retrospective study. SETTING: Clinical investigation among seven tertiary hospitals in different areas of China. PATIENTS: From January 2007 to December 2012, patients with acute liver failure induced by traditional Chinese medicinal herbs were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 30 patients were finally identified, including six men and 24 women. The average age was 39.7 years. The median period from initial symptoms to the development of hepatic encephalopathy was 13 days. Nine patients (30%) had accepted herbal therapies due to their skin disorders before the onset of acute liver failure. Eighteen patients (60%) eventually died, 10 of whom died of heavy bleeding. No patients received liver transplantation. CONCLUSIONS: The model of safety monitoring for traditional Chinese materia medica should be established. For those critically ill patients with herb-induced acute liver failure, coagulopathy is a vital problem in critical care. Additionally, the rate of liver transplantation for acute liver failure in China needs to be improved.",1
13340,24338680,"The promising impact of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the management of lymphoid malignancies","Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Bruton's tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B-cell signaling. Dysregulated Btk results in uncontrolled B-lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment-naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms.",1
13341,24341369,Prophylaxis against hepatitis B reactivation among patients with lymphoma receiving rituximab,"Hepatitis B virus (HBV) reactivation occurs commonly in patients with non-Hodgkin lymphoma, receiving rituximab-based therapeutic regimen. Guidelines from different organizations are not all in agreement with regard to screening and antiviral prophylaxis, given the limited evidence. Antiviral prophylaxis has been recommended for all HBV surface antigen-positive patients. Evidence for benefit from prophylaxis has recently been recognized among HBV surface antigen-negative/HBV core antibody-positive patients. Incidence of HBV reactivation varies in different geographical locations and the decision to start antiviral prophylaxis should consider local incidence data. Given the increased rates of rituximab-associated HBV reactivation and potentially fatal outcome, it is prudent that all patients who receive rituximab should be screened for HBV markers.",1
13342,24344160,"Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis","""OBJECTIVE: To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials. METHODS: Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naive, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naive), with early escape at wk 16 (wk 28, methotrexate-naive); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial. RESULTS: Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for >/=156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma. CONCLUSIONS: SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.""",1
13343,24352180,Risk of hepatotoxicity associated with fluoroquinolones: a national case-control safety study,"""PURPOSE: Results of a pharmacoepidemiologic evaluation of fluoroquinolone-associated hepatotoxicity using national hospital admissions data on Veterans Affairs (VA) patients are reported. METHODS: In a retrospective case-control study, all adults with a primary diagnosis of hepatotoxicity on admission to a VA facility during a 6.5-year period (January 2002-June 2008) were identified. After the exclusion of patients whose records indicated known causes of hepatotoxicity or a history of liver disease, a subgroup of 7,862 patients with exposure to fluoroquinolone antibiotics in the six months prior to hospital admission were matched with nonexposed controls (n = 45,512). Conditional logistic regression was used to assess the overall and drug-specific risks of hepatotoxicity in the case group, controlling for comorbidities, concomitant use of known hepatotoxic medications, and other variables. RESULTS: After adjusting for confounders, logistic regression analysis indicated a significantly higher overall risk of hepatotoxicity development among fluoroquinolone users relative to controls (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.04-1.38). Drug-specific risk analyses focused on three fluoroquinolone agents (ciprofloxacin, levofloxacin, and moxifloxacin) indicated a significant association between ciprofloxacin use and an increased risk of hepatotoxicity (OR, 1.29; 95% CI, 1.05-1.58); when considered as independent variables, levofloxacin use and moxifloxacin use were not significantly associated with hepatotoxicity risk. CONCLUSION: The findings of a national VA safety study suggested an increased hepatotoxicity risk asssociated with fluoroquinolone exposure in the study population.""",1
13344,24362450,Antidepressant-induced liver injury: a review for clinicians,"""OBJECTIVE: Antidepressant drugs can cause drug-induced liver injury (DILI). The authors review clinical data relevant to antidepressant-induced liver injury and provide recommendations for clinical practice. METHOD: A PubMed search was conducted for publications from 1965 onward related to antidepressant-induced liver injury. The search terms were """"liver injury,"""" """"liver failure,"""" """"DILI,"""" """"hepatitis,"""" """"hepatotoxicity,"""" """"cholestasis,"""" and """"aminotransferase,"""" cross-referenced with """"antidepressant."""" RESULTS: Although data on antidepressant-induced liver injury are scarce, 0.5%-3% of patients treated with antidepressants may develop asymptomatic mild elevation of serum aminotransferase levels. All antidepressants can induce hepatotoxicity, especially in elderly patients and those with polypharmacy. Liver damage is in most cases idiosyncratic and unpredictable, and it is generally unrelated to drug dosage. The interval between treatment initiation and onset of liver injury is generally between several days and 6 months. Life-threatening antidepressant-induced liver injury has been described involving fulminant liver failure or death. The underlying lesions are often of the hepatocellular type and less frequently of the cholestatic and mixed types. The antidepressants associated with greater risks of hepatotoxicity are iproniazid, nefazodone, phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine. The antidepressants that seem to have the least potential for hepatotoxicity are citalopram, escitalopram, paroxetine, and fluvoxamine. Cross-toxicity has been described, mainly for tricyclic and tetracyclic antidepressants. CONCLUSIONS: Although an infrequent event, DILI from antidepressant drugs may be irreversible, and clinicians should be aware of it. Aminotransferase surveillance is the most useful tool for detecting DILI, and prompt discontinuation of the drug responsible is essential. The results of antidepressant liver toxicity in all phases of clinical trials should be available and published. Further research is needed before any new and rigorously founded recommendations can be made.""",1
13345,24367885,Hepatitis B reactivation in patient with non-Hodgkin's lymphoma receiving rituximab-based chemotherapy: need for education and attention,"Hepatitis B reactivation can occur in patients with inactive chronic hepatitis B receiving rituximab treatment. Therefore, hepatitis B virus (HBV) screening is recommended in patients planned for chemotherapy and antiviral prophylaxis needs to be started prior to initiating the treatment in patients with evidence of HBV infection. We describe a 58-year-old African American man with history of chronic hepatitis B who developed severe (HBV) reactivation while receiving rituximab treatment for Non-Hodgkin's lymphoma (NHL). The report highlights that greater education is needed amongst clinicians regarding risk of HBV reactivation while receiving chemotherapy, particularly with rituximab-based treatment.",1
13346,24369094,A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: a California Cancer Consortium Study,"We performed a phase II study of belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.",1
13347,24370824,"Ezetimibe markedly attenuates hepatic cholesterol accumulation and improves liver function in the lysosomal acid lipase-deficient mouse, a model for cholesteryl ester storage disease","Lysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wolman disease (WD) when the mutations cause complete loss of LAL activity. A rat model for WD and a mouse model for CESD have been described. In these studies we used LAL-deficient mice to investigate how modulating the amount of intestinally-derived cholesterol reaching the liver might impact its mass, cholesterol content, and function in this model. The main experiment tested if ezetimibe, a potent cholesterol absorption inhibitor, had any effect on CE accumulation in mice lacking LAL. In male Lal(-/-) mice given ezetimibe in their diet (20 mg/day/kg bw) for 4 weeks starting at 21 days of age, both liver mass and hepatic cholesterol concentration (mg/g) were reduced to the extent that whole-liver cholesterol content (mg/organ) in the treated mice (74.3+/-3.4) was only 56% of that in those not given ezetimibe (133.5+/-6.7). There was also a marked improvement in plasma alanine aminotransferase (ALT) activity. Thus, minimizing cholesterol absorption has a favorable impact on the liver in CESD.",1
13348,24373081,HCV direct-acting antiviral agents: the best interferon-free combinations,"For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct-acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan-genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN-based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross-resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.",1
13349,24376563,"Comparative efficacy and safety of deferoxamine, deferiprone and deferasirox on severe thalassemia: a meta-analysis of 16 randomized controlled trials","OBJECTIVE: A meta-analysis was conducted to investigate the efficacy and safety of three main iron chelators, namely, deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX) for thalassemia major (TM) patients. METHODS: Randomized controlled trials comparing mono-therapy DFO, DFP, DFX and combined DFP with DFO therapy in TM patients from January 1990 to December 2012 were searched and selected. Two independent authors assessed data from extracted randomized trials for efficacy and safety in the measurements of serum ferritin (SF), live iron concentration (LIC), myocardial iron content (MIC), left ventricular ejection fraction (LVEF) and adverse events (AEs). RESULTS: Sixteen studies were selected. In the comparison of DFP versus DFO treatment groups, a significant difference was revealed on MIC and LVEF (P=0.01 and P=0.007, respectively) but not on SF or LIC level (P=0.65 and P=0.37, respectively). In comparing combined therapy (DFP plus DFO) versus DFO, a significant difference was shown on MIC and LVEF measurements (P<0.00001 and P=0.003, respectively), but not on SF or LIC levels (P=0.93 and P=0.62, respectively). Moreover, the combined DFP with DFO treatment had significantly higher risk than DFO treatment (RR 1.46 with 95%CI 1.04 to 2.04). When comparing DFX with DFO, a significant difference was shown on the SF level (P=0.003), and there was no difference between DFX and DFO in safety evaluation (RR 1.53 with 95%CI 0.31 to 7.49). CONCLUSION: Findings indicated that the most effective and safe iron chelators remains to be proven, and further large-scale, long-term studies are needed.",1
13350,24378344,Probable linagliptin-induced liver toxicity: a case report,"AIM: Unlike other dipeptidyl peptidase 4 (DPP-4) inhibitors, the excretion of linagliptin is mainly through a biliary route. Despite this fact, liver injury with linagliptin has thus far not been reported in the literature. However, this report describes the first case of probable linagliptin-induced liver toxicity. METHODS: The clinical history, diagnosis, investigations and drug treatment of the patient are reviewed here. RESULTS: A 58-year-old Japanese woman presented with fatigue, nausea, jaundice and marked elevations of hepatic enzymes 4weeks after starting linagliptin 5mg/day as monotherapy. No other medications were taken, and imaging studies revealed no other obvious causes of hepatic injury. Tests for viral serology and antinuclear antigen were negative. Symptoms disappeared and the levels of hepatic parameters (serum aminotransferases and biliary enzymes) slowly recovered after discontinuation of linagliptin. The slow recovery process may have been due to the very long half-life of the drug. The patient's Naranjo scale score was 6 and RUCAM score was 7. CONCLUSION: Although linagliptin currently carries no liver warnings, it may be necessary to monitor hepatic function in some patients upon administration of this drug until further evidence is obtained.",1
13351,24381241,Prolonged Cholestatic Jaundice Associated With Flurbiprofen,"Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed drugs throughout the world for pain relief. Although the adverse effects of NSAIDs to the liver are well known, flurbiprofen-induced liver cholestasis is extremely rare. Herein, we present a patient with prolonged icterus that is associated with the use of flurbiprofen without causing ductopenia.",1
13352,24382909,Albendazole-induced recurrent hepatitis,,1
13353,24388027,Drug-induced liver injury,"""Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of """"English language"""" and """"humans"""" and custom date range of """"January 1, 2000."""" The authors also manually searched bibliographies from key references and included seminal references before the year�2000.""",1
13354,24389305,Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives,"Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.",1
13355,24395543,Transient liver function abnormality following treatment with rabbit antithymocyte globulin for nonmyeloablative hematopoetic stem cell transplant: two case reports,"Rabbit antithymocyte globulin (rATG) is increasingly used in nonmyeloablative hematopoetic stem cell transplant (HSCT). Elevated liver function tests (LFTs) have been reported for antithymocyte globulin in the treatment of aplastic anemia, but not when used in a conditioning regimen for HSCT. We describe two cases of patients receiving a conditioning regimen for HSCT containing rATG who developed a transient, severe transaminase elevation. In the first case, a 66-year-old woman with a history of acute myeloid leukemia received the first dose of rATG and the patient's transaminases were found to be extremely elevated within a few hours. The aspartate transaminase (AST) peaked at 1286 U/L and alanine transaminase (ALT) peaked at 991 U/L and both resolved within a week. In the second case, a 72-year-old woman with a history of non-Hodgkin lymphoma received the first dose of rATG and the AST and ALT were found to be 1212 U/L and 689 U/L, respectively, 1 h after finishing the infusion. Like the previous case, the transaminase elevation resolved within a week. LFT abnormalities induced by rATG during conditioning therapy for HSCT may be transient and have a rapid onset after the first dose, but quickly subside without any complications or sequelae. It is important to follow the LFTs closely, as well as monitor for any signs and symptoms of acute liver failure.",1
13356,24399721,Association between the HLA-B*15:02 allele and carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Han individuals of northeastern China,"BACKGROUND: This study examined the significant association between carbamazepine (CBZ)-induced Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) and HLA-B*15:02 in epilepsy patients of Han ethnicity living in northeastern China. METHODS: CBZ-SJS/TEN patients and CBZ-tolerant control patients were genotyped for HLA-B*15:02 by PCR amplification using sequence-specific primers. Patients then were evaluated for HLA genotypes using PCR with sequence-based typing. RESULTS: Eight of 35 CBZ-SJS/TEN patients carried HLA-B*15:02 (22.9%) versus 2 of 125 in CBZ-tolerant control patients (OR = 18.222, 95% CI = 3.662-90.662, p = 0.000). Our results suggest that HLA-B*15:02 is necessary but is not sufficient to produce SJS/TEN following CBZ treatment among Han individuals from northeastern China. Other HLA alleles, including A*33:03, B*58:01, C*03:02, DQB1*03:03, and DRB1*07:01 may be associated weakly with CBZ-SJS/TEN. CONCLUSIONS: Our results are not consistent with previous studies reporting a strong association between HLA-B*15:02 and CBZ-SJS/TEN among individuals from southern, southwestern, and central China. Other genes may be more tightly associated with CBZ-SJS/TEN. Screening for HLA-B*15:02 still may be recommended for patients in northeastern China before starting CBZ.",1
13357,24400777,"Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A","We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.",1
13358,24403552,"Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype","BACKGROUND: Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites. METHODS: We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy. RESULTS: Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 ?g/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 ?g/mL) and lower N-oxide levels (1.6 vs 2.5 ?g/mL). CONCLUSIONS: CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified.",1
13359,24411083,"A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia","""BACKGROUND: Dihydrotestosterone is the main androgen causative of androgenetic alopecia, a psychologically and physically harmful condition warranting medical treatment. OBJECTIVE: We sought to compare the efficacy and safety of dutasteride (type 1 and 2 5-alpha reductase inhibitor) with finasteride (type 2 5-alpha reductase inhibitor) and placebo in men with androgenetic alopecia. METHODS: Men aged 20 to 50 years with androgenetic alopecia were randomized to receive dutasteride (0.02, 0.1, or 0.5 mg/d), finasteride (1 mg/d), or placebo for 24 weeks. The primary end point was hair count (2.54-cm diameter) at week 24. Other assessments included hair count (1.13-cm diameter) and width, photographic assessments (investigators and panel), change in stage, and health outcomes. RESULTS: In total, 917 men were randomized. Hair count and width increased dose dependently with dutasteride. Dutasteride 0.5 mg significantly increased hair count and width in a 2.54-cm diameter and improved hair growth (frontal view; panel photographic assessment) at week 24 compared with finasteride (P�= .003, P�= .004, and P�= .002, respectively) and placebo (all P < .001). The number and severity of adverse events were similar among treatment groups. LIMITATIONS: The study was limited to 24 weeks. CONCLUSIONS: Dutasteride increased hair growth and restoration in men with androgenetic alopecia and was relatively well tolerated.""",1
13360,24412980,Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre,"""BACKGROUND: Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition. OBJECTIVE: To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS). DESIGN: Retrospective cohort study. PATIENTS: Young people with glycogenic hepatopathy. SETTING: Tertiary paediatric hepatology unit. RESULTS: Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73�to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12�to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c. CONCLUSIONS: Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.""",1
13361,24418480,Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis,,1
13362,24419243,Levomilnacipran (Fetzima) a new SNRI for depression,,1
13363,24419296,New oral anticoagulants for acute venous thromboembolism,,1
13364,24420801,[Drug-induced liver injury with an autoimmune phenotype following anti-TNF Therapy - presentation of cases and review of literature],"Therapeutic agents to inhibit tumour necrosis factor alpha (TNF-?) have dramatically improved the treatment options for patients with autoimmune diseases. Common side effects include an increased susceptibility towards infection. Hepatic side effects are less frequently observed. Elevated liver function tests, hyperbilirubinaemia reactivation of chronic viral hepatitis or even acute liver failure have been described. Some cases have exhibited an autoimmune phenotype with the emergence of autoantibodies and characteristic histological lesions. We report on three patients who received anti-TNF therapy for psoriasis and presented with elevated liver function tests in the further course. Histological and serum analysis revealed an autoimmune phenotype of liver injury. In light of the growing use of anti-TNF therapies, drug-induced liver injury (DILI) with an autoimmune phenotype is an important side effect. Since the pathophysiological mechanisms related to the autoimmune phenotype of liver injury during TNF-inhibition are not well understood, the cases detailed herein should help treating physicians to improve their understanding of the situation.",1
13365,24423162,Albendazole-induced associated acute hepatitis and bicytopenia,"Acute hepatitis induced by albendazole is rarely reported. We describe herein an original case of acute hepatitis associated with bicytopenia after albendazole intake. This paper is the first to describe a possible association of a hematologic disorder and acute hepatitis, both induced by albendazole therapy.",1
13366,24424707,"A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10?mg in acute treatment of adults with generalized anxiety disorder","BACKGROUND: Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies. OBJECTIVE: This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder. METHODS: Subjects (n?=?457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10?mg once daily. The primary efficacy endpoint was reduction in Hamilton Anxiety Scale (HAM-A) total scores from baseline after 8?weeks of treatment. Key secondary outcomes were changes from baseline in HAM-A total scores for the 2.5 and 10?mg dose, Hospital Anxiety and Depression anxiety subscore, 36-Item Short-Form Health Survey, Sheehan Disability Scale, and Clinical Global Impression-Improvement Scale score, as well as HAM-A response rate at week 8. RESULTS: Neither vortioxetine dose achieved a statistically significant improvement over placebo on the primary endpoint (least-squares mean difference???standard error from placebo: -0.87???0.803 [p?=?0.279] for 2.5?mg and -0.81???0.791 [p?=?0.306] for 10?mg vortioxetine) or on any secondary efficacy endpoints. Common adverse events (?5% in either vortioxetine group) were nausea, dry mouth, headache, diarrhea, constipation, and vomiting. CONCLUSIONS: Vortioxetine 2.5 and 10?mg treatment did not significantly improve generalized anxiety disorder symptoms versus placebo. Vortioxetine was safe and well tolerated in this patient population.",1
13367,24428006,"Efficacy and side-effect profiles of lactulose, docusate sodium, and sennosides compared to PEG in opioid-induced constipation: a systematic review","Opioid-induced constipation (OIC) is a side effect of opioid therapy that can affect quality of life, adherence to treatment, and morbidity and possibly mortality. OBJECTIVES: To investigate whether docusate sodium, sennosides, and lactulose have equal efficacy and side effect profiles compared to PEG in the management of OIC in adults. METHODS: A systematic review was undertaken. Randomized controlled trials of adults taking opioids for cancer or non-cancer pain were considered if they met inclusion criteria. CONCLUSIONS: Statistical pooling was not possible as no studies met inclusion criteria. Large, well-powered, randomized controlled trials are feasible. Standard definitions of OIC would assist with the execution of these studies and contribute to their internal and external validity. Further research is strongly encouraged.",1
13368,24428468,Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1,"""BACKGROUND: An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin. METHODS: In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks. RESULTS: Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events. CONCLUSIONS: In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).""",1
13369,24429167,Safety of etanercept and methotrexate in patients with rheumatoid arthritis and hepatitis C virus infection: a multicenter randomized clinical trial,"""OBJECTIVE: To evaluate the safety and efficacy of therapy with etanercept and methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and mild hepatitis C virus (HCV) infection. METHODS: In this prospective open study, 29 patients with active RA were randomly assigned to receive therapy with MTX alone, etanercept alone, or a combination of MTX and etanercept, and monitored up to 54 weeks. The primary endpoint was safety; secondary aims were efficacy as defined by the 44-joint Disease Activity Score (DAS44) and health assessment questionnaire (HAQ). Serum liver enzymes and HCV viral load were serially measured. RESULTS: In the whole cohort, aspartate aminotransferase (AST) serum levels were (mean ? SD) 35 ? 3 at entry, 39 ? 5, 41 ? 7, and 38 ? 4 at 14, 30, and 54 weeks, respectively; alanine aminotransferase (ALT) serum levels were 43 ? 5 at entry, 47 ? 5, 53 ? 9, and 50 ? 6 at 14, 30, and 54 weeks, respectively. HCV viral load was 5.6 ? 0.5 at entry, 5.9 ? 0.6, 5.7 ? 0.3, and 5.6 ? 0.6 at 14, 30, and 54 weeks, respectively. AST and ALT did not significantly change in all 3 arms of treatment, nor did HCV viral load. A significant reduction of DAS44 (p < 0.01) and HAQ (p < 0.04) was detected at 54 weeks compared to baseline. No patient discontinued the therapy because of worsening of liver disease. CONCLUSION: This study showed that patients with RA and chronic HCV and mild hepatitis may be successfully treated with etanercept and MTX without increasing the risk of hepatotoxicity and HCV replication. ClinicalTrials.gov Identifier NCT01543594.""",1
13370,24429311,Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity,"OBJECTIVES: To compare the free and total plasma drug concentrations of rifampicin (RMP), isoniazid and pyrazinamide in subjects with or without anti-tuberculosis drug-induced hepatotoxicity (DIH). METHODS: A total of 110 tuberculosis (TB) patients were administered daily anti-tuberculosis treatment and were prospectively followed for the development of DIH. Plasma drug levels were measured at 0, 1, 2 and 4 h on days 1, 7 and 14 of treatment. Plasma drug levels in 15 patients who developed DIH (cases) were compared with 95 patients who did not (controls). RESULTS: Female sex, body mass index < 17 kg/m(2) and baseline serum albumin < 4 g/dl predicted risk of DIH on univariate analyses. Free and total plasma RMP levels (Cmax and AUC0-4) on days 1, 7 and 14 were significantly higher in cases compared to controls and predicted development of DIH. Day 7 total RMP Cmax and AUC0-4 were higher in cases (mean 26.73, standard deviation [SD] 5.72 and 47.58, SD 33.10) than in controls (7.87, SD 10.95 and 14.01, SD 10.69, respectively). CONCLUSIONS: Plasma RMP levels were higher in cases than in controls and independently predicted subsequent development of DIH. The Cmax of Day 7 total RMP level (cut-off 12.50 mg/l) predicted subsequent development of DIH in 93.3% of the patients.",1
13371,24431394,"Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial","""OBJECTIVES: This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission. METHODS: Patients were randomised 1:1 to CZP (400?mg at weeks 0, 2 and 4, then 200?mg every 2?weeks) or placebo (every 2?weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52. RESULTS: Of 194 patients (CZP=96; placebo=98), >90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p?0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p<0.001) achieved LDA. Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo (19.8% vs 3.1%; p?0.01 and 14.6% vs 4.1%; p?0.05). CZP patients reported improvements in physical function versus placebo (mean Health Assessment Questionnaire-Disability-Index change from baseline: CZP, -0.25 vs placebo, -0.03; p?0.01). During the period following withdrawal of CZP or placebo, only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52, but CZP reinstitution allowed renewed improvement. Adverse and serious adverse event rates were comparable between CZP and placebo groups. CONCLUSIONS: Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity, allowing low-disease activity or remission to be reached in a majority of the patients. However, the data suggest that CZP cannot be withdrawn in patients achieving remission. TRIAL REGISTRATION NUMBER: NCT00674362.""",1
13372,24434524,Safety and efficacy of tolcapone in the long-term use in Parkinson disease: an observational study,"OBJECTIVES: The aim of this observational study was to investigate the safety and efficacy of tolcapone under practice conditions. METHODS: This 12-month non-interventional study was conducted from November 2005 to August 2009. Safety parameters were incidence of adverse drug reactions (ADRs), signs and symptoms of liver failure, and liver monitoring. Efficacy was evaluated on the basis of the assessment by physicians and patients by means of the clinical global impression scale. RESULTS: Data from 391 patients were available for evaluation. Fifty-six ADRs were documented in 45 patients: most frequently, increase in liver enzymes (5.6%), diarrhea (2.6%), and nausea (1.3%). No serious ADRs or fulminant hepatotoxicity occurred. Sixteen patients discontinued the treatment with tolcapone because of adverse events, thereof 7 because of increase in liver enzymes, as prespecified in the protocol. Sixty-two elevations of aspartate aminotransferase or alanine aminotransferase occurred in 34 patients (8.7%), most of them within the first 3 months after initiating tolcapone. Five patients (1.3%) experienced clinically relevant elevations (>2xULN). In most patients with minimally elevated transaminase levels, tolcapone was continued, leading to normalization of transaminase levels in 74% of these patients. Two patients died but without causal relationship to tolcapone. The physicians reported improvement of clinical global impression for 71.7% of the patients after 3 months and for 59.1% of the patients after 12 months. CONCLUSIONS: Under routine practice conditions, tolcapone was shown to be safe and effective in patients with Parkinson disease. Significant liver transaminase elevations were rare and generally returned to normal without intervention in most patients. This study confirms the low risk for hepatotoxicity associated with tolcapone.",1
13373,24438370,Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial,"""OBJECTIVE: This phase 3 study evaluated the endometrial safety of bazedoxifene (BZA)/conjugated estrogens (CE) and bone mineral density (BMD) effects vs BZA alone, hormone therapy, and placebo (PBO). METHODS: The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, PBO- and active-controlled study in postmenopausal women with an intact uterus (N = 1843; aged 40-65 years) seeking treatment for menopausal symptoms. Subjects received daily oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or PBO. Primary endpoints were incidence of endometrial hyperplasia and percent change in lumbar spine BMD at 12 months. Secondary endpoints included additional osteoporosis parameters and assessments of tolerability and safety. RESULTS: At 12 months, endometrial hyperplasia incidence was low (<1%) and similar among groups. The BZA/CE group showed significantly greater increases in lumbar spine and total hip BMD vs decreases with PBO (P < .001); the CE/MPA group had increased lumbar spine BMD compared with that in the BZA/CE group. The BZA 20 mg/CE 0.45 and 0.625 mg groups had cumulative amenorrhea rates similar to those with PBO and BZA and significantly higher than those with CE 0.45 mg/MPA 1.5 mg (P < .001). The incidence of breast tenderness with BZA/CE was similar to that with PBO and BZA and significantly lower than with that with CE/MPA (P < .01). Although adverse event (AE) rates were similar among the groups, the incidence of serious AEs overall and AE-related discontinuation rates were higher with CE/MPA than with BZA/CE, BZA, or PBO. CONCLUSIONS: BZA/CE showed low rates of endometrial hyperplasia and improved lumbar spine and total hip BMD and was generally safe and well tolerated.""",1
13374,24439929,"Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial","""BACKGROUND: Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). We compared afatinib with gemcitabine and cisplatin-a chemotherapy regimen widely used in Asia-for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC. METHODS: This open-label, randomised phase 3 trial was done at 36 centres in China, Thailand, and South Korea. After central testing for EGFR mutations, treatment-naive patients (stage IIIB or IV cancer [American Joint Committee on Cancer version 6], performance status 0-1) were randomly assigned (2:1) to receive either oral afatinib (40 mg per day) or intravenous gemcitabine 1000 mg/m(2) on day 1 and day 8 plus cisplatin 75 mg/m(2) on day 1 of a 3-week schedule for up to six cycles. Randomisation was done centrally with a random number-generating system and an interactive internet and voice-response system. Randomisation was stratified by EGFR mutation (Leu858Arg, exon 19 deletions, or other; block size three). Clinicians and patients were not masked to treatment assignment, but the independent central imaging review group were. Treatment continued until disease progression, intolerable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT01121393. FINDINGS: 910 patients were screened and 364 were randomly assigned (242 to afatinib, 122 to gemcitabine and cisplatin). Median progression-free survival was significantly longer in the afatinib group (11?0 months, 95% CI 9?7-13?7) than in the gemcitabine and cisplatin group (5?6 months, 5?1-6?7; hazard ratio 0?28, 95% CI 0?20-0?39; p<0?0001). The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne (35 [14?6%] of 239 patients), diarrhoea (13 [5?4%]), and stomatitis or mucositis (13 [5?4%]), compared with neutropenia (30 [26?5%] of 113 patients), vomiting (22 [19?5%]), and leucopenia (17 [15?0%]) in the gemcitabine and cisplatin group. Treatment-related serious adverse events occurred in 15 (6?3%) patients in the afatinib group and nine (8?0%) patients in the gemcitabine and cisplatin group. INTERPRETATION: First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC. Afatinib should be considered as a first-line treatment option for this patient population. FUNDING: Boehringer Ingelheim.""",1
13375,24444658,Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders,"""BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection and prior null response (<2 log HCV RNA decline after ? 12 weeks of PegIFN/RBV) have limited options. We evaluated daclatasvir plus once- or twice-daily asunaprevir in non-cirrhotic genotype 1 null responders. METHODS: In this randomized, phase 2a, open-label, 24-week treatment study, 101 patients received daclatasvir (60 mg) once-daily. In addition, 38 genotype 1b patients received asunaprevir (200mg) twice- (DUAL A1) or once-daily (DUAL A2); 36 genotype 1a and 5 genotype 1b patients received asunaprevir twice- (QUAD B1) or once-daily (QUAD B2) plus PegIFN/RBV; and 18 genotype 1a and 4 genotype 1b patients received asunaprevir twice-daily plus ribavirin (TRIPLE B3). The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (sustained virologic response, SVR12). RESULTS: Across all groups, mean HCV RNA was ? 6 log IU/ml, and 99% of patients had a non-CC IL28B genotype. SVR12 rates were 78% (A1), 65% (A2), 95% (B1), and 95% (B2). In B3, most genotype 1a patients experienced virologic breakthrough. The most common adverse events were headache, diarrhea, and asthenia. Grade 3-4 aminotransferase elevations were infrequent and not treatment-limiting. CONCLUSIONS: In genotype 1 null responders, daclatasvir plus twice-daily asunaprevir DUAL therapy is effective for most genotype 1b patients, and daclatasvir, asunaprevir, and PegIFN/RBV QUAD therapy is effective for nearly all genotype 1a and 1b patients; but neither DUAL nor TRIPLE therapy is effective for genotype 1a patients. Interferon-free regimens including daclatasvir and twice-daily asunaprevir for genotype 1 null responders should be tailored to subtype.""",1
13376,24446688,"Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor","Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-alpha and ribavirin in Japan, Canada, and USA.",1
13377,24447897,Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults,"""The Centers for Disease Control and Prevention convened panels of anthrax experts to review and update guidelines for anthrax postexposure prophylaxis and treatment. The panels included civilian and military anthrax experts and clinicians with experience treating anthrax patients. Specialties represented included internal medicine, pediatrics, obstetrics, infectious disease, emergency medicine, critical care, pulmonology, hematology, and nephrology. Panelists discussed recent patients with systemic anthrax; reviews of published, unpublished, and proprietary data regarding antimicrobial drugs and anthrax antitoxins; and critical care measures of potential benefit to patients with anthrax. This article updates antimicrobial postexposure prophylaxis and antimicrobial and antitoxin treatment options and describes potentially beneficial critical care measures for persons with anthrax, including clinical procedures for infected nonpregnant adults. Changes from previous guidelines include an expanded discussion of critical care and clinical procedures and additional antimicrobial choices, including preferred antimicrobial drug treatment for possible anthrax meningitis.""",1
13378,24450506,The ATTAIN trials: efficacy and safety of telavancin compared with vancomycin for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia,"Hospital-acquired bacterial pneumonia (HABP) is the second most common nosocomial infection in the USA and the leading cause of mortality among hospital-acquired infections. An increasing proportion of HABP cases are the result of infection with methicillin-resistant Staphylococcus aureus (MRSA). Telavancin is a once-daily injectable, semisynthetic lipoglycopeptide antimicrobial with bactericidal activity against susceptible Gram-positive pathogens, including MRSA. The two methodologically identical Phase III ATTAIN studies demonstrated that telavancin was noninferior to vancomycin for the treatment of HABP, including ventilator-associated bacterial pneumonia, due to S. aureus (including methicillin-sensitive S. aureus and MRSA). Telavancin showed a similar safety profile to vancomycin, except that in patients with moderate-to-severe renal impairment, there was increased mortality, which warrants caution when using telavancin in this population. Now approved in the USA for the treatment of HABP, including ventilator-associated bacterial pneumonia, caused by susceptible isolates of S. aureus when other alternatives are not suitable, telavancin offers another therapeutic option.",1
13379,24450858,PI3K? inhibition by idelalisib in patients with relapsed indolent lymphoma,"""BACKGROUND: Phosphatidylinositol-3-kinase delta (PI3K?) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3K? inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas. METHODS: In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. RESULTS: The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenstr�m's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). CONCLUSIONS: In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).""",1
13380,24452395,"A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFR?) monoclonal antibody, in patients with advanced solid tumors","""PURPOSE: The platelet-derived growth factor receptor (PDGFR) has an important role in tumorigenesis and tumor progression. Olaratumab (IMC-3G3) is a fully human monoclonal antibody that selectively binds human PDGFR? and blocks ligand binding. This phase I study assessed the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab in patients with advanced solid tumors. METHODS: Patients were enrolled into five dose-escalating cohorts of 3-6 patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1-3) or once every other week at 15 or 20 mg/kg (cohorts 4-5), with 4 weeks/cycle. RESULTS: Nineteen patients were treated in five cohorts. There were no dose-limiting toxicities; the MTD was not identified with the doses studied. The most common olaratumab-related adverse events (AE) were fatigue and infusion reactions (10.5 % each). With the exception of 1 patient (20 mg/kg) experiencing two grade 3 drug-related AEs after the dose-limiting toxicity assessment period, all drug-related AEs were grade 1 or 2. The trough concentrations (C min) for 16 mg/kg weekly and 20 mg/kg biweekly were higher than 155 ?g/mL, and the concentration found to be efficacious in preclinical xenograft models. Twelve patients (63.2 %) had a best response of stable disease [median duration of 3.9 months (95 % CI 2.3-8.7)]. CONCLUSIONS: Olaratumab was well tolerated and showed preliminary antitumor activity. RP2Ds are 16 mg/kg weekly and 20 mg/kg biweekly. Phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.""",1
13381,24453078,Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study,"""OBJECTIVES: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS). METHODS: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed. RESULTS: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19(+) expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. CONCLUSIONS: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions.""",1
13382,24455335,Metronidazole induced liver injury: a rare immune mediated drug reaction,"Drug induced liver injury (DILI) can result either from dose-dependent direct hepatotoxicity or from an unpredictable dose-independent idiosyncratic reaction. Incidence of idiosyncratic DILI is estimated to be approximately 10-15 per 100,000 patient years. Here we report an extremely rare case of metronidazole induced delayed immune-allergic hepatocellular liver injury masquerading as autoimmune hepatitis. A previously healthy 54-year-old Caucasian male, who was treated with metronidazole for Clostridium difficile associated diarrhea, presented 3 months later with right upper quadrant abdominal pain. Laboratory tests revealed total bilirubin level of 12.7?mg/dL, direct bilirubin of 7.2?mg/dL, alanine aminotransferase (ALT) of 973?IU/L, aspartate transaminase (AST) of 867?IU/L, alkaline phosphatase (AP) of 96?IU/L, and an INR of 1.9, suggestive of hepatocellular pattern of injury. A detailed workup for hepatitis revealed no other etiology. A clinical diagnosis of metronidazole induced liver injury was made. With a persistent rise in his bilirubin and transaminase levels, the patient was started on oral prednisone. At the 2-week posthospitalization follow-up visit, the patient reported a significant improvement in his overall sense of being well and liver functions tests trended down substantially (total bilirubin 7.2?mg/dL, ALT 420?IU/L, AST 276?IU/L, AP 183?IU/L, and INR 1.5).",1
13383,24457560,Antiviral drugs for influenza 2013-2014,,1
13384,24459648,Three cases of glycogenic hepatopathy mimicking acute and relapsing hepatitis in type I diabetes mellitus,"""Glycogenic hepatopathy (GH) is an uncommon cause of serum transaminase elevation in type I diabetes mellitus (DM). The clinical signs and symptoms of GH are nonspecific, and include abdominal discomfort, mild hepatomegaly, and transaminase elevation. In this report we describe three cases of patients presenting serum transaminase elevation and hepatomegaly with a history of poorly controlled type I DM. All of the cases showed sudden elevation of transaminase to more than 30 times the upper normal range (like in acute hepatitis) followed by sustained fluctuation (like in relapsing hepatitis). However, the patients did not show any symptom or sign of acute hepatitis. We therefore performed a liver biopsy to confirm the cause of liver enzyme elevation, which revealed GH. Clinicians should be aware of GH so as to prevent diagnostic delay and misdiagnosis, and have sufficient insight into GH; this will be aided by the present report of three cases along with a literature review.""",1
13385,24461574,"Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial","""BACKGROUND: Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. METHODS: This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18-55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5.5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. FINDINGS: Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0.50 [95% CI 0.43-0.58]) than in those assigned to teriflunomide 14 mg (0.32 [0.27-0.38]; p=0.0001) or teriflunomide 7 mg (0.39 [0.33-0.46]; p=0.0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0.68 [95% CI 0.47-1.00]; log-rank p=0.0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0.95 [0.68-1.35]; log-rank p=0.7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). INTERPRETATION: Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis. FUNDING: Genzyme, a Sanofi company.""",1
13386,24464035,Ceftriaxone-induced pseudolithiasis in children treated for perforated appendicitis,"PURPOSE: Ceftriaxone has been associated with development of pseudolithiasis. In our institution, it is used for treatment of perforated appendicitis in children. This study evaluated the occurrence of ceftriaxone-related pseudolithiasis in this population. METHODS: After obtaining IRB approval, we performed a retrospective chart review over 51 months. We included patients undergoing laparoscopic appendectomy for perforated appendicitis. All patients were treated with ceftriaxone post-operatively. Patients without initial or post-treatment gallbladder imaging available for review were excluded. RESULTS: There were 71 patients who met inclusion criteria with a mean (?SD) age of 10.8 ? 3.8 years. Of these, 14 % (n = 10) developed stones or sludge in the gallbladder. The mean duration of ceftriaxone therapy was 8.7 ? 3.8 days. The average time to post-antibiotic imaging was 11.5 ? 10.3 days from initiation of antibiotics. There was no significant difference in duration of ceftriaxone therapy in the children that developed pseudolithiasis or sludge (10.0 ? 4.9 days) compared to those that did not (8.5 ? 3.6, p = 0.26). One child (10 %) with pseudolithiasis went on to become symptomatic, requiring a laparoscopic cholecystectomy. CONCLUSIONS: In our experience, ceftriaxone use for perforated appendicitis is associated with a significant incidence of biliary pseudolithiasis, and is unrelated to duration of ceftriaxone therapy.",1
13387,24465778,"The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1","BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.",1
13388,24469001,Abacavir-induced liver toxicity in an HIV-infected patient,,1
13389,24470826,Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid,"Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.",1
13390,24476812,Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis,"""OBJECTIVE: In recent years, safety alerts have been made warning of the risk of serious drug-induced liver injury (DILI) caused by cardiovascular drugs. The new oral anticoagulants (NOACs) have now reached the market. However, safety concerns have been raised about their hepatic safety. Therefore we aimed to evaluate NOAC liver-related safety. METHODS: Systematic review and meta-analysis of phase III randomised controlled trials (RCTs). Medline and CENTRAL were searched to September 2013. Reviews and reference lists were also searched. Two reviewers independently searched for studies and retrieved data estimates. Primary outcome was DILI (transaminases elevations >3x upper limit of normal (ULN) with total bilirubin >2x ULN). NOACs were compared against any control group. Random-effects meta-analysis was performed, and pooled estimates were expressed as relative risk (RR) and 95% CI heterogeneity was evaluated with I(2) test. RESULTS: Twenty-nine RCTs evaluating 152 116 patients (mean follow-up of 16 months) were included. All RCTs were rated as having low risk of bias. NOAC were not associated with an increased risk of DILI (RR 0.90, 95% CI 0.72 to 1.13, I(2)=0%). Similar results were obtained for individual NOAC (rivaroxaban, apixaban, dabigatran, darexaban, edoxaban) and considering the different control groups (vitamin K antagonists, low molecular weight heparin (LMWH) and placebo). The risk of transaminases elevations (>3xULN) was lower among NOAC-treated patients, in particular in comparison with LMWH-treated patients (RR 0.71, 95% CI 0.59 to 0.85; I(2)=27%) CONCLUSIONS: NOACs are not associated with an increased risk of DILI. The unexpected 'protective' effect of NOAC is probably due to LMWH-associated hepatotoxicity.""",1
13391,24482301,"Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial","""OBJECTIVE: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. METHODS: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (?100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo?45 mg, 45 mg?90 mg, 90 mg?90 mg). The primary endpoint was ?20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ?75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-na?ve (n=132) patients and anti-TNF-experienced (n=180) patients. RESULTS: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p?0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ?1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60. CONCLUSIONS: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.""",1
13392,24485664,Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme,"""BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access programmes (EAPs) were established worldwide, allowing access to cabazitaxel before its commercial availability. Preliminary results of the European CUP/EAP, focusing on the elderly population (aged > or =70 years), are reported. PATIENTS AND METHODS: Enrolled patients with progressive mCRPC received cabazitaxel (25 mg/m2) plus 10mg oral prednisone/prednisolone every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. Safety was analysed by age group (<70, 70-74 and > or =75 years). The influence of selected variables on grade > or =3 neutropenia and/or neutropenic complications was analysed in multivariate analysis. RESULTS: 746 men were enrolled (<70 years, n=421; 70-74, n=180, > or =75 years, n=145). Number of cabazitaxel cycles, dose reductions for any cause, dose delays possibly related to cabazitaxel adverse events, and tolerability were similar in the three age groups. Prophylactic granulocyte colony-stimulating factor (G-CSF) use was more common in men aged > or =0 years. In multivariate analysis, age > or =75 years, treatment cycle 1, and neutrophil count <4000/mm3 before cabazitaxel injection were associated with increased risk of developing grade > or =3 neutropenia and/or neutropenic complications. Prophylactic use of G-CSF at a given cycle significantly reduced this risk by 30% (odds ratio 0.70, p=0.04). CONCLUSION: The results suggest that cabazitaxel has a manageable safety profile in everyday clinical practice. Prophylactic use of G-CSF, especially at cycle 1 and in men aged > or =75 years, is important and improves tolerability in senior adults treated with cabazitaxel.""",1
13393,24493291,Acute pancreatitis following brentuximab vedotin therapy for refractory Hodgkin lymphoma: a case report,,1
13394,24499058,Monitoring of 29 weight loss compounds in foods and dietary supplements by LC-MS/MS,"""Because of the rapid growth in dietary supplement availability and public concern for weight control, the investigation of foods and various dietary supplements illegally adulterated with weight loss compounds has become increasingly important. A total of 29 weight loss compounds, including sennoside, sibutramine, ephedrine and their analogues, found to be adulterated in foods and dietary supplements were simultaneously examined by LC-MS/MS. The 188 samples were collected between 2009 and 2012 in South Korea, and method validation was performed to determine the adulterants to the weight loss compounds. LODs, LOQs and linearity ranged from 0.03 to 7.5 ng ml??, from 0.08 to 30.00 ng ml??, and from 0.990 to 0.999, respectively. The results showed that nine weight loss compounds, namely bisacodyl, desmethylsibutramine, didesmethylsibutramine, ephedrine, fluoxetine, pseudoephedrine, sennoside A, sennoside B and sibutramine, were detected in 62 of all collected samples and were found in order of frequency as follows: sibutramine, 25.7%; sennoside A, 22.9%; sennoside B, 20.0%; fluoxetine, 8.6%; desmethylsibutramine, 7.1%; bisacodyl, ephedrine, and pseudoephedrine, 4.3%; and didesmethylsibutramine, 2.9%. Sibutramine, which was the most frequently found adulterant, ranged in levels from 0.03 to 132.40 mg g?? (2010), from 0.88 to 76.2 mg g?? (2011), and from 0.07 to 0.24 mg g?? (2012). Although the concentrations of most compounds ranged widely, some compounds such as bisacodyl and fluoxetine were found at high concentrations in several samples.""",1
13395,24499969,Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder,"""OBJECTIVE: To describe weight changes and metabolic effects of asenapine compared with placebo and olanzapine in adults. METHOD: Post hoc analyses were performed using data from 17 asenapine trials (13 schizophrenia and 4 bipolar mania trials) with placebo (5-10 mg twice daily; n = 1,748; 1-6 weeks) and/or olanzapine (5-20 mg, once daily; n = 3,430; 3-100 weeks). Data were pooled based on treatment into placebo-controlled and olanzapine-controlled trials. For trials with placebo and olanzapine treatment groups, the asenapine population was included in both pools. Changes from baseline for weight, body mass index, and fasting lipid and glucose levels were determined. The Medical Dictionary for Regulatory Activities was used to define metabolic adverse events. RESULTS: Mean (standard error [SE]) weight change was greater with asenapine than with placebo (1.2 [0.2] vs 0.14 [0.2] kg; P < .0001) and similar in schizophrenia and bipolar disorder. Mean changes differed for asenapine versus placebo in triglycerides (1.8 [6.3] vs -12.2 [5.9] mg/dL; P < .01) and fasting glucose (1.9 [1.7] vs -1.6 [1.5] mg/dL; P < .05). In the olanzapine-controlled trials, weight change was significantly lower with asenapine than with olanzapine (0.9 [0.1] vs 3.1 [0.2] kg; P < .0001). Changes associated with asenapine were lower than those with olanzapine in fasting glucose (2.0 vs 3.3 mg/dL), total cholesterol (-0.4 [1.1] vs 6.2 [1.2] mg/dL; P < .0001), low-density lipoprotein cholesterol (-0.3 [1.1] vs 3.1 [1.2] mg/dL; P < .01), and triglycerides (-0.9 [5.4] vs 24.3 [5.8] mg/dL; P < .0001). CONCLUSIONS: Asenapine was associated with greater weight gain and glucose changes than placebo and not associated with a meaningful change in triglycerides or cholesterol levels. Asenapine was not significantly different from olanzapine in change in glucose levels and lower than olanzapine with respect to triglycerides, weight gain, and increased cholesterol.""",1
13396,24502384,Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation,"""The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1?mL/min (95% confidence interval [CI] -1.3, 21.5?mL/min, p?=?0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4?mL/min/1.73?m(2) (95% CI -0.4, 18.9, p?=?0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5?mL/min/1.73?m(2) (95% CI -1.1, 17.9, p?=?0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p?=?1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.""",1
13397,24504810,"Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study","""OBJECTIVE: To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids. METHODS: This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period. RESULTS: There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an ?20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment. CONCLUSION: Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.""",1
13398,24508124,Ulipristal acetate for emergency contraception: postmarketing experience after use by more than 1 million women,"""OBJECTIVE: To describe the safety of ulipristal acetate in emergency contraception. STUDY DESIGN: Postmarketing pharmacovigilance data collection. RESULTS: A total of 553 women experienced 1049 adverse drug reactions. The most frequent (n,%) were pregnancies (282, 6.8%); nausea, abdominal pain and vomiting (139, 13.3%); headache, dizziness (67, 6.4%); and metrorrhagia, menses delay and breast symptoms (84, 8.0%). Including data from clinical trials, 376 pregnancies have been reported in total, 232 (62%) with a known outcome: 28 live births (29 newborns), 34 miscarriages, 151 induced abortions, 4 ectopics and 15 which are ongoing. CONCLUSIONS: No safety concern emerges from a sizable database of reported adverse reactions following ulipristal acetate exposure among varying ethnicities and regions. Postapproval data confirm the safety profile described during the clinical trials. IMPLICATIONS: Use of ulipristal acetate for emergency contraception in a variety of settings and among diverse populations indicate that it is safe and without unexpected or serious adverse events.""",1
13399,24511438,Toxic effects of psychotropics related to possible p450 enzyme inhibition by kava: report of 2 cases,"""Kava is an herbal remedy popular for centuries among native Pacific Islanders for its sedative effects and use in religious ceremonies. Kava gained popularity in Western countries due to its anxiolytic properties; however, very little is known about potential adverse reactions to kava other than reports of hepatotoxicity. Two cases of patients seen on the psychiatric emergency and consult service who developed severe side effects from psychotropic medications in the context of kava use are presented. In both cases, kava use may have affected the metabolism of the psychotropic medications, leading to serious side effects. Growing research indicates that kava most likely alters concentrations of coadministered psychotropics possibly by inhibiting cytochrome P450 enzymes. This case series highlights the need for greater awareness of safety issues among kava users who also take medications that, when combined with kava, can be life-threatening at toxic levels. Pharmacogenomic testing along with further research about kava and its metabolites could help determine a pharmacologic solution for patients who require psychotropic medications but who would like to preserve cultural traditions and religious practices.""",1
13400,24516026,Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia,"PURPOSE: Asparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults. PATIENTS AND METHODS: Between 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m(2) per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses. RESULTS: The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia and transaminitis, occasionally resulting in subsequent treatment delays. All toxicities resolved spontaneously. Forty-five percent of patients were able to receive all six doses of pegaspargase, and 61% received ? three doses. In only 20% of patients, the drug was discontinued after pegaspargase-related serious toxicity. Ninety-six percent achieved complete remission, almost all within 4 weeks, and a low induction death rate was seen. Seven-year disease-free and overall survival were 58% and 51%, respectively. CONCLUSION: Our dose and schedule of pegaspargase, based on its pharmacokinetics, and our detailed toxicity profile could be applied for safer adaptation of pediatric ALL protocols in adults.",1
13401,24518798,Significance of alanine aminotransferase levels in patients admitted for cocaine intoxication,"BACKGROUND: Experimental studies in animal models and case reports in humans have described the hepatotoxic potential of cocaine. However, there are few data regarding the clinical and laboratory characteristics of patients admitted for cocaine intoxication, particularly regarding the status of the liver enzymes. GOAL: To investigate the significance of alanine aminotransferase (ALT) levels in individuals hospitalized for acute cocaine intoxication. METHODS: Retrospective study with standardized chart review that included patients admitted between January 2003 and December 2010. Bivariate analyses were used to investigate factors associated with ALT above the upper tertile according to gender. Cases of marked ALT elevation were described in detail. RESULTS: Ninety-three patients were included (79% men, mean age of 27.73?9.97 y). ALT above the upper tertile was associated with higher aspartate aminotransferase (AST), creatine phosphokinase, creatinine, and international normalized ratio. Higher levels of ALT were also related to acute renal failure and death. Five subjects had severe ALT elevation during follow-up and all had evidence of hepatocellular dysfunction (jaundice, prolonged prothrombin time with or without hepatic encephalopathy), rhabdomyolysis, and acute renal failure. AST/ALT ratio <2 was present in 2 subjects with severe ALT elevation at admission, but AST/ALT ratio >2 was observed in 3 cases with evidence of progression to acute liver injury. CONCLUSIONS: In acute cocaine intoxication, higher ALT levels were associated with evidence of muscle damage, progression to acute renal failure, and death. Severe liver damage was observed in 5% of the sample and was associated with rhabdomyolysis and renal failure in all cases.",1
13402,24523439,"A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors","PURPOSE: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed. RESULTS: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ? the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation. CONCLUSIONS: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression.",1
13403,24528208,Milestones in understanding platelet production: a historical overview,"The discovery of thrombopoietin (TPO, also termed THPO) in 1994 was a major achievement in understanding the regulation of platelet production. In prior decades, physiological studies had demonstrated that platelets were produced from bone marrow megakaryocytes and that the megakaryocytes responded to thrombocytopenia by increasing their number, size and DNA ploidy. In 1958, it was proposed that a 'thrombopoietin' must exist that regulated this interaction between the circulating platelet mass and the bone marrow megakaryocytes. After over three decades of effort, TPO was finally purified by five independent laboratories. TPO stimulated megakaryocyte colony-forming cell growth and increased the number, size and ploidy of megakaryocytes. When the genes for TPO or TPO receptor were eliminated in mice, megakaryocytes grew and platelets were made, but at 15% of their normal number. A first generation of recombinant human (rh) TPO molecules [rhTPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rhMGDF)] rapidly entered clinical trials in 1995 and increased platelet counts in humans undergoing non-myeloablative chemotherapy but not in those undergoing stem cell transplantation. Antibodies developed against PEG-rhMGDF and development of these recombinant thrombopoietins ended. A second generation of TPO receptor agonists (romiplostim and eltrombopag) was then developed. Neither of these TPO receptor agonists demonstrated any significant untoward effects and both are now licensed in many countries for the treatment of immune thrombocytopenia. This review describes the significant experiments that have surrounded the discovery of TPO and its clinical development.",1
13404,24530203,Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood,"Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.",1
13405,24532785,Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results,"BACKGROUND: Clinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting. OBJECTIVE: To evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings. RESULTS: In this 5-year interim analysis, 4821 patients were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11-44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years. Lower annualised relapse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower baseline EDSS scores, and in patients with lower prenatalizumab relapse rates. Mean EDSS scores remained unchanged up to 5 years. CONCLUSIONS: Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice. TRIAL REGISTRATION NUMBER: NCT00493298.",1
13406,24550331,Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy,"Ceftaroline has been approved for acute bacterial skin infections and community-acquired bacterial pneumonia. Limited clinical experience exists for use outside these indications. The objective of this study was to describe the outcomes of patients treated with ceftaroline for various infections. Retrospective analyses of patients receiving ceftaroline ?72 h from 2011 to 2013 were included. Clinical and microbiological outcomes were analyzed. Clinical success was defined as resolution of all signs and symptoms of infection with no further need for escalation while on ceftaroline treatment during hospitalization. A total of 527 patients received ceftaroline, and 67% were treated for off-label indications. Twenty-eight percent (148/527) of patients had bacteremia. Most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days. A total of 327 (62%) patients were culture positive, and the most prevalent pathogen was Staphylococcus aureus, with a frequency of 83% (271/327). Of these patients, 88.9% (241/271) were infected with methicillin-resistant S. aureus (MRSA). Clinically, 88% (426/484) achieved clinical success and hospital mortality was seen in 8% (40/527). While on ceftaroline, adverse events were experienced in 8% (41/527) of the patients and 9% (28/307) were readmitted within 30 days after discharge for the same infection. Patients treated with ceftaroline for both FDA-approved and off-label infections had favorable outcomes. Further research is necessary to further describe the role of ceftaroline in a variety of infections and its impact on patient outcomes.",1
13407,24551671,A comparative study to evaluate the efficacy and safety of acyclovir and famciclovir in the management of herpes zoster,"BACKGROUND: Over the years, acyclovir has been the oral antiviral agent approved for the treatment of patients with acute herpes zoster,Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established but the effects on post herpetic neuralgia are less clear cut. Famciclovir is a new member of guanine nucleoside family of drugs. It is a well absorbed oral form of penciclovir with longer half life. This was a open comparative randomized study carried out to compare the safety and efficacy of famciclovir administered at 250mg thrice daily with acyclovir 800mg five times daily for the treatment of acute uncomplicated herpes zoster in immunocompetent individuals aged above 40 years. AIM: To assess the clinical profile of Herpes zoster, compare the efficacy and safety of acyclovir and famciclovir in the treatment of herpes zoster and to describe the effectiveness of acyclovir and famciclovir preventing post herpetic neuralgia. METHODS: A total of 100 newly zoster were randomized in 1:1 ratio into acyclovir and famciclovir groups after inclusion criteria were satisfied.Treatment was initiated within 72 hrs of onset of symptoms and was continued for 7 days and evaluated at the end of each week up to six weeks period for full crusting of the lesions, complete healing of the lesion and loss of acute pain. RESULTS: It was observed that famciclovir was as effective as acyclovir with no significant difference in time taken for full crusting, complete healing of lesions or loss of acute pain. Famciclovir was well tolerated with a better safety profile comparable to that of acyclovir. Constipation, headache, nausea and vomiting were the most commonly reported adverse effects, but constipation was considered to have a possible relationship to treatment. CONCLUSION: In conclusion, oral famciclovir administered three times daily for 7 days during acute zoster infection is as effective as acyclovir, administered 800mg five times daily.In addition it offers significant benefit by providing a well tolerated, cost effective, convenient dosage regime and accelerated rate of lesion resolution and a reduced duration of PHN.",1
13408,24554383,Increased incidence of liver enzymes abnormalities in patients treated with isoniazid in combination with disease modifying and/or biologic agents,"Reactivation of latent tuberculosis (LTB) has been described with the use of anti-TNFs. Combined treatment of isoniazid (INH) and disease modifying antirheumatic drugs (DMARDs) can potentially increase the risk of hepatotoxicity. The goal of this study was to investigate the risk of hepatotoxicity in rheumatic patients taking INH while on DMARDs and/or biologics. We reviewed the Institut de Rhumatologie de Montreal database (Rhumadata(R)) for rheumatic patients with positive tuberculin skin test or quantiFERON who took INH between August 2001 and April 2011. Liver function tests (LFTs) were collected at baseline and during therapy, and LFTs up to 9 months prior to INH initiation were used as controls. Of 922 patients screened for LTB, 87 patients tested positive. During INH treatment, 75.9 % were taking DMARDs, 82.8 % were taking biologics. A total of 375 LFTs performed while on INH were compared to 211 available tests collected prior to INH therapy. Twenty-four percent of the patients had abnormal LFTs during INH compared to 12.1 % prior to INH (p = 0.0481). Most of these abnormalities were mild or transient, but 8 % (seven patients) had significant abnormalities leading to INH discontinuation. Among these patients, mean (min, max) was 241 (52, 617) for AST and 262 (92, 669) for ALT. Although the use of INH therapy in combination with DMARDs and/or biologics was generally well tolerated, the rate of LFT abnormalities was higher when patients were exposed to INH, and significant abnormalities were more frequent than reported in the INH literature. It is prudent to closely follow the LFTs of these patients.",1
13409,24559819,Eighteen cases of liver injury following ingestion of Polygonum multiflorum,"""OBJECTIVES: Polygonum multiflorum is a popular Chinese herbal medication. In this case series, we report on 18 otherwise healthy non-viral hepatitis patients who developed liver dysfunction following consumption of P. multiflorum alone. METHODS: Concurrent and retrospective analysis was used in this study. The causality of P. multiflorum in liver injury was graded by the Council for International Organizations of Medical Sciences (CIOMS) toxicity scale. RESULTS: From 2005 to 2012, 18 cases of hepatotoxicity potentially involving P. multiflorum. The median age was 42 years old (range from 18 to 63). Median time of onset of symptoms was 27 days (1-120). Prevailing clinical symptoms were fatigue, loss of appetite and jaundice. Sixteen patients had elevated level of total bilirubin (>21 mol/L); liver enzymes elevated markedly in all patients (ALT>40 U/L, AST>40 U/L, GGT>50 U/L), except for alkaline phosphatase which elevated only in nine patients. Based on the liver enzyme pattern, the type of liver injuries were hepatocellular according to CIOMS. In terms of causality, 14 of 18 patients were evaluated as being highly probable. All patients were responding well to P. multiflorum stoppage, and liver protective-supportive care. CONCLUSIONS: P. multiflorum products can be associated with hepatotoxicity in otherwise healthy non-viral hepatitis infected patients, regardless of herbal processing.""",1
13410,24563479,"A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors","""PURPOSE: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors. EXPERIMENTAL DESIGN: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks. RESULTS: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ?3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ?3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ?3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ?1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed. CONCLUSIONS: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks.""",1
13411,24570131,Considerations regarding the alleged association between Herbalife products and cases of hepatotoxicity: a rebuttal,,1
13412,24573717,Isoniazid hepatotoxicity requiring liver transplantation,,1
13413,24575948,Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome,"""HBsAg-negative/HBcAb-positive haematopoietic stem cell transplant (HSCT) recipients are at high risk of hepatitis B virus (HBV) reactivation. Allogeneic HSCT recipients from years 2000 to 2010 were evaluated in order to study the impact of being HBsAg-negative/HBcAb-positive in this population. Overall, 137 of 764 patients (18%) were HBsAg-negative/HBcAb-positive before HSCT. Overall survival, non-relapse mortality (NRM), acute and chronic graft-vs.-host disease were similar in HBcAb-positive and HBcAb-negative patients. Reactivation occurred in 14 patients (10%) within a median of 19 months after HSCT (range 9-77). Cause-specific hazard for reactivation was decreased in the case of an HBV-immune/exposed donor (HRadjusted = 0.12; 95% CI, 0.02-0.96; p 0.045) and increased in patients who received rituximab treatment (HRadjusted = 2.91; 95%CI, 0.77-10.97; p 0.11). Competing risk analyses documented a protective role of an HBV-immune/exposed donor (p 0.041) and an increased probability associated with the length of treatment with cyclosporine (p <0.001) and treatment with rituximab (but not with low-dose rituximab prophylaxis, p <0.001 at each landmark point). No differences in overall survival and NRM were found between patients with and without HBV reactivation. The donor's immunity was independently and consistently associated with a decreased risk of HBV reactivation, while rituximab and cyclosporine treatments increased the probability.""",1
13414,24576340,Hepatic steatosis secondary to capecitabine: a case report,"INTRODUCTION: There are no known case reports of hepatic steatosis caused by oral fluoropyrimidines such as capecitabine. With increasing use of capecitabine since its approval for the treatment of metastatic colon cancer in 2001, and more recently for adjuvant treatment of colon cancer and treatment of metastatic breast cancer, we can anticipate increased recognition of potential toxicities associated with this 5-fluorouracil derivative. CASE PRESENTATION: We report the case of a 74-year-old Armenian woman who received capecitabine as adjuvant treatment for colon cancer and subsequently developed abnormal liver biochemical tests and radiographic findings in keeping with hepatic steatosis. There was complete reversal of liver enzyme abnormalities with discontinuation of the drug and this patient represents a case of reversible liver injury due to capecitabine. CONCLUSION: In this original case report, capecitabine use was associated with hepatic steatosis. It is important for clinicians to recognize and monitor for this potential toxicity, which may be a cause of abnormal liver enzymes in this patient population.",1
13415,24580023,Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3�years,"""OBJECTIVE: To determine long-term safety and efficacy of adjunctive clobazam for patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients from two randomized controlled trials (Phase II OV-1002 and Phase III OV-1012) were able to enroll in open-label extension (OLE) study OV-1004 beginning in December 2005 and received clobazam until they discontinued (mandatory at 2�years for patients outside the United States) or until study completion in March 2012. Patients in the United States could have received clobazam for 6�years before it became commercially available. Efficacy assessments included changes in rates of drop seizures and total seizures, responder rates (?50%, ?75%, or 100% decreases in seizure frequency vs. baseline), sustained efficacy over time, concomitant antiepileptic drug (AED) use, and global evaluations. Safety assessments included exposure to clobazam, laboratory assessments, physical and neurologic examinations, vital sign monitoring, electrocardiography monitoring, and adverse event reporting. RESULTS: Of 267 patients who enrolled in the OLE, 188 (70%) completed the trial. Two hundred seven patients were from the United States, which was the only country in which patients could be treated with clobazam for >2�years. Forty-four patients were treated with clobazam for 5�years, and 11 for 6�years. Because of the low number of Year 6 patients, this group is not reported separately. Improvements in baseline seizure rates were very stable over the course of the study, with a median 85% decrease in drop seizures at Year 1, 87% at Year 2, 92% at Year 3, 97% at Year 4, and a 91% decrease for patients who had reached Year 5. Similar results were observed for total seizures (79% decrease at both Years 1 and 2, 82% decrease at Year 3, 75% decrease at Year 4, and 85% decrease at Year 5). Responder rates were also stable for the duration of the trial. Of patients who had achieved a ?50% decrease in median drop-seizure frequency from baseline to Month 3, 86% still had that degree of drop-seizure reduction at Year 3 (and 14% lost their initial responses), and 47% were drop-seizure-free. Most patients who had achieved drop-seizure freedom in the original controlled trials remained drop-seizure-free in the OLE. Based on parents' and physicians' ratings of global evaluations, 80% of patients were """"very much improved"""" or """"much improved"""" after 3�years. Of the 43 patients with concomitant AED data who were treated for 5�years, 30% increased, 19% decreased, and 51% had no change in numbers of AEDs versus their Week 4 regimens. The mean modal clobazam dosage was 0.90�mg/kg/day at Year 1 and 0.97�mg/kg/day at Year 5, suggesting that study patients did not need significant increases in dosage over time. The safety profile was what would be expected for clobazam for LGS patients over a 5-year span, and no new safety concerns developed over time. SIGNIFICANCE: In this largest and longest-running trial in LGS, adjunctive clobazam sustained seizure freedom and substantial seizure improvements at stable dosages through 3�years of therapy in this difficult- to-treat patient population. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.""",1
13416,24589497,Riociguat (Adempas) for pulmonary hypertension,,1
13417,24591201,Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study,"""This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.""",1
13418,24592551,Short-term amlodipine induced liver injury : an extremely rare acute complication,,1
13419,24593909,Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury,"Antituberculosis drug-induced liver injury (ATDILI) is the most prevalent hepatotoxicity in many countries. All of the three first-line antituberculosis drugs, isoniazid, rifampicin, and pyrazinamide, may induce hepatic damage, especially isoniazid. The major drug-metabolizing enzyme of isoniazid is N-acetyltransferase (NAT). Other possible enzymes are CYP2E1, glutathione S-transferase (GST) and manganese superoxide dismutase (MnSOD, SOD2). There is evidence that variations of the genes that encode these enzymes may influence the activity of the corresponding drug-metabolizing enzymes. Recent studies have demonstrated that these genetic variations may be associated with the risk of ATDILI. Among them, NAT acetylation status has been most studied. The proposed risk-associated genotypes are NAT2 slow acetylator (without wild-type NAT2*4 allele), CYP2E1 *1A/*1A (homozygous wild type), homozygous null GSTM1 genotype and MnSOD mutant C allele. Although the available data in the field are complex and inconsistent, meta-analyses disclosed that NAT2 slow acetylator status possesses the highest association (odds ratio = 3.18). There are associations of CYP2E1 *1A/*1A and homozygous null GSTM1 genotype with ATDILI by meta-analyses, but the odds ratios were lower than that of NAT2. Of note, there was an ethnic difference in this association. The ATDILI in East Asians seems to have a higher correlation with genetic variations of NAT2, CYP2E1 and GSTM1. However, the meta-analyses could not validate these associations in Caucasians, although some showed positive correlations. To mitigate the crucial ATDILI, this review article underlines the importance of this pharmacogenetic endeavor to identify high-risk patients.",1
13420,24597531,Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans,"CONTEXT: New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate. OBJECTIVE: Characterize ASS in APAP hepatotoxicity. METHODS: ASS was measured in plasma from rodents and humans with APAP hepatotoxicity. RESULTS: In mice, ASS increased before injury, peaked before alanine aminotransferase (ALT) and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all. CONCLUSIONS: ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity.",1
13421,24600226,Long-term efficacy and safety of iloperidone: an update,"Schizophrenia is a devastating neuropsychiatric disease with a worldwide prevalence of approximately 0.5%-1%. Since many patients do not achieve adequate symptom relief from available agents, alternate pharmacotherapeutic approaches are needed. In this context, iloperidone was recently approved by the US Food and Drug Administration for the treatment of schizophrenia. This paper first reviews its pharmacodynamic and pharmacokinetic profiles, emphasizing their clinical relevance. Next, it summarizes the literature on its acute and maintenance efficacy, safety, and tolerability. It then considers pharmacogenetic data which may help to predict response and risk of cardiac arrhythmias with this agent. Finally, it critically positions iloperidone relative to other first- and second-generation antipsychotics.",1
13422,24604476,Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection,"""All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24 ). This study is registered with ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. CONCLUSION: Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083-2091).""",1
13423,24611764,Rheumatoid arthritis complicated with severe liver injury during treatment with abatacept,,1
13424,24615778,A phase 1 study of the PI3K? inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL),"""Idelalisib, an oral inhibitor of phosphatidylinositol-3-kinase ? (PI3K?), was evaluated in a 48-week phase 1 study (50-350 mg daily or twice daily) enrolling 40 patients with relapsed or refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (range, 52-83) and received median of 4 prior therapies (1-14); 17 of 40 patients (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ?3 adverse events (AEs) included (total%/grade ?3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and alanine transaminase or aspartate transaminase elevations (60/20). ORR was 16 of 40 patients (40%), with CR in 2 of 40 patients (5%). Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3K? is a viable strategy and worthy of additional study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT00710528.""",1
13425,24622320,SGLT inhibitors in management of diabetes,"The two main sodium-glucose cotransporters (SGLTs), SGLT1 and SGLT2, provide new therapeutic targets to reduce hyperglycaemia in patients with diabetes. SGLT1 enables the small intestine to absorb glucose and contributes to the reabsorption of glucose filtered by the kidney. SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors with varying specificities for these transporters (eg, dapagliflozin, canagliflozin, and empagliflozin) can slow the rate of intestinal glucose absorption and increase the renal elimination of glucose into the urine. Results of randomised clinical trials have shown the blood glucose-lowering efficacy of SGLT inhibitors in type 2 diabetes when administered as monotherapy or in addition to other glucose-lowering therapies including insulin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Effective SGLT2 inhibition needs adequate glomerular filtration and might increase risk of urinary tract and genital infection, and excessive inhibition of SGLT1 can cause gastro-intestinal symptoms. However, the insulin-independent mechanism of action of SGLT inhibitors seems to offer durable glucose-lowering efficacy with low risk of clinically significant hypoglycaemia at any stage in the natural history of type 2 diabetes. SGLT inhibition might also be considered in conjunction with insulin therapy in type 1 diabetes.",1
13426,24622668,"Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial","BACKGROUND: Metformin is the only first-line oral hypoglycaemic drug for type 2 diabetes recommended by international guidelines with proven efficacy, safety, and cost-effectiveness. However, little information exists about its use in Asian populations. We aimed to ascertain the effectiveness of the ?-glucosidase inhibitor acarbose, extensively adopted in China, compared with metformin as the alternative initial therapy for newly diagnosed type 2 diabetes. METHODS: In this 48-week, randomised, open-label, non-inferiority trial, patients who were newly diagnosed with type 2 diabetes, with a mean HbA1c of 7?5%, were enrolled from 11 sites in China. After a 4-week lifestyle modification run-in, patients were assigned to 24 weeks of monotherapy with metformin or acarbose as the initial treatment, followed by a 24-week therapy phase during which add-on therapy was used if prespecified glucose targets were not achieved. Primary endpoints were to establish whether acarbose was non-inferior to metformin in HbA1c reduction at week 24 and week 48 timepoints. The non-inferiority margin was 0?3%, with an expected null difference in the change from baseline to week 48 in HbA1c. Analysis was done on a modified intention-to-treat population. This study was registered with Chinese Clinical Trial Registry, number ChiCTR-TRC-08000231. FINDINGS: Of the 788 patients randomly assigned to treatment groups, 784 patients started the intended study drug. HbA1c reduction at week 24 was -1?17% in the acarbose group and -1?19% in the metformin group. At week 48, the HbA1c reduction was -1?11% (acarbose) and -1?12% (metformin) with difference 0?01% (95% CI -0?12 to 0?14, p=0?8999). Six (2%) patients in the acarbose group and seven (2%) patients in the metformin group had serious adverse events, and two (1%) and four (1%) had hypoglycaemic episodes. INTERPRETATION: This study provides evidence that acarbose is similar to metformin in efficacy, and is therefore a viable choice for initial therapy in Chinese patients newly diagnosed with type 2 diabetes. FUNDING: Bayer Healthcare (China) and Double Crane Phama.",1
13427,24625554,Efficacy of 5-nitroimidazoles for the treatment of giardiasis: a systematic review of randomized controlled trials,"""BACKGROUND: Giardiasis is one of the most common causes of diarrheal disease worldwide and 5-nitroimidazoles (5-NI) are the most commonly prescribed drugs for the treatment of giardiasis. We evaluated the efficacy of 5-nitroimidazoles (5-NI) in the treatment of giardiasis in a systematic review of randomized controlled trials (RCTs). METHODOLOGY/PRINCIPAL FINDINGS: We conducted a comprehensive literature search in PubMed-Medline, Scopus, Web of Science and Cochrane Library for RCTs evaluating the efficacy of 5-NI vs. control (placebo or active treatment) on parasitological cure in patients with parasitologically-demonstrated giardiasis. The search was performed in May 2013 with no language restriction by two authors independently. The efficacy outcome was parasitological cure, and harmful outcomes were abdominal pain, bitter or metallic taste, and headache. We included 30 RCTs (n?=?3,930). There was a significant and slightly higher response rate with 5-NI in giardiasis treatment (RR 1.06, 95%CI 1.02-1.11, p?=?0.005). There was high heterogeneity among studies (I2?=?72%). The response rates for metronidazole, tinidazole and secnidazole were similar (RR 1.05, 95%CI 1.01-1.09, p?=?0.01; RR 1.32 95%CI 1.10-1.59, p?=?0.003; and RR 1.18 95%CI 0.93-1.449, p?=?0.18, respectively). On subgroup analyses, the response rates did not vary substantially and high heterogeneity persisted (I2?=?57%-80%). Harmful outcomes were uncommon, and 5-NIs were associated with lower risk of abdominal pain, and higher risk of both bitter or metallic taste and headache. CONCLUSIONS: Studies investigating the efficacy of 5-NI in giardiasis treatment are highly heterogeneous. 5-NIs have a slightly better efficacy and worse profile for mild harmful outcomes in the treatment of giardiasis in comparison to controls. Larger high quality RCTs are needed to further assess efficacy and safety profiles of 5-NI.""",1
13428,24630270,Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes,"""OBJECTIVE: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). STUDY DESIGN: UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. RESULTS: Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] mumol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] mumol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. CONCLUSIONS: Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment.""",1
13429,24638012,Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study,"""PURPOSE: Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. PATIENTS AND METHODS: Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. RESULTS: A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. CONCLUSION: These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.""",1
13430,24641566,Axitinib safety in metastatic renal cell carcinoma: suggestions for daily clinical practice based on case studies,"""INTRODUCTION: Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. We review data for axitinib and discuss strategies to manage or prevent adverse events (AEs) and maximize clinical benefit. AREAS COVERED: A literature search identified key advanced RCC trials of axitinib and other targeted therapies. Each author also contributed a clinical case study to illustrate management approaches in patients who received axitinib following sunitinib in the AXIS Phase III trial. Axitinib has demonstrated a predictable and manageable AE profile in clinical trials; most commonly reported treatment-related events are diarrhea, hypertension, fatigue, nausea, vomiting and dysphonia. Case studies demonstrate that successful management requires patient awareness of potential AEs, regular monitoring and dose modification for specific AEs. EXPERT OPINION: Improvement in progression-free survival with axitinib versus sorafenib in a Phase III trial supports preferred selection of axitinib in the second-line setting. The safety profile of axitinib versus mammalian target of rapamycin inhibitors and sorafenib also provides the opportunity to personalize treatment in advanced RCC based on the likelihood for specific AEs to occur and on prior toxicities in the first-line setting.""",1
13431,24647231,Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302),"""BACKGROUND: Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy. OBJECTIVE: Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302. DESIGN, SETTING, AND PARTICIPANTS: Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1). INTERVENTION: Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets ?-spending function was used for OS. Adverse events were summarised descriptively. RESULTS AND LIMITATIONS: With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (?-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports. CONCLUSIONS: The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ?24 mo. TRIAL REGISTRATION: Study COU-AA-302, ClinicalTrials.gov number, NCT00887198. PATIENT SUMMARY: The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.""",1
13432,24650805,Hepatotoxicity of isotretinoin in patients with acne and Gilbert's syndrome: a comparative study,"OBJECTIVES: The objective of our follow-up study is to evaluate liver function tests (LFTs) and lipid profiles in patients with Gilbert's syndrome treated with isotretinoin because of severe acne. SETTING: Dermatology outpatient clinics of three regional hospitals of Ja?n (Spain). PARTICIPANTS: Over 4 years, we included all patients diagnosed with severe acne. Only 37 patients were identified, of which 11 had Gilbert's syndrome. INTERVENTIONS: All patients were treated with isotretinoin and followed-up in our outpatient clinics after 10 and 20 weeks. Patients were subjected to an interview questionnaire which included data on age, gender, complete blood count, coagulation profile, fasting blood glucose, LFTs and lipid profiles. Data and results of patients with severe acne and Gilbert's syndrome were compared with those of 26 patients with only severe acne (control group). PRIMARY OUTCOME: Blood analyses were repeated in the follow-up visits. RESULTS: In patients with Gilbert's syndrome, bilirubin levels showed substantial decrease over the 20-week follow-up, with more decrease after 10 weeks. None of the control group patients had significant increase in total bilirubin levels after 10 and 20 weeks of follow-up. Liver enzymes were maintained within normal levels in both groups. Both study groups did not show significant pathological increase in lipid profile levels. LDL levels were increased in the two study groups, but this increase was less substantial in patients with Gilbert's syndrome. CONCLUSIONS: Our preliminary results suggest that oral isotretinoin could be an effective, safe treatment for patients with Gilbert's syndrome, and may lower bilirubin levels in the first 10 weeks of treatment. Limitations of the study include the small numbers of participants and the fact that it is restricted to one region of Spain.",1
13433,24652320,Update on the biology and treatment options for hairy cell leukemia,"""Hairy cell leukemia (HCL) is an uncommon chronic leukemia of mature B cells. Leukemic B cells of HCL exhibit a characteristic morphology and immunophenotype and coexpress multiple clonally related immunoglobulin isotypes. Precise diagnosis and detailed workup is essential, because the clinical profile of HCL can closely mimic that of other chronic B-cell lymphoproliferative disorders that are treated differently. Variants of HCL, such as HCLv and VH4-34 molecular variant, vary in the immunophenotype and specific VH gene usage, and have been more resistant to available treatments. On the contrary, classic HCL is a highly curable disease. Most patients show an excellent long-term response to treatment with single-agent cladribine or pentostatin, with or without the addition of an anti-CD20 monoclonal antibody such as rituximab. However, approximately 30-40 % of patients with HCL relapse after therapy; this can be treated with the same purine analogue that was used for the initial treatment. Advanced molecular techniques have identified distinct molecular aberrations in the Raf/MEK-ERK pathway and BRAF (V600E) mutations that drive the proliferation and survival of HCL B cells. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. Ongoing and planned clinical trials are assessing various treatment strategies, such as the combination of purine analogues and various anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22 (e.g., moxetumomab pasudotox), BRAF inhibitors, such as vemurafenib, and B-cell receptor signaling inhibitors, such as ibrutinib, which is a Bruton's tyrosine kinase inhibitor. This article provides an update of our current understanding of the pathophysiology of HCL and the treatment options available for patients with classic HCL. Discussion of variant forms of HCL is beyond the scope of this manuscript.""",1
13434,24653794,Human immunodeficiency virus and nodular regenerative hyperplasia of liver: A systematic review,"""AIM: To investigate the diagnosis, pathogenesis, natural history, and management of nodular regenerative hyperplasia (NRH) in patients with human immunodeficiency virus (HIV). METHODS: We performed a systematic review of the medical literature regarding NRH in patients with HIV. Inclusion criteria include reports with biopsy proven NRH. We studied the clinical features of NRH, in particular, related to its presenting manifestation and laboratory values. Combinations of the following keywords were implemented: """"nodular regenerative hyperplasia"""", """"human immunodeficiency virus"""", """"noncirrhotic portal hypertension"""", """"idiopathic portal hypertension"""", """"cryptogenic liver disease"""", """"highly active antiretroviral therapy"""" and """"didanosine"""". The bibliographies of these studies were subsequently searched for any additional relevant publications. RESULTS: The clinical presentation of patients with NRH varies from patients being completely asymptomatic to the development of portal hypertension - namely esophageal variceal bleeding and ascites. Liver associated enzymes are generally normal and synthetic function well preserved. There is a strong association between the occurrence of NRH and the use of antiviral therapies such as didanosine. The management of NRH revolves around treating the manifestations of portal hypertension. The prognosis of NRH is generally good since liver function is preserved. A high index of suspicion is required to make a identify NRH. CONCLUSION: The appropriate management of HIV-infected persons with suspected NRH is yet to be outlined. However, NRH is a clinically subtle condition that is difficult to diagnose, and it is important to be able to manage it according to the best available evidence.""",1
13435,24655568,Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis,"""BACKGROUND: Efficacy of statins has been extensively studied, with much less information reported on their unintended effects. Evidence from randomized controlled trials (RCTs) on unintended effects is often insufficient to support hypotheses generated from observational studies. We aimed to systematically assess unintended effects of statins from observational studies in general populations with comparison of the findings where possible with those derived from randomized trials. METHODS: Medline (1998 to January 2012, week 3) and Embase (1998 to 2012, week 6) were searched using the standard BMJ Cohort studies filter. The search was supplemented with reference lists of all identified studies and contact with experts in the field. We included prospective studies with a sample size larger than 1,000 participants, case control (of any size) and routine health service linkage studies of over at least one year duration. Studies in subgroups of patients or follow-up of patient case series were excluded, as well as hospital-based cohort studies. RESULTS: Ninety studies were identified, reporting on 48 different unintended effects. Statins were associated with lower risks of dementia and cognitive impairment, venous thrombo-embolism, fractures and pneumonia, but these findings were attenuated in analyses restricted to higher quality studies (respectively: OR 0.74 (95% CI 0.62 to 0.87); OR 0.92 (95% CI 0.81 to 1.03); OR 0.97 (95% CI 0.88 to 1.05); OR 0.92 (95% CI 0.83 to 1.02)); and marked heterogeneity of effects across studies remained. Statin use was not related to any increased risk of depression, common eye diseases, renal disorders or arthritis. There was evidence of an increased risk of myopathy, raised liver enzymes and diabetes (respectively: OR 2.63 (95% CI 1.50 to 4.61); OR 1.54 (95% CI 1.47 to 1.62); OR 1.31 (95% CI 0.99 to 1.73)). CONCLUSIONS: Our systematic review and meta-analyses indicate that high quality observational data can provide relevant evidence on unintended effects of statins to add to the evidence from RCTs. The absolute excess risk of the observed harmful unintended effects of statins is very small compared to the beneficial effects of statins on major cardiovascular events.""",1
13436,24661191,Liver injury possibly related to drug interaction after liver transplant: a case report,"WHAT IS KNOWN AND OBJECTIVE: Drug-induced hepatotoxicity is potentially lethal. Liver transplant patients receive a large number of medications and adverse drug reactions, and drug-drug interactions must be closely monitored. CASE SUMMARY: We report a case of a 29-year-old liver transplant patient who suffered liver injury most likely induced by drug interaction between capecitabine and warfarin. Vitamin K1 caused skin rash possibly because of the distribution and metabolism characteristic of the drug in this patient. WHAT IS NEW AND CONCLUSION: Close monitoring and prompt discontinuation of the drugs with high volume of distribution and metabolized through the liver are necessary to avoid drug-drug interaction in liver transplant patients.",1
13437,24662102,"Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis","BACKGROUND: The role of currently available drugs for Alzheimer's disease (AD) has been controversial, with some national formularies restricting their use, and health economists questioning whether the small clinical effects are economically worthwhile. OBJECTIVE: To estimate the efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of AD. METHODS: Double-blind, placebo-controlled, with random assignment to a cholinesterase inhibitor or memantine trials were included into the pooled studies. RESULTS: Cognitive effects were significant for all drugs, ranging from a -1.29 points mean difference (95% CI -2.30 to -0.28) in the 20 mg daily memantine trials to -3.20 points (95% CI -3.28 to -3.12) in the 32 mg daily galantamine group. Only memantine had no effect on the Clinicians' Global Impression of Change scale. No behavioral benefits were observed, except for -2.72 (95% CI -4.92 to -0.52) in the 10 mg daily donepezil group and -1.72 (95% CI -3.12 to -0.33) for 24 mg daily galantamine trial. Only 5 mg daily donepezil had no effect on the function outcome. Compared with placebo, more dropouts and adverse events occurred with the cholinesterase inhibitors, but not with memantine. CONCLUSIONS: Cholinesterase inhibitors and memantine are able to stabilize or slow decline in cognition, function, behavior, and global change.",1
13438,24662957,Ado-trastuzumab emtansine (Kadcyla) for HER2-positive metastatic breast cancer,,1
13439,24662976,Certolizumab pegol (Cimzia) and ustekinumab (Stelara) for psoriatic arthritis,,1
13440,24663031,Macitentan (Opsumit) for pulmonary arterial hypertension,,1
13441,24668331,The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use,"On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph(+)) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph(+) leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication.",1
13442,24669349,Hydroxycut-induced Liver Toxicity,"In the recent era, use of various nutritional supplements is highly encouraged amongst the people of United States. Weight loss supplements are major part of the nutritional supplements and their usage is unregulated in the US. Obesity is a major health concern in the US and Americans spend around $30 billion a year for weight loss supplements. At times, these supplements can be responsible for documented or undocumented adverse drug effects. The health consequences related to these supplements are often overlooked by the general public, even though FDA issues advisories regarding them. One common supplement used for weight loss was Hydroxycut (Iovate Health Sciences Research, Oakville, Ontario, Canada). Hydroxycut was recalled from the market after a FDA warning in May 2009 because of 23 reports of serious health problems ranging from jaundice and elevated liver enzymes to liver damage. 1 This case report adds evidence for Hydroxycut - induced hepatotoxicity. A 27 year old man with right upper quadrant pain and jaundice was found to have elevated liver enzymes and was taking Hydroxycut along with other supplements. Liver biopsy showed drug induced hepatotoxicity. Discontinuation of Hydroxycut dramatically improved liver functions and related symptoms.",1
13443,24670344,Vitamin D intoxication in two brothers: be careful with dietary supplements,"Vitamin D (VitD) intoxication, a well-known cause of hypercalcaemia in children, has renal, cardiac and neurological consequences. Iatrogenic or accidental administrations are the most common causes. We present two cases of hypervitaminosis D due to over-the-counter VitD supplement self-medication. A 12-year-old boy was hospitalised for abdominal pain, constipation and vomiting. Routine biochemistry indicated severe hypercalcaemia and renal failure. Plasma 25-OH VitD level was very high and parathyroid hormone was suppressed. Renal ultrasound showed nephrolithiasis. Hydration, diuretics and prednisone induced a progressive reduction of calcium levels. His brother, who was receiving the same treatment, was hospitalised although asymptomatic. Normal serum calcium and renal function were revealed, while 25-OH VitD was high and parathyroid hormone was suppressed. Renal ultrasound was within the normal range. Examination of the VitD content of the over-the-counter supplement revealed a higher amount than declared. VitD administration implies several risks and must be prescribed only when needed and under strict medical control.",1
13444,24673497,"Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease: results of a pooled analysis of two randomized, double-blind, placebo-controlled trials in Japan","""BACKGROUND: With the increase in the aging population, there is a pressing need to provide effective treatment options for individuals with Alzheimer's disease (AD). Memantine is an N-methyl-D-aspartate receptor antagonist used to treat AD in > 80 countries worldwide, and studies in the USA and Europe have shown it to be effective in improving language deficits; however, there are currently no data on language improvements in Japanese patients treated with memantine. OBJECTIVES: To clarify the efficacy and safety of memantine in Japanese outpatients with moderate to severe AD, using a pooled analysis of two multicenter randomized placebo-controlled trials, a phase 2 dose-finding study and a phase 3 study. RESULTS: The final analysis comprised 633 patients (318 receiving memantine and 315 placebo). Memantine produced better outcomes in terms of Severe Impairment Battery-Japanese version, Clinician's Interview-Based Impression of Change plus-Japanese version, Behavioral Pathology in AD Rating Scale, and language scores, versus placebo. The overall incidence of adverse events and adverse reactions was similar between groups. CONCLUSION: In this pooled analysis of Japanese patients, memantine achieved better outcomes than placebo in terms of cognition, including attention, praxis, visuospatial ability and language, and behavioral and psychological symptoms, including activity disturbances and aggressiveness.""",1
13445,24676202,Acute liver failure in a term neonate after repeated paracetamol administration,"""OBJECTIVE: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. CASE DESCRIPTION: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1 mEq/L), hypoglycemia (18 mg/dL), increased serum aminotransferase activity (AST=4,039 IU/L; ALT=1,087 IU/L) and hyperbilirubinemia (total: 9.57 mg/dL; direct: 6.18 mg/dL) after receiving oral paracetamol (10 mg/kg/dose every 4 hours) for three consecutive days (total dose around 180 mg/kg; serum concentration 36-48 hours after the last dose of 77 ?g/ mL). Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. COMMENTS: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione--which provides greater resistance after overdoses--, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone) that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days.""",1
13446,24679099,Liver toxicity during temozolomide chemotherapy caused by Chinese herbs,"BACKGROUND: Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. CASE PRESENTATION: We report the case of severe liver toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5�cycles without toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no liver toxicity was observed. CONCLUSIONS: We conclude that the observed toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.",1
13447,24680372,"Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial","""BACKGROUND: Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment. METHODS: We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813. FINDINGS: 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38?7 min vs 16?0 min; difference 22?7, 95% CI 16?4 to 29?0; p<0?0001) and sTSO (-18?0 min vs -8?4 min, difference -9?5, -14?6 to -4?5; p=0?0002). INTERPRETATION: Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance. FUNDING: Merck & Co Inc.""",1
13448,24688035,Tedizolid: a new oxazolidinone antimicrobial,"PURPOSE: The mechanism of action, pharmacokinetics, pharmacodynamics, and clinical efficacy and safety of an investigational second-generation oxazolidinone are reviewed. SUMMARY: Tedizolid is a protein synthesis inhibitor in clinical development for the treatment of gram-positive infections. Similar to linezolid, tedizolid works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. Tedizolid has demonstrated potent in vitro activity against multidrug-resistant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, and vancomycin-resistant enterococci (VRE), including some linezolid-resistant strains. Tedizolid has a favorable pharmacokinetic profile that allows for once-daily dosing and easy i.v.-to-oral conversion. Unlike linezolid, tedizolid has not been shown to interact with serotonergic agents in clinical studies. Two Phase III studies in patients with acute bacterial skin and skin structure infections have demonstrated the noninferiority of 6 days of tedizolid therapy (200 mg i.v. or orally once daily) relative to 10 days of linezolid therapy. In clinical trials to date, overall rates of treatment-related adverse effects with linezolid and tedizolid were comparable (40.8% versus 43.3%), with nausea being the most commonly reported adverse effect associated with tedizolid use (16% of patients). Planned studies will investigate tedizolid's potential role in the treatment of community-acquired bacterial pneumonia, hospital-acquired/ventilator-associated bacterial pneumonia, and bacteremia. CONCLUSION: Tedizolid is an investigational oxazolidinone antibiotic for the treatment of multidrug-resistant gram-positive pathogens such as MRSA, Streptococcus pneumoniae, and VRE, including some linezolid-resistant strains.",1
13449,24691094,"Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab","""OBJECTIVES: The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients�with hypercholesterolemia in a phase III trial. BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced LDL-C in phase II trials. METHODS: Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol (LDL-C)�?100 and�<190 mg/dl and Framingham risk scores�?10% were randomized (1:1:1:1:2:2) to oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly. RESULTS: A total of 614 patients were randomized and administered doses. Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p�< 0.001 for all comparisons). Evolocumab treatment also favorably altered other lipoprotein levels. Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: In the largest monotherapy trial using a PCSK9 inhibitor to date, evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia. (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid�Levels-2 [MENDEL-2]; NCT01763827).""",1
13450,24692527,"Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies","""OBJECTIVE: To describe the longterm safety and efficacy profile of tofacitinib in patients with moderate to severe active rheumatoid arthritis (RA). METHODS: Data were pooled from 2 open-label studies (NCT00413699, NCT00661661) involving patients who had participated in qualifying phase I, II, or III index studies of tofacitinib. Safety data included over 60 months of observation; efficacy data are reported up to Month 48. Treatment was initiated with tofacitinib 5 or 10 mg twice daily. Primary endpoints were adverse events (AE) and laboratory safety data. Secondary endpoints included American College of Rheumatology (ACR) response rates, and Disease Activity Score (28 joints) (DAS28)-4[erythrocyte sedimentation rate (ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments. RESULTS: Overall, 4102 patients were treated for 5963 patient-years; mean (maximum) treatment duration was 531 (1844) days; 20.8% of patients discontinued treatment over 60 months. The most common AE were nasopharyngitis (12.7%) and upper respiratory tract infection (10.5%). Serious AE were reported in 15.4% of patients with an exposure-estimated incidence rate of 11.1 events/100 patient-years. Serious infections were reported in 4.5% of patients with an exposure-estimated incidence rate of 3.1 events/100 patient-years (95% CI: 2.66-3.55). Mean values for laboratory variables were stable over time and consistent with phase II and III studies. Persistent efficacy was demonstrated through Month 48, as measured by ACR response rate (ACR20/50/70) DAS28-4-ESR, and HAQ-DI. Safety and efficacy were similar for patients receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs. CONCLUSION: Tofacitinib demonstrated consistent safety and persistent efficacy over 48 months in patients with RA.""",1
13451,24694233,Human leukocyte antigen (HLA) pharmacogenomic tests: potential and pitfalls,"Adverse drug reactions involving a range of prescribed drugs and affecting the skin, liver and other organs show strong associations with particular HLA alleles. For some reactions, HLA typing prior to prescription, so that those positive for the risk allele are not given the drug associated with the reaction, shows high positive and negative predictive values. The best example of clinical implementation relates to the hypersensitivity reaction induced by the anti-HIV drug abacavir. When this reaction is phenotyped accurately, 100% of those who develop it are positive for HLA-B*57:01. Drug regulators worldwide now recommend genotyping for HLA-B*57:01 before abacavir is prescribed. Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrosis can be induced by carbamazepine and other anticonvulsant drugs. In certain East Asians, these reactions are significantly associated with HLA-B*15:02, and typing for this allele is now recommended prior to carbamazepine prescription in these populations. Other HLA associations have been described for skin rash induced by carbamazepine, allopurinol and nevirapine and for liver injury induced by flucloxacillin, amoxicillin-clavulanate, lapatanib, lumiracoxib and ticlopidine. However, the predictive values for typing HLA alleles associated with these adverse reactions are lower. Clinical implementation therefore seems unlikely. Performing HLA typing is relatively complex compared with genotyping assays for single nucleotide polymorphisms. With emphasis on HLA-B*57:01, the approaches used commonly, including use of sequence-specific oligonucleotide PCR primers and DNA sequencing are considered, together with their successful implementation. Genotyping single nucleotide polymorphisms tagging HLA alleles is a simpler alternative to HLA typing but appears insufficiently accurate for clinical use.",1
13452,24694531,"Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab","""OBJECTIVES: This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in�hypercholesterolemic patients who are unable to tolerate effective statin doses. BACKGROUND: Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. METHODS: The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the�mean of weeks 10 and�12, and at week 12. RESULTS: Three hundred seven patients (age 62 ? 10 years; LDL-C 193 ? 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p�<0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the�largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905).""",1
13453,24697745,Vanishing bile duct-like syndrome in a patient with Hodgkin lymphoma - pathological development and restitution,,1
13454,24699910,Phase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancer,"""Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ?12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m(2) IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ?6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1-43); 6 (11 %) received treatment for ?12 months. ORR was 29 % (95 % CI 17.3-42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.""",1
13455,24703047,"Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study","""BACKGROUND: As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs. METHODS: We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ?18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0?6 mg once daily titrated to 1?2 mg at week 1 and 1?8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0?3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894. FINDINGS: 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0?78% (95% CI -0?87 to -0?69) in the albigludite group and -0?99% (-1?08 to -0?90) in the liraglutide group; treatment difference was 0?21% (0?08-0?34; non-inferiority p value=0?0846). Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide (12?9% vs 5?4%; treatment difference 7?5% [95% CI 3?6-11?4]; p=0?0002), whereas the opposite was the case for gastrointestinal events, which occurred in 49?0% of patients in the liraglutide group versus 35?9% in the albiglutide group (treatment difference -13?1% [95% CI -19?9 to -6?4]; p=0?00013). INTERPRETATION: Patients who received once-daily liraglutide had greater reductions in HbA1c than did those who received once-weekly albiglutide. Participants in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than did those in the liraglutide group. FUNDING: GlaxoSmithKline.""",1
13456,24704719,Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis,"BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n�= 299) or boceprevir (n�= 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.",1
13457,24707412,Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease: A Case Series and Review of the Literature,"Background. Biologic therapy to inhibit tumor necrosis factor-alpha (TNF- ? ) is an effective, safe treatment for patients with inflammatory bowel disease (IBD). All TNF- ? inhibitors have been associated with liver toxicity, but many of these cases have been reported in patients receiving therapy for rheumatologic disease. Herein we report the first single-center case series of TNF- ? antagonist related liver injury in patients with IBD. Methods. A retrospective case series was performed at the Henry Ford Inflammatory Bowel Diseases Center. IRB approval was obtained. Results. 2 patients were treated with infliximab, whereas the 3rd patient was treated with adalimumab for IBD. All 3 patients had negative viral markers, normal autoimmune serologies, and normal biliary imaging studies. Liver biopsy was performed in all 3 patients, and evidence of portal inflammation was seen. Liver enzymes normalized after discontinuation of therapy in all patients, and no long term effects have been observed. One patient was successfully transitioned from infliximab to adalimumab without relapse of either IBD or liver injury. Conclusion. Liver injury secondary to TNF- ? antagonist is an underrecognized, important clinical entity with potentially serious consequences. The mechanism of drug-induced injury is idiosyncratic. Larger cohort studies are needed to establish risk factors and injury patterns related to hepatotoxicity in these patients.",1
13458,24708414,A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning,"""INTRODUCTION: Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. METHODS: This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. RESULTS: Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. CONCLUSIONS: Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.""",1
13459,24718886,Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer,"""BACKGROUND: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. PATIENTS AND METHODS: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. RESULTS: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6 months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70-0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis. CONCLUSIONS: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.""",1
13460,24720702,Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis,"""BACKGROUND: High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS: In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS: The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS: Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).""",1
13461,24720932,Dabrafenib for the treatment of melanoma,"INTRODUCTION: Approximately 50% of patients with cutaneous melanoma have an activating mutation in BRAF kinase, leading to constitutive activation of the mitogen-activated protein kinase pathway and unregulated cell growth. Selective inhibitors of the mutated BRAF kinase produce response rates of approximately 50% with median progression-free survival of 6 - 7 months. BRAF-blocking therapies work rapidly, with responses seen within 2 weeks after therapy initiation, and they are associated with generally mild toxicities. The BRAF inhibitor dabrafenib recently was approved for use in patients with BRAF V600-mutated metastatic melanoma. AREAS COVERED: This article discusses the mechanisms of action and pharmacokinetic and pharmacodynamic changes as well as clinical efficacy and safety of dabrafenib for treatment of patients with advanced melanoma including unresectable stage IIIc and stage IV patients who harbor a BRAF V600 mutation. Clinical trial data are reviewed, and efficacy of dabrafenib in patients with brain metastases and in combination with the MEK inhibitor trametinib is discussed. EXPERT OPINION: Despite rapid and significant tumor reduction in a majority of patients with BRAF-mutant metastatic melanoma who are treated with dabrafenib, this drug's use as a single agent is limited because of its relatively short duration of response. Various combinations with drug(s) inhibiting other target kinases and/or with immunomodulating agent(s) will likely be the standard in the near future.",1
13462,24725236,Therapy for hepatitis C--the costs of success,,1
13463,24725238,Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection,"""BACKGROUND: Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS: We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).""",1
13464,24727250,Safety of dronedarone in routine clinical care,"""OBJECTIVES: The aim of this study was to examine mortality and liver disease among patients exposed to dronedarone. BACKGROUND: There has been concern about the safety of dronedarone, especially for patients with heart failure and permanent atrial fibrillation (AF). There have also been suspicions about liver toxicity. METHODS: All 174,995 patients with a diagnosis of AF during 2010 to 2012 were identified in the Swedish Patient Register. Of these, 4,856 patients had received dronedarone according to the Swedish Drug Register, and 170,139 patients who had not were used as a control population. Mean follow-up was 1.6 years, with a minimal follow-up of 6 months. RESULTS: Patients prescribed dronedarone were younger (age 65.5 years vs. 75.7 years, p < 0.0001) and healthier than control patients. The annual mortality rate among patients who received dronedarone was 1.3% compared with 14.0% in the control population. There were no sudden cardiac deaths and no deaths related to liver failure among patients who received treatment with dronedarone. After propensity score matching and adjustment for cofactors, patients who received dronedarone had lower mortality than other AF patients (hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.33 to 0.51). Dronedarone patients with heart failure had lower mortality than other heart failure patients (HR: 0.40; 95% CI: 0.30 to 0.53). They also had lower mortality than expected from the general population (standardized mortality ratio: 0.67; 95% CI: 0.55 to 0.78), which indicates the selection of low-risk patients. The risk of liver disease was not increased (HR: 0.57; 95% CI: 0.34 to 0.92). CONCLUSIONS: Dronedarone, as prescribed to AF patients in Sweden, has not exposed patients to increased risks of death or liver disease.""",1
13465,24727884,Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial,"""AIMS: The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization. METHODS AND RESULTS: We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding. CONCLUSION: In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.""",1
13466,24730465,Prospective long-term study of hepatitis B virus reactivation in patients with hematologic malignancy,"""BACKGROUND AND AIM: To elucidate the clinical characteristics of hepatitis B virus reactivation (HBV-R), we performed a prospective long-term study of patients with hematologic malignancy, including both hepatitis B virus (HBV) carriers and those with resolved HBV infection. METHODS: Twenty-one patients with hematopoietic stem-cell transplants (HSCT) and 36 patients given rituximab-based chemotherapy were enrolled. Entecavir was administered prophylactically to eight patients with HBV surface antigen (HBsAg). HBV-DNA was measured every month in 49 patients with resolved HBV infection, and preemptive therapy was given to eight patients with HBV-R. RESULTS: HBV-R developed in five (26%) of 19 patients with HSCT and three (10%) of 30 patients given rituximab-based chemotherapy. HBV-R occurred a median of 3 months (range: 2-10) after the end of rituximab-based chemotherapy and 22 months (range: 9-36) after HSCT. HBV-R did not develop in patients with an antibodies against HBsAg (anti-HBs) titer exceeding 200?mIU/mL at baseline. Mutations in the """"a"""" determinant region with amino acid replacement were detected in four of the eight patients with HBV-R. Preemptive therapy prevented severe hepatitis related to HBV-R. Entecavir treatment was stopped in four patients with HBV-R. Since the withdrawal of entecavir, HBV-DNA has not been detected in two patients persistently positive for anti-HBs. No patient had fatal hepatitis. CONCLUSIONS: Proper management of patients with HBsAg or resolved HBV infection prevented fatal hepatitis related to HBV-R in patients who received immunosuppressive or cytotoxic therapy. Entecavir could be safely discontinued in patients with HBV-R who had acquired anti-HBs.""",1
13467,24733135,Investigation of pegloticase-associated adverse events from a nationwide reporting system database,"PURPOSE: Pegloticase-associated adverse events reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database in the United States were evaluated. METHODS: Retrospective data-mining analysis of FAERS case reports listing Krystexxa or pegloticase as the suspect drug and specific adverse events (cardiovascular events, infusion-related reactions, gout flares, and anaphylaxis) was conducted from the drug's approval date (September 14, 2010) through August 27, 2012. Initial and follow-up reports with the same primary linked identification number were identified as unique to each patient case. When multiple reports for the same patient were identified with a common case number, the report with the most recent date was used to eliminate duplicate reports. Bayesian confidence propagation neural network methodology was used to identify signals of drug-associated adverse events. A potential signal for drug-adverse event reports is generated when the lower limit of the 95% two-sided confidence interval of the information component is greater than 0. RESULTS: A total of 118 unique cases of adverse events involving pegloticase in the United States were identified during the study period. Fourteen reports were related to pegloticase-associated cardiovascular events, and 35 were related to pegloticase-associated infusion-related reactions. Twenty-six reports were related to pegloticase-associated gout, and 11 were reports of pegloticase-associated anaphylaxis. Bayesian statistics identified potential signals for all pegloticase-associated adverse events (cardiovascular events, infusion reactions, gout flares, and anaphylaxis). CONCLUSION: Analysis of pegloticase-associated adverse events submitted to the FAERS database found that cardiovascular events, infusion-related reactions, gout flares, and anaphylaxis occurred more frequently than was statistically expected.",1
13468,24733796,"Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer","""PURPOSE: Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) -targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR). RESULTS: Sixty-four patients (43 patients in the second-line or greater setting [advanced MBC]; 21 patients in the first-line setting [first-line MBC]) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ? 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively). CONCLUSION: T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.""",1
13469,24737913,Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis,"""OBJECTIVE: To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ? 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ? 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as """"moderate"""" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as """"low."""" There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001]. CONCLUSION: The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.""",1
13470,24739897,"Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study","BACKGROUND: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. METHODS: This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. FINDINGS: 67 men were enrolled into the study. 62 patients (92.5%, 95% CI 86.2-98.8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. INTERPRETATION: Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer.",1
13471,24747798,Safety and efficacy of boceprevir/peginterferon/ribavirin for HCV G1 compensated cirrhotics: meta-analysis of 5 trials,"""BACKGROUND & AIMS: HCV-infected cirrhotics may urgently need therapy but are often under-represented in clinical trials resulting in limited data to guide their management. We performed a meta-analysis of well-compensated cirrhotic patients from five Phase 3 trials. METHODS: Patients received P/R (peginterferon/ribavirin; 4 weeks) followed by BOC (boceprevir)/P/R or P/R for 24, 32, or 44 weeks. Sustained virologic response (SVR) rates were calculated by Metavir score. Multivariate logistic regression (MLR) models identified baseline and on-treatment predictors of SVR. Safety was evaluated by adverse-event (AE) reporting and laboratory monitoring. RESULTS: Pooled meta-estimates for SVR rates (95% confidence interval) in 212 F4 (cirrhotic) patients were 55% (43, 66) with BOC/P/R vs.17% (0, 41) with P/R. MLR identified 4 predictors of SVR in F3/F4 patients: undetectable HCV-RNA at treatment week (TW) 8; ? 1 log10 decline in HCV-RNA from baseline at TW4; male; and baseline HCV-RNA ? 800,000 IU/ml. SVR rate was 89% (65/73) in F4 patients who were HCV-RNA undetectable at TW8. No F3 (0/5) or F4 (0/17) patients with <3 log10 decline and detectable HCV-RNA at TW8 achieved SVR. Anemia and diarrhea occurred more frequently in cirrhotic than non-cirrhotic patients. Serious AEs, discontinuations due to an AE, interventions to manage anemia, infections, and thrombocytopenia occurred more frequently in cirrhotics with BOC/P/R than P/R. Potential hepatic decompensation and/or sepsis were identified in 2 P/R and 3 BOC/P/R recipients. CONCLUSIONS: BOC/P/R appears to have a generally favorable benefit-risk profile in compensated cirrhotic patients. SVR rates were particularly high in cirrhotic patients with undetectable HCV-RNA at TW8.""",1
13472,24755475,"Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study","BACKGROUND: Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study. CASE PRESENTATION: On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 ?M. Over the next three days, although blood cultures remained negative, the patient's condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity. CONCLUSIONS: After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.",1
13473,24757661,Allopurinol-induced DRESS syndrome mimicking biliary obstruction,"An 84-year-old man was admitted to our hospital with fever, jaundice, and itching. He had been diagnosed previously with chronic renal failure and diabetes, and had been taking allopurinol medication for 2 months. A physical examination revealed that he had a fever (38.8), jaundice, and a generalized maculopapular rash. Azotemia, eosinophilia, atypical lymphocytosis, elevation of liver enzymes, and hyperbilirubinemia were detected by blood analysis. Magnetic resonance cholangiography revealed multiple cysts similar to choledochal cysts in the liver along the biliary tree. Obstructive jaundice was suspected clinically, and so an endoscopic ultrasound examination was performed, which ruled out a diagnosis of obstructive jaundice. The patient was diagnosed with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome due to allopurinol. Allopurinol treatment was stopped and steroid treatment was started. The patient died from cardiac arrest on day 15 following admission.",1
13474,24759293,Conjugated estrogens/bazedoxifene (Duavee) for menopausal symptoms and prevention of osteoporosis,,1
13475,24761710,Methylprednisolone-induced liver injury: a diagnostic challenge,,1
13476,24768112,"Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial","""BACKGROUND: Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (?18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0?5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS: Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10?8 months) than in the placebo group (5?8 months; hazard ratio [HR] 0?59, 95% CI 0?45-0?76; p<0?0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98?6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87?6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76?3%), diarrhoea (68?6%), alopecia (67?1%), and rash or desquamation (50?2%). INTERPRETATION: Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).""",1
13477,24777716,Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria,"BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is rare in children, but represents a similarly serious and chronic condition as in adults. Children with PNH frequently experience complications of chronic hemolysis, recurrent thrombosis, marrow failure, serious infections, abdominal pain, chronic fatigue, and decreased quality of life with reduced survival. The terminal complement inhibitor eculizumab is proven to be effective and safe in adults and approved by the FDA for treatment of PNH. PROCEDURE: This 12-week, open-label, multi-center phase I/II study evaluated pharmacokinetics, pharmacodynamics, efficacy, and safety in seven children with PNH 11-17 years of age. Eculizumab was intravenously administered at 600 mg weekly for 4 weeks, 900 mg in week 5, and 900 mg every 2 weeks thereafter (http://clinicaltrials.gov NCT00867932). RESULTS: Eculizumab therapy resulted in complete and sustained inhibition of hemolysis in all participants with a reduction of lactate dehydrogenase to normal levels. All hematological parameters stabilized. No definitive, study drug-related adverse events were observed. Only one severe SAE of hospitalization due to aplastic anemia occurred, which was not study drug-related. CONCLUSION: Eculizumab appears to be a safe and effective therapy for children with PNH.",1
13478,24778392,Nodular Regenerative Hyperplasia After Treatment With Trastuzumab Emtansine,,1
13479,24778403,Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies,"Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.",1
13480,24787143,"A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults","The efficacy of vortioxetine 10 and 20�mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18-65�yr, N�=�602) were randomized (1:1:1) to vortioxetine 10 or 20�mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-?sberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10�mg, p�<�0.0001) and 0.33 (vortioxetine 20�mg, p�<�0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 (10�mg: p�<�0.0001) and -6.7 (20�mg: p�<�0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.",1
13481,24789171,Approval after phase I: ceritinib runs the three-minute mile,,1
13482,24792990,Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction,"Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.",1
13483,24794677,"Internet slimming, thyrotoxicosis and the liver",,1
13484,24795199,Therapy of hepatitis C--back to the future,,1
13485,24795201,Sofosbuvir and ribavirin in HCV genotypes 2 and 3,"""BACKGROUND: In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection. METHODS: We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus. CONCLUSIONS: Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. (Funded by Gilead Sciences; VALENCE ClinicalTrials.gov number, NCT01682720.).""",1
13486,24799836,Patterns of acetaminophen use exceeding 4 grams daily in a hospitalized population at a tertiary care center,"Unintentional acetaminophen-induced hepatotoxicity has been increasingly recognized as a significant problem, prompting increased scrutiny and restrictions from the US Food and Drug Administration on products combining acetaminophen with narcotics. Patterns of acetaminophen use have not previously been reported in the hospitalized patient population, which may be especially vulnerable to liver injury. We aimed to quantify the frequency at which acetaminophen dosing exceeded the recommended maximum of 4 g/day in hospitalized patients. This was a retrospective, single-center, cohort study at a large tertiary care academic hospital. We queried our inpatient electronic medical record database to identify patients admitted between 2008 and 2010 who were receiving cumulative daily acetaminophen doses exceeding 4 g on at least 1 hospital day. Of 43,761 admissions involving acetaminophen administration, the recommended maximum cumulative daily dose of 4 g was exceeded in 1119 (2.6%) cases. Patients who were administered a larger number of acetaminophen-containing medications were more likely to receive doses in excess of the recommended maximum. Alanine aminotransferase (ALT) levels were checked within 14 days following acetaminophen exposure in excess of 4 g in 35 (3.1%) cases. Excessive acetaminophen dosing of hospitalized patients, who may be at increased risk for acetaminophen-induced hepatotoxicity, occurred in a minority of patients. The use of multiple acetaminophen-containing medication formulations contributed to excessive dosing. ALT level monitoring in this group was infrequent, precluding assessment of biochemical evidence of liver injury. This cohort of patients may represent an ideal population for further prospective study with more intensive and longer-term biochemical monitoring to assess for evidence of liver injury.",1
13487,24801642,Daptomycin-induced rhabdomyolysis and acute liver injury,"""Daptomycin use is a known cause of rhabdomyolysis; its role in liver injury is less certain. We report a case of daptomycin-induced rhabdomyolysis with liver injury. This report indicates a role for liver function monitoring while receiving daptomycin, as well as the importance of promptly considering drug toxicities in acute and emergency care settings.""",1
13488,24809388,Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview,"""INTRODUCTION: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events. AREAS COVERED: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs. EXPERT OPINION: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium.""",1
13489,24811412,Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments,"""OBJECTIVES: To describe the potential benefits and harms of zanamivir. DESIGN: Systematic review of clinical study reports of randomised placebo controlled trials and regulatory information DATA SOURCES: Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised placebo controlled trials in adults and children who had confirmed or suspected exposure to natural influenza. MAIN OUTCOME MEASURES: Time to first alleviation of symptoms, influenza outcomes and complications, admissions to hospital, and adverse events in the intention to treat (ITT) population. RESULTS: We included 28 trials in stage 1 (judgment of appropriate study design) and 26 in stage 2 (formal analysis). For treatment of adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, P<0.001, I(2)=9%), which equates to an average 14.4 hours' reduction, or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia (risk difference 0.17%, -0.73% to 0.70%) or radiologically confirmed pneumonia (-0.06%, -6.56% to 2.11%) in adults. The effect on pneumonia in children was also not significant (0.56%, -1.64% to 1.04%). There was no significant effect on otitis media or sinusitis in both adults and children, with only a small effect noted for bronchitis in adults (1.80%, 0.65% to 2.80%), but not in children. There were no data to assess effects on admissions in adults and children. Zanamivir tended to be well tolerated. In zanamivir prophylaxis studies, symptomatic influenza in individuals was significantly reduced (1.98%, (0.98% to 2.54%); reducing event rates from 3.26% to 1.27%, which means 51 people need to be treated to prevent one influenza case (95% confidence interval, 40 to 103). In contrast, the prophylaxis effect on asymptomatic influenza cases was not significant in individuals (risk difference 0.14%, -1.10% to 1.10%) or in households (1.32%, -2.20% to 3.84%). In households treated prophylactically there was an effect on symptomatic influenza (14.84%, 12.18% to 16.55%), but this was based on only two small studies including 824 participants. Prophylaxis in adults reduced unverified pneumonia (0.32%, 0.09% to 0.41%; NNTB (number needed to treat to benefit) 311, 244 to 1086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children (risk difference 0.32%, 0.09% to 0.41%; NNTB 311, 244 to 1086). CONCLUSIONS: Based on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.""",1
13490,24815085,Clinical profiles of Stevens-Johnson syndrome among Thai patients,"The objective of this study was to demonstrate the clinical profiles of Stevens-Johnson syndrome (SJS) in Thai patients, and to compare those clinical features between younger and older patients. Medical records of all patients with SJS who were admitted to Srinagarind Hospital Medical School, Khon Kaen, Thailand, from January 2002 to December 2014 were reviewed. Epidemiological features, etiologies, treatment and clinical outcomes were collected. There were 45 patients with SJS during the 10-year period. Females were the majority (57.8%) and the median age was 49 years. Hepatitis was the most frequent complication (67.5%). Phenytoin (15.6%), sulfonamide drugs (15.6%) and allopurinol (13.3%) were implicated as leading causes of SJS. Steroids were prescribed in 37 cases (82.2%). The mortality rate was 4.4%. Comparing older patients to younger patients, allopurinol appeared to be the main instigating drug to develop SJS with an odds ratio of 5.6 (95% confidence interval, 2.8-10.6). In conclusion, clinical features of Thai patients with SJS were similar to other reports. Allopurinol had the strongest association with SJS in older patients as compared to the younger ones.",1
13491,24818763,"ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection","""BACKGROUND & AIMS: The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir (an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy in patients with hepatitis C virus (HCV) genotype 1b infection-the most prevalent subgenotype worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and dasabuvir to produce high rates of sustained virologic response (SVR) in these patients. METHODS: We performed a multicenter, open-label, phase 3 trial of 179 patients with HCV genotype 1b infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were assigned randomly (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (group 1) or without (group 2) for 12 weeks. The primary end point was SVR 12 weeks after treatment (SVR12). We assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin. RESULTS: Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%; 95% confidence interval, 92.8%-100%; and group 2: 100%; 95% confidence interval, 95.9%-100%). The rate of response in group 2 was noninferior to that of group 1. No virologic failure occurred during the study. Two patients (1.1%) discontinued the study owing to adverse events, both in group 1. The most common adverse events in groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases in hemoglobin level to less than the lower limit of normal were more frequent in group 1 (42.0% vs 5.5% in group 2; P < .001), although only 2 patients had hemoglobin levels less than 10 g/dL. CONCLUSIONS: The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events. ClinicalTrials.gov number: NCT01674725.""",1
13492,24818838,Avanafil (Stendra)--another PDE5 inhibitor for erectile dysfunction,,1
13493,24821719,Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography,"The symptoms of Clostridium difficile infections are caused by two exotoxins, TcdA and TcdB, which target host colonocytes by binding to unknown cell surface receptors, at least in part via their combined repetitive oligopeptide (CROP) domains. A combination of the anti-TcdA antibody actoxumab and the anti-TcdB antibody bezlotoxumab is currently under development for the prevention of recurrent C. difficile infections. We demonstrate here through various biophysical approaches that bezlotoxumab binds to specific regions within the N-terminal half of the TcdB CROP domain. Based on this information, we solved the x-ray structure of the N-terminal half of the TcdB CROP domain bound to Fab fragments of bezlotoxumab. The structure reveals that the TcdB CROP domain adopts a beta-solenoid fold consisting of long and short repeats and that bezlotoxumab binds to two homologous sites within the CROP domain, partially occluding two of the four putative carbohydrate binding pockets located in TcdB. We also show that bezlotoxumab neutralizes TcdB by blocking binding of TcdB to mammalian cells. Overall, our data are consistent with a model wherein a single molecule of bezlotoxumab neutralizes TcdB by binding via its two Fab regions to two epitopes within the N-terminal half of the TcdB CROP domain, partially blocking the carbohydrate binding pockets of the toxin and preventing toxin binding to host cells.",1
13494,24825642,Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial,"""IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS: Patients (n?=?2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n?=?1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.""",1
13495,24828899,"Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis","""OBJECTIVE: Recently, several large randomised controlled trials about the treatments of cognitive impairment or dementia due to Parkinson's disease (CIND-PD or PDD) and dementia with Lewy bodies (DLB) were completed. Here, we systematically reviewed the studies (including the recent reports) to provide updated evidence for the treatments of CIND-PD, PDD and DLB. METHODS: We searched Cochrane Dementia and Cognitive Improvement Group Specialised Register, Pubmed, Embase, and other sources for eligible trials. We selected global impression and cognitive function as primary efficacy outcomes, and dropouts and adverse events as safety outcomes. Furthermore, Meta-analysis and trial sequential analysis (TSA) were used here. RESULTS: Ten trials were included in this study. Cholinesterase inhibitors and memantine produced small global efficacy on clinicians' global impression of change (CGIC), from a weighted mean difference of -0.40 (95% CI -0.77 to -0.03) to -0.65 (95% CI -1.28 to -0.01); however, cholinesterase inhibitors but not memantine significantly improved cognition on Mini-Mental State Examination (MMSE), from 1.04 (95% CI 0.43 to 1.65) to 2.57 (95% CI 0.90 to 4.23). Additionally, both of them had good safety outcomes, although rivastigmine showed an increased risk on adverse events than placebo (risk ratio, RR 1.19, TSA adjusted 95% CI 1.04 to 1.36), these events were usually mild or moderate, and the risk disappeared on serious adverse events. CONCLUSIONS: Cholinesterase inhibitors and memantine slightly improve global impression; however, only cholinesterase inhibitors enhance cognitive function. Besides, all the drugs have good safety outcomes. But the limited trials precluded the generalisation of these outcomes.""",1
13496,24833354,Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma,"Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S+VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P = .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade ?3 adverse-event incidence was 92% on S+VMP and 81% on VMP (P = .09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.gov as #NCT00911859.",1
13497,24836309,Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis,"""BACKGROUND: Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking. METHODS: In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period. RESULTS: At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P=0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P=0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P>0.99). CONCLUSIONS: As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00650091.).""",1
13498,24836312,A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis,"""BACKGROUND: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).""",1
13499,24837159,Reversal of advanced disease in lysosomal acid lipase deficient mice: a model for lysosomal acid lipase deficiency disease,"Lysosomal acid lipase (LAL) is an essential enzyme that hydrolyzes triglycerides (TG) and cholesteryl esters (CE) in lysosomes. Mutations of the LIPA gene lead to Wolman disease (WD) and cholesterol ester storage disease (CESD). The disease hallmarks include hepatosplenomegaly and extensive storage of CE and/or TG. The effects of intravenous investigational enzyme therapy (ET) on survival and efficacy were evaluated in Lipa knock out, lal-/- mice with advanced disease using recombinant human LAL (rhLAL). Comparative ET was conducted with lower doses (weekly, 0.8 and 3.2mg/kg) beginning at 16 weeks (study 1), and with higher dose (10mg/kg) in early (8-weeks), middle (16-weeks) and late (24-weeks) disease stages (study 2). In study 1, rhLAL extended the life span of lal-/- mice in a dose dependent manner by 52 (0.8 mg/kg) or 94 (3.2mg/kg) days. This was accompanied by partial correction of cholesterol and TG levels in spleen and liver. In study 2, the high dose resulted in a significant improvement in organ size (liver, spleen and small intestine) and tissue histology as well as significant decreases in cholesterol and TG in all three groups. In the treated livers and spleens the cholesterol and TG levels were reduced to below treatment initiation levels indicating a reversal of disease manifestations, even in advanced disease. ET diminished liver fibrosis and macrophage proliferation. These results show that LAL deficiency can be improved biochemically and histopathologically by various dosages of ET, even in advanced disease.",1
13500,24839363,Effect of Antiviral Prophylaxis Strategy for Chemotherapy-Associated Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients with Hepatitis B Virus Infection: A Retrospective Cohort Study,"Recent data indicates that nucleoside/nucleotide analogue (NUC) is effective in preventing and controlling hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the ideal antiviral agent and optimal application protocol still needs to be determined. Meanwhile, it is uncertain whether those with past HBV infection require antiviral prophylaxis during chemotherapy. This report retrospectively analyzed non-Hodgkin's lymphoma (NHL) patients seen from January, 2004 to June, 2009 in West China Hospital. We found that the prevalence of chronic HBV infection in our NHL patients was 20.7�% while that of past HBV infection was 21.05�%. Compared with the high rate (25.6�%) of HBV reactivation in patients with chronic HBV infection, none of those with past HBV infection in fact had occult HBV infection thus none experienced reactivation. Of the 82 patients with chronic HBV infection who received chemotherapy, antiviral prophylaxis could significantly reduce the incidence of HBV reactivation (5.0 vs. 45.2�% in the control group) and the incidence of liver function damage (32.5 vs. 73.8�% in the control group). The results of the current study confirmed previous reports that prophylactic NUCs administration can effectively prevent HBV reactivation and significantly reduce the incidence of HBV reactivation especially for patients receiving rituximab-containing regimens. Due to the fact that none of individuals who had past HBV infection developed HBV reactivation reported in our study, antiviral prophylaxis may not be required for patients with past HBV infection. Close observation of alanine aminotransferase and HBV-DNA contributes to early diagnosis and timely treatment of HBV reactivation.",1
13501,24842416,Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis,"BACKGROUND: Biological agents are emerging treatment options for the management of ulcerative colitis (UC). PURPOSE: To assess the comparative efficacy and harm of biological agents in adult patients with moderately to severely active UC who are naive to biological agents. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Library from inception through December 2013, without language restrictions, and ClinicalTrials.gov, European Medicines Agency, and U.S. Food and Drug Administration Web sites. STUDY SELECTION: Randomized, placebo-controlled or head-to-head trials assessing biological agents as induction or maintenance therapy for moderately to severely active UC. DATA EXTRACTION: Two reviewers independently abstracted study data and outcomes and rated each trial's risk of bias. DATA SYNTHESIS: There were no head-to-head trials. There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo. LIMITATION: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials. CONCLUSION: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.",1
13502,24842985,Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3),"""OBJECTIVE: Compare the efficacy and safety of monotherapy with dulaglutide, a once-weekly GLP-1 receptor agonist, to metformin-treated patients with type 2 diabetes. The primary objective compared dulaglutide 1.5 mg and metformin on change from baseline glycosylated hemoglobin A1c (HbA1c) at 26 weeks. RESEARCH DESIGN AND METHODS: This 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients (N = 807) had HbA1c ?6.5% (?48 mmol/mol) and ?9.5% (?80 mmol/mol) with diet and exercise alone or low-dose oral antihyperglycemic medication (OAM) monotherapy; OAMs were discontinued at beginning of lead-in period. RESULTS: At 26 weeks, changes from baseline HbA1c (least squares [LS] mean ? SE) were: dulaglutide 1.5 mg, -0.78 ? 0.06% (-8.5 ? 0.70 mmol/mol); dulaglutide 0.75 mg, -0.71 ? 0.06% (-7.8 ? 0.70 mmol/mol); and metformin, -0.56 ? 0.06% (-6.1 ? 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): -0.22% (-2.4 mmol/mol) and -0.15% (-1.6 mmol/mol) (one-sided P < 0.025, both comparisons), respectively. Greater percentages reached HbA1c targets <7.0% (<53 mmol/mol) and ?6.5% (?48 mmol/mol) with dulaglutide 1.5 and 0.75 mg compared with metformin (P < 0.05, all comparisons). No severe hypoglycemia was reported. Compared with metformin, decrease in weight was similar with dulaglutide 1.5 mg and smaller with dulaglutide 0.75 mg. Over 52 weeks, nausea, diarrhea, and vomiting were the most common adverse events; incidences were similar between dulaglutide and metformin. CONCLUSIONS: Dulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.""",1
13503,24844799,Review article: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations,"BACKGROUND: Although evidence for their therapeutic efficacy is limited, herbal traditional Chinese medicine (TCM) preparations increasingly gain popularity. In contrast to other herbal products, adverse effects by herbal TCM including liver toxicity were rarely reported. In recent years, more cases were published, providing new clinical challenges. AIM: To summarise comprehensively the literature on herbal TCM hepatotoxicity since 2011. METHODS: PubMed was searched using key words related to TCM, the results were restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic 'Drug record: Chinese and other Asian herbal medicines'. RESULTS: Since 2011, new case reports and case series provided evidence for herbal hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four individual TCM herbs with potential health hazards. These were the TCM products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflorum products, Shan Chi, 'White flood' containing the herbal TCM Wu Zhu Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include the establishment of a new and early diagnostic serum marker for hepatotoxicity caused by pyrrolizidine alkaloids, assessed using ultra performance liquid chromatography-mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. CONCLUSION: Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury.",1
13504,24849545,The combination of insulin-like growth factor receptor 1 (IGF1R) antibody cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical carcinoma: a multi-institutional NCI-sponsored trial,"Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an effective systemic treatment. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects. A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC. The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in association with mitotane as a first-line treatment for advanced/metastatic ACC. We conducted a multicenter, randomized double-arm phase II trial in patients with irresectable recurrent/metastatic ACC. The original protocol included two treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12 was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane was 2 g daily, subsequently adjusted according to serum levels/symptoms. The primary endpoint was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients (13 males, 7 females) with a median age of 50.2 years (range 21.9-79.6) were enrolled for the single-arm phase. Therapeutic effects were observed in 8/20 patients, including one partial response and seven stable diseases. The median PFS was 6 weeks (range 2.66-48). Toxic events included two grade 4 (hyperglycemia and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen demonstrated activity in some patients, the relatively low therapeutic efficacy precluded further studies with this combination of drugs.",1
13505,24855212,"Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study","This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ?65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N = 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787.",1
13506,24859203,Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed,"""BACKGROUND & AIMS: There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin ?4?7, as induction therapy. METHODS: Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ?1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ?150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N�= 416), which included patients naive to TNF antagonist therapy (n�= 101). RESULTS: Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P�= .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P�= .001; relative risk, 2.2; 95% confidence interval, 1.3-3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (?100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P�= .001; relative risk, 1.8; 95% confidence interval, 1.2-2.5). Adverse event results were similar among all groups. CONCLUSIONS: Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171.""",1
13507,24865821,"Risk of acute liver injury associated with the use of moxifloxacin and other oral antimicrobials: a retrospective, population-based cohort study","""STUDY OBJECTIVE: To estimate the incidence and relative risk of a hospitalization or emergency visit for noninfectious liver injury in users of eight oral antimicrobials-amoxicillin, amoxicillin-clavulanic acid, clarithromycin, cefuroxime, doxycycline, levofloxacin, moxifloxacin, telithromycin-compared with nonusers of these antimicrobials. DESIGN: Retrospective, observational cohort study with a nested case-control analysis. DATA SOURCE: HealthCore Integrated Research Database. PATIENTS: Adults with continuous health plan enrollment for at least 6 months before study entry who had a new dispensing of a study antimicrobial between July 1, 2001, and March 31, 2009. Cases had diagnoses indicating noninfectious liver injury during follow-up. To control for potentially confounding risk factors, 10 controls at risk for liver injury during follow-up were matched to each case by age, sex, and event date (liver injury date of the case), and analyses were adjusted for medical history, concomitant drugs, and health care service use. MEASUREMENTS AND MAIN RESULTS: Two physician reviewers (blind to exposure) validated the cases. Among 1.3 million antimicrobial users, we identified 607 cases of liver injury, including 82 cases of severe hepatocellular injury and 11 cases of liver failure. Liver injury incidence in nonusers of study antimicrobials was 35/100,000 person-years (95% confidence interval [CI] 29-42/100,000 person-years). For valid cases, the adjusted relative risk among current users of multiple antimicrobials was 3.2 (95% CI 1.6-6.7). Levofloxacin had the highest relative risk for current single use (3.2, 95% CI 1.8-5.8). Relative risks were also elevated for amoxicillin-clavulanic acid (2.5, 95% CI 1.3-5.0), doxycycline (2.5, 95% CI 1.2-5.2), moxifloxacin (2.3, 95% CI 1.1-4.7), and amoxicillin (2.3, 95% CI 1.1-4.7). CONCLUSION: The results support a comparatively high adjusted relative risk of liver injury among patients exposed concurrently to multiple antimicrobials and modest elevations in the risk for several antimicrobials used alone; however, we found little evidence of any strong effect of commonly used antimicrobials on the risk of liver injury.""",1
13508,24868327,CYP2E1 immunoglobulin G4 subclass antibodies after desflurane anesthesia,"""AIM: To investigate CYP2E1 IgG4 autoantibody levels and liver biochemical markers in adult patients after anesthesia with desflurane. METHODS: Forty patients who were > 18 years old and undergoing elective surgery under general anesthesia with desflurane were studied. Alpha-glutathione-S-transferase (?GST) and IgG4 antibodies against CYP2E1 were measured preoperatively and 96 h postoperatively, as well as complete blood count, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), g-glutamyl-transpeptidase (gGT), alkaline phosphatase, total serum proteins, albumin and bilirubin. A separate group of 8 patients who received regional anesthesia was also studied for calibration of the methodology used for CYP2E1 IgG4 and ?GST measurements. Student's t-test and the Mann-Whitney U test were used for comparison of the continuous variables, and Fisher's exact test was used for the categorical variables. All tests were two-tailed, with statistical significance set as P < 0.05. RESULTS: None of the patients developed postoperative liver dysfunction, and all patients were successfully discharged from the hospital. No statistically significant difference was observed regarding liver function tests (SGOT, SGPT, ?GT, bilirubin, INR), ?GST and CYP2E1 IgG4, before and after exposure to desflurane. After dividing patients into two subgroups based on whether or not they had received general anesthesia in the past, no significant difference in the levels of CYP2E1 IgG4 was observed at baseline or 96 h after desflurane administration (P = 0.099 and P = 0.051, respectively). Alpha-GST baseline levels and levels after the intervention also did not differ significantly between these two subgroups (P > 0.1). The mean ?GST differences were statistically elevated in men by 2.15 ng/mL compared to women when adjusted for BMI, duration of anesthesia, number of times anesthesia was administered previously and length of hospital stay. No significant difference was observed between patients who received desflurane and those who received regional anesthesia at any time point. CONCLUSION: There was no difference in CYP2E1 IgG4 or ?GST levels after desflurane exposure; further research is required to investigate their role in desflurane-induced liver injury.""",1
13509,24869714,Eslicarbazepine acetate (aptiom) for epilepsy,,1
13510,24879836,Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1),"""OBJECTIVE: To compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of dulaglutide 1.5 mg versus placebo in HbA1c change at 26 weeks. RESEARCH DESIGN AND METHODS: This 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 ?g, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500-3,000 mg) and pioglitazone (30-45 mg). Mean baseline HbA1c was 8.1% (65 mmol/mol). RESULTS: Least squares mean ? SE HbA1c change from baseline to the primary end point was -1.51 ? 0.06% (-16.5 ? 0.7 mmol/mol) for dulaglutide 1.5 mg, -1.30 ? 0.06% (-14.2 ? 0.7 mmol/mol) for dulaglutide 0.75 mg, -0.99 ? 0.06% (-10.8 ? 0.7 mmol/mol) for exenatide, and -0.46 ? 0.08% (-5.0 ? 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P < 0.001) and exenatide at 26 and 52 weeks (both adjusted one-sided P < 0.001). Greater percentages of patients reached HbA1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P < 0.001). At 26 and 52 weeks, total hypoglycemia incidence was lower in patients receiving dulaglutide 1.5 mg than in those receiving exenatide; no dulaglutide-treated patients reported severe hypoglycemia. The most common gastrointestinal adverse events for dulaglutide were nausea, vomiting, and diarrhea. Events were mostly mild to moderate and transient. CONCLUSIONS: Both once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile.""",1
13511,24879980,"Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs","Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity.",1
13512,24879983,Drug-induced liver injury with autoimmune features,"Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, alpha-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-alpha agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis.",1
13513,24881730,Enzalutamide in metastatic prostate cancer before chemotherapy,"""BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).""",1
13514,24885479,Clinical experience with ipilimumab 3�mg/kg: real-world efficacy and safety data from an expanded access programme cohort,"BACKGROUND: Ipilimumab improves survival in patients with advanced melanoma. The activity and safety of ipilimumab outside of a clinical trial was assessed in an expanded access programme (EAP). METHODS: Ipilimumab was available upon physician request for patients aged 16 or over with pretreated stage III (unresectable)/IV melanoma, for whom no other therapeutic option was available. Patients received ipilimumab 3�mg/kg every 3�weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12. Patients were monitored for adverse events (AEs) within 3 to 4�days of each scheduled visit. RESULTS: Of 855 patients participating in the EAP in Italy, 833 were evaluable for response. Of these, 13% had an objective immune response, and the immune-related disease control rate was 34%. Median progression-free survival and overall survival were 3.7 and 7.2�months, respectively. Efficacy was independent of BRAF and NRAS mutational status. Overall, 33% of patients reported an immune-related AE (irAE). The frequency of irAEs was not associated with response to ipilimumab. CONCLUSIONS: Outside of a clinical trial setting, ipilimumab is a feasible treatment option in patients with pretreated metastatic melanoma, regardless of BRAF and NRAS mutational status. Data from this large cohort of patients support clinical trial evidence that ipilimumab can induce durable disease control and long-term survival in patients who have failed to respond to prior treatment.",1
13515,24891642,Copper-associated hepatitis in a Pembroke Welsh corgi,"""A 6-year-old spayed female Pembroke Welsh corgi dog was diagnosed with copper-associated hepatitis; an uncommon disease to which a variety of breeds are predisposed. This case report describes copper-associated hepatitis in a breed in which the disease has not previously been reported.""",1
13516,24896818,Naloxegol for opioid-induced constipation in patients with noncancer pain,"""BACKGROUND: Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, ?-opioid receptor antagonist, for the treatment of opioid-induced constipation. METHODS: In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (?3 spontaneous bowel movements per week and an increase from baseline of ?1 spontaneous bowel movements for ?9 of 12 weeks and for ?3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements. RESULTS: Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol. CONCLUSIONS: Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).""",1
13517,24897083,Single-dose oritavancin in the treatment of acute bacterial skin infections,"""BACKGROUND: Oritavancin is a lipoglycopeptide with bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and prolonged half-life allow for single-dose treatment. METHODS: We conducted a randomized, double-blind trial in which adults with acute bacterial skin and skin-structure infections received either a single intravenous dose of 1200 mg of oritavancin or a regimen of intravenous vancomycin twice daily for 7 to 10 days. Three efficacy end points were tested for noninferiority. The primary composite end point was defined as cessation of spreading or reduction in lesion size, absence of fever, and no need for administration of a rescue antibiotic 48 to 72 hours after administration of oritavancin. Secondary end points were clinical cure 7 to 14 days after the end of treatment, as determined by a study investigator, and a reduction in lesion size of 20% or more 48 to 72 hours after administration of oritavancin. RESULTS: The modified intention-to-treat population comprised 475 patients who received oritavancin and 479 patients who received vancomycin. All three efficacy end points met the prespecified noninferiority margin of 10 percentage points for oritavancin versus vancomycin: primary end point, 82.3% versus 78.9% (95% confidence interval [CI] for the difference, -1.6 to 8.4 percentage points); investigator-assessed clinical cure, 79.6% versus 80.0% (95% CI for the difference, -5.5 to 4.7 percentage points); and proportion of patients with a reduction in lesion area of 20% or more, 86.9% versus 82.9% (95% CI for the difference, -0.5 to 8.6 percentage points). Efficacy outcomes measured according to type of pathogen, including methicillin-resistant Staphylococcus aureus, were similar in the two treatment groups. The overall frequency of adverse events was also similar, although nausea was more common among those treated with oritavancin. CONCLUSIONS: A single dose of oritavancin was noninferior to twice-daily vancomycin administered for 7 to 10 days for the treatment of acute bacterial skin and skin-structure infections caused by gram-positive pathogens. (Funded by the Medicines Company; SOLO I ClinicalTrials.gov number, NCT01252719.).""",1
13518,24898925,Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study,"""OBJECTIVES: Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study. METHODS: Patients (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed. RESULTS: At data cutoff (February 9, 2012), natalizumab exposure was 3,460 patient-years; a median of 56 (range 1-70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab's known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to natalizumab had lower annualized relapse rates over 240 weeks. CONCLUSIONS: Serious adverse events were consistent with natalizumab's known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.""",1
13519,24902006,Overview and management of dermatologic events associated with targeted therapies for medullary thyroid cancer,"BACKGROUND: Treatment options for patients with advanced or metastatic medullary thyroid cancer (MTC) have, in recent years, expanded with the approval of two tyrosine kinase inhibitors (TKIs): vandetanib and cabozantinib. Other agents, including TKIs, are under clinical investigation for MTC. Although patients treated with TKIs are at risk of developing dermatologic adverse events (AE), these untoward events may be mitigated through AE-driven algorithms. SUMMARY: AE-driven algorithms combine effective nonpharmaceutical and pharmaceutical treatment modalities implemented by a multidisciplinary effort that incorporates nursing interventions, patient education, and referrals to pain-management specialists, podiatrists, and dermatologists, as appropriate. Effective AE prevention and management reduce the need for dose interruptions and modifications, allowing patients the opportunity to derive the maximal benefit from TKI therapy, while maintaining quality of life. CONCLUSIONS: Optimal use of targeted therapies in the treatment of MTC depends on careful patient selection, interdisciplinary communication, and patient education and encouragement to enhance compliance and safety, optimize consistent dosing, and maximize the use of effective therapies.",1
13520,24904120,Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma,"Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.",1
13521,24907225,"Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial","""BACKGROUND: Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. METHODS: In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ?18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782. FINDINGS: Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29?3% [95% CI 20?1-38?6; p<0?0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. INTERPRETATION: Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. FUNDING: Janssen Infectious Diseases-Diagnostics.""",1
13522,24909454,Management of patients with overt or resolved hepatitis B virus infection undergoing rituximab therapy,"INTRODUCTION: Rituximab (RTX), a chimeric mouse anti-human CD20 monoclonal antibody, is indicated for the treatment of patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis and microscopic polyangiitis, and rheumatoid arthritis, but nowadays it is increasingly used for the treatment of many other immune-mediated disorders. Hepatitis B virus (HBV) reactivation in RTX-treated patients, eventually leading to fatal liver failure, has been reported more often among hepatitis B surface antigen (HBsAg)-positive patients (overt infection) than in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) seropositive patients (resolved infection). AREAS COVERED: This paper reviews the safety of RTX in patients with overt or resolved HBV infection, providing recommendations for its safe use in such patients. EXPERT OPINION: Prior to starting RTX treatment, all patients should be screened for HBV infection. While HBsAg-positive active carriers should receive long-term antiviral treatment with entecavir (ETV) or tenofovir, inactive carriers are candidates for universal prophylaxis with lamivudine, or ETV or tenofovir in selected cases, to prevent hepatitis reactivation. Conversely, for HBsAg-negative anti-HBc positive carriers, that is, those with resolved HBV infection, universal prophylaxis with lamivudine is recommended for those with onco-hematological diseases, whereas watchful monitoring of HBsAg/HBV DNA levels is advisable for all the other indications.",1
13523,24912730,Efficacy and safety of rufinamide in children under four years of age with drug-resistant epilepsies,"""BACKGROUND: Studies on the efficacy and tolerability of rufinamide in infants and young children are scarce. Here we report on an open, retrospective, and pragmatic study about safety and efficacy of rufinamide in children aged less than four years, in terms of seizures types and epilepsy syndromes. METHODS: Forty children (mean age 39.5 months; range 22-48) were enrolled in the study. The mean follow-up period was 12.2 months (range 5-21). Rufinamide was initiated at a mean age of 26.7 months (range 12-42). Final rufinamide mean dosage was 31.5�mg/kg/day if associated with valproic acid and 44.2�mg/kg/day if not. RESULTS: The highest seizure reduction rate was observed in the epileptic spasms (46%) and drop attacks (42%) groups. Seizure reduction was also observed in tonic seizures (35%) and in the focal seizure (30%) groups. In terms of epilepsy syndrome, rufinamide was effective in Lennox-Gastaut syndrome. Results were very poor for those affected by Dravet's syndrome. Globally, responder rate was 27.5%, including two (5%) patients seizure-free. Adverse reactions occurred in 37.5% of children and were mainly represented by vomiting, drowsiness, irritability, and anorexia. Discontinuation rate due to treatment-emergent adverse events was 15%. CONCLUSION: The present study concludes that rufinamide may be a safe and effective drug for a broad range of seizures and epilepsy syndromes in infants and young children and represents a valid therapeutic option in this population.""",1
13524,24915778,"A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas","""BACKGROUND: Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. METHODS: Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly ? 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. RESULTS: Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. CONCLUSIONS: The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.""",1
13525,24918129,Drug- and herb-induced liver injury: a case series from a single center,"""BACKGROUND/AIMS: Drug-induced liver injury (DILI) is common worldwide and has a potentially fatal outcome. It accounts for more than half of the cases of acute liver failure in the United States. Herb-induced liver injury (HILI) is a less documented condition but a growing problem. We present here the clinical characteristics and outcome of patients with drug- and herb-induced liver injury from our center. MATERIALS AND METHODS: In this 4-year retrospective study, 82 patients in whom there was a causal or highly probable relationship between herbal medicine or drug use and liver disease are presented. RESULTS: The mean age of patients was 43.1+/-14.8 years; sexual distribution was 53 females and 29 males. The major cause of hepatotoxicity was drugs (87.8%), with herbal medicine accounting for 12.2%. The leading causative agents were nonsteroidal anti-inflammatory drugs (NSAIDs) (23.1%), followed by antibiotics (19.5%). The pattern of hepatotoxicity was hepatocellular in 35 patients (42.6%), mixed in 28 (34.1%), and cholestatic in 19 patients (23.1%). Teucrium polium (known popularly as felty germander), which is a traditionally used herbal medicine of the Labiatae family in our region, was the most common cause of herb-induced liver injury and responsible in 7 of 10 herbal hepatotoxic cases. Acute liver failure developed in 3 patients (two patients related with flurbiprofen and diclofenac and one patient due to an isoniazid-rifampicin combination). CONCLUSION: Antibiotics and NSAIDs were the most common etiologic agents for drug-induced liver injury. Surprisingly, herbs follow these groups of drugs and must be questioned more carefully.""",1
13526,24933332,"Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial","""BACKGROUND: Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. METHODS: In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. FINDINGS: Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10?5 months (IQR 5?1-21?2) for 628 patients allocated ramucirumab plus docetaxel and 9?1 months (4?2-18?0) for 625 patients who received placebo plus docetaxel (hazard ratio 0?86, 95% CI 0?75-0?98; p=0?023). Median progression-free survival was 4?5 months (IQR 2?3-8?3) for the ramucirumab group compared with 3?0 months (1?4-6?9) for the control group (0?76, 0?68-0?86; p<0?0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. INTERPRETATION: Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. FUNDING: Eli Lilly.""",1
13527,24935480,Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis,"INTRODUCTION: Fingolimod (Gilenya�, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod's mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-?-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema. AREAS COVERED: We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS. EXPERT OPINION: Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod.",1
13528,24944159,Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia,"""Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (</=6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received >/=1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P < 0.001; vomiting, 33% vs. 16%; P < 0.001), alanine aminotransferase (33% vs. 9%; P < 0.001) and aspartate aminotransferase (28% vs. 10%; P < 0.001) elevations, and pyrexia (19% vs. 12%; P = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P < 0.001; peripheral, 5% vs. 12%; P = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P = 0.010; muscle cramps, 5% vs. 22%; P < 0.001; bone pain, 4% vs. 11%; P = 0.003), increased creatine phosphokinase (8% vs. 20%; P < 0.001), neutropenia (13% vs. 30%; P < 0.001), and leukopenia (9% vs. 22%; P < 0.001). Between-group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML.""",1
13529,24944464,Hepatitis C virus reactivation in cancer patients in the era of targeted therapies,"""The purpose of this review is to summarize the evidence of hepatitis C reactivation in cancer patients in the era of targeted therapies. Targeted therapies are novel therapeutics frequently used in cancer patients. During treatment with targeted therapies, viral replication is one of the major problems that can occur. The PubMed database, ASCO, and ASCO Gastrointestinal Cancer Symposium abstracts were searched up until September 15, 2013 using the following search keywords: """"targeted therapies, rituximab, alemtuzumab, brentuximab, hepatitis, hepatitis C reactivation, tyrosine kinase inhibitors, imatinib, mammalian target of rapamycin (mTOR) inhibitors, everolimus, anti-HER therapies, trastuzumab, pertuzumab, lapatinib, anti-epidermal growth factor receptor therapies, cetuximab, panitumumab, and ipilimumab"""". Papers considered relevant for the aim of this review were selected by the authors. The data about rituximab-induced hepatic flare in hepatitis C virus (HCV) positive patients is controversial. However, there is the possibility of life-threatening hepatic flare that can develop after HCV ribonucleic acid (HCV-RNA) viral load increases. Routine follow-up of liver function tests should be advised. Especially in high-risk patients, such as those with baseline chronic active hepatitis and cirrhosis, and where there are plans to administer rituximab concomitantly with corticosteroids, it is advised to have close follow-up of HCV viral load. The data is insufficient to make accurate statements about the association of alemtuzumab therapy and HCV reactivation. However, alemtuzumab may cause deep immunosuppression. Due to this, it is better to follow up with liver function tests and HCV RNA levels during alemtuzumab therapy. Brentuximab has effects on antibody dependent cellular toxicity and may decrease humoral immunity. Thus, we believe that during brentuximab treatment of HCV infected patients, clinicians may encounter hepatitis C reactivation. There have been no reported cases of hepatitis C reactivation with imatinib therapy. However, there are many reports of hepatitis B reactivation with imatinib treatment. Based on the evidence of hepatitis B reactivation with imatinib and the effects of imatinib on immune system functions, we suggest that imatinib therapy might be a risk factor for HCV reactivation. Anti-human epidermal growth factor receptor 2 therapies are not associated with hepatic flare in HCV infected patients. Post-transplant studies reported that mTOR was safely administered to patients with active hepatitis C without causing hepatic flare. Cetuximab and panitumumab have not been associated with HCV reactivation. Two cases of HCV infected melanoma were safely treated with ipilimumab without any HCV reactivation or hepatic flare. Targeted therapies are a new and emerging area of oncology treatment modalities. While treating HCV infected cancer patients, clinicians should be mindful of the immunosuppressive properties of targeted therapies. Further randomized trials are needed to establish algorithms for this issue.""",1
13530,24948511,"Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial","""BACKGROUND: Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes. METHODS: In this double-blind phase 3 trial, patients (aged >/=18 years) with type 2 diabetes and HbA1c concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1:1 ratio with a computer-generated random sequence, stratified by HbA1c, estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0.3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing. FINDINGS: Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA1c with empagliflozin versus glimepiride was -0.11% (95% CI -0.19 to -0.02; p=0.0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose </=3.9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride. INTERPRETATION: Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin. FUNDING: Boehringer Ingelheim and Eli Lilly.""",1
13531,24951123,Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group,"""Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n?=?302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20-30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53-10.7)?months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ?2, comorbidities ?3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.""",1
13532,24951338,Cilostazol and outcome in outpatients with peripheral artery disease,"""BACKGROUND: Cilostazol increases the walking distance in patients with intermittent claudication, but there is scarce evidence of any effect on the risk for subsequent ischemic events, bleeding or death. PATIENTS AND METHODS: We used data from the FRENA Registry to compare the clinical outcome in stable outpatients with intermittent claudication, according to the use of cilostazol. RESULTS: As of January 2013, 1,317 patients with intermittent claudication were recruited in FRENA, of whom 191 (14.5%) received cilostazol. Over a mean follow-up of 18months, 39 patients developed myocardial infarction, 23 ischemic stroke, 20 underwent limb amputation, 15 had major bleeding and 70 died. There were no significant differences in the rate of subsequent ischemic events, major bleeding or death between patients receiving or not receiving cilostazol. On multivariate analysis, the use of cilostazol had no influence on the risk for subsequent myocardial infarction (hazard ratio [HR]: 0.97; 95% CI: 0.33-20.8), ischemic stroke (HR: 1.46; 95% CI: 0.48-4.43), limb amputation (HR: 0.34; 95% CI: 0.04-20.6), major bleeding (HR: 1.52; 95% CI: 0.33-7.09) or death (HR: 0.90; 95% CI: 0.40-20.0). CONCLUSIONS: In stable outpatients with intermittent claudication, the use of cilostazol was not associated with increased rates of subsequent ischemic events, major bleeding or death.""",1
13533,24956145,Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA registry,"The AVIDA registry evaluated azacitidine usage and effectiveness in unselected patients with myelodysplastic syndromes (MDS) in community practice. Treating physicians made all treatment decisions. Hematologic improvement (HI) and transfusion independence (TI) assessments used International Working Group (IWG) 2000 criteria. Enrolled were 421 patients with MDS (n = 228 International Prognostic Scoring System [IPSS] lower-risk, n = 106 higher-risk, 86 patients unclassified) from 105 US sites. Median follow-up was 7.6 months (range: 0.1-27.6). HI and red blood cell TI rates were similar regardless of administration route or dosing schedule. Safety and tolerability were consistent with previous reports. The AVIDA registry data support azacitidine effectiveness and safety in patients with lower- or higher-risk MDS treated in community practice.",1
13534,24962711,Results from a Nationwide Cohort Temporary Utilization Authorization (ATU) survey of patients in france treated with Pheburane(�) (Sodium Phenylbutyrate) taste-masked granules,"""OBJECTIVES: The aim of this study was to describe a nationwide system for pre-marketing follow-up (cohort temporary utilization authorization [ATU] protocol; i.e., 'therapeutic utilization') of a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane(�)) in France and to analyze safety and efficacy in this treated cohort of patients with urea cycle disease (UCD). METHODS: In October 2012, a cohort ATU was established in France to monitor the use of Pheburane(�) on a named-patient basis. All treated UCD patients were included in a follow-up protocol developed by the Laboratory (Lucane Pharma) and the French Medicines Agency (ANSM), which recorded demographics, dosing characteristics of NaPB, concomitant medications, adverse events, and clinical outcome during the period of treatment. Following the granting of the Marketing Authorization in Europe, the cohort ATU was terminated approximately 1 year after its initiation, as the product was launched on the French market. RESULTS: The ease of administration and acceptability were much better with the new taste-masked formulation than with the previous treatment. No episodes of metabolic decompensation were observed over a treatment period ranging from 3 to 11�months with Pheburane(�) and the range of ammonia and glutamine plasma levels improved and remained within the normal range. In all, no adverse events were reported with Pheburane(�) treatment. CONCLUSIONS: The recently developed taste-masked formulation of NaPB granules improved the quality of life for UCD patients. This may translate into improved compliance, efficacy, and safety, which may be demonstrated either in further studies or in the post-marketing use of the product.""",1
13535,24964515,[Hepatotoxicity of acetaminophen in a patient treated with capecitabine due to breast cancer],"Toxic liver injury is among the major side effects of paracetamol. It is a direct effect of the drug metabolite on the liver cells and is dependent on the dose. Unintentional overdose is often the result of several days of taking excessive doses of the drug for medical use. It is fostered by patients' self-treatment, the availability of non-prescription drugs and lack of awareness of the actual composition of the medication taken. The authors of this study reported a case of hepatotoxicity in a patient treated with capecitabine for breast cancer. Capecitabine therapy was completed several days before the use of paracetamol. The detailed interview with the patient revealed that the cause of hepatic dysfunction was the fact that she took paracetamol for 3 days in a daily dose of 5.5 grams (the permissible safe dose is 4 grams) due to the viral infection. After symptomatic treatment over several days improved took place.",1
13536,24966207,Fulminant hepatitis following crizotinib administration for ALK-positive non-small-cell lung carcinoma,"We herein report a case of fatal fulminant hepatitis secondary to crizotinib administration. The patient was 54-year-old female with a history of Hepatitis C infection (not current), dermatomyositis and steroid-induced diabetes mellitus. She was diagnosed with advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement. We began 400 mg of crizotinib as first-line therapy. No adverse effects were seen until Day 16. On Day 29, she was admitted to hospital with elevated liver enzymes (aspartate aminotransferase 3236 IU/l, alanine aminotransferase 5201 IU/l) and coagulopathy (prothrombin time <10%), and was diagnosed with crizotinib-induced fulminant hepatitis. We started intensive care, using plasma exchange, continuous hemodiafiltration and high-dose steroid therapy. Unfortunately, she did not respond to therapies, and died on Day 36. The mechanism and risk factors of crizotinib-induced hepatotoxicity are uncertain. Physicians should be aware of possible adverse effects of crizotinib. A systemic survey is imperative to identify possible risk factors of crizotinib-related hepatotoxicity.",1
13537,24973281,A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial,"""BACKGROUND: The phe508del CFTR mutation causes cystic fibrosis by limiting the amount of CFTR protein that reaches the epithelial cell surface. We tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface. METHODS: In this phase 2 clinical trial, we assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. We recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in 1 s (FEV1) of 40% or more than predicted. Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo. Together, cohorts 2 and 3 included phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo. The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). The study is registered with ClinicalTrials.gov, number NCT01225211, and EudraCT, number 2010-020413-90. FINDINGS: Cohort 1 included 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p<0.001) during the combination treatment period in cohort 1. In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0.003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1. INTERPRETATION: We provide evidence that combination lumacaftor and ivacaftor improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting. FUNDING: Vertex Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics Development Network.""",1
13538,24983542,Efficacy and safety of maraviroc vs. efavirenz in treatment-naive patients with HIV-1: 5-year findings,"OBJECTIVE: Maraviroc, a chemokine co-receptor type 5 (CCR5) antagonist, has demonstrated comparable efficacy and safety to efavirenz, each in combination with zidovudine/lamivudine, over 96 weeks in the Maraviroc vs. Efavirenz Regimens as Initial Therapy (MERIT) study. Here we report 5-year findings. DESIGN: A randomized, double-blind, multicenter phase IIb/III study with an open-label extension phase. METHODS: Treatment-naive patients with CCR5-tropic HIV-1 infection (Trofile) received maraviroc 300 mg twice daily or efavirenz 600 mg once daily, and zidovudine/lamivudine 300 mg/150 mg twice daily. After the last patient's week 96 visit, the study was unblinded and patients could enter a nominal 3-year open-label phase. Endpoints at the 5-year nominal visit (week 240) included proportion of patients (CCR5 tropism re-confirmed by enhanced sensitivity Trofile) with viral load (plasma HIV-1 RNA) below 50 and 400 copies/ml, and change from baseline in CD4(+) cell count, as well as safety. RESULTS: The proportion of patients maintaining viral load below 50 copies/ml was similar between treatment arms throughout the study and at week 240 (maraviroc 50.8% vs. efavirenz 45.9%). Maraviroc-treated patients had a greater increase from baseline in mean CD4(+) cell count than efavirenz-treated patients at week 240 (293 vs. 271 cells/mul, respectively). Fewer patients on maraviroc vs. efavirenz experienced treatment-related adverse events (68.9 vs. 81.7%) and discontinued as a result of any adverse event (10.6 vs. 21.3%). CONCLUSION: Maraviroc maintained similar long-term antiviral efficacy to efavirenz over 5 years in treatment-naive patients with CCR5-tropic HIV-1. Maraviroc was generally well tolerated with no unexpected safety findings or evidence of long-term safety concerns.",1
13539,24987187,Acute hepatic injury with atorvastatin: an unusual occurrence,"Atorvastatin, a commonly used and well-tolerated hypolipidemic drug, belongs to the class of statins or hydroxymethylglutaryl-coenzyme A reductase inhibitors. Use of atorvastatin may be associated with minor asymptomatic elevations in serum aminotransferases, but clinically significant hepatotoxicity is usually infrequent. Here we present a case of self-limiting clinically apparent acute hepatic injury attributable to atorvastatin occurring at recommended daily dose of 20 mg once a day. This case was postulated to be an unusual idiosyncratic reaction of the drug.",1
13540,24991411,"CEPP regimen (cyclophosphamide, etoposide, procarbazine and prednisone) as initial treatment for Hodgkin lymphoma patients presenting with severe abnormal liver function","ABVD regimen (doxorubicin, bleomycin, vinblastine and dacarbazine) remains the most commonly used front-line therapy for Hodgkin lymphoma. However, atypical and extranodal presentations present challenges to initial therapy, especially in the presence of renal and liver failure. We hereby present two cases of young male patients with atypical presentation of Hodgkin lymphoma with severe abnormal liver function. Patients showed excellent response to cyclophosphamide, etoposide, procarbazine and prednisone (CEPP regimen).",1
13541,24997638,Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: potent antiviral activity but no clinical benefit if treatment is given late,"""BACKGROUND: We evaluated efficacy and safety of sofosbuvir and daclatasvir?ribavirin in liver transplant recipients with severe recurrent hepatitis C. METHODS: Patients included in an international compassionate use programme for treatment with sofosbuvir and daclatasvir?ribavirin for 24 weeks were prospectively studied. Serum hepatitis C virus RNA was measured at treatment weeks 4, 12, and 24 and during follow-up at weeks 4, 8, and 12. RESULTS: Twelve patients (3 with fibrosing cholestatic hepatitis and 9 with cirrhosis; median model for end-stage liver disease score 20) received sofosbuvir 400mg/day+daclatasvir 60mg/day, and 6 patients (50%) also received ribavirin 200-800mg/day. Nine patients completed 24 weeks of treatment (75%), and all had undetectable hepatitis C virus RNA at week 24; 3 patients died (25%, liver failure, gastrointestinal bleeding and sepsis); 4 patients experienced severe liver disease-related adverse events. Post-treatment hepatitis C virus RNA was available for 5 patients (week 8, n=2; week 4, n=3) and was undetectable in all cases. Mean Child-Pugh score and albumin level improved significantly at week 24. No changes in immunosuppressant doses were needed. CONCLUSION: All-oral sofosbuvir plus daclatasvir combination shows high virological efficacy in liver transplant recipients and does not interact with immunosuppressants. All adverse events were unrelated to study drugs. These data strongly suggest that this combination must be initiated before decompensation.""",1
13542,25003490,The current status of ponatinib in the treatment of chronic myeloid leukemia,,1
13543,25005844,An analysis of the safety profile of proteasome inhibitors for treating various cancers,"INTRODUCTION: Emerging evidence demonstrates that the ubiquitin-proteasome pathway is a promising target for cancer therapy. Bortezomib (Velcade) exhibits great efficacy against multiple myeloma (MM) since the first clinical application. However, there are still several limitations associated with the use of bortezomib, including severe toxicities. To overcome bortezomib's shortcomings and to improve its safety profile, several second-generation proteasome inhibitors, for example, carfilzomib, ixazomib, oprozomib and marizomib, have been developed and currently tested in various clinical trials. AREAS COVERED: A literature search was carried out using PubMed and Google Scholar. The activity and safety profiling of proteasome inhibitors in treatment of various cancers were reviewed. EXPERT OPINION: Bortezomib, as a single or in combination therapy, demonstrates efficacy against MM or other hematological malignancies in clinical settings. However, it encounters two major problems, the acquired resistance and the severe side effects. Future direction in bortezomib-based therapy should focus on how to increase or retain its efficacy but improve its safety profile through, for example, rational combination therapies. Second-generation proteasome inhibitors have shown benefits in both overcoming bortezomib resistance and reducing related side effects, although these encouraging results should be further confirmed in a larger clinic population.",1
13544,25014231,Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation,"INTRODUCTION: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma. AREAS COVERED: This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib. EXPERT OPINION: Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.",1
13545,25015229,Combined use of ursodeoxycholic acid and bosentan prevents liver toxicity caused by endothelin receptor antagonist bosentan monotherapy: two case reports,"INTRODUCTION: Pulmonary arterial hypertension is a fatal disease characterized by progressive remodeling of the pulmonary arteries and an increase in pulmonary vascular resistance. Up to 50% of patients with systemic sclerosis have pulmonary arterial hypertension, which significantly affects the prognosis. The endothelin receptor antagonist bosentan is used for the treatment of pulmonary arterial hypertension and shows a great beneficial effect. However, the most frequent side effect of bosentan is liver toxicity, which often requires dose reduction and discontinuation. CASE PRESENTATION: We report two cases (a 64-year-old Japanese woman and a 69-year old Japanese woman) of systemic sclerosis, both with severe Raynaud's phenomenon and pulmonary arterial hypertension. Both patients had initially received bosentan monotherapy, which caused liver toxicity as indicated by increased levels of alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. After dose reduction or discontinuation of bosentan, these liver function abnormalities were normalized and the patients subsequently received retreatment with a combination of bosentan and ursodeoxycholic acid. The results of liver function tests did not show any abnormalities after this combination therapy. CONCLUSIONS: These reports suggest the usefulness of ursodeoxycholic acid for preventing liver toxicity caused by bosentan. Thus, the addition of ursodeoxycholic acid to the treatment protocol is expected to be useful when liver toxicity emerges as a side effect of bosentan.",1
13546,25018121,"Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial","BACKGROUND: Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. METHODS: We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (?1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7?0% or greater (?53 mmol/mol) and 10?0% or lower (?86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1?5 mg) or once-daily liraglutide (1?8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0?4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. FINDINGS: We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1?42% (SE 0?05) in the dulaglutide group and -1?36% (0?05) in the liraglutide group. Mean treatment difference in HbA1c was -0?06% (95% CI -0?19 to 0?07, pnon-inferiority<0?0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0?34 (SE 1?44) and 0?52 (3?01) events per patient per year, respectively, and no severe hypoglycaemia was reported. INTERPRETATION: Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. FUNDING: Eli Lilly and Company.",1
13547,25022939,"Transdermal rotigotine in advanced Parkinson's disease: a randomized, double-blind, placebo-controlled trial","Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson's disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on-off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were -10.1 ? 9.0 (mean ? standard deviation) in the rotigotine group and -4.4 ? 7.4 in the placebo group (p < 0.001). There was a significantly greater reduction in the off-time (p = 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.",1
13548,25024808,Hepatic failure induced by cyproterone acetate: A case report and literature review,"Cyproterone acetate (CPA) is an anti-androgenic drug that has been used to manage prostate cancer. The drug is well-tolerated, but has hepatotoxic effects. Hepatic failure induced by CPA is rare urologists tend to overlook its severity. We report a patient with metastatic prostate cancer who developed CPA-induced hepatic failure that manifested as bilirubinuria, which was initially misinterpreted as gross hematuria. The patient died despite receiving critical care. The aim of this study is to sound the alarm about CPA-induced hepatic failure.",1
13549,25033383,Efficacy and safety of vismodegib : a new therapeutic agent in the treatment of basal cell carcinoma,"INTRODUCTION: Basal cell carcinoma (BCC) is the most common human malignancy. Treatment options for the minority of patients presenting with locally advanced inoperable or metastatic BCC are very limited. The hedgehog (Hh) pathway plays a crucial role in the pathogenesis of BCC. Recent advances in targeting this pathway have led to the development of a first-in-class, small-molecule oral Hh inhibitor, vismodegib (Erivedge�, Genentech). AREAS COVERED: In this article, we review vismodegib with regard to its mechanism of action, clinical efficacy, safety and tolerability, and we consider the causes of emerging resistance to the drug. EXPERT OPINION: Vismodegib is a welcome addition to the treatment paradigm for BCC. Approval was based on Phase II evidence, the patient number was relatively small, there was no control group or a comparator group and survival data have not been presented so longer term follow-up and larger exposure to the drug is required to fully appreciate its clinical utility into the future. With ongoing use of the drug in the nontrial population and further studies investigating its use in both early- and later-stage disease, we will get a better understanding of the drug and determine its place in the armamentarium against BCC.",1
13550,25034862,Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial,"""BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ?18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0?96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. FUNDING: Merck Sharp and Dohme.""",1
13551,25038354,Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection,"IMPORTANCE: Treatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon. OBJECTIVE: To determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment. DESIGN, SETTING, AND PARTICIPANTS: Open-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/?L or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/?L. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants. INTERVENTIONS: Treatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary study outcome was the proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks (SVR12) after cessation of HCV therapy. RESULTS: Among treatment-naive participants, 87 patients (76%) of 114 (95% CI, 67%-84%) with genotype 1, 23 patients (88%) of 26 with genotype 2 (95% CI, 70%-985), and 28 patients (67%) of 42 with genotype 3 (95% CI, 51%-80%) achieved SVR12. Among treatment-experienced participants, 22 patients (92%) of 24 with genotype 2 (95% CI, 73%-99%) and 16 patients (94%) of 17 (95% CI, 71%-100%) achieved SVR12. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12. Further studies of this oral regimen in diverse populations of coinfected patients are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01667731.",1
13552,25039593,Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis,"""BACKGROUND: Psoriasis is a chronic, recurrent skin disease that affects approximately 2-3% of the world's population, and can significantly impair patients' wellbeing and their physical and mental functioning. AIM: To systematically evaluate the efficacy and safety of ustekinumab versus placebo for psoriasis. METHODS: We performed a systematic review of all the relevant published literature relating to randomized controlled trials (RCTs) of ustekinumab from 1990 to August 2013. Relative ratios (RRs) and 95% confidence intervals (CIs) were calculated, and meta-analysis was conducted with Revman5.2.6 software, while GRADE Profile 3.6 was used to evaluate the quality of the evidence. RESULTS: In total, 9 RCTs involving 11 381 patients were included. The meta-analysis results were as follows. (i) At the end of 12 weeks, the ustekinumab group had a larger number of patients with improvement in Psoriasis Area and Severity Index (PASI) of at least 50% (PASI50), at least 75% (PASI75) and at least 90% (PASI90); a larger number with improvement in Physician's Global Assessment (PGA), and a larger number with improvement in Dermatology Life Quality Index (DLQI) to a score of 0 or 1 (no effect at all on patient's life). (ii) There was no significant difference in efficacy between 45 mg and 90 mg ustekinumab at the end of 12 weeks. (iii) There was no obvious difference between the ustekinumab and placebo groups in the incidence of adverse events over 5 years. There was also no obvious difference between the two doses of ustekinumab after 5 years. CONCLUSION: Our results indicate that ustekinumab is safe for patients with moderate to severe plaque psoriasis over a period of 5 years, and it is effective after 12 weeks. There was no significant superiority in efficacy between the 45 mg and 90 mg doses for short-term therapy. Results of the long-term safety evaluation are consistent with short-term reports of ustekinumab safety. More long-term studies and RCTs are needed to validate these results.""",1
13553,25039930,"Two-year outcomes in initial survivors with acute liver failure: results from a prospective, multicentre study","BACKGROUND & AIMS: The long-term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2-year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG). METHODS: Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed. RESULTS: Two-year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous survivors (SS) (89.5%) and 200 non-APAP SS (75.5%) (P < 0.0001). The causes of death were similar in the three groups but the time to death was significantly longer in the LT recipients (P < 0.0001). Independent predictors of 2-year mortality in the APAP group were a high serum phosphate level and patient age (c-statistic = 0.65 (0.54, 0.76)), patient age and days from jaundice to ALF onset in the non-APAP group (c-statistic = 0.69 (0.60, 0.78)), and patient age, days from jaundice, and higher coma grade in the LT recipients (c-statistic = 0.74 (0.61, 0.87)). The LT recipients were significantly more likely to be employed and have a higher educational level (P < 0.05). CONCLUSIONS: Two-year outcomes in initial survivors of ALF are generally good but non-APAP patients have a significantly lower survival which may relate to pre-existing medical comorbidities. Spontaneous survivors with APAP overdose experience substantial morbidity during follow-up from ongoing psychiatric and substance abuse issues.",1
13554,25041517,Early predictors of severe acetaminophen-induced hepatotoxicity in a paediatric population referred to a tertiary paediatric department,"AIM: The data on severe acetaminophen-induced hepatotoxicity in children are very limited. This study explored the dose-response relationship between ingested acetaminophen and hepatotoxicity, the early biochemical and clinical predictors of hepatotoxicity, the impact of early N-acetylcysteine treatment on hepatotoxicity and the incidence of nephrotoxicity. METHODS: We carried out a retrospective case study on 25 children aged 11-16 years with severe acetaminophen poisoning. RESULTS: Initial biochemical parameters predicted hepatotoxicity, defined as the maximum levels of the international normalised ratio (INR) and alanine aminotransferase (ALT). Significant relationships were found between: (1) the maximal INR and, for example, the initial bilirubin (p = 0.0003) and initial phosphate (p = 0.003), (2) the maximal ALT and, for example, the initial INR (p = 0.0003) and initial creatinine (p = 0.002), (3) the number of prehospital vomiting episodes and, for example, the maximal INR (p = 0.013) and maximum ALT (p = 0.0005) and (4) the time of N-acetylcysteine initiation and, for example, maximum ALT (p = 0.001) and maximum gamma-glutamyl transferase (GGT) (p = 0.007). The incidence of nephrotoxicity was 12%. There was no significant relationship between the amount of ingested acetaminophen and the degree of hepatotoxicity. CONCLUSION: Paediatric patients at increased risk of severe hepatotoxicity were identified by early biochemical parameters, prehospital vomiting episodes and latency time before N-acetylcysteine initiation.",1
13555,25043514,Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study,"""There is no licensed treatment for non-alcoholic fatty liver disease (NAFLD), a condition that increases risk of chronic liver disease, type 2 diabetes and cardiovascular disease. We tested whether 15-18 months treatment with docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (Omacor/Lovaza) (4 g/day) decreased liver fat and improved two histologically-validated liver fibrosis biomarker scores (primary outcomes). Patients with NAFLD were randomised in a double blind placebo-controlled trial [DHA+EPA(n=51), placebo(n=52)]. We quantified liver fat percentage (%) by magnetic resonance spectroscopy in three liver zones. We measured liver fibrosis using two validated scores. We tested adherence to the intervention (Omacor group) and contamination (with DHA and EPA) (placebo group) by measuring erythrocyte percentage DHA and EPA enrichment (gas chromatography). We undertook multivariable linear regression to test effects of: a) DHA+EPA treatment (ITT analyses) and b) erythrocyte DHA and EPA enrichment (secondary analysis). Median (IQR) baseline and end of study liver fat% were 21.7 (19.3) and 19.7 (18.0) (placebo), and 23.0 (36.2) and 16.3 (22.0), (DHA+EPA). In the fully adjusted regression model there was a trend towards improvement in liver fat% with DHA+EPA treatment (?=-3.64 (95%CI -8.0,0.8); p=0.1) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group. Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% (for each 1% enrichment, ?=-1.70 (95%CI -2.9,-0.5); p=0.007). No improvement in the fibrosis scores occurred. Conclusion. Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat%. Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD. (Hepatology 2014;).""",1
13556,25046325,Treatment of atrial fibrillation,,1
13557,25047090,"A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration","BACKGROUND: Acetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days. METHODS: A randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction. RESULTS: 157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction. CONCLUSIONS: A minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued. TRIALS REGISTRATION: Clintrials.gov NCT00743093 registered August 26, 2008.",1
13558,25052739,DRESS syndrome due to antibiotic therapy of osteoarticular infections in children: two case reports,"Osteoarticular infection in children frequently occurs before 10 years of age. Surgical drainage is sometimes required, whereas acute osteomyelitis can be treated with antibiotic therapy alone. The duration of antibiotic therapy varies, 2 weeks is sufficient for septic arthritis, whereas 6 weeks is often required for complicated cases. Some of these antibiotic drugs present direct complications with low clinical impact in certain individuals. Hypersensitivity to these drugs causes different reactions in children. DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe and potentially life-threatening drug reaction. It is characterised by high fever, malaise, lymphadenopathy and skin rash. From a clinical perspective, these symptoms can lead to an exacerbation of the initial infectious process for which treatment was commenced. The liver is the organ most often affected in DRESS syndrome associated with haematological changes, potentially similar to sepsis. We present two cases of children with osteoarticular infections who developed DRESS syndrome after antibiotic therapy. Both patients made a complete recovery after cessation of the antibiotic drugs used.",1
13559,25054756,The use of ustekinumab in a patient with severe psoriasis and positive HBV serology,"Psoriasis is a chronic inflammatory, immune-mediated disease that affects 1% to 2% of the world's population. Immunobiological medications are prescribed for certain patients with severe forms of psoriasis, however, these drugs increase the risk of reactivation of viral diseases such as hepatitis B. We report the case of a patient with severe psoriasis with positive serology for the Hepatitis B virus, who received ustekinumab (a human monoclonal antibody against interleukin 12 and 23). In this patient, the use of ustekinumab did not reactivate the Hepatitis B virus. Given the high prevalence of chronic viral infections in patients who are candidates for biologic therapy, as well as the potential for reactivate chronic viral illness, randomized controlled studies are needed to assess the risks and benefits of such therapy in these populations.",1
13560,25070475,Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience,"OBJECTIVE: Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. METHODS: We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ?50% compared to baseline. RESULTS: Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). SIGNIFICANCE: Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology.",1
13561,25073680,[Toxic hepatocellular hepatitis due to labetalol],,1
13562,25078304,"All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study","""BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (?2% each). INTERPRETATION: Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING: Bristol-Myers Squibb.""",1
13563,25081276,Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice,"BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ?M) and NTBC-levels in the therapeutic range (20-40 ?M). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.",1
13564,25087600,"A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine","""OBJECTIVE: This randomised, double-blind, 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine(10-20 mg/day) versus agomelatine (25-50 mg/day) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) monotherapy. METHODS: Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine. Primary endpoint was change from baseline to week 8 in the Montgomery-?sberg Depression Rating Scale (MADRS) total score analysed by mixed model for repeated measurements, using a noninferiority test followed by a superiority test. Secondary endpoints included response and remission rates, anxiety symptoms(Hamilton Anxiety Rating Scale), Clinical Global Impression, overall functioning (Sheehan Disability Scale), health-related quality of life(EuroQol 5 Dimensions), productivity (work limitation questionnaire) and family functioning (Depression and Family Functioning Scale). RESULTS: Primary endpoint noninferiority was established and vortioxetine (n = 252) was superior to agomelatine (n = 241) by 2.2 MADRS points (p<0.01). Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12; MADRS, Hamilton Anxiety Rating Scale, Clinical Global Impression, Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards; work limitation questionnaire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12. Fewer patients withdrew because of adverse events with vortioxetine (5.9% vs 9.5%). Adverse events (incidence ?5%) were nausea, headache, dizziness and somnolence. CONCLUSIONS: Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy. Vortioxetine was safe and well tolerated.""",1
13565,25091255,Outbreak of severe hepatitis linked to weight-loss supplement OxyELITE Pro,,1
13566,25095897,"Beriberi, a severe complication after metabolic surgery - review of the literature","BACKGROUND: The epidemic growth of morbid obesity has led to an increase in the number of bariatric interventions. During the distribution process of bariatric surgical interventions, the risk for severe nutritious complications such as bariatric beriberi can rise. METHODS: By means of systematic literature review, epidemiological data, clinical characteristics and diagnostic as well as therapeutic recommendations for bariatric beriberi were elicited. Databases and registries such as PubMed, Cochrane and Ovid were searched for a defined time period with the key words 'lack of thiamine' / 'Wernicke-Korsakoff syndrome' / 'encephalopathy' after bariatric surgical interventions. RESULTS: Up to December 2013, overall 255 patients had been found as published cases, indicating that the risk for the postoperative occurrence of thiamine deficiency and Wernicke-Korsakoff syndrome is increased in women. In addition, the risk correlates with patient's age. The majority of patients developed symptoms of a dry beriberi with peripheral neuritis, ataxia and paraplegia, indicating an advanced stage of disease approximately 4-12 weeks postoperatively. Laboratory analysis in case of a suspicious clinical finding is the appropriate diagnostics. As treatment, prompt initiation of parenteral thiamine substitution under clinical monitoring is required. CONCLUSION: Bariatric beriberi can occur within the first 1-3 postoperative months. To minimize the risk of severe consequences, immediate substitution of thiamine in clinical suspicion or prolonged parenteral nutrition is necessary. A delayed diagnosis or missing the correct diagnosis can lead to irreversible damages of the CNS with coma and fatal outcome. Knowledge on the subject, including development of thiamine deficiency, symptomatology and emergency treatment, are considered essential for bariatric surgeons but also for further medical disciplines involved in treatment.",1
13567,25097577,Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard(�)/Depo-Eligard(�)) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study,"INTRODUCTION: The 1-, 3- and 6- month biodegradable polymer matrix depot formulations of leuprorelin acetate (Eligard(�)/Depo-Eligard(�), Astellas Pharma Inc/BV) were shown to reduce testosterone and prostate-specific antigen levels and to be well tolerated in patients with advanced prostate cancer in several clinical trials. This study aimed at evaluating the efficacy, safety and tolerability of the 1- and 3-month leuprorelin acetate depot formulations in daily clinical practice. MATERIAL AND METHODS: A prospective, open-label, non-interventional, phase IV study (MANTA) was conducted in 243 Belgian prostate cancer patients who had been prescribed the 1-month (7.5 mg) or 3-month (22.5 mg) leuprorelin acetate depot formulation. Patients were followed for at least 3 months. RESULTS: Median serum prostate-specific antigen levels were reduced by 95% from 12.0 ng/ml at baseline to 0.60 ng/ml after a median follow-up time of 132 days, while median testosterone levels were reduced by 94% from 360 ng/dl to 20 ng/dl. Partial or complete treatment response was observed in 83% of patients at the final visit (according to the physician's assessment). Ninety-two patients (37.86%) experienced treatment-emergent adverse events, with injection site-related reactions, hot flushes and tumor flare being the most common ones. Overall safety and tolerability of the leuprorelin acetate depot formulation were rated as good or excellent by 90% of physicians. CONCLUSIONS: These data are consistent with efficacy and tolerability results from clinical trials. They confirm that the 1- and 3-month leuprorelin acetate depot formulations are well tolerated and reliably lower serum prostate-specific antigen and testosterone levels in routine clinical practice.",1
13568,25103549,"Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study","PURPOSE: A large, randomized, double-blind, Phase III core study demonstrated that pasireotide LAR was significantly superior to octreotide LAR at providing GH <2.5 ?g/L and normalized IGF-1 after 12 months' treatment in patients with acromegaly. We report the efficacy and safety of pasireotide LAR and octreotide LAR after up to 26 months' treatment. METHODS: Patients with GH <2.5 ?g/L and IGF-1 ?1? ULN at month 12, or patients considered to be experiencing clinical benefit, were eligible to continue receiving their randomized therapy in the extension. Efficacy and safety in the pasireotide LAR and octreotide LAR groups were evaluated for up to 26 months. RESULTS: Overall, 120 patients who completed the core study continued receiving pasireotide LAR (n = 74) or octreotide LAR (n = 46) in the extension. At month 25, biochemical control (GH <2.5 ?g/L and normal IGF-1) was achieved by 48.6% (36/74) and 45.7% (21/46) of patients in the pasireotide LAR and octreotide LAR arms [60.8% (45/74) and 52.2% (24/46) when including patients with IGF-1 < LLN], respectively. In total, 74.7% of pasireotide LAR and 71.6% of octreotide LAR patients had tumor volume decrease ?20% from baseline to month 26. Most AEs were mild or moderate. Hyperglycemia-related AEs were seen in 62.9 and 25.0% of pasireotide LAR and octreotide LAR patients, respectively. No new safety signals were observed in the extension compared with the core study. CONCLUSIONS: GH and IGF-1 suppression is maintained for up to 25 months during pasireotide LAR treatment. The safety profile of pasireotide LAR is typical of a somatostatin analogue, except for the frequency and degree of hyperglycemia.",1
13569,25104617,Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer,"""INTRODUCTION: In the PARAMOUNT (""""A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer"""") trial, patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL. MATERIALS AND METHODS: Patients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m(2), day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed. RESULTS: A median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ? SD 7.9 ? 8.3; placebo 1-38; mean ? SD 5.0 ? 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ? 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms. CONCLUSION: PARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.""",1
13570,25110258,Miscellaneous adverse events with biologic agents (excludes infection and malignancy),"Anti-tumor necrosis factor-alpha (anti-TNF) agents are frequently used in the treatment of inflammatory bowel disease (IBD). Currently, there are 4 anti-TNF therapies that are Food and Drug Administration-approved for moderate to severe IBD: infliximab, adalimumab, golimumab, and certolizumab pegol. For most noninfectious, nonmalignant adverse events, cessation of anti-TNF therapy typically leads to improvement or resolution of drug-induced complications. In this article, the current knowledge regarding the noninfectious and nonmalignant toxicities associated with anti-TNF agents is summarized.",1
13571,25112584,Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation,"""BACKGROUND: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. AIM: To evaluate the long-term safety and tolerability of naloxegol, an oral, peripherally acting ?-opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC. METHODS: A 52-week, multicenter, open-label, randomised, parallel-group phase 3 study was conducted in out-patients taking 30-1000 morphine-equivalent units per day for ?4 weeks. Patients were randomised 2:1 to receive naloxegol 25 mg/day or usual-care (UC; investigator-chosen laxative regimen) treatment for OIC. RESULTS: The safety set comprised 804 patients (naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with naloxegol and 72.2% with UC. Treatment-emergent AEs occurring more frequently for naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most naloxegol-emergent gastrointestinal AEs occurred early, resolving during or after naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations. CONCLUSION: In patients with noncancer pain and opioid-induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.""",1
13572,25114785,"The risk of cutaneous adverse reactions among patients with the HLA-A* 31:01 allele who are given carbamazepine, oxcarbazepine or eslicarbazepine: a perspective review","""Carbamazepine is a drug that is widely used for the treatment of epilepsy, trigeminal neuralgia and bipolar disorder. This drug is also known to cause cutaneous adverse drug reactions (cADRs) in up to 10% of patients. The recent progress in pharmacogenetics has revealed that human leukocyte antigen (HLA) genotypes are associated with a susceptibility to the cADRs caused by particular drugs. For carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis, very strong associations with HLA-B*15:02 have been found mainly in patients of Southeastern Asian origin. In some countries, prescreening HLA-B*15:02 allele has already been put to practical use as a biomarker to avoid the life-threatening adverse drug reactions. In this review, another risk factor for carbamazepine-induced cADRs is discussed, namely HLA-A*31:01. We compare the strength of the association between HLA-A*31:01 and carbamazepine-induced cADRs based on reports for various ethnic populations; discuss the difference between the HLA-A*31:01 and HLA-B*15:02 biomarkers and the usefulness of prescreening HLA-A*31:01 to detect patients at high risk for carbamazepine-induced cADRs; and refer to points that remain to be resolved.""",1
13573,25118801,Glycerol phenylbutyrate (Ravicti) for urea cycle disorders,,1
13574,25131534,Risk of drug-induced liver injury from tumor necrosis factor antagonists,"""BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk. METHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n�= 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n�= 22). RESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n�= 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 ?mol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P�= .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI. CONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.""",1
13575,25134476,A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis,"Existing therapies for multi-drug resistant tuberculosis (MDR-TB) have substantial limitations, in terms of their effectiveness, side-effect profile, and complexity of administration. Bedaquiline is a novel diarylquinoline antibiotic that has recently been investigated as an adjunct to existing therapies for MDR-TB. Currently, limited clinical data are available to evaluate the drug's safety and effectiveness. In two small randomized-controlled clinical studies, bedaquiline given for 8 or 24�weeks has been shown to improve surrogate microbiological markers of treatment response, but trials have not yet evaluated its impact on clinical failure and relapse. Safety concerns include an increased mortality in the bedaquiline arm of one study, an increased incidence of QT segment prolongation on electrocardiogram, and hepatotoxicity. Until further research data are available, the use of bedaquiline should be confined to settings where carefully selected patients can be closely monitored.",1
13576,25136024,Pharmacokinetics of tedizolid in subjects with renal or hepatic impairment,"""Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls ( approximately 8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration ( approximately 9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].).""",1
13577,25146841,Infliximab leading to autoimmune hepatitis: an increasingly recognized side effect,,1
13578,25155146,"Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin","""AIMS: To show that albiglutide, a glucagon-like peptide-1 receptor agonist, is an effective and generally safe treatment to improve glycaemic control in patients with type 2 diabetes mellitus whose hyperglycaemia is inadequately controlled with pioglitazone (with or without metformin). METHODS: In this 3-year, randomized, double-blind, placebo-controlled study, 310 adult patients on a regimen of pioglitazone (with or without metformin) were randomly assigned to receive additional treatment with albiglutide [30 mg subcutaneous (s.c.) once weekly, n = 155] or matching placebo (n = 155). The primary efficacy endpoint was change from baseline to week 52 (intention-to-treat) in glycated haemoglobin (HbA1c). RESULTS: The model-adjusted change from baseline in HbA1c at week 52 was significantly better with albiglutide than with placebo (-0.8%, 95% confidence interval -1.0, -0.6; p < 0.0001). Change from baseline fasting plasma glucose was -1.3 mmol/l in the albiglutide group and +0.4 mmol/l in the placebo group (p < 0.0001); a significantly higher percentage of patients reached the HbA1c goals with albiglutide (p < 0.0001), and the rate of hyperglycaemia rescue up to week 52 for albiglutide was 24.4 versus 47.7% for placebo (p < 0.0001). Albiglutide plus pioglitazone had no impact on weight, and severe hypoglycaemia was observed rarely (n = 2). With few exceptions, the results of safety assessments were similar between the groups, and most adverse events (AEs) were mild or moderate. The 52-week incidence rates for gastrointestinal AEs for albiglutide and placebo were: 31.3 and 29.8%, respectively (diarrhoea: 11.3 and 8.6%; nausea: 10.7 and 11.3%; vomiting: 4.0 and 4.0%). CONCLUSIONS: Albiglutide 30 mg administered once weekly as an add-on to pioglitazone (with or without metformin) provided effective and durable glucose lowering and was generally well tolerated.""",1
13579,25155865,Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban,"IMPORTANCE: Treatment with the new oral anticoagulant rivaroxaban can be associated with severe liver injury. OBSERVATIONS: We report 2 patients with predominantly hepatocellular liver injury that had onset during treatment with rivaroxaban. Both were symptomatic, had massively elevated transaminase activity levels and hyperbilirubinemia, and fulfilled the criteria of Hy's law. Liver biopsy in 1 patient revealed centroacinar hepatocyte necrosis as the predominant finding. Both patients showed a rapid biochemical and clinical recovery after discontinuing rivaroxaban therapy. Between 2008 and 2013, 42 cases of liver injury possibly associated with rivaroxaban treatment have been reported to the Swiss Agency of Therapeutic Products (Swissmedic). Thirteen of these patients fulfilled the criteria of Hy's law. CONCLUSIONS AND RELEVANCE: Treatment with rivaroxaban can be associated with severe, symptomatic liver injury. Physicians should be aware of this adverse drug reaction. We propose rapid discontinuation of treatment with rivaroxaban in case of symptomatic liver injury and, taking into account its severity, avoiding reexposure.",1
13580,25160028,Acetaminophen-induced liver injury in a woman with febrile flare of systemic lupus erythematosus,,1
13581,25163514,Risk factors for severe or fatal drug-induced liver injury from amoxicillin-clavulanic acid,"""AIM: To identify risk factors for severe liver injury or mortality from drug-induced liver injury (DILI) from amoxicillin-clavulanic acid. To determine if co-administration of potentially hepatotoxic drugs was associated with an increased risk of DILI from amoxicillin-clavulanic acid. METHODS: We conducted a systematic review of the published work and data extraction of articles on DILI injury from amoxicillin-clavulanic acid. Potentially hepatotoxic drugs were defined as medications with DILI listed in the package insert or reported in the published work. Individual patient data were entered into an SPSS (version 17.0; Chicago, IL, USA) database and were analyzed using the ?(2) -test or Fisher's exact test; Student's t-test; and non-parametric tests such as Mann-Whitney U-test as appropriate. RESULTS: We identified 3932 articles of which 41 publications with 255 reported cases met inclusion criteria. Mortality from DILI from amoxicillin-clavulanic acid was increased among patients receiving concomitant potentially hepatotoxic drugs compared with patients not on concomitant potential hepatotoxic drugs (21.4% [3/14] vs 2.3% [2/89], P?=?0.017]. The most common classes of concomitant drugs were: antimicrobials, analgesics and hormonal therapy. Female patients were more likely to receive a concomitant potentially hepatotoxic medication (25% vs 9.1% for men, P?=?0.05). CONCLUSION: Patients who developed severe or fatal DILI from amoxicillin-clavulanic acid were more likely to be on concomitant hepatotoxic medications. Female patients were more likely to receive concomitant hepatotoxic drugs. Further studies are needed to investigate drug interaction between amoxicillin-clavulanic acid and concomitant potentially hepatotoxic drugs.""",1
13582,25173087,Rotigotine: the first new chemical entity for transdermal drug delivery,"Rotigotine is the first, and to date, the only new chemical entity to be formulated for transdermal delivery. Although first approved for the management of Parkinson's disease in Europe in 2007 and Restless Leg Syndrome in 2008, the story of rotigotine began more than twenty years earlier. In this review we outline the historical development of this molecule and its route to licensed medicine status. It has very favourable physicochemical properties for transdermal delivery but it took a significant period to develop from concept to market. The stability problems which led to the temporary withdrawal of the patch are examined and the major clinical studies demonstrating efficacy and safety are outlined. Alternative new therapeutic modalities are also considered.",1
13583,25178868,Progression to hepatitis and fibrosis secondary to lomitapide use: selecting the next course of action,,1
13584,25185099,"Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer","""PURPOSE: Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. PATIENTS AND METHODS: In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. RESULTS: Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. CONCLUSION: Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.""",1
13585,25192851,"Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial","""BACKGROUND: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ?3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ?30 days from a preceding clinical event, present for ?24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700. FINDINGS: Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0?574 [95% CI 0?379-0?869]; p=0?0087) and at the 7 mg dose (0?628 [0?416-0?949]; p=0?0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0?651 [95% CI 0?515-0?822]; p=0?0003) and at the 7 mg dose (0?686 [0?540-0?871]; p=0?0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). INTERPRETATION: TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. FUNDING: Genzyme, a Sanofi company.""",1
13586,25196837,"Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial","Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-na?ve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-na?ve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-na?ve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.",1
13587,25199060,Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma,"""BACKGROUND: Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. METHODS: In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. RESULTS: The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P=0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P=0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P=0.04) and a reduction of 0.52 points with respect to asthma symptoms (P=0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. (Funded by GlaxoSmithKline; SIRIUS ClinicalTrials.gov number, NCT01691508.).""",1
13588,25204464,Tasimelteon: a melatonin receptor agonist for non-24-hour sleep-wake disorder,"""OBJECTIVE: To examine the efficacy of tasimelteon for the treatment of non-24-hour sleep-wake disorder using evidence from controlled clinical trials. DATA SOURCES: Citations in Google Scholar and PubMed from January 1, 2008, to May 31, 2014, were identified using tasimelteon as the search term. STUDY SELECTION AND DATA EXTRACTION: Results were limited to human trials published in English. Trials that compared tasimelteon with placebo were included. DATA SYNTHESIS: A phase II trial (n = 39) evaluated the effects of tasimelteon versus placebo on improvements in sleep efficiency and the ability to shift circadian rhythms over 3 days. Significant shifts in circadian rhythm were only observed for 100-mg tasimelteon. A phase III trial (n = 412) evaluated the effects of tasimelteon versus placebo on assessment of latency to persistent sleep and wake after sleep onset; significant advantages were observed in tasimelteon recipients. The SET (Safety and Efficacy of Tasimelteon) trial (n = 84) enrolled blind men and women with Non-24. They received placebo or tasimelteon 20 mg daily. Tasimelteon recipients had significantly (P = 0.0025) better entrainment and N24CRS scores. The RESET (Randomized Withdrawal Study of the Efficacy and Safety of Tasimelteon) trial (n = 20) enrolled entrained participants from the SET trial who received 20 mg of tasimelteon or placebo daily for 8 weeks. The primary objective was to evaluate the maintenance of effect of tasimelteon to entrain circadian rhythms. Tasimelteon was associated with significantly (P = 0.0055) greater entrainment than placebo. CONCLUSION: Tasimelteon improves sleep initiation and maintenance in patients with Non-24 who have a shift in endogenous circadian rhythms. However, the cost of this agent limits its use.""",1
13589,25210144,Incidence and clinical features of drug-induced lung injury in patients with advanced colorectal cancer receiving cetuximab: results of a prospective multicenter registry,"OBJECTIVE: We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system. METHODS: We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy. RESULTS: Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days). CONCLUSIONS: The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients.",1
13590,25211301,Vorapaxar (Zontivity) for prevention of thrombotic cardiovascular events,,1
13591,25211304,Miltefosine (Impavido) for leishmaniasis,,1
13592,25218788,Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET,"""BACKGROUND & AIMS: The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated. METHODS: In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up. RESULTS: A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response. CONCLUSIONS: In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.""",1
13593,25220180,Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: a French multicenter study,"The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5years (range: 1.6-35). Two patients developed Waldenstr�m's macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.",1
13594,25223216,Hereditary tyrosinemia type 1 in Turkey: twenty year single-center experience,"BACKGROUND: Hereditary tyrosinemia type 1(HT1) is a chronic disorder leading to severe hepatic, renal and peripheral nerve damage if left untreated. Despite nitisinone treatment HT1 still carries the risks of hepatocellular carcinoma (HCC) and neuropsychological outcome. METHODS: A retrospective single center study was carried out based on the phenotype, therapy and outcome in 38 Turkish patients with HT1 diagnosed during the last 20 years. RESULTS: None of the patients was diagnosed on newborn screening. The patients were grouped according to acute, subacute and chronic forms of the disorder. The main clinical manifestations were hepatosplenomegaly, liver and renal tubular dysfunction. Thirty-six patients were treated with nitisinone. The mean duration of nitisinone treatment was 64 months and the mean dosage was 1.2 mg/kg/day. Dietary compliance problems were frequent. Eleven patients had cognitive evaluation (mean total IQ, 84 points). Six patients had living donor liver transplantation despite nitisinone treatment: three due to suspected HCC, two for non-compliance to diet, and one for both, at a median age of 90 months. CONCLUSION: Nitisinone treatment is effective and improves both short- and long-term prognosis of HT1. Early diagnosis on newborn screening is needed because delay in treatment increases the risk of the persistence of hepatic disease and HCC. Interruption of the drug can lead to re-occurrence of hepatocellular damage and neurological crisis. Increased ?-fetoprotein and new hypoechoic nodule formation are the warning signs for HCC.",1
13595,25224347,Safety of anti-tumor necrosis factor therapies in arthritis patients,"PURPOSE: Inflammatory and rheumatic arthritis remain leading causes of disability worldwide. The arthritis therapeutic area commands the largest market for the prescription of biological and non-steroidal anti-inflammatory drugs (NSAID). Yet biotechnology and pharmaceutical companies conducting research and providing therapeutics in this area frequently face challenges in patient safety. The purpose of our study was to assess safety of anti-tumor necrosis factor therapies in arthritis patients. METHODS: The present study systematically reviews adverse events of biologicals alone or in the presence of NSAIDs and other immunosuppressant therapeutics such as disease-modifying antirheumatic drugs (DMARD). We assessed the rheumatology literature that included clinical trials with anti-tumor necrosis factor (TNF) biologicals and case reports published between 2010 and 2014. RESULTS: Currently approved anti-TNF biologicals in arthritis include the monoclonal antibodies infliximab, adalimumab, certolizumab pegol and golimumab, and the fusion protein etanercept. The most frequently-reported adverse event was infection. We grouped the adverse reactions as immune-mediated, hypersensitivity syndrome reactions including cutaneous and hepatic manifestation, neurological, hematological, and malignancy. DISCUSSION: Most adverse events are due to the failure of host immunological control, which involves susceptibility to the drug itself, or de novo infection or reactivation of a latent bacterial or viral infection, often with a different expression of disease. Drug-induced liver injury associated with anti-TNF biologicals must be kept in mind when evaluating patients with increased liver enzymes. CONCLUSION: Risk assessment in individuals undergoing treatment with biologicals represents a step towards achieving a personalized medicine approach to identify those patients that will safely benefit from this therapeutic approach. Patients and physicians must be alert of anti-TNF agents as potential causes of drug-induced liver injury and monitor the therapies. Personalizing therapeutic pharmacovigilance promises to optimize benefits while minimizing side effects.",1
13596,25228327,Paracetamol-associated acute liver failure in Australian and New Zealand children: high rate of medication errors,"BACKGROUND: In children, paracetamol overdose due to deliberate self-poisoning, accidental exposure or medication errors can lead to paediatric acute liver failure and death. In Australia and New Zealand, the nature of ingestion and outcomes of paracetamol-associated paediatric acute liver failure have not been described. OBJECTIVE: To describe the nature and outcomes of paracetamol-associated paediatric acute liver failure. DESIGN: Retrospective analysis of paracetamol-associated paediatric acute liver failure cases presenting 2002-2012. SETTING: New Zealand and Queensland Paediatric Liver Transplant Services. RESULTS: 14 of 54 cases of paediatric acute liver failure were attributed to paracetamol, the majority were secondary to medication errors. 12 of the 14 children were under the age of 5?years. Seven children received doses in excess of 120?mg/kg/day. Many of the other children received either a double dose, too frequent administration, coadministration of other medicines containing paracetamol or regular paracetamol for up to 24?days. Three children underwent transplant. One of these and one other child died. CONCLUSIONS: In Australia and New Zealand, paracetamol overdose secondary to medication errors is the leading cause of paediatric acute liver failure. A review of regional safety practices surrounding paracetamol use in children is indicated.",1
13597,25232317,Severe Liver Damage and Nonallergic Bronchitis with Eosinophilia in a Patient with Follicular Lymphoma Treated with Bendamustine plus Rituximab,"A 66-year-old female with follicular lymphoma developed severe liver dysfunction and nonallergic bronchitis after 1 cycle of treatment with bendamustine and rituximab (BR) therapy. Simultaneously, eosinophilia was observed. Further examination revealed negative results for both hepatitis virus-induced liver damage and lymphoma cell invasion into the liver. No bacterial, fungal, or cytomegaloviral infections of the respiratory tract were observed. The patient was treated with steroid pulse therapy followed by prednisolone with complete resolution of her symptoms. This suggests that eosinophilia induced by the treatment with BR may result in liver dysfunction and nonallergic bronchitis.",1
13598,25232777,"Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the Pediatric AIDS Clinical Trials Group Protocol 1020A","""BACKGROUND: Atazanavir (ATV) is an attractive option for the treatment of Pediatric HIV infection, based on once-daily dosing and the availability of a formulation appropriate for younger children. Pediatric AIDS Clinical Trials Group 1020A was a phase I/II open label study of ATV (with/without ritonavir [RTV] boosting)-based treatment of HIV-infected children; here we report the long-term safety and virologic and immunologic responses. METHODS: Antiretroviral-na?ve and experienced children, ages 91 days to 21 years, with baseline plasma HIV RNA > 5000 copies/mL (cpm) were enrolled at sites in the United States and South Africa. RESULTS: Of 195 children enrolled, 142 (73%) subjects received ATV-based regimens at the final protocol recommended dose; 58% were treatment naive. Overall, at week 24, 84/139 subjects (60.4%) and at week 48, 83/142 (58.5%) had HIV RNA ? 400 cpm. At week 48, 69.5% of na?ve and 43.3% of experienced subjects had HIV RNA ? 400 cpm; median CD4 increase was 196.5 cells/mm. The primary adverse event (AE) was increased serum bilirubin; 9% of subjects had levels ? 5.1 times upper limit of normal (ULN) and 1.4% noted jaundice. Three percent of subjects experienced grade 2 or 3 prolongation in PR or QTc intervals. At week 48, there was a 15% increase in total cholesterol (TC), with TC > 199 mg/dL increasing from 1% at baseline to 5.7%. CONCLUSIONS: Use of once-daily ATV, with/without RTV, was safe and well tolerated in children, with acceptable levels of viral suppression and CD4 count increase. The primary AE, as expected, was an increase in bilirubin levels.""",1
13599,25239629,Possible amlodipine-induced hepatotoxicity after stem cell transplant,"""OBJECTIVE: To report the occurrence of hepatotoxicity in a patient initiated on amlodipine. A review of other reports of amlodipine hepatotoxicity is also provided. CASE SUMMARY: A 34-year-old patient was admitted for worsening gastrointestinal graft versus host disease 100 days after an allogeneic stem cell transplant and treated with high-dose systemic steroids. Amlodipine was started for steroid-induced hypertension; 11 days after its initiation, alanine aminotransferase and aspartate aminotransferase peaked at 630 and 421 IU/L, respectively. Total bilirubin and alkaline phosphatase remained normal. A liver biopsy interpreted the liver injury as being possibly drug induced. Amlodipine, the most recently added medication, was discontinued, and transaminases trended down to normal within 2 weeks. DISCUSSION: Allogeneic stem cell transplant patients are often prescribed many medications that carry the risk of hepatotoxicity. Amlodipine, ondansetron, and tacrolimus all have literature support for hepatotoxicity. Amlodipine, however, was the only agent for which initiation and discontinuation followed the acute rise and fall of liver transaminases. An objective causality assessment for liver toxicity, the RUCAM, revealed that the elevation in transaminases was """"possible"""" drug toxicity caused by amlodipine. The package insert and other case reports of amlodipine hepatotoxicity suggest that it can occur both in the acute and chronic setting, and the injury is characterized as either cholestatic or hepatocellular. CONCLUSION: Amlodipine is a commonly used agent in allogeneic stem cell transplant patients. As the first published case in a hematopoietic stem cell transplantation patient, it brings to light a rare, yet important, event of which clinicians should be aware when caring for patients on this agent.""",1
13600,25242045,"Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial","""BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. METHODS: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1?3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6?47 months (IQR 1?81-13?47) in the panobinostat group and 5?59 months (2?14-11?30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11?99 months [95% CI 10?33-12?94] vs 8?08 months [7?56-9?23]; hazard ratio [HR] 0?63, 95% CI 0?52-0?76; p<0?0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33?64 months (95% CI 31?34-not estimable) for the panobinostat group and 30?39 months (26?87-not estimable) for the placebo group (HR 0?87, 95% CI 0?69-1?10; p=0?26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60?7%, 95% CI 55?7-65?6] for panobinostat vs 208 [54?6%, 49?4-59?7] for placebo; p=0?09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27?6%, 95% CI 23?2-32?4] vs 60 [15?7%, 12?2-19?8]; p=0?00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13?14 months (95% CI 11?76-14?92) in the panobinostat group and 10?87 months (9?23-11?76) in the placebo group, and median time to response (partial response or better) was 1?51 months (1?41-1?64) in the panobinostat group and 2?00 months (1?61-2?79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. FUNDING: Novartis Pharmaceuticals.""",1
13601,25242558,"A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis","""BACKGROUND: Patients with moderate to severe plaque psoriasis demonstrated positive responses to ixekizumab, an anti-interleukin-17A monoclonal antibody, in a phase-II, randomized, placebo-controlled trial. OBJECTIVE: We sought to evaluate long-term efficacy and safety of ixekizumab. METHODS: After receiving 10, 25, 75, or 150 mg of ixekizumab or placebo during randomized, placebo-controlled trial, patients with less than 75% improvement from baseline on the Psoriasis Area and Severity Index (PASI) score (PASI75) entered open-label extension (OLE); patients with PASI75 or higher entered a treatment-free period (weeks 20-32), then entered OLE after meeting response criteria. During OLE, patients received 120 mg of subcutaneous ixekizumab every 4 weeks. RESULTS: In all, 120 patients entered OLE; 103 completed 52 weeks or more of treatment. Overall, 77% of patients achieved PASI75 at week 52 (nonresponder imputation). Patients who responded to treatment in the randomized, placebo-controlled trial maintained a high-level response by week 52 of OLE (PASI75 = 95%; 90% improvement from baseline on the PASI score = 94%; 100% improvement from baseline on the PASI score = 82%). Irrespective of dose in the randomized, placebo-controlled trial, each group had similar response rates at week 52 of OLE. The exposure-adjusted incidence rate for adverse events was 0.47 and for serious adverse events was 0.06 per patient-year during OLE. LIMITATIONS: No control group, small sample sizes, and bias toward retention of patients with positive responses limit interpretation. CONCLUSION: A high proportion of patients responded to ixekizumab therapy and maintained clinical responses over 1 year of treatment with no unexpected safety signals.""",1
13602,25246359,"Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection","""OBJECTIVES: To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir (ABT-450/r) ? ribavirin (RBV) in treatment-na?ve, non-cirrhotic adults with chronic HCV genotype 1-3 infection. METHODS: Patients in this open-label, exploratory, phase 2, multicenter study received ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ? RBV for 12 weeks. Primary efficacy endpoint was HCV RNA < lower limit of quantitation (LLOQ) from week 4 through 12. Sustained virologic response 12 weeks post-treatment (SVR12) was a secondary endpoint. RESULTS: Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was<LLOQ from week 4 through 12 in 10 (100%; 95% CI 69-100), 9 (90%; 56-100), and 7 (70%; 35-93) receiving the RBV-containing regimen and 9 (90%; 56-100), 8 (80%; 44-97), and 2 (18%; 2-52) receiving the RBV-free regimen. Among genotype 1-, 2-, and 3-infected patients, respectively, SVR12 was achieved by 10 (100%), 8 (80%), and 5 (50%) receiving the RBV-containing regimen, and 6 (60%), 6 (60%), and 1 (9%) receiving the RBV-free regimen. The most common adverse events were fatigue, nausea, and headache. One patient discontinued due to an adverse event. CONCLUSIONS: In this study, ombitasvir and ABT-450/r ? RBV regimens were generally well-tolerated. Sustained virologic response was achieved in most patients with HCV genotype 1 or 2 infection, but low SVR rates were observed in HCV genotype 3-infected patients.""",1
13603,25250798,Nimesulide-induced fatal acute liver failure in an elderly woman with metastatic biliary adenocarcinoma. A case report,"""CONTEXT: Nimesulide is a selective inhibitor of the enzyme cyclooxygenase 2. Although considered to be a safe drug, cases of acute hepatitis and fulminant liver failure have been reported in Europe, the United States and South America, especially among elderly female patients. Until now, there had not been any reports in the literature relating to Brazilian subjects. CASE REPORT: An 81-year old female who had been using nimesulide therapy for six days presented hematemesis and epistaxis two days before hospitalization. Clinical examination showed an extensive coagulation disorder, diffuse hematomas, hypotension and tachypnea. Laboratory tests revealed abnormalities in coagulation tests; leukocytosis; reduced platelet, hemoglobin and red blood cell counts; and elevated direct bilirubin, serum aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase and renal function biomarkers. Hepatitis B and C tests were not reactive. Carcinoembryonic antigen (CEA), CA-19-9 and CA-125 levels were increased by, respectively, 1,000, 10,000 and 13 fold, whereas the alpha-fetoprotein level was normal, thus indicating a malignant tumor in the bile duct that did not originate from the liver. Thirty-six hours after hospitalization, the patient's condition worsened, leading to death. The necropsy findings included acute hepatitis with hepatocellular collapse, as well as metastasis of a carcinoma, probably from the bile duct. CONCLUSION: Despite the carcinoma presented by the patient, nimesulide use may have contributed towards the fatal acute liver failure. Until this issue has been clarified, caution is required in prescribing nimesulide for liver disease patients.""",1
13604,25254919,Emergency contraception review: evidence-based recommendations for clinicians,"Several options for emergency contraception are available in the United States. This article describes each method, including efficacy, mode of action, safety, side effect profile, and availability. The most effective emergency contraceptive is the copper intrauterine device (IUD), followed by ulipristal acetate and levonorgestrel pills. Levonorgestrel is available for sale without restrictions, whereas ulipristal acetate is available with prescription only, and the copper IUD must be inserted by a clinician. Although EC pills have not been shown to reduce pregnancy or abortion rates at the population level, they are an important option for individual women seeking to prevent pregnancy after sex.",1
13605,25258420,Ceritinib: a new tyrosine kinase inhibitor for non-small-cell lung cancer,"OBJECTIVE: To review ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small-cell lung cancer (NSCLC). DATA SOURCES: Literature searches were conducted in PubMed, EMBASE (1974 to July week 5, 2014), and Google Scholar using the terms ceritinib, LDK378, and non-small-cell lung cancer. STUDY SELECTION AND DATA EXTRACTION: One phase 1 trial and 2 abstracts were identified. DATA SYNTHESIS: Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib. In the phase 1 clinical trial, the maximum tolerated dose was determined to be 750 mg once daily. The overall response rate (ORR) was 58% (95% CI = 48-67) in patients who received ?400 mg daily (n = 114). In this group, the ORR was 56% (95% CI = 41-67) and 62% (95% CI = 44-78) among crizotinib-exposed and -na?ve patients, respectively. The ORR was 59% (95% CI = 47-70) in patients who received 750 mg daily (n = 78). The ORR was 56% (95% CI = 41-70) in crizotinib-treated patients and 64% (95% CI = 44-81) in crizotinib-na?ve patients, respectively, in this subset. The median duration of response was 8.2 months. Median progression-free survival was 7.0 months. The most common adverse reactions included diarrhea, nausea, vomiting, abdominal pain, anorexia, constipation, fatigue, and elevated transaminases. CONCLUSIONS: Ceritinib has activity in crizotinib-resistant and crizotinib-na?ve patients and appears to be a viable alternative for ALK-positive NSCLC. Long-term data are needed to further define the role of ceritinib in the treatment of NSCLC.",1
13606,25260838,"Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial","""BACKGROUND: Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. METHODS: In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2?5 ?g/L and insulin-like growth factor 1 [IGF-1] concentration >1?3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2?5-10 ?g/L and >10 ?g/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2?5 ?g/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. FINDINGS: Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15?4%, 95% CI 7?6-26?5, p=0?0006 for pasireotide 40 mg group, 20?0%, 11?1-31?8, p<0?0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. INTERPRETATION: Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. FUNDING: Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.""",1
13607,25265492,Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma,"""BACKGROUND: Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS: In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS: The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS: A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).""",1
13608,25266613,Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy,"""BACKGROUND: A unicentre, prospective study was performed to investigate the efficacy of lacosamide as adjunctive therapy in children with refractory partial epilepsy. METHODS: The study was performed at a tertiary care hospital over a period of 30 months between November 2011 and May 2014. Seventy-nine children with refractory partial epilepsy (age 5-15 years) who had failed two or more antiepileptic drugs and in whom lacosamide was used as an add-on drug were enrolled. Lacosamide tablets were administered orally, at a dose of 25 mg for 1 week followed by 50 mg twice daily for the remaining period. Efficacy and tolerability evaluation was performed at every visit of titration, maintenance period (3 months), and two follow-up visits at monthly interval. Electrocardiogram and liver function tests were performed before enrollment and at the end of 3 months of lacosamide therapy. Patient's caregiver or investigator observed adverse events were recorded in a predesigned pro forma. RESULTS: A total of 79 patients with uncontrolled partial epilepsy screened from 531 epileptic children were enrolled, after they satisfied the inclusion and exclusion criteria. The mean age of children enrolled was 8.8 ? 3.1 years (range 5-15 years); 53 children (67.0%) were boys. Mean weight of the patients was 24.2 ? 9.8 kg. The mean age at the onset of seizures was 6.4 ? 3.5 years. The mean dose of lacosamide administered was 4.1 mg/kg. Three patients (3.8%) dropped out of the study, because of vomiting, aggressive behavior, and poor response, respectively. Of 76 patients (96.2%) entering the maintenance period, 35 patients (44.3%) were seizure free, 32 patients (40.6%) indicated ?50% reduction in seizure frequency, 3 patients (3.8%) indicated 25-49% seizure reduction, and 9 patients (11.4%) either had no change in seizure frequency or experience increase in seizure frequency. CONCLUSION: Lacosamide is an effective add-on antiepileptic drug for children with refractory partial epilepsy and is well tolerated.""",1
13609,25270036,Levomilnacipran extended-release: a review of its use in adult patients with major depressive disorder,"""Oral levomilnacipran extended-release (ER) [Fetzima�], the more active enantiomer of milnacipran, is the most recent serotonin norepinephrine reuptake inhibitor to be approved in the USA for the treatment of adults with major depressive disorder (MDD). MDD is characterized by depression and impairment of cognitive, social and work functioning. Once-daily levomilnacipran ER 40-120 mg was an effective and generally well-tolerated treatment in adults with MDD participating in 8-week phase III trials and a 1-year extension study. After 8 weeks, levomilnacipran ER treatment was associated with significantly greater and clinically meaningful improvements in depressive symptoms than placebo treatment and, in general, higher Montgomery-Asberg Depression Rating Scale responder rates and greater improvements in functional outcomes than placebo. The efficacy of levomilnacipran ER was maintained during the extension study, with no new safety signals detected; ongoing postmarketing evidence should more fully define the long-term safety of levomilnacipran ER. In the absence of head-to-head clinical trials, the relative position of levomilnacipran ER to that of other antidepressants remains to be determined. In the meantime, it is a useful addition to pharmacological options for the treatment of adult patients with MDD. This article summarizes the clinical use of oral levomilnacipran ER in adults with MDD, and briefly reviews the pharmacological properties of levomilnacipran.""",1
13610,25276228,"Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder","""OBJECTIVES: The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of valrubicin. METHODS: Patients ? 18 years with NMIBC who received had one or more instillations of valrubicin (October 2009- September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed. RESULTS: The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed valrubicin treatment. The median age was 75 years (range 42-95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9-61.3%), 30.4% (20.4-41.1%), and 16.4% (7.9-27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5-4.0) months after the first valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued valrubicin because of adverse events or LARs. CONCLUSIONS: Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate valrubicin safety and efficacy in the broader patient population with NMIBC.""",1
13611,25282519,"PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial","""BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2?6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4?1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59?2% reduction [95% CI 53?4-65?1], monthly dose: 61?3% reduction [53?6-69?0]; both p<0?0001) and at the mean of weeks 10 and 12 (60?2% reduction [95% CI 54?5-65?8] and 65?6% reduction [59?8-71?3]; both p<0?0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.""",1
13612,25284195,Health effects of chronic arsenic exposure,"""Arsenic is a unique element with distinct physical characteristics and toxicity whose importance in public health is well recognized. The toxicity of arsenic varies across its different forms. While the carcinogenicity of arsenic has been confirmed, the mechanisms behind the diseases occurring after acute or chronic exposure to arsenic are not well understood. Inorganic arsenic has been confirmed as a human carcinogen that can induce skin, lung, and bladder cancer. There are also reports of its significant association to liver, prostate, and bladder cancer. Recent studies have also suggested a relationship with diabetes, neurological effects, cardiac disorders, and reproductive organs, but further studies are required to confirm these associations. The majority of research to date has examined cancer incidence after a high exposure to high concentrations of arsenic. However, numerous studies have reported various health effects caused by chronic exposure to low concentrations of arsenic. An assessment of the health effects to arsenic exposure has never been performed in the South Korean population; thus, objective estimates of exposure levels are needed. Data should be collected on the biological exposure level for the total arsenic concentration, and individual arsenic concentration by species. In South Korea, we believe that biological exposure assessment should be the first step, followed by regular health effect assessments.""",1
13613,25294589,"Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial","""INTRODUCTION: This phase 3 trial compared the safety and efficacy of edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy study, patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU (equivalent to 20 mg) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions. RESULTS: Of 716 patients enrolled, 360 and 356 were randomized to receive edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the edoxaban and enoxaparin groups, respectively (relative risk reduction=46.8%), indicating non-inferiority (P <0.001) and superiority (P=0.010) of edoxaban versus enoxaparin. In the edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients (P=0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients (P=0.129), respectively. CONCLUSIONS: Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events.""",1
13614,25301180,Empagliflozin for the treatment of type 2 diabetes,"INTRODUCTION: Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion. AREAS COVERED: This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin , the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin. EXPERT OPINION: Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM.",1
13615,25304641,Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation,"""BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS: Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.""",1
13616,25308083,Drug-induced immunoallergic hepatitis during combination therapy with daclatasvir and asunaprevir,,1
13617,25313095,Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment,"BACKGROUND: Brodalumab (anti-interleukin-17-receptor antibody) was effective in treating moderate to severe psoriasis in a 12-week, dose-ranging, placebo-controlled trial. OBJECTIVE: We sought to evaluate efficacy and safety of long-term brodalumab treatment. METHODS: In this interim analysis at week 120 of an open-label extension study, patients received brodalumab 210 mg every 2 weeks. Protocol amendments reduced the dose (140 mg) in patients weighing 100 kg or less and subsequently increased the dose (210 mg) in patients with inadequate responses. Efficacy was measured by static physician global assessment and 75% or greater, 90% or greater, or 100% improvement in Psoriasis Area and Severity Index score (PASI-75, PASI-90, and PASI-100, respectively). RESULTS: Of 181 patients, 144 completed week 120. Static physician global assessment scores of clear/almost clear and clear were achieved by 90% and 63% of patients, respectively, at week 12 and by 72% and 51% at week 120. The PASI-75, PASI-90, and PASI-100 response rates at week 12 (95%/85%/63%) were sustained through week 120 (86%/70%/51%). Most commonly reported adverse events were nasopharyngitis (26.5%), upper respiratory tract infection (19.9%), arthralgia (16.0%), and back pain (11.0%). Four patients had grade-2 absolute neutrophil count. LIMITATIONS: There was no control group in this open-label extension. CONCLUSION: Brodalumab demonstrated sustained clinical response and an acceptable safety profile through 120 weeks in patients with moderate to severe psoriasis.",1
13618,25320286,Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort,"BACKGROUND: Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant (MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of bedaquiline. METHODS: We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment. RESULTS: A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2-5) other drugs, including linezolid in 33 (94%) cases. At 6 months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8-235 days). Variables independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001), and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a ?60-ms increase in QT interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients (6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis treatment. CONCLUSIONS: The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment.",1
13619,25324442,Octreotide-associated cholestasis and hepatitis in an infant with congenital hyperinsulinism,"""Congenital hyperinsulinism (CHI) is the most common cause of prolonged hypoglycemia in the neonate. It is caused by several genetic mutations that interfere with the cascade of normal insulin secretion from pancreatic beta cells. Octreotide, a somatostatin analog, suppresses insulin secretion from pancreatic beta cells, and is an effective therapy used for both short and long term in the treatment of CHI. It is well tolerated in most patients; however, several adverse effects have been reported, most of them mild and transient. Impaired liver function has been described previously in few children. Here, we describe about a child with CHI treated with continuous intravenous octreotide who developed cholestasis and hepatitis after a short period of treatment. This combination of liver effects with a short duration of treatment has not been reported previously with octreotide use in this population.""",1
13620,25325301,"Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma","""Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ? 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ? 3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ? 3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ? 32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.""",1
13621,25328370,Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir,"""INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), """"preconception"""" atazanavir exposure; 27 started atazanavir-based cART as """"first-line"""" during the pregnancy; and 29 """"switched"""" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.""",1
13622,25333550,Donepezil-induced hepatotoxicity in an elderly adult taking fluoxetine,,1
13623,25340136,"""Renal injury due to vitamin D intoxication; a case of dispensing error""",,1
13624,25348496,Streptozocin chemotherapy for advanced/metastatic well-differentiated neuroendocrine tumors: an analysis of a multi-center survey in Japan,"""BACKGROUND: Neuroendocrine tumors (NETs) are believed to be relatively rare and to follow a generally indolent course. However, liver metastases are common in NET patients and the outcome of NET liver metastasis is poor. In Western countries, streptozocin (STZ) has been established as a first-line anticancer drug for unresectable NET; however, STZ cannot be used in daily practice in Japan. The aim of the present study was to determine the status of STZ usage in Japan and to evaluate the effectiveness and safety of STZ chemotherapy in Japanese NET patients. METHODS: A retrospective multi-center survey was conducted. Five institutions with experience performing STZ chemotherapy participated in the study. The patient demographics, tumor characteristics, context of STZ chemotherapy, and patient outcome were collected and assessed. RESULTS: Fifty-four patients were enrolled. The main recipients of STZ chemotherapy were middle-aged patients with pancreatic NET and unresectable liver metastases. The predominant regimen was the weekly/bi-weekly intravenous administration of STZ combined with other oral anticancer agents. STZ monotherapy was used in one-fourth of the patients. The median progression-free and overall survival periods were 11.8 and 38.7�months, respectively, and sustained stable disease was obtained in some selected patients. The adverse events profile was mild and tolerable. CONCLUSIONS: Our survey showed the clinical benefit and safety of STZ therapy for Japanese patients with unresectable NET. Therefore, we recommend that STZ, which is the only cytotoxic agent available against NET, should be used in daily practice in Japan.""",1
13625,25363449,Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: pooled safety analysis from Phase IIb and III studies,"""This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-alpha/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in 'Photosensitivity' were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.""",1
13626,25366685,Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation,"""PURPOSE: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. PATIENTS AND METHODS: This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ? three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. RESULTS: A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ? 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ? 3 AEs were reported for 54% of patients; anemia was the most common (17%). CONCLUSION: Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.""",1
13627,25369488,Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial,"""IMPORTANCE: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. OBJECTIVE: To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N?=?245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1. INTERVENTIONS: Patients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 ?g subcutaneously, on days 1 to 14 of a 21-day cycle (n?=?123) vs ipilimumab alone (n?=?122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle. MAIN OUTCOMES AND MEASURES: Primary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability. RESULTS: Median follow-up was 13.3 months (range, 0.03-19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P?=?.01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O'Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P?=?.04). CONCLUSION AND RELEVANCE: Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01134614.""",1
13628,25372848,A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C,,1
13629,25374723,Tocilizumab-Induced Acute Liver Injury in Adult Onset Still's Disease,"Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still's disease (AOSD). Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.",1
13630,25374869,Losartan-induced Ischemic Hepatocellular Hepatotoxicity: A Case Report and Literature Review,"With the increasing use of various medications and supplements nowadays, the incidence of abnormal liver function tests and frank hepatic injury is has been increasing. Medications are now considered one of the most common causes of acute hepatic failure in the United States. Losartan was the first angiotensin 1 (AT1) receptor blocker approved by FDA for the treatment of arterial hypertension. It is a well-tolerated medication with few significant adverse effects. However, losartan-related hepatotoxicity has been reported rarely. We report a case of acute hepatic injury in an adult patient treated with losartan as a monotherapy for arterial hypertension.",1
13631,25382392,Dimethyl fumarate for treating relapsing multiple sclerosis,"""INTRODUCTION: Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera� by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm�; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994. AREAS COVERED: This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report. EXPERT OPINION: DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case.""",1
13632,25385737,Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia,"""PURPOSE: Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell-engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. PATIENTS AND METHODS: Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). RESULTS: Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. CONCLUSION: The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.""",1
13633,25386935,T cell-mediated hypersensitivity reactions to drugs,"The immunological mechanisms driving delayed hypersensitivity reactions (HSRs) to drugs mediated by drug-reactive T lymphocytes are exemplified by several key examples and their human leukocyte antigen (HLA) associations: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02, allo-purinol and HLA-B*58:01, and both amoxicillin-clavulanate and nevirapine with multiple class I and II alleles. For HLA-restricted drug HSRs, specific class I and/or II HLA alleles are necessary but not sufficient for tissue specificity and the clinical syndrome. Several models have been proposed to explain the immunopathogenesis of severe T cell-mediated drug HSRs, and our increased understanding of the risk factors and mechanisms involved in the development of these reactions will further the development of sensitive and specific strategies for preclinical screening that will lead to safer and more cost-effective drug design.",1
13634,25392720,Suspected azathioprine induced liver cirrhosis: an unusual side effect,"In recent years, the hepatotoxic potential of thiopurines, in particular 6-thioguanine (6-TG) has been discussed in literature. However, cirrhosis was exceptionally reported. We report the case of a 56-year-old woman with ileocaecal Crohn's disease treated with azathioprine. After taking azathioprine (2 mg/kg daily) for four years, she underwent surgical treatment for acute intestinal obstruction. In peroperative, we noticed a cirrhotic liver. A surgical biopsy was performed and the diagnosis of cirrhosis was confirmed. Autoimmune and viral liver diseases were ruled out by laboratory parameters. Therefore, Azathioprine is believed to be the causative actor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle.",1
13635,25400109,Weight gain and antipsychotics: a drug safety review,"""INTRODUCTION: Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures. AREAS COVERED: We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons. EXPERT OPINION: Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.""",1
13636,25412906,Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg?,"""Reactivation of hepatitis B in the context of immunosuppressive therapy may be severe and potentially fatal. The US Food and Drug Administration has recently drawn attention to the potentially fatal risk of hepatitis B reactivation in patients receiving the anti-CD20 agents ofatumumab or rituximab. This action focuses attention on the broader issue of hepatitis B virus reactivation, which may occur with a wide variety of immunosuppressive therapies in benign or malignant disease. This article summarizes the data behind this issue. These data support the recommendation that all patients undergoing chemotherapy, immunosuppressive therapy, hematopoietic stem cell transplantation, or solid organ transplantation be screened for active or prior hepatitis B viral infection by testing for hepatitis B surface antigen and the antibody to hepatitis B core antigen in serum. Those who are found to be hepatitis B surface antigen-positive should start appropriate antiviral therapy to prevent reactivation. Additionally, even those who have recovered from hepatitis B will benefit from antiviral therapy in certain circumstances because of the risks associated with a form of hepatitis B virus reactivation referred to as """"reverse seroconversion."""" There remain many uncertain areas that warrant further study, and further advances will benefit from close interactions between various medical specialties, regulatory agencies, and researchers. CONCLUSIONS: There is good evidence to support routine screening of all patients for hepatitis B prior to undergoing chemotherapy or immunosuppressive treatment; use of prompt antiviral treatment appears to diminish the risk of severe or fatal reactivation of hepatitis B.""",1
13637,25417679,"Infusion-related reactions with pegloticase, a recombinant uricase for the treatment of chronic gout refractory to conventional therapy","""BACKGROUND: In clinical trials of pegloticase, a PEGylated uricase developed for treatment of gout refractory to conventional therapy, infusion-related reactions (IRs) were the second most frequent adverse event reported. OBJECTIVE: The objective of this study was to provide a detailed account of IRs with pegloticase therapy. METHODS: Data from 2 replicate, 6-month randomized trials and an open-label extension study were pooled. Infusions of pegloticase (8 mg) were administered biweekly or monthly; all patients received prophylaxis (antihistamine, acetaminophen, and corticosteroid) and were tested for urate levels prior to each infusion. An IR was defined by protocol as any otherwise unexplained adverse event or cluster of temporally related events occurring during or within 2 hours of infusion. RESULTS: Infusion-related reactions occurred in 94 (45%) of 208 patients receiving pegloticase; 10 patients reported IRs at first infusion and 84 during subsequent infusions. Chest discomfort (15%), flushing (12%), and dyspnea (11%) were the most common symptoms. Most IRs were rated mild or moderate; 7% were rated severe. All IRs resolved with slowing, interrupting, or stopping the infusion. No patient required blood pressure or ventilatory support. Infusion-related reactions were associated with loss of pegloticase urate-lowering efficacy: 91% of all IRs occurred in patients with preinfusion serum uric acid concentrations (sUA) greater than 6 mg/dL. For patients sustaining preinfusion sUA of less than 6 mg/dL, IRs occurred in fewer than 1 per 100 infusions. CONCLUSIONS: Phase 3 trial data combined with post hoc analyses demonstrated that knowledge of sUA preceding each pegloticase infusion and cessation of therapy when urate-lowering efficacy is lost provide a means to optimize the safety of pegloticase in clinical practice.""",1
13638,25423467,[Allopurinol hypersensitivity syndrome: Liver transplantation after treatment of asymptomatic hyperuricaemia],"ADMISSION FINDINGS: A 41 year old patient started treatment with 300 mg/d allopurinol for asymptomatic hyperuricaemia (9,2 mg/dl). COURSE: 4 weeks later he developed exfoliative skin lesions with haemorrhage, fever, eosinophilia and acute liver and renal failure, typical for an allopurinol hypersensitivity syndrome (AHS).An orthotopic liver-transplantation was performed. CONCLUSION: The AHS is a serious iatrogenic disease. 2 % of the treated patients develop a skin rash. 0,4 % of these patients experience suddenly and unforeseen a severe hypersensitivity with a mortality of 14-30 %. An early diagnosis is often very difficult. In the pathogenesis different causes are discussed. A hereditary component is involved. Of essential importance is the amount of the starting dose, the kidney function and concomitant drugs. In an asymptomatic hyperuricaemia the application of allopurinol is not indicated. If strong indications are present, the allopurinol therapy has to start with the lowest dose (100 mg/d). If required this dose should be increased under consequent supervision only.",1
13639,25424850,"""The high-dose aldesleukin """"select"""" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma""","""PURPOSE: High-dose aldesleukin (HD IL2) received FDA approval for the treatment of metastatic renal cell carcinoma (MRCC) in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL2. EXPERIMENTAL DESIGN: Standard HD IL2 was administered to prospectively evaluate whether the ORR of patients with mRCC with """"good"""" predictive pathologic features based on an """"integrated selection"""" model [ISM (e.g., clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining] was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. RESULTS: One hundred and twenty eligible patients were enrolled between June 11 and September 7; 70% were Memorial Sloan Kettering Cancer Center (New York, NY) intermediate risk, 96% had clear cell RCC, and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI, 17.5%-33.7%, P = 0.0014; 3 complete responses, 27 partial responses) and was higher than a historical ORR. Thirteen patients (11%) remained progression free at 3 years and the median overall survival was 42.8 months. ORR was not statistically different by ISM classification (""""good-risk"""" 23% vs. """"poor-risk"""" 30%; P = 0.39). ORR was positively associated with tumor PD-L1 expression (P = 0.01) by IHC. CONCLUSIONS: In this prospective, biomarker validation study, HD IL2 produced durable remissions and prolonged survival in both """"good"""" and """"poor-risk"""" patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g., tumor PD L1 expression) appeared useful, but require independent validation.""",1
13640,25428503,MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer,"""There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30�years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.""",1
13641,25428710,Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer,"Alectinib (Alecensa(�)) is a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK). Alectinib is approved for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) in Japan, where it has been given orphan drug designation. Approval was based on a phase 1-2 study in ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC who received twice-daily alectinib 300�mg. In the phase 2 portion, 93.5�% of patients achieved an objective response. Treatment response was rapid, with a partial response achieved in two-thirds of patients within 3�weeks (cycle 1). Patient follow-up is ongoing, and after approximately 2�years, 19.6�% of patients had achieved a complete response, and the 2-year progression-free survival rate is 76�%. During treatment with alectinib (median follow-up approximately 8�months), there was no progression of CNS lesions among patients with known CNS metastases at baseline (although prior radiation therapy may have confounded results). In preclinical models, alectinib was active against most ALK fusion-gene mutations related to crizotinib resistance, and preliminary results from clinical trials indicate efficacy in crizotinib-refractory NSCLC. Alectinib was generally well tolerated in clinical trials, and there were no treatment-related grade 4 adverse events or deaths. The most common grade 3 treatment-related adverse events were decreased neutrophil counts and increased creatinine phosphokinase. While more data are needed to confirm the efficacy of alectinib and to evaluate its activity in crizotinib-resistant disease, the drug provides a very promising option for the treatment of ALK-rearranged advanced NSCLC.",1
13642,25432808,Clinical aspects of leprosy,"Leprosy is a chronic, infectious disease caused by Mycobacterium leprae. It mainly affects the peripheral nervous system, skin, and certain other tissues such as the reticulo-endothelial system, bones and joints, mucous membranes, eyes, testes, muscles, and adrenals. Leprosy clinical presentation varies from few to widespread lesions. In most patients, early leprosy presents as macular and hypopigmented lesions. This initial clinical presentation is known as indeterminate leprosy and occurs in individuals who have not developed cell-mediated immunity against M. leprae yet. The number of lesions depends on the genetically determined cellular immunity of the patient. Individuals presenting a vigorous cellular immune response and limited humoral immune responses to M. leprae, usually present few skin lesions. Without treatment, those patients tend to evolve into the polar tuberculoid or borderline tuberculoid form of leprosy. Due to the inability to mount an effective cellular-mediated response to M. leprae and the consequent hematogenous spread of the bacilli, some patients may present with numerous and symmetrically distributed hypochromic lesions. Without treatment these patients evolve to a nonresistant form of leprosy, polar lepromatous.",1
13643,25433810,"Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases","BACKGROUND: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain. METHODS: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities. RESULTS: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 mumol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid. CONCLUSIONS: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.",1
13644,25442758,Vanishing bile duct syndrome and immunodeficiency preceding the diagnosis of Hodgkin lymphoma,"Vanishing bile duct syndrome (VBDS) in association with Hodgkin lymphoma (HL) is well described but not well understood. We report an unusual case of a 75-year-old patient presenting with biopsy-proven VBDS and immunodeficiency, without identifiable cause, which showed a waxing and waning course, culminating in the development of HL 18 months later. To our knowledge, this is the first adult case in which VBDS preceded the diagnosis of HL by such a long period.",1
13645,25452452,Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial,"""PURPOSE: Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. CONCLUSION: Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.""",1
13646,25458543,[Mesalazine-induced acute hepatitis],,1
13647,25461229,Two new drugs for idiopathic pulmonary fibrosis,,1
13648,25467560,"Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial","""BACKGROUND: Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. METHODS: The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10?000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. FINDINGS: 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). INTERPRETATION: Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. FUNDING: Merck & Co, Inc.""",1
13649,25468160,"Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial","""BACKGROUND: The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. METHODS: We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0?0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. FINDINGS: Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1?9, 95% CI 1?3 to 2?8; p=0?0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. INTERPRETATION: Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.""",1
13650,25470094,"Efficacy and safety of vilazodone in major depressive disorder: a randomized, double-blind, placebo-controlled trial","""INTRODUCTION: Vilazodone is a potent serotonin (5-HT) reuptake inhibitor and 5-HT?A receptor partial agonist approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD) in adults. This study evaluated the efficacy and tolerability of vilazodone in the treatment of MDD. METHOD: This 8-week, randomized (1:1), double-blind, placebo-controlled, parallel-group, fixed-dose study conducted from January 2012 to February 2013 compared vilazodone 40 mg/d with placebo in outpatients with DSM-IV-TR-diagnosed MDD. The primary efficacy measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score change from baseline to week 8 analyzed by a mixed-effects model for repeated measures on the intent-to-treat population (placebo = 252, vilazodone = 253). Secondary efficacy outcomes were Clinical Global Impressions-Severity of Illness (CGI-S) Scale score change from baseline and MADRS sustained response rate (total score ? 12 for at least the last 2 consecutive double-blind visits). RESULTS: Approximately 83% of patients completed the study. Least squares mean differences (95% CI) were statistically significant for vilazodone versus placebo on MADRS (-5.117 [-6.886 to -3.347], P < .00001) and CGI-S (-0.622 [-0.845 to -0.399], P < .00001) change from baseline; statistically significant improvements versus placebo occurred at week 2 and persisted for the study duration. The MADRS sustained response rate was 17% for placebo and 27% for vilazodone (P < .01). Patients taking vilazodone versus placebo had higher rates of diarrhea and nausea; most incidences were mild in severity. Weight increase and sexual dysfunction adverse events were low in both groups. CONCLUSIONS: A large and significant treatment effect on the MADRS and statistically significant improvement on the CGI-S demonstrated meaningful depressive symptom improvements. Vilazodone was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01473394.""",1
13651,25471111,Azathioprine-induced hepatitis and cholestasis occurring 1?year after treatment,"Azathioprine is an immunosuppressive medication used in the management of many autoimmune conditions. Commonly reported adverse effects from azathioprine therapy are nausea and bone marrow suppression, while less common side effects include hepatotoxicity. We present the case of a 47-year-old man with a history of myasthenia gravis on azathioprine for 1?year, who presented to our institution with painless jaundice. On initial laboratory evaluation, the level of aspartate aminotransferase, alanine aminotransferase and total bilirubin were markedly elevated. Owing to the potential diagnosis of acute liver failure secondary to azathioprine toxicity, this medication was discontinued. A liver biopsy demonstrating drug-induced liver injury, along with high serum levels of 6-methylmercaptopurine nucleotide confirmed the diagnosis of azathioprine-induced hepatotoxicity. Upon discontinuation of the medication, the patient's transaminases and bilirubin levels improved steadily over the four-day hospital course. This case emphasises azathioprine's potential for hepatotoxicity, even 1?year after the initiation of its use.",1
13652,25474452,Effects of oral isotretinoin on lipids and liver enzymes in acne patients,"""Isotretinoin has been used to treat severe inflammatory acne that is resistant to antibiotics or topical agents; however, it also may cause alterations in lipids and liver enzymes. In this retrospective study, we evaluated changes in lipids and liver enzymes in 322 acne patients who had been treated with oral isotretinoin at our institution over a 3-year period. Each patient's medical records were evaluated to determine baseline triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels compared to levels recorded at 3 and 6 months following initiation of treatment with oral isotretinoin. Overall, statistically significant increases in TG and LDL levels were noted following treatment with isotretinoin (P<.001, respectively), while HDL levels were shown to decrease (P=.016). Although ALT levels also increased, the changes were not statistically significant increases in AST levels also were noted (P=.72). In our study, isotretinoin appeared to have a greater effect on lipids than liver enzymes. Dermatologists should not avoid isotretinoin use for appropriate indications, but close follow-up is important.""",1
13653,25480138,A curious case of cholestasis: oral terbinafine associated with cholestatic jaundice and subsequent erythema nodosum,"Terbinafine is a commonly prescribed antifungal agent used in the treatment of trichophytic onychomycosis and chronic cutaneous mycosis that are resistant to other treatments. This case report highlights a rarely documented but important adverse hepatic reaction that was caused by the use of oral terbinafine. A woman in her thirties presented with a 3-week history of jaundice, malaise, itching, nausea, decreased appetite, weight loss, dark orange urine and intermittent non-radiating epigastric pain. She had recently finished a 3-week course of oral terbinafine for a fungal nail infection. Liver biopsy findings were consistent with chronic active hepatitis secondary to a drug reaction. A few days after initial presentation, the patient developed erythema nodosum. Delayed development of erythema nodosum secondary to terbinafine could not be excluded.",1
13654,25483358,"Evaluation of the pharmacokinetics, safety and clinical efficacy of ziprasidone for the treatment of schizophrenia and bipolar disorder","INTRODUCTION: Multiple strategies exist for the pharmacological treatment of schizophrenia and related disorders. In the last 20 years, several 'new' compounds have been introduced, called 'atypical antipsychotics', which have higher efficacy and better tolerability than first-generation neuroleptics. Among them, ziprasidone (ZPR) is currently finding widespread use, and it has also been shown to be active as an augmenter in bipolar disorder therapy. AREAS COVERED: This review aims to provide the latest information on ZPR, an 'atypical' agent for the pharmacological therapy of schizophrenia and bipolar disorder. A literature search has been carried out with the keywords 'ziprasidone', 'schizophrenia', 'psychosis', 'bipolar', 'pharmacokinetics' and 'clinical trials'. In this process, particular attention has been paid to the drug pharmacokinetic characteristics and its safety in clinical use. EXPERT OPINION: ZPR shares most advantages and disadvantages with other atypical antipsychotics. However, it can be useful for its low tendency to cause metabolic syndrome and hyperprolactinaemia, especially in patients suffering from excess weight, hyperlipidaemia, diabetes or who have suffered from hyperprolactinaemia when using other antipsychotics. However, there are serious doubts as to whether ZPR should be administered to patients suffering from arrhythmias or QTc prolongation, and even more for administration to bipolar patients undergoing polypharmacy with antidepressants.",1
13655,25486948,Thiamine deficiency in stem cell transplant patients: a case series with an accompanying review of the literature,,1
13656,25487792,Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax,"""Although antibiotics treat bacteremia in inhalational anthrax, pathogenesis is mainly driven by bacterial exotoxins. Raxibacumab, an IgG1 monoclonal antibody, binds the protective antigen (PA) of Bacillus anthracis, thus blocking toxin effects and leading to improved survival in the rabbit and monkey models of inhalational anthrax. To assess raxibacumab's added benefit over levofloxacin (LVX) alone, rabbits surviving to 84 h after a challenge with 200 times the median (50%) lethal dose of B. anthracis spores were randomized to receive 3 daily intragastric LVX doses of 50 mg/kg of body weight, with the first LVX dose administered just prior to administration of a single intravenous dose of placebo or 40 mg/kg raxibacumab. The percentages of animals alive at 28 days following the last LVX dose were compared between the 2 treatment groups using a two-sided likelihood-ratio chi-square test. The 82% survival rate for the LVX-raxibacumab combination was higher than the 65% survival rate for LVX alone (P=0.0874). There were nearly 2-fold fewer deaths for the combination (7 deaths; n=39) than for LVX alone (13 deaths; n=37), and the survival time was prolonged for the combination (P=0.1016). Toxin-neutralizing-activity titers were similar for both treatment groups, suggesting that survivors in both groups were able to mount a toxin-neutralizing immune response. Microscopic findings considered consistent with anthrax were present in animals that died or became moribund on study in both treatment groups, and there were no anthrax-related findings in animals that survived. Overall, raxibacumab provided a meaningful benefit over antibiotic alone when administered late in the disease course.""",1
13657,25490172,Hepatotoxicity due to etanercept abated after dose reduction in a patient with pustular psoriasis and without compromised efficacy,,1
13658,25496464,"Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study","""OBJECTIVES: To evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs. METHODS: In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID). PRIMARY ENDPOINT: response rate by American College of Rheumatology (ACR) ? 20% improvement criteria (ACR20) at week 12. RESULTS: ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p < 0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p < 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-cholesterol levels increased with tofacitinib. CONCLUSIONS: Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profile was consistent with that reported from global monotherapy trials.""",1
13659,25500425,Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid,"""BACKGROUND & AIMS: We evaluated the efficacy and safety of obeticholic acid (OCA, ?-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. METHODS: We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. RESULTS: OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of ?-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ? 11 U/L after 12 months vs 285 ? 15 U/L at baseline. CONCLUSIONS: Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, ?-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.""",1
13660,25504398,[Fulminant acute hepatitis B after infliximab treatment in Crohn's disease],,1
13661,25506455,A challenge for diagnosing acute liver injury with concomitant/sequential exposure to multiple drugs: can causality assessment scales be utilized to identify the offending drug?,"Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin) for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only) drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM), Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.",1
13662,25514302,Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial,"""IMPORTANCE: Hepatitis B virus (HBV) reactivation is a serious complication for patients with lymphoma treated with rituximab-containing chemotherapies, despite lamivudine prophylaxis treatment. An optimal prophylactic antiviral protocol has not been determined. OBJECTIVE: To compare the efficacy of entecavir and lamivudine in preventing HBV reactivation in patients seropositive for the hepatitis B surface antigen with untreated diffuse large B-cell lymphoma receiving chemotherapy treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). DESIGN, SETTING, AND PATIENTS: Randomized, open-label, phase 3 study conducted from February 2008 through December 2012 at 10 medical centers in China. This study was a substudy of a parent study designed to compare a 3-week with a 2-week R-CHOP chemotherapy regimen for untreated diffuse large B-cell lymphoma. Patients enrolled in the parent study who were seropositive for the hepatitis B surface antigen and had normal liver function, serum HBV DNA levels of less than 103 copies/mL, and no prior antiviral therapy were randomized to entecavir (n?=?61) or lamivudine (n?=?60). INTERVENTIONS: Daily entecavir (0.5 mg) or lamivudine (100 mg) beginning 1 week before the initiation of R-CHOP treatment to 6 months after completion of chemotherapy. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the incidence of HBV-related hepatitis. The secondary end points included rates of HBV reactivation, chemotherapy disruption due to hepatitis, and treatment-related adverse events. RESULTS: There were 121 patients randomly assigned to receive entecavir (n?=?61) or lamivudine (n?=?60). The date of last patient follow-up was May 25, 2013. The rates were significantly lower for the entecavir group vs the lamivudine group for HBV-related hepatitis (0% vs 13.3%, respectively; difference between groups, 13.3% [95% CI, 4.7% to 21.9%]; P?=?.003), HBV reactivation (6.6% vs 30%; difference, 23.4% [95% CI, 10.2% to 36.6%]; P?=?.001), and chemotherapy disruption (1.6% vs 18.3%; difference, 16.7% [95% CI, 6.4% to 27.0%]; P?=?.002). Of the 61 patients in the entecavir group, 15 (24.6%) experienced treatment-related adverse events. Of 60 patients in the lamivudine group, 18 (30%) experienced treatment-related adverse events (difference between entecavir and lamivudine groups, 5.4% [95% CI, -10.5% to 21.3%]; P?=?.50). CONCLUSIONS AND RELEVANCE: Among patients seropositive for the hepatitis B surface antigen with diffuse large B-cell lymphoma undergoing R-CHOP chemotherapy, the addition of entecavir compared with lamivudine resulted in a lower incidence of HBV-related hepatitis and HBV reactivation. If replicated, these findings support the use of entecavir in these patients. TRIAL REGISTRATIONS: clinicaltrials.gov Identifier: NCT01793844; Chinese Clinical Trial Registry Identifier: CTR-TRC-11001687.""",1
13663,25516686,Sclerosing cholangitis secondary to bleomycin-iodinated embolization for liver hemangioma,Sclerosing cholangitis (SC) is a rarely reported morbidity secondary to transcatheter arterial chemoembolization (TACE) with bleomycin-iodinated oil (BIO) for liver cavernous hemangioma (LCH). This report retrospectively evaluated the diagnostic and therapeutic course of a patient with LDH who presented obstructive jaundice 6 years after TACE with BIO. Preoperative imaging identified a suspected malignant biliary stricture located at the convergence of the left and right hepatic ducts. Operative exploration demonstrated a full-thickness sclerosis of the hilar bile duct with right hepatic duct stricture and right lobe atrophy. Radical hepatic hilar resection with right-side hemihepatectomy and Roux-en-Y hepaticojejunostomy was performed because hilar cancer could not be excluded on frozen biopsy. Pathological results showed chronic pyogenic inflammation of the common and right hepatic ducts with SC in the portal area. Secondary SC is a long-term complication that may occur in LCH patients after TACE with BIO and must be differentiated from hilar malignancy. Hepatic duct plasty is a definitive but technically challenging treatment modality for secondary SC.,1
13664,25521845,Postmarketing review of intravenous acetaminophen dosing based on Food and Drug Administration prescribing guidelines,"STUDY OBJECTIVES: To evaluate the appropriateness of intravenous acetaminophen dosing-prescribed dose, frequency, duration, and indication-based on United States Food and Drug Administration (FDA)-approved prescribing guidelines and to evaluate the adverse effect profile of intravenous acetaminophen. DESIGN: Retrospective chart review. SETTING: United States Navy medical center. PATIENTS: Three hundred patients who received intravenous acetaminophen from August 1, 2011, to August 1, 2012. MEASUREMENTS AND MAIN RESULTS: The indications, dose, frequency, and duration of intravenous acetaminophen were recorded for each patient. Adverse effects of intravenous acetaminophen were analyzed by thoroughly reviewing any adverse effects documented, including nausea, vomiting, headache, or any symptom specifically attributed to the drug. Baseline liver function tests, including aspartate aminotransferase and alanine aminotransferase levels, and elevations 3 times the upper limit of normal during intravenous acetaminophen therapy were recorded. The average patient weight was 78?21 kg, with 12 patients (4%) weighing less than 50 kg and 288 (96%) patients weighing 50 kg or greater. Two hundred forty-one patients (80%) were appropriately dosed, whereas 59 (20%) patients were not appropriately dosed based on the FDA-approved dosing. No patients exceeded the FDA-approved maximum daily dosing recommendations for intravenous acetaminophen (4 g). Sixty-five patients (22%) received intravenous acetaminophen for longer than 24 hours. Intravenous acetaminophen was well tolerated, without any reported adverse effects, including the commonly reported adverse effects of nausea, vomiting, headache, and insomnia. Ten patients (3%) had a documented history of liver disease and did not experience any adverse effects or increases in liver function tests after the administration of intravenous acetaminophen. CONCLUSION: Intravenous acetaminophen appeared to be a safe and effective analgesic and antipyretic agent. Dosing for patients weighing less than 50 kg needs to be appropriately weight adjusted. Intravenous acetaminophen can be used alone or in conjunction with opioids and other analgesics. Limitations of this study include its retrospective design, inability to assess outcomes of reducing opioid use, and short-term observation period.",1
13665,25523716,Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir. II: a pediatric drug use investigation,"Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. In October 2010, an additional indication for pediatric use was approved. We conducted a pediatric drug use investigation of peramivir from October 2010 to February 2012 and evaluated its real-world safety and effectiveness in pediatric patients. We collected the data of 1254 peramivir-treated pediatric patients from 161 facilities across Japan and examined the safety in 1199 patients and effectiveness in 1188 patients. In total, 245 adverse events were observed with an incidence rate of 14.01% (168/1199). Of these, 115 events were adverse drug reactions (ADRs) with an incidence rate of 7.67% (92/1199). Common ADRs were diarrhea and abnormal behavior, with incidence rates of 2.50% (30/1199) and 2.25% (27/1199), respectively. Fourteen serious ADRs were observed in 12 patients (1.00%), including 5 cases each of abnormal behavior and neutrophil count decreased. While 87.0% (100 events) of ADRs occurred within 3 days after the initiation of peramivir administration, 87.8% (101 events) resolved or improved within 7 days after onset. Multivariate analyses indicated that the presence or absence of underlying diseases/complications was significantly related to ADR incidence. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. Thus, this study confirms the pediatric safety of peramivir without any concerns about effectiveness under routine clinical settings.",1
13666,25524800,"Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study","BACKGROUND: Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. METHODS: In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 ?g/day for the first 7 days and 28 ?g/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. FINDINGS: Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. INTERPRETATION: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. FUNDING: Amgen.",1
13667,25526970,Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials,"BACKGROUND: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. METHODS: Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (>/=65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2. RESULTS: Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued. CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.",1
13668,25528898,"Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: Results of a phase III, double-blind, randomized, placebo-controlled trial","OBJECTIVE: To evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures. METHODS: This randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ?16 years and had uncontrolled partial-onset seizures despite treatment with 1-2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n = 226), ESL 800 mg (n = 216), or ESL 1,200 mg (n = 211). Following a 2-week titration period, patients received ESL 800 or 1,200 mg once-daily for 12 weeks. Seizure data were captured and documented using event-entry or daily entry diaries. RESULTS: Standardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200 mg (p = 0.004), and there was a trend toward improvement with ESL 800 mg (p = 0.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800 mg (p = 0.001) and 1,200 mg (p < 0.001) both reduced SSF. There were no statistically significant interactions between treatment response and geographical region (p = 0.38) or diary version (p = 0.76). Responder rate (?50% reduction in SSF) was significantly higher with ESL 1,200 mg (42.6%, p < 0.001) but not ESL 800 mg (30.5%, p = 0.07) than placebo (23.1%). Incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation increased with ESL dose. The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia. SIGNIFICANCE: Adjunctive ESL 1,200 mg once-daily was more efficacious than placebo in adult patients with refractory partial-onset seizures. The once-daily 800 mg dose showed a marginal effect on SSF, but did not reach statistical significance. Both doses were well tolerated. Efficacy assessment was not affected by diary format used.",1
13669,25532076,"Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial","""BACKGROUND: This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. METHODS: Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3-12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. RESULTS: Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3-12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (?50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score?12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (?10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. LIMITATIONS: Lack of active comparator arm; short duration of study. CONCLUSION: In this study, cariprazine 3-12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder.""",1
13670,25533960,Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant,"""The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the beta branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 A resolution. The structure reveals how suvorexant adopts a pi-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous pi-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.""",1
13671,25537186,Acetaminophen hepatotoxicity: an updated review,"""As the most common cause of acute liver failure (ALF) in the USA and UK, acetaminophen-induced hepatotoxicity remains a significant public health concern and common indication for emergent liver transplantation. This problem is largely attributable to acetaminophen combination products frequently prescribed by physicians and other healthcare professionals, with unintentional and chronic overdose accounting for over 50 % of cases of acetaminophen-related ALF. Treatment with N-acetylcysteine can effectively reduce progression to ALF if given early after an acute overdose; however, liver transplantation is the only routinely used life-saving therapy once ALF has developed. With the rapid course of acetaminophen-related ALF and limited supply of donor livers, early and accurate diagnosis of patients that will require transplantation for survival is crucial. Efforts in developing novel treatments for acetaminophen-induced ALF are directed toward bridging patients to recovery. These include auxiliary, artificial, and bioartificial support systems. This review outlines the most recent developments in diagnosis and management of acetaminophen-induced ALF.""",1
13672,25540208,An unusual cause of jaundice in a patient with breast cancer,"A 48-year old woman with metastatic breast cancer and extensive bone marrow infiltration was admitted with extreme lethargy, jaundice and deranged liver function tests. She had been started on anastrozole in May 2013 for bony metastases, detected on a bone scan. A CT scan performed at that time had shown no evidence of metastatic or nodal disease elsewhere. Over the subsequent 2 months, the patient had become progressively jaundiced. Outpatient abdominal ultrasound and CT liver had shown a fatty liver with no focal lesions. She was admitted in August 2013 with bilirubin 567, alkaline phosphatase 385, alanine aminotransferase 98, albumin 25 and international normalised ratio 1.9. The patient ultimately had a liver biopsy, which demonstrated features of drug-induced steatohepatitis, and anastrozole was found to have been the probable cause. This case explores the differentials of jaundice in a patient with cancer and describes a rare cause of drug-induced liver injury.",1
13673,25546878,Drug-induced hepatotoxicity of select herbal therapies,"The use of herbal botanicals and dietary supplements to treat and alleviate disease symptoms has increased over the past decades, and as a result, more research has been done to study the potential damaging effects of herbal products on the liver and other organs. Although reporting rates vary, cases have been published describing liver damage following herbal therapy. Studies have proposed multiple mechanisms of injury for these herbal preparations, and several potential risk factors have been identified including age, gender, polypharmacy, alcohol consumption, and genetic variability. Ingredients and other constituents often differ among products, and lack of standardization in manufacturing of these formulations makes it difficult to determine causality. The potential for drug-induced liver injury is often not known until the postmarketing period due to less rigorous safety testing and regulations.",1
13674,25551211,Acute Liver Failure Due to Acetaminophen Poisoning in Patients With Prior Weight Loss Surgery: A Case Series,"GOALS: To identify an association between prior weight loss surgery (WLS) and acetaminophen-induced acute liver failure (ALF). BACKGROUND: WLS, which has increased in proportion to the global rise of obesity, alters the absorption and metabolism of many drugs including acetaminophen (APAP) and may predispose to toxicity. No study has identified an association between prior WLS and APAP-ALF. STUDY: We retrospectively reviewed a cohort of patients who presented to our center with ALF. We identified 101 patients who presented to our center with ALF between January 2009 and December 2011. All patients were prospectively enrolled into a database using consensus criteria. A history of WLS was obtained through a retrospective chart review. RESULTS: Fifty-four patients (53.5%) had APAP-ALF and 47 (46.5%) had ALF caused by other etiologies. A prior history of WLS was present in 9 of the 54 patients with APAP-ALF versus 0 of the 47 with non-APAP-ALF (P=0.003). Patients with APAP-ALF and prior WLS did not have higher rates of factors commonly associated with APAP overdose, including depression, alcohol abuse, intent to cause self-harm, or use of APAP-narcotic combination drugs. CONCLUSIONS: A history of WLS may predispose to hepatotoxicity and ALF caused by acetaminophen.",1
13675,25555072,Oritavancin (Orbactiv) for skin and skin structure infections,,1
13676,25555075,Siltuximab (Sylvant) for treatment of multicentric castleman's disease,,1
13677,25559757,Severe drug-induced skin and liver injury from rivaroxaban,,1
13678,25562777,The US Food and Drug Administration's perspective on the new antidepressant vortioxetine,"OBJECTIVE: This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. DATA SOURCES: The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. RESULTS: Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. CONCLUSIONS: Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs.",1
13679,25574085,Review of the treatment of liver hydatid cysts,"""A review was carried out in Medline, LILACS and the Cochrane Library. Our database search strategy included the following terms: """"hydatid cyst"""", """"liver"""", """"management"""", """"meta-analysis"""" and """"randomized controlled trial"""". No language limits were used in the literature search. The latest electronic search date was the 7(th) of January 2014. INCLUSION AND EXCLUSION CRITERIA: all relevant studies on the assessment of therapeutic methods for hydatid cysts of the liver were considered for analysis. Information from editorials, letters to publishers, low quality review articles and studies done on animals were excluded from analysis. Additionally, well-structured abstracts from relevant articles were selected and accepted for analysis. Standardized forms were designed for data extraction; two investigators entered the data on patient demographics, methodology, recurrence of HC, mean cyst size and number of cysts per group. Four hundred and fourteen articles were identified using the previously described search strategy. After applying the inclusion and exclusion criteria detailed above, 57 articles were selected for final analysis: one meta-analysis, 9 randomized clinical trials, 5 non-randomized comparative prospective studies, 7 non-comparative prospective studies, and 34 retrospective studies (12 comparative and 22 non-comparative). Our results indicate that antihelminthic treatment alone is not the ideal treatment for liver hydatid cysts. More studies in the literature support the effectiveness of radical treatment compared with conservative treatment. Conservative surgery with omentoplasty is effective in preventing postoperative complications. A laparoscopic approach is safe in some situations. Percutaneous drainage with albendazole therapy is a safe and effective alternative treatment for hydatid cysts of the liver. Radical surgery with pre- and post-operative administration of albendazole is the best treatment option for liver hydatid cysts due to low recurrence and complication rates.""",1
13680,25583832,Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials,"""BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). METHODS: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. RESULTS: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.""",1
13681,25589191,"Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials","""BACKGROUND: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. METHODS: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. FINDINGS: Median follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, the most common afatinib-related grade 3-4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). INTERPRETATION: Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. FUNDING: Boehringer Ingelheim.""",1
13682,25593233,"Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis","OBJECTIVE: To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, over 52 weeks in patients with active psoriatic arthritis (PsA) despite prior treatment. METHODS: Patients were randomized to placebo (n = 168), apremilast 20 mg BID (n = 168), or apremilast 30 mg BID (n = 168). Patients whose swollen and tender joint counts had not improved by >/= 20% at Week 16 were considered nonresponders and were required to be re-randomized (1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo, or continued their initial treatment of apremilast dose. At Week 24, all remaining patients treated with placebo were re-randomized to apremilast 20 mg BID or 30 mg BID. RESULTS: An American College of Rheumatology 20 (ACR20) response at Week 16 was attained by significantly more patients receiving apremilast 20 mg BID (30.4%, p = 0.0166) or 30 mg BID (38.1%, p = 0.0001) than placebo (19.0%). Among patients receiving apremilast continuously for 52 weeks (n = 254), ACR20 response at Week 52 was observed in 63.0% (75/119, 20 mg BID) and 54.6% (71/130, 30 mg BID) of patients. Response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function. The nature, incidence, and severity of adverse events were comparable over the 24-week and 52-week periods. The most common adverse events, diarrhea and nausea, generally occurred early and were self-limited. CONCLUSION: Continuous apremilast treatment resulted in sustained improvements in PsA for up to 52 weeks. Apremilast had an acceptable safety profile and was generally well tolerated. CLINICAL TRIAL REGISTRATION: NCT01172938.",1
13683,25599649,"Pharmacokinetics, safety and efficacy of ritonavir-boosted atazanavir (300/100 mg once daily) in HIV-1-infected pregnant women","BACKGROUND: Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates. METHODS: A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography-mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150-850 ng/ml efficacy-tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery. RESULTS: 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported. CONCLUSIONS: In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.",1
13684,25601959,FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease,"""On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.""",1
13685,25605862,Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane,"""PURPOSE: This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. CONCLUSION: In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.""",1
13686,25609019,"Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis","BACKGROUND: Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled. METHODS: We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks' duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection. RESULTS: Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed. CONCLUSION: At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.",1
13687,25614962,All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study,"""Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment na?ve (n?=?101) or treatment experienced (n?=?51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-na?ve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-na?ve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ?99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. CONCLUSION: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway.""",1
13688,25620390,Safety and tolerability of clofazimine as salvage therapy for atypical mycobacterial infection in solid organ transplant recipients,"""BACKGROUND: The treatment of Mycobacterium avium complex (MAC) requires prolonged, multidrug therapy, which is often not well tolerated. In solid organ transplant (SOT) recipients, drug-drug interactions complicate treatment further. Failure or intolerance requires the use of salvage regimens, and clofazimine is one of the drugs that can be used. No data are available on the safety and tolerability of clofazimine for the treatment of MAC in SOT recipients. METHODS: Retrospective review of all SOT recipients treated for MAC infection with clofazimine at a large transplant center between 2006 and 2013. RESULTS: Five SOT recipients received clofazimine as salvage therapy. Transplanted organs were lungs in 3 patients, and kidney and liver in 1 patient each. Infection was diagnosed at a median of 22�months (range 4-57) post transplant. Sites of infection were the lungs in 2 patients, and septic arthritis, mesenteric, and disseminated disease in 1 patient each. All patients received standard anti-MAC therapy for a median of 26�weeks (range 18-45) before starting clofazimine. Indications for use of clofazimine included a lack of response to previous therapy (3 patients), and poor tolerance of other regimens (3 patients). All patients received at least 2 additional drugs besides clofazimine. Median duration of clofazimine-containing regimen was 8�months (range 2-18). Clofazimine was discontinued because of gastrointestinal intolerance in 1 of the 5 patients. The most common adverse event from clofazimine was skin discoloration, in 60% of patients. No hepatotoxicity or hematologic toxicity occurred. Microbiological clearance and resolution of clinical disease was documented in 2 of 5 patients; and 2 of the 5 patients died of other causes while on therapy. CONCLUSIONS: Clofazimine appears safe and may be considered as a salvage therapeutic option in SOT recipients with MAC infection who are intolerant or unresponsive to standard therapy. The small sample size does not allow conclusions regarding efficacy.""",1
13689,25629810,A 4-drug combination (Viekira Pak) for hepatitis C,,1
13690,25634024,An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing,"""PURPOSE: This study was conducted to evaluate the usefulness of human leukocyte antigen (HLA) typing in preventing allopurinol-induced severe cutaneous adverse reactions (SCARs) through the application of an allopurinol tolerance induction protocol or prescription of other alternative medications in high-risk patients. METHODS: HLA typing was performed in patients with chronic renal insufficiency who needed allopurinol. HLA-B*58:01-negative patients were prescribed the usual dose of allopurinol. For HLA-B*58:01-positive patients, administration of either allopurinol based on a 28-day tolerance induction protocol or alternative medications was initiated. Hypersensitivity reactions were surveyed for 90 days and compared with the result of a previous retrospective cohort study. RESULTS: Among a total of 401 study subjects, no SCARs were noted in HLA-B*58:01-positive patients with application of the tolerance induction protocol (n = 30) or alternative medications (n = 16), nor were any SCARs observed in HLA-B*58:01-negative patients who started allopurinol at the usual dose (n = 355). Compared with the previous retrospective cohort study, a significant reduction in SCARs was observed in HLA-B*58:01-positive patients (0 vs. 18%; P = 0.002). CONCLUSION: This study shows the usefulness of HLA-B*58:01 screening in identifying patients at high risk for the development of allopurinol-induced SCARs and suggests that application of a tolerance induction protocol or alternative medications could be an effective strategy to prevent allopurinol-induced SCARs in HLA-B*58:01-positive patients.""",1
13691,25639506,Final quality of life and safety data for patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279),"OBJECTIVE: To compile the safety profile and quality of life (QoL) data for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel in the UK Early Access Programme (UK EAP). PATIENTS AND METHODS: A total of 112 patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. Patients received cabazitaxel 25 mg/m(2) every 3 weeks with prednisolone 10 mg daily for up to 10 cycles. Safety assessments were performed before each cycle and QoL was recorded at alternate cycles using the EQ-5D-3L questionnaire and visual analogue scale (VAS). The safety profile was compiled after completion of the UK EAP and QoL measures were analysed to record trends. No formal statistical analysis was carried out. RESULTS: The incidences of neutropenic sepsis (6.3%), grade 3 and 4 diarrhoea (4.5%) and grade 3 and 4 cardiac toxicity (0%) were low. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. There were trends towards improved VAS and EQ-5D-3L pain scores during treatment. CONCLUSIONS: The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.",1
13692,25651368,Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies,"Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15?ml/min per 1.73?m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.",1
13693,25656910,Results from a 9-year Intensive Safety Surveillance Scheme (IS(3) ) in miglustat (Zavesca((R)) )-treated patients,"BACKGROUND: Following approval in the EU in 2002 and the USA in 2003, an Intensive Safety Surveillance Scheme (IS(3) ) was initiated to educate prescribers on the appropriate use of miglustat for the treatment of type I Gaucher disease (GD1), and to actively solicit safety-relevant information. This report summarises data from all patients enrolled in IS(3) between its initiation in 2003 and its closure in October 2012. METHODS: The IS(3) was a prospective observational drug registry with a secure internet-based data capture system. All patients receiving miglustat at participating sites received standard medical care according to routine medical practice. Data on patient and disease characteristics were collected at patient enrolment, subsequent follow-up visits and treatment discontinuation (if applicable). Data were summarised using descriptive statistics. RESULTS: During the 9 years of IS(3) , 407 patients were enrolled at 111 sites across 15 European countries. Approximately half (n = 202) had GD1, and half had other diseases (mainly Niemann-Pick disease type C (NP-C), for which miglustat was approved in Europe in 2009). In total, 368 patients had data from at least one follow-up visit, 192 of whom had GD1. IS(3) provided data from 798 patient-years exposure to miglustat. Safety-relevant data were consistent with earlier published 5-year findings from IS(3) , the safety profile reported for miglustat in GD1 clinical trials and other published information on GD1 manifestations. CONCLUSIONS: Overall, the results of this long-term safety surveillance programme were in line with the well-known, documented safety profile of miglustat.",1
13694,25664604,Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial,"BACKGROUND: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. METHODS: We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 ? upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ? 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. RESULTS: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 ? ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ? 1.3 ? ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. CONCLUSIONS: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.",1
13695,25666208,Liver failure after Hydroxycut� use in a patient with undiagnosed hereditary coproporphyria,"We report the case of a young male presenting with cholestatic liver failure. After an extensive workup, the etiology of the liver failure was determined to be due to hereditary coprophorphyria (HCP). The inciting event was the use of Hydroxycut�, an over-the-counter supplement to promote weight loss that has been reported to cause oxidative liver injury in vulnerable populations. Although HCP is a rare cause of cholestatic liver failure, it is treatable if diagnosed correctly and in a timely manner. In this clinical vignette, we discuss a case that highlights the genetic susceptibility to disease that can be unmasked by environmental exposures. We also review the relevant literature on Hydroxycut� and how it can affect hepatic function.",1
13696,25670368,Long-term clinical results of microsomal triglyceride transfer protein inhibitor use in a patient with homozygous familial hypercholesterolemia,"We report the case of a 49-year-old woman with homozygous familial hypercholesterolemia and a complicated cardiovascular history, treated for 5 years with a microsomal triglyceride transfer protein inhibitor in addition to her other lipid-lowering therapy.",1
13697,25671254,Lenvatinib versus placebo in radioiodine-refractory thyroid cancer,"""BACKGROUND: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor ?, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131). METHODS: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety. RESULTS: The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related. CONCLUSIONS: Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).""",1
13698,25673021,Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens,"""Tedizolid phosphate is a novel oxazolidinone prodrug (converted to the active form tedizolid by phosphatases in vivo) that has been developed and recently approved (June 2014) by the United States FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Tedizolid is an oxazolidinone, but differs from other oxazolidinones by possessing a modified side chain at the C-5 position of the oxazolidinone nucleus which confers activity against certain linezolid-resistant pathogens and has an optimized C- and D-ring system that improves potency through additional binding site interactions. The mechanism of action of tedizolid is similar to other oxazolidinones and occurs through inhibition of bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA) of the 50S subunit of the ribosome. As with other oxazolidinones, the spontaneous frequency of resistance development to tedizolid is low. Tedizolid is four- to eightfold more potent in vivo than linezolid against all species of staphylococci, enterococci, and streptococci, including drug-resistant phenotypes such as MRSA and vancomycin-resistant enterococci (VRE) and linezolid-resistant phenotypes. Importantly, tedizolid demonstrates activity against linezolid-resistant bacterial strains harboring the horizontally transmissible cfr gene, in the absence of certain ribosomal mutations conferring reduced oxazolidinone susceptibility. With its half-life of approximately 12 h, tedizolid is dosed once daily. It demonstrates linear pharmacokinetics, has a high oral bioavailability of approximately 90 %, and is primarily excreted by the liver as an inactive, non-circulating sulphate conjugate. Tedizolid does not require dosage adjustment in patients with any degree of renal dysfunction or hepatic dysfunction. Studies in animals have demonstrated that the pharmacodynamic parameter most closely associated with the efficacy of tedizolid is fAUC(0-24h)/MIC. In non-neutropenic animals, a dose-response enhancement was observed with tedizolid and lower exposures were required compared to neutropenic cohorts. Two Phase III clinical trials have demonstrated non-inferiority of a once-daily tedizolid 200 mg dose for 6-10 days versus twice-daily 600 mg linezolid for the treatment of ABSSSIs. Both trials used the primary endpoint of early clinical response at 48-72 h; however, one trial compared oral formulations while the other initiated therapy with the parenteral formulation and allowed oral sequential therapy following initial clinical response. Throughout its development, tedizolid has demonstrated that it is well tolerated and animal studies have shown a lower propensity for neuropathies with long-term use than its predecessor linezolid. Data from the two completed Phase III clinical trials demonstrated that the studied tedizolid regimen (200 mg once daily for 6 days) had significantly less impact on hematologic parameters as well as significantly less gastrointestinal treatment-emergent adverse effects (TEAEs) than its comparator linezolid. As with linezolid, tedizolid is a weak, reversible MAO inhibitor; however, a murine head twitch model validated to assess serotonergic activity reported no increase in the number of head twitches with tedizolid even at doses that exceeded the C max in humans by up to 25-fold. Tyramine and pseudoephedrine challenge studies in humans have also reported no meaningful MAO-related interactions with tedizolid. With its enhanced in vitro activity against a broad-spectrum of Gram-positive aerobic bacteria, convenient once-daily dosing, a short 6-day course of therapy, availability of both oral and intravenous routes of administration, and an adverse effect profile that appears to be more favorable than linezolid, tedizolid is an attractive agent for use in both the hospital and community settings. Tedizolid is currently undergoing additional Phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP).""",1
13699,25680499,Hepatotoxicity of herbal and dietary supplements: an update,"Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.",1
13700,25682022,Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States,"BACKGROUND: Ivacaftor is the first therapeutic agent approved for the treatment of cystic fibrosis (CF) that targets the underlying molecular defect. Patients with severe lung disease were excluded from the randomized Phase 3 trials. This open-label study was designed to provide ivacaftor to patients in critical medical need prior to commercial product availability. METHODS: CF patients aged ?6 years with a G551D-CFTR mutation and FEV1 ? 40% predicted or listed for lung transplant received ivacaftor 150 mg every 12 h. The primary endpoint was safety as determined by adverse events. Secondary endpoints included assessment of lung function and weight. RESULTS: The rate of serious adverse events was consistent with disease severity. At 24 weeks of treatment with ivacaftor, there was a mean absolute increase in percent predicted FEV1 of 5.5 percentage points and a 3.3 kg mean absolute increase in weight from baseline. CONCLUSIONS: In patients with severe lung disease, ivacaftor was well tolerated and was associated with improved lung function and weight gain.",1
13701,25683285,Safety of enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: expanded access in North America,"""BACKGROUND: The open-label, single-arm enzalutamide expanded access program (EAP) in the United States and Canada evaluated the safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel. METHODS: Patients (n?=?507) received enzalutamide 160?mg/day until disease progression, intolerable adverse events (AEs), or commercial availability occurred. AEs and other safety variables were assessed on day 1, weeks 4 and 12, and every 12 weeks thereafter. Data following transition to commercial drug were not collected. RESULTS: Median age was 71 years (range 43-97); 426 patients (83.9%) had a baseline ECOG score of ?1. In addition to docetaxel, the majority of patients had received prior prostate cancer treatments such as abiraterone (76.1%) or cabazitaxel (28.6%). Median study treatment duration was 2.6 months (range 0.03-9.07). The most frequently reported reasons for discontinuation were commercial availability of enzalutamide (46.7%) and progressive disease (33.7%). A total of 88.2% of patients experienced AEs; 45.4% experienced AEs with a maximum grade of 1 or 2. Fatigue (39.1%), nausea (22.7%), and anorexia (14.8%) were the most commonly reported AEs. Seizure was reported in four patients (0.8%). The most commonly reported event leading to death was progression of metastatic prostate cancer (7.7%). CONCLUSION: In this heavily pretreated EAP population with progressive mCRPC, enzalutamide was well tolerated and the safety profile was consistent with that of the AFFIRM trial.""",1
13702,25687353,Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial,"""AIMS: To compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia. METHODS AND RESULTS: COMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104-week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled (August 2012-May 2013). This pre-specified analysis was conducted after the last patient completed 52 weeks. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At Week 24, mean ? SE reductions in LDL-C from baseline were 50.6 ? 1.4% for alirocumab vs. 20.7 ? 1.9% for ezetimibe (difference 29.8 ? 2.3%; P < 0.0001); 77.0% of alirocumab and 45.6% of ezetimibe patients achieved LDL-C <1.8 mmol/L (P < 0.0001). Mean achieved LDL-C at Week 24 was 1.3 ? 0.04 mmol/L with alirocumab and 2.1 ? 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events. CONCLUSION: In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01644188.""",1
13703,25687662,"A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder","This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10-20 mg) on cognitive function in adults (aged 18-65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST (P < 0.05), PDQ (P < 0.01), CGI-I (P < 0.001), MADRS (P < 0.05), and UPSA (P < 0.001). Path analysis indicated that vortioxetine's cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ? 5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.",1
13704,25688781,Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial,"""IMPORTANCE: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. OBJECTIVE: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. INTERVENTIONS: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n?=?20) or placebo (n?=?20) for 9 months. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. RESULTS: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, -36.82% to -23.24%; P?<?.001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P?<?.001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P?=?.007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P?<?.001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. CONCLUSIONS AND RELEVANCE: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00891202.""",1
13705,25689417,Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system,"AIM: We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). METHODS: We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. RESULTS: DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively). CONCLUSIONS: The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.",1
13706,25695911,Vitamin D research and clinical practice: at a crossroads,,1
13707,25701171,"Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study","""BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11.3 months (95% CI 9.5-13.4) in the necitumumab plus pemetrexed and cisplatin group versus 11.5 months (10.1-13.1) in the pemetrexed and cisplatin group (hazard ratio 1.01 [95% CI 0.84-1.21]; p=0.96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING: Eli Lilly and Company.""",1
13708,25703086,Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders,"""BACKGROUND & AIMS: Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population. METHODS: This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60 mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients. RESULTS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90-96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93-100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each). CONCLUSIONS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens.""",1
13709,25704957,Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer,"OBJECTIVES: Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. MATERIALS AND METHODS: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. RESULTS: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n=457) received gefitinib, those in 5 trials (n=513) received erlotinib, and those in 3 trials (n=498) received afatinib. Rash and diarrhea of grade >/=3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade >/=3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade >/=3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. CONCLUSION: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.",1
13710,25708022,"A randomized, placebo-controlled, phase 2 study of the efficacy and safety of droxidopa in patients with intradialytic hypotension","""INTRODUCTION: Intradialytic hypotension (IDH) is the most common complication of hemodialysis (HD), and it plays a significant role in the morbidity and mortality associated with maintenance HD. METHODS: This was a placebo-controlled, parallel-group study evaluating efficacy and safety of droxidopa in improving intradialytic blood pressure (BP) responses in 85 adults with end-stage renal disease (ESRD) and prone to IDH. Following screening and baseline periods, patients received 400 mg or 600 mg droxidopa, or placebo, orally 1 hour before HD for 4 weeks. Primary outcome endpoint was the change between baseline and last 2 treatment weeks in average mean arterial pressure (MAP) during HD. Also assessed were changes from baseline in systolic BP (SBP) and diastolic BP (DBP) during and after HD; number of hypotension-induced interventions and symptoms; and adverse events. RESULTS: Increase in droxidopa intra-HD MAP were not significantly different from placebo, although droxidopa groups showed significant improvements in mean SBP after HD of +4.8 ? 11.6 mm Hg (600-mg) and +3.4 ? 13.1 (400-mg) compared with -4.4 ? 17.9 mm Hg in placebo, and the drop seen in mean nadir SBP pre- to intra-HD was also reduced. Changes in mean DBP pre- and post-HD, changes in mean nadir SBP post-HD, or intra-HD SBP were not significant over the treatment period. HD terminations decreased 5-fold in the 600-mg group and 2-fold in the 400-mg group, whereas the number of discontinuations stayed unchanged in the placebo group. Overall, treatment with 600-mg or 400-mg droxidopa was well tolerated in this population. CONCLUSION: These data suggest that droxidopa may have a role in reducing IDH complications in patients with ESRD on chronic HD.""",1
13711,25709706,Adherence to risk evaluation and mitigation strategies (REMS) requirements for monthly testing of liver function,"BACKGROUND: Risk evaluation and mitigation strategies (REMS), as mandated by the US Food and Drug Administration (FDA) for medications with the potential for harm, are increasingly incorporating rigid protocols for patient evaluation, but little is known about compliance with these programs. Despite the inherent limitations, data on administrative claims may provide an opportunity to investigate adherence to these programs. METHODS: We assessed adherence to liver function test (LFT) requirements included in the REMS program for bosentan through use of administrative claims. Patients observed in the Optum Research Database who were initiators of bosentan from November 20, 2001 to March 31, 2013 were included. Adherence to LFTs was calculated using pharmacy claims for bosentan dispensation and medical claims for laboratory services, and was assessed at the time of drug initiation and within specified time intervals throughout follow-up. RESULTS: Of 742 patients, 523 (70.5%) had >/=1 qualifying LFT. Among patients with >/=12 dispensations, claims for LFTs at individual dispensations were 53.2-64.0%. Median proportion of dispensations with >/=1 LFT was 0.8 among patients with >/=6 (interquartile range, 0.7-1.0) or >/=12 (0.7-0.9) dispensations. Adherence was 90-100% for 33.3% of all initiators, whereas 29.3% of initiators were non-adherent (defined as <50% of on-therapy LFTs). CONCLUSIONS: Analyses of administrative claims suggest that the REMS program for bosentan may not have adequately guaranteed adherence to the program's monthly monitoring of LFTs. Such investigations of existing REMS programs may provide insight on how to accomplish more successful evaluation of REMS.",1
13712,25713599,"Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial","""INTRODUCTION: The efficacy of a cholinesterase inhibitor, donepezil, in patients with dementia with Lewy bodies (DLB) was investigated to confirm the superiority over placebo in the 12-week, double-blind phase of this phase III study. METHODS: Patients with probable DLB (n?=?142) were randomly assigned to placebo or to 5�mg or 10�mg of donepezil administered once daily for 12�weeks. The co-primary endpoints were changes in cognitive function assessed using the Mini-Mental State Examination (MMSE) and behavioral and neuropsychiatric symptoms using the Neuropsychiatric Inventory (NPI-2: hallucinations and fluctuations). The superiority of each active group over placebo was determined with simultaneous statistical significance in both endpoints. Safety evaluations included adverse events (AEs) and the unified Parkinson's disease rating scale (UPDRS) part III. RESULTS: The predefined superiority of donepezil to the placebo was not confirmed in either active group in the primary analysis. MMSE score significantly improved compared to placebo in the 10�mg group (10�mg: 2.2???0.4, placebo: 0.6???0.5 (mean???standard error); P?=?0.016). The change in MMSE score in the 5�mg group was not significant (1.4???0.5 (mean???standard error); P?=?0.232). Although NPI-2 improved compared to baseline in the active groups, the differences from placebo were not significant. Most AEs were mild or moderate. Although the incidence of parkinsonism was slightly higher in the 10�mg group, the change in the UPDRS score was minimal and without a significant difference from the placebo group. CONCLUSIONS: The co-primary endpoints were not achieved in this trial. However, significant improvement in MMSE score was demonstrated with 10�mg, but not 5�mg, of donepezil. The evaluation of psychiatric symptoms might be affected by advanced education and instructions given to caregivers. Overall, donepezil was well tolerated in patients with DLB. With careful attention on gastrointestinal or parkinsonian symptoms, patients with DLB can safely benefit from treatment with donepezil. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01278407 (trial registration date: 14 January 2011).""",1
13713,25717050,"Causes, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China","""BACKGROUND/AIMS: Drug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited. METHODS: All 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied. RESULTS: A total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs. 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs. 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs. 18/39, p=0.031). CONCLUSIONS: Most cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable.""",1
13714,25719997,Ceftolozane/Tazobactam (Zerbaxa)--a new intravenous antibiotic,,1
13715,25723139,Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients,"""BACKGROUND: The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. METHODS: Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. RESULTS: A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. CONCLUSIONS: Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.""",1
13716,25726556,Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis,"Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, progressively destructive lung disease that culminates in respiratory failure and death. Randomised controlled trials have demonstrated that treatment of IPF patients with pirfenidone reduces lung function decline, improves progression-free survival and significantly reduces the risk of all-cause mortality at 1 year. Pirfenidone has been shown to have a favourable safety profile and was generally well tolerated over the long term in clinical trials and real-world experience. However, side-effect management is critical to help some patients remain on treatment over the long term. The primary treatment-related adverse events associated with pirfenidone therapy are gastrointestinal upset, rash and photosensitivity. Gastrointestinal events may be mitigated by ensuring that pirfenidone is taken with food, while skin symptoms may be reduced by avoiding sun exposure and frequent use of sunblock. Educating patients about the potential for these adverse events to occur and providing instructions prior to treatment to avoid adverse drug reactions are an important means of ensuring patients may derive the important benefits provided by long-term treatment with pirfenidone.",1
13717,25733099,Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system,"""BACKGROUND & AIMS: Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. METHODS: We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS: Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively. CONCLUSIONS: Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.""",1
13718,25733509,Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients,"""Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.""",1
13719,25744115,Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial,"""OBJECTIVE: To evaluate the 5-year efficacy and safety of once weekly exenatide. PATIENTS AND METHODS: The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 ?g of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 ?g of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate. RESULTS: Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, -1.6%; 95% CI, -1.8% to -1.4%; vs -1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (-28.8 mg/dL; 95% CI, -36.2 to -21.5 mg/dL), weight (-3.0 kg; 95% CI, -4.6 to -1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed. CONCLUSION: Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00308139.""",1
13720,25746436,Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: A case series,"""OBJECTIVE: Obtaining a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) can decrease hepatic complications and be curative, however, extrahepatic manifestations including mixed cryoglobulinemia (MCN) may persist with interferon-based therapy. Our objective was to review our experience in treating patients with new oral antiviral agents and to assess common factors associated with MCN persistence despite SVR. METHODS: We analyzed a case series of five patients with genotype one chronic HCV complicated by MCN who had persistence of cryoglobulins despite completion of triple therapy with oral antiviral agents (boceprivir, telaprivir or sofosbuvir). RESULTS: Patients with cirrhosis appear to have a decreased ability to clear immune complexes. We observed that early viral response by week 8 of therapy and longer periods of undetectable virus on treatment correlated with eventual clearance of serum cryoglobulins in patients without cirrhosis. Two patients were treated with anti-B-cell agent rituximab prior to starting therapy for HCV; this did not lead to a more effective clearance of cryoglobulins. CONCLUSIONS: We suggest that a longer treatment course than the standard 24 weeks with triple therapy could aid in the clearance of these immune complexes and cryoglobulins in cirrhotics. More studies to determine the ideal duration of treatment for chronic HCV and coincident MCN are needed, especially in light of the new all oral direct-acting antiviral regimens that are now recommended for HCV treatment.""",1
13721,25754159,Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study,"""BACKGROUND & AIMS: The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. METHODS: In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. RESULTS: Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency </=7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. CONCLUSIONS: Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.""",1
13722,25755455,A Randomized Controlled Trial Comparing Efficacy of�Pentoxifylline and Pioglitazone on Metabolic Factors and Liver Histology in Patients with Non-alcoholic Steatohepatitis,"BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) involves increased hepatic macrosteatosis due to increased insulin resistance and non-hepatic processes including oxidative stress, apoptosis, and increased pro-inflammatory cytokines. Present study compared the efficacy of pentoxifylline and pioglitazone therapy in improving the metabolic factors and liver histology in patients with NASH. METHODS: Sixty consecutive biopsy proven NASH patients aged 18-70 years with ALT�>�1.2 times the upper limit of normal were randomized to receive either pentoxifylline 1200�mg/day in three divided doses orally every day or pioglitazone (30�mg/day) daily for 6 months. All the patients were also instructed to reduce their calorie intake by 500�kcal/day as well as to perform modest exercise (brisk walking) regularly at least 5 days per week. Before and after treatment, liver function tests, serum insulin, C-peptide levels, TNF-?, adiponectin, leptin levels, HOMA-IR and hepatocyte injury and fibrosis scores on liver histology were assessed. RESULTS: Both pentoxifylline and pioglitazone were effective in improving transaminases, insulin resistance (HOMA-IR) and adiponectin levels significantly. TNF-? levels improved with either of the drugs but did not achieve significant levels. Both the drugs improved the markers of acute liver injury. However, only steatosis improved significantly with either of the drugs. Patients treated with pioglitazone had significant improvement in lobular inflammation, portal inflammation and Brunts grade. Brunts grade improved significantly with pioglitazone as compared to pentoxifylline at the end of the therapy. CONCLUSIONS: Pioglitazone shows better improvement in both metabolic factors and liver histology in patients with NASH compared to pentoxifylline.",1
13723,25756190,New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease,"BACKGROUND: Anti-tumour necrosis factor ? (anti-TNF) agents have been implicated in drug-induced liver injury. There is minimal data on this occurrence in inflammatory bowel disease (IBD) patients. AIM: To identify the characteristics of liver enzyme elevations following anti-TNF therapy initiation in IBD. METHODS: A retrospective cohort of patients initiating anti-TNF therapy were analysed for new onset alanine transaminase (ALT) elevation (?60 U/L). We collected data on natural history, outcomes and patient characteristics compared with controls with persistent normal liver enzymes. Likelihood of causal association was assessed using the RUCAM score. RESULTS: From 1753 patients initiating an anti-TNF (1170 infliximab, 575 adalimumab, 8 certolizumab), 102 (6%) developed new onset ALT elevation. In 54 (53%), this could be linked to an alternate aetiology. Among those with idiopathic ALT elevations, the median time to ALT elevation from anti-TNF initiation was 18 weeks and median peak ALT was 96 U/L. Six underwent liver biopsy, all demonstrating hepatitis with autoimmune features. Compared to controls, cases were on a lower dose of infliximab (5.7 vs. 6.7 mg/kg, P = 0.02) but were otherwise similar in body mass index, sex and age. On follow-up, 34 continued the anti-TNF, 14 stopped therapy and 4 initiated steroids. Most (85%) normalised their LFTs after a median of 17 weeks including 28 (82%) of those who continued anti-TNF therapy. Ten patients were transitioned to a second anti-TNF without recurrence. CONCLUSIONS: ALT elevations occurred in 6% of IBD patients initiating anti-TNF therapy. Most idiopathic elevations were mild, transient and resolved despite therapy continuation.",1
13724,25758544,Drugs for ADHD,,1
13725,25759554,N-acetylcysteine treats intravenous amiodarone induced liver injury,"We report a case of intravenous (IV) amiodarone drug induced liver injury (DILI). The patient received IV N-acetylcysteine (NAC) which resulted in a rapid improvement in liver enzymes. While the specific mechanisms for the pathogenesis of IV amiodarone DILI and the therapeutic action of IV NAC are both unknown, this case strongly implies at least some commonality. Because IV amiodarone is indicated for the treatment of serious cardiac arrhythmias in an intensive care unit setting, some degree of ischemic hepatitis is likely a cofactor in most cases.",1
13726,25765070,Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer,"""Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.""",1
13727,25773378,Efficacy and safety of alirocumab in reducing lipids and cardiovascular events,"""BACKGROUND: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. METHODS: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. RESULTS: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). CONCLUSIONS: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).""",1
13728,25773757,"Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS)","BACKGROUND: Patients with cirrhosis resulting from chronic hepatitis C virus (HCV) infection are at risk of life-threatening complications, but consistently achieve lower sustained virological response (SVR) than patients without cirrhosis, especially if treatment has previously failed. We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir, with and without ribavirin. METHODS: In this multicentre, double-blind trial, between Oct 21, 2013, and Oct 30, 2014, we enrolled patients with HCV genotype 1 and compensated cirrhosis who had not achieved SVR after successive treatments with pegylated interferon and protease-inhibitor regimens at 20 sites in France. With a computer-generated randomisation sequence, patients were assigned in a 1:1 ratio to receive placebo matched in appearance to study drugs for 12 weeks followed by once daily combination fixed-dose tablets of 90 mg ledipasvir and 400 mg sofosbuvir plus weight-based ribavirin for 12 weeks, or ledipasvir-sofosbuvir plus placebo once daily for 24 weeks. The primary endpoint was SVR 12 weeks after the end of treatment (SVR12), for which 95% CIs were calculated with the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, number NCT01965535. FINDINGS: Of 172 patients screened, 155 entered randomisation, 77 were assigned to receive ledipasvir-sofosbuvir plus ribavirin and 78 ledipasvir-sofosbuvir. 114 (74%) were men, 151 (97%), were white, 98 (63%) had HCV genotype 1a, and 145 (94%) had non-CC IL28B alleles. SVR12 rates were 96% (95% CI 89-99) for patients in the ledipasvir-sofosbuvir plus ribavirin group and 97% (91-100) in the ledipasvir-sofosbuvir group. One patient discontinued treatment because of adverse events while receiving only placebo. The most frequent adverse events were asthenia and headache, pruritus, and fatigue. INTERPRETATION: Ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks provided similarly high SVR12 rates in previous non-responders with HCV genotype 1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat treatment-experienced patients with cirrhosis if longer-term treatment is not possible. FUNDING: Gilead Sciences.",1
13729,25776963,"Education and imaging. Hepatology: Rare Stevens-Johnson syndrome and vanishing bile duct syndrome induced by acetaminophen, requiring liver transplantation",,1
13730,25779750,"Apremilast in Patients With Active Rheumatoid Arthritis: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study","OBJECTIVE: To study the efficacy/safety of apremilast, an oral phosphodiesterase 4 inhibitor, compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX). METHODS: Patients were randomized 1:1:1 to receive placebo, apremilast 20 mg twice a day, or apremilast 30 mg twice a day. Patients whose swollen and tender joint counts had not improved by ?20% were considered nonresponders at week 16 and were required to enter the protocol-defined early escape. At week 24, patients were transitioned in a blinded manner to receive apremilast 20 mg twice a day if they were initially randomized to receive placebo. Patients who were not initially randomized to receive placebo continued to receive their target apremilast dose. Patients were required to take a stable dose of MTX (7.5-25 mg/week) throughout the study. Magnetic resonance imaging (MRI) was performed in a subset of patients. RESULTS: A total of 237 patients who were receiving MTX therapy were randomized and received ?1 dose of study medication. At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In the MRI substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated. CONCLUSION: Apremilast efficacy was not demonstrated in patients who had active RA despite stable MTX therapy.",1
13731,25792124,Efficacy and safety of vorapaxar as approved for clinical use in the United States,"""BACKGROUND: Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA). METHODS AND RESULTS: We examined the efficacy and safety of vorapaxar in the intended use population, considering 20,170 patients randomized in the multinational, double-blinded, placebo-controlled TRA 2 degrees P-TIMI 50 trial. Of these, 16,897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70. CONCLUSIONS: In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long-term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding. CLINICAL TRIAL REGISTRATION: URL: clinicaltrials.gov Unique Identifier: NCT00526474.""",1
13732,25795406,"Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study","BACKGROUND: Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma. METHODS: We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1:1) by the minimisation method to receive either trabectedin (1?2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850. FINDINGS: Between July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n=39) or best supportive care (n=37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5?6 months (95% CI 4?1-7?5) and the best supportive care group was 0?9 months (0?7-1?0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0?07 (90% CI 0?03-0?14 and 95% CI 0?03-0?16) by a Cox proportional hazards model (p<0?0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]). INTERPRETATION: Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population. FUNDING: Taiho Pharmaceutical Co., Ltd.",1
13733,25800129,"Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety","Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing-remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.",1
13734,25801797,Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials,"""Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427.""",1
13735,25804106,[A potentially fatal intoxication with colchicine],"BACKGROUND: Approximately ten times a year the Dutch National Poisons Information Centre (NVIC) is consulted regarding a colchicine intoxication or overdose. CASE DESCRIPTION: An 18-year old woman was admitted to the intensive care unit after a suicide attempt with a potentially lethal dosage of colchicine tablets (0.5 mg/kg body weight). After a few hours the patient developed abdominal pain and vomited. Over subsequent days she developed anaemia, thrombocytopenia and a paralytic ileus. Treatment mainly comprised intensive supportive care, including sedation, ventilation and repeated administration of activated charcoal. After a week she gradually began to recover and was able to leave IC 10 days after ingestion. CONCLUSION: Early recognition and treatment of colchicine intoxication is crucial to preventing a fatal outcome. Complete recovery is possible if extensive supportive treatment is given.",1
13736,25819691,"Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial","""BACKGROUND: The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. METHODS: In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged ?18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28. FINDINGS: Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8?8%; 95% CI -17?6 to 4?2). The lower bound of the 95% CI of -17?6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). INTERPRETATION: Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. FUNDING: Genzyme, a Sanofi company.""",1
13737,25821156,The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment,"Idelalisib, a phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117, an inactive metabolite, and is metabolized to a lesser extent by cytochrome P450 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In a mass balance study, the orally administered idelalisib dose was recovered mainly in feces ( approximately 78%). This study evaluated the pharmacokinetics and safety of a single 150-mg dose of idelalisib in subjects with moderate or severe hepatic impairment and in age-, sex-, and weight-matched, healthy controls. The idelalisib maximum observed plasma concentration was generally comparable in subjects with moderate or severe hepatic impairment versus healthy controls, whereas the mean area under the curve was higher (58% to 59%). GS-563117 exposures were lower in impaired versus healthy control subjects, likely because of lower formation in the setting of liver impairment. Exploratory analyses indicated no relevant relationships between idelalisib or GS-563117 plasma exposures and Child-Pugh-Turcotte scores. Single oral doses of idelalisib 150 mg were well tolerated, with most treatment-emergent adverse events (AEs) and laboratory abnormalities being grades 1 or 2 in severity. As such, no dose adjustment was required when initiating idelalisib treatment in patients with mild or moderate hepatic impairment, although close monitoring for potential AEs is recommended.",1
13738,25823958,"Secukinumab in psoriasis: randomized, controlled phase 3 trial results assessing the potential to improve treatment response in partial responders (STATURE)","""BACKGROUND: Secukinumab, an anti-interleukin-17A monoclonal antibody, has demonstrated rapid and sustained efficacy in phase 3 psoriasis trials. OBJECTIVES: To examine whether partial responders could achieve improved responses with intravenous (IV) secukinumab vs. the same or a higher subcutaneous (SC) dose. METHODS: Forty-three participants with moderate-to-severe psoriasis and partial response [Psoriasis Area and Severity Index (PASI) score improvement of ? 50% but < 75%] after 12 weeks of 300 or 150 mg SC secukinumab therapy were randomized 1 : 1 to secukinumab 10 mg kg(-1) IV (baseline, weeks 2 and 4, respectively) or secukinumab 300 mg SC (baseline, week 4). All participants subsequently received secukinumab 300 mg SC every 4 weeks (weeks 8-36). Co-primary end points were PASI 75 and Investigator's Global Assessment [2011 modified version (IGA mod 2011)] 0/1 response rates at week 8 (IV vs. SC). RESULTS: Higher IGA mod 2011 0/1 response rates (66.7% vs. 33.3%; P = 0.03) and a trend towards higher PASI 75 response rates (90.5% vs. 66.7%; P = 0.06) were observed with secukinumab IV vs. SC at week 8. The primary objective was not met, as the difference was not significant for both co-primary end points. Improved responses in both groups were maintained at week 40 in most participants. Safety profiles for IV and SC secukinumab were similar. The trial was underpowered owing to its small sample size. CONCLUSIONS: Improved response may be attained in patients with psoriasis achieving partial response after 12 weeks of SC secukinumab treatment by continued dosing with 300 mg SC or treatment with higher doses.""",1
13739,25825070,Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients,"""Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single-center treatment protocol of patients with HCV genotype 1 infection who received a 12-week combination regimen of sofosbuvir and simeprevir. Sixty-one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9-8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%-97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%-100%), whereas SVR12 was 89% (95% CI, 74%-95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3-F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%-86%); P?=?0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12-week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse.""",1
13740,25827658,Drug safety evaluation of apremilast for treating psoriatic arthritis,"INTRODUCTION: Apremilast is an orally available small molecule that targets PDE4. PDE4 modulates intracellular signaling and thereby can impact various proinflammatory and anti-inflammatory mediators. Apremilast has been approved by the USA FDA for the treatment of active psoriatic arthritis (PsA) and moderate-to-severe psoriasis (PsO). Although there are several therapies approved and used for the treatment of PsA, there is still an unmet need for additional effective and well-tolerated therapeutic options. In PsA clinical trials, apremilast has been shown to be efficacious and to have an acceptable safety profile. AREAS COVERED: This review article covers the mechanism of action of apremilast, its efficacy in clinical trials and a detailed focus on its safety profile, mainly from Phase III clinical trials. EXPERT OPINION: Based on the available literature, apremilast has proven to be an efficacious therapy for PsA and PsO. It may offer some advantage as compared to other therapeutic options given its favorable safety profile, including a lack of need for routine laboratory monitoring.",1
13741,25830126,Efficacy and safety of eltrombopag in adult refractory immune thrombocytopenia,"BACKGROUND: Eltrombopag is a thrombopoietin receptor agonist with excellent treatment outcomes in immune thrombocytopenia (ITP). Here, we analyzed the dose of eltrombopag required to achieve and maintain safe platelet counts in Korean ITP patients. METHODS: Adult refractory ITP patients (<30,000 platelets/?L) were enrolled. Eltrombopag doses were increased to achieve a target platelet count (?50,000 cells/?L). After achieving the target platelet count, the dose of concomitant ITP medications and eltrombopag was reduced to identify the lowest effective dose required to maintain the platelet count. RESULTS: Among 18 patients, 66.7% achieved complete response, 5.6% achieved platelet counts between 50,000 and 100,000 cells/?L, and 27.8% failed to achieve the target platelet count. The median ITP duration was significantly shorter in patients who achieved the target platelet count. The initial dose required to achieve the target platelet count was 25 mg/d. The adjusted maintenance doses were 25 mg twice per week or 25 mg/d. After discontinuation, 83.3% relapsed, and the median relapse-free survival was 15 days. Two relapsed and 1 failed patient switched to romiplostim. The response to romiplostim was similar to eltrombopag. During eltrombopag treatment, 38.9% showed hepatobiliary laboratory anomalies. Among 9 follow-up bone marrow examinations, 1 revealed fibrosis after 1 year of treatment. CONCLUSION: Eltrombopag was well tolerated with excellent treatment outcomes in refractory adult ITP patients. Low-dose eltrombopag effectively maintained the target platelet count. However, some patients required longer or higher-dose treatment to maintain the target platelet count, especially in heavily pretreated or longer ITP cases.",1
13742,25837829,"Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial","""BACKGROUND: Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. METHODS: In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ?6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. FINDINGS: Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91?6-100]) in the ribavirin-containing regimen and 90?9% (40/44 [95% CI 78?3-97?5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9?16% [95% CI -19?61 to 1?29]; p=0?086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92?7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. INTERPRETATION: An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. FUNDING: AbbVie.""",1
13743,25839406,Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine,"BACKGROUND & AIMS: Hepatitis C virus (HCV)-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy. METHODS: This was a phase II, multicenter, open-label, single-arm study in treatment-na?ve or peginterferon/ribavirin treatment-experienced HCV genotype 1-infected patients on methadone or buprenorphine?naloxone. Patients received 12weeks of co-formulated ombitasvir/paritaprevir/ritonavir (25mg/150mg/100mg once daily) and dasabuvir (250mg twice daily)+weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment. RESULTS: Thirty-eight non-cirrhotic patients on chronic methadone (n=19) or buprenorphine (n=19) were enrolled. A total of 37 patients (97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dl. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required. CONCLUSIONS: The interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin for 12weeks was well tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use.",1
13744,25846144,Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis,"""Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-na?ve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-na?ve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs. CONCLUSIONS: This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-na?ve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks.""",1
13745,25850632,A Case Report of Acute Vitamin A Intoxication due to Ocean Perch Liver Ingestion,"""BACKGROUND: Chronic vitamin A intoxication is well known; however, there are few reports of acute vitamin A intoxication due to the ingestion of food rich in vitamin A, particularly in adults. CASE REPORT: We report a case of a 27-year-old man presenting with chief complaints of flushing, headache, nausea, and joint pain. He had consumed 800 g of grilled ocean perch liver the day before and had experienced numbness shortly after. Although physical examination revealed only facial flushing, we suspected acute vitamin A intoxication due to his diet history. On day 2 after ingestion, his serum retinol levels were elevated at 1577 ng/mL, which confirmed vitamin A intoxication. He returned for follow-up on day 4 after ingestion, by which time his presenting symptoms had improved, but he had developed desquamation of his facial skin. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should consider acute vitamin A intoxication in the differential diagnosis of patients with headache, flushing, desquamation, nausea, and vomiting of unknown etiology. Complete diet histories and checking vitamin A levels are essential for diagnosis. This report highlights the diagnostic difficulties associated with vitamin A intoxication and the importance of an accurate diet history.""",1
13746,25853577,Edoxaban (Savaysa)--the fourth new oral anticoagulant,,1
13747,25853663,Advice for travelers,,1
13748,25859823,Acetaminophen Adducts Detected in Serum of Pediatric Patients With Acute Liver Failure,"""OBJECTIVES: Previous studies in patients with acute liver failure identified acetaminophen (APAP) protein adducts in the serum of 12% and 19% of children and adults, respectively, with acute liver failure of indeterminate etiology. This article details the testing of APAP adducts in a subset (n?=?393) of patients with varied diagnoses in the Pediatric Acute Liver Failure Study Group (PALFSG). METHODS: Serum samples were available from 393 participants included in the PALFSG registry. Adduct measurement was performed using validated methods. Participants were grouped by diagnostic category as known APAP overdose, known other diagnosis, and indeterminate etiology. Demographic and clinical characteristics and participant outcomes were compared by adduct status (positive or negative) within each group. RESULTS: APAP adduct testing was positive in 86% of participants with known APAP overdose, 6% with other known diagnoses, and 11% with an indeterminate cause of liver failure. Adduct-positive participants were noted to have marked elevation of serum alanine aminotransferase and aspartate aminotransferase coupled with total serum bilirubin that was significantly lower than adduct-negative patients. In the indeterminate group, adduct-positive patients had different outcomes than adduct-negative patients (P?=?0.03); spontaneous survival was 16 of 21 (76%) in adduct-positive patients versus 75 of 169 (44%) in adduct-negative patients. Prognosis did not vary by adduct status in patients with known diagnoses. CONCLUSIONS: Furthermore, study is needed to understand the relation of APAP exposure, as determined by the presence of APAP adducts, to the clinical phenotype and outcomes of children with acute liver failure.""",1
13749,25863559,"Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial","""BACKGROUND: Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. METHODS: In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients ?60 kg received 600 mg daily, patients >60 kg to ?80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1?0 mL/s, and a platelet count of at least 50???10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675. FINDINGS: Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98-100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95-100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1?2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29?2%] of 171), headache (12 [7?0%] of 171), and malaise (nine [5?3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23?5%] of 170), anaemia (23 [13?5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8?8%] of 170). INTERPRETATION: Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug-drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients. FUNDING: Gilead Sciences.""",1
13750,25877062,Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings,"BACKGROUND: Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). OBJECTIVE: To report integrated long-term safety data from phase 2/3 fingolimod studies. METHODS: Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received fingolimod 0.5mg (n=1640) or 1.25-0.5mg (n=1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. RESULTS: The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with fingolimod and placebo in FREEDOMS. In the All Studies group, fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with fingolimod 0.5mg and placebo. CONCLUSION: The safety profile of fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo.",1
13751,25877498,"A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate","""OBJECTIVE: To evaluate the efficacy and safety of brodalumab, a human monoclonal antibody inhibitor of the interleukin 17 receptor, in subjects with rheumatoid arthritis (RA). METHODS: Patients (n = 252) with inadequate response to methotrexate (MTX) were randomized to receive subcutaneous injections of brodalumab (70 mg, 140 mg, or 210 mg) or placebo. The primary endpoint was the American College of Rheumatology 50% response (ACR50) at Week 12. RESULTS: Demographics and baseline characteristics were generally balanced among treatment groups. At Week 12, ACR50 occurred in 16% (70 mg), 16% (140 mg), 10% (210 mg), and 13% (placebo; all nonsignificant vs placebo) of subjects. No significant treatment effects were observed for the secondary endpoints, including ACR20, ACR70, and Disease Activity Score in 28 joints. Incidences of all adverse events (AE), including serious AE (SAE), were similar across treatment groups. A total of 7 subjects reported SAE during the study (2 in the placebo group and 5 in the brodalumab groups), none of which was treatment related. There was 1 death (cardiopulmonary failure) ?1 week after the last dose in the 140 mg group. CONCLUSION: Our study failed to find evidence of meaningful clinical efficacy with brodalumab treatment in subjects with RA who had an inadequate response to MTX. These preliminary results do not support further evaluation of brodalumab as a treatment for RA. Clinicaltrials.gov number: NCT00950989.""",1
13752,25878015,Does glatiramer acetate provoke hepatitis in multiple sclerosis?,"An association between multiple sclerosis and autoimmune hepatitis has been described. The latter can also be unmasked or exacerbated by a variety of therapies used in multiple sclerosis, such as beta-Interferon or glatiramer acetate. Two cases of hepatitis occurring after exposure to glatiramer acetate are described here: the first, was possibly due to autoimmune hepatitis, rather than glatiramer acetate induced liver injury, the second was definite autoimmune hepatitis. Both occurred in patients who had already experienced hepatitis exacerbations during previous beta-Interferon treatment. We suggest that glatiramer acetate can unmask hepatitis. Thus, liver enzyme monitoring should be undertaken frequently in those patients with multiple sclerosis receiving glatiramer acetate, with a history of hepatitis during treatment with Interferon beta-1a.",1
13753,25882325,"Efficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Trial","""OBJECTIVE: The efficacy, safety, and tolerability of brexpiprazole and placebo were compared in adults with acute schizophrenia. METHOD: This was a multicenter, randomized, double-blind, placebo-controlled study. Patients with schizophrenia experiencing an acute exacerbation were randomly assigned to daily brexpiprazole at a dosage of 0.25, 2, or 4 mg or placebo (1:2:2:2) for 6 weeks. Outcomes included change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint measure), Clinical Global Impressions Scale (CGI) severity score (key secondary endpoint measure), and other efficacy and tolerability measures. RESULTS: The baseline overall mean PANSS total score was 95.2, and the CGI severity score was 4.9. Study completion rates were 62.2%, 68.1%, and 67.2% for patients in the 0.25-, 2-, and 4-mg brexpiprazole groups, respectively, versus 59.2% in the placebo group. At week 6, compared with placebo, brexpiprazole dosages of 2 and 4 mg produced statistically significantly greater reductions in PANSS total score (treatment differences: -8.72 and -7.64, respectively) and CGI severity score (treatment differences: -0.33 and -0.38). The most common treatment-emergent adverse event for brexpiprazole was akathisia (2 mg: 4.4%; 4 mg: 7.2%; placebo: 2.2%). Weight gain with brexpiprazole was moderate (1.45 and 1.28 kg for 2 and 4 mg, respectively, versus 0.42 kg for placebo at week 6). There were no clinically or statistically significant changes from baseline in lipid and glucose levels and extrapyramidal symptom ratings. CONCLUSIONS: Brexpiprazole at dosages of 2 and 4 mg/day demonstrated statistically significant efficacy compared with placebo and good tolerability for patients with an acute schizophrenia exacerbation.""",1
13754,25884302,Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: long term outcome of the Temporary Authorization for Use programme in France,"BACKGROUND: COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a Temporary Authorization for Use (TAU) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TAU. METHODS: Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TAU for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors. RESULTS: Among the 408 patients, 306 were eligible with a follow-up at 3�years. Median OS was 37.1�months from beginning of CT and 14.6�months from AA introduction. 211 patients (69%) received???3�months of AA and 95 patients (31%) were treated less than 3�months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3�months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3�years. CONCLUSIONS: Biochemical response monitored by PSA changes at 3�months is a strong predictive factor for AA treatment duration. Some high responders' patients could beneficiate from AA for more than 3�years.",1
13755,25891173,Pembrolizumab versus Ipilimumab in Advanced Melanoma,"""BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).""",1
13756,25891304,Nivolumab and ipilimumab versus ipilimumab in untreated melanoma,"""BACKGROUND: In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS: In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. RESULTS: Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. CONCLUSIONS: The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).""",1
13757,25891553,Glatiramer acetate-induced hepatitis in a young female patient with multiple sclerosis,"We report the first Italian case of glatiramer acetate-related acute hepatotoxicity. A 25-years-old woman suffering from multiple sclerosis presented acute hepatitis after eight months of treatment. Neither infective, nor autoimmune markers were detected. Liver biopsy histology was consistent with drug-induced acute injury. Liver function tests became normal after eight weeks of treatment discontinuation. This report points out the importance of monitoring liver function during the first year of treatment with glatiramer acetate.",1
13758,25895618,Recent advances in the treatment of hyperammonemia,"Ammonia is a neurotoxic agent that is primarily generated in the intestine and detoxified in the liver. Toxic increases in systemic ammonia levels predominantly result from an inherited or acquired impairment in hepatic detoxification and lead to potentially life-threatening neuropsychiatric symptoms. Inborn deficiencies in ammonia detoxification mainly affect the urea cycle, an endogenous metabolic removal system in the liver. Hepatic encephalopathy, on the other hand, is a hyperammonemia-related complication secondary to acquired liver function impairment. A range of therapeutic options is available to target either ammonia generation and absorption or ammonia removal. Therapies for hepatic encephalopathy decrease intestinal ammonia production and uptake. Treatments for urea cycle disorders eliminate ammoniagenic amino acids through metabolic transformation, preventing ammonia generation. Therapeutic approaches removing ammonia activate the urea cycle or the second essential endogenous ammonia detoxification system, glutamine synthesis. Recent advances in treating hyperammonemia include using synergistic combination treatments, broadening the indication of orphan drugs, and developing novel approaches to regenerate functional liver tissue. This manuscript reviews the various pharmacological treatments of hyperammonemia and focuses on biopharmaceutical and drug delivery issues.",1
13759,25897158,"Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer","""PURPOSE: Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. PATIENTS AND METHODS: Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. RESULTS: Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. CONCLUSION: Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.""",1
13760,25900924,Evidence for the efficacy and safety of anti-interleukin-5 treatment in the management of refractory eosinophilic asthma,"Two recent phase III trials in patients with severe eosinophilic asthma have shown that anti-interleukin 5 (IL-5) therapy with mepolizumab reduces the frequency of asthma attacks, improves symptoms and allows patients to reduce oral glucocorticoid use without loss of control of asthma. An earlier large 616 patient Dose Ranging Efficacy And safety with Mepolizumab in severe asthma (DREAM) study had shown that the only variables associated with treatment efficacy were a prior history of asthma attacks and the peripheral blood eosinophil count. The link between blood eosinophil counts and treatment efficacy is biologically obvious given that IL-5 has a pivotal role in eosinophil production, proliferation and chemotaxis. It is also clinically relevant as the blood eosinophil count is routinely measured and thus readily available in patients with asthma. Recognition of the link between airway or blood eosinophilia and treatment response was also important in the clinical testing of the alternative IL-5 blocker, such as reslizumab, which is currently being evaluated in a phase III randomized controlled trial (RCT) after having shown to improve lung function, improve symptom score and reduce sputum eosinophilia in a smaller phase IIb study. In addition, benralizumab, an IL-5? receptor blocker, has shown good effects in a phase IIb RCT with patients with severe asthma that had sputum eosinophilia and more recently in a phase IIa trial with patients with eosinophilic chronic obstructive pulmonary disease. Therefore anti-IL-5 treatment seems generally effective in eosinophilic asthma, either assessed by blood or airway eosinophilia. This factor together with the impressive clinical efficacy and good safety profile make anti-IL-5 (mepolizumab, reslizumab) and benralizumab (anti-IL-5 receptor ?) very promising drugs for the treatment of patients with severe eosinophilic asthma, a subgroup that is in desperate need of better treatments.",1
13761,25903392,Seven-year safety and efficacy with velaglucerase alfa for treatment-na?ve adult patients with type 1 Gaucher disease,"Velaglucerase alfa is a human ?-glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7-year experience of the now-completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9-month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ?1 adverse event, no patient withdrew due to a drug-related adverse event or required premedication. No patient developed anti-drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and -42% (-53%, -31%) and -78% (-94%, -62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near-normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters.",1
13762,25909356,"Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial","""BACKGROUND: Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection. OBJECTIVE: To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467). SETTING: 60 centers in the United States, Europe, Australia, Scandinavia, and Asia. PATIENTS: Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection. INTERVENTION: Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy. MEASUREMENTS: Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups. RESULTS: Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%). LIMITATION: The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections. CONCLUSION: Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection. PRIMARY FUNDING SOURCE: Merck & Co.""",1
13763,25911336,EASL Recommendations on Treatment of Hepatitis C 2015,,1
13764,25912374,Liver Injury in Psoriasis Patients Receiving Ustekinumab: A Retrospective Study of 44 Patients Treated in the Clinical Practice Setting,"""INTRODUCTION: The therapy of patients with psoriasis and liver disease can be a challenge due to the increased risk of adverse effects from traditional systemic treatments; in addition, although the anti-tumor necrosis factor agents are considered safer, they have also been associated with drug-induced liver injury and reactivation of viral hepatitis. Ustekinumab has a different mechanism of action and the little that is known of its effects on the liver comes from pivotal studies. The objectives of this study were to estimate the incidence of drug-induced liver injury in patients treated with ustekinumab in daily clinical practice and to analyze liver alterations in those patients with pre-existing liver disease. METHOD: All patients treated with the standard regimen of ustekinumab were included in the study. Variables gathered included age, sex, type of psoriasis, nail involvement, arthritis, previous treatments, history of liver disease, viral serology, Psoriasis Area Severity Index (at baseline and at 12, 16, and 52 weeks), transaminase levels, manifestations of liver disease, liver ultrasound, and factors such as body mass index, alcohol consumption, and ferritin levels. RESULTS: Grade 1 elevation of the transaminases was only observed in 6 patients; no cases of severe hypertransaminasemia were observed. None of the patients with elevation of the transaminases at baseline developed problems during treatment. CONCLUSIONS: Ustekinumab-related liver injury is uncommon and mild. From a hepatic point of view, the drug appears safe, even in patients with pre-existing liver disease and those who have developed altered liver function previously with other drugs.""",1
13765,25913287,Long term HER2+ metastatic breast cancer survivors treated by trastuzumab: Results from the French cohort study LHORA,"""PURPOSE: The LORHA study described the clinical features of patients and tumours in long-term responders from a subset of breast cancer patients who responded to 1st-line trastuzumab and without disease progression. METHODS: This was an ambispective, multicentre, non-interventional study conducted in 57 centres in France. Eligible patients were women with HER2+metastatic or locally-advanced breast cancer, treated with 1st-line therapy, progression-free for ?3 years after starting trastuzumab, and followed-up for 12 months. RESULTS: 160 patients were recruited, 128 were included in the efficacy analysis subset (median age: 61 years; [34-95 years]). A majority (88%) had invasive ductal carcinoma; 53% had SBR grade III carcinoma, and 58% were positive for hormonal receptors. The median time since diagnosis was 8 years [3-26 years]. The most frequent metastatic sites were the bone, liver, lymph nodes, and lungs in 43%, 35%, 20% and 19% of patients, respectively. The median duration of 1st-line trastuzumab was 4.5 years [0.8-12.1], combined with paclitaxel and docetaxel in 35 and 72 patients, respectively. Median PFS (progression-free survival) was 6.4 years [5.7; Not Reached]. No trastuzumab-related deaths were observed. In the safety analysis subset (N = 134), 3 cardiac adverse events considered related to trastuzumab were recorded in 3 patients (2.2%), and only one prospective congestive cardiac failure was of grade ?3. CONCLUSIONS: The LORHA study showed that long term responders to 1st-line trastuzumab for locally advanced or metastatic breast cancer could achieve a median PFS of more than 6 years, with an acceptable safety profile.""",1
13766,25915661,Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis,"""BACKGROUND: Guidelines recommend statins as first-line therapy for dyslipidemia. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new lipid-lowering approach. PURPOSE: To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia. DATA SOURCES: MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015. STUDY SELECTION: Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia. DATA EXTRACTION: Two investigators independently extracted data on study characteristics and lipid and clinical outcomes, and rated risk of bias of trials. Prespecified primary end points were all-cause and cardiovascular mortality. DATA SYNTHESIS: Twenty-four RCTs comprising 10�159 patients were included. Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, -47.49% [95% CI, -69.64% to -25.35%]; P�< 0.001] and other atherogenic lipid fractions, and it reduced all-cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P�= 0.015; heterogeneity P�= 0.63; I2�= 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P�= 0.084; heterogeneity P�= 0.78; I2�= 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P�= 0.030; heterogeneity P�= 0.45; I2�= 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P�= 0.026; heterogeneity P�= 0.65; I2�= 0%). Serious adverse events did not increase with administration of PCSK9 antibodies. LIMITATION: Results were derived from study-level data rather than patient-level data, and clinical outcome data are rare. CONCLUSION: PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia. PRIMARY FUNDING SOURCE: CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.""",1
13767,25920094,"From non-A, non-B hepatitis to hepatitis C virus cure","The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN)-alpha was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-alpha-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-alpha and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low- to middle-income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues.",1
13768,25923540,Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy,"""BACKGROUND AND AIMS: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions. METHODS: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated. RESULTS: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-na?ve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%. CONCLUSION: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.""",1
13769,25931244,"Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)","BACKGROUND: Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. METHODS: ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1?5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. FINDINGS: Of 1083 patients enrolled, 800 (73?9%), of whom 656 (82?0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76?9%] of 398 vs 275 [68?4%] of 402, 95% CI 2?3-14?6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. INTERPRETATION: Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. FUNDING: Cubist Pharmaceuticals.",1
13770,25936229,Selective estrogen receptor modulators in clinical practice: a safety overview,"INTRODUCTION: Selective estrogen receptor (ER) modulators (SERMs) are a class of nonsteroidal compounds that interact with ERs, each with a distinct tissue-specific profile. Depending upon the degree of ER agonism/antagonism at the target tissue, SERMs show efficacy for various indications including osteoporosis, dyspareunia, and breast cancer, and are associated with safety risks. AREAS COVERED: This review describes the safety profile of SERMs (tamoxifen, raloxifene, toremifene, bazedoxifene, lasofoxifene, and ospemifene) and fulvestrant (a pure ER antagonist) from Phase III trials, long-term extension studies, and active comparator studies. Tamoxifen, a first-generation SERM, is indicated for breast cancer prevention and treatment but is associated with serious safety concerns including endometrial cancer, venous thromboembolic events (VTE), and stroke. Toremifene, raloxifene, bazedoxifene, lasofoxifene, and ospemifene present generally improved, though distinctly different, safety profiles compared with tamoxifen, especially with endometrial cancer and stroke. However, the risk of VTE remains a concern for most SERMs. EXPERT OPINION: Each SERM presents a unique risk/benefit profile based on varying indications and tissue-specific ER agonist and antagonist effects, making careful patient selection and ongoing patient monitoring crucial aspects of treatment. Future research may focus on identifying new SERMs for endocrine-resistant and endocrine-responsive cancers and post-menopausal symptoms.",1
13771,25941954,Peginterferon beta-1a (Plegridy) for multiple sclerosis,Pegylated interferon beta-1a (Plegridy) injected subcutaneously every 2 weeks appears to be similar in its efficacy and adverse effects to older interferon formulations that must be injected more frequently.,1
13772,25942724,Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis,"""IMPORTANCE: Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. OBJECTIVE: All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. INTERVENTIONS: All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Sustained virologic response at posttreatment week 12 (SVR12). RESULTS: One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the treatment-experienced group. Three serious adverse events were considered to be treatment related and there were 4 adverse event-related discontinuations. Treatment-emergent grade 3 or 4 alanine aminotransferase elevations were observed in 4 patients, of which 1 had concomitant total bilirubin elevation. CONCLUSIONS AND RELEVANCE: In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12.""",1
13773,25954198,Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps,"Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.",1
13774,25963890,Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: Analysis of phase III ION trials,"In phase III studies, treatment with the once-daily fixed-dose combination tablet of ledipasvir/sofosbuvir (LDV/SOF) with and without ribavirin (RBV) resulted in high rates of sustained virological response (SVR) in patients chronically infected with genotype 1 hepatitis C virus, including those with compensated cirrhosis. We conducted an analysis of data from these trials to compare the safety and tolerability profile of LDV-SOF with and without RBV. We analyzed treatment-emergent adverse events (AEs) and laboratory abnormalities in patients who were randomized to 8, 12, and 24 weeks of LDV/SOF with or without RBV. In total, data from 1,952 patients (of whom 872 received LDV/SOF with RBV and 1,080 received LDV/SOF alone) were analyzed. Overall, 308 patients (16%) were African American, 224 (11%) had compensated cirrhosis, 501 (26%) had a body mass index ?30 kg/m(2) , and 440 (23%) were treatment experienced. Treatment-related AEs occurred in 71% and 45% of patients treated with and without RBV, respectively, including fatigue, insomnia, irritability, and rash/pruritus. Patients receiving RBV with LDV/SOF were more likely to require dose modification, interruptions of treatment resulting from AEs, or require the use of concomitant medications than those receiving LDV/SOF alone. Rates of treatment-related serious AEs and discontinuations resulting from AEs were similarly low (<1%) in both groups. The rate of SVR in those receiving RBV and those not receiving RBV was the same (97%). CONCLUSION: LDV/SOF plus RBV was associated with a greater incidence of AEs as well as concomitant medication use than LDV/SOF alone. Use of RBV did not impact the efficacy of LDV/SOF regimens in the ION phase III studies.",1
13775,25972490,Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial,"""OBJECTIVE: To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS). METHODS: This is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat. RESULTS: Twenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPItotal: 3.2, 95% confidence interval [CI] -3.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95% CI -3.0 to 12.2), quality of life (Quality of Life-Alzheimer's Disease -0.5, 95% CI -2.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI -0.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n = 16; placebo, n = 14, p = 0.36). No effects on vital signs, weight, or episodic memory were observed. CONCLUSIONS: Oral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally well-tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with dementia-related NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is well-tolerated.""",1
13776,25981364,Rivaroxaban-induced liver injury: Results from a venous thromboembolism registry,,1
13777,25981810,"Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial","BACKGROUND: Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. METHODS: BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. FINDINGS: Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13?9 months (IQR 10?1-17?3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. INTERPRETATION: The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. FUNDING: Novartis Pharmaceuticals Corporation.",1
13778,25985734,Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease,"""BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12-�and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and�ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.""",1
13779,25987659,International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts,"""This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ?65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.""",1
13780,25988963,Belinostat (Beleodaq) for peripheral T-Cell lymphoma,,1
13781,25989196,Ivabradine (Corlanor) for heart failure,,1
13782,26011140,Alfuzosin treatment improves the rate and time for stone expulsion in patients with distal uretral stones: a prospective randomized controlled study,"OBJECTIVE: To evaluate the safety and efficacy of alfuzosin treatment on rate and time of stone expulsion in patients with uncomplicated distal ureteral stones. PATIENTS AND METHODS: Prospective, randomized, open-label, controlled study. Patients >�18�years of age presenting to the outpatient urology clinic with uncomplicated radio-opaque stones located in the distal third of the ureter and of size ?�10�mm were included. Patients were randomly assigned to either a control group (n=26) and received standard of care management (daily oral hydration and diclofenac 75�mg IM on demand) or to the alfuzosin group (n=28) and received alfuzosin SR 5�mg twice daily in addition to standard of care management. Patients were followed weekly at office visits and twice weekly by telephone for 4�weeks or until stone expulsion. Assessments included stone passage rate and time, and patients were monitored for occurrence of adverse drug events, complications, number of pain episodes, analgesic consumption, and number of hospital revisits. Mann-Whitney, ?(2) , and Fisher exact test were used for data analysis. RESULTS: All 54 patients completed the study. Stone expulsion rate was higher in the alfuzosin arm (53.6%, 15/28) compared to the control arm (26.9%, 7/26, p=0.04). Median stone passage time was lower in the alfuzosin group than in the control group (9 vs 19�days, respectively, p=0.006). Ureteral sepsis, uncontrollable pain, and hospitalization readmissions were reported in the control group only. There were no differences between groups in number of pain episodes, pain scores, or analgesic consumption. Alfuzosin therapy was tolerable with only minor adverse effects (headache, dizziness, mild postural hypotension, and rhinitis). CONCLUSION: Alfuzosin is safe and effective in increasing stone expulsion rates and shortening stone passage times for uncomplicated distal ureteral stones.",1
13783,26014906,Review article: the efficacy and safety of daclatasvir in the treatment of chronic hepatitis C virus infection,"""BACKGROUND: The treatment of hepatitis C virus (HCV) has evolved dramatically after the introduction of direct acting anti-virals. NS5A protein plays an important role in HCV replication and is an attractive target for drug development. AIM: To review clinical studies on the efficacy and safety of direct-acting anti-virals regimens containing daclastavir, an NS5A inhibitor, in the treatment of chronic hepatitis C. METHODS: A Medline search was undertaken to identify relevant literature using search terms including 'daclatasvir', 'HCV treatment' and 'NS5A inhibitors'. Furthermore, we scanned abstracts presented at the recent international meetings in liver disease, viral hepatitis and infectious disease, as well as the reference lists of the review articles to identify publications not retrieved by electronic searches. RESULTS: Daclatasvir is the first-in-class HCV NS5A inhibitor that has been demonstrated in Phase I-III trials to have a potent anti-viral effect and clinical efficacy across multiple HCV genotypes (GT). Daclastavir is generally safe and well tolerated, with a low barrier to resistance and low potential for drug-drug interaction. When Daclastavir is added to PEG-IFN/RBV platform, sustained virological response (SVR) rates are increased significantly compared with PEG-IFN/RBV alone. The all-oral combination of Daclastavir/asunaprevir (ASV; protease inhibitor) has high SVR rates against GT1b, but less activity against GT1a. Dual combination of Daclastavir/Sofosbuvir (SOF; nucleotide polymerase inhibitor) and triple combination of Daclastavir/ASV/beclabuvir (BCV; non-nucleoside polymerase inhibitor) have demonstrated >90% SVR rates in both treatment na?ve and treatment-experienced patients with GT1. Furthermore, Daclastavir/SOF combination has also demonstrated up to 90% SVR rates in patients with GT3, and in those with human immunodeficiency virus coinfection, cirrhosis and post-transplant HCV recurrence with any GT. Daclastavir/ASV/BCV has primarily demonstrated near 100% SVR rates in patients with GT4. CONCLUSION: Daclastavir-containing regimens, with or without PEG-IFN, have shown promising results in clinical trials, and present an excellent treatment option for those with chronic HCV and for multiple genotypes.""",1
13784,26017304,Pasireotide in Acromegaly: A Review,"""Pasireotide (Signifor(�), Signifor(�) LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide and lanreotide, which bind preferentially to somatostatin receptor (SSTR)-2, pasireotide binds to multiple SSTRs. This article reviews the clinical use and summarizes the pharmacological properties of intramuscular pasireotide in the treatment of acromegaly. The efficacy of pasireotide 40�mg every 28�days was superior to that of intramuscular octreotide 20�mg every 28�days with regard to biochemical control in a 12-month, phase III trial in medically naive patients. Similarly, in a 6-month, phase III trial in patients with acromegaly inadequately controlled with somatostatin analogues for at least 6�months, the efficacy of pasireotide 40 or 60�mg was superior to that of continued octreotide 30�mg or lanreotide autogel 120�mg (each drug was administered once every 28�days) with regard to biochemical control. The tolerability profile of intramuscular pasireotide is generally similar to that of first-generation agents, except for a higher incidence of hyperglycaemia-related adverse events with pasireotide. In clinical trials, the risk of developing pasireotide-associated hyperglycaemia was numerically greater in patients categorized as diabetic or prediabetic at baseline than in those with normal glucose tolerance. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed.""",1
13785,26020712,"Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible-dose, 52-week extension study","""Vortioxetine is approved for the treatment of adults with major depressive disorder. This open-label extension (OLE) study evaluated the safety and tolerability of vortioxetine in the long-term treatment of major depressive disorder patients, as well as evaluated its effectiveness using measures of depression, anxiety, and overall functioning. This was a 52-week, flexible-dose, OLE study in patients who completed one of three randomized, double-blind, placebo-controlled, 8-week vortioxetine trials. All patients were switched to 10 mg/day vortioxetine for week 1, then adjusted between 15 and 20 mg for the remainder of the study, but not downtitrated below 15 mg. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), vital signs, laboratory values, physical examination, and the Columbia-Suicide Severity Rating Scale. Efficacy measures included the Montgomery-Asberg Depression Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Impression Scale-Severity of Illness, and the Sheehan Disability Scale. Of the 1075 patients enrolled, 1073 received at least one dose of vortioxetine and 538 (50.0%) completed the study. A total of 537 patients withdrew early, with 115 (10.7% of the original study population) withdrawing because of TEAEs. Long-term treatment with vortioxetine was well tolerated; the most common TEAEs (>/=10%) were nausea and headache. Laboratory values, vital signs, and physical examinations revealed no trends of clinical concern. The mean Montgomery-Asberg Depression Rating Scale total score was 19.9 at the start of the extension study and 9.0 after 52 weeks of treatment (observed cases). Similar improvements were observed with the Hamilton Anxiety Scale (Delta-4.2), the Clinical Global Impression Scale-Severity of Illness (Delta-1.2), and the Sheehan Disability Scale (Delta-4.7) total scores after 52 weeks of treatment (observed case). In this 52-week, flexible-dose OLE study, 15 and 20 mg vortioxetine were safe and well tolerated. After entry into this study, patients continued to show improvement in depression and anxiety symptoms, as well as overall functioning, throughout the treatment period.""",1
13786,26027431,Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma,"""BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).""",1
13787,26028255,PD-1 Blockade in Tumors with Mismatch-Repair Deficiency,"""BACKGROUND: Somatic mutations have the potential to encode """"non-self"""" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).""",1
13788,26030518,Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer,"""BACKGROUND: Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer. METHODS: This phase 3 study involved 521 patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred. RESULTS: The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. CONCLUSIONS: Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone. (Funded by Pfizer; PALOMA3 ClinicalTrials.gov number, NCT01942135.).""",1
13789,26033499,Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma,"""BACKGROUND: The objective of this study was to determine the efficacy and safety of locoregional therapy (LRT) combined with arsenic trioxide (As2 O3 ) treatment in primary hepatocellular carcinoma (HCC) patients. METHODS: One hundred twenty-five primary HCC patients were recruited for a randomized controlled study. Patients were randomly divided into group A (n = 61) and group B (n = 64). All patients received transarterial chemoembolization. Group A patients were given As2 O3 at 10 mg/d for 4 courses (21 days per course) with a 2-week interval between courses. Survival times, therapeutic responses, extrahepatic metastases, and adverse events were recorded. RESULTS: A better therapeutic response was found in group A patients, as shown by higher objective response rate (ORR) and clinical benefit rate (CBR) values in group A versus group B (ORR, 81.96% [95% confidence interval (CI), 72.32%-91.62%] vs 59.37% [95% CI, 47.34%-71.41%], chi(2) = 7.650, P < .05; CBR, 95.08% [95% CI, 89.66%-100.00%] vs 81.25% [95% CI, 71.69%-90.81%], chi(2) = 5.659, P < .05). There were fewer patients with extrahepatic metastases in group A versus group B (group A, 6 cases or 9.84% [95% CI, 2.36%-17.31%]; group B, 12 cases or 18.75% [95% CI, 9.19%-28.31%]). The survival rate for group A patients was significantly higher than that for group B patients (P < .05). No significant differences were found between the 2 groups in terms of hematology or digestive system, liver, or kidney dysfunction except for facial and limb edema. CONCLUSIONS: LRT combined with As2 O3 treatment prevents extrahepatic metastasis and prolongs the survival time for primary HCC patients.""",1
13790,26034120,Rising trend in vitamin D status from 1993 to 2013: dual concerns for the future,"""BACKGROUND: The Institute of Medicine 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D specified higher intakes for all age groups compared to the 1997 report, but also cautioned against spurious claims about an epidemic of vitamin D deficiency and against advocates of higher intake requirements. Over 40 years, we have noted marked improvement in vitamin D status but we are concerned about hypervitaminosis D. OBJECTIVE: We sought to evaluate the 25-hydroxyvitamin D (25OHD) trend over 20 years. DESIGN: We retrieved all results of serum 25OHD from 1993 to 2013 (n=69 012) that was trimmed to one sample per person (n=43 782). We conducted a time series analysis of the monthly averages for 25OHD using a simple sequence chart and a running median smoothing function. We modelled the data using univariate auto-regressive integrated moving average (ARIMA) and forecast 25OHD levels up to 2016. RESULTS: The time series sequence chart and smoother function demonstrated a steady upward trend with seasonality. The yearly average 25OHD increased from 36.1 nmol/l in 1993 to 57.3 nmol/l in 2013. The ARIMA model was a good fit for the 25OHD time series; it forecasted monthly average 25OHD up to the end of 2016 with a positive stationary R(2) of 0.377. CONCLUSIONS: Vitamin D status improved over the past 40 years, but there remains a dual problem: there are groups at risk of vitamin D deficiency who need public health preventative measures; on the other hand, random members of the population are taking unnecessarily high vitamin D intakes for unsubstantiated claims.""",1
13791,26035746,Drugs for psoriasis,,1
13792,26035749,Drugs for psoriatic arthritis,,1
13793,26039556,Afatinib (Gilotrif) for advanced non-small cell lung cancer,,1
13794,26043900,Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C,"INTRODUCTION: The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy. AREAS COVERED: The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available. EXPERT OPINION: In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug-drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug-drug interactions.",1
13795,26045340,"Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial","""BACKGROUND: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. METHODS: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. FINDINGS: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11.5 months [95% CI 10.4-12.6]) vs 9.9 months [8.9-11.1]; stratified hazard ratio 0.84 [95% CI 0.74-0.96; p=0.01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. INTERPRETATION: Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. FUNDING: Eli Lilly and Company.""",1
13796,26052259,Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial,"BACKGROUND: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. METHODS: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. RESULTS: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean +/- SE): 0.443 +/- 0.042 ft/s versus 0.303 +/- 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. CONCLUSIONS: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.",1
13797,26063212,Nintedanib: A Review of Its Use in Patients with Idiopathic Pulmonary Fibrosis,"""Nintedanib (Ofev(�)) inhibits receptor tyrosine kinases implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This article reviews the efficacy and tolerability of oral nintedanib in the treatment of IPF, as well as summarizing its pharmacological properties. In the randomized, double-blind, multinational, 12-month INPULSIS-1 and -2 trials in patients with IPF, nintedanib significantly reduced the decline in forced vital capacity versus placebo, indicating a slowing of disease progression. The time to first acute exacerbation was significantly increased with nintedanib in INPULSIS-2, but not in INPULSIS-1, and significantly less deterioration in health-related quality of life was seen with nintedanib in INPULSIS-2, but not in INPULSIS-1. Nintedanib had an acceptable tolerability profile in patients with IPF; gastrointestinal adverse events (diarrhoea, nausea, vomiting) were reported most commonly. In conclusion, nintedanib is an important new option for the treatment of IPF.""",1
13798,26070913,"Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial","""BACKGROUND: Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation. METHODS: We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ?18 years) and % predicted FEV1 (<70, ?70 to ?90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis. FINDINGS: After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2?1 percentage points (95% CI -1?13 to 5?35; p=0?20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24?0 mmol/L, 95% CI -28?01 to -19?93; p<0?0001) and CFQ-R respiratory domain (8?4, 2?17 to 14?61; p=0?009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5?0 percentage points, 95% CI 1?15 to 8?78; p=0?01), but not in patients aged 6-11 years (-6?3 percentage points, -11?96 to -0?71; p=0?03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5?0 percentage points [p=0?0005]; ivacaftor-to-ivacaftor, 6?0 percentage points [p=0?006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290). INTERPRETATION: Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease. FUNDING: Vertex Pharmaceuticals Incorporated.""",1
13799,26071414,Lumacaftor/ivacaftor for patients homozygous for Phe508del-CFTR: should we curb our enthusiasm?,,1
13800,26075331,"Ketamine and phencyclidine: the good, the bad and the unexpected","The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms.",1
13801,26076854,Long-term efficacy and safety of lacosamide monotherapy in the treatment of partial-onset seizures: A multicenter evaluation,"PURPOSE: The goal of this study is to report the efficacy and tolerability of lacosamide (LCM) monotherapy, as first-line and conversion regimens, in the treatment of patients with partial-onset seizures. METHODS: We retrospectively reviewed the charts of patients with focal epilepsy on LCM monotherapy from six centers in Spain. Efficacy and tolerability were evaluated in the overall group and in subgroups of patients who were naive to antiepileptic drug (AED) therapy (Group 1) and those who had previously been treated with AEDs (Group 2). RESULTS: Sixty-six patients were identified including 18 patients in Group 1 and 48 patients in Group 2. Patients were followed up for 0.5-54 months in monotherapy (mean 15.5 months). Forty-two (63.6%) patients remained seizure-free during all the follow-up. At 6 and 12 months, seizure-free rates were 77.6% and 72.3%, respectively. The drug was withdrawn in 10 (15%) patients (3 side effects, 6 lack of efficacy, 1 other reason). Fifteen (22.7%) patients reported mild to moderate side effects with the use of LCM. No differences were found between Groups 1 and 2 regarding efficacy outcomes or tolerability issues. CONCLUSIONS: In our series more than two-thirds of the patients remained seizure-free on LCM monotherapy. Side effects were generally mild and led to discontinuation in only 3/66 (4.5%) patients. Our experience suggests that LCM monotherapy, either as first-line or after conversion, may be a valuable option for patients with focal epilepsy.",1
13802,26082511,Hepatitis B Virus Reactivation During Successful Treatment of Hepatitis C Virus With Sofosbuvir and Simeprevir,"Treatment of hepatitis C virus with potent, interferon-free, direct-acting antiviral regimens with no activity against hepatitis B virus (HBV) may increase the risk for HBV reactivation in coinfected patients. We present 2 cases of HBV reactivation during treatment with an all-oral regimen of simeprevir and sofosbuvir and discuss strategies to prevent HBV flare.",1
13803,26091193,Safety and Efficacy from an 8 Week Double-Blind Trial and a 26 Week Open-Label Extension of Asenapine in Adolescents with Schizophrenia,"""OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia. METHODS: In an 8 week, randomized, double-blind placebo-controlled trial, subjects (12-17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5?mg b.i.d., or asenapine 5?mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE). RESULTS: A similar percentage of subjects completed treatment on day 56 (2.5?mg b.i.d. (n=98): 83%; 5?mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (-4.8 for 2.5?mg b.i.d., p=0.070; -5.6 for 5?mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5?mg b.i.d. group versus placebo on day 56 (LS mean -0.3, p=0.024). In the acute phase, ?7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5?mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by -16.1 points in the group previously treated with placebo (n=62) and by -11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26. CONCLUSIONS: Although improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5?mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia. CLINICAL TRIALS REGISTRY: NCT01190254 and NCT1190267 at ClinicalTrials.gov.""",1
13804,26094251,Budesonide MMX for the Induction of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis,"""BACKGROUND AND AIMS: Cumulative safety and tolerability of budesonide MMX, a once-daily oral corticosteroid for inducing mild to moderate ulcerative colitis remission, was examined. METHODS: Data from three randomized, double-blind, placebo-controlled, phase II or III studies [budesonide MMX 9 mg, 6 mg, or 3mg for 8 weeks]; one phase II study [randomisation to budesonide MMX 9 mg or placebo for 4 weeks, then open-label budesonide MMX 9 mg for 4 weeks]; and one open-label study [budesonide MMX 9 mg for 8 weeks] were pooled. RESULTS: Patients randomised to budesonide MMX 9 mg [n = 288], 6 mg [n = 254], or placebo [n = 293] had similar rates of adverse events [AEs] [27.1%, 24.8%, and 23.9%, respectively] and serious AEs [2.4%, 2.0%, and 2.7%, respectively]; treatment-related AEs and serious AEs were reported by 11.8% and 13.5%, and 5.9% and 2.2%, respectively, of patients receiving budesonide MMX 3mg [n = 17] or open-label budesonide MMX 9 mg [n = 89]. Mean morning plasma cortisol concentrations were normal from baseline to final visit across randomised groups; in patients receiving open-label budesonide, mean cortisol concentration was 129.9 nmol/l after 4 weeks, returning to normal concentrations at final visit. Budesonide MMX was not associated with an overall increased risk for glucocorticoid-related adverse effects. CONCLUSIONS: Budesonide MMX 9 mg was associated with normal mean cortisol concentrations at final visit and an AE incidence comparable to placebo. Overall, budesonide MMX was safe and well tolerated for inducing remission of patients with mild to moderate ulcerative colitis.""",1
13805,26096332,Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 in patients with cirrhosis,"UNLABELLED: Interferon (IFN)-free regimens are needed to treat hepatitis C virus (HCV) infection. Combined simeprevir (SMV) and sofosbuvir (SOF) with or without ribavirin (RBV) results in high sustained virological response (SVR) rates along with minimal adverse events (AEs) in patients with hepatitis C genotype 1 (HCV GT1). The aim of this study was to report on the virological response, safety, and tolerability of SOF and SMV with or without RBV in compensated and decompensated patients with cirrhosis with HCV GT1 infection. Patients treated with standardized clinical protocol utilizing SMV+SOF with or without RBV at three transplant centers were retrospectively reviewed. A total of 119 patients (61% male, 87% white, 69% subtype 1a, 30% Child-Pugh-Turcott [CPT]-B liver cirrhosis [LC], and 82% were treatment experienced) received treatment and were followed for a median of 38 weeks (range, 12-58). Sustained virological response (SVR) at week 12 (SVR12) was achieved in 78% (92 of 118) of patients (95% confidence interval: 69-85). Lower pretreatment Model for End Stage Liver Disease (MELD) score was a predictor of SVR12 (P = 0.018). Baseline viral load, previous treatment status, RBV use, or GT1 subtype did not impact SVR 12. The majority of patients with SVR12 showed stability or improvement in MELD score. Treatment was very well tolerated with mild degrees of AEs. CONCLUSIONS: The regimen of SMV+SOF with or without RBV for 12 weeks was very well tolerated and resulted in high SVR12 rates (78%) in HCV GT1 patients with LC. SVR12 was inversely related to pretreatment MELD. SVR12 had favorable short-term impact on MELD score. Long-term impact on disease stability is yet to be determined. Longer treatment duration or the use of different regimen may still be needed in this population.",1
13806,26100497,HCV targeting of patients with cirrhosis,"Interferon (IFN)-free treatments are now the treatment of choice for patients with chronic hepatitis C. Previously difficult to treat patients by IFN-containing treatments can now be treated safely by IFN-free therapies. More than 90% of hepatitis C genotype 1 and 4 patients with compensated cirrhosis or after orthotopic liver transplantation (OLT) can be cured by sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the paritaprevir/ritona-vir/ombitasvir/?dasabuvir (3D) combination. Addition of ribavirin confers to a minimal, if any, benefit to increase SVR. The need for ribavirin is controversial and remains to be studied. The optimal length of treatment is still unknown, and an individual approach may be needed. Most patients require only 12weeks of therapy. The safety of these drugs is not fully explored in patients with decompensated cirrhosis (Child-Pugh C), who should not be treated with protease inhibitors. In cirrhosis hepatitis C virus eradication does not necessarily mean a cure of the disease and patients regularly require follow-up. Drug-drug interactions with immunosuppressant in patients after OLT are easier to manage but still require attention. Better drugs are needed for genotype 3 patients.",1
13807,26104032,Pitavastatin therapy in polymedicated patients is associated with a low risk of drug-drug interactions: analysis of real-world and phase 3 clinical trial data,"OBJECTIVES: Medications that interact with the pathways responsible for statin metabolism may increase the risk of statin-associated myalgia. Pharmacokinetic studies show that pitavastatin is carried into the liver by a range of transporters and is minimally metabolized by cytochrome P450 in healthy volunteers, indicating a reduced potential for drug-drug interactions (DDIs). This post hoc analysis investigates the incidence of adverse events in patients receiving pitavastatin with concomitant medication in two large data sets. METHODS: The largest pitavastatin patient data sets are the LIVALO Effectiveness and Safety (LIVES) postmarketing surveillance study in Japan (n = 19,925) and the European phase 3 clinical trial program (n = 2,396). Adverse events were classified according to the Medical Dictionary for Regulatory Activities (Med-DRA) and whether they occurred in patients taking medications that interact with hepatocyte organic anion-transporting polypeptide or cytochrome P450 (CYP) isoenzyme pathways. RESULTS: Concomitant administration of pitavastatin with other medications was not associated with clinically significant increases in the incidence of adverse drug reactions (ADRs), even when given with medications that interact with CYP2C9, responsible for the minimal CYP metabolism of pitavastatin. There was a significant interaction with biguanides in LIVES, but this was associated with a reduced risk of muscle ADRs. CONCLUSION: In clinical trials, pitavastatin is associated with a low incidence of adverse events related to DDIs, consistent with data from healthy volunteers. Prescribing a metabolically stable statin, such as pitavastatin, may improve patient adherence to medication, thus facilitating the attainment of lipid targets and reducing cardiovascular risk.",1
13808,26111063,"Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus",,1
13809,26113432,Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans,"BACKGROUND: Real-world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. AIM: To assess sustained virological response (SVR) of sofosbuvir (SOF)-based regimens in routine medical practice. METHODS: Observational, intent-to-treat cohort analysis of genotype 1 and 2 HCV-infected veterans initiating SOF-based regimens with recommended treatment duration of 12�weeks. RESULTS: Four thousand and twenty-six veterans with genotype 1 (N�=�3203) and genotype 2 (N�=�823) comprise the cohort. SVR rates for genotype 1 were 66.8% for SOF�+�peginterferon�+�ribavirin (RBV), 75.3% for SOF�+�simeprevir (SIM), 74.1% for SOF�+�SIM�+�RBV and for genotype 2 were 79.0% for SOF�+�RBV. Genotype 1 patients were less likely to achieve SVR with BMI ?30 (OR 0.64, 95% CI 0.49-0.84, P�<�0.001), a history of decompensated liver disease (OR 0.51, 95% CI 0.36-0.71, P�<�0.001), treatment experience (OR 0.58, 95% CI 0.48-0.71, P�<�0.001), APRI >2 (OR 0.44, 95% CI 0.36-0.55, P�<�0.001) and with SOF�+�PEG�+�RBV compared with SOF�+�SIM (OR 0.50, 95% CI 0.40-0.62, P�<�0.001). Age, sex, race/ethnicity, diabetes and genotype subtype did not predict SVR. Odds of achieving SVR with SOF�+�SIM�+�RBV did not differ compared with SOF�+�SIM (OR 1.03, 95% CI 0.75-1.44, P�=�0.86). Genotype 2 patients were less likely to achieve SVR with prior treatment experience (OR 0.55, 95% CI 0.35-0.88, P�=�0.009) and APRI >2 (OR 0.39, 95% CI 0.25-0.62, P�<�0.001). CONCLUSIONS: In this real-world cohort, SVR rates were lower than in clinical trials. Genotype 1 and 2 HCV-infected patients with advanced liver disease by APRI >2 or FIB-4�>�3.25 were significantly less likely to achieve SVR. For genotype 1, a SOF�+�SIM�?�RBV regimen was associated with a higher likelihood of SVR.",1
13810,26114074,A Serendipitous Find: A Case of Cholangiocarcinoma Identified Incidentally After Acute Liver Injury Due to Cascara sagrada Ingestion,"The use of anthranoid laxatives such as Cascara sagrada can, in rare instances, produce a hepatitis that resolves with discontinuation of the offending supplement. However, the clinical presentation of abdominal pain, jaundice, clay-colored stools, and darkening urine can mimic the presentation of a variety of hepatobiliary illnesses, including cholangiocarcinoma. This case report describes a local patient diagnosed with an extrahepatic cholangiocarcinoma following workup for an acute hepatitis due to ingestion of large quantities of Cascara sagrada.",1
13811,26114191,Mesalamine-induced fever: an important reminder to prescribers,,1
13812,26119089,"Echinococcosis: A 15-year epidemiological, clinical and outcome overview","""OBJECTIVE: To analyze the epidemiological and clinical characteristics and mortality of patients with cystic echinococcosis (CE) in northern Spain. PATIENTS AND METHODS: A retrospective study of the medical records of patients diagnosed with CE and hospitalized from 1997 to 2011 in a University Hospital. RESULTS: A total of 76 patients (44 men) were diagnosed with CE. The mean age was 57.8 years (SD: 19.1 years; range: 14.9-92.7). The yearly average incidence was 1.08 cases/100,000 inhabitants. The highest incidence was registered in patients aged 70-79 years (22.7% of all cases). Liver was the main organ involved (92.1%), followed by lung (6.6%) and peritoneum (1.3%). Fifty-five patients (72%) received treatment: 2 (3.6%) medical treatment with albendazole, 27 (49%) surgical treatment, 3 (5.4%) medical treatment combined with cyst drainage, and 23 (42%) combined medical and surgical treatment. Eight patients had a recurrence. Twenty-four (31.2%) patients died. No patient's death was attributed directly to hydatidosis, though mortality was significantly higher in the untreated vs. the treated patient group (57% vs. 22%, p=0.003). CONCLUSIONS: Hydatidosis treatment and diagnostic approaches remain heterogeneous. The liver continues being the main organ affected. Mortality was higher in patients who did not receive treatment. However, this result might have been influenced by other factors, mainly age.""",1
13813,26138527,Hepatotoxicity of New Oral Anticoagulants (NOACs),"""Case reports and analyses of clinical studies and of pharmacovigilance data suggest that new oral anticoagulants (NOACs) are associated with a small risk for hepatotoxicity. The objective of this publication is to summarize the current data about this subject, with a special emphasis on pharmacovigilance data in the World Health Organization (WHO) Global Individual Case Safety Reports (ICSR) database and on potential mechanisms of hepatotoxicity. For that, all available case reports as well as published analyses of clinical studies were obtained with a detailed search in PubMed. In addition, pharmacovigilance data from VigiBase(�), the WHO Global ICRS database, were extracted and analyzed. The data show that liver injury associated with NOACs was reported in clinical studies and in pharmacovigilance databases. Several case reports described potentially life-threatening hepatotoxicity in patients treated with rivaroxaban or dabigatran. For rivaroxaban, most affected patients were symptomatic and liver injury was most often hepatocellular or mixed. The frequency was between 0.1 and 1 % in clinical studies and was by trend lower than for comparators (mostly enoxaparin or warfarin). Comparing the pharmacovigilance reports for the individual NOACs, more hepatic adverse events were reported for rivaroxaban than for dabigatran or apixaban. With the exception of edoxaban, for which only few reports are available, patients with acute liver failure have been reported for every NOAC, but most patients had concomitant drugs or diseases. So far, there are no clear mechanisms explaining the hepatotoxicity of these drugs. We conclude that hepatotoxicity appears to be associated with all NOACs currently on the market. Hepatotoxicity associated with NOACs is idiosyncratic; it appears at therapeutic doses, is rare and the mechanism is not related to the pharmacological action of these drugs. Prescribers should inform patients about possible symptoms of hepatotoxicity and stop these drugs in patients presenting with severe liver injury.""",1
13814,26147895,Eliglustat (Cerdelga)--An Oral Drug for Gaucher Disease,,1
13815,26151676,Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Na?ve Patients with Metastatic Castration Resistant Prostate Cancer,"PURPOSE: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75�years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial. MATERIALS AND METHODS: Patients were stratified and randomized 1:1 to abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively. RESULTS: A total of 350 elderly patients treated with abiraterone-prednisone had significant improvements in overall and radiographic progression-free survival vs�those with prednisone alone (HR 0.71, 95% CI 0.53-0.96 vs HR 0.63, 95%�CI�0.48-0.83), similar to 738 younger patients (HR 0.81, 95% CI 0.63-1.03 vs HR�0.49, 95% CI 0.40-0.59). All secondary end points favored the abiraterone-prednisone arm for both age subgroups. Specific adverse events with abiraterone-prednisone were similar between the age subgroups. Elderly patients in both treatment arms had higher rates of fluid retention and cardiac disorders than younger patients, although rates of dose reduction or treatment interruptions due to adverse events were low in both age subgroups. CONCLUSIONS: Abiraterone acetate demonstrated clinical benefit and was well tolerated in elderly and younger men with chemotherapy na?ve, metastatic castration resistant prostate cancer. Thus, findings support it as a treatment option for�elderly patients who may not tolerate other therapies with greater toxicity.",1
13816,26154612,"""Use of apixaban after development of suspected rivaroxaban-induced hepatic steatosis; a case report""","""Postmarketing reports have emerged associating rivaroxaban with drug-induced liver injury (DILI); however, management strategies of patients with suspected rivaroxaban-induced liver injury requiring continued anticoagulation have not been published. The present report describes a 67-year-old male with atrial fibrillation receiving rivaroxaban who developed a 16-fold elevation in alanine transaminase, a nearly two-fold elevation in total bilirubin, and ultrasound confirmed hepatic steatosis. The patient was switched from rivaroxaban to apixaban with subsequent rapid resolution of laboratory abnormalities. Rapid improvement in liver function tests despite use of an alternative factor Xa inhibitor suggests that rivaroxaban's mechanism of hepatotoxicity may be unrelated to its pharmacologic action. When using rivaroxaban, clinicians should be aware of the small but potentially serious risk of DILI. Because most anticoagulants have been associated with DILI, selection of an alternative anticoagulant may be challenging; however, the use of apixaban in this case suggests it may be a reasonable alternative.""",1
13817,26156651,Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial,"""BACKGROUND: There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung. METHODS: We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov, NCT01523587. FINDINGS: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6?7 months (IQR 3?1-10?2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib (median 2?4 months [95% CI 1?9-2?9] vs 1?9 months [1?9-2?2]; hazard ratio [HR] 0?82 [95% CI 0?68-1?00], p=0?0427). At the time of the primary analysis of overall survival (median follow-up 18?4 months [IQR 13?8-22?4]), overall survival was significantly greater in the afatinib group than in the erloinib group (median 7?9 months [95% CI 7?2-8?7] vs 6?8 months [5?9-7?8]; HR 0?81 [95% CI 0?69-0?95], p=0?0077), as were progression-free survival (median 2?6 months [95% CI 2?0-2?9] vs 1?9 months [1?9-2?1]; HR 0?81 [95% CI 0?69-0?96], p=0?0103) and disease control (201 [51%] of 398 patients vs 157 [40%] of 397; p=0?0020). The proportion of patients with an objective response did not differ significantly between groups (22 [6%] vs 11 [3%]; p=0?0551). Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib (39 [10%] vs nine [2%]), of grade 3 stomatitis with afatinib (16 [4%] vs none), and of grade 3 rash or acne with erlotinib (23 [6%] vs 41 [10%]). INTERPRETATION: The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung. FUNDING: Boehringer Ingelheim.""",1
13818,26157882,SlimQuick-Associated Hepatotoxicity Resulting in Fulminant Liver Failure and Orthotopic Liver Transplantation,"Green tea extract is a popular ingredient in herbal weight loss supplements. There have been reports of hepatotoxicity associated with the use of dietary supplements, some of these cases lead to fatal outcomes. To our knowledge, we report the first case of fulminant hepatic failure requiring orthotopic liver transplantation caused by SlimQuick (Wellnx Life Sciences, Wilmington, DE), a widely available weight loss supplement containing green tea extract.",1
13819,26157932,Amiodarone-Induced Liver Injury and Cirrhosis,"We present a case report of an 80-year-old woman with volume overload thought initially to be secondary to heart failure, but determined to be amiodarone-induced acute and chronic liver injury leading to submassive necrosis and bridging fibrosis consistent with early cirrhosis. Her histopathology was uniquely absent of steatosis and phospholipidosis, which are commonly seen in AIC.",1
13820,26159282,Antiviral Therapy in Patients with Hepatitis C Virus-Induced Cirrhosis,"BACKGROUND: Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon (IFN)-? monotherapy in the early 1990s to the approval of telaprevir- and boceprevir-based triple therapies with pegylated (PEG)-IFN-? and ribavirin (RBV) in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements that may cure virtually all HCV patients with an all-oral, IFN-free regimen are becoming progressively available. Key Messages: Historically, a PEG-IFN/RBV combination therapy of patients with liver cirrhosis was associated with lower virological rates and a worse safety profile. The advent of the first protease inhibitor-based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients. The newer direct-acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or nonnucleosidic inhibitors, the viral protease and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the nonnucleosidic polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve a sustained virological response in up to 95% of naive patients or previously treated patients, even in those who failed prior treatment with first-generation protease inhibitors. The best treatment regimens enable the achievement of comparable results even in cirrhotics, while other regimens still require RBV or a longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimens for cirrhotic patients. The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials. CONCLUSIONS: As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment response and the presence of liver cirrhosis. In the near future, this should allow: (i) a decrease in the complications of HCV-induced cirrhosis, (ii) liver transplantations to be performed in virally cured patients, and (iii) the rescue of patients in the worst clinical situation (decompensated cirrhosis and HCV recurrence on liver graft).",1
13821,26165727,Systematic review on herb-induced liver injury in Korea,"Herbal drugs are generally regarded as safe due to their extensive clinical use especially in East Asian countries. However, the potential toxicity of herbal drugs has become an important medical issue recently, resulting in numerous reports of drug-induced liver injury (DILI). Here, we performed a systematic review of herbal medicines with the potential to cause hepatotoxicity in Korea. A literature search of six databases, including PubMed and five Korean electronic databases, was performed to identify cases of herb-induced liver injury (HILI) in Korea, yielding 31 unique reports, including 21 single herb and 10 multi-herb preparations. From these reports, we identified 97 cases of HILI (47 males, 49 females, and 1 unknown sex) consisting of 74.7% hepatocellular-type injury, 10.8% cholestatic-type injury, and 14.5% mixed-type injury. Causative agents included 21 unique herbal preparations, including 11 single species and 10 multispecies, with Polygoni Multiflori (39.2%) and Dictamnus dasycarpus (37.1%) as the most frequent agents. These analyses presented a feature of HILI, and produced a comprehensive list of herbs with a higher risk of hepatotoxicity in Korea. Further studies will be necessary to ascertain the mechanisms by which these herbs induce HILI and to determine whether these effects are specific to the Korean population.",1
13822,26166142,"Risk Factors, Clinical Presentation, and Outcomes in Overdose With Acetaminophen Alone or With Combination Products: Results From the Acute Liver Failure Study Group","""BACKGROUND AND AIMS: Acetaminophen (APAP) is the most common cause of acute liver failure (ALF) in the west. It is unknown if APAP overdose in combination with diphenhydramine or opioids confers a different clinical presentation or prognosis. Study objectives were to compare (1) baseline patient characteristics; (2) initial clinical presentation; and (3) clinical outcomes among patients with ALF due to APAP alone or in combination with diphenhydramine or opioids. METHODS: We analyzed 666 cases of APAP-related liver failure using the Acute Liver Failure Study Group database from 1998 to 2012. The database contains detailed demographic, laboratory, and clinical outcome data, including hemodialysis, transplantation, and death and in-hospital complications such as arrhythmia and infection. RESULTS: The final sample included 666 patients with APAP liver injury. A total 30.3% of patients were overdosed with APAP alone, 14.1% with APAP/diphenhydramine, and 56.6% with APAP/opioids. Patients taking APAP with opioids were older, had more comorbidities, and were more likely to have unintentional overdose (all P<0.0001). On presentation, 58% in the APAP/opioid group had advanced encephalopathy as compared with 43% with APAP alone (P=0.001) The APAP/diphenhydramine group presented with the highest serum aminotransferase levels, no differences in laboratory values were noted at 3 days postenrollment. No significant differences were observed in clinical outcomes among the groups. CONCLUSIONS: Most patients with APAP-induced ALF were taking APAP combination products. There were significant differences in patient characteristics and clinical presentation based on the type of product ingested, however, there were no differences noted in delayed hepatotoxicity or clinical outcomes.""",1
13823,26174726,Resolution of ipilimumab induced severe hepatotoxicity with triple immunosuppressants therapy,"We describe a case of a patient from Far North Queensland, Australia, with life-threatening hepatotoxicity caused by ipilimumab induced immune-related adverse events (irAEs). Our patient presented with non-specific symptoms including malaise, lethargy and fevers. Her work up revealed acute hepatitis, which was presumed to be related to ipilimumab treatment for her metastatic melanoma. Causality for ipilimumab was assessed with the CIOMS scale (Council for International Organizations of Medical Sciences) and provided a causality level of 'highly probable' (score +9). She was started on methylprednisolone as per guidelines for ipilimumab induced irAEs. On the second day of treatment her transaminases enzymes unexpectedly rose several hundred times. Investigations for other causes of acute hepatitis including abdominal imaging were negative. She was started up front on equine antithymocyte globulin, mycophenolate moefetil and continued on methylprednisolone. She recovered clinically and biochemically in 2 weeks and continues to remain well.",1
13824,26179012,Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent,"Isavuconazole is a new extended-spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble intravenous formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was noninferior to that of voriconazole. An open-label trial that studied primary as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug-drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.",1
13825,26184021,A case of anastrazole-related drug-induced autoimmune hepatitis,"An otherwise asymptomatic 66-year-old British Caucasian female with a history of breast cancer was referred by the oncologists due to progressively abnormal liver function tests (LFTs). After undergoing wide local excision and axillary dissection she was started on the anti-oestrogen drug Arimidex (anastrozole) as the tumour cells were oestrogen receptor positive. With a background of normal LFTs, an absence of risk factors for chronic liver disease and otherwise good health, 6 months after starting Arimidex the oncology team noted deranged LFTs. Her hepatitis screening including hepatitis A-C, HSV, HIV, CMV and EBV serology and metabolic screening was negative. Liver ultrasound was essentially normal.The autoimmune screening was positive for ANA (1:160) and weakly positive for anti-smooth muscle antibody (1:80). A liver biopsy demonstrated heavy portal tract inflammation, associated interface hepatitis, and numerous necroinflammatory foci throughout the liver parenchyma. There was also a moderate to marked mixed inflammatory infiltrate of mainly plasma cells and lymphocytes with scattered eosinophils and neutrophils, which best reflects drug-induced liver injury (DILI), although potentially could also correspond with autoimmune hepatitis.The exact mechanism of liver injury from anastrazole is not very clear, but metabolic and immune-mediated damage and individual susceptibility are likely involved in what are often idiosyncratic reactions. The type of cellular immune recruitment (e.g., T-helper cells) reflects the chronicity of injury, with the potential to prolonged liver derangement months or years beyond the period of drug exposure such that DILI may mimic and/or cause drug-induced autoimmune hepatitis.",1
13826,26187031,"Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study","BACKGROUND: Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections. METHODS: In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS: Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients). INTERPRETATION: Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4. FUNDING: NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and Gilead Sciences.",1
13827,26191473,Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury,"AIM: To investigate the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, sitagliptin, for treating diabetes mellitus complicated by chronic liver injury. METHODS: Sitagliptin was administered for 13.7�?�10.1�months to 122 patients with DM complicated by chronic liver injury (including 19 patients with liver cirrhosis), and changes in hemoglobin A1c (HbA1c) and liver enzymes (transaminases, etc.) were evaluated. RESULTS: HbA1c was reduced from 8.48�?�1.43% to 7.87�?�1.35% (P�<�0.001). Among liver enzymes, alanine aminotransferase (ALT) levels improved from 75.1�?�45.2 to 65.8�?�35.8�IU/L (P�=�0.012) and gamma-glut amyl-trans peptidase from 155.2�?�161.1 to 133.2�?�127.4�IU/L (P�=�0.044). Among the causes of liver injury, non-alcoholic fatty liver disease and alcoholic liver disease both showed the reductions in HbA1c with no deterioration of liver enzymes. An analysis of 19 patients with liver cirrhosis also showed reductions in HbA1c with no deterioration of liver enzymes. CONCLUSION: It is suggested that sitagliptin can be administered effectively and safely to patients with diabetes mellitus complicated by chronic liver injury, including liver cirrhosis.",1
13828,26195720,Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and S?zary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project,"PURPOSE: In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and S?zary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored. PATIENTS AND METHODS: In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety. RESULTS: Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event. CONCLUSION: Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.",1
13829,26196665,Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1,"""BACKGROUND: Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS: We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS: Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).""",1
13830,26198822,Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab,"""Nivolumab, a blockade of programmed cell death 1, is now administrated for advanced malignant melanomas. Nivolumab-associated adverse events include organ-specific autoimmune disorders; autoimmune thyroid disease, vitiligo and insulin-dependent diabetes. However, predisposed persons are currently unknown. Here, we report serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab: one with Hashimoto disease and another with probable subclinical Hashimoto disease. We should verify if nivolumab-related hypothyroidism and hyperthyroidism are predisposed to occur in euthyroid individuals with subclinical autoimmune thyroid disease.""",1
13831,26202488,The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study,"""The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. INTRODUCTION: This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. METHODS: Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. RESULTS: Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. CONCLUSIONS: Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.""",1
13832,26213553,Hepatic glycogenosis in type 1 diabetes mellitus mimicking Mauriac syndrome,"Hepatic glycogenosis in type 1 diabetes mellitus (DM) can be caused by poor glycemic control due to insulin deficiency, excessive insulin treatment for diabetic ketoacidosis, or excessive glucose administration to control hypoglycemia. Mauriac syndrome, which is characterized by hepatomegaly due to hepatic glycogenosis, growth retardation, delayed puberty, and Cushingoid features, is a rare diabetic complication. We report a case of hepatic glycogenosis mimicking Mauriac syndrome. A 14-year-old girl with poorly controlled type 1 DM was admitted to The Catholic University of Korea, Seoul St. Mary's Hospital for abdominal pain and distension. Physical examination revealed hepatomegaly and a Cushingoid face. The growth rate of the patient had decreased, and she had not yet experienced menarche. Laboratory findings revealed elevated liver enzyme levels. A liver biopsy confirmed hepatic glycogenosis. Continuous glucose monitoring showed hyperglycemia after meals and frequent hypoglycemia before meals. To control hyperglycemia, we increased insulin dosage by using an insulin pump. In addition, we prescribed uncooked cornstarch to prevent hypoglycemia. After strict blood glucose control, the patient's liver functions and size normalized. The patient subsequently underwent menarche. Hepatic glycogenosis is a complication of type 1 DM that is reversible with appropriate glycemic control.",1
13833,26215530,Treatment of chronic HCV with sofosbuvir and simeprevir in patients with cirrhosis and contraindications to interferon and/or ribavirin,"""OBJECTIVES: Patients with chronic hepatitis C virus (HCV) and cirrhosis are in critical need of treatment that is both effective and tolerable. The combination of simeprevir (SMV), a protease inhibitor, and sofosbuvir (SOF), a polymerase inhibitor, without peginterferon and/or ribavirin (PEGINF/RBV) has been shown to achieve sustained virologic response (SVR) exceeding 90% in patients with HCV genotype 1 with prior nonresponse and/or cirrhosis. The present report describes the efficacy of SMV and SOF in patients with cirrhosis, prior or current hepatic decompensation, and other contraindications to PEGINF/RBV. METHODS: A total of 120 consecutive patients with cirrhosis and contraindications to PEGINF/RBV were treated with SMV and SOF for 12 weeks. The primary end point was SVR at 12 weeks after the completion of treatment. RESULTS: The mean age of the cohort was 60 years; 63% were male, 48% were Caucasian, 44% were African American, 69% were of genotype 1A, 49% were treatment na?ve, 96% were interleukin-28B non-CC, 33% were of Child class B or C, and 25% had prior hepatic decompensation. The SVR by intention-to-treat was 81% with a relapse rate of 14%. The SVR by per-protocol analysis was 87% with a relapse rate of 13%. The only baseline factor associated with SVR by multifactor analysis was Child class. SVR in patients with Child class A, B, and C was 87, 77, and 67%, respectively. Eleven percent of the patients developed severe adverse events, which included sepsis (two), variceal bleeding (two), hepatocellular carcinoma (two), and hyperbilirubinemia (eight). One of the patients with sepsis died. Two patients developed relapse more than 12 weeks after stopping SMV and SOF. CONCLUSIONS: The combination of SMV and SOF achieves high rates of SVR in patients with advanced cirrhosis but is lower with worsening Child class.""",1
13834,26226440,"Safety and Tolerability of Doripenem in Hospitalized Children With Complicated Intra-Abdominal Infection, Complicated Urinary Tract Infections and Pneumonia","Three multicenter, randomized, controlled studies evaluated doripenem in children 3 months to <18 years of age, with complicated intra-abdominal or urinary tract infections and bacterial pneumonia.In the 66 patients treated with doripenem before early termination of the studies for nonsafety reasons, doripenem was safe and generally well tolerated. Low enrollment limited ability to assess benefits and risks of doripenem in children.",1
13835,26232000,"Efficacy and safety in clinical practice of a rilpivirine, tenofovir and emtricitabine single-tablet regimen in virologically suppressed HIV-positive patients on stable antiretroviral therapy","""INTRODUCTION: Switching to a rilpivirine, tenofovir and emtricitabine (RTE) single-tablet regimen (STR) has been evaluated in a limited number of virologically suppressed patients. The aim of this study was to describe clinical outcomes in HIV-positive patients switched from a suppressive antiretroviral regimen to RTE STR in routine clinical practice. METHODS: In this retrospective study of antiretroviral-treated patients with <50 copies of HIV RNA/mL switched to RTE STR, virological failure (VF) was defined as two consecutive measurements of ?50 copies/mL or a single measurement of ?50 copies/mL followed by any change in treatment. Treatment failure (TF) was defined as VF or discontinuation of the STR for any reason. Univariate mixed-linear models were used to identify differences in laboratory parameters over time. RESULTS AND DISCUSSION: The analysis involved 307 patients (83% males) with a median age of 45.8 years (interquartile range (IQR 39.3-50.9), who were followed up for a median of 7.4 months (IQR 4.6-10.9). VF occurred in three patients (1%) switched from a protease inhibitor (PI)-based regimen, after a median of 2.6 months (IQR 1.6-3.0), and TF in 34 patients (11%) after a median of three months (IQR 1.4-5.8), 24 of whom (71%) were receiving a PI-based regimen at baseline. Overall, there was a slight but statistically significant improvement in the mean monthly change from baseline in CD4+ cell counts (p=0.027), the CD4+/CD8+ ratio (p=0.0001), and Hb (p=0.024), alanine amino transferase (ALT) (p=0.009), total bilirubin (p<0.0001), indirect bilirubin (p<0.0001), total cholesterol (p<0.0001) and triglyceride (p<0.0001) levels. There was also a slight but statistically significant increase in serum creatinine (p=0.0004), aspartate amino transferase (AST) (p=0.001) and liver fibrosis index (FIB-4) (p=0.002), and a decrease in eGFRcreat (p<0.0001) and high-density lipoprotein (HDL) cholesterol (p<0.0001) values. The study limitations include its retrospective design, the relatively short follow-up, and the absence of data concerning the severity of clinical adverse events; however, it does provide new information concerning the laboratory changes that occur in patients switching from PI-based or PI-sparing regimens to RTE STR. CONCLUSIONS: The study findings confirm the efficacy and safety in clinical practice of switching to RTE STR in virologically suppressed patients receiving other antiretrovirals.""",1
13836,26235748,Development of sofosbuvir for the treatment of hepatitis C virus infection,"The nucleotide analog NS5B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified, more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment regimens were especially required for patient populations with limited treatment options, including patients who had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3 HCV infection was the first approved all-oral treatment option. Sofosbuvir is also the backbone of the first regimen available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon-free regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its original FDA approval.",1
13837,26247170,Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort,"BACKGROUND/AIM: This study aimed to report the clinical characteristics and outcomes of Australian patients treated with eculizumab for atypical haemolytic uraemic syndrome (aHUS). METHODS: A retrospective cohort study was undertaken of all patients in Australia treated with eculizumab provided in a compassionate access programme for a clinical diagnosis of aHUS using prospectively collected clinical data. RESULTS: A total of 10 patients with a median age of 23.5 years (interquartile range (IQR) 24.83 years) received compassionate access eculizumab for aHUS in Australia. Eight patients were female, and three had a family history of aHUS. Three received eculizumab for an initial acute aHUS presentation, three for relapsing and refractory acute aHUS, two for de novo aHUS post-renal transplantation, and one each for aHUS recurrence post-transplantation and facilitation of transplantation with a history of aHUS. The median duration of eculizumab therapy has been 911.5 days (IQR 569 days) with a cumulative exposure of 9184 days. At baseline all patients had renal and extra-renal aHUS involvement, with up to three non-renal organs affected. All but one patient, who died from uncontrollable gastrointestinal aHUS manifestations, have continued. The nine continuing patients achieved remission of aHUS. Two of the four patients requiring renal replacement therapy (RRT) at eculizumab commencement subsequently ceased RRT. Clinical events occurring in this cohort while on eculizumab treatment included neutropenia (two), posterior reversible encephalopathy syndrome (one), cardiomyopathy (one), pulmonary embolus (one), antibody-mediated rejection resulting in renal graft failure (one), iron deficiency (one), gastrointestinal haemorrhage (one) and death (one). CONCLUSION: Eculizumab has been an effective therapy for aHUS in this cohort, including when other therapies have failed.",1
13838,26248724,Severe hepatotoxicity associated with asunaprevir and daclatasvir in chronic hepatitis C,,1
13839,26252875,Randomized comparison of daclatasvir + asunaprevir versus telaprevir + peginterferon/ribavirin in Japanese hepatitis C virus patients,"""BACKGROUND AND AIM: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. METHODS: Treatment-naive patients (20-70 years; baseline viral load, ? 100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 ? 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ? 100,000 IU/mL) received daclatasvir plus asunaprevir. RESULTS: In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). CONCLUSION: Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.""",1
13840,26253303,Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge,"""Sofosbuvir and daclatasvir are direct-acting antiviral drugs used to treat chronic hepatitis C virus infection. In 2015, the Food and Drug Administration and European Medical Agency warned that bradycardia could occur when amiodarone was administered in combination with sofosbuvir, but no case reports had been published. We report extreme bradycardia within 2 hrs after intake of sofosbuvir and daclatasvir by 2 patients receiving amiodarone. The first patient had a cardiac asystole 30 min after receiving sofosbuvir and daclatasvir. Amiodarone, sofosbuvir, and daclatasvir treatment were stopped; after 10 days, the cardiac evaluation was normal and patient was discharged. The second patient was taking amiodarone and propranolol; 2 hrs after receiving sofosbuvir and daclatasvir, he had an extreme sinus node dysfunction (heart rate of 27beats/min). Amiodarone and propranolol were stopped, but the patient continued receiving sofosbuvir and daclatasvir for 3 days and sinus bradycardia was recorded each day, 2 hrs after intake of these drugs. When he stopped taking the drugs, no bradycardia was observed. Administration of sofosbuvir and daclatasvir on day 13 induced bradycardia 2 hrs after intake. However, no bradycardia occurred following a rechallenge 8 weeks after the patient stopped taking amiodarone. These observations indicate that patients treated with amiodarone should be continuously monitored within the first 48 hrs following the initiation of sofosbuvir and daclatasvir.""",1
13841,26254052,New approaches for predicting T cell-mediated drug reactions: A role for inducible and potentially preventable autoimmunity,"Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacologic target (type A ADR) or an unintended target (type B ADR). Immunologically mediated type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis, can be severe and result in a diverse set of clinical manifestations that include fever and rash, as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell-mediated ADRs are strikingly similar to those displayed by patients with autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for immunologically mediated type B ADRs. Because methods to predict type 1 diabetes by using genetic and immunologic biomarkers have been developed to a high level of accuracy (predicting 100% of subjects likely to progress), new research strategies based on these methods might also improve the ability to predict drug hypersensitivity.",1
13842,26259299,Azithromycin-Induced Cholestatic Hepatitis,,1
13843,26261843,Brexpiprazole: a new dopamine D?receptor partial agonist for the treatment of schizophrenia and major depressive disorder,"""Brexpiprazole is a dopamine D?receptor partial agonist. Compared with aripiprazole, it is more potent at 5-HT1A receptors and displays less intrinsic activity at D?receptors. Brexpiprazole also has potent antagonistic activity at 5-HT2A as well as alpha-adrenergic receptors. In addition to results from phase II trials, data are available from two pivotal phase III, randomized, placebo-controlled trials of brexpiprazole for the acute treatment of schizophrenia and two pivotal phase III, randomized, placebo-controlled trials of adjunctive brexpiprazole for the acute treatment of major depressive disorder in patients with inadequate response to antidepressant medication treatment. Overall tolerability is promising, with rates of discontinuation due to adverse events lower or slightly higher than that observed for placebo. Although overall akathisia was more commonly observed with brexpiprazole than with placebo, the absolute risk increase attributable to brexpiprazole appears small. Short-term weight gain appears modest; however, outliers with an increase of ? 7% of body weight were evident in open-label long-term safety studies.""",1
13844,26262883,Brexpiprazole (Rexulti) for schizophrenia and depression,,1
13845,26262885,Lenvatinib (Lenvima) for thyroid cancer,,1
13846,26272768,"Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial","""BACKGROUND: Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. METHODS: We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinician's discretion. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed. FINDINGS: Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1?6, 95% CI 1?2-2?0; p=0?0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death. INTERPRETATION: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. FUNDING: TESARO, Inc.""",1
13847,26272772,Role of rolapitant in chemotherapy-induced emesis,,1
13848,26273591,Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease,"Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial beta-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.",1
13849,26278774,Anti-tumour necrosis factor treatment of severe psoriasis complicated by Epstein-Barr Virus hepatitis and subsequently by chronic hepatitis,"A case is described of severe acute hepatitis in 47-year-old woman with chronic psoriasis and psoriatic arthritis treated with infliximab. Although clinical, serological and laboratory results were compatible with acute EBV hepatitis, it was difficult to differentiate between EBV infection and other non-infectious causes of hepatitis. The patient gradually developed chronic hepatitis with liver steatosis and efficient treatment with adalimumab had to be stopped. This case presents an uncommon complication that may arise from the use of biologic therapy and calls for caution in long-term management of psoriatic patients with internal comorbidities.",1
13850,26281838,Treatment of Peripheral T-Cell Lymphoma: Many Shades of Gray,"Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods. Anthracycline-based regimens, often with the inclusion of etoposide, are commonly used during induction therapy. Consolidation with high-dose therapy and autologous stem cell transplantation (ASCT) in first chemosensitive remission appears to provide the best outcome in common nodal PTCL subtypes. The commonly defined nodal subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative anaplastic large-cell lymphoma (ALCL). Four agents have been approved by the US Food and Drug Administration for use in the relapsed/refractory (rel/ref) setting, including belinostat (2014), romidepsin (2011), brentuximab vedotin (2011), and pralatrexate (2009). Brentuximab vedotin was approved only for the ALCL subtype. These agents continue to be studied as combinations in the rel/ref setting and as additions or substitutions for other agents in upfront multiagent chemotherapy regimens. Patients who have responded to treatment in the rel/ref setting and are considered transplant-eligible should be considered for allogeneic stem cell transplantation, especially those with previous ASCT. Upfront allogeneic stem cell transplantation remains a research question in the majority of PTCL subtypes, but data are emerging.",1
13851,26291180,Development of macitentan for the treatment of pulmonary arterial hypertension,"Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event-driven morbidity and mortality study of treatment-naive and background PAH therapy-treated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class II and III PAH patients. Macitentan reduced the incidence of the composite end point of PAH-related hospitalizations and mortality and improved WHO FC and exercise capacity (6-min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.",1
13852,26292191,Relationships between serum asunaprevir concentration and alanine aminotransferase elevation during daclatasvir plus asunaprevir for chronic HCV genotype 1b infection,"Alanine aminotransferase (ALT) elevations were the most frequent adverse events during all-oral combinations with daclatasvir and asunaprevir for patients with hepatitis C virus (HCV) infection, but the underline mechanisms are unclear. Seventy patients with chronic HCV genotype 1b infection, who were introduced daclatasvir 60?mg once daily plus asunaprevir 100?mg twice daily for 24 weeks, were measured serum asunaprevir concentrations at the one point or more of 2, 4, and 8 weeks after the start of treatment. In 4 and 8 weeks after the start of treatment, asunaprevir concentrations in patients with albumin levels <3.6?g/dl at baseline were significantly higher than those in patients with albumin levels ?3.6?g/dl. The baseline factors did not affect to ALT severe elevations (?300 IU/l). At 2 weeks after the start of treatment, ALT severe elevations with asunaprevir concentrations of ?800?ng/ml (54.5%) tended to indicate the higher rates than those of <800?ng/ml (17.6%). Furthermore, the discontinuation or reduction of asunaprevir improved ALT levels, regardless the significant decrease of serum asunaprevir concentrations. In conclusion, serum albumin levels affected to serum asunaprevir concentrations, and serum asunaprevir concentrations might partly affect to ALT severe elevations. Further large-scale prospective studies are needed to investigate the impact of the discontinuation or reduction of asunaprevir to help in the design of more effective therapeutic regimens.",1
13853,26294195,A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose,"""CONTEXT: Risk prediction following acetaminophen (paracetamol, APAP) overdose is based on serum APAP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels. One recently proposed risk stratification tool, the APAPxAT multiplication product, uses either AST or ALT, whichever is higher, yet their interrelation is not well known following APAP-induced hepatic injury. OBJECTIVE: To describe the kinetics of AST and ALT release into and disappearance from the circulation following APAP overdose. MATERIALS AND METHODS: An observational case series of adult patients with peak AST or ALT > 100 IU/L attributable to APAP toxicity. Cases were identified by electronic search of hospital laboratory database and by discharge diagnosis corroborated by structured explicit medical record review. RESULTS: Of 68 cases identified (mean age (SD): 39 (18) years, 63% female, and 21% ethanol co-ingested), 28 (41%) developed hepatotoxicity (peak AST or ALT > 1000 IU/L), 28 (41%) coagulopathy (international normalized ratio or INR > 2), and 21 (31%) both. Three patients (4%) were transferred for liver transplantation and ultimately six (8.8%) died. Serum AST and ALT activity rose in a closely aligned 1:1 AST:ALT ratio, but fell at distinctly different rates: AST activity fell with a half-life (interquartile range [IQR]) of 15.1 (12.2, 19.4) hours, and ALT 39.6 (32.9, 47.6) hours. Using an aminotransferase falling to below 50% of peak as the basis for discontinuing acetylcysteine would have resulted in antidotal treatment being stopped 24 (IQR: 9.6, 40) hours earlier (and in no cases later) using AST rather than ALT. Only six patients had an AST:ALT ratio greater than 2:1 at the time of acetylcysteine administration; of these six, four died and one survivor developed coagulopathy. DISCUSSION: AST and ALT release into the circulation appears tightly linked and numerically similar, except in the sickest patients. Once the aminotransferases peak, AST returns to baseline more quickly. CONCLUSION: Either AST or ALT can be used for early risk stratification tools when only one is known. Any criterion for N-AC discontinuation should be based on the decline of AST rather than ALT, with a potential benefit measured in days.""",1
13854,26297149,Zoledronic acid-induced hepatotoxicity relieved after subsequent infusions in a Chinese woman with glucocorticoid-induced osteoporosis,"BACKGROUND: Zoledronic acid (ZOL) is widely used for treatment of glucocorticoid-induced osteoporosis. The most common adverse effects of ZOL treatment are post-dose symptoms. ZOL-induced hepatotoxicity has very rarely been reported. CASE REPORT: Here, we described a 50-year-old Chinese woman who had vertebral fractures and severe back pain after glucocorticoid therapy for Behcet disease for 13�years. Three days after ZOL 5�mg infusion in April 2012, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) levels increased by 7.7, 4.9 and 3.0 times, respectively, compared with pre-treatment values. Liver protective agents were administered per os. Her hepatic enzyme levels returned to nearly normal range 9�days post-infusion. In the subsequent ZOL infusion with 1�year interval, serum ALT, AST and GGT levels increased slightly after the second infusion and were sustained to be normal after the third infusion. Her post-dose symptoms alleviated in the meantime. CONCLUSIONS: Hepatotoxicity due to ZOL therapy is a rare, but possible adverse effect which may be relieved after subsequent infusions.",1
13855,26300664,An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT,"BACKGROUND: Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). METHODS: The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m(2) over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m(2) over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. RESULTS: Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)-mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). CONCLUSIONS: The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.",1
13856,26301701,"Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants","""OBJECTIVE: To assess the efficacy, tolerability, and safety of brexpiprazole as adjunctive therapy to antidepressant treatments (ADTs) in adults with major depressive disorder (as defined by DSM-IV-TR criteria) and inadequate response to ADTs. METHOD: Patients with historical inadequate response to 1-3 ADTs were enrolled. All patients entered a prospective 8-week phase on physician-determined, open-label ADT. Those with inadequate response were randomized to ADT + brexpiprazole 2 mg/d or ADT + placebo for 6 weeks. The study was conducted between July 2011 and May 2013. The primary efficacy end point was change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The key secondary end point was change from baseline to week 6 in Sheehan Disability Scale (SDS) mean score. The efficacy population comprised all patients who had ? 1 dose of study drug in the double-blind phase and both baseline and ? 1 postrandomization MADRS scores. The efficacy population per final protocol included patients from the efficacy population who met amended randomization criteria of inadequate response throughout prospective treatment. RESULTS: Brexpiprazole (n = 175) reduced mean MADRS total score versus placebo (n = 178) at week 6 in the efficacy population per final protocol (-8.36 vs -5.15, P = .0002). Brexpiprazole improved SDS mean score versus placebo (-1.35 vs -0.89, P = .0349). The most common treatment-related adverse events were weight gain (brexpiprazole, 8.0%; placebo, 3.1%) and akathisia (7.4% vs 1.0%). CONCLUSIONS: Adjunctive brexpiprazole therapy demonstrated efficacy and was well tolerated in patients with major depressive disorder and inadequate response to ADTs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360645.""",1
13857,26305886,Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells,"Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2alpha) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.",1
13858,26308596,Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma,"""BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1? monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ? 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).""",1
13859,26313445,Randomized controlled trial of the NS5A inhibitor daclatasvir plus pegylated interferon and ribavirin for HCV genotype-4 (COMMAND-4),"""BACKGROUND: Treatment options for HCV genotype-4 (GT4) are limited. This Phase III study (COMMAND-4; AI444-042) evaluated the efficacy and safety of daclatasvir (DCV), a pan-genotypic HCV NS5A inhibitor, with pegylated interferon-?2a/ribavirin (PEG-IFN/RBV) in treatment-naive patients with HCV GT4 infection. METHODS: Patients were randomly assigned (2:1; blinded) to treatment with DCV 60 mg (n=82) or placebo (n=42) once daily plus PEG-IFN 180 ?g weekly and RBV 1,000-1,200 mg/day (weight-based) twice daily. DCV-treated patients with undetectable HCV RNA at weeks 4 and 12 (eRVR) received 24 weeks of DCV plus PEG-IFN/RBV; those without eRVR received an additional 24 weeks of PEG-IFN/RBV. All placebo-treated patients received 48 weeks of PEG-IFN/RBV. The primary end point was sustained virological response (SVR) at post-treatment week 12 (SVR12). RESULTS: Patients were 75% IL28B non-CC and 11% had cirrhosis. SVR rates (HCV RNA < lower limit of quantitation [LLOQ]) at post-treatment week 12 or later (imputed to include patients missing SVR12 assessments but had SVR after post-treatment week 12) were 82% (67/82) with DCV plus PEG-IFN/RBV versus 43% (18/42) with PEG-IFN/RBV (P<0.0001). In DCV recipients, SVR12 rates were comparable across subgroups. The safety and tolerability profile of DCV plus PEG-IFN/RBV was comparable to that of PEG-IFN/RBV. Discontinuations due to adverse events occurred in 4.9% of patients receiving DCV plus PEG-IFN/RBV and 7.1% of patients receiving PEG-IFN/RBV. CONCLUSIONS: In treatment-naive patients with HCV GT4 infection, DCV plus PEG-IFN/RBV achieved higher SVR12 rates than PEG-IFN/RBV alone. These data support DCV-based regimens for treatment of HCV GT4 infection, including all-oral combinations with other direct-acting antivirals (AI444-042; ClinicalTrials.gov NCT01448044).""",1
13860,26324355,Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer,"""OBJECTIVE: To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. STUDY SELECTION AND DATA ABSTRACTION: Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. DATA SYNTHESIS: In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a """"breakthrough therapy"""" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). CONCLUSIONS: Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.""",1
13861,26324739,"FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer","""On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2.""",1
13862,26327301,"A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease","BACKGROUND: Multicentric Castleman disease (MCD) is a rare, systemic lymphoproliferative disorder driven by interleukin (IL)-6 overproduction. Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD. METHODS: This preplanned safety analysis was conducted to evaluate the long-term safety of siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study. Dosing was 11 mg/kg administered intravenously every 3 weeks, per protocol, or every 6 weeks at the investigator's discretion. Safety monitoring focused on potential risks associated with the anti-IL-6 mechanism of action. Investigator-assessed disease control status was also documented. RESULTS: Median treatment duration for the 19 patients was 5.1 (range 3.4, 7.2) years, with 14 (74%) patients treated for >4 years. Grade-? 3 adverse events (AEs) reported in >1 patient included hypertension (n = 3) and nausea, cellulitis, and fatigue (n = 2 each). Grade-? 3 AEs at least possibly attributed to siltuximab were leukopenia, lymphopenia, and a serious AE of polycythemia (n = 1 each). Hypertriglyceridemia and hypercholesterolemia (total cholesterol) were reported in 8 and 9 patients, respectively. No disease relapses were observed, and 8 of 19 patients were able to switch to an every-6-week dosing schedule. CONCLUSIONS: All MCD patients in this extension study have received siltuximab for a prolonged duration (up to 7 years) without evidence of cumulative toxicity or treatment discontinuations and with few serious infections. All patients are alive, demonstrate sustained disease control, and continue to receive siltuximab.",1
13863,26330539,Octreotide inhibits the bilirubin carriers organic anion transporting polypeptides 1B1 and 1B3 and the multidrug resistance-associated protein 2,"The somatostatin analog octreotide can lead to hyperbilirubinemia without evidence of liver injury. Here we investigate whether octreotide inhibits the main sinusoidal/canalicular bilirubin carriers and whether it is a transport substrate. Octreotide showed the most potent inhibitory effect toward OATP1B1-mediated transport and weaker inhibition for OATP1B3- and MRP2-mediated transport. Octreotide had no effect on OATP2B1-mediated transport. Octreotide inhibited [(3)H]estradiol-17-beta-glucuronide (E17betaG) influx mediated by OATP1B1, 1B3, and multidrug resistance-associated protein 2 (MRP2) in a concentration-dependent manner, and the IC50 values were computed to be 23 muM (95% confidence interval [CI] 18-29), 68 muM (95% CI 50-91), and 116.6 muM (95% CI 74.5-182.4), respectively. The interaction between octreotide and OATP1B1 was further studied. Inhibition of [(3)H]E17betaG OATP1B1-mediated transport was purely competitive with no changes in maximum transport capacity (Vmax) and a twofold Km increase when the influx kinetics of [(3)H]E17betaG were measured in the presence of octreotide (8.8 +/- 3.1 versus 4.4 +/- 1.2 muM, P = 0.03). The inhibition constant (Ki) of octreotide for the transport of [(3)H]E17betaG was calculated at 33.5 +/- 5.5 muM. Uptake of radiolabeled octreotide by OATP1B1-CHO cells was higher than in wild-type CHO cells and nonlabeled octreotide at the extracellular compartment was able to trans-stimulate the OATP1B1-mediated efflux of intracellular [(3)H]E17betaG, suggesting that octreotide is a substrate of OATP1B1. In summary, this study shows interaction of octreotide on the human hepatocellular bilirubin transporters OATP1B1, OATP1B3, and MRP2, notably OATP1B1. These findings are in line with the clinical observation that a fraction of patients under treatment with octreotide exhibit hyperbilirubinemia.",1
13864,26335142,Safety and efficacy of simeprevir plus sofosbuvir with or without ribavirin in patients with decompensated genotype 1 hepatitis C cirrhosis,"""Combination antiviral therapy involving sofosbuvir (SOF) and simeprevir (SIM) is a treatment option in patients with genotype 1 chronic hepatitis C; however, the safety of this regimen in patients with decompensated cirrhosis is not established. Data from a combined treatment cohort of 2 large hepatology referral centers were evaluated to assess for safety and efficacy of SIM plus SOF with or without ribavirin (RBV) in patients with Child B or C cirrhosis. All (n?=?42) patients included in the analysis had Child B (n?=?35) or C (n?=?7) cirrhosis and received 400?mg daily of SOF plus 150?mg daily of SIM, with (n?=?7) or without (n?=?35) RBV, for 12 weeks. Of the 42 patients in this cohort, 31 (74%) were male, 22 (52%) had failed prior treatments, and 28 (67%) were genotype 1a. Prior decompensating events included encephalopathy (57%), fluid overload (88%), or variceal hemorrhage (24%). Median Model for End-Stage Liver Disease score was 12 (range, 6-25). Treatment was well tolerated overall with more than one-half (57%) reporting no adverse events. In those reporting adverse events, the most common were fatigue (n?=?6), insomnia (n?=?4), headache (n?=?5), nausea (n?=?4), and grade 1 rash (n?=?1). One patient developed chemical pancreatitis that did not require treatment discontinuation. Three of 7 patients who received RBV developed anemia, with 2 requiring blood transfusions and 1 requiring a dose reduction. No episodes of decompensation requiring hospitalization or deaths occurred on treatment. Of 42 patients, 38 (90%) patients had negative viral load at end of treatment (EOT), and 31 of 42 patients (74%) achieved sustained virological response 12 weeks after EOT; 10 of 10 patients (100%) with HCV genotype 1b achieved sustained virological response for 12 weeks (SVR12). In conclusion, SOF plus SIM was very well tolerated in patients with advanced Child B/C decompensated cirrhosis. Overall, 74% of patients achieved SVR12; 100% of patients with genotype 1b decompensated cirrhosis achieved SVR12.""",1
13865,26351349,"Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer","PURPOSE: Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. PATIENTS AND METHODS: Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014. RESULTS: Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination. CONCLUSION: This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).",1
13866,26352819,Lysosomal Acid Lipase Deficiency--A New Therapy for a Genetic Lipid Disease,,1
13867,26357638,"Liver Injury from Herbal, Dietary, and Weight Loss Supplements: a Review","Herbal and dietary supplement usage has increased steadily over the past several years in the United States. Among the non-bodybuilding herbal and dietary supplements, weight loss supplements were among the most common type of HDS implicated in liver injury. While drug induced liver injury is rare, its consequences are significant and on the rise. The purpose of this review is to highlight case reports of weight loss products such as Hydroxycut and OxyElite Pro as one form of HDS that have hepatotoxic potential and to characterize its clinical effects as well as pattern of liver injury. We also propose future strategies in the identification and study of potentially hepatotoxic compounds in an effort to outline a diagnostic approach for identifying any drug induced liver injury.",1
13868,26360703,Cholelithiasis and Nephrolithiasis in HIV-Positive Patients in the Era of Combination Antiretroviral Therapy,"""OBJECTIVES: This study aimed to describe the epidemiology and risk factors of cholelithiasis and nephrolithiasis among HIV-positive patients in the era of combination antiretroviral therapy. METHODS: We retrospectively reviewed the medical records of HIV-positive patients who underwent routine abdominal sonography for chronic viral hepatitis, fatty liver, or elevated aminotransferases between January 2004 and January 2015. Therapeutic drug monitoring of plasma concentrations of atazanavir was performed and genetic polymorphisms, including UDP-glucuronosyltransferase (UGT) 1A1*28 and multidrug resistance gene 1 (MDR1) G2677T/A, were determined in a subgroup of patients who received ritonavir-boosted or unboosted atazanavir-containing combination antiretroviral therapy. Information on demographics, clinical characteristics, and laboratory testing were collected and analyzed. RESULTS: During the 11-year study period, 910 patients who underwent routine abdominal sonography were included for analysis. The patients were mostly male (96.9%) with a mean age of 42.2 years and mean body-mass index of 22.9 kg/m2 and 85.8% being on antiretroviral therapy. The anchor antiretroviral agents included non-nucleoside reverse-transcriptase inhibitors (49.3%), unboosted atazanavir (34.4%), ritonavir-boosted lopinavir (20.4%), and ritonavir-boosted atazanavir (5.5%). The overall prevalence of cholelithiasis and nephrolithiasis was 12.5% and 8.2%, respectively. Among 680 antiretroviral-experienced patients with both baseline and follow-up sonography, the crude incidence of cholelithiasis and nephrolithiasis was 4.3% and 3.7%, respectively. In multivariate analysis, the independent factors associated with incident cholelithiasis were exposure to ritonavir-boosted atazanavir for >2 years (adjusted odds ratio [AOR], 6.29; 95% confidence interval [CI], 1.12-35.16) and older age (AOR, 1.04; 95% CI, 1.00-1.09). The positive association between duration of exposure to ritonavir-boosted atazanavir and incident cholelithiasis was also found (AOR, per 1-year exposure, 1.49; 95% CI, 1.05-2.10). The associated factors with incident nephrolithiasis were hyperlipidemia (AOR, 3.97; 95% CI, 1.32-11.93), hepatitis B or C coinfection (AOR, 3.41; 95% CI, 1.09-10.62), and exposure to abacavir (AOR, 12.01; 95% CI, 1.54-93.54). Of 180 patients who underwent therapeutic drug monitoring of plasma atazanavir concentrations and pharmacogenetic investigations, we found that the atazanavir concentrations and UGT 1A1*28 and MDR1 G2677T/A polymorphisms were not statistically significantly associated with incident cholelithiasis and nephrolithiasis. CONCLUSIONS: In HIV-positive patients in the era of combination antiretroviral therapy, a high prevalence of cholelithiasis and nephrolithiasis was observed, and exposure to ritonavir-boosted atazanavir for >2 years was associated with incident cholelithiasis.""",1
13869,26362997,Panobinostat for the Treatment of Multiple Myeloma,"""Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved by the FDA and EMA for use in combination with bortezomib and dexamethasone in patients with multiple myeloma who have received ?2 prior regimens, including bortezomib and an immunomodulatory drug. Panobinostat was approved based on results from the phase III PANORAMA 1 trial in patients with relapsed or relapsed and refractory multiple myeloma, which showed that panobinostat plus bortezomib and dexamethasone significantly extended progression-free survival (median, 12.0 months) compared with placebo plus bortezomib and dexamethasone (median, 8.1 months; P < 0.0001). Additional ongoing trials are evaluating panobinostat in combination with other partners in the relapsed/refractory and newly diagnosed treatment settings. This review focuses on panobinostat and its mechanism of action, pharmacokinetics, and clinical data in the treatment of relapsed or relapsed and refractory multiple myeloma.""",1
13870,26371152,"Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE","BACKGROUND: The phase 2 C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy) demonstrated a 96.2% sustained virologic response at 12 weeks (SVR12) rate using the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir together with ribavirin in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection. METHODS: C-SALVAGE was a prospective open-label trial of grazoprevir 100 mg once daily and elbasvir 50 mg once daily coadministered with weight-based ribavirin twice daily for 12 weeks in genotype 1-infected cirrhotic and noncirrhotic patients who had failed treatment with ? 4 weeks of pegylated interferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Although the primary efficacy outcome was SVR12, patients were also evaluated 24 weeks after cessation of study therapy. Population sequencing was performed at baseline and periodically in virologic failures throughout the 24-week posttherapy follow-up period. RESULTS: SVR24 rates were 76 of 79 (96.2%) overall, with all 3 relapses occurring by posttherapy week 8. Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow-up period. NS3_A156T emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients. NS5A_Y93H emerged in virus from 2 patients at relapse and persisted for the entire follow-up period. CONCLUSIONS: Grazoprevir and elbasvir with ribavirin for 12 weeks maintained HCV suppression for at least 24 weeks posttherapy without late relapses. Baseline resistance-associated variants (RAVs) stably reappeared at relapse in all 3 patients with virologic failure. NS5A_RAVs emerging at relapse persisted for the full 24-week follow-up period. If confirmed, this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor. CLINICAL TRIALS REGISTRATION: NCT02105454.",1
13871,26379040,A phase II study of bendamustine in combination with rituximab as initial treatment for patients with indolent non-follicular non-Hodgkin lymphoma,"""The purpose of this phase 2 study was to determine the activity and safety of six cycles of bendamustine and eight rituximab (RB) as first-line treatment of adult patients with advanced stage non-follicular indolent non-Hodgkin lymphomas (INFL). The primary end-point was the complete response rate (CRR) with expected CRR of 75%. Sixty-nine patients were enrolled; median age was 65 years (45-75), 65% were male, 93% of patients had stage IV disease. Complete and overall response rates were 48% (95% CI?=?35.6-60.2) and 86% (CI?=?75.0-92.8). The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (7%) and anemia (4%); whereas the rate of febrile neutropenia was very low (3%). At a median follow-up of 22 months (1-43 months), 2-year progression-free survival was 89% (CI?=?79-95) and 2-year overall survival was 96% (CI?=?87-99). RB combination is active and well tolerated in patients with advanced stage previously untreated INFL.""",1
13872,26384238,"Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial","""BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia. METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged >/=16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0.3 mg/kg on days 1-5 of each course, and at 0.25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 x 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535. FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2.17 [95% CI -2.79 to 7.12; p=0.39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group. INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.""",1
13873,26386854,Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis,"""BACKGROUND: Budesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis. AIM: The aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam. METHODS: Data from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam. RESULTS: A similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration. CONCLUSIONS: This integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis.""",1
13874,26393826,Naloxegol (Movantik) for opioid-induced constipation,,1
13875,26394770,Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis,"""BACKGROUND: This meta-analysis has been conducted to determine the risk of elevated transaminases associated with immune checkpoint inhibitors use in patients with cancer. METHODS: Studies eligible for our analysis included randomized Phase II and III trials of patients with cancer on ipilimumab, nivolumab, pembrolizumab, tremelimumab and pidilizumab, which describe events of elevated transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)]. RESULTS: Initial database search revealed 210 relevant citations. After excluding noneligible studies, 10 trials were considered eligible for the quantitative synthesis. The RR of all-grade elevated ALT and AST was 2.36 (95% CI 1.20-4.66; p = 0.01) and 1.53 (95% CI 0.73-3.22; p = 0.26), respectively, whereas for high-grade elevated ALT and AST, it was 11.27 (95% CI 5.38-23.63; p < 0.0001) and 4.9 (95% CI 2.97-8.09; p < 0.0001), respectively. CONCLUSIONS: Our study has shown that the use of immune checkpoint inhibitors has a causal relationship to an increased risk of high-grade elevated ALT and AST. Clinicians using these agents should be attentive of this risk.""",1
13876,26399274,Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: A systematic review and meta-analysis,"Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of small-molecule drugs suppressing PARP enzymes activity, inducing the death of cells deficient in homologous recombination repair (HRR). HRR deficiency is common in tumor cells with BRCA gene mutation. Since their first clinical trial in 2003, PARP inhibitors have shown benefit in the treatment of HRR-deficient tumors. Recently, several randomized clinical trials (RCTs) have been conducted to investigate the potential benefit of administration of PARP inhibitors in cancer patients. However, the results remain controversial. To evaluate the efficiency and safety of PARP inhibitors in patients with cancer, we performed a comprehensive meta-analysis of RCTs. According to our study, PARP inhibitors could clearly improve progression-free survival (PFS), especially in patients with BRCA mutation. However, our study showed no significant difference in overall survival (OS) between the PARP inhibitors and controls, even in the BRCA mutation group. Little toxicity was reported in the rate of treatment correlated adverse events (AEs) in PARP inhibitor group compared with controls. In conclusion, PARP inhibitors do well in improving PFS with little toxicity, especially in patients with BRCA deficiency.",1
13877,26402801,Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis: A Multicenter Cohort Study,"""We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n?=?68) or cirrhosis (F4, n?=?143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm or albumin <35?g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35?g/L and/or platelet count <100,000/mm) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.""",1
13878,26406150,Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma,"""BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. METHODS: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. RESULTS: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. CONCLUSIONS: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).""",1
13879,26411584,"Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings","""In most cases of relapsed/refractory mantle cell lymphoma (MCL), patients respond to salvage therapy, though typically responses are partial and/or transient followed by disease progression, even with newer agents (e.g., ibrutinib). In this multicenter, open-label, single-arm, phase II study, patients with relapsed/refractory non-blastoid MCL received bendamustine 90 mg/m(2) (days 1 and 2) and rituximab 375 mg/m(2) (day 1) for 6 planned 28-day cycles. Functional imaging with 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) was conducted at baseline and after cycle 6. Forty-five patients were enrolled (median age, 70 years; 82 % stage IV disease; median number of prior chemotherapies, 2 [range, 1-4]), showing an overall response rate (ORR; primary efficacy measure) of 82 % (complete response [CR], 40 %; partial response, 42 %). In the 32 patients with complete 18F-FDG PET/CT data, 75 % achieved a complete metabolic response. Median duration of response was 1.6 years, 1-year progression-free survival was 67 %, and 3-year overall survival was 55 %. Main non-hematologic adverse events were nausea (69 %), fatigue (56 %), decreased appetite (42 %), constipation (38 %), diarrhea (36 %), vomiting (36 %), and decreased weight (31 %). Grade 3/4 neutropenia and lymphopenia occurred in 44 and 89 % of patients, respectively. ORR and CR rate compared favorably with single-agent ibrutinib (ORR, 67 %; CR, 23 %); bendamustine-rituximab is an effective therapy with manageable toxicity in relapsed/refractory MCL.""",1
13880,26414341,"Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials","""OBJECTIVE: The objective of this study was to describe a priori protocol-defined analyses to evaluate the safety and tolerability of adjunctive oral lacosamide (200-600 mg/day) in adults (ages 16-70 years) with partial-onset seizures (POS) using data pooled from three similarly designed randomized, double-blind, placebo-controlled trials (SP667, SP754 [NCT00136019], SP755 [NCT00220415]). METHODS: Patients with POS (>/=2 years' duration, >/=2 previous antiepileptic drugs [AEDs]) uncontrolled by a stable dosing regimen of 1-3 concomitant AEDs were randomized to treatment with lacosamide at doses of 200 mg/day, 400 mg/day, or 600 mg/day, or placebo. Studies comprised a 4- to 6-week titration phase to target dose followed by a 12-week maintenance phase. Safety outcomes included treatment-emergent adverse events (TEAEs) of particular relevance to patients with POS, overall TEAEs, and discontinuations due to TEAEs. Post hoc analyses included evaluation of TEAEs potentially related to cognition and TEAEs leading to discontinuation analyzed by concomitant AEDs. RESULTS: One thousand three hundred eight patients were randomized to and received treatment; 944 to lacosamide and 364 to placebo. Most patients (84.4%) were taking 2 or 3 concomitant AEDs. The most common drug-associated TEAEs (reported by >/=5% of patients in any lacosamide dose group and with an incidence at least twice that reported for placebo during the treatment phase) were dizziness (30.6% for lacosamide vs 8.2% for placebo), nausea (11.4% vs 4.4%), and diplopia (10.5% vs 1.9%). Common drug-associated TEAEs generally appeared to be dose-related, and the incidence of each was lower during the 12-week maintenance phase than during the titration phase. Most TEAEs were either mild or moderate in intensity; severe TEAEs were predominantly observed with lacosamide 600 mg/day. No individual serious TEAE occurred in >/=1% of all lacosamide-treated patients. Treatment-emergent adverse events led to discontinuation in 8.1%, 17.2%, and 28.6% of the lacosamide 200-, 400-, and 600-mg/day groups, respectively (vs 4.9% of placebo). Few TEAEs were related to rash, weight loss/gain, changes in clinical chemistry parameters, or psychiatric disturbances, or were seizure-related. The odds of reporting any potential cognition-related TEAE vs placebo increased with dose and were similar between lacosamide doses of 200 and 400mg/day and placebo (odds ratio 1.3, 95% confidence interval 0.7-2.4). Discontinuations due to TEAEs based on most commonly used AEDs taken in combination with lacosamide (all doses combined) were carbamazepine (15.3% [51/334] vs 3.9% [5/129] placebo), lamotrigine (19.2% [56/291] vs 4.3% [5/117]), and levetiracetam (10.1% [28/278] vs 3.9% [4/103]). CONCLUSIONS: The safety and tolerability profile of adjunctive lacosamide in this detailed evaluation was similar to that observed in the individual double-blind trials. Adjunctive lacosamide was associated with TEAEs related to the nervous system and gastrointestinal tract, predominantly during titration.""",1
13881,26422722,Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis,"""BACKGROUND: Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS: In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ?100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS: At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS: Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).""",1
13882,26423714,Boceprevir for chronic HCV genotype 1 infection in treatment-experienced patients with severe fibrosis or cirrhosis: The Greek real-life experience,"BACKGROUND: The aim of our study was to evaluate the safety and efficacy of triple therapy using boceprevir (BOC) with pegylated interferon (pIFN)/ribavirin (RBV) in chronic hepatitis C (CHC) genotype 1 (G1) treatment-experienced patients with advanced fibrosis or compensated cirrhosis. METHODS: We report the Greek experience on the first CHC patients who received BOC-based regimen. From September 2011 to June 2012, 26 treatment-experienced CHC patients and G1 with bridging fibrosis or compensated cirrhosis received 48 weeks of BOC+pIFN+RBV antiviral therapy. Data on complete blood counts and HCV RNA levels were obtained prior to therapy, at treatment weeks 4, 8, 12, 24, 36, 48 and 24 weeks after the end of treatment. RESULTS: A full set analysis was performed in 25 of 26 patients. Nine patients (36%) achieved sustained viral response (SVR). Ten patients (40%) stopped the therapy because of futility rules and 3 (12%) due to adverse events. Four patients (16%) developed a virological breakthrough (3 of those presented futility rules as well) and 2 (8%) relapse. All patients who achieved SVR had G 1b, 6 (67%) were non-cirrhotic and 5 (55%) had >1 log decline in baseline HCV RNA levels at week 4 of the treatment. There were no deaths, while two patients were hospitalized due to side effects. CONCLUSION: The triple therapy with BOC+pIFN+RBV in this cohort of real-life treatment-experienced CHC G1 patients and advanced liver disease was safe offering cure in the majority of those who could tolerate and complete treatment under a close monitoring.",1
13883,26426050,Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax,"""The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay.""",1
13884,26445205,Daclatasvir (Daklinza) for HCV genotype 3 infection,"Daclatasvir (Daklinza) plus sofosbuvir (Sovaldi) is the first all-oral, interferon- and ribavirin-free drug regimen for treatment of hepatitis C virus genotype 3 infection. This combination is effective and convenient, but it is very expensive.",1
13885,26446239,U.S. Food and Drug Administration Approval Summary: Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer Following Disease Progression On or After Platinum-Based Chemotherapy,"""UNLABELLED: On December 12, 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. This approval was based on an improvement in overall survival (OS) with an acceptable toxicity profile in a randomized, multicenter, double-blinded, placebo-controlled trial of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. Patients were randomized 1:1 to receive either ramucirumab in combination with docetaxel or placebo in combination with docetaxel. The primary endpoint was OS. Patients who received ramucirumab in combination with docetaxel had improved OS (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75, 0.98). Median OS was 10.5 months on the ramucirumab plus docetaxel arm versus 9.1 months on the placebo plus docetaxel arm. The most frequent (>/= 30%) adverse reactions in ramucirumab-treated patients were fatigue, neutropenia, and diarrhea. The most frequent (>/= 5%) grade 3 and 4 adverse reactions in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. IMPLICATIONS FOR PRACTICE: This report presents key information on the U.S. Food and Drug Administration approval of ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2, given in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer whose disease has progressed on or after platinum-based chemotherapy. This report specifically addresses the issues of safety in patients with squamous cell tumors, effect of treatment in elderly patients, and uncertainties regarding effects in patients with tumors harboring epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations.""",1
13886,26448890,PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV,"On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1) inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma). Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies) evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV), and/or human immunodeficiency virus (HIV) infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.",1
13887,26452566,Sebelipase alfa: first global approval,"Sebelipase alfa (Kanuma) is a recombinant human lysosomal acid lipase (LAL) developed by Synageva BioPharma Corp. (now Alexion Pharmaceuticals, Inc.) for long-term enzyme replacement therapy in patients with LAL deficiency. The agent, administered by intravenous infusion once weekly or once every other week, acts to replace the deficient enzyme activity in patients with LAL deficiency, reducing lysosomal lipid accumulation, and thereby improving disease-related abnormalities such as dyslipidaemia and liver abnormalities. Sebelipase alfa received its first global approval, in the EU, in August 2015 for long-term enzyme replacement therapy in patients of all ages with LAL deficiency. Regulatory submissions have also been filed in the USA, Mexico and Japan for use in this indication. This article summarizes the milestones in the development of sebelipase alfa leading to this first approval for the treatment of LAL deficiency.",1
13888,26457414,Asparaginase-associated toxicity in children with acute lymphoblastic leukemia,"Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of children with acute lymphoblastic leukemia. Positive outcomes are seen in patients who are able to complete their entire prescribed course of asparaginase therapy. Toxicities associated with asparaginase use include hypersensitivity (clinical and subclinical), pancreatitis, thrombosis, encephalopathy, and liver dysfunction. Depending on the nature and severity of the toxicity, asparaginase therapy may be altered or discontinued in some patients. Clinical hypersensitivity is the most common asparaginase-associated toxicity requiring treatment discontinuation, occurring in up to 30% of patients receiving Escherichia coli-derived asparaginase. The ability to rapidly identify and manage asparaginase-associated toxicity will help ensure patients receive the maximal benefit from asparaginase therapy. This review will provide an overview of the common toxicities associated with asparaginase use and recommendations for treatment management.",1
13889,26460177,Can paracetamol (acetaminophen) be administered to patients with liver impairment?,"Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under-dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed.",1
13890,26467681,Rolapitant: first global approval,"Rolapitant (Varubi�) is an orally active neurokinin-1 receptor antagonist developed by TESARO and approved in the USA for use in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in adults. Unlike other approved agents in this class, rolapitant does not interact with cytochrome P450 (CYP) enzyme CYP3A4. It also has a long elimination half-life which means that a single dose could prevent CINV during the entire at-risk period (0-120�h). An intravenous formulation of rolapitant is under clinical development in the USA. Phase II development of rolapitant in postoperative nausea and vomiting, and cough appears to have been discontinued. This article summarizes the milestones in the development of rolapitant leading to the first approval for the prevention of CINV.",1
13891,26471380,"A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures","""OBJECTIVE: Brivaracetam (BRV), a selective and high-affinity synaptic vesicle protein 2A ligand, is in development as adjunctive treatment for partial-onset (focal) seizures (POS). This phase 3 study (N01358; NCT01261325) aimed to confirm the efficacy and safety/tolerability of BRV in adults (? 16-80 years) with POS. METHODS: This randomized, double-blind, placebo-controlled, multicenter study enrolled patients with uncontrolled POS despite ongoing treatment with 1-2 antiepileptic drugs. Patients exposed to levetiracetam ? 90 days before visit 1 were excluded. Patients entered an 8-week prospective baseline period, followed by a 12-week treatment period when they were randomized 1:1:1 to placebo (PBO), BRV 100 mg/day, or BRV 200 mg/day, started without up-titration. The co-primary efficacy outcomes were percent reduction over placebo in 28-day adjusted POS frequency, and ? 50% responder rate based on percent reduction in POS frequency from baseline to the treatment period. RESULTS: Seven hundred sixty-eight patients were randomized; 760 were included in the efficacy analysis: 259, 252, and 249 in PBO, BRV 100 mg/day, and BRV 200 mg/day groups, respectively. Percent reduction over PBO in 28-day adjusted seizure frequency (95% confidence interval [CI]) was 22.8% for BRV 100 mg/day (13.3-31.2%; p < 0.001) and 23.2% for BRV 200 mg/day (13.8-31.6%; p < 0.001). The ? 50% responder rate (odds ratio vs. PBO; 95% CI) was 21.6% for PBO, 38.9% for BRV 100 mg/day (2.39; 1.6-3.6; p < 0.001), and 37.8% for BRV 200 mg/day (2.19; 1.5-3.3; p < 0.001). Treatment-emergent adverse events (TEAEs) occurred in 155 (59.4%) of 261 PBO patients versus 340 (67.6%) of 503 BRV-treated patients (safety population). Discontinuation rates due to TEAEs were 3.8%, 8.3%, and 6.8% for PBO, BRV 100 mg/day, and BRV 200 mg/day, respectively. Most frequent TEAEs (PBO versus BRV) were somnolence (7.7% vs. 18.1%), dizziness (5.0% vs. 12.3%), and fatigue (3.8% vs. 9.5%). SIGNIFICANCE: Adjunctive BRV 100 and 200 mg/day was efficacious in reducing POS in adults without concomitant levetiracetam use and was well tolerated.""",1
13892,26474360,Mitotane Revisited: A New Target for an Old Drug,,1
13893,26480933,Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment,"""This long-term follow-up analysis evaluated overall survival (OS) and relapse-free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (<10(-4) blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS ?30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ?18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS <30 months.""",1
13894,26487935,Acute Liver Failure in a Pediatric Patient with Congenital Dysery-Thropoietic Anemia Type I Treated with Deferasirox,"Congenital dyserythropoietic anemias (CDA) represent a heterogeneous group of disorders characterized by morphological abnormalities of erythroid precursor cells and various degrees of hemolysis. Iron overload is a result of continuous hemolysis and recurrent transfusions. It is treated with iron chelators, including deferasirox. We present here a case of acute liver failure in a 12 years old girl with CDA type I treated with deferasirox and discuss the approach to treatment.",1
13895,26492567,Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601,"Bortezomib is active in mantle cell lymphoma (MCL), with approval in upfront and relapsed settings. Given inevitable recurrence following induction chemoimmunotherapy, maintenance approaches are a rational strategy to improve clinical outcomes. We conducted a phase II study to evaluate the safety and efficacy of six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus bortezomib (1.3 mg/m2 days 1 and 4 of 21 d cycles) followed by bortezomib maintenance (1.3 mg/m2 days 1, 4, 8, and 11 every 3 months for 2 years). Sixty-five eligible patients were enrolled. The treatment was well tolerated and toxicities were mainly haematological. The rate of grade ?3 peripheral neuropathy was low (5%). With a median follow-up of 6.8 years, 2-year progression-free survival (PFS) was 62%, and 2-year overall survival (OS) was 85%. At 5 years, PFS was 28% and OS was 66%. MCL International Prognostic Index scores were significantly associated with 2-year PFS, but did not predict long-term (?5-year) PFS. Baseline Ki-67 index was significantly associated with survival. Combination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared historically with R-CHOP alone, with prolonged remissions in a subset of patients. These results suggest that inclusion of bortezomib with induction chemotherapy and/or maintenance is promising in MCL and warrants further exploration.",1
13896,26497081,"Effectiveness of Simeprevir Plus Sofosbuvir, With or Without Ribavirin, in Real-World Patients With HCV Genotype 1 Infection","""BACKGROUND & AIMS: The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS: We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS: The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS: In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.""",1
13897,26502771,Voriconazole-Induced Hepatitis via Simvastatin- and Lansoprazole-Mediated Drug Interactions: A Case Report and Review of the Literature,"Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 ?g/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole-induced cholestatic hepatitis. Although the major cytochrome P450 pathways for the metabolism and clearance of lansoprazole and simvastatin are different, they both likely contributed to the reduced hepatic clearance of voriconazole in this patient.",1
13898,26503563,Hepatic hemorrhage as a consequence of rapid response to combined targeted therapy in metastatic melanoma,A middle-aged female with metastatic melanoma was found to have hemoperitoneum after starting systemic therapy with the BRAF and MEK inhibitors dabrafenib and trametinib. Etiology proved to be bleeding from a known hepatic metastasis. The patient was managed conservatively and eventually resumed systemic therapy with ongoing response. This case serves to illustrate the possible deleterious effects of rapid tumor response after initiation of targeted systemic therapy in patients with metastatic melanoma.,1
13899,26507833,Drug-Induced Progressive Multifocal Leukoencephalopathy: A Comprehensive Analysis of the WHO Adverse Drug Reaction Database,"OBJECTIVE: To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML). METHODS: All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved. We identified safety signals by analysing the drug-reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio >2 and a lower 95 % confidence limit >1. RESULTS: We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18-64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with 'progressive multifocal leukoencephalopathy' or 'leukoencephalopathy' as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only 'progressive multifocal leukoencephalopathy' as the Preferred Term). CONCLUSION: We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies.",1
13900,26510944,Cariprazine: First Global Approval,"Cariprazine (Vraylar) is an oral atypical antipsychotic originated by Gedeon Richter. It is a potent dopamine D3 and D2 receptor partial agonist, which preferentially binds to the D3 receptor. Cariprazine also has partial agonist activity at serotonin 5-HT1A receptors. In September 2015, cariprazine received its first global approval in the USA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also in development in a variety of countries for the treatment of schizophrenia with predominant negative symptoms (phase III), as adjunctive therapy for major depressive disorder (phase II/III) and for the treatment of bipolar depression (phase II). This article summarizes the milestones in the development of cariprazine leading to this first approval for schizophrenia and manic or mixed episodes associated with bipolar I disorder.",1
13901,26518665,Infliximab-associated fulminant hepatic failure in ulcerative colitis: a case report,"INTRODUCTION: Infliximab, an antibody against tumor necrosis factor alpha, is used to treat inflammatory bowel disease and has well-established efficacy and proven safety. Complications of this treatment are related to immunosuppression and include higher risk of serious infections and malignant neoplasia. Although extremely rare, fulminant liver damage related to infliximab therapy has been reported. CASE PRESENTATION: We present the case of a 38-year-old Afro-Brazilian woman with refractory ulcerative colitis who was started on infliximab. She had no previous history of liver disease, alcohol abuse, or infection. After the fifth dose of the medication, drug-induced liver injury was diagnosed. Treatment was discontinued but our patient's condition was aggravated by severe cholestasis and grade III/IV encephalopathy, requiring liver transplantation. CONCLUSION: Drug-induced liver injury is an uncommon complication of infliximab. Current consensus recommends screening for liver dysfunction prior to and during therapy. This case emphasizes the need for vigilance and highlights a rare and potentially lethal complication.",1
13902,26524371,[Ursodeoxycholic acid-induced hepatic disease: a case report],,1
13903,26541814,"An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression","""OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression. METHOD: This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-?sberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population. RESULTS: The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was -4.0 (95% CI=-6.3, -1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (-2.5, 95% CI=-4.9, -0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=-0.4, 95% CI=-0.6, -0.1; 3.0 mg/day: -0.3, 95% CI=-0.5, -0.0). The most common adverse events (?10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo. CONCLUSIONS: Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.""",1
13904,26547109,"Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: Efficacy and safety results from a phase II randomized controlled study","BACKGROUND: Brodalumab (KHK4827 or AMG 827) is a human monoclonal antibody that binds to the human interleukin (IL)-17 receptor A and blocks the biological activities of IL-17A, IL-17F, IL-17A/F, and IL-17E also known as IL-25. A 12-week phase 2 trial in the USA, Europe, and other countries showed the good efficacy of brodalumab in treating patients with moderate to severe plaque psoriasis. However, with the exception of a phase 1 study, a clinical trial of brodalumab in psoriasis has not been undertaken in Japan. OBJECTIVE: To evaluate the efficacy and safety of brodalumab in Japanese patients with moderate-to-severe plaque psoriasis, including psoriatic arthritis, in a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparative phase 2 study, and to assess the pharmacokinetics of brodalumab. METHODS: Japanese patients with moderate-to-severe plaque psoriasis, including psoriatic arthritis, were randomized to receive 70mg, 140mg, or 210mg of brodalumab, or placebo, injected subcutaneously at baseline and weeks 1, 2, 4, 6, 8, and 10. The primary efficacy endpoint was the percentage improvement in the Psoriasis Area and Severity Index (PASI) score from baseline to week 12. Secondary efficacy endpoints included the percentage of patients with ?75% reduction of PASI scores (PASI 75), ?90% (PASI 90), and 100% (PASI 100) and the percentage of patients with a static physician's global assessment (sPGA) of 0 (clear) or 1 (almost clear) at week 12. Safety was evaluated by assessing the adverse events (AE) and the patients' hematologic and laboratory values. RESULTS: At week 12, the mean percentage improvements in the PASI scores were 37.7%, 82.2%, 96.8%, and 9.4% in the 70mg, 140mg, 210mg, and placebo groups, respectively, (p<0.001 for all comparisons with placebo). The percentage of patients with PASI 75, PASI 90, and PASI 100 at week 12 were 7.9%, 2.6%, and 0%, respectively, in the placebo group, 25.6%, 15.4%, and 2.6%, respectively, in the 70mg brodalumab group, 78.4%, 64.9%, and 35.1%, respectively, in the 140mg brodalumab group, and 94.6%, 91.9%, and 59.5%, respectively, in the 210mg brodalumab group. Concerning psoriatic arthritis, at week 12, the numbers (%) of patients fulfilling the American College of Rheumatology response criteria for a 20% improvement were 0 (0%) in the placebo group, and 1 (20%), 2 (40%), and 4 (100%) in the 70mg, 140mg, and 210mg brodalumab groups, respectively. The percentages of patients with Dermatology Life Quality Index scores of 0 or 1 at week 12 were greater in the 140mg (54.1%) and the 210mg (56.8%) brodalumab groups than in the placebo group (8.8%). The most common AE in the brodalumab groups were nasopharyngitis (12.4% vs. 7.9% for placebo), diarrhea (5.3% vs. 0%), upper respiratory tract inflammation (3.5% vs. 0%), and folliculitis (3.5% vs. 0%). CONCLUSION: The rapid, robust efficacy of brodalumab and its favorable safety profile shown in the current study confirm previous studies conducted in Caucasian people, further warranting the use of brodalumab as a new treatment option for plaque psoriasis.",1
13905,26549249,"Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with difficult-to-treat nail and scalp psoriasis: Results of 2 phase III randomized, controlled trials (ESTEEM 1 and ESTEEM 2)","""BACKGROUND: In the phase III double-blind Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2, apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated efficacy in moderate to severe psoriasis. OBJECTIVE: We sought to evaluate efficacy of apremilast in nail/scalp psoriasis in ESTEEM 1 and 2. METHODS: A total of 1255 patients were randomized (2:1) to apremilast 30�mg twice daily or placebo. At week 16, placebo patients switched to apremilast through week 32, followed by a randomized withdrawal phase to week 52. A priori efficacy analyses included patients with nail (target nail Nail Psoriasis Severity Index score ?1) and moderate to very severe scalp (Scalp Physician Global Assessment score ?3) psoriasis at baseline. RESULTS: At baseline, 66.1% and 64.7% of patients had nail psoriasis; 66.7% and 65.5% had moderate to very severe scalp psoriasis in ESTEEM 1 and 2. At week 16, apremilast produced greater improvements in Nail Psoriasis Severity Index score versus placebo; mean percent change: -22.5% versus +6.5% (ESTEEM 1; P�<�.0001) and -29.0% versus -7.1% (ESTEEM 2; P�=�.0052). At week 16, apremilast produced greater NAPSI-50 response (50% reduction from baseline in target nail Nail Psoriasis Severity Index score) versus placebo (both studies P�<�.0001) and ScPGA response (Scalp Physician Global Assessment score 0 or 1) versus placebo (both studies P�<�.0001). Improvements were generally maintained over 52�weeks in patients with Psoriasis Area and Severity Index response at week 32. LIMITATIONS: Baseline randomization was not stratified for nail/scalp psoriasis. CONCLUSION: Apremilast reduces the severity of nail/scalp psoriasis.""",1
13906,26551051,Sofosbuvir With Velpatasvir in Treatment-Naive Noncirrhotic Patients With Genotype 1 to 6 Hepatitis C Virus Infection: A Randomized Trial,"""BACKGROUND: Effective, pangenotypic treatments for hepatitis C virus (HCV) infection are needed. OBJECTIVE: To assess the safety and efficacy of sofosbuvir with velpatasvir in patients infected with HCV genotypes 1 to 6. DESIGN: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01858766). SETTING: 48 U.S. sites. PATIENTS: 377 treatment-naive noncirrhotic patients. In part A, patients infected with HCV genotypes 1 to 6 were randomly assigned to sofosbuvir, 400 mg, with velpatasvir, 25 or 100 mg, for 12 weeks. In part B, patients with genotype 1 or 2 HCV infection were randomly assigned to sofosbuvir, 400 mg, and velpatasvir, 25 or 100 mg, with or without ribavirin for 8 weeks. MEASUREMENTS: Sustained virologic response at 12 weeks (SVR12). RESULTS: In part A, SVR12 rates were 96% (26 of 27) with velpatasvir, 25 mg, and 100% (28 of 28) with velpatasvir, 100 mg, for genotype 1; 93% (25 of 27) in both groups for genotype 3; and 96% (22 of 23) with velpatasvir, 25 mg, and 95% (21 of 22) with velpatasvir, 100 mg, for genotypes 2, 4, 5, and 6. In part B, for genotype 1, SVR12 rates were 87% (26 of 30) with velpatasvir, 25 mg; 83% (25 of 30) with velpatasvir, 25 mg, plus ribavirin; 90% (26 of 29) with velpatasvir, 100 mg; and 81% (25 of 31) with velpatasvir, 100 mg, plus ribavirin. For genotype 2, SVR12 rates were 77% (20 of 26) with velpatasvir, 25 mg; 88% (22 of 25) with velpatasvir, 25 mg, plus ribavirin; 88% (23 of 26) with velpatasvir, 100 mg; and 88% (23 of 26) with velpatasvir, 100 mg, plus ribavirin. Adverse events included fatigue (21%), headache (20%), and nausea (12%). One patient committed suicide. LIMITATION: The study was open-label, no inferential statistics were planned, and sample sizes were small. CONCLUSION: Twelve weeks of sofosbuvir, 400 mg, and velpatasvir, 100 mg, was well-tolerated and resulted in high SVR in patients infected with HCV genotypes 1 to 6. PRIMARY FUNDING SOURCE: Gilead Sciences.""",1
13907,26555747,Safety of Abatacept in Rheumatoid Arthritis With Serologic Evidence of Past or Present Hepatitis B Virus Infection,"OBJECTIVE: Rheumatoid arthritis (RA) with concomitant hepatitis B virus (HBV) infection represents a therapeutic challenge due to the risk of HBV reactivation under immunosuppressive treatment. To date there are few data coming from anecdotal case reports that concern HBV reactivation following treatment with abatacept. This observational retrospective study was aimed to assess the safety profile of abatacept in this particular clinical setting. METHODS: Eleven Italian rheumatologic centers provided data from patients with RA and positive HBV serology treated with intravenous abatacept. HBV markers and clinical and laboratory data were checked at followup visits every 3 months. RESULTS: In total, 72 patients were included in the study: 47 inactive carriers, 21 occult carriers, and 4 chronic active carriers for HBV. At baseline all of the patients had normal liver function tests and low or undetectable HBV DNA levels, except for those with chronic active hepatitis. Thirteen patients received prophylaxis with lamivudine, and 4 received treatment with adefovir or tenofovir. At the end of the 24-month followup period, 49 patients were being treated. Data from 316 followup visits showed that abatacept was safe. No patients experienced reactivation of hepatitis B. Treatment withdrawals (23 patients) were due to lack of efficacy, subject decision/lost at followup, or adverse events not related to HBV infection. CONCLUSION: Our study provides reassuring data about the safety profile of abatacept in RA with concomitant HBV infection without universal antiviral prophylaxis. Further prospective studies are needed to confirm these preliminary results.",1
13908,26565676,Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases,"The discovery of the biological functions of the interleukin-23/-17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated diseases. Therapeutic agents targeting these cytokines and/or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.",1
13909,26567759,Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study,"Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47?2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35�g/l to negatively impact the likelihood of achieving response. The median duration of response was 8?4�months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort was 4?9�months (95% confidence interval [CI] 3?8-6?4) and 12?2�months (95% CI 9-not reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity.",1
13910,26568279,Safety of monoclonal antibodies and related therapeutic proteins for the treatment of neovascular macular degeneration: addressing outstanding issues,"INTRODUCTION: The vascular endothelial growth factor (VEGF) inhibitors most widely used to treat neovascular age-dependent macular degeneration (nAMD) are different proteins with structural features potentially relevant to adverse effects (AEs). Two of these are also established in cancer therapy (with higher dosages and AEs). The importance of ocular AE and extraocular activities is still a subject of controversy and ongoing research. AREAS COVERED: Potential risks of intraocular VEGF inhibition based on prospective studies, in vitro investigations, pharmacokinetics, and hints from anti-cancer treatment. EXPERT OPINION: nAMD is a frequently observed chronic clinical condition severely affecting the visual function of elderly persons. Intravitreal injection of VEGF-inactivating proteins is highly effective to prevent loss of vision. Anti-VEGF therapy is well tolerated, and low rates of ocular and systemic AEs in smaller trials suggest a very high benefit/risk ratio. The proteins established in nAMD therapy show similar efficacies. In the controversy over the off-label use of bevacizumab purely on grounds of much lower cost, the small, but potentially relevant differences between the available drugs are easily either dramatized (by pharmaceutical companies) or trivialized (by health insurances) and even political interference is involved. Facing the lack of a convincing body of evidence regarding safety, further long-term study results seem necessary.",1
13911,26571066,"Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection","""BACKGROUND: A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need. METHODS: We conducted a phase 3, double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group. CONCLUSIONS: Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.).""",1
13912,26575250,Effect of canagliflozin on liver function tests in patients with type 2 diabetes,"""AIMS: To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS: Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active-controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS: Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hy's law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS: Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin.""",1
13913,26575982,Efficacy and safety of tofacitinib in US and non-US rheumatoid arthritis patients: pooled analyses of phase II and III,"OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post-hoc pooled analysis assessed commonalities and differences in tofacitinib efficacy and safety for US versus rest of the world (ROW) populations. METHODS: Pooled phase (P) III data from patients receiving tofacitinib 5 or 10 mg twice daily (BID) or placebo were assessed for efficacy at Month 3 and for safety outcomes over 12 months. For adverse events of special interest, data on tofacitinib 5 or 10 mg BID or placebo were pooled from six PII and five PIII randomised studies. RESULTS: PIII data were available for 664 vs. 2447 and PII/PIII data for 943 vs. 3567 US vs. ROW patients, respectively. The US population had a higher proportion of Caucasians (81.5% vs. 54.4%), lower proportion of Asians (1.0% vs. 34.6%), and higher mean body weight (85.7 vs. 66.2 kg) and body mass index (31.5 vs. 25.6 kg/m2) compared with ROW. At Month 3, PIII efficacy was similar between US and ROW as assessed by ACR 20/50/70 response rates, remission rates (DAS 28-4[ESR]<2.6), and HAQ-DI scores. Diarrhoea, peripheral oedema, and upper respiratory tract infection occurred in >5% of PIII patients in the US population. Incidence rates for adverse events of special interest were similar between the US and ROW PII/PIII populations. CONCLUSIONS: Patients in the US achieved similar efficacy and safety with tofacitinib 5 and 10 mg BID compared with patients in ROW.",1
13914,26586473,Glutamine and hyperammonemic crises in patients with urea cycle disorders,"""UNLABELLED: Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. METHODS: The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. RESULTS: The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 mumol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]mumol/L) than patients with baseline glutamine </= 900 mumol/L (26.6 [18.0]mumol/L). Glutamine values >900 mumol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia >/= 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 mumol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia >/= 1.0 ULN (HR=4.62; p=0.0011). CONCLUSIONS: The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.""",1
13915,26596672,"Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial","""BACKGROUND: Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. METHODS: We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596. FINDINGS: Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30?0%; 95% CI 16?6-46?5) patients given afatinib alone (difference vs investigator's choice: -11?9% [95% CI -32?9 to 9?7], p=0?37), 13 (34?2%; 19?6-51?4) given afatinib plus vinorelbine (difference vs investigator's choice: -7?6% [-28?9 to 14?2], p=0?63), and 18 (41?9%; 27?0-57?9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]). INTERPRETATION: Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned. FUNDING: Boehringer Ingelheim.""",1
13916,26597673,"Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status","""BACKGROUND: Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals. METHODS: We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. RESULTS: Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4-14.6]), ketoconazole (19.3 [13.8-26.3]), and itraconazole (24.5 [10.6-48.2]). Rates were higher with voriconazole (181.9 [112.6-278.0]) and posaconazole (191.1 [23.1-690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4-2.7]), ketoconazole (2.9 [1.1-6.3]), and itraconazole (0.0 [0.0-11.2]), but more frequent with voriconazole (16.7 [2.0-60.2]) and posaconazole (93.4 [2.4-520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68-5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56-12.35]). CONCLUSIONS: Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury.""",1
13917,26598747,Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study,"""PURPOSE: Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. PATIENTS AND METHODS: Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). RESULTS: Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. CONCLUSION: Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.""",1
13918,26602778,Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells,,1
13919,26608256,"Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study","""BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. METHODS: This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1?8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. FINDINGS: Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4?3 [95% CI 1?0-17?7]; p=0?019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0?2 [0?1-1?0]; p=0?04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). INTERPRETATION: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. FUNDING: Wellcome Trust, National Institute of Health Research, and Novo Nordisk.""",1
13920,26626645,The mystery of the Hawaii liver disease cluster in summer 2013: A pragmatic and clinical approach to solve the problem,"BACKGROUND AND AIM: In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis. MATERIAL AND METHODS: To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions. RESULTS: We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster. CONCLUSIONS: Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.",1
13921,26628580,Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials,"OBJECTIVE: To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT). METHODS: Through a systematic literature search, sJIA RCTs evaluating biologic agents were identified. The primary efficacy outcome was defined as a 30% improvement according to the modified American College of Rheumatology Paediatric 30 response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. The quality of evidence between biologic agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: From the 493 citations originally identified, 5 RCTs were eligible for inclusion-one each for anakinra, canakinumab and tocilizumab and two for rilonacept: all vs placebo. While all were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab [odds ratio (OR) 0.10 (95% CI 0.02, 0.38), P = 0.001] or tocilizumab [OR 0.12 (95% CI 0.03, 0.44), P = 0.001]. Risks of SAEs were similar among the biologic agents (supported by very low-quality evidence) and not different from placebo. CONCLUSION: Despite heterogeneous eligibility criteria and study designs across the five studies and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Biologic agents in sJIA seem safe and comparable with respect to SAE risk in the short term.",1
13922,26630143,Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome,"""BACKGROUND: Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS: We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.).""",1
13923,26635183,Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis,"OBJECTIVE: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). METHODS: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. RESULTS: Overall, 3882 and 3016 abatacept-na?ve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. CONCLUSIONS: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.",1
13924,26639348,Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia,"""BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).""",1
13925,26647431,Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis,"""Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24?weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120?weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120?weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.""",1
13926,26649445,Apixaban-induced hepatotoxicity,,1
13927,26655425,"Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial","""BACKGROUND: Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. METHODS: For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m(2), day 1) plus either bendamustine (90 mg/m(2), days 1 and 2) or fludarabine (25 mg/m(2), days 1-3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0-2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m(2) every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing). FINDINGS: Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0?76 (95% CI 0?68-0?84) and 0?48 (0?39-0?58) with fludarabine plus rituximab (non-inferiority p<0?0001). At a median follow-up of 96 months (IQR 73?2-112?9), median progression-free survival with bendamustine plus rituximab was 34?2 months (95% CI 23?5-52?7) and 11?7 months (8?0-16?1) with fludarabine plus rituximab (hazard ratio [HR] 0?54 [95% CI 0?38-0?72], log-rank test p<0?0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections. INTERPRETATION: In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. FUNDING: Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).""",1
13928,26661280,Two cases of cutaneous leishmaniasis in Dutch military personnel treated with oral miltefosine,"INTRODUCTION: In the Netherlands, cutaneous leishmaniasis is most commonly seen in military personnel deployed on a mission or training abroad. The treatment of two Dutch soldiers who acquired cutaneous leishmaniasis with oral miltefosine was evaluated. Adverse effects were monitored and the improvement of skin lesions was assessed. CASE REPORTS: A military nurse with a painless Chiclero's ulcer due to Leishmania (Viannia) braziliensis acquired in Belize and a military physical training instructor with itchy swelling and small ulcer of the back of his left elbow due to L. donovani/infantum complex acquired in Ibiza were treated with oral miltefosine 50?mg three times a day for 28?days. DISCUSSION: Both patients responded well to oral miltefosine. Adverse effects were mild. Increase of creatinine levels was seen while liver transaminase levels were unremarkable. CONCLUSIONS: Miltefosine proved to be a convenient, effective and well-tolerated treatment option in the treatment of cutaneous leishmaniasis in Dutch military personnel.",1
13929,26666609,Alternate-day Treatment with Crizotinib for Drug-induced Esophagitis and Liver Damage in a Patient with EML4-ALK Fusion Gene-positive Lung Adenocarcinoma,"A 44-year-old woman who was diagnosed with anaplastic lymphoma kinase-positive lung adenocarcinoma developed brain metastases, multiple spinal metastases and meningeal dissemination. Crizotinib was administered after the failure of first-line chemotherapy. Esophagitis and liver damage were induced by the twice-daily administration of crizotinib at 250 mg and 200 mg, respectively. The alternate-day administration of crizotinib (250 mg, twice daily) was able to control disease progression without any adverse effects for several months. We evaluated the relationship between the serum concentration of crizotinib and the development of esophagitis and liver damage. The alternate-day administration of crizotinib is one of the strategies for managing the severe toxicity of crizotinib.",1
13930,26670894,Abacavir-induced fulminant hepatic failure in a HIV/HCV co-infected patient,"Abacavir hypersensitivity is a rare, yet significant adverse reaction that results in a spectrum of physical and laboratory abnormalities, and has been postulated to stem from a variety of aetiological factors. The major histocompatibility complex haplotype human leucocyte antigen (HLA)-B5701 is a significant risk factor in development of hypersensitivity reactions, yet only 55% of HLA-B5701+ individuals develop such reactions, suggesting a multifactorial aetiology. Nevertheless, prospective screening and avoidance of abacavir in these patients has limited adverse events. Within this spectrum of adverse events, abacavir-induced liver toxicity is exceedingly rare and reported events have ranged from mild elevations of aminotransferases to fulminant hepatic failure. We report the case of a 50-year-old Caucasian woman with a history significant for HIV, hepatitis C virus and a HLA-B5701+ status, transferred to our emergency department in a hypotensive state and found to have acute liver failure, acute renal failure and significant rhabdomyolysis following a change of highly active antiretroviral therapy regimen.",1
13931,26671818,"Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study","""BACKGROUND: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1?3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. FINDINGS: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11?9 months (IQR 9?3-16?1) in the carfilzomib group and 11?1 months (8?2-14?3) in the bortezomib group. Median progression-free survival was 18?7 months (95% CI 15?6-not estimable) in the carfilzomib group versus 9?4 months (8?4-10?4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0?53 [95% CI 0?44-0?65]; p<0?0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). INTERPRETATION: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. FUNDING: Onyx Pharmaceuticals, Inc., an Amgen subsidiary.""",1
13932,26682725,"""Reply to """"Liver failure in human immunodeficiency virus - Hepatitis C virus coinfection treated with sofosbuvir, ledipasvir and antiretroviral therapy""""""",,1
13933,26683763,Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis,"""BACKGROUND & AIMS: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS: In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS: The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.""",1
13934,26686406,"Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study","""BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signalling lymphocytic activation molecule (SLAM) family member 7 (SLAMF7), selectively kills SLAMF7-expressing myeloma cells through direct activation and engagement of the innate immune system, and thus might have clinical benefit in the treatment of myeloma. In phase 1 of this phase 1b-2 study, 82% of patients with relapsed multiple myeloma who were given elotuzumab plus lenalidomide and dexamethasone achieved an overall response. Here we report the final phase 2 results. METHODS: We did this randomised, multicentre, open-label, dose-escalation study (1703) at 17 hospitals in the USA, Canada, France, and Germany. Patients aged at least 18 years with confirmed, relapsed multiple myeloma, Eastern Cooperative Oncology Group performance status 0-2, and one to three previous therapies but no previous lenalidomide were eligible for phase 2. We randomly assigned patients (1:1) to either 10 mg/kg or 20 mg/kg intravenous elotuzumab plus oral lenalidomide (25 mg) and dexamethasone (40 mg). We stratified patients on the basis of the number of previous therapies (one versus two or three), and status of previous treatment with immunomodulatory drugs (yes or no), and used permuted block randomisation with a block size of four. Treatment was given in 28-day cycles until disease progression or unacceptable toxic effects occurred (elotuzumab was given on days 1, 8, 15, and 22 for cycles 1 to 2 and days 1 and 15 for subsequent cycles; lenalidomide was given on days 1-21 and dexamethasone once per week). The primary endpoint was the proportion of patients who achieved an objective response according to International Myeloma Working Group criteria. Primary analyses were done in the intention-to-treat population, and safety was analysed in all patients who received at least one dose of study drugs. This study is registered with ClinicalTrials.gov, number NCT00742560. FINDINGS: Between Jan 4, 2010, and Dec 21, 2010, we recruited and randomly assigned 73 patients to elotuzumab (36 to 10 mg/kg, 37 to 20 mg/kg). At data cutoff (Jan 16, 2014), 13 patients remained on treatment (six on 10 mg/kg, seven on 20 mg/kg). 61 (84%) patients achieved an objective response (33 [92%] with 10 mg/kg, 28 [76%] with 20 mg/kg); 31 (42%) a very good partial response (17 [47%] with 10 mg/kg, 14 [38%] with 20 mg/kg); and 20 (27%) a partial response (10 [28%] with 10 mg/kg, 10 [27%] with 20 mg/kg). The most common treatment-emergent adverse events of any grade were diarrhoea (48 [66%]), muscle spasms (45 [62%]), and fatigue (41 [56%]). 57 (78%) patients had grade 3-4 events, the most common of which were lymphopenia (15 [21%]) and neutropenia (14 [19%]). Three deaths occurred, none related to the study drugs. INTERPRETATION: Elotuzumab combined with lenalidomide and dexamethasone in patients with relapsed multiple myeloma showed acceptable safety and efficacy that seems better than that previously noted with lenalidomide and dexamethasone only. Phase 3 trials are in progress. FUNDING: Bristol-Myers Squibb, AbbVie Biotherapeutics.""",1
13935,26689767,"Boceprevir, peginterferon and ribavirin for acute hepatitis C in HIV infected patients","BACKGROUND & AIMS: Acute hepatitis C virus infections (AHCV) are prevalent among HIV positive men having sex with men and generally treated with pegylated interferon-alpha (PegIFN) and ribavirin (RBV) during 24weeks. The addition of a protease inhibitor could shorten therapy without loss of efficacy. METHODS: We performed an open-label, single arm study to investigate the efficacy and safety of a 12-week course of boceprevir, PegIFN and RBV for AHCV genotype 1 infections in 10 Dutch HIV treatment centers. The primary endpoint of the study was achievement of sustained virological response rate at week 12 (SVR12) in patients reaching a rapid viral response at week 4 (RVR4) and SVR12 in the intent to treat (ITT) entire study population was the most relevant secondary endpoint. RESULTS: One hundred twenty-seven AHCV patients were screened in 16 months, of which 65 AHCV genotype 1 patients were included. After spontaneous clearance in six patients and withdrawal before treatment initiation in two, 57 started therapy within 26 weeks after infection. RVR4 rate was 72%. SVR12 rate was 100% in the RVR4 group. SVR12 rate in the ITT group was 86% and comparable to the SVR12 rate of 84% in 73 historical controls treated for 24 weeks with PegIFN and RBV in the same study centers. CONCLUSION: With the addition of boceprevir to PegIFN and RBV, treatment duration of AHCV genotype 1 can be reduced to 12 weeks without loss of efficacy. Given the high drug costs and limited availability of interferon-free regimens, boceprevir PegIFN and RBV can be a considered a valid treatment option for AHCV. ClinicalTrials.gov, number NCT01912495.",1
13936,26699168,Selexipag for the Treatment of Pulmonary Arterial Hypertension,"""BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 ?g twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain. CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).""",1
13937,26707367,Systematic Review and Meta-Analysis: Macrolides- and Amoxicillin/Clavulanate-induced Acute Liver Injury,"Antibacterials are frequently associated with idiosyncratic drug-induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta-analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials.gov, Livertox and Toxline (1980-2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non-user comparator. We summarized the evidence with a random-effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case-control, one cohort and one case-population studies) and 9 (case-population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 [95% confidence interval (CI) 1.81-4.47], p < 0.0001, I(2) = 57%. Three studies were perceived to be missing in the area of low statistical significance. Year of study and selected exposure window partly explained the variability between studies. For AMC, the risk of DILI was 9.38 (95% CI 0.65-135.41) p = 0.3, I2 = 95%. In conclusion, although spontaneous reports and case series have long established an association between macrolides and AMC with acute liver injury, these SR and MA have assessed the magnitude of this association. The low incidence of DILI and the therapeutic place of these antibiotics might tilt the balance in favour of their benefits.",1
13938,26708155,"Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial","""BACKGROUND: Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib. METHODS: We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment. FINDINGS: Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4?8 months [IQR 3?3-7?1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). INTERPRETATION: Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib. FUNDING: F Hoffmann-La Roche.""",1
13939,26714241,Eluxadoline (Viberzi) for irritable bowel syndrome with diarrhea,,1
13940,26717533,"Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial","""OBJECTIVE: This phase 3 study evaluated the efficacy, safety, and tolerability of cariprazine in patients with acute exacerbation of schizophrenia. METHOD: This multinational, randomized, double-blind, placebo- and active-controlled study was conducted from April 2010 to December 2011. Patients who met DSM-IV-TR criteria for schizophrenia were randomized to placebo (n = 153), cariprazine 3 mg/d (n = 155), cariprazine 6 mg/d (n = 157), or aripiprazole 10 mg/d (n = 152) for 6 weeks of double-blind treatment. The primary and secondary efficacy parameters were mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively. RESULTS: Least squares mean differences (LSMDs) in PANSS total score change at week 6 significantly favored cariprazine 3 and 6 mg/d versus placebo (LSMD [95% CI]: 3 mg/d, -6.0 [-10.1 to -1.9], adjusted P = .0044; 6 mg/d, -8.8 [-12.9 to -4.7], adjusted P < .0001). Cariprazine 3 and 6 mg/d were also associated with significant improvements relative to placebo in CGI-S scores (LSMD [95% CI]: 3 mg/d, -0.4 [-0.6 to -0.2], adjusted P = .0044; 6 mg/d, -0.5 [-0.7 to -0.3], adjusted P < .0001). Significant differences from placebo were also observed with aripiprazole on the PANSS (LSMD [95% CI]: -7.0 [-11.0 to -2.9], P = .0008) and CGI-S (LSMD [95% CI]: -0.4 [-0.6 to -0.2], P = .0001). Common treatment-emergent adverse events (? 10%) were insomnia (all groups), akathisia (cariprazine 6 mg/d), and headache (placebo, cariprazine 6 mg/d). CONCLUSIONS: This study supports the efficacy, safety, and tolerability of cariprazine 3 and 6 mg/d in the treatment of patients with acute exacerbation of schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01104766.""",1
13941,26723501,Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy,"""OBJECTIVE: The efficacy and safety of olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, was investigated in a subgroup of patients with germline BRCA1/2 mutated (gBRCA1/2m) advanced ovarian cancer who had received ?3 prior lines of chemotherapy. Primary data from this Phase II study (Study 42, ClinicalTrials.govNCT01078662) have been reported previously. METHODS: Eligible patients were treated with oral olaparib 400mg bid capsule monotherapy until disease progression according to RECIST v1.1. Objective response rate (ORR) and duration of response (DoR) were assessed for patients with measurable disease at baseline. Safety and tolerability were assessed for all patients by adverse event (AE) incidence and changes in laboratory parameters. Platinum resistance status was obtained retrospectively, and responses to olaparib evaluated. RESULTS: In patients with gBRCA1/2m ovarian cancer, 154/193 (80%) had received ?3 prior lines of chemotherapy, of whom 137/154 (89%) had measurable disease at baseline. ORR was 34% (46/137; 95% confidence interval [CI] 26-42) and median DoR was 7.9 (95% CI 5.6-9.6) months. ORR in platinum-resistant tumors was 30%. Median DoR for platinum-sensitive and platinum-resistant disease was similar: 8.2months (95% CI 5.6-13.5) compared with 8.0months (4.8-14.8), respectively. Six of the 193 (3%) patients had an AE with an outcome of death. None of these AEs at time of occurrence was considered causally related to olaparib. CONCLUSION: Following ?3 prior lines of chemotherapy, olaparib 400mg bid (capsule form) monotherapy demonstrated notable antitumor activity in patients with gBRCA1/2m advanced ovarian cancer. No new safety signals were identified.""",1
13942,26729188,Necitumumab: First Global Approval,"""Eli Lilly is developing necitumumab (Portrazza), an intravenously administered fully human IgG monoclonal antibody directed against the epidermal growth factor receptor (EGFR), which is expressed in a variety of solid tumours and has been implicated in promoting oncogenesis and tumour progression. Necitumumab is approved as a part of combination therapy (with gemcitabine and cisplatin) in the USA for the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), and regulatory submissions have been made in the EU for this same indication. Necitumumab was derived from the proprietary phage display library of Dyax Corp, and originated with ImClone Systems, which was acquired by Eli Lilly in November 2008. Necitumumab was also under phase II development for colorectal cancer in Belgium and Spain; however, no recent development has been reported for this indication. This article summarizes the milestones in the development of necitumumab leading to this first approval for the first-line treatment of metastatic squamous NSCLC, in combination with gemcitabine and cisplatin.""",1
13943,26730841,Ranolazine reduces angina frequency and severity and improves quality of life: Observational study in patients with chronic angina under ranolazine treatment in Greece (OSCAR-GR),"""OBJECTIVE: Primary objectives were to evaluate tolerability, compliance, and perception of ranolazine effectiveness for chronic stable angina in a routine clinical setting. The secondary objective was safety evaluation. METHODS: Prospective, multi-centre, observational, study with a 6-month follow-up and study visits at baseline, 3- and 6 months in patients with chronic stable angina. Ranolazine was administered according to the summary of product characteristics and investigator discretion. Data was collected on patient and disease characteristics, concomitant therapy, angina frequency and severity, quality of life (QoL), perception of effectiveness, compliance, and adverse events. RESULTS: Between July 2010 and July 2012, 189 patients were enrolled at 20 centres. Ranolazine decreased the proportion of patients experiencing angina attacks from 88.4% at baseline to 26.5% at 6 months (p<0.001). Heart rate and blood pressure were not appreciably affected. The proportion of patients without symptoms on normal exertion (Canadian Cardiovascular Society grading class I) increased from 22.3% to 75.3% (p<0.001); patients reporting limitations in daily activities decreased from 80.4% to 35.5%. (p<0.001). Patient- and physician-assessed QoL improved (both p<0.001). Therapeutic efficacy was rated """"good"""" or """"very good"""" in 67.7% of cases by physicians, and by 63.5% of the patients. Physicians rated compliance """"good"""" or """"very good"""" in 73.5% of cases. Adverse events were consistent with previous reports, and consisted of 40 events in 24 patients; 12 were serious. CONCLUSIONS: Ranolazine was associated with decreased angina frequency and severity, and improvements in QoL. The benefits provided by ranolazine in controlled clinical trials are maintained in the clinical setting.""",1
13944,26736079,Liver disease due to illicit substance use,"While the adverse neurological, cardiovascular, renal, haematologic and musculoskeletal consequences of the use of various illicit substances are widely appreciated, less attention has been directed to possible hepatotoxic effects. This is an important issue in view of increasing evidence in both experimental animals and humans that the use of some illicit substances may be associated with substantial liver damage, leading on occasion to acute liver failure. This manuscript reviews the effects on the liver of some of the most commonly used illicit substances, including ecstasy (3,4-methylenedioxymethamphetamine), other amphetamines, cocaine, heroin, angel dust (phencyclidine), lysergic acid diethylamide and marijuana. Additional causes of liver damage in those using illicit substances are discussed.",1
13945,26743322,Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review,"OBJECTIVE: To determine risk factors for progressive multifocal leukoencephalopathy (PML) in systemic lupus erythematosus (SLE) patients, and understand how underlying disease or treatment for SLE may be associated with PML in this population. METHODS: Studies published in English between January 1, 1984 and October 31, 2014 that reported PML in adult SLE patients were included. Immunosuppression was defined as exposure to >/=1 immunosuppressant drug of interest at PML diagnosis: belimumab, rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate and high-dose corticosteroids (>15 mg/day). Minimal immunosuppression was defined as low-dose corticosteroids (</=15 mg/day) and/or anti-malarials. RESULTS: Thirty-five publications met our inclusion criteria: four observational studies, two large case series, and 29 case reports that described 35 cases. Reported PML incidence rates among SLE patients based on observational studies ranged from 1.0 to 2.4 cases/100,000 person-years. Of the 35 case reports, three cases were exposed to no immunosuppressant drugs at PML diagnosis, five cases had minimal immunosuppression, 23 cases had immunosuppression, and four cases were indeterminate. CONCLUSIONS: The evidence from this literature review suggests that, while PML is a very rare disease in SLE patients, there does appear to be an increased risk of PML associated with SLE compared to the general population, potentially due to immunosuppression, other contributing factors in their underlying disease, treatments prescribed to manage disease, or some combination of these factors. Additional large observational studies, designed to assess exposure to drugs of interest and complicated treatment histories, are needed to provide further evidence about potential mechanisms contributing to the onset of PML in SLE patients.",1
13946,26749403,Anakinra-Induced Acute Liver Failure in an Adolescent Patient with Still's Disease,"The interleukin-1 (IL-1) family consists of 11 cytokines that play key regulatory roles in many immune and inflammatory processes. Anakinra (Kineret, Amgen, Inc.) is an IL-1 receptor antagonist (IL-1ra). Increased levels of IL-1 are found in several disease states suggesting that anakinra may be beneficial in disorders associated with elevated IL-1 levels. Anakinra has been effectively used in the treatment of systemic juvenile idiopathic arthritis and adult-onset Still's disease (AOSD). Despite its therapeutic benefits, anakinra also has potential side effects, including hepatotoxicity. We present a case of AOSD in an adolescent male that was treated with anakinra. During treatment, the patient developed acute liver failure that resolved upon withdrawal of anakinra. Although anakinra-induced liver injury has been reported in adults, including one case of subacute liver failure, we believe our case is the first to show severe acute liver failure in an adolescent treated with anakinra. This case provides significant insight into a potentially serious complication associated with anakinra. It is important to further delineate these complications as the treatment indications for this drug expand.",1
13947,26755520,"Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study","""PURPOSE: The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes. PATIENTS AND METHODS: Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non-clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response. RESULTS: Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell-to-regulatory T-cell gene expression ratio correlated with response to atezolizumab. CONCLUSION: Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.""",1
13948,26758422,A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520,"Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4?+?months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP.",1
13949,26761343,Elvitegravir (Vitekta) for HIV,,1
13950,26763284,Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen,"""BACKGROUND: IV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen-protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS. CASE DETAILS: The patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 muM on hospital day 5; expected range for therapeutic dosing <1.1 muM). CASE DISCUSSION: We have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury. CONCLUSION: This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.""",1
13951,26764972,Safety profiles of old and new antimicrobials for the treatment of MRSA infections,"INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA. AREAS COVERED: Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials. EXPERT OPINION: Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections.",1
13952,26768604,Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C,"BACKGROUND: HCV infection in chronic hemodialysis patients is high, has a poor prognosis and high risk of renal graft failure, and requires nosocomial infection control measures. However, options of anti-HCV therapy in such patients are limited and unsatisfactory. In this study, we report effectiveness and safety of HCV-NS5A-inhibitor daclatasvir (DCV) and protease-inhibitor asunaprevir (ASV) combination therapy for hemodialysis patients with HCV infection. METHODS: This study was registered at the UMIN Clinical Trials Registry as UMIN000016355. Thirty-four dialysis patients were treated with DCV/ASV combination therapy between January 2015 and November 2015. Of those, 21 patients who were followed more than 12�weeks after treatment ended were included. We evaluated the 12-week sustained virologic response (SVR12) and adverse events during treatment. RESULTS: Of the 21 patients, four had compensated liver cirrhosis and three had resistance-associated variant of NS5A (NS5A RAVs)-Y93H at baseline. Overall, total of 95.5�% (20/21) of the patients achieved SVR12. Of note, all patients with cirrhosis or NS5A RAVs achieved SVR12. One relapser patient at 4�weeks post-treatment had NS3 D168E RAVs at baseline. A total of 20 patients (95.5�%) completed the 24-week therapy. One patient discontinued treatment at week 12 due to ALT elevations and achieved SVR12. CONCLUSIONS: DAV and ASV combination therapy for chronic hemodialysis patients with HCV infection was highly effective and well tolerated, even in elderly patients and patients with liver cirrhosis and NS5A-RAVs.",1
13953,26774508,"Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study","""BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that has been shown to improve survival in two placebo-controlled phase 3 trials, and is approved for patients with metastatic castration-resistant prostate cancer. The objective of the TERRAIN study was to compare the efficacy and safety of enzalutamide with bicalutamide in patients with metastatic castration-resistant prostate cancer. METHODS: TERRAIN was a double-blind, randomised phase 2 study, that recruited asymptomatic or minimally symptomatic men with prostate cancer progression on androgen-deprivation therapy (ADT) from academic, community, and private health-care provision sites across North America and Europe. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive enzalutamide 160 mg/day or bicalutamide 50 mg/day, both taken orally, in addition to ADT, until disease progression. Patients were stratified by a permutated block method (block size of four), by whether bilateral orchiectomy or receipt of luteinising hormone-releasing hormone agonist or antagonist therapy started before or after the diagnosis of metastases, and by study site. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was progression-free survival, analysed in all randomised patients. Safety outcomes were analysed in all patients who received at least one dose of study drug. The open-label period of the trial is in progress, wherein patients still on treatment at the end of the double-blind treatment period were offered open-label enzalutamide at the discretion of the patient and study investigator. This trial is registered with ClinicalTrials.gov, number NCT01288911. FINDINGS: Between March 22, 2011, and July 11, 2013, 375 patients were randomly assigned, 184 to enzalutamide and 191 to bicalutamide. 126 (68%) and 168 (88%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 20?0 months (IQR 15?0-25?6) in the enzalutamide group and 16?7 months (10?2-21?9) in the bicalutamide group. Patients in the enzalutamide group had significantly improved median progression-free survival (15?7 months [95% CI 11?5-19?4]) compared with patients in the bicalutamide group (5?8 months [4?8-8?1]; hazard ratio 0?44 [95% CI 0?34-0?57]; p<0?0001). Of the most common adverse events, those occurring more frequently with enzalutamide than with bicalutamide were fatigue (51 [28%] of 183 patients in the enzalutamide group vs 38 [20%] of 189 in the bicalutamide group), back pain (35 [19%] vs 34 [18%]), and hot flush (27 [15%] vs 21 [11%]); those occurring more frequently with bicalutamide were nausea (26 [14%] vs 33 [17%]), constipation (23 [13%] vs 25 [13%]), and arthralgia (18 [10%] vs 30 [16%]). The most common grade 3 or worse adverse events in the enzalutamide or bicalutamide treatment groups, respectively, were hypertension (13 [7%] vs eight [4%]), hydronephrosis (three [2%] vs seven [4%]), back pain (five [3%] vs three [2%]), pathological fracture (five [3%] vs two [1%]), dyspnoea (four [2%] vs one [1%]), bone pain (one [1%] vs four [2%]), congestive cardiac failure (four [2%] vs two [1%]), myocardial infarction (five [3%] vs none), and anaemia (four [2%] vs none]). Serious adverse events were reported by 57 (31%) of 183 patients and 44 (23%) of 189 patients in the enzalutamide and bicalutamide groups, respectively. One of the nine deaths in the enzalutamide group was thought to be possibly related to treatment (due to systemic inflammatory response syndrome) compared with none of the three deaths in the bicalutamide group. INTERPRETATION: The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma, Inc and Medivation, Inc.""",1
13954,26778538,"Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial","""BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ?18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR]?+?very good PR?+?complete response [CR]?+?stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.""",1
13955,26784217,Chronic Arsenic Poisoning Probably Caused by Arsenic-Based Pesticides: Findings from an Investigation Study of a Household,"In addition to naturally occurring arsenic, man-made arsenic-based compounds are other sources of arsenic exposure. In 2013, our group identified 12 suspected arsenicosis patients in a household (32 living members). Of them, eight members were diagnosed with skin cancer. Interestingly, all of these patients had lived in the household prior to 1989. An investigation revealed that approximately 2 tons of arsenic-based pesticides had been previously placed near a well that had supplied drinking water to the family from 1973 to 1989. The current arsenic level in the well water was 620 mug/L. No other high arsenic wells were found near the family's residence. Based on these findings, it is possible to infer that the skin lesions exhibited by these family members were caused by long-term exposure to well water contaminated with arsenic-based pesticides. Additionally, biochemical analysis showed that the individuals exposed to arsenic had higher levels of aspartate aminotransferase and gamma-glutamyl transpeptidase than those who were not exposed. These findings might indicate the presence of liver dysfunction in the arsenic-exposed individuals. This report elucidates the effects of arsenical compounds on the occurrence of high levels of arsenic in the environment and emphasizes the severe human health impact of arsenic exposure.",1
13956,26788381,Recurrent Hepatocellular Carcinoma in Patient with Crohn's Disease: Incidental or Expected Outcome of Azathioprine?,"Hepatocellular carcinoma (HCC) usually occurs in patients with underlying risk factors such as liver cirrhosis and chronic hepatitis B. Although patients with Crohn's disease (CD) are at an increased risk to develop malignancies such as colon cancer, the incidence of HCC in this population is extremely rare. We report a case of 62-year-old male with long history of CD treated with azathioprine (AZA) and aminosalicylic acid (ASA) who was incidentally diagnosed with HCC, for which left hepatectomy was done. Four years later during routine follow-up, patient had another hepatic lesion and underwent resection of the mass. The mechanism of occurrence of HCC in patient with CD is still controversial and may include immune mediated changes and medication related complications. AZA was reported in all case reports of CD that developed HCC. Through this report we hope to explore the complex pathophysiological mechanisms contributing to the development of HCC in the Crohn's disease patient population.",1
13957,26789873,Clinical Practice. Postmenopausal Osteoporosis,"""Key Clinical Points Postmenopausal Osteoporosis Fractures and osteoporosis are common, particularly among older women, and hip fractures can be devastating. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk. Bisphosphonates (generic) and denosumab reduce the risk of hip, nonvertebral, and vertebral fractures; bisphosphonates are commonly used as first-line treatment in women who do not have contraindications. Teriparatide reduces the risk of nonvertebral and vertebral fractures. Osteonecrosis of the jaw and atypical femur fractures have been reported with treatment but are rare. The benefit-to-risk ratio for osteoporosis treatment is strongly positive for most women with osteoporosis. Because benefits are retained after discontinuation of alendronate or zoledronic acid, drug holidays after 5 years of alendronate therapy or 3 years of zoledronic acid therapy may be considered for patients at lower risk for fracture.""",1
13958,26792812,"Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3)","""OBJECTIVE: To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents. METHODS: Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20?mg twice daily, or apremilast 30?mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20?mg twice daily or 30?mg twice daily. The efficacy and safety of apremilast were assessed over 52?weeks. RESULTS: At week 16, significantly more patients receiving apremilast 20?mg twice daily (28%) and 30?mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p<0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30?mg twice daily (-0.20) versus placebo (-0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement ?3%, significantly more apremilast 30?mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection. CONCLUSIONS: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52?weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT01212770.""",1
13959,26796981,Clinical Safety and Efficacy of Nilotinib or Dasatinib in Patients With Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia and Pre-Existing Liver and/or Renal Dysfunction,"BACKGROUND: The safety and efficacy of front-line nilotinib and dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML-CP) with pre-existing liver and/or renal dysfunction are unknown. PATIENTS AND METHODS: We analyzed the adverse event rates, response rates, and survival rates of 215 patients with CML-CP with or without renal and/or liver dysfunction who had been treated with front-line nilotinib (n = 108) or dasatinib (n = 107). RESULTS: The overall median follow-up period was 49 months. At baseline, 6 dasatinib-treated patients (6%) had mild renal dysfunction and 13 (12%) had mild liver dysfunction. Also, 8 nilotinib-treated patients (7%) had mild renal dysfunction, 1 (1%) moderate renal dysfunction, and 9 (8%) mild liver dysfunction. No significant differences were found in the rate of complete cytogenetic response, major molecular response, or molecular response by a 4.5 log reduction on the international scale between the organ function cohorts. Dasatinib- or nilotinib-treated patients with baseline renal dysfunction had a greater incidence of transient reversible acute kidney injury (P = .011 and P < .001), and nilotinib-treated patients with renal dysfunction had a greater incidence of bleeding (P < .001). CONCLUSION: Patients with CML-CP and mild to moderate renal or liver dysfunction can be safely treated with front-line dasatinib or nilotinib and can achieve response rates similar to those of patients with CML-CP without organ dysfunction.",1
13960,26803446,"Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study","BACKGROUND: Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5. METHODS: We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10,000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079. FINDINGS: From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83-99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76-100) of the 21 patients who were treatment naive and 19 (95%, 75-100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse events were asthenia (16 [39%] patients), headache (11 [27%] patients), and fatigue (four [10%] patients). One patient had a serious adverse event, worsening depression, which we judged to be unrelated to study treatment. INTERPRETATION: The oral regimen of ledipasvir-sofosbuvir is an effective and well-tolerated treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced. FUNDING: Gilead Sciences.",1
13961,26809244,Elotuzumab: First Global Approval,"Elotuzumab (Empliciti�) is a humanised IgG1 monoclonal antibody developed by Bristol-Myers Squibb (BMS) and AbbVie that has been approved as combination therapy with lenalidomide and dexamethasone for relapsed/refractory multiple myeloma in the US. Elotuzumab binds to the cell surface receptor signalling lymphocytic activation molecule F7 (SLAMF7), which is selectively expressed on myeloma cells and natural killer cells, leading to antibody-dependent cellular cytotoxicity and direct natural killer cell activation. In a phase III clinical trial, addition of elotuzumab to lenalidomide and dexamethasone therapy in patients with relapsed/refractory multiple myeloma was associated with a significant improvement in progression-free survival and overall response rate. This article summarizes the milestones in the development of elotuzumab leading to this first approval for relapsed/refractory multiple myeloma.",1
13962,26816533,Crizotinib versus platinum-based double-agent chemotherapy as the first line treatment in advanced anaplastic lymphoma kinase-positive lung adenocarcinoma,"""BACKGROUND: To explore the efficacy and safety of crizotinib versus platinum-based double agent chemotherapy as the first-line treatment in patients with advanced anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. METHOD: We retrospectively analyzed data from 19 patients with advanced ALK-positive lung adenocarcinoma who had received no previous systemic treatment for advanced disease. Seven patients received oral crizotinib at a dose of 250?mg twice daily; 12 patients were administered standard chemotherapy (pemetrexed, paclitaxel, vinorelbine or gemcitabine plus either cisplatin or carboplatin) every three weeks for up to six cycles. The primary endpoint was overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: The ORR was significantly higher with crizotinib than with chemotherapy (83.3% in the crizotinib vs. 25.0% in the chemotherapy group, P < 0.05); the DCRs were 100% and 75%, respectively (P < 0.05). The common adverse events associated with crizotinib were visual abnormality and diarrhea, whereas those associated with chemotherapy were neutropenia and nausea. In the crizotinib group, liver aminotransferase elevation (adverse events grade 3 or 4) occurred in one patient (14.3%). In the chemotherapy group, the same grade neutropenia adverse event occurred in two patients (16.6%). The incidence of treatment-related grade 3 or 4 adverse events was similar in both groups. Compared with chemotherapy, crizotinib was associated with a greater reduction in lung cancer symptoms and a greater improvement in quality of life. CONCLUSION: As a first-line treatment, crizotinib was superior to platinum-based double chemotherapy in patients with previously untreated advanced ALK-positive lung adenocarcinoma. Therefore, crizotinib is an optimal therapy as a first-line treatment in these patients.""",1
13963,26825712,Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure,"""Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.""",1
13964,26827946,Vitamin D: Historical Overview,"A history of vitamin D has been provided, dating from the earliest description of rickets, the disease resulting from vitamin D deficiency, to a current understanding of vitamin D metabolism and the mechanism of action of its hormonal form in regulating gene expression in target organs. Vitamin D is produced in skin by impact of 280-310 nm light on 7-dehydrocholesterol. The vitamin D is then converted in the liver to a circulating form, 25-hydroxyvitamin D that is converted largely, if not exclusively, in the kidney to the final hormone, 1?,25-dihydroxyvitamin D. This hormone functions through a nuclear receptor that regulates expression of key genes in target organs. Among its many resulting functions are increased intestinal calcium and phosphate absorption, bone calcium mobilization, and renal reabsorption of calcium. The resultant increase in serum calcium and phosphate supports bone mineralization, curing rickets, and osteomalacia. There are many other functions of vitamin D that remain to be described that contribute to its health supporting role.",1
13965,26830816,"A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg","""STUDY QUESTION: Will the use of levonorgestrel (LNG) 1.5 mg taken at each day of coitus by women who have relatively infrequent sex be an efficacious, safe and acceptable contraceptive method? SUMMARY ANSWER: Typical use of LNG 1.5 mg taken pericoitally, before or within 24 h of sexual intercourse, provides contraceptive efficacy of up to 11.0 pregnancies per 100 women-years (W-Y) in the primary evaluable population and 7.1 pregnancies per 100 W-Y in the evaluable population. WHAT IS KNOWN ALREADY: LNG 1.5 mg is an effective emergency contraception following unprotected intercourse. Some users take it repeatedly, as their means of regular contraception. STUDY DESIGN, SIZE, DURATION: This was a prospective, open-label, single-arm, multicentre Phase III trial study with women who have infrequent coitus (on up to 6 days a month). Each woman had a follow-up visit at 2.5, 4.5 and 6.5 months after admission or until pregnancy occurs if sooner, or she decided to interrupt participation. The study was conducted between 10 January 2012 and 15 November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 330 healthy fertile women aged 18-45 years at risk of pregnancy who reported sexual intercourse on up to 6 days a month, were recruited from four university centres located in Bangkok, Thailand; Campinas, Brazil; Singapore and Szeged, Hungary to use LNG 1.5 mg pericoitally (24 h before or after coitus) as their primary method of contraception. The participants were instructed to take one tablet every day she had sex, without taking more than one tablet in any 24-h period, and to maintain a paper diary for recording date and time for every coital act and ingestion of the study tablet, use of other contraceptive methods and vaginal bleeding patterns. Anaemia was assessed by haemoglobin evaluation. Pregnancy tests were performed monthly and pregnancies occurring during product use were assessed by ultrasound. At the 2.5-month and final visit at 6.5 months, acceptability questions were administered. MAIN RESULTS AND THE ROLE OF CHANCE: There were 321 women included in the evaluable population (which includes all eligible women enrolled), with 141.9 woman-years (W-Y) of observation and with a rate (95% confidence interval [CI]) of 7.1 (3.8; 13.1) pregnancies per 100 W-Y of typical use (which reflects use of the study drug as main contraceptive method, but also includes possible use of other contraceptives from admission to end of study) and 7.5 (4.0; 13.9) pregnancies per 100 W-Y of sole use. In the primary evaluable population (which includes only eligible enrolled women <35 years old), the rate was 10.3 (5.4; 19.9) pregnancies per 100 W-Y of typical use, and 11.0 (5.7; 13.1) pregnancies per 100 W-Y of sole use. There were three reported severe adverse events and 102 other mild adverse events (most common were headache, nausea, abdominal and pelvic pain), with high recovery rate. The vaginal bleeding patterns showed a slight decrease in volume of bleeding and the number of bleeding-free days increased over time. There was only one case of severe anaemia, found at the final visit (0.4%). The method was considered acceptable, as over 90% of participants would choose to use it in the future or would recommend it to others. LIMITATIONS, REASONS FOR CAUTION: This was a single-arm study with small sample size, without a control group, designed as a proof of concept study to explore the feasibility of this type of contraception. WIDER IMPLICATIONS OF THE FINDINGS: A larger clinical study evaluating pericoital contraception with LNG is feasible and our data show that this method would be acceptable to many women. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR) and the World Health Organization. Gynuity and the Bill and Melinda Gates Foundation (BMGF) provided financial support for project monitoring. HRA Pharma donated the LNG product. N.K. was the initial project manager when she was with WHO/HRP and was employed by HRA Pharma, which distributes LNG for emergency contraception. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: This study was registered on ANZCTR, Trial ID ACTRN12611001037998. TRIAL REGISTRATION DATE: 4 October 2011. DATE OF FIRST PATIENT'S ENROLMENT: 10 January 2012.""",1
13966,26832650,Simeprevir and Sofosbuvir (SMV-SOF) for 12 Weeks for the Treatment of Chronic Hepatitis C Genotype 1 Infection: A Real World (Transplant) Hepatology Practice Experience,"""OBJECTIVES: The combination of simeprevir (SMV) and sofosbuvir (SOF) was found to be well-tolerated with high sustained virologic response (SVR) rates in patients with genotype 1 chronic hepatitis C in clinical trials. Previous experience with hepatitis C virus (HCV) therapy has shown that patient tolerability and treatment efficacy described in controlled clinical trials did not necessarily mirror the """"real world"""" experience. The goal of this study was to define SVR rates in a """"real world"""" analysis and to explore predictors of treatment response with SMV and SOF. METHODS: This is a retrospective study examining the """"real world"""" treatment of 170 patients with chronic HCV genotype 1 using the combination of SMV and SOF with or without ribavirin (RBV) for a fixed 12-week duration irrespective of prior interferon therapy, transplant status or fibrosis stage. Differences between SVR cohorts were analyzed by both intention-to-treat (ITT) and per protocol. RESULTS: The vast majority of patients were genotype 1a, 77% were cirrhotic in the non-LT group, and 35% of the entire cohort was African-American. Combination treatment with SMV and SOF in genotype 1 chronic HCV patients achieved an overall SVR rate at 12 weeks after completion of therapy (SVR12) of 78% by ITT and 86% by per protocol (84% in non-liver transplant (LT) patients and 89% in post-LT recipients). The presence of hepatocellular carcinoma was found to be a significant negative predictor of SVR12, whereas an undetectable week eight VL was a significant positive predictor of SVR in the entire cohort. CONCLUSIONS: Our data confirm excellent SVR outcomes with favorable safety and tolerability profiles in patients who carry many traditional high-risk features for non-response, including post-LT recipients and patients with advanced liver disease.""",1
13967,26835238,Eribulin in pretreated metastatic breast cancer patients: results of the TROTTER trial-a multicenter retrospective study of eribulin in real life,"""This retrospective multicenter analysis was aimed to evaluate clinical activity and tolerability of eribulin in pretreated metastatic breast cancer patients in clinical practice. Patients treated with eribulin from January 2012 to July 2013 were enrolled in the observational study from 10 italian hospitals. Tumor and toxicity evaluation were performed according to Agenzia Italiana Farmaco. One-hundred and thirteen patients were included in the study. Median age 62�years old. 71.7�% of the patients had visceral involvement and the majority had a burden of disease involving two or more organs with a median number of 2 (1-6). The median number of previous chemotherapy regimens for advanced disease was 3 (1-10). Median number of eribulin cycles was 4 (1-27). Overall response rate was 24�% (95�% CI 16.0-31.8). Clinical benefit rate, was 35.4�% (95�% CI 26.6-44.2). At a median follow-up of 29.6�months (8.3-41.9) the median progression free survival was 3.3�months (0.6-26.7; 95�% CI 2.4-4.2), and the median overall survival 11.6�months (0.6-33.3; 95�% CI 8.7-14.5). No correlation was recorded between subtypes in terms of ORR and CBR. Toxicity was manageable. Main common grade 3-4 toxicities were neutropenia (19.4�%), febrile neutropenia (0.9�%), asthenia (3.5�%), abnormal liver function test (1.8�%), stomatitis (0.9�%). Our results confirm that treatment with eribulin is feasible and safe in real-world patients.""",1
13968,26838489,Idiopathic portal hypertension regarding thiopurine treatment in patients with inflammatory bowel disease,"INTRODUCTION: The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown. MATERIAL AND METHODS: A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment. RESULTS: At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn's disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3). CONCLUSION: Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage.",1
13969,26841296,L-Carnitine for Treatment of Pegasparaginase-Induced Hepatotoxicity,"INTRODUCTION: Similar to pediatric regimens, multiple doses of L-asparaginase (PEG-Asp) are being increasingly used in adults with newly diagnosed acute lymphoblastic leukemia (ALL) with promising results. One of the most common side effects of the drug in adults is high-grade hyperbilirubinemia and transaminitis. Despite being almost always reversible and may not recur, clinicians may still be reluctant to continue with PEG-Asp in patients with liver toxicity, losing the benefit from multiple doses of the drug. CASE REPORT: We describe a case of adult ALL who developed PEG-Asp-related high grade liver toxicity. The rising hyperbilirubinemia and transaminitis rapidly and permanently reversed using the amino-acid derivative L-carnitine. This case goes in line with similar observations in animal models and humans. CONCLUSION: L-Carnitine may show therapeutic benefit in PEG-Asp-related hepatotoxicity and should be considered in clinical trials of the drug.",1
13970,26844013,"Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym((R)), a Mechanistic Model of Drug-Induced Liver Injury","Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors developed as adjunct therapies for treating Parkinson's disease. While both drugs have been shown to cause mitochondrial dysfunction and inhibition of the bile salt export protein (BSEP), liver injury has only been associated with the use of tolcapone. Here we used a multiscale, mechanistic model (DILIsym((R))) to simulate the response to tolcapone and entacapone. In a simulated population (SimPops) receiving recommended doses of tolcapone (200 mg t.i.d.), increases in serum alanine transaminase (ALT) >3x the upper limit of normal (ULN) were observed in 2.2% of the population. In contrast, no simulated patients receiving recommended doses of entacapone (200 mg 8x day) experienced serum ALT >3x ULN. Further, DILIsym((R)) analyses revealed patient-specific risk factors that may contribute to tolcapone-mediated hepatotoxicity. In summary, the simulations demonstrated that differences in mitochondrial uncoupling potency and hepatic exposure primarily account for the difference in hepatotoxic potential for tolcapone and entacapone.",1
13971,26850781,Abiraterone acetate post-docetaxel for metastatic castration-resistant prostate cancer in the Belgian compassionate use program,"BACKGROUND: Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012). PATIENTS AND METHODS: Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease?50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied. RESULTS: Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status?2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design. CONCLUSIONS: These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.",1
13972,26853281,Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia,"Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.",1
13973,26859660,Selexipag (Uptravi) for pulmonary arterial hypertension,,1
13974,26861310,Hepatotoxicity by Drugs: The Most Common Implicated Agents,"Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.",1
13975,26869762,Emerging treatments in Castleman disease - a critical appraisal of siltuximab,"Castleman disease (CD) is a rare, heterogeneous lymphoproliferative disorder for which no standard of care currently exists. Evidence that the pathophysiology of CD is fueled by excessive interleukin-6 (IL-6) has led to considerable interest in therapeutic targeting of this cytokine. Siltuximab, a chimeric monoclonal antibody to IL-6, has thus emerged as a promising treatment option in a disease lacking efficacious therapy. Here, we review the findings of recent studies evaluating single-agent siltuximab treatment in CD, including the first-ever randomized clinical trial in this disease. Although much more work is needed to establish a standardized treatment approach, siltuximab appears to be a safe and effective treatment for patients with newly diagnosed and previously treated CD.",1
13976,26876327,Prospective Pilot Study of Mirabegron in Pediatric Patients with Overactive Bladder,"BACKGROUND: Antimuscarinics are the pharmacologic mainstay of overactive bladder (OAB) management, but side effects limit their use. Mirabegron, a new molecule with a distinct mechanism of action (?3-adrenoreceptor agonist), was recently approved as monotherapy for idiopathic OAB in adults but has not been studied in the pediatric population. OBJECTIVE: To evaluate the efficacy and safety of mirabegron to treat urinary incontinence in children with idiopathic OAB who were refractory to and/or intolerant of antimuscarinics. DESIGN, SETTING, AND PARTICIPANTS: A prospective off-label study using mirabegron was conducted. Pediatric patients without symptom improvement under behavioral and medical therapies and/or with significant side effects with at least two different antimuscarinic agents were recruited. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary outcome was better reported efficacy than with the use of prior anticholinergic medication. Secondary end points were tolerability, safety, and satisfaction. Efficacy and tolerability were assessed with voiding diaries, postvoid residuals, urine cultures, electrocardiogram, and vital signs. Families were questioned for continence, side effects, compliance, and Patient Perception of Bladder Condition (PPBC) questionnaire. The Wilcoxon rank sum test and Wilcoxon signed rank test were used for statistical analysis. RESULTS AND LIMITATIONS: A total of 58 patients were recruited at a median age of 10.1 yr and were on mirabegron for a median of 11.5 mo. Median bladder capacity improved from 150ml to 200ml (p<0.001). Continence improved in 52 of 58, with 13 being completely dry. Median PPBC improved from 4.0 to 2.0 (p<0.001). Eight patients reported mild or moderate side effects. Absence of a placebo group is a limitation of the study. CONCLUSIONS: Mirabegron, a novel first-in-class therapy, appeared as a safe and effective alternative for children with idiopathic OAB refractory to antimuscarinics. PATIENT SUMMARY: We evaluated the efficacy and safety of mirabegron to treat incontinence in pediatric patients. Continence, median voided volumes, and quality of life were improved after the introduction of mirabegron, and few side effects were reported.",1
13977,26880462,Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome,"""Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.""",1
13978,26889372,Sofosbuvir and Simeprevir for the Treatment of Recurrent Hepatitis C with Fibrosing Cholestatic Hepatitis after Liver Transplantation,"Fibrosing cholestatic hepatitis (FCH) is an aggressive form of hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT), which frequently results in graft failure and death. Treatment of FCH remains challenging, and the optimal antiviral therapy is yet to be determined. Between November 2013 and early 2015, 62 patients with HCV cirrhosis underwent OLT at our transplant center, of whom, 5 patients developed recurrence HCV in the form of severe FCH and were treated with sofosbuvir and simeprevir (SOF-SMV) for 24 weeks. All patients achieved significant improvement of HCV viral load and had undetectable viral PCR at 6-8 week of treatment. The HCV RNA remained undetectable throughout treatment course. The first two patients achieved SVR at week 12 after completion of the treatment. There were significant histologic and biomarkers improvements after initiation of the treatment. One patient developed refractory pruritus and acute pancreatitis. The second, fourth and fifth patients had very benign treatment courses with no side effects recorded. The third patient was starting the treatment with multiple comorbid conditions. His course was complicated with hepatic artery thrombosis, and later developed sepsis and renal failure. Therefore, it seems that the combination of SOF-SMV is an efficacious oral regimen in OLT recipient with recurrent hepatitis C and FCH. However, safety profile needs to be carefully evaluated.",1
13979,26893187,Long-term safety and efficacy of dutasteride in the treatment of male patients with androgenetic alopecia,"Androgenetic alopecia is an androgen-induced pattern of progressive hair loss, which occurs in genetically predisposed people. This study aimed to determine long-term safety, tolerability and efficacy of dutasteride 0.5 mg, an inhibitor of 5-?-reductase, in Japanese male patients with androgenetic alopecia. This was a multicenter, open-label, prospective outpatient study (clinicaltrials.gov NCT01831791, GSK identifier ARI114264) in which patients took dutasteride 0.5 mg p.o. once daily for 52 weeks. Primary end-points included adverse event assessment, incidence of drug-related adverse event and premature discontinuations. Secondary end-points included hair growth, hair restoration and global improvement in hair. A total of 120 patients were enrolled, of whom 110 completed 52 weeks of treatment. Nasopharyngitis, erectile dysfunction and decreased libido were the most frequently reported adverse events and most adverse events were mild. Drug-related adverse events were reported with an incidence of 17%, none of which led to study withdrawal. Hair growth (mean target area hair count at week 52), hair restoration (mean target area hair width at week 52) and global appearance of hair (mean of the median score at week 52) improved from baseline during the study. As a potential future treatment option for male androgenetic alopecia, dutasteride 0.5 mg exhibited long-term safety, tolerability and efficacy within this study population.",1
13980,26899352,Simeprevir or telaprevir with peginterferon and ribavirin for recurrent hepatitis C after living-donor liver transplantation: A Japanese multicenter experience,"AIM: This study aimed to clarify the efficacy and safety of simeprevir, a second-generation NS3/4A inhibitor, with peginterferon and ribavirin for recurrent hepatitis C after liver transplantation. METHODS: A retrospective cohort study of living-donor liver transplant recipients with recurrent hepatitis C with the hepatitis C virus genotype 1 treated with either simeprevir- or telaprevir-based triple therapy was carried out at eight Japanese liver transplant centers. RESULTS: Simeprevir- and telaprevir-based triple therapies were given to 79 and 36 patients, respectively. Of the 79 patients treated with simeprevir-based triple therapy, 44 (56%) achieved sustained virological response 12�weeks (SVR12) after treatment ended, and there was no significant difference in the SVR12 between the simeprevir- and telaprevir-based triple therapy groups (69%). The rates of adverse events were not significantly different between the simeprevir- and telaprevir-based triple therapy groups, although the rate of patients who received blood cell transfusion and erythropoietin due to anemia and had renal insufficiency were significantly higher in the telaprevir group than in the simeprevir group. Three baseline factors, the presence of prior dual therapy with peginterferon and ribavirin (P?=?0.001), a non-responder to the prior dual therapy (P?<�0.001), and male sex (P?=?0.040), were identified as significant predictive factors for non-SVR with simeprevir-based triple therapy. CONCLUSION: Simeprevir-based triple therapy for recurrent hepatitis C after living-donor liver transplantation resulted in a high SVR rate and good tolerability, especially in treatment-na?ve patients.",1
13981,26900394,"Health status of male steel workers at an electric arc furnace (EAF) in Trentino, Italy","""BACKGROUND: The aim of this retrospective cohort study was to determine if the workers of an Electric Arc Furnace (EAF), which recycles scrap, had higher mortality and morbidity due to possible exposure to pollutants at work. EAFs do not run on coke ovens. In EAFs 40 % of the particulate matter (PM) is made up of PM 2.5. The foundry dust contained iron, aluminum, zinc, manganese, lead, chromium, nickel, cadmium, mercury, arsenic, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls and dioxins. METHODS: Mortality study: a cohort of 331 exposed workers (6731 person-years) was studied from 19/03/1979 to 31/12/2009 (mean follow up 20.7 years). The group of exposed workers was compared to the general population and to a small control group of 32 workers from the same company. Morbidity study: rates of exemption from health fee for the seven major diseases of 235 exposed workers were compared to the rates of exemption in the Province of Trento. RESULTS: Mortality study: an excess mortality was found in the exposed workers as compared to the general population (SMR 1.13; 95 % CI: 0.76-1.62; 29 deaths) and to the internal group (RR 2.34; 95 % CI: 0.39-95.7). The mortality rate was increased for all tumours (SMR 1.36; 95 % CI: 0.75-2.29; 14 cases), for lung cancer (SMR 3.35; 95 % CI 1.45-6.60; 8 cases), for ischemic heart disease (SMR 1.27; 95 % CI: 0.35-3.26; 4 cases), for chronic liver disease (SMR 1.16; 95 % CI: 0.14-4.20; 2 cases) and for injury and poisoning (SMR 1.32; 95 % CI: 0.48-2.88; 6 cases). Morbidity study: there was a statistically significant increase of diabetes, rheumatoid arthritis, hypertension and cardiovascular diseases in exposed workers. CONCLUSIONS: With the limitations of this relatively small cohort, we found a statistically significant increase of diabetes, cardiovascular diseases and deaths due to lung cancer in exposed workers. These findings cannot be explained by PAH exposure alone; metal particulates are the most important pollutants in the working area of EAFs. A reliable method for measuring metal PM in tissues is urgently needed for exposure assessment. This study underlines the necessity to maximize the standards of security toward foundry dusts/diffuse emission. Further studies on EAF's are needed to confirm our findings and to increase statistical power.""",1
13982,26913560,The safety of pomalidomide for the treatment of multiple myeloma,"INTRODUCTION: Pomalidomide, a derivative of thalidomide and member of the immunomodulatory drugs is licenced for use in relapsed and refractory multiple myeloma (RRMM) in Europe, USA, Canada and Japan. AREAS COVERED: This review details all published trials in which pomalidomide has been used in the treatment of myeloma including phase I, II and III studies via PubMed searches for randomised control trials, observational cohort, case reports, meta-analysis and reviews. In addition abstract searches from the 2015 IMW and ASH conferences have been included. Drug safety has been a main focus with additional detail outlining the current clinical experience and treatment efficacy. Drug related toxicities and management of such events are covered in detail. EXPERT OPINION: Pomalidomide is well tolerated and has been demonstrated to prolong progression free survival and overall survival in RRMM patients in comparison to other agents commonly used later in the disease. Treatment related toxicities are usually easily managed using treatment interruption, dose modification, prophylactic therapies and blood/platelet transfusions. There is scope for the drug to be used in combination with newer agents at disease presentation, relapse and as a long-term maintenance option. At present trials assessing its use in early disease and maintenance are lacking.",1
13983,26914406,"A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis","""BACKGROUND: The interleukin-17 cytokine family plays a central role in psoriasis pathogenesis. OBJECTIVES: To evaluate the efficacy and safety of brodalumab, a human anti-interleukin-17 receptor antibody, in treating patients with moderate-to-severe plaque psoriasis. METHODS: In this phase III, double-blind, placebo-controlled study (NCT01708590; AMAGINE-1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210�mg) or placebo every 2�weeks (Q2W), with an additional dose at week 1, for a 12-week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA�?�3 were re-treated with the induction dose. After ?�12�weeks of retreatment, patients with sPGA 2 for ?�4�weeks or sPGA ?�3 were rescued with brodalumab 210�mg Q2W. At week 12, patients randomized to brodalumab with sPGA ?�2 or placebo received brodalumab 210�mg Q2W. Coprimary end points were the percentage of patients with ?�75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12. RESULTS: There were 661 patients randomized: 220 placebo, 219 brodalumab 140�mg and 222 brodalumab 210�mg. At week 12, 60% (140�mg) and 83% (210�mg) vs. 3% (placebo) achieved PASI 75, and 54% (140�mg) and 76% (210�mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable. CONCLUSIONS: Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate-to-severe plaque psoriasis.""",1
13984,26915677,Randomized phase 1 study of the phosphatidylinositol 3-kinase ? inhibitor idelalisib in patients with allergic rhinitis,"""BACKGROUND: Phosphatidylinositol 3-kinase p110? isoform (PI3K p110?) activity is essential for mast cell activation, suggesting that inhibition of PI3K p110? might be useful in treating allergic diseases. OBJECTIVE: We sought to determine the effect of the PI3K p110?-selective inhibitor idelalisib on allergic responses. METHODS: This phase 1 randomized, double-blind, placebo-controlled, 2-period crossover study was conducted with the Vienna Challenge Chamber. Grass pollen-induced allergic symptoms were documented during screening. Eligible subjects received idelalisib (100�mg twice daily) or placebo for 7�days, with allergen challenge on day 7. After a 2-week washout period, subjects received the alternate treatment and repeated allergen challenge. Study measures included safety, nasal and nonnasal symptoms, nasal airflow, nasal secretions, basophil activation, and plasma cytokine levels. RESULTS: Forty-one patients with allergic rhinitis received idelalisib/placebo (n�=�21) or placebo/idelalisib (n�=�20). Idelalisib treatment was well tolerated. Mean total nasal symptom scores were lower during the combined idelalisib treatment periods compared with placebo (treatment difference [idelalisib�-�placebo], -1.78; 95% CI, -2.53 to -1.03; P�<�.001). Statistically significant differences were also observed for the combined treatment periods for total symptom scores, nasal airflow, nasal secretion weight, and nasal congestion scores. The percentage of ex�vivo-activated basophils (CD63(+)/CCR3(+) cells; after stimulation with grass pollen) was substantially lower for idelalisib-treated compared with placebo-treated subjects. Plasma CCL17 and CCL22 levels were reduced after idelalisib treatment. CONCLUSION: Idelalisib treatment was well tolerated in patients with allergic rhinitis and appears to reduce allergic responses clinically and immunologically after an environmental allergen challenge.""",1
13985,26921514,Pharmacotherapy of inborn errors of metabolism illustrating challenges in orphan diseases,"Orphan diseases (OD) have special challenges based on the rarity of the conditions. Mostly multicentre studies are required, controlled studies are difficult to perform. Based on the often chronic course of OD with slow progress the effect of therapeutic interventions is difficult to assess. Development and production of pharmaceutical substances for OD is difficult, time-consuming and sophisticated. Special incentives by the regulatory bodies like protocol assistance, long marketing exclusivity and reduced licencing fees encourage the development of orphan drugs. Inborn errors of metabolism (IEMs) due to enzyme or transporter deficiencies are taken as an example for OD. Accumulation of substrates proximal to the deficient enzyme during catabolic episodes leads to autointoxication with acute onset of symptoms. IEMs due to transporter deficiency usually have a more stable, chronic course. Therapeutic options are substrate reduction by diet or drugs, vitamin/cofactor supplementation, enzyme replacement, enzyme augmentation and transplantation of organs or cells. Phenylketonuria (PKU) is the prototype of an IEM which can be successfully treated by diet. The outcome of hepatorenal tyrosinaemia type 1 was revolutionarized by substrate reduction using nitisinone (NTBC) which was discovered by chance. Lysosomal storage diseases are examples where enzyme replacement therapy is successful. Enzyme augmentation can be achieved in some IEM-patients with a mild phenotype (residual enzyme activity) by chaperones which stabilize the enzyme. Organ transplantation is an option in those patients who cannot be managed by drugs and/or diet. Bone marrow transplantation is successful in some patients where CNS-involvement occurs. The CNS cannot be reached by enzyme replacement therapy (blood-brain barrier). While safety and efficacy of drugs for OD have been demonstrated pre-marketing, post-marketing surveys are often necessary to include more patients.",1
13986,26932414,Letter: safety and efficacy of sofosbuvir plus daclatasvir with ribavirin for 12 weeks in Chinese treatment-experienced cirrhotic genotype 1b patients with HCV,,1
13987,26938701,Sonidegib (Odomzo) for basal cell carcinoma,,1
13988,26950122,Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States,"In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.",1
13989,26963156,Isavuconazonium sulfate (Cresemba)--a new antifungal,,1
13990,26969258,Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis,"""BACKGROUND: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. METHODS: In a single-arm open-label trial (VITAL study), adult patients (?18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. FINDINGS: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0?595). INTERPRETATION: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.""",1
13991,26973324,"Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial","""BACKGROUND: ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC. METHODS: ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. FINDINGS: Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11?1 months (IQR 6?7-15?2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17?0 months (95% CI 11?3-non-estimable [NE]) in ALK inhibitor-naive patients and 8?3 months (6?8-9?7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18?4 months (95% CI 11?1-NE) in ALK inhibitor-naive patients and 6?9 months (5?6-8?7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. INTERPRETATION: The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases. FUNDING: Novartis Pharmaceuticals Corporation.""",1
13992,26995293,Prevalence of hypercalcemia related to hypervitaminosis D in clinical practice,"BACKGROUND & AIMS: Recent interest in vitamin D has led to a substantial increase in the use of vitamin D supplements. Vitamin D intoxication may be a concern as hypervitaminosis D can result in irreversible calcification of soft tissues so that it is important to detect early markers of vitamin D intoxication. Our aim was to assess the simultaneous presence of biochemical markers of vitamin D toxicity (i.e. hypervitaminosis D, hypercalcemia) and determine the concentrations of 25-OH-vitamin D at which the risk of hypercalcemia, and thus toxicity, might begin. METHODS: We evaluated retrospectively a 6-year period during which 25.567 samples were assessed for 25-OH-vitamin D status by UHPLC. Hypervitaminosis D was defined at serum 25-OH-vitamin D >160 nmol/L. Serum and urine calcium, phosphorus and iPTH were also recorded, if available. Medical history revision was performed in subjects displaying simultaneously hypervitaminosis D and hypercalcemia. RESULTS: Overall, hypervitaminosis D was found in 475 samples (1.86%) of which 51 displayed hypercalcemia (11.1%). A total of 382 samples were identified as the first record of hypervitaminosis D and 39 presented hypercalcemia (10.2%), most of them at 25-OH-vitamin D levels between 161 and 375 nmol/L. Only in 15 subjects, hypercalcemia could be directly attributed to vitamin D and serum 25-OH-vitamin D ranged between 164 and 1139 nmol/l. In no case, serum calcium achieved concentrations considered as critical values (>13 mg/dl). CONCLUSION: Hypercalcemia due to vitamin D represented <4% of the total hypervitaminosis D detected and <0.1% of the tests performed. However, a highly variable response was observed and most subjects presented hypercalcemia at serum concentrations of 25-OH-vitamin D < 375 nmol/L.",1
13993,27003146,Amoxicillin-Clavulanate-Induced Liver Injury,"BACKGROUND AND AIMS: Amoxicillin-clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs. METHODS: Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials. RESULTS: One hundred and seventeen subjects with AC-DILI were identified from the cohort (n�=�1038) representing 11�% of all cases and 24�% of those due to antimicrobial agents (n�=�479). Those with AC-DILI were older (60 vs. 48�years, P�<�0.001). AC-DILI was more frequent in men than women (62 vs. 39�%) compared to the overall cohort (40 vs. 60�%, P�<�0.001). The mean time to symptom onset was 31�days. The Tb, ALT, and ALP were 7�mg/dL, 478, and 325�U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5�mg/dL, occurred on average 55�days after the peak value. Three female subjects required liver transplantation, and none died due to DILI. CONCLUSION: AC-DILI causes a moderately severe, mixed hepatocellular-cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.",1
13994,27015138,Elevated liver enzymes in inflammatory bowel disease: the role and safety of infliximab,"BACKGROUND: Abnormal liver enzymes are frequently encountered in inflammatory bowel disease (IBD) patients. Infliximab has been implicated in inducing drug-induced liver injury, autoimmune hepatitis or reactivation of hepatitis B virus. We aimed to clarify the role of infliximab in liver impairment in an IBD cohort. STUDY: A total of 305 patients with IBD, without evidence of chronic liver disease, were included in the study and retrospectively evaluated. Laboratory and clinical data were retrieved from a prospectively acquired database. In all, 176 consecutive patients treated with infliximab during the last 5 years were compared with a matched population of 129 patients who did not receive any antitumour necrosis factor treatment. RESULTS: Elevation of alanine transaminase (ALT) was frequent in the entire population (36.4%) and it was not significantly associated with the use of infliximab (P=0.284). Elevations more than 3 upper limit of normal were observed in 7.9% and these resolved spontaneously in 83%. The use of immunomodulators was the only factor that was significantly associated with liver enzyme abnormalities in multivariate analysis [odds ratio (OR) 2.666, 95% confidence interval (CI) 1.576-4.511, P<0.005]. Overall, 39% of patients on infliximab had elevated liver enzymes and this was associated with increased ALT before starting infliximab (OR 3.854, 95% CI 1.800-8.251, P=0.001) and with longer duration of infliximab treatment (OR 1.030, 95% CI 1.013-1.047, P=0.001). CONCLUSION: Elevated liver enzymes are frequently found in IBD patients and they usually resolve spontaneously. The use of immunomodulators was independently associated with increased ALT. Infliximab is relatively safe in terms of liver impairment and discontinuation of treatment is rarely required in the setting of modest elevations of ALT.",1
13995,27017611,"Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol","""BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60�mg/day) or allopurinol (300 or 200�mg/day). All patients started to take the study drug 24�h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61�mg�h/dL, and the 95�% confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.""",1
13996,27021239,"Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical trials in patients with moderate to severe psoriasis","""BACKGROUND: Difficult-to-treat palmoplantar psoriasis has a disproportionately negative impact on quality of life. OBJECTIVE: We evaluated the efficacy and safety of apremilast in palmoplantar psoriasis. METHODS: A post hoc analysis of data pooled from phase IIb (PSOR-005) and phase III (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1 and 2) clinical studies was conducted to determine the effect of apremilast 30 mg twice daily versus placebo at week 16 in a subset of patients with moderate to severe plaque psoriasis with active palmoplantar psoriasis (baseline Palmoplantar Psoriasis Physician Global Assessment [PPPGA] score >/=1). RESULTS: Significantly more patients taking apremilast with moderate to severe palmoplantar psoriasis (baseline PPPGA score >/=3) achieved PPPGA score 0 (clear) or 1 (almost clear) compared with placebo at week 16 (48% vs 27%; P = .021). At week 16, 46% of the apremilast group with baseline PPPGA score 1 or higher achieved a PPPGA score of 0 versus 25% of the placebo group (P < .001); 59% of the apremilast group had a PPPGA score of 0 or 1 with 1-point or more improvement versus 39% receiving placebo (P < .001). LIMITATIONS: This post hoc analysis was limited to 16 weeks and did not assess palmoplantar pustules, lesion localization, or surface area involvement. CONCLUSION: Apremilast may be a useful oral treatment option for patients with moderate to severe palmoplantar plaque psoriasis.""",1
13997,27027269,Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy,"""Poorly controlled diabetes mellitus (DM) patients sometimes show serum transaminase elevations due to steatohepatitis. However, we experienced four cases with type 1 DM with sharp elevations in serum transaminases that could not be explained by steatohepatitis alone and showed bright liver. They were diagnosed with glycogenic hepatopathy (GH) clinicopathologically. The four patients had a median age of 22.5�years (range, 19-29�years) and 12.5 (4-15)-year histories of type 1 DM and showed marked increases in serum transaminases (aspartate aminotransferase, 698�U/L [469-2763�U/L]; alanine transaminase, 255�U/L [216-956 U/L]). Diabetes mellitus control was poor and hemoglobin A1c was 12.7% (11-16.5%). Three cases had a past history of diabetic ketoacidosis. Hepatomegaly and hyperdense liver were seen on computed tomography scans. Magnetic resonance imaging showed low intensity in T2-weighted images. The pathological findings revealed pale and swollen hepatocytes and glycogenated nuclei. The architecture of the liver was preserved, and steatosis and fibrosis were mild. The cytoplasm of hepatocytes stained densely positive with periodic acid-Schiff, and the positive staining disappeared after diastase digestion, suggesting glycogen deposition. No other cause of hepatitis was evident, and the diagnosis was GH. Elevated transaminases improved within 1�month with good glycemic control. Transaminase elevations were observed several times in three cases with poor glycemic control. Glycogenic hepatopathy is rare, but extremely high serum elevations of transaminases are important to identify clinically. Despite showing a good clinical course in general, GH sometimes recurs and requires strict glycemic control. Clinicians should be aware of and recognize GH when dealing with uncontrolled DM patients.""",1
13998,27027692,In brief: Dinutuximab (Unituxin) for high-risk neuroblastoma,,1
13999,27031854,Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study,"""BACKGROUND: Taxane-containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. This study compared efficacy and tolerability of epirubicin (E)/cyclophosphamide (C) followed by docetaxel (Doc) with a dose-dense 5-fluorouracil (F)+E+ C regimen. METHODS: The ADEBAR study was a randomised phase III trial for women with primary invasive breast cancer and ?4 metastatic axillary lymph nodes (n=1364). Treatment consisted of four 21-day cycles of E plus C, followed by four 21-day cycles of Doc (EC-Doc), or six 28-day cycles of E plus F plus C (FEC120). RESULTS: Disease-free survival (DFS) was similar in the two treatment arms as shown by multivariate Cox regression adjusted for other prognostic factors (EC-Doc vs FEC120, hazard ratio (HR): 1.087; 95% confidence interval (CI): 0.878-1.346, P=0.444). In addition, there was no significant difference in overall survival (OS) between the two groups (HR: 0.974; 95% CI: 0.750-1.264, P=0.841). Haematologic toxicity was more common in FEC120 recipients; non-haematologic toxicities occurred more frequently in the EC-Doc arm. The serious adverse event rate was significantly higher in the FEC120 group (29.7% vs 22.5%). CONCLUSIONS: EC-Doc provides a feasible and effective alternative therapy option to FEC120 with a different safety profile in this high-risk breast cancer cohort.""",1
14000,27040072,Safe and successful treatment with afatinib in three postoperative non-small cell lung cancer patients with recurrences following gefitinib/erlotinib-induced hepatotoxicity,"BACKGROUND: Gefitinib and/or erlotinib-induced hepatotoxicity sometimes lead to treatment failure in EGFR mutation-positive patients with non-small cell lung cancer (NSCLC), even though the therapeutic effect is evident. CASES: Here, we report three postoperative NSCLC patients with recurrences who experienced severe hepatotoxicity while receiving gefitinib and/or erlotinib treatment but could be safely switched to afatinib treatment. CONCLUSION: Afatinib could be a well-tolerated EGFR-TKI that could be chosen for its relatively low hepatotoxicity, which is attributable to its having a different metabolic mechanism compared to other EGFR-TKIs.",1
14001,27043544,The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges,"""In 2013, physicians at the Honolulu Queen's Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS's and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be """"probable"""" for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC's questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions.""",1
14002,27056586,Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study,"""BACKGROUND: This phase 3 study further characterizes the efficacy and safety of reslizumab (a humanized anti-IL-5 monoclonal antibody) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count�? 400 cells/?L. METHODS: Patients were randomized to receive reslizumab 0.3 or 3.0�mg/kg or placebo administered once every 4�weeks for 16�weeks (total four doses). The primary end point was change from baseline in pre-bronchodilator FEV(1) over 16�weeks. Secondary end points included FVC, forced expiratory flow at 25%�to 75%�of FVC (FEF(25%-75%)), patient-reported control of asthma symptoms, short-acting ?-agonist (SABA) use, blood eosinophil levels, and safety. RESULTS: Reslizumab significantly improved FEV(1) (difference vs�placebo [reslizumab 0.3 and 3.0�mg/kg], 115�mL [95%�CI, 16-215; P�= .0237] and 160�mL [95%�CI, 60-259; P�= .0018]). Clinically meaningful increases in FVC (130�mL) and FEF(25%-75%) (233�mL/s) were observed with reslizumab 3.0�mg/kg. Reslizumab improved scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) vs�placebo (greater effects seen with 3.0�mg/kg; P�<�.05). The minimally important difference was reached for the AQLQ (reslizumab 3.0�mg/kg) but not on the ACQ. Scores on the Asthma Symptom Utility Index and SABA use were improved with reslizumab. The most common adverse events were worsening of asthma, headache, and nasopharyngitis; most events were mild to moderate in severity. CONCLUSIONS: Reslizumab improved lung function, asthma control and symptoms, and quality of life. It was well tolerated in patients with inadequately controlled asthma (despite standard therapy) and elevated blood eosinophil levels. Overall, the 3.0-mg/kg dose of reslizumab provided greater improvements in asthma outcomes vs�the 0.3-mg/kg dose, with comparable safety. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01270464; URL: www.clinicaltrials.gov.""",1
14003,27062188,Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment,"AIM: The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS: Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 ?g or 400 ?g was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS: Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-? ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with mild hepatic impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose-normalized exposure to that of subjects with moderate hepatic impairment. A 1.7-fold increase in the AUC0-? of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS: Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.",1
14004,27067394,"The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma","""BACKGROUND: The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC Outcomes with LDE225 Treatment study. OBJECTIVE: This report provides long-term follow-up data collected up to 12�months after the last patient was randomized. METHODS: In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800�mg. The primary end point was objective response rate assessed by central review. RESULTS: Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6�months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800�mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). LIMITATIONS: No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. CONCLUSION: With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.""",1
14005,27067479,"Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial","""BACKGROUND: Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment. METHODS: Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2?5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at ClinicalTrials.gov, number NCT00863681. FINDINGS: 396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0?0006, 0?0225, and 0?0191, respectively), and at follow-up (p=0?021, 0?0056, and 0?0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment. INTERPRETATION: These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations. FUNDING: Bayer Pharma AG.""",1
14006,27070596,Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics,"Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife products, Hydroxycut, LipoKinetix, UCP-1 and OxyELITE) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.",1
14007,27083334,"Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial","""BACKGROUND: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. METHODS: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. FINDINGS: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27?3 months (IQR 15?3-33?9). Progression-free survival (median 11?0 months [95% CI 10?6-12?9] with afatinib vs 10?9 months [9?1-11?5] with gefitinib; hazard ratio [HR] 0?73 [95% CI 0?57-0?95], p=0?017) and time-to-treatment failure (median 13?7 months [95% CI 11?9-15?0] with afatinib vs 11?5 months [10?1-13?1] with gefitinib; HR 0?73 [95% CI 0?58-0?92], p=0?0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. INTERPRETATION: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. FUNDING: Boehringer Ingelheim.""",1
14008,27089846,Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases,"Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68muM and 30.82muM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.",1
14009,27096888,Hedgehog Pathway Inhibitor Therapy for Locally Advanced and Metastatic Basal Cell Carcinoma: A Systematic Review and Pooled Analysis of Interventional Studies,"""IMPORTANCE: Hedgehog pathway inhibitors (HPIs) were made available by US Food and Drug Administration approval in 2012 for vismodegib and 2015 for sonidegib. Both target the Smoothened molecule and are indicated for locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma (mBCC). OBJECTIVE: To evaluate clinical experience with HPIs, including efficacy and adverse effects. DATA SOURCES: We conducted a systematic review in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EMBASE, using search terms """"vismodegib,"""" """"sonidegib,"""" """"Erivedge,"""" """"Odomza,"""" """"basal cell carcinoma,"""" and """"BCC."""" STUDY SELECTION: We included clinical trials, retrospective medical record reviews, and prospective case series that used HPIs for the treatment of laBCC or mBCC in human subjects. Individual case reports and limited, retrospective case series were excluded from our review. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by 2 reviewers on a predesigned, standardized form. MAIN OUTCOMES AND MEASURES: The following data were recorded: number of patients with laBCC or mBCC, dose and frequency of drug administration, median duration of treatment, clearance and recurrence rates, and adverse effects. RESULTS: Eleven vismodegib articles (published between 2009 and 2015) met criteria for inclusion, and 8 articles were able to be pooled for analysis. The 8 pooled articles included 744 total patients with 704 patients clinically evaluable. Sonidegib did not yield enough publications for a formal analysis. Objective response to vismodegib for laBCC had a weighted average of 64.7% (95% CI, 63.7%-65.6%); complete response averaged 31.1% (95% CI, 30.4%-31.8%). Objective response for mBCC was 33.6% (95% CI, 33.1%-34.2%); complete response averaged 3.9% (95% CI, 3.3%-4.4%). Median duration of therapy was 35.8 weeks (95% CI, 35.1-36.5 weeks). CONCLUSIONS AND RELEVANCE: In a systematic review of HPIs for laBCC and mBCC, vismodegib, but not sonidegib, had enough studies to warrant a pooled analysis. Vismodegib was identified to have a significant, consistent effect on the median duration of therapy of laBCC and mBCC. While mBCC responses are superior to any traditional approach, the response rate for laBCC might be considered in the context of other standard treatment options including surgery and radiation therapy.""",1
14010,27101211,Mifepristone (Mifeprex) label changes,,1
14011,27106510,"Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: results from a 52-week, open-label study","BACKGROUND: A T-helper (Th) cell subset Th17 preferentially produces interleukin (IL)-17 and plays a pivotal role in the pathogenesis of psoriasis. However, the pathological roles of IL-17 cascades in generalized pustular psoriasis (GPP) and psoriatic erythroderma (PsE) have not been well established. OBJECTIVES: To evaluate the efficacy and safety of brodalumab, a human immunoglobulin G2 monoclonal antibody against human IL-17-receptor A (IL-17RA), in Japanese patients with GPP and PsE. METHODS: This was an open-label, multicentre, long-term phase III study in Japanese patients with rare and severe types of psoriasis. Patients received brodalumab 140 mg at day 1 and weeks 1 and 2, and then every 2 weeks until week 52. The primary endpoint was the Clinical Global Impression of Improvement (CGI). Safety evaluations included treatment-emergent adverse events (AEs) and changes in laboratory parameters. RESULTS: A total of 12 patients with GPP and 18 with PsE were enrolled. Ten patients with GPP and 16 with PsE completed the study. At week 52 (last observation carried forward), CGI remission or improvement was achieved in 11 patients with GPP and 18 with PsE. The most commonly reported AE was nasopharyngitis (33?3%). Five serious AEs occurred during the study. However, none was considered treatment-related. CONCLUSIONS: Brodalumab significantly improved the symptoms of patients with GPP and PsE throughout the 52 weeks, and demonstrated favourable safety profiles without any new safety signals. Inhibition of IL-17RA-mediated signalling by brodalumab is expected to be a promising new treatment option for patients with GPP and PsE.",1
14012,27108694,Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research,"""Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.""",1
14013,27119237,"Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma","""BACKGROUND: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).""",1
14014,27127905,"Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials","""Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ?7), and 140 (50.2%) had creatinine clearance ?70�ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission�rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ?7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials.""",1
14015,27131079,Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG),"BRAF kinase gene V600 point mutations drive approximately 40% to 50% of all melanomas, and BRAF inhibitors (BRAFi) have been found to significantly improve survival outcomes. Although radiation therapy (RT) provides effective symptom palliation, there is a lack of toxicity and efficacy data when RT is combined with BRAFi, including vemurafenib and dabrafenib. This literature review provides a detailed analysis of potential increased dermatologic, pulmonary, neurologic, hepatic, esophageal, and bowel toxicity from the combination of BRAFi and RT for melanoma patients described in 27 publications. Despite 7 publications noting potential intracranial neurotoxicity, the rates of radionecrosis and hemorrhage from whole brain RT (WBRT), stereotactic radiosurgery (SRS), or both do not appear increased with concurrent or sequential administration of BRAFis. Almost all grade 3 dermatitis reactions occurred when RT and BRAFi were administered concurrently. Painful, disfiguring nondermatitis cutaneous reactions have been described from concurrent or sequential RT and BRAFi administration, which improved with topical steroids and time. Visceral toxicity has been reported with RT and BRAFi, with deaths possibly related to bowel perforation and liver hemorrhage. Increased severity of radiation pneumonitis with BRAFi is rare, but more concerning was a potentially related fatal pulmonary hemorrhage. Conversely, encouraging reports have described patients with leptomeningeal spread and unresectable lymphadenopathy rendered disease free from combined RT and BRAFi. Based on our review, the authors recommend holding BRAFi and/or MEK inhibitors >/=3 days before and after fractionated RT and >/=1 day before and after SRS. No fatal reactions have been described with a dose <4 Gy per fraction, and time off systemic treatment should be minimized. Future prospective data will serve to refine these recommendations.",1
14016,27141070,PARP inhibitors in ovarian cancer,"BACKGROUND: Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer. DESIGN: In the last decade, olaparib, the first and most-investigated oral PARP inhibitor, has undergone phase I-III trials as a single agent, in comparison with and in addition to chemotherapy, and as a maintenance therapy following chemotherapy. RESULTS: The greatest benefit to-date has been in the maintenance setting, prolonging the progression-free survival of high-grade serous ovarian cancer with a BRCA1/2 mutation. In this group of patients, olaparib has received approval as maintenance following chemotherapy from the EMA, and accelerated approval as a single agent in women who have had three or more lines of therapy. Olaparib can be given for a prolonged period with few significant side-effects in most patients. Similar trials with other PARP inhibitors (rucaparib, niraparib and veliparib) are in progress and include non-BRCA-mutated ovarian cancer. Second-generation studies are exploring the combination of PARP inhibitors with anti-angiogenic drugs. CONCLUSIONS: PARP inhibitors represent a step change in the management of ovarian cancer. BRCA mutations are the first genotypic predictive markers in ovarian cancer and can be used to select patients who will most likely benefit from PARP inhibitors. BRCA testing is now becoming a routine part of the evaluation of women with ovarian cancer, and tests for HRD are being used to evaluate PARP inhibitors in an extended population of non-BRCA-mutated ovarian cancer.",1
14017,27143789,Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes,"OBJECTIVE: Anakinra is approved for the treatment of RA and cryopyrin-associated periodic syndromes (CAPS). While the anakinra safety profile is well established in RA, the long-term safety profile in severe CAPS is less well documented and will therefore be discussed in this report. METHODS: A prospective, open-label, single centre, clinical cohort study was conducted at the National Institutes of Health in the USA, from 2003 to 2010, investigating the efficacy and safety of anakinra treatment for up to 5 years in 43 patients with CAPS. Safety was evaluated using adverse event (AE) reports, laboratory assessments, vital signs and diary reports. RESULTS: In total, 1233 AEs were reported during the study, with a yearly rate of 7.7 AEs per patient. The event rate decreased over time, and dose escalation during the study did not affect AE frequency. Anakinra had similar safety profiles in adults and children. The most frequently reported AEs were typical CAPS disease symptoms such as headache and arthralgia. Injection site reactions occurred mainly during the first month of anakinra treatment. In total, 14 patients experienced 24 serious AEs (SAEs), all of which resolved during the study period. The most common types of SAEs were infections such as pneumonia and gastroenteritis. There were no permanent discontinuations of treatment due to AEs. CONCLUSION: In this study anakinra treatment of patients with severe CAPS for up to 5 years was safe and well tolerated both in paediatric and adult patients, with most AEs emerging during the first months after treatment initiation. TRIAL REGISTRATION: ClincialTrials.gov, clinicaltrials.gov, NCT00069329.",1
14018,27147705,"Antithymocyte Globulin Induction Therapy in Liver Transplant: Old Drug, New Uses","OBJECTIVE: To review the use of rabbit antithymocyte globulin (rATG) induction therapy in liver transplant recipients. DATA SOURCES: A MEDLINE literature search (inception to March 2016) was conducted using the search terms rabbit antithymocyte globulin, liver transplantation, and induction References from extracted sources were further searched for any relevant, missed data sources. STUDY SELECTION AND DATA EXTRACTION: All English-language randomized and observational studies were included. DATA SYNTHESIS: A total of 9 studies were included in this review evaluating rATG's use for induction therapy. All studies were single-center analyses. rATG induction is utilized to delay calcineurin inhibitor initiation and to minimize or avoid steroids. Patients receiving rATG induction tended to have improved renal function compared with patients not receiving induction. Overall, rejection rates tended to be lower in recipients administered rATG. Regimens varied in each study, with most recipients receiving 2 to 3 doses of induction therapy. CONCLUSIONS: rATG induction therapy may lead to improved renal function and lower rejection rates following liver transplant. The use of this medication can help avoid unwanted adverse effects from other immunosuppression agents. Because of the potential benefits with this induction agent, rATG may have a larger role in induction therapy for liver transplant recipients.",1
14019,27148922,Ixekizumab (Taltz)--a second IL-17A inhibitor for psoriasis,,1
14020,27155600,Monotherapy with lanreotide depot for acromegaly: long-term clinical experience in a pituitary center,"""PURPOSE: Long-acting somatostatin analogs are one of the main classes of medical therapy used for acromegaly and most patients require ongoing treatment. Few studies have evaluated the long-term efficacy and safety of lanreotide depot beyond 2 years. The goal of this study was to provide a long-term longitudinal assessment of efficacy and safety of lanreotide depot in lanreotide responders compared to a surgically cured control group. METHODS: In this retrospective longitudinal case-control study, patients with acromegaly receiving lanreotide depot monotherapy continuously for at least 24 months (N = 24) and surgically cured patients (N = 39) were compared. Serum IGF-1, pituitary MRIs, lanreotide dose, co-morbidities and adverse effects were assessed longitudinally. RESULTS: In the lanreotide group, IGF-1 remained normal and unchanged over 6 years; comparable to the surgery only group. There was no difference in prevalence of normal IGF-1 between the lanreotide and surgery only groups at 6 months (100 vs. 97 %), 6 years (89 vs. 90 %) and at last follow-up (96 vs. 92 %). Tumor size remained stable (79 %) or decreased (21 %) in the lanreotide group. In the surgery only group, tumor size remained unchanged in all patients. Hemoglobin A1C did not differ between lanreotide and surgery only groups (baseline 5.8 vs. 6.1 %; last follow-up 6.0 vs. 5.7 %). Two (8 %) of the lanreotide and none of the surgery only group developed new diabetes mellitus. CONCLUSION: Lanreotide depot maintains normalization of IGF-1 in 89 % of responders after 6 years, comparable to surgically cured controls, and controlled tumor size in all without significant adverse effects.""",1
14021,27166295,PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis,"""OBJECTIVES: PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population. METHODS: PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were ? 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative. RESULTS: A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up. CONCLUSIONS: Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.""",1
14022,27178240,"Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study","""BACKGROUND: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. METHODS: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. FINDINGS: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12?1 months (IQR 10?1-14?2), an overall response by independent review was achieved in 85 (79?4%; 95% CI 70?5-86?6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (?5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). INTERPRETATION: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. FUNDING: AbbVie and Genentech.""",1
14023,27185843,Randomized Phase II Study of Trabectedin and Doxorubicin Compared With Doxorubicin Alone as First-Line Treatment in Patients With Advanced Soft Tissue Sarcomas: A Spanish Group for Research on Sarcoma Study,"""PURPOSE: Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients. PATIENTS AND METHODS: In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m(2) in a 3-hour infusion plus doxorubicin 60 mg/m(2) as the experimental arm and doxorubicin 75 mg/m(2) as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome. RESULTS: In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-treat analysis. The trial was stopped for futility after the interim analysis, because the results in the experimental arm showed the risk reduction for the main end point to be < 9.64%. The proportion of patients with grade 3 or 4 thrombocytopenia, asthenia, and liver toxicity was significantly higher in the experimental arm. FAS and p53 were shown to be prognostic factors for PFS (7.0 months if FAS+ and p53-; 3.4 months if FAS+/p53+ or FAS-/p53-; and 0.7 months if FAS- and p53+; P < .001) and for overall survival. CONCLUSION: Trabectedin plus doxorubicin did not show superiority over doxorubicin alone as first-line treatment of advanced STS. The prognostic role of apoptotic key genes, FAS and p53, was shown to be robust enough to continue this research line.""",1
14024,27192621,Three new drugs for multiple myeloma,,1
14025,27195797,Hepatic Safety of Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate Fixed-Dose Single-Tablet Regimen in HIV-Infected Patients with Active Hepatitis C Virus Infection: The hEPAtic Study,"""OBJECTIVES: The aim of this study was to evaluate the frequency of transaminase elevations (TE) and total bilirubin elevations (TBE) during the first year of therapy with a single tablet regimen including RPV/FTC/TDF (EPA) in HIV/hepatitis C virus (HCV)-coinfected subjects in clinical practice. METHODS: In a retrospective analysis, HIV/HCV-coinfected subjects who started EPA at 17 centres throughout Spain were included as cases. Subjects who started an antiretroviral therapy (ART) other than EPA during the study period at the same hospitals were randomly selected as controls in a 1:2 ratio. Primary outcome variables were grade (G) 3-4 TE and G4 TBE. RESULTS: Of the 519 subjects included, 173 individuals started EPA. Nine (5.2%) subjects of the EPA group and 49 (14.2%) controls were na?ve to ART. The median (Q1-Q3) follow-up was 11.2 (9.7-13.9) months. TE was observed in 2 [1.2%; 95% confidence interval (CI): 0.14%-4.1%] subjects receiving EPA and 11 (3.2%; 95%CI: 1.6%-5.6%) controls (p = 0.136), all events were G3. No patient discontinued ART due to TE. One (0.6%; 95%CI: 0.01%-3.1%) subject on EPA and 8 (2.3%; 95%CI: 1%-4.5%) subjects in the control group developed TBE (p = 0.141), without developing any other hepatic event during follow-up. Three (2.3%) subjects with cirrhosis versus 10 (3.1%) without cirrhosis showed G3-4 TE (p = 0.451). CONCLUSION: The frequency of severe liver toxicity in HIV/HCV-coinfected subjects receiving EPA under real-life conditions is very low, TE were generally mild and did not lead to drug discontinuation. All these data suggest that EPA can be safely used in this particular subpopulation.""",1
14026,27198353,LBA2_PR: Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results,,1
14027,27207107,"Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer","""BACKGROUND: SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression. PATIENTS AND METHODS: Patients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m(2) i.v., days 1 and 8) and cisplatin (75 mg/m(2) i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors. RESULTS: A total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine-cisplatin group than in the gemcitabine-cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade >/=3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%). CONCLUSIONS: In line with SQUIRE ITT, addition of necitumumab to gemcitabine-cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors. CLINICAL TRIAL: NCT00981058.""",1
14028,27216216,Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma,"The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ?2 prior therapies and a phase 2 study of patients previously treated with ?3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better.",1
14029,27221323,Brodalumab for the Treatment of Psoriasis: A Review of Phase III Trials,"""INTRODUCTION: Interleukin (IL)-17 inhibitors are the most recent class of monoclonal antibodies approved by the FDA for psoriasis treatment. Preclinical and phase II studies of brodalumab, a high-affinity IL-17 receptor monoclonal antibody, have been encouraging. METHODS: We conducted a literature search using the PubMed database in order to assess the efficacy and safety profile of brodalumab. The search included the following key words: """"psoriasis"""" and """"IL-17"""" or """"brodalumab."""" We also reviewed citations within articles to identify relevant sources. RESULTS: At week 12, the proportion of patients attaining a 75% improvement from the baseline Psoriasis Area and Severity Index (PASI 75) was similar among the three phase III trials (AMAGINE-1, 83%; AMAGINE-2, 86%; AMAGINE-3, 85%). Brodalumab remained efficacious through 52�weeks of treatment. It maintained a satisfactory safety profile; the most frequently reported adverse events consisted of nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. CONCLUSION: Use of brodalumab revealed prompt clinical improvement and a favorable short-term safety profile in phase III trials, although further extension studies are needed to assess long-term safety. Based on the results, brodalumab appears to be a potent therapeutic option for patients with moderate-to-severe plaque-type psoriasis.""",1
14030,27225799,"Arsenicosis, possibly from contaminated groundwater, associated with noncirrhotic intrahepatic portal hypertension","BACKGROUND AND AIMS: Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of the liver caused by arsenicosis from use of contaminated groundwater, was reported from Asia. This study aimed to see, if in the twenty-first century, arsenicosis was present in NCIPH patients at our hospital and, if present, to look for groundwater contamination by arsenic in their residential locality. METHODS: Twenty-seven liver biopsy proven NCIPH patients, 25 portal hypertensive controls with hepatitis B or C related cirrhosis and 25 healthy controls, matched for residential locality, were studied. Eighty-four percent to 96�% of study subjects belonged to middle or lower socioeconomic category. Arsenicosis was looked for by estimation of arsenic levels in finger/toe nails and by skin examination. Arsenic levels in nails and in ground water (in NCIPH patients with arsenicosis) was estimated by mass spectrometry. RESULTS: Nail arsenic levels were raised in five (10�%) portal hypertensive study subjects [two NCIPH patients (both had skin arsenicosis) and three portal hypertensive controls]. All of these five patients were residents of West Bengal or Bangladesh. Skin arsenicosis was noted in three NCIPH patients (11�%) compared to none of disease/healthy controls. Ground water from residential locality of one NCIPH patient with arsenicosis (from Bangladesh) showed extremely high level of arsenic (79.5�?g/L). CONCLUSIONS: Arsenicosis and microangiopathy of liver, possibly caused by environmental contamination continues in parts of Asia. Further studies are needed to understand the mechanisms of such 'poverty-linked thrombophilia'.",1
14031,27228386,Severe drug-induced liver injury related to therapy with dimethyl fumarate,,1
14032,27232660,Update on pulmonary arterial hypertension pharmacotherapy,"Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ? 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs.",1
14033,27240903,"Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-Na?ve or Previously Treated Patients With Hepatitis C Virus Genotype 1 or 3 Infections","BACKGROUND & AIMS: We performed a phase 2 trial of the efficacy and safety of 4, 6, and 8 weeks of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhibitor GS-9857, in patients with hepatitis C virus (HCV) infection. METHODS: We enrolled 161 treatment-na?ve or previously treated patients infected with HCV genotypes 1 or 3 with or without compensated cirrhosis at 2 centers in New Zealand, from September 2014 through March 2015. All patients received sofosbuvir (400 mg) and velpatasvir (100 mg) plus GS-9857 (100 mg) once daily. The primary efficacy end point was sustained virologic response at 12 weeks after therapy (SVR12). The duration of therapy was determined by baseline patient characteristics: 4 or 6 weeks for treatment-na?ve patients without cirrhosis, 6 weeks for treatment-na?ve patients with cirrhosis, and 6 or 8 weeks for treatment-experienced patients with or without cirrhosis. RESULTS: Four weeks of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in 4 of 15 (27%) treatment-na?ve patients with HCV genotype 1 without cirrhosis. Six weeks of this combination produced a SVR12 in 14 of 15 (93%) treatment-na?ve patients with HCV genotype 1 without cirrhosis, in 13 of 15 (87%) treatment-na?ve genotype 1 patients with cirrhosis, in 15 of 18 (83%) treatment-na?ve patients with HCV genotype 3 with cirrhosis, and in 20 of 30 (67%) patients with HCV genotype 1 who had failed an all-oral regimen of 2 or more direct-acting antiviral agents. Eight weeks of the drug combination produced an SVR12 in 17 of 17 (100%) patients with HCV genotype 1, in 19 of 19 (100%) patients with HCV genotype 3 and cirrhosis who had failed pegylated interferon plus ribavirin, in 25 of 28 (89%) patients with HCV genotype 1 who had failed protease inhibitor-based triple therapy, and in 4 of 4 (100%) patients�with HCV genotype 3 who had failed an all-oral regimen of ?2 direct-acting antiviral agents. The most common reported�adverse events were headache, nausea, and fatigue. CONCLUSIONS: Eight weeks of treatment with the combination of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in most treatment-na?ve or previously treated patients with HCV genotype 1 or 3 infections, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT02202980.",1
14034,27249096,Pimavanserin (Nuplazid) for Parkinson's disease psychosis,,1
14035,27260335,Venetoclax: First Global Approval,"Venetoclax (Venclexta) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.",1
14036,27262758,Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence - The ANRS CUPILT study,"""BACKGROUND & AIMS: HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy. METHODS: From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv H?patites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigator's discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment. RESULTS: The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs. CONCLUSIONS: Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence. LAY SUMMARY: The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs.""",1
14037,27269937,"Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer","""PURPOSE: To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). METHODS: A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ? 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. RESULTS: A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). CONCLUSION: Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.""",1
14038,27279544,"Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial","""BACKGROUND: Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. METHODS: In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. FINDINGS: Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18?7 months (IQR 16?1-21?1) in the cabozantinib group and 18?8 months (16?0-21?2) in the everolimus group. Median overall survival was 21?4 months (95% CI 18?7-not estimable) with cabozantinib and 16?5 months (14?7-18?8) with everolimus (hazard ratio [HR] 0?66 [95% CI 0?53-0?83]; p=0?00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0?51 [95% CI 0?41-0?62]; p<0?0001) and objective response (17% [13-22] with cabozantinib vs 3% [2-6] with everolimus; p<0?0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). INTERPRETATION: Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. FUNDING: Exelixis Inc.""",1
14039,27283860,"Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial","""BACKGROUND: BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAF(V600E)-mutant NSCLC. METHODS: In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ?18 years) with pretreated metastatic stage IV BRAF(V600E)-mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. FINDINGS: Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63?2% [95% CI 49?3-75?6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3-4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator). INTERPRETATION: Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF(V600E)-mutant NSCLC. FUNDING: GlaxoSmithKline.""",1
14040,27291995,Olaratumab in soft-tissue sarcomas,,1
14041,27295427,Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes,"""BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).""",1
14042,27299809,Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis,"""BACKGROUND: Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS: We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS: In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS: In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).""",1
14043,27302646,Effect of N-acetylcysteine on liver recovery after resection: A randomized clinical trial,"""BACKGROUND AND OBJECTIVES: Liver failure following hepatic resection is a multifactorial complication. In experimental studies, infusion of N-acetylcysteine (NAC) can minimize hepatic parenchymal injury. METHODS: Patients undergoing liver resection were randomized to postoperative care with or without NAC. No blinding was performed. Overall complication rate was the primary outcome; liver failure, length of stay, and mortality were secondary outcomes. Due to safety concerns, a premature multivariate analysis was performed and included within the model randomization to NAC, preoperative ASA, extent of resection, and intraoperative vascular occlusion as factors. RESULTS: Two hundred and six patients were randomized (110 to conventional therapy; 96 to NAC). No significant differences were noted in overall complications (32.7% and 45.7%, P?=?0.06) or hepatic failure (3.6% and 5.4%, P?=?0.537) between treatment groups. There was significantly more delirium within the NAC group (2.7% and 9.8%, P?<?0.05) that caused early trial termination. In multivariate analysis, only randomization to NAC (OR?=?2.21, 95%CI?=?1.16-4.19) and extensive resections (OR?=?2.28, 95%CI?=?1.22-4.29) were predictive of postoperative complications. CONCLUSIONS: Patients randomized to postoperative NAC received no benefit. There was a trend toward a higher rate of overall complications and a significantly higher rate of delirium in the NAC group. J. Surg. Oncol. 2016;114:446-450. ? 2016 Wiley Periodicals, Inc.""",1
14044,27311491,Once-Daily Liraglutide Versus Lixisenatide as Add-on to Metformin in Type 2 Diabetes: A 26-Week Randomized Controlled Clinical Trial,"""OBJECTIVE: To compare the efficacy and safety of liraglutide versus lixisenatide as add-on to metformin in patients with type 2 diabetes not achieving adequate glycemic control on metformin alone. RESEARCH DESIGN AND METHODS: In this 26-week, randomized, parallel-group, open-label trial, 404 patients were randomized 1:1 to liraglutide 1.8 mg or lixisenatide 20 ?g as add-on to metformin. Liraglutide was administered once daily at any time of the day. Lixisenatide was administered once daily within 1 h prior to the morning or evening meal. RESULTS: At week 26, liraglutide reduced HbA1c (primary end point) more than lixisenatide (estimated treatment difference -0.62% [95% CI -0.8; -0.4]; P < 0.0001), with more patients reaching HbA1c <7% (53 mmol/mol) and ?6.5% (48 mmol/mol) versus lixisenatide (74.2% and 54.6% for liraglutide vs. 45.5% and 26.2% for lixisenatide; P < 0.0001 for both). Liraglutide reduced fasting plasma glucose more than lixisenatide (estimated treatment difference -1.15 mmol/L [95% CI -1.5; -0.8]; P < 0.0001). Liraglutide provided greater reduction in mean 9-point self-measured plasma glucose (P < 0.0001). However, postprandial glucose increments were smaller with lixisenatide for the meal directly after injection compared with liraglutide (P < 0.05), with no differences between treatments across all meals. Both drugs promoted similar body weight decrease (-4.3 kg for liraglutide, -3.7 kg for lixisenatide; P = 0.23). The most common adverse events in both groups were gastrointestinal disorders. Greater increases in pulse, lipase, and amylase were observed with liraglutide. Hypoglycemic episodes were rare and similar between the two treatments. CONCLUSIONS: At the dose levels studied, liraglutide was more effective than lixisenatide as add-on to metformin in improving glycemic control. Body weight reductions were similar. Both treatments were well tolerated, with low risk of hypoglycemia and similar gastrointestinal adverse event profiles.""",1
14045,27318184,Safety and efficacy of mirabegron in daily clinical practice: a prospective observational study,"OBJECTIVE: To determine risks associated with prescribing mirabegron, the first-in-class ?3-adrenoreceptor agonist, to non-selected female patients with overactive bladder. STUDY DESIGN: Routine female patients seeking treatment for overactive bladder (n=221) in a urology/gynecology outpatient clinic. Data on adverse events, cardiovascular outcomes, condition specific symptoms and drug discontinuation was collected at two months follow-up (FU). Non-parametric statistics was used as appropriate. Odds ratios (ORs) with 95% confidence intervals (CIs) for outcome association analyses using logistic regression. RESULTS: 16 patients (7.2%) discontinued treatment because of side effects. There were no significant associations between cardiovascular adverse events and pre-existing cardiovascular disease (OR 0.3, 95% CI 0.3-2.6), or pre-existing ECG abnormalities (OR 2.3, 95% CI 0.3-16.3). At FU ECGs there were no de novo cases of tachyarrhythmias and no significant difference in mean QTc between baseline (403ms, SD 21.7) and the 2 months follow-up ECG (403ms, SD 20.3) (p=0.75). There was a significant decrease in the mean systolic blood pressure (p=0.03) but no significant change in mean diastolic pressure (p=0.8) or heart rates (p=0.2) from baseline to FU. Overactive bladder specific symptoms and quality of life improved significantly (p<0.001 respectively). CONCLUSIONS: Mirabegron treatment is associated with a satisfactory cardiovascular safety profile, as well as, significant symptomatic improvement also in a heterogeneous population of non-selected women with overactive bladder presenting in everyday clinical practice.",1
14046,27329484,A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis?,"Reactivation of hepatitis B virus (HBV) in HBV surface antigen (HBsAg)-positive patients treated with cytotoxic chemotherapy is well known. HBV reactivation in patients with HBV and hepatitis C virus (HCV) coinfection caused by direct-acting antiviral (DAA) therapy has also recently been reported. We report a case of acute hepatitis B in a patient with HCV infection after DAA therapy. An 83-year-old woman was referred for chronic hepatitis C. She was infected with HCV genotype 1b and negative for HBsAg at baseline. She received daclatasvir and asunaprevir therapy, and HCV became negative at 4�weeks and remained negative until 6�months after the end of DAA therapy. Acute hepatitis B developed 5�months after ending DAA therapy. Genome sequencing revealed the subgenotype as B1, and the serological subtype as adr. T118�K mutation at the S region as an immune escape mutant was identified. These virologic features led to HBV reactivation. The presence of hepatitis B core antibody or HBs antibody was not determined before DAA therapy, so prior HBV infection status was unclear. This case is speculated to represent HBV reactivation in a patient with previously resolved HBV induced by DAA therapy, based on virologic analysis and clinical status. The risk might be very low, but DAA therapy can cause HBV reactivation in chronic hepatitis C patients with prior HBV infection. When acute hepatitis emerges in patients who have received DAA therapy for HCV, HBV reactivation should be considered to allow early initiation of anti-HBV therapy.",1
14047,27348483,Ledipasvir/sofosbuvir-based treatment of patients with chronic genotype-1 HCV infection and cirrhosis: results from two Phase II studies,"""BACKGROUND: Ledipasvir/sofosbuvir ? ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis. METHODS: In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRILOGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ? ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety. RESULTS: In both studies, most patients were male (each 65%) and white (92-96%), infected with HCV genotype-1a (62-70%) and had IL28B non-CC genotypes (82-87%). In total, 37-39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRILOGY-1 (82-91%) and TRILOGY-2 (88-95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent. CONCLUSIONS: All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.""",1
14048,27358210,Long-term clinical safety and efficacy of brodalumab in the treatment of Japanese patients with moderate-to-severe plaque psoriasis,"BACKGROUND: Brodalumab (KHK4827) is a human anti-interleukin-17-receptor A monoclonal antibody. In Japanese patients with moderate-to-severe plaque psoriasis, brodalumab showed rapid and robust efficacy and a favourable safety profile in a 12-week, phase 2, double-blind, randomized controlled trial. OBJECTIVES: To evaluate the long-term safety and efficacy of brodalumab, an extension of a phase 2 trial of Japanese patients with moderate-to-severe psoriasis was performed. METHODS: Patients received open-label brodalumab 210 or 140 mg subcutaneously every 2 weeks for 52 weeks. Efficacy was measured using the Psoriasis Area and Severity Index (PASI) score and the static physician global assessment (sPGA) instrument. The endpoint of psoriatic arthritis was 20% improvement in American College of Rheumatology response criteria (ACR 20). The patients were also monitored for treatment-emergent adverse events (AEs), including serious AEs (SAEs). RESULTS: Of 145 patients, 133 completed the study. The percentage of patients with ?75% reduction of PASI scores (PASI 75), ?90% (PASI 90) and 100% (PASI 100) at Week 52 (the last observation carried forward) were 94.4%, 87.5% and 55.6%, respectively, in the 210-mg group, and the corresponding values in the 140-mg group were 78.1%, 71.2% and 43.8%. At Week 52, 75.0% patients in 210-mg group achieved ACR 20, compared with 37.5% patients in 140-mg group. The most commonly reported AEs were nasopharyngitis (35.2%), upper respiratory tract inflammation (10.3%) and contact dermatitis (9.7%). CONCLUSION: Brodalumab showed a sustained clinical response and an acceptable safety profile through 52 weeks in Japanese patients with moderate-to-severe plaque psoriasis in this open-label extension study.",1
14049,27376138,Summary and Recommendations from the National Cancer Institute's Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer,"""The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure).""",1
14050,27382098,CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers,"""PURPOSE: To determine the optimal chemotherapy backbone for testing in future US cooperative group studies for metastatic esophageal and gastroesophageal junction cancers. Cetuximab was added to each treatment arm based on promising preclinical data. PATIENTS AND METHODS: Patients with previously untreated metastatic esophageal or gastroesophageal junction cancer were randomly assigned at a one-to-one-to-one ratio to epirubicin, cisplatin, and continuous-infusion fluorouracil (ECF), irinotecan plus cisplatin (IC), or FOLFOX (oxaliplatin, leucovorin, and bolus and infusional fluorouracil). All treatment programs included cetuximab once per week. The primary end point was response rate. Secondary outcomes included overall survival, progression-free survival, time to treatment failure, and safety. As prespecified, primary and secondary analyses were conducted only among patients with adenocarcinoma. RESULTS: This study randomly assigned 245 patients, including 222 with adenocarcinoma. Among patients with adenocarcinoma, response rate was 60.9% (95% CI, 47.9 to 72.8) for ECF plus cetuximab, 45.0% (95% CI, 33.0 to 57.0) for IC plus cetuximab, and 54.3% (95% CI, 42.0 to 66.2) for FOLFOX plus cetuximab. Median overall survival was 11.6, 8.6, and 11.8 months; median progression-free survival was 7.1, 4.9, and 6.8 months; and median time to treatment failure was 5.6, 4.3, and 6.7 months for each of these arms, respectively. FOLFOX plus cetuximab required fewer treatment modifications compared with ECF plus cetuximab and IC plus cetuximab (P = .013), and fewer patients were removed from treatment because of an adverse event or experienced treatment-related death. CONCLUSION: In combination with cetuximab, ECF and FOLFOX had similar efficacy, but FOLFOX was better tolerated. Although differences were nonsignificant, IC plus cetuximab seemed to be the least effective and most toxic of the three regimens tested.""",1
14051,27396777,Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial,"""BACKGROUND: The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. METHODS: A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12�weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. RESULTS: Patients (n�= 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4�weeks received an implant device and were followed up for 12.1 ? 4.4�months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5%�upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P�< .0001). Plasma treprostinil levels at 1�week postimplantation were highly correlated with baseline levels (r�= 0.91; P�< .0001). The delivery system management time as reported by�the patients was 2.5 ? 1.7 hours per week preimplantation, and this time decreased to 0.6�? 0.8 hour per week at 6�months' postimplantation (P�< .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6�months. There were no catheter-related bloodstream infections or catheter occlusions. CONCLUSIONS: The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.""",1
14052,27403102,Resected Hepatocellular Carcinoma in a Patient with Crohn's Disease on Azathioprine,"Hepatocellular carcinoma rarely occurs in patients without underlying cirrhosis or liver disease. While inflammatory bowel disease has been linked to certain forms of liver disease, hepatocellular carcinoma is exceedingly rare in these patients. We report the twelfth case of hepatocellular carcinoma in a patient with Crohn's disease. The patient is a 61-year-old with longstanding Crohn's disease who was treated with azathioprine and was found to have elevated liver enzymes and a new 3-cm liver mass on ultrasound. A complete workup for underlying liver disease was unremarkable and liver biopsy revealed hepatocellular carcinoma. The patient underwent a hepatic resection, and there is no evidence of recurrence at the 11-month follow-up. The resection specimen showed no evidence of cancer despite the initial biopsy revealing hepatocellular carcinoma. This case represents the third biopsy-proven complete spontaneous regression of hepatocellular carcinoma. Although large studies have failed to show a definite link between azathioprine and hepatocellular carcinoma, the relationship remains concerning given the multiple case reports suggesting a possible association. Clinicians should exercise a high degree of suspicion in patients with Crohn's disease who present with elevated liver enzymes, especially those on azathioprine therapy.",1
14053,27403787,In brief: Cabozantinib (Cabometyx) for advanced renal cell carcinoma,,1
14054,27413075,"FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib","""On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.5 months and 11.2 months. In a pooled analysis of 51 patients with measurable disease in the central nervous system (CNS) at baseline, the CNS ORR was 61% (95% CI, 46-74); the CNS DOR was 9.1 months. The primary safety analysis population included 253 patients. The most common adverse reactions were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). The most common laboratory abnormalities were anemia (56%), increased aspartate aminotransferase (51%), increased alkaline phosphatase (47%), increased creatine phosphokinase (43%), hyperbilirubinemia (39%), hyperglycemia (36%), increased alanine aminotransferase (34%), and hypocalcemia (32%). Dose reductions due to adverse reactions occurred in 12% of patients, whereas 27% of patients had alectinib dosing interrupted for adverse reactions. Permanent discontinuation of alectinib due to adverse reactions occurred in only 6% of patients. With the clinically meaningful ORR and DOR as well as the safety profile observed in these trials, alectinib was determined to have a favorable benefit-risk profile for the treatment of the indicated population. Clin Cancer Res; 22(21); 5171-6. ?2016 AACR.""",1
14055,27422893,"A Phase III, Randomized, Controlled Trial of Apremilast in Patients with Psoriatic Arthritis: Results of the PALACE 2 Trial","OBJECTIVE: Apremilast, an oral phosphodiesterase 4 inhibitor, downregulates intracellular inflammatory mediator synthesis by elevating cyclic adenosine monophosphate levels. The PALACE 2 trial evaluated apremilast efficacy and safety in patients with active psoriatic arthritis (PsA) despite prior conventional disease-modifying antirheumatic drugs and/or biologic therapy. METHODS: Eligible patients were randomized (1:1:1) to placebo, apremilast 20 mg BID, or apremilast 30 mg BID. At Week 16, patients with swollen and tender joint count improvement < 20% entered early escape, with placebo patients rerandomized (1:1) to apremilast 20 mg BID or 30 mg BID while apremilast patients continued on their initial apremilast dose. At Week 24, patients remaining on placebo were rerandomized to apremilast 20 mg BID or 30 mg BID. The primary endpoint was the proportion of patients achieving > 20% improvement in American College of Rheumatology response criteria (ACR20) at Week 16. RESULTS: In the intent-to-treat population (N = 484), ACR20 at Week 16 was achieved by more patients receiving apremilast 20 mg BID [37.4% (p = 0.0002)] and 30 mg BID [32.1% (p = 0.0060)] versus placebo (18.9%). Clinically meaningful improvements in signs and symptoms of PsA, physical function, and psoriasis were observed with apremilast through Week 52. The most common adverse events were diarrhea, nausea, headache, and upper respiratory tract infection. Diarrhea and nausea generally occurred early and usually resolved spontaneously with continued treatment. Laboratory abnormalities were infrequent and transient. CONCLUSION: Apremilast demonstrated clinical improvements in PsA for up to 52 weeks, including signs and symptoms, physical function, and psoriasis. No new safety signals were observed. ClinicalTrials.gov identifier: NCT01212757.",1
14056,27427558,"Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial","""Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy in randomized controlled trials in schizophrenia. This multinational, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia; total study duration was up to 97weeks. Schizophrenia symptoms were treated/stabilized with cariprazine 3-9mg/d during 20-week open-label treatment consisting of an 8-week, flexible-dose run-in phase and a 12-week fixed-dose stabilization phase. Stable patients who completed open-label treatment could be randomized to continued cariprazine (3, 6, or 9mg/d) or placebo for double-blind treatment (up to 72weeks). The primary efficacy parameter was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, or suicidal risk); clinical measures were implemented to ensure safety in case of impending relapse. A total of 264/765 patients completed open-label treatment; 200 eligible patients were randomized to double-blind placebo (n=99) or cariprazine (n=101). Time to relapse was significantly longer in cariprazine- versus placebo-treated patients (P=.0010, log-rank test). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI]=0.45 [0.28, 0.73]). Akathisia (19.2%), insomnia (14.4%), and headache (12.0%) were reported in ?10% of patients during open-label treatment; there were no cariprazine adverse events ?10% during double-blind treatment. Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia. The long-term safety profile in this study was consistent with the safety profile observed in previous cariprazine clinical trials. ClincalTrials.gov identifier: NCT01412060.""",1
14057,27431219,Obiltoxaximab Prevents Disseminated Bacillus anthracis Infection and Improves Survival during Pre- and Postexposure Prophylaxis in Animal Models of Inhalational Anthrax,"The Centers for Disease Control and Prevention recommend adjunctive antitoxins when systemic anthrax is suspected. Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax in combination with antibiotics and for prophylaxis when alternative therapies are not available. The impact of toxin neutralization with obiltoxaximab during pre- and postexposure prophylaxis was explored, and efficacy results that supported the prophylaxis indication are presented here. New Zealand White rabbits and cynomolgus macaques received obiltoxaximab as a single intramuscular or intravenous dose of 2 to 16 mg/kg of body weight at various times relative to Bacillus anthracis aerosol spore challenge. The primary endpoint was survival, and effect of treatment timing was explored. In rabbits, obiltoxaximab administration 9 h postchallenge singly or combined with a 5-day levofloxacin regimen protected 89% to 100% of animals compared to 33% with levofloxacin monotherapy. In cynomolgus macaques, a single intramuscular dose of 16 mg/kg obiltoxaximab led to 100% survival when given 1 to 3 days preexposure and 83% to 100% survival when given 18 to 24 h postexposure and prior to systemic bacteremia onset. Obiltoxaximab administration after bacteremia onset resulted in lower (25% to 50%) survival rates reflective of treatment setting. Prophylactic administration of obiltoxaximab before spore challenge or to spore-challenged animals before systemic bacterial dissemination is efficacious in promoting survival, ameliorating toxemia, and inhibiting bacterial spread to the periphery.",1
14058,27432917,Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2,"""PURPOSE: Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy. PATIENTS AND METHODS: Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires). RESULTS: All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment. CONCLUSION: Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.""",1
14059,27457511,Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2,"""BACKGROUND: The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD). METHODS: Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5 mg three times daily); the primary endpoint was safety and tolerability. RESULTS: In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2 years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. CONCLUSIONS: Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2 years in patients with PAH-CTD. TRIAL REGISTRATION NUMBERS: PATENT-1 (NCT00810693), PATENT-2 (NCT00863681).""",1
14060,27461426,"Long-term Safety of Asenapine in Pediatric Patients Diagnosed With Bipolar I Disorder: A 50-Week Open-Label, Flexible-Dose Trial","""BACKGROUND: Sublingually administered asenapine was approved in March 2015 by the United States Food and Drug Administration for patients aged 10-17�years with an acute manic or mixed episode associated with bipolar I disorder (BP-1). This is the first long-term safety and tolerability study of asenapine in this population. METHODS: Following the 3-week randomized, double-blind, placebo-controlled trial of patients aged 10-17�years with an acute manic or mixed episode associated with BP-1, patients could enroll in this flexible-dose (2.5-10�mg twice daily) open-label extension (OLE) study for an additional 50�weeks, conducted from August 2011 to September 2014 in the United States and Russia. Treatment-emergent adverse events (TEAEs) were assessed and predefined TEAEs of interest reported in addition to metabolic and anthropometric parameters. The Young Mania Rating Scale (YMRS) and Clinical Global Impressions scale in bipolar illness (CGI-BP) were used to assess effectiveness. RESULTS: A total of 321 patients (lead-in study treatment: placebo, n�=�80; asenapine, n�=�241) were included; 267 (83.2�%) reported one or more TEAE and 181 (56.4�%) discontinued early, 48 (15.0�%) due to TEAEs. Of the predefined TEAEs of interest, combined somnolence/sedation/hypersomnia occurred most frequently (42.4�%) followed by oral hypoesthesia/dysgeusia (7.5�%). In total, 109 (34.8�%) patients experienced clinically significant weight gain (?7�% increase). No clinically meaningful changes were noted for laboratory parameters measured. Eighteen patients met the criteria for new-onset metabolic syndrome (MBS) post-baseline during the extension study, whereas 10 patients who met MBS criteria at baseline did not meet MBS criteria at endpoint. A total of 12 patients met MBS at baseline and endpoint. Mean change in YMRS total score from OLE baseline was -9.2 points at week 50, and change in CGI-BP severity overall score was similar among all treatment groups (those who initially received asenapine and those who initially received placebo). After 26�weeks of treatment in the OLE, 79.2�% of patients were classified as YMRS 50�% responders relative to acute trial baseline. CONCLUSIONS: Asenapine was generally well tolerated in pediatric patients with BP-1 during ?50�weeks of open-label treatment; among predefined TEAEs of interest, the combination of somnolence/sedation/hypersomnia was the most common. Trial�registration ClinicalTrials.gov: NCT01349907.""",1
14061,27464489,Interim analysis of post-marketing surveillance of eculizumab for paroxysmal nocturnal hemoglobinuria in Japan,"Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1�month's treatment with eculizumab (p�<�0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1�year of treatment with eculizumab (p�<�0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ?150�?�10(9)/L. Approximately 97�% of patients showed maintenance or improvement of renal function. Overall survival rate was about 90�% (median follow-up 1.9�years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.",1
14062,27466751,Venetoclax (Venclexta) for chronic lymphocytic leukemia,,1
14063,27469384,Ciprofloxacin and statin interaction: a cautionary tale of rhabdomyolysis,"A 62-year-old woman presented to hospital, on general practitioner (GP) advice, with a 15-day history of slowly progressing muscle weakness. Results showed newly deranged liver function and creatine kinase (CK) of >24 000. Prior medical history includes previous myocardial infarction and recurrent urinary tract infection. 4 days prior to symptom onset, the patient developed typical urinary tract infection symptoms, treated with ciprofloxacin. The patient had been taking simvastatin (40 mg nocte) for 13 years and had never previously taken ciprofloxacin. Initial management included intravenous crystalloid fluids and discontinuation of simvastatin. CK level fell, liver function slowly improved and renal function remained stable. Muscle weakness improved and the patient became independently able to perform activities of daily living. While the interactions between statins and other antibiotics are well documented, the interaction between statins and ciprofloxacin is less so. The consequences of this interaction can have potentially serious outcomes.",1
14064,27480090,Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation,"Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment option for myelofibrosis (MF) despite the emergence of novel targeted therapies. To reduce graft rejection and graft-versus-host disease (GvHD), current allo-HCT protocols often include in vivo T lymphocyte depletion using polyclonal anti-thymocyte globulin (ATG). Shortly after ATG administration, an immediate inflammatory response with fever, chills, and laboratory alterations such as cytopenias, elevation of serum C-reactive protein, bilirubin, and transaminases can develop. Here, we explore whether MF patients, who commonly exhibit extramedullary hematopoiesis in the liver, might be particularly susceptible to ATG-induced liver toxicity. To test this hypothesis, we analyzed 130 control and 94 MF patients from three transplant centers treated with or without ATG during the allo-HCT conditioning regimen. Indeed, hyperbilirubinemia was found in nearly every MF patient treated with ATG (MF-ATG 54/60?=?90�%) as compared to non-ATG treated MF (MF-noATG 15/34?=?44.1�%, p?<?0.001) and respectively ATG-treated non-MF patients of the control group (control-ATG, 43/77?=?56�%, p?<?0.001). In contrast, transaminases were only inconsistently elevated. Hyperbilirubinemia was in most cases self-limiting and not predictive of increased incidence of non-relapse mortality, hepatic sinusoidal obstruction syndrome (SOS) or liver GvHD. In sum, awareness of this stereotypic bilirubin elevation in MF patients treated with ATG provides a relatively benign explanation for hyperbilirubinemia occurring in these patients during the early transplant. However, attention to drug levels of biliary excreted drugs is warranted, since altered bile flow may influence their clearance and enhance toxicity (e.g., busulfan, antifungal agents).",1
14065,27481309,"A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn's Disease","OBJECTIVES: To assess the safety and efficacy of brodalumab, a human anti-interleukin-17 receptor monoclonal antibody, in patients with moderate-to-severe Crohn's disease (CD). METHODS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in patients with moderate-to-severe CD and evidence of active inflammation. Patients were randomized 1:1:1:1 to receive brodalumab (210, 350, or 700?mg at baseline and week 4) or placebo. The primary end point was proportion of patients achieving Crohn's disease activity index (CDAI) remission (?150) at week 6. Secondary end points included proportion of patients with CDAI response (reduction from baseline of ?100) at week 6 and change from baseline in CDAI at week 6. RESULTS: The study was terminated early based on an imbalance in worsening CD in active treatment groups. At the time of termination, 130 patients had been randomized. At week 6, remission rates were 3% (210?mg), 15% (350?mg), 9% (700?mg), and 3% (placebo) and CDAI response occurred in 16% (210?mg), 27% (350?mg), 15% (700?mg), and 13% (placebo) of patients. Mean change in CDAI at week 6 was -8.7 (95.3) (210?mg), -35.4 (105.6) (350?mg), -0.6 (105.9) (700?mg), and -28.2 (86.0) (placebo). Besides worsening of CD, overall incidences of adverse events were similar across treatment groups. CONCLUSIONS: Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD.",1
14066,27486034,"Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With�Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial","""BACKGROUND & AIMS: The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection. METHODS: We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among treatment-naive patients without cirrhosis, 71% (24 of�34; 95% confidence interval [CI], 53-85) achieved SVR12�after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31�of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63-93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.""",1
14067,27486112,No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection,"Postmarketing cases of hepatitis B virus (HBV) reactivation during hepatitis C treatment have been reported. We analyzed serum samples from patients in a clinical trial of ledipasvir-sofosbuvir in Taiwan and Korea. Of the 173 patients enrolled, 103 (60%) had been previously infected with HBV. None showed evidence of HBV reactivation.",1
14068,27493115,�Efficacy and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy,"""�Background and aims. Patients with intrahepatic cholestasis of pregnancy (ICP) benefit from ursodeoxycholic acid (UDCA) treatment. Since there is still certain reluctance to use UDCA in pregnant women, mainly due to warnings in the official SPC information in respective drug leaflets, our objective was to assess the efficacy and safety of UDCA during pregnancy. MATERIAL AND METHODS: Our retrospective multicentric study was performed on 191 consecutive pregnant women with ICP treated with UDCA. Any maternal and/or fetal complications of the UDCA treatment were searched for; healthy pregnant women (n = 256) served as controls. RESULTS: The UDCA treatment improved liver disease status in the majority of the affected women (86.1%). This treatment was well tolerated, with only negligible skin reactions (0.5%) and mild diarrhea (4.7%). No complications attributable to UDCA treatment were detected during the fetal life, delivery, or the early neonatal period. CONCLUSION: We confirmed the good efficacy and safety of UDCA treatment in pregnancy for both mothers and fetuses/neonates.""",1
14069,27500949,"Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A)","""BACKGROUND: The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS). OBJECTIVE: To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices. METHODS: In the first 12�weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80�kg, 80-100�kg, >100�kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160-mg initial dose at week 0, patients received subcutaneous 80-mg ixekizumab as a single injection every 2�weeks for 12�weeks. Blood samples were collected following the initial 160-mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (C(max) ) and area under the curve (AUC(0-tlast) ) where t(last) is the time of last sample (14�days�?�24�h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety. RESULTS: Of 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean C(max) (90% CI) [15.0�?g/mL (13.9-16.1) vs. 14.8�?g/mL (13.8-15.9)] and geometric mean AUC(0-tlast) (90% CI) [157�?g�?�day/mL (147-168) vs. 154�?g�?�day/mL (144-165)]. When comparing C(max) and AUC(0-tlast) of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab. CONCLUSION: The PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191.""",1
14070,27513614,Real-world efficacy and safety of daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients,"""BACKGROUND AND AIMS: Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown. METHODS: A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24?weeks of daclatasvir and asunaprevir combination therapy. Plasma concentrations of daclatasvir and asunaprevir at day 5 of treatment, end-of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed. RESULT: Plasma asunaprevir concentration was significantly higher, and daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre-treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR. CONCLUSION: Patients with compensated liver cirrhosis have similar virological response and tolerance for daclatasvir plus asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected-patients with compensated cirrhosis.""",1
14071,27517972,Arsenic trioxide intravenous infusion combined with transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with pulmonary metastasis: Long-term outcome analysis,"OBJECTIVE: To evaluate the safety, clinical efficacy, and long-term outcome of arsenic trioxide (As2 O3 ) intravenous infusion for pulmonary metastases in patients with HCC. MATERIALS AND METHODS: Sixty consecutive patients who were diagnosed with advanced hepatocellular carcinoma (HCC) with pulmonary metastasis were randomized 1:1 into the treatment and control groups. Treatment group underwent transcatheter arterial chemoembolization (TACE) for the primary liver tumor and then underwent As2 O3 treatment, whereas control group underwent TACE alone. The treatment group underwent a continuous 5-h intravenous infusion of 10 mg/day As2 O3 . The course of As2 O3 treatment was initiated 3-5 days after TACE (to allow liver and gastrointestinal function to recover) and continued for 14 consecutive days. All patients in the treatment group underwent at least four treatment courses. Response to treatment was evaluated after four treatment courses. RESULT: In treatment group, two patients had a complete response (CR), six had a partial response (PR), 10 had stable disease (SD), and 12 had progressive disease. A clinically effective rate (CR + PR) was achieved in 26.7%, and the clinical benefit rate (CR + PR + SD) was 60%. In the control group, no patients had a CR or PR, five had SD, and 25 had progressive disease. The clinically effective rate was 0%, and the clinical benefit rate was 16.7%. The overall 1-year survival was 56.7% in treatment group and 36.7% in control group. The overall 2-year survival was 16.7% in treatment group and 3.3% in control group. CONCLUSION: Transcatheter arterial chemoembolization plus an intravenous infusion of As2 O3 effectively controlled pulmonary metastasis and prolonged overall survival in patients with HCC compared with TACE alone.",1
14072,27524882,Paclitaxel plus valproic acid versus paclitaxel alone as second- or third-line therapy for advanced gastric cancer: a randomized Phase II trial,"""BACKGROUND: Weekly paclitaxel (wPTX) is the preferred second-line chemotherapy for gastric cancer in Japan. Histone deacetylase inhibitors have been shown to decrease proliferation through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One histone deacetylase inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis and enhances the efficacy of paclitaxel (PTX), shown in a murine gastric cancer model. This Phase II trial was designed to evaluate the benefits of adding VPA to wPTX in patients with gastric cancer refractory to first-line treatment with fluoropyrimidine. PATIENTS AND METHODS: The patients were randomly assigned in a 1:1 ratio to receive PTX 80 mg/m(2) intravenously on days 1, 8, and 15, every 4 weeks, or a dose of PTX plus VPA taken everyday at 7.5 mg/kg twice daily. Random assignment was carried out at the data center with a minimization method adjusted by the Eastern Cooperative Oncology Group performance status (0-1 vs 2), prior chemotherapy (first-line vs second-line), and measurable lesions (presence vs absence). The primary end point was the overall survival (OS) rate, and the secondary end points were the progression-free survival rate and safety analysis. RESULTS: Sixty-six patients were randomly assigned to receive wPTX (n=33) or wPTX plus VPA (n=33). The median OS was 9.8 months in the wPTX group and 8.7 months in the wPTX plus VPA group (hazard ratio 1.19; 95% CI 0.702-2.026; P=0.51). The median progression-free survival was 4.5 months in the wPTX group and 3.0 months in the wPTX plus VPA group (hazard ratio 1.29; 95% CI 0.753-2.211; P=0.35). Grade 3-4 adverse events were neutropenia (3.1%), pneumonia (1.6%), liver injury (1.6%), brain infarction (1.6%), and rupture of aorta (1.6%). CONCLUSION: No statistically significant difference was observed between wPTX and wPTX plus VPA for OS.""",1
14073,27532829,A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis,"""BACKGROUND: Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS: In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS: Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 ?mol per liter], respectively, vs. 0.12 mg per deciliter [2.0 ?mol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS: Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).""",1
14074,27535952,Sofosbuvir and Ledipasvir for 8 Weeks for the Treatment of Chronic Hepatitis C Virus (HCV) Infection in HCV-Monoinfected and HIV-HCV-Coinfected Individuals: Results From the German Hepatitis C Cohort (GECCO-01),"""BACKGROUND: Shortening the duration of treatment with HCV direct-acting antivirals (DAAs) leads to substantial cost reductions. According to the label, sofosbuvir and ledipasvir can be prescribed for 8 weeks (SL8) in noncirrhotic women or men with HCV genotype 1 and low viral loads. However, real-world data about the efficacy and safety of SL8 are largely missing. METHODS: Interim results from an ongoing prospective, multicenter cohort of 9 treatment centers in Germany (GECCO). All patients started on treatment with HCV DAAs since January 2014 were included. This report describes safety and efficacy outcomes in 210 patients with HCV monoinfection and 35 with human immunodeficiency virus (HIV)-HCV coinfection given SL8 in a real-world setting. RESULTS: Of 1353 patients included into the GECCO cohort until December 2015, a total of 1287 had complete data sets for this analysis; 337 (26.2%) fulfilled the criteria for SL8 according to the package insert, but only 193 (57.2%) were eventually treated for 8 weeks. Another 52 patients did not fulfill the criteria but were treated for 8 weeks. SL8 was generally well tolerated. The overall sustained virologic response rate 12 weeks after the end of treatment was 93.5% (186 of 199). The on-treatment response rate was 99.4% (159 of 160) in HCV-monoinfected and 96.4% (27 of 28) in HIV-HCV-coinfected patients. Ten patients were lost to follow-up. CONCLUSIONS: SL8 seems highly effective and safe in well-selected HCV-monoinfected and HIV-HCV-coinfected patients in a real-world setting.""",1
14075,27542322,Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial,"""BACKGROUND & AIMS: Direct-acting antiviral agents have improved treatment outcomes for patients with hepatitis C virus (HCV) infection; however, head-to-head comparisons are limited. The C-EDGE Head-2-Head Study compared the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) with sofosbuvir plus pegylated interferon/ribavirin (SOF/PR) in patients with HCV infection. METHODS: This was a randomized, open-label, phase III trial. Two hundred fifty-seven patients with HCV genotype (GT)1 or 4 infection and baseline viral load >10,000IU/ml were randomized to receive 12weeks of EBR/GZR 50mg/100mg once daily (n=129) or sofosbuvir (400mg once daily) plus PR (n=128). Primary efficacy objective was sustained virologic response 12weeks after the end of therapy (SVR12, HCV RNA <15IU/ml). The primary safety objective was the proportion of patients experiencing a tier 1 safety event. RESULTS: The majority of patients were non-cirrhotic (83.1%), treatment-na?ve (74.9%) and had HCV GT1b infection (82.0%). SVR12 rates were 99.2% (128/129) and 90.5% (114/126) in the EBR/GZR and SOF/PR groups, respectively. The estimated adjusted difference in SVR12 was 8.8% (95% confidence interval [CI], 3.6-15.3%). Because the lower bound of the 1-sided 1-sample exact test was greater than -10% and greater than zero, both non-inferiority and superiority of EBR/GZR vs. SOF/PR were established. The frequency of tier 1 safety events was lower among patients receiving EBR/GZR than SOF/PR (0.8% vs. 27.8%, between group difference, 27.0% [95% CI, -35.5% to -19.6%; p<0.001]). CONCLUSIONS: EBR/GZR has a superior efficacy and safety profile in patients with HCV GT1 or 4 infection compared with SOF/PR. LAY SUMMARY: The combination of elbasvir/grazoprevir for 12weeks was highly effective in treating patients with chronic hepatitis C, genotypes 1 or 4 infection. This regimen was more effective than sofosbuvir/pegylated interferon/ribavirin for 12weeks, and was notably superior in patients regarded as difficult to treat, including those with previous treatment failure, cirrhosis, or a high baseline viral load. The combination of elbasvir/grazoprevir also demonstrated a superior safety and tolerability profile based on fewer serious adverse events, no serious drug-related adverse events, and no treatment discontinuations. CLINICAL TRIAL REGISTRATION: Clinical trials.gov Identifier: NCT02358044.""",1
14076,27543197,Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T-cell lymphomas,"Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)-selective retinoid, were evaluated in Japanese patients with stage IIB-IVB and relapsed/refractory stage IB-IIA cutaneous T-cell lymphomas (CTCL). This study was conducted as a multicenter, open-label, historically controlled, single-arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m(2) for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m(2) in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m(2) met the response criteria using the modified severity-weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose-limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m(2) : two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m(2) bexarotene. In the 13 patients at 300 mg/m(2) , common drug-related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment-related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m(2) once daily and effective in Japanese patients with CTCL.",1
14077,27552384,A Review of Azathioprine-Associated Hepatotoxicity and Myelosuppression in Myasthenia Gravis,"OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disorder in which antibodies interfere with neuromuscular transmission. Azathioprine (AZA) is an immunosuppressant frequently used for treatment of various autoimmune conditions, including MG. The literature suggests that the rates of AZA-associated hepatotoxicity and myelosuppression in MG are highly variable. Published studies have not formally analyzed their pattern, severity, timing, and/or recovery. We assessed the prevalence, pattern and timing of AZA associated toxicity in a large group of MG patients. METHODS: We identified 113 patients with MG with AZA-associated toxicity among 571 managed with this immunosuppressant. The timing of when toxicities occurred as well as pattern of laboratory abnormalities was assessed. RESULTS: The overall prevalence of hepatotoxicity and myelosuppression was 15.2% and 9.1%, respectively. The most common pattern of hepatotoxicity seen was gamma-glutamyl transpeptidase (GGT) enzyme elevation in 67.8% of patients. Of note, 21.2% of patients with myelosuppression had normocytic anemia, 17.3% had pancytopenia, and another 17.3% developed macrocytic anemia. CONCLUSIONS: AZA-associated hepatotoxicity and myelosuppression in MG are not uncommon and may be underrecognized depending on the timing, frequency, and specific tests ordered for blood work monitoring.",1
14078,27557302,"Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma","""BACKGROUND: Daratumumab, a human IgG? monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).""",1
14079,27568215,Pharmacokinetics and Tolerability of Obiltoxaximab: A Report of 5 Healthy Volunteer Studies,"""PURPOSE: This report describes the safety, immunogenicity, and pharmacokinetic results of obiltoxaximab treatment in healthy subjects from 5 clinical trials. METHODS: Healthy men and women were enrolled in randomized, double-blind studies of obiltoxaximab versus placebo (studies 1-3), an open-label, parallel-group study of obiltoxaximab alone versus obiltoxaximab and ciprofloxacin (study 4), or a randomized, double-blind, placebo-controlled study involving administration of a second dose of obiltoxaximab 13 or 119 days after an initial dose (study 5). Obiltoxaximab was administered intravenously in all studies. The safety profile was characterized by physical examinations, including focused examinations of the skin and infusion sites; study drug infusion discontinuations; and assessment of adverse events, vital signs, electrocardiographic findings, laboratory parameters, and immunogenicity. Studies 3 to 5 were the primary safety profile studies. Pharmacokinetic parameters were calculated using noncompartmental methods. FINDINGS: Results of 2 multiple dose studies (studies 1 and 2) revealed that obiltoxaximab exposure increased proportionally. Pharmacokinetic results were consistent across studies. After administration of 16 mg/kg of obiltoxaximab, serum concentrations decreased in a biexponential or multiexponential fashion with a terminal half-life of 17 to 23 days. Mean volume of distribution was approximately 6.3 to 7.5�L, suggesting obiltoxaximab distribution outside the vascular compartment and potentially into tissues. Mean systemic clearance was approximately 0.27 L/d, suggesting that hepatic metabolism and/or renal excretion are not critical to obiltoxaximab elimination. Obiltoxaximab was generally well tolerated. Hypersensitivity reactions were the most common adverse reactions in the safety profile clinical trials, occurring in 34 of 320 subjects (10.6%) receiving obiltoxaximab and 4 of 70 subjects (5.7%) receiving placebo. The most common adverse events were headache, pruritus, upper respiratory tract infection, cough, infusion site swelling, bruising and/or pain, nasal congestion, urticaria, and extremity pain. Of the 320 subjects in the primary safety profile studies who received ?1 dose of 16 mg/kg of obiltoxaximab, 8 (2.5%) tested positive for a exposure-emergent antiobiltoxaximab response; however, quantitative titers were low (1:20-1:320). IMPLICATIONS: On the basis of consistent results of 5 clinical trials in healthy volunteers, the pharmacokinetic properties of obiltoxaximab after a 16-mg/kg IV infusion can be considered adequately characterized, a criteria of the Animal Rule. Obiltoxaximab appears to be generally well tolerated. ClinicalTrials.gov identifiers: NCT00829582, NCT01453907, NCT01929226, NCT01952444, NCT01932242.""",1
14080,27569726,"In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores","""BACKGROUND & AIMS: No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. METHODS: We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10�centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ?65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52�weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis. RESULTS: There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P�= .34). However, children receiving CBDR had significant changes in�prespecified secondary outcomes: reduced mean levels of�alanine aminotransferase (reduction, 53 ? 88 U/L vs 8 ? 77 U/L in the placebo group; P�= .02) and aspartate aminotransferase (reduction, 31 ? 52 vs 4 ? 36 U/L in the placebo group; P�= .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P�= .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P�= .005). CONCLUSIONS: In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.""",1
14081,27585384,Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting ?2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial,"""RATIONALE: Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease. OBJECTIVES: To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting ?2-agonist with or without a long-acting muscarinic antagonist (LAMA). METHODS: In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting ?2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 ?g (n?=?1,178), or placebo (n?=?1,176). Stratification was based on LAMA use. MEASUREMENTS AND MAIN RESULTS: Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; P?=?0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants. CONCLUSIONS: Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).""",1
14082,27592805,"Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial","""BACKGROUND: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. METHODS: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ?18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. FINDINGS: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10?4 months (IQR 8?6-13?1). The proportion of patients who achieved an objective response was 28 (31?8% [95?9% CI 21?9-43?1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). INTERPRETATION: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING: Merck KGaA, Darmstadt, Germany.""",1
14083,27600795,"A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Efficacy and Safety of Ethyl-Ester Omega-3 Fatty Acid in Taiwanese Hypertriglyceridemic Patients","AIM: Information regarding the effects of omega-3 fatty acid on hypertriglyceridemic patients in Chinese is still limited. This study aimed to investigate the efficacy and safety of Omacor(�), a prescription ethyl-ester omega-3 fatty acid for the treatment of hypertriglyceridemia, administered at doses of 2 g/day and 4 g/day to Taiwanese hypertriglyceridemic patients. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel study in adults with hypertriglyceridemia was conducted. After a five-week diet lead in period patients with triglycerides =200-1000 mg/dL were randomized to receive Omacor(�), a concentrated preparation of omega-3 eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) in a dose of 1 g twice daily (2 g Omacor(�)), 2 g twice daily (4 g Omacor(�)) or placebo, for eight weeks. The primary endpoint was the percentage change in triglyceride serum levels from baseline to the end of treatment. RESULTS: A total of 253 Taiwanese patients were randomized, of which 65.6% (166) were men. At the end of the treatment, the percentage change in triglyceride serum levels in both the Omacor(�) 4 g/day (?32.1%) and 2 g/day (?29.7%) groups was larger than in the placebo group (?5.4%) (p?0.001). The incidence of drug-related adverse events was as follows: 0.0%, 1.2%, and 0.0% in Omacor(�) 4 g/day, Omacor(�) 2 g/day, and placebo groups, respectively. No drug-related serious adverse events were reported during the study. CONCLUSIONS: Omacor(�) may be a feasible option to treat hypertriglyceridemia in Taiwanese patients.",1
14084,27605198,Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole,"A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug-drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins-simvastatin, atorvastatin and lovastatin-are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment.",1
14085,27614103,Nonalcoholic steatohepatitis is associated with a state of betaine-insufficiency,"BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, which includes changes in the liver methylome. Betaine plays a pivotal role in the regulation of methylogenesis. We performed a two-stage case-control study, which included patients with biopsy-proven NAFLD to explore circulating levels of betaine and its association with the histological spectrum. We also explored the association between a missense rs1805074, p.Ser646Pro variant in DMGDH (dimethylglycine dehydrogenase mitochondrial) and NAFLD severity (n=390). RESULTS: In the discovery phase (n=48), betaine levels were associated with the disease severity (P=.0030), including liver inflammation (Spearman R:-0.51, P=.001), ballooning degeneration (R: -0.50, P=.01) and fibrosis (R: -0.54, P=.0008). Betaine levels were significantly decreased in nonalcoholic steatohepatitis (NASH) in comparison with nonalcoholic fatty liver (NAFL). Further replication (n=51) showed that betaine levels were associated with advanced NAFLD (P=.0085), and patients with NASH had a 1.26-fold decrease in betaine levels compared with those with NAFL. The rs1805074 was significantly associated with the disease severity (P=.011). CONCLUSION: NAFLD severity is associated with a state of betaine-insufficiency.",1
14086,27617661,"Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial","""BACKGROUND: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm). METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years' follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided ? of 0?95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545. FINDINGS: Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0?73 [95% CI 0?55-0?96]; nominal p=0?025, which did not meet the required threshold for statistical significance [p<0?0095]; median overall survival was 29?8 months [95% CI 26?9-35?7] for those treated with olaparib vs 27?8 months [24?9-33?7] for those treated with placebo), and in patients with BRCAm (HR 0?62 [95% CI 0?41-0?94] nominal p=0?025; 34?9 months [95% CI 29?2-54?6] vs 30?2 months [23?1-40?7]). The overall survival data in patients with BRCA wild-type were HR 0?83 (95% CI 0?55-1?24, nominal p=0?37; 24?5 months [19?8-35?0] for those treated with olaparib vs 26?6 months [23?1-32?5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment. INTERPRETATION: Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer. FUNDING: AstraZeneca.""",1
14087,27622858,Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients,"""BACKGROUND & AIMS: We report the first real-life results of the sofosbuvir+daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients. METHODS: The France REcherche Nord&Sud Sida-hiv H?patites (ANRS) CO22 HEPATHER """"Therapeutic options for hepatitis B and C: A French cohort"""" is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n=768) with a HCV genotype 1 who initiated sofosbuvir (400mg/day) and daclatasvir (60mg/day) before October 1st 2014, with or without ribavirin (1-1.2g/day) for a duration of 12weeks or 24weeks. The main endpoint criterion was sustained virological response at 12weeks (SVR12), defined by the absence of detectable HCV-RNA 12weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n=45), otherwise considered as virological failure (n=18). RESULTS: A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir+daclatasvir) to 99% (24-week sofosbuvir+daclatasvir+ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p=0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p=0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p=0.0054). CONCLUSION: The sofosbuvir+daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12weeks in non-cirrhotic and 24weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact. LAY SUMMARY: The sofosbuvir+daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir+daclatasvir combination seems to be 12weeks in non-cirrhotic patients and 24weeks for those with cirrhosis. Clinical trial number: NCT01953458.""",1
14088,27637899,Detection of Primary T Cell Responses to Drugs and Chemicals in HLA-Typed Volunteers: Implications for the Prediction of Drug Immunogenicity,"""A number of serious adverse drug reactions are caused by T cells. An association with HLA alleles has been identified with certain reactions, which makes it difficult to develop standardized preclinical tests to predict chemical liability. We have recently developed a T cell priming assay using the drug metabolite nitroso sulfamethoxazole (SMX-NO). We now report on reproducibility of the assay, establishment of a biobank of PBMC from 1000 HLA-typed volunteers, and generation of antigen-specific responses to a panel of compounds. Forty T cell priming assays were performed with SMX-NO; 5 gave weak responses (1.5-1.9) and 34 showed good (SI 2.0-3.9) or strong responses (SI ?> 4.0) using readouts for proliferation and cytokine release. Thus, SMX-NO can be used as a model reagent for in vitro T cell activation. Good to strong responses were also generated to haptenic compounds (amoxicillin, piperacillin and Bandrowski's base) that are not associated with an HLA risk allele. Furthermore, responses were detected to carbamazepine (in HLA-B*15:02 donors), flucloxacillin (in 1 HLA-B*57:01 donor) and oxypurinol (in HLA-B*58:01 donors), which are associated with HLA-class I-restricted forms of hypersensitivity. In contrast, na?ve T cell priming to ximelagatran, lumiracoxib, and lapatinib (HLA-class II-restricted forms of hypersensitivity) yielded negative results. Abacavir, which activates memory T cells in patients, did not activate na?ve T cells from HLA-B*57:01 donors. This work shows that the priming assay can be used to assess primary T cell responses to drugs and to study mechanisms T cell priming for drugs that display HLA class I restriction. Additional studies are required to investigate HLA-class II-restricted reactions.""",1
14089,27648552,Azathioprine and 6-Mercaptopurine-induced Liver Injury: Clinical Features and Outcomes,"""OBJECTIVE: The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines. BACKGROUND: Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist. METHODS: Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed. RESULTS: Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset. CONCLUSIONS: Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.""",1
14090,27651407,Apixaban-induced liver injury,"An 81-year-old woman with well-controlled hypertension presented to the emergency department with new-onset atrial fibrillation with rapid ventricular response. Treatment for atrial fibrillation was initiated, including rate control and anticoagulation with 5 mg of apixaban two times per day for primary stroke prophylaxis. Three days after initiation of apixaban, the patient noted new-onset abdominal pain, worsening shortness of breath and weakness. Laboratory results showed elevated liver enzymes. Workup for elevated transaminase did not reveal any underlying infectious or autoimmune process. Apixaban, a probable cause for the hepatocellular injury, was discontinued and replaced with intravenous unfractionated heparin to bridge anticoagulation with warfarin. The patient's symptoms resolved as her transaminases improved by discontinuation of apixaban. We illustrate this case of drug-induced hepatotoxicity secondary to treatment with apixaban. It is important for physicians to be aware of this rare adverse effect caused by a widely used novel oral anticoagulant.",1
14091,27658762,Efficacy and safety of canakinumab in Schnitzler syndrome: A�multicenter randomized placebo-controlled study,"BACKGROUND: Schnitzler syndrome is an adult-onset autoinflammatory disease characterized by urticarial exanthema and monoclonal gammopathy accompanied by systemic symptoms such as fever, bone, and muscle pain. Up to now, approved treatment options are not available. OBJECTIVE: We assessed effects of the anti-IL-1? mAb canakinumab on the clinical signs and symptoms of Schnitzler syndrome. METHODS: In this phase II, randomized placebo-controlled multicenter study, 20 patients with active disease enrolled in 4 German study centers. Patients were randomly assigned to receive single subcutaneous canakinumab 150�mg or placebo injections for 7�days, followed by a 16-week open-label phase with canakinumab injections on confirmed relapse of symptoms. The primary end point was the proportion of patients with complete clinical response evaluated by physician global assessment at day 7. Key secondary end points included changes in patient-reported disease activity (Schnitzler activity score), inflammation markers (C-reactive protein and serum amyloid A), and quality-of-life assessments (Dermatology Life Quality Index and 36-item short form health survey). RESULTS: The proportion of patients with complete clinical response at day 7 was significantly higher (P�=�.001) in the canakinumab-treated group (n�=�5 of 7) than in the placebo group (n�=�0 of 13). Levels of inflammation markers C-reactive protein and serum amyloid A�and quality-of-life scores were significantly reduced in canakinumab-treated but not in placebo-treated individuals. Positive effects continued up to 16�weeks. Adverse events were manageable and included respiratory tract infections, gastrointestinal symptoms, and hypertension. CONCLUSIONS: In this first placebo-controlled study, canakinumab was effective in patients with Schnitzler syndrome, and thus canakinumab may be further evaluated as a therapeutic option for this rare disease.",1
14092,27661862,Ombitasvir-Paritaprevir-Ritonavir-Dasabuvir (Viekira Pak)-Induced Lactic Acidosis,"OBJECTIVE: To report a case series of three patients with hepatitis C virus infection who all presented with severe type B lactic acidosis shortly after starting treatment with ombitasvir-paritaprevir-ritonavir-dasabuvir. DESIGN: Case series. SETTING: ICU. PATIENTS: Three patients, all who had HCV cirrhosis with mild hepatic impairment (Child-Pugh A) and had started taking ombitasvir-paritaprevir-ritonavir-dasabuvir within the preceding 2 weeks, presented with similar nonspecific symptoms of lethargy, fatigue, and nausea. All had elevated lactate levels at admission without evidence of hypovolemia, cardiogenic failure, or vasodilatory shock. INTERVENTIONS: All patients were given appropriate supportive intensive care for what was initially suspected to be sepsis, including a minimum of 30 mL/kg of IV fluids, infectious workup including blood cultures, broad-spectrum antibiotics, and mechanical ventilatory support. The first patient received continuous veno-venous hemofiltration. The second patient received hemodialysis. The third patient was initially started on hemodialysis despite high norepinephrine requirements and ultimately transitioned to continuous veno-venous hemofiltration. MEASUREMENTS AND MAIN RESULTS: The first patient died despite maximal intensive care. The second patient improved immediately upon starting hemodialysis and was extubated within 48 hours and discharged home. The third patient eventually became hypotensive and was treated with repeated sessions of renal replacement therapy. He ultimately was extubated and discharged home. The infectious workup was negative for all three patients, and antibiotics were discontinued after 2 days in the second and third patients. CONCLUSIONS: Ombitasvir-paritaprevir-ritonavir-dasabuvir may cause type B lactic acidosis. Further study is warranted to identify risk factors and elucidate the mechanisms of excessive lactate production.",1
14093,27677775,Liver injury from herbal and dietary supplements,"""Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).""",1
14094,27695622,Mirabegron in overactive bladder patients: efficacy review and update on drug safety,"Overactive bladder is a common condition, which significantly affects people's quality of life. The use of anticholinergic medication has been the mainstay of managing overactive bladder when conservative measures are not enough. Many patients stop anticholinergic medication because of the side effects and more recently the concerns about the effect of an anticholinergic burden and the development of dementia have been studied. Activation of ?3 adrenoceptors has been shown to relax the detrusor muscle and subsequently lead to the development of the first ?3 adrenoceptor agonist. Mirabegron is the first drug in this class to be approved for the use in overactive bladder. It has been extensively studied in phase II and III trials and has significant improvement in key overactive bladder parameters when compared with placebo. The incidence of side effects such as constipation, hypertension and tachycardia were comparable to anticholinergic medication but there was significantly less dry mouth incidence in the mirabegron groups. Mirabegron has been shown to be used safely in combination with solifenacin and tamsulosin. Head-to-head studies comparing efficacy and safety of mirabegron with anticholinergic medication would further help in the management strategy for overactive bladder.",1
14095,27701080,Cobimetinib,"OBJECTIVE: To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation. DATA SOURCES: A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016. STUDY SELECTION AND DATA EXTRACTION: The literature search was confined to human studies published in English. Trials of cobimetinib for melanoma were prioritized. DATA SYNTHESIS: Cobimetinib is a reversible inhibitor of MEK1 and MEK2. Its FDA approval was based on a phase III, randomized trial of vemurafenib monotherapy (n = 248) or vemurafenib and cobimetinib (n = 247) in unresectable stage IIIC or IV melanoma with a BRAFV600 mutation. Cobimetinib was administered as 60 mg orally daily for 21 days/7 days off, whereas vemurafenib was administered as 960 mg twice daily. Vemurafenib and cobimetinib were associated with an objective response rate of 68%, and median progression-free survival of 9.9 months. The overall survival was not reached at the time of first interim analysis. Clinically relevant grade ?3 adverse events were diarrhea (6%), rash (6%), photosensitivity (2%), elevated liver function tests (LFTs) (8%-12%), increased creatine kinase (11%), and retinal detachment (3%). CONCLUSION: Cobimetinib combined with vemurafenib is an alternative BRAF/MEK inhibitor therapy for unresectable or metastatic melanoma with BRAFV600 mutation. The role of cobimetinib in melanoma and other solid tumors is likely to expand as the results from ongoing studies become available.",1
14096,27705267,"Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma","""BACKGROUND: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. RESULTS: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10(5) white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. CONCLUSIONS: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).""",1
14097,27717303,"Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer","""BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29?10(-5). RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29?10(-6) for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).""",1
14098,27726163,"Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J)","""Psoriasis, a chronic, immune-mediated skin disease characterized by red, scaly plaques, affects approximately 0.3% of the population in Japan. The aim of this open-label study was to evaluate the long-term efficacy and safety of ixekizumab, a humanized, anti-interleukin-17A monoclonal antibody, in Japanese patients with plaque psoriasis (n = 78, including 11 psoriatic arthritis), erythrodermic psoriasis (n = 8) and generalized pustular psoriasis (n = 5). Ixekizumab was administrated s.c. at baseline (week 0, 160 mg), from weeks 2 to 12 (80 mg every 2 weeks), and from weeks 16 to 52 (80 mg every 4 weeks). At week 52, 92.3% of patients with plaque psoriasis achieved Psoriasis Area and Severity Index (PASI) 75, 80.8% achieved PASI 90, 48.7% achieved PASI 100, and 52.6% had remission of plaques (by static Physician Global Assessment, sPGA [0]). Difficult to treat areas of psoriasis (nail or scalp) also responded to ixekizumab. All patients with psoriatic arthritis who were assessed (5/5) achieved an American College of Rheumatology 20 response. Most patients with erythrodermic psoriasis or generalized pustular psoriasis responded to ixekizumab and the clinical outcome was maintained over 52 weeks (75% and 60% of patients achieved sPGA [0, 1] at week 52, respectively). Mostly mild or moderate treatment-emergent adverse events were reported by 79 of 91 patients; the most common were nasopharyngitis, eczema, seborrheic dermatitis, urticaria and injection site reactions. In conclusion, 52-week ixekizumab treatment was efficacious and well tolerated in Japanese patients with plaque psoriasis. Efficacy was also observed in patients with erythrodermic psoriasis, generalized pustular psoriasis and psoriatic arthritis.""",1
14099,27742338,Drug-Induced Lung Injury in a Liver Transplant Patient Treated With Sofosbuvir,"New direct-acting antivirals (DAAs) have dramatically improved sustained virologic response (SVR) rates in patients treated for chronic hepatitis C. Although the safety of these agents has been very good in registration trials, unexpected side effects have been reported after much broader use of DAAs on marketing. We retrospectively examined all liver transplant recipients with chronic hepatitis C that received sofosbuvir-based regimens at our clinic. A total of 24 liver transplant recipients with recurrent chronic hepatitis C had received sofosbuvir up to April 2015. Regimens were as follows: sofosbuvir+simeprevir (8), SOF+ledipasvir (6), sofosbuvir+daclatasvir (5) and sofosbuvir+ribavirin (5). Overall, treatment was very well tolerated with only mild adverse events in 42% of patients. However, a 52-year-old woman developed severe respiratory failure within 10 days after beginning sofosbuvir+daclatasvir. High-resolution computerized tomography showed areas of diffused ground-glass opacities in both lungs, suggesting drug-induced lung injury. The bronchoalveolar lavage showed marked signs of acute inflammation without recovering any infectious agent. The patient was treated with high-dose corticosteroids and steadily recovered. DAA therapy was not discontinued, but sofosbuvir was replaced by simeprevir. She reached sustained virologic response after completing 24 weeks of DAA therapy. Given the close temporal association, radiologic and bronchoalveolar lavage findings, and negative work-up for infectious agents, we postulated that sofosbuvir was the most likely explanation for drug-induced lung injury in our patient.",1
14100,27745994,Effects of granulocyte-colony stimulating factor (G-CSF) on stem cell mobilization in patients with liver failure,,1
14101,27755511,In brief: Hepatitis B reactivation with direct-acting antiviral drugs for hepatitis C,,1
14102,27766916,A real-world risk analysis of biological treatment (adalimumab and etanercept) in a country with a high prevalence of tuberculosis and chronic liver disease: a nationwide population-based study,"OBJECTIVES: Few studies on tumour necrosis factor (TNF) inhibitor-associated tuberculosis (TB) and hepatic events have been performed in regions where these risks are elevated. This study aimed to provide a direct comparison between adalimumab and etanercept in a high-risk population and to address the implications for physicians working with patients in such an environment. METHOD: Data collected from the National Health Insurance Research Database (NHIRD) in Taiwan between 2007 and 2011 were analysed retrospectively for incidences of eight adverse events associated with TNF-alpha inhibitors. Hazard ratios (HRs) of adalimumab vs. etanercept were calculated using a Cox proportional hazards model. RESULTS: During this 5-year period, 86 events of TB were reported after 5317 person-years of exposure to adalimumab (1.62 events per 100 person-years), compared to 44 events after 7690 person-years of exposure to etanercept (0.57 events per 100 person-years). For serious hepatic events that led to hospitalization, 0.75 events were reported per 100 person-years of exposure to adalimumab compared to 0.39 events per 100 person-years of exposure to etanercept. Adjusted HRs for TB [aHR 3.06, 95% confidence interval (CI) 2.09-4.49, p < 0.0001], hospitalization due to a hepatic event (aHR 2.05, 95% CI 1.27-3.30, p = 0.0035), and serious infection (aHR 1.48, 95% CI 1.19-1.84, p = 0.0005) attained significance. CONCLUSIONS: TNF-alpha-targeting therapies with the monoclonal antibody adalimumab confers significant added risk of TB and serious hepatic events compared to therapies with the soluble fusion protein etanercept. Tailored strategies to attenuate these risks are warranted in high-risk regions such as Taiwan.",1
14103,27773786,Monoclonal antibody therapy for the treatment of asthma and chronic obstructive pulmonary disease with eosinophilic inflammation,"""Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala� (mepolizumab; anti-interleukin [IL]-5) and Cinquair� (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils.""",1
14104,27798749,A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study,"""PURPOSE: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC). METHODS: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360�mg/m(2) doxorubicin or equivalent were allowed. Left ventricular ejection fraction of�>50�% was required. Patients received PLD 50�mg/m(2) every 28�days or capecitabine 1250�mg/m(2) twice daily for 14�days every 21�days. The primary endpoint was time-to-disease progression (TTP). RESULTS: 210 patients were randomized (n�=�105, PLD and n�=�105, capecitabine). Adjuvant anthracyclines were given to 37�% (PLD) and 36�% (capecitabine) of patients. No significant difference was observed in TTP [HR�=�1.21 (95�% confidence interval, 0.838-1.750)]. Median TTP was 6.0�months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P�=�0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3�months vs. 26.8�months) and time-to-treatment failure (median, 4.6�months vs. 3.7�months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P�=�0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8�%; P�=�0.31). CONCLUSION: Both PLD and capecitabine are effective first-line agents for MBC.""",1
14105,27805836,Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR,"""RATIONALE: Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients. OBJECTIVES: In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR. METHODS: Patients (N?=?58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications. MEASUREMENTS AND MAIN RESULTS: Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n?=?1; rash, n?=?1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV(1) were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P?=?0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P?<?0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P?<?0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P?=?0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N(2) concentration (-0.88; 95% CI, -1.40 to -0.37; P?=?0.0018). CONCLUSIONS: Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).""",1
14106,27815858,A retrospective study of azacitidine treatment in patients with intermediate-2 or high risk myelodysplastic syndromes in a real-world clinical setting in Greece,"For patients with intermediate-2 or high risk [according to the International Prognostic Scoring System (IPSS)] myelodysplastic syndromes (MDS), azacitidine treatment offers hematologic improvement (HI) but also has the potential to modify the natural disease course. 'RETRO-AZA-MDS-001', a retrospective chart review study was conducted from February to November 2012 across 17 hematology hospital sites of Greece, aiming to evaluate the clinical efficacy and safety profile of azacitidine in IPSS intermediate-2/high risk adult MDS patients in routine care. A total of 88 patients (median age 74.7�years), with a 6.6�month median (range 1.0-49.5) azacitidine treatment duration were enrolled. The overall response rate [complete response (CR), marrow CR and partial response] was 37.7% (23/61), while stable disease with HI was achieved by 21.3% (13/61). The HI rate was 33.0�% (29/88) and the AML transformation rate 6.8% (6/88). Of the transfusion-dependent patients, 7.3% (3/41) became transfusion-independent during azacitidine treatment. The incidence of non-serious and serious adverse events related to azacitidine was 50.0 and 42.0%, respectively. Patients not receiving prior ESA therapy were expected to be 7.6 times more likely to achieve a clinical response (p�=�0.012). The study corroborates the favorable risk-benefit profile of azacitidine for intermediate-2/high risk MDS patients in routine clinical practice.",1
14107,27825636,"Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial","""BACKGROUND: RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. METHODS: We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day. The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET-rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508. FINDINGS: Between July 13, 2012, and April 30, 2016, 26 patients with RET-rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12-49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events. INTERPRETATION: The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment. FUNDING: Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748.""",1
14108,27833376,Transarterial chemoembolization with drug-eluting beads in hepatocellular carcinoma,"Transarterial chemoembolization (TACE) is a widely used standard treatment for patients with hepatocellular carcinoma (HCC) who are not suitable candidates for curative treatments. The rationale for TACE is that intra-arterial chemotherapy using lipiodol and chemotherapeutic agents, followed by selective vascular embolization, results in a strong cytotoxic effect as well as ischemia (conventional TACE). Recently, drug-eluting beads (DC Beads(�)) have been developed for transcatheter treatment of HCC to deliver higher doses of the chemotherapeutic agent and to prolong contact time with the tumor. DC Beads(�) can actively sequester doxorubicin hydrochloride from solution and release it in a controlled sustained fashion. Treatment with DC Beads(�) substantially reduced the amount of chemotherapeutic agent that reached the systemic circulation compared with conventional, lipiodol-based regimens, significantly reducing drug-related adverse events. In this article, we describe the treatment response, survival, and safety of TACE used with drug-eluting beads for the treatment of HCC and discuss future therapeutic possibilities.",1
14109,27836529,Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project,"""We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-na?ve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-na?ve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate na?ve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.""",1
14110,27842767,Drug Hepatotoxicity: Newer Agents,"Idiosyncratic hepatotoxicity is one of the most common reasons for an approved drug being restricted. This article focuses on hepatotoxicity of selected and recently introduced agents, such as, tyrosine kinase inhibitors, monoclonal antibodies, novel oral anticoagulants, newer antiplatelets, antibiotics, anti-diabetics, anti-epileptics, anti-depressants, anti-psychotics and anti-retrovirals. Overall, the incidence of clinically relevant hepatotoxicity from newer agents seems to be lower than that of the older agents. Nevertheless, cases of severe hepatotoxicity have been reported due to some of these newer agents, including, trastuzumab, ipilimumab, infliximab, imatinib, bosutinib, dasatinib, gefitinib, erlotinib, sunitinib, ponatinib, lapatinib, vemurafenib, dabigatran, rivaroxaban, felbamate, lamotrigine, levetiracetam, venlafaxine, duloxetine, darunavir, and maraviroc.",1
14111,27847886,"Leishmaniasis revisited: Current aspects on epidemiology, diagnosis and treatment","Leishmaniasis is a vector-borne disease caused by protozoan parasites of the genus Leishmania. It is transmitted by phlebotomine female sand flies of the genera Phlebotomus and Lutzomyia in the old and new world, respectively. More than 20 well-recognized Leishmania species are known to infect humans and cause visceral (VL), cutaneous (CL) and mucocutaneous (ML) forms of the disease. Approximately 350 million people are at risk of contracting the disease and an estimated 1.6 million new cases occur annually. The disease mainly affects poor people in Africa, Asia and Latin America, and is associated with malnutrition, population migration, poor residency conditions, frail immune system and lack of resources. Previously, diagnosis of leishmaniasis relied mainly on invasive techniques of detecting parasites in splenic and bone marrow aspirates. Nevertheless, serological tests using the recombinant kinesin antigen (rK39) and molecular methods (polymerase chain reaction) are considered the best options for diagnosis today, despite problems related to varying sensitivities and specificities and field adaptability. Therapy of leishmaniasis ranges from local treatment of cutaneous lesions to systemic often toxic, therapy for disseminated CL, ML and VL. Agents with efficacy against leishmaniasis include amphotericin B, pentavalent antimonial drugs, paromomycin and miltefosine. No single therapy of VL currently offers satisfactory efficacy along with safety. This article provides a brief and updated systematic review on the epidemiology, diagnosis and treatment of this neglected disease.",1
14112,27856432,"Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial","""OBJECTIVES: To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response. METHODS: MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200?mg every 2?weeks (q2w)) or adalimumab (40?mg q2w) monotherapy for 24?weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24. RESULTS: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p?0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences. CONCLUSIONS: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects. TRIAL REGISTRATION NUMBER: NCT02332590.""",1
14113,27860410,Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors,"""OBJECTIVE: To evaluate the efficacy and safety of sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with active moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response or intolerance to anti-tumor necrosis factor (anti-TNF) therapy. METHODS: Patients were randomly allocated to receive sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks for 24 weeks with background conventional synthetic DMARDs. The co-primary end points were the proportion of patients achieving a response according to the American College of Rheumatology 20% criteria for improvement (ACR20) at week 24, and change from baseline in the Health Assessment Questionnaire disability index (HAQ DI) at week 12. Each sarilumab dose was evaluated against placebo; differences between the 2 sarilumab doses were not assessed. RESULTS: The baseline characteristics of the treatment groups were similar. The ACR20 response rate at week 24 was significantly higher with sarilumab 150 mg and sarilumab 200 mg every 2 weeks compared with placebo (55.8%, 60.9%, and 33.7%, respectively; P?<?0.0001). The mean change from baseline in the HAQ DI score at week 12 was significantly greater for sarilumab (least squares mean change: for 150 mg, -0.46 [P?=?0.0007]; for 200 mg, -0.47 [P?=?0.0004]) versus placebo (-0.26). Infections were the most frequently reported treatment-emergent adverse events. Serious infections occurred in 1.1%, 0.6%, and 1.1% of patients receiving placebo, sarilumab 150 mg, and sarilumab 200 mg, respectively. Laboratory abnormalities included decreased absolute neutrophil count and increased transaminase levels in both sarilumab groups compared with placebo. In this study, reductions in the absolute neutrophil count were not associated with an increased incidence of infections or serious infections. CONCLUSION: Sarilumab 150 mg and sarilumab 200 mg every 2 weeks plus conventional synthetic DMARDs improved the signs and symptoms of RA and physical function in patients with an inadequate response or intolerance to anti-TNF agents. Safety data were consistent with interleukin-6 receptor blockade and the known safety profile of sarilumab.""",1
14114,27888600,[Darunavir/cobicistat monotherapy. Experience in a tertiary hospital],"""OBJECTIVE: Ritonavir-boosted protease inhibitor (IP/r) monotherapy: darunavir/ritonavir (DRV/r) or lopinavir/ritonavir (LPV/r) monotherapy is only provided in the major treatment guidelines in pretreated patients to prevent toxicity associated with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), reduce costs and simplify antiretroviral treatment. To start IP/r monotherapy, according to GESIDA guidelines 2016, patients need to meet the following criteria: absence of chronic hepatitis B, plasma viral load <50 copies/ mL for at least 6 months and absence of protease inhibitors mutations or previous virologic failures to IP/r. Currently, there are no studies that evaluate the efficacy and safety of darunavir/cobicistat (DRV/COBI) monotherapy. METHODS: This prospective study analyzed pretreated HIV patients with DRV/r monotherapy that were switched to DRV/COBI monotherapy. The aim of the study is to describe the effectiveness and safety of the DRV/COBI monotherapy. RESULTS: Seventy-eight patients were evaluated. Patients had a median of 31.29 months of DRV/r monotherapy before DRV/COBI monotherapy. Nine of the 78 patients developed """"blips"""" (plasma viral load: 50-200 copies/ml) and four patients had plasma viral load ?200 copies/mL. An 83.3% (65/78) of the patients remained with undetectable plasma viral load. As for safety, there were no significant differences in lipid profile, liver function (transaminases) and renal function between DRV/r and DRV/COBI monotherapy. CONCLUSIONS: DRV/COBI monotherapy seems to be effective and safe (lipid profile, liver and kidney function). However, it will be necessary to design specific studies comparing DRV/r vs DRV/COBI monotherapy to confirm these results.""",1
14115,27893170,Safety profiles of iron chelators in young patients with haemoglobinopathies,"BACKGROUND: This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies. METHODS: Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions. RESULTS: Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies. CONCLUSION: Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.",1
14116,27895330,FDA approves antitoxin antibody,,1
14117,27898234,Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR,"RATIONALE: In a prior study, lumacaftor/ivacaftor treatment (?28 d) in patients with cystic fibrosis (CF) heterozygous for F508del-CFTR did not improve lung function. OBJECTIVES: To evaluate an optimized lumacaftor/ivacaftor dosing regimen with a longer duration in a cohort of patients heterozygous for F508del-CFTR. METHODS: Patients aged 18 years or older with a confirmed CF diagnosis and percent predicted FEV(1) (ppFEV(1)) of 40 to 90 were randomized to lumacaftor/ivacaftor (400 mg/250 mg every 12 h) or placebo daily for 56 days. Primary outcomes were change in ppFEV(1) at Day 56 and safety. Other disease markers were evaluated. MEASUREMENTS AND MAIN RESULTS: Of 126 patients, 119 (94.4%) completed the study. Lumacaftor/ivacaftor was well tolerated, although chest tightness and dyspnea occurred more frequently with active treatment than with placebo (27.4% vs. 14.3% and 14.5% vs. 6.3%, respectively). Mean (SD) ppFEV(1) values at baseline were 62.9 (14.3) in the active treatment group and 60.1 (14.0) in the placebo group. Absolute changes in ppFEV(1) (least squares mean [SE]) at Day 56 were -0.6 (0.8) percentage points in the active treatment group and -1.2 (0.8) percentage points in the placebo group (P?=?0.60). CF respiratory symptom scores in the active treatment group improved by a mean of 5.7 points versus a decrease of -0.8 in the placebo group (P?<?0.01). No changes in body mass index occurred. Changes from baseline in sweat chloride (least squares mean [SE]) at Day 56 were -11.8 (1.3) mmol/L in the active treatment group and -0.8 (1.2) mmol/L in the placebo group (P?<?0.0001). CONCLUSIONS: Sweat chloride and respiratory symptom scores improved with lumacaftor/ivacaftor, though no meaningful benefit was seen in ppFEV(1) or body mass index in patients heterozygous for F508del-CFTR. Clinical trial registered with www.clinicaltrials.gov (NCT01225211).",1
14118,27912207,Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials,"""BACKGROUND: Evidence of the clinical safety of endothelin receptor antagonists (ERAs) is limited and derived mainly from individual trials; therefore, we conducted a meta-analysis. METHODS AND RESULTS: After systematic searches of the Medline, Embase, and Cochrane Library databases and the ClinicalTrials.gov website, randomized controlled trials with patients receiving ERAs (bosentan, macitentan, or ambrisentan) in at least 1 treatment group were included. All reported adverse events of ERAs were evaluated. Summary relative risks and 95% CIs were calculated using random- or fixed-effects models according to between-study heterogeneity. In total, 24 randomized trials including 4894 patients met the inclusion criteria. Meta-analysis showed that the incidence of abnormal liver function (7.91% versus 2.84%; risk ratio [RR] 2.38, 95% CI 1.36-4.18), peripheral edema (14.36% versus 9.68%; RR 1.44, 95% CI 1.20-1.74), and anemia (6.23% versus 2.44%; RR 2.69, 95% CI 1.78-4.07) was significantly higher in the ERA group compared with placebo. In comparisons of individual ERAs with placebo, bosentan (RR 3.78, 95% CI 2.42-5.91) but not macitentan (RR 1.17, 95% CI 0.42-3.31) significantly increased the risk of abnormal liver function, whereas ambrisentan (RR 0.06, 95% CI 0.01-0.45) significantly decreased that risk. Bosentan (RR 1.47, 95% CI 1.06-2.03) and ambrisentan (RR 2.02, 95% CI 1.40-2.91) but not macitentan (RR 1.08, 95% CI 0.81-1.46) significantly increased the risk of peripheral edema. Bosentan (RR 3.09, 95% CI 1.52-6.30) and macitentan (RR 2.63, 95% CI 1.54-4.47) but not ambrisentan (RR 1.30, 95% CI 0.20-8.48) significantly increased the risk of anemia. ERAs were not found to increase other reported adverse events compared with placebo. CONCLUSIONS: The present meta-analysis showed that the main adverse effects of treatment with ERAs were hepatic transaminitis (bosentan), peripheral edema (bosentan and ambrisentan), and anemia (bosentan and macitentan).""",1
14119,27922029,Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea,"""OBJECTIVES: Eluxadoline is a mixed mu-opioid receptor (OR) and kappa-OR agonist and delta-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events. RESULTS: 2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were five events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use. CONCLUSIONS: Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association.""",1
14120,27935168,Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort,"""Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24�weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75?10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.""",1
14121,27959700,Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer,"""BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).""",1
14122,27973926,Drug-induced liver injury: a cohort study on patients referred to the Danish transplant center over a five year period,"OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors of poor outcome. MATERIALS AND METHODS: We identified all patients diagnosed with DILI at the Department of Hepatology, Rigshospitalet, from March 2007 to November 2012. The following parameters were registered from patient files: drug causing DILI, symptoms, comorbidity, biochemistry, treatment and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent biochemical findings included bilirubin elevated to above 3.2 x ULN, ALT elevated to above 9 x ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome.",1
14123,27981315,"A Case of Acute Liver Failure during Ritonavir-Boosted Paritaprevir, Ombitasvir and Dasabuvir Therapy in a Patient with HCV Genotype 1b Cirrhosis","BACKGROUND: Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin is one of the current recommended therapies for HCV genotype 1b monoinfected patients in compensated (Child-Pugh A) cirrhosis. Whether it is known that the worsening of liver function is a rare but possible complication of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir therapy, to our knowledge no description of treatment-related acute liver failure is available in the literature. CASE PRESENTATION: An 84-year-old Caucasian man with chronic compensated HCV genotype 1b cirrhosis received Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy. After 13 days he developed grade 4 hyperbilirubinaemia and ascites. Even though treatment was promptly stopped, patient's clinical condition worsened, and he underwent hospitalization, several paracentheses, and developed sub-acute kidney injury. The bilirubinemia returned under three times the upper normal limit only after five months. Notably, he achieved sustained virological response despite the very short duration of therapy. CONCLUSION: Hepatic decompensation and acute liver failure are rare but severe complications of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy in patients with compensated cirrhosis. Close monitoring for signs or symptoms of worsening of liver disease is mandatory, and further research for stratifying risk factors are required.",1
14124,27993813,High incidence of interstitial lung disease following practical use of osimertinib in patients who had undergone immediate prior nivolumab therapy,,1
14125,28007626,"Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non-Small Cell Lung Cancer","INTRODUCTION: Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment. METHODS: We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI. RESULTS: Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs. CONCLUSIONS: EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.",1
14126,28011037,"Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study","""BACKGROUND: The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. METHODS: PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV(1) (ppFEV(1)) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. FINDINGS: Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV(1) was 0?5 (95% CI -0?4 to 1?5) at extension week 72 and 0?5 (-0?7 to 1?6) at extension week 96; change in BMI was 0?69 (0?56 to 0?81) at extension week 72 and 0?96 (0?81 to 1?11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0?65, 0?56 to 0?75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV(1) decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1?33, -1?80 to -0?85 vs -2?29, -2?56 to -2?03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. INTERPRETATION: The long-term safety profile of lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV(1) decline than in matched registry controls. FUNDING: Vertex Pharmaceuticals Incorporated.""",1
14127,28017537,Human leukocyte antigen and idiosyncratic adverse drug reactions,"A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis. T-cells from carbamazepine SJS/TEN patients are activated by direct pharmacological interaction between carbamazepine and HLA-B*15:02 expressed on antigen presenting cells (APCs). Abacavir-specific, HLA-B*57:01-restricted T-cells are activated by APCs presenting peptides which are only displayed by the HLA molecule when abacavir is bound during peptide loading. Finally, HLA-B*57:01-restricted activation of T-cells from patients with flucloxacillin-induced liver injury is dependent on processing of drug protein adducts. Based on these observations, it is now possible to utilize blood from healthy drug-na?ve volunteers to study the priming of na?ve T-cells to drugs. Future development of these methodologies may lead to the development of assays that predict intrinsic immunogenicity of drugs and chemicals at the preclinical stage of drug development.",1
14128,28026833,Antiviral drugs for seasonal influenza 2016-2017,,1
14129,28044114,Viekira Pak Induced Fatal Lactic Acidosis: A Case Report of an Unusual Side Effect,"Viekira Pak is a new direct-acting antiviral agent that has an excellent efficacy in treating patients with chronic HCV. FDA released a safety warning that Viekira Pak can cause serious liver injury mostly in patients with underlying advanced liver disease. We report the first case of fatal lactic acidosis presenting 3 days after initiating therapy with Viekira Pak. Although it is very hard to precisely determine the cause of lactic acidosis, our case highlights an unusual side effect that ensued after starting the medication. Given the complexity of drug-drug interactions that can happen with the new direct-acting antiviral agents and the paucity of data regarding coadministration and methods of monitoring, a thorough review should be pursued prior to initiating these medications.",1
14130,28057799,Prospective study of oral anticoagulants and risk of liver injury in patients with atrial fibrillation,"OBJECTIVE: To assess the risk of liver injury hospitalisation in patients with atrial fibrillation (AF) after initiation of direct oral anticoagulants (DOACs) or warfarin and to determine predictors of liver injury hospitalisation in this population. METHODS: We studied 113 717 patients (mean age 70, 39% women) with AF included in the MarketScan Commercial and Medicare Supplemental databases with a first prescription for oral anticoagulation after 4 November 2011, followed through 31 December 2014. Of these, 56 879 initiated warfarin, 17 286 initiated dabigatran, 30 347 initiated rivaroxaban and 9205 initiated apixaban. Liver injury hospitalisation and comorbidities were identified from healthcare claims. RESULTS: During a median follow-up of 12 months, 960 hospitalisations with liver injury were identified. Rates of liver injury hospitalisation (per 1000 person-years) by oral anticoagulant were 9.0 (warfarin), 4.0 (dabigatran), 6.6 (rivaroxaban) and 5.6 (apixaban). After multivariable adjustment, liver injury hospitalisation rates were lower in initiators of DOACs compared with warfarin: HR (95% CI) of 0.57 (0.46 to 0.71), 0.88 (0.75 to 1.03) and 0.70 (0.50 to 0.97) for initiators of dabigatran, rivaroxaban, and apixaban, respectively (vs. warfarin). Compared with dabigatran initiators, rivaroxaban initiators had a 56% increased risk of liver injury hospitalisation (HR 1.56, 95% CI 1.22 to 1.99). In addition to type of anticoagulant, prior liver, gallbladder and kidney disease, cancer, anaemia, heart failure and alcoholism significantly predicted liver injury hospitalisation. A predictive model including these variables had adequate discriminative ability (C-statistic 0.67, 95% CI 0.64 to 0.70). CONCLUSIONS: Among patients with non-valvular AF, DOACs were associated with lower risk of liver injury hospitalisation compared with warfarin, with dabigatran showing the lowest risk.",1
14131,28071678,Multiple myeloma in 2016: Fresh perspectives on treatment and moments of clarity,,1
14132,28076339,Drugs for type 2 diabetes,,1
14133,28089635,Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study,"""BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m(2) in month 1 and 500 mg/m(2) in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. FINDINGS: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. INTERPRETATION: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. FUNDING: AbbVie Inc and Genentech Inc.""",1
14134,28093797,Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system,"AIMS: Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS: Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO-Vigibase was also queried. RESULTS: From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase. CONCLUSIONS: The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.",1
14135,28104973,Unusual Case of an Alcoholic with Liver Injury from Sulfasalazine Use,"A 57-year-old male with a history of alcoholism presented to the emergency room with abdominal pain, jaundice, transaminitis, and hyperbilirubinemia. Due to the history of alcoholism, it was initially presumed that the patient had alcoholic hepatitis but further investigation revealed that he was recently started on sulfasalazine for the treatment of rheumatoid arthritis. Upon cessation of the drug, the patient's liver function tests significantly improved over a few days and eventually normalized within weeks. This case was interesting as the patient's history of alcoholism disguised the actual diagnosis. Furthermore, the late presentation of sulfasalazine-induced liver injury is uncommon as it commonly presents 2-4 weeks after initiation of therapy.",1
14136,28116908,Osimertinib for the treatment of non-small cell lung cancer,"The T790�M mutation of the epidermal growth factor receptor (EGFR) gene is the most common mechanism underlying resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR TKI, shows robust clinical efficacy in patients with T790�M-mutated lung cancer. Areas covered: We analyzed and reviewed clinical data for which patients who experienced acquired resistance to first- or second-generation EGFR TKIs. In addition, we briefly reviewed the potential role of osimertinib as a first-line therapy. Expert opinion: Osimertinib was recently licensed for use in NSCLC patients with acquired resistance to other EGFR TKIs due to a T790�M mutation. However, unresolved issues surrounding the optimal application of osimertinib remain, specifically the development of a plasma-based mutation test to overcome the difficulty of repeat biopsy, the efficacy of osimertinib for brain or leptomeningeal metastases, the development of resistance to osimertinib, and the use of osimertinib therapy as a first-line treatment. Many ongoing studies are currently exploring these issues.",1
14137,28118533,"Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study","""OBJECTIVE: To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE). METHODS: Patients with moderate-to-severe SLE (score of >/=8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results. RESULTS: Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA-SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25-2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35-0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by >/=25% (to </=7.5 mg/day) during weeks 40-52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95-2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by >/=2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo. CONCLUSION: In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.""",1
14138,28121498,Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection,"""BACKGROUND: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS: In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).""",1
14139,28122572,Artemether-lumefantrine and liver enzyme abnormalities in non-severe Plasmodium falciparum malaria in returned travellers: a retrospective comparative study with quinine-doxycycline in a Portuguese centre,"BACKGROUND: Artemisinin-based therapy is the current standard treatment for non-severe malaria due to Plasmodium falciparum. The potential for asymptomatic liver toxicity of this therapy and its implication in clinical practice is currently unknown. The aim of this study is to assess the hepatic function in patients treated with a standard three-day artemisinin-based regimen and to compare it with the quinine-doxycycline regimen. METHODS: Retrospective and comparative study of returned adult travellers admitted with non-severe P. falciparum malaria. Fifty-seven patients were included: 19 treated with artemisinin-based therapy and 38 with quinine-doxycycline therapy. RESULTS: During treatment, when compared with quinine-doxycycline group, the artemisinin-lumefantrine group presented a higher proportion of significant liver enzyme abnormalities (42 vs. 5%, p�<�0.01) and a higher peak value of aspartate aminotransferase (131 vs. 64 U/L, p�<�0.01) and alanine aminotransferase (99 vs. 75�U/L, p�=�0.05). None of the patients was symptomatic, there were no treatment interruptions and all patients achieved clinical cure. CONCLUSIONS: Treatment of uncomplicated falciparum malaria with artemisinin-based therapy might cause asymptomatic liver enzyme abnormalities in the first days of treatment. Nevertheless, these liver enzyme abnormalities seem to be harmless, asymptomatic and self-limited.",1
14140,28126860,Colchicine in overdose,,1
14141,28185672,"Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial","""BACKGROUND: Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms. METHODS: In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4?5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36. FINDINGS: Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4?2 mg (SD 0?6) for cariprazine and 3?8 mg (0?4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8?90 points for cariprazine vs -7?44 points for risperidone; least squares mean difference -1?46, 95% CI -2?39 to -0?53; p=0?0022; effect size 0?31). One patient in the risperidone group died of a cause regarded as unrelated to treatment. INTERPRETATION: Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia. FUNDING: Gedeon Richter Plc.""",1
14142,28189751,"Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort","BACKGROUND & AIMS: Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS: Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV?ribavirin (RBV) (n=1567) or LDV/SOF?RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS: The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV?RBV and 95.8% with LDV/SOF?RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV?RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV?RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS: In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY: In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.",1
14143,28220020,Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer,"""BACKGROUND: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer. METHODS: Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m(2) orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM?+?CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR?+ CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics. RESULTS: Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM?+?CAP, 7.3 (6.3-13.0) weeks on ICR?+?CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p?=?.1315, RAM?+?CAP versus CAP; 1.480, p?=?.0851, ICR?+ CAP versus CAP). Median OS was 67.4 weeks on RAM?+?CAP, 62.1 weeks on ICR?+?CAP, and 71.6 weeks on CAP (HRs: 1.833, p?=?.0283, RAM?+?CAP versus CAP; 1.468, p?=?.1550, ICR?+ CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ?10%) on RAM?+?CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ?10%) on ICR?+?CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea. CONCLUSION: Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.""",1
14144,28221264,Efficacy and Safety of Combined Oral Chelation With Deferiprone and Deferasirox in Children With ?-Thalassemia Major: An Experience From North India,"""OBJECTIVE: A combination of desferrioxamine with either deferiprone (DFP) or deferasirox (DFX) for patients with ?-thalassemia major who do not achieve negative iron balance with monotherapy has been studied widely. However, poor compliance resulting from the need for parentral administration of desferrioxamine and its cost necessicitates combining 2 oral chelators. METHODS: A prospective study was conducted in patients with transfusion-dependent ?-thalassemia major in a tertiary care center over 2 years. Patients on either DFP or DFX who were not improving on monotherapy over a long period and persistently maintaining serum ferritin >2500 ?g/L were enrolled. Efficacy was assessed by serum ferritin levels assessed at 12 months and 2 years. Complete blood counts and liver and kidney function tests were monitored to assess the safety of the combination of drugs. RESULTS: In total, 33 patients with a mean age of 12.67 years (7.5 to 17.5 y) and a mean ferritin of 4835.2394?1443.85 ?g/L formed the study cohort.In total, 28 patients completed the 1-year study period; and 12 patients completed 2 years. Mean serum ferritin reduction at 1 and 2 years was 34.99%?18.13% (range, -34.36% to 56.17%) and 44.67%?13.78% (range, 22.17% to 62.74%), respectively. The combination therapy was well tolerated. CONCLUSIONS: Combined oral chelation with DFP and DFX has better efficacy than either drug used alone. The combination of drugs was well tolerated and no new adverse effects were observed.""",1
14145,28221867,Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component,"""Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ? 3, < 1%) and rash (grouped terms; 40%; grade ? 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.""",1
14146,28230928,Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis B virus infection treated with direct acting antivirals,"BACKGROUND AND AIM: Hepatitis B virus (HBV) may reactivate when treating chronic hepatitis C (CHC) with direct acting antivirals (DAA). We aim to investigate the risk of HBV reactivation during DAA therapy. METHODS: Chronic hepatitis C patients receiving pan-oral DAA therapy from December 2013 to August 2016 were evaluated. Fifty-seven patients that had a past HBV infection (negative hepatitis B surface antigen [HBsAg] and positive hepatitis B core antibody) and seven patients that had a current HBV infection (positive HBsAg) were enrolled. Serum HBV and hepatitis C virus (HCV) markers were regularly measured. The endpoints were the HCV sustained virological response (SVR) and the HBV virological/clinical reactivation. RESULTS: The overall SVR(12) rate was 96.9%, and two patients, one with positive HBsAg, had a relapse of HCV. No episodes of HBV virological reactivation were observed among the patients with a past HBV infection. For the seven patients with a current HBV infection, HBV virological reactivation was found in four (57.1%) of the seven patients. Clinical reactivation of HBV was observed in one patient with pretreatment detectable HBV DNA and recovered after entecavir administration. For the other three patients with HBV virological reactivation, the reappearance of low level HBV DNA without clinical reactivation was observed. HBsAg levels demonstrated only small fluctuations in all the patients. CONCLUSIONS: There was a minimal impact of hepatitis B core antibody seropositivity on HCV efficacy and safety. For CHC patients with current HBV infection, the risk of HBV reactivation was present, and monitoring the HBV DNA level during therapy is warranted.",1
14147,28249141,Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia,"""BACKGROUND: Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. METHODS: In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. RESULTS: Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. CONCLUSIONS: Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).""",1
14148,28249893,FDA Drug Approval: Elotuzumab in Combination with Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma,"""On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR). The key secondary endpoint was overall survival, but these data were not mature at the time of clinical database cutoff. The trial demonstrated a statistically significant improvement in PFS, with an estimated HR of 0.70 for E-Ld over Ld [95% confidence interval (CI), 0.57-0.85; P = 0.0004). Estimated median PFS was 19.4 months in the E-Ld arm and 14.9 months in the Ld arm. ORR was 75.8% in the E-Ld arm compared with 65.5% in the Ld arm. Serious adverse reactions were reported in 65% of patients in the E-Ld arm compared with 57% in the Ld arm. The FDA approved elotuzumab with the following warnings and precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with the determination of complete response. Clin Cancer Res; 23(22); 6759-63. (c)2017 AACR.""",1
14149,28257550,Tolerability of Switch to Macitentan from Bosentan in Pulmonary Arterial Hypertension,"OBJECTIVES: Pulmonary arterial hypertension (PAH) is a progressive disease that can be treated with several medications. Macitentan, an endothelin receptor antagonist (ERA), has received approval as a PAH therapy. We report our data regarding the tolerability in patients with PAH who were switched from bosentan to macitentan. METHODS: At the Baylor Pulmonary Hypertension Program, 24 patients with PAH who had been taking bosentan and were switched to macitentan were identified in this retrospective study. Data from these patients who switched from bosentan 125 mg orally twice per day to macitentan 10 mg orally daily (between October 2013 and February 2015) when macitentan became commercially available were collected. Patients were advised to take their last evening dose of bosentan and then take the first dose of macitentan the following morning within 12 to 24 hours of the last bosentan dose. Baseline data and postswitch data, including 6-minute walk distance, brain naturietic peptide, alanine transaminase (ALT) and aspartate transaminase (AST) levels, World Health Organization Functional Class (WHO FC), Borg dyspnea score, presence of peripheral edema. RESULTS: At the time of the switch, the mean age was 58 ? 13 (mean ? standard deviation) years, the duration of disease was 6.6 ? 4.4 years, 21 patients were women, 54% were white, and 25% had idiopathic PAH. The mean duration of follow-up after the switch was 5.7 ? 1.5 months. The 6-minute walk distance was 344 ? 106 m preswitch and 319 ? 85 m postswitch (P = 0.18). Brain naturietic peptide levels were 91 ? 170 pg/mL preswitch and 90 ? 137 pg/mL postswitch (P = 0.93). At the time of the switch, 42% were WHO FC II and 50% had edema, and 55% had edema. AST and ALT remained unchanged postswitch. Two patients did not tolerate the switch to macitentan and had to be returned to bosentan: one patient with portopulmonary hypertension developed elevated AST and ALT and the second patient's macitentan was stopped because of malaise and tachyarrhythmia. One patient who underwent a successful liver transplant had macitentan stopped following the transplant. CONCLUSIONS: A rapid switch from bosentan to macitentan was well tolerated and safe with maintained WHO FC, with no significant change in edema and liver enzyme levels. The switch from bosentan to macitentan eliminates the need for monthly liver function test monitoring and removes the potential for bosentan treatment interruption.",1
14150,28267814,Safety after extended repeated use of ulipristal acetate for uterine fibroids,"OBJECTIVE: To assess long term safety of extended repeated 3-month courses of ulipristal acetate (UPA) 10 mg/day, for up to 8 courses, with focus on endometrial and laboratory safety parameters. METHODS: This long-term, multi-center, open-label cohort, follow up study consisted of up to 8 consecutive 3-month courses of daily UPA 10 mg, each separated by a drug free period of 2 spontaneous menstrual bleeds. Sixty-four pre-menopausal women, with moderate to severe symptomatic uterine myoma(s) and heavy bleeding were enrolled and were studied for approximately 4 years. The main outcome measures were endometrial histology, laboratory parameters and general safety. RESULTS: All data was reported in a descriptive manner with no formal statistical comparisons. In the 64 women, non-physiological changes (mostly cyst formation, epithelial and vascular changes) in endometrial histology at screening and after treatment courses 4 and 8 were observed in 18.0%, 21.4% and 16.3% of biopsies, respectively. After treatment cessation, such changes were observed in 9.1% of biopsies. All endometrial biopsies were benign after course 8. The median endometrial thickness was 7.0 mm, 10-18 days after the start of menses following treatment courses 5-8, compared to 9.0 mm at screening (before UPA treatment). No changes in the number and type of laboratory results outside the normal ranges were observed with the increasing treatment courses. In total, adverse events were reported in 10 (16%), 12 (19%), 8 (14%) and 5 (9%) subjects, during treatment courses 5, 6, 7 and 8, respectively of which the most frequent adverse events were headache and hot flush. CONCLUSION: The results of this study further support the safety profile of extended repeated 3 months treatment of symptomatic fibroids with ulipristal acetate 10 mg/day. Repeated UPA treatment courses did not result in any changes of concern in endometrial histology, endometrial thickness, or laboratory safety measures.",1
14151,28290137,Sarilumab: First Global Approval,"Sarilumab (Kevzara�) is a fully human IgG1 monoclonal antibody that binds specifically to both soluble and membrane-bound interleukin (IL)-6 receptors (sIL-6R? and mIL-6R?) and thereby inhibits IL-6-mediated signalling through these receptors. Subcutaneous sarilumab is approved in Canada for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biological or non-biological disease-modifying anti-rheumatic drugs. It is under regulatory review for use in rheumatoid arthritis in other countries, including in the EU, USA and Japan. Sarilumab is also under phase II investigation for the treatment of juvenile idiopathic arthritis. This article summarizes the milestones in the development of sarilumab leading to its first global approval for the treatment of rheumatoid arthritis.",1
14152,28296163,Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST),"""BACKGROUND: Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. PROCEDURE: Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. RESULTS: In total, 267 patients (mean age 3.2 years) predominantly with beta-thalassemia (n = 176, 65.9%) were enrolled. Mean +/- standard deviation deferasirox dose was 25.8 +/- 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (>/=7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. CONCLUSIONS: Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.""",1
14153,28319159,Drug therapy for alcohol dependence in primary care in the UK: A Clinical Practice Research Datalink study,"""AIM: To evaluate drug therapy for alcohol dependence in the 12 months after first diagnosis in UK primary care. DESIGN: Open cohort study. SETTING: General practices contributing data to the UK Clinical Practice Research Database. PARTICIPANTS: 39,980 people with an incident diagnosis of alcohol dependence aged 16 years or older between 1 January 1990 and 31 December 2013. MAIN OUTCOME MEASURE: Use of pharmacotherapy (acamprosate, disulfiram, naltrexone, baclofen and topiramate) to promote abstinence from alcohol or reduce drinking to safe levels in the first 12 months after a recorded diagnosis of alcohol dependence. FINDINGS: Only 4,677 (11.7%) of the cohort received relevant pharmacotherapy in the 12 months following diagnosis. Of the 35,303 that did not receive pharmacotherapy, 3,255 (9.2%) received psychosocial support. The remaining 32,048 (80.2%) did not receive either mode of treatment in the first 12 months. Factors that independently reduced the likelihood of receiving pharmacotherapy included: being male (Odds Ratio [OR] 0.74; 95% CI 0.69 to 0.78); older (65-74 years: OR 0.61; 95% CI 0.49 to 0.77); being from a practice based in the most deprived quintile (OR 0.58; 95% CI 0.53 to 0.64); and being located in Northern Ireland (OR 0.78; 95% CI 0.67 to 0.91). The median duration to initiation of pharmacotherapy was 0.80 months (95% CI 0.70 to 1.00) for acamprosate and 0.60 months (95% CI 0.43 to 0.73) for disulfiram. Persistence analysis for those receiving acamprosate and disulfiram revealed that many patients never received a repeat prescription; persistence at 6 months was 27.7% for acomprosate and 33.2% for disulfiram. The median duration of therapy was 2.10 months (95% CI 1.87 to 2.53) for acamprosate and 3.13 months (95% CI 2.77 to 3.36) for disulfiram. CONCLUSION: Drug therapy to promote abstinence in alcohol dependent patients was low, with the majority of patients receiving no therapy, either psychological or pharmacological. When drug therapy was prescribed, persistence was low with most patients receiving only one prescription. Our data show that treatment for alcohol dependence is haphazard, and there is an urgent need to explore strategies for improving clinical management of this patient group.""",1
14154,28329471,First report of mesalamine (5-aminosalicylic acid) as the causative agent in a case of acute generalized exanthamous pustulosis,"""Acute generalized exanthamous pustulosis (AGEP)is a rare eruption of non-follicular sterile pustuleson a diffuse background of erythema and edema,commonly associated with fever and leukocytosis.Antibiotics are implicated in most cases; however,other drugs have been reported to cause AGEP. Wereport a case of a 73-year-old man with a historyof ulcerative colitis who presented with a diffusepustular rash, renal failure, elevated liver functiontests, and leukocytosis with neutrophilia. A week priorto admission, the patient was started on mesalamineto treat colitis. Upon admission, a workup includinga skin biopsy was performed and was consistentwith AGEP. Mesalamine was discontinued, and thepatient's skin eruption, renal function, liver functiontests, and leukocytosis subsequently improved.Mesalamine has an unknown mechanism of action.However, it is thought to be an anti-inflammatoryagent that blocks the production of leukotrienesand prostaglandins and is an immunosuppressantthat increases the release of adenosine, whichinterferes with leukocyte function. The decrease inprostaglandin synthesis or deregulation of leukocytefunction caused by mesalamine may be the etiologyin this case. Discontinuation of the offending agentleads to resolution of AGEP, as it did in this patient.""",1
14155,28338123,Potential pitfalls of Viekira Pak therapy in patients with HCV genotype 1b cirrhosis,,1
14156,28361290,Efficacy and safety of atazanavir/ritonavir-based antiretroviral therapy for HIV-1 infected subjects: a systematic review and meta-analysis,"Atazanavir (ATZ) is a well-tolerated protease inhibitor that can be boosted with ritonavir (r) to treat infection with resistant strains of human immunodeficiency virus 1 (HIV-1). The aim of this meta-analysis was to compare the efficacy, safety, and metabolic effects of ATZ/r regimen versus commonly used antiretroviral drugs such as lopinavir (LPV) and darunavir (DRV) in HIV-1-infected patients. We searched PubMed, Scopus, Embase and Cochrane CENTRAL, using relevant keywords. Data were extracted from eligible randomized trials and pooled as risk ratios (RR) or standardized mean differences (SMD) in a meta-analysis model using RevMan software. Nine randomized controlled trials (RCTs) (3292 patients) were eligible for the final analysis. After 96 weeks of treatment, the pooled effect estimate did not favor either ATZ/r or LPV/r in terms of virological failure rate (RR 1.11, 95% CI [0.74, 1.66]). However, ATZ/r was marginally superior to LPV/r in terms of increasing the proportion of patients with HIV RNA <50 copies/ml (RR 1.09, 95% CI [1.01, 1.17]). The pooled effect estimate did not favor ATZ/r over DRV/r regarding the change in plasma levels of total cholesterol, triglycerides, or high-density lipoprotein at 24, 48, and 96 weeks. Moreover, no significant difference was found between the two regimens (ATZ/r and DRV/r) in terms of change in visceral (SMD -0.06, 95%CI [-0.33, 0.21]) or subcutaneous adipose tissue (SMD 0.12, 95% CI [-0.15, 0.39]). The ATZ/r regimen was generally as effective and well-tolerated as the LPV/r regimen for the treatment of HIV-1 patients. Compared to the DRV/r regimen, ATZ/r has no favorable effect on the plasma lipid profile or adipose tissue distribution.",1
14157,28373005,"Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial","""BACKGROUND: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). METHODS: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. FINDINGS: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8?8 months (IQR 7?2-11?9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (?3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. INTERPRETATION: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. FUNDING: Merck KGaA and Pfizer.""",1
14158,28373007,"Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial","""BACKGROUND: Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. METHODS: This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3?+?3 cohort design and assigned patients sequentially at trial entry according to the 3?+?3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. FINDINGS: Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3?9-4?1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. INTERPRETATION: Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. FUNDING: National Cancer Institute and Merck KGaA.""",1
14159,28379592,Severe hepatocytotoxicity linked to denosumab,"OBJECTIVE: Denosumab (Prolia, Amgen, Thousand Oaks, CA, USA) is a fully human antibody to the receptor activator of nuclear factor-KB ligand (RANKL). We present a case of submassive hepatic necrosis with evidence implicating cytokine induction resulting from an immune reaction to denosumab. CASE REPORT: A 72-year-old lady presented with elevated liver enzymes. One month previously, she received a s/c administration of 60 mg of denosumab. Viral hepatitis A, B and C and human herpes viruses 6-7 were negative as were routine autoimmune serology. Transaminases reached more than 50 x ULN, and gamma-glutamyl-transpeptidase (GGT) increased to more than 30 x ULN. Serum bilirubin reached 13.8 mg/dL. The serum albumin level decreased to 2.8 g/L. Prednisone (40 mg) and ursodeoxycholic acid (900 mg) were administered. The Naranjo Adverse Drug Reaction probability score was 6, consistent with a probable adverse drug reaction. A liver biopsy revealed sub-massive hepatic necrosis consistent with drug-induced liver injury (DILI). During steroid tapering, there was a slow decline in the levels of both the transaminases and the GGT, and a concomitant increase in the serum albumin. A month after stopping prednisone and ursodeoxycholic acid, there was an acute increase in the level of the transaminases and a decrease in the serum albumin. Steroid reintroduction resulted in normalization of the liver enzymes and synthetic capacity. A lymphocyte toxicity assay to denosumab was demonstrated a hypersensitivity reaction to denosumab resulting in 31% toxicity. The control patient showed no toxicity to denosumab. Cytokine levels (pg/mL) were as follows: Interleukin (IL)1 was 1193 (normal-24.5), IL8 357 (20-60), RANKL 224 (60-80), RANTES 215 (15-50), TNF-a 850 (25-50), TGF-b 546 (20-40), VEGF 735 (25-30). Serum RANKL was markedly reduced in the presence of denosumab (16 pg/mL). The elevated markers of apoptosis ccK18(M-30)(68-132) 140 IU and K18 apoptosis+ necrosis (M65) (62-213) 322 U/L implicate necrosis. CONCLUSIONS: We suggest that RANKL inhibition can produce severe hepatic necrosis together with an increase in proinflammatory cytokines.",1
14160,28392927,Liraglutide for weight management: a critical review of the evidence,"""OBJECTIVE: To review the efficacy, safety, and clinical applicability of liraglutide for weight management from phase III clinical trials. METHODS: A search of the English language literature was performed using PubMed search terms: """"liraglutide"""", """"glucagon-like peptide-1 receptor agonist"""", and """"randomized clinical trial"""". Articles and bibliographies relevant to the subject were reviewed and additional references known to the authors were included. RESULTS: Five randomized, placebo-controlled trials of liraglutide for weight management were identified. In addition to recommended diet and physical activity, liraglutide consistently resulted in a 4 to 6?kg weight loss, with a greater proportion of patients achieving at least 5 and 10% weight loss compared with placebo. The most common adverse effects were gastrointestinal and primarily occurred early in the treatment course. Comparative data suggest that weight loss with liraglutide is greater than that seen with orlistat or lorcaserin, but slightly less that seen with phentermine/topiramate. Liraglutide 1.8?mg was recently shown to have cardiovascular benefit in a large outcomes trial; applicability of these results for the 3.0?mg formulation in a more diverse weight loss population at high cardiovascular risk is not currently known. Barriers to real-world clinical use as a first-line agent include gastrointestinal side effects, high cost, and need for injection. CONCLUSIONS: Liraglutide helps to induce and sustain weight loss in patients with obesity. Its efficacy is comparable to other available agents but it offers the unique benefit of improved glycemic control. Additional studies are needed to determine its long term efficacy and safety profile.""",1
14161,28405499,Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study,"Acute graft versus host disease (aGVHD) remains a major problem after allogeneic hematopoietic stem cell transplantation. Standard frontline therapy for aGVHD involves corticosteroids. However, fewer than half of patients have a lasting complete response. The long-term mortality rate of steroid-refractory aGVHD (SR-aGVHD) remains around 70%. To date, no consensus has been reached regarding the optimal salvage treatment for SR-aGVHD. We performed the first prospective, multi-center clinical trial to assess the efficacy and safety of a novel approach to treat severe (grades III-IV) SR-aGVHD with the combination of basiliximab and etanercept. Sixty-five patients with severe SR-aGVHD from six centers were included. The median number of basiliximab infusions was 4 (range 2-11) and of etanercept was 9 (range 2-12). At day 28 after starting the combination treatment, overall response (complete and partial response: CR+PR) to second-line treatment was 90.8% with 75.4% being CR. The incidences of CR per organ were 100%, 73.8%, and 79.7% for skin, liver, and gut involvement, respectively. Patients >30-y old (p = 0.043, RR = 3.169), development of grades III-IV liver aGVHD (p = 0.007, RR = 5.034) and cytomegalovirus (CMV) reactivation (p = 0.035, RR = 4.02) were independent predictors for incomplete response. Combined treatment with basiliximab and etanercept resulted in improved CR to visceral aGVHD and significantly superior 2-y overall survival (54.7% vs. 14.8%, p <0.001) compared with classical salvage treatments. Our data suggest that the combination of basiliximab and etanercept may constitute a promising new treatment option for SR-aGVHD.",1
14162,28419076,In brief: Pancreatitis with eluxadoline (Viberzi) in patients without a gallbladder,,1
14163,28437794,Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System,"BACKGROUND: Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV-HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis. OBJECTIVE: To assess whether HBV-R is a safety concern in patients receiving HCV DAAs. DESIGN: Descriptive case series. SETTING: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). PATIENTS: 29 patients with HBV-R receiving HCV DAAs. MEASUREMENTS: Clinical and laboratory data. RESULTS: The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others. LIMITATIONS: The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported. CONCLUSION: Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV-HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection. PRIMARY FUNDING SOURCE: None.",1
14164,28449795,Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials,"""OBJECTIVES: The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND: Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. METHODS: In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction�<35% to receive placebo or bosentan (target dose 125�mg�twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed�by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or�hospitalization for heart failure. RESULTS: Bosentan did not influence clinical status at 9 months in either trial (p�= 0.928 and p = 0.263). In addition, 321�patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p�= 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI:�0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had�acute or chronic liver failure. CONCLUSIONS: Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.""",1
14165,28456944,Avelumab: First Global Approval,"Avelumab (Bavencio(�)) is an intravenously administered programmed cell death ligand-1-blocking human antibody initially developed by EMD Serono Inc. (the biopharmaceutical division of Merck KGaA, Darmstadt, Germany) [now jointly developed and commercialized by EMD Serono Inc. and Pfizer] for the treatment of various tumours. It has received accelerated approval in the USA for the treatment of metastatic Merkel cell carcinoma (mMCC) in adults and paediatric patients aged ?12�years. The marketing authorization application for avelumab in the treatment of mMCC is undergoing regulatory review in the EU, the biologics license application for avelumab in the treatment of urothelial carcinoma is undergoing priority review by the FDA, and avelumab is in various stages of development internationally for a variety of cancers. This article summarizes the milestones in the development of avelumab leading to this first approval for mMCC.",1
14166,28474297,Niraparib: First Global Approval,"Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy. In the multinational, phase 3 NOVA trial in adult patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly prolonged median progression-free survival, irrespective of the presence or absence of a germline BRCA (gBRCA) mutation and irrespective of the presence or absence of homologous recombinant deficiency. Niraparib is also in development for use in other solid tumours, including breast and prostate cancer. This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.",1
14167,28475803,Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation,"OBJECTIVES: The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken. METHODS: This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression. RESULTS: One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220)?ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P? < ? 0.001), ALT ( P? < ? 0.001), alkaline phosphatase (ALK) ( P? < ? 0.001), total bilirubin (TBILI) ( P? < ? 0.001) and QTc ( P? = ? 0.05) from baseline. Posaconazole levels were not associated with increases in AST [? (SE)?=?-0.33 (2.2), P? = ? 0.88], log ALT [? (SE)?=?-0.02 (0.03), P? = ? 0.63], ALK [? (SE)?=?2.2 (2.9), P? = ? 0.46] and TBILI [? (SE)?=?-0.01 (0.04), P? = ? 0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13?mg/dL ( P? = ? 0.02) and ALK of 7.1?U/L ( P? = ? 0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found. CONCLUSIONS: We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.",1
14168,28480518,Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany,"OBJECTIVE: To evaluate factors predicting efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. METHODS: A multicenter, retrospective cohort study recruiting all patients who started BRV between February and November 2016 with observation time between 3 and 12 months. RESULTS: Of a total of 262 patients (mean age 40, range 5-81 years, 129 male) treated with BRV, 227 (87%) were diagnosed to have focal, 19 (7%) idiopathic generalized and 8 (3%) symptomatic generalized epilepsy, whereas 8 (3%) were unclassified. The length of exposure to BRV ranged from 1 day to 12 months, with a median retention time of 6.1 months, resulting in a total exposure time to BRV of 1,504 months. The retention rate was 79.4% at 3 months and 75.8% at 6 months. Efficacy at 3 months was 41.2% (50% responder rate) with 14.9% seizure-free for 3 months and, at 6 months, 40.5% with 15.3% seizure-free. Treatment-emergent adverse events were observed in 37.8% of the patients, with the most common being somnolence, dizziness, and behavioral adverse events (BAEs). BAE that presented under previous levetiracetam (LEV) treatment improved upon switch to BRV in 57.1% (20/35) and LEV-induced somnolence improved in 70.8% (17/24). Patients with BAE on LEV were more likely to develop BAE on BRV (odds ratio [OR] 3.48, 95% confidence interval [CI] 1.53-7.95). SIGNIFICANCE: BRV in broad clinical postmarketing use is a well-tolerated anticonvulsant drug with 50% responder rates, similar to those observed in the regulatory trials, even though 90% of the patients included had previously been exposed to LEV. An immediate switch from LEV to BRV at a ratio of 10:1 to 15:1 is feasible. The only independent significant predictor of efficacy was the start of BRV in patients not currently taking LEV. The occurrence of BAE during previous LEV exposure predicted poor psychobehavioral tolerability of BRV treatment. A switch to BRV can be considered in patients with LEV-induced BAE.",1
14169,28488360,Cabazitaxel in patients with metastatic castration-resistant prostate cancer: safety and quality of life data from the Australian early access program,"""AIM: Cabazitaxel is a next generation taxane that has been shown to improve overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed during or after docetaxel-based therapy. A worldwide early access program (EAP) study was established to provide access to cabazitaxel ahead of commercial availability and to evaluate its safety and tolerability. The Australian EAP included patient-reported outcomes to evaluate the impact of cabazitaxel on quality of life (QoL). The final safety and QoL results from the Australian EAP for cabazitaxel are reported. METHODS: Australian patients with mCRPC previously treated with a docetaxel-containing regimen received cabazitaxel (25 mg/m(2) ) every 3 weeks plus prednisone/prednisolone (10 mg daily) until disease progression, death, unacceptable toxicity, physician's decision or patient's refusal of further treatment. QoL data was collected using the AQoL-8D questionnaire. RESULTS: 104 patients from 18 Australian sites (median age at baseline, 70) enrolled in the EAP and completed at least one AQoL-8D questionnaire. Patients received a median of 6 cycles of cabazitaxel. 67 patients (64.4%) experienced grade ?3 treatment-emergent adverse events (TEAEs); the most frequent TEAEs were neutropenia, febrile neutropenia, diarrhoea, and vomiting. QoL scores remained stable with increasing treatment cycles. CONCLUSION: The results suggest that the safety profile cabazitaxel is manageable in the Australian clinical practice setting and that QoL is maintained with little or no detrimental effect of cabazitaxel in patients continuing on treatment without disease progression.""",1
14170,28498551,Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen,"""The optimal retreatment strategy for patients chronically infected with hepatitis C virus who experience virologic failure after treatment with direct-acting antiviral-based therapies remains unclear. In this multicenter, open-label, phase 2 study, we evaluated the efficacy and safety of a fixed-dose combination of sofosbuvir-velpatasvir (400 mg/100 mg) plus weight-adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response after prior treatment with direct-acting antiviral regimens that included the nucleotide analogue nonstructural protein 5B inhibitor sofosbuvir plus the nonstructural protein 5A inhibitor velpatasvir with or without the nonstructural protein 3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval, 82%-97%) patients achieved sustained virologic response at 12 weeks, including 36 of 37 (97%; 95% confidence interval, 86%-100%) patients with hepatitis C virus genotype 1 infection, 13 of 14 (93%; 95% confidence interval, 66%-100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% confidence interval, 52%-94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all study drugs due to an adverse event (irritability). CONCLUSION: Retreatment of patients who previously failed direct-acting antiviral-based therapies with sofosbuvir-velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with hepatitis C virus genotype 1 or 2 infection. (Hepatology 2017;66:1083-1089).""",1
14171,28501140,"Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial","""BACKGROUND: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. METHODS: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). FINDINGS: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0?34 [99?7% CI 0?17-0?71], stratified log-rank p<0?0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20?3-not estimated) and was 10?2 months (8?2-12?0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. INTERPRETATION: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. FUNDING: Chugai Pharmaceutical Co, Ltd.""",1
14172,28503869,Letter: hepatitis B reactivation in patients with chronic hepatitis C during direct-acting antiviral therapy-authors' reply,,1
14173,28509573,Adverse Events of Atomoxetine in a Double-Blind Placebo-Controlled Study in Children with Autism,"OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) symptoms, including inattention and over activity, occur in approximately one-third of children with autism spectrum disorder (ASD). We describe the rate and duration of adverse events in a randomized controlled trial of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance in children with ASD. METHODS: We conducted a 10-week, double-blind, 2???2 trial of ATX and PT with 128 children (ages 5-14) randomized to ATX alone, ATX+PT, placebo+PT, or placebo alone. For 6 weeks, ATX (or placebo) doses were clinically adjusted to a maximum of 1.8?mg/(kg?day) and maintained for an additional 4 weeks. An average of seven PT sessions were conducted in the two PT arms. Adverse events (AEs) were assessed through parent ratings of common symptoms on a seven-point Likert severity scale and through direct interviews with study medical staff. RESULTS: ATX was associated with decreased appetite and fatigue, but was otherwise well tolerated. Most reported AEs lasted 4 weeks or less. Unlike reports with typically developing (TD) children, there were no concerns with QTc changes or suicidal ideation. CONCLUSIONS: This study extends the findings of previous studies of ATX in ASD by documenting that the type of AEs was similar to that of TD children, with no significant safety concerns.",1
14174,28523950,Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature,"Asparaginase is a chemotherapeutic agent that is commonly used in combination with other medications for the treatment of acute lymphoblastic leukemia. An adverse effect of asparaginase includes hepatotoxicity, which can lead to severe liver failure and death. Several reports have documented successful treatment of asparaginase-induced hepatotoxicity using levocarnitine (l-carnitine) and vitamin B complex. Herein, we report a patient with acute lymphoblastic leukemia that experienced acute liver injury following pegaspargase administration. Our patient was successfully treated with l-carnitine and vitamin B complex for 8 days and achieved recovery of hepatic function. Furthermore, we review the current literature and provide a recommendation on a regimen that can be used as an option for the treatment of asparaginase-induced hepatic injury.",1
14175,28546286,Three Drugs Approved for Urothelial Carcinoma by FDA,"The FDA has approved one PD-1 checkpoint inhibitor, pembrolizumab, and two PD-L1 checkpoint inhibitors, avelumab and durvalumab, to treat metastatic urothelial carcinoma in patients whose disease continues to progress despite platinum-based chemotherapy. This brings the total number of checkpoint inhibitors for the disease to five, prompting questions about how best to use them.",1
14176,28578607,"Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer","""BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. RESULTS: After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. CONCLUSIONS: The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).""",1
14177,28592387,"Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial","""BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAF(V600)-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases. METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF(V600E)-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAF(V600E)-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAF(V600D/K/R)-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAF(V600D/E/K/R)-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947. FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8?5 months (IQR 5?5-14?0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF(V600)-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. FUNDING: Novartis.""",1
14178,28606562,The Efficacy and Safety of 3 Types of Interventions for Stroke Prevention in Patients With Cardiovascular and Cerebrovascular Diseases: A Network Meta-analysis,"""PURPOSE: The goal of this study was to compare the relative efficacy and safety of different types of interventions for stroke prevention in patients with cardiovascular and cerebrovascular diseases. METHODS: This network meta-analysis (NMA) was conducted with a random effects model of Bayesian framework using Stata version 12.0. Odds ratios (ORs) and their credible intervals (CrIs) were applied for the efficacy and safety evaluation of various medical interventions, including aspirin, dipyridamole, ticlopidine, warfarin, and apixaban. In addition, the ranking of probability of every clinical outcome was estimated by comparing the surface under the cumulative ranking curve. FINDINGS: Compared with dabigatran, both edoxaban and aspirin + warfarin exhibited a higher rate of all-cause stroke (OR, 2.84 [95% CrI, 1.17-6.97]; OR, 3.42 [95% CrI, 1.20-9.84]). With respect to intracranial hemorrhage, aspirin + clopidogrel yielded worse outcomes than 7 treatments, including placebo, apixaban, aspirin, aspirin + dipyridamole, cilostazol, clopidogrel, and dabigatran (OR, 2.21 [95% CrI, 1.45-3.40]; OR, 2.11 [95% CrI, 1.05-4.17]; OR, 1.53 [95% CrI, 1.11-2.15]; OR, 1.78 [95% CrI, 1.01-3.03]; OR, 4.17 [95% CrI, 1.37-14.28]; OR, 1.85 [95% CrI, 1.22-2.86]; and OR, 2.56 [95% CrI, 1.37-4.76]). In terms of ischemic stroke, dabigatran provided better efficacy than placebo, aspirin, and aspirin + dipyridamole (OR, 0.36 [95% CrI, 0.18-0.72]; OR, 0.43 [95% CrI, 0.21-0.84]; and OR, 0.41 [95% CrI, 0.17-0.94]). As for mortality, dabigatran resulted in a lower mortality compared with aspirin, aspirin + clopidogrel, edoxaban, and warfarin (OR, 0.48 [95% CrI, 0.23-0.97]; OR, 0.40 [95% CrI, 0.17-0.92]; OR, 0.27 [95% CrI, 0.10-0.72]; and OR, 0.52 [95% CrI, 0.28-0.92]). IMPLICATIONS: There are still some limitations to our NMA research. For instance, the lack of direct evidence for some therapies resulted in inconsistencies, particularly for warfarin compared with placebo and clopidogrel under different end points. Moreover, the included randomized controlled trials for patients with cardiovascular and cerebrovascular diseases are relatively broad, involving atrial fibrillation, myocardial infarction, and large-artery atherosclerosis stroke. Although further research is needed, dabigatran is highly recommended based on the present NAM for the treatment of cardiovascular and cerebrovascular diseases due to the drug's efficacy and safety.""",1
14179,28618307,Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: Palbociclib and ribociclib,"""PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib and ribociclib are associated with distinct adverse effects (AEs) compared to other targeted therapies. This meta-analysis of clinical trials summarizes these agents' toxicity profile. METHODS: A librarian-guided literature search was conducted in March of 2017. The trials needed to have at least one of the study arms consisting of palbociclib or ribociclib monotherapy at currently FDA approved dose regimens. Heterogeneity across studies was analyzed using I(2) statistics. Data were analyzed using random effects meta-analysis for absolute risks. RESULTS: Seven randomized trials and 1,332 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies for serious AEs but not for death. The pooled absolute risk (AR) for all-causality serious AEs and treatment-related death were 16% and 0%, respectively. Patients treated with CDK 4/6 inhibitors had an AR of grade 3/4 neutropenia of 61%; neutropenic fever and infections were rare (1% and 3%, respectively). Grade 3/4 nausea, vomiting, and rash were rare. There was no significant correlation between age of patients at study entry and the risk of grade 3/4 neutropenia. CONCLUSION: Treatment with CDK 4/6 inhibitors is well tolerated and associated with a low risk of treatment-related deaths. There is an increased AR of grade 3/4 neutropenia but a low AR of associated infections.""",1
14180,28627791,No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort,"""BACKGROUND: Hepatitis B virus (HBV) reactivation has been observed following interferon (IFN)-based treatment in HBV/hepatitis C virus (HCV) co-infected patients. Recent reports suggest that reactivation may also occur in both hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative patients during HCV treatment with direct-acting antivirals (DAAs). AIM: To investigate the rate of patients with HBV reactivation during IFN-based and IFN-free HCV treatment in a large real-world cohort. METHODS: A total of 848 patients with chronic hepatitis C were treated with different combinations of DAAs. Among patients with available outcome and HBV data, there were 272 patients hepatitis B core antibody (HBcAb)-positive (HBsAg-positive, n=9; HBsAg-negative, n=263), and 536 were HBcAb-negative. All HBcAb-positive patients were tested for HBV DNA at the end of DAA therapy and alanine transaminase (ALT) levels were frequently measured during therapy and follow-up. RESULTS: Seventy-three percent (n=192/263) of HBsAg-negative/HBcAb-positive patients had elevated ALT levels at baseline, which declined to normal values in all but 18 patients, and no HBV reactivation was observed. Eight patients had detectable but not quantifiable HBV DNA (<20 IU/mL) at end of treatment, but none were associated with elevated ALT. Five of nine HBsAg-positive/HBcAb-positive patients experienced transient or permanent HBV reactivation, three of whom required nucleos(t)ide treatment during (n=1) or after (n=2) DAA therapy. CONCLUSIONS: HBV reactivation was not observed in HBsAg-negative/HBcAb-positive patients but common in HBsAg-positive/HBcAb-positive patients treated with different combinations of DAAs for HCV.""",1
14181,28643244,Durvalumab: First Global Approval,"""Intravenous durvalumab (Imfinzi�; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab ? tremelimumab is under phase III clinical trials in urothelial carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma.""",1
14182,28651927,"Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial","""BACKGROUND: Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. METHODS: We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m(2) via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m(2) intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. FINDINGS: Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1?06, 95% CI 0?88-1?29; p=0?527), with a median overall survival of 18?4 months (95% CI 15?6-22?1) with doxorubicin plus evofosfamide versus 19?0 months (16?2-22?4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). INTERPRETATION: The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. FUNDING: Threshold Pharmaceuticals.""",1
14183,28693853,Multidrug therapy for leprosy: a game changer on the path to elimination,"""Leprosy is present in more than 100 countries, where it remains a major cause of peripheral neuropathy and disability. Attempts to eliminate the disease have faced various obstacles, including characteristics of the causative bacillus Mycobacterium leprae: the long incubation period, limited knowledge about its mode of transmission, and its poor growth on culture media. Fortunately, the leprosy bacillus is sensitive to several antibiotics. The first antibiotic to be widely used for leprosy treatment was dapsone in the 1950s, which had to be taken over several years and was associated with increasing bacterial resistance. Therefore, in 1981, WHO recommended that all registered patients with leprosy should receive combination therapy with three antibiotics: rifampicin, clofazimine, and dapsone. Global implementation of this highly effective multidrug therapy took about 15 years. In 1985, 5.3 million patients were receiving multidrug therapy; by 1991, this figure had decreased to 3.1 million (a decrease of 42%) and, by 2000, to 597 232 (a decrease of almost 90%). This reduction in the number of patients registered for treatment was due to shortening of the treatment regimen and achievement of 100% coverage with multidrug therapy. This achievement, which owed much to WHO and the donors of the multidrug therapy components, prompted WHO in 1991 to set a global target of less than one case per 10 000 population by 2000 to eliminate the disease as a public health problem. All but 15 countries achieved this target. Since 2000, about 250 000 new cases of leprosy have been detected every year. We believe an all-out campaign by a global leprosy coalition is needed to bring that figure down to zero.""",1
14184,28703895,HBV reactivation in patients with HCV/HBV cirrhosis on treatment with direct-acting antivirals,"Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or cleared by direct-acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV-RNA and HBV-DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow-up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV-DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues [NUCs] and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti-HBc positive, 12 anti-HBc/anti-HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty-seven patients (64.4%) were HCV-RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg-positive patients treated with NUCs remained HBV-DNA negative, but three of four untreated patients showed an increase in HBV-DNA of 2-3 log without a biochemical flare and achieved HBV-DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV-DNA remained not detectable in all 37 anti-HBc-positive patients but in three of them (8.1%) HBV-DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV-coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre-emptive therapy with NUCs should be considered in this setting. Anti-HBc-positive patients rarely reactivate HBV without clinical or virological outcomes.",1
14185,28706414,Risk of hepatitis B reactivation in patients treated with direct-acting antivirals for hepatitis C,"""The recent introduction of direct-acting antiviral drugs (DAAs) for treatment of the hepatitis C virus (HCV) has greatly improved the management of HCV for infected patients. These viral protein inhibitors act rapidly, allowing HCV clearance and increasing the sustained virological response rates. However, hepatitis B virus (HBV) reactivation has been reported in HCV/HBV co-infected patients. Hepatitis B reactivation refers to an abrupt increase in the HBV and is well-documented in patients with previously undetected HBV DNA due to inactive or resolved HBV infection. Reactivation can occur spontaneously, but in most cases, it is triggered by various factors. Reactivation can be transient, without clinical symptoms; however, it usually causes a hepatitis flare. HBV reactivation may occur regardless of HCV genotype and type of DAA regimen. HBV screening is strongly recommended for co-infected HCV/HBV patients before initiation and during DAA therapy regardless of HBV status, HCV genotype and class of DAAs used. HBV reactivation can be prevented with pretreatment screening and prophylactic treatment when necessary. Additional data are required to evaluate the underlying mechanisms of HBV reactivation in this setting.""",1
14186,28717089,An Autopsy Case of Fulminant Hepatitis in a Patient with Multiple Sclerosis Treated by Interferon-Beta-1a,"A 44-year-old woman with multiple sclerosis (MS) receiving interferon (IFN)-beta-1a treatment was admitted to a local hospital for severe icterus and liver injury. She was transferred to our university hospital because fulminant hepatitis (FH) was suspected. She was diagnosed with acute-type FH based on hepatic coma, severe liver injury and liver failure, and she received plasma exchange and continuous hemodiafiltration therapy. On hospital day 6, she died from liver failure despite intensive care. An autopsy revealed histological findings consistent with FH. Physicians should monitor the hepatic function of MS patients receiving IFN-beta-1a treatment, as serious events can occur in rare cases.",1
14187,28748630,Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high-risk neuroblastoma: A case series,"Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.",1
14188,28762471,Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a Critically Appraised Topic,"""CONTEXT: Many physicians monitor liver function tests during terbinafine therapy. OBJECTIVES: To evaluate the symptoms of published cases of terbinafine-associated severe drug-induced liver injury (DILI) to assess the utility of laboratory monitoring. DATA SOURCES: We based our search on the LiverTox database of the National Institutes of Health, but we also searched both PubMed and Embase. In addition, we hand searched the references of the papers we found. STUDY SELECTION: All reports of patients with DILI on terbinafine and with reported clinical symptoms, or absence thereof, were evaluated. DATA EXTRACTION: Two independent reviewers (J.A. and O.N.K.) assessed articles for eligibility of inclusion, and collected and evaluated the data. DATA SYNTHESIS: Thirty-eight papers fulfilled the inclusion criteria, with reports of 69 symptomatic patients. The mean duration of terbinafine treatment until onset of symptoms was 30.2 days (range 5-84). Symptoms in order of frequency were jaundice, flu-like symptoms, dark urine and pruritus. Patients experienced symptoms for a mean and median of 14.8 and 16 days, respectively (range 0-42) until seeking medical attention. CONCLUSIONS: Patients who had DILI were symptomatic, usually with jaundice, abdominal pain and general malaise, but also with severe pruritus. No asymptomatic patient was identified through laboratory screening. The timeline of DILI onset varies significantly, but most cases occur between 4 and 6 weeks. There was no time point at which monitoring was meaningful, and we do not recommend monitoring of liver function tests on terbinafine; however, patients should be advised to discontinue treatment and look for medical care when symptoms of DILI occur.""",1
14189,28774880,Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN,"""Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m(2) intravenously/subcutaneously daily or decitabine 20 mg/m(2) intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% (P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine (P = .2). Cytogenetic response rates were 61% and 25% (P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively (P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225).""",1
14190,28818546,"Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial","BACKGROUND: The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS: We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432. FINDINGS: Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events. INTERPRETATION: Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden. FUNDING: AbbVie.",1
14191,28838955,Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease,"""Overactivation of Src has been linked to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). This phase 2, multisite study assessed the efficacy and safety of bosutinib, an oral dual Src/Bcr-Abl tyrosine kinase inhibitor, in patients with ADPKD. Patients with ADPKD, eGFR?60 ml/min per 1.73 m(2), and total kidney volume ?750 ml were randomized 1:1:1 to bosutinib 200 mg/d, bosutinib 400 mg/d, or placebo for ?24 months. The primary endpoint was annualized rate of kidney enlargement in patients treated for ?2 weeks who had at least one postbaseline magnetic resonance imaging scan that was preceded by a 30-day washout (modified intent-to-treat population). Of 172 enrolled patients, 169 received at least one study dose. Per protocol amendment, doses for 24 patients who initially received bosutinib at 400 mg/d were later reduced to 200 mg/d. The annual rate of kidney enlargement was reduced by 66% for bosutinib 200 mg/d versus placebo (1.63% versus 4.74%, respectively; P=0.01) and by 82% for pooled bosutinib versus placebo (0.84% versus 4.74%, respectively; P<0.001). Over the treatment period, patients receiving placebo or bosutinib had similar annualized eGFR decline. Gastrointestinal and liver-related adverse events were the most frequent toxicities. In conclusion, compared with placebo, bosutinib at 200 mg/d reduced kidney growth in patients with ADPKD. The overall gastrointestinal and liver toxicity profile was consistent with the profile in prior studies of bosutinib; no new toxicities were identified. (ClinicalTrials.gov: NCT01233869).""",1
14192,28868484,Acute Hepatitis in the DRESS Syndrome,"Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, idiosyncratic reaction characterized by diffuse maculopapular rash, facial edema, lymphadenopathy, fever, eosinophilia and/or other leukocyte abnormalities, and involvement of internal organs as liver, kidney, heart and lung. Diagnosing this entity is specifically complicated due to the multiplicity of organs involved. DRESS syndrome must be recognized promptly and the causative drug withdrawn in order to improve patient outcomes. Indeed, it is a potentially life-threatening condition, with a reported mortality between 5 and 20%. We describe a case of a 22-year old woman admitted to our hospital with acute diffuse, pruritic rash associated with crampy abdominal pain, vomiting, diarrhea and fever three weeks after starting sulfasalazine therapy. Initially, laboratory parameters revealed normal white blood cell count and normal liver enzymes, but during hospitalization, eosinophilia developed and liver enzymes, including transaminases and cholestatic parameters, dramatically increased. The diagnostic of DRESS syndrome was made and sulfasalazine was withdrawn and as there were signs of disease severity, systemic corticotherapy was initiated, with gradually improvement of the rash and symptoms resolution. The patient was discharged home after thirty days of hospitalization.",1
14193,28882536,Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial,"""BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m(2) on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m(2) on days 1 and 8 and intravenous docetaxel 75 mg/m(2) on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (?18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15?7-29?3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46?3% [95% CI 37?5-54?6] vs 46?4% [37?5-54?8]); median progression-free survival (23?3 weeks [95% CI 19?6-30?4] vs 23?7 weeks [18?1-20?0]; hazard ratio [HR] for progression-free survival 1?28, 95% CI 0?99-1?65, p=0?06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.""",1
14194,28926120,Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial,"""This study assessed the efficacy and safety of ribavirin-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR-II, Part 3 was a partially randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon or pegylated interferon???ribavirin or sofosbuvir plus ribavirin???pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300?mg/120?mg) once daily. Treatment-naive or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72-97) and 95% (21/22; 95% CI, 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87-99) of treatment-naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514-523).""",1
14195,28978627,Risk of severe liver injury with ? daclizumab (Zinbryta),,1
14196,29033779,A Patient with Nafcillin-Associated Drug-Induced Liver Failure,"Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient's lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient's liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.",1
14197,29059031,Dolutegravir-induced liver injury leading to sub-acute liver failure requiring transplantation: a case report and review of literature,"A patient with human immunodeficiency virus-1 infection presented with sub-acute liver failure, temporally related to commencement of an antiretroviral therapy regimen containing dolutegravir (Triumeq). The patient was not a carrier of HLA-B5701, and abacavir hypersensitivity was unlikely. We believe this is the first report of severe dolutegravir-related hepatotoxicity resulting in sub-acute liver failure and transplantation and highlights a potential need for closer monitoring after drug initiation.",1
14198,29079595,Long-term safety of deferiprone treatment in children from the Mediterranean region with beta-thalassemia major: the DEEP-3 multi-center observational safety study,,1
14199,29091196,Efficacy and safety of direct antiviral agents in a cohort of cirrhotic HCV/HIV-coinfected patients,"""BACKGROUND: New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients. METHODS: A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12?weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated. RESULTS: Patients (n?=?170) were mostly male (n?=?125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6?kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1?IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n?=?127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n?=?36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir?+?ribavirin, 43 (25.3%) patients; sofosbuvir?+?simeprevir?+?ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir?+?daclatasvir?+?ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P?=?0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6?kPa (95% CI 1.8-9.2; P?=?0.004). CONCLUSIONS: In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness.""",1
14200,29119631,Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: A randomized controlled trial,"""Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion-dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N?=?64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ?6 transfusions; serum ferittin (SF) >400 to?<?1000 ng/mL were randomized to """"early start deferiprone"""" (.ES-DFP) at a low dose (50 mg/kg/day) or to """"delay chelation"""" (DC), and remained in the study until their serum ferritin (SF) level reached ?1000 ?g/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF?>?1000 ?g/L and TSAT?>?70% compared with none in the ES-DFP group. LPI level?>?0.6 ?M was observed in 97% vs. 40% of the DS and ES groups, respectively, (P?<?0.001). The time to reach SF?>?1000 ?g/L was delayed by 6 months in the ES-DFP group (P?<?0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES-DFP group.""",1
14201,29159388,Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus,,1
14202,29174546,Efficacy of Ledipasvir and Sofosbuvir Treatment of HCV Infection in Patients Coinfected With HBV,"""BACKGROUND & AIMS: There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection. METHODS: We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection. All but 1 were positive for the hepatitis B surface antigen (HBsAg); 1 patient who was HBsAg-positive at screening was found to be HBsAg-negative at baseline. Overall, 33% of participants had received prior treatment for HCV and 5% had previously been treated for HBV; no patient was on HBV therapy at the start of the study. All patients received a fixed-dose combination of 90 mg of the HCV NS5A inhibitor ledipasvir with 400 mg of the NS5B nucleotide analogue inhibitor sofosbuvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS: All 111 patients (100%) achieved a sustained virologic response. Of the 37 patients with baseline HBV DNA below 20 IU/mL, 31 (84%) had at least 1 episode of quantifiable HBV DNA through posttreatment week 12. Of the 74 patients with baseline HBV DNA levels of 20 IU/mL or more, 39 (53%) had increases of HBV DNA greater than 1 log(10) IU/mL through posttreatment week 12. Overall, 5 patients had increased levels of HBV DNA concomitant with a level of alanine aminotransferase >2 times the upper limit of normal through posttreatment week 12. Of these, 3 patients started HBV treatment. In addition, 1 patient with HBV reactivation since week 8 and concomitant alanine aminotransferase elevation >2 times upper limit of normal at posttreatment week 48 started treatment at posttreatment week 53. This patient had clinical signs and symptoms associated with HBV reactivation. The most common adverse events were headache, upper respiratory infection, and fatigue. CONCLUSIONS: In a prospective study, the combination of ledipasvir and sofosbuvir for 12 weeks produced a sustained virologic response in 100% of patients with HCV infection who were coinfected with HBV. Most patients had an increase in level of HBV DNA not associated with signs or symptoms. ClinicalTrials.gov no: NCT02613871.""",1
14203,29194858,Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy,"To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ?2000�IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level <2000�IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P�=�.79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level <2000�IU/mL before DAA therapy.",1
14204,29296102,Efficacy and safety of sofosbuvir-based therapies in patients with advanced liver disease in a real-life cohort,"""Background: The combination of sofosbuvir (SOF) with ribavirin (RBV) or daclatasvir (DCV) or simeprevir (SIM) for the treatment of patients infected by chronic hepatitis C (CHC) have led to significantly increased rates of sustained virological response (SVR). However, there is only limited data regarding factors associated with treatment failure in a """"real-life"""" cohort. Patients and methods: Consecutive treatment-naive and treatment-experienced patients F3-F4 were treated with SOF-based interferon-free therapy in our hospital from November 2013 to July 2015. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after cessation of therapy (SVR12). Results: A total of 167 treatment-naive and 207 treatment-experienced patients were treated and followed up for 2 years (n=383). Overall, 71% were men; among them, 54% had cirrhosis and the median age was 53 years. SVR12 was achieved by 82% of the patients receiving SOF+RBV, 92% receiving SOF+DCV, and 79% receiving SOF+SIM. Metavir F4 and albumin serum were found as independent risk factors associated with treatment failure in groups receiving SOF+RBV (p=0.008 and p=0.001), SOF+DCV (p=0.038 and p=0.043), and SOF+SIM+/-RBV (p=0.014 and p=0.017), respectively. The most common adverse events were fatigue, nausea, headache, and anemia. Three patients discontinued the treatment due to an adverse event. Conclusion: These findings suggest that 12-week SOF-based regimen plus RBV or DCV or SIM is an efficacious and well-tolerated treatment in CHC patients with fibrosis stage F3-F4. Patients, who display risk factors for cirrhosis, should be referred to an experienced viral hepatitis center.""",1